Pyridine derivatives, their preparation and use

Abstract

Provided are compounds of formula I, their stereoisomers or pharma- ceutically acceptable salts, pharmaceutical compositions containing them, processes for their preparation, and their use in the manufacture of a medicament for treating a disease associated with LSD1. TIFF2025503099000107.tif2037

Description

[Technical field]

[0001] The present application relates to the field of medicinal chemistry, specifically to pyridine derivatives or pharma- ceutically acceptable salts thereof as lysine-specific demethylase 1 (LSD1) inhibitors, and their preparation and use. [Background technology]

[0002] Histone lysine-specific demethylase 1 (LSD1) is the first reported histone demethylase that can specifically recognize H3K4 and H3K9 substrates and remove their mono- or dimethyl modifications with the help of flavin adenine dinucleotide (FAD). LSD1 can also form transcriptional regulatory complexes with various factors and be recruited by transcription factors to reach the promoter regions of specified genes, thereby controlling gene expression.

[0003] Studies have shown that LSD1 is associated with various diseases, is highly expressed in various tumor cells, and is closely related to poor tumor prognosis, and downregulating the expression of LSD1 or inhibiting its activity can significantly inhibit tumor cell growth. Therefore, the development of efficient and specific LSD1 inhibitors is of great importance for the treatment of tumors and other diseases. Summary of the Invention [Problem to be solved by the invention]

[0004] The present application relates to pyridine derivatives as LSD1 inhibitors, in particular pyridine derivatives and their preparation method, as well as their pharmaceutical use, in particular pyridine derivatives as shown in the following formula I and their use in the preparation of a drug for treating LSD1 mediated diseases, more particularly in the preparation of a drug suitable for tumors. [Means for solving the problem]

[0005] In one aspect of the present application, there is provided a pyridine derivative having the structure represented by the following formula I, a stereoisomer thereof, or a pharma- ceutically acceptable salt thereof.

[0006] [ka] (where: Ring A represents a saturated cycloalkyl, a saturated heterocycloalkyl, an unsaturated cyclohydrocarbyl, or an unsaturated heterocyclohydrocarbyl; Ring B represents a monocyclic or bicyclic unsaturated hydrocarbyl or a monocyclic or bicyclic unsaturated heterocyclohydrocarbyl; R 1 , R 2 are each independently hydrogen, fluorine, cyano, Selected from TIFF2025503099000003.tif1853 and R 1 , R 2 cannot be hydrogen or fluorine at the same time, and R 1 If is hydrogen, R 2 is not fluorine, but R 1 is fluorine, R 2 is not hydrogen or R 1 and R 2 are cyclized together with the carbon atoms to which they are attached. Form TIFF2025503099000004.tif1643, R 3 is selected from halogen, cyano, oxo, hydroxy, substituted or unsubstituted amino, C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, or C3-C8 cycloalkyloxy, wherein said C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, or C3-C8 cycloalkyloxy is unsubstituted or substituted by one or more substituents selected from halogen, cyano, hydroxy, amino, C1-C6 alkyl, C1-C6 alkoxy, or C1-C6 alkylamino, and preferably, when m is 2 to 5, R 3 may be selected from different groups, R4 is selected from halogen, cyano, oxo, hydroxy, substituted or unsubstituted amino, C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, or C3-C8 cycloalkyloxy, wherein said C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, or (C3-C8)cycloalkyloxy is unsubstituted or substituted by one or more substituents selected from halogen, cyano, hydroxy, amino, C1-C6 alkyl, C1-C6 alkoxy, or C1-C6 alkylamino, preferably, when n is 2 to 5, R 4 may be selected from different groups, R 5 is selected from halogen, hydroxy, substituted or unsubstituted amino, C1-C6 alkyl, C1-C6 alkoxy, (C3-C8) cycloalkyl, or (C3-C8) cycloalkyloxy, wherein said C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, or C3-C8 cycloalkyloxy is unsubstituted or substituted by one or more substituents selected from halogen, cyano, hydroxy, amino, C1-C6 alkyl, or C1-C6 alkoxy; R 6 , R 7 are each independently selected from hydrogen, C1-C6 alkyl, or C3-C8 cycloalkyl; m is selected from 0, 1, 2, 3, 4, or 5; n is selected from 0, 1, 2, 3, 4, or 5; q is selected from 0, 1, 2, 3, or 4.

[0007] In some embodiments, ring A is a C 13 cycloalkyl, or 3- to 13-membered heterocycloalkyl, the heterocycloalkyl containing 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom, or a sulfur atom; Preferably, ring A is C4-C8 monocycloalkyl, C7-C 13spirocycloalkyl, 3- to 10-membered monoheterocycloalkyl, or 7- to 13-membered spiroheterocycloalkyl, wherein the heterocycloalkyl contains 1 to 3 heteroatoms selected from nitrogen or oxygen atoms; More preferably, ring A is C5-C7 monocycloalkyl, C8-C 12 or ring A is selected from a C5-C7 monocycloalkyl (e.g., a C6 monocycloalkyl), a 3-8 membered monoheterocycloalkyl (e.g., a 4-7 membered monoheterocycloalkyl), or an 8-12 membered spiroheterocycloalkyl (e.g., a 9-10 membered spiroheterocycloalkyl), and the heterocycloalkyl contains 1 to 3 heteroatoms selected from a nitrogen atom or an oxygen atom; Alternatively, preferably, Ring A is selected from piperidinyl, tetrahydropyridyl, piperazinyl, azacyclobutyl, azacyclopentyl, azacyclohexyl, azacycloheptyl, homopiperazinyl, cyclohexyl, cyclobutyl, cyclopentyl, cycloheptyl, diazaspirononyl, diazaspirodecyl, oxazaspirononyl, oxazaspirodecyl.

[0008] In some embodiments, ring B is a C 10 Cycloalkenyl, 5-10 membered heterocycloalkenyl, C5-C 10 aryl, and 5-10 membered heteroaryl, wherein the heterocycloalkenyl or heteroaryl contains 1-3 heteroatoms selected from a nitrogen atom, an oxygen atom, or a sulfur atom; Preferably, ring B is selected from C5-C8 aryl, 8-10 membered heteroaryl, said heterocycloalkenyl or heteroaryl containing 1-3 heteroatoms selected from nitrogen atom, oxygen atom, or sulfur atom; Alternatively, preferably, ring B is selected from phenyl, pyridyl, dihydropyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, a 5-6 membered benzoheterocycloalkenyl containing 1-3 heteroatoms selected from a nitrogen atom or an oxygen atom (e.g., indolyl, isoindolyl, isoindolinyl, dihydroindolyl, indazolyl, dihydroindazolyl, benzoxazolyl, benzisoxazolyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, benzodioxolyl, benzofuranyl, benzimidazolyl, benzodihydroxazinyl).

[0009] In some embodiments, R 1 , R 2 are each independently hydrogen, cyano, Selected from TIFF2025503099000005.tif1753 or R 1 and R 2 are cyclized together with the carbon atoms to which they are attached. Form TIFF2025503099000006.tif1742, R 6 , R 7 are each independently selected from hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl; Preferably, R 1 is hydrogen, cyano, Selected from TIFF2025503099000007.tif15125, R 2 is hydrogen, cyano, Selected from TIFF2025503099000008.tif52134 or R 1 and R 2 are cyclized together with the carbon atoms to which they are attached. Form TIFF2025503099000009.tif1880, R 6 , R 7 are each independently selected from hydrogen, C1-C5 alkyl (eg, C1-C4 alkyl, C1-C3 alkyl), or C3-C5 cycloalkyl (eg, C3-C4 cycloalkyl, cyclopropyl).

[0010] In some embodiments, m is 0, 1, 2, 3, 4, or 5, and R 3 is selected from halogen (including fluorine, chlorine, bromine or iodine), oxo, hydroxy, substituted or unsubstituted amino, C1-C6 alkyl, or C1-C6 alkoxy, wherein said C1-C6 alkyl or C1-C6 alkoxy is unsubstituted or substituted by one or more substituents selected from halogen, cyano, hydroxy, amino, and preferably, when m is 2 to 5, a plurality of R 3 may be selected from different groups, Alternatively, in some embodiments, m is 0, 1, 2, or 3 (preferably, 0, 1, or 2), and R 3 is selected from fluorine, chlorine, bromine, oxo, hydroxy, amino, or C1-C6 alkyl (e.g., C1-C3 alkyl), wherein the C1-C6 alkyl (e.g., C1-C3 alkyl) is unsubstituted or substituted by amino, and preferably, when m is 2, two R 3 may be the same or different.

[0011] In some embodiments, n is selected from 0, 1, 2, 3, 4, or 5; R 4 is selected from halogen (including fluorine, chlorine, bromine or iodine), oxo, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, or C3-C6 cycloalkyloxy, wherein said C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, or C3-C6 cycloalkyloxy is unsubstituted or substituted by one or more substituents selected from halogen, hydroxy, amino, and preferably, when m is 2 to 5, a plurality of R 4 may be selected from different groups, Alternatively, in some embodiments, n is selected from 0, 1, 2, 3, or 4; R 4is selected from fluorine, chlorine, bromine, oxo, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, wherein said C1-C6 alkyl or C1-C6 alkoxy is unsubstituted or substituted by one or more substituents selected from halogen or hydroxy, and preferably, when n is 2 to 4, a plurality of R 4 may be selected from different groups.

[0012] In some embodiments, q is selected from 0, 1, or 2; R 5 is selected from halogen, hydroxy, amino, C1-C6 alkyl, C1-C6 alkoxy, wherein said C1-C6 alkyl or C1-C6 alkoxy is unsubstituted or substituted by one or more substituents selected from halogen or hydroxy; Alternatively, in some embodiments, q is 1 or 2 and R 5 is selected from halogen, preferably R 5 is selected from fluorine, chlorine, or bromine.

[0013] Preferably, in the compound of formula I, its stereoisomer or its pharma- ceutically acceptable salt, Ring A is selected from a 5-8 membered saturated monocycloalkyl, a 4-10 membered saturated monocyclic heterocycloalkyl, or a spiroheterocycloalkyl, wherein the heterocycloalkyl contains 1-3 nitrogen atoms as heteroatoms; Ring B is selected from 5- to 8-membered unsaturated monocyclohydrocarbyl, 5- to 14-membered unsaturated monocyclic or bicyclic heterocyclohydrocarbyl, wherein the heterocyclohydrocarbyl contains 0-4 nitrogen atoms and 0-2 oxygen atoms as heteroatoms, and contains at least one of nitrogen and oxygen; R 1 , R 2 are each independently hydrogen, fluorine, cyano, Selected from TIFF2025503099000010.tif1655 and R 1 , R 2cannot be hydrogen or fluorine at the same time, and R 1 If is hydrogen, R 2 is not fluorine, but R 1 is fluorine, R 2 is not hydrogen or R 1 and R 2 are cyclized together with the carbon atoms to which they are attached. Form TIFF2025503099000011.tif1539, R 3 is selected from halogen, cyano, oxo, hydroxy, substituted or unsubstituted amino, C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, or C3-C8 cycloalkyloxy, wherein said C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, or C3-C8 cycloalkyloxy is unsubstituted or substituted by one or more substituents selected from halogen, cyano, hydroxy, amino, C1-C6 alkyl, or C1-C6 alkoxy; R 4 is selected from halogen, cyano, oxo, hydroxy, substituted or unsubstituted amino, C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, or (C3-C8)cycloalkyloxy, wherein said (C1-C6)alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, or C3-C8 cycloalkyloxy is unsubstituted or substituted by one or more substituents selected from halogen, cyano, hydroxy, amino, C1-C6 alkyl, or C1-C6 alkoxy; R 5 is selected from halogen, hydroxy, substituted or unsubstituted amino, C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, or C3-C8 cycloalkyloxy, wherein said C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, or C3-C8 cycloalkyloxy is unsubstituted or substituted by one or more substituents selected from halogen, cyano, hydroxy, amino, C1-C6 alkyl, or C1-C6 alkoxy; R 6 , R 7 are each independently selected from hydrogen, C1-C6 alkyl, or C3-C8 cycloalkyl; m is selected from 0, 1, 2, 3, 4, or 5; n is selected from 0, 1, 2, 3, 4, or 5; q is selected from 0, 1, 2, 3, or 4.

[0014] Preferably, in the compound of formula I, its stereoisomer or its pharma- ceutically acceptable salt, Ring A is selected from 4-10 membered saturated monocyclic heterocycloalkyl or spiroheterocycloalkyl, wherein the heterocycloalkyl contains 1-3 nitrogen atoms as heteroatoms, preferably 1-2 nitrogen atoms as heteroatoms; or Ring A is selected from piperidinyl, piperazinyl, azacyclobutyl, azacycloheptyl, homopiperazinyl, diazaspirononyl, diazaspirodecyl, or oxazaspirodecyl; Ring B is selected from 6-membered unsaturated monocyclohydrocarbyl or 6-10-membered unsaturated bicyclic heterocyclohydrocarbyl, wherein the heterocyclohydrocarbyl contains 0-4 nitrogen atoms and 0-2 oxygen atoms as heteroatoms, and contains at least one of nitrogen and oxygen; preferably, Ring B is selected from 6-10-membered aryl or heterocycloaryl, wherein the heterocycloaryl contains 1-2 nitrogen atoms and 0-2 oxygen atoms as heteroatoms, and contains at least one of nitrogen and oxygen; more preferably, Ring B is selected from phenyl, pyridyl, indolyl, dihydroindolyl, indazolyl, benzisoxazolyl, benzoxazolyl, benzodioxolyl, or benzodihydroxazinyl; R 1 , R 2 are each independently hydrogen, fluorine, cyano, Selected from TIFF2025503099000012.tif1451 and R 1 , R 2cannot be hydrogen or fluorine at the same time, and R 1 If is hydrogen, R 2 is not fluorine, but R 1 is fluorine, R 2 is not hydrogen or R 1 and R 2 are cyclized together with the carbon atoms to which they are attached. TIFF2025503099000013.tif1539 is formed, preferably in R 1 , R 2 are each independently hydrogen, fluorine, cyano, Selected from TIFF2025503099000014.tif55139 and R 1 , R 2 cannot be hydrogen or fluorine at the same time, and R 1 If is hydrogen, R 2 is not fluorine, but R 1 is fluorine, R 2 is not hydrogen or R 1 and R 2 are cyclized together with the carbon atoms to which they are attached. Form TIFF2025503099000015.tif1938, R 3 is selected from halogen, cyano, oxo, hydroxy, substituted or unsubstituted amino, C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, or C3-C8 cycloalkyloxy, wherein said C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, or C3-C8 cycloalkyloxy is unsubstituted or substituted by one or more substituents selected from halogen, cyano, hydroxy, amino, C1-C6 alkyl, or C1-C6 alkoxy, and preferably R 3is selected from halogen, cyano, oxo, hydroxy, substituted or unsubstituted amino, C1-C3 alkyl, C1-C3 alkoxy, C3-C5 cycloalkyl, or C3-C5 cycloalkyloxy, and the C1-C3 alkyl, C1-C3 alkoxy, C3-C5 cycloalkyl, or C3-C5 cycloalkyloxy is unsubstituted or substituted by one or more substituents selected from halogen, cyano, hydroxy, amino, C1-C6 alkyl, or C1-C6 alkoxy, and preferably, R 3 is selected from fluorine, chlorine, oxo, hydroxy, amino or C1-C3 alkyl (e.g., methyl), wherein said C1-C3 alkyl (e.g., methyl) is unsubstituted or substituted by amino; R 4 is selected from halogen, cyano, oxo, hydroxy, substituted or unsubstituted amino, C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, or C3-C8 cycloalkyloxy, wherein said C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, or C3-C8 cycloalkyloxy is unsubstituted or substituted by one or more substituents selected from halogen, cyano, hydroxy, amino, C1-C6 alkyl, or C1-C6 alkoxy, preferably said C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, or C3-C8 cycloalkyloxy is C1-C3 alkyl, C1-C3 alkoxy, C3-C5 cycloalkyl, or C3-C5 cycloalkyloxy, and is unsubstituted or substituted by one or more substituents selected from halogen, cyano, hydroxy, amino, C1-C6 alkyl, or C1-C6 alkoxy, preferably 4 is fluorine, chlorine, oxo, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, Selected from TIFF2025503099000016.tif39145, R 5is selected from halogen, hydroxy, substituted or unsubstituted amino, C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, or C3-C8 cycloalkyloxy, wherein said C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, or C3-C8 cycloalkyloxy is unsubstituted or substituted by one or more substituents selected from halogen, cyano, hydroxy, amino, C1-C6 alkyl, or C1-C6 alkoxy, and preferably R 5 is selected from fluorine, chlorine, bromine, methyl, methoxy, trifluoromethyl or trifluoromethoxy, for example, R 5 is selected from fluorine, chlorine, or bromine; R 6 , R 7 are each independently selected from hydrogen, C1-C6 alkyl, or C3-C8 cycloalkyl, preferably R 6 , R 7 are each independently selected from hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl; m is selected from 0, 1, 2, 3, 4, or 5, preferably m is selected from 0, 1, 2, or 3; n is selected from 0, 1, 2, 3, 4, or 5, preferably n is selected from 0, 1, 2, 3, or 4; q is selected from 0, 1, 2, 3, or 4; preferably, q is selected from 1 or 2.

[0015] In some embodiments, in a compound of formula I, a stereoisomer thereof, or a pharma- ceutically acceptable salt thereof, Ring A is selected from piperidinyl, piperazinyl, azacyclobutyl, azacycloheptyl, homopiperazinyl, diazaspirononyl, diazaspirodecyl, or oxazaspirodecyl; Ring B is selected from phenyl, pyridyl, indolyl, dihydroindolyl, indazolyl, benzisoxazolyl, benzoxazolyl, benzodioxolyl, or benzodihydroxazinyl; R 1 , R2 are each independently hydrogen, cyano, Selected from TIFF2025503099000017.tif38134 or R 1 and R 2 are cyclized together with the carbon atoms to which they are attached. Form TIFF2025503099000018.tif1838, R 3 is selected from fluorine, chlorine, bromine, oxo, hydroxy, amino or C1-C3 alkyl, wherein said C1-C3 alkyl is unsubstituted or substituted by amino; R 4 is selected from fluorine, chlorine, bromine, oxo, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, wherein said C1-C6 alkyl is unsubstituted or substituted by one or more substituents selected from halogen or hydroxy; R 5 is selected from fluorine, chlorine, or bromine; m is selected from 0, 1, 2, or 3; n is selected from 0, 1, 2, 3, or 4; q is selected from 1 or 2.

[0016] Preferably, the compound of formula I, its stereoisomer, or a pharma- ceutically acceptable salt thereof further has the structure shown in formula II:

[0017] [ka] (where: Ring A is selected from cyclohexyl, piperidinyl, piperazinyl, azacycloheptyl, or homopiperazinyl, preferably said piperidinyl, piperazinyl, azacycloheptyl, or homopiperazinyl is bonded to the pyridine ring via an N atom; Ring B is selected from phenyl, pyridyl, indolyl, dihydroindolyl, or indazolyl; R 2is selected from hydrogen or fluorine, R 3 is selected from fluorine, chlorine, oxo, hydroxy or amino, R 4 is fluorine, chlorine, oxo, methyl, methoxy, Selected from TIFF2025503099000020.tif1444, m is selected from 0, 1, 2, or 3; n is selected from 0, 1, 2, 3, or 4.

[0018] Alternatively, in some embodiments, in the compound of formula II, a stereoisomer thereof, or a pharma- ceutically acceptable salt thereof, Ring A is selected from cyclohexyl, piperidinyl, piperazinyl, azacyclobutyl, azacycloheptyl, homopiperazinyl, diazaspirononyl, or diazaspirodecyl, preferably said piperidinyl, piperazinyl, azacyclobutyl, azacycloheptyl, homopiperazinyl, diazaspirononyl, or diazaspirodecyl is bonded to the pyridine ring via an N atom; Ring B is selected from phenyl, pyridyl, indolyl, dihydroindolyl, indazolyl, benzisoxazolyl, benzoxazolyl, or benzodioxolyl; R 2 is hydrogen, cyano, Selected from TIFF2025503099000021.tif1636, R 6 , R 7 are each independently selected from hydrogen, C1-C5 alkyl, or C3-C5 cycloalkyl; R 3 is selected from fluorine, chlorine, bromine, oxo, hydroxy, amino or C1-C6 alkyl, wherein said C1-C6 alkyl is unsubstituted or substituted by amino; R 4is selected from fluorine, chlorine, bromine, oxo, C1-C6 alkyl, C1-C6 alkoxy, wherein said C1-C6 alkyl is unsubstituted or substituted by one or more substituents selected from halogen or hydroxy; m is selected from 0, 1, 2, or 3; n is selected from 0, 1, 2, 3, or 4.

[0019] More preferably, the heterocyclic derivative having the structure represented by formula I, its stereoisomer or its pharma- ceutically acceptable salt is selected from the following compounds, their stereoisomers or their pharma- ceutically acceptable salts: TIFF2025503099000022.tif218157 TIFF2025503099000023.tif131157

[0020] The present application also includes aspects obtained by any combination, deletion, or substitution of each of the above-described embodiments and preferred modes.

[0021] Another aspect of the present application provides a method for preparing a pyridine derivative having the structure shown in formula I above, comprising the steps of:

[0022] Method 1 [ka] (wherein LG represents a leaving group, and the leaving group includes, but is not limited to, a halogen atom, methanesulfonyloxy, p-tosyloxy, etc.) 1 , R 2 , R 3 , R 4 , R 5 , ring A, ring B, m, n, and q are the same as those defined above for the pyridine derivative having the structure represented by formula I. (1) Compound I-1 is reacted with compound I-2 to obtain compound I-3.

[0023] The reaction is preferably carried out in a suitable organic solvent. The organic solvent may be selected from tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, 1,4-dioxane, and any combination thereof, preferably N,N-dimethylformamide. The reaction is preferably carried out in the presence of a suitable alkali and / or in the presence of a transition metal catalyst and a ligand. The alkali may be selected from triethylamine, pyridine, 4-dimethylaminopyridine, diisopropylethylamine, potassium carbonate, cesium carbonate, sodium carbonate, or potassium tert-butoxide, preferably potassium carbonate. The transition metal catalyst may be selected from Pd(dppf)Cl2, Pd(OAc)2, Pd2(dba)3, Pd(PPh3)4, or RuPhos-Pd-G3. The reaction is preferably carried out at a suitable temperature, preferably 50-80°C. The reaction is preferably carried out for a suitable time, for example, 2-8 hours.

[0024] (2) Compound I-3 is subjected to a substitution reaction to obtain compound I-4.

[0025] The reaction is preferably carried out in a suitable organic solvent. The organic solvent may be selected from acetonitrile, toluene, chloroform, tetrahydrofuran, and any combination thereof, preferably acetonitrile. The reaction is preferably carried out in the presence of a suitable brominating reagent. The brominating reagent may be selected from N-bromosuccinimide, liquid bromine, pyridinium bromide, preferably N-bromosuccinimide. The reaction is preferably carried out at a suitable temperature, preferably 20-50° C. The reaction is preferably carried out for a suitable time, for example, 2-6 hours.

[0026] (3) Compound I-4 is subjected to a coupling reaction with the boronic acid or boronic ester of compound I-5 to obtain compound I-6.

[0027] The reaction is preferably carried out in a suitable organic solvent. The organic solvent may be selected from tetrahydrofuran, 1,4-dioxane, toluene, acetonitrile, ethanol, water, and any combination thereof, preferably a combination of 1,4-dioxane and water. The reaction is preferably carried out in the presence of a suitable catalyst. The catalyst may be selected from Pd(dppf)Cl2, Pd(OAc)2, Pd2(dba)3, Pd(PPh3)4, preferably Pd(dppf)Cl2. The reaction is preferably carried out in the presence of a suitable alkali. The alkali may be selected from triethylamine, pyridine, 4-dimethylaminopyridine, diisopropylethylamine, potassium carbonate, cesium carbonate, sodium carbonate, preferably potassium carbonate. The reaction is preferably carried out at a suitable temperature, the temperature being preferably 80 to 120°C. The reaction is preferably carried out for a suitable time, for example, 8 to 12 hours.

[0028] (4) Compound I-6 and compound I-7 are subjected to a coupling reaction to obtain a compound having a structure represented by formula I.

[0029] The reaction is preferably carried out in a suitable organic solvent. The organic solvent may be selected from tetrahydrofuran, 1,4-dioxane, toluene, acetonitrile, ethanol, water, and any combination thereof, preferably a combination of 1,4-dioxane and water. The reaction is preferably carried out in the presence of a suitable catalyst. The catalyst may be selected from Pd(dppf)Cl2, Pd(OAc)2, Pd2(dba)3, Pd(PPh3)4, preferably Pd(dppf)Cl2. The reaction is preferably carried out in the presence of a suitable alkali. The alkali may be selected from triethylamine, pyridine, 4-dimethylaminopyridine, diisopropylethylamine, potassium carbonate, cesium carbonate, sodium carbonate, preferably potassium carbonate. The reaction is preferably carried out at a suitable temperature, preferably 80 to 120°C. The reaction is preferably carried out for a suitable time, for example, 8 to 12 hours.

[0030] Method 2 [ka] (wherein LG represents a leaving group, and the leaving group includes, but is not limited to, a halogen atom, methanesulfonyloxy, p-tosyloxy, etc.) 1 , R 2 , R 3 , R 4 , R 5 , ring A, ring B, m, n, and q are the same as those defined above for the pyridine derivative having the structure represented by formula I. (1) Compound I-1 is subjected to a substitution reaction to obtain compound I-8.

[0031] The reaction is preferably carried out in a suitable organic solvent. The organic solvent may be selected from acetonitrile, toluene, chloroform, tetrahydrofuran, and any combination thereof, preferably acetonitrile. The reaction is preferably carried out in the presence of a suitable brominating reagent. The brominating reagent may be selected from N-bromosuccinimide, liquid bromine, pyridinium bromide, preferably N-bromosuccinimide. The reaction is preferably carried out at a suitable temperature, preferably 20-50° C. The reaction is preferably carried out for a suitable time, for example, 2-6 hours.

[0032] (2) Compound I-8 is subjected to a coupling reaction with the boronic acid or boronic ester of compound I-5 to obtain compound I-9.

[0033] The reaction is preferably carried out in a suitable organic solvent. The organic solvent may be selected from tetrahydrofuran, 1,4-dioxane, toluene, acetonitrile, ethanol, water, and any combination thereof, preferably a combination of 1,4-dioxane and water. The reaction is preferably carried out in the presence of a suitable catalyst. The catalyst may be selected from Pd(dppf)Cl2, Pd(OAc)2, Pd2(dba)3, Pd(PPh3)4, preferably Pd(dppf)Cl2. The reaction is preferably carried out in the presence of a suitable alkali. The alkali may be selected from triethylamine, pyridine, 4-dimethylaminopyridine, diisopropylethylamine, potassium carbonate, cesium carbonate, sodium carbonate, preferably potassium carbonate. The reaction is preferably carried out at a suitable temperature, preferably 80 to 120°C. The reaction is preferably carried out for a suitable time, for example, 8 to 12 hours.

[0034] (3) Compound I-9 and compound I-7 are subjected to a coupling reaction to obtain compound I-10.

[0035] The reaction is preferably carried out in a suitable organic solvent. The organic solvent may be selected from tetrahydrofuran, 1,4-dioxane, toluene, acetonitrile, ethanol, water, and any combination thereof, preferably a combination of 1,4-dioxane and water. The reaction is preferably carried out in the presence of a suitable catalyst. The catalyst may be selected from Pd(dppf)Cl2, Pd(OAc)2, Pd2(dba)3, Pd(PPh3)4, preferably Pd(dppf)Cl2. The reaction is preferably carried out in the presence of a suitable alkali. The alkali may be selected from triethylamine, pyridine, 4-dimethylaminopyridine, diisopropylethylamine, potassium carbonate, cesium carbonate, sodium carbonate, preferably potassium carbonate. The reaction is preferably carried out at a suitable temperature, preferably 80 to 120°C. The reaction is preferably carried out for a suitable time, for example, 8 to 12 hours.

[0036] (4) Compound I-10 is reacted with compound I-2 to obtain a compound having the structure represented by formula I.

[0037] The reaction is preferably carried out in a suitable organic solvent. The organic solvent may be selected from tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, 1,4-dioxane, and any combination thereof, preferably N,N-dimethylformamide. The reaction is preferably carried out in the presence of a suitable alkali and / or in the presence of a transition metal catalyst and a ligand. The alkali may be selected from triethylamine, pyridine, 4-dimethylaminopyridine, diisopropylethylamine, potassium carbonate, cesium carbonate, sodium carbonate, or potassium tert-butoxide, preferably potassium carbonate. The transition metal catalyst may be selected from Pd(dppf)Cl2, Pd(OAc)2, Pd2(dba)3, Pd(PPh3)4, or RuPhos-Pd-G3. The reaction is preferably carried out at a suitable temperature, preferably 50-80°C. The reaction is preferably carried out for a suitable time, for example, 2-8 hours.

[0038] Method 3 [ka] (wherein LG represents a leaving group, and the leaving group includes, but is not limited to, a halogen atom, methanesulfonyloxy, p-tosyloxy, etc.) 1 , R 2 , R 3 , R 4 , R 5 , ring A, ring B, m, n, and q are the same as those defined above for the pyridine derivative having the structure represented by formula I. (1) Compound I-3 and compound I-7 are subjected to a coupling reaction to obtain compound I-11.

[0039] The reaction is preferably carried out in a suitable organic solvent. The organic solvent may be selected from tetrahydrofuran, 1,4-dioxane, toluene, acetonitrile, ethanol, water, and any combination thereof, preferably a combination of 1,4-dioxane and water. The reaction is preferably carried out in the presence of a suitable catalyst. The catalyst may be selected from Pd(dppf)Cl2, Pd(OAc)2, Pd2(dba)3, Pd(PPh3)4, preferably Pd(dppf)Cl2. The reaction is preferably carried out in the presence of a suitable alkali. The alkali may be selected from triethylamine, pyridine, 4-dimethylaminopyridine, diisopropylethylamine, potassium carbonate, cesium carbonate, sodium carbonate, preferably potassium carbonate. The reaction is preferably carried out at a suitable temperature, preferably 80 to 120°C. The reaction is preferably carried out for a suitable time, for example, 8 to 12 hours.

[0040] (2) Compound I-11 is subjected to a substitution reaction to obtain compound I-12.

[0041] The reaction is preferably carried out in a suitable organic solvent. The organic solvent may be selected from acetonitrile, toluene, chloroform, tetrahydrofuran, and any combination thereof, preferably acetonitrile. The reaction is preferably carried out in the presence of a suitable brominating reagent. The brominating reagent may be selected from N-bromosuccinimide, liquid bromine, pyridinium bromide, preferably N-bromosuccinimide. The reaction is preferably carried out at a suitable temperature, preferably 20-50° C. The reaction is preferably carried out for a suitable time, for example, 2-6 hours.

[0042] (3) Compound I-12 is subjected to a coupling reaction with the boronic acid or boronic ester of compound I-5 to obtain compound I.

[0043] The reaction is preferably carried out in a suitable organic solvent. The organic solvent may be selected from tetrahydrofuran, 1,4-dioxane, toluene, acetonitrile, ethanol, water, and any combination thereof, preferably a combination of 1,4-dioxane and water. The reaction is preferably carried out in the presence of a suitable catalyst. The catalyst may be selected from Pd(dppf)Cl2, Pd(OAc)2, Pd2(dba)3, Pd(PPh3)4, preferably Pd(dppf)Cl2. The reaction is preferably carried out in the presence of a suitable alkali. The alkali may be selected from triethylamine, pyridine, 4-dimethylaminopyridine, diisopropylethylamine, potassium carbonate, cesium carbonate, sodium carbonate, preferably potassium carbonate. The reaction is preferably carried out at a suitable temperature, preferably 80 to 120°C. The reaction is preferably carried out for a suitable time, for example, 8 to 12 hours.

[0044] The specific conditions of each of the above reaction steps are well known in the art and are not specifically limited in this application. Based on the teachings of this application and the common knowledge of those skilled in the art, those skilled in the art can select and replace each substituent in the general formula to prepare different compounds. These selections and replacements are within the scope of protection of this application.

[0045] The present application further relates to a pharmaceutical composition comprising a compound of formula I above, its stereoisomer or a pharma- ceutically acceptable salt thereof, and pharma- ceutically acceptable auxiliary materials.

[0046] The present application further relates to the use of the above-mentioned compound of formula I, its stereoisomer or its pharma- ceutically acceptable salt, or the above-mentioned pharmaceutical composition in the manufacture of a medicament for preventing or treating a disease associated with LSD1. Alternatively, the present application further relates to a compound of formula I, its stereoisomer or its pharma- ceutically acceptable salt, or the above-mentioned pharmaceutical composition for preventing or treating a disease associated with LSD1. Alternatively, the present application further relates to a method for preventing or treating a disease associated with LSD1, comprising administering to a subject in need thereof the above-mentioned compound of formula I, its stereoisomer or its pharma- ceutically acceptable salt, or the above-mentioned pharmaceutical composition.

[0047] In some embodiments, the disease associated with LSD1 is selected from tumors or cancers, such as acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), lymphoma, malignant sarcoma, breast cancer, cervical cancer, colon cancer, lung cancer, oral cancer, brain cancer, gastric cancer, liver cancer, colorectal cancer, pancreatic cancer, skin cancer, prostate cancer, bone cancer, kidney cancer, ovarian cancer, bladder cancer, fallopian tube tumor, peritoneal tumor, melanoma, glioma, glioblastoma, mastoid malignant tumor, head and neck tumor, or myeloma.

[0048] The present application further relates to the above-mentioned compound of formula I, its stereoisomer or its pharma- ceutically acceptable salt, or the above-mentioned pharmaceutical composition in the manufacture of an LSD1 inhibitor.Alternatively, the present application further relates to the above-mentioned compound of formula I, its stereoisomer or its pharma- ceutically acceptable salt, or the above-mentioned pharmaceutical composition as an LSD1 inhibitor.Alternatively, the present application further relates to a method for inhibiting LSD1, comprising administering to a subject in need thereof the above-mentioned compound of formula I, its stereoisomer or its pharma- ceutically acceptable salt, or the above-mentioned pharmaceutical composition.

[0049] In the present application, it has been discovered that an LSD1 inhibitor having a novel structure represented by formula I has excellent inhibitory activity. [Brief description of the drawings]

[0050] [Figure 1] The change in tumor volume in mice in the test compound group and the vehicle group is shown, where Cpd represents the compound. [Diagram 2] Changes in tumor weight in the test compound and vehicle groups are shown. [Diagram 3] The percent weight change of mice in the test compound group and the vehicle group is shown. [Figure 4] The change in tumor volume in mice in the test compound group and the vehicle group is shown. [Diagram 5] The percent weight change of mice in the test compound group and the vehicle group is shown. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0051] In order to make the aspects and technical solutions of the present application clearer, the present application will be described in more detail below with reference to specific examples. It should be understood that these examples are only used to explain the present application, and are not intended to limit the scope of the present application. In addition, all specific experimental methods not described in the following examples are in accordance with conventional experimental methods. Definitions and Explanations

[0052] [Definitions and Explanations] Unless otherwise specified, terms used in this application have the following meanings: Certain terms should not be considered uncertain or indefinite in the absence of a specific definition, but should be understood according to their ordinary meaning in the art.

[0053] When a covalent bond in any structural unit or group in this application is not attached to a specific atom, it is meant that the covalent bond may be attached to any atom within the structural unit or group, provided that valence bond principles are not violated.

[0054] As used herein, unless otherwise noted, "alkoxy" refers to --O-alkyl.

[0055] As used herein, unless otherwise specified, "halogen" refers to fluorine, chlorine, bromine or iodine.

[0056] As used herein, unless otherwise noted, "cycloalkyloxy" refers to --O-cycloalkyl.

[0057] As used herein, unless otherwise specified, "saturated cycloalkyl" refers to a fully saturated alicyclic hydrocarbon, including monocyclic, bicyclic bridged rings, bicyclic spiro rings, and the like. For example, cycloalkyl in this specification refers to a C3-C 10 Single ring, C5~C 15 Spiro ring or C4-C 12 Non-limiting examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, spiropentyl, spirohexyl, spiroheptyl, spirooctyl, spirononyl, spirodecyl, spiroundecyl, and the like.

[0058] As used herein, unless otherwise specified, "saturated heterocycloalkyl" refers to a cycloalkyl in which one or more (e.g., 1 to 6, 1 to 5, 1 to 3, 1 or 2) carbon atoms are replaced by a heteroatom selected from N, O or S.

[0059] As used herein, unless otherwise specified, "cyclohydrocarbyl" refers to hydrocarbyl in which the carbon atoms form a ring, including saturated cyclohydrocarbyl and unsaturated cyclohydrocarbyl (e.g., aromatic groups). As used herein, unsaturated cyclohydrocarbyl is also referred to as unsaturated cycloalkyl. As used herein, cyclohydrocarbyl may be a monocyclic bridged ring, a bicyclic bridged ring, a bicyclic spiro ring, or a bicyclic fused ring, for example, C3-C 10 Monocyclic cyclohydrocarbyl, C5-C 15 Spirocyclohydrocarbyl, C4-C 12 It may also be a bridged ring cyclohydrocarbyl.

[0060] As used herein, unless otherwise specified, "substituted or unsubstituted amino" is intended to include unsubstituted amino or amino substituted with a group selected from C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, or halogen.

[0061] As used herein, unless otherwise specified, the term "Cm-Cn" means that there are m to n carbon atoms (where n is greater than m and both are integers) in the moiety modified by the term. For example, C1-C6 means that the modified moiety has 1 to 6 carbon atoms, such as 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms.

[0062] The term "subject" is synonymous with "patient" and "individual" and means a human or non-human animal (e.g., a mammal, such as a primate, rodent, etc.). "Mammal" includes humans and domestic animals (e.g., laboratory mammals and household pets, such as cats, dogs, pigs, sheep, cows, ewes, goats, horses, rabbits, etc.), and non-domestic mammals, such as wild mammals.

[0063] The term "treatment" refers to the administration of a compound or formulation described herein to improve or eliminate a disease or one or more symptoms associated with said disease, including inhibiting the progression of the disease or condition, or ameliorating the disease or condition.

[0064] The term "pharmaceutical acceptable" means that a carrier, vehicle, diluent, auxiliary material, and / or formed salt is ordinarily chemically or physically compatible with the other ingredients that make up a drug dosage form, but is physiologically compatible with the receptor without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0065] In this application, the terms "comprise", "including" and "containing" and the like are to be understood in an open and non-exclusive sense, i.e., "including, but not limited to," meaning that in addition to the recited elements, components, and steps, other elements, components, and steps not specified may be included. As used herein, singular terms include plurals and vice versa unless the context clearly dictates otherwise. Similarly, the word "or" is intended to include "and" unless the context clearly dictates otherwise.

[0066] Unless otherwise specified, in this specification, parameter values ​​expressing amounts of ingredients or physicochemical properties or reaction conditions, etc., should be understood in all cases as being modified by the term "about". When the term "about" is used in the description of this application, the term "about" means that there is an error value, for example, a change within a range of ±5%, for example ±1% or ±0.1% of a specific value.

[0067] In this application, when a chemical name and a structural formula conflict, the structural formula shall control unless the chemical name is inferred from the context rather than the structural formula.

[0068] The abbreviations used in this specification have the following meanings: TIFF2025503099000027.tif68157

[0069] The structure of the compound was determined by mass spectrometry (MS) or nuclear magnetic resonance ( 1 1H NMR) is used to determine the 1 H NMR) shifts (δ) are given in parts per million (ppm). 1 H NMR was measured using a Bruker AVANCE-400 nuclear magnetometer. The solvent used was deuterated dimethyl sulfoxide (DMSO-d6), the internal standard was tetramethylsilane (TMS), and the chemical shifts were 10 -6The unit of the concentration is given in ppm. Mass spectrometry (MS) was measured using a FINNIGAN LCQAd(ESI) mass spectrometer (manufacturer: Therm, model: Finnigan LCQ advantage MAX). Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate was used as thin layer silica gel. Yantai Huanghai silica gel 200-300 mesh silica gel was usually used as the carrier for column chromatography.

[0070] Unless otherwise specified herein, all reactions referred to herein are carried out under a nitrogen atmosphere. The term "nitrogen atmosphere" herein refers, for example, to connecting a reaction flask to a 1 L volume of nitrogen balloon.

[0071] The term "hydrogen atmosphere" in this application refers, for example, to connecting a reaction flask to a 1 L volume hydrogen balloon.

[0072] Unless otherwise specified in this application, the solutions referred to in reactions in this application are aqueous solutions.

[0073] The term "room temperature" in this application refers to a temperature between 10°C and 25°C.

[0074] All patents, patent applications, and other identified publications are expressly incorporated herein by reference for purposes of illustration and disclosure. These publications are provided solely for their disclosure prior to the filing date of the present application. Any statement as to the date of these documents or the representation of the contents of these documents is based on the information available to the applicants and does not constitute any admission as to the correctness of the dates of these documents or the contents of these documents. Furthermore, the reference to these publications in this specification is not an admission that the publications form part of the common general knowledge in the art in any country.

[0075] The present application will be described in more detail below with reference to examples, but those skilled in the art will understand that the scope of protection of the present application is not limited thereto. Those skilled in the art may make various modifications, changes, combinations, etc. to the embodiments and examples of the present application without departing from the spirit or scope of the present application. The adjusted solutions obtained in this manner are also included in the scope of protection of the present application.

[0076] Example 1 Preparation of 6-(4-aminopiperid-1-yl)-2-(4-cyano-3-fluorophenyl)-3-(3-fluoro-4-methoxyphenyl)isonicotinonitrile (1) [ka] First step: Preparation of tert-butyl (1-(6-chloro-4-cyanopyrid-2-yl)piperid-4-yl)carbamate (1b) Compound 1a (550 mg, 3.18 mmol), 4-tert-butoxycarbonylaminopiperidine (643 mg, 3.21 mmol), and K2CO3 (658 mg, 4.76 mmol) were dissolved in N,N-dimethylformamide (10 mL), and the system was heated to 80°C and stirred overnight to react. The reaction system was cooled to room temperature, the reaction liquid was poured into water, extracted three times with ethyl acetate, and the combined organic phase was washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (856 mg, 80% yield). Second step: Preparation of tert-butyl (1-(5-bromo-6-chloro-4-cyanopyrid-2-yl)piperid-4-yl)carbamate (1c) Compound 1b (538 mg, 1.60 mmol) was dissolved in acetonitrile (15 mL), NBS (288 mg, 1.62 mmol) was slowly added to the system in an ice bath, and the reaction system was stirred at room temperature for 2 hours to react. The reaction system was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to obtain the target compound (542 mg, yield 82%). Third step: Preparation of tert-butyl [1-(6-chloro-4-cyano-5-(3-fluoro-4-methoxyphenyl)pyrid-2-yl)piperid-4-yl]carbamate (1d) Compound 1c (231 mg, 0.56 mmol), 3-fluoro-4-methoxyphenylboronic acid (97 mg, 0.57 mmol), K2CO3 (116 mg, 0.84 mmol) were dissolved in 1,4-dioxane (5 mL) and water (1 mL), nitrogen substitution was performed, Pd(dppf)Cl2 (44 mg, 0.06 mmol) was added, nitrogen substitution was further performed, the reaction system was heated to 100 ° C., and the reaction was allowed to proceed overnight with stirring. The reaction system was cooled to room temperature, the reaction liquid was poured into water, extracted three times with ethyl acetate, the organic phase was combined and washed with saturated saline, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to obtain the target compound (126 mg, yield 49%). Fourth step: Preparation of tert-butyl (1-(4-cyano-6-(4-cyano-3-fluorophenyl)-5-(3-fluoro-4-methoxyphenyl)pyrid-2-yl)piperid-4-yl)carbamate (1e) Compound 1d (47 mg, 0.10 mmol), 3-fluoro-4-cyanophenylboronic acid (25 mg, 0.15 mmol), K2CO3 (41 mg, 0.30 mmol) were dissolved in 1,4-dioxane (1 mL) and water (0.2 mL), nitrogen replacement was performed, Pd(dppf)Cl2 (7 mg, 0.01 mmol) was added, nitrogen replacement was further performed, the reaction system was heated to 100 ° C., and the reaction was allowed to proceed overnight with stirring. The reaction system was cooled to room temperature, the reaction liquid was poured into water, extracted three times with ethyl acetate, the organic phase was combined and washed with saturated saline, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to obtain the target compound (27 mg, yield 49%). Fifth step: Preparation of 6-(4-aminopiperid-1-yl)-2-(4-cyano-3-fluorophenyl)-3-(3-fluoro-4-methoxyphenyl)isonicotinonitrile (1) Compound 1e (27 mg, 0.05 mmol) was dissolved in ethyl acetate (1 mL), then hydrochloric acid-ethyl acetate solution (1 mL, 3M in EA) was added, and the reaction system was stirred at room temperature for 1 hour to react. The reaction system was concentrated under reduced pressure, diluted with water, and the pH value of the system was adjusted to about 8 with saturated sodium bicarbonate solution, and extracted three times with ethyl acetate. The organic phase was combined and washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by thin-layer silica gel plate to obtain the target compound (16 mg, yield 73%). LC-MS (ESI) m / z (M+H) + :446.2 1 H NMR(400MHz,DMSO-d6)δ 7.83-7.77(m,1H),7.53(s,1H),7.37(dd,J=10.8,1.2Hz,1H),7.21-7.10(m,3H),6.98-6.93(m,1H),4.3 4-4.25(m,2H),3.84(s,3H),3.08-2.98(m,2H),2.89-2.79(m,1H),1.82-1.73(m,2H),1.25-1.14(m,2H).

[0077] Example 2 Preparation of 6-(4-aminopiperid-1-yl)-2-(4-cyano-3-fluorophenyl)-3-(3-fluoro-4-methoxyphenyl)isonicotinamide (2) [ka] First step: Preparation of tert-butyl [1-(4-carbamoyl-6-chloro-5-(3-fluoro-4-methoxyphenyl)pyrid-2-yl)piperid-4-yl]carbamate (2a) Compound 1d (125 mg, 0.27 mmol) was dissolved in a methanol solution (1 mL), then dimethyl sulfoxide (1 mL), NaOH (32 mg, 0.80 mmol) were added in sequence, and H2O2 (153 mg, 1.35 mmol, 30% aqueous solution) was slowly added dropwise while stirring the reaction system, and the reaction system was stirred at 50 ° C for 2 hours to react. The reaction system was cooled to room temperature, the reaction liquid was poured into water, extracted with ethyl acetate three times, the organic phase was combined and washed with saturated saline, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to obtain the target compound (90 mg, yield 69%). Second step: Preparation of tert-butyl (1-(4-carbamoyl-6-(4-cyano-3-fluorophenyl)-5-(3-fluoro-4-methoxyphenyl)pyrid-2-yl)piperid-4-yl)carbamate (2b) Compound 2a (55 mg, 0.11 mmol), 3-fluoro-4-cyanophenylboronic acid (28 mg, 0.17 mmol), K2CO3 (46 mg, 0.33 mmol) were dissolved in 1,4-dioxane (1 mL) and water (0.2 mL), nitrogen substitution was performed, Pd(dppf)Cl2 (8 mg, 0.01 mmol) was added, nitrogen substitution was further performed, the reaction system was heated to 100 ° C., and the reaction was allowed to proceed overnight with stirring. The reaction system was cooled to room temperature, the reaction liquid was poured into water, extracted three times with ethyl acetate, the organic phase was combined and washed with saturated saline, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to obtain the target compound (48 mg, yield 77%). Third step: Preparation of 6-(4-aminopiperid-1-yl)-2-(4-cyano-3-fluorophenyl)-3-(3-fluoro-4-methoxyphenyl)isonicotinamide (2) Compound 2b (48 mg, 0.09 mmol) was dissolved in ethyl acetate (1 mL), then hydrochloric acid-ethyl acetate solution (1 mL, 3M in EA) was added, and the reaction system was stirred at room temperature for 1 hour. The reaction system was concentrated under reduced pressure, diluted with water, and the pH value of the system was adjusted to about 8 with saturated sodium bicarbonate solution, and extracted three times with ethyl acetate. The organic phase was combined and washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by thin-layer silica gel plate to obtain the target compound (31 mg, 79% yield). LC-MS (ESI) m / z (M+H) + :464.2 1 H NMR (400 MHz, DMSO-d6) δ 7.80-7.72 (m, 2H), 7.45-7.40 (m, 1H), 7.31 (dd, J = 10.8, 1.2 Hz, 1H), 7.14 (dd, J = 8.0, 1.2 Hz, 1H), 7.02 (t, J = 8.4 Hz, 1H), 6.95 (dd, J = 12.4, 2.4 Hz, 1H), 6.88 (s, 1H), 6.88-6.72 (m, 1H), 4.32-4.23 (m, 2H), 3.80 (s, 3H), 3.02-2.92 (m, 2H), 2.86-2.77 (m, 1H), 1.85-1.73 (m, 2H), 1.26-1.13 (m, 2H).

[0078] Example 3 Preparation of 4-(4-(4-aminopiperid-1-yl)-7-(3-fluoro-4-methoxyphenyl)-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyrid-6-yl)-2-fluorobenzonitrile (3) [ka] First step: Preparation of 2,6-dichloro-4-iodonicotinic acid (3b) Compound 3a (10.0 g, 36.51 mmol) was dissolved in dry tetrahydrofuran (110 mL), purged with nitrogen, and the system was placed at -50 ° C. LDA (20 mL, 40.00 mmol, 2 mol / L in THF / heptane / ethylbenzene) was slowly added dropwise to the system, and after the addition was completed, the system was maintained at -50 ° C. and stirred for another 2 hours to react. The reaction solution was quickly poured into a measuring cup containing crushed dry ice and stirred, and slowly returned to room temperature, and the reaction solution was poured into water and extracted three times with ethyl acetate. The organic phase was combined and washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the crude product was directly used in the next step reaction without further purification. Second step: Preparation of methyl 2,6-dichloro-4-iodonicotinate (3c) Compound 3b (12.0 g, 37.75 mmol) was dissolved in N,N-dimethylformamide (130 mL), followed by the addition of K2CO3 (7.9 g, 57.16 mmol) and methyl iodide (8.1 g, 57.04 mmol) in that order, and the reaction system was stirred at room temperature for 1 hour to react. The reaction solution was poured into water, extracted three times with ethyl acetate, and the combined organic phase was washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (8.3 g, 68% overall yield for two steps). Third step: Preparation of methyl 2,6-dichloro-4-cyanonicotinate (3d) Compound 3c (4.3 g, 12.95 mmol) and Zn(CN)2 (4.56 g, 38.85 mmol) were dissolved in N,N-dimethylformamide (40 mL), nitrogen replacement was performed, Pd(PPh3)4 (750 mg, 0.65 mmol) was added, nitrogen replacement was further performed, and the reaction system was placed at 100 ° C. and stirred overnight to react. The reaction system was cooled to room temperature, the reaction liquid was poured into water, extracted three times with ethyl acetate, the organic phase was combined and washed with saturated saline, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to obtain the target compound (1.0 g, yield 33%). Fourth step: Preparation of methyl 2-(4-((tert-butoxycarbonyl)amino)piperid-1-yl)-6-chloro-4-cyanonicotinate (3e) Compound 3d (1.0 g, 4.33 mmol), 4-tert-butoxycarbonylaminopiperidine (1.3 g, 6.49 mmol), and triethylamine (900 mg, 8.89 mmol) were dissolved in tetrahydrofuran (10 mL). The system was heated to 50° C. and stirred for 3 hours to react. The reaction system was cooled to room temperature, the reaction solution was poured into water, extracted three times with ethyl acetate, and the combined organic phase was washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (647 mg, yield 38%). Fifth step: Preparation of tert-butyl (1-(6-chloro-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyrid-4-yl)piperid-4-yl)carbamate (3f) Compound 3e (647 mg, 1.64 mmol) dissolved in methanol (10 mL) was added to the reaction flask, then ammonia water (10 drops) and Raney-Ni (267 mg) were added in that order, hydrogen substitution was performed, and the reaction system was reacted overnight at room temperature in a hydrogen atmosphere. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the crude product was purified by a thin-layer silica gel plate to obtain the target compound (218 mg, yield 36%). Sixth step: Preparation of tert-butyl (1-(7-bromo-6-chloro-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyrid-4-yl)piperid-4-yl)carbamate (3g) Compound 3f (175 mg, 0.48 mmol) was dissolved in acetonitrile (4 mL), and NBS (128 mg, 0.72 mmol) was slowly added to the system under ice bath, and the reaction was stirred for 1 hour while maintaining the reaction system under ice bath. The reaction solution was poured into water, extracted three times with ethyl acetate, and the organic phases were combined and washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by thin-layer silica gel plate to obtain the target compound (210 mg, 99% yield). Seventh step: Preparation of tert-butyl (1-(6-chloro-7-(3-fluoro-4-methoxyphenyl)-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyrid-4-yl)piperid-4-yl)carbamate (3h) Compound 3g (120 mg, 0.27 mmol), 3-fluoro-4-methoxyphenylboronic acid (46 mg, 0.27 mmol), K2CO3 (112 mg, 0.81 mmol) were dissolved in 1,4-dioxane (2 mL) and water (0.2 mL), nitrogen replacement was performed, Pd(dppf)Cl2 (36 mg, 0.05 mmol) was added, nitrogen replacement was further performed, the reaction system was heated to 70 ° C., and the reaction was allowed to proceed overnight with stirring. The reaction system was cooled to room temperature, the reaction liquid was poured into water, extracted three times with ethyl acetate, the organic phase was combined and washed with saturated saline, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the crude product was purified by thin-layer silica gel plate to obtain the target compound (33 mg, yield 25%). Eighth step: Preparation of tert-butyl (1-(6-(4-cyano-3-fluorophenyl)-7-(3-fluoro-4-methoxyphenyl)-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyrid-4-yl)piperid-4-yl)carbamate (3i) Compound 3h (33 mg, 0.07 mmol), 3-fluoro-4-cyanophenylboronic acid (16 mg, 0.01 mmol), K2CO3 (56 mg, 0.40 mmol) were dissolved in 1,4-dioxane (1 mL) and water (0.1 mL), nitrogen replacement was performed, Pd(dppf)Cl2 (22 mg, 0.03 mmol) was added, nitrogen replacement was further performed, the reaction system was heated to 100 ° C., and the reaction was allowed to proceed overnight with stirring. The reaction system was cooled to room temperature, the reaction liquid was poured into water, extracted three times with ethyl acetate, the organic phase was combined and washed with saturated saline, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the crude product was purified by thin-layer silica gel plate to obtain the target compound (34 mg, yield 88%). Ninth step: Preparation of 4-(4-(4-aminopiperid-1-yl)-7-(3-fluoro-4-methoxyphenyl)-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyrid-6-yl)-2-fluorobenzonitrile (3) Compound 3i (34 mg, 0.06 mmol) was dissolved in 1,4-dioxane (2 mL), then hydrochloric acid-1,4-dioxane solution (2 mL, 4 M in 1,4-dioxane) was added, and the reaction system was stirred at room temperature for 2 hours. The reaction system was concentrated under reduced pressure, diluted with water, and the pH value of the system was adjusted to about 8 with saturated sodium bicarbonate solution, and extracted three times with ethyl acetate. The organic phases were combined and washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by thin-layer silica gel plate to obtain the target compound (12 mg, 43% yield). LC-MS (ESI) m / z (M+H) + :476.2 1 H NMR (400 MHz, DMSO-d6) δ 8.54 (s, 1H), 7.84-7.78 (m, 1H), 7.45 (dd, J = 10.8, 1.2 Hz, 1H), 7.24 (dd, J = 8.0, 1.6 Hz, 1H), 7.18 (dd, J = 12.0, 2.0 Hz, 1H), 7.12 (t, J = 8.8 Hz, 1H), 6.95-6.90 (m, 1H), 4.49-4.37 (m, 2H), 4.15 (s, 2H), 3.83 (s, 3H), 3.06-2.95 (m, 2H), 2.87-2.76 (m, 1H), 2.03-1.93 (m, 1H), 1.86-1.74 (m, 2H), 1.39-1.33 (m, 1H).

[0079] Example 4 Preparation of 6-(4-aminopiperid-1-yl)-2-(4-cyano-3-fluorophenyl)-3-(1-methyl-1H-indazol-5-yl)isonicotinonitrile (4) [ka] First step: Preparation of tert-butyl (1-(6-chloro-4-cyano-5-(1-methyl-1H-indazol-5-yl)pyrid-2-yl)piperid-4-yl)carbamate (4a) Compound 1c (130 mg, 0.31 mmol), 1-methylindazole-5-boronic acid (56 mg, 0.32 mmol), K2CO3 (64 mg, 0.46 mmol) were dissolved in 1,4-dioxane (3 mL) and water (0.6 mL), nitrogen replacement was performed, Pd(dppf)Cl2 (22 mg, 0.03 mmol) was added, nitrogen replacement was further performed, the reaction system was heated to 100 ° C, and the reaction was allowed to proceed overnight with stirring. The reaction system was cooled to room temperature, the reaction liquid was poured into water, extracted three times with ethyl acetate, the organic phase was combined and washed with saturated saline, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the crude product was purified by thin-layer silica gel plate to obtain the target compound (120 mg, yield 82%). Second step: Preparation of tert-butyl (1-(4-cyano-6-(4-cyano-3-fluorophenyl)-5-(1-methyl-1H-indazol-5-yl)pyrid-2-yl)piperid-4-yl)carbamate (4b) Compound 4a (50 mg, 0.11 mmol), 3-fluoro-4-cyanophenylboronic acid (28 mg, 0.17 mmol), K2CO3 (46 mg, 0.33 mmol) dissolved in 1,4-dioxane (1 mL) and water (0.2 mL) were added to a reaction flask, nitrogen replacement was performed, Pd(dppf)Cl2 (8 mg, 0.01 mmol) was added, nitrogen replacement was further performed, the reaction system was heated to 100 ° C, and the reaction was allowed to proceed overnight with stirring. The reaction system was cooled to room temperature, the reaction liquid was poured into water, extracted three times with ethyl acetate, the organic phase was combined and washed with saturated saline, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to obtain the target compound (20 mg, yield 34%). Third step: Preparation of 6-(4-aminopiperid-1-yl)-2-(4-cyano-3-fluorophenyl)-3-(1-methyl-1H-indazol-5-yl)isonicotinonitrile (4) Compound 4b (20 mg, 0.04 mmol) was dissolved in ethyl acetate (0.5 mL), and then hydrochloric acid-ethyl acetate solution (0.5 mL, 3 M) was added, and the reaction system was stirred at room temperature for 1 hour. The reaction system was concentrated under reduced pressure, diluted with water, and the pH value of the system was adjusted to about 8 with saturated sodium bicarbonate solution, and extracted three times with ethyl acetate. The organic phases were combined and washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by thin-layer silica gel plate to obtain the target compound (15 mg, yield 92%). LC-MS (ESI) m / z (M+H) + :452.2 1 H NMR (400 MHz, DMSO-d6) δ 8.06 (d, J = 0.8 Hz, 1H), 7.75-7.70 (m, 1H), 7.69-7.67 (m, 1H), 7.63-7.59 (m, 1H), 7.57 (s, 1H), 7.38 (dd, J = 10.8, 1.2 Hz, 1H), 7.18-7.12 (m, 2H), 4.38-4.28 (m, 2H), 4.05 (s, 3H), 3.10-3.00 (m, 2H), 2.91-2.81 (m, 1H), 1.85-1.74 (m, 2H), 1.26-1.16 (m, 2H).

[0080] Example 5 Preparation of 6-(4-amino-3-hydroxypiperid-1-yl)-2-(4-cyano-3-fluorophenyl)-3-(3-fluoro-4-methoxyphenyl)isonicotinonitrile (5) [ka] First step: Preparation of benzyl 4-amino-3-hydroxypiperidine-1-carboxylate (5b) Compound 5a (1.0 g, 4.29 mmol) was dissolved in ethanol (5 mL), then aqueous ammonia (5 mL) was added, the reaction system was sealed, and then heated to 70° C. and stirred overnight. The reaction system was cooled to room temperature, extracted with ethyl acetate three times, and the combined organic phase was washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the crude product was used directly in the next step reaction without purification. Second step: Preparation of benzyl 4-((tert-butoxycarbonyl)amino)-3-hydroxypiperidine-1-carboxylate (5c) Compound 5b (700 mg, 2.80 mmol) was dissolved in dichloromethane (10 mL), and triethylamine (424 mg, 4.19 mmol) and di-tert-butyl dicarbonate (610 mg, 2.80 mmol) were added to the system in an ice bath in that order, and the reaction system was left at room temperature and stirred overnight to react. Water was added to the system to quench the reaction, and the system was extracted three times with dichloromethane. The organic phases were combined and washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (500 mg, two-stage total yield 33%). Third step: Preparation of tert-butyl (3-hydroxypiperid-4-yl)carbamate (5d) Compound 5c (500 mg, 1.43 mmol) was dissolved in isopropyl alcohol (5 mL), and then Pd / C (50 mg, 10%) was added to replace the air in the system with hydrogen. The system was then stirred overnight at room temperature in a hydrogen atmosphere and reacted for 4 hours. The reaction system was filtered and concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to obtain the target compound (200 mg, yield 65%). Fourth step: Preparation of 2-chloro-6-((4-methoxybenzyl)amino)isonicotinonitrile (5e) Compound 1a (7.0 g, 40.46 mmol) was dissolved in DMSO (70 mL), followed by the addition of DIEA (5.3 g, 41.09 mmol) and p-methoxybenzylamine (5.7 g, 41.55 mmol) in that order, and the reaction system was placed at 100° C. and stirred overnight. The reaction system was cooled to room temperature, poured into water, extracted three times with ethyl acetate, and the combined organic phase was washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the crude product was used in the next step without purification. Fifth step: Preparation of 2-amino-6-chloroisonicotinonitrile (5f) Compound 5e (9.0 g, 32.88 mmol) was dissolved in dichloromethane (50 mL), and then trifluoroacetic acid (50 mL) was added. The reaction system was placed at room temperature and stirred for 6 hours. The reaction system was concentrated under reduced pressure, diluted with water, and the pH value of the system was adjusted to about 8 with saturated sodium bicarbonate solution, and extracted three times with ethyl acetate. The organic phases were combined and washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained crude product was purified by thin-layer silica gel plate to obtain the target compound (5.0 g, two-stage total yield 81%). Sixth step: Preparation of 6-amino-3-bromo-2-chloroisonicotinonitrile (5 g) Compound 5f (5.0 g, 32.56 mmol) was dissolved in acetonitrile (50 mL), and bromine (5.3 g, 33.13 mmol) was slowly added dropwise to the system under ice bath, and the reaction system was placed at room temperature and stirred for 6 hours to react. The reaction system was concentrated under reduced pressure, diluted with water, and the pH value of the system was adjusted to about 8 with saturated sodium bicarbonate solution, and extracted three times with ethyl acetate. The organic phase was combined and washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by thin-layer silica gel plate to obtain the target compound (4.0 g, yield 53%). Seventh step: Preparation of 6-amino-2-chloro-3-(3-fluoro-4-methoxyphenyl)isonicotinonitrile (5h) Compound 5g (2.0g, 8.60mmol) was dissolved in 1,4-dioxane (20mL) and water (4mL), then 3-fluoro-4-methoxyphenylboronic acid (1.5g, 8.83mmol) and K2CO3 (3.6g, 26.05mmol) were added in sequence, nitrogen substitution was performed, Pd(dppf)Cl2 (628mg, 0.86mmol) was added, and nitrogen substitution was further performed, and the reaction system was placed at 80°C and stirred for 6 hours to react. The reaction system was cooled to room temperature, the reaction liquid was concentrated under reduced pressure, the system was diluted with water, extracted three times with ethyl acetate, the organic phase was combined and washed with saturated saline, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to obtain the target compound (1.5g, yield 63%). Eighth step: Preparation of 6-amino-2-(4-cyano-3-fluorophenyl)-3-(3-fluoro-4-methoxyphenyl)isonicotinonitrile (5i) Compound 5h (1.5 g, 5.40 mmol) was dissolved in 1,4-dioxane (15 mL) and water (3 mL), and then 3-fluoro-4-cyanophenylboronic acid (2.7 g, 16.37 mmol) and K2CO3 (2.3 g, 16.64 mmol) were added in sequence, nitrogen substitution was performed, Pd(dppf)Cl2 (395 mg, 0.54 mmol) was added, and nitrogen substitution was further performed, and the reaction system was placed at 80 ° C. and stirred for 9 hours to react. The reaction system was cooled to room temperature, the reaction liquid was concentrated under reduced pressure, the system was diluted with water, extracted three times with ethyl acetate, the organic phase was combined and washed with saturated saline, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to obtain the target compound (1.5 g, yield 77%). Ninth step: Preparation of 2-(4-cyano-3-fluorophenyl)-3-(3-fluoro-4-methoxyphenyl)-6-iodoisonicotinonitrile (5j) Compound 5i (1.5 g, 4.14 mmol) was dissolved in acetonitrile (15 mL), followed by the addition of potassium iodide (4.1 g, 24.70 mmol) and isoamyl nitrite (2.9 g, 24.75 mmol) in that order, and the reaction system was placed at 75° C. and stirred for 36 hours. The reaction system was cooled to room temperature, the reaction solution was concentrated under reduced pressure, the system was diluted with water, and extracted three times with ethyl acetate. The organic phases were combined, washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (700 mg, yield 36%). Tenth step: Preparation of tert-butyl (1-(4-cyano-6-(4-cyano-3-fluorophenyl)-5-(3-fluoro-4-methoxyphenyl)pyrid-2-yl)-3-hydroxypiperid-4-yl)carbamate (5k) Compound 5j (50 mg, 0.11 mmol) was dissolved in 1,4-dioxane (3 mL), and then compound 5d (48 mg, 0.22 mmol) and Cs2CO3 (108 mg, 0.33 mmol) were added in order, nitrogen substitution was performed, RuPhos-Pd-G3 (9 mg, 0.01 mmol) was added, nitrogen substitution was further performed, the reaction system was heated to 80 ° C, and the reaction was allowed to proceed with stirring for 3 hours. The reaction system was cooled to room temperature, the reaction liquid was concentrated under reduced pressure, the system was diluted with water, extracted three times with ethyl acetate, the organic phase was combined and washed with saturated saline, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the crude product was purified by thin-layer silica gel plate to obtain the target compound (20 mg, yield 34%). Eleventh step: Preparation of 6-(4-amino-3-hydroxypiperid-1-yl)-2-(4-cyano-3-fluorophenyl)-3-(3-fluoro-4-methoxyphenyl)isonicotinonitrile (5) Compound 5k (20 mg, 0.04 mmol) was dissolved in 1,4-dioxane solution (2 mL), then hydrochloric acid-1,4-dioxane solution (2 mL, 4 M in 1,4-dioxane) was added, and the reaction system was placed at room temperature and stirred for 1 hour. The reaction system was concentrated under reduced pressure, diluted with water, and the pH value of the system was adjusted to about 8 with saturated sodium bicarbonate solution, and extracted three times with ethyl acetate. The organic phase was combined and washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by thin-layer silica gel plate to obtain the target compound (8 mg, 49% yield). LC-MS (ESI) m / z (M+H) + :462.2

[0081] Example 6 Preparation of 6-(4-(aminomethyl)-4-hydroxypiperid-1-yl)-2-(4-cyano-3-fluorophenyl)-3-(3-fluoro-4-methoxyphenyl)isonicotinonitrile (6) [ka] First step: Preparation of 4-(aminomethyl)-1-benzylpiperidin-4-ol (6b) Compound 6-1 (500 mg, 2.46 mmol) was dissolved in methanol (2 mL), then aqueous ammonia (5 mL) was added, the system was sealed, and the reaction was stirred at room temperature for 4 hours. The reaction was cooled to room temperature, extracted with ethyl acetate three times, the combined organic phase was washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the crude product was used directly in the next step reaction without purification. Second step: Preparation of tert-butyl ((1-benzyl-4-hydroxypiperid-4-yl)methyl)carbamate (6c) Compound 6b (500 mg, 2.27 mmol) was dissolved in dichloromethane (10 mL), and di-tert-butyl dicarbonate (495 mg, 2.27 mmol) was added to the system under ice bath, and the reaction system was placed at room temperature and stirred overnight to react. Water was added to the system to quench the reaction, and the system was extracted three times with dichloromethane. The organic phases were combined and washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (600 mg, 76% overall yield for two stages). Third step: Preparation of tert-butyl ((4-hydroxypiperid-4-yl)methyl)carbamate (6d) Compound 6c (300 mg, 0.94 mmol) was dissolved in isopropyl alcohol (5 mL), and then palladium hydroxide carbon (30 mg, 10%) was added at room temperature to replace the air in the system with hydrogen, and the system was then stirred overnight at room temperature in a hydrogen atmosphere. The reaction system was filtered, and the filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to obtain the target compound (100 mg, yield 46%). Fourth step: Preparation of tert-butyl ((1-(4-cyano-6-(4-cyano-3-fluorophenyl)-5-(3-fluoro-4-methoxyphenyl)pyrid-2-yl)-4-hydroxypiperid-4-yl)methyl)carbamate (6e) Compound 5j (50 mg, 0.11 mmol) was dissolved in 1,4-dioxane (3 mL), and then compound 6d (51 mg, 0.22 mmol) and Cs2CO3 (108 mg, 0.33 mmol) were added in order, nitrogen substitution was performed, RuPhos-Pd-G3 (9 mg, 0.01 mmol) was added, and nitrogen substitution was further performed, and the reaction system was placed at 80 ° C. and stirred for 3 hours to react. The reaction system was cooled to room temperature, the reaction liquid was concentrated under reduced pressure, the system was diluted with water, extracted three times with ethyl acetate, the organic phase was combined and washed with saturated saline, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the crude product was purified by thin-layer silica gel plate to obtain the target compound (22 mg, yield 36%). Fifth step: Preparation of 6-(4-(aminomethyl)-4-hydroxypiperid-1-yl)-2-(4-cyano-3-fluorophenyl)-3-(3-fluoro-4-methoxyphenyl)isonicotinonitrile (6) Compound 6e (22 mg, 0.04 mmol) was dissolved in 1,4-dioxane solution (2 mL), then hydrochloric acid-1,4-dioxane solution (2 mL, 4 M in 1,4-dioxane) was added, the reaction system was placed at room temperature, and stirred for 1 hour. The reaction system was concentrated under reduced pressure, diluted with water, and the pH value of the system was adjusted to about 8 with saturated sodium bicarbonate solution, and extracted three times with ethyl acetate. The organic phase was combined and washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by thin-layer silica gel plate to obtain the target compound (10 mg, yield 55%). LC-MS (ESI) m / z (M+H) + :476.2 1 H NMR (400 MHz, DMSO-d6) δ 7.86-7.77 (m, 1H), 7.60-7.53 (m, 1H), 7.43-7.36 (m, 1H), 7.23-7.10 (m, 3H), 7.00-6.92 (m, 1H), 4.60 (brs, 1H), 4.21-4.07 (m, 2H), 3.85 (s, 3H), 3.52-3.36 (m, 2H), 2.54 (s, 2H), 1.58-1.39 (m, 4H).

[0082] Example 7 Preparation of 6-(3-aminoazetidin-1-yl)-2-(4-cyano-3-fluorophenyl)-3-(3-fluoro-4-methoxyphenyl)isonicotinonitrile (7) [ka] First step: Preparation of tert-butyl (1-(4-cyano-6-(4-cyano-3-fluorophenyl)-5-(3-fluoro-4-methoxyphenyl)pyrid-2-yl)azetidin-3-yl)carbamate (7a) Compound 5j (50 mg, 0.11 mmol) was dissolved in 1,4-dioxane (3 mL), and then tert-butyl azetidin-3-yl carbamate (38 mg, 0.22 mmol) and Cs2CO3 (108 mg, 0.33 mmol) were added in order, nitrogen replacement was performed, RuPhos-Pd-G3 (9 mg, 0.01 mmol) was added, nitrogen replacement was further performed, and the reaction system was placed at 80 ° C. and stirred for 3 hours to react. The reaction system was cooled to room temperature, the reaction liquid was concentrated under reduced pressure, the system was diluted with water, extracted three times with ethyl acetate, the organic phase was combined and washed with saturated saline, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the crude product was purified by thin-layer silica gel plate to obtain the target compound (22 mg, yield 40%). Second step: Preparation of 6-(3-aminoazetidin-1-yl)-2-(4-cyano-3-fluorophenyl)-3-(3-fluoro-4-methoxyphenyl)isonicotinonitrile (7) Compound 7a (22 mg, 0.04 mmol) was dissolved in dichloromethane (2 mL), then trifluoroacetic acid (1 mL) was added, and the reaction system was placed at room temperature and stirred for 1 hour. The reaction system was concentrated under reduced pressure, diluted with water, and the pH value of the system was adjusted to about 8 with saturated sodium bicarbonate solution, and extracted three times with ethyl acetate. The organic phase was combined and washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by thin-layer silica gel plate to obtain the target compound (15 mg, yield 85%). LC-MS (ESI) m / z (M+H) + :418.2 1 H NMR (400 MHz, DMSO-d6) δ 7.81 (dd, J = 8.0, 6.8 Hz, 1H), 7.37 (dd, J = 10.4, 1.2 Hz, 1H), 7.19-7.10 (m, 3H), 7.09 (s, 1H), 6.97-6.91 (m, 1H), 4.27-4.19 (m, 2H), 3.89-3.81 (m, 4H), 3.70-3.63 (m, 2H).

[0083] Example 8 Preparation of 4-(4-(4-aminopiperid-1-yl)-7-(1-methyl-1H-indazol-5-yl)-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyrid-6-yl)-2-fluorobenzonitrile (8) [ka] First step: Preparation of tert-butyl (1-(6-(4-cyano-3-fluorophenyl)-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyrid-4-yl)piperid-4-ylcarbamate (8a) Compound 3f (287 mg, 0.78 mmol), 3-fluoro-4-cyanophenylboronic acid (193 mg, 1.17 mmol), K2CO3 (647 mg, 4.68 mmol) were dissolved in 1,4-dioxane (4 mL) and water (0.4 mL), nitrogen replacement was performed, Pd(dppf)Cl2 (29 mg, 0.04 mmol) was added, nitrogen replacement was further performed, and the reaction system was placed at 100 ° C. and stirred for 2 hours to react. The reaction system was cooled to room temperature, the reaction liquid was poured into water, extracted three times with ethyl acetate, the organic phase was combined and washed with saturated saline, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to obtain the target compound (315 mg, yield 89%). Second step: Preparation of tert-butyl (1-(7-bromo-6-(4-cyano-3-fluorophenyl)-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyrid-4-yl)piperid-4-yl)carbamate (8b) Compound 8a (310 mg, 0.69 mmol) was dissolved in acetonitrile (12 mL), and NBS (246 mg, 1.38 mmol) was slowly added to the system under ice bath, and the reaction system was stirred for 1 hour while maintaining the reaction system under ice bath. The reaction solution was poured into water, extracted three times with ethyl acetate, and the organic phases were combined and washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (364 mg, 100% yield). Third step: Preparation of tert-butyl (1-(6-(4-cyano-3-fluorophenyl)-7-(1-methyl-1H-indazol-5-yl)-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyrid-4-yl)piperid-4-yl)carbamate (8c) Compound 8b (70 mg, 0.13 mmol), 1-methylindazole-5-boronic acid (35 mg, 0.20 mmol), K2CO3 (108 mg, 0.78 mmol) were dissolved in 1,4-dioxane (4 mL) and water (0.4 mL), nitrogen replacement was performed, Pd(dppf)Cl2 (15 mg, 0.02 mmol) was added, nitrogen replacement was further performed, and the reaction system was placed at 100 ° C. and stirred for 1 hour. The reaction system was cooled to room temperature, the reaction liquid was poured into water, extracted three times with ethyl acetate, the organic phase was combined and washed with saturated saline, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the crude product was purified by thin-layer silica gel plate to obtain the target compound (57 mg, yield 74%). Fourth step: Preparation of 4-(4-(4-aminopiperid-1-yl)-7-(1-methyl-1H-indazol-5-yl)-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyrid-6-yl)-2-fluorobenzonitrile (8) Compound 8c (57 mg, 0.10 mmol) was dissolved in dichloromethane (3 mL), and then trifluoroacetic acid (3 mL) was added at 0° C., and the reaction was stirred for 2 h while maintaining the reaction system at 0° C. The reaction system was concentrated under reduced pressure, diluted with water, and the pH value of the system was adjusted to about 8 with saturated sodium bicarbonate solution, and extracted three times with ethyl acetate. The organic phases were combined and washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by thin-layer silica gel plate to obtain the target compound (15 mg, yield 32%). LC-MS (ESI) m / z (M+H) + :482.2 1H NMR (400 MHz, DMSO- d6) δ 8.60 (s, 1H), 8.02 (s, 1H), 7.77-7.70 (m, 1H), 7.68 (s, 1H), 7.62 (d, J = 8.4 Hz, 1H), 7.49 (d, J = 10.4 Hz, 1H), 7.20 (d, J = 8.0 Hz, 1H), 7.16 (d, J = 8.4 Hz, 1H), 4.61-4.51 (m, 2H), 4.15 (s, 2H), 4.06 (s, 3H), 3.30-3.17 (m, 1H), 3.07-2.95 (m, 2H), 2.04-1.92 (m, 2H), 1.72-1.58 (m, 2H).

[0084] Example 9 Preparation of 4-(4-(4-aminopiperid-1-yl)-7-(6-fluoro-1-(2-hydroxy-2-methylpropyl)-1H-indazol-5-yl)-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyrid-6-yl)-2-fluorobenzonitrile (9) [ka] First step: Preparation of 1-(5-bromo-6-fluoro-1H-indazol-1-yl)-2-methylpropan-2-ol (9b) Compound 9a (430 mg, 2.00 mmol) was dissolved in N,N-dimethylformamide (10 mL), and then Cs2CO3 (2.0 g, 6.14 mmol) and 1,1-dimethylethylene oxide (216 mg, 3.00 mmol) were added in that order, and the reaction system was heated to 100 ° C. and stirred overnight. The reaction system was cooled to room temperature, and the reaction liquid was poured into water and extracted three times with ethyl acetate. The organic phases were combined and washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (488 mg, 85% yield). Second step: Preparation of 1-(6-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxybenzaldehyde-2-yl)-1H-indazol-1-yl)-2-methylpropan-2-ol (9c) Compound 9b (286 mg, 1.00 mmol), bis(pinacolato)diboron (381 mg, 1.50 mmol), potassium acetate (196 mg, 0.10 mmol) were dissolved in N,N-dimethylformamide (5 mL), nitrogen substitution was performed, triphenylphosphine (52 mg, 0.20 mmol), Pd(AcO)2 (23 mg, 0.10 mmol) were added in sequence, nitrogen substitution was further performed, the reaction system was heated to 100 ° C, and the reaction was allowed to proceed overnight with stirring. The reaction system was cooled to room temperature, the reaction liquid was poured into water, extracted three times with ethyl acetate, the organic phase was combined and washed with saturated saline, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to obtain the target compound (296 mg, yield 89%). Third step: Preparation of tert-butyl (1-(6-(4-cyano-3-fluorophenyl)-7-(6-fluoro-1-(2-hydroxy-2-methylpropyl)-1H-indazol-5-yl)-3-oxo)-2,3-dihydro-1H-pyrrolo[3,4-c]pyrid-4-yl)piperid-4-yl)carbamate (9d) Compound 8b (110 mg, 0.21 mmol), compound 9c (107 mg, 0.32 mmol), K2CO3 (175 mg, 1.27 mmol) were dissolved in 1,4-dioxane (2 mL) and water (0.2 mL), nitrogen replacement was performed, Pd(dppf)Cl2 (15 mg, 0.02 mmol) was added, nitrogen replacement was further performed, the reaction system was heated to 100 ° C, and the reaction was allowed to proceed with stirring for 5 hours. The reaction system was cooled to room temperature, the reaction liquid was poured into water, extracted three times with ethyl acetate, the organic phase was combined and washed with saturated saline, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the crude product was purified by thin-layer silica gel plate to obtain the target compound (12 mg, yield 9%). Fourth step: Preparation of 4-(4-(4-aminopiperid-1-yl)-7-(6-fluoro-1-(2-hydroxy-2-methylpropyl)-1H-indazol-5-yl)-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyrid-6-yl)-2-fluorobenzonitrile (9) Compound 9d (12 mg, 0.02 mmol) was dissolved in ethyl acetate (1 mL), then hydrochloric acid-ethyl acetate solution (1 mL, 3M in EA) was added, and the reaction system was stirred at room temperature for 1 hour. The reaction system was concentrated under reduced pressure, diluted with water, and the pH value of the system was adjusted to about 8 with saturated sodium bicarbonate solution, and extracted three times with ethyl acetate. The organic phases were combined and washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by thin-layer silica gel plate to obtain the target compound (6 mg, yield 59%). LC-MS (ESI) m / z (M+H) + :558.2 1 H NMR (400 MHz, DMSO- d6) δ 8.55 (s, 1H), 8.08 (s, 1H), 7.86 (d, J = 7.2 Hz, 1H), 7.80-7.72 (m, 1H), 7.54 (d, J = 10.8 Hz, 1H), 7.44 (d, J = 10.4 Hz, 1H), 7.27 (d, J = 8.4 Hz, 1H), 4.65 (s, 1H), 4.55-4.42 (m, 2H), 4.40-4.22 (m, 3H), 3.96-3.87 (m, 1H), 3.11-2.98 (m, 2H), 2.87-2.75 (m, 1H), 1.89-1.75 (m, 2H), 1.44-1.32 (m, 2H), 1.16 (s, 3H), 1.10 (s, 3H).

[0085] Example 10 Preparation of 6-(4-aminopiperid-1-yl)-2-(4-cyano-3-fluorophenyl)-3-(1-methyl-1H-indazol-5-yl)isonicotinamide (10) [ka] First step: Preparation of tert-butyl (1-(4-carbamoyl-6-chloro-5-(1-methyl-1H-indazol-5-yl)pyrid-2-yl)piperid-4-yl)carbamate (10a) Compound 4a (190 mg, 0.41 mmol) was dissolved in a methanol solution (4 mL), and then dimethyl sulfoxide (2 mL), NaOH (49 mg, 1.23 mmol), and H2O2 (232 mg, 2.05 mmol, 30% aqueous solution) were added in order, and the reaction system was stirred at 50 ° C for 2 hours to react. The reaction system was cooled to room temperature, the reaction solution was poured into water, extracted three times with ethyl acetate, and the organic phases were combined and washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (126 mg, yield 64%). Second step: Preparation of tert-butyl (1-(4-carbamoyl-6-(4-cyano-3-fluorophenyl)-5-(1-methyl-1H-indazol-5-yl)pyrid-2-yl)piperid-4-yl)carbamate (10b) Compound 10a (100 mg, 0.21 mmol), 3-fluoro-4-cyanophenylboronic acid (53 mg, 0.32 mmol), K2CO3 (87 mg, 0.63 mmol) were dissolved in 1,4-dioxane (4 mL) and water (0.4 mL), nitrogen replacement was performed, Pd(dppf)Cl2 (15 mg, 0.02 mmol) was added, nitrogen replacement was further performed, the reaction system was heated to 100 ° C, and the reaction was allowed to proceed overnight with stirring. The reaction system was cooled to room temperature, the reaction liquid was poured into water, extracted three times with ethyl acetate, the organic phase was combined and washed with saturated saline, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to obtain the target compound (95 mg, yield 81%). Third step: Preparation of 6-(4-aminopiperid-1-yl)-2-(4-cyano-3-fluorophenyl)-3-(1-methyl-1H-indazol-5-yl)isonicotinamide (10) Compound 10b (95 mg, 0.17 mmol) was dissolved in ethyl acetate (2 mL), then hydrochloric acid-ethyl acetate solution (2 mL, 3M in EA) was added, the reaction system was placed at room temperature, and stirred for 1 hour. The reaction system was concentrated under reduced pressure, diluted with water, and the pH value of the system was adjusted to about 8 with saturated sodium bicarbonate solution, and extracted three times with ethyl acetate. The organic phase was combined and washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by thin-layer silica gel plate to obtain the target compound (31 mg, 40% yield). LC-MS (ESI) m / z (M+H) + :470.2 1 H NMR (400 MHz, DMSO-d6) δ 7.98 (d, J = 0.4 Hz, 1H), 7.73-7.64 (m, 2H), 7.51-7.46 (m, 2H), 7.34-7.31 (m, 1H), 7.31 (dd, J = 9.2, 1.2 Hz, 1H), 7.10 (dd, J = 8.0, 1.2 Hz, 1H), 7.10 (dd, J = 8.4, 1.6 Hz, 1H), 6.91 (s, 1H), 4.35-4.25 (m, 2H), 4.02 (s, 3H), 3.03-2.93 (m, 2H), 2.89-2.79 (m, 1H), 1.85-1.74 (m, 2H), 1.29-1.16 (m, 2H).

[0086] Example 11 Preparation of 2-(4-aminopiperid-1-yl)-6-(4-cyano-3-fluorophenyl)-5-(1-methyl-1H-indazol-5-yl)nicotinamide (11) [ka] First step: Preparation of 2,6-dichloronicotinamide (11b) Compound 11a (3.0 g, 15.63 mmol) was dissolved in chloroform (30 mL), and thionyl chloride (18.6 g, 156.30 mmol) was slowly added to the system under ice bath, and the system was heated to 70 ° C. and stirred for 3 hours to react. The reaction system was concentrated under reduced pressure, dissolved in tetrahydrofuran (10 mL), and then dropped into a solution of ammonia water (30 mL) in tetrahydrofuran (10 mL) cooled in an ice bath, and stirred for 30 minutes to react. Water was added to the reaction system, and the mixture was extracted three times with ethyl acetate, and the organic phase was washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (2.8 g, yield 94%). Second step: Preparation of tert-butyl (1-(3-carbamoyl-6-chloropyrid-2-yl)piperid-4-yl)carbamate (11c) Compound 11b (2.8 g, 14.66 mmol), 4-tert-butoxycarbonylaminopiperidine (4.9 g, 24.47 mmol), and triethylamine (3.0 g, 29.65 mmol) were dissolved in acetonitrile (30 mL), and the system was heated to 70° C. and stirred for 3 hours to react. The reaction system was cooled to room temperature, and the reaction solution was poured into water and extracted three times with ethyl acetate. The organic phases were combined and washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (4.4 g, yield 88%). Third step: Preparation of tert-butyl (1-(3-carbamoyl-6-(4-cyano-3-fluorophenyl)pyrid-2-yl)piperid-4-yl)carbamate (11d) Compound 11c (400 mg, 1.13 mmol), 3-fluoro-4-cyanophenylboronic acid (280 mg, 1.70 mmol), K2CO3 (937 mg, 6.78 mmol) were dissolved in 1,4-dioxane (5 mL) and water (0.5 mL), nitrogen substitution was performed, Pd(dppf)Cl2 (41 mg, 0.06 mmol) was added, nitrogen substitution was further performed, the reaction system was heated to 100 ° C., and the reaction was allowed to proceed with stirring for 4 hours. The reaction system was cooled to room temperature, the reaction liquid was poured into water, extracted three times with ethyl acetate, the organic phase was combined and washed with saturated saline, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to obtain the target compound (448 mg, yield 90%). Fourth step: Preparation of tert-butyl (1-(5-bromo-3-carbamoyl-6-(4-cyano-3-fluorophenyl)pyrid-2-yl)piperid-4-yl)carbamate (11e) Compound 11d (448 mg, 1.02 mmol) was dissolved in N,N-dimethylformamide (5 mL), and NBS (200 mg, 1.12 mmol) was slowly added to the system under ice bath, and the reaction was stirred for 2 hours while maintaining the reaction system at 0° C. The reaction solution was poured into water, extracted three times with ethyl acetate, and the combined organic phase was washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (528 mg, 100% yield). Fifth step: Preparation of tert-butyl (1-(3-carbamoyl-6-(4-cyano-3-fluorophenyl)-5-(1-methyl-1H-indazol-5-yl)pyrid-2-yl)piperid-4-yl)carbamate (11f) Compound 11e (518 mg, 1.00 mmol), 1-methylindazole-5-boronic acid (263 mg, 1.49 mmol), K2CO3 (829 mg, 6.00 mmol) were dissolved in 1,4-dioxane (6 mL) and water (0.6 mL), nitrogen replacement was performed, Pd(dppf)Cl2 (37 mg, 0.05 mmol) was added, nitrogen replacement was further performed, the reaction system was heated to 100 ° C, and the reaction was allowed to proceed with stirring for 3 hours. The reaction system was cooled to room temperature, the reaction liquid was poured into water, extracted three times with ethyl acetate, the organic phase was combined and washed with saturated saline, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel to obtain the target compound (423 mg, yield 74%). Sixth step: Preparation of 2-(4-aminopiperid-1-yl)-6-(4-cyano-3-fluorophenyl)-5-(1-methyl-1H-indazol-5-yl)nicotinamide (11) Compound 11f (30 mg, 0.05 mmol) was dissolved in ethyl acetate (1 mL), then hydrochloric acid-ethyl acetate solution (1 mL, 3M in EA) was added, and the reaction system was stirred at room temperature for 1 hour to react. The reaction system was concentrated under reduced pressure, diluted with water, and the pH value of the system was adjusted to about 8 with saturated sodium bicarbonate solution, and extracted three times with ethyl acetate. The organic phase was combined and washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by thin-layer silica gel plate to obtain the target compound (6 mg, yield 24%). LC-MS (ESI) m / z (M+H) + :470.2 1H NMR (400 MHz, DMSO-d6) δ 8.02 (s, 1H), 8.00-7.95 (m, 1H), 7.79 (s, 1H), 7.79-7.73 (m, 1H), 7.68-7.62 (m, 2H), 7.58-7.54 (m, 1H), 7.50-7.45 (m, 1H), 7.22 (dd, J = 8.4, 1.6 Hz, 1H), 7.22 (dd, J = 8.8, 1.6 Hz, 1H), 4.04 (s, 3H), 3.91-3.80 (m, 2H), 3.02-2.90 (m, 2H), 2.84-2.73 (m, 1H), 1.86-1.74 (m, 2H), 1.43-1.32 (m, 2H).

[0087] Example 12 Preparation of 2-(4-aminopiperid-1-yl)-6-(4-cyano-3-fluorophenyl)-5-(1-methyl-1H-indazol-5-yl)nicotinonitrile (12) [ka] First step: Preparation of tert-butyl (1-(3-cyano-6-(4-cyano-3-fluorophenyl)-5-(1-methyl-1H-indazol-5-yl)pyrid-2-yl)piperid-4-yl)carbamate (12a) Compound 11f (200 mg, 0.35 mmol) was dissolved in tetrahydrofuran (6 mL), nitrogen substitution was performed, and pyridine (194 mg, 2.45 mmol) and a solution of trifluoroacetic anhydride (147 mg, 0.70 mmol) in dichloromethane (1 mL) were added in sequence under ice bath, the reaction system was slowly returned to room temperature, and the reaction was allowed to proceed overnight by stirring. The reaction solution was poured into water, extracted three times with ethyl acetate, the organic phase was combined and washed with saturated saline, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the crude product was purified by thin-layer silica gel plate to obtain the target compound (10 mg, yield 5%). Second step: Preparation of 2-(4-aminopiperid-1-yl)-6-(4-cyano-3-fluorophenyl)-5-(1-methyl-1H-indazol-5-yl)nicotinonitrile (12) Compound 12a (10 mg, 0.02 mmol) was dissolved in ethyl acetate (1 mL), then hydrochloric acid-ethyl acetate solution (1 mL, 3M in EA) was added, and the reaction system was stirred at room temperature for 1 hour. The reaction system was concentrated under reduced pressure, diluted with water, and the pH value of the system was adjusted to about 8 with saturated sodium bicarbonate solution, and extracted three times with ethyl acetate. The organic phases were combined and washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by thin-layer silica gel plate to obtain the target compound (1 mg, 12% yield). LC-MS (ESI) m / z (M+H) + :452.2

[0088] Example 13 Preparation of 6-(4-amino-3-fluoropiperid-1-yl)-2-(4-cyano-3-fluorophenyl)-3-(3-fluoro-4-methoxyphenyl)isonicotinonitrile (13) [ka] First step: Preparation of tert-butyl 4-amino-3-fluoropiperidine-1-carboxylate (13b) Compound 13-1 (1.0 g, 4.60 mmol) was dissolved in methanol (10 mL), and ammonium acetate (2.5 g, 32.43 mmol) and sodium cyanoborohydride (375 mg, 5.97 mmol) were added in that order. The reaction system was left at room temperature and stirred overnight to react. The reaction system was diluted with water and extracted three times with ethyl acetate. The combined organic phase was washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (500 mg, 50% yield). Second step: Preparation of tert-butyl 4-(((benzyloxy)carbonyl)amino)-3-fluoropiperidine-1-carboxylate (13c) Compound 13b (500 mg, 2.29 mmol) was dissolved in ethyl acetate (5 mL), then saturated sodium bicarbonate solution (10 mL) was added, and benzyl chloroformate (391 mg, 2.29 mmol) was added to the system under ice bath, and the reaction system was placed at room temperature and stirred overnight to react. The reaction solution was extracted three times with ethyl acetate, and the combined organic phase was washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (420 mg, yield 52%). Third step: Preparation of (3-fluoropiperid-4-yl)benzylcarbamate hydrochloride (13d) Compound 13c (200 mg, 0.57 mmol) was dissolved in ethyl acetate (10 mL), then hydrochloric acid-ethyl acetate solution (4 mL, 3 M in EA) was added, and the reaction system was stirred at room temperature for 1 h. The reaction system was concentrated under reduced pressure, and the crude product was used in the next step without purification. Fourth step: Preparation of (1-(4-cyano-6-(4-cyano-3-fluorophenyl)-5-(3-fluoro-4-methoxyphenyl)pyrid-2-yl)-3-fluoropiperid-4-yl)benzyl carbamate (13e) Compound 5j (50 mg, 0.11 mmol) was dissolved in 1,4-dioxane (3 mL), and then compound 13d (64 mg, 0.22 mmol) and t-BuONa (53 mg, 0.55 mmol) were added in order, nitrogen substitution was performed, RuPhos-Pd-G3 (9 mg, 0.01 mmol) was added, and nitrogen substitution was further performed, and the reaction system was placed at 80 ° C. and stirred for 3 hours to react. The reaction system was cooled to room temperature, the reaction liquid was concentrated under reduced pressure, the system was diluted with water, and extracted three times with ethyl acetate, and the organic phase was combined and washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by thin-layer silica gel plate to obtain the target compound (21 mg, yield 33%). Fifth step: Preparation of 6-(4-amino-3-fluoropiperid-1-yl)-2-(4-cyano-3-fluorophenyl)-3-(3-fluoro-4-methoxyphenyl)isonicotinonitrile (13) Compound 13e (21 mg, 0.04 mmol) was dissolved in ethyl acetate (2 mL), and then Pd / C (2 mg, 10%) was added at room temperature to replace the air in the system with hydrogen, and then the system was heated to 35° C. under a hydrogen atmosphere and reacted with stirring for 4 hours. The reaction system was filtered and concentrated under reduced pressure, and the crude product was purified by a thin-layer silica gel plate to obtain the target compound (10 mg, yield 61%). LC-MS (ESI) m / z (M+H) + :464.2 1 H NMR (400 MHz, DMSO-d6) δ 7.95-7.78 (m, 1H), 7.64 (s, 1H), 7.41 (dd, J = 10.8, 1.6 Hz, 1H), 7.23-7.11 (m, 3H), 7.00-6.94 (m, 1H), 4.22-4.15 (m, 2H), 4.10-4.00 (m, 1H), 3.85 (s, 3H), 3.45-3.33 (m, 2H), 3.03-2.92 (m, 1H), 1.93-1.82 (m, 1H), 1.41-1.30 (m, 1H).

[0089] Example 14 Preparation of 6-(4-aminocyclohexyl)-2-(4-cyano-3-fluorophenyl)-3-(3-fluoro-4-methoxyphenyl)isonicotinonitrile (14) [ka] First step: Preparation of tert-butyl (4-(4-cyano-6-(4-cyano-3-fluorophenyl)-5-(3-fluoro-4-methoxyphenyl)pyrid-2-yl)cyclohex-3-en-1-yl)carbamate (14a) Compound 5j (80 mg, 0.17 mmol) was dissolved in 1,4-dioxane (3 mL) and water (0.5 mL), and (4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-en-1-yl)carbamate tert-butyl (165 mg, 0.51 mmol) and K2CO3 (70 mg, 0.51 mmol) were added in sequence, nitrogen replacement was performed, Pd(dppf)Cl2 (15 mg, 0.02 mmol) was added, nitrogen replacement was further performed, the system was heated to 80 ° C., and the reaction was performed by stirring for 2 hours. The reaction system was cooled to room temperature, diluted with water, extracted three times with ethyl acetate, and the organic phase was washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the crude product was purified by thin-layer silica gel plate to obtain the target compound (79 mg, yield 86%). Second step: Preparation of tert-butyl (4-(4-cyano-6-(4-cyano-3-fluorophenyl)-5-(3-fluoro-4-methoxyphenyl)pyrid-2-yl)cyclohexyl)carbamate (14b) Compound 14a (40 mg, 0.07 mmol) was dissolved in ethyl acetate (2 mL), and then Pd / C (4 mg, 10%) was added at room temperature to replace the air in the system with hydrogen, and the system was stirred overnight at room temperature in a hydrogen atmosphere to react. The reaction system was filtered, and the filtrate was concentrated under reduced pressure, and the crude product was purified using a thin-layer silica gel plate to obtain the target compound (23 mg, 57% yield). Third step: Preparation of 6-(4-aminocyclohexyl)-2-(4-cyano-3-fluorophenyl)-3-(3-fluoro-4-methoxyphenyl)isonicotinonitrile (14) Compound 14b (23 mg, 0.04 mmol) was dissolved in ethyl acetate (5 mL), then hydrochloric acid-ethyl acetate solution (4 mL, 3M in EA) was added, and the reaction system was stirred at room temperature for 1 hour. The reaction system was concentrated under reduced pressure, diluted with water, and the pH value of the system was adjusted to about 8 with saturated sodium bicarbonate solution, and extracted three times with ethyl acetate. The organic phases were combined and washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by thin-layer silica gel plate to obtain the target compound (11 mg, yield 59%). LC-MS (ESI) m / z (M+H) + :445.2 1 H NMR (400 MHz, DMSO-d6) δ 8.08 (s, 0.48H), 8.01 (s, 0.47H), 7.89-7.82 (m, 1H), 7.48-7.41 (m, 1H), 7.55-7.28 (m, 1H), 7.25-7.16 (m, 2H), 7.11-7.05 (m, 1H), 3.88-3.84 (m, 3H), 3.16-3.10 (m, 0.5H), 2.95-2.86 (m, 0.5H), 2.86-2.68 (m, 1H), 2.15-1.89 (m, 3H), 1.75-1.60 (m, 4H), 1.33-1.21 (m, 1H).

[0090] Example 15 Preparation of 2-(4-cyano-3-fluorophenyl)-6-(1,4-diazacyclohept-1-yl)-3-(3-fluoro-4-methoxyphenyl)isonicotinonitrile (15) [ka] First step: Preparation of tert-butyl 4-(4-cyano-6-(4-cyano-3-fluorophenyl)-5-(3-fluoro-4-methoxyphenyl)pyrid-2-yl)-1,4-diazacycloheptane-1-carboxylate (15a) Compound 5j (50 mg, 0.11 mmol) was dissolved in 1,4-dioxane (3 mL), 1,4-diazacycloheptane-1-carboxylate tert-butyl (44 mg, 0.22 mmol), Cs2CO3 (108 mg, 0.33 mmol) were added in order, nitrogen substitution was performed, RuPhos-Pd-G3 (9 mg, 0.01 mmol) was added, nitrogen substitution was further performed, the system was heated to 80 ° C, and the reaction was performed by stirring for 3 hours. The reaction system was cooled to room temperature, concentrated under reduced pressure to remove solvent, the system was diluted with water, extracted three times with ethyl acetate, the organic phase was combined and washed with saturated saline, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the crude product was purified by thin-layer silica gel plate to obtain the target compound (24 mg, yield 42%). Second step: Preparation of 2-(4-cyano-3-fluorophenyl)-6-(1,4-diazacyclohept-1-yl)-3-(3-fluoro-4-methoxyphenyl)isonicotinonitrile (15) Compound 15a (24 mg, 0.04 mmol) was dissolved in ethyl acetate (5 mL), then hydrochloric acid-ethyl acetate solution (4 mL, 3M in EA) was added, and the reaction system was stirred at room temperature for 1 hour. The reaction system was concentrated under reduced pressure, diluted with water, and the pH value of the system was adjusted to about 8 with saturated sodium bicarbonate solution, and extracted three times with ethyl acetate. The organic phase was combined and washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by thin-layer silica gel plate to obtain the target compound (10 mg, yield 51%). LC-MS (ESI) m / z (M+H) + :446.2 1 H NMR (400 MHz, DMSO- d6) δ 7.85-7.79 (m, 1H), 7.42-7.34 (m, 2H), 7.23-7.11 (m, 3H), 7.00-6.93 (m, 1H), 3.85 (s, 3H), 3.80-3.68 (m, 4H), 2.93-2.86 (m, 2H), 2.76-2.69 (m, 2H), 1.84-1.73 (m, 2H).

[0091] Example 16 Preparation of 6-(4-aminopiperid-1-yl)-2-(4-cyano-3-fluorophenyl)-3-(6-fluoro-1-(2-hydroxy-2-methylpropyl)-1H-indazol-5-yl)isonicotinonitrile (16) [ka] First step: Preparation of tert-butyl (1-(4-cyano-6-(4-cyano-3-fluorophenyl)pyrid-2-yl)piperid-4-yl)carbamate (16a) Compound 1b (1.7 g, 5.05 mmol), 3-fluoro-4-cyanophenylboronic acid (1.2 g, 7.28 mmol), K2CO3 (2.1 g, 15.20 mmol) were dissolved in acetonitrile (20 mL) and water (10 mL), nitrogen substitution was performed, Pd(PPh3)4 (289 mg, 0.25 mmol) was added, nitrogen substitution was further performed, the reaction system was heated to 100 ° C, and the reaction was allowed to proceed overnight with stirring. The reaction system was cooled to room temperature, the reaction liquid was poured into water, extracted three times with ethyl acetate, the organic phase was combined and washed with saturated saline, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to obtain the target compound (1.8 g, yield 85%). Second step: Preparation of tert-butyl (1-(5-bromo-4-cyano-6-(4-cyano-3-fluorophenyl)pyrid-2-yl)piperid-4-yl)carbamate (16b) Compound 16a (421 mg, 1.00 mmol) was dissolved in acetonitrile (15 mL), and NBS (182 mg, 1.02 mmol) was slowly added to the system under ice bath, and the reaction system was placed at room temperature and stirred for 3 hours to react. The reaction system was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to obtain the target compound (450 mg, yield 90%). Third step: Preparation of tert-butyl (1-(4-cyano-6-(4-cyano-3-fluorophenyl)-5-(6-fluoro-1-(2-hydroxy-2-methylpropyl)-1H-indazol-5-yl)pyrid-2-yl)piperid-4-yl)carbamate (16c) Compound 16b (100 mg, 0.20 mmol), compound 9c (100 mg, 0.30 mmol), K2CO3 (83 mg, 0.60 mmol) were dissolved in 1,4-dioxane (2 mL) and water (0.2 mL), nitrogen replacement was performed, Pd(dppf)Cl2 (15 mg, 0.02 mmol) was added, nitrogen replacement was further performed, the reaction system was heated to 100 ° C, and the reaction was allowed to proceed overnight with stirring. The reaction system was cooled to room temperature, the reaction liquid was poured into water, extracted three times with ethyl acetate, the organic phase was combined and washed with saturated saline, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the crude product was purified by thin-layer silica gel plate to obtain the target compound (30 mg, yield 24%). Fourth step: Preparation of 6-(4-aminopiperid-1-yl)-2-(4-cyano-3-fluorophenyl)-3-(6-fluoro-1-(2-hydroxy-2-methylpropyl)-1H-indazol-5-yl)isonicotinonitrile (16) Compound 16c (30 mg, 0.05 mmol) was dissolved in ethyl acetate (1 mL), then hydrochloric acid-ethyl acetate solution (1 mL, 3M in EA) was added, and the reaction system was stirred at room temperature for 1 hour. The reaction system was concentrated under reduced pressure, diluted with water, and the pH value of the system was adjusted to about 8 with saturated sodium bicarbonate solution, and extracted three times with ethyl acetate. The organic phase was combined and washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by thin-layer silica gel plate to obtain the target compound (24 mg, yield 95%). LC-MS (ESI) m / z (M+H) + :528.2 1H NMR (400 MHz, DMSO-d6) δ 8.11 (s, 1H), 7.80-7.72 (m, 2H), 7.61 (s, 1H), 7.57 (d, J = 10.8 Hz, 1H), 7.40-7.34 (m, 1H), 7.18 (dd, J = 8.0, 1.2 Hz, 1H), 4.68 (s, 1H), 4.40-4.24 (m, 4H), 3.12-3.01 (m, 2H), 2.92-2.82 (m, 1H), 1.85-1.75 (m, 2H), 1.27-1.19 (m, 2H), 1.14 (s, 3H), 1.10 (s, 3H).

[0092] Example 17 Preparation of 6-(4-aminopiperid-1-yl)-2-(4-cyano-3-fluorophenyl)-3-(6-fluoro-1-(2-hydroxy-2-methylpropyl)-1H-indazol-5-yl)isonicotinamide (17) [ka] First step: Preparation of tert-butyl (1-(6-chloro-4-cyano-5-(6-fluoro-1-(2-hydroxy-2-methylpropyl)-1H-indazol-5-yl)pyrid-2-yl)piperid-4-yl)carbamate (17a) Compound 1c (229 mg, 0.55 mmol), compound 9c (368 mg, 1.10 mmol), K2CO3 (228 mg, 1.65 mmol) were dissolved in 1,4-dioxane (5 mL) and water (1 mL), nitrogen replacement was performed, Pd(dppf)Cl2 (44 mg, 0.06 mmol) was added, nitrogen replacement was further performed, the reaction system was heated to 100 ° C, and the reaction was allowed to proceed overnight with stirring. The reaction system was cooled to room temperature, the reaction liquid was poured into water, extracted three times with ethyl acetate, the organic phase was combined and washed with saturated saline, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the crude product was purified by thin-layer silica gel plate to obtain the target compound (138 mg, yield 46%). Second step: Preparation of tert-butyl (1-(4-carbamoyl-6-chloro-5-(6-fluoro-1-(2-hydroxy-2-methylpropyl)-1H-indazol-5-yl)pyrid-2-yl)piperid-4-yl)carbamate (17b) Compound 17a (138 mg, 0.25 mmol) was dissolved in a methanol solution (1 mL), then dimethyl sulfoxide (1 mL), NaOH (30 mg, 0.75 mmol), and H2O2 (170 mg, 1.50 mmol, 30% aqueous solution) were added in sequence, and the reaction system was placed at 50 ° C. and stirred for 2 hours. The reaction system was cooled to room temperature, the reaction solution was poured into water, extracted three times with ethyl acetate, the organic phases were combined and washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to obtain the target compound (126 mg, 88% yield). Third step: Preparation of tert-butyl (1-(4-carbamoyl-6-(4-cyano-3-fluorophenyl)-5-(6-fluoro-1-(2-hydroxy-2-methylpropyl)-1H-indazol-5-yl)pyrid-2-yl)piperid-4-yl)carbamate (17c) Compound 17b (126 mg, 0.22 mmol), 3-fluoro-4-cyanophenylboronic acid (54 mg, 0.33 mmol), K2CO3 (91 mg, 0.66 mmol) were dissolved in 1,4-dioxane (2 mL) and water (0.4 mL), nitrogen replacement was performed, Pd(dppf)Cl2 (15 mg, 0.02 mmol) was added, nitrogen replacement was further performed, the reaction system was heated to 100 ° C, and the reaction was allowed to proceed overnight with stirring. The reaction system was cooled to room temperature, the reaction liquid was poured into water, extracted three times with ethyl acetate, the organic phase was combined and washed with saturated saline, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to obtain the target compound (74 mg, yield 51%). Fourth step: Preparation of 6-(4-aminopiperid-1-yl)-2-(4-cyano-3-fluorophenyl)-3-(6-fluoro-1-(2-hydroxy-2-methylpropyl)-1H-indazol-5-yl)isonicotinamide (17) Compound 17c (74 mg, 0.11 mmol) was dissolved in ethyl acetate (1 mL), then hydrochloric acid-ethyl acetate solution (1 mL, 3M in EA) was added, and the reaction system was stirred at room temperature for 1 hour. The reaction system was concentrated under reduced pressure, diluted with water, and the pH value of the system was adjusted to about 8 with saturated sodium bicarbonate solution, and extracted three times with ethyl acetate. The organic phase was combined and washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by thin-layer silica gel plate to obtain the target compound (24 mg, 38% yield). LC-MS (ESI) m / z (M+H) + :546.2 1 H NMR (400 MHz, DMSO-d6) δ 8.03 (d, J = 0.8, 1H), 7.85 (s, 1H), 7.25-7.67 (m, 1H), 7.59 (d, J = 7.2, 1H), 7.42-7.34 (m, 2H), 7.27 (dd, J = 10.4, 1.2 Hz, 1H), 7.16 (dd, J = 8.0, 1.6 Hz, 1H), 6.96 (s, 1H), 4.66 (s, 1H), 4.37-4.19 (m, 4H), 3.04-2.94 (m, 2H), 2.88-2.48 (m, 1H), 1.85-1.75 (m, 2H), 1.27-1.19 (m, 2H), 1.13 (s, 3H), 1.07 (s, 3H).

[0093] Example 18 Preparation of 6-(4-aminopiperid-1-yl)-2-(4-cyano-3-fluorophenyl)-3-(1-methyl-2-oxoindol-5-yl)isonicotinonitrile (18) [ka] First step: Preparation of tert-butyl (1-(4-cyano-6-(4-cyano-3-fluorophenyl)-5-(1-methyl-2-oxoindol-5-yl)pyrid-2-yl)piperid-4-yl)carbamate (18a) Compound 18b (75 mg, 0.15 mmol), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)dihydroindol-2-one (63 mg, 0.23 mmol), K2CO3 (62 mg, 0.46 mmol) were dissolved in 1,4-dioxane (1 mL) and water (0.2 mL), nitrogen replacement was performed, Pd(dppf)Cl2 (15 mg, 0.02 mmol) was added, nitrogen replacement was further performed, the reaction system was heated to 100 ° C, and the reaction was allowed to proceed overnight with stirring. The reaction system was cooled to room temperature, the reaction liquid was poured into water, extracted three times with ethyl acetate, the organic phase was combined and washed with saturated saline, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the crude product was purified by thin-layer silica gel plate to obtain the target compound (36 mg, yield 42%). Second step: Preparation of 6-(4-aminopiperid-1-yl)-2-(4-cyano-3-fluorophenyl)-3-(1-methyl-2-oxoindol-5-yl)isonicotinonitrile (18) Compound 18a (36 mg, 0.06 mmol) was dissolved in ethyl acetate (1 mL), then hydrochloric acid-ethyl acetate solution (1 mL, 3M in EA) was added, and the reaction system was stirred at room temperature for 1 hour. The reaction system was concentrated under reduced pressure, diluted with water, and the pH value of the system was adjusted to about 8 with saturated sodium bicarbonate solution, and extracted three times with ethyl acetate. The organic phases were combined and washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by thin-layer silica gel plate to obtain the target compound (18 mg, yield 61%). LC-MS (ESI) m / z (M+H) + :467.2 1H NMR (400 MHz, DMSO-d6) δ 7.77 (dd, J = 8.0, 7.2 Hz, 1H), 7.53 (s, 1H), 7.39 (dd, J = 10.8, 1.2 Hz, 1H), 7.19-7.12 (m, 2H), 7.09-7.07 (m, 1H), 7.00-6.96 (m, 1H), 4.34-4.26 (m, 2H), 3.51 (s, 2H), 3.12 (s, 3H), 3.08-2.98 (m, 2H), 2.89-2.80 (m, 1H), 1.82-1.74 (m, 2H), 1.26-1.17 (m, 2H).

[0094] Example 19 Preparation of 6-(4-aminopiperid-1-yl)-2-(4-cyano-3-fluorophenyl)-3-(2-fluoro-4-(2-hydroxy-2-methylpropyl)phenyl)isonicotinonitrile (19) [ka] First step: Preparation of methyl 2-(4-bromo-3-fluorophenyl)acetate (19b) Compound 19a (1.0 g, 4.29 mmol) was dissolved in acetonitrile (40 mL), followed by the addition of K2CO3 (1.8 g, 13.02 mmol) and methyl iodide (1.5 g, 10.57 mmol) in that order, and the reaction system was heated to 60°C and stirred for 3 hours. The reaction system was cooled to room temperature, the reaction solution was poured into water, extracted three times with ethyl acetate, the combined organic phase was washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (1.0 g, 94% yield). Second step: Preparation of 1-(4-bromo-3-fluorophenyl)-2-methylpropan-2-ol (19c) Compound 19b (815 mg, 3.30 mmol) was dissolved in dry tetrahydrofuran (30 mL), and then methylmagnesium bromide (5.5 mL, 3 M in THF) was slowly added dropwise in an ice-water bath. After the completion of the dropwise addition, the temperature of the reaction system was slowly returned to room temperature, and the reaction was allowed to proceed with stirring overnight. The reaction system was cooled to 0°C, and an appropriate amount of water was slowly added to quench the reaction, filtered, and the filtrate was extracted three times with ethyl acetate. The organic phases were combined and washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (366 mg, 45% yield). Third step: Preparation of 1-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxybenzaldehyde-2-yl)phenyl)-2-methylpropan-2-ol (19d) Compound 19c (360 mg, 1.46 mmol), bis(pinacolato)diboron (741 mg, 2.92 mmol), potassium acetate (429 mg, 4.37 mmol) were dissolved in 1,4-dioxane (15 mL), nitrogen substitution was performed, Pd(dppf)Cl2 (107 mg, 0.15 mmol) was added, nitrogen substitution was further performed, the reaction system was heated to 100 ° C, and the reaction was allowed to proceed with stirring for 24 hours. The reaction system was cooled to room temperature, the reaction liquid was poured into water, extracted three times with ethyl acetate, the organic phase was combined and washed with saturated saline, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to obtain the target compound (177 mg, yield 41%). Fourth step: Preparation of tert-butyl (1-(4-cyano-6-(4-cyano-3-fluorophenyl)-5-(2-fluoro-4-(2-hydroxy-2-methylpropyl)phenyl)pyrid-2-yl)piperid-4-yl)carbamate (19e) Compound 16b (100 mg, 0.20 mmol), compound 19d (118 mg, 0.40 mmol), K2CO3 (83 mg, 0.60 mmol) were dissolved in 1,4-dioxane (2 mL) and water (0.2 mL), nitrogen replacement was performed, Pd(dppf)Cl2 (15 mg, 0.02 mmol) was added, nitrogen replacement was further performed, the reaction system was heated to 100 ° C, and the reaction was allowed to proceed overnight with stirring. The reaction system was cooled to room temperature, the reaction liquid was poured into water, extracted three times with ethyl acetate, the organic phase was combined and washed with saturated saline, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the crude product was purified by thin-layer silica gel plate to obtain the target compound (50 mg, yield 43%). Fifth step: Preparation of 6-(4-aminopiperid-1-yl)-2-(4-cyano-3-fluorophenyl)-3-(2-fluoro-4-(2-hydroxy-2-methylpropyl)phenyl)isonicotinonitrile (19) Compound 19e (50 mg, 0.09 mmol) was dissolved in ethyl acetate (1 mL), then hydrochloric acid-ethyl acetate solution (1 mL, 3M in EA) was added, and the reaction system was stirred at room temperature for 1 hour. The reaction system was concentrated under reduced pressure, diluted with water, and the pH value of the system was adjusted to about 8 with saturated sodium bicarbonate solution, and extracted three times with ethyl acetate. The organic phase was combined and washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by thin-layer silica gel plate to obtain the target compound (36 mg, yellow solid, 87% yield). LC-MS (ESI) m / z (M+H) + :488.2 1 H NMR (400 MHz, DMSO-d6) δ 7.82-7.76 (m, 1H), 7.59 (s, 1H), 7.27-7.17 (m, 3H), 7.08 (s, 1H), 7.07-7.04 (m, 1H), 4.56 (s, 1H), 4.37-4.27 (m, 2H), 3.10-3.00 (m, 2H), 2.91-2.80 (m, 1H), 2.68 (s, 2H), 1.85-1.74 (m, 2H), 1.27-1.17 (m, 2H), 1.04 (s, 3H), 1.03 (s, 3H).

[0095] Example 20 Preparation of 2-(4-cyano-3-fluorophenyl)-6-(1,4-diazaanilin-1-yl)-3-(1-methyl-1H-indazol-5-yl)isonicotinonitrile (20) [ka] First step: Preparation of tert-butyl 4-(6-chloro-4-cyanopyrid-2-yl)-1,4-diazane-1-carboxylate (20a) Compound 1a (1.5 g, 8.67 mmol), 1,4-diazacycloheptane-1-tert-butyl formate (1.7 g, 8.49 mmol), and K2CO3 (2.4 g, 17.36 mmol) were dissolved in acetonitrile (20 mL), and the system was heated to 80 ° C. and stirred overnight to react. The reaction system was cooled to room temperature, and the reaction liquid was poured into water and extracted three times with ethyl acetate. The organic phases were combined and washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (2.1 g, 72% yield). Second step: Preparation of tert-butyl 4-(4-cyano-6-(4-cyano-3-fluorophenyl)pyrid-2-yl)-1,4-diazane-1-carboxylate (20b) Compound 20a (1.0 g, 2.97 mmol), 3-fluoro-4-cyanophenylboronic acid (735 mg, 4.46 mmol), Na2CO3 (630 mg, 5.94 mmol) were dissolved in acetonitrile (10 mL) and water (5 mL), nitrogen substitution was performed, Pd(PPh3)4 (173 mg, 0.15 mmol) was added, nitrogen substitution was further performed, the reaction system was heated to 85 ° C., and the reaction was allowed to proceed with stirring for 6 hours. The reaction system was cooled to room temperature, the reaction liquid was poured into water, extracted three times with ethyl acetate, the organic phase was combined and washed with saturated saline, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to obtain the target compound (800 mg, yield 64%). Third step: Preparation of tert-butyl 4-(5-bromo-4-cyano-6-(4-cyano-3-fluorophenyl)pyrid-2-yl)-1,4-diazane-1-carboxylate (20c) Compound 20b (500 mg, 1.19 mmol) was dissolved in acetonitrile (5 mL), and NBS (211 mg, 1.19 mmol) was slowly added to the system under ice bath, and the reaction system was placed at room temperature and stirred for 3 hours to react. The reaction system was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to obtain the target compound (420 mg, yield 71%). Fourth step: Preparation of tert-butyl 4-(4-cyano-6-(4-cyano-3-fluorophenyl)-5-(1-methyl-1H-indazol-5-yl)pyrid-2-yl)-1,4-diazane-1-carboxylate (20d) Compound 20c (50 mg, 0.10 mmol), 1-methylindazole-5-boronic acid (53 mg, 0.30 mmol), K2CO3 (41 mg, 0.30 mmol) were dissolved in 1,4-dioxane (2 mL) and water (0.4 mL), nitrogen replacement was performed, Pd(dppf)Cl2 (7 mg, 0.01 mmol) was added, nitrogen replacement was further performed, the reaction system was heated to 80 ° C, and the reaction was allowed to proceed overnight with stirring. The reaction system was cooled to room temperature, the reaction liquid was poured into water, extracted three times with ethyl acetate, the organic phase was combined and washed with saturated saline, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the crude product was purified by thin-layer silica gel plate to obtain the target compound (30 mg, yield 54%). Fifth step: Preparation of 2-(4-cyano-3-fluorophenyl)-6-(1,4-diazaanilin-1-yl)-3-(1-methyl-1H-indazol-5-yl)isonicotinonitrile (20) Compound 20d (30 mg, 0.05 mmol) was dissolved in ethyl acetate (1 mL), then hydrochloric acid-ethyl acetate solution (2 mL, 3M in EA) was added, and the reaction system was stirred at room temperature for 1 hour. The reaction system was concentrated under reduced pressure, diluted with water, and the pH value of the system was adjusted to about 8 with saturated sodium bicarbonate solution, and extracted three times with ethyl acetate. The organic phase was combined and washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by thin-layer silica gel plate to obtain the target compound (20 mg, yield 82%). LC-MS (ESI) m / z (M+H) + :452.2 1 H NMR (400 MHz, DMSO-d6) δ 8.07-8.05 (m, 1H), 7.75-7.70 (m, 1H), 7.69-7.66 (m, 1H), 7.63-7.59 (m, 1H), 7.40-7.35 (m, 2H), 7.18-7.13 (m, 2H), 4.06 (s, 3H), 3.83-3.67 (m, 4H), 2.93-2.87 (m, 2H), 2.76-2.69 (m, 2H), 1.85-1.74 (m, 2H).

[0096] Example 21 Preparation of 2-(4-cyano-3-fluorophenyl)-6-(1,4-diazaanilin-1-yl)-(6-fluoro-1-(2-hydroxy-2-methylpropyl)-1H-indazol-5-yl)isonicotinonitrile (21) [ka] First step: Preparation of tert-butyl 4-(4-cyano-6-(4-cyano-3-fluorophenyl)-5-(6-fluoro-1-(2-hydroxy-2-methylpropyl)-1H-indazol-5-yl)pyrid-2-yl)-1,4-diazane-1-carboxylate (21a) Compound 20c (50 mg, 0.10 mmol), compound 9c (100 mg, 0.30 mmol), K2CO3 (41 mg, 0.30 mmol) were dissolved in 1,4-dioxane (2 mL) and water (0.4 mL), nitrogen replacement was performed, Pd(dppf)Cl2 (7 mg, 0.01 mmol) was added, nitrogen replacement was further performed, the reaction system was heated to 80 ° C, and the reaction was allowed to proceed overnight with stirring. The reaction system was cooled to room temperature, the reaction liquid was poured into water, extracted three times with ethyl acetate, the organic phase was combined and washed with saturated saline, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the crude product was purified by thin-layer silica gel plate to obtain the target compound (10 mg, yield 16%). Second step: Preparation of 2-(4-cyano-3-fluorophenyl)-6-(1,4-diazaanilin-1-yl)-3-(6-fluoro-1-(2-hydroxy-2-methylpropyl)-1H-indazol-5-yl)isonicotinonitrile (21) Compound 21a (10 mg, 0.02 mmol) was dissolved in ethyl acetate (1 mL), then hydrochloric acid-ethyl acetate solution (2 mL, 3M in EA) was added, and the reaction system was stirred at room temperature for 1 hour. The reaction system was concentrated under reduced pressure, diluted with water, and the pH value of the system was adjusted to about 8 with saturated sodium bicarbonate solution, and extracted three times with ethyl acetate. The organic phases were combined and washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by thin-layer silica gel plate to obtain the target compound (4 mg, 48% yield). LC-MS (ESI) m / z (M+H) + :528.2 1H NMR (400 MHz, DMSO- d6) δ 8.11 (s, 1H), 7.79-7.73 (m, 2H), 7.58 (d, J = 10.4 Hz, 1H), 7.41 (s, 1H), 7.39-7.33 (m, 1H), 7.21-7.16 (m, 1H), 4.67 (s, 1H), 4.32-4.23 (m, 2H), 3.88-3.67 (m, 4H), 2.94-2.85 (m, 2H), 2.76-2.68 (m, 2H), 1.86-1.72 (m, 2H), 1.15 (s, 3H), 1.10 (s, 3H).

[0097] Example 22 Preparation of 2-(4-cyano-3-fluorophenyl)-3-(3-fluoro-4-methoxyphenyl)-6-(2,7-diazaspiro[3.5]non-7-yl)isonicotinonitrile (22) [ka] First step: Preparation of tert-butyl 7-(4-cyano-6-(4-cyano-3-fluorophenyl)-5-(3-fluoro-4-methoxyphenyl)pyrid-2-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (22a) Compound 5j (50 mg, 0.11 mmol) was dissolved in 1,4-dioxane (3 mL), and then 2-tert-butoxycarbonyl-2,7-diazaspiro[3.5]nonane (50 mg, 0.22 mmol) and Cs2CO3 (107 mg, 0.33 mmol) were added in order, nitrogen replacement was performed, RuPhos-Pd-G3 (9 mg, 0.01 mmol) was added, and nitrogen replacement was further performed. The system was heated to 80 ° C. and stirred for 3 hours to react. The reaction system was cooled to room temperature, the reaction liquid was concentrated under reduced pressure, the system was diluted with water, extracted three times with ethyl acetate, the organic phase was combined and washed with saturated saline, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the crude product was purified by thin-layer silica gel plate to obtain the target compound (30 mg, yield 50%). Second step: Preparation of 2-(4-cyano-3-fluorophenyl)-3-(3-fluoro-4-methoxyphenyl)-6-(2,7-diazaspiro[3.5]non-7-yl)isonicotinonitrile (22) Compound 22a (30 mg, 0.05 mmol) was dissolved in dichloromethane (2 mL), then trifluoroacetic acid (1 mL) was added, and the reaction system was stirred at room temperature for 1 hour. The reaction system was concentrated under reduced pressure, diluted with water, and the pH value of the system was adjusted to about 8 with saturated sodium bicarbonate solution, and extracted three times with ethyl acetate. The organic phase was combined and washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by thin-layer silica gel plate to obtain the target compound (15 mg, yield 61%). LC-MS (ESI) m / z (M+H) + :472.2 1 H NMR (400 MHz, DMSO-d6) δ 7.85-7.78 (m, 1H), 7.59 (s, 1H), 7.44-7.36 (m, 1H), 7.22-7.11 (m, 3H), 6.99-6.93 (m, 1H), 3.85 (s, 3H), 3.72-3.56 (m, 8H), 1.85-1.67 (m, 4H).

[0098] Example 23 Preparation of 6-(4-aminocyclohexyl)-2-(4-cyano-3-fluorophenyl)-3-(1-methyl-1H-indazol-5-yl)isonicotinonitrile (23-1, 23-2) [ka] First step: Preparation of 6-amino-2-chloro-3-(1-methyl-1H-indazol-5-yl)isonicotinonitrile (23a) Compound 5g (1.5g, 6.45mmol) was dissolved in 1,4-dioxane (20mL) and water (3mL), then 1-methylindazole-5-boronic acid (1.1g, 6.25mmol) and K2CO3 (1.8g, 13.02mmol) were added in sequence, nitrogen substitution was performed, Pd(dppf)Cl2 (472mg, 0.64mmol) was added, nitrogen substitution was further performed, and the reaction system was placed at 80°C and reacted with stirring for 3 hours. The reaction system was cooled to room temperature, diluted with water, extracted three times with ethyl acetate, the organic phase was combined and washed with saturated saline, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to obtain the target compound (1.1g, yield 60%). Second step: Preparation of 6-amino-2-(4-cyano-3-fluorophenyl)-3-(1-methyl-1H-indazol-5-yl)isonicotinonitrile (23b) Compound 23a (1.1 g, 3.88 mmol) was dissolved in 1,4-dioxane (30 mL) and water (3 mL), and then 3-fluoro-4-cyanophenylboronic acid (1.9 g, 11.52 mmol) and K2CO3 (1.6 g, 11.58 mmol) were added in sequence, nitrogen substitution was performed, Pd(dppf)Cl2 (278 mg, 0.38 mmol) was added, and nitrogen substitution was further performed, and the reaction system was placed at 80 ° C. and stirred overnight to react. The reaction system was cooled to room temperature, diluted with water, extracted three times with ethyl acetate, and the organic phase was washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to obtain the target compound (1.1 g, yield 77%). Third step: Preparation of 2-(4-cyano-3-fluorophenyl)-6-iodo-3-(1-methyl-1H-indazol-5-yl)isonicotinonitrile (23c) Compound 23b (500 mg, 1.36 mmol) was dissolved in acetonitrile (10 mL), followed by the addition of potassium iodide (451 mg, 2.72 mmol) and isoamyl nitrite (319 mg, 2.72 mmol) in that order, and the reaction system was placed at 80° C. and stirred overnight. The reaction system was cooled to room temperature, the reaction solution was concentrated under reduced pressure, the system was diluted with water, and extracted three times with ethyl acetate. The organic phases were combined, washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (90 mg, 14% yield). Fourth step: Preparation of tert-butyl (4-(4-cyano-6-(4-cyano-3-fluorophenyl)-5-(1-methyl-1H-indazol-5-yl)pyrid-2-yl)cyclohex-3-en-1-yl)carbamate (23d) Compound 23c (90 mg, 0.19 mmol) was dissolved in 1,4-dioxane (3 mL) and water (0.6 mL), and then (4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-en-1-yl)carbamate tert-butyl (184 mg, 0.57 mmol) and K2CO3 (79 mg, 0.57 mmol) were added in sequence, nitrogen replacement was performed, Pd(dppf)Cl2 (14 mg, 0.02 mmol) was added, and nitrogen replacement was further performed. The reaction system was placed at 80 ° C. and stirred for 2 hours to react. The reaction system was cooled to room temperature, diluted with water, extracted three times with ethyl acetate, and the organic phase was washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (80 mg, yield 78%). Fifth step: Preparation of tert-butyl (4-(4-cyano-6-(4-cyano-3-fluorophenyl)-5-(1-methyl-1H-indazol-5-yl)pyrid-2-yl)cyclohexyl)carbamate (23e) Compound 23d (80 mg, 0.14 mmol) was dissolved in ethyl acetate (3 mL), and then Pd / C (8 mg, 10%) was added at room temperature to replace the air in the system with hydrogen, and the system was stirred overnight at room temperature in a hydrogen atmosphere to react. The reaction system was filtered, and the filtrate was concentrated under reduced pressure, and the crude product was purified by a thin-layer silica gel plate to obtain the target compound (67 mg, 83% yield). Sixth step: Preparation of 6-(4-aminocyclohexyl)-2-(4-cyano-3-fluorophenyl)-3-(1-methyl-1H-indazol-5-yl)isonicotinonitrile (23-1, 23-2) Compound 23e (67 mg, 0.12 mmol) was dissolved in ethyl acetate (1 mL), then hydrochloric acid-ethyl acetate solution (3 mL, 3M in EA) was added, the reaction system was placed at room temperature and stirred for 1 hour. The reaction system was concentrated under reduced pressure, diluted with water, and the pH value of the system was adjusted to about 8 with saturated sodium bicarbonate solution, extracted with ethyl acetate three times, the organic phase was combined and washed with saturated saline, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the crude product was purified by thin-layer silica gel plate (DCM / MeOH=10:1) to obtain the target compound 23-1 (top point: R f =0.3) (10 mg, yield 18%), and the target compound 23-2 (lower point: R f =0.25) (10 mg, 18% yield). Top point LC-MS (ESI) m / z (M+H) + :451.2 1 H NMR (400 MHz, DMSO-d6) δ 8.13-8.08 (m, 2H), 7.83-7.80 (m, 1H), 7.79-7.73 (m, 1H), 7.69-7.64 (m, 1H), 7.49-7.44 (m, 1H), 7.26-7.22 (m, 1H), 7.21-7.16 (m, 1H), 4.07 (s, 3H), 3.24-3.18 (m, 1H), 3.03-2.92 (m, 1H), 2.15-2.02 (m, 2H), 1.80-1.60 (m, 4H), 1.25-1.10 (m, 2H). Lower point LC-MS (ESI) m / z (M+H) + :451.2 1 H NMR (400 MHz, DMSO-d6) δ 8.12~8.10 (m, 1H), 8.03 (s, 1H), 7.82-7.80 (m, 1H), 7.79-7.73 (m, 1H), 7.68-7.64 (m, 1H), 7.46-7.41 (m, 1H), 7.26-7.22 (m, 1H), 7.20-7.16 (m, 1H), 4.07 (s, 3H), 2.88-2.72 (m, 2H), 2.03-1.91 (m, 4H), 1.75-1.62 (m, 2H), 1.36-1.25 (m, 2H).

[0099] Example 24 Preparation of 2-(4-cyano-3-fluorophenyl)-3-(3-fluoro-4-methoxyphenyl)-6-(7-oxo-1,4-diazal-1-yl)isonicotinonitrile (24) [ka] First step: Preparation of tert-butyl 4-(4-cyano-6-(4-cyano-3-fluorophenyl)-5-(3-fluoro-4-methoxyphenyl)pyrid-2-yl)-5-oxy-1,4-diazane-1-carboxylate (24a) Compound 5j (50 mg, 0.11 mmol) was dissolved in 1,4-dioxane (3 mL), and then 1-tert-butoxycarbonyl-1,4-diaza-5-cycloheptanone (47 mg, 0.22 mmol) and Cs2CO3 (107 mg, 0.33 mmol) were added in order, nitrogen replacement was performed, RuPhos-Pd-G3 (9 mg, 0.01 mmol) was added, and nitrogen replacement was further performed. The system was heated to 80 ° C. and stirred for 3 hours to react. The reaction system was cooled to room temperature, the reaction liquid was concentrated under reduced pressure, the system was diluted with water, extracted three times with ethyl acetate, the organic phase was combined and washed with saturated saline, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the crude product was purified by thin-layer silica gel plate to obtain the target compound (40 mg, yield 68%). Second step: Preparation of 2-(4-cyano-3-fluorophenyl)-3-(3-fluoro-4-methoxyphenyl)-6-(7-oxo-1,4-diazal-1-yl)isonicotinonitrile (24) Compound 24a (40 mg, 0.07 mmol) was dissolved in dichloromethane (2 mL), then trifluoroacetic acid (1 mL) was added, and the reaction system was stirred at room temperature for 1 hour. The reaction system was concentrated under reduced pressure, diluted with water, and the pH value of the system was adjusted to about 8 with saturated sodium bicarbonate solution, and extracted three times with ethyl acetate. The organic phase was combined and washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by thin-layer silica gel plate to obtain the target compound (16 mg, yield 49%). LC-MS (ESI) m / z (M+H) + :460.2 1 H NMR (400 MHz, DMSO-d6) δ 8.29 (s, 1H), 7.89-7.82 (m, 1H), 7.49 (dd, J = 10.4, 1.2 Hz, 1H), 7.31 (dd, J = 12.0, 2.0 Hz, 1H), 7.25-7.18 (m, 2H), 7.11-7.05 (m, 1H), 4.29-4.19 (m, 2H), 3.85 (s, 3H), 3.03-2.94 (m, 4H), 2.91-2.84 (m, 2H).

[0100] Example 25 Preparation of 6-(4-aminopiperid-1-yl)-2-(4-cyano-3-fluorophenyl)-3-(2,2-difluorobenzo[1,3-d]dioxacyclo-5-yl)isonicotinonitrile (25) [ka] First step: Preparation of tert-butyl (1-(4-cyano-6-(4-cyano-3-fluorophenyl)-5-(2,2-difluorobenzo[1,3-d]dioxacyclo-5-yl)pyrid-2-yl)piperid-4-yl)carbamate (25a) Compound 16b (75 mg, 0.15 mmol), (2,2-difluorobenzo[1,3-d]dioxacyclopenten-5-yl)boronic acid (46 mg, 0.23 mmol), K2CO3 (62 mg, 0.45 mmol) were dissolved in 1,4-dioxane (1.5 mL) and water (0.3 mL), nitrogen replacement was performed, Pd(dppf)Cl2 (15 mg, 0.02 mmol) was added, nitrogen replacement was further performed, the reaction system was heated to 100 ° C, and the reaction was allowed to proceed overnight with stirring. The reaction system was cooled to room temperature, the reaction liquid was poured into water, extracted three times with ethyl acetate, the organic phase was combined and washed with saturated saline, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the crude product was purified by thin-layer silica gel plate to obtain the target compound (53 mg, yield 61%). Second step: Preparation of 6-(4-aminopiperid-1-yl)-2-(4-cyano-3-fluorophenyl)-3-(2,2-difluorobenzo[1,3-d]dioxacyclo-5-yl)isonicotinonitrile (25) Compound 25a (53 mg, 0.09 mmol) was dissolved in ethyl acetate (1 mL), then hydrochloric acid-ethyl acetate solution (1 mL, 3M in EA) was added, and the reaction system was stirred at room temperature for 1 hour. The reaction system was concentrated under reduced pressure, diluted with water, and the pH value of the system was adjusted to about 8 with saturated sodium bicarbonate solution, and extracted three times with ethyl acetate. The organic phases were combined and washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by thin-layer silica gel plate to obtain the target compound (34 mg, 78% yield). LC-MS (ESI) m / z (M+H) + :478.2 1H NMR (400 MHz, DMSO-d6) δ 7.80 (dd, J = 8.0, 6.8 Hz, 1H), 7.57 (s, 1H), 7.44 (d, J = 1.6 Hz, 1H), 7.43-7.38 (m, 2H), 7.15 (dd, J = 8.0, 1.2 Hz, 1H), 7.04 (dd, J = 8.0, 1.2 Hz, 1H), 4.36-4.26 (m, 2H), 3.10-3.00 (m, 2H), 2.90-2.80 (m, 1H), 1.83-1.73 (m, 2H), 1.26-1.14 (m, 2H).

[0101] Example 26 Preparation of 6-(4-cyano-3-fluorophenyl)-2-(1,4-diazal-1-yl)-5-(1-methyl-1H-indazol-5-yl)nicotinamide (26) [ka] First step: Preparation of tert-butyl 4-(3-carbamoyl-6-chloropyrid-2-yl)-1,4-diazane-1-carboxylate (26a) Compound 11b (550 mg, 2.88 mmol), tert-butyl 1,4-diazacycloheptane-1-formate (572 mg, 2.86 mmol), and K2CO3 (792 mg, 5.73 mmol) were dissolved in acetonitrile (7 mL), and the system was heated to 80° C. and stirred overnight to react. The reaction system was cooled to room temperature, and the reaction solution was poured into water and extracted three times with ethyl acetate. The combined organic phase was washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (620 mg, 61% yield). Second step: Preparation of tert-butyl 4-(3-carbamoyl-6-(4-cyano-3-fluorophenyl)pyrid-2-yl)-1,4-diazane-1-carboxylate (26b) Compound 26a (620 mg, 1.75 mmol), 3-fluoro-4-cyanophenylboronic acid (433 mg, 2.63 mmol), K2CO3 (723 mg, 5.23 mmol) were dissolved in 1,4-dioxane (7 mL) and water (0.7 mL), nitrogen replacement was performed, Pd(dppf)Cl2 (64 mg, 0.09 mmol) was added, nitrogen replacement was further performed, the reaction system was heated to 100 ° C., and the reaction was allowed to proceed overnight with stirring. The reaction system was cooled to room temperature, the reaction liquid was poured into water, extracted three times with ethyl acetate, the organic phase was combined and washed with saturated saline, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to obtain the target compound (754 mg, yield 98%). Third step: Preparation of tert-butyl 4-(5-bromo-3-carbamoyl-6-(4-cyano-3-fluorophenyl)pyrid-2-yl)-1,4-diazane-1-carboxylate (26c) Compound 26b (754 mg, 1.72 mmol) was dissolved in N,N-dimethylformamide (9 mL), and NBS (609 mg, 3.42 mmol) was slowly added to the system under ice bath, and the reaction system was stirred at room temperature for 2 hours to react. The reaction solution was poured into water, extracted three times with ethyl acetate, and the organic phases were combined and washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (315 mg, yield 35%). Fourth step: Preparation of tert-butyl 4-(3-carbamoyl-6-(4-cyano-3-fluorophenyl)-5-(1-methyl-1H-indazol-5-yl)pyrid-2-yl)-1,4-diazane-1-carboxylate (26d) Compound 26c (160 mg, 0.31 mmol), 1-methylindazole-5-boronic acid (82 mg, 0.47 mmol), K2CO3 (128 mg, 0.93 mmol) were dissolved in 1,4-dioxane (3 mL) and water (0.3 mL), nitrogen replacement was performed, Pd(dppf)Cl2 (12 mg, 0.02 mmol) was added, nitrogen replacement was further performed, the reaction system was heated to 100 ° C, and the reaction was allowed to proceed overnight with stirring. The reaction system was cooled to room temperature, the reaction liquid was poured into water, extracted three times with ethyl acetate, the organic phase was combined and washed with saturated saline, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel to obtain the target compound (145 mg, yield 82%). Fifth step: Preparation of 6-(4-cyano-3-fluorophenyl)-2-(1,4-diazal-1-yl)-5-(1-methyl-1H-indazol-5-yl)nicotinamide (26) Compound 26d (72 mg, 0.13 mmol) was dissolved in ethyl acetate (1 mL), then hydrochloric acid-ethyl acetate solution (1 mL, 3M in EA) was added, and the reaction system was stirred at room temperature for 2 hours. The reaction system was concentrated under reduced pressure, diluted with water, and the pH value of the system was adjusted to about 8 with saturated sodium bicarbonate solution, and extracted three times with ethyl acetate. The organic phases were combined and washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by thin-layer silica gel plate to obtain the target compound (49 mg, yield 83%). LC-MS (ESI) m / z (M+H) + :470.2 1H NMR (400 MHz, DMSO-d6) δ 8.02 (s, 1H), 8.02-7.98 (m, 1H), 7.79-7.74 (m, 1H), 7.73-7.69 (m, 1H), 7.68-7.64 (m, 1H), 7.58-7.53 (m, 1H), 7.51-7.41 (m, 2H), 7.26-7.21 (m, 1H), 7.14-7.08 (m, 1H), 4.04 (s, 3H), 3.76-3.66 (m, 2H), 3.56-3.49 (m, 2H), 2.98-2.91 (m, 2H), 2.77-2.70 (m, 2H), 1.91-1.78 (m, 2H).

[0102] Example 27 Preparation of 6-(4-cyano-3-fluorophenyl)-2-(1,4-diazaanilin-1-yl)-N,N-dimethyl-5-(1-methyl-1H-indazol-5-yl)nicotinamide (27) [ka] First step: Preparation of 2,6-dichloro-N,N-dimethylnicotinamide (27a) Compound 11a (500 mg, 2.60 mmol) was dissolved in tetrahydrofuran (5 mL), then dimethylamine hydrochloride (636 mg, 7.80 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (1.2 g, 3.16 mmol), and N,N-diisopropylethylamine (1.0 g, 7.74 mmol) were added, and the mixture was stirred at room temperature overnight to react. The reaction solution was poured into water, extracted with ethyl acetate three times, and the combined organic phase was washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 570 mg of the target compound, which was used directly in the next step reaction without purification. Second step: Preparation of tert-butyl 4-(6-chloro-3-(dimethylcarbamoyl)pyrid-2-yl)-1,4-diazane-1-carboxylate (27b) Compound 27a (570 mg, 2.60 mmol), tert-butyl 1,4-diazacycloheptane-1-formate (518 mg, 2.59 mmol), and K2CO3 (708 mg, 5.12 mmol) were dissolved in acetonitrile (7 mL), and the system was heated to 80° C. and stirred overnight to react. The reaction system was cooled to room temperature, and the reaction solution was poured into water and extracted three times with ethyl acetate. The combined organic phase was washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (653 mg, 65% overall yield for two steps). Third step: Preparation of tert-butyl 4-(6-(4-cyano-3-fluorophenyl)-3-(dimethylcarbamoyl)pyrid-2-yl)-1,4-diazane-1-carboxylate (27c) Compound 27b (520 mg, 1.36 mmol), 3-fluoro-4-cyanophenylboronic acid (335 mg, 2.03 mmol), K2CO3 (559 mg, 4.04 mmol) were dissolved in 1,4-dioxane (7 mL) and water (0.7 mL), nitrogen replacement was performed, Pd(dppf)Cl2 (50 mg, 0.07 mmol) was added, nitrogen replacement was further performed, the reaction system was heated to 100 ° C., and the reaction was allowed to proceed overnight with stirring. The reaction system was cooled to room temperature, the reaction liquid was poured into water, extracted three times with ethyl acetate, the organic phase was combined and washed with saturated saline, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to obtain the target compound (399 mg, yield 63%). Fourth step: Preparation of tert-butyl 4-(5-bromo-6-(4-cyano-3-fluorophenyl)-3-(dimethylcarbamoyl)pyrid-2-yl)-1,4-diazane-1-carboxylate (27d) Compound 27c (389 mg, 0.83 mmol) was dissolved in N,N-dimethylformamide (4 mL), NBS (295 mg, 1.66 mmol) was slowly added to the system under ice bath, and the reaction system was stirred at room temperature for 2 hours to react. The reaction solution was poured into water, extracted three times with ethyl acetate, the organic phase was combined and washed with saturated saline, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to obtain the target compound (311 mg, yield 68%). Fifth step: Preparation of tert-butyl 4-(6-(4-cyano-3-fluorophenyl)-3-(dimethylcarbamoyl)-5-(1-methyl-1H-indazol-5-yl)pyrid-2-yl)-1,4-diazane-1-carboxylate (27e) Compound 27d (160 mg, 0.29 mmol), 1-methylindazole-5-boronic acid (76 mg, 0.43 mmol), K2CO3 (120 mg, 0.87 mmol) were dissolved in 1,4-dioxane (3 mL) and water (0.3 mL), nitrogen replacement was performed, Pd(dppf)Cl2 (11 mg, 0.02 mmol) was added, nitrogen replacement was further performed, the reaction system was heated to 100 ° C, and the reaction was allowed to proceed overnight with stirring. The reaction system was cooled to room temperature, the reaction liquid was poured into water, extracted three times with ethyl acetate, the organic phase was combined and washed with saturated saline, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel to obtain the target compound (53 mg, yield 30%). Sixth step: Preparation of 6-(4-cyano-3-fluorophenyl)-2-(1,4-diazaanilin-1-yl)-N,N-dimethyl-5-(1-methyl-1H-indazol-5-yl)nicotinamide (27) Compound 27e (53 mg, 0.09 mmol) was dissolved in ethyl acetate (1 mL), then hydrochloric acid-ethyl acetate solution (1 mL, 3M in EA) was added, and the reaction system was stirred at room temperature for 3 hours. The reaction system was concentrated under reduced pressure, diluted with water, and the pH value of the system was adjusted to about 8 with saturated sodium bicarbonate solution, and extracted three times with ethyl acetate. The organic phase was combined and washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by thin-layer silica gel plate to obtain the target compound (31 mg, 70% yield). LC-MS (ESI) m / z (M+H) + :498.3 1 H NMR (400 MHz, DMSO-d6) δ 8.01 (s, 1H), 7.79-7.73 (m, 1H), 7.65 (s, 1H), 7.57-7.52 (m, 2H), 7.49-7.43 (m, 1H), 7.26-7.21 (m, 1H), 7.12-7.06 (m, 1H), 4.03 (s, 3H), 3.73-3.40 (m, 4H), 3.00 (s, 3H), 2.95 (s, 3H), 2.94-2.89 (m, 2H), 2.79-2.71 (m, 2H), 1.90-1.74 (m, 2H).

[0103] Example 28 Preparation of 6-(4-cyano-3-fluorophenyl)-N-cyclopropyl-2-((1,4-diazaanilin-1-yl)-5-(1-methyl-1H-indazol-5-yl)nicotinamide (28) [ka] First step: Preparation of 2,6-dichloro-N-cyclopropylnicotinamide (28a) Compound 11a (500 mg, 2.60 mmol) was dissolved in chloroform (10 mL), nitrogen substitution was performed, and thionyl chloride (3.1 g, 26.00 mmol) was slowly added to the system in an ice bath, nitrogen substitution was further performed, and the system was heated to 70 ° C. and stirred for 2 hours to react. The reaction system was concentrated under reduced pressure, dissolved in dichloromethane (1 mL), and then added dropwise to a dichloromethane (1 mL) solution of cyclopropylamine (327 mg, 5.73 mmol) cooled in an ice bath, and stirred for 1 hour to react. Cold water was added to the reaction system to precipitate a solid, which was filtered to obtain 600 mg of the target compound, which was used directly in the next step reaction without purification. Second step: Preparation of tert-butyl 4-(6-chloro-3-(cyclopropylcarbamoyl)pyrid-2-yl)-1,4-diazane-1-carboxylate (28b) Compound 28a (600 mg, 2.60 mmol), tert-butyl 1,4-diazacycloheptane-1-formate (520 mg, 2.60 mmol), and K2CO3 (718 mg, 5.20 mmol) were dissolved in acetonitrile (8 mL), and the system was heated to 80° C. and stirred overnight to react. The reaction system was cooled to room temperature, and the reaction solution was poured into water and extracted three times with ethyl acetate. The combined organic phase was washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (913 mg, 89% overall yield for two steps). Third step: Preparation of tert-butyl 4-(6-(4-cyano-3-fluorophenyl)-3-(cyclopropylcarbamoyl)pyrid-2-yl)-1,4-diazane-1-carboxylate (28c) Compound 28b (520 mg, 1.32 mmol), 3-fluoro-4-cyanophenylboronic acid (327 mg, 1.98 mmol), K2CO3 (547 mg, 3.96 mmol) were dissolved in 1,4-dioxane (5 mL) and water (0.5 mL), nitrogen replacement was performed, Pd(dppf)Cl2 (48 mg, 0.07 mmol) was added, nitrogen replacement was further performed, the reaction system was heated to 100 ° C, and the reaction was allowed to proceed overnight with stirring. The reaction system was cooled to room temperature, the reaction liquid was poured into water, extracted three times with ethyl acetate, the organic phase was combined and washed with saturated saline, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to obtain the target compound (630 mg, 100% yield). Fourth step: Preparation of tert-butyl 4-(5-bromo-6-(4-cyano-3-fluorophenyl)-3-(cyclopropylcarbamoyl)pyrid-2-yl)-1,4-diazane-1-carboxylate (28d) Compound 28c (630 mg, 1.31 mmol) was dissolved in N,N-dimethylformamide (8 mL), NBS (480 mg, 2.70 mmol) was slowly added to the system under ice bath, and the reaction system was stirred at room temperature for 2 hours to react. The reaction solution was poured into water, extracted three times with ethyl acetate, the organic phase was combined, washed with saturated saline, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to obtain the target compound (315 mg, yield 43%). Fifth step: Preparation of tert-butyl 4-(6-(4-cyano-3-fluorophenyl)-3-(cyclopropylcarbamoyl)-5-(1-methyl-1H-indazol-5-yl)pyrid-2-yl)-1,4-diazane-1-carboxylate (28e) Compound 28d (160 mg, 0.29 mmol), 1-methylindazole-5-boronic acid (76 mg, 0.43 mmol), K2CO3 (120 mg, 0.87 mmol) were dissolved in 1,4-dioxane (3 mL) and water (0.3 mL), nitrogen replacement was performed, Pd(dppf)Cl2 (11 mg, 0.02 mmol) was added, nitrogen replacement was further performed, the reaction system was heated to 100 ° C, and the reaction was allowed to proceed overnight with stirring. The reaction system was cooled to room temperature, the reaction liquid was poured into water, extracted three times with ethyl acetate, the organic phase was combined and washed with saturated saline, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel to obtain the target compound (52 mg, yield 30%). Sixth step: Preparation of 6-(4-cyano-3-fluorophenyl)-N-cyclopropyl-2-((1,4-diazaanilin-1-yl)-5-(1-methyl-1H-indazol-5-yl)nicotinamide (28) Compound 28e (52 mg, 0.09 mmol) was dissolved in ethyl acetate (1 mL), then hydrochloric acid-ethyl acetate solution (1 mL, 3M in EA) was added, and the reaction system was stirred at room temperature for 5 hours. The reaction system was concentrated under reduced pressure, diluted with water, and the pH value of the system was adjusted to about 8 with saturated sodium bicarbonate solution, and extracted three times with ethyl acetate. The organic phases were combined and washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by thin-layer silica gel plate to obtain the target compound (20 mg, yield 46%). LC-MS (ESI) m / z (M+H) + :510.3 1H NMR (400 MHz, DMSO-d6) δ 8.60-8.57 (m, 1H), 8.01 (s, 1H), 7.79-7.73 (m, 1H), 7.66 (s, 1H), 7.60 (s, 1H), 7.57-7.52 (m, 1H), 7.47-7.41 (m, 1H), 7.25-7.20 (m, 1H), 7.11-7.06 (m, 1H), 4.01 (s, 3H), 3.71-3.64 (m, 2H), 3.54-3.47 (m, 2H), 2.96-2.88 (m, 2H), 2.84-2.76 (m, 1H), 2.75-2.68 (m, 2H), 1.89-1.77 (m, 2H), 0.72-0.65 (m, 2H), 0.54-0.48 (m, 2H).

[0104] Example 29 Preparation of 2-(4-cyano-3-fluorophenyl)-3-(3-fluoro-4-methoxyphenyl)-6-(2,8-diazaspiro[4.5]dec-8-yl)isonicotinonitrile (29) [ka] First step: Preparation of tert-butyl 8-(4-cyano-6-(4-cyano-3-fluorophenyl)-5-(3-fluoro-4-methoxyphenyl)pyrid-2-yl)-2,8-diazaspiro[4.5]decane-2-carboxylate (29a) Compound 5j (50 mg, 0.11 mmol) was dissolved in 1,4-dioxane (3 mL), and then 2,8-diazaspiro[4.5]decane-2-carboxylate tert-butyl (53 mg, 0.22 mmol) and Cs2CO3 (107 mg, 0.33 mmol) were added in sequence, nitrogen replacement was performed, RuPhos-Pd-G3 (9 mg, 0.01 mmol) was added, and nitrogen replacement was further performed. The system was heated to 80 ° C. and stirred for 3 hours to react. The reaction system was cooled to room temperature, the reaction liquid was concentrated under reduced pressure, the system was diluted with water, extracted three times with ethyl acetate, the organic phase was combined and washed with saturated saline, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the crude product was purified by thin-layer silica gel plate to obtain the target compound (32 mg, yield 52%). Second step: Preparation of 2-(4-cyano-3-fluorophenyl)-3-(3-fluoro-4-methoxyphenyl)-6-(2,8-diazaspiro[4.5]dec-8-yl)isonicotinonitrile (29) Compound 29a (32 mg, 0.05 mmol) was dissolved in ethyl acetate (1 mL), then hydrochloric acid-ethyl acetate solution (2 mL, 3M in EA) was added, and the reaction system was stirred at room temperature for 1 hour. The reaction system was concentrated under reduced pressure, diluted with water, and the pH value of the system was adjusted to about 8 with saturated sodium bicarbonate solution, and extracted three times with ethyl acetate. The organic phase was combined and washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by thin-layer silica gel plate to obtain the target compound (16 mg, yield 60%). LC-MS (ESI) m / z (M+H) + :486.3 1 H NMR (400 MHz, DMSO-d6) δ 7.85-7.77 (m, 1H), 7.57 (s, 1H), 7.46-7.36 (m, 1H), 7.24-7.11 (m, 3H), 7.01-6.92 (m, 1H), 3.85 (s, 3H), 3.81-3.57 (m, 4H), 3.50-3.24 (m, 3H), 2.96-2.88 (m, 1H), 1.81-1.72 (m, 1H), 1.65-1.58 (m, 1H), 1.58-1.48 (m, 4H).

[0105] Example 30 Preparation of 6-(aza-4-yl)-2-(4-cyano-3-fluorophenyl)-3-(3-fluoro-4-methoxyphenyl)isonicotinonitrile (30) [ka] First step: Preparation of tert-butyl 4-((((trifluoromethyl)sulfonyl)oxy)-2,3,6,7-tetrahydro-1H-aza-1-carboxylate (30b) Compound 30a (3.0 g, 14.07 mmol) was dissolved in tetrahydrofuran (50 mL), substituted with nitrogen, cooled to -78 ° C, added dropwise with lithium bis(trimethylsilyl)amide (19 mL, 1M in THF), reacted at -78 ° C for 1 hour, then added with N-phenylbis(trifluoromethanesulfonyl)imide (6.5 g, 18.19 mmol) and reacted for another 0.5 hours, returned to room temperature and reacted for 14 hours, diluted with water, extracted with ethyl acetate three times, combined organic phase washed with saturated saline, dried over anhydrous sodium sulfate, filtered, concentrated the filtrate under reduced pressure, and purified the crude product by silica gel column chromatography to obtain the target compound (2.0 g, yield 41%). Second step: Preparation of tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxybenzaldehyde-2-yl)-2,3,6,7-tetrahydro-1H-azacyclo-1-carboxylate (30c) Compound 30b (500 mg, 1.45 mmol), bis(pinacolato)diboron (1.1 g, 4.33 mmol), potassium acetate (426 mg, 4.34 mmol) were dissolved in 1,4-dioxane (5 mL), nitrogen substitution was performed, Pd(dppf)Cl2 (106 mg, 0.15 mmol) was added, nitrogen substitution was further performed, the reaction system was heated to 90 ° C, and the reaction was allowed to proceed overnight with stirring. The reaction system was cooled to room temperature, the reaction liquid was poured into water, extracted three times with ethyl acetate, the organic phase was combined and washed with saturated saline, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to obtain the target compound (300 mg, yield 64%). Third step: Preparation of tert-butyl 4-(4-cyano-6-(4-cyano-3-fluorophenyl)-5-(3-fluoro-4-methoxyphenyl)pyrid-2-yl)-2,3,6,7-tetrahydro-1H-azapyridine-1-carboxylate (30d) Compound 5j (50 mg, 0.11 mmol), compound 30c (177 mg, 0.55 mmol), K2CO3 (45 mg, 0.33 mmol) were dissolved in 1,4-dioxane (2 mL) and water (0.4 mL), nitrogen replacement was performed, Pd(dppf)Cl2 (7 mg, 0.01 mmol) was added, nitrogen replacement was further performed, the reaction system was heated to 80 ° C, and the reaction was allowed to proceed overnight with stirring. The reaction system was cooled to room temperature, the reaction liquid was poured into water, extracted three times with ethyl acetate, the organic phase was combined and washed with saturated saline, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the crude product was purified by thin-layer silica gel plate to obtain the target compound (20 mg, yield 35%). Fourth step: Preparation of tert-butyl 4-(4-cyano-6-(4-cyano-3-fluorophenyl)-5-(3-fluoro-4-methoxyphenyl)pyrid-2-yl)azacycloheptane-1-carboxylate (30e) Compound 30d (20 mg, 0.04 mmol) was dissolved in ethyl acetate (2 mL), and then Pd / C (2 mg, 10%) was added at room temperature to replace the air in the system with hydrogen, and the system was stirred overnight at room temperature in a hydrogen atmosphere to react. The reaction system was filtered, and the filtrate was concentrated under reduced pressure, and the crude product was purified on a thin-layer silica gel plate to obtain the target compound (10 mg, 50% yield). Fifth step: Preparation of 6-(aza-4-yl)-2-(4-cyano-3-fluorophenyl)-3-(3-fluoro-4-methoxyphenyl)isonicotinonitrile (30) Compound 30e (10 mg, 0.02 mmol) was dissolved in ethyl acetate (1 mL), then hydrochloric acid-ethyl acetate solution (2 mL, 3M in EA) was added, and the reaction system was stirred at room temperature for 1 hour. The reaction system was concentrated under reduced pressure, diluted with water, and the pH value of the system was adjusted to about 8 with saturated sodium bicarbonate solution, and extracted three times with ethyl acetate. The organic phase was combined and washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by thin-layer silica gel plate to obtain the target compound (6 mg, 74% yield). LC-MS (ESI) m / z (M+H) + :445.2 1H NMR (400 MHz, DMSO-d6) δ 8.03-7.98 (m, 1H), 7.88-7.82 (m, 1H), 7.46-7.41 (m, 1H), 7.33-7.28 (m, 1H), 7.24-7.16 (m, 2H), 7.10-7.04 (m, 1H), 3.86 (s, 3H), 3.66-3.45 (m, 1H), 3.22-3.10 (m, 1H), 3.08-2.88 (m, 2H), 2.87-2.74 (m, 1H), 2.05-1.58 (m, 6H).

[0106] Example 31 Preparation of 2-(4-cyano-3-fluorophenyl)-3-(3-fluoro-4-methoxyphenyl)-6-(6-hydroxy-1,4-diazal-1-yl)isonicotinonitrile (31) [ka] First step: Preparation of N,N'-(ethane-1,2-diyl)bis(4-methylbenzenesulfonamide) (31b) Compound 31a (10.0 g, 75.18 mmol) was dissolved in pyridine (200 mL), and then p-toluenesulfonyl chloride (28.0 g, 146.87 mmol) was added, and the system was heated to 100° C. and reacted with stirring for 16 hours. The reaction system was cooled to room temperature and poured into water to precipitate a solid, which was filtered and dried in vacuum to obtain the target compound (18.0 g, 65% yield). Second step: Preparation of 1,4-di-p-toluenesulfonyl-1,4-diaza-6-ol (31c) Compound 31b (5.8 g, 15.74 mmol) was dissolved in acetonitrile (100 mL), potassium hydroxide (2.2 g, 39.21 mmol) was added, the reaction system was heated to 80 ° C., reacted for 0.5 hours, the system was cooled to room temperature, then 1,3-dibromo-2-propanol (4.1 g, 18.82 mmol) was added, the reaction system was heated again to 80 ° C., and reacted for 16 hours. The reaction system was cooled to room temperature, concentrated under reduced pressure, diluted with water, extracted three times with dichloromethane, the organic phase was combined, washed with saturated saline, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to obtain the target compound (5.3 g, yield 79%). Third step: Preparation of 1,4-diaza-6-ol hydrobromide (31d) Compound 31c (2.0 g, 4.71 mmol) was dissolved in aqueous hydrogen bromide (20 mL, 40%) and the reaction was heated to 100° C. for 22 h. The reaction was cooled to room temperature, concentrated under reduced pressure, and then slurried with methyl tert-butyl ether to give the crude product (600 mg, 46% yield). Fourth step: Preparation of 2-(4-cyano-3-fluorophenyl)-3-(3-fluoro-4-methoxyphenyl)-6-(6-hydroxy-1,4-diaz-1-yl)isonicotinonitrile (31) Compound 5j (50 mg, 0.11 mmol) was dissolved in 1,4-dioxane (3 mL), and then compound 31d (214 mg, 0.77 mmol) and Cs2CO3 (358 mg, 1.10 mmol) were added in order, nitrogen replacement was performed, RuPhos-Pd-G3 (9 mg, 0.01 mmol) was added, and nitrogen replacement was further performed. The system was heated to 80 ° C. and stirred for 3 hours to react. The reaction system was cooled to room temperature, the reaction liquid was concentrated under reduced pressure, the system was diluted with water, extracted three times with ethyl acetate, the organic phase was combined and washed with saturated saline, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the crude product was purified by thin-layer silica gel plate to obtain the target compound (5 mg, yield 10%). LC-MS (ESI) m / z (M+H) + :462.2

[0107] Example 32 Preparation of 2-(4-cyano-3-fluorophenyl)-6-(6-fluoro-1,4-diaz-1-yl)-3-(3-fluoro-4-methoxyphenyl)isonicotinonitrile (32-1, 32-2) [ka] First step: Preparation of 6-fluoro-1,4-di-p-toluenesulfonyl-1,4-diazane (32a) Compound 31c (2.5 g, 5.89 mmol) was dissolved in dichloromethane (30 mL), nitrogen substitution was performed, the system was cooled to 0 ° C., then diethylamine sulfur trifluoride (1.9 g, 11.79 mmol) was added, the reaction system was heated to room temperature, and reacted for 16 hours. Next, the reaction was quenched by adding water, extracted three times with dichloromethane, the organic phase was combined, washed with saturated saline, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to obtain the target compound (1.6 g, yield 64%). Second step: Preparation of 6-fluoro-1,4-diazacycloheptane (32b) Compound 32a (1.6 g, 3.75 mmol) was dissolved in aqueous hydrogen bromide (20 mL, 40%) and the reaction was heated to 120° C. for 22 h. The reaction was cooled to room temperature, concentrated under reduced pressure, and then slurried with methyl tert-butyl ether to give the crude product (700 mg, 67% yield). Third step: Preparation of 2-(4-cyano-3-fluorophenyl)-3-(3-fluoro-4-methoxyphenyl)-6-(6-hydroxy-1,4-diaz-1-yl)isonicotinonitrile (32-1, 32-2) Compound 5j (50 mg, 0.11 mmol) was dissolved in 1,4-dioxane (3 mL), and then compound 32b (216 mg, 0.77 mmol) and Cs2CO3 (358 mg, 1.10 mmol) were added in order, nitrogen replacement was performed, RuPhos-Pd-G3 (9 mg, 0.01 mmol) was added, and nitrogen replacement was further performed. The system was heated to 80 ° C. and stirred for 3 hours to react. The reaction system was cooled to room temperature, the reaction liquid was concentrated under reduced pressure, the system was diluted with water, extracted three times with ethyl acetate, the organic phase was combined and washed with saturated saline, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the crude product was purified by thin-layer silica gel plate to obtain the target compounds 32-1 (3 mg, yield 6%) and 32-2 (4 mg, yield 8%). 32-1: LC-MS (ESI) m / z (M+H) + :464.2 1 H NMR (400 MHz, DMSO-d6) δ 7.85-7.78 (m, 1H), 7.56 (s, 1H), 7.43-7.38 (m, 1H), 7.24-7.12 (m, 3H), 7.00-6.94 (m, 1H), 4.53-4.44 (m, 1H), 4.41-4.28 (m, 2H), 4.26-4.18 (m, 1H), 3.85 (s, 3H), 3.03-2.88 (m, 2H), 2.78-2.65 (m, 2H), 2.03-1.95 (m, 1H). 32-2: LC-MS (ESI) m / z (M+H) + :464.2 1 H NMR (400 MHz, DMSO-d6) δ 7.85-7.79 (m, 1H), 7.47 (s, 1H), 7.40 (dd, J = 10.8, 1.2 Hz, 1H), 7.23-7.12 (m, 3H), 6.99-6.93 (m, 1H), 4.20-3.91 (m, 2H), 3.85 (s, 3H), 3.80-3.69 (m, 2H), 3.00-2.75 (m, 4H), 2.03-1.94 (m, 1H).

[0108] Example 33 Preparation of 6-(4-aminopiperid-1-yl)-2-(4-cyano-3-fluorophenyl)-3-(5-fluoro-3-methylbenzo[d]isoxazol-6-yl)isonicotinonitrile (33) [ka] First step: Preparation of 3-bromo-4-fluorophenyl acetate (33b) Compound 33a (2.0 g, 10.47 mmol) was dissolved in dichloromethane (20 mL), and triethylamine (1.6 g, 15.81 mmol) was slowly added to the system under ice bath, followed by slowly adding acetyl chloride (1.2 g, 15.29 mmol), and the reaction system was returned to room temperature and stirred for 1 hour to react. The reaction solution was poured into water, extracted three times with dichloromethane, and the combined organic phase was washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (2.4 g, 98% yield). Second step: Preparation of 1-(4-bromo-5-fluoro-2-hydroxyphenyl)ethan-1-one (33c) Compound 33b (2.4 g, 10.30 mmol) was dissolved in boron trifluoride acetic acid solution (26 mL, 33% BF3), nitrogen was replaced, and the reaction system was heated to 150 ° C. and stirred for 8 hours. The reaction system was cooled to room temperature, and the reaction solution was poured into water to precipitate a solid, which was filtered to obtain 1.6 g of the crude product of the target compound, which was used in the next step without purification. Third step: Preparation of 6-bromo-5-fluoro-3-methylbenzo[d]isoxazole (33d) Compound 33c (1.6 g, 6.87 mmol) was dissolved in methanol (16 mL), then hydroxylamine hydrochloride (963 mg, 13.86 mmol) and sodium acetate (853 mg, 10.40 mmol) were added, the reaction system was heated to 60 ° C., and stirred for 1 hour. The reaction system was cooled to room temperature, the reaction liquid was poured into cold water, a solid was precipitated, filtered, and the filter cake was dried to obtain a brown solid. The obtained solid was dissolved in acetic anhydride (6 mL), the reaction system was heated to 60 ° C., and stirred for 2 hours. The reaction system was cooled to room temperature, the reaction liquid was poured into cold water, and extracted three times with ethyl acetate. The organic phase was combined and washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was dissolved in N,N-dimethylformamide (10 mL), and then K2CO3 (1.9 g, 13.75 mmol) was added, and the reaction system was stirred at room temperature overnight to react. The reaction solution was poured into water, extracted three times with ethyl acetate, and the combined organic phase was washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (693 mg, 29% yield for two steps). Fourth step: Preparation of 5-fluoro-3-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxybenzaldehyde-2-yl)benzo[d]isoxazole (33e) Compound 33d (693 mg, 3.01 mmol), bis(pinacolato)diboron (914 mg, 3.60 mmol), potassium acetate (588 mg, 5.99 mmol) were dissolved in 1,4-dioxane (7 mL), nitrogen substitution was performed, Pd(dppf)Cl2 (66 mg, 0.09 mmol) was added, nitrogen substitution was further performed, the reaction system was heated to 100 ° C, and the reaction was allowed to proceed overnight with stirring. The reaction system was cooled to room temperature, the reaction liquid was poured into water, extracted three times with ethyl acetate, the organic phase was combined and washed with saturated saline, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to obtain the target compound (757 mg, yield 91%). Fifth step: Preparation of tert-butyl (1-(4-cyano-6-(4-cyano-3-fluorophenyl)-5-(5-fluoro-3-methylbenzo[d]isoxazol-6-yl)pyrid-2-yl)piperid-4-yl)carbamate (33f) Compound 16b (150 mg, 0.30 mmol), compound 33e (166 mg, 0.60 mmol), K2CO3 (124 mg, 0.90 mmol) were dissolved in 1,4-dioxane (2 mL) and water (0.2 mL), nitrogen replacement was performed, Pd(dppf)Cl2 (15 mg, 0.02 mmol) was added, nitrogen replacement was further performed, the reaction system was heated to 100 ° C, and the reaction was allowed to proceed overnight with stirring. The reaction system was cooled to room temperature, the reaction liquid was poured into water, extracted three times with ethyl acetate, the organic phase was combined and washed with saturated saline, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the crude product was purified by thin-layer silica gel plate to obtain the target compound (41 mg, yield 24%). Sixth step: Preparation of 6-(4-aminopiperid-1-yl)-2-(4-cyano-3-fluorophenyl)-3-(5-fluoro-3-methylbenzo[d]isoxazol-6-yl)isonicotinonitrile (33) Compound 33f (41 mg, 0.07 mmol) was dissolved in ethyl acetate (1 mL), then ethyl hydrochloride solution (1 mL, 3M in EA) was added, and the reaction system was stirred at room temperature for 1 hour. The reaction system was concentrated under reduced pressure, diluted with water, and the pH value of the system was adjusted to about 8 with saturated sodium bicarbonate solution, and extracted three times with ethyl acetate. The organic phase was combined and washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by thin-layer silica gel plate to obtain the target compound (12 mg, yellow solid, 35% yield). LC-MS (ESI) m / z (M+H) + :471.2 1H NMR (400 MHz, DMSO-d6) δ 7.90-7.87 (m, 1H), 7.82-7.74 (m, 2H), 7.66 (s, 1H), 7.47-7.42 (m, 1H), 7.16 (dd, J = 8.0, 1.6 Hz, 1H), 4.42-4.26 (m, 2H), 3.14-3.03 (m, 2H), 2.92-2.82(m, 1H), 2.55 (s, 3H), 1.84-1.74 (m, 2H), 1.26-1.16 (m, 2H).

[0109] Example 34 Preparation of 6-(4-aminopiperid-1-yl)-2-(4-cyano-3-fluorophenyl)-3-(3,3-difluoro-1-methyl-2-oxindole-5-yl)isonicotinonitrile (34) [ka] First step: Preparation of 5-bromo-3,3-difluoroindol-2-one (34b) Compound 34a (2.0 g, 8.85 mmol) was dissolved in dichloromethane (30 mL), nitrogen substitution was performed, and the system was cooled to 0°C. Then, diethylamine sulfur trifluoride (4.3 g, 26.68 mmol) was added, and the reaction system was placed at room temperature and reacted for 16 hours. Water was added to the system to quench the reaction, and the system was extracted three times with dichloromethane. The organic phases were combined and washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (1.8 g, yield 82%). Second step: Preparation of 5-bromo-3,3-difluoro-1-methylindol-2-one (34c) Compound 34b (1.0 g, 4.03 mmol) was dissolved in acetonitrile (15 mL), then methyl iodide (1.1 g, 7.75 mmol) and Cs2CO3 (2.0 g, 6.14 mmol) were added, and the reaction system was placed at room temperature and stirred for 16 hours. The reaction solution was concentrated under reduced pressure, diluted with water, extracted three times with ethyl acetate, and the combined organic phase was washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (900 mg, 85% yield). Third step: Preparation of 3,3-difluoro-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxybenzaldehyde-2-yl)indol-2-one (34d) Compound 34c (500 mg, 1.91 mmol), bis(pinacolato)diboron (1.5 g, 5.91 mmol), potassium acetate (562 mg, 5.73 mmol) were dissolved in 1,4-dioxane (5 mL), nitrogen replacement was performed, Pd(dppf)Cl2 139 mg, 0.19 mmol) was added, nitrogen replacement was further performed, the reaction system was heated to 90 ° C, and the reaction was allowed to proceed overnight with stirring. The reaction system was cooled to room temperature, the reaction liquid was poured into water, extracted three times with ethyl acetate, the organic phase was combined and washed with saturated saline, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to obtain the target compound (420 mg, yield 71%). Fourth step: Preparation of tert-butyl (1-(4-cyano-6-(4-cyano-3-fluorophenyl)-5-(3,3-difluoro-1-methyl-2-oxoindol-5-yl)pyrid-2-yl)piperid-4-yl)carbamate (34e) Compound 16b (80 mg, 0.16 mmol), compound 34d (247 mg, 0.80 mmol), K2CO3 (66 mg, 0.48 mmol) were dissolved in 1,4-dioxane (2 mL) and water (0.4 mL), nitrogen replacement was performed, Pd(dppf)Cl2 (15 mg, 0.02 mmol) was added, nitrogen replacement was further performed, the reaction system was heated to 80 ° C, and the reaction was allowed to proceed overnight with stirring. The reaction system was cooled to room temperature, the reaction liquid was poured into water, extracted three times with ethyl acetate, the organic phase was combined and washed with saturated saline, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the crude product was purified by thin-layer silica gel plate to obtain the target compound (30 mg, yield 31%). Fifth step: Preparation of 6-(4-aminopiperid-1-yl)-2-(4-cyano-3-fluorophenyl)-3-(3,3-difluoro-1-methyl-2-oxindole-5-yl)isonicotinonitrile (34) Compound 34e (30 mg, 0.05 mmol) was dissolved in ethyl acetate (1 mL), then hydrochloric acid-ethyl acetate solution (2 mL, 3M in EA) was added, and the reaction system was stirred at room temperature for 1 hour. The reaction system was concentrated under reduced pressure, diluted with water, and the pH value of the system was adjusted to about 8 with saturated sodium bicarbonate solution, and extracted three times with ethyl acetate. The organic phase was combined and washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by thin-layer silica gel plate to obtain the target compound (22 mg, 88% yield). LC-MS (ESI) m / z (M+H) + :503.2 1 H NMR (400 MHz, DMSO-d6) δ 7.85-7.78 (m, 1H), 7.63-7.54 (m, 2H), 7.51-7.45 (m, 1H), 7.44-7.38 (m, 1H), 7.26-7.20 (m, 1H), 7.19-7.13 (m, 1H), 4.40-4.26 (m, 2H), 3.18 (s, 3H), 3.11-2.98 (m, 2H), 2.95-2.82(m, 1H), 1.86-1.73 (m, 2H), 1.27-1.15 (m, 2H).

[0110] Example 35 Preparation of 6-(4-aminopiperid-1-yl)-2-(4-cyano-3-fluorophenyl)-3-(4-(1,1-difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)isonicotinonitrile (35) [ka] First step: Preparation of ethyl 2-(4-bromo-3-fluorophenyl)-2,2-difluoroacetate (35b) Compound 35a (1.3 g, 4.32 mmol) was dissolved in dimethyl sulfoxide (20 mL), nitrogen substitution was performed, copper powder (707 mg, 11.13 mmol) was added, and the mixture was stirred at room temperature for 1 hour. Then, 2-bromo-2,2-difluoroethyl acetate (2.3 g, 11.33 mmol) was added, and the reaction system was heated to 80 ° C. and stirred for 2 hours to react. The reaction system was cooled to room temperature, filtered, the filtrate was poured into water, extracted three times with ethyl acetate, the organic phase was combined, washed with saturated saline, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to obtain the target compound (719 mg, yield 56%). Second step: Preparation of 1-(4-bromo-3-fluorophenyl)-1,1-difluoro-2-methylpropan-2-ol (35c) Compound 35b (719 mg, 2.42 mmol) was dissolved in dry tetrahydrofuran (20 mL), and then methylmagnesium bromide reagent (4.1 mL, 3 M in THF) was slowly added dropwise in an ice-water bath. After the addition was completed, the reaction system was slowly returned to room temperature and stirred overnight to react. The reaction system was cooled to 0°C, and an appropriate amount of water was slowly added to quench the reaction, filtered, and the filtrate was extracted three times with ethyl acetate. The organic phase was combined and washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (577 mg, 84% yield). Third step: Preparation of 1,1-difluoro-1-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxybenzaldehyde-2-yl)phenyl)-2-methylpropan-2-ol (35d) Compound 35c (577 mg, 2.04 mmol), bis(pinacolato)diboron (1.0 g, 3.94 mmol), potassium acetate (600 mg, 6.12 mmol) were dissolved in 1,4-dioxane (20 mL), nitrogen substitution was performed, Pd(dppf)Cl2 (146 mg, 0.20 mmol) was added, nitrogen substitution was further performed, the reaction system was heated to 100 ° C, and the reaction was allowed to proceed with stirring for 24 hours. The reaction system was cooled to room temperature, the reaction liquid was poured into water, extracted three times with ethyl acetate, the organic phase was combined and washed with saturated saline, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to obtain the target compound (364 mg, yield 54%). Fourth step: Preparation of tert-butyl (1-(4-cyano-6-(4-cyano-3-fluorophenyl)-5-(4-(1,1-difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)pyrid-2-yl)piperid-4-yl)carbamate (35e) Compound 16b (100 mg, 0.20 mmol), compound 35d (132 mg, 0.40 mmol), K2CO3 (83 mg, 0.60 mmol) were dissolved in 1,4-dioxane (2 mL) and water (0.2 mL), nitrogen replacement was performed, Pd(dppf)Cl2 (15 mg, 0.02 mmol) was added, nitrogen replacement was further performed, the reaction system was heated to 100 ° C, and the reaction was allowed to proceed overnight with stirring. The reaction system was cooled to room temperature, the reaction liquid was poured into water, extracted three times with ethyl acetate, the organic phase was combined and washed with saturated saline, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the crude product was purified by thin-layer silica gel plate to obtain the target compound (57 mg, yield 46%). Fifth step: Preparation of 6-(4-aminopiperid-1-yl)-2-(4-cyano-3-fluorophenyl)-3-(4-(1,1-difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)isonicotinonitrile (35) Compound 35e (57 mg, 0.09 mmol) was dissolved in ethyl acetate (1 mL), then hydrochloric acid-ethyl acetate solution (1 mL, 3M in EA) was added, and the reaction system was stirred at room temperature for 1 hour. The reaction system was concentrated under reduced pressure, diluted with water, and the pH value of the system was adjusted to about 8 with saturated sodium bicarbonate solution, and extracted three times with ethyl acetate. The organic phase was combined and washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by thin-layer silica gel plate to obtain the target compound (37 mg, yellow solid, 77% yield). LC-MS (ESI) m / z (M+H) + :524.2 1 H NMR (400 MHz, DMSO-d6) δ 7.84-7.78 (m, 1H), 7.64 (s, 1H), 7.50-7.43 (m, 1H), 7.39-7.28 (m, 3H), 7.24-7.19 (m, 1H), 5.49 (s, 1H), 4.40-4.28 (m, 2H), 3.14-3.03 (m, 2H), 2.91-2.82(m, 1H), 1.85-1.75 (m, 2H), 1.28-1.18 (m, 2H), 1.15 (s, 6H).

[0111] Example 36 Preparation of 6-(4-aminopiperid-1-yl)-2-(4-cyano-3-fluorophenyl)-3-(3,6-difluoro-1-(2-hydroxy-2-methylpropyl)-1H-indazol-5-yl)isonicotinonitrile (36) [ka] First step: Preparation of 5-bromo-3,6-difluoro-1H-indazole (36a) Compound 9a (500 mg, 2.33 mmol) was dissolved in acetonitrile (7.5 mL), and glacial acetic acid (0.75 mL) and 1-chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octane bis(tetrafluoroborate) (1.6 g, 4.66 mmol) were added in that order. The reaction system was heated to 80 ° C. and stirred for 5 hours to react. The reaction system was cooled to room temperature, water was added to the system to quench the reaction, and the mixture was extracted three times with ethyl acetate. The organic phases were combined and washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (300 mg, yield 55%). Second step: Preparation of 1-(5-bromo-3,6-difluoro-1H-indazol-1-yl)-2-methylpropan-2-ol (36b) Compound 36a (300 mg, 1.29 mmol) was dissolved in acetonitrile (10 mL), and then Cs2CO3 (630 mg, 1.94 mmol) and 1,1-dimethylethylene oxide (185 mg, 2.57 mmol) were added in that order, and the reaction system was heated to 80°C and stirred for 16 hours. The reaction system was cooled to room temperature, and the reaction solution was poured into water and extracted three times with ethyl acetate. The organic phases were combined and washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (150 mg, 38% yield). Third step: Preparation of 1-(3,6-difluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxybenzaldehyde-2-yl)-1H-indazol-1-yl)-2-methylpropan-2-ol (36c) Compound 36b (150 mg, 0.49 mmol), bis(pinacolato)diboron (373 mg, 1.47 mmol), potassium acetate (144 mg, 1.47 mmol) were dissolved in 1,4-dioxane (5 mL), nitrogen replacement was performed, Pd(dppf)Cl2 (37 mg, 0.05 mmol) was added, nitrogen replacement was further performed, the reaction system was heated to 90 ° C, and the reaction was allowed to proceed overnight with stirring. The reaction system was cooled to room temperature, the reaction solution was poured into water, extracted three times with ethyl acetate, the organic phase was combined and washed with saturated saline, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to obtain the target compound (76 mg, yield 44%). Fourth step: Preparation of tert-butyl (1-(4-cyano-6-(4-cyano-3-fluorophenyl)-5-(3,6-difluoro-1-(2-hydroxy-2-methylpropyl)-1H-indazol-5-yl)pyrid-2-yl)piperid-4-yl)carbamate (36d) Compound 16b (107 mg, 0.21 mmol), compound 36c (74 mg, 0.21 mmol), K2CO3 (87 mg, 0.63 mmol) were dissolved in 1,4-dioxane (2 mL) and water (0.4 mL), nitrogen replacement was performed, Pd(dppf)Cl2 (15 mg, 0.02 mmol) was added, nitrogen replacement was further performed, the reaction system was heated to 80 ° C, and the reaction was allowed to proceed overnight with stirring. The reaction system was cooled to room temperature, the reaction liquid was poured into water, extracted three times with ethyl acetate, the organic phase was combined and washed with saturated saline, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the crude product was purified by thin-layer silica gel plate to obtain the target compound (35 mg, yield 26%). Fifth step: Preparation of 6-(4-aminopiperid-1-yl)-2-(4-cyano-3-fluorophenyl)-3-(3,6-difluoro-1-(2-hydroxy-2-methylpropyl)-1H-indazol-5-yl)isonicotinonitrile (36) Compound 36d (35 mg, 0.05 mmol) was dissolved in ethyl acetate (1 mL), then hydrochloric acid-ethyl acetate solution (2 mL, 3M in EA) was added, and the reaction system was stirred at room temperature for 1 hour. The reaction system was concentrated under reduced pressure, diluted with water, and the pH value of the system was adjusted to about 8 with saturated sodium bicarbonate solution, and extracted three times with ethyl acetate. The organic phase was combined and washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by thin-layer silica gel plate to obtain the target compound (23 mg, 78% yield). LC-MS (ESI) m / z (M+H) + :546.3 1 H NMR (400 MHz, DMSO-d6) δ 7.86-7.81 (m, 1H), 7.80-7.74 (m, 1H), 7.62 (s, 1H),7.60-7.54 (m, 1H), 7.44-7.38 (m, 1H), 7.19 (dd, J = 8.0, 1.2 Hz, 1H), 4.67 (brs, 1H), 4.40-4.28 (m, 2H), 4.20-4.07 (m, 2H), 3.13-3.01 (m, 2H), 2.94-2.82(m, 1H), 1.86-1.75 (m, 2H), 1.30-1.18 (m, 2H), 1.14 (s, 3H), 1.10 (s, 3H).

[0112] Biological evaluation Compounds 1 to 36 used in the following Test Examples were produced by the synthesis methods of Examples 1 to 36, respectively.

[0113] Test Example 1: Testing LSD1 enzyme activity 1. Purpose of the study In this study, homogeneous time-resolved fluorescence technology (HTRF) was used to detect the inhibitory activity of compounds against LSD1 enzyme in a two-step method. In the first step, LSD1 enzyme, various concentrations of compounds, and biotin-labeled methylated peptide substrate (H3(1-21)K4 me1-biotin) were incubated at room temperature for a certain time, and in the second step, the antibody for demethylated peptide substrate (Anti-H3K4 me0-Eu(K)) and streptomycin labeled with XL-665 (SA-XL665) detection reagent were added and incubated at room temperature for a certain time. The signal value Intensity (665nM) / Intensity (615nM) was read using EnVision to measure the content of demethylated peptide substrate and evaluate the effect of the test compound on LSD1 enzyme activity, and the inhibition rate was used to determine the IC of the test compound against LSD1 enzyme. 50 values ​​were calculated. 2. Test materials 2.1. Compounds to be tested Positive drug: CC-90011, Chengdu Haibowei Pharmaceutical Co., Ltd., batch number HBW-013-177-77 Test drugs: Compounds 1 to 36 2.2. Test Reagents and Apparatus LSD1, Active Motif DMSO, Sigma OptiPlate-384, PerkinElmer Sonic Pipette, Labcyte Microplate reader (EnVision), PerkinElmer Centrifuge, Eppendorf 3. Test Method 3.1. Preparation of Compounds Preparation of 10 mM stock solution of compound: Compound powder was dissolved in 100% DMSO to prepare 10 mM stock solutions of each compound. 3.2. Enzyme reaction process (1) A 1x buffer solution was prepared according to the LSD1 enzyme kit provided by Active Motif (product number: 31432). (2) Preparation of compound solutions: IC of compounds 50The final concentration tested for was 500nM and diluted 5-fold to 6 concentrations, with single / duplicate wells for detection per concentration. Solutions were diluted in the 384-well Source plate to a final concentration of 1000x and 10nL was transferred to the 384-well reaction plate for testing using the Echo550. 10nL of 100% DMSO was transferred to each of the Min and Max wells. (3) A 2x enzyme solution was prepared using the 1x reaction solution. (4) A 2x substrate mixture solution was prepared using the 1x reaction solution. (5) 5 μL of 2× enzyme solution was added to each well, and 5 μL of 1× reaction solution was added to the Min well. The mixture was centrifuged at 1,000 rpm for 1 minute and incubated at room temperature for 15 minutes. (6) 5 μL of 2× substrate mixture was added to each well of the reaction plate to initiate the reaction, followed by centrifugation at 1000 rpm for 1 minute and incubation at room temperature for 60 minutes. (7) 10 μL of detection solution was added to each well, centrifuged at 1,000 rpm for 1 minute, and incubated at room temperature for 60 minutes. (8) The signal value Intensity(665nM) / Intensity(615nM) was read using EnVision. Data Analysis The inhibition rate was calculated using the maximum, minimum and signal values ​​(maximum: fluorescence intensity of 2x enzyme solution 5μL + 2x substrate mixed solution 5μL + 100% DMSO 10nL + detection solution 10μL; minimum: fluorescence intensity of 1x reaction solution 5μL + 2x substrate mixed solution 5μL + 100% DMSO 10nL + detection solution 10μL; signal value: fluorescence intensity of 2x enzyme solution 5μL + 2x substrate mixed solution 5μL + diluted test compound 10nL + detection solution 10μL). The calculation formula is as follows:

number

[0114] Test Example 2: Kasumi-1 cell proliferation inhibition test 1. Test Principle Studies have confirmed that LSD1 plays an important role in the development of various types of cancer, including small cell lung cancer (SCLC) and acute myeloid leukemia (AML). Therefore, we used a human acute myeloid leukemia (Kasumi-1) cell line and measured the intracellular ATP content at various drug concentrations using the Celltiter GLO assay kit. The luminescence intensity reflected the cell activity, and the inhibition rate was used to determine the IC of various compounds against Kasumi-1 cells. 50 The values ​​were calculated. To evaluate the antitumor efficacy of the test compounds at the cellular level, the inhibitory effect of the compounds of the present application on the proliferation of Kasumi-1 cells was studied. 2. Test materials 2.1. Compounds Positive drug: CC-90011, Chengdu Haibowei Pharmaceutical Co., Ltd., batch number HBW-013-177-77 Test drugs: Compounds 4, 16, 18, and 21 2.2. Test Reagents and Apparatus RPMI 1640, Gibico Penicillin-Streptomycin: Penicillin-Streptomycin, Gibico Fetal Bovine Serum (FBS), Gibico Phosphate Buffered Saline (PBS), Gibico Dimethyl sulfoxide: DMSO, Sigma CelltiterGlo assay Kit (CTG), Promega White 384-well cell culture plates, PerkinElmer Plate shaker, QILINBE Centrifuge, Eppendorf CO2 incubator, Thermo Scientific Microscope, OLYMPUS Automated cell counter, Gibco 384-well Source Plate, Echo Qualified 384-Well Polypropylene, LABCYTE Echo, LABCYTE Multi-function microplate reader (Envision), PerkinElmer 2.3. Test Cells Kasumi-1 cells, purchased from ATCC 3. Test Method 3.1. Test steps On day 1, the cells were seeded into a 384-well cell culture plate and cultured overnight in a 37° C., 5% CO 2 cell culture incubator. On day 0, the test compound was prepared in 10 mM stock solution with DMSO, diluted 3-fold from 1 μM to give 10 concentrations, and two double wells were set up. The diluted compound was added to a 384-well cell culture plate and cultured for 7 days in a 37°C, 5% CO2 cell culture incubator. The DMSO concentration in the cell culture system was 0.1 vol%. On the 7th day, Celltiter GLO was added to the 384-well cell culture plate according to a volume ratio of culture system:Celltiter GLO=1:1, shaken on a plate shaker in the dark for 3 min, then left at room temperature in the dark for 30 min, and the plate was read using a multi-function microplate reader. Data Analysis The inhibition rate was calculated based on the luminescence intensity of the DMSO group (DMSO added), the test group (test compound or positive control solution added), and the blank group (untreated cells). The calculation formula is as follows:

number

[0115] Test Example 3: NCI-H1417 cell proliferation inhibition test 1. Test Principle Studies have confirmed that LSD1 plays an important role in the development of various types of cancer, including small cell lung cancer (SCLC) and acute myeloid leukemia (AML). Therefore, we used a human small cell lung cancer cell line (NCI-H1417) and measured the intracellular ATP content at various drug concentrations using the Celltiter GLO assay kit. The luminescence intensity reflected the cell activity, and the inhibition rate was used to determine the IC of various compounds against NCI-H1417 cells. 50 The values ​​were calculated. To evaluate the antitumor efficacy of the test compounds at the cellular level, the inhibitory effect of the compounds of the present application on the proliferation of NCI-H1417 cells was studied. 2. Test materials 2.1. Compounds Positive drug: CC-90011, Chengdu Haibowei Pharmaceutical Co., Ltd., batch number HBW-013-177-77 Test drugs: Compounds 4, 16, 18, and 21 2.2. Test Reagents and Apparatus RPMI 1640, Gibico Penicillin-Streptomycin: Penicillin-Streptomycin, Gibico Fetal Bovine Serum (FBS), Gibico Phosphate Buffered Saline (PBS), Gibico Dimethyl sulfoxide: DMSO, Sigma CelltiterGlo assay Kit (CTG), Promega White 384-well cell culture plates, PerkinElmer Plate shaker, QILINBE Centrifuge, Eppendorf CO2 incubator, Thermo Scientific Microscope, OLYMPUS Automated cell counter, Gibco 384-well Source Plate, Echo Qualified 384-Well Polypropylene, LABCYTE Echo, LABCYTE Multi-function microplate reader (Envision), PerkinElmer 2.3. Test Cells NCI-H1417 cells, purchased from ATCC 3. Test Method 3.1. Test steps On day 1, cells were seeded into 384-well cell culture plates and cultured overnight in a 37°C, 5% CO2 cell culture incubator. On day 0, the test compound was prepared in 10 mM stock solution with DMSO, and diluted 3-fold from 1 μM to give 10 concentrations, and two double wells were set up. The diluted compound was added to a 384-well cell culture plate and cultured for 7 days in a 37°C, 5% CO2 cell culture incubator. The DMSO concentration in the cell culture system was 0.1%. On the 7th day, Celltiter GLO was added to the 384-well cell culture plate according to a volume ratio of culture system:Celltiter GLO=1:1, shaken on a plate shaker in the dark for 3 min, then left at room temperature in the dark for 30 min, and the plate was read using a multi-function microplate reader. Data Analysis The inhibition rate was calculated based on the luminescence intensity of the DMSO group (DMSO added), the test group (test compound or positive control solution added), and the blank group (untreated cells). The calculation formula is as follows:

number

[0116] Test Example 4: Study on pharmacokinetics after oral administration to rats 1. Test Principle SD rats were used as test animals, and the plasma drug concentration of the compound of the present application was measured at each time point after oral administration of the compound of the present application by clear cassette administration using LC-MS / MS method.The pharmacokinetic parameters of the compound of the present application in rats were obtained, and its pharmacokinetic properties were studied. 2. Test materials 2.1. Compounds Positive drug: CC-90011, Chengdu Haibowei Pharmaceutical Co., Ltd., batch number HBW-013-177-77 Test drugs: Compounds 1, 4, 14-16, 18, 20, 21, and 36. 2.2. Test equipment Shimadzu LC-30A AB API4500 tandem mass spectrometer, vacuum blood collection tubes, blood collection needles, filter paper, syringes, etc. 2.3. Test animals SD rats, male, weighing 180-220g, 3 per group. After purchase, the animals were kept in an animal room, and after an adaptation period of at least 3 days, they were quarantined before being used in the study. 3. Test Method 3.1. Grouping: The rats were randomly assigned to groups according to Table 4. After grouping, there was no statistical difference in the body weight of the SD rats among the groups. [Table 4] 3.2. Blood sample collection and measurement According to Table 4, the rats in each group were forced to orally administer the corresponding test drug or positive drug. Before administration, and 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, and 24 h after administration, a certain volume of blood was collected through the orbit, placed into EDTA-K2 anticoagulant tubes, and centrifuged at 8000 rpm for 1 min. The plasma was separated into centrifuge tubes and frozen in a refrigerator at -20°C. 3.3.Analysis method Plasma stored at -20°C was removed at each time point, acetonitrile was added to it, vortexed at 1500 rpm for 2 min, centrifuged for 15 min (3500 r / min), and a fixed volume of the supernatant was collected for LC-MS / MS analysis. 4. Calculation of Pharmacokinetic Parameters Noncompartmental model fitting was performed for the pharmacokinetic behavior of the test compounds, and the main pharmacokinetic parameters (T 1 / 2 , T max , C max , AUC last etc.) were calculated. 5. Test Results [Table 5] As can be seen from the test results in Table 5, compared with the positive group (CC-90011), the groups administered with Compound 1, Compound 4, Compounds 14-16, Compound 18, Compounds 20-21 and Compound 36 are superior to CC-90011 in terms of plasma exposure, etc., indicating that the pharmacokinetic properties of the compounds prepared in Examples 1, 4, 14, 15, 16, 18, 20, 21 and 36 of the present application are significantly improved compared to CC-90011. Therefore, the compounds of the present application can exhibit good pharmacokinetic properties.

[0117] Test Example 5: Pharmacokinetics study in rats after oral and intravenous administration 1. Test Principle SD rats are used as test animals, and the plasma drug concentration of the compound of the present application is measured at each time point after oral and intravenous administration by LC-MS / MS method.The pharmacokinetic parameters and bioavailability of the compound of the present application in rats are obtained, and its pharmacokinetic properties are studied. 2. Test materials 2.1. Compounds Positive drug: CC-90011, Chengdu Haibowei Pharmaceutical Co., Ltd., batch number HBW-013-177-77 Test drug: Compound 16 2.2. Test equipment Shimadzu LC-30A AB API4500 tandem mass spectrometer, vacuum blood collection tubes, blood collection needles, filter paper, syringes, etc. 2.3.Experimental animals SD rats, male, weighing 180-220g, 3 per group. After purchase, the animals were kept in an animal room, and after an adaptation period of at least 3 days and quarantined, they were used in the study. 3. Test Method 3.1. Grouping: The rats were randomly grouped according to Table 6. After grouping, there was no statistical difference in the body weight of the SD rats among the groups. 3.2. Solvent: po: 0.5% sodium methylcellulose aqueous solution iv:5% DMSO+10% Solutol+85% Saline [Table 6] 3.2. Blood sample collection and measurement According to Table 6, the rats in each group were forced to orally administer the corresponding test drug or positive drug. Before administration, and 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, 10 h, and 24 h after administration, a certain volume of blood was collected through the orbit, placed into EDTA-K2 anticoagulant tubes, and centrifuged at 8000 rpm for 1 min. The plasma was separated into centrifuge tubes and frozen in a refrigerator at -20°C. 3.3.Analysis method Plasma stored at -20°C was removed at each time point, acetonitrile was added to it, vortexed at 1500 rpm for 2 min, centrifuged for 15 min (3500 r / min), and a fixed volume of the supernatant was collected for LC-MS / MS analysis. 4. Calculation of Pharmacokinetic Parameters Noncompartmental model fitting was performed for the pharmacokinetic behavior of the test compounds, and the main pharmacokinetic parameters (T 1 / 2 , T max , C max , AUC last etc.) were calculated. 5. Test Results [Table 7] From the test results in Table 7, it can be seen that when compound 16 is orally and intravenously administered at the same dose, it is superior to CC-90011 in terms of plasma exposure, maximum blood concentration, bioavailability, etc. The compound prepared in Example 16 of the present application shows significantly improved pharmacokinetic properties compared to CC-90011.

[0118] Test Example 6: Study on pharmacokinetics when administered orally to mice 1. Test Principle Balb / c mice were used as test animals, and the plasma drug concentrations of the compounds of the present application were measured at various time points in mice administered with the compounds under various solvent conditions using LC-MS / MS. The pharmacokinetic parameters of the compounds of the present application in mice under various solvent conditions were obtained, and their pharmacokinetic properties were studied. 2. Test materials 2.1. Compounds Positive drug: CC-90011, Chengdu Haibowei Pharmaceutical Co., Ltd., batch number HBW-013-177-77 Test drug: Compound 16 2.2. Test equipment Shimadzu LC-30A AB API4500 tandem mass spectrometer, vacuum blood collection tubes, blood collection needles, filter paper, syringes, etc. 2.3.Experimental animals Balb / c mice, male, weighing 18-22 g, 6 per group. After purchase, the animals were kept in an animal room, and after an adaptation period of at least 3 days and quarantined, they were used in the study. 3. Test Method 3.1. Grouping: Mice were randomly grouped according to Table 8. After grouping, there was no statistical difference in the body weight of Balb / c mice among the groups. [Table 8] 3.2. Blood sample collection and measurement According to Table 8, the rats in each group were forced to orally administer the corresponding test drug or positive drug. Before administration, and 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, 10 h, and 24 h after administration, a certain volume of blood was collected through the orbit, placed into an EDTA-K2 anticoagulant tube, and centrifuged at 8000 rpm for 1 min. The plasma was separated into a centrifuge tube and frozen in a refrigerator at -20°C. 3.3.Analysis method Plasma stored at -20°C was removed at each time point, acetonitrile was added to it, vortexed at 1500 rpm for 2 min, centrifuged for 15 min (3500 r / min), and a fixed volume of the supernatant was collected for LC-MS / MS analysis. 4. Calculation of Pharmacokinetic Parameters Noncompartmental model fitting was performed for the pharmacokinetic behavior of the test compounds, and the main pharmacokinetic parameters (T 1 / 2 , T max , C max , AUC last etc.) were calculated. 5. Test Results [Table 9] From the test results in Table 9, it was found that, compared with the positive group (CC-90011), compound 16 is superior to CC-90011 in terms of plasma exposure and maximum blood concentration under various solvent conditions. The compound prepared in Example 16 of the present application has significantly improved pharmacokinetic properties compared with CC-90011, indicating that it has pharmacokinetic advantages under various solvent conditions.

[0119] Test Example 7: Experiments to test liver microsome stability 1. Test Principle In the liver microsome inhydro incubation method, liver microsomes were used to carry out metabolic reactions in a simulated physiological environmental condition in hydro, assisted by an NADPH regeneration system. After a certain period of reaction, the contents of prototype drugs and metabolites in the incubation solution were measured and preliminarily analyzed using LC-MS / MS. Studying the liver microsome stability of drugs in different species is important for understanding the transformation of drugs in vivo. 2. Test materials 2.1. Liver microsomes from various species: rat, mouse, human, dog and monkey 2.2. Compounds Positive drug: CC-90011, Chengdu Haibowei Pharmaceutical Co., Ltd., batch number HBW-013-177-77 Test drugs: Compounds 16 and 36 Positive testing reference compounds: testosterone, diclofenac, propafenone 2.3. Test equipment Shimadzu LC-30A AB API4500 tandem mass spectrometer, electric thermostatic shaker, multi-tube vortex oscillator, and various range-compatible pipettes 3. Test Method According to the instructions of the Phase I metabolic stability kit, the liver microsome incubation system was prepared, and the PBS buffer, liver microsomes, NADPH regenerating system A solution, NADPH regenerating system B solution mixture, and the test substance were added in order and incubated at 37°C. Each sample was run in parallel three times, and the sample without NADPH generating system was used as a negative control. The reaction was stopped after 0, 5, 15, 30, 45, and 60 minutes by adding the same volume of pre-cooled acetonitrile, and the content of the prototype drug in the incubation solution was measured using LC-MS / MS. 4. Test Results [Table 10] The above experimental results show that compounds 16 and 36 have high metabolic stability in human, rat, mouse, dog and monkey liver microsomes. Therefore, the compounds of the present application can show good druggability.

[0120] Test Example 8: Inhydro hERG inhibitory activity measurement experiment 1. Test Principle The rapidly activated human delayed rectifier outward potassium channel current is mainly mediated by the hERG ion channel and is involved in the repolarization of human cardiomyocytes. Blockade of this current with drugs is a major cause of clinical long QT syndrome, as well as acute cardiac arrhythmias and sudden death. Using the whole-cell patch clamp technique, we detected the blocking effect of compounds on the hERG channel in HEK293 cells stably expressing the hERG channel, and determined the half inhibitory concentration (IC) of the compounds. 50 As part of the cardiac safety evaluation, a preliminary evaluation of cardiotoxicity safety was performed in the in-hydro screening. 2. Test materials 2.1. Test cell lines HEK293 cells stably expressing the hERG ion channel 2.2. Compounds Positive drug: CC-90011, Chengdu Haibowei Pharmaceutical Co., Ltd., batch number HBW-013-177-77 Test drug: Compound 16 2.3. Test equipment Patch clamp instrument: PC-505B Microcontroller: MP-225 Micropipette puller: PC-10 (Narishige, Japan) 3. Test Method The cells were transferred to a perfusion tank and perfused with extracellular solution prepared with 137 mM NaCl, 4 mM KCl, 1.8 mM CaCl2, 1 mM MgCl2, 10 mM HEPES, and 10 mM glucose, adjusted to pH 7.4 with NaOH. Electrodes were pulled with a PC-10 (Narishige, Japan). Recordings were made by whole-cell patch clamp, and noise was filtered at one-fifth the sampling frequency. The cells were clamped at -80 mV, then depolarized with a square wave to 40 mV for 4 s and hyperpolarized with a square wave to -40 mV for 2 s to obtain hERG tail currents. This process was repeated every 20 s. The hERG tail current is the pure hERG current. The maximum current induced by the second square wave was detected, and once the maximum current stabilized, the test compound was perfused, and once the response stabilized, the strength of the block was calculated. 4. Test Results [Table 11] The above experimental results show that the IC of compound 16 for hERG inhibition is higher than that of the positive drug (CC-90011). 50 Values ​​greater than 10 μM indicate that the compounds of the present application pose a lower risk of cardiotoxicity than the positive control.

[0121] Test Example 9: In vivo efficacy test in Kasumi-1 cell subcutaneous xenograft tumor model 1. Test Method 1.1 Cell culture RPMI 1640 medium containing 20% ​​fetal bovine serum (FBS), 37℃, 5% CO2 1.2 Compound Solvent: 0.5% methylcellulose in water Test drugs: Compounds 16 and 36 1.3 Experimental process CB17 SCID mice, female, 6-8 weeks old, weighing approximately 18-22 g. Inject 0.1 mL (1 × 10 7 Kasumi-1 cells (cells + Matrigel) were subcutaneously inoculated. When the average tumor volume reached 100-200 cubic millimeters, the mice were divided into groups and administered drugs. The dosage and administration method are shown in the table below (Table 12). The tumor volume was measured twice a week, and the mouse weight, tumor length and width were recorded at each measurement. Tumor volume = length x width x width / 2 mm 3 When the average tumor volume of the vehicle group grew to more than 3000 cubic millimeters, administration was terminated, the mice of each group were sacrificed, the tumor masses were dissected, the tumor weight of each mouse was measured, the tumor volume was measured, and the difference in the average tumor volume between the test compound group and the vehicle group was compared. The tumor inhibition effect of the compound was evaluated by TGI (%), which can reflect the tumor growth inhibition rate. Calculation of TGI(%): TGI(%)=[1-(mean tumor volume at administration of compound-mean tumor volume at start of compound) / (mean tumor volume at administration of vehicle group-mean tumor volume at start of vehicle group)]×100% The changes in tumor volume and tumor weight in each group of mice are shown in FIGS. 2. Test Results [Table 12] 3. Conclusion of the study The above test results show that compounds 16 and 36 of the present application exhibit good in vivo efficacy in a human acute myeloid leukemia Kasumi-1 cell subcutaneous xenograft tumor model, have significant tumor inhibitory activity (TGI>60%), and the test animals show good tolerance to compounds 16 and 36, and the body weight of the mice does not decrease after administration (see FIG. 3). Therefore, the compounds of the present application can exhibit good antitumor effects in vivo.

[0122] Test Example 10: In vivo efficacy test in HL-60 cell subcutaneous xenograft tumor model 1. Test Method 1.1 Cell culture DMEM medium containing 10% fetal bovine serum (FBS), 37℃, 5% CO2 1.2 Compound Positive drug: CC-90011, Chengdu Haibowei Pharmaceutical Co., Ltd., batch number HBW-013-203-33 Solvent: 0.5% methylcellulose in water Test drug: Compound 16 1.3 Experimental process Balb / Cnu mice, female, 6–8 weeks old, weighing approximately 18–22 g. 0.1 mL (1 × 10 7 HL-60 cells (cells + Matrigel) were subcutaneously inoculated. When the average tumor volume reached 100-200 cubic millimeters, the mice were divided into groups and administered drugs. The dosage and administration method are shown in the table below (Table 13). The tumor volume was measured twice a week, and the mouse weight, tumor length, and tumor width were recorded at each measurement. Tumor volume = length x width x width / 2 mm 3 When the average tumor volume of the vehicle group grew to more than 3000 cubic millimeters, administration was terminated and the difference in average tumor volume between the test compound group and the vehicle group was compared. The tumor inhibitory effect of the compound was evaluated by TGI (%), which can reflect the tumor growth inhibition rate. Calculation of TGI(%): TGI(%)=[1-(mean tumor volume at administration of compound-mean tumor volume at start of compound) / (mean tumor volume at administration of vehicle group-mean tumor volume at start of vehicle group)]×100% The changes in tumor volume in each group of mice are shown in FIG. 2. Test Results [Table 13] 3. Conclusion of the study The above test results show that, compared with the positive compound CC-90011, the compound of the present application exhibits good in vivo efficacy in human myeloid leukemia HL-60 cell subcutaneous xenograft tumor model, has significant tumor inhibitory effect (TGI>60%), and the test animals show good tolerance to the compound of the present application, and the mice do not lose weight after administration (see Figure 5).

[0123] It should be understood that the foregoing detailed description and the accompanying examples are merely illustrative and should not be construed as limiting the scope of the present application, which is defined solely by the appended claims and their equivalents. Various changes and modifications to the disclosed embodiments will be readily apparent to those skilled in the art. Changes and modifications that may be made without departing from the spirit or scope of the present application include, but are not limited to, those related to the chemical structures, substituents, derivatives, intermediates, synthetic methods, formulations and / or methods of use of the present application. All publications, patents, and patent applications cited herein are incorporated herein by reference in their entirety for all purposes.

Claims

1. A compound of formula I, a stereoisomer thereof, or a pharma- ceutically acceptable salt thereof. 【Chemistry 1】 wherein Ring A is selected from a saturated cycloalkyl, a saturated heterocycloalkyl, an unsaturated cyclohydrocarbyl, or an unsaturated heterocyclohydrocarbyl, wherein said cycloalkyl, heterocycloalkyl, cyclohydrocarbyl, or heterocyclohydrocarbyl may be selected from a monocyclic bridged ring, a bicyclic bridged ring, or a bicyclic spiro ring; Ring B is selected from unsaturated cyclohydrocarbyl, unsaturated heterocyclohydrocarbyl, wherein said unsaturated cyclohydrocarbyl, unsaturated heterocyclohydrocarbyl may be selected from monocyclic or bicyclic rings; R 1 , R 2 are each independently hydrogen, fluorine, cyano, 【change】 and R 1 , R 2 cannot be hydrogen or fluorine at the same time, R 1 is hydrogen, R 2 is not fluorine, but R 1 is fluorine, R 2 is not hydrogen, or R 1 and R 2 are cyclized together with the carbon atoms to which they are attached. 【change】 Forming R 3 is halogen, cyano, oxo, hydroxy, substituted or unsubstituted amino, C 1 ~C 6 Alkyl, C 1 ~C 6 Alkoxy, C 3 ~C 8 Cycloalkyl, or C 3 ~C 8 cycloalkyloxy, wherein said C 1 ~C 6 Alkyl, C 1 ~C 6 Alkoxy, C 3 ~C 8 Cycloalkyl, or C 3 ~C 8 Cycloalkyloxy is unsubstituted or substituted with halogen, cyano, hydroxy, amino, C 1 ~C 6 Alkyl or C 1 ~C 6 alkoxy; R 4 is halogen, cyano, oxo, hydroxy, substituted or unsubstituted amino, C 1 ~C 6 Alkyl, C 1 ~C 6 Alkoxy, C 3 ~C 8 Cycloalkyl, or C 3 ~C 8 cycloalkyloxy, wherein said C 1 ~C 6 Alkyl, C 1 ~C 6 Alkoxy, C 3 ~C 8 Cycloalkyl, or C 3 ~C 8 Cycloalkyloxy is unsubstituted or substituted with halogen, cyano, hydroxy, amino, C 1 ~C 6 Alkyl or C 1 ~C 6 alkoxy; R 5 is halogen, hydroxy, substituted or unsubstituted amino, C 1 ~C 6 Alkyl, C 1 ~C 6 Alkoxy, C 3 ~C 8 Cycloalkyl, or C 3 ~C 8 cycloalkyloxy, wherein said C 1 ~C 6 Alkyl, C 1 ~C 6 Alkoxy, C 3 ~C 8 Cycloalkyl, or C 3 ~C 8 Cycloalkyloxy is unsubstituted or substituted with halogen, cyano, hydroxy, amino, C 1 ~C 6 Alkyl or C 1 ~C 6 alkoxy; R 6 , R 7 are each independently hydrogen, C 1 ~C 6 Alkyl, or C 3 ~C 8 cycloalkyl; m is selected from 0, 1, 2, 3, 4, or 5; n is selected from 0, 1, 2, 3, 4, or 5; q is selected from 0, 1, 2, 3, or 4.

2. Ring A is C 4 ~C 13 cycloalkyl, or 3- to 13-membered heterocycloalkyl, said heterocycloalkyl containing 1 to 3 heteroatoms selected from nitrogen, oxygen, or sulfur atoms; Ring B is C 5 ~C 10 Cycloalkenyl, 5-10 membered heterocycloalkenyl, C 5 ~C 10 aryl, 5- to 10-membered heteroaryl, wherein said heterocycloalkenyl or heteroaryl contains 1 to 3 heteroatoms selected from nitrogen, oxygen, or sulfur atoms; R 1 , R 2 are each independently hydrogen, cyano, Alternatively, R 1 and R 2 are cyclized together with the carbon atoms to which they are attached. Forming R 6 , R 7 are each independently hydrogen, C 1 ~C 6 Alkyl, or C 3 ~C 6 cycloalkyl; m is 0, 1, 2, 3, 4, or 5; R 3 is halogen, oxo, hydroxy, substituted or unsubstituted amino, C 1 ~C 6 Alkyl, or C 1 ~C 6 alkoxy, wherein said C 1 ~C 6 Alkyl, or C 1 ~C 6 The alkoxy is unsubstituted or substituted by one or more substituents selected from halogen, cyano, hydroxy, amino; n is selected from 0, 1, 2, 3, 4, or 5; R 4 is halogen, oxo, hydroxy, C 1 ~C 6 Alkyl, C 1 ~C 6 Alkoxy, C 3 ~C 6 Cycloalkyl, or C 3 ~C 6 cycloalkyloxy, wherein said C 1 ~C 6 Alkyl, C 1 ~C 6 Alkoxy, C 3 ~C 6 Cycloalkyl, or C 3 ~C 6 Cycloalkyloxy is unsubstituted or substituted by one or more substituents selected from halogen, hydroxy, amino; q is selected from 0, 1, or 2; R 5 is halogen, hydroxy, amino, C 1 ~C 6 Alkyl, C 1 ~C 6 alkoxy, wherein said C 1 ~C 6 Alkyl, or C 1 ~C 6 2. The compound of formula I according to claim 1, wherein alkoxy is unsubstituted or substituted with one or more substituents selected from halogen or hydroxy, a stereoisomer thereof or a pharma- ceutically acceptable salt thereof.

3. Ring A is C 5 ~C 7 a monocycloalkyl, a 3- to 8-membered monoheterocycloalkyl, or an 8- to 12-membered spiroheterocycloalkyl, said heterocycloalkyl containing 1 to 3 heteroatoms selected from nitrogen or oxygen atoms; Ring B is C 5 ~C 8 aryl, 8- to 10-membered heteroaryl, wherein said heterocycloalkenyl or heteroaryl contains 1 to 3 heteroatoms selected from nitrogen, oxygen, or sulfur atoms; R 1 is hydrogen, cyano, is selected from R 2 is hydrogen, cyano, Alternatively, R 1 and R 2 are cyclized together with the carbon atoms to which they are attached. Forming R 6 , R 7 are each independently hydrogen, C 1 ~C 5 Alkyl, or C 3 ~C 5 cycloalkyl; m is 0, 1, 2, or 3; R 3 is fluorine, chlorine, bromine, oxo, hydroxy, amino or C 1 ~C 6 alkyl, wherein said C 1 ~C 6 Alkyl is unsubstituted or substituted by amino; n is selected from 0, 1, 2, 3, or 4; R 4 is fluorine, chlorine, bromine, oxo, hydroxy, C 1 ~C 6 Alkyl, C 1 ~C 6 alkoxy, wherein said C 1 ~C 6 Alkyl, or C 1 ~C 6 alkoxy is unsubstituted or substituted by one or more substituents selected from halogen or hydroxy; q is 1 or 2; R 5 3. The compound of formula I according to claim 1 or 2, a stereoisomer thereof or a pharma- ceutically acceptable salt thereof, wherein is selected from halogen.

4. Ring A is selected from a 5- to 8-membered saturated monocycloalkyl, a 4- to 10-membered saturated monocyclic heterocycloalkyl, or a spiroheterocycloalkyl, wherein said heterocycloalkyl contains 1 to 3 nitrogen atoms as heteroatoms; Ring B is selected from 5- to 8-membered unsaturated monocyclohydrocarbyl, 5- to 14-membered unsaturated monocyclic or bicyclic heterocyclohydrocarbyl, wherein said heterocyclohydrocarbyl contains 0-4 nitrogen atoms and 0-2 oxygen atoms as heteroatoms, and at least one of nitrogen and oxygen; R 1 , R 2 are each independently hydrogen, fluorine, cyano, and R 1 , R 2 cannot be hydrogen or fluorine at the same time, R 1 is hydrogen, R 2 is not fluorine, but R 1 is fluorine, R 2 is not hydrogen, or R 1 and R 2 are cyclized together with the carbon atoms to which they are attached. Forming R 3 is halogen, cyano, oxo, hydroxy, substituted or unsubstituted amino, C 1 ~C 6 Alkyl, C 1 ~C 6 Alkoxy, C 3 ~C 8 Cycloalkyl, or C 3 ~C 8 cycloalkyloxy, wherein said C 1 ~C 6 Alkyl, C 1 ~C 6 Alkoxy, C 3 ~C 8 Cycloalkyl, or C 3 ~C 8 Cycloalkyloxy is unsubstituted or substituted with halogen, cyano, hydroxy, amino, C 1 ~C 6 Alkyl or C 1 ~C 6 alkoxy; R 4 is halogen, cyano, oxo, hydroxy, substituted or unsubstituted amino, C 1 ~C 6 Alkyl, C 1 ~C 6 Alkoxy, C 3 ~C 8 Cycloalkyl, or C 3 ~C 8 cycloalkyloxy, wherein said C 1 ~C 6 Alkyl, C 1 ~C 6 Alkoxy, C 3 ~C 8 Cycloalkyl, or C 3 ~C 8 Cycloalkyloxy is unsubstituted or substituted with halogen, cyano, hydroxy, amino, C 1 ~C 6 Alkyl or C 1 ~C 6 alkoxy; R 5 is halogen, hydroxy, substituted or unsubstituted amino, C 1 ~C 6 Alkyl, C 1 ~C 6 Alkoxy, C 3 ~C 8 Cycloalkyl, or C 3 ~C 8 cycloalkyloxy, wherein said C 1 ~C 6 Alkyl, C 1 ~C 6 Alkoxy, C 3 ~C 8 Cycloalkyl, or C 3 ~C 8 Cycloalkyloxy is unsubstituted or substituted with halogen, cyano, hydroxy, amino, C 1 ~C 6 Alkyl or C 1 ~C 6 alkoxy; R 6 , R 7 are each independently hydrogen, C 1 ~C 6 Alkyl, or C 3 ~C 8 cycloalkyl; m is selected from 0, 1, 2, 3, 4, or 5; n is selected from 0, 1, 2, 3, 4, or 5; 2. The compound of formula I according to claim 1, wherein q is selected from 0, 1, 2, 3, or 4, a stereoisomer thereof, or a pharma- ceutically acceptable salt thereof.

5. Ring A is selected from 4-10 membered saturated monocyclic heterocycloalkyl or spiroheterocycloalkyl, wherein said heterocycloalkyl contains 1-3 nitrogen atoms, preferably 1-2 nitrogen atoms, as heteroatoms; Ring B is selected from 6-membered unsaturated monocyclohydrocarbyl, 6-10 membered unsaturated bicyclic heterocyclohydrocarbyl, wherein said heterocyclohydrocarbyl contains 0-4 nitrogen atoms and 0-2 oxygen atoms as heteroatoms, and at least one of nitrogen and oxygen; preferably, Ring B is selected from 6-10 membered aryl or heterocycloaryl, wherein said heterocycloaryl contains 1-2 nitrogen atoms and 0-2 oxygen atoms as heteroatoms, and at least one of nitrogen and oxygen; R 1 , R 2 are each independently hydrogen, fluorine, cyano, and R 1 , R 2 cannot be hydrogen or fluorine at the same time, R 1 is hydrogen, R 2 is not fluorine, but R 1 is fluorine, R 2 is not hydrogen, or R 1 and R 2 are cyclized together with the carbon atoms to which they are attached. Forming R 3 is halogen, cyano, oxo, hydroxy, substituted or unsubstituted amino, C 1 ~C 6 Alkyl, C 1 ~C 6 Alkoxy, C 3 ~C 8 Cycloalkyl, or C 3 ~C 8 cycloalkyloxy, wherein said C 1 ~C 6 Alkyl, C 1 ~C 6 Alkoxy, C 3 ~C 8 Cycloalkyl, or C 3 ~C 8 Cycloalkyloxy is unsubstituted or substituted with halogen, cyano, hydroxy, amino, C 1 ~C 6 Alkyl or C 1 ~C 6 alkoxy, preferably R 3 is fluorine, chlorine, oxo, hydroxy, amino or is selected from R 4 is halogen, cyano, oxo, hydroxy, substituted or unsubstituted amino, C 1 ~C 6 Alkyl, C 1 ~C 6 Alkoxy, C 3 ~C 8 Cycloalkyl, or C 3 ~C 8 cycloalkyloxy, wherein said C 1 ~C 6 Alkyl, C 1 ~C 6 Alkoxy, C 3 ~C 8 Cycloalkyl, or C 3 ~C 8 Cycloalkyloxy is unsubstituted or substituted with halogen, cyano, hydroxy, amino, C 1 ~C 6 Alkyl or C 1 ~C 6 alkoxy, preferably R 4 is fluorine, chlorine, oxo, methyl, methoxy, is selected from R 5 is halogen, hydroxy, substituted or unsubstituted amino, C 1 ~C 6 Alkyl, C 1 ~C 6 Alkoxy, C 3 ~C 8 Cycloalkyl, or C 3 ~C 8 cycloalkyloxy, wherein said C 1 ~C 6 Alkyl, C 1 ~C 6 Alkoxy, C 3 ~C 8 Cycloalkyl, or C 3 ~C 8 Cycloalkyloxy is unsubstituted or substituted with halogen, cyano, hydroxy, amino, C 1 ~C 6 Alkyl or C 1 ~C 6 alkoxy, preferably R 5 is selected from fluorine, chlorine, bromine, methyl, methoxy, trifluoromethyl or trifluoromethoxy; R 6 , R 7 are each independently hydrogen, C 1 ~C 6 Alkyl, or C 3 ~C 8 cycloalkyl; m is selected from 0, 1, 2, 3, 4, or 5, preferably m is selected from 0, 1, 2, or 3; n is selected from 0, 1, 2, 3, 4, or 5, preferably n is selected from 0, 1, 2, 3, or 4; 5. The compound of formula I, its stereoisomer or a pharma- ceutically acceptable salt thereof according to claim 1 or 4, wherein q is selected from 0, 1, 2, 3 or 4, preferably q is selected from 1 or 2.

6. The compound of formula I according to any one of claims 1 and 4-5, wherein the compound of formula I has the structure of formula II, a stereoisomer thereof, or a pharma- ceutically acceptable salt thereof. 【Chemistry 2】 (where: Ring A is selected from cyclohexyl, piperidinyl, piperazinyl, azacycloheptyl, or homopiperazinyl, preferably said piperidinyl, piperazinyl, azacycloheptyl, or homopiperazinyl is bonded to the pyridine ring via an N atom; Ring B is selected from phenyl, pyridyl, indolyl, dihydroindolyl, and indazolyl; R 2 is selected from hydrogen or fluorine, R 3 is selected from fluorine, chlorine, oxo, hydroxy or amino, R 4 is fluorine, chlorine, oxo, methyl, methoxy, 【change】 is selected from m is selected from 0, 1, 2, or 3; n is selected from 0, 1, 2, 3, or 4.

7. The compound of formula I has the structure of formula II: Ring A is selected from cyclohexyl, piperidinyl, piperazinyl, azacyclobutyl, azacycloheptyl, homopiperazinyl, diazaspirononyl, or diazaspirodecyl, preferably said piperidinyl, piperazinyl, azacyclobutyl, azacycloheptyl, homopiperazinyl, diazaspirononyl, or diazaspirodecyl is bonded to the pyridine ring via an N atom; Ring B is selected from phenyl, pyridyl, indolyl, dihydroindolyl, indazolyl, benzisoxazolyl, benzoxazolyl, or benzodioxolyl; R 2 is hydrogen, cyano, is selected from R 6 , R 7 are each independently hydrogen, C 1 ~C 5 Alkyl, or C 3 ~C 5 cycloalkyl; R 3 is fluorine, chlorine, bromine, oxo, hydroxy, amino or C 1 ~C 6 alkyl, wherein said C 1 ~C 6 Alkyl is unsubstituted or substituted by amino; R 4 is fluorine, chlorine, bromine, oxo, C 1 ~C 6 Alkyl, C 1 ~C 6 alkoxy, wherein said C 1 ~C 6 alkyl is unsubstituted or substituted by one or more substituents selected from halogen or hydroxy; m is selected from 0, 1, 2, or 3; The compound of formula I according to any one of claims 1 to 3, wherein n is selected from 0, 1, 2, 3, or 4, a stereoisomer thereof, or a pharma- ceutically acceptable salt thereof.

8. Ring A is selected from piperidinyl, tetrahydropyridyl, piperazinyl, azacyclobutyl, azacyclopentyl, azacyclohexyl, azacycloheptyl, homopiperazinyl, cyclohexyl, cyclobutyl, cyclopentyl, cycloheptyl, diazaspirononyl, diazaspirodecyl, oxazaspirononyl, oxazaspirodecyl; Ring B is selected from 5-6 membered benzoheterocycloalkenyl containing 1-3 heteroatoms selected from phenyl, pyridyl, dihydropyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, nitrogen atom or oxygen atom; R 1 is hydrogen, cyano, is selected from R 2 is hydrogen, cyano, Alternatively, R 1 and R 2 are cyclized together with the carbon atoms to which they are attached. Forming R 6 , R 7 are each independently hydrogen, C 1 ~C 4 Alkyl, or C 3 ~C 4 cycloalkyl; m is 0, 1, or 2; R 3 is fluorine, chlorine, bromine, oxo, hydroxy, amino or C 1 ~C 3 alkyl, wherein said C 1 ~C 3 Alkyl is unsubstituted or substituted by amino; n is selected from 0, 1, 2, 3, or 4; R 4 is fluorine, chlorine, bromine, oxo, hydroxy, C 1 ~C 6 Alkyl, C 1 ~C 6 alkoxy, wherein said C 1 ~C 6 Alkyl, or C 1 ~C 6 alkoxy is unsubstituted or substituted by one or more substituents selected from halogen or hydroxy; q is 1 or 2; R 5 The compound of formula I, its stereoisomer or a pharma- ceutically acceptable salt thereof according to any one of claims 1 to 3, wherein is selected from fluorine, chlorine or bromine.

9. 9. The compound of formula I according to claim 8, its stereoisomer or a pharma- ceutically acceptable salt thereof, wherein ring B is selected from phenyl, pyridyl, dihydropyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, indolyl, isoindolyl, isoindolinyl, dihydroindolyl, indazolyl, dihydroindazolyl, benzoxazolyl, benzisoxazolyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, benzodioxolyl, benzofuranyl, benzimidazolyl, benzodihydroxazinyl.

10. Ring A is selected from piperidinyl, piperazinyl, azacyclobutyl, azacycloheptyl, homopiperazinyl, diazaspirononyl, diazaspirodecyl, or oxazaspirodecyl; Ring B is selected from phenyl, pyridyl, indolyl, dihydroindolyl, indazolyl, benzisoxazolyl, benzoxazolyl, benzodioxolyl, or benzodihydroxazinyl; R 1 , R 2 are each independently hydrogen, cyano, Alternatively, R 1 and R 2 are cyclized together with the carbon atoms to which they are attached. Forming R 3 is fluorine, chlorine, bromine, oxo, hydroxy, amino or C 1 ~C 3 alkyl, wherein said C 1 ~C 3 Alkyl is unsubstituted or substituted by amino; R 4 is fluorine, chlorine, bromine, oxo, hydroxy, C 1 ~C 6 Alkyl, C 1 ~C 6 alkoxy, wherein said C 1 ~C 6 alkyl is unsubstituted or substituted by one or more substituents selected from halogen or hydroxy; R 5 is selected from fluorine, chlorine, or bromine; m is selected from 0, 1, 2, or 3; n is selected from 0, 1, 2, 3, or 4; 10. The compound of formula I according to claim 8 or 9, wherein q is selected from 1 or 2, a stereoisomer thereof or a pharma- ceutically acceptable salt thereof.

11. The compound of formula I according to any one of claims 1 to 10, wherein the compound is selected from the following: a stereoisomer thereof or a pharma- ceutically acceptable salt thereof.

12. A pharmaceutical composition comprising a compound of formula I according to any one of claims 1 to 11, a stereoisomer thereof or a pharma- ceutically acceptable salt thereof, and pharma- ceutically acceptable auxiliary materials.

13. The compound of formula I according to any one of claims 1 to 11, its stereoisomer or its pharma- ceutically acceptable salt, or the pharmaceutical composition according to claim 12, for preventing or treating a LSD1 mediated disease, preferably, the lysine-specific demethylase 1 mediated disease is selected from tumors or cancers, more preferably, the disease is selected from acute myeloid leukemia, chronic myeloid leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, small cell lung cancer, non-small cell lung cancer, lymphoma, malignant sarcoma, breast cancer, cervical cancer, colon cancer, lung cancer, oral cancer, brain cancer, stomach cancer, liver cancer, colorectal cancer, pancreatic cancer, skin cancer, prostate cancer, bone cancer, kidney cancer, ovarian cancer, bladder cancer, fallopian tube tumor, peritoneal tumor, melanoma, glioma, glioblastoma, papillary malignant tumor, head and neck tumor, or myeloma.

14. Use of a compound of formula I according to any one of claims 1 to 11, a stereoisomer thereof or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to claim 12 as an LSD1 inhibitor.

15. 【Chemical 3】 (1) reacting compound I-1 with compound I-2 to obtain compound I-3; (2) subjecting compound I-3 to a substitution reaction to obtain compound I-4; (3) coupling compound I-4 with a boronic acid or boronic ester of compound I-5 to obtain compound I-6; (4) coupling compound I-6 with compound I-7 to obtain the compound of formula I; Or, 【Chemistry 4】 (1) subjecting compound I-1 to a substitution reaction to obtain compound I-8; (2) coupling compound I-8 with the boronic acid or boronic ester of compound I-5 to obtain compound I-9; (3) coupling compound I-9 with compound I-7 to obtain compound I-10; (4) reacting compound I-10 with compound I-2 to obtain the compound of formula I; or 【Chemistry 5】 (1) coupling compound I-3 with compound I-7 to obtain compound I-11; (2) subjecting compound I-11 to a substitution reaction to obtain compound I-12; (3) coupling compound I-12 with the boronic acid or boronic ester of compound I-5 to obtain the compound of formula I; wherein LG represents a leaving group, preferably said leaving group is selected from a halogen atom, methanesulfonyloxy, or p-tosyloxy. A method for preparing a compound of formula I, its stereoisomer, or a pharma- ceutically acceptable salt thereof according to any one of claims 1 to 11.

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