Triazolyl-containing compounds, methods of making and uses thereof

Abstract

The application belongs to the field of pharmaceutical chemistry, and provides a triazolyl-containing compound and a preparation method thereof, and particularly relates to a crystalline or solvate of a compound of formula I and use thereof in the preparation of a drug for treating tumors.

Description

[0001] This application is a divisional application of the following application: application date: April 26, 2024; application number: 202480027333.5; invention title: "Compounds containing triazole groups".

[0002] Cross-reference to related applications This application claims priority and benefit to Chinese patent application No. 202310493340.1, filed with the China National Intellectual Property Administration on April 28, 2023, the contents of which are incorporated herein by reference in their entirety. Technical Field

[0003] This disclosure pertains to the field of medicinal chemistry and provides a triazole-containing compound and a method for preparing the same, specifically relating to its crystallization or solvate, and its use in the preparation of drugs for treating tumors. Background of the Invention

[0004] Nuclear exportin-1 (also known as CRM-1 or XPO-1) has become a key “carrier” protein for transporting several key growth regulators and tumor suppressor factors from the nucleus of eukaryotic cells to the cytoplasm. When the efflux of exportin-1 becomes abnormally high (e.g., by overexpression of XPO-1), the depletion of these nuclear regulators can trigger a wide variety of diseases.

[0005] XPO1 is the only nuclear export factor that transports tumor suppressor proteins (e.g., p53, p27, FOXO1, IkB), and it is overexpressed in various solid tumors and hematologic malignancies (e.g., GBM, ovarian cancer, pancreatic cancer, cervical cancer, AML, MM, CLL, and NHL). The primary reason for XPO1 carcinogenesis is the overexpression of the XPO1 protein in multiple cancer cell types and its association with the proliferating cell cycle, which depletes the nucleus of tumor suppressor proteins (e.g., p53, p27, FOXO1, IkB), allowing cancer cell growth (e.g., M.L. Crochiere et al., Oncotarget v.7, pp. 1863–1877 (2015)). Typically, selective inhibitors of nuclear export (SINE) are small molecules that inhibit the nuclear export of cargo proteins by covalently binding to cysteine ​​residue 528 (Cys528) in the cargo-binding pocket of Exportin 1 (XPO1, also known as CRM1 (chromosome maintenance protein 1)), thereby exerting an antiproliferative effect. The interaction between XPO1 and the activated small G-protein Ran (Ran-GTP) in the nucleus promotes its binding to the cargo protein, which contains a short amino acid sequence of hydrophobic residues known as the nuclear export signal (NES).

[0006] Based on preclinical results, many inflammatory, neurodegenerative, and autoimmune diseases also involve similar pathologies. Therefore, glucocorticoids, for example, are widely used anti-inflammatory and immunomodulatory drugs whose efficacy / mechanism is primarily based on restoring sufficient steroid-activated glucocorticoid receptors (GRs) to interfere with the excessive activity of transcription factors (such as NF-κB) in the cell nucleus.

[0007] Currently, although drugs that inhibit diseases caused by excessive XPO-1 efflux have been proven to have clinical efficacy by the US FDA, many diseases still urgently require new drug treatments. Summary of the Invention

[0008] On the one hand, this disclosure provides compounds of formula I, their stereoisomers, their pharmaceutically acceptable salts, or their solvates:

[0009] in, R 1 Selected from -NH2, C 1-6 Alkyl-O-, C 1-6Alkyl-NH- or (C 1-6 Alkyl)2N-; Ring A is selected from C 6-10 Aromatic ring group or 5-10 membered heteroaryl ring group; R is selected from halogen, CN, OH, NH2, C 1-6 Alkyl, C 1-6 Alkyl-O-, C 1-6 Alkyl-S-, Halogenated C 1-6 Alkyl-O-, Halogenated C 1-6 Alkyl-S-, Halogenated C 1-6 Alkyl, 3-10 membered heterocyclic alkyl-substituted C 1-6 Alkyl, R a NH- or (R a )2N-; R a Selected from C 1-6 Alkyl, C 3-10 Cycloalkyl or 3-10 membered heterocycloalkyl, wherein R a Optionally, it is selected from one or more halogens, CN, OH, NH2, C 1-6 Alkyl, C 1-6 Alkyl O- or 5-6 membered heterocyclic alkyl groups are substituted; n is selected from 0, 1, 2, 3 or 4; R 2 Selected from cyclopropyl or trifluoromethyl.

[0010] On the other hand, this disclosure provides crystalline or amorphous forms of Formula I compounds, or crystalline or amorphous forms of their stereoisomers, or pharmaceutically acceptable salts of Formula I compounds, or solvates of Formula I compounds.

[0011] On the other hand, this disclosure provides crystalline or amorphous forms of compounds of formula I, or crystalline or amorphous forms of stereoisomers thereof, or pharmaceutically acceptable salts of compounds of formula I, or solvates of compounds of formula I.

[0012] On the other hand, this disclosure provides crystalline or amorphous forms of compounds of formula I, or crystalline or amorphous forms of their stereoisomers, or pharmaceutically acceptable salts of compounds of formula I, or crystalline or amorphous forms of solvates of compounds of formula I.

[0013] On the other hand, this disclosure provides crystals of a compound of formula I, crystals of its stereoisomers, crystals of a pharmaceutically acceptable salt of a compound of formula I, or solvates of a compound of formula I.

[0014] On the other hand, this disclosure provides crystals of Formula I compounds, crystals of their stereoisomers, or crystals or amorphous forms of pharmaceutically acceptable salts of Formula I compounds, or crystals or amorphous forms of solvates of Formula I compounds.

[0015] On the other hand, this disclosure provides crystallization of a compound of formula I, crystallization of its stereoisomers, crystallization of a pharmaceutically acceptable salt of a compound of formula I, or crystallization of a solvate of a compound of formula I.

[0016] On the other hand, this disclosure provides crystalline or amorphous forms of compounds of formula I, or solvates of compounds of formula I.

[0017] On the other hand, this disclosure provides crystals of Formula I compounds or solvates of Formula I compounds.

[0018] On the other hand, this disclosure provides crystals of Formula I compounds, or crystals or amorphous forms of solvates of Formula I compounds.

[0019] On the other hand, this disclosure provides crystallization of the compound of formula I.

[0020] On the other hand, this disclosure provides pharmaceutically acceptable salts of compounds of formula I.

[0021] On the other hand, this disclosure provides a solvate of compound I.

[0022] On the other hand, this disclosure provides that the solvates of Formula I are crystalline or amorphous.

[0023] In some embodiments, the compound of formula I is either crystalline or amorphous.

[0024] In some embodiments, the compound of formula I is a crystal of the compound of formula I.

[0025] In some embodiments, the compound of formula I is an amorphous form of the compound of formula I.

[0026] In some embodiments, the stereoisomer of Formula I is a crystalline or amorphous stereoisomer of Formula I.

[0027] In some embodiments, the pharmaceutically acceptable salt of the Formula I compound is a crystalline or amorphous form of the pharmaceutically acceptable salt of the Formula I compound.

[0028] In some embodiments, the solvate of Formula I is either crystalline or amorphous.

[0029] In some embodiments, the Formula I compound, its stereoisomer, its pharmaceutically acceptable salt, or its solvate is selected from crystals of the Formula I compound, crystals or amorphous forms of its stereoisomers, crystals or amorphous forms of pharmaceutically acceptable salts of the Formula I compound, or solvates of the Formula I compound.

[0030] In some embodiments, the Formula I compound, its stereoisomer, its pharmaceutically acceptable salt, or its solvate is selected from crystals of the Formula I compound, crystals or amorphous forms of its stereoisomers, crystals or amorphous forms of pharmaceutically acceptable salts of the Formula I compound, or crystals or amorphous forms of solvates of the Formula I compound.

[0031] In some embodiments, the solvent content in the solvate of the Formula I compound is approximately: 0.5%~50%wt; 0.5%~40%wt; 0.5%~30%wt; 0.5%~20%wt; 1%~15%wt; 1.5%~12%wt; 2%~10%wt; or 2%~7%wt. In some embodiments, the solvent content in the solvate of the Formula I compound is approximately: 1%wt, 2%wt, 3%wt, 4%wt, 5%wt, 6%wt, 7%wt, 8%wt, 9%wt, 10%wt, 11%wt, 12%wt, 13%wt, 14%wt, 15%wt, 16%wt, 17%wt, 18%wt, 19%wt, or 20%wt, or any range of the above values. In some embodiments, the solvent content in the solvate of Formula I is approximately 2% wt, 4% wt, 6% wt, 7% wt, 8% wt, or 10% wt, or any range of the foregoing values.

[0032] In some embodiments, the molar ratio of Formula I compound to solvent in the solvate is selected from 1:0.1~50, 1:0.1~30, 1:0.1~20, 1:0.1~15, 1:0.1~10, 1:0.15~10, 1:0.2~10, 1:0.2~8, 1:0.2~8, 1:0.2~6, 1:0.2~5, 1:0.2~4, 1:0.2~3, 1:0.2~2, 1:0.2~1, or 1:0.3~1.

[0033] In some embodiments, the molar ratio of Formula I compound to solvent in the solvate is approximately 1:0.2, 1:0.3, 1:0.4, 1:0.5, 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9 or 1:10, or any range of the above values.

[0034] In some embodiments, the molar ratio of Formula I compound to solvent in the solvate of Formula I is about 1:0.5 or 1:1, or any range thereof. In some embodiments, the molar ratio of Formula I compound to solvent in the solvate of Formula I is about 1:0.5. In some embodiments, the molar ratio of Formula I compound to solvent in the solvate of Formula I is about 1:1.

[0035] In some embodiments, the solvent in the solvate of the Formula I compound is selected from one or more solvents selected from water, hydrocarbons, alcohols, ethers, esters, amides, sulfoxides, ketones, or nitriles.

[0036] In some embodiments, the solvent in the solvate of Formula I is selected from one or more solvents selected from water, hydrocarbons, alcohols, ethers, esters, amides, sulfoxides, or ketones. In some embodiments, the solvent in the solvate of Formula I is selected from one or more solvents selected from water, alcohols, ethers, esters, or ketones.

[0037] In some embodiments, the solvent in the solvate of Formula I is selected from water, C 5-10 Hydrocarbons, C 1-10 alcohols, C 2-10 Ethers, C 2-10 Esters, C 2-10 Amides, C 2-10 sulfoxides, C 2-10 Ketones or C 2-10 One or more of nitrile solvents.

[0038] In some embodiments, the solvent in the solvate of Formula I is selected from water, C 5-10 Hydrocarbons, C 1-10 alcohols, C 2-10 Ethers, C 2-10 Esters, C 2-10 Amides, C 2-10 sulfoxides or C 2-10 One or more of the ketone solvents.

[0039] In some embodiments, the solvent in the solvate of Formula I is selected from water, C 5-10 Hydrocarbons, C 1-6 alcohols, C 2-6 Ethers, C 2-6 Esters, C 2-6 Amides, C 2-6 sulfoxides, C 2-6 Ketones or C 2-6One or more of nitrile solvents.

[0040] In some embodiments, the solvent in the solvate of Formula I is selected from water, C 5-10 Hydrocarbons, C 1-6 alcohols, C 2-6 Ethers, C 2-6 Esters, C 2-6 Amides, C 2-6 sulfoxides or C 2-6 One or more of the ketone solvents.

[0041] In some embodiments, the solvent in the solvate of Formula I is selected from water, C 1-10 alcohols, C 2-10 Ethers, C 2-10 Esters or C 2-10 Ketones or C 2-10 One or more of nitrile solvents.

[0042] In some embodiments, the solvent in the solvate of Formula I is selected from water, C 1-10 alcohols, C 2-10 Ethers, C 2-10 Esters or C 2-10 One or more of the ketone solvents.

[0043] In some embodiments, the solvent in the solvate of Formula I is selected from water, C 1-6 alcohols, C 2-6 Ethers, C 2-6 Esters, C 2-6 Ketones or C 2-6 One or more of nitrile solvents.

[0044] In some embodiments, the solvent in the solvate of Formula I is selected from water, C 1-6 alcohols, C 2-6 Ethers, C 2-6 Esters or C 2-6 One or more of the ketone solvents.

[0045] In some embodiments, the solvent in the solvate of Formula I is selected from water, C 1-3 alcohols, C 2-6 Ethers, C 4-6 Esters or C 3-4 One or more of the ketone solvents.

[0046] In some embodiments, the solvent in the solvate of Formula I is selected from water, C 1-3 alcohols, C 4-5 One or more of esters or C3 ketone solvents.

[0047] In some embodiments, the solvent in the solvate of Formula I is selected from water, C 1-6 alcohols or C 2-6 One or more of the ester solvents.

[0048] In some embodiments, the solvent in the solvate of Formula I is selected from water, C 1-6 alcohols, C 2-6 Ethers, C 2-6 Esters, C 3-4 Ketones or C 2-4 One or more of nitrile solvents.

[0049] In some embodiments, the solvent in the solvate of Formula I is selected from water, C 1-3 alcohols, C 5-6 Ethers, C 4-5 One or more of the following solvents: esters, C3 ketones, or C2 nitriles.

[0050] In some embodiments, the solvent in the solvate of the Formula I compound is selected from one or more of water, methanol, ethanol, isopropanol, 1,4-dioxane, tetrahydrofuran, ethyl acetate, isopropyl acetate, acetone, or acetonitrile.

[0051] In some embodiments, the solvent in the solvate of the Formula I compound is selected from one or more of water, methanol, ethanol, isopropanol, ethyl acetate, isopropyl acetate, or acetone.

[0052] In some embodiments, the solvent in the solvate of the Formula I compound is selected from one or more of water, a mixture of water and ethyl acetate, methanol, a mixture of methanol and isopropyl acetate, a mixture of methanol, isopropyl acetate and water, ethanol, isopropanol, isopropyl acetate or acetone.

[0053] In some embodiments, the solvent in the solvate of the Formula I compound is selected from one or more of water, a mixture of water and ethyl acetate, methanol, ethanol, isopropanol, isopropyl acetate, or acetone.

[0054] In some embodiments, the solvent in the solvate of the Formula I compound is selected from one or more of water, methanol, ethanol, isopropanol, or ethyl acetate.

[0055] In some embodiments, the solvent in the solvate of Formula I comprises water, or a mixture of water and ethyl acetate. In some embodiments, the solvent in the solvate of Formula I comprises water. In some embodiments, the solvent in the solvate of Formula I comprises a mixture of water and ethyl acetate.

[0056] In some embodiments, the solvent in the solvate of the Formula I compound comprises one or more of methanol, ethanol, or isopropanol.

[0057] In some embodiments, the solvent in the solvate of Formula I comprises ethyl acetate or isopropyl acetate.

[0058] In some embodiments, the solvent in the solvate of the Formula I compound comprises acetone.

[0059] In some embodiments, the solvent in the solvate of the Formula I compound comprises acetonitrile.

[0060] In some embodiments, the solvent in the solvate of the Formula I compound comprises tetrahydrofuran.

[0061] In some embodiments, the solvent in the solvate of the Formula I compound comprises 1,4-dioxane.

[0062] In some embodiments, the groups in the Formula I compound are as defined in this disclosure.

[0063] In some implementations, the R 1 Selected from -NH2, C 1-4 Alkyl-O- or C 1-4 Alkyl-NH- or (C 1-4 Alkyl)2N-.

[0064] In some implementations, the R 1 Selected from -NH2, C 1-3 Alkyl-O- or C 1-3 Alkyl-NH- or (C 1-3 Alkyl)2N-.

[0065] In some implementations, the R 1 Selected from -NH2, isopropyl-O-, or methyl-NH-. In some embodiments, the R... 1 Selected from -NH2 or isopropyl-O-. In some embodiments, the R 1 Selected from -NH2.

[0066] In some embodiments, ring A is selected from phenyl or 5-10-membered heteroaryl groups. In some embodiments, ring A is selected from 5-, 6-, 7-, 8-, 9-, or 10-membered heteroaryl groups. In some embodiments, ring A is selected from 5-6- or 9-10-membered heteroaryl groups. In some embodiments, ring A is selected from 6- or 10-membered heteroaryl groups. In some embodiments, ring A is selected from 10-membered heteroaryl groups. In some embodiments, ring A is selected from 5-6-membered heteroaryl groups. In some embodiments, ring A is selected from 6-membered heteroaryl groups.

[0067] In some embodiments, ring A is selected from pyrimidinyl, pyridinyl, pyrazolyl, isoxazolyl, oxazolyl, quinolinyl, indazoleyl, pyridazinyl, thiazolyl, furanyl, pyranyl, thiophenyl, pyrroleyl, pyrazinyl, isothiazolyl, oxazolyl, indolyl, naphridinyl, isoquinolinyl, quinazolinyl, and benzofuranyl.

[0068] In some embodiments, ring A is selected from pyrimidinyl, pyridinyl, pyrazolyl, isoxazolyl, quinolinyl, indazoleyl, naphridinyl, or isoquinolinyl. In some embodiments, ring A is selected from pyrimidinyl, pyridinyl, or naphridinyl. In some specific embodiments, ring A is selected from pyrimidinyl; in some specific embodiments, ring A is selected from pyridinyl; in some specific embodiments, ring A is selected from pyrazolyl or isoxazolyl; in some specific embodiments, ring A is selected from quinolinyl, indazoleyl, naphridinyl, or isoquinolinyl; in some specific embodiments, ring A is selected from quinolinyl or naphridinyl.

[0069] In some implementations, ring A is selected from... , , , , , , , , , , , , , or .

[0070] In some implementations, ring A is selected from... , , , , , , , , , , , , or .

[0071] In some embodiments, R is selected from halogens, CN, OH, NH2, C. 1-4 Alkyl, C 1-4 Alkyl-O-, C 1-4 Alkyl-S-, Halogenated C 1-4 Alkyl-O-, Halogenated C 1-4 Alkyl-S-, Halogenated C 1-4 Alkyl, R a NH- or (R a )2N-.

[0072] In some embodiments, R is selected from halogens, CN, OH, NH2, C. 1-3 Alkyl, C 1-3 Alkyl-O-, C 1-3 Alkyl-S-, Halogenated C 1-3 Alkyl-O-, Halogenated C 1-3 Alkyl-S-, Halogenated C 1-3 Alkyl, R a NH- or (R a )2N-. In some embodiments, R is selected from fluorine, chlorine, CN, OH, NH2, C 1-3 Alkyl, C 1-3 Alkyl-O-, Halogenated C 1-3 Alkyl or R a NH-.

[0073] In some embodiments, R is selected from fluorine, CN, NH2, methyl, methoxy, trifluoromethyl, or R. a NH-.

[0074] In some implementations, the R a Selected from C 1-4 Alkyl, C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl, wherein R a Optionally substituted with one or more groups selected from halogens, CN, OH, NH2 or 5-6 membered heterocyclic alkyl groups.

[0075] In some implementations, the R a Selected from C 1-3 Alkyl, C 5-6 Cycloalkyl or 5-6 membered heterocycloalkyl, wherein R a Optionally substituted with one or more groups selected from halogens, CN, OH, NH2 or 5-6 membered heterocyclic alkyl groups.

[0076] In some implementations, the R a Selected from C 1-3Alkyl or 5-6 membered heterocyclic alkyl, wherein R a Optionally substituted with one or more groups selected from halogens, CN, OH, NH2 or 5-6 membered heterocyclic alkyl groups.

[0077] In some implementations, the R a Selected from C 1-3 Alkyl or 6-membered heterocyclic alkyl, wherein R a Optionally substituted with one or more groups selected from fluorine, chlorine, bromine, CN, OH, NH2 or 6-membered heterocyclic alkyl groups.

[0078] In some implementations, the R a Selected from methyl, ethyl, propyl or tetrahydropyranyl, wherein R a Optionally substituted with one or more fluorine or dioxane.

[0079] In some implementations, the R a Selected from FCH2CH2-, F2CHCH2-, F3CCH2-, CF3CH(CH3)-, CH3CF2CH2-, tetrahydropyranyl or dioxane-CH2-.

[0080] In some embodiments, R is selected from fluorine, CN, NH2, methyl, methoxy, trifluoromethyl, , , , , , , , , , or .

[0081] In some embodiments, the R is selected from methyl or In some implementations, R is selected from... .

[0082] In some implementations, n is selected from 0, 1, 2, or 3.

[0083] In some implementations, n is selected from 0, 1, or 2.

[0084] In some implementations, n is selected from 0 or 1. In some implementations, n is selected from 0, and in some implementations, n is selected from 1.

[0085] In some implementation schemes, R 2 Selected from cyclopropyl.

[0086] In some implementation schemes, structural units Selected from , , , , , , , , , , , , , or .

[0087] In some implementation schemes, structural units Selected from , , , , , , , or .

[0088] In some implementation schemes, structural units Selected from , , , , , , or In some implementations, structural units Selected from , , , , , or In some implementations, structural units Selected from .

[0089] In some implementation schemes, structural units Selected from , , , , , , , , , , , , , , , , , , , , , or .

[0090] In some implementation schemes, structural units Selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

[0091] In some implementation schemes, structural units Selected from , , , , , , , , , , , , or .

[0092] In some implementation schemes, structural units Selected from , , , , or .

[0093] In some implementation schemes, structural units Selected from , , , , , , or .

[0094] In some implementation schemes, structural units Selected from , , or .

[0095] In some implementation schemes, structural units Selected from In some implementations, structural units Selected from .

[0096] In some implementation schemes, structural units Selected from , , , , , , , , , , , , , , , , , , , , or .

[0097] In some implementation schemes, structural units Selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

[0098] In some embodiments, the compound of formula I is selected from compounds of formula I-1 or I-2.

[0099] Wherein, R and n are as described in this disclosure, T 1 T 2 T 3 T 4 or T 5 Each is independently selected from bond, O, S, N or CH, wherein no more than one is selected from bond and at least one is selected from N; Indicates a single bond or a double bond.

[0100] In some implementations, T 1 T 2 T 3 T 4 or T 5Each is independently selected from N or CH, and at least one is selected from N.

[0101] In some implementations, T 2 and T 4 Selected from N, T 1 T 3 and T 5 Selected from CH.

[0102] In some implementations, T 3 Selected from N, T 1 T 2 T 4 and T 5 Selected from CH.

[0103] In some implementations, T 2 Selected from N, T 1 T 3 T 4 and T 5 Selected from CH.

[0104] In some implementation schemes, structural units Selected from .

[0105] In some implementation schemes, structural units Selected from .

[0106] In some implementation schemes, structural units Selected from , , , , or In some implementations, structural units Selected from , , or In some implementations, structural units Selected from In some implementations, structural units Selected from .

[0107] In some implementations, this disclosure includes the variables defined above and their implementations, as well as any combination thereof.

[0108] In the above-mentioned heterocyclic alkyl or heteroaromatic groups, the heteroatom is selected from nitrogen, oxygen, or sulfur, and the remaining ring atoms are selected from carbon. In some embodiments, the number of heteroatoms is selected from 1, 2, 3, or 4. In some embodiments, the number of heteroatoms is selected from 1, 2, or 3. In some embodiments, the number of heteroatoms is selected from 1 or 2.

[0109] In some embodiments, the compound of formula I is selected from the following compounds: .

[0110] In some embodiments, the compound of formula I is selected from compounds 2-A, 3-A, 11-A, 15-A, 21-A, 25-A, 38-A, or 59-A. or .

[0111] In some embodiments, the compound of formula I is selected from compounds 3-A, 15-A, 21-A, or 25-A. or .

[0112] In some embodiments, the compound of formula I is selected from compound 2-A. .

[0113] In some embodiments, the compound of formula I is selected from compound 3-A. .

[0114] In some embodiments, the compound of formula I is selected from compound 11-A. .

[0115] In some embodiments, the compound of formula I is selected from compound 15-A. .

[0116] In some embodiments, the compound of formula I is selected from compound 21-A. .

[0117] In some embodiments, the compound of formula I is selected from compound 25-A. .

[0118] In some embodiments, the compound of formula I is selected from compound 38-A. .

[0119] In some embodiments, the compound of formula I is selected from compound 59-A. .

[0120] On the other hand, this disclosure provides compounds 21-A, 2-A, 3-A, 11-A, 15-A, 25-A, 38-A or 59-A, their stereoisomers, their pharmaceutically acceptable salts, or their solvates.

[0121] On the other hand, this disclosure provides compounds 21-A, 3-A, 15-A or 25-A, their stereoisomers, their pharmaceutically acceptable salts, or their solvates.

[0122] On the other hand, this disclosure provides crystalline or amorphous forms of compounds 21-A, 2-A, 3-A, 11-A, 15-A, 25-A, 38-A, or 59-A, crystalline or amorphous forms of their stereoisomers, crystalline or amorphous forms of pharmaceutically acceptable salts of compounds 21-A, 2-A, 3-A, 11-A, 15-A, 25-A, 38-A, or 59-A, or solvates of compounds 21-A, 2-A, 3-A, 11-A, 15-A, 25-A, 38-A, or 59-A.

[0123] On the other hand, this disclosure provides crystalline or amorphous forms of compounds 21-A, 3-A, 15-A, or 25-A, crystalline or amorphous forms of their stereoisomers, crystalline or amorphous forms of pharmaceutically acceptable salts of compounds 21-A, 3-A, 15-A, or 25-A, or solvates of compounds 21-A, 3-A, 15-A, or 25-A.

[0124] On the other hand, this disclosure provides crystals of compounds 21-A, 2-A, 3-A, 11-A, 15-A, 25-A, 38-A or 59-A, crystals of their stereoisomers, crystals of pharmaceutically acceptable salts of compounds 21-A, 2-A, 3-A, 11-A, 15-A, 25-A, 38-A or 59-A, or solvates of compounds 21-A, 2-A, 3-A, 11-A, 15-A, 25-A, 38-A or 59-A.

[0125] On the other hand, this disclosure provides crystals of compound 21-A, 3-A, 15-A or 25-A, crystals of their stereoisomers, crystals of pharmaceutically acceptable salts of compound 21-A, 3-A, 15-A or 25-A, or solvates of compound 21-A, 3-A, 15-A or 25-A.

[0126] On the other hand, this disclosure provides crystals of compound 21-A, 2-A, 3-A, 11-A, 15-A, 25-A, 38-A or 59-A, pharmaceutically acceptable salts of compound 21-A, 2-A, 3-A, 11-A, 15-A, 25-A, 38-A or 59-A, or solvates of compound 21-A, 2-A, 3-A, 11-A, 15-A, 25-A, 38-A or 59-A.

[0127] On the other hand, this disclosure provides crystals of compound 21-A, 3-A, 15-A or 25-A, pharmaceutically acceptable salts of compound 21-A, 3-A, 15-A or 25-A, or solvates of compound 21-A, 3-A, 15-A or 25-A.

[0128] On the other hand, this disclosure provides crystalline or amorphous forms of compounds 21-A, 2-A, 3-A, 11-A, 15-A, 25-A, 38-A, or 59-A; crystalline or amorphous forms of pharmaceutically acceptable salts of compounds 21-A, 2-A, 3-A, 11-A, 15-A, 25-A, 38-A, or 59-A; or solvates of compounds 21-A, 2-A, 3-A, 11-A, 15-A, 25-A, 38-A, or 59-A.

[0129] On the other hand, this disclosure provides crystalline or amorphous forms of compounds 21-A, 3-A, 15-A or 25-A, crystalline or amorphous forms of pharmaceutically acceptable salts of compounds 21-A, 3-A, 15-A or 25-A, or solvates of compounds 21-A, 3-A, 15-A or 25-A.

[0130] On the other hand, this disclosure provides crystals of compound 21-A, 2-A, 3-A, 11-A, 15-A, 25-A, 38-A or 59-A, crystals or amorphous forms of pharmaceutically acceptable salts of compound 21-A, 2-A, 3-A, 11-A, 15-A, 25-A, 38-A or 59-A, or solvates of compound 21-A, 2-A, 3-A, 11-A, 15-A, 25-A, 38-A or 59-A.

[0131] On the other hand, this disclosure provides crystals of compound 21-A, 3-A, 15-A or 25-A, crystals or amorphous forms of pharmaceutically acceptable salts of compound 21-A, 3-A, 15-A or 25-A, or solvates of compound 21-A, 3-A, 15-A or 25-A.

[0132] In some embodiments, the pharmaceutically acceptable salts of compounds 21-A, 2-A, 3-A, 11-A, 15-A, 25-A, 38-A, or 59-A are selected from crystalline or amorphous forms of pharmaceutically acceptable salts of compounds 21-A, 2-A, 3-A, 11-A, 15-A, 25-A, 38-A, or 59-A.

[0133] In some embodiments, the solvates of compounds 21-A, 2-A, 3-A, 11-A, 15-A, 25-A, 38-A, or 59-A are selected from crystalline or amorphous forms of the solvates of compounds 21-A, 2-A, 3-A, 11-A, 15-A, 25-A, 38-A, or 59-A.

[0134] In some embodiments, the solvates of compounds 21-A, 3-A, 15-A, or 25-A are selected from crystalline or amorphous forms of the solvates of compounds 21-A, 3-A, 15-A, or 25-A, respectively.

[0135] In some embodiments, crystals of compound 21-A, 2-A, 3-A, 11-A, 15-A, 25-A, 38-A, or 59-A, pharmaceutically acceptable salts of compound 21-A, 2-A, 3-A, 11-A, 15-A, 25-A, 38-A, or 59-A, or solvates of compound 21-A, 2-A, 3-A, 11-A, 15-A, 25-A, 38-A, or 59-A are selected respectively. Crystallization or amorphous formation of the following compounds: 21-A, 2-A, 3-A, 11-A, 15-A, 25-A, 38-A, or 59-A; pharmaceutically acceptable salts of 21-A, 2-A, 3-A, 11-A, 15-A, 25-A, 38-A, or 59-A; or solvates of 21-A, 2-A, 3-A, 11-A, 15-A, 25-A, 38-A, or 59-A.

[0136] In some embodiments, crystals of compound 21-A, 3-A, 15-A, or 25-A, pharmaceutically acceptable salts of compound 21-A, 3-A, 15-A, or 25-A, or solvates of compound 21-A, 3-A, 15-A, or 25-A are selected from crystals of compound 21-A, 3-A, 15-A, or 25-A, pharmaceutically acceptable salts of compound 21-A, 3-A, 15-A, or 25-A, crystals or amorphous forms, or solvates of compound 21-A, 3-A, 15-A, or 25-A, crystals or amorphous forms.

[0137] In another aspect, this application provides crystalline or amorphous forms of compounds 21-A, 2-A, 3-A, 11-A, 15-A, 25-A, 38-A or 59-A, or solvates of compounds 21-A, 2-A, 3-A, 11-A, 15-A, 25-A or 38-A.

[0138] In another aspect, this application provides crystalline or amorphous forms of compounds 21-A, 3-A, 15-A, or 25-A, or solvates of compounds 21-A, 3-A, 15-A, or 25-A.

[0139] In another aspect, this application provides crystals of compound 21-A, 2-A, 3-A, 11-A, 15-A, 25-A, 38-A or 59-A, or solvates of compound 21-A, 2-A, 3-A, 11-A, 15-A, 25-A or 38-A.

[0140] In another aspect, this application provides crystals of compound 21-A, 3-A, 15-A or 25-A, or solvates of compound 21-A, 3-A, 15-A or 25-A.

[0141] In another aspect, this application provides crystals of compound 21-A, 2-A, 3-A, 11-A, 15-A, 25-A, 38-A or 59-A, or crystals or amorphous forms of solvates of compound 21-A, 2-A, 3-A, 11-A, 15-A, 25-A, 38-A or 59-A.

[0142] In another aspect, this application provides crystals of compounds 21-A, 2-A, 3-A, 11-A, 15-A, 25-A, 38-A, or 59-A.

[0143] Furthermore, this application provides solvates of compounds 21-A, 2-A, 3-A, 11-A, 15-A, 25-A, 38-A, or 59-A. Also, this application provides crystalline or amorphous forms of solvates of compounds 21-A, 2-A, 3-A, 11-A, 15-A, 25-A, 38-A, or 59-A.

[0144] In some embodiments, the solvent content in the solvates of compounds 21-A, 2-A, 3-A, 11-A, 15-A, 25-A, 38-A, or 59-A is approximately: 0.5%~50%wt, 0.5%~40%wt, 0.5%~30%wt, 0.5%~20%wt, 1%~15%wt, 1.5%~12%wt, 2%~10%wt, or 2%~7%wt. In some embodiments, the solvent content in the solvates of compounds 21-A, 2-A, 3-A, 11-A, 15-A, 25-A, 38-A, or 59-A is approximately 1%wt, 2%wt, 3%wt, 4%wt, 5%wt, 6%wt, 7%wt, 8%wt, 9%wt, 10%wt, 11%wt, 12%wt, 13%wt, 14%wt, 15%wt, 16%wt, 17%wt, 18%wt, 19%wt, or 20%wt, or any range of the foregoing values. In some embodiments, the solvent content in the solvates of compounds 21-A, 2-A, 3-A, 11-A, 15-A, 25-A, 38-A, or 59-A is approximately 2%wt, 4%wt, 6%wt, 7%wt, 8%wt, or 10%wt, or any range of the foregoing values. In some embodiments, the solvent content in the solvates of compounds 21-A, 2-A, 3-A, 11-A, 15-A, 25-A, 38-A, or 59-A is approximately 2%wt, 4%wt, 6%wt, 7%wt, or 10%wt, or any range of the foregoing values. In some embodiments, the solvent content in the solvates of compounds 21-A, 2-A, 3-A, 11-A, 15-A, 25-A, 38-A, or 59-A is approximately 2%wt, 4%wt, or 7%wt, or any range of the foregoing values. In some embodiments, the solvent content in the solvates of compounds 21-A, 2-A, 3-A, 11-A, 15-A, 25-A, 38-A, or 59-A is approximately 4%wt, 6%wt, 7%wt, 8%wt, or 10%wt, or any range of the foregoing values. In some embodiments, the solvent content in the solvates of compounds 21-A, 2-A, 3-A, 11-A, 15-A, 25-A, 38-A, or 59-A is approximately 4%wt, 6%wt, or 10%wt, or any range of the above values.

[0145] In some embodiments, the molar ratio of compound 21-A, 2-A, 3-A, 11-A, 15-A, 25-A, 38-A, or 59-A solvates to solvents is selected from about 1:0.1~50, 1:0.1~30, 1:0.1~20, 1:0.1~15, 1:0.1~10, 1:0.15~10, 1:0.2~10, 1:0.2~8, 1:0.2~8, 1:0.2~6, 1:0.2~5, 1:0.2~4, 1:0.2~3, 1:0.2~2, 1:0.2~1, or 1:0.3~1.

[0146] In some embodiments, the molar ratio of compound 21-A, 2-A, 3-A, 11-A, 15-A, 25-A, 38-A, or 59-A solvates to solvents is approximately 1:0.2, 1:0.3, 1:0.4, 1:0.5, 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, or 1:10, or any range of the above values. In some embodiments, the molar ratio of compound 21-A, 2-A, 3-A, 11-A, 15-A, 25-A, 38-A, or 59-A in the solvate of compound 21-A, 2-A, 3-A, 11-A, 15-A, 25-A, 38-A, or 59-A to the solvent is approximately 1:0.5 or 1:1, or any range of the foregoing values. In some embodiments, the molar ratio of compound 21-A, 2-A, 3-A, 11-A, 15-A, 25-A, 38-A, or 59-A in the solvate of compound 21-A, 2-A, 3-A, 11-A, 15-A, 25-A, 38-A, or 59-A to the solvent is approximately 1:0.5. In some embodiments, the molar ratio of compound 21-A, 2-A, 3-A, 11-A, 15-A, 25-A, 38-A, or 59-A solvates to solvents is approximately 1:1.

[0147] In some embodiments, the solvent in the solvates of compounds 21-A, 2-A, 3-A, 11-A, 15-A, 25-A, 38-A, or 59-A is selected from one or more solvents selected from water, hydrocarbons, alcohols, ethers, esters, amides, sulfoxides, ketones, or nitriles.

[0148] In some embodiments, the solvent in the solvates of compounds 21-A, 2-A, 3-A, 11-A, 15-A, 25-A, 38-A, or 59-A is selected from one or more solvents selected from water, hydrocarbons, alcohols, ethers, esters, amides, sulfoxides, or ketones.

[0149] In some embodiments, the solvent in the solvates of compounds 21-A, 2-A, 3-A, 11-A, 15-A, 25-A, 38-A, or 59-A is selected from one or more solvents selected from water, alcohols, ethers, esters, ketones, or nitrile solvents.

[0150] In some embodiments, the solvent in the solvates of compounds 21-A, 2-A, 3-A, 11-A, 15-A, 25-A, 38-A, or 59-A is selected from one or more solvents selected from water, alcohols, ethers, esters, or ketones.

[0151] In some embodiments, the solvent in the solvates of compounds 21-A, 2-A, 3-A, 11-A, 15-A, 25-A, 38-A, or 59-A is selected from water, C 5-10 Hydrocarbons, C 1-10 alcohols, C 2-10 Ethers, C 2-10 Esters, C 2-10 Amides, C 2-10 sulfoxides, C 2-10 Ketones or C 2-10 One or more of nitrile solvents.

[0152] In some embodiments, the solvent in the solvates of compounds 21-A, 2-A, 3-A, 11-A, 15-A, 25-A, 38-A, or 59-A is selected from water, C 5-10 Hydrocarbons, C 1-10 alcohols, C 2-10 Ethers, C 2-10 Esters, C 2-10 Amides, C 2-10 sulfoxides or C 2-10 One or more of the ketone solvents.

[0153] In some embodiments, the solvent in the solvates of compounds 21-A, 2-A, 3-A, 11-A, 15-A, 25-A, 38-A, or 59-A is selected from water, C 5-10 Hydrocarbons, C 1-6 alcohols, C 2-6 Ethers, C 2-6 Esters, C 2-6 Amides, C 2-6 sulfoxides, C 2-6 Ketones or C 2-6One or more of nitrile solvents.

[0154] In some embodiments, the solvent in the solvates of compounds 21-A, 2-A, 3-A, 11-A, 15-A, 25-A, 38-A, or 59-A is selected from water, C 5-10 Hydrocarbons, C 1-6 alcohols, C 2-6 Ethers, C 2-6 Esters, C 2-6 Amides, C 2-6 sulfoxides or C 2-6 One or more of the ketone solvents.

[0155] In some embodiments, the solvent in the solvates of compounds 21-A, 2-A, 3-A, 11-A, 15-A, 25-A, 38-A, or 59-A is selected from water, C 1-10 alcohols, C 2-10 Ethers, C 2-10 Esters, C 2-10 Ketones or C 2-10 One or more of nitrile solvents.

[0156] In some embodiments, the solvent in the solvates of compounds 21-A, 2-A, 3-A, 11-A, 15-A, 25-A, 38-A, or 59-A is selected from water, C 1-10 alcohols, C 2-10 Ethers, C 2-10 Esters or C 2-10 One or more of the ketone solvents.

[0157] In some embodiments, the solvent in the solvates of compounds 21-A, 2-A, 3-A, 11-A, 15-A, 25-A, 38-A, or 59-A is selected from water, C 1-6 alcohols, C 2-6 Ethers, C 2-6 Esters, C 2-6 Ketones, C 2-6 One or more of nitrile solvents.

[0158] In some embodiments, the solvent in the solvates of compounds 21-A, 2-A, 3-A, 11-A, 15-A, 25-A, 38-A, or 59-A is selected from water, C 1-6 alcohols, C 2-6 Ethers, C 2-6 Esters or C 2-6 One or more of the ketone solvents.

[0159] In some embodiments, the solvent in the solvates of compounds 21-A, 2-A, 3-A, 11-A, 15-A, 25-A, 38-A, or 59-A is selected from water, C 1-3 alcohols, C 2-6 Ethers, C 4-6 Esters, C 3-4 Ketones or C 2-4 One or more of nitrile solvents.

[0160] In some embodiments, the solvent in the solvates of compounds 21-A, 2-A, 3-A, 11-A, 15-A, 25-A, 38-A, or 59-A is selected from water, C 1-3 alcohols, C 2-6 Ethers, C 4-6 Esters or C 3-4 One or more of the ketone solvents.

[0161] In some embodiments, the solvent in the solvates of compounds 21-A, 2-A, 3-A, 11-A, 15-A, 25-A, 38-A, or 59-A is selected from water, C 1-3 alcohols, C 4-5 Esters, C 5-6 One or more of the following: ethers, C3 ketones, and C2 nitrile solvents.

[0162] In some embodiments, the solvent in the solvates of compounds 21-A, 2-A, 3-A, 11-A, 15-A, 25-A, 38-A, or 59-A is selected from water, C 1-3 alcohols, C 4-5 One or more of esters or C3 ketone solvents.

[0163] In some embodiments, the solvent in the solvates of compounds 21-A, 2-A, 3-A, 11-A, 15-A, 25-A, 38-A, or 59-A is selected from water, C 1-6 alcohols, C 2-6 Ethers, C 2-6 Esters, C 3-4 Ketones or C 2-4 One or more of nitrile solvents.

[0164] In some embodiments, the solvent in the solvates of compounds 21-A, 2-A, 3-A, 11-A, 15-A, 25-A, 38-A, or 59-A is selected from water, C 1-6 alcohols or C 2-6 One or more of the ester solvents.

[0165] In some embodiments, the solvent in the solvates of compounds 21-A, 2-A, 3-A, 11-A, 15-A, 25-A, 38-A, or 59-A is selected from one or more of water, methanol, ethanol, isopropanol, 1,4-dioxane, tetrahydrofuran, ethyl acetate, isopropyl acetate, acetone, or acetonitrile. In some embodiments, the solvent in the solvates of compounds 21-A, 2-A, 3-A, 11-A, 15-A, 25-A, 38-A, or 59-A is selected from one or more of water, methanol, ethanol, isopropanol, ethyl acetate, isopropyl acetate, or acetone.

[0166] In some embodiments, the solvent in the solvates of compounds 21-A, 2-A, 3-A, 11-A, 15-A, 25-A, 38-A, or 59-A is selected from one or more of water, a mixture of water and ethyl acetate, methanol, a mixture of methanol and isopropyl acetate, a mixture of methanol, isopropyl acetate, and water, ethanol, isopropanol, isopropyl acetate, acetone, 1,4-dioxane, tetrahydrofuran, or acetonitrile.

[0167] In some embodiments, the solvent in the solvates of compounds 21-A, 2-A, 3-A, 11-A, 15-A, 25-A, 38-A, or 59-A is selected from one or more of water, a mixture of water and ethyl acetate, methanol, a mixture of methanol and isopropyl acetate, a mixture of methanol, isopropyl acetate, and water, ethanol, isopropanol, isopropyl acetate, or acetone.

[0168] In some embodiments, the solvent in the solvates of compounds 21-A, 2-A, 3-A, 11-A, 15-A, 25-A, 38-A, or 59-A is selected from one or more of water, a mixture of water and ethyl acetate, methanol, ethanol, isopropanol, isopropyl acetate, or acetone.

[0169] In some embodiments, the solvent in the solvates of compounds 21-A, 2-A, 3-A, 11-A, 15-A, 25-A, 38-A, or 59-A is selected from one or more of water, methanol, ethanol, isopropanol, or ethyl acetate.

[0170] In some embodiments, the solvent in the solvates of compounds 21-A, 2-A, 3-A, 11-A, 15-A, 25-A, 38-A, or 59-A comprises water, or a mixture of water and ethyl acetate. In some embodiments, the solvent in the solvates of compounds 21-A, 2-A, 3-A, 11-A, 15-A, 25-A, 38-A, or 59-A comprises water. In some embodiments, the solvent in the solvates of compounds 21-A, 2-A, 3-A, 11-A, 15-A, 25-A, 38-A, or 59-A comprises ethyl acetate. In some embodiments, the solvent in the solvates of compounds 21-A, 2-A, 3-A, 11-A, 15-A, 25-A, 38-A, or 59-A comprises a mixture of water and ethyl acetate.

[0171] In some embodiments, the solvent in the solvate of compound 21-A comprises water, ethyl acetate, isopropyl acetate, methanol, isopropanol, or acetone.

[0172] In some embodiments, the solvent in the solvate of compound 3-A comprises acetonitrile, 1,4-dioxane, or tetrahydrofuran.

[0173] In some embodiments, the solvent in the solvate of compound 15-A comprises acetonitrile. In some embodiments, the solvent in the solvates of compounds 21-A, 2-A, 3-A, 11-A, 15-A, 25-A, 38-A, or 59-A comprises one or more of methanol, ethanol, or isopropanol.

[0174] In some embodiments, the solvent in the solvates of compounds 21-A, 2-A, 3-A, 11-A, 15-A, 25-A, 38-A, or 59-A comprises ethyl acetate or isopropyl acetate.

[0175] In some embodiments, the solvent in the solvates of compounds 21-A, 2-A, 3-A, 11-A, 15-A, 25-A, 38-A, or 59-A comprises acetone.

[0176] In some embodiments, the solvent in the solvates of compounds 21-A, 2-A, 3-A, 11-A, 15-A, 25-A, 38-A, or 59-A comprises tetrahydrofuran or 1,4-dioxane.

[0177] In some embodiments, the solvent in the solvates of compounds 21-A, 2-A, 3-A, 11-A, 15-A, 25-A, 38-A, or 59-A comprises acetonitrile.

[0178] Furthermore, this disclosure provides the crystal form of compound 3-A, or a solvate of compound 3-A.

[0179] Furthermore, this disclosure provides the crystal form of compound 3-A, or the crystal or amorphous form of the solvate of compound 3-A.

[0180] Furthermore, this disclosure provides the crystal form of compound 3-A, or the crystallization of the solvate of compound 3-A.

[0181] Furthermore, this disclosure provides the crystal form of compound 3-A.

[0182] Furthermore, this disclosure provides a solvate of compound 3-A.

[0183] Furthermore, this disclosure provides crystalline or amorphous forms of the solvate of compound 3-A.

[0184] Furthermore, this disclosure provides crystallization of the solvate of compound 3-A.

[0185] In another aspect, this disclosure provides the crystal form of compound 15-A, or the solvate of compound 15-A.

[0186] Furthermore, this disclosure provides the crystal form of compound 15-A, or the crystal or amorphous form of the solvate of compound 15-A.

[0187] In another aspect, this disclosure provides the crystal form of compound 15-A, or the crystallization of the solvate of compound 15-A.

[0188] Furthermore, this disclosure provides the crystal form of compound 15-A.

[0189] Furthermore, this disclosure provides a solvate of compound 15-A.

[0190] Furthermore, this disclosure provides crystalline or amorphous forms of the solvate of compound 15-A.

[0191] Furthermore, this disclosure provides crystallization of the solvate of compound 15-A.

[0192] In another aspect, this disclosure provides the crystal form of compound 21-A, or the solvate of compound 21-A.

[0193] Furthermore, this disclosure provides the crystal form of compound 21-A, or the crystal or amorphous form of the solvate of compound 21-A.

[0194] In another aspect, this disclosure provides the crystal form of compound 21-A, or the crystallization of the solvate of compound 21-A.

[0195] Furthermore, this disclosure provides the crystal form of compound 21-A.

[0196] Furthermore, this disclosure provides a solvate of compound 21-A.

[0197] Furthermore, this disclosure provides crystalline or amorphous forms of the solvate of compound 21-A.

[0198] Furthermore, this disclosure provides crystallization of the solvate of compound 21-A.

[0199] Furthermore, this disclosure provides the crystal form of compound 25-A.

[0200] In some embodiments, the solvent is selected from water or C 1-10 Alcohols.

[0201] In some embodiments, the solvent is selected from water or C 1-6 Alcohols.

[0202] In some embodiments, the solvent is selected from water or C 1-3 Alcohols.

[0203] In some embodiments, the solvent is selected from one or more of water, methanol, ethanol, or isopropanol.

[0204] In some embodiments, the solvent is selected from C 1-6 Alcohols.

[0205] In some embodiments, the solvent is selected from C 1-3 Alcohols.

[0206] In some embodiments, the solvent is selected from water.

[0207] In some embodiments, the solvent is selected from one or more of methanol, ethanol, or isopropanol.

[0208] This disclosure provides an A-form of compound 21-A, which, in X-ray powder diffraction (XRPD) patterns using Cu Kα rays, exhibits diffraction peaks at approximately 6.44 ± 0.20°, 8.19 ± 0.20°, or 12.84 ± 0.20°, expressed as a 2θ angle. In some embodiments, the aforementioned A-form exhibits diffraction peaks at approximately 6.44 ± 0.20°, 8.19 ± 0.20°, 12.84 ± 0.20°, 15.49 ± 0.20°, or 21.82 ± 0.20°. In some embodiments, the aforementioned crystal form A exhibits diffraction peaks at approximately 6.44±0.20°, 8.19±0.20°, 12.84±0.20°, 15.49±0.20°, 18.20±0.20°, 21.82±0.20°, or 25.86±0.20°. In some embodiments, the aforementioned crystal form A exhibits diffraction peaks at approximately 6.44±0.20°, 8.19±0.20°, 8.65±0.20°, 12.84±0.20°, 15.49±0.20°, 18.20±0.20°, 21.82±0.20°, 22.75±0.20°, or 25.86±0.20°. In some embodiments, the aforementioned crystal form A has diffraction peaks at approximately 6.44±0.20°, 8.19±0.20°, 8.65±0.20°, 11.49±0.20°, 12.84±0.20°, 15.49±0.20°, 16.84±0.20°, 18.20±0.20°, 21.08±0.20°, 21.82±0.20°, 22.75±0.20°, or 25.86±0.20°. In some embodiments, the aforementioned crystal form A has diffraction peaks at approximately 6.44±0.20°, 8.19±0.20°, 8.65±0.20°, 11.49±0.20°, 12.84±0.20°, 15.49±0.20°, 16.84±0.20°, 18.20±0.20°, 21.08±0.20°, 21.82±0.20°, 22.75±0.20°, 23.05±0.20°, or 25.86±0.20°.

[0209] In some embodiments, in X-ray powder diffraction (XRPD) patterns using Cu Kα rays, the aforementioned A crystal form has at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10 or more characteristic diffraction peaks at 2θ values ​​selected from about 6.44±0.20°, 8.19±0.20°, 8.65±0.20°, 11.49±0.20°, 12.84±0.20°, 15.49±0.20°, 16.84±0.20°, 18.20±0.20°, 21.08±0.20°, 21.82±0.20°, 22.75±0.20°, 23.05±0.20° or 25.86±0.20°.

[0210] In some embodiments of this disclosure, the XRPD pattern of the above-mentioned A-type crystal is as follows: Figure 1 As shown.

[0211] In some embodiments of this disclosure, the XRPD pattern of the above-mentioned crystal form A has characteristic diffraction peaks at the following 2θ angles, as shown in Table 1: Table 1: XRPD spectral data of crystal form A .

[0212] In some embodiments of this disclosure, the thermogravimetric analysis (TGA) curve of the above-mentioned A crystal form shows almost no weight loss when heated to 150°C.

[0213] In some embodiments of this disclosure, the TGA spectra of the aforementioned crystal form A are as follows: Figure 2 As shown.

[0214] On the other hand, this disclosure provides a method for preparing the above-mentioned crystal form A, comprising: 1) mixing compound 21-A with isopropyl acetate; 2) separating the solid to obtain crystal form A.

[0215] The above-mentioned method for preparing crystal form A, step 1) further includes mixing followed by heating and reflux (e.g., 60~100℃ or 90℃). Optionally, further, after the above heating and reflux, a gradient cooling is performed. The gradient cooling includes cooling from 60~100℃ or 90℃ to 0~30℃ or 0~10℃.

[0216] In some embodiments, the solid obtained in step 2) of the preparation method of the A crystal form is dried (at a temperature optionally 50~80°C or 60°C).

[0217] In some embodiments, the method for preparing the A crystal form includes: 1) adding compound 21-A to isopropyl acetate, heating and refluxing to dissolve (the temperature can optionally be 60~100℃ or 90℃), gradually cooling to (0~30℃ or 0~10℃) and stirring; 2) separating the solid; drying (the temperature can optionally be 50~80℃ or 60℃) the obtained solid to obtain the A crystal form.

[0218] In some embodiments, in the method for preparing the A crystal form, the mass-to-volume ratio of compound 21-A to isopropyl acetate in step 1) is selected from 1g:1~50mL, 1g:5~40mL, 1g:5~30mL, 1g:5~25mL, 1g:5~20mL, 1g:5~15mL, 1g:5~10mL, or 1g:8mL.

[0219] Furthermore, this disclosure provides a hydrate of compound 21-A. Furthermore, this disclosure provides a hydrate of compound 21-A that is crystalline or amorphous. Furthermore, this disclosure provides a hydrate of compound 21-A that is crystalline.

[0220] This disclosure provides a B-form of compound 21-A, which, in an X-ray powder diffraction (XRPD) pattern using Cu Kα rays, exhibits diffraction peaks at approximately 7.15 ± 0.20°, 9.71 ± 0.20°, or 21.78 ± 0.20°, expressed as a 2θ angle. In some embodiments, the aforementioned B-form exhibits diffraction peaks at approximately 7.15 ± 0.20°, 9.71 ± 0.20°, 14.35 ± 0.20°, 21.78 ± 0.20°, or 27.99 ± 0.20°. In some embodiments, the aforementioned B crystal form exhibits diffraction peaks at approximately 7.15±0.20°, 9.71±0.20°, 14.35±0.20°, 18.73±0.20°, 21.78±0.20°, 25.09±0.20°, or 27.99±0.20°. In some embodiments, the aforementioned B crystal form exhibits diffraction peaks at approximately 7.15±0.20°, 9.71±0.20°, 14.35±0.20°, 16.55±0.20°, 18.73±0.20°, 21.78±0.20°, 22.93±0.20°, 25.09±0.20°, or 27.99±0.20°. In some embodiments, the aforementioned B crystal form has diffraction peaks at approximately 7.15±0.20°, 9.71±0.20°, 10.05±0.20°, 14.35±0.20°, 16.55±0.20°, 17.32±0.20°, 18.73±0.20°, 21.78±0.20°, 22.93±0.20°, 25.09±0.20°, or 27.99±0.20°. In some embodiments, the aforementioned B crystal form exhibits diffraction peaks at approximately 7.15±0.20°, 9.71±0.20°, 10.05±0.20°, 14.35±0.20°, 16.55±0.20°, 17.32±0.20°, 18.73±0.20°, 19.74±0.20°, 21.78±0.20°, 22.93±0.20°, 25.09±0.20°, 27.99±0.20°, or 28.94±0.20°. In some embodiments, the aforementioned B crystal form exhibits diffraction peaks at approximately 7.15±0.20°, 9.71±0.20°, 10.05±0.20°, 14.35±0.20°, 16.07±0.20°, 16.55±0.20°, 17.32±0.20°, 18.73±0.20°, 19.74±0.20°, 21.78±0.20°, 22.51±0.20°, 22.93±0.20°, 25.09±0.20°, 27.99±0.20°, or 28.94±0.20°.

[0221] In some embodiments, in X-ray powder diffraction (XRPD) patterns using Cu Kα rays, the aforementioned B crystal form is selected from approximately 7.15±0.20°, 9.71±0.20°, 10.05±0.20°, 14.35±0.20°, 16.07±0.20°, 16.55±0.20°, 17.32±0.20°, 18.73±0.20°, 19.74±0.20°. It has at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10 or more characteristic diffraction peaks at 2θ values ​​of 0.20°, 21.78±0.20°, 22.51±0.20°, 22.93±0.20°, 25.09±0.20°, 27.99±0.20° or 28.94±0.20°.

[0222] In some implementations, the XRPD pattern of the B crystal form described above is as follows: Figure 3 As shown.

[0223] In some embodiments, the XRPD pattern of the B crystal form has characteristic diffraction peaks at the following 2θ angles, as shown in Table 2.

[0224] Table 2: XRPD pattern data of B crystal form .

[0225] In some implementations, the thermogravimetric analysis (TGA) curve of the B-type crystal shows a weight loss change of approximately 3.8% when the temperature is raised to 150°C.

[0226] In some embodiments of this disclosure, the TGA spectra of the B crystal form are as follows: Figure 4 As shown.

[0227] In some embodiments, the aforementioned crystal form B is either a hydrate or an amorphous form of compound 21-A. In some embodiments, the aforementioned crystal form B is the hydrate crystal form of compound 21-A.

[0228] In some embodiments of this disclosure, the molar ratio (i.e., the number of water molecules in the B crystal form described above) is approximately selected from 1:0.1~10, 1:0.5~10, 1:0.5~8, 1:0.5~7, 1:0.5~6, 1:0.5~5, 1:0.5~4, 1:0.5~3, 1:0.5~2, or 1:0.5~1. In some embodiments of this disclosure, the molar ratio (of compound 21-A to water molecules in the B crystal form described above) is approximately selected from 1:0.5, 1:1, 1:2, 1:3, or 1:4, or any range formed by the above values. In some embodiments of this disclosure, the molar ratio (of compound I to water molecules in the B crystal form described above) is approximately selected from 1:1.

[0229] In some embodiments, the aforementioned crystal form B is the hydrated crystal form of compound 21-A, wherein the water content is approximately 0.5%~20%wt, 1%~15%wt, 1%~12%wt, 1%~10%wt, 1%~8%wt, 1%~6%wt, 1%~4%wt, 2%~4%wt, or 3%~4%wt. In some embodiments, the aforementioned crystal form B is the hydrated crystal form of compound 21-A, wherein the water content is approximately 1%wt, 2%wt, 3%wt, 4%wt, 5%wt, 6%wt, 7%wt, 8%wt, 9%wt, 10%wt, 11%wt, 12%wt, 13%wt, 14%wt, or 15%wt, or any range of the aforementioned values. In some embodiments, the aforementioned crystal form B is the hydrated crystal form of compound 21-A, wherein the water content is approximately 4 wt%.

[0230] On the other hand, this disclosure provides a method for preparing the above-mentioned crystal form B, comprising: mixing compound 21-A with isopropyl acetate and water to obtain crystal form B.

[0231] In some embodiments, the method for preparing the B crystal form includes 1) mixing compound 21-A with isopropyl acetate and water; separating the solid; 2) adding water to the obtained solid and separating to obtain the B crystal form.

[0232] In some embodiments, the method for preparing the B crystal form includes: 1) mixing compound 21-A with isopropyl acetate and water and heating (the heating temperature may optionally be 70~100℃ or 90℃) to dissolve the solid, cooling the solution, and separating the solid; 2) optionally dissolving the obtained solid in water, heating (40~100℃, 40~70℃ or 50℃) and stirring the solution, and further optionally cooling the solution after heating and stirring to separate the solid.

[0233] In some embodiments, the method for preparing the B crystal form, step 1) cooling is a gradient cooling; optionally, cooling from 70~100℃ or 90℃ to 0~30℃ or 0~10℃.

[0234] In some embodiments, the method for preparing the B crystal form, step 2), cooling is a gradient cooling; optionally, cooling from 40~100℃, 40~70℃, or 50℃ to 10~30℃ or 20~30℃. In some embodiments, the solid obtained in step 2) of the method for preparing the B crystal form is dried.

[0235] In some embodiments, the method for preparing the B crystal form includes: 1) adding compound 21-A to a mixed solvent of isopropyl acetate:water = 100:1 (v:v), heating and refluxing to dissolve (temperature optionally 70~100℃ or 90℃), gradually cooling to (0~30℃ or 0~10℃) and stirring, and separating the solid; 2) further, adding the obtained solid to water (mass-volume ratio of solid to water 1g:5~50mL, 1g:5~30mL, 1g:5~20mL, 1g:5~10mL, or 1g:10mL), stirring (temperature 40~100℃, 40~70℃ or 50℃), cooling (to 10~30℃ or 20~30℃), stirring, separating the solid, and drying (temperature optionally 30~50℃ or 40℃) the obtained solid to obtain the B crystal form.

[0236] In some embodiments, in the method for preparing the B crystal form, the mass-to-volume ratio of compound 21-A to isopropyl acetate in step 1) is selected from 1g:10~50mL; or 1g:10~40mL; or 1g:10~30mL; or 1g:15~25mL; or 1g:20mL.

[0237] In some embodiments, in the method for preparing the B crystal form, the mass-volume ratio of compound 21-A to water in step 2) is selected from 1g:5~50mL, 1g:5~40mL, 1g:5~30mL, 1g:5~20mL, 1g:5~15mL, 1g:8~12mL, or 1g:10mL.

[0238] This disclosure provides the C-form of compound 21-A, which, in X-ray powder diffraction (XRPD) patterns using Cu Kα rays, exhibits diffraction peaks at approximately 9.51 ± 0.20°, 18.91 ± 0.20°, or 19.97 ± 0.20°, expressed as a 2θ angle. In some embodiments, the aforementioned C-form exhibits diffraction peaks at approximately 9.51 ± 0.20°, 13.46 ± 0.20°, 18.91 ± 0.20°, 19.97 ± 0.20°, or 20.55 ± 0.20°. In some embodiments, the aforementioned C-form exhibits diffraction peaks at approximately 9.51±0.20°, 13.46±0.20°, 15.30±0.20°, 18.91±0.20°, 19.97±0.20°, 20.55±0.20°, or 22.09±0.20°. In some embodiments, the aforementioned C-form exhibits diffraction peaks at approximately 9.16±0.20°, 9.51±0.20°, 13.46±0.20°, 15.30±0.20°, 17.67±0.20°, 18.91±0.20°, 19.97±0.20°, 20.55±0.20°, or 22.09±0.20°. In some implementations, the aforementioned C crystal form exhibits diffraction peaks at approximately 9.16±0.20°, 9.51±0.20°, 13.46±0.20°, 15.30±0.20°, 17.20±0.20°, 17.67±0.20°, 18.91±0.20°, 19.16±0.20°, 19.97±0.20°, 20.55±0.20°, 22.09±0.20°, or 28.35±0.20°.

[0239] In some embodiments, in X-ray powder diffraction (XRPD) patterns using Cu Kα rays, the aforementioned C crystal form has at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10 or more characteristic diffraction peaks at 2θ values ​​selected from about 9.16±0.20°, 9.51±0.20°, 13.46±0.20°, 15.30±0.20°, 17.20±0.20°, 17.67±0.20°, 18.91±0.20°, 19.16±0.20°, 19.97±0.20°, 20.55±0.20°, 22.09±0.20° or 28.35±0.20°.

[0240] In some embodiments of this disclosure, the XRPD pattern of the above-mentioned C-type crystal is as follows: Figure 5 As shown.

[0241] In some embodiments of this disclosure, the XRPD pattern of the C crystal form exhibits characteristic diffraction peaks at the following 2θ angles, as shown in Table 3: Table 3: XRPD spectral data of C-type crystals .

[0242] In some embodiments of this disclosure, the thermogravimetric analysis (TGA) curves of the C-type described above show almost no weight loss when heated to 150°C.

[0243] In some embodiments of this disclosure, the TGA spectra of the C-type crystal are as follows: Figure 6 As shown.

[0244] On the other hand, this disclosure provides a method for preparing the above-mentioned C crystal form, comprising: 1) mixing compound 21-A with acetone; 2) separating the solid to obtain the C crystal form.

[0245] In some embodiments, in the above-described method for preparing the C-form, compound 21-A is mixed with acetone and dissolved by heating and / or stirring. In some embodiments, in the method for preparing the C-form, the solid obtained in step 2) is dried (optionally at a temperature of 30-50°C or 40°C).

[0246] In some embodiments of this disclosure, in the above-mentioned method for preparing the C crystal form, the mass-volume ratio of compound 21-A to acetone is selected from 1g:5~50 mL, 1g:10~40 mL, 1g:10~30 mL, 1g:15~25 mL, 1g:8~12 mL, or 1g:10 mL.

[0247] In some embodiments, in the above-mentioned method for preparing the C crystal form, compound 21-A is mixed with acetone and optionally dissolved at 20-30°C, or dissolved by heating at 40-70°C, 40-60°C, 45-50°C, or 50°C.

[0248] This disclosure provides a D-form of compound 21-A, which, in an X-ray powder diffraction (XRPD) pattern using Cu Kα rays, exhibits diffraction peaks at approximately 7.87 ± 0.20° or 23.01 ± 0.20° at a 2θ angle. In some embodiments, the aforementioned D-form exhibits diffraction peaks at approximately 7.87 ± 0.20°, 8.38 ± 0.20°, 22.39 ± 0.20°, or 23.01 ± 0.20°. In some embodiments, the aforementioned D-form exhibits diffraction peaks at approximately 7.87 ± 0.20°, 8.38 ± 0.20°, 11.50 ± 0.20°, 22.39 ± 0.20°, 23.01 ± 0.20°, or 24.73 ± 0.20°. In some implementations, the aforementioned D crystal form exhibits diffraction peaks at approximately 7.87±0.20°, 8.38±0.20°, 11.50±0.20°, 12.72±0.20°, 14.81±0.20°, 18.23±0.20°, 22.39±0.20°, 23.01±0.20°, or 24.73±0.20°. In some implementations, the aforementioned D crystal form exhibits diffraction peaks at approximately 7.87±0.20°, 8.38±0.20°, 11.50±0.20°, 12.72±0.20°, 14.81±0.20°, 18.23±0.20°, 19.35±0.20°, 20.01±0.20°, 22.39±0.20°, 23.01±0.20°, or 24.73±0.20°. In some implementations, the aforementioned D crystal form exhibits diffraction peaks at approximately 7.87±0.20°, 8.38±0.20°, 11.06±0.20°, 11.50±0.20°, 12.72±0.20°, 14.81±0.20°, 18.23±0.20°, 19.35±0.20°, 20.01±0.20°, 21.64±0.20°, 22.39±0.20°, 23.01±0.20°, 23.77±0.20°, or 24.73±0.20°.

[0249] In some embodiments, in X-ray powder diffraction (XRPD) patterns using Cu Kα rays, the aforementioned D crystal form has at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10 or more characteristic diffraction peaks at 2θ values ​​selected from about 7.87±0.20°, 8.38±0.20°, 11.06±0.20°, 11.50±0.20°, 12.72±0.20°, 14.81±0.20°, 18.23±0.20°, 19.35±0.20°, 20.01±0.20°, 21.64±0.20°, 22.39±0.20°, 23.01±0.20°, 23.77±0.20° or 24.73±0.20°.

[0250] In some of the schemes disclosed herein, the XRPD patterns of the aforementioned D-type crystal are as follows: Figure 7 As shown.

[0251] In some embodiments of this disclosure, the XRPD pattern of the above-mentioned D crystal form exhibits characteristic diffraction peaks at the following 2θ angles, as shown in Table 4: Table 4: XRPD spectral data of D crystal form .

[0252] In some embodiments of this disclosure, the thermogravimetric analysis (TGA) curves of the above-mentioned D crystal form show a weight loss of 1.9% at 80°C and / or 3.9% at 150°C.

[0253] In some embodiments of this disclosure, the TGA spectra of the aforementioned D-type crystal are as follows: Figure 8 As shown.

[0254] In some embodiments of this disclosure, the above-mentioned D crystal form is the isopropanol complex crystal form of compound 21-A.

[0255] In some embodiments of this disclosure, the molar ratio (number ratio) of compound 21-A to isopropanol in the aforementioned D-crystal form is approximately selected from 1:0.2~5, 1:0.2~4, 1:0.2~3, 1:0.2~2, or 1:0.2~1. In some embodiments of this disclosure, the molar ratio (number ratio) of compound 21-A to isopropanol in the aforementioned D-crystal form is approximately selected from 1:0.3, 1:0.5, 1:1, 1:2, or 1:3, or any range formed by the aforementioned values. In some embodiments of this disclosure, the molar ratio (number ratio) of compound 21-A to isopropanol in the aforementioned D-crystal form is approximately selected from 1:0.5 or 1:1.

[0256] In some embodiments, the isopropanol content in the D-form is approximately 1%~20%wt, 1%~15%wt, 1%~12%wt, 1%~10%wt, 1%~8%wt, 1%~6%wt, or 3%~9%wt. In some embodiments, the isopropanol content in the D-form is approximately 1%wt, 2%wt, 3%wt, 4%wt, 5%wt, 6%wt, 7%wt, 8%wt, 9%wt, 10%wt, 11%wt, 12%wt, 13%wt, 14%wt, or 15%wt, or any range of the above values. In some embodiments, the isopropanol content in the D-form is approximately 4%wt, 6%wt, or 8%wt. In some embodiments, the isopropanol content in the D-form is approximately 4%wt. In some embodiments, the isopropanol content in the D-form is approximately 6%wt.

[0257] On the other hand, this disclosure provides a method for preparing the above-mentioned D crystal form, comprising: 1) mixing compound 21-A isopropanol; 2) separating the solid to obtain the D crystal form.

[0258] In some embodiments of this disclosure, in the above-mentioned method for preparing the D crystal form, the mass-volume ratio of compound 21-A to isopropanol is selected from 1g:5~50 mL, 1g:10~40 mL, 1g:10~30 mL, 1g:15~25 mL, 1g:8~12 mL, or 1g:10 mL.

[0259] This disclosure provides the E-form of compound 21-A, which, in X-ray powder diffraction (XRPD) patterns using Cu Kα rays, exhibits diffraction peaks at approximately 7.38 ± 0.20° or 23.40 ± 0.20° at a 2θ angle. In some embodiments, the aforementioned E-form exhibits diffraction peaks at approximately 7.38 ± 0.20°, 17.45 ± 0.20°, 23.40 ± 0.20°, or 25.04 ± 0.20°. In some embodiments, the aforementioned E-form exhibits diffraction peaks at approximately 7.38 ± 0.20°, 11.57 ± 0.20°, 17.45 ± 0.20°, 17.87 ± 0.20°, 23.40 ± 0.20°, or 25.04 ± 0.20°. In some embodiments, the aforementioned E-type crystal has diffraction peaks at approximately 7.38 ±0.20°, 11.57 ±0.20°, 17.45 ±0.20°, 17.87 ±0.20°, 19.05 ±0.20°, 23.40 ±0.20°, 23.63 ±0.20°, or 25.04 ±0.20°. In some embodiments, the aforementioned E-type crystal has diffraction peaks at approximately 7.38 ±0.20°, 11.57 ±0.20°, 17.25 ±0.20°, 17.45 ±0.20°, 17.87 ±0.20°, 18.45 ±0.20°, 19.05 ±0.20°, 23.40 ±0.20°, 23.63 ±0.20°, or 25.04 ±0.20°. In some implementations, the aforementioned E-type crystal has diffraction peaks at approximately 7.38 ±0.20°, 11.57 ±0.20°, 17.25 ±0.20°, 17.45 ±0.20°, 17.87 ±0.20°, 18.45 ±0.20°, 19.05 ±0.20°, 19.45 ±0.20°, 22.08 ±0.20°, 22.53 ±0.20°, 23.40 ±0.20°, 23.63 ±0.20°, 25.04 ±0.20°, or 28.62 ±0.20°.

[0260] In some embodiments, in X-ray powder diffraction (XRPD) patterns using Cu Kα rays, the aforementioned E crystal form has at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10 or more characteristic diffraction peaks at 2θ values ​​selected from about 7.38 ± 0.20°, 11.57 ± 0.20°, 17.25 ± 0.20°, 17.45 ± 0.20°, 17.87 ± 0.20°, 18.45 ± 0.20°, 19.05 ± 0.20°, 19.45 ± 0.20°, 22.08 ± 0.20°, 22.53 ± 0.20°, 23.40 ± 0.20°, 23.63 ± 0.20°, 25.04 ± 0.20° or 28.62 ± 0.20°.

[0261] In some embodiments of this disclosure, the XRPD pattern of the above-mentioned E-crystal form is as follows: Figure 9 As shown.

[0262] In some embodiments of this disclosure, the XRPD patterns of the above-mentioned E-type crystal have characteristic diffraction peaks at the following 2θ angles, as shown in Table 5: Table 5: XRPD spectral data of E-type crystals .

[0263] In some embodiments of this disclosure, the thermogravimetric analysis (TGA) curve of the E-type crystal shows a weight loss of 9.6% when heated to 150°C.

[0264] In some embodiments of this disclosure, the TGA spectra of the above-mentioned E-crystal form are as follows: Figure 10 As shown.

[0265] In some embodiments of this disclosure, the above-mentioned E crystal form is the ethanolic form of compound 21-A.

[0266] In some embodiments of this disclosure, the molar ratio of compound 21-A to ethanol in the E-form is approximately selected from 1:0.5~5, 1:0.5~4, 1:0.5~3, 1:0.5~2, 1:0.5~1.5; or 1:0.5~1. In some embodiments of this disclosure, the molar ratio of compound 21-A to ethanol in the E-form is approximately selected from 1:0.5, 1:1, 1:2, 1:3, 1:4, 1:5, or 1:6. In some embodiments of this disclosure, the molar ratio of compound 21-A to ethanol in the E-form is approximately selected from 1:1.

[0267] In some embodiments, the ethanol content in the E-crystal form is approximately 1-40% wt, 1-30% wt, 1%-20% wt, 2%-15% wt, 5%-10% wt, 5%-10% wt, or 7%-10% wt. In some embodiments, the ethanol content in the E-crystal form is approximately 1% wt, 2% wt, 3% wt, 4% wt, 5% wt, 6% wt, 7% wt, 8% wt, 9% wt, 10% wt, 11% wt, 12% wt, 13% wt, 14% wt, or 15% wt, or any range of the above values. In some embodiments, the ethanol content in the E-crystal form is approximately 7% wt or 10% wt. In some embodiments, the ethanol content in the E-crystal form is approximately 7% wt. In some embodiments, the ethanol content in the E-crystal form is approximately 10% wt.

[0268] On the other hand, this disclosure provides a method for preparing the above-mentioned E crystal form, comprising: 1) dissolving compound 21-A in a mixed solvent of ethanol and water; 2) separating the solid to obtain the E crystal form.

[0269] In some embodiments of this disclosure, in the above-mentioned method for preparing the E crystal form, the mass-volume ratio of compound 21-A to ethanol is selected from 1g:5~50 mL, 1g:10~40 mL, 1g:10~30 mL, 1g:15~25 mL, 1g:8~12 mL, or 1g:10 mL.

[0270] In some embodiments of this disclosure, in the above-mentioned method for preparing the E crystal form, the mass-to-volume ratio of compound 21-A to water is selected from 1g: 0.1~10mL, 1g: 0.1~8mL, 1g: 0.1~5mL, 1g: 0.1~4mL, 1g: 0.1~3mL, 1g: 0.1~2mL, 1g: 0.1~1.0mL, 1g: 0.1~0.5mL, or 1g: 0.2mL.

[0271] This disclosure provides the F-form of compound 21-A, which, in X-ray powder diffraction (XRPD) patterns using Cu Kα rays, exhibits diffraction peaks at approximately 7.59 ± 0.20°, 23.28 ± 0.20°, or 24.94 ± 0.20°, expressed as a 2θ angle. In some embodiments, the aforementioned F-form exhibits diffraction peaks at approximately 7.59 ± 0.20°, 11.83 ± 0.20°, 17.77 ± 0.20°, 23.28 ± 0.20°, or 24.94 ± 0.20°. In some embodiments, the aforementioned F crystal form exhibits diffraction peaks at approximately 7.59±0.20°, 11.83±0.20°, 17.77±0.20°, 19.44±0.20°, 23.28±0.20°, 23.70±0.20°, or 24.94±0.20°. In some embodiments, the aforementioned F crystal form exhibits diffraction peaks at approximately 7.59±0.20°, 8.05±0.20°, 11.83±0.20°, 17.77±0.20°, 19.44±0.20°, 22.60±0.20°, 23.28±0.20°, 23.70±0.20°, or 24.94±0.20°. In some implementations, the aforementioned F crystal form exhibits diffraction peaks at approximately 7.59±0.20°, 8.05±0.20°, 11.83±0.20°, 17.77±0.20°, 19.44±0.20°, 22.60±0.20°, 23.28±0.20°, 23.70±0.20°, 24.20±0.20°, 24.94±0.20°, or 28.68±0.20°.

[0272] In some embodiments, in X-ray powder diffraction (XRPD) patterns using Cu Kα rays, the aforementioned F crystal form has at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10 or more characteristic diffraction peaks at 2θ values ​​selected from about 7.59±0.20°, 8.05±0.20°, 11.83±0.20°, 17.77±0.20°, 19.44±0.20°, 22.60±0.20°, 23.28±0.20°, 23.70±0.20°, 24.20±0.20°, 24.94±0.20° or 28.68±0.20°.

[0273] In some embodiments of this disclosure, the XRPD pattern of the above-mentioned F crystal form is as follows: Figure 11 As shown.

[0274] In some embodiments of this disclosure, the XRPD patterns of the above-mentioned F crystal form exhibit characteristic diffraction peaks at the following 2θ angles, as shown in Table 6: Table 6: XRPD spectral data of F crystal form .

[0275] In some embodiments of this disclosure, the thermogravimetric analysis (TGA) curve of the above-mentioned F crystal form shows a weight loss of 3.7% when the temperature is raised to 150±3℃.

[0276] In some embodiments of this disclosure, the TGA spectra of the aforementioned F crystal form are as follows: Figure 12 As shown.

[0277] In some embodiments of this disclosure, the above-mentioned F crystal form is the methanolic crystal form of compound 21-A.

[0278] In some embodiments of this disclosure, the molar ratio (number of compounds 21-A to methanol in the F-crystal form is approximately selected from 1:0.1~6, 1:0.1~5, 1:0.1~4, 1:0.5~4, 1:0.5~3, 1:0.5~2, 1:0.5~1, or 1:1. In some embodiments of this disclosure, the molar ratio (number of compounds 21-A to methanol in the F-crystal form is approximately selected from 1:0.1, 1:0.5, 1:1, 1:1.5, 1:2, 1:3, 1:4, 1:5, or 1:6, or any range of the above values. In some embodiments of this disclosure, the molar ratio (number of compounds 21-A to methanol in the F-crystal form is approximately selected from 1:0.5 or 1:1.

[0279] In some embodiments, the methanol content in the F-crystal form is approximately 1%~20%wt, 1%~15%wt, 1%~12%wt, 1%~10%wt, 1%~8%wt, 2%~6%wt, or 2%~4%wt. In some embodiments, the methanol content in the F-crystal form is approximately 1%wt, 2%wt, 3%wt, 4%wt, 5%wt, 6%wt, 7%wt, 8%wt, 9%wt, 10%wt, 11%wt, 12%wt, 13%wt, 14%wt, or 15%wt, or any range of the above values. In some embodiments, the methanol content in the F-crystal form is approximately 2%wt or 4%wt. In some embodiments, the methanol content in the F-crystal form is approximately 2%wt. In some embodiments, the methanol content in the F-crystal form is approximately 4%wt.

[0280] On the other hand, this disclosure provides a method for preparing the above-mentioned F crystal form, comprising: 1) dissolving compound 21-A in a mixed solvent of isopropyl acetate, methanol and water; 2) separating the solid to obtain the F crystal form.

[0281] In some embodiments of this disclosure, in the above-mentioned method for preparing the F crystal form, the mass-volume ratio of compound 21-A to isopropyl acetate is selected from 1g:5~50 mL, 1g:10~40 mL, 1g:10~30 mL, 1g:10~25 mL, 1g:10~20 mL, or 1g:15 mL.

[0282] In some embodiments of this disclosure, in the above-mentioned method for preparing the F crystal form, the mass-volume ratio of compound 21-A to methanol is selected from 1g: 0.1~10mL, 1g: 0.2~8mL, 1g: 0.2~5mL, 1g: 0.5~4mL, 1g: 1~3mL, 1g: 2~3mL, or 1g: 2.5mL.

[0283] In some embodiments of this disclosure, in the above-mentioned method for preparing the F crystal form, the mass-volume ratio of compound 21-A to water is selected from 1g: 0.1~10mL, 1g: 0.2~8mL, 1g: 0.2~5mL, 1g: 0.2~4mL, 1g: 0.2~2mL, 1g: 0.2~1mL, or 1g: 0.5mL.

[0284] In one specific embodiment, this disclosure provides a G crystal form of compound 21-A, characterized by: a monoclinic crystal system; space group P-1; cell parameters: a = 10.9919(3) Å, b = 14.7579(4) Å, c = 16.0678(4) Å, α = 108.8840(10)°, β = 105.1420(10)°, γ = 98.9680(10)°; Z = 2.

[0285] In one specific embodiment, the G crystal form of compound 21-A is wherein the molecular ratio (molar ratio) is compound 21-A: ethyl acetate: water = 2:1:3.

[0286] This disclosure provides the A crystal form of compound 3-A, which, in X-ray powder diffraction (XRPD) patterns using Cu Kα rays, exhibits diffraction peaks at approximately 10.48 ± 0.20°, 19.46 ± 0.20°, 21.56 ± 0.20°, or 23.28 ± 0.20°, expressed as a 2θ angle.

[0287] In some embodiments, the A crystal form of compound 3-A has diffraction peaks at approximately 10.48±0.20°, 12.78±0.20°, 19.46±0.20°, 20.74±0.20°, 21.56±0.20°, 21.94±0.20° or 23.28±0.20°.

[0288] In some embodiments, the A crystal form of compound 3-A has diffraction peaks at approximately 10.48±0.20°, 12.78±0.20°, 14.68±0.20°, 18.49±0.20°, 19.07±0.20°, 19.46±0.20°, 21.02±0.20°, 20.74±0.20°, 21.56±0.20°, 21.94±0.20°, or 23.28±0.20°.

[0289] In some embodiments, the A crystal form of compound 3-A exhibits diffraction peaks at approximately 10.48±0.20°, 11.89±0.20°, 12.78±0.20°, 14.68±0.20°, 18.49±0.20°, 19.07±0.20°, 19.46±0.20°, 21.02±0.20°, 20.74±0.20°, 21.56±0.20°, 21.94±0.20°, 22.33±0.20°, or 23.28±0.20°.

[0290] In some embodiments, in X-ray powder diffraction (XRPD) patterns using Cu Kα rays, the A crystal form of the above compound 3-A has at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10 or more characteristic diffraction peaks at 2θ values ​​selected from about 10.48±0.20°, 11.89±0.20°, 12.78±0.20°, 14.68±0.20°, 18.49±0.20°, 19.07±0.20°, 19.46±0.20°, 21.02±0.20°, 20.74±0.20°, 21.56±0.20°, 21.94±0.20°, 22.33±0.20° or 23.28±0.20°.

[0291] In some embodiments of this disclosure, the XRPD pattern of the A crystal form of the above-mentioned compound 3-A is as follows: Figure 14 As shown.

[0292] In some embodiments of this disclosure, the XRPD pattern of the A crystal form of the above-mentioned compound 3-A exhibits characteristic diffraction peaks at the following 2θ angles, as shown in Table 7: Table 7: XRPD data of crystal form A of compound 3-A .

[0293] In some embodiments of this disclosure, the thermogravimetric analysis (TGA) curve of the A crystal form of the above-mentioned compound 3-A shows a weight loss of 0.10% when heated to approximately 150 ± 3 °C. In some embodiments of this disclosure, the TGA spectrum of the A crystal form of the above-mentioned compound 3-A is as follows: Figure 15As shown.

[0294] In some embodiments of this disclosure, the differential scanning calorimetry (DSC) curve of the A crystal form of the above-mentioned compound 3-A has an endothermic peak at 248.05±3℃.

[0295] In some embodiments of this disclosure, the differential scanning calorimetry (DSC) curves of the A crystal form of the above-mentioned compound 3-A are as follows: Figure 16 As shown.

[0296] In some embodiments of this disclosure, the A crystal form of the above-mentioned compound 3-A is the anhydrous crystal form of compound 3-A.

[0297] On the other hand, this disclosure provides a method for preparing the A crystal form of the above-mentioned compound 3-A, comprising: 1) mixing compound 3-3 with pyridine and Boc anhydride in 1,4-dioxane; 2) mixing with ammonium bicarbonate; 3) mixing with isopropyl acetate and n-heptane; 4) mixing with isopropyl acetate; 5) separating the solid to obtain the A crystal form of compound 3-A.

[0298] On the other hand, this disclosure provides a method for preparing the A crystal form of the above-mentioned compound 3-A, comprising: mixing compound 3-A with isopropyl acetate (or, and n-heptane), separating the solid, and obtaining the A crystal form of compound 3-A.

[0299] In some embodiments, the method for preparing the A crystal form of compound 3-A, step 4) further includes mixing with isopropyl acetate, heating to 60~100℃ or 80℃ and stirring, then cooling to 10~30℃ or stirring at room temperature.

[0300] In some embodiments, the mass-volume ratio of compound 3-3 in step 1) to isopropyl acetate / n-heptane (v / v=1:1) in step 3) is 1g: 1~50mL, 1g: 5~40mL, 1g: 5~30mL, 1g: 5~25mL, 1g: 5~20mL, 1g: 5~15mL, 1g: 5~10mL, or 1g: 10mL.

[0301] In some embodiments, the mass-to-volume ratio of compound 3-3 in step 1) to isopropyl acetate in step 4) is 1g: 1~50mL, 1g: 5~40mL, 1g: 5~30mL, 1g: 5~25mL, 1g: 5~20mL, 1g: 5~15mL, 1g: 5~10mL, or 1g: 10mL.

[0302] This disclosure provides the B crystal form of compound 3-A, in which the C crystal form of compound 3-A, represented by a 2θ angle, has diffraction peaks at approximately 7.21 ± 0.20°, 23.03 ± 0.20°, or 24.18 ± 0.20° in X-ray powder diffraction (XRPD) patterns using Cu Kα rays.

[0303] In some embodiments, the B crystal form of compound 3-A has diffraction peaks at approximately 7.21±0.20°, 19.74±0.20°, 21.31±0.20°, 21.68±0.20°, 22.03±0.20°, 23.03±0.20°, or 24.18±0.20°.

[0304] In some embodiments, the B crystal form of compound 3-A has diffraction peaks at approximately 7.21±0.20°, 12.56±0.20°, 13.47±0.20°, 13.87±0.20°, 19.74±0.20°, 21.31±0.20°, 21.68±0.20°, 22.03±0.20°, 23.03±0.20°, or 24.18±0.20°.

[0305] In some embodiments, the B crystal form of compound 3-A exhibits diffraction peaks at approximately 7.21±0.20°, 12.56±0.20°, 13.47±0.20°, 13.87±0.20°, 18.31±0.20°, 18.60±0.20°, 19.74±0.20°, 21.31±0.20°, 21.68±0.20°, 22.03±0.20°, 23.03±0.20°, 24.18±0.20°, or 24.95±0.20°.

[0306] In some embodiments, in X-ray powder diffraction (XRPD) patterns using Cu Kα rays, the B crystal form of the above compound 3-A has at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10 or more characteristic diffraction peaks at 2θ values ​​selected from about 7.21±0.20°, 12.56±0.20°, 13.47±0.20°, 13.87±0.20°, 18.31±0.20°, 18.60±0.20°, 19.74±0.20°, 21.31±0.20°, 21.68±0.20°, 22.03±0.20°, 23.03±0.20°, 24.18±0.20° or 24.95±0.20°.

[0307] In some embodiments of this disclosure, the XRPD pattern of the B crystal form of the above-mentioned compound 3-A is as follows: Figure 17 As shown.

[0308] In some embodiments of this disclosure, the XRPD pattern of the B crystal form of the above-mentioned compound 3-A exhibits characteristic diffraction peaks at the following 2θ angles, as shown in Table 9: Table 9: XRPD data of crystal form B of compound 3-A .

[0309] In some embodiments of this disclosure, the thermogravimetric analysis (TGA) curve of the B crystal form of the above-mentioned compound 3-A shows a weight loss of 6.8% during the heating process.

[0310] In some embodiments of this disclosure, the thermogravimetric analysis (TGA) curves of the B crystal form of the above-mentioned compound 3-A are as follows: Figure 17-A As shown.

[0311] In some embodiments of this disclosure, the B crystal form of the above-mentioned compound 3-A is the 1,4-dioxane solvate crystal form of compound 3-A.

[0312] In some embodiments of this disclosure, the molar ratio of compound 3-A to 1,4-dioxane in the B crystal form of the above-mentioned compound 3-A is approximately selected from: 1:0.2~2; or 1:0.2~1; or 1:0.3~0.8; or 1:0.5.

[0313] In some embodiments, the content of 1,4-dioxane in the B-crystal form of compound 3-A is approximately 4%~15%wt, 5%~10%wt, or 6%~8%wt. In some embodiments, the content of 1,4-dioxane in the B-crystal form of compound 3-A is approximately 4%wt, 5%wt, 6%wt, 7%wt, 8%wt, 9%wt, 10%wt, 11%wt, 12%wt, 13%wt, 14%wt, or 15%wt, or any range of the above values. In some embodiments, the content of 1,4-dioxane in the B-crystal form of compound 3-A is approximately 6%wt, 7%wt, or 8%wt.

[0314] On the other hand, this disclosure provides a method for preparing the B crystal form of the above-mentioned compound 3-A, comprising: 1) mixing compound 3-A with 1,4-dioxane; 2) adding petroleum ether to crystallize; and 3) separating the solid to obtain the B crystal form.

[0315] On the other hand, this disclosure provides a method for preparing the B crystal form of the above-mentioned compound 3-A, comprising: 1) mixing the A crystal of compound 3-A with 1,4-dioxane; 2) adding petroleum ether to crystallize; 3) separating the solid to obtain the B crystal form.

[0316] In some embodiments, in the method for preparing the B crystal form of the above-mentioned compound 3-A, the A crystal of compound 3-A is mixed with 1,4-dioxane and then further dissolved in a water bath by heating (the temperature can be optionally 50~80°C, 50~70°C, 60~70°C or 65°C).

[0317] In some embodiments, the method for preparing the B crystal form of the above compound 3-A, step 3) includes centrifugation, removal of supernatant, and drying (at a temperature optionally 30~60°C, 30~50°C or 40°C) to obtain the B crystal form.

[0318] In some embodiments, the method for preparing the B crystal form of the above-mentioned compound 3-A, wherein the mass-volume ratio of the A crystal of compound 3-A to 1,4-dioxane is selected from 1g:50~500 mL, 1g:50~400 mL, 1g:50~300 mL, 1g:50~200 mL, 1g:100~200 mL or 1g:100 mL.

[0319] In some embodiments, the method for preparing the B crystal form of the above-mentioned compound 3-A, wherein the mass-volume ratio of the A crystal of compound 3-A to petroleum ether is selected from 1g:1000~5000 mL, 1g:1000~4000 mL, 1g:2000~4000 mL, 1g:2000~3000 mL, or 1g:2500 mL.

[0320] This disclosure provides the C crystal form of compound 3-A, in which the D crystal form of compound 3-A, represented by a 2θ angle, has diffraction peaks at approximately 8.40±0.20°, 19.29±0.20°, 22.11±0.20°, or 22.89±0.20° in X-ray powder diffraction (XRPD) patterns using Cu Kα rays.

[0321] In some embodiments, the C crystal form of compound 3-A has diffraction peaks at approximately 8.40±0.20°, 18.62±0.20°, 19.29±0.20°, 20.35±0.20°, 21.30±0.20°, 22.11±0.20°, 22.89±0.20° or 26.27±0.20°.

[0322] In some embodiments, the C crystal form of compound 3-A exhibits diffraction peaks at approximately 8.40±0.20°, 14.87±0.20°, 16.83±0.20°, 17.10±0.20°, 18.62±0.20°, 19.29±0.20°, 20.35±0.20°, 21.30±0.20°, 22.11±0.20°, 22.89±0.20°, or 26.27±0.20°.

[0323] In some embodiments, the C crystal form of compound 3-A exhibits diffraction peaks at approximately 8.40±0.20°, 13.08±0.20°, 14.58±0.20°, 14.87±0.20°, 16.83±0.20°, 17.10±0.20°, 18.62±0.20°, 19.29±0.20°, 20.35±0.20°, 21.30±0.20°, 22.11±0.20°, 22.89±0.20°, 23.47±0.20°, 25.43±0.20°, or 26.27±0.20°.

[0324] In some embodiments, in X-ray powder diffraction (XRPD) patterns using Cu Kα rays, the C crystal form of the above compound 3-A is selected from about 8.40±0.20°, 13.08±0.20°, 14.58±0.20°, 14.87±0.20°, 16.83±0.20°, 17.10±0.20°, 18.62±0.20°, 19.29±0.20°, and 20. It has at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10 or more characteristic diffraction peaks at 2θ values ​​of 35±0.20°, 21.30±0.20°, 22.11±0.20°, 22.89±0.20°, 23.47±0.20°, 25.43±0.20° or 26.27±0.20°.

[0325] In some embodiments of this disclosure, the XRPD pattern of the C-crystal form of the above-mentioned compound 3-A is as follows: Figure 18 As shown.

[0326] In some embodiments of this disclosure, the thermogravimetric analysis (TGA) curve of the C crystal form of the above-mentioned compound 3-A shows a weight loss of 5.63% during the heating process.

[0327] In some embodiments of this disclosure, the thermogravimetric analysis (TGA) curves of the C-crystal form of the above-mentioned compound 3-A are shown in the figure. Figure 18-A As stated above.

[0328] In some embodiments of this disclosure, the C crystal form of compound 3-A is the tetrahydrofuran solvate crystal form of compound 3-A.

[0329] In some embodiments of this disclosure, the molar ratio of compound 3-A to tetrahydrofuran in the C crystal form of the above-mentioned compound 3-A is approximately selected from: 1:0.2~2; or 1:0.2~1; or 1:0.3~0.8; or 1:0.5.

[0330] In some embodiments, the tetrahydrofuran content in the C-crystal form of compound 3-A is approximately 4%~15%wt, 5%~10%wt, or 5%~8%wt. In some embodiments, the tetrahydrofuran content in the C-crystal form of compound 3-A is approximately 4%wt, 5%wt, 6%wt, 7%wt, 8%wt, 9%wt, 10%wt, 11%wt, 12%wt, 13%wt, 14%wt, or 15%wt, or any range of the above values. In some embodiments, the tetrahydrofuran content in the C-crystal form of compound 3-A is approximately 5%wt, 6%wt, or 7%wt.

[0331] On the other hand, this disclosure provides a method for preparing the C crystal form of the above-mentioned compound 3-A, comprising: 1) mixing compound 3-A with tetrahydrofuran; 2) heating to remove tetrahydrofuran to obtain the C crystal form.

[0332] On the other hand, this disclosure provides a method for preparing the C crystal form of the above-mentioned compound 3-A, comprising: 1) mixing the A crystal of compound 3-A with tetrahydrofuran; 2) heating to remove the tetrahydrofuran to obtain the C crystal form.

[0333] In some embodiments, in the method for preparing the C crystal form of the above-mentioned compound 3-A, the A crystal of compound 3-A is mixed with tetrahydrofuran and dried at 50~80°C to obtain the C crystal form.

[0334] In some embodiments, in the method for preparing the C crystal form of the above-mentioned compound 3-A, the A crystal of compound 3-A is mixed with tetrahydrofuran and then optionally dried in a water bath at 50~80°C, 50~70°C, 60~70°C, or 65°C to obtain the C crystal form.

[0335] In some embodiments of this disclosure, in the above-mentioned method for preparing the C crystal form, the mass-volume ratio of the A crystal of compound 3-A to tetrahydrofuran is selected from 1g:1000~5000 mL, 1g:1000~4000 mL, 1g:1000~3000 mL or 1g:2000 mL.

[0336] In some embodiments of this disclosure, the XRPD pattern of the C-type crystal form of the above-mentioned compound 3-A exhibits characteristic diffraction peaks at the following 2θ angles, as shown in Table 10: Table 10: XRPD data of the C-crystal form of compound 3-A .

[0337] This disclosure provides the A crystal form of compound 15-A, which, in X-ray powder diffraction (XRPD) patterns using Cu Kα rays, exhibits diffraction peaks at approximately 17.08 ± 0.20°, 20.23 ± 0.20°, or 20.97 ± 0.20°, expressed as a 2θ angle.

[0338] In some embodiments, the A crystal form of compound 15-A has diffraction peaks at approximately 8.13±0.20°, 15.63±0.20°, 17.08±0.20°, 19.94±0.20°, 20.23±0.20°, 20.97±0.20°, 21.87±0.20°, or 23.63±0.20°.

[0339] In some embodiments, the A crystal form of compound 15-A exhibits diffraction peaks at approximately 8.13±0.20°, 9.63±0.20°, 14.27±0.20°, 15.63±0.20°, 17.08±0.20°, 19.22±0.20°, 19.94±0.20°, 20.23±0.20°, 20.97±0.20°, 21.32±0.20°, 21.87±0.20°, 22.48±0.20°, or 23.63±0.20°.

[0340] In some embodiments, the A crystal form of compound 15-A exhibits diffraction peaks at approximately 8.13±0.20°, 9.63±0.20°, 11.78±0.20°, 13.36±0.20°, 14.27±0.20°, 15.63±0.20°, 17.08±0.20°, 19.22±0.20°, 19.94±0.20°, 20.23±0.20°, 20.97±0.20°, 21.32±0.20°, 21.87±0.20°, 22.48±0.20°, 23.63±0.20°, 24.26±0.20°, or 25.05±0.20°.

[0341] In some embodiments, in X-ray powder diffraction (XRPD) patterns using Cu Kα rays, the A crystal form of the above compound 15-A is selected from about 8.13±0.20°, 9.63±0.20°, 11.78±0.20°, 13.36±0.20°, 14.27±0.20°, 15.63±0.20°, 17.08±0.20°, 19.22±0.20°, 19.94±0.20°, and 20. It has at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10 or more characteristic diffraction peaks at 2θ values ​​of 23±0.20°, 20.97±0.20°, 21.32±0.20°, 21.87±0.20°, 22.48±0.20°, 23.63±0.20°, 24.26±0.20° or 25.05±0.20°.

[0342] In some embodiments of this disclosure, the XRPD pattern of the A crystal form of the above-mentioned compound 15-A is as follows: Figure 19 As shown.

[0343] In some embodiments of this disclosure, the thermogravimetric analysis (TGA) curve of the A crystal form of the above-mentioned compound 15-A shows a weight loss of 0.4% when heated to 150±3°C.

[0344] In some embodiments of this disclosure, the TGA spectrum of the A crystal form of the above-mentioned compound 15-A is as follows: Figure 20 As shown.

[0345] In some embodiments of this disclosure, the A crystal form of compound 15-A is the anhydrous crystal form of compound 15-A.

[0346] In some embodiments of this disclosure, the differential scanning calorimetry (DSC) curve of the A crystal form of the above-mentioned compound 15-A has an endothermic peak at 242.95±3℃.

[0347] In some embodiments of this disclosure, the differential scanning calorimetry (DSC) curve of the A crystal form of the above-mentioned compound 15-A is as follows: Figure 21 As shown.

[0348] On the other hand, this disclosure provides a method for preparing the A crystal form of the above-mentioned compound 15-A, comprising: 1) mixing compound 15-3 with pyridine and Boc anhydride in 1,4-dioxane; 2) mixing with ammonium bicarbonate; 3) mixing with isopropyl acetate; 4) separating the solid to obtain the A crystal form of compound 15-A.

[0349] On the other hand, this disclosure provides a method for preparing the A crystal form of the above-mentioned compound 15-A, comprising: mixing compound 15-A with isopropyl acetate; separating the solid to obtain the A crystal form of compound 15-A.

[0350] The method for preparing the A crystal form of the above compound 15-A, step 1) further includes mixing and reacting at 10~30℃ (e.g., room temperature).

[0351] In some embodiments, the method for preparing the A crystal form of compound 15-A, step 2) further includes mixing, stirring at 10~30°C (e.g., room temperature), adding water, and stirring to precipitate the product.

[0352] In some embodiments, the method for preparing the A crystal form of compound 15-A, step 2) further includes filtering the precipitated product, extracting the filter cake with ethyl acetate, washing, drying, and concentrating to obtain a crude product.

[0353] In some embodiments, the method for preparing the A crystal form of compound 15-A, step 3) includes recrystallization after mixing with isopropyl acetate.

[0354] In some embodiments, the mass-volume ratio of compound 15-3 in step 1) to isopropyl acetate in step 3) is 1g: 5~30mL, 1g: 5~20mL, 1g: 5~15mL, 1g: 8~12mL, 1g: 8~10mL, or 1g: 9.23mL.

[0355] In some embodiments of this disclosure, the XRPD pattern of the A crystal form of the above-mentioned compound 15-A exhibits characteristic diffraction peaks at the following 2θ angles, as shown in Table 11: Table 11: XRPD data of crystal form A of compound 15-A .

[0356] This disclosure provides the B crystal form of compound 15-A, which, in X-ray powder diffraction (XRPD) patterns using Cu Kα rays, exhibits diffraction peaks at approximately 6.30 ± 0.20°, 16.79 ± 0.20°, or 24.00 ± 0.20°, expressed as 2θ angles.

[0357] In some embodiments, the B crystal form of compound 15-A has diffraction peaks at approximately 6.30±0.20°, 7.85±0.20°, 16.79±0.20°, 18.43±0.20°, 22.85±0.20° or 24.00±0.20°.

[0358] In some embodiments, the B crystal form of compound 15-A exhibits diffraction peaks at approximately 6.30±0.20°, 7.85±0.20°, 10.18±0.20°, 12.21±0.20°, 15.69±0.20°, 16.79±0.20°, 17.69±0.20°, 18.43±0.20°, 18.80±0.20°, 22.85±0.20°, and 24.00±0.20°.

[0359] In some embodiments, the B crystal form of compound 15-A exhibits diffraction peaks at approximately 6.30±0.20°, 7.85±0.20°, 10.18±0.20°, 12.21±0.20°, 14.71±0.20°, 15.69±0.20°, 16.79±0.20°, 17.69±0.20°, 18.43±0.20°, 18.80±0.20°, 22.85±0.20°, 24.00±0.20°, or 26.08±0.20°.

[0360] In some embodiments, the B crystal form of compound 15-A exhibits diffraction peaks at approximately 6.30±0.20°, 7.85±0.20°, 10.18±0.20°, 12.21±0.20°, 14.71±0.20°, 15.69±0.20°, 16.79±0.20°, 17.69±0.20°, 18.43±0.20°, 18.80±0.20°, 21.23±0.20°, 22.85±0.20°, 24.00±0.20°, 26.08±0.20°, or 26.72±0.20°.

[0361] In some embodiments, in X-ray powder diffraction (XRPD) patterns using Cu Kα rays, the B crystal form of the above compound 15-A is selected from about 6.30±0.20°, 7.85±0.20°, 10.18±0.20°, 12.21±0.20°, 14.71±0.20°, 15.69±0.20°, 16.79±0.20°, 17.69±0.20°, 18. It has at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10 or more characteristic diffraction peaks at 2θ values ​​of 43±0.20°, 18.80±0.20°, 21.23±0.20°, 22.85±0.20°, 24.00±0.20°, 26.08±0.20° or 26.72±0.20°.

[0362] In some embodiments of this disclosure, the XRPD pattern of the B crystal form of the above-mentioned compound 15-A is as follows: Figure 22 As shown.

[0363] In some embodiments of this disclosure, the thermogravimetric analysis (TGA) curve of the B crystal form of compound 15-A shows a weight loss of 6.46% during the heating process. In some embodiments of this disclosure, the B crystal form of compound 15-A is the acetonitrile form of compound 15-A.

[0364] In some embodiments of this disclosure, the molar ratio of compound 15-A to acetonitrile in the B crystal form of the above-mentioned compound 15-A is approximately selected from: 1:0.2~2; or 1:0.5~1.5; or 1:0.5~1; or 1:1.

[0365] In some embodiments, the acetonitrile content in the B-crystal form of compound 15-A is approximately 4%~15%wt, 5%~10%wt, or 6%~8%wt. In some embodiments, the acetonitrile content in the B-crystal form of compound 15-A is approximately 4%wt, 5%wt, 6%wt, 7%wt, 8%wt, 9%wt, 10%wt, 11%wt, 12%wt, 13%wt, 14%wt, or 15%wt, or any range of the above values. In some embodiments, the acetonitrile content in the B-crystal form of compound 15-A is approximately 6%wt, 7%wt, or 8%wt.

[0366] On the other hand, this disclosure provides a method for preparing the B crystal form of the above-mentioned compound 15-A, comprising: 1) mixing compound 15-A with acetonitrile; 2) cooling and crystallizing to obtain the B crystal form.

[0367] On the other hand, this disclosure provides a method for preparing the B crystal form of the above-mentioned compound 15-A, comprising: 1) mixing the A crystal of compound 15-A with acetonitrile; 2) cooling and crystallizing to obtain the B crystal form.

[0368] In some embodiments, in the method for preparing the B crystal form of the above-mentioned compound 15-A, the A crystal of compound 15-A is mixed with acetonitrile and then cooled to crystallize. Further, optionally, it is dried at 30~60°C, 30~50°C, or 40°C to obtain the B crystal form.

[0369] In some embodiments of this disclosure, in the above-mentioned method for preparing crystal form B, the mass-volume ratio of crystal A of compound 15-A to acetonitrile is selected from 1g:100~500 mL, 1g:100~400 mL, 1g:200~400 mL, 1g:250~350 mL or 1g:300 mL.

[0370] In some embodiments of this disclosure, the XRPD pattern of the B crystal form of the above-mentioned compound 15-A exhibits characteristic diffraction peaks at the following 2θ angles, as shown in Table 12: Table 12: XRPD data of crystal form B of compound 15-A .

[0371] This disclosure provides the A crystal form of compound 25-A, which, in X-ray powder diffraction (XRPD) patterns using Cu Kα rays, exhibits diffraction peaks at approximately 4.53 ± 0.20°, 7.13 ± 0.20°, 16.30 ± 0.20°, or 20.50 ± 0.20°, expressed as a 2θ angle.

[0372] In some embodiments, the A crystal form of compound 25-A has diffraction peaks at approximately 4.53±0.20°, 7.13±0.20°, 9.04±0.20°, 16.30±0.20°, 19.21±0.20°, 20.50±0.20°, 20.87±0.20°, 24.54±0.20°, or 25.92±0.20°.

[0373] In some embodiments, the A crystal form of compound 25-A exhibits diffraction peaks at approximately 4.53±0.20°, 7.13±0.20°, 9.04±0.20°, 11.29±0.20°, 16.30±0.20°, 17.24±0.20°, 17.65±0.20°, 19.21±0.20°, 20.50±0.20°, 20.87±0.20°, 22.29±0.20°, 24.54±0.20°, or 25.92±0.20°.

[0374] In some embodiments, the A crystal form of compound 25-A exhibits diffraction peaks at approximately 4.53±0.20°, 7.13±0.20°, 9.04±0.20°, 11.29±0.20°, 16.30±0.20°, 17.24±0.20°, 17.65±0.20°, 18.12±0.20°, 19.21±0.20°, 20.50±0.20°, 20.87±0.20°, 22.29±0.20°, 24.54±0.20°, 25.29±0.20°, 25.92±0.20°, or 30.47±0.20°.

[0375] In some embodiments, in X-ray powder diffraction (XRPD) patterns using Cu Kα rays, the A crystal form of the above-mentioned compound 25-A is selected from about 4.53±0.20°, 7.13±0.20°, 9.04±0.20°, 11.29±0.20°, 16.30±0.20°, 17.24±0.20°, 17.65±0.20°, 18.12±0.20°, and 19.21±0.20°. It has at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10 or more characteristic diffraction peaks at 2θ values ​​of 0°, 20.50±0.20°, 20.87±0.20°, 22.29±0.20°, 24.54±0.20°, 25.29±0.20°, 25.92±0.20° or 30.47±0.20°.

[0376] In some embodiments of this disclosure, the XRPD pattern of the A crystal form of the above-mentioned compound 25-A is as follows: Figure 23 As shown.

[0377] On the other hand, this disclosure provides a method for preparing the A crystal form of the above-mentioned compound 25-A, including: 1) Mix compound 25-3 with pyridine and Boc anhydride in 1,4-dioxane; 2) Mix with ammonium bicarbonate; 3) Mix with isopropyl acetate; 4) Separate the solid to obtain the A crystal form of compound 25-A.

[0378] On the other hand, this disclosure provides a method for preparing the A crystal form of the above-mentioned compound 25-A, comprising: mixing compound 25-A with isopropyl acetate; and separating the solid.

[0379] The method for preparing the A crystal form of the above compound 25-A, step 1) further includes mixing and reacting at 10~30℃ (e.g., room temperature).

[0380] In some embodiments, the method for preparing the A crystal form of compound 25-A, step 2) further includes mixing, stirring at 10~30°C (e.g., room temperature), adding water to the reaction solution, and stirring to precipitate the product.

[0381] In some embodiments, the method for preparing the A crystal form of compound 25-A, step 2) further includes filtering the precipitated product, extracting the filter cake with ethyl acetate, washing, drying, and concentrating to obtain a crude product.

[0382] In some embodiments, the method for preparing the A crystal form of compound 25-A, step 3) includes mixing the crude product obtained in step 2) with isopropyl acetate, heating to dissolve (the temperature may optionally be 60~100°C, 70~90°C or 80°C), cooling to 10~30°C (e.g., room temperature) and stirring.

[0383] In some embodiments, the method for preparing the A crystal form of compound 25-A includes step 4) of filtering and drying the solid obtained in step 3) to obtain the A crystal form of compound 25-A.

[0384] In some embodiments, the method for preparing the A-crystal form of compound 25-A includes: 1) mixing compound 25-3 with pyridine and Boc anhydride in 1,4-dioxane and reacting at 10-30°C (e.g., room temperature); 2) mixing with ammonium bicarbonate, stirring at 10-30°C (e.g., room temperature), adding water, stirring to precipitate the product, filtering the product, extracting the filter cake with ethyl acetate, washing, drying, and concentrating to obtain a crude product; 3) adding isopropyl acetate, heating to dissolve (the temperature may optionally be 60-100°C, 70-90°C, or 80°C), cooling to 10-30°C (e.g., room temperature), and stirring; 4) filtering and drying to obtain the A-crystal form of compound 25-A.

[0385] In some embodiments, the mass-volume ratio of compound 25-3 in step 1) to isopropyl acetate in step 3) is 1g: 5~30mL, 1g: 5~20mL, 1g: 5~15mL, 1g: 8~12mL, 1g: 9~11mL, or 1g: 10.20mL.

[0386] In some embodiments of this disclosure, the XRPD pattern of the A crystal form of the above-mentioned compound 25-A exhibits characteristic diffraction peaks at the following 2θ angles, as shown in Table 13: Table 13: XRPD data of crystal form A of compound 25-A .

[0387] On another aspect, this disclosure provides a crystal form composition comprising the above-mentioned crystal form, wherein the crystal form described in this disclosure accounts for more than 50% by weight of the crystal form composition, preferably more than 80%, more preferably more than 90%, and most preferably more than 95%.

[0388] In another aspect, this disclosure provides a pharmaceutical composition comprising a therapeutically effective amount of the compound of this disclosure (crystalline or amorphous), its stereoisomer (crystalline or amorphous), a pharmaceutically acceptable salt of the compound (crystalline or amorphous), a solvate of the compound (crystalline or amorphous), or a combination of the crystal forms thereof. The pharmaceutical compositions of this disclosure may or may not contain pharmaceutically acceptable excipients. Furthermore, the pharmaceutical compositions of this disclosure may further comprise one or more other therapeutic agents.

[0389] This disclosure also provides the use of the compounds (crystalline or amorphous), their stereoisomers (crystalline or amorphous), pharmaceutically acceptable salts of the compounds (crystalline or amorphous), solvates of the compounds (crystalline or amorphous), or combinations thereof, or pharmaceutical compositions thereof, in the preparation of medicaments for the prevention or treatment of various XPO-1-related diseases.

[0390] This disclosure also provides a method for preventing or treating various XPO-1-related diseases, comprising administering to a mammal, preferably a human, a therapeutically effective amount of the compound of this disclosure (crystalline or amorphous), its stereoisomers (crystalline or amorphous), a pharmaceutically acceptable salt of the compound (crystalline or amorphous), a solvate of the compound (crystalline or amorphous), or a combination thereof, or a pharmaceutical composition thereof.

[0391] This disclosure also provides the compounds (crystalline or amorphous), stereoisomers thereof (crystalline or amorphous), pharmaceutically acceptable salts of the compounds (crystalline or amorphous), solvates of the compounds (crystalline or amorphous), or combinations thereof, for the prevention or treatment of various XPO-1-related diseases.

[0392] This disclosure also provides the use of the compounds (crystalline or amorphous), their stereoisomers (crystalline or amorphous), pharmaceutically acceptable salts of the compounds (crystalline or amorphous), solvates of the compounds (crystalline or amorphous), or combinations thereof, or pharmaceutical compositions thereof, in the prevention or treatment of various XPO-1-related diseases.

[0393] In some embodiments, the prevention or treatment of various XPO-1-related diseases is selected from tumors; in some embodiments, the various XPO-1-related diseases are selected from leukemia or lymphoma.

[0394] Technical effect The disclosed compound exhibits cell proliferation inhibitory activity (e.g., against Jurkat cells and / or OCI-LY10 cells); it is metabolically stable in liver microsomes in vitro and has good stability in human whole blood; it has good in vivo pharmacokinetic data (e.g., parameters such as AUC, Cmax, Tmax, or absolute bioavailability), in vivo pharmacodynamic data, and in vivo safety data (parameters such as brain-blood ratio).

[0395] The compounds of formula I disclosed herein (specifically, compounds 2-A, 3-A, 11-A, 15-A, 21-A, 25-A, 38-A, or 59-A) possess one or more of the following properties: stable crystal form (including under conditions of high humidity, high temperature, light, acid, or alkalinity), minimally affected by light, heat, and humidity, good solubility, promising prospects for drug development, and favorable pharmacokinetic properties, making them suitable for drug use. These pharmacokinetic properties can be determined in preclinical animal studies, such as in SD rats or beagle dogs, or in clinical human trials. The crystal forms disclosed herein contribute to the solid-state form of the compounds.

[0396] Definitions and Explanations Unless otherwise stated, the following terms and phrases as used herein are intended to have the following meanings. A particular phrase or term should not be considered uncertain or unclear unless specifically defined, but should be understood in its ordinary sense. When trade names appear herein, they are intended to refer to the corresponding product or its active ingredient.

[0397] It should be noted that in powder X-ray diffraction spectroscopy, the position or relative intensity of peaks may vary due to factors such as the measuring instrument, method / conditions, etc. For any given crystal form, the peak position may have errors; the measurement error for the 2θ value can be ±0.2°. Therefore, this error should be taken into account when determining each crystal form, and such errors are also within the scope of this disclosure.

[0398] The phenomenon where the lattice planes or edges of some grains within a crystal are predominantly arranged along certain directions and planes is called preferred orientation. In powder diffraction, the calculation of the relative intensity of diffraction lines requires that the crystals in the powder sample be completely randomly oriented. If the number of oriented crystals in the sample increases, the intensity will inevitably increase. This establishes a certain correspondence between the intensity of diffraction lines and the degree of orientation. (X-ray Structure Analysis, edited by Qi Jingyu, Tongji University Press, 1st edition, April 2003).

[0399] The significant tendency of grains in a sample to a particular crystallographic direction is called preferred orientation. For materials with strong cleavage, preferred orientation is easily observed visually. For such materials, such as plate-like or needle-like crystals, preferred orientation tends to occur during sample preparation. For example, in a cylindrical sample tube, the plate-like crystal faces tend to coincide with the axis of the sample tube. In a flat sample holder of a diffractometer, the normals of the plate-like crystal faces tend to be perpendicular to the base plane of the sample holder. When collecting diffraction data using a standard θ-2θ linked Bragg-Brentano diffractometer, the diffraction intensity of the preferred orientation crystal faces will be abnormally enhanced. Even after multiple sample preparations, although some improvement can be achieved, it is still difficult to completely overcome the preferred orientation phenomenon (Powder Diffraction Method for Determining Crystal Structure, edited by Liang Jingkui, Science Press, 1st edition, April 2003).

[0400] Preferred orientation can affect the results of powder diffraction (PDD) determination of crystal structure. Different batches of crystal forms may show variations in XRPD results, but this does not prevent those skilled in the art from determining whether they are the same crystal form.

[0401] It should be noted that for the same crystal form, the location of the endothermic peak in DSC may vary due to factors such as the measuring instrument, measuring method / conditions, etc. For any specific crystal form, the location of the endothermic peak may have an error, which can be ±5℃ or ±3℃. Therefore, this error should be taken into account when determining each crystal form, and anything within this error range is also within the scope of this disclosure.

[0402] The term "solvate" refers to a substance formed by combining a compound of Formula I (specifically, for example, 2-A, 3-A, 11-A, 15-A, 21-A, 25-A, 38-A, or 59-A) with a pharmaceutically acceptable solvent. Pharmaceutically acceptable solvents include water, methanol, ethanol, isopropanol, 1,4-dioxane, tetrahydrofuran, acetic acid, acetonitrile, ethyl acetate, isopropyl acetate, or acetone, etc. Solvates include stoichiometric solvates and non-stoichiometric solvates.

[0403] When the covalent bonds in certain structural units or groups in an application are not connected to specific atoms, it means that the covalent bonds can be connected to any atom in the structural unit or group, as long as the rules of valence bond connection are not violated.

[0404] The term "substitution" refers to the substitution of one or more hydrogen atoms on a specific atom by a substituent, provided that the valence state of the specific atom is normal and the resulting compound is stable. When the substituent is oxo (i.e., =O), it means that two hydrogen atoms are substituted; oxo substitution does not occur on aromatic groups.

[0405] The terms “optional” or “optionally” mean that the event or condition subsequently described may or may not occur, including both the occurrence and non-occurrence of said event or condition. For example, the ethyl group “optionally” being halogenated means that the ethyl group can be unsubstituted (CH2CH3), monosubstituted (e.g., CH2CH2F), polysubstituted (e.g., CHFCH2F, CH2CHF2, etc.), or fully substituted (CF2CF3). Those skilled in the art will understand that for any group containing one or more substituents, no substitution or substitution pattern that is spatially impossible and / or cannot be synthesized is introduced.

[0406] In this article, "one or more" refers to an integer from one to ten. For example, "one or more" means one, two, three, four, five, six, seven, eight, nine, or ten; or, "one or more" means one, two, three, four, five, or six; or, "one or more" means one, two, or three.

[0407] C in this article m-n This means that the part has an integer number of carbon atoms within a given range. For example, "C 1-6 "" means that the group can have 1, 2, 3, 4, 5, or 6 carbon atoms. For example, C 1-3 This means that the group can have 1 carbon atom, 2 carbon atoms, or 3 carbon atoms.

[0408] When any variable (e.g., R) appears more than once in the composition or structure of a compound, its definition is independent in each case. Therefore, for example, if a group is substituted by two Rs, each R has an independent option.

[0409] When the number of a linking group is 0, such as -(CH2)0-, it indicates that the linking group is a covalent bond.

[0410] When one of the variables is selected as a covalent bond, it means that the two groups connected to it are directly linked. For example, when L' represents a covalent bond in A-L'-Z, it means that the structure is actually AZ.

[0411] When a substituent is cross-bonded to two atoms on a ring, it can bond to any atom on that ring. For example, structural units. or This indicates that it can be substituted at any position on the cyclohexyl group or cyclohexadiene.

[0412] The term "halogen" or "halogen" refers to fluorine, chlorine, bromine, and iodine.

[0413] The term "alkyl" refers to a compound with the general formula C1. n H 2n+1 The alkyl group is a hydrocarbon group. This alkyl group can be straight-chain or branched. For example, the term "C1-6 alkyl" refers to an alkyl group containing 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, etc.). Similarly, the alkyl portion (i.e., alkyl) of alkoxy, alkylamino, dialkylamino, alkylsulfonyl, and alkylthio groups has the same definition as above. As another example, the term "C1-3 alkyl" refers to an alkyl group containing 1 to 3 carbon atoms (e.g., methyl, ethyl, propyl, and isopropyl).

[0414] The term "alkoxy" refers to -O-alkyl.

[0415] The term "cycloalkyl" refers to a fully saturated carbon ring that can exist as a monocyclic, bridged, or spirocyclic ring. Unless otherwise indicated, the carbon ring is typically a 3- to 10-membered ring (e.g., 3-, 4-, 5-, 6-, 7-, 8-, 9-, or 10-membered ring). Non-limiting examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl (bicyclo[2.2.1]heptyl), bicyclo[2.2.2]octyl, adamantyl, bicyclo[1.1.1]pent-1-yl, etc. For example, C 3-4 Cycloalkyl groups include cyclopropyl and cyclobutyl groups.

[0416] The term "heterocyclic alkyl" refers to a fully saturated cyclic group that may exist as a monocyclic, bridged (including fused) or spirocyclic ring. Unless otherwise indicated, the heterocycle is typically a 3- to 7-membered ring (e.g., 3-, 4-, 5-, 6-, or 7-membered ring) containing 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from sulfur, oxygen, and / or nitrogen. Examples of 3-membered heterocyclic alkyl groups include, but are not limited to, ethylene oxide, cyclothioethylene, and cycloazoethylene; non-limiting examples of 4-membered heterocyclic alkyl groups include, but are not limited to, acridine, oxadiazolyl, and thiobutyl; examples of 5-membered heterocyclic alkyl groups include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, imidazolyl, and tetrahydropyrazolyl; examples of 6-membered heterocyclic alkyl groups include, but are not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiaranyl, morpholinyl, piperazine, 1,4-thiaoxane, 1,4-dioxane, thiomorpholinyl, 1,3-dithiaalkyl, and 1,4-dithiaalkyl; and examples of 7-membered heterocyclic alkyl groups include, but are not limited to, azirheptanyl, oxeheptanyl, and thioheptanyl. Monocyclic heterocyclic alkyl groups having 5 or 6 ring atoms are preferred.

[0417] The term "aryl" refers to an aromatic ring group consisting of an all-carbon monocyclic or fused polycyclic ring with a conjugated π-electron system. For example, an aryl group can have 6-20 carbon atoms, 6-14 carbon atoms, or 6-12 carbon atoms. Non-limiting examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracene, and 1,2,3,4-tetrahydronaphthalene.

[0418] The term "heteroaryl" or "heterocyclic aryl" refers to a monocyclic or fused polycyclic system containing at least one ring atom selected from N, O, and S, with the remaining ring atoms being C, and having at least one aromatic ring. Preferred heteroaryls have a single 5- to 8-membered ring (e.g., a 5-, 6-, 7-, or 8-membered ring), or multiple fused rings containing 6 to 14, particularly 6 to 10, ring atoms (e.g., a 6-, 7-, 8-, 9-, or 10-membered ring). Non-limiting examples of heteroaryls include, but are not limited to, pyrroleyl, furanyl, thiopheneyl, imidazolyl, oxazolyl, isoxazolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, quinolinyl, isoquinolinyl, tetrazolyl, triazolyl, triazinyl, benzofuranyl, benzothiopheneyl, indoleyl, naphthidyl, indazoleyl, and isoindoleyl.

[0419] The terms “comprise” or “include” and their English variations such as “comprises” or “comprising” should be understood in an open, non-exclusive sense, meaning “including but not limited to”.

[0420] The term "therapeutic effective amount" means (i) the amount of the disclosed compound used to treat or prevent a particular disease, condition, or disorder; (ii) to reduce, improve, or eliminate one or more symptoms of a particular disease, condition, or disorder; or (iii) to prevent or delay the onset of one or more symptoms of a particular disease, condition, or disorder described herein. The amount of the disclosed compound constituting a "therapeutic effective amount" varies depending on the compound, the disease state and its severity, the route of administration, and the age of the mammal to be treated, but may routinely be determined by a person skilled in the art based on their own knowledge and the content of this disclosure.

[0421] The term "pharmaceutically acceptable" refers to compounds, materials, compositions, and / or dosage forms that, within the bounds of reliable medical judgment, are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, in proportion to a reasonable benefit / risk ratio. "Pharmaceutically acceptable excipients" refer to inert substances that, when administered co-administered with the active ingredient, facilitate the administration of the active ingredient, including but not limited to any flow aids, sweeteners, diluents, preservatives, dyes / colorants, flavor enhancers, surfactants, wetting agents, dispersants, disintegrants, suspending agents, stabilizers, isotonic agents, solvents, or emulsifiers permitted by the National Medical Products Administration for use in humans or animals (e.g., livestock). Non-limiting examples of such excipients include calcium carbonate, calcium phosphate, various sugars and starches, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycol.

[0422] As pharmaceutically acceptable salts, for example, metal salts, ammonium salts, salts formed with organic bases, salts formed with inorganic acids, salts formed with organic acids, and salts formed with basic or acidic amino acids may be mentioned.

[0423] The term "pharmaceutical composition" refers to a mixture of one or more compounds of the present disclosure or salts thereof with pharmaceutically acceptable excipients. The purpose of a pharmaceutical composition is to facilitate the administration of the disclosed compounds to an organism.

[0424] The term "pharmaceuticalally acceptable excipient" refers to those excipients that do not cause significant irritation to the organism and do not impair the biological activity and properties of the active compound. Suitable excipients are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and / or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, etc. The compounds and intermediates of this disclosure may also exist in different tautomeric forms, and all such forms are included within the scope of this disclosure. The terms "tautomeric" or "tautomeric form" refer to structural isomers of different energies that can interconvert via low energy barriers. For example, proton tautomeric (also known as proton transfer tautomeric) includes interconversion via proton migration, such as keto-enol and imine-enamine isomerization. A specific example of a proton tautomeric is the imidazole moiety, in which a proton can migrate between two ring nitrogens. Valence tautomeric includes interconversion via the recombination of some bonding electrons.

[0425] This disclosure also includes compounds of this disclosure that are identical to those described herein, but in which one or more atoms are labeled with isotopes whose atomic weights or mass numbers differ from those commonly found in nature. Examples of isotopes that can be incorporated into compounds of this disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as... 2 H, 3 H, 11 C 13 C 14 C 13 N、 15 N、 15 O、 17 O、 18 O、 31 P, 32 P, 35 S, 18 F, 123 I, 125 I and 36 Cl, etc.

[0426] Certain isotope-labeled compounds of this disclosure (e.g., using...) 3 H and 14Those labeled with C can be used in the analysis of compound and / or substrate tissue distribution. Tritiumization (i.e. 3 H) and carbon-14 (i.e. 14 C) Isotopes are particularly preferred due to their ease of preparation and detectability. Positron-emitting isotopes, such as... 15 O、 13 N、 11 C and 18 F can be used in positron emission tomography (PET) studies to determine substrate occupancy. The isotopically labeled compounds of this disclosure can typically be prepared by replacing the unlabeled reagent with an isotopically labeled reagent using a procedure similar to those disclosed in the schemes and / or examples below.

[0427] In addition, heavier isotopes (such as deuterium) are used. 2 H)) substitution can provide certain therapeutic advantages resulting from higher metabolic stability (e.g., increased in vivo half-life or reduced dose requirement), and may therefore be preferred in certain situations, wherein deuterium substitution can be partial or complete, and partial deuterium substitution means that at least one hydrogen is substituted by at least one deuterium, and all such compounds are included within the scope of this disclosure.

[0428] The compounds disclosed herein may be asymmetric, for example, having one or more stereoisomers. Unless otherwise stated, all stereoisomers include, for example, enantiomers and diastereomers. The compounds containing asymmetric carbon atoms of this disclosure can be isolated in optically active pure form or in racemic form. The optically active pure form can be resolved from racemic mixtures or synthesized using chiral starting materials or chiral reagents.

[0429] The pharmaceutical compositions disclosed herein can be prepared by combining the compounds disclosed herein with suitable pharmaceutically acceptable excipients, for example, in solid, semi-solid, liquid or gaseous formulations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalers, gels, microspheres and aerosols.

[0430] Typical routes of administration of the crystal form or pharmaceutical composition described herein include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, vaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, and intravenous administration.

[0431] The pharmaceutical compositions disclosed herein can be manufactured using methods well known in the art, such as conventional mixing, dissolving, granulation, sugar-coated pill making, grinding, emulsification, freeze drying, etc.

[0432] In some embodiments, the pharmaceutical composition is in an oral form. For oral administration, the pharmaceutical composition can be formulated by mixing the active compound with pharmaceutically acceptable excipients well known in the art. These excipients enable the compounds of this disclosure to be formulated into tablets, pills, lozenges, sugar-coated tablets, capsules, liquids, gels, pastes, suspensions, etc., for oral administration to patients.

[0433] The therapeutic dose of the disclosed compound may be determined based on factors such as the specific therapeutic purpose, the manner of administration of the compound, the patient's health and condition, and the prescribing physician's judgment. The proportion or concentration of the disclosed compound in the pharmaceutical composition may not be fixed and may depend on a variety of factors, including dosage, chemical properties (e.g., hydrophobicity), and route of administration.

[0434] The term "treatment" means administering the compounds or preparations described in this disclosure to improve or eliminate a disease or one or more symptoms related to said disease, and includes: (i) Suppress the disease or disease state, that is, curb its development; (ii) To alleviate a disease or disease state, even if the disease or disease state subsides.

[0435] The term “prevention” means administering the compounds or preparations described in this disclosure to prevent a disease or one or more symptoms associated with the disease, and includes: preventing the occurrence of a disease or disease state in mammals, particularly when such mammals are susceptible to the disease state but have not yet been diagnosed with the disease state.

[0436] For the purposes of pharmaceuticals or pharmacologically active agents, the term "therapeutic effective amount" refers to a sufficient quantity of a drug or agent that is non-toxic but achieves the desired effect. The determination of the effective amount varies from person to person, depending on the recipient's age and general condition, as well as the specific active substance. The appropriate effective amount in a given case can be determined by a person skilled in the art based on routine testing.

[0437] The therapeutically effective dose of the crystal form described in this disclosure is from about 0.0001 to 20 mg / kg body weight / day, for example from 0.001 to 10 mg / kg body weight / day.

[0438] The dosing frequency of the crystal form described in this disclosure is determined by the individual patient's needs, for example, once or twice daily, or more times daily. Dosing may be intermittent, for example, wherein the patient receives a daily dose of the crystal form for a period of several days, followed by a period of several or more days during which the patient does not receive a daily dose of the crystal form.

[0439] The intermediate compounds disclosed herein can be prepared by a variety of synthetic methods known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthetic methods, and equivalent substitutions known to those skilled in the art. Preferred embodiments include, but are not limited to, the embodiments disclosed herein.

[0440] The chemical reactions in the specific embodiments of this disclosure are carried out in a suitable solvent, which must be suitable for the chemical changes of this disclosure and the reagents and materials required therefor. In order to obtain the compounds of this disclosure, it is sometimes necessary for those skilled in the art to modify or select the synthesis steps or reaction flow based on existing embodiments.

[0441] An important consideration in synthetic route planning in this field is the selection of appropriate protecting groups for reactive functional groups (such as amino groups in this disclosure), for example, see Greene's Protective Groups in Organic Synthesis (4th Ed). Hoboken, New Jersey: John Wiley & Sons, Inc. The present disclosure will be described in detail below through embodiments, which are not intended to limit the present disclosure in any way.

[0442] In some embodiments, the compounds disclosed herein can be prepared using the following preparation routes combined with methods known in the art:

[0443] , Among them, rings A, R, n, R 2 and R 1 The definition is as described in this disclosure.

[0444] All solvents used in this disclosure are commercially available and can be used without further purification.

[0445] Specific methods for XRPD, DSC, and TGA (including device model and parameters) This disclosure describes a powder X-ray diffractometer (XRPD) method. X-ray powder diffraction (XRPD): Bruker D8 X-ray diffractometer; target tube - Cu.

[0446] Thermogravimetric analysis (TGA): Instrument model NETZSCH TG 209F3; Temperature range: 30-500℃; Heating rate: 10℃ / min.

[0447] Differential scanning calorimetry (DSC): Instrument model: METTLER TOLEDO DSC3; Temperature range: 25-300℃; Heating rate: 10K / min, N 250mL / min.

[0448] Gas chromatography conditions:

[0449] (1) Blank solvent: dimethyl sulfoxide.

[0450] (2) Test solution: Weigh about 0.1g of the test sample accurately, place it in a headspace bottle, add 2mL of dimethyl sulfoxide accurately, seal, and shake well to obtain the solution.

[0451] (3) Reference solution 1: Take appropriate amounts of methanol, ethanol, isopropanol and ethyl acetate, accurately weigh them, dissolve them in dimethyl sulfoxide and dilute them quantitatively to prepare a mixed solution containing approximately 150 μg of methanol, 250 μg of ethanol, 250 μg of isopropanol and 250 μg of ethyl acetate per 1 mL. Accurately measure 2 mL, place it in a headspace bottle, seal it, and you will get the solution.

[0452] Reference solution 2: Weigh an appropriate amount of isopropyl acetate accurately, dissolve it in dimethyl sulfoxide and dilute quantitatively to prepare a solution containing approximately 250 μg of isopropyl acetate per 1 mL. Accurately measure 2 mL, place it in a headspace bottle, seal it, and the solution is ready.

[0453] Single crystal detection method Diffraction intensity data were collected using a Bruker D8 venture diffractometer with Cukα radiation as the light source and φ / ω scanning mode. Attached Figure Description

[0454] Figure 1 XRPD pattern of the A crystal form of compound 21-A; Figure 2 TGA spectrum of the A crystal form of compound 21-A; Figure 3 XRPD pattern of the B crystal form of compound 21-A; Figure 4 TGA spectrum of the B crystal form of compound 21-A; Figure 5 XRPD pattern of the C-crystal form of compound 21-A; Figure 6 TGA spectrum of the C-crystal form of compound 21-A; Figure 7 XRPD pattern of the D crystal form of compound 21-A; Figure 8 TGA spectrum of the D crystal form of compound 21-A; Figure 9 XRPD pattern of the E crystal form of compound 21-A; Figure 10 TGA spectrum of the E crystal form of compound 21-A; Figure 11 XRPD pattern of the F-crystal form of compound 21-A; Figure 12 TGA spectrum of the F-crystal form of compound 21-A; Figure 13 Projected molecular stereostructure of single-crystal G of compound 21-A; Figure 14 XRPD pattern of the A crystal form of compound 3-A; Figure 15 TGA spectrum of the A crystal form of compound 3-A; Figure 16 DSC spectrum of the A crystal form of compound 3-A; Figure 17 XRPD pattern of the B crystal form of compound 3-A; Figure 17-A TGA spectrum of the B crystal form of compound 3-A; Figure 18 XRPD pattern of the C-crystal form of compound 3-A; Figure 18-A TGA spectrum of the C-crystal form of compound 3-A; Figure 19 XRPD pattern of the A crystal form of compound 15-A; Figure 20 TGA spectrum of the A crystal form of compound 15-A; Figure 21 DSC spectrum of the A crystal form of compound 15-A; Figure 22 XRPD pattern of the B crystal form of compound 15-A; Figure 23 XRPD pattern of the A crystal form of compound 25-A.

[0455] The following abbreviations are used in this disclosure: Pd(dppf)Cl2 represents [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride; DMF represents N,N-dimethylformamide; DABCO represents triethylenediamine; THF represents tetrahydrofuran; SEM represents trimethylsilylethoxymethyl.

[0456] For clarity, this disclosure is further illustrated by examples, but these examples are not intended to limit the scope of this disclosure. All reagents used in this disclosure are commercially available and can be used without further purification. Detailed Implementation

[0457] Example 1

[0458] (1) Preparation of compounds 1-2 Pinaryl diboronate (2.13 g), 4,4'-di-tert-butyl-2,2'-dipyridine (18.7 mg), and methoxy(cyclooctadiene)iridium dimer (23.1 mg) were added to cyclohexane (30 mL). The mixture was stirred for ten minutes under nitrogen protection. Then, 3,5-bis(trifluoromethyl)pyridine (compound 1-1, 3.0 g) was added, and the mixture was stirred at 55°C under nitrogen protection. After the reaction was complete, the reaction solution was quenched with ice water (20 mL), extracted with ethyl acetate (30 mL x 3), and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to obtain compound 1-2, which was used directly in the next reaction.

[0459] (2) Preparation of compounds 1-3 Compounds 1-2 (4.7 g) were added to ethylene glycol dimethyl ether (50 mL), followed by 3-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazole (3.9 g) and potassium carbonate (5.8 g) aqueous solution (10 mL). The mixture was stirred at room temperature under nitrogen protection. After 1 h, tetra(triphenylphosphine)palladium (805.8 mg) was added and stirred at 90 °C under nitrogen protection. After the reaction was complete, the reaction solution was quenched with ice water (40 mL), extracted with ethyl acetate (100 mL), and the organic phase was collected and washed with brine (50 mL * 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to obtain compounds 1-3, which were directly used in the next reaction.

[0460] (3) Preparation of compounds 1-4 Compounds 1-3 (5.7 g) were dispersed in 4M HCl / dioxane (50 mL), 60 o Stirring at C until the reaction is complete, slowly pour the reaction solution into an ice-cold saturated sodium bicarbonate solution. Adjust the pH to 6-7 with sodium bicarbonate, extract with ethyl acetate (100 mL * 3), wash the organic phase (100 mL) with saturated brine, dry with anhydrous sodium sulfate, concentrate under reduced pressure until no liquid flows out, and purify by column chromatography to obtain compounds 1-4.

[0461] (4) Preparation of compounds 1-5 Compounds 1-4 (900 mg) were dispersed in DMF (20 mL), and DABCO (716 mg) was added. 20-25 mL of the solution was then added. o After stirring for 30 minutes, cool to 0-10°C. oC, add compound 1-4a (1.15 g) dropwise, after the addition is complete, 20-25 o Stirring at C for 1.5 hours until the reaction is complete, pour the reaction solution into 50 mL of water, extract with ethyl acetate (50 mL * 2), combine the organic phases, dry to anhydrous sodium sulfate, and precipitate by column chromatography to obtain compounds 1-5 (750 mg).

[0462] (5) Preparation of compounds 1-6 Compounds 1-5 (750 mg) were added to dichloromethane (20 mL), the mixture was cooled to 0 °C, and liquid bromine (605 mg) was added dropwise over 15 minutes. The mixture was then slowly heated to room temperature and stirred for 4 hours. After the reaction was complete, the reaction mixture was poured into 30 mL of ice water and extracted with dichloromethane (30 mL x 3). The organic phases were combined, washed with saturated sodium bisulfite solution (30 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure until no liquid eluent was obtained, and purified by column chromatography to give compounds 1-6.

[0463] (6) Preparation of compounds 1-7 Compounds 1-6 (1.05 g) were added to THF (20 mL), and the mixture was cooled to 0 °C. Triethylamine (383.5 mg) was then added dropwise. After the addition was complete, the mixture was slowly heated to room temperature and reacted for 12 hours. Once the reaction was complete, 20 mL of water was added to dilute the reaction solution, and the mixture was extracted with ethyl acetate (30 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and purified by column chromatography to obtain compounds 1-7.

[0464] (7) Preparation of compounds 1-8 Compounds 1-7 (700 mg), 5-pyrimidineboronic acid (220 mg), potassium acetate (435.7 mg), and Pd(dppf)Cl2 (54 mg) were added to 20 mL of dioxane and 2 mL of water. The mixture was heated to 90 °C under nitrogen protection and the reaction was completed. The reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (30 mL * 3). The organic phase was collected, dried over anhydrous sodium sulfate, filtered, evaporated under reduced pressure, and purified by column chromatography to obtain compounds 1-8 (200 mg).

[0465] (8) Preparation of compounds 1-9 Compounds 1-8 (200 mg) were dissolved in tetrahydrofuran (15 mL), and a solution of sodium hydroxide (33.9 mg) and water (15 mL) was added dropwise under an ice-water bath. The reaction was allowed to proceed overnight at room temperature. The reaction solution was adjusted to acidity (pH 3-5) with hydrochloric acid, extracted with ethyl acetate (30 mL * 3), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to obtain compounds 1-9, which were used directly in the next reaction.

[0466] (9) Preparation of Example 1 Compounds 1-9 (182 mg) were added to tetrahydrofuran (15 mL), and N-methylmorpholine (85.6 mg) and isobutyl chloroformate (115.5 mg) were added under ice-water bath conditions. The mixture was stirred for 30 minutes, and ammonia water (88.8 mg) was added dropwise. The reaction was carried out under ice-water bath conditions for 10 minutes, and the reaction was quenched with water. The mixture was extracted with ethyl acetate (30 mL * 3), dried over anhydrous sodium sulfate, and concentrated until no liquid flowed out. The solution was purified by preparative liquid chromatography to obtain Example 1 (13 mg). ESI-MS: m / z = 430.26 [M+H] + . 1 H NMR (500 MHz, DMSO- d 6) δ9.22 (d, J = 9.8 Hz, 2H), 8.74 (s, 2H), 8.45 (s, 1H), 8.07 (s, 2H), 7.68 (s, 1H), 7.44 (s, 1H). Example 2

[0467] (1) Preparation of compound 2-2: Compounds 1-7 (394 mg) and 2-1 (285 mg) were dispersed in 1,4-dioxane (8 mL), potassium acetate (244 mg), Pd(dppf)Cl2 (29 mg) and water (0.8 mL) were added, and the mixture was heated to 90 °C under nitrogen protection. After the reaction was completed, the reaction solution was concentrated under reduced pressure and purified by column chromatography to obtain compound 2-2.

[0468] (2) Preparation of compounds 2-3: Compound 2-2 (100 mg) was dissolved in tetrahydrofuran (5 mL), and a solution of lithium hydroxide hydrate (38.1 mg) and water (5 mL) was added dropwise under an ice-water bath. The reaction was carried out at room temperature for 2 h. The pH of the reaction solution was adjusted to 3-5 with hydrochloric acid, extracted with ethyl acetate (20 mL*2), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to obtain compound 2-3, which was directly used in the next step of the reaction.

[0469] (3) Preparation of compound 2-A: Compound 2-3 (91 mg) was dispersed in tetrahydrofuran (5 mL). N-methylmorpholine (36 mg) and isobutyl chloroformate (49 mg) were added under ice-water bath conditions. The mixture was stirred for 30 minutes, and ammonia (38 mg) was added dropwise. The reaction was continued under ice-water bath conditions for 10 minutes. The reaction was quenched with water, extracted with ethyl acetate (20 mL x 2), dried over anhydrous sodium sulfate, and concentrated until no liquid flowed out. Compound 2-A (41 mg) was purified by preparative liquid chromatography. ESI-MS: m / z = 509.32 [M+H]+ .

[0470] 1 H NMR (500 MHz, DMSO- d 6) δ 9.14 (s, 1H), 8.25 (d, J = 10.4 Hz, 5H), 7.76 (t, J = 6.2 Hz, 1H), 7.58 (s, 1H), 7.43 (s, 1H), 6.09 (tt, J = 56.5, 4.2 Hz,1H), 3.74 (dddd, J = 19.0, 14.9, 8.2, 5.2 Hz, 2H). Example 3

[0471] (1) Preparation of compound 3-2: Compounds 1-7 (394 mg) and 3-1 (299 mg) were dispersed in 1,4-dioxane (8 mL), potassium acetate (244 mg), Pd(dppf)Cl2 (29 mg) and water (0.8 mL) were added, and the mixture was heated to 90 °C under nitrogen protection. After the reaction was completed, the reaction solution was concentrated under reduced pressure and purified by column chromatography to obtain compound 3-2.

[0472] (2) Preparation of compound 3-3: Compound 3-2 (360 mg) was dissolved in tetrahydrofuran (5 mL), and a solution of lithium hydroxide hydrate (133.6 mg) and water (5 mL) was added dropwise under an ice-water bath. The reaction was carried out at room temperature for 2 h. The pH of the reaction solution was adjusted to 3-5 with hydrochloric acid, extracted with ethyl acetate (20 mL * 2), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to obtain compound 3-3, which was directly used in the next step of the reaction.

[0473] (3) Preparation of compound 3-A: Compound 3-3 (335 mg) was dispersed in tetrahydrofuran (10 mL). N-methylmorpholine (129 mg) and isobutyl chloroformate (175 mg) were added under ice-water bath conditions. The mixture was stirred for 30 minutes, then ammonia (134 mg) was added dropwise. The reaction was continued under ice-water bath conditions for 10 minutes. The reaction was quenched with water, extracted with ethyl acetate (20 mL x 2), dried over anhydrous sodium sulfate, and concentrated until no liquid eluates. Compound 3-A (90 mg) was purified by preparative liquid chromatography. ESI-MS: m / z = 523.37 [M+H] + .

[0474] 1 H NMR (500 MHz, DMSO- d 6) δ 9.14 (s, 1H), 8.26 (s, 2H), 8.21 (d, J = 5.5Hz, 3H), 7.76 (t, J = 6.6 Hz, 1H), 7.57 (s, 1H), 7.45 (s, 1H), 3.83 (td, J =13.6, 6.6 Hz, 2H), 1.61 (t, J = 19.0 Hz, 3H). Example 4 (1) Preparation of compound 4-2: Compounds 1-7 (300 mg) and 4-1 (230 mg) were dispersed in 1,4-dioxane (8 mL), potassium acetate (186.6 mg), Pd(dppf)Cl2 (46 mg) and water (0.8 mL) were added, and the mixture was heated to 90 °C under nitrogen protection. After the reaction was completed, the reaction solution was concentrated under reduced pressure and purified by column chromatography to obtain compound 4-2.

[0475] (2) Preparation of compound 4-3: Compound 4-2 (302 mg) was dissolved in tetrahydrofuran (10 mL), and a solution of lithium hydroxide hydrate (44.6 mg) and water (10 mL) was added dropwise under an ice-water bath. The reaction was carried out at room temperature for 3 h. The pH of the reaction solution was adjusted to 3-5 with hydrochloric acid, extracted with ethyl acetate (20 mL * 2), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to obtain compound 4-3, which was directly used in the next step of the reaction.

[0476] (3) Preparation of compound 4: Compound 4-3 (280 mg) was dispersed in tetrahydrofuran (15 mL). N-methylmorpholine (107 mg) and isobutyl chloroformate (145 mg) were added under ice-water bath conditions. The mixture was stirred for 30 minutes, and ammonia (111 mg) was added dropwise. The reaction was quenched with water after 10 minutes in an ice-water bath. The mixture was extracted with ethyl acetate (20 mL x 2), dried over anhydrous sodium sulfate, and concentrated until no liquid flowed out. Compound 4 (30 mg) was obtained by preparative liquid chromatography. ESI-MS: m / z = 527.17 [M+H] + .

[0477] 1 H NMR (500 MHz, DMSO- d 6) δ 9.16 (s, 1H), 8.24 (d, J= 4.6 Hz, 5H), 7.99(t, J = 6.7 Hz, 1H), 7.57 (s, 1H), 7.45 (s, 1H), 4.18 (q, J = 8.7, 8.3 Hz, 2H). Example 5

[0478] (1) Preparation of compound 5-2: Compounds 1-7 (300 mg) and 5-1 (241 mg) were dispersed in 1,4-dioxane (8 mL), potassium acetate (187 mg), Pd(dppf)Cl2 (23 mg) and water (0.8 mL) were added, and the mixture was heated to 90 °C under nitrogen protection. After the reaction was completed, the reaction solution was concentrated under reduced pressure and purified by column chromatography to obtain compound 5-2.

[0479] (2) Preparation of compound 5-3: Compound 5-2 (200 mg) was dissolved in tetrahydrofuran (10 mL), and a solution of lithium hydroxide hydrate (29 mg) and water (10 mL) was added dropwise under an ice-water bath. The reaction was carried out at 0-10 °C for 3 h. The pH of the reaction solution was adjusted to 3-5 with hydrochloric acid, extracted with ethyl acetate (20 mL*2), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to obtain compound 5-3, which was directly used in the next step of the reaction.

[0480] (3) Preparation of compound 5: Compound 5-3 (185 mg) was dispersed in tetrahydrofuran (15 mL). N-methylmorpholine (69 mg) and isobutyl chloroformate (94 mg) were added under ice-water bath conditions. The mixture was stirred for 30 minutes, then ammonia (72 mg) was added dropwise. The reaction was continued under ice-water bath conditions for 10 minutes. The reaction was quenched with water, extracted with ethyl acetate (20 mL x 2), dried over anhydrous sodium sulfate, and concentrated until no liquid eluates. Compound 5 (50 mg) was purified by preparative liquid chromatography. ESI-MS: m / z = 541.25 [M+H] + .

[0481] 1 H NMR (500 MHz, DMSO- d 6) δ 9.17 (d, J = 3.5 Hz, 1H), 8.25 (q, J = 3.8 Hz, 5H), 7.96 (dd, J= 9.3, 3.2 Hz, 1H), 7.58 (s, 1H), 7.47 (s, 1H), 5.02 – 4.86(m, 1H), 1.36 (dd, J = 7.3, 3.2 Hz, 3H). Example 6 (1) Preparation of compound 6-1: Compound 1-7 (200 mg) and pyridine-4-boronic acid (62.35 mg) were dispersed in 1,4-dioxane (10 mL), potassium acetate (124.4 mg), Pd(dppf)Cl2 (15.5 mg) and water (1 mL) were added, and the mixture was heated to 90 °C under nitrogen protection. After the reaction was completed, the reaction solution was concentrated under reduced pressure and purified by column chromatography to obtain compound 6-1.

[0482] (2) Preparation of compound 6-2: Compound 6-1 (150 mg) was dissolved in tetrahydrofuran (10 mL), and a solution of lithium hydroxide hydrate (67.14 mg) and water (10 mL) was added dropwise under an ice-water bath. The reaction was carried out at room temperature for 3 h. The pH of the reaction solution was adjusted to 3-5 with hydrochloric acid, extracted with ethyl acetate (20 mL * 2), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to obtain compound 6-2, which was directly used in the next step of the reaction.

[0483] (3) Preparation of compound 6: Compound 6-2 (137.4 mg) was dispersed in tetrahydrofuran (10 mL). N-methylmorpholine (64.74 mg) and isobutyl chloroformate (87.41 mg) were added under ice-water bath conditions. The mixture was stirred for 30 minutes, and ammonia (67.2 mg) was added dropwise. The reaction was quenched with water after 10 minutes in an ice-water bath. The mixture was extracted with ethyl acetate (20 mL x 2), dried over anhydrous sodium sulfate, and concentrated until no liquid flowed out. Compound 6 (10 mg) was purified by preparative liquid chromatography. ESI-MS: m / z = 429.19 [M+H] + .

[0484] 1 H NMR (500 MHz, DMSO- d 6) δ 9.02 (s, 1H), 8.65 (d, J = 5.0 Hz, 2H), 8.26(s, 1H), 8.10 (s, 2H), 7.66 (s, 1H), 7.32 (d, J = 5.0 Hz, 2H), 7.23 (s, 1H). Example 7

[0485] (1) Preparation of compound 7-1: Compound 1-7 (300 mg) and 1-methylpyrazole-4-boronic acid pinacol ester (158.3 mg) were dispersed in 1,4-dioxane (8 mL), potassium acetate (186.6 mg), Pd(dppf)Cl2 (46 mg) and water (0.8 mL) were added, and the mixture was heated to 90 °C under nitrogen protection. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain compound 7-1, which was directly used in the next step of the reaction. (2) Preparation of compound 7-2: Compound 7-1 (298 mg) was dissolved in tetrahydrofuran (10 mL), and a solution of lithium hydroxide hydrate (52.87 mg) and water (10 mL) was added dropwise under an ice-water bath. The reaction was carried out at room temperature for 3 h. The pH of the reaction solution was adjusted to 3-5 with hydrochloric acid, extracted with ethyl acetate (20 mL * 2), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to obtain compound 7-2, which was directly used in the next step of the reaction.

[0486] (3) Preparation of compound 7: Compound 7-2 (270 mg) was dispersed in tetrahydrofuran (15 mL). N-methylmorpholine (127.45 mg) and isobutyl chloroformate (154.41 mg) were added under ice-water bath conditions. The mixture was stirred for 30 minutes, followed by dropwise addition of ammonia (132.3 mg). After reacting in an ice-water bath for 10 minutes, the reaction was quenched with water. The mixture was extracted with ethyl acetate (20 mL x 2), dried over anhydrous sodium sulfate, and concentrated until no liquid flowed out. Compound 7 (77 mg) was purified by preparative liquid chromatography. ESI-MS: m / z = 432.18 [M+H] + .

[0487] 1 H NMR (500 MHz, DMSO- d 6) δ 8.87 (s, 1H), 8.48 (s, 2H), 7.84 (s, 1H), 7.73 (s, 1H), 7.58 (s, 1H), 7.54 (s, 1H), 7.26 (d, J = 0.9 Hz, 1H), 3.85 (s, 3H). Example 8

[0488] (1) Preparation of compound 8-1: Compound 1-7 (200 mg) and 5-fluoro-3-pyridineboronic acid (75.03 mg) were dispersed in 1,4-dioxane (10 mL), potassium acetate (124.4 mg), Pd(dppf)Cl2 (15.5 mg) and water (1 mL) were added, and the mixture was heated to 90 °C under nitrogen protection. After the reaction was completed, the reaction solution was concentrated under reduced pressure and purified by column chromatography to obtain compound 8-1.

[0489] (2) Preparation of compound 8-2: Compound 8-1 (150 mg) was dissolved in tetrahydrofuran (10 mL), and a solution of lithium hydroxide hydrate (65.1 mg) and water (10 mL) was added dropwise under an ice-water bath. The reaction was carried out at room temperature for 3 h. The pH of the reaction solution was adjusted to 3-5 with hydrochloric acid, extracted with ethyl acetate (20 mL * 2), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to obtain compound 8-2, which was directly used in the next step of the reaction.

[0490] (3) Preparation of compound 8: Compound 8-2 (138.65 mg) was dispersed in tetrahydrofuran (10 mL). N-methylmorpholine (62.71 mg) and isobutyl chloroformate (84.68 mg) were added under ice-water bath conditions. The mixture was stirred for 30 minutes, and ammonia (65.1 mg) was added dropwise. The reaction was continued under ice-water bath conditions for 10 minutes, and the reaction was quenched with water. The mixture was extracted with ethyl acetate (20 mL x 2), dried over anhydrous sodium sulfate, and concentrated until no liquid flowed out. Compound 8 (43 mg) was purified by preparative liquid chromatography. ESI-MS: m / z = 447.14 [M+H] + .

[0491] 1 H NMR (500 MHz, DMSO- d 6) δ 9.15 (s, 1H), 8.63 (d, J = 2.8 Hz, 1H), 8.39(s, 1H), 8.34 (d, J = 1.8 Hz, 1H), 8.09 (s, 2H), 7.76 (dt, J = 10.0, 2.2 Hz, 1H),7.67 (s, 1H), 7.28 (s, 1H). Example 9

[0492] (1) Preparation of compound 9-1: Compounds 1-7 (500 mg) were dissolved in tetrahydrofuran (12 mL), and a solution of sodium hydroxide (84.5 mg) and water (12 mL) was added dropwise under an ice-water bath. The reaction was allowed to proceed overnight at room temperature. The pH of the reaction solution was adjusted to 3-5 with hydrochloric acid, extracted with ethyl acetate (30 mL*2), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to obtain compound 9-1, which was used directly in the next reaction.

[0493] (2) Preparation of compound 9-2: Compound 9-1 (455 mg) was dispersed in tetrahydrofuran (15 mL). N-methylmorpholine (213.7 mg) and isobutyl chloroformate (288.6 mg) were added under ice-water bath conditions. The mixture was stirred for 30 minutes, and ammonia (222 mg) was added dropwise. The reaction was continued under ice-water bath conditions for 10 minutes. The reaction was quenched with water, extracted with ethyl acetate (20 mL x 2), dried over anhydrous sodium sulfate, and concentrated until no liquid flowed out, yielding 9-2. ESI-MS: m / z = 430.04 / 432.06 [M+H] + .

[0494] (3) Preparation of compound 9: Compound 9-2 (180 mg) and 2-trifluoromethylpyridine 4-boronic acid (95.9 mg) were dispersed in 1,4-dioxane (6 mL), and potassium acetate (123 mg), Pd(dppf)Cl2 (15.3 mg), and water (0.6 mL) were added. The mixture was heated to 90 °C under nitrogen protection. After the reaction was completed, the reaction solution was concentrated under reduced pressure and purified by preparative liquid chromatography to obtain compound 9 (18 mg). ESI-MS: m / z = 497.09 [M+H] + .

[0495] 1 H NMR (500 MHz, DMSO- d 6) δ 9.21 (s, 1H), 8.83 (d, J = 4.9 Hz, 1H), 8.39(s, 1H), 7.99 (s, 2H), 7.89 (s, 1H), 7.69 (s, 1H), 7.62 (d, J = 4.9 Hz, 1H), 7.29 (s, 1H). Example 10 (1) Preparation of compound 10-1: Compound 1-7 (200 mg) and 5-cyano-3-pyridylboronic acid (75.03 mg) were dispersed in 1,4-dioxane (10 mL), potassium acetate (124.4 mg), Pd(dppf)Cl2 (15.5 mg) and water (1 mL) were added, and the mixture was heated to 90 °C under nitrogen protection. After the reaction was completed, the reaction solution was concentrated under reduced pressure and purified by column chromatography to obtain compound 10-1.

[0496] (2) Preparation of compound 10-2: Compound 10-1 (173 mg) was dissolved in tetrahydrofuran (10 mL), and a solution of lithium hydroxide hydrate (73.12 mg) and water (10 mL) was added dropwise under an ice-water bath. The reaction was carried out at room temperature for 3 h. The pH of the reaction solution was adjusted to 3-5 with hydrochloric acid, extracted with ethyl acetate (20 mL * 2), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to obtain compound 10-2, which was directly used in the next step of the reaction.

[0497] (3) Preparation of compound 10: Compound 10-2 (159 mg) was dispersed in tetrahydrofuran (10 mL). N-methylmorpholine (70.8 mg) and isobutyl chloroformate (95.6 mg) were added under ice-water bath conditions. The mixture was stirred for 30 minutes, and ammonia (73.5 mg) was added dropwise. The reaction was quenched with water after 10 minutes in an ice-water bath. The mixture was extracted with ethyl acetate (20 mL x 2), dried over anhydrous sodium sulfate, and concentrated until no liquid flowed out. Compound 10 (23 mg) was purified by preparative liquid chromatography. ESI-MS: m / z = 454.20 [M+H] + .

[0498] 1 H NMR (500 MHz, DMSO- d 6) δ 9.21 (s, 1H), 9.09 (d, J = 2.0 Hz, 1H), 8.76(d, J = 2.1 Hz, 1H), 8.45 (s, 1H), 8.36 (t, J = 2.1 Hz, 1H), 8.05 (s, 2H), 7.70 (s, 1H), 7.30 (s, 1H). Example 11 (1) Preparation of compound 11-1: Compound 1-7 (300 mg) and 3-quinolineboronic acid (131.61 mg) were dispersed in 1,4-dioxane (8 mL), potassium acetate (186.6 mg), Pd(dppf)Cl2 (46 mg) and water (0.8 mL) were added, and the mixture was heated to 90 °C under nitrogen protection. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain compound 11-1, which was directly used in the next step of the reaction. (2) Preparation of compound 11-2: Compound 11-1 (328 mg) was dissolved in tetrahydrofuran (10 mL), and a solution of lithium hydroxide hydrate (52.87 mg) and water (10 mL) was added dropwise under an ice-water bath. The reaction was carried out at room temperature for 3 h. The pH of the reaction solution was adjusted to 3-5 with hydrochloric acid, extracted with ethyl acetate (20 mL * 2), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to obtain compound 11-2, which was directly used in the next step of the reaction.

[0499] (3) Preparation of compound 11-A: Compound 11-2 (301 mg) was dispersed in tetrahydrofuran (15 mL). N-methylmorpholine (127.45 mg) and isobutyl chloroformate (154.41 mg) were added under ice-water bath conditions. The mixture was stirred for 30 minutes, and ammonia (132.3 mg) was added dropwise. The reaction was continued under ice-water bath conditions for 10 minutes. The reaction was quenched with water, extracted with ethyl acetate (20 mL x 2), dried over anhydrous sodium sulfate, and concentrated until no liquid flowed out. Compound 11-A (30 mg) was purified by preparative liquid chromatography. ESI-MS: m / z = 479.31 [M+H] + .

[0500] 1 H NMR (500 MHz, DMSO- d 6) δ 9.17 (s, 1H), 8.76 (d, J = 2.2 Hz, 1H), 8.43(s, 1H), 8.30 (d, J = 2.2 Hz, 1H), 8.08 (d, J = 8.4 Hz, 1H), 8.01 (dd, J = 8.1, 1.4Hz, 1H), 7.88 (s, 2H), 7.84 (ddd, J = 8.5, 6.9, 1.5 Hz, 1H), 7.70 – 7.62 (m,2H), 7.36 (s, 1H). Example 12

[0501] (1) Preparation of compound 12-1: Compound 1-7 (300 mg) and indazole-6-boronic acid (123.22 mg) were dispersed in 1,4-dioxane (8 mL), potassium acetate (186.6 mg), Pd(dppf)Cl2 (46 mg) and water (0.8 mL) were added, and the mixture was heated to 90 °C under nitrogen protection. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain compound 12-1, which was directly used in the next step of the reaction. (2) Preparation of compound 12-2: Compound 12-1 (321 mg) was dissolved in tetrahydrofuran (10 mL), and a solution of lithium hydroxide hydrate (52.87 mg) and water (10 mL) was added dropwise under an ice-water bath. The reaction was carried out at room temperature for 3 h. The pH of the reaction solution was adjusted to 3-5 with hydrochloric acid, extracted with ethyl acetate (20 mL * 2), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to obtain compound 12-2, which was directly used in the next step of the reaction.

[0502] (3) Preparation of compound 12: Compound 12-2 (295 mg) was dispersed in tetrahydrofuran (15 mL). N-methylmorpholine (127.45 mg) and isobutyl chloroformate (154.41 mg) were added under ice-water bath conditions. The mixture was stirred for 30 minutes, and ammonia water (132.3 mg) was added dropwise. The reaction was carried out under ice-water bath conditions for 10 minutes. The reaction was quenched with water, and the mixture was extracted with ethyl acetate (20 mL x 2). The extract was dried over anhydrous sodium sulfate and concentrated until no liquid flowed out. Compound 12 (40 mg) was purified by preparative liquid chromatography. ESI-MS: m / z = 468.22 [M+H] + .

[0503] 1 H NMR (500 MHz, DMSO- d 6) δ 13.11 (s, 1H), 8.63 (s, 1H), 8.19 (s, 1H),8.13 (t, J = 1.3 Hz, 1H), 8.09 (s, 2H), 7.82 (d, J = 8.2 Hz, 1H), 7.62 (s, 1H), 7.47 – 7.43 (m, 1H), 7.11 (s, 1H), 6.95 (dd, J = 8.3, 1.4 Hz, 1H). Example 13

[0504] (1) Preparation of compound 13-2: Compound 13-1 (15 g), cyclopropylboronic acid (11.4 g), potassium carbonate (27.5 g), and Pd(dppf)Cl2 (2.4 g) were dispersed in 150 mL of dioxane and 15 mL of water. The mixture was heated to 90 °C under nitrogen protection. After the reaction was complete, the reaction solution was diluted with water (1000 mL) and extracted with ethyl acetate (100 mL * 3). The organic phase was collected, dried with anhydrous sodium sulfate, filtered, evaporated under reduced pressure, and purified by column chromatography to obtain compound 13-2.

[0505] (2) Preparation of compound 13-3: Pinaryl diboronate (6.51 g), 4,4'-di-tert-butyl-2,2'-dipyridine (76.16 mg), and methoxy(cyclooctadiene)iridium dimer (70.82 mg) were dispersed in cyclohexane (80 mL) and stirred under nitrogen protection for 10 minutes. Compound 13-2 (8.0 g) was then added, and the mixture was stirred at 55°C under nitrogen protection. After the reaction was complete, the reaction solution was quenched with ice water (80 mL), extracted with ethyl acetate (80 mL x 3), and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to obtain compound 13-3, which was directly used in the next reaction.

[0506] (3) Preparation of compound 13-4: 13-3 (10.7 g) was dispersed in ethylene glycol dimethyl ether (80 mL), and 10.5 g of 3-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazole and 14.18 g of potassium carbonate aqueous solution (16 mL) were added. The mixture was stirred at room temperature under nitrogen protection. After 1 h, 1.97 g of tetra(triphenylphosphine)palladium was added, and the mixture was stirred at 90 °C under nitrogen protection. After the reaction was complete, the reaction solution was quenched with ice water (60 mL), extracted with ethyl acetate (100 mL*3), and the organic phase was collected and washed with brine (60 mL*2). The organic layer was dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to obtain compound 13-4, which was directly used in the next reaction.

[0507] (4) Preparation of compound 13-5: Compound 13-4 (6.0 g) was dispersed in a 4.0 M, 50 mL solution of 1,4-dioxane hydrogen chloride. o After stirring until the reaction is complete, slowly pour the reaction solution into an ice-cold saturated sodium bicarbonate solution, adjust the pH to 7-8 with sodium bicarbonate, extract with ethyl acetate (100 mL * 3), wash the organic phase with saturated brine (100 mL), dry with anhydrous sodium sulfate, concentrate under reduced pressure until no liquid flows out, and purify by column chromatography to obtain compound 13-5.

[0508] (5) Preparation of compound 13-6: Compound 13-5 (4 g) was dispersed in DMF (20 mL) and dioxane (20 mL), and DABCO (3.5 g) was added. 20-25 o After stirring for 30 minutes, cool to 0-10°C. o C, add compound 13-5a (5.6 g) dropwise, after the addition is complete, 20-25 o Stir for 1.5 hours. After the reaction is complete, pour the reaction solution into 100 mL of water, extract with ethyl acetate (100 mL * 2), combine the organic phases, dry with anhydrous sodium sulfate, and purify by column chromatography to give compound 13-6 (3.0 g).

[0509] (6) Preparation of compounds 13-7: Compound 13-6 (3 g) was dispersed in dichloromethane (30 mL), cooled to 0 °C, and liquid bromine (2.6 g) was added dropwise over 15 minutes. The mixture was then slowly brought to room temperature and stirred for 6 hours. After the reaction was complete, the reaction mixture was poured into 40 mL of ice water and extracted with dichloromethane (40 mL x 3). The organic phases were combined, washed with saturated sodium bisulfite solution (30 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure until no liquid eluent was obtained, and purified by column chromatography to give compound 13-7.

[0510] (7) Preparation of compounds 13-8: Compound 13-7 (4.3 g) was dispersed in tetrahydrofuran (40 mL), and triethylamine (1.65 g) was added dropwise after the temperature was lowered to 0 °C. After the addition was complete, the mixture was slowly raised to room temperature and reacted for 6 hours. After the reaction was complete, 40 mL of water was added to dilute the reaction solution, and the mixture was extracted with ethyl acetate (40 mL * 3). The organic phases were combined, dried over anhydrous sodium sulfate, and purified by column chromatography to obtain compound 13-8 (2 g).

[0511] (8) Preparation of compounds 13-9: 13-8 (300 mg), 5-pyrimidineboronic acid (100 mg), potassium acetate (198 mg), and Pd(dppf)Cl2 (24.6 mg) were dispersed in 8 mL of dioxane and 0.8 mL of water. The mixture was heated to 90 °C under nitrogen protection. After the reaction was completed, the reaction solution was diluted with water (15 mL) and extracted with ethyl acetate (20 mL * 3). The organic phase was collected, dried with anhydrous sodium sulfate, filtered, evaporated under reduced pressure, and purified by column chromatography to obtain compound 13-9 (200 mg).

[0512] (9) Preparation of compounds 13-10: Compound 13-9 (200 mg) was dissolved in tetrahydrofuran (8 mL), and a solution of sodium hydroxide (36 mg) and water (8 mL) was added dropwise under an ice-water bath. The reaction was allowed to proceed overnight at room temperature. The pH of the reaction solution was adjusted to 3-5 with hydrochloric acid, extracted with ethyl acetate (20 mL * 3), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to obtain compound 13-10, which was used directly in the next reaction.

[0513] (10) Preparation of compound 13: Compound 13-10 (181 mg) was dispersed in tetrahydrofuran (10 mL). N-methylmorpholine (91 mg) and isobutyl chloroformate (123 mg) were added under ice-water bath conditions. The mixture was stirred for 30 minutes, then ammonia (95 mg) was added dropwise. The reaction was continued under ice-water bath conditions for 10 minutes. The reaction was quenched with water, extracted with ethyl acetate (20 mL x 3), dried over anhydrous sodium sulfate, and concentrated until no liquid eluates. Compound 13 (57 mg) was purified by preparative liquid chromatography. ESI-MS: m / z = 402.27 [M+H] + .

[0514] 1 H NMR (500 MHz, DMSO- d 6) δ 9.24 (s, 1H), 9.13 (s, 1H), 8.73 (s, 2H), 8.42 (s, 1H), 7.69 (s, 1H), 7.65 (s, 1H), 7.49 (s, 1H), 7.41 (s, 1H), 2.28(tt, J = 8.3, 4.7 Hz, 1H), 1.10 (dq, J = 6.6, 3.8 Hz, 2H), 0.99 – 0.91 (m, 2H). Example 14

[0515] (1) Preparation of compound 14-2: Compounds 13-8 (300 mg) and 14-1 (228 mg) were dispersed in 1,4-dioxane (15 mL), potassium acetate (196 mg), Pd(dppf)Cl2 (22 mg) and water (1.5 mL) were added, and the mixture was heated to 90 °C under nitrogen protection. After the reaction was completed, the reaction solution was concentrated under reduced pressure and purified by column chromatography to obtain compound 14-2.

[0516] (2) Preparation of compound 14-3: Compound 14-2 (100 mg) was dissolved in tetrahydrofuran (5 mL), and a solution of lithium hydroxide hydrate (40.1 mg) and water (5 mL) was added dropwise under an ice-water bath. The reaction was carried out at room temperature for 2 h. The pH of the reaction solution was adjusted to 3-5 with hydrochloric acid, extracted with ethyl acetate (20 mL * 2), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to obtain compound 14-3, which was directly used in the next step of the reaction.

[0517] (3) Preparation of compound 14: Compound 14-3 (60 mg) was dispersed in tetrahydrofuran (5 mL). N-methylmorpholine (26 mg) and isobutyl chloroformate (35 mg) were added under ice-water bath conditions. The mixture was stirred for 30 minutes, then ammonia (27 mg) was added dropwise. The reaction was continued under ice-water bath conditions for 10 minutes. The reaction was quenched with water, extracted with ethyl acetate (20 mL x 2), dried over anhydrous sodium sulfate, and concentrated until no liquid eluates. Compound 14 (10 mg) was purified by preparative liquid chromatography. ESI-MS: m / z = 481.3 [M+H] + .

[0518] 1 H NMR (500 MHz, DMSO- d 6) δ 9.05 (s, 1H), 8.21 (s, 3H), 7.84 (d, J = 1.3Hz, 1H), 7.76 (t, J = 6.2 Hz, 1H), 7.71 (d, J = 1.3 Hz, 1H), 7.55 (s, 1H), 7.40(s, 1H), 6.10 (tt, J = 56.5, 4.2 Hz, 1H), 3.74 (tdd, J = 15.0, 6.2, 4.1 Hz, 2H),2.30 (tt, J = 8.1, 4.7 Hz, 1H), 1.08 (dt, J = 8.1, 3.2 Hz, 2H), 0.99 – 0.95 (m,2H). Example 15

[0519] (1) Preparation of compound 15-2: Compounds 13-8 (371 mg) and 15-1 (299 mg) were dispersed in 1,4-dioxane (55 mL), potassium acetate (244 mg), Pd(dppf)Cl2 (30 mg) and water (1.5 mL) were added, and the mixture was heated to 90 °C under nitrogen protection. After the reaction was completed, the reaction solution was concentrated under reduced pressure and purified by column chromatography to obtain compound 15-2.

[0520] (2) Preparation of compound 15-3: Compound 15-2 (340 mg) was dissolved in tetrahydrofuran (5 mL), and a solution of lithium hydroxide hydrate (132.7 mg) and water (5 mL) was added dropwise under an ice-water bath. The reaction was carried out at room temperature for 2 h. The pH of the reaction solution was adjusted to 3-5 with hydrochloric acid, extracted with ethyl acetate (20 mL * 2), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to obtain compound 15-3, which was directly used in the next step of the reaction.

[0521] (3) Preparation of compound 15-A: Compound 15-3 (312 mg) was dispersed in tetrahydrofuran (5 mL). N-methylmorpholine (127 mg) and isobutyl chloroformate (172 mg) were added under ice-water bath conditions. The mixture was stirred for 30 minutes, then ammonia (132 mg) was added dropwise. The reaction was continued under ice-water bath conditions for 10 minutes. The reaction was quenched with water, extracted with ethyl acetate (20 mL x 2), dried over anhydrous sodium sulfate, and concentrated until no liquid flowed out. Compound 15-A (70 mg) was purified by preparative liquid chromatography. ESI-MS: m / z = 495.39 [M+H] + .

[0522] 1 H NMR (500 MHz, DMSO- d 6) δ 9.05 (s, 1H), 8.20 (d, J = 3.2 Hz, 3H), 7.84(d, J = 1.2 Hz, 1H), 7.77 (t, J = 6.6 Hz, 1H), 7.73 (d, J = 1.3 Hz, 1H), 7.54 (s,1H), 7.42 (s, 1H), 3.83 (td, J = 13.6, 6.6 Hz, 2H), 2.29 (tt, J = 8.3, 4.7 Hz, 1H), 1.61 (t, J = 19.0 Hz, 3H), 1.08 (dt, J= 8.0, 3.2 Hz, 2H), 1.00 – 0.94 (m,2H). Example 16

[0523] (1) Preparation of compound 16-2: Compounds 13-8 (400 mg) and 16-1 (327 mg) were dispersed in 1,4-dioxane (15 mL), potassium acetate (264 mg), Pd(dppf)Cl2 (65.7 mg) and water (1.5 mL) were added, and the mixture was heated to 90 °C under nitrogen protection. After the reaction was completed, the reaction solution was concentrated under reduced pressure and purified by column chromatography to obtain compound 16-2.

[0524] (2) Preparation of compound 16-3: Compound 16-2 (300 mg) was dissolved in tetrahydrofuran (10 mL), and a solution of lithium hydroxide hydrate (46.5 mg) and water (10 mL) was added dropwise under an ice-water bath. The reaction was carried out at room temperature for 3 h. The pH of the reaction solution was adjusted to 3-5 with hydrochloric acid, extracted with ethyl acetate (20 mL * 2), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to obtain compound 16-3, which was directly used in the next step of the reaction.

[0525] (3) Preparation of compound 16: Compound 16-3 (276 mg) was dispersed in tetrahydrofuran (15 mL). N-methylmorpholine (112 mg) and isobutyl chloroformate (151 mg) were added under ice-water bath conditions. The mixture was stirred for 30 minutes, and ammonia (116 mg) was added dropwise. The reaction was continued under ice-water bath conditions for 10 minutes. The reaction was quenched with water, extracted with ethyl acetate (20 mL x 2), dried over anhydrous sodium sulfate, and concentrated until no liquid eluates. Compound 16 (58.4 mg) was purified by preparative liquid chromatography. ESI-MS: m / z = 499.28 [M+H] + .

[0526] 1 H NMR (500 MHz, DMSO- d 6) δ 9.07 (s, 1H), 8.23 ​​(d, J = 6.1 Hz, 3H), 8.00(t, J = 6.7 Hz, 1H), 7.83 (d, J = 1.3 Hz, 1H), 7.70 (d, J = 1.3 Hz, 1H), 7.55 (s,1H), 7.42 (s, 1H), 4.18 (qd, J= 9.5, 6.6 Hz, 2H), 2.28 (tt, J = 8.1, 4.7 Hz, 1H), 1.08 (dt, J = 8.0, 3.2 Hz, 2H), 0.99 – 0.94 (m, 2H). Example 17

[0527] (1) Preparation of compound 17-2: Compounds 13-8 (400 mg) and 17-1 (342 mg) were dispersed in 1,4-dioxane (15 mL), potassium acetate (264 mg), Pd(dppf)Cl2 (65.7 mg) and water (1.5 mL) were added, and the mixture was heated to 90 °C under nitrogen protection. After the reaction was completed, the reaction solution was concentrated under reduced pressure and purified by column chromatography to obtain compound 17-2.

[0528] (2) Preparation of compound 17-3: Compound 17-2 (400 mg) was dissolved in tetrahydrofuran (10 mL), and a solution of lithium hydroxide hydrate (91 mg) and water (10 mL) was added dropwise under an ice-water bath. The reaction was carried out at 0-10℃ for 3 h. The pH of the reaction solution was adjusted to 3-5 with hydrochloric acid, extracted with ethyl acetate (20 mL * 2), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to obtain compound 17-3, which was directly used in the next step of the reaction.

[0529] (3) Preparation of compound 17: Compound 17-3 (370 mg) was dispersed in tetrahydrofuran (15 mL). N-methylmorpholine (146 mg) and isobutyl chloroformate (197 mg) were added under ice-water bath conditions. The mixture was stirred for 30 minutes, and ammonia (151 mg) was added dropwise. The reaction was continued under ice-water bath conditions for 10 minutes. The reaction was quenched with water, extracted with ethyl acetate (20 mL x 2), dried over anhydrous sodium sulfate, and concentrated until no liquid eluates. Compound 17 (49 mg) was purified by preparative liquid chromatography. ESI-MS: m / z = 513.33 [M+H] + .

[0530] 1 H NMR (500 MHz, DMSO- d 6) δ 9.07 (s, 1H), 8.23 ​​(d, J = 7.2 Hz, 3H), 7.96 (d, J = 9.1 Hz, 1H), 7.85 (s, 1H), 7.71 (d, J= 1.3 Hz, 1H), 7.54 (s, 1H), 7.43(s, 1H), 4.95 (h, J = 7.2 Hz, 1H), 2.29 (tt, J = 8.3, 4.7 Hz, 1H), 1.35 (d, J = 7.0Hz, 3H), 1.07 (dt, J = 8.3, 3.1 Hz, 2H), 0.98 (dq, J = 7.0, 3.4 Hz, 2H). Example 18 (1) Preparation of compound 18-2: Compound 1-7 (300 mg) and 2-fluoropyridine-4-boronic acid (18-1, 107 mg) were dispersed in 1,4-dioxane (8 mL), potassium acetate (186.6 mg), Pd(dppf)Cl2 (23.2 mg) and water (0.8 mL) were added, and the mixture was heated to 90 °C under nitrogen protection. The reaction was monitored by TLC until the reactants were completely reacted. The reaction solution was concentrated under reduced pressure and purified by column chromatography to obtain compound 18-2.

[0531] (2) Preparation of compound 18-3: Compound 18-2 (240 mg) was dissolved in tetrahydrofuran (10 mL), and a solution of lithium hydroxide hydrate (61.7 mg) and water (10 mL) was added dropwise under an ice-water bath. The reaction was carried out at 0-5 °C for 2 h. The pH of the reaction solution was adjusted to 6-7 with hydrochloric acid, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to obtain compound 18-3, which was directly used in the next step of the reaction.

[0532] (3) Preparation of compound 18: Compound 18-3 (219 mg) was dispersed in tetrahydrofuran (15 mL). N-methylmorpholine (99 mg) and isobutyl chloroformate (133.8 mg) were added under ice-water bath conditions. The mixture was stirred for 30 minutes, and ammonia (102.9 mg) was added dropwise. The reaction was continued under ice-water bath conditions for 10 minutes, and the reaction was quenched with water. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated until no liquid eluates. Compound 18 (57 mg) was purified by preparative liquid chromatography. ESI-MS: m / z = 447.17 [M+H] + .

[0533] 1 H NMR (500 MHz, DMSO- d6) δ 9.13 (s, 1H), 8.34 (s, 1H), 8.30 (d, J = 5.1Hz, 1H), 8.09 (s, 2H), 7.68 (s, 1H), 7.26 (dt, J = 5.1, 1.7 Hz, 1H), 7.21 (s,1H), 7.19 (d, J = 1.6 Hz, 1H). Example 19

[0534] (1) Preparation of compound 19-2: Compound 1-7 (200 mg) and 2-fluoropyridine-5-boronic acid (19-1, 71.5 mg) were dispersed in 1,4-dioxane (10 mL), potassium acetate (124.4 mg), Pd(dppf)Cl2 (15.5 mg) and water (1 mL) were added, and the reaction was carried out at 90 °C under nitrogen protection. The reaction was monitored by TLC until the reactants were completely reacted. The reaction solution was concentrated under reduced pressure and purified by column chromatography to obtain compound 19-2.

[0535] (2) Preparation of compound 19-3: Compound 19-2 (205 mg) was dissolved in tetrahydrofuran (10 mL), and a solution of lithium hydroxide hydrate (35.4 mg) and water (10 mL) was added dropwise under an ice-water bath. The reaction was carried out at room temperature for 3 h. The pH of the reaction solution was adjusted to 6-7 with hydrochloric acid, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to obtain compound 19-3, which was directly used in the next step of the reaction.

[0536] (3) Preparation of compound 19: Compound 19-3 (137.4 mg) was dispersed in tetrahydrofuran (10 mL). N-methylmorpholine (64.74 mg) and isobutyl chloroformate (87.41 mg) were added under ice-water bath conditions. The mixture was stirred for 30 minutes, then ammonia (67.2 mg) was added dropwise. The reaction was continued under ice-water bath conditions for 10 minutes, quenched with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated until no liquid eluates. Compound 19 (70 mg) was purified by preparative liquid chromatography. ESI-MS: m / z = 447.15 [M+H] + .

[0537] 1 H NMR (500 MHz, DMSO- d 6) δ 9.14 (s, 1H), 8.37 (s, 1H), 8.14 (d, J= 2.4Hz, 1H), 8.11 (s, 2H), 7.89 (td, J = 8.1, 2.5 Hz, 1H), 7.64 (s, 1H), 7.27 (dd, J = 8.4, 2.7 Hz, 2H). Example 20

[0538] (1) Preparation of compound 20-2: Compound 1-7 (200 mg) and 2-fluoropyridine-3-boronic acid (20-1, 71.5 mg) were dispersed in 1,4-dioxane (10 mL), potassium acetate (124.4 mg), Pd(dppf)Cl2 (15.5 mg) and water (1 mL) were added, and the mixture was heated to 90 °C under nitrogen protection. The reaction was monitored by TLC until the reactants were completely reacted. The reaction solution was concentrated under reduced pressure and purified by column chromatography to obtain compound 20-2.

[0539] (2) Preparation of compound 20-3: Compound 20-2 (205 mg) was dissolved in tetrahydrofuran (10 mL), and a solution of lithium hydroxide hydrate (35.4 mg) and water (10 mL) was added dropwise under an ice-water bath. The reaction was carried out at room temperature for 3 h. The pH of the reaction solution was adjusted to 6-7 with hydrochloric acid, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to obtain compound 20-3, which was directly used in the next step of the reaction.

[0540] (3) Preparation of compound 20: Compound 20-3 (137.4 mg) was dispersed in tetrahydrofuran (10 mL). N-methylmorpholine (64.74 mg) and isobutyl chloroformate (87.41 mg) were added under ice-water bath conditions. The mixture was stirred for 30 minutes, then ammonia (67.2 mg) was added dropwise. The reaction was continued under ice-water bath conditions for 10 minutes, quenched with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated until no liquid eluates. Compound 20 (15 mg) was purified by preparative liquid chromatography. ESI-MS: m / z = 447.16 [M+H] + Example 21

[0541] (1) Preparation of compound 21-2: Compound 1-7 (300 mg) and 6-methylpyridine-3-boronic acid (21-1, 104 mg) were dispersed in 1,4-dioxane (8 mL), potassium acetate (186.6 mg), Pd(dppf)Cl2 (23.2 mg) and water (0.8 mL) were added, and the mixture was heated to 90 °C under nitrogen protection. The reaction was monitored by TLC until the reactants were completely reacted. The reaction solution was concentrated under reduced pressure and purified by column chromatography to obtain compound 21-2. (2) Preparation of compound 21-3: Compound 21-2 (120 mg) was dissolved in tetrahydrofuran (10 mL), and a solution of lithium hydroxide hydrate (20.7 mg) and water (10 mL) was added dropwise under an ice-water bath. The reaction was carried out at 0-5 °C for 2 h. The pH of the reaction solution was adjusted to 6-7 with hydrochloric acid, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to obtain compound 21-3, which was directly used in the next step of the reaction.

[0542] (3) Preparation of compound 21-A: Compound 21-3 (109 mg) was dispersed in tetrahydrofuran (15 mL). N-methylmorpholine (50 mg) and isobutyl chloroformate (67.5 mg) were added under ice-water bath conditions. The mixture was stirred for 30 minutes, then ammonia (51.9 mg) was added dropwise. The reaction was continued under ice-water bath conditions for 10 minutes. The reaction was quenched with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated until no liquid flowed out. Compound 21-A (42 mg) was obtained by preparative liquid chromatography. ESI-MS: m / z = 443.17 [M+H] + 1 H NMR (500 MHz, DMSO- d 6) δ 9.05 (s, 1H), 8.32 (d, J = 2.1 Hz, 1H), 8.29(s, 1H), 8.11 (s, 2H), 7.61 (s, 1H), 7.57 (dd, J = 7.9, 2.3 Hz, 1H), 7.34 (d, J =7.9 Hz, 1H), 7.23 (s, 1H), 2.54 (s, 3H). Example 22

[0543] (1) Preparation of compound 22-2: Compound 1-7 (300 mg) and 2-methylpyridine-4-boronic acid (22-1, 104 mg) were dispersed in 1,4-dioxane (8 mL), potassium acetate (186.6 mg), Pd(dppf)Cl2 (23.2 mg) and water (0.8 mL) were added, and the mixture was heated to 90 °C under nitrogen protection. The reaction was monitored by TLC until the reactants were completely reacted. The reaction solution was concentrated under reduced pressure and purified by column chromatography to obtain compound 22-2. (2) Preparation of compound 22-3: Compound 22-2 (170 mg) was dissolved in tetrahydrofuran (10 mL), and a solution of lithium hydroxide hydrate (29 mg) and water (10 mL) was added dropwise under an ice-water bath. The reaction was carried out at 0-5 °C for 2 h. The pH of the reaction solution was adjusted to 6-7 with hydrochloric acid, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to obtain compound 22-3, which was directly used in the next step of the reaction.

[0544] (3) Preparation of compound 22 Compound 22-3 (155 mg) was dispersed in tetrahydrofuran (15 mL). N-methylmorpholine (70.8 mg) and isobutyl chloroformate (95.6 mg) were added under ice-water bath conditions. The mixture was stirred for 30 minutes, then ammonia (73.5 mg) was added dropwise. The reaction was continued under ice-water bath conditions for 10 minutes. The reaction was quenched with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated until no liquid eluates. Compound 22 (57 mg) was purified by preparative liquid chromatography. ESI-MS: m / z = 443.16 [M+H] + .

[0545] 1 H NMR (500 MHz, DMSO- d 6) δ 8.99 (s, 1H), 8.49 (dd, J = 5.0, 0.8 Hz,1H), 8.23 ​​(s, 1H), 8.12 (s, 2H), 7.64 (s, 1H), 7.21 – 7.19 (m, 1H), 7.17 (s,1H), 7.06 (dd, J = 5.1, 1.6 Hz, 1H), 2.49 (s, 3H). Example 23

[0546] (1) Preparation of compound 23-2 Compound 1-7 (300 mg) and 6-methoxy-3-pyridineboronic acid (23-1, 116.23 mg) were dispersed in 1,4-dioxane (10 mL), potassium acetate (186.7 mg), Pd(dppf)Cl2 (23.2 mg) and water (1 mL) were added, and the reaction was carried out at 90 °C under nitrogen protection. The reaction was monitored by TLC until the reactants were completely reacted. The reaction solution was concentrated under reduced pressure and purified by column chromatography to obtain compound 23-2.

[0547] (2) Preparation of compound 23-3 Compound 23-2 (306 mg) was dissolved in tetrahydrofuran (10 mL), and a solution of lithium hydroxide hydrate (53.2 mg) and water (10 mL) was added dropwise under an ice-water bath. The reaction was carried out at room temperature for 3 h. The pH of the reaction solution was adjusted to 6-7 with hydrochloric acid, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to obtain compound 23-3, which was directly used in the next step of the reaction.

[0548] (3) Preparation of compound 23 Compound 23-3 (289 mg) was dispersed in tetrahydrofuran (10 mL). N-methylmorpholine (128.3 mg) and isobutyl chloroformate (173.2 mg) were added under ice-water bath conditions. The mixture was stirred for 30 minutes, then ammonia (133.1 mg) was added dropwise. The reaction was continued under ice-water bath conditions for 10 minutes, quenched with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated until no liquid eluates. Compound 23 (100 mg) was purified by preparative liquid chromatography. ESI-MS: m / z = 459.22 [M+H] + .

[0549] 1 H NMR (500 MHz, DMSO- d 6) δ 9.04 (s, 1H), 8.25 (s, 1H), 8.17 (s, 2H), 8.07 – 8.04 (m, 1H), 7.58 (dd, J = 8.5, 2.5 Hz, 2H), 7.23 (s, 1H), 6.90 (dd, J =8.6, 0.7 Hz, 1H), 3.91 (s, 3H). Example 24 (1) Preparation of compound 24-2 Compound 1-7 (300 mg) and 2-methylpyridine-3-boronic acid (24-1, 104 mg) were dispersed in 1,4-dioxane (8 mL), potassium acetate (186.6 mg), Pd(dppf)Cl2 (23.2 mg) and water (0.8 mL) were added, and the mixture was heated to 90 °C under nitrogen protection. The reaction was monitored by TLC until the reactants were completely reacted. The reaction solution was concentrated under reduced pressure and purified by column chromatography to obtain compound 24-2.

[0550] (1) Preparation of compound 24-3 Compound 24-2 (150 mg) was dissolved in tetrahydrofuran (10 mL), and a solution of lithium hydroxide hydrate (38.9 mg) and water (10 mL) was added dropwise under an ice-water bath. The reaction was carried out at 0-25 °C for 2 h. The pH of the reaction solution was adjusted to 6-7 with hydrochloric acid, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to obtain compound 24-3, which was directly used in the next step of the reaction.

[0551] (3) Preparation of compound 24 Compound 24-3 (137 mg) was dispersed in tetrahydrofuran (15 mL). N-methylmorpholine (62.5 mg) and isobutyl chloroformate (84.4 mg) were added under ice-water bath conditions. The mixture was stirred for 30 minutes, then ammonia (64.9 mg) was added dropwise. The reaction was continued under ice-water bath conditions for 10 minutes. The reaction was quenched with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated until no liquid eluates. Compound 24 (82 mg) was purified by preparative liquid chromatography. ESI-MS: m / z = 443.28 [M+H] + .

[0552] 1 H NMR (500 MHz, DMSO- d 6) δ 9.07 (s, 1H), 8.51 (dd, J = 4.9, 1.7 Hz,1H), 8.34 (s, 1H), 8.05 (s, 2H), 7.59 (s, 1H), 7.51 (dd, J = 7.6, 1.7 Hz, 1H), 7.29 (dd, J = 7.6, 4.9 Hz, 1H), 7.18 (s, 1H), 2.28 (s, 3H). Example 25

[0553] (1) Preparation of compound 25-2: Compounds 1-7 (300 mg) and 25-1 (195 mg) were dispersed in 1,4-dioxane (8 mL), potassium acetate (186.6 mg), Pd(dppf)Cl2 (46 mg) and water (0.8 mL) were added, and the mixture was heated to 90 °C under nitrogen protection. The reaction was monitored by TLC until the reactants were completely reacted. The reaction solution was concentrated under reduced pressure to obtain compound 25-2.

[0554] (2) Preparation of compound 25-3: Compound 25-2 (240 mg) was dissolved in tetrahydrofuran (10 mL), and a solution of lithium hydroxide hydrate (57.8 mg) and water (10 mL) was added dropwise under an ice-water bath. The reaction was carried out at room temperature for 3 h. The pH of the reaction solution was adjusted to 6-7 with hydrochloric acid, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to obtain compound 25-3, which was directly used in the next step of the reaction.

[0555] (3) Preparation of compound 25-A: Compound 25-3 (220 mg) was dispersed in tetrahydrofuran (15 mL). N-methylmorpholine (93 mg) and isobutyl chloroformate (125 mg) were added under ice-water bath conditions. The mixture was stirred for 30 minutes, then ammonia (96 mg) was added dropwise. The reaction was continued under ice-water bath conditions for 10 minutes. The reaction was quenched with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated until no liquid eluates. Compound 25-A (86 mg) was purified by preparative liquid chromatography. ESI-MS: m / z = 480.24 [M+H] + .

[0556] 1 H NMR (500 MHz, DMSO- d 6) δ 9.22 (s, 1H), 9.04 (dd, J = 4.2, 1.7 Hz, 1H), 8.89 (d, J = 2.1 Hz, 1H), 8.53 – 8.45 (m, 2H), 8.34 (d, J = 2.1 Hz, 1H), 7.88 (dd, J = 8.5, 4.2 Hz, 1H), 7.82 (s, 2H), 7.70 (s, 1H), 7.38 (s, 1H). Example 26

[0557] (1) Preparation of compound 26-2: Compound 13-8 (200 mg) and 3-quinolineboronic acid (26-1, 76.6 mg) were dispersed in 1,4-dioxane (5 mL), potassium acetate (132.5 mg), Pd(dppf)Cl2 (14.6 mg) and water (0.5 mL) were added, and the mixture was heated to 90 °C under nitrogen protection. The reaction was monitored by TLC until the reactants were completely reacted. The reaction solution was concentrated under reduced pressure and then purified by column chromatography to obtain compound 26-2.

[0558] (2) Preparation of compound 26-3: Compound 26-2 (120 mg) was dissolved in tetrahydrofuran (4 mL), and a solution of lithium hydroxide hydrate (30.6 mg) and water (4 mL) was added dropwise under an ice-water bath. The reaction was carried out at room temperature for 4 h. The pH of the reaction solution was adjusted to 6-7 with hydrochloric acid, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to obtain compound 26-3, which was directly used in the next step of the reaction.

[0559] (3) Preparation of compound 26: Compound 26-3 (100 mg) was dispersed in tetrahydrofuran (5 mL), and N-methylmorpholine (44.5 mg) and isobutyl chloroformate (60.1 mg) were added under ice-water bath conditions. The mixture was stirred for 30 minutes, and ammonia water (46.2 mg) was added dropwise. The reaction was carried out under ice-water bath conditions for 10 minutes, and the reaction was quenched with water. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated until no liquid flowed out. Compound 26 (40 mg) was purified by preparative liquid chromatography. ESI-MS: m / z = 451.20 [M+H] + .

[0560] 1 H NMR (500 MHz, DMSO- d 6) δ 9.07 (s, 1H), 8.74 (d, J = 2.2 Hz, 1H), 8.40(s, 1H), 8.29 (d, J = 2.2 Hz, 1H), 8.09 (dd, J = 8.4, 1.1 Hz, 1H), 8.01 (dd, J =8.1, 1.5 Hz, 1H), 7.82 (ddd, J = 8.5, 6.9, 1.5 Hz, 1H), 7.64 (ddd, J = 8.1, 6.9,1.2 Hz, 2H), 7.48 (d, J = 1.4 Hz, 1H), 7.33 (s, 1H), 7.29 (d, J= 1.3 Hz, 1H), 2.07 (tt, J = 8.1, 4.7 Hz, 1H), 1.06 – 0.97 (m, 2H), 0.83 – 0.75 (m, 2H). Example 27

[0561] (1) Preparation of compound 27-2: Compound 13-8 (200 mg) and 5-fluoro-3-pyridineboronic acid (27-1, 76.1 mg) were dispersed in 1,4-dioxane (5 mL), potassium acetate (132.5 mg), Pd(dppf)Cl2 (14.6 mg) and water (0.5 mL) were added, and the reaction was carried out at 90 °C under nitrogen protection. The reaction was monitored by TLC until the reactants were completely reacted. The reaction solution was concentrated under reduced pressure and then purified by column chromatography to obtain compound 27-2.

[0562] (2) Preparation of compound 27-3: Compound 27-2 (120 mg) was dissolved in tetrahydrofuran (4 mL), and a solution of lithium hydroxide hydrate (32.8 mg) and water (4 mL) was added dropwise under an ice-water bath. The reaction was carried out at room temperature for 4 h. The pH of the reaction solution was adjusted to 6-7 with hydrochloric acid, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to obtain compound 27-3, which was directly used in the next step of the reaction.

[0563] (3) Preparation of compound 27: Compound 27-3 (100 mg) was dispersed in tetrahydrofuran (5 mL). N-methylmorpholine (48.6 mg) and isobutyl chloroformate (65.6 mg) were added under ice-water bath conditions. The mixture was stirred for 30 minutes, then ammonia (50.4 mg) was added dropwise. The reaction was continued under ice-water bath conditions for 10 minutes. The reaction was quenched with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated until no liquid eluates. Compound 27 (40 mg) was purified by preparative liquid chromatography. ESI-MS: m / z = 419.22 [M+H] + .

[0564] 1 H NMR (500 MHz, DMSO- d 6) δ 9.05 (s, 1H), 8.63 (d, J = 2.8 Hz, 1H), 8.34(d, J= 19.3 Hz, 2H), 7.79 – 7.69 (m, 2H), 7.64 (s, 1H), 7.51 (s, 1H), 7.25 (s,1H), 2.28 (tt, J = 8.4, 4.7 Hz, 1H), 1.10 (dd, J = 8.0, 3.0 Hz, 2H), 0.93 (dd, J =4.7, 2.6 Hz, 2H). Example 28

[0565] (1) Preparation of compound 28-2: Compound 13-8 (200 mg) and 2-aminopyrimidine-5-boronic acid (28-1, 75 mg) were dispersed in 1,4-dioxane (5 mL), potassium acetate (132.5 mg), Pd(dppf)Cl2 (14.6 mg) and water (0.5 mL) were added, and the mixture was heated to 90 °C under nitrogen protection. The reaction was monitored by TLC until the reactants were completely reacted. The reaction solution was concentrated under reduced pressure and then subjected to column chromatography to obtain compound 28-2.

[0566] (2) Preparation of compound 28-3: Compound 28-2 (102 mg) was dissolved in tetrahydrofuran (4 mL), and a solution of lithium hydroxide hydrate (27.7 mg) and water (4 mL) was added dropwise under an ice-water bath. The reaction was carried out at room temperature for 4 h. The pH of the reaction solution was adjusted to 6-7 with hydrochloric acid, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to obtain compound 28-3, which was directly used in the next step of the reaction.

[0567] (3) Preparation of compound 28: Compound 28-3 (100 mg) was dispersed in tetrahydrofuran (5 mL), and N-methylmorpholine (48.6 mg) and isobutyl chloroformate (65.6 mg) were added under ice-water bath. The mixture was stirred for 30 minutes, and ammonia water (50.4 mg) was added dropwise. The reaction was carried out under ice-water bath for 10 minutes, and the reaction was quenched with water. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated until no liquid flowed out. Compound 28 (45 mg) was purified by preparative liquid chromatography. ESI-MS: m / z = 417.22 [M+H] + .

[0568] 1 H NMR (500 MHz, DMSO- d 6) δ 9.00 (s, 1H), 8.15 (s, 1H), 8.08 (s, 2H), 7.85 (d,J = 1.2 Hz, 1H), 7.78 (d, J = 1.3 Hz, 1H), 7.53 (s, 1H), 7.41 (s, 1H), 6.84 (s, 2H), 2.36 – 2.28 (m, 1H), 1.09 (dt, J = 8.0, 3.2 Hz, 2H), 0.98 (dq, J =6.9, 3.9 Hz, 2H). Example 29

[0569] (1) Preparation of compound 29-2: Compound 13-8 (200 mg) and 1-methyl-1H-pyrazole-4-boronic acid (29-1, 68 mg) were dispersed in 1,4-dioxane (5 mL), potassium acetate (132.5 mg), Pd(dppf)Cl2 (14.6 mg) and water (0.5 mL) were added, and the mixture was heated to 90 °C under nitrogen protection. The reaction was monitored by TLC until the reactants were completely reacted. The reaction solution was concentrated under reduced pressure and then purified by column chromatography to obtain compound 29-2.

[0570] (2) Preparation of compound 29-3: Compound 29-2 (100 mg) was dissolved in tetrahydrofuran (4 mL), and a solution of lithium hydroxide hydrate (27.7 mg) and water (4 mL) was added dropwise under an ice-water bath. The reaction was carried out at room temperature for 4 h. The pH of the reaction solution was adjusted to 6-7 with hydrochloric acid, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to obtain compound 29-3, which was directly used in the next step of the reaction.

[0571] (3) Preparation of compound 29: Compound 29-3 (88.96 mg) was dispersed in tetrahydrofuran (5 mL). N-methylmorpholine (44.5 mg) and isobutyl chloroformate (60.09 mg) were added under ice-water bath conditions. The mixture was stirred for 30 minutes, then ammonia (46.2 mg) was added dropwise. The reaction was continued under ice-water bath conditions for 10 minutes. The reaction was quenched with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated until no liquid eluates. Compound 29 (30 mg) was purified by preparative liquid chromatography. ESI-MS: m / z = 404.24 [M+H] + .

[0572] 1 H NMR (500 MHz, DMSO- d6) δ 8.75 (s, 1H), 8.08 – 8.03 (m, 1H), 7.94(d, J = 1.3 Hz, 1H), 7.82 (s, 1H), 7.72 (s, 1H), 7.55 (s, 1H), 7.49 (s, 1H),7.25 (s, 1H), 3.85 (s, 3H), 2.37 (tt, J = 8.1, 4.7 Hz, 1H), 1.10 (dt, J = 8.1, 3.2 Hz, 2H), 1.00 (dq, J = 7.0, 4.3, 3.9 Hz, 2H). Example 30

[0573] (1) Preparation of compound 30-2: Compound 13-8 (200 mg) and 5-cyanopyridine-3-boronic acid (30-1, 79.8 mg) were dispersed in 1,4-dioxane (5 mL), potassium acetate (132.5 mg), Pd(dppf)Cl2 (14.6 mg) and water (0.5 mL) were added, and the mixture was heated to 90 °C under nitrogen protection. The reaction was monitored by TLC until the reactants were completely reacted. The reaction solution was concentrated under reduced pressure and then purified by column chromatography to obtain compound 30-2. (2) Preparation of compound 30-3: Compound 30-2 (150 mg) was dissolved in tetrahydrofuran (4 mL), and a solution of lithium hydroxide hydrate (40.28 mg) and water (4 mL) was added dropwise under an ice-water bath. The reaction was carried out at room temperature for 4 h. The pH of the reaction solution was adjusted to 6-7 with hydrochloric acid, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to obtain compound 30-3, which was directly used in the next step of the reaction.

[0574] (3) Preparation of compound 30: Compound 30-3 (136.44 mg) was dispersed in tetrahydrofuran (5 mL). N-methylmorpholine (64.74 mg) and isobutyl chloroformate (87.4 mg) were added under ice-water bath conditions. The mixture was stirred for 30 minutes, then ammonia (67.2 mg) was added dropwise. The reaction was continued under ice-water bath conditions for 10 minutes. The reaction was quenched with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated until no liquid flowed out. Compound 30 (45 mg) was purified by preparative liquid chromatography. ESI-MS: m / z = 426.21 [M+H] + .

[0575] 1H NMR (500 MHz, DMSO- d 6) δ 9.12 (s, 1H), 9.09 (d, J = 2.0 Hz, 1H), 8.75(d, J = 2.1 Hz, 1H), 8.42 (s, 1H), 8.35 (t, J = 2.1 Hz, 1H), 7.70 (d, J = 1.3 Hz,1H), 7.66 (s, 1H), 7.45 (d, J = 1.3 Hz, 1H), 7.28 (s, 1H), 2.29 (tt, J = 8.1, 4.7Hz, 1H), 1.10 (dt, J = 8.1, 3.3 Hz, 2H), 0.97 – 0.89 (m, 2H). Example 31 (1) Preparation of compound 31-2: Compound 13-8 (200 mg) and 3,5-dimethylisoxazole-4-boronic acid (31-1, 76.1 mg) were dispersed in 1,4-dioxane (5 mL), potassium carbonate (186.6 mg), Pd(dppf)Cl2 (14.6 mg) and water (0.5 mL) were added, and the mixture was heated to 90 °C under nitrogen protection. The reaction was monitored by TLC until the reactants were completely reacted. The reaction solution was concentrated under reduced pressure and then purified by column chromatography to obtain compound 31-2.

[0576] (2) Preparation of compound 31-3: Compound 31-2 (150 mg) was dissolved in tetrahydrofuran (4 mL), and a solution of lithium hydroxide hydrate (41.54 mg) and water (4 mL) was added dropwise under an ice-water bath. The reaction was carried out at room temperature for 4 h. The pH of the reaction solution was adjusted to 6-7 with hydrochloric acid, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to obtain compound 31-3, which was directly used in the next step of the reaction.

[0577] (3) Preparation of compound 31: Compound 31-3 (134 mg) was dispersed in tetrahydrofuran (5 mL). N-methylmorpholine (64.74 mg) and isobutyl chloroformate (87.4 mg) were added under ice-water bath conditions. The mixture was stirred for 30 minutes, then ammonia (67.2 mg) was added dropwise. The reaction was continued under ice-water bath conditions for 10 minutes. The reaction was quenched with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated until no liquid eluates. Compound 31 (30 mg) was purified by preparative liquid chromatography. ESI-MS: m / z = 419.23 [M+H] + .

[0578] 1 H NMR (500 MHz, DMSO- d 6) δ 9.07 (s, 1H), 8.38 (s, 1H), 7.86 (d, J = 1.3Hz, 1H), 7.78 (d, J = 1.3 Hz, 1H), 7.52 (s, 1H), 7.37 (s, 1H), 2.31 (tt, J = 8.1,4.7 Hz, 1H), 2.17 (s, 3H), 1.96 (s, 3H), 1.14 – 1.08 (m, 2H), 1.01 – 0.95 (m, 2H). Example 32 (1) Preparation of compound 32-2: Compound 13-8 (200 mg) and 2-fluoro-pyridine-3-boronic acid (32-1, 76.1 mg) were dispersed in 1,4-dioxane (5 mL), potassium carbonate (186.6 mg), Pd(dppf)Cl2 (14.6 mg) and water (0.5 mL) were added, and the mixture was heated to 90 °C under nitrogen protection. The reaction was monitored by TLC until the reactants were completely reacted. The reaction solution was concentrated under reduced pressure and then purified by column chromatography to obtain compound 32-2.

[0579] (2) Preparation of compound 32-3: Compound 32-2 (70 mg) was dissolved in tetrahydrofuran (4 mL), and a solution of lithium hydroxide hydrate (18.9 mg) and water (4 mL) was added dropwise under an ice-water bath. The reaction was carried out at room temperature for 4 h. The pH of the reaction solution was adjusted to 6-7 with hydrochloric acid, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to obtain compound 32-3, which was directly used in the next step of the reaction.

[0580] (3) Preparation of compound 32: Compound 32-3 (50 mg) was dispersed in tetrahydrofuran (5 mL). N-methylmorpholine (24.3 mg) and isobutyl chloroformate (32.7 mg) were added under ice-water bath conditions. The mixture was stirred for 30 minutes, and ammonia (25.2 mg) was added dropwise. The reaction was continued under ice-water bath conditions for 10 minutes. The reaction was quenched with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated until no liquid flowed out. Compound 32 (10 mg) was purified by preparative liquid chromatography. ESI-MS: m / z = 419.21 [M+H] 1 H NMR (500 MHz, DMSO- d 6) δ 9.13 (s, 1H), 8.39 (s, 1H), 8.32 (dd, J =5.0, 1.9 Hz, 1H), 7.86 (ddd, J = 9.5, 7.3, 1.9 Hz, 1H), 7.69 (d, J = 1.3 Hz, 1H),7.59 (s, 1H), 7.50 (d, J = 1.3 Hz, 1H), 7.44 (ddd, J = 7.1, 4.9, 1.9 Hz, 1H),7.40 (s, 1H), 2.27 (tt, J = 8.2, 4.7 Hz, 1H), 1.10 (dt, J = 8.1, 3.3 Hz, 2H),0.97 – 0.90 (m, 2H). Example 33 (1) Preparation of compound 33-2: Compound 13-8 (200 mg) and [1,5]naphthyl-3-boronic acid (33-1, 138.3 mg) were dispersed in 1,4-dioxane (5 mL), potassium acetate (132.5 mg), Pd(dppf)Cl2 (14.6 mg) and water (0.5 mL) were added, and the mixture was heated to 90 °C under nitrogen protection. The reaction was monitored by TLC until the reactants were completely reacted. The reaction solution was concentrated under reduced pressure and then subjected to column chromatography to obtain compound 33-2.

[0581] (2) Preparation of compound 33-3: Compound 33-2 (160 mg) was dissolved in tetrahydrofuran (4 mL), and a solution of lithium hydroxide hydrate (40.28 mg) and water (4 mL) was added dropwise under an ice-water bath. The reaction was carried out at room temperature for 4 h. The pH of the reaction solution was adjusted to 6-7 with hydrochloric acid, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to obtain compound 33-3, which was directly used in the next step of the reaction.

[0582] (3) Preparation of compound 33: Compound 33-3 (144.7 mg) was dispersed in tetrahydrofuran (5 mL). N-methylmorpholine (64.74 mg) and isobutyl chloroformate (87.4 mg) were added under ice-water bath conditions. The mixture was stirred for 30 minutes, then ammonia (67.2 mg) was added dropwise. The reaction was continued under ice-water bath conditions for 10 minutes. The reaction was quenched with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated until no liquid flowed out. Compound 33 (20 mg) was purified by preparative liquid chromatography. ESI-MS: m / z = 452.21 [M+H] + .

[0583] 1 H NMR (500 MHz, DMSO- d 6) δ 9.12 (s, 1H), 9.03 (dd, J = 4.2, 1.7 Hz, 1H), 8.87 (d, J = 2.2 Hz, 1H), 8.51 (d, J = 8.5 Hz, 1H), 8.46 (s, 1H), 8.31 (d, J =2.2 Hz, 1H), 7.86 (dd, J = 8.5, 4.2 Hz, 1H), 7.65 (s, 1H), 7.51 (s, 1H), 7.34(s, 1H), 7.20 – 7.14 (m, 1H), 2.10 (tt, J = 8.4, 4.7 Hz, 1H), 1.01 (dt, J = 6.4, 3.3 Hz, 2H), 0.79 (dq, J = 6.9, 4.0 Hz, 2H). Example 34 (1) Preparation of compound 34-2: Compound 13-8 (200 mg) and 2-methoxypyridine-5-boronic acid (34-1, 82.6 mg) were dispersed in 1,4-dioxane (5 mL), potassium acetate (132.5 mg), Pd(dppf)Cl2 (14.6 mg) and water (0.5 mL) were added, and the mixture was heated to 90 °C under nitrogen protection. The reaction was monitored by TLC until the reactants were completely reacted. The reaction solution was concentrated under reduced pressure and then purified by column chromatography to obtain compound 34-2.

[0584] (2) Preparation of compound 34-3: Compound 34-2 (180 mg) was dissolved in tetrahydrofuran (4 mL), and a solution of lithium hydroxide hydrate (47.9 mg) and water (4 mL) was added dropwise under an ice-water bath. The reaction was carried out at room temperature for 4 h. The pH of the reaction solution was adjusted to 6-7 with hydrochloric acid, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to obtain compound 34-3, which was directly used in the next step of the reaction.

[0585] (3) Preparation of compound 34: Compound 34-3 (163.9 mg) was dispersed in tetrahydrofuran (5 mL). N-methylmorpholine (76.8 mg) and isobutyl chloroformate (103.8 mg) were added under ice-water bath conditions. The mixture was stirred for 30 minutes, then ammonia (79.8 mg) was added dropwise. The reaction was continued under ice-water bath conditions for 10 minutes. The reaction was quenched with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated until no liquid eluates. Compound 34 (80 mg) was purified by preparative liquid chromatography. ESI-MS: m / z = 431.19 [M+H] + .

[0586] 1 H NMR (500 MHz, DMSO- d 6) δ 8.91 (s, 1H), 8.21 (s, 1H), 8.04 (d, J = 2.4Hz, 1H), 7.81 (d, J = 1.3 Hz, 1H), 7.61 (d, J = 1.3 Hz, 1H), 7.58 (d, J = 2.4 Hz, 1H), 7.56 (d, J = 2.5 Hz, 1H), 7.55 (s, 1H), 7.20 (s, 1H), 6.89 (d, J = 8.5 Hz,1H), 3.91 (s, 3H), 2.29 (tt, J= 8.1, 4.8 Hz, 1H), 1.12 – 1.05 (m, 2H), 0.98 –0.93 (m, 2H). Example 35

[0587] (1) Preparation of compound 35-1: Compound 13-8 (200 mg) was dissolved in tetrahydrofuran (4 mL), and a solution of lithium hydroxide hydrate (56.65 mg) and water (4 mL) was added dropwise under an ice-water bath. The reaction was carried out at room temperature for 4 h. The pH of the reaction solution was adjusted to 6-7 with hydrochloric acid, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to obtain compound 35-1, which was directly used in the next step of the reaction.

[0588] (2) Preparation of compound 35-2: Compound 35-1 (181.4 mg) was dispersed in tetrahydrofuran (5 mL), and N-methylmorpholine (91.04 mg) and isobutyl chloroformate (122.9 mg) were added under an ice-water bath. The mixture was stirred for 30 minutes, and ammonia (94.5 mg) was added dropwise. The reaction was carried out under an ice-water bath for 10 minutes, and the reaction was quenched with water. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated until no liquid flowed out to obtain compound 35-2, which was used directly in the next reaction.

[0589] (2) Preparation of compound 35: Compound 35-2 (200 mg) and 2-fluoro-pyrimidine-5-boronic acid (35-3, 134.4 mg) were dispersed in 1,4-dioxane (5 mL), followed by the addition of potassium acetate (147.21 mg), Pd(dppf)Cl2 (18.3 mg), and water (0.5 mL). The reaction was carried out under nitrogen protection at 90 °C. TLC was monitored until the reaction proceeded completely. The reaction solution was concentrated under reduced pressure and purified by preparative liquid chromatography to obtain compound 35 (30 mg). ESI-MS: m / z = 420.19 [M+H] + 1 H NMR (500 MHz, DMSO- d 6) δ 9.18 (s, 1H), 8.74 (s, 2H), 8.47 (s, 1H), 7.74 (s, 1H), 7.66 (s, 1H), 7.49 (s, 1H), 7.35 (s, 1H), 2.28 (tt, J = 8.4, 4.7Hz, 1H), 1.11 (dq, J= 6.7, 3.9 Hz, 2H), 1.00 – 0.89 (m, 2H). Example 36 (1) Preparation of compound 36-2: Compound 13-8 (200 mg) and 2-fluoro-pyridine-4-boronic acid (36-1, 76.09 mg) were dispersed in 1,4-dioxane (5 mL), potassium acetate (132.5 mg), Pd(dppf)Cl2 (14.6 mg) and water (0.5 mL) were added, and the mixture was heated to 90 °C under nitrogen protection. The reaction was monitored by TLC until the reactants were completely reacted. The reaction solution was concentrated under reduced pressure and then purified by column chromatography to obtain compound 36-2.

[0590] (2) Preparation of compound 36-3: Compound 36-2 (150 mg) was dissolved in tetrahydrofuran (4 mL), and a solution of lithium hydroxide hydrate (40.3 mg) and water (4 mL) was added dropwise under an ice-water bath. The reaction was carried out at room temperature for 4 h. The pH of the reaction solution was adjusted to 6-7 with hydrochloric acid, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to obtain compound 36-3, which was directly used in the next step of the reaction.

[0591] (3) Preparation of compound 36: Compound 36-3 (100 mg) was dispersed in tetrahydrofuran (5 mL). N-methylmorpholine (48.5 mg) and isobutyl chloroformate (65.5 mg) were added under ice-water bath conditions. The mixture was stirred for 30 minutes, then ammonia (50.4 mg) was added dropwise. The reaction was continued under ice-water bath conditions for 10 minutes. The reaction was quenched with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated until no liquid flowed out. Compound 36 (30 mg) was purified by preparative liquid chromatography. ESI-MS: m / z = 419.19 [M+H] + .

[0592] 1 H NMR (500 MHz, DMSO- d 6) δ 9.03 (s, 1H), 8.29 (d, J = 5.3 Hz, 2H), 7.68(s, 1H), 7.63 (s, 1H), 7.53 (s, 1H), 7.25 (d, J = 5.0 Hz, 1H), 7.18 (d, J = 6.6Hz, 2H), 2.26 (tt, J = 8.3, 4.7 Hz, 1H), 1.10 (dq, J= 6.8, 3.9 Hz, 2H), 0.94(dq, J = 6.7, 4.0 Hz, 2H). Example 37 (1) Preparation of compound 37-2: Compound 13-8 (200 mg) and 6-fluoro-pyridine-2-boronic acid (37-1, 76.09 mg) were dispersed in 1,4-dioxane (5 mL), potassium acetate (132.5 mg), Pd(dppf)Cl2 (14.6 mg) and water (0.5 mL) were added, and the mixture was heated to 90 °C under nitrogen protection. The reaction was monitored by TLC until the reactants were completely reacted. The reaction solution was concentrated under reduced pressure and then purified by column chromatography to obtain compound 37-2.

[0593] (2) Preparation of compound 37-3: Compound 37-2 (170 mg) was dissolved in tetrahydrofuran (4 mL), and a solution of lithium hydroxide hydrate (46.4 mg) and water (4 mL) was added dropwise under an ice-water bath. The reaction was carried out at room temperature for 4 h. The pH of the reaction solution was adjusted to 6-7 with hydrochloric acid, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to obtain compound 37-3, which was directly used in the next step of the reaction.

[0594] (3) Preparation of compound 37: Compound 37-3 (155.2 mg) was dispersed in tetrahydrofuran (5 mL). N-methylmorpholine (74.8 mg) and isobutyl chloroformate (101.1 mg) were added under ice-water bath conditions. The mixture was stirred for 30 minutes, then ammonia (77.7 mg) was added dropwise. The reaction was continued under ice-water bath conditions for 10 minutes. The reaction was quenched with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated until no liquid flowed out. Compound 37 (40 mg) was purified by preparative liquid chromatography. ESI-MS: m / z = 419.19 [M+H] + .

[0595] 1 H NMR (500 MHz, DMSO- d 6) δ 9.01 (d, J = 1.4 Hz, 1H), 8.27 (d, J = 1.4 Hz, 1H), 8.05 (q, J = 8.1 Hz, 1H), 7.73 (s, 1H), 7.60 (s, 1H), 7.51 (d, J = 1.4 Hz, 1H), 7.34 (dd, J= 7.4, 2.3 Hz, 1H), 7.23 (dd, J = 8.5, 2.3 Hz, 2H), 2.29 (tt, J =8.4, 4.7 Hz, 1H), 1.09 (dq, J = 6.5, 3.8 Hz, 2H), 0.94 (dt, J = 5.0, 3.3 Hz, 2H). Example 38

[0596] (1) Preparation of compound 38-2: Compound 13-8 (200 mg) and 2-methylpyridine-5-boronic acid (38-1, 73.95 mg) were dispersed in 1,4-dioxane (5 mL), potassium acetate (132.5 mg), Pd(dppf)Cl2 (14.6 mg) and water (0.5 mL) were added, and the mixture was heated to 90 °C under nitrogen protection. The reaction was monitored by TLC until the reactants were completely reacted. The reaction solution was concentrated under reduced pressure and then purified by column chromatography to obtain compound 38-2.

[0597] (2) Preparation of compound 38-3: Compound 38-2 (105 mg) was dissolved in tetrahydrofuran (4 mL), and a solution of lithium hydroxide hydrate (28.95 mg) and water (4 mL) was added dropwise under an ice-water bath. The reaction was carried out at room temperature for 4 h. The pH of the reaction solution was adjusted to 6-7 with hydrochloric acid, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to obtain compound 38-3, which was directly used in the next step of the reaction.

[0598] (3) Preparation of compound 38-A: Compound 38-3 (95.5 mg) was dispersed in tetrahydrofuran (5 mL). N-methylmorpholine (46.5 mg) and isobutyl chloroformate (62.8 mg) were added under ice-water bath conditions. The mixture was stirred for 30 minutes, then ammonia (48.3 mg) was added dropwise. The reaction was continued under ice-water bath conditions for 10 minutes. The reaction was quenched with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated until no liquid eluates. Compound 38-A (30 mg) was purified by preparative liquid chromatography. ESI-MS: m / z = 415.24 [M+H] + .

[0599] 1 H NMR (500 MHz, DMSO- d 6) δ 8.93 (s, 1H), 8.30 (d, J= 2.3 Hz, 1H), 8.24(s, 1H), 7.78 (s, 1H), 7.56 (dd, J = 8.0, 2.4 Hz, 2H), 7.53 (d, J = 1.3 Hz, 1H), 7.33 (d, J = 7.9 Hz, 1H), 7.20 (s, 1H), 2.54 (s, 3H), 2.29 (tt, J = 8.3, 4.7 Hz, 1H), 1.09 (dt, J = 8.1, 3.3 Hz, 2H), 1.00 – 0.89 (m, 2H). Example 39

[0600] (1) Preparation of compound 39-2: Compound 13-8 (200 mg) and 2-fluoro-pyridine-5-boronic acid (39-1, 76.09 mg) were dispersed in 1,4-dioxane (5 mL), potassium acetate (132.5 mg), Pd(dppf)Cl2 (14.6 mg) and water (0.5 mL) were added, and the reaction was carried out at 90 °C under nitrogen protection. The reaction was monitored by TLC until the reactants were completely reacted. The reaction solution was concentrated under reduced pressure and then purified by column chromatography to obtain compound 39-2.

[0601] (2) Preparation of compound 39-3: Compound 39-2 (180 mg) was dissolved in tetrahydrofuran (4 mL), and a solution of lithium hydroxide hydrate (49.1 mg) and water (4 mL) was added dropwise under an ice-water bath. The reaction was carried out at room temperature for 4 h. The pH of the reaction solution was adjusted to 6-7 with hydrochloric acid, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to obtain compound 39-3, which was directly used in the next step of the reaction.

[0602] (3) Preparation of compound 39: Compound 39-3 (163 mg) was dispersed in tetrahydrofuran (5 mL). N-methylmorpholine (78.9 mg) and isobutyl chloroformate (106.5 mg) were added under ice-water bath conditions. The mixture was stirred for 30 minutes, then ammonia (81.9 mg) was added dropwise. The reaction was continued under ice-water bath conditions for 10 minutes. The reaction was quenched with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated until no liquid eluates. Compound 39 (40 mg) was purified by preparative liquid chromatography. ESI-MS: m / z = 419.20 [M+H] + .

[0603] 1H NMR (500 MHz, DMSO- d 6) δ 9.04 (s, 1H), 8.33 (s, 1H), 8.13 (d, J = 2.4Hz, 1H), 7.88 (td, J = 8.2, 2.5 Hz, 1H), 7.75 (d, J = 1.2 Hz, 1H), 7.61 (s, 1H), 7.52 (d, J = 1.3 Hz, 1H), 7.27 (dd, J = 8.4, 2.7 Hz, 1H), 7.24 (s, 1H), 2.28 (tt, J = 8.0, 4.7 Hz, 1H), 1.09 (dt, J = 8.0, 3.3 Hz, 2H), 0.99 – 0.89 (m, 2H). Example 40

[0604] (1) Preparation of compound 40-2: Compound 13-8 (200 mg, 0.45 mmol, 1.0 eq) and 2-trifluoroethylaminopyridine-5-boronic acid (40-1, 118.08 mg) were dispersed in 1,4-dioxane (5 mL), potassium acetate (132.5 mg), Pd(dppf)Cl2 (14.6 mg) and water (0.5 mL) were added, and the reaction was carried out at 90 °C under nitrogen protection. The reaction was monitored by TLC until the reactants were completely reacted. The reaction solution was concentrated under reduced pressure and then purified by column chromatography to obtain compound 40-2.

[0605] (2) Preparation of compound 40-3: Compound 40-2 (130 mg) was dissolved in tetrahydrofuran (4 mL), and a solution of lithium hydroxide hydrate (30.3 mg) and water (4 mL) was added dropwise under an ice-water bath. The reaction was carried out at room temperature for 4 h. The pH of the reaction solution was adjusted to 6-7 with hydrochloric acid, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to obtain compound 40-3, which was directly used in the next step of the reaction.

[0606] (3) Preparation of compound 40: Compound 40-3 (119.6 mg) was dispersed in tetrahydrofuran (5 mL). N-methylmorpholine (48.6 mg) and isobutyl chloroformate (65.6 mg) were added under ice-water bath conditions. The mixture was stirred for 30 minutes, then ammonia (50.4 mg) was added dropwise. The reaction was continued under ice-water bath conditions for 10 minutes. The reaction was quenched with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated until no liquid flowed out. Compound 40 (50 mg) was purified by preparative liquid chromatography. ESI-MS: m / z = 498.29 [M+H] + .

[0607] 1 H NMR (500 MHz, DMSO- d 6) δ 8.78 (s, 1H), 8.05 (s, 1H), 7.88 (d, J = 2.0Hz, 2H), 7.75 (d, J = 1.3 Hz, 1H), 7.56 – 7.49 (m, 1H), 7.39 (t, J = 6.6 Hz, 1H), 7.32 (dd, J = 8.5, 2.4 Hz, 1H), 7.24 (s, 1H), 6.69 (d, J = 8.5 Hz, 1H), 4.19 (qd, J = 9.7, 6.5 Hz, 2H), 2.30 (tt, J = 8.2, 4.7 Hz, 1H), 1.08 (dt, J = 8.0, 3.2 Hz,2H), 1.02 – 0.91 (m, 2H). Example 41

[0608] (1) Preparation of compound 41-2: Compound 13-8 (200 mg) and 6-(2,2-difluoroethylamino)pyridine-3-boronic acid (41-1, 108.86 mg) were dispersed in 1,4-dioxane (5 mL), potassium acetate (132.5 mg), Pd(dppf)Cl2 (14.6 mg) and water (0.5 mL) were added, and the reaction was carried out at 90 °C under nitrogen protection. The reaction was monitored by TLC until the reactants were completely reacted. After the reaction solution was concentrated under reduced pressure, compound 41-2 was extracted by column chromatography.

[0609] (2) Preparation of compound 41-3: Compound 41-2 (120 mg) was dissolved in tetrahydrofuran (4 mL), and a solution of lithium hydroxide hydrate (28.9 mg) and water (4 mL) was added dropwise under an ice-water bath. The reaction was carried out at room temperature for 4 h. The pH of the reaction solution was adjusted to 6-7 with hydrochloric acid, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to obtain compound 41-3, which was directly used in the next step of the reaction.

[0610] (3) Preparation of compound 41: Compound 41-3 (110.5 mg) was dispersed in tetrahydrofuran (5 mL). N-methylmorpholine (46.5 mg) and isobutyl chloroformate (62.8 mg) were added under ice-water bath conditions. The mixture was stirred for 30 minutes, then ammonia (48.3 mg) was added dropwise. The reaction was continued under ice-water bath conditions for 10 minutes. The reaction was quenched with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated until no liquid flowed out. Compound 41 (40 mg) was purified by preparative liquid chromatography. ESI-MS: m / z = 480.31 [M+H] + .

[0611] 1 H NMR (500 MHz, DMSO- d 6) δ 8.74 (s, 1H), 8.03 (s, 1H), 7.90 (d, J = 1.3Hz, 1H), 7.87 (d, J = 2.4 Hz, 1H), 7.77 (d, J = 1.2 Hz, 1H), 7.53 (s, 1H), 7.27(dd, J = 8.6, 2.4 Hz, 1H), 7.25 – 7.18 (m, 2H), 6.64 (d, J = 8.6 Hz, 1H), 6.09(tt, J = 56.6, 4.1 Hz, 1H), 3.73 (tdd, J = 15.4, 6.1, 4.1 Hz, 2H), 2.31 (tt, J =8.1, 4.7 Hz, 1H), 1.08 (dt, J = 8.0, 3.2 Hz, 2H), 1.00 – 0.94 (m, 2H). Example 42

[0612] (1) Preparation of compound 42-2: Compound 13-8 (200 mg) and pyridine-3-boronic acid (42-1, 66.37 mg) were dispersed in 1,4-dioxane (5 mL), potassium acetate (132.5 mg), Pd(dppf)Cl2 (14.6 mg) and water (0.5 mL) were added, and the mixture was heated to 90 °C under nitrogen protection. The reaction was monitored by TLC until the reactants were completely reacted. After the reaction solution was concentrated under reduced pressure, compound 42-2 was extracted by column chromatography.

[0613] (2) Preparation of compound 42-3: Compound 42-2 (85 mg) was dissolved in tetrahydrofuran (4 mL), and a solution of lithium hydroxide hydrate (24.1 mg) and water (4 mL) was added dropwise under an ice-water bath. The reaction was carried out at room temperature for 4 h. The pH of the reaction solution was adjusted to 6-7 with hydrochloric acid, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to obtain compound 42-3, which was directly used in the next step of the reaction.

[0614] (3) Preparation of compound 42: Compound 42-3 (76.28 mg) was dispersed in tetrahydrofuran (5 mL). N-methylmorpholine (38.4 mg) and isobutyl chloroformate (51.9 mg) were added under ice-water bath conditions. The mixture was stirred for 30 minutes, then ammonia (39.9 mg) was added dropwise. The reaction was continued under ice-water bath conditions for 10 minutes. The reaction was quenched with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated until no liquid flowed out. Compound 42 (20 mg) was purified by preparative liquid chromatography. ESI-MS: m / z = 401.32 [M+H] + .

[0615] Example 43

[0616] (1) Preparation of compound 43-2: Compound 13-8 (200 mg) and 4-pyridineboronic acid (43-1, 66.37 mg) were dispersed in 1,4-dioxane (5 mL), potassium acetate (132.5 mg), Pd(dppf)Cl2 (14.6 mg) and water (0.5 mL) were added, and the mixture was heated to 90 °C under nitrogen protection. The reaction was monitored by TLC until the reactants were completely reacted. The reaction solution was concentrated under reduced pressure and then purified by column chromatography to obtain compound 43-2.

[0617] (2) Preparation of compound 43-3: Compound 43-2 (120 mg) was dissolved in tetrahydrofuran (4 mL), and a solution of lithium hydroxide hydrate (34.06 mg) and water (4 mL) was added dropwise under an ice-water bath. The reaction was carried out at room temperature for 4 h. The pH of the reaction solution was adjusted to 6-7 with hydrochloric acid, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to obtain compound 43-3, which was directly used in the next step of the reaction.

[0618] (3) Preparation of compound 43: Compound 43-3 (108.4 mg) was dispersed in tetrahydrofuran (5 mL). N-methylmorpholine (54.6 mg) and isobutyl chloroformate (73.7 mg) were added under ice-water bath conditions. The mixture was stirred for 30 minutes, then ammonia (56.7 mg) was added dropwise. The reaction was continued under ice-water bath conditions for 10 minutes. The reaction was quenched with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated until no liquid eluates. Compound 43 (60 mg) was purified by preparative liquid chromatography. ESI-MS: m / z = 401.24 [M+H] + .

[0619] Example 44

[0620] (1) Preparation of compound 44-2: Compound 1-7 (200 mg) and pyridine-3-boronic acid (44-1, 62.4 mg) were dispersed in 1,4-dioxane (8 mL), potassium carbonate (175 mg), Pd(dppf)Cl2 (15.5 mg) and water (0.8 mL) were added, and the mixture was heated to 90 °C under nitrogen protection. The reaction was monitored by TLC until the reactants were completely reacted. The reaction solution was concentrated under reduced pressure and purified by column chromatography to obtain compound 44-2.

[0621] (2) Preparation of compound 44-3: Compound 44-2 (100 mg) was dissolved in tetrahydrofuran (5 mL), and a solution of lithium hydroxide hydrate (290 mg) and water (5 mL) was added dropwise under an ice-water bath. The reaction was carried out at room temperature for 2 h. The pH of the reaction solution was adjusted to 6-7 with hydrochloric acid, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to obtain compound 44-3, which was directly used in the next step of the reaction.

[0622] (3) Preparation of compound 44: Compound 44-3 (91 mg) was dispersed in tetrahydrofuran (10 mL), and N-methylmorpholine (42.9 mg) and isobutyl chloroformate (58 mg) were added under ice-water bath. The mixture was stirred for 30 minutes, and ammonia (44.5 mg) was added dropwise. The reaction was carried out under ice-water bath for 10 minutes, and the reaction was quenched with water. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated until no liquid flowed out. Compound 44 (60 mg) was purified by preparative liquid chromatography. ESI-MS: m / z = 429.29 M+H + .

[0623] 1 H NMR (500 MHz, DMSO- d 6) δ 9.05 (s, 1H), 8.62 (d, J = 4.9 Hz, 1H), 8.46(d, J = 2.2 Hz, 1H), 8.31 (s, 1H), 8.10 (s, 2H), 7.70 (dt, J = 7.9, 1.9 Hz, 1H),7.64 (s, 1H), 7.48 (dd, J = 7.8, 4.8 Hz, 1H), 7.28 (s, 1H). Example 45

[0624] (1) Preparation of compound 45-2: Compound 1-7 (200 mg) and 3,5-dimethylisoxazole-4-boronic acid (45-1, 71.6 mg) were dispersed in 1,4-dioxane (8 mL), potassium carbonate (175 mg), Pd(dppf)Cl2 (15.5 mg) and water (0.8 mL) were added, and the reaction was carried out at 90 °C under nitrogen protection. The reaction was monitored by TLC until the reactants were completely reacted. The reaction solution was concentrated under reduced pressure and purified by column chromatography to obtain compound 45-2.

[0625] (2) Preparation of compound 45-3: Compound 45-2 (159 mg) was dissolved in tetrahydrofuran (10 mL), and a solution of lithium hydroxide hydrate (44.7 mg) and water (10 mL) was added dropwise under an ice-water bath. The reaction was carried out at room temperature for 2 h. The pH of the reaction solution was adjusted to 6-7 with hydrochloric acid, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to obtain compound 45-3, which was directly used in the next step of the reaction.

[0626] (3) Preparation of compound 45: Compound 45-3 (145 mg) was dispersed in tetrahydrofuran (10 mL). N-methylmorpholine (65.7 mg) and isobutyl chloroformate (88.7 mg) were added under ice-water bath conditions. The mixture was stirred for 30 minutes, then ammonia (68 mg) was added dropwise. The reaction was continued under ice-water bath conditions for 10 minutes. The reaction was quenched with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated until no liquid eluates. Compound 45 (66 mg) was purified by preparative liquid chromatography. ESI-MS: m / z = 447.29 [M+H] + .

[0627] 1 H NMR (500 MHz, DMSO- d 6) δ 9.16 (s, 1H), 8.41 (s, 1H), 8.31 (s, 2H), 7.57 (s, 1H), 7.42 (s, 1H), 2.18 (s, 3H), 1.97 (s, 3H). Example 46

[0628] (1) Preparation of compound 46-2: Compound 1-7 (250 mg) and 6-(2,2,2-trifluoroethylamino)pyridine-3-boronic acid (46-1, 140 mg) were dispersed in 1,4-dioxane (8 mL), potassium carbonate (219 mg), Pd(dppf)Cl2 (19.3 mg) and water (0.8 mL) were added, and the reaction was carried out at 90 °C under nitrogen protection. The reaction was monitored by TLC until the reactants were completely reacted. The reaction solution was concentrated under reduced pressure and purified by column chromatography to obtain compound 46-2.

[0629] (2) Preparation of compound 46-3: Compound 46-2 (220 mg) was dissolved in tetrahydrofuran (10 mL), and a solution of lithium hydroxide hydrate (48.7 mg) and water (10 mL) was added dropwise under an ice-water bath. The reaction was carried out at room temperature for 2 h. The pH of the reaction solution was adjusted to 6-7 with hydrochloric acid, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to obtain compound 46-3, which was directly used in the next step of the reaction.

[0630] (3) Preparation of compound 46: Compound 46-3 (203 mg) was dispersed in tetrahydrofuran (10 mL). N-methylmorpholine (78 mg) and isobutyl chloroformate (106 mg) were added under ice-water bath conditions. The mixture was stirred for 30 minutes, then ammonia (81 mg) was added dropwise. The reaction was continued under ice-water bath conditions for 10 minutes. The reaction was quenched with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated until no liquid eluates. Compound 46 (30 mg) was purified by preparative liquid chromatography. ESI-MS: m / z = 526.33 [M+H] + .

[0631] 1 H NMR (500 MHz, DMSO- d 6) δ 8.91 (s, 1H), 8.28 (s, 2H), 8.08 (s, 1H), 7.89 (d, J = 2.3 Hz, 1H), 7.55 (s, 1H), 7.40 (t, J = 6.5 Hz, 1H), 7.33 (dd, J =8.6, 2.4 Hz, 1H), 7.27 (s, 1H), 6.68 (d, J = 8.6 Hz, 1H), 4.18 (qd, J = 9.7, 6.4Hz, 2H). Example 47

[0632] (1) Preparation of compound 47-2: Compound 1-7 (200 mg) and 4-quinolineboronic acid (47-1, 87.7 mg) were dispersed in 1,4-dioxane (8 mL), potassium acetate (124 mg), Pd(dppf)Cl2 (15.5 mg) and water (0.8 mL) were added, and the mixture was heated to 90 °C under nitrogen protection. The reaction was monitored by TLC until the reactants were completely reacted. The reaction solution was concentrated under reduced pressure and purified by column chromatography to obtain compound 47-2.

[0633] (2) Preparation of compound 47-3: Compound 47-2 (200 mg) was dissolved in tetrahydrofuran (10 mL), and a solution of lithium hydroxide hydrate (48 mg) and water (10 mL) was added dropwise under an ice-water bath. The reaction was carried out at room temperature for 2 h. The pH of the reaction solution was adjusted to 6-7 with hydrochloric acid, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to obtain compound 47-3, which was directly used in the next step of the reaction.

[0634] (3) Preparation of compound 47: Compound 47-3 (184 mg) was dispersed in tetrahydrofuran (10 mL). N-methylmorpholine (77.7 mg) and isobutyl chloroformate (105 mg) were added under ice-water bath conditions. The mixture was stirred for 30 minutes, then ammonia (80 mg) was added dropwise. The reaction was continued under ice-water bath conditions for 10 minutes. The reaction was quenched with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated until no liquid eluates. Compound 47 (90 mg) was purified by preparative liquid chromatography. ESI-MS: m / z = 479.22 [M+H] + .

[0635] 1 H NMR (500 MHz, DMSO- d 6) δ 9.10 (s, 1H), 8.95 (d, J = 4.4 Hz, 1H), 8.57(s, 1H), 8.12 (d, J = 8.4 Hz, 1H), 7.77 (dd, J = 8.4, 1.4 Hz, 1H), 7.74 (ddd, J =8.3, 6.8, 1.4 Hz, 1H), 7.63 (s, 1H), 7.61 (s, 2H), 7.52 (ddd, J = 8.2, 6.8, 1.2Hz, 1H), 7.42 (d, J = 4.4 Hz, 1H), 7.22 (s, 1H). Example 48

[0636] (1) Preparation of compound 48-2: Compound 1-7 (200 mg) and 8-isoquinolineboronic acid (48-1, 87.7 mg) were dispersed in 1,4-dioxane (8 mL), potassium acetate (124 mg), Pd(dppf)Cl2 (15.5 mg) and water (0.8 mL) were added, and the mixture was heated to 90 °C under nitrogen protection. The reaction was monitored by TLC until the reactants were completely reacted. The reaction solution was concentrated under reduced pressure and purified by column chromatography to obtain compound 48-2.

[0637] (2) Preparation of compound 48-3: Compound 48-2 (170 mg) was dissolved in tetrahydrofuran (10 mL), and a solution of lithium hydroxide hydrate (41 mg) and water (10 mL) was added dropwise under an ice-water bath. The reaction was carried out at room temperature for 2 h. The pH of the reaction solution was adjusted to 6-7 with hydrochloric acid, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to obtain compound 48-3, which was directly used in the next step of the reaction.

[0638] (3) Preparation of compound 48: Compound 48-3 (156 mg) was dispersed in tetrahydrofuran (10 mL). N-methylmorpholine (66 mg) and isobutyl chloroformate (89 mg) were added under ice-water bath conditions. The mixture was stirred for 30 minutes, then ammonia (68 mg) was added dropwise. The reaction was continued under ice-water bath conditions for 10 minutes. The reaction was quenched with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated until no liquid eluates. Compound 48 (45 mg) was purified by preparative liquid chromatography. ESI-MS: m / z = 479.24 [M+H] + .

[0639] 1 H NMR (500 MHz, DMSO- d 6) δ 9.10 (d, J = 43.7 Hz, 2H), 8.54 (d, J = 37.6Hz, 2H), 8.08 (d, J = 8.1 Hz, 1H), 7.99 – 7.81 (m, 2H), 7.66 (s, 3H), 7.55 (d, J = 7.0 Hz, 1H), 7.28 (s, 1H). Example 49

[0640] (1) Preparation of compound 49-2: Compound 1-7 (200 mg) and 5-quinolineboronic acid (49-1, 87.7 mg) were dispersed in 1,4-dioxane (8 mL), potassium carbonate (175 mg), Pd(dppf)Cl2 (15.5 mg) and water (0.8 mL) were added, and the mixture was heated to 90 °C under nitrogen protection. The reaction was monitored by TLC until the reactants were completely reacted. The reaction solution was concentrated under reduced pressure and purified by column chromatography to obtain compound 49-2.

[0641] (2) Preparation of compound 49-3: Compound 49-2 (200 mg) was dissolved in tetrahydrofuran (10 mL), and a solution of lithium hydroxide hydrate (48 mg) and water (10 mL) was added dropwise under an ice-water bath. The reaction was carried out at room temperature for 2 h. The pH of the reaction solution was adjusted to 6-7 with hydrochloric acid, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to obtain compound 49-3, which was directly used in the next step of the reaction.

[0642] (3) Preparation of compound 49: Compound 49-3 (184 mg) was dispersed in tetrahydrofuran (10 mL). N-methylmorpholine (77.7 mg) and isobutyl chloroformate (105 mg) were added under ice-water bath conditions. The mixture was stirred for 30 minutes, then ammonia (80 mg) was added dropwise. The reaction was continued under ice-water bath conditions for 10 minutes. The reaction was quenched with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated until no liquid eluates. Compound 49 (62 mg) was purified by preparative liquid chromatography. ESI-MS: m / z = 479.25 [M+H] + .

[0643] 1 H NMR (500 MHz, DMSO- d 6) δ 8.98 (s, 1H), 8.93 (d, J = 4.4 Hz, 1H), 8.56(s, 1H), 8.18 (dd, J = 18.0, 8.5 Hz, 2H), 7.88 (t, J = 7.8 Hz, 1H), 7.72 (s, 2H), 7.63 (s, 1H), 7.59 – 7.43 (m, 2H), 7.15 (s, 1H). Example 50

[0644] (1) Preparation of compound 50-2: Compound 1-7 (200 mg) and 6-quinolineboronic acid (50-1, 87.7 mg) were dispersed in 1,4-dioxane (8 mL), potassium carbonate (175 mg), Pd(dppf)Cl2 (15.5 mg) and water (0.8 mL) were added, and the mixture was heated to 90 °C under nitrogen protection. The reaction was monitored by TLC until the reactants were completely reacted. The reaction solution was concentrated under reduced pressure and purified by column chromatography to obtain compound 50-2.

[0645] (2) Preparation of compound 50-3: Compound 50-2 (150 mg) was dissolved in tetrahydrofuran (10 mL), and a solution of lithium hydroxide hydrate (36 mg) and water (10 mL) was added dropwise under an ice-water bath. The reaction was carried out at room temperature for 2 h. The pH of the reaction solution was adjusted to 6-7 with hydrochloric acid, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to obtain compound 50-3, which was directly used in the next step of the reaction.

[0646] (3) Preparation of compound 50: Compound 50-3 (138 mg) was dispersed in tetrahydrofuran (10 mL). N-methylmorpholine (58 mg) and isobutyl chloroformate (78.7 mg) were added under ice-water bath conditions. The mixture was stirred for 30 minutes, then ammonia (60.5 mg) was added dropwise. The reaction was continued under ice-water bath conditions for 10 minutes. The reaction was quenched with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated until no liquid eluates. Compound 50 (87 mg) was purified by preparative liquid chromatography. ESI-MS: m / z = 479.22 [M+H] + .

[0647] 1 H NMR (500 MHz, DMSO- d 6) δ 9.00 (dd, J = 4.3, 1.7 Hz, 1H), 8.95 (s,1H), 8.45 (dd, J = 8.4, 1.8 Hz, 1H), 8.32 (s, 1H), 8.09 (d, J = 8.6 Hz, 1H), 7.98(d, J = 1.9 Hz, 1H), 7.92 (s, 2H), 7.67 (s, 1H), 7.65 – 7.62 (m, 1H), 7.62 –7.58 (m, 1H), 7.19 (s, 1H). Example 51

[0648] (1) Preparation of compound 51-2: Compound 1-7 (200 mg) and 5-quinolineboronic acid (51-1, 87.7 mg) were dispersed in 1,4-dioxane (8 mL), potassium carbonate (175 mg), Pd(dppf)Cl2 (15.5 mg) and water (0.8 mL) were added, and the mixture was heated to 90 °C under nitrogen protection. The reaction was monitored by TLC until the reactants were completely reacted. The reaction solution was concentrated under reduced pressure and purified by column chromatography to obtain compound 51-2.

[0649] (2) Preparation of compound 51-3: Compound 51-2 (200 mg) was dissolved in tetrahydrofuran (10 mL), and a solution of lithium hydroxide hydrate (48 mg) and water (10 mL) was added dropwise under an ice-water bath. The reaction was carried out at room temperature for 2 h. The pH of the reaction solution was adjusted to 6-7 with hydrochloric acid, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to obtain compound 51-3, which was directly used in the next step of the reaction.

[0650] (3) Preparation of compound 51: Compound 51-3 (184 mg) was dispersed in tetrahydrofuran (10 mL). N-methylmorpholine (77.7 mg) and isobutyl chloroformate (105 mg) were added under ice-water bath conditions. The mixture was stirred for 30 minutes, then ammonia (80 mg) was added dropwise. The reaction was continued under ice-water bath conditions for 10 minutes. The reaction was quenched with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated until no liquid eluates. Compound 51 (29 mg) was purified by preparative liquid chromatography. ESI-MS: m / z = 479.23 [M+H] + .

[0651] 1 H NMR (500 MHz, DMSO- d 6) δ 9.39 (s, 1H), 9.02 (s, 1H), 8.56 (s, 1H), 8.42 (d, J = 5.8 Hz, 1H), 8.24 (d, J = 8.2 Hz, 1H), 7.90 – 7.49 (m, 6H), 7.16 (s,1H). Example 52

[0652] (1) Preparation of compound 52-1: Compound 1-7 (300 mg) and 5-quinolineboronic acid (131.6 mg) were dispersed in 1,4-dioxane (8 mL), potassium carbonate (263 mg), Pd(dppf)Cl2 (23.2 mg) and water (0.8 mL) were added, and the mixture was heated to 90 °C under nitrogen protection. The reaction was completed, and the reaction solution was concentrated under reduced pressure and purified by column chromatography to obtain compound 52-1.

[0653] (2) Preparation of compound 52-2: Compound 52-1 (200 mg) was dissolved in tetrahydrofuran (10 mL), and a solution of lithium hydroxide hydrate (48 mg) and water (10 mL) was added dropwise under an ice-water bath. The reaction was carried out at room temperature for 2 h. The pH of the reaction solution was adjusted to 6-7 with hydrochloric acid, extracted with ethyl acetate (20 mL*2), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to obtain compound 52-2, which was directly used in the next step of the reaction.

[0654] (3) Preparation of compound 52: Compound 52-2 (184 mg) was dispersed in tetrahydrofuran (10 mL). N-methylmorpholine (77.7 mg) and isobutyl chloroformate (105 mg) were added under ice-water bath conditions. The mixture was stirred for 30 minutes, then ammonia (80 mg) was added dropwise. The reaction was continued under ice-water bath conditions for 10 minutes, followed by quenching with water. The mixture was extracted with ethyl acetate (20 mL x 2), dried over anhydrous sodium sulfate, and concentrated until no liquid flowed out. The final product was purified by preparative liquid chromatography to obtain 90 mg of compound 52. ESI-MS: m / z = 479.14 [M+H] + .

[0655] 1 H NMR (500 MHz, DMSO- d 6) δ 8.96 (s, 1H), 8.92 (dd, J = 4.2, 1.7 Hz, 1H), 8.44 (dd, J = 8.5, 1.8 Hz, 1H), 8.31 (s, 1H), 8.04 (d, J = 8.4 Hz, 1H), 7.94(d, J = 1.6 Hz, 1H), 7.91 (s, 2H), 7.65 (s, 1H), 7.61 (dd, J = 8.3, 4.2 Hz, 1H), 7.47 (dd, J = 8.3, 1.7 Hz, 1H), 7.19 (s, 1H). Example 53

[0656] (1) Preparation of compound 53-1: Compound 1-7 (300 mg) and 6-trifluoromethyl-3-pyridineboronic acid (145 mg) were dispersed in 1,4-dioxane (8 mL), potassium carbonate (138.2 mg), Pd(dppf)Cl2 (23.2 mg) and water (0.8 mL) were added, and the mixture was heated to 90 °C under nitrogen protection. The reaction was completed, and the reaction solution was concentrated under reduced pressure and purified by column chromatography to obtain compound 53-1.

[0657] (2) Preparation of compound 53-2: Compound 53-1 (300 mg) was dissolved in tetrahydrofuran (10 mL), and a solution of lithium hydroxide hydrate (70 mg) and water (10 mL) was added dropwise under an ice-water bath. The reaction was carried out at room temperature for 3 h. The pH of the reaction solution was adjusted to 6-7 with hydrochloric acid, extracted with ethyl acetate (20 mL*2), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to obtain compound 53-2, which was directly used in the next step of the reaction.

[0658] (3) Preparation of compound 53: Compound 53-2 (276 mg) was dispersed in tetrahydrofuran (10 mL). N-methylmorpholine (112 mg) and isobutyl chloroformate (152 mg) were added under ice-water bath conditions. The mixture was stirred for 30 minutes, followed by dropwise addition of ammonia (117 mg). The reaction was then quenched with water under ice-water bath conditions for 10 minutes. The mixture was extracted with ethyl acetate (20 mL x 2), dried over anhydrous sodium sulfate, and concentrated until no liquid flowed out. The final product was purified by preparative liquid chromatography to obtain 150 mg of compound 53. ESI-MS: m / z = 497.05 [M+H] + .

[0659] 1 H NMR (500 MHz, DMSO- d 6) δ 9.22 (s, 1H), 8.68 (d, J = 2.0 Hz, 1H), 8.44(s, 1H), 8.01 (d, J = 4.4 Hz, 3H), 7.98 (d, J = 8.0 Hz, 1H), 7.67 (s, 1H), 7.33(s, 1H). Example 54

[0660] (1) Preparation of compound 54-1: 5-Bromo-2-chloropyridine (2.4 g) and 2,2-difluoroethylamine (1.76 g) were dispersed in 1,4-dioxane (30 mL), and bis(dibenzylacetone)palladium (420 mg), 1,1'-bis(di-tert-butylphosphine)ferrocene (710 mg) and potassium tert-butoxide (5.6 g) were added. The mixture was heated to 90 °C under nitrogen protection and the reaction was completed. The reaction solution was concentrated under reduced pressure and then subjected to column chromatography to obtain compound 54-1.

[0661] (2) Preparation of compound 54-2: Compound 54-1 (200 mg) was dispersed in 1,4-dioxane (10 mL), and pinacol diboronic acid ester (236 mg), potassium acetate (331 mg), and Pd(dppf)Cl2 (62 mg) were added. The mixture was reacted at 90 °C for 3 hours under nitrogen protection. The mixture was then diluted with water (10 mL), extracted with ethyl acetate (20 mL x 2), dried over anhydrous sodium sulfate, and concentrated until no liquid flowed out to obtain compound 54-2.

[0662] (3) Preparation of compound 54-3: Compounds 1-7 (332 mg) and 54-2 (240 mg) were dispersed in 1,4-dioxane (10 mL), potassium acetate (207 mg), Pd(dppf)Cl2 (25.7 mg) and water (1 mL) were added, and the mixture was heated to 90 °C under nitrogen protection. The reaction was completed, and the reaction solution was concentrated under reduced pressure and then subjected to column chromatography to obtain compound 54-3.

[0663] (4) Preparation of compound 54-4: Compound 54-3 (180 mg) was dissolved in tetrahydrofuran (8 mL), and a solution of lithium hydroxide hydrate (41 mg) and water (8 mL) was added dropwise under an ice-water bath. The reaction was carried out at room temperature for 4 h. The pH of the reaction solution was adjusted to 6-7 with hydrochloric acid, extracted with ethyl acetate (20 mL*2), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to obtain compound 54-4, which was directly used in the next step of the reaction.

[0664] (5) Preparation of compound 54: Compound 54-4 (166 mg) was dispersed in tetrahydrofuran (10 mL). N-methylmorpholine (66 mg) and isobutyl chloroformate (89 mg) were added under ice-water bath conditions. The mixture was stirred for 30 minutes, then ammonia (69 mg) was added dropwise. The reaction was continued under ice-water bath conditions for 10 minutes, followed by quenching with water. The mixture was extracted with ethyl acetate (20 mL x 2), dried over anhydrous sodium sulfate, and concentrated until no liquid flowed out. The resulting product was purified by preparative liquid chromatography to give 73 mg of compound 54. ESI-MS: m / z = 508.16 [M+H] + .

[0665] 1 H NMR (500 MHz, DMSO- d 6) δ 8.87 (s, 1H), 8.31 (s, 2H), 8.06 (s, 1H), 7.88 (d, J = 2.4 Hz, 1H), 7.55 (s, 1H), 7.31 – 7.19 (m, 3H), 6.64 (dd, J = 8.6, 0.8 Hz, 1H), 6.08 (tt, J = 56.6, 4.1 Hz, 1H), 3.73 (tdd, J = 15.4, 6.1, 4.2 Hz, 2H). Example 55

[0666] (1) Preparation of compound 55-1: Compound 13-8 (200 mg) and isoquinoline-8-boronic acid (93.4 mg) were dispersed in 1,4-dioxane (5 mL), potassium carbonate (186.57 mg), Pd(dppf)Cl2 (14.6 mg) and water (0.5 mL) were added, and the mixture was heated to 90 °C under nitrogen protection. The reaction was completed, and the reaction solution was concentrated under reduced pressure and then subjected to column chromatography to obtain compound 55-1.

[0667] (2) Preparation of compound 55-2: Compound 55-1 (170 mg) was dissolved in tetrahydrofuran (4 mL), and a solution of lithium hydroxide hydrate (43.4 mg) and water (4 mL) was added dropwise under an ice-water bath. The reaction was carried out at room temperature for 4 h. The pH of the reaction solution was adjusted to 6-7 with hydrochloric acid, extracted with ethyl acetate (20 mL * 2), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to obtain compound 55-2, which was directly used in the next step of the reaction.

[0668] (3) Preparation of compound 55: Compound 55-2 (171.5 mg) was dispersed in tetrahydrofuran (5 mL). N-methylmorpholine (76.8 mg) and isobutyl chloroformate (103.8 mg) were added under ice-water bath conditions. The mixture was stirred for 30 minutes, then ammonia (79.8 mg) was added dropwise. The reaction was continued under ice-water bath conditions for 10 minutes, followed by quenching with water. The mixture was extracted with ethyl acetate (20 mL x 2), dried over anhydrous sodium sulfate, and concentrated until no liquid flowed out. The solution was purified by preparative liquid chromatography to obtain 30 mg of compound 55. ESI-MS: m / z = 451.23 [M+H] + .

[0669] 1 H NMR (500 MHz, DMSO- d 6) δ 9.12 (s, 1H), 8.93 (s, 1H), 8.51 (d, J =12.6 Hz, 2H), 8.07 (d, J = 8.2 Hz, 1H), 8.01 – 7.76 (m, 2H), 7.71 – 7.47 (m,2H), 7.38 (s, 1H), 7.22 (s, 1H), 7.03 (s, 1H), 2.18 (s, 1H), 1.05 (d, J = 8.3Hz, 2H), 0.84 (s, 2H). Example 56

[0670] (1) Preparation of compound 56-1: Compound 13-8 (200 mg) and quinoline-4-boronic acid (93.4 mg) were dispersed in 1,4-dioxane (5 mL), potassium carbonate (186.57 mg), Pd(dppf)Cl2 (14.6 mg) and water (0.5 mL) were added, and the mixture was heated to 90 °C under nitrogen protection. The reaction was completed, and the reaction solution was concentrated under reduced pressure and then subjected to column chromatography to obtain compound 56-1.

[0671] (2) Preparation of compound 56-2: Compound 56-1 (160 mg) was dissolved in tetrahydrofuran (4 mL), and a solution of lithium hydroxide hydrate (40.8 mg) and water (4 mL) was added dropwise under an ice-water bath. The reaction was carried out at room temperature for 4 h. The pH of the reaction solution was adjusted to 6-7 with hydrochloric acid, extracted with ethyl acetate (20 mL * 2), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to obtain compound 56-2, which was directly used in the next step of the reaction.

[0672] (3) Preparation of compound 56: Compound 56-2 (144.4 mg) was dispersed in tetrahydrofuran (5 mL). N-methylmorpholine (64.7 mg) and isobutyl chloroformate (87.4 mg) were added under ice-water bath conditions. The mixture was stirred for 30 minutes, followed by dropwise addition of ammonia (67.2 mg). The reaction was then quenched with water under ice-water bath conditions for 10 minutes. The mixture was extracted with ethyl acetate (20 mL x 2), dried over anhydrous sodium sulfate, and concentrated until no liquid flowed out. The resulting product was purified by preparative liquid chromatography to yield 60 mg of compound 56. ESI-MS: m / z = 451.26 [M+H] + .

[0673] 1 H NMR (500 MHz, DMSO- d 6) δ 9.00 (s, 1H), 8.95 (d, J = 4.3 Hz, 1H), 8.54(s, 1H), 8.13 (d, J = 8.4 Hz, 1H), 7.82 – 7.70 (m, 2H), 7.59 (s, 1H), 7.52 (t, J = 7.6 Hz, 1H), 7.42 (d, J = 4.3 Hz, 1H), 7.23 (s, 1H), 7.18 (s, 1H), 7.05 (s,1H), 2.14 (tt, J = 8.3, 4.7 Hz, 1H), 1.06 (dd, J = 8.1, 3.0 Hz, 2H), 0.90 – 0.75(m, 2H). Example 57

[0674] (1) Preparation of compound 57-1: Compound 13-8 (200 mg) and quinoline-6-boronic acid (93.4 mg) were dispersed in 1,4-dioxane (5 mL), potassium carbonate (186.57 mg), Pd(dppf)Cl2 (14.6 mg) and water (0.5 mL) were added, and the mixture was heated to 90 °C under nitrogen protection. The reaction was completed, and the reaction solution was concentrated under reduced pressure and then subjected to column chromatography to obtain compound 57-1.

[0675] (2) Preparation of compound 57-2: Compound 57-1 (150 mg) was dissolved in tetrahydrofuran (4 mL), and a solution of lithium hydroxide hydrate (38.3 mg) and water (4 mL) was added dropwise under an ice-water bath. The reaction was carried out at room temperature for 4 h. The pH of the reaction solution was adjusted to 6-7 with hydrochloric acid, extracted with ethyl acetate (20 mL * 2), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to obtain compound 57-2, which was directly used in the next step of the reaction.

[0676] (3) Preparation of compound 57: Compound 57-2 (135.4 mg) was dispersed in tetrahydrofuran (5 mL). N-methylmorpholine (60.7 mg) and isobutyl chloroformate (81.9 mg) were added under ice-water bath conditions. The mixture was stirred for 30 minutes, then ammonia (63 mg) was added dropwise. The reaction was continued under ice-water bath conditions for 10 minutes, followed by quenching with water. The mixture was extracted with ethyl acetate (20 mL x 2), dried over anhydrous sodium sulfate, and concentrated until no liquid flowed out. The solution was purified by preparative liquid chromatography to obtain 30 mg of compound 57. ESI-MS: m / z = 451.21 [M+H] + .

[0677] 1 H NMR (500 MHz, DMSO- d 6) δ 8.96 (dd, J = 4.2, 1.7 Hz, 1H), 8.81 (s,1H), 8.39 (dd, J = 8.6, 1.8 Hz, 1H), 8.27 (s, 1H), 8.07 (d, J = 8.6 Hz, 1H), 7.93(d, J = 1.9 Hz, 1H), 7.65 – 7.53 (m, 4H), 7.37 (d, J = 1.3 Hz, 1H), 7.15 (s, 1H), 2.10 (ddd, J = 8.2, 6.5, 4.1 Hz, 1H), 1.03 – 0.98 (m, 2H), 0.82 – 0.77 (m, 2H). Example 58

[0678] (1) Preparation of compound 58-1: Compound 13-8 (200 mg) and isoquinoline-5-boronic acid (93.4 mg) were dispersed in 1,4-dioxane (5 mL), potassium carbonate (186.57 mg), Pd(dppf)Cl2 (14.6 mg) and water (0.5 mL) were added, and the mixture was heated to 90 °C under nitrogen protection. The reaction was completed, and the reaction solution was concentrated under reduced pressure and then subjected to column chromatography to obtain compound 58-1.

[0679] (2) Preparation of compound 58-2: Compound 58-1 (160 mg) was dissolved in tetrahydrofuran (4 mL), and a solution of lithium hydroxide hydrate (40.8 mg) and water (4 mL) was added dropwise under an ice-water bath. The reaction was carried out at room temperature for 4 h. The pH of the reaction solution was adjusted to 6-7 with hydrochloric acid, extracted with ethyl acetate (20 mL * 2), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to obtain compound 58-2, which was directly used in the next step of the reaction.

[0680] (3) Preparation of compound 58: Compound 58-2 (144.4 mg) was dispersed in tetrahydrofuran (5 mL). N-methylmorpholine (64.7 mg) and isobutyl chloroformate (87.4 mg) were added under ice-water bath conditions. The mixture was stirred for 30 minutes, then ammonia (67.2 mg) was added dropwise. The reaction was continued under ice-water bath conditions for 10 minutes, followed by quenching with water. The mixture was extracted with ethyl acetate (20 mL x 2), dried over anhydrous sodium sulfate, and concentrated until no liquid flowed out. The solution was purified by preparative liquid chromatography to obtain 40 mg of compound 58. ESI-MS: m / z = 451.20 [M+H] + .

[0681] 1 H NMR (500 MHz, DMSO- d 6) δ 9.39 (s, 1H), 8.89 (s, 1H), 8.51 (s, 1H), 8.41 (d, J = 5.9 Hz, 1H), 8.23 ​​(d, J = 8.2 Hz, 1H), 7.76 (dd, J = 8.2, 7.1 Hz, 1H), 7.66 (dd, J = 7.0, 1.2 Hz, 1H), 7.56 (s, 1H), 7.54 (d, J = 5.9 Hz, 1H), 7.37 (d, J = 1.2 Hz, 1H), 7.11 (s, 1H), 7.04 (d, J = 1.2 Hz, 1H), 2.18 (tt, J = 8.1, 4.7 Hz, 1H), 1.05 (dd, J = 8.2, 2.9 Hz, 2H), 0.85 (d, J = 7.0 Hz, 2H). Example 59

[0682] (1) Preparation of compound 59-1: Compound 13-8 (200 mg) and quinoline-7-boronic acid (93.4 mg) were dispersed in 1,4-dioxane (5 mL), potassium carbonate (186.57 mg), Pd(dppf)Cl2 (14.6 mg) and water (0.5 mL) were added, and the mixture was heated to 90 °C under nitrogen protection. The reaction was completed, and the reaction solution was concentrated under reduced pressure and then subjected to column chromatography to obtain compound 59-1.

[0683] (2) Preparation of compound 59-2: Compound 59-1 (145 mg) was dissolved in tetrahydrofuran (4 mL), and a solution of lithium hydroxide hydrate (37 mg) and water (4 mL) was added dropwise under an ice-water bath. The reaction was carried out at room temperature for 4 h. The pH of the reaction solution was adjusted to 6-7 with hydrochloric acid, extracted with ethyl acetate (20 mL*2), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to obtain compound 59-2, which was directly used in the next step of the reaction.

[0684] (3) Preparation of compound 59-A: Compound 59-2 (135.4 mg) was dispersed in tetrahydrofuran (5 mL). N-methylmorpholine (60.6 mg) and isobutyl chloroformate (81.9 mg) were added under ice-water bath conditions. The mixture was stirred for 30 minutes, then ammonia (63 mg) was added dropwise. The reaction was continued under ice-water bath conditions for 10 minutes, followed by quenching with water. The mixture was extracted with ethyl acetate (20 mL x 2), dried over anhydrous sodium sulfate, and concentrated until no liquid flowed out. The solution was purified by preparative liquid chromatography to obtain 40 mg of compound 59-A. ESI-MS: m / z = 451.22 [M+H] + .

[0685] 1 H NMR (500 MHz, DMSO- d 6) δ 8.93 (dd, J = 4.2, 1.8 Hz, 1H), 8.83 (s,1H), 8.44 (dd, J = 8.4, 1.8 Hz, 1H), 8.27 (s, 1H), 8.04 (d, J = 8.4 Hz, 1H), 7.93(d, J = 1.6 Hz, 1H), 7.66 – 7.55 (m, 3H), 7.46 (dd, J = 8.4, 1.7 Hz, 1H), 7.32(d, J = 1.3 Hz, 1H), 7.17 (s, 1H), 2.12 (tt, J= 8.4, 4.7 Hz, 1H), 1.01 (dt, J =8.1, 3.3 Hz, 2H), 0.83 – 0.77 (m, 2H). Example 60

[0686] (1) Preparation of compound 60-1: Compound 13-8 (200 mg) and 6-trifluoromethylpyridine-3-boronic acid (103.1 mg) were dispersed in 1,4-dioxane (5 mL), potassium carbonate (186.57 mg), Pd(dppf)Cl2 (14.6 mg) and water (0.5 mL) were added, and the mixture was heated to 90 °C under nitrogen protection. The reaction was completed, and the reaction solution was concentrated under reduced pressure and then subjected to column chromatography to obtain compound 60-1.

[0687] (2) Preparation of compound 60-2: Compound 60-1 (130 mg) was dissolved in tetrahydrofuran (4 mL), and a solution of lithium hydroxide hydrate (32 mg) and water (4 mL) was added dropwise under an ice-water bath. The reaction was carried out at room temperature for 4 h. The pH of the reaction solution was adjusted to 6-7 with hydrochloric acid, extracted with ethyl acetate (20 mL*2), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to obtain compound 60-2, which was directly used in the next step of the reaction.

[0688] (3) Preparation of compound 60: Compound 60-2 (117.3 mg) was dispersed in tetrahydrofuran (5 mL). N-methylmorpholine (50.6 mg) and isobutyl chloroformate (68.3 mg) were added under ice-water bath conditions. The mixture was stirred for 30 minutes, then ammonia (52.5 mg) was added dropwise. The reaction was continued under ice-water bath conditions for 10 minutes, followed by quenching with water. The mixture was extracted with ethyl acetate (20 mL x 2), dried over anhydrous sodium sulfate, and concentrated until no liquid flowed out. The solution was purified by preparative liquid chromatography to obtain 45 mg of compound 60. ESI-MS: m / z = 469.19 [M+H] + .

[0689] 1 H NMR (500 MHz, DMSO- d 6) δ 9.13 (s, 1H), 8.66 (d, J = 2.0 Hz, 1H), 8.41(s, 1H), 8.04 – 7.94 (m, 2H), 7.74 (s, 1H), 7.64 (s, 1H), 7.38 (s, 1H), 7.30(s, 1H), 2.24 (tt, J= 8.3, 4.7 Hz, 1H), 1.06 (dt, J = 8.0, 3.3 Hz, 2H), 0.99 –0.86 (m, 2H). Example 61

[0690] (1) Preparation of compound 61-1: Compound 13-8 (200 mg) and quinoline-5-boronic acid (93.4 mg) were dispersed in 1,4-dioxane (5 mL), potassium carbonate (186.57 mg), Pd(dppf)Cl2 (14.6 mg) and water (0.5 mL) were added, and the mixture was heated to 90 °C under nitrogen protection. The reaction was completed, and the reaction solution was concentrated under reduced pressure and then subjected to column chromatography to obtain compound 61-1.

[0691] (2) Preparation of compound 61-2: Compound 61-1 (220 mg) was dissolved in tetrahydrofuran (4 mL), and a solution of lithium hydroxide hydrate (56.6 mg) and water (4 mL) was added dropwise under an ice-water bath. The reaction was carried out at room temperature for 4 h. The pH of the reaction solution was adjusted to 6-7 with hydrochloric acid, extracted with ethyl acetate (20 mL * 2), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to obtain compound 61-2, which was directly used in the next step of the reaction.

[0692] (3) Preparation of compound 61: Compound 61-2 (203.1 mg) was dispersed in tetrahydrofuran (5 mL). N-methylmorpholine (91 mg) and isobutyl chloroformate (123 mg) were added under ice-water bath conditions. The mixture was stirred for 30 minutes, then ammonia (94 mg) was added dropwise. The reaction was continued under ice-water bath conditions for 10 minutes, followed by quenching with water. The mixture was extracted with ethyl acetate (20 mL x 2), dried over anhydrous sodium sulfate, and concentrated until no liquid flowed out. The resulting product was purified by preparative liquid chromatography to give 70 mg of compound 61. ESI-MS: m / z = 451.21 [M+H] + .

[0693] 1 H NMR (500 MHz, DMSO- d 6) δ 8.89 (dd, J = 4.1, 1.7 Hz, 1H), 8.83 (s,1H), 8.51 (s, 1H), 8.18 – 8.08 (m, 2H), 7.84 (dd, J = 8.5, 7.1 Hz, 1H), 7.57(s, 1H), 7.50 (dd, J= 7.0, 1.2 Hz, 1H), 7.45 (dd, J = 8.5, 4.1 Hz, 1H), 7.32 (d, J = 1.3 Hz, 1H), 7.17 (d, J = 1.4 Hz, 1H), 7.09 (s, 1H), 2.16 (tt, J = 8.0, 4.7Hz, 1H), 1.06 (dd, J = 8.2, 2.8 Hz, 2H), 0.85 (q, J = 4.2 Hz, 2H). Example 62

[0694] (1) Preparation of compound 62-1: Compound 13-8 (200 mg) and 2-methylpyridine-3-boronic acid (73.95 mg) were dispersed in 1,4-dioxane (5 mL), potassium carbonate (186.6 mg), Pd(dppf)Cl2 (14.6 mg) and water (0.5 mL) were added, and the mixture was heated to 90 °C under nitrogen protection. The reaction was completed, and the reaction solution was concentrated under reduced pressure and purified by column chromatography to obtain compound 62-1.

[0695] (2) Preparation of compound 62-2: Compound 62-1 (140 mg) was dissolved in tetrahydrofuran (5 mL), and a solution of lithium hydroxide hydrate (38.5 mg) and water (5 mL) was added dropwise under an ice-water bath. The reaction was carried out at room temperature for 2 h. The pH of the reaction solution was adjusted to 6-7 with hydrochloric acid, extracted with ethyl acetate (20 mL * 2), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to obtain compound 62-2, which was directly used in the next step of the reaction.

[0696] (3) Preparation of compound 62: Compound 62-2 (124.6 mg) was dispersed in tetrahydrofuran (5 mL). N-methylmorpholine (60.7 mg) and isobutyl chloroformate (81.9 mg) were added under ice-water bath conditions. The mixture was stirred for 30 minutes, then ammonia (63 mg) was added dropwise. The reaction was continued under ice-water bath conditions for 10 minutes, followed by quenching with water. The mixture was extracted with ethyl acetate (20 mL x 2), dried over anhydrous sodium sulfate, and concentrated until no liquid flowed out. Compound 62 (72 mg) was purified by preparative liquid chromatography. ESI-MS: m / z = 415.27 [M+H] + .

[0697] 1H NMR (500 MHz, DMSO- d 6) δ 8.95 (s, 1H), 8.52 (dd, J = 4.9, 1.8 Hz,1H), 8.31 (s, 1H), 7.66 (d, J = 1.3 Hz, 1H), 7.57 – 7.52 (m, 1H), 7.50 (dt, J =4.4, 2.4 Hz, 2H), 7.29 (dd, J = 7.6, 4.9 Hz, 1H), 7.14 (s, 1H), 2.28 (s, 3H), 2.27 – 2.23 (m, 1H), 1.09 (dt, J = 8.3, 3.2 Hz, 2H), 0.96 – 0.90 (m, 2H). Example 63 Preparation of A-crystal of compound 21-A: Weigh 5g of compound 21-A sample, add 40mL of isopropyl acetate, heat to 90℃ and reflux to dissolve, then gradually lower the temperature to 0-10℃ and stir for 6h. Filter, and dry the filter cake under vacuum at 60℃ for 6h to obtain crystal form A. Its XRPD pattern is shown below. Figure 1 As shown; TGA diagram as follows Figure 2 As shown.

[0698] Example 64 Preparation of B-crystal of compound 21-A: Weigh 5g of compound 21-A sample, add 100mL of a mixture of isopropyl acetate and 1mL of water, heat to 90℃ and reflux to dissolve, then gradually cool to 0-10℃ and stir for 6h, filter; add 50mL of water to the filter cake, heat to 50℃ and stir for 3h, cool to 20-30℃ and stir for 12h, filter, and dry the filter cake at 40℃ for 6h to obtain B-crystal form, with a moisture content (approximately) 4 wt% [Moisture analyzer: METTLER TOLEDO V20S; Method: Take this sample, use anhydrous methanol and N,N-dimethylformamide (1:1) as solvent, and determine the moisture content according to the method of determination of water (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0832, Method 1)]. The molar ratio of compound 21-A to water molecules is approximately 1:1, and its XRPD spectrum is as follows. Figure 3 As shown; TGA diagram as follows Figure 4 As shown.

[0699] Example 65 Preparation of C-crystals of compound 21-A: 2 g of compound 21-A sample was weighed, added to 20 mL of acetone, heated to 50 °C and stirred for 10 min. The mixture was then slowly cooled and stirred at 20-30 °C for 4 h. The mixture was filtered, and the filter cake was vacuum dried at 40 °C for 6 h to obtain the C-crystal form. Its XRPD pattern is shown below. Figure 5 As shown.

[0700] Preparation of C-crystals of compound 21-A (II): Weigh 5g of compound 21-A sample, add 50mL of acetone, stir at 20-30℃ for 6h, filter, and vacuum dry the filter cake at 40℃ for 6h to obtain the C-crystal form. Its TGA image is shown below. Figure 6 As shown.

[0701] Example 66 Preparation of D-crystals of compound 21-A: 5 g of compound 21-A sample was weighed, added to 50 mL of isopropanol, stirred at 20-30 °C for 12 h, filtered, and the filter cake was dried under vacuum at 60 °C for 6 h to obtain the D-crystal form. Its XRPD pattern is shown below. Figure 7 As shown; TGA diagram as follows Figure 8 As shown. Based on the gas phase content, the isopropanol content is approximately 4 wt%.

[0702] Example 67 Preparation of E-crystals of compound 21-A: 5 g of compound 21-A sample was weighed and added to a mixed solvent of 50 mL ethanol and 1 mL water. The mixture was stirred at 20-30 °C for 12 h, filtered, and the filter cake was dried under vacuum at 60 °C for 6 h to obtain the E-crystal form. Its XRPD pattern is shown below. Figure 9 As shown; TGA diagram as follows Figure 10 As shown. Based on the gas phase content, the ethanol content is approximately 7% wt.

[0703] Example 68 Preparation of F-crystal of compound 21-A: 5 g of compound 21-A sample was weighed, and 75 mL of isopropyl acetate, 12.5 mL of methanol, and 2.5 mL of water were added. The mixture was heated under reflux and stirred for 10 min, then slowly cooled and stirred at 20-30 °C for 12 h. The mixture was then filtered, and the filter cake was dried under vacuum at 60 °C for 6 h to obtain the F-crystal form. Its XRPD pattern is shown below. Figure 11 As shown; TGA diagram as follows Figure 12 As shown. Based on the gas phase content, the methanol content is approximately 2 wt%.

[0704] Example 69 Preparation of single crystal G: 15 mg of compound 21-A sample was weighed and dissolved in 1.5 mL of ethyl acetate. This solution was then added to a large glass bottle containing 3 mL of n-hexane (antisolvent), sealed, and a smaller bottle was placed inside the larger one to allow the hexane to continuously evaporate into the ethyl acetate. After approximately 9 days, blocky single crystals grew. These single crystals were selected and sent for analysis to obtain the single crystal results. The molecular stereoscopic structure projection is shown below. Figure 13 As shown.

[0705] The unit cell parameters, crystallographic data, and atomic coordinates of single crystal G are shown in Tables 14 and 15 below.

[0706] Table 14 Crystallographic Data and Structure Refinement

[0707] Table 15 Atomic coordinates (×10) 4 ) and equivalent isotropic displacement parameters (Å2×10 3 )

[0708]

[0709] Example 70 Preparation of A-crystals of compound 3-A:

[0710] Compound 3-3 (24 g) was dispersed in 1,4-dioxane (240 mL), pyridine (11.52 g) and Boc anhydride (27.12 g) were added, and the reaction was carried out at room temperature for 30 minutes. Ammonium bicarbonate (9.84 g) was then added, and the mixture was stirred at room temperature for 12 hours. Water (500 mL) was added to the reaction mixture, and the product was stirred to precipitate. The product was filtered, and the filter cake was dispersed in ethyl acetate (2.0 L). The product was washed successively with sodium bicarbonate aqueous solution and sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and then filtered and concentrated. 240 mL of isopropyl acetate / n-heptane (v / v = 1:1) was added to the concentrate, and the mixture was stirred at room temperature for 30 minutes. The product was filtered to obtain a filter cake, dried, and then heated to 80 °C with 240 mL of isopropyl acetate and stirred for 30 minutes. The mixture was then slowly cooled to room temperature and stirred for 4 hours. The product was filtered and dried to obtain 9 g of the A crystal form of compound 3-A. Its XRPD pattern is shown below. Figure 14 As shown; TGA diagram as follows Figure 15 As shown; DSC diagram as follows Figure 16 As shown.

[0711] Example 71 Preparation of crystal B of compound 3-A: Weigh 50 mg of crystal A of compound 3-A prepared in Example 70, add 5 mL of 1,4-dioxane, dissolve in a water bath at 65 °C, add 25 mL of petroleum ether to crystallize, centrifuge, discard the supernatant, and dry at 40 °C to obtain crystal B. Its XRPD pattern is shown below. Figure 17 As shown. TGA diagram as follows. Figure 17-AAs shown; based on calculations of gas phase content or TGA results, the molar ratio of compound 3-A to 1,4-dioxane in the B crystal form of compound 3-A is approximately 1:0.5.

[0712] Example 72 Preparation of C crystals of compound 3-A: Weigh 50 mg of A crystals of compound 3-A prepared in Example 70, dissolve in 10 mL of tetrahydrofuran, and dry in a water bath at 65 °C to obtain the C crystal form. Its XRPD pattern is shown below. Figure 18 As shown. TGA diagram as follows. Figure 18-A As shown; based on calculations of gas phase content or TGA results, the molar ratio of compound 3-A to tetrahydrofuran in the C crystal form of compound 3-A is approximately 1:0.5.

[0713] Example 73 Preparation of A-crystals of compound 15-A:

[0714] Compound 15-3 (32.5 g) was dispersed in 1,4-dioxane (300 mL), pyridine (15.42 g) and Boc anhydride (36 g) were added, and the reaction was carried out at room temperature for 30 minutes. Ammonium bicarbonate (13.05 g) was then added, and the mixture was stirred at room temperature for 12 hours. Water (600 mL) was added to the reaction mixture, and the mixture was stirred until a solid precipitated. The solid was filtered, and the filter cake was dispersed in ethyl acetate (2.4 L). The solid was washed successively with sodium bicarbonate aqueous solution and sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and concentrated by filtration. The concentrate was recrystallized from isopropyl acetate (300 mL), filtered, and dried to obtain 9 g of the A crystal form of compound 15-A. Its XRPD pattern is shown below. Figure 19 As shown; TGA diagram as follows Figure 20 As shown, the DSC diagram is as follows Figure 21 As shown.

[0715] Example 74 Preparation of B crystal of compound 15-A: 100 mg of A crystal of compound 15-A prepared in Example 73 was weighed, dissolved in 30 mL of acetonitrile, cooled to crystallize, and dried at 40 °C to obtain B crystal form of compound 15-A. Its XRPD pattern is shown below. Figure 22 As shown. Based on calculations of gas phase content or TGA results, the molar ratio of compound 15-A to acetonitrile in the B crystal form of compound 15-A is approximately 1:1.

[0716] Example 75 Preparation of A-crystals of compound 25-A:

[0717] Compound 25-3 (14.7 g) was dispersed in 1,4-dioxane (150 mL), pyridine (7.74 g) and Boc anhydride (18 g) were added, and the reaction was carried out at room temperature for 30 minutes. Ammonium bicarbonate (6.53 g) was then added, and the mixture was stirred at room temperature for 12 hours. Water (300 mL) was added to the reaction mixture, and the mixture was stirred to precipitate a solid. The solid was filtered, and the filter cake was dispersed in ethyl acetate (1.2 L). The cake was washed successively with sodium bicarbonate aqueous solution and sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and then concentrated by filtration. The concentrate was dispersed in 150 mL of isopropyl acetate, heated to 80 °C and stirred for 30 minutes, then slowly cooled to room temperature and stirred for 4 hours. The mixture was filtered and dried to obtain 6 g of compound 25-A in crystal form A. Its XRPD pattern is shown below. Figure 23 As shown.

[0718] Experimental Example 1: In vitro cell proliferation inhibitory activity 1.1 Jurkat cell proliferation inhibitory activity assay Collect Jurkat cells in good growth condition into centrifuge tubes and adjust the cell density to 5 × 10⁻⁶. 4 The compound was seeded at a concentration of 100 μL / well in a 96-well plate and cultured overnight. The compound was then added using a nanoparticle pipette to a final concentration of 1000 nM - 0.46 nM, with two replicates. A control was also included. After culturing for 72 hours, the assay reagent CCK-8 (manufacturer: Beijing Tongren Chemical, 10 μL / well) was added. After incubation for 2 hours, the absorbance was measured at 450 nm using an Envision microplate reader. Four-parameter analysis was performed, a dose-response curve was fitted, and the IC50 was calculated. 50 .

[0719] 1.2 Assay of OCI-LY10 cell proliferation inhibition activity Collect OCI-LY10 cells in good growth condition into centrifuge tubes and adjust the cell density to 9 × 10⁶ cells / mL. 4 The compound was seeded at a concentration of 100 μL / well in a 96-well plate and cultured overnight. The compound was then added using a nanoparticle pipette to a final concentration of 1000 nM - 0.46 nM, with two replicates. A control was also included. After culturing for 72 hours, the assay reagent CCK-8 (manufacturer: Beijing Tongren Chemical, 10 μL / well) was added. After incubation for 2 hours, the absorbance was measured at 450 nm using an Envision microplate reader. Four-parameter analysis was performed, a dose-response curve was fitted, and the IC50 was calculated. 50 .

[0720] 1.3 Assay of RPMI-8226 cell proliferation inhibition activity RPMI-8226 cells in good growth condition were collected into centrifuge tubes, and the cell density was adjusted. The cells were then seeded into 96-well plates and cultured overnight in a cell culture incubator. Compounds were added using a nanoparticle pipette, and a control was set up. Cells were further cultured in the incubator, and the assay reagents were added. After incubation for a period of time, the absorbance was measured using an Envision microplate reader. Four-parameter analysis was performed, a dose-response curve was fitted, and the IC50 was calculated. 50 .

[0721] The specific results are shown in Table 16, regarding the inhibitory activity against Jurkat cell proliferation, where A represents IC50. 50 ≤20 nM; Inhibitory activity against OCI-LY10 cell proliferation, + indicates IC50. 50 ≤40nM.

[0722] Table 16 Results of Compound Activity Tests

[0723] The disclosed compounds showed good results in in vitro cell proliferation inhibition assays.

[0724] Experimental Example 2: In vitro liver microsomal stability Liver microsomal incubation samples were prepared by incubating with a mixture of PBS buffer (pH=7.4), liver microsomal solution (0.5 mg / mL), the test compound, and NADPH+MgCl2 solution at 37°C and 300 rpm for 1 hour. Samples prepared at 0 hours were prepared with a mixture of PBS buffer (pH=7.4), liver microsomal solution (0.5 mg / mL), and the test compound. Acetonitrile solution containing an internal standard was added to the samples for protein precipitation to prepare the supernatant, which was then diluted for LC / MS / MS analysis. The results are shown in Table 17.

[0725] Table 17. In vitro hepatic microsomal metabolic stability of relevant compounds

[0726] The compounds disclosed herein exhibited favorable properties in liver microsomal stability tests.

[0727] Experimental Example 3: In vivo pharmacokinetics 3.1 Pharmacokinetics in mice ICR mice, weighing 18-22 g, were acclimatized for 3-5 days and then randomly divided into groups of 9 mice each, and were administered the mice by gavage at a dose of 3 mg / kg.

[0728] Blood was collected at 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, 10 h, and 24 h from the orbital cavity to prepare plasma samples for testing.

[0729] Take 20 µL of the plasma sample to be tested and the standard sample, add acetonitrile solution containing internal standard, and obtain the supernatant by protein precipitation. After dilution, use it for LC / MS / MS determination.

[0730] The pharmacokinetic parameters were fitted using a non-compartmental model, and the experimental results are shown in Table 18.

[0731] Table 18

[0732] The compounds disclosed herein exhibit favorable properties in pharmacokinetic studies, including but not limited to good bioavailability and AUC.

[0733] 3.2 Distribution of the mouse brain ICR mice, weighing 20-26 g, were acclimatized for 3-5 days and then randomly divided into groups of 3 mice each, and were administered the mice by gavage at a dose of 5 mg / kg.

[0734] Blood was collected 3 hours after the procedure, from the orbital bone, to prepare plasma samples for testing. Simultaneously, brain tissue samples were collected at each time point and weighed for homogenization.

[0735] Take 20 µL of the plasma and tissue homogenate sample to be tested and the standard sample, add acetonitrile solution, and obtain the supernatant after protein precipitation. After dilution, use it for LC / MS / MS determination and calculate the brain blood ratio.

[0736] The compounds disclosed herein have a brain-to-blood ratio of less than 1, indicating a low brain entry rate.

[0737] Experimental Example 4: In vivo pharmacodynamics Efficacy evaluation of OCI-LY10 human diffuse large B-cell lymphoma NOD-SCID mouse subcutaneous xenograft tumor model (1) OCI-LY10 human diffuse large B-cell lymphoma cells were subcutaneously injected into the right axilla of SPF-grade female NOD-SCID mice (source: Jiangsu Huachuang Xinno Pharmaceutical Technology Co., Ltd.), 1×10 7 One mouse per tumor. Tumors were targeted until the average volume reached 200 mm². 3 When the animals were in the right position, they were divided into two groups: a control group (solvent control group) and a treatment group (compound group).

[0738] The dosage included 1 mg / kg, 2 mg / kg and 4 mg / kg, and the frequency of administration was once a day. The day of grouping was day 0. Gavage administration started on day 0 of grouping and continued for 21 days. Alternatively, the dosage is 4 mg / kg, administered 5 times a week, with the grouping day being day 0. Gavage administration begins on day 0 of the group and continues 5 times a week for two consecutive weeks.

[0739] Tumor volume was measured every 3 days, and mouse weight was also recorded. The general performance of the mice was observed and recorded daily. After the experiment, the tumor was removed, weighed, and photographed.

[0740] The detection indicators and calculation formulas are as follows: Tumor volume, TV (mm) 3 ) = 1 / 2 × (a × b 2 ); where a is the long diameter of the tumor and b is the short diameter of the tumor.

[0741] Relative to tumor volume, RTV = TV t / TV0; where TV0 is the tumor volume on day 0, TV t This represents the tumor volume at each measurement.

[0742] Relative tumor proliferation rate, T / C (%) = T RTV / C RTV × 100%; where T RTV For the treatment group, RTV; C RTV The solvent control group is RTV.

[0743] Tumor growth inhibition rate, TGI(%) = (1 - TW / TW0) × 100%; where TW is the tumor weight in the treatment group and TW0 is the tumor weight in the solvent control group.

[0744] Weight change rate, WCR (%) = (Wt) t -Wt0) / Wt0× 100%; where Wt0 is the mouse's body weight on day 0, Wt t The mouse's weight at each measurement.

[0745] The specific test results are shown in Tables 19 and 20.

[0746] Table 19 Effects on subcutaneous xenografts of OCI-LY10 cells (NOD-SCID) in mice

[0747] Note: Compared with the control group, * p<0.05, ** p<0.01.

[0748] Table 20 Effects on subcutaneous xenografts of OCI-LY10 cells (NOD-SCID) in mice

[0749] Note: Compared with the control group, ** p<0.01.

[0750] The disclosed compound showed no obvious toxicity in the tests, and the results demonstrated a good tumor growth inhibition rate.

[0751] Experimental Example 5: Study on the Stability of Crystal Forms Take the crystals of the test sample and conduct (routine) stability or influencing factor (including high temperature, high humidity, light) investigation tests.

[0752] Place the crystals of the test sample in an open, suitable, clean, flat weighing bottle and incubate at 60°C; or at 92.5%RH / 25°C (or 75%RH / 40°C); high humidity (75%RH / 25°C); or high temperature and high humidity (60°C±2°C, 75%RH); or at room temperature (25°C±2°C) for 7 days (10 days, 30 days, 2 months, or 3 months); or in a pharmaceutical strong light irradiation test chamber (temperature 25°C, illuminance approximately 5000 Lux, near-ultraviolet energy 85.0 μW / cm²). 2 After placing the sample in the container, test its crystal form and chemical purity (appearance, purity, total impurities, and maximum single impurity content).

[0753] Related substances determination methods: Test solution: Take an appropriate amount of the test sample, accurately weigh it, dissolve and dilute it with solvent to prepare a solution containing about 0.5 mg per 1 mL.

[0754] Chromatographic conditions: Octadecylsilane-bonded silica gel was used as the stationary phase; 0.1% ammonia solution (adjusted to pH 5.0 with formic acid) was used as mobile phase A, and acetonitrile was used as mobile phase B. Linear gradient elution was performed according to the table below; the flow rate was 1.0 mL / min; the column temperature was 40℃; the detection wavelength was 276 nm; and the injection volume was 10 μL. Linear elution was performed.

[0755] Under light conditions (without packaging), after a period of time, the total impurity increase in the crystals of the compounds of formula (I) of this application or their solvates (e.g., compounds 21-A, 3-A, 15-A, or 25-A) is ≤0.2% (some crystal forms remain almost unchanged, e.g., ≤0.02%), and the maximum single impurity increase is ≤0.1% (some crystal forms remain almost unchanged). For example, after 7 days or longer.

[0756] Under high temperature (60°C) and / or high humidity (75%RH) conditions, the total impurity and maximum single impurity content of the crystals of the compounds of formula (I) of this application or their solvates (e.g., compounds 21-A, 3-A, 15-A or 25-A) hardly increase, for example, after being left for 7 days or longer.

[0757] Under standard stability test conditions (25°C, pharmaceutical-grade low-density polyethylene bag), the total impurity and maximum single impurity content of the crystals of this application (e.g., compounds 21-A, 3-A, 15-A, or 25-A) hardly increased, even after 7 days or longer.

[0758] Test results show that the crystal forms of the compounds of formula (I) disclosed herein or their solvates (e.g., compounds 21-A, 3-A, 15-A or 25-A) have good stability, and their properties, related substances and purity do not change significantly under high temperature, high humidity and light conditions.

[0759] Experimental Example 6: Hygroscopicity Study The hygroscopicity of the active pharmaceutical ingredient of formula (I) of this application was determined in accordance with the guidelines for drug hygroscopicity testing in Part IV, 9103 of the 2020 edition of the Chinese Pharmacopoeia. A dynamic moisture adsorption analyzer (DVS) was used to determine the hygroscopicity within a relative humidity range of 0% to 90%.

[0760] The results show that, in terms of hygroscopicity, the crystal form of the compound of formula (I) of this application or its solvates (e.g., compounds 21-A, 3-A, 15-A or 25-A) has a hygroscopic weight gain of less than 0.2%, is almost non-hygroscopic, and has good stability.

[0761] Experimental Example 7: Solubility Take appropriate amounts of 0.1 mol / L hydrochloric acid solution, purified water, pH 4.5 acetate buffer, and pH 6.8 phosphate buffer, add appropriate amounts of different crystals of the test sample to each, place them in a constant temperature shaker at 37℃, and take them out after 2 hours and 24 hours respectively to determine the apparent solubility and saturated solubility of the product.

[0762] Experimental Example 8: Inherent Dissolution Rate Take approximately 100 mg of different crystals of the test sample and use 700 mL of 0.1 mol / L hydrochloric acid solution, pH 4.5 acetate buffer, and pH 6.8 phosphate buffer as dissolution media to determine the inherent dissolution rate of the drug.

[0763] Experiment 9: Degradation Experiment Acid degradation: Weigh different crystals of the test sample, add HCl aqueous solution, and let stand at room temperature for 24 hours (or in a water bath at 80℃ for 4 hours), then neutralize with NaOH aqueous solution. Dilute the solution to volume with diluent (acetonitrile and / or water); take an appropriate amount of this solution for testing.

[0764] Test results show that the crystals of the compound of formula (I) or its solvates (e.g., compounds 21-A, 3-A, 15-A or 25-A) of this application are stable under acidic conditions, and after acid degradation tests, the sample solution produces fewer degradation impurities.

[0765] Alkali degradation: Weigh different crystals of the test sample, add NaOH aqueous solution, and let stand at room temperature for 24 hours (or in a water bath at 80℃ for 4 hours), then neutralize with HCl aqueous solution. Dilute the solution to volume with diluent (acetonitrile and / or water); take an appropriate amount of this solution for testing.

[0766] Test results show that after the crystals of this application are subjected to alkaline degradation test, the content of degradation impurities generated in the test sample solution is <3%.

[0767] Experimental Example 10: Crystal Habit (Scanning Electron Microscopy) The morphology of different crystal forms was observed using a scanning electron microscope.

[0768] Experimental Example 11: Pharmacokinetic Study Mouse experiment: ICR mice were randomly divided into groups and administered the drug by gavage.

[0769] Test animals were fasted for 12 hours before drug administration and fed 4 hours after drug administration. Water was available freely before, during, and after the experiment. Blood was collected at 0.25 (15 min), 0.5 (30 min), 1, 2, 4, 6, 8, 10, and 24 hours after drug administration, from the orbital sinus to prepare plasma samples for testing. The plasma samples and standard curve samples were aspirated, and acetonitrile solution containing the internal standard was added. Protein precipitation was performed to obtain the supernatant, which was then diluted for LC / MS / MS analysis, and the chromatograms were recorded.

[0770] Rat experiment: Male SD rats were divided into groups and administered the drug by gavage.

[0771] Animals were fasted for 12 hours before drug administration and fed 4 hours after administration. They had free access to water before, during, and after the experiment. Blood samples were collected at 0.25 (15 min), 0.5 (30 min), 1, 2, 4, 6, 8, 10, and 24 hours after drug administration. Whole blood was collected via the fundus venous plexus and placed in EDTA-K2 anticoagulant tubes. Samples were centrifuged, and plasma was transferred to centrifuge tubes and stored at -80°C until analysis. Proteins in the plasma were extracted using protein precipitation, and the extracts were analyzed by LC / MS / MS, with chromatograms recorded.

[0772] Beagle test: Male beagles, after a period of acclimatization, were randomly assigned to groups and administered the drug via gavage.

[0773] Test animals (male beagles) were fasted for 12 hours before drug administration and given food 4 hours after administration. Water was allowed free access before, during, and after the experiment. Blood was collected from the forelimb vein at 0.25 (15 min), 0.5 (30 min), 1, 2, 4, 6, 8, 10, 24, 30, 48, and 72 hours after drug administration. The blood was collected in EDTA-K2 anticoagulant vacuum blood collection tubes and centrifuged to separate the plasma. All collected plasma was immediately stored at -80°C for analysis. The plasma sample and standard curve sample were aspirated, and acetonitrile solution containing the internal standard (diazepam) was added. The mixture was shaken, centrifuged, and the supernatant was collected, diluted with ultrapure water, mixed, and used for LC / MS / MS analysis. The chromatogram was recorded.

[0774] The oral exposure of different crystal forms of the compound in this application was evaluated by in vivo pharmacokinetic experiments in mice, rats, or beagle dogs.

Claims

1. A compound of formula I, its stereoisomers, or a pharmaceutically acceptable salt thereof, in, R 1 Selected from -NH2, C 1-6 Alkyl-O-, C 1-6 Alkyl-NH- or (C 1-6 Alkyl)2N-; Ring A is selected from C 6-10 Aromatic ring group or 5-10 membered heteroaryl ring group; R is selected from halogen, CN, OH, NH2, C 1-6 Alkyl, C 1-6 Alkyl-O-, C 1-6 Alkyl-S-, Halogenated C 1-6 Alkyl-O-, Halogenated C 1-6 Alkyl-S-, Halogenated C 1-6 Alkyl, 3-10 membered heterocyclic alkyl-substituted C 1-6 Alkyl, R a NH- or (R a )2N-; R a Selected from C 1-6 Alkyl, C 3-10 Cycloalkyl or 3-10 membered heterocycloalkyl, wherein R a Optionally, it is selected from one or more halogens, CN, OH, NH2, C 1-6 Alkyl, C 1-6 Alkyl O- or 5-6 membered heterocyclic alkyl groups are substituted; n is selected from 0, 1, 2, 3 or 4; R 2 Selected from cyclopropyl or trifluoromethyl; The compound of Formula I, its stereoisomers, or pharmaceutically acceptable salts thereof, are selected from crystalline or amorphous forms of the compound of Formula I, crystalline or amorphous forms of its stereoisomers, crystalline or amorphous forms of its pharmaceutically acceptable salts, or solvates of the compound of Formula I.

2. The compound of claim 1, its stereoisomers, or pharmaceutically acceptable salts thereof, selected from crystalline or amorphous forms of compounds of formula I, or solvates of compounds of formula I.

3. The compound of claim 1, its stereoisomers, or pharmaceutically acceptable salts thereof, selected from crystals of compound I or solvates of compound I.

4. The compound of claim 1, its stereoisomers, or pharmaceutically acceptable salts thereof, wherein the solvate of formula I is selected from crystalline or amorphous forms of solvates of formula I.

5. The compound, its stereoisomer, or a pharmaceutically acceptable salt thereof according to any one of claims 1-4, wherein the solvent content in the solvate of the compound of formula I is: 0.5%~50%wt; 0.5%~40%wt; 0.5%~30%wt; 0.5%~20%wt; 1%~15%wt; 1.5%~12%wt; 2%~10%wt; or, 2%~7%wt; Alternatively, the solvent content in the solvate of the compound of Formula I is: 1% wt, 2% wt, 3% wt, 4% wt, 5% wt, 6% wt, 7% wt, 8% wt, 9% wt, 10% wt, 11% wt, 12% wt, 13% wt, 14% wt, 15% wt, 16% wt, 17% wt, 18% wt, 19% wt, or 20% wt, or any range of the above values.

6. The compound, its stereoisomer, or a pharmaceutically acceptable salt thereof according to any one of claims 1-5, wherein the molar ratio of the compound of formula I to the solvent in the solvate is selected from 1:0.1-50, 1:0.1-30, 1:0.1-20, 1:0.1-15, 1:0.1-10, 1:0.15-10, 1:0.2-10, 1:0.2-8, 1:0.2-8, 1:0.2-6, 1:0.2-5, 1:0.2-4, 1:0.2-3, 1:0.2-2, 1:0.2-1, or 1:0.3-1; Alternatively, in the solvate of the compound of formula I, the molar ratio of the compound of formula I to the solvent is 1:0.2, 1:0.3, 1:0.4, 1:0.5, 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9 or 1:10, or any range of the above values.

7. The compound of any one of claims 1-6, its stereoisomers, or pharmaceutically acceptable salts thereof, wherein the solvent in the solvate of the compound of formula I is selected from one or more solvents selected from water, hydrocarbons, alcohols, ethers, esters, amides, sulfoxides, ketones, or nitriles; Alternatively, the solvent in the solvate of the compound of formula I is selected from water, C 5-10 Hydrocarbons, C 1-10 alcohols, C 2-10 Ethers, C 2-10 Esters, C 2-10 Amides, C 2-10 sulfoxides, C 2-10 Ketones or C 2-10 One or more of nitrile solvents; Alternatively, the solvent in the solvate of the compound of formula I is selected from water, C 1-3 alcohols, C 2-6 Ethers, C 4-6 Esters, C 3-4 Ketones, or C 2-4 One or more of nitrile solvents; Alternatively, the solvent in the solvate of the compound of Formula I is selected from one or more of water, methanol, ethanol, isopropanol, 1,4-dioxane, tetrahydrofuran, ethyl acetate, isopropyl acetate, acetone, or acetonitrile.

8. The compound, its stereoisomer, or a pharmaceutically acceptable salt thereof, according to any one of claims 1-7, wherein R 1 Selected from -NH2, C 1-4 Alkyl-O- or C 1-4 Alkyl-NH- or (C 1-4 Alkyl)2N-; Or, R 1 Selected from -NH2, isopropyl-O-, or methyl-NH-; Optionally, ring A is selected from phenyl or 5-10 membered heteroaryl groups; Alternatively, ring A can be selected from 5-membered, 6-membered, 7-membered, 8-membered, 9-membered, or 10-membered heterocyclic aromatic groups; Alternatively, ring A may be selected from 6-membered or 10-membered heterocyclic aromatic groups; Optionally, R is selected from halogen, CN, OH, NH2, C 1-4 Alkyl, C 1-4 Alkyl-O-, C 1-4 Alkyl-S-, Halogenated C 1-4 Alkyl-O-, Halogenated C 1-4 Alkyl-S-, Halogenated C 1-4 Alkyl, R a NH- or (R a )2N-; Alternatively, R can be selected from halogen, CN, OH, NH2, C. 1-3 Alkyl, C 1-3 Alkyl-O-, C 1-3 Alkyl-S-, Halogenated C 1-3 Alkyl-O-, Halogenated C 1-3 Alkyl-S-, Halogenated C 1-3 Alkyl, R a NH- or (R a )2N-; Alternatively, R is selected from fluorine, CN, NH2, methyl, methoxy, trifluoromethyl, or R. a NH-; Optionally, the R a Selected from C 1-4 Alkyl, C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl, wherein R a Optionally substituted with one or more groups selected from halogens, CN, OH, NH2 or 5-6 membered heterocyclic alkyl groups; Or, R a Selected from C 1-3 Alkyl or 6-membered heterocyclic alkyl, wherein R a Optionally substituted with one or more groups selected from fluorine, chlorine, bromine, CN, OH, NH2 or 6-membered heterocyclic alkyl groups; Or, R a Selected from FCH2CH2-, F2CHCH2-, F3CCH2-, CF3CH(CH3)-, CH3CF2CH2-, tetrahydropyranyl or dioxane-CH2-; Optionally, n is selected from 0, 1, 2, or 3; Alternatively, n can be selected from 0, 1, or 2; Alternatively, n can be selected from 0 or 1.

9. The compound of any one of claims 1-8, its stereoisomers, or pharmaceutically acceptable salts thereof, wherein the compound of formula I is selected from compounds of formula I-1 or I-2. in, T 1 T 2 T 3 T 4 or T 5 Each is independently selected from bond, O, S, N or CH, wherein no more than one is selected from bond and at least one is selected from N; Indicates a single bond or a double bond.

10. The compound of any one of claims 1-9, its stereoisomers, or pharmaceutically acceptable salts thereof, wherein the compound of formula I is selected from the group consisting of: ； Alternatively, the compound of formula I is selected from the following compounds: or ; Alternatively, it may be selected from the following compounds or Crystallization, crystallization of its stereoisomers, or solvates thereof; optionally, the solvates are selected from crystallized solvates; Alternatively, selected from the following compounds or Crystals of or solvates thereof, optionally, the solvates are selected from crystals or amorphous forms of their solvates.

11. The compound, its stereoisomer, or a pharmaceutically acceptable salt thereof according to any one of claims 1-10, wherein the compound is selected from crystals of 21-A or its solvates; Alternatively, it may be selected from the hydrate of compound 21-A; Optionally, the molar ratio of compound 21-A to water molecules is selected from 1:0.1~10, 1:0.5~10, 1:0.5~8, 1:0.5~7, 1:0.5~6, 1:0.5~5, 1:0.5~4, 1:0.5~3, 1:0.5~2, or 1:0.5~1; Alternatively, the molar ratio of compound 21-A to water molecules is selected from 1:0.5, 1:1, 1:2, 1:3, or 1:4, or any range of the above values; Alternatively, the molar ratio of compound 21-A to water molecules is selected as 1:1; Optionally, the water content in the hydrate of compound 21-A is 0.5%~20%wt, 1%~15%wt, 1%~12%wt, 1%~10%wt, 1%~8%wt, 1%~6%wt, 1%~4%wt, 2%~4%wt, or 3%~4%wt; Alternatively, the water content in the hydrate of compound 21-A is 1%wt, 2%wt, 3%wt, 4%wt, 5%wt, 6%wt, 7%wt, 8%wt, 9%wt, 10%wt, 11%wt, 12%wt, 13%wt, 14%wt or 15%wt, or any range of the above values; Alternatively, the water content in the hydrate of compound 21-A is 4 wt%. Alternatively, it may be an isopropanol compound of compound 21-A; Optionally, the molar ratio of compound 21-A to isopropanol is selected from 1:0.2~5, 1:0.2~4, 1:0.2~3, 1:0.2~2, or 1:0.2~1; Alternatively, the molar ratio of compound 21-A to isopropanol is selected from 1:0.3, 1:0.5, 1:1, 1:2, or 1:3, or any range formed by the above values; Alternatively, the molar ratio of compound 21-A to isopropanol is selected from 1:0.5 or 1:1; Optionally, the isopropanol content in the isopropanol compound 21-A is 1%~20%wt, 1%~15%wt, 1%~12%wt, 1%~10%wt, 1%~8%wt, 1%~6%wt, or 3%~9%wt; Alternatively, the isopropanol content in the isopropanol compound of compound 21-A is 1%wt, 2%wt, 3%wt, 4%wt, 5%wt, 6%wt, 7%wt, 8%wt, 9%wt, 10%wt, 11%wt, 12%wt, 13%wt, 14%wt or 15%wt, or any range of the above values; Alternatively, the isopropanol content in the isopropanol compound of said compound 21-A is 4%wt, 6%wt, or 8%wt; Alternatively, it is an ethanolic compound of compound 21-A; Optionally, the molar ratio of compound 21-A to ethanol is selected from 1:0.5~5, 1:0.5~4, 1:0.5~3, 1:0.5~2, or 1:0.5~1.5; Alternatively, the molar ratio of compound 21-A to ethanol is selected from 1:0.5, 1:1, 1:2, 1:3, 1:4, 1:5, or 1:6; or, the molar ratio of compound 21-A to ethanol is selected from 1:

1. Optionally, the ethanol content in the compound 21-A ethanol compound is 1-40% wt, 1-30% wt, 1%-20% wt, 2%-15% wt, 5%-10% wt, 5%-10% wt, or 7%-10% wt; Alternatively, the ethanol content in the compound 21-A ethanol compound is 1%wt, 2%wt, 3%wt, 4%wt, 5%wt, 6%wt, 7%wt, 8%wt, 9%wt, 10%wt, 11%wt, 12%wt, 13%wt, 14%wt or 15%wt, or any range of the above values; Alternatively, the ethanol content in the compound 21-A ethanol compound is 7%wt or 10%wt; Alternatively, it may be a methanolic compound of compound 21-A; Optionally, the molar ratio of compound 21-A to methanol is selected from 1:0.1~6, 1:0.1~5, 1:0.1~4, 1:0.5~4, 1:0.5~3, 1:0.5~2, 1:0.5~1, or 1:1; Alternatively, the molar ratio of compound 21-A to methanol is selected from 1:0.1, 1:0.5, 1:1, 1:1.5, 1:2, 1:3, 1:4, 1:5, or 1:6, or any range of the above values; Alternatively, the molar ratio of compound 21-A to methanol is selected from 1:0.5 or 1:1; Optionally, the methanol content in the methanol compound of compound 21-A is 1%~20%wt, 1%~15%wt, 1%~12%wt, 1%~10%wt, 1%~8%wt, 2%~6%wt, or 2%~4%wt; Alternatively, the methanol content in the methanolic compound 21-A is 1%wt, 2%wt, 3%wt, 4%wt, 5%wt, 6%wt, 7%wt, 8%wt, 9%wt, 10%wt, 11%wt, 12%wt, 13%wt, 14%wt or 15%wt, or any range of the above values; Alternatively, the methanol content in the methyl methacrylate of compound 21-A is 2%wt or 4%wt.

12. The compound according to any one of claims 1-10, its stereoisomers, or pharmaceutically acceptable salts thereof, selected from crystals of compound 3-A, Alternatively, it can be selected from the crystallization of a solvate of compound 3-A. Optionally, the crystallization of the solvate of compound 3-A is the crystallization of the 1,4-dioxane solvate of compound 3-A; Optionally, the molar ratio of compound 3-A to 1,4-dioxane in the crystallization of the 1,4-dioxane solvate of compound 3-A is approximately selected from: 1:0.2~2; or 1:0.2~1; or 1:0.3~0.8; or 1:0.5; Optionally, the crystallization of the solvate of compound 3-A is the crystallization of the tetrahydrofuran solvate of compound 3-A; Optionally, the molar ratio of compound 3-A to tetrahydrofuran in the crystallization of the tetrahydrofuran solvate of compound 3-A is approximately selected from: 1:0.2~2; or 1:0.2~1; or 1:0.3~0.8; or 1:0.5; Alternatively, it is selected from the crystals of compound 15-A. Optionally, it is selected from the crystallization of a solvate of compound 15-A. Optionally, the crystallization of the solvate of compound 15-A is the crystallization of the acetonitrile compound of compound 15-A; Optionally, the molar ratio of compound 15-A to acetonitrile in the acetonitrile compound crystals of said compound 15-A is selected from: 1:0.2~2; or 1:0.5~1.5; or 1:0.5~1; or 1:1; Optionally, it is selected from the crystals of compound 25-A.

13. A pharmaceutical composition comprising a therapeutically effective amount of the compound, its stereoisomer, or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1-12.

14. The use of the compound, its stereoisomer, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 13, in the preparation of a medicament for the prevention or treatment of a related disease; Optionally, the relevant disease is selected from tumors; alternatively, the relevant disease is selected from leukemia or lymphoma.

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