Tetrazolyl-substituted pyran galactoside derivative and preparation method therefor and use thereof

Abstract

Disclosed in the present invention are a compound represented by formula (I) and a pharmaceutically acceptable salt thereof. Specifically, disclosed in the present invention are a tetrazolyl-substituted pyran galactoside derivative as a Gal-3 inhibitor and a preparation method therefor and a use thereof.

Description

Tetrazolyl-substituted pyranogalactoside derivatives, and methods of making and using the same

[0001] The present invention claims the following priority:

[0002] Application No. CN2024108667341, filing date: June 28, 2024;

[0003] Application No. CN2025107743126, filing date: June 10, 2025; TECHNICAL FIELD

[0004] The present invention relates to compounds represented by formula (I) and pharmaceutically acceptable salts thereof, in particular, the present invention relates to a class of tetrazolyl-substituted pyranogalactoside derivatives, and methods of making and using the same. BACKGROUND

[0005] Galectins are a family of S-type lectins that specifically bind to β-galactosides. To date, approximately 15 galectins have been found in mammals. Galectins can regulate different biological processes, such as cell adhesion, growth regulation, apoptosis, inflammation, fibrogenesis, tumorigenesis and progression, thus they have a wide range of functions, including mediating intercellular interactions, intercellular matrix adhesion and transmembrane signal transduction.

[0006] Galectin-3 (Gal-3) is a β-galactoside-binding lectin of about 30 KDa, which is the only chimeric animal lectin among the 15 galectin families found so far, and can specifically recognize and bind β-galactoside. Gal-3 is located in various cell sites, such as cytoplasm, and can also be expressed in the nucleus or secreted to the cell membrane surface.

[0007] Gal-3 is involved in the development of fibrosis processes in several organs, such as the lung, liver and kidney. Gal-3 is involved in physiological processes such as apoptosis, adhesion, angiogenesis, cell migration, cell proliferation, cell differentiation, etc., and its main role is to induce inflammatory and fibrotic processes, leading to organ fibrosis and tumor progression. Gal-3 has also been identified as a biomarker of heart failure, indicating that modulation of Gal-3 has potential use in the treatment of heart failure. At the same time, Gal-3 inhibitors have been shown to have a positive effect when used in combination with immunotherapy. By inhibiting Gal-3, various fibrotic diseases, tumors, nervous system and inflammatory-related diseases can be treated, such as pulmonary fibrosis, liver fibrosis, kidney fibrosis, heart fibrosis, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, sepsis, atopic dermatitis, psoriasis, cancer, brain cancer, head and neck cancer, melanoma, breast cancer, colorectal cancer, kidney cancer, liver cancer, lung cancer, pancreatic cancer, bladder cancer, gastric cancer, hematologic malignancies, Alzheimer's disease, neurodegenerative diseases, diabetes, diabetic nephropathy, diabetic retinopathy, etc. Therefore, the development of Gal-3 inhibitors has great market value. SUMMARY

[0008] In one aspect of the present application, the present application provides a compound represented by formula (I), an optical isomer thereof, or a pharmaceutically acceptable salt thereof,

[0009] wherein,

[0010] Ring A is selected from C 3-20 cycloalkyl, 3-20 membered heterocycloalkyl, C 4-20 cycloalkenyl, 4-20 membered heterocycloalkenyl, C 6-20 aryl or 5-20 membered heteroaryl;

[0011] Ring B is selected from C 3-20 cycloalkyl, 3-20 membered heterocycloalkyl, C 4-20 cycloalkenyl, 4-20 membered heterocycloalkenyl, C 6-20 aryl or 5-20 membered heteroaryl;

[0012] X1 is selected from C and X2 is selected from N; or X1 is selected from N and X2 is selected from C;

[0013] Z1 is selected from C(R3) or N, Z2 is selected from C or N, Z3 is selected from C or N, and at least one of Z1, Z2 and Z3 is selected from N;

[0014] L is selected from a single bond, -(CR aa R bb ) p -, -O-(CR aa R bb ) p -, -O-(CRaa R bb ) p C(O)-, -S-(CR aa R bb ) p -, -S-(CR aa R bb ) p C(O)-, -N(R aa )-(CR aa R bb ) p - or -N(R aa )-(CR aa R bb ) p C(O)-;

[0015] R1is selected from -H, -D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SF5, -NO2, -CHO, -COOH, -C(=O)NH2, C 1-20 alkyl, C 2-20 alkenyl, C 2-20 alkynyl, C 1-20 heteroalkyl, C 3-20 cycloalkyl, 3-20 membered heterocycloalkyl, C 6-20 aryl, or 5-20 membered heteroaryl, said C 1-20 alkyl, C 2-20 alkenyl, C 2-20 alkynyl, C 1-20 heteroalkyl, C 3-20 cycloalkyl, 3-20 membered heterocycloalkyl, C 6-20 aryl, and 5-20 membered heteroaryl are optionally substituted with 1, 2, 3, or 4 R;

[0016] R2, R3are each independently selected from -H, -D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SF5, -NO2, -CHO, -COOH, -C(=O)NH2, C 1-12 alkyl, or C 1-12 heteroalkyl, said C 1-12 alkyl and C 1-12 heteroalkyl are optionally substituted with 1, 2, 3, or 4 R;

[0017] R a is independently selected at each occurrence from -H, -D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SF5, -NO2, -CHO, -COOH, -C(=O)NH2, C 1-12 alkyl, or C 1-12 heteroalkyl, said C 1-12 alkyl and C1-12 heteroalkyl is optionally substituted with 1, 2, 3, or 4 R;

[0018] or, two R a form a C 3-12 cycloalkyl, 3-12 membered heterocycloalkyl, C 6-12 aryl or 5-12 membered heteroaryl, said C 3-12 cycloalkyl, 3-12 membered heterocycloalkyl, C 6-12 aryl and 5-12 membered heteroaryl are optionally substituted with 1, 2, 3, or 4 R;

[0019] R b each occurrence is independently selected from the group consisting of -H, -D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SF5, -NO2, -CHO, -COOH, -C(=O)NH2, C 1-12 alkyl or C 1-12 heteroalkyl, said C 1-12 alkyl and C 1-12 heteroalkyl is optionally substituted with 1, 2, 3, or 4 R;

[0020] or, two R b form a C 3-12 cycloalkyl, 3-12 membered heterocycloalkyl, C 6-12 aryl or 5-12 membered heteroaryl, said C 3-12 cycloalkyl, 3-12 membered heterocycloalkyl, C 6-12 aryl and 5-12 membered heteroaryl are optionally substituted with 1, 2, 3, or 4 R;

[0021] R aa , R bb each occurrence is independently selected from the group consisting of -H, -D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SF5, -NO2, -CHO, -COOH, -C(=O)NH2, C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl or C 1-12 heteroalkyl, said C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl and C 1-12 heteroalkyl is optionally substituted with 1, 2, 3, or 4 R;

[0022] R each occurrence is independently selected from the group consisting of -H, -D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SF5, -NO2, -CHO, -COOH, -C(=O)NH2, C 1-20 alkyl, C 1-20 heteroalkyl, C3-20 cycloalkyl, 3-20 membered heterocycloalkyl, C 6-20 aryl or 5-20 membered heteroaryl, said C 1-20 alkyl, C 1-20 heteroalkyl, C 3-20 cycloalkyl, 3-20 membered heterocycloalkyl, C 6-20 aryl and 5-20 membered heteroaryl are optionally substituted with 1, 2, or 3 R’;

[0023] R’ is independently selected at each occurrence from -H, -D, -F, -Cl, -Br, -I, -OH, -NH2, -CH3, -CF3, -C2H5, -CN, -SF5, -CHO, -COOH, or -C(=O)NH2;

[0024] m, n are independently selected from an integer from 0 to 5;

[0025] p is independently selected at each occurrence from an integer from 0 to 6;

[0026] the above C 1-12 heteroalkyl, C 1-20 heteroalkyl, 3-12 membered heterocycloalkyl, 3-20 membered heterocycloalkyl, 4-20 membered heterocycloalkenyl, 5-12 membered heteroaryl, and 5-20 membered heteroaryl contain 1, 2, or 3 heteroatoms independently selected from O, N, and S or a heteroatom group selected from -C(=O)O-, -C(=O)-, -C(=S)-, -S(=O), -S(=O)2-, -S(=O)(=NH)-, -C(=O)N(H)-, -N(H)-, -C(=NH)-, -S(=O)2N(H)-, and -S(=O)N(H)-.

[0027] In some embodiments of the present application, the compound of formula (I) has a structure as shown in formula (II) or (III):

[0028] In some embodiments of the present application, the compound of formula (I) has a structure as shown in any one of formula (II-1) to (II-6):

[0029] In some embodiments of the present application, R2 is selected from -H, -D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SF5, -NO2, -CHO, -COOH, -C(=O)NH2, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylamino, -C 1-6 alkyl-OH, -C 1-6 alkyl-NH2, -C(=O)-C 1-6alkyl or -NH-C(=O)-C 1-6 alkyl, said C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylamino, -C 1-6 alkyl-OH, -C 1-6 alkyl-NH2, -C(=O)-C 1-6 alkyl and -NH-C(=O)-C 1-6 alkyl is optionally substituted with 1, 2, or 3 R'; other variables are as defined herein.

[0030] In some embodiments of the application, R2is selected from -H, -D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SF5, -NO2, -CHO, -COOH, -C(=O)NH2, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylthio or C 1-3 alkylamino, said C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylthio and C 1-3 alkylamino is optionally substituted with 1, 2, or 3 R'; other variables are as defined herein.

[0031] In some embodiments of the application, R3is selected from -H, -D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SF5, -NO2, -CHO, -COOH, -C(=O)NH2, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylamino, -C 1-6 alkyl-OH, -C 1-6 alkyl-NH2, -C(=O)-C 1-6 alkyl or -NH-C(=O)-C 1-6 alkyl, said C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylamino, -C 1-6 alkyl-OH, -C 1-6 alkyl-NH2, -C(=O)-C 1-6 alkyl and -NH-C(=O)-C 1-6 alkyl is optionally substituted with 1, 2, or 3 R'; other variables are as defined herein.

[0032] In some embodiments of the application, R3is selected from -H, -D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SF5, -NO2, -CHO, -COOH, -C(=O)NH2, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylthio, or C 1-3 alkylamino, said C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylthio, and C 1-3 alkylamino is optionally substituted with 1, 2, or 3 R'; other variables are as defined in the application.

[0033] In some embodiments of the application, R is independently selected from -H, -D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SF5, -CHO, -COOH, -C(=O)NH2, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylamino, C 1-6 alkyl-C 1-6 alkoxy-, C 1-6 alkyl-C 1-6 alkylthio-, C 1-6 alkyl-C 1-6 alkylamino-, -C 1-6 alkyl-OH, -C 1-6 alkyl-NH2, -C(=O)-C 1-6 alkyl, -C 1-6 alkyl-C(=O)-C 1-6 alkyl, -NH-C(=O)-C 1-6 alkyl, -C 1-6 alkyl-NH-C(=O)-C 1-6 alkyl, -NH-S(=O)2-C 1-6 alkyl, -C 1-6 alkyl-NH-S(=O)2-C 1-6 alkyl, C 3-6 cycloalkyl, phenyl, naphthyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, piperidinyl, piperazinyl, pyranyl, furanyl, thiazolyl, oxazolyl, or thiopyranyl,

[0034] alkyl, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylamino, C 1-6 alkyl-C 1-6alkyl-C 1-6 alkyl-C 1-6 alkyl-C 1-6 alkyl-C 1-6 alkyl-C 1-6 alkyl-C 1-6 alkyl-C 1-6 alkyl-C 1-6 alkyl-C 1-6 alkyl-C 1-6 alkyl-C 1-6 alkyl-C 1-6 alkyl-C 1-6 alkyl-C 1-6 alkyl-C 1-6 alkyl-C 3-6 cycloalkyl, phenyl, naphthyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, piperidinyl, piperazinyl, pyranyl, furanyl, thiazolyl, oxazolyl, and thiopyranyl, optionally substituted with 1, 2, or 3 R’;

[0035] the other variables are as defined in the application.

[0036] In some embodiments of the application, R is independently selected from the group consisting of -H, -D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SF5, -CHO, -COOH, -C(=O)NH2, C 1-4 alkyl-C 1-4 alkyl-C 1-4 alkyl-C 1-4 alkyl-C 1-4 alkyl-C 1-4 alkyl-C 1-4 alkyl-C 1-4 alkyl-C

[0037] the C 1-4 alkyl-C 1-4 alkyl-C 1-4 alkyl-C 1-4 alkyl-C 1-4 alkyl-C 1-4 alkyl-C 1- alkyl-C 1-4 alkyl-C optionally substituted with 1, 2, or 3 R’; the other variables are as defined in the application.

[0038] In some embodiments of the application, R is independently selected from -H, -D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SF5, -CHO, -COOH, -C(=O)NH2, -CH3, -CF3, -CHF2, -CH2F, -CF2Cl, -CF2Br, -CF2I, -OCH3, -NHCH3, or -N(CH3)2. 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylthio, or C 1-3 alkylamino, -C

[0039] said C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylthio, and C 1-3 alkylamino is optionally substituted with 1, 2, or 3 R'; other variables are as defined in the application.

[0040] In some embodiments of the application, R is independently selected from -H, -D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SF5, -CHO, -COOH, -C(=O)NH2, -CH3, -CF3, -CHF2, -CH2F, -CF2Cl, -CF2Br, -CF2I, -OCH3, -NHCH3, or -N(CH3)2.

[0041] In some embodiments of the application, R aa , R bb is independently selected at each occurrence from -H, -D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SF5, -NO2, -CHO, -COOH, -C(=O)NH2, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylamino, -C 1- 6alkyl-OH, -C 1-6 alkyl-NH2, -C(=O)-C 1-6 alkyl, or -NH-C(=O)-C 1-6 alkyl, said C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylamino, -C 1-6 6alkyl-OH, -C 1-6 alkyl-NH2, -C(=O)-C 1-6 alkyl, and -NH-C(=O)-C 1-6 alkyl is optionally substituted with 1, 2, or 3 R'; other variables are as defined in the application.

[0042] In some embodiments of the application, R aa , R bbindependently at each occurrence selected from -H, -D, -F, -CI, -Br, -I, -OH, -NH2, -CN, -SF5, -NO2, -CHO, -COOH, -C(=O)NH2, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylthio, or C 1-3 alkylamino, said C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylthio, and C 1-3 alkylamino is optionally substituted with 1, 2, or 3 R'; other variables are as defined herein.

[0043] In some embodiments of the application, L is selected from a single bond, -O-, -O-C(R aa R bb )-, -O-C(R aa R bb )-C(R aa R bb )-, -O-C(R aa R bb )-C(R aa R bb )-C(R aa R bb )-, -O-C(R aa R bb )-C(O)-, -O-C(R aa R bb )-C(R aa R bb )-C(O)-, -O-C(R aa R bb )-C(R aa R bb )-C(R aa R bb )-C(O)-, -S-, -S-C(R aa R bb )-, -S-C(R aa R bb )-C(R aa R bb )-, -S-C(R aa R bb )-C(R aa R bb )-C(R aa R bb )-, -S-C(R aa R bb )-C(O)-, -S-C(R aa R bb )-C(Raa R bb )-C(O)-, -S-C(R aa R bb )-C(R aa R bb )-C(R aa R bb )-C(O)-, -N(R aa )-, -N(R aa )-C(R aa R bb )-, -N(R aa )-C(R aa R bb )-C(R aa R bb )-, -N(R aa )-C(R aa R bb )-C(R aa R bb )-C(R aa R bb )-, -N(R aa )-C(R aa R bb )-C(O)-, -N(R aa )-C(R aa R bb )-C(R aa R bb )-C(O)- or -N(R aa )-C(R aa R bb )-C(R aa R bb )-C(R aa R bb )-C(O)-; the other variables are as defined in the application.

[0044] In some embodiments of the application, L is selected from a single bond, -O-, -O-C(R aa R bb )-, -O-C(R aa R bb )-C(R aa R bb )-, -O-C(R aa R bb )-C(R aa R bb )-C(R aa R bb )-, -O-C(R aa R bb )-C(O)-, -O-C(R aa Rbb )-C(R aa R bb -C(O)- or -OC(R) aa R bb )-C(R aa R bb )-C(R aa R bb )-C(O)-; other variables are as defined in this invention.

[0045] In some embodiments of the present invention, L is selected from single bonds, -O-, -OC(R) aa R bb )-、-OC(R aa R bb )-C(R aa R bb )-、-OC(R aa R bb -C(O)- or -OC(R) aa R bb )-C(R aa R bb )-C(O)-; other variables are as defined in this invention.

[0046] In some embodiments of the present invention, L is selected from single bonds, -O-, -OCH2-, -OCH2CH2-, -OCH2CH2CH2-,

[0047] In some embodiments of the present invention, L is selected from single bonds, -O-, -OCH2-, -OCH2CH2-, ...

[0048] In some embodiments of the present invention, R1 is selected from -H, -D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SF5, -NO2, -CHO, -COOH, -C(=O)NH2, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6-12 Aryl or 5-12 heteroaryl, wherein C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1- 6-alkylthio, C 1-6 Alkylamino, C3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 6-12 aryl and 5-12 membered heteroaryl are optionally substituted with 1, 2, 3, or 4 R; other variables are as defined herein.

[0049] In some embodiments of the application, R1is selected from -H, -D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SF5, -NO2, -CHO, -COOH, -C(=O)NH2, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 1-4 alkylthio, or C 1-4 alkylamino, said C 1- 4alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 1-4 alkylthio, and C 1-4 alkylamino is optionally substituted with 1, 2, 3, or 4 R; other variables are as defined herein.

[0050] In some embodiments of the application, R1is selected from -H, -D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SF5, -NO2, -CHO, -COOH, -C(=O)NH2, C

[0051] In some embodiments of the application, the structural unit -L-R1is selected from -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SF5, -NO2, -CHO, -COOH, -C(=O)NH2, C

[0052] In some embodiments of the application, ring A is selected from phenyl, naphthyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, piperidinyl, piperazinyl, pyranyl, furanyl, thiazolyl, oxazolyl, thiopyranyl, morpholinyl, benzothiazolyl, benzoxazolyl, benzopyrazolyl, indolyl, benzodioxolanyl, or benzodithiolanyl.

[0053] In some embodiments of the application, R a is independently selected at each occurrence from -H, -D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SF5, -NO2, -CHO, -COOH, -C(=O)NH2, C1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, or C 1-6 alkylamino, said C 1- 4alkyl, C 1-6 alkoxy, C 1-6 alkylthio, and C 1-6 alkylamino is optionally substituted with 1, 2, 3, or 4 R;

[0054] or, two adjacent R a form a phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, piperidinyl, piperazinyl, pyranyl, furanyl, thiazolyl, oxazolyl, thiopyranyl, morpholinyl, cyclopropyl, cyclobutyl, cyclopentyl, dioxolanyl, or dithiolanyl, optionally substituted with 1, 2, 3, or 4 R;

[0055] the other variables are as defined herein.

[0056] In some embodiments of the application, R a each occurrence is independently selected from -H, -D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SF5, -NO2, -CHO, -COOH, -C(=O)NH2, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio, or C 1-4 alkylamino, said C 1- 4alkyl, C 1-4 alkoxy, C 1-4 alkylthio, and C 1-4 alkylamino is optionally substituted with 1, 2, 3, or 4 R;

[0057] or, two adjacent R a form a pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, piperidinyl, piperazinyl, pyranyl, furanyl, thiazolyl, oxazolyl, thiopyranyl, dioxolanyl, or dithiolanyl, optionally substituted with 1, 2, 3, or 4 R;

[0058] the other variables are as defined herein.

[0059] In some embodiments of the application, R a each occurrence is independently selected from -H, -D, -F, -CI, -Br, -I, -OH, -NH2, -CN, -SF5, -N02, -CHO, -COOH, -C(=0)NH2, or C 1-3 alkyl, said C 1-3 alkyl is optionally substituted with 1, 2, 3, or 4 R;

[0060] or, two R a form said is optionally substituted with 1 or 2 R;

[0061] The other variables are as defined in the application.

[0062] In some embodiments of the application, R a each occurrence is independently selected from -H, -D, -F, -CI, -Br, -I, -OH, -NH2, -CN, -SF5, -N02, -CHO, -COOH, -C(=0)NH2, -CH3, -CH2F, -CHF2, or -CF3;

[0063] or, two R a form

[0064] In some embodiments of the application, structural unit is selected from said is optionally substituted with 1, 2, 3, 4, or 5 R; the other variables are as defined in the application.

[0065] In some embodiments of the application, structural unit is selected from

[0066] In some embodiments of the application, ring B is selected from phenyl, naphthyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, piperidinyl, piperazinyl, pyranyl, furanyl, thiazolyl, oxazolyl, thiopyranyl, morpholinyl, benzothiazolyl, benzoxazolyl, benzopyrazolyl, indolyl, benzodioxolanyl, or benzodithiolanyl.

[0067] In some embodiments of the application, R beach occurrence is independently selected from -H, -D, -F, -CI, -Br, -I, -OH, -NH2, -CN, -SF5, -NO2, -CHO, -COOH, -C(=O)NH2, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, or C 1-6 alkylamino, said C 1- alkyl, C 1-6 alkoxy, C 1-6 alkylthio, and C 1-6 alkylamino is optionally substituted with 1, 2, 3, or 4 R;

[0068] or, two R b form a phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, piperidinyl, piperazinyl, pyranyl, furanyl, thiazolyl, oxazolyl, thiopyranyl, morpholinyl, cyclopropyl, cyclobutyl, cyclopentyl, dioxolanyl, or dithiolanyl, which phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, piperidinyl, piperazinyl, pyranyl, furanyl, thiazolyl, oxazolyl, thiopyranyl, morpholinyl, cyclopropyl, cyclobutyl, cyclopentyl, dioxolanyl, and dithiolanyl is optionally substituted with 1, 2, 3, or 4 R;

[0069] the other variables are as defined in the application.

[0070] In some embodiments of the application, R b each occurrence is independently selected from -H, -D, -F, -CI, -Br, -I, -OH, -NH2, -CN, -SF5, -NO2, -CHO, -COOH, -C(=O)NH2, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio, or C 1-4 alkylamino, said C 1- alkyl, C 1-4 alkoxy, C 1-4 alkylthio, and C 1-4 alkylamino is optionally substituted with 1, 2, 3, or 4 R;

[0071] or, two R bform a pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, piperidinyl, piperazinyl, pyranyl, furanyl, thiazolyl, oxazolyl, thiopyranyl, dioxolanyl, or dithiolanyl group, optionally substituted with 1, 2, 3, or 4 R;

[0072] The other variables are as defined in the application.

[0073] In some embodiments of the application, R b each occurrence is independently selected from -H, -D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SF5, -NO2, -CHO, -COOH, -C(=O)NH2, -CH3, -CH2F, -CHF2, or -CF3; 1-3 alkyl, said C 1-3 alkyl is optionally substituted with 1, 2, 3, or 4 R;

[0074] or, two R b form said optionally substituted with 1 or 2 R; the other variables are as defined in the application.

[0075] In some embodiments of the application, R b each occurrence is independently selected from -H, -D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SF5, -NO2, -CHO, -COOH, -C(=O)NH2, -CH3, -CH2F, -CHF2, or -CF3;

[0076] or, two R b form

[0077] In some embodiments of the application, the structural unit is selected from said optionally substituted with 1, 2, 3, 4, or 5 R; the other variables are as defined in the application.

[0078] In some embodiments of the application, the structural unit is selected from

[0079] In some embodiments of the application, when the structural unit -L-R1is selected from -OCH3,

[0080] Structural unit selected from

[0081] The present application also provides a compound of the following formula, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, which is selected from

[0082] In some embodiments of the present application, the above-mentioned compound, an optical isomer thereof, or a pharmaceutically acceptable salt thereof is selected from

[0083] In still another aspect of the present application, the present application also provides a pharmaceutical composition. In some embodiments of the present application, the above-mentioned pharmaceutical composition protects the above-mentioned compound, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

[0084] In some embodiments of the present application, the above-mentioned pharmaceutical composition further comprises a pharmaceutical adjuvant.

[0085] In still another aspect of the present application, the present application also provides the use of the above-mentioned compound, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, or the above-mentioned pharmaceutical composition in the manufacture of a medicament for preventing or treating cancer, systemic disease, inflammatory disease, immune system disease, cardiovascular disease, gastrointestinal disease, hepatobiliary disease, liver disease, autoimmune disease, kidney disease, metabolic disease, ocular disease, liver fibrosis, respiratory disease, transplant rejection, pulmonary fibrosis, connective tissue disease, kidney fibrosis, scleroderma, cirrhosis, nervous system disease, intensive care medicine, atopic dermatitis, head and neck cancer, non-small cell lung cancer, liver cirrhosis, diabetic nephropathy, myocardial fibrosis, metastatic melanoma, nonalcoholic steatohepatitis, plaque psoriasis, and / or esophageal varices.

[0086] Definitions and Descriptions

[0087] Unless otherwise indicated, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be construed as undefined or unclear unless specifically defined, but should be interpreted in accordance with the ordinary meaning. When a trade name appears herein, it is intended to refer to its corresponding product or active ingredient thereof.

[0088] The term "pharmaceutically acceptable" as used herein, with respect to compounds, materials, compositions, and / or dosage forms, means those that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0089] The term "pharmaceutically acceptable salt" means a salt of a compound of the present application that is found to be suitable for use in pharmaceutical applications, which is prepared from a compound of the present application having a specific substituent with a relatively nontoxic acid or base. When a compound of the present application contains a relatively acidic functional group, a base addition salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of the appropriate base in a pure solution or in a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt. When a compound of the present application contains a relatively basic functional group, an acid addition salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of the appropriate acid in a pure solution or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include salts of inorganic acids, such as hydrochloric, hydrobromic, nitric, carbonic, bicarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, bisulfuric, hydroiodic, phosphorous, and the like; and salts of organic acids, such as acetic, propionic, isobutyric, trifluoroacetic, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-toluenesulfonic, citric, tartaric, and methanesulfonic acid and the like; also salts of amino acids, such as arginine and the like, and salts of organic acids like glucuronic acid and the like. Certain specific compounds of the present application contain both basic and acidic functionalities and as such can be converted into either base or acid addition salts.

[0090] The pharmaceutically acceptable salts of the present application can be synthesized from the parent compound that contains an acid or a base moiety by conventional chemical methods. Generally, such salts can be prepared by contacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent or in a mixture of both.

[0091] The compounds of the present application can exist in particular geometric or stereoisomeric forms. The present application contemplates all such compounds, including cis- and trans-isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)- isomers, (L)-isomers, as well as racemic mixtures and other mixtures thereof, e.g., mixtures of enantiomers or diastereomers, all of which are intended to be within the scope of the present application. Additional asymmetric carbon atoms can be present in a substituent group. All such isomers, as well as mixtures thereof, are included within the scope of the present application.

[0092] Unless otherwise indicated, the term "tautomer" or "tautomer forms" refers to different functional group isomers that are in dynamic equilibrium at room temperature and can rapidly interconvert. If tautomers are possible (as in solution), a chemical equilibrium of the tautomers can be reached. For example, proton tautomers (also known as prototropic tautomers) include interconversions by proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include interconversions by reorganization of some of the bonding electrons. A specific example of keto-enol tautomerization is the interconversion between pentane-2,4-dione and 4-hydroxypent-3-en-2-one, two tautomers.

[0093] The compounds of the present application can contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds can be radiolabeled with radioactive isotopes, such as for example tritium ( 3 H), iodine-125 ( 125 I) or carbon-14 ( 14 C). For example, deuterium can be substituted for hydrogen to form deuterated drugs, which have advantages over non-deuterated drugs, such as reduced toxicity, increased stability, enhanced efficacy, and increased biological half-life. All isotopic variations of the compounds of the present application, whether radioactive or not, are encompassed within the scope of the present application.

[0094] "Optional" or "optionally" means that the subsequently described event or circumstance can or can not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not.

[0095] The term "substituted" means that any one or more hydrogen atoms on the particular atom is replaced with a substituent group, which can include variants of deuterium and hydrogen, as long as the valency of the particular atom is not exceeded and the substituted compound is stable. The term "optionally substituted" means that the atom can or can not be substituted and that the types and number of substituents, if any, are optional and can be any chemically feasible.

[0096] When any variable (e.g., R) occurs more than one time in a compound, its definition in each occurrence is independent of its definition at every other place. Thus, for example, if a group is substituted with 1, 2, or 3 R groups, then the group is optionally substituted with up to three R groups, and the R group is selected independently for each occurrence. Also, combinations of substituents and / or variants thereof are permissible only if such combinations result in stable compounds. may be selected from etc.

[0097] When one of the variables is selected from a single bond, it indicates that the two groups to which it is attached are directly connected, such as When L2 represents a single bond, it indicates that the structure is actually A dash ("-") that is not between two letters or symbols is used to indicate a point of attachment for a substituent. For example, -CH2- means two carbon atoms linked by a single bond. 1-6 alkylcarbonyl- means a C 1-6 alkyl group attached to the remainder of the molecule through a carbonyl group. However, when the point of attachment of a substituent is apparent to one of ordinary skill in the art, for example, a halogen substituent, the "-" can be omitted.

[0098] Unless otherwise indicated, a dashed line indicates a point of attachment for a group, for example in .

[0099] When a recited substituent is not designated as to which atom of the recited substituent is connected to the recited substituted group, the substituent can be bonded through any atom thereof, for example, a pyridyl group as a substituent can be connected to the recited substituted group through any one of the carbon atoms of the pyridyl ring.

[0100] When a recited linking group is not designated as to its direction of attachment, its direction of attachment is arbitrary, for example, wherein the linking group L is in which case the phenyl and cyclopentyl groups can be connected in the same direction as the reading order from left to right to form or in the opposite direction to the reading order from left to right to form Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0101] Unless otherwise specified, the number of atoms in a ring indicates the number of atoms that are bonded together to form the ring itself (e.g., monocyclic compounds, fused ring compounds, spiro ring compounds, bridged ring compounds, crosslinked compounds, carbocyclic compounds, heterocyclic compounds). The number of atoms in a ring is often defined as the ring member number, for example, a "4-6 membered ring" refers to a "ring" that has 4-6 atoms arranged in a ring. When a ring is substituted, the atoms included in the substituent are not included in the ring member number. Unless otherwise specified, benzene is a 6-membered ring, naphthalene is a 10-membered ring, and thiophene is a 5-membered ring.

[0102] Unless otherwise specified, the term "alkyl" means a saturated hydrocarbon group including primary (normal), or secondary carbon atoms, or tertiary carbon atoms, or quaternary carbon atoms, or a combination thereof, which can be straight-chained or branched, which can be monovalent (such as methyl), divalent (such as methylene) or multivalent (such as methine). Unless otherwise specified, alkyl groups can be optionally substituted.

[0103] Unless otherwise specified, the term "C 1-20 alkyl" is used to denote a straight-chained or branched saturated hydrocarbon group consisting of 1 to 20 carbon atoms. The C 1-20 alkyl group includes C 1-19 , C 1-15 , C 1-10 , C 1-5 , C 1-4 , C 2-20 , C 2-12 , C 2-6 alkyl, etc.; which can be monovalent (such as methyl), divalent (such as methylene) or multivalent (such as methine). C 1-20 Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, sec-butyl, n-pentyl, n-hexyl, 1-methylhexyl, n-nonyl, n-decyl, adamantyl, n-undecyl, n-dodecyl, 2- ethyldodecyl, 2-butyldodecyl, n-icosyl, methylene, 1,2-ethanediyl, 1,3-propanediyl, 1,4- butanediyl, 1,5-pentanediyl, 1,6-hexanediyl, 1,7-heptanediyl, 1,8-octanediyl, 1,9-nonanediyl, 1,10-decanediyl, 1,12-dodecanediyl, 1,14-tetradecanediyl, 1,16-hexadecanediyl, 1,18- octadecanediyl, 1,20-icosanediyl, etc.

[0104] Unless otherwise specified, the term "C 1-6 alkyl" is used to denote a straight-chained or branched saturated hydrocarbon group consisting of 1 to 6 carbon atoms. The C 1-6 alkyl group includes C 1-5 , C 1-4 , C 2-6 alkyl, etc.; which can be monovalent (such as methyl), divalent (such as methylene) or multivalent (such as methine). C 1-6 Examples of alkyl groups include, but are not limited to, methyl ("Me"), ethyl ("Et"), propyl such as n-propyl ("n-Pr") or isopropyl ("i-Pr"), butyl such as n-butyl ("n-Bu"), isobutyl ("i-Bu"), sec-butyl ("s-Bu"), or t-butyl ("t-Bu"), pentyl, hexyl, methylene, 1,2-ethanediyl, 1,3-propanediyl, 1,4-butanediyl, 1,5-pentanediyl, 1,6-hexanediyl, etc.

[0105] Unless otherwise specified, the term "alkenyl" refers to a compound containing at least one unsaturated site, i.e., a carbon-carbon sp group. 2 The double-bonded hydrocarbon group can represent a straight-chain and / or branched alkenyl group, where branching refers to one or more alkyl groups, such as methyl, ethyl, or propyl, attached to the straight-chain alkenyl chain. It can be monovalent, divalent, or polyvalent. Unless otherwise specified in the specification, the alkenyl group may optionally be substituted.

[0106] Unless otherwise specified, "C 2-12 "Alkenyl" is used to denote a hydrocarbon group consisting of 2 to 12 carbon atoms, either straight-chain or branched, containing at least one carbon-carbon double bond. The carbon-carbon double bond can be located at any position within the group. The C... 2-12 Alkenes include C 2-11 C 2-10 C 2-5 C 2- 4. C 3-20 C 4-12 C 5-6 Alkenes, etc.; they can be monovalent, divalent, or polyvalent. C 2-12 Examples of alkenyl groups include, but are not limited to, vinyl, propenyl, n-butenyl, 3-methylbut-2-enyl, pentenyl, hexenyl, butadienyl, pentodienyl, hexadienyl, octenyl, decenyl, n-undecenyl, vinylidene, propenylidene, sec-butenylidene, 2-methylbutenylidene, etc.

[0107] Unless otherwise specified, "C 2-6 "Alkenyl" is used to denote a hydrocarbon group consisting of 2 to 6 carbon atoms, either straight-chain or branched, containing at least one carbon-carbon double bond. The carbon-carbon double bond can be located at any position within the group. The C... 2-6 Alkenes include C 2-4 C 2-3 C4, C3, and C2 alkenyl groups, etc.; they can be monovalent, divalent, or polyvalent. 2-6 Examples of alkenyl groups include, but are not limited to, vinyl, propenyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl, vinylidene, propenylidene, sec-butenyl, etc.

[0108] Unless otherwise specified, "-CH=C 3-20 "Cycloalkyl" is used to indicate a compound with one carbon atom and C. 3-20 A group in which a cycloalkyl group is linked by a double bond can be represented structurally as follows: Ring A is selected from C. 3-20 Cycloalkyl. For example, "-CH=C3 cycloalkyl" indicates...

[0109] Unless otherwise specified, the term "alkynyl" refers to a hydrocarbon group containing at least one unsaturated site, i.e., a carbon-carbon sp triple bond, which can represent a straight-chain and / or branched alkynyl group. A branched group refers to one or more alkyl groups, such as methyl, ethyl, or propyl, attached to the straight-chain alkynyl group. It can be monovalent, divalent, or polyvalent. Unless specifically stated in the specification, the alkynyl group may optionally be substituted.

[0110] Unless otherwise specified, the term "C" 2-12 "Alkyne" is used to denote a straight-chain or branched hydrocarbon group consisting of 2 to 12 carbon atoms containing at least one carbon-carbon triple bond, which can be located at any position within the group. 2-12 Alkyne groups include C 2-11 C 2-10 C 2- 5. C 2-4 C 3-20 C 4-12 C 5-6 Alkyne groups, etc.; they can be monovalent, divalent, or polyvalent. C 2-12 Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, ethynylene, propynylene, penynyl, penynylene, 1-butynyl, butyrynyl, cyclopropylethynyl, 3-methyl-2-pentynylene, etc.

[0111] Unless otherwise specified, the term "C" 2-6 "Alkyne" is used to denote a hydrocarbon group consisting of 2 to 6 carbon atoms, either straight-chain or branched, containing at least one carbon-carbon triple bond. The carbon-carbon triple bond can be located at any position within the group. It can be monovalent, divalent, or polyvalent. The C... 2-6 Alkyne groups include C 2-5 C 2-4 C 2-3 C2, C 2-6 C6 and C5 acetylinyl groups, etc. C 2-6 Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, ethynylene, propynylene, penynyl, and penynylene.

[0112] Unless otherwise specified, the term "heteroalkyl," by itself or in combination with another term, means, unless otherwise anchored, an stable straight or branched chain, or combination thereof, of carbon atoms, and at least one heteroatom or heteroatom group, wherein "alkyl" is as defined herein. In some embodiments, the heteroatom is selected from B, O, N, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen heteroatom is optionally quaternized. In other embodiments, the heteroatom group is selected from -C(=O)O-, -C(=O)-, -C(=S)-, -S(=O), -S(=O)2-, -C(=O)N(H)-, -N(H)-, -C(=NH)-, -S(=O)2N(H)-, and -S(=O)N(H)-. In some embodiments, the heteroalkyl is C 1-20 heteroalkyl; in some embodiments, the heteroalkyl is C 1-6 heteroalkyl; in other embodiments, the heteroalkyl is C 1-3 heteroalkyl. The heteroatom or heteroatom group can be located at any interior position of the heteroalkyl group, including the position at which the alkyl group is attached to the remainder of the molecule. Examples of heteroalkyl include, but are not limited to, -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH2(CH3)2, -CH2-CH2-O-CH3, -NHCH3, -N(CH3)2, -NHCH2CH3, -N(CH3)(CH2CH3), -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -SCH3, -SCH2CH3, -SCH2CH2CH3, -SCH2(CH3)2, -CH2-S-CH2-CH3, -CH2-CH2, -S(=O)-CH3, -CH2-CH2-S(=O)2-CH3, and the like; up to two of the heteroatoms can be consecutive, such as, for example, -CH2-NH-OCH3. Unless otherwise noted, heteroalkyl is optionally substituted. Unless otherwise specified, the term "alkoxy" means an alkyl group, as defined herein, attached to the remainder of the molecule through an oxygen atom. Unless otherwise noted, alkoxy is optionally substituted.

[0113] Unless otherwise specified, the term "C 1-6 alkoxy" means those alkyl groups containing 1 to 6 carbon atoms attached to the remainder of the molecule through an oxygen atom. The C 1-6 alkoxy groups include C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-4 , C6, C5, C4, and C3 alkoxy groups, and the like. The C 1-6Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), butoxy (including n-butoxy, isobutoxy, s-butoxy and t-butoxy), pentoxy (including n-pentoxy, isopentoxy and neopentoxy), hexoxy, methyleneoxy, ethoxy, propoxy, butoxy, pentylooxy, etc.

[0114] Unless otherwise specified, the term "C" 1-4 "Alkoxy" refers to alkyl groups containing 1 to 4 carbon atoms that are attached to the rest of the molecule by an oxygen atom. The C 1-4 Alkoxy groups include C 1-3 C 1-2 C 2-4 C4 and C3 alkoxy groups, etc. 1-6 Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), butoxy (including n-butoxy, isobutoxy, s-butoxy and t-butoxy), methyleneoxy, ethoxy, propoxy, butoxy, etc.

[0115] Unless otherwise specified, the term "C" 1-3 "Alkoxy" refers to alkyl groups containing 1 to 3 carbon atoms that are attached to the rest of the molecule by an oxygen atom. The C 1-3 Alkoxy groups include C 1-2 C 2-3 C3 and C2 alkoxy groups, etc. 1-3 Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), methyleneoxy, ethoxy, propoxy, etc.

[0116] Unless otherwise specified, the term "amino" can be monovalent. Bivalent Or multiple prices

[0117] Unless otherwise specified, the term "alkylamino" refers to an alkyl group attached to the remainder of a molecule by an amino group as defined above, wherein "alkyl" in "alkyl group" is defined as described above. Alkylamino groups may optionally be substituted unless specifically stated in the specification.

[0118] Unless otherwise specified, the term "C" 1-6 "Alkylamino" refers to alkyl groups containing 1 to 6 carbon atoms that are attached to the rest of the molecule via an amino group. The C 1-6 Alkylamino groups include C 1-4 C 1-3 C 1-2 C 2-6 C2-4 , C6, C5, C4, C3, and C2 alkylamino groups, and the like. C 1-6 Examples of alkylamino groups include, but are not limited to, -NHCH3, -N(CH3)2, -NHCH2CH3, -N(CH3)CH2CH3, -N(CH2CH3)(CH2CH3), -NHCH2CH2CH3, -NHCH2(CH3)2, -NHCH2CH2CH2CH3, and the like.

[0119] The term "C 1-4 "alkylamino" means those alkyl groups, containing from 1 to 4 carbon atoms, attached to the remainder of the molecule through an amino group. The C 1-4 alkylamino groups include C 1-3 , C 1-2 , C 2-4 , C4, C3, and C2 alkylamino groups, and the like. C 1-4 Examples of alkylamino groups include, but are not limited to, -NHCH3, -N(CH3)2, -NHCH2CH3, -N(CH3)CH2CH3, -N(CH2CH3)(CH2CH3), -NHCH2CH2CH3, -NHCH2(CH3)2, -NHCH2CH2CH2CH3, and the like.

[0120] The term "C 1-3 "alkylamino" means those alkyl groups, containing from 1 to 3 carbon atoms, attached to the remainder of the molecule through an amino group. The C 1-3 alkylamino groups include C 1-2 , C3, and C2 alkylamino groups, and the like. C 1-3 Examples of alkylamino groups include, but are not limited to, -NHCH3, -N(CH3)2, -NHCH2CH3, -N(CH3)CH2CH3, -NHCH2CH2CH3, -NHCH2(CH3)2, and the like.

[0121] The term "alkylthio" means, unless otherwise specified, an alkyl group, as defined above in the application, attached to the remainder of the molecule through a sulfur atom. Unless otherwise specified in the specification, an alkylthio group can be optionally substituted.

[0122] The term "C 1-6 "alkylthio" means those alkyl groups, containing from 1 to 6 carbon atoms, attached to the remainder of the molecule through a sulfur atom. The C 1-6 alkylthio groups include C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-4C6, C5, C4, C3, and C2 alkylthio groups, etc. C 1-6 Examples of alkylthio groups include, but are not limited to, -SCH3, -SCH2CH3, -SCH2CH2CH3, -SCH2(CH3)2, etc.

[0123] Unless otherwise specified, the term "C" 1-4 "Alkylthio" refers to alkyl groups containing 1 to 4 carbon atoms that are attached to the rest of the molecule via a sulfur atom. The C 1-4 Alkyl thio groups include C 1-3 C 1-2 C 2-4 C4, C3, and C2 alkylthio groups, etc. C 1-4 Examples of alkylthio groups include, but are not limited to, -SCH3, -SCH2CH3, -SCH2CH2CH3, -SCH2(CH3)2, etc.

[0124] Unless otherwise specified, the term "C" 1-3 "Alkylthio" refers to alkyl groups containing 1 to 3 carbon atoms that are attached to the rest of the molecule via a sulfur atom. The C 1-3 Alkyl thio groups include C 1-3 C 1-2 And C3 alkylthio groups, etc. C 1-3 Examples of alkylthio groups include, but are not limited to, -SCH3, -SCH2CH3, -SCH2CH2CH3, -SCH2(CH3)2, etc.

[0125] Unless otherwise specified, the term "cycloalkyl" refers to a stable, non-aromatic monocyclic or polycyclic saturated hydrocarbon group consisting of carbon and hydrogen atoms, which may include fused, spirocyclic, and / or bridged ring systems. Monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyl groups include, but are not limited to, adamantyl, norbornyl, decahydronaphthyl, 7,7-dimethyl-bicyclo[2.2.1]heptyl, etc. 4-6 "Cycloalkyl" indicates a cycloalkyl group having 4-6 carbon atoms in the ring. Similarly, "C 3-4 "Cycloalkyl" refers to a cycloalkyl group having 3-4 carbon atoms in the ring. Unless otherwise specified in the specification, the cycloalkyl group may be optionally substituted.

[0126] Unless otherwise specified, "C 3-20 "Cycloalkyl" refers to a saturated monocyclic or polycyclic hydrocarbon group having 3-20 ring carbon atoms, for example 3-15 ring carbon atoms, for example 3-6 ring carbon atoms; it can be monovalent, divalent, or polyvalent. C 3-20 Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

[0127] Unless otherwise specified, "C 3-6 "Cycloalkyl" refers to a saturated monocyclic or bicyclic hydrocarbon group having 3-6 ring carbon atoms, for example 3-5 ring carbon atoms, for example 3-4 ring carbon atoms; it can be monovalent, divalent, or polyvalent. C 3-6 Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0128] Unless otherwise specified, "C 4-6 "Cycloalkyl" refers to a saturated cyclic hydrocarbon group consisting of 4 to 6 carbon atoms, which can be monocyclic or bicyclic. 4-6 Cycloalkyl groups include C 4-5 C 5-6 C4, C5, and C6 cycloalkyl groups, etc.; they can be monovalent, divalent, or polyvalent. 4-6 Examples of cycloalkyl groups include, but are not limited to, cyclobutyl, cyclopentyl, cyclohexyl, etc.

[0129] Unless otherwise specified, the term "heterocyclic alkyl" means a non-aromatic saturated cyclic group existing as a monocyclic, fused, spirocyclic, and / or bridged ring, wherein at least one ring atom is a heteroatom or heteroatomic group, and the remainder are carbon atoms; in some embodiments, the heteroatom is selected independently from B, O, N, and S each time it appears, wherein the nitrogen and sulfur atoms are optionally oxidized (i.e., NO and S(O)). p (p is 1 or 2), the nitrogen heteroatom is optionally quaternized, and in other embodiments, each occurrence of the heterogroup is independently selected from -C(=O)O-, -C(=O)-, -C(=S)-, -S(=O), -S(=O)2-, -C(=O)N(H)-, -N(H)-, -C(=NH)-, -S(=O)2N(H)-, and -S(=O)N(H)-. The heteroatom or heterogroup can be located at any internal position of the heterocyclic alkyl group, including the position where the heterocyclic alkyl group is connected to the rest of the molecule. In some embodiments, the heterocyclic alkyl group is a 3-20-membered heterocyclic alkyl group; in some embodiments, the heterocyclic alkyl group is a 3-10-membered heterocyclic alkyl group; in other embodiments, the heterocyclic alkyl group is a 3-6-membered heterocyclic alkyl group. Unless otherwise specifically stated in the specification, the heterocyclic alkyl group may optionally be substituted. Unless otherwise specified, the term "3-6 membered heterocyclic alkyl" on its own or in combination with other terms respectively refers to a saturated cyclic group consisting of 3 to 6 ring atoms, wherein 1, 2, 3, or 4 of the ring atoms are heteroatoms independently selected from B, O, S, and N or heteroatomic groups as described above, and the remainder are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., NO and S(O)). p, p is 1 or 2). It includes monocyclic and bicyclic ring systems, where the bicyclic ring systems include spiro, fused, and bridged rings. Further, with respect to this "3-6 membered heterocycloalkyl," the heteroatom or heteroatom group can be positioned at any interior position of the heterocycloalkyl group, including can occupy the position of attachment of the heterocycloalkyl group to the remainder of the molecule. The 3-6 membered heterocycloalkyl group includes 5-6 membered, 4 membered, 5 membered, and 6 membered heterocycloalkyl groups, and the like. Examples of 3-6 membered heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, and the like), tetrahydrofuranyl (including tetrahydrofuran-2-yl, and the like), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl, and 3-piperidinyl, and the like), piperazinyl (including 1-piperazinyl and 2-piperazinyl, and the like), morpholinyl (including 3-morpholinyl and 4-morpholinyl, and the like), dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiazinyl, hexahydropyridazinyl, homopiperazinyl, or homopiperidinyl, and the like.

[0130] Unless otherwise specified, the term "cycloalkenyl" as used herein refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon group consisting of carbon and hydrogen atoms, having one or more carbon-carbon sp 2 Double bonds, which can include fused, spiro, and / or bridged ring systems. Monocyclic cycloalkenyl groups include, but are not limited to, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, and the like. Polycyclic cycloalkenyl groups include, but are not limited to, bicyclo[2.2.1]hept-2-enyl, and the like. Unless otherwise specified, a cycloalkenyl group can be optionally substituted. "C 3-7 Cycloalkenyl groups include C3, C4, C5, C6, and C7 cycloalkenyl groups. Examples of cycloalkenyl groups include, but are not limited to, cyclobutenyl, cyclopentenyl, and cyclohexenyl.

[0131] Unless otherwise specified, the term "heterocycloalkenyl" as used herein refers to a cyclic alkenyl group comprising several heteroatoms or heteroatom groups, which in some embodiments are independently selected at each occurrence from B, O, N, and S, wherein the nitrogen and sulfur atoms are optionally oxidized (i.e., NO and S(O) p, p is 1 or 2), the nitrogen atom is optionally quaternized, in other embodiments, the heteroatom group is independently selected for each occurrence from -C(=O)O-, -C(=O)-, -C(=S)-, -S(=O), -S(=O)2-, -C(=O)N(H)-, -N(H)-, -C(=NH)-, -S(=O)2N(H)-, and -S(=O)N(H)-. "5-6 membered heterocycloalkenyl" by itself or in combination with other terminology means an unsaturated cyclic group consisting of 5 to 6 ring atoms, 1, 2, 3, or 4 of which are heteroatoms independently selected from B, O, S, and N, or a heteroatom group as described above, and the remainder of which are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms can be optionally oxidized (i.e., NO and S(O) p Examples of heterocycloalkenyl groups include, but are not limited to Heterocycloalkenyl groups can be optionally substituted unless otherwise specified in the specification.

[0132] Unless otherwise specified, when a substituent attached to ring A can be connected to ring A to form a ring, it means that the substituent can be connected to any site of ring A to form a new ring, including fused, spiro, or bridged rings; wherein ring A can be selected from cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, heteroaryl, etc. as described above. For example, R in may be connected to to form a 6-membered ring, examples of which include, but are not limited to

[0133] Unless otherwise specified, C n-n+m or C n -C n+m includes any specific case of n to n+m carbons, for example C 1-12 includes C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 , C 11 , and C 12 also includes any range of n to n+m, for example C 1-12 includes C 1-3 , C 1-6 , C 1-9 , C 3-6 , C 3-9 , C 3-12 , C 6-9 , C 6-12 , and C 9-12 ​etc. Similarly, n- to n+m-membered means the number of atoms in the ring is n to n+m, for example, 3- to 12-membered ring includes 3-membered, 4-membered, 5-membered, 6-membered, 7-membered, 8-membered, 9-membered, 10-membered, 11-membered, and 12-membered rings, and also includes any range within n to n+m, for example, 3- to 6-membered ring, 3- to 9-membered ring, 5- to 6-membered ring, 5- to 7-membered ring, 6- to 7-membered ring, 6- to 8-membered ring, and 6- to 10-membered ring, etc.

[0134] Unless otherwise specified, the term "aryl" means a hydrocarbon ring system group comprising at least one aromatic ring. In the present invention, aryl groups can be monocyclic, bicyclic, tricyclic, or tetracyclic ring systems, which can include fused, spiro, and / or bridged ring systems. Aryl groups include, but are not limited to, benzene, naphthalene, anthracene, fluoranthene, phenanthrene, chrysene, pyrene, tetracene, phenalene, fluorene, and derivatives thereof. Unless otherwise specified in the specification, aryl groups can be optionally substituted.

[0135] Unless otherwise specified, the term "heteroaryl" means a heteroaromatic system comprising 1 to 4 heteroatoms, 5 to 20 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. Heteroaryl groups are preferably 5- to 10-membered, containing 1 to 3 heteroatoms; more preferably 5- or 6-membered, containing 1 to 3 heteroatoms; non-limiting examples are pyrazolyl, imidazolyl, furanyl, thienyl, thiazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl, etc. Heteroaryl groups can be attached to the rest of the molecule through a heteroatom or a carbon atom. The heteroaryl ring can be fused to an aryl, heterocycloalkyl, or cycloalkyl ring, where the ring that is attached to the parent structure is the heteroaryl ring, non-limiting examples of which include: etc. Similarly, n- to n+m-membered means the number of atoms in the ring is n to n+m, for example, 3- to 12-membered ring includes 3-membered, 4-membered, 5-membered, 6-membered, 7-membered, 8-membered, 9-membered, 10-membered, 11-membered, and 12-membered rings, and also includes any range within n to n+m, for example, 3- to 6-membered ring, 3- to 9-membered ring, 5- to 6-membered ring, 5- to 7-membered ring, 6- to 7-membered ring, 6- to 8-membered ring, and 6- to 10-membered ring, etc.

[0136] The term "substituted" as used herein means that at least one hydrogen atom in any of the above groups (i.e., alkyl, alkenyl, alkynyl, heteroalkyl, alkoxy, alkylamino, alkylthio, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, heteroaryl) is replaced with a bond to a non-hydrogen atom including, but not limited to, halogen atoms (e.g., F, Cl, Br, I), oxygen-containing groups (e.g., hydroxyl, alkoxy, ester), sulfur-containing groups (e.g., thiol, thioalkyl, sulfone, sulfonyl, sulfoxide), nitrogen-containing groups (e.g., amine, amide, dialkylamine, arylamine, aryl-alkyl-amine, diarylamine, N-oxide, imide, enamine), silicon-containing groups (e.g., trialkylsilyl, dialkylarylsilyl, alkylbisarylsilyl, triarylsilyl), and other heteroatoms in various other groups.

[0137] The term "substituted" as used herein also means that one or more hydrogen atoms in any of the above groups (i.e., alkyl, alkenyl, alkynyl, heteroalkyl, alkoxy, alkylamino, alkylthio, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, heteroaryl) is replaced with a higher order bond (e.g., a double or triple bond) to a heteroatom, such as the oxygen in carbonyl, carboxyl, and ester groups, and the nitrogen in imine, oxime, hydrazone, and nitrile groups. For example, "substituted" means that one or more hydrogen atoms in any of the above groups is replaced with -NR g R h , -NR g C(=O)R h , -NR g C(=O)NR g R h , -NR g C(=O)OR h , -NR g SO2R h , -OC(=O)NR g R h , -OR g , -SR g , -SOR g , SO2R g , -OSO2R g , -SO2OR g , =NSO2R g , and -SO2NR g R h . "Substituted" can also mean that one or more hydrogen atoms in any of the above groups is replaced with -C(=O)R g , -C(=O)OR g , -C(=O)NR g R h , -CH2SO2R g , -CH2SO2NRg R h Replacement. The R g With R h The groups, whether identical or different, are independently selected from hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkyl-alkyl, haloalkyl, haloalkenyl, haloalkynyl, heterocyclic, N-heterocyclic, heterocyclic alkyl-alkyl, heteroaryl, N-heteroaryl, and heteroaryl-alkyl. "Substituted" may also indicate that one or more hydrogen atoms in any of the above groups are substituted with amino, cyano, hydroxyl, imino, nitro, oxo, thio, halogen, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkyl-alkyl, haloalkyl, haloalkenyl, haloalkynyl, heterocyclic, N-heterocyclic, heterocyclic alkyl-alkyl, heteroaryl, N-heteroaryl, and heteroaryl-alkyl. Additionally, each of the above substituents may optionally be substituted with one or more of the above substituents.

[0138] Those skilled in the art will understand that some compounds of formula (I) may contain one or more chiral centers, and thus have two or more stereoisomers. Therefore, the compounds of the present invention may exist as a single stereoisomer (e.g., enantiomer, diastereomer) and mixtures thereof in any proportion, such as racemates, and, where appropriate, as tautomers and geometric isomers.

[0139] As used in this article, "stereoisomer" refers to compounds that have the same chemical composition but differ in the spatial arrangement of atoms or groups. Stereoisomers include enantiomers, diastereomers, and conformational isomers.

[0140] The term "enantiomer" as used in this article refers to two stereoisomers of a compound that are non-overlapping mirror images of each other.

[0141] As used herein, the term "diastereomer" refers to a stereoisomer that has two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers possess different physical properties, such as melting point, boiling point, spectral properties, or biological activity. Mixtures of diastereomers can be separated using high-resolution analytical methods such as electrophoresis and chromatography such as HPLC.

[0142] Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light. In describing optical activity, the prefixes D and L or R and S are used to denote the absolute configuration of the molecule about its chiral center. The prefixes d and 1 or (+) and (-) are employed to designate the sign of the rotation of plane-polarized light by the compound, with (-) or 1 indicating that the compound is levorotatory. A compound with the (+) or d prefix is dextrorotary. For a given chemical structure, these stereoisomers are identical except that they are mirror images of one another. A specific stereoisomer can also be referred to as an enantiomer when there are two stereoisomers and a mixture of such isomers is often referred to as an enantiomeric mixture. A 50:50 mixture of enantiomers is referred to as a racemic mixture or racmate, which can occur where there has been no stereoselection or stereospecificity in a chemical reaction or process. The terms "racemic mixture" and "racmate" refer to an equimolar mixture of two enantiomeric forms lacking optical activity.

[0143] Racemic mixtures can be used as themselves or resolved into their individual isomers. A stereochemically pure compound or a mixture enriched in one or more isomers can be obtained by resolution. Methods for separating isomers are well known, including physical methods such as chromatography employing a chiral adsorbant. Individual isomers can be prepared in chiral form from chiral precursors. Alternatively, individual isomers can be obtained chemically from mixtures by forming diastereomeric salts with a chiral acid (such as the individual enantiomers of 10-camphorsulfonic acid, camphoric acid, a-bromocamphoric acid, tartaric acid, diacetyltartaric acid, malic acid, pyrrolidine-5-carboxylic acid, and the like), fractional crystallization of the salts, and then freeing the resolved base of one or both of the enantiomers, optionally repeating the process to obtain one or both isomers substantially free of the other, i.e., optical purity of a desired stereoisomer of, for example, at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.5% by weight. Alternatively, the racmate can be covalently bonded to a chiral compound (chiral auxiliary) to give a diastereomeric mixture, as is well known to those skilled in the art.

[0144] The terms "tautomers" or "tautomerically" as used herein refer to different energy structures that can interconvert via low energy barriers. For example, prototropic tautomers (also known as proton-shift tautomers) include interconversions by proton migration, such as keto-enol and imine-enamine isomerization. Valence-bond tautomers include interconversions by reorganization of some of the bonding electrons.

[0145] The compounds of the present application can be prepared by a variety of synthetic processes known to those skilled in the art, including the specific embodiments set forth below, embodiments formed by a combination of the specific embodiments set forth below with other chemical synthetic processes known to those skilled in the art, and equivalents thereof as known to those skilled in the art, preferred embodiments including, but not limited to, the examples of the present application.

[0146] Technical and scientific terms used herein that are not specifically defined have the meanings that would be given to them by one of ordinary skill in the art to which this application pertains. DETAILED DESCRIPTION

[0147] The present application is described in detail below by way of examples, but it is not meant to present any limitations on the present application. The present application has been described in detail, and specific embodiments thereof have been disclosed, it will be apparent to those skilled in the art that various changes and modifications can be made therein without departing from the spirit and scope of the present application.

[0148] Example 1: Synthesis of Compound 1

[0149] Step 1: Preparation of Compound 1-2

[0150] Compound 1-1 (150 mg, CAS: 2305622-80-2) was dissolved in dichloromethane (5 mL) under nitrogen protection, 3,5-dichloroaniline (60.8 mg), pyridine (68.5 mg) and phosphorus oxychloride (48.7 mg) were added successively under stirring. The resulting reaction solution was stirred at 25 °C for 1 hour until the reaction was completed. The reaction solution was concentrated under reduced pressure, and the obtained crude product was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain compound 1-2 (60 mg). LC-MS (ESI) [M+H] + : 663.0.

[0151] Step 2: Preparation of Compound 1-3

[0152] Compound 1-2 (55 mg) was dissolved in dichloromethane (3 mL) under nitrogen protection, pyridine (64.3 mg) and phosphorus pentachloride (33.8 mg) were added successively, and the resulting reaction solution was stirred at 70 °C for 2 hours. The reaction solution was cooled to 25 °C, and azidotrimethylsilane (12.9 mg) was added. The resulting reaction solution was warmed to 70 °C and stirred for 16 hours until the reaction was completed. The reaction solution was cooled to 25 °C, and saturated aqueous sodium bicarbonate solution (5 mL) was added to quench, and extracted with dichloromethane (3 mL x 2). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 1-3 crude product (55.6 mg), which was directly used in the next step without purification. LC-MS (ESI) [M+H]+ :688.0.

[0153] Step 3: Preparation of compound 1-4

[0154] Compound 1-3 (50 mg) was dissolved in ammonia in methanol solution (3 mL, 7 mol / L) under nitrogen protection, and the resulting reaction solution was reacted at 25 °C for 2 hours until the reaction was completed. The reaction solution was concentrated under reduced pressure to remove the solvent to obtain the crude product of compound 1-4 (40 mg). LC-MS (ESI) [M+H] + :646.2.

[0155] Step 4: Preparation of compound 1

[0156] Compound 1-4 (40 mg) was dissolved in trifluoroacetic acid (3 mL) under nitrogen protection, and the resulting reaction solution was stirred at 25 °C for 1 hour until the reaction was completed. After the reaction solution was concentrated under reduced pressure to remove the solvent, the crude product was obtained, which was prepared and purified by HPLC (column: Agilent 10 Prep-C8 250x21.2mm; column temperature: 25 °C; mobile phase: water (0.1% FA)-acetonitrile; mobile phase acetonitrile ratio 30%-50% in 9 min; flow rate 30 ml / min) to obtain compound 1 (7.0 mg). LC-MS (ESI) [M+H] + :558.0.

[0157] 1 H NMR (400 MHz, Methanol-d4) δ 8.59 (s, 1H), 7.91 (d, J = 1.9 Hz, 2H), 7.84 (t, J = 1.8 Hz, 1H), 7.68 (dd, J = 8.8, 6.6 Hz, 2H), 5.05 - 4.99 (m, 2H), 4.87 - 4.82 (m, 1H), 4.19 (q, J = 1.1 Hz, 1H), 4.01 (ddd, J = 7.3, 4.5, 1.1 Hz, 1H), 3.83 (dd, J = 11.7, 7.3 Hz, 1H), 3.74 (dd, J = 11.7, 4.5 Hz, 1H).

[0158] Example 2: Synthesis of compound 2

[0159] Step 1: Preparation of compound 2-1

[0160] Compound 1-1 (400 mg) was dissolved in dichloromethane (10 mL) under nitrogen protection, 2-amino-4-chlorobenzotrifluoride (180.7 mg), pyridine (182.7 mg) and phosphorus oxychloride (129.9 mg) were added successively under stirring. The resulting reaction solution was reacted at 25 °C for 1 hour until the reaction was completed. The reaction solution was concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain compound 2-1 (95 mg). LC-MS (ESI) [M+H] + : 697.2.

[0161] Step 2: Preparation of compound 2-2

[0162] Compound 2-1 (90 mg) was dissolved in dichloromethane (5 mL) under nitrogen protection, pyridine (100.1 mg) and phosphorus pentachloride (52.7 mg) were added successively. The resulting reaction solution was stirred at 70 °C for 2 hours until the reaction was completed. The reaction solution was cooled to 25 °C and azidotrimethylsilane (20.0 mg) was added, and then the resulting reaction solution was stirred at 70 °C for 18 hours until the reaction was completed. The reaction solution was quenched with saturated aqueous sodium bicarbonate solution (5 mL), extracted with dichloromethane (3 mL x 2), and the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain compound 2-2 (43 mg). LC-MS (ESI) [M+H] + : 722.2.

[0163] Step 3: Preparation of compound 2-3

[0164] Compound 2-2 (43 mg) was dissolved in ammonia methanol solution (2 mL, 4 mol / L) under nitrogen protection, and stirred at 25 °C for 16 hours until the reaction was completed. The reaction solution was concentrated under reduced pressure to obtain the crude product of compound 2-3 (40 mg). LC-MS (ESI) [M+H] + : 680.2.

[0165] Step 4: Preparation of compound 2-4

[0166] Compound 2-3 (40 mg) was dissolved in tetrahydrofuran (4 mL) under nitrogen protection, and sodium hydride (7.1 mg, 60% content) was added. The resulting reaction solution was stirred at 25 °C for 20 minutes, and tert-butyl bromoacetate (23.0 mg) was added. The resulting reaction solution was stirred at 25 °C for 16 hours until the reaction was completed, and then poured into water (5 mL) and quenched. The reaction solution was extracted with ethyl acetate (3 mL x 3), and the organic phase was washed with saturated brine (3 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 2-4 (30 mg). LC-MS (ESI) [M+H] + : 794.2.

[0167] Step 5: Preparation of compound 2

[0168] Compound 2-4 (25 mg) was dissolved in trifluoroacetic acid (1 mL) under nitrogen protection, and the reaction was stirred at 25 °C for 1 h until completion. The reaction solution was concentrated under reduced pressure, and the obtained crude product was separated and purified by HPLC (column: Agilent 10 Prep-C8 250x21.2mm; column temperature: 25 °C; mobile phase: water (0.1% FA) - acetonitrile; acetonitrile proportion in mobile phase: 30%-50% in 9 min; flow rate: 30 mL / min) to obtain compound 2 (3.9 mg). LC-MS (ESI) [M+H] + : 650.0.

[0169] 1 H NMR (400 MHz, Methanol-d4) d 8.77 (d, J = 3.0 Hz, 1H), 8.13 - 8.09 (m, 1H), 8.05 (d, J = 8.6 Hz, 1H), 8.00 - 7.93 (m, 1H), 7.68 (dd, J = 8.7, 6.5 Hz, 2H), 5.13 - 4.96 (m, 2H), 4.78 (d, J = 9.1 Hz, 1H), 4.12 (d, J = 2.7 Hz, 1H), 3.98 (d, J = 16.2 Hz, 1H), 3.74 (m, 2H), 3.60 (m, 2H).

[0170] Example 3: Synthesis of compound 3

[0171] Step 1: Preparation of compound 3-1

[0172] 1-bromo-2,3-difluoro-4-methylbenzene (5.0 g) and trimethylsilylacetylene (2.6 g) were dissolved in triethylamine (20 mL) under nitrogen protection, and bis(triphenylphosphine)palladium dichloride (339.1 mg) and cuprous iodide (230.0 mg) were added. The obtained reaction solution was stirred at 70 °C for 6 h until completion. The reaction solution was concentrated under reduced pressure, and the obtained crude product was separated and purified by silica gel column chromatography (eluent: petroleum ether) to obtain compound 3-1 (3.8 g).

[0173] Step 2: Preparation of compound 3-2

[0174] Compound 3-1 (1.2 g) and (2R,3R,4R,5R,6S)-2-(acetyloxymethyl)-4-azido-6- cyanotetrahydro-2H-pyran-3,5-diyl diacetate (2.4 g, CAS: 2575614-08-1) were dissolved in a mixed solvent of N,N-dimethylformamide (16 mL) and water (4 mL) under nitrogen protection, copper sulfate pentahydrate (871.7 mg) and vitamin C sodium salt (691.6 mg) were added, after addition, the obtained reaction solution was stirred at 85°C for 2 hours until the reaction was completed. The reaction solution was diluted with ethyl acetate (30 mL) and stirred to obtain a suspension, which was filtered with diatomite, the filtrate was poured into water (20 mL), extracted with ethyl acetate (30 mL x 3), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2:1) to obtain compound 3-2 (750 mg). LC-MS (ESI) [M+H] + : 493.2.

[0175] Step 3: Preparation of compound 3-3

[0176] Compound 3-2 (700 mg) was placed in a 50 mL sealed tube under nitrogen protection, hydrogen chloride methanol solution (10 mL, 4 mol / L) was added, after addition, the sealed tube was sealed, the obtained reaction solution was stirred at 65°C for 18 hours until the reaction was completed. The reaction solution was concentrated under reduced pressure to obtain a crude product of compound 3-3 (556 mg), the yield was 100%, which was directly used in the next step reaction without purification. LC-MS (ESI) [M+H] + : 400.2.

[0177] Step 4: Preparation of compound 3-4

[0178] Compound 3-3 (556 mg) and benzaldehyde dimethyl acetal (211.9 mg) were dissolved in acetonitrile (10 mL) under nitrogen protection, methyl sulfonic acid (160.6 mg) was added, after addition, the obtained reaction solution was stirred at 25°C for 16 hours until the reaction was completed. Triethylamine (169.1 mg) was added to quench the reaction, and stirred for 20 minutes, the obtained reaction solution was concentrated under reduced pressure to remove the solvent, and the obtained crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain compound 3-4 (610 mg). LC-MS (ESI) [M+H] + : 488.2.

[0179] Step 5: Preparation of compound 3-5

[0180] Compound 3-4 (340 mg) was dissolved in tetrahydrofuran (10 mL) under nitrogen protection, sodium hydride (110.5 mg, 60% content) was added after stirring for 1 hour, 2- (trimethylsilyl) ethoxymethyl chloride (345.4 mg) was added, and the obtained reaction solution was stirred at 25°C for 16 hours until the reaction was completed. The reaction solution was quenched by pouring into water (5 mL), extracted with ethyl acetate (15 mL x 3), and the organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 3-5 crude product (426 mg), which was directly used in the next step reaction without purification. LC-MS (ESI) [M+H] + : 618.4.

[0181] Step 6: Preparation of compound 3-6

[0182] Compound 3-5 (430 mg) was dissolved in a mixed solvent of tetrahydrofuran (3 mL) and methanol (3 mL) under nitrogen protection, and a solution of lithium hydroxide (33.3 mg) in water (2 mL) was added, and the obtained reaction solution was stirred at 25°C for 2 hours until the reaction was completed. The reaction solution was concentrated under reduced pressure to remove the organic solvent, and the obtained aqueous phase was adjusted to neutral pH with dilute hydrochloric acid (1 mol / L), and purified with C18 reverse column (mobile phase: water: acetonitrile = 35%-90% (containing 0.1% FA) to obtain compound 3-6 (270 mg). LC-MS (ESI) [M+H] + : 604.4.

[0183] Step 7: Preparation of compound 3-7

[0184] Compound 3-6 (75 mg) and 2-amino-4-chlorobenzotrifluoride (28.9 mg) were dissolved in dichloromethane (3 mL) under nitrogen protection, and the obtained mixture was cooled to 0°C, pyridine (48.6 mg) and phosphorus oxychloride (20.7 mg) were added in turn, and the obtained reaction system was stirred at 0°C for 1 hour until the reaction was completed. The reaction solution was directly purified by silica gel column chromatography (dichloromethane: methanol = 15:1) to obtain compound 3-7 (92 mg). LC-MS (ESI) [M+H] + : 781.3.

[0185] Step 8: Preparation of compound 3-8

[0186] Compound 3-7 (85 mg) and pyridine (85.2 mg, 86.8 μL) were dissolved in dichloromethane (8 mL) under nitrogen protection, phosphorus pentachloride (67.3 mg) was added and the temperature was raised to 65 °C, after stirring for 1 hour, the reaction was cooled to 25 °C, azidotrimethylsilane (49.6 mg) was added, after addition, the resulting reaction solution was stirred at 65 °C for 16 hours until the reaction was completed. The reaction solution was cooled in an ice bath, saturated sodium bicarbonate solution (0.5 mL) was added to quench the reaction, extracted with dichloromethane (5 mL x 2), the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give compound 3-8 (87 mg), which was used directly in the next step without purification. LC-MS (ESI) [M+H] + : 806.4.

[0187] Step 9: Preparation of compound 3

[0188] Compound 3-8 (80 mg) was dissolved in trifluoroacetic acid (1 mL) under nitrogen protection, stirred at 0 °C for 1 hour until the reaction was completed. The reaction solution was concentrated under reduced pressure, and the obtained crude product was purified and separated by C18 reverse phase column (mobile phase: acetonitrile: water = 70% ~ 95%, containing 0.5% FA) to give compound 3 (30.3 mg). LC-MS (ESI) [M+H] + : 588.2.

[0189] 1 H NMR (400 MHz, Methanol-d4) δ 8.39 (d, J = 3.3 Hz, 1H), 8.02 (d, J = 8.6 Hz, 1H), 7.97 - 7.93 (m, 1H), 7.89 (d, J = 2.1 Hz, 1H), 7.77 - 7.72 (m, 1H), 7.12 (t, J = 7.6 Hz, 1H), 4.95 - 4.92 (m, 1H), 4.67 (d, J = 8.9 Hz, 1H), 4.60 (s, 1H), 4.11 (dd, J = 2.5, 1.0 Hz, 1H), 3.78 (td, J = 6.1, 1.1 Hz, 1H), 3.64 - 3.57 (m, 2H), 2.33 (d, J = 2.1 Hz, 3H).

[0190] Example 4: Synthesis of compound 4

[0191] Step 1: Preparation of compound 4-1

[0192] Compound 1-1 (150 mg, CAS: 2305622-80-2) was dissolved in dichloromethane (5 mL) under nitrogen protection, 2,5-dichloroaniline (60.8 mg), pyridine (68.5 mg) and phosphorus oxychloride (48.7 mg) were added successively under stirring. The resulting reaction solution was stirred at 25 °C for 1 h until the reaction was completed. The reaction solution was concentrated under reduced pressure, and the obtained crude product was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain compound 4-1 (40 mg). LC-MS (ESI) [M+H] + : 663.2.

[0193] Step 2: Preparation of compound 4-2

[0194] Compound 4-1 (35 mg) was dissolved in dichloromethane (4 mL) under nitrogen protection, pyridine (40.9 mg) and phosphorus pentachloride (21.5 mg) were added successively. The resulting reaction solution was stirred at 70 °C for 3 h until the reaction was completed. The reaction solution was cooled to 25 °C and azidotrimethylsilane (8.2 mg) was added. The resulting reaction solution was stirred at 70 °C for 16 h until the reaction was completed. The reaction solution was cooled to 25 °C and saturated aqueous sodium bicarbonate solution (5 mL) was added to quench the reaction. The reaction solution was extracted with dichloromethane (3 mL x 2), and the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain compound 4-2 (30 mg). The crude product was used directly in the next reaction without purification. LC-MS (ESI) [M+H] + : 690.2.

[0195] Step 3: Preparation of compound 4-3

[0196] Compound 4-2 (30 mg) was dissolved in ammonia methanol solution (2 mL, 4 mol / L) under nitrogen protection. The resulting reaction solution was reacted at 25 °C for 2 h until the reaction was completed. The solvent was removed from the reaction solution by rotary evaporation under reduced pressure to obtain compound 4-3 (25 mg). LC-MS (ESI) [M+H] + : 646.2.

[0197] Step 4: Preparation of compound 4

[0198] Compound 4-3 (25 mg) was dissolved in trifluoroacetic acid (2 mL) under nitrogen protection. The resulting reaction solution was stirred at 25 °C for 1 h until the reaction was completed. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was prepared and purified by HPLC (column: Agilent 10Prep-C8 250x21.2mm; column temperature: 25 °C; mobile phase: water (0.1% FA)-acetonitrile; mobile phase acetonitrile ratio: 30%-50% in 9 min; flow rate: 30 ml / min) to obtain compound 4 (3.0 mg). LC-MS (ESI) [M+H]+ :558.2.

[0199] 1 H NMR (400 MHz, Methanol-d4) δ 8.54 (s, 1H), 7.82 (d, J = 2.2 Hz, 1H), 7.78 - 7.72 (m, 2H), 7.67 - 7.61 (m, 2H), 4.93 (dd, J = 10.6, 2.8 Hz, 2H), 4.69 (d, J = 9.1 Hz, 1H), 4.12 (dd, J = 2.7, 1.1 Hz, 1H), 3.82 (td, J = 6.0, 1.1 Hz, 1H), 3.71 - 3.58 (m, 2H).

[0200] Example 5: Synthesis of compound 5

[0201] Step 1: Preparation of compound 5-1

[0202] Under nitrogen protection, (2R,3R,4R,5R,6S)-2-(acetoxymethyl)-4-azido-6- cyanotetrahydro-2H-pyran-3,5-diyl bis-acetate (2.3 g, CAS: 2575614-08-1) and 1- bromo-2,3-difluoro-4-[2-(trimethylsilyl)ethynyl]benzene (1.9 g, CAS: 2491661-89-1) were dissolved in a mixed solvent of N,N-dimethylformamide (32 mL) and water (8 mL), copper sulfate pentahydrate (1.7 g) and vitamin C sodium salt (1.3 g) were added, after addition, the obtained reaction solution was stirred at 85 °C for 2 hours until the reaction was completed. Ethyl acetate (50 mL) was added to the reaction solution and stirred for 5 minutes to obtain a suspension, which was filtered through diatomite, the filtrate was poured into water (40 mL), extracted with ethyl acetate (50 mL x 2), the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (dichloromethane:methanol = 15:1) to obtain compound 5-1 (2 g). LC-MS (ESI) [M+H] + :557.2.

[0203] Step 2: Preparation of compound 5-2

[0204] Under nitrogen protection, compound 5-1 (2 g) was placed in a 10 mL sealed tube, hydrogen chloride methanol solution (30 mL, 4 mol / L) was added, after addition, the sealed tube was sealed, the obtained reaction solution was stirred at 65 °C for 18 hours until the reaction was completed. The reaction solution was concentrated to obtain compound 5-2 (1.67 g), which was used directly in the next step reaction without purification. LC-MS (ESI) [M+H] + :466.0.

[0205] Step 3: Preparation of compound 5-3

[0206] Compound 5-2 (1.7 g) and benzaldehyde dimethyl acetal (657.0 mg) were dissolved in acetonitrile under nitrogen protection, and methanesulfonic acid (414.9 mg) was added. After addition was completed, the resulting reaction solution was stirred at 25 °C for 16 hours until the reaction was completed. Triethylamine (436.8 mg) was added to quench the reaction, and the resulting reaction solution was stirred for 20 minutes. The resulting reaction solution was concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain compound 5-3 (1.25 g). LC-MS (ESI) [M+H] + : 554.0.

[0207] Step 4: Preparation of compound 5-4

[0208] Compound 5-3 (300 mg) was dissolved in a mixed solvent of methanol (3.5 mL) and tetrahydrofuran (3.5 mL) under nitrogen protection, and a solution of lithium hydroxide monohydrate (27.4 mg) in water (0.5 mL) was added. After addition was completed, the resulting reaction solution was stirred at 25 °C for 1 hour until the reaction was completed. The reaction solution was adjusted to neutral pH with dilute hydrochloric acid (1 mol / L), extracted with ethyl acetate (10 mL x 2), and the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 5-4 crude product (292 mg), which was directly used in the next step reaction without purification. LC-MS (ESI) [M+H] + : 538.0.

[0209] Step 5: Preparation of compound 5-5

[0210] Compound 5-4 (500 mg) was dissolved in dichloromethane (5 mL) under nitrogen protection, and pyridine (291 mg, 296.3 μL) and acetic anhydride (281.6 mg) were added. After addition was completed, the resulting reaction solution was stirred at 25 °C for 4 hours until the reaction was completed. The reaction solution was quenched with water, extracted with dichloromethane (5 mL x 2), and the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 5-5 crude product (534 mg), which was directly used in the next step reaction without purification. LC-MS (ESI) [M+H] + : 582.2.

[0211] Step 6: Preparation of compound 5-6

[0212] Compound 5-5 (100 mg) and 2-amino-4-chlorobenzotrifluoride (66.1 mg) were dissolved in dichloromethane (3 mL) under nitrogen protection, pyridine (66.8 mg) and phosphorus oxychloride (31.1 mg) were added successively at 0 °C, after addition, the obtained reaction solution was stirred at 0 °C for 1 hour until the reaction was completed. The reaction solution was directly separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain compound 5-6 (59 mg). LC-MS (ESI) [M+H] + : 759.2.

[0213] Step 7: Preparation of compound 5-7

[0214] Compound 5-6 (54 mg) was dissolved in dichloromethane (4 mL) under nitrogen protection, pyridine (55.3 mg) and phosphorus pentachloride (43.6 mg) were added successively, the reaction solution was stirred at 65 °C for 2 hours, then cooled to 25 °C, azidotrimethylsilane (40.2 mg) was added, after addition, the obtained reaction solution was stirred at 25 °C for 18 hours until the reaction was completed. The reaction solution was cooled to 0 °C, saturated sodium bicarbonate aqueous solution (3 mL) was added for quenching, extracted with dichloromethane (10 mL x 2), the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain compound 5-7 (55 mg), which was used directly in the next step reaction without purification. LC-MS (ESI) [M+H] + : 782.2.

[0215] Step 8: Preparation of compound 5-8

[0216] Compound 5-7 (52 mg) was dissolved in a mixed solvent of methanol (0.3 mL) and tetrahydrofuran (0.3 mL) under nitrogen protection, the obtained mixture was cooled to 0 °C, a solution of lithium hydroxide (3.2 mg) in water (0.1 mL) was added slowly dropwise, after addition, the obtained reaction solution was stirred at 0 °C for 1 hour until the reaction was completed. The reaction solution was concentrated under reduced pressure to obtain compound 5-8 (49 mg), which was used directly in the next step reaction without purification. LC-MS (ESI) [M+H] + : 742.2.

[0217] Step 9: Preparation of compound 5

[0218] Compound 5-8 (48 mg) was dissolved in trifluoroacetic acid (1 mL) at 0 °C under nitrogen protection. The resulting reaction solution was stirred at 0 °C for 1 h until the reaction was completed. The reaction solution was concentrated under reduced pressure. The obtained crude product was purified by HPLC (separation conditions: column: Agilent 10 Prep-C8 250x21.2mm; column temperature: 25 °C; mobile phase: water (0.1% FA) - acetonitrile; mobile phase acetonitrile ratio 30%-50% in 9 min; flow rate 30 ml / min) to give compound 5 (9.14 mg). LC-MS (ESI) [M+H] + : 654.2.

[0219] 1 H NMR (400 MHz, Methanol-d4) δ 8.49 (d, J = 3.4 Hz, 1H), 8.07 (d, J = 8.6 Hz, 1H), 8.01 - 7.97 (m, 1H), 7.94 - 7.86 (m, 2H), 7.60 - 7.55 (m, 1H), 5.01 - 4.97 (m, 1H), 4.94 (s, 1H), 4.72 (d, J = 9.0 Hz, 1H), 4.15 (dd, J = 2.5, 1.0 Hz, 1H), 3.82 (td, J = 6.1, 1.1 Hz, 1H), 3.68 - 3.60 (m, 2H).

[0220] Example 6: Synthesis of compound 6

[0221] Step 1: Preparation of compound 6-1

[0222] Compound 5-3 (177 mg) was dissolved in THF (5 mL) under nitrogen protection, cooled to 0 °C, and sodium hydride (25.4 mg, 60%) was added and stirred for 10 min. Methyl iodide (64.8 mg) was added, and the resulting reaction solution was stirred at 0 °C for 4 h until the reaction was completed. Water (2 mL) was added under ice bath cooling to quench, and extracted with ethyl acetate (5 mL x 2). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give compound 6-1 crude (175 mg), which was used directly in the next step without purification. LC-MS (ESI) [M+H] + : 554.0.

[0223] Step 2: Preparation of compound 6-2

[0224] Compound 6-1 (125 mg) and 3-amino-5-chlorobenzonitrile (51.8 mg) were dissolved in dichloromethane (3 mL) under nitrogen protection, pyridine (89.5 mg) and phosphorus oxychloride (41.6 mg) were added successively at 0 °C, after addition, the obtained reaction solution was stirred at 0 °C for 2 hours until the reaction was completed. The reaction solution was directly separated and purified by silica gel column chromatography (dichloromethane:methanol = 20:1) to obtain compound 6-2 (81 mg). LC-MS (ESI) [M+H] + : 686.0.

[0225] Step 3: Preparation of compound 6-3

[0226] Compound 6-2 (40 mg) was dissolved in dichloromethane (1 mL) under nitrogen protection, pyridine (45.1 mg) and phosphorus pentachloride (35.7 mg) were added successively, the reaction solution was heated to 70 °C and stirred for 2 hours, then cooled to 25 °C and azidotrimethylsilane (32.9 mg) was added, after addition, the obtained reaction solution was stirred at 25 °C for 16 hours until the reaction was completed. The reaction was quenched by adding saturated aqueous sodium bicarbonate solution under ice bath cooling, extracted with dichloromethane (4 mL x 2), the obtained organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain compound 6-3 (41 mg), which was directly used in the next step reaction without purification. LC-MS (ESI) [M+H] + : 711.0.

[0227] Step 4: Preparation of compound 6

[0228] Compound 6-3 (35 mg) was dissolved in trifluoroacetic acid (0.5 mL) at 0 °C under nitrogen protection, the obtained reaction solution was stirred at 0 °C for 1 hour until the reaction was completed. The reaction solution was concentrated under reduced pressure, the obtained crude product was prepared and purified by HPLC (separation condition: column: Agilent 10Prep-C8 250x21.2mm; column temperature: 25 °C; mobile phase: water (0.1% FA)-acetonitrile; mobile phase acetonitrile ratio 30%-50% in 9 min; flow rate 30 ml / min) to obtain compound 6 (6.6 mg). LC-MS (ESI) [M+H] + : 625.0.

[0229] 1H NMR (400 MHz, Methanol-d4) δ 8.57 (d, J = 3.4 Hz, 1H), 8.18 - 8.16 (m, 1H), 8.08 (t, J = 1.6 Hz, 1H), 7.80 - 7.76 (m, 1H), 7.49 - 7.45 (m, 1H), 5.01 (dd, J = 10.3, 2.9 Hz, 1H), 4.70 (d, J = 10.1 Hz, 1H), 4.07 - 4.05 (m, 1H), 3.89 - 3.85 (m, 1H), 3.72 - 3.67 (m, 1H), 3.63 - 3.59 (m, 1H), 2.88 (s, 3H).

[0230] Example 7: Synthesis of compound 7

[0231] Step 1: Preparation of compound 7-1

[0232] Methyl (4aR,6R,7R,8R,8aR)-7-hydroxy-2-phenyl-8-(4-(3,4,5-trifluorophenyl)-1H-1,2,3- triazol-1-yl)hexahydropyrano[3,2-d][1,3]dioxole-6-carboxylate (1 g, CAS: 2305621-15-0) was dissolved in tetrahydrofuran (20 mL) under nitrogen protection, sodium hydride (244.2 mg, 60%) was added, the mixture was stirred at 25 °C for 20 minutes, 2-(trimethylsilyl)ethoxymethyl chloride (678.5 mg) was added, and the reaction was stirred at 25 °C for 3 hours until the reaction was completed. The reaction solution was poured into water (30 ml) to quench, extracted with acetic acid (20 ml x 3), the organic phase was combined, washed with saturated brine (20 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give compound 7-1 (1 g). LC-MS (ESI) [M+H] + : 622.3.

[0233] Step 2: Preparation of compound 7-2

[0234] Compound 7-1 (1 g) was dissolved in a mixed solvent of tetrahydrofuran (9 mL), methanol (3 mL) and water (3 mL) under nitrogen protection, and lithium hydroxide monohydrate (202.5 mg) was added. The reaction solution was reacted at 25 °C for 1 hour until the reaction was completed. Water (10 ml) was added to the reaction solution, and the pH was adjusted to 4-5 with dilute hydrochloric acid aqueous solution (1 mol / L). The organic phase was extracted with ethyl acetate (5 ml x 3), washed with saturated brine (5 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give compound 7-2 (950 mg). LC-MS (ESI) [M+H] + : 608.2.

[0235] Step 3: Preparation of compound 7-3

[0236] Compound 7-2 (150 mg) was dissolved in dichloromethane (5 mL) under nitrogen protection, 2-amino-4-chlorobenzotrifluoride (58.0 mg), pyridine (58.6 mg), and phosphorus oxychloride (41.6 mg) were added successively under stirring. The reaction was carried out at 25 °C for 1 hour under nitrogen protection. LCMS showed that the starting material was consumed and the product was generated. The reaction solution was concentrated, and then was subjected to silica gel column chromatography (petroleum ether: ethyl acetate = 1:1) to give compound 7-3 (65 mg). LC-MS (ESI) [M+H] + : 785.3.

[0237] Step 4: Preparation of compound 7-4

[0238] Compound 7-3 (65 mg) was dissolved in dichloromethane (5 mL) under nitrogen protection, pyridine (64.2 mg) and phosphorus pentachloride (33.8 mg) were added successively. The reaction was carried out at 70 °C for 2 hours under stirring. After the reaction solution was cooled to 25 °C, azidotrimethylsilane (12.8 mg) was added. The reaction was carried out at 70 °C for 18 hours under stirring. The reaction was quenched by adding saturated aqueous sodium bicarbonate solution (5 mL), and then was extracted with dichloromethane (3 mL x 2). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give compound 7-4 (30 mg). LC-MS (ESI) [M+H] + : 810.2.

[0239] Step 5: Preparation of compound 7

[0240] Compound 7-4 (30 mg) was dissolved in trifluoroacetic acid (2 mL) under nitrogen protection. The reaction was carried out at 25 °C for 1 hour. The reaction solution was concentrated under reduced pressure. The obtained crude product was separated and purified by HPLC (column: Agilent 10 Prep-C8 250 x 21.2 mm; column temperature: 25 °C; mobile phase: water (0.1% FA) - acetonitrile; acetonitrile proportion in mobile phase: 30% - 50% in 9 min; flow rate: 30 ml / min) to give compound 7 (3.7 mg). LC-MS (ESI) [M+H] + : 592.0.

[0241] 1H NMR (400 MHz, Methanol-d4) δ 8.57 (s, 1H), 8.04 (d, J = 8.6 Hz, 1H), 7.96 (ddd, J = 8.6, 2.1, 0.9 Hz, 1H), 7.90 (s, 1H), 7.69 - 7.62 (m, 2H), 4.93 (d, J = 3.8 Hz, 2H), 4.70 - 4.61 (m, 1H), 4.12 (q, J = 1.2 Hz, 1H), 3.79 (td, J = 6.1, 1.1 Hz, 1H), 3.62 (dd, J = 6.1, 3.0 Hz, 2H).

[0242] Example 8: Synthesis of compound 8

[0243] Step 1: Preparation of compound 8-1

[0244] Compound 3-4 (250 mg) was dissolved in tetrahydrofuran (10 mL) under nitrogen protection, sodium hydride (36.9 mg) was added and the reaction was stirred for 1 hour, methyl iodide (145.6 mg) was added, after addition, the resulting reaction solution was stirred at 25 °C for 16 hours until the reaction was completed. The reaction solution was concentrated under reduced pressure to remove the organic solvent, and the remaining aqueous phase was adjusted to neutral pH with dilute hydrochloric acid (1 mol / L), and separated and purified with a C18 reverse column (mobile phase: acetonitrile: water = 35% to 90%, containing 0.1% FA) to give compound 8-1 (115 mg). LC-MS (ESI) [M+H] + : 488.2.

[0245] Step 2: Preparation of compound 8-2

[0246] Compound 8-1 (50 mg) and 2-amino-4-chlorobenzotrifluoride (39.7 mg) were dissolved in dichloromethane (3 mL) under nitrogen protection, the resulting reaction solution was cooled to 0 °C, pyridine (40.2 mg) and phosphorus oxychloride (23.4 mg) were added in turn, after addition, the resulting reaction solution was stirred at 0 °C for 1 hour until the reaction was completed. The reaction solution was directly separated and purified by silica gel column chromatography (dichloromethane:methanol = 15:1) to give compound 8-2 (60 mg). LC-MS (ESI) [M+H] + : 665.2.

[0247] Step 3: Preparation of compound 8-3

[0248] Compound 8-2 (55 mg) was dissolved in dichloromethane (8 mL) under nitrogen protection, pyridine (64.8 mg), phosphorus pentachloride (51.2 mg) were added successively, the reaction was stirred at 65 °C for 1 h, then cooled to 25 °C and azidotrimethylsilane (37.7 mg, 327.5 μmol) was added, after addition, the resulting reaction solution was stirred at 65 °C for 4 h until the reaction was completed. The reaction solution was quenched with saturated sodium bicarbonate solution (0.5 mL) under ice bath cooling, extracted with dichloromethane (5 mL x 2), the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give compound 8-3 (57 mg), which was used directly in the next step without purification. LC-MS (ESI) [M+H] + : 690.2.

[0249] Step 4: Preparation of compound 8

[0250] Compound 8-3 (50 mg) was dissolved in trifluoroacetic acid (2 mL) at 0 °C under nitrogen protection, the resulting reaction solution was stirred at 0 °C for 1 h until the reaction was completed. The reaction solution was concentrated under reduced pressure to give a crude product, which was separated and purified by C18 reverse phase column (mobile phase: acetonitrile: water = 70% to 95%, containing 0.5% FA) to give compound 8 (35.6 mg). LC-MS (ESI) [M+H] + : 602.2.

[0251] 1 H NMR (400 MHz, Methanol-d4) δ 8.59 (d, J = 3.3 Hz, 1H), 8.05 (d, J = 8.5 Hz, 1H), 8.01 - 7.90 (m, 2H), 7.77 (ddd, J = 8.4, 6.6, 1.9 Hz, 1H), 7.18 - 7.12 (m, 1H), 5.03 (dd, J = 10.3, 2.9 Hz, 1H), 4.75 (d, J = 10.0 Hz, 1H), 4.67 (d, J = 9.3 Hz, 1H), 4.11 (dd, J = 2.9, 1.0 Hz, 1H), 3.78 - 3.73 (m, 1H), 3.68 - 3.58 (m, 2H), 3.02 (s, 3H), 2.35 (d, J = 2.1 Hz, 3H).

[0252] Example 9: Synthesis of compound 9

[0253] Step 1: Preparation of compound 9-1

[0254] Compound 5-5 (100 mg) and 3,5-dichloroaniline (32.8 mg) were dissolved in dichloromethane (1 mL) under nitrogen protection, pyridine (66.8 mg) and phosphorus oxychloride (31.1 mg) were added successively at 0 °C, after addition, the obtained reaction solution was stirred at 0 °C for 1 h until the reaction was completed. The reaction solution was directly separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain compound 9-1 (54 mg). LC-MS (ESI) [M+H] + : 725.0.

[0255] Step 2: Preparation of compound 9-2

[0256] Compound 9-1 (50 mg) was dissolved in dichloromethane (3 mL) under nitrogen protection, pyridine (42.8 mg) and phosphorus pentachloride (28.2 mg) were added successively, the reaction solution was stirred at 65 °C for 2 h, after the reaction solution was cooled to 25 °C, azidotrimethylsilane (31.2 mg) was added, after addition, the obtained reaction solution was stirred at 25 °C for 18 h until the reaction was completed. The reaction solution was cooled to 0 °C, saturated aqueous sodium bicarbonate solution (1 mL) was added for quenching, extracted with dichloromethane (5 mL x 2), the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain compound 9-2 (51 mg), which was used directly in the next reaction without purification. LC-MS (ESI) [M+H] + : 750.0.

[0257] Step 3: Preparation of compound 9-3

[0258] Compound 9-2 (50 mg) was dissolved in a mixed solvent of methanol (0.5 mL) and tetrahydrofuran (0.5 mL) under nitrogen protection, after cooling to 0 °C, a solution of lithium hydroxide (3.2 mg) in water (0.2 mL) was added slowly dropwise, after addition, the obtained reaction solution was stirred at 0 °C for 1 h until the reaction was completed. The reaction solution was concentrated under reduced pressure to obtain compound 9-3 (47 mg), which was used directly in the next reaction without purification. LC-MS (ESI) [M+H] + : 708.2.

[0259] Step 4: Preparation of compound 9

[0260] Compound 9-3 (47 mg) was dissolved in trifluoroacetic acid (1 mL) at 0 °C under nitrogen protection. The resulting reaction solution was stirred at 0 °C for 1 h until the reaction was completed. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by HPLC (column: Agilent 10 Prep-C8 250x21.2mm; column temperature: 25 °C; mobile phase: water (0.1% FA) - acetonitrile; mobile phase acetonitrile ratio: 30%-50% in 9 min; flow rate: 30 ml / min) to obtain compound 9 (10.5 mg). LC-MS (ESI) [M+H] + : 620.0.

[0261] 1 H NMR (400 MHz, Methanol-d4) d 8.36 (d, J = 3.4 Hz, 1H), 7.82 - 7.76 (m, 3H), 7.73 (t, J = 1.9 Hz, 1H), 7.45 (td, J = 6.4, 3.1 Hz, 1H), 4.95 (dd, J = 10.6, 2.8 Hz, 1H), 4.87 (d, J = 9.3 Hz, 1H), 4.74 (s, 1H), 4.09 (d, J = 2.8 Hz, 1H), 3.90 (dd, J = 7.3, 4.6 Hz, 1H), 3.75 - 3.69 (m, 1H), 3.62 (dd, J = 11.8, 4.5 Hz, 1H).

[0262] Example 10: Synthesis of compound 10

[0263] Step 1: Preparation of compound 10-1

[0264] Compound (2R,3R,4R,5R,6S)-2-(acetoxymethyl)-4-azido-6-cyanotetrahydro-2H-pyran-3,5-diyl diacetate (500 mg, CAS: 2575614-08-1) was dissolved in acetonitrile (10 mL) under nitrogen protection. 1-ethynyl-3-fluorobenzene (229.5 mg), cuprous iodide (279.8 mg) and N,N-diisopropylethylamine (569.7 mg) were added in turn. After addition, the reaction was stirred at 60 °C for 1 h until the reaction was completed. The reaction solution was diluted with ethyl acetate (20 mL) to obtain a suspension, which was filtered through diatomite. The filter cake was eluted with ethyl acetate, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 6:1) to obtain compound 10-1 (620 mg). LC-MS (ESI) [M+H] + : 461.2.

[0265] Step 2: Preparation of compound 10-2

[0266] Compound 10-1 (620 mg) was dissolved in 10 mL sealed tube, hydrogen chloride methanol solution (5 mL, 4 mol / L) was added, the resulting reaction solution was stirred at 65 °C for 5 hours until the reaction was completed. The reaction solution was concentrated under reduced pressure to give compound 10-2 (494 mg), which was used in the next step without purification. LC-MS (ESI) [M+H] + : 368.2.

[0267] Step 3: Preparation of compound 10-3

[0268] Compound 10-2 (494 mg) and benzaldehyde dimethyl acetal (266.1 mg) were dissolved in acetonitrile (5 mL) under nitrogen protection, methyl sulfonic acid (193.9 mg) was added, the resulting reaction solution was stirred at 25 °C for 16 hours until the reaction was completed. Triethylamine (204.1 mg) was added to quench the reaction, and after stirring for 20 minutes, the reaction solution was concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1) to give compound 10-3 (600 mg). LC-MS (ESI) [M+H] + : 456.2.

[0269] Step 4: Preparation of compound 10-4

[0270] Compound 10-3 (120 mg) was dissolved in tetrahydrofuran (3 mL) under nitrogen protection, sodium hydride (12.5 mg) was added, and stirred at 25 °C for 10 minutes, 2-(trimethylsilyl)ethoxymethyl chloride (87.0 mg) was added, the resulting reaction solution was stirred at 25 °C for 16 hours until the reaction was completed. The reaction solution was quenched with water, extracted with ethyl acetate (10 mL x 2), the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give compound 10-4 (153 mg), which was used in the next step without purification. LC-MS (ESI) [M+H] + : 586.3.

[0271] Step 5: Preparation of compound 10-5

[0272] Compound 10-4 (145 mg) was dissolved in a mixture solvent of methanol (0.3 mL) and tetrahydrofuran (0.3 mL) under nitrogen protection, cooled to 0 °C, and a solution of lithium hydroxide (11.9 mg) in water (0.1 mL) was added. After the addition, the resulting reaction solution was stirred at 0 °C for 1 hour until the reaction was completed. The reaction solution was concentrated under reduced pressure to remove the organic solvent, and the remaining aqueous solution was adjusted to neutral pH with dilute hydrochloric acid (1 mol / L). The resulting solution was separated and purified by a C18 reverse phase column (mobile phase: acetonitrile: water = 30% to 50%, containing 0.5% FA) to obtain compound 10-5 (68 mg). LC-MS (ESI) [M+H] + : 572.2.

[0273] Step 6: Preparation of compound 10-6

[0274] Compound 10-5 (68 mg) and 2-amino-4-chlorobenzotrifluoride (27.6 mg) were dissolved in dichloromethane (3 mL) under nitrogen protection, cooled to 0 °C, and pyridine (55.9 mg) and phosphorus oxychloride (21.7 mg) were added in sequence. After the addition, the resulting reaction solution was stirred at 0 °C for 1 hour until the reaction was completed. The reaction solution was directly separated and purified by silica gel column chromatography (dichloromethane:methanol = 15:1) to obtain compound 10-6 (83 mg). LC-MS (ESI) [M+H] + : 749.4.

[0275] Step 7: Preparation of compound 10-7

[0276] Compound 10-6 (75 mg) was dissolved in dichloromethane (3 mL) under nitrogen protection, and pyridine (79.2 mg) and phosphorus pentachloride (62.5 mg) were added in sequence. The reaction solution was warmed to 65 °C and stirred for 2 hours, and then cooled to 25 °C. Azidotrimethylsilane (46.1 mg) was added, and the resulting reaction solution was stirred at 25 °C for 16 hours until the reaction was completed. The reaction solution was quenched with saturated sodium bicarbonate solution under ice bath cooling, and extracted with dichloromethane (5 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 10-7 (77.5 mg), which was used directly in the next step without purification. LC-MS (ESI) [M+H] + : 774.4.

[0277] Step 8: Preparation of compound 10

[0278] Compound 10-7 (70 mg) was dissolved in dichloromethane (1 mL) under nitrogen protection, trifluoroacetic acid (1 mL) was added at 0 °C, after addition, the resulting reaction solution was stirred at 0 °C for 1 hour until the reaction was completed. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was separated and purified by HPLC (column: Agilent 10 Prep-C8 250x21.2mm; column temperature: 25 °C; mobile phase: water (0.1% FA)-acetonitrile; mobile phase acetonitrile ratio 30%-50% in 9 min; flow rate 30 ml / min) to obtain compound 10 (20.52 mg). LC-MS (ESI) [M+H] + : 556.2.

[0279] 1 H NMR (400 MHz, Methanol-d4) δ 8.50 (s, 1H), 8.03 (d, J = 8.6 Hz, 1H), 7.97-7.92 (m, 1H), 7.89 (s, 1H), 7.65 (dt, J = 7.8, 1.2 Hz, 1H), 7.59 (ddd, J = 10.1, 2.6, 1.5 Hz, 1H), 7.47-7.41 (m, 1H), 7.09-7.04 (m, 1H), 4.91 (d, J = 2.9 Hz, 2H), 4.65 (d, J = 8.9 Hz, 1H), 4.11 (q, J = 1.1 Hz, 1H), 3.77 (td, J = 6.1, 1.1 Hz, 1H), 3.65-3.57 (m, 2H).

[0280] Example 11: Synthesis of compound 11

[0281] Step 1: Preparation of compound 11-1

[0282] Compound 3-6 (75 mg) and m-chloroaniline (18.8 mg) were dissolved in dichloromethane (3 mL) under nitrogen protection, the resulting mixture was cooled to 0 °C, pyridine (48.6 mg) and phosphorus oxychloride (20.7 mg) were added in turn, after addition, the resulting reaction solution was stirred at 0 °C for 1 hour until the reaction was completed. The reaction solution was directly purified by silica gel column chromatography (dichloromethane:methanol = 15:1) to obtain compound 11-1 (84 mg). LC-MS (ESI) [M+H] + : 713.3.

[0283] Step 2: Preparation of compound 11-2

[0284] Compound 11-1 (75 mg) and pyridine (82.3 mg) were dissolved in dichloromethane (8 mL) under nitrogen protection, phosphorus pentachloride (65.0 mg) was added and the reaction was stirred at 65 °C for 1 hour. After the reaction was completed, the reaction was cooled to 25 °C, and azidotrimethylsilane (48.0 mg) was added. The resulting reaction solution was stirred at 65 °C for 16 hours until the reaction was completed. The reaction solution was quenched with saturated sodium bicarbonate solution (0.5 mL) under ice bath cooling, extracted with dichloromethane (5 mL x 2), and the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give compound 11-2 (77 mg). The crude product was used directly in the next reaction without purification. LC-MS (ESI) [M+H] + 738.3.

[0285] Step 3: Preparation of compound 11

[0286] Compound 11-2 (70 mg) was dissolved in trifluoroacetic acid (1 mL) under nitrogen protection, and the reaction was stirred at 0 °C for 1 hour until the reaction was completed. The reaction solution was concentrated under reduced pressure, and the obtained crude product was separated and purified by C18 reverse phase column (mobile phase: acetonitrile: water = 70% to 95%, containing 0.5% FA) to give compound 11 (29.77 mg). LC-MS (ESI) [M+H] + 520.2.

[0287] 1 H NMR (400 MHz, Methanol-d4) δ 8.39 (d, J = 3.3 Hz, 1H), 7.88 (t, J = 2.0 Hz, 1H), 7.77 - 7.64 (m, 4H), 7.12 (t, J = 7.5 Hz, 1H), 4.99 (s, 1H), 4.79 - 4.75 (m, 1H), 4.60 (s, 1H), 4.16 (s, 1H), 3.95 (dd, J = 7.7, 4.6 Hz, 1H), 3.79 (dd, J = 11.7, 7.3 Hz, 1H), 3.70 (dd, J = 11.7, 4.6 Hz, 1H), 2.33 (d, J = 2.2 Hz, 3H).

[0288] Example 12: Synthesis of compound 12

[0289] Step 1: Preparation of compound 12-1

[0290] Compound 5-5 (100 mg) and 3-amino-5-chlorobenzonitrile (51.5 mg) were dissolved in dichloromethane (3 mL) under nitrogen protection, pyridine (66.8 mg) and phosphorus oxychloride (38.8 mg) were added successively at 0 °C, after addition, the obtained reaction solution was stirred at 0 °C for 1 hour until the reaction was completed. The reaction solution was directly purified by silica gel column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain compound 12-1 (45 mg). LC-MS (ESI) [M+H] + : 716.2.

[0291] Step 2: Preparation of compound 12-2

[0292] Compound 12-1 (40 mg) and pyridine (43.4 mg) were dissolved in dichloromethane (1 mL) under nitrogen protection, phosphorus pentachloride (34.3 mg) was added, the obtained reaction solution was stirred at 75 °C for 1 hour, then cooled to 25 °C, azidotrimethylsilane (12.6 mg) was added, after addition, the obtained reaction solution was stirred at 25 °C for 16 hours until the reaction was completed. The reaction solution was concentrated under reduced pressure to obtain compound 12-2 (40 mg), which was directly used in the next reaction without purification. LC-MS (ESI) [M+H] + : 741.2.

[0293] Step 3: Preparation of compound 12-3

[0294] Compound 12-2 (40 mg) was dissolved in a mixed solvent of methanol (0.5 mL) and tetrahydrofuran (0.5 mL) under nitrogen protection, cooled to 0 °C, and a solution of lithium hydroxide (2.6 mg) in water (0.2 mL) was added, after addition, the obtained reaction solution was stirred at 0 °C for 3 hours until the reaction was completed. The reaction solution was concentrated under reduced pressure at low temperature to remove the organic solvent, the obtained aqueous solution was adjusted to pH 6 with dilute hydrochloric acid (1 mol / L) at 0 °C, extracted with ethyl acetate (5 mL x 2), the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 12-3 (38 mg), which was directly used in the next reaction without purification. LC-MS (ESI) [M+H] + : 699.2.

[0295] Step 4: Preparation of compound 12

[0296] Compound 12-3 (40 mg) was dissolved in trifluoroacetic acid (0.5 mL) at 0 °C under nitrogen protection. The resulting reaction solution was stirred at 0 °C for 1 h until the reaction was completed. The reaction solution was concentrated under reduced pressure. The obtained crude product was purified by HPLC preparation (column: Agilent 10 Prep-C8 250x21.2 mm; column temperature: 25 °C; mobile phase: water (0.1% FA) - acetonitrile; mobile phase acetonitrile ratio 30% - 50% in 9 min; flow rate 30 mL / min) to give compound 12 (1.37 mg). LC-MS (ESI) [M+H] + : 611.2.

[0297] 1 H NMR (400 MHz, Methanol-d4) δ 8.34 (d, J = 3.4 Hz, 1H), 8.15 (dt, J = 8.7, 1.9 Hz, 2H), 8.09 - 8.06 (m, 1H), 7.78 (ddd, J = 8.9, 6.8, 2.1 Hz, 1H), 7.45 (td, J = 4.1, 2.1 Hz, 1H), 4.96 - 4.92 (m, 1H), 4.82 - 4.80 (m, 2H), 4.08 (dd, J = 2.9, 1.0 Hz, 1H), 3.92 - 3.87 (m, 1H), 3.73 - 3.67 (m, 1H), 3.62 (dd, J = 11.8, 4.4 Hz, 1H).

[0298] Example 13: Synthesis of compound 13

[0299] Step 1: Preparation of compound 13-1

[0300] Compound 8-1 (54 mg) and m-chloroaniline (28.0 mg) were dissolved in dichloromethane (3 mL) under nitrogen protection, cooled to 0 °C, and pyridine (43.4 mg) and phosphorus oxychloride (25.2 mg) were added successively under stirring. After addition, the resulting reaction solution was stirred at 0 °C for 1 h until the reaction was completed. The reaction solution was directly separated and purified by silica gel column chromatography (dichloromethane:methanol = 15:1) to give compound 13-1 (62 mg). LC-MS (ESI) [M+H] + : 597.2.

[0301] Step 2: Preparation of compound 13-2

[0302] Compound 13-1 (57 mg) and pyridine (74.8 mg) were dissolved in dichloromethane (8 mL) under nitrogen protection, phosphorus pentachloride (59.1 mg) was added and the reaction was stirred at 65 °C for 1 hour, then cooled to 25 °C, azidotrimethylsilane (43.6 mg) was added, after addition, the resulting reaction solution was warmed to 65 °C and stirred for 4 hours until the reaction was completed. The reaction solution was cooled in an ice bath and quenched with saturated sodium bicarbonate solution (0.5 mL), extracted with dichloromethane (5 mL x 2), the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give compound 13-2 (59 mg), which was used directly in the next step without purification. LC-MS (ESI) [M+H] + : 622.2.

[0303] Step 3: Preparation of compound 13

[0304] Compound 13-2 (53 mg) was dissolved in trifluoroacetic acid (1 mL) at 0 °C under nitrogen protection, the resulting reaction solution was cooled to 0 °C and stirred for 1 hour until the reaction was completed. The reaction solution was concentrated under reduced pressure to give a crude product, which was purified by C18 reverse phase column (mobile phase: acetonitrile: water = 70% to 95%, containing 0.5% FA) to give compound 13 (16.3 mg). LC-MS (ESI) [M+H] + : 534.2.

[0305] 1 H NMR (400 MHz, Methanol-d4) δ 8.59 (d, J = 3.3 Hz, 1H), 7.89 (t, J = 2.0 Hz, 1H), 7.82 - 7.75 (m, 2H), 7.74 - 7.67 (m, 2H), 7.15 (t, J = 7.5 Hz, 1H), 5.09 (dd, J = 10.0, 2.9 Hz, 1H), 4.78 (s, 1H), 4.62 (s, 1H), 4.17 - 4.15 (m, 1H), 3.96 - 3.93 (m, 1H), 3.81 (dd, J = 11.7, 7.4 Hz, 1H), 3.71 (dd, J = 11.7, 4.5 Hz, 1H), 2.95 (s, 3H), 2.35 (d, J = 2.1 Hz, 3H).

[0306] Example 14: Synthesis of compound 14

[0307] Step 1: Preparation of compound 14-1

[0308] Under nitrogen protection, compound 5-5 (100 mg) and 3,4-dichloroaniline (32.8 mg) were dissolved in dichloromethane (1 mL). Pyridine (66.8 mg) and phosphorus oxychloride (31.1 mg) were added sequentially at 0 °C. After the addition was complete, the reaction mixture was stirred at 0 °C for 1 hour until the reaction was complete. The reaction mixture was then purified directly by silica gel column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain compound 14-1 (50 mg). LC-MS (ESI) [M+H] + :725.0.

[0309] Step 2: Preparation of compound 14-2

[0310] Under nitrogen protection, compound 14-1 (45 mg) was dissolved in dichloromethane (1 mL), followed by the addition of pyridine (48.2 mg) and phosphorus pentachloride (25.4 mg). The reaction mixture was stirred at 70 °C for 2 hours. The temperature was then lowered to 25 °C, and azidotrimethylsilane (9.6 mg) was added. After the addition was complete, the reaction mixture was stirred at 25 °C for 18 hours until the reaction was complete. The reaction was quenched by adding saturated sodium bicarbonate aqueous solution (1 mL) to the reaction mixture at 0 °C. The mixture was extracted with dichloromethane (10 mL × 2). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 14-2 (46 mg). The crude product yield was 100%, and it could be used directly in the next reaction without purification. LC-MS (ESI) [M+H] + :750.0.

[0311] Step 3: Preparation of compound 14-3

[0312] Under nitrogen protection, compound 14-2 (45 mg) was dissolved in a mixed solvent of methanol (0.5 mL) and tetrahydrofuran (0.5 mL). The resulting mixture was cooled to 0 °C, and a solution of lithium hydroxide (2.9 mg) in water (0.2 mL) was slowly added dropwise with stirring. After the addition was complete, the reaction mixture was stirred at 0 °C for 2 hours until the reaction was complete. The reaction mixture was concentrated under reduced pressure to obtain compound 14-3 (42 mg). This crude product can be used directly in the next reaction without purification. LC-MS (ESI) [M+H] + :708.0.

[0313] Step 4: Preparation of Compound 14

[0314] Compound 14-3 (40 mg) was dissolved in trifluoroacetic acid (1 mL) under nitrogen protection, and the reaction was stirred at 0 °C for 2 hours until completion. The reaction solution was concentrated under reduced pressure, and the obtained crude product was purified by HPLC preparation (column: Agilent 10 Prep-C8 250x21.2mm; column temperature: 25 °C; mobile phase: water (0.1% FA) - acetonitrile; mobile phase acetonitrile ratio 30%-50% in 9 min; flow rate 30 ml / min) to obtain compound 14 (5.50 mg). LC-MS (ESI) [M+H] + : 620.0.

[0315] 1 H NMR (400 MHz, Methanol-d4) δ 8.37 (d, J = 3.4 Hz, 1H), 7.98 (d, J = 2.4 Hz, 1H), 7.81 - 7.75 (m, 2H), 7.68 (dd, J = 8.6, 2.4 Hz, 1H), 7.45 (ddd, J = 8.5, 6.3, 2.0 Hz, 1H), 4.97 - 4.87 (m, 2H), 4.71 (dd, J = 8.4, 0.8 Hz, 1H), 4.08 (dd, J = 2.5, 1.0 Hz, 1H), 3.88 (ddd, J = 7.4, 4.5, 1.1 Hz, 1H), 3.71 (dd, J = 11.7, 7.4 Hz, 1H), 3.62 (dd, J = 11.7, 4.5 Hz, 1H).

[0316] Example 15: Synthesis of compound 15

[0317] Step 1: Preparation of compound 15-1

[0318] Compound 5-5 (100 mg) and m-amino benzonitrile (39.9 mg) were dissolved in dichloromethane (3 mL) under nitrogen protection, and pyridine (66.8 mg) and phosphorus oxychloride (38.8 mg) were added successively under stirring at 0 °C. After addition, the obtained reaction solution was stirred at 0 °C for 1 hour until completion. The reaction solution was directly purified by silica gel column chromatography (petroleum ether: ethyl acetate = 3: 1) to obtain compound 15-1 (57 mg). LC-MS (ESI) [M+H] + : 682.2.

[0319] Step 2: Preparation of compound 15-2

[0320] Compound 15-1 (49 mg) and pyridine (55.8 mg) were dissolved in dichloromethane (1 mL) under nitrogen protection, phosphorus pentachloride (44.1 mg) was added, the resulting reaction solution was warmed to 75 °C and stirred for 1 hour until the reaction was completed, then cooled to 25 °C, azidotrimethylsilane (16.3 mg) was added, after addition, the resulting reaction solution was stirred at 25 °C for 16 hours until the reaction was completed. The reaction solution was concentrated under reduced pressure to obtain compound 15-2 (50 mg), which was used directly in the next step without purification. LC-MS (ESI) [M+H] + : 707.2.

[0321] Step 3: Preparation of compound 15-3

[0322] Compound 15-2 (49 mg) was dissolved in a mixed solvent of methanol (1 mL) and tetrahydrofuran (1 mL) under nitrogen protection, a solution of lithium hydroxide (3.3 mg) in water (0.3 mL) was added, after addition, the resulting reaction solution was stirred at 0 °C for 3 hours until the reaction was completed. The reaction solution was concentrated under reduced pressure to remove the organic solvent, the resulting aqueous solution was adjusted to pH 6 with dilute hydrochloric acid (1 mol / L) at 0 °C, extracted with ethyl acetate (5 mL x 2), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain compound 15-3 (46 mg), which was used directly in the next step without purification. LC-MS (ESI) [M+H] + : 663.2.

[0323] Step 4: Preparation of compound 15

[0324] Compound 15-3 (46 mg) was dissolved in trifluoroacetic acid (1 mL) under nitrogen protection, and stirred at 0 °C for 1 hour until the reaction was completed. The crude product was obtained after the reaction solution was concentrated under reduced pressure, and the crude product was purified by HPLC preparation (chromatographic column: Agilent 10Prep-C8 250x21.2mm; column temperature: 25 °C; mobile phase: water (0.1% FA)-acetonitrile; mobile phase acetonitrile ratio 30%-50% in 9 min; flow rate 30 ml / min) to obtain compound 15 (6.34 mg). LC-MS (ESI) [M+H] + : 577.2.

[0325] 1H NMR (400 MHz, Methanol-d4) δ 8.35 (d, J = 3.4 Hz, 1H), 8.20 (t, J = 1.9 Hz, 1H), 8.03 (ddd, J = 8.2, 2.2, 1.1 Hz, 1H), 7.97 (dt, J = 7.9, 1.4 Hz, 1H), 7.78 (dd, J = 8.8, 7.1 Hz, 2H), 7.47 - 7.43 (m, 1H), 4.96 - 4.84 (m, 2H), 4.74 (d, J = 9.1 Hz, 1H), 4.08 (dd, J = 2.8, 0.9 Hz, 1H), 3.90 - 3.87 (m, 1H), 3.71 (dd, J = 11.7, 7.4 Hz, 1H), 3.62 (dd, J = 11.7, 4.3 Hz, 1H).

[0326] Example 16: Synthesis of compound 16

[0327] Step 1: Preparation of compound 16-1

[0328] Compound 10-3 (100 mg) was dissolved in tetrahydrofuran (5 mL) under nitrogen protection, sodium hydride (26.4 mg, 60%) was added at 0 °C, the reaction was stirred at 25 °C for 5 min, then the reaction was cooled to 0 °C and methyl iodide (93.5 mg) was added, after addition, the obtained reaction was warmed to 25 °C and stirred for 2 h until the reaction was completed. The reaction was concentrated under reduced pressure to remove the organic solvent, the remaining aqueous phase was adjusted to neutral with dilute hydrochloric acid (1 mol / L), then extracted with ethyl acetate (5 mL x 2), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give compound 16-1 (100 mg), which was used directly in the next step without purification. LC-MS (ESI) [M+H] + : 456.2.

[0329] Step 2: Preparation of compound 16-2

[0330] Compound 16-1 (95 mg) and 2-amino-4-chlorobenzotrifluoride (48.5 mg) were dissolved in dichloromethane (3 mL) under nitrogen protection, cooled to 0 °C, and pyridine (98.0 mg) and phosphorus oxychloride (38.0 mg) were added in turn, after addition, the obtained reaction was stirred at 0 °C for 1 h until the reaction was completed. The reaction was directly separated and purified by silica gel column chromatography (dichloromethane:methanol = 15:1) to give compound 16-2 (120 mg). LC-MS (ESI) [M+H] + : 633.2.

[0331] Step 3: Preparation of compound 16-3

[0332] Under nitrogen protection, compound 16-2 (115 mg) was dissolved in dichloromethane (5 mL), followed by the sequential addition of pyridine (140.8 mg) and phosphorus pentachloride (111.2 mg). The reaction mixture was heated to 70 °C and stirred for 2 hours, then cooled to 25 °C and azidotrimethylsilane (82.1 mg) was added. After the addition was complete, the reaction mixture was stirred at 25 °C for 16 hours until the reaction was complete. The reaction was quenched by adding saturated sodium bicarbonate solution (2 mL) under ice bath cooling, and extracted with dichloromethane (5 mL × 2). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 16-3 (117 mg). This crude product can be used directly in the next reaction without purification. LC-MS (ESI) [M+H] + :658.2.

[0333] Step 4: Preparation of Compound 16

[0334] Under nitrogen protection, compound 16-3 (110 mg) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (2 mL) was added at 0 °C. After the addition was complete, the reaction solution was stirred at 0 °C for 1 hour until the reaction was complete. The reaction solution was concentrated under reduced pressure to remove the solvent, and the crude product was analyzed by HPLC (column: [column information missing]). 1810 μm 21.2 × 250 mm; Mobile phase: [water (10 mM ammonium bicarbonate) - acetonitrile]; Flow rate: 30 mL / min / (Separation conditions: Column: Agilent 10 Prep-C8 250 × 21.2 mm; Column temperature: 25℃; Mobile phase: water (0.1% FA) - acetonitrile; Acetonitrile ratio 30%-50% in the mobile phase; Flow rate: 30 mL / min) Compound 16 (38.96 mg) was prepared and purified. LC-MS (ESI) [M+H] + :570.2.

[0335] 1 H NMR(400MHz, Methanol-d4)δ8.73(s,1H),8.04(d,J=8.6Hz,1H),7.98–7.94(m,1H),7.91 (s,1H),7.68(dt,J=7.8,1.1Hz,1H),7.62(ddd,J=10.1,2.6,1.5Hz,1H),7.48–7.42(m,1H ),7.10–7.05(m,1H),4.98(dd,J=10.4,2.9Hz,1H),4.76(d,J=10.0Hz,1H),4.63(d,J=9. 3Hz, 1H), 4.07 (dd, J = 2.9, 1.0Hz, 1H), 3.75–3.71 (m, 1H), 3.65–3.57 (m, 2H), 3.02 (s, 3H).

[0336] Example 17: Synthesis of Compound 17

[0337] Step 1: Preparation of Compound 17-1

[0338] Under nitrogen protection, (3R,4S,5R,6R)-6-(acetoxymethyl)-4-azidotetrahydro-2H-pyran-2,3,5-triacetate triester (1g, CAS:155417-78-0) and 1-bromo-2,3-difluoro-4-[2-(trimethylsilyl)ethynyl]benzene (813.4mg, CAS:2491661-89-1) were dissolved in a mixed solvent of N,N-dimethylformamide (20mL) and water (5mL). Copper sulfate pentahydrate (668.8mg) and sodium vitamin C salt (530.7mg) were added. After the addition was complete, the resulting reaction solution was stirred at 85°C for 1.5 hours until the reaction was complete. Ethyl acetate (50 mL) was added to the reaction solution and stirred for 5 minutes to obtain a suspension. The suspension was filtered through diatomaceous earth, and the filtrate was quenched in water (50 mL). Extraction was performed with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) to give compound 17-1 (1.1 g). LC-MS (ESI) [M+H] + :590.0.

[0339] Step 2: Preparation of compound 17-2

[0340] Under nitrogen protection, compound 17-1 (1.2 g) was dissolved in dichloromethane (10 mL), followed by the addition of acetic anhydride (1 mL) and 33% hydrobromic acid (5 mL). After the addition was complete, the reaction mixture was reacted at 25 °C for 16 hours until the reaction was complete. The reaction mixture was then quenched in 100 mL of ice water and extracted with dichloromethane (30 mL × 3). The organic phase was washed successively with saturated sodium bicarbonate and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain compound 17-2 (1 g). LC-MS (ESI) [M+H] + :611.8.

[0341] Step 3: Preparation of compound 17-3

[0342] Compound 17-3 (560 mg) was obtained by the above procedure. LC-MS (ESI) [M+H] + : 575.0.

[0343] Step 4: Preparation of compound 17-4

[0344] Compound 17-3 (500 mg) was dissolved in a mixture solvent of methanol (3 mL) and tetrahydrofuran (3 mL) under nitrogen protection, and a solution of lithium hydroxide (81.9 mg) in water (0.6 mL) was added dropwise. After the addition was completed, the resulting reaction solution was stirred at 25 °C for 2 hours until the reaction was completed. The reaction solution was directly purified by C18 reverse phase column (MeCN: H2O (0.5% TFA) = 5% ~ 95%) to obtain compound 17-4 (370 mg). LC-MS (ESI) [M+H] + : 449.0.

[0345] Step 5: Preparation of compound 17-5

[0346] Compound 17-4 (370 mg) and benzaldehyde dimethyl acetal (249.3 mg) were dissolved in acetonitrile (10 mL) under nitrogen protection, and methyl sulfonic acid (118.1 mg) was added. After the addition was completed, the resulting reaction solution was stirred at 25 °C for 4 hours until the reaction was completed. Triethylamine (124.3 mg) was added to the reaction solution to quench the reaction, and the resulting reaction solution was stirred for 20 minutes. The resulting reaction solution was concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain compound 17-5 (390 mg). LC-MS (ESI) [M+H] + : 535.0.

[0347] Step 6: Preparation of compound 17-6

[0348] Compound 17-5 (200 mg) was dissolved in tetrahydrofuran (0.5 mL) under nitrogen protection, sodium hydride (29.6 mg, 60%) was added, the reaction was stirred for 10 minutes, 2- (trimethylsilyl) ethoxymethyl chloride (123.3 mg) was added, and the obtained reaction solution was stirred at 25°C for 2 hours until the reaction was completed. The reaction solution was quenched with water, extracted with ethyl acetate (10 mL x 2), and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The obtained crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2: 1) to obtain compound 17-6 (244 mg). LC-MS (ESI) [M+H] + : 667.2.

[0349] Step 7: Preparation of compound 17-7

[0350] Compound 17-6 (244 mg) was dissolved in tetrahydrofuran (0.5 mL), platinum carbon (76.3 mg) was added, the reaction system was replaced with hydrogen for 3 times, and the obtained reaction system was stirred at 25°C for 18 hours until the reaction was completed. The reaction solution was filtered through diatomite, and the filtrate was concentrated to obtain a crude product of compound 17-7 (230 mg), which was directly used in the next step reaction without purification. LC-MS (ESI) [M+H] + : 641.0.

[0351] Step 8: Preparation of compound 17-8

[0352] Compound 17-7 (125 mg) and 3-chloro-5-cyanobenzoic acid (41.5 mg) were dissolved in dichloromethane (1 mL) under nitrogen protection, pyridine (69.6 mg) and phosphorus oxychloride (29.7 mg) were added in turn at 0°C, and the obtained reaction solution was stirred at 0°C for 1 hour until the reaction was completed. The reaction solution was directly purified by silica gel column chromatography (petroleum ether: ethyl acetate = 3: 1) to obtain compound 17-8 (65 mg). LC-MS (ESI) [M+H] + : 804.2.

[0353] Step 9: Preparation of compound 17-9

[0354] Under nitrogen protection, compound 17-8 (60 mg) was dissolved in dichloromethane (5 mL), followed by the sequential addition of pyridine (115.8 mg) and phosphorus pentachloride (45.7 mg). The reaction mixture was heated to 70 °C and stirred for 2 hours, then cooled to 25 °C and azidotrimethylsilane (42.2 mg) was added. After the addition was complete, the reaction mixture was stirred at 25 °C for 16 hours until the reaction was complete. The reaction was quenched by adding saturated sodium bicarbonate solution (1 mL) under ice bath cooling, and extracted with dichloromethane (5 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain crude compound 17-9 (60 mg). This crude product can be used directly in the next reaction without purification. LC-MS (ESI) [M+H] + :829.2.

[0355] Step 10: Preparation of Compound 17

[0356] Under nitrogen protection, compound 17-9 (55 mg) was dissolved in trifluoroacetic acid (0.3 mL) at 0 °C. The resulting reaction system was stirred at 0 °C for 2 hours until the reaction was complete. The reaction solution was concentrated under reduced pressure to obtain the crude product, which was then purified by HPLC (column: [column information missing]). 1810 μm (21.2 × 250 mm); Mobile phase: [water (10 mM ammonium bicarbonate) - acetonitrile]; Flow rate: 30 mL / min) yielded compound 17 (2.95 mg, a mixture of C-1 chiral isomers). LC-MS (ESI) [M+H] + :611.2.

[0357] 1 H NMR(400MHz, Methanol-d4)δ8.35-8.47(m,1H),8.25–8.22(m,1H),8.15–8.04(m,2H),7.82–7.76(m,1H),7.47 –7.43(m,1H),5.92–6.35(m,1H),5.05–5.80(m,2H),4.29–4.32(m,1H),4.09–4.14(m,1H),3.65–3.84(m,2H).

[0358] Example 18: Synthesis of Compound 18

[0359] Step 1: Preparation of compound 18-1

[0360] Compound (4aR,6R,7R,8R,8aR)-8-(4-(4-chloro-2,3-difluorophenyl)-1H-1,2,3- triazol-1-yl)-7-hydroxy-2-phenylhexahydropyrano[3,2-d][1,3]dioxole-6-carboxylic acid (1.9 g, CAS: 3064003-30-8) was dissolved in dichloromethane (30 mL) under nitrogen protection, pyridine (1.2 g) and acetic anhydride (1.2 g) were added, after addition, the obtained reaction solution was stirred at 25 °C for 4 hours until the reaction was completed. The reaction solution was quenched with water (50 mL), extracted with dichloromethane (30 mL x 3), the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give compound 18-1 (2 g). LC-MS (ESI) [M+H] + : 536.1.

[0361] Step 2: Preparation of compound 18-2

[0362] Compound 18-1 (300 mg) and m-chloroaniline (78.6 mg) were dissolved in dichloromethane (7 mL) under nitrogen protection, pyridine (132.9 mg) and phosphorus oxychloride (94.4 mg) were added at 0 °C, after addition, the obtained reaction solution was stirred at 25 °C for 1 hour until the reaction was completed. The reaction solution was directly separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1) to give compound 18-2 (105 mg). LC-MS (ESI) [M+H] + : 645.2.

[0363] Step 3: Preparation of compound 18-3

[0364] Compound 18-2 (100 mg) was dissolved in dichloromethane (7 mL) under nitrogen protection, pyridine (120.1 mg) and phosphorus pentachloride (63.2 mg) were added, the reaction solution was stirred at 70 °C for 2 hours, then cooled to 25 °C, azidotrimethylsilane (24 mg) was added, after addition, the obtained reaction solution was stirred at 70 °C for 16 hours until the reaction was completed. The reaction solution was cooled to 0 °C, quenched with saturated aqueous sodium bicarbonate solution (10 mL), extracted with dichloromethane (5 mL x 2), the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure, the obtained crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1) to give compound 18-3 (70 mg). LC-MS (ESI) [M+H] + : 670.2.

[0365] Step 4: Preparation of compound 18-4

[0366] Compound 18-4 (18 mg) was dissolved in trifluoroacetic acid (2 mL) under nitrogen protection at 0 °C, the resulting reaction solution was stirred at 25 °C for 1 hour until the reaction was completed. The reaction solution was concentrated under reduced pressure, and the obtained crude product was purified by HPLC (separation conditions: column: Agilent 10 Prep-C8 250 x 21.2 mm; column temperature: 25 °C; mobile phase: water (0.1% FA) - acetonitrile; mobile phase acetonitrile ratio 30% - 50% in 9 min; flow rate 30 ml / min) to give compound 18 (4.4 mg). LC-MS (ESI) [M+H] + : 628.2.

[0367] Step 5: Preparation of compound 18

[0368] Compound 18-4 (18 mg) was dissolved in trifluoroacetic acid (2 mL) under nitrogen protection at 0 °C, the resulting reaction solution was stirred at 25 °C for 1 hour until the reaction was completed. The reaction solution was concentrated under reduced pressure, and the obtained crude product was purified by HPLC (separation conditions: column: Agilent 10 Prep-C8 250 x 21.2 mm; column temperature: 25 °C; mobile phase: water (0.1% FA) - acetonitrile; mobile phase acetonitrile ratio 30% - 50% in 9 min; flow rate 30 ml / min) to give compound 18 (4.4 mg). LC-MS (ESI) [M+H] + : 540.2.

[0369] 1 H NMR (400 MHz, Methanol-d4) δ 8.46 (d, J = 3.3 Hz, 1H), 7.96 - 7.87 (m, 2H), 7.78 - 7.64 (m, 3H), 7.41 (ddt, J = 8.6, 6.7, 1.8 Hz, 1H), 5.02 (dd, J = 5.2, 1.6 Hz, 2H), 4.81 - 4.75 (m, 1H), 4.18 (q, J = 1.1 Hz, 1H), 3.99 - 3.94 (m, 1H), 3.81 (dd, J = 11.7, 7.3 Hz, 1H), 3.71 (dd, J = 11.7, 4.5 Hz, 1H).

[0370] Example 19: Synthesis of compound 19

[0371] Step 1: Preparation of compound 19-1

[0372] Compound 18-4 (25 mg) was dissolved in N,N-dimethylformamide (2 mL) under nitrogen protection, sodium hydride (3.2 mg, 60% purity) was added at 0 °C, the resulting mixture was reacted at 0 °C for 30 minutes, and then iodomethane (16.9 mg) was added. The resulting reaction solution was stirred at 0 °C for 2 hours until the reaction was completed. The reaction was quenched by pouring into water (3 mL), extracted with ethyl acetate (2 mL x 3), and the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give compound 19-1 (15 mg). LC-MS (ESI) [M+H]+ 642.2.

[0373] Step 2: Preparation of compound 19

[0374] Compound 19-1 (15 mg) was dissolved in trifluoroacetic acid (2 mL) under nitrogen protection, and the reaction was stirred at 25 °C for 1 h until completion. The reaction solution was concentrated under reduced pressure to remove the solvent, and the obtained crude product was prepared and purified by HPLC (column: Agilent 10 Prep-C8 250x21.2mm; column temperature: 25 °C; mobile phase: water (0.1% FA) - acetonitrile; mobile phase acetonitrile ratio 30%-50% in 9 min; flow rate 30 ml / min) to obtain compound 19 (8.0 mg). LC-MS (ESI) [M+H] + 554.0.

[0375] 1 H NMR (400 MHz, Methanol-d4) δ 8.66 (d, J = 3.4 Hz, 1H), 7.98 - 7.86 (m, 2H), 7.81 - 7.64 (m, 3H), 7.43 (ddd, J = 8.8, 6.7, 2.0 Hz, 1H), 5.10 (dd, J = 10.1, 2.9 Hz, 1H), 4.86 - 4.75 (m, 2H), 4.17 - 4.13 (m, 1H), 3.94 (ddd, J = 7.3, 4.5, 1.1 Hz, 1H), 3.81 (dd, J = 11.7, 7.3 Hz, 1H), 3.71 (dd, J = 11.7, 4.5 Hz, 1H), 2.95 (s, 3H).

[0376] Example 20: Synthesis of compound 20

[0377] Step 1: Preparation of compound 20-1

[0378] Compound 18-1 (170 mg) and 5-bromo-3-aminopyridine (60.4 mg) were dissolved in dichloromethane (7 mL) under nitrogen protection, and pyridine (75.3 mg) and phosphorus oxychloride (53.5 mg) were added successively at 0 °C. After addition, the obtained reaction solution was stirred at 25 °C for 1 h until completion. The reaction solution was directly separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain compound 20-1 (85 mg). LC-MS (ESI) [M+H] + 690.4.

[0379] Step 2: Preparation of compound 20-2

[0380] Compound 20-1 (80 mg) was dissolved in dichloromethane (7 mL) under nitrogen protection, pyridine (89.8 mg) and phosphorus pentachloride (47.3 mg) were added successively, the reaction solution was stirred at 70 °C for 2 hours until the reaction was completed, then cooled to 25 °C, azidotrimethylsilane (18 mg) was added, after addition, the obtained reaction solution was stirred at 70 °C for 16 hours until the reaction was completed. The reaction solution was cooled to 0 °C, saturated sodium bicarbonate aqueous solution (10 mL) was added for quenching, extracted with dichloromethane (5 mL x 2), the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, the obtained crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain compound 20-2 (36 mg). LC-MS (ESI) [M+H] + : 715.0.

[0381] Step 3: Preparation of compound 20-3

[0382] Compound 20-2 (33 mg) was dissolved in ammonium methanol solution (2 mL, 4M) under nitrogen protection, the obtained reaction solution was stirred at 25 °C for 1 hour until the reaction was completed. The reaction solution was concentrated under reduced pressure to obtain compound 20-3 (30 mg). LC-MS (ESI) [M+H] + : 673.0.

[0383] Step 4: Preparation of compound 20-4

[0384] Compound 20-3 (200 mg) was dissolved in tetrahydrofuran (10 mL) under nitrogen protection, sodium hydride (23.7 mg, 60% purity) was added at 0 °C, the obtained mixture was reacted at 0 °C for 20 minutes, then iodomethane (126.4 mg) was added. The obtained reaction solution was stirred at 0 °C for 7 hours until the reaction was completed. The reaction was poured into water (10 mL) for quenching, extracted with dichloromethane (5 mL x 3), the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, the obtained crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain compound 20-4 (130 mg). LC-MS (ESI) [M+H] + : 687.0.

[0385] Step 5: Preparation of compound 20

[0386] Compound 20-4 (130 mg) was dissolved in trifluoroacetic acid (3 mL) under nitrogen protection. The reaction was stirred at 25 °C for 1 hour until completion. The reaction solution was concentrated under reduced pressure to remove the solvent. The obtained crude product was prepared and purified by HPLC (column: Agilent 10 Prep-C8 250x21.2mm; column temperature: 25 °C; mobile phase: water (0.1% FA) - acetonitrile; mobile phase acetonitrile ratio 30%-50% in 9 min; flow rate 30 ml / min) to obtain compound 20 (72.1 mg). LC-MS (ESI) [M+H] + : 599.0.

[0387] 1 H NMR (400 MHz, DMSO-d6) δ 9.06 (d, J = 2.1 Hz, 1H), 9.01 (d, J = 2.2 Hz, 1H), 8.81 (d, J = 3.1 Hz, 1H), 8.65 (t, J = 2.2 Hz, 1H), 7.96 (ddd, J = 9.0, 7.1, 2.1 Hz, 1H), 7.58 (ddd, J = 8.8, 6.8, 1.8 Hz, 1H), 5.64 (d, J = 6.6 Hz, 1H), 5.21 (dd, J = 10.5, 2.9 Hz, 1H), 5.02 (d, J = 9.4 Hz, 1H), 4.85 (t, J = 5.6 Hz, 1H), 4.73 (dd, J = 10.5, 9.4 Hz, 1H), 4.03 - 3.90 (m, 2H), 3.48 (t, J = 5.8 Hz, 2H), 2.90 (s, 3H).

[0388] Example 21: Synthesis of compound 21

[0389] Step 1: Preparation of compound 21-1

[0390] Compound 18-1 (300 mg) and 3,5-dichloroaniline (99.8 mg) were dissolved in dichloromethane (7 mL) under nitrogen protection. Pyridine (132.9 mg) and phosphorus oxychloride (94.4 mg) were added successively at 0 °C. After addition, the obtained reaction solution was stirred at 25 °C for 1 hour until completion. The reaction solution was directly separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain compound 21-1 (140 mg). LC-MS (ESI) [M+H] + : 681.2.

[0391] Step 2: Preparation of compound 21-2

[0392] Compound 21-1 (130 mg) was dissolved in dichloromethane (7 mL) under nitrogen protection, pyridine (148.2 mg) and phosphorus pentachloride (78.2 mg) were added successively, the reaction solution was stirred at 70 °C for 2 hours until the reaction was completed, then cooled to 25 °C, azidotrimethylsilane (29.6 mg) was added, after addition, the obtained reaction solution was stirred at 70 °C for 16 hours until the reaction was completed. The reaction solution was cooled to 0 °C, saturated sodium bicarbonate aqueous solution (10 mL) was added for quenching, extracted with dichloromethane (5 mL x 2), the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, the obtained crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain compound 21-2 (85 mg). LC-MS (ESI) [M+H] + : 704.2.

[0393] Step 3: Preparation of compound 21-3

[0394] Compound 21-2 (85 mg) was dissolved in ammonium methanol solution (2 mL, 4M) under nitrogen protection, the obtained reaction solution was stirred at 25 °C for 1 hour until the reaction was completed. The reaction solution was concentrated under reduced pressure to obtain compound 21-3 (75 mg). LC-MS (ESI) [M+H] + : 662.8.

[0395] Step 4: Preparation of compound 21-4

[0396] Compound 21-3 (75 mg) was dissolved in tetrahydrofuran (8 mL) under nitrogen protection, sodium hydride (9.1 mg, 60% purity) was added at 0 °C, the obtained mixture was reacted at 0 °C for 20 minutes, then iodomethane (48.2 mg) was added. The obtained reaction solution was stirred at 0 °C for 4 hours until the reaction was completed. The reaction was poured into water (10 mL) for quenching, extracted with dichloromethane (5 mL x 3), the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, the obtained crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain compound 21-4 (60 mg). LC-MS (ESI) [M+H] + : 676.2.

[0397] Step 5: Preparation of compound 21

[0398] Compound 21-4 (55 mg) was dissolved in trifluoroacetic acid (3 mL) under nitrogen protection. The reaction was stirred at 25 °C for 1 hour until completion. The reaction solution was concentrated under reduced pressure to remove the solvent. The obtained crude product was prepared and purified by HPLC (column: Agilent 10 Prep-C8 250x21.2mm; column temperature: 25 °C; mobile phase: water (0.1% FA) - acetonitrile; mobile phase acetonitrile ratio 30%-50% in 9 min; flow rate 30 ml / min) to obtain compound 21 (23 mg). LC-MS (ESI) [M+H] + : 590.0.

[0399] 1 H NMR (400 MHz, Methanol-d4) δ 8.66 (d, J = 3.4 Hz, 1H), 7.93 (ddd, J = 9.0, 7.0, 2.2 Hz, 1H), 7.89 (d, J = 1.9 Hz, 2H), 7.82 (t, J = 1.8 Hz, 1H), 7.42 (ddd, J = 8.7, 6.7, 2.0 Hz, 1H), 5.12 (ddd, J = 8.8, 2.9, 1.3 Hz, 1H), 4.82 (d, J = 9.1 Hz, 2H), 4.16 (dd, J = 2.7, 1.2 Hz, 1H), 3.97 (dd, J = 7.3, 4.5 Hz, 1H), 3.81 (dd, J = 11.7, 7.3 Hz, 1H), 3.71 (dd, J = 11.7, 4.5 Hz, 1H), 2.96 (s, 3H).

[0400] Example 22: Synthesis of compound 22

[0401] Step 1: Preparation of compound 22-1

[0402] Compound 1-1 (800 mg) and 5-bromo-3-aminopyridine (293.1 mg) were dissolved in dichloromethane (8 mL) under nitrogen protection. Pyridine (365.5 mg) and phosphorus oxychloride (259.8 mg) were added successively at 0 °C. The obtained reaction solution was stirred at 25 °C for 1 hour until completion. The reaction solution was directly separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:2) to obtain compound 22-1 (315 mg). LC-MS (ESI) [M+H] + : 674.0.

[0403] Step 2: Preparation of compound 22-2

[0404] Compound 22-1 (310 mg) was dissolved in dichloromethane (20 mL) under nitrogen protection, pyridine (356.3 mg) and phosphorus pentachloride (187.6 mg) were added successively, the reaction solution was stirred at 70 °C for 2 hours until the reaction was completed, then cooled to 25 °C, azidotrimethylsilane (71.3 mg) was added, after addition, the obtained reaction solution was stirred at 70 °C for 16 hours until the reaction was completed. The reaction solution was cooled to 0 °C, saturated sodium bicarbonate aqueous solution (20 mL) was added for quenching, extracted with dichloromethane (10 mL x 3), the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, the obtained crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:2) to obtain compound 22-2 (150 mg). LC-MS (ESI) [M+H] + : 701.0.

[0405] Step 3: Preparation of compound 22-3

[0406] Compound 22-2 (150 mg) was dissolved in ammonium methanol solution (5 mL, 4M) under nitrogen protection, the obtained reaction solution was stirred at 25 °C for 16 hours until the reaction was completed. The reaction solution was concentrated under reduced pressure to obtain compound 22-3 (120 mg). LC-MS (ESI) [M+H] + : 657.0.

[0407] Step 4: Preparation of compound 22-4

[0408] Compound 22-3 (100 mg) was dissolved in tetrahydrofuran (8 mL) under nitrogen protection, cooled to 0 °C, then sodium hydride (12.2 mg, 60% purity) was added. The obtained reaction solution was reacted at 0 °C for 30 minutes, then iodomethane (64.8 mg) was added, and the stirring was continued at 0 °C for 4 hours until the reaction was completed. The reaction solution was poured into water (10 ml) for quenching, extracted with ethyl acetate (5 ml x 3), the organic phase was washed with saturated brine (5 ml), dried over anhydrous sodium sulfate, then concentrated under reduced pressure, the obtained crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:2) to obtain compound 22-4 (70 mg). LC-MS (ESI) [M+H] + : 671.2.

[0409] Step 5: Preparation of compound 22

[0410] Compound 22-4 (60 mg) was dissolved in trifluoroacetic acid (3 mL) at 0 °C under nitrogen protection, the resulting reaction solution was stirred at 25 °C for 1 hour until the reaction was completed. The reaction solution was concentrated under reduced pressure, and the obtained crude product was purified by HPLC (separation conditions: column: Agilent 10Prep-C8 250x21.2mm; column temperature: 25 °C; mobile phase: water (0.1% FA)-acetonitrile; mobile phase acetonitrile ratio 30%-50% in 9 min; flow rate 30 ml / min) to obtain compound 22 (26.4 mg). LC-MS (ESI) [M+H] + 583.0.

[0411] 1 H NMR (400 MHz, Methanol-d4) δ 8.97 (t, J = 2.2 Hz, 2H), 8.79 (s, 1H), 8.58 (t, J = 2.1 Hz, 1H), 7.69 (dd, J = 8.8, 6.5 Hz, 2H), 5.08 (dd, J = 10.4, 2.8 Hz, 1H), 4.90 (s, 1H), 4.76 (dd, J = 10.4, 9.4 Hz, 1H), 4.12 (d, J = 2.8 Hz, 1H), 3.95 (dd, J = 7.4, 4.6 Hz, 1H), 3.77 (dd, J = 11.7, 7.3 Hz, 1H), 3.68 (dd, J = 11.6, 4.6 Hz, 1H), 2.98 (s, 3H).

[0412] Experimental Example 1 Galectin-3 (human) affinity SPR assay

[0413] 1. Experimental instruments

[0414] The information of other reagents and consumables required for the experiment is shown in Table 1.

[0415] Table 1

[0416] 2. Experimental materials

[0417] The principle of surface plasmon resonance (SPR) used in the experiment is that when incident light is incident on the interface of two media with different refractive indices (such as gold or silver coating on the surface of glass) at the critical angle, resonance of free electrons in the metal can be caused. Due to resonance, the electrons absorb light energy, thereby greatly weakening the reflected light at a certain angle. The incident angle at which the reflected light is completely lost at a certain angle is called the SPR angle. SPR changes with the change of surface refractive index, and the change of refractive index is proportional to the mass of the biological molecules bound to the metal surface. Therefore, by obtaining the dynamic changes of SPR angle in the biological reaction process, the specificity signal of the interaction between biological molecules can be obtained.

[0418] The information of other reagents and consumables required in the experiment is shown in Table 2.

[0419] Table 2

[0420] 3. Experimental method

[0421] The hGal-3 protein (Yiqioshen, 10289-H08H1) was diluted to a certain concentration with acetic acid solution of different pH values to perform pH scouting test, and the suitable pH value buffer for fixing the ligand protein on the CM5 chip (Cytiva, BR100530) was screened.

[0422] The method for fixing the ligand protein on the chip was designed, and the parameters were chip activation for 420 s, ligand coupling for 500 s, chip blocking for 420 s, completion of ligand fixation, and fixation of 8 channels, with a fixed amount of about 2000 RU for each channel.

[0423] The Xiangshen molecule was diluted at 12 gradients of 1000-0.49 nM, and the remaining test compounds were diluted at 12 gradients of 20000-9.77 nM. The multi-cycle kinetic run was performed at 25°C, and the parameters were binding for 60 seconds and dissociation for 150 seconds. The run used 1xPBS pH7.4, 0.05% Tween-20, 5% DMSO buffer. The regeneration condition was to continue to flush the chip with the running reagent for 150 seconds.

[0424] 4. Data analysis

[0425] The raw data was imported into Biacore™ Insight Evaluation Software 4.0., and the method of Evaluation of multi-cycle kinetics for samples, to calculate kinetic rate constants was selected. Kinetic curve fitting was performed with a 1:1 binding fitting model, and the affinity constant (KD) was obtained.

[0426] 5. Experimental results and conclusions

[0427] The experimental results are shown in Table 3.

[0428] Table 3

[0429] The above tests show that the compounds of the present application have good Galectin-3 binding activity.

[0430] Experimental Example 2: QPCR test of LX-2 cell anti-fibrosis related genes

[0431] 1. Experimental method

[0432] LX-2 cells (FuHeng, Cat# FH0108) were plated in 6-well plates (Corning, Cat# 3516) and cultured to 80% confluence. The culture medium was removed and washed twice with PBS warmed to 37°C. Serum-free medium was added for incubation, and after 24 hours of serum starvation, 10 ng / mL TGF-β1 (MCE, Cat# HY-P70543) and compounds were added for co-culture for 24 hours. According to the manufacturer's instructions, total RNA was extracted from the cells using the Mini Handbook kit (QIAGEN, Cat# 74106). The RNA was quantified by spectrophotometry using a Nanodrop One (ThermoFisher, Cat# 840-317400).

[0433] The total RNA was reverse transcribed into cDNA using the High Capacity cDNA Reverse Transcription Kits kit (Thermo Fisher, Cat# 4368814) and a PCR instrument (Bio-Rad, Cat# 1861096): the reaction was incubated at 25°C for 10 minutes, then at 37°C for 120 minutes, and finally at 85°C for 5 minutes. The QuantStudio 6 Flex Real-Time PCR System (Thermo Fisher, Cat# 4483900) was used to perform the QPCR test. The primers used are shown in Table 4. TM ​6Flex Real-Time PCR System (Thermo Fisher, Cat# 4485694) was used for quantitative real-time PCR. 4 μL of cDNA was used for each PCR reaction. The reference gene, β-Actin, was used as a standardization reference. The 10 ng / mL TGF-β1 and DMSO-treated samples were used as blank controls.

[0434] The primer pair sequence of α smooth muscle actin (α-SMA) is: 5'-AGCCAAGCACTGTCAGGAATC-3' and 5'-GGGCAACACGAAGCTCATTG-3';

[0435] Collagen type I alpha-1 (COL1A1): 5' CAAAGAAGGCGGCAAAGGTC-3' and 5'-CCCTCACGTCCAGATTCACC-3';

[0436] Reference gene β-Actin: 5'-CACCATTGGCAATGAGCGGTTC-3' and 5'-AGGTCTTTGCGGATGTCCACGT-3';

[0437] PCR reactions were catalyzed by PowerUp SYBR Green Master Mix (Thermo Fisher, Cat# A25742), and the SYBR fluorescence signal was measured during each of the 40 cycles, and the cycle number required to exceed the detection threshold (Ct) was listed. The Ct of each specific reaction was standardized to the Ct obtained with β-Actin, and the standardized Ct was further referenced to the control-treated sample to obtain the relative expression level of each gene. Three replicates were set for each sample.

[0438] 2. Data analysis

[0439] Data calculation method: RQ = 2^(-ΔΔCt)

[0440] ΔCt = Ct of target gene - average Ct of reference gene

[0441] ΔΔCt = mean of (Ct of each target gene - (Ct of target gene - average Ct of reference gene))

[0442] 3. Experimental results and conclusions

[0443] The experimental results are shown in Table 4.

[0444] Table 4

[0445] The above tests show that the compound of the present application has good anti-fibrosis activity.

[0446] The exemplary embodiments of the present application have been described above. It is understood, however, that the scope of the application is not limited to the above-described exemplary embodiments. Any modifications, equivalents, improvements, and the like made by those skilled in the art within the spirit and principles of the present application are included in the scope of the present application.

Claims

1. The compound represented by formula (Ⅰ), its optical isomer, or its pharmacologically acceptable salt, in, Ring A is selected from C 3-20 Cycloalkyl, 3-20 membered heterocycloalkyl, C 4-20 Cycloalkenyl, 4-20 membered heterocyclic alkenyl, C 6-20 Aryl or 5-20 heteroaryl groups; Ring B is selected from C 3-20 Cycloalkyl, 3-20 membered heterocycloalkyl, C 4-20 Cycloalkenyl, 4-20 membered heterocyclic alkenyl, C 6-20 Aryl or 5-20 heteroaryl groups; X1 is selected from C, and X2 is selected from N; or X1 is selected from N, and X2 is selected from C; Z1 is selected from C(R3) or N, Z2 is selected from C or N, Z3 is selected from C or N, and at least one of Z1, Z2 and Z3 is selected from N; L is selected from a single bond, -(CR aa R bb ) p -, -O-(CR aa R bb ) p -, -O-(CR aa R bb ) p C(O)-, -S-(CR aa R bb ) p -, -S-(CR aa R bb ) p C(O)-, -N(R aa )-(CR aa R bb ) p - or -N(R aa )-(CR aa R bb )[[ID=4�]] p C(O)-; R1 is selected from -H, -D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SF5, -NO2, -CHO, -COOH, -C(=O)NH2, C 1-20 Alkyl, C 2-20 alkenyl, C 2-20 alkynyl group, C 1-20 Heteroalkyl, C 3-20 Cycloalkyl, 3-20 membered heterocycloalkyl, C 6-20 Aryl or 5-20 heteroaryl, wherein C 1-20 Alkyl, C 2-20 alkenyl, C 2-20 alkynyl group, C 1-20 Heteroalkyl, C 3-20 Cycloalkyl, 3-20 membered heterocycloalkyl, C 6-20 Aryl and 5-20 heteroaryl groups may be substituted by 1, 2, 3 or 4 Rs; R2 and R3 are independently selected from -H, -D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SF5, -NO2, -CHO, -COOH, -C(=O)NH2, C 1-12 Alkyl or C 1-12 Heteroalkyl, the C 1-12 Alkyl and C 1-12 The heteroalkyl group may be optionally substituted with 1, 2, 3 or 4 Rs; R a Each occurrence is independently selected from -H, -D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SF5, -NO2, -CHO, -COOH, -C(=O)NH2, C 1-12 Alkyl or C 1-12 Heteroalkyl, the C 1-12 Alkyl and C 1-12 The heteroalkyl group may be optionally substituted with 1, 2, 3 or 4 Rs; Or, two adjacent R a Formation C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, C 6-12 Aryl or 5-12 heteroaryl, wherein C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, C 6-12 The aryl and 5-12 heteroaryl groups may be optionally substituted with 1, 2, 3 or 4 Rs; R b Each occurrence is independently selected from -H, -D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SF5, -NO2, -CHO, -COOH, -C(=O)NH2, C 1-12 Alkyl or C 1-12 Heteroalkyl, the C 1-12 Alkyl and C 1-12 The heteroalkyl group may be optionally substituted with 1, 2, 3 or 4 Rs; Or, two adjacent R b Formation C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, C 6-12 Aryl or 5-12 heteroaryl, wherein C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, C 6-12 The aryl and 5-12 heteroaryl groups may be optionally substituted with 1, 2, 3 or 4 Rs; R aa R bb Each occurrence is independently selected from -H, -D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SF5, -NO2, -CHO, -COOH, -C(=O)NH2, C 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl or C 1-12 Heteroalkyl, the C 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group and C 1-12 The heteroalkyl group may be optionally substituted with 1, 2, 3 or 4 Rs; Each occurrence of R is independently selected from -H, -D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SF5, -NO2, -CHO, -COOH, -C(=O)NH2, C 1-20 Alkyl, C 1-20 Heteroalkyl, C 3-20 Cycloalkyl, 3-20 membered heterocycloalkyl, C 6-20 Aryl or 5-20 heteroaryl, wherein C 1-20 Alkyl, C 1-20 Heteroalkyl, C 3-20 Cycloalkyl, 3-20 membered heterocycloalkyl, C 6-20 Aryl and 5-20 heteroaryl groups may be optionally substituted by 1, 2 or 3 R's; Each time R' appears, it is independently selected from -H, -D, -F, -Cl, -Br, -I, -OH, -NH2, -CH3, -CF3, -C2H5, -CN, -SF5, -CHO, -COOH or -C(=O)NH2; m and n are independently selected from integers from 0 to 5; Each occurrence of p is independently selected from integers from 0 to 6; The above C 1-12 Heteroalkyl, C 1-20 Heteroalkyl, 3-12-membered heterocyclic alkyl, 3-20-membered heterocyclic alkyl, 4-20-membered heterocyclic alkenyl, 5-12-membered heteroaryl and 5-20-membered heteroaryl contain 1, 2 or 3 heteroatoms independently selected from O, N and S or heteroatoms selected from -C(=O)O-, -C(=O)-, -C(=S)-, -S(=O), -S(=O)2-, -S(=O)(=NH)-, -C(=O)N(H)-, -N(H)-, -C(=NH)-, -S(=O)2N(H)- and -S(=O)N(H)-.

2. The compound according to claim 1, its optical isomer, or a pharmacologically acceptable salt thereof, wherein, The structure of the compound shown in formula (I) is shown in formula (II) or (III):

3. The compound according to claim 1 or 2, its optical isomer, or a pharmacologically acceptable salt thereof, wherein, R is independently selected from -H, -D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SF5, -CHO, -COOH, -C(=O)NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 1-6 Alkyl-C 1-6 Alkoxy-, C 1-6 Alkyl-C 1-6 Alkylthio-, C 1-6 Alkyl-C 1-6 Alkylamino-, -C 1-6 Alkyl -OH, -C 1-6 Alkyl group -NH2, -C(=O)-C 1-6 Alkyl, -C 1-6 Alkyl-C(=O)-C 1-6 Alkyl group, -NH-C(=O)-C 1-6 Alkyl, -C 1-6 Alkyl-NH-C(=O)-C 1-6 Alkyl group, -NH-S(=O)2-C 1-6 Alkyl, -C 1-6 Alkyl-NH-S(=O)2-C 1-6 Alkyl, C 3-6 Cycloalkyl, phenyl, naphthyl, pyridyl, pyrimidinyl, pyridazinyl, thiophene, pyrroleyl, pyrazolyl, imidazoleyl, triazolyl, piperidinyl, piperazinyl, pyranyl, furanyl, thiazolyl, oxazolyl, or thiaranyl. The C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 1-6 Alkyl-C 1-6 Alkoxy-, C 1-6 Alkyl-C 1-6 Alkylthio-, C 1-6 Alkyl-C 1-6 Alkylamino-, -C 1-6 Alkyl -OH, -C 1-6 Alkyl group -NH2, -C(=O)-C 1-6 Alkyl, -C 1-6 Alkyl-C(=O)-C 1-6 Alkyl group, -NH-C(=O)-C 1-6 Alkyl, -C 1-6 Alkyl-NH-C(=O)-C 1-6 Alkyl group, -NH-S(=O)2-C 1-6 Alkyl, -C 1-6 Alkyl-NH-S(=O)2-C 1-6 Alkyl, C 3-6 Cycloalkyl, phenyl, naphthyl, pyridyl, pyrimidinyl, pyridazinyl, thiophene, pyrroleyl, pyrazolyl, imidazoleyl, triazolyl, piperidinyl, piperazinyl, pyranyl, furanyl, thiazolyl, oxazolyl, and thiaranyl may be optionally substituted with 1, 2, or 3 R's.

4. The compound according to claim 3, its optical isomer, or a pharmacologically acceptable salt thereof, wherein, R is independently selected from -H, -D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SF5, -CHO, -COOH, -C(=O)NH2, -CH3, -CF3, -CHF2, -CH2F, -CF2Cl, -CF2Br, -CF2I, -OCH3, -NHCH3, or -N(CH3)2.

5. The compound according to claim 1 or 2, its optical isomer, or a pharmacologically acceptable salt thereof, wherein, L is selected from single bond, -O-, -OC(R) aa R bb )-、-OC(R aa R bb )-C(R aa R bb )-、-OC(R aa R bb -C(O)- or -OC(R) aa R bb )-C(R aa R bb )-C(O)-.

6. The compound according to claim 5, its optical isomer, or a pharmacologically acceptable salt thereof, wherein, L is selected from single bond, -O-, -OCH2-, -OCH2CH2-, 7. The compound according to claim 1 or 2, its optical isomer, or a pharmacologically acceptable salt thereof, wherein, R1 is selected from -H, -D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SF5, -NO2, -CHO, -COOH, -C(=O)NH2, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6-12 Aryl or 5-12 heteroaryl, wherein C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6-12 The aryl and 5-12 heteroaryl groups may be optionally substituted with 1, 2, 3 or 4 Rs.

8. The compound according to claim 7, its optical isomer, or a pharmacologically acceptable salt thereof, wherein, R1 is selected from -H, -D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SF5, -NO2, -CHO, -COOH, -C(=O)NH2, -CH3, -OCH3, -CH2CH3, -OCH2CH3.

9. The compound according to any one of claims 5 to 8, its optical isomer, or a pharmacologically acceptable salt thereof, wherein, The structural unit -L-R1 is selected from -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SF5, -NO2, -CHO, -COOH, -C(=O)NH2, -OCH3, -OCH2CH3, 10. The compound according to claim 1 or 2, its optical isomer, or a pharmacologically acceptable salt thereof, wherein, Ring A is selected from phenyl, naphthyl, pyridinyl, pyrimidinyl, pyridazinyl, thiophene, pyrroleyl, pyrazolyl, imidazoleyl, triazolyl, piperidinyl, piperazinyl, pyranyl, furanyl, thiazolyl, oxazolyl, thiaranyl, morpholinyl, benzothiazolyl, benzooxazolyl, benzopyrazolyl, indolyl, benzodioxapentylcycloyl or benzodithiapentylcycloyl.

11. The compound according to claim 1 or 2, its optical isomer, or a pharmacologically acceptable salt thereof, wherein, R a Each occurrence is independently selected from -H, -D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SF5, -NO2, -CHO, -COOH, -C(=O)NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 alkylthio or C 1-6 Alkylamino, the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 alkylthio and C 1-6 The alkylamino group can be optionally substituted with 1, 2, 3 or 4 Rs; Or, two adjacent R a Forming phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, thiopheneyl, pyrroleyl, pyrazolyl, imidazolyl, triazolyl, piperidinyl, piperazinyl, pyranyl, furanyl, thiazolyl, oxazolyl, thiaranyl, morpholinyl, cyclopropyl, cyclobutyl, cyclopentyl, dioxapentyl, or dithiapentyl, wherein the phenyl, pyridinyl, pyrimidinyl, pyridazinyl, thiopheneyl, pyrroleyl, pyrazolyl, imidazolyl, triazolyl, piperidinyl, piperazinyl, pyranyl, furanyl, thiazolyl, oxazolyl, thiaranyl, morpholinyl, cyclopropyl, cyclobutyl, cyclopentyl, dioxapentyl, and dithiapentyl groups are optionally substituted with 1, 2, 3, or 4 Rs.

12. The compound according to claim 11, its optical isomer, or a pharmacologically acceptable salt thereof, wherein, R a Each occurrence is independently selected from -H, -D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SF5, -NO2, -CHO, -COOH, -C(=O)NH2, -CH3, -CH2F, -CHF2, or -CF3; Or, two adjacent R a form 13. The compound according to any one of claims 10-12, its optical isomer, or a pharmacologically acceptable salt thereof, wherein, Structural unit Selected from 14. The compound according to claim 1 or 2, its optical isomer, or a pharmacologically acceptable salt thereof, wherein, Ring B is selected from phenyl, naphthyl, pyridinyl, pyrimidinyl, pyridazinyl, thiophene, pyrroleyl, pyrazolyl, imidazoleyl, triazolyl, piperidinyl, piperazinyl, pyranyl, furanyl, thiazolyl, oxazolyl, thiaranyl, morpholinyl, benzothiazolyl, benzooxazolyl, benzopyrazolyl, indolyl, benzodioxapentylcycloyl or benzodithiapentylcycloyl.

15. The compound according to claim 1 or 2, its optical isomer, or a pharmacologically acceptable salt thereof, wherein, R b Each occurrence is independently selected from -H, -D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SF5, -NO2, -CHO, -COOH, -C(=O)NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 alkylthio or C 1-6 Alkylamino, the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 alkylthio and C 1-6 The alkylamino group can be optionally substituted with 1, 2, 3 or 4 Rs; Or, two adjacent R b Forming phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, thiopheneyl, pyrroleyl, pyrazolyl, imidazolyl, triazolyl, piperidinyl, piperazinyl, pyranyl, furanyl, thiazolyl, oxazolyl, thiaranyl, morpholinyl, cyclopropyl, cyclobutyl, cyclopentyl, dioxapentyl, or dithiapentyl, wherein the phenyl, pyridinyl, pyrimidinyl, pyridazinyl, thiopheneyl, pyrroleyl, pyrazolyl, imidazolyl, triazolyl, piperidinyl, piperazinyl, pyranyl, furanyl, thiazolyl, oxazolyl, thiaranyl, morpholinyl, cyclopropyl, cyclobutyl, cyclopentyl, dioxapentyl, and dithiapentyl groups are optionally substituted with 1, 2, 3, or 4 Rs.

16. The compound according to claim 15, its optical isomer, or a pharmacologically acceptable salt thereof, wherein, R b Each occurrence is independently selected from -H, -D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SF5, -NO2, -CHO, -COOH, -C(=O)NH2, -CH3, -CH2F, -CHF2, or -CF3; Or, two adjacent R b form 17. The compound according to any one of claims 14 to 16, its optical isomer, or a pharmacologically acceptable salt thereof, wherein, Structural unit Selected from 18. A compound of the following formula, its optical isomer, or a pharmacologically acceptable salt thereof, selected from...

19. The compound of claim 18, its optical isomer, or a pharmacologically acceptable salt thereof, wherein the compound is selected from...

20. A pharmaceutical composition, wherein, It includes the compound of any one of claims 1 to 19, its optical isomer, or a pharmaceutically acceptable salt thereof.

21. The use of the compound of any one of claims 1 to 19, its optical isomer or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 20 in the preparation of a drug for the prevention or treatment of cancer, systemic diseases, inflammatory diseases, immune system diseases, cardiovascular diseases, gastrointestinal diseases, hepatobiliary diseases, liver diseases, autoimmune diseases, kidney diseases, metabolic diseases, eye diseases, liver fibrosis, respiratory diseases, transplant rejection, pulmonary fibrosis, connective tissue diseases, renal fibrosis, scleroderma, sclerosis, nervous system diseases, intensive care medicine, atopic dermatitis, head and neck cancer, non-small cell lung cancer, cirrhosis, diabetic nephropathy, myocardial fibrosis, metastatic melanoma, non-alcoholic steatohepatitis, plaque psoriasis, and / or esophageal varices.

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