Compounds targeting integrin and their use in RNAi agents

Abstract

The invention provides a ligand compound targeting integrin, which can be conjugated with a small nucleic acid drug molecule in a covalent coupling manner to realize in vivo delivery of the small nucleic acid drug molecule, especially for non-hepatocyte delivery. The invention also provides an RNAi agent comprising the integrin ligand compound.

Description

Compounds targeting integrins and their use in RNAi agents Technical Field

[0001] The present invention relates to small molecule compounds targeting integrins and their use as targeting ligands in RNAi agents. The present invention also relates to intermediates for preparing the small molecule compounds, and RNAi agents, pharmaceutical compositions, disease treatment methods, and uses comprising the small molecule compounds. Background Art

[0002] Integrins are ubiquitous heterodimeric transmembrane glycoprotein receptors that primarily function as signaling proteins in mammals. Each integrin is composed of an α-subunit and a β-subunit, of which there are 18 and 8 variants, respectively, resulting in 24 known heterodimers. The α- and β-subunits form a complex by non-covalent association, forming a ligand-binding site on the surface. As adhesion receptors, integrins possess the remarkable ability to transmit signals in both directions across the membrane. They either bind to extracellular ligands or interact with the cytoskeleton through their intracellular domains. Thus, integrins enable human cells to respond to changes in the extracellular environment (via outside-in signaling) and to influence the extracellular environment itself (via inside-out signaling). When ligands bind to receptors, information from the extracellular space is transmitted intracellularly, leading to changes in cell polarity, cytoskeletal structure, gene expression, cell survival, and proliferation. Conversely, intracellular activators such as talin-1 bind to the cytoplasmic tail of the β subunit, causing conformational changes that shift integrin into a high-affinity state, making it more susceptible to binding to extracellular ligands, thereby promoting cell migration and the assembly and remodeling of the extracellular matrix (ECM). Currently, drugs targeting integrins have been widely developed in areas including cardiovascular disease, inflammatory bowel disease / multiple sclerosis, and dry eye disease.

[0003] siRNA drugs have demonstrated strong therapeutic advantages, and several siRNA drugs have been approved for marketing, but due to the delivery vectors, they are limited to liver targeting. Expanding the application of siRNA drugs to non-liver diseases depends on the development of suitable delivery vectors. Based on the characteristics of integrins as transmembrane proteins, studies on the use of RGD peptides targeting integrins to deliver small nucleic acid drugs have been reported for a long time, but no related drugs have been approved for marketing. Designing small molecule target heads that specifically target integrin receptors and achieving non-liver delivery of small nucleic acid drugs for the treatment of non-liver diseases by covalently coupling and conjugating small nucleic acid drug molecules has important clinical significance.

[0004] Summary of the Invention

[0005] The present invention designs and synthesizes a series of small molecule ligand target heads targeting integrins, which are conjugated to small nucleic acid drug molecules through covalent coupling to achieve in vivo delivery of small nucleic acid drug molecules and expand the disease treatment field of small nucleic acid drugs.

[0006] In one aspect, the present invention provides a compound, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug, or solvate thereof, wherein the compound has the structure shown in Formula Ia:

[0007] in,

[0008] T1 and T2 are independently C or N, and at least one is N, preferably both T1 and T2 are N;

[0009] T3 and T4 are independently C or N, preferably one of T3 and T4 is N, more preferably both T3 and T4 are C;

[0010] Ring B is or absent, where junction 2 is connected to L2;

[0011] R4, R5 and R6 are independently H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl or cyclobutyl, preferably R4, R5 and R6 are independently methyl;

[0012] L1 is -(CH2) n -、-(CH2) m C(O)NH(CH2) n -or-(CH2) m NHC(O)(CH2) n -, m and n are independently an integer from 1 to 10, preferably m and n are independently 1, 2, 3, 4, 5 or 6;

[0013] L2 is -(OCH2CH2) p -、-(CH2) q (OCH2CH2) p -, -NHC(O)(CH2CH2O) p -, -NHC(O)(CH2) q -(OCH2CH2) p -,-C(O)NH(CH2CH2O) p -、-C(O)NH(CH2) q (OCH2CH2) p -, -C(O)(CH2CH2O) p -or-C(O)(CH2) q(OCH2CH2) p -, wherein the left side is connected to the B ring and the right side is connected to R1, and p and q are independently an integer from 1 to 10, preferably q is 2 or 3, preferably p is 3, 4, 5, 6 or 7;

[0014] R1 is -N3, -NH2, -COOH, -NHC(O)CH2SC(O)CH3 or

[0015] Preferably, the compound is selected from compounds 4, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33 and 34.

[0016] In one aspect, the present invention provides a compound, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug, or solvate thereof, wherein the compound has the structure shown in Formula Ib:

[0017] in,

[0018] T1 and T2 are independently C or N, and at least one is N, preferably both T1 and T2 are N;

[0019] T3 and T4 are independently C or N, preferably one of T3 and T4 is N, more preferably both T3 and T4 are C;

[0020] One of e1 and e2 is 1, and the other is 0;

[0021] Ring B is or does not exist, where junction 2 is connected to L2 and junction 2 does not exist when e1 is 0;

[0022] R4 and R5 are independently H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl or cyclobutyl, preferably R4, R5 and R6 are independently methyl;

[0023] L1 is -(CH2) n -、-(CH2) m C(O)NH(CH2) n -or-(CH2) m NHC(O)(CH2) n -, m and n are independently an integer from 1 to 10, preferably m and n are independently 1, 2, 3, 4, 5 or 6;

[0024] When e1 is 1, L2 is -(OCH2CH2) p -、-(CH2) q (OCH2CH2)p -, -NHC(O)(CH2CH2O) p -, -NHC(O)(CH2) q (OCH2CH2) p -,-C(O)NH(CH2CH2O) p -、-C(O)NH(CH2) q (OCH2CH2) p -, -C(O)(CH2CH2O) p -or-C(O)(CH2) q (OCH2CH2) p -, wherein the right side is connected to R1, and p and q are independently an integer from 1 to 10, preferably q is 2 or 3, preferably p is 3, 4, 5, 6 or 7;

[0025] When e2 is 1, L2 is -NHC(O)(CH2)q(OCH2CH2) p -, wherein the right side is connected to R1, p and q are independently an integer from 1 to 10, preferably q is 2 or 3, preferably p is 3, 4, 5, 6 or 7;

[0026] R1 is -N3, -NH2, -COOH, -NHC(O)CH2SC(O)CH3 or

[0027] R9 is H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl or cyclobutyl, R 10 H, or R9, R 10 Together with the C and N to which they are attached, they form a piperidinyl group; preferably R9 is methyl and R 10 H or R9, R 10 Together with the C and N to which they are attached, they form a piperidinyl group;

[0028] Preferably, the compound is compound 35.

[0029] In one aspect, the present invention provides a compound, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug, or solvate thereof, wherein the compound has a structure shown in Formula IIa or IIb:

[0030] in,

[0031] T3 and T4 are independently C or N, preferably one of T3 and T4 is N, more preferably both T3 and T4 are C;

[0032] Ring A is wherein the connection point 1 is connected to L1, and R8 is H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl or halogen, preferably H or halogen, more preferably H or F;

[0033] Ring B is or absent, where junction 2 is connected to L2;

[0034] R4, R5, R6 and R7 are independently H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl or cyclobutyl, wherein preferably R4, R5 and R6 are independently methyl; preferably R7 is H;

[0035] L1 is -(CH2) n -、-(CH2) m C(O)NH(CH2) n -or-(CH2) m NHC(O)(CH2) n -, m and n are independently an integer from 1 to 10, preferably m and n are independently 1, 2, 3, 4, 5 or 6;

[0036] L2 is -(OCH2CH2) p -、-(CH2) q (OCH2CH2) p -, -NHC(O)(CH2CH2O) p -, -NHC(O)(CH2) q -(OCH2CH2) p -,-C(O)NH(CH2CH2O) p -、-C(O)NH(CH2) q (OCH2CH2) p -, -C(O)(CH2CH2O) p -or-C(O)(CH2) q (OCH2CH2) p -, wherein the left side is connected to the B ring and the right side is connected to R1, and p and q are independently an integer from 1 to 10, preferably q is 2 or 3, preferably p is 3, 4, 5, 6 or 7;

[0037] R1 is -N3, -NH2, -COOH, -NHC(O)CH2SC(O)CH3 or

[0038] Preferably, the compound is any one of compounds 5, 36, 37, 38, 39, 40, 41, 42, 43 or 44.

[0039] In one aspect, the present invention provides a compound, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug, or solvate thereof, wherein the compound has a structure shown in Formula IIIa or IIIb:

[0040] in,

[0041] T3 and T4 are independently C or N, preferably one of T3 and T4 is N, more preferably both T3 and T4 are C;

[0042] One of e1 and e2 is 1, and the other is 0;

[0043] Ring B is or does not exist, where junction 2 is connected to L2 and junction 2 does not exist when e1 is 0;

[0044] R4 and R5 are independently H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl or cyclobutyl, preferably methyl;

[0045] L1 is -(CH2) m -、-(CH2) m C(O)NH(CH2) n -or-(CH2) m NHC(O)(CH2) n -, m is an integer from 1 to 10, preferably m is 1, 2, 3, 4, 5 or 6, n is an integer from 0 to 10, preferably n is 0, 1, 2 or 3;

[0046] When e1 is 1, L2 is -(OCH2CH2) p -、-(CH2) q (OCH2CH2) p -, -NHC(O)(CH2CH2O) p -, -NHC(O)(CH2) q (OCH2CH2) p -,-C(O)NH(CH2CH2O) p -、-C(O)NH(CH2) q (OCH2CH2) p -, -C(O)(CH2CH2O) p -or-C(O)(CH2) q (OCH2CH2) p -, wherein the right side is connected to R1, and p and q are independently an integer from 1 to 10, preferably q is 2 or 3, preferably p is 3, 4, 5, 6 or 7;

[0047] When e2 is 1, L2 is -NHC(O)(CH2)q(OCH2CH2) p -, wherein the right side is connected to R1, p and q are independently an integer from 1 to 10, preferably q is 2 or 3, preferably p is 3, 4, 5, 6 or 7;

[0048] R1 is -N3, -NH2, -COOH, -NHC(O)CH2SC(O)CH3 or

[0049] R9 is H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl or cyclobutyl, R 10 H, or R9, R 10 Together with the C and N to which they are attached, they form a piperidinyl group; preferably R9 is methyl and R 10 H or R9, R 10 Together with the C and N to which they are attached, they form a piperidinyl group;

[0050] Preferably, the compound is compound 6, 7, 8, 9, 45, 46 or 47.

[0051] In one aspect, the present invention provides a compound, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug, or solvate thereof, wherein the compound has the structure shown in Formula IVa:

[0052] in,

[0053] One of e1, e2, and e3 is 1, and the other two are 0;

[0054] Ring B is or does not exist, where junction 2 is connected to L2 and junction 2 does not exist when e1 is 0;

[0055] R4 and R5 are independently H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl or cyclobutyl, preferably R4 and R5 are both methyl;

[0056] When e1 or e3 is 1, L2 is -(OCH2CH2) p -、-(CH2) q (OCH2CH2) p -、-NHC(O)-(CH2CH2O) p -, -NHC(O)(CH2) q (OCH2CH2) p -,-C(O)NH(CH2CH2O) p-、-C(O)NH(CH2) q -(OCH2CH2) p -, -C(O)(CH2CH2O) p -or-C(O)(CH2) q (OCH2CH2) p -, wherein the right side is connected to R1, and p and q are independently an integer from 1 to 10, preferably q is 2 or 3, preferably p is 3, 4, 5, 6 or 7;

[0057] When e2 is 1, L2 is -NHC(O)(CH2)q(OCH2CH2) p -, wherein the right side is connected to R1, p and q are independently an integer from 1 to 10, preferably q is 2 or 3, preferably p is 3, 4, 5, 6 or 7;

[0058] R1 is -N3, -NH2, -COOH, -NHC(O)CH2SC(O)CH3 or

[0059] R 11 H, halogen, halogenated C 1-4 alkyl, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, phenyl, morpholinyl, methoxyethoxy or ethoxymethoxy;

[0060] Preferably, the compound is compound 13, 14, 15, 18, 20, 48, 49, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 71, 72, 73, 83, 84, 85, 86 or 87.

[0061] In one aspect, the present invention provides a compound, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug, or solvate thereof, wherein the compound has the structure shown in Formula IVb:

[0062] One of e1 and e2 is 1, and the other is 0;

[0063] Ring B is or absent, where junction 2 is connected to L2;

[0064] R4, R5 and R6 are independently H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl or cyclobutyl, preferably R4, R5 and R6 are all methyl;

[0065] L2 is -(OCH2CH2) p -、-(CH2) q(OCH2CH2) p -, -NHC(O)(CH2CH2O) p -, -NHC(O)(CH2) q -(OCH2CH2) p -,-C(O)NH(CH2CH2O) p -、-C(O)NH(CH2) q (OCH2CH2) p -, -C(O)(CH2CH2O) p -or-C(O)(CH2) q (OCH2CH2) p -, wherein the left side is connected to the B ring and the right side is connected to R1, and p and q are independently an integer from 1 to 10, preferably q is 2 or 3, preferably p is 3, 4, 5, 6 or 7;

[0066] R1 is -N3, -NH2, -COOH, -NHC(O)CH2SC(O)CH3 or

[0067] L1 is -(CH2) m -、-(CH2) m C(O)NH(CH2) n -or-(CH2) m NHC(O)(CH2) n -, m is an integer from 1 to 10, preferably m is 1, 2, 3, 4, 5 or 6, n is an integer from 0 to 10, preferably n is 0, 1, 2 or 3;

[0068] R 11 is H, halogen, halomethyl, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, phenyl, morpholinyl, methoxyethoxy or ethoxymethoxy, preferably R 11 is H;

[0069] Preferably, the compound is compound 50, 51, 52, 74, 75, 76, 77, 78, 79 or 80.

[0070] In one aspect, the present invention provides a compound, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug, or solvate thereof, wherein the compound has the structure shown in Formula Va:

[0071] One of e1, e2, and e3 is 1, and the other two are 0;

[0072] R9 is H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl or cyclobutyl, R 10 H, or R9, R 10 Together with the C and N atoms to which they are attached, they form a piperidinyl group, preferably R9 is methyl and R 10 is H;

[0073] R 13 and R 14 Each is H, or R 13 、R 14 Together with the C and N atoms to which they are attached, they form a piperidinyl group;

[0074] L1 and L1' are independently -(CH2) m -、-(CH2) m C(O)NH(CH2) n -or-(CH2) m NHC(O)(CH2) n -, m is an integer from 1 to 10, preferably m is 1, 2, 3, 4, 5 or 6, n is an integer from 0 to 10, preferably n is 0, 1, 2 or 3;

[0075] When e1 is 1, L2 is -(OCH2CH2) p -、-(CH2) q (OCH2CH2) p -, -NHC(O)(CH2CH2O) p -, -NHC(O)(CH2) q (OCH2CH2) p -,-C(O)NH(CH2CH2O) p -、-C(O)NH(CH2) q (OCH2CH2) p -, -C(O)(CH2CH2O) p -or-C(O)(CH2) q (OCH2CH2) p -, wherein the right side is connected to R1, and p and q are independently an integer from 1 to 10, preferably q is 2 or 3, preferably p is 3, 4, 5, 6 or 7;

[0076] When e2 is 1, L2 is -(CH2)q(OCH2CH2) p -, wherein the right side is connected to R1, p and q are independently an integer from 1 to 10, preferably q is 1 or 2, preferably p is 3, 4, 5, 6 or 7;

[0077] When e3 is 1, L2 is -NHC(O)(CH2)q(OCH2CH2) p-, wherein the right side is connected to R1, p and q are independently an integer from 1 to 10, preferably q is 2 or 3, preferably p is 3, 4, 5, 6 or 7;

[0078] R1 is -N3, -NH2, -COOH, -NHC(O)CH2SC(O)CH3 or

[0079] Preferably, the compound is compound 16, 17, 64, 65, 66 or 67.

[0080] In one aspect, the present invention provides a compound, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug, or solvate thereof, wherein the compound has a structure shown in Formula Vb:

[0081] in

[0082] One of e1 and e2 is 1, and the other is 0;

[0083] R6 is H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl or cyclobutyl, preferably methyl;

[0084] R 13 and R 14 Each is H, or R 13 、R 14 Together with the C and N atoms to which they are attached, they form a piperidinyl group;

[0085] L1 and L1' are independently -(CH2) m -、-(CH2) m C(O)NH(CH2) n -or-(CH2) m NHC(O)(CH2) n -, m is an integer from 1 to 10, preferably m is 1, 2, 3, 4, 5 or 6, n is an integer from 0 to 10, preferably n is 0, 1, 2 or 3;

[0086] When e1 is 1, L2 is -(OCH2CH2) p -、-(CH2) q (OCH2CH2) p -, -NHC(O)(CH2CH2O) p -, -NHC(O)(CH2) q (OCH2CH2) p -,-C(O)NH(CH2CH2O) p -、-C(O)NH(CH2) q(OCH2CH2) p -, -C(O)(CH2CH2O) p -or-C(O)(CH2) q (OCH2CH2) p -, wherein the right side is connected to R1, and p and q are independently an integer from 1 to 10, preferably q is 2 or 3, preferably p is 3, 4, 5, 6 or 7;

[0087] When e2 is 1, L2 is -(CH2)q(OCH2CH2) p -, wherein the right side is connected to R1, p and q are independently an integer from 1 to 10, preferably q is 1 or 2, preferably p is 3, 4, 5, 6 or 7;

[0088] R1 is -N3, -NH2, -COOH, -NHC(O)CH2SC(O)CH3 or

[0089] Preferably, the compound is compound 69 or 70.

[0090] In one aspect, the present invention provides a compound, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug, or solvate thereof, wherein the compound has the structure shown in Formula Vc:

[0091] One of e1, e2, and e3 is 1, and the other two are 0;

[0092] R9 is H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl or cyclobutyl, R 10 H, or R9, R 10 Together with the C and N atoms to which they are attached, they form a piperidinyl group, preferably R9 is methyl and R 10 is H;

[0093] R 13 and R 14 Each is H, or R 13 、R 14 Together with the C and N atoms to which they are attached, they form a piperidinyl group;

[0094] L1 is -(CH2) m -、-(CH2) m C(O)NH(CH2) n -or-(CH2) m NHC(O)(CH2) n-, m is an integer from 1 to 10, preferably m is 1, 2, 3, 4, 5 or 6, n is an integer from 0 to 10, preferably n is 0, 1, 2 or 3;

[0095] When e1 is 1, L2 is -(OCH2CH2) p -、-(CH2) q (OCH2CH2) p -, -NHC(O)(CH2CH2O) p -, -NHC(O)(CH2) q (OCH2CH2) p -,-C(O)NH(CH2CH2O) p -、-C(O)NH(CH2) q (OCH2CH2) p -, -C(O)(CH2CH2O) p -or-C(O)(CH2) q (OCH2CH2) p -, wherein the right side is connected to R1, and p and q are independently an integer from 1 to 10, preferably q is 2 or 3, preferably p is 3, 4, 5, 6 or 7;

[0096] When e2 is 1, L2 is -(CH2)q(OCH2CH2) p -, wherein the right side is connected to R1, p and q are independently an integer from 1 to 10, preferably q is 1 or 2, preferably p is 3, 4, 5, 6 or 7;

[0097] When e3 is 1, L2 is -NHC(O)(CH2)q(OCH2CH2) p -, wherein the right side is connected to R1, p and q are independently an integer from 1 to 10, preferably q is 2 or 3, preferably p is 3, 4, 5, 6 or 7;

[0098] R1 is -N3, -NH2, -COOH, -NHC(O)CH2SC(O)CH3 or

[0099] Ring B is or does not exist, where junction 2 is connected to L2 and junction 2 does not exist when e1 is 0;

[0100] R4 and R5 are independently H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl or cyclobutyl, preferably R4 and R5 are both methyl;

[0101] Preferably, the compound is compound 68.

[0102] In one aspect, the present invention provides a compound, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug, or solvate thereof, wherein the compound has the structure shown in Formula Ia':

[0103] T1 and T2 are independently C or N, and at least one is N, preferably both T1 and T2 are N;

[0104] T3 and T4 are independently C or N, preferably one of T3 and T4 is N, more preferably both T3 and T4 are C;

[0105] Ring B is or does not exist;

[0106] R4, R5 and R6 are independently H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl or cyclobutyl, preferably R4, R5 and R6 are independently methyl;

[0107] L1 is -(CH2) n -、-(CH2) m C(O)NH(CH2) n -or-(CH2) m NHC(O)(CH2) n -, m and n are independently an integer from 1 to 10, preferably m and n are independently 1, 2, 3, 4, 5 or 6;

[0108] Preferably, the compound is selected from compounds 4', 21', 22', 23', 24', 31', 32', 33' and 34'.

[0109] In one aspect, the present invention provides a compound, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug, or solvate thereof, wherein the compound has a structure shown in Formula Ib':

[0110] in,

[0111] T1 and T2 are independently C or N, and at least one is N, preferably both T1 and T2 are N;

[0112] T3 and T4 are independently C or N, preferably one of T3 and T4 is N, more preferably both T3 and T4 are C;

[0113] Ring B is or does not exist;

[0114] R4 and R5 are independently H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl or cyclobutyl, preferably R4, R5 and R6 are independently methyl;

[0115] R3 is H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, amino or C 1-3 Alkylamino, preferably R3 is H or methylamino;

[0116] L1 is -(CH2) n -、-(CH2) m C(O)NH(CH2) n -or-(CH2) m NHC(O)(CH2) n -, m and n are independently an integer from 1 to 10, preferably m and n are independently 1, 2, 3, 4, 5 or 6;

[0117] R9 is H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl or cyclobutyl, R 10 H, or R9, R 10 Together with the C and N to which they are attached, they form a piperidinyl group; preferably R9 is methyl and R 10 H or R9, R 10 Together with the C and N to which they are attached, they form a piperidinyl group;

[0118] Preferably, the compound is compound 35'.

[0119] In one aspect, the present invention provides a compound, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug, or solvate thereof, wherein the compound has a structure shown in Formula IIa' or IIb':

[0120] in,

[0121] T3 and T4 are independently C or N, preferably one of T3 and T4 is N, more preferably both T3 and T4 are C;

[0122] Ring A is wherein the connection point 1 is connected to L1, and R8 is H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl or halogen, preferably H or halogen, more preferably H or F;

[0123] Ring B is or does not exist;

[0124] R4, R5, R6 and R7 are independently H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl or cyclobutyl, wherein preferably R4, R5 and R6 are independently methyl; preferably R7 is H;

[0125] L1 is -(CH2) n -、-(CH2) m C(O)NH(CH2) n -or-(CH2) m NHC(O)(CH2) n -, m and n are independently an integer from 1 to 10, preferably m and n are independently 1, 2, 3, 4, 5 or 6;

[0126] Preferably, the compound is any one of compounds 5', 36', 37', 38', 39', 40', 41 ', 42', 43' or 44'.

[0127] In one aspect, the present invention provides a compound, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug, or solvate thereof, wherein the compound has a structure shown in Formula IIIa' or IIIb':

[0128] in,

[0129] T3 and T4 are independently C or N, preferably one of T3 and T4 is N, more preferably both T3 and T4 are C;

[0130] Ring B is

[0131] R4 and R5 are independently H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl or cyclobutyl, preferably methyl;

[0132] L1 is -(CH2) m -、-(CH2) m C(O)NH(CH2) n -or-(CH2) m NHC(O)(CH2) n -, m is an integer from 1 to 10, preferably m is 1, 2, 3, 4, 5 or 6, n is an integer from 0 to 10, preferably n is 0, 1, 2 or 3;

[0133] R3 is H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, amino or C 1-3 Alkylamino, preferably R3 is H or methylamino;

[0134] R9 is H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl or cyclobutyl, R 10 H, or R9, R 10 Together with the C and N to which they are attached, they form a piperidinyl group; preferably R9 is methyl and R 10 H or R9, R 10 Together with the C and N to which they are attached, they form a piperidinyl group;

[0135] Preferably, the compound is compound 6', 7', 8', 9' or 47'.

[0136] In one aspect, the present invention provides a compound, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug, or solvate thereof, wherein the compound has a structure shown in Formula IVa':

[0137] in,

[0138] Ring B is

[0139] R4 and R5 are independently H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl or cyclobutyl, preferably R4 and R5 are both methyl;

[0140] R3 is H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, amino or C 1-3 Alkylamino, preferably R3 is H or methylamino;

[0141] R 11 H, halogen, halogenated C 1-4 alkyl, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, phenyl, morpholinyl, methoxyethoxy or ethoxymethoxy;

[0142] Preferably, the compound is compound 48', 49', 59', 60', 73' or 85'.

[0143] In one aspect, the present invention provides a compound, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug, or solvate thereof, wherein the compound has a structure shown in Formula IVb':

[0144] in

[0145] Ring B is or does not exist;

[0146] R4, R5 and R6 are independently H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl or cyclobutyl, preferably R4, R5 and R6 are all methyl;

[0147] L1 is -(CH2) m -、-(CH2) m C(O)NH(CH2) n -or-(CH2) m NHC(O)(CH2) n -, m is an integer from 1 to 10, preferably m is 1, 2, 3, 4, 5 or 6, n is an integer from 0 to 10, preferably n is 0, 1, 2 or 3;

[0148] R 11 is H, halogen, halomethyl, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, phenyl, morpholinyl, methoxyethoxy or ethoxymethoxy, preferably R 11 is H;

[0149] Preferably, the compound is compound 50', 51', 52', 76' or 79'.

[0150] In one aspect, the present invention provides a compound, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug, or solvate thereof, wherein the compound has a structure shown in Formula Va':

[0151] in

[0152] R3 is H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, amino or C 1-3 Alkylamino, preferably R3 is H or methylamino;

[0153] R9 is H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl or cyclobutyl, R 10 H, or R9, R 10 Together with the C and N atoms to which they are attached, they form a piperidinyl group, preferably R9 is methyl and R 10 is H;

[0154] R 12 is methyl, ethyl, n-propyl, isopropyl, cyclopropyl or cyclobutyl, preferably R 12 is methyl;

[0155] R 13 、R 14 Together with the C and N atoms to which they are attached, they form a piperidinyl group;

[0156] L1 and L1' are independently -(CH2) m -、-(CH2) m C(O)NH(CH2) n -or-(CH2) m NHC(O)(CH2) n -, m is an integer from 1 to 10, preferably m is 1, 2, 3, 4, 5 or 6, n is an integer from 0 to 10, preferably n is 0, 1, 2 or 3;

[0157] Preferably, the compound is compound 64'.

[0158] In one aspect, the present invention provides a compound, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug, or solvate thereof, wherein the compound has a structure shown in Formula Vb':

[0159] in,

[0160] R6 is H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl or cyclobutyl, preferably methyl;

[0161] R 12 is methyl, ethyl, n-propyl, isopropyl, cyclopropyl or cyclobutyl, preferably R 12 is methyl;

[0162] R 13 and R 14 Each is H, or R 13 、R 14 Together with the C and N atoms to which they are attached, they form a piperidinyl group;

[0163] L1 and L1' are independently -(CH2) m -、-(CH2) m C(O)NH(CH2) n -or-(CH2) m NHC(O)(CH2) n -, m is an integer from 1 to 10, preferably m is 1, 2, 3, 4, 5 or 6, n is an integer from 0 to 10, preferably n is 0, 1, 2 or 3;

[0164] Preferably, the compound is compound 69' or 70'.

[0165] In one aspect, the present invention provides a compound, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug, or solvate thereof, wherein the compound has a structure shown in Formula Vc':

[0166] R3 is H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, amino or C 1-3 Alkylamino, preferably R3 is H or methylamino;

[0167] R9 is H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl or cyclobutyl, R 10 H, or R9, R 10 Together with the C and N atoms to which they are attached, they form a piperidinyl group, preferably R9 is methyl and R 10 is H;

[0168] R 12 is methyl, ethyl, n-propyl, isopropyl, cyclopropyl or cyclobutyl, preferably R 12 is methyl;

[0169] R 13 and R 14 Each is H, or R 13 、R 14 Together with the C and N atoms to which they are attached, they form a piperidinyl group;

[0170] L1 is -(CH2) m -、-(CH2) m C(O)NH(CH2) n -or-(CH2) m NHC(O)(CH2) n -, m is an integer from 1 to 10, preferably m is 1, 2, 3, 4, 5 or 6, n is an integer from 0 to 10, preferably n is 0, 1, 2 or 3;

[0171] Ring B is or does not exist;

[0172] R4 and R5 are independently H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl or cyclobutyl, preferably R4 and R5 are both methyl;

[0173] Preferably, the compound is compound 68'.

[0174] In one aspect, the present invention provides a compound, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug, or solvate thereof, wherein the compound has the structure shown in Formula Ia":

[0175] T1 and T2 are independently C or N, and at least one is N, preferably both T1 and T2 are N;

[0176] T3 and T4 are independently C or N, preferably one of T3 and T4 is N, more preferably both T3 and T4 are C;

[0177] Ring B is or not present, wherein the connection point 2 is a wavy line in Formula Ia", the wavy line Indicates a key;

[0178] R4, R5 and R6 are independently H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl or cyclobutyl, preferably R4, R5 and R6 are independently methyl;

[0179] L1 is -(CH2) n -、-(CH2) m C(O)NH(CH2) n -or-(CH2) m NHC(O)(CH2) n -, m and n are independently an integer from 1 to 10, preferably m and n are independently 1, 2, 3, 4, 5 or 6;

[0180] Preferably, the compound is selected from the group consisting of: 4", 21", 22", 23", 24", 31", 32", 33" and 34".

[0181] In one aspect, the present invention provides a compound, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug, or solvate thereof, wherein the compound has a structure shown in Formula Ib":

[0182] in,

[0183] T1 and T2 are independently C or N, and at least one is N, preferably both T1 and T2 are N;

[0184] T3 and T4 are independently C or N, preferably one of T3 and T4 is N, more preferably both T3 and T4 are C;

[0185] Ring B is or absent, wherein connection point 2 is the wavy line connected to ring B in Formula Ib";

[0186] R4 and R5 are independently H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl or cyclobutyl, preferably R4 and R5 are independently methyl;

[0187] L1 is -(CH2) n -、-(CH2) m C(O)NH(CH2) n -or-(CH2) m NHC(O)(CH2) n -, m and n are independently an integer from 1 to 10, preferably m and n are independently 1, 2, 3, 4, 5 or 6;

[0188] R9 is H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl or cyclobutyl, R 10 H, or R9, R 10 Together with the C and N to which they are attached, they form a piperidinyl group; preferably R9 is methyl and R 10 H or R9, R 10 Together with the C and N to which they are attached, they form a piperidinyl group; and

[0189] The wavy line in Formula Ib" indicates a bond, and one of the two tildes is absent;

[0190] Preferably, the compound has the structure shown in Formula Ib"-1:

[0191] Among them, T1, T2, T3, T4, L1, R9, R 10 and the wavy line have the same definitions as the corresponding substituents in formula Ib",

[0192] Ring B is or absent, wherein R4 and R5 are independently H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl or cyclobutyl, preferably R4 and R5 are independently methyl;

[0193] Preferably, the compound is compound 35".

[0194] In one aspect, the present invention provides a compound, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug, or solvate thereof, wherein the compound has a structure shown in Formula IIa" or IIb":

[0195] in,

[0196] T3 and T4 are independently C or N, preferably one of T3 and T4 is N, more preferably both T3 and T4 are C;

[0197] Ring A is wherein the connection point 1 is connected to L1, and R8 is H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl or halogen, preferably H or halogen, more preferably H or F;

[0198] Ring B is or not present, wherein the connection point 2 is a wavy line in Formula IIa" or IIb", the wavy line Indicates a key;

[0199] R4, R5, R6 and R7 are independently H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl or cyclobutyl, wherein preferably R4, R5 and R6 are independently methyl; preferably R7 is H;

[0200] L1 is -(CH2) n -、-(CH2) m C(O)NH(CH2) n -or-(CH2) m NHC(O)(CH2) n -, m and n are independently an integer from 1 to 10, preferably m and n are independently 1, 2, 3, 4, 5 or 6;

[0201] Preferably, the compound is selected from the group consisting of: 5", 36", 37", 38", 39", 40", 41", 42", 43" and 44".

[0202] In one aspect, the present invention provides a compound, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug, or solvate thereof, wherein the compound has a structure shown in Formula IIIa" or IIIb":

[0203] in,

[0204] T3 and T4 are independently C or N, preferably one of T3 and T4 is N, more preferably both T3 and T4 are C;

[0205] Ring B is or absent, wherein the connection point 2 is the wavy line connected to the B ring in Formula IIIa" or IIIb';

[0206] R4 and R5 are independently H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl or cyclobutyl, preferably methyl;

[0207] L1 is -(CH2) m -、-(CH2) m C(O)NH(CH2) n -or-(CH2) m NHC(O)(CH2) n -, m is an integer from 1 to 10, preferably m is 1, 2, 3, 4, 5 or 6, n is an integer from 0 to 10, preferably n is 0, 1, 2 or 3;

[0208] R9 is H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl or cyclobutyl, R 10 H, or R9, R 10 Together with the C and N to which they are attached, they form a piperidinyl group; preferably R9 is methyl and R 10 H or R9, R 10 Together with the C and N to which they are attached, they form a piperidinyl group; and

[0209] The wavy lines in Formula IIIa" and Formula IIIb" indicates a bond, and one of the two tildes is absent;

[0210] Alternatively, the compound has a structure shown in Formula IIIa"-1 or IIIb"-1:

[0211] Among them, T3, T4, L1, R9, R 10 and the wavy line have the same definitions as the corresponding substituents in formula IIIa" or IIIb",

[0212] Ring B is or absent, wherein R4 and R5 are independently H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl or cyclobutyl, preferably R4 and R5 are independently methyl;

[0213] Preferably, the compound is selected from the group consisting of: 6", 7", 8", 9", 45", 46" and 47".

[0214] In one aspect, the present invention provides a compound, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug, or solvate thereof, wherein the compound has a structure shown in Formula IVa":

[0215] in,

[0216] Ring B is or absent, wherein the connection point 2 is the wavy line connected to the B ring in Formula IVa";

[0217] R4 and R5 are independently H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl or cyclobutyl, preferably R4 and R5 are both methyl;

[0218] R 11 H, halogen, halogenated C 1-4 alkyl, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, phenyl, morpholinyl, methoxyethoxy, or ethoxymethoxy; and

[0219] The wavy line in Formula IVa indicates a bond, and one of the two tildes is absent;

[0220] Alternatively, the compound has the structure shown in Formula IVa"-1:

[0221] where R 11 and the wavy line has the same meaning as R in Formula IVa"' 11 Same definition as the wavy line,

[0222] Ring B is or absent, wherein R4 and R5 are independently H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl or cyclobutyl, preferably R4 and R5 are independently methyl;

[0223] Preferably, the compound is selected from the group consisting of: 13", 14", 15", 18", 20", 48", 49", 53", 54", 55", 56", 57", 58", 59", 60", 61", 62", 63", 71", 72", 73", 83", 84", 85", 86" and 87".

[0224] In one aspect, the present invention provides a compound, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug, or solvate thereof, wherein the compound has a structure shown in Formula IVb":

[0225] Ring B is or not present, wherein the connection point 2 is a wavy line in Formula IVb", Indicates a key;

[0226] R4, R5 and R6 are independently H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl or cyclobutyl, preferably R4, R5 and R6 are all methyl;

[0227] L1 is -(CH2) m -、-(CH2) m C(O)NH(CH2) n -or-(CH2) m NHC(O)(CH2) n -, m is an integer from 1 to 10, preferably m is 1, 2, 3, 4, 5 or 6, n is an integer from 0 to 10, preferably n is 0, 1, 2 or 3;

[0228] R 11 is H, halogen, halomethyl, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, phenyl, morpholinyl, methoxyethoxy or ethoxymethoxy, preferably R 11 is H;

[0229] Preferably, the compound is selected from the group consisting of: 50", 51", 52", 74", 75", 76", 77", 78", 79" and 80".

[0230] In one aspect, the present invention provides a compound, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug, or solvate thereof, wherein the compound has a structure shown in Formula Va":

[0231] in

[0232] R9 is H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl or cyclobutyl, R 10 H, or R9, R 10 Together with the C and N atoms to which they are attached, they form a piperidinyl group, preferably R9 is methyl and R 10 is H;

[0233] R 13 and R 14 Each is H, or R 13 、R 14 Together with the C and N atoms to which they are attached, they form a piperidinyl group;

[0234] L1 and L1' are independently -(CH2) m -、-(CH2) m C(O)NH(CH2) n -or-(CH2) m NHC(O)(CH2) n-, m is an integer from 1 to 10, preferably m is 1, 2, 3, 4, 5 or 6, n is an integer from 0 to 10, preferably n is 0, 1, 2 or 3; and

[0235] The wavy line in formula Va indicates a bond, and two of the three tildes are absent;

[0236] Alternatively, the compound has a structure shown in formula Va"-1, Va"-2 or Va"-3:

[0237] Among them, R9, R 10 、R 13 、R 14 , L1, L1' and the wavy line have the same definitions as the corresponding substituents in formula Va";

[0238] Preferably, the compound is selected from the group consisting of: 16", 17", 64", 65", 66" and 67".

[0239] In one aspect, the present invention provides a compound, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug, or solvate thereof, wherein the compound has a structure shown in Formula Vb":

[0240] in,

[0241] R6 is H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl or cyclobutyl, preferably methyl;

[0242] R 13 and R 14 Each is H, or R 13 、R 14 Together with the C and N atoms to which they are attached, they form a piperidinyl group;

[0243] L1 and L1' are independently -(CH2) m -、-(CH2) m C(O)NH(CH2) n -or-(CH2) m NHC(O)(CH2) n -, m is an integer from 1 to 10, preferably m is 1, 2, 3, 4, 5 or 6, n is an integer from 0 to 10, preferably n is 0, 1, 2 or 3; and

[0244] The wavy line in formula Vb" indicates a bond, and one of the two tildes is absent;

[0245] Alternatively, the compound has a structure shown in Formula Vb"-1 or Vb"-2:

[0246] Among them, R6, R 13 、R 14 , L1, L1' and the wavy line have the same definitions as the corresponding substituents in formula Vb";

[0247] Preferably, the compound is selected from: 69" and 70".

[0248] In one aspect, the present invention provides a compound, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug, or solvate thereof, wherein the compound has a structure shown in Formula Vc":

[0249] in

[0250] R9 is H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl or cyclobutyl, R 10 H, or R9, R 10 Together with the C and N atoms to which they are attached, they form a piperidinyl group, preferably R9 is methyl and R 10 is H;

[0251] R 13 and R 14 Each is H, or R 13 、R 14 Together with the C and N atoms to which they are attached, they form a piperidinyl group;

[0252] L1 is -(CH2) m -、-(CH2) m C(O)NH(CH2) n -or-(CH2) m NHC(O)(CH2) n -, m is an integer from 1 to 10, preferably m is 1, 2, 3, 4, 5 or 6, n is an integer from 0 to 10, preferably n is 0, 1, 2 or 3;

[0253] Ring B is or absent, wherein connection point 2 is the wavy line connected to ring B in formula Vc”;

[0254] R4 and R5 are independently H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl or cyclobutyl, preferably R4 and R5 are both methyl; and

[0255] The wavy line in the formula Vc indicates a bond, and two of the three tildes are absent;

[0256] Alternatively, the compound has the structure shown in Formula Vc"-1:

[0257] Among them, R9, R 10 、R 13 、R 14 , L1, B ring and wavy line have the same definitions as the corresponding substituents in formula Vc";

[0258] Alternatively, the compound has a structure shown in formula Vc"-2 or Vc"-3:

[0259] Among them, R9, R 10 、R 13 、R 14 , L1 and the wavy line have the same definitions as the corresponding substituents in formula Vc", and

[0260] Ring B is or absent, wherein R4 and R5 are independently H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl or cyclobutyl, preferably R4 and R5 are independently methyl;

[0261] Preferably, the compound is compound 68".

[0262] In one aspect, the present invention provides an RNAi agent or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein the RNAi agent has a structure shown in Formula VI, VIa, VIb, VIc, VId, VIe, VIf, VIg, VIh, VIi, VIj or VIk:

[0263] in,

[0264] It is an oligonucleotide, preferably siRNA or ASO, wherein the siRNA or ASO is linked to L via a phosphate group, a phosphorothioate group 21 and / or L 11 connected;

[0265] z1 and z2 are independently 0 or 1, and z1 and z2 are not 0 at the same time;

[0266] y1 and y2 are independently 1, 2 or 3;

[0267] Each Ligand is independently selected from Formula Ia" of claim 19, Formula Ib" or Formula Ib"-1 of claim 20, Formula IIa" or IIb" of claim 21, Formula IIIa", IIIb", IIIa"-1 or IIIb"-1 of claim 22, Formula IVa" or IVa"-1 of claim 23, Formula IVb" of claim 24, Formula Va", Va"-1, Va"-2 or Va"-3 of claim 25, Formula Vb", Vb"-1 or Vb"-2 of claim 26, and Formula Vc", Vc"-1, Vc"-2 or Vc"-3 of claim 27;

[0268] L 11 and L 21 Independently selected from:

[0269] wherein n and m are integers from 0 to 10, preferably from 2 to 6, and the attachment point 1 is connected to the oligonucleotide, and the attachment point 2 is connected to L 12 or L 22 ;

[0270] L 12 and L 22 are independently a bond or a branching group, the branching group being independently selected from:

[0271] wherein n is an integer from 0 to 10, preferably an integer from 2 to 6, and the connection point 1 is connected to L 11 or L 21 , connect points 2, 3 and 4 to L 13 or L 23 ;

[0272] L 13 and L 23 Independently selected from:

[0273] wherein n and m are integers from 0 to 10, preferably integers from 2 to 6, and the wavy line on the left side of the formula is connected to L 12 or L 22 , the wavy line on the right side of the formula is connected to Ligand;

[0274] Preferably, L 21 , L 22 and L 23 Together they form a structure selected from the following, wherein the left side of the formula is linked to the oligonucleotide via a phosphate group or a phosphorothioate group:

[0275] Preferably, L 11 , L 12 and L13 Together they form a structure selected from the following, wherein the left side of the formula is linked to the oligonucleotide via a phosphate group or a phosphorothioate group:

[0276] Preferably, the structure of the RNAi agent is selected from the group consisting of Formula 201-21, 202-21, 203-21, 204-21, 205-21, 206-21, 207-21, 208-21, 209-21, 210-21, 211-21, 212-21, 213-5, 214-5, 215-5, 216-5, 217-5, 218-5, 219-5, 220-5, 221-5, 222-5, 223-5, 224-5, 225-6, 226-6, 227-6, 228-6, 229-6, 230-6, 231-6, 232-6, 233-6, 234-6, 235-6, 236-6, 237-7 , 238-7, 239-7, 240-7, 241-7, 242-7, 243-7, 244-7, 245-7, 246-7, 247-7, 248-7, 249-8, 250-8, 251-8, 252-8, 253-8, 254-8, 255-8, 256-8, 257-8, 258- 8, 259-8, 260-8, 261-9, 262-9, 263-9, 264-9, 265-9, 266-9, 267-9, 268-9, 269-9, 270-9, 271-9, 272-9, 273-13, 274-13, 275-13, 276-13, 277-13, 278- 13, 279-13, 280-13, 281-13, 282-13, 283-13, 284-13, 285-14, 286-14, 287-14, 288-14, 289-14, 290-14, 291-14, 292-14, 293-14, 294-14, 295-14, 296 -14, 297-15, 298-15, 299-15, 300-15, 301-15, 302-15, 303-15, 304-15, 305-15, 306-15, 307-15, 308-15, 309-18, 310-18, 311-18, 312-18, 313-18, 314-18 4-18, 315-18, 316-18, 317-18, 318-18, 319-18, 320-18, 321-20, 322-20, 323-20, 324-20, 325-20, 326-20, 327-20, 328-20, 329-20, 330-20, 331-20, 3 32-20, 333-16, 334-16, 335-16, 336-16, 337-16, 338-16, 339-16, 340-16, 341-16, 342-16, 343-16, 344-16, 345-17, 346-17, 347-17, 348-17, 349-17,The structural formula shown in any one of 350-17, 351-17, 352-17, 353-17, 354-17, 355-17 and 356-17. BRIEF DESCRIPTION OF THE DRAWINGS

[0277] FIG1 shows that some compounds of the present invention can effectively inhibit RAGE-mRNA in rats.

[0278] FIG2 shows that some compounds of the present invention can effectively inhibit the expression of RAGE protein in rat serum. DETAILED DESCRIPTION

[0279] definition

[0280] In the present invention, the compounds of the present invention include tautomers, mesoforms, racemates, enantiomers, and / or diastereomers of the compounds.

[0281] In the present invention, the term "diastereomer" generally refers to a stereoisomer with two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers may have different physical properties, for example, melting points, boiling points, spectral properties and reactivity.

[0282] In the present invention, the terms "tautomer" or "tautomeric form" are used interchangeably and generally refer to structural isomers of different energies that are interconvertible via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include interconversions via reorganization of some of the bonding electrons.

[0283] As used herein, the term "meso" generally refers to a molecule containing asymmetric atoms but possessing symmetry factors resulting in a total optical rotation of zero. The term "racemate" or "racemic mixture" refers to a composition consisting of equimolar amounts of two enantiomeric species.

[0284] In the present invention, some atoms of the compounds of the present invention may appear in more than one isotopic form. For example, hydrogen may appear in the form of protium ( 1 H), deuterium ( 2 H) and tritium ( 3 H), carbon can exist in three different isotopes ( 12 C. 13 C and 14C) naturally occurring. Examples of isotopes that can be incorporated into the compounds of the present invention also include, but are not limited to 15 N. 18 O. 17 O. 18 F. 32 P. 33 P. 129 I. 131 I. 123 I. 124 I. 125 I, or similar isotopes. Thus, the compounds of the present invention may be enriched in one or more of these isotopes relative to their natural abundance. As is known to those skilled in the art, such isotopically enriched compounds may be used in a variety of applications. For example, heavy isotopes such as deuterium ( 2 Deuterium (H) substitution may offer certain therapeutic advantages, possibly due to greater metabolic stability. 2 The natural abundance of deuterium (H) is approximately 0.015%. Thus, there is approximately one deuterium atom for every 6,500 hydrogen atoms in nature. Therefore, the deuterium-containing compounds of the present invention have a deuterium abundance greater than 0.015% at one or more positions (as appropriate). Unless otherwise indicated, the structures described herein may also include compounds that differ only in the presence or absence of one or more isotopically enriched atoms. For example, compounds that are identical to the structures of the present invention except for the replacement of hydrogen atoms by deuterium or tritium, or the replacement of carbon atoms by carbon-13 or carbon-14, are within the scope of the present invention.

[0285] The term "halogen" refers to a halogen group. For example, "halogen" may refer to a fluorine (F), chlorine (Cl), bromine (Br), or iodine (I) group.

[0286] In the present invention, the term "pharmaceutical composition" generally refers to a mixture containing one or more compounds of the present invention, or their physiologically / pharmaceutically acceptable salts or prodrugs, and other chemical components, as well as other components such as physiologically / pharmaceutically acceptable carriers and excipients. Pharmaceutical compositions can facilitate administration to an organism, facilitating the absorption of the active ingredient and thereby exerting its biological activity. Conventional pharmaceutical compositions can be prepared using techniques commonly used in the art.

[0287] In the present invention, the term "pharmaceutically acceptable salt" or "pharmaceutically usable salt" generally refers to a salt of the compound of the present invention or ligand-drug conjugate, or a salt of the compound described in the present invention. Such salts may be safe and / or effective when used in mammals and may have the desired biological activity. The compound of the present invention may form a salt with an acid. Non-limiting examples of pharmaceutically acceptable salts include: hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, citrate, acetate, succinate, ascorbate, oxalate, nitrate, sorbate, hydrogen phosphate, dihydrogen phosphate, salicylate, hydrogen citrate, tartrate, maleate, fumarate, formate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, or p-toluenesulfonate.

[0288] In the present invention, the term "pharmaceutically acceptable carrier" generally refers to a carrier for delivering a therapeutic agent. The term refers to any drug carrier that does not itself induce the production of antibodies harmful to the individual receiving the composition and can be administered without producing excessive toxicity. For example, a pharmaceutically acceptable carrier can be distinguished from a nucleic acid vector used to contain a target gene in genetic engineering. Suitable carriers can be large, slowly metabolized macromolecules such as proteins, polysaccharides, polylactic acid, polyglycolic acid, polyamino acids, amino acid copolymers, lipid aggregates, and inactivated viral particles. Those skilled in the art are familiar with these carriers. Pharmaceutically acceptable carriers in therapeutic compositions may include liquids such as water, saline, glycerol, and ethanol. Auxiliary substances, such as wetting agents or emulsifiers, pH buffer substances, etc., may also be present in these carriers.

[0289] As used herein, the term "effective amount" generally refers to an amount of a therapeutic agent that treats, alleviates, or prevents a target disease or condition, or an amount that exhibits a detectable therapeutic or preventive effect. The precise effective amount for a given subject depends on the subject's size and health, the nature and severity of the condition, and the therapeutic agent and / or combination of therapeutic agents selected for administration. Therefore, it is not useful to specify an exact effective amount in advance. However, for a given condition, the effective amount can be determined by routine experimentation and is within the judgment of the clinician.

[0290] Unless otherwise specified, all compounds mentioned in the present invention are intended to include all possible optical isomers, such as single chiral compounds or mixtures of various chiral compounds (i.e., racemates). In all compounds of the present invention, each chiral carbon atom may optionally be in the R configuration or the S configuration, or a mixture of the R and S configurations.

[0291] As used herein, the term "RNAi agent" refers to an agent comprising an RNA molecule that can downregulate the expression of a target gene through an RNA interference mechanism when introduced into a cell. The term "RNAi agent of the present invention," "RNAi agent described herein," or similar expressions include naked or modified RNAi agents, regardless of sequence and target gene. RNA interference refers to a process in which a nucleic acid molecule induces the cutting and degradation of a target RNA molecule (such as an mRNA molecule) in a sequence-specific manner, such as through an RNA-induced silencing complex (RISC) pathway. RNAi agents herein include siRNA, shRNA, and DNA / RNA hybrid molecules, sometimes also collectively referred to herein as double-stranded RNA (dsRNA), which comprises two antiparallel continuous nucleotide chains that are sufficiently complementary to each other to hybridize to form a double-stranded region. "Hybridization" refers to the pairing of complementary polynucleotides, typically through hydrogen bonds (such as Watson-Crick hydrogen bonds, Wobble hydrogen bonds, Hoogsteen hydrogen bonds, or reverse Hoogsteen hydrogen bonds) between complementary bases in two polynucleotides. "Double-stranded region" refers to a region in two complementary or substantially complementary polynucleotides that hybridize to form base pairs, thereby forming a double strand between the two polynucleotide chains.

[0292] The term "antisense strand" refers to the strand of a dsRNA that contains a region that is substantially complementary to the target sequence. The term "positive strand" or "sense strand" refers to the strand of a dsRNA that contains a region that is substantially complementary to the antisense strand region as defined herein. The term "substantially complementary region" refers to a region that is fully complementary or incompletely complementary. When the complementary region is not fully complementary to the target sequence, mismatches may be located in the interior or terminal regions of the molecule. Typically, the most tolerable mismatches are located in the terminal regions, for example, 5, 4, 3, or 2 at the 5' and / or 3' ends of the dsRNA.

[0293] "siRNA" refers to a nucleic acid that forms double-stranded RNA that has the ability to reduce or inhibit the expression of a target gene when the siRNA and the target gene are present in the same cell. siRNAs are typically about 15 to about 30 base pairs in length, most typically about 19 to 25 base pairs in length, e.g., 19, 20, 21, 22, 23, 24, or 25 nucleotide pairs in length.

[0294] shRNA refers to a short hairpin RNA that includes two short inverted repeats and an intermediate stem-loop structure connecting the two. The stem-loop may contain at least one unpaired nucleotide, for example, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 20, at least 23 or more unpaired nucleotides. The stem-loop may be 10 or fewer nucleotides. The stem-loop may be 8 or fewer unpaired nucleotides. The stem-loop may be 4 to 10 unpaired nucleotides. The stem-loop may be 4 to 8 nucleotides.

[0295] The two substantially complementary chains of a dsRNA need not but may also be covalently linked. The maximum number of base pairs is the number of nucleotides in the shortest chain of the dsRNA minus any overhangs present in the duplex. In addition to the duplex structure, the dsRNA may also comprise one or more nucleotide overhangs. Overhanging nucleotides refer to one or more unpaired nucleotides that extend beyond the double-stranded region at the end of the chain. When the 3' end of a chain extends beyond the 5' end of the other chain, or when the 5' end of a line extends beyond the 3' end of the other line, nucleotide overhangs are usually produced. For example, at least one chain comprises a 3' overhang of at least 1 nucleotide, for example, 1 to 4 nucleotides overhang. For another example, at least one chain comprises a 5' overhang of at least 1 nucleotide, for example, 1 to 4 nucleotides overhang. In other embodiments, both the 3' end and the 5' end of a chain of the dsRNA comprise an overhang of at least 1 nucleotide.

[0296] As used herein, the terms "blunt-ended" or "blunt-ended" with respect to dsRNA refer to the absence of unpaired nucleotides or nucleotide analogs at a given end of the dsRNA, i.e., the absence of nucleotide overhangs. One or both ends of a dsRNA may be blunt. If both ends of a dsRNA are blunt-ended, the dsRNA is said to be blunt-ended. It should be noted that a "blunt-ended" dsRNA is a dsRNA with both ends blunt-ended, i.e., there are no nucleotide overhangs at either end of the molecule. In most cases, such molecules are double-stranded throughout their entire length. As used herein, the term "nucleotide overhang" refers to at least one unpaired nucleotide that protrudes from the duplex structure of a dsRNA. For example, a nucleotide overhang is present when the 3' end of one strand of a dsRNA extends beyond the 5' end of the other strand, or vice versa. Nucleotide overhangs may comprise or consist of nucleotide / nucleoside analogs, including deoxynucleotides / nucleosides. The overhangs may be on the sense strand, the antisense strand, or any combination thereof. Furthermore, overhanging nucleotides may be present at the 5' end, the 3' end, or both ends of the antisense or sense strand of the dsRNA.

[0297] The dsRNA molecule may include chemical modifications to ribonucleotides, including modifications to the ribose, bases, or backbone components of the ribonucleic acid, as described herein or modifications known in the art. Any such modifications, as used in double-stranded ribonucleic acid molecules (such as siRNA, shRNA, etc.), are encompassed by the term "dsRNA" for the purposes of this disclosure. "Modified" nucleotides refer to nucleotides that independently have modified sugar moieties, modified internucleotide linkages, and / or modified core bases. Therefore, the term "modified nucleotides" includes substitutions, additions, or removals of, for example, functional groups or atoms of internucleoside linkages, sugar moieties, or core bases. Modifications suitable for use in the present invention include all types of modifications disclosed herein or known in the art. For example, the modified nucleotides are selected from 2'-deoxy-thymine (dT) nucleotides, 2'-O-methyl modified nucleotides, 2'-fluoro modified nucleotides, 2'-deoxy-modified nucleotides, locked nucleic acids (LNA), open ring nucleic acids (UNA), bridge nucleic acids (BNA), glycol nucleic acids (GNA), athreose nucleic acids (TNA), conformationally restricted nucleotides, restricted ethyl nucleotides, 2'-amino-modified nucleotides, 2'-O- Allyl-modified nucleotides, 2'-C-alkyl-modified nucleotides, 2'-methoxyethyl-modified nucleotides, abasic nucleotides, inverted abasic nucleotides, inverted nucleotides, morpholino nucleotides, phosphoramidates, tetrahydropyran-modified nucleotides, 1,5-anhydrohexitol-modified nucleotides, cyclohexenyl-modified nucleotides, nucleotides containing phosphorothioate groups, nucleotides containing methylphosphonate groups, nucleotides containing 5'-phosphates, and nucleotides containing 5'-phosphate mimetics; preferably selected from 2'-O-methyl-modified nucleotides, 2'-fluoro-modified nucleotides, and nucleotides containing phosphorothioate internucleotide linkages.

[0298] The term "treatment" encompasses prevention, therapy, and cure. The patient receiving such treatment is generally any animal in need thereof, including primates (particularly humans) and other mammals such as horses, cattle, pigs, sheep, poultry, and pets.

[0299] Integrin ligands for RNAi agents

[0300] Described herein are compounds that have affinity for certain integrins, including αvβ6, that can be used as ligands (referred to herein as "integrin ligands" or "αvβ6 ligands") to selectively target compounds or other molecules to which they are attached to cells or tissues that express the integrin αvβ6. The integrin ligands disclosed herein can be conjugated to oligonucleotide molecules (e.g., oligonucleotides in RNAi agents, such as siRNAs or ASOs) to facilitate delivery of the oligonucleotide molecules to cells or tissues that express the integrin αvβ6.

[0301] In some embodiments, the present invention provides a compound, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug, or solvate thereof, wherein the compound has the structure shown in Formula Ia:

[0302] in,

[0303] T1 and T2 are independently C or N, and at least one is N;

[0304] T3 and T4 are independently C or N;

[0305] Ring B is or absent, where junction 2 is connected to L2;

[0306] R4, R5 and R6 are independently H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl or cyclobutyl;

[0307] L1 is -(CH2) n -、-(CH2) m C(O)NH(CH2) n -or-(CH2) m NHC(O)(CH2) n -, m and n are independently an integer from 1 to 10;

[0308] L2 is -(OCH2CH2) p -、-(CH2) q (OCH2CH2) p -, -NHC(O)(CH2CH2O) p -, -NHC(O)(CH2) q -(OCH2CH2) p -,-C(O)NH(CH2CH2O) p -、-C(O)NH(CH2) q (OCH2CH2) p -, -C(O)(CH2CH2O) p -or-C(O)(CH2) q (OCH2CH2) p -, wherein the left side is connected to the B ring and the right side is connected to R1, and p and q are independently an integer from 1 to 10, preferably q is 2 or 3, preferably p is 3, 4, 5, 6 or 7;

[0309] R1 is -N3, -NH2, -COOH, -NHC(O)CH2SC(O)CH3 or

[0310] In a preferred embodiment, T1 and T2 are both N. In a preferred embodiment, one of T3 and T4 is N. In a preferred embodiment, T3 and T4 are both C. In a preferred embodiment, R4, R5 and R6 are independently methyl. In a preferred embodiment, Ring B is In a preferred embodiment, m and n are independently 1, 2, 3, 4, 5 or 6. In a preferred embodiment, L1 is -(CH2) n -, n is 1, 2, 3, 4, 5 or 6. In a preferred embodiment, p is 3, 4, 5, 6 or 7. In a preferred embodiment, L2 is -(OCH2CH2) p -, p is 3, 4, 5, 6 or 7. In a preferred embodiment, R1 is -N3. In a preferred embodiment, the compound is selected from compounds 4, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33 and 34.

[0311] In some embodiments, the present invention provides a compound, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug, or solvate thereof, wherein the compound has the structure shown in Formula Ib:

[0312] in,

[0313] T1 and T2 are independently C or N, and at least one is N;

[0314] T3 and T4 are independently C or N;

[0315] One of e1 and e2 is 1, and the other is 0;

[0316] Ring B is or does not exist, where junction 2 is connected to L2 and junction 2 does not exist when e1 is 0;

[0317] R4 and R5 are independently H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl or cyclobutyl;

[0318] L1 is -(CH2) n -、-(CH2) m C(O)NH(CH2) n -or-(CH2) m NHC(O)(CH2) n -, m and n are independently an integer from 1 to 10;

[0319] When e1 is 1, L2 is -(OCH2CH2)p -、-(CH2) q (OCH2CH2) p -, -NHC(O)(CH2CH2O) p -, -NHC(O)(CH2) q (OCH2CH2) p -,-C(O)NH(CH2CH2O) p -、-C(O)NH(CH2) q (OCH2CH2) p -, -C(O)(CH2CH2O) p -or-C(O)(CH2) q (OCH2CH2) p -, wherein the right side is connected to R1, and p and q are independently an integer from 1 to 10, preferably q is 2 or 3, preferably p is 3, 4, 5, 6 or 7;

[0320] When e2 is 1, L2 is -NHC(O)(CH2) q (OCH2CH2) p -, wherein the right side is connected to R1, p and q are independently integers from 1 to 10;

[0321] R1 is -N3, -NH2, -COOH, -NHC(O)CH2SC(O)CH3 or

[0322] R9 is H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl or cyclobutyl, R 10 H, or R9, R 10 Together with the C and N to which they are attached they form a piperidinyl group.

[0323] In a preferred embodiment, T1 and T2 are both N. In a preferred embodiment, one of T3 and T4 is N. In a preferred embodiment, T3 and T4 are both C. In a preferred embodiment, Ring B is

[0324] In a preferred embodiment, R4, R5 and R6 are independently methyl. In a preferred embodiment, m and n are independently 1, 2, 3, 4, 5 or 6. In a preferred embodiment, when e1 is 1, L1 is -(CH2) n -, n is 1, 2, 3, 4, 5 or 6. In a preferred embodiment, p is 3, 4, 5, 6 or 7. In a preferred embodiment, L2 is -(OCH2CH2) p-, p is 3, 4, 5, 6 or 7. In a preferred embodiment, q is 2 or 3. In a preferred embodiment, R1 is -N3. In a preferred embodiment, R9 is methyl and R 10 is H. In a preferred embodiment, R9, R 10 Together with the C and N to which they are attached, they form a piperidinyl group. In a preferred embodiment, the compound is compound 35.

[0325] In some embodiments, the present invention provides a compound, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug, or solvate thereof, wherein the compound has a structure shown in Formula IIa or IIb:

[0326] in,

[0327] T3 and T4 are independently C or N;

[0328] Ring A is wherein the connection point 1 is connected to L1, and R8 is H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl or halogen;

[0329] Ring B is or absent, where junction 2 is connected to L2;

[0330] R4, R5, R6 and R7 are independently H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl or cyclobutyl;

[0331] L1 is -(CH2) n -、-(CH2) m C(O)NH(CH2) n -or-(CH2) m NHC(O)(CH2) n -, m and n are independently an integer from 1 to 10;

[0332] L2 is -(OCH2CH2) p -、-(CH2) q (OCH2CH2) p -, -NHC(O)(CH2CH2O) p -, -NHC(O)(CH2) q -(OCH2CH2) p -,-C(O)NH(CH2CH2O) p -、-C(O)NH(CH2) q (OCH2CH2) p-, -C(O)(CH2CH2O) p -or-C(O)(CH2) q (OCH2CH2) p -, wherein the left side is connected to the B ring and the right side is connected to R1, and p and q are independently an integer from 1 to 10, preferably q is 2 or 3, preferably p is 3, 4, 5, 6 or 7;

[0333] R1 is -N3, -NH2, -COOH, -NHC(O)CH2SC(O)CH3 or

[0334] In a preferred embodiment, one of T3 and T4 is N. In a preferred embodiment, both T3 and T4 are C. In a preferred embodiment, R8 is H or halogen, more preferably H or F. In a preferred embodiment, Ring A is And R8 is H.

[0335] In a preferred embodiment, Ring B is In a preferred embodiment, R4, R5 and R6 are independently methyl. In a preferred embodiment, R7 is H. In a preferred embodiment, m and n are independently 1, 2, 3, 4, 5 or 6. In a preferred embodiment, L1 is -(CH2) n -, n is 1, 2, 3, 4, 5 or 6. In a preferred embodiment, p is 3, 4, 5, 6 or 7. In a preferred embodiment, R1 is -N3. In a preferred embodiment, the compound is any one of compounds 5, 36, 37, 38, 39, 40, 41, 42, 43 or 44.

[0336] In some embodiments, the present invention provides a compound, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug, or solvate thereof, wherein the compound has a structure shown in Formula IIIa or IIIb:

[0337] in,

[0338] T3 and T4 are independently C or N;

[0339] One of e1 and e2 is 1, and the other is 0;

[0340] Ring B is or does not exist, where junction 2 is connected to L2 and junction 2 does not exist when e1 is 0;

[0341] R4 and R5 are independently H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl or cyclobutyl;

[0342] L1 is -(CH2) m -、-(CH2) m C(O)NH(CH2) n -or-(CH2) m NHC(O)(CH2) n -, m is an integer from 1 to 10, and n is an integer from 0 to 10;

[0343] When e1 is 1, L2 is -(OCH2CH2) p -、-(CH2) q (OCH2CH2) p -, -NHC(O)(CH2CH2O) p -、- NHC(O)(CH2) q (OCH2CH2) p -,-C(O)NH(CH2CH2O) p -、-C(O)NH(CH2) q (OCH2CH2) p -, -C(O)(CH2CH2O) p -or-C(O)(CH2) q (OCH2CH2) p -, wherein the right side is connected to R1, and p and q are independently an integer from 1 to 10, preferably q is 2 or 3, preferably p is 3, 4, 5, 6 or 7;

[0344] When e2 is 1, L2 is -NHC(O)(CH2) q (OCH2CH2) p -, wherein the right side is connected to R1, p and q are independently integers from 1 to 10;

[0345] R1 is -N3, -NH2, -COOH, -NHC(O)CH2SC(O)CH3 or

[0346] R9 is H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl or cyclobutyl, R 10 H, or R9, R 10 Together with the C and N to which they are attached they form a piperidinyl group.

[0347] In a preferred embodiment, one of T3 and T4 is N. In a preferred embodiment, both T3 and T4 are C. In a preferred embodiment, Ring B is In a preferred embodiment, R4 and R5 are independently methyl. In a preferred embodiment, m is 1, 2, 3, 4, 5 or 6. In a preferred embodiment, n is 0, 1, 2 or 3. In a preferred embodiment, L1 is -(CH2) m -, m is 1, 2, 3, 4, 5 or 6. In a preferred embodiment, p is 3, 4, 5, 6 or 7. In a preferred embodiment, q is 2 or 3. In a preferred embodiment, when e1 is 1, L2 is -(OCH2CH2) p -, p is 3, 4, 5, 6 or 7. In a preferred embodiment, R1 is -N3. In a preferred embodiment, R9 is methyl and R 10 is H. In a preferred embodiment, R9, R 10 Together with the C and N to which they are attached, they form a piperidinyl group. In a preferred embodiment, the compound is compound 6, 7, 8, 9, 45, 46 or 47.

[0348] In some embodiments, the present invention provides a compound, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug, or solvate thereof, wherein the compound has a structure shown in Formula IVa:

[0349] in,

[0350] One of e1, e2, and e3 is 1, and the other two are 0;

[0351] Ring B is or does not exist, where junction 2 is connected to L2 and junction 2 does not exist when e1 is 0;

[0352] R4 and R5 are independently H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl or cyclobutyl;

[0353] When e1 or e3 is 1, L2 is -(OCH2CH2) p -、-(CH2) q (OCH2CH2) p -, -NHC(O)(CH2CH2O) p -, -NHC(O)(CH2) q -(OCH2CH2) p -,-C(O)NH(CH2CH2O) p -、-C(O)NH(CH2) q (OCH2CH2) p -, -C(O)(CH2CH2O) p-or-C(O)(CH2) q (OCH2CH2) p -, wherein the right side is connected to R1, and p and q are independently an integer from 1 to 10, preferably q is 2 or 3, preferably p is 3, 4, 5, 6 or 7;

[0354] When e2 is 1, L2 is -NHC(O)(CH2) q (OCH2CH2) p -, wherein the right side is connected to R1, p and q are independently integers from 1 to 10;

[0355] R1 is -N3, -NH2, -COOH, -NHC(O)CH2SC(O)CH3 or

[0356] R 11 H, halogen, halogenated C 1-4 alkyl, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, phenyl, morpholinyl, methoxyethoxy or ethoxymethoxy.

[0357] In a preferred embodiment, Ring B is

[0358] In a preferred embodiment, R4 and R5 are both methyl. In a preferred embodiment, q is 1, 2 or 3. In a preferred embodiment, p is 3, 4, 5, 6 or 7. In a preferred embodiment, when e1 or e3 is 1, L2 is -(OCH2CH2) p -, p is 3, 4, 5, 6 or 7. In a preferred embodiment, R1 is -N3. In a preferred embodiment, R 11 is H. In a preferred embodiment, the compound is compound 13, 14, 15, 18, 20, 48, 49, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 71, 72, 73, 83, 84, 85, 86 or 87.

[0359] In some embodiments, the present invention provides a compound, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug, or solvate thereof, wherein the compound has the structure shown in Formula IVb:

[0360] One of e1 and e2 is 1, and the other is 0;

[0361] Ring B is or absent, where junction 2 is connected to L2;

[0362] R4, R5 and R6 are independently H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl or cyclobutyl;

[0363] L2 is -(OCH2CH2) p -、-(CH2) q (OCH2CH2) p -, -NHC(O)(CH2CH2O) p -, -NHC(O)(CH2) q -(OCH2CH2) p -,-C(O)NH(CH2CH2O) p -、-C(O)NH(CH2) q (OCH2CH2) p -, -C(O)(CH2CH2O) p -or-C(O)(CH2) q (OCH2CH2) p -, wherein the left side is connected to the B ring and the right side is connected to R1, and p and q are independently an integer from 1 to 10, preferably q is 2 or 3, preferably p is 3, 4, 5, 6 or 7;

[0364] R1 is -N3, -NH2, -COOH, -NHC(O)CH2SC(O)CH3 or

[0365] L1 is -(CH2) m -、-(CH2) m C(O)NH(CH2) n -or-(CH2) m NHC(O)(CH2) n -, m is an integer from 1 to 10, and n is an integer from 0 to 10;

[0366] R 11 is H, halogen, halomethyl, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, phenyl, morpholinyl, methoxyethoxy or ethoxymethoxy.

[0367] In a preferred embodiment, Ring B is In a preferred embodiment, R4, R5 and R6 are all methyl. In a preferred embodiment, q is 2 or 3. In a preferred embodiment, p is 3, 4, 5, 6 or 7. In a preferred embodiment, L2 is -(OCH2CH2) p-, p is 3, 4, 5, 6 or 7. In a preferred embodiment, R1 is -N3. In a preferred embodiment, m is 1, 2, 3, 4, 5 or 6. In a preferred embodiment, n is 0, 1, 2 or 3. In a preferred embodiment, L1 is -(CH2) m -, m is 1, 2, 3, 4, 5 or 6. In a preferred embodiment, preferably R 11 is H. In a preferred embodiment, the compound is compound 50, 51, 52, 74, 75, 76, 77, 78, 79 or 80.

[0368] In some embodiments, the present invention provides a compound, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug, or solvate thereof, wherein the compound has the structure shown in Formula Va:

[0369] One of e1, e2, and e3 is 1, and the other two are 0;

[0370] R9 is H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl or cyclobutyl, R 10 H, or R9, R 10 Together with the C and N atoms to which they are attached, they form a piperidinyl group;

[0371] R 13 and R 14 Each is H, or R 13 、R 14 Together with the C and N atoms to which they are attached, they form a piperidinyl group;

[0372] L1 and L1' are independently -(CH2) m -、-(CH2) m C(O)NH(CH2) n -or-(CH2) m NHC(O)(CH2) n -, m is an integer from 1 to 10, and n is an integer from 0 to 10;

[0373] When e1 is 1, L2 is -(OCH2CH2) p -、-(CH2) q (OCH2CH2) p -, -NHC(O)(CH2CH2O) p -, -NHC(O)(CH2) q (OCH2CH2) p -,-C(O)NH(CH2CH2O) p-、-C(O)NH(CH2) q (OCH2CH2) p -, -C(O)(CH2CH2O) p -or-C(O)(CH2) q (OCH2CH2) p -, wherein the right side is connected to R1, and p and q are independently an integer from 1 to 10, preferably q is 2 or 3, preferably p is 3, 4, 5, 6 or 7;

[0374] When e2 is 1, L2 is -(CH2) q (OCH2CH2) p -, wherein the right side is connected to R1, p and q are independently integers from 1 to 10;

[0375] When e3 is 1, L2 is -NHC(O)(CH2) q (OCH2CH2) p -, wherein the right side is connected to R1, p and q are independently integers from 1 to 10;

[0376] R1 is -N3, -NH2, -COOH, -NHC(O)CH2SC(O)CH3 or

[0377] In a preferred embodiment, R9 is methyl and R 10 is H. In a preferred embodiment, m is 1, 2, 3, 4, 5 or 6. In a preferred embodiment, n is 0, 1, 2 or 3. In a preferred embodiment, L1 and L1' are -(CH2) m -, m is 1, 2, 3, 4, 5 or 6. Preferably, the compound is compound 16, 17, 64, 65, 66 or 67. In a preferred embodiment, q is 1, 2 or 3. In a preferred embodiment, p is 3, 4, 5, 6 or 7. In a preferred embodiment, when e1 is 1, L2 is -(OCH2CH2) p -, p is 3, 4, 5, 6 or 7. In a preferred embodiment, R1 is -N3. In a preferred embodiment, the compound is compound 16, 17, 64, 65, 66 or 67.

[0378] In some embodiments, the present invention provides a compound, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug, or solvate thereof, wherein the compound has a structure shown in Formula Vb:

[0379] in

[0380] One of e1 and e2 is 1, and the other is 0;

[0381] R6 is H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl or cyclobutyl;

[0382] R 13 and R 14 Each is H, or R 13 、R 14 Together with the C and N atoms to which they are attached, they form a piperidinyl group;

[0383] L1 and L1' are independently -(CH2) m -、-(CH2) m C(O)NH(CH2) n -or-(CH2) m NHC(O)(CH2) n -, m is an integer from 1 to 10, and n is an integer from 0 to 10;

[0384] When e1 is 1, L2 is -(OCH2CH2) p -、-(CH2) q (OCH2CH2) p -, -NHC(O)(CH2CH2O) p -, -NHC(O)(CH2) q (OCH2CH2) p -,-C(O)NH(CH2CH2O) p -、-C(O)NH(CH2) q (OCH2CH2) p -, -C(O)(CH2CH2O) p -or-C(O)(CH2) q (OCH2CH2) p -, wherein the right side is connected to R1, and p and q are independently an integer from 1 to 10, preferably q is 2 or 3, preferably p is 3, 4, 5, 6 or 7;

[0385] When e2 is 1, L2 is -(CH2) q (OCH2CH2) p -, wherein the right side is connected to R1, p and q are independently integers from 1 to 10;

[0386] R1 is -N3, -NH2, -COOH, -NHC(O)CH2SC(O)CH3 or

[0387] In a preferred embodiment, R6 is methyl. In a preferred embodiment, m is 1, 2, 3, 4, 5 or 6. In a preferred embodiment, n is 0, 1, 2 or 3. In a preferred embodiment, L1 and L1' are -(CH2) m -, m is 1, 2, 3, 4, 5 or 6. In a preferred embodiment, p is 3, 4, 5, 6 or 7. In a preferred embodiment, q is 1, 2 or 3. In a preferred embodiment, when e1 is 1, L2 is -(OCH2CH2) p -, p is 3, 4, 5, 6 or 7. In a preferred embodiment, R1 is -N3. In a preferred embodiment, the compound is compound 69 or 70.

[0388] In some embodiments, the present invention provides a compound, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug, or solvate thereof, wherein the compound has the structure shown in Formula Vc:

[0389] One of e1, e2, and e3 is 1, and the other two are 0;

[0390] R9 is H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl or cyclobutyl, R 10 H, or R9, R 10 Together with the C and N atoms to which they are attached, they form a piperidinyl group;

[0391] R 13 and R 14 Each is H, or R 13 、R 14 Together with the C and N atoms to which they are attached, they form a piperidinyl group;

[0392] L1 is -(CH2) m -、-(CH2) m C(O)NH(CH2) n -or-(CH2) m NHC(O)(CH2) n -, m is an integer from 1 to 10, and n is an integer from 0 to 10;

[0393] When e1 is 1, L2 is -(OCH2CH2) p -、-(CH2) q (OCH2CH2) p -, -NHC(O)(CH2CH2O) p -, -NHC(O)(CH2) q (OCH2CH2) p-,-C(O)NH(CH2CH2O) p -、-C(O)NH(CH2) q (OCH2CH2) p -, -C(O)(CH2CH2O) p -or-C(O)(CH2) q (OCH2CH2) p -, wherein the right side is connected to R1, and p and q are independently an integer from 1 to 10, preferably q is 2 or 3, preferably p is 3, 4, 5, 6 or 7;

[0394] When e2 is 1, L2 is -(CH2)q(OCH2CH2) p -, wherein the right side is connected to R1, p and q are independently integers from 1 to 10;

[0395] When e3 is 1, L2 is -NHC(O)(CH2)q(OCH2CH2) p -, wherein the right side is connected to R1, p and q are independently integers from 1 to 10;

[0396] R1 is -N3, -NH2, -COOH, -NHC(O)CH2SC(O)CH3 or

[0397] Ring B is or does not exist, where junction 2 is connected to L2 and junction 2 does not exist when e1 is 0;

[0398] R4 and R5 are independently H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl or cyclobutyl.

[0399] In a preferred embodiment, R9 is methyl and R 10 is H. In a preferred embodiment, m is 1, 2, 3, 4, 5 or 6. In a preferred embodiment, n is 0, 1, 2 or 3. In a preferred embodiment, L1 is -(CH2) m -, m is 1, 2, 3, 4, 5 or 6. In a preferred embodiment, p is 3, 4, 5, 6 or 7. In a preferred embodiment, q is 1, 2 or 3. In a preferred embodiment, when e1 is 1, L2 is -(OCH2CH2) p -, p is 3, 4, 5, 6 or 7. In a preferred embodiment, R1 is -N3.

[0400] In a preferred embodiment, Ring B is In a preferred embodiment, R4 and R5 are both methyl. In a preferred embodiment, the compound is Compound 68.

[0401] The structural formulas of the specific compounds mentioned above are as follows.

[0402] In some embodiments, the present invention provides a compound, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug, or solvate thereof, wherein the compound has the structure shown in Formula Ia':

[0403] T1 and T2 are independently C or N, and at least one is N;

[0404] T3 and T4 are independently C or N;

[0405] Ring B is or does not exist;

[0406] R4, R5 and R6 are independently H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl or cyclobutyl;

[0407] L1 is -(CH2) n -、-(CH2) m C(O)NH(CH2) n -or-(CH2) m NHC(O)(CH2) n -, m and n are independently integers from 1 to 10.

[0408] In a preferred embodiment, T1 and T2 are both N. In a preferred embodiment, one of T3 and T4 is N. In a preferred embodiment, T3 and T4 are both C.

[0409] In a preferred embodiment, Ring B is In a preferred embodiment, R4, R5 and R6 are independently methyl. In a preferred embodiment, m and n are independently 1, 2, 3, 4, 5 or 6. In a preferred embodiment, L1 is -(CH2) n -, n is 1, 2, 3, 4, 5 or 6. In a preferred embodiment, the compound is selected from compounds 4', 21', 22', 23', 24', 31', 32', 33' and 34'.

[0410] In some embodiments, the present invention provides a compound, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug, or solvate thereof, wherein the compound has a structure shown in Formula Ib':

[0411] in,

[0412] T1 and T2 are independently C or N, and at least one is N;

[0413] T3 and T4 are independently C or N;

[0414] Ring B is or does not exist;

[0415] R4 and R5 are independently H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl or cyclobutyl;

[0416] R3 is H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, amino or C 1-3 Alkylamino, preferably R3 is H or methylamino;

[0417] L1 is -(CH2) n -、-(CH2) m C(O)NH(CH2) n -or-(CH2) m NHC(O)(CH2) n -, m and n are independently an integer from 1 to 10;

[0418] R9 is H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl or cyclobutyl, R 10 H, or R9, R 10 Together with the C and N to which they are attached they form a piperidinyl group.

[0419] In a preferred embodiment, T1 and T2 are both N. In a preferred embodiment, one of T3 and T4 is N. In a preferred embodiment, T3 and T4 are both C.

[0420] In a preferred embodiment, Ring B is In a preferred embodiment, R4, R5 and R6 are independently methyl. In a preferred embodiment, m and n are independently 1, 2, 3, 4, 5 or 6. In a preferred embodiment, L1 is -(CH2) n -, n is 1, 2, 3, 4, 5 or 6. In a preferred embodiment, R9 is methyl and R 10 is H. In a preferred embodiment, R9, R 10Together with the C and N to which they are attached, they form a piperidinyl group. In a preferred embodiment, the compound is compound 35'.

[0421] In some embodiments, the present invention provides a compound, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug, or solvate thereof, wherein the compound has a structure shown in Formula IIa' or IIb':

[0422] in,

[0423] T3 and T4 are independently C or N;

[0424] Ring A is wherein the connection point 1 is connected to L1, and R8 is H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl or halogen;

[0425] Ring B is or does not exist;

[0426] R4, R5, R6 and R7 are independently H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl or cyclobutyl;

[0427] L1 is -(CH2) n -、-(CH2) m C(O)NH(CH2) n -or-(CH2) m NHC(O)(CH2) n -, m and n are independently integers from 1 to 10.

[0428] In a preferred embodiment, one of T3 and T4 is N. In a preferred embodiment, both T3 and T4 are C. In a preferred embodiment, R8 is H or halogen, more preferably H or F. In a preferred embodiment, Ring A is and R8 is H. In a preferred embodiment, Ring B is In a preferred embodiment, R4, R5 and R6 are independently methyl. In a preferred embodiment, R7 is H. In a preferred embodiment, m and n are independently 1, 2, 3, 4, 5 or 6. In a preferred embodiment, L1 is -(CH2) n -, n is 1, 2, 3, 4, 5 or 6. In a preferred embodiment, the compound is any one of compounds 5', 36', 37', 38', 39', 40', 41', 42', 43' or 44'.

[0429] In some embodiments, the present invention provides a compound, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug, or solvate thereof, wherein the compound has a structure shown in Formula IIIa' or IIIb':

[0430] in,

[0431] T3 and T4 are independently C or N;

[0432] Ring B is

[0433] R4 and R5 are independently H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl or cyclobutyl;

[0434] L1 is -(CH2) m -、-(CH2) m C(O)NH(CH2) n -or-(CH2) m NHC(O)(CH2) n -, m is an integer from 1 to 10, and n is an integer from 0 to 10;

[0435] R3 is H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, amino or C 1-3 Alkylamino;

[0436] R9 is H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl or cyclobutyl, R 10 H, or R9, R 10 Together with the C and N to which they are attached they form a piperidinyl group.

[0437] In a preferred embodiment, one of T3 and T4 is N. In a preferred embodiment, both T3 and T4 are C. In a preferred embodiment, Ring B is In a preferred embodiment, R4 and R5 are methyl. In a preferred embodiment, m is 1, 2, 3, 4, 5 or 6. In a preferred embodiment, n is 0, 1, 2 or 3. In a preferred embodiment, L1 is -(CH2) m -, m is 1, 2, 3, 4, 5 or 6. In a preferred embodiment, R3 is H or methylamino. In a preferred embodiment, R9 is methyl and R 10 is H. In a preferred embodiment, R9, R 10 Together with the C and N to which they are attached, they form a piperidinyl group. In a preferred embodiment, the compound is compound 6', 7', 8', 9' or 47'.

[0438] In some embodiments, the present invention provides a compound, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug, or solvate thereof, wherein the compound has a structure shown in Formula IVa':

[0439] in,

[0440] Ring B is

[0441] R4 and R5 are independently H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl or cyclobutyl;

[0442] R3 is H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, amino or C 1-3 Alkylamino;

[0443] R 11 H, halogen, halogenated C 1-4 alkyl, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, phenyl, morpholinyl, methoxyethoxy or ethoxymethoxy.

[0444] In a preferred embodiment, Ring B is In a preferred embodiment, R4 and R5 are methyl. In a preferred embodiment, R3 is H or methylamino. In a preferred embodiment, the compound is compound 48', 49', 59', 60', 73" or 85'.

[0445] In some embodiments, the present invention provides a compound, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug, or solvate thereof, wherein the compound has a structure shown in Formula IVb':

[0446] in

[0447] Ring B is or does not exist;

[0448] R4, R5 and R6 are independently H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl or cyclobutyl;

[0449] L1 is -(CH2) m -、-(CH2) m C(O)NH(CH2) n -or-(CH2) m NHC(O)(CH2)n -, m is an integer from 1 to 10, and n is an integer from 0 to 10;

[0450] R 11 is H, halogen, halomethyl, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, phenyl, morpholinyl, methoxyethoxy or ethoxymethoxy.

[0451] In a preferred embodiment, Ring B is In a preferred embodiment, R4, R5 and R6 are all methyl. In a preferred embodiment, m is 1, 2, 3, 4, 5 or 6. In a preferred embodiment, n is preferably 0, 1, 2 or 3. In a preferred embodiment, L1 is -(CH2) m -, m is 1, 2, 3, 4, 5 or 6. In a preferred embodiment, R 11 is H. In a preferred embodiment, the compound is compound 50', 51', 52', 76' or 79'.

[0452] In some embodiments, the present invention provides a compound, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug, or solvate thereof, wherein the compound has a structure shown in Formula Va':

[0453] in

[0454] R3 is H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, amino or C 1-3 Alkylamino;

[0455] R9 is H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl or cyclobutyl, R 10 H, or R9, R 10 Together with the C and N atoms to which they are attached, they form a piperidinyl group;

[0456] R 12 is methyl, ethyl, n-propyl, isopropyl, cyclopropyl or cyclobutyl;

[0457] R 13 、R 14 Together with the C and N atoms to which they are attached, they form a piperidinyl group;

[0458] L1 and L1' are independently -(CH2) m -、-(CH2) m C(O)NH(CH2) n -or-(CH2) m NHC(O)(CH2)n -, m is an integer from 1 to 10, and n is an integer from 0 to 10.

[0459] In a preferred embodiment, R3 is H or methylamino. In a preferred embodiment, R9 is methyl and R 10 is H. In a preferred embodiment, R 12 In a preferred embodiment, m is 1, 2, 3, 4, 5 or 6. In a preferred embodiment, n is 0, 1, 2 or 3. In a preferred embodiment, L1 is -(CH2) m -, m is 1, 2, 3, 4, 5 or 6. In a preferred embodiment, the compound is compound 64'.

[0460] In some embodiments, the present invention provides a compound, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug, or solvate thereof, wherein the compound has a structure shown in Formula Vb':

[0461] in,

[0462] R6 is H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl or cyclobutyl;

[0463] R 12 is methyl, ethyl, n-propyl, isopropyl, cyclopropyl or cyclobutyl;

[0464] R 13 and R 14 Each is H, or R 13 、R 14 Together with the C and N atoms to which they are attached, they form a piperidinyl group;

[0465] L1 and L1' are independently -(CH2) m -、-(CH2) m C(O)NH(CH2) n -or-(CH2) m NHC(O)(CH2) n -, m is an integer from 1 to 10, and n is an integer from 0 to 10.

[0466] In a preferred embodiment, R6 is methyl. 12 In a preferred embodiment, m is 1, 2, 3, 4, 5 or 6. In a preferred embodiment, n is 0, 1, 2 or 3. In a preferred embodiment, L1 is -(CH2) m-, m is 1, 2, 3, 4, 5 or 6. In a preferred embodiment, the compound is compound 69' or 70'.

[0467] In some embodiments, the present invention provides a compound, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug, or solvate thereof, wherein the compound has a structure shown in Formula Vc':

[0468] R3 is H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, amino or C 1-3 Alkylamino;

[0469] R9 is H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl or cyclobutyl, R 10 H, or R9, R 10 Together with the C and N atoms to which they are attached, they form a piperidinyl group;

[0470] R 12 is methyl, ethyl, n-propyl, isopropyl, cyclopropyl or cyclobutyl;

[0471] R 13 and R 14 Each is H, or R 13 、R 14 Together with the C and N atoms to which they are attached, they form a piperidinyl group;

[0472] L1 is -(CH2) m -、-(CH2) m C(O)NH(CH2) n -or-(CH2) m NHC(O)(CH2) n -, m is an integer from 1 to 10, and n is an integer from 0 to 10;

[0473] Ring B is or does not exist;

[0474] R4 and R5 are independently H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl or cyclobutyl.

[0475] In a preferred embodiment, R3 is H or methylamino. In a preferred embodiment, R9 is methyl and R 10 is H. In a preferred embodiment, R 12 In a preferred embodiment, m is 1, 2, 3, 4, 5 or 6. In a preferred embodiment, n is 0, 1, 2 or 3. In a preferred embodiment, L1 is -(CH2) m-, m is 1, 2, 3, 4, 5 or 6. In a preferred embodiment, Ring B is In a preferred embodiment, R4 and R5 are both methyl. In a preferred embodiment, the compound is compound 68'.

[0476] In a specific embodiment, the compound provided by the present invention is selected from:

[0477] In some embodiments, the present invention provides a compound, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug, or solvate thereof, wherein the compound has a structure shown in Formula Ia":

[0478] T1 and T2 are independently C or N, and at least one is N;

[0479] T3 and T4 are independently C or N;

[0480] Ring B is or not present, wherein the connection point 2 is a wavy line in Formula Ia", the wavy line Indicates a key;

[0481] R4, R5 and R6 are independently H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl or cyclobutyl;

[0482] L1 is -(CH2) n -、-(CH2) m C(O)NH(CH2) n -or-(CH2) m NHC(O)(CH2) n -, m and n are independently integers from 1 to 10.

[0483] In a preferred embodiment, T1 and T2 are both N. In a preferred embodiment, one of T3 and T4 is N. In a preferred embodiment, T3 and T4 are both C.

[0484] In a preferred embodiment, Ring B is In a preferred embodiment, R4, R5 and R6 are independently methyl. In a preferred embodiment, m and n are independently 1, 2, 3, 4, 5 or 6. In a preferred embodiment, L1 is -(CH2) n -, n is 1, 2, 3, 4, 5 or 6.

[0485] In a preferred embodiment, the compound structure is shown below:

[0486] In some embodiments, the present invention provides a compound, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug, or solvate thereof, wherein the compound has a structure shown in Formula Ib":

[0487] in,

[0488] T1 and T2 are independently C or N, and at least one is N;

[0489] T3 and T4 are independently C or N;

[0490] Ring B is or absent, wherein connection point 2 is the wavy line connected to ring B in Formula Ib";

[0491] R4 and R5 are independently H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl or cyclobutyl;

[0492] L1 is -(CH2) n -、-(CH2) m C(O)NH(CH2) n -or-(CH2) m NHC(O)(CH2) n -, m and n are independently an integer from 1 to 10;

[0493] R9 is H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl or cyclobutyl, R 10 H, or R9, R 10 Together with the C and N to which they are attached, they form a piperidinyl group; and

[0494] The wavy line in Formula Ib" indicates a bond, and one of the two tildes is absent.

[0495] In a preferred embodiment, T1 and T2 are both N. In a preferred embodiment, one of T3 and T4 is N. In a preferred embodiment, T3 and T4 are both C.

[0496] In a preferred embodiment, Ring B is In a preferred embodiment, R4 and R5 are independently methyl. In a preferred embodiment, m and n are independently 1, 2, 3, 4, 5 or 6. In a preferred embodiment, L1 is -(CH2) n -, n is 1, 2, 3, 4, 5 or 6. In a preferred embodiment, R9 is methyl and R 10is H. In a preferred embodiment, R9, R 10 Together with the C and N to which they are attached they form a piperidinyl group.

[0497] In a preferred embodiment, the present invention provides a compound, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug, or solvate thereof, wherein the compound has the structure shown in Formula Ib"-1:

[0498] Among them, T1, T2, T3, T4, L1, R9, R 10 and wavy lines have the same definitions and preferred embodiments as the corresponding substituents in formula Ib",

[0499] Ring B is or absent, wherein R4 and R5 are independently H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl or cyclobutyl, preferably R4 and R5 are independently methyl.

[0500] In a preferred embodiment, the compound structure is shown below:

[0501] In some embodiments, the present invention provides a compound, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug, or solvate thereof, wherein the compound has a structure shown in Formula IIa" or IIb":

[0502] in,

[0503] T3 and T4 are independently C or N;

[0504] Ring A is wherein the connection point 1 is connected to L1, and R8 is H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl or halogen;

[0505] Ring B is or not present, wherein the connection point 2 is a wavy line in Formula IIa" or IIb", the wavy line Indicates a key;

[0506] R4, R5, R6 and R7 are independently H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl or cyclobutyl;

[0507] L1 is -(CH2) n -、-(CH2) m C(O)NH(CH2) n-or-(CH2) m NHC(O)(CH2) n -, m and n are independently an integer from 1 to 10.

[0508] In a preferred embodiment, one of T3 and T4 is N. In a preferred embodiment, both T3 and T4 are C. In a preferred embodiment, R8 is H or halogen, more preferably H or F. In a preferred embodiment, Ring A is and R8 is H. In a preferred embodiment, Ring B is In a preferred embodiment, R4, R5 and R6 are independently methyl. In a preferred embodiment, R7 is H. In a preferred embodiment, m and n are independently 1, 2, 3, 4, 5 or 6. In a preferred embodiment, L1 is -(CH2) n -, n is 1, 2, 3, 4, 5 or 6.

[0509] In a preferred embodiment, the compound structure is shown below:

[0510] In some embodiments, the present invention provides a compound, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug, or solvate thereof, wherein the compound has a structure shown in Formula IIIa" or IIIb":

[0511] in,

[0512] T3 and T4 are independently C or N;

[0513] Ring B is or absent, wherein the connection point 2 is the wavy line connected to the B ring in Formula IIIa" or IIIb';

[0514] R4 and R5 are independently H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl or cyclobutyl;

[0515] L1 is -(CH2) m -、-(CH2) m C(O)NH(CH2) n -or-(CH2) m NHC(O)(CH2) n -, m is an integer from 1 to 10, n is an integer from 0 to 10,;

[0516] R9 is H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl or cyclobutyl, R 10H, or R9, R 10 Together with the C and N to which they are attached, they form a piperidinyl group; and

[0517] The wavy lines in formula IIIa" and IIIb" indicates a bond, and one of the two tildes is absent.

[0518] In a preferred embodiment, one of T3 and T4 is N. In a preferred embodiment, both T3 and T4 are C. In a preferred embodiment, Ring B is In a preferred embodiment, R4 and R5 are independently methyl. In a preferred embodiment, m is 1, 2, 3, 4, 5 or 6. In a preferred embodiment, n is 0, 1, 2 or 3. In a preferred embodiment, L1 is -(CH2) m -, m is 1, 2, 3, 4, 5 or 6. In a preferred embodiment, R9 is methyl and R 10 is H. In a preferred embodiment, R9, R 10 Together with the C and N to which they are attached they form a piperidinyl group.

[0519] In some embodiments, the present invention provides a compound, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug, or solvate thereof, wherein the compound has a structure shown in Formula IIIa"-1 or IIIb"-1:

[0520] Among them, T3, T4, L1, R9, R 10 and the wavy line have the same definitions and preferred embodiments as the corresponding substituents in formula IIIa" or IIIb",

[0521] Ring B is or absent, wherein R4 and R5 are independently H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl or cyclobutyl, preferably R4 and R5 are independently methyl.

[0522] In a preferred embodiment, the compound structure is shown below:

[0523] In some embodiments, the present invention provides a compound, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug, or solvate thereof, wherein the compound has a structure shown in Formula IVa":

[0524] in,

[0525] Ring B is or absent, wherein the connection point 2 is the wavy line connected to the B ring in Formula IVa";

[0526] R4 and R5 are independently H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl or cyclobutyl;

[0527] R 11 H, halogen, halogenated C 1-4 alkyl, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, phenyl, morpholinyl, methoxyethoxy, or ethoxymethoxy; and

[0528] The wavy line in Formula IVa indicates a bond, and one of the two tildes is absent.

[0529] In some embodiments, the present invention provides a compound, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug, or solvate thereof, wherein the compound has the structure shown in Formula IVa"-1:

[0530] where R 11 and the wavy line has the same meaning as R in Formula IVa"' 11 Same definition and preferred embodiment as the wavy line,

[0531] Ring B is or absent, wherein R4 and R5 are independently H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl or cyclobutyl, preferably R4 and R5 are independently methyl.

[0532] In a preferred embodiment, the compound structure is shown below:

[0533] In some embodiments, the present invention provides a compound, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug, or solvate thereof, wherein the compound has a structure shown in Formula IVb":

[0534] Ring B is or not present, wherein the connection point 2 is a wavy line in Formula IVb", Indicates a key;

[0535] R4, R5 and R6 are independently H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl or cyclobutyl;

[0536] L1 is -(CH2) m -、-(CH2) m C(O)NH(CH2) n -or-(CH2) m NHC(O)(CH2) n -, m is an integer from 1 to 10, and n is an integer from 0 to 10;

[0537] R 11 is H, halogen, halomethyl, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, phenyl, morpholinyl, methoxyethoxy or ethoxymethoxy.

[0538] In a preferred embodiment, Ring B is In a preferred embodiment, R4, R5 and R6 are all methyl. In a preferred embodiment, m is 1, 2, 3, 4, 5 or 6. In a preferred embodiment, n is 0, 1, 2 or 3. In a preferred embodiment, L1 is -(CH2) m -, m is 1, 2, 3, 4, 5 or 6. In a preferred embodiment, R 11 For H.

[0539] In a preferred embodiment, the compound structure is shown below:

[0540] In some embodiments, the present invention provides a compound, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug, or solvate thereof, wherein the compound has a structure shown in Formula Va":

[0541] in

[0542] R9 is H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl or cyclobutyl, R 10 H, or R9, R 10 Together with the C and N atoms to which they are attached, they form a piperidinyl group;

[0543] R 13 and R 14 Each is H, or R 13 、R 14 Together with the C and N atoms to which they are attached, they form a piperidinyl group;

[0544] L1 and L1' are independently -(CH2) m -、-(CH2) m C(O)NH(CH2) n-or-(CH2) m NHC(O)(CH2) n -, m is an integer from 1 to 10, and n is an integer from 0 to 10; and

[0545] The wavy line in formula Va indicates a bond, and two of the three tildes are not present.

[0546] In a preferred embodiment, R9 is methyl and R 10 is H. In a preferred embodiment, m is 1, 2, 3, 4, 5 or 6. In a preferred embodiment, n is 0, 1, 2 or 3. In a preferred embodiment, L1 and L1' are independently -(CH2) m -, m is 1, 2, 3, 4, 5 or 6.

[0547] In some embodiments, the present invention provides a compound, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug, or solvate thereof, wherein the compound has a structure shown in Formula Va"-1, Va"-2, or Va"-3:

[0548] Among them, R9, R 10 、R 13 、R 14 , L1, L1' and the wavy line have the same definitions and preferred embodiments as the corresponding substituents in formula Va".

[0549] In a preferred embodiment, the compound structure is shown below:

[0550] In some embodiments, the present invention provides a compound, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug, or solvate thereof, wherein the compound has a structure shown in Formula Vb":

[0551] in,

[0552] R6 is H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl or cyclobutyl;

[0553] R 13 and R 14 Each is H, or R 13 、R 14 Together with the C and N atoms to which they are attached, they form a piperidinyl group;

[0554] L1 and L1' are independently -(CH2) m -、-(CH2) m C(O)NH(CH2) n -or-(CH2) m NHC(O)(CH2) n -, m is an integer from 1 to 10, and n is an integer from 0 to 10; and

[0555] The wavy line in formula Vb" indicates a bond, and one of the two tildes is absent.

[0556] In a preferred embodiment, R6 is methyl. In a preferred embodiment, m is 1, 2, 3, 4, 5 or 6. In a preferred embodiment, n is 0, 1, 2 or 3. In a preferred embodiment, L1 and L1' are independently -(CH2) m -, m is 1, 2, 3, 4, 5 or 6.

[0557] In some embodiments, the present invention provides a compound, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug, or solvate thereof, wherein the compound has a structure shown in Formula Vb"-1 or Vb"-2:

[0558] Among them, R6, R 13 、R 14 , L1, L1' and the wavy line have the same definitions and preferred embodiments as the corresponding substituents in formula Vb".

[0559] In a preferred embodiment, the compound structure is shown below:

[0560] In some embodiments, the present invention provides a compound, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug, or solvate thereof, wherein the compound has a structure shown in Formula Vc":

[0561] in

[0562] R9 is H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl or cyclobutyl, R 10 H, or R9, R 10 Together with the C and N atoms to which they are attached, they form a piperidinyl group;

[0563] R 13and R 14 Each is H, or R 13 、R 14 Together with the C and N atoms to which they are attached, they form a piperidinyl group;

[0564] L1 is -(CH2) m -、-(CH2) m C(O)NH(CH2) n -or-(CH2) m NHC(O)(CH2) n -, m is an integer from 1 to 10, and n is an integer from 0 to 10;

[0565] Ring B is or absent, wherein connection point 2 is the wavy line connected to ring B in formula Vc”;

[0566] R4 and R5 are independently H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl or cyclobutyl; and

[0567] The wavy line in the formula Vc indicates a bond, and two of the three tildes are not present.

[0568] In a preferred embodiment, R9 is methyl and R 10 H, or R9, R 10 Together with the C and N atoms to which they are attached, they form a piperidinyl group. In a preferred embodiment, m is 1, 2, 3, 4, 5 or 6. In a preferred embodiment, n is 0, 1, 2 or 3. In a preferred embodiment, L1 is -(CH2) m -, m is 1, 2, 3, 4, 5 or 6. In a preferred embodiment, Ring B is In a preferred embodiment, R4 and R5 are both methyl.

[0569] In some embodiments, the present invention provides a compound, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug, or solvate thereof, wherein the compound has the structure shown in Formula Vc"-1:

[0570] Among them, R9, R 10 、R 13 、R 14 , L1, B ring and wavy line have the same definitions and preferred embodiments as the corresponding substituents in formula Vc".

[0571] In some embodiments, the present invention provides a compound, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug, or solvate thereof, wherein the compound has a structure shown in Formula Vc"-2 or Vc"-3:

[0572] Among them, R9, R 10 、R 13 、R 14 , L1 and the wavy line have the same definitions and preferred embodiments as the corresponding substituents in formula Vc", and

[0573] Ring B is or absent, wherein R4 and R5 are independently H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl or cyclobutyl, preferably R4 and R5 are independently methyl.

[0574] In a preferred embodiment, the compound structure is shown below:

[0575] RNAi agents

[0576] Another aspect of the present invention provides an RNAi agent or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein the RNAi agent has a structure shown in Formula VI, VIa, VIb, VIc, VId, VIe, VIf, VIg, VIh, VIi, VIj or VIk:

[0577] in,

[0578] It is an oligonucleotide, preferably siRNA or ASO, wherein the siRNA or ASO is linked to L via a phosphate group, a phosphorothioate group 21 and / or L 11 connected;

[0579] z1 and z2 are independently 0 or 1, and z1 and z2 are not 0 at the same time;

[0580] y1 and y2 are independently 1, 2 or 3;

[0581] Each Ligand is independently selected from compounds of Formula Ia", Formula Ib", Formula Ib"-1, Formula IIa", Formula IIb", Formula IIIa", Formula IIIb", Formula IIIa"-1, Formula IIIb"-1, Formula IVa", Formula IVa"-1, Formula IVb", Formula Va", Formula Va"-1, Formula Va"-2, Formula Va"-3, Formula Vb", Formula Vb"-1, Formula Vb"-2, Formula Vc", Formula Vc"-1, Formula Vc"-2, and Formula Vc"-3;

[0582] L 11 and L 21 Independently selected from:

[0583] wherein n and m are independently integers from 0 to 10, preferably from 2 to 6, and attachment point 1 is connected to the oligonucleotide, and attachment point 2 is connected to L 12 or L 22 ;

[0584] L 12 and L 22 are independently a bond or a branching group, the branching group being independently selected from:

[0585] wherein n is an integer from 0 to 10, preferably an integer from 2 to 6, and the connection point 1 is connected to L 11 or L 21 , connect points 2, 3 and 4 to L 13 or L 23 ;

[0586] L 13 and L 23 Independently selected from:

[0587] wherein n and m are independently integers of 0 to 10, preferably integers of 2 to 6, and the wavy line on the left side of the formula is connected to L 12 or L 22 , the wavy line on the right side of the formula is connected to Ligand.

[0588] In a preferred embodiment, L 21 , L 22 and L 23 Together they form a structure selected from the following, wherein the left side of the formula is linked to the oligonucleotide via a phosphate group or a phosphorothioate group:

[0589] In a preferred embodiment, L 11 , L 12 and L 13Together they form a structure selected from the following, wherein the left side of the formula is linked to the oligonucleotide via a phosphate group or a phosphorothioate group:

[0590] In some embodiments, oligonucleotide molecules can be directly covalently coupled to the integrin ligand compound of the present invention. The oligonucleotide molecules that can be used for covalent coupling can have the following structure, wherein oligonucleotides represents an oligonucleotide, such as siRNA or ASO, and n is an integer from 0 to 10, preferably an integer from 2 to 6.

[0591] In some embodiments, an oligonucleotide molecule can be covalently coupled to multiple (e.g., 1 to 4) integrin ligand compounds of the present invention. The oligonucleotide molecule that can be used for such covalent coupling can have the following structure, wherein oligonucleotides represents an oligonucleotide, such as siRNA or ASO; n is an integer from 0 to 10, preferably an integer from 2 to 6.

[0592] In a preferred embodiment, the present invention provides an RNAi agent with a structural formula as shown in any one of the following tables, wherein Indicates siRNA or ASO, X=O or S.

[0593] Pharmaceutical composition

[0594] The present invention also includes pharmaceutical compositions and preparations, which include RNAi agents as described herein (such as any one of formulas 201 to 356) and pharmaceutically acceptable carriers, excipients or diluents. Such compositions and preparations can be used to reduce the expression of target genes in patients in need. In the case of considering clinical application, pharmaceutical compositions and preparations will be prepared in the form suitable for intended application. Typically, this will require preparation of a composition that is substantially free of pyrogens and other impurities that may be harmful to humans or animals.

[0595] The composition and method for preparing the pharmaceutical composition depend on many standards, including but not limited to route of administration, the type and degree of the disease to be treated or the condition or the dosage to be administered. In some embodiments, the pharmaceutical composition is prepared based on the expected route of delivery. For example, in certain embodiments, the pharmaceutical composition is formulated for parenteral delivery. Parenteral administration forms include intravenous, intraarterial, subcutaneous, intrathecal, intraperitoneal or intramuscular injection or infusion. In one embodiment, the pharmaceutical composition is formulated for intravenous delivery. In such an embodiment, the pharmaceutical composition can include a lipid-based delivery vehicle. In another embodiment, the pharmaceutical composition is formulated for subcutaneous delivery.

[0596] In some embodiments, the pharmaceutical composition comprises an effective amount of RNAi agent as described herein. "Effective amount" refers to an amount sufficient to produce a beneficial or desired clinical result. In some embodiments, an effective amount is an amount sufficient to reduce target gene expression in a patient's specific tissue or cell type. The effective amount of the RNAi agent of the present invention can be from about 0.01 mg / kg body weight to about 100 mg / kg body weight, and can be administered daily, weekly, monthly or at longer intervals. Accurately determining a specific effective dosage and dosing frequency may be based on several factors, including the patient's size, age and general condition, the type of disease to be treated, the specific RNAi agent used, and the route of administration.

[0597] The administration of the pharmaceutical composition of the present invention can be carried out by any common route, as long as the target tissue can be obtained by the route. These routes include but are not limited to parenteral (e.g., subcutaneous, intramuscular, intraperitoneal or intravenous), oral, nasal, oral, intradermal, transdermal and sublingual routes, or by direct injection into liver tissue or delivered by the portal vein. In some embodiments, the pharmaceutical composition is parenteral. For example, in certain embodiments, the pharmaceutical composition is administered intravenously. In other embodiments, the pharmaceutical composition is administered subcutaneously.

[0598] Colloidal dispersion systems can be used as delivery vehicles for the RNAi agents of the present invention, such as macromolecular complexes, nanocapsules, microspheres, beads, and lipid-based systems, including oil-in-water emulsions, micelles, mixed micelles, and liposomes. Commercially available fat emulsions suitable for transporting nucleic acids of the present invention include Intralipid (Baxter International Inc.), Liposyn (Abbott Pharmaceuticals), Lipsyn II (Hospira), Liposyn III (Hospire), Nutrilipid (B.Braun Medical Inc.), and other similar fat emulsions. A preferred colloidal system for use as an in vivo delivery vehicle is a liposome (i.e., an artificial membrane vesicle). The RNAi agent of the present invention can be encapsulated within a liposome, or can form a complex therewith, particularly with a cationic liposome. Alternatively, the RNAi agent of the present invention can be complexed with lipids, particularly with cationic lipids. Suitable cationic lipids are, for example, diol tetramethylaminopropyl (DOTAP) and diol phosphatidylethanolamine (DOTMA).

[0599] Liposomal formulations are particularly well-suited for topical administration, and liposomes offer several advantages over other formulations. These advantages include reduced side effects associated with high systemic absorption of the administered drug, increased accumulation of the administered drug at the desired target, and the ability to administer RNAi agents to the skin. In some embodiments, liposomes are used to deliver RNAi agents to epidermal cells and also enhance the penetration of RNAi agents into dermal tissue, such as the skin.

[0600] RNAi agent of the present invention can be fully encapsulated in lipid formulations, such as LNP or other nucleic acid-lipid particles. As used herein, term " LNP " refers to stable nucleic acid-lipid particles. LNP generally comprises cationic lipids, non-cationic lipids and the lipid (such as PEG-lipid conjugate) that prevents particle aggregation. LNP is very useful for systemic application because they show prolonged circulation time after intravenous (iv) injection, and accumulate in distal sites (such as the position physically separated from the administration site). LNP includes " pSPLP ", which includes the condensing agent-nucleic acid complex of the encapsulation described in WO00 / 03683. LNP particles of the present invention generally have an average diameter of about 50nm to about 150nm, more typically about 60nm to about 130nm, more typically about 70nm to about 110nm, most typically about 70nm to about 90nm, and substantially nontoxic. In addition, when nucleic acid is present in nucleic acid-lipid particles of the present invention, it has resistance to the degradation of nuclease in aqueous solution. Nucleic acid-lipid particles and methods for preparing the same are disclosed in, for example, U.S. Patent Nos. 5,976,567; 5,981,501; 6,534,484; 6,586,410; 6,815,432; U.S. Publication Nos. 2010 / 0324120 and WO 96 / 40964. In one embodiment, the lipid to drug ratio (mass / mass ratio) (e.g., lipid to RNAi agent ratio) will be in the range of about 1:1 to about 50:1, about 1:1 to about 25:1, about 3:1 to about 15:1, about 4:1 to about 10:1, about 5:1 to about 9:1, or about 6:1 to about 9:1.

[0601] The cationic lipid can be, for example, N,N-dioleyl-N,N-dimethylammonium chloride (DODAC), N,N-distearyl-N,N-dimethylammonium bromide (DDAB), N-(1-(2,3-dioleyloxy)propyl)-N,N,N-trimethylammonium chloride (DOTAP), N-(1-(2,3-dioleyloxy)propyl)-N,N,N-trimethylammonium chloride (DOTMA), N,N-dimethyl-2,3-dioleyloxy)propylamine (DODMA), 1,2-dioleyloxy-N,N-dimethylaminopropane (DLinDMA), 1,2-dioleyloxy-N,N-dimethylaminopropane (DLenDMA), 1,2-dioleyloxy-N,N-dimethylaminopropane (DLenDMA), 1,2-dioleyloxy-N,N-dimethylaminopropane (DLenDMA), 1,2-dioleyloxy-N,N-dimethylaminopropane (DLenDMA). Dioleylcarbamoyloxy-3-dimethylaminopropane (DLin-C-DAP), 1,2-dihydroxypropoxy-3-(dimethylamino)acetoxypropane (DLin-DAC), 1,2-dihydroxypropoxy-3-morpholinopropane (DLin-MA), 1,2-dilinoyl-3-dimethylaminopropane (DLinDAP), 1,2-dilinoleylthio-3-dimethylaminopropane (DLin-S-DMA), 1-linoleoyl-2-linoleyloxy-3-dimethylaminopropane (DLin-2-DMAP), 1,2-dilinoleyloxy-3-trimethylaminopropane chloride (DLin-TMA.Cl), 1,2-di Linoleoyl-3-trimethylaminopropane chloride (DLin-TAP.Cl), 1,2-dilinoleoyloxy-3-(N-methylpiperazino)propane (DLin-MPZ) or 3-(N,N-dilinoleylamino)-1,2-propanediol (DLinAP), 3-(N,N-dioleylamino)-1,2-propanediol (DOAP), 1,2-dilinoleyloxy-3-(2-N,N-dimethylamino)ethoxypropane (DLin-EG-DMA), 1,2-dilinolenoyloxy-N,N-dimethylaminopropane (DLinDMA), 2,2-dilinoleyl-4-dimethylaminomethyl-[1,3]-dioxolane (DLin -K-DMA) or its analogues, (3aR,5s,6aS)-N,N-dimethyl-2,2-di((9Z,12Z)-octadeca-9,12-dienyl)tetrahydro-3aH-cyclopenta[d][1,3]dioxol-5-amine (ALN100), (6Z,9Z,28Z,31Z)-heptatriacontac-6,9,28,31-tetraen-19-yl 4-(dimethylamino)butyrate (MC3), 1,1'-(2-(4-(2-((2-(bis(2-(bis(2-hydroxydodecyl)amino)ethyl)(2-hydroxydodecyl)amino)ethyl)piperazin-1-yl)ethylazadiyl)didecadecan-2-ol (Tech G1) or mixtures thereof.The cationic lipid may comprise from about 20 mol% to about 50 mol%, or about 40 mol% of the total lipid present in the particle.

[0602] In some embodiments, the compound 2,2-dilinoleyl-4-dimethylaminoethyl-[1,3]-dioxolane can be used to prepare lipid-siRNA nanoparticles. In some embodiments, the lipid-siRNA particles comprise 40% 2,2-dilinoleyl-4-dimethylaminoethyl-[1,3]-dioxolane: 10% DSPC: 40% cholesterol: 10% PEG-C-DOMG (molar percentage), have a particle size of 63.0±20 nm, and a siRNA / lipid ratio of 0.027.

[0603] The ionizable / non-cationic lipids can be anionic lipids or neutral lipids, including but not limited to distearoylphosphatidylcholine (DSPC), dioleoylphosphatidylcholine (DOPC), dipalmitoylphosphatidylcholine (DPPC), dioleoylphosphatidylglycerol (DOPG), dipalmitoyl DP-acylglyceroglycerophosphatidylethanolamine (DOPE), palmitoyloleoylphosphatidylcholine (POPC), palmitoyloleoylphosphatidylethanolamine (POPE), oleoylphosphatidylcholine (POPC), palmitoyloleoylphosphatidylethanolamine (POPE), oleoylphosphatidylcholine (POPC), palmitoylphosphatidylcholine ...DPPC), palmitoylphosphatidylcholine (DPPC), palmitoylphosphatidylcholine (DPPC), palmitoylphosphatidylcholine (DPPC), palmitoylphosphatidylcholine (DPPC), palmitoylphosphatidylcholine (DPPC), palmitoylphosphatidylcholine (DPPC), palmitoylphosphatidylcholine (DPPC), palmitoylphosphatidylcholine (DPPC), palmitoylphosphatidylcholine (DPPC), palmitoylphosphatidylcholine (DPPC The non-cationic lipid may be present in an amount of about 5 mol % to about 90 mol %, about 10 mol %, or about 58 mol % (if cholesterol is included) of the total lipids present in the particle.

[0604] In some embodiments, the nucleic acid-lipid particle further comprises cholesterol, for example, PEG-diacylglycerol (DAG), PEG-dialkoxypropyl (DAA), PEG-phospholipid, PEG-ceramide (Cer) or a mixture thereof. The PEG-DAA conjugate can be, for example, PEG-docosyloxypropyl (C12), PEG-dimyristyloxypropyl (C14), PEG-dipalmityloxypropyl (C14) or PEG-distearyloxypropyl (C18). Preventing particle aggregation and coupled lipid can be 0mol% to about 20mol% of the total lipid present in the particle, or about 2mol%. In some embodiments, the nucleic acid-lipid particle further comprises cholesterol, for example, accounting for about 10mol% to about 60mol% of the total lipid present in the particle, or about 48mol%.

[0605] In one embodiment, lipidoid ND98·4HCl (molecular weight 1487) (see U.S. Patent Application No. 12 / 056,230, incorporated herein by reference), cholesterol (Sigma-Aldrich), and PEG-ceramide C16 (Avanti Polar Lipids) can be used to prepare lipid-dsRNA nanoparticles (i.e., LNP01 particles). Each stock solution in ethanol can be prepared as follows: ND98, 133 mg / ml; cholesterol, 25 mg / ml; PEG-ceramide C16, 100 mg / ml. The stock solutions of ND98, cholesterol, and PEG-ceramide C16 can then be mixed in a molar ratio of, for example, 42:48:10. The combined lipid solution can be mixed with aqueous siRNA (e.g., in sodium acetate at pH 5) to a final ethanol concentration of approximately 35-45% and a final sodium acetate concentration of approximately 100-300 mM. Lipid-siRNA nanoparticles typically form spontaneously upon mixing.

[0606] Other exemplary lipid-siRNA formulations can be found in, for example, WO2009 / 127060 (SNALP), PCT / US2010 / 022614 (XTC), US2010 / 0324120 (MC3), PCT / US09 / 63933 (ALNY-100), and WO2010 / 129709 (C12-200).

[0607] Pharmaceutical compositions suitable for injection include, for example, sterile aqueous solutions or dispersions and sterile powders for the immediate preparation of sterile injectable solutions or dispersions. In general, these preparations are sterile and, to a certain extent, fluid and easy to inject. The preparation should remain stable under production and storage conditions and should be preserved to prevent contamination by microorganisms such as bacteria and fungi. Suitable solvents or dispersion media can include, for example, water, ethanol, polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycol, etc.), suitable mixtures thereof, and vegetable oils. For example, suitable fluidity can be maintained by using a coating such as lecithin, by maintaining the desired particle size in the case of dispersion, and by using a surfactant. The effects of microorganisms can be prevented by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, etc. In many cases, it is preferred to include isotonic agents, such as sugar or sodium chloride. Prolonged absorption of injectable compositions can be achieved by using agents that delay absorption in the composition, such as aluminum monostearate and gelatin.

[0608] Sterile injectable solutions can be prepared by adding an appropriate amount of the active compound to a solvent along with any other ingredients (e.g., those listed above) and then sterilizing by filtration. Typically, dispersions are prepared by adding the various sterilized active ingredients to a dispersion medium containing an alkaline dispersion medium and the desired other ingredients, e.g., as described above. In the case of sterile powders for the preparation of sterile injectable solutions, preferred preparation methods include vacuum drying and freeze drying techniques, which produce a powder of the active ingredient and any additional desired ingredients from a previously sterile-filtered solution thereof.

[0609] The compositions of the present invention can generally be formulated in neutral form or salt form. Pharmaceutically acceptable salts include, for example, acid addition salts (formed by free amino groups) derived from inorganic acids (such as hydrochloric acid or phosphoric acid) or organic acids (such as acetic acid, oxalic acid, tartaric acid, mandelic acid, etc.). Salts formed with free carboxyl groups can also be derived from inorganic bases (such as sodium, potassium, ammonium, calcium or iron oxide) or organic bases (such as isopropylamine, trimethylamine, histidine, procaine, etc.). In some embodiments, the RNAi agent of the present invention is formulated as a sodium salt.

[0610] For example, for parenteral administration in the form of an aqueous solution, the solution is generally appropriately buffered, and the liquid diluent is first made isotonic with, for example, enough saline or glucose. Such an aqueous solution can be used for, for example, intravenous, intramuscular, subcutaneous, and intraperitoneal administration. Preferably, a sterile aqueous medium is used. For example, a single dose can be dissolved in 1 ml of isotonic NaCl solution and added to 1000 ml of subcutaneous infusion liquid, or injected at the infusion site of the suggestion. For human administration, the preparation should meet the sterility, pyrogenicity, general safety, and purity standards required by the local Food and Drug Administration. In certain embodiments, the pharmaceutical composition of the present invention comprises sterile saline solution and RNAi agent as described herein or consists of the two. In other embodiments, the pharmaceutical composition of the present invention comprises RNAi agent as described herein and sterile water (e.g., water for injection, WFI) or consists of the two. In other embodiments, the pharmaceutical composition of the present invention comprises RNAi agent as described herein and phosphate buffered saline (PBS) or consists of it.

[0611] In some embodiments, the pharmaceutical compositions of the present invention are packaged with or stored within a drug delivery device. Devices for injecting formulations include, but are not limited to, injection ports, prefilled syringes, autoinjectors, syringe pumps, intracorporeal syringes, and injection pens. Devices for aerosolizing or powdered formulations include, but are not limited to, inhalers, insufflators, aspirators, and the like. Thus, the present invention includes a drug delivery device containing a pharmaceutical composition of the present invention for use in treating or preventing one or more diseases or conditions described herein.

[0612] Treatment methods and uses

[0613] The present invention provides a method for reducing or inhibiting the expression of a target gene in a cell (e.g., a hepatocyte) by contacting the cell with any one of the RNAi agents described herein (e.g., any one of Formulas 201 to 356). The cell can be in vitro or in vivo. Target gene expression can be assessed by measuring the amount or level of target gene mRNA or target gene expressed protein (target protein).

[0614] In certain embodiments, the expression of the target gene in the cell is reduced by at least 40%, at least 45% or at least 50% by the RNAi agent of the present invention. In some embodiments, the expression of the target gene in the cell is reduced by at least 60%, at least 65%, at least 70%, at least 75%, at least 80% or at least 85% by the RNAi agent of the present invention. In other embodiments, the expression of the target gene in the cell is reduced by about 90% or more, such as 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more by the RNAi agent of the present invention. The percentage reduction of target gene expression can be measured by any method described herein and other methods known in the art. In some embodiments, the cell is not a hepatocyte.

[0615] In some embodiments, the present invention can target oligonucleotide molecules for delivery to cells other than hepatocytes. In some embodiments, the RNAi agents provided by the present invention can be targeted for delivery to skeletal muscle cells, type I alveolar epithelial cells, type II alveolar epithelial cells, goblet cells, secretory epithelial cells, ciliated epithelial cells, corneal epithelial cells, conjunctival epithelial cells, dermal epithelial cells, bile duct cells, intestinal epithelial cells, ductal epithelial cells, glandular epithelial cells or epithelial tumor cells.

[0616] In some embodiments, disclosed herein is a method of delivering an oligonucleotide molecule to a skeletal muscle cell, a type I alveolar epithelial cell, a type II alveolar epithelial cell, a goblet cell, a secretory epithelial cell, a ciliated epithelial cell, a corneal epithelial cell, a conjunctival epithelial cell, a dermal epithelial cell, a bile duct cell, an intestinal epithelial cell, a ductal epithelial cell, a glandular epithelial cell, or an epithelial tumor cell in vivo, wherein the method comprises administering to the subject one or more RNAi agents of the present invention. In some embodiments, disclosed herein is a method of inhibiting the expression of a target gene in a skeletal muscle cell, a type I alveolar epithelial cell, a type II alveolar epithelial cell, a goblet cell, a secretory epithelial cell, a ciliated epithelial cell, a corneal epithelial cell, a conjunctival epithelial cell, a dermal epithelial cell, a bile duct cell, an intestinal epithelial cell, a ductal epithelial cell, a glandular epithelial cell, or an epithelial tumor cell in vivo, wherein the method comprises administering to the subject one or more RNAi agents of the present invention.

[0617] Example

[0618] Example 1: Synthesis of ligand small molecule compounds

[0619] Compound 1 was synthesized according to patent WO2019089765A1

[0620] LCMS: (ESI) m / z = 786.4 [M+H] + ; 379.9[M+2H] / 2 +

[0621] HPLC: RT = 11.459 min

[0622] Mobile phase: A: Water (0.05% TFA) B: ACN (0.05% TFA)

[0623] Gradient: 20% B to 80% B in 20 min, then to 95% B in 1 min, held for 5 min, and then decreased to 5% B in 0.1 min.

[0624] Flow rate: 1mL / min

[0625] Column: XBridge Peptide BEH C18, 4.6 x 150 mm, 3.5 μm,

[0626] Column temperature: 40℃

[0627] Compound 2 was synthesized according to the literature (Anderson NA, Campbell IB, Fallon BJ, Lynn SM, Macdonald SJ, Pritchard JM, Procopiou PA, Sollis SL, Thorp LR. Synthesis and determination of absolute configuration of a non-peptidic αvβ6 integrin antagonist for the treatment of idiopathic pulmonary fibrosis. Org Biomol Chem. 2016Jul 7;14(25):5992-6009.doi:10.1039 / c6ob00496b.Epub 2016 May 26.PMID:27226381).

[0628] 50 mg of compound 2 was purified by SFC (chromatographic column: OJ-H 4.6*100 mm, 5 μm), mobile phase: [carbon dioxide-methanol (0.2% ammonia water, 7 M in MeOH)], B%: 20%, isobaric elution mode) to obtain white solid isomer 1:2-P1 (Minor) and isomer 2:2-P2 (Major).

[0629] Isomer1:2.4mg

[0630] MS m / z(ESI):488.2[M+H] + ;

[0631] Analytical chiral SFC: RT = 1.591 min, >99.5%, column: OJ-H 4.6*100 mm, 5 μm, CO2-methanol (0.2% ammonia, 7 M in MeOH), B%: 20%, flow rate 3 mL / min. 1 H NMR (400MHz, DMSO-d6) δ7.38(dd,J=7.6,8.0Hz,1H),7.33(s,1H),7.29(d,J=8.0Hz,1H),7.24(d,J=8 .0Hz,1H),7.00(d,J=7.2Hz,1H),6.25(s,1H,NH),6.23(d,J=7.6Hz,1H),6.05(s,1H),3.31-3.25(m,1 H),3.24-3.18(m,2H),2.89-2.74(m,4H),2.68-2.55(m,4H),2.48-2.31(m,4H),2.27(s,3H),2.17(s ,3H),2.06-1.96(m,1H),1.94-1.82(m,1H),1.77-1.69(m,2H),1.64-1.53(m,2H),1.38-1.28(m,1H).

[0632] Isomer2:15mg

[0633] MS m / z(ESI):488.5[M+H] + ;

[0634] Analytical chiral SFC: RT = 2.485 min, >99.5%, column: OJ-H 4.6*100 mm, 5 μm, CO2-methanol (0.2% ammonia, 7 M in MeOH), B%: 20%, flow rate 3 mL / min. 1H NMR (400MHz, DMSO-d6+D2O) δ7.41(dd,J=7.6,8.0Hz,1H),7.33(s,1H),7.30(d,J=8.0Hz,1H),7.25(d,J=8.0 Hz,1H),7.03(d,J=7.6Hz,1H),6.26(d,J=7.6Hz,1H),6.07(s,1H),3.33-3.25(m,1H),3.24-3.19(m,2H),2. 99-2.91(m,1H),2.90-2.84(m,1H),2.84-2.72(m,2H),2.69-2.56(m,4H),2.48-2.32(m,4H),2.27(s,3H),2 .18(s,3H),2.09-1.99(m,1H),1.97-1.86(m,1H),1.78-1.70(m,2H),1.65-1.54(m,2H),1.42-1.31(m,1H).

[0635] Synthesis of compound 4

[0636] Synthesis of intermediate 4-2

[0637] At 25 ° C, compound 4-1 (5.00 g, 22.41 mmol) was dissolved in N, N-dimethylformamide (50 mL), potassium carbonate (4.65 g, 33.62 mmol) and benzyl bromide (3.83 g, 22.41 mmol, 2.66 mL) were added, and stirred at 25 ° C for 4 hours. After the reaction was completed, saturated ammonium chloride solution (10 mL) was added to quench the reaction, diluted with water (200 mL) and extracted with ethyl acetate (200 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and filtered to obtain compound 4-2 (5.00 g, 71.2% yield) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ8.28(d,J=8.00Hz,1H),8.08(d,J=8.38Hz,1H),7.77(d,J=8.38Hz,1H),7.71(m,J=8.32,7.00,1.19H z,1H),7.65-7.59(m,1H),7.55(d,J=7.13Hz,2H),7.47-7.40(m,2H),7.40-7.32(m,1H),7.03(d,J=8.38Hz,1H),5.31(s,2H).

[0638] Synthesis of intermediate 4-3

[0639] At 25 ° C, compound 4-2 (8.33 g, 26.59 mmol) was dissolved in tetrahydrofuran (140 mL), then nitrogen purged 3 times, n-butyl lithium (2.5 M, 12.49 mL) was added at -78 ° C and stirred at -78 ° C for half an hour, and finally triisopropyl borate (5.00 g, 26.59 mmol, 6.11 mL) was added dropwise, and the reaction solution was slowly warmed to room temperature and stirred for 1.5 hours. After the reaction was completed, saturated ammonium chloride solution (150 mL) was added to quench the reaction, diluted with water (300 mL) and extracted with ethyl acetate (300 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and dried to obtain yellow oily compound 4-3 (6.00 g, 81.2% yield). MS m / z (ESI): 277.0 [MH] - .

[0640] Synthesis of intermediates 4-6

[0641] At 25°C, N-BOC piperazine (4-5, 17.18 g, 92.25 mmol) was dissolved in tetrahydrofuran (150 mL), then nitrogen purged three times, n-butyl lithium (2.5 M, 35.75 mL) was added at -78°C and stirred at -78°C for half an hour, and finally compound 4-4 (13.9 g, 57.66 mmol) was added dropwise and the reaction solution was stirred at -78°C for 1.5 hours. After completion of the reaction, saturated ammonium chloride solution (100 mL) was added to quench the reaction, diluted with water (200 mL) and extracted with ethyl acetate (200 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and dried. The residue was purified by flash silica gel chromatography (eluent: 0-40% tetrahydrofuran / petroleum ether) to give compound 4-6 (6.00 g, 24.4% yield) as a white solid. MS m / z (ESI): 427.2 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ7.52(d,J=8.25Hz,2H),7.24(d,J=8.38Hz,2H),3.98(t,J=7.75Hz,1 H), 3.52 (s, 3H), 3.23 (d, J = 3.38Hz, 4H), 3.06-2.71 (m, 2H), 2.33-2.14 (m, 4H), 1.34 (s, 9H).

[0642] Synthesis of intermediates 4-7

[0643] At 25 ° C, compound 4-3 (3.58 g, 12.87 mmol), 4-6 (5.50 g, 12.87 mmol) and potassium carbonate (5.34 g, 38.61 mmol) were dissolved in tetrahydrofuran (80 mL) and water (10 mL), then nitrogen purged three times, chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl) [2-(2'-amino-1,1'-biphenyl)] palladium (II) (1.01 g, 1.29 mmol) and 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (1.23 g, 2.57 mmol) were added and stirred at 60 ° C for 8 hours. After completion of the reaction, it was diluted with water (100 mL) and extracted with ethyl acetate (100 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and dried. The residue was purified by flash silica gel chromatography (eluent: 0-70% tetrahydrofuran / petroleum ether) to give compound 4-7 (6.60 g, 88.3% yield) as a yellow oil. MS m / z (ESI): 581.4 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ8.37-8.29(m,1H),7.83-7.75(m,1H),7.59(d,J=7.13Hz,2H),7.54(m ,J=7.82,5.75,1.56Hz,2H),7.48-7.43(m,2H),7.42-7.32(m,6H),7.15(d,J=8.13Hz,1H),5. 37(s,2H),4.11(t,J=7.69Hz,1H),3.58(s,3H),3.28(d,J=3.13Hz,4H),3.10(dd,J=14.88,7. 75Hz, 1H), 2.83 (dd, J = 15.01, 7.63Hz, 1H), 2.46-2.38 (m, 2H), 2.32-2.25 (m, 2H), 1.36 (s, 9H).

[0644] Synthesis of intermediates 4-8

[0645] At 25°C, compound 4-7 (5.00 g, 8.61 mmol) was dissolved in dichloromethane (50 mL), and trifluoroacetic acid (12 mL) was added and stirred at 25°C for 1 hour. After the reaction was completed, the mixture was dried to obtain a black solid compound 4-8 (4.00 g, 96.7% yield). MS m / z (ESI): 481.3 [M+H] + .

[0646] Synthesis of intermediates 4-9

[0647] At 25°C, compound 4-8 (4.00 g, 8.32 mmol) was dissolved in methanol (50 mL), and then the atmosphere was replaced with nitrogen three times. Wet palladium carbon (4.43 g, 10% purity) was added and replaced with hydrogen three times. The mixture was stirred at 25°C under a hydrogen atmosphere (20 psi) for 12 hours. After the reaction was completed, the mixture was filtered and dried to obtain a crude product. The crude product was purified by reverse-phase high-performance liquid chromatography (0.1% trifluoroacetic acid) to obtain compound 4-9 (1.00 g, 30.8% yield) as a white solid. MS m / z (ESI): 391.2 [M+H] + ; 1 HNMR(400MHz,DMSO-d6)δ10.41-10.22(m,1H),8.46(s,2H),8.26-8.18(m,1H),7.82-7.71(m,1H),7.53-7.38(m,6H),7. 23(d,J=7.75Hz,1H),6.95(d,J=7.75Hz,1H),4.23(t,J=7.63Hz,1H),3.59(s,3H),3.18–2.88(m,7H),2.76-2.56(m,4H).

[0648] Synthesis of intermediate 4-13

[0649] 4-12 (80 mg, 0.27 mmol) was dissolved in DMF (3 mL), and 4-9 (100 mg, 0.26 mmol), EDCI (67 mg, 0.35 mmol), HOBT (47 mg, 0.35 mmol), and DIPEA (208 mg, 1.56 mmol) were added in sequence. The reaction mixture was stirred at room temperature for 3 hours, and the reaction mixture was directly purified by preparative chromatography (Xbridge C18, 19 x 250 mm, 10 μm, Mobile phase: A: water (containing 10 mmol / L NH4HCO3), B: ACN; gradient: 35% B to 95% B over 20 minutes) to afford 4-12 (39 mg, yield: 25%) as a white solid. LCMS: (ESI) m / z = 667.5 [M+H] + .

[0650] Synthesis of intermediate 4-14

[0651] 4-13 (33 mg, 0.048 mmol) was dissolved in DMF (5 mL) and N3-PEG5-Tos (azido-triethylene glycol-carboxylic acid) (40 mg, 0.096 mmol) was added. The reaction mixture was stirred at 75°C for 16 hours. The reaction mixture was directly purified by preparative chromatography (Xbridge C18, 19 x 250 mm, 10 μm, Mobile phase: A: water (containing 10 mmol / L NH4HCO3) B: ACN; gradient: 35% B to 95% B over 20 minutes) to afford 4-14 (38 mg, yield: 83%) as a white solid. LCMS: (ESI) m / z = 913.3 [M+H] + .

[0652] Synthesis of compound 4

[0653] 4-14 (35 mg, 0.038 mmol) was dissolved in THF (1 mL) and H2O (1 mL), and LiOH·H2O (6 mg, 0.15 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours. The reaction was complete as monitored by LCMS. The reaction mixture was acidified with 3N dilute hydrochloric acid and concentrated. The concentrated compound was dissolved in DCM (3 mL), and glacial TFA (3 mL) was added. The reaction mixture was stirred at room temperature for 16 hours. The reaction was complete as monitored by LCMS. The reaction mixture was concentrated and dried under vacuum to obtain crude product 4. It was used directly in the next reaction. LCMS: (ESI) m / z = 798.3 [M+H] + .

[0654] Synthesis of compound 5

[0655] Synthesis of intermediate 5-2

[0656] Compound 5-1 (20.0 g, 185 mmol) was dissolved in tert-butyl alcohol (200 mL) at room temperature, and di-tert-butyl dicarbonate (44.4 g, 203 mmol, 46.7 mL) was added. The reaction solution was stirred at 25°C for 3 hours. The reaction solution was concentrated, and the residue was slurried with 200 mL of tert-methyl ether. The filtrate was concentrated to dryness. The residue was recrystallized from isopropanol to obtain white crystals of compound 5-2 (23.0 g, 59.7% yield). 1 H NMR (400MHz, CDCl3) δ9.42 (s, 1H), 8.28-8.07 (m, 1H), 7.85 (s, 1H), 6.77 (d, J = 5.0Hz, 1H), 2.35 (s, 3H), 1.55 (s, 9H).

[0657] Synthesis of intermediate 5-4

[0658] Compound 5-3 (24.0 g, 245 mmol) was added to nitromethane (360 mL) at room temperature, followed by the addition of 1,8-diazabicyclo[5.4.0]undec-7-ene (4.84 g, 31.8 mmol). The reaction mixture was stirred at 25°C for 16 hours. After completion of the reaction, the reaction mixture was concentrated, and the resulting residue was dissolved in 800 mL of dichloromethane. The residue was washed sequentially with 3.0 M hydrochloric acid (500 mL), water (500 mL), saturated aqueous sodium bicarbonate solution (500 mL), and saturated brine (500 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to afford compound 5-4 (30.0 g, 77.1% yield) as an amber oil. 1 H NMR (400MHz, CDCl3) δ4.74-4.51(m,2H),4.42-4.33(m,1H),4.25-4.14(m,1H) ,2.72-2.59(m,1H),2.52-2.37(m,2H),2.27-2.16(m,1H),2.05-1.93(m,1H).

[0659] Synthesis of Intermediate 5-5

[0660] Compound 5-4 (28.0 g, 176 mmol), magnesium sulfate (23.3 g, 194 mmol), and methanol (60 mL) were added to a stainless steel hydrogenation bottle at room temperature. Raney nickel (21.1 g) was slowly added under a nitrogen stream. After the addition was complete, the hydrogen atmosphere was replaced three times. The reaction was continued at 50°C under a hydrogen atmosphere (50 psi) for 30 hours. After the reaction was completed, the mixture was filtered and the filtrate was concentrated to obtain compound 5-5 (30.5 g, crude product) as a brown oil. 1 H NMR (400MHz, CDCl3) δ7.08(s,1H),4.53(s,1H),3.71-3.57(m,2H),3.37-3.26(m,2H),2. 57-2.46(m,1H),2.35-2.24(m,1H),1.89-1.76(m,2H),1.65(m,J=5.3,9.3,14.4Hz,1H).

[0661] Synthesis of intermediate 5-6

[0662] Compound 5-5 (37.0 g, 286 mmol), imidazole (48.8 g, 716 mmol) and tert-butyldimethylsilyl chloride (64.8 g, 430 mmol) were added to dichloromethane (370 mL) at room temperature, and the reaction solution was stirred at 25°C for 8 hours. The reaction solution was poured into 500 mL of water and extracted with dichloromethane (500 mL × 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated to obtain a residue, which was purified by flash silica gel chromatography (eluent: 0-50% ethyl acetate / petroleum ether) to obtain a colorless liquid compound 5-6 (26.4 g, 37.9% yield). 1 H NMR (400MHz, CDCl3) δ6.35 (s, 1H), 3.81-3.66 (m, 2H), 3.39-3.26 (m, 2H), 2.47 (m, J = 4.3, 9.2Hz, 1H), 2.38-2.27 (m ,1H),2.12(m,J=4.4,6.6,13.6Hz,1H),1.84(m,J=8.9,12.5Hz,1H),1.58-1.45(m,1H),0.89(s,9H),0.05(s,6H).

[0663] Synthesis of intermediate 5-7

[0664] Sodium hydride (4.77 g, 119 mmol, 60% purity) was added to tetrahydrofuran (130 mL) under a nitrogen stream. The reactor was purged with nitrogen three times and then cooled to 0°C. A solution of compound 5-5 (26.4 g, 108 mmol) previously dissolved in tetrahydrofuran (130 mL) was added to the reaction solution, and the reaction solution was stirred at 0°C for 30 minutes. Subsequently, ethyl 2-bromoacetate (19.0 g, 114 mmol) was added at 0°C, and the reaction solution was stirred at 25°C for 16 hours. After the reaction was completed, the reaction was quenched with saturated aqueous ammonium chloride (500 mL) at 25°C and extracted with ethyl acetate (400 mL×2). The combined organic phases were washed with saturated brine (400 mL) and dried over anhydrous sodium sulfate, filtered and concentrated to obtain a light yellow liquid compound 5-7 (34.0 g, 99.4% yield). 1H NMR (400MHz, CDCl3) δ4.18 (q, J = 7.1Hz, 2H), 4.12-3.96 (m, 2H), 3.80-3.69 (m, 2H), 3.47-3.34 (m, 2H), 2.58 (m, J = 4.6, 8.9Hz, 1H), 2.33-2. 22(m,1H),2.19-2.09(m,1H),1.80(m,J=8.7,12.5Hz,1H),1.54(dt,J=5.9,14.5Hz,1H),1.27(t,J=7.1Hz,3H),0.89(s,9H),0.05(s,6H).

[0665] Synthesis of intermediates 5-8

[0666] Compound 5-7 (45.0 g, 143 mmol) was dissolved in tetrahydrofuran (675 mL), and a solution of tetrabutylammonium fluoride (1 M, 172 mL) in tetrahydrofuran was added at 0°C. The reaction mixture was stirred at 25°C for 4 hours. The reaction mixture was concentrated, and the residue was purified by flash silica gel chromatography (eluent: 0-40% tetrahydrofuran / petroleum ether) to afford compound 5-8 (14.8 g, 51.6% yield) as a light orange liquid. 1 H NMR (400MHz, CDCl3) δ4.19 (q, J = 7.1Hz, 2H), 4.14-3.95 (m, 2H), 3.87-3.70 (m, 3H), 3.55-3.46 (m, 1H), 3.46-3.39 (m, 1H), 2.66(m,J=5.7,8.9Hz,1H),2.35-2.24(m,1H),1.92(m,J=4.5,9.0,13.9Hz,1H),1.86-1.72(m,2H),1.27(t,J=7.1Hz,3H).

[0667] Synthesis of intermediates 5-9

[0668] Compound 5-8 (16.2 g, 80.5 mmol) was dissolved in dichloromethane (100 mL). Triphenylphosphine (31.7 g, 121 mmol) and a solution of carbon tetrabromide (32.0 g, 96.6 mmol) previously dissolved in dichloromethane (100 mL) were added sequentially with stirring. The mixture was stirred at 25°C for 4 hours. The reaction solution was concentrated, and the residue was purified by flash silica gel chromatography (eluent: 0-50% ethyl acetate / petroleum ether) to obtain compound 5-9 (18.2 g, 85.6% yield) as a colorless liquid. 1H NMR (400MHz, CDCl3) δ4.18(q,J=7.1Hz,2H),4.04(s,2H),3.63(td,J=6.6,10.0Hz,1H),3.55-3.48(m,1H),3.47-3.36(m,2H),2.68 (m,J=6.1,8.7Hz,1H),2.48-2.37(m,1H),2.36-2.26(m,1H),1.98-1.86(m,1H),1.74(m,J=8.8,12.5Hz,1H),1.27(t,J=7.1Hz,3H).

[0669] Synthesis of Intermediates 5-10

[0670] Under nitrogen flow, sodium hydride (2.75 g, 68.8 mmol, 60% purity) was added to N,N-dimethylformamide (15 mL), and the reaction solution was cooled to 0°C. A solution of compound 5-2 (13.3 g, 63.7 mmol) previously dissolved in N,N-dimethylformamide (15 mL) was added to the reaction solution and stirred at 0°C for 30 minutes under nitrogen flow. Compound 5-9 (18.0 g, 68.2 mmol) was then added and stirred at 25°C for 3 hours. After the reaction was completed, the reaction was quenched with saturated aqueous ammonium chloride (100 mL) at 25°C, followed by the addition of 100 mL of water and extraction with ethyl acetate (250 mL × 2). The organic phases were combined, washed with saturated brine (500 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash silica gel chromatography (eluent: 0-60% ethyl acetate / petroleum ether) to give a colorless oil 5-10 (16.1 g, 64.6% yield). 1 H NMR (400MHz, CDCl3) δ8.20(d,J=4.9Hz,1H),7.37(s,1H),6.83(d,J=4.8Hz,1H),4.16(q,J=7.1Hz,2H),4.09-3.93(m,4H),3.45-3.32(m,2H),2. 51-2.40(m,1H),2.32(s,3H),2.29-2.15(m,2H),1.80(m,J=8.4,12.5Hz ,1H),1.62(m,J=4.6,8.9,13.6Hz,1H),1.49(s,9H),1.28-1.22(m,3H).

[0671] Synthesis of intermediate 5-11

[0672] Compound 5-10 (5.00 g, 12.8 mmol) was dissolved in tetrahydrofuran (40 mL) at room temperature, and water (10 mL), lithium hydroxide monohydrate (2.14 g, 51.09 mmol), and 4-dimethylaminopyridine (156 mg, 1.28 mmol) were added. The reaction mixture was stirred at 25°C for 2 hours. Water (100 mL) and dichloromethane (100 mL) were added to the reaction mixture. The aqueous phase was separated and a saturated aqueous citric acid solution was added dropwise to adjust the pH to approximately 5. The mixture was then extracted with dichloromethane (100 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash silica gel chromatography (eluent: 0-30% tetrahydrofuran / petroleum ether) to afford a colorless oil. Finally, the mixture was slurried with tert-methyl ether to afford compound 5-11 (2.00 g, 43.1% yield) as a white solid. MS m / z(ESI):378.1[M+H] + ; 1 H NMR (400MHz, CDCl3) δ8.74-8.36(m,1H),8.26(d,J=5.1Hz,1H),7.31(s,1H),6.90(d,J=5.0Hz,1H),4.11-3.87(m,4H),3.48-3.34(m,2 H), 2.50 (m, J = 4.1, 9.0Hz, 1H), 2.34 (s, 3H), 2.29-2.19 (m, 1H), 2.19-2.08 (m, 1H), 1.82-1.73 (m, 1H), 1.69-1.57 (m, 1H), 1.48 (s, 9H).

[0673] Synthesis of Intermediates 5-14

[0674] 4-2 (1.57 g, 5.0 mmol, 1.0 equiv.) was dissolved in THF (25 mL) and cooled to -78°C in a dry ice acetone bath. n-Butyl lithium (2.4 mL, 6.0 mmol) was added dropwise. After the addition was complete, the reaction mixture was stirred at -78°C for 10 minutes. Triisopropyl borate (1.22 g, 6.5 mmol) was then added dropwise. After the addition was complete, the reaction mixture was slowly warmed to room temperature and stirred for 2 hours. The reaction mixture was quenched with 2N hydrochloric acid (10 mL), extracted with ethyl acetate (100 mL), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was dissolved in ethyl acetate (5 mL) and petroleum ether (50 mL) was added dropwise with stirring. A white precipitate was formed, which was filtered and dried to afford 5-14 (1.0 g, yield: 71.9%) as a white solid. LCMS: (ESI) m / z = 279.3 [M+H] + ,301.1[M+Na] + .

[0675] Synthesis of intermediate 5-16

[0676] A 100 mL flask was charged with 5-14 (0.582 g, 2.1 mmol, 1.5 equiv.), 5-15 (500 mg, 1.4 mmol), XPhos Pd G2 (220 mg, 0.28 mmol), potassium phosphate (594 mg, 2.8 mol), and tetrahydrofuran (10 mL). The atmosphere was purged with nitrogen twice and the reaction was stirred at room temperature for 16 hours. Water (10 mL) was added to the reaction solution, which was then extracted with ethyl acetate (50 mL x 2), washed with saturated brine (20 mL), filtered, dried over anhydrous sodium sulfate, and concentrated. The residue was purified on a silica gel column to afford 5-16 (640 mg, yield: 88.5%) as a light yellow solid. LCMS: (ESI) m / z = 534.3 [M+Na] + ,1045.4[2M+Na] + ; 1 H NMR(DMSO-d6,400MHz)δ8.31(d,J=8.0Hz,1H),7.78(d,J=8.4Hz,1H),7.61-7.36(m,12H),7.33(d,J=8.4Hz ,1H),7.14(d,J=8.0Hz,1H),5.36(s,2H),5.09-4.99(m,1H),3.61(s,3H),2.87-1.74(m,2H),1.39(s,9H).

[0677] Synthesis of Intermediate 5-17

[0678] Intermediate 5-16 (0.64 g) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (3 mL) was carefully added. The mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated, and the residue was purified using a reverse phase column to obtain 5-17 (600 mg, yield: 91.3%) as a white solid. LCMS: (ESI) m / z = 434.3 [M+Na] + .

[0679] Synthesis of intermediate 5-18

[0680] 5-17 (118 mg, 0.27 mmol) was dissolved in DMF (3 mL), and 5-11 (100 mg, 0.27 mmol), EDCI (62 mg, 0.33 mmol), HOBT (44 mg, 0.33 mmol) and DIPEA (208 mg, 1.62 mmol) were added in sequence. The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was directly purified by preparative chromatography (Xbridge C18, 19×250 mm, 10 μm, Mobile phase: A: water (containing 10 mmol / L NH4HCO3); B: ACN; gradient: 35% B to 65% B over 20 minutes) to afford 5-18 (103 mg, yield: 49%) as a white solid. LCMS: (ESI) m / z = 771.5 [M+H] + .

[0681] Synthesis of Intermediate 5-19

[0682] 5-18 (100 mg, 0.153 mmol) was dissolved in MeOH (5 mL) and Pd / C (26 mg, 10% purity) was added. The reaction mixture was stirred at room temperature for 2 hours under a stream of hydrogen. The reaction mixture was filtered and concentrated to give the crude product of 5-19 as a white solid, which was used directly in the next step. LCMS: (ESI) m / z 681.2 [M+H] + .

[0683] Synthesis of Intermediate 5-20

[0684] 5-19 (100 mg, crude) was dissolved in DMF (5 mL) and N3-PEG5-Tos (112 mg, 0.268 mmol) was added. The reaction mixture was stirred at 75°C for 16 hours. The reaction mixture was directly purified by preparative chromatography (Xbridge C18, 19×250 mm, 10 μm, Mobile phase: A: water (containing 10 mmol / L NH4HCO3); B: ACN; gradient: 35% B to 95% B over 20 minutes) to afford 5-20 (89 mg, yield: 73%) as a white solid. LCMS: (ESI) m / z = 926.5 [M+H] + .

[0685] Synthesis of compound 5

[0686] 5-20 (87 mg, 0.094 mmol, 1.0 equiv.) was dissolved in THF (3 mL) and H₂O (3 mL), and LiOH·H₂O (15 mg, 0.38 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours. LCMS monitored the reaction to be complete. The reaction mixture was acidified with 3M dilute hydrochloric acid, concentrated to dryness, dissolved in DCM (2 mL), and glacial TFA (2 mL) was added. The reaction mixture was stirred at room temperature for 16 hours. LCMS monitored the reaction to be complete. The mixture was then concentrated and dried under vacuum to give compound 5 (HPLC purity 95.27%). LCMS: (ESI) m / z = 812.5 [M+H] +The compound was purified by SFC (chromatographic column: OD-3 4.6*100 mm, 3 μm, mobile phase: [carbon dioxide-methanol (0.2% NH3 in MeOH)], B%: 50%, isobaric elution mode) to obtain yellow oily compounds isomer1:5-P1 and isomer2:5-P2.

[0687] 300 mg of compound 5 was purified by SFC (chromatographic column: OD 25*250 mm, 10 μm, mobile phase: [carbon dioxide-methanol (0.5% NH3 in MeOH)], B%: 50%, isobaric elution mode) to obtain yellow solid compounds isomer1:5-P1 and yellow solid compounds isomer2:5-P2.

[0688] Isomer1:100mg

[0689] MS m / z(ESI):812.2[M+H] + ;

[0690] Analytical chiral SFC: RT = 2.004 min, >99.5%, OD-3 4.6*100 mm, 3 μm, carbon dioxide-methanol (0.2% NH 3 in MeOH)], B%: 40%, flow rate 3 mL / min. 1 H NMR (500MHz, CDCl3) δ9.46 (s, 1H), 9.16 (d, J = 7.1Hz, 1H), 8.36 (d, J = 8.3Hz, 1H), 7.87 (d, J = 8.4Hz, 1H), 7.61 (d, J = 6.2Hz, 1H) ,7.55–7.32(m,7H),7.28(d,J=7.3Hz,1H),6.86(d,J=7.9Hz,1H),6.49–6.36(m,2H),5.39(dt,J=8.5,4.4Hz,1H),4.37(dd,J =15.3,10.7Hz,3H),4.12–3.98(m,2H),3.84(dd,J=5.7,3.8Hz,2H),3.79(d,J=16.4Hz,1H),3.76–3.60(m,12H),3.58–3.41( m,4H),3.41–3.34(m,2H),2.91(d,J=4.5Hz,2H),2.84(dt,J=16.0,8.2Hz,1H),2.33(s,3H),2.30–2.19(m,1H),2.19–1.98(m, 3H).

[0691] Isomer2:80mg

[0692] MS m / z(ESI):812.2[M+H] + ;

[0693] Analytical chiral SFC: RT = 2.564 min, 99.1%, OD-3 4.6*100 mm, 3 μm, carbon dioxide-methanol (0.2% NH 3 in MeOH)], B%: 40%, flow rate 3 mL / min. 1 H NMR (500MHz, CDCl3) δ9.65(s,1H),8.93(d,J=7.4Hz,1H),8.35(d,J=7.8Hz,1H),7.87(d,J=8.4Hz,1H),7.64(d,J=6.1Hz,1H),7.54–7.33 (m,6H),7.28(d,J=3.3Hz,1H),6.86(d,J=8.0Hz,1H),6.50–6.35(m,2H),5.31(dd,J=12.4,5.4Hz,1H),4.41–4.27(m,2H),4.20(d,J=16.4 Hz,1H),4.09–3.98(m,2H),3.90(d,J=16.4Hz,1H),3.83(dd,J=5.7,3.8Hz,2H),3.75–3.63(m,12H),3.60(dd,J=16.6,6.9Hz,2H),3.51– 3.40(m,2H),3.40–3.32(m,2H),2.86(ddd,J=39.3,15.4,5.3Hz,2H),2.73(dt,J=16.3,8.1Hz,1H),2.44–2.20(m,4H),2.17–1.92(m,3H).

[0694] Synthesis of compound 6

[0695] Synthesis of intermediate 6-2

[0696] Compound 6-1 (5.00 g, 24.0 mmol) was dissolved in N,N-dimethylformamide (100 mL). Sodium hydride (1.20 g, 30.0 mmol, 60% purity) was added at 0°C and stirred at 0°C for half an hour. Methyl iodide (5.11 g, 36.0 mmol) was then added dropwise and stirred at 25°C for 2 hours. After the reaction was complete, water (200 mL) was added to quench the mixture and the mixture was extracted with ethyl acetate (100 mL x 2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and filtered to obtain compound 6-2 (5.00 g, 93.7% yield) as a white solid. 1H NMR (400MHz, CDCl3) δ7.51-7.38(m,1H),7.31(d,J=8.3Hz,1H),6.79(d,J=7.4Hz,1H),3.31(s,3H),2.42(s,3H),1.43(s,9H).

[0697] Synthesis of intermediate 6-3

[0698] Compound 6-3 (4.80 g, 21.6 mmol) was dissolved in tetrahydrofuran (50 mL), then the atmosphere was replaced with nitrogen three times. Lithium diisopropylamide (2.5 M, 21.6 mL) was added dropwise over 10 minutes at -78°C and stirred for 10 minutes. Finally, a solution of diethyl carbonate (3.06 g, 25.9 mmol) in tetrahydrofuran (50 mL) was added dropwise, and the reaction mixture was stirred at -78°C for 1 hour. After completion, the reaction was quenched by the addition of saturated ammonium chloride solution (100 mL), diluted with water (200 mL), and extracted with ethyl acetate (250 mL x 2). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and dried. The residue was purified by flash silica gel chromatography (eluent: 0-40% ethyl acetate / petroleum ether) to afford compound 6-4 (5.00 g, 78.7% yield) as a white solid. 1 H NMR (400MHz, CDCl3) δ7.68-7.51(m,2H),7.08-6.95(m,1H),4.21(q,J=7.1Hz,2H),3.83(s,2H),3.41(s,3H),1.54(s,9H),1.29(t,J=7.1Hz,3H).

[0699] Synthesis of intermediate 6-4

[0700] Compound 6-3 (2.00 g, 6.79 mmol) was dissolved in tetrahydrofuran (20 mL), and methanol (4 mL), water (4 mL) and lithium hydroxide monohydrate (285.1 mg, 6.79 mmol) were added sequentially. The reaction solution was stirred at 25 ° C for 12 hours. After the reaction was completed, the tetrahydrofuran and methanol were removed by concentration under reduced pressure. The aqueous phase was adjusted to pH = 5 with 12M hydrochloric acid and extracted with ethyl acetate (25 mL × 2). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and dried. The residue was purified by flash silica gel chromatography (eluent: 0-60% tetrahydrofuran / petroleum ether) to obtain white solid compound 6-4 (1.00 g, 55.4% yield). MS m / z (ESI): 267.0 [M+H] + ; 1H NMR (400MHz, CDCl3) δ14.36-13.68(m,1H),7.77-7.57(m,2H),7.01-6.85(m,1H),3.88(s,2H),3.43(s,3H),1.55(s,9H).

[0701] Synthesis of intermediate 6-5

[0702] 6-4 (100 mg, 0.38 mmol) was dissolved in DMF (3 mL), and glycine methyl ester (49 mg, 0.39 mmol), EDCI (88 mg, 0.46 mmol), HOBt (62 mg, 0.46 mmol) and DIPEA (294 mg, 2.28 mmol) were added in sequence. The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was directly purified by preparative chromatography (Xbridge C18, 19×250 mm, 10 μm, Mobile phase: A: water (containing 10 mmol / L NH4HCO3); B: ACN; gradient: 20% B to 80% B over 20 minutes) to afford 6-5 (85 mg, yield: 66%) as a white solid. LCMS: (ESI) m / z = 338.4 [M+H] + .

[0703] Synthesis of intermediate 6-6

[0704] 6-5 (85 mg, 0.252 mmol) was dissolved in THF (2 mL) and H2O (2 mL), and NaOH (50 mg, 1.26 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was acidified with 3N dilute hydrochloric acid. The reaction mixture was directly purified by preparative chromatography (Xbridge C18, 19×250 mm, 10 μm, Mobile phase: A: water (containing 10 mmol / L NH4HCO3); B: ACN; gradient: 20% B to 80% B over 20 minutes) to afford 6-6 (53 mg, yield: 65%) as a white solid. LCMS: (ESI) m / z = 324.2 [M+H] + .

[0705] Synthesis of intermediate 6-7

[0706] 6-6 (53 mg, 0.164 mmol) was dissolved in DMF (2 mL), and 5-17 (67 mg, 0.164 mmol), EDCI (37 mg, 0.197 mmol), HOBt (27 mg, 0.197 mmol) and DIPEA (126 mg, 0.984 mmol) were added in sequence. The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was directly purified by preparative chromatography (Xbridge C18, 19×250 mm, 10 μm, Mobile phase: A: water (containing 10 mmol / L NH4HCO3); B: ACN; gradient: 35% B to 95% B over 20 minutes) to afford 6-7 (60 mg, yield: 52%) as a white solid. LCMS: (ESI) m / z = 717.3 [M+H] + .

[0707] Synthesis of intermediate 6-8

[0708] Dissolve 6-7 (60 mg, 0.84 mmol) in MeOH (5 mL) and add Pd / C (10% on carbonate, 21 mg). Stir the reaction mixture at room temperature for 2 hours under a stream of hydrogen. The reaction mixture is filtered and concentrated to give the crude product of 6-8 as a white solid. LCMS: (ESI) m / z = 627.1 [M+H] + .

[0709] Synthesis of intermediate 6-9

[0710] 6-8 (54 mg, crude) was dissolved in DMF (5 mL) and N3-PEG5-Tos (75 mg, 0.179 mmol) was added. The reaction mixture was stirred at 75°C for 16 hours. The reaction mixture was directly purified by preparative chromatography (Xbridge C18, 19×250 mm, 10 μm, Mobile phase: A: water (containing 10 mmol / L NH4HCO3); B: ACN; gradient: 35% B to 95% B over 20 minutes) to afford 6-9 (36 mg, yield: 42%) as a white solid. LCMS: (ESI) m / z = 873.3 [M+H] + .

[0711] Synthesis of compound 6

[0712] 6-9 (36 mg, 0.045 mmol) was dissolved in THF (5 mL) and H2O (5 mL), and LiOH·H2O (7.5 mg, 0.18 mmol) was added. The reaction solution was stirred at room temperature for 13 hours. The reaction was complete after LCMS monitoring. The reaction mixture was acidified with 3N dilute hydrochloric acid. The reaction mixture was concentrated and dried, then dissolved in DCM (3 mL), and glacial TFA (3 mL) was added. The reaction solution was stirred at room temperature for 16 hours. The reaction was complete after LCMS monitoring. The crude product was then concentrated and dried in vacuo to obtain the crude product, which was purified by preparative chromatography (Xbridge C18, 19×250 mm, 10 μm, Mobile phase: A: water (containing 10 mmol / L NH4HCO3); B: ACN; gradient: 25% B to 95% B over 20 minutes) to afford 6 (15 mg, yield: 45%) as a white solid. LCMS: (ESI) m / z = 758.2 [M+H] + .

[0713] Synthesis of compound 7

[0714] Synthesis of intermediate 7-2

[0715] Compound 7-1 (9.00 g, 32.95 mmol) was dissolved in N,N-dimethylformamide (100 mL) at 0°C. The mixture was then purged with N2 three times, and sodium hydride (2.64 g, 65.90 mmol, 60% purity) was added. The mixture was stirred at 0°C for 1 hour. Iodomethane (14.03 g, 98.86 mmol) was then added dropwise at 0°C, and stirred at 0°C for 1 hour. After completion of the reaction, saturated ammonium chloride solution (10 mL) was added to quench the mixture, which was then diluted with water (200 mL) and extracted with ethyl acetate (150 mL x 2). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and spun down. The residue was purified by flash silica gel chromatography (eluent: 0-8% ethyl acetate / petroleum ether) to afford compound 7-2 (9.20 g, 97.2% yield) as a colorless oil. MS m / z(ESI):231.0 / 233.0[M-56+H] + ; 1 H NMR (400MHz, CDCl3) δ7.73 (d, J = 8.3 Hz, 1H), 7.46 (t, J = 7.9 Hz, 1H), 7.15 (d, J = 7.6 Hz, 1H), 3.39 (s, 3H), 1.52 (s, 9H).

[0716] Synthesis of intermediate 7-3

[0717] At 25°C, compound 7-2 (5.00 g, 17.41 mmol), ethyl 4-pentynoate (3.29 g, 26.12 mmol), triethylamine (5.29 g, 52.24 mmol), bis(triphenylphosphine)palladium(II) chloride (611.08 mg, 870.62 μmol), and cuprous iodide (165.81 mg, 870.62 μmol) were dissolved in acetonitrile (60 mL). The entire mixture was purged with nitrogen three times and stirred at 60°C for 12 hours. After completion of the reaction, the solvent was dried, and the residue was diluted with water (200 mL) and extracted with ethyl acetate (150 mL x 2). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and dried. The residue was purified by flash silica gel chromatography (eluent: 0-10% ethyl acetate / petroleum ether) to afford compound 7-3 (5.30 g, 91.6% yield) as a colorless oil. MS m / z(ESI):355.1[M+Na] + ; 1 H NMR (400MHz, CDCl3) δ7.7-7.5(m,2H),7.09(dd,J=1.0,7.1Hz,1H),4.17(q,J=7.1Hz,2 H), 3.38 (s, 3H), 2.8-2.7 (m, 2H), 2.7-2.6 (m, 2H), 1.49 (s, 9H), 1.27 (t, J = 7.1Hz, 3H).

[0718] Synthesis of intermediate 7-4

[0719] At 25°C, compound 7-3 (5.00 g, 17.41 mmol) was dissolved in ethyl acetate (60 mL), and wet palladium on carbon (1.00 g, 10% purity) was added under a nitrogen atmosphere. The mixture was replaced with hydrogen three times to a pressure of 15 psi and stirred at 25°C for 3 hours. After the reaction was complete, the mixture was directly filtered and dried to obtain compound 7-4 (4.00 g, 98.8% yield) as a colorless oil. MS m / z (ESI): 337.2 [M+H] + ; 1 H NMR (400MHz, CDCl3) δ7.6-7.5(m,1H),7.5-7.4(m,1H),6.83(d,J=7.3Hz,1H),4.11(q,J=7.1Hz,2H),3.37 (s,3H),2.73(t,J=7.3Hz,2H),2.33(t,J=7.3Hz,2H),1.8-1.6(m,4H),1.50(s,9H),1.24(t,J=7.1Hz,3H).

[0720] Synthesis of intermediate 7-5

[0721] Compound 7-4 (2.50 g, 7.43 mmol) was dissolved in a mixed solvent of water (3 mL), tetrahydrofuran (15 mL), and methanol (3 mL) at 25°C. Lithium hydroxide monohydrate (623.67 mg, 14.86 mmol) was then added and stirred at 25°C for 1 hour. After completion of the reaction, water (100 mL) and ethyl acetate (50 mL) were added. The aqueous phase was collected and washed with ethyl acetate (50 mL × 3). Citric acid monohydrate (4.68 g) was then added for acidification. After acidification, the mixture was extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with water (50 mL × 2), dried over anhydrous sodium sulfate, and filtered to obtain compound 7-5 (1 g, 48.0% yield) as a pink solid. MS m / z (ESI): 331.1 [M+Na] + ; 1 H NMR (400MHz, CDCl3) δ9.25 (s, 1H), 7.6-7.5 (m, 1H), 7.42 (d, J = 8.3Hz, 1H), 6.85 (d, J = 7.3Hz, 1H), 3.38 (s, 3H), 2.75 (t, J = 7.4Hz, 2H), 2.40 (t, J = 7.3Hz, 2H), 1.9-1.7 (m, 4H), 1.51 (s, 9H).

[0722] Synthesis of intermediate 7-6

[0723] To a 50 mL flask were added 7-5 (47 mg, 0.152 mmol, 1.0 equiv.), 5-17 (80 mg, 0.152 mmol), HOAt (31 mg, 0.228 mmol), EDCI (44 mg, 0.228 mmol), and DMF (2 mL), followed by DIPEA (78 μL). The mixture was stirred at room temperature for 16 hours. The reaction was quenched with 20 mL of water while stirring, resulting in the formation of a white solid. The supernatant was removed by centrifugation and dried in vacuo to afford 7-6 (100 mg, 94% yield) as a light yellow solid. LCMS: (ESI) m / z = 702.4 [M+H] + .

[0724] Synthesis of Intermediate 7-7

[0725] To a 50 mL flask were added 7-6 (100 mg, 0.142 mmol, 1.0 equiv.), Pd / C (30 mg, 0.142 mmol), and methanol (5 mL). The system was replaced with hydrogen twice and stirred under hydrogen for 2 hours. The reaction mixture was filtered, the Pd / C was washed with methanol (1 mL x 2), and concentrated to afford 7-7 (90 mg) as a light yellow viscous liquid. LCMS: (ESI) m / z = 612.4 [M+H]+ .

[0726] Synthesis of intermediate 7-8

[0727] To a 100 mL flask, 7-7 (90 mg, 0.147 mmol, 1.0 equiv.), N3-PEG5-Tos (123 mg, 0.294 mmol), potassium carbonate (42 mg, 0.305 mmol), and DMF (2 mL) were added sequentially. The mixture was stirred at 80°C for 16 hours. The reaction mixture was filtered, and the filtrate was directly purified by reverse-phase chromatography to afford 7-8 (80 mg, yield: 63%) as a colorless, viscous liquid. LCMS: (ESI) m / z = 857.5 [M+H] + ,879.5[M+Na] + .

[0728] Synthesis of compound 7

[0729] 7-8 (80 mg, 0.0933 mmol, 1.0 equiv.) was dissolved in THF (1 mL), cooled to 0°C, and sodium hydroxide solution (0.933 mmol / L, 1 mL, 0.933 mmol) was added. The mixture was stirred at 0°C for 3 hours. The reaction solution was concentrated and dried. The residue was dissolved in dichloromethane (1 mL), and trifluoroacetic acid (3 mL) was carefully added. The mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated to obtain a crude product (140 mg) which was directly used for the next reaction. 100 mg of the crude product was purified by reverse phase preparative chromatography (Xbridge C18 21.2 mm × 250 mm, 10 μm, Mobile phase: A: water (containing 0.05% TFA), B: acetonitrile (containing 0.05% TFA); gradient: 20% B to 80% B over 20 minutes) to afford compound 7 (40 mg, yield: 70%) as a white solid. LCMS: (ESI) m / z = 743.4 [M+H] + . 1H NMR (DMSO-d6+D2O, 400MHz) δ8.29(d,J=8.4Hz,1H),7.80-7.72(m,2H),7.59-7.48(m,2H),7.46(d,J=8.4Hz,2H),7. 39(d,J=8.4Hz,2H),7.32(d,J=7.6Hz,1H),7.07(d,J=8.4Hz,1H),6.78(d,J=9.2Hz,1H),8.67(d,J=7.2Hz,1H),5.3 0(dd,J=7.2,7.6Hz,1H),4.37-4.30(m,2H),3.97-3.91(m,2H),3.73-3.67(m,2H),3.62-3.57(m,2H),3.57-3.48(m ,10H),3.36-3.30(m,2H),2.90(s,3H),2.82-2.77(m,2H),2.74-2.67(m,2H),2.25-2.16(m,2H),1.65-1.52(m,4H).

[0730] Synthesis of compound 8

[0731] Synthesis of intermediate 8-2

[0732] Compound 8-1 (50.0 g, 347 mmol) was dissolved in dichloroethane (100 mL) and methanol (250 mL) at room temperature, and concentrated sulfuric acid (1.70 g, 17.3 mmol, 924 μL) was added, followed by stirring at 90° C. for 12 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by flash silica gel chromatography (eluent: 0-20% ethyl acetate / petroleum ether) to give compound 8-2 (50.0 g, 91.1% yield) as a yellow oil. 1 H NMR (400MHz, CDCl3) δ3.65 (s, 3H), 2.44 (t, J = 6.57Hz, 2H), 2.31 (t, J = 6.75Hz, 2H), 2.13 (s, 3H), 1.65-1.55 (m, 4H).

[0733] Synthesis of intermediate 8-3

[0734] Compound 8-2 (5.00 g, 31.6 mmol) was dissolved in methanol (50 mL) at room temperature, and 2-amino-3-pyridinecarboxaldehyde (3.86 g, 31.6 mmol) and L-proline (1.82 g, 15.8 mmol) were added. The mixture was stirred at 80°C for 12 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by flash silica gel chromatography (eluent: 0-50% ethyl acetate / petroleum ether) to obtain compound 8-3 (2.70 g, 35.0% yield) as a yellow solid. MS m / z (ESI): 245.1 [M+H] + ; 1 H NMR (400MHz, CDCl3) δ9.09 (dd, J=3.94, 1.69Hz, 1H), 8.16 (dd, J=8.00, 1.63Hz, 1H), 8.11 (d, J=8.38Hz, 1H), 7.45 (dd, J=8.00, 4.25 Hz,1H),7.40(d,J=8.25Hz,1H),3.66(s,3H),3.08(t,J=7.69Hz,2H),2.39(t,J=7.50Hz,2H),2.02-1.92(m,2H),1.83-1.73(m,2H).

[0735] Synthesis of intermediate 8-4

[0736] At room temperature, compound 8-3 (2.70 g, 11.1 mmol) was dissolved in methanol (30 mL) and the atmosphere was replaced with nitrogen three times. Wet palladium on carbon (1.18 g, 1.11 mmol, 10% purity) was added. The mixture was evacuated, replaced with nitrogen three times and then with hydrogen three times, and stirred at 25°C under a hydrogen atmosphere (15 psi) for 12 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by flash silica gel chromatography (eluent: 0-30% ethyl acetate / petroleum ether) to afford compound 8-4 (2.50 g, 91.1% yield) as a pale yellow solid. MS m / z (ESI): 249.1 [M+H] + ; 1 H NMR (400MHz, CDCl3) δ7.05 (d, J = 7.25Hz, 1H), 6.37-6.31 (m, 1H), 4.74 (s, 1H), 3.66 (d, J = 2.13Hz, 3H), 3. 44-3.35(m,2H),2.69(t,J=6.13Hz,2H),2.55(s,2H),2.37-2.30(m,2H),1.94-1.87(m,2H),1.69(s,4H).

[0737] Synthesis of intermediate 8-5

[0738] Compound 8-4 (2.00 g, 8.05 mmol) was dissolved in 1,4-dioxane (20 mL) at room temperature, and di-tert-butyl dicarbonate (8.79 g, 40.3 mmol, 9.25 mL) was added. The mixture was stirred at 80°C for 5 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by flash silica gel chromatography (eluent: 0-15% ethyl acetate / petroleum ether) to give compound 8-5 (1.80 g, 64.1% yield) as a colorless oil. MS m / z (ESI): 349.0 [M+H] + ; 1 H NMR (400MHz, CDCl3) δ7.29(d,J=7.63Hz,1H),6.81(d,J=7.63Hz,1H),3.80-3.72(m,2H),3.66(s,3 H), 2.76-2.69 (m, 4H), 2.35 (t, J = 7.32Hz, 2H), 1.96-1.88 (m, 2H), 1.78-1.68 (m, 4H), 1.52 (s, 9H).

[0739] Synthesis of intermediate 8-6

[0740] At room temperature, compound 8-5 (1.80 g, 5.17 mmol) was dissolved in tetrahydrofuran (4 mL) and water (1 mL), lithium hydroxide monohydrate (867 mg, 20.7 mmol) was added, and stirred at 25 ° C for 15 hours. The reaction solution was diluted with ethyl acetate (10 mL) and extracted with water (5 mL × 3). The aqueous phases were combined, adjusted to pH 6 with citric acid, extracted with ethyl acetate (10 mL × 3), and the combined organic phases were dried over anhydrous sodium sulfate, filtered and dried. The crude product was purified by beating with methyl tert-ether to obtain white solid compound 8-6 (1.30 g, 75.3% yield). MS m / z (ESI): 335.0 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ11.98(s,1H),7.40(d,J=7.63Hz,1H),6.88(d,J=7.63Hz,1H),3.65-3.58(m,2H),2.68(t,J=6.63Hz,2 H), 2.61 (t, J = 7.57Hz, 2H), 2.22 (t, J = 7.32Hz, 2H), 1.85-1.77 (m, 2H), 1.67 (t, J = 7.57Hz, 2H), 1.59-1.50 (m, 2H), 1.43 (s, 9H).

[0741] Synthesis of intermediate 8-7

[0742] A 50 mL flask was charged with 8-6 (50 mg, 0.152 mmol, 1.0 equiv.), 5-17 (80 mg, 0.152 mmol), HOAt (31 mg, 0.228 mmol), EDCI (44 mg, 0.228 mmol), and DMF (2 mL). DIPEA (78 μL) was then added, and the mixture was stirred at room temperature for 16 hours. Water (20 mL) was added to the stirred reaction solution, resulting in a solid precipitate. The mixture was centrifuged, the supernatant was discarded, and the residue was dried under vacuum to afford the crude product 8-7 (110 mg, 100% yield) as a light yellow solid. LCMS: (ESI) m / z = 728.4 [M+H] + .

[0743] Synthesis of Intermediate 8-8

[0744] A 100 mL flask was charged with 8-7 (110 mg, 0.151 mmol, 1.0 equiv.), Pd / C (10%, 25 mg), and methanol (5 mL). The system was replaced with hydrogen twice and stirred under a hydrogen atmosphere for 2 hours. The reaction solution was filtered, concentrated, and dried under vacuum to afford 8-8 (100 mg, yield: 100%) as a light yellow viscous liquid. LCMS: (ESI) m / z = 638.4 [M+H] + .

[0745] Synthesis of intermediate 8-9

[0746] A 50 mL flask was charged with 8-8 (100 mg g, 0.15 mmol, 1.0 equiv.), N3-PEG5-Tos (131 mg, 0.30 mmol), potassium carbonate (42 mg, 0.30 mmol), and DMF (2 mL). The mixture was stirred at 80°C for 16 hours. The reaction solution was cooled to room temperature and directly purified using a reverse-phase column (mobile phase: A: water (containing 0.05% trifluoroacetic acid), B: acetonitrile; gradient: 25% B to 70% B over 20 minutes) to afford 8-9 (110 mg, yield: 83%) as a colorless, viscous liquid. LCMS: (ESI) m / z = 883.5 [M+H] + (50.59%),783.5[M+H] + (de-Boc, 40.41%).

[0747] Synthesis of compound 8

[0748] 8-9 (110 mg, 0.124 mmol, 1.0 equiv.) was dissolved in THF (1 mL) and cooled to 0°C. 1.24 mmol / L NaOH solution (1 mL) was then added and the mixture was stirred at 0°C for 3 hours. The reaction solution was concentrated and dried. The residue was dissolved in dichloromethane (1 mL) and trifluoroacetic acid (3 mL) was carefully added. The mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated and the residue was purified by preparative chromatography (Xbridge C18 21.2 mm × 250 mm, 10 μm, Mobile phase: A: water (containing 0.05% TFA), B: acetonitrile (containing 0.05% TFA); gradient: 25% B to 80% B over 20 minutes) to afford 8 (46 mg, yield: 67%) as a white solid. LCMS: (ESI) m / z = 769.5 [M+H] + . 1 H NMR (DMSO-d6+D2O, 400MHz) δ8.31(d,J=8.0Hz,1H),7.73(d,J=8.0Hz,1H),7.57(dd,J=7.2,7.6Hz,1H),7.51(dd,J=7.6,8 .4Hz,1H),7.46(d,J=7.6Hz,2H),7.38(d,J=8.0Hz,2H),7.33(d,J=8.0Hz,1H),7.08(d,J=8.0Hz,1H),6.53(d,J=7.2Hz,1H ),5.30(dd,J=7.2,7.6Hz,1H),4.36-4.31(m,2H),3.97-3.92(m,2H),3.74-3.69(m,2H),3.65-3.59(m,2H),3.58-3.48(m ,10H),3.35-3.28(m,4H),2.85-2.78(m,2H),2.65-2.57(m,4H),2.45-2.18(m,2H),1.76-1.68(m,2H),1.62-1.47(m,4H).

[0749] Synthesis of compound 9

[0750] Synthesis of Intermediate 9-2

[0751] At 25°C, liquid bromine (5.50 g, 34.4 mmol, 1.77 mL) was added to a solution of compound 8-5 (12.0 g, 34.4 mmol) in dichloromethane (100 mL), and the mixture was stirred at 25°C for 3 hours. After the reaction was completed, saturated sodium bicarbonate solution (50 mL) was added to quench the reaction and extracted with ethyl acetate (100 mL × 2). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and dried. The residue was purified by flash silica gel chromatography (eluent: 0-10% ethyl acetate / petroleum ether) to give compound 9-2 (8.20 g, 55.7% yield) as a colorless oil. MS m / z (ESI): 427.1 [M+H] + ; 1 HNMR (400MHz, CDCl3) δ7.49 (s, 1H), 3.77-3.71 (m, 2H), 3.67 (s, 3H), 2.87 (t, J = 7.32Hz, 2H), 2.72 (t ,J=6.63Hz,2H),2.38(t,J=7.07Hz,2H),1.91(quin,J=6.28Hz,2H),1.79-1.72(m,4H),1.51(s,9H).

[0752] Synthesis of intermediate 9-3

[0753] At 25°C, tetrakistriphenylphosphine palladium (2.43 g, 2.11 mmol) and zinc cyanide (4.95 g, 42.1 mmol) were added to N,N-dimethylformamide (110 mL) in which compound 9-2 (9.00 g, 21.1 mmol) was dissolved. After the addition was complete, the entire mixture was purged with nitrogen three times and stirred at 120°C for 3 hours. After the reaction was completed, saturated sodium bicarbonate solution (50 mL) was added to quench the reaction and the mixture was extracted with ethyl acetate (100 mL × 2). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and dried. The residue was purified by flash silica gel chromatography (eluent: 0-15% ethyl acetate / petroleum ether) to obtain compound 9-3 (5.80 g, 73.7% yield) as a colorless oil. MS m / z (ESI): 374.2 [M+H] + ; 1 H NMR (400MHz, CDCl3) δ7.52 (s, 1H), 3.81-3.72 (m, 2H), 3.65 (s, 3H), 2.91 (t, J = 7.57Hz, 2H), 2.73 (t, J=6.50Hz, 2H), 2.36 (t, J=7.32Hz, 2H), 1.93 (quin, J=6.25Hz, 2H), 1.84-1.69 (m, 4H), 1.52 (s, 9H).

[0754] Synthesis of intermediate 9-4

[0755] At 25°C, under nitrogen protection, wet palladium on carbon (1.65 g, 10% purity) was added to a solution of compound 9-3 (5.80 g, 15.5 mmol) in ethyl acetate (50 mL) and triethylamine (12.5 mL). After the addition was complete, the entire mixture was purged with nitrogen three times, then replaced with hydrogen three times, and stirred at 25°C under a hydrogen atmosphere (50 psi) for 96 hours. After completion of the reaction, the mixture was filtered and the filtrate was concentrated to give compound 9-4 (5.00 g, crude product). MS m / z (ESI): 378.2 [M+H] + ; 1 H NMR (400MHz, CDCl3) δ7.35 (s, 1H), 3.84 (s, 2H), 3.80-3.71 (m, 2H), 3.67 (s, 3H), 2.74 (q, J = 6. 25Hz, 4H), 2.37 (t, J = 6.94Hz, 2H), 1.92 (quin, J = 6.28Hz, 2H), 1.84-1.70 (m, 4H), 1.52 (s, 9H).

[0756] Synthesis of intermediate 9-5

[0757] At 25 ° C, triethylamine (4.64 g, 45.9 mmol, 6.39 mL) and benzyloxycarbonyl succinimide (3.59 g, 14.4 mmol) were added to dichloromethane (50 mL) in which compound 9-4 (4.95 g, 13.1 mmol) was dissolved. After the addition, the mixture was stirred at 25 ° C for 30 minutes. After the reaction was completed, it was diluted with water (50 mL) and extracted with dichloromethane (50 mL × 2). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and dried. The residue was purified by flash silica gel chromatography (eluent: 0-26% ethyl acetate / petroleum ether) to give compound 9-5 (4.40 g, 65.6% yield) as a white solid. MS m / z (ESI): 512.3 [M+H] + ; 1 H NMR (400MHz, CDCl3) δ7.42-7.29(m,5H),7.27(d,J=3.38Hz,1H),5.14(s,2H),4.34(d,J=5.50Hz,2H),3.78-3.69(m ,2H),3.65(s,3H),2.78-2.64(m,4H),2.35(t,J=6.75Hz,2H),1.90(quin,J=6.22Hz,2H),1.74(s,4H),1.51(s,9H).

[0758] Synthesis of intermediate 9-6

[0759] At 25 ° C, lithium hydroxide monohydrate (1.03 g, 24.6 mmol) was added to tetrahydrofuran (40 mL) and water (20 mL) in which compound 9-5 (4.20 g, 8.21 mmol) was dissolved. After the addition, the mixture was stirred at 25 ° C for 12 hours. After the reaction was completed, the tetrahydrofuran was concentrated to remove the tetrahydrofuran, the pH was adjusted to 6 with saturated citric acid, and extracted with ethyl acetate (25 mL × 2). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and dried. The crude product was slurried with methyl tert-ether to obtain compound 9-6 (1.00 g, 24.5% yield) as a white solid. MS m / z (ESI): 498.3 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ11.98(s,1H),7.76(t,J=5.75Hz,1H),7.43-7.20(m,6H),5.04(s,2H),4.16(d,J=5.88Hz,2H),3 .63-3.58(m,2H),2.69-2.60(m,4H),2.23(t,J=7.13Hz,2H),1.80(quin,J=6.19Hz,2H),1.70-1.51(m,4H),1.42(s,9H).

[0760] Synthesis of intermediate 9-8

[0761] Methanol (50 mL) was added to a 250 mL flask and cooled to 0°C in an ice bath. SOCl2 (0.5 mL, 6.9 mmol) was slowly added dropwise with stirring, followed by acetone (20 mL) and Boc-(S)-3-amino-3-(4-bromophenyl)-propionic acid (1.0 g, 2.9 mmol). The mixture was stirred at room temperature for 16 hours. The reaction solution was concentrated and drained, and the residue was dissolved in dichloromethane (20 mL). Triethylamine (1.2 mL, 8.7 mmol) and (Boc)2O (759 mg, 3.48 mmol) were added sequentially. The mixture was stirred at room temperature for another 2 hours. The reaction solution was concentrated, and the residue was purified on a silica gel column to give 9-8 (0.9 g, yield: 86.6%) as a light yellow solid. LCMS: (ESI) m / z = 380.1 [M+Na] + .

[0762] Synthesis of intermediate 9-9

[0763] A 100 mL flask was charged with 4-(1-naphthyl)phenylboronic acid (258 mg, 1.5 mmol, 1.5 equiv.), 9-8 (358 mg, 1.0 mmol), XPhos Pd G2 (157 mg, 0.2 mmol), K3PO4 (424 mg, 2.0 mol), and THF (10 mL). The system was purged with nitrogen twice and the reaction was stirred at room temperature under nitrogen for 16 hours. The reaction mixture was filtered and concentrated, and the crude product was purified on a silica gel column to afford 9-9 (425 mg, yield: 69.9%) as a light yellow solid. LCMS: (ESI) m / z = 428.3 [M+Na] + ,833.4[2M+Na] + .

[0764] Synthesis of intermediate 9-10

[0765] Methanol (10 mL) was added to a 100 mL flask. Trifluoroacetic acid (2 mL) was carefully added with stirring. The mixture was stirred at room temperature for 10 minutes. 9-9 (0.425 g) was then added. The mixture was stirred at room temperature for 2 hours and concentrated. The residue was dissolved in acetonitrile (5 mL), water (50 mL) was added, and lyophilized to give the crude product 9-10 (370 mg, yield: 100%) as a light yellow solid. LCMS: (ESI) m / z = 306.3 [M+H] + .

[0766] Synthesis of intermediates 9-11

[0767] A 100 mL flask was charged with 9-10 (100 mg, 0.2 mmol, 1.0 equiv.), 9-6 (69 mg, 0.2 mmol), HOAT (41 mg, 0.3 mmol), EDCI (58 mg, 0.3 mmol), and DMF (2 mL). DIPEA (102 μL) was then added, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was directly purified by reverse phase chromatography to afford 9-11 (130 mg, yield: 82.8%) as a light yellow solid. LCMS: (ESI) m / z = 785.5 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ8.43(d,J=8.4Hz,1H),8.00(d,J=8.0Hz,1H),7.95(d,J=8 .4Hz,1H),7.81-7.73(m,2H),7.60-7.51(m,2H),7.50-7.39(m,6H),7.37-7.17(m ,6H),5.37-5.29(m,1H),5.03(s,2H),5.17(d,J=5.6Hz,2H),3.62-3.52(m,2H),3 .57(s,3H),2.88-2.81(m,2H),1.82-1.72(m,2H),1.68-1.52(m,4H),1.41(s,9H).

[0768] Synthesis of intermediates 9-12

[0769] A 100 mL flask was charged with 9-11 (130 mg, 0.166 mmol, 1.0 equiv.), 10% Pd / C (60 mg), and methanol (10 mL). The system was purged with hydrogen twice, and the mixture was stirred at room temperature under hydrogen for 70 minutes. The reaction mixture was filtered and concentrated to afford 9-12 (102 mg, 94% yield) as a light yellow viscous liquid. LCMS: (ESI) m / z = 651.5 [M+H] + .

[0770] Synthesis of intermediates 9-14

[0771] To a 100 mL flask were added 9-12 (102 mg, 0.166 mmol, 1.0 equiv.), BocNH-PEG5-COOH (61 mg, 0.166 mmol), HOAT (34 mg, 0.249 mmol), EDCI (48 mg, 0.249 mmol), and DMF (2 mL) in sequence, followed by DIPEA (83 μL). The mixture was stirred at room temperature for 16 hours. The reaction mixture was directly purified by reverse phase chromatography to afford 9-14 (130 mg, 83% yield) as a light yellow solid. LCMS: (ESI) m / z = 998.3 [M+H] + .

[0772] Synthesis of compounds 9-15

[0773] In a 100 mL flask, 9-14 (130 mg, 0.13 mmol, 1.0 equiv.) and THF (5 mL) were added, followed by the addition of 2 mL of NaOH solution (0.975 mol / L, 1.95 mmol), and the mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated to dryness, the residue was dissolved in dichloromethane (1 mL), and trifluoroacetic acid (3 mL) was carefully added. The mixture was stirred at room temperature for 4 hours. The reaction solution was concentrated and dried to obtain 180 mg of crude product, which was used directly in the next reaction. 90 mg of the crude product was purified by preparative reverse phase chromatography (Xbridge C18 21.2 mm × 250 mm, 10 μm, Mobile phase: A: water (containing 0.05% TFA), B: acetonitrile (containing 0.05% TFA); gradient: 20% B to 80% B over 20 minutes) to afford 9 (42 mg, yield: 63%) as a white solid. LCMS: (ESI) m / z = 784.5 [M+H] + . 1 H NMR (400MHz, DMSO-d6+D2O) δ8.45(t,J=5.6Hz,1H,NH),8.02(d,J=8.0Hz,1H),7.97(d,J=7.6Hz,1H),7. 78(d,J=8.4Hz,1H),7.63-7.54(m,2H),7.52-7.39(m,7H),5.31(t,J=7.6Hz,1H),4.11(s,2H),3.63-3.5 7(m,4H),3.57-3.51(m,4H),3.50(s,4H),3.47(s,4H),3.36-3.29(m,2H),3.00-2.94(m,2H),2.82-2.76 (m,2H),2.72-2.62(m,4H),2.39-2.32(m,2H),2.24-2.15(m,2H),1.80-1.71(m,2H),1.64-1.48(m,4H).

[0774] Synthesis of compounds 9-17

[0775] To a 100 mL flask were added 9-12 (200 mg, 0.307 mmol, 1.0 equiv.), N3-PEG5-COOH (89 mg, 0.307 mmol), HOAT (63 mg, 0.46 mmol), EDCI (88 mg, 0.46 mmol), and DMF (5 mL) in sequence, followed by DIPEA (83 μL). The mixture was stirred at room temperature for 16 hours. The reaction mixture was directly purified by reverse phase chromatography to afford 9-17 (120 mg, 42% yield) as a light yellow solid. LCMS: (ESI) m / z = 924.5 [M+H] + .

[0776] Synthesis of compound 9

[0777] A 100 mL flask was charged with 9-17 (120 mg, 0.13 mmol, 1.0 equiv.) and THF (5 mL), followed by a 2 mL aqueous solution of NaOH (78 mg, 1.95 mmol). The mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated to dryness, and the residue was dissolved in dichloromethane (1 mL). Trifluoroacetic acid (3 mL) was carefully added, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated and dried. The crude product was purified by preparative reverse-phase chromatography (eluting phase: A: water (containing 10 mmol / L NH₄HCO₃), B: acetonitrile; gradient: 5% B to 50% B over 20 minutes) to afford 9 (65 mg, yield: 62%) as a white solid. LCMS: (ESI) m / z = 810.3 [M+H] + .

[0778] Synthesis of compound 13

[0779] Synthesis of Intermediate 13-2

[0780] 3-Bromophenylhydrazine hydrochloride (11.12 g, 50 mmol, 1.0 equiv.) was dissolved in ethanol (40 mL), and 2,4-pentanedione (5.5 g, 55 mmol) and potassium acetate (5.9 g, 60 mmol) were added sequentially. The mixture was stirred and refluxed for 3 hours. The reaction solution was concentrated to remove most of the ethanol, and the residue was dissolved in ethyl acetate (200 mL), washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography to give 13-2 (7.5 g, yield: 60%) as a light yellow oily liquid. LCMS: (ESI) m / z = 252.0 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ7.72 (dd, J=1.6, 2.0Hz, 1H), 7.59-7.55 (m, 1H), 7.55-7 .51(m,1H),7.45(dd,J=8.0,8.0Hz,1H),6.09(s,1H),2.32(s,3H),2.18(s,3H).

[0781] Synthesis of Intermediate 13-3

[0782] A solution of 13-2 (2.51 g, 10.0 mmol, 1.0 equiv.) in THF (30 mL) was cooled to -78°C in a dry ice bath. n-Butyllithium solution (4.8 mL, 12.0 mmol) was added dropwise. After the addition was complete, the reaction was stirred at this temperature for 10 minutes. Triisopropyl borate (2.44 g, 13 mmol) was carefully added dropwise over 20 minutes. After the addition was complete, the temperature was slowly warmed to room temperature and the reaction was stirred at room temperature for 2 hours. The reaction solution was quenched with 2N hydrochloric acid and the pH was adjusted to 5-6. The solution was extracted with ethyl acetate (100 mL), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was dissolved in ethyl acetate (5 mL) and petroleum ether (50 mL) was slowly added with stirring. A white precipitate was formed, which was filtered and dried in vacuo to afford 13-3 (1.0 g, yield: 46%) as a white solid. LCMS: (ESI) m / z = 217.0 [M+H] + .

[0783] Synthesis of Intermediate 13-5

[0784] Methyl 4-bromo-2-butenoate (5.0 g, 27.9 mmol) was dissolved in acetonitrile (40 mL), and sodium acetate (3.4 g, 41.9 mmol) was added. The mixture was stirred at 50°C for 3 days. LCMS analysis indicated that the starting material was largely converted. The reaction mixture was filtered and concentrated, and the residue was purified by reverse-phase chromatography to afford compound 13-5 (1.9 g, 43% yield) as a dry oil. LCMS: (ESI) m / z = 181.1 [M+Na] + .

[0785] Synthesis of Intermediate 13-7

[0786] Triphenylphosphine (17.3 g, 66 mmol) and imidazole (3.97 g, 66 mmol) were placed in a 500 mL three-necked flask equipped with a stirrer and vacuum-evacuated for 20 minutes. The atmosphere was then replaced with nitrogen. 200 mL of anhydrous dichloromethane was then added via syringe and the mixture was cooled to 0°C. Iodine (16.8 g, 66.0 mmol) was quickly added under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 10 minutes until all the iodine dissolved. The mixture was then recooled to 0°C. (R)-N-tert-Butyloxycarbonyl-3-hydroxymethyl-tetrahydropyrrole (10.05 g, 50 mmol) dissolved in 20 mL of anhydrous dichloromethane was added dropwise to the reaction mixture. After the addition was complete, the mixture was stirred at 0°C for 16 hours. The reaction mixture was filtered to remove the solid precipitate and concentrated. The residue was purified by silica gel chromatography to afford 13-7 (7.5 g, 48% yield) as a light yellow oily liquid. LCMS: (ESI) m / z = 255.9 [M+H-56] + ; 1 H NMR(400MHz,DMSO-d6)δ3.47-3.35(m,2H),3.32(s,1H),3.30(s,1H),3.26-3.15(m,1H), 2.93-2.84(m,1H),2.47-2.35(m,1H),2.03-1.92(m,1H),1.63-1.47(m,1H),1.39(s,9H).

[0787] Synthesis of Intermediate 13-8

[0788] 2-Methyl-[1,8]-naphthyridine (1.94 g, 13.5 mmol) and 13-7 (4.2 g, 13.5 mmol) were dissolved in tetrahydrofuran (20 mL) and cooled to 0°C. LiHMDS (14.85 mL, 14.85 mmol) was added dropwise. After the addition was complete, the reaction was stirred at 0°C for 16 hours. The reaction was quenched with water (50 mL) and extracted with ethyl acetate (100 mL × 2). The mixture was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by reverse phase chromatography to afford 13-8 (2.2 g, yield: 50%) as a brown solid. LCMS: (ESI) m / z = 328.1 [M+H] + ; 1H NMR (400MHz, DMSO-d6) δ9.04(d,J=4.0Hz,1H),8.43(d,J=8.4Hz,1H),8.38(d,J=8.4 Hz,1H),7.59(d,J=8.8Hz,1H),7.58(dd,J=4.0,4.0Hz,1H),3.52-3.40(m,1H),3.36 -3.30(m,1H),3.20-3.08(m,1H),3.05-2.92(m,2H),2.90-2.78(m,1H),2.22-2.05( m,1H),2.04-1.93(m,1H),1.93-1.82(m,2H),1.60-1.44(m,1H),1.39-1.38(m,9H).

[0789] Synthesis of Intermediate 13-9

[0790] Intermediate 13-8 (3.9 g, 11.9 mmol) was dissolved in ethanol (50 mL), and Ru / C (500 mg) was added. The reaction system was replaced with hydrogen twice and stirred at room temperature under hydrogen for 6 hours. The mixture was filtered, washed with ethanol (2 mL x 2), and concentrated. The residue was purified by reverse phase chromatography to afford 13-9 (3.3 g, yield: 84%) as a light yellow liquid. LCMS: (ESI) m / z = 784.5 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ7.01(d,J=7.2Hz,1H),6.27(s,1H),6.26(d,J=7.2Hz,1H ),3.45-3.35(m,1H),3.33-3.26(m,1H),3.26-3.19(m,2H),3.18-3.05(m,1H),2. 76(dd,J=8.4,10.0Hz,1H),2.59(t,J=6.4Hz,2H),2.48-2.37(m,2H),2.12-1.98( m,1H),1.98-1.87(m,1H),1.78-1.70(m,2H),1.62(q,J=7.6Hz,2H),1.38(s,9H).

[0791] Synthesis of Intermediate 13-10

[0792] Intermediate 13-9 (662 mg, 2.0 mmol, 1.0 equiv.) was dissolved in acetonitrile (10 mL) and NIS (675 mg, 3.0 mmol) was added. The mixture was stirred at room temperature for 16 hours. The reaction solution was added to 100 mL of ethyl acetate, washed with saturated NaSO solution (30 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified on a silica gel column to afford 13-10 (670 mg, yield: 90.7%) as a light yellow oil. LCMS: (ESI) m / z = 458.0 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ7.42(s,1H),6.59(s,1H),3.45-3.39(m,1H),3.34-3.26(m,1H),3.25-3.18(m,2H),3.17-3.11(m,1H),2.83-2.75( m,1H),2.66-2.55(m,4H),2.16-2.05(m,1H),2.05-1.90(m,1H),1.75-1.64(m,2H),1.60(q,J=7.6Hz,2H),1.56-1.38(m,1H),1.39(s,9H).

[0793] Synthesis of intermediate 13-12

[0794] 13-10 (660 mg, 1.31 mmol) was dissolved in DMF (20 mL), and Zn(CN)2 (308 mg, 2.62 mmol), Pd2(dba)3 (119 mg, 0.13 mmol), Pd(dppf)2Cl2 (105 mg, 0.13 mmol), zinc powder (426 mg), and water (0.2 mL) were added sequentially. The mixture was stirred at 115°C for 16 hours. The reaction solution was cooled and purified by preparative chromatography to afford 13-12 (310 mg, yield: 66%) as a brown solid. LCMS: (ESI) m / z = 356.7 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ7.54(s,1H),7.39(s,1H),3.45-3.39(m,1H),3.34-3.26(m,3H),3.21-3.10(m,1H),2.81-2.75(m,1H),2. 66-2.57(m,4H),2.16-2.02(m,1H),2.02-1.90(m,1H),1.75-1.66(m,2H),1.68(q,J=7.2Hz,2H),1.54-1.37(m,1H),1.38(s,9H).

[0795] Synthesis of Intermediate 13-13

[0796] 13-12 (0.3 g, 0.84 mmol) was dissolved in DCM (5 mL), cooled to 0°C, and trifluoroacetic acid (2 mL) was added. The mixture was stirred at 0°C for 4 hours. LCMS monitored the reaction completion, and the mixture was concentrated to dryness to give the crude product 13-13 (410 mg) as a light yellow solid. LCMS: (ESI) m / z = 257.0 [M+H] + .

[0797] Synthesis of intermediate 13-14

[0798] 13-5 (133 mg, 0.84 mmol) and Pd(dppf)2Cl2 (34 mg) were dissolved in anhydrous dichloromethane (10 mL) and stirred under nitrogen for 10 minutes. A dichloromethane solution (10 mL) of 13-13 (407 mg, 0.84 mmol) and DIPEA (0.86 mL, 5.04 mmol) were then added, and the mixture was stirred at 0°C for 4 hours. The reaction was monitored for completion by LCMS. The reaction solution was filtered and concentrated, and the residue was purified by preparative chromatography to afford 13-14 (100 mg, total yield for the two-step reaction: 33.5%) as a light yellow oil. LCMS: (ESI) m / z = 354.9 [M+H] + .

[0799] Synthesis of Intermediates 13-15

[0800] To a 50 mL round-bottom flask were added 13-14 (100 mg, 0.282 mmol), 13-3 (183 mg, 0.846 mmol), potassium hydroxide (32 mg, 0.564 mmol), water (148 μL), (1,5-cyclooctadiene)chlororhodium(I) dimer (23 mg, 0.045 mmol), R-(+)-1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (35 mg, 0.028 mmol), and 1,4-dioxane (3 mL). The mixture was stirred at 90°C for 6 hours. After monitoring the reaction completion, the reaction solution was filtered and concentrated. The crude product was purified by reverse phase chromatography to afford 13-15 (96 mg, yield: 64.9%) as a light yellow oil. LCMS: (ESI) m / z = 527.1 [M+H] + .

[0801] Synthesis of intermediates 13-16

[0802] To a 50 mL round-bottom flask were added 13-16 (48 mg, 0.091 mmol), Ra-Ni (50 mg), ammonia methanol solution (7N, 0.5 mL, 3.5 mmol), and methanol (5 mL). The reaction system was purged with hydrogen twice and stirred at room temperature under hydrogen overnight. LCMS monitoring indicated approximately 50% conversion of the starting material. The reaction solution was filtered and concentrated to yield the crude product 13-16 (50 mg) as a light yellow oil. LCMS: (ESI) m / z = 531.2 [M+H] + .

[0803] Synthesis of intermediates 13-17

[0804] The crude product 13-16 (~0.091 mmol) obtained in the previous step was dissolved in DMF (2 mL). N3-PEG5-Tos (16 mg), PyBOP (33 mg, 0.0637 mmol), and DIPEA (31 μL) were added sequentially. The mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction solution was directly purified by preparative chromatography to obtain 13-17 (16 mg, total yield for the two-step reaction: 21.9%) as a light yellow oil. LCMS: (ESI) m / z = 804.6 [M+H] + ;403.0[M+2H] / 2 + .

[0805] Synthesis of compound 13

[0806] 13-15 (16 mg, 0.02 mmol) was dissolved in tetrahydrofuran (1 mL), and sodium hydroxide solution (1 mL, 0.62 mmol / L) was added. The mixture was stirred at room temperature for 2 hours. LCMS monitored the reaction completion, and the reaction was quenched with a small amount of dry ice. The reaction solution was directly purified by preparative chromatography to afford 13 (8 mg, yield: 50%) as a colorless oil. LCMS: (ESI) m / z = 790.7 [M+H] + ;812.5[M+Na] + ; 396.0[M+2H] / 2 + ; 1H NMR (400MHz, DMSO-d6+D2O) δ8.09(dd,J=4.4,4.8Hz,1H),7.42(dd,J=8.0,8.0Hz,1H),7.33(s,1H),7.30(d,J=8.0Hz,1H),7.26(d,J= 8.0Hz,1H),6.98(s,1H),6.07(s,1H),4.07(d,J=5.6Hz,2H),3.60-3.45(m,16H),3.37(t,J=4.8Hz,2H),3.36-3.22(m,1H),3.22-3.1 5(m,2H),3.05-2.97(m,1H),2.97-2.89(m,1H),2.85-2.76(m,2H),2.75-2.65(m,3H),2.61-2.55(m,2H),2.52-2.40(m,2H),2.35-2. 30(m,3H),2.27(s,3H),2.17(s,3H),2.17-2.05(m,1H),2.02-1.90(m,1H),1.79-1.70(m,2H),1.65-1.50(m,2H),1.47-1.37(m,1H).

[0807] 400 mg of compound 13 was purified by SFC (chromatographic column: OX 25*250 mm, 10 μm), mobile phase: [carbon dioxide-acetonitrile / methanol (0.5% ammonia, 7 M in MeOH)], B%: 45%, isobaric elution mode) to obtain white solid isomer 1:13-P1 (Major) and isomer 2:13-P2 (Minor).

[0808] Isomer1:155mg

[0809] MS m / z(ESI):395.8[M+2H] / 2 + ;

[0810] Analytical chiral SFC: RT = 2.202 min, >99.5%, column: RR-Whelk-O1 4.6*100 mm, 5 μm, CO2-50% acetonitrile / methanol (0.2% ammonia, 7 M in MeOH), B%: 45%, flow rate 3 mL / min. 1H NMR (400MHz, DMSO-d6+D2O) δ8.09(dd,J=4.4,4.8Hz,1H),7.45(dd,J=7.6,7.6Hz,1H),7.34(s,2H),7.30(d,J=7.6H z,1H),7.01(s,1H),6.09(s,1H),4.09(s,2H),3.62-3.45(m,16H),3.37-3.28(m,4H),3.26-3.05(m,2H),3.20-3.10 (m,1H),23.10-2.95(m,2H),2.91-2.95(m,1H),2.85-2.70(m,2H),2.65-2.56(m,2H),2.53-2.41(m,3H),2.34(t,J =6.4Hz,2H),2.28(s,3H),2.27-2.16(m,1H),2.18(s,3H),2.14-2.00(m,1H),1.79-1.70(m,2H),1.65-1.46(m,3H).

[0811] Isomer2:15mg

[0812] MS m / z(ESI):395.7[M+2H] / 2 + ;

[0813] Analytical chiral SFC: RT = 2.600 min, >99.5%, column: RR-Whelk-O1 4.6*100 mm, 5 μm, CO2-50% acetonitrile / methanol (0.2% ammonia, 7 M in MeOH), B%: 45%, flow rate 3 mL / min. 1 H NMR (400MHz, DMSO-d6+D2O) δ8.11(dd,J=5.2,5.2Hz,1H),7.40(dd,J=7.6,7.6Hz,1H),7.29(d,J=4.4Hz, 2H),7.25(dd,J=6.8,7.6Hz,1H),6.96(s,1H),6.05(s,1H),4.05(s,2H),3.60-3.41(m,16H),3.38-3.25( m,3H),3.23-3.05(m,4H),2.92-2.70(m,4H),2.60-2.53(m,2H),2.48-2.35(m,4H),2.30(t,J=6.0Hz,2H ),2.25(s,3H),2.20-2.06(m,1H),2.19(s,3H),2.02-1.90(m,1H),1.75-1.65(m,2H),1.62-1.38(m,3H).

[0814] Synthesis of compound 14

[0815] Synthesis of Intermediate 14-2

[0816] 14-1 (5.0 g, 24.2 mmol, 1.0 eq.) was dissolved in ethyl acetate (100 mL), and NIS (5.99 g, 26.6 mmol) was added all at once. The mixture was stirred at room temperature for 16 hours. The reaction solution was washed with saturated sodium sulfite solution (20 mL) and saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography to afford 14-2 (7.3 g, yield: 90%) as a light yellow solid. LCMS: (ESI) m / z = 333.0 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ7.61 (dd, J = 2.0, 2.4Hz, 1H), 7.57-7.46 (m, 3H), 2.34 (s, 3H), 2.19 (s, 3H).

[0817] Synthesis of intermediate 14-3

[0818] A 500 mL round-bottom flask was charged with 14-2 (7.0 g, 21 mmol, 1.0 eq.), 3,4,7,8-tetramethyl-1,10-phenanthroline (995 mg, 4.2 mmol), benzyl alcohol (4.54 g, 42 mmol), cuprous iodide (800 mg, 4.2 mmol), cesium carbonate (13.7 g, 42 mmol), and 100 mL of toluene. The mixture was stirred and refluxed under nitrogen for 72 hours. LCMS analysis indicated the formation of the product. The reaction mixture was cooled, filtered, and concentrated. The residue was purified by silica gel column chromatography to afford 14-3 (1.2 g, yield: 18%) as a colorless oil. LCMS: (ESI) m / z = 313.0 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ7.58-7.34(m,9H),4.88(s,2H),2.19(s,3H),2.10(s,3H).

[0819] Synthesis of Intermediate 14-4

[0820] 14-3 (1.2 g, 3.85 mmol) was dissolved in 1,4-dioxane (100 mL), and pinacol diboronate (1.95 g, 7.69 mmol), Pd2(dba)3 (528 mg, 0.578 mmol), X-Phos (366 mg, 0.769 mmol), and potassium acetate (1.13 g, 11.55 mmol) were added sequentially. The mixture was stirred at 115°C under a nitrogen atmosphere for 16 hours. The reaction was monitored by LCMS. The mixture was filtered, concentrated, and the crude product was purified by reverse phase chromatography to afford 14-4 (1.3 g, yield: 83.8%) as a brown solid. LCMS: (ESI) m / z = 405.0 [M+H] + ; 322.7 (depinacol product) [M+H] + .

[0821] Synthesis of Intermediate 14-5

[0822] Intermediate 13-9 (1.6 g, 4.89 mmol) was dissolved in dichloromethane (10 mL), cooled to 0°C, and then hydrogen chloride-dioxane solution (4N, 20 mL) was added. The mixture was stirred at 0°C for 4 hours. LCMS monitored the reaction completion, and the mixture was concentrated and dried under vacuum to give the crude product 14-5 (1.2 g) as a light yellow solid. LCMS: (ESI) m / z = 232.1 [M+H] + .

[0823] Synthesis of Intermediate 14-6

[0824] 13-5 (514 mg, 3.25 mmol) and Pd(dppf)2Cl2 (146 mg) were dissolved in dichloromethane (DCM) (30 mL) and stirred at room temperature for 10 minutes. The mixture was cooled to 0°C and a dichloromethane solution (20 mL) of 14-5 (1.1 g, 3.61 mmol) and DIPEA (3.7 mL, 21.66 mmol) was added. The mixture was stirred at 0°C under nitrogen for 16 hours. The reaction was monitored for completion by LCMS. The mixture was filtered and concentrated, and the crude product was purified by reverse phase chromatography to afford 14-6 (1.0 g, yield: 84%) as a light brown oil. LCMS: (ESI) m / z = 330.1 [M+H] + ; 1H NMR(400MHz,DMSO-d6)δ7.00(d,J=7.6Hz,1H),6.85(dt,J=5.6,16.0Hz,1H),6.2 5(s,1H),6.23(d,J=7.6Hz,1H),5.98(d,J=16.0Hz,1H),3.66(s,3H),3.26-3.10( m,4H),2.68(t,J=7.2Hz,1H),2.62-2.51(m,3H),2.45-2.31(m,4H),2.11-1.96(m ,2H),1.95-1.83(m,1H),179-1.68(m,2H),1.65-1.54(m,2H),1.38-1.25(m,1H).

[0825] Synthesis of Intermediate 14-7

[0826] To a 50 mL round-bottom flask were added 14-6 (310 mg, 0.9141 mmol), 14-4 (1.14 g, 2.82 mmol), potassium hydroxide (105 mg, 1.88 mmol), water (500 μL), (1,5-cyclooctadiene)rhodium(I) chloride dimer (46 mg, 0.0491 mmol), R-(+)-1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (117 mg, 0.188 mmol), and 1,4-dioxane (8 mL). The system was purged with nitrogen twice and stirred in an oil bath at 90°C under nitrogen for 6 hours. After completion of the reaction, the mixture was filtered and concentrated. The crude product was purified by reverse phase chromatography to afford 14-7 (550 mg, 96% yield) as a light yellow solid. LCMS: (ESI) m / z = 607.7 [M+H] + ; 304.4[M+2H] / 2 + .

[0827] Synthesis of Intermediate 14-8

[0828] 14-7 (100 mg, 0.164 mmol, 1.0 equiv.) and di-tert-butyl dicarbonate (72 mg, 0.329 mmol) were dissolved in tetrahydrofuran (3 mL) under nitrogen atmosphere and cooled to 0°C. LiHMDS (1N in THF, 0.25 mL, 0.25 mmol) was added dropwise. After the addition was complete, the reaction was stirred at 0°C for 6 hours. The reaction was quenched with 10% ammonium chloride solution, extracted with ethyl acetate (20 mL x 2), washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by preparative chromatography to afford 14-8 (45 mg, yield: 38%) as a white solid. LCMS: (ESI) m / z = 708.3 [M+H] + .

[0829] Synthesis of Intermediate 14-9

[0830] 14-8 (45 mg, 0.064 mmol) was dissolved in methanol (4 mL), and Pd / C (10 mg) was added. The reaction system was replaced with hydrogen twice and stirred at room temperature under hydrogen for 3 hours. After completion of the reaction, the mixture was filtered and concentrated to give the crude product 14-9 (40 mg) as a yellow solid. LCMS: (ESI) m / z = 618.2 [M+H] + .

[0831] Synthesis of Intermediate 14-10

[0832] 14-9 (40 mg, 0.064 mmol, 1.0 equiv.) was dissolved in DMF (2 mL) and cooled to 0°C. NaH (60%, 30 mg) was added under nitrogen and stirred for 2 minutes. N3-PEG5-Tos (53 mg, 0.128 mmol) was then added, and the mixture was stirred at 0°C for 4 hours. LCMS monitored the reaction completion. The reaction was quenched with water (5 mL) and a small amount of dry ice (approximately 2 g). A precipitate formed, and the supernatant was removed by centrifugation. The residual solid was vacuum-evacuated to afford crude product 14-10 (60 mg), which was used directly in the next reaction. LCMS: (ESI) m / z = 863.7 [M+H] + ; 432.5[M+2H] / 2 + .

[0833] Synthesis of compound 14

[0834] The crude product 14-10 (60 mg, approximately 0.064 mmol) obtained in the previous step was dissolved in tetrahydrofuran (1 mL), 0.62 mol / L sodium hydroxide solution (1 mL) was added, and the mixture was stirred at room temperature for 2 hours. LCMS monitored the reaction to completion, the reaction solution was concentrated and drained, and the residue was dissolved in dichloromethane (2 mL), trifluoroacetic acid (TFA) (4 mL) was added, and the reaction was stirred at room temperature overnight. LCMS monitored the reaction to completion, the solution was concentrated, and the residue was purified by preparative chromatography to give 14 (13 mg, total yield of the three-step reaction: 27%) as a white solid. LCMS: (ESI) m / z = 749.57 [M+H] + ; 375.5[M+2H] / 2 + ; 1H NMR (400MHz, DMSO-d6+D2O) δ7.39(dd,J=7.6,8.0Hz,1H),7.30(s,1H),7.27(d,J=8.0Hz,1H),7.22(d,J=8.0H z,1H),7.02(d,J=7.6Hz,1H),6.25(d,J=7.6Hz,1H),3.99-3.93(m,2H),3.66-3.49(m,16H),3.37(t,J=4.8Hz, 2H),3.33-3.25(m,1H),3.25-3.20(m,2H),2.93-2.81(m,2H),2.75-2.55(m,6H),2.42-2.26(m,4H),2.22(s,3 H),2.16(s,3H),2.05-1.96(m,1H),1.94-1.84(m,1H),1.78-1.70(m,2H),1.65-1.54,2H),1.40-1.29(m,1H).

[0835] 190 mg of compound 14 was purified by SFC (column: OJ-H 25*250 mm, 10 μm), mobile phase: [carbon dioxide-methanol (0.2% ammonia, 7 M in MeOH)], B%: 25%, isobaric elution mode) to give white solid isomer 1:14-P1 (Minor) and isomer 2:14-P2 (Major).

[0836] Isomer1:10mg

[0837] MS m / z(ESI):375.3[M+2H] / 2 + ;

[0838] Analytical chiral SFC: RT = 2.580 min, >99.5% purity, column: OJ-H 4.6*100 mm, 5 μm, CO2-methanol (0.2% ammonia, 7 M in MeOH), B%: 20%, flow rate 3 mL / min. 1H NMR(400MHz, DMSO-d6+D2O)δ(dd,J=7.6,8.0Hz,1H),7.30(s,1H),7.27(d,J=8.0Hz,1H),7.21(d,J= 7.6Hz,1H),7.00(d,J=7.2Hz,1H),6.23(d,J=7.6Hz,1H),3.97-3.92(m,2H),3.66-3.49(m,16H),3. 36(t,J=4.8Hz,2H),3.33-3.25(m,1H),3.25-3.18(m,2H),2.96-2.86(m,2H),2.80-2.61(m,4H),2. 60-2.53(m,2H),2.47-2.13(m,3H),2.29-2.18(m,1H),2.21(s,3H),2.14(s,3H),2.07-1.97(m,1H), 1.96-1.84(m,1H),1.75-1.67(m,2H),1.64-1.52(m,2H),1.40-1.29(m,1H).

[0839] Isomer2:65mg

[0840] MS m / z(ESI):375.2[M+H] / 2 + ;

[0841] Analytical chiral SFC: RT = 3.498 min, >99.5% purity, column: OJ-H 4.6*100 mm, 5 μm, CO2-methanol (0.2% ammonia, 7 M in MeOH), B%: 20%, flow rate 3 mL / min. 1H NMR (400MHz, DMSO-d6+D2O) δ7.42(dd,J=7.2,8.0Hz,1H),7.33(s,1H),7.31(d,J=8.0Hz,1H),7.24(d,J=7.6Hz,1H),7.04(d ,J=7.2Hz,1H),6.27(d,J=7.6Hz,1H),3.99-3.93(m,2H),3.68-3.60(m,2H),3.60-3.51(m,14H),3.37(t,J=4.8Hz,2H),3.35 -3.25(m,1H),3.25-3.21(m,2H),3.13-3.08(m,1H),3.00-2.94(m,1H),2.81-2.69(m,4H),2.63-2.57(m,2H),2.50-2.35(m, 3H),2.23(s,3H),2.17(s,3H),2.13-2.04(m,1H),2.03-1.90(m,1H),1.78-1.70(m,2H),1.68-1.54,2H),1.46-1.35(m,1H).

[0842] Synthesis of compound 15

[0843] Synthesis of Intermediate 15-2

[0844] (3-Bromophenyl)-1-propanone (5.0 g, 23.47 mmol) was dissolved in dichloromethane (30 mL), and bromine (1.2 mL, 23.47 mmol) was carefully added dropwise. The mixture was stirred at room temperature for 4 hours. The reaction solution was poured into water (50 mL) and extracted with dichloromethane (100 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product 15-2 (8.9 g) as a colorless liquid. LCMS: (ESI) m / z = 292.5 [M+H] + .

[0845] Synthesis of Intermediate 15-3

[0846] Acetamidine hydrochloride (2.88 g, 30.5 mmol) was dissolved in DMF (20 mL), and potassium carbonate (8.4 g, 61 mmol) was added. The mixture was stirred at 50°C for 30 minutes. A solution of 15-2 (8.9 g, 30.5 mmol) in chloroform (10 mL) was then added, and the mixture was stirred at 50°C overnight. The reaction was monitored for completion by LCMS. The product was filtered and concentrated, and the residue was purified by reverse phase chromatography to afford 1.6 g of crude product. The crude product was dissolved in dichloromethane (10 mL), and petroleum ether (20 mL) was added portionwise with stirring. A precipitate formed. Stirring was continued for 30 minutes, and the mixture was filtered, washed with petroleum ether (1 mL x 2), and dried under vacuum to afford 15-3 (1.1 g, total yield for the two-step reaction: 14%) as a light yellow solid. LCMS: (ESI) m / z = 333.0 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ11.73(s,1H),7.78(s,1H),7.57(s,1H),7.32(s,2H),2.34(s,3H),2.25(s,3H).

[0847] Synthesis of Intermediate 15-4

[0848] 15-3 (1.0 g, 3.98 mmol) was dissolved in dichloromethane (20 mL), and di-tert-butyl dicarbonate (1.3 g, 5.97 mmol), DMAP (49 mg), and TEA (1.66 mL) were added sequentially. The mixture was stirred at room temperature overnight. LCMS monitored the reaction completion. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography to give 15-4 (1.1 g, yield: 78%) as a light yellow solid. LCMS: (ESI) m / z = 295.0 [M+H-56] + ; 1 H NMR (400MHz, DMSO-d6) δ7.72(dd,J=1.6,2.0Hz,1H),7.55(ddd,J=1.2,1.6,8.0Hz,1H),7.49(d dd,J=1.2,2.0,8.0Hz,1H),7.38(dd,J=8.0,8.0Hz,1H),2.51(s,3H),2.45(s,3H),1.60(s,9H).

[0849] Synthesis of Intermediate 15-5

[0850] 15-4 (1.0 g, 2.85 mmol) was dissolved in 1,4-dioxane (50 mL), and diboronic acid pinacol ester (1.16 g, 4.56 mmol), Pd(dppf)2Cl2 (346 mg, 0.427 mmol), and potassium acetate (839 mg) were added sequentially. The system was purged with nitrogen twice, and the mixture was stirred at 90°C under nitrogen protection overnight. LCMS monitoring indicated the formation of the desired product. The reaction was filtered, concentrated, and the crude product was purified by silica gel column chromatography to afford 15-5 (750 mg, yield: 69%) as a light yellow oil. LCMS: (ESI) m / z = 399.1 [M+H] + ; 343.1[M+H-56] + .

[0851] Synthesis of Intermediate 15-6

[0852] To a 50 mL round-bottom flask were added 14-6 (150 mg, 0.455 mmol), 15-5 (543 mg, 1.365 mmol), potassium hydroxide (51 mg, 0.911 mmol), water (240 μL), (1,5-cyclooctadiene)rhodium(I) chloride dimer (23 mg, 0.045 mmol), R-(+)-1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (62 mg, 0.091 mmol), and 1,4-dioxane (4 mL). The mixture was stirred at 90°C under nitrogen for 6 hours. The reaction was monitored for completion by LCMS. The mixture was filtered, concentrated, and the crude product was purified by preparative chromatography to afford 15-6 (66 mg, yield: 29%) as a white solid. LCMS: (ESI) m / z = 502.1 [M+H] + ; 251.6[M+2H] / 2 + .

[0853] Synthesis of Intermediate 15-7

[0854] To a 50 mL round-bottom flask, a mixture of 15-6 (25 mg, 0.05 mmol), potassium carbonate (21 mg, 0.15 mmol), N3-PEG5-Tos (104 mg, 0.25 mmol), and DMF (2 mL) was added sequentially and stirred at 80°C overnight. LCMS monitoring indicated approximately 50% conversion of the starting material. The reaction solution was cooled to room temperature and water (10 mL) was added with stirring, resulting in the formation of a precipitate. The supernatant was removed by centrifugation and the residue was vacuum-evacuated to afford the crude product 15-7, which was used directly in the next step. LCMS: (ESI) m / z = 747.3 [M+H] + .

[0855] Synthesis of compound 15

[0856] The crude product 15-7 (approximately 0.05 mmol) obtained in the previous step was dissolved in tetrahydrofuran (1 mL) and cooled to 0°C. 0.5N sodium hydroxide solution (1 mL) was then added, and the mixture was stirred at 0°C for 2 hours. The reaction was monitored for completion by LMCS, quenched with a small amount of dry ice, and the reaction solution was directly purified by preparative chromatography to afford 15 (6.6 mg, total yield for the two-step reaction: 18%) as a white solid. LCMS: (ESI) m / z = 733.3 [M+H] + ; 367.2[M+2H] / 2 + ; 1 H NMR (400MHz, DMSO-d6+D2O) δ7.44(s,1H),7.40(d,J=8.0Hz,1H),7.34(dd,J=7.6Hz,1H),7.12(d,J=7.2Hz,2H ),6.33(d,J=7.6Hz,1H),4.05(t,J=4.8Hz,2H),3.65(t,J=4.2Hz,2H),3.59-3.45(m,16H),3.40-3.31(m,4H) ,3.28-3.00(m,6H),2.98-2.88(m,1H),2.86-2.75(m,1H),2.65-2.58(m,2H),2.49-2.42(m,2H),2.35(s,3H) ,2.34(s,3H),2.25-2.14(m,1H),2.13-2.01(m,1H),1.78-1.71(m,2H),1.70-1.60(m,2H),1.59-1.47(m,1H).

[0857] Synthesis of compound 16

[0858] Synthesis of intermediate 16-12

[0859] At 0 ° C, under nitrogen protection, 2- [2- [2- [2- (2-hydroxyethoxy) ethoxy] ethoxy] -ethoxy] -ethanol (10 g, 35.42 mmol), triethylamine (14.34 g, 141.68 mmol) in dichloromethane (100 mL) was added methylsulfonyl chloride (8.93 g, 77.92 mmol), and the mixture was stirred at 25 ° C for 16 hours. LCMS showed that the starting material was completely consumed and the product was detected. The mixture was filtered and the filtrate was washed with 0.1N hydrochloric acid solution (100 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 16-12 (13.00 g, crude product) as a brown oil, which was used directly in the next step. LCMS: (ESI) m / z = 358.10 [M-28 + H] + .

[0860] Synthesis of intermediate 16-13

[0861] To a solution of 16-12 (13 g, 29.65 mmol) in acetonitrile (130 mL) was added sodium azide (2.41 g, 37.06 mmol) at 25 ° C., and the mixture was stirred at 85 ° C. for 16 hours. LCMS showed that the starting material was completely consumed and the product was detected. The mixture was filtered and the filtrate was concentrated to give a crude product. The crude product was purified by silica gel column chromatography (EA / PE=70%) to give 16-13 (6.00 g, 14.01 mmol, 23.63% yield, 90% purity) as a brown oil. LCMS: (ESI) m / z=358.10 [M-28+H] + .

[0862] Synthesis of intermediate 16-14

[0863] To a solution of 16-13 (6 g, 15.57 mmol) in tetrahydrofuran (60 mL) was added lithium bromide (6.76 g, 77.83 mmol) at 25 ° C., and the mixture was stirred at 70 ° C. for 6 hours. LCMS showed that the starting material was completely consumed and the product was detected. The mixture was filtered and the filtrate was concentrated to obtain a residue. The residue was added with water, extracted with ethyl acetate (100 mL×2), and washed with brine (100 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to obtain a crude product. The crude product was purified by silica gel column chromatography (EA / PE=60%) to give 16-14 (4.10 g, 9.97 mmol, 64.02% yield, 90% purity) as a brown oil. LCMS: (ESI) m / z=342.20[M-28+H] + .

[0864] Synthesis of Intermediate 16-1

[0865] To a mixture of 2-aminopyridine-3-carboxaldehyde (25 g, 204.71 mmol) and L-proline (11.78 g, 102.35 mmol) in ethanol (300 mL) was added ethyl acetobutyrate (32.38 g, 204.75 mmol) at 25 ° C., and the mixture was stirred at 80 ° C for 16 hours. LCMS showed that the starting material was completely consumed and the product was detected. The mixture was concentrated to obtain a residue. The residue was added with water, extracted with ethyl acetate (500 mL×2), and washed with brine (500 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to obtain a crude product. The crude product was purified by silica gel column chromatography (EA / PE=50%) to obtain 16-1 (31.00 g, 114.21 mmol, 27.90% yield, 90% purity) as a yellow solid. LCMS: (ESI) m / z=245.1[M+H]+ ; 1 H NMR (400MHz, CDCl3) δ9.09 (dd, J=4.3, 2.0Hz, 1H), 8.17 (dd, J=8.1, 2.0Hz, 1H), 8.12 (d, J=8.3Hz, 1H), 7.46 (dd, J=8.1, 4.3Hz, 1H) ,7.41(d,J=8.3Hz,1H),4.12(q,J=7.1Hz,2H),3.14–3.08(m,2H),2.45(t,J=7.4Hz,2H),2.30–2.22(m,2H),1.25(t,J=7.1Hz,3H).

[0866] Synthesis of Intermediate 16-2

[0867] At -78 ° C, under nitrogen protection, lithium aluminum hydride (1M, 92.10 mL) was added to a solution of ethyl 4-(1,8-naphthyridin-2-yl)butanoate (15 g, 61.40 mmol) in tetrahydrofuran (200 mL), and the mixture was stirred at -78 ° C for 1 hour. The mixture was then stirred at 25 ° C for 2 hours. LCMS showed that the starting material was completely consumed and the product was detected. Water (4 mL), aqueous sodium hydroxide solution (4 mL, 15%), and water (12 mL) were added to the mixture and stirred for 0.5 hours. The mixture was filtered, the filtrate was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a crude product. The crude product was purified by silica gel column chromatography (EA / PE=90%) to give 16-2 (7.00 g, 25.70 mmol, 20.93% yield, 75% purity) as a yellow oil. LCMS: (ESI) m / z=205.1[M+H] + .

[0868] Synthesis of Intermediate 16-3

[0869] A mixture of 16-2 (7 g, 34.27 mmol) and palladium hydroxide on carbon (1 g) in methanol (50 mL) was stirred at 25 ° C. under a hydrogen atmosphere for 16 h. LCMS showed that the starting material was completely consumed and the product was detected. The mixture was filtered and the filtrate was concentrated in vacuo to give a crude product. The crude product was purified by silica gel column chromatography (MeOH / DCM=4%) to give 16-3 (5.80 g, 25.30 mmol, 36.92% yield, 90% purity) as a brown oil. LCMS: (ESI) m / z=207.1[M+H] + ; 1H NMR(400MHz, DMSO-d6)δ7.02(d,J=7.3Hz,1H),6.29–6.21(m,2H),4.35(s,1H),3.38(t,J=6.2Hz,2H),3.23–3.2 1(m,2H),2.59(t,J=6.2Hz,2H),2.41(t,J=7.6Hz,2H),1.77–1.71(m,2H),1.61–1.54(m,2H),1.44–1.38(m,2H).

[0870] Synthesis of Intermediate 16-4

[0871] To a solution of 16-3 (5.35 g, 36.36 mmol) and triphenylphosphine (9.54 g, 36.36 mmol) in tetrahydrofuran (100 mL) was added diisopropyl azodicarboxylate (10.78 g, 53.32 mmol, 10.47 mL) at 0 ° C, and the mixture was stirred at 25 ° C for 16 hours. LCMS showed that the starting material was completely consumed and the product was detected. The mixture was added with water and extracted with ethyl acetate (200 mL × 2). The combined organic layer was washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a crude product. The crude product was purified by silica gel column chromatography (EA / PE = 40%) to give 16-4 (8.00 g, 14.31 mmol, 59.04% yield, 60% purity) as a brown oil.

[0872] Synthesis of Intermediate 16-5

[0873] To a solution of 16-4 (8 g, 23.85 mmol) in ethanol (60 mL) was added hydrazine hydrate (3.82 g, 95.41 mmol, 3.82 mL, 80% purity) at 25 ° C., and the mixture was stirred at 70 ° C. for 5 hours. LCMS showed that the starting material was completely consumed and the product was detected. The mixture was filtered and the filtrate was concentrated in vacuo to give a crude product. The crude product was purified by silica gel column chromatography (MeOH / DCM=9%) to give 16-5 (1.60 g, crude product) as a brown oil. LCMS: (ESI) m / z=206.20 [M+H] + .

[0874] Synthesis of intermediate 16-6

[0875] At 25 ° C, to a mixed solution of 16-5 (2 g, 9.74 mmol), potassium carbonate (2.69 g, 19.48 mmol) in dioxane (20 mL) and water (5 mL) was added benzyl chloroformate (1.83 g, 10.72 mmol), and the mixture was stirred at 25 ° C for 5 hours. LCMS showed that the starting material was completely consumed and the product was detected. The mixture was added with water, extracted with ethyl acetate (100 mL × 2), and washed with brine (100 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a crude product. The crude product was purified by silica gel column chromatography (EA / PE = 60%) to give 16-6 (1.40 g, 3.71 mmol, 38.10% yield, 90% purity) as a brown oil. LCMS: (ESI) m / z = 340.20 [M + H] + .

[0876] Synthesis of Intermediate 16-7

[0877] To a solution of 16-6 (1.4 g, 4.12 mmol) in methanol (15 mL) was added palladium on carbon (0.3 g, 10%) at 25°C, and the reaction mixture was stirred under a hydrogen atmosphere for 16 hours. LCMS showed that the starting material was completely consumed and the product was detected. The reaction mixture was filtered, and the filtrate was concentrated in vacuo to give 16-7 (700.00 mg, crude) as a brown oil. LCMS: (ESI) m / z = 206.1 [M+H] + .

[0878] Synthesis of Intermediate 16-8

[0879] At 25 ° C, to a mixture of 16-7 (0.7 g, 3.41 mmol) and potassium carbonate (942.47 mg, 6.82 mmol) in DMF (10 mL) was added 16-14 (1.26 g, 3.41 mmol), and the mixture was stirred at 70 ° C for 16 hours. LCMS showed that the starting material was completely consumed and the product was detected. The mixture was added with water and extracted with dichloromethane (100 mL × 2). The combined organic layer was washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a crude product. The crude product was purified by silica gel column chromatography (MeOH / DCM = 8%) to give 16-8 (800.00 mg, 1.46 mmol, 42.69% yield, 90% purity) as a brown oil.

[0880] Synthesis of intermediate 16-9

[0881] To a mixture of 16-8 (0.8 g, 1.62 mmol), methyl (2S)-2-(tert-butoxycarbonylamino)-4-oxobutanoate (411.41 mg, 1.78 mmol) in 1,2-dichloroethane (10 mL) were added acetic acid (145.69 mg, 2.43 mmol, 138.88 μL) and sodium triacetoxyborohydride (514.18 mg, 2.43 mmol) at 0 ° C. The mixture was stirred at 25 ° C for 2 hours. LCMS showed that the starting material was completely consumed and the product was detected. The mixture was added with water and extracted with dichloromethane (50 mL×2). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a crude product. The crude product was purified by silica gel column chromatography (MeOH / DCM=5%) to give 16-9 (700.00 mg, 887.48 μmol, yield 54.87%, purity 90%). LCMS: (ESI) m / z=710.6 [M+H] + .

[0882] Synthesis of Intermediate 16-10

[0883] At 25 ° C, trifluoroacetic acid (4 mL) was added to a solution of 16-9 (0.7 g, 986.09 μmol) in dichloromethane (10 mL), and the mixture was stirred at 25 ° C for 2 hours. LCMS showed that the starting material was completely consumed and the product was detected. The mixture was concentrated to obtain a residue. Aqueous sodium carbonate solution was added to the residue to adjust the pH to 8. The mixture was extracted with dichloromethane (100 mL×2). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to obtain 16-10 (500.00 mg, crude product) as a brown oil. LCMS: (ESI) m / z=610.5[M+H] + .

[0884] Synthesis of intermediate 16-11

[0885] To a solution of 16-10 (0.5 g, 820.00 μmol) in isopropanol (5 mL) was added 4-chloroquinazoline (148.46 mg, 902.00 μmol) at 25° C. The mixture was concentrated in vacuo to give a crude product. The crude product was purified by silica gel column chromatography (MeOH / DCM=5%) to give 16-11 (260.00 mg, 281.89 μmol, 34.38% yield, 80% purity) as a brown oil. LCMS: (ESI) m / z=738.5 [M+H] + .

[0886] Synthesis of compound 16

[0887] Compound 16-11 (0.26 g, 352.36 μmol) was dissolved in methanol (1 mL), tetrahydrofuran (1 mL), and water (0.5 mL). Lithium hydroxide (67.51 mg, 2.82 mmol) was added at 25°C. The mixture was stirred at 25°C for 2 h. LCMS showed complete consumption of the starting material and the presence of product. The mixture was filtered, and the filtrate was collected to obtain the crude product. The crude product was purified by preparative HPLC (column: Welchmax C18 21.2 × 250 mm, 10 μm: 25-25% (A = H2O, B = ACN)) to obtain compound 16 (50.00 mg, 66.05 μmol, 18.74% yield, 95.62% purity) as a gray gum. LCMS: (ESI) m / z = 724.5 [M+H] + ; 1 H NMR(400MHz, DMSO-d6)δ8.39(s,1H),8.09–7.96(m,2H),7.77–7.70(m,1H),7.64(d,J=9.1Hz,1H),7.53–7.43(m,1H) ,6.96(d,J=7.2Hz,1H),6.30(s,1H),6.16(d,J=7.3Hz,1H),4.24–4.17(m,1H),3.60–3.57(m,2H),3.56–3.51(m,4H), 3.50–3.48(m,4H),3.46–3.43(m,4H),3.39–3.37(m,10H),3.23–3.19(m,2H),2.58(t,J=6.3Hz,2H),2.48–2.34(m,4H ),2.34–2.30(m,2H),2.13–2.01(m,1H),1.94–1.83(m,1H),1.75–1.70(m,2H),1.51–1.41(m,2H),1.34–1.24(m,2H).

[0888] Synthesis of compound 17

[0889] Synthesis of Intermediate 17-10

[0890] Sodium hydride (974.80 mg, 24.37 mmol, 60% purity) was added to a solution of benzyl alcohol (2.64 g, 24.37 mmol, 2.52 mL) in N, N-dimethylformamide (20 mL). 7-Fluoroquinazolin-4-ol (2 g, 12.18 mmol) was then added and the mixture was heated to 140 ° C for 4 hours. After cooling to room temperature, the reaction was quenched with ice water, and then 4 M concentrated hydrochloric acid was added to adjust the pH to 3 to obtain a precipitate. The precipitate was filtered off and washed with water and diethyl ether. The solid was dried under vacuum to give 17-10 (2.80 g, crude product) as a gray solid. LCMS: m / z [M + H] + =253.1,RT=0.891min.

[0891] Synthesis of intermediate 17-11

[0892] A mixture of 17-10 (2.8 g, 11.10 mmol), thionyl chloride (10.00 mL) and DMF (0.3 mL) was heated at 90°C for 3 hours. Excess thionyl chloride was removed by swirl, and the residue was azeotroped with toluene and dried under vacuum to give 17-11 as a gray solid (2.80 g, crude product), which was used directly in the next step without further purification. LCMS: m / z = 271.0 [M+H] + .

[0893] Synthesis of Intermediate 17-1

[0894] To a solution of 16-1 (5 g, 20.47 mmol) in ethanol (50 mL) was added 10% palladium on carbon (800 mg, 6.59 mmol). The reaction was stirred under a hydrogen atmosphere for 16 hours. Liquid chromatography detected that all the starting materials were converted to product. The catalyst was filtered off and the filtrate was concentrated under reduced pressure to give 17-1 (4.80 g, crude product) as a yellow oil. 1 H NMR (400MHz, CDCl3) δ7.02(s,1H),6.31(s,1H),4.82(s,1H),4.12–4.04(m,2H),3.41–3.32(m,2H),2.66(s,2H),2.56(d,J=8. 6Hz,2H),2.31(d,J=15.1Hz,2H),1.98(q,J=7.7Hz,2H),1.88(p,J=6.0Hz,2H),1.22(d,J=14.3Hz,3H).LCMS:m / z=249.1[M+H] + .

[0895] Synthesis of Intermediate 17-2

[0896] At 25 ° C, lithium hydroxide monohydrate (3.97 g, 94.64 mmol) was added to a solution of 17-1 (4.7 g, 18.93 mmol) in tetrahydrofuran (30 mL), and the mixture was stirred at 60 ° C for 4 hours. LCMS showed that the raw material was converted to the product. The mixture was added 4M HCl (aq), the pH was adjusted to 6, and extracted with (20% isopropanol in dichloromethane) (100 mL × 2). The combined organic layer was washed with brine (50 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 17-2 (4.10 g, crude product) as a white solid, which was used in the next step without further purification. 1 H NMR(400MHz,CD3OD)δ7.56(d,J=9.4Hz,1H),6.60(d,J=7.3Hz,1H),3.53–3.43(m,2H) ,2.87–2.68(m,4H),2.35(t,J=7.2Hz,2H),2.02–1.87(m,4H).LCMS:m / z=221.1[M+H] + .

[0897] Synthesis of Intermediate 17-3

[0898] At 0 ° C, 17-2 (4.1 g, 18.61 mmol) in dichloromethane (40 mL) solution was added 1,1'-carbonyldiimidazole (3.32 g, 20.48 mmol) and 2-methoxyethylamine (1.54 g, 20.44 mmol), and the mixture was stirred at 25 ° C for 2 hours. Liquid chromatography showed that the raw material was converted into the product. The mixture was diluted with water, extracted with dichloromethane (50 mL × 2), and washed with brine (50 mL × 2). The combined organic layer was dried over anhydrous sulfuric acid, filtered and concentrated in vacuo. The crude product was washed with methyl tert-butyl ether and filtered to give 17-3 (2.90 g, 10.46 mmol, 56.17% yield) as a white solid. 1 H NMR (400MHz, CD3Cl) δ7.06(d,J=7.3Hz,1H),6.32(d,J=7.3Hz,1H),5.37(s,1H),3.48(q,J=3.5,3.1Hz,4H),3.41–3.37(m,2H ),3.37(s,3H),2.68(t,J=6.3Hz,2H),2.58(t,J=7.0Hz,2H),2.19(t,J=7.0Hz,2H),1.97–1.84(m,4H).LCMS:m / z=278.1[M+H] + .

[0899] Synthesis of Intermediate 17-4

[0900] To a solution of 17-3 (2.4 g, 8.65 mmol) in dioxane (19 mL) was added lithium aluminum hydride (1 M, 19.04 mL) at 0 ° C, and the mixture was stirred at 110 ° C for 1 hour. Liquid chromatography showed that the raw material was converted into the product. The mixture was cooled to room temperature, and then water (2 mL), sodium hydroxide aqueous solution (1 M, 2 mL), and water (2 mL) were carefully added in sequence. The mixture was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to give 17-4 (2.20 g, crude product) as a yellow oil. 1 H NMR (400MHz, CD3Cl) δ7.03(d,J=7.3Hz,1H),6.32(d,J=7.3Hz,1H),4.83(s,1H),3.48(t,J=5.1Hz,2H),3.38(t,J=5.5Hz,2H),3.34(s,3H ),2.80–2.73(m,2H),2.69–2.62(m,4H),2.57–2.51(m,2H),1.91–1.86(m,2H),1.66(d,J=7.9Hz,2H),1.56(s,2H).LCMS:m / z=264.1[M+H] + .

[0901] Synthesis of Intermediate 17-5

[0902] To a mixture of 17-4 (250 mg, 949.21 μmol) and methyl (2S)-2-(tert-butoxycarbonylamino)-4-oxobutanoate (241.45 mg, 1.04 mmol) in dichloroethane (4 mL) was added sodium triacetoxyborohydride (301.76 mg, 1.42 mmol) and acetic acid (85.50 mg, 1.42 mmol) at 0°C. The mixture was stirred at 25°C for 2 hours. The reaction solution was diluted with methanol and then concentrated in vacuo. The concentrate was dissolved in dichloromethane and saturated aqueous sodium bicarbonate solution. The organic phase was separated and the aqueous layer was extracted with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered, and concentrated in vacuo to give the crude product. The crude product was purified by column chromatography (0-10% methanol: dichloromethane) to give 17-5 (265.00 mg, 553.67 μmol, 58.33% yield), LCMS: m / z = 479.4 [M+H] + .

[0903] Synthesis of Intermediate 17-6

[0904] At 25 ° C, trifluoroacetic acid (1 mL) was added to a solution of 17-5 (265 mg, 553.67 μmol) in dichloromethane (2 mL). The mixture was stirred at 25 ° C for 2 hours. The raw material was converted into the product. The solvent was removed by rotary evaporation and the residue was diluted with water. The pH value of the solution was then adjusted to 7-8 with aqueous sodium bicarbonate solution. It was then extracted with dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the crude product 17-6 (200.00 mg, crude product) as a yellow oil. 1 H NMR (400MHz, DMSO-d6) δ7.01(d,J=7.3Hz,1H),6.24(d,J=7.2Hz,2H),3.59(s,3H),3.27–3.16(m,6H),2.59(t,J=6.2Hz,2H),2.39(dt, J=13.7,7.7Hz,6H),1.93(s,2H),1.71(d,J=12.6Hz,4H),1.51(dd,J=20.7,8.5Hz,4H),1.41–1.32(m,2H).LCMS: (ESI)m / z=379.3[M+H] + .

[0905] Synthesis of Intermediate 17-7

[0906] A mixture of 17-6 (200 mg, 528.39 μmol) and 7-benzyloxy-4-chloroquinazoline (143.04 mg, 528.35 μmol) in acetonitrile (5 mL) was refluxed at 90° C. for 16 hours. After cooling to room temperature, the solvent was removed and the residue was purified by column chromatography (methanol: dichloromethane = 0-3%) to give 17-7 (120.00 mg, 195.84 μmol, 37.06% yield) as a yellow oil. LCMS: (ESI) m / z=613.4 [M+H] + .

[0907] Synthesis of Intermediate 17-8

[0908] To a solution of 17-7 (200 mg, 326.39 μmol) in ethyl acetate (10 mL) was added palladium hydroxide on carbon (40 mg), and the reaction was heated to 70° C. under a hydrogen atmosphere and stirred for 16 hours. LCMS showed that the starting material was consumed and the product was detected. The reaction mixture was cooled to room temperature. The reaction mixture was filtered, the precipitated solid was washed with ethyl acetate, and the filtrate was concentrated under vacuum to give 17-8 (130.00 mg, crude product) as a yellow oil. LCMS: (ESI) m / z=523.4[M+H] + ; 1H NMR (400MHz, DMSO-d6) δ10.33(s,1H),8.34(d,J=7.0Hz,1H),8.27(s,1H),8.11(d,J=9. 1Hz,1H),6.99(s,1H),6.91(d,J=6.6Hz,2H),6.16(s,1H),6.09(d,J=7.2Hz,1H),4.80( s,1H),3.59(s,3H),3.20–3.16(m,2H),3.07(s,3H),2.63–2.51(m,5H),2.38–2.25(m,3 H), 1.96 (d, J = 20.3Hz, 2H), 1.74–1.67 (m, 2H), 1.56–1.25 (m, 6H), 1.22 (d, J = 9.7Hz, 2H).

[0909] Synthesis of Intermediate 17-9

[0910] To a solution of 17-8 in N,N-dimethylformamide (3 mL) was added potassium carbonate (68.65 mg, 497.48 μmol) and 1-azido-2-[2-[2-[2-(2-bromoethoxy)ethoxy]ethoxy]-ethane (113.59 mg, 348.23 μmol), and the resulting reaction mixture was heated at 80 ° C for 3 hours. LCMS showed that the starting material was consumed and the product was detected. The reaction solution was cooled to ambient temperature, quenched with water, and extracted with ethyl acetate. The combined organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to give 17-9 (190.00 mg, crude product) as a yellow oil. LCMS: (ESI) m / z = 768.6 [M + H] + .

[0911] Synthesis of compound 17

[0912] To a solution of 17-9 (190 mg, 247.42 μmol) in tetrahydrofuran (3 mL) were added water (1 mL) and LiOH·OH (51.91 mg, 1.24 mmol), and the resulting reaction mixture was stirred at 25 ° C for 2 hours. LC-MS showed that the starting material was consumed and the product was detected. The reaction mixture was filtered and concentrated. The residue was subjected to high performance liquid chromatography reverse phase preparation to give compound 17 (25 mg, 33.16 μmol, 13.40% yield) as a white solid. LCMS: (ESI) m / z = 754.6 [M + H] + ; 1H NMR (400MHz, DMSO-d6) δ8.36(s,1H),8.18(d,J=4.4Hz,1H),8.12(d,J=9.1Hz,1H),7.17-7.12(m,1H),7.09(d,J=2 .5Hz,1H),6.97(d,J=7.1Hz,1H),6.32(s,1H),6.16(d,J=7.4Hz,1H),4.60(d,J=5.8Hz,1H),4.23(t,J=4.4Hz,2H), 3.80(t,J=4.3Hz,2H),3.62-3.52(m,11H),3.38(s,8H),3.21(t,J=5.1Hz,2H),3.14(s,3H),2.80-2.70(m,2H),2.6 7-2.54(m,4H),2.47-2.43(m,1H),2.34(t,J=7.3Hz,2H),2.10-1.91(m,2H),1.76-1.70(m,2H),1.57-1.34(m,4H).

[0913] Synthesis of compound 18

[0914] Synthesis of Intermediate 18-1

[0915] Under nitrogen protection, N,N-diisopropylethylamine (2.50 g, 19.36 mmol) was added to a solution of 14-5 (1.35 g, 3.87 mmol) in dichloromethane (20 mL). The reaction solution was cooled to 0°C and methyl (E)-4-bromobutyrate (693.07 mg, 3.87 mmol) was slowly added. The reaction was stirred at room temperature for 18 h. LCMS showed product formation. The reaction mixture was diluted with 30 mL of water. The organic phase was separated and the aqueous layer was further extracted with dichloromethane (50 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column elution with 0-20% methanol / dichloromethane to obtain 18-1 (0.786 g, 2.34 mmol, yield 60.39%) as a yellow oil, which was stored at 0-4°C. LCMS: m / z = 330.2 [M+H] + ; 1H NMR (400MHz, CDCl3) δ7.08 (d, J = 6.7Hz, 1H), 6.97 (dt, J = 15.5, 5.9Hz, 1H), 6.33 (d, J = 7. 1Hz,1H),5.97(d,J=15.7Hz,1H),3.73(s,3H),3.40(s,2H),3.29–3.15(m,2H),2.83(d,J =7.4Hz,1H),2.76–2.61(m,4H),2.59–2.41(m,3H),2.15(p,J=7.9Hz,2H),2.01(dd,J=1 2.4,8.0Hz,1H),1.95–1.86(m,2H),1.73(q,J=7.6Hz,2H),1.45(dq,J=14.8,6.8Hz,1H).

[0916] Synthesis of intermediate 18-2

[0917] To a solution of 18-1 (530 mg, 1.61 mmol) in dioxane (3 mL) were added potassium hydroxide (3.8 M, 1.27 mL) and 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (1.77 g, 8.04 mmol). The mixture was deoxygenated with argon for 15 minutes. In a separate bottle, R-BINAP (120.21 mg, 193.06 μmol) and [RhCl(COD)]2 (39.66 mg, 80.44 μmol) were dissolved in 1 mL of 1,4-dioxane and deoxygenated with argon for 15 minutes each. The mixture was mixed and deoxygenated with argon for 10 minutes. The reaction mixture was stirred at 50°C for 18 hours. LCMS indicated the formation of the product. The reaction mixture was diluted with 5 mL of water. The organic phase was separated, and the aqueous phase was further extracted with ethyl acetate (20 mL x 2). The combined organic phases were dried over sodium sulfate, filtered, and concentrated. The crude product was purified by preparative HPLC to afford 18-2 (221.00 mg, 516.57 μmol, 32.11% yield, 99% purity) as an off-white solid. LCMS: m / z = 424.4 [M+H] + ; 1H NMR (400MHz, CDCl3) δ7.14–7.05(m,2H),6.74–6.59(m,3H),6.31(d,J=7.3Hz,1H),5.31(s,1H),3.58(d,J=6.4Hz,3H),3.38(t,J= 5.2Hz,2H),3.25(p,J=7.3Hz,1H),2.90–2.29(m,14H),2.19–2.01(m,2H),1.76–1.56(m,2H),1.36(ddt,J=13.6,9.6,6.9Hz,1H).

[0918] Synthesis of intermediate 18-3

[0919] To a stirred solution of 18-2 (150 mg, 354.15 μmol) in N,N-dimethylformamide (3 mL) were added potassium carbonate (97.89 mg, 708.30 μmol) and 1-azido-2-[2-[2-[2-[2-(2-bromoethoxy)ethoxy]ethoxy]butyrate ethoxyethane (161.73 mg, 495.81 μmol). The reaction was stirred at 100°C overnight. LCMS indicated the formation of the product. The reaction was cooled to room temperature, quenched with water, and extracted with ethyl acetate. The organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. Purification on a silica gel column (MeOH:DCM = 0-10%) afforded 18-3 (130.00 mg, 192.43 μmol, 54.33% yield, 99% purity) as a yellow oil. LCMS: m / z = 669.5 [M-N2+H] + ; 1 H NMR (400MHz, CDCl3) δ7.23–7.07(m,2H),6.83–6.69(m,3H),6.32(d,J=7.4H z,1H),4.15–4.05(m,2H),3.87–3.79(m,2H),3.75–3.61(m,16H),3.56(s,3H) ),3.42–3.35(m,4H),2.86(dd,J=15.5,6.4Hz,1H),2.69(t,J=6.4Hz,2H),2 .59–2.31(m,5H),2.25–1.84(m,10H),1.78–1.66(m,2H),1.44–1.36(m,1H).

[0920] Synthesis of compound 18

[0921] To a solution of 18-3 (130 mg, 194.37 μmol) in tetrahydrofuran / water (3.0 mL) was added lithium hydroxide (18.62 mg, 777.49 μmol). The reaction mixture was stirred at 25°C for 18 h, and LCMS indicated the formation of the product. The solvent was removed by swirl, and the crude product was dissolved in ACN / H₂O (1:1) and purified by HPLC (Nanochrom ChromCore C₁8 21.2×250 mm, 10 μm, H₂O-ACN 40-60%) to afford 18 (55.73 mg, 81.22 μmol, 41.78% yield, 95.423% purity, SFC: ee% = 64.89%) as a yellow oil. LCMS: m / z = 655.6 [M+H] + ; 1 H NMR (400MHz, CDCl3) δ7.21(t,J=8.0Hz,1H),7.15–7.04(m,1H),6.84–6.71(m,3H),6.29(d,J=7.1Hz,1H),4.16–4.08(m,2H),3.89–3.83(m,2 H),3.77–3.65(m,14H),3.48–3.37(m,5H),3.08–2.66(m,8H),2.59–2 .41(m,3H),2.29(s,1H),2.20–1.98(m,2H),1.88(d,3H),1.52(d,2H).

[0922] The compound was purified by SFC (chromatographic column: DAICEL CHIRALPAK AD (250mm*50mm, 10μm), mobile phase: [carbon dioxide-acetonitrile / methanol (0.1% ammonia water)], B%: 50%, isobaric elution mode) to obtain yellow oily compound isomer1:18-P1 and yellow oily compound isomer2:18-P2.

[0923] Isomer1:294.1mg

[0924] MS m / z(ESI):655.4[M+H] + ;

[0925] Analytical chiral SFC: RT = 0.963 min, >99.5% purity, Chiralpak AD-3 50*4.6 mm ID, 3 μm, carbon dioxide-methanol / acetonitrile = 4 / 1 (0.05% DEA), B%: 40%, flow rate 4 mL / min. 1H NMR (400MHz, CDCl3) δ7.26-7.19 (m, 1H), 7.14 (d, J = 7.0Hz, 1H), 6.84-6.74 (m,3H),6.30(d,J=7.3Hz,1H),4.19-4.09(m,2H),3.91-3.84(m,2H),3.81 -3.59(m,15H),3.48-3.37(m,5H),3.09-2.91(m,2H),2.81-2.66(m,5H),2 .59-2.36(m,3H),2.35-1.98(m,3H),1.97-1.82(m,3H),1.68-1.39(m,2H).

[0926] Isomer2:88.21mg

[0927] MS m / z(ESI):655.4[M+H] + ;

[0928] Analytical chiral SFC: RT = 1.465 min, 98.4% purity, Chiralpak AD-3 50*4.6 mm ID, 3 μm, carbon dioxide-methanol / acetonitrile = 4 / 1 (0.05% DEA), B%: 40%, flow rate 4 mL / min.

[0929] 1 H NMR (400MHz, CDCl3) δ7.23(t,J=7.9Hz,1H),7.09(d,J=7.5Hz,1H),6.85-6.69(m,3H),6.32( d,J=7.3Hz,1H),5.71-5.34(m,1H),4.17-4.07(m,2H),3.87(t,J=4.8Hz,2H),3.77-3.55(m, 15H),3.45-3.37(m,4H),3.36-3.00(m,4H),2.88-2.78(m,3H),2.71(t,J=6.3Hz,2H),2.56( t,J=7.3Hz,3H),2.40-2.25(m,1H),2.22-2.06(m,1H),1.96-1.71(m,4H),1.69-1.52(m,1H).

[0930] Synthesis of compound 20

[0931] Synthesis of Intermediate 20-1

[0932] To a solution of 18-1 (600 mg, 1.82 mmol) in dioxane (8 mL) were added potassium hydroxide (3.8 M, 1.44 mL) and 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (2.00 g, 9.11 mmol). The mixture was deoxygenated with argon for 15 minutes. In a separate bottle, R-BINAP (136.09 mg, 218.56 μmol) and [RhCl(COD)]2 (44.90 mg, 91.06 μmol) were dissolved in 3 mL of 1,4-dioxane and deoxygenated with argon for 15 minutes each. The mixture was mixed and deoxygenated with argon for 10 minutes. The reaction mixture was stirred at 50°C for 18 hours. LCMS indicated the formation of the product. The reaction mixture was diluted with 5 mL of water. The organic phase was separated, and the aqueous phase was further extracted with ethyl acetate (20 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to afford 20-1 (206.00 mg, 481.51 μmol, 26.44% yield, 99% purity) as a yellow oil. LCMS: m / z = 424.3 [M+H] + ; 1 H NMR (400MHz, CDCl3) δ7.07(d,J=7.3Hz,1H),6.96(dd,J=8.4,5.7Hz,2H),6.62–6.57(m,2H),6.34–6.30(m,1H),5.03(s,1H),3.55(s,3H),3.41–3. 34(m,2H),3.19(p,J=7.2,6.8Hz,1H),2.90–2.20(m,14H),2.05(dq,J=25 .6, 8.3Hz, 2H), 1.66 (p, J = 7.2Hz, 2H), 1.34 (td, J = 13.2, 12.5, 6.2Hz, 1H).

[0933] Synthesis of Intermediate 20-2

[0934] To a stirred solution of 20-1 (206 mg, 486.37 μmol) in N,N-dimethylformamide (3 mL) were added potassium carbonate (134.44 mg, 972.74 μmol) and 1-azido-2-[2-[2-[2-[2-(2-bromoethoxy)ethoxy]ethoxy]butyrate ethoxyethane (222.11 mg, 680.92 μmol). The reaction was stirred at 100°C overnight. LCMS indicated product formation. The reaction was cooled to room temperature, quenched with water, and extracted with ethyl acetate. The organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. Purification on a silica gel column (MeOH:DCM = 0-10%) afforded 20-2 (214.00 mg, 310.37 μmol, 63.81% yield, 97% purity) as an orange oil. LCMS: m / z = 669.5 [M-N2+H] + ; 1 H NMR (400MHz, CDCl3) δ7.12–7.04(m,3H),6.82(d,J=8.7Hz,2H),6.32(d,J=7.3Hz,1H),4. 11–4.06(m,2H),3.85–3.81(m,2H),3.72–3.70(m,2H),3.66(d,J=1.7Hz,12H),3.54(d,J =1.5Hz,3H),3.39–3.35(m,3H),2.86(dd,J=15.3,6.1Hz,1H),2.68(t,J=6.3Hz,3H),2.6 1–2.27(m,6H),2.24–1.83(m,9H),1.69(ddt,J=10.9,8.3,4.0Hz,2H),1.44–1.33(m,1H).

[0935] Synthesis of compound 20

[0936] Lithium hydroxide (38.32 mg, 1.60 mmol) was added to a solution of 20-2 (214 mg, 319.97 μmol) in tetrahydrofuran / water (4.0 mL). The reaction mixture was stirred at 25°C for 18 h. LCMS indicated the formation of the product. The reaction solution was spin-dried. The crude product was dissolved in ACN / H2O (1:1) and purified by HPLC (Nanochrom ChromCore C18 21.2×250 mm, 10 μm, (0.1% FA) H2O-ACN 35-54%) to give compound 20 (102.20 mg, 148.45 μmol, 46.40% yield, 95% purity, SFC: ee% = 55.6%) as a yellow oil. LCMS: m / z = 655.5 [M+H] + ;1 H NMR (400MHz, CDCl3) δ7.11–7.01 (m, 3H), 6.83 (d, J = 8.7Hz, 2H), 6.27 (t, J = 7. 1Hz,1H),4.12–4.06(m,2H),3.85–3.79(m,2H),3.73–3.63(m,16H),3.37(q,J =6.0,5.0Hz,5H),3.29–3.06(m,1H),3.04–2.62(m,7H),2.59–2.23(m,4H),2. 19–1.95(m,2H),1.92–1.75(m,3H),1.51(dtd,J=55.2,10.1,9.0,5.0Hz,2H).

[0937] The compound was purified by SFC (chromatographic column: DAICEL CHIRALPAK AD (250mm*50mm, 10μm), mobile phase: [carbon dioxide-acetonitrile / methanol (0.1% ammonia water)], B%: 50%, isobaric elution mode) to obtain yellow oily compound isomer1:20-P1 and yellow oily compound isomer2:20-P2.

[0938] Isomer1:800.0mg

[0939] MS m / z(ESI):655.4[M+H] + ;

[0940] Analytical chiral SFC: RT = 1.325 min, >99.5% purity, Chiralpak AD-3 50*4.6 mm ID, 3 μm, carbon dioxide-methanol / acetonitrile = 4 / 1 (0.05% DEA), B%: 40%, flow rate 4 mL / min. 1 H NMR (400MHz, CDCl3) δ7.14-7.10(m,3H),6.89-6.86(m,2H),6.30(d,J=7.2Hz,1H),4.14-4.12(m,2H),3.87-3.80(m,2H),3.7 5-3.67(m,15H),3.42-3.40(m,6H),2.99(m,2H),2.74-2.69(m,5H),2.55-2.50(m,3H),2.20-1.87(m,5H),1.63-1.44(m,2H).

[0941] Isomer2:88.2mg

[0942] MS m / z(ESI):655.4[M+H] + ;

[0943] Analytical chiral SFC: RT = 1.835 min, 97.3% purity, Chiralpak AD-3 50*4.6 mm ID, 3 μm, carbon dioxide-methanol / acetonitrile = 4 / 1 (0.05% DEA), B%: 40%, flow rate 4 mL / min.

[0944] 1 H NMR (400MHz, CDCl3) δ7.14-7.07(m,3H),6.87(d,J=8.4Hz,2H),6.32(d,J=7.6Hz,1H),4.13-4.11(m,2H),3.86-3.74(m,2H),3.73-3.67(m, 15H),3.42-3.40(m,5H),3.30-3.05(m,4H),2.95-2.75(m,3H),2.73- 2.69(m,2H),2.59-2.56(m,2H),2.40-2.05(m,2H),1.93-1.61(m,5H).

[0945] Compounds 53, 57, 58, 59, 61, 72, 83, 86, 87, 49, 71, and 84 were synthesized in the same manner as 18 and 20. The general synthesis method is as follows:

[0946] Synthesis of compounds 53, 57, 58, 59, 61, 72, 83, 86, and 87

[0947] Compound 53: Yellow oily compound, 98.08% purity, SFC: ee%: 55.52%. MS m / z (ESI): 673.5 [M+H] + ; 1 H NMR (400MHz, CDCl3) δ7.08-6.92(m,2H),6.67-6.47(m,2H),6.29-6.16(m,1H),4.0 7-3.98(m,2H),3.77(t,J=4.8Hz,2H),3.68-3.54(m,14H),3.37-3.24(m,4H),3.23- 3.00(m,1H),2.97-2.79(m,2H),2.75-2.56(m,5H),2.50-2.31(m,3H),2.30-2.15( m,1H),2.13-1.89(m,2H),1.87-1.71(m,3H),1.57-1.30(m,2H),1.29-1.05(m,1H).

[0948] Compound 57: Yellow oily compound, >99.5% purity, SFC: ee%: 26.98%. MS m / z (ESI): 729.3 [M+H] + ; 1 H NMR (400MHz, CDCl3) δ7.16(d,J=7.1Hz,1H),6.39(s,2H),6.36-6.24(m,2H),4.10(d,J=4.8Hz,4H),3.86(d ,J=5.0Hz,2H),3.77-3.73(m,4H),3.72-3.67(m,12H),3.48-3.46(m,3H),3.42-3.39(m,2H),3.23-3.15(m, 1H),3.07-2.93(m,2H),2.90-2.82(m,2H),2.80-2.69(m,5H),2.64-2.57(m,2H),2.54-2.45(m,2H),2.41-2 .27(m,2H),2.20-2.16(m,1H),2.10-2.04(m,1H),1.96-1.91(m,2H),1.67-1.57(m,1H),1.54-1.42(m,1H).

[0949] Compound 58: Yellow oily compound, 99.0% purity, SFC: ee%: 88.76%. MS m / z (ESI): 781.3 [M+H] + ; 1 H NMR(400MHz, DMSO-d6)δ7.02(d,J=7.3Hz,1H),6.71-6.63(m,3H),6.31-6.21(m, 2H),4.14-4.03(m,2H),3.74-3.71(m,2H),3.62-3.57(m,5H),3.56-3.52(m,10H) ,3.38(s,2H),3.25-3.22(m,2H),2.84-2.57(m,8H),2.44-2.33(m,4H),2.27(s, 1H),2.07-1.85(m,2H),1.78-1.69(m,2H),1.65-1.55(m,2H),1.39-1.29(m,1H).

[0950] Compound 59: Yellow oily compound, 99.4% purity, SFC: ee%: 41.84%. MS m / z (ESI): 731.5 [M+H] + ; 1H NMR(400MHz, CDCl3)δ7.57(t,J=8.9Hz,2H),7.45(t,J=7.5Hz,2H),7.41-7 .32(m,1H),7.18-7.08(m,1H),7.06-6.92(m,2H),6.80-6.67(m,1H),6.37- 6.22(m,1H),4.21(s,2H),3.90(t,J=4.6Hz,2H),3.76(d,J=5.0Hz,2H),3.7 3-3.64(m,11H),3.51-3.19(m,6H),3.07-2.30(m,12H),2.23-1.50(m,7H).

[0951] Compound 61: Yellow oily compound, 99.4% purity, SFC: ee%: 72.42%. MS m / z (ESI): 731.5 [M+H] + ; 1 H NMR (400MHz, CDCl3) δ7.62-7.52(m,2H),7.44-7.38(m,2H),7.36-7.30(m,1H),7.19-7.05(m ,3H),6.94(d,J=8.3Hz,1H),6.36-6.27(m,1H),4.11(t,J=4.7Hz,2H),3.78(t,J=4.5Hz,2H), 3.70-3.63(m,10H),3.62-3.59(m,4H),3.51-3.36(m,5H),3.33-3.14(m,2H),2.84(m,4H),2. 81-2.69(m,4H),2.64-2.41(m,3H),2.33-2.00(m,3H),1.97-1.81(m,3H),1.53-1.37(m,1H).

[0952] Compound 72: yellow solid compound, >99.5% purity, SFC: ee%: 21.66%. MS m / z (ESI): 781.5 [M+H] + ; 1H NMR (400MHz, CDCl3) δ7.88-7.79(m,2H),7.58(dd,J=8.3,19.1Hz,1H),7.53-7.41(m,2H),7.41-7.33(m,2H),7.23(dd,J=3.7,7.6Hz,1H) ,7.11(dd,J=7.2,19.6Hz,1H),6.95-6.80(m,2H),6.30(dd,J=7.3,10.5Hz,1H),4.00(q,J=4.7Hz,2H),3.65-3.60(m,6H),3.58-3.53(m,3 H),3.50-3.39(m,7H),3.38-3.35(m,2H),3.23(q,J=4.8Hz,3H),3.18-3.07(m,3H),3.06-2.89(m,3H),2.88-2.73(m,2H),2.73-2.67(m, 2H),2.66-2.54(m,2H),2.48(ddd,J=5.9,12.3,18.3Hz,1H),2.40-2.27(m,1H),2.24-1.99(m,2H),1.89-1.74(m,2H),1.70-1.39(m,2H).

[0953] Compound 83: Yellow oily compound, >99.5% purity, SFC: ee%: 72.38%. MS m / z (ESI): 673.6 [M+H] + ; 1 H NMR(400MHz, CDCl3)δ7.16(d,J=7.3Hz,1H),7.02-6.79(m,3H),6.30(d,J=7.3Hz,1H) ,4.19(t,J=4.9Hz,2H),3.88(t,J=4.9Hz,2H),3.80-3.73(m,2H),3.72-3.67(m,11H), 3.48-3.35(m,5H),3.05-2.90(m,2H),2.83-2.77(m,1H),2.76-2.65(m,4H),2.63-2.5 7(m,1H),2.51-2.39(m,3H),2.19-1.99(m,4H),1.97-1.82(m,4H),1.48-1.38(m,1H).

[0954] Compound 86: Yellow oily compound, >99.5% purity, SFC: ee%: 62.76%. MS m / z (ESI): 673.4 [M+H] + ; 1H NMR (400MHz, CDCl3) δ7.20-7.08(m,1H),7.05-6.95(m,1H),6.88-6.65(m,2H),6.36-6.25(m,1 H),4.24-4.17(m,2H),3.89(t,J=4.7Hz,2H),3.79-3.73(m,2H),3.73-3.65(m,11H),3.47-3.3 8(m,4H),3.01-2.93(m,1H),2.80(d,J=6.4Hz,2H),2.75-2.66(m,4H),2.58(d,J=7.1Hz,1H),2 .51-2.37(m,4H),2.17-2.01(m,3H),1.97-1.76(m,4H),1.64-1.53(m,1H),1.45-1.35(m,1H).

[0955] Compound 87: Yellow oily compound, 98.6% purity, SFC: ee%: 35.20%. MS m / z (ESI): 695.4 [M+H] + ; 1 H NMR(400MHz, CDCl3)δ7.15-7.06(m,1H),6.57-6.45(m,3H),6.36-6.27(m,1H),4.16-4.05(m,2H), 3.85(t,J=4.9Hz,2H),3.80-3.63(m,15H),3.49-3.34(m,5H),3.17(m,1H),3.03-2.94(m,1H),2.8 8-2.80(m,1H),2.78-2.66(m,4H),2.59-2.41(m,3H),2.34(m,1H),2.19-2.01(m,2H),1.97-1.70( m,5H),1.68-1.52(m,1H),1.50-1.38(m,1H),0.96(ddd,J=1.5,4.6,9.0Hz,2H),0.75-0.64(m,2H).

[0956] Synthesis of compounds 49, 71, and 84

[0957] Compound 49: Yellow oily compound, 98.4% purity, SFC: ee%: 78.58%. MS m / z (ESI): 781.3 [M+H] + ; 1H NMR (400MHz, DMSO-d6) δ8.31-8.24(m,1H),8.17(s,1H),7.78(d,J=7.8Hz,1H),7.53(t,J=7.4Hz,2H),7.38(s,3H),7.34(d,J =7.9Hz,1H),7.05(t,J=7.4Hz,2H),6.40(s,1H),6.27(d,J=7.3Hz,1H),4.40-4.28(m,2H),3.96-3.89(m,2H),3.72-3.68(m,2 H),3.63-3.49(m,13H),3.40-3.31(m,4H),3.27-3.21(m,2H),2.98(s,1H),2.92-2.84(m,2H),2.83-2.76(m,1H),2.71-2.57( m,4H),2.43(t,J=7.9Hz,2H),2.13-2.02(m,1H),2.01-1.90(m,1H),1.79-1.71(m,2H),1.70-1.57(m,2H),1.50-1.33(m,2H).

[0958] Compound 71: Yellow oily compound, 99.2% purity, SFC: ee%: 54.01%. MS m / z (ESI): 781.4 [M+H] + ; 1 H NMR (400MHz, CDCl3) δ8.34 (d, J = 8.4Hz, 1H), 7.56-7.48 (m, 2H), 7.47-7.39 (m,3H),7.29(s,3H),7.17-7.07(m,1H),6.86(d,J=7.5Hz,1H),6.36-6.27( m,1H),4.35(t,J=4.9Hz,2H),4.04(t,J=4.9Hz,2H),3.89-3.81(m,2H),3.7 9-3.52(m,13H),3.50-3.35(m,5H),3.33-2.44(m,11H),2.41-1.39(m,8H).

[0959] Compound 84: Yellow oily compound, 97.8% purity, SFC: ee%: 24.20%. MS m / z (ESI): 731.4 [M+H] + ; 1H NMR (400MHz, CDCl3) δ7.58-7.45(m,4H),7.28-7.20(m,2H),7.16-7.06(m,1H),7.03-6.95(m,2H),6.30(t,J=7.0Hz,1H),4.23 -4.13(m,2H),3.95-3.86(m,2H),3.79-3.74(m,2H),3.64(s,12H),3.58-2.64(m,14H),2.61-2.25(m,1H),2.61-1.36(m,10H).

[0960] Synthesis of compound 85

[0961] Synthesis of intermediate 85-2

[0962] At 25°C, oxalyl chloride (289.3 mg, 2.28 mmol) was dissolved in dichloromethane (6 mL). After cooling to -65°C, dimethyl sulfoxide (534.2 mg, 6.84 mmol) was added dropwise to the reaction solution. After the addition was complete, the reaction was stirred at -65°C for 30 minutes. Compound 85-1 (500.0 mg, 1.90 mmol) was then added to the reaction solution, and the reaction was stirred at -65°C for 30 minutes. Triethylamine (1.38 g, 13.7 mmol) was added, and the reaction was stirred at -65°C for 20 minutes, then raised to 15°C and reacted for 2 hours. After the reaction was completed, water (10 mL) was added to dilute the mixture and the mixture was extracted with dichloromethane (6 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and dried to obtain the crude product, compound 85-2 (400.0 mg), as a colorless oil. The crude product was used directly in the next reaction. 1 H NMR (400MHz, CDCl3) δ9.72 (s, 1H), 4.15 (d, J = 0.7Hz, 2H), 3.74-3.64 (m, 14H), 3.38 (t, J = 5.1Hz, 2H).

[0963] Synthesis of intermediate 85-3

[0964] At 25°C, compound 18-1 (4.00 g, 12.1 mmol) was dissolved in tetrahydrofuran (100 mL), and then di-tert-butyl dicarbonate (3.44 g, 15.8 mmol) was added at 25°C. The mixture was cooled to 0°C under nitrogen, and lithium bis(trimethylsilyl)amide (14.6 mL, 1 M, 14.6 mmol) was slowly added dropwise to the reaction solution. The mixture was stirred at 0°C for 0.5 hours. After completion of the reaction, saturated ammonium chloride solution (150 mL) was added to dilute the mixture and extracted with ethyl acetate (100 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and dried. The residue was purified by flash silica gel chromatography (eluent: 0-50% tetrahydrofuran / ethyl acetate) to obtain compound 85-3 (2.20 g, 42.18% yield) as a yellow oil. 1 H NMR (400MHz, CDCl3) δ7.30-7.26 (m, 1H), 6.98 (td, J=6.1, 15.7Hz, 1H), 6.78 (d, J=7 .6Hz,1H),5.98(td,J=1.6,15.6Hz,1H),3.81-3.68(m,5H),3.31-3.14(m,2H),2.8 5(t,J=7.7Hz,1H),2.76-2.63(m,5H),2.51-2.41(m,1H),2.28-2.12(m,2H),2.09- 1.98(m,1H),1.90(quin,J=6.4Hz,2H),1.80(q,J=7.6Hz,2H),1.43-1.58(m,10H).

[0965] Synthesis of Intermediate 85-5

[0966] At 25°C, compound 85-3 (400.0 mg, 1.21 mmol) was dissolved in dioxane (12 mL), and compound 85-4 (420.0 mg, 1.25 mmol) and potassium hydroxide (156.8 mg, 2.79 mmol) were added. (R)-(+)-2,2-bis(diphenylphosphino)-1,1-binaphthyl (58.0 mg, 93.1 μmol) and (1,5-cyclooctadiene)chlororhodium(I) dimer (23.0 mg, 46.6 μmol) were added under nitrogen protection. The mixture was stirred at 80°C under nitrogen protection for 4 hours. After the reaction was completed, water (20 mL) was added to dilute the mixture and the mixture was extracted with ethyl acetate (15 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and dried. The residues from other batches were combined and purified by flash silica gel chromatography (eluent: 0-50% tetrahydrofuran / petroleum ether, later changed to 0-5% methanol / dichloromethane) to afford compound 85-5 (220.0 mg) as a dark yellow oil. The crude product was used directly in the next reaction. MS m / z (ESI): 627.6 [M+H] + .

[0967] Synthesis of Intermediate 85-7

[0968] At 25 ° C, compound 85-5 (200.0 mg) was dissolved in dichloromethane (4 mL), and compound 85-2 (82.0 mg, 313.98 μmol) and acetic acid (9.20 mg, 153.16 μmol) were added. Cool to 0 ° C and stir to react for 30 minutes. Sodium triacetoxyborohydride (48.7 mg, 229.7 μmol) was added. Stir at 25 ° C for 6 hours. After the reaction is completed, water (10 mL) was added to dilute and extracted with dichloromethane (6 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and dried. The residues from other batches were combined and purified by flash silica gel chromatography (eluent: 0-20% tetrahydrofuran / petroleum ether, then changed to 0-5% methanol / dichloromethane) to obtain a yellow oil compound 85-7 (160.0 mg). MS m / z (ESI): 872.6 [M+H] + .

[0969] Synthesis of compound 85

[0970] Compound 85-7 (400.0 mg) was dissolved in dichloromethane (2 mL) at 25°C, and then hydrochloric acid / dioxane (4 M, 10 mL) was added at 25°C. The mixture was stirred at 25°C for 2 hours. After completion of the reaction, it was filtered and dried. The residue was purified by high performance liquid chromatography (column: C18 150*40 mm, mobile phase: [water (formic acid)-acetonitrile], gradient: 7% to 47% B, time: 9 min) and lyophilized to obtain white solid compound 85 (36.0 mg, 42.48% yield, 96.9 purity, SFC: ee% = 55.06%). MS m / z (ESI): 772.3 [M+H] + ; 1 H NMR (400MHz, CDCl3) δ10.37(s,1H),8.52(s,1H),7.47(d,J=8.2Hz,2H),7.25-7.21(m,1H),7.20-7.13(m,2H),6.88-6. 82(m,1H),6.67(d,J=7.6Hz,1H),6.62(dd,J=1.3,7.6Hz,1H),6.28(d,J=7.2Hz,1H),4.25-4.14(m,2H),3.73-3.69(m,2 H),3.68-3.59(m,14H),3.51(t,J=5.9Hz,2H),3.46(t,J=4.5Hz,4H),3.37(t,J=5.0Hz,3H),3.34-3.10(m,3H),3.04(s, 2H),2.97-2.85(m,3H),2.76-2.61(m,4H),2.41-2.29(m,1H),2.25-2.13(m,1H),1.95-1.74(m,4H),1.71-1.59(m,1H).

[0971] Synthesis of 5FAM-labeled compounds

[0972] General method of synthesis:

[0973] Propargylamine-5FAM (1.1 equiv.) was dissolved in a mixture of isopropanol and water (1:1). Azide (1.0 equiv.), CuSO4 (3.0 equiv.), and ascorbic acid (4.0 equiv.) were added sequentially. The mixture was stirred at room temperature for 2 hours. LCMS confirmed the reaction was complete, and the filtrate was filtered. The filtrate was purified by preparative chromatography to yield the 5FAM-labeled compound as a yellow solid.

[0974] 1-5FAM: LCMS: (ESI)m / z=600.6[M+2H] / 2+ ; 400.7[M+3H] / 3 +

[0975] HPLC: 97.50% (214 nm), RT = 17.80 min. Mobile phase: A: Water (0.05% TFA) B: ACN (0.05% TFA). Gradient: 20% B for 3 minutes, increasing to 80% B over 20 minutes, then increasing to 95% B over 2 minutes, holding for 5 minutes, and decreasing to 20% B over 0.1 minutes. Flow rate: 1.0 mL / min. Column: XBridge peptide BEH column C18, 4.6 x 150 mm, 3.5 μm, Column temperature: 40℃.

[0976] 1NG-5FAM:

[0977] LCMS: (ESI)m / z=657.3[M+2H] / 2+

[0978] HPLC: 97.06% (214 nm), RT = 15.98 min. Mobile phase: A: Water (0.05% TFA) B: ACN (0.05% TFA). Gradient: 5% B for 3 minutes, increasing to 65% B over 20 minutes, then increasing to 95% B over 2 minutes, holding for 5 minutes, and decreasing to 5% B over 0.1 minutes. Flow rate: 1.0 mL / min. Column: XBridge peptide BEH column C18, 4.6 x 150 mm, 3.5 μm, Column temperature: 40℃.

[0979] 1-3-5FAM:

[0980] LCMS: (ESI)m / z=1184.3[M+3H] / 3 + ;888.7[M4+H] / 4 + ;711.3[M+5H] / 5 +

[0981] HPLC: 83.92% (214 nm), RT = 13.95 min. Mobile phase: A: Water (0.05% TFA) B: ACN (0.05% TFA). Gradient: 20% B for 3 minutes, increasing to 80% B over 20 minutes, then increasing to 95% B over 2 minutes, holding for 5 minutes, and decreasing to 20% B over 0.1 minutes. Flow rate: 1.0 mL / min. Column: XBridge peptide BEH column C18, 4.6 × 150 mm, 3.5 μm, Column temperature: 40℃.

[0982] 4-5FAM: LCMS: (ESI)m / z=1212.7[M+H] +

[0983] Preparation conditions:

[0984] Chromatographic column: Gemini C18 21.2mm×250mm, 10μm, Mobile phase: A: Water (containing 10 mmol / L NH4HCO3) B: ACN; Gradient: 5% B to 65% B over 20 minutes. HPLC: 97.08% (214 nm), RT = 16.53 min. Mobile phase: A: Water (0.05% TFA) B: ACN (0.05% TFA). Gradient: 5% B for 3 minutes, then 65% B over 20 minutes, then 95% B over 2 minutes, held for 5 minutes, and then 5% B over 0.1 minutes. Flow rate: 1.0 mL / min. Column: XBridge peptide BEH column C18, 4.6×150 mm, 3.5 μm, Column temperature: 40℃.

[0985] 5-5FAM: LCMS: (ESI)m / z=613.5[M+2H] / 2 +

[0986] Preparation conditions:

[0987] Chromatographic column: Gemini C18 21.2mm×250mm, 10μm, Mobile phase: A: Water (containing 10 mmol / L NH4HCO3) B: ACN; Gradient: 5% B to 65% B over 20 minutes. HPLC: 95.26% (214 nm), RT = 18.53 min. Mobile phase: A: Water (0.05% TFA) B: ACN (0.05% TFA). Gradient: 5% B for 3 minutes, then 65% B over 20 minutes, then 95% B over 2 minutes, held for 5 minutes, and then 5% B over 0.1 minutes. Flow rate: 1.0 mL / min. Column: XBridge peptide BEH column C18, 4.6×150 mm, 3.5 μm, Column temperature: 40℃.

[0988] 6-5FAM: LCMS: (ESI)m / z=586.4[M+2H] / 2+

[0989] Preparation conditions:

[0990] Chromatographic column: Gemini C18 21.2mm×250mm, 10μm, Mobile phase: A: Water (containing 10 mmol / L NH4HCO3) B: ACN; Gradient: 5% B to 65% B over 20 minutes. HPLC: 96.93% (214 nm), RT = 17.53 min. Mobile phase: A: Water (0.05% TFA) B: ACN (0.05% TFA). Gradient: 5% B for 3 minutes, then 65% B over 20 minutes, then 95% B over 2 minutes, held for 5 minutes, and then 5% B over 0.1 minutes. Flow rate: 1.0 mL / min. Column: XBridge peptide BEH column C18, 4.6 × 150 mm, 3.5 μm, Column temperature: 40℃.

[0991] 7-5FAM: LCMS: (ESI)m / z=1156.5[M+H] + ; 579.0[M+2H] / 2 +

[0992] Preparation conditions:

[0993] Reversed phase chromatography column: Gemini C18 21.2mm×250mm, 10μm, Mobile phase: A: Water (containing 10 mmol / L NH4HCO3), B: Acetonitrile; Gradient: 5% B to 65% B over 20 minutes. HPLC: 95.99% (214 nm), RT = 18.55 min. Mobile phase: A: Water (0.05% TFA), B: ACN (0.05% TFA). Gradient: 5% B for 3 minutes, then 65% B over 20 minutes, then 95% B over 2 minutes, held for 5 minutes, and then 5% B over 0.1 minutes. Flow rate: 1.0 mL / min. Column: XBridge peptide BEH column C18, 4.6×150 mm, 3.5 μm, Column temperature: 40℃.

[0994] 8-5FAM: LCMS: (ESI)m / z=1182.5[M+H] + ; 591.5[M+2H] / 2 +

[0995] Preparation conditions:

[0996] Reversed phase chromatography column: Gemini C18 21.2mm×250mm, 10μm, Mobile phase: A: Water (containing 10 mmol / L NH4HCO3), B: Acetonitrile; Gradient: 5% B to 65% B over 20 minutes. HPLC: 96.34% (214 nm), RT = 18.16 min. Mobile phase: A: Water (0.05% TFA), B: ACN (0.05% TFA). Gradient: 5% B for 3 minutes, then 65% B over 20 minutes, then 95% B over 2 minutes, held for 5 minutes, and then 5% B over 0.1 minutes. Flow rate: 1.0 mL / min. Column: XBridge peptide BEH column C18, 4.6×150 mm, 3.5 μm, Column temperature: 40℃.

[0997] 16-5FMA:LCMS:(ESI)m / z=569.2[M+2H] / 2 +

[0998] Preparation conditions:

[0999] Column: Gemini C18, 19×250mm, 10μm, Mobile phase: A: Water (containing 10 mmol / L NH4HCO3) B: ACN; Gradient: 5% B to 65% B over 20 minutes. HPLC: 93.18% (214 nm), RT = 13.89 min. Mobile phase: A: Water (0.05% TFA) B: ACN (0.05% TFA). Gradient: 5% B for 3 minutes, then 65% B over 20 minutes, then 95% B over 2 minutes, held for 5 minutes, and then decreased to 5% B over 0.1 minutes. Flow rate: 1.0 mL / min. Column: XBridge peptide BEH column C18, 4.6×150 mm, 3.5 μm, Column temperature: 40℃.

[1000] 17-5FAM:LCMS:(ESI)m / z=584.2[M+2H] / 2 +

[1001] Preparation conditions:

[1002] Column: Gemini C18, 19×250mm, 10μm, Mobile phase: A: Water (containing 10 mmol / L NH4HCO3) B: ACN; Gradient: 5% B to 65% B over 20 minutes. HPLC: 94.10% (214 nm), RT = 14.49 min. Mobile phase: A: Water (0.05% TFA) B: ACN (0.05% TFA). Gradient: 5% B for 3 minutes, increasing to 45% B over 20 minutes, then increasing to 95% B over 2 minutes, holding for 5 minutes, and decreasing to 5% B over 0.1 minutes. Flow rate: 1.0 mL / min. Column: XBridge peptide BEH column C18, 4.6×150 mm, 3.5 μm, Column temperature: 40℃.

[1003] 18-5FAM:LCMS:(ESI)m / z=535.0[M+2H] / 2 +

[1004] Preparation conditions:

[1005] Chromatographic column: Gemini C18 21.2mm×250mm, 10μm, Mobile phase: A: Water (containing 10 mmol / L NH4HCO3) B: ACN; Gradient: 5% B to 65% B over 20 minutes. HPLC: 95.83% (214 nm), RT = 15.58 min. Mobile phase: A: Water (0.05% TFA) B: ACN (0.05% TFA). Gradient: 5% B for 3 minutes, then 65% B over 20 minutes, then 95% B over 2 minutes, held for 5 minutes, and then decreased to 5% B over 0.1 minutes. Flow rate: 1.0 mL / min. Column: XBridge peptide BEH column C18, 4.6×150 mm, 3.5 μm, Column temperature: 25℃.

[1006] 20-5FAM:LCMS:(ESI)m / z=535.0[M+2H] / 2 +

[1007] Preparation conditions:

[1008] Chromatographic column: Gemini C18 21.2mm×250mm, 10μm, Mobile phase: A: Water (containing 10 mmol / L NH4HCO3) B: ACN; Gradient: 5% B to 65% B over 20 minutes. HPLC: 94.50% (214 nm), RT = 15.46 min. Mobile phase: A: Water (0.05% TFA) B: ACN (0.05% TFA). Gradient: 5% B for 3 minutes, then 65% B over 20 minutes, then 95% B over 2 minutes, held for 5 minutes, and then 5% B over 0.1 minutes. Flow rate: 1.0 mL / min. Column: XBridge peptide BEH column C18, 4.6×150 mm, 3.5 μm, Column temperature: 40℃.

[1009] Synthesis of 9-5FAM labeled compounds

[1010] Compound 9-15 (90 mg, 0.065 mmol, 1.0 equiv.) was dissolved in a mixture of water (2 mL) and acetonitrile (1 mL), and 5-FAM-OSu (31 mg, 0.065 mmol) and saturated NaHCO3 solution (1 mL) were added sequentially. The reaction mixture was stirred at room temperature in the dark for 2 hours. The reaction mixture was directly purified by preparative reverse phase chromatography (Gemini C18 21.2 mm × 250 mm, 10 μm, Mobile phase: A: water (containing 10 mmol / L NH4HCO3), B: acetonitrile; gradient: 26% B to 36% B over 20 minutes) to afford 9-5FAM (22 mg, yield: 30%) as a yellow solid. LCMS: (ESI) m / z = 1142.5 [M+H] + ;572.2[M+2H] / 2 + . HPLC: 99.13% (214nm), RT=15.00min.

[1011] Preparation conditions:

[1012] Mobile phase: A: Water (0.05% TFA) B: ACN (0.05% TFA). Gradient: 20% B for 3 minutes, increasing to 80% B over 20 minutes, then increasing to 95% B over 2 minutes, holding for 5 minutes, and decreasing to 20% B over 0.1 minutes. Flow rate: 1.0 mL / min. Column: XBridge Peptide BEH Column C18, 4.6 × 150 mm, 3.5 μm, Column temperature: 40℃.

[1013] Example 2. Synthesis of oligonucleotides

[1014] The oligonucleotide synthesis method is similar to conventional phosphoramidite solid-phase synthesis (all synthesized by Suzhou Beixin Biotechnology Co., Ltd.), consisting of four steps: deprotection, coupling, capping, and oxidation or sulfurization. Starting with a solid support, the nucleoside monomers are sequentially linked from the 3' to the 5' end. Nucleoside phosphoramidite monomer raw materials, such as 2'-F RNA and 2'-OMe RNA, were purchased from Shanghai Zhaowei Technology Development Co., Ltd. After solid-phase synthesis, the solid support was transferred to a centrifuge tube and soaked in a 3:1 solution of 28% ammonia and ethanol at 50°C for 16 hours to cleave the oligonucleotide from the solid support into solution. The supernatant was centrifuged and transferred to another centrifuge tube, concentrated and evaporated to dryness, then redissolved in deionized water and purified using a C18 reverse-phase chromatography column with a mobile phase of 0.1 M TEAA and acetonitrile. The target oligonucleotide was collected, lyophilized, identified as the target product by LC-MS, and quantified by UV spectroscopy (260 nm). The obtained sense strand and antisense strand are annealed according to the molar ratio to obtain complementary paired double-stranded siRNA, and the concentration is adjusted to the required value.

[1015] Example 3. Coupling reaction of small molecule ligand compound and oligonucleotide

[1016] A synthesized tri-alkyne oligonucleotide (1.0 equiv.) was dissolved in a 3:1 buffered saline / DMSO solution. An azide-modified small molecule ligand (15 equiv.) dissolved in DMSO was added and vortexed. A pre-mixed THPTA:CuSO₄·5H₂O solution (15 equiv. and 3 equiv., respectively) was added. Vortexed, sodium ascorbyl palmitate (25 equiv.) was quickly added. The reaction system was incubated at 40°C for 2 h. After completion of the reaction, LCMS was monitored and reverse-phase HPLC was used to purify the desired oligonucleotide. The target oligonucleotide was collected, lyophilized, and identified as the target product by LC-MS. The resulting sense and antisense strands were annealed at a fixed molar ratio to yield complementary double-stranded siRNA, which was then adjusted to the desired concentration.

[1017] Table 1. siRNA compounds targeting RAGE-mRNA in lung tissue

[1018] Where m represents 2'-O-methyl modification, f represents 2'-fluoro modification, and * represents phosphorothioate modification.

[1019] Example 4. In vitro evaluation of small molecule ligand and integrin binding ability

[1020] A. Homogeneous time-resolved fluorescence (HTRF) was used to evaluate the binding activity of compounds to integrin αvβ6 receptors

[1021] Main reagents and consumables for the experiment

[1022] Experimental methods

[1023] Compound Preparation: Reference (Cilengitide) and test compounds were prepared as 10 mM stock solutions in DMSO. The positive reference was diluted three-fold in DMSO in an ECHO-Qualified 384-well plate at 10 concentration points, starting at 10 mM (final DMSO concentration of 0.5%, positive reference concentration of 2.54-50,000 nM). Test compounds were also diluted three-fold in DMSO in an ECHO-Qualified 384-well plate at 10 concentration points, starting at 0.02 mM (final DMSO concentration of 0.5%, positive reference concentration of 0.005-100 nM).

[1024] Reagent preparation: Prepare the experimental buffer, and use the buffer to prepare 40nM integrin receptor protein αvβ6, 20nM ligand protein LAP (TGFβ1), and detection reagents 1nM Anti-His Tb and 20nM SA-XL665.

[1025] Experimental operation and detection: First use 100 nL of serially diluted reference (Cilengitide), test compound, and DMSO solution (positive and negative controls) were transferred from ECHO-Qualified 384-Well plates to Opti-384 plates. Then, 5 μL of the integrin receptor protein αvβ6 (5 μL of assay buffer for the negative control) was added and incubated at room temperature for 20 minutes. Next, 5 μL of the ligand protein LAP and 10 μL of a mixture of Anti-His Tb and SA-XL665 were added and incubated at room temperature for 1 hour. The plates were then placed on an EnVision (PerkinElmer, SN: 1051284) monitor with excitation at 340 nm and emission at 615 nm and 665 nm.

[1026] Data processing

[1027] The inhibition rate and IC50 were calculated using Excel and XL-Fit, respectively. The formulas are as follows:

[1028] Inhibition%=(Max-Signal) / (Max-Min)*100

[1029] Y=Bottom+(Top-Bottom) / (1+(IC50 / X)*HillSlope), where Y and X represent %inhibition and compound concentration, respectively.

[1030] Experimental results

[1031] Table 1. Binding activity of compounds to integrin αvβ6 receptor

[1032] Table 3. Binding activity of compounds to integrin αvβ6 receptor

[1033] The results showed that the ligand small molecules all had excellent in vitro binding ability to the αvβ6 receptor.

[1034] B. Evaluate the binding activity of compounds to integrin αvβ5 receptor using homogeneous time-resolved fluorescence (HTRF)

[1035] Main reagents and consumables for the experiment

[1036] Experimental methods

[1037] Compound preparation: Same as A.

[1038] Reagent preparation: Prepare the experimental buffer, and use the buffer to prepare 20nM integrin receptor protein αvβ5, 40nM ligand protein Vitronectin (VTN), and detection reagents 1nM SA-Tb and 14nM Anti-His XL665.

[1039] Experimental operation and detection: First use 200 nL of serially diluted reference (Cilengitide), test compound, and DMSO solution (positive and negative controls) were transferred from ECHO-Qualified 384-Well plates to Opti-384 plates. 5 μL of the integrin receptor protein αvβ5 (5 μL of assay buffer for the negative control) was then added, followed by a 20-minute incubation at room temperature. Next, 5 μL of the ligand protein VTN and 10 μL of a mixture of SA-Tb and Anti-His XL665 were added, followed by a 1-hour incubation at room temperature. The plates were then placed on an EnVision (PerkinElmer, SN: 1051284) monitor with excitation at 340 nm and emission at 615 and 665 nm.

[1040] Data processing: same as A

[1041] The experimental results are shown in Table 4

[1042] C. Fluorescence polarization (FP) technology was used to evaluate the binding activity of compounds to integrin αvβ1 receptors.

[1043] Main reagents and consumables for the experiment

[1044] Experimental methods

[1045] Compound preparation: Same as A.

[1046] Reagent preparation: Prepare the experimental buffer, and use the buffer to prepare 20 nM integrin receptor protein αvβ1 and 10 nM ligand polypeptide Cyclo[-RGDy-K(5-FAM)].

[1047] Experimental operation and detection: First use 200 nL of serially diluted reference (Cilengitide), test compounds, and DMSO solution (positive and negative controls) were transferred from ECHO-Qualified 384-Well plates to Opti-384 plates. Then, 10 μL of the integrin receptor protein αvβ1 (negative control plus 10 μL of assay buffer) was added and incubated at room temperature for 20 minutes. Then, 10 μL of the ligand peptide Cyclo[-RGDy-K(5-FAM)] was added and incubated at room temperature for 1 hour. The plates were detected using an EnVision (PerkinElmer, SN: 1051284) monitor with excitation at 480 nm and emission at 535 nm (S) and 535 nm (P).

[1048] Data processing: same as A

[1049] The experimental results are shown in Table 4

[1050] Table 4. Binding activity of compounds to different integrin receptors

[1051] The results showed that the ligand small molecules 5-P1 and 5-P2 exhibited specific binding ability to the αvβ6 receptor.

[1052] Example 5. Screening of RAGE targets in rats by small molecule ligand delivery

[1053] Male SD rats, 8 per group, were intratracheally administered once on Day 0 (Compound D1, D4, D5, D6, D8, D9 and D10). The compound dose was 2 mg / kg, the preparation concentration was set at 2 mg / mL, and the administration volume was 1 mL / kg. On Day-4, Day 14 and Day 28, the rats were anesthetized with 1-4% isoflurane and blood was collected from the orbital cavity (without fasting). About 150 μL of serum was collected (the whole blood sample was allowed to stand at room temperature for 30 minutes, and then centrifuged at 4°C, 2000g, for 10 minutes to obtain serum), and temporarily stored in a -80°C refrigerator. Used for ELISA detection of sRAGE, single-well detection. Lungs were taken to detect RAGE mRNA.

[1054] The results showed that all compounds tested in this invention effectively inhibited RAGE mRNA (Figure 1) and protein (Figure 2) expression in rats. D9 (ligand 5-p1), D10 (ligand 5-p2), and D4 (ligand 9) showed comparable inhibition of sRAGE protein as D1 (ligand 1).

Claims

1. A compound, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug, or solvate thereof, wherein the compound has a structure shown in Formula Ia: in, T1 and T2 are independently C or N, and at least one is N, preferably both T1 and T2 are N; T3 and T4 are independently C or N, preferably one of T3 and T4 is N, more preferably both T3 and T4 are C; Ring B is or not present, where junction 2 is connected to L2; R4, R5 and R6 are independently H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl or cyclobutyl, preferably R4, R5 and R6 are independently methyl; L1 is -(CH2) n -、-(CH2) m C(O)NH(CH2) n -or-(CH2) m NHC(O)(CH2) n -, m and n are independently an integer from 1 to 10, preferably m and n are independently 1, 2, 3, 4, 5 or 6; L2 is -(OCH2CH2) p -、-(CH2) q (OCH2CH2) p -、-NHC(O)(CH2CH2O) p -、-NHC(O)(CH2) q -(OCH2CH2) p -,-C(O)NH(CH2CH2O) p -、-C(O)NH(CH2) q (OCH2CH2) p -、-C(O)(CH2CH2O) p -or-C(O)(CH2) q (OCH2CH2) p -, wherein the left side is connected to the B ring, the right side is connected to R1, and p and q are independently integers from 1 to 10, preferably q is 2 or 3, preferably p is 3, 4, 5, 6 or 7; R1 is -N3, -NH2, -COOH, -NHC(O)CH2SC(O)CH3 or Preferably, the compound is selected from compounds 4, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33 and 34.

2. A compound, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug, or solvate thereof, wherein the compound has the structure shown in Formula Ib: in, T1 and T2 are independently C or N, and at least one is N, preferably both T1 and T2 are N; T3 and T4 are independently C or N, preferably one of T3 and T4 is N, more preferably both T3 and T4 are C; One of e1 and e2 is 1, and the other is 0; Ring B is or does not exist, where connection point 2 is connected to L2, and connection point 2 does not exist when e1 is 0; R4 and R5 are independently H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl or cyclobutyl, preferably R4, R5 and R6 are independently methyl; L1 is -(CH2) n -、-(CH2) m C(O)NH(CH2) n -or-(CH2) m NHC(O)(CH2) n -, m and n are independently an integer from 1 to 10, preferably m and n are independently 1, 2, 3, 4, 5 or 6; When e1 is 1, L2 is -(OCH2CH2) p -、-(CH2) q (OCH2CH2) p -、-NHC(O)(CH2CH2O) p -、-NHC(O)(CH2) q (OCH2CH2) p -,-C(O)NH(CH2CH2O) p -、-C(O)NH(CH2) q (OCH2CH2) p -、-C(O)(CH2CH2O) p -or-C(O)(CH2) q (OCH2CH2) p -, wherein the right side is connected to R1, and p and q are independently integers from 1 to 10, preferably q is 2 or 3, preferably p is 3, 4, 5, 6 or 7; When e2 is 1, L2 is -NHC(O)(CH2) q (OCH2CH2) p -, wherein the right side is connected to R1, p and q are independently integers from 1 to 10, preferably q is 2 or 3, preferably p is 3, 4, 5, 6 or 7; R1 is -N3, -NH2, -COOH, -NHC(O)CH2SC(O)CH3 or R9 is H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl or cyclobutyl, R 10 H, or R9, R 10 Together with the C and N to which they are attached, they form a piperidinyl group; preferably R9 is methyl and R 10 H or R9, R 10 Together with the C and N to which they are attached, they form a piperidinyl group; Preferably, the compound is compound 35.

3. A compound, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug, or solvate thereof, wherein the compound has a structure shown in Formula IIa or IIb: in, T3 and T4 are independently C or N, preferably one of T3 and T4 is N, more preferably both T3 and T4 are C; Ring A is wherein the connection point 1 is connected to L1, and R8 is H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl or halogen, preferably H or halogen, more preferably H or F; Ring B is or not present, where junction 2 is connected to L2; R4, R5, R6 and R7 are independently H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl or cyclobutyl, wherein preferably R4, R5 and R6 are independently methyl; preferably R7 is H; L1 is -(CH2) n -、-(CH2) m C(O)NH(CH2) n -or-(CH2) m NHC(O)(CH2) n -, m and n are independently an integer from 1 to 10, preferably m and n are independently 1, 2, 3, 4, 5 or 6; L2 is -(OCH2CH2) p -、-(CH2) q (OCH2CH2) p -、-NHC(O)(CH2CH2O) p -、-NHC(O)(CH2) q -(OCH2CH2) p -,-C(O)NH(CH2CH2O) p -、-C(O)NH(CH2) q (OCH2CH2) p -、-C(O)(CH2CH2O) p -or-C(O)(CH2) q (OCH2CH2) p -, wherein the left side is connected to the B ring, the right side is connected to R1, and p and q are independently integers from 1 to 10, preferably q is 2 or 3, preferably p is 3, 4, 5, 6 or 7; R1 is -N3, -NH2, -COOH, -NHC(O)CH2SC(O)CH3 or Preferably, the compound is any one of compounds 5, 36, 37, 38, 39, 40, 41, 42, 43 or 44.

4. A compound, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug, or solvate thereof, wherein the compound has a structure shown in Formula IIIa or IIIb: in, T3 and T4 are independently C or N, preferably one of T3 and T4 is N, more preferably both T3 and T4 are C; One of e1 and e2 is 1, and the other is 0; Ring B is or does not exist, where connection point 2 is connected to L2, and connection point 2 does not exist when e1 is 0; R4 and R5 are independently H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl or cyclobutyl, preferably methyl; L1 is -(CH2) m -、-(CH2) m C(O)NH(CH2) n -or-(CH2) m NHC(O)(CH2) n -, m is an integer from 1 to 10, preferably m is 1, 2, 3, 4, 5 or 6, n is an integer from 0 to 10, preferably n is 0, 1, 2 or 3; When e1 is 1, L2 is -(OCH2CH2) p -、-(CH2) q (OCH2CH2) p -、-NHC(O)(CH2CH2O) p -、-NHC(O)(CH2) q (OCH2CH2) p -,-C(O)NH(CH2CH2O) p -、-C(O)NH(CH2) q (OCH2CH2) p -、-C(O)(CH2CH2O) p -or-C(O)(CH2) q (OCH2CH2) p -, wherein the right side is connected to R1, and p and q are independently integers from 1 to 10, preferably q is 2 or 3, preferably p is 3, 4, 5, 6 or 7; When e2 is 1, L2 is -NHC(O)(CH2)q(OCH2CH2) p -, wherein the right side is connected to R1, p and q are independently integers from 1 to 10, preferably q is 2 or 3, preferably p is 3, 4, 5, 6 or 7; R1 is -N3, -NH2, -COOH, -NHC(O)CH2SC(O)CH3 or R9 is H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl or cyclobutyl, R 10 H, or R9, R 10 Together with the C and N to which they are attached, they form a piperidinyl group; preferably R9 is methyl and R 10 H or R9, R 10 Together with the C and N to which they are attached, they form a piperidinyl group; Preferably, the compound is compound 6, 7, 8, 9, 45, 46 or 47.

5. A compound, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein the compound has a structure shown in Formula IVa: in, One of e1, e2 and e3 is 1, and the other two are 0; Ring B is or does not exist, where connection point 2 is connected to L2, and connection point 2 does not exist when e1 is 0; R4 and R5 are independently H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl or cyclobutyl, preferably R4 and R5 are both methyl; When e1 or e3 is 1, L2 is -(OCH2CH2) p -、-(CH2) q (OCH2CH2) p -、-NHC(O)(CH2CH2O) p -、-NHC(O)(CH2) q (OCH2CH2) p -,-C(O)NH(CH2CH2O) p -、-C(O)NH(CH2) q (OCH2CH2) p -、-C(O)(CH2CH2O) p -or-C(O)(CH2) q (OCH2CH2) p -, wherein the right side is connected to R1, and p and q are independently integers from 1 to 10, preferably q is 2 or 3, preferably p is 3, 4, 5, 6 or 7; When e2 is 1, L2 is -NHC(O)(CH2)q(OCH2CH2) p -, wherein the right side is connected to R1, p and q are independently integers from 1 to 10, preferably q is 2 or 3, preferably p is 3, 4, 5, 6 or 7; R1 is -N3, -NH2, -COOH, -NHC(O)CH2SC(O)CH3 or R 11 H, halogen, halogenated C 1-4 alkyl, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, phenyl, morpholinyl, methoxyethoxy or ethoxymethoxy; Preferably, the compound is compound 13, 14, 15, 18, 20, 48, 49, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 71, 72, 73, 83, 84, 85, 86 or 87.

6. A compound, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug, or solvate thereof, wherein the compound has a structure shown in Formula IVb: One of e1 and e2 is 1, and the other is 0; Ring B is or not present, where junction 2 is connected to L2; R4, R5 and R6 are independently H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl or cyclobutyl, preferably R4, R5 and R6 are all methyl; L2 is -(OCH2CH2) p -、-(CH2) q (OCH2CH2) p -、-NHC(O)(CH2CH2O) p -、-NHC(O)(CH2) q -(OCH2CH2) p -,-C(O)NH(CH2CH2O) p -、-C(O)NH(CH2) q (OCH2CH2) p -、-C(O)(CH2CH2O) p -or-C(O)(CH2) q (OCH2CH2) p -, wherein the left side is connected to the B ring, the right side is connected to R1, and p and q are independently integers from 1 to 10, preferably q is 2 or 3, preferably p is 3, 4, 5, 6 or 7; R1 is -N3, -NH2, -COOH, -NHC(O)CH2SC(O)CH3 or L1 is -(CH2) m -、-(CH2) m C(O)NH(CH2) n -or-(CH2) m NHC(O)(CH2) n -, m is an integer from 1 to 10, preferably m is 1, 2, 3, 4, 5 or 6, n is an integer from 0 to 10, preferably n is 0, 1, 2 or 3; R 11 is H, halogen, halomethyl, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, phenyl, morpholinyl, methoxyethoxy or ethoxymethoxy, preferably R 11 is H; Preferably, the compound is compound 50, 51, 52, 74, 75, 76, 77, 78, 79 or 80.

7. A compound, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug, or solvate thereof, wherein the compound has a structure shown in Formula Va: One of e1, e2 and e3 is 1, and the other two are 0; R9 is H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl or cyclobutyl, R 10 H, or R9, R 10 Together with the C and N atoms to which they are attached, they form a piperidinyl group, preferably R9 is methyl and R 10 is H; R 13 and R 14 Each is H, or R 13 , R 14 Together with the C and N atoms to which they are attached, they form a piperidinyl group; L1 and L1' are independently -(CH2) m -、-(CH2) m C(O)NH(CH2) n -or-(CH2) m NHC(O)(CH2) n -, m is an integer from 1 to 10, preferably m is 1, 2, 3, 4, 5 or 6, n is an integer from 0 to 10, preferably n is 0, 1, 2 or 3; When e1 is 1, L2 is -(OCH2CH2) p -、-(CH2) q (OCH2CH2) p -、-NHC(O)(CH2CH2O) p -、-NHC(O)(CH2) q (OCH2CH2) p -,-C(O)NH(CH2CH2O) p -、-C(O)NH(CH2) q (OCH2CH2) p -、- C(O)(CH2CH2O) p -or-C(O)(CH2) q (OCH2CH2) p -, wherein the right side is connected to R1, and p and q are independently integers from 1 to 10, preferably q is 2 or 3, preferably p is 3, 4, 5, 6 or 7; When e2 is 1, L2 is -(CH2)q(OCH2CH2) p -, wherein the right side is connected to R1, p and q are independently integers from 1 to 10, preferably q is 1 or 2, preferably p is 3, 4, 5, 6 or 7; When e3 is 1, L2 is -NHC(O)(CH2)q(OCH2CH2) p -, wherein the right side is connected to R1, p and q are independently integers from 1 to 10, preferably q is 2 or 3, preferably p is 3, 4, 5, 6 or 7; R1 is -N3, -NH2, -COOH, -NHC(O)CH2SC(O)CH3 or Preferably, the compound is compound 16, 17, 64, 65, 66 or 67.

8. A compound, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug, or solvate thereof, wherein the compound has a structure shown in Formula Vb: in One of e1 and e2 is 1, and the other is 0; R6 is H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl or cyclobutyl, preferably methyl; R 13 and R 14 Each is H, or R 13 , R 14 Together with the C and N atoms to which they are attached, they form a piperidinyl group; L1 and L1' are independently -(CH2) m -、-(CH2) m C(O)NH(CH2) n -or-(CH2) m NHC(O)(CH2) n -, m is an integer from 1 to 10, preferably m is 1, 2, 3, 4, 5 or 6, n is an integer from 0 to 10, preferably n is 0, 1, 2 or 3; When e1 is 1, L2 is -(OCH2CH2) p -、-(CH2) q (OCH2CH2) p -、-NHC(O)(CH2CH2O) p -、-NHC(O)(CH2) q (OCH2CH2) p -,-C(O)NH(CH2CH2O) p -、-C(O)NH(CH2) q (OCH2CH2) p -、-C(O)(CH2CH2O) p -or-C(O)(CH2) q (OCH2CH2) p -, wherein the right side is connected to R1, and p and q are independently integers from 1 to 10, preferably q is 2 or 3, preferably p is 3, 4, 5, 6 or 7; When e2 is 1, L2 is -(CH2)q(OCH2CH2) p -, wherein the right side is connected to R1, p and q are independently integers from 1 to 10, preferably q is 1 or 2, preferably p is 3, 4, 5, 6 or 7; R1 is -N3, -NH2, -COOH, -NHC(O)CH2SC(O)CH3 or Preferably, the compound is compound 69 or 70.

9. A compound, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug, or solvate thereof, wherein the compound has a structure shown in Formula Vc: One of e1, e2 and e3 is 1, and the other two are 0; R9 is H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl or cyclobutyl, R 10 H, or R9, R 10 Together with the C and N atoms to which they are attached, they form a piperidinyl group, preferably R9 is methyl and R 10 is H; R 13 and R 14 Each is H, or R 13 , R 14 Together with the C and N atoms to which they are attached, they form a piperidinyl group; L1 is -(CH2) m -、-(CH2) m C(O)NH(CH2) n -or-(CH2) m NHC(O)(CH2) n -, m is an integer from 1 to 10, preferably m is 1, 2, 3, 4, 5 or 6, n is an integer from 0 to 10, preferably n is 0, 1, 2 or 3; When e1 is 1, L2 is -(OCH2CH2) p -、-(CH2) q (OCH2CH2) p -、-NHC(O)(CH2CH2O) p -、-NHC(O)(CH2) q (OCH2CH2) p -,-C(O)NH(CH2CH2O) p -、-C(O)NH(CH2) q (OCH2CH2) p -、-C(O)(CH2CH2O) p -or-C(O)(CH2) q (OCH2CH2) p -, wherein the right side is connected to R1, and p and q are independently integers from 1 to 10, preferably q is 2 or 3, preferably p is 3, 4, 5, 6 or 7; When e2 is 1, L2 is -(CH2)q(OCH2CH2) p -, wherein the right side is connected to R1, p and q are independently integers from 1 to 10, preferably q is 1 or 2, preferably p is 3, 4, 5, 6 or 7; When e3 is 1, L2 is -NHC(O)(CH2)q(OCH2CH2) p -, wherein the right side is connected to R1, p and q are independently integers from 1 to 10, preferably q is 2 or 3, preferably p is 3, 4, 5, 6 or 7; R1 is -N3, -NH2, -COOH, -NHC(O)CH2SC(O)CH3 or Ring B is or does not exist, where connection point 2 is connected to L2, and connection point 2 does not exist when e1 is 0; R4 and R5 are independently H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl or cyclobutyl, preferably R4 and R5 are both methyl; Preferably, the compound is compound 68.

10. A compound, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug, or solvate thereof, wherein the compound has a structure shown in Formula Ia': T1 and T2 are independently C or N, and at least one is N, preferably both T1 and T2 are N; T3 and T4 are independently C or N, preferably one of T3 and T4 is N, more preferably both T3 and T4 are C; Ring B is or does not exist; R4, R5 and R6 are independently H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl or cyclobutyl, preferably R4, R5 and R6 are independently methyl; L1 is -(CH2) n -、-(CH2) m C(O)NH(CH2) n -or-(CH2) m NHC(O)(CH2) n -, m and n are independently an integer from 1 to 10, preferably m and n are independently 1, 2, 3, 4, 5 or 6; Preferably, the compound is selected from compounds 4', 21', 22', 23', 24', 31', 32', 33' and 34'.

11. A compound, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug, or solvate thereof, wherein the compound has a structure shown in Formula Ib': in, T1 and T2 are independently C or N, and at least one is N, preferably both T1 and T2 are N; T3 and T4 are independently C or N, preferably one of T3 and T4 is N, more preferably both T3 and T4 are C; Ring B is or does not exist; R4 and R5 are independently H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl or cyclobutyl, preferably R4, R5 and R6 are independently methyl; R3 is H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, amino or C 1-3 Alkylamino, preferably R3 is H or methylamino; L1 is -(CH2) n -、-(CH2) m C(O)NH(CH2) n -or-(CH2) m NHC(O)(CH2) n -, m and n are independently an integer from 1 to 10, preferably m and n are independently 1, 2, 3, 4, 5 or 6; R9 is H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl or cyclobutyl, R 10 H, or R9, R 10 Together with the C and N to which they are attached, they form a piperidinyl group; preferably R9 is methyl and R 10 H or R9, R 10 Together with the C and N to which they are attached, they form a piperidinyl group; Preferably, the compound is compound 35'.

12. A compound, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound form, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein the compound has a structure shown in Formula IIa' or IIb': in, T3 and T4 are independently C or N, preferably one of T3 and T4 is N, more preferably both T3 and T4 are C; Ring A is wherein the connection point 1 is connected to L1, and R8 is H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl or halogen, preferably H or halogen, more preferably H or F; Ring B is or does not exist; R4, R5, R6 and R7 are independently H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl or cyclobutyl, wherein preferably R4, R5 and R6 are independently methyl; preferably R7 is H; L1 is -(CH2) n -、-(CH2) m C(O)NH(CH2) n -or-(CH2) m NHC(O)(CH2) n -, m and n are independently an integer from 1 to 10, preferably m and n are independently 1, 2, 3, 4, 5 or 6; Preferably, the compound is any one of compounds 5', 36', 37', 38', 39', 40', 41 ', 42', 43' or 44'.

13. A compound, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug, or solvate thereof, wherein the compound has a structure shown in Formula IIIa' or IIIb': in, T3 and T4 are independently C or N, preferably one of T3 and T4 is N, more preferably both T3 and T4 are C; Ring B is R4 and R5 are independently H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl or cyclobutyl, preferably methyl; L1 is -(CH2) m -、-(CH2) m C(O)NH(CH2) n -or-(CH2) m NHC(O)(CH2) n -, m is an integer from 1 to 10, preferably m is 1, 2, 3, 4, 5 or 6, n is an integer from 0 to 10, preferably n is 0, 1, 2 or 3; R3 is H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, amino or C 1-3 Alkylamino, preferably R3 is H or methylamino; R9 is H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl or cyclobutyl, R 10 H, or R9, R 10 Together with the C and N to which they are attached, they form a piperidinyl group; preferably R9 is methyl and R 10 H or R9, R 10 Together with the C and N to which they are attached, they form a piperidinyl group; Preferably, the compound is compound 6', 7', 8', 9' or 47'.

14. A compound, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug, or solvate thereof, wherein the compound has a structure shown in Formula IVa': in, Ring B is R4 and R5 are independently H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl or cyclobutyl, preferably R4 and R5 are both methyl; R3 is H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, amino or C 1-3 Alkylamino, preferably R3 is H or methylamino; R 11 H, halogen, halogenated C 1-4 alkyl, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, phenyl, morpholinyl, methoxyethoxy or ethoxymethoxy; Preferably, the compound is compound 48', 49', 59', 60', 73' or 85'.

15. A compound, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug, or solvate thereof, wherein the compound has a structure shown in Formula IVb': in Ring B is or does not exist; R4, R5 and R6 are independently H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl or cyclobutyl, preferably R4, R5 and R6 are all methyl; L1 is -(CH2) m -、-(CH2) m C(O)NH(CH2) n -or-(CH2) m NHC(O)(CH2) n -, m is an integer from 1 to 10, preferably m is 1, 2, 3, 4, 5 or 6, n is an integer from 0 to 10, preferably n is 0, 1, 2 or 3; R 11 is H, halogen, halomethyl, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, phenyl, morpholinyl, methoxyethoxy or ethoxymethoxy, preferably R 11 is H; Preferably, the compound is compound 50', 51', 52', 76' or 79'.

16. A compound, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug, or solvate thereof, wherein the compound has a structure shown in formula Va': in R3 is H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, amino or C 1-3 Alkylamino, preferably R3 is H or methylamino; R9 is H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl or cyclobutyl, R 10 H, or R9, R 10 Together with the C and N atoms to which they are attached, they form a piperidinyl group, preferably R9 is methyl and R 10 is H; R 12 is methyl, ethyl, n-propyl, isopropyl, cyclopropyl or cyclobutyl, preferably R 12 is methyl; R 13 , R 14 Together with the C and N atoms to which they are attached, they form a piperidinyl group; L1 and L1' are independently -(CH2) m -、-(CH2) m C(O)NH(CH2) n -or-(CH2) m NHC(O)(CH2) n -, m is an integer from 1 to 10, preferably m is 1, 2, 3, 4, 5 or 6, n is an integer from 0 to 10, preferably n is 0, 1, 2 or 3; Preferably, the compound is compound 64'.

17. A compound, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug, or solvate thereof, wherein the compound has a structure shown in Formula Vb': in, R6 is H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl or cyclobutyl, preferably methyl; R 12 is methyl, ethyl, n-propyl, isopropyl, cyclopropyl or cyclobutyl, preferably R 12 is methyl; R 13 and R 14 Each is H, or R 13 , R 14 Together with the C and N atoms to which they are attached, they form a piperidinyl group; L1 and L1' are independently -(CH2) m -、-(CH2) m C(O)NH(CH2) n -or-(CH2) m NHC(O)(CH2) n -, m is an integer from 1 to 10, preferably m is 1, 2, 3, 4, 5 or 6, n is an integer from 0 to 10, preferably n is 0, 1, 2 or 3; Preferably, the compound is compound 69' or 70'.

18. A compound, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug, or solvate thereof, wherein the compound has a structure shown in Formula Vc': R3 is H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, amino or C 1-3 Alkylamino, preferably R3 is H or methylamino; R9 is H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl or cyclobutyl, R 10 H, or R9, R 10 Together with the C and N atoms to which they are attached, they form a piperidinyl group, preferably R9 is methyl and R 10 is H; R 12 is methyl, ethyl, n-propyl, isopropyl, cyclopropyl or cyclobutyl, preferably R 12 is methyl; R 13 and R 14 Each is H, or R 13 , R 14 Together with the C and N atoms to which they are attached, they form a piperidinyl group; L1 is -(CH2) m -、-(CH2) m C(O)NH(CH2) n -or-(CH2) m NHC(O)(CH2) n -, m is an integer from 1 to 10, preferably m is 1, 2, 3, 4, 5 or 6, n is an integer from 0 to 10, preferably n is 0, 1, 2 or 3; Ring B is or does not exist; R4 and R5 are independently H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl or cyclobutyl, preferably R4 and R5 are both methyl; Preferably, the compound is compound 68'.

19. A compound, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug, or solvate thereof, wherein the compound has a structure shown in Formula Ia": T1 and T2 are independently C or N, and at least one is N, preferably both T1 and T2 are N; T3 and T4 are independently C or N, preferably one of T3 and T4 is N, more preferably both T3 and T4 are C; Ring B is or not present, wherein the connection point 2 is a wavy line in Formula Ia", the wavy line Indicates the key; R4, R5 and R6 are independently H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl or cyclobutyl, preferably R4, R5 and R6 are independently methyl; L1 is -(CH2) n -、-(CH2) m C(O)NH(CH2) n -or-(CH2) m NHC(O)(CH2) n -, m and n are independently an integer from 1 to 10, preferably m and n are independently 1, 2, 3, 4, 5 or 6; Preferably, the compound is selected from the group consisting of: 4", 21", 22", 23", 24", 31", 32", 33" and 34".

20. A compound, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug, or solvate thereof, wherein the compound has a structure shown in Formula Ib": in, T1 and T2 are independently C or N, and at least one is N, preferably both T1 and T2 are N; T3 and T4 are independently C or N, preferably one of T3 and T4 is N, more preferably both T3 and T4 are C; Ring B is or not present, wherein the connection point 2 is the wavy line connected to the B ring in Formula Ib"; R4 and R5 are independently H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl or cyclobutyl, preferably R4 and R5 are independently methyl; L1 is -(CH2) n -、-(CH2) m C(O)NH(CH2) n -or-(CH2) m NHC(O)(CH2) n -, m and n are independently an integer from 1 to 10, preferably m and n are independently 1, 2, 3, 4, 5 or 6; R9 is H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl or cyclobutyl, R 10 H, or R9, R 10 Together with the C and N to which they are attached, they form a piperidinyl group; preferably R9 is methyl and R 10 H or R9, R 10 Together with the C and N to which they are attached, they form a piperidinyl group; and The wavy line in Formula Ib" indicates a bond, and one of the two tildes is absent; Preferably, the compound has a structure shown in Formula Ib"-1: Among them, T1, T2, T3, T4, L1, R9, R 10 and the wavy line have the same definitions as the corresponding substituents in Formula Ib", Ring B is or absent, wherein R4 and R5 are independently H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl or cyclobutyl, preferably R4 and R5 are independently methyl; More preferably, the compound is selected from: 35".

21. A compound, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound form, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein the compound has a structure shown in Formula IIa" or IIb": in, T3 and T4 are independently C or N, preferably one of T3 and T4 is N, more preferably both T3 and T4 are C; Ring A is wherein the connection point 1 is connected to L1, and R8 is H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl or halogen, preferably H or halogen, more preferably H or F; Ring B is or not present, wherein the connection point 2 is a wavy line in Formula IIa" or IIb", the wavy line Indicates the key; R4, R5, R6 and R7 are independently H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl or cyclobutyl, wherein preferably R4, R5 and R6 are independently methyl; preferably R7 is H; L1 is -(CH2) n -、-(CH2) m C(O)NH(CH2) n -or-(CH2) m NHC(O)(CH2) n -, m and n are independently an integer from 1 to 10, preferably m and n are independently 1, 2, 3, 4, 5 or 6; Preferably, the compound is selected from the group consisting of: 5", 36", 37", 38", 39", 40", 41", 42", 43" and 44".

22. A compound, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug, or solvate thereof, wherein the compound has a structure shown in Formula IIIa" or IIIb": in, T3 and T4 are independently C or N, preferably one of T3 and T4 is N, more preferably both T3 and T4 are C; Ring B is or absent, wherein the connection point 2 is the wavy line connected to the B ring in formula IIIa" or IIIb'; R4 and R5 are independently H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl or cyclobutyl, preferably methyl; L1 is -(CH2) m -、-(CH2) m C(O)NH(CH2) n -or-(CH2) m NHC(O)(CH2) n -, m is an integer from 1 to 10, preferably m is 1, 2, 3, 4, 5 or 6, n is an integer from 0 to 10, preferably n is 0, 1, 2 or 3; R9 is H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl or cyclobutyl, R 10 H, or R9, R 10 Together with the C and N to which they are attached, they form a piperidinyl group; preferably R9 is methyl and R 10 H or R9, R 10 Together with the C and N to which they are attached, they form a piperidinyl group; and The wavy lines in formula IIIa" and formula IIIb" indicates a bond, and one of the two tildes is absent; Alternatively, the compound has a structure shown in formula IIIa"-1 or IIIb"-1: Among them, T3, T4, L1, R9, R 10 and the wavy line have the same definitions as the corresponding substituents in formula IIIa" or IIIb", Ring B is or absent, wherein R4 and R5 are independently H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl or cyclobutyl, preferably R4 and R5 are independently methyl; Preferably, the compound is selected from the group consisting of: 6", 7", 8", 9", 45", 46" and 47".

23. A compound, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein the compound has a structure shown in Formula IVa": in, Ring B is or not present, wherein the connection point 2 is the wavy line connected to the B ring in Formula IVa"; R4 and R5 are independently H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl or cyclobutyl, preferably R4 and R5 are both methyl; R 11 H, halogen, halogenated C 1-4 alkyl, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, phenyl, morpholinyl, methoxyethoxy or ethoxymethoxy; and The wavy line in Formula IVa indicates a bond, and one of the two tildes is absent; Alternatively, the compound has a structure shown in Formula IVa"-1: Where R 11 and the wavy line has the same meaning as R in Formula IVa"' 11 Same definition as the wavy line, Ring B is or absent, wherein R4 and R5 are independently H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl or cyclobutyl, preferably R4 and R5 are independently methyl; Preferably, the compound is selected from the group consisting of: 13", 14", 15", 18", 20", 48", 49", 53", 54", 55", 56", 57", 58", 59", 60", 61", 62", 63", 71", 72", 73", 83", 84", 85", 86" and 87".

24. A compound, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug, or solvate thereof, wherein the compound has a structure shown in Formula IVb": Ring B is or not present, wherein the connection point 2 is the wavy line in Formula IVb", the wavy line Indicates the key; R4, R5 and R6 are independently H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl or cyclobutyl, preferably R4, R5 and R6 are all methyl; L1 is -(CH2) m -、-(CH2) m C(O)NH(CH2) n -or-(CH2) m NHC(O)(CH2) n -, m is an integer from 1 to 10, preferably m is 1, 2, 3, 4, 5 or 6, n is an integer from 0 to 10, preferably n is 0, 1, 2 or 3; R 11 is H, halogen, halomethyl, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, phenyl, morpholinyl, methoxyethoxy or ethoxymethoxy, preferably R 11 is H; Preferably, the compound is selected from the group consisting of: 50", 51", 52", 74", 75", 76", 77", 78", 79" and 80".

25. A compound, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug, or solvate thereof, wherein the compound has a structure shown in Formula Va": in R9 is H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl or cyclobutyl, R 10 H, or R9, R 10 Together with the C and N atoms to which they are attached, they form a piperidinyl group, preferably R9 is methyl and R 10 is H; R 13 and R 14 Each is H, or R 13 , R 14 Together with the C and N atoms to which they are attached, they form a piperidinyl group; L1 and L1' are independently -(CH2) m -、-(CH2) m C(O)NH(CH2) n -or-(CH2) m NHC(O)(CH2) n -, m is an integer from 1 to 10, preferably m is 1, 2, 3, 4, 5 or 6, n is an integer from 0 to 10, preferably n is 0, 1, 2 or 3; and The wavy line in the formula Va indicates a bond, and two of the three tildes are absent; Alternatively, the compound has a structure shown in formula Va"-1, Va"-2 or Va"-3: in, R9, R 10 , R 13 , R 14 , L1, L1' and the wavy line have the same definitions as the corresponding substituents in formula Va"; preferably, the compound is selected from: 16", 17", 64", 65", 66" and 67".

26. A compound, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug, or solvate thereof, wherein the compound has a structure shown in Formula Vb": in, R6 is H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl or cyclobutyl, preferably methyl; R 13 and R 14 Each is H, or R 13 , R 14 Together with the C and N atoms to which they are attached, they form a piperidinyl group; L1 and L1' are independently -(CH2) m -、-(CH2) m C(O)NH(CH2) n -or-(CH2) m NHC(O)(CH2) n -, m is an integer from 1 to 10, preferably m is 1, 2, 3, 4, 5 or 6, n is an integer from 0 to 10, preferably n is 0, 1, 2 or 3; and The wavy line in formula Vb" indicates a bond, and one of the two tildes is absent; Alternatively, the compound has a structure shown in Formula Vb"-1 or Vb"-2: Among them, R6, R 13 , R 14 , L1, L1' and the wavy line have the same definitions as the corresponding substituents in formula Vb"; Preferably, the compound is selected from: 69" and 70".

27. A compound, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug, or solvate thereof, wherein the compound has a structure shown in Formula Vc": Wherein R9 is H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl or cyclobutyl, R 10 H, or R9, R 10 Together with the C and N atoms to which they are attached, they form a piperidinyl group, preferably R9 is methyl and R 10 is H; R 13 and R 14 Each is H, or R 13 , R 14 Together with the C and N atoms to which they are attached, they form a piperidinyl group; L1 is -(CH2) m -、-(CH2) m C(O)NH(CH2) n -or-(CH2) m NHC(O)(CH2) n -, m is an integer from 1 to 10, preferably m is 1, 2, 3, 4, 5 or 6, n is an integer from 0 to 10, preferably n is 0, 1, 2 or 3; Ring B is or not present, wherein the connection point 2 is the wavy line connected to the B ring in the formula Vc"; R4 and R5 are independently H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl or cyclobutyl, preferably R4 and R5 are both methyl; and The wavy line in the formula Vc indicates a bond, and two of the three tildes are absent; Alternatively, the compound has a structure shown in Formula Vc"-1: Among them, R9, R 10 , R 13 , R 14 , L1, B ring and wavy line have the same definitions as the corresponding substituents in formula Vc"; Alternatively, the compound has a structure shown in formula Vc"-2 or Vc"-3: Among them, R9, R 10 , R 13 , R 14 , L1 and the wavy line have the same definitions as the corresponding substituents in formula Vc", and Ring B is or absent, wherein R4 and R5 are independently H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl or cyclobutyl, preferably R4 and R5 are independently methyl; Preferably, the compound is selected from: 68".

28. An RNAi agent or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein the RNAi agent has a structure shown in Formula VI, VIa, VIb, VIc, VId, VIe, VIf, VIg, VIh, VIi, VIj or VIk: in, is an oligonucleotide, preferably siRNA or ASO, wherein the siRNA or ASO is linked to L via a phosphate group, a phosphorothioate group 21 and / or L 11 connected; z1 and z2 are independently 0 or 1, and z1 and z2 are not 0 at the same time; y1 and y2 are independently 1, 2 or 3; Each Ligand is independently selected from Formula Ia" of claim 19, Formula Ib" or Formula Ib"-1 of claim 20, Formula IIa" or IIb" of claim 21, Formula IIIa", IIIb", IIIa"-1 or IIIb"-1 of claim 22, Formula IVa" or IVa"-1 of claim 23, Formula IVb" of claim 24, Formula Va", Va"-1, Va"-2 or Va"-3 of claim 25, Formula Vb", Vb"-1 or Vb"-2 of claim 26, and Formula Vc", Vc"-1, Vc"-2 or Vc"-3 of claim 27; L 11 and L 21 Independently selected from: wherein n and m are integers from 0 to 10, preferably integers from 2 to 6, and the connection point 1 is connected to the oligonucleotide, and the connection point 2 is connected to L 12 or L 22 ; L 12 and L 22 is independently a bond or a branching group, the branching group being independently selected from: wherein n is an integer from 0 to 10, preferably an integer from 2 to 6, and connection point 1 is connected to L 11 or L 21 , connect points 2, 3 and 4 to L 13 or L 23 ; L 13 and L 23 Independently selected from: Wherein n and m are integers from 0 to 10, preferably integers from 2 to 6, and the wavy line on the left side of the formula is connected to L 12 or L 22 , the wavy line on the right side of the formula is connected to Ligand; Preferably, L 21 , L 22 and L 23 Together they form a structure selected from the following, wherein the left side of the formula is linked to the oligonucleotide via a phosphate group or a phosphorothioate group: Preferably, L 11 , L 12 and L 13 Together they form a structure selected from the following, wherein the left side of the formula is linked to the oligonucleotide via a phosphate group or a phosphorothioate group: Preferably, the structure of the RNAi agent is selected from the group consisting of structural formula 201-21, 202-21, 203-21, 204-21, 205-21, 206-21, 207-21, 208-21, 209-21, 210-21, 211-21, 212-21, 213-5, 214-5, 215-5, 216-5, 217-5, 218-5, 219-5, 220-5, 221-5, 222-5, 223-5, 224-5, 225-6, 226-6, 227-6, 228-6, 229-6, 230-6, 231-6, 232-6, 233-6, 234-6, 235-6, 236-6, 237-6 37-7, 238-7, 239-7, 240-7, 241-7, 242-7, 243-7, 244-7, 245-7, 246-7, 247-7, 248-7, 249-8, 250-8, 251-8, 252-8, 253-8, 254-8, 255-8, 256-8, 257-8 , 258-8, 259-8, 260-8, 261-9, 262-9, 263-9, 264-9, 265-9, 266-9, 267-9, 268-9, 269-9, 270-9, 271-9, 272-9, 273-13, 274-13, 275-13, 276-13, 277-13 , 278-13, 279-13, 280-13, 281-13, 282-13, 283-13, 284-13, 285-14, 286-14, 287-14, 288-14, 289-14, 290-14, 291-14, 292-14, 293-14, 294-14, 295- 14, 296-14, 297-15, 298-15, 299-15, 300-15, 301-15, 302-15, 303-15, 304-15, 305-15, 306-15, 307-15, 308-15, 309-18, 310-18, 311-18, 312-18, 313 -18, 314-18, 315-18, 316-18, 317-18, 318-18, 319-18, 320-18, 321-20, 322-20, 323-20, 324-20, 325-20, 326-20, 327-20, 328-20, 329-20, 330-20, 331-20 31-20, 332-20, 333-16, 334-16, 335-16, 336-16, 337-16, 338-16, 339-16, 340-16, 341-16, 342-16, 343-16, 344-16, 345-17, 346-17, 347-17, 348-17,349-17, 350-17, 351-17, 352-17, 353-17, 354-17, 355-17 and 356-17.

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