Triazolyl-containing compound as well as preparation method and application thereof

Abstract

Provided are a triazolyl-containing compound, a preparation method and use thereof, which can be used to promote the attachment of a targeting group, a pharmacokinetic (PK) enhancer or modifier, or other presenting agent to an oligonucleotide, exhibiting improved reaction yield, stability and biological activity.

Description

Triazole-containing compound, preparation method and use Technical Field

[0001] The present disclosure relates to the field of medicine, and in particular to a triazole-containing compound, a preparation method and uses thereof. Background Art

[0002] Synthetic oligonucleotides, such as antisense compounds, aptamers, ribozymes, and RNA interference (RNAi) agents or molecules, are increasingly used in biomedical research, diagnosis, and therapy. These synthetic oligonucleotides have been used to inhibit or knock down gene expression in vitro, in situ, and in vivo in a sequence-dependent manner.

[0003] RNA interference (siRNA) is an effective method for silencing gene expression. According to statistics, over 80% of disease-related proteins in the human body cannot be targeted by currently available small-molecule drugs or biopharmaceuticals, making them undruggable. Using RNA interference technology, we can design appropriate siRNAs based on the mRNA encoding these proteins, specifically targeting and degrading the target mRNA, thereby inhibiting the production of the associated proteins. Therefore, siRNA holds great promise for drug development. However, achieving therapeutic RNA interference in vivo requires delivering siRNA molecules to specific cells within the body.

[0004] The strategy usually adopted is that targeting group or other pharmacologically active molecules are optionally connected to synthetic oligonucleotides by connecting chains for in vivo delivery. The connecting chains used should be able to adapt to different synthetic oligonucleotides and different targeting groups or pharmacologically active molecules. In addition, the connecting chains themselves are nontoxic and do not produce toxic or other harmful by-products. The connecting chains should also have the characteristics of easy fracture in the target location (such as target cell), and the stable characteristics of other positions (such as circulation, subcutaneous space or extracellular space) beyond the target location.

[0005] Summary of the Invention

[0006] The present disclosure provides an alkynyl-containing compound or a pharmaceutically acceptable salt thereof as shown in Formula I,

[0007] Among them, R 1 、R 2 and R 3 Each is independently C optionally substituted by one or more substituents 1-6 Alkyl, the substituent is halogen, hydroxyl or cyano;

[0008] L1 is a C optionally interrupted by one or more groups 1-10 Alkyl, the group selected from -O-, -S-, -N- and -C(=O)-;

[0009] X is a bond, -C(=O), -C(=O)-NH-, or -NH-C(=O)-;

[0010] Q is

[0011] L2 is each independently -O-(CH2) p1 -C(=O)-NH-(CH2CH2O) p2 -(CH2) p3 、-C(=O)-NH-(CH2CH2O) p4 -(CH2) p5 or -C(=O)-(CH2CH2O) p6 -(CH2) p7 ;

[0012] n is 3 or 4;

[0013] m1, m2, m3, m4, m5, m6, m7, m8, m9, m10, m11, m12, m13 and m14 are each independently 0, 1, 2, 3, 4, 5 or 6;

[0014] p1, p2, p3, p4, p5, p6 and p7 are each independently 0, 1, 2, 3 or 4;

[0015] The condition is that when Q is When L2 is not simultaneously -C(=O)-NH-(CH2CH2O) p4 -(CH2) p5 .

[0016] In some embodiments, R 1 、R 2 and R 3 Each is independently C optionally substituted by one or more substituents 1-4 Alkyl, the substituent is halogen, hydroxyl or cyano.

[0017] In some embodiments, R 1 、R 2 and R 3 Each is independently methyl, ethyl, propyl, isopropyl, optionally substituted by one or more substituents, wherein the substituent is fluoro, chloro, bromo, hydroxy or cyano.

[0018] In some embodiments, R 1 and R 2 All are isopropyl.

[0019] In some embodiments, R 3 for

[0020] In some embodiments, Q is L2 is each independently -O-(CH2) p1 -C(=O)-NH-(CH2CH2O) p2 -(CH2) p3 , m1, m2, m3, p1, p2 and p3 are as defined in Formula I.

[0021] In some embodiments, Q is L2 is each independently -C(=O)-NH-(CH2CH2O) p4 -(CH2) p5 , m4, m5, m9, m10, p4 and p5 are as defined in Formula I.

[0022] In some embodiments, Q is L2 is each independently -C(=O)-(CH2CH2O) p6 -(CH2) p7 , m6, m7, m8, p6 and p7 are as defined in Formula I.

[0023] In some embodiments, Q is L2 is each independently -O-(CH2) p1 -C(=O)-NH-(CH2CH2O) p2 -(CH2) p3 , m11, m12, m13, m14, p1, p2 and p3 are as defined in Formula I.

[0024] In some embodiments, L2 are the same.

[0025] In some embodiments, L1 is C optionally interrupted by one or more groups. 1-10 Alkyl, said group being selected from -O-, -N- and -C(=O)-.

[0026] In some embodiments, L1 is -(CH2) q1 -、-(CH2) q2 -NH-C(=O)-(CH2) q3 -or-(CH2) q4 -O-(CH2) q5 -, q1, q2, q3, q4 and q5 are each independently an integer of 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10).

[0027] In some embodiments, L1 is -(CH2) q1 -、-(CH2) q2-NH-C(=O)-(CH2) q3 -or-(CH2) q4 -O-(CH2) q5 -, q1, q2, q3, q4 and q5 are each independently an integer of 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10), wherein -(CH2) q1 -、-(CH2) q2 -NH-C(=O)-(CH2) q3 -or-(CH2) q4 -O-(CH2) q5 The right side of - is connected to X.

[0028] In some embodiments, L1 is -(CH2)6-, -(CH2)6-NH-C(=O)-(CH2)3-, or -(CH2)6-O-CH2-.

[0029] In some embodiments, L1 is -(CH2)6-, -(CH2)6-NH-C(=O)-(CH2)3-, or -(CH2)6-O-CH2-, wherein the right side of -(CH2)6-, -(CH2)6-NH-C(=O)-(CH2)3-, or -(CH2)6-O-CH2- is connected to X.

[0030] In some embodiments, Q is wherein the a end is connected to X, and m1, m2, m3, m4, m5, m6, m7, m8, m9, m10, m11, m12, m13 and m14 are as defined in Formula I.

[0031] In some embodiments, Q is

[0032] In some embodiments, Q is Among them, the a end is connected to X.

[0033] In some embodiments, each L2 is independently

[0034] In some embodiments, each L2 is independently Among them, the b end is connected to Q.

[0035] The present disclosure provides an alkynyl-containing compound or a pharmaceutically acceptable salt thereof, wherein the alkynyl-containing compound is selected from:

[0036] The present disclosure provides a conjugate of a nucleic acid and an alkynyl-containing moiety or a pharmaceutically acceptable salt thereof, which comprises a nucleic acid and one or more alkynyl-containing moieties, wherein the alkynyl-containing moieties are the same or different, and the structure of the alkynyl-containing moiety is as shown in Formula II.

[0037] wherein L1 is a C optionally interrupted by one or more groups 1-10 Alkyl, the group selected from -O-, -S-, -N- and -C(=O)-;

[0038] X is a bond, -C(=O), -C(=O)-NH-, or -NH-C(=O)-;

[0039] Q is

[0040] L2 is each independently -O-(CH2) p1 -C(=O)-NH-(CH2CH2O) p2 -(CH2) p3 、-C(=O)-NH-(CH2CH2O) p4 -(CH2) p5 or -C(=O)-(CH2CH2O) p6 -(CH2) p7 ;

[0041] n is 3 or 4;

[0042] m1, m2, m3, m4, m5, m6, m7, m8, m9, m10, m11, m12, m13 and m14 are each independently 0, 1, 2, 3, 4, 5 or 6;

[0043] p1, p2, p3, p4, p5, p6 and p7 are each independently 0, 1, 2, 3 or 4;

[0044] The condition is that when Q is When L2 is not simultaneously -C(=O)-NH-(CH2CH2O) p4 -(CH2) p5 .

[0045] In some embodiments, Q is L2 is each independently -O-(CH2) p1 -C(=O)-NH-(CH2CH2O) p2 -(CH2) p3 , m1, m2, m3, p1, p2 and p3 are as defined in Formula II.

[0046] In some embodiments, Q is L2 is each independently -C(=O)-NH-(CH2CH2O) p4 -(CH2) p5 , m4, m5, m9, m10, p4 and p5 are as defined in Formula II.

[0047] In some embodiments, Q is L2 is each independently -C(=O)-(CH2CH2O) p6 -(CH2) p7 , m6, m7, m8, p6 and p7 are as defined in Formula II.

[0048] In some embodiments, Q is L2 is each independently -O-(CH2) p1 -C(=O)-NH-(CH2CH2O) p2 -(CH2) p3 , m11, m12, m13, m14, p1, p2 and p3 are as defined in Formula II.

[0049] In some embodiments, L2 are the same.

[0050] In some embodiments, L1 is C optionally interrupted by one or more groups. 1-10 Alkyl, said group being selected from -O-, -N- and -C(=O)-.

[0051] In some embodiments, L1 is -(CH2) q1 -、-(CH2) q2 -NH-C(=O)-(CH2) q3 -or-(CH2) q4 -O-(CH2) q5 -, q1, q2, q3, q4 and q5 are each independently an integer of 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10).

[0052] In some embodiments, L1 is -(CH2) q1 -、-(CH2) q2 -NH-C(=O)-(CH2) q3 -or-(CH2) q4 -O-(CH2) q5 -, q1, q2, q3, q4 and q5 are each independently an integer of 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10), wherein -(CH2) q1 -、-(CH2) q2-NH-C(=O)-(CH2) q3 -or-(CH2) q4 -O-(CH2) q5 The right side of - is connected to X.

[0053] In some embodiments, L1 is -(CH2)6-, -(CH2)6-NH-C(=O)-(CH2)3-, or -(CH2)6-O-CH2-.

[0054] In some embodiments, L1 is -(CH2)6-, -(CH2)6-NH-C(=O)-(CH2)3-, or -(CH2)6-O-CH2-, wherein the right side of -(CH2)6-, -(CH2)6-NH-C(=O)-(CH2)3-, or -(CH2)6-O-CH2- is connected to X.

[0055] In some embodiments, Q is wherein the a end is connected to X, and m1, m2, m3, m4, m5, m6, m7, m8, m9, m10, m11, m12, m13 and m14 are as defined in Formula II.

[0056] In some embodiments, Q is

[0057] In some embodiments, Q is Among them, the a end is connected to X.

[0058] In some embodiments, each L2 is independently

[0059] In some embodiments, each L2 is independently Among them, the b end is connected to Q.

[0060] In some embodiments, the nucleic acid is linked to the alkyne-containing moiety through a phosphate group, a phosphorothioate group, or a phosphonic acid group.

[0061] In some embodiments, the nucleic acid is linked to the alkyne-containing moiety through a phosphate group.

[0062] In some embodiments, the nucleic acid is linked to the alkyne-containing moiety through a phosphorothioate group.

[0063] In some embodiments, the phosphate group is a phosphodiester group.

[0064] In some embodiments, the phosphorothioate group is a phosphorothioate diester group.

[0065] In some embodiments, the nucleic acid includes, but is not limited to, single-stranded oligonucleotides, single-stranded antisense oligonucleotides, short interfering RNA (siRNA, comprising partially complementary sense and antisense strands), double-stranded RNA (dsRNA), microRNA (miRNA), short hairpin RNA (shRNA), and Dicer substrates.

[0066] In some embodiments, the 3' end of the nucleic acid is conjugated to an alkyne-containing moiety.

[0067] In some embodiments, the 5' end of the nucleic acid is conjugated to an alkyne-containing moiety.

[0068] In some embodiments, both the 3' end and the 5' end of the nucleic acid are conjugated to an alkyne-containing moiety.

[0069] The aforementioned 3' end and / or 5' end of the nucleic acid conjugated to the alkyne-containing moiety refers to the 3' end and / or 5' end of the nucleic acid chain conjugated to the alkyne-containing moiety.

[0070] In some embodiments, the nucleic acid is an siRNA, the 5' end of the sense strand of which is conjugated to an alkyne-containing moiety.

[0071] In some embodiments, the nucleic acid is single-stranded nucleic acid.

[0072] In some embodiments, the single-stranded nucleic acid is the sense strand of an siRNA.

[0073] In some embodiments, the single-stranded nucleic acid is the antisense strand of a siRNA.

[0074] In some embodiments, the nucleic acid is a double-stranded nucleic acid.

[0075] In some embodiments, the double-stranded nucleic acid comprises at least one duplex region in which the first strand of nucleic acid is at least partially complementary to the second strand of nucleic acid, wherein:

[0076] (1) The first strand nucleic acid is not conjugated to an alkynyl-containing moiety at both ends; and the second strand nucleic acid is conjugated to an alkynyl-containing moiety at the 5' end and not at the 3' end, or the second strand nucleic acid is conjugated to an alkynyl-containing moiety at the 3' end and not at the 5' end, or both the 3' end and the 5' end of the second strand nucleic acid are conjugated to an alkynyl-containing moiety;

[0077] (2) Both ends of the second strand nucleic acid are not conjugated to an alkynyl-containing moiety; and the 5' end of the first strand nucleic acid is conjugated to an alkynyl-containing moiety, but the 3' end is not conjugated to an alkynyl-containing moiety, or the 3' end of the first strand nucleic acid is conjugated to an alkynyl-containing moiety, but the 5' end is not conjugated to an alkynyl-containing moiety, or both the 3' end and the 5' end of the first strand nucleic acid are conjugated to an alkynyl-containing moiety;

[0078] (3) The 5' end of the first strand nucleic acid and the second strand nucleic acid are both conjugated to an alkynyl-containing moiety, and the 3' end of neither is conjugated to an alkynyl-containing moiety; or the 3' end of the first strand nucleic acid and the second strand nucleic acid are both conjugated to an alkynyl-containing moiety, and the 5' end of neither is conjugated to an alkynyl-containing moiety; or the 3' end and 5' end of the first strand nucleic acid and the second strand nucleic acid are both conjugated to an alkynyl-containing moiety; or the 3' end of the first strand nucleic acid and the 5' end of the second strand nucleic acid are both conjugated to an alkynyl-containing moiety, and neither the 5' end of the first strand nucleic acid nor the 3' end of the second strand nucleic acid is conjugated to an alkynyl-containing moiety; or the 5' end of the first strand nucleic acid and the 3' end of the second strand nucleic acid are both conjugated to an alkynyl-containing moiety, and neither the 3' end of the first strand nucleic acid nor the 5' end of the second strand nucleic acid is conjugated to an alkynyl-containing moiety;

[0079] (4) Both the 3' and 5' ends of the first strand nucleic acid are conjugated to an alkynyl-containing moiety, and either the 5' or 3' end of the second strand nucleic acid is conjugated to an alkynyl-containing moiety; or both the 3' and 5' ends of the second strand nucleic acid are conjugated to an alkynyl-containing moiety, and either the 5' or 3' end of the first strand nucleic acid is conjugated to an alkynyl-containing moiety.

[0080] In some embodiments, the nucleic acid is siRNA.

[0081] In some embodiments, the nucleic acid is an siRNA targeting RAGE.

[0082] In some embodiments, the nucleic acid is an siRNA targeting MUC5B.

[0083] In some embodiments, the nucleic acid is an siRNA targeting APP.

[0084] In some embodiments, the nucleic acid includes one or more modified nucleotides.

[0085] In some embodiments, the conjugate of the nucleic acid and the alkynyl-containing moiety is represented by Formula II-A,

[0086] Wherein, R is nucleic acid; W is OH, SH, O - or S - ; L1, L2, X, Q and n are as defined in Formula II.

[0087] In some embodiments, W is OH or O - .

[0088] In some embodiments, W is SH or S- .

[0089] The present disclosure provides a conjugate of a nucleic acid and an alkynyl-containing moiety or a pharmaceutically acceptable salt thereof, wherein the conjugate of the nucleic acid and the alkynyl-containing moiety is selected from the following structures,

[0090] Wherein, R is a nucleic acid, and the nucleic acid is the same as described above.

[0091] In some embodiments, the 5' end of the nucleic acid is conjugated to an alkyne-containing moiety.

[0092] The present disclosure provides a targeting ligand as shown in Formula III or a pharmaceutically acceptable salt thereof,

[0093] wherein L1 is a C optionally interrupted by one or more groups 1-10 Alkyl, the group selected from -O-, -S-, -N- and -C(=O)-;

[0094] X is a bond, -C(=O), -C(=O)-NH-, or -NH-C(=O)-;

[0095] Q is

[0096] L2 is each independently -O-(CH2) p1 -C(=O)-NH-(CH2CH2O) p2 -(CH2) p3 、-C(=O)-NH-(CH2CH2O) p4 -(CH2) p5 or -C(=O)-(CH2CH2O) p6 -(CH2) p7 ;

[0097] TL are each independently a targeting group;

[0098] n is 3 or 4;

[0099] m1, m2, m3, m4, m5, m6, m7, m8, m9, m10, m11, m12, m13 and m14 are each independently 0, 1, 2, 3, 4, 5 or 6;

[0100] p1, p2, p3, p4, p5, p6 and p7 are each independently 0, 1, 2, 3 or 4;

[0101] The condition is that when Q is When L2 is not simultaneously -C(=O)-NH-(CH2CH2O) p4 -(CH2) p5 .

[0102] In some embodiments, Q is L2 is each independently -O-(CH2) p1 -C(=O)-NH-(CH2CH2O) p2 -(CH2) p3 , m1, m2, m3, p1, p2 and p3 are as defined in Formula III.

[0103] In some embodiments, Q is L2 is each independently -C(=O)-NH-(CH2CH2O) p4 -(CH2) p5 , m4, m5, m9, m10, p4 and p5 are as defined in Formula III.

[0104] In some embodiments, Q is L2 is each independently -C(=O)-(CH2CH2O) p6 -(CH2) p7 , m6, m7, m8, p6 and p7 are as defined in Formula III.

[0105] In some embodiments, Q is L2 is each independently -O-(CH2) p1 -C(=O)-NH-(CH2CH2O) p2 -(CH2) p3 , m11, m12, m13, m14, p1, p2 and p3 are as defined in Formula III.

[0106] In some embodiments, L2 are the same.

[0107] In some embodiments, L1 is C optionally interrupted by one or more groups. 1-10 Alkyl, said group being selected from -O-, -N- and -C(=O)-.

[0108] In some embodiments, L1 is -(CH2) q1 -、-(CH2) q2 -NH-C(=O)-(CH2) q3 -or-(CH2) q4 -O-(CH2) q5 -, q1, q2, q3, q4 and q5 are each independently an integer of 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10).

[0109] In some embodiments, L1 is -(CH2) q1 -、-(CH2) q2 -NH-C(=O)-(CH2) q3 -or-(CH2) q4 -O-(CH2) q5 -, q1, q2, q3, q4 and q5 are each independently an integer of 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10), wherein -(CH2) q1 -、-(CH2) q2 -NH-C(=O)-(CH2) q3 -or-(CH2) q4 -O-(CH2) q5 The right side of - is connected to X.

[0110] In some embodiments, L1 is -(CH2)6-, -(CH2)6-NH-C(=O)-(CH2)3-, or -(CH2)6-O-CH2-.

[0111] In some embodiments, L1 is -(CH2)6-, -(CH2)6-NH-C(=O)-(CH2)3-, or -(CH2)6-O-CH2-, wherein the right side of -(CH2)6-, -(CH2)6-NH-C(=O)-(CH2)3-, or -(CH2)6-O-CH2- is connected to X.

[0112] In some embodiments, Q is wherein the a terminal is connected to X, and m1, m2, m3, m4, m5, m6, m7, m8, m9, m10, m11, m12, m13 and m14 are as defined in Formula III.

[0113] In some embodiments, Q is

[0114] In some embodiments, Q is Among them, the a end is connected to X.

[0115] In some embodiments, each L2 is independently

[0116] In some embodiments, each L2 is independently Among them, the b end is connected to Q.

[0117] In some embodiments, the targeting group is an integrin targeting group.

[0118] In some embodiments, the integrin targeting group is an αvβ6 integrin targeting group.

[0119] In some embodiments, the targeting group TL is of formula (III-a):

[0120] Wherein Y is a 5-14 membered heteroaryl, said heteroaryl being optionally substituted by one or more of the following groups: halogen, hydroxy, oxo, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyloxy, C 2-6 Alkynyloxy, C 3-6 Cycloalkoxy, 3 to 6 membered heterocycloalkoxy, C 3-8 Cycloalkenyloxy, phenyl or 5 to 6 membered heteroaryl, said C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyloxy, C 2-6 Alkynyloxy, C 3-6 Cycloalkoxy, 3 to 6 membered heterocycloalkoxy, C 3-8 Cycloalkenyloxy, phenyl or 5- to 6-membered heteroaryl is optionally substituted by one or more substituents selected from halogen, hydroxy, oxo, nitro, and cyano;

[0121] B is selected from -CH2-, -NH-, or does not exist;

[0122] A is selected from -CH2-, -NH-, -O- or is absent;

[0123] Z is selected from OR 13 、N(R 13 )2 or SR 13 ;

[0124] R 21 Selected from H, C 1-6 Alkyl, OH, COOH, CON(R 5 )2、OR 6 Or formula (L) wherein a* represents the connection point with the phenyl group, b* represents the connection point with the triazole group in formula III, n1 is selected from an integer of 2-20 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20), and the C 1-6 The alkyl group is optionally substituted with one or more halogen, hydroxy or cyano groups;

[0125] Each R 5 、R 6 Independently selected from H or C 1-6 Alkyl, the C 1-6 The alkyl group is optionally substituted with one or more halogen, hydroxy or cyano groups;

[0126] R 22 、R P1 and R P2 Each is independently selected from H, halogen, 3 to 20-membered cycloalkylene, 6 to 14-membered arylene, 3 to 12-membered heterocycloalkylene, 5 to 14-membered heteroarylene or formula (L) wherein a* represents the point of attachment to the phenyl group, b* represents the point of attachment to the triazole group in formula III, and n1 is selected from an integer of 2-20 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20); the cycloalkylene, arylene, heterocycloalkylene, heteroarylene groups are optionally substituted with one or more of the following groups: halogen, hydroxyl, oxo, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyloxy, C 2-6 Alkynyloxy, C 3-6 Cycloalkoxy, 3 to 6 membered heterocycloalkoxy, C 3-8 Cycloalkenyloxy, phenyl or 5 to 6 membered heteroaryl, said C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyloxy, C 2-6 Alkynyloxy, C 3-6 Cycloalkoxy, 3 to 6 membered heterocycloalkoxy, C 3-8 Cycloalkenyloxy, phenyl or 5- to 6-membered heteroaryl is optionally substituted by one or more substituents selected from halogen, hydroxy, oxo, nitro, and cyano;

[0127] R 11 、R 12 Each independently selected from H or C 1-6 Alkyl, the C 1-6 The alkyl group is optionally substituted with one or more halogen, hydroxy or cyano groups;

[0128] Each R 13 Each independently selected from H, C 1-6 Alkyl or formula (L) wherein a* represents the point of connection to the phenyl group, b* represents the point of connection to the triazole group in formula III, and n1 is selected from an integer of 2-20 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20); 1-6The alkyl group is optionally substituted with one or more halogen, hydroxy or cyano groups;

[0129] The condition is that R 21 、R 22 、R 13 、R P1 and R P2 There is only one formula (L).

[0130] In some embodiments, R 22 Formula (L), R P1 、R P2 Each is H.

[0131] In some embodiments, group Y is a 5- to 12-membered heteroaryl group optionally substituted with one or more of the following groups: halogen, hydroxy, oxo, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyloxy, C 2-6 Alkynyloxy, C 3-6 Cycloalkoxy, 3 to 6 membered heterocycloalkoxy, C 3-8 Cycloalkenyloxy, phenyl or 5 to 6 membered heteroaryl, said C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyloxy, C 2-6 Alkynyloxy, C 3-6 Cycloalkoxy, 3 to 6 membered heterocycloalkoxy, C 3-8 The cycloalkenyloxy, phenyl or 5- to 6-membered heteroaryl is optionally substituted by one or more substituents selected from halogen, hydroxy, oxo, nitro and cyano.

[0132] In some embodiments, group Y is a 5-membered or 6-membered heteroaryl group, which is optionally substituted with one or more of the following groups: halogen, hydroxy, oxo, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, the C 1-6 Alkyl, C 1-6 The alkoxy group is optionally substituted with one or more substituents selected from halogen, hydroxy, oxo, nitro, and cyano.

[0133] In some embodiments, group Y is pyridyl substituted with one or more methyl groups.

[0134] In some embodiments, group Y is selected from

[0135] In some embodiments, group Y is selected from

[0136] In some embodiments, the group B of the targeting group TL is -NH- or is absent.

[0137] In some embodiments, group B of the targeting group TL is absent.

[0138] In some embodiments, the group A of the targeting group TL is selected from -CH2-, -NH-, -O-, or is absent.

[0139] In some embodiments, the group A of the targeting group TL is -CH2-.

[0140] In some embodiments, the group A of the targeting group TL is -NH-.

[0141] In some embodiments, the group A of the targeting group TL is -O-.

[0142] In some embodiments, group A of the targeting group TL is absent.

[0143] In some specific embodiments, the groups Y, B, and A in the targeting group TL are -NH-, -NH-;

[0144] or groups Y, B, and A are -NH-, -O-;

[0145] or groups Y, B, and A are -NH-, -CH2-;

[0146] Or groups Y and A are -CH2-, B does not exist;

[0147] Or group Y is B. A does not exist;

[0148] or groups Y, B, and A are -NH-, -CH2-.

[0149] In some embodiments, the targeting group TL is of formula (III-b):

[0150] wherein Y is a 5-14 membered heteroaryl group; the heteroaryl group is optionally substituted by one or more of the following groups: halogen, hydroxy, oxo, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyloxy, C 2-6 Alkynyloxy, C 3-6 Cycloalkoxy, 3 to 6 membered heterocycloalkoxy, C 3-8Cycloalkenyloxy, phenyl or 5 to 6 membered heteroaryl, said C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyloxy, C 2-6 Alkynyloxy, C 3-6 Cycloalkoxy, 3 to 6 membered heterocycloalkoxy, C 3-8 Cycloalkenyloxy, phenyl or 5- to 6-membered heteroaryl is optionally substituted by one or more substituents selected from halogen, hydroxy, oxo, nitro, and cyano;

[0151] B is selected from -CH2-, -NH-, or does not exist;

[0152] A is selected from -CH2-, -NH-, -O- or is absent;

[0153] R 21 Selected from H, C 1-6 Alkyl, OH, COOH, CH2CH2CH2NH2, CONHR 5 , OR 6 Or formula (L) wherein a* represents the point of attachment to the phenyl group, b* represents the point of attachment to the triazole group in formula III, and n1 is selected from an integer of 2 to 20 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20);

[0154] R 5 、R 6 Each independently selected from H or C 1-6 Alkyl, the C 1-6 The alkyl group is optionally substituted with one or more halogen, hydroxy or cyano groups;

[0155] R 22 is selected from 3 to 20-membered cycloalkylene, 6 to 14-membered arylene, 3 to 12-membered heterocycloalkylene, 5 to 14-membered heteroarylene or a group of formula (L) wherein a* represents the point of attachment to the phenyl group, b* represents the point of attachment to the triazole group in formula III, and n1 is selected from an integer of 2-20 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20); the cycloalkylene, arylene, heterocycloalkylene, heteroarylene groups are optionally substituted with one or more of the following groups: halogen, hydroxyl, oxo, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyloxy, C 2-6 Alkynyloxy, C 3-6 Cycloalkoxy, 3 to 6 membered heterocycloalkoxy, C 3-8Cycloalkenyloxy, phenyl or 5 to 6 membered heteroaryl, said C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyloxy, C 2-6 Alkynyloxy, C 3-6 Cycloalkoxy, 3 to 6 membered heterocycloalkoxy, C 3-8 Cycloalkenyloxy, phenyl or 5- to 6-membered heteroaryl is optionally substituted by one or more substituents selected from halogen, hydroxy, oxo, nitro, and cyano;

[0156] The condition is that R 21 、R 22 There is only one formula (L) in ;

[0157] R 11 、R 12 、R 13 Each independently selected from H or C 1-6 Alkyl, the C 1-6 The alkyl group is optionally substituted with one or more halogen, hydroxy or cyano groups.

[0158] In some embodiments, group Y is a 5- to 12-membered heteroaryl group optionally substituted with one or more of the following groups: halogen, hydroxy, oxo, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyloxy, C 2-6 Alkynyloxy, C 3-6 Cycloalkoxy, 3 to 6 membered heterocycloalkoxy, C 3-8 Cycloalkenyloxy, phenyl or 5 to 6 membered heteroaryl, said C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyloxy, C 2-6 Alkynyloxy, C 3-6 Cycloalkoxy, 3 to 6 membered heterocycloalkoxy, C 3-8 The cycloalkenyloxy, phenyl or 5- to 6-membered heteroaryl is optionally substituted by one or more substituents selected from halogen, hydroxy, oxo, nitro and cyano.

[0159] In some embodiments, group Y is a 5-membered or 6-membered heteroaryl group, which is optionally substituted with one or more of the following groups: halogen, hydroxy, oxo, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, the C 1-6 Alkyl, C 1-6 The alkoxy group is optionally substituted with one or more substituents selected from halogen, hydroxy, oxo, nitro, and cyano.

[0160] In some embodiments, group Y is pyridyl substituted with one or more methyl groups.

[0161] In some embodiments, group Y is selected from

[0162] In some embodiments, group Y is selected from

[0163] In some embodiments, the group B of the targeting group TL is -NH- or is absent.

[0164] In some embodiments, group B of the targeting group TL is absent.

[0165] In some embodiments, the group A of the targeting group TL is selected from -CH2-, -NH-, -O-, or is absent.

[0166] In some embodiments, the group A of the targeting group TL is -CH2-.

[0167] In some embodiments, the group A of the targeting group TL is -NH-.

[0168] In some embodiments, the group A of the targeting group TL is -O-.

[0169] In some embodiments, group A of the targeting group TL is absent.

[0170] In some specific embodiments, the groups Y, B, and A in the targeting group TL are -NH-, -NH-;

[0171] or groups Y, B, and A are -NH-, -O-;

[0172] or groups Y, B, and A are -NH-, -CH2-;

[0173] Or groups Y and A are -CH2-, B does not exist;

[0174] Or group Y is B. A does not exist;

[0175] or groups Y, B, and A are -NH-, -CH2-.

[0176] In some embodiments, the targeting group TL is of formula (III-c):

[0177] Wherein Y is a 5-14 membered heteroaryl, said heteroaryl being optionally substituted by one or more of the following groups: halogen, hydroxy, oxo, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyloxy, C 2-6 Alkynyloxy, C 3-6 Cycloalkoxy, 3 to 6 membered heterocycloalkoxy, C 3-8 Cycloalkenyloxy, phenyl or 5 to 6 membered heteroaryl, said C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyloxy, C 2-6 Alkynyloxy, C 3-6 Cycloalkoxy, 3 to 6 membered heterocycloalkoxy, C 3-8 Cycloalkenyloxy, phenyl or 5- to 6-membered heteroaryl is optionally substituted by one or more substituents selected from halogen, hydroxy, oxo, nitro, and cyano;

[0178] B is selected from -CH2-, -NH-, or does not exist;

[0179] A is selected from -CH2-, -NH-, -O- or is absent;

[0180] R 21 Formula (L) a* represents the point of attachment to the phenyl group, and b* represents the point of attachment to the triazole group in Formula III; wherein n1 is an integer selected from 2 to 20 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20);

[0181] R 22 is selected from cycloalkyl, aryl, heteroaryl or heterocycloalkyl having 2 to 10 carbon atoms, wherein the heteroaryl, cycloalkyl, aryl or heterocycloalkyl is optionally substituted by one or more of the following groups: halogen, hydroxy, oxo, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyloxy, C 2-6 Alkynyloxy, C 3-6 Cycloalkoxy, 3 to 6 membered heterocycloalkoxy, C 3-8 Cycloalkenyloxy, phenyl or 5 to 6 membered heteroaryl, said C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyloxy, C 2-6 Alkynyloxy, C 3-6 Cycloalkoxy, 3 to 6 membered heterocycloalkoxy, C 3-8The cycloalkenyloxy, phenyl or 5- to 6-membered heteroaryl is optionally substituted by one or more substituents selected from halogen, hydroxy, oxo, nitro and cyano.

[0182] In some embodiments, group Y is a 5- to 12-membered heteroaryl group optionally substituted with one or more of the following groups: halogen, hydroxy, oxo, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyloxy, C 2-6 Alkynyloxy, C 3-6 Cycloalkoxy, 3 to 6 membered heterocycloalkoxy, C 3-8 Cycloalkenyloxy, phenyl or 5 to 6 membered heteroaryl, said C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyloxy, C 2-6 Alkynyloxy, C 3-6 Cycloalkoxy, 3 to 6 membered heterocycloalkoxy, C 3-8 The cycloalkenyloxy, phenyl or 5- to 6-membered heteroaryl is optionally substituted by one or more substituents selected from halogen, hydroxy, oxo, nitro and cyano.

[0183] In some embodiments, group Y is a 5-membered or 6-membered heteroaryl group, which is optionally substituted with one or more of the following groups: halogen, hydroxy, oxo, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, the C 1-6 Alkyl, C 1-6 The alkoxy group is optionally substituted with one or more substituents selected from halogen, hydroxy, oxo, nitro, and cyano.

[0184] In some embodiments, group Y is pyridyl substituted with one or more methyl groups.

[0185] In some embodiments, group Y is selected from

[0186] In some embodiments, group Y is selected from

[0187] In some embodiments, the group B of the targeting group TL is -NH- or is absent.

[0188] In some embodiments, group B of the targeting group TL is absent.

[0189] In some embodiments, the group A of the targeting group TL is selected from -CH2-, -NH-, -O-, or is absent.

[0190] In some embodiments, the group A of the targeting group TL is -CH2-.

[0191] In some embodiments, the group A of the targeting group TL is -NH-.

[0192] In some embodiments, the group A of the targeting group TL is -O-.

[0193] In some embodiments, group A of the targeting group TL is absent.

[0194] In some specific embodiments, the groups Y, B, and A in the targeting group TL are -NH-, -NH-;

[0195] or groups Y, B, and A are -NH-, -O-;

[0196] or groups Y, B, and A are -NH-, -CH2-;

[0197] Or groups Y and A are -CH2-, B does not exist;

[0198] Or group Y is B. A does not exist;

[0199] or groups Y, B, and A are -NH-, -CH2-.

[0200] In some embodiments, the targeting group TL is of formula (III-d):

[0201] where R 22 Formula (L) a* represents the point of attachment to the naphthyl group, b* represents the point of attachment to the triazole group in formula III; wherein n1 is selected from an integer of 2-20 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20); wherein Y is a 5-14 membered heteroaryl group, which is optionally substituted by one or more of the following groups: halogen, hydroxy, oxo, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyloxy, C 2-6 Alkynyloxy, C 3-6 Cycloalkoxy, 3 to 6 membered heterocycloalkoxy, C 3-8 Cycloalkenyloxy, phenyl or 5 to 6 membered heteroaryl, said C 1-6 Alkyl, C 1-6Alkoxy, C 2-6 Alkenyloxy, C 2-6 Alkynyloxy, C 3-6 Cycloalkoxy, 3 to 6 membered heterocycloalkoxy, C 3-8 Cycloalkenyloxy, phenyl or 5- to 6-membered heteroaryl is optionally substituted by one or more substituents selected from halogen, hydroxy, oxo, nitro, and cyano;

[0202] B is selected from -CH2-, -NH-, or does not exist;

[0203] A is selected from -CH2-, -NH-, -O- or is absent.

[0204] In some embodiments, group Y is a 5- to 12-membered heteroaryl group optionally substituted with one or more of the following groups: halogen, hydroxy, oxo, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyloxy, C 2-6 Alkynyloxy, C 3-6 Cycloalkoxy, 3 to 6 membered heterocycloalkoxy, C 3-8 Cycloalkenyloxy, phenyl or 5 to 6 membered heteroaryl, said C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyloxy, C 2-6 Alkynyloxy, C 3-6 Cycloalkoxy, 3 to 6 membered heterocycloalkoxy, C 3-8 The cycloalkenyloxy, phenyl or 5- to 6-membered heteroaryl is optionally substituted by one or more substituents selected from halogen, hydroxy, oxo, nitro and cyano.

[0205] In some embodiments, group Y is a 5-membered or 6-membered heteroaryl group, which is optionally substituted with one or more of the following groups: halogen, hydroxy, oxo, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, the C 1-6 Alkyl, C 1-6 The alkoxy group is optionally substituted with one or more substituents selected from halogen, hydroxy, oxo, nitro, and cyano.

[0206] In some embodiments, group Y is pyridyl substituted with one or more methyl groups.

[0207] In some embodiments, group Y is selected from

[0208] In some embodiments, group Y is selected from

[0209] In some embodiments, the group B of the targeting group TL is -NH- or is absent.

[0210] In some embodiments, group B of the targeting group TL is absent.

[0211] In some embodiments, the group A of the targeting group TL is selected from -CH2-, -NH-, -O-, or is absent.

[0212] In some embodiments, the group A of the targeting group TL is -CH2-.

[0213] In some embodiments, the group A of the targeting group TL is -NH-.

[0214] In some embodiments, the group A of the targeting group TL is -O-.

[0215] In some embodiments, group A of the targeting group TL is absent.

[0216] In some specific embodiments, the groups Y, B, and A in the targeting group TL are -NH-, -NH-;

[0217] or groups Y, B, and A are -NH-, -O-;

[0218] or groups Y, B, and A are -NH-, -CH2-;

[0219] Or groups Y and A are -CH2-, B does not exist;

[0220] Or group Y is B. A does not exist;

[0221] or groups Y, B, and A are -NH-, -CH2-.

[0222] In some embodiments, n1 is selected from an integer ranging from 2-15.

[0223] In some embodiments, n1 is selected from an integer of 2-10.

[0224] In some embodiments, n1 is selected from an integer of 2-5.

[0225] In some embodiments, n1 is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.

[0226] In some embodiments, the targeting group TL is of formula (III-e):

[0227] Wherein Y is a 5-14 membered heteroaryl, said heteroaryl being optionally substituted by one or more of the following groups: halogen, hydroxy, oxo, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyloxy, C 2-6 Alkynyloxy, C 3-6 Cycloalkoxy, 3 to 6 membered heterocycloalkoxy, C 3-8 Cycloalkenyloxy, phenyl or 5 to 6 membered heteroaryl, said C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyloxy, C 2-6 Alkynyloxy, C 3-6 Cycloalkoxy, 3 to 6 membered heterocycloalkoxy, C 3-8 Cycloalkenyloxy, phenyl or 5- to 6-membered heteroaryl is optionally substituted by one or more substituents selected from halogen, hydroxy, oxo, nitro, and cyano;

[0228] B is selected from -CH2-, -NH-, or does not exist;

[0229] A is selected from -CH2-, -NH-, -O- or is absent.

[0230] In some embodiments, group Y is a 5- to 12-membered heteroaryl group optionally substituted with one or more of the following groups: halogen, hydroxy, oxo, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyloxy, C 2-6 Alkynyloxy, C 3-6 Cycloalkoxy, 3 to 6 membered heterocycloalkoxy, C 3-8 Cycloalkenyloxy, phenyl or 5 to 6 membered heteroaryl, said C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyloxy, C 2-6 Alkynyloxy, C 3-6 Cycloalkoxy, 3 to 6 membered heterocycloalkoxy, C 3-8 The cycloalkenyloxy, phenyl or 5- to 6-membered heteroaryl is optionally substituted by one or more substituents selected from halogen, hydroxy, oxo, nitro and cyano.

[0231] In some embodiments, group Y is a 5-membered or 6-membered heteroaryl group, which is optionally substituted with one or more of the following groups: halogen, hydroxy, oxo, nitro, cyano, C 1-6 Alkyl, C1-6 Alkoxy, the C 1-6 Alkyl, C 1-6 The alkoxy group is optionally substituted with one or more substituents selected from halogen, hydroxy, oxo, nitro, and cyano.

[0232] In some embodiments, group Y is pyridyl substituted with one or more methyl groups.

[0233] In some embodiments, group Y is selected from

[0234] In some embodiments, group Y is selected from

[0235] In some embodiments, the group B of the targeting group TL is -NH- or is absent.

[0236] In some embodiments, group B of the targeting group TL is absent.

[0237] In some embodiments, the group A of the targeting group TL is selected from -CH2-, -NH-, -O-, or is absent.

[0238] In some embodiments, the group A of the targeting group TL is -CH2-.

[0239] In some embodiments, the group A of the targeting group TL is -NH-.

[0240] In some embodiments, the group A of the targeting group TL is -O-.

[0241] In some embodiments, group A of the targeting group TL is absent.

[0242] In some specific embodiments, the groups Y, B, and A in the targeting group TL are -NH-, -NH-;

[0243] or groups Y, B, and A are -NH-, -O-;

[0244] or groups Y, B, and A are -NH-, -CH2-;

[0245] Or groups Y and A are -CH2-, B does not exist;

[0246] Or group Y is B. A does not exist;

[0247] or groups Y, B, and A are -NH-, -CH2-.

[0248] In some embodiments, the targeting group TL is of formula (III-e-1):

[0249] Wherein Y is a 5-14 membered heteroaryl, said heteroaryl being optionally substituted by one or more of the following groups: halogen, hydroxy, oxo, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyloxy, C 2-6 Alkynyloxy, C 3-6 Cycloalkoxy, 3 to 6 membered heterocycloalkoxy, C 3-8 Cycloalkenyloxy, phenyl or 5 to 6 membered heteroaryl, said C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyloxy, C 2-6 Alkynyloxy, C 3-6 Cycloalkoxy, 3 to 6 membered heterocycloalkoxy, C 3-8 The cycloalkenyloxy, phenyl or 5- to 6-membered heteroaryl is optionally substituted by one or more substituents selected from halogen, hydroxy, oxo, nitro and cyano.

[0250] In some embodiments, group Y is a 5- to 12-membered heteroaryl group optionally substituted with one or more of the following groups: halogen, hydroxy, oxo, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyloxy, C 2-6 Alkynyloxy, C 3-6 Cycloalkoxy, 3 to 6 membered heterocycloalkoxy, C 3-8 Cycloalkenyloxy, phenyl or 5 to 6 membered heteroaryl, said C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyloxy, C 2-6 Alkynyloxy, C 3-6 Cycloalkoxy, 3 to 6 membered heterocycloalkoxy, C 3-8 The cycloalkenyloxy, phenyl or 5- to 6-membered heteroaryl is optionally substituted by one or more substituents selected from halogen, hydroxy, oxo, nitro and cyano.

[0251] In some embodiments, group Y is a 5-membered or 6-membered heteroaryl group, which is optionally substituted with one or more of the following groups: halogen, hydroxy, oxo, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, the C 1-6 Alkyl, C 1-6The alkoxy group is optionally substituted with one or more substituents selected from halogen, hydroxy, oxo, nitro, and cyano.

[0252] In some embodiments, group Y is pyridyl substituted with one or more methyl groups.

[0253] In some embodiments, group Y is selected from

[0254] In some embodiments, group Y is selected from

[0255] In some embodiments, the targeting group TL is of formula (III-e-2):

[0256] Wherein A is selected from -O- or -CH2-, Y is a 5-14 membered heteroaryl, said heteroaryl being optionally substituted by one or more of the following groups: halogen, hydroxy, oxo, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyloxy, C 2-6 Alkynyloxy, C 3-6 Cycloalkoxy, 3 to 6 membered heterocycloalkoxy, C 3-8 Cycloalkenyloxy, phenyl, or 5- to 6-membered heteroaryl, the C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyloxy, C 2-6 Alkynyloxy, C 3-6 Cycloalkoxy, 3 to 6 membered heterocycloalkoxy, C 3-8 The cycloalkenyloxy, phenyl or 5- to 6-membered heteroaryl is optionally substituted by one or more substituents selected from halogen, hydroxy, oxo, nitro and cyano.

[0257] In some embodiments, group Y is a 5- to 12-membered heteroaryl group optionally substituted with one or more of the following groups: halogen, hydroxy, oxo, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyloxy, C 2-6 Alkynyloxy, C 3-6 Cycloalkoxy, 3 to 6 membered heterocycloalkoxy, C 3-8 Cycloalkenyloxy, phenyl or 5 to 6 membered heteroaryl, said C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyloxy, C 2-6 Alkynyloxy, C 3-6 Cycloalkoxy, 3 to 6 membered heterocycloalkoxy, C 3-8The cycloalkenyloxy, phenyl or 5- to 6-membered heteroaryl is optionally substituted by one or more substituents selected from halogen, hydroxy, oxo, nitro and cyano.

[0258] In some embodiments, group Y is a 5-membered or 6-membered heteroaryl group, which is optionally substituted with one or more of the following groups: halogen, hydroxy, oxo, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, the C 1-6 Alkyl, C 1-6 The alkoxy group is optionally substituted with one or more substituents selected from halogen, hydroxy, oxo, nitro, and cyano.

[0259] In some embodiments, group Y is pyridyl substituted with one or more methyl groups.

[0260] In some embodiments, group Y is selected from

[0261] In some embodiments, group Y is selected from

[0262] In some embodiments, the group A of the targeting group TL is -CH2-.

[0263] In some embodiments, the group A of the targeting group TL is -O-.

[0264] In some embodiments, the targeting group TL is selected from (III-f)-(III-p),

[0265] The present disclosure provides a targeting ligand or a pharmaceutically acceptable salt thereof, wherein the targeting ligand is selected from the following structures, wherein TL is the same as described above:

[0266] The present disclosure provides a targeting ligand or a pharmaceutically acceptable salt thereof, wherein the targeting ligand is selected from the following structures,

[0267] The present disclosure also provides a compound represented by formula (III-a') or a pharmaceutically acceptable salt thereof

[0268] Wherein Y is a 5-14 membered heteroaryl, said heteroaryl being optionally substituted by one or more of the following groups: halogen, hydroxy, oxo, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyloxy, C 2-6 Alkynyloxy, C3-6 Cycloalkoxy, 3 to 6 membered heterocycloalkoxy, C 3-8 Cycloalkenyloxy, phenyl or 5 to 6 membered heteroaryl, said C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyloxy, C 2-6 Alkynyloxy, C 3-6 Cycloalkoxy, 3 to 6 membered heterocycloalkoxy, C 3-8 Cycloalkenyloxy, phenyl or 5- to 6-membered heteroaryl is optionally substituted by one or more substituents selected from halogen, hydroxy, oxo, nitro, and cyano;

[0269] B is selected from -CH2-, -NH-, or does not exist;

[0270] A is selected from -CH2-, -NH-, -O- or is absent, and when Y is When, B and A are not simultaneously -NH- or -CH2-;

[0271] Z is selected from OR 13 、N(R 13 )2 or SR 13 ;

[0272] R 21 Selected from H, C 1-6 Alkyl, OH, COOH, CON(R 5 )2、OR 6 Or formula (L1) n2 is an integer selected from 2-20 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20), the wavy line represents the connection point with formula (III-a'), the C 1-6 The alkyl group is optionally substituted with one or more halogen, hydroxy or cyano groups;

[0273] Each R 5 、R 6 Each independently selected from H or C 1-6 Alkyl, the C 1-6 The alkyl group is optionally substituted with one or more halogen, hydroxy or cyano groups;

[0274] R 22 、R P1 and R P2 Each is independently selected from H, a 3- to 20-membered cycloalkylene group, a 6- to 14-membered arylene group, a 3- to 12-membered heterocycloalkylene group, a 5- to 14-membered heteroarylene group, or a group of formula (L1) n2 is an integer selected from 2 to 20 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20), the wavy line indicates the point of connection with the phenyl group, and the cycloalkylene, arylene, heterocycloalkylene, and heteroarylene groups are optionally substituted with one or more of the following groups: halogen, hydroxyl, oxo, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyloxy, C 2-6 Alkynyloxy, C 3-6 Cycloalkoxy, 3 to 6 membered heterocycloalkoxy, C 3-8 Cycloalkenyloxy, phenyl or 5 to 6 membered heteroaryl, said C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyloxy, C 2-6 Alkynyloxy, C 3-6 Cycloalkoxy, 3 to 6 membered heterocycloalkoxy, C 3-8 Cycloalkenyloxy, phenyl or 5- to 6-membered heteroaryl is optionally substituted by one or more substituents selected from halogen, hydroxy, oxo, nitro, and cyano;

[0275] R 11 、R 12 Each independently selected from H or C 1-6 Alkyl, the C 1-6 The alkyl group is optionally substituted with one or more halogen, hydroxy or cyano groups;

[0276] Each R 13 Each independently selected from H, C 1-6 Alkyl or formula (L1) n2 is an integer selected from 2-20 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20), the wavy line represents the point of connection with the phenyl group, the C 1-6 The alkyl group is optionally substituted with one or more halogen, hydroxy or cyano groups;

[0277] The condition is that R 21 、R 22 、R 13 、R P1 and R P2 There is only one formula (L1).

[0278] In some embodiments, R 22 Formula (L1), R P1 、R P2 Each is H.

[0279] In some embodiments, n2 is selected from an integer ranging from 2-15.

[0280] In some embodiments, n2 is selected from an integer ranging from 2-10.

[0281] In some embodiments, n2 is selected from an integer of 2-5.

[0282] In some embodiments, n2 is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.

[0283] In some embodiments, group Y is a 5- to 12-membered heteroaryl group optionally substituted with one or more of the following groups: halogen, hydroxy, oxo, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyloxy, C 2-6 Alkynyloxy, C 3-6 Cycloalkoxy, 3 to 6 membered heterocycloalkoxy, C 3-8 Cycloalkenyloxy, phenyl or 5 to 6 membered heteroaryl, said C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyloxy, C 2-6 Alkynyloxy, C 3-6 Cycloalkoxy, 3 to 6 membered heterocycloalkoxy, C 3-8 The cycloalkenyloxy, phenyl or 5- to 6-membered heteroaryl is optionally substituted by one or more substituents selected from halogen, hydroxy, oxo, nitro and cyano.

[0284] In some embodiments, group Y is a 5-membered or 6-membered heteroaryl group, which is optionally substituted with one or more of the following groups: halogen, hydroxy, oxo, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, the C 1-6 Alkyl, C 1-6 The alkoxy group is optionally substituted with one or more substituents selected from halogen, hydroxy, oxo, nitro, and cyano.

[0285] In some embodiments, group Y is pyridyl substituted with one or more methyl groups.

[0286] In some embodiments, group Y is selected from

[0287] In some embodiments, group Y is selected from

[0288] In some embodiments, the group B of the targeting group TL is -NH- or is absent.

[0289] In some embodiments, group B of the targeting group TL is absent.

[0290] In some embodiments, the group A of the targeting group TL is selected from -CH2-, -NH-, -O-, or is absent.

[0291] In some embodiments, the group A of the targeting group TL is -CH2-.

[0292] In some embodiments, the group A of the targeting group TL is -NH-.

[0293] In some embodiments, the group A of the targeting group TL is -O-.

[0294] In some embodiments, group A of the targeting group TL is absent.

[0295] In some specific embodiments, groups Y, B, and A are -NH-, -NH-;

[0296] or groups Y, B, and A are -NH-, -O-;

[0297] or groups Y, B, and A are -NH-, -CH2-;

[0298] Or groups Y and A are -CH2-, B does not exist;

[0299] Or group Y is B. A does not exist;

[0300] or groups Y, B, and A are -NH-, -CH2-.

[0301] The present disclosure also provides a compound represented by formula (III-d') or a pharmaceutically acceptable salt thereof:

[0302] where R 22 Formula (L1) wherein n2 is selected from an integer of 2-20 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20), and the wavy line indicates the point of attachment to the naphthyl group;

[0303] Wherein Y is a 5-14 membered heteroaryl, said heteroaryl being optionally substituted by one or more of the following groups: halogen, hydroxy, oxo, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6Alkenyloxy, C 2-6 Alkynyloxy, C 3-6 Cycloalkoxy, 3 to 6 membered heterocycloalkoxy, C 3-8 Cycloalkenyloxy, phenyl or 5 to 6 membered heteroaryl, said C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyloxy, C 2-6 Alkynyloxy, C 3-6 Cycloalkoxy, 3 to 6 membered heterocycloalkoxy, C 3-8 Cycloalkenyloxy, phenyl or 5- to 6-membered heteroaryl is optionally substituted by one or more substituents selected from halogen, hydroxy, oxo, nitro, and cyano;

[0304] B is selected from -CH2-, -NH-, or does not exist;

[0305] A is selected from -CH2-, -NH-, -O- or is absent, and when Y is When B and A are not the same as -NH- or -CH2-.

[0306] In some embodiments, group Y is a 5- to 12-membered heteroaryl group optionally substituted with one or more of the following groups: halogen, hydroxy, oxo, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyloxy, C 2-6 Alkynyloxy, C 3-6 Cycloalkoxy, 3 to 6 membered heterocycloalkoxy, C 3-8 Cycloalkenyloxy, phenyl or 5 to 6 membered heteroaryl, said C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyloxy, C 2-6 Alkynyloxy, C 3-6 Cycloalkoxy, 3 to 6 membered heterocycloalkoxy, C 3-8 The cycloalkenyloxy, phenyl or 5- to 6-membered heteroaryl is optionally substituted by one or more substituents selected from halogen, hydroxy, oxo, nitro and cyano.

[0307] In some embodiments, n2 is selected from an integer ranging from 2-15.

[0308] In some embodiments, n2 is selected from an integer ranging from 2-10.

[0309] In some embodiments, n2 is selected from an integer of 2-5.

[0310] In some embodiments, n2 is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.

[0311] In some embodiments, group Y is a 5-membered or 6-membered heteroaryl group, which is optionally substituted with one or more of the following groups: halogen, hydroxy, oxo, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, the C 1-6 Alkyl, C 1-6 The alkoxy group is optionally substituted with one or more substituents selected from halogen, hydroxy, oxo, nitro, and cyano.

[0312] In some embodiments, group Y is pyridyl substituted with one or more methyl groups.

[0313] In some embodiments, group Y is selected from

[0314] In some embodiments, group Y is selected from

[0315] In some embodiments, the group B of the targeting group TL is -NH- or is absent.

[0316] In some embodiments, group B of the targeting group TL is absent.

[0317] In some embodiments, the group A of the targeting group TL is selected from -CH2-, -NH-, -O-, or is absent.

[0318] In some embodiments, the group A of the targeting group TL is -CH2-.

[0319] In some embodiments, the group A of the targeting group TL is -NH-.

[0320] In some embodiments, the group A of the targeting group TL is -O-.

[0321] In some embodiments, group A of the targeting group TL is absent.

[0322] In some specific embodiments, groups Y, B, and A are -NH-, -NH-;

[0323] or groups Y, B, and A are -NH-, -O-;

[0324] or groups Y, B, and A are -NH-, -CH2-;

[0325] Or groups Y and A are -CH2-, B does not exist;

[0326] Or group Y is B. A does not exist;

[0327] or groups Y, B, and A are -NH-, -CH2-.

[0328] The present disclosure also provides a compound represented by formula (III-e') or a pharmaceutically acceptable salt thereof:

[0329] Y is a 5-14 membered heteroaryl group, which is optionally substituted by one or more of the following groups: halogen, hydroxy, oxo, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyloxy, C 2-6 Alkynyloxy, C 3-6 Cycloalkoxy, 3 to 6 membered heterocycloalkoxy, C 3-8 Cycloalkenyloxy, phenyl or 5 to 6 membered heteroaryl, said C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyloxy, C 2-6 Alkynyloxy, C 3-6 Cycloalkoxy, 3 to 6 membered heterocycloalkoxy, C 3-8 Cycloalkenyloxy, phenyl or 5- to 6-membered heteroaryl is optionally substituted by one or more substituents selected from halogen, hydroxy, oxo, nitro, and cyano;

[0330] B is selected from -CH2-, -NH-, or does not exist;

[0331] A is selected from -CH2-, -NH-, -O- or is absent, and when Y is When B and A are not the same as -NH- or -CH2-.

[0332] In some embodiments, group Y is a 5- to 12-membered heteroaryl group optionally substituted with one or more of the following groups: halogen, hydroxy, oxo, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyloxy, C 2-6 Alkynyloxy, C 3-6 Cycloalkoxy, 3 to 6 membered heterocycloalkoxy, C 3-8 Cycloalkenyloxy, phenyl or 5 to 6 membered heteroaryl, said C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyloxy, C 2-6 Alkynyloxy, C 3-6Cycloalkoxy, 3 to 6 membered heterocycloalkoxy, C 3-8 The cycloalkenyloxy, phenyl or 5- to 6-membered heteroaryl is optionally substituted by one or more substituents selected from halogen, hydroxy, oxo, nitro and cyano.

[0333] In some embodiments, group Y is a 5-membered or 6-membered heteroaryl group, which is optionally substituted with one or more of the following groups: halogen, hydroxy, oxo, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, the C 1-6 Alkyl, C 1-6 The alkoxy group is optionally substituted with one or more substituents selected from halogen, hydroxy, oxo, nitro, and cyano.

[0334] In some embodiments, group Y is pyridyl substituted with one or more methyl groups.

[0335] In some embodiments, group Y is selected from

[0336] In some embodiments, group Y is selected from

[0337] In some embodiments, the group B of the targeting group TL is -NH- or is absent.

[0338] In some embodiments, group B of the targeting group TL is absent.

[0339] In some embodiments, the group A of the targeting group TL is selected from -CH2-, -NH-, -O-, or is absent.

[0340] In some embodiments, the group A of the targeting group TL is -CH2-.

[0341] In some embodiments, the group A of the targeting group TL is -NH-.

[0342] In some embodiments, the group A of the targeting group TL is -O-.

[0343] In some embodiments, group A of the targeting group TL is absent.

[0344] In some specific embodiments, groups Y, B, and A are -NH-, -NH-;

[0345] or groups Y, B, and A are -NH-, -O-;

[0346] or groups Y, B, and A are -NH-, -CH2-;

[0347] Or groups Y and A are -CH2-, B does not exist;

[0348] Or group Y is B. A does not exist;

[0349] or groups Y, B, and A are -NH-, -CH2-.

[0350] The present disclosure also provides a compound as shown in formula (III-e'-1) or a pharmaceutically acceptable salt thereof

[0351] Y is a 5-14 membered heteroaryl group, which is optionally substituted by one or more of the following groups: halogen, hydroxy, oxo, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyloxy, C 2-6 Alkynyloxy, C 3-6 Cycloalkoxy, 3 to 6 membered heterocycloalkoxy, C 3-8 Cycloalkenyloxy, phenyl or 5 to 6 membered heteroaryl, said C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyloxy, C 2-6 Alkynyloxy, C 3-6 Cycloalkoxy, 3 to 6 membered heterocycloalkoxy, C 3-8 The cycloalkenyloxy, phenyl or 5- to 6-membered heteroaryl is optionally substituted by one or more substituents selected from halogen, hydroxy, oxo, nitro and cyano.

[0352] In some embodiments, group Y is a 5- to 12-membered heteroaryl group optionally substituted with one or more of the following groups: halogen, hydroxy, oxo, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyloxy, C 2-6 Alkynyloxy, C 3-6 Cycloalkoxy, 3 to 6 membered heterocycloalkoxy, C 3-8 Cycloalkenyloxy, phenyl or 5 to 6 membered heteroaryl, said C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyloxy, C 2-6 Alkynyloxy, C 3-6 Cycloalkoxy, 3 to 6 membered heterocycloalkoxy, C 3-8 The cycloalkenyloxy, phenyl or 5- to 6-membered heteroaryl is optionally substituted by one or more substituents selected from halogen, hydroxy, oxo, nitro and cyano.

[0353] In some embodiments, group Y is a 5-membered or 6-membered heteroaryl group, which is optionally substituted with one or more of the following groups: halogen, hydroxy, oxo, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, the C 1-6 Alkyl, C 1-6 The alkoxy group is optionally substituted with one or more substituents selected from halogen, hydroxy, oxo, nitro, and cyano.

[0354] In some embodiments, group Y is pyridyl substituted with one or more methyl groups.

[0355] In some embodiments, group Y is selected from

[0356] In some embodiments, group Y is selected from

[0357] The present disclosure also provides a compound as shown in formula (III-e'-2) or a pharmaceutically acceptable salt thereof,

[0358] Wherein Y is a 5-14 membered heteroaryl, said heteroaryl being optionally substituted by one or more of the following groups: halogen, hydroxy, oxo, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyloxy, C 2-6 Alkynyloxy, C 3-6 Cycloalkoxy, 3 to 6 membered heterocycloalkoxy, C 3-8 Cycloalkenyloxy, phenyl or 5 to 6 membered heteroaryl, said C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyloxy, C 2-6 Alkynyloxy, C 3-6 Cycloalkoxy, 3 to 6 membered heterocycloalkoxy, C 3-8 Cycloalkenyloxy, phenyl or 5- to 6-membered heteroaryl is optionally substituted by one or more substituents selected from halogen, hydroxy, oxo, nitro, and cyano;

[0359] A is selected from -O- or -CH2-.

[0360] In some embodiments, group Y is a 5- to 12-membered heteroaryl group optionally substituted with one or more of the following groups: halogen, hydroxy, oxo, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyloxy, C 2-6 Alkynyloxy, C 3-6Cycloalkoxy, 3 to 6 membered heterocycloalkoxy, C 3-8 Cycloalkenyloxy, phenyl or 5 to 6 membered heteroaryl, said C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyloxy, C 2-6 Alkynyloxy, C 3-6 Cycloalkoxy, 3 to 6 membered heterocycloalkoxy, C 3-8 The cycloalkenyloxy, phenyl or 5- to 6-membered heteroaryl is optionally substituted by one or more substituents selected from halogen, hydroxy, oxo, nitro and cyano.

[0361] In some embodiments, group Y is a 5-membered or 6-membered heteroaryl group, which is optionally substituted with one or more of the following groups: halogen, hydroxy, oxo, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, the C 1-6 Alkyl, C 1-6 The alkoxy group is optionally substituted with one or more substituents selected from halogen, hydroxy, oxo, nitro, and cyano.

[0362] In some embodiments, group Y is pyridyl substituted with one or more methyl groups.

[0363] In some embodiments, group Y is selected from

[0364] In some embodiments, group Y is selected from

[0365] In some embodiments, group A is -O-.

[0366] In some embodiments, group A is -CH2-.

[0367] The present disclosure also provides a compound as shown in formula (III-f') to formula (III-p') or a pharmaceutically acceptable salt thereof,

[0368] The present disclosure provides a nucleic acid targeting ligand conjugate or a pharmaceutically acceptable salt thereof, wherein the nucleic acid targeting ligand conjugate comprises a nucleic acid and one or more targeting ligands conjugated to the nucleic acid, wherein the targeting ligands are as described above, and each targeting ligand is the same or different.

[0369] In some embodiments, the TL in the targeting ligand is selected from Formula (III-a)-(III-p).

[0370] In some embodiments, the nucleic acid is linked to the targeting ligand via a phosphate group, a phosphorothioate group, or a phosphonic acid group.

[0371] In some embodiments, the nucleic acid is linked to the alkyne-containing moiety through a phosphate group.

[0372] In some embodiments, the nucleic acid is linked to the alkyne-containing moiety through a phosphorothioate group.

[0373] In some embodiments, the phosphate group is a phosphodiester group.

[0374] In some embodiments, the phosphorothioate group is a phosphorothioate diester group.

[0375] In some embodiments, the nucleic acid includes, but is not limited to, single-stranded oligonucleotides, single-stranded antisense oligonucleotides, short interfering RNA (siRNA, comprising partially complementary sense and antisense strands), double-stranded RNA (dsRNA), microRNA (miRNA), short hairpin RNA (shRNA), and Dicer substrates.

[0376] In some embodiments, the 3' end of the nucleic acid is conjugated to a targeting ligand.

[0377] In some embodiments, the 5' end of the nucleic acid is conjugated to a targeting ligand.

[0378] In some embodiments, both the 3' end and the 5' end of the nucleic acid are conjugated to a targeting ligand.

[0379] The aforementioned 3' end and / or 5' end of the nucleic acid conjugated to the targeting ligand refers to the 3' end and / or 5' end of the nucleic acid chain conjugated to the targeting ligand.

[0380] In some embodiments, the nucleic acid is an siRNA, the 5' end of the sense strand of which is conjugated to a targeting ligand.

[0381] In some embodiments, the nucleic acid is single-stranded nucleic acid.

[0382] In some embodiments, the single-stranded nucleic acid is the sense strand of an siRNA.

[0383] In some embodiments, the single-stranded nucleic acid is the antisense strand of a siRNA.

[0384] In some embodiments, the nucleic acid is a double-stranded nucleic acid.

[0385] In some embodiments, the double-stranded nucleic acid comprises at least one duplex region in which the first strand of nucleic acid is at least partially complementary to the second strand of nucleic acid, wherein:

[0386] (1) Both ends of the first-strand nucleic acid are not conjugated to the targeting ligand; and the 5' end of the second-strand nucleic acid is conjugated to the targeting ligand, and the 3' end is not conjugated to the targeting ligand, or the 3' end of the second-strand nucleic acid is conjugated to the targeting ligand, and the 5' end is not conjugated to the targeting ligand, or both the 3' end and the 5' end of the second-strand nucleic acid are conjugated to the targeting ligand;

[0387] (2) Both ends of the second strand nucleic acid are not conjugated to the targeting ligand; and the 5' end of the first strand nucleic acid is conjugated to the targeting ligand, but the 3' end is not conjugated to the targeting ligand, or the 3' end of the first strand nucleic acid is conjugated to the targeting ligand, but the 5' end is not conjugated to the targeting ligand, or both the 3' end and the 5' end of the first strand nucleic acid are conjugated to the targeting ligand;

[0388] (3) The 5' ends of the first and second strands of nucleic acid are both conjugated to the targeting ligand, and the 3' ends are not conjugated to the targeting ligand; or the 3' ends of the first and second strands of nucleic acid are both conjugated to the targeting ligand, and the 5' ends are not conjugated to the targeting ligand; or the 3' ends and 5' ends of the first and second strands of nucleic acid are both conjugated to the targeting ligand; or the 3' ends of the first and second strands of nucleic acid are both conjugated to the targeting ligand, and the 5' ends of the first and second strands of nucleic acid are not conjugated to the targeting ligand; or the 5' ends of the first and second strands of nucleic acid are both conjugated to the targeting ligand, and the 3' ends of the first and second strands of nucleic acid are not conjugated to the targeting ligand;

[0389] (4) Both the 3' and 5' ends of the first nucleic acid chain are conjugated to the targeting ligand, and either the 5' or 3' end of the second nucleic acid chain is conjugated to the targeting ligand; or both the 3' and 5' ends of the second nucleic acid chain are conjugated to the targeting ligand, and either the 5' or 3' end of the first nucleic acid chain is conjugated to the targeting ligand.

[0390] In some embodiments, the nucleic acid is siRNA.

[0391] In some embodiments, the nucleic acid is an siRNA targeting RAGE.

[0392] In some embodiments, the nucleic acid is an siRNA targeting MUC5B.

[0393] In some embodiments, the nucleic acid is an siRNA targeting APP.

[0394] In some embodiments, the nucleic acid includes one or more modified nucleotides.

[0395] In some embodiments, the nucleic acid targeting ligand conjugate is as shown in Formula V,

[0396] Wherein, R is nucleic acid; W is OH, SH, O - or S - ; L1, L2, X, Q and TL are as defined in Formula III.

[0397] In some embodiments, W is OH or O - .

[0398] In some embodiments, W is SH or S - .

[0399] The present disclosure provides a nucleic acid-targeting ligand conjugate or a pharmaceutically acceptable salt thereof, wherein the nucleic acid-targeting ligand conjugate is selected from the following structures:

[0400]

[0401]

[0402]

[0403]

[0404] Wherein, R is a nucleic acid, the nucleic acid is the same as described above, and TL is the same as described above.

[0405] In some embodiments, TL is as described by Formula (III-a) to Formula (III-p).

[0406] In some embodiments, the 5' end of the nucleic acid is conjugated to a targeting ligand.

[0407] The present disclosure provides a pharmaceutical composition comprising the above-mentioned nucleic acid-targeting ligand conjugate or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

[0408] In some embodiments, the unit dose of the pharmaceutical composition may be 0.001 mg-1000 mg.

[0409] In some embodiments, based on the total weight of the pharmaceutical composition, the content of the nucleic acid-targeting conjugate may be 0.01-99.99%, 0.1-99.9%, 0.5%-99.5%, 1%-99%, and even 2%-98%.

[0410] In some embodiments, based on the total weight of the pharmaceutical composition, the content of the pharmaceutically acceptable excipient may be 0.01-99.99%, further 0.1-99.9%, further 0.5%-99.5%, further 1%-99%, and further 2%-98%.

[0411] In some embodiments, the nucleic acid targeting ligand conjugate is in a therapeutically effective amount.

[0412] In some embodiments, the pharmaceutically acceptable excipient may be an excipient commonly used in the art, such as a carrier, a vehicle, a diluent, and / or a delivery polymer.

[0413] The present disclosure provides a use of the above-mentioned nucleic acid-targeting ligand conjugate or a pharmaceutically acceptable salt thereof, or the above-mentioned pharmaceutical composition in preparing a medicament for preventing and / or treating a disease, wherein the disease is a respiratory disease.

[0414] The present disclosure provides a use of the above-mentioned nucleic acid-targeting ligand conjugate or a pharmaceutically acceptable salt thereof, or the above-mentioned pharmaceutical composition for inhibiting the expression of mRNA or target genes in a patient.

[0415] The present disclosure provides a use of the aforementioned nucleic acid-targeting ligand conjugate or a pharmaceutically acceptable salt thereof, or the aforementioned pharmaceutical composition in the preparation of a medicament for preventing and / or treating a disease mediated by RAGE gene expression. In some embodiments, the disease is a respiratory disease.

[0416] The present disclosure provides a nucleic acid-targeting ligand conjugate or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition for preventing and / or treating a disease, wherein the disease is a respiratory disease. The nucleic acid-targeting ligand conjugate or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition is the same as described above.

[0417] The present disclosure provides a nucleic acid-targeting ligand conjugate or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition for inhibiting the expression of mRNA or target gene in a patient. The nucleic acid-targeting ligand conjugate or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition is the same as described above.

[0418] The present disclosure provides a nucleic acid-targeting ligand conjugate or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition for preventing and / or treating a disease mediated by RAGE gene expression, wherein the nucleic acid-targeting ligand conjugate or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition is as described above. In some embodiments, the disease is a respiratory disease.

[0419] The present disclosure provides a nucleic acid-targeting ligand conjugate or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition for delivering one or more transported molecules to cells. The nucleic acid-targeting ligand conjugate or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition is the same as described above.

[0420] The present disclosure provides a method for treating a disease, comprising administering a therapeutically effective amount of the aforementioned nucleic acid-targeting ligand conjugate or a pharmaceutically acceptable salt thereof, or the aforementioned pharmaceutical composition to a patient, wherein the disease is a respiratory disease.

[0421] The present disclosure provides a method for inhibiting the expression of mRNA or target gene in a patient, comprising administering to the patient a therapeutically effective amount of the above-mentioned nucleic acid-targeting ligand conjugate or a pharmaceutically acceptable salt thereof, or the above-mentioned pharmaceutical composition.

[0422] The present disclosure provides a method for preventing and / or treating diseases mediated by RAGE gene expression, comprising administering to a patient a therapeutically effective amount of the aforementioned nucleic acid-targeting ligand conjugate or a pharmaceutically acceptable salt thereof, or the aforementioned pharmaceutical composition.

[0423] In some embodiments, the respiratory diseases mentioned above include but are not limited to cystic fibrosis, chronic bronchitis, non-cystic fibrosis bronchiectasis, idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD), asthma, respiratory tract infection, and primary ciliary dyskinesia.

[0424] In some embodiments, the cystic fibrosis includes but is not limited to lung cancer cystic fibrosis. The present disclosure provides a method for delivering one or more transported molecules to cells, comprising administering to a patient a therapeutically effective amount of the aforementioned nucleic acid-targeting ligand conjugate or a pharmaceutically acceptable salt thereof, or the aforementioned pharmaceutical composition.

[0425] In some embodiments, the cell is a type I and type II alveolar epithelial cell, a goblet cell, a secretory epithelial cell, a ciliated epithelial cell, a corneal and conjunctival epithelial cell, a dermal epithelial cell, a bile duct epithelial cell, an intestinal epithelial cell, a ductal epithelial cell, a glandular epithelial cell, an epithelial tumor (cancer), or a kidney cell.

[0426] In some embodiments, delivery can be by local administration (e.g., direct injection or implantation) or systemic administration, and can also be administered orally, rectally or parenterally, including but not limited to subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection, transdermal administration, inhalation administration (e.g., aerosol), mucosal administration (e.g., sublingual, intranasal administration), intracranial administration, etc.

[0427] In some embodiments, the nucleic acid-targeting ligand conjugates or pharmaceutical compositions provided herein can be administered by injection, for example, intravenous, intramuscular, intradermal, subcutaneous, intraduodenal, or intraperitoneal injection.

[0428] In some embodiments, the nucleic acid-targeting ligand conjugates or pharmaceutical compositions provided by the present disclosure can be packaged in a kit.

[0429] The present disclosure also provides a cell comprising the above-mentioned nucleic acid-targeting ligand conjugate.

[0430] The present disclosure also provides a kit comprising the aforementioned nucleic acid-targeting ligand conjugate or the aforementioned pharmaceutical composition.

[0431] The present disclosure provides a method for preparing the above-mentioned nucleic acid-targeting ligand conjugate, which includes the step of preparing the nucleic acid-targeting ligand conjugate from nucleic acid.

[0432] The present disclosure provides a method for preparing the above-mentioned nucleic acid-targeting ligand conjugate, which comprises the following steps: starting with a universal CPG carrier, connecting nucleoside monomers one by one from the 3'-5' direction according to the nucleotide arrangement order, connecting the alkynyl-containing compound represented by the above-mentioned formula I with a synthetic nucleic acid chain, and then connecting the above-mentioned targeting group with the alkynyl-containing portion, and annealing to obtain the nucleic acid-targeting ligand conjugate.

[0433] In some embodiments, the targeting group is as described by Formula (III-a)-(III-p).

[0434] In some embodiments, each connection of a monomer includes four steps of deprotection, coupling, capping, oxidation or sulfurization. After the connection of the last monomer is completed, the nucleic acid sequence connected to the solid phase support is cut, deprotected, purified, and desalted in sequence to obtain a nucleic acid targeting ligand conjugate.

[0435] Definition of terms

[0436] On the other hand, where the present disclosure does not limit a particular configuration, the compounds of the present disclosure may exist in specific geometric or stereoisomeric forms. The present disclosure contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present disclosure. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All of these isomers and their mixtures are included within the scope of the present disclosure.

[0437] In addition, the compounds and intermediates of the present disclosure can also exist in different tautomeric forms, and all such forms are included in the scope of the present disclosure. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that can interconvert via a low energy barrier. For example, proton tautomers (also referred to as prototransfer tautomers) include interconversions via proton migration, such as keto-enol and imine-enamine, lactam-lactim isomerization. The lactam-lactim equilibrium example is between A and B as shown below.

[0438] All compounds in this disclosure can be drawn as either Form A or Form B. All tautomeric forms are within the scope of this disclosure. The naming of the compounds does not exclude any tautomers.

[0439] The compounds of the present disclosure may be asymmetric, for example, having one or more stereoisomers. Unless otherwise indicated, all stereoisomers are included, such as enantiomers and diastereomers. The compounds of the present disclosure containing asymmetric carbon atoms can be isolated in optically pure forms or racemic forms. Optically pure forms can be resolved from racemic mixtures or synthesized by using chiral starting materials or chiral reagents.

[0440] Optically active (R)- and (S)-isomers, as well as D and L isomers, can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the present disclosure is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary groups are cleaved to provide the pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), diastereomeric salts are formed with an appropriate optically active acid or base, followed by diastereomeric resolution by conventional methods known in the art, and then the pure enantiomers are recovered. In addition, separation of enantiomers and diastereoisomers is typically accomplished using chromatography using a chiral stationary phase, optionally combined with chemical derivatization (e.g., to form carbamates from amines).

[0441] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 30 carbon atoms, preferably an alkyl group containing 1 to 12 carbon atoms, more preferably an alkyl group containing 1 to 10 carbon atoms, more preferably an alkyl group containing 1 to 6 carbon atoms, and further preferably an alkyl group containing 1 to 2, 1 to 3, 1 to 4, or 1 to 5 carbon atoms. Most preferred are alkyl groups containing 1, 2, 3, 4, 5, or 6 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, and the like. The alkyl group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available point of attachment. The substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate.

[0442] The term "cycloalkyl" or "carbocycle" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent, wherein the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 7 carbon atoms. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, and the like; polycyclic cycloalkyls include spirocyclic, fused, and bridged cycloalkyls. Cycloalkyls may be substituted or unsubstituted, and when substituted, the substituents may be substituted at any available point of attachment, preferably one or more of the following groups, independently selected from halogen, hydroxy, oxo, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyloxy, C 2-6 Alkynyloxy, C 3-6 Cycloalkoxy, 3 to 6 membered heterocycloalkoxy, C 3-8 Cycloalkenyloxy, phenyl or 5 to 6 membered heteroaryl, said C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyloxy, C 2-6 Alkynyloxy, C 3-6 Cycloalkoxy, 3 to 6 membered heterocycloalkoxy, C 3-8 The cycloalkenyloxy, phenyl or 5- to 6-membered heteroaryl is optionally substituted by one or more groups selected from halogen, hydroxy, oxo, nitro and cyano.

[0443] The cycloalkyl ring may be fused to an aryl or heteroaryl ring, wherein the ring attached to the parent structure is a cycloalkyl, non-limiting examples of which include indanyl, tetrahydronaphthyl, benzocycloheptanyl, etc. The cycloalkyl may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups, which are independently selected from halogen, hydroxy, oxo, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyloxy, C 2-6 Alkynyloxy, C 3-6 Cycloalkoxy, 3 to 6 membered heterocycloalkoxy, C 3-8 Cycloalkenyloxy, phenyl or 5 to 6 membered heteroaryl, said C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyloxy, C 2-6 Alkynyloxy, C 3-6 Cycloalkoxy, 3 to 6 membered heterocycloalkoxy, C 3-8 The cycloalkenyloxy, phenyl or 5- to 6-membered heteroaryl is optionally substituted by one or more groups selected from halogen, hydroxy, oxo, nitro and cyano.

[0444] The term "heterocycloalkyl" or "heterocycle" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent containing 3 to 20 ring atoms, one or more of which is selected from nitrogen, oxygen or S(O) m (wherein m is an integer from 0 to 2) heteroatoms, but excluding the ring portion of -OO-, -OS- or -SS-, the remaining ring atoms are carbon. Preferably, it contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably, it contains 3 to 7 ring atoms. Non-limiting examples of monocyclic heterocycloalkyl groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, etc. Polycyclic heterocycloalkyl groups include spirocyclic, fused ring and bridged heterocycloalkyl groups. Non-limiting examples of "heterocycloalkyl" include:

[0445]

[0446] etc.

[0447] The heterocycloalkyl ring may be fused to an aryl or heteroaryl ring, wherein the ring attached to the parent structure is a heterocycloalkyl, non-limiting examples of which include:

[0448] wait.

[0449] Heterocycloalkyl may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more of the following groups independently selected from halogen, hydroxy, oxo, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyloxy, C 2-6 Alkynyloxy, C 3-6 Cycloalkoxy, 3 to 6 membered heterocycloalkoxy, C 3-8 Cycloalkenyloxy, phenyl or 5 to 6 membered heteroaryl, said C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyloxy, C 2-6 Alkynyloxy, C 3-6 Cycloalkoxy, 3 to 6 membered heterocycloalkoxy, C 3-8 The cycloalkenyloxy, phenyl or 5- to 6-membered heteroaryl is optionally substituted by one or more groups selected from halogen, hydroxy, oxo, nitro and cyano.

[0450] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (i.e., rings sharing adjacent pairs of carbon atoms) group having a conjugated π electron system, preferably 6- to 12-membered, such as phenyl and naphthyl. The aryl ring may be fused to a heteroaryl, heterocycloalkyl, or cycloalkyl ring, wherein the ring attached to the parent structure is the aryl ring, non-limiting examples of which include:

[0451] Aryl may be substituted or unsubstituted. When substituted, the substituents are preferably one or more of the following groups independently selected from halogen, hydroxy, oxo, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyloxy, C 2-6 Alkynyloxy, C 3-6 Cycloalkoxy, 3 to 6 membered heterocycloalkoxy, C 3-8 Cycloalkenyloxy, phenyl or 5 to 6 membered heteroaryl, said C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyloxy, C 2-6 Alkynyloxy, C 3-6 Cycloalkoxy, 3 to 6 membered heterocycloalkoxy, C 3-8 The cycloalkenyloxy, phenyl or 5- to 6-membered heteroaryl is optionally substituted by one or more groups selected from halogen, hydroxy, oxo, nitro and cyano.

[0452] The term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. The heteroaryl group is preferably 5 to 12-membered, more preferably 5-membered or 6-membered. For example, non-limiting examples include: imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl, triazolyl, indazolyl, benzimidazolyl, wait.

[0453] The heteroaryl ring may be fused to an aryl, heterocycloalkyl or cycloalkyl ring, wherein the ring attached to the parent structure is a heteroaryl ring, non-limiting examples of which include:

[0454] Heteroaryl may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more of the following groups independently selected from halogen, hydroxy, oxo, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyloxy, C 2-6 Alkynyloxy, C 3-6Cycloalkoxy, 3 to 6 membered heterocycloalkoxy, C 3-8 Cycloalkenyloxy, phenyl or 5 to 6 membered heteroaryl, said C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyloxy, C 2-6 Alkynyloxy, C 3-6 Cycloalkoxy, 3 to 6 membered heterocycloalkoxy, C 3-8 The cycloalkenyloxy, phenyl or 5- to 6-membered heteroaryl is optionally substituted by one or more groups selected from halogen, hydroxy, oxo, nitro and cyano.

[0455] The cycloalkyl, heterocyclyl, aryl and heteroaryl groups mentioned above include residues derived from a parent ring atom by removing one hydrogen atom, or residues derived from the same parent ring atom or two different ring atoms by removing two hydrogen atoms, i.e., "cycloalkylene", "heterocyclylene", "arylene" and "heteroarylene".

[0456] The term "spirocyclic" refers to a compound in which two rings share one atom.

[0457] The term "spiroalkyl" refers to a polycyclic group that shares a carbon atom (called a spiro atom) between 5 to 20 monocyclic rings, which may contain one or more double bonds, but no ring has a completely conjugated π electron system. Preferably, it is 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of spiro atoms shared between the rings, the spiroalkyl is divided into a single spiroalkyl, a double spiroalkyl or a multi-spiroalkyl, preferably a single spiroalkyl and a double spiroalkyl. More preferably, it is 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6 yuan single spiroalkyl. "Spiro carbocycle" refers to the ring system in the spiroalkyl. Non-limiting examples of spiroalkyl include:

[0458] The term "spiroheterocyclyl" refers to a polycyclic heterocyclic group in which the monocyclic rings of 5 to 20 members share one atom (called a spiro atom), wherein one or more ring atoms are selected from nitrogen, oxygen or S(O) m (wherein m is an integer 0 to 2) heteroatom, and the remaining ring atoms are carbon. It may contain one or more double bonds, but no ring has a completely conjugated π electron system. It is preferably 6 to 14 members, more preferably 7 to 10 members. According to the number of shared spiral atoms between the rings, the spiro heterocyclic group is divided into a monospiro heterocyclic group, a dispiro heterocyclic group or a polyspiro heterocyclic group, preferably a monospiro heterocyclic group and a dispiro heterocyclic group. More preferably, it is a 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered or 5-membered / 6-membered monospiro heterocyclic group. "Spiro heterocycle" refers to the ring system in the spiro heterocyclic group. Non-limiting examples of spiro heterocyclic groups include:

[0459] The term "fused ring" refers to a compound in which two or more rings are fused by sharing two adjacent atoms.

[0460] The term "fused cycloalkyl" refers to a 5 to 20-membered, all-carbon polycyclic group in which each ring in the system shares a pair of adjacent carbon atoms with the other rings in the system, wherein one or more rings may contain one or more double bonds, but no ring has a completely conjugated π electron system. Preferably, it is 6 to 14 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl, preferably bicyclic or tricyclic, more preferably 5-membered / 5-membered or 5-membered / 6-membered bicyclic alkyl. Non-limiting examples of fused cycloalkyl include:

[0461] The term "fused heterocyclyl" refers to a polycyclic heterocyclic group of 5 to 20 members, wherein each ring in the system shares a pair of adjacent atoms with other rings in the system, one or more rings may contain one or more double bonds, but no ring has a completely conjugated π electron system, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O) m (wherein m is an integer from 0 to 2) heteroatoms, the remaining ring atoms being carbon. Preferably, it is 6 to 14 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups, preferably bicyclic or tricyclic, more preferably 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused heterocyclic groups. "Fused heterocycle" refers to the ring system in a fused heterocyclic group. Non-limiting examples of fused heterocyclic groups include:

[0462] The term "fused heteroaryl" may be an unsaturated aromatic fused ring structure containing 5-14 ring atoms (including at least one heteroatom), which is formed by two or more ring structures sharing two adjacent atoms, and includes the case where the carbon atoms, nitrogen atoms and sulfur atoms may be oxidized. Preferably, "5-12 membered fused heteroaryl", "7-12 membered fused heteroaryl", "9-12 membered fused heteroaryl" and the like are used, such as benzofuranyl, benzisofuranyl, benzothiophenyl, indolyl, isoindolyl, benzoxazolyl, benzimidazolyl, indazolyl, benzotriazolyl, quinolyl, 2-quinolinonyl, 4-quinolinonyl, 1-isoquinolinonyl, isoquinolyl, acridinyl, phenanthridinyl, benzopyridazinyl, phthalazinyl, quinazolinyl, quinoxalinyl, phenolazinyl, pteridinyl, purinyl, naphthyridinyl, phenazinyl, phenothiazinyl and the like. "Fused heteroaryl ring" refers to the ring system within a fused heteroaryl group.

[0463] The fused heteroaryl group may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

[0464] The term "bridged ring" refers to a structure formed by two or more cyclic structures sharing two non-adjacent ring atoms.

[0465] The term "bridged cycloalkyl" refers to a 5-20 membered, all-carbon polycyclic group in which any two rings share two carbon atoms that are not directly connected, which may contain one or more double bonds, but no ring has a completely conjugated π electron system. Preferably, it is 6-14 members, more preferably 7-10 members. Depending on the number of constituent rings, it can be classified as a bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl group, preferably a bicyclic, tricyclic or tetracyclic group, more preferably a bicyclic or tricyclic group. Non-limiting examples of bridged cycloalkyl groups include:

[0466] The term "bridged heterocyclyl" refers to a 5- to 14-membered polycyclic heterocyclic group in which any two rings share two atoms that are not directly connected, which may contain one or more double bonds but no ring has a completely conjugated π electron system, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O) m (wherein m is an integer from 0 to 2) heteroatoms, the remaining ring atoms being carbon. Preferably, it is 6 to 14 members, more preferably 7 to 10 members. Depending on the number of constituent rings, it can be classified as a bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic group, preferably a bicyclic, tricyclic or tetracyclic group, more preferably a bicyclic or tricyclic group. Non-limiting examples of bridged heterocyclic groups include:

[0467] The term "alkoxy" refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl), wherein alkyl is as defined above. Non-limiting examples of alkoxy include: methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy. Alkoxy may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from halogen, hydroxy, oxo, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyloxy, C 2-6 Alkynyloxy, C 3-6 Cycloalkoxy, 3 to 6 membered heterocycloalkoxy, C 3-8 Cycloalkenyloxy, phenyl or 5 to 6 membered heteroaryl, said C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6Alkenyloxy, C 2-6 Alkynyloxy, C 3-6 Cycloalkoxy, 3 to 6 membered heterocycloalkoxy, C 3-8 The cycloalkenyloxy, phenyl, or 5- to 6-membered heteroaryl groups are optionally substituted with one or more halogen, hydroxy, oxo, nitro, and cyano groups. Similarly, the definitions of "alkynyloxy," "alkenyloxy," "cycloalkoxy," "heterocycloalkoxy," and "cycloalkenyloxy" are the same as those for "alkoxy" above.

[0468] The term "hydroxy" refers to -OH.

[0469] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0470] The term "haloalkyl" refers to an alkyl group substituted with a halogen, wherein alkyl is as defined above.

[0471] The term "cyano" refers to -CN.

[0472] The term "nitro" refers to -NO2.

[0473] The term "oxo" refers to a =0 group, for example, a carbon atom connected to an oxygen atom via a double bond, whereby a ketone or aldehyde group is formed.

[0474] The term "amino" refers to -NH2.

[0475] The term "carboxy" refers to -C(O)OH.

[0476] The term "aldehyde" refers to -CHO.

[0477] The term "benzoyl" refers to -Bz.

[0478] The term "methoxyphenylbenzhydryl" refers to -MMTr.

[0479] The term "dimethoxytrityl" refers to -DMTr.

[0480] "Optionally" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs or does not occur. For example, "optionally substituted C 1-6 The term "alkyl" means that halogen or cyano may but need not be present, and the description includes both the case where the alkyl is substituted by halogen or cyano and the case where the alkyl is not substituted by halogen and cyano.

[0481] The term "substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms in a group are replaced independently of one another by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions and a person skilled in the art can determine (by experiment or theory) which substitutions are possible or impossible without undue effort.

[0482] "Substituted by one or more..." means that the compound may be substituted by a single or multiple substituents. When substituted by multiple substituents, the substituents may be multiple identical substituents or a combination of one or more different substituents.

[0483] The term "linked," when referring to a connection between two molecules, means that the two molecules are joined by a covalent bond or that the two molecules are associated via a non-covalent bond (eg, a hydrogen bond or an ionic bond).

[0484] In the chemical structures of the compounds disclosed herein, the bond Indicates that the configuration is not specified, that is, if chiral isomers exist in the chemical structure, the bond Can be or include both Although all the above structural formulas are drawn as certain isomers for the sake of simplicity, the present disclosure may include all isomers, such as tautomers, rotational isomers, geometric isomers, diastereomers, racemates and enantiomers. In the chemical structures of the compounds described in the present disclosure, the bonds No configuration is specified, i.e. the bond The configuration can be E-type or Z-type, or include both E and Z configurations.

[0485] Unless otherwise specified, the symbols used in this paper are It means that it can be linked to one or more any groups according to the disclosure described herein.

[0486] Unless otherwise indicated, the variables shown can be oriented so that any one point of attachment on the variable is connected to any one point of attachment on the compound of Formula I. For example, the variable L1 has two points of attachment to the compound of Formula I. Although L1 is shown as -(CH2)6-O-CH2- in one embodiment, this embodiment should also be understood to encompass compounds where L1 is -CH2-O-(CH2)6-.

[0487] In the present disclosure, the terms "comprising" and "including" can be replaced with "consisting of".

[0488] The term "pharmaceutical composition" refers to a mixture of one or more compounds described herein, or their physiologically acceptable salts or precursors, with other chemical components, as well as other components such as physiologically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitating absorption of the active ingredient and thereby exerting its biological activity.

[0489] The term "pharmaceutically acceptable excipient" or "pharmaceutically acceptable excipient" includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye / colorant, flavoring agent, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent or emulsifier that has been approved by the U.S. Food and Drug Administration as acceptable for use in humans or domestic animals.

[0490] The terms "pharmaceutically acceptable salt" and "pharmaceutically acceptable salt" are used interchangeably and include pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts. As used herein, the term "inhibit" can be used interchangeably with "reduce," "silence," "downregulate," "suppress" and other similar terms, and includes any level of inhibition. Inhibition can be assessed by a reduction in the absolute or relative level of one or more of these variables compared to a control level. The control level can be any type of control level used in the art, such as a pre-dose baseline level or a level determined from a similar untreated or control (e.g., a buffer only control or an inert agent control) treated subject, cell, or sample. For example, the residual mRNA expression level can be used to characterize the degree of inhibition of target gene expression by siRNA, such as the residual mRNA expression level being no higher than 99%, no higher than 95%, no higher than 90%, no higher than 85%, no higher than 80%, no higher than 75%, no higher than 70%, no higher than 65%, no higher than 60%, no higher than 55%, no higher than 50%, no higher than 45%, no higher than 40%, no higher than 35%, no higher than 30%, no higher than 25%, no higher than 20%, no higher than 15%, or no higher than 10%. The inhibition rate of target gene expression can be expressed as follows: The Luciferase Assay System was used to measure the chemiluminescence values ​​of firefly and Renilla, respectively, and the relative value (Ratio = Ren / Fir) was calculated. In the present disclosure, the ratio of remaining mRNA expression (or remaining activity %) = Ratio (siRNA-treated group) / Ratio (no siRNA control group), and the inhibition rate (%) = 100% - remaining mRNA expression (%).

[0491] "Effective amount," "effective dose," "effective therapeutic amount," or "therapeutically effective amount" refers to the amount of a drug, compound, or pharmaceutical composition necessary to achieve any one or more beneficial or desired therapeutic results. For prophylactic uses, beneficial or desired results include eliminating or reducing the risk, reducing the severity, or delaying the onset of a condition, including the biochemical, histological, and / or behavioral symptoms of the condition, its complications, and intermediate pathological phenotypes that present during the progression of the condition. For therapeutic applications, beneficial or desired results include clinical results, such as reducing the incidence of various target gene, target mRNA, or target protein-related conditions of the present invention or improving one or more symptoms of the condition, reducing the dose of other agents required to treat the condition, enhancing the efficacy of another agent, and / or delaying the progression of a target gene, target mRNA, or target protein-related condition of the present invention in a patient. An effective amount also means an amount sufficient to allow or facilitate diagnosis. The effective amount for a particular patient or veterinary subject may vary depending on, for example, the condition to be treated, the patient's overall health, the method, route, and dosage of administration, and the severity of side effects. An effective amount can be the maximum dose or dosing regimen that avoids significant side effects or toxic effects.

[0492] As used herein, "subject," "patient," "subject," or "individual" are used interchangeably and include humans or non-human animals, such as mammals, eg, humans or monkeys.

[0493] In this disclosure, the term "nucleic acid" refers to a polymeric form of nucleotides of any length. They may include one or more ribonucleotides or deoxyribonucleotides. Therefore, the term includes, but is not limited to, single-stranded, double-stranded or multi-stranded DNA or RNA, genomic DNA, cDNA, DNA-RNA hybrids, or polymers comprising purine and pyrimidine bases or other natural, chemically or biochemically modified, non-natural or derivatized nucleotide bases, such as locked nucleic acids (LNAs), peptide nucleic acids (PNAs). Preferably, the nucleic acids include, but are not limited to, single-stranded oligonucleotides, single-stranded antisense oligonucleotides, short interfering RNA (siRNA, the siRNA comprising partially complementary sense and antisense strands), double-stranded RNA (dsRNA), microRNA (miRNA), short hairpin RNA (shRNA) and Dicer substrates.

[0494] In this disclosure, "phosphate group," "phosphate group," and "phosphate bond" are used interchangeably to include monoesters, phosphodiesters, or phosphotriesters. "Phosphate group" in "phosphorothioate group" also has the same meaning. Unless otherwise specified, a natural internucleotide phosphate group is a phosphodiester group.

[0495] As used herein, in the context of RNA-mediated gene silencing, the positive strand of siRNA (also referred to as SS, SS strand or sense strand) refers to a strand comprising a sequence identical or substantially identical to the target mRNA sequence; the antisense strand of siRNA (also referred to as AS or AS strand) refers to a strand having a sequence complementary to the target mRNA sequence.

[0496] As used herein, the first strand may be referred to as the antisense strand and the second strand may be referred to as the sense strand. The terms first strand and antisense strand or second strand and sense strand should be considered interchangeable.

[0497] In this disclosure, the "5' region," also known as the "5' end," or "5' terminus" of the sense or antisense strand may be used interchangeably. For example, nucleotides 2 through 8 in the 5' region of the antisense strand may be replaced with nucleotides 2 through 8 at the 5' terminus of the antisense strand. Similarly, the "3' region," "3' terminus," and "3' terminus" of the sense or antisense strand may be used interchangeably.

[0498] As used herein, the term "base" encompasses any known DNA and RNA base, base analogs such as purine or pyrimidine, and also includes the natural compounds adenine, thymine, guanine, cytosine, uracil, inosine, and natural analogs.

[0499] Unless otherwise specified, in the context of this disclosure, "G," "C," "A," "T," and "U" represent nucleotides, including the bases guanine, cytosine, adenine, thymidine, and uracil, respectively. It is well known to those skilled in the art that substitution of T and U does not significantly affect the properties of the nucleic acid sequence. U in the sequences of this disclosure can be arbitrarily replaced with T, and the resulting sequences are also within the scope of protection of this disclosure. In the sequences disclosed herein, for the same nucleic acid chain, from the 5' end to the 3' end as the left-to-right direction, the lowercase letter m indicates that the nucleoside adjacent to the left of the letter m is a 2'-methoxy-modified nucleoside; the lowercase letter f indicates that the nucleoside adjacent to the left of the letter f is a 2'-fluoro-modified nucleoside; the lowercase letter s indicates that the two nucleosides adjacent to the letter s are linked by a thiophosphate diester group. Unless otherwise specified, the two nucleosides are linked by a phosphodiester group; VP indicates that the 5'-end of the nucleoside adjacent to the left / right of the letter is a 5'-vinyl phosphodiester group, and the 5'-vinyl phosphodiester group can be cis or trans, that is, it can be a 5'-E-VP isomer (i.e., a trans-vinyl phosphodiester group), a 5'-Z-VP isomer (i.e., a cis-vinyl phosphodiester group), or a mixture thereof; IB indicates an inverted abasic nucleoside; and (-)hmpNA indicates that one of the nucleosides in the brackets adjacent to it is a nucleoside with an hmpNA modification. Unless otherwise specified, the "nucleotides", "compounds", "chemical modifications", "oligonucleotides", "siRNA", "dsRNA" and "nucleic acids" of the present disclosure may independently exist in the form of salts, mixed salts or non-salts (e.g., free acids or free bases). When present in the form of a salt or a mixed salt, it may be a pharmaceutically acceptable salt. The term "pharmaceutically acceptable salt" includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts. When it exists in the form of a salt, some groups may be ionized to form anions / cations. For example, a phosphodiester group and a thiophosphonic acid diester group may exist in the form of anions. The salt forms corresponding to the following structures are also within the scope of protection of the present disclosure.

[0500] The above-mentioned modification and linking groups have the structures shown in the following table, where Base represents a base:

[0501] The terms "pharmaceutically acceptable salts" and "pharmaceutically usable salts" are used interchangeably and are meant to include pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[0502] "Pharmaceutically acceptable acid addition salts" refer to salts formed with inorganic or organic acids that retain the biological effectiveness of the free base without other side effects and can be prepared by methods known in the art. "Pharmaceutically acceptable base addition salts" refer to salts formed with inorganic or organic bases that retain the biological effectiveness of the free acid without other side effects and can be prepared by methods known in the art.

[0503] As used herein, the terms "complementary" and "reverse complement" are used interchangeably and have the meanings known to those skilled in the art, i.e., in a double-stranded nucleic acid molecule, the bases of one chain are paired with bases on the other chain in a complementary manner. In DNA, the purine base adenine (A) is always paired with the pyrimidine base thymine (T) (or uracil (U) in RNA); the purine base guanine (C) is always paired with the pyrimidine base cytosine (G). Each base pair consists of a purine and a pyrimidine. When adenine on one chain is always paired with thymine (or uracil) on the other chain, and guanine is always paired with cytosine, the two chains are considered to be complementary to each other, and the sequence of the chain can be inferred from the sequence of its complementary chain. Accordingly, "mismatch" means in the art that the bases at corresponding positions in a double-stranded nucleic acid are not paired in a complementary manner.

[0504] The term "partial complementarity" refers to a portion of a continuous sequence in the sequence of the sense strand of the siRNA that is complementary to a portion of a continuous sequence in the sequence of the antisense strand, thereby enabling the sense strand and the antisense strand to bind complementary to each other. In one embodiment, the complementary region can be 10 or more consecutive nucleotides (e.g., 19, 20, 21, 30, 40, 50, 100, etc.), and the non-complementary region can be 1 consecutive nucleotide, 2 nucleotides, 3 nucleotides, 4 nucleotides, 5 nucleotides, etc., or a continuous nucleotide of 10 or more fragments (20, 30, 40, 50, etc.).

[0505] As used herein, "chemically modified" or "modification" means a structure that is chemically different when compared to a naturally occurring counterpart, including all changes by chemical means, such as the addition or removal of a chemical moiety, or the substitution of one chemical moiety for another.

[0506] As used herein, the term "2'-fluoro modified nucleotide" refers to a nucleotide in which the hydroxyl group at the 2' position of the ribose group of the nucleotide is replaced by fluorine; the "methoxy modified nucleotide" or "2'-methoxy modified nucleotide" refers to a nucleotide in which the 2'-hydroxyl group of the ribose group is replaced by a methoxy group. BRIEF DESCRIPTION OF THE DRAWINGS

[0507] Figure 1 shows the inhibitory activity of TJR101470, TJR101471, and TJR101472 on RAGE in mouse lungs after 14 days of administration. Data are presented as mean ± SD. ** indicates p < 0.01, and * indicates p < 0.05 compared to the saline group.

[0508] Figure 2 shows the inhibitory activity of TJR101401, TJR101468-08, and TJR101468-13 against RAGE in mouse lungs after 14 days of administration. Data are presented as mean ± SD. **** indicates p < 0.0001, *** indicates p < 0.001, and ** indicates p < 0.01 compared to the saline group. # indicates p < 0.05, and ## indicates p < 0.01 compared to the TJR101401 group.

[0509] Figure 3 shows the inhibitory activity of TJR101401, TJR101468-11, and TJR101468-13 against RAGE in mouse lungs after 28 days of administration. Data are presented as mean ± SD. **** indicates p < 0.0001, * indicates p < 0.05 compared to the saline group. # indicates p < 0.05, and ## indicates p < 0.01 compared to the TJR101401 group.

[0510] Figure 4 shows the inhibitory activity of TJR103427-11 and TJR103428-1 on MUC5B in mouse lungs after 28 days of administration. Data are presented as mean ± SD. * indicates p < 0.05 compared to the saline group. # indicates p < 0.05 compared to the TJR103428-1 group.

[0511] Figure 5 shows the inhibitory activity of TJR103427-1, TJR103700-1, and TJR103701-1 on MUC5B in mouse lungs after 14 days of administration. Data are presented as mean ± SD. ** indicates p < 0.01, and * indicates p < 0.05 compared to the saline group. Specific implementation plan

[0512] The present disclosure is further described below with reference to the following examples, but these examples are not intended to limit the scope of this disclosure. Experimental methods in the examples disclosed herein, where specific conditions are not specified, were generally performed under conventional conditions or as recommended by the raw material or commercial manufacturer. Reagents whose sources are not specified can be obtained from any molecular biology reagent supplier of a quality / purity suitable for molecular biology applications.

[0513] Abbreviations FmocCl: 9-fluorenylmethyl chloroformate DCM: dichloromethane DIPEA, DIEA: N-ethyldiisopropylamine TBTU O-benzotriazole-N,N,N',N'-tetramethyluronium Tetrafluoroborate TEA, Et3N: triethylamine DMF: N,N-dimethylformamide EDCI: 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride MeOH: methanol EtOH: ethanol TFA: trifluoroacetic acid DMSO: dimethyl sulfoxide NMM: N-methylmorpholine TDBSPCl: tert-butyl(chloro)diphenylsilane DMAP: 4-(dimethylamino)pyridine THF: tetrahydrofuran PE: petroleum ether EA: ethyl acetate N3-PEG5-Tos azide-pentapolyethylene glycol-p-toluenesulfonyl ester NaHMDS sodium bis(trimethylsilyl)amine HATU 2-(7-Azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate LCMS liquid chromatography mass spectrometry NMR nuclear magnetic resonance

[0514] Example 1: Synthesis of Compound I-1

[0515] Unless otherwise specified, the reagents used in the following examples are all commercially available products. The synthetic route of compound I-1 is as follows:

[0516] The synthesis and identification of the specific intermediates and final products involved in the above route are as follows:

[0517] Compound 2:

[0518] A solution of compound 1 (3.00 g, 5.93 mmol) in DCM (70 mL) was added to a 20% solution of Na2CO3 (30 mL). A solution of 9-fluorenylmethyl chloroformate (4.60 g, 17.8 mmol) in DCM (20 mL) was slowly added. The mixture was stirred at room temperature overnight. LCMS analysis indicated completion. After the reaction mixture was allowed to stand and separate, the organic phase was separated, washed with saturated brine, and dried over Na2SO4. The crude product obtained after concentration was purified using a normal phase silica gel column (eluent PE:EA = 5:1, product peak at 20%) and dried to afford compound 2 (3.20 g, 74.07% yield).

[0519] LCMS: tR=3.62min, MS(ESI)m / z=750.8[M+Na] + .

[0520] Compound 3:

[0521] Compound 2 (3.2 g, 4.40 mmol) was dissolved in formic acid (10 ml) and stirred overnight. LCMS monitoring showed that the reaction was complete. The reaction solution was dried to give crude compound 3 (2.50 g), which was used directly in the next step.

[0522] LCMS: tR=0.99min, MS(ESI)m / z=560.5[M+H] + .

[0523] Compound 4:

[0524] Compound 3 (2.50 g, 4.46 mmol) was dissolved in DCM (20 ml) at 0°C. Under nitrogen, TBTU (5.74 g, 17.87 mmol) and propargyl-triethylene glycol-amino (2.56 g, 17.87 mmol) were added sequentially. DIPEA (4.4 ml, 26.8 mmol) was then slowly added dropwise over 5 minutes. The reaction mixture was stirred at room temperature for two hours, after which LCMS analysis indicated the disappearance of the starting material. The reaction mixture was quenched with water, and the organic phase was separated, washed with saturated brine, and dried over Na2SO4. The organic phase was concentrated to yield the crude product, which was purified by reverse-phase column chromatography to afford compound 4 (3.89 g, 93.11% yield).

[0525] LCMS: tR=2.37min, MS(ESI)m / z=935.9[M+H] + .

[0526] Compound 5:

[0527] Triethylamine (7.5 ml) was added to a solution of compound 4 (3.89 g, 4.16 mmol) in DMF (20 ml) at 0°C. After stirring overnight at room temperature, glutaric anhydride (0.62 g, 5.40 mmol) was added and the reaction continued for 2 hours. LCMS analysis indicated the disappearance of the starting material, indicating the reaction was complete. The reaction solution was concentrated and directly purified using a reverse-phase column to obtain compound 5 (3.20 g, 93.02% yield).

[0528] LCMS: tR=1.22min, MS(ESI)m / z=827.8[M+H] + .

[0529] Compound 6:

[0530] To a DMF solution of compound 5 (3.20 g, 3.87 mmol) at 0°C, 4-nitrophenol (0.81 g, 5.80 mmol) and EDCI (1.11 g, 5.80 mmol) were added. The reaction was stirred at room temperature overnight. LCMS indicated the reaction was complete. The reaction was quenched with water and extracted three times with ethyl acetate (40 ml). The combined organic phases were washed with brine and dried over Na2SO4. The concentrated organic phases yielded a crude product, which was purified using a reverse-phase column to afford compound 6 (3.00 g, 81.74% yield).

[0531] LCMS:tR=1.67min MS(ESI)m / z=948.8[M+H] + .

[0532] Compound 7:

[0533] To a solution of compound 6 (2.90 g, 3.06 mmol) in DCM (20 ml) were added compound 6-amino-1-hexanol (0.50 g, 4.28 mmol) and Et3N (0.94 ml, 6.73 mmol). The reaction was stirred overnight, and LCMS confirmed the reaction was complete. The reaction solution was quenched with brine, and the organic phase was dried over Na2SO4. The resulting crude product was purified by reverse phase column chromatography to afford compound 7 (2.31 g, 81.62% yield).

[0534] LCMS: tR=1.42min, MS(ESI)m / z=926.9[M+H] + .

[0535] Compound I-1:

[0536] At 0 degrees and under nitrogen protection, 3A molecular sieves were added to a dry acetonitrile (15 ml) solution of compound 7 (2.20 g, 2.37 mmol). After stirring for 5 minutes, bis(diisopropylamino)(2-cyanoethoxy)phosphine (1.58 g, 5.22 mmol) and a pre-prepared dry acetonitrile solution (5.28 ml) of 1H-tetrazole (0.45 M) and N-methylimidazole (0.18 M) were added, and then the mixture was warmed to room temperature for 2 hours. LCMS detection showed that the reaction was complete. A 5% aqueous sodium bicarbonate solution (40 ml) was added to the reaction solution and shaken for 1 minute to quench the mixture. The mixture was then extracted twice with dichloromethane (50 ml). The combined organic phases were washed with saturated brine and dried over sodium sulfate. After filtration and concentration, the crude compound I-1 (2.45 g) was obtained and used directly in subsequent solid phase synthesis.

[0537] LCMS: tR=1.84min, MS(ESI)m / z=1149.2[M+Na] + . 31PNMR(400MHz,DMSO-d6)δ146.25.

[0538] Example 2: Synthesis of Compound I-2

[0539] Unless otherwise specified, the reagents used in the following examples are all commercially available products. The synthetic route of compound I-2 is as follows:

[0540] The synthesis and identification of the specific intermediates and final products involved in the above route are as follows:

[0541] Compound 2-2:

[0542] Compound 2-1 (5.03 g, 14.92 mmol) was added to dichloromethane (40 mL). HATU (6.48 g, 17.04 mmol) and DIEA (5.87 ml, 35.5 mmol) were added at 10°C. The reaction temperature was naturally raised to room temperature for 30 minutes. L-glutamic acid di-tert-butyl ester hydrochloride (4.20 g, 14.21 mmol) was then added and the reaction was allowed to proceed overnight at room temperature. LCMS analysis indicated the reaction was complete. The reaction solution was washed with 30 ml of water and dried over Na2SO4. The organic phase was concentrated, and the resulting crude product was purified using a normal phase column to yield compound 2-2 (7.20 g, 87.59% yield). LCMS: MS (ESI) m / z = 579.8 [M+H] + .

[0543] Compound 2-3:

[0544] Compound 2-2 (7.20 g, 12.44 mmol) was dissolved in methanol (50 ml) and then Pd / C (700 mg) was added. The gas was replaced twice with a hydrogen balloon and the reaction was allowed to proceed overnight at room temperature. After LCMS monitoring showed the reaction was complete, the reaction solution was filtered through celite and the filtrate was concentrated under reduced pressure to obtain compound 2-3 (4.80 g, yield 86.8%). LCMS: MS (ESI) m / z = 445.8 [M+H] + .

[0545] Compound 2-4:

[0546] To a solution of compound 2-3 (4.74 g, 10.66 mmol) in dichloromethane (120 ml) were added water (50 ml) and sodium bicarbonate (1.07 g, 12.79 mmol), followed by a solution of Fmoc-Cl (3.03 g, 11.73 mmol) in DCM (5 ml) which was slowly added dropwise. The mixture was stirred at room temperature overnight. LCMS analysis indicated the disappearance of the starting material. The reaction mixture was allowed to stand, and the organic phase was separated and dried over Na2SO4. The organic phase was concentrated to obtain the crude product, which was purified by a normal phase column chromatography to yield compound 2-4 (7.00 g, 98.45% yield). LCMS: MS (ESI) m / z = 667.9 [M+H] + .

[0547] Compound 2-5:

[0548] To a dichloromethane solution (10 ml) of compound 2-4 (6.92 g, 10.39 mmol), trifluoroacetic acid (20 ml) was added and the mixture was stirred at room temperature for 4 h. LCMS analysis indicated the reaction was complete. The reaction solution was directly dried to afford compound 2-5 (5.61 g), which was used directly in the next reaction. LCMS: MS (ESI) m / z = 499.7 [M+H] + .

[0549] Compound 2-6:

[0550] To a solution of compound 2-5 (6.92 g, 10.38 mmol) in dichloromethane (50 ml) at 0°C, TBTU (10.99 g, 34.23 mmol) and propargyl-triethylene glycol-amino (4.9 g, 34.23 mmol) were added sequentially, followed by the slow dropwise addition of DIPEA (10.3 ml, 62.23 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 4 hours. LCMS analysis indicated the reaction was complete. The reaction mixture was quenched with water, and the organic phase was separated, washed with saturated brine, and dried over Na2SO4. The organic phase was concentrated to yield the crude product, which was purified by a normal phase column to afford compound 2-6 (8.20 g, 90.51% yield). LCMS: MS (ESI) m / z = 875.1 [M+H] + .

[0551] Compound 2-7:

[0552] To a solution of compound 2-6 (8.11 g, 9.27 mmol) in DMF (10 ml) was added triethylamine (7.73 ml, 55.61 mmol). After reacting at room temperature for 4 h, glutaric anhydride (1.16 g, 10.20 mmol) was added. The reaction solution was stirred at room temperature for 1 hour. LCMS analysis indicated the reaction was complete. The reaction solution was concentrated and directly purified using a reverse phase column to obtain compound 2-7 (3.30 g, 46.48% yield). LCMS: MS (ESI) m / z = 767.0 [M+H] + .

[0553] Compound 2-8:

[0554] At 0°C, p-nitrophenol (0.67 g, 4.8 mmol) and EDC-HCl (0.92 g, 4.8 mmol) were added to a solution of compound 2-7 (3.34 g, 4.36 mmol) in DMF (30 ml). The reaction was allowed to warm to room temperature and stirred for 2 hours. LCMS analysis indicated the reaction was complete. The reaction solution was quenched by the addition of water (100 ml), and a large amount of solid precipitated. The filter cake was filtered and washed with water (50 ml x 2) to obtain compound 2-8 (2.4 g, 62.02% yield). LCMS: MS (ESI) m / z = 888.2 [M+H] + .

[0555] Compound 2-9:

[0556] To a solution of compound 2-8 (2.40 g, 2.71 mmol) in DCM (10 ml) was added 6-amino-1-hexanol (0.35 g, 2.98 mmol) and triethylamine (0.75 ml, 5.41 mmol) was added dropwise. After stirring at room temperature for 1 hour, LCMS analysis indicated the reaction was complete. The reaction solution was concentrated and directly purified using a reverse phase column to obtain compound 2-9 (1.96 g, 83.74% yield). LCMS: MS (ESI) m / z = 866.3 [M+H] + .

[0557] Compound I-2:

[0558] At 0 degrees and under nitrogen protection, 3A molecular sieves were added to a dry dichloromethane (10 ml) and acetonitrile (10 ml) solution of compound 2-9 (1.60 g, 1.85 mmol). After stirring for 5 minutes, bis(diisopropylamino)(2-cyanoethoxy)phosphine (1.39 g, 4.62 mmol) and a pre-prepared dry acetonitrile solution (5 ml) of 1H-tetrazole (0.45 M) and N-methylimidazole (0.18 M) were added, and then the mixture was warmed to room temperature for 2 hours. LCMS detection showed that the reaction was complete. Saturated sodium bicarbonate aqueous solution (30 ml) was added to the reaction solution and shaken for 1 minute to quench, and then extracted twice with dichloromethane (40 ml). The combined organic phase was washed with saturated brine and dried over sodium sulfate. After filtration and concentration, crude compound I-2 (2.50 g) was obtained and used directly in subsequent solid phase synthesis. LCMS:MS(ESI)m / z=1088.12[M+Na] + . 31 PNMR(400MHz,DMSO-d6)δ146.32.

[0559] Example 3: Synthesis of Compound I-3

[0560] Unless otherwise specified, the reagents used in the following examples are all commercially available products. The synthetic route of compound I-3 is as follows:

[0561] The synthesis and identification of the specific intermediates and final products involved in the above route are as follows:

[0562] Compound 3-2:

[0563] Potassium hydroxide (74.2 g, 1322.1 mmol) was added to a solution of pentaerythritol (180.0 g, 1322.07 mmol) in DMSO (8000 ml). The reaction was stirred at room temperature for 15 minutes, and then a solution of compound 3-1 (29.6 mL, 132.21 mmol) in DMSO (100 ml) was slowly added dropwise. The reaction mixture was stirred at room temperature overnight. After LCMS monitoring showed the reaction was complete, the reaction mixture was adjusted to pH = 1 with 3M HCl and extracted with DCM (2000 ml * 4). The combined organic phases were washed with saturated brine and dried over Na2SO4. The concentrated crude product was purified using a normal phase column to obtain compound 3-2 (20 g, 46.3% yield). LCMS: MS (ESI) m / z = 327.2 [M+H] + .

[0564] Compound 3-3:

[0565] Under nitrogen protection at 0°C, N-methylmorpholine (30.3 mL, 275.71 mmol) was added to a solution of compound 3-2 in dichloromethane (200 mL) in sequence, followed by the slow dropwise addition of ethyl propiolate (24.83 mL, 245.07 mmol). The reaction was allowed to warm to room temperature and allowed to react for 2 hours. LCMS monitoring indicated the reaction was complete. The reaction solution was concentrated and purified using a normal phase column to afford compound 3-3 (25 g, 65.7% yield). LCMS: MS (ESI) m / z = 643.4 [M+Na] + .

[0566] Compound 3-4:

[0567] Pd / C (300 mg) was added to compound 3-3 (3.00 g, 4.79 mmol) in ethanol (30 mL). The atmosphere was replaced twice with a hydrogen balloon and the mixture was stirred at room temperature for 4 h. LCMS monitoring indicated the reaction was complete. The reaction solution was filtered through celite and the filtrate was concentrated under reduced pressure to yield compound 3-4 (2.50 g, 97.33%). LCMS: MS (ESI) m / z = 537.8 [M+H] + .

[0568] Compound 3-5:

[0569] Imidazole (0.48 g, 6.99 mmol), TBDPSCl (1.41 g, 5.12 mmol), and DMAP (0.57 g, 4.66 mmol) were added sequentially to a DMF (20 ml) solution of compound 3-4 (2.50 g, 4.66 mmol). The reaction was heated to 70°C and stirred overnight. LCMS monitoring indicated the reaction was nearly complete. The reaction solution was quenched with water (100 ml) and extracted with ethyl acetate (50 ml x 2). The combined organic phases were washed with saturated brine, dried over Na2SO4, and concentrated to obtain the crude product, which was purified by normal phase column chromatography to yield compound 3-5 (3.10 g, 85.86% yield). LCMS: MS (ESI) m / z = 776.1 [M+H] + .

[0570] Compound 3-6:

[0571] Lithium hydroxide monohydrate (0.49 g, 11.61 mmol) was added to a mixture of compound 3-5 (3.10 g, 3.87 mmol) in THF (15 ml) and water (15 ml). The mixture was stirred at room temperature overnight. LCMS analysis indicated the disappearance of the starting material. The reaction mixture was concentrated, and the crude product was acidified to pH 1-2 with 1N HCl and extracted with ethyl acetate (20 ml x 2). The combined organic phases were washed with 20 ml of saturated brine and dried over Na2SO4. The filtrate was concentrated to yield compound 3-6 (3.00 g, 112.18% yield). LCMS: MS (ESI) m / z = 692.0 [M+H] + .

[0572] Compound 3-7:

[0573] Compound 3-6 (3.00 g, 4.34 mmol) was dissolved in DCM (30 ml) at 0°C. Under nitrogen, TBTU (4.59 g, 14.33 mmol) and propargyl-triethylene glycol-amino (2.05 g, 14.33 mmol) were added sequentially. DIPEA (2.5 ml, 15.20 mmol) was then slowly added dropwise over 5 minutes. The reaction mixture was stirred at room temperature for two hours, and LCMS analysis showed the disappearance of the starting material. The reaction mixture was quenched with water, and the organic phase was separated and washed with saturated brine, then dried over Na2SO4. The organic phase was concentrated to yield the crude product, which was purified by normal phase column chromatography to yield compound 3-7 (4.30 g, 92.86% yield). LCMS: MS (ESI) m / z = 1067.4 [M+H] + .

[0574] Compound 3-8:

[0575] Compound 3-7 (4.00 g, 3.75 mmol) was added to dioxane hydrochloride (20 ml) and allowed to react at room temperature for 4 hours. LCMS confirmed the reaction was complete. The reaction solution was concentrated and directly purified using a reverse phase column to obtain compound 3-8 (2.20 g, 70.84% ​​yield). LCMS: MS (ESI) m / z = 829.3 [M+H] + .

[0576] Compound I-3:

[0577] At 0°C under nitrogen, 3A molecular sieves were added to a solution of compound 3-8 (1.48 g, 1.79 mmol) in dry dichloromethane (10 ml). After stirring for 5 minutes, bis(diisopropylamino)(2-cyanoethoxy)phosphine (1.19 g, 3.93 mmol) and a pre-prepared solution of 1H-tetrazole (0.45 M) and N-methylimidazole (0.18 M) in dry acetonitrile (4 ml) were added. The mixture was then warmed to room temperature and reacted for 2 hours. LCMS confirmed the reaction was complete. Saturated aqueous sodium bicarbonate solution (30 ml) was added to the reaction solution and shaken for 1 minute to quench the reaction. The mixture was then extracted twice with dichloromethane (40 ml). The combined organic phases were washed with saturated brine and dried over Na2SO4. Filtration and concentration afforded crude compound I-3 (2.30 g), which was used directly in subsequent solid-phase synthesis. LCMS: MS (ESI) m / z = 1051.04 [M+Na] + . 31 P NMR (400 MHz, DMSO) δ 146.29.

[0578] Example 4: Synthesis of Compound I-4

[0579] Unless otherwise specified, the reagents used in the following examples are commercially available. The synthetic route of compound I-4 is as follows:

[0580] The synthesis and identification of the specific intermediates and final products involved in the above route are as follows:

[0581] Compound 4-2:

[0582] To a solution of compound 4-1 (3.30 g, 17.52 mmol) in DCM (50 mL) were added 3-{[2-(prop-2-ynyloxy)ethyl]oxy}propanoic acid (6.64 g, 38.55 mmol), TBTU (16.88 g, 52.57 mmol), and DIEA (14.48 mL, 87.62 mmol) in sequence. The reaction was allowed to react at room temperature for 1 hour, monitored by LCMS. 3-{[2-(prop-2-ynyloxy)ethyl]oxy}propanoic acid (3.02 g, 17.523 mmol) and TBTU (5.63 g, 17.523 mmol) were then added to the reaction system. After stirring at room temperature for 1 hour, the reaction was complete, as monitored by LCMS. The reaction solution was concentrated to obtain the crude product, which was purified by reverse phase column chromatography to yield compound 4-2 (4.00 g, 35.07% yield). LCMS: MS (ESI) m / z = 652.0 [M+H] + .

[0583] Compound 4-3:

[0584] Under nitrogen, TEA (10 mL) and glutaric anhydride (0.98 g, 8.605 mmol) were added to a solution of compound 4-2 (4.00 g, 6.15 mmol) in DMF (50 mL). The mixture was allowed to react at room temperature for 2 hours, and the reaction was complete as monitored by LCMS. The reaction solution was filtered, and the filtrate was purified using a reverse-phase column to obtain compound 4-3 (3.80 g, 80.83% yield). LCMS: MS (ESI) m / z = 766.3 [M+H] + .

[0585] Compound 4-4:

[0586] To a DMF solution of compound 4-3 (3.80 g, 4.97 mmol) at room temperature were added 4-nitrophenol (1.04 g, 7.45 mmol) and EDCI (1.43 g, 7.45 mmol). The reaction was stirred at room temperature overnight. LCMS indicated the reaction was complete. The reaction solution was quenched with water and extracted three times with dichloromethane (50 ml). The combined organic phases were washed with brine and dried over Na2SO4. The crude product was concentrated and purified using a reverse phase column to afford compound 4-4 (2.50 g, 56.80% yield). LCMS: MS (ESI) m / z = 887.3 [M+H] + .

[0587] Compound 4-5:

[0588] To a solution of compound 4-4 (2.50 g, 2.82 mmol) in DMF (20 ml) were added 6-amino-1-hexanol (0.50 g, 4.23 mmol) and Et3N (0.78 ml, 5.64 mmol). The reaction was stirred overnight and the reaction was complete by LCMS. The reaction solution was quenched with brine and extracted three times with dichloromethane (50 ml). The combined organic phases were washed with brine and dried over Na2SO4. The crude product was concentrated and purified using a reverse phase column to obtain compound 4-5 (2.00 g, 82.03% yield). LCMS: MS (ESI) m / z = 865.4 [M+H] + .

[0589] Compound I-4

[0590] At 0 degrees and under nitrogen protection, 3A molecular sieves were added to a dry acetonitrile (15 mL) solution of compound 4-5 (2.00 g, 2.32 mmol). After stirring for 5 minutes, bis(diisopropylamino)(2-cyanoethoxy)phosphine (1.88 g, 6.25 mmol) and a pre-prepared dry acetonitrile solution (5.14 mL) of 1H-tetrazole (0.45 M) and N-methylimidazole (0.18 M) were added, and then the mixture was warmed to room temperature for 2 hours. LCMS detected that the reaction was complete. 5% aqueous sodium bicarbonate solution (40 mL) was added to the reaction solution and shaken for 1 minute to quench, and then extracted twice with dichloromethane (50 mL). The combined organic phase was washed with saturated brine and dried over sodium sulfate. After filtration and concentration, crude compound I-4 (3.03 g) was obtained and used directly for subsequent solid phase synthesis. LCMS: MS (ESI) m / z = 1109.1 [M+46] + . 31 P-NMR (162 MHz, DMSO) δ 146.28.

[0591] Example 5: Synthesis of Compound I-5

[0592] Unless otherwise specified, the reagents used in the following examples are all commercially available products. The synthetic route of compound I-5 is as follows:

[0593] The synthesis and identification of the specific intermediates and final products involved in the above route are as follows:

[0594] Compound 5-2:

[0595] Compound 5-1 (3.00 g, 8.23 ​​mmol) was dissolved in anhydrous DMF (30 mL). N-Boc-L-lysine methyl ester hydrochloride (2.36 g, 9.05 mmol), DIEA (4.1 mL, 24.68 mmol), EDC﹒HCl (1.89 g, 9.87 mmol), and HOBt (1.33 g, 9.87 mmol) were added sequentially with stirring. The mixture was stirred at room temperature for 3 hours. LCMS analysis indicated completion. The reaction solution was diluted with ethyl acetate and washed twice with 5% aqueous citric acid, twice with saturated sodium bicarbonate, and then with saturated brine. The organic phase was dried over Na2SO4, filtered, and concentrated to obtain crude product 5-2 (4.50 g, 92.91% yield), which was used directly in the next reaction. LCMS: MS (ESI) m / z = 589.9 [M+H] + .

[0596] Compound 5-3:

[0597] Compound 5-2 (4.5 g, 7.64 mmol) was dissolved in DCM (18 mL), trifluoroacetic acid (9 mL) was added, and the mixture was stirred at room temperature overnight. LCMS monitoring showed that the reaction was complete. The reaction solution was dried to give the crude trifluoroacetic acid salt of compound 5-3 (8 g), which was used directly in the next step. LCMS: MS (ESI) m / z = 289.5 [M+H] + .

[0598] Compound 5-4:

[0599] Compound 5-3 (7.70 g, 7.92 mmol) was dissolved in anhydrous DCM (25 mL) and placed in an ice bath under nitrogen. DIPEA (15.7 mL, 95 mmol) and TBTU (10.17 g, 31.67 mmol) were added sequentially. The reaction mixture was slowly warmed to room temperature and allowed to react for 30 minutes. Propargyl-PEG2-acid (5.45 g, 31.67 mmol) was then added. The reaction mixture was stirred at room temperature for 1 hour. LCMS analysis showed the disappearance of the starting material. The reaction mixture was quenched with water, and the organic phase was separated and washed with saturated brine and dried over Na2SO4. The organic phase was concentrated to obtain the crude product, which was purified by reverse phase column chromatography to yield compound 5-4 (4.00 g, 67.28% yield). LCMS: MS (ESI) m / z = 752.0 [M+H] + .

[0600] Compound 5-5:

[0601] Compound 5-4 (3.72 g, 4.93 mmol) was dissolved in a THF / H2O (4:1, 35 mL) solution, and lithium hydroxide monohydrate (0.39 g, 9.36 mmol) was added. The mixture was allowed to react at room temperature for 30 minutes. LCMS analysis revealed the disappearance of the starting material. After the reaction, 1 M hydrochloric acid was added to adjust the pH to 5-6. The mixture was extracted with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to afford compound 5-5 (3.59 g, 99.15% yield). LCMS: MS (ESI) m / z = 738.0 [M+H] + .

[0602] Compound 5-6:

[0603] To a DMF solution of compound 5-5 (3.55 g, 4.89 mmol) at 0°C, 4-nitrophenol (1.02 g, 7.33 mmol) and EDCI (1.4 g, 7.33 mmol) were added. The mixture was allowed to warm to room temperature and the reaction continued for 1 hour. LCMS analysis indicated the reaction was complete. The reaction solution was quenched with water and extracted three times with ethyl acetate (40 mL). The combined organic phases were washed with brine and dried over Na2SO4. The crude product obtained from the concentrated organic phases was purified using a reverse phase column to yield compound 5-6 (3.68 g, 88.27% yield). LCMS: MS (ESI) m / z = 859.3 [M+H] + .

[0604] Compounds 5-7:

[0605] To a solution of compound 5-6 (3.65 g, 4.31 mmol) in DCM (10 mL) were added compound 6-amino-1-hexanol (0.61 g, 5.18 mmol) and Et3N (1.2 mL, 8.63 mmol). The mixture was allowed to react at room temperature for 10 minutes, and the reaction was complete by LCMS. The reaction solution was quenched with brine, and the organic phase was dried over Na2SO4. The crude product was purified by reverse phase column chromatography to afford compound 5-7 (2.00 g, 55.4% yield). LCMS: MS (ESI) m / z = 837.3 [M+H] + .

[0606] Compound I-5:

[0607] At 0°C under nitrogen protection, 3A molecular sieves were added to a dry acetonitrile (10 mL) solution of compound 5-7 (1.35 g, 1.62 mmol). After stirring for 5 minutes, bis(diisopropylamino)(2-cyanoethoxy)phosphine (1.07 g, 3.55 mmol) and a pre-prepared dry acetonitrile solution (4.3 mL) of 1H-tetrazole (0.45 M) and N-methylimidazole (0.18 M) were added. The mixture was then warmed to room temperature and reacted for 2 hours. LCMS detected the reaction to be complete. 5% aqueous sodium bicarbonate solution (40 mL) was added to the reaction solution and shaken for 1 minute to quench the mixture. The mixture was then extracted twice with dichloromethane (50 mL). The combined organic phases were washed with saturated brine and dried over sodium sulfate. After filtration and concentration, crude compound I-5 (2.10 g) was obtained and used directly in subsequent solid phase synthesis. LCMS: MS (ESI) m / z = 1058.98 [M+Na] + . 31 P NMR (400 MHz, DMSO) δ 146.28.

[0608] Example 6 Synthesis of Compound III-f'

[0609] The synthetic route of compound III-f' is as follows:

[0610] The synthesis and identification of the specific intermediates and final products involved in the above route are as follows:

[0611] Compound f-2:

[0612] To a solution of compound f-1 (0.77 g, 6.32 mmol) in methanol (10 ml), methyl 5-acetylvalerate (1.00 g, 6.32 mmol) and L-proline (0.36 g, 3.16 mmol) were added sequentially. The reaction was heated to reflux and allowed to proceed overnight. LCMS analysis indicated completion. The reaction solution was cooled to room temperature and then dried by spin drying. The concentrated crude product was purified by normal phase silica gel column chromatography to yield compound f-2 (720 mg, 46.6% yield). LCMS: MS (ESI) m / z = 245.1 [M+Na] + .

[0613] Compound f-3:

[0614] To a solution of compound f-2 (412 mg, 1.69 mmol) in methanol (10 ml), palladium on carbon (42 mg) was added. The mixture was stirred at room temperature overnight under a hydrogen atmosphere. LCMS monitoring indicated the reaction was complete. Filtered through celite, the filtrate was dried, and compound f-3 (410 mg, 97.9% yield) was obtained. LCMS: MS (ESI) m / z = 249.2 [M+H] + .

[0615] Compound f-4:

[0616] To a solution of compound f-3 (300 mg, 1.21 mmol) in 1,4-dioxane (3 ml), di-tert-butyl dicarbonate (395 mg, 1.81 mmol) was added. The reaction was heated to 90°C and stirred for 2 hours. LCMS analysis indicated completion. The reaction solution was cooled to room temperature and then dried. The concentrated crude product was purified by normal phase silica gel column chromatography to yield compound f-4 (380 mg, 90.2% yield). LCMS: MS (ESI) m / z = 349.2 [M+H] + .

[0617] Compound f-5:

[0618] To a mixture of compound f-4 (380 mg, 1.09 mmol) in water (2 ml) and tetrahydrofuran (2 ml) was added lithium hydroxide monohydrate (54.9 mg, 1.31 mmol). The mixture was allowed to react at room temperature for 30 minutes. LCMS confirmed the reaction was complete. The reaction solution was directly spin-dried to obtain crude product f-5, which was directly used in the next step. LCMS: MS (ESI) m / z = 335.3 [M+H]+ .

[0619] Compound f-6:

[0620] To a solution of compound f-5 (400 mg, 1.2 mmol) in N,N-dimethylformamide (4 mL) were added glycine methyl ester hemihydrochloride (180 mg, 1.44 mmol), O-benzotriazole-N,N,N',N'-tetramethyluronium tetrafluoroboric acid (461 mg, 1.44 mmol), and N,N-diisopropylethylamine (464 mg, 3.59 mmol) in N,N-dimethylformamide (4 mL). The mixture was allowed to react at room temperature for 30 minutes. LCMS analysis indicated completion. The reaction mixture was quenched with 100 mL of water, extracted with ethyl acetate (40 mL x 3), washed with saturated brine, and dried over anhydrous sodium sulfate. The concentrated crude product was purified by normal phase silica gel column chromatography to afford compound f-6 (340 mg, 70.1% yield). LCMS: MS (ESI) m / z = 406.3 [M+H] + .

[0621] Compound f-7:

[0622] To a mixture of compound f-6 (340 mg, 0.84 mmol) in water (2 ml) and tetrahydrofuran (2 ml) was added lithium hydroxide monohydrate (42 mg, 1.00 mmol). The mixture was allowed to react at room temperature for 30 minutes. LCMS confirmed the reaction was complete. The reaction mixture was directly dried to afford crude product f-7, which was then used directly in the next step. LCMS: MS (ESI) m / z = 392.2 [M+H] + .

[0623] Compound f-8:

[0624] To a solution of compound f-7 (173 mg, 0.44 mmol) in N,N-dimethylformamide (2 mL) were added compound Inter-1 (180 mg, 0.4 mmol), O-benzotriazole-N,N,N',N'-tetramethyluronium tetrafluoroboric acid (142 mg, 0.44 mmol), and N,N-diisopropylethylamine (156 mg, 1.21 mmol) in sequence. The mixture was allowed to react at room temperature for 30 minutes. LCMS analysis indicated completion. The reaction mixture was quenched with 10 mL of water, extracted with ethyl acetate (40 mL x 3), washed with saturated brine, and dried over anhydrous sodium sulfate. The concentrated crude product was purified by normal phase silica gel column chromatography to afford compound f-8 (120 mg, 38.1% yield). LCMS: MS (ESI) m / z = 785.4 [M+Na] + .

[0625] Compound f-9:

[0626] To compound f-8 (240 mg, 0.31 mmol) in tetrahydrofuran (3 mL) and ethyl acetate (6 mL) was added 10% palladium on carbon (120 mg). After hydrogen exchange three times, the mixture was stirred at room temperature overnight. LCMS confirmed the reaction was complete. The reaction solution was filtered, and the organic phase was concentrated to afford compound f-9 (205 mg, 96.5% yield) as a white solid. LCMS: MS (ESI) m / z = 695.4 [M+H] + .

[0627] Compound f-10:

[0628] To a solution of compound f-9 (205 mg, 0.29 mmol) in N,N-dimethylformamide (4 mL) at 0°C were added azide-pentaethylene glycol-p-toluenesulfonyl ester (148 mg, 0.35 mmol) and potassium carbonate (82 mg, 0.59 mmol). The reaction was stirred at 80°C for 6 hours. After completion of the reaction, as monitored by LCMS, the mixture was quenched with saturated sodium bicarbonate solution, extracted with ethyl acetate (40 mL*3), washed with saturated brine, and dried over anhydrous sodium sulfate. The concentrated crude product was purified using a normal phase silica gel column (dichloromethane:methanol = 10 / 1) to obtain compound f-10 (240 mg, 86.5% yield) as a light yellow oil. LCMS: MS (ESI) m / z = 962.2 [M+H] + .

[0629] Compound III-f':

[0630] To a mixed solution of compound f-10 (240 mg, 0.25 mmol) in water (2 ml) and tetrahydrofuran (2 ml) was added lithium hydroxide monohydrate (0.021 mL, 0.76 mmol) and stirred at room temperature for two hours. LCMS confirmed the reaction was complete. The reaction solution was concentrated to obtain a crude product, which was then added back to dichloromethane (1.5 mL) and trifluoroacetic acid (1.5 mL). The product was stirred at room temperature overnight and the reaction was complete as determined by LCMS. The crude product was concentrated and purified by preparative HPLC to yield compound III-f' (140 mg) as a yellow solid. LCMS: MS (ESI) m / z = 826.3 [M+H] + . 1H NMR (400MHz, DMSO) δ13.15(s,1H),8.49(d,J=0.8Hz,1H),8.27(d,J=0.8Hz,1H),8.11(t,J=0.8Hz,1H),7.77(1H ,s),7.76(d,J=0.8Hz,1H),7.53-7.49(m,2H),7.49-7.31(m,6H),7.06(d,J=1.2Hz,1H),5.35-5.27(m,1H),4.3 3(t,J=0.4Hz,2H),3.92(t,J=0.4Hz,2H),3.76-3.65(m,4H),3.63-3.49(m,10H),3.38-3.29(m,6H),2.78(d,J= 0.8Hz,2H),2.69-2.64(m,2H),2.62-2.57(m,2H),2.17(t,J=0.8Hz,2H),1.81-1.75(m,2H),1.62-1.50(m,4H).

[0631] Example 7 Synthesis of Compound III-g'

[0632] The synthetic route of compound III-g' is as follows:

[0633] The synthesis and identification of the specific intermediates and final products involved in the above route are as follows:

[0634] Compound g-2:

[0635] Under nitrogen at -78°C, sodium bis(trimethylsilyl)amide (13.55 ml, 27.11 mmol) was slowly added dropwise to a solution of triethyl phosphinoacetate (6.75 g, 30.11 mmol) in tetrahydrofuran (30 ml). After stirring at this temperature for 30 minutes, a solution of compound g-1 (3.00 g, 15.06 mmol) in tetrahydrofuran (10 ml) was added and the reaction continued for 30 minutes. LCMS monitoring indicated the reaction was complete. The reaction solution was quenched with water (100 ml), extracted with ethyl acetate (40 mL x 3), washed with saturated brine, and dried over anhydrous sodium sulfate. The concentrated crude product was purified by normal phase silica gel column chromatography to yield compound g-2 (1.85 g, 45.6% yield). LCMS: MS (ESI) m / z = 170.1 [M-100+H] + .

[0636] Compound g-3:

[0637] To compound g-2 (1.00 g, 3.71 mmol) in methanol (10 ml), 10% palladium on carbon (100 mg) was added and stirred overnight at room temperature under a hydrogen atmosphere. LCMS monitoring indicated the reaction was complete. Filter through celite, and the filtrate was dried to give compound g-3 (1.00 g, 99.2% yield). LCMS: MS (ESI) m / z = 172.1 [M-100+H] + .

[0638] Compound g-4:

[0639] Compound g-3 (1.00 g, 3.69 mmol) was added to a 4N solution of hydrogen chloride in ethyl acetate (20 ml). After stirring at room temperature for 1 hour, LCMS monitoring indicated the reaction was complete. The reaction solution was spin-dried to give crude product g-4 (0.81 g), which was directly used in the next step. LCMS: MS (ESI) m / z = 172.1 [M+H] + .

[0640] Compound g-5:

[0641] To a solution of compound g-4 (500 mg, 2.41 mmol) in dimethyl sulfoxide (5 ml), 2-fluoro-4-methylpyridine (401 mg, 3.61 mmol) and potassium carbonate (665 mg, 4.82 mmol) were added sequentially. Microwave-assisted reaction was carried out at 140°C for 1.5 hours. LCMS monitoring indicated the reaction was complete. The reaction solution was quenched with water, extracted with ethyl acetate (40 mL x 3), washed with saturated brine, and dried over anhydrous sodium sulfate. The concentrated crude product was purified by normal phase silica gel column chromatography to afford compound g-5 (240 mg, 38.0% yield). LCMS: MS (ESI) m / z = 263.2 [M+H] + .

[0642] Compound g-6:

[0643] To a mixture of compound g-5 (320 mg, 1.22 mmol) in water (2 ml) and tetrahydrofuran (2 ml) was added lithium hydroxide monohydrate (61.4 mg, 1.46 mmol). The mixture was allowed to react at room temperature for 30 minutes. LCMS confirmed the reaction was complete. The reaction solution was directly dried to afford crude product g-6 (350 mg) which was used in the next step. LCMS: MS (ESI) m / z = 235.1 [M+H] + .

[0644] Compound g-7:

[0645] To a solution of compound g-6 (260 mg, 1.11 mmol) in N,N-dimethylformamide (3 ml) were added glycine methyl ester hemihydrochloride (167 mg, 1.33 mmol), O-benzotriazole-N,N,N',N'-tetramethyluronium tetrafluoroborate (428 mg, 1.33 mmol), and N,N-diisopropylethylamine (430 mg, 3.33 mmol) in sequence. After reacting at room temperature for 30 minutes, LCMS analysis indicated completion. The reaction solution was quenched with water, extracted with ethyl acetate (40 mL x 3), washed with saturated brine, and dried over anhydrous sodium sulfate. The concentrated crude product was purified by normal phase silica gel column chromatography to afford compound g-7 (240 mg, 70.8% yield). LCMS: MS (ESI) m / z = 306.2 [M+H] + .

[0646] Compound g-8:

[0647] To a mixture of compound g-7 (240 mg, 0.79 mmol) in water (1.5 ml) and tetrahydrofuran (1.5 ml) was added lithium hydroxide monohydrate (40 mg, 0.94 mmol). The mixture was allowed to react at room temperature for 30 minutes. LCMS confirmed the reaction was complete. The reaction solution was directly purified by reverse-phase column chromatography to afford compound g-8 (140 mg, 61.1% yield). LCMS: MS (ESI) m / z = 292.2 [M+H] + .

[0648] Compound g-9:

[0649] To a solution of compound g-8 (220 mg, 0.79 mmol) in N-dimethylformamide (5 mL) at room temperature were added N,N-diisopropylethylamine (0.39 mL, 2.36 mmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (300 mg, 0.94 mmol), and compound Inter-1 (370 mg, 0.91 mmol). The reaction mixture was stirred for 2 hours, and LCMS indicated the reaction was complete. Water was added dropwise to the reaction mixture, and the mixture was extracted with ethyl acetate (40 mL x 3), washed with saturated brine, and dried over anhydrous sodium sulfate. The concentrated crude product was purified on a normal phase silica gel column (dichloromethane:methanol = 20 / 1) to afford compound g-9 (120 mg, 22.2% yield). LCMS (ESI) observed: 685.4 [M+H] + .

[0650] Compound g-10:

[0651] Palladium on carbon (100 mg) was added to a solution of compound g-9 (120 mg, 0.17 mmol) in ethyl acetate (3 mL). The system was purged with hydrogen three times and stirred at room temperature overnight. LCMS showed the reaction was complete. The reaction mixture was filtered through celite and concentrated to give compound g-10 (70 mg, 61.7% yield) as a yellow-white solid. LCMS (ESI) measured: 595.4 [M+H] + .

[0652] Compound g-11:

[0653] To a solution of compound g-10 (70 mg, 0.12 mmol) in NN-dimethylformamide (2 mL), add azide-pentaethylene glycol-p-toluenesulfonyl ester (64 mg, 0.15 mmol) and potassium carbonate (33 mg, 0.24 mmol). The reaction was stirred at 80°C overnight. After LCMS showed the reaction was complete, saturated sodium bicarbonate solution was added to quench the reaction. Extract with ethyl acetate (40 mL*3), wash with saturated brine, and dry over anhydrous sodium sulfate. The concentrated crude product was purified on a normal phase silica gel column (petroleum ether:ethyl acetate = 1 / 1) to obtain compound g-11 (46 mg, 46.5% yield) as a yellow solid. LCMS (ESI) measured: 840.3 [M+H] + .

[0654] Compound III-g':

[0655] Compound g-11 (45 mg, 0.05 mmol) was dissolved in a mixture of tetrahydrofuran (1 mL) and water (1 mL), and lithium hydroxide monohydrate (7 mg, 0.16 mmol) was added. Stir at room temperature for two hours. LCMS confirmed the reaction was complete. The pH of the reaction solution was adjusted to 2 with 1N hydrochloric acid, extracted with ethyl acetate (40 mL*3), washed with saturated brine, and dried over anhydrous sodium sulfate. The crude product was concentrated and purified by preparative HPLC to yield compound III-g' (35 mg) as a yellow solid. LCMS: MS (ESI) m / z = 826.4 [M+H] + . 1H NMR (400MHz, DMSO) δ8.72(d,J=0.8Hz,1H),8.37(s,1H),8.26(d,J=0.8Hz,1H),8.17(t,J=0.8Hz,1H),7.82(d,J=0.8Hz,1H),7.77(d,J=0.8Hz,1H),7 .53-7.49(m,2H),7.49-7.45(m,2H),7.45-7.37(m,2H),7.31-7.28(m,1H) ,7.03(d,J=0.8Hz,1H),6.34(s,1H),6.21(s,1H),5.26(dd,J=1.2,0.8Hz,1 H),4.35-4.31(m,2H),3.93-3.85(m,2H),3.76-3.73(m,2H),3.69-3.67(m ,2H),3.61-3.52(m,10H),3.49-3.41(m,2H),3.36(d,J=0.8Hz,2H),3.28-3 .23(m,2H),2.91(dd,J=0.8,0.4Hz,1H),2.76-2.69(m,2H),2.28-2.21(m, 2H),2.17(s,3H),2.14-2.08(m,1H),1.69-1.63(m,2H),1.61-1.53(m,1H).

[0656] Example 8 Synthesis of Compound III-h'

[0657] The synthetic route of compound III-h' is as follows:

[0658] The synthesis and identification of the specific intermediates and final products involved in the above route are as follows:

[0659] Compound h-2:

[0660] Compound h-1 (1.30 g, 6.24 mmol) was added to NN-dimethylformamide (10 mL). Sodium hydride (324.59 mg, 8.11 mmol) was slowly added at 0°C under nitrogen protection. After stirring for 30 minutes, ethyl bromoacetate (0.83 mL, 7.49 mmol) was added while maintaining the temperature at 0°C. The mixture was stirred overnight at room temperature. LCMS indicated the reaction was complete. Water was added dropwise to quench the reaction, followed by extraction with ethyl acetate (40 mL x 3), washing with saturated brine, and drying over anhydrous sodium sulfate. The concentrated crude product was purified on a normal phase silica gel column (petroleum ether:ethyl acetate = 5 / 1) to afford compound h-2 (1.50 g, 81.64% yield) as a colorless oily liquid. LCMS (ESI) measured: 295.4 [M+H] + . 1H NMR (400MHz, CDCl3) δ8.17(d,J=5.0Hz,1H),7.70(s,1H),6.84(d,J=5.0Hz,1H),4. 71(s,2H),4.22(q,J=7.0Hz,2H),2.36(s,3H),1.54(s,9H),1.28(t,J=7.0Hz,3H).

[0661] Compound h-3:

[0662] Under N2 protection, 1N lithium aluminum hydride (10.2 mL, 10.20 mol) was added to a solution of compound h-2 (1.50 g, 5.10 mmol) in tetrahydrofuran (20 mL). The reaction mixture was stirred at room temperature for 1 hour. LCMS indicated the reaction was complete. Water was added dropwise to the reaction mixture, and the mixture was extracted with ethyl acetate (40 mL x 3), washed with saturated brine, and dried over anhydrous sodium sulfate. The concentrated crude product was purified using a normal phase silica gel column (petroleum ether:ethyl acetate = 5:1) to obtain compound h-3 (400 mg, 31.1% yield) as a colorless oily liquid. LCMS (ESI) measured: 253.4 [M+H] + .

[0663] Compound h-4:

[0664] Compound h-3 (200 mg, 0.80 mmol) was dissolved in dichloromethane (5 mL), and N,N-diisopropylethylamine (0.33 mL, 1.98 mmol) and 4-nitrobenzene chloroformate (159.77 mg, 0.80 mmol) were added at room temperature. The reaction mixture was stirred at room temperature for 3 hours. LCMS indicated the reaction was complete. The reaction mixture was washed with saturated brine and dried over anhydrous sodium sulfate. The intermediate product was concentrated and redissolved in dichloromethane (4 mL). Triethylamine (0.5 mL, 3.57 mmol) and compound Inter-1 (371.41 mg, 0.80 mmol) were added sequentially at room temperature. The reaction mixture was stirred at room temperature for another 2 hours. LCMS indicated the reaction was complete. The reaction mixture was washed with saturated brine and dried over anhydrous sodium sulfate. The concentrated crude product was purified using a normal phase silica gel column (petroleum ether:ethyl acetate = 1 / 1) to afford compound h-4 (180 mg, 30.4% yield) as a yellow solid. LCMS (ESI) found: 747.6 [M+H] + .

[0665] Compound h-5:

[0666] To a solution of compound h-4 (150 mg, 0.20 mmol) in methanol (30 mL) at room temperature was added 10% palladium on carbon (50 mg). The system was purged with hydrogen three times and stirred at room temperature overnight. LCMS indicated the reaction was complete. The reaction mixture was filtered through celite and concentrated to afford compound h-5 (130 mg, 98.5% yield) as an off-white solid. LCMS (ESI) measured: 657.2 [M+H] + .

[0667] Compound h-6:

[0668] To a solution of compound h-5 (120 mg, 0.183 mmol) in NN-dimethylformamide (5 mL) were added azide-pentaethylene glycol-p-toluenesulfonyl ester (152.56 mg, 0.37 mmol) and potassium carbonate (50.51 mg, 0.37 mmol), and the reaction was stirred at 80°C overnight. LCMS showed the reaction was complete. The reaction solution was quenched with saturated sodium bicarbonate solution, extracted with ethyl acetate (40 mL*3), washed with saturated brine, and dried over anhydrous sodium sulfate. The concentrated crude product was purified using a normal phase silica gel column (petroleum ether:ethyl acetate = 1:1) to obtain compound h-6 (113 mg, 68.5% yield) as a yellow solid. LCMS (ESI) measured: 902.2 [M+H] + .

[0669] Compound h-7:

[0670] To a solution of compound h-6 (100 mg, 0.11 mmol) in tetrahydrofuran (5 ml) was added 1N lithium hydroxide monohydrate (5 ml, 5.0 mmol) at room temperature. After stirring for 2 hours, LCMS indicated the reaction was complete. The pH of the reaction solution was adjusted to 2 with 1N hydrochloric acid, extracted with ethyl acetate (40 mL x 3), washed with saturated brine, and dried over anhydrous sodium sulfate. After concentration, compound h-7 (95 mg, 96.5% yield) was obtained as a yellow solid. LCMS (ESI) measured: 888.1 [M+H] + .

[0671] Compound III-h':

[0672] A 4M 1,4-dioxane hydrochloride solution (1 mL) was added to a solution of compound h-7 (100 mg, 0.11 mmol) in dichloromethane (2 mL) at room temperature. The reaction mixture was stirred at room temperature for 3 hours. LCMS indicated the reaction was complete. The reaction mixture was concentrated to obtain the crude product, which was purified by preparative HPLC to afford compound III-h' (53.6 mg, 60.4% yield) as a yellow solid. LCMS (ESI) measured: 788.5 [M+H] + . 1H NMR(400MHz,DMSO)δ8.52(d,J=8.2Hz,1H),8.36–8.16(m,1H),7.79(dd,J=18.4,6.7Hz,2H),7 .56-7.29(m,7H),7.05(d,J=8.0Hz,1H),6.63(s,1H),6.56(d,J=5.9Hz,1H),5.29(dd,J=15.0, 7.3Hz,1H),4.40-4.30(m,2H),4.12(t,J=5.6Hz,2H),3.96-3.90(m,2H),3.72-3.64(m,9H),3 .59(dd,J=11.3,6.1Hz,8H),3.40-3.35(m,6H),2.79(d,J=7.1Hz,2H),2.22(d,J=14.6Hz,3H).

[0673] Example 9 Synthesis of Compound III-i'

[0674] The synthetic route of compound III-i' is as follows:

[0675] The synthesis and identification of the specific intermediates and final products involved in the above route are as follows:

[0676] Compound i-2:

[0677] At 0°C, sodium hydride (0.29 g, 7.20 mmol) was added to a solution of compound i-1 (1.00 g, 4.802 mmol) in N,N-dimethylformamide (20 mL). The reaction solution was stirred at 0°C for 30 minutes, followed by the addition of bromoacetonitrile (0.40 mL, 5.762 mmol). Stirring was continued at room temperature for 3 hours. After LCMS monitoring showed that the reaction was complete, the reaction solution was quenched with water and extracted with ethyl acetate (40 mL*3). The combined organic phases were washed with saturated brine and dried over sodium sulfate. The concentrated crude product was purified on a normal phase silica gel column (petroleum ether:ethyl acetate = 5 / 1) to obtain compound i-2 (932 mg, 78.5% yield) as a yellow oil. LCMS (ESI) measured: 231.1 [M+H] + . 1 H NMR (400MHz, CDCl3) δ8.25 (d, J = 5.1 Hz, 1H), 7.67 (s, 1H), 6.92 (d, J = 5.1 Hz, 1H), 4.91 (s, 2H), 2.39 (s, 3H), 1.60 (s, 9H).

[0678] Compound i-3:

[0679] Ammonia (3 mL) and Raney nickel were added sequentially to a solution of compound i-2 (932 mg, 3.77 mmol) in ethanol (30 mL). The mixture was stirred at room temperature overnight under a hydrogen atmosphere. LCMS monitoring indicated that the reaction was complete. The filtered reaction solution was concentrated to give compound i-3 (837 mg, 88.4% yield). LCMS (ESI) measured: 252.4 [M+H] + .

[0680] Compound i-4:

[0681] Under N2 protection, N,N-carbonyldiimidazole (260 mg, 1.60 mmol) was added to a solution of compound i-3 (500 mg, 1.07 mmol) in dichloromethane (20 mL). After stirring at room temperature for 2.5 hours, thin layer chromatography showed that the reaction was complete. A dichloromethane solution of compound Inter-1 (322 mg, 1.28 mmol) was added to the previous reaction solution and continued to stir at room temperature overnight. After LCMS monitoring showed that the reaction was complete, the reaction solution was diluted with saturated brine. The separated organic layer was dried over sodium sulfate, and the concentrated crude product was purified by normal phase silica gel column (petroleum ether: ethyl acetate = 2 / 3) to obtain compound i-4 (471 mg, yield 59.2%). LCMS (ESI) measured: 746.5 [M+H] + .

[0682] Compound i-5:

[0683] To compound i-4 (100 mg, 0.13 mmol) in methanol (25 mL), 10% palladium on carbon (50 mg, 0.134 mmol) was added, and the reaction was stirred at room temperature overnight under a hydrogen atmosphere. LCMS monitoring showed that the reaction was complete. The filtered reaction solution was concentrated to give compound i-5 (85 mg, 96.7% yield). LCMS (ESI) measured: 656.5 [M+H] + .

[0684] Compound i-6:

[0685] At 0°C, to a solution of compound i-5 (85 mg, 0.12 mmol) in N,N-dimethylformamide (10 mL) were added azide-pentaethylene glycol-p-toluenesulfonyl ester (108 mg, 0.26 mmol) and potassium carbonate (36 mg, 0.26 mmol), and stirred at 80°C overnight. LCMS showed that the reaction was complete. The reaction solution was quenched with saturated sodium bicarbonate solution, extracted with ethyl acetate (40 mL*3), washed with saturated brine, and dried over anhydrous sodium sulfate. The solution was concentrated to obtain crude compound i-6 (200 mg). LCMS (ESI) measured: 901.7 [M+H]+ .

[0686] Compound i-7:

[0687] To a solution of compound i-6 (220 mg, 0.24 mmol) in tetrahydrofuran (5 mL) and water (5 mL) was added lithium hydroxide monohydrate (17 mg, 0.73 mmol). The reaction was stirred at room temperature for 1 hour. LCMS showed that the reaction was complete. The pH of the reaction solution was adjusted to 2 with 1N hydrochloric acid, extracted with ethyl acetate (40 mL*3), washed with saturated brine, and dried over anhydrous sodium sulfate. After concentration, compound i-7 (167 mg, yield 77.1%) was obtained. LCMS (ESI) measured: 887.7 [M+H] + .

[0688] Compound III-i'

[0689] Trifluoroacetic acid (0.8 mL) was added to a solution of compound i-7 (167 mg, 0.19 mmol) in dichloromethane (5 mL). The reaction was stirred at room temperature overnight. After LCMS showed that the reaction was complete, the reaction solution was concentrated and the crude product was purified by reverse phase preparative purification to give compound III-i' (31.6 mg, 21.3% yield) as a yellow oil. LCMS (ESI) measured: 787.6 [M+H] + . 1 H NMR(400MHz,DMSO)δ8.50(d,J=8.3Hz,1H),8.32-8.18(m,1H),7.77(dd,J=13.9,3.7Hz,2H),7.58- 7.48(m,2H),7.45(d,J=8.2Hz,2H),7.39(d,J=8.1Hz,2H),7.32(d,J=7.9Hz,1H),7.05(d,J=8.1Hz, 1H),6.47(s,2H),6.31(d,J=27.3Hz,2H),5.30(q,J=7.4Hz,1H),4.37-4.29(m,2H),3.97-3.88(m, 2H), 3.75-3.63 (m, 11H), 3.63-3.57 (m, 9H), 3.25-3.14 (m, 4H), 2.78 (d, J = 7.1Hz, 2H), 2.20 (s, 3H).

[0690] Example 10 Synthesis of Compound III-j'

[0691] The synthetic route of compound III-j' is as follows:

[0692] The synthesis and identification of the specific intermediates and final products involved in the above route are as follows:

[0693] Compound j-2:

[0694] Under nitrogen at 0°C, sodium hydride (0.78 g, 19.48 mmol) was slowly added to a solution of compound j-1 (1.00 g, 14.98 mmol) in NN-dimethylformamide (30 mL). After stirring for 30 minutes, ethyl 4-bromobutyrate (2.92 g, 14.98 mmol) was added and stirred at room temperature overnight. LCMS indicated the reaction was complete. Water was added dropwise to quench the reaction, followed by extraction with ethyl acetate (40 mL x 3), washing with saturated brine, and drying over anhydrous sodium sulfate. The concentrated crude product was purified on a normal phase silica gel column (petroleum ether:ethyl acetate = 5 / 1) to afford compound j-2 (1.50 g, 81.6% yield) as a colorless oily liquid. LCMS (ESI) measured: 315.1 [M+H] + . 1 H NMR(400MHz, CDCl3) δ7.39(d,J=3.6Hz,1H),6.91(d,J=3.6Hz,1H),4.16(dd,J=12.5,5.4Hz,2H),4 .10(t,J=7.1Hz,2H),2.36(t,J=7.5Hz,2H),2.08-2.00(m,2H),1.58(s,9H),1.24(t,J=7.1Hz,3H).

[0695] Compound j-3:

[0696] To a solution of compound j-2 (100 mg, 0.11 mmol) in tetrahydrofuran (5 ml) at room temperature was added 1N lithium hydroxide monohydrate (5 ml, 5.00 mmol) and stirred at room temperature for 2 hours. After completion of the reaction (LCMS), the pH of the reaction system was adjusted to 2 with 1N HCl. The mixture was extracted with ethyl acetate (40 mL x 3), washed with saturated brine, and dried over anhydrous sodium sulfate. The filtrate was concentrated to afford compound j-3 (87 mg, 95.5% yield) as a yellow solid. LCMS (ESI) measured: 287.1 [M+H] + .

[0697] Compound j-4:

[0698] At room temperature, N,N-diisopropylethylamine (0.32 mL, 1.92 mmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (175.28 mg, 0.46 mmol), and compound Inter-1 (180 mg, 0.38 mmol) were added to a solution of compound j-3 (110 mg, 0.38 mmol) in N-dimethylformamide (5 mL). The reaction mixture was stirred for 2 hours, and LCMS showed the reaction was complete. Water was added dropwise to the reaction mixture, and the mixture was extracted with ethyl acetate (40 mL*3), washed with saturated brine, and dried over anhydrous sodium sulfate. The concentrated crude product was purified on a normal phase silica gel column (petroleum ether:ethyl acetate = 5 / 1) to obtain compound j-4 (275 mg, 97.1% yield) as a yellow solid. LCMS (ESI) measured: 737.1 [M+H] + .

[0699] Compound j-5:

[0700] 10% palladium on carbon (250 mg) was added to a solution of compound j-4 (250 mg, 0.34 mmol) in methanol (30 mL). The system was purged with hydrogen three times and stirred at room temperature overnight. LCMS showed the reaction was complete. The reaction mixture was filtered through celite and concentrated to give compound j-5 (200 mg, 63.8% yield) as a yellow-white solid. LCMS (ESI) measured: 647.1 [M+H] + .

[0701] Compound j-6:

[0702] To a solution of compound j-5 (150 mg, 0.23 mmol) in NN-dimethylformamide (5 mL) were added azide-pentaethylene glycol-p-toluenesulfonyl ester (193.65 mg, 0.46 mmol) and potassium carbonate (64.11 mg, 0.46 mmol). The reaction was stirred at 80°C overnight. After LCMS showed the reaction was complete, saturated sodium bicarbonate solution was added to quench the reaction. The mixture was extracted with ethyl acetate (40 mL*3), washed with saturated brine, and dried over anhydrous sodium sulfate. The concentrated crude product was purified on a normal phase silica gel column (petroleum ether:ethyl acetate = 1 / 1) to obtain compound j-6 (120 mg, 58.0% yield) as a yellow solid. LCMS (ESI) measured: 892.2 [M+H] + .

[0703] Compound j-7:

[0704] To a solution of compound j-6 (70 mg, 0.08 mmol) in tetrahydrofuran (5 ml) was added 1N lithium hydroxide monohydrate (5 ml, 5.00 mmol) at room temperature. After stirring at room temperature for 2 hours, LCMS indicated the reaction was complete. The pH of the reaction solution was adjusted to 2 with 1N HCl, extracted with ethyl acetate (40 mL*3), washed with saturated brine, and dried over anhydrous sodium sulfate. The filtrate was concentrated to obtain compound j-7 (65 mg, 94.3% yield) as a yellow solid. LCMS (ESI) measured: 878.1 [M+H] + .

[0705] Compound III-j':

[0706] To a solution of compound j-7 (100 mg, 0.11 mmol) in dichloromethane (2 mL) was added a 4 M 1,4-dioxane hydrochloride solution (1 mL). The reaction mixture was stirred at room temperature for 3 hours. LCMS indicated the reaction was complete. The reaction mixture was concentrated to obtain the crude product, which was purified by preparative HPLC to afford compound III-j' (53.6 mg, 60.4% yield) as a yellow solid. LCMS (ESI) measured: 778.5. 1 H NMR (400MHz, DMSO) δ8.97(s,1H),8.50(t,J=8.8Hz,1H),8.28(dd,J=8.1,6.2Hz,1H),8.15(t,J=5.8Hz ,1H),7.81-7.64(m,1H),7.59-7.14(m,8H),7.06(d,J=8.0Hz,1H),6.81(d,J=4.0Hz,1H),5.30(q,J=7 .4Hz,1H),4.37-4.27(m,2H),3.96-3.89(m,2H),3.76(d,J=5.7Hz,3H),3.69(dd,J=5.7,3.7Hz,3H),3 .60-3.55(m,7H),3.39-3.30(m,8H),2.79(d,J=7.3Hz,2H),2.24(t,J=7.3Hz,2H),1.87-1.75(m,2H).

[0707] Example 11 Synthesis of Compound III-k'

[0708] The synthetic route of compound III-k' is as follows:

[0709] The synthesis and identification of the specific intermediates and final products involved in the above route are as follows:

[0710] Compound k-2

[0711] To a solution of compound k-1 (1.50 g, 12.30 mmol) in methanol (50.0 mL), methyl 4-acetobutyrate (2.0 g, 13.89 mmol), L-proline (2.10 g, 18.01 mmol), and concentrated sulfuric acid (0.1 mL) were added sequentially. The reaction solution was heated under reflux overnight, and LCMS analysis showed that the reaction was complete. The reaction solution was concentrated to half of its original volume, quenched with water, and extracted with ethyl acetate (50 mL*3). The combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. The concentrated crude product was purified on a normal phase silica gel column to obtain compound k-2 (2.00 g, yield 71%). LCMS (ESI) measured: 231.4 [M+H] + .

[0712] Compound k-3

[0713] To a solution of compound k-2 (2.00 g, 8.68 mmol) in methanol (30.0 mL) was added palladium on carbon (0.20 g) under a hydrogen atmosphere. The reaction was heated to 50°C and stirred overnight. LCMS analysis indicated the reaction was complete. The reaction solution was filtered through celite and concentrated to afford compound k-3 (2.00 g, 98% yield). LCMS (ESI) measured: 235.5 [M+H] + .

[0714] Compound k-4

[0715] To a solution of compound k-3 (2.00 g, 8.48 mmol) in 1,4-dioxane (30.0 mL) was added di-tert-butyl dicarbonate (5.60 g, 25.61 mmol). The reaction was heated to reflux and stirred overnight. LCMS analysis showed that the reaction was complete. The reaction solution was concentrated to half of its original volume, quenched with water, and extracted with ethyl acetate (50 mL*3). The combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. The concentrated crude product was purified on a normal phase silica gel column to obtain compound k-4 (2.00 g, 70% yield). LCMS (ESI) measured: 335.5 [M+H] + .

[0716] Compound k-5

[0717] To a mixed solution of compound k-4 (2.00 g, 6.01 mmol) in tetrahydrofuran (8.0 mL) and water (2.0 mL) was added lithium hydroxide monohydrate (0.75 g, 18.02 mmol) and stirred overnight. After completion of the reaction, the reaction solution was adjusted to pH 5 with 1N HCl and extracted with ethyl acetate (50 mL*3). The combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. After concentration, compound k-5 (1.80 g, 94% yield) was obtained. LCMS (ESI) measured: 321.5 [M+H] + .

[0718] Compound k-6

[0719] To a solution of compound k-5 (0.50 g, 1.58 mmol) in N,N-dimethylformamide (10.0 mL) were added glycine methyl ester hydrochloride (0.29 g, 2.28 mmol), O-benzotriazole-N,N,N',N'-tetramethyluronium tetrafluoroborate (0.75 g, 2.31 mmol), and N,N-diisopropylethylamine (1.00 mL, 6.21 mmol). The reaction was stirred at room temperature for 1 hour. LCMS analysis indicated the reaction was complete. The reaction solution was concentrated to half its original volume, quenched with water, and extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. The concentrated crude product was purified on a normal phase silica gel column to yield compound k-6 (0.25 mg, 41% yield). LCMS (ESI) measured: 392.5 [M+H] + .

[0720] Compound k-7

[0721] To a mixed solution of compound k-6 (0.25 g, 0.61 mmol) in tetrahydrofuran (4.0 mL) and water (1.0 mL) was added lithium hydroxide monohydrate (0.08 g, 1.91 mmol). The reaction was stirred at room temperature overnight. LCMS detection showed that the reaction was complete. The reaction solution was adjusted to pH 5 with 1N HCl and extracted with ethyl acetate (50 mL*3). The combined organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. After concentration, compound k-7 (0.20 g, yield 83%) was obtained. LCMS (ESI) measured: 378.5 [M+H] + .

[0722] Compound K-8

[0723] Compound Inter-1 (0.16 g, 0.41 mmol), N,N-diisopropylethylamine (0.13 mL, 0.81 mmol) and O-benzotriazole-N,N,N',N'-tetramethyluronium tetrafluoroboric acid (0.15 g, 0.50 mmol) were added to a solution of compound k-7 (0.10 g, 0.27 mmol) in anhydrous N,N-dimethylformamide (2.0 mL) in sequence. The reaction solution was stirred at room temperature for 2 hours. LCMS detection showed that the reaction was complete. The reaction solution was quenched with saturated sodium bicarbonate solution and extracted with ethyl acetate (30 mL*3). The combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. The concentrated crude product was purified on a normal phase silica gel column to obtain compound k-8 (0.08 g, yield 39%). LCMS (ESI) measured: 771.6 [M+H] + .

[0724] Compound K-9

[0725] To a mixed solution of compound k-8 (0.08 g, 0.11 mmol) in tetrahydrofuran (1.5 mL) and ethyl acetate (1.5 mL) was added palladium carbon (0.05 g) under a hydrogen atmosphere. The reaction was stirred at room temperature overnight. LCMS analysis showed that the reaction was complete. The reaction solution was filtered through celite and concentrated to give compound k-9 (0.05 g, 71% yield). LCMS (ESI) measured: 681.6 [M+H] + .

[0726] Compound k-10

[0727] Azide-pentaethylene glycol-p-toluenesulfonyl ester (0.06 g, 0.11 mmol) and potassium carbonate (0.02 g, 0.11 mmol) were added to a solution of compound k-9 (0.05 g, 0.10 mmol) in anhydrous N,N-dimethylformamide (3.0 mL). The reaction mixture was heated to 80 degrees and stirred for 3 hours. LCMS analysis showed that the reaction was complete. The reaction mixture was quenched with water and extracted with ethyl acetate (20 mL*3). The combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. The concentrated crude product was purified on a normal phase silica gel column to obtain compound k-10 (0.05 g, yield 73%). LCMS (ESI) measured: 926.7 [M+H] + .

[0728] Compound III-k'

[0729] To a mixed solution of compound k-10 (0.05 g, 0.11 mmol) in tetrahydrofuran (1.6 mL) and water (0.4 mL), lithium hydroxide monohydrate (0.01 g, 0.24 mmol) was added. The reaction was stirred at room temperature for 1 hour, and LCMS detection showed that the reaction was complete. The reaction solution was adjusted to pH 3 with 1N HCl and extracted with ethyl acetate (10 mL*3). The combined organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The concentrated crude product was re-dissolved in dichloromethane (2.0 mL) and trifluoroacetic acid (1 mL) was added. The reaction solution was stirred at room temperature for 6 hours, and LCMS detection showed that the reaction was complete. The crude product obtained by concentration of the reaction solution was purified by preparative high-performance liquid chromatography to obtain compound III-k' (0.02 g, yield 65%). LCMS (ESI) measured: 812.6 [M+H] + . 1 H NMR (400MHz, chloroform-d) δ9.12-.78 (m, 1H), 8.33 (d, J = 8.3Hz, 1H), 8.26 -8.09(m,1H),7.80(d,J=8.3Hz,2H),7.54-7.32(m,6H),7.23-7.12(m,2H),6.82(d,J =7.9Hz,1H),6.33(d,J=7.1Hz,1H),5.59-5.47(m,1H),4.32(t,J=4.8Hz,2H),4.02(t, J=4.9Hz,2H),3.84–3.80(m,2H),3.74-3.70(m,2H),3.68-3.60(m,10H),3.35(t,J=5. 1Hz,2H),3.06-2.84(m,2H),2.75-2.59(m,4H),2.11-1.94(m,2H),1.90-1.81(m,2H).

[0730] Example 12 Synthesis of Compound III-1'

[0731] The synthetic route of compound III-1' is as follows:

[0732] The synthesis and identification of the specific intermediates and final products involved in the above route are as follows:

[0733] Compound 1-2

[0734] Compound l-1 (1.00 g, 4.81 mmol) was dissolved in a 4.0 M solution of 1,4-dioxane in hydrochloric acid (5.0 mL). The reaction was stirred at room temperature for 2 hours. LCMS monitoring indicated the reaction was complete. The reaction solution was concentrated to give compound l-2 (0.70 g, 90% yield). LCMS (ESI) measured: 163.2 [M+H]+ .

[0735] Compound 1-3

[0736] To compound l-2 (0.70 g, 4.31 mmol) in anhydrous tetrahydrofuran (10.0 mL), methoxymethyltriphenylphosphonium bromide (2.20 g, 5.19 mmol) and potassium tert-butoxide (0.70 g, 6.42 mmol) were added. The reaction was heated to 50 degrees and stirred overnight. LCMS monitoring showed that the reaction was complete. The reaction solution was quenched with water and extracted with ethyl acetate (30 mL*3). The combined organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The concentrated crude product was purified on a normal phase silica gel column to obtain compound l-3 (0.80 g, yield 85%). LCMS (ESI) measured: 219.4 [M+H] + .

[0737] Compound 1-4

[0738] To a solution of compound 1-3 (0.80 g, 3.69 mmol) in tetrahydrofuran (10.0 mL) was added palladium on carbon (0.11 g) under a hydrogen atmosphere. The reaction was heated to 50°C and stirred overnight. LCMS analysis indicated the reaction was complete. The reaction solution was filtered through celite and concentrated to afford compound 1-4 (0.80 g, 99% yield). LCMS (ESI) measured: 221.4 [M+H] + .

[0739] Compound 1-5

[0740] To a solution of compound l-4 (0.80 g, 3.59 mmol) in 1,4-dioxane (10.0 mL) was added di-tert-butyl dicarbonate (1.60 g, 7.32 mmol). The reaction solution was refluxed and stirred overnight. LCMS detection showed that the reaction was complete. The reaction solution was concentrated to half of its original volume, quenched with water, and extracted with ethyl acetate (50 mL*3). The combined organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The concentrated crude product was purified on a normal phase silica gel column to obtain compound l-5 (0.60 g, yield 52%). LCMS (ESI) measured: 321.5 [M+H] + .

[0741] Compound 1-6

[0742] To a mixed solution of compound l-5 (0.50 g, 1.58 mmol) in tetrahydrofuran (4.0 mL) and water (1.0 mL) was added lithium hydroxide monohydrate (0.19 g, 4.61 mmol). The reaction was stirred at room temperature overnight. LCMS detection showed that the reaction was complete. The reaction solution was adjusted to pH 5 with 1N HCl and extracted with ethyl acetate (50 mL*3). The combined organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. After concentration, compound l-6 (0.40 g, yield 83%) was obtained. LCMS (ESI) measured: 307.5 [M+H] + .

[0743] Compound 1-7

[0744] To a solution of compound l-6 (0.20 g, 0.61 mmol) in anhydrous N,N-dimethylformamide (3.0 mL) were added glycine methyl ester hydrochloride (0.12 g, 1.31 mmol), O-benzotriazole-N,N,N',N'-tetramethyluronium tetrafluoroboric acid (0.42 g, 1.31 mmol) and N,N-diisopropylethylamine (0.3 mL, 1.91 mmol). The reaction was stirred at room temperature for 1 hour. LCMS monitoring showed that the reaction was complete. The reaction solution was quenched with water and extracted with ethyl acetate (30 mL*3). The combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. The concentrated crude product was purified on a normal phase silica gel column to obtain compound l-7 (0.15 g, 61% yield). LCMS (ESI) measured: 378.5 [M+H] + .

[0745] Compound 1-8

[0746] To a mixed solution of compound l-7 (0.15 g, 0.4 mmol) in tetrahydrofuran (1.6 mL) and water (0.4 mL) was added lithium hydroxide (0.05 g, 1.2 mmol). The reaction was stirred at room temperature for 1 hour. LCMS analysis showed that the reaction was complete. The reaction solution was adjusted to pH 5 with 1N HCl and extracted with ethyl acetate (50 mL*3). The combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. After concentration, compound l-8 (0.10 g, yield 69%) was obtained. LCMS (ESI) measured: 364.5 [M+H] + .

[0747] Compound 1-9

[0748] Compound l-8 (0.10 g, 0.30 mmol) in anhydrous N, N-dimethylformamide (2.0 mL) was added to compound inter-1 (0.14 g, 0.33 mmol), N, N-diisopropylethylamine (0.13 mL, 0.82 mmol) and O-benzotriazole-N, N, N', N'-tetramethyluronium tetrafluoroboric acid (0.13 g, 0.41 mmol) in sequence at zero degrees. The reaction was stirred at room temperature for 2 hours. LCMS detection showed that the reaction was complete. The reaction solution was quenched with saturated sodium bicarbonate aqueous solution and extracted with ethyl acetate (30 mL*3). The combined organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The concentrated crude product was purified on a normal phase silica gel column to obtain compound l-9 (0.80 g, yield 38%). LCMS (ESI) measured: 757.6 [M+H] + .

[0749] Compound 1-10

[0750] To a solution of compound l-10 (0.08 g, 0.11 mmol) in tetrahydrofuran (1.5 mL) and ethyl acetate (1.5 mL) was added palladium on carbon (0.03 g) under a hydrogen atmosphere. The reaction was heated to 50°C and stirred overnight. LCMS analysis indicated the reaction was complete. The reaction solution was filtered through celite and concentrated to afford compound l-10 (0.05 g, 71% yield). LCMS (ESI) measured: 667.6 [M+H] + .

[0751] Compound 1-11

[0752] To a solution of compound l-10 (0.05 g, 0.10 mmol) in anhydrous N,N-dimethylformamide (3.0 mL) were added azide-pentaethylene glycol-p-toluenesulfonyl ester (0.05 g, 0.12 mmol) and potassium carbonate (0.02 g, 0.24 mmol). The reaction was heated to 80 degrees and stirred for 3 hours. LCMS analysis showed that the reaction was complete. The reaction solution was quenched with water and extracted with ethyl acetate (20 mL*3). The combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. The concentrated crude product was purified on a normal phase silica gel column to obtain compound l-11 (0.05 g, 73% yield). LCMS (ESI) measured: 926.8 [M+H] + .

[0753] Compound III-1'

[0754] To a mixed solution of compound l-11 (50 mg, 0.05 mmol) in tetrahydrofuran (1.6 mL) and water (0.4 mL), lithium hydroxide (0.01 g, 0.25 mmol) was added. The reaction was stirred at room temperature for 1 hour, and LCMS monitoring showed that the reaction was complete. The reaction solution was adjusted to pH 3 with 1N HCl and extracted with ethyl acetate (10 mL*3). The combined organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The concentrated crude product was re-dissolved in dichloromethane (2.0 mL) and trifluoroacetic acid (1.0 mL) was added. The reaction was stirred at room temperature for 6 hours, and LCMS detection showed that the reaction was complete. The crude product obtained by concentration of the reaction solution was purified by preparative high-performance liquid chromatography to obtain compound III-l' (20 mg, yield 45.7%). LCMS (ESI) measured: 798.7 [M+H] + . 1 H NMR (400MHz, chloroform-d) δ9.19-8.93(m,1H),8.33(d,J=8.3Hz,1H),8.26-8.19(m,1H),8.18-8.09(m,1H),7.7 9(d,J=8.4Hz,1H),7.52-7.32(m,6H),7.19(t,J=6.6Hz,2H),6.80(d,J=7.9Hz,1H),6.36(d,J=7.2Hz,1H ),5.61-5.39(m,1H),4.31(t,J=4.9Hz,2H),4.01(t,J=4.8Hz,2H),3.81(t,J=4.7Hz,2H),3.71(t,J=4.8 Hz,2H),3.69-3.59(m,10H),3.38-3.33(m,2H),3.01-2.92(m,2H),2.70-2.57(m,4H),1.87-1.77(m,2H).

[0755] Example 13 Synthesis of Compound III-m'

[0756] The synthetic route of compound III-m' is as follows:

[0757] The synthesis and identification of the specific intermediates and final products involved in the above route are as follows:

[0758] Compound Inter-0

[0759] To a solution of commercially available N-tert-butyloxycarbonylglycine (28.00 g, 159.8 mmol) in N-dimethylformamide (200 mL) were added N,N-diisopropylethylamine (132 mL, 799.2 mmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (66.85 g, 175.8 mmol), and compound SM1 (78.93 g, 191.8 mmol, prepared according to the method described in patent application WO2019089765A1). The mixture was purged with nitrogen three times. The reaction was stirred at room temperature under a nitrogen atmosphere for 3 hours. LCMS monitoring indicated the reaction was complete. The reaction solution was quenched with water and extracted with ethyl acetate. The combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. The concentrated crude product was purified on a normal phase silica gel column to afford compound Inter-0 (60.0 g, 66% yield). LCMS:MS(ESI)m / z=513.6[M+H-56] + .

[0760] Compound m-1

[0761] To a solution of compound Inter-0 (2.30 g, 4.05 mmol) in methanol (30.0 mL) was added 10% palladium on carbon (0.23 g) under a hydrogen atmosphere. The reaction was stirred at room temperature for 8 hours. LCMS monitoring indicated the reaction was complete. The reaction mixture was filtered and concentrated to afford compound m-1 (1.80 g, 93% yield). 1 H NMR (400MHz, DMSO) δ10.27(s,1H),8.39(d,J=8.4Hz,1H),8.30-8.09(m,1H),7.75(dd,J=6.4,3.2Hz,1H),7.54-7.40(m,4H),7.37(d,J=8.4Hz,2H), 7.23(d,J=7.6Hz,1H),6.95(dd,J=14.0,6.8Hz,2H),5.32(q,J=7.6Hz,1H ), 3.60 (s, 3H), 3.57 (d, J = 6.0Hz, 2H), 2.88 (t, J = 6.0Hz, 2H), 1.39 (s, 9H).

[0762] Compound m-2

[0763] To a solution of compound m-1 (1.00 g, 2.09 mmol) in N,N-dimethylformamide (10.0 mL) were added azide-pentaethylene glycol-p-toluenesulfonyl ester (1.74 g, 4.18 mmol) and potassium carbonate (0.58 g, 4.18 mmol). The reaction was heated to 80°C and stirred overnight. LCMS monitoring indicated the reaction was complete. The reaction solution was quenched with saturated sodium bicarbonate solution and extracted with ethyl acetate (40 mL x 3). The combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. The concentrated crude product was purified on a normal phase silica gel column to yield compound m-2 (1.30 g, 85% yield). LCMS: MS (ESI) m / z = 724.5 [M+H] + .

[0764] Compound m-3

[0765] To a solution of compound m-2 (1.30 g, 1.79 mmol) in dichloromethane (20.0 mL) was added a 1,4-dioxane hydrochloride solution (20.0 mL). The reaction was stirred at room temperature overnight. LCMS monitoring indicated the reaction was complete. The reaction solution was concentrated to afford compound m-3 (1.10 g, 98% yield). LCMS: MS (ESI) m / z = 624.4 [M+H] + .

[0766] Compound m-5

[0767] To a solution of compound m-4 (0.50 g, 3.50 mmol) in trifluoroacetic acid (20.0 mL), platinum dioxide (50.00 mg) was added under a hydrogen atmosphere. The reaction mixture was stirred overnight at room temperature. LCMS monitoring showed that the reaction was complete. The reaction solution was filtered through diatomaceous earth and washed with ethyl acetate. The solid mixture was concentrated to obtain a solid mixture, which was then dissolved in ethyl acetate, washed with saturated sodium bicarbonate and saturated brine, and dried over anhydrous sodium sulfate. The crude product obtained after concentration was redissolved in a mixed solvent of methanol (20.0 mL) and water (20.0 mL), and potassium carbonate was added. The reaction was stirred at 40°C for 3 hours. LCMS monitoring showed that the reaction was complete. The reaction solution was diluted with water, extracted with ethyl acetate (50 mL*3), and the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain compound m-5 (0.50 g, yield 97%). LCMS (ESI) measured: 149.4 [M+H] + . 1 H NMR (400MHz, DMSO) δ7.67 (s, 1H), 6.19 (s, 1H), 5.49 (s, 2H), 2.65-2.56 (m, 4H), 1.72 (dt, J = 6.4, 3.2Hz, 4H).

[0768] Compound m-6

[0769] To a solution of compound m-5 (0.50 g, 3.40 mmol) in tert-butyl alcohol (20.0 mL) was added di-tert-butyl dicarbonate (1.10 g, 5.01 mmol). Stirring was continued overnight at room temperature. LCMS monitoring indicated the reaction was complete. The reaction solution was concentrated to obtain a crude product which was purified on a normal phase silica gel column to afford compound m-6 (0.33 g, 39% yield). LCMS (ESI) measured: 249.4 [M+H] + . 1 H NMR (400MHz, CDCl3) δ8.44(m,1H),7.94(s,1H),7.60(s,1H),2.69(d,J=5.6Hz,2H),2.59(d,J=5.6Hz,2H),1.75-1.68(m,4H),1.47(s,9H).

[0770] Compound m-7

[0771] To compound m-6 (0.33 g, 1.31 mmol) in NN-dimethylformamide (10.0 mL), sodium hydride (0.06 g, 1.61 mmol) was slowly added under nitrogen at 0°C. After stirring at the same temperature for 30 minutes, ethyl 4-bromobutyrate (0.31 g, 1.61 mmol) was added. Stirring was continued overnight at the reaction temperature. LCMS monitoring indicated that the reaction was complete. The reaction solution was quenched with water and extracted with ethyl acetate (50 mL*3). The combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. The crude product obtained after concentration was purified on a normal phase silica gel column to obtain compound m-7 (0.35 g, 72% yield). LCMS (ESI) measured: 363.5 [M+H] + .

[0772] Compound m-8

[0773] To a solution of compound m-7 (0.35 g, 0.91 mmol) in tetrahydrofuran (10.0 mL) was added 1N aqueous lithium hydroxide solution (3.0 mL). The reaction was stirred at room temperature for 1 hour. LCMS analysis indicated the reaction was complete. The reaction solution was adjusted to pH 2 with 1N hydrochloric acid and extracted with ethyl acetate (40 mL x 3). The combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. After concentration, compound m-8 (0.30 g, 92% yield) was obtained. LCMS (ESI) measured: 335.4 [M+H] + .

[0774] Compound m-9

[0775] Compound m-8 (0.15 g, 0.41 mmol) in NN-dimethylformamide (5.0 mL) was then added to compound m-3 (0.28 g, 0.51 mmol), N,N-diisopropylethylamine (0.29 g, 2.21 mmol), and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (0.20 g, 0.51 mmol). The reaction was stirred at room temperature for 2 hours. LCMS analysis indicated the reaction was complete. The reaction solution was quenched with water and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product which was purified on a normal phase silica gel column to yield compound m-9 (0.40 g, 94% yield). LCMS (ESI) measured: 940.6 [M+H] + .

[0776] Compound m-10

[0777] To a solution of compound m-9 (0.40 g, 0.38 mmol) in tetrahydrofuran (5.0 mL) was added 1N aqueous lithium hydroxide solution (3.0 mL). The reaction was stirred at room temperature for 2 hours. LCMS analysis indicated the reaction was complete. The reaction solution was adjusted to pH 2 with 1N hydrochloric acid and extracted with ethyl acetate (40 mL x 3). The combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. After concentration, compound m-10 (0.39 g, 98% yield) was obtained. LCMS (ESI) measured: 926.6 [M+H] + .

[0778] Compound III-m'

[0779] Trifluoroacetic acid (3.0 mL) was added to a solution of compound m-10 (0.39 g, 0.41 mmol) in dichloromethane (5.0 mL). The reaction was stirred at room temperature for 3 hours. LCMS analysis indicated the reaction was complete. The reaction solution was concentrated to obtain a crude product, which was purified by preparative HPLC to yield compound III-m' (0.20 g, 58% yield). LCMS (ESI) measured: 826.7 [M+H] + . 1H NMR (400MHz, DMSO) δ13.22(s,1H),8.55(d,J=8.4Hz,1H),8.35(s,1H),8.30-8.25(m,1H),8.20(t,J=5.6Hz,1H),7.76(dd,J=7.6,1.7Hz,1 H),7.66(s,1H),7.56-7.48(m,2H),7.46(d,J=8.4Hz,2H),7.39(d,J=8.4Hz,2H),7.32(d,J=8.0Hz,1H),7.05(d,J=8.0Hz,1H),6.77(s,1H) ,5.31(q,J=7.2Hz,1H),4.34-4.31(m,2H),3.95-3.91(m,2H),3.77(d,J=5.6Hz,2H),3.69(dd,J=6.0,3.6Hz,2H),3.61-3.51(m,12H),3.3 9-3.35(m,2H),3.28(dd,J=12.0,6.4Hz,2H),2.80(d,J=7.2Hz,2H),2.73(s,2H),2.58(s,2H),2.26(t,J=7.2Hz,2H),1.81(dd,J=14.0,7.2 Hz, 2H), 1.66 (t, J = 3.2Hz, 4H).

[0780] Example 14 Synthesis of Compound III-n'

[0781] The synthetic route of compound III-n' is as follows:

[0782] The synthesis and identification of the specific intermediates and final products involved in the above route are as follows:

[0783] Compound n-2

[0784] To a solution of compound n-1 (4.48 mL, 34.68 mmol) in tert-butyl alcohol (40.0 mL) was added di-tert-butyl dicarbonate (7.57 g, 34.68 mmol). The reaction was stirred at room temperature overnight. LCMS monitoring indicated the reaction was complete. The reaction solution was concentrated and the resulting crude product was purified by slurry to afford compound n-2 (7.59 g, 89% yield). LCMS: MS (ESI) m / z = 245.2 [M+H] + . 1H NMR(400MHz,DMSO)δ9.74(s,1H),8.27(d,J=5.6Hz,1H),8.06(d,J=8.4Hz,1H),7 .95(d,J=8.0Hz,1H),7.76(t,J=7.2Hz,1H),7.65(t,J=7.2Hz,2H),1.47(s,9H).

[0785] Compound n-3

[0786] To a solution of compound n-2 (0.50 g, 2.05 mmol) in N,N-dimethylformamide (5.0 mL) at zero degrees Celsius, sodium hydride (0.10 g, 2.45 mmol) was added. After stirring at room temperature for 30 minutes, ethyl 4-bromobutyrate (0.44 mL, 3.07 mmol) was added. The reaction was stirred at room temperature overnight. LCMS monitoring showed that the reaction was complete. The reaction solution was quenched with water and extracted with ethyl acetate (50 mL*3). The combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. The concentrated crude product was purified on a normal phase silica gel column to obtain compound n-3 (0.59 g, 81% yield). LCMS: MS (ESI) m / z = 359.4 [M+H] + .

[0787] Compound n-4

[0788] To a mixed solution of compound n-3 (0.59 g, 1.64 mmol) in tetrahydrofuran (5.0 mL) and water (2.0 mL) was added lithium hydroxide monohydrate (0.12 g, 4.94 mmol). The reaction was stirred at room temperature for 1 hour. LCMS monitoring showed that the reaction was complete. The reaction solution was adjusted to pH 2 with 1N HCl and extracted with ethyl acetate (40 mL*3). The combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. Concentration gave compound n-4 (0.53 g, yield 97%). LCMS: MS (ESI) m / z = 331.1 [M+H] + .

[0789] Compound n-5

[0790] To a solution of compound n-4 (0.27 g, 0.82 mmol) in dichloromethane (10.0 mL) were added N,N-diisopropylethylamine (0.85 mL, 4.90 mmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (0.37 g, 0.98 mmol), and compound Inter-1 (0.46 g, 0.98 mmol). The reaction was stirred at room temperature for 2 hours. LCMS monitoring indicated the reaction was complete. The reaction solution was quenched with water and extracted with ethyl acetate (40 mL*3). The combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. The concentrated crude product was purified on a normal phase silica gel column to obtain compound n-5 (0.46 g, 72% yield). LCMS: MS (ESI) m / z = 781.5 [M+H] + .

[0791] Compound n-6

[0792] To a solution of compound n-5 (0.15 g, 0.192 mmol) in methanol (30.0 mL) was added palladium on carbon (0.12 g) under a hydrogen atmosphere. The reaction mixture was stirred at room temperature for 8 hours. LCMS monitoring indicated the reaction was complete. The reaction mixture was filtered and concentrated to give a mixture of compound n-6 ​​and compound o-1 (0.07 g, 56% yield). Compound n-6: LCMS: MS (ESI) m / z = 691.1 [M+H] + Compound o-1: LCMS: MS (ESI) m / z = 695.5 [M+H] + .

[0793] Compound n-7

[0794] A mixture of compound n-6 ​​and compound o-1 (0.07 g, 0.10 mmol) in N,N-dimethylformamide (2 mL) was added with azide-pentaethylene glycol-p-toluenesulfonyl ester (0.08 g, 0.20 mmol) and potassium carbonate (0.03 g, 0.20 mmol). The reaction was heated to 80°C and stirred for 6 hours. LCMS monitoring showed that the reaction was complete. The reaction solution was quenched by adding saturated sodium bicarbonate solution and extracted with ethyl acetate (40 mL*3). The combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. The crude product obtained by concentration was purified by preparative high-performance liquid chromatography to obtain compound n-7 (14.0 mg, yield 15%). Compound n-7: LCMS: MS (ESI) m / z = 936.6 [M+H] + .

[0795] Compound n-8

[0796] To a mixed solution of compound n-7 (20.00 mg, 0.02 mmol) in tetrahydrofuran (1.0 mL) and water (1.0 mL) was added lithium hydroxide monohydrate (2.00 mg, 0.06 mmol). The reaction was stirred at room temperature for 2 hours. LCMS monitoring showed that the reaction was complete. The reaction solution was adjusted to pH 2 with 1N HCl, extracted with ethyl acetate (20 mL*3), and the combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. The filtrate was concentrated to give compound n-8 (19.0 mg, yield 96%). LCMS: MS (ESI) m / z = 922.6 [M+H] + .

[0797] Compound III-n'

[0798] Trifluoroacetic acid (1 mL) was added to a solution of compound n-8 (19.00 mg, 0.02 mmol) in dichloromethane (1.0 mL). The reaction was stirred at room temperature for 6 hours. LCMS analysis indicated the reaction was complete. The crude product obtained by concentration of the reaction solution was purified by preparative HPLC to yield compound III-n' (17.60 mg, 73% yield). LCMS: MS (ESI) m / z = 822.8 [M+H] + . 1 H NMR (400MHz, DMSO) δ8.54(d,J=8.3Hz,1H),8.46(d,J=8.4Hz,1H),8.31-8.21(m,2H),7.86(d,J=6.4Hz,2H),7.78-7.73(m,1 H),7.69(t,J=7.6Hz,2H),7.57-7.48(m,2H),7.47(dd,J=8.4,4.8Hz,2H),7.39(d,J=8.4Hz,2H),7.31(d,J=8.0Hz,1H),7.13 (d,J=6.4Hz,1H),7.04(d,J=8.0Hz,1H),5.31(q,J=7.6Hz,1H),4.36-4.25(m,2H),4.00-3.87(m,2H),3.78(d,J=5.6Hz,2H), 3.69(dd,J=5.6,3.7Hz,2H), 3.62-3.47(m,18H), 2.79(d,J=7.2Hz,2H), 2.35(t,J=7.2Hz,2H), 1.96(dd,J=14.0,6.8Hz,2H).

[0799] Example 15 Synthesis of Compound III-o'

[0800] The synthetic route of compound III-o' is as follows:

[0801] The synthesis and identification of the specific intermediates and final products involved in the above route are as follows:

[0802] Compound o-3

[0803] To a mixed solution of compound o-2 (24.00 mg, 0.03 mmol) in tetrahydrofuran (1.0 mL) and water (0.2 mL) was added lithium hydroxide monohydrate (2.00 mg, 0.08 mmol). The reaction was stirred at room temperature for 2 hours. LCMS monitoring showed that the reaction was complete. The reaction solution was adjusted to pH 2 with 1N HCl and extracted with ethyl acetate (20 mL*3). The combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. The filtrate was concentrated to give compound o-3 (21.00 mg, yield 89%). LCMS: MS (ESI) m / z = 926.7 [M+H] + .

[0804] Compound III-o'

[0805] Trifluoroacetic acid (1.0 mL) was added to a solution of compound o-3 (21.00 mg, 0.02 mmol) in dichloromethane (1.0 mL). The reaction was stirred at room temperature for 6 hours. LCMS analysis indicated the reaction was complete. The crude product obtained by concentration of the reaction solution was purified by preparative HPLC to yield compound III-o' (14.00 mg, 53% yield). LCMS: MS (ESI) m / z = 826.8 [M+H] + . 1H NMR (400MHz, DMSO) δ8.54(d,J=8.4Hz,1H),8.26(dt,J=11.6,3.6Hz,2H),7.81-7.71(m,1H),7.65(d,J=6.4Hz,1H),7.57-7.48(m,2H),7.45(d,J= 8.4Hz,2H),7.39(d,J=8.4Hz,2H),7.32(d,J=8.0Hz,1H),7.05(d,J=8.0Hz,1H),6.58(d,J=6.4Hz,1H),5.30(q,J=7.2Hz,1H),4.37-4.28(m,2H), 3.98-3.89(m,2H),3.77(d,J=5.6Hz,2H),3.69(dd,J=5.6,3.6Hz,2H),3.61-3.49(m,18H),2.79(d,J=7.2Hz,2H),2.65(t,J =5.6Hz, 2H), 2.32 (dt, J = 14.0, 6.4Hz, 4H), 1.83 (p, J = 7.2Hz, 2H), 1.75 (dd, J = 11.6, 5.6Hz, 2H), 1.66 (dd, J = 7.2, 3.6Hz, 2H).

[0806] Example 16 Synthesis of Compound III-p'

[0807] The synthetic route of compound III-p' is as follows:

[0808] The synthesis and identification of the specific intermediates and final products involved in the above route are as follows:

[0809] Compound p-2

[0810] To a solution of compound p-1 (2.90 g, 20.11 mmol) in tert-butyl alcohol (50.0 mL) was added di-tert-butyl dicarbonate (6.58 g, 30.17 mmol). The reaction was stirred at room temperature overnight. LCMS analysis indicated the reaction was complete. The crude product obtained by concentration of the reaction solution was purified on a normal phase silica gel column to obtain compound p-2 (3.90 g, 79% yield). LCMS: MS (ESI) m / z = 245.4 [M+H] + .

[0811] Compound p-3

[0812] To a solution of compound p-2 (0.98 g, 4.00 mmol) in N,N-dimethylformamide (10.0 mL) at zero degrees Celsius, sodium hydride (0.19 g, 4.80 mmol) was added. After stirring at room temperature for 30 minutes, ethyl 4-bromobutyrate (0.93 mL, 4.81 mmol) was added. The reaction was stirred at room temperature overnight. LCMS monitoring showed that the reaction was complete. The reaction solution was quenched with water and extracted with ethyl acetate (50 mL*3). The combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. The concentrated crude product was purified on a normal phase silica gel column to obtain compound p-3 (1.30 g, 91% yield). LCMS: MS (ESI) m / z = 359.5 [M+H] + .

[0813] Compound p-4

[0814] To a solution of compound p-3 (1.30 g, 3.63 mmol) in tetrahydrofuran (20.0 mL) was added 1N lithium hydroxide (20.0 mL). The reaction was stirred at room temperature for 2 hours. LCMS monitoring indicated the reaction was complete. The reaction solution was adjusted to pH 2 with 1N HCl and extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. The filtrate was concentrated to yield compound p-4 (1.18 g, 98% yield). LCMS: MS (ESI) m / z = 331.1 [M+H] + .

[0815] Compound p-5

[0816] To compound p-4 (0.20 g, 0.61 mmol) in N-dimethylformamide (5.0 mL) were added N,N-diisopropylethylamine (0.39 g, 3.03 mmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (0.28 g, 0.73 mmol), and compound m-3 (0.28 g, 0.72 mmol). The reaction was stirred at room temperature for 2 hours. LCMS monitoring indicated the reaction was complete. The reaction solution was quenched with water and extracted with ethyl acetate (40 mL x 3). The combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. The concentrated crude product was purified on a normal phase silica gel column to yield compound p-5 (0.30 g, 53% yield). LCMS: MS (ESI) m / z = 936.7 [M+H] + .

[0817] Compound p-6

[0818] To a solution of compound p-5 (0.07 g, 0.08 mmol) in tetrahydrofuran (2.0 mL) was added 1N lithium hydroxide (2.0 mL). The reaction was stirred at room temperature for 2 hours. LCMS monitoring indicated the reaction was complete. The reaction solution was adjusted to pH 2 with 1N HCl and extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. The filtrate was concentrated to yield compound p-6 (0.27 g, 91% yield). LCMS: MS (ESI) m / z = 922.1 [M+H] + .

[0819] Compound III-p'

[0820] To a solution of compound p-6 (0.27 g, 0.29 mmol) in dichloromethane (4.0 mL) was added trifluoroacetic acid (4.0 mL). The reaction was stirred at room temperature for 3 hours. LCMS analysis indicated the reaction was complete. The reaction solution was concentrated to obtain a crude product which was purified by preparative HPLC to yield compound III-p' (0.09 g, 37% yield). LCMS: MS (ESI) m / z = 822.1 [M+H] + . 1 H NMR (400MHz, DMSO) δ8.97 (s, 1H), 8.51 (d, J = 8.4Hz, 1H), 8.33-8.23 (m, 1H), 8.15 (t, J = 5.6Hz, 1H), 7.88 (d, J = 8.4Hz, 1H), 7. 79-7.72(m,1H),7.63(d,J=8.4Hz,1H),7.51(m,8H),7.31(d,J=8.0Hz,1H),7.26-7.20(m,1H),7.04(d,J=8.0Hz,1H),6.91(s ,1H),5.32(q,J=7.2Hz,1H),4.34-4.31(m,2H),3.95-3.91(m,2H),3.78(d,J=5.6Hz,2H),3.69(dd,J=6.0,3.6Hz,2H),3.61- 3.50(m,13H),3.38-3.34(m,2H),3.29(t,J=7.2Hz,2H),2.80(d,J=7.2Hz,2H),2.29(t,J=7.2Hz,2H),1.86(p,J=7.2Hz,2H).

[0821] SM6.1-αvβ6 and Inter-1 as shown in the above structural formula were prepared according to the method described in patent application WO2019089765A1.

[0822] TA14 shown in the above structural formula was prepared according to the method described in patent application WO2019161213A1.

[0823] Example 17: Conjugation of targeting ligands to siRNA

[0824] A. Synthesis of Alkyne-Functionalized Sense Chains

[0825] The synthesis of dsRNA is similar to conventional phosphoramidite solid-phase synthesis. The synthesis process is briefly described as follows: Nucleoside phosphoramidite monomers are linked one by one according to the synthesis procedure on a Dr. Oligo 48 synthesizer (Biolytic), starting with a universal CPG carrier. Finally, an alkyne-containing phosphoramidite monomer is attached to the 5' end of the sense strand. Nucleoside monomer raw materials, such as 2'-F RNA and 2'-O-methyl RNA, were purchased from Shanghai Zhaowei or Suzhou Jima. Alkyne-containing phosphoramidite monomers were prepared according to the methods described in Examples 1-5. 5-Ethylthio-1H-tetrazole (ETT) was used as an activator (0.6 M acetonitrile solution), a 0.22 M PADS solution dissolved in a 1:1 volume ratio of acetonitrile and collidine (Suzhou Kelema) was used as a sulfurization reagent, and an iodine pyridine / water solution (Kelema) was used as an oxidant.

[0826] After solid-phase synthesis, the oligonucleotides were cleaved from the solid support and soaked in a 3:1 solution of 28% ammonia and ethanol at 50°C for 16 hours. The mixture was then centrifuged, and the supernatant was transferred to another centrifuge tube. After evaporation, the supernatant was subjected to anion exchange chromatography using mobile phase A consisting of 10 mM NaOH and mobile phase B consisting of 10 mM NaOH and 1 M NaCl. The target oligonucleotides were collected, lyophilized, and identified as the desired product by LC-MS. The product was then quantified using a NanoDrop UV light microscope (260 nm).

[0827] B. Conjugation with targeting groups

[0828] The 5' alkyne-functionalized sense strand was conjugated to an αvβ6 integrin targeting group. The following describes the conjugation of the αvβ6 integrin targeting group:

[0829] Prepare stock solutions of 0.5 M tris(3-hydroxypropyltriazolylmethyl)amine (THPTA), 0.5 M copper(II) sulfate pentahydrate (Cu(II)SO₄·5H₂O), and 2 M sodium ascorbate in deionized water. Dissolve the alkyne-functionalized sense strand (2.5 μmol) in 2 M TEAA in a centrifuge tube to a concentration of 10,000-15,000 ng / μL. Separately, dissolve the αvβ6 integrin ligand (35-50 μmol) in DMSO and vortex until the ligand is clear. A DMSO solution of the αvβ6 integrin ligand was added to a 2M TEAA solution containing an alkyne-functionalized sense chain and shaken to mix. 75uL of 0.5M Cu(II) (Cu(II)SO4·5H2O), 75uL of 0.5M THPTA, and 18uL of 2M ascorbate were then added to the centrifuge tube in sequence. After shaking in a thermostatic reactor for 1 hour, the reaction was detected by LCMS. After centrifugation, the supernatant was purified by hydrophobic chromatography (A: ammonium sulfate buffer, B: pure water) to obtain the target product.

[0830] C. Formation of dsRNA with conjugates

[0831] The obtained single-stranded oligonucleotides were annealed according to complementary pairing in an equal molar ratio, and the resulting dsRNA was dissolved in 1× PBS and adjusted to the required concentration for the experiment.

[0832] Example 18: αvβ6 Binding Ability Test

[0833] αvβ6 binding assay by fluorescence polarization (FP)

[0834] This assay is based on the competition of fluorescently labeled RGD peptide for αvβ6 binding. The binding ability of the test compounds is evaluated by the change in FP value.

[0835] Add 3.5 μL of test compound to a 384-well black plate. Set 12 concentration points for each test compound, with the highest concentration being 10 μM, and dilute 3-fold. DMSO control wells are used to determine the maximum signal. 500 nM of compound CWHM-12 A control well (MCE, HY-18644) was used to provide the lowest signal. Next, 3.5 μL of 4X human recombinant αvβ6 protein working solution (Acrobiosystem) was added. After incubation at room temperature for 15 minutes, 7 μL of 2X fluorescent RGD peptide solution (Sangon Biotech) was added to each well. The cells were incubated at room temperature for 1 hour, and the FP signal was then read using Envision. Inhibition curves were fitted and IC values ​​were calculated using GraphPad Prism. 50 value,

[0836] Calculate IC using the following formula 50 Values ​​(Z factor > 0.5):

[0837] Curve fitting formula: Y = Bottom + (Top-Bottom) / (1 + 10^((LogIC 50 -X)*Hill Slope))

[0838] X: logarithmic value of inhibitor concentration; Y: inhibition percentage; Bottom: minimum response; Top: maximum response; Hill Slope: curve slope.

[0839] Table 1. Test data of the binding ability of the disclosed compounds (III-h')-(III-m') to αvβ6

[0840] Example 19: Design of mouse RAGE, MUC5B, and APP dsRNA

[0841] Using the mouse RAGE, mouse MUC5B, and mouse APP genes as target genes, 21 / 21 nt or 21 / 23 nt dsRNAs were designed to meet the general criteria for active dsRNA. Unmodified sense and antisense strand sequences are shown in Table 2. Sense and antisense strand sequences modified with 2'-fluoro, 2'-methoxy, or other modifications are detailed in Tables 3 and 4. Preparation methods were the same as in Example 17.

[0842] Table 2. Unmodified sense and antisense strands of dsRNA

[0843] Table 3. Alkyne-functionalized sense chain structures

[0844] Among them, the structure of II-1 is as follows:

[0845] The structure of II-5 is shown below:

[0846] The structure of II-3 is shown below:

[0847] The structure of II-2 is shown below:

[0848] The structure of TA14' is shown below:

[0849] Table 4. Sense and antisense strands

[0850] Among them, the structure of III-1 is as follows:

[0851] The structure of III-5 is shown below:

[0852] The structure of III-3 is shown below:

[0853] The structure of III-2 is shown below:

[0854] The structure of III-S1113-8 is shown below:

[0855] The structure of III-S1113-11 is as follows:

[0856] The structure of III-S1113-13 is as follows:

[0857] The structure of TA14 is as follows:

[0858] The above III-1, III-2, III-3, III-5, III-S1113-8, III-S1113-11, III-S1113-13, and TA14" are connected to adjacent nucleotides through phosphodiester bonds.

[0859] The lowercase letter m indicates that the nucleoside adjacent to the left of the letter m is a 2'-methoxy-modified nucleoside; the lowercase letter f indicates that the nucleoside adjacent to the left of the letter f is a 2'-fluoro-modified nucleoside; the lowercase letter s indicates that the two nucleosides adjacent to the letter s are connected by a thiophosphate diester group. Unless otherwise specified, the two nucleosides are connected by a phosphodiester group.

[0860] The VPUms structure is as follows:

[0861] The IB structure is represented as follows:

[0862] Im = hypoxanthine 2'-OMe ribonucleoside.

[0863] Example 20: In vitro activity

[0864] Inhibitory activity of mouse RAGE in MLE 12 cells

[0865] The siRNA activity was screened in MLE 12 cells (Starfish Bio) using two concentration gradients (100 nM and 10 nM).

[0866] MLE 12 was frozen in liquid nitrogen and 24 h before transfection, MLE 12 was revived and inoculated into 96-well plates at a density of 1.5 × 10 per well. 4 Cells were plated with 100 μL of culture medium per well. SiRNA was transfected using Lipofectamine RNAi MAX (ThermoFisher, 13778150) according to the product instructions at two concentrations: 100 nM and 10 nM, with duplicate wells for each concentration. After 24 hours of treatment, total RNA was extracted using a high-throughput RNA extraction kit, followed by reverse transcription and quantitative real-time PCR. Mouse RAGE mRNA levels were measured and corrected for GAPDH levels.

[0867] In the real-time quantitative PCR detection, a probe Q-PCR detection experiment was used. The primer information is shown in Table 5. The primers were ordered from Sangon Biotech (Shanghai) Co., Ltd.

[0868] Table 5. Taqman primer information table

[0869] Result analysis method

[0870] After the Q-PCR test is completed, the corresponding Ct value is obtained according to the threshold value automatically set by the system. The expression of a gene can be relatively quantified by comparing the Ct value: Comparative Ct refers to calculating the gene expression difference by the difference between the Ct value and the internal reference gene, also known as 2 -△△Ct , △△Ct=[(Ct experimental group target gene-Ct experimental group internal reference)-(Ct control group target gene-Ct control group internal reference)], and the remaining expression of the target gene was counted.

[0871] The results are shown in Table 6 as the remaining percentage of mouse RAGE mRNA expression relative to that of cells treated with control siRNA.

[0872] Table 6. siRNA activity results in MLE 12 cells

[0873] Example 21: In vitro activity

[0874] Inhibitory activity of mouse RAGE in MLE 12 cells

[0875] Seven concentration gradients were used to screen RNAi agents for molecular mimicry of endogenous cell activity in MLE 12 cells.

[0876] MLE 12 was frozen in liquid nitrogen. During transfection, MLE 12 was revived and inoculated into 96-well plates at a density of 2 × 10 per well. 4 cells, 100 μL of culture medium per well. According to the instructions, RNAi MAX transfection reagent (ThermoFisher13778150) was used to transfect the cells with RNAi agents, using 0.3 μL RNAi MAX transfection reagent per well. A total of 7 concentration points were set for the RNAi agent, with the highest concentration point having a final concentration of 100 nM, 5-fold gradient dilution, 100.0000 nM, 20 nM, 4 nM, 0.8 nM, 0.16 nM, 0.032 nM, 0.0064 nM, and duplicate wells for each concentration. After 48 hours of treatment, a high-throughput cell RNA extraction kit was used for total cell RNA extraction, RNA reverse transcription experiment, and quantitative real-time PCR detection to determine the mRNA level of mouse RAGE, which was corrected according to the level of the GAPDH internal reference gene.

[0877] Among them, in the real-time quantitative PCR detection, a probe Q-PCR detection experiment was used, and its primer information is shown in Table 5.

[0878] Result analysis method

[0879] After the Q-PCR test is completed, the corresponding Ct value is obtained according to the threshold value automatically set by the system. The expression of a gene can be relatively quantified by comparing the Ct value: Comparative Ct refers to calculating the gene expression difference by the difference between the Ct value and the internal reference gene, also known as 2 -△△Ct , △△Ct=[(Ct experimental group target gene-Ct experimental group internal reference)-(Ct control group target gene-Ct control group internal reference)], and the remaining expression of the target gene was counted.

[0880] The results are shown in Table 7 as the remaining percentage of mouse RAGE mRNA expression relative to that of cells treated with control siRNA.

[0881] Table 7. siRNA activity results in MLE 12 cells

[0882] Example 22: In vivo activity of TJR101402

[0883] 7-week-old C57BL / 6J male mice (purchased from Zhejiang Weitong Lihua Experimental Animal Technology Co., Ltd.) were adapted to the animal facility for 3-7 days. 20 mice were weighed and divided into 4 groups, 5 mice / group, namely G1-normal saline group, G2-4 group for TJR101402 0.3mg / kg, 1mg / kg, 3mg / kg. Weighed and grouped on the first day of the experiment, after isoflurane anesthesia, a mouse lung drug delivery device (Yuyan Instrument) was used to administer the drug through the trachea, and a single dose of different concentrations of TJR101402 was injected. On the 8th day of the experiment, the mice were euthanized, and the whole lungs were taken out after cardiac blood sampling, and stored at -80°C after quick freezing in liquid nitrogen. The RAGE mRNA level in the mouse lung tissue was detected by real-time quantitative PCR, and the primer information was the same as in Example 20.

[0884] Table 8. Activity results of TJR101402 on mouse lung RAGE

[0885] As shown above, 7 days after administration, the expression of RAGE in the lungs of mice in the TJR101402 0.3 mg / kg, 1 mg / kg and 3 mg / kg dose groups was significantly lower than that in the normal saline group.

[0886] Example 23: In vivo activity of TJR101470, TJR101471 and TJR101472

[0887] 7-week-old C57BL / 6J male mice (purchased from Zhejiang Weitong Lihua Experimental Animal Technology Co., Ltd.) were adapted to the animal facility for 3-7 days. 40 mice were weighed and divided into 4 groups, 10 mice / group, namely G1-normal saline group, G2-4 groups were TJR101470, TJR101471 and TJR101472 respectively. They were weighed and divided into groups on the first day of the experiment, and after isoflurane anesthesia, they were administered through the trachea using a mouse lung drug delivery device (Yuyan Instrument), and the single-dose injection dose was 1 mg / kg. On the 15th day of the experiment, the mice were euthanized, and the whole lungs were taken out after cardiac blood sampling, and stored at -80°C after quick freezing in liquid nitrogen. The RAGE mRNA level in the mouse lung tissue was detected by real-time quantitative PCR, and the primer information was the same as in Example 20. The experimental results are shown in Figure 1. After 14 days of administration, TJR101470, TJR101471 and TJR101472 all showed significant knockdown activity on the expression of RAGE in the mouse lungs, with the inhibition rates of RAGE expression in the mouse lungs being 62.4%, 54.0% and 66.6%, respectively.

[0888] Example 24: In vivo activity of TJR101401, TJR101468-8 and TJR101468-13

[0889] 7-week-old C57BL / 6J male mice (purchased from Zhejiang Weitong Lihua Experimental Animal Technology Co., Ltd.) were adapted to the animal facility for 3-7 days. 20 mice were weighed and divided into 4 groups, 5 mice / group, namely G1-normal saline group, G2-4 groups were TJR101401, TJR101468-08 and TJR101468-13 respectively. Weighed and grouped on the first day of the experiment, after isoflurane anesthesia, the mice were administered through the trachea using a mouse lung drug delivery device (Yuyan Instrument), and the single-dose injection dose was 1 mg / kg. On the 15th day of the experiment, the mice were euthanized, and the whole lungs were taken out after cardiac blood sampling, and stored at -80°C after quick freezing in liquid nitrogen. The RAGE mRNA level in the mouse lung tissue was detected by real-time quantitative PCR, and the primer information was the same as in Example 20. The experimental results are shown in Figure 2. They show that after 14 days of administration, TJR101401, TJR101468-8, and TJR101468-13 all exhibited significant knockdown activity on RAGE expression in mouse lungs, with average inhibition rates of 44.2%, 66.8%, and 75.6%, respectively. These data indicate that TJR101468-8 and TJR101468-13 significantly knocked down RAGE expression in mouse lungs more significantly than TJR101401.

[0890] Example 25: In vivo activity of TJR101401, TJR101468-11 and TJR101468-13

[0891] 7-week-old C57BL / 6J male mice (purchased from Zhejiang Weitong Lihua Experimental Animal Technology Co., Ltd.) were adapted to the animal facility for 3-7 days. 40 mice were weighed and divided into 4 groups, 10 mice / group, namely G1-normal saline group, G2-4 groups TJR101401, TJR101468-11 and TJR101468-13 respectively. Weighed and grouped on the first day of the experiment, after isoflurane anesthesia, the mice were administered through the trachea using a mouse lung drug delivery device (Yuyan Instrument), and the single-dose injection dose was 0.3 mg / kg. On the 29th day of the experiment, the mice were euthanized, and the whole lungs were taken out after cardiac blood sampling, and stored at -80°C after quick freezing in liquid nitrogen. The RAGE mRNA level in the mouse lung tissue was detected by real-time quantitative PCR, and the primer information was the same as in Example 20. The experimental results are shown in Figure 3. After 28 days of administration, TJR101401, TJR101468-11, and TJR101468-13 all demonstrated significant knockdown activity on RAGE expression in mouse lungs, with average inhibition rates of 34.7%, 69.1%, and 60.9%, respectively. These data demonstrate that TJR101468-11 and TJR101468-13 significantly knocked down RAGE expression in mouse lungs compared to TJR101401.

[0892] Example 26: In vitro activity

[0893] Inhibitory activity of mouse MUC5B in MLE 12 cells

[0894] Seven concentration gradients were used to screen RNAi agents for molecular mimicry of endogenous cell activity in MLE 12 cells.

[0895] MLE 12 was frozen in liquid nitrogen. During transfection, MLE 12 was revived and inoculated into 96-well plates at a density of 2 × 10 per well. 4 cells, 100 μL of culture medium per well. According to the instructions, RNAi MAX transfection reagent (ThermoFisher 13778150) was used to transfect the cells with RNAi agents, using 0.3 μL of RNAi MAX transfection reagent per well. A total of 7 concentration points of RNAi agents were set, with the highest concentration point having a final concentration of 100 nM, and 5-fold gradient dilutions, 100.0000 nM, 20 nM, 4 nM, 0.8 nM, 0.16 nM, 0.032 nM, 0.0064 nM, and duplicate wells for each concentration. After 48 hours of treatment, total cell RNA was extracted, RNA reverse transcription experiments were performed, and quantitative real-time PCR was performed to measure the mRNA level of mouse RAGE. The mRNA level of mouse MUC5B was corrected according to the level of the GAPDH internal reference gene.

[0896] In the real-time quantitative PCR detection, a probe Q-PCR detection experiment was used. The primer information is shown in Table 9. The primers were ordered from Sangon Biotech (Shanghai) Co., Ltd.

[0897] Table 9. Taqman primer information table

[0898] Result analysis method

[0899] After the Q-PCR test is completed, the corresponding Ct value is obtained according to the threshold value automatically set by the system. The expression of a gene can be relatively quantified by comparing the Ct value: Comparative Ct refers to calculating the gene expression difference by the difference between the Ct value and the internal reference gene, also known as 2 -△△Ct , △△Ct=[(Ct experimental group target gene-Ct experimental group internal reference)-(Ct control group target gene-Ct control group internal reference)], and the remaining expression of the target gene was counted.

[0900] The results are expressed as the remaining percentage of mouse MUC5B mRNA expression relative to cells treated with control siRNA, and are shown in Table 10.

[0901] Table 10. siRNA activity results in MLE 12 cells

[0902] Example 27: In vivo activity of TJR103427-11 and TJR103428-1

[0903] 7-week-old C57BL / 6J male mice (purchased from Zhejiang Weitong Lihua Experimental Animal Technology Co., Ltd.) were acclimated for 3-7 days after entering the animal facility. 15 mice were weighed and divided into 3 groups, 5 mice / group, namely G1-normal saline group, G2-3 group TJR103427-11 and TJR103428-1 respectively. On the first day of the experiment, they were weighed and divided into groups, and after isoflurane anesthesia, they were administered through the trachea using a mouse lung drug delivery device (Yuyan Instrument), with a single dose injection dose of 3 mg / kg. On the 29th day of the experiment, the mice were euthanized, and the whole lungs were taken out after cardiac blood sampling, and stored at -80°C after quick freezing in liquid nitrogen. The MUC5B mRNA level in the mouse lung tissue was detected by real-time quantitative PCR, and the primer information was the same as in Example 26. The experimental results are shown in FIG4 . After 28 days of administration, TJR103427-11 exhibited significant knockdown activity on MUC5B expression in mouse lungs, with an average inhibition rate of 58.1%, while TJR103428-1 showed no knockdown activity.

[0904] Example 28: In vivo activity of TJR103427-1, TJR103700-1 and TJR103701-1

[0905] 7-week-old C57BL / 6J male mice (purchased from Zhejiang Weitong Lihua Experimental Animal Technology Co., Ltd.) were acclimated for 3-7 days after entering the animal facility. 40 mice were weighed and divided into 4 groups, 10 mice / group, namely G1-normal saline group, G2-4 groups TJR103427-1, TJR103700-1 and TJR103701-1 respectively. On the first day of the experiment, the mice were weighed and divided into groups. After isoflurane anesthesia, the mice were administered through the trachea using a mouse lung drug delivery device (Yuyan Instruments), and the single dose injection dose was 3 mg / kg. On the 15th day of the experiment, the mice were euthanized, and the whole lungs were taken out after cardiac blood sampling, and stored at -80°C after quick freezing in liquid nitrogen. The MUC5B mRNA level in the mouse lung tissue was detected by real-time quantitative PCR, and the primer information was the same as in Example 26. The experimental results are shown in FIG5 . 14 days after administration, TJR103427-1, TJR103700-1, and TJR103701-1 all exhibited significant knockdown activity on MUC5B expression in mouse lungs, with average inhibition rates of 24.5%, 32.1%, and 33.2%, respectively.

[0906] Example 29 In vitro activity

[0907] Inhibitory activity of APP in A172 cells

[0908] Seven concentration gradients were used to screen RNAi agents for molecular-level mimicking of endogenous cell activity in A172 cells.

[0909] A172 cells were cultured in DMEM + 10% FBS complete medium at 37°C and 5% CO2. 24 hours before transfection, A172 cells were seeded in 96-well plates at a seeding density of 1×10 cells per well. 4 cells, 100 μL culture medium per well.

[0910] According to the instructions, RNAi MAX transfection reagent (ThermoFisher13778150) was used to transfect the cells with RNAi agents, using 0.3 μL RNAi MAX transfection reagent per well. A total of 7 concentration points were set for the RNAi agent, with the highest concentration point having a final concentration of 10 nM, 7-fold gradient dilution, 10.0000 nM, 1.428 nM, 0.204 nM, 0.0291 nM, 0.004 nM, 0.00059 nM, 0.00008 nM, and duplicate wells for each concentration. After 48 hours of treatment, a high-throughput cell RNA extraction kit was used for total cell RNA extraction, RNA reverse transcription experiment, and quantitative real-time PCR detection to determine the mRNA level of human APP, which was corrected according to the level of the GAPDH internal reference gene.

[0911] Among them, in the real-time quantitative PCR detection, a probe Q-PCR detection experiment was used, and its primer information is shown in Table 11.

[0912] Table 11. Taqman primer information table

[0913] Result analysis method

[0914] After the Q-PCR test is completed, the corresponding Ct value is obtained according to the threshold value automatically set by the system. The expression of a gene can be relatively quantified by comparing the Ct value: Comparative Ct refers to calculating the gene expression difference by the difference between the Ct value and the internal reference gene, also known as 2 -△△Ct , △△Ct=[(Ct experimental group target gene-Ct experimental group internal reference)-(Ct control group target gene-Ct control group internal reference)], and the remaining expression of the target gene was counted.

[0915] The results are expressed as the remaining percentage of human APP mRNA expression relative to cells treated with control siRNA, and are shown in Table 12.

[0916] Table 12. siRNA activity results in A172 cells

Claims

1. A targeting ligand of formula III or a pharmaceutically acceptable salt thereof, in, L1 is -(CH2) q1 -、-(CH2) q2 -NH-C(=O)-(CH2) q3 -or-(CH2) q4 -O-(CH2) q5 -, q1, q2, q3, q4 and q5 are each independently an integer from 1 to 10; X is a bond, -C(=O), -C(=O)-NH- or -NH-C(=O)-; TL are each independently a targeting group; n is 3 or 4; Q and L2 are any of the following combinations: Combination 1: Q is L2 is each independently -O-(CH2) p1 -C(=O)-NH-(CH2CH2O) p2 -(CH2) p3 ; Combination 2: Q is L2 is each independently -C(=O)-NH-(CH2CH2O) p4 -(CH2) p5 ; Combination 3: Q is L2 is each independently -C(=O)-(CH2CH2O) p6 -(CH2) p7 ; Combination 4: Q is L2 is each independently -O-(CH2) p1 -C(=O)-NH-(CH2CH2O) p2 -(CH2) p3 ; m1, m2, m3, m4, m5, m6, m7, m8, m9, m10, m11, m12, m13 and m14 are each independently 0, 1, 2, 3, 4, 5 or 6; p1, p2, p3, p4, p5, p6 and p7 are each independently 0, 1, 2, 3 or 4.

2. The targeting ligand of formula III or a pharmaceutically acceptable salt thereof according to claim 1, wherein: L1 is -(CH2)6-, -(CH2)6-NH-C(=O)-(CH2)3- or -(CH2)6-O-CH2-.

3. The targeting ligand of formula III or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein the targeting group TL is of formula (III-d): Where R 22 Formula (L) wherein a* represents the point of connection with the naphthyl group, b* represents the point of connection with the triazole group in formula III, and n1 is selected from an integer of 2-20; Y is a 5-14 membered heteroaryl group, which is optionally substituted by one or more of the following groups: halogen, hydroxy, oxo, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyloxy, C 2-6 Alkynyloxy, C 3-6 Cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 cycloalkenyloxy, phenyl or 5- to 6-membered heteroaryl, the C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyloxy, C 2-6 Alkynyloxy, C 3-6 Cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 Cycloalkenyloxy, phenyl or 5- to 6-membered heteroaryl is optionally substituted by one or more substituents selected from halogen, hydroxy, oxo, nitro, cyano; B is selected from -CH2-, -NH-, or does not exist; A is selected from -CH2-, -NH-, -O- or is absent.

4. The targeting ligand of formula III or a pharmaceutically acceptable salt thereof according to claim 3, wherein Y is selected from 5. The targeting ligand of formula III or a pharmaceutically acceptable salt thereof according to claim 3 or 4, wherein the targeting group TL is of formula (III-e-1) or formula (III-e-2): wherein Y is as defined in claim 3 or 4, and A is as defined in claim 3.

6. The targeting ligand of formula III or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, wherein the targeting group TL is selected from (III-f)-(III-p), 7. The targeting ligand of formula III or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, wherein the targeting ligand is selected from the following structures, in, TL is as defined in any one of claims 1-6.

8. The targeting ligand of formula III or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, wherein the targeting ligand is selected from the following structures, 9. A nucleic acid targeting ligand conjugate or a pharmaceutically acceptable salt thereof, wherein the nucleic acid targeting conjugate comprises a nucleic acid and one or more targeting ligands conjugated to the nucleic acid, wherein the targeting ligand is as described in any one of claims 1 to 8, and each of the targeting ligands is the same or different.

10. The nucleic acid targeting ligand conjugate or a pharmaceutically acceptable salt thereof according to claim 9, wherein: The nucleic acid is siRNA, and the siRNA comprises a partially complementary sense strand and an antisense strand; Preferably, the nucleic acid is siRNA targeting RAGE, siRNA targeting MUC5B or siRNA targeting siRNA for APP; Preferably, the 5' end of the sense strand in the siRNA is conjugated to a targeting ligand.

11. The nucleic acid targeting ligand conjugate or a pharmaceutically acceptable salt thereof according to claim 9 or 10, wherein: The nucleic acid targeting ligand conjugate is shown in Formula V, Wherein, R is nucleic acid; W is OH, SH, O - or S - ; L1, L2, X, Q and TL are as defined in any of 1-6.

12. The nucleic acid-targeting ligand conjugate or a pharmaceutically acceptable salt thereof according to any one of claims 9 to 11, wherein the nucleic acid-targeting ligand conjugate is selected from the following structures: in, R is a nucleic acid as defined in claim 10; TL is as defined in any one of claims 1-6.

13. A pharmaceutical composition comprising the nucleic acid-targeting ligand conjugate or a pharmaceutically acceptable salt thereof according to any one of claims 9 to 12, and one or more pharmaceutically acceptable excipients.

14. Use of the nucleic acid-targeting ligand conjugate or a pharmaceutically acceptable salt thereof according to any one of claims 9 to 12, or the pharmaceutical composition according to claim 13, in the preparation of a medicament for preventing and / or treating respiratory diseases.

15. A method for preparing a nucleic acid-targeting ligand conjugate according to any one of claims 9 to 12, comprising the step of preparing the nucleic acid-targeting ligand conjugate from nucleic acid.

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