Rnai agent and pharmaceutical use thereof

Abstract

The present disclosure relates to an RNAi agent and a pharmaceutical use thereof. Specifically, the present disclosure relates to an MMP7-targeting RNAi agent, and a pharmaceutical composition and a use thereof.

Description

An RNAi agent and its medicinal uses

[0001] This application claims priority to Chinese patent application CN202411867710.4 filed on December 18, 2024, Chinese patent application CN202511168819.3 filed on August 20, 2025, and Chinese patent application CN202511488438.3 filed on October 17, 2025. Technical Field

[0002] This disclosure pertains to the field of biomedicine and specifically relates to RNAi agents targeting matrix metalloproteinase 7 (MMP7), pharmaceutical compositions, and their pharmaceutical uses. Background Technology

[0003] Matrix metalloproteinase 7 (MMP7) is the smallest member (28 kDa) of the metalloproteinase family (MMPs). MMPs comprise 23 family members with different substrates and functions, capable of degrading all components of the extracellular matrix (e.g., elastin, proteoglycans, type IV collagen, fibronectin, etc.) and many non-matrix proteins, such as cytokines. These functional roles in extracellular matrix remodeling and cytokine signaling link MMP family members to common pathogenic mechanisms leading to cancer, chronic inflammation, and fibrosis. MMP7 is primarily expressed and secreted by epithelial cells of organs throughout the body, playing a crucial role in epithelial cell repair. Increased MMP7 expression is associated with pathogenic fibrosis in the lungs, liver, and kidneys. In idiopathic pulmonary fibrosis (IPF), MMP7 gene and protein expression levels are significantly elevated in lung tissue and also significantly upregulated in bronchoalveolar lavage fluid (BAL). Serum MMP7 expression is a potent serum biomarker for IPF, correlated with IPF severity and progression.

[0004] MMP7 is associated with pathogenic fibrosis through multiple potential mechanisms, including promoting epithelial-mesenchymal transition (EMT), extracellular matrix degradation, abnormal matrix repair, and tissue remodeling. MMP7 promotes fibrosis by cleaving E-cadherin to activate epithelial cells and by proteolytic activation of heparin-bound epidermal growth factor precursor (pro-HB-EGF) to release active HB-EGF. Studies have shown that MMP7 knockout mice have a protective effect against bleomycin-induced pulmonary fibrosis, exhibiting reduced lung inflammation, fibrosis, and mortality, suggesting that MMP7 knockdown may have a therapeutic effect on pulmonary fibrosis. Summary of the Invention

[0005] This disclosure provides an RNAi agent comprising a sense strand and an antisense strand forming a double-stranded region;

[0006] The positive strand comprises at least 15 consecutive nucleotides that differ from the nucleotide sequences shown in any of SEQ ID NO:1 to SEQ ID NO:14 by no more than 3 nucleotides; and / or

[0007] The antisense strand comprises at least 15 consecutive nucleotides that differ from the nucleotide sequences shown in any of SEQ ID NO:15 to SEQ ID NO:28 by no more than 3 nucleotides.

[0008] In some embodiments, "difference of no more than 3 nucleotides" means a difference of 0, 1, 2, or 3 nucleotides. In some embodiments, "at least 15 consecutive nucleotides" means at least 15, 16, 17, 18, 19, 20, or 21 consecutive nucleotides. In some embodiments, it means at least 17, 18, 19, 20, or 21 consecutive nucleotides.

[0009] In some implementations, the antisense strand is at least partially complementary to the target sequence to mediate RNA interference. In some implementations, there are no more than 5, 4, 3, 2, or 1 mismatches between the antisense strand and the target sequence. In some implementations, the antisense strand is completely anticomplementary to the target sequence.

[0010] In some embodiments, the RNAi agent disclosed herein comprises one or two blunt ends.

[0011] In some embodiments, the sense and / or antisense strands of the RNAi agent disclosed herein each independently contain one or two unpaired nucleotides. In some embodiments, the 3' end of the antisense strand includes a protrusion formed by unpaired nucleotides.

[0012] In some embodiments, the sense strand and antisense strand are each independently composed of 16 to 35, 16 to 34, 17 to 34, 17 to 33, 18 to 33, 18 to 32, 18 to 31, 18 to 30, 18 to 29, 18 to 28, 18 to 27, 18 to 26, 18 to 25, 18 to 24, 18 to 23, 19 to 25, 19 to 24, or 19 to 23 nucleotides. In some embodiments, the sense strand and antisense strand are each independently composed of 18, 19, 20, 21, 22, or 23 nucleotides.

[0013] In some implementations, the sense strand and the antisense strand may be the same length or different, with the sense strand being 19-23 nucleotides long and the antisense strand being 19-26 nucleotides long. Therefore, the length ratio of the sense strand to the antisense strand of the RNAi agent provided in this disclosure can be 19 / 19, 19 / 20, 19 / 21, 19 / 22, 19 / 23, 19 / 24, 19 / 25, 19 / 26, 20 / 19, 20 / 20, 20 / 21, 20 / 22, 20 / 23, 20 / 24, 20 / 25, 20 / 26, 21 / 20, 21 / 21, 21 / 22, 21 / 23, 21 / 24, 21 / 25, 21 / 26, 22 / 20, 22 / 21, 22 / 22, 22 / 23, 22 / 24, 22 / 25, 22 / 26, 23 / 20, 23 / 21, 23 / 22, 23 / 23, 23 / 24, 23 / 25, or 23 / 26. In some embodiments, the length ratio of the sense strand to the antisense strand of the RNAi agent is 19 / 19, 20 / 21, 19 / 21, 21 / 21, 21 / 23, 23 / 23, or 23 / 25. In some embodiments, the length ratio of the sense strand to the antisense strand is 19 / 21, 20 / 21, or 21 / 23.

[0014] In some embodiments, the positive strand comprises at least 17 consecutive nucleotides that differ from the nucleotide sequences shown in any of SEQ ID NO:1 to SEQ ID NO:14 by no more than 3 nucleotides;

[0015] And / or the antisense strand comprises at least 17 consecutive nucleotides that differ from the nucleotide sequences shown in any of SEQ ID NO:15 to SEQ ID NO:28 by no more than 3 nucleotides;

[0016] In some embodiments, the positive strand comprises at least 19 consecutive nucleotides that differ from the nucleotide sequences shown in any of SEQ ID NO:1 to SEQ ID NO:14 by no more than 3 nucleotides;

[0017] And / or the antisense strand comprises at least 21 consecutive nucleotides that differ from the nucleotide sequences shown in any of SEQ ID NO:15 to SEQ ID NO:28 by no more than 3 nucleotides.

[0018] In some embodiments, the sense strand comprises a nucleotide sequence as shown in any of SEQ ID NO:1 to SEQ ID NO:14; and / or the antisense strand comprises a nucleotide sequence as shown in any of SEQ ID NO:15 to SEQ ID NO:28.

[0019] In some embodiments, the sense strand is selected from any of the nucleotide sequences shown in SEQ ID NO:1 to SEQ ID NO:14; and / or the antisense strand is selected from any of the nucleotide sequences shown in SEQ ID NO:15 to SEQ ID NO:28.

[0020] In some embodiments, the RNAi agent comprises or is selected from the group consisting of a sense strand and an antisense strand:

[0021] Group 1) The sense chain shown in SEQ ID NO: 1 and the antisense chain shown in SEQ ID NO: 15;

[0022] Group 2) such as the sense chain shown in SEQ ID NO: 2 and the antisense chain shown in SEQ ID NO: 16;

[0023] Group 3) such as the sense chain shown in SEQ ID NO: 3 and the antisense chain shown in SEQ ID NO: 17;

[0024] Group 4) such as the sense chain shown in SEQ ID NO: 4 and the antisense chain shown in SEQ ID NO: 18;

[0025] Group 5) such as the sense chain shown in SEQ ID NO: 5 and the antisense chain shown in SEQ ID NO: 19;

[0026] Group 6) such as the sense chain shown in SEQ ID NO: 6 and the antisense chain shown in SEQ ID NO: 20;

[0027] Group 7) such as the sense chain shown in SEQ ID NO: 7 and the antisense chain shown in SEQ ID NO: 21;

[0028] Group 8) such as the sense chain shown in SEQ ID NO: 8 and the antisense chain shown in SEQ ID NO: 22;

[0029] Group 9) such as the sense chain shown in SEQ ID NO: 9 and the antisense chain shown in SEQ ID NO: 23;

[0030] Group 10) such as the sense chain shown in SEQ ID NO: 10 and the antisense chain shown in SEQ ID NO: 24;

[0031] Group 1) such as the sense chain shown in SEQ ID NO: 11 and the antisense chain shown in SEQ ID NO: 25;

[0032] Group 2) such as the sense chain shown in SEQ ID NO: 12 and the antisense chain shown in SEQ ID NO: 26;

[0033] Group 3) such as the sense chain shown in SEQ ID NO: 13 and the antisense chain shown in SEQ ID NO: 27; and

[0034] Group 4) such as the sense chain shown in SEQ ID NO: 14 and the antisense chain shown in SEQ ID NO: 28.

[0035] In some embodiments, at least one nucleotide in the sense strand and / or antisense strand is a modified nucleotide. In some embodiments, all nucleotides in the sense strand and / or antisense strand are modified nucleotides.

[0036] In some embodiments, the positive strand contains three consecutive 2'-fluorinated nucleosides. In some embodiments, the nucleosides at positions 7, 8, and 9 of the 5' end of the positive strand are 2'-fluorinated nucleosides. In some embodiments, the nucleosides at positions 7, 8, and 9 of the 5' end of the positive strand are 2'-fluorinated nucleosides, and the remaining nucleotides are non-fluorinated nucleosides. In some embodiments, the non-fluorinated nucleosides are 2'-methoxylated nucleosides or reverse-base-free nucleosides. In some embodiments, the first nucleoside at the 3' end of the positive strand is a reverse-base-free nucleoside. In some embodiments, the nucleosides at positions 7, 8, and 9 of the 5' end of the positive strand are 2'-fluorinated nucleosides, the first nucleoside at the 3' end is a reverse-base-free nucleotide, and the remaining nucleosides are 2'-methoxylated nucleosides.

[0037] Unless otherwise specified, in the context of this disclosure, the reverse abasic nucleoside has a structure as shown in formula (IV-1), formula (IV-2), or formula (IV-3), wherein when the reverse abasic nucleoside is the first nucleoside at the 5' end of the sequence, it has a structure as shown in formula (IV-1); when it is the first nucleoside at the 3' end, it has a structure as shown in formula (IV-2); and when it is located in the middle of the sequence, it has a structure as shown in formula (IV-3).

[0038] In some embodiments, the antisense strand contains at least five 2'-fluorinated nucleosides, for example, five, six, seven, eight, nine, or ten 2'-fluorinated nucleosides. In some embodiments, the nucleosides at positions 2, 6, 12, 14, and 16 of the antisense strand are each independently 2'-fluorinated nucleosides, following a direction from the 5' end to the 3' end. In some embodiments, the antisense strand contains five 2'-fluorinated nucleosides, and the nucleotides at positions 2, 6, 12, 14, and 16 of the antisense strand are each independently 2'-fluorinated nucleosides, while the nucleotides at the remaining positions are non-fluorinated nucleosides. In some embodiments, the antisense strand contains eight 2'-fluorinated nucleosides, wherein the nucleosides at positions 2, 4, 6, 10, 12, 14, 16, and 18 of the antisense strand are each independently 2'-fluorinated nucleosides, and the nucleosides at the remaining positions are non-fluorinated nucleosides. In some embodiments, the non-fluorinated nucleotides are 2'-methoxyinated nucleosides.

[0039] In some embodiments, at least one phosphodiester group in the sense strand and / or antisense strand is a phosphodiester group with a modifying group. The modifying group increases the stability of the RNAi agent in a biological sample or environment. In some embodiments, the sense strand and / or antisense strand includes multiple phosphodiester groups with modifying groups, for example, 1, 2, 3, 4, 5, 6, or 7 phosphodiester groups with modifying groups. In some embodiments, both the sense strand and the antisense strand contain multiple phosphodiester groups with modifying groups. In some embodiments, the sense strand contains 1, 2, 3, or 4 phosphodiester groups with modifying groups; the antisense strand contains 1, 2, 3, 4, or 5 phosphodiester groups with modifying groups.

[0040] In some embodiments, the sense chain contains four phosphodiester groups with modifying groups, and the antisense chain contains five phosphodiester groups with modifying groups; or the sense chain contains two phosphodiester groups with modifying groups, and the antisense chain contains one phosphodiester group with a modifying group; or the sense chain contains two phosphodiester groups with modifying groups, and the antisense chain contains four phosphodiester groups with modifying groups; or the sense chain contains four phosphodiester groups with modifying groups, and the antisense chain contains one phosphodiester group with a modifying group.

[0041] In some embodiments, the phosphodiester group with the modifying group is present at one or more locations selected from: between any two adjacent nucleotides from the first to the fourth nucleotide at the 5' end and / or the 3' end of the sense chain, and / or between any two adjacent nucleotides from the first to the fourth nucleotide at the 5' end and / or the 3' end of the antisense chain. For example, it may be located between the first and second nucleotides at the 5' end of the sense chain;

[0042] Between the second and third nucleotides at the 5' end of the positive chain;

[0043] Between the first and second nucleotides at the 3' end of the positive chain;

[0044] Between the second and third nucleotides at the 3' end of the positive chain;

[0045] Between the first and second nucleotides at the 5' end of the antisense strand;

[0046] Between the second and third nucleotides at the 5' end of the antisense strand;

[0047] Between the third and fourth nucleotides at the 5' end of the antisense strand;

[0048] Between the first and second nucleotides at the 3' end of the antisense strand; and

[0049] Between the second and third nucleotides at the 3' end of the antisense strand.

[0050] In some embodiments, the phosphate diester group having the modifying group is a thiophosphate diester group.

[0051] In some embodiments, the 5' position of the sugar ring of the first nucleotide at the 5' end of the sense or antisense strand is a 5'-vinyl phosphate diester group. In some embodiments, the 5'-vinyl phosphate diester group is a trans-vinyl phosphate diester group (E-VP).

[0052] In some embodiments, the positive strand is selected from or comprises any of the nucleotide sequences shown in SEQ ID NO:29 to SEQ ID NO:105;

[0053] And / or the antisense strand is selected from or contains any of the nucleotide sequences shown in SEQ ID NO:106 to SEQ ID NO:182.

[0054] In some embodiments, the positive strand is selected from or comprises a nucleotide sequence such as any one of SEQ ID NO:355 to SEQ ID NO:371;

[0055] In some embodiments, the antisense strand is selected from or includes nucleotide sequences such as any of SEQ ID NO:372 to SEQ ID NO:378.

[0056] In some embodiments, the RNAi agent further comprises one or more targeting ligands that have affinity for cellular receptors expressed on epithelial cells. In some embodiments, the RNAi agent comprises one targeting ligand. In some embodiments, the RNAi agent comprises multiple targeting ligands, such as two, three, four, or five targeting ligands.

[0057] In some embodiments, the targeting ligand comprises one or more integrin targeting groups, for example, it may comprise one, two, three, four or five integrin targeting groups.

[0058] In some embodiments, the integrin targeting group is the αvβ6 integrin targeting group.

[0059] In some embodiments, the targeting ligand is an integrin targeting ligand as described in PCT application WO2025067423A, the entire contents of which are incorporated herein by reference. In some embodiments, the targeting ligand is a targeting ligand as shown in Formula III or a regiomeric isoform thereof:

[0060] Wherein, L1 is a C1 arbitrarily interrupted by one or more groups. 1-10 Alkyl group, wherein the group is selected from -O-, -S-, -N- and -C(=O)-;

[0061] X is a bond, -C(=O), -C(=O)-NH- or -NH-C(=O)-;

[0062] Q is

[0063] Each L2 molecule is 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 ;

[0064] Each TL is an independent targeting group;

[0065] n is 3 or 4;

[0066] 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;

[0067] p1, p2, p3, p4, p5, p6 and p7 are each independently 0, 1, 2, 3 or 4;

[0068] The condition is that when Q is At the same time, L2 is not simultaneously -C(=O)-NH-(CH2CH2O) p4 -(CH2) p5 .

[0069] In some implementations, Q is Each L2 molecule is independently -O-(CH2). p1 -C(=O)-NH-(CH2CH2O) p2 -(CH2) p3 m1, m2, m3, p1, p2 and p3 are as defined in Equation III.

[0070] In some implementations, Q is Each L2 molecule is independently -C(=O)-NH-(CH2CH2O) p4 -(CH2) p5 m4, m5, m9, m10, p4 and p5 are as defined in Equation III.

[0071] In some implementations, Q is Each L2 is independently -C(=O)-(CH2CH2O) p6 -(CH2) p7 m6, m7, m8, p6 and p7 are as defined in Equation III.

[0072] In some implementations, Q is Each L2 molecule is independently -O-(CH2). p1 -C(=O)-NH-(CH2CH2O) p2 -(CH2) p3 m11, m12, m13, m14, p1, p2 and p3 are as defined in Equation III.

[0073] In some implementations, L2 is the same.

[0074] In some embodiments, L1 is a C1 column optionally interrupted by one or more groups.1-10 Alkyl group, wherein the group is selected from -O-, -N- and -C(=O)-.

[0075] In some implementations, 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 independent integers from 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10).

[0076] In some implementations, 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 independent integers from 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10), where -(CH2) q1 -、-(CH2) q2 -NH-C(=O)-(CH2) q3 -or-(CH2) q4 -O-(CH2) q5 - is connected to X in Equation III on the right side.

[0077] In some implementations, L1 is -(CH2)6-, -(CH2)6-NH-C(=O)-(CH2)3-, or -(CH2)6-O-CH2-.

[0078] In some implementations, 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.

[0079] In some implementations, Q is Among them, end a is connected to X, and m1, m2, m3, m4, m5, m6, m7, m8, m9, m10, m11, m12, m13 and m14 are as defined in Equation III.

[0080] In some implementations, Q is

[0081] In some implementations, Q is Among them, end a is connected to X.

[0082] In some implementations, L2 is independently...

[0083] In some implementations, L2 is independently... Among them, the b end is connected to Q.

[0084] In some embodiments, the targeting group is an integrin targeting group.

[0085] In some embodiments, the integrin targeting group is the αvβ6 integrin targeting group.

[0086] In some embodiments, the targeting group TL is of formula (III-a):

[0087] Wherein Y is a 5-14 membered heteroaryl group, and the heteroaryl group is optionally substituted by one or more of the following groups: halogen, hydroxyl, oxo, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 2- 6-olefin, C 2-6 Acryloxy group, C 3-6 Cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 Cycloalkenyloxy, phenyl, or 5- to 6-membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyloxy group, C 2-6 Acryloxy group, C 3-6 Cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 The cycloalkenyloxy, phenyl, or 5- to 6-membered heteroaryl group may be optionally substituted by one or more substituents selected from halogen, hydroxyl, oxo, nitro, or cyano groups;

[0088] B is selected from -CH2-, -NH-, Or it may not exist;

[0089] The group A of the target group TL is selected from -CH2-, -NH-, -O-, or is not present;

[0090] Z is selected from OR 13 、N(R 13 )2 or SR 13 ;

[0091] R 21 Selected from H, C 1-6 Alkyl, OH, COOH, CON(R) 5 2. OR 6 Or (L) Where a* represents the connection point with the phenyl group, b* represents the connection point with the triazole group in Formula III, and n1 is selected from an integer 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), and C 1-6 The alkyl group may be optionally substituted with one or more halogens, hydroxyl groups, or cyano groups;

[0092] Each R 5 R 6 Independently selected from H or C 1-6 Alkyl, the C 1-6 The alkyl group may be optionally substituted with one or more halogens, hydroxyl groups, or cyano groups;

[0093] 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 heteroalkylene, 5 to 14-membered heteroarylene, or of formula (L). Where a* represents the connection point with the phenyl group, b* represents the connection point with the triazolyl group in Formula III, and n1 is selected from an integer 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 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 group, C 2-6 Acryloxy group, C 3-6 Cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 Cycloalkenyloxy, phenyl, or 5- to 6-membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyloxy group, C 2-6 Acryloxy group, C 3-6 Cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 The cycloalkenyloxy, phenyl, or 5- to 6-membered heteroaryl group may be optionally substituted by one or more substituents selected from halogen, hydroxyl, oxo, nitro, or cyano groups;

[0094] R 11 R12 Each is independently selected from H or C 1-6 Alkyl, the C 1-6 The alkyl group may be optionally substituted with one or more halogens, hydroxyl groups, or cyano groups;

[0095] Each R 13 Each is independently selected from H and C. 1-6 Alkyl or (L) Where a* represents the connection point with the phenyl group, b* represents the connection point with the triazole group in Formula III, and n1 is selected from an integer 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 C 1- The 6-alkyl group may optionally be substituted with one or more halogens, hydroxyl groups, or cyano groups;

[0096] The condition is that R 21 R 22 R 13 R P1 and R P2 There is one and only one of them that is the formula (L).

[0097] In some implementation schemes, R 22 For formula (L), R P1 R P2 Each is represented by H.

[0098] In some embodiments, group Y is a 5- to 12-membered heteroaryl group, which is 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 group, C 2-6 Acryloxy group, C 3-6 Cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 Cycloalkenyloxy, phenyl, or 5- to 6-membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyloxy group, C 2-6 Acryloxy group, C 3-6 Cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 The cycloalkenyloxy, phenyl, or 5- to 6-membered heteroaryl group may be optionally substituted by one or more substituents selected from halogen, hydroxyl, oxo, nitro, or cyano groups.

[0099] In some embodiments, group Y is a 5- or 6-membered heteroaryl group, which is optionally substituted with one or more of the following groups: halogen, hydroxyl, oxo, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, the C1-6 Alkyl, C 1-6 The alkoxy group may be optionally replaced by one or more substituents selected from halogen, hydroxyl, oxo, nitro, and cyano groups.

[0100] In some embodiments, group Y is pyridyl, which is replaced by one or more methyl groups.

[0101] In some specific implementations, the group Y is selected from...

[0102] In some specific implementations, the group Y is selected from...

[0103] In some embodiments, the group B of the targeting group TL is -NH- or absent.

[0104] In some embodiments, the group B of the targeting group TL is absent.

[0105] In some embodiments, the group A of the targeting group TL is selected from -CH2-, -NH-, -O-, or is absent.

[0106] In some embodiments, the group A of the targeting group TL is -CH2-.

[0107] In some embodiments, the group A of the targeting group TL is -NH-.

[0108] In some embodiments, the group A of the targeting group TL is -O-.

[0109] In some embodiments, group A of the targeting group TL is absent.

[0110] In some specific implementations, the groups Y, B, and A in the targeting group TL are respectively -NH-, -NH-;

[0111] Or, the groups Y, B, and A in the target group TL are respectively -NH-, -O-;

[0112] Or, the groups Y, B, and A in the target group TL are respectively -NH-, -CH2-;

[0113] Or, in the target group TL, groups Y and A are respectively -CH2-, B does not exist;

[0114] Or the target group TL contains group Y. B and A do not exist;

[0115] Or, the groups Y, B, and A in the target group TL are respectively -NH-, -CH2-.

[0116] In some embodiments, the targeting group TL is of formula (III-b):

[0117] Wherein Y is a 5-14 membered heteroaryl group; the heteroaryl group is optionally substituted by one or more of the following groups: halogen, hydroxyl, oxo, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyloxy group, C 2-6 Acryloxy group, C 3-6 Cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 Cycloalkenyloxy, phenyl, or 5- to 6-membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyloxy group, C 2-6 Acryloxy group, C 3-6 Cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 The cycloalkenyloxy, phenyl, or 5- to 6-membered heteroaryl group may be optionally substituted by one or more substituents selected from halogen, hydroxyl, oxo, nitro, or cyano groups;

[0118] B is selected from -CH2-, -NH-, Or it may not exist;

[0119] The group A of the target group TL is selected from -CH2-, -NH-, -O-, or is not present;

[0120] R 21 Selected from H, C 1-6 Alkyl, OH, COOH, CH2CH2CH2NH2, CONHR 5 OR 6 Or (L) Where a* represents the connection point with the phenyl group, b* represents the connection point with the triazole group in formula III, and n1 is selected from an integer 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).

[0121] R 5 R 6 Each is independently selected from H or C 1-6 Alkyl, the C 1-6 The alkyl group may be optionally substituted with one or more halogens, hydroxyl groups, or cyano groups;

[0122] R 22Selected from 3- to 20-membered cycloalkylene, 6- to 14-membered arylene, 3- to 12-membered heterocycloalkylene, 5- to 14-membered heteroarylene, or of formula (L). Where a* represents the connection point with the phenyl group, b* represents the connection point with the triazolyl group in Formula III, and n1 is selected from an integer 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 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 group, C 2-6 Acryloxy group, C 3-6 Cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 Cycloalkenyloxy, phenyl, or 5- to 6-membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyloxy group, C 2-6 Acryloxy group, C 3-6 Cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 The cycloalkenyloxy, phenyl, or 5- to 6-membered heteroaryl group may be optionally substituted by one or more substituents selected from halogen, hydroxyl, oxo, nitro, or cyano groups;

[0123] The condition is that R 21 R 22 There is one and only one expression (L);

[0124] R 11 R 12 R 13 Each is independently selected from H or C 1-6 Alkyl, the C 1-6 The alkyl group may be optionally substituted with one or more halogens, hydroxyl groups, or cyano groups.

[0125] In some embodiments, group Y is a 5- to 12-membered heteroaryl group, which is 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 group, C 2-6 Acryloxy group, C 3-6 Cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 Cycloalkenyloxy, phenyl, or 5- to 6-membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyloxy group, C 2-6 Acryloxy group, C3-6 Cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 The cycloalkenyloxy, phenyl, or 5- to 6-membered heteroaryl group may be optionally substituted by one or more substituents selected from halogen, hydroxyl, oxo, nitro, or cyano groups.

[0126] In some embodiments, group Y is a 5- or 6-membered heteroaryl group, which is optionally substituted with one or more of the following groups: halogen, hydroxyl, oxo, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, the C 1-6 Alkyl, C 1-6 The alkoxy group may be optionally replaced by one or more substituents selected from halogen, hydroxyl, oxo, nitro, and cyano groups.

[0127] In some embodiments, group Y is pyridyl, which is replaced by one or more methyl groups.

[0128] In some embodiments, the group Y is selected from...

[0129] In some specific implementations, the group Y is selected from...

[0130] In some embodiments, the group B of the targeting group TL is -NH- or absent.

[0131] In some embodiments, the group B of the targeting group TL is absent.

[0132] In some embodiments, the group A of the targeting group TL is selected from -CH2-, -NH-, -O-, or is absent.

[0133] In some embodiments, the group A of the targeting group TL is -CH2-.

[0134] In some embodiments, the group A of the targeting group TL is -NH-.

[0135] In some embodiments, the group A of the targeting group TL is -O-.

[0136] In some embodiments, group A of the targeting group TL is absent.

[0137] In some specific implementations, the groups Y, B, and A in the targeting group TL are respectively -NH-, -NH-;

[0138] Or, the groups Y, B, and A in the target group TL are respectively -NH-, -O-;

[0139] Or, the groups Y, B, and A in the target group TL are respectively -NH-, -CH2-;

[0140] Or, in the target group TL, groups Y and A are respectively -CH2-, B does not exist;

[0141] Or the target group TL contains group Y. B and A do not exist;

[0142] Or, the groups Y, B, and A in the target group TL are respectively -NH-, -CH2-.

[0143] In some embodiments, the targeting group TL is of formula (III-c):

[0144] Wherein Y is a 5-14 membered heteroaryl group, and the heteroaryl group is optionally substituted by one or more of the following groups: halogen, hydroxyl, oxo, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyloxy group, C 2-6 Acryloxy group, C 3-6 Cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 Cycloalkenyloxy, phenyl, or 5- to 6-membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyloxy group, C 2-6 Acryloxy group, C 3-6 Cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 The cycloalkenyloxy, phenyl, or 5- to 6-membered heteroaryl group may be optionally substituted by one or more substituents selected from halogen, hydroxyl, oxo, nitro, or cyano groups;

[0145] B is selected from -CH2-, -NH-, Or it may not exist;

[0146] In the target group TL, group A is selected from -CH2-, -NH-, -O-, or is absent;

[0147] R 21 For formula (L) a* represents the connection point with the phenyl group, and b* represents the connection point with the triazole group in formula III; where n1 is selected from integers 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);

[0148] R22 Selected from cycloalkyl, aryl, heteroaryl, or heterocycloalkyl groups having 2-10 carbon atoms, wherein the heteroaryl, cycloalkyl, aryl, or heterocycloalkyl group is 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 group, C 2-6 Acryloxy group, C 3-6 Cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 Cycloalkenyloxy, phenyl, or 5- to 6-membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyloxy group, C 2-6 Acryloxy group, C 3-6 Cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 The cycloalkenyloxy, phenyl, or 5- to 6-membered heteroaryl group may be optionally substituted by one or more substituents selected from halogen, hydroxyl, oxo, nitro, or cyano groups.

[0149] In some embodiments, group Y is a 5- to 12-membered heteroaryl group, which is 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 group, C 2-6 Acryloxy group, C 3-6 Cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 Cycloalkenyloxy, phenyl, or 5- to 6-membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyloxy group, C 2-6 Acryloxy group, C 3-6 Cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 The cycloalkenyloxy, phenyl, or 5- to 6-membered heteroaryl group may be optionally substituted by one or more substituents selected from halogen, hydroxyl, oxo, nitro, or cyano groups.

[0150] In some embodiments, group Y is a 5- or 6-membered heteroaryl group, which is optionally substituted with one or more of the following groups: halogen, hydroxyl, oxo, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, the C 1-6 Alkyl, C 1-6 The alkoxy group may be optionally replaced by one or more substituents selected from halogen, hydroxyl, oxo, nitro, and cyano groups.

[0151] In some embodiments, group Y is pyridyl, which is replaced by one or more methyl groups.

[0152] In some specific implementations, the group Y is selected from...

[0153] In some specific implementations, the group Y is selected from...

[0154] In some embodiments, the group B of the targeting group TL is -NH- or absent.

[0155] In some embodiments, the group B of the targeting group TL is absent.

[0156] In some embodiments, the group A of the targeting group TL is selected from -CH2-, -NH-, -O-, or is absent.

[0157] In some embodiments, the group A of the targeting group TL is -CH2-.

[0158] In some embodiments, the group A of the targeting group TL is -NH-.

[0159] In some embodiments, the group A of the targeting group TL is -O-.

[0160] In some embodiments, group A of the targeting group TL is absent.

[0161] In some specific implementations, the groups Y, B, and A in the targeting group TL are respectively -NH-, -NH-;

[0162] Or, the groups Y, B, and A in the target group TL are respectively -NH-, -O-;

[0163] Or, the groups Y, B, and A in the target group TL are respectively -NH-, -CH2-;

[0164] Or, in the target group TL, groups Y and A are respectively -CH2-, B does not exist;

[0165] Or the target group TL contains group Y. B and A do not exist;

[0166] Or, the groups Y, B, and A in the target group TL are respectively -NH-, -CH2-.

[0167] In some embodiments, the targeting group TL is of formula (II):

[0168] Where R 22 For formula (L) a* represents the connection point with the naphthyl group, and b* represents the connection point with the triazole group in Formula III; where n1 is selected from an integer 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); where Y is a 5-14 member heteroaryl group, which is optionally substituted by one or more of the following groups: halogen, hydroxyl, oxo, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyloxy group, C 2-6 Acryloxy group, C 3-6 Cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 Cycloalkenyloxy, phenyl, or 5- to 6-membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyloxy group, C 2-6 Acryloxy group, C 3-6 Cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 The cycloalkenyloxy, phenyl, or 5- to 6-membered heteroaryl group may be optionally substituted by one or more substituents selected from halogen, hydroxyl, oxo, nitro, or cyano groups;

[0169] B is selected from -CH2-, -NH-, Or it may not exist;

[0170] In the target group TL, group A is selected from -CH2-, -NH-, -O-, or is not present.

[0171] In some embodiments, group Y is a 5- to 12-membered heteroaryl group, which is 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 group, C 2-6 Acryloxy group, C 3-6 Cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 Cycloalkenyloxy, phenyl, or 5- to 6-membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyloxy group, C 2-6 Acryloxy group, C 3-6 Cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8The cycloalkenyloxy, phenyl, or 5- to 6-membered heteroaryl group may be optionally substituted by one or more substituents selected from halogen, hydroxyl, oxo, nitro, or cyano groups.

[0172] In some embodiments, group Y is a 5- or 6-membered heteroaryl group, which is optionally substituted with one or more of the following groups: halogen, hydroxyl, oxo, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, the C 1-6 Alkyl, C 1-6 The alkoxy group may be optionally replaced by one or more substituents selected from halogen, hydroxyl, oxo, nitro, and cyano groups.

[0173] In some embodiments, group Y is pyridyl, which is replaced by one or more methyl groups.

[0174] In some specific implementations, the group Y is selected from...

[0175] In some specific implementations, the group Y is selected from...

[0176] In some embodiments, the group B of the targeting group TL is -NH- or absent.

[0177] In some embodiments, the group B of the targeting group TL is absent.

[0178] In some embodiments, the group A of the targeting group TL is selected from -CH2-, -NH-, -O-, or is absent.

[0179] In some embodiments, the group A of the targeting group TL is -CH2-.

[0180] In some embodiments, the group A of the targeting group TL is -NH-.

[0181] In some embodiments, the group A of the targeting group TL is -O-.

[0182] In some embodiments, group A of the targeting group TL is absent.

[0183] In some specific implementations, the groups Y, B, and A in the targeting group TL are respectively -NH-, -NH-;

[0184] Or, the groups Y, B, and A in the target group TL are respectively -NH-, -O-;

[0185] Or, the groups Y, B, and A in the target group TL are respectively -NH-, -CH2-;

[0186] Or, in the target group TL, groups Y and A are respectively -CH2-, B does not exist;

[0187] Or the target group TL contains group Y. B and A do not exist;

[0188] Or, the groups Y, B, and A in the target group TL are respectively -NH-, -CH2-.

[0189] In some implementations, n1 is selected from integers between 2 and 15.

[0190] In some implementations, n1 is selected from integers from 2 to 10.

[0191] In some implementations, n1 is selected from integers between 2 and 5.

[0192] In some specific implementations, n1 is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20.

[0193] In some embodiments, the targeting group TL is of formula (III-e):

[0194] Wherein Y is a 5-14 membered heteroaryl group, wherein the heteroaryl group is optionally substituted by one or more of the following groups: halogen, hydroxyl, oxo, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyloxy group, C 2-6 Acryloxy group, C 3-6 Cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 Cycloalkenyloxy, phenyl, or 5- to 6-membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyloxy group, C 2-6 Acryloxy group, C 3-6 Cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 The cycloalkenyloxy, phenyl, or 5- to 6-membered heteroaryl group may be optionally substituted by one or more substituents selected from halogen, hydroxyl, oxo, nitro, or cyano groups;

[0195] B is selected from -CH2-, -NH-, Or it may not exist;

[0196] The group A of the target group TL is selected from -CH2-, -NH-, -O-, or is not present.

[0197] In some embodiments, group Y is a 5- to 12-membered heteroaryl group, which is 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 group, C 2-6 Acryloxy group, C 3-6 Cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 Cycloalkenyloxy, phenyl, or 5- to 6-membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyloxy group, C 2-6 Acryloxy group, C 3-6 Cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 The cycloalkenyloxy, phenyl, or 5- to 6-membered heteroaryl group may be optionally substituted by one or more substituents selected from halogen, hydroxyl, oxo, nitro, or cyano groups.

[0198] In some embodiments, group Y is a 5- or 6-membered heteroaryl group, which is optionally substituted with one or more of the following groups: halogen, hydroxyl, oxo, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, the C 1-6 Alkyl, C 1-6 The alkoxy group may be optionally replaced by one or more substituents selected from halogen, hydroxyl, oxo, nitro, and cyano groups.

[0199] In some embodiments, group Y is pyridyl, which is replaced by one or more methyl groups.

[0200] In some specific implementations, the group Y is selected from...

[0201] In some specific implementations, the group Y is selected from...

[0202] In some embodiments, the group B of the targeting group TL is -NH- or absent.

[0203] In some embodiments, the group B of the targeting group TL is absent.

[0204] In some embodiments, the group A of the targeting group TL is selected from -CH2-, -NH-, -O-, or is absent.

[0205] In some embodiments, the group A of the targeting group TL is -CH2-.

[0206] In some embodiments, the group A of the targeting group TL is -NH-.

[0207] In some embodiments, the group A of the targeting group TL is -O-.

[0208] In some embodiments, group A of the targeting group TL is absent.

[0209] In some specific implementations, the groups Y, B, and A in the targeting group TL are respectively -NH-, -NH-;

[0210] Or, the groups Y, B, and A in the target group TL are respectively -NH-, -O-;

[0211] Or, the groups Y, B, and A in the target group TL are respectively -NH-, -CH2-;

[0212] Or, in the target group TL, groups Y and A are respectively -CH2-, B does not exist;

[0213] Or the target group TL contains group Y. B and A do not exist;

[0214] Or, the groups Y, B, and A in the target group TL are respectively -NH-, -CH2-.

[0215] In some embodiments, the targeting group TL is of formula (III-e-1):

[0216] Wherein Y is a 5-14 membered heteroaryl group, wherein the heteroaryl group is optionally substituted by one or more of the following groups: halogen, hydroxyl, oxo, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyloxy group, C 2-6 Acryloxy group, C 3-6 Cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 Cycloalkenyloxy, phenyl, or 5- to 6-membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyloxy group, C 2-6 Acryloxy group, C 3-6 Cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 The cycloalkenyloxy, phenyl, or 5- to 6-membered heteroaryl group may be optionally substituted by one or more substituents selected from halogen, hydroxyl, oxo, nitro, or cyano groups.

[0217] In some embodiments, group Y is a 5- to 12-membered heteroaryl group, which is 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 group, C 2-6 Acryloxy group, C 3-6 Cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 Cycloalkenyloxy, phenyl, or 5- to 6-membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyloxy group, C 2-6 Acryloxy group, C 3-6 Cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 The cycloalkenyloxy, phenyl, or 5- to 6-membered heteroaryl group may be optionally substituted by one or more substituents selected from halogen, hydroxyl, oxo, nitro, or cyano groups.

[0218] In some embodiments, group Y is a 5- or 6-membered heteroaryl group, which is optionally substituted with one or more of the following groups: halogen, hydroxyl, oxo, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, the C 1-6 Alkyl, C 1-6 The alkoxy group may be optionally replaced by one or more substituents selected from halogen, hydroxyl, oxo, nitro, and cyano groups.

[0219] In some embodiments, group Y is pyridyl, which is replaced by one or more methyl groups.

[0220] In some specific implementations, the group Y is selected from...

[0221] In some specific implementations, the group Y is selected from...

[0222] In some embodiments, the targeting group TL is of formula (III-e-2):

[0223] The target group TL has a group A selected from -O- or -CH2-, and Y is a 5-14 membered heteroaryl group, wherein the heteroaryl group is optionally substituted by one or more of the following groups: halogen, hydroxyl, oxo, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyloxy group, C 2-6 Acryloxy group, C 3-6 Cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8Cycloalkenyloxy, phenyl, or 5- to 6-membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyloxy group, C 2-6 Acryloxy group, C 3-6 Cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 The cycloalkenyloxy, phenyl, or 5- to 6-membered heteroaryl group may be optionally substituted by one or more substituents selected from halogen, hydroxyl, oxo, nitro, or cyano groups.

[0224] In some embodiments, group Y is a 5- to 12-membered heteroaryl group, which is 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 group, C 2-6 Acryloxy group, C 3-6 Cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 Cycloalkenyloxy, phenyl, or 5- to 6-membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyloxy group, C 2-6 Acryloxy group, C 3-6 Cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 The cycloalkenyloxy, phenyl, or 5- to 6-membered heteroaryl group may be optionally substituted by one or more substituents selected from halogen, hydroxyl, oxo, nitro, or cyano groups.

[0225] In some embodiments, group Y is a 5- or 6-membered heteroaryl group, which is optionally substituted with one or more of the following groups: halogen, hydroxyl, oxo, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, the C 1-6 Alkyl, C 1-6 The alkoxy group may be optionally replaced by one or more substituents selected from halogen, hydroxyl, oxo, nitro, and cyano groups.

[0226] In some embodiments, group Y is pyridyl, which is replaced by one or more methyl groups.

[0227] In some specific implementations, the group Y is selected from...

[0228] In some specific implementations, the group Y is selected from...

[0229] In some embodiments, the group A of the targeting group TL is -CH2-.

[0230] In some embodiments, the group A of the targeting group TL is -O-.

[0231] In some implementations, the TL is selected from:

[0232] In some embodiments, the targeting ligand is selected from the following structures or their regioisomers, wherein the definition and selection range of TL are the same as described in any of the embodiments in the context:

[0233] In some embodiments, the targeting ligand is selected from structures as shown in formula (I-1), formula (I-2), or formula (I-3) or their regioisomers, wherein the regioisomers of the structures shown in formula (I-1), formula (I-2), or formula (I-3) have structures as shown in formula (I-1A), formula (I-2A), and (I-3A), respectively, wherein the group R n1 R n2 R n3 Choose from any combination shown in Table A below:

[0234] Table A.

[0235] In Table A above, + indicates -express TL indicates the site where the target ligand TL is linked.

[0236] In some embodiments, the one or more targeting groups are linked to any one or more nucleosides of the sense or antisense strand of the RNAi agent; in some embodiments, the one or more targeting groups are linked to the sense strand of the RNAi agent; in some embodiments, the one or more targeting groups are linked to the antisense strand of the RNAi agent.

[0237] In some embodiments, the targeting ligand is linked to the 5' or 3' end of the sense strand. In some embodiments, the targeting ligand is linked to the first nucleotide at the 5' end of the sense strand.

[0238] In some implementations, the targeting ligand is linked to the first nucleotide at the 5' end of the sense strand.

[0239] In some embodiments, the targeting ligand and the sense and / or antisense chains are linked by phosphodiester groups, phosphodiester groups with modifying groups, and / or phosphate groups.

[0240] In some embodiments, the sense strand comprises or is selected from any of the nucleotide sequences shown in SEQ ID NO:183 to SEQ ID NO:273; and / or the antisense strand comprises or is selected from any of the nucleotide sequences shown in SEQ ID NO:274 to SEQ ID NO:364.

[0241] In some embodiments, the RNAi agent is selected from any of the RNAi agents shown in Tables 2A, 2B, 2C, or 2D. In some embodiments, the RNAi agent is selected from TJR104478-11, TJR105958-13, TJR105958-08, TJR101183-11, TJR105961-13, TJR105961-08, TJR101184-1-11, TJR105962-13, TJR105962-08, TJR101181-11, TJR105959-13, TJR105959-08, TJR101104-11, TJR105960- 13. TJR105960-08, TJR104480-11, TJR105963-13, TJR105963-08, TJR104481-11, TJR105964-13, TJR105964-08, TJR101 189-11, TJR101179-1-11, TJR101103-11, TJR101184-11, TJR101179-11, TJR101182-11, TJR104479-11, TJR107178-08.

[0242] In some embodiments, the RNAi agent is selected from TJR105958-13, TJR105958-08, TJR105961-08, TJR105962-08, TJR105959-08, TJR105960-08, TJR105963-08, TJR107178-08, and TJR105964-08.

[0243] On the other hand, this disclosure provides a pharmaceutical composition comprising the RNAi agent described herein and one or more pharmaceutically acceptable excipients, such as vehicles, carriers, diluents, and / or drug delivery systems (e.g., delivery polymers). Various drug delivery systems are known and can be used with the RNAi agent of this disclosure, such as encapsulation in liposomes, microparticles, microcapsules, recombinant cells capable of expressing the RNAi agent, receptor-mediated endocytosis, and constructing nucleic acids as part of retroviruses or other vectors. In some embodiments, the pharmaceutical composition is a liposome encapsulating the RNAi agent of this disclosure, the liposome comprising the RNAi agent described herein and a lipid compound.

[0244] In some embodiments, the pharmaceutical composition may further comprise pharmaceutically acceptable excipients and / or adjuvants, which may be one or more formulations or compounds conventionally used in the art. For example, the pharmaceutically acceptable excipients may include at least one of pH buffers, protectants, and osmotic pressure regulators.

[0245] In some embodiments, the unit dose of the pharmaceutical composition is 0.001 mg to 1000 mg.

[0246] In some embodiments, the pharmaceutical composition contains 0.01-99.99% of the RNAi agent of this disclosure or its pharmaceutically acceptable salt or isotopic substitution, based on the total weight of the composition. In some embodiments, the pharmaceutical composition contains 0.1-99.9% of the RNAi agent of this disclosure or its pharmaceutically acceptable salt or isotopic substitution. In some embodiments, the pharmaceutical composition contains 0.5%-99.5% of the RNAi agent of this disclosure or its pharmaceutically acceptable salt or isotopic substitution. In some embodiments, the pharmaceutical composition contains 1%-99% of the RNAi agent of this disclosure or its pharmaceutically acceptable salt or isotopic substitution. In some embodiments, the pharmaceutical composition contains 2%-98% of the RNAi agent of this disclosure or its pharmaceutically acceptable salt or isotopic substitution.

[0247] In some embodiments, the pharmaceutical composition contains 0.01% to 99.99% pharmaceutically acceptable excipients based on the total weight of the composition. In some embodiments, the pharmaceutical composition contains 0.1% to 99.9% pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition contains 0.5% to 99.5% pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition contains 1% to 99% pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition contains 2% to 98% pharmaceutically acceptable excipients.

[0248] In some embodiments, when the RNAi agent or pharmaceutical composition of this disclosure comes into contact with cells expressing a target gene, it is determined by, for example, psiCHECK activity screening and luciferase reporter gene assay, other methods such as PCR or branched DNA (bDNA) based methods, or protein-based methods such as immunofluorescence assays, such as Western blotting or flow cytometry, that the RNAi agent or pharmaceutical composition of this disclosure inhibits the expression of the target gene by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%.

[0249] In some embodiments, when the RNAi agent or pharmaceutical composition of this disclosure comes into contact with cells expressing the target gene, the percentage of residual expression of the target gene mRNA induced by the RNAi agent or pharmaceutical composition of this disclosure is determined by, for example, psiCHECK activity screening and luciferase reporter gene assay, other methods such as PCR or branched DNA (bDNA) based methods, or protein-based methods such as immunofluorescence analysis, such as Western blotting or flow cytometry, to be 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%.

[0250] In some embodiments, when the RNAi agent or pharmaceutical composition described herein comes into contact with cells expressing a target gene, as determined by, for example, psiCHECK activity screening and luciferase reporter gene assay, other methods such as PCR or branched DNA (bDNA) based methods, or protein-based methods such as immunofluorescence assays, such as Western blotting, or flow cytometry, the RNAi agent reduces off-target activity by at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, or at least 75% while maintaining target activity.

[0251] In some embodiments, when the RNAi agent or pharmaceutical composition described herein comes into contact with cells expressing a target gene, the RNAi agent, as determined by, for example, psiCHECK activity screening and luciferase reporter gene assay, other methods such as PCR or branched DNA (bDNA) based methods, or protein-based methods such as immunofluorescence assays, such as Western blotting, or flow cytometry, reduces off-target activity by at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, or at least 75% while reducing target activity by at least 20%, at least 19%, at least 15%, at most 10%, at most 5%, or more than 1%.

[0252] In some embodiments, when the RNAi agent or pharmaceutical composition described herein comes into contact with cells expressing a target gene, the RNAi agent, as determined by, for example, psiCHECK activity screening and luciferase reporter gene assay, other methods such as PCR or branched DNA (bDNA) based methods, or protein-based methods such as immunofluorescence assays, such as Western blotting, or flow cytometry, reduces off-target activity by at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, or at least 80%, while increasing target activity by at least 1%, at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, or at least 75%.

[0253] On the other hand, this disclosure provides a cell containing the RNAi agent of this disclosure. This cell cannot develop into a complete plant or animal.

[0254] On the other hand, this disclosure provides a kit containing the RNAi agent or pharmaceutical composition of the present disclosure.

[0255] On the other hand, this disclosure also provides the use of the RNAi agent, pharmaceutical composition, and kit disclosed herein as a medicine.

[0256] On the other hand, this disclosure also provides a method for reducing MMP7 gene expression, the method comprising administering to a subject the RNAi agent, pharmaceutical composition, or kit of this disclosure.

[0257] On the other hand, this disclosure provides a method for treating and / or preventing a disease in a subject, comprising administering the subject the RNAi agent or pharmaceutical composition of this disclosure. In some embodiments, the disease is a disease associated with MMP7 gene expression.

[0258] On the other hand, this disclosure provides the use of the RNAi agents and / or pharmaceutical compositions of this disclosure in the preparation of medicaments for treating and / or preventing diseases.

[0259] In some embodiments, the disease is a disease associated with MMP7 gene expression. In some embodiments, the disease is selected from idiopathic pulmonary fibrosis (IPF), asthma, other types of fibrosis, chronic inflammation, interstitial lung disease (ILD), SARS-CoV-2 or other types of infectious diseases, acute respiratory distress syndrome (ARDS) or other types of acute lung injury, pulmonary hypertension, cancer, renal fibrosis, and liver fibrosis.

[0260] On the other hand, this disclosure provides the use of the RNAi agents, pharmaceutical compositions, and kits described herein in the preparation of medicaments for inhibiting MMP7 gene expression.

[0261] On the other hand, this disclosure provides a method for in vivo delivery of an RNAi agent that inhibits MMP7 gene expression and / or replication to the lungs, including administering the RNAi agent of this disclosure, a pharmaceutical composition, or a kit to a subject.

[0262] On the other hand, this disclosure provides a method for preparing an RNAi agent or pharmaceutical composition, the method comprising synthesizing the RNAi agent or pharmaceutical composition disclosed herein.

[0263] The RNAi agents or pharmaceutical compositions and methods disclosed herein can reduce the level of target mRNA in cells, cell populations, tissues, or subjects, including administering a therapeutically effective amount of the RNAi agent or pharmaceutical composition described herein to a subject, thereby inhibiting the expression of target mRNA in the subject.

[0264] In some embodiments, the subject has been identified as having pathological upregulation of the target gene in the targeted cells or tissues prior to administration of the RNAi agent and / or pharmaceutical composition disclosed herein.

[0265] The subjects mentioned in this disclosure refer to subjects who are diagnosed with (or suspected of having, or are susceptible to) a disease or condition that would benefit from a reduction or inhibition of target mRNA expression.

[0266] The RNAi agents and / or pharmaceutical compositions disclosed herein can be administered via local (e.g., direct injection, implantation, or topical administration) or systemic administration. This includes administration via subcutaneous, intravenous, intraperitoneal, or parenteral routes, such as intracranial (e.g., intraventricular, intraparenchymal, and intrasheathal), intramuscular, transdermal, airway (aerosol), nasal, oral, rectal, buccal, and sublingual administration, or any suitable route of administration commonly found in the art. Alternatively, the pharmaceutical compositions provided herein can be administered by injection, for example, intravenous, intramuscular, intradermal, subcutaneous, duodenal, or intraperitoneal injection.

[0267] This disclosure also provides a method for silencing mRNA of a target gene in cells, the method comprising the step of introducing the RNAi agent of this disclosure or a pharmaceutical composition into the cell.

[0268] This disclosure also provides a method for silencing a target gene or its mRNA in cells in vivo or in vitro, the method comprising the step of introducing an RNAi agent or pharmaceutical composition according to this disclosure into the cell.

[0269] This disclosure also provides a method for inhibiting the expression of a target gene or its mRNA, the method comprising administering the RNAi agent, pharmaceutical composition, or kit of the disclosure to a subject in need.

[0270] In some implementations, the target gene is the MMP7 gene, and the target mRNA is the mRNA expressed by the target gene.

[0271] The pharmaceutically acceptable salts of the compounds described in this disclosure are selected from inorganic or organic salts, and the compounds described in this disclosure can react with acidic or basic substances to form the corresponding salts. The compounds described in this disclosure include the RNAi agents of this disclosure. Unless otherwise specified, "RNAi agent" in this disclosure should be understood to encompass the scope of its pharmaceutically acceptable salts. In some embodiments, the compounds of this disclosure are present in the form of sodium salts. In some embodiments, one or more phosphodiester groups or phosphodiester groups with modifying groups in the antisense oligonucleotides of this disclosure form sodium phosphodiester salts. In some specific embodiments, all phosphodiester groups or phosphodiester groups with modifying groups in the antisense oligonucleotides of this disclosure form sodium phosphodiester salts.

[0272] In some embodiments, one or more phosphodiester groups or phosphodiester groups with modifying groups in the RNAi agent of this disclosure form a sodium phosphodiester salt. In some specific embodiments, all phosphodiester groups or phosphodiester groups with modifying groups in the RNAi agent of this disclosure form a sodium phosphodiester salt.

[0273] On the other hand, without specifying the configuration, the compounds described in this disclosure may exist in specific geometric or stereoisomeric forms. This disclosure envisions all such compounds, including cis and trans isomers, (-)- and (+)- enantiomers, (R)- and (S)- enantiomers, diastereomers, (D)- isomers, (L)- isomers, and racemic mixtures thereof, as well as other mixtures, such as mixtures enriched with enantiomers or diastereomers, all of which are within the scope of this disclosure. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are included within the scope of this disclosure.

[0274] Furthermore, without specifying the configuration, the compounds and intermediates of this disclosure may also exist in different tautomer forms, and all such forms are included within the scope of this disclosure. The terms "tautomer" or "tautomer form" refer to structural isomers with different energies that can interconvert via low energy barriers.

[0275] The term "regiosomer" as used in this disclosure refers to a regiosomer of the chemical structure of this disclosure. Unless otherwise specified, "regiosomer" as used in this disclosure includes both a single regiosomer and a mixture of two or more regiosomers. For example, the scope of "the targeting ligand is selected from the structure shown in Formula (I-1) or a regiosomer thereof" includes the case where the targeting ligand is selected from the structure shown in Formula (I-1), the targeting ligand is selected from a single regiosomer of Formula (I-1), the targeting ligand is a mixture of the structure shown in Formula (I-1) and one or more of its regiosomers, and the targeting ligand is a mixture of two or more regiosomers of the structure shown in Formula (I). Similar expressions in the context of this disclosure should be understood in the same way. The regiosomer of the targeting ligand in this disclosure may be an azide compound regiosomer generated by a click chemical reaction. Specifically, it may be a regiosomer containing...

[0276] The regioisomers, where TL represents the connection site with the target group.

[0277] The compounds disclosed herein may be asymmetric, for example, having one or more stereoisomers. Unless otherwise stated, all stereoisomers include, for example, enantiomers and diastereomers. The compounds containing asymmetric carbon atoms of this disclosure can be isolated in optically active pure form or in racemic form. The optically active pure form can be resolved from racemic mixtures or synthesized using chiral starting materials or chiral reagents.

[0278] Optically active (R)- and (S)- isomers, as well as D- and L- isomers, can be prepared by chiral synthesis, chiral reagents, or other conventional techniques. To obtain an enantiomer of a compound disclosed herein, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide the desired enantiomer in pure form. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), a salt of the diastereomeric isomer is formed with a suitable optically active acid or base, followed by diastereomeric resolution using conventional methods known in the art, and then the pure enantiomer is recovered. Furthermore, the separation of enantiomers and diastereomeric isomers is typically accomplished by using chromatography employing a chiral stationary phase and optionally combined with chemical derivatization (e.g., from amines to carbamates).

[0279] This disclosure also includes compounds identical to those described herein, but in which one or more atoms are labeled with isotopes whose atomic weights or mass numbers differ from those commonly found in nature. Examples of isotopes that can be incorporated into compounds of this disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as... 2 H, 3 H, 11 C 13 C 14 C 13 N、 15 N、 15 O、 17 O、 18 O、 31 P, 32 P, 35 S, 18 F, 123 I, 125 I and 36 Cl, etc.

[0280] Without specifying the configuration, in the chemical structure of this disclosure, the bonds are... This indicates that the configuration is not specified; that is, if chiral isomers exist in the chemical structure, the bond... It can be Or simultaneously include Two configurations. Although all structural formulas described herein are represented in certain isomer forms for simplicity, this disclosure can include all isomers, such as tautomers, rotatimers, geometric isomers, diastereomers, racemates, and enantiomers. In the chemical structure of the compounds described herein, bonds... No configuration was specified, i.e., key The configuration can be E-type or Z-type, or it can contain both E-type and Z-type configurations.

[0281] This publication incorporates the full text of WO2019089765A1, WO2025067423A, and WO2024255759A.

[0282] Terminology Explanation

[0283] To facilitate understanding of this disclosure, some technical and scientific terms are specifically defined below. Unless otherwise expressly defined herein, all other technical and scientific terms used herein have the meanings commonly understood by one of ordinary skill in the art to which this disclosure pertains.

[0284] As used herein, “RNAi agent” refers to an RNA or RNA-like (e.g., chemically modified RNA) oligonucleotide molecule capable of degrading, inactivating, or inhibiting (e.g., under appropriate conditions, degrading, inactivating, or inhibiting) the translation of a messenger RNA (mRNA) transcript of a target mRNA in a sequence-specific manner. RNAi agents used herein may act via RNA interference mechanisms (i.e., by interacting with RNA interference pathway mechanisms in mammalian cells, such as RNA-induced silencing complexes or RISC) or through any alternative mechanism or pathway. Although the term RNAi agent as used herein is considered to act primarily through RNA interference mechanisms, the disclosed RNAi agents are not bound to or limited by any particular pathway or mechanism of action. The disclosed RNAi agents comprise, or consist of, a sense strand and an antisense strand, or are composed of a sense strand and an antisense strand; for example, the RNAi agents disclosed herein may be presented in the form of short (or small) interfering RNA (siRNA). The antisense strand of the RNAi agent described herein is at least partially complementary to the targeted mRNA. RNAi agents may contain one or more modified nucleotides and / or one or more phosphodiester groups having modifying groups.

[0285] Unless otherwise specified, the terms "matrix metalloproteinase 7" and "MMP7" are used interchangeably in the context of this disclosure. MMP7 includes, but is not limited to, human MMP7, cynomolgus monkey MMP7, mouse MMP7, and rat MMP7, whose amino acid and complete coding sequences and mRNA sequences are readily available from publicly available databases, such as GenBank, UniProt, OMIM, and the Macaca Genome Project website.

[0286] The term "MMP7" also refers to naturally occurring DNA sequence variations in the MMP7 gene, such as single nucleotide polymorphisms (SNPs) in the MMP7 gene. Exemplary SNPs can be found in the dbSNP database.

[0287] The term "target sequence" refers to a continuous portion of the nucleotide sequence of the mRNA molecule formed during MMP7 transcription, including the mRNA of the RNA processing product, which is the primary transcription product. In one embodiment, the target sequence is located within the protein-coding region of MMP7.

[0288] As used in this article, in the case of RNA-mediated gene silencing, the sense strand (also known as SS, SS chain, or sense strand) is a strand that contains a sequence that is identical or substantially identical to the target mRNA sequence; the antisense strand (also known as AS, AS chain) is a strand that has a sequence that is complementary to the target mRNA sequence.

[0289] In the context of describing the sense strand of the RNAi agent described herein, the term "the sense strand comprises at least 15 consecutive nucleotides differing from the nucleotide sequences shown in any of SEQ ID NO:1 to SEQ ID NO:14 by no more than 3 nucleotides" is intended to mean that the sense strand of the RNAi agent described herein comprises at least 15 consecutive nucleotides as in any of the sense strands shown in SEQ ID NO:1 to SEQ ID NO:14, or differs from at least 15 consecutive nucleotides of any of the sense strands shown in SEQ ID NO:1 to SEQ ID NO:14 by no more than 3 nucleotides (optionally, by no more than 2 nucleotides; alternatively, by 1 nucleotide). Other similar descriptions in the context of this disclosure should also be understood similarly, and "difference" as used herein does not include nucleotides containing different modifications; that is, nucleotides containing the same bases but different modifications are not considered differing nucleotides as described herein. Other similar descriptions of the sense strand and / or antisense strand in the context of this disclosure should also be understood similarly.

[0290] Unless otherwise specified, in the context of this disclosure, "G", "C", "A", "T" and "U" represent nucleotides, which respectively contain the bases of guanine, cytosine, adenine, thymine, and uracil. It is well known to those skilled in the art that the substitution of bases T and U will not significantly affect the properties of the RNAi agent sequence. U in the sequence of this disclosure can be arbitrarily replaced with T, and the resulting sequence is also within the scope of protection of this disclosure. In the sequence of this disclosure, for the same nucleic acid chain, the direction from the 5' end to the 3' end is considered left to right. 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, or the nucleoside and the target ligand, are linked by a phosphothioester group. Unless otherwise specified, the two nucleosides or the nucleoside and the target ligand are linked by a phosphoester group; VP indicates that the two nucleosides adjacent to the letter s are... The 5' end of each nucleoside is a 5'-vinylphosphodiester group, which can be cis or trans, i.e., a 5'-E-VP isomer (i.e., trans-vinylphosphodiester group), a 5'-Z-VP isomer (i.e., cis-vinylphosphodiester group), or a mixture thereof. IB represents the reverse unmodified nucleoside. I-1-, I-2-, and I-3- represent the chemical structures and targeting ligands or their regioisomers shown in NA0159, formula (I-1), formula (I-2), and formula (I-3) in Table 1 below, respectively. Unless otherwise specified, the terms "RNAi agent," "nucleotide," "compound," "chemical modification," "oligonucleotide," "double-stranded RNAi inhibitor molecule," "siRNA," "dsRNA," "nucleic acid," and "RNAi" in this disclosure can exist independently in the form of a salt, a mixed salt, or a non-salt (e.g., a free acid or a free base). When present in the form of a salt or a mixed salt, it can be a pharmaceutically acceptable salt. The term "pharmaceutical-grade salt" includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts. When present in salt form, some groups may ionize to form anions / cations; for example, phosphodiester groups and thiophosphonate diester groups may exist in anionic form. Unless otherwise stated, the salt forms of the following structures are also within the scope of this disclosure. Unless otherwise specified, the 3' position of the first nucleotide at the 3' end of each chain is a hydroxyl group; the 5' position of the first nucleotide at the 5' end of each chain is a hydroxyl group.

[0291] The above-mentioned modifications and linking groups have the structures shown in Table 1 below, where Base represents the base at the corresponding position:

[0292] Table 1

[0293] As used herein, the terms “complementary” or “reverse complementary” are used interchangeably and have the meaning known to those skilled in the art: in a double-stranded nucleic acid molecule, the bases of one strand are paired in a complementary manner with the bases of the other strand. In DNA, the purine base adenine always pairs with the pyrimidine base thymine (or uracil in RNA); the purine base guanine always pairs with the pyrimidine base cytosine. Each base pair consists of one purine and one pyrimidine. When adenine on one strand always pairs with thymine (or uracil) on the other strand, and guanine always pairs with cytosine, the two strands are considered complementary, and the sequence of the complementary strand can be inferred from its sequence. Correspondingly, “mismatch” in the art means, in the case of a double-stranded nucleic acid, that the bases at corresponding positions are not paired in a complementary manner.

[0294] As used herein, the term “inhibition” may be used interchangeably with “reduction,” “silencing,” “downregulation,” “blocking,” and other similar terms, and includes any level of inhibition. Inhibition can be assessed by a reduction in one or more of these variables at an absolute or relative level compared to a control level. This control level can be any type of control level used in the art, such as a baseline level before administration or a level determined from a subject, cell, or sample that has been treated untreated or with a control (e.g., a buffer-only control or an inert control). For example, the degree of inhibition of target gene expression by an RNAi agent can be characterized by residual mRNA expression levels such as not exceeding 99%, not exceeding 95%, not exceeding 90%, not exceeding 85%, not exceeding 80%, not exceeding 75%, not exceeding 70%, not exceeding 65%, not exceeding 60%, not exceeding 55%, not exceeding 50%, not exceeding 45%, not exceeding 40%, not exceeding 35%, not exceeding 30%, not exceeding 25%, not exceeding 20%, not exceeding 15%, or not exceeding 10%. The inhibition rate of target gene expression can be measured using... The Luciferase Assay System was used to detect the chemiluminescence values ​​of fireflies (Fir) and sea urchins (Ren), and the relative value Ratio = Ren / Fir was calculated. In this disclosure, the proportion of remaining mRNA expression (or remaining activity %) = Ratio (RNAi agent treatment group) / Ratio (no RNAi agent control group), and the inhibition rate (%) = 100% - remaining mRNA expression (%).

[0295] Unless otherwise specified, the terms "compound," "ligand," "nucleic acid ligand conjugate," "nucleic acid," "conjugate," "chemical modification," "targeting ligand," "dsRNA," "siRNA," and "RNAi agent" in this disclosure can exist independently as a salt, a mixture of salts, or a non-salt (e.g., a free acid or a free base). When present as a salt or a mixture of salts, it is a pharmaceutically acceptable salt. In the context of this disclosure, the scope of "compound" includes the RNAi agents of this disclosure.

[0296] The term "medicinal salt" includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[0297] "Pharmaceutically acceptable acid addition salts" refer to salts formed with inorganic or organic acids that retain the bioavailability of the free base without other side effects. Inorganic acid salts include, but are not limited to, hydrochlorides, hydrobroms, sulfates, nitrates, and phosphates; organic acid salts include, but are not limited to, formates, acetates, 2,2-dichloroacetate, trifluoroacetate, propionates, hexanoates, octanoates, decanoates, undecenoates, glycolates, gluconates, lactates, sebates, adipates, glutarate, malonates, oxalates, maleates, succinates, fumarates, tartrates, citrates, palmitates, stearates, oleates, cinnamates, laurates, malates, glutamates, pyroglutamates, aspartate, benzoates, methanesulfonates, benzenesulfonates, p-toluenesulfonates, alginates, ascorbic acid salts, salicylates, 4-aminosalicylic acid salts, and naphthalene disulfonates. These salts can be prepared by methods known in the art.

[0298] "Pharmaceutically acceptable base addition salts" refer to salts formed with inorganic or organic bases that retain the bioavailability of the free acid without other side effects. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum salts. In some implementations, the inorganic salts are ammonium, sodium, potassium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, the following: primary amines, secondary amines, and tertiary amines; substituted amines, including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, triethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, choline, betaine, ethylenediamine, glucosamine, methylglucosamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resins, etc. Some embodiments include organic bases such as isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine. These salts can be prepared by methods known in the art.

[0299] "Effective amount" or "effective dose" means the amount of a drug, compound, or pharmaceutical composition necessary to achieve any one or more beneficial or desired therapeutic outcome. For preventative use, beneficial or desired outcomes include eliminating or reducing risk, mitigating severity, or delaying the onset of a condition, including the condition itself, its complications, and the biochemical, histological, and / or behavioral symptoms of intermediate pathological phenotypes present during the development of the condition. For therapeutic use, beneficial or desired outcomes include clinical outcomes such as reducing the incidence of various disease-related conditions associated with the target genes, target mRNAs, or target proteins of this disclosure, or improving one or more symptoms of said conditions, reducing the dosage of other agents required to treat the condition, enhancing the efficacy of another agent, and / or delaying the progression of a patient's disease-related condition associated with the target genes, target mRNAs, or target proteins of this disclosure.

[0300] As used herein, the terms "patient," "subject," or "individual" are used interchangeably and include human or non-human animals, such as mammals, such as humans or monkeys. In some specific implementations, "subject" may even include test cells, test models, or tissues, depending on the context.

[0301] The RNAi agents provided in this disclosure can be obtained using conventional preparation methods in the art (e.g., solid-phase synthesis and liquid-phase synthesis). Solid-phase synthesis is already available as a commercially available custom service. Modified nucleotide groups can be introduced into the RNAi agents described in this disclosure using appropriately modified nucleoside monomers. Methods for preparing appropriately modified nucleoside monomers and for introducing modified nucleotide groups into RNAi agents are also well known to those skilled in the art.

[0302] The term “chemical modification” or “modification” includes all alterations to nucleotides by chemical means, such as the addition or removal of a chemical moiety, or the substitution of one chemical moiety for another.

[0303] The term "base" includes any known DNA and RNA base, base analogues such as purines or pyrimidines, and also includes natural compounds such as adenine, thymine, guanine, cytosine, uracil, hypoxanthoside, and natural analogues.

[0304] The terms "blunt-ended" or "knuckle-ended" are used interchangeably and refer to the absence of unpaired nucleotides or nucleotide analogues at a given end of an RNAi agent; that is, no nucleotide protrusions. In most cases, RNAi agents with blunt ends will be double-stranded throughout their entire length.

[0305] The terms “about” and “approximately” mean that a numerical value is within an acceptable margin of error for a specific value as determined by a person skilled in the art, the numerical value depending in part on how it is measured or measured (i.e., the limits of the measurement system). For example, “about” may mean within or above 1 standard deviation. Alternatively, “about” or “substantially includes” may mean a range of up to 20%, such as between 1% and 15%, between 1% and 10%, between 1% and 5%, between 0.5% and 5%, or between 0.5% and 1%. In this disclosure, each instance of a number or range of values ​​preceded by the term “about” also includes embodiments of a given number. Unless otherwise stated, when a specific value appears in this application and claims, the meaning of “about” or “substantially includes” should be assumed to be within an acceptable margin of error for that specific value.

[0306] Unless otherwise stated, "optionally," "optionally," "optional," or "optional" means that the event or situation described below may but does not have to occur, and this description includes the possibility that the event or situation may or may not occur. For example, "optionally, R1 and R2 are directly connected to form a loop" means that R1 and R2 being directly connected to form a loop may occur but is not required to exist, and this description includes both the case where R1 and R2 are directly connected to form a loop and the case where R1 and R2 are not connected to form a loop.

[0307] In the chemical structural formula disclosed herein, It can be connected with one or more groups according to the scope of the invention described herein.

[0308] The term "connection" refers to the link between two molecules, either through a covalent bond or through a non-covalent bond (e.g., hydrogen bond or ionic bond), including direct and indirect connections.

[0309] The term "direct link" refers to the connection between a first compound or group and a second compound or group without any intercalating atoms or atomic groups.

[0310] The term "indirect link" refers to the connection between a first compound or group and a second compound or group through an intermediate group, compound, or molecule (e.g., a linking group).

[0311] The term "substituted" means that any one or more hydrogen atoms on a specified atom (typically carbon, oxygen, or nitrogen atoms) are replaced by any group defined herein, provided that the substitution does not exceed the normal valence of the specified atom and yields a stable compound. Non-limiting examples of substituents include C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, cyano, hydroxyl, oxo, carboxyl, cycloalkyl, cycloalkenyl, heterocyclic, heteroaryl, aryl, ketone, alkoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, or halogens (e.g., F, Cl, Br, I). When the substituent is a ketone or oxo (i.e., =O), two (2) hydrogen atoms on the atom are substituted.

[0312] "Being replaced by one or more..." means that it can be replaced by a single or multiple substituents. When replaced by multiple substituents, it can be a plurality of identical substituents or a combination of one or a plurality of different substituents. Detailed Implementation

[0313] The present disclosure is further described below with reference to embodiments, but these embodiments are not intended to limit the scope of the disclosure. Experimental methods in the embodiments of this disclosure that do not specify specific conditions are generally performed under conventional conditions or as recommended by the raw material or product manufacturer. Reagents whose source is not specified can be obtained from any supplier of molecular biology reagents at the quality / purity required for molecular biology applications.

[0314] Example 1. Synthesis of the RNAi agent disclosed herein

[0315] The synthesis of the RNAi agent disclosed herein is no different from the conventional solid-phase synthesis of phosphorus amides. The synthesis process is briefly described below: Using a Dr. Oligo48 synthesizer (Biolytic), starting with a universal CPG carrier, unmodified nucleoside phosphorus amide monomers or nucleoside phosphorus amide monomers modified at corresponding positions in the sequence are sequentially linked according to the synthesis program. The nucleoside phosphorus amide monomers used in the embodiments of this disclosure were purchased from Shanghai Zhaowei Co., Ltd. and Suzhou Jima Co., Ltd. 5-Ethylthio-1H-tetrazole (ETT) was used as the activator (0.6M acetonitrile solution), 0.22M PADS dissolved in a 1:1 volume ratio of acetonitrile and 3-methylpyridine (Shanghai Lingjiang) solution was used as the sulfiding agent, and iodopyridine / aqueous solution (Shanghai Lingjiang) was used as the oxidizing agent.

[0316] 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 concentration and evaporation to dryness, purification was performed using C18 reverse-phase chromatography with 0.1M TEAA and acetonitrile as the mobile phase. The target oligonucleotides were collected, lyophilized, and identified as the target product by LC-MS, followed by quantification using UV (260 nm). The obtained single-stranded oligonucleotides were annealed according to complementary pairing in equimolar ratios. The resulting double-stranded RNAi agent was dissolved in 1×PBS and adjusted to the required concentration for experimental use.

[0317] RNAi agents containing NA0159, formula (I-1), (I-2) or (I-3) can be prepared according to the method disclosed in WO2025067423A.

[0318] The sequences of the RNAi agents disclosed herein are shown in Tables 2A, 2B, 2C and 2D below.

[0319] Table 2A. RNAi agents disclosed herein

[0320] Table 2B. RNAi agents disclosed herein

[0321] Table 2C. RNAi agents disclosed herein

[0322] Table 2D. RNAi agents disclosed herein

[0323] In Tables 2A to 2D above, the direction from the 5' end to the 3' end is considered as the left-to-right direction. G, C, A, and U represent nucleosides containing the bases of guanine, cytosine, adenine, and uracil, respectively. The lowercase letter m indicates that the nucleoside adjacent to the left of the letter m is 2'-methoxy modified; the lowercase letter f indicates that the nucleoside adjacent to the left of the letter f is 2'-fluorinated modified; the lowercase letter s indicates that the two nucleosides adjacent to the letter s or the adjacent target ligand or chemical structure are connected by a thiophosphate diester group. Unless otherwise specified, the two nucleosides or the nucleoside and the adjacent target ligand or chemical structure are connected by a phosphate diester group; VP indicates that the 5' end of the nucleoside adjacent to the left / right of the letter is 5'-trans-vinylphosphate diester group; IB indicates the reverse unmodified nucleoside; NA0159, I-1-, I-2- and I-3- respectively represent NA0159, the chemical structure shown in formula (I-1), formula (I-2) and formula (I-3) in Table 1 above, and the target ligand or its regioisomer. Unless otherwise specified, the 3' position of the first nucleotide at the 3' end of each strand is a hydroxyl group; the 5' position of the first nucleotide at the 5' end of each strand is a hydroxyl group.

[0324] The aforementioned modifications and linking groups have structures as shown in Table 1, where Base represents the base at the corresponding position. When the RNAi agent of this disclosure exists in salt form, such as in sodium salt form, the salt form structure corresponding to the structure in the table is also within the protection scope of this disclosure.

[0325] Example 2. RNAi agent psiCHECK 9 concentration points on target activity

[0326] The RNAi agent disclosed herein was screened for in vitro molecular-level target activity simulation using nine concentration gradients in HEK293A cells (purchased from Kebai Biotechnology).

[0327] HEK293A cells were cultured in DMEM high-glucose medium containing 10% fetal bovine serum at 37°C and 5% CO2. 24 hours before transfection, HEK293A cells were seeded into 96-well plates at a density of 1 × 10⁶ cells per well. 4 100 μL of culture medium per well for each cell.

[0328] Following the instructions, cells were co-transfected with the RNAi agent and corresponding plasmid using Lipofectamine 2000 (ThermoFisher, 11668019), with 0.3 μL of Lipofectamine 2000 per well. The plasmid transfection volume was 20 ng per well. Nine concentration points were set for the RNAi agent for the target sequence plasmid, with the highest concentration being 20 nM. Three-fold serial dilutions were used: 20.0000 nM, 6.6667 nM, 2.2222 nM, 0.7407 nM, 0.2469 nM, 0.0823 nM, 0.0274 nM, 0.0091 nM, and 0.0030 nM. Target levels were detected 24 h post-transfection using the Dual-Luciferase Reporter Assay System (Promega, E2940).

[0329] The results are shown in Table 2E. The results in Table 2E indicate that the RNAi agents disclosed herein all exhibited good MMP7 mRNA target activity in the in vitro psiCHECK system.

[0330] Table 2E. RNAi agents in the psiCHECK system IC 50 Activity results

[0331] Example 3. RNAi agent psiCHECK 9 concentration points on target activity

[0332] The RNAi agent disclosed herein was screened for in vitro molecular-level target activity at nine concentration gradients in HEK293A cells.

[0333] HEK293A cells were cultured in DMEM high-glucose medium containing 10% fetal bovine serum at 37°C and 5% CO2. 24 hours before transfection, HEK293A cells were seeded into 96-well plates at a density of 1 × 10⁶ cells per well. 4 100 μL of culture medium per well for each cell.

[0334] Following the instructions, Lipofectamine 2000 (ThermoFisher, 11668019) was used to co-transfect cells with the RNAi agent and corresponding plasmid, with 0.3 μL of Lipofectamine 2000 per well. The plasmid transfection volume was 20 ng per well. For the target sequence plasmid, nine concentration points were set, with the highest concentration point being 20 nM. Three-fold serial dilutions were used: 20.0000 nM, 6.6667 nM, 2.2222 nM, 0.7407 nM, 0.2469 nM, 0.0823 nM, 0.0274 nM, 0.0091 nM, and 0.0030 nM. Target levels were detected 24 h post-transfection using the Dual-Luciferase Reporter Assay System (Promega, E2940). The results are shown in Table 3. The RNAi agent disclosed herein exhibited good target activity of MMP7 mRNA in the psiCHECK system.

[0335] Table 3. Target activity of RNAi agents at 9 concentration points (psiCHECK)

[0336] Example 4. Target activity of RNAi agents at 7 concentration points in endogenous cells

[0337] In vitro molecular-level activity screening of RNAi agents was performed in HCC38 cells (purchased from Kebai Biotechnology) using seven concentration gradients.

[0338] HCC38 cells were cultured in 1640 medium containing 10% fetal bovine serum at 37°C and 5% CO2. 24 hours before transfection, HCC38 cells were seeded into 96-well plates at a density of 1.5 × 10⁶ cells per well. 4 100 μL of culture medium per well for each cell.

[0339] Following the instructions, Lipofectamine RNAi Max (Invitrogen, 13778-150) was used to transfect cells with the RNAi agent, with 0.3 μL of Lipofectamine RNAi Max used per well. Seven concentrations of the RNAi agent were set: 20.0000 nM, 4.0000 nM, 0.8000 nM, 0.1600 nM, 0.0320 nM, 0.0064 nM, and 0.0013 nM. 24 h post-transfection, RNA was extracted and Q-PCR was performed to detect RNAi agent activity. The results are shown in Table 4. The RNAi agent disclosed in this study exhibited good target activity against MMP7 mRNA in HCC38 cells.

[0340] Table 4. IC50 of RNAi agents at the HCC38 cell level 50 Activity results

[0341] Example 5. RNAi agent psiCHECK 9 concentration points on target activity

[0342] The RNAi agent disclosed herein was screened for in vitro molecular-level target activity at nine concentration gradients in HEK293A cells.

[0343] HEK293A cells were cultured in DMEM high-glucose medium containing 10% fetal bovine serum at 37°C and 5% CO2. 24 hours before transfection, HEK293A cells were seeded into 96-well plates at a density of 1 × 10⁶ cells per well. 4 100 μL of culture medium per well for each cell.

[0344] Following the instructions, Lipofectamine 2000 (ThermoFisher, 11668019) was used to co-transfect cells with the RNAi agent and corresponding plasmid, with 0.3 μL of Lipofectamine 2000 per well. The plasmid transfection volume was 20 ng per well. For the target sequence plasmid, nine concentration points were set, with the highest concentration point being 20 nM. Three-fold serial dilutions were used: 20.0000 nM, 5 nM, 1.25 nM, 0.3125 nM, 0.078125 nM, 0.019531 nM, 0.004883 nM, 0.001221 nM, and 0.000305 nM. Target levels were detected 24 h post-transfection using the Dual-Luciferase Reporter Assay System (Promega, E2940). The results are shown in Table 5; NA indicates no detection. As shown in Table 5, the RNAi agents disclosed herein all exhibited good MMP7 mRNA target activity in the psiCHECK system.

[0345] Table 5A. Target activity at 9 concentration points using the psiCHECK system for RNAi agents

[0346] Table 5B. Target activity of RNAi agents at 9 concentration points using the psiCHECK system

[0347] Table 5C. Target activity of RNAi agents at 9 concentration points using the psiCHECK system.

[0348] Example 6. Target activity of RNAi agents at 7 concentration points in endogenous cells

[0349] In vitro molecular-level activity screening of RNAi agents was performed in A549 cells (purchased from Kebai Biotechnology) using seven concentration gradients.

[0350] A549 cells were cultured in F12K medium containing 10% fetal bovine serum at 37°C and 5% CO2. 24 hours before transfection, A549 cells were seeded into 96-well plates at a density of 2 × 10⁶ cells per well. 4 100 μL of culture medium per well for each cell.

[0351] Following the instructions, Lipofectamine RNAi Max (Invitrogen, 13778-150) was used to transfect cells with the RNAi agent, with 0.3 μL of Lipofectamine RNAi Max used per well. Seven concentrations of the RNAi agent were set: 10 nM, 2 nM, 0.4 nM, 0.08 nM, 0.016 nM, 0.0032 nM, and 0.00064 nM. 24 h post-transfection, RNA was extracted and Q-PCR was performed to detect RNAi agent activity. The results are shown in Table 6. The RNAi agent disclosed in this study exhibited good target activity against MMP7 mRNA in A549 cells.

[0352] Table 6. IC50 of RNAi agents at the A549 cell level 50 Activity results

Claims

1. An RNAi agent comprising a sense strand and an antisense strand forming a double-stranded region; The positive strand comprises at least 15 consecutive nucleotides that differ from the nucleotide sequences shown in any of SEQ ID NO:1 to SEQ ID NO:14 by no more than 3 nucleotides; and The antisense strand comprises at least 15 consecutive nucleotides that differ from the nucleotide sequences shown in any of SEQ ID NO:15 to SEQ ID NO:28 by no more than 3 nucleotides.

2. The RNAi agent according to claim 1, wherein: The positive strand comprises at least 17 consecutive nucleotides that differ from any of the nucleotide sequences shown in SEQ ID NO:1 to SEQ ID NO:14 by no more than 3 nucleotides; The antisense strand comprises at least 17 consecutive nucleotides that differ from any of the nucleotide sequences shown in SEQ ID NO:15 to SEQ ID NO:28 by no more than 3 nucleotides; Preferably, the positive strand comprises at least 19 consecutive nucleotides that differ from the nucleotide sequences shown in any of SEQ ID NO:1 to SEQ ID NO:14 by no more than 3 nucleotides; The antisense strand comprises at least 21 consecutive nucleotides that differ from the nucleotide sequences shown in any of SEQ ID NO:15 to SEQ ID NO:28 by no more than 3 nucleotides.

3. The RNAi agent according to claim 1, wherein, The positive strand comprises a nucleotide sequence as shown in any of SEQ ID NO:1 to SEQ ID NO:14; The antisense strand comprises a nucleotide sequence as shown in any of SEQ ID NO:15 to SEQ ID NO:28; Preferably, the RNAi agent comprises or is selected from any of the following: a sense strand and an antisense strand: Group 1) The sense chain shown in SEQ ID NO: 1 and the antisense chain shown in SEQ ID NO: 15; Group 2) such as the sense chain shown in SEQ ID NO: 2 and the antisense chain shown in SEQ ID NO: 16; Group 3) such as the sense chain shown in SEQ ID NO: 3 and the antisense chain shown in SEQ ID NO: 17; Group 4) such as the sense chain shown in SEQ ID NO: 4 and the antisense chain shown in SEQ ID NO: 18; Group 5) such as the sense chain shown in SEQ ID NO: 5 and the antisense chain shown in SEQ ID NO: 19; Group 6) such as the sense chain shown in SEQ ID NO: 6 and the antisense chain shown in SEQ ID NO: 20; Group 7) such as the sense chain shown in SEQ ID NO: 7 and the antisense chain shown in SEQ ID NO: 21; Group 8) such as the sense chain shown in SEQ ID NO: 8 and the antisense chain shown in SEQ ID NO: 22; Group 9) such as the sense chain shown in SEQ ID NO: 9 and the antisense chain shown in SEQ ID NO: 23; Group 10) such as the sense chain shown in SEQ ID NO: 10 and the antisense chain shown in SEQ ID NO: 24; Group 1) such as the sense chain shown in SEQ ID NO: 11 and the antisense chain shown in SEQ ID NO: 25; Group 2) such as the sense chain shown in SEQ ID NO: 12 and the antisense chain shown in SEQ ID NO: 26; Group 3) such as the sense chain shown in SEQ ID NO: 13 and the antisense chain shown in SEQ ID NO: 27; and Group 4) such as the sense chain shown in SEQ ID NO: 14 and the antisense chain shown in SEQ ID NO:

28.

4. The RNAi agent according to any one of claims 1-3, wherein, At least one nucleotide in the sense strand and / or the antisense strand is a modified nucleotide.

5. The RNAi agent according to claim 4, wherein, The positive chain contains three consecutive 2'-fluorinated nucleosides; Preferably, the nucleosides at positions 7, 8, and 9 of the positive chain are 2'-fluoro-modified nucleosides, following the direction from the 5' end to the 3' end.

6. The RNAi agent according to claim 4 or 5, wherein, The positive chain contains at least one nucleoside with reverse base-free modification; Preferably, the first nucleoside at the 3' end of the positive chain is a nucleoside without reverse base modification.

7. The RNAi agent according to any one of claims 4-6, wherein, The antisense chain contains at least five 2'-fluoro-modified nucleosides; Preferably, the antisense chain contains five 2'-fluorinated nucleosides, and the nucleosides at positions 2, 6, 12, 14 and 16 of the antisense chain are 2'-fluorinated nucleosides in the direction from the 5' end to the 3' end, while the nucleosides at the remaining positions are non-fluorinated nucleosides. Alternatively, the antisense chain contains eight 2'-fluorinated nucleosides, and in the direction from the 5' end to the 3' end, the nucleosides at positions 2, 4, 6, 10, 12, 14, 16 and 18 of the antisense chain are 2'-fluorinated nucleosides, while the nucleosides at the remaining positions are non-fluorinated nucleosides. More preferably, the non-fluorinated nucleoside is selected from: 2'-methoxy-modified nucleosides and nucleosides without reverse base modification.

8. The RNAi agent according to any one of claims 4-7, wherein, The first nucleoside at the 5' end of the antisense chain has a 5'-vinyl phosphate diester group at the 5' position; Preferably, the 5'-vinyl phosphate diester group is a 5'-trans-vinyl phosphate diester group.

9. The RNAi agent according to any one of claims 1-8, wherein, At least one phosphate diester group in the sense chain and / or antisense chain is a phosphate diester group with a modifying group; Preferably, the phosphate diester group with the modifying group is a thiophosphate diester group.

10. The RNAi agent according to claim 9, wherein, The phosphate diester group with the modifying group is present at at least one of the following positions: Between any two adjacent nucleotides from the first to the fourth nucleotide at the 5' end and / or the 3' end of the positive chain, and / or Between any two adjacent nucleotides from the first to the fourth nucleotide at the 5' end and / or 3' end of the antisense strand.

11. The RNAi agent according to any one of claims 1-10, wherein The positive strand comprises a nucleotide sequence as shown in any one of SEQ ID NO:29 to SEQ ID NO:105 and SEQ ID NO:355 to SEQ ID NO:371; The antisense strand comprises a nucleotide sequence as shown in any one of SEQ ID NO:106 to SEQ ID NO:182, SEQ ID NO:372 to SEQ ID NO:

378.

12. The RNAi agent according to any one of claims 1-11, wherein the RNAi agent further comprises one or more targeting ligands having affinity for cellular receptors expressed on epithelial cells; Preferably, the RNAi agent contains a targeting ligand; Preferably, the targeting ligand comprises an integrin targeting group; More preferably, the targeting ligand comprises an αvβ6 integrin targeting group.

13. The RNAi agent according to claim 12, wherein the targeting ligand is selected from the structure shown in formula (I) or a regioisomer thereof: In formula (I), TL represents the αvβ6 integrin targeting group; Preferably, TL has a structure as shown in formula (II): Where R 22 For formula (L) Where a* represents the connection point with the naphthyl group, b* represents the connection point with the triazole group in formula (I), and n1 is selected from integers from 2 to 20; Y is a 5-14-membered heteroaryl group, wherein the 5-14-membered heteroaryl group is optionally substituted by one or more of the following groups: halogen, hydroxyl, oxo, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyloxy group, C 2-6 Acryloxy group, C 3-6 Cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 Cycloalkenyloxy, phenyl, or 5- to 6-membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyloxy group, C 2-6 Acryloxy group, C 3-6 Cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 The cycloalkenyloxy, phenyl, or 5- to 6-membered heteroaryl group may be optionally substituted by one or more substituents selected from halogen, hydroxyl, oxo, nitro, or cyano groups; B is selected from -CH2-, -NH-, Or it may not exist; A is selected from -CH2-, -NH-, -O-, or does not exist.

14. The RNAi agent according to claim 13, wherein the targeting ligand is selected from the structure shown in formula (I-1), formula (I-2) or formula (I-3) or its regioisomers:

15. The RNAi agent according to any one of claims 12-14, wherein the targeting ligand is linked to the sense strand; Preferably, the targeting ligand is connected to the 5' or 3' end of the justice chain; More preferably, the targeting ligand is linked to the first nucleotide at the 5' end of the sense chain.

16. The RNAi agent according to any one of claims 1-15, wherein The sense strand comprises a nucleotide sequence as shown in any one of SEQ ID NO:183 to SEQ ID NO:273; the antisense strand comprises a nucleotide sequence as shown in any one of SEQ ID NO:274 to SEQ ID NO:364; Preferably, the RNAi agent is selected from TJR105958-13, TJR105958-08, TJR105961-08, TJR105962-08, TJR105959-08, TJR105960-08, TJR105963-08, TJR107178-08, and TJR105964-08.

17. A pharmaceutical composition comprising: The RNAi agent according to any one of claims 1-16, and At least one pharmaceutically acceptable excipient.

18. A cell comprising an RNAi agent according to any one of claims 1-16.

19. A kit comprising an RNAi agent according to any one of claims 1-16, or a pharmaceutical composition according to claim 17.

20. A method for reducing matrix metalloproteinase 7 (MMP7) expression in vitro, comprising: The subject is given the RNAi agent according to any one of claims 1-16, the pharmaceutical composition according to claim 17, or the kit according to claim 19.

21. A method for treating and / or preventing a disease in a subject, comprising: The subject is given the RNAi agent according to any one of claims 1-16, the pharmaceutical composition according to claim 17, or the kit according to claim 19; Preferably, the disease is selected from asthma, fibrosis, chronic inflammation, interstitial lung disease, infectious diseases, acute lung injury, pulmonary hypertension, and cancer.

22. A method for in vivo delivery of an RNAi agent that inhibits MMP7 expression and / or replication to the lungs, comprising administering to a subject the RNAi agent according to any one of claims 1-16, or the pharmaceutical composition according to claim 17, or the kit according to claim 19.

23. A method for preparing an RNAi agent or pharmaceutical composition, comprising: Synthesize the RNAi agent according to any one of claims 1-16 or the pharmaceutical composition according to claim 17.

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