Macrocyclic compound, intermediate thereof, preparation method therefor and use thereof

Abstract

The present invention discloses a macrocyclic compound, an intermediate thereof, a preparation method therefor, and the use thereof. Specifically provided is a compound represented by formula (I) or a pharmaceutically acceptable salt thereof. The compound of the present invention has one or more of the following advantageous effects: (1) good inhibitory activity against KRAS G12C mutation; (2) good inhibitory activity against KRAS G12V mutation; (3) good inhibitory activity against KRAS G12D mutation; (4) long half-life; (5) high oral bioavailability; (6) good hepatic microsomal stability; (7) high target tissue distribution; and (8) good pharmacokinetic characteristics and druglikeness.

Description

A macrocyclic compound, its intermediate, its preparation method and its application

[0001] This application claims priority to Chinese patent application 2024114657737, filed on October 18, 2024; Chinese patent application 2025102598569, filed on March 5, 2025; and Chinese patent application 2025114303402, filed on September 30, 2025. The full text of the aforementioned Chinese patent applications is incorporated herein by reference. Technical Field

[0002] This invention relates to the field of pharmaceutical technology, specifically to a macrocyclic compound, its intermediate, its preparation method, and its applications. Background Technology

[0003] The RAS signaling pathway plays a crucial role in cell growth, differentiation, and survival. RAS (including KRAS, NRAS, and HRAS) are downstream of growth factor receptors such as EGFR and are small GTPases that act as molecular switches, serving as key nodes in the RAS-RAF-MEK-ERK and PI3K-AKT-mTOR signaling pathways. These pathways regulate important biological events such as cell proliferation and survival. In normal cells, RAS switches between an active state (RAS ON) and an inactive state (RAS OFF) by binding GTP and GDP. However, when the RAS gene is mutated, the RAS protein remains in the GTP-bound (RAS ON) active state, continuously stimulating cell proliferation and survival, ultimately leading to tumor formation and development. RAS mutations are common in various cancers, particularly lung, colorectal, and pancreatic cancers, and these mutations significantly affect patient prognosis and treatment response.

[0004] Approximately 30% of all cancer patients have RAS-mutated cancers, with KRAS, NRAS, and HRAS mutations accounting for 85%, 11%, and 4%, respectively. KRAS mutations are most common in non-small cell lung cancer, colorectal cancer, and pancreatic cancer, while NRAS mutations are mainly found in melanoma and hematologic malignancies. HRAS mutations are relatively rare, but occur in a certain proportion of head and neck squamous cell carcinomas. Each RAS variant has nearly 20 mutation types, such as KRAS. G12C KRAS G12D KRAS G12V KRAS G12R KRAS G13C KRAS G13D There are many different types of mutations. Because RAS mutations are an important factor in the development and progression of cancer, mutant RAS has become an important target for cancer treatment.

[0005] Despite KRAS G12C Inhibitors such as sotorasib and adagrasib in KRAS G12C Significant success has been achieved in mutant non-small cell lung cancer, but other types of KRAS mutations (such as KRAS) have not yet been successful. G12D KRAS G12V KRAS G13C Cancers with RAS and NRAS mutations still lack effective targeted therapies. This is mainly because the structural and functional characteristics of different RAS mutations vary significantly, making it difficult for existing targeted drugs to comprehensively cover all mutation types. Therefore, developing inhibitors targeting a broad spectrum of RAS mutations has become an urgent problem to be solved.

[0006] As early as 2020, Revolution Medicines, Inc. pioneered the development of a new class of macrocyclic compounds (WO2020132597, WO2021091982, WO2021091967, WO2021091956, WO2022060836, WO2022235870, WO2022235864, WO2023060253, WO2023172940, WO2023133543, WO2023240263). These compounds exert their antitumor effects by forming a ternary complex with the chaperone protein CypA and activated RAS (RAS ON). The ternary complex inhibits the key RAS-RAF-MEK-ERK and PI3K-AKT signaling pathways by blocking the binding of RAS downstream of RAS, thereby inhibiting tumor growth and spread. Compared with traditional covalently bound KRAS... G12C Inhibitors, these macrocyclic compounds have a wider range of inhibition.

[0007] Besides Revolution, several other pharmaceutical companies, such as Roche (WO2023025832, WO2023232776, WO2024008610, WO2024008834, WO2024017859), Biomea Fusion Inc (WO2023086341), Yudao Bio (WO2023015559), Hansoh Pharmaceutical (WO2023208005), Arno Pharma (WO2024060966), and Nanjing Mingde (WO2024067857), have also developed macrocyclic compounds. These companies continuously optimize the structure and function of their compounds, aiming to improve the efficacy and safety of their drugs.

[0008] However, targeted therapy for RAS mutations still faces many challenges in the field of cancer treatment. Further optimizing the structure of compounds and developing suitable RAS inhibitors is of great clinical significance. Summary of the Invention

[0009] This invention provides a macrocyclic compound, its intermediate, its preparation method, and its application. The compound of this invention has one or more of the following advantages: (1) good inhibitory activity against KRAS G12C mutation; (2) good inhibitory activity against KRAS G12V mutation; (3) good inhibitory activity against KRAS G12D mutation; (4) long half-life; (5) high oral bioavailability; (6) good stability in liver microsomes; (7) high distribution in target tissues; and (8) good pharmacokinetic characteristics and drug-likeness.

[0010] The present invention solves the technical problem of the present invention through the following technical solution:

[0011] This invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0012] Ring A is selected from

[0013] X is either Se or S;

[0014] When X is Se, R 1 and R 2 Each is independently selected from H, D, and C. 1-4 Alkyl, Halogenated C 1-4 Alkyl and deuterated C 1-4 Alkyl; or R 1 and R 2 Together with the indole group to which it is attached, it forms

[0015] When X is S, and ring A is At that time, R 1 and R 2 Together with the indole group to which it is attached, it forms

[0016] When X is S, and ring A is At that time, R 1 and R 2 Together with the indole group to which it is attached, it forms

[0017] R 4 R 5 R 6 R8 R 9 R 10 R 11 R 12 and R 13 Each is independently selected from H, D, hydroxyl, halogen, C 1-4 Alkyl, -OC 1-4 Alkyl, Halogenated C 1-4 Alkyl and deuterated C 1-4 alkyl;

[0018] R, R 3 R 7 and R 15 Each is independently selected from D, hydroxyl, halogen, and C. 1-4 Alkyl, -OC 1-4 Alkyl, Halogenated C 1-4 Alkyl and deuterated C 1-4 alkyl;

[0019] m and p are each an independent integer from 0 to 2, n is an integer from 0 to 8, and q is an integer from 0 to 6;

[0020] R 14 Selected from H, D, hydroxyl, halogen, C 1-4 Alkyl, -OC 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl and -C 2-4 alkynyl-3-6-membered heterocyclic alkyl, wherein the C 1-4 Alkyl, -OC 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl and -C 2-4 Alkyne-3-6-membered heterocyclic alkyl group optionally surrounded by one or more R 14-1 replace;

[0021] R 14-1 Each is independently selected from D, hydroxyl, halogen, and C. 1-4 Alkyl, -OC 1-4 Alkyl and C 3-6 cycloalkyl, wherein the C 1-4 Alkyl, -OC 1-4 Alkyl and C 3-6 The cycloalkyl group may optionally be substituted by one or more substituents selected from D, hydroxyl and halogen;

[0022] R 16 Selected from H, D, hydroxyl, halogen and C 1-4 Alkyl, wherein the C 1-4 Alkyl groups are optionally surrounded by one or more R 16-1 replace;

[0023] R16-1 Each is independently selected from D, hydroxyl, halogen, and -OC. 1-4 alkyl;

[0024] L is selected from C 3-6 Cycloalkyl, 3-6 membered heterocyclic alkyl, Wherein C 3-6 Cycloalkyl and 3-6 membered heterocyclic alkyl groups are optionally surrounded by one or more R a replace;

[0025] R a Each is independently selected from D, hydroxyl, halogen, and C. 1-4 Alkyl, -OC 1-4 Alkyl, Halogenated C 1-4 Alkyl and deuterated C 1-4 alkyl;

[0026] L 1 L 2 L 5 and L 6 Each is independently selected from H, D, hydroxyl, halogen, C 1-4 Alkyl, -OC 1-4 Alkyl and C 3-6 cycloalkyl, wherein the C 1-4 Alkyl, -OC 1-4 Alkyl and C 3-6 cycloalkyl groups are optionally surrounded by one or more R b replace;

[0027] R b Each is independently selected from D, hydroxyl, halogen, and C. 1-4 Alkyl and -OC 1-4 alkyl;

[0028] L 3 Selected from H, C 1-4 Alkyl and C 3-6 cycloalkyl, wherein the C 1-4 Alkyl and C 3-6 cycloalkyl groups are optionally surrounded by one or more R c replace;

[0029] R c Each is independently selected from D, hydroxyl, halogen, and C. 1-4 Alkyl and -OC 1-4 alkyl;

[0030] L 4 and L 7 Each is independently a 3-9 membered heterocyclic alkyl group, wherein the 3-9 membered heterocyclic alkyl group is optionally surrounded by one or more R d replace;

[0031] Rd Each is independently selected from D, hydroxyl, halogen, oxo group, C 1-4 Alkyl, -OC 1-4 Alkyl, C 3-6 Cycloalkyl, -C(=O)-C 1-4 Alkyl, -C(=O)-C 2-6 alkynyl group, -C(=O)-C 3-6 Cycloalkyl and -C(=O)-3-6-membered heterocycloalkyl, wherein the C 1-4 Alkyl, -OC 1-4 Alkyl, C 3-6 Cycloalkyl, -C(=O)-C 1-4 Alkyl, -C(=O)-C 2-6 alkynyl group, -C(=O)-C 3-6 The cycloalkyl and -C(=O)-3-6-membered heterocycloalkyl groups may be optionally substituted by one or more substituents selected from D, hydroxyl, halogen, -CH3, -N(CH3)2 and cyclopropyl.

[0032] In some implementation schemes, R, R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11 R 12 R 13 R 14 R 14- 1 R 15 R 16 R 16-1 L 1 L 2 L 3 L 5 L 6 R a R b R c and R d In, the C 1-4 Alkyl (e.g., "C") 1-4 Alkyl group, halogenated C 1-4 Alkyl group, deuterated C 1-4 Alkyl group, -OC 1-4 Alkyl groups and -C(=O)-C 1-4 C in "alkyl" 1-4The alkyl groups are each independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl.

[0033] In some implementation schemes, R, R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11 R 12 R 13 R 14 R 14- 1 R 15 R 16 R 16-1 L 1 L 2 L 3 L 5 L 6 R a R b R c and R d In, the C 1-4 Alkyl (e.g., "C") 1-4 Alkyl group, halogenated C 1-4 Alkyl group, deuterated C 1-4 Alkyl group, -OC 1-4 Alkyl groups and -C(=O)-C 1-4 C in "alkyl" 1-4 The alkyl groups are each independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl.

[0034] In some implementation schemes, R, R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11 R 12 R 13 R 15 and R a In the above, the halogenated C 1-4 The halogen in the alkyl group is independently F, Cl, Br, or I. The halogenated C 1-4The maximum number of halogens in alkyl groups is C. 1-4 The number of substituted H atoms in an alkyl group, for example, the number of halogens is 1, 2, 3, 4, 5, 6, 7, 8 or 9.

[0035] In some implementation schemes, R, R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11 R 12 R 13 R 15 and R a In the context, the deuterated C 1-4 The maximum number of deuterium atoms in alkyl groups is C. 1-4 The number of H atoms that can be substituted in an alkyl group, for example, the number of deuterium atoms is 1, 2, 3, 4, 5, 6, 7, 8 or 9.

[0036] In some implementation schemes, R, R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11 R 12 R 13 R 14 R 14-1 R 15 R 16 R 16-1 L 1 L 2 L 5 L 6 R a R b R c and R d In this context, each of the halogens is independently F, Cl, Br, or I.

[0037] In some implementation schemes, R 14 R 14-1 L, L 1 L 2 L 3 L 5 L 6 and R d In, the C 3-6cycloalkyl (e.g., "C") 3-6 cycloalkyl and -C(=O)-C 3-6 C in "cycloalkyl" 3-6 Each cycloalkyl group is independently C10. 3-6 Monocyclic cycloalkyl or C 5-6 Dicyclic cycloalkyl groups, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.

[0038] In some implementation schemes, R 14 R 14-1 L, L 1 L 2 L 3 L 5 L 6 and R d In, the C 3-6 cycloalkyl (e.g., "C") 3-6 cycloalkyl and -C(=O)-C 3-6 C in "cycloalkyl" 3-6 Each cycloalkyl group is independently C10. 3-6 Monocyclic cycloalkyl or C 5-6 Dicyclic cycloalkyl groups, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or...

[0039] In some implementation schemes, R 14-1 In, the C 3-6 Cycloalkyl group is C 3-6 Monocyclic cycloalkyl, for example, cyclopropyl.

[0040] In some implementations, in L, the C 3-6 Cycloalkyl group is C 3-6 Monocyclic cycloalkyl or C 5-6 Dicyclic cycloalkyl groups, such as cyclopropyl groups,

[0041] In some implementations, in L, the C 3-6 Cycloalkyl group is C 3-6 Monocyclic cycloalkyl or C 5-6 Dicyclic cycloalkyl, such as cyclopropyl or

[0042] In some implementations, L 5 and L 6 In, the C 3-6 Each cycloalkyl group is independently C10. 3-6 Monocyclic cycloalkyl, for example, cyclopentyl.

[0043] In some implementation schemes, R 14 L and R dIn this context, the 3-6 membered heterocyclic alkyl group (e.g., "3-6 membered heterocyclic alkyl group", "-C") refers to... 2-4 The 3-6-membered heterocyclic alkyl group in "alkynyl-3-6-membered heterocyclic alkyl" and "-C(=O)-3-6-membered heterocyclic alkyl" is independently a 3-6-membered monocyclic heterocyclic alkyl or a 5-6-membered difused heterocyclic alkyl group having one or two heteroatoms or heteroatoms selected from N, NH and O, such as piperazine, morpholino, etc.

[0044] In some implementation schemes, R 14 L and R d In this context, the 3-6 membered heterocyclic alkyl group (e.g., "3-6 membered heterocyclic alkyl group", "-C") refers to... 2-4 The 3-6-membered heterocyclic alkyl group in "alkynyl-3-6-membered heterocyclic alkyl" and "-C(=O)-3-6-membered heterocyclic alkyl" is independently a 3-6-membered monocyclic heterocyclic alkyl or a 5-6-membered difused heterocyclic alkyl group having one or two heteroatoms or heteroatoms selected from N, NH and O, such as piperazine, morpholino, etc.

[0045] In some implementation schemes, R 14 In this context, the 3-6 membered heterocyclic alkyl group (e.g., "3-6 membered heterocyclic alkyl group" and "-C") 2-4 The 3-6-membered heterocyclic alkyl group in "alkynyl-3-6-membered heterocyclic alkyl group" is a 3-6-membered monocyclic heterocyclic alkyl group having two heteroatoms or heteroatom groups selected from N, NH and O, preferably a 5-6-membered monocyclic heterocyclic alkyl group, such as piperazine or morpholino.

[0046] In some embodiments, in L, the 3-6 membered heterocyclic alkyl group is a 3-6 membered difused heterocyclic alkyl group having one heteroatom selected from N, NH, and O, for example...

[0047] In some embodiments, in L, the 3-6 membered heterocyclic alkyl group is a 3-6 membered difused heterocyclic alkyl group having one heteroatom selected from N, NH, and O, for example...

[0048] In some implementation schemes, R d In this context, the 3-6 membered heterocyclic alkyl group (e.g., the 3-6 membered heterocyclic alkyl group in "-C(=O)-3-6 membered heterocyclic alkyl group") is a 3-6 membered monocyclic heterocyclic alkyl group having one heteroatom selected from N, NH, and O, for example,

[0049] In some implementations, L 4 and L 7In this context, each of the 3-9 membered heterocyclic alkyl groups is independently a 3-9 membered monocyclic heterocyclic alkyl group or a 5-9 membered bicyclic heterocyclic alkyl group having one or two heteroatoms or heteroatom groups selected from N, NH and O, preferably a 3-6 membered monocyclic heterocyclic alkyl group or a 5-9 membered bicyclic heterocyclic alkyl group, more preferably a 3-6 membered monocyclic heterocyclic alkyl group or a 5-9 membered spirocyclic heterocyclic alkyl group, such as piperidinyl, Aza-heterocyclic butyl, pyrrolidinyl, or morpholino.

[0050] In some implementations, L 4 In this context, the 3-9 membered heterocyclic alkyl group is a 3-9 membered monocyclic heterocyclic alkyl group having one or two heteroatoms or heteroatomic groups selected from N, NH and O, preferably a 3-6 membered monocyclic heterocyclic alkyl group having one heteroatom or heteroatomic group selected from N and NH, such as piperidinyl, aziridine, pyrrolidinyl or morpholinyl.

[0051] In some implementations, L 7 In this context, the 3-9 membered heterocyclic alkyl group is a 5-9 membered bicyclic heterocyclic alkyl group having one or two heteroatoms or heteroatom groups selected from N, NH, and O, preferably a 5-9 membered spirocyclic heterocyclic alkyl group having two heteroatoms or heteroatom groups selected from N and NH, for example...

[0052] In some implementations, when R 1 and R 2 Together with the indole group to which it is attached, it forms When q is any integer from 0 to 6.

[0053] In some implementations, when R 1 and R 2 Together with the indole group to which it is attached, it forms When q is any integer from 0 to 4.

[0054] In some implementations, when R 1 and R 2 Together with the indole group to which it is attached, it forms When q is any integer from 0 to 4.

[0055] In some implementations, ring A is Preferred

[0056] In some implementations, ring A is Preferred

[0057] In some implementations, X is Se.

[0058] In some implementations, X is S.

[0059] In some implementations, when X is Se, R 1 and R 2 Each is independently selected from H and C. 1-4 Alkyl, Halogenated C 1-4 Alkyl and deuterated C 1-4 Alkyl groups, preferably selected from H and C 1-4 alkyl.

[0060] In some implementations, when X is Se, R 1 and R 2 Each is independently selected from H, -CH3, -CF3, -CHF2, -CH2F, -CD3, -CHD2, -CH2D, -CH2CH3, -CH2CF3, -CF2CF3, -CD2CD3, and -CH2CD3; preferably selected from H, -CH2CH3, -CH2CF3, -CD2CD3, and -CH2CD3.

[0061] In some implementations, when X is Se, R 1 Selected from C 1-4 Alkyl, Halogenated C 1-4 Alkyl and deuterated C 1-4 Alkyl group, preferably C 1- 4-alkyl group.

[0062] In some implementations, when X is Se, R 1 It is selected from -CH3, -CHF2, -CH2F, -CH2CH3, -CH2CF3, -CF2CF3, -CD2CD3 and -CH2CD3; preferably selected from -CH2CH3, -CH2CF3, -CD2CD3 and -CH2CD3; more preferably -CH2CH3.

[0063] In some implementations, when X is Se, R 2 For H.

[0064] In some implementations, when X is Se, R 1 and R 2 Each is independently selected from H and C. 1-4 Alkyl, Halogenated C 1-4 Alkyl and deuterated C 1-4 Alkyl groups, preferably selected from H and C 1-4 alkyl;

[0065] Preferably, R 1 Selected from C 1-4 Alkyl, Halogenated C 1-4 Alkyl and deuterated C 1-4 Alkyl group, preferably C 1-4 Alkyl; R 2 For H;

[0066] Or R 1 and R 2 Together with the indole group to which it is attached, it forms Preferred Formation More preferably formed

[0067] In some implementations, when X is Se, R 1 and R 2 Each of the following is independently selected from H, -CH3, -CF3, -CHF2, -CH2F, -CD3, -CHD2, -CH2D, -CH2CH3, -CH2CF3, -CF2CF3, -CD2CD3, and -CH2CD3; preferably selected from H, -CH2CH3, -CH2CF3, -CD2CD3, and -CH2CD3;

[0068] Preferably, R 1 Selected from -CH3, -CHF2, -CH2F, -CH2CH3, -CH2CF3, -CF2CF3, -CD2CD3, and -CH2CD3, preferably selected from -CH2CH3, -CH2CF3, -CD2CD3, and -CH2CD3, more preferably -CH2CH3; R 2 For H;

[0069] Or R 1 and R 2 Together with the indole group to which it is attached, it forms Preferred Formation More preferably formed

[0070] In some implementations, when X is S and ring A is At that time, R 1 and R 2 Together with the indole group to which it is attached, it forms

[0071] In some implementation schemes, R 4 R 5 R 6 R 8 R 9 R 12 and R 13 Each is independently represented by H.

[0072] In some implementation schemes, R 10 and R 11 Each independently is C 1-4 Alkyl group, preferably methyl group.

[0073] In some implementations, m, n, p, and q are each independently 0.

[0074] In some implementation schemes, R 14 Selected from H, 3-6 membered heterocyclic alkyl groups and -C 2-4 alkynyl-3-6-membered heterocyclic alkyl, wherein the 3-6-membered heterocyclic alkyl and -C 2-4 Alkyne-3-6-membered heterocyclic alkyl group optionally surrounded by one or more R 14-1 replace.

[0075] In some implementation schemes, R 14 Selected from H and 3-6 membered heterocyclic alkyl groups, wherein the 3-6 membered heterocyclic alkyl group is optionally surrounded by one or more R groups. 14-1 replace.

[0076] In some implementation schemes, R 14 It is a 3-6 membered heterocyclic alkyl group, wherein the 3-6 membered heterocyclic alkyl group is optionally surrounded by one or more R 14-1 replace.

[0077] In some implementation schemes, R 14 Selected from H, piperazinyl, morpholinyl, and -propynyl-morpholinyl, wherein the piperazinyl, morpholinyl, and -propynyl-morpholinyl are optionally separated by one or more R 14-1 replace.

[0078] In some implementation schemes, R 14 Selected from H, piperazine, and morpholino, wherein the piperazine and morpholino groups are optionally separated by one or more R groups. 14-1 replace.

[0079] In some implementation schemes, R 14 The piperazine group is optionally surrounded by one or more R groups. 14-1 replace.

[0080] In some implementation schemes, R 14 Selected from H, The above Optional by one or more R 14-1 replace.

[0081] In some implementation schemes, R 14 Selected from H, The above Optional by one or more R 14-1 replace.

[0082] In some implementation schemes, R 14 for The above Optional by one or more R 14-1 replace.

[0083] In some implementation schemes, R 14-1 Each was independently selected from C 1-4 Alkyl and C 3-6 Cycloalkyl, preferably C 1-4 Alkyl; wherein the C 1- 4-alkyl and C 3-6 The cycloalkyl group may optionally be substituted by one or more substituents selected from D, hydroxyl and halogen.

[0084] In some implementation schemes, R 14-1 Each was independently selected from C 1-4 Alkyl and C 3-6 Cycloalkyl, preferably C 1-4 Alkyl; wherein the C 1- 4-alkyl and C 3-6 The cycloalkyl group may optionally be substituted with one or more D atoms.

[0085] In some implementation schemes, R 14-1 Each independently is C 1-4 alkyl.

[0086] In some implementation schemes, R 14-1 Each is independently selected from -CH3, -CF3, -CHF2, -CH2F, -CD3, -CHD2, -CH2D, -CH2CH3, -CH2CF3, -CF2CF3, -CD2CD3, -CH2CD3, -CH2OH and cyclopropyl.

[0087] In some implementation schemes, R 14-1 Each is independently selected from -CH3, -CD3, -CH2CH3, -CH2OH and cyclopropyl.

[0088] In some implementation schemes, R 14-1 Each is independently selected from -CH3, -CD3, -CH2CH3 and cyclopropyl.

[0089] In some implementation schemes, R 14-1 Each is independently -CH3.

[0090] In some implementation schemes, R 14 Selected from H,

[0091] In some implementation schemes, R 14 Selected from H,

[0092] In some implementation schemes, R14 for

[0093] In some implementation schemes, R 16 C 1-4 Alkyl, the C 1-4 Alkyl groups are optionally surrounded by one or more R 16-1 replace.

[0094] In some implementation schemes, R 16 The ethyl group is ethyl, which is optionally mixed with one or more R groups. 16-1 replace.

[0095] In some implementation schemes, R 16-1 Each independently as -OC 1-4 alkyl.

[0096] In some implementation schemes, R 16-1 Each is independently -OCH3.

[0097] In some implementation schemes, R 16 It is -CH(CH3)-OCH3, for example,

[0098] In some implementations, L is selected from C. 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl and The C 3-6 Cycloalkyl and 3-6 membered heterocyclic alkyl groups are optionally surrounded by one or more R a replace.

[0099] In some implementations, L is selected from C. 3-6 Cycloalkyl and 3-6 membered heterocycloalkyl, wherein C 3-6 Cycloalkyl and 3-6 membered heterocyclic alkyl groups are optionally surrounded by one or more R a replace.

[0100] In some implementations, L is C 3-6 cycloalkyl, the C 3-6 cycloalkyl groups are optionally surrounded by one or more R a replace.

[0101] In some implementation schemes, R a Each is independently selected from halogens, C 1-4 Alkyl and Halogenated C 1-4 alkyl.

[0102] In some implementations, L 1 L 2 L 5 and L 6 Each is independently selected from H and C. 1-4 Alkyl and C3-6 Cycloalkyl.

[0103] In some implementations, L 3 C 1-4 Alkyl group, preferably methyl group.

[0104] In some implementation schemes, R d Each is independently selected from halogens, oxo groups, and -C(=O)-C. 1-4 Alkyl, -C(=O)-C 2-6 Alkynyl and -C(=O)-3-6-membered heterocyclic alkyl, wherein -C(=O)-C 1-4 Alkyl, -C(=O)-C 2-6 The alkynyl group and the -C(=O)-3-6-membered heterocyclic alkyl group may be optionally substituted by one or more substituents selected from halogens, -CH3, -N(CH3)2 and cyclopropyl groups.

[0105] In some implementation schemes, Selected from

[0106] In some implementation schemes, Selected from

[0107] In some implementation schemes, Selected from

[0108] In some implementation schemes, Selected from

[0109] In some implementation schemes, Selected from

[0110] In some implementation schemes, Selected from

[0111] In some implementation schemes, L is selected from

[0112] In some implementation schemes, L is selected from In some implementation schemes, L is selected from

[0113] In some implementation schemes, L is selected from In some implementation schemes, L is selected from

[0114] In some implementation schemes, L is selected from In some implementation schemes, L is selected from

[0115] In some implementation schemes, L is selected from

[0116] In some implementation schemes, L is selected from

[0117] In some implementation schemes, L is selected from

[0118] In some implementation schemes, L is selected from

[0119] In some implementation schemes, L is selected from

[0120] In some implementation schemes, L is selected from

[0121] In some implementation schemes, L is selected from

[0122] In some implementation schemes, L is selected from

[0123] In some implementation schemes, L is selected from

[0124] In some implementation schemes, L is selected from

[0125] In some implementation schemes, for Where the 'a' bond represents resistance to rotation, it can be represented as: Preferred

[0126] In some implementation schemes, R 10 and R 11 Each independently is C 1-4 Alkyl groups, preferably methyl groups;

[0127] R 14It is a 3-6 membered heterocyclic alkyl group, wherein the 3-6 membered heterocyclic alkyl group is optionally surrounded by one or more R 14-1 replace;

[0128] R 14-1 Each is independently preferred to be C 1-4 Alkyl, more preferably methyl;

[0129] R 16 C 1-4 Alkyl, wherein the C 1-4 Alkyl groups are optionally surrounded by one or more R 16-1 replace;

[0130] R 16-1 Each is independently preferred to be OC 1-4 alkyl;

[0131] L is C 3-6 Monocyclic cycloalkyl, wherein the C 3-6 Monocyclic cycloalkyl groups are optionally surrounded by one or more R a replace;

[0132] R a Each independently selects from C 1-4 Alkyl and Halogenated C 1-4 alkyl.

[0133] In some embodiments, compounds of formula (I) are used, wherein,

[0134] Ring A is selected from

[0135] X is either Se or S;

[0136] When X is Se

[0137] R 1 Selected independently from C 1-4 Alkyl, Halogenated C 1-4 Alkyl and deuterated C 1-4 Alkyl group; preferably selected from -CH2CH3, -CH2CF3, -CD2CD3 and -CH2CD3;

[0138] R 2 Independently selected from H;

[0139] Or R 1 and R 2 Together with the indole group to which it is attached, it forms

[0140] When X is S, and ring A is At that time, R 1 and R 2Together with the indole group to which it is attached, it forms

[0141] When X is S, and ring A is At that time, R 1 and R 2 Together with the indole group to which it is attached, it forms

[0142] R 4 R 5 R 6 R 8 R 9 R 12 and R 13 Each is independently selected from H;

[0143] R 10 and R 11 Each independently is C 1-4 Alkyl or deuterated C 1-4 Alkyl; preferably methyl;

[0144] m, n, p, and q are each independently 0;

[0145] R 14 Selected from H and 5-6 membered monocyclic heterocyclic alkyl groups (piperazinyl or morpholinyl), wherein the 5-6 membered monocyclic heterocyclic alkyl group is optionally surrounded by one or more R groups. 14-1 replace,

[0146] R 14-1 Each was independently selected from C 1-4 Alkyl and C 3-6 cycloalkyl (C 3-6 Monocyclic cycloalkyl), the C 1-4 Alkyl and C 3-6 The cycloalkyl group may optionally be substituted with one or more D atoms;

[0147] (R 14 H is preferred. );

[0148] R 16 C 1-4 Alkyl, wherein the C 1-4 Alkyl groups are optionally surrounded by one or more R 16-1 Replace, R 16-1 Each independently as -OC 1-4 Alkyl; R 16 Preferably, it is -CH(CH3)-OCH3;

[0149] L is selected from C 3-6 cycloalkyl (C 3-6 Monocyclic cycloalkyl or C 5-6Dicyclic cycloalkyl), 5-6 membered dicyclic heterocyclic alkyl (having one 5-6 membered dicyclic heterocyclic alkyl group selected from O atom) and Wherein C 3-6 cycloalkyl groups are formed by one or more R groups a Replace, R a Each was independently selected from C 1-4 Alkyl, Halogenated C 1-4 Alkyl and deuterated C 1-4 alkyl;

[0150] L 5 and L 6 Each is independently selected from H and C. 3-6 cycloalkyl (C 3-6 Monocyclic cycloalkyl); L 7 Selected from 5-9 membered bicyclic heterocyclic alkyl groups (5-9 membered spirocyclic heterocyclic alkyl groups), wherein the 5-9 membered bicyclic heterocyclic alkyl group is optionally surrounded by one or more R groups. d Replace, R d Each is independently a -C(=O)-3-6 membered monocyclic heterocyclic alkyl (a 3-6 membered monocyclic heterocyclic alkyl having 1 N atom), wherein the -C(=O)-3-6 membered monocyclic heterocyclic alkyl is optionally substituted by one or more substituents selected from -CH3 and cyclopropyl;

[0151] (L is preferred) More preferably ).

[0152] In some embodiments, compounds of formula (I) are used, wherein,

[0153] Ring A is selected from

[0154] X is either Se or S;

[0155] When X is Se, R 1 C 1-4 Alkyl, preferably ethyl; R 2 For H; or R 1 and R 2 Together with the indole group to which it is attached, it forms

[0156] When X is S, and ring A is At that time, R 1 and R 2 Together with the indole group to which it is attached, it forms

[0157] When X is S, and ring A is At that time, R1 and R 2 Together with the indole group to which it is attached, it forms

[0158] R 4 R 5 R 6 R 8 R 9 R 12 and R 13 Each is independently selected from H;

[0159] R 10 and R 11 Each independently is C 1-4 Alkyl groups, preferably methyl groups;

[0160] m, n, p, and q are each independently 0;

[0161] R 14 For optional use by one or more R 14-1 The substituted 3-6 membered heterocyclic alkyl group, preferably optionally replaced by one or more R 14-1 Substituted 3-6 membered monocyclic heterocyclic alkyl groups; R 14-1 Each independently is C 1-4 Alkyl group, preferably methyl group; R 14 For example,

[0162] R 16 C 1-4 Alkyl, wherein the C 1-4 Alkyl groups are optionally surrounded by one or more R 16-1 Replace; R 16-1 Each independently as -OC 1-4 Alkyl group, preferably -OCH3; R 16 Preferably, it is -CH(CH3)-OCH3, for example,

[0163] L is arbitrarily assigned to one or more R. a Replacement C 3-6 cycloalkyl; R a Each was independently selected from C 1-4 Alkyl and Halogenated C 1-4 Alkyl; L, for example, is

[0164] In some embodiments, the compound represented by formula (I) is the compound represented by formula (I').

[0165] Among them, rings A, X, and R 1 R 2 R 3R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11 R 12 R 13 R 14 R 15 R 16 The definitions of L, m, n and p are as described above.

[0166] In some embodiments, the compound represented by formula (I) is the compound represented by formula (II).

[0167] Among them, rings A and R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11 R 12 R 13 R 14 R 15 R 16 The definitions of L, m, n and p are as described above.

[0168] In some embodiments, the compound is as shown in formula (II), wherein

[0169] Ring A is selected from

[0170] R 1 Selected from C 1-4 Alkyl, Halogenated C 1-4 Alkyl and deuterated C 1-4 Alkyl group; preferably selected from -CH2CH3, -CH2CF3, -CD2CD3 and -CH2CD3;

[0171] R 2 Selected from H;

[0172] Or R 1 and R 2 Together with the indole group to which it is attached, it forms

[0173] R 4 R 5 R6 R 8 R 9 R 12 and R 13 Each is independently selected from H;

[0174] R 10 and R 11 Each independently is C 1-4 Alkyl or deuterated C 1-4 Alkyl; preferably methyl;

[0175] m, n, p, and q are each independently 0;

[0176] R 14 Selected from H and 5-6 membered monocyclic heterocyclic alkyl groups (piperazinyl or morpholinyl), wherein the 5-6 membered monocyclic heterocyclic alkyl group is optionally surrounded by one or more R groups. 14-1 replace,

[0177] R 14-1 Each was independently selected from C 1-4 Alkyl and C 3-6 cycloalkyl (C 3-6 Monocyclic cycloalkyl), the C 1-4 Alkyl and C 3-6 The cycloalkyl group may optionally be substituted with one or more D atoms;

[0178] R 14 H is preferred.

[0179] R 16 C 1-4 Alkyl, wherein the C 1-4 Alkyl groups are optionally surrounded by one or more R 16-1 Replace, R 16-1 Each independently as -OC 1-4 Alkyl; R 16 Preferably, it is -CH(CH3)-OCH3;

[0180] L is selected from C 3-6 cycloalkyl (C 3-6 Monocyclic cycloalkyl or C 5-6 Dicyclic cycloalkyl), 5-6 membered dicyclic heterocyclic alkyl (having one 5-6 membered dicyclic heterocyclic alkyl group selected from O atom) and

[0181] Wherein C 3-6 cycloalkyl groups are formed by one or more R groups a Replace, R a Each was independently selected from C 1-4 Alkyl, Halogenated C 1-4 Alkyl and deuterated C 1-4 alkyl;

[0182] L 5 and L 6 Each is independently selected from H and C. 3-6 cycloalkyl (C 3-6 Monocyclic cycloalkyl); L 7 Selected from 5-9 membered bicyclic heterocyclic alkyl groups (5-9 membered spirocyclic heterocyclic alkyl groups), wherein the 5-9 membered bicyclic heterocyclic alkyl group is optionally surrounded by one or more R groups. d Replace, R d Each is independently a -C(=O)-3-6 membered monocyclic heterocyclic alkyl (a 3-6 membered monocyclic heterocyclic alkyl having 1 N atom), wherein the -C(=O)-3-6 membered monocyclic heterocyclic alkyl is optionally substituted by one or more substituents selected from -CH3 and cyclopropyl;

[0183] (L is preferred) ).

[0184] In some embodiments, the compound is as shown in formula (II), wherein

[0185] Ring A is selected from

[0186] R 1 C 1-4 Alkyl, preferably ethyl; R 2 For H; or R 1 and R 2 Together with the indole group to which it is attached, it forms

[0187] R 4 R 5 R 6 R 8 R 9 R 12 and R 13 Each is independently selected from H;

[0188] R 10 and R 11 Each independently is C 1-4 Alkyl groups, preferably methyl groups;

[0189] m, n, p, and q are each independently 0;

[0190] R 14 For optional use by one or more R 14-1 The substituted 3-6 membered heterocyclic alkyl group, preferably optionally replaced by one or more R 14-1 Substituted 3-6 membered monocyclic heterocyclic alkyl groups; R 14-1 Each independently is C 1-4 Alkyl group, preferably methyl group; R14 For example,

[0191] R 16 C 1-4 Alkyl, wherein the C 1-4 Alkyl groups are optionally surrounded by one or more R 16-1 Replace; R 16-1 Each independently as -OC 1-4 Alkyl group, preferably -OCH3; R 16 Preferably, it is -CH(CH3)-OCH3, for example,

[0192] L is arbitrarily assigned to one or more R. a Replacement C 3-6 cycloalkyl; R a Each was independently selected from C 1-4 Alkyl and Halogenated C 1-4 Alkyl; L, for example, is

[0193] In some embodiments, the compound represented by formula (I) is the compound represented by formula (II').

[0194] Among them, rings A and R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11 R 12 R 13 R 14 R 15 R 16 The definitions of L, m, n and p are as described above.

[0195] In some embodiments, the compound represented by formula (I) is the compound represented by formula (III).

[0196] Among them, ring A is selected from

[0197] When ring A is At that time, R 1 and R 2 Together with the indole group to which it is attached, it forms

[0198] When ring A is At that time, R 1 and R 2 Together with the indole group to which it is attached, it forms

[0199] R, R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11 R 12 R 13 R 14 R 15 R 16 The definitions of L, m, n, p, and q are as described above.

[0200] In some embodiments, compounds of formula (III) are used, wherein

[0201] Ring A is selected from

[0202] When ring A is At that time, R 1 and R 2 Together with the indole group to which it is attached, it forms

[0203] When ring A is At that time, R 1 and R 2 Together with the indole group to which it is attached, it forms

[0204] R 4 R 5 R 6 R 8 R 9 R 12 and R 13 Each is independently selected from H;

[0205] R 10 and R 11 Each independently is C 1-4 Alkyl or deuterated C 1-4 Alkyl groups, preferably methyl groups;

[0206] m, n, p, and q are each independently 0;

[0207] R 14Selected from H and 5-6 membered monocyclic heterocyclic alkyl groups (piperazinyl or morpholinyl), wherein the 5-6 membered monocyclic heterocyclic alkyl group is optionally surrounded by one or more R groups. 14-1 replace,

[0208] R 14-1 Each was independently selected from C 1-4 Alkyl and C 3-6 cycloalkyl (C 3-6 Monocyclic cycloalkyl), the C 1-4 Alkyl and C 3-6 The cycloalkyl group may optionally be substituted with one or more D atoms;

[0209] R 14 H is preferred.

[0210] R 16 C 1-4 Alkyl, wherein the C 1-4 Alkyl groups are optionally surrounded by one or more R 16-1 Replace, R 16-1 Each independently as -OC 1-4 Alkyl; R 16 Preferably, it is -CH(CH3)-OCH3;

[0211] L is selected from C 3-6 cycloalkyl (C 3-6 Monocyclic cycloalkyl or C 5-6 Dicyclic cycloalkyl), 5-6 membered dicyclic heterocyclic alkyl (having one 5-6 membered dicyclic heterocyclic alkyl group selected from O atom) and

[0212] Wherein C 3-6 cycloalkyl groups are formed by one or more R groups a Replace, R a Each was independently selected from C 1-4 Alkyl, Halogenated C 1-4 Alkyl and deuterated C 1-4 alkyl;

[0213] L 5 and L 6 Each is independently selected from H and C. 3-6 cycloalkyl (C 3-6 Monocyclic cycloalkyl); L 7 Selected from 5-9 membered bicyclic heterocyclic alkyl groups (5-9 membered spirocyclic heterocyclic alkyl groups), wherein the 5-9 membered bicyclic heterocyclic alkyl group is optionally surrounded by one or more R groups. d Replace, R dEach is independently a -C(=O)-3-6 membered monocyclic heterocyclic alkyl (a 3-6 membered monocyclic heterocyclic alkyl having 1 N atom), wherein the -C(=O)-3-6 membered monocyclic heterocyclic alkyl is optionally substituted by one or more substituents selected from -CH3 and cyclopropyl;

[0214] (L is preferred) ).

[0215] In some embodiments, compounds of formula (III) are used, wherein

[0216] Ring A is selected from

[0217] When ring A is At that time, R 1 and R 2 Together with the indole group to which it is attached, it forms

[0218] When ring A is At that time, R 1 and R 2 Together with the indole group to which it is attached, it forms

[0219] R 4 R 5 R 6 R 8 R 9 R 12 and R 13 Each is independently selected from H;

[0220] R 10 and R 11 Each independently is C 1-4 Alkyl groups, preferably methyl groups;

[0221] m, n, p, and q are each independently 0;

[0222] R 14 For optional use by one or more R 14-1 The substituted 3-6 membered heterocyclic alkyl group, preferably optionally replaced by one or more R 14-1 Substituted 3-6 membered monocyclic heterocyclic alkyl groups; R 14-1 Each independently is C 1-4 Alkyl group, preferably methyl group; R 14 For example,

[0223] R 16 C 1-4 Alkyl, wherein the C 1-4Alkyl groups are optionally surrounded by one or more R 16-1 Replace; R 16-1 Each independently as -OC 1-4 Alkyl group, preferably -OCH3; R 16 Preferably, it is -CH(CH3)-OCH3, for example,

[0224] L is arbitrarily assigned to one or more R. a Replacement C 3-6 cycloalkyl; R a Each was independently selected from C 1-4 Alkyl and Halogenated C 1-4 Alkyl; L, for example, is

[0225] In some embodiments, the compound represented by formula (I) is the compound represented by formula (III').

[0226] Among them, ring A is selected from

[0227] When ring A is At that time, R 1 and R 2 Together with the indole group to which it is attached, it forms

[0228] When ring A is At that time, R 1 and R 2 Together with the indole group to which it is attached, it forms

[0229] R, R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11 R 12 R 13 R 14 R 15 R 16 The definitions of L, m, n, p, and q are as described above.

[0230] In some embodiments, the compound represented by formula (I) is the compound represented by formula (II-1) or the compound represented by formula (II-2).

[0231] Among them, R 1 R2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11 R 12 R 13 R 14 R 15 R 16 The definitions of L, m, n and p are as described above.

[0232] In some embodiments, compounds of formula (II-1) and formula (II-2) are used, wherein

[0233] R 1 Selected from C 1-4 Alkyl, Halogenated C 1-4 Alkyl and deuterated C 1-4 Alkyl group; preferably selected from -CH2CH3, -CH2CF3, -CD2CD3 and -CH2CD3;

[0234] R 2 Selected from H;

[0235] Or R 1 and R 2 Together with the indole group to which it is attached, it forms

[0236] R 4 R 5 R 6 R 8 R 9 R 12 and R 13 Each is independently selected from H;

[0237] R 10 and R 11 Each independently is C 1-4 Alkyl or deuterated C 1-4 Alkyl; preferably methyl;

[0238] m, n, p, and q are each independently 0;

[0239] R 14 Selected from H and 5-6 membered monocyclic heterocyclic alkyl groups (piperazinyl or morpholinyl), wherein the 5-6 membered monocyclic heterocyclic alkyl group is optionally surrounded by one or more R groups. 14-1 replace,

[0240] R 14-1Each was independently selected from C 1-4 Alkyl and C 3-6 cycloalkyl (C 3-6 Monocyclic cycloalkyl), the C 1-4 Alkyl and C 3-6 The cycloalkyl group may optionally be substituted with one or more D atoms;

[0241] R 14 H is preferred.

[0242] R 16 C 1-4 Alkyl, wherein the C 1-4 Alkyl groups are optionally surrounded by one or more R 16-1 Replace, R 16-1 Each independently as -OC 1-4 Alkyl; R 16 Preferably, it is -CH(CH3)-OCH3;

[0243] L is selected from C 3-6 cycloalkyl (C 3-6 Monocyclic cycloalkyl or C 5-6 Dicyclic cycloalkyl), 5-6 membered dicyclic heterocyclic alkyl (having one 5-6 membered dicyclic heterocyclic alkyl group selected from O atom) and

[0244] Wherein C 3-6 cycloalkyl groups are formed by one or more R groups a Replace, R a Each was independently selected from C 1-4 Alkyl, Halogenated C 1-4 Alkyl and deuterated C 1-4 alkyl;

[0245] L 5 and L 6 Each is independently selected from H and C. 3-6 cycloalkyl (C 3-6 Monocyclic cycloalkyl); L 7 Selected from 5-9 membered bicyclic heterocyclic alkyl groups (5-9 membered spirocyclic heterocyclic alkyl groups), wherein the 5-9 membered bicyclic heterocyclic alkyl group is optionally surrounded by one or more R groups. d Replace, R d Each is independently a -C(=O)-3-6 membered monocyclic heterocyclic alkyl (a 3-6 membered monocyclic heterocyclic alkyl having 1 N atom), wherein the -C(=O)-3-6 membered monocyclic heterocyclic alkyl is optionally substituted by one or more substituents selected from -CH3 and cyclopropyl;

[0246] L is preferred

[0247] In some embodiments, compounds of formula (II-1) and formula (II-2) are used, wherein

[0248] R 1 C 1-4 Alkyl, preferably ethyl; R 2 For H; or R 1 and R 2 Together with the indole group to which it is attached, it forms

[0249] R 4 R 5 R 6 R 8 R 9 R 12 and R 13 Each is independently selected from H;

[0250] R 10 and R 11 Each independently is C 1-4 Alkyl groups, preferably methyl groups;

[0251] m, n, p, and q are each independently 0;

[0252] R 14 For optional use by one or more R 14-1 The substituted 3-6 membered heterocyclic alkyl group, preferably optionally replaced by one or more R 14-1 Substituted 3-6 membered monocyclic heterocyclic alkyl groups; R 14-1 Each independently is C 1-4 Alkyl group, preferably methyl group; R 14 For example,

[0253] R 16 C 1-4 Alkyl, wherein the C 1-4 Alkyl groups are optionally surrounded by one or more R 16-1 Replace; R 16-1 Each independently as -OC 1-4 Alkyl group, preferably -OCH3; R 16 Preferably, it is -CH(CH3)-OCH3, for example,

[0254] L is arbitrarily assigned to one or more R. a Replacement C 3-6 cycloalkyl; R a Each was independently selected from C 1-4 Alkyl and Halogenated C 1-4 Alkyl; L, for example, is

[0255] In some embodiments, the compound represented by formula (I) is the compound represented by formula (II-1') or the compound represented by formula (II-2').

[0256] Among them, R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11 R 12 R 13 R 14 R 15 R 16 The definitions of L, m, n and p are as described above.

[0257] In some embodiments, the compound represented by formula (I) is the compound represented by formula (II-1a), the compound represented by formula (II-1b), the compound represented by formula (II-1c), or the compound represented by formula (II-1d).

[0258] Among them, R 1 and R 2 Each is independently selected from H, D, and C. 1-4 Alkyl, Halogenated C 1-4 Alkyl and deuterated C 1-4 alkyl;

[0259] R, R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11 R 12 R 13 R 14 R 15 R 16 The definitions of L, m, n, p, and q are as described above.

[0260] In some embodiments, the compound represented by formula (I) is the compound represented by formula (II-1a'), the compound represented by formula (II-1b'), the compound represented by formula (II-1c'), or the compound represented by formula (II-1d').

[0261] Among them, R 1 and R 2 Each is independently selected from H, D, and C. 1-4 Alkyl, Halogenated C 1-4 Alkyl and deuterated C 1-4 alkyl;

[0262] R, R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11 R 12 R 13 R 14 R 15 R 16 The definitions of L, m, n, p, and q are as described above.

[0263] In some embodiments, the compound represented by formula (I) is the compound represented by formula (II-2a), the compound represented by formula (II-2b), the compound represented by formula (II-2c), or the compound represented by formula (II-2d).

[0264] Among them, R 1 and R 2 Each is independently selected from H, D, and C. 1-4 Alkyl, Halogenated C 1-4 Alkyl and deuterated C 1-4 alkyl;

[0265] R, R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11 R 12 R 13 R 14 R 15 R 16 The definitions of L, m, n, p, and q are as described above.

[0266] In some embodiments, the compound represented by formula (I) is the compound represented by formula (II-2a'), the compound represented by formula (II-2b'), the compound represented by formula (II-2c'), or the compound represented by formula (II-2d').

[0267] Among them, R 1 and R 2 Each is independently selected from H, D, and C. 1-4 Alkyl, Halogenated C 1-4 Alkyl and deuterated C 1-4 alkyl;

[0268] R, R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11 R 12 R 13 R 14 R 15 R 16 The definitions of L, m, n, p, and q are as described above.

[0269] In some embodiments, compounds of formula (II-1a), formula (II-2a), formula (II-1a'), and formula (II-2a') are used, wherein...

[0270] R 1 Selected from C 1-4 Alkyl, Halogenated C 1-4 Alkyl and deuterated C 1-4 Alkyl group; preferably selected from -CH2CH3, -CH2CF3, -CD2CD3 and -CH2CD3;

[0271] R 2 Selected from H;

[0272] R 4 R 5 R 6 R 8 R 9 R 12 and R 13 Each is independently selected from H;

[0273] R 10 and R 11 Each independently is C 1-4 Alkyl or deuterated C 1-4 Alkyl; preferably methyl;

[0274] m, n, p, and q are each independently 0;

[0275] R 14Selected from H and 5-6 membered monocyclic heterocyclic alkyl groups (piperazinyl or morpholinyl), wherein the 5-6 membered monocyclic heterocyclic alkyl group is optionally surrounded by one or more R groups. 14-1 replace,

[0276] R 14-1 Each was independently selected from C 1-4 Alkyl and C 3-6 cycloalkyl (C 3-6 Monocyclic cycloalkyl), the C 1-4 Alkyl and C 3-6 The cycloalkyl group may optionally be substituted with one or more D atoms;

[0277] R 14 H is preferred.

[0278] R 16 C 1-4 Alkyl, wherein the C 1-4 Alkyl groups are optionally surrounded by one or more R 16-1 Replace, R 16-1 Each independently as -OC 1-4 Alkyl; R 16 Preferably, it is -CH(CH3)-OCH3;

[0279] L is selected from C 3-6 cycloalkyl (C 3-6 Monocyclic cycloalkyl or C 5-6 Dicyclic cycloalkyl), 5-6 membered dicyclic heterocyclic alkyl (having one 5-6 membered dicyclic heterocyclic alkyl group selected from O atom) and

[0280] Wherein C 3-6 cycloalkyl groups are formed by one or more R groups a Replace, R a Each was independently selected from C 1-4 Alkyl, Halogenated C 1-4 Alkyl and deuterated C 1-4 alkyl;

[0281] L 5 and L 6 Each is independently selected from H and C. 3-6 cycloalkyl (C 3-6 Monocyclic cycloalkyl); L 7 Selected from 5-9 membered bicyclic heterocyclic alkyl groups (5-9 membered spirocyclic heterocyclic alkyl groups), wherein the 5-9 membered bicyclic heterocyclic alkyl group is optionally surrounded by one or more R groups. d Replace, R dEach is independently a -C(=O)-3-6 membered monocyclic heterocyclic alkyl (a 3-6 membered monocyclic heterocyclic alkyl having 1 N atom), wherein the -C(=O)-3-6 membered monocyclic heterocyclic alkyl is optionally substituted by one or more substituents selected from -CH3 and cyclopropyl;

[0282] L is preferred

[0283] In some embodiments, compounds of formula (II-1a), formula (II-2a), formula (II-1a'), and formula (II-2a') are used, wherein...

[0284] R 1 C 1-4 Alkyl, preferably ethyl; R 2 For H;

[0285] R 4 R 5 R 6 R 8 R 9 R 12 and R 13 Each is independently selected from H;

[0286] R 10 and R 11 Each independently is C 1-4 Alkyl groups, preferably methyl groups;

[0287] m, n, p, and q are each independently 0;

[0288] R 14 For optional use by one or more R 14-1 The substituted 3-6 membered heterocyclic alkyl group, preferably optionally replaced by one or more R 14-1 Substituted 3-6 membered monocyclic heterocyclic alkyl groups; R 14-1 Each independently is C 1-4 Alkyl group, preferably methyl group; R 14 For example,

[0289] R 16 C 1-4 Alkyl, wherein the C 1-4 Alkyl groups are optionally surrounded by one or more R 16-1 Replace; R 16-1 Each independently as -OC 1-4 Alkyl group, preferably -OCH3; R 16 Preferably, it is -CH(CH3)-OCH3, for example,

[0290] L is arbitrarily assigned to one or more R. a Replacement C 3-6 cycloalkyl; R a Each was independently selected from C 1-4 Alkyl and Halogenated C 1-4 Alkyl; L, for example, is

[0291] In some embodiments, compounds of formula (II-1b), (II-1c), (II-1d), (II-2b), (II-2c), (II-2d), (II-1b'), (II-1c'), (II-1d'), (II-2b'), (II-2c'), and (II-2d') are used, wherein...

[0292] R 4 R 5 R 6 R 8 R 9 R 12 and R 13 Each is independently selected from H;

[0293] R 10 and R 11 Each independently is C 1-4 Alkyl or deuterated C 1-4 Alkyl; preferably methyl;

[0294] m, n, p, and q are each independently 0;

[0295] R 14 Selected from H and 5-6 membered monocyclic heterocyclic alkyl groups (piperazinyl or morpholinyl), wherein the 5-6 membered monocyclic heterocyclic alkyl group is optionally surrounded by one or more R groups. 14-1 replace,

[0296] R 14-1 Each was independently selected from C 1-4 Alkyl and C 3-6 cycloalkyl (C 3-6 Monocyclic cycloalkyl), the C 1-4 Alkyl and C 3-6 The cycloalkyl group may optionally be substituted with one or more D atoms;

[0297] R 14 H is preferred.

[0298] R 16 C 1-4Alkyl, wherein the C 1-4 Alkyl groups are optionally surrounded by one or more R 16-1 Replace, R 16-1 Each independently as -OC 1-4 Alkyl; R 16 Preferably, it is -CH(CH3)-OCH3;

[0299] L is selected from C 3-6 cycloalkyl (C 3-6 Monocyclic cycloalkyl or C 5-6 Dicyclic cycloalkyl), 5-6 membered dicyclic heterocyclic alkyl (having one 5-6 membered dicyclic heterocyclic alkyl group selected from O atom) and

[0300] Wherein C 3-6 cycloalkyl groups are formed by one or more R groups a Replace, R a Each was independently selected from C 1-4 Alkyl, Halogenated C 1-4 Alkyl and deuterated C 1-4 alkyl;

[0301] L 5 and L 6 Each is independently selected from H and C. 3-6 cycloalkyl (C 3-6 Monocyclic cycloalkyl); L 7 Selected from 5-9 membered bicyclic heterocyclic alkyl groups (5-9 membered spirocyclic heterocyclic alkyl groups), wherein the 5-9 membered bicyclic heterocyclic alkyl group is optionally surrounded by one or more R groups. d Replace, R d Each is independently a -C(=O)-3-6 membered monocyclic heterocyclic alkyl (a 3-6 membered monocyclic heterocyclic alkyl having 1 N atom), wherein the -C(=O)-3-6 membered monocyclic heterocyclic alkyl is optionally substituted by one or more substituents selected from -CH3 and cyclopropyl;

[0302] L is preferred

[0303] In some embodiments, compounds of formula (II-1b), (II-1c), (II-1d), (II-2b), (II-2c), (II-2d), (II-1b'), (II-1c'), (II-1d'), (II-2b'), (II-2c'), and (II-2d') are used, wherein

[0304] R 4 R5 R 6 R 8 R 9 R 12 and R 13 Each is independently selected from H;

[0305] R 10 and R 11 Each independently is C 1-4 Alkyl groups, preferably methyl groups;

[0306] m, n, p, and q are each independently 0;

[0307] R 14 For optional use by one or more R 14-1 The substituted 3-6 membered heterocyclic alkyl group, preferably optionally replaced by one or more R 14-1 Substituted 3-6 membered monocyclic heterocyclic alkyl groups; R 14-1 Each independently is C 1-4 Alkyl group, preferably methyl group; R 14 For example,

[0308] R 16 C 1-4 Alkyl, wherein the C 1-4 Alkyl groups are optionally surrounded by one or more R 16-1 Replace; R 16-1 Each independently as -OC 1-4 Alkyl group, preferably -OCH3; R 16 Preferably, it is -CH(CH3)-OCH3, for example,

[0309] L is arbitrarily assigned to one or more R. a Replacement C 3-6 cycloalkyl; R a Each was independently selected from C 1-4 Alkyl and Halogenated C 1-4 Alkyl; L, for example, is

[0310] In some embodiments, the compound represented by formula (I) is a compound represented by formula (III-1), a compound represented by formula (III-2), a compound represented by formula (III-3), or a compound represented by formula (III-4).

[0311] Among them, R, R 3 R 4 R 5 R 6 R 7 R8 R 9 R 10 R 11 R 12 R 13 R 14 R 15 R 16 The definitions of L, m, n, p, and q are as described above.

[0312] In some embodiments, the compound represented by formula (I) is the compound represented by formula (III-1), the compound represented by formula (III-2), the compound represented by formula (III-3), and the compound represented by formula (III-4), wherein,

[0313] R 4 R 5 R 6 R 8 R 9 R 12 and R 13 Each is independently selected from H;

[0314] R 10 and R 11 Each independently is C 1-4 Alkyl or deuterated C 1-4 Alkyl; preferably methyl;

[0315] m, n, p, and q are each independently 0;

[0316] R 14 Selected from H and 5-6 membered monocyclic heterocyclic alkyl groups (piperazinyl or morpholinyl), wherein the 5-6 membered monocyclic heterocyclic alkyl group is optionally surrounded by one or more R groups. 14-1 replace,

[0317] R 14-1 Each was independently selected from C 1-4 Alkyl and C 3-6 cycloalkyl (C 3-6 Monocyclic cycloalkyl), the C 1-4 Alkyl and C 3-6 The cycloalkyl group may optionally be substituted with one or more D atoms;

[0318] R 14 H is preferred.

[0319] R 16 C 1-4 Alkyl, wherein the C 1-4 Alkyl groups are optionally surrounded by one or more R 16-1 Replace, R 16-1 Each independently as -OC 1-4 Alkyl; R16 Preferably, it is -CH(CH3)-OCH3;

[0320] L is selected from C 3-6 cycloalkyl (C 3-6 Monocyclic cycloalkyl or C 5-6 Dicyclic cycloalkyl), 5-6 membered dicyclic heterocyclic alkyl (having one 5-6 membered dicyclic heterocyclic alkyl group selected from O atom) and

[0321] Wherein C 3-6 cycloalkyl groups are formed by one or more R groups a Replace, R a Each was independently selected from C 1-4 Alkyl, Halogenated C 1-4 Alkyl and deuterated C 1-4 alkyl;

[0322] L 5 and L 6 Each is independently selected from H and C. 3-6 cycloalkyl (C 3-6 Monocyclic cycloalkyl); L 7 Selected from 5-9 membered bicyclic heterocyclic alkyl groups (5-9 membered spirocyclic heterocyclic alkyl groups), wherein the 5-9 membered bicyclic heterocyclic alkyl group is optionally surrounded by one or more R groups. d Replace, R d Each is independently a -C(=O)-3-6 membered monocyclic heterocyclic alkyl (a 3-6 membered monocyclic heterocyclic alkyl having 1 N atom), wherein the -C(=O)-3-6 membered monocyclic heterocyclic alkyl is optionally substituted by one or more substituents selected from -CH3 and cyclopropyl;

[0323] L is preferred

[0324] In some embodiments, the compound represented by formula (I) is the compound represented by formula (III-1), the compound represented by formula (III-2), the compound represented by formula (III-3), and the compound represented by formula (III-4), wherein...

[0325] R 4 R 5 R 6 R 8 R 9 R 12 and R 13 Each is independently selected from H;

[0326] R 10 and R 11 Each independently is C 1-4 Alkyl groups, preferably methyl groups;

[0327] m, n, p, and q are each independently 0;

[0328] R 14 For optional use by one or more R 14-1 The substituted 3-6 membered heterocyclic alkyl group, preferably optionally replaced by one or more R 14-1 Substituted 3-6 membered monocyclic heterocyclic alkyl groups; R 14-1 Each independently is C 1-4 Alkyl group, preferably methyl group; R 14 For example,

[0329] R 16 C 1-4 Alkyl, wherein the C 1-4 Alkyl groups are optionally surrounded by one or more R 16-1 Replace; R 16-1 Each independently as -OC 1-4 Alkyl group, preferably -OCH3; R 16 Preferably, it is -CH(CH3)-OCH3, for example,

[0330] L is arbitrarily assigned to one or more R. a Replacement C 3-6 cycloalkyl; R a Each was independently selected from C 1-4 Alkyl and Halogenated C 1-4 Alkyl; L, for example, is

[0331] In some embodiments, the compound represented by formula (I) is a compound represented by formula (III-1'), a compound represented by formula (III-2'), a compound represented by formula (III-3'), or a compound represented by formula (III-4'), or a pharmaceutically acceptable salt thereof.

[0332] Among them, R, R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11 R 12 R 13 R 15 The definitions of L, m, n, p, and q are as described above.

[0333] In some embodiments, the compound represented by formula (I) is selected from compounds of any of the following structural formulas:

[0334] The present invention also provides a pharmaceutical composition comprising:

[0335] (1) The compound represented by formula (I) above, or a pharmaceutically acceptable salt thereof, and

[0336] (2) Pharmaceutically acceptable excipients.

[0337] The present invention also provides an application of substance A, wherein substance A comprises a compound of formula (I) above or a pharmaceutically acceptable salt thereof, or the above pharmaceutical composition, which is used as a medicine.

[0338] The present invention also provides the use of substance A in the preparation of RAS inhibitors, wherein substance A comprises the compound shown in formula (I) above or a pharmaceutically acceptable salt thereof, or the above pharmaceutical composition.

[0339] In some implementations, the RAS inhibitor is a RAS mutation inhibitor.

[0340] In some embodiments, the RAS inhibitor can be used in mammalian organisms; it can also be used in vitro, primarily for experimental purposes, such as providing a standard or control sample for comparison, or preparing a kit according to conventional methods in the art to provide rapid detection of the effect of inhibiting RAS mutations.

[0341] The present invention also provides the use of substance A in the preparation of a pharmaceutical, wherein substance A comprises the compound shown in formula (I) above or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition described above.

[0342] In some implementations, the drug is used to treat diseases associated with RAS.

[0343] In some implementations, the RAS-related disease is a disease associated with RAS mutations.

[0344] In some implementations, the disease associated with RAS mutations is RAS mutation-associated cancer.

[0345] In some implementations, the RAS mutation is selected from one or more of the KRAS mutation, NRAS mutation, and HRAS mutation.

[0346] In some implementations, the KRAS mutation is selected from KRAS. G12C Mutation, KRAS G12DMutation, KRAS G12V Mutation, KRAS G12R Mutation, KRAS G13C Mutations and KRAS G13D One or more of the mutations.

[0347] In some implementations, the disease associated with RAS mutations is selected from one or more of the following: digestive system cancers, respiratory system cancers, and hematologic cancers.

[0348] In some implementations, the drug is used to treat one or more of the following: digestive system cancers, respiratory system cancers, and hematologic system cancers.

[0349] The present invention also provides the use of substance A in the preparation of a medicament for treating RAS-related diseases, wherein substance A comprises a compound represented by formula (I) above or a pharmaceutically acceptable salt thereof, or the above pharmaceutical composition.

[0350] In some implementations, the RAS-related disease is a disease associated with RAS mutations.

[0351] In some implementations, the disease associated with RAS mutations is RAS mutation-associated cancer.

[0352] In some implementations, the RAS mutation is selected from one or more of the KRAS mutation, NRAS mutation, and HRAS mutation.

[0353] In some implementations, the KRAS mutation is selected from KRAS. G12C Mutation, KRAS G12D Mutation, KRAS G12V Mutation, KRAS G12R Mutation, KRAS G13C Mutations and KRAS G13D One or more of the mutations.

[0354] In some implementations, the disease associated with RAS mutations is selected from one or more of the following: digestive system cancers, respiratory system cancers, and hematologic cancers.

[0355] The present invention also provides a method for treating and / or preventing RAS-related diseases, comprising administering to a subject in need a therapeutic and / or preventive effective amount of substance A, wherein substance A comprises a compound represented by formula (I) above or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition described above.

[0356] In some implementations, the RAS-related disease is a disease associated with RAS mutations.

[0357] In some implementations, the disease associated with RAS mutations is RAS mutation-associated cancer.

[0358] In some implementations, the RAS mutation is selected from one or more of the KRAS mutation, NRAS mutation, and HRAS mutation.

[0359] In some implementations, the KRAS mutation is selected from KRAS. G12C Mutation, KRAS G12D Mutation, KRAS G12V Mutation, KRAS G12R Mutation, KRAS G13C Mutations and KRAS G13D One or more of the mutations.

[0360] In some implementations, the disease associated with RAS mutations is selected from one or more of the following: digestive system cancers, respiratory system cancers, and hematologic cancers.

[0361] This invention also provides compounds selected from any of the following structural formulas and pharmaceutically acceptable salts thereof:

[0362] The present invention also provides a method for preparing the compound of formula (I) or a pharmaceutically acceptable salt thereof, comprising the following steps:

[0363] In an organic solvent, in the presence of a condensing agent and an organic base, the compound shown in formula (Ia) undergoes a self-condensation reaction to give the compound shown in formula (I).

[0364] Among them, rings A, X, and R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11 R 12 R 13 R 15 R 16 The definitions of L, m, n and p are as described above.

[0365] In the method for preparing the compound shown in formula (I), the organic solvent can be a conventional organic solvent for such reactions in the art, such as a haloalkane solvent, preferably dichloromethane. The condensing agent can be a conventional condensing agent for such reactions in the art, such as EDCI and HOBt. Preferably, the organic base can be a conventional organic base for such reactions in the art, such as an aliphatic amine, preferably diisopropylethylamine.

[0366] The present invention also provides a method for preparing the compound shown in formula (I-1), which includes the following steps:

[0367] In a solvent, in the presence of an acid, formaldehyde, and a reducing agent, the compound shown in formula (I-2) undergoes a methylation reaction to give the compound shown in formula (I-1);

[0368] Among them, rings A and R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11 R 12 R 13 R 15 R 16 The definitions of L, m, n and p are as described above.

[0369] In the preparation method of the compound shown in formula (I-1), the reaction conditions for the methylation reaction can be conventional reaction conditions for such reactions in the art. The solvent can be a conventional solvent for such reactions in the art. The acid can be a conventional acid for such reactions in the art. The reducing agent can be a conventional reducing agent for such reactions in the art.

[0370] The present invention also provides a method for preparing the compound shown in formula (I-2), which includes the following steps:

[0371] In a solvent, in the presence of a Cbz-removing reagent, the compound shown in formula (II) undergoes a Cbz-removing reaction to give the compound shown in formula (I-2);

[0372] Among them, rings A and R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R9 R 10 R 11 R 12 R 13 R 15 R 16 The definitions of L, m, n, and p are as described above, as well as R 14 for

[0373] In the preparation method of the compound shown in formula (I-2), the reaction conditions for the Cbz removal reaction can be conventional reaction conditions for such reactions in the art. The solvent can be a conventional solvent for such reactions in the art. The Cbz removal reagent can be a conventional Cbz removal reagent for such reactions in the art.

[0374] The present invention also provides a method for preparing the compound shown in formula (II), which includes the following steps:

[0375] In a solvent, in the presence of a base and a condensing agent, the compound shown in formula (II-1-1) undergoes a condensation reaction with the compound shown in formula (a) to obtain the compound shown in formula (II).

[0376] Among them, rings A and R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11 R 12 R 13 R 14 R 15 R 16 The definitions of L, m, n and p are as described above.

[0377] In the method for preparing the compound shown in formula (II), the reaction conditions for the condensation reaction can be conventional reaction conditions for such reactions in the art. The solvent can be a conventional solvent for such reactions in the art. The base can be a conventional base for such reactions in the art. The condensing agent can be a conventional condensing agent for such reactions in the art.

[0378] The present invention also provides a method for preparing the compound shown in formula (II-1-1), which includes the following steps:

[0379] In a solvent, in the presence of an acid, the compound shown in formula (II-1-2) undergoes a deBoc protection reaction to give the compound shown in formula (II-1-1).

[0380] Among them, rings A and R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11 R 12 R 13 R 14 R 15 R 16 The definitions of m, n and p are as described above.

[0381] The present invention also provides a method for preparing the compound shown in formula (II-1-1), which includes the following steps:

[0382] In a solvent, in the presence of an acid, the compound shown in formula (II-1-2) undergoes a deBoc protection reaction to give the compound shown in formula (II-1-1).

[0383] Among them, rings A and R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11 R 12 R 13 R 14 R 15 R 16 The definitions of m, n and p are as described above.

[0384] In the preparation method of the compound shown in formula (II-1-1), the reaction conditions for the deBoc protection reaction can be the conventional reaction conditions for such reactions in the art. The solvent can be a conventional organic solvent for such reactions in the art. The acid can be a conventional acid for such reactions in the art.

[0385] The present invention also provides a method for preparing the compound shown in formula (II-1-2), which includes the following steps:

[0386] In a solvent, in the presence of a condensing agent and a base, the compound shown in formula (II-1-3) undergoes a self-condensation reaction to give the compound shown in formula (II-1-2);

[0387] Among them, rings A and R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11 R 12 R 13 R 14 R 15 R 16 The definitions of m, n and p are as described above.

[0388] In the preparation method of the compound shown in formula (II-1-2), the reaction conditions for the self-condensation reaction can be conventional reaction conditions for such reactions in the art. The solvent can be a conventional solvent for such reactions in the art. The base can be a conventional base for such reactions in the art. The condensing agent can be a conventional condensing agent for such reactions in the art.

[0389] The present invention also provides a method for preparing the compound shown in formula (II-1-3), which includes the following steps:

[0390] In a solvent, in the presence of a base, the compound shown in formula (II-1-4) undergoes a deprotection reaction to give the compound shown in formula (II-1-3);

[0391] Among them, rings A and R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11 R 12 R 13 R 14 R 15 R 16 The definitions of m, n and p are as described above.

[0392] In the preparation method of the compound shown in formula (II-1-3), the reaction conditions for the deprotection reaction can be conventional reaction conditions for such reactions in the art. The solvent can be a conventional solvent for such reactions in the art. The base can be a conventional base for such reactions in the art.

[0393] The present invention also provides a method for preparing the compound shown in formula (II-1-4), which includes the following steps:

[0394] In a solvent, in the presence of a base, the compound shown in formula (II-1-5) undergoes ester hydrolysis to give the compound shown in formula (II-1-4);

[0395] Among them, rings A and R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11 R 12 R 13 R 14 R 15 R 16 The definitions of m, n and p are as described above.

[0396] In the preparation method of the compound shown in formula (II-1-4), the reaction conditions for the ester hydrolysis reaction can be conventional reaction conditions for such reactions in the art. The solvent can be a conventional solvent for such reactions in the art. The base can be a conventional base for such reactions in the art.

[0397] The present invention also provides a method for preparing the compound shown in formula (II-1-5), which includes the following steps:

[0398] In a solvent, in the presence of a base and a condensing agent, the compound shown in formula (II-1-6) undergoes a condensation reaction with the compound shown in formula (b) to give the compound shown in formula (II-1-5).

[0399] Among them, rings A and R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11 R 12 R 13 R 14 R 15 R 16 The definitions of m, n and p are as described above.

[0400] In the preparation method of the compound shown in formula (II-1-5), the reaction conditions for the condensation reaction can be conventional reaction conditions for such reactions in the art. The solvent can be a conventional solvent for such reactions in the art. The base can be a conventional base for such reactions in the art. The condensing agent can be a conventional condensing agent for such reactions in the art.

[0401] The present invention also provides a method for preparing the compound shown in formula (II-1-6), which includes the following steps:

[0402] In a solvent, in the presence of a base, the compound shown in formula (II-1-7) undergoes ester hydrolysis to give the compound shown in formula (II-1-6);

[0403] Among them, R 1 R 2 R 3 R 4 R 5 R 6 R 8 R 9 R 10 R 11 R 12 R 13 R 14 R 15 R 16 The definitions of m and p are as described above.

[0404] In the preparation method of the compound shown in formula (II-1-6), the reaction conditions for the ester hydrolysis reaction can be conventional reaction conditions for such reactions in the art. The solvent can be a conventional solvent for such reactions in the art. The base can be a conventional base for such reactions in the art.

[0405] The present invention also provides a method for preparing the compound shown in formula (II-1-7), which includes the following steps:

[0406] In a solvent, the compound shown in formula (II-1-8) undergoes a cyclization reaction with the compound shown in formula (c) to give the compound shown in formula (II-1-7);

[0407] Among them, R 1 R 2 R 3 R 4 R 5 R 6 R 8 R 9 R 10 R 11 R 12R 13 R 14 R 15 R 16 The definitions of m and p are as described above.

[0408] In the preparation method of the compound shown in formula (II-1-7), the reaction conditions for the cyclization reaction can be the conventional reaction conditions for such reactions in the art. The solvent can be a conventional solvent for such reactions in the art.

[0409] The present invention also provides a method for preparing the compound shown in formula (c), which includes the following steps:

[0410] In a solvent, in the presence of phosphorus pentaselenide, the compound shown in formula (c-1) undergoes a reductive selenization reaction to obtain the compound shown in formula (c).

[0411] Among them, R 5 and R 6 The definition is as described above.

[0412] In the preparation method of the compound shown in formula (c), the reaction conditions for the reductive selenization reaction can be the conventional reaction conditions for such reactions in the art. The solvent can be a conventional solvent for such reactions in the art.

[0413] The present invention also provides a method for preparing the compound shown in formula (c-1), which includes the following steps:

[0414] In a solvent, in the presence of a base and an oxidizing agent, the compound shown in formula (c-2) undergoes an oxidation reaction to give the compound shown in formula (c-1);

[0415] Among them, R 5 and R 6 The definition is as described above.

[0416] In the preparation method of the compound shown in formula (c-1), the reaction conditions for the oxidation reaction can be conventional reaction conditions for such reactions in the art. The solvent can be a conventional solvent for such reactions in the art. The base can be a conventional base for such reactions in the art. The oxidizing agent can be a conventional oxidizing agent for such reactions in the art.

[0417] The present invention also provides a method for preparing the compound shown in formula (II-1-8), which includes the following steps:

[0418] In a solvent, in the presence of a brominating agent, the compound shown in formula (II-1-9) undergoes a bromination reaction to give the compound shown in formula (II-1-8);

[0419] Among them, R 1 R 2 R 3 R 4 R 8 R 9 R 10 R 11 R 12 R 13 R 14 R 15 R 16 The definitions of m and p are as described above.

[0420] In the preparation method of the compound shown in formula (II-1-8), the reaction conditions for the bromination reaction can be conventional reaction conditions for such reactions in the art. The solvent can be a conventional solvent for such reactions in the art. The brominating agent can be a conventional brominating agent for such reactions in the art.

[0421] The present invention also provides a method for preparing the compound shown in formula (II-1-9), which includes the following steps:

[0422] In a solvent, in the presence of a base and TBSOTf, the compound shown in formula (II-1-10) undergoes an enol tautomerization followed by a hydroxyl protection reaction to give the compound shown in formula (II-1-9).

[0423] Among them, R 1 R 2 R 3 R 4 R 8 R 9 R 10 R 11 R 12 R 13 R 14 R 15 R 16 The definitions of m and p are as described above.

[0424] In the preparation method of the compound shown in formula (II-1-9), the reaction conditions for the hydroxyl protection reaction can be conventional reaction conditions for such reactions in the art. The solvent can be a conventional solvent for such reactions in the art. The base can be a conventional base for such reactions in the art.

[0425] The present invention also provides a method for preparing the compound shown in formula (II-1-10), which includes the following steps:

[0426] In a solvent, in the presence of an oxidizing agent, the compound shown in formula (II-1-11) undergoes an oxidation reaction to give the compound shown in formula (II-1-10);

[0427] Among them, R 1 R 2 R 3 R 4 R 8 R 9 R 10 R 11 R 12 R 13 R 14 R 15 R 16 The definitions of m and p are as described above.

[0428] In the preparation method of the compound shown in formula (II-1-10), the reaction conditions for the oxidation reaction can be conventional reaction conditions for such reactions in the art. The solvent can be a conventional solvent for such reactions in the art. The oxidant can be a conventional oxidant for such reactions in the art.

[0429] The present invention also provides a method for preparing the compound shown in formula (II-1-11), which includes the following steps:

[0430] In a solvent, in the presence of a base and a catalyst, the compound shown in formula (II-1-12) undergoes a coupling reaction with the compound shown in formula (d) to give the compound shown in formula (II-1-11).

[0431] Among them, R 1 R 2 R 3 R 4 R 8 R 9 R 10 R 11 R 12 R 13 R 14 R 15 R 16 The definitions of m and p are as described above.

[0432] In the method for preparing the compound shown in formula (II-1-11), the reaction conditions for the coupling reaction can be conventional reaction conditions for such reactions in the art. The solvent can be a conventional solvent for such reactions in the art. The base can be a conventional base for such reactions in the art. The catalyst can be a conventional catalyst for such reactions in the art.

[0433] The present invention also provides a method for preparing the compound shown in formula (II-1-12), which includes the following steps:

[0434] In a solvent, in the presence of a base and TBDPSCl, the compound shown in formula (II-1-13) undergoes a hydroxyl protection reaction to give the compound shown in formula (II-1-12);

[0435] Among them, R 1 R 2 R 3 R 8 R 9 R 10 R 11 R 12 R 13 R 14 R 15 R 16 The definitions of m and p are as described above.

[0436] In the method for preparing the compound shown in formula (II-1-12), the reaction conditions for the hydroxyl protection reaction can be conventional reaction conditions for such reactions in the art. The solvent can be a conventional solvent for such reactions in the art. The base can be a conventional base for such reactions in the art.

[0437] In some embodiments, in the methods for preparing the compound represented by formula (II), the compound represented by formula (II-1-1), the compound represented by formula (II-1-2), the compound represented by formula (II-1-3), the compound represented by formula (II-1-4), the compound represented by formula (II-1-5), the compound represented by formula (II-1-6), the compound represented by formula (II-1-7), the compound represented by formula (II-1-8), the compound represented by formula (II-1-9), the compound represented by formula (II-1-10), the compound represented by formula (II-1-11), and the compound represented by formula (II-1-12), when R 14 When -NH2 or -NH- is present, the -NH2 or -NH- is protected by an amino protecting group, such as Cbz. The amino protecting group can be a conventional amino protecting group for this type of reaction in the art, such as Cbz. 14 For example,

[0438] In some embodiments, in the methods for preparing the compound shown in formula (II-1-3), the compound shown in formula (II-1-4), the compound shown in formula (II-1-5), the compound shown in formula (II-1-6), the compound shown in formula (II-1-7), the compound shown in formula (II-1-8), the compound shown in formula (II-1-9), the compound shown in formula (II-1-10), the compound shown in formula (II-1-11), and the compound shown in formula (II-1-12), TBSCl can be used to replace TBDPSCl to prepare an intermediate with a substituent of -OSBT.

[0439] The present invention also provides a method for preparing the compound shown in formula (A-1), which includes the following steps:

[0440] In a solvent, in the presence of an acid, formaldehyde, and a reducing agent, the compound shown in formula (A-2) undergoes a methylation reaction to give the compound shown in formula (A-1);

[0441] Among them, rings A, X, and R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11 R 12 R 13 R 15 R 16 The definitions of L, m, n and p are as described above.

[0442] In the method for preparing the compound shown in formula (A-1), the reaction conditions for the methylation reaction can be conventional reaction conditions for such reactions in the art. The solvent can be a conventional solvent for such reactions in the art. The acid can be a conventional acid for such reactions in the art. The reducing agent can be a conventional reducing agent for such reactions in the art.

[0443] The present invention also provides a method for preparing the compound shown in formula (A-2), which includes the following steps:

[0444] In a solvent, in the presence of a deamination protecting group (e.g., Cbz) reagent, the compound shown in formula (A-3) undergoes a deprotection reaction to give the compound shown in formula (A-2);

[0445] Among them, rings A, X, and R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11 R 12 R 13 R 15 R 16 The definitions of L, m, n, and p are as described above, as well as PG. 1 It is an amino protecting group, for example, Cbz.

[0446] In the preparation method of the compound shown in formula (A-2), the reaction conditions for the deprotection reaction can be conventional reaction conditions for such reactions in the art. The solvent can be a conventional solvent for such reactions in the art. The deamination protecting group (e.g., Cbz) reagent can be a conventional deamination protecting group (e.g., Cbz) reagent for such reactions in the art.

[0447] The present invention also provides a method for preparing the compound shown in formula (A-3), which includes the following steps:

[0448] In a solvent, in the presence of a base and a condensing agent, the compound shown in formula (A-4) undergoes a condensation reaction with the compound shown in formula (a) to obtain the compound shown in formula (A-3).

[0449] Among them, rings A, X, and PG 1 R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11 R 12 R 13 R 15 R 16 The definitions of L, m, n and p are as described above.

[0450] In the method for preparing the compound shown in formula (A-3), the reaction conditions for the condensation reaction can be conventional reaction conditions for such reactions in the art. The solvent can be a conventional solvent for such reactions in the art. The base can be a conventional base for such reactions in the art. The condensing agent can be a conventional condensing agent for such reactions in the art.

[0451] The present invention also provides a method for preparing the compound shown in formula (A-4), which includes the following steps:

[0452] In a solvent, in the presence of an acid, the compound shown in formula (A-5) undergoes a deBoc protection reaction to give the compound shown in formula (A-4).

[0453] Among them, rings A, X, and PG 1 R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11 R 12 R 13 R 15 R 16 The definitions of m, n and p are as described above.

[0454] In the preparation method of the compound shown in formula (A-4), the reaction conditions for the deBoc protection reaction can be the conventional reaction conditions for such reactions in the art. The solvent can be a conventional organic solvent for such reactions in the art. The acid can be a conventional acid for such reactions in the art.

[0455] The present invention also provides a method for preparing the compound shown in formula (A-5), which includes the following steps:

[0456] In a solvent, in the presence of a condensing agent and a base, the compound shown in formula (A-6) undergoes a self-condensation reaction to give the compound shown in formula (A-5).

[0457] Among them, rings A, X, and PG 1 R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R10 R 11 R 12 R 13 R 15 R 16 The definitions of m, n and p are as described above.

[0458] In the method for preparing the compound shown in formula (A-5), the reaction conditions for the self-condensation reaction can be conventional reaction conditions for such reactions in the art. The solvent can be a conventional solvent for such reactions in the art. The base can be a conventional base for such reactions in the art. The condensing agent can be a conventional condensing agent for such reactions in the art.

[0459] The present invention also provides a method for preparing the compound shown in formula (A-6), which includes the following steps:

[0460] In a solvent, in the presence of a base, the compound shown in formula (A-7) undergoes a deprotection reaction to give the compound shown in formula (A-6);

[0461] Among them, rings A, X, and PG 1 R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11 R 12 R 13 R 15 R 16 The definitions of m, n, and p are as described above, as well as PG. 2 It is a hydroxyl protecting group, such as TBDPS or TBS.

[0462] In the preparation method of the compound shown in formula (A-6), the deprotection reaction conditions can be conventional reaction conditions for such reactions in the art. The solvent can be a conventional solvent for such reactions in the art. The base can be a conventional base for such reactions in the art.

[0463] The present invention also provides a method for preparing the compound shown in formula (A-7), which includes the following steps:

[0464] In a solvent, in the presence of a base, the compound shown in formula (A-8) undergoes an ester hydrolysis reaction to give the compound shown in formula (A-7);

[0465] Among them, rings A, X, and PG1 PG 2 R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11 R 12 R 13 R 15 R 16 The definitions of m, n and p are as described above.

[0466] In the preparation method of the compound shown in formula (A-7), the reaction conditions for the ester hydrolysis reaction can be conventional reaction conditions for such reactions in the art. The solvent can be a conventional solvent for such reactions in the art. The base can be a conventional base for such reactions in the art.

[0467] The present invention also provides a method for preparing the compound shown in formula (A-8), which includes the following steps:

[0468] In a solvent, in the presence of a base and a condensing agent, the compound shown in formula (A-9) undergoes a condensation reaction with the compound shown in formula (b) to give the compound shown in formula (A-8).

[0469] Among them, rings A, X, and PG 1 PG 2 R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11 R 12 R 13 R 15 R 16 The definitions of m, n and p are as described above.

[0470] In the preparation method of the compound shown in formula (A-8), the reaction conditions for the condensation reaction can be conventional reaction conditions for such reactions in the art. The solvent can be a conventional solvent for such reactions in the art. The base can be a conventional base for such reactions in the art. The condensing agent can be a conventional condensing agent for such reactions in the art.

[0471] The present invention also provides a method for preparing the compound shown in formula (A-9), which includes the following steps:

[0472] In a solvent, in the presence of a base, the compound shown in formula (A-10) undergoes an ester hydrolysis reaction to give the compound shown in formula (A-9);

[0473] Among them, X and PG 1 PG 2 R 1 R 2 R 3 R 4 R 5 R 6 R 8 R 9 R 10 R 11 R 12 R 13 R 15 R 16 The definitions of m and p are as described above.

[0474] In the preparation method of the compound shown in formula (A-9), the reaction conditions for the ester hydrolysis reaction can be conventional reaction conditions for such reactions in the art. The solvent can be a conventional solvent for such reactions in the art. The base can be a conventional base for such reactions in the art.

[0475] The present invention also provides a method for preparing the compound shown in formula (A-10), which includes the following steps:

[0476] In a solvent, the compound shown in formula (A-11) undergoes a cyclization reaction with the compound shown in formula (c) to obtain the compound shown in formula (A-10);

[0477] Among them, X and PG 1 PG 2 R 1 R 2 R 3 R 4 R 5 R 6 R 8 R 9 R 10 R 11 R 12 R 13 R 15 R 16 The definitions of m and p are as described above.

[0478] In the preparation method of the compound shown in formula (A-10), the reaction conditions for the cyclization reaction can be the conventional reaction conditions for such reactions in the art. The solvent can be a conventional solvent for such reactions in the art.

[0479] The present invention also provides a method for preparing the compound shown in formula (A-11), which includes the following steps:

[0480] In a solvent, in the presence of a brominating agent, the compound shown in formula (A-12) undergoes a bromination reaction to give the compound shown in formula (A-11);

[0481] Among them, PG 1 PG 2 R 1 R 2 R 3 R 4 R 8 R 9 R 10 R 11 R 12 R 13 R 15 R 16 The definitions of m and p are as described above, as well as PG 3 It is a hydroxyl protecting group, such as TBS.

[0482] In the preparation method of the compound shown in formula (A-11), the reaction conditions for the bromination reaction can be conventional reaction conditions for such reactions in the art. The solvent can be a conventional solvent for such reactions in the art. The brominating agent can be a conventional brominating agent for such reactions in the art.

[0483] The present invention also provides a method for preparing the compound shown in formula (A-12), which includes the following steps:

[0484] In a solvent, in the presence of a base and a hydroxyl protecting agent (e.g., TBSOTf), the compound shown in formula (A-13) undergoes an enol tautomerization followed by a hydroxyl protecting reaction to yield the compound shown in formula (A-12).

[0485] Among them, PG 1 PG 2 PG 3 R 1 R 2 R 3 R 4 R 8 R 9 R 10 R 11 R 12R 13 R 15 R 16 The definitions of m and p are as described above.

[0486] In the preparation method of the compound shown in formula (A-12), the reaction conditions for the hydroxyl protection reaction can be conventional reaction conditions for such reactions in the art. The hydroxyl protecting agent can be a conventional hydroxyl protecting agent for such reactions in the art, such as TBSOTf. The solvent can be a conventional solvent for such reactions in the art. The base can be a conventional base for such reactions in the art.

[0487] The present invention also provides a method for preparing the compound shown in formula (A-13), which includes the following steps:

[0488] In a solvent, in the presence of an oxidizing agent, the compound shown in formula (A-14) undergoes an oxidation reaction to give the compound shown in formula (A-13);

[0489] Among them, PG 1 PG 2 R 1 R 2 R 3 R 4 R 8 R 9 R 10 R 11 R 12 R 13 R 15 R 16 The definitions of m and p are as described above.

[0490] In the preparation method of the compound shown in formula (A-13), the reaction conditions for the oxidation reaction can be conventional reaction conditions for such reactions in the art. The solvent can be a conventional solvent for such reactions in the art. The oxidant can be a conventional oxidant for such reactions in the art.

[0491] The present invention also provides a method for preparing the compound shown in formula (A-14), which includes the following steps:

[0492] In a solvent, in the presence of a base and a catalyst, the compound shown in formula (A-15) undergoes a coupling reaction with the compound shown in formula (d) to give the compound shown in formula (A-14).

[0493] Among them, X and PG 1 PG 2 R 1 R 2 R 3 R4 R 8 R 9 R 10 R 11 R 12 R 13 R 15 R 16 The definitions of m and p are as described above.

[0494] In the method for preparing the compound shown in formula (A-14), the reaction conditions for the coupling reaction can be conventional reaction conditions for such reactions in the art. The solvent can be a conventional solvent for such reactions in the art. The base can be a conventional base for such reactions in the art. The catalyst can be a conventional catalyst for such reactions in the art.

[0495] The present invention also provides a method for preparing the compound shown in formula (A-15), which includes the following steps:

[0496] In a solvent, in the presence of a base and a hydroxyl protecting agent (e.g., TBSCl or TBDPSCl), the compound shown in formula (A-16) undergoes a hydroxyl protection reaction to give the compound shown in formula (A-15).

[0497] Among them, PG 1 PG 2 R 1 R 2 R 3 R 8 R 9 R 10 R 11 R 12 R 13 R 15 R 16 The definitions of m and p are as described above.

[0498] In the preparation method of the compound shown in formula (A-15), the reaction conditions for the hydroxyl protection reaction can be conventional reaction conditions for such reactions in the art. The hydroxyl protecting agent can be a conventional hydroxyl protecting agent for such reactions in the art, such as TBSCl or TBDPSCl. The solvent can be a conventional solvent for such reactions in the art. The base can be a conventional base for such reactions in the art.

[0499] In some embodiments, the method for preparing the compound represented by formula (I-1) further includes the method for preparing the compound represented by formula (I-2).

[0500] In some embodiments, the method for preparing the compound represented by formula (I-2) further includes the method for preparing the compound represented by formula (II).

[0501] In some embodiments, the method for preparing the compound represented by formula (II) further includes the method for preparing the compound represented by formula (II-1-1).

[0502] In some embodiments, the method for preparing the compound shown in formula (II-1-1) further includes the method for preparing the compound shown in formula (II-1-2).

[0503] In some embodiments, the method for preparing the compound shown in formula (II-1-2) further includes the method for preparing the compound shown in formula (II-1-3).

[0504] In some embodiments, the method for preparing the compound shown in formula (II-1-3) further includes the method for preparing the compound shown in formula (II-1-4).

[0505] In some embodiments, the method for preparing the compound shown in formula (II-1-4) further includes the method for preparing the compound shown in formula (II-1-5).

[0506] In some embodiments, the method for preparing the compound shown in formula (II-1-5) further includes the method for preparing the compound shown in formula (II-1-6).

[0507] In some embodiments, the method for preparing the compound shown in formula (II-1-6) further includes the method for preparing the compound shown in formula (II-1-7).

[0508] In some embodiments, the method for preparing the compound shown in formula (II-1-7) further includes the method for preparing the compound shown in formula (c).

[0509] In some embodiments, the method for preparing the compound shown in formula (c) further includes the method for preparing the compound shown in formula (c-1).

[0510] In some embodiments, the method for preparing the compound shown in formula (II-1-7) further includes the method for preparing the compound shown in formula (II-1-8).

[0511] In some embodiments, the method for preparing the compound represented by formula (II-1-8) further includes the method for preparing the compound represented by formula (II-1-9).

[0512] In some embodiments, the method for preparing the compound represented by formula (II-1-9) further includes the method for preparing the compound represented by formula (II-1-10).

[0513] In some embodiments, the method for preparing the compound represented by formula (II-1-10) further includes the method for preparing the compound represented by formula (II-1-11).

[0514] In some embodiments, the method for preparing the compound represented by formula (II-1-11) further includes the method for preparing the compound represented by formula (II-1-12).

[0515] In some embodiments, the method for preparing the compound shown in formula (A-1) further includes the method for preparing the compound shown in formula (A-2).

[0516] In some embodiments, the method for preparing the compound shown in formula (A-2) further includes the method for preparing the compound shown in formula (A-3).

[0517] In some embodiments, the method for preparing the compound shown in formula (A-3) further includes the method for preparing the compound shown in formula (A-4).

[0518] In some embodiments, the method for preparing the compound shown in formula (A-4) further includes the method for preparing the compound shown in formula (A-5).

[0519] In some embodiments, the method for preparing the compound shown in formula (A-5) further includes the method for preparing the compound shown in formula (A-6).

[0520] In some embodiments, the method for preparing the compound shown in formula (A-6) further includes the method for preparing the compound shown in formula (A-7).

[0521] In some embodiments, the method for preparing the compound shown in formula (A-7) further includes the method for preparing the compound shown in formula (A-8).

[0522] In some embodiments, the method for preparing the compound shown in formula (A-8) further includes the method for preparing the compound shown in formula (A-9).

[0523] In some embodiments, the method for preparing the compound shown in formula (A-9) further includes the method for preparing the compound shown in formula (A-10).

[0524] In some embodiments, the method for preparing the compound represented by formula (A-10) further includes the method for preparing the compound represented by formula (A-11).

[0525] In some embodiments, the method for preparing the compound represented by formula (A-11) further includes the method for preparing the compound represented by formula (A-12).

[0526] In some embodiments, the method for preparing the compound shown in formula (A-12) further includes the method for preparing the compound shown in formula (A-13).

[0527] In some embodiments, the method for preparing the compound shown in formula (A-13) further includes the method for preparing the compound shown in formula (A-14).

[0528] In some embodiments, the method for preparing the compound shown in formula (A-14) further includes the method for preparing the compound shown in formula (A-15).

[0529] In some embodiments, the method for preparing the compound of formula (I) includes any one or more of the above preparation methods.

[0530] Terminology Explanation

[0531] In addition to the foregoing, when used in the specification and claims of this invention, the following terms shall have the following meanings unless otherwise specifically indicated.

[0532] In this invention, a "pharmaceutical composition" refers to a formulation comprising the compounds of this invention and a medium generally accepted in the art for delivering bioactive compounds to mammals (e.g., humans). This medium includes pharmaceutically acceptable excipients. The purpose of the pharmaceutical composition is to facilitate administration to the organism, thereby promoting the absorption of the active ingredient and the exertion of its bioactivity.

[0533] In this invention, "pharmaceutical acceptable" means a substance (such as a pharmaceutical excipient) that does not affect the biological activity or properties of the compounds of this invention and is relatively non-toxic, that is, the substance can be administered to an individual without causing an adverse biological reaction or interacting with any component contained in the composition in an undesirable manner.

[0534] In this invention, the term "pharmaceutically acceptable salt" refers to a salt obtained by reacting a compound with a pharmaceutically acceptable acid or base. When a compound contains a relatively acidic functional group, a base addition salt can be obtained by contacting the compound with a sufficient amount of a pharmaceutically acceptable base in a suitable inert solvent. When a compound contains a relatively basic functional group, an acid addition salt can be obtained by contacting the compound with a sufficient amount of a pharmaceutically acceptable acid in a suitable inert solvent. See Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl, Camille G. Wermuth, 2011, 2nd Revised Edition).

[0535] In this invention, the term "pharmaceuticalally acceptable excipients" refers to excipients and additives used in the production of pharmaceuticals and the dispensing of prescriptions; these are all substances contained in pharmaceutical preparations, excluding the active ingredient. See the Pharmacopoeia of the People's Republic of China (2015 Edition), Part IV, or the Handbook of Pharmaceutical Excipients (Raymond C. Rowe, 2009 Sixth Edition).

[0536] The pharmaceutical compositions of the present invention can be prepared using any method known to those skilled in the art, based on the disclosure.

[0537] In this invention, the term "treatment" refers to a therapeutic approach or a remission measure. When a specific condition is involved, treatment means: (1) alleviating one or more biological manifestations of the disease or condition; (2) interfering with (a) one or more points in a biological cascade that causes or induces the condition or (b) one or more biological manifestations of the condition; (3) improving one or more symptoms, effects, or side effects associated with the condition, or one or more symptoms, effects, or side effects associated with the condition or its treatment; or (4) slowing the progression of the disease or one or more biological manifestations of the condition. "Treatment" may also refer to extending survival compared to expected survival without treatment.

[0538] Unless otherwise stated, this invention employs traditional methods of mass spectrometry and elemental analysis, and the steps and conditions can be referred to conventional operating procedures and conditions in the field.

[0539] Unless otherwise specified, this invention employs standard nomenclature and standard laboratory procedures and techniques of analytical chemistry, organic synthetic chemistry, and optics. In some cases, standard techniques are used in chemical synthesis and chemical analysis.

[0540] Furthermore, it should be noted that, unless otherwise explicitly stated, the descriptive phrase "...independently (as / selected from)" used in this invention should be interpreted broadly, meaning that the described entities are independent of each other and can independently be the same or different specific functional groups. More specifically, the descriptive phrase "...independently (as / selected from)" can mean either that the specific options expressed by the same symbol in different functional groups do not affect each other, or that the specific options expressed by the same symbol in the same functional group do not affect each other.

[0541] In this invention, groups and their substituents can be selected by those skilled in the art to provide stable structural moieties and compounds. Certain chemical groups defined herein are preceded by simplified symbols to indicate the total number of carbon atoms present in that group. For example, C 1-4 Alkyl refers to an alkyl group having a total of 1, 2, 3 or 4 carbon atoms as defined below.

[0542] In this invention, the numerical ranges defined in the substituents, such as 3-9, 1-4, 2-6, 3-6, etc., indicate integers within that range, such as 1-4 being 1, 2, 3, 4.

[0543] In this invention, the term "optionally replaced by one or more Rs" refers to both cases of not being replaced by Rs and cases of being replaced by one or more Rs.

[0544] In this invention, the term "replaced by" means that any one or more hydrogen atoms on a specific atom are replaced by a substituent, provided that the valence state of the specific atom is normal and the substituted compound is stable.

[0545] In this invention, the term "substitution" means that one or more hydrogen atoms in the given structure are substituted by a specific substituent. Further, when the group is substituted by more than one of the said substituents, the substituents are independent of each other; that is, the more than one substituent can be different or the same. Unless otherwise indicated, a substituent group can be substituted at each substituted position of the substituted group. When more than one position in the given structural formula can be substituted by one or more substituents selected from a specific group, the substituents can be substituted at the same or different positions.

[0546] In this invention, the substituents of the disclosed compounds are disclosed according to the type or range of functional groups. Specifically, this invention includes every independent secondary combination of each member of these types and ranges of functional groups. The term "C" is used in this context. x-y "Alkyl" refers to a straight-chain or branched saturated hydrocarbon group containing x to y carbon atoms. For example, the term "C 1-4 "Alkyl" specifically refers to independently disclosed methyl, ethyl, C3 alkyl (i.e. propyl, including n-propyl and isopropyl) and C4 alkyl (i.e. butyl, including n-butyl, isobutyl, sec-butyl and tert-butyl).

[0547] When the listed substituents do not specify which atom they are attached to in the general chemical formula (including but not specifically mentioned compounds), such substituents may be bonded to any of their atoms. Combinations of substituents and / or their variants are permitted only if such combinations produce stable compounds.

[0548] When any variable (e.g., R) appears multiple times in the definition of a compound, the definition of that variable at each position is independent of the definitions at the other positions; their meanings are mutually independent and do not affect each other. Therefore, if a group is substituted by one, two, or three R groups—that is, if the group may be substituted by up to three R groups—the definition of R at one position is independent of the definitions of R at the other positions. Furthermore, combinations of substituents and / or variables are only permitted if the combination produces a stable compound.

[0549] When a listed group does not explicitly indicate that it has a substituent, the group refers only to the unsubstituted group. For example, when "C 1-4 When "alkyl" is not specified as "substituted or unsubstituted," it refers only to "C". 1-4 "alkyl" itself or "unsubstituted C" 1- C4 alkyl.

[0550] In this invention, linking substituents are described. When the structure clearly requires a linking group, the Markush variables listed for that group should be understood as linking groups. For example, if the structure requires a linking group and the Markush group definition for that variable lists "alkyl", then it should be understood that "alkyl" represents a linked alkylene group.

[0551] In some specific structures, when the alkyl group is clearly indicated as a linking group, then the alkyl group represents a linked alkylene group, for example, the group "halogenated C". 1-4 C in "alkyl" 1-4 Alkyl should be understood as C 1-4 Alkylene.

[0552] In this invention, the structural segments This refers to the structural segment being connected to the rest of the molecule via this bond. For example, This refers to the cyclopropyl group being linked to the rest of the molecule through this bond.

[0553] In this invention, the "-" at the end of a group indicates that the group is connected to the rest of the molecule through that site. For example, -OH indicates that a hydroxyl group is connected to the rest of the molecule through that site.

[0554] It should be understood that the singular forms used in this invention, such as "a," include plural references unless otherwise specified.

[0555] In this invention, the term "one or more" refers to 1, 2, 3, 4, 5, 6, 7, 8, 9 or more. For example, 1, 2 or 3.

[0556] In this invention, the term B "replaced by one or more A's" means that when B is replaced by "multiple" A's, the A's are the same or different.

[0557] In this invention, the term "halogen" refers to fluorine, chlorine, bromine or iodine, especially F, Cl or Br.

[0558] In this invention, as a group or part of other groups (e.g., in haloalkyl, deuteralkyl, etc.), the term "alkyl" refers to a saturated aliphatic hydrocarbon group comprising branched and straight chains having a specified number of carbon atoms, consisting only of carbon and hydrogen atoms, having, for example, 1 to 4 carbon atoms, and connected to the rest of the molecule by a single bond. Examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl.

[0559] In this invention, as a group or part of other groups, the term "alkynyl" refers to a straight-chain or branched hydrocarbon group having at least one triple bond, consisting only of carbon and hydrogen atoms, having, for example, 2 to 4 carbon atoms, and connected to the rest of the molecule by single bonds, such as including but not limited to ethynyl, 1-propynyl, n-propynyl, but-1-alkynyl, but-2-alkynyl, etc.

[0560] In this invention, as a group or part of other groups, the term "cycloalkyl" refers to a saturated monocyclic or polycyclic (e.g., bicyclic, tricyclic or more bridging rings, fused rings, or spirocyclic systems) carbocyclic substituent that can be connected to the rest of the molecule via a single bond through any suitable carbon atom.

[0561] In this invention, as part of a group or other group, the term "heterocyclic alkyl" refers to a non-aromatic cyclic group consisting of a carbon atom and 1, 2, 3, 4, 5, 6, 7 or 8 (e.g., 1 or 2) non-aromatic cyclic groups composed of stable saturated or partially unsaturated monocyclic or polycyclic (e.g., bicyclic bridged rings, fused rings, or spirocyclic systems) selected from heteroatoms or heteroatom groups.

[0562] Based on common knowledge in the field, the above-mentioned preferred conditions / implementations can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[0563] The reagents and raw materials used in this invention are all commercially available.

[0564] The positive and progressive effects of the present invention are as follows: the compounds of the present invention have one or more of the following advantages: (1) good inhibitory activity against KRAS G12C mutation; (2) good inhibitory activity against KRAS G12V mutation; (3) good inhibitory activity against KRAS G12D mutation; (4) long half-life; (5) high oral bioavailability; (6) good liver microsomal stability; (7) high distribution in target tissues; (8) good pharmacokinetic characteristics and drug-likeness. Detailed Implementation

[0565] The present invention is further illustrated below by way of embodiments, but the invention is not limited to the scope of the embodiments described herein. Experimental methods in the following embodiments that do not specify specific conditions were performed according to conventional methods and conditions, or as selected according to the product instructions.

[0566] Example 1: Synthesis of Compound I-001

[0567] Step 1: Synthesis of intermediates 1-2

[0568] Compound 1-1 (750 mg, 3.04 mmol, 1 eq) was dissolved in 15 mL of dichloromethane, and triethylamine (1.38 g, 13.7 mmol, 4 eq) was added. The reaction system was cooled to 0 °C, and trifluoroacetic anhydride (1.26 g, 5.99 mmol, 2 eq) was slowly added dropwise. After the addition was complete, the reaction system was stirred at 25 °C for 2 hours. LCMS monitoring showed complete consumption of the starting material and formation of the product. The reaction solution was washed successively with water (20 mL × 3), saturated brine (10 mL × 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the residue, which was then subjected to silica gel column chromatography (mobile phase: n-heptane: ethyl acetate = 2:1) to give intermediate 1-2 as a white solid (620 mg, yield: 89.35%). LCMS (ESI): m / z C 10 H 17 N2O4 + [M+H] + Calculated value = 229.12, measured value = 229.1.

[0569] Step 2: Synthesis of intermediates 1-3

[0570] Red phosphorus powder (0.5 g, 16.1 mmol, 1 eq) and selenium powder (3.18 g, 40.25 mmol, 2.5 eq) were mixed and heated to a molten state (200℃~300℃) under nitrogen protection. After cooling the system to room temperature, phosphorus pentaselenide was obtained as a black glassy solid (3.42 g), which was then ground into powder for later use (it is hygroscopic and requires nitrogen protection for long-term storage).

[0571] Intermediate 1-2 (2.8 g, 12.2 mmol, 1 eq) was dissolved in 28 mL of ethanol, and the prepared phosphorus pentaselenide powder (3.62 g, 7.93 mmol, 0.65 eq) was added. The reaction system was heated to 80 °C and stirred for 2 hours under nitrogen protection. Then 1.5 mL of water was added, and stirring was continued at 80 °C for another 2 hours. LCMS monitoring showed product formation. The system was cooled to room temperature, and 50 mL of saturated brine and 50 mL of ethyl acetate were added. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (25 mL × 2). After combining the organic phases, the mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to the residue, and then subjected to silica gel column chromatography (mobile phase: n-heptane: ethyl acetate = 6:1 to 3:1) to give intermediate 1-3, which was light brown (1.3 g, yield: 34.46%). LCMS (ESI): m / z C 10 H 19 N2O4Se + [M+H] + Calculated value = 311.05, measured value = 311.0. 1 H NMR (400MHz, CDCl3) δppm 8.78-8.27 (m, 2H), 5.71 (d, J = 6.8Hz, 1H), 4.64-4.59 (m, 1H), 3.80 (s, 3H), 3.39-3.21 (m, 2H), 1.45 (s, 9H).

[0572] Step 3: Synthesis of intermediates 1-5

[0573] Compounds 1-4 (5 g, 7.53 mmol, 1 eq) (Preparation method reference WO2022060836A1) (LCMS(ESI): m / z C 35 H 44 BrN4O4 + [M+H] + Calculated values ​​= 663.25, 665.25. Measured values ​​= 663.2, 665.2. 1H NMR (400MHz, CDCl3) δppm 8.52(d,J=3.0Hz,1H),7.89(d,J=1.8Hz,1H),7.42-7.38(m,4H),7.35(dd,J=1.9,8.7Hz,2H),7.25(d,J=8.8H z,1H),7.16(d,J=2.8Hz,1H),5.18(s,2H),4.07-3.89(m,3H),3.74-3.70(m,4H),3.25(s,6H),3.08(s,3H),2 The following solutions were dissolved in 20 mL of DMF: 0.71 (d, J = 14.3 Hz, 1H), 2.28 (d, J = 14.3 Hz, 1H), 1.47 (d, J = 6.3 Hz, 3H), 1.30–1.26 (m, 1H), 1.28 (d, J = 14.3 Hz, 2H), and 0.81 (d, J = 2.3 Hz, 6H). Imidazole (2.05 g, 30.14 mmol, 4 eq) and TBDPSCl (6.21 g, 22.60 mmol, 3 eq) were added sequentially. The reaction mixture was stirred at 25 °C for 12 hours. TLC (petroleum ether: ethyl acetate = 1:1) was used to monitor complete consumption of the starting materials and the formation of products. The reaction solution was diluted with 300 mL of water and 230 mL of ethyl acetate, the organic phase was separated, and the aqueous phase was extracted with ethyl acetate (100 mL × 2). After combining the organic phases, the mixture was washed sequentially with water (100 mL × 2), then with saturated brine (50 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to the residue. The residue was then subjected to silica gel column chromatography (ISCO Preparative Liquid Chromatography System; column model: 80g). Intermediates 1-5 were prepared using a Silica Flash Column (mobile phase gradient: 0-60% ethyl acetate / petroleum ether; flow rate: 80 mL / min), as white, foamy solids (5.8 g, yield: 85.39%). LCMS (ESI): m / z C 51 H 62 BrN4O4Si + [M+H] + Calculated values ​​= 901.37, 903.37. Measured values ​​= 901.3, 903.3. 1H NMR (400MHz, CDCl3) δppm 8.48(d,J=2.8Hz,1H),7.86(d,J=1.8Hz,1H),7.61(d,J=7.3Hz,4H),7.46-7.33(m,12H),7.27-7.2 2(m,1H),7.05(d,J=3.0Hz,1H),5.19(s,2H),4.04-3.85(m,3H),3.66(dd,J=3.9,5.9Hz,4H),3.42( d,J=9.5Hz,1H),3.29(d,J=9.5Hz,1H),3.13(s,4H),3.07(s,3H),2.75(d,J=14.1Hz,1H),2.38(d,J =14.1Hz, 1H), 1.43 (d, J = 6.3Hz, 3H), 1.20 (t, J = 7.2Hz, 3H), 1.02 (s, 9H), 0.79 (s, 3H), 0.71 (s, 3H).

[0574] Step 4: Synthesis of intermediates 1-6

[0575] Intermediate 1-5 (5.4 g, 5.99 mmol, 1 eq) was dissolved in 100 mL of dioxane, and compound 1-5a (1.51 g, 8.98 mmol, 1.5 eq), Pd(dppf)Cl2 (438.03 mg, 598.64 μmol, 0.1 eq), and 5.99 mL of potassium phosphate aqueous solution (2 M, 11.98 mmol, 2 eq) were added sequentially. The reaction system was evacuated and then purged three times with nitrogen. The reaction was carried out under nitrogen protection and stirred at 110 °C for 2 hours. TLC (petroleum ether:ethyl acetate = 1:2) monitored complete consumption of the starting materials and formation of the main product. The reaction system was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure to the residue. The residue was dissolved in 100 mL of ethyl acetate and washed successively with water (30 mL × 2), saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to the residue. The residue was then subjected to silica gel column chromatography (ISCO Preparative Liquid Chromatography; column model: 80g). Intermediates 1-6 were prepared using a Silica Flash Column (mobile phase gradient: 0-90% ethyl acetate / petroleum ether; flow rate: 80 mL / min), as white, foamy solids (5.1 g, yield: 98.69%). LCMS (ESI): m / z C 54 H 67 N4O4Si + [M+H] + Calculated value = 863.49. Measured value = 863.6. 1H NMR (400MHz, CDCl3) δppm 8.48(d,J=2.8Hz,1H),7.76(s,1H),7.60(d,J=6.5Hz,4H),7.49-7.45(m,1H),7.44 -7.31(m,12H),7.08(d,J=2.0Hz,1H),5.39(s,1H),5.19(s,2H),5.06(s,1H),4.17 -4.13(m,2H),4.08-3.97(m,2H),3.95-3.83(m,1H),3.67-3.62(m,4H),3.42(d,J=9.0Hz,1H),3.34-3.29(m,1H),3.09(s,6H),2.86 -2.78(m,1H),2.44(d,J=14.1Hz,1H),1.95(s,2H),1.43(d,J=6.3Hz,3H),1.23-1.20(m,3H),1.00(s,9H),0.88(s,3H),0.76(s,3H).

[0576] Step 5: Synthesis of intermediates 1-7

[0577] Intermediate 1-6 (5.1 g, 5.91 mmol, 1 eq) was dissolved in 100 mL of dioxane, and 1 M sodium periodate aqueous solution (11.82 mL, 11.82 mmol, 2 eq) and potassium osmium tetroxide dihydrate (217.69 mg, 590.82 μmol, 0.1 eq) were added sequentially. The reaction system was stirred at 40 °C for 5 hours. LC-MS was used to monitor complete consumption of the starting material and the formation of products. The reaction system was diluted with 300 mL of ethyl acetate and 300 mL of saturated sodium sulfite solution, and the organic phase was separated. The aqueous phase was extracted with ethyl acetate (50 mL × 2). The combined organic phases were washed with saturated brine (100 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to the residue, followed by silica gel column chromatography (ISCO Preparative Liquid Chromatography System; column model: 40 g). Intermediates 1-7 were prepared using a Silica Flash Column (mobile phase gradient: 0-80% ethyl acetate / petroleum ether; flow rate: 40 mL / min), as white, foamy solids (3.6 g, yield: 70.43%). LCMS (ESI): m / z C 53 H 65 N4O5Si + [M+H] + Calculated value = 865.47. Measured value = 865.3. 1H NMR (400MHz, CDCl3) δppm 8.33(s,1H),7.99(dd,J=1.3,8.6Hz,1H),7.60-7.55(m,1H),7.57(dd,J=4.7,6.5Hz,3H),7.47(d,J=2.0H z,1H),7.44-7.31(m,13H),5.19(s,2H),4.11-3.99(m,2H),3.85(dd,J=7.3,14.7Hz,1H),3.66(s,4H),3. 46(d,J=9.4Hz,1H),3.36(d,J=9.5Hz,1H),3.30(s,4H),3.20(s,3H),2.86(d,J=14.2Hz,1H),2.65(s,3H) ,2.42(d,J=14.1Hz,1H),1.42-1.39(m,3H),1.23(t,J=7.1Hz,3H),0.97(s,9H),0.94(s,3H),0.82(s,3H).

[0578] Step 6: Synthesis of intermediates 1-8

[0579] Intermediate 1-7 (3.4 g, 3.93 mmol, 1 eq) was dissolved in 50 mL of dichloromethane, and triethylamine (1.59 g, 15.72 mmol, 2.19 mL, 4 eq) was added dropwise. Trifluorosulfonic acid tert-butyl dimethylsilyl trifluorosulfonate (TBSOTf) (3.12 g, 11.79 mmol, 3 eq) was slowly added dropwise to the above reaction solution. After the addition was complete, the reaction system was stirred at 20 °C for 1 hour. TLC (petroleum ether: ethyl acetate = 1:2) monitored complete consumption of the starting material and formation of the main product. The reaction solution was diluted with 30 mL of dichloromethane and 30 mL of water, and the organic phase was separated. The aqueous phase was extracted with dichloromethane (10 mL × 2). After combining the organic phases, the mixture was washed with saturated brine (10 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate 1-8, a light yellow oily substance (4.0 g, crude product). LCMS (ESI): m / z C 59 H 79 N4O5Si2 + [M+H] + Calculated value = 979.56. Measured value = 979.4.

[0580] Step 7: Synthesis of intermediates 1-9

[0581] Intermediate 1-8 (4.0 g, crude) was dissolved in 100 mL of tetrahydrofuran and 10 mL of H2O, and N-bromosuccinimide (726.88 mg, 4.08 mmol) was added. The reaction mixture was stirred at 30 °C for 1 hour. LCMS was used to monitor complete consumption of the starting material and the formation of the product. The reaction mixture was concentrated under reduced pressure to the residue, dissolved in 50 mL of ethyl acetate, washed with saturated brine (10 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to the residue, followed by silica gel column chromatography (ISCO Preparative Liquid Chromatography; column model: 40 g). Intermediates 1-9 were prepared using a Silica Flash Column (mobile phase gradient: 0-90% ethyl acetate / petroleum ether; flow rate: 50 mL / min), as white, foamy solids (3.4 g, overall yield of steps 6 and 7: 91.63%). LCMS (ESI): m / z C 53 H 64 BrN4O5Si + [M+H] + Calculated values ​​= 943.38, 945.38. Measured values ​​= 943.4, 945.4. 1 H NMR (400MHz, CDCl3) δppm 8.48(d,J=2.9Hz,1H),8.34(s,1H),7.95(dd,J=1.1,8.6Hz,1H),7.58(dd,J=4.4,6.3Hz,4H),7.45-7.2 9(m,12H),7.05(d,J=2.7Hz,1H),5.18(s,2H),4.55-4.42(m,2H),4.09-3.90(m,3H),3.65(s,4H),3.47- 3.38(m,1H),3.32(d,J=9.3Hz,1H),3.18-3.07(m,4H),3.07-2.99(m,3H),2.82(d,J=14.1Hz,1H),2.48 (d,J=14.1Hz,1H),1.44(d,J=6.2Hz,3H),1.23(t,J=7.2Hz,3H),0.99(s,9H),0.88(s,3H),0.76(s,3H).

[0582] Step 8: Synthesis of intermediates 1-10

[0583] Intermediate 1-9 (3.40 g, 3.60 mmol, 1 eq) was dissolved in 10 mL of acetone, and intermediate 1-3 (1.11 g, 3.60 mmol, 1 eq) was added. The reaction mixture was stirred at 60 °C for 1 hour. LC-MS was used to monitor complete consumption of the starting material and the formation of products. The reaction mixture was concentrated under reduced pressure to the residue and subjected to silica gel column chromatography (ISCO Preparative Liquid Chromatography; column model: 40 g). Intermediate 1-10 was prepared by a Silica Flash Column (mobile phase gradient: 0-100% ethyl acetate / petroleum ether; flow rate: 40 mL / min) as a white solid (2.2 g, yield: 52.93%). LCMS (ESI): m / z C 63 H 79 N6O8SeSi + [M+H] + Calculated value = 1155.49. Measured value = 1155.6. 1 H NMR (400MHz, CDCl3) δppm 8.40(d,J=2.7Hz,1H),8.06(s,1H),7.79-7.68(m,2H),7.49(d,J=6.8Hz,4H),7.35-7.22(m,12H),6.99(d,J=2.5Hz,1H), 5.70(d,J=8.1Hz,1H),5.10(s,2H),4.75-4.61(m,1H),4.00-3.90(m,2H),3.83-3.80(m,1H),3.70-3.65(m,1H),3.68(s, 2H),3.64-3.53(m,5H),3.51-3.45(m,1H),3.38(d,J=9.4Hz,1H),3.24(d,J=9.4Hz,1H),3.07-2.97(m,7H),2.77-2.71(m ,1H),2.39(d,J=14.1Hz,1H),1.42-1.29(m,12H),1.16-1.11(m,3H),0.92-0.87(m,9H),0.86-0.81(m,3H),0.73(s,3H).

[0584] Step 9: Synthesis of intermediates 1-11

[0585] Intermediate 1-10 (801 mg, 693.88 μmol, 1 eq) was dissolved in 20 mL of methanol, and 2 M lithium hydroxide aqueous solution (1.39 mL, 2.78 mmol, 4 eq) was added. The reaction system was stirred at 40 °C for 1 hour under nitrogen protection. LC-MS monitoring showed complete consumption of the starting material and product formation. The reaction solution was concentrated under reduced pressure to remove methanol. The remaining aqueous phase was adjusted to pH 5 with 1 N citric acid aqueous solution and extracted with ethyl acetate (30 mL × 2). The combined organic phases were washed with saturated brine (5 mL) and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to the residue and subjected to silica gel column chromatography (ISCO Preparative Liquid Chromatography System; column model: 24 g). Intermediate 1-11 was prepared using a Silica Flash Column (mobile phase gradient: 0-100% ethyl acetate / petroleum ether; flow rate: 45 mL / min), as a pale yellow oil (530 mg, yield: 66.98%). LCMS (ESI): m / z C 62 H 77 N6O8SeSi + [M+H] + Calculated value = 1141.47. Measured value = 1141.5. 1 H NMR (400MHz, CDCl3) δppm 8.49(d,J=2.6Hz,1H),8.03(s,1H),7.80(s,1H),7.67(d,J=8.6Hz,1H),7.57(dd,J=4.9,6.5Hz,4H),7.45-7.28(m,12H ),7.07(d,J=2.7Hz,1H),5.97(d,J=4.9Hz,1H),5.18(s,2H),4.72(s,1H),4.08-3.97(m,2H),3.94-3.78(m,2H),3.64(s ,4H),3.46(d,J=9.5Hz,1H),3.43-3.35(m,1H),3.32(d,J=9.5Hz,1H),3.11(s,4H),3.06(s,3H),2.81(d,J=14.1Hz,1H) ,2.46(d,J=14.2Hz,1H),1.47(s,9H),1.43(d,J=6.2Hz,3H),1.25-1.18(m,3H),0.97(s,9H),0.88(s,3H),0.78(s,3H).

[0586] Step 10: Synthesis of intermediates 1-12

[0587] Intermediate 1-11 (530.00 mg, 464.77 μmol, 1 eq) and compound 1-11a (134.32 mg, 743.63 μmol, 1.6 eq) were dissolved in 30 mL of dichloromethane, and N-methylmorpholine (282.06 mg, 2.79 mmol, 6 eq) and HOBt (62.8 mg, 464.77 μmol, 1 eq) were added sequentially. After the reaction mixture was cooled to 0 °C with stirring, EDCI (178.19 mg, 929.54 μmol, 2 eq) was added. The mixture was stirred at 0 °C for 1 hour, then slowly heated to 20 °C and stirred for another hour. LCMS was used to monitor complete consumption of the starting materials and the formation of products. The reaction mixture was diluted with 30 mL of water and extracted with dichloromethane (10 mL × 3). After combining the organic phases, the mixture was washed successively with saturated ammonium chloride solution (10 mL × 3), water (10 mL), and saturated saline solution (10 mL × 2). The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to the residue. The residue was then subjected to silica gel column chromatography (ISCO Preparative Liquid Chromatography System; column model: 24 g). Intermediates 1-12 were prepared using a Silica Flash Column (mobile phase gradient: 0-90% ethyl acetate / petroleum ether; flow rate: 40 mL / min), as a pale yellow oil (530 mg, yield: 90.04%). LCMS (ESI): m / z C 68 H 87 N8O9SeSi + [M+H] + Calculated value = 1267.55. Measured value = 1267.7. 1H NMR (400MHz, CDCl3) δppm 8.46(d,J=2.4Hz,1H),8.10(s,1H),7.89-7.75(m,2H),7.57(d,J=7.2Hz,4H),7.41-7.29(m,12H),7.07(d,J=2.5Hz,1H),5.74(d,J=7.4H z,1H),5.47(d,J=5.6Hz,1H),5.18(s,2H),4.27(d,J=12.2Hz,1H),4.07-3.98(m,2H),3.97-3.81(m,2H),3.75-3.60(m,8H),3.52(dd,J= 5.3,11.5Hz,1H),3.44(d,J=9.4Hz,1H),3.31(d,J=9.4Hz,1H),3.10(s,4H),3.06(s,3H),2.82(d,J=14.1Hz,2H),2.47(d,J=13.9Hz,1H) ,2.02-1.93(m,1H),1.69-1.57(m,2H),1.46(s,9H),1.42(d,J=6.1Hz,3H),1.22(t,J=7.0Hz,3H),0.97(s,9H),0.88(s,3H),0.79(s,3H).

[0588] Step 11: Synthesis of intermediates 1-13

[0589] Intermediate 1-12 (530 mg, 418.48 μmol, 1 eq) was dissolved in 30 mL of methanol, and 1 M lithium hydroxide (4.18 mL, 10 eq) was added. The reaction system was stirred at 50 °C for 1 hour under nitrogen protection. LC-MS monitoring showed complete consumption of the starting material and formation of the product. The reaction solution was concentrated under reduced pressure to remove methanol. The remaining aqueous phase was adjusted to pH 5 with 1 N dilute hydrochloric acid and extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated brine (5 mL) and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to the residue and subjected to silica gel column chromatography (ISCO Preparative Liquid Chromatography System; column model: 12 g). Intermediate 1-13 was prepared by Silica Flash Column with a mobile phase gradient of 0-100% (ethyl acetate:methanol = 10:1) / petroleum ether; flow rate: 30 mL / min, as a pale yellow solid (510 mg, yield: 97.3%). LCMS (ESI): m / z C 67 H 85 N8O9SeSi + [M+H] + Calculated value = 1253.48. Measured value = 1253.4.

[0590] Step 12: Synthesis of intermediates 1-14

[0591] Intermediate 1-13 (500 mg, 399.21 μmol, 1 eq) was dissolved in 6 mL of DMF, and cesium fluoride (363.84 mg, 2.40 mmol, 6 eq) was added. The reaction mixture was stirred at 70 °C for 39 hours. LCMS monitoring showed complete consumption of the starting material and product formation. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to the residue. The residue was dissolved in 30 mL of dichloromethane and washed successively with 1 N citric acid solution (10 mL), water (10 mL), and saturated brine (10 mL × 2). The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate 1-14 as a yellow solid (350 mg, yield: 86.45%). LCMS (ESI): m / z C 51 H 67 N8O9Se + [M+H] + Calculated value = 1015.42. Measured value = 1015.4.

[0592] Step 13: Synthesis of intermediates 1-15

[0593] Intermediate 1-14 (350 mg, 345.14 μmol, 1 eq) was dissolved in 30 mL of dichloromethane, and diisopropylethylamine (1.34 g, 10.35 mmol, 1.80 mL, 30 eq), EDCI (1.85 g, 9.66 mmol, 28 eq), and HOBt (233.18 mg, 1.73 mmol, 5 eq) were added sequentially. The reaction mixture was stirred at 25 °C for 2 hours. LC-MS was used to monitor complete consumption of the starting material and the formation of products. The reaction mixture was washed sequentially with 1 N hydrochloric acid solution (5 mL × 3), water (5 mL), saturated sodium bicarbonate solution (5 mL × 2), and saturated sodium chloride solution (5 mL × 2). After drying with anhydrous sodium sulfate, the mixture was filtered, and the filtrate was concentrated under reduced pressure to the residue. The residue was then subjected to silica gel column chromatography (ISCO Preparative Liquid Chromatography System; column model: 12 g). Intermediate 1-15 was prepared using a Silica Flash Column with a mobile phase gradient of 0-100% (ethyl acetate = 10:1) / petroleum ether and a flow rate of 30 mL / min. It was a pale yellow solid (103 mg, yield: 29.96%). LCMS (ESI): m / z C 51 H 65 N8O8Se + [M+H] + Calculated value = 997.41. Measured value = 997.5. 1H NMR (400MHz, CDCl3) δppm 8.52(s,1H),8.40(d,J=2.7Hz,1H),7.86(s,1H),7.55(d,J=8.5Hz,1H),7.33-7.24(m,6H),7.01(d,J=2.7Hz,1H),5.51(t,J=9. 6Hz,1H),5.37-5.24(m,1H),5.09(s,2H),4.52(d,J=13.1Hz,1H),4.29-4.04(m,4H),3.93(d,J=12.2Hz,1H),3.80-3.74(m,1H) ,3.69-3.61(m,5H),3.39-3.29(m,4H),3.16(s,4H),3.09-2.98(m,2H),2.61(dt,J=2.2,12.7Hz,1H),2.34(d,J=14.7Hz,1H),2 .15-2.07(m,1H),1.88(d,J=13.5Hz,1H),1.39(s,9H),1.36(d,J=6.1Hz,3H),0.88(t,J=7.0Hz,3H),0.84(s,3H),0.35(s,3H).

[0594] Step 14: Synthesis of intermediates 1-16

[0595] Intermediate 1-15 (102 mg, 102.40 μmol, 1 eq) was dissolved in 10 mL of dioxane solution. The reaction system was cooled to 0 °C, and 40 mL of 4 M dioxane hydrochloride solution was added dropwise. After the addition was complete, the system was stirred at 40 °C for 2 hours. LCMS monitoring showed complete consumption of the starting material. The system was concentrated under reduced pressure to the residue, redissolved with 10 mL of dioxane, and concentrated again under reduced pressure to obtain intermediate 1-16, a white solid hydrochloride (90 mg, crude product). LCMS (ESI): m / z C 46 H 57 N8O6Se + [M+H] + Calculated value = 897.36. Measured value = 897.2.

[0596] Step 15: Synthesis of intermediates 1-17

[0597] Intermediate 1-16 (90 mg, 96.52 μmol, 1 eq) and compound 1-16a (11.60 mg, 115.83 μmol, 1.2 eq) were dissolved in 20 mL of dichloromethane. The system was cooled to 0 °C, and diisopropylethylamine (62.38 mg, 482.62 μmol, 5 eq) and HATU (47.71 mg, 125.48 μmol, 1.3 eq) were added sequentially. The reaction system was slowly heated to 25 °C with stirring and stirred continuously for 2 hours. LCMS monitoring showed complete consumption of the starting materials and product formation. The reaction solution was concentrated under reduced pressure to the residue and subjected to silica gel column chromatography (ISCO Preparative Liquid Chromatography; column model: 12g). Intermediate 1-17 was prepared using a Silica Flash Column with a mobile phase gradient of 0-100% (ethyl acetate:methanol = 10:1) / petroleum ether; flow rate: 30 mL / min, as a white solid (64 mg, 67.8%). LCMS (ESI): m / z C 51 H 63 N8O7Se + [M+H] + Calculated value = 979.40. Measured value = 979.3.

[0598] Step 16: Synthesis of intermediates 1-18

[0599] Intermediate 1-17 (60.0 mg, 61.35 μmol, 1 eq) was dissolved in 5 mL of hexafluoroisopropanol, and aluminum trichloride (81.80 mg, 613.47 μmol, 10 eq) was added under nitrogen protection. The reaction system was stirred at 30 °C for 24 hours under nitrogen protection. LCMS monitoring showed complete consumption of the starting material and formation of the product. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to the residue. The organic phase was separated by 10 mL of saturated sodium bicarbonate and 5 mL of ethyl acetate, and the aqueous phase was extracted with ethyl acetate (5 mL × 3). The combined organic phases were concentrated under reduced pressure to give intermediate 1-18, a pale yellow oil (50 mg, crude product). LCMS (ESI): m / z C 43 H 57 N8O5Se + [M+H] + Calculated value = 845.36. Measured value = 845.4.

[0600] Step 17: Synthesis of Compound I-001

[0601] Intermediate 1-18 (50 mg, 59.25 μmol, 1 eq) was dissolved in 3 mL of methanol, and acetic acid (10.67 mg, 177.75 μmol, 3 eq) was added. Then, 37% formaldehyde aqueous solution (12.02 mg, 148.13 μmol, 2.5 eq) and sodium cyanoborohydride (4.47 mg, 71.1 μmol, 1.2 eq) were added to the reaction solution. The reaction system was stirred at 25 °C for 1 hour. LCMS monitoring showed complete consumption of the starting material and product formation. The reaction was quenched with 1 mL of water and concentrated under reduced pressure to the residue. The residue was dissolved in 10 mL of dichloromethane, washed with water (5 mL × 2), washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to the residue. The purified compound I-001 was prepared by reversed-phase column chromatography (column: 44-Phenomenex Gemini NX C18 150*30mm*3μm, mobile phase: [water (0.05% NH3H2O ​​+ 10mM NH4HCO3)-acetonitrile], gradient: 50%-80% B, 7 min), as a white solid (18.8 mg, yield: 36.98%). LCMS (ESI): m / z C 44 H 59 N8O5Se + [M+H] + Calculated value = 859.38, measured value = 859.4. 1H NMR (400MHz, CDCl3) δppm 8.57(s,1H),8.48(d,J=3.0Hz,1H),7.91(s,1H),7.61(dd,J=1.3,8.5Hz,1H),7.34(d,J=8. 8Hz,1H),7.08(d,J=2.8Hz,1H),6.50(d,J=9.5Hz,1H),5.92(t,J=9.0Hz,1H),4.59(d,J=12. 3Hz,1H),4.32-4.21(m,3H),4.19-4.11(m,1H),4.03(d,J=12.3Hz,1H),3.87-3.82(m,1H),3 .76-3.70(m,1H),3.46(d,J=14.8Hz,1H),3.36(s,3H),3.35-3.31(m,4H),3.16(dd,J=8.8,1 4.8Hz,1H),3.10(d,J=14.6Hz,1H),2.72-2.66(m,5H),2.47(d,J=14.3Hz,1H),2.41(s,3H) ,2.20(dd,J=2.4,13.2Hz,1H),1.97(s,1H),1.81-1.76(m,1H),1.64-1.54(m,1H),1.43(d,J =6.0Hz,3H),1.36(dt,J=2.8,5.8Hz,1H),1.28(d,J=3.5Hz,1H),1.20(dd,J=4.1,8.7Hz,1H) ,1.11(d,J=5.8Hz,3H),0.97(t,J=7.0Hz,3H),0.91(s,3H),0.68-0.62(m,1H),0.45(s,3H).

[0602] Example 2: Synthesis of Compound I-002

[0603] Referring to the synthesis method in Example 1, and replacing the corresponding starting materials, compound I-002 was prepared using compound 2-1 as the starting material. It is a white solid. LCMS(ESI): m / z C 45 H 61 N8O5Se + [M+H] + Calculated value = 873.39, measured value = 873.3. 1¹H NMR (400MHz, CDCl₃) δppm 8.56(s,1H),8.52-8.42(m,1H),7.92(s,1H),7.61(d,J=8.5Hz,1H),7.34(d ,J=8.5Hz,1H),7.08(s,1H),6.42(d,J=9.3Hz,1H),5.91(t,J=8.3Hz,1H),4. 58(d,J=12.5Hz,1H),4.40-4.12(m,4H),4.03(d,J=12.3Hz,1H),3.90-3.78 (m,1H),3.76-3.70(m,1H),3.46(d,J=14.6Hz,1H),3.40-3.26(m,7H),3.19- 3.13(m,1H),3.12-3.05(m,1H),2.78(s,4H),2.72-2.62(m,1H),2.50-2.43 (m,4H),2.20-2.16(m,1H),1.95(d,J=12.3Hz,1H),1.83-1.72(m,1H),1.65- 1.55(m,1H),1.44(d,J=6.0Hz,5H),1.27(d,J=8.5Hz,1H),1.15(d,J=5.3Hz, 3H), 1.10 (d, J = 5.3Hz, 3H), 0.97 (t, J = 6.9Hz, 3H), 0.90 (s, 3H), 0.45 (s, 3H).

[0604] Example 3: Synthesis of Compound I-003

[0605] Step 1: Synthesis of intermediate 3-2

[0606] Intermediate 1-11 (700 mg, 613.85 μmol, 1 eq) and intermediate 3-1a (225 mg, 982.16 μmol, 1.6 eq) (preparation method reference WO2024067857A1) were dissolved in 6 mL of dichloromethane, and N-methylmorpholine (372.55 mg, 3.68 mmol, 6 eq) and a 50% ethyl acetate solution of n-butylphosphine anhydride (884.58 mg, 1.23 mmol, 2 eq) were added sequentially. The reaction system was stirred at 0 °C for 1 hour, then slowly increased to 20 °C and stirred for another hour. LCMS was used to monitor complete consumption of the starting materials and formation of the main product. The reaction solution was diluted with 20 mL of water and extracted with dichloromethane (8 mL × 3). After combining the organic phases, the mixture was washed successively with saturated ammonium chloride solution (8 mL × 3), water (10 mL), and saturated saline solution (5 mL × 2). The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to the residue. The residue was then subjected to silica gel column chromatography (ISCO Preparative Liquid Chromatography System; column model: 24g). Intermediate 3-2 was prepared using a Silica Flash Column (mobile phase gradient: 0-90% ethyl acetate / petroleum ether; flow rate: 40 mL / min), as a pale yellow oil (680 mg, yield: 86.64%). LCMS (ESI): m / z C 69 H 87 N8O9SeSi + [M+H] + Calculated value = 1279.55. Measured value = 1279.8.

[0607] Step 2: Synthesis of intermediates 3-7

[0608] Referring to the synthesis method of steps 11 to 15 in Example 1, and replacing some of the raw materials, intermediate 3-7, a white solid, was prepared using intermediate 3-2. LCMS(ESI): m / z C 53 H 65 N8O7Se + [M+H] + Calculated value = 1005.41, measured value = 1005.4. 1¹H NMR (400MHz, CDCl₃) δppm 8.46(d,J=2.8Hz,1H),8.34(d,J=1.0Hz,1H),7.92(s,1H),7.60(dd,J=1.5,8 .5Hz,1H),7.43-7.29(m,6H),7.10(d,J=3.0Hz,1H),6.83(d,J=8.0Hz,1H),5. 57-5.47(m,1H),5.31-5.24(m,1H),5.17(s,2H),4.81-4.67(m,2H),4.30-4.2 1(m,2H),4.20-4.08(m,1H),3.77-3.67(m,5H),3.65-3.57(m,1H),3.49(dd,J =3.1,15.2Hz,1H),3.35(s,3H),3.24(s,4H),3.20-3.13(m,1H),3.13-3.05(m ,1H),2.76-2.71(m,1H),2.61-2.53(m,1H),2.48-2.37(m,2H),2.15-2.06(m, 1H),1.69-1.62(m,1H),1.58-1.46(m,2H),1.45-1.40(m,3H),1.18-1.13(m,3 H),1.12-1.09(m,3H),0.96(t,J=7.0Hz,3H),0.91(s,3H),0.48-0.36(m,3H).

[0609] Step 3: Synthesis of Compound I-003

[0610] Referring to the synthesis method in steps 16 and 17 of Example 1, and replacing some of the raw materials, compound I-003 was prepared using compounds 3-7 as raw materials. It is a white solid. LCMS(ESI): m / z C 46 H 61 N8O5Se + [M+H] + Calculated value = 885.39, measured value = 885.5. 1HNMR(400MHz,CDCl3)δppm 8.48(d,J=2.8Hz,1H),8.34(s,1H),7.92(s,1H),7.60(dd,J=1.4,8.7Hz,1H),7.35(d ,J=8.5Hz,1H),7.09(d,J=2.8Hz,1H),6.81(d,J=8.0Hz,1H),5.56-5.45(m,1H),5.27 (d,J=10.8Hz,1H),4.80-4.66(m,2H),4.33-4.21(m,2H),4.21-4.09(m,1H),3.76-3. 68(m,1H),3.68-3.57(m,1H),3.49(dd,J=3.0,15.1Hz,1H),3.35(s,3H),3.34-3.30( m,4H),3.17(dd,J=5.3,15.1Hz,1H),3.10(d,J=14.6Hz,1H),2.76-2.72(m,1H),2.71 -2.65(m,4H),2.59-2.53(m,1H),2.46(d,J=14.3Hz,1H),2.44-2.37(m,4H),2.11-2. 07(m,1H),1.66(t,J=9.5Hz,1H),1.59-1.46(m,2H),1.42(d,J=6.0Hz,3H),1.15(d,J =6.0Hz, 3H), 1.11 (d, J = 6.0Hz, 3H), 0.97 (t, J = 7.0Hz, 3H), 0.92 (s, 3H), 0.43 (s, 3H).

[0611] Example 4: Synthesis of Compound I-004

[0612] Referring to the synthesis method in steps 15 to 17 of Example 1, and replacing the corresponding starting materials, compound I-004 was prepared using compounds 3-6 and 4-1 as starting materials. It is a white solid. LCMS(ESI): m / z C 45 H 57 F2N8O5Se + [M+H] + Calculated value = 907.36, measured value = 907.4. 1¹H NMR (400MHz, CDCl₃) δppm 8.48(d,J=2.7Hz,1H),8.34(s,1H),7.93(s,1H),7.60(d,J=8.7Hz,1H),7.36(d ,J=8.6Hz,1H),7.10(d,J=3.0Hz,2H),6.09-5.68(m,1H),5.53(d,J=2.5Hz,1H) ,5.30(d,J=10.8Hz,1H),4.85-4.65(m,2H),4.32-4.21(m,2H),4.19-4.05(m,1 H),3.75-3.69(m,1H),3.66-3.60(m,1H),3.51(dd,J=2.7,15.4Hz,1H),3.43-3. 31(m,7H),3.18(dd,J=5.2,15.3Hz,1H),3.10(d,J=14.3Hz,1H),2.85-2.72(m, 5H),2.62-2.55(m,1H),2.49(s,3H),2.43(dd,J=5.2,10.8Hz,2H),1.99-1.94( m,1H),1.87-1.83(m,1H),1.67(t,J=9.6Hz,1H),1.43(d,J=6.1Hz,3H),1.39-1 .35(m,1H),1.19-1.09(m,1H),0.97(t,J=7.0Hz,3H),0.92(s,3H),0.43(s,3H).

[0613] Example 5: Synthesis of Compound I-005

[0614] Step 1: Synthesis of intermediate 5-2

[0615] Compound 5-1 (500 mg, 1.42 mmol, 1 eq) and intermediate 3-1a (438.80 mg) were dissolved in 10 mL of dichloromethane, and N-methylmorpholine (864.00 mg, 8.54 mmol, 6 eq) and HATU (866.09 mg, 2.28 mmol, 1.6 eq) were added sequentially. The reaction mixture was stirred at 0 °C for 1 hour, then slowly increased to 20 °C and stirred for another hour. The mixture was washed sequentially with saturated ammonium chloride solution (5 mL × 2), water (5 mL), and saturated brine (5 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to the residue. The residue was then subjected to silica gel column chromatography (ISCO Preparative Liquid Chromatography System; column model: 24 g). Intermediate 5-2 was prepared using a Silica Flash Column (mobile phase gradient: 0-90% ethyl acetate / petroleum ether; flow rate: 40 mL / min), as a colorless oil (600 mg, yield: 86.34%). LCMS (ESI): m / z C 18 H 26 BrN4O5S + [M+H] + Calculated values ​​= 489.08, 491.08. Measured values ​​= 489.0, 491.1. 1 H NMR (400MHz, CDCl3) δppm 7.11(s,1H),5.62(d,J=7.3Hz,1H),5.35(d,J=9.5Hz,2H),4.71-4.67(m,1H),4.17(d,J=10.0Hz,1H),3.78(s,3H),3.52-3.45(m,2 H), 2.72-2.68 (m, 1H), 2.45 (dd, J = 4.9, 9.7Hz, 1H), 2.36-2.31 (m, 1H), 1.98 (t, J = 10.2Hz, 1H), 1.82 (t, J = 9.7Hz, 1H), 1.44 (s, 9H).

[0616] Step 2: Synthesis of intermediate 5-4

[0617] Intermediate 5-3 (200 mg, 296.01 μmol, 1 eq) (synthesized according to patent WO2024169914A1) was a light yellow solid. LCMS (ESI): m / z C 36 H 44 BrN4O4 + [M+H] + Calculated values ​​= 675.25, 677.25. Measured values ​​= 675.2, 675.2. 1H NMR (400MHz, CDCl3) δppm 8.48(d,J=2.5Hz,1H),7.67(s,1H),7.41-7.30(m,5H),7.11(d,J=2.3Hz,1H),7.08(s,1H),5.17(s,2H),4.13-4.06(m,1 H),3.89-3.74(m,2H),3.69(d,J=5.3Hz,4H),3.30-3.17(m,6H),3.02(s,3H),2.98(t,J=5.6Hz,2H),2.69(d,J=14.3Hz, The reaction mixture (1H), 2.31 (d, J = 14.6 Hz, 1H), 2.25–2.17 (m, 1H), 2.15–2.07 (m, 1H), 1.46 (d, J = 6.0 Hz, 3H), 0.80 (s, 6H)) was dissolved in 5 mL of dioxane, and compound 5-3a (150.34 mg, 592.02 μmol, 2 eq), potassium acetate (87.15 mg, 888.03 μmol, 3 eq), and Pd(dppf)Cl2 (21.66 mg, 29.60 μmol, 0.1 eq) were added sequentially. The reaction mixture was stirred at 100 °C for 2 hours. LC-MS monitoring showed complete consumption of the starting materials and formation of the main product. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to the residue, which was then subjected to silica gel column chromatography (ISCO Preparative Liquid Chromatography; column model: 40 g). Intermediate 5-4 was prepared using a Silica Flash Column (mobile phase gradient: 0-100% ethyl acetate / petroleum ether; flow rate: 35 mL / min), as a colorless oil (210 mg, yield: 98.16%). LCMS (ESI): m / z C 42 H 56 BN4O6 + [M+H] + Calculated value = 723.43. Measured value = 723.4.

[0618] Step 3: Synthesis of intermediate 5-5

[0619] Intermediate 5-2 (162.51 mg, 332.08 μmol, 1.2 eq) and intermediate 5-4 (200.00 mg, 276.73 μmol, 1 eq) were dissolved in 4 mL of dioxane and 1 mL of water. Potassium phosphate trihydrate (147.39 mg, 553.47 μmol, 2 eq) and Pd(dppf)Cl2 (20.25 mg, 27.67 μmol, 0.1 eq) were added sequentially. The reaction system was stirred at 100 °C for 2 hours. LC-MS monitoring showed complete consumption of the starting materials and product formation. The reaction system was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure to the residue. The residue was dissolved in 80 mL of dichloromethane and washed sequentially with water (30 mL × 2), saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to the residue. The residue was then subjected to silica gel column chromatography (ISCO Preparative Liquid Chromatography System; column model: 12g). Intermediate 5-5 was prepared using a Silica Flash Column (mobile phase gradient: 0-100% ethyl acetate / petroleum ether; flow rate: 35 mL / min), as a white, foamy solid (180 mg, yield: 64.71%). LCMS (ESI): m / z C 54 H 69 N8O9S + [M+H] + Calculated value = 1005.49. Measured value = 1005.5.

[0620] Step 4: Synthesis of intermediates 5-6

[0621] Intermediate 5-5 (180 mg, 179.06 μmol, 1 eq) was dissolved in 3 mL of tetrahydrofuran, and 895.30 μL of 1 M lithium hydroxide aqueous solution (5 eq) was added. The reaction system was stirred at 50 °C for 1 hour. LC-MS monitoring showed complete consumption of the starting material and product formation. The reaction solution was concentrated under reduced pressure to remove methanol, and the remaining aqueous phase was adjusted to pH approximately 4.5 with 1 M dilute hydrochloric acid and extracted with dichloromethane (3 mL × 3). The combined organic phases were washed with saturated brine (4 mL) and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to the residue and subjected to silica gel column chromatography (ISCO Preparative Liquid Chromatography System; column model: 12 g). Intermediate 5-6 was prepared using a Silica Flash Column with a mobile phase gradient of 0-100% (ethyl acetate:methanol = 10:1) / petroleum ether; flow rate: 35 mL / min. It was a foamy solid (140 mg, yield: 78.88%). LCMS (ESI): m / z C 53 H 67 N8O9S + [M+H] +Calculated value = 991.47. Measured value = 991.4.

[0622] Step 5: Synthesis of intermediates 5-7

[0623] Intermediate 5-6 (140 mg, 141.24 μmol, 1 eq) was dissolved in 4 mL of dichloromethane, and diisopropylethylamine (730.17 mg, 5.65 mmol, 984.05 μL, 40 eq), EDCI (947.67 mg, 4.94 mmol, 35 eq), and HOBt (114.51 mg, 847.46 μmol, 6 eq) were added sequentially. The reaction system was stirred at 25 °C for 24 hours. LC-MS was used to monitor complete consumption of the starting materials and the formation of products. The reaction solution was washed sequentially with 1N hydrochloric acid solution (3 mL × 3), water (3 mL), saturated sodium bicarbonate solution (2 mL × 2), and saturated sodium chloride solution (2 mL × 2). After drying with anhydrous sodium sulfate, the solution was filtered, and the filtrate was concentrated under reduced pressure to the residue. The residue was then subjected to silica gel column chromatography (ISCO Preparative Liquid Chromatography System; column model: 12g). Intermediate 5-7 was prepared using a Silica Flash Column with a mobile phase gradient of 0-90% (ethyl acetate = 10:1) / petroleum ether; flow rate: 30 mL / min, as a foamy solid (120 mg, yield: 87.3%). LCMS (ESI): m / z C 53 H 65 N8O8S + [M+H] + Calculated value = 973.46. Measured value = 973.5.

[0624] Step 6: Synthesis of intermediates 5-8

[0625] Intermediate 5-7 (120 mg, 123.31 μmol, 1 eq) was dissolved in 2 mL of dichloromethane, and trifluoroacetic acid (1.41 g, 12.33 mmol, 100 eq) was added dropwise. The reaction mixture was stirred at 25 °C for 2 hours. LCMS monitoring showed complete consumption of the starting material and formation of product. The reaction solution was concentrated under reduced pressure to the residue, and dissolved in 5 mL of ethyl acetate and 5 mL of saturated sodium bicarbonate solution. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (3 mL × 2). The combined organic phases were washed with saturated brine (3 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give intermediate 5-8, a pale yellow foamy solid (80 mg, crude product). LCMS (ESI): m / z C 48 H 57 N8O6S + [M+H] + Calculated value = 873.41. Measured value = 873.4.

[0626] Step 7: Synthesis of intermediates 5-9

[0627] Compound 2-1 (31.38 mg, 274.89 μmol, 3 eq) was dissolved in 4 mL of dichloromethane, and diisopropylethylamine (59.21 mg, 458.15 μmol, 5 eq) and HATU (104.52 mg, 274.89 μmol, 3 eq) were added. The reaction mixture was stirred at 0 °C for 30 min. Intermediate 5-8 (80 mg, 91.63 μmol, 1 eq) was added to the above mixture. Subsequently, the reaction mixture was slowly heated to 25 °C and stirred for another 30 min. LC-MS monitoring showed complete consumption of the starting material and formation of the product. The mixture was washed successively with saturated ammonium chloride solution (1 mL × 2), water (2 mL), and saturated brine (2 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to the residue. The residue was then subjected to silica gel column chromatography (ISCO Preparative Liquid Chromatography System; column model: 12g). Intermediates 5-9 were prepared using a Silica Flash Column with a mobile phase gradient of 0-100% (ethyl acetate:methanol (10:1)) / petroleum ether; flow rate: 30 mL / min. The intermediates were white, foamy solids (50 mg, yield: 56.30%). LCMS (ESI): m / z C 54 H 65 N8O7S + [M+H] + Calculated value = 969.47. Measured value = 969.4. 1H NMR (400MHz, CDCl3) δppm 8.47(d,J=2.8Hz,1H),8.21(s,1H),7.39-7.33(m,4H),7.32(s,1H),7.25(s,1H),7.06(d ,J=2.8Hz,1H),6.75(d,J=8.5Hz,1H),5.60-5.52(m,1H),5.30(d,J=10.5Hz,1H),5.17(s ,2H),4.86(d,J=10.8Hz,1H),4.75(q,J=4.9Hz,1H),4.42-4.28(m,2H),3.78-3.67(m,5H ),3.63(d,J=10.8Hz,1H),3.59-3.50(m,1H),3.45(dd,J=2.3,15.1Hz,1H),3.42-3.36(m, 3H),3.24(s,4H),3.19-3.11(m,2H),3.08-3.02(m,1H),3.01-2.92(m,1H),2.76(q,J=5. 7Hz,1H),2.62-2.54(m,1H),2.48-2.38(m,2H),2.34-2.25(m,1H),2.23-2.17(m,1H),2. 13-2.06(m,1H),1.70(t,J=9.7Hz,1H),1.59-1.46(m,2H),1.43(d,J=6.0Hz,3H),1.16(d ,J=6.3Hz,3H),1.11(d,J=6.0Hz,3H),0.97(s,3H),0.93-0.89(m,1H),0.49-0.40(m,3H).

[0628] Step 8: Synthesis of Compound I-005

[0629] Compound 5-9 (50 mg, 51.59 μmol, 1 eq) was dissolved in 10 mL of methanol, and ammonium formate (32.53 mg, 515.9 μmol, 10 eq), 10% palladium on carbon (10.98 mg, 10.32 μmol, 0.2 eq), and 52 mL of 30% formaldehyde aqueous solution were added sequentially. The reaction system was evacuated, purged three times with nitrogen, and stirred at 65 °C for 24 hours under nitrogen protection. LC-MS monitoring showed the formation of the main product and some reactants remaining. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to the residue. The purified compound I-005 was prepared by reversed-phase column chromatography (column: Phenomenex Gemini-NX C18 75*30 mm*3 μm, mobile phase: [water (0.225% formic acid)-acetonitrile], gradient: 25%-55% B, 7 min), which was a white solid. LC-MS (ESI): m / z C47 H 61 N8O5S + [M+H] + Calculated value = 849.45, measured value = 849.3. 1 H NMR (400MHz, CDCl3) δppm 8.47(d,J=2.5Hz,1H),8.21(s,1H),7.31(s,1H),7.25(s,1H),7.05(d,J=2.3Hz,1H),6.71( d,J=8.5Hz,1H),5.56(s,1H),5.30(d,J=10.8Hz,1H),4.85(d,J=10.5Hz,1H),4.78-4.70(m, 1H),4.39-4.28(m,2H),3.78-3.71(m,1H),3.63(d,J=10.8Hz,1H),3.55(t,J=8.5Hz,1H),3. 44(d,J=15.3Hz,1H),3.40(s,3H),3.30(d,J=4.3Hz,4H),3.19-3.09(m,2H),3.07-3.02(m,1 H),3.01-2.91(m,1H),2.76(q,J=5.3Hz,1H),2.65(s,4H),2.61-2.54(m,1H),2.47(d,J=14 .3Hz,1H),2.43-2.35(m,4H),2.29(td,J=4.5,8.7Hz,1H),2.20(d,J=3.8Hz,1H),2.10-2.06 (m,1H),1.69(t,J=9.8Hz,1H),1.59-1.52(m,1H),1.50-1.45(m,1H),1.44-1.35(m,3H),1.1 8-1.13(m,3H),1.12-1.06(m,3H),0.99-0.93(m,3H),0.92-0.88(m,1H),0.49-0.41(m,3H).

[0630] Example 6: Synthesis of Compound I-006

[0631] Step 1: Synthesis of intermediate 6-1

[0632] Following the synthesis method in step 7 of Example 5, and replacing the corresponding starting materials, compound 6-1 was prepared using compound 4-1 as the starting material. This compound was a white, foamy solid. LCMS(ESI): m / z C 53 H 61 F2N8O7S + [M+H] +Calculated value = 991.43, measured value = 991.3. 1 H NMR (400MHz, CDCl3) δppm 8.49(d,J=2.8Hz,1H),8.23(s,1H),7.42-7.31(m,6H),7.12-7.04(m,2H),6.00-5.68 (m,1H),5.60(d,J=2.8Hz,1H),5.34(d,J=10.8Hz,1H),5.18(s,2H),4.87(d,J=10.5H z,1H),4.77(q,J=4.7Hz,1H),4.46-4.27(m,2H),3.81-3.69(m,5H),3.69-3.62(m,1H ),3.56(ddd,J=2.8,8.7,11.9Hz,1H),3.48(dd,J=2.3,15.1Hz,1H),3.42(s,3H),3.3 1-3.22(m,4H),3.21-3.12(m,2H),3.09-3.03(m,1H),3.02-2.93(m,1H),2.82-2.75( m,1H),2.67-2.56(m,1H),2.50-2.40(m,2H),2.38-2.26(m,2H),2.25-2.16(m,1H),2 .15-2.08(m,1H),2.00-1.91(m,1H),1.89-1.81(m,1H),1.77-1.68(m,1H),1.52-1.4 2(m,3H),1.41-1.35(m,1H),1.20-1.12(m,1H),1.00-0.97(m,3H),0.50-0.42(m,3H).

[0633] Step 2: Synthesis of Compound I-006

[0634] Following the synthesis method in step 8 of Example 5, and replacing the corresponding starting materials, compound I-006 was prepared using compound 6-1 as the starting material. It is a white solid. LCMS(ESI): m / z C 46 H 57 F2N8O5S + [M+H] + Calculated value = 871.41, measured value = 871.4. 1H NMR (400MHz, CDCl3) δppm 8.47(d,J=2.5Hz,1H),8.21(s,1H),7.31(s,1H),7.26(s,1H),7.07-7.01(m,2H),6.00 -5.68(m,1H),5.58(s,1H),5.32(d,J=10.8Hz,1H),4.86(d,J=10.5Hz,1H),4.75(q,J= 4.9Hz,1H),4.42-4.28(m,2H),3.75(d,J=11.0Hz,1H),3.68-3.61(m,1H),3.59-3.51( m,1H),3.50-3.43(m,1H),3.40(s,3H),3.35-3.29(m,4H),3.20-3.11(m,2H),3.04(dd ,J=5.3,10.5Hz,1H),3.01-2.91(m,1H),2.78(s,1H),2.70(d,J=4.5Hz,4H),2.60(dd, J=4.3,10.0Hz,1H),2.50-2.40(m,5H),2.30(dd,J=4.1,8.7Hz,1H),2.22-2.15(m,1H) ,2.10(t,J=10.0Hz,1H),1.99-1.90(m,1H),1.84-1.82(m,1H),1.70(t,J=9.5Hz,1H), 1.43(d,J=6.0Hz,3H),1.39-1.33(m,1H),1.19-1.10(m,1H),0.97(s,3H),0.46(s,3H).

[0635] Example 7: Synthesis of Compound I-007

[0636] Step 1: Synthesis of intermediate 7-7

[0637] Following the synthesis method described in steps 3 to 9 of Example 1, and replacing the corresponding raw materials and reagents, using intermediate 5-3 as the raw material and replacing TBDPSCl with TBSCl, key intermediate 7-7 was prepared, which is a white, foamy solid. LCMS(ESI): m / z C 53 H 73 N6O8SeSi + [M+H] + Calculated value = 1029.44, measured value = 1029.4. 1H NMR (400MHz, CDCl3) δppm 8.50(s,1H),7.90(d,J=9.2Hz,2H),7.44-7.32(m,6H),7.13(d,J=2.1Hz,1H),5.97(s,1H),5.17(s, 2H),4.73(s,1H),4.22-4.13(m,2H),3.81(s,3H),3.68(d,J=4.4Hz,4H),3.49-3.41(m,1H),3.31(d, J=9.3Hz,1H),3.22(s,5H),3.11-2.93(m,6H),2.71(d,J=13.9Hz,1H),2.39(d,J=13.9Hz,1H),2.29 -2.20(m,1H),2.18-2.09(m,1H),1.47(s,9H),0.84(s,3H),0.80(s,9H),0.70(s,3H),-0.04(s,6H).

[0638] Step 2: Synthesis of intermediates 7-13

[0639] Following the synthesis method described in steps 10 to 15 of Example 1, and replacing the corresponding raw materials and reagents, intermediate 7-13 was prepared using intermediate 7-7 and compound 2-1 as raw materials. It was a white, foamy solid. LCMS(ESI): m / z C 53 H 65 N8O7Se + [M+H] + Calculated value = 1005.41, measured value = 1005.5. 1¹H NMR (400MHz, CDCl₃) δppm 8.46(d,J=2.8Hz,1H),8.40(s,1H),7.86(s,1H),7.42-7.34(m,5H),7.32(s,1H) ,7.04(d,J=2.8Hz,1H),6.39(d,J=9.5Hz,1H),5.91(t,J=9.3Hz,1H),5.17(s,2H ),4.80(s,1H),4.63-4.54(m,1H),4.38(q,J=6.1Hz,1H),4.32-4.21(m,2H),4.0 4(d,J=12.3Hz,1H),3.86(d,J=11.0Hz,1H),3.77(d,J=10.8Hz,1H),3.73-3.64( m,5H),3.59-3.51(m,1H),3.49-3.44(m,1H),3.41(s,3H),3.24(s,4H),3.16-3. 05(m,3H),2.73-2.62(m,1H),2.44(d,J=14.1Hz,1H),2.32-2.25(m,1H),2.22-2 .15(m,2H),2.02(s,3H),1.49(d,J=5.0Hz,1H),1.43(d,J=6.0Hz,3H),1.16(d,J =5.8Hz,3H),1.10(d,J=6.0Hz,3H),0.93(s,3H),0.91-0.89(m,1H),0.48(s,3H).

[0640] Step 3: Synthesis of intermediate 7-14

[0641] Intermediate 7-13 (50 mg, 49.79 μmol, 1 eq) was dissolved in 30 mL of hexafluoroisopropanol, and methanesulfonic acid (709.38 mg, 7.38 mmol, 150 eq) was added dropwise under nitrogen protection. The reaction mixture was stirred at 20 °C for 1 hour. LC-MS monitoring showed complete consumption of the starting material and formation of the main product. The reaction solution was diluted with 10 mL of sodium bicarbonate solution and extracted with ethyl acetate (5 mL × 4). After combining the organic phases, the mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give intermediate 7-14 as a white solid (43 mg, crude product). LC-MS (ESI): m / z C 45 H 59 N8O5Se + [M+H] + Calculated value = 871.38, measured value = 871.3.

[0642] Step 4: Synthesis of Compound I-007

[0643] Following the synthesis method in step 17 of Example 1, and replacing the corresponding starting materials and reagents, compound I-007 was prepared using intermediate 7-14 as the starting material. It is a white solid. LCMS (ESI): m / z C 46 H 61 N8O5Se + [M+H] + Calculated value = 885.39, measured value = 885.4. 1 HNMR(400MHz,CDCl3)δppm 8.47(s,1H),8.40(s,1H),7.86(s,1H),7.32(s,1H),7.04(s,1H),6.47(d,J=9.3Hz,1H),5.99-5.84(m,1H),4.58(d,J=11.0Hz,1H),4.38( d,J=5.8Hz,1H),4.33-4.17(m,2H),4.04(d,J=11.5Hz,1H),3.86(d,J=10.8Hz,1H),3.77(d,J=11.0Hz,1H),3.61-3.50(m,1H),3.49-3.38( m,4H),3.34(s,4H),3.20-3.10(m,2H),3.07-2.93(m,2H),2.75-2.57(m,6H),2.46(s,3H),2.35-2.26(m,1H),2.20(s,2H),1.98-1.89(m, 1H),1.85-1.69(m,1H),1.59(d,J=11.3Hz,1H),1.49-1.38(m,5H),1.15(d,J=5.0Hz,3H),1.09(d,J=5.0Hz,3H),0.93(s,4H),0.48(s,3H).

[0644] Example 8: Synthesis of Compound I-008

[0645] Following the synthesis method described in steps 2 to 4 of Example 7, and replacing the corresponding starting materials, compound I-008 was prepared using compound 4-1 as the starting material. It is a white solid. LCMS(ESI): m / z C 45 H 57 F2N8O5Se + [M+H] + Calculated value = 907.36, measured value = 907.2. 1H NMR (400MHz, CDCl3) δppm 8.47(s,1H),8.40(s,1H),7.86(s,1H),7.32(s,1H),7.04(s,1H),6.84(d,J =9.5Hz,1H),6.02-5.66(m,2H),4.59(d,J=12.0Hz,1H),4.38(d,J=6.0Hz,1 H),4.34-4.19(m,2H),4.06(d,J=12.3Hz,1H),3.91-3.84(m,1H),3.80-3.7 4(m,1H),3.56(t,J=8.7Hz,1H),3.48(d,J=14.8Hz,1H),3.40(s,3H),3.32( s,4H),3.18(dd,J=9.0,14.8Hz,1H),3.11(d,J=14.6Hz,1H),3.06-2.94(m, 2H),2.70(s,5H),2.49-2.47(m,1H),2.45(s,1H),2.42(s,3H),2.22(d,J=1 4.1Hz,2H),2.03-1.88(m,2H),1.86-1.71(m,2H),1.68-1.54(m,1H),1.44( d,J=6.0Hz,3H),1.35-1.26(m,1H),1.15(s,1H),0.94(s,3H),0.49(s,3H).

[0646] Example 9: Synthesis of Compound I-009

[0647] Following the synthesis method described in steps 2 to 4 of Example 7, and replacing the corresponding starting materials, compound I-009 was prepared using compound 3-1a as the starting material. It is a white solid. LCMS (ESI): m / z C 47 H 61 N8O5Se + [M+H] + Calculated value = 897.39, measured value = 897.4. 1H NMR (400MHz, CDCl3) δppm 8.47(d,J=2.5Hz,1H),8.18(s,1H),7.87(s,1H),7.32(s,1H),7.05(d,J=2.8Hz,1H), 6.78(d,J=8.0Hz,1H),5.50(d,J=3.0Hz,1H),5.29(d,J=10.8Hz,1H),4.79(d,J=10.8H z,1H),4.76-4.71(m,1H),4.41-4.27(m,2H),3.78-3.71(m,1H),3.67-3.62(m,1H),3. 60-3.53(m,1H),3.52-3.46(m,1H),3.40(s,3H),3.29(s,4H),3.18-3.10(m,2H),3.07 -3.02(m,1H),3.01-2.92(m,1H),2.76(q,J=5.9Hz,1H),2.64-2.56(m,5H),2.46(d,J =14.6Hz,1H),2.43-2.39(m,1H),2.38(s,3H),2.33-2.24(m,1H),2.23-2.16(m,1H),2 .09(t,J=10.0Hz,1H),1.69(s,1H),1.57-1.47(m,2H),1.43(d,J=6.0Hz,3H),1.16(d, J=6.0Hz, 3H), 1.11 (d, J=6.0Hz, 3H), 0.95 (s, 3H), 0.92 (t, J=4.3Hz, 1H), 0.46 (s, 3H).

[0648] Example 10: Synthesis of Compound I-010

[0649] Following the synthesis method described in steps 2 to 4 of Example 7, and replacing the corresponding starting materials, compound I-010 was prepared using intermediate 9-5 and compound 4-1 as starting materials. It is a white solid. LCMS(ESI): m / z C 46 H 57 F2N8O5Se + [M+H] + Calculated value = 919.36, measured value = 919.1 1H NMR (400MHz, CDCl3) δppm 8.49(d,J=2.5Hz,1H),8.19(s,1H),7.90(s,1H),7.34(s,1H),7.12-6.95( m,2H),6.05-5.70(m,1H),5.61-5.48(m,1H),5.33(d,J=10.8Hz,1H),4.81 (d,J=10.5Hz,1H),4.78-4.71(m,1H),4.44-4.28(m,2H),3.79-3.74(m,1H ),3.70-3.65(m,1H),3.62-3.50(m,2H),3.42(s,7H),3.21-3.13(m,2H),3 .10-3.03(m,1H),2.87-2.77(m,5H),2.65-2.57(m,1H),2.54-2.49(m,3H) ,2.48-2.39(m,2H),2.33-2.25(m,2H),2.21(s,1H),2.13(d,J=9.8Hz,1H) ,2.01-1.94(m,1H),1.89-1.82(m,1H),1.71(t,J=9.4Hz,1H),1.44(d,J=6 .0Hz,3H),1.40-1.36(m,1H),1.22-1.14(m,1H),0.98(s,3H),0.48(s,3H).

[0650] The preparation methods for other similar compounds in this invention are the same as those in the above embodiments.

[0651] Biological Test Example 1: In Vitro Cell Viability

[0652] The inhibitory activity of the compounds of this invention on the proliferation of KRAS-mutant tumor cells was evaluated.

[0653] 1. KRAS mutant tumor cell inhibitory activity IC 50 test

[0654] Methods: Cultured tumor cells were seeded at appropriate concentrations (95 μL per well) into 96-well plates and incubated at 37°C with 5% CO2 for 24 h. The test compound was serially diluted two-fold (5 μL per well) and added to the cell plate in replicates for each concentration. A blank control (without the drug) was also included. Cells were cultured for another 72 h. Cell viability was assessed using a CellTiter-Gio chemiluminescence assay kit, and the IC50 was calculated. 50 .

[0655] Results: The compound showed an inhibitory activity (IC50) on cell proliferation in three KRAS-mutant cell lines: MIA PaCa-2 (KRAS G12C), SW620 (KRAS G12V), and GP2d (KRAS G12D). 50 See Table 1.

[0656] Table 1. Inhibitory activity (IC50) of compounds against the proliferation of KRAS-mutant tumor cells 50 (nM)

[0657] Note: A < 1nM; 1 ≤ B < 5nM; C ≥ 5nM.

[0658] 2. KRAS mutant tumor cell inhibitory activity IC50 50 test

[0659] Methods: Tumor cells cultured in vitro were seeded at an appropriate concentration into 384-well plates (50 μL per well) and incubated overnight at 37°C with 5% CO2. Gradient loading was performed using an HPD300 micropipette, and the cells were cultured for another 3 days. Cell viability was assessed using a CellTiter-Gio chemiluminescence assay kit, and IC50 was calculated. 50 .

[0660] Results: The inhibitory activity of the test compound on cell proliferation in two KRAS-mutant cell lines, MIA PaCa-2 (KRAS G12C) and SW620 (KRAS G12V), was [IC50]%. 50 See Table 2.

[0661] Table 2. Inhibitory activity of compounds against the proliferation of KRAS-mutant tumor cells (IC50) (nM)

[0662] Note: A < 1nM; 1 ≤ B < 5nM;

[0663] The compounds of this invention exhibit strong inhibitory activity against KRAS-mutant tumor cells, IC50. 50 All are at the nM level.

[0664] Biological Test Example 2: Rat Pharmacokinetics

[0665] The pharmacokinetic characteristics of the compounds of this invention in SD rats were evaluated.

[0666] 1. PK study of intravenous administration (1 mg / kg) in SD rats

[0667] Methods: The test compound was dissolved (Solutol Hs15:20% Hp-β-CD = 6:94 (v:v)). Three male SD rats were administered the test compound intravenously once at a dose of 1 mg / kg in a volume of 10 mL / kg. Blood samples were collected at 0.083, 0.25, 0.5, 1, 2, 4, 6, 8 and 24 h after administration. Blood drug concentration was detected by LC-MS-MS and pharmacokinetic parameters were calculated.

[0668] Results: The pharmacokinetic parameters of the compounds are shown in Table 3.

[0669] Table 3. Pharmacokinetic parameters of the tested compounds in SD rats

[0670] The compound of this invention has a long half-life, high exposure level, low clearance rate, and good pharmacokinetic characteristics.

[0671] 2. Comparison study of oral administration (1 mg / kg) and intravenous administration (0.1 mg / kg) in SD rats

[0672] Method: The test compounds were treated with 10% (v / v) DMSO + 10% (v / v) DMSO. Solutol HS15, in combination with 80% 0.9% sodium chloride solution, is prepared into a clear solution with a concentration of 0.02 mg / mL for intravenous administration at a dose of 0.1 mg / kg in a volume of 5 mL / kg. Solutol Hs15:20% Hp-β-CD = 6:94 (v:v) is also prepared into a clear solution with a concentration of 0.1 mg / mL for gavage administration at a dose of 1 mg / kg in a volume of 10 mL / kg.

[0673] Three male SD rats were used in each group. Blood samples were collected at 0.083, 0.25, 0.5, 1, 2, 4, 6, 8 and 24 h after drug administration. Blood drug concentration was detected by LC-MS-MS and pharmacokinetic parameters were calculated.

[0674] Results: The pharmacokinetic parameters of the compounds are shown in Table 4.

[0675] Table 4. Pharmacokinetic parameters of the tested compounds in SD rats

[0676] The compounds of this invention have long half-lives, high oral bioavailability, and good pharmacokinetic and drug-like properties. Compounds I-003 and I-009 have long half-lives and significantly better bioavailability (F%) than the control compounds (RMC-6236 and compound 6A).

[0677] Biological Test Example 3: Metabolic Stability

[0678] The metabolic stability of the compounds of this invention in liver microsomes was evaluated in different species.

[0679] method:

[0680] 1. Prepare 1.0L Buffer A: containing 1.0mM EDTA and 0.1M KH2PO4. Prepare 1.0L Buffer B: containing 1.0mM EDTA and 0.1M K2HPO4. Take 700mL of Buffer B, titrate with Buffer A, and adjust to pH 7.4 using a pH calibrator to obtain phosphate-buffered saline (PBS).

[0681] 2. Weigh the sample of the compound to be tested, dissolve it in dimethyl sulfoxide (DMSO), and prepare a 10 mM stock solution. Take 2 μL of the 10 mM stock solution and add it to 198 μL of 50% acetonitrile (ACN) to prepare a 0.1 mM working solution.

[0682] 3. Add 200 μL of ACN-IS (acetonitrile solution containing internal standard) to the deep well plate and store it in a refrigerator at 2–8°C for later use.

[0683] 4. Dissolve NADPH in phosphate buffer (PBS) to prepare a 5mM NADPH solution.

[0684] 5. Take 5 μL (20 mg / mL) of liver microsomes from humans, monkeys, dogs, rats, and mice respectively, and add them to 153 μL of phosphate buffer to prepare a 0.63 mg / mL liver microsome solution. Take 158 μL of the liver microsome solution, add 2 μL of positive control (Verapamil, RMC-6236, compound 6A) or the working solution of the compound of this invention (0.1 mM), and mix thoroughly by inverting. Place the reaction system in a 37°C water bath and pre-incubate with shaking at 100–200 rpm for 5 minutes.

[0685] 6. Sample at 0 min: Add 24 μL of the reaction mixture to the precipitant, then add 6 μL of NADPH solution. Samples at other time points: Directly add 34 μL of NADPH solution to start the reaction and mix well. At 5, 15, 30, and 60 min, add 30 μL of the reaction mixture to 200 μL of ACN-IS to terminate the reaction and vortex mix well.

[0686] 7. Centrifuge the reacted sample at 4℃ and 4000rpm for 10 minutes. Take 50μL of the supernatant and add it to 150μL of aqueous solution containing 0.1% formic acid. Vortex to mix and then perform LC-MS / MS analysis.

[0687] 8. Based on the LC-MS / MS responses of the samples at each time point, calculate the residual rate of the prototype at each time point relative to the 0 min time point. Plot a curve between the logarithm of the residual rate and the incubation time to calculate the elimination half-life T. 1 / 2 Inherent clearance rate CL int And liver uptake rate ER.

[0688] Results: The results of liver microsomal metabolic stability are shown in Table 5.

[0689] Table 5. Stability of compounds in liver microsomes of different species

[0690] The compounds of this invention exhibit good stability in liver microsomes of different species. The half-lives of compounds I-003 and I-009 are significantly better than those of the control compounds (RMC-6236 and compound 6A) in multiple species.

[0691] Biological Test Example 4: Tissue Distribution

[0692] The tissue distribution of the compounds of this invention in SD rats was evaluated.

[0693] Methods: The test compound was prepared into a clear solution with a concentration of 0.1 mg / mL using Solutol Hs15:20% Hp-β-CD = 6:94 (v:v). Male SD rats were administered the solution via gavage at a dose of 1 mg / kg, with a volume of 10 mL / kg. Three rats were in each group. Tissues and organs were collected 24 hours after administration, homogenized, and the drug was extracted. The drug concentration in the tissues was determined by LC-MS-MS.

[0694] Results: The average drug concentrations in major tissues after compound administration are shown in Table 6.

[0695] Table 6. Average drug concentrations (ng / mL) in different organs 24 hours after compound administration

[0696] The compounds of this invention exhibit high distribution in major tissues. At the same dosage, the drug concentrations of compounds I-003 and I-009 were significantly higher than those of the control compounds (RMC-6236 and compound 6A) 24 hours after administration.

[0697] Biological Test Example 5: Pharmacokinetics in Beagle Dogs

[0698] Evaluate the pharmacokinetic characteristics of the compounds of this invention in Beagle dogs.

[0699] method:

[0700] Weigh the compound to be tested and prepare a solution with a concentration of 1 mg / mL using Solutol Hs15:20% Hp-β-CD=6:94 (v:v). Administer the solution orally to adult Beagle dogs aged 16-18 months by gavage at a dose of 1 mg / kg. Fast for 12-18 hours before administration, but allow free access to water. Resume feeding 3 hours after administration.

[0701] Blood samples were collected at 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours after drug administration. The samples were placed in heparin sodium anticoagulant tubes, with crushed ice or ice packs on top, and centrifuged within 2 hours of collection (4°C, 3500 rpm, 5 min). After plasma collection, the samples were separated into two aliquots: tube 1 contained at least 150 μL, and the remaining sample was placed in tube 2 as a backup. All aliquots were then placed in a container filled with dry ice and frozen at ≤-65°C as soon as possible.

[0702] After thawing the plasma samples to be tested on wet ice, 30 μL of plasma was added to 200 μL of acetonitrile solution containing IS, and the mixture was vortexed for 5 min to precipitate. Then, it was centrifuged at 5000 rpm and 4℃ for 5 min. 50 μL of the supernatant was transferred to a 96-well plate, and 150 μL of pure water was added to each well to reconstitute the drug. The blood drug concentration was detected by LC-MS-MS, and the pharmacokinetic parameters were calculated.

[0703] Results: The pharmacokinetic parameters of the compounds are shown in Table 7.

[0704] Table 7. Pharmacokinetic parameters of compounds in Beagle dogs

[0705] The compounds of this invention exhibit favorable pharmacokinetic characteristics and drug-like properties. The half-life (T) of compound I-009 is... 1 / 2 ), Exposure (C max (AUC) is better.

[0706] In the above biological test examples 2-4, Verapamil, RMC-6236, and compound 6A were positive control compounds, and their structures are shown in the table below:

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof, Ring A is selected from X is either Se or S; When X is Se, R 1 and R 2 Each is independently selected from H, D, and C. 1-4 Alkyl, Halogenated C 1-4 Alkyl and deuterated C 1-4 Alkyl; or R 1 and R 2 Together with the indole group to which it is attached, it forms When X is S, and ring A is At that time, R 1 and R 2 Together with the indole group to which it is attached, it forms When X is S, and ring A is At that time, R 1 and R 2 Together with the indole group to which it is attached, it forms R 4 R 5 R 6 R 8 R 9 R 10 R 11 R 12 and R 13 Each is independently selected from H, D, hydroxyl, halogen, C 1-4 Alkyl, -OC 1-4 Alkyl, Halogenated C 1-4 Alkyl and deuterated C 1-4 alkyl; R, R 3 R 7 and R 15 Each is independently selected from D, hydroxyl, halogen, and C. 1-4 Alkyl, -OC 1-4 Alkyl, Halogenated C 1-4 Alkyl and deuterated C 1-4 alkyl; m and p are each an independent integer from 0 to 2, n is an integer from 0 to 8, and q is an integer from 0 to 6; R 14 Selected from H, D, hydroxyl, halogen, C 1-4 Alkyl, -OC 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl and -C 2-4 alkynyl-3-6-membered heterocyclic alkyl, wherein the C 1-4 Alkyl, -OC 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl and -C 2-4 Alkyne-3-6-membered heterocyclic alkyl group optionally surrounded by one or more R 14-1 replace; R 14-1 Each is independently selected from D, hydroxyl, halogen, and C. 1-4 Alkyl, -OC 1-4 Alkyl and C 3-6 cycloalkyl, wherein the C 1-4 Alkyl, -OC 1-4 Alkyl and C 3-6 The cycloalkyl group may optionally be substituted by one or more substituents selected from D, hydroxyl and halogen; R 16 Selected from H, D, hydroxyl, halogen and C 1-4 Alkyl, wherein the C 1-4 Alkyl groups are optionally surrounded by one or more R 16-1 replace; R 16-1 Each is independently selected from D, hydroxyl, halogen, and -OC. 1-4 alkyl; L is selected from C 3-6 Cycloalkyl, 3-6 membered heterocyclic alkyl, Wherein C 3-6 Cycloalkyl and 3-6 membered heterocyclic alkyl groups are optionally surrounded by one or more R a replace; R a Each is independently selected from D, hydroxyl, halogen, and C. 1-4 Alkyl, -OC 1-4 Alkyl, Halogenated C 1-4 Alkyl and deuterated C 1-4 alkyl; L 1 L 2 L 5 and L 6 Each is independently selected from H, D, hydroxyl, halogen, C 1-4 Alkyl, -OC 1-4 Alkyl and C 3-6 cycloalkyl, wherein the C 1-4 Alkyl, -OC 1-4 Alkyl and C 3-6 cycloalkyl groups are optionally surrounded by one or more R b replace; R b Each is independently selected from D, hydroxyl, halogen, and C. 1-4 Alkyl and -OC 1-4 alkyl; L 3 Selected from H, C 1-4 Alkyl and C 3-6 cycloalkyl, wherein the C 1-4 Alkyl and C 3-6 cycloalkyl groups are optionally surrounded by one or more R c replace; R c Each is independently selected from D, hydroxyl, halogen, and C. 1-4 Alkyl and -OC 1-4 alkyl; L 4 and L 7 Each is independently a 3-9 membered heterocyclic alkyl group, wherein the 3-9 membered heterocyclic alkyl group is optionally surrounded by one or more R d replace; R d Each is independently selected from D, hydroxyl, halogen, oxo group, C 1-4 Alkyl, -OC 1-4 Alkyl, C 3-6 Cycloalkyl, -C(=O)-C 1-4 Alkyl, -C(=O)-C 2-6 alkynyl group, -C(=O)-C 3-6 Cycloalkyl and -C(=O)-3-6-membered heterocycloalkyl, wherein the C 1-4 Alkyl, -OC 1-4 Alkyl, C 3-6 Cycloalkyl, -C(=O)-C 1-4 Alkyl, -C(=O)-C 2-6 alkynyl group, -C(=O)-C 3-6 The cycloalkyl and -C(=O)-3-6-membered heterocycloalkyl groups may be optionally substituted by one or more substituents selected from D, hydroxyl, halogen, -CH3, -N(CH3)2 and cyclopropyl.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein it satisfies one or more of the following conditions: (1) R, R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11 R 12 R 13 R 14 R 14-1 R 15 R 16 R 16- 1 L 1 L 2 L 3 L 5 L 6 R a R b R c and R d In, the C 1-4 Each alkyl group is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl; (2) R, R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11 R 12 R 13 R 15 and R a In the above, the halogenated C 1- The halogens in the four alkyl groups are each independently F, Cl, Br, or I; (3) R, R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11 R 12 R 13 R 14 R 14-1 R 15 R 16 R 16-1 L 1 L 2 L 5 L 6 R a R b R c and R d In this context, each of the halogens is independently F, Cl, Br, or I; (4)R 14 R 14-1 L, L 1 L 2 L 3 L 5 L 6 and R d In, the C 3-6 Each cycloalkyl group is independently C10. 3-6 Monocyclic cycloalkyl or C 5-6 Dicyclic cycloalkyl groups, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc. Preferably, R 14-1 In, the C 3-6 Cycloalkyl group is C 3-6 Monocyclic cycloalkyl, for example cyclopropyl; in L, the C 3-6 Cycloalkyl group is C 3-6 Monocyclic cycloalkyl or C 5-6 Dicyclic cycloalkyl groups, such as cyclopropyl groups, L 5 and L 6 In, the C 3-6 Each cycloalkyl group is independently C10. 3-6 Monocyclic cycloalkyl groups, such as cyclopentyl; (5)R 14 L and R d In this context, each of the 3-6 membered heterocyclic alkyl groups is independently a 3-6 membered monocyclic heterocyclic alkyl group or a 5-6 membered difused heterocyclic heterocyclic alkyl group having one or two heteroatoms or heteroatom groups selected from N, NH, and O, such as piperazine, morpholino, etc. Preferably, R 14 In the first part, the 3-6 membered heterocyclic alkyl group is a 3-6 membered monocyclic heterocyclic alkyl group having two heteroatoms or heteroatom groups selected from N, NH, and O, preferably a 5-6 membered monocyclic heterocyclic alkyl group, such as piperazine or morpholinyl; in the second part, the 3-6 membered heterocyclic alkyl group is a 5-6 membered difused heterocyclic alkyl group having one heteroatom selected from N, NH, and O, such as... R d In this context, the 3-6 membered heterocyclic alkyl group is a 3-6 membered monocyclic heterocyclic alkyl group having one heteroatom selected from N, NH, and O, for example... (6)L 4 and L 7 In this context, each of the 3-9 membered heterocyclic alkyl groups is independently a 3-9 membered monocyclic heterocyclic alkyl group or a 5-9 membered bicyclic heterocyclic alkyl group having one or two heteroatoms or heteroatom groups selected from N, NH and O, preferably a 3-6 membered monocyclic heterocyclic alkyl group or a 5-9 membered bicyclic heterocyclic alkyl group, more preferably a 3-6 membered monocyclic heterocyclic alkyl group or a 5-9 membered spirocyclic heterocyclic alkyl group, such as piperidinyl, Aza-heterocyclic butyl, pyrrolidinyl, or morpholino; Preferably, L 4 In this context, the 3-9 membered heterocyclic alkyl group is a 3-9 membered monocyclic heterocyclic alkyl group having one or two heteroatoms or heteroatom groups selected from N, NH, and O, preferably a 3-6 membered monocyclic heterocyclic alkyl group having one heteroatom or heteroatom group selected from N and NH, such as piperidinyl, aziridine, pyrrolidinyl, or morpholinyl; L 7 In this context, the 3-9 membered heterocyclic alkyl group is a 5-9 membered bicyclic heterocyclic alkyl group having one or two heteroatoms or heteroatom groups selected from N, NH, and O, preferably a 5-9 membered spirocyclic heterocyclic alkyl group having two heteroatoms or heteroatom groups selected from N and NH, for example... (7) When R 1 and R 2 Together with the indole group to which it is attached, it forms When q is any integer from 0 to 6; when R 1 and R 2 Together with the indole group to which it is attached, it forms When q is any integer from 0 to 4; when R 1 and R 2 Together with the indole group to which it is attached, it forms When q is any integer from 0 to 4.

3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein it satisfies one or more of the following conditions: (1) Ring A is Preferred Or ring A is Preferred (2) When X is Se, R 1 and R 2 Each is independently selected from H and C. 1-4 Alkyl, Halogenated C 1-4 Alkyl and deuterated C 1-4 Alkyl groups, preferably selected from H and C 1-4 alkyl; Preferably, R 1 Selected from C 1-4 Alkyl, Halogenated C 1-4 Alkyl and deuterated C 1-4 Alkyl group, preferably C 1-4 Alkyl; R 2 For H; Or R 1 and R 2 Together with the indole group to which it is attached, it forms Preferred Formation More preferably formed (3) When X is S, and ring A is At that time, R 1 and R 2 Together with the indole group to which it is attached, it forms (4)R 4 R 5 R 6 R 8 R 9 R 12 and R 13 Each is independently represented by H; (5)R 10 and R 11 Each independently is C 1-4 Alkyl groups, preferably methyl groups; (6) m, n, p and q are each independently 0; (7)R 14 Selected from H, 3-6 membered heterocyclic alkyl groups and -C 2-4 Alkynyl-3-6-membered heterocyclic alkyl, preferably selected from H and 3-6-membered heterocyclic alkyl, more preferably 3-6-membered heterocyclic alkyl; wherein the 3-6-membered heterocyclic alkyl and -C 2-4 Alkyne-3-6-membered heterocyclic alkyl group optionally surrounded by one or more R 14- 1 replace; (8)R 14-1 Each was independently selected from C 1-4 Alkyl and C 3-6 cycloalkyl; wherein the C 1-4 Alkyl and C 3-6 The cycloalkyl group may optionally be substituted with one or more substituents selected from D, hydroxyl, and halogen, preferably optionally substituted with one or more D groups; R 14-1 C is preferred 1-4 alkyl; (9)R 16 C 1-4 Alkyl, the C 1-4 Alkyl groups are optionally surrounded by one or more R 16-1 Replace; R 16 Preferably ethyl, said ethyl is optionally mixed with one or more R 16-1 replace; (10)R 16-1 Each independently as -OC 1-4 Alkyl group, preferably -OCH3; (11) L is selected from C 3-6 cycloalkyl (e.g., C10) 3-6 Monocyclic cycloalkyl), 3-6 membered heterocyclic alkyl and Preferred selection from C 3-6 Cycloalkyl and 3-6 membered heterocyclic alkyl, more preferably C 3-6 cycloalkyl (e.g., C10) 3-6 Monocyclic cycloalkyl); the C 3-6 cycloalkyl (e.g., C10) 3-6 Monocyclic cycloalkyl groups and 3-6-membered heterocyclic alkyl groups are optionally separated by one or more R groups. a replace; (12)R a Each is independently selected from halogens, C 1-4 Alkyl and Halogenated C 1-4 alkyl; (13)L 1 L 2 L 5 and L 6 Each is independently selected from H and C. 1-4 Alkyl and C 3-6 cycloalkyl; (14)L 3 C 1-4 Alkyl groups, preferably methyl groups; (15)R d Each is independently selected from halogens, oxo groups, and -C(=O)-C. 1-4 Alkyl, -C(=O)-C 2-6 Alkynyl and -C(=O)-3-6-membered heterocyclic alkyl, wherein -C(=O)-C 1-4 Alkyl, -C(=O)-C 2-6 The alkynyl group and the -C(=O)-3-6-membered heterocyclic alkyl group may be optionally substituted by one or more substituents selected from halogens, -CH3, -N(CH3)2 and cyclopropyl groups.

4. The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein it satisfies one or more of the following conditions: (1) When X is Se, R 1 and R 2 Each of the following is independently selected from H, -CH3, -CF3, -CHF2, -CH2F, -CD3, -CHD2, -CH2D, -CH2CH3, -CH2CF3, -CF2CF3, -CD2CD3, and -CH2CD3; preferably selected from H, -CH2CH3, -CH2CF3, -CD2CD3, and -CH2CD3; Preferably, R 1 Selected from -CH3, -CHF2, -CH2F, -CH2CH3, -CH2CF3, -CF2CF3, -CD2CD3, and -CH2CD3, preferably selected from -CH2CH3, -CH2CF3, -CD2CD3, and -CH2CD3, more preferably -CH2CH3; R 2 For H; Or R 1 and R 2 Together with the indole group to which it is attached, it forms Preferred Formation More preferably formed (2)R 14 The group is selected from H, piperazinyl, morpholinyl, and -propynyl-morpholinyl, preferably from H, piperazinyl, and morpholinyl, more preferably from piperazinyl; wherein the piperazinyl, morpholinyl, and -propynyl-morpholinyl are optionally separated by one or more R 14-1 replace; Preferably, R 14 Selected from H, Preferred selection from H, More preferably The above Optional by one or more R 14-1 replace; (3)R 14-1 Each group is independently selected from -CH3, -CF3, -CHF2, -CH2F, -CD3, -CHD2, -CH2D, -CH2CH3, -CH2CF3, -CF2CF3, -CD2CD3, -CH2CD3, -CH2OH, and cyclopropyl, preferably selected from -CH3, -CD3, -CH2CH3, -CH2OH, and cyclopropyl; more preferably selected from -CH3, -CD3, -CH2CH3, and cyclopropyl, for example, -CH3; (4)R 16 It is -CH(CH3)-OCH3, for example, (5) Selected from Preferred selection (6) Selected from For example, Preferably, Selected from For example, 5. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein it satisfies one or more of the following conditions: (1)R 14 Selected from H, Preferred selection from H, More preferably (2) L is selected from Preferred selection More preferably selected from Further selection from Preferably, L is selected from Preferred selection More preferably selected from Further selection from More preferably, L is selected from Preferred selection More preferably selected from Further selection from 6. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein, The compound represented by formula (I) is the compound represented by formula (II), the compound represented by formula (III), the compound represented by formula (II-1), or the compound represented by formula (II-2). Among them, rings A and R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11 R 12 R 13 R 14 R 15 R 16 The definitions of L, m, n, and p are as described in any one of claims 1-5; Preferably, the compound represented by formula (I) is the compound represented by formula (II-1a), formula (II-1b), formula (II-1c), formula (II-1d), formula (II-2a), formula (II-2b), formula (II-2c), formula (II-2d), formula (III-1), formula (III-2), formula (III-3), or formula (III-4). Among them, R, R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11 R 12 R 13 R 14 R 15 R 16 The definitions of L, m, n, p, and q are as described in any one of claims 1-5; in the compounds shown in formula (II-1a) and formula (II-2a), R 1 and R 2 Each is independently selected from H, D, and C. 1-4 Alkyl, Halogenated C 1-4 Alkyl and deuterated C 1-4 alkyl; Preferably, In the compounds shown in formula (II-1a) and formula (II-2a), R 1 Selected from C 1-4 Alkyl, Halogenated C 1-4 Alkyl and deuterated C 1-4 Alkyl groups (preferably selected from -CH2CH3, -CH2CF3, -CD2CD3 and -CH2CD3); R 2 Selected from H; R 4 R 5 R 6 R 8 R 9 R 12 and R 13 Each is independently selected from H; R 10 and R 11 Each independently is C 1-4 Alkyl or deuterated C 1-4 Alkyl (preferably methyl); m, n, p, and q are each independently 0; R 14 Selected from H and 5-6 membered monocyclic heterocyclic alkyl groups (piperazinyl or morpholinyl), wherein the 5-6 membered monocyclic heterocyclic alkyl group is optionally surrounded by one or more R groups. 14-1 Replace; R 14-1 Each was independently selected from C 1-4 Alkyl and C 3-6 cycloalkyl (C 3-6 Monocyclic cycloalkyl), the C 1-4 Alkyl and C 3-6 Each cycloalkyl group may be independently and optionally substituted with one or more D molecules; (R 14 H is preferred. )； R 16 C 1-4 Alkyl, wherein the C 1-4 Alkyl groups are optionally surrounded by one or more R 16-1 Replace, R 16-1 Each independently as -OC 1-4 alkyl; (R 16 Preferably -CH(CH3)-OCH3); L is selected from C 3-6 cycloalkyl (C 3-6 Monocyclic cycloalkyl or C 5-6 Dicyclic cycloalkyl), 5-6 membered dicyclic heterocyclic alkyl (having one 5-6 membered dicyclic heterocyclic alkyl group selected from O atom) and Wherein C 3-6 cycloalkyl groups are formed by one or more R groups a Replace, R a Each was independently selected from C 1-4 Alkyl, Halogenated C 1-4 Alkyl and deuterated C 1-4 Alkyl; L 5 and L 6 Each is independently selected from H and C. 3-6 cycloalkyl (C 3- 6 monocyclic cycloalkyl); L 7 Selected from 5-9 membered bicyclic heterocyclic alkyl groups (5-9 membered spirocyclic heterocyclic alkyl groups), wherein the 5-9 membered bicyclic heterocyclic alkyl group is optionally surrounded by one or more R groups. d Replace, R d Each is independently a -C(=O)-3-6 membered monocyclic heterocyclic alkyl (a 3-6 membered monocyclic heterocyclic alkyl having 1 N atom), wherein the -C(=O)-3-6 membered monocyclic heterocyclic alkyl is optionally substituted by one or more substituents selected from -CH3 and cyclopropyl; (L is preferred) )； Alternatively, in the compounds shown in formula (II-1a) and formula (II-2a), R 1 C 1-4 Alkyl (preferably ethyl); R 2 For H; R 4 R 5 R 6 R 8 R 9 R 12 and R 13 Each is independently selected from H; R 10 and R 11 Each independently is C 1-4 Alkyl (preferably methyl); m, n, p, and q are each independently 0; R 14 For optional use by one or more R 14-1 Substituted 3-6 membered heterocyclic alkyl groups (preferably optionally replaced by one or more R groups) 14-1 Substituted 3-6 membered monocyclic heterocyclic alkyl groups); R 14-1 Each independently is C 1-4 Alkyl (preferably methyl); (R 14 For example, )； R 16 C 1-4 Alkyl, wherein the C 1-4 Alkyl groups are optionally surrounded by one or more R 16-1 Replace; R 16-1 Each independently as -OC 1-4 Alkyl group (preferably -OCH3); (R 16 Preferably, it is -CH(CH3)-OCH3, for example, )； L is arbitrarily assigned to one or more R. a Replacement C 3-6 cycloalkyl; R a Each was independently selected from C 1-4 Alkyl and Halogenated C 1-4 alkyl; (L is, for example) )； Among the compounds shown in formula (II-1b), (II-1c), (II-1d), (II-2b), (II-2c), (II-2d), (III-1), (III-2), (III-3), and (III-4), R 4 R 5 R 6 R 8 R 9 R 12 and R 13 Each is independently selected from H; R 10 and R 11 Each independently is C 1-4 Alkyl or deuterated C 1-4 Alkyl (preferably methyl); m, n, p, and q are each independently 0; R 14 Selected from H and 5-6 membered monocyclic heterocyclic alkyl groups (piperazinyl or morpholinyl), wherein the 5-6 membered monocyclic heterocyclic alkyl group is optionally surrounded by one or more R groups. 14-1 Replace; R 14-1 Each was independently selected from C 1-4 Alkyl and C 3-6 cycloalkyl (C 3-6 Monocyclic cycloalkyl), the C 1-4 Alkyl and C 3-6 The cycloalkyl group may optionally be substituted with one or more D atoms; (R 14 H is preferred. )； R 16 C 1-4 Alkyl, wherein the C 1-4 Alkyl groups are optionally surrounded by one or more R 16-1 Replace, R 16-1 Each independently as -OC 1-4 Alkyl; (R) 16 Preferably -CH(CH3)-OCH3); L is selected from C 3-6 cycloalkyl (C 3-6 Monocyclic cycloalkyl or C 5-6 Dicyclic cycloalkyl), 5-6 membered dicyclic heterocyclic alkyl (having one 5-6 membered dicyclic heterocyclic alkyl group selected from O atom) and Wherein C 3-6 cycloalkyl groups are formed by one or more R groups a Replace, R a Each was independently selected from C 1-4 Alkyl, Halogenated C 1-4 Alkyl and deuterated C 1-4 Alkyl; L 5 and L 6 Each is independently selected from H and C. 3-6 cycloalkyl (C 3- 6 monocyclic cycloalkyl); L 7 Selected from 5-9 membered bicyclic heterocyclic alkyl groups (5-9 membered spirocyclic heterocyclic alkyl groups), wherein the 5-9 membered bicyclic heterocyclic alkyl group is optionally surrounded by one or more R groups. d Replace, R d Each is independently a -C(=O)-3-6 membered monocyclic heterocyclic alkyl (a 3-6 membered monocyclic heterocyclic alkyl having 1 N atom), wherein the -C(=O)-3-6 membered monocyclic heterocyclic alkyl is optionally substituted by one or more substituents selected from -CH3 and cyclopropyl; (L is preferred) )； Alternatively, the compounds shown in formula (II-1b), (II-1c), (II-1d), (II-2b), (II-2c), (II-2d), (III-1), (III-2), (III-3), and (III-4) may be included. R 4 R 5 R 6 R 8 R 9 R 12 and R 13 Each is independently selected from H; R 10 and R 11 Each independently is C 1-4 Alkyl (preferably methyl); m, n, p, and q are each independently 0; R 14 For optional use by one or more R 14-1 Substituted 3-6 membered heterocyclic alkyl groups (preferably optionally replaced by one or more R groups) 14-1 Substituted 3-6 membered monocyclic heterocyclic alkyl groups); R 14-1 Each independently is C 1-4 Alkyl (preferably methyl); (R 14 For example, )； R 16 C 1-4 Alkyl, wherein the C 1-4 Alkyl groups are optionally surrounded by one or more R 16-1 Replace; R 16-1 Each independently as -OC 1-4 Alkyl group, preferably -OCH3; (R 16 Preferably, it is -CH(CH3)-OCH3, for example, )； L is arbitrarily assigned to one or more R. a Replacement C 3-6 cycloalkyl groups (preferably optionally surrounded by one or more R groups) a Replacement C 3-6 (Monocyclic cycloalkyl); R a Each was independently selected from C 1-4 Alkyl and Halogenated C 1-4 alkyl; (L is, for example) )。 7. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein, The compound represented by formula (I) is the compound represented by formula (I'), the compound represented by formula (II'), the compound represented by formula (III'), the compound represented by formula (II-1'), or the compound represented by formula (II-2'). Among them, rings A and R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11 R 12 R 13 R 14 R 15 R 16 The definitions of L, m, n, and p are as described in any one of claims 1-6; Preferably, the compound represented by formula (I) is the compound represented by formula (II-1a'), the compound represented by formula (II-1b'), the compound represented by formula (II-1c'), the compound represented by formula (II-1d'), the compound represented by formula (II-2a'), the compound represented by formula (II-2b'), the compound represented by formula (II-2c'), the compound represented by formula (II-2d'), the compound represented by formula (III-1'), the compound represented by formula (III-2'), the compound represented by formula (III-3'), or the compound represented by formula (III-4'). Among them, R, R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11 R 12 R 13 R 14 R 15 R 16 The definitions of L, m, n, p, and q are as described in any one of claims 1-6; in the compounds shown in formula (II-1a') and formula (II-2a'), R 1 and R 2 Each is independently selected from H, D, and C. 1-4 Alkyl, Halogenated C 1-4 Alkyl and deuterated C 1-4 alkyl; Preferably, Among the compounds shown in formula (II-1a') and formula (II-2a'), R 1 Selected from C 1-4 Alkyl, Halogenated C 1-4 Alkyl and deuterated C 1-4 Alkyl groups (preferably selected from -CH2CH3, -CH2CF3, -CD2CD3 and -CH2CD3); R 2 Selected from H; R 4 R 5 R 6 R 8 R 9 R 12 and R 13 Each is independently selected from H; R 10 and R 11 Each independently is C 1-4 Alkyl or deuterated C 1-4 Alkyl (preferably methyl); m, n, p, and q are each independently 0; R 14 Selected from H and 5-6 membered monocyclic heterocyclic alkyl groups (piperazinyl or morpholinyl), wherein the 5-6 membered monocyclic heterocyclic alkyl group is optionally surrounded by one or more R groups. 14-1 Replace; R 14-1 Each was independently selected from C 1-4 Alkyl and C 3-6 cycloalkyl (C 3-6 Monocyclic cycloalkyl), the C 1-4 Alkyl and C 3-6 Each cycloalkyl group may be independently and optionally substituted with one or more D molecules; (R 14 H is preferred. )； R 16 C 1-4 Alkyl, wherein the C 1-4 Alkyl groups are optionally surrounded by one or more R 16-1 Replace, R 16-1 Each independently as -OC 1-4 alkyl; (R 16 Preferably -CH(CH3)-OCH3); L is selected from C 3-6 cycloalkyl (C 3-6 Monocyclic cycloalkyl or C 5-6 Dicyclic cycloalkyl), 5-6 membered dicyclic heterocyclic alkyl (having one 5-6 membered dicyclic heterocyclic alkyl group selected from O atom) and Wherein C 3-6 cycloalkyl groups are formed by one or more R groups a Replace, R a Each was independently selected from C 1-4 Alkyl, Halogenated C 1-4 Alkyl and deuterated C 1-4 Alkyl; L 5 and L 6 Each is independently selected from H and C. 3-6 cycloalkyl (C 3- 6 monocyclic cycloalkyl); L 7 Selected from 5-9 membered bicyclic heterocyclic alkyl groups (5-9 membered spirocyclic heterocyclic alkyl groups), wherein the 5-9 membered bicyclic heterocyclic alkyl group is optionally surrounded by one or more R groups. d Replace, R d Each is independently a -C(=O)-3-6 membered monocyclic heterocyclic alkyl (a 3-6 membered monocyclic heterocyclic alkyl having 1 N atom), wherein the -C(=O)-3-6 membered monocyclic heterocyclic alkyl is optionally substituted by one or more substituents selected from -CH3 and cyclopropyl; (L is preferred) )； Alternatively, in the compounds shown in formula (II-1a') and formula (II-2a'), R 1 C 1-4 Alkyl (preferably ethyl); R 2 For H; R 4 R 5 R 6 R 8 R 9 R 12 and R 13 Each is independently selected from H; R 10 and R 11 Each independently is C 1-4 Alkyl (preferably methyl); m, n, p, and q are each independently 0; R 14 For optional use by one or more R 14-1 Substituted 3-6 membered heterocyclic alkyl groups (preferably optionally replaced by one or more R groups) 14-1 Substituted 3-6 membered monocyclic heterocyclic alkyl groups); R 14-1 Each independently is C 1-4 Alkyl (preferably methyl); (R 14 For example, )； R 16 C 1-4 Alkyl, wherein the C 1-4 Alkyl groups are optionally surrounded by one or more R 16-1 Replace; R 16-1 Each independently as -OC 1-4 Alkyl group (preferably -OCH3); (R 16 Preferably, it is -CH(CH3)-OCH3, for example, )； L is arbitrarily assigned to one or more R. a Replacement C 3-6 cycloalkyl; R a Each was independently selected from C 1-4 Alkyl and Halogenated C 1-4 alkyl; (L is, for example) )； Among the compounds shown in formula (II-1b'), (II-1c'), (II-1d'), (II-2b'), (II-2c'), (II-2d'), (III-1'), (III-2'), (III-3'), and (III-4'), R 4 R 5 R 6 R 8 R 9 R 12 and R 13 Each is independently selected from H; R 10 and R 11 Each independently is C 1-4 Alkyl or deuterated C 1-4 Alkyl (preferably methyl); m, n, p, and q are each independently 0; R 14 Selected from H and 5-6 membered monocyclic heterocyclic alkyl groups (piperazinyl or morpholinyl), wherein the 5-6 membered monocyclic heterocyclic alkyl group is optionally surrounded by one or more R groups. 14-1 Replace; R 14-1 Each was independently selected from C 1-4 Alkyl and C 3-6 cycloalkyl (C 3-6 Monocyclic cycloalkyl), the C 1-4 Alkyl and C 3-6 The cycloalkyl group may optionally be substituted with one or more D atoms; (R 14 H is preferred. )； R 16 C 1-4 Alkyl, wherein the C 1-4 Alkyl groups are optionally surrounded by one or more R 16-1 Replace, R 16-1 Each independently as -OC 1-4 alkyl; (R 16 Preferably -CH(CH3)-OCH3); L is selected from C 3-6 cycloalkyl (C 3-6 Monocyclic cycloalkyl or C 5-6 Dicyclic cycloalkyl), 5-6 membered dicyclic heterocyclic alkyl (having one 5-6 membered dicyclic heterocyclic alkyl group selected from O atom) and Wherein C 3-6 cycloalkyl groups are formed by one or more R groups a Replace, R a Each was independently selected from C 1-4 Alkyl, Halogenated C 1-4 Alkyl and deuterated C 1-4 Alkyl; L 5 and L 6 Each is independently selected from H and C. 3-6 cycloalkyl (C 3- 6 monocyclic cycloalkyl); L 7 Selected from 5-9 membered bicyclic heterocyclic alkyl groups (5-9 membered spirocyclic heterocyclic alkyl groups), wherein the 5-9 membered bicyclic heterocyclic alkyl group is optionally surrounded by one or more R groups. d Replace, R d Each is independently a -C(=O)-3-6 membered monocyclic heterocyclic alkyl (a 3-6 membered monocyclic heterocyclic alkyl having 1 N atom), wherein the -C(=O)-3-6 membered monocyclic heterocyclic alkyl is optionally substituted by one or more substituents selected from -CH3 and cyclopropyl; (L is preferred) )； Alternatively, the compounds shown in formula (II-1b'), (II-1c'), (II-1d'), (II-2b'), (II-2c'), (II-2d'), (III-1'), (III-2'), (III-3'), and (III-4') are also included. R 4 R 5 R 6 R 8 R 9 R 12 and R 13 Each is independently selected from H; R 10 and R 11 Each independently is C 1-4 Alkyl (preferably methyl); m, n, p, and q are each independently 0; R 14 For optional use by one or more R 14-1 Substituted 3-6 membered heterocyclic alkyl groups (preferably optionally replaced by one or more R groups) 14-1 Substituted 3-6 membered monocyclic heterocyclic alkyl groups); R 14-1 Each independently is C 1-4 Alkyl (preferably methyl); (R 14 For example, )； R 16 C 1-4 Alkyl, wherein the C 1-4 Alkyl groups are optionally surrounded by one or more R 16-1 Replace; R 16-1 Each independently as -OC 1-4 Alkyl group (preferably -OCH3); (R 16 Preferably, it is -CH(CH3)-OCH3, for example, )； L is arbitrarily assigned to one or more R. a Replacement C 3-6 cycloalkyl groups (preferably optionally surrounded by one or more R groups) a Replacement C 3-6 (Monocyclic cycloalkyl); R a Each was independently selected from C 1-4 Alkyl and Halogenated C 1-4 alkyl; (L is, for example) )。 8. The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein, The compound represented by formula (I) is selected from compounds with any of the following structural formulas:

9. A pharmaceutical composition comprising: (1) The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, and (2) Pharmaceutically acceptable excipients.

10. Use of substance A in the preparation of a RAS inhibitor, wherein substance A is a compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 9; the RAS inhibitor is preferably a RAS mutation inhibitor; the RAS mutation is preferably selected from one or more of KRAS mutations, NRAS mutations, and HRAS mutations; the KRAS mutation is preferably selected from KRAS... G12C Mutation, KRAS G12D Mutation, KRAS G12V Mutation, KRAS G12R Mutation, KRAS G13C Mutations and KRAS G13D One or more of the mutations.

11. Use of substance A in the preparation of a medicament for treating RAS-related diseases, wherein substance A is a compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 9; The RAS-related diseases are preferably those related to RAS mutations; The diseases associated with RAS mutations are preferably cancers associated with RAS mutations, and more preferably selected from one or more of digestive system cancers, respiratory system cancers, and hematological cancers; The RAS mutation is preferably selected from one or more of KRAS mutation, NRAS mutation, and HRAS mutation; The KRAS mutation is preferably selected from KRAS. G12C Mutation, KRAS G12D Mutation, KRAS G12V Mutation, KRAS G12R Mutation, KRAS G13C Mutations and KRAS G13D One or more of the mutations.

12. A compound selected from any of the following structural formulas or a pharmaceutically acceptable salt thereof:

13. A method for preparing a compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof, comprising one or more of the following steps: (1) In a solvent, in the presence of an acid, formaldehyde and a reducing agent, the compound shown in formula (A-2) undergoes a methylation reaction to give the compound shown in formula (A-1); in, Rings A, X, R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11 R 12 R 13 R 15 R 16 The definitions of L, m, n and p are as described in any one of claims 1-8; (2) In a solvent, in the presence of a condensing agent and a base, the compound shown in formula (A-6) undergoes a self-condensation reaction to obtain the compound shown in formula (A-5). Among them, rings A, X, and PG 1 R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11 R 12 R 13 R 15 R 16 The definitions of , m, n and p are as described in any one of claims 1-8, PG 1 It is an amino protecting group (e.g., Cbz).

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