Cyclic lactone compound and medical use thereof

Abstract

The present invention belongs to the field of pharmaceutical chemistry, and relates to a cyclic lactone compound and a medical use thereof. Specifically, disclosed are a cyclic lactone derivative, and a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof; also disclosed is a preparation method for this type of compound, and a use thereof in an antitumor drug. This type of compound has good protein inhibitory activity, and has important application prospects in the field of tumor treatment.

Description

Cyclic lactone compounds and their pharmaceutical uses Technical Field

[0001] This invention belongs to the field of medicinal chemistry and relates to a cyclic lactone derivative and its preparation method, as well as the application of this type of compound in the prevention and / or treatment of tumor diseases. Background Technology

[0002] RAS proteins are a small family of GTPases that play crucial roles in various cellular processes, including proliferation, differentiation, migration, and cell growth. RAS act as molecular switches, cycling between an inactive state bound to GDP and an active state bound to GTP based on extracellular signals. RAS activation is regulated by guanine nucleotide exchange factor (GEF), which catalyzes the exchange of GDP for GTP. Once activated, RAS interacts with effector proteins, rapidly activating multiple downstream signaling pathways such as RAF-MEK-ERK and PI3K-AKT-mTOR, promoting cell growth and survival.

[0003] Oncogenic mutations in RAS (KRAS, HRAS, and NRAS) proto-oncogenes cause up to 30% of human cancers, with KRAS being the most common subtype mutation, prevalent in PDAC (92%), CRC (49%), and NSCLC (29%). Mutation hotspots for KRAS include G12 (80%), G13 (15%), and Q61 (less than 5%), with mutations occurring at codon 12 including G12D, G12V, G12C, G12A, G12S, and G12R.

[0004] Discovering drugs targeting KRAS has been challenging due to the lack of a clearly defined druggable pocket on the KRAS protein and its high affinity for its natural substrates GDP and GTP. In 2013, the Shokat lab, through covalent binding to cysteine ​​residues of KRAS G12C, first discovered compounds that irreversibly bind to the pocket below the Switch II region (SWIIP), propelling the development of KRAS inhibitors and ultimately demonstrating that KRAS is not "undrugable." Targeting oncogenic KRAS by inactivating it through Switch II binding using the popular covalent inhibitor concept has become a promising therapeutic strategy. Currently, KRAS G12C inhibitors such as sotorasib (AMG510, 2021) and adagrasib (MRTX849, 2022) have received FDA approval.

[0005] However, KRAS G12C inhibitors often lead to clinically acquired resistance after about 6 months of treatment, resulting in disease progression. Secondary RAS mutations have been observed in mutation hotspots (such as G12 / G13 / Q61) and switch II pockets (such as H95, R68, and Y96), leading to reactivation of RAS-MAPK signaling. Furthermore, over 85% of cancers driven by RAS mutations or wild-type amplification still lack new drugs, leaving a significant unmet clinical need. Further research and development of new and effective RAS inhibitors are necessary to treat RAS mutation-driven cancers. Summary of the Invention

[0006] This invention discloses a macrocyclic derivative panRAS inhibitor. This class of compounds exerts its effect by mediating the formation of a high-affinity ternary complex between ubiquitous intracellular chaperone proteins (such as cyclophilin A) and RAS(ON) proteins. The formation of this ternary complex can sterically block the binding of RAS to its downstream effector molecules (such as RAF), inhibiting the activation of MAPK and PI3K-ATK signaling pathways, thereby inhibiting the occurrence and development of cancer and playing a therapeutic role in cancer and other diseases. The compounds provided by this invention exhibit good RAS inhibitory activity and show promising application prospects in the prevention and / or treatment of cancers associated with RAS mutations.

[0007] This invention provides a compound of formula (V), its stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0008] Among them, X1, X2, X3, X4, and X5 are each independently selected from nitrogen atoms or CR4;

[0009] Y is selected from -O- and -NH-;

[0010] L1 is selected from substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, or substituted or unsubstituted alkenyl.

[0011] Ring A is selected from substituted or unsubstituted aryl groups and substituted or unsubstituted heteroaryl groups;

[0012] W is selected from oxygen or sulfur atoms;

[0013] Ring B is selected from substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl;

[0014] L2 is selected from substituted or unsubstituted alkyl groups and substituted or unsubstituted heteroalkyl groups;

[0015] R4, R5, and R6 are each independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, substituted or unsubstituted amino, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0016] The ring C is selected from substituted or unsubstituted cycloalkyl groups and substituted or unsubstituted heterocyclic alkyl groups;

[0017] L is selected from the following structures:

[0018] Among them, each R 7a R 7b R 8a R 8b R 9a R 9b R 9c R 9d R 9e Each is independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, substituted or unsubstituted amino, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or R 7a and R 7b R 9a and R 9b R 9c and R 9d They, together with the carbon atoms to which they are attached, form C=CH2, C=O, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl;

[0019] r is selected from 0, 1, 2, or 3;

[0020] s is selected from 1, 2, 3, or 4;

[0021] m can be selected from 1, 2, 3 or 4.

[0022] This invention provides a compound of formula (A), its stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0023] Among them, ring B is selected from the following structures:

[0024] In this configuration, position 1 is connected to an indole ring, and position 3 is connected to an alkylene ring.

[0025] X1 is selected from NR 2g oxygen atoms or sulfur atoms;

[0026] R 1a R 1b R 1c R 2a R 2b R 2c R 2d R 2e R 2f R 2g Each is independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 Deuterated alkenyl, C 2-6 alkynyl group, C 2-6 Deuterated alkynyl group, C 3-8 Cycloalkyl, 3-10 membered heterocyclic alkyl, C 6-10 Aryl or 5-10 heteroaryl groups;

[0027] Ring C is selected from the following structures:

[0028] Among them, bit 1 is connected to -C(O)-, and bit 3 is connected to -C(O)O-;

[0029] Each R3 group is independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 Deuterated alkenyl, C 2-6 alkynyl group, C 2-6 Deuterated alkynyl group, C 3-8 Cycloalkyl, 3-10 membered heterocyclic alkyl, C 6-10 Aryl or 5-10 heteroaryl groups;

[0030] n is selected from 1, 2, 3, 4, or 5;

[0031] X is selected from CR 4e Or nitrogen atoms;

[0032] R 4a R 4b R 4c R 4d R 4e R5 and R6 are each independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, and -OR.a -SR a -NR a R b -C(O)R a C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Heteroalkyl, C 1- 6-alkoxy, C 2-6 alkenyl, C 2-6 Deuterated alkenyl, C 2-6 alkynyl group, C 2-6 Deuterated alkynyl group, C 3-8 Cycloalkyl, 3-10 membered heterocyclic alkyl, C 6-10 aryl or 5-10-membered heteroaryl, wherein the alkyl, heteroalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group is further selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, oxo, -OR a -SR a -NR a R b -C(O)R a C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 Deuterated alkenyl, C 2-6 alkynyl group, C 2-6 Deuterated alkynyl group, C 3-8 Cycloalkyl, 3-10 membered heterocyclic alkyl, C 6-10 The aryl group or one or more substituents in a 5-10 membered heteroaryl group are substituted;

[0033] R a R b Each is independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Heteroalkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 Deuterated alkenyl, C 2-6 alkynyl group, C 2-6 Deuterated alkynyl group, C 3-8 Cycloalkyl, 3-10 membered heterocyclic alkyl, C 6-10aryl or 5-10-membered heteroaryl, wherein the alkyl, heteroalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group is further selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, oxo, -OR a -SR a -NR a R b -C(O)R a C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 Deuterated alkenyl, C 2-6 alkynyl group, C 2-6 Deuterated alkynyl group, C 3-8 Cycloalkyl, 3-10 membered heterocyclic alkyl, C 6-10 The aryl group or one or more substituents in a 5-10 membered heteroaryl group are substituted;

[0034] Structural fragments Selected from the following structures:

[0035] Among them, each R 7a R 7b R 8a R 8b R 9a R 9b R 9c R 9d R 9e Each is independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 Deuterated alkenyl, C 2-6 alkynyl group, C 2-6 Deuterated alkynyl group, C 3-8 Cycloalkyl, 3-10 membered heterocyclic alkyl, C 6-10 Aryl or 5-10 heteroaryl groups;

[0036] Or R 7a and R 7b R 9a and R 9b R 9c and R 9d They respectively form C=CH2, C=O, and C with the carbon atoms they are attached to. 3-8 Cycloalkyl or 3-10 membered heterocyclic alkyl;

[0037] r is selected from 0, 1, 2, or 3;

[0038] s is selected from 1, 2, 3, or 4;

[0039] m is selected from 1, 2, 3, or 4;

[0040] R 11a R 11b R 11c R 11d R 11e R 11f R 12a R 12b Each is independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl or C 1-6 Alkyl group.

[0041] This invention provides a compound of formula (II), its stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0042] Among them, ring B is selected from the following structures:

[0043] In this configuration, position 1 is connected to an indole ring, and position 3 is connected to an alkylene ring.

[0044] R 1a R 1b R 1c R 2a R 2b R 2c R 2d R 2e R 2f Each is independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 Deuterated alkenyl, C 2-6 alkynyl group, C 2-6 Deuterated alkynyl or C 3-8 cycloalkyl;

[0045] Ring C is selected from the following structures:

[0046] Among them, bit 1 is connected to -C(O)-, and bit 3 is connected to -C(O)O-;

[0047] Each R3 is independently selected from hydrogen, deuterium, halogen, and C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl or C 1- 6-alkoxy;

[0048] n is selected from 0, 1, 2, 3, 4 or 5;

[0049] X is selected from CR 4e Or nitrogen atoms;

[0050] R 4a R 4b R 4c R 4d R 4e Each is independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, -OR a -SR a -NR a R b -C(O)R a , -CH(CH3)(OCH3), -CH(CH3)(OCD3), C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1- 6-Hydroalkyl, C 1-6 Heteroalkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 Deuterated alkenyl, C 2-6 alkynyl group, C 2-6 Deuterated alkynyl group, C 3-8 Cycloalkyl, 3-10 membered heterocyclic alkyl, C 6-10 aryl or 5-10-membered heteroaryl, wherein the alkyl, heteroalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group is further selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, oxo, -OR a -SR a -NR a R b -C(O)R a C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Heteroalkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 Deuterated alkenyl, C 2-6 alkynyl group, C 2-6 Deuterated alkynyl group, C 3-8 Cycloalkyl, 3-10 membered heterocyclic alkyl, C 6-10The aryl group or one or more substituents in the 5-10 membered heteroaryl group are substituted;

[0051] R a R b Each is independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Heteroalkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 Deuterated alkenyl, C 2-6 alkynyl group, C 2-6 Deuterated alkynyl group, C 3-8 Cycloalkyl, 3-10 membered heterocyclic alkyl, C 6-10 aryl or 5-10-membered heteroaryl, wherein the alkyl, heteroalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group is further selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, oxo, -OR a -SR a -NR a R b -C(O)R a C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 Deuterated alkenyl, C 2-6 alkynyl group, C 2-6 Deuterated alkynyl group, C 3-8 Cycloalkyl, 3-10 membered heterocyclic alkyl, C 6-10 The aryl group or one or more substituents in a 5-10 membered heteroaryl group are substituted;

[0052] R5, R 6a R 6b R 6c R 6d R 6e Each is independently selected from hydrogen, deuterium, halogens, and carbon. 1-6 Alkyl, C 1-6 Deuterated alkyl or C 1-6 Halogenated alkyl; or R 6a and R 6b R 6d and R 6e Together with the carbon atom it is attached to, they form C 3-8 Cycloalkyl or 3-10 membered heterocycloalkyl; or one of the R 6a and R 6c Together with the atoms attached to it, they form C3-8 Cycloalkyl or 3-10 membered heterocyclic alkyl;

[0053] p is selected from 1, 2, or 3;

[0054] R 9a R 9b R 9c R 9d R 9e Each is independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 Deuterated alkenyl, C 2-6 alkynyl group, C 2-6 Deuterated alkynyl or C 3-8 cycloalkyl; or R 9a and R 9b R 9c and R 9d Together with the carbon atom it is attached to, it forms C=CH2, C=O, or C 3-8 cycloalkyl;

[0055] R 11a R 11b R 11c R 11d R 11e R 11f R 12a R 12b Each is independently selected from hydrogen, deuterium, halogen, hydroxyl, and C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl or C 1-6 Alkyl group.

[0056] This invention provides a compound of formula (II-1), its stereoisomer, tautomer, or a pharmaceutically acceptable salt thereof.

[0057] Among them, Y1 is selected from nitrogen atoms or CH;

[0058] X1 is selected from nitrogen atoms or CR. 4a ;

[0059] M is selected from chemical bond, oxygen atom, sulfur atom, or NR. 8c ;

[0060] Ring C is selected from the following structures:

[0061] Bit 1 is connected to -C(O)-, and bit 3 is connected to -C(O)O-.

[0062] R 1a R 1b R 1c R 2a R 4a R 4b R 4c Each is independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 2-6 alkenyl or C 2-6 Deuterated alkenyl;

[0063] R5, R 10 Each is independently selected from hydrogen, deuterium, and C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 Deuterated alkenyl, C 2-6 alkynyl group, C 2-6 Deuterated alkynyl or C 3-6 cycloalkyl;

[0064] R 7a R 7b Each is independently selected from hydrogen, deuterium, and C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 Deuterated alkenyl, C 2-6 alkynyl group, C 2-6 Deuterated alkynyl or C 3-6 cycloalkyl;

[0065] R 8a R 8b R 8c Each is independently selected from hydrogen, deuterium, halogens, and carbon. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl or C 1-6 alkoxy; or R 8a and R 8b Together with the atoms they are attached to, they form C. 3-8 cycloalkyl;

[0066] R 9a R9b R 9c R 9d R 9e Each is independently selected from hydrogen, deuterium, halogens, and carbon. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1- 6-Hydroalkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 Deuterated alkenyl or C 3-8 cycloalkyl; or R 9a and R 9b R 9a and R 9c Each of them, together with the atoms they are connected to, forms C. 3-8 cycloalkyl or 3-8 membered heterocyclic alkyl;

[0067] R 10a R 10c R 10e R 10g Each is independently selected from hydrogen, deuterium, halogens, and carbon. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl or C 1-6 alkoxy; or R 10e and R 10g Together with the atoms attached to them, they form 8-12 membered heterocyclic alkyl groups;

[0068] R 11a R 11b R 11c R 11d R 11e R 11f R 12a R 12b Each is independently selected from hydrogen, deuterium, halogens, and carbon. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 Deuterated alkenyl, C 2-6 alkynyl group, C 2-6 Deuterated alkynyl group, C 3-6 cycloalkyl, C 6-10 aryl, 3-10 membered heterocyclic alkyl or 5-10 membered heteroaryl; or R 11a and R 11b R 11c and R 11d R 11e and R 11f R 12a and R12b Each of them, together with the carbon atoms they are attached to, forms C. 3-6 cycloalkyl;

[0069] q can be selected from 1, 2, 3 or 4.

[0070] This invention provides a compound of formula (III), its stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0071] Among them, ring B is selected from the following structures:

[0072] In this configuration, position 1 is connected to an indole ring, and position 3 is connected to an alkylene ring.

[0073] R 1a R 1b R 1c R 2a R 2b R 2c R 2d R 2e R 2f Each is independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 Deuterated alkenyl, C 2-6 alkynyl group, C 2-6 Deuterated alkynyl or C 3-8 cycloalkyl;

[0074] Ring C is selected from the following structures:

[0075] Among them, bit 1 is connected to -C(O)-, and bit 3 is connected to -C(O)O-;

[0076] Each R3 is independently selected from hydrogen, deuterium, halogen, and C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl or C 1- 6-alkoxy;

[0077] n is selected from 0, 1, 2, 3, 4 or 5;

[0078] X is selected from CR 4e Or nitrogen atoms;

[0079] R 4a R 4b R 4d R4e Each is independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, -OR a -SR a -NR a R b -C(O)R a , -CH(CH3)(OCH3), -CH(CH3)(OCD3), C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Heteroalkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 Deuterated alkenyl, C 2-6 alkynyl group, C 2-6 Deuterated alkynyl group, C 3- 8-cyclic alkyl, 3-10-membered heterocyclic alkyl, C 6-10 aryl or 5-10-membered heteroaryl, wherein the alkyl, heteroalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group is further selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, oxo, -OR a -SR a -NR a R b -C(O)R a C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 Deuterated alkenyl, C 2-6 alkynyl group, C 2-6 Deuterated alkynyl group, C 3-8 The alkyl group or one or more substituents in a cycloalkyl or 3-10 membered heterocycloalkyl group are substituted;

[0080] R a R b Each is independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 Deuterated alkenyl, C 2-6 alkynyl group, C 2-6 Deuterated alkynyl group, C 3-8 Cycloalkyl or 3-10 membered heterocyclic alkyl;

[0081] R5, R 6a R6b R 6c R 6d R 6e Each is independently selected from hydrogen, deuterium, halogens, and carbon. 1-6 Alkyl, C 1-6 Deuterated alkyl or C 1-6 Halogenated alkyl; or R 6a and R 6b R 6d and R 6e Together with the carbon atom it is attached to, they form C 3-8 cycloalkyl;

[0082] p is selected from 1, 2, or 3;

[0083] R 9a R 9b R 9c R 9d R 9e Each is independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 Deuterated alkenyl, C 2-6 alkynyl group, C 2-6 Deuterated alkynyl or C 3-8 cycloalkyl; or R 9a and R 9b Together with the carbon atom it is attached to, it forms C=CH2 or C 3-8 cycloalkyl;

[0084] R 10a R 10b R 10c R 10d R 10 Each is independently selected from hydrogen, deuterium, and C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Heteroalkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 Deuterated alkenyl, C 2-6 alkynyl group, C 2-6 Deuterated alkynyl group, C 3- 8-cyclic alkyl, 3-10-membered heterocyclic alkyl, C 6-10 aryl or 5-10 heteroaryl; or R 10 and R 10c R 10b and R 10cTogether with the atoms they are attached to, they form 3-10 membered heterocyclic alkyl groups;

[0085] R 11a R 11b R 11c R 11d R 11e R 11f R 12a R 12b Each is independently selected from hydrogen, deuterium, halogen, hydroxyl, and C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl or C 1-6 Alkyl group.

[0086] This invention provides a compound of formula (IIIA), its stereoisomer, tautomer, or a pharmaceutically acceptable salt thereof.

[0087] Among them, ring C is selected from the following structures:

[0088] Among them, bit 1 is connected to -C(O)-, and bit 3 is connected to -C(O)O-;

[0089] R 1a R 1b R 1c R 2a Each is independently selected from hydrogen, deuterium, halogens, and carbon. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl or C 2-6 Deuterated alkenyl;

[0090] X is selected from CH or nitrogen atoms;

[0091] R 4b R 4d Each is independently selected from hydrogen, deuterium, halogen, cyano, -OR a -SR a -NR a R b -C(O)R a C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 Deuterated alkenyl, C 2-6 alkynyl group, C 2-6 Deuterated alkynyl group, C 3- 8-membered cycloalkyl or 3-10-membered heterocyclic alkyl;

[0092] R5, R 6a R 6b R 6c R 6d R 6e Each is independently selected from hydrogen, deuterium, halogens, and carbon. 1-6 Alkyl, C 1-6 Deuterated alkyl or C 1-6 Halogenated alkyl, or R 6a and R 6b Together with the carbon atom it is attached to, they form C 3-8 cycloalkyl;

[0093] R 9a R 9b R 9c R 9d R 9e Each is independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, and C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 Deuterated alkenyl, C 2-6 alkynyl group, C 2-6 Deuterated alkynyl or C 3-8 cycloalkyl;

[0094] X2 is selected from CR 10i SiR 10i Or nitrogen atoms;

[0095] R 10a R 10b R 10c R 10d R 10i Each is independently selected from hydrogen, deuterium, and C. 1-6 Alkyl, C 1-6 Deuterated alkyl or C 1-6 Halogenated alkyl groups;

[0096] R 10 Selected from hydrogen, deuterium, and -NR a R b -OR a C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 Deuterated alkenyl, C 2-6 alkynyl group, C 2-6 Deuterated alkynyl group, C 3-8 Cycloalkyl or 3-10 membered heterocyclic alkyl;

[0097] R a R b Each is independently selected from hydrogen, deuterium, and C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 Deuterated alkenyl, C 2-6 alkynyl group, C 2-6 Deuterated alkynyl group, C 3-8 Cycloalkyl or 3-10 membered heterocyclic alkyl;

[0098] R 11a R 11b R 11c R 11d R 11e R 11f R 12a R 12b R 13a R 13b R 14 Each is independently selected from hydrogen, deuterium, halogens, and carbon. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 3-8 cycloalkyl;

[0099] p is selected from 1, 2, or 3.

[0100] This invention provides a compound of formula (III-1), its stereoisomer, tautomer, or a pharmaceutically acceptable salt thereof.

[0101] Among them, ring C is selected from the following structures:

[0102] Among them, bit 1 is connected to -C(O)-, and bit 3 is connected to -C(O)O-;

[0103] R 1a R 1b R 1c R 2a Each is independently selected from hydrogen, deuterium, halogens, and carbon. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl or C 2-6 Deuterated alkenyl;

[0104] X is selected from CH or nitrogen atoms;

[0105] R 4a R 4b R 4d Each is independently selected from hydrogen, deuterium, halogen, cyano, -OR a -SR a -NR a R b -C(O)R a , -CH(CH3)(OCH3), -CH(CH3)(OCD3), C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 Deuterated alkenyl, C 2-6 alkynyl group, C 2-6 Deuterated alkynyl group, C 3-8 Cycloalkyl or 3-10-membered heterocycloalkyl, wherein the alkyl, alkenyl, ynyl, cycloalkyl, or heterocycloalkyl group is further selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, oxo, -OR a -SR a -NR a R b -C(O)R a C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 2- 6-olefin, C 2-6 Deuterated alkenyl, C 2-6 alkynyl group, C 2-6 Deuterated alkynyl group, C 3-8 The alkyl group or one or more substituents in a cycloalkyl or 3-10 membered heterocycloalkyl group are substituted;

[0106] R a R b Each is independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 Deuterated alkenyl, C 2-6 alkynyl group, C 2-6 Deuterated alkynyl group, C 3-8 Cycloalkyl or 3-10 membered heterocyclic alkyl;

[0107] R 6a R 6b R 6c R 6d R6e Each is independently selected from hydrogen, deuterium, halogens, and carbon. 1-6 Alkyl, C 1-6 Deuterated alkyl or C 1- 6-Hydroalkyl; or R 6a and R 6b Together with the carbon atom it is attached to, they form C 3-8 cycloalkyl;

[0108] R 9a R 9b R 9c R 9d R 9e Each is independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, and C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 Deuterated alkenyl, C 2-6 alkynyl group, C 2-6 Deuterated alkynyl or C 3-8 cycloalkyl;

[0109] R 10a R 10b R 10c R 10d Each is independently selected from hydrogen, deuterium, and C. 1-6 Alkyl, C 1-6 Deuterated alkyl or C 1-6 Halogenated alkyl groups;

[0110] R 10 Selected from hydrogen, deuterium, and C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Heteroalkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 Deuterated alkenyl, C 2-6 alkynyl group, C 2-6 Deuterated alkynyl group, C 3-8 Cycloalkyl or 3-10 membered heterocyclic alkyl;

[0111] p is selected from 1, 2, or 3.

[0112] This invention provides a compound of formula (III-2), its stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0113] Among them, ring C is selected from the following structures:

[0114] Among them, bit 1 is connected to -C(O)-, and bit 3 is connected to -C(O)O-;

[0115] R 1a R 1b R 1c R 2a Each is independently selected from hydrogen, deuterium, halogens, and carbon. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl or C 2-6 Deuterated alkenyl;

[0116] X is selected from CH or nitrogen atoms;

[0117] R 13 Selected from C 1-6 Alkyl or C 1-6 Deuterated alkyl groups;

[0118] R 4b R 4d Each is independently selected from hydrogen, deuterium, halogen, cyano, -OR a -SR a -NR a R b -C(O)R a C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 Deuterated alkenyl, C 2-6 alkynyl group, C 2-6 Deuterated alkynyl group, C 3- 8-membered cycloalkyl or 3-10-membered heterocyclic alkyl, wherein the alkyl, alkenyl, ynyl, cycloalkyl, or heterocyclic alkyl is further selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, oxo, -OR a -SR a -NR a R b -C(O)R a C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 Deuterated alkenyl, C 2-6 alkynyl group, C 2-6 Deuterated alkynyl group, C 3-8 The alkyl group or one or more substituents in a cycloalkyl or 3-10 membered heterocycloalkyl group are substituted;

[0119] Ra R b Each is independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 Deuterated alkenyl, C 2-6 alkynyl group, C 2-6 Deuterated alkynyl group, C 3-8 Cycloalkyl or 3-10 membered heterocyclic alkyl;

[0120] R 6a R 6b R 6c R 6d R 6e Each is independently selected from hydrogen, deuterium, halogens, and carbon. 1-6 Alkyl, C 1-6 Deuterated alkyl or C 1- 6-Hydroalkyl; or R 6a and R 6b Together with the carbon atom it is attached to, they form C 3-8 cycloalkyl;

[0121] R 9a R 9b R 9c R 9d R 9e Each is independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, and C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 Deuterated alkenyl, C 2-6 alkynyl group, C 2-6 Deuterated alkynyl or C 3-8 cycloalkyl;

[0122] R 10a R 10b R 10c R 10d Each is independently selected from hydrogen, deuterium, and C. 1-6 Alkyl, C 1-6 Deuterated alkyl or C 1-6 Halogenated alkyl groups;

[0123] R 10 Selected from hydrogen, deuterium, and C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6Alkoxy, C 2-6 alkenyl, C 2- 6-deuterated alkenyl, C 2-6 alkynyl group, C 2-6 Deuterated alkynyl group, C 3-8 Cycloalkyl or 3-10 membered heterocyclic alkyl;

[0124] p is selected from 1, 2, or 3.

[0125] This invention provides a compound of formula (IIIA-1), its stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0126] Among them, ring C is selected from the following structures:

[0127] Among them, bit 1 is connected to -C(O)-, and bit 3 is connected to -C(O)O-;

[0128] R 4b R 4d Each is independently selected from hydrogen, deuterium, halogens, and carbon. 1-6 Alkyl or C 1-6 Deuterated alkyl groups;

[0129] R 6a R 6b R 6c R 6d R 6e Each is independently selected from hydrogen, deuterium, halogens, and carbon. 1-6 Alkyl, C 1-6 Deuterated alkyl or C 1- 6-Hydroalkyl;

[0130] R 9a R 9c Each is independently selected from C 1-6 Alkyl, C 1-6 Deuterated alkyl or C 1-6 Halogenated alkyl groups;

[0131] R 10a R 10b R 10c R 10d Each is independently selected from hydrogen, deuterium, and C. 1-6 Alkyl, C 1-6 Deuterated alkyl or C 1-6 Halogenated alkyl groups;

[0132] R 10 Selected from hydrogen, -NR a R b -OR a C 1-6 Alkyl, C 1-6Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Heteroalkyl, C 1- 6-alkoxy or C 3-8 cycloalkyl;

[0133] R a R b Each is independently selected from hydrogen and C. 1-6 Alkyl, C 1-6 Deuterated alkyl or C 1-6 Halogenated alkyl groups;

[0134] R 11a R 11b R 11e R 11f Each is independently selected from either hydrogen or deuterium;

[0135] R 13a Selected from C 1-6 Alkyl, C 1-6 Deuterated alkyl or C 1-6 Halogenated alkyl groups;

[0136] p is selected from 1, 2, or 3.

[0137] This invention provides the following compounds, their stereoisomers, tautomers, or pharmaceutically acceptable salts thereof.

[0138] This invention provides the following compounds, their stereoisomers, tautomers, or pharmaceutically acceptable salts thereof.

[0139] This invention provides a compound of formula (IB), its stereoisomer, tautomer, or a pharmaceutically acceptable salt thereof.

[0140] Wherein, X1 is selected from nitrogen atoms or CR 4a ;

[0141] Y is selected from nitrogen atom or CR. 10i ;

[0142] Each W is independently selected from oxygen atom, sulfur atom, -S(O)-, -S(O)2-, or -P(O)(C 1-6 alkyl)-;

[0143] Ring B is selected from substituted or unsubstituted cycloalkyl, heterocycloalkyl, aryl or heteroaryl, preferably from the following structures:

[0144] The 1-position is connected to the indole ring, and the 3-position is connected to the alkylene group;

[0145] The ring C is selected from substituted or unsubstituted heterocyclic alkyl groups, preferably from the following structures:

[0146] Bit 1 is connected to -C(O)-, and bit 3 is connected to -C(O)O-.

[0147] Each R 1a R 1b R 1c R 2a R 2b R 2c R 2d R 2e R 2f R 2g R3, R 4a R 4b R 4c Each is independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 Deuterated alkenyl, C 2-6 alkynyl group, C 2-6 Deuterated alkynyl group, C 3-6 cycloalkyl, C 6-10 Aryl, 3-8 membered heterocyclic alkyl or 5-10 membered heteroaryl;

[0148] R5, R6, R 7a R 7b Each is independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C 1-6 Alkyl, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 Deuterated alkenyl, C 2-6 alkynyl group, C 2-6 Deuterated alkynyl group, C 3-6 cycloalkyl, C 3-6 cycloalkyl C 1-6 Alkyl, C 6-10 Aryl, 3-8 membered heterocyclic alkyl or 5-10 membered heteroaryl;

[0149] R9a R 9b R 9c R 9d R 9e Each is independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 Deuterated alkenyl, C 2-6 alkynyl group, C 2-6 Deuterated alkynyl group, C 3-8 cycloalkyl, C 6-10 aryl, 3-8 membered heterocyclic alkyl or 5-10 membered heteroaryl; or R 9a and R 9b R 9a and R 9c Each of them, together with the carbon atoms they are attached to, forms C. 3-8 cycloalkyl or 3-8 membered heterocyclic alkyl;

[0150] R 10a R 10b R 10c R 10d R 10e R 10f R 10g R 10h R 10i Each is independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 Deuterated alkenyl, C 2-6 alkynyl group, C 2-6 Deuterated alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 aryl or 5-10 heteroaryl; or R 10e and R 10g Together with the atoms attached to them, they form 8-12 membered heterocyclic alkyl groups;

[0151] R 11a R 11b R 11c R 11d R 11e R 11f R 12a R12b R 12c R 13 Each is independently selected from hydrogen, deuterium, halogens, and carbon. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 Deuterated alkenyl, C 2-6 alkynyl group, C 2-6 Deuterated alkynyl group, C 3-6 cycloalkyl, C 6-10 aryl, 3-8 membered heterocyclic alkyl or 5-10 membered heteroaryl; or R 11a and R 11b R 11c and R 11d R 11e and R 11f R 12a and R 12b Each of them, together with the carbon atoms they are attached to, forms C. 3-6 cycloalkyl or 3-8 membered heterocyclic alkyl;

[0152] n is an integer selected from 1 to 20;

[0153] q is selected from 0, 1, 2, 3, 4 or 5.

[0154] This invention provides a compound of formula (IIB), its stereoisomer, tautomer, or a pharmaceutically acceptable salt thereof.

[0155] Where M is selected from chemical bonds, C 1-6 Alkylene or C 1-6 Heteroalkyl;

[0156] Each W is independently selected from oxygen atoms, sulfur atoms, -S(O)- or -S(O)2-;

[0157] X1 is selected from nitrogen atoms or CR. 4a ;

[0158] Ring C is selected from the following structures:

[0159] Bit 1 is connected to -C(O)-, and bit 3 is connected to -C(O)O-.

[0160] R 1a R 1b R 1c R 2a R 4a R 4b R4c R5 is independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Heteroalkyl, C 2-6 alkenyl or C 2-6 Deuterated alkenyl;

[0161] Each R 6a R 6b R 6c R 6d R 6e Each is independently selected from hydrogen, deuterium, halogens, and carbon. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Heteroalkyl; or R 6a and R 6b R 6d and R 6e Each of them, together with the atoms they are connected to, forms C. 3-8 cycloalkyl;

[0162] R 7a R 7b Each is independently selected from hydrogen, deuterium, and C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 Deuterated alkenyl, C 2-6 alkynyl group, C 2-6 Deuterated alkynyl or C 3-6 cycloalkyl;

[0163] R 9a R 9b R 9c R 9d R 9e Each is independently selected from hydrogen, deuterium, halogens, and carbon. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1- 6-Hydroalkyl, C 1-6 Alkoxy, C 1-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 Deuterated alkenyl or C 3-8 cycloalkyl; or R 9a and R 9bR 9a and R 9c Each of them, together with the atoms they are connected to, forms C. 3-8 cycloalkyl or 3-8 membered heterocyclic alkyl;

[0164] R 10a R 10c R 10e R 10g Each is independently selected from hydrogen, deuterium, halogens, and carbon. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Heteroalkyl; or R 10e and R 10g Together with the atoms attached to them, they form 8-12 membered heterocyclic alkyl groups;

[0165] R 11a R 11b R 11c R 11d R 11e R 11f R 12a R 12b R 13 Each is independently selected from hydrogen, deuterium, halogens, and carbon. 1- 6-alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Heteroalkyl; or R 11a and R 11b R 11c and R 11d R 11e and R 11f R 12a and R 12b Each of them, together with the carbon atoms they are attached to, forms C. 3-6 cycloalkyl;

[0166] p is selected from 1, 2, 3, or 4;

[0167] n is an integer selected from 0 to 20.

[0168] This invention provides a compound of formula (IIIB), its stereoisomer, tautomer, or a pharmaceutically acceptable salt thereof.

[0169] Wherein, M is selected from -(CH2)2- or -(CH2)2-O-(CH2)2-;

[0170] Each W is independently selected from an oxygen atom or -S(O)2-;

[0171] Ring C is selected from the following structures:

[0172] Bit 1 is connected to -C(O)-, and bit 3 is connected to -C(O)O-.

[0173] R 7a R 7b Each is independently selected from C 1-6 Alkyl, C 1-6 Deuterated alkyl or C 1-6 Halogenated alkyl groups;

[0174] Each R 6a R 6b R 6c R 6d R 6e Each is independently selected from hydrogen, deuterium, halogens, and carbon. 1-6 Alkyl, C 1-6 Deuterated alkyl or C 1-6 Halogenated alkyl groups;

[0175] R 9a R 9c Each is independently selected from hydrogen, deuterium, halogens, and carbon. 1-6 Alkyl, C 1-6 Deuterated alkyl or C 1-6 Halogenated alkyl groups;

[0176] R 4b R 4c R 10a R 10c R 10e R 10g Each is independently selected from hydrogen, deuterium, halogens, and carbon. 1-6 Alkyl or C 1-6 Deuterated alkyl groups;

[0177] R 11a R 11b R 11e R 11f Each is independently selected from hydrogen, deuterium, halogens, and carbon. 1-6 Alkyl or C 1-6 Deuterated alkyl groups;

[0178] R 13 Selected from hydrogen, C 1-6 Alkyl or C 1-6 Deuterated alkyl groups;

[0179] p is selected from 1, 2, or 3;

[0180] n is an integer selected from 0 to 10.

[0181] This invention provides a compound of formula (IVB), its stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0182] Among them, ring C is selected from the following structures:

[0183] Bit 1 is connected to -C(O)-, and bit 3 is connected to -C(O)O-.

[0184] R 7a R 7b Each is independently selected from C 1-6 Alkyl, C 1-6 Deuterated alkyl or C 1-6 Halogenated alkyl groups;

[0185] Each R 6a R 6b R 6c R 6d R 6e Each is independently selected from hydrogen, deuterium, halogens, and carbon. 1-6 Alkyl, C 1-6 Deuterated alkyl or C 1-6 Halogenated alkyl groups;

[0186] R 9a R 9c Each is independently selected from hydrogen, deuterium, halogens, and carbon. 1-6 Alkyl, C 1-6 Deuterated alkyl or C 1-6 Halogenated alkyl groups;

[0187] R 4b R 4c R 10a R 10c R 10e R 10g Each is independently selected from hydrogen, deuterium, halogens, and carbon. 1-6 Alkyl or C 1-6 Deuterated alkyl groups;

[0188] R 11a R 11b R 11e R 11f Each is independently selected from hydrogen, deuterium, halogens, and carbon. 1-6 Alkyl or C 1-6 Deuterated alkyl groups;

[0189] R 13 Selected from hydrogen, C 1-6 Alkyl or C 1-6 Deuterated alkyl groups;

[0190] p is selected from 1, 2, or 3;

[0191] n is an integer selected from 1 to 10.

[0192] This invention provides the following compounds, their stereoisomers, tautomers, or pharmaceutically acceptable salts thereof.

[0193] The present invention provides a pharmaceutical composition comprising a therapeutically effective dose of any of the compounds described in the present invention, its stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier.

[0194] The use of any of the compounds described in this invention, their stereoisomers, tautomers or pharmaceutically acceptable salts thereof, or pharmaceutical compositions according to this invention as a medicine (i.e. for therapeutic purposes).

[0195] The use of any of the compounds described in this invention, their stereoisomers, tautomers or pharmaceutically acceptable salts thereof, or the pharmaceutical compositions described in this invention in the preparation of medicaments for the prevention and / or treatment of cancer.

[0196] The use of any of the compounds described in this invention, their stereoisomers, tautomers or pharmaceutically acceptable salts thereof, or the pharmaceutical compositions described in this invention in the preparation of medicaments for the prevention and / or treatment of RAS mutation-mediated cancers.

[0197] The use of any of the compounds described in this invention, their stereoisomers, tautomers or pharmaceutically acceptable salts thereof, or pharmaceutical compositions according to this invention in the preparation of medicaments for the prevention and / or treatment of KRAS mutation-mediated cancers.

[0198] In the present invention, the cancer is selected from pancreatic cancer, colorectal cancer, lung cancer, kidney cancer, liver cancer, breast cancer, esophageal cancer, acute myeloid leukemia, multiple myeloma, thyroid adenocarcinoma, squamous cell carcinoma, gastric cancer, renal cell carcinoma, sarcoma, bile duct cancer, prostate cancer, ovarian cancer, hematologic cancer, MYH-related polyposis, uterine cancer, mesothelioma, cervical cancer, bladder cancer, etc.

[0199] The present invention provides a method for inhibiting RAS protein in cells, the method comprising contacting the cells with an effective amount of any of the compounds of the present invention, their stereoisomers, tautomers or pharmaceutically acceptable salts thereof, or pharmaceutical compositions of the present invention.

[0200] The present invention provides a method for preventing and / or treating cancer, comprising administering to a patient an effective amount of any of the compounds described in the present invention, their stereoisomers, tautomers or pharmaceutically acceptable salts thereof, or pharmaceutical compositions described in the present invention.

[0201] The present invention provides a method for preventing and / or treating RAS mutant-mediated cancers, comprising administering to a patient an effective amount of a compound as described in any one of the present invention, its stereoisomers, tautomers or its pharmaceutically acceptable salts, or a pharmaceutical composition as described in the present invention.

[0202] The present invention provides a method for preventing and / or treating KRAS mutant-mediated cancers, comprising administering to a patient an effective amount of a compound as described in any one of the present invention, its stereoisomers, tautomers or its pharmaceutically acceptable salts, or a pharmaceutical composition as described in the present invention.

[0203] The method for preventing and / or treating cancers in the present invention, wherein the cancers are selected from pancreatic cancer, colorectal cancer, lung cancer, kidney cancer, liver cancer, breast cancer, esophageal cancer, acute myeloid leukemia, multiple myeloma, thyroid adenocarcinoma, squamous cell carcinoma, gastric cancer, renal cell carcinoma, sarcoma, cholangiocarcinoma, prostate cancer, ovarian cancer, hematological cancers, MYH-related polyposis cancer, uterine cancer, mesothelioma, cervical cancer, bladder cancer, etc.

[0204] Detailed Description of the Invention

[0205] All technical and scientific terms used in this specification have the meanings commonly understood by those of ordinary skill in the art.

[0206] The term "hydrogen" refers to H herein.

[0207] The term "deuterium" refers to D herein.

[0208] The term "nitrogen atom" refers to N herein.

[0209] The term "oxygen atom" refers to O herein.

[0210] The term "sulfur atom" refers to S herein.

[0211] The term "cyano" refers to -CN herein.

[0212] The term "hydroxyl" refers to -OH herein.

[0213] The term "halogen" refers to -F, -Cl, -Br and -I in the text.

[0214] The term "amino" or "amine" can interchangeably refer to -NR2 group herein, where each R is, for example, H or a substituent. In some embodiments, the amino group is further substituted to form an ammonium ion, such as -NR 3+The ammonium moiety is specifically included in the definition of "amino" or "amine". Substituents may be, for example, alkyl, deuteralkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, amide, or carboxylic acid ester. The R group may be further substituted by one or more (e.g., 1 to 4) groups selected from: halogen, cyano, alkenyl, alkynyl, alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, urea, carbonyl, carboxylic acid ester, amine, and amide.

[0215] The term "alkyl" herein refers to a saturated aliphatic hydrocarbon group having a plurality of carbon atoms, preferably 1-10 carbon atoms, more preferably 1-6 carbon atoms. This term includes both straight-chain and branched hydrocarbon groups. When an alkyl group is preceded by a carbon number limitation, such as C... 1-6 Alkyl means having 1 to 6 carbon atoms. Non-limiting examples of alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, neopentyl, n-hexyl, etc. Alkyl groups described herein may optionally be substituted with one or more of the following substituents: deuterium, fluorine, chlorine, bromine, iodine, cyano, nitro, hydroxyl, carboxyl, amino, alkyl, alkoxy, acyl, acyloxy, oxo, amide, ester, amino, sulfonyl, sulfinyl, cycloalkyl, heterocyclic, cycloalkenyl, heterocyclic alkyl, alkenyl, alkenyloxy, alkynyl, cycloalkoxy, heterocyclic alkyloxy, aryloxy, heteroaryloxy, aryl, or heteroaryl.

[0216] The term "deuterated alkyl" as used herein refers to an alkyl group obtained by substituting a "alkyl" group by deuterium. Non-limiting examples of deuterated alkyl groups include deuterated methyl, deuterated ethyl, etc.

[0217] The term "haloalkyl" as used herein refers to an alkyl group obtained by substituting an alkyl group by a halogen, wherein the halogen includes fluorine, chlorine, bromine, iodine, etc. Non-limiting examples of haloalkyl groups include monofluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, etc.

[0218] The term "heteroalkyl" in this document refers to an alkyl group obtained by replacing at least one carbon atom with a heteroatom (e.g., O, N, S, SO, SO2) as defined above. The heteroatom may appear in the middle or at the end of the group.

[0219] The term "alkylene" herein refers to a saturated aliphatic hydrocarbon group comprising, or without, a branched or straight-chain group having a specified number of carbon atoms, and which is a residue derived by removing two hydrogen atoms from the same or two different carbon atoms of a parent alkane. For example, "C 1-6"alkylene" refers to an alkylene group having 1, 2, 3, 4, 5, or 6 carbon atoms. Examples of alkylene groups include, but are not limited to, methylene (-CH2-), ethylene (-CH2CH2-), propylene (e.g., -(CH2)3-, -(CHCH3)CH2-, -(CHCH2CH)-), butylene (e.g., -(CH2)4-, -CH2CH(CH2CH3)-, -CH2(CHCH2CH)-, etc.), and pentylene (e.g., - (CH2)5-, -CH2CH(CH(CH3)2)-, -CH2(CHCH2CH)CH2-, etc., and hexanediols (e.g., -(CH2)6-, -CH2CH2CH(CH(CH3)2)-, -CH2(CHCH(CH3)CH)CH2-, etc.). In this document, alkylene groups are preferably alkylene groups having 1-8, 1-6, 1-4, or 1-3 carbon atoms. In this document, alkylene groups are preferably alkylene groups that do not contain cyclic alkyl groups.

[0220] The term "heteroalkylene" as used herein refers to an alkylene group obtained by replacing at least one carbon atom with a heteroatom (e.g., O, N, S, SO, SO2) as defined above. The heteroatom may appear in the middle or at the end of the group.

[0221] The term "alkoxy" refers to the formula -OR a Group, wherein R a Alkyl groups as defined above. When the alkoxy group is preceded by a carbon number qualifier, such as C... 1-6 An alkoxy group is defined as an alkoxy group containing 1 to 6 carbon atoms. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, isopropoxy, n-propoxy, n-butoxy, tert-butoxy, and n-pentoxy.

[0222] An alkenyl group is an unsaturated hydrocarbon group containing a carbon-carbon double bond. The term "alkenyl" herein refers to an alkyl group containing a carbon-carbon double bond in a molecule, wherein the alkyl group, as defined above, has 2 to 10 carbon atoms, preferably 2 to 8 carbon atoms, and more preferably 2 to 6 carbon atoms. When the alkenyl group is preceded by a carbon atom number qualifier, such as C... 2-6 Alkenyl refers to an alkenyl group containing 2 to 6 carbon atoms. The alkenyl groups described herein may optionally be substituted with one or more of the following substituents: deuterium, fluorine, chlorine, bromine, iodine, cyano, nitro, hydroxyl, carboxyl, amino, oxo, alkyl, alkoxy, acyl, amide, ester, amino, sulfonyl, sulfinyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, cycloalkoxy, mercapto, alkyl mercapto, deuterated alkyl mercapto, sulfone, sulfoxide, silyl, phosphono, deuterated alkyl, heterocyclic, aryl, heteroaryl, alkynyl, alkenyl, arylalkyl. Non-limiting examples of alkenyl groups include vinyl, propenyl, allyl, isopropenyl, butenyl, isobutenyl, etc.

[0223] The term "deuterated alkenyl" in this document refers to the alkenyl group obtained by substituting "alkenyl" as defined above with deuterium. Non-limiting examples of deuterated alkenyl groups include deuterated vinyl, deuterated propenyl, deuterated allyl, deuterated isopropenyl, deuterated butenyl, etc.

[0224] The term "alkenyl" in this document refers to an alkyl group containing a carbon-carbon double bond in a molecule, which is a residue derived by removing two hydrogen atoms from the same carbon atom or two different carbon atoms of the parent alkyl group. For example, "C 2-6 "Alkenyl" refers to an alkenyl group having 2, 3, 4, 5, or 6 carbon atoms. Examples of alkenyl groups include, but are not limited to, vinylene (-CH=CH-), propylene (e.g., -CH2CH=CH-, -CH=CH2CH2-), butylene (e.g., -CH2CH2CH=CH-, -CH2CH=CHCH2-, -CH=CHCH2CH2-, etc.).

[0225] An alkynyl group is an unsaturated hydrocarbon group containing a carbon-carbon triple bond. The term "alkynyl" herein refers to an alkyl group containing a carbon-carbon triple bond in a molecule, wherein the alkyl group, as defined above, has 2 to 10 carbon atoms, preferably 2 to 8 carbon atoms, and more preferably 2 to 6 carbon atoms. When the alkynyl group is preceded by a carbon number qualifier, such as C... 2-6 The alkynyl group refers to a group containing 2 to 6 carbon atoms. The alkynyl group may optionally be substituted by one or more of the following substituents: deuterium, fluorine, chlorine, bromine, iodine, cyano, nitro, hydroxyl, carboxyl, amino, alkyl, oxo, alkoxy, acyl, amide, ester, amino, sulfonyl, sulfinyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, cycloalkoxy, mercapto, alkyl mercapto, deuterated alkyl mercapto, sulfone, sulfoxide, silyl, phosphono, deuterated alkyl, heterocyclic, aryl, heteroaryl, alkynyl, alkenyl, arylalkyl. Non-limiting examples of alkynyl groups include ethynyl, 1-propynyl, 2-propynyl, 1-, 2-, or 3-butynyl, etc.

[0226] The term "deuterated alkynyl" in this document refers to the alkynyl group obtained by substituting "alkynyl" as defined above with deuterium. Non-limiting examples of deuterated alkynyl groups include deuterated ethynyl, deuterated 1-propynyl, deuterated 2-propynyl, deuterated 1-, 2- or 3-butynyl, etc.

[0227] The term "cycloalkyl" refers to a stable, non-aromatic monocyclic or polycyclic hydrocarbon group consisting only of carbon and hydrogen atoms. It may include fused ring systems, spirocyclic systems, or bridged ring systems, having 3 to 15 carbon atoms, preferably 3 to 10 carbon atoms, more preferably 3 to 8 carbon atoms, or 3 to 6 carbon atoms. It may be saturated or unsaturated and may be linked to the rest of the molecule via a single bond through any suitable carbon atom. When the cycloalkyl group is preceded by a carbon number limitation, such as C... 3-6Cycloalkyl means that the cycloalkyl group contains 3 to 6 carbon atoms. Non-limiting examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 1H-indenyl, 2,3-dihydroindenyl, 1,2,3,4-tetrahydro-naphthyl, 5,6,7,8-tetrahydro-naphthyl, 8,9-hydro-7H-benzocyclohepten-6-yl, 6,7,8,9-tetrahydro-5H-benzocycloheptenyl, 5,6,7,8,9,10-hexahydro-benzocyclooctenyl, and fluorenyl. Bicyclo[2.2.1]heptyl, 7,7-dimethyl-bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl, bicyclo[2.2.2]octyl, bicyclo[3.1.1]heptyl, bicyclo[3.2.1]octyl, bicyclo[2.2.2]octenyl, bicyclo[3.2.1]octenyl, adamantyl, octahydro-4,7-methylene-1H-indenyl and octahydro-2,5-methylene-cyclopentadienyl, etc. The cycloalkyl groups described herein may optionally be substituted with one or more of the following substituents: deuterium, fluorine, chlorine, bromine, iodine, cyano, nitro, hydroxyl, oxo, carboxyl, amino, alkyl, alkoxy, acyl, amide, ester, amino, sulfonyl, sulfinyl, cycloalkyl, heterocyclic, cycloalkenyl, heterocyclic, alkenyl, alkynyl, cycloalkoxy, aryl, and heteroaryl.

[0228] The term "heterocyclic group" refers to a substituted or unsubstituted saturated or unsaturated aromatic or non-aromatic ring containing at least 1 to 5 heteroatoms selected from N, O, or S. The aromatic or non-aromatic ring can be a 3- to 10-membered monocyclic ring, a 4- to 20-membered spirocyclic ring, a fused ring, or a bridged ring. The selectively substituted N and S in the heterocyclic group ring can be oxidized to various oxidation states. Preferably, it is a 3- to 12-membered heterocyclic ring. Non-limiting embodiments include oxetyl propane, oxetyl butyl, oxetyl pentyl, oxetyl hexyl, oxetyl heptyl, oxetyl octyl, aziridine propane, aziridine butyl, aziridine pentyl, aziridine hexyl, aziridine propenyl, 1,3-dioxocyclopentyl, 1,4-dioxocyclopentyl, 1,3-dithiocyclopentyl, 1,3-dioxocyclohexyl, 1,3-dithiocyclohexyl, aziridine heptenyl, morpholinyl, piperazine, pyridinyl, furanyl, thiophene, pyrrole, pyranyl, N-alkylpyrrole, pyrimidinyl, pyrazine, pyridazine, imidazolyl, piperidinyl, thiomorpholinyl, dihydropyran, thiadiazolyl, oxazolyl, oxadiazolyl, pyrazolyl, 1,4-dioxetyl hexadienyl, etc. The heterocyclic groups described herein may optionally be substituted with one or more of the following substituents: deuterium, fluorine, chlorine, bromine, iodine, cyano, nitro, hydroxyl, carboxyl, amino, alkyl, alkoxy, acyl, amide, ester, amino, sulfonyl, sulfinyl, cycloalkyl, heterocyclic, cycloalkenyl, heterocyclic, alkenyl, alkynyl, cycloalkoxy, aryl, and heteroaryl.

[0229] The term "heterocyclic alkyl" refers to a cyclic structure in which at least one carbon atom in the cycloalkyl ring is replaced by a heteroatom selected from N, O, or S. The N atom may optionally be quaternized, and the N and S atoms may optionally be oxidized (i.e., NO, O, and SO2). It includes monocyclic, bicyclic, and tricyclic heterocyclic systems, wherein bicyclic and tricyclic heterocyclic systems include spirocyclic, fused, and bridged heterocyclic systems. Heterocyclic alkyl groups can be unsubstituted or substituted, and when substituted, they can be substituted at any usable junction. The substituents are preferably one or more selected from halogens, hydroxyl groups, amino groups, cyano groups, oxo groups, alkyl groups, alkoxy groups, haloalkyl groups, cycloalkyl groups, heterocyclic alkyl groups, aryl groups, and heteroaryl groups. In this invention, the heterocyclic alkyl group is preferably 3-12 membered, 3-10 membered, and more preferably 3-8 membered. Non-limiting examples of heterocyclic alkyl groups include, but are not limited to, azahexacyclic butyl, oxacyclobutyl, thiohexacyclic butyl, pyrrolidinyl, pyrazolyl, imidazoalkyl, tetrahydrothiopheneyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, dioxane, dithiaalkyl, isoxazolyl, isothiazolyl, 1,2-oxazinyl, 1,2-thiazinyl or hexahydropyridazinyl, homopiperazinyl, homopiperidinyl, tetrahydropyridinyl, etc.

[0230] The term "aryl" herein refers to a 6- to 10-membered all-carbon monocyclic or fused polycyclic (i.e., a ring sharing adjacent carbon atom pairs) group having a conjugated π-electron system, such as phenyl and naphthyl, more preferably phenyl. The aryl ring may be fused to a heteroaryl, heterocyclic, or cycloalkyl ring, wherein the ring connected to the parent nucleus is an aryl ring. The aryl groups described herein may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups: deuterium, fluorine, chlorine, bromine, iodine, cyano, nitro, hydroxyl, carboxyl, amino, alkyl, alkoxy, acyl, amide, ester, sulfonyl, sulfinyl, cycloalkyl, heterocyclic, cycloalkenyl, alkenyl, alkynyl, heterocyclic, cycloalkoxy, aryl, and heteroaryl.

[0231] The term "heteroaryl" herein refers to an aromatic group consisting of 5 to 10 atoms and containing at least one heteroatom selected from N, O, or S. The term may have a single ring (non-limiting examples include furan, thiophene, imidazole, triazole, pyrazole, pyridine, pyrazine, oxazole, thiazole, etc.) or multiple fused rings (non-limiting examples include benzothiophene, benzofuran, indole, isoindole, etc.), wherein the fused ring may or may not be an aromatic group containing a heteroatom, assuming the connecting point is through an atom of the aromatic heteroaryl group. The heteroaryl group described herein may optionally be substituted with one or more of the following substituents: deuterium, fluorine, chlorine, bromine, iodine, cyano, nitro, hydroxyl, amino, oxo, alkyl, alkoxy, acyl, acyloxy, amide, ester, amino, sulfonyl, sulfinyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, alkenyl, alkynyl, heterocyclic, cycloalkoxy, aryl, and heteroaryl.

[0232] This invention also includes isotopically labeled compounds of the invention, i.e., those with the same structure as disclosed above, but in which one or more atoms are replaced by atoms having the same number of protons but a different number of neutrons. Isotopic embodiments of the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine, chlorine, and iodine, respectively as follows: 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 35 S, 18 F, 36 Cl and 131 I. The compounds of the present invention, their stereoisomers, tautomers, or pharmaceutically acceptable salts, as well as compounds in the above-described forms containing the aforementioned isotopes and / or other atomic isotopes, are all within the scope of the present invention. Certain isotopically labeled compounds of the present invention, such as those labeled with… 3 H or 14 The compounds labeled C can be used in drug tissue distribution assays, therefore, these 3 H or 14 C isotopes are particularly preferred due to their ease of preparation and detection. Heavier isotopes, such as... 2 H, 18 Some of the compounds of this invention replaced by O have certain therapeutic advantages due to their better metabolic stability, such as increased in vivo half-life and lower dosage, etc. 2 H, 18 O is also preferred in some cases.

[0233] The term “optional” or “optionally” means that the event or situation described below may, but not necessarily, occur, and the description includes both the cases in which the event or situation occurs and the cases in which it does not occur.

[0234] The term "compound of the present invention" (unless otherwise specifically stated) in this text refers to compounds of formulas (V), (A), (II), (II-1), (III), (IIIA), (III-1), (III-2), (IIIA-1), (IB), (IIB), (IIIB), and (IVB), and all their pure and mixed stereoisomers, geometric isomers, tautomers, solvates, hydrates, prodrugs, and isotopically labeled compounds and any pharmaceutically acceptable salts. A solvate of a compound of the present invention refers to a compound or its salts, such as hydrates, ethanolates, methanolates, etc., combined with stoichiometric and non-stoichiometric solvents. Compounds may also exist in one or more crystalline states, i.e., as eutectic, polymorphic, or as an amorphous solid. All such forms are covered by the claims.

[0235] The term "pharmaceutically acceptable" means that a substance or composition must be chemically and / or toxicologically compatible with the other components constituting the formulation and / or the mammals to which it is treated.

[0236] The term "optionally substituted from..." means that the structure is either unsubstituted or substituted by one or more substituents as described in this invention. The term "substituted" herein means any group that is monosubstituted or polysubstituted by a specified substituent to the extent that such monosubstituted or polysubstituted substitution (including multiple substitutions in the same part) is chemically permissible, each substituent may be located at any available position on the group and may be connected by any available atom on the substituent. "Any available position" means any position on the group that is chemically obtainable by methods known in the art or taught herein and does not produce an excessively unstable molecule. When there are two or more substituents on any group, each substituent is defined independently of any other substituent and therefore may be the same or different.

[0237] Throughout this specification, substituents of the compounds of the present invention are disclosed in the form of groups or ranges. This specifically means that the invention includes each member or subcombination of each individual member of such groups and ranges. As the term "C" indicates... 1-6 "alkyl" specifically means methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl and C6 alkyl.

[0238] The term "stereoisomer" in this text refers to compounds with different chiralities having one or more stereocenters. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotational isomers), geometrical isomers (cis / trans) isomers, blocked isomers, and so on.

[0239] The term "tautomer" in this document refers to structural isomers with different energies that can cross a low energy barrier and thus interconvert. Examples include proton tautomers, which interconvert via proton migration, such as enol-keto tautomers and imine-enamine tautomers, or tautomers containing heteroaryl groups attached to ring atoms of the -NH- and =N- moieties, such as pyrazoles, imidazoles, benzimidazoles, triazoles, and tetraazoles. Valence tautomers include some interconversions due to bonding electron rearrangement.

[0240] The compounds of this invention can be used in the form of salts, such as "pharmaceutically acceptable salts" derived from inorganic or organic acids. These include, but are not limited to, the following: acetates, adipates, alginates, citrates, aspartates, benzoates, benzenesulfonates, hydrogen sulfates, butates, camphorates, camphorsulfonates, digluconate, cyclopentanepropionate, sodium dodecylbenzenesulfonate sulfate, ethanesulfonates, glucono-heptate, glycerophosphates, hemisulfates, heptanate, hexanoates, fumarates, hydrochlorides, hydrobromide, hydroiodates, 2-hydroxyethanesulfonate, lactates, maleates, methanesulfonates, hydrochlorides, 2-naphthalenesulfonate, oxalates, pectin esters, sulfates, 3-phenylpropionate, picrates, trimethylacetate, propionates, succinates, tartrates, thiocyanates, p-toluenesulfonates, and silicates, etc.

[0241] Representative examples of "cancer or tumor" as described in this invention may include, but are not limited to, skin cancer, bladder cancer, ovarian cancer, breast cancer, stomach cancer, pancreatic cancer, prostate cancer, lung cancer, bone cancer, brain cancer, neurocytoma, rectal cancer, colon cancer, familial adenomatous polyposis, hereditary nonpolyposis colorectal cancer, esophageal cancer, lip cancer, laryngeal cancer, hypopharyngeal cancer, tongue cancer, salivary gland cancer, gastric cancer, adenocarcinoma, medullary thyroid carcinoma, papillary thyroid carcinoma, kidney cancer, renal parenchymal carcinoma, ovarian cancer, cervical cancer, uterine endometrial cancer, choriocarcinoma, testicular cancer, urinary tract cancer, melanoma, brain tumors such as glioblastoma, astrocytoma, meningioma, medulloblastoma, and peripheral neuroblastoma. Germ cell tumors, Hodgkin's lymphoma, non-Hodgkin's lymphoma, Burkitt's lymphoma, acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), adult T-cell leukemia lymphoma, diffuse large B-cell lymphoma (DLBCL), hepatocellular carcinoma, gallbladder cancer, bronchial carcinoma, small cell lung cancer, non-small cell lung cancer, multiple myeloma, basal cell tumor, teratoma, retinoblastoma, choroidal melanoma, seminoma, rhabdomyosarcoma, craniopharyngioma, osteosarcoma, chondrosarcoma, myoma, liposarcoma, fibrosarcoma, Ewing's sarcoma, or plasmacytoma, etc. Detailed Implementation

[0242] The present invention is further illustrated below with examples, but is not limited thereto. Throughout this application, various embodiments of the compounds and methods of the present invention are mentioned. The present invention is not limited to these embodiments; the following embodiments are merely illustrative of methods for practicing the present invention and do not limit the scope of the invention in any way.

[0243] The compounds provided by this invention can be prepared using standard synthetic methods known in the art. This specification provides a general method for preparing the compounds of this invention. The starting materials and control compound (RMC-6236, CAS No.: 2765081-21-6) are generally commercially available, for example, via Alfa. It can be purchased from companies such as TCI, or prepared using methods known to those skilled in the art.

[0244] The compounds of formula (II) of this invention, their stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, can be prepared using the following procedure:

[0245] The compounds of formula (IB) described in this invention, their stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, can be prepared using the following process:

[0246] The following examples further explain and illustrate the compounds of the present invention and their corresponding preparation methods. It should be understood that although typical or preferred reaction conditions (such as reaction temperature, time, molar ratio of reactants, reaction solvent, etc.) are given in the specific examples, other reaction conditions may be used by those skilled in the art. Optimal reaction conditions may vary depending on the specific reaction substrate or solvent used, but these conditions can be determined by those skilled in the art through conventional optimization.

[0247] The structures of the compounds in the following examples were characterized by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). Using a Bruker Ascend 400MHz NMR spectrometer, the compounds were dissolved in a suitable deuterated reagent and analyzed at ambient temperature with TMS as an internal standard. 1 H-NMR analysis. NMR chemical shifts (δ) are expressed in ppm and are referred to as follows: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; brs, broad singlet.

[0248] The reaction starting materials, intermediates, and compounds of the examples can be separated and purified by techniques such as precipitation, filtration, crystallization, evaporation, distillation, and chromatography (such as silica gel column chromatography, preparative chromatography, etc.).

[0249] intermediate preparation

[0250] Intermediate 1

[0251] Step 1

[0252] Under nitrogen protection, (S)-3-bromo-2-(1-methoxyethyl)pyridine (20.0 g), pinacol diboronic acid ester (35.3 g), 4,4'-di-tert-butyl-2,2'-dipyridine (3.7 g), methoxy(cyclooctadiene)iridium dimer (1.8 g), and tetrahydrofuran (80 mL) were added to a 250 mL three-necked flask. After addition, the mixture was heated to 80 °C and stirred for 6 h. The reaction solution was concentrated, and the concentrate was diluted with methyl tert-butyl ether / petroleum ether (2 / 1) and the pH was adjusted to 10. The mixture was separated, and the aqueous phase was collected. The aqueous phase was extracted with ethyl acetate, and the pH of the organic phase was adjusted to 6 with hydrochloric acid (6N). A solid precipitated and was obtained by filtration as a yellow solid. 1 HNMR (400MHz, DMSO-d6): δ 8.84 (d, J = 1.2 Hz, 1H), 8.54 (s, 2H), 8.29 (d, J = 1.6 Hz, 1H), 4.82 (q, J = 6.4 Hz, 1H), 3.15 (s, 3H), 1.39 (d, J = 6.4 Hz, 3H). MS:[M+H] + =260.0.

[0253] Step 2

[0254] Under nitrogen protection, the product from the previous step (19 g), N-iodosuccinimide (41.1 g), and acetonitrile (200 mL) were added to a 500 mL three-necked flask. After addition, the mixture was heated to 80 °C and stirred for 18 h. The reaction solution was concentrated to a small volume, the concentrate was diluted with dichloromethane, washed with sodium thiosulfate aqueous solution, dried, and then concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography to give a white solid. 1 HNMR (400MHz, DMSO-d6): δ 8.81 (d, J = 3.6 Hz, 1H), 8.49 (d, J = 3.6 Hz, 1H), 4.77 (q, J = 6.4 Hz, 1H), 3.15 (s, 3H), 1.37 (d, J = 6.4 Hz, 3H). MS:[M+H] + =341.9.

[0255] Step 3

[0256] Under nitrogen protection, the product from the previous step (16.7 g), benzyl piperazine-1-carboxylate (10.8 g), palladium acetate (548 mg), 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (608 mg), cesium carbonate (39.8 g), and toluene (330 mL) were added to the reaction flask. After the addition was complete, the mixture was heated to 100 °C and stirred for 4 h. The reaction solution was concentrated, and the concentrate was purified by silica gel column chromatography to obtain a white solid. MS: [M+H] + =434.1.

[0257] Step 4

[0258] Under nitrogen protection, the product from the previous step (5.0 g), pinacol diborate (11.7 g), potassium pentovane (3.5 g), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (840 mg), dimethyl sulfoxide (1.8 g), and toluene (125 mL) were added to the reaction flask. After addition, the mixture was heated to 80 °C and stirred for 3 h. The reaction solution was concentrated, and the concentrate was purified by silica gel column chromatography to obtain a brown solid. 1 HNMR (400MHz, DMSO-d6): δ8.27(d,J=3.6Hz,1H),7.41-7.36(m,4H),7.35-7.31(m,2H),5.12(s,2H) ,4.58(q,J=6.4Hz,1H),3.56(s,4H),3.17(s,4H),3.08(s,3H),1.35(d,J=7.2Hz,3H),1.31(s,12H).

[0259] Intermediate 2

[0260] Step 1

[0261] 21.0 g of 3-hydroxy-2,2-dimethylpropionic acid and 120 mL of pyridine were added to a 250 mL single-necked flask. The mixture was stirred and cooled to 0 °C. Acetyl chloride (14.4 g) was slowly added dropwise to the reaction flask. After the addition was complete, the mixture was stirred at 0 °C for 1 h, and then slowly heated to room temperature and stirred for 2 h. The pH of the reaction mixture was adjusted to 4–5 with 2 M dilute hydrochloric acid. The mixture was extracted with ethyl acetate, and the organic phases were combined, dried, and concentrated to give 20.0 g of a pale yellow solid. 1 HNMR (400MHz, DMSO-d6): δ12.38(brs,1H),4.01(s,2H),2.01(s,3H),1.12(s,6H).

[0262] Step 2

[0263] Under nitrogen protection, the product from the previous step (56.0 g), acetonitrile (1.7 L), and N,N-dimethylformamide (3 mL) were added to a 3 L single-necked flask. After the addition was complete, the mixture was stirred and cooled to 0 °C. Oxaloyl chloride was then added dropwise to the reaction solution. After the addition was complete, the reaction flask was moved to room temperature and stirred for 2 h. The reaction solution was concentrated to obtain 69.0 g of product, which was directly used in the next reaction step.

[0264] Step 3

[0265] Dichloromethane (510 mL), the product from the previous step (69.0 g), and ferric chloride (28.4 g) were added to a 1 L single-necked flask, and the mixture was stirred for 10 min after the addition. Then, 5-bromoindole (34.0 g) was added to the reaction flask, and the mixture was heated to 40 °C and stirred for 12 h. The reaction mixture was poured into water, and the organic phase was separated. The aqueous phase was extracted with ethyl acetate, and the organic phases were combined. The organic phase was concentrated under reduced pressure, slurried with a dichloromethane / n-heptane mixed solvent, filtered, and dried to obtain 44.0 g of a brownish-red solid. 1 HNMR (400MHz, DMSO-d6): δ12.16(s,1H),8.51(d,J=3.2Hz,1H),8.43(d,J=2.0Hz,1H),7.44( d, J=8.4Hz, 1H), 7.34 (dd, J1=8.4Hz, J2=2.0Hz, 1H), 4.31 (s, 2H), 1.95 (s, 3H), 1.36 (s, 6H).

[0266] Step 4

[0267] Add the product from the previous step (1.0 g) and tetrahydrofuran (20 mL) to a 100 mL three-necked flask, stir, and cool to 0 °C. Then, slowly add lithium aluminum hydride (337 mg) in portions to the reaction flask. After the addition is complete, gradually raise the temperature to room temperature and stir for 3 h. Pour the reaction mixture into ice water, add ethyl acetate, and stir for 5 min. Filter, separate the liquid from the liquid, collect the organic phase, dry, and concentrate under reduced pressure. Purify the concentrate by silica gel column chromatography to give 800 mg of a white solid. 1 HNMR (400MHz, DMSO-d6): δ11.13(s,1H),7.82(d,J=2.0Hz,1H),7.31(d,J=8.8Hz,1H),7.21(d,J=2.4Hz,1H),7.14(dd,J1=8.4Hz,J1=2.0Hz ,1H),4.95(d,J=3.6Hz,1H),4.78(d,J=4.0Hz,1H),4.55(t,J=1.6Hz,1H),3.38-3.34(m,1H),3.23-3.16(m,1H),0.88(s,3H),0.72(s,3H).

[0268] Step 5

[0269] Add the product from the previous step (800 mg), dichloromethane (5 mL), and tetrahydrofuran (1 mL) to a 50 mL single-necked flask, and stir while cooling to 5–10 °C. Add 342 mg of 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester and 26 mg of p-toluenesulfonic acid monohydrate to the reaction flask. After the addition is complete, maintain the reaction temperature below 10 °C and stir for 2 h. Filter and concentrate the reaction solution. Purify the concentrate by silica gel column chromatography to obtain 700 mg of a white solid. 1 HNMR (400MHz, DMSO-d6): δ11.06(s,1H),7.71(d,J=1.6Hz,1H),7.30(d,J=8.8Hz,1H),7. 15-7.12(m,2H),4.58(t,J=1.2Hz,1H),3.12(d,J=5.2Hz,2H),2.56(s,2H),0.80(s,6H).

[0270] Step 6

[0271] Add the product from the previous step (1.5 g), imidazole (395 mg), and dichloromethane (15 mL) to a 50 mL single-necked flask, stir, and cool to 0 °C. Add tert-butyldimethylchlorosilane (900 mg) to the reaction flask, then slowly raise the temperature to room temperature and stir for 4 h. Concentrate the reaction solution under reduced pressure, dilute the concentrate with ethyl acetate, wash with water, dry, and concentrate to obtain 1.7 g of a colorless, transparent liquid. 1 HNMR (400MHz, DMSO-d6): δ11.07(s,1H),7.71(d,J=2.0Hz,1H),7.30(d,J=8.8Hz,1H) ,7.15-7.11(m,2H),3.22(s,2H),2.58(s,2H),0.94(s,9H),0.81(s,6H),0.06(s,6H).

[0272] Step 7

[0273] Add the product from the previous step (1.7 g), silver trifluoromethanesulfonate (1.3 g), and tetrahydrofuran (50 mL) to a 250 mL single-necked flask, and cool to -20 °C with stirring. Then, slowly add a tetrahydrofuran solution of iodine (1.1 g iodine dissolved in 30 mL tetrahydrofuran) dropwise to the system. After the addition is complete, continue stirring at -20 °C for 2 min. Dilute the reaction solution with ethyl acetate, wash with sodium thiosulfate aqueous solution, dry, and concentrate the organic phase to obtain 2.2 g of a yellow solid. 1HNMR (400MHz, DMSO-d6): δ11.71(s,1H),7.74(d,J=1.6Hz,1H),7.23(d,J=8.4Hz,1H),7.13(d d, J1=8.4Hz, J2=1.6Hz,1H),3.30(s,2H),2.55(s,2H),0.95(s,9H),0.86(s,6H),0.08(s,6H). MS:[M+H] + =522.0.

[0274] Step 8

[0275] Under nitrogen protection, the product from the previous step (2.2 g), intermediate 1 (3.0 g), [1,1′-bis(diphenylphosphine)ferrocene]palladium dichloride (307 mg), potassium phosphate (2.2 g), 1,4-dioxane (55 mL), water (17 mL), and toluene (17 mL) were added to a 250 mL three-necked flask. After addition, the mixture was heated to 70 °C and stirred for 3 h. The reaction solution was concentrated, and the concentrate was purified by silica gel column chromatography to give 2.2 g of a brown solid. MS: [M+H] + =749.3.

[0276] Intermediate 3

[0277] Step 1

[0278] Under nitrogen protection, zinc powder (9.5 g), 1,2-dibromoethane (11.7 g), and N,N-dimethylformamide (100 mL) were added to a 1 L single-necked flask. After addition, the mixture was heated to 90 °C and stirred for 30 min. The reaction solution was cooled to room temperature, and then trimethylchlorosilane (1.4 g) was added to the flask. After addition, the mixture was stirred at room temperature for 30 min. Methyl (R)-2-((tert-butyloxycarbonyl)amino)-3-iodopropionate (29.8 g) in N,N-dimethylformamide (100 mL) was added dropwise. After addition, the mixture was stirred at room temperature for 10 min, then heated to 35 °C and stirred for 2 h. A solution of tetrakis(triphenylphosphine)palladium (2.4 g) and 2,4-dibromothiazole (10.0 g) in N,N-dimethylformamide (100 mL) was added dropwise. After addition, the mixture was heated to 70 °C and stirred for 2 h. The reaction mixture was poured into water, extracted with ethyl acetate, and the organic phases were combined, dried, and concentrated. The concentrate was purified by silica gel column chromatography to give 12.0 g of a pale yellow solid. MS: [M+H] + =365.0. 1H NMR (400MHz, CDCl3): δ7.15 (s, 1H), 5.49 (d, J = 7.4Hz, 1H), 4.76-4.63 (m, 1H), 3.78 (s, 3H), 3.52 (d, J = 5.3Hz, 2H), 1.46 (s, 9H).

[0279] Step 2

[0280] Add 12.0 g of the product from the previous step, 60 mL of tetrahydrofuran, and 24 mL of water to a 250 mL single-necked flask, stirring at room temperature after the addition is complete. Slowly add 4.2 g of lithium hydroxide monohydrate to the reaction flask, and continue stirring at room temperature for 1 h after the addition is complete. Pour the reaction solution into water, adjust the pH to 5-6 with 2 M dilute hydrochloric acid, extract the aqueous phase with ethyl acetate, combine the organic phases, and concentrate under reduced pressure to obtain 12.6 g of a brown oily substance, which can be used directly in the next reaction. MS: [MH] - =349.0.

[0281] Step 3

[0282] Under nitrogen protection, the product from the previous step (12.6 g) and dichloromethane (126 mL) were added to a 250 mL single-necked flask, and the system was cooled to 0 °C and stirred. Then, N-methylmorpholine (36.4 g), 1-hydroxybenzotriazole (7.3 g), and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (10.4 g) were added, and the mixture was stirred at 0 °C for 30 min after the addition was complete. Then, (S)-hexahydropyridazine-3-carboxylate trifluoroacetate (20.1 g) was added to the reaction flask, and the mixture was gradually cooled to room temperature and stirred for 12 h. The reaction mixture was poured into water, extracted with dichloromethane, and the organic phases were combined and concentrated. The concentrate was purified by silica gel column chromatography to give 11.8 g of the product. MS: [M+H] + =477.1. 1 H NMR (400MHz, DMSO-d6): δ7.69(s,1H),6.71(d,J=8.8Hz,1H),5.45-5.13(m,2H),3.76(br s,1H),3.66(s,3H),3.59(br s,1H),3.31-3.23(m,1H),3.15-3.04(m,2H),1.90-1.79(m,1H),1.77-1.48(m,3H),1.44(s,9H).

[0283] Intermediate 4

[0284] Step 1

[0285] (S)-4-(5-(5-bromo-3-(3-((tert-butyldimethylsilyl)oxy)-2,2-dimethylpropyl)-1H-indol-2-yl)-6-(1-methoxyethyl)pyridin-3-yl)piperazine-1-carboxylic acid benzyl ester (intermediate 2, 5.0 g), cesium carbonate (6.5 g), and N,N-dimethylformamide (50 mL) were added to a 100 mL single-necked flask. After the addition was complete, the mixture was stirred at 10 °C. Then, allyl bromide (1.6 g) was added to the reaction flask, and the mixture was gradually brought to room temperature and stirred for 6 h. The reaction solution was poured into water, extracted with ethyl acetate, dried, and concentrated to give 4.5 g of a yellow solid.

[0286] Step 2

[0287] Add 4.5 g of the product from the previous step, 9.0 g of tetrabutylammonium fluoride trihydrate, and 90 mL of tetrahydrofuran to a 100 mL single-necked flask, and heat to 60 °C with stirring for 6 h. Concentrate the reaction mixture, dilute the concentrate with ethyl acetate, wash with water, dry the organic phase, and concentrate again. Purify the concentrate by silica gel column chromatography to give 1.6 g of a yellow solid. MS: [M+H] + =675.3.

[0288] Step 3

[0289] Under nitrogen protection, the product from the previous step (1.6 g), pinacol diborate (903 mg), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (173 mg), potassium pentovalinate (499 mg), toluene (30 mL), and dimethyl sulfoxide (370 mg) were added to a 100 mL three-necked flask. After addition, the mixture was heated to 75 °C and stirred for 11 h. The reaction solution was diluted with ethyl acetate, washed with water, dried, and concentrated. The concentrate was purified by silica gel column chromatography to give 1.5 g of a yellow solid. MS: [M+H] + =723.4.

[0290] Step 4

[0291] Under nitrogen protection, the product from the previous step (1.7 g), methyl (S)-1-((S)-3-(4-bromothiazo-2-yl)-2-((tert-butyloxycarbonyl)amino)propionyl)hexahydropyridazine-3-carboxylate (intermediate 3, 1.5 g), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (172 mg), potassium phosphate (1.5 g), 1,4-dioxane (12 mL), water (12 mL), and toluene (35 mL) were added to the reaction flask. After addition, the mixture was heated to 80 °C and stirred for 14 h. The reaction solution was diluted with ethyl acetate, washed with water, dried, and concentrated. The concentrate was purified by silica gel column chromatography to give 1.5 g of a yellow solid. MS: [M+H] + =993.5.

[0292] Step 5

[0293] The product from the previous step (1.5 g), lithium hydroxide monohydrate (315 mg), tetrahydrofuran (15 mL), and water (15 mL) were added to the reaction flask. The mixture was stirred at room temperature for 3 h. The reaction solution was concentrated to a small volume, the pH was adjusted to 5 with dilute hydrochloric acid, and then extracted with dichloromethane. The organic phase was dried and concentrated to give 1.4 g of a yellow solid. MS: [M+H] + =979.5.

[0294] Step 6

[0295] Under nitrogen protection, 1-hydroxybenzotriazole (1.2 g), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.7 g), N,N-dimethylaminopyridine (1.1 g), and tetrahydrofuran (1500 mL) were added to a reaction flask. After addition, the temperature was raised to 60 °C and the mixture was stirred for 10 min. Then, a tetrahydrofuran solution (100 mL) of the product from the first step (1.5 g) was added dropwise to the reaction flask, and the mixture was stirred at 60 °C for 2 h. The reaction solution was concentrated to a small volume, and water and ethyl acetate were added to the concentrate. The extract was extracted, separated, dried, and concentrated. The concentrate was purified by silica gel column chromatography to give 1.1 g of a yellow solid. MS: [M+H] + =961.5.

[0296] Intermediate 5

[0297] Referring to the synthesis method of intermediate 3, intermediate 5 was prepared in step 3 by replacing (S)-hexahydropyridazine-3-carboxylate with (S)-2,3-diazabicyclo[3.1.1]heptane-4-carboxylate. The specific synthesis steps are as follows:

[0298] Preparation of methyl (S)-2,3-diazabicyclo[3.1.1]heptane-4-carboxylate:

[0299] Step 1

[0300] 2-(3-oxocyclobutyl)acetic acid (8.8 g), (S)-4-benzyloxazoline-2-one (13.4 g), 4-dimethylaminopyridine (838 mg), triethylamine (20.8 g), and dichloromethane (180 mL) were added to a 500 mL three-necked flask. After the addition was complete, the mixture was stirred at room temperature for 10 min. Then, 2-chloro-1-methylpyridine (salt) iodide (29.7 g) was added to the reaction system in portions. After the addition was complete, the mixture was stirred at room temperature for another 2 h. The reaction solution was poured into water, the organic phase was separated, washed with water, dried, and concentrated to obtain 19.0 g of a green viscous substance.

[0301] Step 2

[0302] Add the product from the previous step (23.0 g), glacial acetic acid (9.6 g), and tetrahydrofuran (230 mL) to a 500 mL three-necked flask. After the addition is complete, stir at 0 °C until dissolved. Add sodium cyanoborohydride (2.4 g) in portions to the reaction flask. After the addition is complete, gradually return to room temperature and stir for 2 h. Pour the reaction solution into a saturated ammonium chloride aqueous solution and separate the organic phase. Concentrate the organic phase, dilute the concentrate with ethyl acetate, wash with water, dry, and concentrate to obtain 21.7 g of a light yellow viscous substance.

[0303] Step 3

[0304] Add the product from the previous step (21.7 g), 4-dimethylaminopyridine (7.3 g), N,N-diisopropylethylamine (14.5 g), and dichloromethane (220 mL) to a 500 mL three-necked flask, and stir at room temperature after the addition is complete. Add p-Toluenesulfonyl chloride (15.7 g) to the reaction flask in portions, and stir at room temperature for 14 h after the addition is complete. Pour the reaction solution into water, extract with dichloromethane, dry and concentrate the organic phase, and purify the concentrate by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1, v / v) to give 22.0 g of a pale yellow viscous substance.

[0305] Step 4

[0306] Add the product from the previous step (22.0 g), lithium bromide (8.6 g), and N-methylpyrrolidone (220 mL) to a 500 mL single-necked flask, heat to 90 °C, and stir for 3 h. Pour the reaction solution into water, extract with ethyl acetate, wash the organic phase with water, dry, and concentrate to obtain 13.1 g of a light green oil.

[0307] Step 5

[0308] Add 12.0 g of the product from the previous step and 300 mL of anhydrous tetrahydrofuran to a 1 L three-necked flask, and cool to -78 °C. Slowly add 25.5 mL of diisopropylaminolithium (2 M tetrahydrofuran solution) dropwise to the reaction flask, and stir at -78 °C for 30 min after the addition is complete. Add 9.4 g of a tetrahydrofuran solution of di-tert-butyl azodicarbonate (dissolved in 40 mL of tetrahydrofuran) dropwise to the reaction flask, and stir at -78 °C for 30 min after the addition is complete. Pour the reaction solution into 500 mL of dilute hydrochloric acid and adjust the pH to 5–7. Extract with ethyl acetate, dry and concentrate. Purify the concentrate by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1, v / v) to give 15.0 g of white solid. The white solid was added to a 1L single-necked flask, along with cesium carbonate (10.1g) and N,N-dimethylformamide (300L). The mixture was stirred at room temperature for 5 hours. The reaction solution was poured into 2L of dilute hydrochloric acid, and the pH was adjusted to 5–7. The solution was extracted with ethyl acetate, dried, and concentrated. The concentrate was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1, v / v) to give 6.0g of a white solid. MS: [M+Na] + =524.3.

[0309] Step 6

[0310] The product from the previous step (6.0 g), lithium hydroxide monohydrate (1.5 g), water (60 mL), and tetrahydrofuran (60 mL) were added to a 250 mL single-necked flask. The mixture was stirred at room temperature for 1.5 h after the addition was complete. The tetrahydrofuran was removed by concentration, and the mixture was extracted with ethyl acetate. The organic phase was dried and concentrated to give 1.7 g of a yellow solid. MS: [M+Na] + =365.2.

[0311] Step 7

[0312] Add the product from the previous step (1.7 g), potassium bicarbonate (1.0 g), N,N-dimethylformamide (17 mL), and methyl iodide (1.4 g) to a 100 mL single-necked flask. After addition, stir the mixture at room temperature for 20 min. Pour the mixture into water, extract with ethyl acetate, dry, and concentrate. Purify the concentrate by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1, v / v) to give 1.1 g of a white solid. MS: [M+Na] + =379.2.

[0313] Step 8

[0314] Add 1.1 g of the product from the previous step, 20 mL of dichloromethane, and 5 mL of trifluoroacetic acid to a 100 mL single-necked flask. After the addition is complete, stir the mixture at room temperature for 1 h. Concentrate the reaction solution, add methyl tert-butyl ether to the concentrate to precipitate a solid, filter, and dry to obtain 600 mg of a white solid. 1HNMR (400MHz, DMSO-d6): δ4.27 (d, J=3.6Hz, 1H), 3.97-3.93 (m, 1H), 3.69 (s, 3H), 2.88-2 .83(m,1H),2.54-2.49(m,1H),2.39-2.33(m,1H),2.04-1.99(m,1H),1.76-1.71(m,1H). MS:[M+H] + =157.1.

[0315] Preparation of intermediate 5:

[0316] Add (S)-3-(4-bromothiazol-2-yl)-2-((tert-butyloxycarbonyl)amino)propionic acid (546 mg), N-methylmorpholine (1.6 g), and dichloromethane (10 mL) to the reaction flask. After addition, cool to 0 °C and stir for 10 min. Add 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (598 mg) and 1-hydroxybenzotriazole (422 mg) to the system, and continue stirring at 0 °C for 30 min. Then add trifluoroacetate of (S)-2,3-diazabicyclo[3.1.1]heptane-4-carboxylate (600 mg) and N-methylmorpholine (800 mg) to the system. After addition, raise to room temperature and stir for 1.5 h. Pour the reaction solution into water, extract with ethyl acetate, dry the organic phase, and concentrate. Purify the concentrate by silica gel column chromatography to give 700 mg of yellow solid. MS:[M+H] + =489.1.

[0317] Intermediate 6

[0318] Referring to the synthesis method of intermediate 4, intermediate 6 is prepared by replacing intermediate 3 with intermediate 5 in step 4.

[0319] Intermediate 7

[0320] Step 1

[0321] Add 1 L of dichloromethane, 271.8 g of trimethylsilyl trifluoromethanesulfonate, 123.7 g of triethylamine, and 10 g of silver trifluoromethanesulfonate to a reaction flask. Slowly add a solution of 100 g of ethyl propargyl propionate in 100 mL of dichloromethane. After the addition is complete, stir the reaction mixture at room temperature for 30 min, then concentrate under reduced pressure. Extract the concentrated residue with n-hexane, combine the organic phases, wash with saturated ammonium chloride solution, dry the n-hexane phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain a pale yellow liquid.

[0322] Step 2

[0323] Add the product from the previous step (50 g), diethyl ether (500 mL), sodium borodeuteride (17.3 g), lithium chloride (17.4 g), and heavy water (8.2 g) to the reaction flask. After addition, stir the mixture at room temperature for 40 min, then heat to 33 °C and stir for 8 h. Slowly add the reaction solution to 500 mL of 10% acetic acid aqueous solution, extract with n-hexane, wash the organic phase with 1 N hydrochloric acid solution, wash the organic phase with water until neutral, dry with anhydrous sodium sulfate, and concentrate under reduced pressure to obtain a pale yellow liquid. 1 H NMR (400MHz, DMSO-d6): δ5.20 (brs, 1H), 0.13 (s, 9H).

[0324] Step 3

[0325] Add the product from the previous step (6.0 g) and dichloromethane (75 mL) to the reaction flask, and lower the system temperature to -10 °C. Then, add phosphorus tribromide (30.0 mg) dropwise to the system. After the addition is complete, raise the reaction system to room temperature and stir for 1 h. Pour the reaction solution into ice water, adjust the pH to neutral with saturated sodium bicarbonate aqueous solution, extract with dichloromethane, combine the organic phases, dry and concentrate to obtain a colorless transparent liquid.

[0326] Intermediate 8

[0327] A similar synthetic method described in the references (Angew. Chem. Int. Ed., 2011, 50(21), 4983; J. Org. Chem., 2013, 78(4), 1559; Org. Lett., 2010, 12(6), 1184) uses acryloyl chloride as a raw material, which is reduced to prop-2-en-1,1-d2-1-ol by lithium deuterated aluminum hydride, and then brominated with phosphorus tribromide to obtain intermediate 8.

[0328] Intermediate 9

[0329] Step 1

[0330] (S)-4-(5-(1-allyl-5-bromo-3-(3-hydroxy-2,2-dimethylpropyl)-1H-indol-2-yl)-6-(1-methoxyethyl)pyridin-3-yl)piperazine-1-carboxylic acid benzyl ester (13.6 g) and trifluoroacetic acid (60 mL) were added to a 500 mL single-necked flask. The mixture was stirred at 70 °C for 2 h after the addition was complete. After the reaction was complete, the reaction solution was poured into an aqueous sodium bicarbonate solution to adjust the pH to approximately 8. The solution was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was dissolved in tetrahydrofuran (200 mL), followed by the addition of an aqueous lithium hydroxide solution (200 mL, 0.2 M), and stirred at room temperature for 30 min. The pH of the system was adjusted to neutral with dilute hydrochloric acid, extracted with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give 10.0 g of a brown solid. MS: [M+H] + =541.2.

[0331] Step 2

[0332] The product from the previous step (3.73 g), methanol (80 mL), and acetic acid (1.24 g) were added to a 100 mL three-necked flask, and the system was stirred at room temperature for 15 min. Acetaldehyde (608 mg) was added dropwise to the reaction system, followed by sodium cyanoborohydride (651 mg). After the addition was complete, the mixture was stirred at room temperature for 1 h. The reaction solution was poured into a saturated sodium bicarbonate aqueous solution, extracted with ethyl acetate, dried, and concentrated. The concentrate was purified by silica gel column chromatography to give 2.08 g of a yellow solid. MS: [M+H] + =569.2.

[0333] Intermediate 10

[0334] To a 100 mL three-necked flask, add (S)-3-(1-allyl-5-bromo-2-(2-(1-methoxyethyl)-5-(piperazin-1-yl)pyridin-3-yl)-1H-indol-3-yl)-2,2-dimethylprop-1-ol (3.1 g), 1,2-dichloroethane (60 mL), cyclopropylboronic acid (986 mg), 2,2'-bipyridine (896 mg), copper acetate (1.04 g), and sodium carbonate (1.22 g). Under oxygen protection, heat to 70 °C and stir for 6 h. After cooling, pour the reaction solution into an aqueous solution, extract with ethyl acetate, dry to anhydrous sodium sulfate, filter and concentrate. The concentrate is purified by silica gel column chromatography to give 1.82 g of a yellow solid. MS: [M+H] + =581.2.

[0335] Intermediate 11

[0336] (S)-3-(1-allyl-5-bromo-2-(2-(1-methoxyethyl)-5-(piperazin-1-yl)pyridin-3-yl)-1H-indol-3-yl)-2,2-dimethylprop-1-ol (2.68 g), methanol (60 mL), and acetic acid (893 mg) were added to a 100 mL three-necked flask, and the mixture was stirred at room temperature for 15 min. Acetone (576 mg) was added dropwise to the reaction mixture, followed by sodium cyanoborohydride (468 mg). After the addition was complete, the mixture was stirred at room temperature for 1 h. The reaction mixture was poured into a saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was purified by silica gel column chromatography to give 1.75 g of a yellow solid. MS: [M+H] + =583.3.

[0337] Intermediate 12

[0338] Step 1

[0339] Under nitrogen protection, (S)-3-bromo-5-iodo-2-(1-methoxyethyl)pyridine (10.0 g), N-tert-butoxycarbonyl-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester (10.9 g), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (2.1 g), potassium carbonate (10.0 g), 1,4-dioxane (150 mL), and water (30 mL) were added to a reaction flask. After the addition was complete, the mixture was stirred at 70 °C for 16 h. The reaction solution was cooled to room temperature, separated, and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, dried, and concentrated. The concentrate was purified by silica gel column chromatography to give 4.0 g of a white solid. MS: [M+H] + =397.1.

[0340] Step 2

[0341] Under nitrogen protection, the product from the previous step (13.0 g), pinacol diboronate (18.3 g), [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride (2.4 g), potassium pentovalinate (10.1 g), toluene (260 mL), and dimethyl sulfoxide (5.1 g) were added to the reaction flask. After the addition was complete, the mixture was stirred at 75 °C for 3 h. An aqueous solution of sodium chloride was added to the reaction system, and the mixture was separated. The aqueous phase was extracted with ethyl acetate, and the organic phases were combined, dried, and concentrated. The concentrate was purified by silica gel column chromatography to give 14.5 g of a yellow oil.

[0342] Step 3

[0343] The product from the previous step (18.0 g), methanol (200 mL), and 10% palladium on carbon (4.0 g) were added to the reaction flask. The mixture was purged with hydrogen and stirred at room temperature for 40 h under a hydrogen atmosphere. The reaction solution was filtered, concentrated, and purified by silica gel column chromatography to obtain 13.7 g of a yellow oil.

[0344] Step 4

[0345] Under nitrogen protection, the product from the previous step (6.5 g), 5-bromo-3-(3-(tert-butyldimethylsilyl)oxy)-2,2-dimethylpropyl)-2-iodo-1H-indole (7.6 g), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (1.1 g), potassium carbonate (7.7 g), 1,4-dioxane (160 mL), toluene (50 mL), and water (50 mL) were added to the reaction flask. After the addition was complete, the mixture was stirred at 75 °C for 13 h. The reaction solution was cooled to room temperature, separated, and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, dried, and concentrated. The concentrate was purified by silica gel column chromatography to give 5.5 g of a yellow solid. MS: [M+H] + =714.3.

[0346] Step 5

[0347] The product from the previous step (5.5 g), cesium carbonate (7.5 g), N,N-dimethylformamide (110 mL), and 3-bromopropene (1.9 g) were added to a 250 mL three-necked flask. The mixture was stirred at room temperature for 2 h after the addition was complete. The reaction was quenched with water, extracted with ethyl acetate, and the organic phases were combined, dried, and concentrated to give 5.8 g of a brownish-yellow oil. MS: [M+H] + =754.4.

[0348] Step 6

[0349] The product from the previous step (6.0 g), tetrabutylammonium fluoride trihydrate (12.0 g), and tetrahydrofuran (120 mL) were added to a 250 mL three-necked flask. The mixture was stirred at 45 °C for 11 h after the addition was complete. The reaction was quenched with water, extracted with ethyl acetate, and the organic phases were combined, dried, and concentrated. The concentrate was purified by silica gel column chromatography to give 2.0 g of a yellow solid. MS: [M+H] + =640.3.

[0350] Step 7

[0351] The product from the previous step (2.0 g), trifluoroacetic acid (10 mL), and dichloromethane (50 mL) were added to a 250 mL three-necked flask. The mixture was stirred at room temperature for 1 h after the addition was complete. The reaction solution was concentrated, and the concentrate was dissolved in ethyl acetate and washed with saturated sodium bicarbonate aqueous solution. The organic phase was then concentrated to give 1.7 g of a yellow solid. MS: [M+H] + =540.2.

[0352] Step 8

[0353] The product from the previous step (2.2 g), methanol (60 mL), and glacial acetic acid (733 mg) were added to a 250 mL three-necked flask. After the addition was complete, the mixture was stirred at room temperature for 15 min. Then, 10% formaldehyde aqueous solution (2.4 g) and sodium cyanoborohydride (305 mg) were added, and the mixture was stirred at room temperature for another 0.5 h. The reaction system was concentrated, and the concentrate was dissolved in ethyl acetate and washed with saturated sodium bicarbonate aqueous solution. The organic phase was concentrated to give 2.3 g of a yellow solid. MS: [M+H] + =554.3.

[0354] Intermediate 13

[0355] Using (S)-4-(5-(1-allyl-5-bromo-3-(3-hydroxy-2,2-dimethylpropyl)-1H-indol-2-yl)-6-(1-methoxyethyl)pyridin-3-yl)piperazine-1-carboxylic acid benzyl ester as the starting material, it was oxidized to a carboxylic acid according to the reference (J.Am.Chem.Soc.2016,138,27,8344-8347), reacted with iodomethane to generate a methyl ester, and reduced by LiAlD4 to generate a deuterated product; then intermediate 13 was synthesized according to the preparation method of intermediate 9, wherein formaldehyde was used instead of acetaldehyde in step 2.

[0356] Intermediate 14

[0357] Intermediate 14 was synthesized from 3-(5-bromo-1H-indol-3-yl)-2,2-dimethyl-3-oxopropyl acetate under reflux conditions by reduction with lithium deuterated aluminum hydride, and then by referring to the preparation methods of intermediates 2, 4 and 9 mentioned above.

[0358] Intermediate 15

[0359] Step 1:

[0360] Add 1.6 g of 2-(2-bromoethoxy)ethyl-1-ol, 1.3 g of 2-(2-methoxyethoxy)ethyl-1-thiol, 1.3 g of potassium carbonate, and 50 mL of acetonitrile to a single-necked flask. Heat the mixture to 65 °C and stir for 16 h. After the reaction solution cools to room temperature, filter to remove insoluble matter, collect the filtrate, and use it directly for the next reaction step.

[0361] Step 2:

[0362] To the filtrate from the previous step, add 344 mg of 4-dimethylaminopyridine, 1.9 g of triethylamine, and 2.7 g of p-toluenesulfonyl chloride. Heat to 50 °C and stir for 2 h. Pour the reaction mixture into water, extract with ethyl acetate, collect the organic phase, dry, and concentrate. Purify the concentrate by silica gel column chromatography to obtain 2.6 g of a colorless oil.

[0363] Step 3:

[0364] Add the product from the previous step (2.7 g) and dichloromethane (80 mL) to a single-necked flask, stir until dissolved, then add m-chloroperoxybenzoic acid (4.9 g), and stir at room temperature for 2 h. Pour the reaction solution into water, extract with ethyl acetate, collect the organic phase, dry and concentrate. Purify the concentrate by silica gel column chromatography to obtain 2.2 g of a colorless oily product. MS: [M+Na] + =433.1.

[0365] Intermediate 16

[0366] Step 1:

[0367] Add 2-mercaptoethanol (2.0 g), 2-chloroethyl methyl sulfide (3.1 g), potassium carbonate (7.1 g), and N,N-dimethylformamide (20 mL) to a single-necked flask, heat to 65 °C, and stir for 4 h. After the reaction solution cools to room temperature, filter, collect the filtrate, and proceed directly to the next step of the reaction.

[0368] Step 2:

[0369] Triethylamine (2.8 g), p-toluenesulfonyl chloride (5.3 g), and 4-dimethylaminopyridine (300 mg) were added to the filtrate from the previous step, and the mixture was heated to 50 °C and stirred for 8 h. The reaction mixture was poured into water, extracted with ethyl acetate, and the organic phase was collected, dried, and concentrated. The concentrate was purified by silica gel column chromatography to give 2.0 g of a light brown oily substance.

[0370] Step 3:

[0371] Add the product from the previous step (2.0 g) and dichloromethane (40 mL) to a single-necked flask, stir until dissolved, then add m-chloroperoxybenzoic acid (9.0 g), and stir the reaction mixture at room temperature for 8 h. Pour the reaction solution into a saturated sodium bicarbonate aqueous solution, extract with ethyl acetate, collect the organic phase, dry and concentrate. The concentrate was purified by silica gel column chromatography to give 400 mg of a light brown oily substance.

[0372] Intermediate 17

[0373] Step 1:

[0374] Add 939 mg of 2-mercaptoethanol, 2.0 g of 1-bromo-2-(2-methoxyethoxy)ethane, 3.8 g of potassium carbonate, and 20 mL of acetonitrile to a single-necked flask, and stir the mixture at room temperature for 2 h. Filter the reaction mixture and collect the filtrate for the next step of the reaction.

[0375] Step 2:

[0376] Add p-toluenesulfonyl chloride (4.2 g) and triethylamine (2 mL) to the filtrate from the previous step, and stir the mixture at 50 °C for 12 h. Pour the reaction mixture into water, extract with ethyl acetate, collect the organic phase, dry and concentrate. The concentrate was purified by silica gel column chromatography to give 400 mg of a yellow oil.

[0377] Step 3:

[0378] Add the product from the previous step (300 mg), m-chloroperoxybenzoic acid (1.2 g), and dichloromethane (10 mL) to a single-necked flask, and heat to 37 °C with stirring for 3 h. Pour the reaction mixture into a saturated sodium bicarbonate aqueous solution, extract with ethyl acetate, collect the organic phase, dry, and concentrate. Purify the concentrate by silica gel column chromatography to obtain 190 mg of a colorless oil.

[0379] Intermediate 18

[0380] Intermediate 18 was prepared using intermediate 14M as the raw material, following a similar method to intermediate 4.

[0381] Intermediate 19

[0382] Intermediate 19 was prepared using a similar method to intermediate 4, with bromoethane used instead of allyl bromide in step 1.

[0383] Intermediate 20

[0384] Intermediate 20 was prepared using intermediate 14M as a raw material, following a similar method to intermediate 4. In step 1, bromoethane was used instead of allyl bromide for preparation.

[0385] Compound preparation

[0386] Example 1

[0387] Step 1

[0388] Intermediate 4 (1.1 g), dichloromethane (10 mL), and trifluoroacetic acid (3 mL) were added to the reaction flask. After addition, the mixture was stirred at room temperature for 1 h. The reaction solution was poured into an aqueous sodium bicarbonate solution, extracted with dichloromethane, dried, and concentrated. The organic phase was then used directly in the next reaction. MS: [M+H] +=861.4.

[0389] Step 2

[0390] The product from the previous step (900 mg), (1S,2S)-2-methylcyclopropane-1-carboxylic acid (126 mg), N,N-diisopropylethylamine (814 mg), 2-(7-azabenzotriazole)-N,N,N′,N′-tetramethylurea hexafluorophosphate (1.2 g), and N,N-dimethylformamide (10 mL) were added to the reaction flask. The mixture was stirred at room temperature for 1.5 h. The reaction solution was poured into water, extracted with ethyl acetate, dried, and concentrated. The concentrate was purified by silica gel column chromatography to give 700 mg of a white solid. MS: [M+Na] + =965.4.

[0391] Step 3

[0392] The product from the previous step (400 mg) and trifluoroacetic acid (5 mL) were added to the reaction flask, and the mixture was heated to 70 °C and stirred for 2 h. The reaction solution was poured into an aqueous sodium bicarbonate solution, extracted with ethyl acetate, dried, and concentrated to give 280 mg of a yellow solid. MS: [M+Na] + =831.4.

[0393] Step 4

[0394] Add the product from the previous step (280 mg) and methanol (5 mL) to the reaction flask, and stir at room temperature until dissolved. Then add acetic acid (68 mg) and continue stirring for 15 min. Next, add formaldehyde aqueous solution (220 mg) and sodium cyanoborohydride (28 mg) to the reaction flask, and continue stirring at room temperature for 2 h. Adjust the pH to neutral by adding sodium carbonate aqueous solution, extract with ethyl acetate, dry, and concentrate the organic phase. Purify the concentrate by silica gel column chromatography to give 105 mg of a white solid. f :0.32 (DCM:MeOH=10:1). MS:[M+Na] + =845.4.

[0395] Example 2

[0396] Following the synthetic method of intermediate 4, allyl bromide was replaced with intermediate 8 (3-bromoprop-1-ene-3,3-d2) to obtain the deuterated derivative of intermediate 4 (intermediate 4M), and then compound 3-17 was obtained following the synthetic method of Example 1. f :0.32(DCM:MeOH=10:1).

[0397] Example 3

[0398] Referring to Example 1, using intermediate 4 as a raw material, and replacing (1S,2S)-2-methylcyclopropane-1-carboxylic acid with (1r,2R,3S)-2,3-dimethylcyclopropane-1-carboxylic acid in step 2, compound 3-20 was prepared. f :0.33 (DCM:MeOH=10:1). MS:[M+H] + =837.4.

[0399] The detailed synthesis steps are as follows:

[0400] Step 1

[0401] Intermediate 4 (22 g), dichloromethane (200 mL), and trifluoroacetic acid (60 mL) were added to the reaction flask. After addition, the mixture was stirred at room temperature until complete. The reaction solution was poured into an aqueous sodium bicarbonate solution, extracted with dichloromethane, dried, and concentrated. The organic phase was then used directly in the next reaction. MS: [M+H] + =861.4.

[0402] Step 2

[0403] Add the product from the previous step (6.03 g), (1r,2R,3S)-2,3-dimethylcyclopropane-1-carboxylic acid (975 mg), N,N-diisopropylethylamine (2.73 g), 2-(7-azabenzotriazole)-N,N,N′,N′-tetramethylurea hexafluorophosphate (5.34 g), and N,N-dimethylformamide (75 mL) to the reaction flask. After addition, stir the mixture at room temperature until complete. Pour the reaction solution into water, extract with ethyl acetate, combine the organic phases, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate the organic phase. Purify the concentrate by silica gel column chromatography to give 4.89 g of an off-white product. MS: [M+H] + =957.5.

[0404] Step 3

[0405] The product from the previous step (4.80 g) and trifluoroacetic acid (75 mL) were added to the reaction flask, and the mixture was heated to 70 °C and stirred until complete. After cooling, the reaction solution was poured into an aqueous sodium bicarbonate solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated to give 3.37 g of a yellow solid. MS: [M+H] + =823.4.

[0406] Step 4

[0407] Add the product from the previous step (500 mg), methanol (20 mL), glacial acetic acid (109 mg), and formaldehyde aqueous solution (360 mg) to a 100 mL single-necked flask. After the addition is complete, stir the mixture at room temperature for 15 min. Then add sodium cyanoborohydride (76 mg) to the system, and continue stirring at room temperature for 1 h. Pour the reaction solution into water, extract with ethyl acetate, collect the organic phase, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate. Purify the concentrate by silica gel column chromatography to give 260 mg of white solid. δ8.48(s,1H),8.44(d,J=2.8Hz,1H),8.39(d,J=8.9Hz,1H),7.79(s,1H),7.70(dd,J1=8.6Hz,J2=1.4Hz,1H),7 .49(d,J=8.7Hz,1H),7.14(d,J=2.8Hz,1H),5.62-5.53(m,2H),5.07(d,J=12.2Hz,1H),4.92-4.80(m,2H),4.74 -4.65(m,1H),4.59(d,J=17.2Hz,1H),4.28-4.09(m,3H),3.58(s,2H),3.31-3 .09(m,9H),2.93(d,J=14.4Hz,1H),2.80-2.69(m,1H),2.51-2.42(m,5H),2.23 (s,3H),2.06(d,J=10.1Hz,1H),1.84-1.69(m,2H),1.58-1.43(m,1H),1.33(d, J=6.1Hz,3H),1.18-1.13(m,2H),1.10-1.02(m,7H),0.90(s,3H),0.37(s,3H).

[0408] Example 4

[0409] Compound 3-22 was prepared using intermediate 6 as a starting material, following Example 1. f :0.33(DCM:MeOH=10:1).

[0410] 1H NMR (400MHz, DMSO-d6): δ8.53(d,J=8.9Hz,1H),8.46-8.37(m,2H),7.79(s,1H),7.70(dd,J1=8 .5Hz,J2=1.5Hz,1H),7.49(d,J=8.7Hz,1H),7.14(d,J=2.9Hz,1H),5.95(d,J=11.2Hz,1H),5.65 -5.51(m,1H),5.45-5.34(m,1H),4.93-4.81(m,2H),4.75-4.53(m,3H),4.52-4.44(m,1H),4.20-4.10(m,1H),3.62 -3.48(m,2H),3.27-3.16(m,9H),2.92(d,J=14.3Hz,1H),2.66-2.57(m,1H),2.48-2.39(m,5H),2.36-2.27(m,1H),2.22(s,3H) ,2.16(t,J=9.7Hz,1H),1.61-1.52(m,1H),1.38-1.30(m,4H),1.26-1.20(m,6H),1.07(s,3H),0.60-0.52(m,1H),0.35(s,3H). MS:[M+H] + =835.4.

[0411] Example 5

[0412] B-3 was prepared using a similar method to intermediate 4, except that in step 1, intermediate 8 (3-bromoprop-1-ene-3,3-d2) was used instead of allyl bromide, and in step 4, intermediate 5 was used instead of intermediate 3. Compound 3-23 was then prepared using a similar method to that in Example 1. f :0.33(DCM:MeOH=10:1).

[0413] Example 6

[0414] Referring to Example 5, compound 3-27 was prepared by replacing (1S,2S)-2-methylcyclopropane-1-carboxylic acid with (1r,2R,3S)-2,3-dimethylcyclopropane-1-carboxylic acid. f :0.34(DCM:MeOH=10:1).

[0415] Example 7

[0416] Using intermediate 6 as a raw material, and referring to Example 1, compound 3-26 was prepared in step 2 by replacing (1S,2S)-2-methylcyclopropane-1-carboxylic acid with (1r,2R,3S)-2,3-dimethylcyclopropane-1-carboxylic acid.

[0417] 1 H NMR (400MHz, DMSO-d6): δ8.46-8.39(m,3H),7.80(s,1H),7.71(dd,J1=8.6Hz,J2=1.5Hz,1H),7.50(d,J=8.7Hz,1H),7.15(d,J=2.8Hz,1H),5. 95(d,J=11.1Hz,1H),5.65-5.51(m,1H),5.45-5.34(m,1H),4.93-4.81 (m,2H),4.75-4.53(m,3H),4.52-4.45(m,1H),4.21-4.13(m,1H),3.64 -3.49(m,2H),3.30-3.08(m,9H),2.92(d,J=14.3Hz,1H),2.66-2.59(m,1H),2.49-2.40(m,5H),2.36-2.27(m,1H),2.22(s,3H),2. 16(t,J=9.9Hz,1H),1.56(t,J=9.3Hz,1H),1.35(d,J=6.1Hz,3H),1.28-1.21(m,4H),1.12-1.03(m,6H),0.88(s,3H),0.36(s,3H). MS:[M+H] + =849.4.

[0418] Example 8

[0419] Step 1

[0420] Under nitrogen protection, intermediate 9 (2.08 g), pinacol diborate (1.86 g), potassium pentovalinate (1.13 g), dimethyl sulfoxide (572 mg), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (268 mg), and toluene (25 mL) were added to a reaction flask. After addition, the mixture was heated to 75 °C and stirred for 12 h. The reaction solution was poured into water, extracted with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was purified by silica gel column chromatography to give 1.81 g of a yellow solid. MS: [M+H] + =617.4.

[0421] Step 2

[0422] Under nitrogen protection, the product from the previous step (1.81 g), intermediate 5 (1.71 g), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (191 mg), potassium phosphate (1.56 g), cesium fluoride (446 mg), toluene (54 mL), 1,4-dioxane (18 mL), and water (18 mL) were added to the reaction flask. After addition, the mixture was stirred at 70 °C for 6 h. The reaction solution was poured into a saturated ammonium chloride aqueous solution, extracted with ethyl acetate, dried, and concentrated. The concentrate was purified by silica gel column chromatography to give 1.95 g of a yellow solid. MS: [M+H] + =899.5.

[0423] Step 3

[0424] Add the product from the previous step (1.06 g) and tetrahydrofuran (20 mL) to the reaction flask, followed by dropwise addition of an aqueous solution of lithium hydroxide monohydrate (99 mg, 10 mL). After the addition is complete, continue stirring the system at room temperature for 2 h. Adjust the pH of the system to 8 with 1 M dilute hydrochloric acid, extract with ethyl acetate, dry, and concentrate. Purify the concentrate by silica gel column chromatography to give 1.0 g of a yellow solid.

[0425] Step 4

[0426] Under nitrogen protection, the product from the previous step (1.0 g) and dichloromethane (1000 mL) were added to the reaction flask, and the system was cooled to below 10 °C. 1-Hydroxybenzotriazole (611 mg) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (867 mg) were added to the system, and the mixture was stirred for 30 min after the addition was complete, then stirred at room temperature for another 30 min. N,N-Dimethylaminopyridine (690 mg) was added to the system, and the mixture was then heated to reflux and stirred for 6 h. The reaction solution was concentrated, the concentrate was diluted with ethyl acetate, water was added, the mixture was stirred, separated, the organic phase was collected, dried, and concentrated. The concentrate was purified by silica gel column chromatography to give 300 mg of an off-white solid. MS: [M+H] + =867.5.

[0427] Step 5

[0428] Add the product from the previous step (300 mg), dichloromethane (12 mL), and trifluoroacetic acid (3 mL) to the reaction flask. After addition, stir the mixture at room temperature for 2.5 h. Pour the reaction solution into an ice-water solution of sodium bicarbonate, extract with ethyl acetate, dry, and concentrate to obtain 240 mg of a yellow solid. Add N,N-dimethylformamide (10 mL) to the concentrate, cool in an ice bath, and then add (1r,2R,3S)-2,3-dimethylcyclopropyl-1-carboxylic acid (71 mg), 2-(7-azabenzotriazole)-N,N,N′,N′-tetramethylurea hexafluorophosphate (357 mg), and N,N-diisopropylethylamine (243 mg). After addition, continue stirring at 0 °C for 2 h. Quench the reaction solution with water, extract with dichloromethane, collect the organic phase, dry, and concentrate. Purify the concentrate by silica gel column chromatography to obtain 40 mg of an off-white solid. MS:[M+H] + =863.5.

[0429] Example 9

[0430] The intermediate 10 was used as a raw material and synthesized according to Example 8.

[0431] 1 H NMR (400MHz, DMSO-d6): δ8.48-8.36(m,3H),7.80(s,1H),7.71(d,J=8.6Hz,1 H),7.50(d,J=8.7Hz,1H),7.14(d,J=2.7Hz,1H),5.94(d,J=11.0Hz,1H),5.66 -5.53(m,1H),5.45-5.33(m,1H),4.95-4.81(m,2H),4.76-4.55(m,3H),4.53-4.45(m,1H),4.22-4.13(m,1H),3.66 -3.48(m,2H),3.30-3.08(m,10H),2.92(d,J=14.1Hz,1H),2.74-2.59(m,6H),2.38-2.26(m,1H),2.16(t,J=9.8Hz,1H),172-1.61(m,1 H), 1.56 (t, J = 9.2Hz, 1H), 1.38-1.32 (m, 4H), 1.29-1.20 (m, 2H), 1.13-1.04 (m, 6H), 0.88 (s, 3H), 0.47-0.41 (m, 2H), 0.40-0.30 (m, 5H). MS:[M+H] + =875.5.

[0432] Example 10

[0433] The intermediate 11 was used as a raw material and synthesized according to Example 8.

[0434] 1 H NMR (400MHz, DMSO-d6): δ8.50-8.35(m,3H),7.80(s,1H),7.71(d,J=8.6Hz,1H),7.50(d,J=8.6Hz,1H),7.14(s,1H),5.94(d,J=11.1Hz,1H),5.66 -5.53(m,1H),5.45-5.32(m,1H),4.95-4.81(m,2H),4.76-4.55(m,3H),4.53-4.45(m,1H), 4.22-4.13(m,1H),3.66-3.48(m,2H),3.30-3.08(m,10H),2.92(d,J=13.7Hz,1H),2.74-2.5 6(m,5H),2.37-2.26(m,2H),2.16(t,J=9.6Hz,1H),1.56(t,J=9.1Hz,1H),1.35(d,J=6.2Hz, 3H), 1.28-1.20 (m, 4H), 1.13-1.05 (m, 6H), 1.01 (d, J = 5.7Hz, 6H), 0.88 (s, 3H), 0.36 (s, 3H). MS:[M+H] + =877.5.

[0435] Example 11

[0436] Using intermediate 12 as a raw material, the synthesis was carried out according to Example 8. MS: [M+H] + =848.4.

[0437] Example 12

[0438] Using intermediate 13 as a raw material, it was synthesized according to Example 8. f :0.34(DCM:MeOH=10:1).

[0439] Example 13

[0440] Using intermediate 14 as a raw material, the synthesis was carried out according to Example 8, wherein intermediate 3 was used instead of intermediate 5 in step 2. f :0.33(DCM:MeOH=10:1).

[0441] Example 14

[0442] Using intermediate 14 as a raw material, it was synthesized according to Example 8. f :0.34(DCM:MeOH=10:1).

[0443] Example 15

[0444] The compound was prepared using a method similar to that in Example 2, but with (1r,2R,3S)-2,3-dimethylcyclopropane-1-carboxylic acid used instead of (1S,2S)-2-methylcyclopropane-1-carboxylic acid. f :0.33(DCM:MeOH=10:1).

[0445] Example 16

[0446] The compound was prepared using intermediate 13 as a raw material, following a method similar to that in Example 8, and in step 2, intermediate 3 was used instead of intermediate 5 to prepare the compound. f :0.33(DCM:MeOH=10:1).

[0447] Example 17

[0448] Step 1

[0449] Intermediate 4 (22 g), dichloromethane (200 mL), and trifluoroacetic acid (60 mL) were added to the reaction flask. After addition, the mixture was stirred at room temperature until complete. The reaction solution was poured into an aqueous sodium bicarbonate solution, extracted with dichloromethane, dried, and concentrated. The organic phase was then used directly in the next reaction. MS: [M+H] + =861.4.

[0450] Step 2

[0451] Add the product from the previous step (6.03 g), (1r,2R,3S)-2,3-dimethylcyclopropane-1-carboxylic acid (975 mg), N,N-diisopropylethylamine (2.73 g), 2-(7-azabenzotriazole)-N,N,N′,N′-tetramethylurea hexafluorophosphate (5.34 g), and N,N-dimethylformamide (75 mL) to the reaction flask. After addition, stir the mixture at room temperature until the reactants have completely reacted. Pour the reaction solution into water, extract with ethyl acetate, combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate. Purify the concentrate by silica gel column chromatography to give 4.89 g of an off-white product. MS: [M+H] + =957.5.

[0452] Step 3

[0453] The product from the previous step (4.80 g) and trifluoroacetic acid (75 mL) were added to the reaction flask, and the mixture was heated to 70 °C and stirred until complete. The reaction solution was poured into an aqueous sodium bicarbonate solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated to give 3.37 g of a yellow solid. MS: [M+H] + =823.4.

[0454] Step 4

[0455] Add the product from the previous step (600 mg), 1-bromo-2-(2-methoxyethoxy)ethane (160 mg), potassium carbonate (200 mg), and acetonitrile (10 mL) to the reaction flask. After addition, heat to 70 °C and react until complete. Quench the reaction solution with water, extract with ethyl acetate, dry the organic phase with anhydrous sodium sulfate, filter and concentrate the organic phase. Purify the concentrate by silica gel column chromatography to obtain an off-white solid. R f :0.52 (DCM:MeOH=10:1). MS:[M+H] + =925.5.

[0456] Example 18

[0457] Add (1r,2R,3S)-N-((6) to a 50mL single-necked flask. 3 S,4S,Z)-1 1 -allyl-1 2 -(2-((S)-1-methoxyethyl)-5-(piperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indolyl-6(1,3)-pyridazinylcycloundecane-4-yl)-2,3-dimethylcyclopropane-1-carboxamide (300 mg), potassium iodide (57 mg), potassium carbonate (100 mg), intermediate 15 (224 mg), and N,N-dimethylacetamide (10 mL) were added and the mixture was heated to 50 °C and stirred for 8 hours. The reaction mixture was poured into water, extracted with ethyl acetate, and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was purified by silica gel column chromatography to obtain the crude product. The crude product was further purified by preparative HPLC to obtain 30 mg of a yellow solid. MS: [M+H] + =1061.5.

[0458] Example 19

[0459] Add (1r,2R,3S)-N-((6) to a 100mL single-necked flask. 3 S,4S,Z)-1 1 -allyl-1 2 -(2-((S)-1-methoxyethyl)-5-(piperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indolyl-6(1,3)-pyridazinylcycloundecane-4-yl)-2,3-dimethylcyclopropane-1-carboxamide (175 mg), intermediate 17 (144 mg), potassium iodide (354 mg), potassium carbonate (136 mg), and N,N-dimethylacetamide (5 mL) were added and the mixture was heated to 50 °C and stirred for 36 h. The reaction solution was poured into water and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was purified by silica gel column chromatography to obtain a crude product. The crude product was further purified by preparative HPLC to give 31 mg of a yellow solid. MS: [M+H] + =1017.6.

[0460] Example 20

[0461] Add (1r,2R,3S)-N-((6) to a 100mL single-necked flask. 3 S,4S,Z)-1 1 -allyl-1 2 -(2-((S)-1-methoxyethyl)-5-(piperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indolyl-6(1,3)-pyridazinylcycloundecane-4-yl)-2,3-dimethylcyclopropane-1-carboxamide (200 mg), intermediate 16 (180 mg), potassium iodide (41 mg), potassium carbonate (67 mg), and N,N-dimethylacetamide (5 mL) were added and the mixture was heated to 50 °C and stirred for 12 h. The reaction solution was poured into water and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was purified by silica gel column chromatography to obtain the crude product. The crude product was further purified by preparative HPLC to obtain 5 mg of a yellow solid. MS: [M+H] + =1021.5.

[0462] Example 21

[0463] The intermediate 4M was used as a raw material and synthesized using a method similar to that in Examples 17 and 19. f :0.49 (DCM:MeOH=10:1).

[0464] Example 22

[0465] The synthesis was carried out using a similar method to that of Example 19, with intermediate 17 replaced by 2-((2-(2-(methoxy-d3)ethoxy)ethyl)sulfonyl)ethyl 4-methylbenzenesulfonate. f :0.49 (DCM:MeOH=10:1).

[0466] Example 23

[0467] Using intermediate 18 as a raw material, it was synthesized using a method similar to that in Examples 17 and 19. f :0.49 (DCM:MeOH=10:1).

[0468] Example 24

[0469] Using intermediate 19 as a raw material, it was synthesized using a method similar to that of Examples 17 and 19. f :0.47 (DCM:MeOH=10:1).

[0470] Example 25

[0471] Using intermediate 20 as a raw material, it was synthesized using a method similar to that in Examples 17 and 19. f :0.47 (DCM:MeOH=10:1).

[0472] Example 26

[0473] The synthesis was carried out using a similar method to Example 24, wherein intermediate 17 was replaced with 2-((2-(2-(methoxy-d3)ethoxy)ethyl)sulfonyl)ethyl 4-methylbenzenesulfonate. f :0.47 (DCM:MeOH=10:1).

[0474] Example 27

[0475] Step 1

[0476] Intermediate 19 (1.1 g), dichloromethane (10 mL), and trifluoroacetic acid (3 mL) were added to the reaction flask. After addition, the mixture was stirred at room temperature for 1 h. The reaction solution was poured into an aqueous sodium bicarbonate solution, extracted with dichloromethane, dried, and concentrated. The organic phase was then used directly in the next reaction. MS: [M+H] + =849.4.

[0477] Step 2

[0478] The product from the previous step (900 mg), (1S,2S)-2-methylcyclopropane-1-carboxylic acid (127 mg), N,N-diisopropylethylamine (273 mg), 2-(7-azabenzotriazole)-N,N,N′,N′-tetramethylurea hexafluorophosphate (604 mg), and N,N-dimethylformamide (10 mL) were added to the reaction flask. The mixture was stirred at room temperature for 1.5 h. The reaction solution was poured into water, extracted with ethyl acetate, dried, and concentrated. The concentrate was purified by silica gel column chromatography to give 700 mg of a white solid. MS: [M+H] + =931.4.

[0479] Step 3

[0480] The product from the previous step (400 mg) and trifluoroacetic acid (5 mL) were added to the reaction flask, and the mixture was heated to 70 °C and stirred for 2 h. The reaction solution was poured into an aqueous sodium bicarbonate solution, extracted with ethyl acetate, dried, and concentrated to give 280 mg of a yellow solid. MS: [M+H] + =797.4.

[0481] Step 4

[0482] The product from the previous step (200 mg), dimethylchloromethylphosphine oxide (47 mg), acetonitrile (8 mL), potassium carbonate (70 mg), and potassium iodide (42 mg) were added to the reaction flask. After addition, the mixture was stirred at 70 °C for 18 h. The reaction solution was quenched with water, extracted with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was purified by silica gel column chromatography to obtain 48 mg of the product. f :0.31 (DCM:MeOH=10:1). MS:[M+Na] + =909.4.

[0483] Example 28

[0484] Step 1

[0485] Intermediate 4 (22 g), dichloromethane (200 mL), and trifluoroacetic acid (60 mL) were added to the reaction flask. After addition, the mixture was stirred at room temperature until complete. The reaction solution was poured into an aqueous sodium bicarbonate solution, extracted with dichloromethane, dried, and concentrated. The organic phase was then used directly in the next reaction. MS: [M+H] + =861.4.

[0486] Step 2

[0487] Add the product from the previous step (6.03 g), (1r,2R,3S)-2,3-dimethylcyclopropane-1-carboxylic acid (975 mg instead of (1S,2S)-2-methylcyclopropane-1-carboxylic acid), N,N-diisopropylethylamine (2.73 g), 2-(7-azabenzotriazole)-N,N,N′,N′-tetramethylurea hexafluorophosphate (5.34 g), and N,N-dimethylformamide (75 mL) to the reaction flask. After addition, stir the mixture at room temperature until the reactants have completely reacted. Pour the reaction solution into water, extract with ethyl acetate, combine the organic phases, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate the organic phase. Purify the concentrate by silica gel column chromatography to give 4.89 g of an off-white product. MS: [M+H] + =957.5.

[0488] Step 3

[0489] The product from the previous step (4.80 g) and trifluoroacetic acid (75 mL) were added to the reaction flask, and the mixture was heated to 70 °C and stirred until complete. The reaction solution was poured into an aqueous sodium bicarbonate solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated to give 3.37 g of a yellow solid. MS: [M+H] + =823.4.

[0490] Step 4

[0491] Under nitrogen protection, the product from the previous step (500 mg), 2-bromoethyl methyl sulfide (110 mg), potassium carbonate (167 mg), and acetonitrile (10 mL) were added to the reaction flask. After addition, the mixture was heated to 70 °C and reacted overnight. The reaction solution was poured into water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, concentrated, and the concentrate was purified by silica gel column chromatography to obtain a pale yellow solid. MS: [M+H] + =897.4.

[0492] Example 29

[0493] Under nitrogen protection, (1r,2R,3S)-N-((6) 3 S,4S,Z)-1 1 -allyl-1 2 -(2-((S)-1-methoxyethyl)-5-(piperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazo-1(5,3)-indol-6(1,3)-pyridazinecycloundecane-4-yl)-2,3-dimethylcyclopropane-1-carboxamide (500 mg), 1-bromo-2-(methylsulfinyl)ethane (200 mg), potassium carbonate (167 mg), acetonitrile (10 mL), were added and the mixture was heated to 70 °C and reacted overnight. The reaction solution was concentrated, and the concentrate was purified by silica gel column chromatography to obtain a pale yellow solid. MS: [M+H] + =913.4.

[0494] Example 30

[0495] Under nitrogen protection, (1r,2R,3S)-N-((6) 3 S,4S,Z)-1 1 -allyl-1 2 -(2-((S)-1-methoxyethyl)-5-(piperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1H-8-oxa-2(4,2)-thiazo-1(5,3)-indol-6(1,3)-pyridazinecycloundecane-4-yl)-2,3-dimethylcyclopropane-1-carboxamide (500 mg), 2-bromoethylmethyl sulfone (130 mg), potassium carbonate (167 mg), acetonitrile (10 mL) were added, and the mixture was heated to 70 °C and reacted overnight. The reaction solution was poured into water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to give a pale yellow solid. MS: [M+H] + =929.4.

[0496] Example 31

[0497] Add (1r,2R,3S)-N-((6) to a 50mL single-necked flask 3 S,4S,Z)-1 1 -allyl-1 2 -(2-((S)-1-methoxyethyl)-5-(piperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indolyl-6(1,3)-pyridazinecycloundecane-4-yl)-2,3-dimethylcyclopropane-1-carboxamide (130 mg), N,N-dimethylformamide (10 mL), potassium carbonate (87 mg), and potassium iodide (105 mg) were added dropwise, followed by 16-bromo-2,5,8,11,14-pentahexadecane (199 mg). The mixture was stirred at 50 °C for 8 h. The system was poured into water, extracted with ethyl acetate, and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was purified by silica gel column chromatography to give 50 mg of a yellow solid. MS: [M+H] + =1057.6.

[0498] Biological testing

[0499] 1. Inhibitory activity against the proliferation of tumor cells SW620

[0500] The inhibitory activity of the compounds of this invention against the proliferation of colorectal cancer cells SW620 was tested using the CellTiter-Glo reagent method. The specific method is as follows: SW620 cells in logarithmic growth phase were digested, diluted to an appropriate cell density using DMEM complete medium containing 10% FBS and 1% PS, and seeded into 96-well plates for incubation at 5% CO2. A series of concentration gradients of the test compounds were added, and the cells were incubated in a 5% CO2 incubator. After incubation, lysis was detected using the CellTiter-Glo reagent. Chemiluminescence values ​​were measured using a microplate reader, and the data were fitted using Graphpad Prism software to calculate the IC50 of the test compounds. 50 Value. The experimental results are shown in the table below, where "A" indicates the inhibitory activity IC50. 50 <50 nM, "B" indicates inhibitory activity 50 nM ≤ IC 50 <100nM, "C" indicates inhibitory activity IC50 50 ≥100nM.

[0501] Experimental results show that the compound of the present invention has significant inhibitory activity against the proliferation of colorectal cancer cells SW620.

[0502] 2. Inhibitory activity against the proliferation of tumor cells SW620

[0503] Following the method described in Biological Assay 1, the inhibitory activity of the compound against the proliferation of colorectal cancer cells SW620 was tested. The experimental results are shown in the table below, where "A" indicates the inhibitory activity IC50. 50 <50 nM, "B" indicates inhibitory activity 50 nM ≤ IC 50 <100nM, "C" indicates inhibitory activity IC50 50 ≥100nM.

[0504] Experimental results show that the compound of the present invention has significant inhibitory activity against the proliferation of colorectal cancer cells SW620.

[0505] 3. Inhibitory activity against the proliferation of SW620 tumor cells

[0506] Following the method described in Bioassay 1, the CellTiter-Glo reagent method was used to test the inhibitory activity of the compounds of this invention against the proliferation of colorectal cancer cells SW620. The specific method is as follows: SW620 cells in logarithmic growth phase were digested, diluted to a suitable cell density using DMEM complete medium containing 10% FBS and 1% PS, and seeded into 96-well plates for 5% CO2 incubation. A series of test compounds at varying concentrations were added, and the cells were incubated in a 5% CO2 incubator. After incubation, lysis was detected using the CellTiter-Glo reagent. Chemiluminescence values ​​were measured using a microplate reader, and the data were fitted using Graphpad Prism software to calculate the IC50 of the test compounds. 50 Value. The experimental results are shown in the table below, where "A" indicates the inhibitory activity IC50. 50 <50 nM, "B" indicates inhibitory activity 50 nM ≤ IC 50 <100nM, "C" indicates inhibitory activity IC50 50 ≥100nM.

[0507] Experimental results show that the compound of the present invention has significant inhibitory activity against the proliferation of colorectal cancer cells SW620.

[0508] 4. Inhibitory activity against the proliferation of SW620 tumor cells

[0509] Following the method described in Biological Assay 1, the inhibitory activity of the compound against the proliferation of colorectal cancer cells SW620 was tested. The experimental results are shown in the table below.

[0510] The results showed that the compounds of this invention had better inhibitory activity against the proliferation of colorectal cancer cells SW620 than RMC-6236.

[0511] 5. Inhibitory activity against the proliferation of NCI-H358 tumor cells

[0512] The CellTiter-Glo reagent method was used to detect the proliferative activity of antitumor cells. The experimental procedure was as follows: NCI-H358 cells in the logarithmic growth phase were digested and seeded into 96-well plates at appropriate densities and cultured in a cell culture incubator. Culture medium containing a series of concentration gradients of the test substance was added to the experimental wells, and control culture medium was added to the control wells. The plates were incubated in a 5% CO2 incubator. After incubation, CellTiter-Glo reagent was added to each well for lysis detection; the chemiluminescence value was measured using a microplate reader. Data were fitted using Graphpad Prism software, and the IC50 of the test substance was calculated. 50 The values ​​and test results are shown in the table below:

[0513] The results showed that compounds 3-20, 3-26 and 3B-2 had significant inhibitory activity against the proliferation of NCI-H358 lung cancer cells, and were significantly better than RMC-6236.

[0514] 6. Inhibitory activity of the compound on the proliferation of non-KRAS mutant tumor cells

[0515] The CellTiter-Glo assay was used to detect the anti-tumor cell proliferation activities of compounds 3-20 and 3-26 against COLO201, HT29, A375, MCF7, NCI-H520, NCI-H1299, and HS578T cells. Tumor cells in logarithmic growth phase were digested and seeded into 96-well plates at appropriate densities and incubated in a cell culture incubator. Experimental wells were added with culture medium containing a series of concentration gradients of the test compounds, and control wells were added with control culture medium. Incubation was performed in a 5% CO2 incubator. After incubation, CellTiter-Glo reagent was added to each well for lysis detection; chemiluminescence values ​​were measured using a microplate reader. Data were fitted using Graphpad Prism software, and the IC50 values ​​of the test compounds were calculated. 50 value.

[0516] The results showed that compounds 3-20 and 3-26 had an IC50 inhibitory activity against the proliferation of the aforementioned non-KRAS mutant tumor cells. 50 All values ​​are greater than 1000 nM, indicating that it has good selectivity.

[0517] 7. Pharmacodynamic Trial of AsPC-1 Subcutaneous Xenograft Tumor Model of Pancreatic Cancer Cells

[0518] AsPC-1 cells in the logarithmic growth phase, stable in vitro for 2–3 weeks, were collected, washed, thoroughly mixed with a substrate gel, and inoculated into female Balb / c-nu mice. The cells were allowed to harden and grow to 200–250 mm. 3 Six animals were randomly divided into a solvent control group and a compound 3-20 group (3 mg / kg) in each group. The drugs were administered orally by gavage once a day for 21 consecutive days.

[0519] Daily observations should be conducted, including but not limited to the administration site, physical appearance, general behavior, mental state, mortality, and other abnormalities.

[0520] Tumor volume (TV) = 0.5 * (tumor long diameter * tumor short diameter * tumor short diameter). Tumor growth inhibition rate (TGI) = [1 - (mean tumor volume at the end of treatment - mean tumor volume at the beginning of treatment) / (mean tumor volume at the end of control - mean tumor volume at the beginning of control)] × 100%.

[0521] "+" indicates a tumor inhibition rate of <60%; "++" indicates a tumor inhibition rate of 60% to 100%; "+++" indicates a tumor inhibition rate of >100%.

[0522] Experimental results showed that compound 3-20 of this invention significantly inhibited the growth of subcutaneous xenografts of pancreatic cancer cells (AsPC-1) in nude mice. During the administration period, the animals in each treatment group maintained normal diet, weight, and activity levels, demonstrating good safety.

[0523] 8. Pharmacodynamic study of SW620 subcutaneous xenograft model of colorectal cancer cells

[0524] SW620 cells in the logarithmic growth phase, stable in vitro for 2–3 weeks, were collected, washed, thoroughly mixed with a substrate gel, and inoculated into female Balb / c-nu mice. The inoculated cells were allowed to harden and grow to 200–250 mm. 3 Six animals were randomly divided into three groups: a solvent control group, a compound 3-20 group (3 mg / kg), and an RMC-6236 group (3 mg / kg), with six animals in each group. The drugs were administered orally by gavage once a day for 25 consecutive days.

[0525] Daily observations should be conducted, including but not limited to the administration site, physical appearance, general behavior, mental state, mortality, and other abnormalities.

[0526] Tumor volume (TV) = 0.5 * (tumor long diameter * tumor short diameter * tumor short diameter). Tumor growth inhibition rate (TGI) = [1 - (mean tumor volume at the end of treatment - mean tumor volume at the beginning of treatment) / (mean tumor volume at the end of control - mean tumor volume at the beginning of control)] × 100%.

[0527] "+" indicates a tumor inhibition rate of <60%; "++" indicates a tumor inhibition rate of 60% to 80%; "+++" indicates a tumor inhibition rate of 80% to 100%; and "++++" indicates a tumor inhibition rate of >100%.

[0528] Experimental results showed that compound 3-20 had a significant inhibitory effect on the growth of subcutaneous xenografts of colorectal cancer cells SW620 in nude mice, and was superior to RMC-6236.

[0529] 9. Pharmacodynamic test of NCI-H358 subcutaneous xenograft tumor model of lung cancer cells

[0530] Collect NCI-H358 cells in logarithmic growth phase that have been stably cultured in vitro for 2–3 weeks. After washing, mix thoroughly with the inoculation matrix gel and inoculate into female Balb / c-nu mice. Allow the inoculated cells to harden and grow to 200–250 mm. 3 Six animals were randomly divided into three groups: a solvent control group, a compound 3-20 group (3 mg / kg), and an RMC-6236 group (3 mg / kg), with six animals in each group. The drugs were administered orally by gavage once a day for 26 consecutive days.

[0531] Daily observations should be conducted, including but not limited to the administration site, physical appearance, general behavior, mental state, mortality, and other abnormalities.

[0532] Tumor volume (TV) = 0.5 * (tumor long diameter * tumor short diameter * tumor short diameter). Tumor growth inhibition rate (TGI) = [1 - (mean tumor volume at the end of treatment - mean tumor volume at the beginning of treatment) / (mean tumor volume at the end of control - mean tumor volume at the beginning of control)] × 100%.

[0533] "+" indicates a tumor inhibition rate of <60%; "++" indicates a tumor inhibition rate of 60% to 80%; "+++" indicates a tumor inhibition rate of 80% to 100%; and "++++" indicates a tumor inhibition rate of >100%.

[0534] The results showed that compound 3-20 significantly inhibited the growth of NCI-H358 lung cancer cell subcutaneous xenografts in nude mice, and was significantly better than RMC-6236.

Claims

1. A compound of Formula (II), a stereoisomer, a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein, Ring B is selected from the following structures: wherein 1 is attached to the indole ring and 3 is attached to the alkylene group; R 1a , R 1b , R 1c , R 2a , R 2b , R 2c , R 2d , R 2e , R 2f are each independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C 1-6 alkyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 deuteroalkenyl, C 2-6 alkynyl, C 2-6 deuteroalkynyl, or C 3-8 cycloalkyl; Ring C is selected from the following structures: wherein 1 is attached to the -C(O)- and 3 is attached to the -C(O)O-; each R3is independently selected from hydrogen, deuterium, halogen, C 1-6 alkyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, or C 1- 6alkoxy; n is selected from 0, 1, 2, 3, 4 or 5; X is selected from CR 4e or a nitrogen atom; R 4a , R 4b , R 4c , R 4d , R 4e are each independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, -OR a , -SR a , -NR a R b , -C(O)R a , -CH(CH3)(OCH3), -CH(CH3)(OCD3), C 1-6 alkyl, C 1-6 deuteroalkyl, C 1- 6haloalkyl, C 1-6 heteroalkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 deuteroalkenyl, C 2-6 alkynyl, C 2-6 deuteroalkynyl, C 3-8 cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 aryl, or 5-10 membered heteroaryl, wherein the alkyl, heteroalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is further substituted with one or more substituents optionally selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, oxo, -OR a , -SR a , -NR a R b , -C(O)R a , C 1-6 alkyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 heteroalkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 deuteroalkenyl, C 2-6 alkynyl, C 2-6 deuteroalkynyl, C 3-8 cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 aryl, or 5-10 membered heteroaryl; R a , R b are each independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C 1-6 alkyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 heteroalkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 deuteroalkenyl, C 2-6 alkynyl, C 2-6 deuteroalkynyl, C 3-8 cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 aryl, or 5-10 membered heteroaryl, wherein the alkyl, heteroalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is further substituted with one or more substituents optionally selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, oxo, -OR a , -SR a , -NR a R b , -C(O)R a , C 1-6 alkyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 deuteroalkenyl, C 2-6 alkynyl, C 2-6 deuteroalkynyl, C 3-8 cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 aryl, or 5-10 membered heteroaryl; R5, R 6a R 6b R 6c R 6d R 6e Each is independently selected from hydrogen, deuterium, halogens, and carbon. 1-6 Alkyl, C 1-6 Deuterated alkyl or C 1-6 Halogenated alkyl; or R 6a and R 6b R 6d and R 6e Together with the carbon atom it is attached to, they form C 3-8 Cycloalkyl or 3-10 membered heterocycloalkyl; or one of the R 6a and R 6c Together with the atoms attached to it, they form C 3-8 Cycloalkyl or 3-10 membered heterocyclic alkyl; p is selected from 1, 2 or 3; R 9a , R 9b , R 9c , R 9d , R 9e are each independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C 1-6 alkyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 deuteroalkenyl, C 2-6 alkynyl, C 2-6 deuteroalkynyl, or C 3-8 cycloalkyl; or R 9a and R 9b , R 9c and R 9d together with the carbon atom to which they are attached form C=CH2, C=O, or C 3-8 cycloalkyl; R 11a , R 11b , R 11c , R 11d , R 11e , R 11f , R 12a , R 12b each independently is selected from hydrogen, deuterium, halogen, hydroxyl, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, or C 1-6 alkoxy.

2. A compound represented by formula (II-1), a stereoisomer, a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein, Y1is selected from a nitrogen atom or CH; X1is selected from a nitrogen atom or CR 4a ; M is selected from a chemical bond, an oxygen atom, a sulfur atom, or NR 8c ; Ring C is selected from the following structures: 1 is attached to the -C(O)- and 3 is attached to the -C(O)O-; R 1a , R 1b , R 1c , R 2a , R 4a , R 4b , R 4c are each independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C 1-6 alkyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 2-6 alkenyl, or C 2-6 deuteroalkenyl; R5, R 10 each independently selected from hydrogen, deuterium, C 1-6 alkyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 deuteroalkenyl, C 2-6 alkynyl, C 2-6 deuteroalkynyl, or C 3-6 cycloalkyl; R 7a , R 7b are each independently selected from hydrogen, deuterium, C 1-6 alkyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 deuteroalkenyl, C 2-6 alkynyl, C 2-6 deuteroalkynyl, or C 3-6 cycloalkyl; R 8a , R 8b , R 8c are each independently selected from hydrogen, deuterium, halogen, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 halogenated alkyl, or C 1-6 alkoxy; or R 8a and R 8b together with the atom to which they are attached form a C 3-8 cycloalkyl; R 9a R 9b R 9c R 9d R 9e Each is independently selected from hydrogen, deuterium, halogens, and carbon. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1- 6-Hydroalkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 Deuterated alkenyl or C 3-8 cycloalkyl; or R 9a and R 9b R 9a and R 9c Each of them, together with the atoms they are connected to, forms C. 3-8 cycloalkyl or 3-8 membered heterocyclic alkyl; R 10a , R 10c , R 10e , R 10g are each independently selected from hydrogen, deuterium, halogen, C 1-6 alkyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, or C 1-6 alkoxy; or R 10e and R 10g , together with the atoms to which they are attached, form an 8-12 membered heterocycloalkyl group; R 11a , R 11b , R 11c , R 11d , R 11e , R 11f , R 12a , R 12b are each independently selected from hydrogen, deuterium, halogen, C 1-6 alkyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 deuteroalkenyl, C 2-6 alkynyl, C 2-6 deuteroalkynyl, C 3-6 cycloalkyl, C 6-10 aryl, 3-10 membered heterocycloalkyl, or 5-10 membered heteroaryl; or R 11a and R 11b , R 11c and R 11d , R 11e and R 11f , R 12a and R 12b are each taken together with the carbon atom to which they are attached to form a C 3-6 cycloalkyl; q is selected from 1, 2, 3 or 4.

3. A compound of formula (III), a stereoisomer, a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein Ring B is selected from the following structures: wherein 1 is attached to the indole ring and 3 is attached to the alkylene group; R 1a , R 1b , R 1c , R 2a , R 2b , R 2c , R 2d , R 2e , R 2f are each independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C 1-6 alkyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 deuteroalkenyl, C 2-6 alkynyl, C 2-6 deuteroalkynyl, or C 3-8 cycloalkyl; Ring C is selected from the following structures: wherein 1 is attached to the -C(O)- and 3 is attached to the -C(O)O-; each R3is independently selected from hydrogen, deuterium, halogen, C 1-6 alkyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, or C 1- 6alkoxy; n is selected from 0, 1, 2, 3, 4 or 5; X is selected from CR 4e or a nitrogen atom; R 4a , R 4b , R 4d , R 4e are each independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, -OR a , -SR a , -NR a R b , -C(O)R a , -CH(CH3)(OCH3), -CH(CH3)(OCD3), C 1-6 alkyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 heteroalkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 deuteroalkenyl, C 2-6 alkynyl, C 2-6 deuteroalkynyl, C 3- cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 aryl, or 5-10 membered heteroaryl, wherein the alkyl, heteroalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is further substituted with one or more substituents optionally selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, oxo, -OR a , -SR a , -NR a R b , -C(O)R a , C 1-6 alkyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 deuteroalkenyl, C 2-6 alkynyl, C 2-6 deuteroalkynyl, C 3-8 cycloalkyl, or 3-10 membered heterocycloalkyl; R a , R b are each independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C 1-6 alkyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 deuteroalkenyl, C 2-6 alkynyl, C 2-6 deuteroalkynyl, C 3-8 cycloalkyl, or 3-10 membered heterocycloalkyl; R5, R 6a R 6b R 6c R 6d R 6e Each is independently selected from hydrogen, deuterium, halogens, and carbon. 1-6 Alkyl, C 1-6 Deuterated alkyl or C 1-6 Halogenated alkyl; or R 6a and R 6b R 6d and R 6e Together with the carbon atom it is attached to, they form C 3-8 cycloalkyl; p is selected from 1, 2 or 3; R 9a , R 9b , R 9c , R 9d , R 9e are each independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C 1-6 alkyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 deuteroalkenyl, C 2-6 alkynyl, C 2-6 deuteroalkynyl, or C 3-8 cycloalkyl; or R 9a and R 9b together with the carbon atom to which they are attached form C=CH2or C 3-8 cycloalkyl; R 10a , R 10b , R 10c , R 10d , R 10 are each independently selected from hydrogen, deuterium, C 1-6 alkyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 heteroalkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 deuteroalkenyl, C 2-6 alkynyl, C 2-6 deuteroalkynyl, C 3- 8cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 aryl, or 5-10 membered heteroaryl; or R 10 and R 10c , R 10b and R 10c , together with the atom to which they are attached, form a 3-10 membered heterocycloalkyl; R 11a , R 11b , R 11c , R 11d , R 11e , R 11f , R 12a , R 12b are each independently selected from hydrogen, deuterium, halogen, hydroxyl, C 1-6 alkyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, or C 1-6 alkoxy.

4. A compound of Formula (IIIA), a stereoisomer, a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein, Ring C is selected from the following structures: wherein 1 is attached to the -C(O)- and 3 is attached to the -C(O)O-; R 1a , R 1b , R 1c , R 2a are each independently selected from hydrogen, deuterium, halogen, C 1-6 alkyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 2-6 alkenyl, or C 2-6 deuteroalkenyl; X is selected from CH or a nitrogen atom; R 4b , R 4d are each independently selected from hydrogen, deuterium, halogen, cyano, -OR a , -SR a , -NR a R b , -C(O)R a , C 1-6 1-6 alkyl, C 1-6 1-6 deuterated alkyl, C 1-6 1-6 halogenated alkyl, C 2-6 2-6 alkenyl, C 2-6 2-6 deuterated alkenyl, C 2-6 2-6 alkynyl, C 2-6 2-6 deuterated alkynyl, C 3- 8 cycloalkyl, or 3-10 membered heterocycloalkyl; R5, R 6a , R 6b , R 6c , R 6d , R 6e are each independently selected from hydrogen, deuterium, halogen, C 1-6 alkyl, C 1-6 deuterated alkyl, or C 1-6 halogenated alkyl, or R 6a and R 6b together with the carbon atom to which they are attached form a C 3-8 cycloalkyl; R 9a , R 9b , R 9c , R 9d , R 9e are each independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, C 1-6 alkyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 deuteroalkenyl, C 2-6 alkynyl, C 2-6 deuteroalkynyl, or C 3-8 cycloalkyl; X2is selected from CR 10i , SiR 10i or a nitrogen atom; R 10a , R 10b , R 10c , R 10d , R 10i are each independently selected from hydrogen, deuterium, C 1-6 alkyl, C 1-6 deuteroalkyl, or C 1-6 haloalkyl; R 10 selected from hydrogen, deuterium, -NR a R b , -OR a , C 1-6 alkyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 deuteroalkenyl, C 2-6 alkynyl, C 2-6 deuteroalkynyl, C 3-8 cycloalkyl, or 3-10 membered heterocycloalkyl; R a , R b are each independently selected from hydrogen, deuterium, C 1-6 alkyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 deuteroalkenyl, C 2-6 alkynyl, C 2-6 deuteroalkynyl, C 3-8 cycloalkyl, or 3-10 membered heterocycloalkyl; R 11a , R 11b , R 11c , R 11d , R 11e , R 11f , R 12a , R 12b , R 13a , R 13b , R 14 are each independently selected from hydrogen, deuterium, halogen, C 1-6 alkyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, or C 3-8 cycloalkyl; p is selected from 1, 2 or 3.

5. A compound represented by formula (III-1), a stereoisomer, a tautomer thereof, or a pharmaceutically acceptable salt thereof, ###0005### (III-1) wherein Ring C is selected from the following structures: wherein 1 is attached to the -C(O)- and 3 is attached to the -C(O)O-; R 1a , R 1b , R 1c , R 2a are each independently selected from hydrogen, deuterium, halogen, C 1-6 alkyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 2-6 alkenyl, or C 2-6 deuteroalkenyl; X is selected from CH or a nitrogen atom; R 4a , R 4b , R 4d are each independently selected from hydrogen, deuterium, halogen, cyano, -OR a , -SR a , -NR a R b , -C(O)R a , -CH(CH3)(OCH3), -CH(CH3)(OCD3), C 1-6 alkyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 deuteroalkenyl, C 2-6 alkynyl, C 2-6 deuteroalkynyl, C 3-8 cycloalkyl, or 3-10 membered heterocycloalkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl are further substituted with one or more substituents optionally selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, oxo, -OR a , -SR a , -NR a R b , -C(O)R a , C 1-6 alkyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 2- 6alkenyl, C 2-6 deuteroalkenyl, C 2-6 alkynyl, C 2-6 deuteroalkynyl, C 3-8 cycloalkyl, or 3-10 membered heterocycloalkyl; R a , R b are each independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C 1-6 alkyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 deuteroalkenyl, C 2-6 alkynyl, C 2-6 deuteroalkynyl, C 3-8 cycloalkyl, or 3-10 membered heterocycloalkyl; R 6a , R 6b , R 6c , R 6d , R 6e are each independently selected from hydrogen, deuterium, halogen, C 1-6 alkyl, C 1-6 deuteroalkyl, or C 1- 6haloalkyl; or R 6a and R 6b together with the carbon atom to which they are attached form a C 3-8 cycloalkyl; R 9a , R 9b , R 9c , R 9d , R 9e are each independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, C 1-6 alkyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 deuteroalkenyl, C 2-6 alkynyl, C 2-6 deuteroalkynyl, or C 3-8 cycloalkyl; R 10a , R 10b , R 10c , R 10d are each independently selected from hydrogen, deuterium, C 1-6 alkyl, C 1-6 deuteroalkyl, or C 1-6 haloalkyl; R 10 selected from hydrogen, deuterium, C 1-6 alkyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 heteroalkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 deuteroalkenyl, C 2-6 alkynyl, C 2-6 deuteroalkynyl, C 3-8 cycloalkyl or 3-10 membered heterocycloalkyl; p is selected from 1, 2 or 3.

6. A compound of Formula (IIIA-1), a stereoisomer, a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein Ring C is selected from the following structures: wherein 1 is attached to the -C(O)- and 3 is attached to the -C(O)O-; R 4b , R 4d are each independently selected from hydrogen, deuterium, halogen, C 1-6 alkyl or C 1-6 deuterated alkyl; R 6a , R 6b , R 6c , R 6d , R 6e are each independently selected from hydrogen, deuterium, halogen, C 1-6 alkyl, C 1-6 deuteroalkyl, or C 1- 6haloalkyl; R 9a , R 9c are each independently selected from the group consisting of C 1-6 alkyl, C 1-6 deuteroalkyl or C 1-6 haloalkyl; R 10a , R 10b , R 10c , R 10d are each independently selected from hydrogen, deuterium, C 1-6 alkyl, C 1-6 deuteroalkyl, or C 1-6 haloalkyl; R 10 selected from hydrogen, -NR a R b , -OR a , C 1-6 alkyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 heteroalkyl, C 1- 6alkoxy, or C 3-8 cycloalkyl; R a , R b are each independently selected from hydrogen, C 1-6 alkyl, C 1-6 deuteroalkyl, or C 1-6 haloalkyl; R 11a , R 11b , R 11e , R 11f are each independently selected from hydrogen or deuterium; R 13a selected from C 1-6 alkyl, C 1-6 deuteroalkyl or C 1-6 haloalkyl; p is selected from 1, 2 or 3.

7. A compound of the following formula, a stereoisomer, a tautomer thereof, or a pharmaceutically acceptable salt thereof, 8. A compound of the following formula, a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, 9. A compound of formula (IB), a stereoisomer, a tautomer thereof or a pharmaceutically acceptable salt thereof, wherein X1is selected from a nitrogen atom or CR 4a ; Y is selected from a nitrogen atom or CR 10i ; each W is independently selected from an oxygen atom, a sulfur atom, -S(O)-, -S(O)2-, or -P(O)(C 1-6 alkyl)-; Ring B is selected from substituted or unsubstituted cycloalkyl, heterocycloalkyl, aryl or heteroaryl, preferably from the following structures: 1 is attached to the indole ring and 3 is attached to the alkylene group; Ring C is selected from substituted or unsubstituted heterocycloalkyl, preferably from the following structures: 1 is attached to the -C(O)- and 3 is attached to the -C(O)O-; each R 1a , R 1b , R 1c , R 2a , R 2b , R 2c , R 2d , R 2e , R 2f , R 2g , R3, R 4a , R 4b , R 4c is each independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C 1-6 alkyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 heteroalkyl, C 2-6 alkenyl, C 2-6 deuteroalkenyl, C 2-6 alkynyl, C 2-6 deuteroalkynyl, C 3-6 cycloalkyl, C 6-10 aryl, 3-8 membered heterocycloalkyl, or 5-10 membered heteroaryl; R5, R6, R 7a , R 7b are each independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C 1-6 alkyl, C 1-6 alkoxy C 1-6 alkyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 heteroalkyl, C 2-6 alkenyl, C 2-6 deuteroalkenyl, C 2-6 alkynyl, C 2-6 deuteroalkynyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl C 1-6 alkyl, C 6-10 aryl, 3-8 membered heterocycloalkyl, or 5-10 membered heteroaryl; R 9a , R 9b , R 9c , R 9d , R 9e are each independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C 1-6 alkyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 heteroalkyl, C 2-6 alkenyl, C 2-6 deuteroalkenyl, C 2-6 alkynyl, C 2-6 deuteroalkynyl, C 3-8 cycloalkyl, C 6-10 aryl, 3-8 membered heterocycloalkyl, or 5-10 membered heteroaryl; or R 9a and R 9b , R 9a and R 9c each, together with the carbon atom to which they are attached, form a C 3-8 cycloalkyl or 3-8 membered heterocycloalkyl; R 10a , R 10b , R 10c , R 10d , R 10e , R 10f , R 10g , R 10h , R 10i are each independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C 1-6 alkyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 heteroalkyl, C 2-6 alkenyl, C 2-6 deuteroalkenyl, C 2-6 alkynyl, C 2-6 deuteroalkynyl, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 aryl, or 5-10 membered heteroaryl; or R 10e and R 10g , together with the atom to which they are attached, form an 8-12 membered heterocycloalkyl; R 11a , R 11b , R 11c , R 11d , R 11e , R 11f , R 12a , R 12b , R 12c , R 13 are each independently selected from hydrogen, deuterium, halogen, C 1-6 alkyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 heteroalkyl, C 2-6 alkenyl, C 2-6 deuteroalkenyl, C 2-6 alkynyl, C 2-6 deuteroalkynyl, C 3-6 cycloalkyl, C 6-10 aryl, 3-8 membered heterocycloalkyl, or 5-10 membered heteroaryl; or R 11a and R 11b , R 11c and R 11d , R 11e and R 11f , R 12a and R 12b are each taken together with the carbon atom to which they are attached to form a C 3-6 cycloalkyl or 3-8 membered heterocycloalkyl; n is selected from an integer from 1 to 20; q is selected from 0, 1, 2, 3, 4 or 5.

10. A compound of Formula (IIB), stereoisomers, tautomers or pharmaceutically acceptable salts thereof, wherein, M is selected from a chemical bond, C 1-6 alkylene or C 1-6 heteroalkylene; each W is independently selected from an oxygen atom, a sulfur atom, -S(O)- or -S(O)2-; X1is selected from a nitrogen atom or CR 4a ; Ring C is selected from the following structures: 1 is attached to the -C(O)- and 3 is attached to the -C(O)O-; R 1a , R 1b , R 1c , R 2a , R 4a , R 4b , R 4c , each R5is independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C 1-6 alkyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 heteroalkyl, C 2-6 alkenyl, or C 2-6 deuteroalkenyl; each R 6a , R 6b , R 6c , R 6d , R 6e is each independently selected from hydrogen, deuterium, halogen, C 1-6 alkyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, or C 1-6 heteroalkyl; or R 6a and R 6b , R 6d and R 6e are each taken together with their intervening atoms to form a C 3-8 cycloalkyl; R 7a , R 7b are each independently selected from hydrogen, deuterium, C 1-6 alkyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 heteroalkyl, C 2-6 alkenyl, C 2-6 deuteroalkenyl, C 2-6 alkynyl, C 2-6 deuteroalkynyl, or C 3-6 cycloalkyl; R 9a R 9b R 9c R 9d R 9e Each is independently selected from hydrogen, deuterium, halogens, and carbon. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1- 6-Hydroalkyl, C 1-6 Alkoxy, C 1-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 Deuterated alkenyl or C 3-8 cycloalkyl; or R 9a and R 9b R 9a and R 9c Each of them, together with the atoms they are connected to, forms C. 3-8 cycloalkyl or 3-8 membered heterocyclic alkyl; R 10a , R 10c , R 10e , R 10g are each independently selected from hydrogen, deuterium, halogen, C 1-6 alkyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, or C 1-6 heteroalkyl; or R 10e and R 10g , together with the atoms to which they are attached, form an 8-12 membered heterocycloalkyl group; R 11a , R 11b , R 11c , R 11d , R 11e , R 11f , R 12a , R 12b , R 13 are each independently selected from hydrogen, deuterium, halogen, C 1- 6alkyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, or C 1-6 heteroalkyl; or R 11a and R 11b , R 11c and R 11d , R 11e and R 11f , R 12a and R 12b each together with the carbon atom to which they are attached form a C 3-6 cycloalkyl; p is selected from 1, 2, 3 or 4; n is selected from an integer from 0 to 20.

11. A compound of Formula (IIIB), a stereoisomer, a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein, M is selected from -(CH2)2- or -(CH2)2-O-(CH2)2-; each W is independently selected from an oxygen atom or -S(O)2-; Ring C is selected from the following structures: 1 is attached to the -C(O)- and 3 is attached to the -C(O)O-; R 7a , R 7b are each independently selected from the group consisting of C 1-6 alkyl, C 1-6 deuteroalkyl or C 1-6 haloalkyl; each R is independently selected from hydrogen, deuterium, halogen, C 6a , R 6b , R 6c , R 6d , R 6e is independently selected from hydrogen, deuterium, halogen, C 1-6 alkyl, C 1-6 deuteroalkyl, or C 1-6 haloalkyl; R 9a , R 9c are each independently selected from hydrogen, deuterium, halogen, C 1-6 alkyl, C 1-6 deuteroalkyl, or C 1-6 haloalkyl; R 4b , R 4c , R 10a , R 10c , R 10e , R 10g are each independently selected from hydrogen, deuterium, halogen, C 1-6 alkyl or C 1-6 deuteroalkyl; R 11a , R 11b , R 11e , R 11f are each independently selected from hydrogen, deuterium, halogen, C 1-6 alkyl or C 1-6 deuteroalkyl; R 13 selected from hydrogen, C 1-6 alkyl or C 1-6 deuteroalkyl; p is selected from 1, 2 or 3; n is selected from an integer from 0 to 10.

12. A compound of Formula (IVB), a stereoisomer, a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein, Ring C is selected from the following structures: 1 is attached to the -C(O)- and 3 is attached to the -C(O)O-; R 7a , R 7b are each independently selected from the group consisting of C 1-6 alkyl, C 1-6 deuteroalkyl or C 1-6 haloalkyl; each R 6a , R 6b , R 6c , R 6d , R 6e is independently selected from hydrogen, deuterium, halogen, C 1-6 alkyl, C 1-6 deuteroalkyl, or C 1-6 haloalkyl; R 9a , R 9c are each independently selected from hydrogen, deuterium, halogen, C 1-6 alkyl, C 1-6 deuteroalkyl, or C 1-6 haloalkyl; R 4b , R 4c , R 10a , R 10c , R 10e , R 10g are each independently selected from hydrogen, deuterium, halogen, C 1-6 alkyl or C 1-6 deuteroalkyl; R 11a , R 11b , R 11e , R 11f are each independently selected from hydrogen, deuterium, halogen, C 1-6 alkyl or C 1-6 deuterated alkyl; R 13 selected from hydrogen, C 1-6 alkyl or C 1-6 deuteroalkyl; p is selected from 1, 2 or 3; n is selected from an integer from 1 to 10.

13. A compound of the following formula, a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, 14. A pharmaceutical composition comprising a therapeutically effective amount of a compound of any one of claims 1 to 13, a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

15. Use of a compound of any one of claims 1 to 13, a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 14 for the manufacture of a medicament for the prevention and / or treatment of cancer.

16. Use of a compound of any one of claims 1 to 13, a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 14 for the manufacture of a medicament for the prevention and / or treatment of RAS mutation-mediated cancer.

17. Use of a compound according to any one of claims 1 to 13, a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 14, for the manufacture of a medicament for the prevention and / or treatment of a KRAS mutation-mediated cancer.

18. The use according to any one of claims 15 to 17, wherein the cancer is selected from the group consisting of pancreatic cancer, colorectal cancer, lung cancer, kidney cancer, liver cancer, breast cancer, esophageal cancer, acute myeloid leukemia, multiple myeloma, thyroid adenocarcinoma, squamous cell carcinoma, gastric cancer, renal cell carcinoma, sarcoma, cholangiocarcinoma, prostate cancer, ovarian cancer, hematological cancer, MYH-associated polyposis cancer, uterine cancer, mesothelioma, cervical cancer, bladder cancer, and the like.

19. A method of inhibiting a RAS protein in a cell, the method comprising contacting the cell with an effective amount of a compound according to any one of claims 1 to 13, a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 14.

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