Tetra-heterocyclic compound as well as preparation method and application thereof

Abstract

The invention discloses a tetra-heterocyclic compound as well as a preparation method and application thereof. The invention provides a compound as shown in a formula I, and a stereoisomer or pharmaceutically acceptable salt thereof. The compound has good inhibitory activity on KRAS mutation, for example, the compound has good proliferation inhibitory activity on NCI-H358, AsPC-1 and Capan-1 cancer cells containing KRAS mutation, has relatively weak proliferation inhibitory activity on KRAS wild PC-9 cells, has good selectivity, and is expected to treat and / or prevent KRAS mediated diseases.

Description

Technical Field

[0001] This invention relates to a tetracyclic heterocyclic compound, its preparation method, and its applications. Background Technology

[0002] RAS protein is a 21 kDa guanine trinucleotide phosphate (GTP)-binding protein located on the cell membrane, composed of 188 or 189 amino acids. The activity state of RAS protein influences cell growth, differentiation, cytoskeleton, protein transport, and secretion, and its activity is regulated by binding to GTP or guanine dinucleotide phosphate (GDP). When RAS protein binds to GDP, it is in an "inactive" state; when stimulated by specific upstream cell growth factors, guanine nucleotide exchange factor (GEF) catalyzes the release of GDP from RAS protein, which then binds to GTP, placing it in an "activated" state. GTP-bound RAS protein can activate downstream proteins and downstream signaling pathways. RAS protein itself possesses weak GTPase activity, capable of hydrolyzing GTP to GDP, thus achieving the transition from an activated to an inactive state. This hydrolysis process also requires the participation of GTPase activator protein (GAP), which interacts with RAS protein and significantly enhances its ability to hydrolyze GTP to GDP. Any mutation in the RAS protein that affects its own GTPase activity, its interaction with GAP, or its ability to hydrolyze GTP to GDP will result in the RAS protein being in a prolonged activated state. This prolonged activated RAS protein continues to send growth signals to downstream proteins, leading to continuous cell growth and differentiation, which may ultimately result in cancer. The RAS gene family has three members: KRAS, NRAS, and HRAS.

[0003] KRAS mutations are the most common oncogenic drivers, present in various cancers: lung adenocarcinoma (32%), colorectal cancer (41%), and pancreatic cancer (86%). G12 mutations at codon 12 are the most common KRAS mutations; for example, in KRAS-mutant lung adenocarcinoma, colorectal cancer, and pancreatic cancer, G12 mutations account for 85%, 68%, and 91%, respectively. G12 mutations include G12C, G12D, G12V, and G12R forms. In patients with KRAS G12-mutant lung adenocarcinoma, colorectal cancer, and pancreatic cancer, the proportion of patients with KRAS G12 mutations is 17%, 45%, and 45%, respectively, while the proportion of patients with KRAS G12V mutations is 23%, 30%, and 35%, respectively (e.g., see Moore, AR et al. Nat Rev Drug Discov 19, 533 (2020)).

[0004] Currently, only inhibitors targeting KRAS G12C mutations are on the market, and inhibitors targeting KRAS G12D mutations have entered clinical trials. However, the patient population that benefits from KRAS G12C inhibitors is only a small fraction of the population carrying KRAS mutations. More than 85% of KRAS-mutant cancers still lack effective treatments (see Marco, HH et al. CancerDiscov 12, 924 (2022)). Patients still need therapies targeting other KRAS mutations (such as G12V, G12R, G12A).

[0005] Pan-KRAS inhibitors can inhibit a variety of KRAS mutants and have the potential to treat a wider range of patient populations, representing a significant unmet clinical need. Summary of the Invention

[0006] The technical problem this invention aims to solve is the lack of structural diversity in existing Pan-KRAS inhibitors. This invention provides a tetracyclic heterocyclic compound, its preparation method, and its applications. The compound exhibits good inhibitory activity against KRAS mutations, such as strong inhibitory activity against the proliferation of KRAS-mutant NCI-H358, AsPC-1, and Capan-1 cancer cells, while showing relatively weak inhibitory activity against the proliferation of wild-type KRAS PC-9 cells. This compound demonstrates good selectivity and holds promise for the treatment and / or prevention of KRAS-mediated diseases.

[0007] This invention provides a compound of Formula I, its stereoisomer, or a pharmaceutically acceptable salt thereof.

[0008]

[0009] in,

[0010] X1 is C(R) 3 )2, O, S, S(O), S(O)2 or NR 4 ;

[0011] X2 and X3 are independently O, S, and CR, respectively. 5A , N or NR 5B ;

[0012] X4, X8, and X9 are each independently C or N;

[0013] It is a single or double bond, ring B is aromatic, and at least one of X2, X3, X4, X8, and X9 is O, S, N, or NR. 5B ;

[0014] X5 is C(R) 6 )2 or NR 7;

[0015] X6 and X7 are each independently C(R) 8 )2;

[0016] m can be 0, 1, 2, 3, 4, or 5;

[0017] n is 0, 1, or 2;

[0018] Each R 3 R 5A and R 8 Each can be independently represented by hydrogen, deuterium, halogen, cyano, nitro, hydroxyl, or -N(R) 9 )2、-S(O)2R 10 -C(O)R 10 -C(O)OR 10 -OC(O)R 10 -CON(R) 10 )2、-S(O)2N(R 10 2. C 1-6 Alkyl, with one or more R 3a Replacement C 1-6 Alkyl, -OC 1-6 Alkyl, with one or more R 3b Replacement -OC 1-6 Alkyl, -SC 1-6 Alkyl, with one or more R 3c Replacement -SC 1-6 Alkyl, C 2-6 alkenyl, with one or more R 3d Replacement C 2-6 alkenyl, C 2-6 alkynyl group, with one or more R 3e Replacement C 2-6 alkynyl group, C 3-12 cycloalkyl, with one or more R 3f Replacement C 3-12 cycloalkyl, C 3-12 Cycloalkenyl, with one or more R 3g Replacement C 3-12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, with one or more R 3h Substituted 3-12-membered heterocyclic alkyl, 3-12-membered heterocyclic alkenyl, or substituted with one or more R 3i Substituted 3-12 membered heterocyclic alkenyl groups, C 6-10 aryl, with one or more R 3j Replacement C 6-10 aryl, 5-10 heteroaryl, or with one or more R 3k Substituted 5-10 heteroaryl groups;

[0019] Each R 3a R 3b R 3c R 3d R 3e R 3f R 3g R 3h R 3i R 3j and R 3k Each can be independently represented as deuterium, halogen, cyano, hydroxyl, oxo (=O), -NH2, or -NH(C). 1-6 alkyl), -N(C) 1-6 Alkyl)2, C 1-6 Alkyl groups, C substituted with one or more halogens 1-6 Alkyl groups, C groups substituted with one or more hydroxyl groups 1-6 Alkyl groups, C atoms substituted with one or more deuterium atoms 1-6 Alkyl, -OC 1-6 Alkyl groups, -OC groups substituted with one or more halogens 1-6 Alkyl, -SC 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 cycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, 3-12 membered heterocyclic alkenyl, C 6-10 Aryl or 5-10 heteroaryl groups;

[0020] Or, two R atoms on the same ring carbon atom 8 Formation of oxygen groups;

[0021] Each R 5B Independently hydrogen, hydroxyl, cyano, -N(R) 9 )2、-S(O)2R 10 -C(O)R 10 -C(O)OR 10 -CON(R) 10 )2、-S(O)2N(R 10 2. C 1-6 Alkyl, with one or more R 5b1 Replacement C 1-6 Alkyl, C 2-6 alkenyl, with one or more R 5b2 Replacement C 2-6 alkenyl, C 2-6 alkynyl group, with one or more R 5b3 Replacement C 2-6 alkynyl group, C 3-12 cycloalkyl, with one or more R 5b4 Replacement C 3-12 cycloalkyl, C3-12 Cycloalkenyl, with one or more R 5b5 Replacement C 3-12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, with one or more R 5b6 Substituted 3-12-membered heterocyclic alkyl, 3-12-membered heterocyclic alkenyl, or substituted with one or more R 5b7 Substituted 3-12 membered heterocyclic alkenyl groups, C 6-10 aryl, with one or more R 5b8 Replacement C 6-10 aryl, 5-10 heteroaryl, or with one or more R 5b9 Substituted 5-10 heteroaryl groups;

[0022] Each R 5b1 R 5b2 R 5b3 R 5b4 R 5b5 R 5b6 R 5b7 R 5b8 and R 5b9 Each can be independently represented as deuterium, halogen, cyano, hydroxyl, oxo (=O), -NH2, or -NH(C). 1-6 alkyl), -N(C) 1-6 Alkyl)2, C 1-6 Alkyl groups, C substituted with one or more halogens 1-6 Alkyl groups, C groups substituted with one or more hydroxyl groups 1-6 Alkyl groups, C atoms substituted with one or more deuterium atoms 1-6 Alkyl, -OC 1-6 Alkyl groups, -OC groups substituted with one or more halogens 1-6 Alkyl, -SC 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 cycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, 3-12 membered heterocyclic alkenyl, C 6-10 Aryl or 5-10 heteroaryl groups;

[0023] R 4 Hydrogen, hydroxyl, cyano, -N(R) 9 )2、-S(O)2R 10 -C(O)R 10 -C(O)OR 10 -CON(R) 10 )2、-S(O)2N(R 10 2. C 1-6 Alkyl, with one or more R 4a Replacement C 1-6 Alkyl, C2-6 alkenyl, with one or more R 4b Replacement C 2-6 alkenyl, C 2-6 alkynyl group, with one or more R 4c Replacement C 2-6 alkynyl group, C 3-12 cycloalkyl, with one or more R 4d Replacement C 3-12 cycloalkyl, C 3-12 Cycloalkenyl, with one or more R 4e Replacement C 3-12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, with one or more R 4f Substituted 3-12-membered heterocyclic alkyl, 3-12-membered heterocyclic alkenyl, or substituted with one or more R 4g Substituted 3-12 membered heterocyclic alkenyl groups, C 6-10 aryl, with one or more R 4h Replacement C 6-10 aryl, 5-10 heteroaryl, or with one or more R 4i Substituted 5-10 heteroaryl groups;

[0024] Each R 4a R 4b R 4c R 4d R 4e R 4f R 4g R 4h and R 4i Each can be independently represented as deuterium, halogen, cyano, hydroxyl, oxo (=O), -NH2, or -NH(C). 1-6 alkyl), -N(C) 1-6 Alkyl)2, C 1-6 Alkyl groups, C substituted with one or more halogens 1-6 Alkyl groups, C groups substituted with one or more hydroxyl groups 1-6 Alkyl groups, C atoms substituted with one or more deuterium atoms 1-6 Alkyl, -OC 1-6 Alkyl groups, -OC groups substituted with one or more halogens 1-6 Alkyl, -SC 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 cycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, 3-12 membered heterocyclic alkenyl, C 6-10 Aryl or 5-10 heteroaryl groups;

[0025] Each R 6Independently hydrogen, deuterium, halogen, cyano, nitro, hydroxyl, -N(R) 9 )2、-S(O)2R 12 -C(O)R 12 C 1-6 Alkyl, with one or more R 6a Replacement C 1-6 Alkyl, -OC 1-6 Alkyl, with one or more R 6b Replacement -OC 1-6 Alkyl, -SC 1-6 Alkyl, with one or more R 6c Replacement -SC 1-6 Alkyl, C 2-6 alkenyl, with one or more R 6d Replacement C 2-6 alkenyl, C 2-6 alkynyl group, with one or more R 6e Replacement C 2-6 alkynyl group, C 3-12 cycloalkyl, with one or more R 6f Replacement C 3-12 cycloalkyl, C 3-12 Cycloalkenyl, with one or more R 6g Replacement C 3-12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, with one or more R 6h Substituted 3-12-membered heterocyclic alkyl, 3-12-membered heterocyclic alkenyl, or substituted with one or more R 6i Substituted 3-12 membered heterocyclic alkenyl groups, C 6-10 aryl, with one or more R 6j Replacement C 6-10 aryl, 5-10 heteroaryl, or with one or more R 6k Substituted 5-10 heteroaryl groups;

[0026] Each R 9 Independently hydrogen, hydroxyl, cyano, C 1-6 Alkyl, C 3-12 cycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, or 3-12 membered heterocyclic alkenyl;

[0027] Each R 6a R 6b R 6c R 6d R 6e R 6f R 6g R 6h R 6i R 6j and R 6kEach is independently a deuterium, halogen, cyano, hydroxyl, -N(R) 9 )2、-S(O)2R 10 -C(O)N(R) 10 )2、-C(O)R 10 -C(O)OR 10 , , C 1-6 Alkyl, with one or more R 6-a Replacement C 1-6 Alkyl, -OC 1-6 Alkyl, with one or more R 6-b Replacement -OC 1-6 Alkyl, -SC 1-6 Alkyl, with one or more R 6-c Replacement -SC 1-6 Alkyl, C 2-6 alkenyl, with one or more R 6-d Replacement C 2-6 alkenyl, C 2-6 alkynyl group, with one or more R 6-e Replacement C 2-6 alkynyl group, C 3-12 cycloalkyl, with one or more R 6-f Replacement C 3-12 cycloalkyl, C 3-12 Cycloalkenyl, with one or more R 6-g Replacement C 3-12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, with one or more R 6-h Substituted 3-12-membered heterocyclic alkyl, 3-12-membered heterocyclic alkenyl, or substituted with one or more R 6-i Substituted 3-12 membered heterocyclic alkenyl groups, C 6-10 aryl, with one or more R 6-j Replacement C 6-10 aryl, 5-10 heteroaryl, or with one or more R 6-k Substituted 5-10 heteroaryl groups;

[0028] Each R 10 Independently hydrogen, C 1-6 Alkyl, C 3-12 cycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, or 3-12 membered heterocyclic alkenyl;

[0029] Each R 4-i Independently hydrogen or C 1-6 alkyl;

[0030] Each R 6-a R 6-b R6-c R 6-d R 6-e R 6-f R 6-g R 6-h R 6-i R 6-j and R 6-k Each can be independently represented by deuterium, halogen, cyano, hydroxyl, oxo (=O), or -N (R). 11 )2、-S(O)2R 13 -C(O)N(R) 13 )2、-C(O)R 13 C 1-6 Alkyl, with one or more R 6-a-1 Replacement C 1-6 Alkyl, -OC 1-6 Alkyl, with one or more R 6-a-2 Replacement -OC 1-6 Alkyl, -SC 1-6 Alkyl, with one or more R 6-a-3 Replacement -SC 1-6 Alkyl, C 2-6 alkenyl, with one or more R 6-a-4 Replacement C 2-6 alkenyl, C 2-6 alkynyl group, with one or more R 6-a-5 Replacement C 2-6 alkynyl group, C 3-12 cycloalkyl, with one or more R 6-a-6 Replacement C 3-12 cycloalkyl, C 3-12 Cycloalkenyl, with one or more R 6-a-7 Replacement C 3-12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, with one or more R 6-a-8 Substituted 3-12-membered heterocyclic alkyl, 3-12-membered heterocyclic alkenyl, or substituted with one or more R 6-a-9 Substituted 3-12 membered heterocyclic alkenyl groups, C 6-10 aryl, with one or more R 6-a-10 Replacement C 6-10 aryl, 5-10 heteroaryl, or with one or more R 6-a-11 Substituted 5-10 heteroaryl groups;

[0031] Each R 11 Independently hydrogen, hydroxyl, cyano, C 1-6 Alkyl, -C(O)-C 1-6 Alkyl, C 3-12 cycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, or 3-12 membered heterocyclic alkenyl;

[0032] Each R 13 Independently hydrogen, hydroxyl, C 1-6 Alkyl, C 3-12 cycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, or 3-12 membered heterocyclic alkenyl;

[0033] Each R 6-a-1 R 6-a-2 R 6-a-3 R 6-a-4 R 6-a-5 R 6-a-6 R 6-a-7 R 6-a-8 R 6-a-9 R 6-a-10 and R 6-a-11 Each can be independently classified as deuterium, halogen, cyano, hydroxyl, -NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl)2, C 1-6 Alkyl or -OC 1-6 alkyl;

[0034] Or, in X6, R 8 and R 6 Together with their respective attached ring atoms, they form C 3-12 cycloalkyl, with one or more R 8a1 Replacement C 3-12 cycloalkyl, C 3-12 Cycloalkenyl, with one or more R 8b1 Replacement C 3-12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, with one or more R 8c1 Substituted 3-12-membered heterocyclic alkyl, 3-12-membered heterocyclic alkenyl, or substituted with one or more R 8d1 Substituted 3-12 membered heterocyclic alkenyl groups, C 6-10 aryl, with one or more R 8e1 Replacement C 6-10 aryl, 5-10 heteroaryl, or with one or more R 8f1 Substituted 5-10 heteroaryl groups;

[0035] Each R 8a1 R 8b1 R 8c1 R 8d1 R 8e1 and R 8f1 Each can be independently classified as deuterium, halogen, cyano, hydroxyl, -NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl)2, C 1-6 Alkyl or -OC 1-6alkyl;

[0036] Each R 12 Independently hydrogen, halogen, hydroxyl, -NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl)2, C 1-6 Alkyl, with one or more R 12a Replacement C 1-6 Alkyl, -OC 1-6 Alkyl, with one or more R 12b Replacement -OC 1-6 Alkyl, C 2-6 alkenyl, with one or more R 12c Replacement C 2-6 alkenyl, C 2-6 alkynyl group, with one or more R 12d Replacement C 2-6 alkynyl group, C 3-12 cycloalkyl, with one or more R 12e Replacement C 3-12 cycloalkyl, C 3-12 Cycloalkenyl, with one or more R 12f Replacement C 3-12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, with one or more R 12g Substituted 3-12-membered heterocyclic alkyl, 3-12-membered heterocyclic alkenyl, or substituted with one or more R 12h Substituted 3-12 membered heterocyclic alkenyl groups, C 6-10 aryl, with one or more R 12i Replacement C 6-10 aryl, 5-10 heteroaryl, or with one or more R 12j Substituted 5-10 heteroaryl groups;

[0037] Each R 12a R 12b R 12c R 12d R 12e R 12f R 12g R 12h R 12i and R 12j Each can be independently represented as deuterium, halogen, cyano, oxo, hydroxyl, -NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl)2, C 1-6 Alkyl or -OC 1-6 alkyl;

[0038] R 7 Hydrogen, hydroxyl, cyano, -N(R) 9’)2、-S(O)2R 12’ -C(O)R 12’ C 1-6 Alkyl, with one or more R 7a Replacement C 1-6 Alkyl, C 2-6 alkenyl, with one or more R 7b Replacement C 2-6 alkenyl, C 2-6 alkynyl group, with one or more R 7c Replacement C 2-6 alkynyl group, C 3-12 cycloalkyl, with one or more R 7d Replacement C 3-12 cycloalkyl, C 3-12 Cycloalkenyl, with one or more R 7e Replacement C 3-12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, with one or more R 7f Substituted 3-12-membered heterocyclic alkyl, 3-12-membered heterocyclic alkenyl, or substituted with one or more R 7g Substituted 3-12 membered heterocyclic alkenyl groups, C 6-10 aryl, with one or more R 7h Replacement C 6-10 aryl, 5-10 heteroaryl, or with one or more R 7i Substituted 5-10 heteroaryl groups;

[0039] Each R 9’ Independently hydrogen, hydroxyl, cyano, C 1-6 Alkyl, C 3-12 cycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, or 3-12 membered heterocyclic alkenyl;

[0040] Each R 7a R 7b R 7c R 7d R 7e R 7f R 7g R 7h and R 7i Each is independently a deuterium, halogen, cyano, hydroxyl, -N(R) 9’ )2、-S(O)2R 10’ -C(O)N(R) 10’ )2、-C(O)R 10’ -C(O)OR 10’ , , C 1-6 Alkyl, with one or more R 7-a Replacement C1-6 Alkyl, -OC 1-6 Alkyl, with one or more R 7-b Replacement -OC 1-6 Alkyl, -SC 1-6 Alkyl, with one or more R 7-c Replacement -SC 1-6 Alkyl, C 2-6 alkenyl, with one or more R 7-d Replacement C 2-6 alkenyl, C 2-6 alkynyl group, with one or more R 7-e Replacement C 2-6 alkynyl group, C 3-12 cycloalkyl, with one or more R 7-f Replacement C 3-12 cycloalkyl, C 3-12 Cycloalkenyl, with one or more R 7-g Replacement C 3-12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, with one or more R 7-h Substituted 3-12-membered heterocyclic alkyl, 3-12-membered heterocyclic alkenyl, or substituted with one or more R 7-i Substituted 3-12 membered heterocyclic alkenyl groups, C 6-10 aryl, with one or more R 7-j Replacement C 6-10 aryl, 5-10 heteroaryl, or with one or more R 7-k Substituted 5-10 heteroaryl groups;

[0041] Each R 10’ Independently hydrogen, C 1-6 Alkyl, C 3-12 cycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, or 3-12 membered heterocyclic alkenyl;

[0042] Each R 7-a R 7-b R 7-c R 7-d R 7-e R 7-f R 7-g R 7-h R 7-i R 7-j and R 7-k Each can be independently represented by deuterium, halogen, cyano, hydroxyl, oxo (=O), or -N(R). 11’ )2、-S(O)2R 13’ -C(O)N(R) 13’ )2、-C(O)R 13’ C 1-6Alkyl, with one or more R 7-a-1 Replacement C 1-6 Alkyl, -OC 1-6 Alkyl, with one or more R 7-a-2 Replacement -OC 1-6 Alkyl, -SC 1-6 Alkyl, with one or more R 7-a-3 Replacement -SC 1-6 Alkyl, C 2-6 alkenyl, with one or more R 7-a-4 Replacement C 2-6 alkenyl, C 2-6 alkynyl group, with one or more R 7-a-5 Replacement C 2-6 alkynyl group, C 3-12 cycloalkyl, with one or more R 7-a-6 Replacement C 3-12 cycloalkyl, C 3-12 Cycloalkenyl, with one or more R 7-a-7 Replacement C 3-12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, with one or more R 7-a-8 Substituted 3-12-membered heterocyclic alkyl, 3-12-membered heterocyclic alkenyl, or substituted with one or more R 7-a-9 Substituted 3-12 membered heterocyclic alkenyl groups, C 6-10 aryl, with one or more R 7-a-10 Replacement C 6-10 aryl, 5-10 heteroaryl, or with one or more R 7-a-11 Substituted 5-10 heteroaryl groups;

[0043] Each R 11’ Independently hydrogen, hydroxyl, cyano, C 1-6 Alkyl, -C(O)-C 1-6 Alkyl, C 3-12 cycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, or 3-12 membered heterocyclic alkenyl;

[0044] Each R 13’ Independently hydrogen, hydroxyl, C 1-6 Alkyl, C 3-12 cycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, or 3-12 membered heterocyclic alkenyl;

[0045] Each R 7-a-1 R 7-a-2 R 7-a-3 R 7-a-4 R 7-a-5 R 7-a-6 R 7-a-7 R7-a-8 R 7-a-9 R 7-a-10 and R 7-a-11 Each can be independently classified as deuterium, halogen, cyano, hydroxyl, -NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl)2, C 1-6 Alkyl or -OC 1-6 alkyl;

[0046] Or, in X6, R 8 and R 7 Together with their respective attached ring atoms, they form C 3-12 cycloalkyl, with one or more R 8a2 Replacement C 3-12 cycloalkyl, C 3-12 Cycloalkenyl, with one or more R 8b2 Replacement C 3-12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, with one or more R 8c2 Substituted 3-12-membered heterocyclic alkyl, 3-12-membered heterocyclic alkenyl, or substituted with one or more R 8d2 Substituted 3-12 membered heterocyclic alkenyl groups, C 6-10 aryl, with one or more R 8e2 Replacement C 6-10 aryl, 5-10 heteroaryl, or with one or more R 8f2 Substituted 5-10 heteroaryl groups;

[0047] Each R 8a2 R 8b2 R 8c2 R 8d2 R 8e2 and R 8f2 Each can be independently classified as deuterium, halogen, cyano, hydroxyl, -NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl)2, C 1-6 Alkyl or -OC 1-6 alkyl;

[0048] Each R 12’ Independently hydrogen, halogen, hydroxyl, -NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl)2, C 1-6 Alkyl, with one or more R 12a’ Replacement C 1-6 Alkyl, -OC 1-6 Alkyl, with one or more R 12b’ Replacement -OC 1-6 Alkyl, C 2-6alkenyl, with one or more R 12c’ Replacement C 2-6 alkenyl, C 2-6 alkynyl group, with one or more R 12d’ Replacement C 2-6 alkynyl group, C 3-12 cycloalkyl, with one or more R 12e’ Replacement C 3-12 cycloalkyl, C 3-12 Cycloalkenyl, with one or more R 12f’ Replacement C 3-12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, with one or more R 12g’ Substituted 3-12-membered heterocyclic alkyl, 3-12-membered heterocyclic alkenyl, or substituted with one or more R 12h’ Substituted 3-12 membered heterocyclic alkenyl groups, C 6-10 aryl, with one or more R 12i’ Replacement C 6-10 aryl, 5-10 heteroaryl, or with one or more R 12j’ Substituted 5-10 heteroaryl groups;

[0049] Each R 12a’ R 12b’ R 12c’ R 12d’ R 12e’ R 12f’ R 12g’ R 12h’ R 12i’ and R 12j’ Each can be independently represented as deuterium, halogen, cyano, oxo, hydroxyl, -NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl)2, C 1-6 Alkyl or -OC 1-6 alkyl;

[0050] Ring A is C 7-15 cycloalkyl, C 7-15 Cycloalkenyl, 7-15 membered heterocyclic alkyl, or 7-15 membered heterocyclic alkenyl;

[0051] Each R 2 Independently deuterium, halogen, cyano, nitro, oxo, -N(R) 14 2. -B(OR) 14 )2、-OR 14 -SR 14 -S(O)2R 14 -S(O)2N(R) 14 )2、-NR 14 S(O)2R 14 -C(O)N(R)14 )2、-C(O)NR 14 OR 14 -NR 14 C(O)R 14 -NR 14 C(O)N(R 14 )2、-NR 14 C(O)OR 14 -C(O)R 14 -C(O)OR 14 -OC(O)R 14 -OC(O)N(R) 14 )2、-CH2C(O)N(R 14 2. C 1-6 Alkyl, with one or more R 2a Replacement C 1-6 Alkyl, C 2-6 alkenyl, with one or more R 2b Replacement C 2-6 alkenyl, C 2-6 alkynyl group, with one or more R 2c Replacement C 2-6 alkynyl group, C 3-12 cycloalkyl, with one or more R 2d Replacement C 3-12 cycloalkyl, C 3-12 Cycloalkenyl, with one or more R 2e Replacement C 3-12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, with one or more R 2f Substituted 3-12-membered heterocyclic alkyl, 3-12-membered heterocyclic alkenyl, or substituted with one or more R 2g Substituted 3-12 membered heterocyclic alkenyl groups, C 6-10 aryl, with one or more R 2h Replacement C 6-10 aryl, 5-10 heteroaryl, or with one or more R 2i Substituted 5-10 heteroaryl groups;

[0052] Each R 2a R 2b R 2c R 2d R 2e R 2f R 2g R 2h and R 2i Each independently constitutes deuterium, -N(R) 15 2. Hydroxyl group, halogen, cyano group, nitro group, oxo group, thio group (=S), C 1-6 Alkyl, with one or more R 2-aReplacement C 1-6 Alkyl, -OC 1-6 Alkyl, with one or more R 2-b Replacement -OC 1-6 Alkyl, C 2-6 alkenyl, with one or more R 2-c Replacement C 2-6 alkenyl, C 2-6 alkynyl group, with one or more R 2-d Replacement C 2-6 alkynyl group, C 3-12 cycloalkyl, with one or more R 2-e Replacement C 3-12 cycloalkyl, C 3-12 Cycloalkenyl, with one or more R 2-f Replacement C 3-12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, with one or more R 2-g Substituted 3-12-membered heterocyclic alkyl, 3-12-membered heterocyclic alkenyl, or substituted with one or more R 2-h Substituted 3-12 membered heterocyclic alkenyl groups, C 6-10 aryl, with one or more R 2-i Replacement C 6-10 aryl, 5-10 heteroaryl, or with one or more R 2-j Substituted 5-10 heteroaryl groups;

[0053] Each R 2-a R 2-b R 2-c R 2-d R 2-e R 2-f R 2-g R 2-h R 2-i and R 2-j Each independently constitutes deuterium, -N(R) 16 2. Hydroxyl group, halogen, cyano group, nitro group, oxo group, C 1-6 Alkyl or -OC 1-6 alkyl;

[0054] Each R 14 R 15 and R 16 Each independently is hydrogen, C 1-6 Alkyl, with one or more R 14a Replacement C 1-6 Alkyl, C 2-6 alkenyl, with one or more R 14b Replacement C 2-6 alkenyl, C 2-6 alkynyl group, with one or more R 14c Replacement C2-6 alkynyl group, C 3-12 cycloalkyl, with one or more R 14d Replacement C 3-12 cycloalkyl, C 3-12 Cycloalkenyl, with one or more R 14e Replacement C 3-12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, with one or more R 14f Substituted 3-12-membered heterocyclic alkyl, 3-12-membered heterocyclic alkenyl, or substituted with one or more R 14g Substituted 3-12 membered heterocyclic alkenyl groups, C 6-10 aryl, with one or more R 14h Replacement C 6-10 aryl, 5-10 heteroaryl, or with one or more R 14i Substituted 5-10 heteroaryl groups;

[0055] Each R 14a R 14b R 14c R 14d R 14e R 14f R 14g R 14h and R 14i Each is independently of deuterium, -NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl group, hydroxyl group, halogen group, cyano group, nitro group, oxo group, =NH group, C group 1-6 Alkyl groups, C substituted with one or more halogens 1-6 Alkyl, -OC 1-6 Alkyl, C 3-12 cycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, 3-12 membered heterocyclic alkenyl, C 6-10 Aryl or 5-10 heteroaryl groups;

[0056] L is -(CR) La R Lb ) n1 -、-O-(CR La R Lb ) n2 -、-O-(CR La R Lb ) n7 -CR Lc R Ld -(CR La R Lb ) n8 -、-S-(CR La R Lb ) n3-、-N(R 17 )-(CR La R Lb ) n4 -、-S(O)-(CR La R Lb ) n5 -or-S(O)2-(CR La R Lb ) n6 -;

[0057] R 17 It is hydrogen, hydroxyl, cyano, C1-6 alkyl, C2-6 alkenyl, C 2-6 alkynyl group, C 3-12 cycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, or 3-12 membered heterocyclic alkenyl;

[0058] Each R La and R Lb Each of these can be independently represented by hydrogen, deuterium, halogen, cyano, hydroxyl, C1-6 alkyl, or -OC. 1-6 Alkyl, C1-6 alkyl substituted with one or more halogens, C1-6 alkyl substituted with one or more deuteriums, or 5-10 heteroaryl groups;

[0059] R Lc R Ld Together with the carbon atoms that are bonded together, they form C 3-12 cycloalkyl or with one or more R La-1 Replacement C 3-12 cycloalkyl;

[0060] Each R La-1 Independently deuterium, halogen, cyano, hydroxyl, -NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl)2, C 1-6 Alkyl or -OC 1-6 alkyl;

[0061] n1, n2, n3, n4, n5, n6, n7, and n8 are each independently 0, 1, 2, or 3; (when 0, it indicates a connection key).

[0062] R 1 It is hydrogen, C1-6 alkyl, or formed by one or more R 1a Substituted C1-6 alkyl, -O-C1-6 alkyl, or substituted with one or more R 1b Substituted -O-C1-6 alkyl, C 3-12 cycloalkyl, with one or more R 1c Replacement C 3-12 cycloalkyl, C 3-12Cycloalkenyl, with one or more R 1d Replacement C 3-12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, with one or more R 1e Substituted 3-12-membered heterocyclic alkyl, 3-12-membered heterocyclic alkenyl, or substituted with one or more R 1f Substituted 3-12 membered heterocyclic alkenyl groups, C6- 10 aryl, with one or more R 1g Replacement C6- 10 aryl, 5-10 heteroaryl, with one or more R 1h Substituted 5-10 heteroaryl groups, -C(O)OR 18 -C(O)R 18 -N(R) 18 )2、-NR 18 C(=NR 18 )N(R 18 )2、-C(O)N(R 18 )2 or -NR 18 C(O)R 18 ;

[0063] Each R 1a R 1b R 1c R 1d R 1e R 1f R 1g and R 1h Each can be independently halogenated, deuterated, cyano, oxo, or -OR. 19 -SR 19 -C(O)R 19 -C(O)OR 19 -OC(O)R 19 -S(O)2R 19 -C(O)N(R) 19 )2、-NR 19 C(O)R 19 -N(R) 19 )2、-OC(O)N(R 19 )2、-CH2OC(O)N(R 19 )2、-SO2F、-CH2NR 19 C(O)OR 19 -CH2NR 19 C(O)N(R 19 )2、-CH2NR 19 C(O)R 19 -CH2NR 19 S(O)2R 19 -CH2OC(O)R19 -CH2R 19 =C(R) 1-k )2, C1-6 alkyl, with one or more R 1-a Substituted C1-6 alkyl, with one or more R 1-b Substituted -O-C1-6 alkyl, C2-6 alkenyl, or with one or more R 1-c Substituted C2-6 alkenyl, C2-6 ynyl, or with one or more R 1-d Substituted C2-6 ynyl group, C 3-12 cycloalkyl, with one or more R 1-e Replacement C 3-12 cycloalkyl, C 3-12 Cycloalkenyl, with one or more R 1-f Replacement C 3-12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, with one or more R 1-g Substituted 3-12-membered heterocyclic alkyl, 3-12-membered heterocyclic alkenyl, or substituted with one or more R 1-h Substituted 3-12 membered heterocyclic alkenyl groups, C6- 10 aryl, with one or more R 1-i Replacement C6- 10 aryl, 5-10 heteroaryl, or with one or more R 1-j Substituted 5-10 heteroaryl groups;

[0064] Each R 1-a R 1-b R 1-c R 1-d R 1-e R 1-f R 1-g R 1-h R 1-i and R 1-j Each can be independently deuterium, cyano, halogen, hydroxyl, C1-6 alkyl, -O-C1-6 alkyl, C2-6 alkenyl, C 2-6 alkynyl group, C 3-12 cycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, 3-12 membered heterocyclic alkenyl, C6- 10 Aryl or 5-10 heteroaryl groups;

[0065] Each R 1-k Independently hydrogen, deuterium, cyano, halogen, hydroxyl, C1-6 alkyl, -O-C1-6 alkyl, C2-6 alkenyl, C 2-6 alkynyl group, C 3-12 cycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, 3-12 membered heterocyclic alkenyl, C6- 10Aryl or 5-10 heteroaryl groups;

[0066] Each R 18 and R 19 Each independently is hydrogen, C 1-6 Alkyl, C 3-12 cycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, 3-12 membered heterocyclic alkenyl, C6- 10 Aryl or 5-10 heteroaryl, wherein the C 1-6 Alkyl, C 3-12 cycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, 3-12 membered heterocyclic alkenyl, C6- 10 Aryl or 5-10 heteroaryl groups are optionally surrounded by one or more R groups. 18a replace;

[0067] Each R 18a Independently, it can be deuterium, -C(O)H, halogen, cyano, hydroxyl, oxo, C1-6 alkyl, or -OC. 1-6 Alkyl groups, C1-6 alkyl groups substituted with one or more halogens, C 3-12 cycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, 3-12 membered heterocyclic alkenyl, C6- 10 Aryl or 5-10 heteroaryl groups;

[0068] In each "heterocyclic alkyl", the heteroatoms are independently selected from one, two or more of N, O and S, and the number of heteroatoms is independently 1, 2, 3 or 4.

[0069] In each "heterocyclic alkenyl", the heteroatoms are independently selected from one, two or more of N, O and S, and the number of heteroatoms is independently 1, 2, 3 or 4.

[0070] In each "heteroaryl", the heteroatoms are independently selected from one, two or more of N, O and S, and the number of heteroatoms is independently 1, 2, 3 or 4.

[0071] In one embodiment, certain groups in the compound represented by Formula I, its stereoisomers or pharmaceutically acceptable salts thereof have the following definitions, and the definitions of groups not mentioned are as described in any embodiment of the present invention (hereinafter referred to as "in one embodiment").

[0072] In one embodiment, each halogen can independently be fluorine, chlorine, bromine, or iodine, preferably fluorine.

[0073] In a certain scheme, each C 1-6The alkyl group can independently be methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, or sec-butyl, such as methyl or ethyl.

[0074] In one scheme, each -OC 1-6 The alkyl group can independently be -O-methyl, -O-ethyl, -O-n-propyl, -O-isopropyl, -O-n-butyl, -O-tert-butyl, -O-isobutyl or -O-sec-butyl, for example -O-methyl.

[0075] In a certain scheme, each -SC 1-6 The alkyl group can independently be -S-methyl, -S-ethyl, -S-n-propyl, -S-isopropyl, -S-n-butyl, -S-tert-butyl, -S-isobutyl, or -S-sec-butyl, for example -S-methyl.

[0076] In a certain scheme, each C 2-6 The alkenyl group can independently be vinyl, propenyl, allyl, 1-butenyl, or 1-pentenyl.

[0077] In a certain scheme, each C 2-6 The alkynyl group can independently be ethynyl, propynyl, propynyl, 1-butynyl, or 1-pentynyl.

[0078] In a certain scheme, each C 3-12 cycloalkyl groups can independently be C 3-8 Cycloalkyl groups, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, and again, cyclopropyl.

[0079] In a certain scheme, each C 3-12 The cycloalkenyl group can independently be C 3-10 Cycloalkenyl, preferably C 5-6 Cycloalkenyl.

[0080] In a certain scheme, each C 3-12 The cycloalkenyl group independently contains one or more carbon-carbon sp groups. 2 Double bond.

[0081] In one scheme, the heteroatom types of each 3-12 membered heterocyclic alkyl group are independently selected from one or two of N, O and S, and the number of heteroatoms is independently 1, 2 or 3.

[0082] In one embodiment, each 3-12 membered heterocyclic alkyl group can independently be monocyclic or polycyclic, wherein the polycyclic group can be a bridged ring, fused ring, or spirocyclic ring, and the polycyclic group can also be bicyclic or tricyclic; preferably, each 3-12 membered heterocyclic alkyl group can independently be a 3-7 membered monocyclic heterocyclic alkyl group, an 8-10 membered bicyclic heterocyclic alkyl group, or a 10-12 membered tricyclic heterocyclic alkyl group, such as tetrahydropyrrolyl, morpholinyl, piperidinyl, piperazineyl, etc. , or For example, , , , , , or For example, , , , , , , , , , , or .

[0083] In one scheme, the heteroatom species of each 3-12 membered heterocyclic alkenyl group are independently selected from one or two of N, O and S, and the number of heteroatoms is independently 1, 2 or 3.

[0084] In one embodiment, each 3-12 membered heterocyclic alkenyl group can independently be a monocyclic or polycyclic ring, wherein the polycyclic ring can be a bridged ring, a fused ring, or a spirocyclic ring, and the polycyclic ring can also be a bicyclic or tricyclic ring; preferably, each 3-12 membered heterocyclic alkenyl group can independently be a 3-7 membered monocyclic heterocyclic alkenyl group or an 8-10 membered bicyclic heterocyclic alkenyl group, for example For example, .

[0085] In one scheme, each 3-12 membered heterocyclic alkenyl group independently contains one or more sp atoms. 2 Double bond.

[0086] In one embodiment, the heteroatom of each 7-15 member heterocyclic alkenyl group is independently selected from one or two of N, O and S, and the number of heteroatoms is independently 1, 2 or 3; preferably, the heteroatom is S and the number of heteroatoms is 1.

[0087] In one embodiment, each 7-15 member heterocyclic alkenyl group can be independently monocyclic or polycyclic, wherein the polycyclic group can be a bridged ring, a fused ring, or a spirocyclic ring, and the polycyclic group can also be a bicyclic or tricyclic ring; preferably, each 7-15 member heterocyclic alkenyl group can be independently an 8-10 member bicyclic heterocyclic alkenyl group, such as 5,6-dihydro-4H-cyclopentano[b]thiopheneyl or 4,5,6,7-tetrahydrobenzo[b]thiopheneyl.

[0088] In one scheme, each 7-15 membered heterocyclic alkenyl group independently contains one or more sp atoms. 2 Double bonds, preferably containing 2 sp bonds. 2 Double bond.

[0089] In a certain scheme, each C 6-10 The aryl group can independently be phenyl or naphthyl, such as phenyl.

[0090] In one embodiment, each 5-10 membered heteroaryl group can independently be a 5-6 membered monocyclic heteroaryl group or a 9-10 membered bicyclic heteroaryl group, such as pyridyl, or for example... .

[0091] In one scheme, the heteroatom species of each 5-10 aryl group are independently selected from one or two of N, O and S, and the number of heteroatoms is independently 1, 2 or 3.

[0092] In a certain scheme, each C 7-15 cycloalkyl groups can independently be C 7-10 Cycloalkyl, preferably C 8-9 Cycloalkyl.

[0093] In a certain scheme, each C 7-15 The cycloalkyl group can be monocyclic or polycyclic, and the polycyclic group can be a bridged ring, a fused ring, or a spirocyclic ring. The polycyclic group can also be a bicyclic or a tricyclic ring.

[0094] In a certain scheme, each C 7-15 The cycloalkenyl group can independently be C 7-10 Cycloalkenyl, preferably C 8-9 Cycloalkenyl.

[0095] In a certain scheme, each C 7-15 The cycloalkenyl group can be monocyclic or polycyclic, and the polycyclic group can be a bridged ring, a fused ring, or a spirocyclic ring. The polycyclic group can also be bicyclic or tricyclic.

[0096] In a certain scheme, each C 7-15 The cycloalkenyl group independently contains one or more carbon-carbon sp groups. 2 Double bond.

[0097] In one scheme, the heteroatom types of each 7-15 membered heterocyclic alkyl group are independently selected from one or two of N, O and S, and the number of heteroatoms is independently 1, 2 or 3.

[0098] In one embodiment, each 7-15 membered heterocyclic alkyl group can be independently monocyclic or polycyclic, wherein the polycyclic group can be a bridged ring, a fused ring, or a spirocyclic ring, and the polycyclic group can also be a bicyclic or tricyclic ring; preferably, each 7-15 membered heterocyclic alkyl group can be independently a 7-membered monocyclic heterocyclic alkyl group, an 8-10 membered bicyclic heterocyclic alkyl group, or a 10-12 membered tricyclic heterocyclic alkyl group.

[0099] In one embodiment, the stereoisomer may be a cis-trans isomer or an optical isomer.

[0100] In one scheme, X1 is C(R)3 )2, O, S or NR 4 Preferably C(R) 3 )2 or O, more preferably O.

[0101] In one scheme, X2 and X3 are each independently CR 5A Or N.

[0102] In one of the solutions, It is a single or double bond, ring B is aromatic, and at least one of X2, X3, X4, X8 and X9 is N.

[0103] In one scheme, X5 is NR. 7 .

[0104] In a certain scheme, m can be 0, 1, 2 or 3, preferably 2.

[0105] In one particular scheme, n is 1.

[0106] In a certain scheme, each R 3 R 5A and R 8 Each is independently hydrogen or C 1-6 Alkyl group, preferably hydrogen.

[0107] In one particular scheme, R 4 It is hydrogen or C 1-6 alkyl.

[0108] In one particular scheme, R 7 For one or more R 7a Replacement C 1-6 alkyl.

[0109] In a certain scheme, each R 7a Independently 5-10 membered heteroaryl or surrounded by one or more R 7-k The substituted 5-10 aryl group is preferably replaced by one or more R groups. 7-k Substituted 5-10 heteroaryl groups.

[0110] In a certain scheme, each R 7-k Independently for C 1-6 Alkyl, halogen or -N(R) 11’ )2, preferably -N(R) 11’ )2.

[0111] In a certain scheme, each R 11’ Independently hydrogen or C 1-6 Alkyl group, preferably hydrogen.

[0112] In one scheme, ring A is a 7-15 membered heterocyclic alkenyl group.

[0113] In a certain scheme, each R 2 Independently halogen, cyano, oxo, C 1-6 Alkyl, -OR 14 C 2-6 alkenyl, C 2-6 alkynyl or -N(R) 14 )2, preferably cyano or -N(R) 14 )2.

[0114] In a certain scheme, each R 14 Independently hydrogen or C 1-6 Alkyl group, preferably hydrogen.

[0115] In one scheme, L is -O-(CR) La R Lb ) n2 - *** or -O-(CR) La R Lb ) n7 -CR Lc R Ld -(CR La R Lb ) n8 - *** Preferably -O-(CR) La R Lb ) n2 - *** More preferably, wherein the symbol " *** "End and R" 1 Connected.

[0116] In a certain scheme, each R La and R Lb Each is independently hydrogen, deuterium, or C1-6 alkyl, preferably hydrogen.

[0117] In one particular scheme, R Lc R Ld Together with the carbon atoms that are bonded together, they form C 3-12 Cycloalkyl.

[0118] In a certain scheme, n2 is 0, 1 or 2, preferably 0 or 1.

[0119] In a certain scheme, n7 and n8 are each independently 1 or 2, preferably 1.

[0120] In one particular scheme, R 1 For one or more R 1a Substituted C1-6 alkyl, C 3-12 cycloalkyl, with one or more R 1c Replacement C 3-12Cycloalkyl, 3-12 membered heterocyclic alkyl, with one or more R 1e Substituted 3-12-membered heterocyclic alkyl, 3-12-membered heterocyclic alkenyl, or substituted with one or more R 1f The substituted 3-12 membered heterocyclic alkenyl group is preferably replaced by one or more R groups. 1a Substituted C1-6 alkyl, with one or more R 1c Replacement C 3-12 Cycloalkyl, 3-12 membered heterocyclic alkyl, with one or more R 1e The substituted 3-12-membered heterocyclic alkyl or 3-12-membered heterocyclic alkenyl groups, more preferably substituted with one or more R groups, are preferred. 1a Substituted C1-6 alkyl or with one or more R 1e Substituted 3-12 membered heterocyclic alkyl groups.

[0121] In a certain scheme, each R 1a R 1c R 1e and R 1f Each is independently a halogen, deuterium, cyano, or -OR group. 19 -SR 19 -CH2R 19 =C(R) 1-k )2, C1-6 alkyl, with one or more R 1-a Substituted C1-6 alkyl, with one or more R 1-b Substituted -O-C1-6 alkyl, 3-12 membered heterocyclic alkyl, or substituted with one or more R 1-g The substituted 3-12 membered heterocyclic alkyl group is preferably halogen, deuterium, or -OR. 19 -SR 19 -CH2R 19 =C(R) 1-k )2, C1-6 alkyl, with one or more R 1-a Substituted C1-6 alkyl or with one or more R 1-g The substituted 3-12 membered heterocyclic alkyl group, more preferably halogen or CH2R, is preferred. 19 C1-6 alkyl or containing one or more R 1-g Substituted 3-12 membered heterocyclic alkyl groups.

[0122] In a certain scheme, each R 1-a R 1-b and R 1-g Each of these can be independently halogen, hydroxyl, C1-6 alkyl, -O-C1-6 alkyl, C2-6 alkenyl, C 2-6Alkyne, 3-12-membered heterocyclic alkyl or 3-12-membered heterocyclic alkenyl, preferably halogen, C1-6 alkyl, -O-C1-6 alkyl, 3-12-membered heterocyclic alkyl or 3-12-membered heterocyclic alkenyl, more preferably halogen or C1-6 alkyl.

[0123] In a certain scheme, each R 1-k It is independently hydrogen, halogen or C1-6 alkyl, preferably hydrogen or halogen.

[0124] In a certain scheme, each R 19 Each independently is hydrogen, C 1-6 Alkyl, 3-12 membered heterocyclic alkyl or 3-12 membered heterocyclic alkenyl, preferably hydrogen.

[0125] In one scheme, X2 and X3 are each independently CR 5A Or N, and at least one of X2 and X3 is N.

[0126] In one scheme, X1 is O, NH, N(CH3), S, or CH2.

[0127] In one scheme, structural fragments for , , , , , , , or The a1 end is connected to X7, and the a2 end is connected to the spiro atom in ring A.

[0128] In one scheme, X5 is NR. 7 R 7 for , or .

[0129] In one scheme, X6 and X7 are CH2.

[0130] In one particular scheme, L is -O- *** , *** , *** , *** , *** , *** or *** Among them, marked " *** "End and R" 1 Connected.

[0131] In one particular scheme, R 1 for , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

[0132] In one scheme, structural fragment -LR 1 for , , , , , , , , , , , , , , , , , , , , , , , , , or .

[0133] In one scheme, structural fragments for or Preferred or In the structural segment, end b1 is connected to X9, and end b2 is connected to X1.

[0134] In one of the solutions,

[0135] X1 is C(R) 3 )2, O, S or NR 4 ;

[0136] X2 and X3 are each independently CR 5AOr N;

[0137] X4, X8, and X9 are each independently C or N;

[0138] It is a single or double bond, ring B is aromatic, and at least one of X2, X3, X4, X8 and X9 is N;

[0139] X5 is NR 7 ;

[0140] X6 and X7 are each independently C(R) 8 )2;

[0141] m can be 0, 1, 2, or 3;

[0142] n is 1;

[0143] Each R 3 R 5A and R 8 Each is independently hydrogen or C 1-6 alkyl;

[0144] R 4 It is hydrogen or C 1-6 alkyl;

[0145] R 7 For one or more R 7a Replacement C 1-6 alkyl;

[0146] Each R 7a Independently 5-10 membered heteroaryl or surrounded by one or more R 7-k Substituted 5-10 heteroaryl groups;

[0147] Each R 7-k Independently for C 1-6 Alkyl, halogen or -N(R) 11’ )2;

[0148] Each R 11’ Independently hydrogen or C 1-6 alkyl;

[0149] Ring A is a 7-15 membered heterocyclic alkenyl group;

[0150] Each R 2 Independently halogen, cyano, oxo, C 1-6 Alkyl, -OR 14 C 2-6 alkenyl, C 2-6 alkynyl or -N(R) 14 )2;

[0151] Each R 14 Independently hydrogen or C1-6 alkyl;

[0152] L is -O-(CR) La R Lb ) n2 - *** or -O-(CR) La R Lb ) n7 -CR Lc R Ld -(CR La R Lb ) n8 - *** Among them, marked " *** "End and R" 1 Connected;

[0153] Each R La and R Lb Each is independently hydrogen, deuterium, or C1-6 alkyl;

[0154] R Lc R Ld Together with the carbon atoms that are bonded together, they form C 3-12 cycloalkyl;

[0155] n2 is 0, 1, or 2;

[0156] n7 and n8 are each independently 1 or 2;

[0157] R 1 For one or more R 1a Substituted C1-6 alkyl, C 3-12 cycloalkyl, with one or more R 1c Replacement C 3-12 Cycloalkyl, 3-12 membered heterocyclic alkyl, with one or more R 1e Substituted 3-12-membered heterocyclic alkyl, 3-12-membered heterocyclic alkenyl, or substituted with one or more R 1f Substituted 3-12 membered heterocyclic alkenyl groups;

[0158] Each R 1a R 1c R 1e and R 1f Each is independently a halogen, deuterium, cyano, or -OR group. 19 -SR 19 -CH2R 19 =C(R) 1-k 2. C1-6 alkyl, with one or more R 1-a Substituted C1-6 alkyl, with one or more R 1-b Substituted -O-C1-6 alkyl, 3-12 membered heterocyclic alkyl, or substituted with one or more R1-g Substituted 3-12 membered heterocyclic alkyl groups;

[0159] Each R 1-a R 1-b and R 1-g Each of these can be independently halogen, hydroxyl, C1-6 alkyl, -O-C1-6 alkyl, C2-6 alkenyl, C 2-6 Alkynyl, 3-12 membered heterocyclic alkyl, or 3-12 membered heterocyclic alkenyl;

[0160] Each R 1-k It is independently hydrogen, halogen, or C1-6 alkyl;

[0161] Each R 19 Each independently is hydrogen, C 1-6 Alkyl, 3-12 membered heterocyclic alkyl or 3-12 membered heterocyclic alkenyl;

[0162] In each "heterocyclic alkyl", the heteroatoms are independently selected from one, two or more of N, O and S, and the number of heteroatoms is independently 1, 2, 3 or 4.

[0163] In each "heterocyclic alkenyl", the heteroatoms are independently selected from one, two or more of N, O and S, and the number of heteroatoms is independently 1, 2, 3 or 4.

[0164] In each "heteroaryl", the heteroatoms are independently selected from one, two or more of N, O and S, and the number of heteroatoms is independently 1, 2, 3 or 4.

[0165] In one embodiment, the compound represented by Formula I is the compound represented by Formula II.

[0166]

[0167] Among them, R 1 R 2 R 7 X 1 X 2 X 3 X 4 X 8 X 9 L The definitions of ring B and m are as described above;

[0168] q is 1 or 2.

[0169] In one embodiment, the compound represented by Formula I is the compound represented by Formula III.

[0170]

[0171] Among them, R 1 R 2 R 7 X 2 X 3 The definitions of L and m are as described above;

[0172] q is 1 or 2.

[0173] In one embodiment, the compound represented by Formula I is the compound represented by Formula II.

[0174]

[0175] in,

[0176] X1 is C(R) 3 )2, O, S or NR 4 ;

[0177] X2 and X3 are each independently CR 5A Or N;

[0178] X4, X8, and X9 are each independently C or N;

[0179] It is a single or double bond, ring B is aromatic, and at least one of X2, X3, X4, X8 and X9 is N;

[0180] m can be 0, 1, 2, or 3;

[0181] q is 1 or 2;

[0182] Each R 3 and R 5A Each is independently hydrogen or C 1-6 alkyl;

[0183] R 4 It is hydrogen or C 1-6 alkyl;

[0184] R 7 For one or more R 7a Replacement C 1-6 alkyl;

[0185] Each R 7a Independently 5-10 membered heteroaryl or surrounded by one or more R 7-k Substituted 5-10 heteroaryl groups;

[0186] Each R 7-k Independently for C 1-6 Alkyl, halogen or -N(R) 11’ )2;

[0187] Each R11’ Independently hydrogen or C 1-6 alkyl;

[0188] Each R 2 Independently halogen, cyano, oxo, C 1-6 Alkyl, -OR 14 C 2-6 alkenyl, C 2-6 alkynyl or -N(R) 14 )2;

[0189] Each R 14 Independently hydrogen or C 1-6 alkyl;

[0190] L is -O-(CR) La R Lb ) n2 - *** or -O-(CR) La R Lb ) n7 -CR Lc R Ld -(CR La R Lb ) n8 - *** Among them, marked " *** "End and R" 1 Connected;

[0191] Each R La and R Lb Each is independently hydrogen, deuterium, or C1-6 alkyl;

[0192] R Lc R Ld Together with the carbon atoms that are bonded together, they form C 3-12 cycloalkyl;

[0193] n7 and n8 are each independently 1 or 2;

[0194] n2 can be 0, 1, or 2 independently;

[0195] R 1 For one or more R 1a Substituted C1-6 alkyl, C 3-12 cycloalkyl, with one or more R 1c Replacement C 3-12 Cycloalkyl, 3-12 membered heterocyclic alkyl, with one or more R 1e Substituted 3-12-membered heterocyclic alkyl, 3-12-membered heterocyclic alkenyl, or substituted with one or more R 1f Substituted 3-12 membered heterocyclic alkenyl groups;

[0196] Each R1a R 1c R 1e and R 1f Each is independently a halogen, deuterium, cyano, or -OR group. 19 -SR 19 -CH2R 19 =C(R) 1-k 2. C1-6 alkyl, with one or more R 1-a Substituted C1-6 alkyl, with one or more R 1-b Substituted -O-C1-6 alkyl, 3-12 membered heterocyclic alkyl, or substituted with one or more R 1-g Substituted 3-12 membered heterocyclic alkyl groups;

[0197] Each R 1-a R 1-b and R 1-g Each of these can be independently halogen, hydroxyl, C1-6 alkyl, -O-C1-6 alkyl, C2-6 alkenyl, C 2-6 Alkynyl, 3-12 membered heterocyclic alkyl, or 3-12 membered heterocyclic alkenyl;

[0198] Each R 1-k It is independently hydrogen, halogen, or C1-6 alkyl;

[0199] Each R 19 Each independently is hydrogen, C 1-6 Alkyl, 3-12 membered heterocyclic alkyl or 3-12 membered heterocyclic alkenyl;

[0200] In each "heterocyclic alkyl", the heteroatoms are independently selected from one, two or more of N, O and S, and the number of heteroatoms is independently 1, 2, 3 or 4.

[0201] In each "heterocyclic alkenyl", the heteroatoms are independently selected from one, two or more of N, O and S, and the number of heteroatoms is independently 1, 2, 3 or 4.

[0202] In each "heteroaryl", the heteroatoms are independently selected from one, two or more of N, O and S, and the number of heteroatoms is independently 1, 2, 3 or 4.

[0203] In one embodiment, the compound represented by Formula I is the compound represented by Formula III.

[0204]

[0205] X2 and X3 are each independently CH or N; preferably, X2 is CH or N, and X3 is N;

[0206] m can be 0, 1, 2 or 3, preferably 2;

[0207] q is 1 or 2;

[0208] R 7 For one or more R 7a Replacement C 1-6 alkyl;

[0209] Each R 7a Independently 5-10 membered heteroaryl or surrounded by one or more R 7-k The substituted 5-10 aryl group is preferably replaced by one or more R groups. 7-k Substituted 5-10 heteroaryl groups;

[0210] Each R 7-k Independently for C 1-6 Alkyl, halogen or -N(R) 11’ )2, preferably -N(R) 11’ )2;

[0211] Each R 11’ Independently hydrogen or C 1-6 Alkyl groups, preferably hydrogen;

[0212] Each R 2 Independently halogen, cyano, oxo, C 1-6 Alkyl, -OR 14 C 2-6 alkenyl, C 2-6 Alkyne group or -NH2, preferably cyano group or -NH2;

[0213] L is -O-(CR) La R Lb ) n2 - *** or -O-(CR) La R Lb ) n7 -CR Lc R Ld -(CR La R Lb ) n8 - *** Preferably -O-(CR) La R Lb ) n2 - *** Among them, marked " *** "End and R" 1 Connected;

[0214] Each R La and R Lb Each can be independently hydrogen, deuterium, or C. 1-6 Alkyl groups, preferably hydrogen;

[0215] R Lc R Ld Together with the carbon atoms that are bonded together, they form C 3-12 cycloalkyl;

[0216] n2 can be 0, 1 or 2 independently, preferably 0 or 1;

[0217] n7 and n8 are each independently 1 or 2, preferably 1;

[0218] R 1 For one or more R 1a Replacement C 1-6 Alkyl, C 3-12 cycloalkyl, with one or more R 1c Replacement C 3-12 Cycloalkyl, 3-12 membered heterocyclic alkyl, with one or more R 1e Substituted 3-12-membered heterocyclic alkyl, 3-12-membered heterocyclic alkenyl, or substituted with one or more R 1f The substituted 3-12 membered heterocyclic alkenyl group is preferably replaced by one or more R groups. 1a Replacement C 1-6 Alkyl, with one or more R 1c Replacement C 3-12 Cycloalkyl, 3-12 membered heterocyclic alkyl, with one or more R 1e The substituted 3-12-membered heterocyclic alkyl or 3-12-membered heterocyclic alkenyl groups, more preferably substituted with one or more R groups, are preferred. 1a Replacement C 1-6 Alkyl or with one or more R 1e Substituted 3-12 membered heterocyclic alkyl groups;

[0219] Each R 1a R 1c R 1e and R 1f Each is independently a halogen, deuterium, cyano, or -OR group. 19 -SR 19 -CH2R 19 =C(R) 1-k 2. C 1-6 Alkyl, with one or more R 1-a Replacement C 1-6 Alkyl, with one or more R 1-b Replacement -OC 1-6 Alkyl, 3-12 membered heterocyclic alkyl, or with one or more R 1-g The substituted 3-12 membered heterocyclic alkyl group is preferably halogen, deuterium, or -OR. 19 -SR 19 -CH2R 19 =C(R) 1-k)2、C 1-6 Alkyl, with one or more R 1-a Replacement C 1-6 Alkyl or with one or more R 1-g The substituted 3-12 membered heterocyclic alkyl group, more preferably halogen or CH2R, is preferred. 19 C 1-6 Alkyl or with one or more R 1-g Substituted 3-12 membered heterocyclic alkyl groups;

[0220] Each R 1-a R 1-b and R 1-g Each is independently a halogen, hydroxyl, C 1-6 Alkyl, -OC 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne, 3-12 membered heterocyclic alkyl or 3-12 membered heterocyclic alkenyl, preferably halogen, C 1-6 Alkyl, -OC 1-6 Alkyl, 3-12 membered heterocyclic alkyl or 3-12 membered heterocyclic alkenyl, more preferably halogen or C 1-6 alkyl;

[0221] Each R 1-k Independently hydrogen, halogen or C 1-6 Alkyl groups, preferably hydrogen or halogens;

[0222] Each R 19 Each independently is hydrogen, C 1-6 Alkyl, 3-12-membered heterocyclic alkyl or 3-12-membered heterocyclic alkenyl, preferably hydrogen;

[0223] In each "heterocyclic alkyl", the heteroatoms are independently selected from one, two or more of N, O and S, and the number of heteroatoms is independently 1, 2, 3 or 4.

[0224] In each "heterocyclic alkenyl", the heteroatoms are independently selected from one, two or more of N, O and S, and the number of heteroatoms is independently 1, 2, 3 or 4.

[0225] In each "heteroaryl", the heteroatoms are independently selected from one, two or more of N, O and S, and the number of heteroatoms is independently 1, 2, 3 or 4.

[0226] In one embodiment, the compound represented by Formula I is the compound represented by Formula IV.

[0227]

[0228] m can be 0, 1, 2 or 3, preferably 2;

[0229] q is 1 or 2, preferably 2;

[0230] R 7 For one or more R 7a Replacement C 1-6 alkyl;

[0231] Each R 7a Independently for one or more R 7-k Substituted 5-6 aryl groups;

[0232] Each R 7-k Independently for -N(R) 11’ )2;

[0233] Each R 11’ Independently hydrogen;

[0234] Each R 2 It can be independently a cyano group or -NH2;

[0235] L is -O-(CR) La R Lb ) n2 - *** Among them, marked " *** "End and R" 1 Connected;

[0236] Each R La and R Lb Each can be independently hydrogen, deuterium, or C. 1-6 Alkyl groups, preferably hydrogen;

[0237] n2 is 1;

[0238] R 1 It is a 3-12 membered heterocyclic alkyl group, with one or more R 1e Substituted 3-12-membered heterocyclic alkyl, 3-12-membered heterocyclic alkenyl, or substituted with one or more R 1f The substituted 3-12 membered heterocyclic alkenyl group is preferably replaced by one or more R groups. 1e Substituted 3-12 membered heterocyclic alkyl groups;

[0239] Each R 1e and R 1f Each is independently a halogen or C 1-6 alkyl;

[0240] In each "heterocyclic alkyl", the heteroatoms are independently selected from one, two or more of N, O and S, and the number of heteroatoms is independently 1, 2, 3 or 4.

[0241] In each "heterocyclic alkenyl", the heteroatoms are independently selected from one, two or more of N, O and S, and the number of heteroatoms is independently 1, 2, 3 or 4.

[0242] In each "heteroaryl", the heteroatoms are independently selected from one, two or more of N, O and S, and the number of heteroatoms is independently 1, 2, 3 or 4.

[0243] In one particular scheme, the compound represented by Formula I above is any of the following compounds:

[0244]

[0245]

[0246]

[0247]

[0248]

[0249]

[0250]

[0251]

[0252]

[0253]

[0254]

[0255] .

[0256] In one particular scheme, the compound represented by Formula I above is any of the following compounds:

[0257] Compounds that elute first under the following conditions: Column: Sunfire® Prep C18OBD TM The mobile phase is 19*250mm*5μm, and the mobile phase is [A: water (0.1% ammonia, v / v) B: acetonitrile], with the volume percentage of B in the mobile phase being 45-55%, the flow rate being 25mL / min, and the detection wavelength being 214 / 254 nm; preferably, under the conditions described, the retention time of the first eluting compound is 3.7 min.

[0258] Compounds that elute under the following conditions: Column: Sunfire® Prep C18OBD TM The mobile phase is 19*250mm*5μm, and the mobile phase is [A: water (0.1% ammonia, v / v) B: acetonitrile], with the volume percentage of B in the mobile phase being 45-55%, the flow rate being 25mL / min, and the detection wavelength being 214 / 254 nm; preferably, under the conditions described, the retention time of the later-eluting compound is 5.3 min.

[0259] This invention also provides the following compounds:

[0260] , or .

[0261] The present invention also provides a pharmaceutical composition comprising substance A and a pharmaceutical excipient; said substance A is a compound represented by Formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. The substance A may be in a therapeutically effective amount.

[0262] The present invention also provides the use of substance A or the above-described pharmaceutical composition in the preparation of a medicament for treating and / or preventing KRAS-mediated diseases, wherein substance A is a compound represented by Formula I, its stereoisomer, or a pharmaceutically acceptable salt thereof. The KRAS-mediated disease is preferably cancer.

[0263] The present invention also provides the use of substance A or the above-described pharmaceutical composition in the preparation of a medicament for treating and / or preventing cancer, wherein substance A is a compound represented by Formula I, its stereoisomer, or a pharmaceutically acceptable salt thereof.

[0264] This invention also provides the use of substance A or the above-described pharmaceutical composition in the preparation of a KRAS inhibitor, wherein substance A is a compound represented by Formula I, its stereoisomer, or a pharmaceutically acceptable salt thereof. In the described application, the KRAS inhibitor can be used in mammalian organisms; it can also be used in vitro, primarily for experimental purposes, such as providing a standard or control sample for comparison, or preparing a kit according to conventional methods in the art to provide rapid detection of the effect of KRAS inhibition.

[0265] The present invention also provides a method for inhibiting KRAS, comprising administering to a patient a therapeutically effective amount of substance A or the above-described pharmaceutical composition; wherein substance A is a compound represented by Formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0266] The present invention also provides a method for treating and / or preventing KRAS-mediated diseases, comprising administering to a patient a therapeutically effective amount of substance A or the pharmaceutical composition described above; said substance A is a compound represented by Formula I, its stereoisomer, or a pharmaceutically acceptable salt thereof. The KRAS-mediated disease is preferably cancer.

[0267] The present invention also provides a method for treating and / or preventing cancer, comprising administering to a patient a therapeutically effective amount of substance A or the above-described pharmaceutical composition; said substance A is the above-described compound as shown in Formula I, its stereoisomer, or a pharmaceutically acceptable salt thereof.

[0268] As mentioned above, KRAS can be mutated, such as KRAS G12C, KRAS G12D, KRAS G12V, KRAS G12A, KRAS G12R, KRAS G12S, KRAS G13C, KRAS G13D, KRAS Q61H, KRAS Q61K or KRAS Q61R mutations, and for example KRAS G12C, KRAS G12D or KRAS G12V mutations.

[0269] As described above, cancer can be associated with at least one of the following mutations: KRAS G12C, KRAS G12D, KRAS G12V, KRAS G12A, KRAS G12R, KRAS G12S, KRAS G13C, KRAS G13D, KRAS Q61H, KRAS Q61K, and KRAS Q61R, particularly with at least one of the following mutations: KRAS G12C, KRAS G12D, and KRAS G12V.

[0270] As described above, the cancer may be selected from one or more of the following: breast cancer, prostate cancer, lung cancer, brain cancer, ovarian cancer, cervical cancer, kidney cancer, head and neck cancer, bone cancer, skin cancer, liver cancer, colorectal cancer, esophageal cancer, stomach cancer, thyroid cancer, bladder cancer, lymphoma, leukemia, melanoma, and pancreatic cancer, preferably lung cancer, pancreatic cancer, or colorectal cancer; more preferably, the lung cancer is non-small cell lung cancer or small cell lung cancer; more preferably, the colorectal cancer is colon cancer or rectal cancer.

[0271] The compound shown in Formula I of this invention can be prepared by various synthetic methods known to those skilled in the art, without particular limitation. For example, it can be prepared by the following scheme provided by this invention. It should be understood that the synthetic method of the compound shown in Formula (I) of this invention is not limited to this scheme, and those skilled in the art can make conventional substitutions and improvements.

[0272] Option 1: When for (Where, end a1 connects to X7, and end a2 connects to the spiro atom in ring A), X5 is NR. 7 , for When (where end b1 is connected to X9 and end b2 is connected to X1), the preparation method is as follows:

[0273]

[0274]

[0275]

[0276] Where Y is hydrogen or halogen, Z is sulfur, sulfoxide, or sulfone, and PG1, PG2, PG3, and PG4 are amino, hydroxyl, or mercapto protecting groups, including but not limited to benzyl (Bn-), 4-methoxybenzyl (PMB-), bis(4-methoxybenzyl), benzyloxyformyl (Cbz-), tert-butyloxyformyl (Boc-), bis-tert-butyloxyformyl, methoxymethyl ether (MOM-), tert-butyldimethylsiloxane (TBS-), tert-butyldiphenylsiloxane (TBDPS-), phthaloyl, N-diphenylmethylene, etc., and each PG1, PG2, PG3, and PG4 may be the same or different. PG1 can be located at any position on the five-membered heterocycle X2, X3, or N; if no protecting group is needed, PG1~PG4 may be absent. n' is 0, 1, 2, 3, or 4. n, X1, X2, X3, X6, X7, R 1 R 4 R 7 The definitions of L are as described in any embodiment of the present invention.

[0277] Metallization of compound a-1 followed by carbonyl addition to compound a-2 yields compound a-3, which can be further converted to a-3'. The reaction of compound a-3 or a-3' with a-4 yields compound a-5. a-5 undergoes cyclization via intermolecular C-H activated coupling to give compound a-6, which is further deprotected by protecting group PG1 to yield compound a-7. The reaction of compound a-7 with a-8 yields compound a-9. Cyclation of a-9 (including but not limited to the Mitsunobu reaction) yields compound a-10, which is further deprotected by protecting group PG2 to yield compound a-11. The reaction of a-11 with a-12 yields compound a-13. Deprotection of a-13 by ketal protection yields compound a-14 (if R...). 7If the protecting group is also removed, then reprotection is required. a-14 can be further converted into compound a-15. Protecting the amino group on a-15 yields a-16, which can be further oxidized to yield sulfone or sulfoxide compound a-16'. Compound a-16' reacts with a-17 to yield compound a-18. Finally, removing all protecting groups yields the compound shown in formula a.

[0278] Unless otherwise specified, the following terms have the meanings shown below.

[0279] Certain chemical groups defined herein are preceded by simplified symbols to indicate the total number of carbon atoms present in the group. For example, C1-C6 alkyl or C1-6 alkyl refers to an alkyl group having a total of 1, 2, 3, 4, 5, or 6 carbon atoms as defined below.

[0280] In this paper, the numerical ranges defined in the substituents, such as 0 to 10, 1-6, 1-3, etc., indicate integers within that range. For example, 1-6 means 1, 2, 3, 4, 5, or 6.

[0281] The term "comprising" is an open-ended expression, meaning it includes the contents specified in this invention, but does not exclude other aspects.

[0282] The terms “substituted” or “replaced” refer to the substitution of one or more hydrogen atoms on a specific atom by a substituent, provided that the valence state of the specific atom is normal and the substituted compound is stable.

[0283] Generally, the terms "substituted" or "substituted" indicate that one or more hydrogen atoms in a given structure are substituted by specific substituents. Further, when the group is substituted by more than one of the substituents, the substituents are independent of each other; that is, the more than one substituent can be different or the same. Unless otherwise indicated, a substituent can be substituted at each substituted position of the substituted group. When more than one position in a given structural formula can be substituted by one or more substituents selected from specific groups, the substituents can be substituted at the same or different positions. For example... R represents 2 The substitution site can be on the thiophene ring (e.g. or It can also be applied to cyclopentane (e.g.) or ).

[0284] Those skilled in the art will understand that, according to conventions used in the art, the use of "" in the structural formulas describing the functional groups in this invention is appropriate. This means that the corresponding group R is linked to other segments or groups in the compound through this site. When the linking site is not specified, the group can be linked to other parts of the molecule through any permissible linking site; for example... This means that any permissible ring atom on any ring can be connected to other parts of the molecule, for example... , , or .

[0285] Unless otherwise specified, use wedge-shaped solid line keys ( ) and wedge-shaped dashed key ( ) represents the absolute configuration of the center of a solid. It is represented by a straight solid line key ( ) and straight dashed key ( ) indicates the relative configuration of the center of the solid.

[0286] The terms “part,” “structural part,” “chemical part,” “group,” and “chemical group” used in this article refer to specific segments or functional groups in a molecule.

[0287] When the listed substituents do not specify which atom they are attached to in the general chemical formula (including but not specifically mentioned compounds), such substituents may be bonded to any of their atoms. Combinations of substituents and / or their variants are permitted only if such combinations produce stable compounds.

[0288] When a listed group does not explicitly indicate that it has a substituent, the group refers only to the unsubstituted group. For example, when "C 1-6 When "alkyl" is not specified as "substituted or unsubstituted," it refers only to "C". 1-6 "alkyl" itself or "unsubstituted C" 1-6 alkyl".

[0289] The term "multiple" refers to 2, 3, 4, or 5.

[0290] When the term "one or more" is used to define the number of a certain group, it means 1, 2, 3, 4 or more.

[0291] In the claims, "one or more" in "satisfies one or more of the following conditions" means 1, 2, 3, 4 or more, and the maximum value of "more" is the largest number of conditions recorded in each claim. For example, if a claim records 8 conditions, then "one or more" in "satisfies one or more of the following conditions" in that claim is any integer from 1 to 8, such as 1, 2, 3, 4, 5, 6, 7 or 8.

[0292] "Halogens" refer to F, Cl, Br, and I.

[0293] In this invention, the term "alkyl" refers to a saturated straight-chain or branched monovalent hydrocarbon group. 1-6 Alkyl refers to an alkyl group having 1-6 carbon atoms, preferably an alkyl group having 1-4 carbon atoms. 1-4 Alkyl groups, specifically methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl.

[0294] In this invention, the term "-OC" 1-6 "alkyl" refers to alkoxy, where "C" is the carbon atom. 1-6 "Alkyl" is defined above. Preferably, it is an alkoxy group having 1 to 4 carbon atoms, such as -O-methyl, -O-ethyl, -O-n-propyl, -O-isopropyl, -O-n-butyl, -O-tert-butyl, -O-isobutyl or -O-sec-butyl.

[0295] In this invention, the term "-SC" 1-6 "C" in "alkyl" 1-6 "alkyl" is as defined above. Preferably -SC 1-4 Alkyl groups, such as -S-methyl, -S-ethyl, -S-n-propyl, -S-isopropyl, -S-n-butyl, -S-tert-butyl, -S-isobutyl, or -S-sec-butyl.

[0296] In this invention, the term "-C(O)-C" is used. 1-6 "C" in "alkyl" 1-6 "Alkyl" is defined above, for example -C(O)-CH3, -C(O)-CH2CH3.

[0297] In this invention, the term "-NH(C)" is used. 1-6 Alkyl group), -N(C) 1-6 In "alkyl)2", "C" 1-6 "Alkyl" is as defined above.

[0298] In this invention, the term "alkynyl" refers to having a specified number of carbon atoms (e.g., C2-6 or C6). 2-4 A straight-chain or branched, unsaturated monovalent hydrocarbon group having one or more (e.g., 1, 2, or 3) carbon-carbon sp triple bonds, preferably C. 2-4 Alkyne group.

[0299] In this invention, the term "alkenyl" refers to having a specified number of carbon atoms (e.g., C2-6 or C6). 2-4 A straight-chain or branched, unsaturated monovalent hydrocarbon group having one or more (e.g., 1, 2, or 3) carbon-carbon sp groups. 2 Double bond, C preferred 2-4 Alkenyl group.

[0300] The term "oxo" refers to =O, where an oxygen atom replaces two hydrogen atoms on the same atom. For example, methylene (-CH2-) becomes carbonyl (-C(=O)-) after being oxosubstituted.

[0301] The term "cycloalkyl" refers to a ring with a specified number of carbon atoms (e.g., C10, C20, C30, C40, C50, C60, C7 ... 7-15 C 7-10 C 8-9 C 3-8 Or C 3-12 Cycloalkyl groups are saturated monocyclic or polycyclic (spirocyclic, bridged, or fused) cyclic groups consisting only of carbon atoms; the polycyclic groups may consist of two or three rings. Cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0302] In this invention, the term "cycloalkenyl" refers to a group having at least one carbon-carbon sp. 2 Non-aromatic carbocyclic substituents (e.g., C10, C20, C30, C40, C50, C60, C70, C80, C9 ... 7-15 Cycloalkenyl, C 7-10 Cycloalkenyl, C 8-9 Cycloalkenyl, C 3-12 Cycloalkenyl, C 3-10 Cycloalkenyl or C 5-6 Cycloalkenyl groups. Examples of cycloalkenyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, and cyclohexenyl.

[0303] In this invention, the term "heterocyclic alkyl" refers to a saturated monovalent group having a specified number of ring atoms (e.g., 3-12, 3-10, 3-7, 8-10, 10-12, 7, 7-10, or 7-15), a specified number of heteroatoms (e.g., 1, 2, 3, 4, or 5), a specified type of heteroatom (one, two, or more of N, O, and S), and being monocyclic or polycyclic (e.g., bridged rings, fused rings, or spirocyclic systems of bicyclic, tricyclic, or more rings), connected to the remainder of the molecule by a carbon atom or heteroatom. Preferably, the "heterocyclic alkyl" may be a 3-7 member monocyclic heterocyclic alkyl, an 8-10 member bicyclic heterocyclic alkyl, or a 10-12 member tricyclic heterocyclic alkyl. Examples of such heterocyclic alkyl groups include, but are not limited to, tetrahydropyrrolyl, morpholinyl, piperidinyl, piperazineyl, etc. , or For example, , , , , , or For example, , , , , , , , , , , or .

[0304] In this invention, the term "heterocyclic alkenyl" refers to a cyclic, unsaturated monovalent hydrocarbon group having a specified number of ring atoms (e.g., 3-12, 3-8, 3-7, 8-10, 7-10, or 7-15), a specified number of heteroatoms (e.g., 1, 2, 3, 4, or 5), and a specified type of heteroatom (one, two, or more of N, O, and S); it has one or more (e.g., 1, 2, or 3) sp... 2 The double bond, which is monocyclic or polycyclic (e.g., bridged rings, fused rings, or spirocyclic systems of bicyclic, tricyclic, or more rings), is non-aromatic. The heterocyclic alkenyl group is attached to the rest of the molecule via a carbon atom or heteroatom. The heterocyclic alkenyl group is preferably a 3-7 membered monocyclic heterocyclic alkenyl group or an 8-10 membered bicyclic heterocyclic alkenyl group. Examples of such heterocyclic alkenyl groups include, but are not limited to, those mentioned above. (For example ), 5,6-dihydro-4H-cyclopentano[b]thiophene or 4,5,6,7-tetrahydrobenzo[b]thiophene, etc.

[0305] The term "aryl" refers to an aryl group having a specified number of carbon atoms in its ring (e.g., C10, C20, C30, C40, C50, C60, C7 ...60, C70, C60, C70, C6 6-10 The aromatic group of aryl groups. Examples of aryl groups include, but are not limited to, phenyl or naphthyl groups.

[0306] In this invention, the term "heteroaryl" refers to a cyclic, unsaturated monovalent group having a specified number of ring atoms (e.g., 5-10, 5-6, 9-10), a specified number of heteroatoms (e.g., 1, 2, 3, 4, or 5), and a specified type of heteroatom (one, two, or more of N, O, and S). It can be monocyclic (e.g., 5-6 member monocyclic heteroaryl) or polycyclic (e.g., 9-10 member bicyclic heteroaryl). When polycyclic, each pair of monocyclic rings shares two atoms and one bond, and at least one ring is aromatic. The heteroaryl group is attached to the rest of the molecule via a carbon atom or a heteroatom; the heteroaryl group is attached to the rest of the molecule via a ring with or without heteroatoms; the heteroaryl group is attached to the rest of the molecule via an aromatic ring or a non-aromatic ring. The heteroaryl group can be pyridyl, for example... .

[0307] The term "pharmaceutical acceptable" means that something is relatively non-toxic, safe, and suitable for patient use.

[0308] The term "pharmaceuticalally acceptable salt" refers to a salt obtained by reacting a compound with a pharmaceutically acceptable acid or base. When a compound contains a relatively acidic functional group, a base addition salt can be obtained by contacting the compound with a sufficient amount of a pharmaceutically acceptable base in a suitable inert solvent. Pharmaceutically acceptable base addition salts include, but are not limited to, lithium, sodium, potassium, calcium, aluminum, magnesium, zinc, bismuth, ammonium, and diethanolamine salts. When a compound contains a relatively basic functional group, an acid addition salt can be obtained by contacting the compound with a sufficient amount of a pharmaceutically acceptable acid in a suitable inert solvent. Pharmaceutically acceptable acids include inorganic and organic acids. See Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl, Camille G. Wermuth, 2011, 2nd Revised Edition) for details.

[0309] The term "pharmaceutical excipients" refers to all substances contained in a pharmaceutical preparation other than the active pharmaceutical ingredient, and are generally divided into two main categories: excipients and additives. For details, please refer to the Pharmacopoeia of the People's Republic of China (2020 Edition) and Handbook of Pharmaceutical Excipients (Paul J Sheskey, Bruno C Hancock, Gary P Moss, David J Goldfarb, 2020, 9th Edition).

[0310] The term “treatment” refers to a therapeutic approach. When a specific condition is involved, treatment means: (1) alleviating one or more biological manifestations of the disease or condition; (2) interfering with (a) one or more points in a biological cascade that causes or induces the condition or (b) one or more biological manifestations of the condition; (3) improving one or more symptoms, effects or side effects associated with the condition, or one or more symptoms, effects or side effects associated with the condition or its treatment; or (4) slowing the development of the condition or one or more biological manifestations of the condition.

[0311] The term "prevention" refers to the reduction of the risk of acquiring or developing a disease or disorder.

[0312] The term "therapeutic effective amount" refers to the amount of compound administered to a patient that is sufficient to effectively treat the disease. Therapeutic effective amount will vary depending on the type of compound, the type of disease, the severity of the disease, the patient's age, etc., but may be adjusted as appropriate by those skilled in the art.

[0313] The term "patient" refers to any animal, preferably a mammal, that is about to receive or has already received administration of the compound or composition according to embodiments of the invention, with humans being the most preferred. The term "mammal" includes any mammal. Examples of mammals include, but are not limited to, cattle, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, and humans, with humans being the most preferred.

[0314] The term "stereoisomer" includes conformational isomers and configurational isomers. Configurational isomers primarily include cis-trans isomers and optical isomers. The compounds described in this invention can exist in stereoisomer form, and therefore encompass all possible stereoisomer forms, including but not limited to cis-trans isomers, enantiomers, diastereomers, and optical isomers. The compounds described in this invention can exist in any of the aforementioned single stereoisomer forms, or in any combination or mixture of the aforementioned stereoisomers (e.g., cis-trans isomers, meso compounds, racemic compounds, enantiomers, diastereomers, optical isomers, or any mixture thereof).

[0315] Without violating common sense in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[0316] The reagents and raw materials used in this invention are all commercially available.

[0317] The positive and progressive effects of this invention are as follows: the compounds of this invention have good inhibitory activity against KRAS mutations, such as good inhibitory activity against the proliferation of NCI-H358, AsPC-1 and Capan-1 cancer cells containing KRAS mutations, while the inhibitory activity against the proliferation of KRAS wild-type PC-9 cells is relatively weak, showing good selectivity, and are expected to treat and / or prevent KRAS-mediated diseases. Detailed Implementation

[0318] The present invention is further illustrated below by way of embodiments, but the invention is not limited to the scope of the embodiments described herein. Experimental methods in the following embodiments that do not specify specific conditions were performed according to conventional methods and conditions, or as selected according to the product instructions.

[0319] I. Examples of Compound Preparation of the Invention

[0320] The structures of the compounds of this invention were determined by nuclear magnetic resonance (NMR) and / or liquid chromatography-mass spectrometry (LCMS). NMR chemical shifts (δ) are given in parts per million (ppm). NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer, with deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), or deuterated methanol (CD3OD) as the solvent, and tetramethylsilane (TMS) as the internal standard. LCMS measurements were performed using an Agilent 6410 Triple Quad LC / MS instrument.

[0321] The compounds of this invention, when purified by preparative high-performance liquid chromatography, have the following separation conditions:

[0322] Pillar: Sunfire®Prep C18 OBD TM 19*250mm*5μm, flow rate 25mL / min. Mobile phase: [A: water (0.1% ammonia, v / v) B: acetonitrile] or [A: water (0.1% formic acid, v / v) B: acetonitrile]; Mobile phase B%: isocratic or gradient elution; Detection wavelength: 214 / 254 nm.

[0323] In this invention, room temperature refers to ambient temperature, typically 10-35 ℃; overnight refers to 8-16 hours. Reflux refers to the solvent reflux temperature under normal pressure.

[0324] Example 1:

[0325] Compound 1-1 (shorter retention time): 2'-amino-9-[1-(2-aminopyridin-3-yl)ethyl]-6-({[(2R,7aS)-2-fluoro-2,3,5,6,7,7a-hexahydro-1H-pyridine-7a-yl]methyl}oxy)-6',7'-dihydro-5'H-spiro[3-oxa-5,7,9,12,13-pentazatetracyclo[6.6.2.0] 4,16 .0 12,15 [Hexadec-1(15),4(16),5,7,13-pentane-2,4'-cyclohexano[1,2-b]thiophene]-3'-formonitrile]

[0326]

[0327] Compounds 1-2 (longer retention times): 2'-amino-9-[1-(2-aminopyridin-3-yl)ethyl]-6-({[(2R,7aS)-2-fluoro-2,3,5,6,7,7a-hexahydro-1H-pyridine-7a-yl]methyl}oxy)-6',7'-dihydro-5'H-spiro[3-oxa-5,7,9,12,13-pentazatetracyclo[6.6.2.0] 4,16.0 12,15 [Hexadec-1(15),4(16),5,7,13-pentane-2,4'-cyclohexano[1,2-b]thiophene]-3'-formonitrile]

[0328]

[0329] Step 1: 6-[1-(3,4,5,6-tetrahydro-2H-pyran-2-yl)pyrazol-4-yl]-1,4-dioxaspiro[4,5]dec-6-ol

[0330]

[0331] 4-Iodo-1-(3,4,5,6-tetrahydro-2H-pyran-2-yl)pyrazole (2.5 g, 8.99 mmol) was dissolved in tetrahydrofuran (30 mL). A 1.3 mol / L tetrahydrofuran solution of isopropyl magnesium chloride and lithium chloride (10.4 mL, 13.5 mmol) was added under ice bath conditions. The reaction was carried out under nitrogen protection in an ice bath for 1 hour. Then, a tetrahydrofuran solution of 1,4-dioxaspiro[4.5]dec-6-one (1.68 g, 10.79 mmol) (5 mL) was added dropwise to the above reaction system, and the reaction was continued for 2 hours. The reaction was quenched with saturated ammonium chloride aqueous solution (20 mL), extracted with ethyl acetate (20 mL × 2), and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether / tetrahydrofuran = 4:1, v / v) to give the product as a yellow solid (1.7 g, 61% yield). ESI-MS m / z: 309.2 [M+1] + . 1 H NMR (400 MHz, CDCl3) δ 7.69-7.63 (m, 1H), 7.63-7.56 (m, 1H), 5.47-5.32 (m, 1H), 4.15-4.02(m, 1H), 3.95-3.62 (m, 4H), 3.49-3.35 (m, 1H), 2.39 (brs, 1H), 2.10-1.85 (m,6H), 1.77-1.40 (m, 8H).

[0332] Step 2: 5-Bromo-4-chloro-2-(methylthio)-6-({6-[1-(3,4,5,6-tetrahydro-2H-pyran-2-yl)pyrazol-4-yl]-1,4-dioxaspiro[4,5]dec-6-yl}oxy)pyrimidine

[0333]

[0334] 6-[1-(3,4,5,6-tetrahydro-2H-pyran-2-yl)pyrazol-4-yl]-1,4-dioxaspiro[4,5]dec-6-ol (1 g, 3.24 mmol) was dissolved in N,N'-dimethylformamide (10 mL), and 60% sodium hydride (190 mg, 4.86 mmol) was added under ice bath conditions, and the reaction was allowed to proceed for 10 minutes. Then, a solution of 5-bromo-4,6-dichloro-2-(methylthio)pyrimidine (1.07 g, 3.89 mmol) in N,N'-dimethylformamide (5 mL) was added dropwise to the above reaction system, and the reaction was allowed to continue for 2 hours. The reaction was quenched with water (10 mL), extracted with ethyl acetate (10 mL × 3), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether / tetrahydrofuran = 3:1, v / v) to give the product, a white solid (1.2 g, 68% yield). ESI-MS m / z: 545.2 [M+1] + .

[0335] Step 3: 9'-chloro-7'-(methylthio)-1'-(3,4,5,6-tetrahydro-2H-pyran-2-yl)spiro[1,4-dioxaspiro[4.5]decane-6,4'-pyrazolo[3',4':4,5]pyrano[2,3-d]pyrimidine]

[0336]

[0337] 5-Bromo-4-chloro-2-(methylthio)-6-({6-[1-(3,4,5,6-tetrahydro-2H-pyran-2-yl)pyrazol-4-yl]-1,4-dioxaspiro[4,5]dec-6-yl}oxy)pyrimidine (700 mg, 1.28 mmol) was dissolved in xylene (15 mL), and potassium carbonate (354 mg, 2.56 mmol), palladium acetate (28.8 mg, 0.13 mmol), and di(1-adamantyl)-n-butylphosphine (92 mg, 0.26 mmol) were added. The reaction was carried out under nitrogen protection at 130 °C for 2 hours. Ten batches of the above reaction were fed in parallel. The combined reaction solutions were concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether / tetrahydrofuran = 3:1, v / v) to give the product, a yellow oil (560 mg, yield 9%). ESI-MS m / z: 465.2 [M+1] + . 1H NMR (400 MHz, CDCl3) δ8.16 (s, 1H), 5.81 (dd, J = 9.6, 2.8 Hz, 1H), 4.09-4.00 (m, 1H), 3.83-3.49(m, 5H), 2.56 (s, 3H), 2.50-2.00 (m, 6H), 1.90-1.50 (m, 8H).

[0338] Step 4: 9'-chloro-7'-(methylthio)-1'H-spiro[1,4-dioxaspiro[4.5]decane-6,4'-pyrazolo[3',4':4,5]pyrano[2,3-d]pyrimidine]

[0339]

[0340] 9'-Chloro-7'-(methylthio)-1'-(3,4,5,6-tetrahydro-2H-pyran-2-yl)spiro[1,4-dioxaspiro[4.5]decane-6,4'-pyrazolo[3',4':4,5]pyrano[2,3-d]pyrimidine] (700 mg, 1.51 mmol) was dissolved in dioxane (10 mL), and 6 mol / L hydrochloric acid aqueous solution (10 mL) was added. The reaction was carried out at room temperature for 3 hours. The pH was adjusted to 7 with aqueous sodium hydroxide solution, and the resulting mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether / tetrahydrofuran = 3:1, v / v) to give the product, a yellow oil (450 mg, 78% yield). ESI-MS m / z: 381.1 [M+1] + .

[0341] Step 5: 2-{[(4-methoxyphenyl)methyl][7'-(methylthio)-1'H-spiro[1,4-dioxaspiro[4.5]decane-6,4'-pyrazolo[3',4':4,5]pyrano[2,3-d]pyrimidin]-9'-yl]amino} ethyl-1-ol

[0342]

[0343] 9'-chloro-7'-(methylthio)-1'H-spiro[1,4-dioxaspiro[4.5]decane-6,4'-pyrazolo[3',4':4,5]pyrano[2,3-d]pyrimidine] (450 mg, 1.18 mmol) was dissolved in dimethyl sulfoxide (10 mL), and 2-{[(4-methoxyphenyl)methyl]amino}ethane-1-ol (320 mg, 1.77 mmol) and diisopropylethylamine (458 mg, 3.54 mmol) were added. The reaction mixture was subjected to nitrogen protection at 120 °C for 3 hours. The mixture was diluted with water (10 mL), and the reaction solution was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether / tetrahydrofuran = 3:1, v / v) to give the product, a yellow oil (580 mg, 90% yield). ESI-MS m / z: 526.1 [M+1] + .

[0344] Step 6: 12'-[(4-methoxyphenyl)methyl]-9'-(methylthio)spiro[1,4-dioxaspiro[4.5]decane-6,5'-6-oxa-1,2,8,10,12-pentazatetracyclo[9.3.2.0] 4,15 .0 7,16 [Hexadecyl-2,4(15),7(16),8,10-pentanes]

[0345]

[0346] Triphenylphosphine (868 mg, 3.31 mmol) was dissolved in tetrahydrofuran (10 mL), and diisopropyl azodicarbonate (670 mg, 3.31 mmol) was added. Then, a tetrahydrofuran solution (10 mL) of 2-{[(4-methoxyphenyl)methyl][7'-(methylthio)-1'H-spiro[1,4-dioxaspiro[4.5]decane-6,4'-pyrazolo[3',4':4,5]pyrano[2,3-d]pyrimidin]-9'-yl]amino}ethane-1-ol (580 mg, 1.10 mmol) was added dropwise to the above reaction system. The reaction was carried out at room temperature for 2 hours under nitrogen protection. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether / tetrahydrofuran = 3:1, v / v) to give the product, a yellow oil (560 mg, crude). ESI-MS m / z: 508.1 [M+1] + .

[0347] Step 7: 9'-(methylthio)spiro[1,4-dioxaspiro[4.5]decane-6,5'-6-oxa-1,2,8,10,12-pentazatetracyclo[9.3.2.04,15.07,16]hexadecane-2,4(15),7(16),8,10-pentaene]

[0348]

[0349] 12'-[(4-methoxyphenyl)methyl]-9'-(methylthio)spiro[1,4-dioxaspiro[4.5]decane-6,5'-6-oxa-1,2,8,10,12-pentazatetracyclo[9.3.2.04,15.07,16]hexadecyl-2,4(15),7(16),8,10-pentaene] (560 mg, crude) was dissolved in trifluoroacetic acid (5 mL), followed by the addition of trifluoromethanesulfonic acid (1 mL), and the reaction was carried out at room temperature for 2 hours. The mixture was diluted with water (10 mL), and the pH was adjusted to 7 with saturated sodium bicarbonate solution. The resulting mixture was extracted with ethyl acetate (10 mL × 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether / tetrahydrofuran = 3:1, v / v) to give the product, a yellow oil (380 mg, 88% yield in two steps). ESI-MS m / z: 388.1 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.91 (s, 1H), 7.27(s, 1H), 4.60-4.38 (m, 1H), 4.35-4.16 (m, 1H), 3.85-3.66 (m, 4H), 3.45-3.00(m, 2H), 2.43 (s, 3H), 2.15-1.75 (m, 4H), 1.72-1.47 (m, 4H).

[0350] Step 8: 2-[(diphenylmethyl)amino]-3-ethylpyridine

[0351]

[0352] 2-Bromo-3-ethylpyridine (1 g, 5.37 mmol) and benzophenone imine (1.46 g, 8.06 mmol) were dissolved in 1,4-dioxane (20 mL), followed by the addition of 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (0.49 g, 0.54 mmol) and tris(dibenzylacetone)palladium (0.31 g, 0.54 mmol), and then cesium carbonate (3.5 g, 10.75 mmol). The reaction was carried out under nitrogen protection at 100 °C for 4 hours. The mixture was diluted with water (10 mL), extracted with ethyl acetate (20 mL × 3), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was then subjected to silica gel column chromatography (petroleum ether / tetrahydrofuran = 1:2, v / v) to give the product as a yellow oil (1.1 g, 72% yield). ESI-MS m / z: 287.2 [M+1] + . 1 HNMR (400 MHz, CDCl3) δ 8.11 (dd, J = 4.8, 2.0 Hz, 1H), 7.80-7.10 (m, 11H), 6.87 (dd, J = 7.6, 4.8 Hz, 1H), 2.51 (q, J = 7.6 Hz, 2H), 1.21 (d, J = 7.6Hz, 3H).

[0353] Step 9: 3-(1-Bromoethyl)-2-[(diphenylmethyl)amino]pyridine

[0354]

[0355] 2-[(diphenylmethylimide)amino]-3-ethylpyridine (1.1 g, 3.84 mmol) was dissolved in carbon tetrachloride (20 mL), and N-bromosuccinimide (0.75 g, 4.23 mmol) and azobisisobutyronitrile (0.06 g, 0.38 mmol) were added. The reaction mixture was reacted overnight at 90 °C under nitrogen protection. The reaction solution was diluted with sodium bicarbonate aqueous solution (10 mL), extracted with ethyl acetate (20 mL × 3), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the residue was concentrated under reduced pressure and subjected to silica gel column chromatography (petroleum ether / ethyl acetate = 5:1, v / v) to give the product as a yellow oil (570 mg, yield 41%). ESI-MS m / z: 365.2 [M+1] + . 1H NMR (400 MHz, CDCl3) δ 8.11 (dd, J = 4.8, 1.6 Hz, 1H), 7.85 (dd, J = 7.6, 1.6 Hz, 1H), 7.78-7.20 (m, 10H), 6.97 (dd, J = 8.0, 4.8Hz, 1H), 5.53 (q, J = 6.8 Hz, 1H), 2.00 (d, J = 6.8 Hz, 3H).

[0356] Step 10: 12'-(1-{2-[(diphenylmethylimino)amino]pyridin-3-yl}ethyl)-9'-(methylthio)spiro[1,4-dioxaspiro[4.5]decane-6,5'-6-oxa-1,2,8,10,12-pentazatetracyclo[9.3.2.0] 4,15 .0 7,16 [Hexadecyl-2,4(15),7(16),8,10-pentanes]

[0357]

[0358] 9'-(methylthio)spiro[1,4-dioxaspiro[4.5]decane-6,5'-6-oxa-1,2,8,10,12-pentazatetracyclo[9.3.2.0] 4,15 .0 7,16 [Hexadecyl-2,4(15),7(16),8,10-pentaene] was dissolved in N,N-dimethylformamide (3 mL), and 60% sodium hydride (20 mg, 0.49 mmol) was added. After reacting for 10 minutes, 3-(1-bromoethyl)-2-[(diphenylmethylethylene)amino]pyridine was added, and the reaction was carried out at 25 °C for 1 hour. The reaction solution was quenched with water (10 mL) and extracted with ethyl acetate (2 × 10 mL). The organic phases were combined and washed with saturated brine (1 × 10 mL). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (tetrahydrofuran / petroleum ether, 0-50% gradient elution) to give the product, a yellow oil (40 mg, yield 61%). ESI-MS m / z: 672.2 [M+1] + .

[0359] Step 11: 7-[1-(2-aminopyridin-3-yl)ethyl]-10-(methylthio)spiro[13-oxa-3,4,7,9,11-pentazatetracyclo[6.6.2.0] 4,15 .0 12,16 [hexadec-1(15),2,8(9),10,12(16)-pentane-14,1'-cyclohexane]-2'-one

[0360]

[0361] 12'-(1-{2-[(diphenylmethylimino)amino]pyridin-3-yl}ethyl)-9'-(methylthio)spiro[1,4-dioxaspiro[4.5]decane-6,5'-6-oxa-1,2,8,10,12-pentazatetracyclo[9.3.2.0] 4,15 .0 7,16 [Hexadecyl-2,4(15),7(16),8,10-pentaene] (40 mg, 0.06 mmol) was dissolved in 4 mol / L hydrochloric acid / dioxane solution (0.5 mL), and 4 mol / L hydrochloric acid aqueous solution (0.5 mL) was added. The reaction mixture was stirred overnight at 80 °C. The reaction mixture was cooled to room temperature and slowly added dropwise to saturated sodium bicarbonate solution (10 mL). The resulting mixture was extracted with ethyl acetate (2 × 10 mL). The organic phases were combined and washed with saturated brine (1 × 20 mL). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (tetrahydrofuran-petroleum ether, 0-80% gradient elution) to give the product, a yellow oil (40 mg, crude). ESI-MS m / z: 464.3 [M+1] + .

[0362] Step 12: ({[(2-methylprop-2-yl)oxy]carbonyl}(3-{1-[10-(methylthio)-2'-oxoylidenespiro[13-oxa-3,4,7,9,11-pentazatetracyclo[6.6.2.0]) 4,15 .0 12,16 [Hexadecyl-1(15),2,8(9),10,12(16)-pentane-14,1'-cyclohexane]-7-yl]ethylpyridin-2-yl)amino)methane-2-methylpropyl-2-yl ester]

[0363]

[0364] 7-[1-(2-aminopyridin-3-yl)ethyl]-10-(methylthio)spiro[13-oxa-3,4,7,9,11-pentazatetracyclo[6.6.2.0] 4,15 .0 12,16Hexadecyl-1(15),2,8(9),10,12(16)-pentane-14,1'-cyclohexane]-2'-one was dissolved in dichloromethane (2 mL), and di-tert-butyl dicarbonate (57 mg, 0.26 mmol) and 4-dimethylaminopyridine (11 mg, 0.09 mmol) were added. The reaction mixture was stirred at 25 °C for 3 hours. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (2 × 10 mL). The organic phases were combined and washed with saturated brine (1 × 10 mL). The organic phases were dried over anhydrous sodium sulfate and filtered. After concentration of the filtrate under reduced pressure, the residue was purified by silica gel column chromatography (tetrahydrofuran / petroleum ether, 0-50% gradient elution) to give ({[(2-methylpropyl-2-yl)oxy]carbonyl}(3-{1-[10-(methylthio)-2'-oxoylidenespiro[13-oxa-3,4,7,9,11-pentazatetracyclo[6.6.2.0]). 4,15 .0 12,16 Hexadecyl-1(15),2,8(9),10,12(16)-pentaen-14,1'-cyclohexane]-7-yl]ethyl}pyridin-2-yl)amino)methane-2-methylpropyl-2-yl ester, yellow oil (112 mg, crude). ESI-MS m / z: 664.4 [M+1] + .

[0365] Step 13: [(3-{1-[2'-amino-3'-cyano-9-(methylthio)-6',7'-dihydro-5'H-spiro[6-oxa-1,2,8,10,12-pentazatetracyclo[9.3.2.0]] 4,15 .0 7,16 [Hexadecyl-2,4(15),7(16),8,10-pentaen-5,4'-cyclohexano[1,2-b]thiophene]-12-yl]ethyl}pyridin-2-yl){[(2-methylprop-2-yl)oxy]carbonyl}amino]methane-2-methylprop-2-yl ester]

[0366]

[0367] To ({[(2-methylprop-2-yl)oxy]carbonyl}(3-{1-[10-(methylthio)-2'-oxoylspiro[13-oxa-3,4,7,9,11-pentazatetracyclo[6.6.2.0] 4,15 .0 12,16L-proline (25 mg, 0.17 mmol), 4 Å molecular sieve (98 mg), and sulfur powder (216 mg, 0.84 mmol) were added to an ethanol solution (2 mL) of hexadecene-1(15),2,8(9),10,12(16)-pentene-14,1'-cyclohexane]-7-yl]ethyl}pyridin-2-yl)amino)methane-2-methylpropyl-2-yl ester (112 mg, 0.17 mmol) and malononitrile (56 mg, 0.84 mmol). The reaction mixture was stirred overnight at 80 °C under argon protection. The reaction mixture was cooled to room temperature, diluted with water (10 mL), and extracted with ethyl acetate (2 × 10 mL). The organic phases were combined and washed with saturated brine (1 × 10 mL). The organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (tetrahydrofuran / petroleum ether, elution gradient 0-80%) to give the product, a yellow oil (60 mg). ESI-MS m / z: 744.4 [M+1] + .

[0368] Step 14: {[3'-cyano-3-(methylthio)-6-{1-[2-(2,2,8,8-tetramethyl-4,6-dioxane-5-aza-3,7-dioxane-5-yl)pyridin-3-yl]ethyl}-6',7'-dihydro-5'H-spiro[15-oxa-2,4,6,9,10-pentazatetracyclo[10.2.2.0] 5,14 .0 9,13 [Hexadec-1(14),2,4,10,12(13)-pentaen-16,4'-cyclohexano[1,2-b]thiophene]-2'-yl]{[(2-methylprop-2-yl)oxy]carbonyl}amino}methane-2-methylprop-2-yl ester]

[0369]

[0370] [(3-{1-[2'-amino-3'-cyano-9-(methylthio)-6',7'-dihydro-5'H-spiro[6-oxa-1,2,8,10,12-pentazatetracyclo[9.3.2.0]] 4,15 .0 7,16Hexadecyl-2,4(15),7(16),8,10-pentene-5,4'-cyclohexano[1,2-b]thiophene]-12-yl]ethyl}pyridin-2-yl){[(2-methylprop-2-yl)oxy]carbonyl}amino]methane-2-methylprop-2-yl ester (60 mg, 0.08 mmol) was dissolved in dichloromethane (4 mL), and 4-dimethylaminopyridine (10 mg, 0.08 mmol) and di-tert-butyl dicarbonate (88 mg, 0.4 mmol) were added. The reaction was carried out at 40 °C for 6 hours under nitrogen protection. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / tetrahydrofuran = 3:1, v / v) to give the product as a yellow oil (50 mg, yield 66%). ESI-MS m / z: 944.1 [M+1] + .

[0371] Step 15: ({3'-cyano-10-[methyl(oxoyne)-λ4-thio]-7-{1-[2-({[(2-methylprop-2-yl)oxy]carbonyl}amino)pyridin-3-yl]ethyl}-6',7'-dihydro-5'H-spiro[13-oxa-3,4,7,9,11-pentazatetracyclo[6.6.2.0]) 4,15 .0 12,16 [Hexadecyl-1(15),2,8(9),10,12(16)-pentane-14,4'-cyclohexano[1,2-b]thiophene]-2'-yl}amino)methane-2-methylpropyl-2-yl ester]

[0372]

[0373] The following is a list of compounds: {[3'-cyano-3-(methylthio)-6-{1-[2-(2,2,8,8-tetramethyl-4,6-dioxane-5-aza-3,7-dioxane-5-yl)pyridin-3-yl]ethyl}-6',7'-dihydro-5'H-spiro[15-oxa-2,4,6,9,10-pentazatetracyclo[10.2.2.0] 5,14 .0 9,13Hexadecyl-1(14),2,4,10,12(13)-pentene-16,4'-cyclohexano[1,2-b]thiophene]-2'-yl]{[(2-methylpropyl-2-yl)oxy]carbonyl}amino}methane-2-methylpropyl-2-yl ester (20 mg, 0.02 mmol) was dissolved in tetrahydrofuran (0.5 mL) and water (0.5 mL), and potassium peroxymonosulfonate (19 mg, 0.03 mmol) was added. The reaction mixture was stirred at 25 °C for 2 hours. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (2 × 10 mL). The organic phases were combined and washed with saturated brine (1 × 50 mL). The organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give the product, a yellow oil (20 mg, crude). ESI-MS m / z: 760.1 [M+1] + .

[0374] Step 16: {[3'-cyano-6-({[(2R,7aS)-2-fluoro-2,3,5,6,7,7a-hexahydro-1H-pyridine-7a-yl]methyl}oxy)-9-{1-[2-({[(2-methylprop-2-yl)oxy]carbonyl}amino)pyridin-3-yl]ethyl}-6',7'-dihydro-5'H-spiro[3-oxa-5,7,9,12,13-pentazatetracyclo[6.6.2.0]} 4,16 .0 12,15 Hexadecyl-1(15),4(16),5,7,13-pentane-2,4'-cyclohexano[1,2-b]thiophene]-2'-yl]aminomethane-2-methylpropyl-2-yl ester

[0375]

[0376] [(2R,7aS)-2-fluoro-2,3,5,6,7,7a-hexahydro-1H-pyridine-7a-yl]methanol (40 mg, 0.25 mmol) was dissolved in tetrahydrofuran (2 mL), and 1 mol / L potassium tert-butoxide tetrahydrofuran solution (0.22 mL, 0.22 mmol) was added, and the mixture was stirred for 10 minutes. Under nitrogen protection, [(2R,7aS)-2-fluoro-2,3,5,6,7,7a-hexahydro-1H-pyridine-7a-yl]methanol (30 mg, 0.03 mmol) was added, and the reaction mixture was stirred at 25 °C for 1 hour. The reaction mixture was cooled to room temperature, diluted with water (10 mL), and extracted with ethyl acetate (2 × 10 mL). The organic phases were combined and washed with saturated brine (1 × 20 mL). The organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the product, a colorless oil (32 mg, crude product). ESI-MS m / z: 855.1 [M+1]+ .

[0377] Step 17: 2'-Amino-9-[1-(2-aminopyridin-3-yl)ethyl]-6-({[(2R,7aS)-2-fluoro-2,3,5,6,7,7a-hexahydro-1H-pyridine-7a-yl]methyl}oxy)-6',7'-dihydro-5'H-spiro[3-oxa-5,7,9,12,13-pentazatetracyclo[6.6.2.0] 4,16 .0 12,15 [Hexadecyl-1(15),4(16),5,7,13-pentaen-2,4'-cyclohexano[1,2-b]thiophene]-3'-carboxynitrile (compound 1-1) and 2'-amino-9-[1-(2-aminopyridin-3-yl)ethyl]-6-({[(2R,7aS)-2-fluoro-2,3,5,6,7,7a-hexahydro-1H-pyridine-7a-yl]methyl}oxy)-6',7'-dihydro-5'H-spiro[3-oxa-5,7,9,12,13-pentazatetracyclo[6.6.2.0] 4,16 .0 12,15 [Hexadec-1(15),4(16),5,7,13-pentane-2,4'-cyclohexano[1,2-b]thiophene]-3'-formonitrile (compounds 1-2)

[0378]

[0379] {[3'-cyano-6-({[(2R,7aS)-2-fluoro-2,3,5,6,7,7a-hexahydro-1H-pyridine-7a-yl]methyl}oxy)-9-{1-[2-({[(2-methylprop-2-yl)oxy]carbonyl}amino)pyridin-3-yl]ethyl}-6',7'-dihydro-5'H-spiro[3-oxa-5,7,9,12,13-pentazatetracyclo[6.6.2.0] 4,16 .0 12,15 Hexadecyl-1(15),4(16),5,7,13-pentene-2,4'-cyclohexano[1,2-b]thiophene]-2'-yl]aminomethane-2-methylpropyl-2-yl ester (40 mg, crude) was dissolved in dichloromethane (1 mL) and trifluoroacetic acid (0.5 mL) was added. The reaction mixture was stirred at 25 °C for 2 hours. The reaction mixture was diluted with water (10 mL), and the pH was adjusted to 7 with saturated sodium bicarbonate aqueous solution. The resulting mixture was extracted with ethyl acetate (2 × 10 mL). The organic phases were combined and washed with saturated brine (1 × 10 mL). The organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by preparative high performance liquid chromatography [mobile phase: A: water (0.1% ammonia, v / v), B: acetonitrile; B%: 45-55%, v / v], yielding two products.

[0380] Under preparative high-performance liquid chromatography (HPLC) conditions, compound 1-1, a nearly white solid (0.35 mg), was retained for 3.7 minutes. ESI-MS m / z: 655.3 [M+1] + . 1 H NMR (400 MHz, CD3OD) δ 7.93 (s, 1H),7.75 (d, J = 7.2 Hz, 1H), 7.68-7.52 (m, 1H), 7.13 (s, 1H), 6.84-6.70 (m, 1H),6.36-6.10 (m, 1H), 1.65 (d, J= 6.8 Hz, 3H). 19 F NMR (377 MHz, DMSO-d6) δ -173.39- -173.65.

[0381] Under preparative high-performance liquid chromatography (HPLC) conditions, compounds 1-2, a near-white solid (0.2 mg), were retained for 5.3 minutes. ESI-MS m / z: 655.3 [M+1] + . 1 H NMR (400 MHz, CD3OD) δ 7.94 (s, 1H), 7.76 (d, J = 7.6 Hz, 1H), 7.68-7.52 (m, 1H), 7.14 (s, 1H), 6.83-6.70 (m, 1H), 6.27-6.09 (m, 1H), 5.28 (d, J = 54.0 Hz, 1H), 4.45-4.10 (m, 4H), 3.35-3.07(m, 5H), 3.06-2.92 (m, 1H), 2.74-2.50 (m, 3H), 2.43-2.07 (m, 5H), 2.05-1.83(m, 4H), 1.65 (d, J = 6.8 Hz, 3H). 19 F NMR (377 MHz, DMSO-d6) δ -173.53.

[0382] II. Examples of Biological Testing

[0383] Test Example 1: Inhibitory activity of the compound on the proliferation of human non-small cell lung cancer cells NCI-H358 (KRAS G12C mutation), human metastatic pancreatic adenocarcinoma cells AsPC-1 (KRAS G12D mutation), human pancreatic cancer cells Capan-1 (KRAS G12V mutation), and human lung cancer cells PC-9 (KRAS wild-type).

[0384] Cell sources: Human non-small cell lung cancer cells NCI-H358 were purchased from Shanghai Dijin Biotechnology Co., Ltd.; human metastatic pancreatic adenocarcinoma cells AsPC-1 were purchased from the Institute of Cell Biology, Chinese Academy of Sciences; human pancreatic cancer cells Capan-1 were purchased from Shanghai Dior Biotechnology Co., Ltd.; and human lung cancer cells PC-9 were purchased from Nanjing Kebai Biotechnology Co., Ltd.

[0385] Cells in the logarithmic growth phase were seeded in 96-well plates and cultured at 37°C and 5% CO2 for 1 day. Then, serially diluted test compounds were added. Specifically, the compound stock solution (10 mmol / L) pre-dissolved in DMSO was serially diluted (4-fold) to 10 different concentrations. Each 96-well plate was then diluted 10-fold with culture medium to the target concentration. Finally, 10 μl of the compound solution was added to each well of the cell-seedled 96-well plate to achieve the target concentrations (10000, 2500, 625, 156, 39, 10, 2.5, 0.6, 0.15, 0.04 nmol / L). Each concentration was tested in triplicate, and control groups were set up with cell culture medium and cell-free culture medium. After culturing at 37°C and 5% CO2 for 72 hours, 50 μl of CellTiter-Glo was added to each well. ® 2.0 Reagent (luciferase-ATP bioluminescence assay reagent, purchased from Promega, catalog number G9243): After shaking for 2 min and incubating at room temperature for 8 min, the luminescence intensity was measured (collection time was 100 ms). The inhibition rate of cell proliferation by each concentration of the compound was calculated.

[0386]

[0387] Data was analyzed using GraphPad Prism 8.3 software. A nonlinear S-curve regression was used to fit the data to derive the dose-response curve, from which the IC was calculated. 50 The values ​​are shown in Table 1.

[0388] Table 1

[0389]

[0390] Where A: ≤0.02μM; 0.02μM <B≤0.1μM; 0.1μM<C≤1μM; 1μM<D≤5μM; E: > 5μM; "\" indicates not tested.

[0391] The test results show that the compound of the present invention has good inhibitory activity on the proliferation of NCI-H358, AsPC-1 and Capan-1 cells containing KRAS mutations, while its inhibitory activity on the proliferation of wild-type KRAS PC-9 cells is relatively weak, showing good selectivity.

[0392] Test Example 2: Pharmacokinetic Properties of the Compound in SD Rats

[0393] 1. Experimental Materials

[0394] SD rats (female, 180-220 g, 6-8 weeks old, purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd.)

[0395] 2. Experimental Procedure

[0396] After animals were fasted overnight, the pharmacokinetic characteristics of the compound were tested after a single tail vein injection and oral administration. The compound was prepared as a clear solution or a homogeneous suspension. The intravenous injection dose was 1 mg / kg, and the oral dose was 5 mg / kg. Whole blood samples were collected from the submandibular vein at 0.083h, 0.25h, 0.5h, 1h, 2h, 4h, 6h, 8h, and 24h, and plasma samples were obtained by centrifugation at 4℃ and 8000 rpm for 5 minutes.

[0397] Take 40 μL of the above plasma sample into a 96-well plate, add 300 μL of acetonitrile solution containing the internal standard (containing 50 ng / mL tolbutamide), vortex thoroughly for 10 minutes, and centrifuge at 4℃ and 6000 rpm for 20 minutes. Take 100 μL of the supernatant, dilute it with 300 μL of ultrapure water, and inject it into the plate for LC-MS / MS quantitative analysis of the blood drug concentration, and calculate the main pharmacokinetic parameters.

[0398] 3. Experimental Results

[0399] Table 2: Pharmacokinetic Results of SD Rats

[0400]

[0401] 4. Experimental Conclusions

[0402] Test results show that the compound of the present invention has good pharmacokinetic properties and absolute bioavailability, and can be administered orally.

Claims

1. A compound of Formula I, its stereoisomer, or a pharmaceutically acceptable salt thereof, in, X1 is C(R) 3 )2, O, S, S(O), S(O)2 or NR 4 ; X2 and X3 are independently O, S, and CR, respectively. 5A , N or NR 5B ; X4, X8, and X9 are each independently C or N; It is a single or double bond, ring B is aromatic, and at least one of X2, X3, X4, X8, and X9 is O, S, N, or NR. 5B ; X5 is C(R) 6 )2 or NR 7 ; X6 and X7 are each independently C(R) 8 )2; m can be 0, 1, 2, 3, 4, or 5; n is 0, 1, or 2; Each R 3 R 5A and R 8 Each can be independently represented by hydrogen, deuterium, halogen, cyano, nitro, hydroxyl, or -N(R) 9 )2、-S(O)2R 10 -C(O)R 10 -C(O)OR 10 -OC(O)R 10 -CON(R) 10 )2、-S(O)2N(R 10 2. C 1-6 Alkyl, with one or more R 3a Replacement C 1-6 Alkyl, -OC 1-6 Alkyl, with one or more R 3b Replacement -OC 1-6 Alkyl, -SC 1-6 Alkyl, with one or more R 3c Replacement -SC 1-6 Alkyl, C 2-6 alkenyl, with one or more R 3d Replacement C 2-6 alkenyl, C 2-6 alkynyl group, with one or more R 3e Replacement C 2-6 alkynyl group, C 3-12 cycloalkyl, with one or more R 3f Replacement C 3-12 cycloalkyl, C 3-12 Cycloalkenyl, with one or more R 3g Replacement C 3-12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, with one or more R 3h Substituted 3-12-membered heterocyclic alkyl, 3-12-membered heterocyclic alkenyl, or substituted with one or more R 3i Substituted 3-12 membered heterocyclic alkenyl groups, C 6-10 aryl, with one or more R 3j Replacement C 6-10 aryl, 5-10 heteroaryl, or with one or more R 3k Substituted 5-10 heteroaryl groups; Each R 3a R 3b R 3c R 3d R 3e R 3f R 3g R 3h R 3i R 3j and R 3k Each can be independently represented as deuterium, halogen, cyano, hydroxyl, oxo (=O), -NH2, or -NH(C). 1-6 alkyl), -N(C) 1-6 Alkyl)2, C 1-6 Alkyl groups, C substituted with one or more halogens 1-6 Alkyl groups, C groups substituted with one or more hydroxyl groups 1-6 Alkyl groups, C atoms substituted with one or more deuterium atoms 1-6 Alkyl, -OC 1-6 Alkyl groups, -OC groups substituted with one or more halogens 1-6 Alkyl, -SC 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 cycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, 3-12 membered heterocyclic alkenyl, C 6-10 Aryl or 5-10 heteroaryl groups; Or, two R atoms on the same ring carbon atom 8 Formation of oxygen groups; Each R 5B Independently hydrogen, hydroxyl, cyano, -N(R) 9 )2、-S(O)2R 10 -C(O)R 10 -C(O)OR 10 -CON(R) 10 )2、-S(O)2N(R 10 2. C 1-6 Alkyl, with one or more R 5b1 Replacement C 1-6 Alkyl, C 2-6 alkenyl, with one or more R 5b2 Replacement C 2-6 alkenyl, C 2-6 alkynyl group, with one or more R 5b3 Replacement C 2-6 alkynyl group, C 3-12 cycloalkyl, with one or more R 5b4 Replacement C 3-12 cycloalkyl, C 3-12 Cycloalkenyl, with one or more R 5b5 Replacement C 3-12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, with one or more R 5b6 Substituted 3-12-membered heterocyclic alkyl, 3-12-membered heterocyclic alkenyl, or substituted with one or more R 5b7 Substituted 3-12 membered heterocyclic alkenyl groups, C 6-10 aryl, with one or more R 5b8 Replacement C 6-10 aryl, 5-10 heteroaryl, or with one or more R 5b9 Substituted 5-10 heteroaryl groups; Each R 5b1 R 5b2 R 5b3 R 5b4 R 5b5 R 5b6 R 5b7 R 5b8 and R 5b9 Each can be independently represented as deuterium, halogen, cyano, hydroxyl, oxo (=O), -NH2, or -NH(C). 1-6 alkyl), -N(C) 1-6 Alkyl)2, C 1-6 Alkyl groups, C substituted with one or more halogens 1-6 Alkyl groups, C groups substituted with one or more hydroxyl groups 1-6 Alkyl groups, C atoms substituted with one or more deuterium atoms 1-6 Alkyl, -OC 1-6 Alkyl groups, -OC groups substituted with one or more halogens 1-6 Alkyl, -SC 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 cycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, 3-12 membered heterocyclic alkenyl, C 6-10 Aryl or 5-10 heteroaryl groups; R 4 Hydrogen, hydroxyl, cyano, -N(R) 9 )2、-S(O)2R 10 -C(O)R 10 -C(O)OR 10 -CON(R) 10 )2、-S(O)2N(R 10 2. C 1-6 Alkyl, with one or more R 4a Replacement C 1-6 Alkyl, C 2-6 alkenyl, with one or more R 4b Replacement C 2-6 alkenyl, C 2-6 alkynyl group, with one or more R 4c Replacement C 2-6 alkynyl group, C 3-12 cycloalkyl, with one or more R 4d Replacement C 3-12 cycloalkyl, C 3-12 Cycloalkenyl, with one or more R 4e Replacement C 3-12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, with one or more R 4f Substituted 3-12-membered heterocyclic alkyl, 3-12-membered heterocyclic alkenyl, or substituted with one or more R 4g Substituted 3-12 membered heterocyclic alkenyl groups, C 6-10 aryl, with one or more R 4h Replacement C 6-10 aryl, 5-10 heteroaryl, or with one or more R 4i Substituted 5-10 heteroaryl groups; Each R 4a R 4b R 4c R 4d R 4e R 4f R 4g R 4h and R 4i Each can be independently represented as deuterium, halogen, cyano, hydroxyl, oxo (=O), -NH2, or -NH(C). 1-6 alkyl), -N(C) 1-6 Alkyl)2, C 1-6 Alkyl groups, C substituted with one or more halogens 1-6 Alkyl groups, C groups substituted with one or more hydroxyl groups 1-6 Alkyl groups, C atoms substituted with one or more deuterium atoms 1-6 Alkyl, -OC 1-6 Alkyl groups, -OC groups substituted with one or more halogens 1-6 Alkyl, -SC 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 cycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, 3-12 membered heterocyclic alkenyl, C 6-10 Aryl or 5-10 heteroaryl groups; Each R 6 Independently hydrogen, deuterium, halogen, cyano, nitro, hydroxyl, -N(R) 9 )2、-S(O)2R 12 -C(O)R 12 C 1-6 Alkyl, with one or more R 6a Replacement C 1-6 Alkyl, -OC 1-6 Alkyl, with one or more R 6b Replacement -OC 1-6 Alkyl, -SC 1-6 Alkyl, with one or more R 6c Replacement -SC 1-6 Alkyl, C 2-6 alkenyl, with one or more R 6d Replacement C 2-6 alkenyl, C 2-6 alkynyl group, with one or more R 6e Replacement C 2-6 alkynyl group, C 3-12 cycloalkyl, with one or more R 6f Replacement C 3-12 cycloalkyl, C 3-12 Cycloalkenyl, with one or more R 6g Replacement C 3-12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, with one or more R 6h Substituted 3-12-membered heterocyclic alkyl, 3-12-membered heterocyclic alkenyl, or substituted with one or more R 6i Substituted 3-12 membered heterocyclic alkenyl groups, C 6-10 aryl, with one or more R 6j Replacement C 6-10 aryl, 5-10 heteroaryl, or with one or more R 6k Substituted 5-10 heteroaryl groups; Each R 9 Independently hydrogen, hydroxyl, cyano, C 1-6 Alkyl, C 3-12 cycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, or 3-12 membered heterocyclic alkenyl; Each R 6a R 6b R 6c R 6d R 6e R 6f R 6g R 6h R 6i R 6j and R 6k Each is independently a deuterium, halogen, cyano, hydroxyl, -N(R) 9 )2、-S(O)2R 10 -C(O)N(R) 10 )2、-C(O)R 10 -C(O)OR 10 , , C 1-6 Alkyl, with one or more R 6-a Replacement C 1-6 Alkyl, -OC 1-6 Alkyl, with one or more R 6-b Replacement -OC 1-6 Alkyl, -SC 1-6 Alkyl, with one or more R 6-c Replacement -SC 1-6 Alkyl, C 2-6 alkenyl, with one or more R 6-d Replacement C 2-6 alkenyl, C 2-6 alkynyl group, with one or more R 6-e Replacement C 2-6 alkynyl group, C 3-12 cycloalkyl, with one or more R 6-f Replacement C 3-12 cycloalkyl, C 3-12 Cycloalkenyl, with one or more R 6-g Replacement C 3-12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, with one or more R 6-h Substituted 3-12-membered heterocyclic alkyl, 3-12-membered heterocyclic alkenyl, or substituted with one or more R 6-i Substituted 3-12 membered heterocyclic alkenyl groups, C 6-10 aryl, with one or more R 6-j Replacement C 6-10 aryl, 5-10 heteroaryl, or with one or more R 6-k Substituted 5-10 heteroaryl groups; Each R 10 Independently hydrogen, C 1-6 Alkyl, C 3-12 cycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, or 3-12 membered heterocyclic alkenyl; Each R 4-i Independently hydrogen or C 1-6 alkyl; Each R 6-a R 6-b R 6-c R 6-d R 6-e R 6-f R 6-g R 6-h R 6-i R 6-j and R 6-k Each can be independently represented by deuterium, halogen, cyano, hydroxyl, oxo (=O), or -N (R). 11 )2、-S(O)2R 13 -C(O)N(R) 13 )2、-C(O)R 13 C 1-6 Alkyl, with one or more R 6 -a-1 Replacement C 1-6 Alkyl, -OC 1-6 Alkyl, with one or more R 6-a-2 Replacement -OC 1-6 Alkyl, -SC 1-6 Alkyl, with one or more R 6-a-3 Replacement -SC 1-6 Alkyl, C 2-6 alkenyl, with one or more R 6-a-4 Replacement C 2-6 alkenyl, C 2-6 alkynyl group, with one or more R 6-a-5 Replacement C 2-6 alkynyl group, C 3-12 cycloalkyl, with one or more R 6-a-6 Replacement C 3-12 cycloalkyl, C 3-12 Cycloalkenyl, with one or more R 6-a-7 Replacement C 3-12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, with one or more R 6-a-8 Substituted 3-12-membered heterocyclic alkyl, 3-12-membered heterocyclic alkenyl, or substituted with one or more R 6-a-9 Substituted 3-12 membered heterocyclic alkenyl groups, C 6-10 aryl, with one or more R 6-a-10 Replacement C 6-10 aryl, 5-10 heteroaryl, or with one or more R 6-a-11 Substituted 5-10 heteroaryl groups; Each R 11 Independently hydrogen, hydroxyl, cyano, C 1-6 Alkyl, -C(O)-C 1-6 Alkyl, C 3-12 cycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, or 3-12 membered heterocyclic alkenyl; Each R 13 Independently hydrogen, hydroxyl, C 1-6 Alkyl, C 3-12 cycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, or 3-12 membered heterocyclic alkenyl; Each R 6-a-1 R 6-a-2 R 6-a-3 R 6-a-4 R 6-a-5 R 6-a-6 R 6-a-7 R 6-a-8 R 6-a-9 R 6-a-10 and R 6-a-11 Each can be independently classified as deuterium, halogen, cyano, hydroxyl, -NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl)2, C 1-6 Alkyl or -OC 1-6 alkyl; Or, in X6, R 8 and R 6 Together with their respective attached ring atoms, they form C 3-12 cycloalkyl, with one or more R 8a1 Replacement C 3-12 cycloalkyl, C 3-12 Cycloalkenyl, with one or more R 8b1 Replacement C 3-12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, with one or more R 8c1 Substituted 3-12-membered heterocyclic alkyl, 3-12-membered heterocyclic alkenyl, or substituted with one or more R 8d1 Substituted 3-12 membered heterocyclic alkenyl groups, C 6-10 aryl, with one or more R 8e1 Replacement C 6-10 aryl, 5-10 heteroaryl, or with one or more R 8f1 Substituted 5-10 heteroaryl groups; Each R 8a1 R 8b1 R 8c1 R 8d1 R 8e1 and R 8f1 Each can be independently classified as deuterium, halogen, cyano, hydroxyl, -NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl)2, C 1-6 Alkyl or -OC 1-6 alkyl; Each R 12 Independently hydrogen, halogen, hydroxyl, -NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl)2, C 1-6 Alkyl, with one or more R 12a Replacement C 1-6 Alkyl, -OC 1-6 Alkyl, with one or more R 12b Replacement -OC 1-6 Alkyl, C 2-6 alkenyl, with one or more R 12c Replacement C 2-6 alkenyl, C 2-6 alkynyl group, with one or more R 12d Replacement C 2-6 alkynyl group, C 3-12 cycloalkyl, with one or more R 12e Replacement C 3-12 cycloalkyl, C 3-12 Cycloalkenyl, with one or more R 12f Replacement C 3-12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, with one or more R 12g Substituted 3-12-membered heterocyclic alkyl, 3-12-membered heterocyclic alkenyl, or substituted with one or more R 12h Substituted 3-12 membered heterocyclic alkenyl groups, C 6-10 aryl, with one or more R 12i Replacement C 6-10 aryl, 5-10 heteroaryl, or with one or more R 12j Substituted 5-10 heteroaryl groups; Each R 12a R 12b R 12c R 12d R 12e R 12f R 12g R 12h R 12i and R 12j Each can be independently represented as deuterium, halogen, cyano, oxo, hydroxyl, -NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl)2, C 1-6 Alkyl or -OC 1-6 alkyl; R 7 Hydrogen, hydroxyl, cyano, -N(R) 9’ )2、-S(O)2R 12’ -C(O)R 12’ C 1-6 Alkyl, with one or more R 7a Replacement C 1-6 Alkyl, C 2-6 alkenyl, with one or more R 7b Replacement C 2-6 alkenyl, C 2-6 alkynyl group, with one or more R 7c Replacement C 2-6 alkynyl group, C 3-12 cycloalkyl, with one or more R 7d Replacement C 3-12 cycloalkyl, C 3-12 Cycloalkenyl, with one or more R 7e Replacement C 3-12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, with one or more R 7f Substituted 3-12-membered heterocyclic alkyl, 3-12-membered heterocyclic alkenyl, or substituted with one or more R 7g Substituted 3-12 membered heterocyclic alkenyl groups, C 6-10 aryl, with one or more R 7h Replacement C 6-10 aryl, 5-10 heteroaryl, or with one or more R 7i Substituted 5-10 heteroaryl groups; Each R 9’ Independently hydrogen, hydroxyl, cyano, C 1-6 Alkyl, C 3-12 cycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, or 3-12 membered heterocyclic alkenyl; Each R 7a R 7b R 7c R 7d R 7e R 7f R 7g R 7h and R 7i Each is independently a deuterium, halogen, cyano, hydroxyl, -N(R) 9’ )2、-S(O)2R 10’ -C(O)N(R) 10’ )2、-C(O)R 10’ -C(O)OR 10’ , , C 1-6 Alkyl, with one or more R 7-a Replacement C 1-6 Alkyl, -OC 1-6 Alkyl, with one or more R 7-b Replacement -OC 1-6 Alkyl, -SC 1-6 Alkyl, with one or more R 7-c Replacement -SC 1-6 Alkyl, C 2-6 alkenyl, with one or more R 7-d Replacement C 2-6 alkenyl, C 2-6 alkynyl group, with one or more R 7-e Replacement C 2-6 alkynyl group, C 3-12 cycloalkyl, with one or more R 7-f Replacement C 3-12 cycloalkyl, C 3-12 Cycloalkenyl, with one or more R 7-g Replacement C 3-12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, with one or more R 7-h Substituted 3-12-membered heterocyclic alkyl, 3-12-membered heterocyclic alkenyl, or substituted with one or more R 7-i Substituted 3-12 membered heterocyclic alkenyl groups, C 6-10 aryl, with one or more R 7-j Replacement C 6-10 aryl, 5-10 heteroaryl, or with one or more R 7-k Substituted 5-10 heteroaryl groups; Each R 10’ Independently hydrogen, C 1-6 Alkyl, C 3-12 cycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, or 3-12 membered heterocyclic alkenyl; Each R 7-a R 7-b R 7-c R 7-d R 7-e R 7-f R 7-g R 7-h R 7-i R 7-j and R 7-k Each can be independently represented by deuterium, halogen, cyano, hydroxyl, oxo (=O), or -N(R). 11’ )2、-S(O)2R 13’ -C(O)N(R) 13’ )2、-C(O)R 13’ C 1-6 Alkyl, with one or more R 7-a-1 Replacement C 1-6 Alkyl, -OC 1-6 Alkyl, with one or more R 7-a-2 Replacement -OC 1-6 Alkyl, -SC 1-6 Alkyl, with one or more R 7-a-3 Replacement -SC 1-6 Alkyl, C 2-6 alkenyl, with one or more R 7-a-4 Replacement C 2-6 alkenyl, C 2-6 alkynyl group, with one or more R 7-a-5 Replacement C 2-6 alkynyl group, C 3-12 cycloalkyl, with one or more R 7-a-6 Replacement C 3-12 cycloalkyl, C 3-12 Cycloalkenyl, with one or more R 7-a-7 Replacement C 3-12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, with one or more R 7-a-8 Substituted 3-12-membered heterocyclic alkyl, 3-12-membered heterocyclic alkenyl, or substituted with one or more R 7-a-9 Substituted 3-12 membered heterocyclic alkenyl groups, C 6-10 aryl, with one or more R 7-a-10 Replacement C 6-10 aryl, 5-10 heteroaryl, or with one or more R 7-a-11 Substituted 5-10 heteroaryl groups; Each R 11’ Independently hydrogen, hydroxyl, cyano, C 1-6 Alkyl, -C(O)-C 1-6 Alkyl, C 3-12 cycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, or 3-12 membered heterocyclic alkenyl; Each R 13’ Independently hydrogen, hydroxyl, C 1-6 Alkyl, C 3-12 cycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, or 3-12 membered heterocyclic alkenyl; Each R 7-a-1 R 7-a-2 R 7-a-3 R 7-a-4 R 7-a-5 R 7-a-6 R 7-a-7 R 7-a-8 R 7-a-9 R 7-a-10 and R 7-a-11 Each can be independently classified as deuterium, halogen, cyano, hydroxyl, -NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl)2, C 1-6 Alkyl or -OC 1-6 alkyl; Or, in X6, R 8 and R 7 Together with their respective attached ring atoms, they form C 3-12 cycloalkyl, with one or more R 8a2 Replacement C 3-12 cycloalkyl, C 3-12 Cycloalkenyl, with one or more R 8b2 Replacement C 3-12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, with one or more R 8c2 Substituted 3-12-membered heterocyclic alkyl, 3-12-membered heterocyclic alkenyl, or substituted with one or more R 8d2 Substituted 3-12 membered heterocyclic alkenyl groups, C 6-10 aryl, with one or more R 8e2 Replacement C 6-10 aryl, 5-10 heteroaryl, or with one or more R 8f2 Substituted 5-10 heteroaryl groups; Each R 8a2 R 8b2 R 8c2 R 8d2 R 8e2 and R 8f2 Each can be independently classified as deuterium, halogen, cyano, hydroxyl, -NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl)2, C 1-6 Alkyl or -OC 1-6 alkyl; Each R 12’ Independently hydrogen, halogen, hydroxyl, -NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl)2, C 1-6 Alkyl, with one or more R 12a’ Replacement C 1-6 Alkyl, -OC 1-6 Alkyl, with one or more R 12b’ Replacement -OC 1-6 Alkyl, C 2-6 alkenyl, with one or more R 12c’ Replacement C 2-6 alkenyl, C 2-6 alkynyl group, with one or more R 12d’ Replacement C 2-6 alkynyl group, C 3-12 cycloalkyl, with one or more R 12e’ Replacement C 3-12 cycloalkyl, C 3-12 Cycloalkenyl, with one or more R 12f’ Replacement C 3-12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, with one or more R 12g’ Substituted 3-12-membered heterocyclic alkyl, 3-12-membered heterocyclic alkenyl, or substituted with one or more R 12h’ Substituted 3-12 membered heterocyclic alkenyl groups, C 6-10 aryl, with one or more R 12i’ Replacement C 6-10 aryl, 5-10 heteroaryl, or with one or more R 12j’ Substituted 5-10 heteroaryl groups; Each R 12a’ R 12b’ R 12c’ R 12d’ R 12e’ R 12f’ R 12g’ R 12h’ R 12i’ and R 12j’ Each can be independently represented as deuterium, halogen, cyano, oxo, hydroxyl, -NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl)2, C 1-6 Alkyl or -OC 1-6 alkyl; Ring A is C 7-15 cycloalkyl, C 7-15 Cycloalkenyl, 7-15 membered heterocyclic alkyl, or 7-15 membered heterocyclic alkenyl; Each R 2 Independently deuterium, halogen, cyano, nitro, oxo, -N(R) 14 2. -B(OR) 14 )2、-OR 14 -SR 14 -S(O)2R 14 -S(O)2N(R) 14 )2、-NR 14 S(O)2R 14 -C(O)N(R) 14 )2、-C(O)NR 14 OR 14 -NR 14 C(O)R 14 -NR 14 C(O)N(R 14 )2、-NR 14 C(O)OR 14 -C(O)R 14 -C(O)OR 14 -OC(O)R 14 -OC(O)N(R) 14 )2、-CH2C(O)N(R 14 2. C 1-6 Alkyl, with one or more R 2a Replacement C 1-6 Alkyl, C 2-6 alkenyl, with one or more R 2b Replacement C 2-6 alkenyl, C 2-6 alkynyl group, with one or more R 2c Replacement C 2-6 alkynyl group, C 3-12 cycloalkyl, with one or more R 2d Replacement C 3-12 cycloalkyl, C 3-12 Cycloalkenyl, with one or more R 2e Replacement C 3-12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, with one or more R 2f Substituted 3-12-membered heterocyclic alkyl, 3-12-membered heterocyclic alkenyl, or substituted with one or more R 2g Substituted 3-12 membered heterocyclic alkenyl groups, C 6-10 aryl, with one or more R 2h Replacement C 6-10 aryl, 5-10 heteroaryl, or with one or more R 2i Substituted 5-10 heteroaryl groups; Each R 2a R 2b R 2c R 2d R 2e R 2f R 2g R 2h and R 2i Each independently constitutes deuterium, -N(R) 15 2. Hydroxyl group, halogen, cyano group, nitro group, oxo group, thio group (=S), C 1-6 Alkyl, with one or more R 2-a Replacement C 1-6 Alkyl, -OC 1-6 Alkyl, with one or more R 2-b Replacement -OC 1-6 Alkyl, C 2-6 alkenyl, with one or more R 2-c Replacement C 2-6 alkenyl, C 2-6 alkynyl group, with one or more R 2-d Replacement C 2-6 alkynyl group, C 3-12 cycloalkyl, with one or more R 2-e Replacement C 3-12 cycloalkyl, C 3-12 Cycloalkenyl, with one or more R 2-f Replacement C 3-12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, with one or more R 2-g Substituted 3-12-membered heterocyclic alkyl, 3-12-membered heterocyclic alkenyl, or substituted with one or more R 2-h Substituted 3-12 membered heterocyclic alkenyl groups, C 6-10 aryl, with one or more R 2-i Replacement C 6-10 aryl, 5-10 heteroaryl, or with one or more R 2-j Substituted 5-10 heteroaryl groups; Each R 2-a R 2-b R 2-c R 2-d R 2-e R 2-f R 2-g R 2-h R 2-i and R 2-j Each independently constitutes deuterium, -N(R) 16 2. Hydroxyl group, halogen, cyano group, nitro group, oxo group, C 1-6 Alkyl or -OC 1-6 alkyl; Each R 14 R 15 and R 16 Each independently is hydrogen, C 1-6 Alkyl, with one or more R 14a Replacement C 1-6 Alkyl, C 2-6 alkenyl, with one or more R 14b Replacement C 2-6 alkenyl, C 2-6 alkynyl group, with one or more R 14c Replacement C 2-6 alkynyl group, C 3-12 cycloalkyl, with one or more R 14d Replacement C 3-12 cycloalkyl, C 3-12 Cycloalkenyl, with one or more R 14e Replacement C 3-12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, with one or more R 14f Substituted 3-12-membered heterocyclic alkyl, 3-12-membered heterocyclic alkenyl, or substituted with one or more R 14g Substituted 3-12 membered heterocyclic alkenyl groups, C 6-10 aryl, with one or more R 14h Replacement C 6-10 aryl, 5-10 heteroaryl, or with one or more R 14i Substituted 5-10 heteroaryl groups; Each R 14a R 14b R 14c R 14d R 14e R 14f R 14g R 14h and R 14i Each is independently of deuterium, -NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl group, hydroxyl group, halogen group, cyano group, nitro group, oxo group, =NH group, C group 1-6 Alkyl groups, C substituted with one or more halogens 1-6 Alkyl, -OC 1-6 Alkyl, C 3-12 cycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, 3-12 membered heterocyclic alkenyl, C 6-10 Aryl or 5-10 heteroaryl groups; L is -(CR La R Lb ) n1 -, -O-(CR La R Lb ) n2 -, -O-(CR La R Lb ) n7 -CR Lc R Ld -(CR La R Lb ) n8 -, -S-(CR La R Lb ) n3 -, -N(R 17 )-(CR La R Lb ) n4 -, -S(O)-(CR La R Lb ) n5 - or -S(O)2-(CR La R Lb ) n6 -; R 17 It is hydrogen, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 cycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, or 3-12 membered heterocyclic alkenyl; Each R La and R Lb Each of these can be independently represented by hydrogen, deuterium, halogen, cyano, hydroxyl, C1-6 alkyl, or -OC. 1-6 Alkyl, C1-6 alkyl substituted with one or more halogens, C1-6 alkyl substituted with one or more deuteriums, or 5-10 heteroaryl groups; R Lc R Ld Together with the carbon atoms that are bonded together, they form C 3-12 cycloalkyl or with one or more R La-1 Replacement C 3-12 cycloalkyl; Each R La-1 Independently deuterium, halogen, cyano, hydroxyl, -NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl)2, C 1-6 Alkyl or -OC 1-6 alkyl; n1, n2, n3, n4, n5, n6, n7, and n8 are each independently 0, 1, 2, or 3; (when 0, it indicates a connection key). R 1 It is hydrogen, C1-6 alkyl, or formed by one or more R 1a Substituted C1-6 alkyl, -O-C1-6 alkyl, or substituted with one or more R 1b Substituted -O-C1-6 alkyl, C 3-12 cycloalkyl, with one or more R 1c Replacement C 3-12 cycloalkyl, C 3-12 Cycloalkenyl, with one or more R 1d Replacement C 3-12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, with one or more R 1e Substituted 3-12-membered heterocyclic alkyl, 3-12-membered heterocyclic alkenyl, or substituted with one or more R 1f Substituted 3-12 membered heterocyclic alkenyl groups, C6- 10 aryl, with one or more R 1g Replacement C6- 10 aryl, 5-10 heteroaryl, with one or more R 1h Substituted 5-10 heteroaryl groups, -C(O)OR 18 -C(O)R 18 -N(R) 18 )2、-NR 18 C(=NR 18 )N(R 18 )2、-C(O)N(R 18 )2 or -NR 18 C(O)R 18 ; Each R 1a R 1b R 1c R 1d R 1e R 1f R 1g and R 1h Each can be independently halogenated, deuterated, cyano, oxo, or -OR. 19 -SR 19 -C(O)R 19 -C(O)OR 19 -OC(O)R 19 -S(O)2R 19 -C(O)N(R) 19 )2、-NR 19 C(O)R 19 -N(R) 19 )2、-OC(O)N(R 19 )2、-CH2OC(O)N(R 19 )2、-SO2F、-CH2NR 19 C(O)OR 19 -CH2NR 19 C(O)N(R 19 )2、-CH2NR 19 C(O)R 19 -CH2NR 19 S(O)2R 19 -CH2OC(O)R 19 -CH2R 19 =C(R) 1-k )2, C1-6 alkyl, with one or more R 1-a Substituted C1-6 alkyl, with one or more R 1-b Replacement -OC 1-6 Alkyl, C 2-6 alkenyl, with one or more R 1-c Substituted C2-6 alkenyl, C2-6 ynyl, or with one or more R 1-d Substituted C2-6 ynyl group, C 3-12 cycloalkyl, with one or more R 1-e Replacement C 3-12 cycloalkyl, C 3-12 Cycloalkenyl, with one or more R 1-f Replacement C 3-12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, with one or more R 1-g Substituted 3-12-membered heterocyclic alkyl, 3-12-membered heterocyclic alkenyl, or substituted with one or more R 1-h Substituted 3-12 membered heterocyclic alkenyl groups, C6- 10 aryl, with one or more R 1-i Replacement C6- 10 aryl, 5-10 heteroaryl, or with one or more R 1-j Substituted 5-10 heteroaryl groups; Each R 1-a R 1-b R 1-c R 1-d R 1-e R 1-f R 1-g R 1-h R 1-i and R 1-j Each is independently a deuterium, cyano, halogen, hydroxyl, C1-6 alkyl, -OC 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 cycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, 3-12 membered heterocyclic alkenyl, C6- 10 Aryl or 5-10 heteroaryl groups; Each R 1-k Independently hydrogen, deuterium, cyano, halogen, hydroxyl, C1-6 alkyl, -OC 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 cycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, 3-12 membered heterocyclic alkenyl, C6- 10 Aryl or 5-10 heteroaryl groups; Each R 18 and R 19 Each independently is hydrogen, C 1-6 Alkyl, C 3-12 cycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, 3-12 membered heterocyclic alkenyl, C6- 10 Aryl or 5-10 heteroaryl, wherein the C 1-6 Alkyl, C 3-12 cycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, 3-12 membered heterocyclic alkenyl, C6- 10 Aryl or 5-10 heteroaryl groups are optionally surrounded by one or more R groups. 18a replace; Each R 18a Independently, it can be deuterium, -C(O)H, halogen, cyano, hydroxyl, oxo, C1-6 alkyl, or -OC. 1-6 Alkyl groups, C1-6 alkyl groups substituted with one or more halogens, C 3-12 cycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, 3-12 membered heterocyclic alkenyl, C6- 10 Aryl or 5-10 heteroaryl groups; In each "heterocyclic alkyl", the heteroatoms are independently selected from one, two or more of N, O and S, and the number of heteroatoms is independently 1, 2, 3 or 4. In each "heterocyclic alkenyl", the heteroatoms are independently selected from one, two or more of N, O and S, and the number of heteroatoms is independently 1, 2, 3 or 4. In each "heteroaryl", the heteroatoms are independently selected from one, two or more of N, O and S, and the number of heteroatoms is independently 1, 2, 3 or 4.

2. The compound of formula I as claimed in claim 1, its stereoisomers, or pharmaceutically acceptable salts thereof, characterized in that, It meets one or more of the following conditions: (1) Each halogen is independently fluorine, chlorine, bromine or iodine, preferably fluorine; (2) Each C 1-6 The alkyl group is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, or sec-butyl, for example, methyl or ethyl; (3) Each -OC 1-6 The alkyl group is independently -O-methyl, -O-ethyl, -O-n-propyl, -O-isopropyl, -O-n-butyl, -O-tert-butyl, -O-isobutyl or -O-sec-butyl, for example -O-methyl; (4) Each -SC 1-6 The alkyl group is independently -S-methyl, -S-ethyl, -S-n-propyl, -S-isopropyl, -S-n-butyl, -S-tert-butyl, -S-isobutyl or -S-sec-butyl, for example -S-methyl; (5) Each C 2-6 The alkenyl group can be vinyl, propenyl, allyl, 1-butenyl, or 1-pentenyl independently; (6) Each C 2-6 The alkynyl group can be independently ethynyl, propynyl, propynyl, 1-butynyl, or 1-pentynyl; (7) Each C 3-12 The cycloalkyl group is independently C 3-8 Cycloalkyl groups, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, and cyclopropyl, for example; (8) Each C 3-12 The cycloalkenyl group is independently C 3-10 Cycloalkenyl, preferably C 5-6 Cycloalkenyl; (9) Each C 3-12 The cycloalkenyl group independently contains one or more carbon-carbon sp groups. 2 Double bond; (10) The heteroatoms of each 3-12 membered heterocyclic alkyl group are independently selected from one or two of N, O and S, and the number of heteroatoms is independently 1, 2 or 3; (11) Each 3-12 membered heterocyclic alkyl group is independently monocyclic or polycyclic, wherein the polycyclic group may be a bridged ring, fused ring, or spirocyclic ring, and may also be bicyclic or tricyclic; preferably, each 3-12 membered heterocyclic alkyl group may be independently a 3-7 membered monocyclic heterocyclic alkyl group, an 8-10 membered bicyclic heterocyclic alkyl group, or a 10-12 membered tricyclic heterocyclic alkyl group, such as tetrahydropyrroleyl, morpholinyl, piperidinyl, piperazineyl, etc. , or For example, , , , , , or For example, , , , , , , , , , , or ; (12) The heteroatoms of each 3-12 membered heterocyclic alkenyl group are independently selected from one or two of N, O and S, and the number of heteroatoms is independently 1, 2 or 3. (13) Each 3-12 membered heterocyclic alkenyl group is independently monocyclic or polycyclic, wherein the polycyclic group may be a bridged ring, fused ring, or spirocyclic ring, and may also be bicyclic or tricyclic; preferably, each 3-12 membered heterocyclic alkenyl group may be independently a 3-7 membered monocyclic heterocyclic alkenyl group or an 8-10 membered bicyclic heterocyclic alkenyl group, for example For example, ; (14) Each 3-12 membered heterocyclic alkenyl group independently contains one or more sp atoms. 2 Double bond; (15) Each 7-15 member heterocyclic alkenyl group is independently monocyclic or polycyclic, the polycyclic group may be a bridged ring, a fused ring or a spirocyclic ring, and the polycyclic group may also be a bicyclic or tricyclic ring; preferably, each 7-15 member heterocyclic alkenyl group may be independently an 8-10 member bicyclic heterocyclic alkenyl group, such as 5,6-dihydro-4H-cyclopentano[b]thiophene or 4,5,6,7-tetrahydrobenzo[b]thiophene; (16) The heteroatoms of each 7-15 member heterocyclic alkenyl group are independently selected from one or two of N, O and S, and the number of heteroatoms is independently 1, 2 or 3; preferably, the heteroatom is S and the number of heteroatoms is 1. (17) Each 7-15 membered heterocyclic alkenyl group independently contains one or more sp atoms. 2 Double bonds, preferably containing 2 sp bonds. 2 Double bond; (18) Each C 6-10 The aryl group can be phenyl or naphthyl, for example, phenyl; (19) Each 5-10 member heteroaryl group is independently a 5-6 member monocyclic heteroaryl or a 9-10 member bicyclic heteroaryl, such as pyridyl, or for example ; (20) The heteroatoms of each 5-10 aryl group are independently selected from one or two of N, O and S, and the number of heteroatoms is independently 1, 2 or 3. (21) Each C 7-15 The cycloalkyl group is independently C 7-10 Cycloalkyl, preferably C 8-9 cycloalkyl; (22) Each C 7-15 The cycloalkyl group can be a monocyclic or polycyclic compound, and the polycyclic compound can be a bridged ring, a fused ring, or a spirocyclic compound, and the polycyclic compound can also be a bicyclic or a tricyclic compound; (23) Each C 7-15 The cycloalkenyl group is independently C 7-10 Cycloalkenyl, preferably C 8-9 Cycloalkenyl; (24) Each C 7-15 The cycloalkenyl group can be a monocyclic or polycyclic compound, and the polycyclic compound can be a bridged ring, a fused ring, or a spirocyclic compound. The polycyclic compound can also be a bicyclic or a tricyclic compound. (25) Each C 7-15 The cycloalkenyl group independently contains one or more carbon-carbon sp groups. 2 Double bond; (26) The heteroatoms of each 7-15 membered heterocyclic alkyl group are independently selected from one or two of N, O, and S, and the number of heteroatoms is independently 1, 2, or 3; and (27) Each 7-15 member heterocyclic alkyl group is independently monocyclic or polycyclic, and the polycyclic group may be a bridged ring, a fused ring or a spirocyclic ring, and the polycyclic group may also be a bicyclic or a tricyclic ring; preferably, each 7-15 member heterocyclic alkyl group may be independently a 7-membered monocyclic heterocyclic alkyl group, an 8-10 membered bicyclic heterocyclic alkyl group or a 10-12 membered tricyclic heterocyclic alkyl group.

3. The compound of formula I as claimed in claim 1, its stereoisomers, or pharmaceutically acceptable salts thereof, characterized in that, It meets one or more of the following conditions: (1) X1 is C(R) 3 )2, O, S or NR 4 Preferably C(R) 3 )2 or O, more preferably O; (2) X2 and X3 are each independently CR 5A Or N; preferably, at least one of X2 and X3 is N; (3) It is a single or double bond, ring B is aromatic, and at least one of X2, X3, X4, X8 and X9 is N; (4) X5 is NR 7 ; (5) m is 0, 1, 2 or 3, preferably 2; (6) n is 1; (7) Each R 3 R 5A and R 8 Each is independently hydrogen or C 1-6 Alkyl groups, preferably hydrogen; (8) R 4 It is hydrogen or C 1-6 alkyl; (9) R 7 For one or more R 7a Replacement C 1-6 alkyl; (10) Each R 7a Independently 5-10 membered heteroaryl or surrounded by one or more R 7-k The substituted 5-10 aryl group is preferably replaced by one or more R groups. 7-k Substituted 5-10 heteroaryl groups; (11) Each R 7-k Independently for C 1-6 Alkyl, halogen or -N(R) 11’ )2, preferably -N(R) 11’ )2; (12) Each R 11’ Independently hydrogen or C 1-6 Alkyl groups, preferably hydrogen; (13) Ring A is a 7-15 membered heterocyclic alkenyl group; (14) Each R 2 Independently halogen, cyano, oxo, C 1-6 Alkyl, -OR 14 C 2-6 alkenyl, C 2-6 alkynyl or -N(R) 14 )2, preferably cyano or -N(R) 14 )2; (15) Each R 14 Independently hydrogen or C 1-6 Alkyl groups, preferably hydrogen; (16) L is -O-(CR) La R Lb ) n2 - *** or -O-(CR) La R Lb ) n7 -CR Lc R Ld -(CR La R Lb ) n8 - *** Preferably -O-(CR) La R Lb ) n2 - *** More preferably, the inscription " *** "End and R" 1 Connected; (17) Each R La and R Lb Each is independently hydrogen, deuterium, or C1-6 alkyl, preferably hydrogen; (18)R Lc R Ld Together with the carbon atoms that are bonded together, they form C 3-12 cycloalkyl; (19) n2 is 0, 1 or 2, preferably 0 or 1; (20) n7 and n8 are each independently 1 or 2, preferably 1; (21) R 1 For one or more R 1a Substituted C1-6 alkyl, C 3-12 cycloalkyl, with one or more R 1c Replacement C 3-12 Cycloalkyl, 3-12 membered heterocyclic alkyl, with one or more R 1e Substituted 3-12-membered heterocyclic alkyl, 3-12-membered heterocyclic alkenyl, or substituted with one or more R 1f The substituted 3-12 membered heterocyclic alkenyl group is preferably replaced by one or more R groups. 1a Substituted C1-6 alkyl, with one or more R 1c Replacement C 3-12 Cycloalkyl, 3-12 membered heterocyclic alkyl, with one or more R 1e The substituted 3-12-membered heterocyclic alkyl or 3-12-membered heterocyclic alkenyl groups, more preferably substituted with one or more R groups, are preferred. 1a Substituted C1-6 alkyl or with one or more R 1e Substituted 3-12 membered heterocyclic alkyl groups; (22) Each R 1a R 1c R 1e and R 1f Each is independently a halogen, deuterium, cyano, or -OR group. 19 -SR 19 -CH2R 19 =C(R) 1-k )2, C1-6 alkyl, with one or more R 1-a Substituted C1-6 alkyl, with one or more R 1-b Replacement -OC 1-6 Alkyl, 3-12 membered heterocyclic alkyl, or with one or more R 1-g The substituted 3-12 membered heterocyclic alkyl group is preferably halogen, deuterium, or -OR. 19 -SR 19 -CH2R 19 =C(R) 1-k )2、C 1-6 Alkyl, with one or more R 1-a Substituted C1-6 alkyl or with one or more R 1-g The substituted 3-12 membered heterocyclic alkyl group, more preferably halogen or CH2R, is preferred. 19 C1-6 alkyl or containing one or more R 1-g Substituted 3-12 membered heterocyclic alkyl groups; (23) Each R 1-a R 1-b and R 1-g Each is independently a halogen, hydroxyl, C 1-6 Alkyl, -OC 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne, 3-12 membered heterocyclic alkyl or 3-12 membered heterocyclic alkenyl, preferably halogen, C 1-6 Alkyl, -OC 1-6 Alkyl, 3-12-membered heterocyclic alkyl or 3-12-membered heterocyclic alkenyl, more preferably halogen or C1-6 alkyl; (24) Each R 1-k Independently hydrogen, halogen, or C1-6 alkyl, preferably hydrogen or halogen; and (25) Each R 19 Each independently is hydrogen, C 1-6 Alkyl, 3-12 membered heterocyclic alkyl or 3-12 membered heterocyclic alkenyl, preferably hydrogen.

4. The compound of formula I as claimed in any one of claims 1-3, its stereoisomers, or its pharmaceutically acceptable salts, characterized in that, It meets one or more of the following conditions: (1) X1 is O, NH, N(CH3), S or CH2; (2) Structural fragments for , , , , , , , or The a1 end is connected to X7, and the a2 end is connected to the spiro atom in ring A. (3) X5 is NR 7 R 7 for , or ; (4) X6 and X7 are CH2; (5) L is -O- *** , *** , *** , *** , *** , *** or *** Among them, the mark " *** "End and R" 1 Connected; (6) R 1 for , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or ; (7) Structural fragment - LR 1 for , , , , , , , , , , , , , , , , , , , , , , , , , or ;and (8) Structural fragments for or Preferred or In the structural segment, end b1 is connected to X9, and end b2 is connected to X1.

5. The compound of formula I as claimed in any one of claims 1-4, its stereoisomers, or its pharmaceutically acceptable salts, characterized in that, It satisfies one of the following options: Option 1, Option 2, Option 3, Option 4, Option 5, and Option 6: Option 1: X1 is C(R) 3 )2, O, S or NR 4 ; X2 and X3 are each independently CR 5A Or N; X4, X8, and X9 are each independently C or N; It is a single or double bond, ring B is aromatic, and at least one of X2, X3, X4, X8 and X9 is N; X5 is NR 7 ; X6 and X7 are each independently C(R) 8 )2; m can be 0, 1, 2, or 3; n is 1; Each R 3 R 5A and R 8 Each is independently hydrogen or C 1-6 alkyl; R 4 It is hydrogen or C 1-6 alkyl; R 7 For one or more R 7a Replacement C 1-6 alkyl; Each R 7a Independently 5-10 membered heteroaryl or surrounded by one or more R 7-k Substituted 5-10 heteroaryl groups; Each R 7-k Independently for C 1-6 Alkyl, halogen or -N(R) 11’ )2; Each R 11’ Independently hydrogen or C 1-6 alkyl; Ring A is a 7-15 membered heterocyclic alkenyl group; Each R 2 Independently halogen, cyano, oxo, C 1-6 Alkyl, -OR 14 C 2-6 alkenyl, C 2-6 alkynyl or -N(R) 14 )2; Each R 14 Independently hydrogen or C 1-6 alkyl; L is -O-(CR) La R Lb ) n2 - *** or -O-(CR) La R Lb ) n7 -CR Lc R Ld -(CR La R Lb ) n8 - *** Among them, the mark " *** "End and R" 1 Connected; Each R La and R Lb Each is independently hydrogen, deuterium, or C1-6 alkyl; R Lc R Ld Together with the carbon atoms that are bonded together, they form C 3-12 cycloalkyl; n2 is 0, 1, or 2; n7 and n8 are each independently 1 or 2; R 1 For one or more R 1a Substituted C1-6 alkyl, C 3-12 cycloalkyl, with one or more R 1c Replacement C 3-12 Cycloalkyl, 3-12 membered heterocyclic alkyl, with one or more R 1e Substituted 3-12-membered heterocyclic alkyl, 3-12-membered heterocyclic alkenyl, or substituted with one or more R 1f Substituted 3-12 membered heterocyclic alkenyl groups; Each R 1a R 1c R 1e and R 1f Each is independently a halogen, deuterium, cyano, or -OR group. 19 -SR 19 -CH2R 19 =C(R) 1-k )2, C1-6 alkyl, with one or more R 1-a Substituted C1-6 alkyl, with one or more R 1-b Replacement -OC 1-6 Alkyl, 3-12 membered heterocyclic alkyl, or with one or more R 1-g Substituted 3-12 membered heterocyclic alkyl groups; Each R 1-a R 1-b and R 1-g Each is independently a halogen, hydroxyl, C1-6 alkyl, -OC 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkynyl, 3-12 membered heterocyclic alkyl, or 3-12 membered heterocyclic alkenyl; Each R 1-k It is independently hydrogen, halogen, or C1-6 alkyl; Each R 19 Each independently is hydrogen, C 1-6 Alkyl, 3-12 membered heterocyclic alkyl or 3-12 membered heterocyclic alkenyl; In each "heterocyclic alkyl", the heteroatoms are independently selected from one, two or more of N, O and S, and the number of heteroatoms is independently 1, 2, 3 or 4. In each "heterocyclic alkenyl", the heteroatoms are independently selected from one, two or more of N, O and S, and the number of heteroatoms is independently 1, 2, 3 or 4. In each "heteroaryl", the heteroatoms are independently selected from one, two or more of N, O and S, and the number of heteroatoms is independently 1, 2, 3 or 4. Option 2: The compound represented by Formula I is the same as the compound represented by Formula II. Among them, R 1 R 2 R 7 X 1 X 2 X 3 X 4 X 8 X 9 L The definitions of ring B and m are as described in any one of claims 1-4; q is 1 or 2; Option 3: The compound represented by Formula I is the same as the compound represented by Formula III. Among them, R 1 R 2 R 7 X 2 X 3 The definitions of L and m are as described in any one of claims 1-4; q is 1 or 2; Option 4: The compound represented by Formula I is the same as the compound represented by Formula II. in, X1 is C(R) 3 )2, O, S or NR 4 ; X2 and X3 are each independently CR 5A Or N; X4, X8, and X9 are each independently C or N; It is a single or double bond, ring B is aromatic, and at least one of X2, X3, X4, X8 and X9 is N; m can be 0, 1, 2, or 3; q is 1 or 2; Each R 3 and R 5A Each is independently hydrogen or C 1-6 alkyl; R 4 It is hydrogen or C 1-6 alkyl; R 7 For one or more R 7a Replacement C 1-6 alkyl; Each R 7a Independently 5-10 membered heteroaryl or surrounded by one or more R 7-k Substituted 5-10 heteroaryl groups; Each R 7-k Independently for C 1-6 Alkyl, halogen or -N(R) 11’ )2; Each R 11’ Independently hydrogen or C 1-6 alkyl; Each R 2 Independently halogen, cyano, oxo, C 1-6 Alkyl, -OR 14 C 2-6 alkenyl, C 2-6 alkynyl or -N(R) 14 )2; Each R 14 Independently hydrogen or C 1-6 alkyl; L is -O-(CR) La R Lb ) n2 - *** or -O-(CR) La R Lb ) n7 -CR Lc R Ld -(CR La R Lb ) n8 - *** Among them, the mark " *** "End and R" 1 Connected; Each R La and R Lb Each can be independently hydrogen, deuterium, or C. 1-6 alkyl; R Lc R Ld Together with the carbon atoms that are bonded together, they form C 3-12 cycloalkyl; n7 and n8 are each independently 1 or 2; n2 can be 0, 1, or 2 independently; R 1 For one or more R 1a Replacement C 1-6 Alkyl, C 3-12 cycloalkyl, with one or more R 1c Replacement C 3-12 Cycloalkyl, 3-12 membered heterocyclic alkyl, with one or more R 1e Substituted 3-12-membered heterocyclic alkyl, 3-12-membered heterocyclic alkenyl, or substituted with one or more R 1f Substituted 3-12 membered heterocyclic alkenyl groups; Each R 1a R 1c R 1e and R 1f Each is independently a halogen, deuterium, cyano, or -OR group. 19 -SR 19 -CH2R 19 =C(R) 1-k )2, C1-6 alkyl, with one or more R 1-a Substituted C1-6 alkyl, with one or more R 1-b Replacement -OC 1-6 Alkyl, 3-12 membered heterocyclic alkyl, or with one or more R 1-g Substituted 3-12 membered heterocyclic alkyl groups; Each R 1-a R 1-b and R 1-g Each is independently a halogen, hydroxyl, C1-6 alkyl, -OC 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkynyl, 3-12 membered heterocyclic alkyl, or 3-12 membered heterocyclic alkenyl; Each R 1-k It is independently hydrogen, halogen, or C1-6 alkyl; Each R 19 Each independently is hydrogen, C 1-6 Alkyl, 3-12 membered heterocyclic alkyl or 3-12 membered heterocyclic alkenyl; In each "heterocyclic alkyl", the heteroatoms are independently selected from one, two or more of N, O and S, and the number of heteroatoms is independently 1, 2, 3 or 4. In each "heterocyclic alkenyl", the heteroatoms are independently selected from one, two or more of N, O and S, and the number of heteroatoms is independently 1, 2, 3 or 4. In each "heteroaryl", the heteroatoms are independently selected from one, two or more of N, O and S, and the number of heteroatoms is independently 1, 2, 3 or 4. Option 5: The compound represented by Formula I is the same as the compound represented by Formula III. X2 and X3 are each independently CH or N; preferably, X2 is CH or N, and X3 is N; m can be 0, 1, 2 or 3, preferably 2; q is 1 or 2; R 7 For one or more R 7a Replacement C 1-6 alkyl; Each R 7a Independently 5-10 membered heteroaryl or surrounded by one or more R 7-k The substituted 5-10 aryl group is preferably replaced by one or more R groups. 7-k Substituted 5-10 heteroaryl groups; Each R 7-k Independently for C 1-6 Alkyl, halogen or -N(R) 11’ )2, preferably -N(R) 11’ )2; Each R 11’ Independently hydrogen or C 1-6 Alkyl groups, preferably hydrogen; Each R 2 Independently halogen, cyano, oxo, C 1-6 Alkyl, -OR 14 C 2-6 alkenyl, C 2-6 Alkyne group or -NH2, preferably cyano group or -NH2; L is -O-(CR) La R Lb ) n2 - *** or -O-(CR) La R Lb ) n7 -CR Lc R Ld -(CR La R Lb ) n8 - *** Preferably -O-(CR) La R Lb ) n2 - *** Among them, the mark " *** "End and R" 1 Connected; Each R La and R Lb Each can be independently hydrogen, deuterium, or C. 1-6 Alkyl groups, preferably hydrogen; R Lc R Ld Together with the carbon atoms that are bonded together, they form C 3-12 cycloalkyl; n2 can be 0, 1 or 2 independently, preferably 0 or 1; n7 and n8 are each independently 1 or 2, preferably 1; R 1 For one or more R 1a Replacement C 1-6 Alkyl, C 3-12 cycloalkyl, with one or more R 1c Replacement C 3-12 Cycloalkyl, 3-12 membered heterocyclic alkyl, with one or more R 1e Substituted 3-12-membered heterocyclic alkyl, 3-12-membered heterocyclic alkenyl, or substituted with one or more R 1f The substituted 3-12 membered heterocyclic alkenyl group is preferably replaced by one or more R groups. 1a Replacement C 1-6 Alkyl, with one or more R 1c Replacement C 3-12 Cycloalkyl, 3-12 membered heterocyclic alkyl, with one or more R 1e The substituted 3-12-membered heterocyclic alkyl or 3-12-membered heterocyclic alkenyl groups, more preferably substituted with one or more R groups, are preferred. 1a Replacement C 1-6 Alkyl or with one or more R 1e Substituted 3-12 membered heterocyclic alkyl groups; Each R 1a R 1c R 1e and R 1f Each is independently a halogen, deuterium, cyano, or -OR group. 19 -SR 19 -CH2R 19 =C(R) 1-k )2、C 1-6 Alkyl, with one or more R 1-a Replacement C 1-6 Alkyl, with one or more R 1-b Replacement -OC 1-6 Alkyl, 3-12 membered heterocyclic alkyl, or with one or more R 1-g The substituted 3-12 membered heterocyclic alkyl group is preferably halogen, deuterium, or -OR. 19 -SR 19 -CH2R 19 =C(R) 1-k )2、C 1-6 Alkyl, with one or more R 1-a Replacement C 1-6 Alkyl or with one or more R 1-g The substituted 3-12 membered heterocyclic alkyl group, more preferably halogen or CH2R, is preferred. 19 C 1-6 Alkyl or with one or more R 1-g Substituted 3-12 membered heterocyclic alkyl groups; Each R 1-a R 1-b and R 1-g Each is independently a halogen, hydroxyl, C 1-6 Alkyl, -OC 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne, 3-12 membered heterocyclic alkyl or 3-12 membered heterocyclic alkenyl, preferably halogen, C 1-6 Alkyl, -OC 1-6 Alkyl, 3-12 membered heterocyclic alkyl or 3-12 membered heterocyclic alkenyl, more preferably halogen or C 1-6 alkyl; Each R 1-k Independently hydrogen, halogen or C 1-6 Alkyl groups, preferably hydrogen or halogens; Each R 19 Each independently is hydrogen, C 1-6 Alkyl, 3-12-membered heterocyclic alkyl or 3-12-membered heterocyclic alkenyl, preferably hydrogen; In each "heterocyclic alkyl", the heteroatoms are independently selected from one, two or more of N, O and S, and the number of heteroatoms is independently 1, 2, 3 or 4. In each "heterocyclic alkenyl", the heteroatoms are independently selected from one, two or more of N, O and S, and the number of heteroatoms is independently 1, 2, 3 or 4. In each "heteroaryl", the heteroatoms are independently selected from one, two or more of N, O and S, and the number of heteroatoms is independently 1, 2, 3 or 4. Option Six: The compound represented by Formula I is the same as the compound represented by Formula IV. m can be 0, 1, 2 or 3, preferably 2; q is 1 or 2, preferably 2; R 7 For one or more R 7a Replacement C 1-6 alkyl; Each R 7a Independently for one or more R 7-k Substituted 5-6 aryl groups; Each R 7-k Independently for -N(R) 11’ )2; Each R 11’ Independently hydrogen; Each R 2 It can be independently a cyano group or -NH2; L is -O-(CR) La R Lb ) n2 - *** Among them, the mark " *** "End and R" 1 Connected; Each R La and R Lb Each can be independently hydrogen, deuterium, or C. 1-6 Alkyl groups, preferably hydrogen; n2 is 1; R 1 It is a 3-12 membered heterocyclic alkyl group, with one or more R 1e Substituted 3-12-membered heterocyclic alkyl, 3-12-membered heterocyclic alkenyl, or substituted with one or more R 1f The substituted 3-12 membered heterocyclic alkenyl group is preferably replaced by one or more R groups. 1e Substituted 3-12 membered heterocyclic alkyl groups; Each R 1e and R 1f Each is independently a halogen or C 1-6 alkyl; In each "heterocyclic alkyl", the heteroatoms are independently selected from one, two or more of N, O and S, and the number of heteroatoms is independently 1, 2, 3 or 4. In each "heterocyclic alkenyl", the heteroatoms are independently selected from one, two or more of N, O and S, and the number of heteroatoms is independently 1, 2, 3 or 4. In each "heteroaryl", the heteroatoms are independently selected from one, two or more of N, O and S, and the number of heteroatoms is independently 1, 2, 3 or 4.

6. The compound of formula I as claimed in claim 1, its stereoisomers, or pharmaceutically acceptable salts thereof, characterized in that, The compound represented by Formula I is any of the following compounds: ； Preferably, the compound represented by formula (I) is any of the following compounds: Compounds that elute first under the following conditions: Column: Sunfire® Prep C18 OBD TM The mobile phase is 19*250mm*5μm, and the mobile phase is [A: water (0.1% ammonia, v / v) B: acetonitrile], with the volume percentage of B in the mobile phase being 45-55%, the flow rate being 25mL / min, and the detection wavelength being 214 / 254 nm; preferably, under the conditions described, the retention time of the first eluting compound is 3.7 min. Compounds that elute under the following conditions: Column: Sunfire® Prep C18 OBD TM The mobile phase is 19*250mm*5μm, and the mobile phase is [A: water (0.1% ammonia, v / v) B: acetonitrile], with the volume percentage of B in the mobile phase being 45-55%, the flow rate being 25mL / min, and the detection wavelength being 214 / 254 nm; preferably, under the conditions described, the retention time of the later-eluting compound is 5.3 min.

7. A compound as shown in any of the following: , or .

8. A pharmaceutical composition comprising substance A and a pharmaceutical excipient; wherein substance A is a compound of formula I as described in any one of claims 1-6, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof; wherein substance A may be in a therapeutically effective amount.

9. The use of a substance A or a pharmaceutical composition as described in claim 8, wherein the use comprises one or more of the following: (1) To prepare drugs for the treatment and / or prevention of cancer; (2) To prepare medicines for the treatment and / or prevention of KRAS-mediated diseases; and (3) Preparation of KRAS inhibitors; The substance A is a compound of formula I as described in any one of claims 1-6, its stereoisomer, or a pharmaceutically acceptable salt thereof.

10. The application as described in claim 9, characterized in that, The application meets one or more of the following conditions: (1) The disease mediated by KRAS is cancer; (2) The KRAS is a KRAS mutation, such as KRAS G12C, KRAS G12D, KRAS G12V, KRAS G12A, KRAS G12R, KRAS G12S, KRAS G13C, KRAS G13D, KRAS Q61H, KRAS Q61K or KRAS Q61R mutation, or KRAS G12C, KRAS G12V or KRAS G12D mutation; (3) The cancer is associated with at least one of the following mutations: KRAS G12C, KRAS G12D, KRAS G12V, KRAS G12A, KRAS G12R, KRAS G12S, KRAS G13C, KRAS G13D, KRAS Q61H, KRAS Q61K and KRAS Q61R, particularly with at least one of the following mutations: KRAS G12C, KRAS G12D and KRAS G12V. (4) The cancer is selected from one or more of breast cancer, prostate cancer, lung cancer, brain cancer, ovarian cancer, cervical cancer, kidney cancer, head and neck cancer, bone cancer, skin cancer, liver cancer, colorectal cancer, esophageal cancer, stomach cancer, thyroid cancer, bladder cancer, lymphoma, leukemia, melanoma and pancreatic cancer, preferably lung cancer, pancreatic cancer or colorectal cancer; preferably, the lung cancer is non-small cell lung cancer or small cell lung cancer; preferably, the colorectal cancer is colon cancer or rectal cancer.

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