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 disclosed by the invention has good proliferation inhibition activity on one or more cancer cells of human non-small cell lung cancer cells NCI-H358 (KRAS G12C mutation) containing KRAS mutation, human metastatic pancreatic adenocarcinoma cells AsPC-1 (KRAS G12D mutation) and human pancreatic cancer cells Capan-1 (KRAS G12V mutation). Formula I.

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 one or more cancer cells among those containing KRAS mutations: human non-small cell lung cancer cells NCI-H358 (KRAS G12C mutation), human metastatic pancreatic adenocarcinoma cells AsPC-1 (KRAS G12D mutation), and human pancreatic cancer cells Capan-1 (KRAS G12V mutation).

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

[0008]

[0009] Formula I

[0010] in,

[0011] Each It can be a single bond or a double bond independently;

[0012] X 1 and X 2 Each independently for CR 6 R 6 CR 6 NR 7 N, O, S, -CR 6 =CR 6 -、-N=N- or -CR 6 =N-;

[0013] X 3 X 4 and X 5 Each independently for CR 6 C or N;

[0014] R 6 and R 7 Each is independently hydrogen, deuterium, halogen, -CN, -NR 9 R 9 -OR 9 C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, 3-10 membered heterocyclic alkyl, with one or more R 6a Substituted C1-C6 alkyl groups, with one or more R 6b Substituted C2-C6 alkenyl groups, with one or more R 6c Substituted C2-C6 ynyl group, with one or more R 6d Replacement C3-C 10 cycloalkyl or with one or more R 6e Substituted 3-10 membered heterocyclic alkyl groups;

[0015] R 6a R 6b R 6c R 6d and R 6e Each can be independently deuterium, -CN, halogen, -OH, or -NH2;

[0016] Y is -NR 8 -、-O-、-S-、-(CR 8 R 8 ) p1 -or-(CR) 8 R 8 ) p2 NR 8 -;

[0017] p1 and p2 are each independently 1, 2 or 3;

[0018] R 8 Independently hydrogen, -NR 9 R 9 -OR 9 C1-C6 alkyl, C3-C 10 cycloalkyl, C3-C 10 Cycloalkenyl, 3-10 heterocyclic alkyl, 3-10 heterocyclic alkenyl, 5-10 heteroaryl, C6-C 10 Aryl, -SO2R 8h , by one or more R 8a Substituted C1-C6 alkyl groups, with one or more R 8b Replacement C3-C 10 cycloalkyl, with one or more R 8c Replacement C3-C 10Cycloalkenyl, with one or more R 8d Substituted 3-10 membered heterocyclic alkyl groups, with one or more R 8e Substituted 3-10 membered heterocyclic alkenyl groups, with one or more R 8f Substituted 5-10 heteroaryl groups or substituted with one or more R 8g Replacement C6-C 10 Aryl;

[0019] R 8a R 8b R 8c R 8d R 8e R 8f R 8g and R 8h Each can be independently represented by a halogen, =O, -CN, carboxyl, or -OR. 9 -NR 9 R 9 -SR 9 -SOR 9 -SO2R 9 -C(O)NR 9 R 9 -C(O)R 9 C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, C3-C 10 Cycloalkenyl, 3-10 heterocyclic alkyl, 3-10 heterocyclic alkenyl, 5-10 heteroaryl, C6-C 10 aryl, with one or more R 8-a Substituted C1-C6 alkyl groups, with one or more R 8-b Substituted C2-C6 alkenyl groups, with one or more R 8-c Substituted C2-C6 ynyl group, with one or more R 8-d Replacement C3-C 10 cycloalkyl, with one or more R 8-e Replacement C3-C 10 Cycloalkenyl, with one or more R 8-f Substituted 3-10 membered heterocyclic alkyl groups, with one or more R 8-g Substituted 3-10 membered heterocyclic alkenyl groups, with one or more R 8-h Substituted 5-10 heteroaryl groups or substituted with one or more R 8-i Replacement C6-C 10 Aryl;

[0020] R 8-a R 8-b R 8-c R 8-d R 8-eR 8-f R 8-g R 8-h and R 8-i Each is independently a halogen, =O, -CN, -OR 9 -NR 9 R 9 -SR 9 -SOR 9 -SO2R 9 -C(O)NR 9 R 9 -C(O)R 9 C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, C3-C 10 Cycloalkenyl, 3-10 heterocyclic alkyl, 3-10 heterocyclic alkenyl, 5-10 heteroaryl, C6-C 10 aryl, with one or more R 8-a-1 Substituted C1-C6 alkyl groups, with one or more R 8-a-2 Substituted C2-C6 alkenyl groups, with one or more R 8-a-3 Substituted C2-C6 ynyl group, with one or more R 8-a-4 Replacement C3-C 10 cycloalkyl, with one or more R 8-a-5 Replacement C3-C 10 Cycloalkenyl, with one or more R 8-a-6 Substituted 3-10 membered heterocyclic alkyl groups, with one or more R 8-a-7 Substituted 3-10 membered heterocyclic alkenyl groups, with one or more R 8-a-8 Substituted 5-10 heteroaryl groups or substituted with one or more R 8-a-9 Replacement C6-C 10 Aryl;

[0021] R 8-a-1 R 8-a-2 R 8-a-3 R 8-a-4 R 8-a-5 R 8-a-6 R 8-a-7 R 8-a-8 and R 8-a-9 Each can be independently a halogen, =O, -CN, -C(O)CH3, -C(O)NH2, -OH, -NH2, -SCH3, -SO2CH3, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, C3-C 10 Cycloalkenyl, 3-10 heterocyclic alkyl, 3-10 heterocyclic alkenyl, 5-10 heteroaryl and C6-C 10Aryl;

[0022] R 9 Independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, C3-C 10 Cycloalkenyl, 3-10 heterocyclic alkyl, 3-10 heterocyclic alkenyl, 5-10 heteroaryl, C6-C 10 aryl, with one or more R 9a Substituted C1-C6 alkyl groups, with one or more R 9b Substituted C2-C6 alkenyl groups, with one or more R 9c Substituted C2-C6 ynyl group, with one or more R 9d Replacement C3-C 10 cycloalkyl, with one or more R 9e Replacement C3-C 10 Cycloalkenyl, with one or more R 9f Substituted 3-10 membered heterocyclic alkyl groups, with one or more R 9g Substituted 3-10 membered heterocyclic alkenyl groups, with one or more R 9h Substituted 5-10 heteroaryl groups or substituted with one or more R 9i Replace C6-C 10 Aryl;

[0023] R 9a R 9b R 9c R 9d R 9e R 9f R 9g R 9h and R 9i Each can be independently deuterium, -CN, halogen, -OH, or -NH2;

[0024] R 1 It is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, C3-C 10 Cycloalkenyl, 3-10 heterocyclic alkyl, 3-10 heterocyclic alkenyl, 5-10 heteroaryl, C6-C 10 aryl, with one or more R 1a Substituted C1-C6 alkyl groups, with one or more R 1b Substituted C2-C6 alkenyl groups, with one or more R 1c Substituted C2-C6 ynyl group, with one or more R 1d Replacement C3-C 10 cycloalkyl, with one or more R 1e Replacement C3-C10 Cycloalkenyl, with one or more R 1f Substituted 3-10 membered heterocyclic alkyl groups, with one or more R 1g Substituted 3-10 membered heterocyclic alkenyl groups, with one or more R 1h Substituted 5-10 heteroaryl groups or substituted with one or more R 1i Replacement C6-C 10 Aryl;

[0025] R 1a R 1b R 1c R 1d R 1e R 1f R 1g R 1h and R 1i Each is independently of deuterium, halogen, -CN, -NR. 9 R 9 -OR 9 -SR 9 -(CH2)-C(=O)N(R 9 2. C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, C3-C 10 Cycloalkenyl, 3-10 heterocyclic alkyl, 3-10 heterocyclic alkenyl, 5-10 heteroaryl, C6-C 10 aryl, with one or more R 1-a Substituted C1-C6 alkyl groups, with one or more R 1-b Substituted C2-C6 alkenyl groups, with one or more R 1-c Substituted C2-C6 ynyl group, with one or more R 1-d Replacement C3-C 10 cycloalkyl, with one or more R 1-e Replacement C3-C 10 Cycloalkenyl, with one or more R 1-f Substituted 3-10 membered heterocyclic alkyl groups, with one or more R 1-g Substituted 3-10 membered heterocyclic alkenyl groups, with one or more R 1-h Substituted 5-10 heteroaryl groups or substituted with one or more R 1-i Replacement C6-C 10 Aryl;

[0026] Or two adjacent R 1d R 1e R 1f R 1g R 1h and R 1iThe atoms bonded to them together form C3-C 10 cycloalkyl, C3-C 10 Cycloalkenyl, 3-10 membered heterocyclic alkyl, 3-10 membered heterocyclic alkenyl, C6-C 10 aryl, 5-10 heteroaryl, with one or more R 1-j Replacement C3-C 10 cycloalkyl, with one or more R 1-k Replacement C3-C 10 Cycloalkenyl, with one or more R 1-l Substituted 3-10 membered heterocyclic alkyl groups, with one or more R 1-m Substituted 3-10 membered heterocyclic alkenyl groups, with one or more R 1-n Replacement C6-C 10 aryl, with one or more R 1-o Substituted 5-10 heteroaryl groups;

[0027] 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 R 1-j R 1-k R 1-l R 1-m R 1-n and R 1-o Each can be independently classified as deuterium, halogen, -CN, -OH, or -NR. 9 R 9 -OR 9 -SR 9 C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, C3-C 10 Cycloalkenyl, 3-10 membered heterocyclic alkyl, 3-10 membered heterocyclic alkenyl, C6-C 10 aryl, 5-10 heteroaryl, with one or more R 1-a-1 Substituted C1-C6 alkyl groups, with one or more R 1-a-2 Substituted C2-C6 alkenyl groups, with one or more R 1-a-3 Substituted C2-C6 ynyl group, with one or more R 1-a-4 Replacement C3-C 10 cycloalkyl, with one or more R 1-a-5 Replacement C3-C 10 Cycloalkenyl, with one or more R 1-a-6Substituted 3-10 membered heterocyclic alkyl groups, with one or more R 1-a-7 Substituted 3-10 membered heterocyclic alkenyl groups, with one or more R 1-a-8 Replacement C6-C 10 aryl or aryl with one or more R 1-a-9 Substituted 5-10 heteroaryl groups;

[0028] R 1-a-1 R 1-a-2 R 1-a-3 R 1-a-4 R 1-a-5 R 1-a-6 R 1-a-7 R 1-a-8 and R 1-a-9 Each can be independently deuterium, halogen, -CN, -OH, -NH2, C1-C6 alkyl, C1-C6 alkyl-O-, C1-C6 alkyl-S-, or C3-C 10 cycloalkyl;

[0029] L is the connector key, -O-(CR) 10 R 10 ) n1 -、-O-(CR 10 R 10 ) n6 -CR 12 R 13 -(CR 10 R 10 ) n7 -、-S-(CR 10 R 10 ) n2 -、-NR 11 -(CR 10 R 10 ) n3 -、-SO-(CR 10 R 10 ) n4 -or-SO2-(CR 10 R 10 ) n5 -;

[0030] n1, n2, n3, n4, n5, n6, and n7 are each independently 0, 1, 2, 3, 4, or 5; (when it is 0, it indicates a connection key).

[0031] R 10 and R 11 Each independently represents hydrogen, deuterium, and -OR 9 -NR 9 R 9 C1-C6 alkyl, C3-C 10 cycloalkyl, C3-C10 Cycloalkenyl, 3-10 heterocyclic alkyl, 3-10 heterocyclic alkenyl, 5-10 heteroaryl, C6-C 10 aryl, with one or more R 10a Substituted C1-C6 alkyl groups, with one or more R 10b Replacement C3-C 10 cycloalkyl, with one or more R 10c Replacement C3-C 10 Cycloalkenyl, with one or more R 10d Substituted 3-10 membered heterocyclic alkyl groups, with one or more R 10e Substituted 3-10 membered heterocyclic alkenyl groups, with one or more R 10f Substituted 5-10 heteroaryl groups or substituted with one or more R 10g Replacement C6-C 10 Aryl;

[0032] R 12 R 13 Together with the carbon atoms they are connected to, they form C3-C. 10 cycloalkyl, C3-C 10 Cycloalkenyl, 3-10 membered heterocyclic alkyl, 3-10 membered heterocyclic alkenyl, with one or more R 10h Replacement C3-C 10 cycloalkyl, with one or more R 10i Replacement C3-C 10 Cycloalkenyl, with one or more R 10j Substituted 3-10 membered heterocyclic alkyl groups or substituted with one or more R 10k Substituted 3-10 membered heterocyclic alkenyl groups;

[0033] R 10a R 10b R 10c R 10d R 10e R 10f R 10g R 10h R 10i R 10j and R 10k Each can be independently represented as deuterium, halogen, =O, -CN, carboxyl, or -OR. 9 -SR 9 -NR 9 R 9 C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, C3-C 10 Cycloalkenyl, 3-10 heterocyclic alkyl, 3-10 heterocyclic alkenyl, 5-10 heteroaryl, C6-C 10aryl, with one or more R 10-a Substituted C1-C6 alkyl groups, with one or more R 10-b Substituted C2-C6 alkenyl groups, with one or more R 10-c Substituted C2-C6 ynyl group, with one or more R 10-d Replacement C3-C 10 cycloalkyl, with one or more R 10-e Replacement C3-C 10 Cycloalkenyl, with one or more R 10-f Substituted 3-10 membered heterocyclic alkyl groups, with one or more R 10-g Substituted 3-10 membered heterocyclic alkenyl groups, with one or more R 10-h Substituted 5-10 heteroaryl groups or substituted with one or more R 10-i Replacement C6-C 10 Aryl;

[0034] R 10-a R 10-b R 10-c R 10-d R 10-e R 10-f R 10-g R 10-h and R 10-i Each is independently represented as deuterium, halogen, =O, -CN, -OR 9 -SR 9 -NR 9 R 9 C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, C3-C 10 Cycloalkenyl, 3-10 heterocyclic alkyl, 3-10 heterocyclic alkenyl, 5-10 heteroaryl or C6-C 10 Aryl;

[0035] R 2 It is hydrogen, deuterium, -COOH, C1-C6 alkyl, C3-C 10 cycloalkyl, C3-C 10 Cycloalkenyl, 3-10 heterocyclic alkyl, 3-10 heterocyclic alkenyl, 5-10 heteroaryl, C6-C 10 aryl, with one or more R 2a Substituted C1-C6 alkyl groups, with one or more R 2b Replacement C3-C 10 cycloalkyl, with one or more R 2c Replacement C3-C 10 Cycloalkenyl, with one or more R 2d Substituted 3-10 membered heterocyclic alkyl groups, with one or more R2e Substituted 3-10 membered heterocyclic alkenyl groups, with one or more R 2f Substituted 5-10 heteroaryl groups or substituted with one or more R 2g Replacement C6-C 10 Aryl;

[0036] R 2a R 2b R 2c R 2d R 2e R 2f and R 2g Each is independently a deuterium, halogen, =O, -CN, =CR 2-a-10 R 2-a-10 -NR 9 R 9 -OR 9 -SR 9 -C(=O)R 9 -C(O)NR 9 R 9 -SO2R 9 -SOR 9 C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, C3-C 10 Cycloalkenyl, 3-10 heterocyclic alkyl, 3-10 heterocyclic alkenyl, 5-10 heteroaryl, C6-C 10 aryl, with one or more R 2-a-1 Substituted C1-C6 alkyl groups, with one or more R 2-a-2 Substituted C2-C6 alkenyl groups, with one or more R 2 -a-3 Substituted C2-C6 ynyl group, with one or more R 2-a-4 Replacement C3-C 10 cycloalkyl, with one or more R 2-a-5 Replacement C3-C 10 Cycloalkenyl, with one or more R 2-a-6 Substituted 3-10 membered heterocyclic alkyl groups, with one or more R 2-a-7 Substituted 3-10 membered heterocyclic alkenyl groups, with one or more R 2-a-8 Substituted 5-10 heteroaryl groups or substituted with one or more R 2-a-9 Replacement C6-C 10 Aryl;

[0037] R 2-a-1 R 2-a-2 R 2-a-3 R 2-a-4 R 2-a-5 R 2-a-6R 2-a-7 R 2-a-8 and R 2-a-9 Each is independently of deuterium, -CN, halogen, -NR. 9 R 9 -OR 9 -SR 9 C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, C3-C 10 Cycloalkenyl, 3-10 heterocyclic alkyl, 3-10 heterocyclic alkenyl, 5-10 heteroaryl or C6-C 10 Aryl;

[0038] R 2-a-10 Independently hydrogen, deuterium, -CN, halogen, -NR 9 R 9 -OR 9 -SR 9 C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, C3-C 10 Cycloalkenyl, 3-10 heterocyclic alkyl, 3-10 heterocyclic alkenyl, 5-10 heteroaryl or C6-C 10 Aryl;

[0039] R 3 and R 4 Each is independently hydrogen, deuterium, halogen, -CN, -NR 9 R 9 -OR 9 -SR 9 C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, C3-C 10 Cycloalkenyl, 3-10 heterocyclic alkyl, 3-10 heterocyclic alkenyl, 5-10 heteroaryl, C6-C 10 aryl, with one or more R 3a Substituted C1-C6 alkyl groups, with one or more R 3b Substituted C2-C6 alkenyl groups, with one or more R 3c Substituted C2-C6 ynyl group, with one or more R 3d Replacement C3-C 10 cycloalkyl, with one or more R 3e Replacement C3-C 10 Cycloalkenyl, with one or more R 3f Substituted 3-10 membered heterocyclic alkyl groups, with one or more R 3g Substituted 3-10 membered heterocyclic alkenyl groups, with one or more R 3hSubstituted 5-10 heteroaryl groups or substituted with one or more R 3i Replacement C6-C 10 Aryl;

[0040] Or R 3 and R 4 Together they form an oxygen group;

[0041] R 3a R 3b R 3c R 3d R 3e R 3f R 3g R 3h and R 3i Each is independently of deuterium, -CN, halogen, -NR. 9 R 9 -OR 9 or -SR 9 ;

[0042] m can be 0, 1, 2, 3, or 4; (when m is 0, R) 5 (Does not exist);

[0043] R 5 Independent of deuterium, halogen, -NR 9 R 9 -OR 9 -SR 9 C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, C3-C 10 Cycloalkenyl, 3-10 heterocyclic alkyl, 3-10 heterocyclic alkenyl, 5-10 heteroaryl, C6-C 10 aryl, with one or more R 5a Substituted C1-C6 alkyl groups, with one or more R 5b Substituted C2-C6 alkenyl groups, with one or more R 5c Substituted C2-C6 ynyl group, with one or more R 5d Replacement C3-C 10 cycloalkyl, with one or more R 5e Replacement C3-C 10 Cycloalkenyl, with one or more R 5f Substituted 3-10 membered heterocyclic alkyl groups, with one or more R 5g Substituted 3-10 membered heterocyclic alkenyl groups, with one or more R 5h Substituted 5-10 heteroaryl groups or substituted with one or more R 5i Replacement C6-C 10 Aryl;

[0044] R 5a R 5b R 5c R 5d R 5e R 5f R 5g R 5h and R 5i Each is independently a halogen, =O, -CN, -NR 9 R 9 -OR 9 -SR 9 C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, with one or more R 5-a Substituted C1-C6 alkyl groups, with one or more R 5-b Substituted C2-C6 alkenyl groups, with one or more R 5-c Substituted C2-C6 ynyl group or with one or more R 5-d Replacement C3-C 10 cycloalkyl;

[0045] R 5-a R 5-b R 5-c and R 5-d Each can be independently deuterium, halogen, =O, -CN, -OH, -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C3-C 10 cycloalkyl;

[0046] The heteroatoms in each of the 3-10-membered heterocyclic alkyl, 3-10-membered heterocyclic alkenyl and 5-10-membered heteroaryl groups are independently selected from one or more of N, O and S, and the number of heteroatoms is independently 1, 2 or 3.

[0047] 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").

[0048] In one embodiment, each halogen can independently be fluorine, chlorine, bromine, or iodine, preferably fluorine or chlorine.

[0049] In one embodiment, each C1-C6 alkyl group may independently be methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, or sec-butyl, for example, methyl or ethyl.

[0050] In one embodiment, each C1-C6 alkyl-O- can independently be methyl-O-, ethyl-O-, n-propyl-O-, isopropyl-O-, n-butyl-O-, tert-butyl-O-, isobutyl-O-, or sec-butyl-O-.

[0051] In one embodiment, each C1-C6 alkyl-S- can independently be methyl-S-, ethyl-S-, n-propyl-S-, isopropyl-S-, n-butyl-S-, tert-butyl-S-, isobutyl-S-, or sec-butyl-S-.

[0052] In one embodiment, each C2-C6 alkenyl group may independently be vinyl, propenyl, allyl, 1-butenyl, or 1-pentenyl.

[0053] In one scheme, each C2-C6 ynyl group can independently be ethynyl, propynyl, propynyl, 1-butynyl, or 1-pentynyl.

[0054] In one scheme, each C3-C 10 The cycloalkyl group can independently be a C3-C8 cycloalkyl group, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[0055] In one embodiment, the heteroatom types of each 3-10 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; preferably, the heteroatom types are independently selected from one or two of N and O, and the number of heteroatoms is independently 1 or 2.

[0056] In one embodiment, each 3-10 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 3-10 membered heterocyclic alkyl group can independently be a 4-6 membered monocyclic heterocyclic alkyl group, an 8-10 membered bicyclic heterocyclic alkyl group, or a 10 membered tricyclic heterocyclic alkyl group; preferably... (For example or ), (For example or ), (For example or ), (For example ), (For example or )or (For example or ).

[0057] In one scheme, each C3-C 10The cycloalkenyl group can be independently a C5-C6 cycloalkenyl group.

[0058] In one scheme, each C3-C 10 The cycloalkenyl group independently contains one or more carbon-carbon sp groups. 2 Double bond.

[0059] In one embodiment, each 3-10 membered heterocyclic alkenyl group can independently be a 3-9 membered heterocyclic alkenyl group, preferably. (For example ), (For example )or (For example ).

[0060] In one embodiment, the heteroatom types of each 3-10 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; preferably, the heteroatom types are independently selected from one or two of N and S, and the number of heteroatoms is independently 1 or 2.

[0061] In one embodiment, each 3-10 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 3-10 member heterocyclic alkenyl group can be independently a 3-6 member monocyclic heterocyclic alkenyl group or an 8-10 member bicyclic heterocyclic alkenyl group.

[0062] In one scheme, each 3-10 membered heterocyclic alkenyl group independently contains one or more sp atoms. 2 Double bond.

[0063] In one scheme, each C6-C 10 The aryl group can independently be phenyl or naphthyl, such as phenyl.

[0064] In one embodiment, 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; preferably, the heteroatom species are independently selected from one or two of N and S, and the number of heteroatoms is independently 1 or 2.

[0065] In one embodiment, each 5-10 member heteroaryl group can independently be a monocyclic or polycyclic compound, wherein the polycyclic compound can be fused or bicyclic; the polycyclic compound can be bicyclic or tricyclic; preferably, each 5-10 member heteroaryl group can be a 5-6 member monocyclic heteroaryl group or a 9-10 member bicyclic heteroaryl group; preferably... (For example )or (For example ).

[0066] In one of the plans, X3 X 4 and X 5 Each can be either C or N independently.

[0067] In one of the plans, X 1 and X 2 Each independently for CR 6 R 6 CR 6 NR 7 Or N, preferably CR 6 NR 7 Or N.

[0068] In one of the plans, X 1 X 2 X 3 X 4 and X 5 At least one of them is N or NR. 7 .

[0069] In one scheme, the ring It has aromatic properties.

[0070] In one particular scheme, R 6 and R 7 Each is independently hydrogen or C1-C6 alkyl, preferably hydrogen.

[0071] In one particular scheme, Y is -NR 8 -

[0072] In one particular scheme, R 8 For one or more R 8a Substituted C1-C6 alkyl groups.

[0073] In one particular scheme, R 8a Independently 5-10 member heteroaryl, C6-C 10 aryl, with one or more R 8-h Substituted 5-10 heteroaryl groups or substituted with one or more R 8-i Replacement C6-C 10 Aryl group, preferably with one or more R groups 8-h Substituted 5-10 heteroaryl groups.

[0074] In one particular scheme, R 8-h and R 8-i Each is independently a halogen, -CN, or -NR. 9 R 9 Or C1-C6 alkyl, preferably -NR 9 R 9 .

[0075] In one particular scheme, R9 It is independently hydrogen or C1-C6 alkyl.

[0076] In one particular scheme, R 1 It is hydrogen, C1-C6 alkyl, C3-C 10 cycloalkyl, 3-10 membered heterocyclic alkenyl, 5-10 membered heteroaryl, C6-C 10 aryl, with one or more R 1d Replacement C3-C 10 cycloalkyl, with one or more R 1g Substituted 3-10 membered heterocyclic alkenyl groups, with one or more R 1h Substituted 5-10 heteroaryl groups or substituted with one or more R 1i Replacement C6-C 10 aryl, preferably hydrogen, surrounded by one or more R 1g Substituted 3-10 membered heterocyclic alkenyl groups, with one or more R 1h Substituted 5-10 heteroaryl groups or substituted with one or more R 1i Replacement C6-C 10 aryl, more preferably composed of one or more R 1h Substituted 5-10 heteroaryl groups or substituted with one or more R 1i Replacement C6-C 10 Aryl.

[0077] In one particular scheme, R 1d R 1g R 1h and R 1i Each is independently of deuterium, halogen, -CN, -NR. 9 R 9 OR 9 C1-C6 alkyl or containing one or more R 1-a The substituted C1-C6 alkyl group is preferably halogenated, -CN, or -NR. 9 R 9 C1-C6 alkyl or containing one or more R 1-a Substituted C1-C6 alkyl groups.

[0078] In one particular scheme, R 1-a Independently deuterium, halogen, -CN, -NR 9 R 9 -OR 9 -SR 9 Or C1-C6 alkyl, preferably halogen.

[0079] In one scheme, L is -O-(CR) 10 R 10 ) n1 - bor -O-(CR) 10 R 10 ) n6 -CR 12 R 13 -(CR 10 R 10 ) n7 - b ; L's b side and R 2 Connected.

[0080] In a certain scheme, n1, n6 and n7 are each independently 1, 2 or 3, preferably 1.

[0081] In one particular scheme, R 10 It can be hydrogen, deuterium, or C1-C6 alkyl independently.

[0082] In one particular scheme, R 12 R 13 Together with the carbon atoms they are connected to, they form C3-C. 10 Cycloalkyl.

[0083] In one particular scheme, R 2 For C3-C 10 cycloalkyl, C3-C 10 Cycloalkenyl, 3-10 membered heterocyclic alkyl, 3-10 membered heterocyclic alkenyl, with one or more R 2b Replacement C3-C 10 cycloalkyl, with one or more R 2c Replacement C3-C 10 Cycloalkenyl, with one or more R 2d Substituted 3-10 membered heterocyclic alkyl groups or substituted with one or more R 2e The substituted 3-10-membered heterocyclic alkenyl group is preferably a 3-10-membered heterocyclic alkyl group, a 3-10-membered heterocyclic alkenyl group, or a group substituted with one or more R groups. 2d Substituted 3-10 membered heterocyclic alkyl groups.

[0084] In one particular scheme, R 2b R 2c R 2d and R 2e Each is independently classified as deuterium, halogen, -CN, =CR 2-a-10 R 2-a-10 -NR 9 R 9 -OR 9 -SR 9 C1-C6 alkyl groups, with one or more R 2-a-1 Substituted C1-C6 alkyl groups, preferably halogens, =CR 2-a-10 R 2 -a-10 -OR9 -SR 9 C1-C6 alkyl groups, with one or more R 2-a-1 Substituted C1-C6 alkyl groups.

[0085] In one particular scheme, R 2d For deuterium, halogen, =CR 2-a-10 R 2-a-10 -OR 9 -SR 9 C1-C6 alkyl groups, with one or more R 2-a-1 The substituted C1-C6 alkyl group is preferably deuterium, halogen, or C1-C6 alkyl.

[0086] In one particular scheme, R 2-a-1 For deuterium, -CN, halogen, -NR 9 R 9 or -OR 9 Halogen is preferred.

[0087] In one particular scheme, R 2-a-10 It is independently hydrogen, deuterium or halogen, preferably hydrogen or halogen.

[0088] In one particular scheme, R 3 and R 4 Each is independently hydrogen, deuterium, halogen, or C1-C6 alkyl, or R 3 and R 4 Together they form an oxy group; preferably, R 3 and R 4 Each is independently hydrogen or deuterium, or R 3 and R 4 Together they form an oxygen group.

[0089] In a certain scheme, m can be 0, 1 or 2, preferably 0.

[0090] In one particular scheme, R 5 It can be independently deuterium, halogen, or C1-C6 alkyl.

[0091] In one scheme, structural fragments for , , , , , , , or The a-terminus is connected to the N atom.

[0092] In one particular scheme, L is , , , , or ; where L's b-side is related to R 2 Connected.

[0093] In one particular scheme, R 2 for , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

[0094] In one particular scheme, Y is -NR 8 -, R 8 for .

[0095] In one particular scheme, R 1 For hydrogen, , , , or .

[0096] In one particular scheme, R 1 It is a 5-10 membered heterocyclic alkenyl group or is surrounded by one or more R groups. 1g The substituted 5-10 membered heterocyclic alkenyl group, preferably R 1 It is an 8-10 membered bicyclic heterocyclic alkenyl group or is surrounded by one or more R groups. 1g Substituted 8-10 membered bicyclic heterocyclic alkenyl groups, for example or .

[0097] In one of the solutions,

[0098] Each It can be a single bond or a double bond independently;

[0099] X 3 X 4 and X 5 Each can be independently represented as C or N;

[0100] X 1 and X 2 Each independently for CR 6 R 6 CR 6 NR 7 Or N;

[0101] And X 1 X 2 X 3 X 4 and X 5 At least one of them is N or NR 7 ;

[0102] R 6 and R 7 Each is independently hydrogen or C1-C6 alkyl;

[0103] Y is -NR 8 -;

[0104] R 8 For one or more R 8a Substituted C1-C6 alkyl groups;

[0105] R 8a Independently 5-10 member heteroaryl, C6-C 10 aryl, with one or more R 8-h Substituted 5-10 heteroaryl groups or substituted with one or more R 8-i Replacement C6-C 10 Aryl;

[0106] R 8-h and R 8-i Each is independently a halogen, -CN, or -NR. 9 R 9 Or C1-C6 alkyl;

[0107] R 9 Independently hydrogen or C1-C6 alkyl;

[0108] R 1 It is hydrogen, C1-C6 alkyl, 3-10 membered heterocyclic alkenyl, 5-10 membered heteroaryl, C6-C 10 aryl, with one or more R 1g Substituted 3-10 membered heterocyclic alkenyl groups, with one or more R 1h Substituted 5-10 heteroaryl groups or substituted with one or more R 1i Replacement C6-C 10 Aryl;

[0109] R 1g R 1h and R 1i Each is independently a halogen, -CN, or -NR. 9 R 9 C1-C6 alkyl or containing one or more R 1-a Substituted C1-C6 alkyl groups;

[0110] R 1-a Independently deuterium or halogen;

[0111] L is -O-(CR) 10 R 10 ) n1 - b or -O-(CR) 10 R 10 ) n6 -CR 12 R 13 -(CR 10 R 10 ) n7 - b ; where L's b-side is related to R 2 Connected;

[0112] n1, n6, and n7 are each independently 1, 2, or 3;

[0113] R 10 It is independently hydrogen, deuterium, or C1-C6 alkyl;

[0114] R 12 R 13 Together with the carbon atoms they are connected to, they form C3-C. 10cycloalkyl;

[0115] R 2 For C3-C 10 cycloalkyl, C3-C 10 Cycloalkenyl, 3-10 membered heterocyclic alkyl, 3-10 membered heterocyclic alkenyl, with one or more R 2b Replacement C3-C 10 cycloalkyl, with one or more R 2c Replacement C3-C 10 Cycloalkenyl, with one or more R 2d Substituted 3-10 membered heterocyclic alkyl groups or substituted with one or more R 2e Substituted 3-10 membered heterocyclic alkenyl groups;

[0116] R 2b R 2c R 2d and R 2e Each is independently a halogen, =CR 2-a-10 R 2-a-10 -OR 9 -SR 9 C1-C6 alkyl groups, with one or more R 2-a-1 Substituted C1-C6 alkyl groups;

[0117] R 2-a-1 Halogens are independent of each other;

[0118] R 2-a-10 It can be hydrogen, deuterium, or halogen independently;

[0119] R 3 and R 4 Each is independently hydrogen, deuterium, halogen, or C1-C6 alkyl, or R 3 and R 4 Together they form an oxygen group;

[0120] m is 0, 1, or 2;

[0121] R 5 It can be independently deuterium, halogen, or C1-C6 alkyl;

[0122] The heteroatoms in each of the 3-10-membered heterocyclic alkyl, 3-10-membered heterocyclic alkenyl and 5-10-membered heteroaryl groups are independently selected from one or more of N, O and S, and the number of heteroatoms is independently 1, 2 or 3.

[0123] In one embodiment, the compound represented by Formula I is the compound represented by Formula II.

[0124]

[0125] Formula II

[0126] Among them, R 1 R 2 R 3 R 4 R 8 The definitions of L and L are as described above;

[0127] Structural fragments for , , , , , , , or The a-terminus is connected to the N atom.

[0128] In one embodiment, the compound represented by Formula I is the compound represented by Formula III.

[0129]

[0130] Formula III

[0131] Among them, R 1 R 2 R 8 The definitions of L are as described above.

[0132] In one embodiment, the compound represented by Formula I is the compound represented by Formula II.

[0133]

[0134] Formula II

[0135] Among them, structural fragments for , , , , , , , or The a-terminus is connected to the N atom.

[0136] R 8 For one or more R 8a Substituted C1-C6 alkyl groups;

[0137] R 8a Independently for one or more R 8-h Substituted 5-10 heteroaryl groups;

[0138] R 8-h Independently for -NR9 R 9 ;

[0139] R 9 Independently hydrogen or C1-C6 alkyl;

[0140] R 1 For hydrogen, by one or more R 1g Substituted 3-10 membered heterocyclic alkenyl groups, with one or more R 1h Substituted 5-10 heteroaryl groups or substituted with one or more R 1i Replacement C6-C 10 Aryl;

[0141] R 1g R 1h and R 1i Each is independently a halogen, -CN, or -NR. 9 R 9 C1-C6 alkyl or containing one or more R 1-a Substituted C1-C6 alkyl groups;

[0142] R 1-a Halogens are independent of each other;

[0143] L is -O-(CR) 10 R 10 ) n1 - b or -O-(CR) 10 R 10 ) n6 -CR 12 R 13 -(CR 10 R 10 ) n7 - b ; where L's b-side is related to R 2 Connected;

[0144] n1, n6, and n7 are each independently 1;

[0145] R 10 It is independently hydrogen, deuterium, or C1-C6 alkyl;

[0146] R 12 R 13 Together with the carbon atoms they bond together, they form C3-C 10 cycloalkyl;

[0147] R 2 It is a 3-10 membered heterocyclic alkyl group, a 3-10 membered heterocyclic alkenyl group, or is surrounded by one or more R groups. 2d Substituted 3-10 membered heterocyclic alkyl groups;

[0148] R2d Independently halogen, =CR 2-a-10 R 2-a-10 -OR 9 -SR 9 C1-C6 alkyl groups, with one or more R 2-a-1 Substituted C1-C6 alkyl groups;

[0149] R 2-a-1 Halogens are independent of each other;

[0150] R 2-a-10 Independently hydrogen or halogen;

[0151] R 3 and R 4 Each is independently hydrogen or deuterium, or R 3 and R 4 Together they form an oxygen group;

[0152] The heteroatoms in each of the 3-10-membered heterocyclic alkyl, 3-10-membered heterocyclic alkenyl and 5-10-membered heteroaryl groups are independently selected from one or more of N, O and S, and the number of heteroatoms is independently 1, 2 or 3.

[0153] In one embodiment, the compound represented by Formula I is the compound represented by Formula III.

[0154]

[0155] Formula III

[0156] in,

[0157] R 8 For one or more R 8a Substituted C1-C6 alkyl groups;

[0158] R 8a Independently for one or more R 8-h Substituted 5-10 heteroaryl groups;

[0159] R 8-h Independently for -NR 9 R 9 ;

[0160] R 9 Independently hydrogen or C1-C6 alkyl;

[0161] R 1 For hydrogen, by one or more R 1h Substituted 5-10 heteroaryl groups or substituted with one or more R 1i Replacement C6-C 10 Aryl;

[0162] R1h and R 1i Each is independently a halogen, -CN, -NH2, C1-C6 alkyl, or associated with one or more R groups. 1-a Substituted C1-C6 alkyl groups;

[0163] R 1-a Halogens are independent of each other;

[0164] L is -O-(CR) 10 R 10 ) n1 - b or -O-(CR) 10 R 10 ) n6 -CR 12 R 13 -(CR 10 R 10 ) n7 - b ; where L's b-side is related to R 2 Connected;

[0165] n1, n6, and n7 are all 1;

[0166] R 10 It is independently hydrogen, deuterium, or C1-C6 alkyl;

[0167] R 12 R 13 Together with the carbon atoms they are connected to, they form C3-C. 10 cycloalkyl;

[0168] R 2 It is a 3-10 membered heterocyclic alkyl group, a 3-10 membered heterocyclic alkenyl group, or is surrounded by one or more R groups. 2d Substituted 3-10 membered heterocyclic alkyl groups;

[0169] R 2d Independently halogen, =CR 2-a-10 R 2-a-10 -OR 9 -SR 9 C1-C6 alkyl groups, with one or more R 2-a-1 Substituted C1-C6 alkyl groups;

[0170] R 2-a-1 Halogens are independent of each other;

[0171] R 2-a-10 Independently hydrogen or halogen;

[0172] The heteroatoms in each of the 3-10-membered heterocyclic alkyl, 3-10-membered heterocyclic alkenyl and 5-10-membered heteroaryl groups are independently selected from one or more of N, O and S, and the number of heteroatoms is independently 1, 2 or 3.

[0173] In one of the solutions,

[0174] The compound represented by Formula I is the same as the compound represented by Formula III.

[0175]

[0176] Formula III

[0177] in,

[0178] R 8 For one or more R 8a Substituted C1-C6 alkyl groups;

[0179] R 8a Independently for one or more R 8-h Substituted 5-10 heteroaryl groups;

[0180] R 8-h Independently for -NR 9 R 9 ;

[0181] R 9 Independently hydrogen or C1-C6 alkyl;

[0182] R 1 It is a 5-10 membered heterocyclic alkenyl group or is surrounded by one or more R groups. 1g Substituted 5-10 membered heterocyclic alkenyl groups;

[0183] R 1g It is independently a halogen, -CN, -NH2, C1-C6 alkyl, or is oxidized by one or more R 1-a Substituted C1-C6 alkyl groups;

[0184] R 1-a Halogens are independent of each other;

[0185] L is -O-(CR) 10 R 10 ) n1 - b or -O-(CR) 10 R 10 ) n6 -CR 12 R 13 -(CR 10 R 10 ) n7 - b ; where L's b-side is related to R2 Connected;

[0186] n1, n6, and n7 are all 1;

[0187] R 10 It is independently hydrogen, deuterium, or C1-C6 alkyl;

[0188] R 12 R 13 Together with the carbon atoms they are connected to, they form C3-C. 10 cycloalkyl;

[0189] R 2 It is a 3-10 membered heterocyclic alkyl group, a 3-10 membered heterocyclic alkenyl group, or is surrounded by one or more R groups. 2d Substituted 3-10 membered heterocyclic alkyl groups;

[0190] R 2d Independently halogen, =CR 2-a-10 R 2-a-10 -OR 9 -SR 9 C1-C6 alkyl groups, with one or more R 2-a-1 Substituted C1-C6 alkyl groups;

[0191] R 2-a-1 Halogens are independent of each other;

[0192] R 2-a-10 Independently hydrogen or halogen;

[0193] The heteroatoms in each of the 3-10-membered heterocyclic alkyl, 3-10-membered heterocyclic alkenyl and 5-10-membered heteroaryl groups are independently selected from one or more of N, O and S, and the number of heteroatoms is independently 1, 2 or 3.

[0194] In one of the solutions,

[0195] The compound represented by Formula I is the same as the compound represented by Formula III.

[0196]

[0197] Formula III

[0198] in,

[0199] R 8 For one or more R 8a Substituted C1-C6 alkyl groups;

[0200] R 8a Independently for one or more R 8-h Substituted 5-6 aryl groups;

[0201] R8-h Independently for -NR 9 R 9 ;

[0202] R 9 Independently hydrogen or C1-C6 alkyl;

[0203] R 1 It is an 8-10 membered bicyclic heterocyclic alkenyl group or is surrounded by one or more R groups. 1g Substituted 8-10 membered bicyclic heterocyclic alkenyl groups;

[0204] R 1g It is independently a halogen, -CN, -NH2, C1-C6 alkyl, or is oxidized by one or more R 1-a Substituted C1-C6 alkyl groups;

[0205] R 1-a Halogens are independent of each other;

[0206] L is -O-(CR) 10 R 10 )- b ; where L's b-side is related to R 2 Connected;

[0207] R 10 It is independently hydrogen, deuterium, or C1-C6 alkyl;

[0208] R 2 It is a 4-10 membered heterocyclic alkyl, a 4-10 membered heterocyclic alkenyl, or is surrounded by one or more R 2d Substituted 4-10 membered heterocyclic alkyl groups;

[0209] R 2d Independently halogen, =CR 2-a-10 R 2-a-10 -OR 9 -SR 9 C1-C6 alkyl groups, with one or more R 2-a-1 Substituted C1-C6 alkyl groups;

[0210] R 2-a-1 Halogens are independent of each other;

[0211] R 2-a-10 Independently hydrogen or halogen;

[0212] Each heteroatom in each of the 4-10-membered heterocyclic alkyl, 4-10-membered heterocyclic alkenyl, 8-10-membered bicyclic heterocyclic alkenyl and 5-6-membered heteroaryl groups is independently selected from one or more of N, O and S, and the number of heteroatoms is independently 1, 2 or 3.

[0213] In one particular scheme, the compound represented by Formula I above is any of the following compounds:

[0214] , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

[0215] The present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of the compound represented by Formula I above, its stereoisomer or a pharmaceutically acceptable salt thereof, and pharmaceutical excipients.

[0216] The present invention also provides the use of the compounds represented by Formula I above, their stereoisomers, or pharmaceutically acceptable salts thereof, or the pharmaceutical compositions thereof, in the preparation of medicaments for treating and / or preventing KRAS-mediated diseases. The KRAS-mediated diseases are preferably tumors.

[0217] The present invention also provides the use of the compound represented by Formula I above, its stereoisomer or a pharmaceutically acceptable salt thereof, or the above pharmaceutical composition in the preparation of a medicament for treating and / or preventing tumors.

[0218] The present invention also provides the use of the compound represented by Formula I above, its stereoisomer or a pharmaceutically acceptable salt thereof, or the above pharmaceutical composition in the preparation of a KRAS inhibitor.

[0219] The present invention also provides a method for inhibiting KRAS, comprising administering to a patient a therapeutically effective amount of a compound represented by Formula I above, its stereoisomer, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition thereof.

[0220] 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 a compound of Formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0221] The present invention also provides a method for treating and / or preventing tumors, comprising administering to a patient a therapeutically effective amount of a compound represented by Formula I above, its stereoisomer, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition thereof.

[0222] As described above, KRAS can be a KRAS mutation; the KRAS mutation is a KRAS G12C, KRAS G12D, KRAS G12V, KRAS G12A, KRAS G12R, KRAS G12S, KRAS G13C, KRAS G13D, KRAS Q61H, KRAS Q61K, or KRASQ61R mutation; preferably, the KRAS mutation is a KRAS G12C, KRAS G12D, or KRAS G12V mutation.

[0223] As described above, the tumor may 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, or KRAS Q61R; preferably, the tumor may be associated with at least one of the following mutations: KRAS G12C, KRAS G12D, and KRAS G12V.

[0224] As described above, the tumor 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; the lung cancer may be non-small cell lung cancer or small cell lung cancer; the colorectal cancer may be colon cancer or rectal cancer.

[0225] Unless otherwise specified, the following terms have the meanings shown below.

[0226] 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.

[0227] In this paper, the numerical ranges defined in the substituents, such as 3-10, 8-10, 5-10, 4-6, 3-8, etc., indicate integers within that range, such as 4-6 which means 4, 5, or 6.

[0228] The term "comprising" is an open-ended expression, meaning it includes the contents specified in this invention, but does not exclude other aspects.

[0229] 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.

[0230] Generally, the terms "substituted" or "substituted" indicate that one or more hydrogen atoms in a given structure are substituted by a specific substituent. Further, when the group is substituted by more than one of the stated substituents, the substituents are independent of each other; that is, the more than one substituent can be different or the same. Unless otherwise stated, a substituent group can be substituted at each substituted position of the substituted group. When more than one position in the given structural formula can be substituted by one or more substituents selected from a specific group, the substituents can be substituted at the same or different positions.

[0231] 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. "" means that the corresponding group R is connected to other fragments or groups in the compound through this site.

[0232] Unless otherwise specified, use wedge-shaped solid line keys ( ) and wedge-shaped dashed key ( ) represents the absolute configuration of a solid center.

[0233] The terms “part,” “structural part,” “chemical part,” “structural segment,” “group,” and “chemical group” used in this article refer to specific segments or functional groups in a molecule.

[0234] 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.

[0235] When a listed group does not explicitly indicate that it has a substituent, the group refers only to the unsubstituted group. For example, when "C1-C6 alkyl" is not limited to "substituted or unsubstituted", it refers only to "C1-C6 alkyl" itself or "unsubstituted C1-C6 alkyl".

[0236] The term "multiple" refers to 2, 3, 4, or 5.

[0237] When the term "one or more" is used to define the number of a certain group, it means 1, 2, 3, 4 or more.

[0238] 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.

[0239] "Halogens" refer to F, Cl, Br, and I.

[0240] In this invention, the term "alkyl" refers to a saturated straight-chain or branched monovalent hydrocarbon group. C1-C6 alkyl refers to an alkyl group having 1-6 carbon atoms, preferably a C1-C4 alkyl group having 1-4 carbon atoms, specifically methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, preferably methyl or ethyl.

[0241] In this invention, the term "C1-C6 alkyl-O-" refers to an alkoxy group, wherein "C1-C6 alkyl" is as defined above. Preferably, it is an alkoxy group having 1-4 carbon atoms, such as methyl-O-, ethyl-O-, n-propyl-O-, isopropyl-O-, n-butyl-O-, tert-butyl-O-, isobutyl-O-, or sec-butyl-O-.

[0242] In this invention, "C1-C6 alkyl" in the term "C1-C6 alkyl-S-" is as defined above. Preferably, it is C1-C4 alkyl-S-, such as methyl-S-, ethyl-S-, n-propyl-S-, isopropyl-S-, n-butyl-S-, tert-butyl-S-, isobutyl-S-, or sec-butyl-S-.

[0243] In this invention, the term "alkynyl" refers to a straight-chain or branched, unsaturated monovalent hydrocarbon group having a specified number of carbon atoms (e.g., C2-C6 or C2-C4) and having one or more (e.g., 1, 2 or 3) carbon-carbon sp triple bonds, preferably C2-C4 alkynyl.

[0244] In this invention, the term "alkenyl" refers to a straight-chain or branched, unsaturated monovalent hydrocarbon group having a specified number of carbon atoms (e.g., C2-C6 or C2-C4) and having one or more (e.g., 1, 2, or 3) carbon-carbon sp groups. 2 Double bonds, preferably C2-C4 alkenyl groups.

[0245] The term "oxo" refers to =O, where an oxygen atom replaces two hydrogen atoms on the same atom. For example, the methylene group (-(CH2-) becomes a carbonyl group (-C(=O)-) after being oxidized.

[0246] The term "cycloalkyl" refers to a ring with a specified number of carbon atoms (e.g., C3-C). 10 , C3-C6, C3-C4, C3-C8, C3-C9 or C3-C 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.

[0247] In this invention, the term "cycloalkenyl" refers to a group having at least one carbon-carbon sp. 2 Non-aromatic carbocyclic substituents (e.g., C7-C) of partially unsaturated monocyclic or polycyclic (e.g., bicyclic, tricyclic or more bridging rings, fused rings, or spirocyclic systems) of double bonds. 15 Cycloalkenyl, C7-C 10 Cycloalkenyl, C8-C9 cycloalkenyl, C3-C 12 Cycloalkenyl, C3-C 10 Cycloalkenyl or C5-C6 cycloalkenyl. Examples of cycloalkenyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, and cyclohexenyl.

[0248] In this invention, the term "heterocyclic alkyl" refers to a saturated monovalent group having a specified number of ring atoms (e.g., 3-10, 3-9, 4-6, 8-10, 4-10), 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., bicyclic, tricyclic, or more ring-bridged rings, fused rings, or spirocyclic systems), connected to the remainder of the molecule by a carbon atom or heteroatom. Preferably, the "heterocyclic alkyl" may be a 4-6 member monocyclic heterocyclic alkyl or an 8-10 member bicyclic heterocyclic alkyl. Examples of the heterocyclic alkyl include, but are not limited to, those listed below. (For example or ), (For example or ), (For example or ), (For example ), (For example or )or (For example or )wait.

[0249] In this invention, the term "heterocyclic alkenyl" refers to a cyclic, unsaturated monovalent group having a specified number of ring atoms (e.g., 3-10, 3-6, or 8-10), 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); and having 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 3-6 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 ), (For example )or (For example ).

[0250] The term "aryl" refers to an aryl group having a specified number of carbon atoms in its ring (e.g., C6-C). 10 The aromatic group of aryl groups. Examples of aryl groups include, but are not limited to, phenyl or naphthyl groups.

[0251] 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), which can be monocyclic or polycyclic; when polycyclic, each pair of monocyclic rings shares two atoms and one bond, and at least one ring is aromatic. The heteroaryl group is connected to the rest of the molecule via a carbon atom or a heteroatom; the heteroaryl group is connected to the rest of the molecule via a ring with or without heteroatoms; the heteroaryl group is connected to the rest of the molecule via an aromatic ring or a non-aromatic ring. Examples of the heteroaryl group include, but are not limited to, those described above. (For example )or (For example ).

[0252] The term "pharmaceutical acceptable" refers to a substance that is relatively non-toxic, safe, and suitable for patient use, and does not affect the biological activity or properties of the compounds of this invention (such as pharmaceutical excipients).

[0253] The term "pharmaceutically acceptable salt" refers to a salt obtained by reacting a compound with a pharmaceutically acceptable acid or base. When a compound contains a relatively acidic functional group, a base addition salt can be obtained by contacting the compound with a sufficient amount of a pharmaceutically acceptable base in a suitable inert solvent. Pharmaceutically acceptable base addition salts include, but are not limited to, lithium, sodium, potassium, calcium, aluminum, magnesium, zinc, bismuth, ammonium, or 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. The pharmaceutically acceptable acid includes inorganic acids and organic acids (e.g., trifluoroacetic acid, hydrochloric acid, or formic acid). See Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl, Camille G. Wermuth, 2011, 2nd Revised Edition) for details, such as formate salts.

[0254] 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).

[0255] The term “treatment” refers to a therapeutic approach or a remission measure. When a specific condition is involved, treatment means: (1) alleviating one or more biological manifestations of the disease or condition; (2) interfering with (a) one or more points in a biological cascade that causes or precipitates 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.

[0256] The term "prevention" refers to the reduction of the risk of acquiring or developing a disease or disorder.

[0257] 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.

[0258] 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 stereoisomeric forms, including but not limited to cis-trans isomers, enantiomers, diastereomers, optical isomers, rotation-blocked isomers, meso compounds, or racemic compounds.

[0259] 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.

[0260] The reagents and raw materials used in this invention are all commercially available.

[0261] The positive and progressive effects of this invention are as follows: the compounds of this invention have good proliferative inhibitory activity against one or more of the following cancer cells: human non-small cell lung cancer cells NCI-H358 (KRAS G12C mutation), human metastatic pancreatic adenocarcinoma cells AsPC-1 (KRAS G12D mutation), and human pancreatic cancer cells Capan-1 (KRAS G12V mutation). Detailed Implementation

[0262] 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.

[0263] The abbreviations in this application are as follows:

[0264] PMB: p-methoxybenzyl; DMF: dimethylformamide; Boc: tert-butyloxycarbonyl.

[0265] Example 1: Compound 1-P1 and Compound 1-P2

[0266] Compound 1-P1 (shorter retention time): 2-amino-4-{7-[1-(2-aminopyridin-3-yl)ethyl]-10-({[(2S)-1-methyltetrahydro-1H-pyrrolo-2-yl]methyl}oxy)-16-oxoylide-3,4,7,9,11,15-hexaazatetracyclo[10.2.2.04,14.08,13]hexadec-1(14),2,8(13),9,11-penten-15-yl}-4,5,6,7-tetrahydrocyclohexano[1,2-b]thiophene-3-carboxynitrile

[0267]

[0268] Compound 1-P2 (longer retention time): 2-amino-4-{7-[1-(2-aminopyridin-3-yl)ethyl]-10-({[(2S)-1-methyltetrahydro-1H-pyrrolo-2-yl]methyl}oxy)-16-oxonyl-3,4,7,9,11,15-hexaazatetracyclo[10.2.2.04,14.08,13]hexadecyl-1(14),2,8(13),9,11-penten-15-yl}-4,5,6,7-tetrahydrocyclohexano[1,2-b]thiophene-3-carboxynitrile

[0269]

[0270] Step 1: 1-(2-{[(4-methoxyphenyl)methyl]amino}ethyl)-4-nitropyrazole

[0271]

[0272] 1-(2-Bromoethyl)-4-nitropyrazole (84.0 g, 381.8 mmol, 1.0 eq) was dissolved in N,N-dimethylformamide (1000 mL), and potassium carbonate (158.3 g, 1145.3 mmol, 3.0 eq) and (4-methoxyphenyl)methylamine (157.1 g, 1145.3 mmol, 3.0 eq) were added sequentially at room temperature. The mixture was then stirred at room temperature for 8 hours. After the reaction was completed, the mixture was filtered, and the filter cake was washed with ethyl acetate (200 mL). The filtrate was extracted with ethyl acetate (500 mL × 3). The organic phases were combined, and then the mixture was further treated with water (500 mL × 3) and saturated brine (500 mL × 3). Washed with anhydrous sodium sulfate (mL), dried over a solution of 1-(2-{[(4-methoxyphenyl)methyl]amino}ethyl)-4-nitropyrazole (approximately 61.0 g, yield: 57%), filtered, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (tetrahydrofuran / petroleum ether = 1:1, v / v) to give a yellow oily product, 1-(2-{[(4-methoxyphenyl)methyl]amino}ethyl)-4-nitropyrazole (approximately 61.0 g, yield: 57%). MS m / z: 277.2 [M+H) + . 1 H NMR(400 MHz, DMSO-d6) δ 8.84 (s, 1H), 8.25 (s, 1H), 7.18 (d, J = 8.6 Hz, 2H), 6.85 (d, J = 8.6 Hz, 2H), 4.23 (t, J = 6.0 Hz, 2H), 3.72 (s, 3H), 3.61 (s,2H), 2.97 – 2.83 (m, 2H).

[0273] Step 2: 2-Chloro-5-iodo-6-{[(4-methoxyphenyl)methyl][2-(4-nitropyrazole-1-yl)ethyl]amino}pyrimidine-4-carboxylic acid methyl ester

[0274]

[0275] Methyl 2,6-dichloro-5-iodopyrimidine-4-carboxylate (18.0 g, 54.1 mmol, 1.0 eq) and 1-(2-{[(4-methoxyphenyl)methyl]amino}ethyl)-4-nitropyrazole (14.9 g, 54.1 mmol, 1.0 eq) were dissolved in chloroform (250 mL), and triethylamine (15.0 mL, 108.1 mmol, 2.0 eq) was added at room temperature, followed by heating at 70°C for 3 hours. After cooling to room temperature, water (250 mL) was added, and the mixture was extracted with dichloromethane (250 mL × 3). The combined organic phases were washed with saturated brine (250 mL), dried over anhydrous sodium sulfate, filtered, concentrated by vacuum distillation, and the crude product was separated by silica gel column chromatography (tetrahydrofuran / petroleum ether = 3:20, v / v) to give a white, viscous product, methyl 2-chloro-5-iodo-6-{[(4-methoxyphenyl)methyl][2-(4-nitropyrazol-1-yl)ethyl]amino}pyrimidine-4-carboxylate (15.3 g, yield: 49%). MS m / z: 573.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.89 (d, J = 0.7 Hz, 1H), 8.12 (d, J = 0.7 Hz,1H), 7.23 – 7.04 (m, 2H), 6.96 – 6.78 (m, 2H), 4.73 (s, 2H), 4.49-4.40 (m,2H), 4.00 – 3.91 (m, 2H), 3.88 (s, 3H), 3.74 (s, 3H).

[0276] Step 3: 2-({[(2S)-1-methyltetrahydro-1H-pyrrolo-2-yl]methyl}oxy)-5-iodo-6-{[(4-methoxyphenyl)methyl][2-(4-nitropyrazole-1-yl)ethyl]amino}pyrimidine-4-carboxylic acid methyl ester

[0277]

[0278] 2-({[(2S)-1-methyltetrahydro-1H-pyrrolo-2-yl]methyl}oxy)-5-iodo-6-{[(4-methoxyphenyl)methyl][2-(4-nitropyrazol-1-yl)ethyl]amino}pyrimidine-4-carboxylic acid methyl ester (15.0 g, 26.2 mmol, 1.0 eq) was dissolved in anhydrous toluene (250 mL). [(2S)-1-methyltetrahydro-1H-pyrrolo-2-yl]methanol (30.2 g, 261.9 mmol, 10.0 eq) was added at room temperature. The mixture was protected under nitrogen purging and heated at 110 °C for 2 hours. After cooling to room temperature, water (250 mL) was added, and the mixture was extracted with ethyl acetate (250 mL × 3). The combined organic phases were then separated and saturated with brine (250 mL × 3). Washed (mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure by distillation, and the crude product was separated by silica gel column chromatography (methanol:dichloromethane = 3:97) to give a yellow viscous solid product methyl 2-({[(2S)-1-methyltetrahydro-1H-pyrrolo-2-yl]methyl}oxy)-5-iodo-6-{[(4-methoxyphenyl)methyl][2-(4-nitropyrazol-1-yl)ethyl]amino}pyrimidine-4-carboxylate (12.6 g, yield: 74%). MS m / z: 651.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.84 (s, 1H), 8.12 (s, 1H), 7.17 –7.06 (m, 2H), 6.92 – 6.82 (m, 2H), 4.68 (s, 2H), 4.45 (t, J = 5.7 Hz, 2H),4.20-4.13 (m, 1H), 4.05-3.96 (m, 1H), 3.93-3.88 (m, 2H), 3.86 (s, 3H), 3.78-3.64 (m, 4H), 2.98-2.89 (m, 1H), 2.31 (s, 3H), 2.22-2.13 (m, 1H), 1.94-1.83(m, 1H), 1.72 – 1.62 (m, 2H), 1.59-1.50 (m, 1H).

[0279] Step 4: 3-({[(2S)-1-methyltetrahydro-1H-pyrrolo-2-yl]methyl}oxy)-5-[(4-methoxyphenyl)methyl]-11-nitro-6,7-dihydro-5H-pyrimidino[4,5-e]pyrazolo[5,1-g][1,4]diazacycloheptan-1-carboxylic acid methyl ester

[0280]

[0281] 2-({[(2S)-1-methyltetrahydro-1H-pyrrolo-2-yl]methyl}oxy)-5-iodo-6-{[(4-methoxyphenyl)methyl][2-(4-nitropyrazol-1-yl)ethyl]amino}pyrimidine-4-carboxylate (12.0 g, 18.4 mmol, 1.0 eq) was dissolved in anhydrous xylene (480 mL), and 2,2-dimethylpropionic acid (0.6 mL, 5.5 mmol, 0.3 eq), palladium acetate (0.4 g, 1.8 mmol, 0.1 eq), n-butyldi(1-adamantyl)phosphine (1.3 g, 3.7 mmol, 0.2 eq) and cesium carbonate (12.0 g, 36.8 mmol, 2.0 eq) were added at room temperature under nitrogen purging protection. The solution was then heated to 130 °C. The reaction was heated at °C for 5 hours. After the reaction was completed, the mixture was filtered through diatomaceous earth. The filtrate was distilled under reduced pressure to remove xylene. Water (500 mL) was added, and the mixture was extracted with dichloromethane (500 mL × 3). The combined organic phases were washed with saturated brine (250 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was separated by silica gel column chromatography (methanol:dichloromethane = 3:97) to give a yellow viscous solid product methyl 3-({[(2S)-1-methyltetrahydro-1H-pyrrolo-2-yl]methyl}oxy)-5-[(4-methoxyphenyl)methyl]-11-nitro-6,7-dihydro-5H-pyrimidino[4,5-e]pyrazolo[5,1-g][1,4]diazacycloheptamonyl-1-carboxylate (5.0 g, yield: 52%). MS m / z: 524.3 [M+H] + .

[0282] Step 5: 3-({[(2S)-1-methyltetrahydro-1H-pyrrolo-2-yl]methyl}oxy)-11-nitro-6,7-dihydro-5H-pyrimidino[4,5-e]pyrazolo[5,1-g][1,4]diazacycloheptan-1-carboxylic acid methyl ester

[0283]

[0284] Methyl 3-({[(2S)-1-methyltetrahydro-1H-pyrrolo-2-yl]methyl}oxy)-5-[(4-methoxyphenyl)methyl]-11-nitro-6,7-dihydro-5H-pyrimidino[4,5-e]pyrazolo[5,1-g][1,4]diazacycloheptam-1-carboxylate (3.6 g, 6.9 mmol, 1.0 eq) was dissolved in trifluoroacetic acid (50 mL), and trifluoromethanesulfonic acid (5 mL) was added. The mixture was stirred at 60 °C for 1 h. After the reaction was complete, the solution was concentrated under reduced pressure. The crude product was dissolved in dichloromethane and added to ice water (150 mL). The solution was extracted with dichloromethane (100 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Crude methyl 3-({[(2S)-1-methyltetrahydro-1H-pyrrolo-2-yl]methyl}oxy)-11-nitro-6,7-dihydro-5H-pyrimidino[4,5-e]pyrazolo[5,1-g][1,4]diazacycloheptam-1-carboxylate (3.6 g) was obtained. It was a yellowish-brown solid. MS m / z: 404.2 [M+H] + .

[0285] Step 6: 3-({[(2S)-1-methyltetrahydro-1H-pyrrolo-2-yl]methyl}oxy)-1-(methoxycarbonyl)-11-nitro-6,7-dihydro-5H-pyrimidino[4,5-e]pyrazolo[5,1-g][1,4]diazacycloheptan-5-carboxylic acid-2-methylpropyl-2-yl ester

[0286]

[0287] 3-({[(2S)-1-methyltetrahydro-1H-pyrrolo-2-yl]methyl}oxy)-11-nitro-6,7-dihydro-5H-pyrimidino[4,5-e]pyrazolo[5,1-g][1,4]diazacycloheptan-1-carboxylate (3.6 g, 8.9 mmol, 1.0 eq) was dissolved in tetrahydrofuran (50 mL), and 4-dimethylaminopyridine (160.0 mg, 1.3 mmol, 0.15 eq), triethylamine (12.4 mL, 89.2 mmol, 10.0 eq), and di-tert-butyl dicarbonate (6.1 mL, 26.8 mmol, 3.0 eq) were added. The mixture was stirred at 50 °C for 1 h. After the reaction was complete, the mixture was cooled to room temperature, added to water (150 mL), extracted with ethyl acetate (200 mL × 3), washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / dichloromethane = 15:1, v / v) to give the product 3-({[(2S)-1-methyltetrahydro-1H-pyrrolo-2-yl]methyl}oxy)-1-(methoxycarbonyl)-11-nitro-6,7-dihydro-5H-pyrimidino[4,5-e]pyrazolo[5,1-g][1,4]diazacycloheptan-5-carboxylic acid-2-methylpropyl-2-yl ester (2.4 g, yield: 44%), a yellow solid. ESI-MS m / z: 504.2 [M+H] + . 1 H NMR (400 MHz, Chloroform-d) δ 8.22 (s, 1H), 4.68 – 4.41 (m, 4H), 4.34-4.20 (m, 1H), 3.91 (s, 3H), 3.23-3.10 (m, 1H), 2.85 – 2.72 (m, 1H), 2.54 (d,J = 9.9 Hz, 3H), 2.44-2.30 (m, 1H), 2.20 – 2.06 (m, 1H), 1.87 – 1.76 (m, 4H), 1.38 (d, J = 1.8 Hz, 9H).

[0288] Step 7: 11-Amino-1-(hydroxymethyl)-3-({[(2S)-1-methyltetrahydro-1H-pyrrolo-2-yl]methyl}oxy)-6,7-dihydro-5H-pyrimidino[4,5-e]pyrazolo[5,1-g][1,4]diazacycloheptan-5-carboxylic acid-2-methylpropyl-2-yl ester

[0289]

[0290] Sodium borohydride (0.6 g, 16.7 mmol, 6.0 eq) was added to a methanol (20 mL) solution of 3-({[(2S)-1-methyltetrahydro-1H-pyrrolo-2-yl]methyl}oxy)-1-(methoxycarbonyl)-11-nitro-6,7-dihydro-5H-pyrimidino[4,5-e]pyrazolo[5,1-g][1,4]diazacycloheptan-5-carboxylic acid-2-methylpropyl-2-yl ester (1.4 g, 2.8 mmol, 1.0 eq). The reaction mixture was stirred at room temperature for 0.5 h, and then zinc powder (1.8 g, 27.8 mmol, 10.0 eq) and ammonium chloride (3.0 g, 55.6 mmol, 20.0 eq) were added. The reaction mixture was stirred at room temperature for 4 h. After the reaction was completed and monitored by LCMS, the mixture was filtered. The filter cake was washed with dichloromethane (200 mL), the filtrate was washed with water (20 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated to obtain crude 11-amino-1-(hydroxymethyl)-3-({[(2S)-1-methyltetrahydro-1H-pyrrolo-2-yl]methyl}oxy)-6,7-dihydro-5H-pyrimidino[4,5-e]pyrazolo[5,1-g][1,4]diazacycloheptan-5-carboxylic acid-2-methylpropyl-2-yl ester (700 mg). It was a yellow solid. The crude product was used directly in the next step without purification. MS m / z: 446.4 [M+H] + . 1 H NMR(400 MHz, Chloroform-d) δ 7.28 (s, 1H), 4.98 (d, J = 15.3 Hz, 1H), 4.62 –4.27 (m, 5H), 4.11 – 3.96 (m, 1H), 3.87-3.74 (m, 1H), 3.18-3.10 (m, 1H),2.80-2.68 (m, 1H), 2.53 (d, J = 5.0 Hz, 3H), 2.38-2.27 (m, 1H), 2.15 – 2.04(m, 1H), 1.95 – 1.69 (m, 4H), 1.42 (d, J = 1.2 Hz, 9H).

[0291] Step 8: 1-(hydroxymethyl)-3-({[(2S)-1-methyltetrahydro-1H-pyrrolo-2-yl]methyl}oxy)-11-(1,4-dioxaspiro[4.5]dec-6-ylamino)-6,7-dihydro-5H-pyrimidino[4.5-e]pyrazolo[5.1-g][1.4]diazacycloheptan-5-carboxylic acid-2-methylpropyl-2-yl ester

[0292]

[0293] At room temperature, glacial acetic acid (92.8 mg, 1.6 mmol, 1.0 eq) was added to a solution of crude 11-amino-1-(hydroxymethyl)-3-({[(2S)-1-methyltetrahydro-1H-pyrrolo-2-yl]methyl}oxy)-6,7-dihydro-5H-pyrimidino[4,5-e]pyrazolo[5,1-g][1,4]diazacycloheptam-5-carboxylic acid-2-methylpropyl-2-yl ester (700 mg, 1.6 mmol, 1.0 eq) and 1,4-dioxaspiro[4.5]dec-6-one (245.4 mg, 1.6 mmol, 1.0 eq) in dichloromethane (20 mL). After stirring the reaction solution at room temperature for 0.5 hours, sodium triacetoxyborohydride (1.0 g, 4.7 mmol, 3.0 eq) was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction was monitored by LCMS until completion. The reaction mixture was added dropwise to a saturated sodium bicarbonate aqueous solution (20 mL), and extracted with dichloromethane (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated to obtain the crude product. The crude product was purified by column chromatography (dichloromethane:methanol = 10:1) to give 1-(hydroxymethyl)-3-({[(2S)-1-methyltetrahydro-1H-pyrrolo-2-yl]methyl}oxy)-11-(1,4-dioxaspiro[4.5]dec-6-ylamino)-6,7-dihydro-5H-pyrimidino[4,5-e]pyrazolo[5,1-g][1,4]diazacycloheptamon-5-carboxylic acid-2-methylpropyl-2-yl ester (800 mg, yield: 87%). Yellow solid. MS m / z: 586.5 [M+H] + . 1 H NMR (400 MHz, Chloroform-d) δ 7.28 (s,1H), 5.07 – 4.70 (m, 1H), 4.62 – 4.24 (m, 4H), 4.15 – 3.87 (m, 4H), 3.85 –3.72 (m, 1H), 3.19-3.08 (m, 1H), 3.00-2.83 (m, 1H), 2.81 – 2.67 (m, 1H), 2.59– 2.45 (m, 2H), 2.34 (d, J = 8.8 Hz, 1H), 2.15-2.08 (m, 1H), 1.98 – 1.67 (m,4H), 1.62 (s, 1H), 1.50 – 1.26 (m, 9H).

[0294] Step 9: 10-({[(2S)-1-methyltetrahydro-1H-pyrrolo-2-yl]methyl}oxy)-15-(1,4-dioxaspiro[4.5]dec-6-yl)-3,4,7,9,11,15-hexaazatetracyclo[10.2.2.04,14.08,13]hexadecyl-1(14),2,8(13),9,11-pentaen-7-carboxylic acid-2-methylpropyl-2-yl ester

[0295]

[0296] At 0 °C, methanesulfonyl chloride (234.7 mg, 2.1 mol, 1.5 eq) was added dropwise to a solution of 1-(hydroxymethyl)-3-({[(2S)-1-methyltetrahydro-1H-pyrrolo-2-yl]methyl}oxy)-11-(1,4-dioxaspiro[4.5]dec-6-ylamino)-6,7-dihydro-5H-pyrimidino[4,5-e]pyrazolo[5,1-g][1,4]diazacycloheptam-5-carboxylic acid-2-methylpropyl-2-yl ester (0.8 g, 1.4 mmol, 1.0 eq) and triethylamine (0.7 g, 6.8 mmol, 5.0 eq) in dichloromethane (30 mL). The reaction mixture was allowed to react at 0 °C for 10 minutes, and the reaction was monitored by LCMS until completion. Saturated ammonium chloride aqueous solution (10 mL) was added to the reaction solution, followed by extraction with dichloromethane (10 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated to obtain crude product (800 mg) of 10-({[(2S)-1-methyltetrahydro-1H-pyrrolo-2-yl]methyl}oxy)-15-(1,4-dioxaspiro[4.5]dec-6-yl)-3,4,7,9,11,15-hexaazatetracyclo[10.2.2.04,14.08,13]hexadecyl-1(14),2,8(13),9,11-pentaen-7-carboxylic acid-2-methylpropyl-2-yl ester. Yellow solid. MS m / z: 568.5 [M+H] + .

[0297] Step 10: 10-({[(2S)-1-methyltetrahydro-1H-pyrrolo-2-yl]methyl}oxy)-16-oxoylide-15-(1,4-dioxaspiro[4.5]dec-6-yl)-3,4,7,9,11,15-hexaazatetracyclo[10.2.2.04,14.08,13]hexadecyl-1(14),2,8(13),9,11-pentene-7-carboxylic acid-2-methylpropyl-2-yl ester

[0298]

[0299] At room temperature, activated manganese dioxide (4.9 g, 56.4 mmol, 40 eq) was added to 100 mL of dichloromethane containing 10-({[(2S)-1-methyltetrahydro-1H-pyrrole-2-yl]methyl}oxy)-15-(1,4-dioxaspiro[4.5]dec-6-yl)-3,4,7,9,11,15-hexaazatetracyclo[10.2.2.04,14.08,13]hexadec-1(14),2,8(13),9,11-pentaen-7-carboxylic acid-2-methylpropyl-2-yl ester (0.8 g, 1.4 mmol, 1.0 eq). The reaction mixture was stirred at room temperature for 16 hours. The reaction was monitored by LCMS until completion. The reaction mixture was filtered, and the filter cake was washed with 50 mL of dichloromethane. Organic phase rotation and solvent drying yielded 10-({[(2S)-1-methyltetrahydro-1H-pyrrolo-2-yl]methyl}oxy)-16-oxoylide-15-(1,4-dioxaspiro[4.5]dec-6-yl)-3,4,7,9,11,15-hexaazatetracyclo[10.2.2.04,14.08,13]hexadecyl-1(14),2,8(13),9,11-pentaen-7-carboxylic acid-2-methylpropyl-2-yl ester (0.8 g). Yellow solid. MS m / z: 568.5 [M+H] + .

[0300] Step 11: 7-({[(2S)-1-methyltetrahydro-1H-pyrrolo-2-yl]methyl}oxy)-11-(1,4-dioxaspiro[4.5]dec-6-yl)-1,4,6,8,11,14-hexaazatetracyclo[7.5.2.012,15.05,16]hexadecyl-5(16),6,8,12(15),13-pentaen-10-one

[0301]

[0302] At room temperature, trifluoroacetic acid (2 mL) was added to a solution of 10-({[(2S)-1-methyltetrahydro-1H-pyrrolo-2-yl]methyl}oxy)-16-oxoylide-15-(1,4-dioxaspiro[4.5]dec-6-yl)-3,4,7,9,11,15-hexaazatetracyclo[10.2.2.04,14.08,13]hexadecyl-1(14),2,8(13),9,11-pentene-7-carboxylic acid-2-methylpropyl-2-yl ester (1.1 g, 1.9 mmol, 1.0 eq) in dichloromethane (20 mL). The reaction mixture was stirred at room temperature for 15 minutes. The reaction was monitored by LCMS until completion. After the solvent was evaporated under reduced pressure, saturated sodium bicarbonate aqueous solution (10 mL) was added, followed by extraction with dichloromethane (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated to give a crude product of 7-({[(2S)-1-methyltetrahydro-1H-pyrrolo-2-yl]methyl}oxy)-11-(1,4-dioxaspiro[4.5]dec-6-yl)-1,4,6,8,11,14-hexaazatetracyclo[7.5.2.012,15.05,16]hexadecyl-5(16),6,8,12(15),13-pentaen-10-one (0.9 g). Yellow solid. MS m / z: 468.5 [M+H] + . 1 HNMR (400 MHz, Chloroform-d) δ 8.04 (d, J = 9.8 Hz, 2H), 5.78-5.68 (m, 1H), 4.81 – 4.43 (m, 4H), 3.99 (s, 2H), 3.89-3.77 (m, 2H), 3.66-3.46 (m, 2H), 3.19(d, J = 8.4 Hz, 1H), 2.79 (s, 1H), 2.73 – 2.45 (m, 5H), 2.44 – 2.22 (m, 3H), 2.19 – 1.85 (m, 6H), 1.66-1.50 (t, J = 12.9 Hz, 2H).

[0303] Step 12: 2-[(diphenylmethyl)amino]-3-ethylpyridine

[0304]

[0305] 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 mixture was then subjected to nitrogen protection for 100 minutes. o React at C for 4 hours. Dilute with water (10 mL), extract with ethyl acetate (20 mL × 3), wash the organic phase with saturated brine, dry to anhydrous sodium sulfate, filter, concentrate under reduced pressure, and precipitate by silica gel column chromatography (petroleum ether / tetrahydrofuran = 1:2, v / v) to give the product, a yellow oil (1.1 g, yield 71.5%). ESI-MS m / z: 287.2 [M+1] + .

[0306] Step 13: 3-(1-Bromoethyl)-2-[(diphenylmethyl)amino]pyridine

[0307]

[0308] 2-[(diphenylmethyl)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 mixture was then protected with nitrogen for 90 minutes. o The reaction mixture was reacted overnight. The reaction solution was diluted with 10 mL of sodium bicarbonate aqueous solution, 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 purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1, v / v) to give the product, a yellow oil (570 mg, yield 40.6%). ESI-MS m / z: 366.2 [M+1] + .

[0309] Step 14: 7-(1-{2-[(diphenylmethyl)amino]pyridin-3-yl}ethyl)-10-({[(2S)-1-methyltetrahydro-1H-pyrrolo-2-yl]methyl}oxy)-15-(1,4-dioxaspiro[4.5]dec-6-yl)-3,4,7,9,11,15-hexaazatetracyclo[10.2.2.04,14.08,13]hexadec-1(14),2,8(13),9,11-pentaen-16-one

[0310]

[0311] Under nitrogen protection at 0 °C, sodium hydroxide (124.6 mg, 3.1 mmol, 3.0 eq, 60%) was added to a DMF (10 mL) solution of crude 7-({[(2S)-1-methyltetrahydro-1H-pyrrolo-2-yl]methyl}oxy)-11-(1,4-dioxaspiro[4.5]dec-6-yl)-1,4,6,8,11,14-hexaazatetracyclo[7.5.2.012,15.05,16]hexadecyl-5(16),6,8,12(15),13-pentaen-10-one (0.5 g, 1.0 mmol, 1.0 eq). The reaction mixture was stirred at 0 °C for 0.5 h. Add 3-(1-bromoethyl)-2-[(diphenylmethyl)amino]pyridine (303.4 mg, 0.8 mmol, 0.8 eq) to the reaction solution. Stir the reaction solution at 0 °C for 0.5 h. Monitor the reaction for completion by LCMS. Add the reaction solution dropwise to a saturated ammonium chloride aqueous solution (20 mL), and extract with dichloromethane (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated. The solution was purified by silica gel column chromatography (dichloromethane:methanol = 10:1) to give 7-(1-{2-[(diphenylmethyl)amino]pyridin-3-yl}ethyl)-10-({[(2S)-1-methyltetrahydro-1H-pyrrolo-2-yl]methyl}oxy)-15-(1,4-dioxaspiro[4.5]dec-6-yl)-3,4,7,9,11,15-hexaazatetracyclo[10.2.2.04,14.08,13]hexadec-1(14),2,8(13),9,11-pentaen-16-one (460.0 mg, yield: 58%). Yellow solid. MS m / z: 766.5 [M+H] + . 1H NMR (400 MHz, DMSO-d6)δ 8.33-8.24 (m, 1H), 7.94 (s, 1H), 7.83 (t, J = 7.5 Hz, 1H), 7.62 – 6.68 (m,11H), 6.24 – 6.02 (m, 1H), 5.70-5.52 (m, 1H), 4.48-4.30 (m, 1H), 3.95 – 3.68 (m, 4H), 3.60-3.43 (m, 2H), 3.27 – 3.06 (m, 1H), 3.05-2.98 (m, 1H), 2.79 –2.53 (m, 2H), 2.43 – 2.07 (m, 4H), 2.06 – 1.82 (m, 4H), 1.80-1.74 (m, 1H), 1.71-1.60 (m, 4H), 1.58-1.38 (m, 5H), 1.38 – 1.24 (m, 2H).

[0312] Step 15: 7-(1-{2-[(diphenylmethyl)amino]pyridin-3-yl}ethyl)-10-({[(2S)-1-methyltetrahydro-1H-pyrrolo-2-yl]methyl}oxy)-15-(2-oxoylidenecyclohexyl)-3,4,7,9,11,15-hexaazatetracyclo[10.2.2.04,14.08,13]hexadecyl-1(14),2,8(13),9,11-pentaen-16-one

[0313]

[0314] At room temperature, trifluoroacetic acid (2 mL) and trifluoromethanesulfonic acid (1 mL) were added to a solution of 7-(1-{2-[(diphenylmethylethylene)amino]pyridin-3-yl}ethyl)-10-({[(2S)-1-methyltetrahydro-1H-pyrrolo-2-yl]methyl}oxy)-15-(1,4-dioxaspiro[4.5]dec-6-yl)-3,4,7,9,11,15-hexaazatetracyclo[10.2.2.04,14.08,13]hexadecyl-1(14),2,8(13),9,11-penten-16-one (460.0 mg, 0.6 mmol) in dichloromethane (20 mL). The reaction mixture was stirred at room temperature for 0.5 hours. The reaction was monitored by LCMS until completion. The mixture was extracted with saturated sodium bicarbonate aqueous solution (20 mL) and dichloromethane (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and purified by silica gel column chromatography (dichloromethane:methanol = 10:1) after solvent removal to give 7-(1-{2-[(diphenylmethyl)amino]pyridin-3-yl}ethyl)-10-({[(2S)-1-methyltetrahydro-1H-pyrrolo-2-yl]methyl}oxy)-15-(2-oxoylidenecyclohexyl)-3,4,7,9,11,15-hexaazatetracyclo[10.2.2.04,14.08,13]hexadec-1(14),2,8(13),9,11-pentaen-16-one (0.4 g, yield: 92%). Brown solid. MS m / z: 722.5 [M+H] + .

[0315] 1 H NMR (400 MHz, DMSO-d6) δ 8.37 – 8.26 (m, 1H), 7.88-7.84 (m, 1H), 7.82-7.77 (m, 1H), 7.58 – 6.84 (m, 11H), 6.22-6.18 (m, 1H), 6.08-6.00 (m,1H), 4.65-4.49 (m, 1H), 4.25-4.08 (m, 1H), 3.90-3.83 (m, 1H), 3.77-3.48 (m,4H), 3.43 – 3.37 (m, 2H), 3.21 – 3.08 (m, 1H), 3.05-2.78 (m, 3H), 2.63-2.54(m, 2H), 2.31-2.25 (m, 1H), 2.20-1.77 (m, 6H), 1.75-1.69 (m, 1H), 1.66-1.27(m, 4H).

[0316] Step 16: 2-Amino-4-{7-[1-(2-aminopyridin-3-yl)ethyl]-10-({[(2S)-1-methyltetrahydro-1H-pyrrolo-2-yl]methyl}oxy)-16-oxoylide-3,4,7,9,11,15-hexaazatetracyclo[10.2.2.04,14.08,13]hexadec-1(14),2,8(13),9,11-penten-15-yl}-4,5,6,7-tetrahydrocyclohexano[1,2-b]thiophene-3-carboxynitrile (compounds 1-P1 and 1-P2)

[0317] At room temperature, 7-(1-{2-[(diphenylmethyl)amino]pyridin-3-yl}ethyl)-10-({[(2S)-1-methyltetrahydro-1H-pyrrolo-2-yl]methyl}oxy)-15-(2-oxoylidenecyclohexyl)-3,4,7,9,11,15-hexaazatetracyclo[10.2.2.04,14.08,13]hexadecyl-1(14),2,8(13),9,11-pentaen-16-one (120.0 mg, 0.17 mmol, 1.0 eq), malononitrile (54.9 mg, 0.83 mmol, 5.0 eq), 3-aminoglutaric acid (24.5 mg, 0.17 mmol, 1.0 eq), and sulfur (218.0 mg, 0.85 mmol, 5.0 eq) were reacted with pyridoxine (218.0 mg, 0.85 mmol, 5.0 eq). 4A molecular sieve (96.5 mg, 0.33 mmol, 2.0 eq) was added to anhydrous ethanol (20 mL). The reaction mixture was stirred at 80 °C for 16 hours. The reaction was monitored by LCMS until completion. Dichloromethane (100 mL) was added to the reaction mixture, filtered, and evaporated to dryness to obtain the crude product. The crude product was purified by preparative HPLC (HPLC separation conditions: column: Phenomenex C18 80*40mm*3μm; mobile phase: [A (ammonia / water 1 / 999)-B (acetonitrile)]; B%: 15%-40%, 9 min; flow rate: 25 mL / min) to obtain compound 1-P1 with a retention time of 5.27 min and compound 1-P2 (5.4 mg) with a retention time of 6.95 min.

[0318] Compound 1-P1 (retention time 5.27 min):

[0319] MS m / z: 638.4 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 7.98 (s, 1H), 7.72 –7.54 (m, 2H), 7.21 (s, 1H), 7.01 (s, 1H), 6.92 (s, 1H), 6.68 (s, 2H), 6.22(s, 1H), 5.33 (t, J = 4.8 Hz, 1H), 4.50-4.29 (m, 2H), 3.19-2.97 (m, 6H), 2.10-1.95 (m, 4H), 1.76 – 1.58 (m, 3H), 1.56-1.43 (m, 2H), 1.28-1.18 (m, 8H).

[0320] Compound 1-P2 (retention time 6.95 min):

[0321] MS m / z: 638.4 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.98 (s, 1H), 7.71 –7.53 (m, 3H), 7.22 (s, 1H), 7.01 (s, 1H), 6.68 (s, 2H), 6.22 (s, 1H), 5.33(t, J = 4.7 Hz, 1H), 4.43 (s, 2H), 3.22-3.09 (m, 6H), 2.06-1.90 (m, 4H), 1.70 (s, 2H), 1.68-1.63 (m, 2H), 1.57-1.40 (m, 1H), 1.33-1.20 (m, 8H).

[0322] Biological test examples

[0323] Test Example 1: Inhibitory activity against 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).

[0324] 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.

[0325] 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 of these 10 concentrations was then diluted 10-fold with culture medium in another 96-well plate. 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), shake for 2 min, incubate at room temperature for 8 min, and then measure the luminescence intensity (collection time is 100 ms). Calculate the inhibition rate of cell proliferation for each concentration of compound: Cell proliferation inhibition rate (%) = [(luminescence intensity)] 72小时含细胞培养基对照组 - Luminous intensity 72小时化合物组 ) / (luminous intensity) 72小时含细胞培养基对照组 – Luminous intensity 72小时无细胞培养基对照组 The dose-response curve was calculated using GraphPad Prism 8.3 software, with the IC100% calculated. The data was analyzed using nonlinear S-curve regression to fit the data and derive the dose-response curve. 50 The values ​​are shown in Table 1.

[0326] Table 1

[0327]

[0328] The " / " indicates that it was not tested.

[0329] Test results show that the compound of the present invention has good inhibitory activity against the proliferation of NCI-H358 and Capan-1 cells containing KRAS mutations, but weak inhibitory activity against the proliferation of wild-type KRAS PC-9 cells.

Claims

1. A compound of Formula I, its stereoisomer, or a pharmaceutically acceptable salt thereof, Formula I in, Each It can be a single bond or a double bond independently; X 1 and X 2 Each independently for CR 6 R 6 CR 6 NR 7 N, O, S, -CR 6 =CR 6 -、-N=N- or -CR 6 =N-; X 3 X 4 and X 5 Each independently for CR 6 C or N; R 6 and R 7 Each is independently hydrogen, deuterium, halogen, -CN, -NR 9 R 9 -OR 9 C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, 3-10 membered heterocyclic alkyl, with one or more R 6a Substituted C1-C6 alkyl groups, with one or more R 6b Substituted C2-C6 alkenyl groups, with one or more R 6c Substituted C2-C6 ynyl group, with one or more R 6d Replacement C3-C 10 cycloalkyl or with one or more R 6e Substituted 3-10 membered heterocyclic alkyl groups; R 6a R 6b R 6c R 6d and R 6e Each can be independently deuterium, -CN, halogen, -OH, or -NH2; Y is -NR 8 -, -O-, -S-, -(CR 8 R 8 ) p1 - or -(CR 8 R 8 ) p2 NR 8 -; p1 and p2 are each independently 1, 2 or 3; R 8 Independently hydrogen, -NR 9 R 9 -OR 9 C1-C6 alkyl, C3-C 10 cycloalkyl, C3-C 10 Cycloalkenyl, 3-10 heterocyclic alkyl, 3-10 heterocyclic alkenyl, 5-10 heteroaryl, C6-C 10 Aryl, -SO2R 8h , by one or more R 8a Substituted C1-C6 alkyl groups, with one or more R 8b Replacement C3-C 10 cycloalkyl, with one or more R 8c Replacement C3-C 10 Cycloalkenyl, with one or more R 8d Substituted 3-10 membered heterocyclic alkyl groups, with one or more R 8e Substituted 3-10 membered heterocyclic alkenyl groups, with one or more R 8f Substituted 5-10 heteroaryl groups or substituted with one or more R 8g Replacement C6-C 10 Aryl; R 8a R 8b R 8c R 8d R 8e R 8f R 8g and R 8h Each can be independently represented by a halogen, =O, -CN, carboxyl, or -OR. 9 -NR 9 R 9 -SR 9 -SOR 9 -SO2R 9 -C(O)NR 9 R 9 -C(O)R 9 C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, C3-C 10 Cycloalkenyl, 3-10 heterocyclic alkyl, 3-10 heterocyclic alkenyl, 5-10 heteroaryl, C6-C 10 aryl, with one or more R 8-a Substituted C1-C6 alkyl groups, with one or more R 8-b Substituted C2-C6 alkenyl groups, with one or more R 8-c Substituted C2-C6 ynyl group, with one or more R 8-d Replacement C3-C 10 cycloalkyl, with one or more R 8-e Replacement C3-C 10 Cycloalkenyl, with one or more R 8-f Substituted 3-10 membered heterocyclic alkyl groups, with one or more R 8-g Substituted 3-10 membered heterocyclic alkenyl groups, with one or more R 8-h Substituted 5-10 heteroaryl groups or substituted with one or more R 8-i Replacement C6-C 10 Aryl; R 8-a R 8-b R 8-c R 8-d R 8-e R 8-f R 8-g R 8-h and R 8-i Each is independently a halogen, =O, -CN, -OR 9 -NR 9 R 9 -SR 9 -SOR 9 -SO2R 9 -C(O)NR 9 R 9 -C(O)R 9 C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, C3-C 10 Cycloalkenyl, 3-10 heterocyclic alkyl, 3-10 heterocyclic alkenyl, 5-10 heteroaryl, C6-C 10 aryl, with one or more R 8 -a-1 Substituted C1-C6 alkyl groups, with one or more R 8-a-2 Substituted C2-C6 alkenyl groups, with one or more R 8-a-3 Substituted C2-C6 ynyl group, with one or more R 8-a-4 Replacement C3-C 10 cycloalkyl, with one or more R 8-a-5 Replacement C3-C 10 Cycloalkenyl, with one or more R 8-a-6 Substituted 3-10 membered heterocyclic alkyl groups, with one or more R 8-a-7 Substituted 3-10 membered heterocyclic alkenyl groups, with one or more R 8-a-8 Substituted 5-10 heteroaryl groups or substituted with one or more R 8-a-9 Replacement C6-C 10 Aryl; R 8-a-1 R 8-a-2 R 8-a-3 R 8-a-4 R 8-a-5 R 8-a-6 R 8-a-7 R 8-a-8 and R 8-a-9 Each can be independently a halogen, =O, -CN, -C(O)CH3, -C(O)NH2, -OH, -NH2, -SCH3, -SO2CH3, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, C3-C 10 Cycloalkenyl, 3-10 heterocyclic alkyl, 3-10 heterocyclic alkenyl, 5-10 heteroaryl and C6-C 10 Aryl; R 9 Independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, C3-C 10 Cycloalkenyl, 3-10 heterocyclic alkyl, 3-10 heterocyclic alkenyl, 5-10 heteroaryl, C6-C 10 aryl, with one or more R 9a Substituted C1-C6 alkyl groups, with one or more R 9b Substituted C2-C6 alkenyl groups, with one or more R 9c Substituted C2-C6 ynyl group, with one or more R 9d Replacement C3-C 10 cycloalkyl, with one or more R 9e Replacement C3-C 10 Cycloalkenyl, with one or more R 9f Substituted 3-10 membered heterocyclic alkyl groups, with one or more R 9g Substituted 3-10 membered heterocyclic alkenyl groups, with one or more R 9h Substituted 5-10 heteroaryl groups or substituted with one or more R 9i Replace C6-C 10 Aryl; R 9a R 9b R 9c R 9d R 9e R 9f R 9g R 9h and R 9i Each can be independently deuterium, -CN, halogen, -OH, or -NH2; R 1 It is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, C3-C 10 Cycloalkenyl, 3-10 heterocyclic alkyl, 3-10 heterocyclic alkenyl, 5-10 heteroaryl, C6-C 10 aryl, with one or more R 1a Substituted C1-C6 alkyl groups, with one or more R 1b Substituted C2-C6 alkenyl groups, with one or more R 1c Substituted C2-C6 ynyl group, with one or more R 1d Replacement C3-C 10 cycloalkyl, with one or more R 1e Replacement C3-C 10 Cycloalkenyl, with one or more R 1f Substituted 3-10 membered heterocyclic alkyl groups, with one or more R 1g Substituted 3-10 membered heterocyclic alkenyl groups, with one or more R 1h Substituted 5-10 heteroaryl groups or substituted with one or more R 1i Replacement C6-C 10 Aryl; R 1a R 1b R 1c R 1d R 1e R 1f R 1g R 1h and R 1i Each is independently of deuterium, halogen, -CN, -NR. 9 R 9 -OR 9 -SR 9 -(CH2)-C(=O)N(R 9 2. C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, C3-C 10 Cycloalkenyl, 3-10 heterocyclic alkyl, 3-10 heterocyclic alkenyl, 5-10 heteroaryl, C6-C 10 aryl, with one or more R 1-a Substituted C1-C6 alkyl groups, with one or more R 1-b Substituted C2-C6 alkenyl groups, with one or more R 1-c Substituted C2-C6 ynyl group, with one or more R 1-d Replacement C3-C 10 cycloalkyl, with one or more R 1-e Replacement C3-C 10 Cycloalkenyl, with one or more R 1-f Substituted 3-10 membered heterocyclic alkyl groups, with one or more R 1-g Substituted 3-10 membered heterocyclic alkenyl groups, with one or more R 1-h Substituted 5-10 heteroaryl groups or substituted with one or more R 1-i Replacement C6-C 10 Aryl; Or two adjacent R 1d R 1e R 1f R 1g R 1h and R 1i The atoms bonded to them together form C3-C 10 cycloalkyl, C3-C 10 Cycloalkenyl, 3-10 membered heterocyclic alkyl, 3-10 membered heterocyclic alkenyl, C6-C 10 aryl, 5-10 heteroaryl, with one or more R 1-j Replacement C3-C 10 cycloalkyl, with one or more R 1-k Replacement C3-C 10 Cycloalkenyl, with one or more R 1-l Substituted 3-10 membered heterocyclic alkyl groups, with one or more R 1-m Substituted 3-10 membered heterocyclic alkenyl groups, with one or more R 1-n Replacement C6-C 10 aryl, with one or more R 1-o Substituted 5-10 heteroaryl groups; 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 R 1-j R 1-k R 1-l R 1-m R 1-n and R 1-o Each can be independently classified as deuterium, halogen, -CN, -OH, or -NR. 9 R 9 -OR 9 -SR 9 C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, C3-C 10 Cycloalkenyl, 3-10 membered heterocyclic alkyl, 3-10 membered heterocyclic alkenyl, C6-C 10 aryl, 5-10 heteroaryl, with one or more R 1-a-1 Substituted C1-C6 alkyl groups, with one or more R 1-a-2 Substituted C2-C6 alkenyl groups, with one or more R 1-a-3 Substituted C2-C6 ynyl group, with one or more R 1-a-4 Replacement C3-C 10 cycloalkyl, with one or more R 1-a-5 Replacement C3-C 10 Cycloalkenyl, with one or more R 1-a-6 Substituted 3-10 membered heterocyclic alkyl groups, with one or more R 1-a-7 Substituted 3-10 membered heterocyclic alkenyl groups, with one or more R 1-a-8 Replacement C6-C 10 aryl or aryl with one or more R 1-a-9 Substituted 5-10 heteroaryl groups; R 1-a-1 R 1-a-2 R 1-a-3 R 1-a-4 R 1-a-5 R 1-a-6 R 1-a-7 R 1-a-8 and R 1-a-9 Each can be independently deuterium, halogen, -CN, -OH, -NH2, C1-C6 alkyl, C1-C6 alkyl-O-, C1-C6 alkyl-S-, or C3-C 10 cycloalkyl; L is a linking group, -O-(CR 10 R 10 ) n1 -, -O-(CR 10 R 10 ) n6 -CR 12 R 13 -(CR 10 R 10 ) n7 -, -S-(CR 10 R 10 ) n2 -, -NR 11 -(CR 10 R 10 ) n3 -, -SO-(CR 10 R 10 ) n4 - or -SO2-(CR 10 R 10 ) n5 -; n1, n2, n3, n4, n5, n6 and n7 are each independently 0, 1, 2, 3, 4 or 5; R 10 and R 11 Each independently represents hydrogen, deuterium, and -OR 9 -NR 9 R 9 C1-C6 alkyl, C3-C 10 cycloalkyl, C3-C 10 Cycloalkenyl, 3-10 heterocyclic alkyl, 3-10 heterocyclic alkenyl, 5-10 heteroaryl, C6-C 10 aryl, with one or more R 10a Substituted C1-C6 alkyl groups, with one or more R 10b Replacement C3-C 10 cycloalkyl, with one or more R 10c Replacement C3-C 10 Cycloalkenyl, with one or more R 10d Substituted 3-10 membered heterocyclic alkyl groups, with one or more R 10e Substituted 3-10 membered heterocyclic alkenyl groups, with one or more R 10f Substituted 5-10 heteroaryl groups or substituted with one or more R 10g Replacement C6-C 10 Aryl; R 12 R 13 Together with the carbon atoms they are connected to, they form C3-C. 10 cycloalkyl, C3-C 10 Cycloalkenyl, 3-10 membered heterocyclic alkyl, 3-10 membered heterocyclic alkenyl, with one or more R 10h Replacement C3-C 10 cycloalkyl, with one or more R 10i Replacement C3-C 10 Cycloalkenyl, with one or more R 10j Substituted 3-10 membered heterocyclic alkyl groups or substituted with one or more R 10k Substituted 3-10 membered heterocyclic alkenyl groups; R 10a R 10b R 10c R 10d R 10e R 10f R 10g R 10h R 10i R 10j and R 10k Each can be independently represented as deuterium, halogen, =O, -CN, carboxyl, or -OR. 9 -SR 9 -NR 9 R 9 C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, C3-C 10 Cycloalkenyl, 3-10 heterocyclic alkyl, 3-10 heterocyclic alkenyl, 5-10 heteroaryl, C6-C 10 aryl, with one or more R 10-a Substituted C1-C6 alkyl groups, with one or more R 10-b Substituted C2-C6 alkenyl groups, with one or more R 10-c Substituted C2-C6 ynyl group, with one or more R 10-d Replacement C3-C 10 cycloalkyl, with one or more R 10-e Replacement C3-C 10 Cycloalkenyl, with one or more R 10-f Substituted 3-10 membered heterocyclic alkyl groups, with one or more R 10-g Substituted 3-10 membered heterocyclic alkenyl groups, with one or more R 10-h Substituted 5-10 heteroaryl groups or substituted with one or more R 10-i Replacement C6-C 10 Aryl; R 10-a R 10-b R 10-c R 10-d R 10-e R 10-f R 10-g R 10-h and R 10-i Each is independently represented as deuterium, halogen, =O, -CN, -OR 9 -SR 9 -NR 9 R 9 C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, C3-C 10 Cycloalkenyl, 3-10 heterocyclic alkyl, 3-10 heterocyclic alkenyl, 5-10 heteroaryl or C6-C 10 Aryl; R 2 It is hydrogen, deuterium, -COOH, C1-C6 alkyl, C3-C 10 cycloalkyl, C3-C 10 Cycloalkenyl, 3-10 heterocyclic alkyl, 3-10 heterocyclic alkenyl, 5-10 heteroaryl, C6-C 10 aryl, with one or more R 2a Substituted C1-C6 alkyl groups, with one or more R 2b Replacement C3-C 10 cycloalkyl, with one or more R 2c Replacement C3-C 10 Cycloalkenyl, with one or more R 2d Substituted 3-10 membered heterocyclic alkyl groups, with one or more R 2e Substituted 3-10 membered heterocyclic alkenyl groups, with one or more R 2f Substituted 5-10 heteroaryl groups or substituted with one or more R 2g Replacement C6-C 10 Aryl; R 2a R 2b R 2c R 2d R 2e R 2f and R 2g Each is independently a deuterium, halogen, =O, -CN, =CR 2-a-10 R 2-a-10 -NR 9 R 9 -OR 9 -SR 9 -C(=O)R 9 -C(O)NR 9 R 9 -SO2R 9 -SOR 9 C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, C3-C 10 Cycloalkenyl, 3-10 heterocyclic alkyl, 3-10 heterocyclic alkenyl, 5-10 heteroaryl, C6-C 10 aryl, with one or more R 2-a-1 Substituted C1-C6 alkyl groups, with one or more R 2-a-2 Substituted C2-C6 alkenyl groups, with one or more R 2-a-3 Substituted C2-C6 ynyl group, with one or more R 2-a-4 Replacement C3-C 10 cycloalkyl, with one or more R 2-a-5 Replacement C3-C 10 Cycloalkenyl, with one or more R 2-a-6 Substituted 3-10 membered heterocyclic alkyl groups, with one or more R 2-a-7 Substituted 3-10 membered heterocyclic alkenyl groups, with one or more R 2-a-8 Substituted 5-10 heteroaryl groups or substituted with one or more R 2-a-9 Replacement C6-C 10 Aryl; R 2-a-1 R 2-a-2 R 2-a-3 R 2-a-4 R 2-a-5 R 2-a-6 R 2-a-7 R 2-a-8 and R 2-a-9 Each is independently of deuterium, -CN, halogen, -NR. 9 R 9 -OR 9 -SR 9 C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, C3-C 10 Cycloalkenyl, 3-10 heterocyclic alkyl, 3-10 heterocyclic alkenyl, 5-10 heteroaryl or C6-C 10 Aryl; R 2-a-10 Independently hydrogen, deuterium, -CN, halogen, -NR 9 R 9 -OR 9 -SR 9 C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, C3-C 10 Cycloalkenyl, 3-10 heterocyclic alkyl, 3-10 heterocyclic alkenyl, 5-10 heteroaryl or C6-C 10 Aryl; R 3 and R 4 Each is independently hydrogen, deuterium, halogen, -CN, -NR 9 R 9 -OR 9 -SR 9 C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, C3-C 10 Cycloalkenyl, 3-10 heterocyclic alkyl, 3-10 heterocyclic alkenyl, 5-10 heteroaryl, C6-C 10 aryl, with one or more R 3a Substituted C1-C6 alkyl groups, with one or more R 3b Substituted C2-C6 alkenyl groups, with one or more R 3c Substituted C2-C6 ynyl group, with one or more R 3d Replacement C3-C 10 cycloalkyl, with one or more R 3e Replacement C3-C 10 Cycloalkenyl, with one or more R 3f Substituted 3-10 membered heterocyclic alkyl groups, with one or more R 3g Substituted 3-10 membered heterocyclic alkenyl groups, with one or more R 3h Substituted 5-10 heteroaryl groups or substituted with one or more R 3i Replacement C6-C 10 Aryl; Or R 3 and R 4 Together they form an oxygen group; R 3a R 3b R 3c R 3d R 3e R 3f R 3g R 3h and R 3i Each is independently of deuterium, -CN, halogen, -NR. 9 R 9 -OR 9 or -SR 9 ; m can be 0, 1, 2, 3, or 4; R 5 Independent of deuterium, halogen, -NR 9 R 9 -OR 9 -SR 9 C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, C3-C 10 Cycloalkenyl, 3-10 heterocyclic alkyl, 3-10 heterocyclic alkenyl, 5-10 heteroaryl, C6-C 10 aryl, with one or more R 5a Substituted C1-C6 alkyl groups, with one or more R 5b Substituted C2-C6 alkenyl groups, with one or more R 5c Substituted C2-C6 ynyl group, with one or more R 5d Replacement C3-C 10 cycloalkyl, with one or more R 5e Replacement C3-C 10 Cycloalkenyl, with one or more R 5f Substituted 3-10 membered heterocyclic alkyl groups, with one or more R 5g Substituted 3-10 membered heterocyclic alkenyl groups, with one or more R 5h Substituted 5-10 heteroaryl groups or substituted with one or more R 5i Replacement C6-C 10 Aryl; R 5a R 5b R 5c R 5d R 5e R 5f R 5g R 5h and R 5i Each is independently a halogen, =O, -CN, -NR 9 R 9 -OR 9 -SR 9 C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, with one or more R 5-a Substituted C1-C6 alkyl groups, with one or more R 5-b Substituted C2-C6 alkenyl groups, with one or more R 5-c Substituted C2-C6 ynyl group or with one or more R 5-d Replacement C3-C 10 cycloalkyl; R 5-a R 5-b R 5-c and R 5-d Each can be independently deuterium, halogen, =O, -CN, -OH, -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C3-C 10 cycloalkyl; The heteroatoms in each of the 3-10-membered heterocyclic alkyl, 3-10-membered heterocyclic alkenyl and 5-10-membered heteroaryl groups are independently selected from one or more of N, O and S, and the number of heteroatoms is independently 1, 2 or 3.

2. 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 satisfies one or more of the following conditions: (1) Each halogen is independently fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine; (2) Each C1-C6 alkyl group is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl or sec-butyl, for example methyl or ethyl; (3) Each C1-C6 alkyl-O- is independently methyl-O-, ethyl-O-, n-propyl-O-, isopropyl-O-, n-butyl-O-, tert-butyl-O-, isobutyl-O- or sec-butyl-O-; (4) Each C1-C6 alkyl-S- is independently methyl-S-, ethyl-S-, n-propyl-S-, isopropyl-S-, n-butyl-S-, tert-butyl-S-, isobutyl-S- or sec-butyl-S-; (5) Each C2-C6 alkenyl group is independently vinyl, propenyl, allyl, 1-butenyl or 1-pentenyl; (6) Each C2-C6 ynyl group is independently ethynyl, propynyl, propynyl, 1-butynyl or 1-pentynyl; (7) Each C3-C 10 The cycloalkyl group is independently a C3-C8 cycloalkyl group, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; (8) The heteroatoms of each 3-10 member 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; preferably, the heteroatoms are independently selected from one or two of N and O, and the number of heteroatoms is independently 1 or 2. (9) Each 3-10 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 3-10 membered heterocyclic alkyl group may be independently a 4-6 membered monocyclic heterocyclic alkyl group, an 8-10 membered bicyclic heterocyclic alkyl group, or a 10 membered tricyclic heterocyclic alkyl group; preferably , , , , or More preferably , , , , , , , , , or ; (10) Each C3-C 10 The cycloalkenyl group is independently a C5-C6 cycloalkenyl group; (11) Each C3-C 10 The cycloalkenyl group independently contains one or more carbon-carbon sp groups. 2 Double bond; (12) Each 3-10 membered heterocyclic alkenyl group is independently a 3-9 membered heterocyclic alkenyl group, preferably , or More preferably , or ; (13) The heteroatoms of each 3-10 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 heteroatoms are independently selected from one or two of N and S, and the number of heteroatoms is independently 1 or 2. (14) Each 3-10 member heterocyclic alkenyl group is independently monocyclic or polycyclic, and the polycyclic group can be a bridged ring, a fused ring or a spiro ring, and the polycyclic group can also be a bicyclic or a tricyclic ring; preferably, each 3-10 member heterocyclic alkenyl group can be independently a 3-6 member monocyclic heterocyclic alkenyl group or an 8-10 member bicyclic heterocyclic alkenyl group; (15) Each 3-10 membered heterocyclic alkenyl group independently contains one or more sp atoms. 2 Double bond; (16) Each C6-C 10 The aryl group can be phenyl or naphthyl, for example, phenyl; (17) 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; preferably, the heteroatoms are independently selected from one or two of N and S, and the number of heteroatoms is independently 1 or 2; and (18) Each 5-10 nucleotide heteroaryl group is independently a monocyclic or polycyclic compound, wherein the polycyclic compound may be a fused ring; the polycyclic compound may be a bicyclic or tricyclic compound; preferably, each 5-10 nucleotide heteroaryl group is a 5-6 nucleotide monocyclic heteroaryl group or a 9-10 nucleotide bicyclic heteroaryl group; preferably or More preferably or .

3. 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 satisfies one or more of the following conditions: (1) X 3 X 4 and X 5 Each can be independently represented as C or N; (2) X 1 and X 2 Each independently for CR 6 R 6 CR 6 NR 7 Or N, preferably CR 6 NR 7 Or N; (3)X 1 X 2 X 3 X 4 and X 5 At least one of them is N or NR. 7 ; (4) Ring It has aromatic properties; (5) R 6 and R 7 Each is independently hydrogen or C1-C6 alkyl, preferably hydrogen; (6) Y is -NR 8 -; (7) R 8 For one or more R 8a Substituted C1-C6 alkyl groups; (8) R 8a Independently 5-10 member heteroaryl, C6-C 10 aryl, with one or more R 8-h Substituted 5-10 heteroaryl groups or substituted with one or more R 8-i Replacement C6-C 10 Aryl group, preferably with one or more R groups 8-h Substituted 5-10 heteroaryl groups; (9) R 8-h and R 8-i Each is independently a halogen, -CN, or -NR. 9 R 9 Or C1-C6 alkyl, preferably -NR 9 R 9 ; (10) R 9 Independently hydrogen or C1-C6 alkyl; (11) R 1 It is hydrogen, C1-C6 alkyl, C3-C 10 cycloalkyl, 3-10 membered heterocyclic alkenyl, 5-10 membered heteroaryl, C6-C 10 aryl, with one or more R 1d Replacement C3-C 10 cycloalkyl, with one or more R 1g Substituted 3-10 membered heterocyclic alkenyl groups, with one or more R 1h Substituted 5-10 heteroaryl groups or substituted with one or more R 1i Replacement C6-C 10 aryl, preferably hydrogen, surrounded by one or more R 1g Substituted 3-10 membered heterocyclic alkenyl groups, with one or more R 1h Substituted 5-10 heteroaryl groups or substituted with one or more R 1i Replacement C6-C 10 aryl, more preferably composed of one or more R 1h Substituted 5-10 heteroaryl groups or substituted with one or more R 1i Replacement C6-C 10 Aryl; (12) R 1d R 1g R 1h and R 1i Each is independently of deuterium, halogen, -CN, -NR. 9 R 9 OR 9 C1-C6 alkyl or containing one or more R 1-a The substituted C1-C6 alkyl group is preferably halogenated, -CN, or -NR. 9 R 9 C1-C6 alkyl or containing one or more R 1-a Substituted C1-C6 alkyl groups; (13) R 1-a Independently deuterium, halogen, -CN, -NR 9 R 9 -OR 9 -SR 9 Or C1-C6 alkyl, preferably halogen; (14) L is -O-(CR) 10 R 10 ) n1 - b or -O-(CR) 10 R 10 ) n6 -CR 12 R 13 -(CR 10 R 10 ) n7 - b ; where L's b-side is related to R 2 Connected; (15) n1, n6 and n7 are each independently 1, 2 or 3, preferably 1; (16) R 10 It is independently hydrogen, deuterium, or C1-C6 alkyl; (17) R 12 R 13 Together with the carbon atoms they are connected to, they form C3-C. 10 cycloalkyl; (18)R 2 For C3-C 10 cycloalkyl, C3-C 10 Cycloalkenyl, 3-10 membered heterocyclic alkyl, 3-10 membered heterocyclic alkenyl, with one or more R 2b Replacement C3-C 10 cycloalkyl, with one or more R 2c Replacement C3-C 10 Cycloalkenyl, with one or more R 2d Substituted 3-10 membered heterocyclic alkyl groups or substituted with one or more R 2e The substituted 3-10-membered heterocyclic alkenyl group is preferably a 3-10-membered heterocyclic alkyl group, a 3-10-membered heterocyclic alkenyl group, or a group substituted with one or more R groups. 2d Substituted 3-10 membered heterocyclic alkyl groups; (19)R 2b R 2c R 2d and R 2e Each is independently classified as deuterium, halogen, -CN, =CR 2-a-10 R 2-a-10 -NR 9 R 9 -OR 9 -SR 9 C1-C6 alkyl groups, with one or more R 2-a-1 Substituted C1-C6 alkyl groups, preferably halogens, =CR 2-a-10 R 2-a-10 -OR 9 -SR 9 C1-C6 alkyl groups, with one or more R 2-a-1 Substituted C1-C6 alkyl groups; (20)R 2-a-1 For deuterium, -CN, halogen, -NR 9 R 9 or -OR 9 Halogen is preferred; (21) R 2-a-10 It is independently hydrogen, deuterium, or halogen, preferably hydrogen or halogen; (22)R 3 and R 4 Each is independently hydrogen, deuterium, halogen, or C1-C6 alkyl, or R 3 and R 4 Together they form an oxy group; preferably, R 3 and R 4 Each is independently hydrogen or deuterium, or R 3 and R 4 Together they form an oxygen group; (23) m is 0, 1, or 2, preferably 0; and (24) R 5 It can be independently deuterium, halogen, or C1-C6 alkyl.

4. 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 satisfies one or more of the following conditions: (1) Structural fragments for , , , , , , , or The a-terminus is connected to the N atom. (2) L is , , , , or ; where L's b-side is related to R 2 Connected; (3) R 2 for , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or ; (4) Y is -NR 8 -, R 8 for ;and (5) R 1 For hydrogen, , , , or .

5. The compound of formula I as claimed in claim 1, its stereoisomers, or pharmaceutically acceptable salts thereof, characterized in that, R 1 It is a 5-10 membered heterocyclic alkenyl group or is surrounded by one or more R groups. 1g The substituted 5-10 membered heterocyclic alkenyl group, preferably R 1 It is an 8-10 membered bicyclic heterocyclic alkenyl group or is surrounded by one or more R groups. 1g Substituted 8-10 membered bicyclic heterocyclic alkenyl groups, for example or .

6. The compound of formula I as claimed in any one of claims 1-5, its stereoisomers, or pharmaceutically acceptable salts thereof, characterized in that, The compound represented by Formula I satisfies one of the following schemes: Scheme 1, Scheme 2, Scheme 3, Scheme 4, Scheme 5, Scheme 6, or Scheme 7: Option 1: Each It can be a single bond or a double bond independently; X 3 X 4 and X 5 Each can be independently represented as C or N; X 1 and X 2 Each independently for CR 6 R 6 CR 6 NR 7 Or N; And X 1 X 2 X 3 X 4 and X 5 At least one of them is N or NR 7 ; R 6 and R 7 Each is independently hydrogen or C1-C6 alkyl; Y is -NR 8 -; R 8 For one or more R 8a Substituted C1-C6 alkyl groups; R 8a Independently 5-10 member heteroaryl, C6-C 10 aryl, with one or more R 8-h Substituted 5-10 heteroaryl groups or substituted with one or more R 8-i Replacement C6-C 10 Aryl; R 8-h and R 8-i Each is independently a halogen, -CN, or -NR. 9 R 9 Or C1-C6 alkyl; R 9 Independently hydrogen or C1-C6 alkyl; R 1 It is hydrogen, C1-C6 alkyl, 3-10 membered heterocyclic alkenyl, 5-10 membered heteroaryl, C6-C 10 aryl, with one or more R 1g Substituted 3-10 membered heterocyclic alkenyl groups, with one or more R 1h Substituted 5-10 heteroaryl groups or substituted with one or more R 1i Replacement C6-C 10 Aryl; R 1g R 1h and R 1i Each is independently a halogen, -CN, or -NR. 9 R 9 C1-C6 alkyl or containing one or more R 1-a Substituted C1-C6 alkyl groups; R 1-a Independently deuterium or halogen; L is -O-(CR) 10 R 10 ) n1 - b or -O-(CR) 10 R 10 ) n6 -CR 12 R 13 -(CR 10 R 10 ) n7 - b ; where L's b-side is related to R 2 Connected; n1, n6, and n7 are each independently 1, 2, or 3; R 10 It is independently hydrogen, deuterium, or C1-C6 alkyl; R 12 R 13 Together with the carbon atoms they are connected to, they form C3-C. 10 cycloalkyl; R 2 For C3-C 10 cycloalkyl, C3-C 10 Cycloalkenyl, 3-10 membered heterocyclic alkyl, 3-10 membered heterocyclic alkenyl, with one or more R 2b Replacement C3-C 10 cycloalkyl, with one or more R 2c Replacement C3-C 10 Cycloalkenyl, with one or more R 2d Substituted 3-10 membered heterocyclic alkyl groups or substituted with one or more R 2e Substituted 3-10 membered heterocyclic alkenyl groups; R 2b R 2c R 2d and R 2e Each is independently a halogen, =CR 2-a-10 R 2-a-10 -OR 9 -SR 9 C1-C6 alkyl groups, with one or more R 2-a-1 Substituted C1-C6 alkyl groups; R 2-a-1 Halogens are independent of each other; R 2-a-10 It can be hydrogen, deuterium, or halogen independently; R 3 and R 4 Each is independently hydrogen, deuterium, halogen, or C1-C6 alkyl, or R 3 and R 4 Together they form an oxygen group; m is 0, 1, or 2; R 5 It can be independently deuterium, halogen, or C1-C6 alkyl; The heteroatoms in each of the 3-10-membered heterocyclic alkyl, 3-10-membered heterocyclic alkenyl and 5-10-membered heteroaryl groups are independently selected from one or more of N, O and S, and the number of heteroatoms is independently 1, 2 or 3. Option 2: The compound represented by Formula I is the same as the compound represented by Formula II. Formula II Among them, R 1 R 2 R 3 R 4 R 8 The definition of L is as described in any one of claims 1-5; Structural fragments for , , , , , , , or The a-terminus is connected to the N atom. Option 3: The compound represented by Formula I is the same as the compound represented by Formula III. Formula III Among them, R 1 R 2 R 8 The definition of L is as described in any one of claims 1-5; Option 4: The compound represented by Formula I is the same as the compound represented by Formula II. Formula II Among them, structural fragments for , , , , , , , or The a-terminus is connected to the N atom. R 8 For one or more R 8a Substituted C1-C6 alkyl groups; R 8a Independently for one or more R 8-h Substituted 5-10 heteroaryl groups; R 8-h Independently for -NR 9 R 9 ; R 9 Independently hydrogen or C1-C6 alkyl; R 1 For hydrogen, by one or more R 1g Substituted 3-10 membered heterocyclic alkenyl groups, with one or more R 1h Substituted 5-10 heteroaryl groups or substituted with one or more R 1i Replacement C6-C 10 Aryl; R 1g R 1h and R 1i Each is independently a halogen, -CN, or -NR. 9 R 9 C1-C6 alkyl or containing one or more R 1-a Substituted C1-C6 alkyl groups; R 1-a Halogens are independent of each other; L is -O-(CR) 10 R 10 ) n1 - b or -O-(CR) 10 R 10 ) n6 -CR 12 R 13 -(CR 10 R 10 ) n7 - b ; where L's b-side is related to R 2 Connected; n1, n6, and n7 are each independently 1; R 10 It is independently hydrogen, deuterium, or C1-C6 alkyl; R 12 R 13 Together with the carbon atoms they bond together, they form C3-C 10 cycloalkyl; R 2 It is a 3-10 membered heterocyclic alkyl group, a 3-10 membered heterocyclic alkenyl group, or is surrounded by one or more R groups. 2d Substituted 3-10 membered heterocyclic alkyl groups; R 2d Independent of halogen, =CR 2-a-10 R 2-a-10 -OR 9 -SR 9 C1-C6 alkyl groups, with one or more R 2-a-1 Substituted C1-C6 alkyl groups; R 2-a-1 Halogens are independent of each other; R 2-a-10 Independently hydrogen or halogen; R 3 and R 4 Each is independently hydrogen or deuterium, or R 3 and R 4 Together they form an oxygen group; The heteroatoms in each of the 3-10-membered heterocyclic alkyl, 3-10-membered heterocyclic alkenyl and 5-10-membered heteroaryl groups are each independently selected from one or more of N, O and S, and the number of heteroatoms is independently 1, 2 or 3. Option 5: The compound represented by Formula I is the same as the compound represented by Formula III. Formula III in, R 8 For one or more R 8a Substituted C1-C6 alkyl groups; R 8a Independently for one or more R 8-h Substituted 5-10 heteroaryl groups; R 8-h Independently for -NR 9 R 9 ; R 9 Independently hydrogen or C1-C6 alkyl; R 1 For hydrogen, by one or more R 1h Substituted 5-10 heteroaryl groups or substituted with one or more R 1i Replacement C6-C 10 Aryl; R 1h and R 1i Each is independently a halogen, -CN, -NH2, C1-C6 alkyl, or associated with one or more R groups. 1-a Substituted C1-C6 alkyl groups; R 1-a Halogens are independent of each other; L is -O-(CR) 10 R 10 ) n1 - b or -O-(CR) 10 R 10 ) n6 -CR 12 R 13 -(CR 10 R 10 ) n7 - b ; where L's b-side is related to R 2 Connected; n1, n6, and n7 are all 1; R 10 It is independently hydrogen, deuterium, or C1-C6 alkyl; R 12 R 13 Together with the carbon atoms they are connected to, they form C3-C. 10 cycloalkyl; R 2 It is a 3-10 membered heterocyclic alkyl group, a 3-10 membered heterocyclic alkenyl group, or is surrounded by one or more R groups. 2d Substituted 3-10 membered heterocyclic alkyl groups; R 2d Independently halogen, =CR 2-a-10 R 2-a-10 -OR 9 -SR 9 C1-C6 alkyl groups, with one or more R 2-a-1 Substituted C1-C6 alkyl groups; R 2-a-1 Halogens are independent of each other; R 2-a-10 Independently hydrogen or halogen; The heteroatoms in each of the 3-10-membered heterocyclic alkyl, 3-10-membered heterocyclic alkenyl and 5-10-membered heteroaryl groups are independently selected from one or more of N, O and S, and the number of heteroatoms is independently 1, 2 or 3. Option Six: The compound represented by Formula I is the same as the compound represented by Formula III. Formula III in, R 8 For one or more R 8a Substituted C1-C6 alkyl groups; R 8a Independently for one or more R 8-h Substituted 5-10 heteroaryl groups; R 8-h Independently for -NR 9 R 9 ; R 9 Independently hydrogen or C1-C6 alkyl; R 1 It is a 5-10 membered heterocyclic alkenyl group or is surrounded by one or more R groups. 1g Substituted 5-10 membered heterocyclic alkenyl groups; R 1g It is independently a halogen, -CN, -NH2, C1-C6 alkyl, or is oxidized by one or more R 1-a Substituted C1-C6 alkyl groups; R 1-a Halogens are independent of each other; L is -O-(CR) 10 R 10 ) n1 - b or -O-(CR) 10 R 10 ) n6 -CR 12 R 13 -(CR 10 R 10 ) n7 - b ; where L's b-side is related to R 2 Connected; n1, n6, and n7 are all 1; R 10 It is independently hydrogen, deuterium, or C1-C6 alkyl; R 12 R 13 Together with the carbon atoms they are connected to, they form C3-C. 10 cycloalkyl; R 2 It is a 3-10 membered heterocyclic alkyl group, a 3-10 membered heterocyclic alkenyl group, or is surrounded by one or more R groups. 2d Substituted 3-10 membered heterocyclic alkyl groups; R 2d Independent of halogen, =CR 2-a-10 R 2-a-10 -OR 9 -SR 9 C1-C6 alkyl groups, with one or more R 2-a-1 Substituted C1-C6 alkyl groups; R 2-a-1 Halogens are independent of each other; R 2-a-10 Independently hydrogen or halogen; The heteroatoms in each of the 3-10-membered heterocyclic alkyl, 3-10-membered heterocyclic alkenyl and 5-10-membered heteroaryl groups are independently selected from one or more of N, O and S, and the number of heteroatoms is independently 1, 2 or 3. Option Seven: The compound represented by Formula I is the same as the compound represented by Formula III. Formula III in, R 8 For one or more R 8a Substituted C1-C6 alkyl groups; R 8a Independently for one or more R 8-h Substituted 5-6 aryl groups; R 8-h Independently for -NR 9 R 9 ; R 9 Independently hydrogen or C1-C6 alkyl; R 1 It is an 8-10 membered bicyclic heterocyclic alkenyl group or is surrounded by one or more R groups. 1g Substituted 8-10 membered bicyclic heterocyclic alkenyl groups; R 1g It is independently a halogen, -CN, -NH2, C1-C6 alkyl, or is oxidized by one or more R 1-a Substituted C1-C6 alkyl groups; R 1-a Halogens are independent of each other; L is -O-(CR) 10 R 10 )- b ; where L's b-side is related to R 2 Connected; R 10 It is independently hydrogen, deuterium, or C1-C6 alkyl; R 2 It is a 4-10 membered heterocyclic alkyl, a 4-10 membered heterocyclic alkenyl, or is surrounded by one or more R 2d Substituted 4-10 membered heterocyclic alkyl groups; R 2d Independently halogen, =CR 2-a-10 R 2-a-10 -OR 9 -SR 9 C1-C6 alkyl groups, with one or more R 2-a-1 Substituted C1-C6 alkyl groups; R 2-a-1 Halogens are independent of each other; R 2-a-10 Independently hydrogen or halogen; Each heteroatom in each of the 4-10-membered heterocyclic alkyl, 4-10-membered heterocyclic alkenyl, 8-10-membered bicyclic heterocyclic alkenyl and 5-6-membered heteroaryl groups is independently selected from one or more of N, O and S, and the number of heteroatoms is independently 1, 2 or 3.

7. 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: , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

8. A pharmaceutical composition comprising a therapeutically effective amount of the compound of formula I as claimed in any one of claims 1-7, its stereoisomer or a pharmaceutically acceptable salt thereof, and a pharmaceutical excipient.

9. The use of a compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described in any one of claims 1-7, wherein the use comprises one or more of the following: (1) To prepare drugs for the treatment and / or prevention of tumors; (2) To prepare medicines for the treatment and / or prevention of KRAS-mediated diseases; and (3) Preparation of KRAS inhibitors.

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 a tumor; (2) The tumor is 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; the lung cancer may be non-small cell lung cancer or small cell lung cancer; the colorectal cancer may be colon cancer or rectal cancer. (3) The tumor 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, or KRAS Q61R; preferably, the tumor is associated with at least one of the following mutations: KRAS G12C, KRAS G12D, and KRAS G12V; and (4) The KRAS is a KRAS mutation; the KRAS mutation is a KRAS G12C, KRAS G12D, KRAS G12V, KRAS G12A, KRAS G12R, KRAS G12S, KRAS G13C, KRAS G13D, KRAS Q61H, KRAS Q61K or KRAS Q61R mutation, preferably a KRAS G12C, KRAS G12D or KRAS G12V mutation.

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