Nitrogen-containing heterocyclic compound, preparation method therefor and use thereof

Abstract

Disclosed are a nitrogen-containing heterocyclic compound, a preparation method therefor and a use thereof. Specifically disclosed is a compound represented by formula I, a stereoisomer thereof or a pharmaceutically acceptable salt thereof. The nitrogen-containing heterocyclic compound provided by the present invention has proliferation inhibitory activity against at least one of KRAS-mutant NCI-H358, Capan-1 and AsPC-1 cancer cells, and exhibits relatively weak proliferation inhibitory activity against KRAS wild-type PC-9 cells, thereby demonstrating favorable selectivity, and showing potential in treatment and / or prevention of KRAS-mediated diseases.

Description

A nitrogen-containing heterocyclic compound, a preparation method thereof and application thereof

[0001] This application claims priority to Chinese Patent Application No. 2024106685400, filed on May 27, 2024, Chinese Patent Application No. 2024112077012, filed on August 29, 2024, Chinese Patent Application No. 2024118168301, filed on December 10, 2024, and Chinese Patent Application No. 2025106207028, filed on May 13, 2025. This application incorporates the entirety of the above-mentioned Chinese patent applications. TECHNICAL FIELD

[0002] The present application relates to a nitrogen-containing heterocyclic compound, a preparation method thereof and application thereof. BACKGROUND

[0003] RAS protein is a guanine triphosphate (GTP) binding protein with a molecular weight of 21 kDa located on the cell membrane, which is composed of 188 or 189 amino acids. The activity state of RAS protein has an impact on cell growth, differentiation, cytoskeleton, protein transport and secretion, etc., and its activity is regulated by binding with GTP or guanine diphosphate (GDP). When RAS protein binds with GDP, it is in an "inactivated" state; when stimulated by specific cell growth factors upstream, guanine nucleotide exchange factor (GEF) catalyzes RAS protein to release GDP and bind with GTP, and is in an "activated" state. RAS protein bound with GTP can activate downstream proteins and activate downstream signaling pathways. RAS protein itself has weak GTPase activity, which can hydrolyze GTP to GDP, thereby realizing the transformation from the activated state to the inactivated state. In this hydrolysis process, GTPase-activating protein (GAP) is also needed to participate, which can interact with RAS protein and greatly promote its ability to hydrolyze GTP to GDP. Any mutation in RAS protein that affects its own GTPase activity or its interaction with GAP or its ability to hydrolyze GTP to GDP will cause the RAS protein to be in a prolonged activated state, and the prolonged activated RAS protein continues to give growth signals to downstream proteins, leading to continuous cell growth and differentiation, which may eventually lead to cancer. There are three members in the RAS gene family: KRAS, NRAS and HRAS.

[0004] KRAS mutations are the most common oncogenic drivers, present in a variety of tumors: lung adenocarcinoma (32%), colorectal cancer (41%), pancreatic cancer (86%). KRAS mutations are most commonly G12 mutations in codon 12, for example, G12 mutations account for 85%, 68%, and 91% of KRAS-mutant lung adenocarcinoma, colorectal cancer, and pancreatic cancer, respectively; G12 mutations include G12C, G12D, G12V, G12R, and other mutant forms. In patients with KRAS G12 mutant lung adenocarcinoma, colorectal cancer, and pancreatic cancer, KRAS G12D mutant patients account for 17%, 45%, and 45%, respectively, and KRAS G12V mutant patients account for 23%, 30%, and 35%, respectively (see, e.g., Moore, A.R. et al. Nat Rev Drug Discov 19, 533 (2020)).

[0005] Currently, only inhibitors targeting KRAS G12C mutations are on the market, and inhibitors targeting KRAS G12D mutations are also in clinical research, but the patient population benefiting from KRAS G12C inhibitors only accounts for a small part of the KRAS variant-carrying population, and more than 85% of KRAS mutant cancers still lack effective treatment methods (see Marco, H.H. et al. Cancer Discov 12, 924 (2022)), and patients still need therapies targeting other KRAS variants (such as G12V, G12R, G12A).

[0006] Pan-KRAS inhibitors can inhibit a variety of KRAS mutants and have the potential to treat a wider patient population, and there is a huge unmet clinical need. SUMMARY

[0007] The technical problem to be solved by the present application is to overcome the single structure of Pan-KRAS inhibitors in the prior art, and provide a nitrogen-containing heterocyclic compound, a preparation method thereof, and an application thereof. The nitrogen-containing heterocyclic compound provided by the present application has a proliferation inhibitory activity on at least one of NCI-H358, Capan-1, and AsPC-1 cancer cells containing KRAS mutations, and a relatively weak proliferation inhibitory activity on KRAS wild-type PC-9 cells, has good selectivity, and is expected to treat and / or prevent diseases mediated by KRAS.

[0008] The present application provides a compound represented by Formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof,

[0009] wherein,

[0010] X is -C(R 6 )2- or -NR 7-O-, -S-, -SO-, -NR

[0011] Y is -NR 8 -O-, -S-, -SO-, -NR 8 SO2-, or -SO2-;

[0012] t is 0 or 1 ;

[0013] each R 6 is independently hydrogen, deuterium, halogen, cyano, nitro, -NH2, -OH, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, -O-C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 6a substituted C1-C6 alkyl, -O-C1-C6 alkyl, C3-C 6b substituted C1-C6 alkyl, -O-C1-C6 alkyl, C3-C 6c substituted C1-C6 alkyl, -O-C1-C6 alkyl, C3-C 6d substituted C1-C6 alkyl, -O-C1-C6 alkyl, C3-C 12 substituted C1-C6 alkyl, -O-C1-C6 alkyl, C3-C 6e substituted C1-C6 alkyl, -O-C1-C6 alkyl, C3-C 12 substituted C1-C6 alkyl, -O-C1-C6 alkyl, C3-C 12 substituted C1-C6 alkyl, -O-C1-C6 alkyl, C3-C 6f substituted C1-C6 alkyl, -O-C1-C6 alkyl, C3-C 12 substituted C1-C6 alkyl, -O-C1-C6 alkyl, C3-C 6g substituted C1-C6 alkyl, -O-C1-C6 alkyl, C3-C 6h substituted C1-C6 alkyl, -O-C1-C6 alkyl, C3-C 10 substituted C1-C6 alkyl, -O-C1-C6 alkyl, C3-C 6i substituted C1-C6 alkyl, -O-C1-C6 alkyl, C3-C 10 substituted C1-C6 alkyl, -O-C1-C6 alkyl, C3-C 6j substituted C1-C6 alkyl, -O-C1-C6 alkyl, C3-C

[0014] each R 6a , R 6b , R 6c , R 6d , R 6e , R 6f , R 6g , R 6h , R 6i , and R 6j are each independently deuterium, hydroxyl, halogen, cyano, nitro, oxo, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, -O-C1-C6 alkyl, C3-C 12Cycloalkyl or C1-C6 alkyl groups substituted with one or more substituents selected from deuterium, hydroxyl and halogen;

[0015] R 7 It is hydrogen, C1-C6 alkyl, and is formed by one or more R 7a Substituted C1-C6 alkyl, C2-C6 alkenyl, or with one or more R 7b Substituted C2-C6 alkenyl, C2-C6 alkynyl, or with one or more R 7c Substituted C2-C6 ynyl group, C3-C 12 cycloalkyl, with one or more R 7d Replacement C3-C 12 cycloalkyl, C3-C 12 Cycloalkenyl, with one or more R 7e Replacement C3-C 12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, with one or more R 7f Substituted 3-12-membered heterocyclic alkyl, 3-12-membered heterocyclic alkenyl, or substituted with one or more R 7g Substituted 3-12 membered heterocyclic alkenyl groups, C6-C 10 aryl, with one or more R 7h Replacement C6-C 10 aryl, 5-10 heteroaryl, or with one or more R 7i Substituted 5-10 heteroaryl groups;

[0016] Each R 7a R 7b R 7c R 7d R 7e R 7f R 7g R 7h and R 7i Each of the following can be independently represented as deuterium, hydroxyl, halogen, cyano, nitro, -NH2, -NH (C1-C6 alkyl), -N (C1-C6 alkyl)2, C1-C6 alkyl, -O-C1-C6 alkyl, C3-C 12 Cycloalkyl, or C1-C6 alkyl groups substituted with one or more substituents selected from deuterium, hydroxyl and halogen;

[0017] R 8 It is hydrogen, C1-C6 alkyl, and is formed by one or more R 8a Substituted C1-C6 alkyl, C2-C6 alkenyl, or with one or more R 8b Substituted C2-C6 alkenyl, C2-C6 alkynyl, or with one or more R 8c Substituted C2-C6 ynyl group, C3-C 12 cycloalkyl, with one or more R 8dsubstituted C3-C 12 cycloalkyl, C3-C 12 cycloalkenyl, one or more R 8e substituted C3-C 12 cycloalkenyl, 3-12 membered heterocycloalkyl, one or more R 8f substituted 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, one or more R 8g substituted 3-12 membered heterocycloalkenyl, C6-C 10 aryl, one or more R 8h substituted C6-C 10 aryl, 5-10 membered heteroaryl, or one or more R 8i substituted 5-10 membered heteroaryl;

[0018] each R 8a , R 8b , R 8c , R 8d , R 8e , R 8f , R 8g , R 8h , and R 8i are each independently deuterium, hydroxyl, halogen, cyano, nitro, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, -O-C1-C6 alkyl, C3-C 12 cycloalkyl, or C1-C6 alkyl substituted with one or more substituents selected from deuterium, hydroxyl, and halogen;

[0019] R 1 and R 1’ are each independently hydrogen, deuterium, C1-C6 alkyl, one or more R 1a substituted C1-C6 alkyl, C2-C6 alkenyl, one or more R 1b substituted C2-C6 alkenyl, C2-C6 alkynyl, one or more R 1c substituted C2-C6 alkynyl, C3-C 12 cycloalkyl, one or more R 1d substituted C3-C 12 cycloalkyl, C3-C 12 cycloalkenyl, one or more R 1e substituted C3-C 12 cycloalkenyl, 3-12 membered heterocycloalkyl, one or more R 1f substituted 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, one or more R 1g substituted 3-12 membered heterocycloalkenyl, C6-C 10 aryl, one or more R 1hReplacement C6-C 10 aryl, 5-10 heteroaryl, or with one or more R 1i Substituted 5-10 heteroaryl groups;

[0020] Or R 1 and R 1’ Together they form = O;

[0021] Or, R 1 R 1’ Together with the carbon atoms it is attached to, they form C3-C 12 cycloalkyl or with one or more R 1j Replacement C3-C 12 cycloalkyl;

[0022] Each R 1a R 1b R 1c R 1d R 1e R 1f R 1g R 1h R 1i and R 1j Each of the following can be independently represented as deuterium, hydroxyl, halogen, cyano, nitro, oxo, -NH2, -NH (C1-C6 alkyl), -N (C1-C6 alkyl)2, C1-C6 alkyl, -O-C1-C6 alkyl, C3-C 12 Cycloalkyl or C1-C6 alkyl groups substituted with one or more halogens;

[0023] Ring A is C6-C 10 Aryl, 5-10 heteroaryl or C3-C 12 cycloalkyl;

[0024] Each R 5 Independently deuterium, halogen, cyano, nitro, -OR 9 -SR 9 -N(R) 9 )2、-S(O) 1-2 R 9 -(CH2) m1 C(O)N(R 9 2、-(CH2) m2 OC(O)N(R 9 2、-(CH2) m3 NR 9 C(O)OR 9 -(CH2) m4 NR 9 C(O)N(R 9 2、-(CH2) m5 NR9 C(O)R 9 -(CH2) m6 NR 9 S(O)2R 9 -(CH2) m7 OC(O)R 9 -(CH2) m8 C(O)R 9 -(CH2) m9 C(O)OR 9 C1-C6 alkyl groups, with one or more R 5a Substituted C1-C6 alkyl, C2-C6 alkenyl, or with one or more R 5b Substituted C2-C6 alkenyl, C2-C6 alkynyl, or with one or more R 5c Substituted C2-C6 ynyl group, C3-C 12 cycloalkyl, with one or more R 5d Replacement C3-C 12 cycloalkyl, C3-C 12 Cycloalkenyl, with one or more R 5e Replacement C3-C 12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, with one or more R 5f Substituted 3-12-membered heterocyclic alkyl, 3-12-membered heterocyclic alkenyl, or substituted with one or more R 5g Substituted 3-12 membered heterocyclic alkenyl groups, C6-C 10 aryl, with one or more R 5h Replacement C6-C 10 aryl, 5-10 heteroaryl, or with one or more R 5i Substituted 5-10 heteroaryl groups;

[0025] Each R 5a R 5b R 5c R 5d R 5e R 5f R 5g R 5h and R 5i Each can be independently represented as deuterium, hydroxyl, halogen, cyano, nitro, oxo, or -(CH2). m10 NH2、-(CH2) m11 NH (C1-C6 alkyl), -(CH2) m12 N(C1-C6 alkyl)2, -O-C1-C6 alkyl, C3-C 12 Cycloalkyl, C1-C6 alkyl, or C1-C6 alkyl substituted with one or more substituents selected from deuterium, halogens, and hydroxyl groups;

[0026] m can be 0, 1, 2, 3, 4, or 5;

[0027] m1, m2, m3, m4, m5, m6, m7, m8, m9, m10, m11 and m12 are each independently 0, 1, 2 or 3;

[0028] Each R 9 Independently hydrogen, C1-C6 alkyl, and composed of one or more R 9a Substituted C1-C6 alkyl, -O-C1-C6 alkyl, or substituted with one or more R 9b Substituted -O-C1-C6 alkyl, C2-C6 alkenyl, or with one or more R 9c Substituted C2-C6 alkenyl, C2-C6 alkynyl, or with one or more R 9d Substituted C2-C6 ynyl group, C3-C 12 cycloalkyl, with one or more R 9e Replacement C3-C 12 cycloalkyl, C3-C 12 Cycloalkenyl, with one or more R 9f Replacement C3-C 12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, with one or more R 9g Substituted 3-12-membered heterocyclic alkyl, 3-12-membered heterocyclic alkenyl, or substituted with one or more R 9h Substituted 3-12 membered heterocyclic alkenyl groups, C6-C 10 aryl, with one or more R 9i Replacement C6-C 10 aryl, 5-10 heteroaryl, or with one or more R 9j Substituted 5-10 heteroaryl groups;

[0029] Each R 9a R 9b R 9c R 9d R 9e R 9f R 9g R 9h R 9i and R 9j Each is independently of deuterium, -NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl group, hydroxyl group, halogen group, cyano group, nitro group, oxo group, C1-C6 alkyl group, -O-C1-C6 alkyl group, C3-C 12 Cycloalkyl or C1-C6 alkyl groups substituted with one or more substituents selected from deuterium, hydroxyl and halogen;

[0030] L represents a chemical bond, -O-(CR)10 R 11 ) q1 -、-O-(CR 10 R 11 ) q2 -CR 12 R 13 -(CR 10 R 11 ) q3 -、-S-(CR 10 R 11 ) q4 -、-N(R 14 )-(CR 10 R 11 ) q5 -、-S(O)-(CR 10 R 11 ) q6 -or-S(O)2-(CR 10 R 11 ) q7 -;

[0031] Each R 10 and R 11 Each can be independently hydrogen, deuterium, halogen, cyano, hydroxyl, C1-C6 alkyl, -O-C1-C6 alkyl, C3-C 12 Cycloalkyl, 5-10-membered heteroaryl, or C1-C6 alkyl group substituted with one or more substituents selected from deuterium, hydroxyl, and halogen;

[0032] R 12 R 13 Together with the carbon atoms they are connected to, they form C3-C. 12 cycloalkyl or with one or more R 12a Replacement C3-C 12 cycloalkyl;

[0033] Or, R 12 and R 13 Each can be independently hydrogen, deuterium, halogen, cyano, hydroxyl, C1-C6 alkyl, -O-C1-C6 alkyl, C3-C 12 Cycloalkyl, 5-10-membered heteroaryl, or C1-C6 alkyl group substituted with one or more substituents selected from deuterium, hydroxyl, and halogen;

[0034] Each R 12a Independently, it can be deuterium, halogen, cyano, hydroxyl, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, or -O-C1-C6 alkyl;

[0035] R 14It can be hydrogen, hydroxyl, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C3-C 12 cycloalkyl, C3-C 12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, or 3-12 membered heterocyclic alkenyl;

[0036] q1, q2, q3, q4, q5, q6, and q7 are each independently 0, 1, 2, or 3; (when 0, it indicates a connection key);

[0037] R 2 It is hydrogen, C1-C6 alkyl, and is formed by one or more R 2a Substituted C1-C6 alkyl, C3-C 12 cycloalkyl, with one or more R 2b Replacement C3-C 12 cycloalkyl, C3-C 12 Cycloalkenyl, with one or more R 2c Replacement C3-C 12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, with one or more R 2d Substituted 3-12-membered heterocyclic alkyl, 3-12-membered heterocyclic alkenyl, or substituted with one or more R 2e Substituted 3-12 membered heterocyclic alkenyl groups, C6-C 10 aryl, with one or more R 2f Replacement C6-C 10 aryl, 5-10 heteroaryl, with one or more R 2g Substituted 5-10 heteroaryl groups, -C(O)OR 15 -C(O)R 15 -N(R) 15 )2、-NR 15 C(=NR 15 )N(R 15 )2、-C(O)N(R 15 )2 or -NR 15 C(O)R 15 ;

[0038] Each R 2a R 2b R 2c R 2d R 2e R 2f and R 2g Each can be independently represented by halogen, deuterium, cyano, oxo, or -OR. 16 -SR 16 -N(R) 16 )2、-S(O) 1-2 R 16 -SO2F, -(CH2)r1 C(O)N(R 16 2、-(CH2) r2 OC(O)N(R 16 2、-(CH2) r3 NR 16 C(O)OR 16 -(CH2) r4 NR 16 C(O)N(R 16 2、-(CH2) r5 NR 16 C(O)R 16 -(CH2) r6 NR 16 S(O)2R 16 -(CH2) r7 OC(O)R 16 -(CH2) r8 C(O)R 16 -(CH2) r9 C(O)OR 16 =CR 2-j R 2-j C1-C6 alkyl groups, with one or more R 2-a Substituted C1-C6 alkyl, C2-C6 alkenyl, or with one or more R 2-b Substituted C2-C6 alkenyl, C2-C6 alkynyl, or with one or more R 2-c Substituted C2-C6 ynyl group, C3-C 12 cycloalkyl, with one or more R 2-d Replacement C3-C 12 cycloalkyl, C3-C 12 Cycloalkenyl, with one or more R 2-e Replacement C3-C 12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, with one or more R 2-f Substituted 3-12-membered heterocyclic alkyl, 3-12-membered heterocyclic alkenyl, or substituted with one or more R 2-g Substituted 3-12 membered heterocyclic alkenyl groups, C6-C 10 aryl, with one or more R 2-h Replacement C6-C 10 aryl, 5-10 heteroaryl, or with one or more R 2-i Substituted 5-10 heteroaryl groups;

[0039] Each R 2-a R 2-b R 2-c R 2-d R 2-e R 2-f R2-g R 2-h and R 2-i Each is independently a deuterium, cyano, halogen, or hydroxyl group. C1-C6 alkyl, -O-C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C 12 cycloalkyl, C3-C 12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, 3-12 membered heterocyclic alkenyl, C6-C 10 aryl, 5-10 heteroaryl, or with one or more R 2-a-1 Substituted 3-12 membered heterocyclic alkyl groups;

[0040] Each R 2-a-1 R 2-a-2 and R 2-a-3 Each can be independently deuterium, cyano, halogen, hydroxyl, C1-C6 alkyl, -O-C1-C6 alkyl, 3-7 membered cycloalkyl-O-, 3-7 membered cycloalkenyl-O-, 4-10 membered heterocycloalkyl-O-, 4-10 membered heterocycloalkenyl-O-, phenyl-O-, phenyl-CH2-O- or 5-6 membered heteroaryl-O-;

[0041] Each R 2-j Independently, it can be hydrogen, deuterium, cyano, halogen, hydroxyl, C1-C6 alkyl, -O-C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C3-C 12 cycloalkyl, C3-C 12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, 3-12 membered heterocyclic alkenyl, C6-C 10 Aryl or 5-10 heteroaryl groups;

[0042] Each R 15 and R 16 Each is independently hydrogen, C1-C6 alkyl, and composed of one or more R groups. 15a Substituted C1-C6 alkyl, C3-C 12 cycloalkyl, with one or more R 15b Replacement C3-C 12 cycloalkyl, C3-C 12 Cycloalkenyl, with one or more R 15c Replacement C3-C 12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, with one or more R 15d Substituted 3-12-membered heterocyclic alkyl, 3-12-membered heterocyclic alkenyl, or substituted with one or more R 15e Substituted 3-12 membered heterocyclic alkenyl groups, C6-C 10 aryl, with one or more R 15f Replacement C6-C 10 aryl, 5-10 heteroaryl, or with one or more R15g Substituted 5-10 heteroaryl groups;

[0043] Each R 15a R 15b R 15c R 15d R 15e R 15f and R 15g Each can be independently represented as deuterium, halogen, cyano, hydroxyl, oxo, -SO2F, -C(O)H, C1-C6 alkyl, -O-C1-C6 alkyl, C3-C 12 cycloalkyl, C3-C 12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, 3-12 membered heterocyclic alkenyl, C6-C 10 Aryl, 5-10-membered heteroaryl, or C1-C6 alkyl group substituted with one or more substituents selected from deuterium, hydroxyl, and halogen;

[0044] r1, r2, r3, r4, r5, r6, r7, r8 and r9 are each independently 0, 1, 2 or 3;

[0045] Each R 3 Independently hydrogen, deuterium, halogen, cyano, nitro, oxo, -N(R) 17 )2、-OR 17 C1-C6 alkyl groups, with one or more R 3a Substituted C1-C6 alkyl, C2-C6 alkenyl, or with one or more R 3b Substituted C2-C6 alkenyl, C2-C6 alkynyl, or with one or more R 3c Substituted C2-C6 ynyl group, C3-C 12 cycloalkyl, with one or more R 3d Replacement C3-C 12 cycloalkyl, C3-C 12 Cycloalkenyl, with one or more R 3e Replacement C3-C 12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, with one or more R 3f Substituted 3-12-membered heterocyclic alkyl, 3-12-membered heterocyclic alkenyl, or substituted with one or more R 3g Substituted 3-12 membered heterocyclic alkenyl groups, C6-C 10 aryl, with one or more R 3h Replacement C6-C 10 aryl, 5-10 heteroaryl, or with one or more R 3i Substituted 5-10 heteroaryl groups;

[0046] Each R 3a R 3b R3c R 3d R 3e R 3f R 3g R 3h and R 3i Each of the following can be independently represented as deuterium, hydroxyl, halogen, cyano, nitro, oxo, -NH2, -NH (C1-C6 alkyl), -N (C1-C6 alkyl)2, C1-C6 alkyl, -O-C1-C6 alkyl, C3-C 12 Cycloalkyl or C1-C6 alkyl groups substituted with one or more substituents selected from deuterium, hydroxyl and halogen;

[0047] Each R 17 Independently hydrogen, C1-C6 alkyl, and composed of one or more R 17a Substituted C1-C6 alkyl, C3-C 12 cycloalkyl, with one or more R 17b Replacement C3-C 12 cycloalkyl, C3-C 12 Cycloalkenyl, with one or more R 17c Replacement C3-C 12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, with one or more R 17d Substituted 3-12-membered heterocyclic alkyl, 3-12-membered heterocyclic alkenyl, or substituted with one or more R 17e Substituted 3-12 membered heterocyclic alkenyl groups, C6-C 10 aryl, with one or more R 17f Replacement C6-C 10 aryl, 5-10 heteroaryl, or with one or more R 17g Substituted 5-10 heteroaryl groups;

[0048] Each R 17a R 17b R 17c R 17d R 17e R 17f and R 17g Each can be independently deuterium, halogen, cyano, hydroxyl, oxo, C1-C6 alkyl, -O-C1-C6 alkyl, C3-C 12 Cycloalkyl or C1-C6 alkyl groups substituted with one or more substituents selected from deuterium, hydroxyl and halogen;

[0049] n is 1, 2, 3 or 4;

[0050] Ring B is C7-C 15 cycloalkyl, C7-C 15 Cycloalkenyl, 7-15 membered heterocyclic alkyl, or 7-15 membered heterocyclic alkenyl;

[0051] Each R 4 Independently deuterium, halogen, cyano, nitro, oxo, -N(R) 18 2. -B(OR) 18 )2、-OR 18 -SR 18 -S(O) 1-2 R 18 -S(O) 1-2 N(R 18 )2、-NR 18 S(O) 1-2 R 18 -(CH2) p1 C(O)NR 18 OR 18 -(CH2) p2 NR 18 C(O)R 18 -(CH2) p3 NR 18 C(O)N(R 18 2、-(CH2) p4 NR 18 C(O)OR 18 -(CH2) p5 OC(O)N(R 18 2、-(CH2) p6 C(O)N(R 18 2、-(CH2) p7 C(O)R 18 -(CH2) p8 C(O)OR 18 -(CH2) p9 OC(O)R 18 C1-C6 alkyl groups, with one or more R 4a Substituted C1-C6 alkyl, C2-C6 alkenyl, or with one or more R 4b Substituted C2-C6 alkenyl, C2-C6 alkynyl, or with one or more R 4c Substituted C2-C6 ynyl group, C3-C 12 cycloalkyl, with one or more R 4d Replacement C3-C 12 cycloalkyl, C3-C 12 Cycloalkenyl, with one or more R 4e Replacement C3-C 12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, with one or more R 4f Substituted 3-12-membered heterocyclic alkyl, 3-12-membered heterocyclic alkenyl, or substituted with one or more R 4g Substituted 3-12 membered heterocyclic alkenyl groups, C6-C10 aryl, with one or more R 4h Replacement C6-C 10 aryl, 5-10 heteroaryl, or with one or more R 4i Substituted 5-10 heteroaryl groups;

[0052] Each R 4a R 4b R 4c R 4d R 4e R 4f R 4g R 4h and R 4i Each independently constitutes deuterium, -N(R) 19 2. Hydroxyl, halogen, cyano, nitro, oxo, thio (=S), C1-C6 alkyl, with one or more R 4-a Substituted C1-C6 alkyl, -O-C1-C6 alkyl, or substituted with one or more R 4-b Substituted -O-C1-C6 alkyl, C2-C6 alkenyl, or with one or more R 4-c Substituted C2-C6 alkenyl, C2-C6 alkynyl, or with one or more R 4-d Substituted C2-C6 ynyl group, C3-C 12 cycloalkyl, with one or more R 4-e Replacement C3-C 12 cycloalkyl, C3-C 12 Cycloalkenyl, with one or more R 4-f Replacement C3-C 12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, with one or more R 4-g Substituted 3-12-membered heterocyclic alkyl, 3-12-membered heterocyclic alkenyl, or substituted with one or more R 4-h Substituted 3-12 membered heterocyclic alkenyl groups, C6-C 10 aryl, with one or more R 4-i Replacement C6-C 10 aryl, 5-10 heteroaryl, or with one or more R 4-j Substituted 5-10 heteroaryl groups;

[0053] Each R 4-a R 4-b R 4-c R 4-d R 4-e R 4-f R 4-g R 4-h R 4-i and R 4-jEach of the following is independently deuterium, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, hydroxyl, halogen, cyano, nitro, oxo, C1-C6 alkyl, -O-C1-C6 alkyl, or a C1-C6 alkyl group substituted with one or more substituents selected from deuterium, hydroxyl and halogen;

[0054] Each R 18 and R 19 Each is independently hydrogen, C1-C6 alkyl, and composed of one or more R groups. 18a Substituted C1-C6 alkyl, C3-C 12 cycloalkyl, with one or more R 18b Replacement C3-C 12 cycloalkyl, C3-C 12 Cycloalkenyl, with one or more R 18c Replacement C3-C 12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, with one or more R 18d Substituted 3-12-membered heterocyclic alkyl, 3-12-membered heterocyclic alkenyl, or substituted with one or more R 18e Substituted 3-12 membered heterocyclic alkenyl groups, C6-C 10 aryl, with one or more R 18f Replacement C6-C 10 aryl, 5-10 heteroaryl, or with one or more R 18g Substituted 5-10 heteroaryl groups;

[0055] Each R 18a R 18b R 18c R 18d R 18e R 18f and R 18g Each can be independently represented as deuterium, halogen, cyano, hydroxyl, oxo, -NH2, -NH (C1-C6 alkyl), -N (C1-C6 alkyl)2, C1-C6 alkyl, -O-C1-C6 alkyl, C3-C 12 Cycloalkyl or C1-C6 alkyl groups substituted with one or more substituents selected from deuterium, hydroxyl and halogen;

[0056] p is 0, 1, 2, 3, 4, 5, 6, 7 or 8;

[0057] p1, p2, p3, p4, p5, p6, p7, p8 and p9 are each independently 0, 1, 2 or 3;

[0058] In each "heterocyclic alkyl", the heteroatom is independently selected from one or more of N, O and S, and the number of heteroatoms is independently 1, 2, 3 or 4.

[0059] In each "heterocyclic alkenyl", the heteroatom is independently selected from one or more of N, O and S, and the number of heteroatoms is independently 1, 2, 3 or 4.

[0060] In each "heteroaryl", the heteroatoms are independently selected from one or more of N, O and S, and the number of heteroatoms is independently 1, 2, 3 or 4.

[0061] This invention provides a compound of Formula I, its stereoisomer, or a pharmaceutically acceptable salt thereof.

[0062] in,

[0063] X is -C(R) 6 )2-、-NR 7 -, -O-, -S-, -SO- or -SO2-;

[0064] Y is -NR 8 -、-O-、-S-、-SO-、-NR 8 SO2- or -SO2-;

[0065] t is 0 or 1;

[0066] Each R 6 Independently hydrogen, deuterium, halogen, cyano, nitro, -NH2, -OH, -NH (C1-C6 alkyl), -N (C1-C6 alkyl)2, C1-C6 alkyl, or with one or more R 6a Substituted C1-C6 alkyl, -O-C1-C6 alkyl, or substituted with one or more R 6b Substituted -O-C1-C6 alkyl, C2-C6 alkenyl, or with one or more R 6c Substituted C2-C6 alkenyl, C2-C6 alkynyl, or with one or more R 6d Substituted C2-C6 ynyl group, C3-C 12 cycloalkyl, with one or more R 6e Replacement C3-C 12 cycloalkyl, C3-C 12 Cycloalkenyl, with one or more R 6f Replacement C3-C 12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, with one or more R 6g Substituted 3-12-membered heterocyclic alkyl, 3-12-membered heterocyclic alkenyl, or substituted with one or more R 6h Substituted 3-12 membered heterocyclic alkenyl groups, C6-C 10 aryl, with one or more R 6i Replacement C6-C 10aryl, 5-10 heteroaryl, or with one or more R 6j Substituted 5-10 heteroaryl groups;

[0067] Each R 6a R 6b R 6c R 6d R 6e R 6f R 6g R 6h R 6i and R 6j Each of the following can be independently represented as deuterium, hydroxyl, halogen, cyano, nitro, oxo, -NH2, -NH (C1-C6 alkyl), -N (C1-C6 alkyl)2, C1-C6 alkyl, -O-C1-C6 alkyl, C3-C 12 Cycloalkyl or C1-C6 alkyl groups substituted with one or more substituents selected from deuterium, hydroxyl and halogen;

[0068] R 7 It is hydrogen, C1-C6 alkyl, and is formed by one or more R 7a Substituted C1-C6 alkyl, C2-C6 alkenyl, or with one or more R 7b Substituted C2-C6 alkenyl, C2-C6 alkynyl, or with one or more R 7c Substituted C2-C6 ynyl group, C3-C 12 cycloalkyl, with one or more R 7d Replacement C3-C 12 cycloalkyl, C3-C 12 Cycloalkenyl, with one or more R 7e Replacement C3-C 12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, with one or more R 7f Substituted 3-12-membered heterocyclic alkyl, 3-12-membered heterocyclic alkenyl, or substituted with one or more R 7g Substituted 3-12 membered heterocyclic alkenyl groups, C6-C 10 aryl, with one or more R 7h Replacement C6-C 10 aryl, 5-10 heteroaryl, or with one or more R 7i Substituted 5-10 heteroaryl groups;

[0069] Each R 7a R 7b R 7c R 7d R 7e R 7f R 7g R 7h and R 7iEach of the following can be independently represented as deuterium, hydroxyl, halogen, cyano, nitro, -NH2, -NH (C1-C6 alkyl), -N (C1-C6 alkyl)2, C1-C6 alkyl, -O-C1-C6 alkyl, C3-C 12 Cycloalkyl, or C1-C6 alkyl groups substituted with one or more substituents selected from deuterium, hydroxyl and halogen;

[0070] R 8 It is hydrogen, C1-C6 alkyl, and is formed by one or more R 8a Substituted C1-C6 alkyl, C2-C6 alkenyl, or with one or more R 8b Substituted C2-C6 alkenyl, C2-C6 alkynyl, or with one or more R 8c Substituted C2-C6 ynyl group, C3-C 12 cycloalkyl, with one or more R 8d Replacement C3-C 12 cycloalkyl, C3-C 12 Cycloalkenyl, with one or more R 8e Replacement C3-C 12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, with one or more R 8f Substituted 3-12-membered heterocyclic alkyl, 3-12-membered heterocyclic alkenyl, or substituted with one or more R 8g Substituted 3-12 membered heterocyclic alkenyl groups, C6-C 10 aryl, with one or more R 8h Replacement C6-C 10 aryl, 5-10 heteroaryl, or with one or more R 8i Substituted 5-10 heteroaryl groups;

[0071] Each R 8a R 8b R 8c R 8d R 8e R 8f R 8g R 8h and R 8i Each of the following can be independently represented as deuterium, hydroxyl, halogen, cyano, nitro, -NH2, -NH (C1-C6 alkyl), -N (C1-C6 alkyl)2, C1-C6 alkyl, -O-C1-C6 alkyl, C3-C 12 Cycloalkyl or C1-C6 alkyl groups substituted with one or more substituents selected from deuterium, hydroxyl and halogen;

[0072] R 1 and R 1’ Each is independently hydrogen, deuterium, C1-C6 alkyl, or formed by one or more R 1aSubstituted C1-C6 alkyl, C2-C6 alkenyl, or with one or more R 1b Substituted C2-C6 alkenyl, C2-C6 alkynyl, or with one or more R 1c Substituted C2-C6 ynyl group, C3-C 12 cycloalkyl, with one or more R 1d Replacement C3-C 12 cycloalkyl, C3-C 12 Cycloalkenyl, with one or more R 1e Replacement C3-C 12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, with one or more R 1f Substituted 3-12-membered heterocyclic alkyl, 3-12-membered heterocyclic alkenyl, or substituted with one or more R 1g Substituted 3-12 membered heterocyclic alkenyl groups, C6-C 10 aryl, with one or more R 1h Replacement C6-C 10 aryl, 5-10 heteroaryl, or with one or more R 1i Substituted 5-10 heteroaryl groups;

[0073] Or R 1 and R 1’ Together they form = O;

[0074] Each R 1a R 1b R 1c R 1d R 1e R 1f R 1g R 1h and R 1i Each of the following can be independently represented as deuterium, hydroxyl, halogen, cyano, nitro, oxo, -NH2, -NH (C1-C6 alkyl), -N (C1-C6 alkyl)2, C1-C6 alkyl, -O-C1-C6 alkyl, C3-C 12 Cycloalkyl or C1-C6 alkyl groups substituted with one or more halogens;

[0075] Ring A is C6-C 10 Aryl or 5-10 heteroaryl groups;

[0076] Each R 5 Independently deuterium, halogen, cyano, nitro, -OR 9 -SR 9 -N(R) 9 )2、-S(O) 1-2 R 9 -(CH2) m1 C(O)N(R 9 2、-(CH2)m2 OC(O)N(R 9 2、-(CH2) m3 NR 9 C(O)OR 9 -(CH2) m4 NR 9 C(O)N(R 9 2、-(CH2) m5 NR 9 C(O)R 9 -(CH2) m6 NR 9 S(O)2R 9 -(CH2) m7 OC(O)R 9 -(CH2) m8 C(O)R 9 -(CH2) m9 C(O)OR 9 C1-C6 alkyl groups, with one or more R 5a Substituted C1-C6 alkyl, C2-C6 alkenyl, or with one or more R 5b Substituted C2-C6 alkenyl, C2-C6 alkynyl, or with one or more R 5c Substituted C2-C6 ynyl group, C3-C 12 cycloalkyl, with one or more R 5d Replacement C3-C 12 cycloalkyl, C3-C 12 Cycloalkenyl, with one or more R 5e Replacement C3-C 12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, with one or more R 5f Substituted 3-12-membered heterocyclic alkyl, 3-12-membered heterocyclic alkenyl, or substituted with one or more R 5g Substituted 3-12 membered heterocyclic alkenyl groups, C6-C 10 aryl, with one or more R 5h Replacement C6-C 10 aryl, 5-10 heteroaryl, or with one or more R 5i Substituted 5-10 heteroaryl groups;

[0077] Each R 5a R 5b R 5c R 5d R 5e R 5f R 5g R 5h and R 5i Each can be independently represented as deuterium, hydroxyl, halogen, cyano, nitro, oxo, or -(CH2).m10 NH2、-(CH2) m11 NH (C1-C6 alkyl), -(CH2) m12 N(C1-C6 alkyl)2, -O-C1-C6 alkyl, C3-C 12 Cycloalkyl, C1-C6 alkyl, or C1-C6 alkyl substituted with one or more substituents selected from deuterium, halogens, and hydroxyl groups;

[0078] m can be 0, 1, 2, 3, 4, or 5;

[0079] m1, m2, m3, m4, m5, m6, m7, m8, m9, m10, m11 and m12 are each independently 0, 1, 2 or 3;

[0080] Each R 9 Independently hydrogen, C1-C6 alkyl, and composed of one or more R 9a Substituted C1-C6 alkyl, -O-C1-C6 alkyl, or substituted with one or more R 9b Substituted -O-C1-C6 alkyl, C2-C6 alkenyl, or with one or more R 9c Substituted C2-C6 alkenyl, C2-C6 alkynyl, or with one or more R 9d Substituted C2-C6 ynyl group, C3-C 12 cycloalkyl, with one or more R 9e Replacement C3-C 12 cycloalkyl, C3-C 12 Cycloalkenyl, with one or more R 9f Replacement C3-C 12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, with one or more R 9g Substituted 3-12-membered heterocyclic alkyl, 3-12-membered heterocyclic alkenyl, or substituted with one or more R 9h Substituted 3-12 membered heterocyclic alkenyl groups, C6-C 10 aryl, with one or more R 9i Replacement C6-C 10 aryl, 5-10 heteroaryl, or with one or more R 9j Substituted 5-10 heteroaryl groups;

[0081] Each R 9a R 9b R 9c R 9d R 9e R 9f R 9g R 9h R 9i and R 9j Each is independently of deuterium, -NH2, -NH(C)1-6 alkyl), -N(C) 1-6 Alkyl group, hydroxyl group, halogen group, cyano group, nitro group, oxo group, C1-C6 alkyl group, -O-C1-C6 alkyl group, C3-C 12 Cycloalkyl or C1-C6 alkyl groups substituted with one or more substituents selected from deuterium, hydroxyl and halogen;

[0082] L is -O-(CR) 10 R 11 ) q1 -、-O-(CR 10 R 11 ) q2 -CR 12 R 13 -(CR 10 R 11 ) q3 -、-S-(CR 10 R 11 ) q4 -、-N(R 14 )-(CR 10 R 11 ) q5 -、-S(O)-(CR 10 R 11 ) q6 -or-S(O)2-(CR 10 R 11 ) q7 -;

[0083] Each R 10 and R 11 Each can be independently hydrogen, deuterium, halogen, cyano, hydroxyl, C1-C6 alkyl, -O-C1-C6 alkyl, C3-C 12 Cycloalkyl, 5-10-membered heteroaryl, or C1-C6 alkyl group substituted with one or more substituents selected from deuterium, hydroxyl, and halogen;

[0084] R 12 R 13 Together with the carbon atoms they are connected to, they form C3-C. 12 cycloalkyl or with one or more R 12a Replacement C3-C 12 cycloalkyl;

[0085] Each R 12a Independently, it can be deuterium, halogen, cyano, hydroxyl, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, or -O-C1-C6 alkyl;

[0086] R 14It can be hydrogen, hydroxyl, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C3-C 12 cycloalkyl, C3-C 12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, or 3-12 membered heterocyclic alkenyl;

[0087] q1, q2, q3, q4, q5, q6, and q7 are each independently 0, 1, 2, or 3; (when 0, it indicates a connection key);

[0088] R 2 It is hydrogen, C1-C6 alkyl, and is formed by one or more R 2a Substituted C1-C6 alkyl, C3-C 12 cycloalkyl, with one or more R 2b Replacement C3-C 12 cycloalkyl, C3-C 12 Cycloalkenyl, with one or more R 2c Replacement C3-C 12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, with one or more R 2d Substituted 3-12-membered heterocyclic alkyl, 3-12-membered heterocyclic alkenyl, or substituted with one or more R 2e Substituted 3-12 membered heterocyclic alkenyl groups, C6-C 10 aryl, with one or more R 2f Replacement C6-C 10 aryl, 5-10 heteroaryl, with one or more R 2g Substituted 5-10 heteroaryl groups, -C(O)OR 15 -C(O)R 15 -N(R) 15 )2、-NR 15 C(=NR 15 )N(R 15 )2、-C(O)N(R 15 )2 or -NR 15 C(O)R 15 ;

[0089] Each R 2a R 2b R 2c R 2d R 2e R 2f and R 2g Each can be independently represented by halogen, deuterium, cyano, oxo, or -OR. 16 -SR 16 -N(R) 16 )2、-S(O) 1-2 R 16 -SO2F, -(CH2)r1 C(O)N(R 16 2、-(CH2) r2 OC(O)N(R 16 2、-(CH2) r3 NR 16 C(O)OR 16 -(CH2) r4 NR 16 C(O)N(R 16 2、-(CH2) r5 NR 16 C(O)R 16 -(CH2) r6 NR 16 S(O)2R 16 -(CH2) r7 OC(O)R 16 -(CH2) r8 C(O)R 16 -(CH2) r9 C(O)OR 16 =CR 2-j R 2-j C1-C6 alkyl groups, with one or more R 2-a Substituted C1-C6 alkyl, C2-C6 alkenyl, or with one or more R 2-b Substituted C2-C6 alkenyl, C2-C6 alkynyl, or with one or more R 2-c Substituted C2-C6 ynyl group, C3-C 12 cycloalkyl, with one or more R 2-d Replacement C3-C 12 cycloalkyl, C3-C 12 Cycloalkenyl, with one or more R 2-e Replacement C3-C 12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, with one or more R 2-f Substituted 3-12-membered heterocyclic alkyl, 3-12-membered heterocyclic alkenyl, or substituted with one or more R 2-g Substituted 3-12 membered heterocyclic alkenyl groups, C6-C 10 aryl, with one or more R 2-h Replacement C6-C 10 aryl, 5-10 heteroaryl, or with one or more R 2-i Substituted 5-10 heteroaryl groups;

[0090] Each R 2-a R 2-b R 2-c R 2-d R 2-e R 2-f R2-g R 2-h and R 2-i Each is independently a deuterium, cyano, halogen, or hydroxyl group. C1-C6 alkyl, -O-C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C 12 cycloalkyl, C3-C 12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, 3-12 membered heterocyclic alkenyl, C6-C 10 aryl, 5-10 heteroaryl, or with one or more R 2-a-1 Substituted 3-12 membered heterocyclic alkyl groups;

[0091] Each R 2-a-1 R 2-a-2 and R 2-a-3 Each can be independently deuterium, cyano, halogen, hydroxyl, C1-C6 alkyl, -O-C1-C6 alkyl, 3-7 membered cycloalkyl-O-, 3-7 membered cycloalkenyl-O-, 4-10 membered heterocycloalkyl-O-, 4-10 membered heterocycloalkenyl-O-, phenyl-O-, phenyl-CH2-O- or 5-6 membered heteroaryl-O-;

[0092] Each R 2-j Independently, it can be hydrogen, deuterium, cyano, halogen, hydroxyl, C1-C6 alkyl, -O-C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C3-C 12 cycloalkyl, C3-C 12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, 3-12 membered heterocyclic alkenyl, C6-C 10 Aryl or 5-10 heteroaryl groups;

[0093] Each R 15 and R 16 Each is independently hydrogen, C1-C6 alkyl, and composed of one or more R groups. 15a Substituted C1-C6 alkyl, C3-C 12 cycloalkyl, with one or more R 15b Replacement C3-C 12 cycloalkyl, C3-C 12 Cycloalkenyl, with one or more R 15c Replacement C3-C 12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, with one or more R 15d Substituted 3-12-membered heterocyclic alkyl, 3-12-membered heterocyclic alkenyl, or substituted with one or more R 15e Substituted 3-12 membered heterocyclic alkenyl groups, C6-C 10 aryl, with one or more R 15f Replacement C6-C 10 aryl, 5-10 heteroaryl, or with one or more R15g Substituted 5-10 heteroaryl groups;

[0094] Each R 15a R 15b R 15c R 15d R 15e R 15f and R 15g Each can be independently represented as deuterium, halogen, cyano, hydroxyl, oxo, -SO2F, -C(O)H, C1-C6 alkyl, -O-C1-C6 alkyl, C3-C 12 cycloalkyl, C3-C 12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, 3-12 membered heterocyclic alkenyl, C6-C 10 Aryl, 5-10-membered heteroaryl, or C1-C6 alkyl group substituted with one or more substituents selected from deuterium, hydroxyl, and halogen;

[0095] r1, r2, r3, r4, r5, r6, r7, r8 and r9 are each independently 0, 1, 2 or 3;

[0096] Each R 3 Independently hydrogen, deuterium, halogen, cyano, nitro, oxo, -N(R) 17 )2、-OR 17 C1-C6 alkyl groups, with one or more R 3a Substituted C1-C6 alkyl, C2-C6 alkenyl, or with one or more R 3b Substituted C2-C6 alkenyl, C2-C6 alkynyl, or with one or more R 3c Substituted C2-C6 ynyl group, C3-C 12 cycloalkyl, with one or more R 3d Replacement C3-C 12 cycloalkyl, C3-C 12 Cycloalkenyl, with one or more R 3e Replacement C3-C 12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, with one or more R 3f Substituted 3-12-membered heterocyclic alkyl, 3-12-membered heterocyclic alkenyl, or substituted with one or more R 3g Substituted 3-12 membered heterocyclic alkenyl groups, C6-C 10 aryl, with one or more R 3h Replacement C6-C 10 aryl, 5-10 heteroaryl, or with one or more R 3i Substituted 5-10 heteroaryl groups;

[0097] Each R 3a R 3b R3c R 3d R 3e R 3f R 3g R 3h and R 3i Each of the following can be independently represented as deuterium, hydroxyl, halogen, cyano, nitro, oxo, -NH2, -NH (C1-C6 alkyl), -N (C1-C6 alkyl)2, C1-C6 alkyl, -O-C1-C6 alkyl, C3-C 12 Cycloalkyl or C1-C6 alkyl groups substituted with one or more substituents selected from deuterium, hydroxyl and halogen;

[0098] Each R 17 Independently hydrogen, C1-C6 alkyl, and composed of one or more R 17a Substituted C1-C6 alkyl, C3-C 12 cycloalkyl, with one or more R 17b Replacement C3-C 12 cycloalkyl, C3-C 12 Cycloalkenyl, with one or more R 17c Replacement C3-C 12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, with one or more R 17d Substituted 3-12-membered heterocyclic alkyl, 3-12-membered heterocyclic alkenyl, or substituted with one or more R 17e Substituted 3-12 membered heterocyclic alkenyl groups, C6-C 10 aryl, with one or more R 17f Replacement C6-C 10 aryl, 5-10 heteroaryl, or with one or more R 17g Substituted 5-10 heteroaryl groups;

[0099] Each R 17a R 17b R 17c R 17d R 17e R 17f and R 17g Each can be independently deuterium, halogen, cyano, hydroxyl, oxo, C1-C6 alkyl, -O-C1-C6 alkyl, C3-C 12 Cycloalkyl or C1-C6 alkyl groups substituted with one or more substituents selected from deuterium, hydroxyl and halogen;

[0100] n is 1, 2, 3 or 4;

[0101] Ring B is C7-C 15 cycloalkyl, C7-C 15 Cycloalkenyl, 7-15 membered heterocyclic alkyl, or 7-15 membered heterocyclic alkenyl;

[0102] Each R 4 Independently deuterium, halogen, cyano, nitro, oxo, -N(R) 18 2. -B(OR) 18 )2、-OR 18 -SR 18 -S(O) 1-2 R 18 -S(O) 1-2 N(R 18 )2、-NR 18 S(O) 1-2 R 18 -(CH2) p1 C(O)NR 18 OR 18 -(CH2) p2 NR 18 C(O)R 18 -(CH2) p3 NR 18 C(O)N(R 18 2、-(CH2) p4 NR 18 C(O)OR 18 -(CH2) p5 OC(O)N(R 18 2、-(CH2) p6 C(O)N(R 18 2、-(CH2) p7 C(O)R 18 -(CH2) p8 C(O)OR 18 -(CH2) p9 OC(O)R 18 C1-C6 alkyl groups, with one or more R 4a Substituted C1-C6 alkyl, C2-C6 alkenyl, or with one or more R 4b Substituted C2-C6 alkenyl, C2-C6 alkynyl, or with one or more R 4c Substituted C2-C6 ynyl group, C3-C 12 cycloalkyl, with one or more R 4d Replacement C3-C 12 cycloalkyl, C3-C 12 Cycloalkenyl, with one or more R 4e Replacement C3-C 12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, with one or more R 4f Substituted 3-12-membered heterocyclic alkyl, 3-12-membered heterocyclic alkenyl, or substituted with one or more R 4g Substituted 3-12 membered heterocyclic alkenyl groups, C6-C10 aryl, with one or more R 4h Replacement C6-C 10 aryl, 5-10 heteroaryl, or with one or more R 4i Substituted 5-10 heteroaryl groups;

[0103] Each R 4a R 4b R 4c R 4d R 4e R 4f R 4g R 4h and R 4i Each independently constitutes deuterium, -N(R) 19 2. Hydroxyl, halogen, cyano, nitro, oxo, thio (=S), C1-C6 alkyl, with one or more R 4-a Substituted C1-C6 alkyl, -O-C1-C6 alkyl, or substituted with one or more R 4-b Substituted -O-C1-C6 alkyl, C2-C6 alkenyl, or with one or more R 4-c Substituted C2-C6 alkenyl, C2-C6 alkynyl, or with one or more R 4-d Substituted C2-C6 ynyl group, C3-C 12 cycloalkyl, with one or more R 4-e Replacement C3-C 12 cycloalkyl, C3-C 12 Cycloalkenyl, with one or more R 4-f Replacement C3-C 12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, with one or more R 4-g Substituted 3-12-membered heterocyclic alkyl, 3-12-membered heterocyclic alkenyl, or substituted with one or more R 4-h Substituted 3-12 membered heterocyclic alkenyl groups, C6-C 10 aryl, with one or more R 4-i Replacement C6-C 10 aryl, 5-10 heteroaryl, or with one or more R 4-j Substituted 5-10 heteroaryl groups;

[0104] Each R 4-a R 4-b R 4-c R 4-d R 4-e R 4-f R 4-g R 4-h R 4-i and R 4-jEach of the following is independently deuterium, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, hydroxyl, halogen, cyano, nitro, oxo, C1-C6 alkyl, -O-C1-C6 alkyl, or a C1-C6 alkyl group substituted with one or more substituents selected from deuterium, hydroxyl and halogen;

[0105] Each R 18 and R 19 Each is independently hydrogen, C1-C6 alkyl, and composed of one or more R groups. 18a Substituted C1-C6 alkyl, C3-C 12 cycloalkyl, with one or more R 18b Replacement C3-C 12 cycloalkyl, C3-C 12 Cycloalkenyl, with one or more R 18c Replacement C3-C 12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, with one or more R 18d Substituted 3-12-membered heterocyclic alkyl, 3-12-membered heterocyclic alkenyl, or substituted with one or more R 18e Substituted 3-12 membered heterocyclic alkenyl groups, C6-C 10 aryl, with one or more R 18f Replacement C6-C 10 aryl, 5-10 heteroaryl, or with one or more R 18g Substituted 5-10 heteroaryl groups;

[0106] Each R 18a R 18b R 18c R 18d R 18e R 18f and R 18g Each can be independently represented as deuterium, halogen, cyano, hydroxyl, oxo, -NH2, -NH (C1-C6 alkyl), -N (C1-C6 alkyl)2, C1-C6 alkyl, -O-C1-C6 alkyl, C3-C 12 Cycloalkyl or C1-C6 alkyl groups substituted with one or more substituents selected from deuterium, hydroxyl and halogen;

[0107] p is 0, 1, 2, 3, 4, 5, 6, 7 or 8;

[0108] p1, p2, p3, p4, p5, p6, p7, p8 and p9 are each independently 0, 1, 2 or 3;

[0109] In each "heterocyclic alkyl", the heteroatom is independently selected from one or more of N, O and S, and the number of heteroatoms is independently 1, 2, 3 or 4.

[0110] In each "heterocyclic alkenyl", the heteroatom is independently selected from one or more of N, O and S, and the number of heteroatoms is independently 1, 2, 3 or 4.

[0111] In each "heteroaryl", the heteroatoms are independently selected from one or more of N, O and S, and the number of heteroatoms is independently 1, 2, 3 or 4.

[0112] This invention provides a compound of Formula I, its stereoisomer, or a pharmaceutically acceptable salt thereof.

[0113] in,

[0114] X is -C(R) 6 )2-、-NR 7 -, -O-, -S-, -SO- or -SO2-;

[0115] Y is -NR 8 -、-O-、-S-、-SO-、-NR 8 SO2- or -SO2-;

[0116] t is 0 or 1;

[0117] Each R 6 Independently hydrogen, deuterium, halogen, cyano, nitro, -NH2, -OH, -NH (C1-C6 alkyl), -N (C1-C6 alkyl)2, C1-C6 alkyl, or with one or more R 6a Substituted C1-C6 alkyl, -O-C1-C6 alkyl, or substituted with one or more R 6b Substituted -O-C1-C6 alkyl, C2-C6 alkenyl, or with one or more R 6c Substituted C2-C6 alkenyl, C2-C6 alkynyl, or with one or more R 6d Substituted C2-C6 ynyl group, C3-C 12 cycloalkyl, with one or more R 6e Replacement C3-C 12 cycloalkyl, C3-C 12 Cycloalkenyl, with one or more R 6f Replacement C3-C 12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, with one or more R 6g Substituted 3-12-membered heterocyclic alkyl, 3-12-membered heterocyclic alkenyl, or substituted with one or more R 6h Substituted 3-12 membered heterocyclic alkenyl groups, C6-C 10 aryl, with one or more R 6i Replacement C6-C 10aryl, 5-10 heteroaryl, or with one or more R 6j Substituted 5-10 heteroaryl groups;

[0118] Each R 6a R 6b R 6c R 6d R 6e R 6f R 6g R 6h R 6i and R 6j Each of the following can be independently represented as deuterium, hydroxyl, halogen, cyano, nitro, oxo, -NH2, -NH (C1-C6 alkyl), -N (C1-C6 alkyl)2, C1-C6 alkyl, -O-C1-C6 alkyl, C3-C 12 Cycloalkyl or C1-C6 alkyl groups substituted with one or more substituents selected from deuterium, hydroxyl and halogen;

[0119] R 7 It is hydrogen, C1-C6 alkyl, and is formed by one or more R 7a Substituted C1-C6 alkyl, C2-C6 alkenyl, or with one or more R 7b Substituted C2-C6 alkenyl, C2-C6 alkynyl, or with one or more R 7c Substituted C2-C6 ynyl group, C3-C 12 cycloalkyl, with one or more R 7d Replacement C3-C 12 cycloalkyl, C3-C 12 Cycloalkenyl, with one or more R 7e Replacement C3-C 12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, with one or more R 7f Substituted 3-12-membered heterocyclic alkyl, 3-12-membered heterocyclic alkenyl, or substituted with one or more R 7g Substituted 3-12 membered heterocyclic alkenyl groups, C6-C 10 aryl, with one or more R 7h Replacement C6-C 10 aryl, 5-10 heteroaryl, or with one or more R 7i Substituted 5-10 heteroaryl groups;

[0120] Each R 7a R 7b R 7c R 7d R 7e R 7f R 7g R 7h and R 7iEach of the following can be independently represented as deuterium, hydroxyl, halogen, cyano, nitro, -NH2, -NH (C1-C6 alkyl), -N (C1-C6 alkyl)2, C1-C6 alkyl, -O-C1-C6 alkyl, C3-C 12 Cycloalkyl, or C1-C6 alkyl groups substituted with one or more substituents selected from deuterium, hydroxyl and halogen;

[0121] R 8 It is hydrogen, C1-C6 alkyl, and is formed by one or more R 8a Substituted C1-C6 alkyl, C2-C6 alkenyl, or with one or more R 8b Substituted C2-C6 alkenyl, C2-C6 alkynyl, or with one or more R 8c Substituted C2-C6 ynyl group, C3-C 12 cycloalkyl, with one or more R 8d Replacement C3-C 12 cycloalkyl, C3-C 12 Cycloalkenyl, with one or more R 8e Replacement C3-C 12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, with one or more R 8f Substituted 3-12-membered heterocyclic alkyl, 3-12-membered heterocyclic alkenyl, or substituted with one or more R 8g Substituted 3-12 membered heterocyclic alkenyl groups, C6-C 10 aryl, with one or more R 8h Replacement C6-C 10 aryl, 5-10 heteroaryl, or with one or more R 8i Substituted 5-10 heteroaryl groups;

[0122] Each R 8a R 8b R 8c R 8d R 8e R 8f R 8g R 8h and R 8i Each of the following can be independently represented as deuterium, hydroxyl, halogen, cyano, nitro, -NH2, -NH (C1-C6 alkyl), -N (C1-C6 alkyl)2, C1-C6 alkyl, -O-C1-C6 alkyl, C3-C 12 Cycloalkyl or C1-C6 alkyl groups substituted with one or more substituents selected from deuterium, hydroxyl and halogen;

[0123] R 1 and R 1’ Each is independently hydrogen, deuterium, C1-C6 alkyl, or formed by one or more R 1aSubstituted C1-C6 alkyl, C2-C6 alkenyl, or with one or more R 1b Substituted C2-C6 alkenyl, C2-C6 alkynyl, or with one or more R 1c Substituted C2-C6 ynyl group, C3-C 12 cycloalkyl, with one or more R 1d Replacement C3-C 12 cycloalkyl, C3-C 12 Cycloalkenyl, with one or more R 1e Replacement C3-C 12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, with one or more R 1f Substituted 3-12-membered heterocyclic alkyl, 3-12-membered heterocyclic alkenyl, or substituted with one or more R 1g Substituted 3-12 membered heterocyclic alkenyl groups, C6-C 10 aryl, with one or more R 1h Replacement C6-C 10 aryl, 5-10 heteroaryl, or with one or more R 1i Substituted 5-10 heteroaryl groups;

[0124] Or R 1 and R 1’ Together they form = O;

[0125] Each R 1a R 1b R 1c R 1d R 1e R 1f R 1g R 1h and R 1i Each of the following can be independently represented as deuterium, hydroxyl, halogen, cyano, nitro, oxo, -NH2, -NH (C1-C6 alkyl), -N (C1-C6 alkyl)2, C1-C6 alkyl, -O-C1-C6 alkyl, C3-C 12 Cycloalkyl or C1-C6 alkyl groups substituted with one or more halogens;

[0126] Ring A is C6-C 10 Aryl or 5-10 heteroaryl groups;

[0127] Each R 5 Independently deuterium, halogen, cyano, nitro, -OR 9 -SR 9 -N(R) 9 )2、-S(O) 1-2 R 9 -(CH2) m1 C(O)N(R 9 2、-(CH2)m2 OC(O)N(R 9 2、-(CH2) m3 NR 9 C(O)OR 9 -(CH2) m4 NR 9 C(O)N(R 9 2、-(CH2) m5 NR 9 C(O)R 9 -(CH2) m6 NR 9 S(O)2R 9 -(CH2) m7 OC(O)R 9 -(CH2) m8 C(O)R 9 -(CH2) m9 C(O)OR 9 C1-C6 alkyl groups, with one or more R 5a Substituted C1-C6 alkyl, C2-C6 alkenyl, or with one or more R 5b Substituted C2-C6 alkenyl, C2-C6 alkynyl, or with one or more R 5c Substituted C2-C6 ynyl group, C3-C 12 cycloalkyl, with one or more R 5d Replacement C3-C 12 cycloalkyl, C3-C 12 Cycloalkenyl, with one or more R 5e Replacement C3-C 12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, with one or more R 5f Substituted 3-12-membered heterocyclic alkyl, 3-12-membered heterocyclic alkenyl, or substituted with one or more R 5g Substituted 3-12 membered heterocyclic alkenyl groups, C6-C 10 aryl, with one or more R 5h Replacement C6-C 10 aryl, 5-10 heteroaryl, or with one or more R 5i Substituted 5-10 heteroaryl groups;

[0128] Each R 5a R 5b R 5c R 5d R 5e R 5f R 5g R 5h and R 5i Each can be independently represented as deuterium, hydroxyl, halogen, cyano, nitro, oxo, or -(CH2).m10 NH2、-(CH2) m11 NH (C1-C6 alkyl), -(CH2) m12 N(C1-C6 alkyl)2, -O-C1-C6 alkyl, C3-C 12 Cycloalkyl, C1-C6 alkyl, or C1-C6 alkyl substituted with one or more substituents selected from deuterium, halogens, and hydroxyl groups;

[0129] m can be 0, 1, 2, 3, 4, or 5;

[0130] m1, m2, m3, m4, m5, m6, m7, m8, m9, m10, m11 and m12 are each independently 0, 1, 2 or 3;

[0131] Each R 9 Independently hydrogen, C1-C6 alkyl, and composed of one or more R 9a Substituted C1-C6 alkyl, -O-C1-C6 alkyl, or substituted with one or more R 9b Substituted -O-C1-C6 alkyl, C2-C6 alkenyl, or with one or more R 9c Substituted C2-C6 alkenyl, C2-C6 alkynyl, or with one or more R 9d Substituted C2-C6 ynyl group, C3-C 12 cycloalkyl, with one or more R 9e Replacement C3-C 12 cycloalkyl, C3-C 12 Cycloalkenyl, with one or more R 9f Replacement C3-C 12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, with one or more R 9g Substituted 3-12-membered heterocyclic alkyl, 3-12-membered heterocyclic alkenyl, or substituted with one or more R 9h Substituted 3-12 membered heterocyclic alkenyl groups, C6-C 10 aryl, with one or more R 9i Replacement C6-C 10 aryl, 5-10 heteroaryl, or with one or more R 9j Substituted 5-10 heteroaryl groups;

[0132] Each R 9a R 9b R 9c R 9d R 9e R 9f R 9g R 9h R 9i and R 9j Each is independently of deuterium, -NH2, -NH(C)1-6 alkyl), -N(C) 1-6 Alkyl group, hydroxyl group, halogen group, cyano group, nitro group, oxo group, C1-C6 alkyl group, -O-C1-C6 alkyl group, C3-C 12 Cycloalkyl or C1-C6 alkyl groups substituted with one or more substituents selected from deuterium, hydroxyl and halogen;

[0133] L is -O-(CR) 10 R 11 ) q1 -、-O-(CR 10 R 11 ) q2 -CR 12 R 13 -(CR 10 R 11 ) q3 -、-S-(CR 10 R 11 ) q4 -、-N(R 14 )-(CR 10 R 11 ) q5 -、-S(O)-(CR 10 R 11 ) q6 -or-S(O)2-(CR 10 R 11 ) q7 -;

[0134] Each R 10 and R 11 Each can be independently hydrogen, deuterium, halogen, cyano, hydroxyl, C1-C6 alkyl, -O-C1-C6 alkyl, C3-C 12 Cycloalkyl, 5-10-membered heteroaryl, or C1-C6 alkyl group substituted with one or more substituents selected from deuterium, hydroxyl, and halogen;

[0135] R 12 R 13 Together with the carbon atoms they are connected to, they form C3-C. 12 cycloalkyl or with one or more R 12a Replacement C3-C 12 cycloalkyl;

[0136] Each R 12a Independently, it can be deuterium, halogen, cyano, hydroxyl, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, or -O-C1-C6 alkyl;

[0137] R 14It can be hydrogen, hydroxyl, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C3-C 12 cycloalkyl, C3-C 12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, or 3-12 membered heterocyclic alkenyl;

[0138] q1, q2, q3, q4, q5, q6, and q7 are each independently 0, 1, 2, or 3; (when 0, it indicates a connection key);

[0139] R 2 It is hydrogen, C1-C6 alkyl, and is formed by one or more R 2a Substituted C1-C6 alkyl, C3-C 12 cycloalkyl, with one or more R 2b Replacement C3-C 12 cycloalkyl, C3-C 12 Cycloalkenyl, with one or more R 2c Replacement C3-C 12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, with one or more R 2d Substituted 3-12-membered heterocyclic alkyl, 3-12-membered heterocyclic alkenyl, or substituted with one or more R 2e Substituted 3-12 membered heterocyclic alkenyl groups, C6-C 10 aryl, with one or more R 2f Replacement C6-C 10 aryl, 5-10 heteroaryl, with one or more R 2g Substituted 5-10 heteroaryl groups, -C(O)OR 15 -C(O)R 15 -N(R) 15 )2、-NR 15 C(=NR 15 )N(R 15 )2、-C(O)N(R 15 )2 or -NR 15 C(O)R 15 ;

[0140] Each R 2a R 2b R 2c R 2d R 2e R 2f and R 2g Each can be independently represented by halogen, deuterium, cyano, oxo, or -OR. 16 -SR 16 -N(R) 16 )2、-S(O) 1-2 R 16 -SO2F, -(CH2)r1 C(O)N(R 16 2、-(CH2) r2 OC(O)N(R 16 2、-(CH2) r3 NR 16 C(O)OR 16 -(CH2) r4 NR 16 C(O)N(R 16 2、-(CH2) r5 NR 16 C(O)R 16 -(CH2) r6 NR 16 S(O)2R 16 -(CH2) r7 OC(O)R 16 -(CH2) r8 C(O)R 16 -(CH2) r9 C(O)OR 16 =CR 2-j R 2-j C1-C6 alkyl groups, with one or more R 2-a Substituted C1-C6 alkyl, C2-C6 alkenyl, or with one or more R 2-b Substituted C2-C6 alkenyl, C2-C6 alkynyl, or with one or more R 2-c Substituted C2-C6 ynyl group, C3-C 12 cycloalkyl, with one or more R 2-d Replacement C3-C 12 cycloalkyl, C3-C 12 Cycloalkenyl, with one or more R 2-e Replacement C3-C 12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, with one or more R 2-f Substituted 3-12-membered heterocyclic alkyl, 3-12-membered heterocyclic alkenyl, or substituted with one or more R 2-g Substituted 3-12 membered heterocyclic alkenyl groups, C6-C 10 aryl, with one or more R 2-h Replacement C6-C 10 aryl, 5-10 heteroaryl, or with one or more R 2-i Substituted 5-10 heteroaryl groups;

[0141] Each R 2-a R 2-b R 2-c R 2-d R 2-e R 2-f R2-g R 2-h and R 2-i Each can be independently deuterium, cyano, halogen, hydroxyl, C1-C6 alkyl, -O-C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C 12 cycloalkyl, C3-C 12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, 3-12 membered heterocyclic alkenyl, C6-C 10 Aryl or 5-10 heteroaryl groups;

[0142] Each R 2-j Independently, it can be hydrogen, deuterium, cyano, halogen, hydroxyl, C1-C6 alkyl, -O-C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C3-C 12 cycloalkyl, C3-C 12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, 3-12 membered heterocyclic alkenyl, C6-C 10 Aryl or 5-10 heteroaryl groups;

[0143] Each R 15 and R 16 Each is independently hydrogen, C1-C6 alkyl, and composed of one or more R groups. 15a Substituted C1-C6 alkyl, C3-C 12 cycloalkyl, with one or more R 15b Replacement C3-C 12 cycloalkyl, C3-C 12 Cycloalkenyl, with one or more R 15c Replacement C3-C 12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, with one or more R 15d Substituted 3-12-membered heterocyclic alkyl, 3-12-membered heterocyclic alkenyl, or substituted with one or more R 15e Substituted 3-12 membered heterocyclic alkenyl groups, C6-C 10 aryl, with one or more R 15f Replacement C6-C 10 aryl, 5-10 heteroaryl, or with one or more R 15g Substituted 5-10 heteroaryl groups;

[0144] Each R 15a R 15b R 15c R 15d R 15e R 15f and R 15g Each can be independently represented as deuterium, halogen, cyano, hydroxyl, oxo, -SO2F, -C(O)H, C1-C6 alkyl, -O-C1-C6 alkyl, C3-C 12cycloalkyl, C3-C 12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, 3-12 membered heterocyclic alkenyl, C6-C 10 Aryl, 5-10-membered heteroaryl, or C1-C6 alkyl group substituted with one or more substituents selected from deuterium, hydroxyl, and halogen;

[0145] r1, r2, r3, r4, r5, r6, r7, r8 and r9 are each independently 0, 1, 2 or 3;

[0146] Each R 3 Independently hydrogen, deuterium, halogen, cyano, nitro, oxo, -N(R) 17 )2、-OR 17 C1-C6 alkyl groups, with one or more R 3a Substituted C1-C6 alkyl, C2-C6 alkenyl, or with one or more R 3b Substituted C2-C6 alkenyl, C2-C6 alkynyl, or with one or more R 3c Substituted C2-C6 ynyl group, C3-C 12 cycloalkyl, with one or more R 3d Replacement C3-C 12 cycloalkyl, C3-C 12 Cycloalkenyl, with one or more R 3e Replacement C3-C 12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, with one or more R 3f Substituted 3-12-membered heterocyclic alkyl, 3-12-membered heterocyclic alkenyl, or substituted with one or more R 3g Substituted 3-12 membered heterocyclic alkenyl groups, C6-C 10 aryl, with one or more R 3h Replacement C6-C 10 aryl, 5-10 heteroaryl, or with one or more R 3i Substituted 5-10 heteroaryl groups;

[0147] Each R 3a R 3b R 3c R 3d R 3e R 3f R 3g R 3h and R 3i Each of the following can be independently represented as deuterium, hydroxyl, halogen, cyano, nitro, oxo, -NH2, -NH (C1-C6 alkyl), -N (C1-C6 alkyl)2, C1-C6 alkyl, -O-C1-C6 alkyl, C3-C 12 Cycloalkyl or C1-C6 alkyl groups substituted with one or more substituents selected from deuterium, hydroxyl and halogen;

[0148] Each R 17 Independently hydrogen, C1-C6 alkyl, and composed of one or more R 17a Substituted C1-C6 alkyl, C3-C 12 cycloalkyl, with one or more R 17b Replacement C3-C 12 cycloalkyl, C3-C 12 Cycloalkenyl, with one or more R 17c Replacement C3-C 12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, with one or more R 17d Substituted 3-12-membered heterocyclic alkyl, 3-12-membered heterocyclic alkenyl, or substituted with one or more R 17e Substituted 3-12 membered heterocyclic alkenyl groups, C6-C 10 aryl, with one or more R 17f Replacement C6-C 10 aryl, 5-10 heteroaryl, or with one or more R 17g Substituted 5-10 heteroaryl groups;

[0149] Each R 17a R 17b R 17c R 17d R 17e R 17f and R 17g Each can be independently deuterium, halogen, cyano, hydroxyl, oxo, C1-C6 alkyl, -O-C1-C6 alkyl, C3-C 12 Cycloalkyl or C1-C6 alkyl groups substituted with one or more substituents selected from deuterium, hydroxyl and halogen;

[0150] n is 1, 2, 3 or 4;

[0151] Ring B is C7-C 15 cycloalkyl, C7-C 15 Cycloalkenyl, 7-15 membered heterocyclic alkyl, or 7-15 membered heterocyclic alkenyl;

[0152] Each R 4 Independently deuterium, halogen, cyano, nitro, oxo, -N(R) 18 2. -B(OR) 18 )2、-OR 18 -SR 18 -S(O) 1-2 R 18 -S(O) 1-2 N(R 18 )2、-NR 18 S(O) 1-2 R18 -(CH2) p1 C(O)NR 18 OR 18 -(CH2) p2 NR 18 C(O)R 18 -(CH2) p3 NR 18 C(O)N(R 18 2、-(CH2) p4 NR 18 C(O)OR 18 -(CH2) p5 OC(O)N(R 18 2、-(CH2) p6 C(O)N(R 18 2、-(CH2) p7 C(O)R 18 -(CH2) p8 C(O)OR 18 -(CH2) p9 OC(O)R 18 C1-C6 alkyl groups, with one or more R 4a Substituted C1-C6 alkyl, C2-C6 alkenyl, or with one or more R 4b Substituted C2-C6 alkenyl, C2-C6 alkynyl, or with one or more R 4c Substituted C2-C6 ynyl group, C3-C 12 cycloalkyl, with one or more R 4d Replacement C3-C 12 cycloalkyl, C3-C 12 Cycloalkenyl, with one or more R 4e Replacement C3-C 12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, with one or more R 4f Substituted 3-12-membered heterocyclic alkyl, 3-12-membered heterocyclic alkenyl, or substituted with one or more R 4g Substituted 3-12 membered heterocyclic alkenyl groups, C6-C 10 aryl, with one or more R 4h Replacement C6-C 10 aryl, 5-10 heteroaryl, or with one or more R 4i Substituted 5-10 heteroaryl groups;

[0153] Each R 4a R 4b R 4c R 4d R 4e R 4f R 4gR 4h and R 4i Each independently constitutes deuterium, -N(R) 19 2. Hydroxyl, halogen, cyano, nitro, oxo, thio (=S), C1-C6 alkyl, with one or more R 4-a Substituted C1-C6 alkyl, -O-C1-C6 alkyl, or substituted with one or more R 4-b Substituted -O-C1-C6 alkyl, C2-C6 alkenyl, or with one or more R 4-c Substituted C2-C6 alkenyl, C2-C6 alkynyl, or with one or more R 4-d Substituted C2-C6 ynyl group, C3-C 12 cycloalkyl, with one or more R 4-e Replacement C3-C 12 cycloalkyl, C3-C 12 Cycloalkenyl, with one or more R 4-f Replacement C3-C 12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, with one or more R 4-g Substituted 3-12-membered heterocyclic alkyl, 3-12-membered heterocyclic alkenyl, or substituted with one or more R 4-h Substituted 3-12 membered heterocyclic alkenyl groups, C6-C 10 aryl, with one or more R 4-i Replacement C6-C 10 aryl, 5-10 heteroaryl, or with one or more R 4-j Substituted 5-10 heteroaryl groups;

[0154] Each R 4-a R 4-b R 4-c R 4-d R 4-e R 4-f R 4-g R 4-h R 4-i and R 4-j Each of the following is independently deuterium, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, hydroxyl, halogen, cyano, nitro, oxo, C1-C6 alkyl, -O-C1-C6 alkyl, or a C1-C6 alkyl group substituted with one or more substituents selected from deuterium, hydroxyl and halogen;

[0155] Each R 18 and R 19 Each is independently hydrogen, C1-C6 alkyl, and composed of one or more R groups. 18a Substituted C1-C6 alkyl, C3-C 12 cycloalkyl, with one or more R 18b Replacement C3-C12 cycloalkyl, C3-C 12 Cycloalkenyl, with one or more R 18c Replacement C3-C 12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, with one or more R 18d Substituted 3-12-membered heterocyclic alkyl, 3-12-membered heterocyclic alkenyl, or substituted with one or more R 18e Substituted 3-12 membered heterocyclic alkenyl groups, C6-C 10 aryl, with one or more R 18f Replacement C6-C 10 aryl, 5-10 heteroaryl, or with one or more R 18g Substituted 5-10 heteroaryl groups;

[0156] Each R 18a R 18b R 18c R 18d R 18e R 18f and R 18g Each can be independently represented as deuterium, halogen, cyano, hydroxyl, oxo, -NH2, -NH (C1-C6 alkyl), -N (C1-C6 alkyl)2, C1-C6 alkyl, -O-C1-C6 alkyl, C3-C 12 Cycloalkyl or C1-C6 alkyl groups substituted with one or more substituents selected from deuterium, hydroxyl and halogen;

[0157] p is 0, 1, 2, 3, 4, 5, 6, 7 or 8;

[0158] p1, p2, p3, p4, p5, p6, p7, p8 and p9 are each independently 0, 1, 2 or 3;

[0159] In each "heterocyclic alkyl", the heteroatom is independently selected from one or more of N, O and S, and the number of heteroatoms is independently 1, 2, 3 or 4.

[0160] In each "heterocyclic alkenyl", the heteroatom is independently selected from one or more of N, O and S, and the number of heteroatoms is independently 1, 2, 3 or 4.

[0161] In each "heteroaryl", the heteroatoms are independently selected from one or more of N, O and S, and the number of heteroatoms is independently 1, 2, 3 or 4.

[0162] In some embodiments of the present invention, certain groups in the compounds of Formula I, their stereoisomers, or pharmaceutically acceptable salts thereof are defined as follows, and groups not mentioned are as described in any embodiment of this application (hereinafter referred to as "in some embodiments of the present invention").

[0163] In some embodiments of the invention, each halogen is independently fluorine, chlorine, bromine, or iodine, such as fluorine.

[0164] In some embodiments of the invention, each halogen is independently chlorine.

[0165] In some embodiments of the invention, each halogen is independently either fluorine or chlorine.

[0166] In some embodiments of the invention, each C1-C6 alkyl group is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, or sec-butyl, for example, methyl.

[0167] In some embodiments of the invention, each C1-C6 alkyl group is independently ethyl.

[0168] In some embodiments of the invention, each C1-C6 alkyl group is independently methyl or ethyl.

[0169] In some embodiments of the invention, each -O-C1-C6 alkyl group is independently -O-C1-C4 alkyl group, such as methoxy, ethoxy, n-propoxy, or isopropoxy.

[0170] In some embodiments of the invention, each C2-C6 alkenyl group is independently vinyl, propenyl, allyl, or...

[0171] In some embodiments of the present invention, each C2-C6 ynyl group is independently an acetylene group.

[0172] In some embodiments of the present invention, each C3-C 12 The cycloalkyl group is independently a C3-C8 cycloalkyl group, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, and again cyclopropyl.

[0173] In some embodiments of the present invention, each C3-C 12 The cycloalkyl group is independently cyclobutyl.

[0174] In some embodiments of the present invention, each C3-C 12 The cycloalkyl group is independently cyclopropyl or cyclobutyl.

[0175] In some embodiments of the present invention, the heteroatom species of each 3-12 membered heterocyclic alkyl group is independently selected from one or two of N, O and S, and the number of heteroatoms is independently 1, 2 or 3; preferably, the heteroatom species is independently N, and the number of heteroatoms is independently 1.

[0176] In some embodiments of the present invention, the heteroatom species of each 3-12 membered heterocyclic alkyl group are independently selected from one or two of N and O, and the number of heteroatoms is independently one or two.

[0177] In some embodiments of the present invention, each 3-12 membered heterocyclic alkyl group is independently monocyclic or polycyclic; the polycyclic group may be a bridged ring, a fused ring, or a spirocyclic ring; preferably a fused ring.

[0178] In some embodiments of the invention, each 3-12 membered heterocyclic alkyl group is independently monocyclic or polycyclic, wherein the polycyclic group is bicyclic or tricyclic.

[0179] In some embodiments of the invention, each 3-12 membered heterocyclic alkyl group is independently a 4-6 membered monocyclic heterocyclic alkyl group or an 8-12 membered bicyclic heterocyclic alkyl group; preferably tetrahydropyrrole or... For example For example

[0180] In some embodiments of the present invention for A mixture.

[0181] In some embodiments of the invention, each 3-12 membered heterocyclic alkyl group is independently morpholino, isoxazolyl, piperidinyl, or... For example (for example) (or mixtures thereof) (for example) (or mixtures thereof)

[0182] In some embodiments of the invention, each 3-12 membered heterocyclic alkyl group is independently tetrahydropyrrolyl, morpholinyl, isoxazolyl, piperidinyl, For example (for example) (or mixtures thereof) (for example) (or mixtures thereof) (for example) (or mixtures thereof)

[0183] In some embodiments of the invention, each 3-12 membered heterocyclic alkyl group is independently an azacyclic butyl group. For example (for example) ), (for example) ), (for example) ), (for example) ), (for example) ),

[0184] In some embodiments of the invention, each 3-12 membered heterocyclic alkyl group is independently... (For example ), (For example ), (For example ),

[0185] In some embodiments of the invention, each 3-12 membered heterocyclic alkyl group is independently an azacyclic butyl, tetrahydropyrrolyl, morpholinyl, isoxazolyl, piperidinyl, or... For example (for example) ), (for example) (or mixtures thereof) (for example) ), (for example) (or mixtures thereof) (for example) (or mixtures thereof) (for example) ), (for example) ), (for example) ), (for example) ), (for example) ), (for example) ),

[0186] In some embodiments of the present invention, each C3-C 12 The cycloalkenyl group is independently a C5-C6 cycloalkenyl group.

[0187] In some embodiments of the present invention, each C3-C 12 The cycloalkenyl group independently contains one or more carbon-carbon sp groups. 2 It has double bonds and is not aromatic.

[0188] In some embodiments of the present invention, the heteroatom species in each 3-12 membered heterocyclic alkenyl group are independently selected from one or two of N, O and S, and the number of heteroatoms is independently 1, 2 or 3.

[0189] In some embodiments of the present invention, each 3-12 membered heterocyclic alkenyl group is independently monocyclic or polycyclic; the polycyclic group may be a bridged ring, a fused ring, or a spirocyclic ring; the polycyclic group may also be a bicyclic or tricyclic ring; preferably, each 3-12 membered heterocyclic alkenyl group is independently a 3-6 membered monocyclic heterocyclic alkenyl group or an 8-10 membered bicyclic heterocyclic alkenyl group.

[0190] In some embodiments of the present invention, each 3-12 membered heterocyclic alkenyl group independently contains one or more sp atoms. 2 It has double bonds and is not aromatic.

[0191] In some embodiments of the invention, each 3-12 membered heterocyclic alkenyl group is independently...

[0192] In some embodiments of the present invention, each C6-C 10 The aryl group can be phenyl or naphthyl, for example, phenyl.

[0193] In some embodiments of the present invention, the heteroatom species in each 5-10 aryl group is independently selected from one or two of N, O and S, and the number of heteroatoms is independently 1, 2 or 3; preferably, the heteroatom species is independently N, and the number of heteroatoms is independently 1.

[0194] In some embodiments of the present invention, the heteroatom in each 5-10 member heteroaryl group is of the type N, and the number of heteroatoms is independently 1, 2 or 3.

[0195] In some embodiments of the present invention, each 5-10 member heteroaryl group is independently monocyclic or bicyclic; preferably, each 5-10 member heteroaryl group is independently a 5-6 member monocyclic heteroaryl group or a 9-10 member bicyclic heteroaryl group; for example, pyridyl; and for example...

[0196] In some embodiments of the invention, each 5-10 member heteroaryl group is independently pyrazolyl, 1H-1,2,4-triazolyl, pyridazinyl, pyrazinyl, or pyrimidinyl; for example

[0197] In some embodiments of the invention, each 5-10 member heteroaryl group is independently pyrazolyl, pyridyl, 1H-1,2,4-triazolyl, pyridazinyl, pyrazinyl, or pyrimidinyl; for example

[0198] In some embodiments of the present invention, each 5-10 member heteroaryl group is independently thiazolyl, isothiazolyl, pyrazolyl, oxazolyl, isoxazolyl, indazole, 1H-pyrazolo[4,3-c]pyridinyl, 1H-imidazo[4,5-c]pyridinyl, or 1H-pyrazolo[3,4-c]pyridinyl; for example

[0199] In some embodiments of the present invention, each 5-10-membered heteroaryl group is independently pyrazolyl, pyridyl, 1H-1,2,4-triazolyl, pyridazinyl, pyrazinyl, pyrimidinyl, thiazolyl, isothiazolyl, pyrazolyl, oxazolyl, isoxazolyl, indazole, 1H-pyrazolo[4,3-c]pyridyl, 1H-imidazo[4,5-c]pyridyl, or 1H-pyrazolo[3,4-c]pyridyl; for example

[0200] In some embodiments of the present invention, each C7-C 15 The cycloalkyl group can be a monocyclic or polycyclic compound, and the polycyclic compound can be a bridged ring, a fused ring, or a spirocyclic compound.

[0201] In some embodiments of the present invention, each C7-C 15 The cycloalkyl group is independently C7-C 10 Cycloalkyl, preferably C8-C9 cycloalkyl.

[0202] In some embodiments of the present invention, each C7-C 15 The cycloalkenyl group can be a monocyclic or polycyclic compound, and the polycyclic compound can be a bridged ring, a fused ring, or a spirocyclic compound. The polycyclic compound can also be a bicyclic or a tricyclic compound.

[0203] In some embodiments of the present invention, each C7-C 15 The cycloalkenyl group is independently 1,2,3,4-tetrahydronaphthyl, 1,2-dihydronaphthyl, or 3',4'-dihydro-2'H-spiro[cyclopropane-1,1'-naphthyl]yl.

[0204] In some embodiments of the present invention, each C7-C 15The cycloalkenyl group is independently C7-C. 10 Cycloalkenyl, preferably C8-C9 cycloalkenyl.

[0205] In some embodiments of the present invention, each C7-C 15 The cycloalkenyl group is independently C 10 -C 12 Cycloalkenyl.

[0206] In some embodiments of the present invention, each C7-C 15 The cycloalkenyl group is independently C8-C9 cycloalkenyl or C 10 -C 12 Cycloalkenyl.

[0207] In some embodiments of the present invention, each C7-C 15 The cycloalkenyl group independently contains one or more carbon-carbon sp groups. 2 It has double bonds and is not aromatic.

[0208] In some embodiments of the present invention, each C7-C 15 The cycloalkenyl group independently contains 3 or 4 sp groups. 2 It has double bonds and is not aromatic.

[0209] In some embodiments of the present invention, the heteroatom species of each 7-15 membered heterocyclic alkyl group are independently selected from one or two of N, O and S, and the number of heteroatoms is independently 1, 2 or 3.

[0210] In some embodiments of the present invention, each 7-15 membered heterocyclic alkyl group may be a monocyclic or polycyclic ring, wherein the polycyclic ring may be a bridged ring, a fused ring, or a spirocyclic ring, and the polycyclic ring may also be a bicyclic or a tricyclic ring.

[0211] In some embodiments of the invention, each 7-15 member heterocyclic alkyl group is independently a 7-membered monocyclic heterocyclic alkyl group or an 8-10 membered bicyclic heterocyclic alkyl group.

[0212] In some embodiments of the present invention, the heteroatom species of each 7-15 member heterocyclic alkenyl group is independently selected from one or two of N, O and S, and the number of heteroatoms is independently 1, 2 or 3; preferably, the heteroatom species is independently S, and the number of heteroatoms is 1.

[0213] In some embodiments of the present invention, each 7-15 membered heterocyclic alkenyl group has an independently unique heteroatom species of O and a heteroatom number of 1.

[0214] In some embodiments of the present invention, each 7-15 membered heterocyclic alkenyl group has an independently defined heteroatom species of O or S, and the number of heteroatoms is 1.

[0215] In some embodiments of the present invention, each 7-15 member heterocyclic alkenyl group is independently monocyclic or polycyclic, the polycyclic group being a bridged ring, a fused ring, or a spirocyclic ring, preferably a fused ring; the polycyclic group may also be bicyclic or tricyclic; preferably, each 7-15 member heterocyclic alkenyl group is independently an 8-10 member bicyclic heterocyclic alkenyl group, such as 5,6-dihydro-4H-cyclopentano[b]thiopheneyl or 4,5,6,7-tetrahydrobenzo[b]thiopheneyl.

[0216] In some embodiments of the invention, each 7-15 membered heterocyclic alkenyl group is independently 3,4-dihydro-2H-chromenyl.

[0217] In some embodiments of the invention, each 7-15 membered heterocyclic alkenyl group is independently 5,6-dihydro-4H-cyclopentano[b]thiophene, 4,5,6,7-tetrahydrobenzo[b]thiophene, or 3,4-dihydro-2H-chromoyl.

[0218] In some embodiments of the present invention, each 7-15 membered heterocyclic alkenyl group independently contains one or more sp atoms. 2 Double bonds, preferably containing 2 sp bonds. 2 Double bond.

[0219] In some embodiments of the invention, each 7-15 membered heterocyclic alkenyl group independently contains 3 sp atoms. 2 Double bond.

[0220] In some embodiments of the present invention, X is -NR 7 -, -O- or -S-, preferably -NR 7 - or -O-, more preferably -O-.

[0221] In some embodiments of the present invention, Y is -NR 8 -、-O-、-S- or *-NR 8 SO2-, wherein the * end is connected to the pyrimidine ring in the parent nucleus; preferably -NR. 8 -、-O- or *-NR 8 SO2-, wherein the * end is connected to the pyrimidine ring in the parent nucleus; more preferably -NR 8 -

[0222] In some embodiments of the present invention, R 7 It is hydrogen, C1-C6 alkyl, and is formed by one or more R 7a Substituted C1-C6 alkyl, C3-C 12 cycloalkyl or with one or more R 7d Replacement C3-C 12 Cycloalkyl, preferably C1-C6 alkyl or alkylated by one or more R 7a Substituted C1-C6 alkyl groups.

[0223] In some embodiments of the present invention, R 7 It is a C1-C6 alkyl group.

[0224] In some embodiments of the present invention, each R 7a and R 7d Each is independently deuterium, halogen, C1-C6 alkyl, -O-C1-C6 alkyl, or C3-C 12 Cycloalkyl groups, preferably deuterium.

[0225] In some embodiments of the present invention, R 8 It is hydrogen, C1-C6 alkyl, and is formed by one or more R 8a Substituted C1-C6 alkyl, C3-C 12 cycloalkyl or with one or more R 8d Replacement C3-C 12 Cycloalkyl, preferably hydrogen, C1-C6 alkyl, or alkyl grouped by one or more R 8a The substituted C1-C6 alkyl group is more preferably hydrogen or C1-C6 alkyl.

[0226] In some embodiments of the present invention, R 8 It is a C1-C6 alkyl group or is composed of one or more R groups. 8a Substituted C1-C6 alkyl groups.

[0227] In some embodiments of the present invention, each R 8a and R 8d Each is independently deuterium, hydroxyl, halogen, -O-C1-C6 alkyl or C3-C 12 Cycloalkyl groups, preferably deuterium.

[0228] In some embodiments of the present invention, R 1 and R 1’ Each is independently hydrogen, deuterium, C2-C6 ynyl, C1-C6 alkyl, or formed by one or more R groups. 1a Substituted C1-C6 alkyl, C3-C 12 cycloalkyl or with one or more R 1d Replacement C3-C 12 cycloalkyl; or R 1 and R 1’ Together they form = O;

[0229] Or R 1 R 1’ Together with the carbon atoms it is attached to, they form C3-C 12 Cycloalkyl.

[0230] In some embodiments of the present invention, R 1 and R 1’Each is independently a C2-C6 ynyl group; or R 1 R 1’ Together with the carbon atoms it is attached to, they form C3-C 12 Cycloalkyl.

[0231] In some embodiments of the present invention, R 1 and R 1’ Each is independently hydrogen, deuterium, C1-C6 alkyl, or formed by one or more R 1a Substituted C1-C6 alkyl, C3-C 12 cycloalkyl or with one or more R 1d Replacement C3-C 12 cycloalkyl; or R 1 and R 1’ Together they form = O.

[0232] In some embodiments of the present invention, R 1 and R 1’ Each is independently hydrogen or C1-C6 alkyl; or R 1 and R 1’ Together they form = O.

[0233] In some embodiments of the present invention, R 1 and R 1’ Each is independently hydrogen or C1-C6 alkyl.

[0234] In some embodiments of the present invention, R 1 and R 1’ Each is independently hydrogen, C1-C6 alkyl, or composed of one or more R... 1a Substituted C1-C6 alkyl groups.

[0235] In some embodiments of the present invention, R 1 It is hydrogen.

[0236] In some embodiments of the present invention, R 1 It is deuterium.

[0237] In some embodiments of the present invention, R 1 It is either hydrogen or deuterium.

[0238] In some embodiments of the present invention, R 1’ It is a C1-C6 alkyl group or is composed of one or more R groups. 1a Substituted C1-C6 alkyl groups.

[0239] In some embodiments of the present invention, R 1’ It is a C2-C6 acetylene or C3-C 12 Cycloalkyl.

[0240] In some embodiments of the present invention, R 1’ It is C1-C6 alkyl, C2-C6 alkynyl, C3-C 12 cycloalkyl or with one or more R 1a Substituted C1-C6 alkyl groups.

[0241] In some embodiments of the present invention, each R 1a and R 1d Each can be independently deuterium, halogen, oxo group or -O-C1-C6 alkyl.

[0242] In some embodiments of the present invention, each R 1a and R 1d Each is an independent hydroxyl group.

[0243] In some embodiments of the present invention, each R 1a and R 1d Each can be independently deuterium, hydroxyl, halogen, oxo group or -O-C1-C6 alkyl.

[0244] In some embodiments of the present invention, each R 1a It can be either deuterium or halogen.

[0245] In some embodiments of the present invention, ring A is a 5-10 member heteroaryl group.

[0246] In some embodiments of the present invention, ring A is a 5-6 membered monocyclic heteroaryl group.

[0247] In some embodiments of the present invention, ring A is C3-C. 12 Cycloalkyl.

[0248] In some embodiments of the present invention, ring A is a 5-10 membered heteroaryl group or a C3-C group. 12 Cycloalkyl.

[0249] In some embodiments of the present invention, each R 5 Independently deuterium, halogen, cyano, nitro, -OR 9 -SR 9 -N(R) 9 )2、-S(O) 1-2 R 9 C1-C6 alkyl or C3-C 12 Cycloalkyl, preferably -OR 9 -SR 9 -N(R) 9 )2 or C1-C6 alkyl, more preferably -N(R 9 )2.

[0250] In some embodiments of the present invention, each R 5Independently for -N(R) 9 )2 or C1-C6 alkyl.

[0251] In some embodiments of the present invention, each R 5 Halogens are independent of each other.

[0252] In some embodiments of the present invention, each R 5 Independent halogen, -N(R) 9 )2 or C1-C6 alkyl.

[0253] In some embodiments of the present invention, each R 9 It is independently hydrogen, C1-C6 alkyl, or composed of one or more R 9a The substituted C1-C6 alkyl group is preferably H.

[0254] In some embodiments of the present invention, each R 9a It can be either deuterium or halogen.

[0255] In some embodiments of the present invention, m is 0, 1, 2 or 3, preferably 1.

[0256] In some embodiments of the present invention, m is 0 or 1.

[0257] In some embodiments of the present invention, m is 0, 1 or 2.

[0258] In some embodiments of the present invention, L is -O-(CR) 10 R 11 ) q1 - a or -O-(CR) 10 R 11 ) q2 -CR 12 R 13 -(CR 10 R 11 ) q3 - a The a end and R 2 Connection; preferably -O-(CR) 10 R 11 ) q1 - a The a end and R 2 connect.

[0259] In some embodiments of the present invention, L represents a chemical bond.

[0260] In some embodiments of the present invention, L represents a chemical bond, -O-(CR) 10 R 11 ) q1 - aor -O-(CR) 10 R 11 ) q2 -CR 12 R 13 -(CR 10 R 11 ) q3 - a The a end and R 2 connect.

[0261] In some embodiments of the present invention, each R 10 and R 11 Each is independently hydrogen, halogen, or C1-C6 alkyl, preferably hydrogen.

[0262] In some embodiments of the present invention, each R 10 and R 11 Each is independently a deuterium.

[0263] In some embodiments of the present invention, each R 10 and R 11 Each of them is independently hydrogen, deuterium, halogen or C1-C6 alkyl, preferably hydrogen, deuterium or C1-C6 alkyl, more preferably hydrogen or deuterium.

[0264] In some embodiments of the present invention, R 12 R 13 Together with the carbon atoms they are connected to, they form C3-C. 12 Cycloalkyl.

[0265] In some embodiments of the present invention, R 12 R 13 Together with the carbon atoms they are connected to, they form C3-C8 cycloalkyl groups.

[0266] In some embodiments of the present invention, R 12 and R 13 Each is independently hydrogen, deuterium, halogen, C1-C6 alkyl, C3-C 12 Cycloalkyl, or C1-C6 alkyl substituted with one or more substituents selected from deuterium, hydroxyl and halogen, preferably C1-C6 alkyl.

[0267] In some embodiments of the present invention, q1, q2 and q3 are each independently 1, 2 or 3, preferably 1.

[0268] In some embodiments of the present invention, q1, q2 and q3 are each independently 0.

[0269] In some embodiments of the present invention, q1, q2 and q3 are each independently 0, 1, 2 or 3, preferably 0 or 1.

[0270] In some embodiments of the present invention, R 2 -N(R) 15 )2, 3-12 membered heterocyclic alkyl groups, with one or more R 2d Substituted 3-12-membered heterocyclic alkyl, 3-12-membered heterocyclic alkenyl, or substituted with one or more R 2e Substituted 3-12 membered heterocyclic alkenyl groups.

[0271] In some embodiments of the present invention, R 2 -N(R) 15 )2.

[0272] In some embodiments of the present invention, R 2 It is a 3-12 membered heterocyclic alkyl group, surrounded by one or more R 2d Substituted 3-12-membered heterocyclic alkyl, 3-12-membered heterocyclic alkenyl, or substituted with one or more R 2e The substituted 3-12 membered heterocyclic alkenyl group is preferably replaced by one or more R groups. 2d Substituted 3-12 membered heterocyclic alkyl groups.

[0273] In some embodiments of the present invention, R 2 It is a 3-12 membered heterocyclic alkyl group or is composed of one or more R groups. 2d Substituted 3-12 membered heterocyclic alkyl groups.

[0274] In some embodiments of the present invention, each R 2d and R 2e Each is independently a 3-12 membered heterocyclic alkyl group, C6-C 10 aryl or aryl with one or more R 2-h Replacement C6-C 10 Aryl.

[0275] In some embodiments of the present invention, each R 2d and R 2e Each is independently a halogen, oxo group, or -OR 16 -SR 16 -N(R) 16 )2、=CR 2-j R 2-j C1-C6 alkyl or containing one or more R 2-a The substituted C1-C6 alkyl group is preferably a halogen or a C1-C6 alkyl group, more preferably a halogen.

[0276] In some embodiments of the present invention, each R 2d and R 2e Each is independently a deuterium.

[0277] In some embodiments of the present invention, each R 2dand R 2e Each independently constitutes deuterium, -OR 16 =CR 2-j R 2-j Or by one or more R 2-a Substituted C1-C6 alkyl groups, preferably -OR 16 =CR 2-j R 2-j Or by one or more R 2-a Substituted C1-C6 alkyl groups.

[0278] In some embodiments of the present invention, each R 2d and R 2e Each is independently a halogen, deuterium, oxo group, or -OR. 16 -SR 16 -N(R) 16 )2、=CR 2-j R 2-j C1-C6 alkyl or containing one or more R 2-a The substituted C1-C6 alkyl group is preferably halogen, deuterium, or -OR. 16 =CR 2- j R 2-j C1-C6 alkyl or containing one or more R 2-a Substituted C1-C6 alkyl groups, preferably halogens, -OR 16 =CR 2-j R 2-j C1-C6 alkyl or containing one or more R 2-a Substituted C1-C6 alkyl groups.

[0279] In some embodiments of the present invention, each R 2d and R 2e Each is independently a halogen, deuterium, oxo group, or -OR. 16 -SR 16 -N(R) 16 )2、=CR 2-j R 2-j C1-C6 alkyl, 3-12 membered heterocyclic alkyl, C6-C 10 aryl, with one or more R 2-a Substituted C1-C6 alkyl groups or those with one or more R 2-h Replacement C6-C 10 Aryl; preferably halogen, deuterium, -OR 16 =CR 2-j R 2-j C1-C6 alkyl, 3-12 membered heterocyclic alkyl, C6-C 10 aryl, with one or more R 2-aSubstituted C1-C6 alkyl groups or those with one or more R 2-h Replacement C6-C 10 Aryl.

[0280] In some embodiments of the present invention, each R 2-a It can be independently deuterium, halogen, or -O-C1-C6 alkyl.

[0281] In some embodiments of the present invention, each R 2-a Independently hydroxyl, 3-12 membered heterocyclic alkyl groups or those containing one or more R groups 2-a-1 Substituted 3-12 membered heterocyclic alkyl groups.

[0282] In some embodiments of the present invention, each R 2-a Independently deuterium, halogen, hydroxyl, 3-12 membered heterocyclic alkyl, -O-C1-C6 alkyl, or with one or more R 2-a-1 The substituted 3-12 membered heterocyclic alkyl group is preferably a hydroxyl group.

[0283] In some embodiments of the present invention, each R 2-a-1 R 2-a-2 and R 2-a-3 Each is independently deuterium, halogen, hydroxyl or C1-C6 alkyl, preferably hydroxyl or C1-C6 alkyl.

[0284] In some embodiments of the present invention, each R 2-h It is independently deuterium, halogen, or C1-C6 alkyl; preferably halogen.

[0285] In some embodiments of the present invention, each R 2-j It can be hydrogen or halogen independently.

[0286] In some embodiments of the present invention, each R 15 It is independently hydrogen or C1-C6 alkyl; preferably C1-C6 alkyl.

[0287] In some embodiments of the present invention, each R 16 It is independently hydrogen or C1-C6 alkyl.

[0288] In some embodiments of the present invention, each R 16 It is independently a C1-C6 alkyl group.

[0289] In some embodiments of the present invention, each R 3 It is independently hydrogen, halogen, or C1-C6 alkyl, preferably hydrogen.

[0290] In some embodiments of the present invention, n is 1 or 2, preferably 1.

[0291] In some embodiments of the present invention, ring B is a 7-15 membered heterocyclic alkyl or a 7-15 membered heterocyclic alkenyl, preferably a 7-15 membered heterocyclic alkenyl.

[0292] In some embodiments of the present invention, ring B is C7-C. 15 Cycloalkenyl.

[0293] In some embodiments of the present invention, ring B is a 7-15 membered heterocyclic alkyl group, C7-C65. 15 Cycloalkenyl or 7-15 membered heterocyclic alkenyl, preferably C7-C 15 Cycloalkenyl or 7-15 membered heterocyclic alkenyl.

[0294] In some embodiments of the present invention, each R 4 Independently deuterium, halogen, cyano, -N(R) 18 )2、-OR 18 -SR 18 Or C1-C6 alkyl, preferably cyano or -N(R) 18 )2.

[0295] In some embodiments of the present invention, each R 4 Independent of an oxo group or by one or more R groups 4a Substituted C1-C6 alkyl groups.

[0296] In some embodiments of the present invention, each R 4a Halogens are independent of each other.

[0297] In some embodiments of the present invention, each R 4 Independently deuterium, halogen, cyano, oxo, -N(R) 18 )2、-OR 18 -SR 18 C1-C6 alkyl or containing one or more R 4a Substituted C1-C6 alkyl groups; preferably halogen, cyano, oxo, or -N(R) 18 2. C1-C6 alkyl or containing one or more R 4a Substituted C1-C6 alkyl groups.

[0298] In some embodiments of the present invention, each R 4 Independently halogen, cyano, -N(R) 18 2. C1-C6 alkyl or containing one or more R 4a Substituted C1-C6 alkyl groups.

[0299] In some embodiments of the present invention, each R 18 It is independently hydrogen, C1-C6 alkyl or C3-C12 Cycloalkyl, preferably hydrogen.

[0300] In some embodiments of the present invention, p is 0, 1, 2 or 3, preferably 2.

[0301] In some embodiments of the present invention, p is 3, 4 or 5.

[0302] In some embodiments of the present invention, p is 2, 3, 4 or 5.

[0303] In some embodiments of the present invention, structural units for The b end is connected to X.

[0304] In some embodiments of the present invention, structural units for (For example ), (For example ), The b end is connected to X.

[0305] In some embodiments of the present invention, structural units for (For example ), (For example ), The b end is connected to X.

[0306] In some embodiments of the present invention, X is -NR 7 -、-O- or -S-;

[0307] Y is -NR 8 -、-O-、-S- or *-NR 8 SO2-, the * end is connected to the pyrimidine ring in the parent nucleus;

[0308] t is 0 or 1;

[0309] R 7 It is hydrogen, C1-C6 alkyl, and is formed by one or more R 7a Substituted C1-C6 alkyl, C3-C 12 cycloalkyl or with one or more R 7d Replacement C3-C 12 cycloalkyl; each R 7a and R 7d Each is independently deuterium, halogen, C1-C6 alkyl, -O-C1-C6 alkyl, or C3-C 12 cycloalkyl;

[0310] R 8 It is hydrogen, C1-C6 alkyl, and is formed by one or more R 8a Substituted C1-C6 alkyl, C3-C 12 cycloalkyl or with one or more R 8d Replacement C3-C 12 cycloalkyl; each R 8a and R 8d Each is independently deuterium, hydroxyl, halogen, -O-C1-C6 alkyl or C3-C 12 cycloalkyl;

[0311] R 1 and R 1’ Each is independently hydrogen, deuterium, C1-C6 alkyl, or formed by one or more R 1a Substituted C1-C6 alkyl, C3-C 12 cycloalkyl or with one or more R 1d Replacement C3-C 12 cycloalkyl; or, R 1 and R 1’ Together they form = O;

[0312] Each R 1a and R 1d Each can be independently deuterated, halogenated, oxo-, or -O-C1-C6 alkyl.

[0313] Ring A is a 5-10 member heteroaryl group;

[0314] Each R 5 Independently deuterium, halogen, cyano, nitro, -OR 9 -SR 9 -N(R) 9 )2、-S(O) 1-2 R 9 C1-C6 alkyl or C3-C 12 cycloalkyl;

[0315] Each R 9 It is independently hydrogen, C1-C6 alkyl, or composed of one or more R 9a Substituted C1-C6 alkyl groups; each R 9a It can be either deuterium or a halogen independently;

[0316] m can be 0, 1, 2, or 3;

[0317] L is -O-(CR) 10 R 11 ) q1 - a or -O-(CR) 10 R 11 )q2 -CR 12 R 13 -(CR 10 R 11 ) q3 - a The a end and R 2 connect;

[0318] Each R 10 and R 11 Each is independently hydrogen, halogen, or C1-C6 alkyl;

[0319] R 12 R 13 Together with the carbon atoms they are connected to, they form C3-C. 12 cycloalkyl;

[0320] q1, q2, and q3 are each independently 1, 2, or 3;

[0321] R 2 It is a 3-12 membered heterocyclic alkyl group, surrounded by one or more R 2d Substituted 3-12-membered heterocyclic alkyl, 3-12-membered heterocyclic alkenyl, or substituted with one or more R 2e Substituted 3-12 membered heterocyclic alkenyl groups;

[0322] Each R 2d and R 2e Each is independently a halogen, oxo group, or -OR 16 -SR 16 -N(R) 16 )2、=CR 2-j R 2-j C1-C6 alkyl or containing one or more R 2-a Substituted C1-C6 alkyl groups;

[0323] Each R 2-a It can be independently deuterium, halogen, or -O-C1-C6 alkyl;

[0324] Each R 2-j Independently hydrogen or halogen;

[0325] Each R 16 Independently hydrogen or C1-C6 alkyl;

[0326] Each R 3 It is independently hydrogen, halogen, or C1-C6 alkyl;

[0327] n is 1 or 2;

[0328] Ring B is a 7-15 membered heterocyclic alkyl or a 7-15 membered heterocyclic alkenyl;

[0329] Each R4 Independently deuterium, halogen, cyano, -N(R) 18 )2、-OR 18 -SR 18 Or C1-C6 alkyl;

[0330] Each R 18 It is independently hydrogen, C1-C6 alkyl or C3-C 12 cycloalkyl;

[0331] p can be 0, 1, 2, or 3.

[0332] In some embodiments of the present invention, X is -NR 7 -or -O-;

[0333] Y is -NR 8 -、-O- or *-NR 8 SO2-, the * end is connected to the pyrimidine ring in the parent nucleus;

[0334] t is 0 or 1;

[0335] R 7 It is a C1-C6 alkyl group or is composed of one or more R groups. 7a Substituted C1-C6 alkyl groups; each R 7a Deuterium is independent of other substances;

[0336] R 8 It is hydrogen, C1-C6 alkyl, or composed of one or more R 8a Substituted C1-C6 alkyl groups; each R 8a Deuterium is independent of other substances;

[0337] R 1 and R 1’ Each is independently hydrogen or C1-C6 alkyl; or R 1 and R 1’ Together they form = O;

[0338] Ring A is a 5-10 member heteroaryl group;

[0339] Each R 5 Independently for -N(R) 9 )2; Each R 9 Independently hydrogen;

[0340] m is 1;

[0341] L is -O-(CR) 10 R 11 ) q1 - a The a end and R 2 Connection; each R 10 and R 11Each is independently hydrogen; q1 is 1;

[0342] R 2 It is a 3-12 membered heterocyclic alkyl group or is composed of one or more R groups. 2d Substituted 3-12 membered heterocyclic alkyl groups; R 2d It is independently a halogen or a C1-C6 alkyl group;

[0343] R 3 It is hydrogen;

[0344] n is 1;

[0345] Cycle B is a 7-15 membered heterocyclic alkenyl group;

[0346] Each R 4 Independently cyano or -N(R) 18 )2; Each R 18 Independently hydrogen;

[0347] p is 2.

[0348] In some embodiments of the present invention, the compound represented by Formula I is the compound represented by Formula I-1.

[0349] Among them, X, Y, R 1 R 1’ R 2 R 3 R 4 R 5 The definitions of L, ring A, t, m, n and p are as described above, and y1 is 1 or 2.

[0350] In some embodiments of the present invention, the compound represented by Formula I is the compound represented by Formula I-2.

[0351] Where X is -NR 7 -or -O-;

[0352] Y is -NR 8 -or -O-; preferably -NR 8 -;

[0353] t is 1;

[0354] R 7 It is a C1-C6 alkyl group or is composed of one or more R groups. 7a Substituted C1-C6 alkyl groups; each R 7a Deuterium is independent of other substances;

[0355] R 8 It is hydrogen, C1-C6 alkyl, or composed of one or more R 8a Substituted C1-C6 alkyl groups; each R8a Deuterium is independent of other substances;

[0356] R 1 and R 1’ Each is independently hydrogen or C1-C6 alkyl; or R 1 and R 1’ Together they form = O;

[0357] Ring A is a 5-10 member heteroaryl group;

[0358] Each R 5 Independently for -N(R) 9 )2; Each R 9 Independently hydrogen;

[0359] m is 1;

[0360] L is -O-(CR) 10 R 11 ) q1 - a The a end and R 2 Connection; each R 10 and R 11 Each is independently hydrogen; q1 is 1;

[0361] R 2 It is a 3-12 membered heterocyclic alkyl group or is composed of one or more R groups. 2d Substituted 3-12 membered heterocyclic alkyl groups; R 2d It is independently a halogen or a C1-C6 alkyl group;

[0362] Each R 4 Independently cyano or -N(R) 18 )2; Each R 18 Independently hydrogen;

[0363] p is 2;

[0364] y1 is 1 or 2.

[0365] In some embodiments of the present invention, X is -NR 7 -、-O- or -S-;

[0366] Y is -NR 8 -、-O-、-S- or *-NR 8 SO2-, the * end is connected to the pyrimidine ring in the parent nucleus;

[0367] t is 0 or 1;

[0368] R 7 It is hydrogen, C1-C6 alkyl, and is formed by one or more R 7a Substituted C1-C6 alkyl, C3-C 12cycloalkyl or with one or more R 7d Replacement C3-C 12 cycloalkyl; each R 7a and R 7d Each is independently deuterium, halogen, C1-C6 alkyl, -O-C1-C6 alkyl, or C3-C 12 cycloalkyl;

[0369] R 8 It is hydrogen, C1-C6 alkyl, and is formed by one or more R 8a Substituted C1-C6 alkyl, C3-C 12 cycloalkyl or with one or more R 8d Replacement C3-C 12 cycloalkyl; each R 8a and R 8d Each is independently deuterium, hydroxyl, halogen, -O-C1-C6 alkyl or C3-C 12 cycloalkyl;

[0370] R 1 and R 1’ Each is independently hydrogen, deuterium, C1-C6 alkyl, or formed by one or more R 1a Substituted C1-C6 alkyl, C3-C 12 cycloalkyl or with one or more R 1d Replacement C3-C 12 cycloalkyl; or, R 1 and R 1’ Together they form = O;

[0371] Each R 1a and R 1d Each can be independently deuterium, hydroxyl, halogen, oxo group or -O-C1-C6 alkyl;

[0372] Ring A is a 5-10 member heteroaryl group;

[0373] Each R 5 Independently deuterium, halogen, cyano, nitro, -OR 9 -SR 9 -N(R) 9 )2、-S(O) 1-2 R 9 C1-C6 alkyl or C3-C 12 cycloalkyl;

[0374] Each R 9 It is independently hydrogen, C1-C6 alkyl, or composed of one or more R 9a Substituted C1-C6 alkyl groups; each R 9a It can be either deuterium or a halogen independently;

[0375] m can be 0, 1, 2, or 3;

[0376] L is -O-(CR) 10 R 11 ) q1 - a or -O-(CR) 10 R 11 ) q2 -CR 12 R 13 -(CR 10 R 11 ) q3 - a The a end and R 2 connect;

[0377] Each R 10 and R 11 Each is independently hydrogen, halogen, or C1-C6 alkyl;

[0378] R 12 R 13 Together with the carbon atoms they are connected to, they form C3-C. 12 cycloalkyl;

[0379] q1, q2, and q3 are each independently 1, 2, or 3;

[0380] R 2 It is a 3-12 membered heterocyclic alkyl group, surrounded by one or more R 2d Substituted 3-12-membered heterocyclic alkyl, 3-12-membered heterocyclic alkenyl, or substituted with one or more R 2e Substituted 3-12 membered heterocyclic alkenyl groups;

[0381] Each R 2d and R 2e Each is independently a halogen, oxo group, or -OR 16 -SR 16 -N(R) 16 )2、=CR 2-j R 2-j C1-C6 alkyl or containing one or more R 2-a Substituted C1-C6 alkyl groups;

[0382] Each R 2-a It can be independently deuterium, halogen, or -O-C1-C6 alkyl;

[0383] Each R 2-j Independently hydrogen or halogen;

[0384] Each R 16 Independently hydrogen or C1-C6 alkyl;

[0385] Each R3 It is independently hydrogen, halogen, or C1-C6 alkyl;

[0386] n is 1 or 2;

[0387] Ring B is a 7-15 membered heterocyclic alkyl group, C7-C 15 Cycloalkenyl or 7-15 membered heterocyclic alkenyl;

[0388] Each R 4 Independently deuterium, halogen, cyano, oxo, -N(R) 18 )2、-OR 18 -SR 18 C1-C6 alkyl or containing one or more R 4a Substituted C1-C6 alkyl groups;

[0389] Each R 18 It is independently hydrogen, C1-C6 alkyl or C3-C 12 cycloalkyl; each R 4a Halogens are independent of each other;

[0390] p can be 0, 1, 2, 3, 4 or 5.

[0391] In some embodiments of the present invention, X is -NR 7 -or -O-;

[0392] Y is -NR 8 -、-O- or *-NR 8 SO2-, the * end is connected to the pyrimidine ring in the parent nucleus;

[0393] t is 0 or 1;

[0394] R 7 It is a C1-C6 alkyl group or is composed of one or more R groups. 7a Substituted C1-C6 alkyl groups; each R 7a Deuterium is independent of other substances;

[0395] R 8 It is hydrogen, C1-C6 alkyl, or composed of one or more R 8a Substituted C1-C6 alkyl groups; each R 8a Deuterium is independent of other substances;

[0396] R 1 and R 1’ Each is independently hydrogen, C1-C6 alkyl, or composed of one or more R... 1a Substituted C1-C6 alkyl; or R 1 and R 1’ Together form = O; each R 1a Independently, it is a hydroxyl group;

[0397] Ring A is a 5-10 member heteroaryl group;

[0398] Each R 5 Independently for -N(R) 9 )2; Each R 9 Independently hydrogen;

[0399] m is 1;

[0400] L is -O-(CR) 10 R 11 ) q1 - a The a end and R 2 Connection; each R 10 and R 11 Each is independently hydrogen; q1 is 1;

[0401] R 2 It is a 3-12 membered heterocyclic alkyl group or is composed of one or more R groups. 2d Substituted 3-12 membered heterocyclic alkyl groups; R 2d It is independently a halogen or a C1-C6 alkyl group;

[0402] R 3 It is hydrogen;

[0403] n is 1;

[0404] Ring B is C7-C 15 Cycloalkenyl or 7-15 membered heterocyclic alkenyl;

[0405] Each R 4 Independently halogen, cyano, oxo, -N(R) 18 2. C1-C6 alkyl or containing one or more R 4a Substituted C1-C6 alkyl groups; each R 18 Independently hydrogen; each R 4a Halogens are independent of each other;

[0406] p is 2, 3, 4 or 5.

[0407] In some embodiments of the present invention, the compound represented by Formula I is the compound represented by Formulas I-3.

[0408] Where X is -NR 7 -or -O-;

[0409] Y is -NR 8 -;

[0410] t is 1;

[0411] R 7 It is a C1-C6 alkyl group or is composed of one or more R groups. 7aSubstituted C1-C6 alkyl groups; each R 7a Deuterium is independent of other substances;

[0412] R 8 It is hydrogen, C1-C6 alkyl, or composed of one or more R 8a Substituted C1-C6 alkyl groups; each R 8a Deuterium is independent of other substances;

[0413] R 1 and R 1’ Each is independently hydrogen or C1-C6 alkyl; or R 1 and R 1’ Together they form = O;

[0414] Ring A is a 5-10 member heteroaryl group;

[0415] Each R 5 Independently for -N(R) 9 )2; Each R 9 Independently hydrogen;

[0416] m is 1;

[0417] L is -O-(CR) 10 R 11 ) q1 - a The a end and R 2 Connection; each R 10 and R 11 Each is independently hydrogen; q1 is 1;

[0418] R 2 It is a 3-12 membered heterocyclic alkyl group or is composed of one or more R groups. 2d Substituted 3-12 membered heterocyclic alkyl groups; R 2d It is independently a halogen or a C1-C6 alkyl group;

[0419] R 3 It is hydrogen;

[0420] n is 1;

[0421] Each R 4 Independently halogen, cyano, oxo, -N(R) 18 2. C1-C6 alkyl or containing one or more R 4a Substituted C1-C6 alkyl groups; each R 18 Independently hydrogen; each R 4a Halogens are independent of each other;

[0422] p is 2 or 3.

[0423] In some embodiments of the present invention, the compound represented by Formula I is a compound represented by Formula I-3A or I-3B.

[0424] Where X is -NR 7 -or -O-;

[0425] Y is -NR 8 -;

[0426] t is 1;

[0427] R 7 It is a C1-C6 alkyl group or is composed of one or more R groups. 7a Substituted C1-C6 alkyl groups; each R 7a Deuterium is independent of other substances;

[0428] R 8 It is hydrogen, C1-C6 alkyl, or composed of one or more R 8a Substituted C1-C6 alkyl groups; each R 8a Deuterium is independent of other substances;

[0429] R 1 and R 1’ Each is independently hydrogen or C1-C6 alkyl; or R 1 and R 1’ Together they form = O;

[0430] Ring A is a 5-10 member heteroaryl group;

[0431] Each R 5 Independently for -N(R) 9 )2; Each R 9 Independently hydrogen;

[0432] m is 1;

[0433] L is -O-(CR) 10 R 11 ) q1 - a The a end and R 2 Connection; each R 10 and R 11 Each is independently hydrogen; q1 is 1;

[0434] R 2 It is a 3-12 membered heterocyclic alkyl group or is composed of one or more R groups. 2d Substituted 3-12 membered heterocyclic alkyl groups; R 2d It is independently a halogen or a C1-C6 alkyl group;

[0435] R 3 It is hydrogen;

[0436] n is 1;

[0437] Each R 4 Independently halogen, cyano, oxo, -N(R) 18 2. C1-C6 alkyl or containing one or more R 4a Substituted C1-C6 alkyl groups; each R 18 Independently hydrogen; each R 4a Halogens are independent of each other;

[0438] p is 2 or 3.

[0439] In some embodiments of the present invention, X is -NR 7 -、-O- or -S-;

[0440] Y is -NR 8 -、-O-、-S- or *-NR 8 SO2-, the * end is connected to the pyrimidine ring in the parent nucleus;

[0441] t is 0 or 1;

[0442] R 7 It is hydrogen, C1-C6 alkyl, and is formed by one or more R 7a Substituted C1-C6 alkyl, C3-C 12 cycloalkyl or with one or more R 7d Replacement C3-C 12 cycloalkyl; each R 7a and R 7d Each is independently deuterium, halogen, C1-C6 alkyl, -O-C1-C6 alkyl, or C3-C 12 cycloalkyl;

[0443] R 8 It is hydrogen, C1-C6 alkyl, and is formed by one or more R 8a Substituted C1-C6 alkyl, C3-C 12 cycloalkyl or with one or more R 8d Replacement C3-C 12 cycloalkyl; each R 8a and R 8d Each is independently deuterium, hydroxyl, halogen, -O-C1-C6 alkyl or C3-C 12 cycloalkyl;

[0444] R 1 and R 1’ Each is independently hydrogen, deuterium, C1-C6 alkyl, or formed by one or more R 1a Substituted C1-C6 alkyl, C3-C 12 cycloalkyl or with one or more R 1d Replacement C3-C 12cycloalkyl; or, R 1 and R 1’ Together they form = O;

[0445] Each R 1a and R 1d Each can be independently deuterium, hydroxyl, halogen, oxo group or -O-C1-C6 alkyl;

[0446] Ring A is a 5-10 member heteroaryl group;

[0447] Each R 5 Independently deuterium, halogen, cyano, nitro, -OR 9 -SR 9 -N(R) 9 )2、-S(O) 1-2 R 9 C1-C6 alkyl or C3-C 12 cycloalkyl;

[0448] Each R 9 It is independently hydrogen, C1-C6 alkyl, or composed of one or more R 9a Substituted C1-C6 alkyl groups; each R 9a It can be either deuterium or a halogen independently;

[0449] m can be 0, 1, 2, or 3;

[0450] L is -O-(CR) 10 R 11 ) q1 - a or -O-(CR) 10 R 11 ) q2 -CR 12 R 13 -(CR 10 R 11 ) q3 - a The a end and R 2 connect;

[0451] Each R 10 and R 11 Each is independently hydrogen, deuterium, halogen, or C1-C6 alkyl;

[0452] R 12 R 13 Together with the carbon atoms they are connected to, they form C3-C. 12 cycloalkyl;

[0453] q1, q2, and q3 are each independently 1, 2, or 3;

[0454] R 2It is a 3-12 membered heterocyclic alkyl group, surrounded by one or more R 2d Substituted 3-12-membered heterocyclic alkyl, 3-12-membered heterocyclic alkenyl, or substituted with one or more R 2e Substituted 3-12 membered heterocyclic alkenyl groups;

[0455] Each R 2d and R 2e Each is independently a halogen, deuterium, oxo group, or -OR. 16 -SR 16 -N(R) 16 )2、=CR 2-j R 2-j C1-C6 alkyl or containing one or more R 2-a Substituted C1-C6 alkyl groups;

[0456] Each R 2-a Independently deuterium, halogen, hydroxyl, 3-12 membered heterocyclic alkyl, -O-C1-C6 alkyl, or with one or more R 2-a-1 Substituted 3-12 membered heterocyclic alkyl groups;

[0457] Each R 2-j Independently hydrogen or halogen;

[0458] Each R 2-a-1 R 2-a-2 and R 2-a-3 Each is independently deuterium, halogen, hydroxyl, or C1-C6 alkyl;

[0459] Each R 16 Independently hydrogen or C1-C6 alkyl;

[0460] Each R 3 It is independently hydrogen, halogen, or C1-C6 alkyl;

[0461] n is 1 or 2;

[0462] Ring B is a 7-15 membered heterocyclic alkyl group, C7-C 15 Cycloalkenyl or 7-15 membered heterocyclic alkenyl;

[0463] Each R 4 Independently deuterium, halogen, cyano, oxo, -N(R) 18 )2、-OR 18 -SR 18 C1-C6 alkyl or containing one or more R 4a Substituted C1-C6 alkyl groups;

[0464] Each R 18 It is independently hydrogen, C1-C6 alkyl or C3-C 12 cycloalkyl; each R4a Halogens are independent of each other;

[0465] p can be 0, 1, 2, 3, 4 or 5.

[0466] In some embodiments of the present invention, X is -NR 7 -or -O-;

[0467] Y is -NR 8 -、-O- or *-NR 8 SO2-, the * end is connected to the pyrimidine ring in the parent nucleus;

[0468] t is 0 or 1;

[0469] R 7 It is a C1-C6 alkyl group or is composed of one or more R groups. 7a Substituted C1-C6 alkyl groups; each R 7a Deuterium is independent of other substances;

[0470] R 8 It is hydrogen, C1-C6 alkyl, or composed of one or more R 8a Substituted C1-C6 alkyl groups; each R 8a Deuterium is independent of other substances;

[0471] R 1 and R 1’ Each is independently hydrogen, C1-C6 alkyl, or composed of one or more R... 1a Substituted C1-C6 alkyl; or R 1 and R 1’ Together form = O; each R 1a Independently, it can be deuterium, halogen, or hydroxyl;

[0472] Ring A is a 5-10 member heteroaryl group;

[0473] Each R 5 Independently for -N(R) 9 )2 or C1-C6 alkyl; each R 9 Independently hydrogen;

[0474] m is 0 or 1;

[0475] L is -O-(CR) 10 R 11 ) q1 - a or -O-(CR) 10 R 11 ) q2 -CR 12 R 13 -(CR 10 R 11 ) q3 -a The a end and R 2 Connection; each R 10 and R 11 Each is independently hydrogen, deuterium, or C1-C6 alkyl; q1, q2, and q3 are each independently 1;

[0476] R 12 R 13 Together with the carbon atoms they are connected to, they form C3-C. 12 cycloalkyl;

[0477] R 2 It is a 3-12 membered heterocyclic alkyl group or is composed of one or more R groups. 2d Substituted 3-12 membered heterocyclic alkyl groups;

[0478] R 2d Independent of halogen, deuterium, -OR 16 =CR 2-j R 2-j C1-C6 alkyl or containing one or more R 2-a Substituted C1-C6 alkyl groups;

[0479] R 16 Independently hydrogen or C1-C6 alkyl;

[0480] Each R 2-j Independently hydrogen or halogen;

[0481] Each R 2-a Independently, it is deuterium, halogen, hydroxyl, -O-PO(OH)2, 3-12 membered heterocyclic alkyl, -O-C1-C6 alkyl, or is associated with one or more R 2-a-1 Substituted 3-12 membered heterocyclic alkyl groups;

[0482] Each R 2-a-1 Independently, it is a C1-C6 alkyl group;

[0483] R 3 It is hydrogen;

[0484] n is 1;

[0485] Ring B is C7-C 15 Cycloalkenyl or 7-15 membered heterocyclic alkenyl;

[0486] Each R 4 Independently halogen, cyano, oxo, -N(R) 18 2. C1-C6 alkyl or containing one or more R 4a Substituted C1-C6 alkyl groups; each R 18 Independently hydrogen; each R 4a Halogens are independent of each other;

[0487] p is 2, 3, 4 or 5.

[0488] In some embodiments of the present invention, the compound represented by Formula I is the compound represented by Formulas I-4.

[0489] in,

[0490] It can be a single bond or a double bond;

[0491] X is -NR 7 -or -O-;

[0492] Y is -NR 8 -;

[0493] t is 1;

[0494] R 7 It is a C1-C6 alkyl group or is composed of one or more R groups. 7a Substituted C1-C6 alkyl groups; each R 7a Deuterium is independent of other substances;

[0495] R 8 It is hydrogen, C1-C6 alkyl, or composed of one or more R 8a Substituted C1-C6 alkyl groups; each R 8a Deuterium is independent of other substances;

[0496] R 1 and R 1’ Each is independently hydrogen, C1-C6 alkyl, or composed of one or more R... 1a Substituted C1-C6 alkyl groups;

[0497] Each R 1a Independently, it can be deuterium, halogen, or hydroxyl;

[0498] Ring A is a 5-10 member heteroaryl group;

[0499] Each R 5 Independently for -N(R) 9 )2; Each R 9 Independently hydrogen;

[0500] m is 1;

[0501] L is -O-(CR) 10 R 11 ) q1 - a or -O-(CR) 10 R 11 ) q2 -CR 12 R 13 -(CR 10 R11 ) q3 - a The a end and R 2 Connection; each R 10 and R 11 Each is independently hydrogen or deuterium; q1, q2 and q3 are each independently 1;

[0502] R 12 R 13 Together with the carbon atoms they are connected to, they form C3-C. 12 cycloalkyl;

[0503] R 2 It is a 3-12 membered heterocyclic alkyl group or is composed of one or more R groups. 2d Substituted 3-12 membered heterocyclic alkyl groups; R 2d Independent of halogen, deuterium, =CR 2- j R 2-j -OR 16 C1-C6 alkyl or containing one or more R 2-a Substituted C1-C6 alkyl groups;

[0504] Each R 2-j Independently hydrogen or halogen;

[0505] Each R 2-a Independently, it can be deuterium, halogen, or hydroxyl;

[0506] R 16 It is hydrogen or C1-C6 alkyl;

[0507] R 3 It is hydrogen;

[0508] n is 1;

[0509] Each R 4 Independently halogen, cyano, oxo, -N(R) 18 2. C1-C6 alkyl or containing one or more R 4a Substituted C1-C6 alkyl groups; each R 18 Independently hydrogen; each R 4a Halogens are independent of each other;

[0510] p is 2 or 3.

[0511] In some embodiments of the present invention, the compound represented by Formula I is a compound represented by Formula I-4A or I-4B.

[0512] in,

[0513] It can be a single bond or a double bond;

[0514] X is -NR 7 -or -O-;

[0515] Y is -NR 8 -;

[0516] t is 1;

[0517] R 7 It is a C1-C6 alkyl group or is composed of one or more R groups. 7a Substituted C1-C6 alkyl groups; each R 7a Deuterium is independent of other substances;

[0518] R 8 It is hydrogen, C1-C6 alkyl, or composed of one or more R 8a Substituted C1-C6 alkyl groups; each R 8a Deuterium is independent of other substances;

[0519] R 1 and R 1’ Each is independently hydrogen, C1-C6 alkyl, or composed of one or more R... 1a Substituted C1-C6 alkyl groups;

[0520] Each R 1a Independently, it can be deuterium, halogen, or hydroxyl;

[0521] Ring A is a 5-10 member heteroaryl group;

[0522] Each R 5 Independently for -N(R) 9 )2; Each R 9 Independently hydrogen;

[0523] m is 1;

[0524] L is -O-(CR) 10 R 11 ) q1 - a or -O-(CR) 10 R 11 ) q2 -CR 12 R 13 -(CR 10 R 11 ) q3 - a The a end and R 2 Connection; each R 10 and R 11 Each is independently hydrogen or deuterium; q1, q2 and q3 are each independently 1;

[0525] R 12 R 13Together with the carbon atoms they are connected to, they form C3-C. 12 cycloalkyl;

[0526] R 2 It is a 3-12 membered heterocyclic alkyl group or is composed of one or more R groups. 2d Substituted 3-12 membered heterocyclic alkyl groups; R 2d Independent of halogen, deuterium, =CR 2- j R 2-j -OR 16 C1-C6 alkyl or containing one or more R 2-a Substituted C1-C6 alkyl groups;

[0527] Each R 2-j Independently hydrogen or halogen;

[0528] Each R 2-a Independently, it can be deuterium, halogen, or hydroxyl;

[0529] R 16 It is hydrogen or C1-C6 alkyl;

[0530] R 3 It is hydrogen;

[0531] n is 1;

[0532] Each R 4 Independently halogen, cyano, oxo, -N(R) 18 2. C1-C6 alkyl or containing one or more R 4a Substituted C1-C6 alkyl groups; each R 18 Independently hydrogen; each R 4a Halogens are independent of each other;

[0533] p is 2 or 3.

[0534] In some embodiments of the present invention, the compounds represented by Formula I-4 as described above are compounds represented by Formula I-4C.

[0535] in, It can be a single bond or a double bond;

[0536] X, Y, L, ring A, R 1’ R 2 R 3 R 4 R 5 The definitions of m, n, and p are as described in any of the above items.

[0537] In some embodiments of the present invention, as described above, Formula I-4A is the compound represented by Formula I-4A-1.

[0538] in, It can be a single bond or a double bond;

[0539] X, Y, L, ring A, R 1’ R 2 R 3 R 4 R 5 The definitions of m, n, and p are as described in any of the above items.

[0540] In some embodiments of the present invention, as described above, Formula I-4B is a compound represented by Formula I-4B-1.

[0541] in, It can be a single bond or a double bond;

[0542] X, Y, L, ring A, R 1’ R 2 R 3 R 4 R 5 The definitions of m, n, and p are as described in any of the above items.

[0543] In some embodiments of the present invention, X is -NR 7 -、-O- or -S-;

[0544] Y is -NR 8 -、-O-、-S- or *-NR 8 SO2-, the * end is connected to the pyrimidine ring in the parent nucleus;

[0545] t is 0 or 1;

[0546] R 7 It is hydrogen, C1-C6 alkyl, and is formed by one or more R 7a Substituted C1-C6 alkyl, C3-C 12 cycloalkyl or with one or more R 7d Replacement C3-C 12 cycloalkyl; each R 7a and R 7d Each is independently deuterium, halogen, C1-C6 alkyl, -O-C1-C6 alkyl, or C3-C 12 cycloalkyl;

[0547] R 8 It is hydrogen, C1-C6 alkyl, and is formed by one or more R 8a Substituted C1-C6 alkyl, C3-C 12 cycloalkyl or with one or more R 8d Replacement C3-C 12 cycloalkyl; each R8a and R 8d Each is independently deuterium, hydroxyl, halogen, -O-C1-C6 alkyl or C3-C 12 cycloalkyl;

[0548] R 1 and R 1’ Each is independently hydrogen, deuterium, C2-C6 ynyl, C1-C6 alkyl, or formed by one or more R groups. 1a Substituted C1-C6 alkyl, C3-C 12 cycloalkyl or with one or more R 1d Replacement C3-C 12 cycloalkyl; or, R 1 and R 1’ Together they form = O;

[0549] Or, R 1 R 1’ Together with the carbon atoms it is attached to, they form C3-C 12 cycloalkyl;

[0550] Each R 1a and R 1d Each can be independently deuterium, hydroxyl, halogen, oxo group or -O-C1-C6 alkyl;

[0551] Ring A is a 5-10 membered heteroaryl group or a C3-C ring. 12 cycloalkyl;

[0552] Each R 5 Independently deuterium, halogen, cyano, nitro, -OR 9 -SR 9 -N(R) 9 )2、-S(O) 1-2 R 9 C1-C6 alkyl or C3-C 12 cycloalkyl;

[0553] Each R 9 It is independently hydrogen, C1-C6 alkyl, or composed of one or more R 9a Substituted C1-C6 alkyl groups; each R 9a It can be either deuterium or a halogen independently;

[0554] m can be 0, 1, 2, or 3;

[0555] L represents a chemical bond, -O-(CR) 10 R 11 ) q1 - a or -O-(CR) 10 R 11 ) q2 -CR 12R 13 -(CR 10 R 11 ) q3 - a The a end and R 2 connect;

[0556] Each R 10 and R 11 Each is independently hydrogen, deuterium, halogen, or C1-C6 alkyl;

[0557] R 12 R 13 Together with the carbon atoms they are connected to, they form C3-C. 12 cycloalkyl;

[0558] Or, R 12 and R 13 Each is independently hydrogen, deuterium, halogen, C1-C6 alkyl, C3-C 12 Cycloalkyl, or C1-C6 alkyl groups substituted with one or more substituents selected from deuterium, hydroxyl and halogen;

[0559] q1, q2, and q3 are each independently 0, 1, 2, or 3;

[0560] R 2 -N(R) 15 )2, 3-12 membered heterocyclic alkyl groups, with one or more R 2d Substituted 3-12-membered heterocyclic alkyl, 3-12-membered heterocyclic alkenyl, or substituted with one or more R 2e Substituted 3-12 membered heterocyclic alkenyl groups;

[0561] Each R 2d and R 2e Each is independently a halogen, deuterium, oxo group, or -OR. 16 -SR 16 -N(R) 16 )2、=CR 2-j R 2-j C1-C6 alkyl, 3-12 membered heterocyclic alkyl, C6-C 10 aryl, with one or more R 2-a Substituted C1-C6 alkyl groups or those with one or more R 2-h Replacement C6-C 10 Aryl;

[0562] Each R 2-a Independently deuterium, halogen, hydroxyl, 3-12 membered heterocyclic alkyl, -O-C1-C6 alkyl, or with one or more R 2-a-1 Substituted 3-12 membered heterocyclic alkyl groups;

[0563] Each R 2-h It can be independently deuterium, halogen, or C1-C6 alkyl;

[0564] Each R 2-j Independently hydrogen or halogen;

[0565] Each R 2-a-1 R 2-a-2 and R 2-a-3 Each is independently deuterium, halogen, hydroxyl, or C1-C6 alkyl;

[0566] Each R 15 Independently hydrogen or C1-C6 alkyl;

[0567] Each R 16 Independently hydrogen or C1-C6 alkyl;

[0568] Each R 3 It is independently hydrogen, halogen, or C1-C6 alkyl;

[0569] n is 1 or 2;

[0570] Ring B is a 7-15 membered heterocyclic alkyl group, C7-C 15 Cycloalkenyl or 7-15 membered heterocyclic alkenyl;

[0571] Each R 4 Independently deuterium, halogen, cyano, oxo, -N(R) 18 )2、-OR 18 -SR 18 C1-C6 alkyl or containing one or more R 4a Substituted C1-C6 alkyl groups;

[0572] Each R 18 It is independently hydrogen, C1-C6 alkyl or C3-C 12 cycloalkyl; each R 4a Halogens are independent of each other;

[0573] p can be 0, 1, 2, 3, 4 or 5.

[0574] In some embodiments of the present invention, the compound represented by Formula I is the compound represented by Formulas I-5.

[0575] X is -NR 7 -or -O-;

[0576] Y is -NR 8 -、-O- or *-NR 8 SO2-, the * end is connected to the pyrimidine ring in the parent nucleus;

[0577] t is 0 or 1;

[0578] R 7 It is a C1-C6 alkyl group or is composed of one or more R groups. 7a Substituted C1-C6 alkyl groups; each R 7a Deuterium is independent of other substances;

[0579] R 8 It is hydrogen, C1-C6 alkyl, or composed of one or more R 8a Substituted C1-C6 alkyl groups; each R 8a Deuterium is independent of other substances;

[0580] R 1 and R 1’ Each can be independently hydrogen, deuterium, C2-C6 alkynyl, C1-C6 alkyl, or C3-C 12 cycloalkyl or with one or more R 1a Substituted C1-C6 alkyl; or R 1 and R 1’ Together they form = O; or, R 1 R 1’ Together with the carbon atoms it is attached to, they form C3-C 12 cycloalkyl;

[0581] Each R 1a Independently, it can be deuterium, halogen, or hydroxyl;

[0582] Ring A is a 5-10 membered heteroaryl group or a C3-C ring. 12 cycloalkyl;

[0583] Each R 5 Independently halogen, -N(R) 9 )2 or C1-C6 alkyl; each R 9 Independently hydrogen;

[0584] m is 0, 1, or 2;

[0585] L represents a chemical bond, -O-(CR) 10 R 11 ) q1 - a or -O-(CR) 10 R 11 ) q2 -CR 12 R 13 -(CR 10 R 11 ) q3 - a The a end and R 2 Connection; each R 10 and R 11Each is independently hydrogen, deuterium, or C1-C6 alkyl; q1, q2, and q3 are each independently 0 or 1;

[0586] R 12 R 13 Together with the carbon atoms they are connected to, they form C3-C. 12 cycloalkyl;

[0587] Or, R 12 and R 13 Each is independently a C1-C6 alkyl group;

[0588] R 2 -N(R) 15 )2, 3-12 membered heterocyclic alkyl groups, with one or more R 2d Substituted 3-12-membered heterocyclic alkyl, 3-12-membered heterocyclic alkenyl, or substituted with one or more R 2e Substituted 3-12 membered heterocyclic alkenyl groups;

[0589] Each R 2d and R 2e Each independently constitutes halogen, deuterium, -OR 16 =CR 2-j R 2-j C1-C6 alkyl, 3-12 membered heterocyclic alkyl, C6-C 10 aryl, with one or more R 2-a Substituted C1-C6 alkyl groups or those with one or more R 2-h Replacement C6-C 10 Aryl;

[0590] Each R 15 Independently, it is a C1-C6 alkyl group;

[0591] R 16 Independently hydrogen or C1-C6 alkyl;

[0592] Each R 2-h Halogens are independent of each other;

[0593] Each R 2-j Independently hydrogen or halogen;

[0594] Each R 2-a Independently, it is deuterium, halogen, hydroxyl, -O-PO(OH)2, 3-12 membered heterocyclic alkyl, -O-C1-C6 alkyl, or is associated with one or more R 2-a-1 Substituted 3-12 membered heterocyclic alkyl groups;

[0595] Each R 2-a-1 Independently, it is a C1-C6 alkyl group;

[0596] Each R 4Independently halogen, cyano, oxo, -N(R) 18 2. C1-C6 alkyl or containing one or more R 4a Substituted C1-C6 alkyl groups; each R 18 Independently hydrogen; each R 4a Halogens are independent of each other;

[0597] p is 2, 3, 4 or 5.

[0598] In some embodiments of the present invention, the compound represented by Formula I is the compound represented by Formulas I-5.

[0599] in,

[0600] It can be a single bond or a double bond;

[0601] X is -NR 7 -or -O-;

[0602] Y is -NR 8 -;

[0603] t is 1;

[0604] R 7 It is a C1-C6 alkyl group or is composed of one or more R groups. 7a Substituted C1-C6 alkyl groups; each R 7a Deuterium is independent of other substances;

[0605] R 8 It is hydrogen, C1-C6 alkyl, or composed of one or more R 8a Substituted C1-C6 alkyl groups; each R 8a Deuterium is independent of other substances;

[0606] R 1 and R 1’ Each of the following is independently hydrogen, deuterium, C1-C6 alkyl, C2-C6 alkynyl, or C3-C 12 cycloalkyl or with one or more R 1a Substituted C1-C6 alkyl groups;

[0607] Each R 1a Independently, it can be deuterium, halogen, or hydroxyl;

[0608] Ring A is a 5-10 member heteroaryl group;

[0609] Each R 5 Independently for -N(R) 9 )2 or halogen; each R 9 Independently hydrogen;

[0610] m is 0, 1, or 2;

[0611] L is -O-(CR) 10 R 11 ) q1 - a or -O-(CR) 10 R 11 ) q2 -CR 12 R 13 -(CR 10 R 11 ) q3 - a The a end and R 2 connect;

[0612] Each R 10 and R 11 Each is independently hydrogen or deuterium; q1, q2 and q3 are each independently 1;

[0613] R 12 R 13 Together with the carbon atoms they are connected to, they form C3-C. 12 cycloalkyl;

[0614] Or, R 12 and R 13 Each is independently a C1-C6 alkyl group;

[0615] R 2 -N(R) 15 )2, 3-12 membered heterocyclic alkyl groups, with one or more R 2d Substituted 3-12-membered heterocyclic alkyl, 3-12-membered heterocyclic alkenyl, or substituted with one or more R 2e Substituted 3-12 membered heterocyclic alkenyl groups;

[0616] Each R 2d and R 2e Each independently constitutes halogen, deuterium, and CR. 2-j R 2-j -OR 16 C1-C6 alkyl, C6-C 10 aryl, with one or more R 2-a Substituted C1-C6 alkyl groups or those with one or more R 2-h Replacement C6-C 10 Aryl;

[0617] Each R 2-h Halogens are independent of each other;

[0618] Each R 2-j Independently hydrogen or halogen;

[0619] Each R 2-aIndependently deuterium, halogen, hydroxyl group, or by one or more R 2-a-1 Substituted 3-12 membered heterocyclic alkyl groups;

[0620] Each R 2-a-1 Independently, it is a C1-C6 alkyl group;

[0621] Each R 15 Independently, it is a C1-C6 alkyl group;

[0622] R 16 It is hydrogen or C1-C6 alkyl;

[0623] Each R 4 Independently halogen, cyano, -N(R) 18 2. C1-C6 alkyl or containing one or more R 4a Substituted C1-C6 alkyl groups; each R 18 Independently hydrogen; each R 4a Halogens are independent of each other;

[0624] p is 2 or 3.

[0625] In some embodiments of the present invention, the compound represented by Formula I is a compound represented by Formula I-5A or I-5B.

[0626] in,

[0627] It can be a single bond or a double bond;

[0628] X is -NR 7 -or -O-;

[0629] Y is -NR 8 -;

[0630] t is 1;

[0631] R 7 It is a C1-C6 alkyl group or is composed of one or more R groups. 7a Substituted C1-C6 alkyl groups; each R 7a Deuterium is independent of other substances;

[0632] R 8 It is hydrogen, C1-C6 alkyl, or composed of one or more R 8a Substituted C1-C6 alkyl groups; each R 8a Deuterium is independent of other substances;

[0633] R 1 and R 1’ Each of the following is independently hydrogen, deuterium, C1-C6 alkyl, C2-C6 alkynyl, or C3-C 12 cycloalkyl or with one or more R 1aSubstituted C1-C6 alkyl groups; and R 1 and R 1’ Different;

[0634] Each R 1a Independently, it can be deuterium, halogen, or hydroxyl;

[0635] Ring A is a 5-10 member heteroaryl group;

[0636] Each R 5 Independently for -N(R) 9 )2 or halogen; each R 9 Independently hydrogen;

[0637] m is 0, 1, or 2;

[0638] L is -O-(CR) 10 R 11 ) q1 - a or -O-(CR) 10 R 11 ) q2 -CR 12 R 13 -(CR 10 R 11 ) q3 - a The a end and R 2 connect;

[0639] Each R 10 and R 11 Each is independently hydrogen or deuterium; q1, q2 and q3 are each independently 1;

[0640] R 12 R 13 Together with the carbon atoms they are connected to, they form C3-C. 12 cycloalkyl;

[0641] Or, R 12 and R 13 Each is independently a C1-C6 alkyl group;

[0642] R 2 -N(R) 15 )2, 3-12 membered heterocyclic alkyl groups, with one or more R 2d Substituted 3-12-membered heterocyclic alkyl, 3-12-membered heterocyclic alkenyl, or substituted with one or more R 2e Substituted 3-12 membered heterocyclic alkenyl groups;

[0643] Each R 2d and R 2e Each independently constitutes halogen, deuterium, and CR. 2-j R 2-j-OR 16 C1-C6 alkyl, C6-C 10 aryl, with one or more R 2-a Substituted C1-C6 alkyl groups or those with one or more R 2-h Replacement C6-C 10 Aryl;

[0644] Each R 2-h Halogens are independent of each other;

[0645] Each R 2-j Independently hydrogen or halogen;

[0646] Each R 2-a Independently deuterium, halogen, hydroxyl group, or by one or more R 2-a-1 Substituted 3-12 membered heterocyclic alkyl groups;

[0647] Each R 2-a-1 Independently, it is a C1-C6 alkyl group;

[0648] Each R 15 Independently, it is a C1-C6 alkyl group;

[0649] R 16 It is hydrogen or C1-C6 alkyl;

[0650] Each R 4 Independently halogen, cyano, -N(R) 18 2. C1-C6 alkyl or containing one or more R 4a Substituted C1-C6 alkyl groups; each R 18 Independently hydrogen; each R 4a Halogens are independent of each other;

[0651] p is 2 or 3.

[0652] In some embodiments of the present invention, X is -N(CH3)-, -N(CD3)-, or -O-.

[0653] In some embodiments of the present invention, X is -N(CH2CH3)-.

[0654] In some embodiments of the present invention, X is -N(CH3)-, -N(CD3)-, -O-, or -N(CH2CH3)-.

[0655] In some embodiments of the present invention, Y is -NH-, -O-, -N(CH3)-, -N(CD3)-, or The * end is connected to the pyrimidine ring in the parent nucleus.

[0656] In some embodiments of the present invention, R 1 and R1’ Each is independently hydrogen or -CH3; or, R 1 and R 1’ Together they form = O.

[0657] In some embodiments of the present invention, R 1 and R 1’ Each can be independently H, -CH2OH, or -CH2CH2OH.

[0658] In some embodiments of the present invention, R 1 and R 1’ Each can be independently H, -CH3, -CH2OH, or -CH2CH2OH; or, R 1 and R 1’ Together they form = O.

[0659] In some embodiments of the present invention, R 1 and R 1’ Each independently constitutes deuterium, -CHF2, -CF3, -CH2CHF2, -CH2CH3, -CH2F, -CD3 Or, R 1 R 1’ It forms together with the carbon atoms it is attached to.

[0660] In some embodiments of the present invention, R 1 and R 1’ Each can be independently H, deuterium, -CH3, -CH2OH, -CH2CH2OH, -CHF2, -CF3, -CH2CHF2, -CH2CH3, -CH2F, -CD3 Or, R 1 and R 1’ Together they form = O; or, R 1 R 1’ It forms together with the carbon atoms it is attached to.

[0661] In some embodiments of the present invention, each R 5 Independently -NH2.

[0662] In some embodiments of the present invention, each R 5 It can be -NH2 or -CH3 independently.

[0663] In some embodiments of the present invention, each R 5 Independently -F.

[0664] In some embodiments of the present invention, each R 5 It can be -F, -NH2, or -CH3 independently.

[0665] In some embodiments of the present invention, structural units for

[0666] In some embodiments of the present invention, structural units for

[0667] In some embodiments of the present invention, structural units for

[0668] In some implementation schemes, structural units for

[0669] In some embodiments of the present invention, L is -OCH2- a The a end and R 2 connect.

[0670] In some embodiments of the present invention, L is -OCH2- a , The a end and R 2 connect.

[0671] In some embodiments of the present invention, L represents a chemical bond, -O-, or... The a end and R 2 connect.

[0672] In some embodiments of the present invention, L represents a chemical bond, -O-, or -OCH2-. a , The a end and R 2 connect.

[0673] In some embodiments of the present invention, R 2 for

[0674] In some embodiments of the present invention, R 2 for

[0675] In some embodiments of the present invention, R 2 for

[0676] In some embodiments of the present invention, R 2 for

[0677] In some embodiments of the present invention, R 4 It can be -F, -Cl, -CN, -NH2, oxo group, -CH3, or -CF3.

[0678] In some embodiments of the present invention, structural units for The b end is connected to X.

[0679] In some embodiments of the present invention, structural units for The b end is connected to X.

[0680] In some embodiments of the present invention, structural units for The b end is connected to X.

[0681] In some embodiments of the present invention, structural units for The b end is connected to X.

[0682] In some embodiments of the present invention, the compound represented by Formula I is any of the following compounds:

[0683] In some embodiments of the present invention, the compound represented by Formula I is any of the following compounds:

[0684] The compound that elutes first under the following conditions: a C18 OBD column (19*250mm*5μm), a mobile phase of water (0.1% formic acid, v / v) and acetonitrile (acetonitrile volume percentage 10%), a flow rate of 25mL / min, and a detection wavelength of 214 / 254nm; preferably, under these conditions, the retention time of the compound that elutes first is 4.58 minutes.

[0685] The compound that elutes later in the chromatogram is selected under the following conditions: a C18 OBD column (19*250mm*5μm), a mobile phase of water (0.1% formic acid, v / v) and acetonitrile (acetonitrile volume percentage 10%), a flow rate of 25mL / min, and a detection wavelength of 214 / 254nm; preferably, under these conditions, the retention time of the compound that elutes later is 5.45 minutes.

[0686] The compound that elutes first under the following conditions: a C18 OBD column (19*250mm*5μm), a mobile phase of water (0.1% formic acid, v / v) and acetonitrile (acetonitrile volume percentage 10%), a flow rate of 25mL / min, and a detection wavelength of 214 / 254nm; preferably, under these conditions, the retention time of the compound that elutes first is 3.7 minutes.

[0687] The compound that elutes later in the chromatogram is determined under the following conditions: a C18 OBD column (19*250mm*5μm), a mobile phase consisting of water (containing 0.1% formic acid, v / v) and acetonitrile (acetonitrile volume percentage 10%), a flow rate of 25mL / min, and a detection wavelength of 214 / 254nm; preferably, under these conditions, the retention time of the compound that elutes later is 7.0 min.

[0688] The compound that elutes first under the following conditions: a C18 OBD column (19*250mm*5μm), a mobile phase of water (0.1% formic acid, v / v) and acetonitrile (acetonitrile volume percentage 10%), a flow rate of 25mL / min, and a detection wavelength of 214 / 254nm; preferably, under these conditions, the retention time of the compound that elutes first is 4.5 minutes.

[0689] The compound that elutes later in the chromatogram is determined under the following conditions: a C18 OBD column (19*250mm*5μm), a mobile phase of water (0.1% formic acid, v / v) and acetonitrile (acetonitrile volume percentage 10%), a flow rate of 25mL / min, and a detection wavelength of 214 / 254nm; preferably, under these conditions, the retention time of the compound that elutes later is 6.8 minutes.

[0690] The compound that elutes first under the following conditions: a C18 OBD column (19*250mm*5μm), a mobile phase of water (0.1% ammonia, v / v) and acetonitrile (acetonitrile volume percentage 55-57%), a flow rate of 25mL / min, and a detection wavelength of 214 / 254nm; preferably, under these conditions, the retention time of the compound that elutes first is 5.47 minutes.

[0691] The compound that elutes later in the chromatogram is selected under the following conditions: a C18 OBD column (19*250mm*5μm), a mobile phase of water (0.1% ammonia, v / v) and acetonitrile (acetonitrile volume percentage 55-57%), a flow rate of 25mL / min, and a detection wavelength of 214 / 254nm; preferably, under these conditions, the retention time of the compound that elutes later is 7.43 minutes.

[0692] The compound that elutes first under the following conditions: a C18 OBD column (19*250mm*5μm), a mobile phase of water (0.1% ammonia, v / v) and acetonitrile (acetonitrile volume percentage 50-53%), a flow rate of 25mL / min, and a detection wavelength of 214 / 254nm; preferably, under these conditions, the retention time of the compound that elutes first is 7.37 minutes.

[0693] The compound that elutes later in the chromatogram is selected under the following conditions: a C18 OBD column (19*250mm*5μm), a mobile phase of water (0.1% ammonia, v / v) and acetonitrile (acetonitrile volume percentage 50-53%), a flow rate of 25mL / min, and a detection wavelength of 214 / 254nm; preferably, under these conditions, the retention time of the compound that elutes later is 9.92 minutes.

[0694] The compound that elutes first under the following conditions: a C18 OBD column (19*250mm*5μm), a mobile phase of water (0.1% ammonia, v / v) and acetonitrile (acetonitrile volume percentage 45-55%), a flow rate of 25mL / min, and a detection wavelength of 214 / 254nm; preferably, under these conditions, the retention time of the compound that elutes first is 4.71 minutes.

[0695] The compound that elutes later in the chromatogram is selected under the following conditions: a C18 OBD column (19*250mm*5μm), a mobile phase of water (0.1% ammonia, v / v) and acetonitrile (acetonitrile volume percentage 45-55%), a flow rate of 25mL / min, and a detection wavelength of 214 / 254nm; preferably, under these conditions, the retention time of the compound that elutes later is 6.25 minutes.

[0696] The compound that elutes first under the following conditions: a C18 OBD column (19*250mm*5μm), a mobile phase of water (0.1% ammonia, v / v) and acetonitrile (acetonitrile volume percentage 45-55%), a flow rate of 25mL / min, and a detection wavelength of 214 / 254nm; preferably, under these conditions, the retention time of the compound that elutes first is 4.74 minutes.

[0697] The compound that elutes later in the chromatogram is selected under the following conditions: a C18 OBD column (19*250mm*5μm), a mobile phase of water (0.1% ammonia, v / v) and acetonitrile (acetonitrile volume percentage 45-55%), a flow rate of 25mL / min, and a detection wavelength of 214 / 254nm; preferably, under these conditions, the retention time of the compound that elutes later is 6.42 minutes.

[0698] The compound that elutes first under the following conditions: a C18 OBD column (19*250mm*5μm), a mobile phase of water (0.1% ammonia, v / v) and acetonitrile (acetonitrile volume percentage 55-65%), a flow rate of 25mL / min, and a detection wavelength of 214 / 254nm; preferably, under these conditions, the retention time of the compound that elutes first is 6.22 minutes.

[0699] The compound that elutes later in the chromatogram is determined under the following conditions: a C18 OBD column (19*250mm*5μm), a mobile phase of water (0.1% ammonia, v / v) and acetonitrile (acetonitrile volume percentage 55-65%), a flow rate of 25mL / min, and a detection wavelength of 214 / 254nm; preferably, under these conditions, the retention time of the compound that elutes later is 8.37 minutes.

[0700] The compound that elutes first under the following conditions: a C18 OBD column (19*250mm*5μm), a mobile phase of water (0.1% ammonia, v / v) and acetonitrile (acetonitrile volume percentage 53%), a flow rate of 25mL / min, and a detection wavelength of 214 / 254nm; preferably, under these conditions, the retention time of the compound that elutes first is 7.6 minutes.

[0701] The compound that elutes later in the chromatogram is determined under the following conditions: a C18 OBD column (19*250mm*5μm), a mobile phase of water (0.1% ammonia, v / v) and acetonitrile (acetonitrile volume percentage 53%), a flow rate of 25mL / min, and a detection wavelength of 214 / 254nm; preferably, under these conditions, the retention time of the compound that elutes later is 9.5 minutes.

[0702] The compound that elutes first under the following conditions: a C18 OBD column (19*250mm*5μm), a mobile phase of water (0.1% formic acid, v / v) and acetonitrile (acetonitrile volume percentage 19%), a flow rate of 25mL / min, and a detection wavelength of 214 / 254nm; preferably, under these conditions, the retention time of the compound that elutes first is 7.58 minutes.

[0703] The compound that elutes later in the chromatogram is determined under the following conditions: a C18 OBD column (19*250mm*5μm), a mobile phase of water (0.1% formic acid, v / v) and acetonitrile (acetonitrile volume percentage 19%), a flow rate of 25mL / min, and a detection wavelength of 214 / 254nm; preferably, under these conditions, the retention time of the compound that elutes later is 8.35 minutes.

[0704] The compound that elutes first under the following conditions: a C18 OBD column (19*250mm*5μm), a mobile phase of water (0.1% ammonia, v / v) and acetonitrile (acetonitrile volume percentage 57%), a flow rate of 25mL / min, and a detection wavelength of 214 / 254nm; preferably, under these conditions, the retention time of the compound that elutes first is 6.23 minutes.

[0705] The compound that elutes later in the chromatogram is determined under the following conditions: a C18 OBD column (19*250mm*5μm), a mobile phase of water (0.1% ammonia, v / v) and acetonitrile (acetonitrile volume percentage 57%), a flow rate of 25mL / min, and a detection wavelength of 214 / 254nm; preferably, under these conditions, the retention time of the compound that elutes later is 8.95 minutes.

[0706] The compound that elutes first under the following conditions: a C18 OBD column (19*250mm*5μm), a mobile phase of water (0.1% ammonia, v / v) and acetonitrile, with acetonitrile comprising 46-56% by volume, a flow rate of 25mL / min, and a detection wavelength of 214 / 254nm; preferably, under these conditions, the retention time of the compound that elutes first is 5.66 minutes.

[0707] The compound that elutes later in the chromatogram is determined under the following conditions: a C18 OBD column (19*250mm*5μm), a mobile phase of water (0.1% ammonia, v / v) and acetonitrile (acetonitrile volume percentage 46-56%), a flow rate of 25mL / min, and a detection wavelength of 214 / 254nm; preferably, under these conditions, the retention time of the compound that elutes later is 8.61 minutes.

[0708] The compound that elutes first under the following conditions: a C18 OBD column (19*250mm*5μm), a mobile phase of water (0.1% ammonia, v / v) and acetonitrile, with acetonitrile comprising 46-56% by volume, a flow rate of 25mL / min, and a detection wavelength of 214 / 254nm; preferably, under these conditions, the retention time of the compound that elutes first is 5.56 minutes.

[0709] The compound that elutes later in the chromatogram is selected under the following conditions: a C18 OBD column (19*250mm*5μm), a mobile phase of water (0.1% ammonia, v / v) and acetonitrile (acetonitrile volume percentage 46-56%), a flow rate of 25mL / min, and a detection wavelength of 214 / 254nm; preferably, under these conditions, the retention time of the compound that elutes later is 8.59 minutes.

[0710] The compound that elutes first under the following conditions: a C18 OBD column (19*250mm*5μm), a mobile phase of water (0.1% ammonia, v / v) and acetonitrile (acetonitrile volume percentage 40-60%), a flow rate of 25mL / min, and a detection wavelength of 214 / 254nm; preferably, under these conditions, the retention time of the compound that elutes first is 5.0 min.

[0711] The compound that elutes later in the chromatogram is selected under the following conditions: a C18 OBD column (19*250mm*5μm), a mobile phase of water (0.1% ammonia, v / v) and acetonitrile (acetonitrile volume percentage 40-60%), a flow rate of 25mL / min, and a detection wavelength of 214 / 254nm; preferably, under these conditions, the retention time of the compound that elutes later is 8.50 min.

[0712] The compound that elutes first under the following conditions: a C18 OBD column (19*250mm*5μm), a mobile phase of water (0.1% ammonia, v / v) and acetonitrile (acetonitrile volume percentage 46-56%), a flow rate of 25mL / min, and a detection wavelength of 214 / 254nm; preferably, under these conditions, the retention time of the compound that elutes first is 5.5 minutes.

[0713] The compound that elutes later in the chromatogram is selected under the following conditions: a C18 OBD column (19*250mm*5μm), a mobile phase of water (0.1% ammonia, v / v) and acetonitrile (acetonitrile volume percentage 46-56%), a flow rate of 25mL / min, and a detection wavelength of 214 / 254nm; preferably, under these conditions, the retention time of the compound that elutes later is 7.0 min.

[0714] The compound that elutes first under the following conditions: a C18 OBD column (19*250mm*5μm), a mobile phase of water (0.1% ammonia, v / v) and acetonitrile (acetonitrile volume percentage 45-55%), a flow rate of 25mL / min, and a detection wavelength of 214 / 254nm; preferably, under these conditions, the retention time of the compound that elutes first is 7.27 minutes.

[0715] The compound that elutes later in the chromatogram is selected under the following conditions: a C18 OBD column (19*250mm*5μm), a mobile phase of water (0.1% ammonia, v / v) and acetonitrile (acetonitrile volume percentage 45-55%), a flow rate of 25mL / min, and a detection wavelength of 214 / 254nm; preferably, under these conditions, the retention time of the compound that elutes later is 8.83 minutes.

[0716] The compound that elutes first under the following conditions: a C18 OBD column (19*250mm*5μm), a mobile phase of water (0.1% ammonia, v / v) and acetonitrile (acetonitrile volume percentage 65-80%), a flow rate of 25mL / min, and a detection wavelength of 214 / 254nm; preferably, under these conditions, the retention time of the compound that elutes first is 5.5 minutes.

[0717] The compound that elutes later in the chromatogram is selected under the following conditions: a C18 OBD column (19*250mm*5μm), a mobile phase of water (0.1% ammonia, v / v) and acetonitrile (acetonitrile volume percentage 65-80%), a flow rate of 25mL / min, and a detection wavelength of 214 / 254nm; preferably, under these conditions, the retention time of the compound that elutes later is 8.5 minutes.

[0718] The compound that elutes first under the following conditions: a C18 OBD column (19*250mm*5μm), a mobile phase of water (0.1% ammonia, v / v) and acetonitrile (acetonitrile volume percentage 53%), a flow rate of 25mL / min, and a detection wavelength of 214 / 254nm; preferably, under these conditions, the retention time of the compound that elutes first is 7.6 minutes.

[0719] The compound that elutes later in the chromatogram is determined under the following conditions: a C18 OBD column (19*250mm*5μm), a mobile phase of water (0.1% ammonia, v / v) and acetonitrile (acetonitrile volume percentage 53%), a flow rate of 25mL / min, and a detection wavelength of 214 / 254nm; preferably, under these conditions, the retention time of the compound that elutes later is 9.5 minutes.

[0720] The compound that elutes first under the following conditions: a C18 OBD column (19*250mm*5μm), a mobile phase of water (0.1% ammonia, v / v) and acetonitrile (acetonitrile volume percentage 10%), a flow rate of 25mL / min, and a detection wavelength of 214 / 254nm; preferably, under these conditions, the retention time of the compound that elutes first is 7.2 minutes.

[0721] The compound that elutes later in the chromatogram is determined under the following conditions: a C18 OBD column (19*250mm*5μm), a mobile phase of water (0.1% ammonia, v / v) and acetonitrile (acetonitrile volume percentage 10%), a flow rate of 25mL / min, and a detection wavelength of 214 / 254nm; preferably, under these conditions, the retention time of the compound that elutes later is 9.9 minutes.

[0722] The compound that elutes first under the following conditions: a C18 OBD column (19*250mm*5μm), a mobile phase of water (0.1% ammonia, v / v) and acetonitrile (acetonitrile volume percentage 53%), a flow rate of 25mL / min, and a detection wavelength of 214 / 254nm; preferably, under these conditions, the retention time of the compound that elutes first is 7.6 minutes.

[0723] The compound that elutes later in the chromatogram is determined under the following conditions: a C18 OBD column (19*250mm*5μm), a mobile phase of water (0.1% ammonia, v / v) and acetonitrile (acetonitrile volume percentage 53%), a flow rate of 25mL / min, and a detection wavelength of 214 / 254nm; preferably, under these conditions, the retention time of the compound that elutes later is 9.5 minutes.

[0724] The compound that elutes first under the following conditions: a C18 OBD column (19*250mm*5μm), a mobile phase of water (0.1% ammonia, v / v) and acetonitrile (acetonitrile volume percentage 41%), a flow rate of 25mL / min, and a detection wavelength of 214 / 254nm; preferably, under these conditions, the retention time of the compound that elutes first is 7.63 minutes.

[0725] The compound that elutes later in the chromatogram is determined under the following conditions: a C18 OBD column (19*250mm*5μm), a mobile phase of water (0.1% ammonia, v / v) and acetonitrile (acetonitrile volume percentage 41%), a flow rate of 25mL / min, and a detection wavelength of 214 / 254nm; preferably, under these conditions, the retention time of the compound that elutes later is 8.3 minutes.

[0726] The compound that elutes first under the following conditions: a C18 OBD column (19*250mm*5μm), a mobile phase of water (0.1% ammonia, v / v) and acetonitrile (acetonitrile volume percentage 45-55%), a flow rate of 25mL / min, and a detection wavelength of 214 / 254nm; preferably, under these conditions, the retention time of the compound that elutes first is 6.08 minutes.

[0727] The compound that elutes later in the chromatogram is selected under the following conditions: a C18 OBD column (19*250mm*5μm), a mobile phase of water (0.1% ammonia, v / v) and acetonitrile (acetonitrile volume percentage 45-55%), a flow rate of 25mL / min, and a detection wavelength of 214 / 254nm; preferably, under these conditions, the retention time of the compound that elutes later is 8.58 minutes.

[0728] The compound that elutes first under the following conditions: a C18 OBD column (19*250mm*5μm), a mobile phase of water (0.1% ammonia, v / v) and acetonitrile, with an acetonitrile volume percentage of 38-62%, a flow rate of 25mL / min, and a detection wavelength of 214 / 254nm; preferably, under these conditions, the retention time of the compound that elutes first is 7.5 minutes.

[0729] The compound that elutes later in the chromatogram is selected under the following conditions: a C18 OBD column (19*250mm*5μm), a mobile phase of water (0.1% ammonia, v / v) and acetonitrile (acetonitrile volume percentage 38-62%), a flow rate of 25mL / min, and a detection wavelength of 214 / 254nm; preferably, under these conditions, the retention time of the compound that elutes later is 11.2 minutes.

[0730] The compound that elutes first under the following conditions: a C18 OBD column (19*250mm*5μm), a mobile phase of water (0.1% ammonia, v / v) and acetonitrile (acetonitrile volume percentage 51%), a flow rate of 25mL / min, and a detection wavelength of 214 / 254nm; preferably, under these conditions, the retention time of the compound that elutes first is 5.57 minutes.

[0731] The compound that elutes later in the chromatogram is determined under the following conditions: a C18 OBD column (19*250mm*5μm), a mobile phase of water (0.1% ammonia, v / v) and acetonitrile (acetonitrile volume percentage 51%), a flow rate of 25mL / min, and a detection wavelength of 214 / 254nm; preferably, under these conditions, the retention time of the compound that elutes later is 7.53 minutes.

[0732] The compound that elutes first under the following conditions: a C18 OBD column (19*250mm*5μm), a mobile phase of water (0.1% ammonia, v / v) and acetonitrile (acetonitrile volume percentage 10%), a flow rate of 25mL / min, and a detection wavelength of 214 / 254nm; preferably, under these conditions, the retention time of the compound that elutes first is 5.9 minutes.

[0733] The compound that elutes later in the chromatogram is determined under the following conditions: a C18 OBD column (19*250mm*5μm), a mobile phase of water (0.1% ammonia, v / v) and acetonitrile (acetonitrile volume percentage 10%), a flow rate of 25mL / min, and a detection wavelength of 214 / 254nm; preferably, under these conditions, the retention time of the compound that elutes later is 7.3 minutes.

[0734] The compound that elutes first under the following conditions: a C18 OBD column (19*250mm*5μm), a mobile phase of water (0.1% formic acid, v / v) and acetonitrile (acetonitrile volume percentage 15%), a flow rate of 25mL / min, and a detection wavelength of 214 / 254nm; preferably, under these conditions, the retention time of the compound that elutes first is 6.5 minutes.

[0735] The compound that elutes later in the chromatogram is determined under the following conditions: a C18 OBD column (19*250mm*5μm), a mobile phase of water (0.1% formic acid, v / v) and acetonitrile (acetonitrile volume percentage 15%), a flow rate of 25mL / min, and a detection wavelength of 214 / 254nm; preferably, under these conditions, the retention time of the compound that elutes later is 7.6 minutes.

[0736] The compound that elutes first under the following conditions: a C18 OBD column (19*250mm*5μm), a mobile phase of water (0.1% formic acid, v / v) and acetonitrile (acetonitrile volume percentage 15%), a flow rate of 25mL / min, and a detection wavelength of 214 / 254nm; preferably, under these conditions, the retention time of the compound that elutes first is 6.0 min.

[0737] The compound that elutes later in the chromatogram is determined under the following conditions: a C18 OBD column (19*250mm*5μm), a mobile phase of water (0.1% formic acid, v / v) and acetonitrile (acetonitrile volume percentage 15%), a flow rate of 25mL / min, and a detection wavelength of 214 / 254nm; preferably, under these conditions, the retention time of the compound that elutes later is 7.8 minutes.

[0738] The compound that elutes first under the following conditions: a C18 OBD column (19*250mm*5μm), a mobile phase of water (0.1% ammonia, v / v) and acetonitrile (acetonitrile volume percentage 46-56%), a flow rate of 25mL / min, and a detection wavelength of 214 / 254nm; preferably, under these conditions, the retention time of the compound that elutes first is 4.6 minutes.

[0739] The compound that elutes later in the chromatogram is selected under the following conditions: a C18 OBD column (19*250mm*5μm), a mobile phase of water (0.1% ammonia, v / v) and acetonitrile (acetonitrile volume percentage 46-56%), a flow rate of 25mL / min, and a detection wavelength of 214 / 254nm; preferably, under these conditions, the retention time of the compound that elutes later is 6.1 minutes.

[0740] The compound that elutes first under the following conditions: a C18 OBD column (19*250mm*5μm), a mobile phase of water (0.1% ammonia, v / v) and acetonitrile (acetonitrile volume percentage 45-55%), a flow rate of 25mL / min, and a detection wavelength of 214 / 254nm; preferably, under these conditions, the retention time of the compound that elutes first is 5.3 minutes.

[0741] The compound that elutes later in the chromatogram is selected under the following conditions: a C18 OBD column (19*250mm*5μm), a mobile phase of water (0.1% ammonia, v / v) and acetonitrile (acetonitrile volume percentage 45-55%), a flow rate of 25mL / min, and a detection wavelength of 214 / 254nm; preferably, under these conditions, the retention time of the compound that elutes later is 6.5 minutes.

[0742] The compound that elutes first under the following conditions: a C18 OBD column (19*250mm*5μm), a mobile phase of water (0.1% ammonia, v / v) and acetonitrile (acetonitrile volume percentage 46-56%), a flow rate of 25mL / min, and a detection wavelength of 214 / 254nm; preferably, under these conditions, the retention time of the compound that elutes first is 6.47 minutes.

[0743] The compound that elutes later in the chromatogram is selected under the following conditions: a C18 OBD column (19*250mm*5μm), a mobile phase of water (0.1% ammonia, v / v) and acetonitrile (acetonitrile volume percentage 46-56%), a flow rate of 25mL / min, and a detection wavelength of 214 / 254nm; preferably, under these conditions, the retention time of the compound that elutes later is 7.81 minutes.

[0744] The compound that elutes first under the following conditions: a C18 OBD column (19*250mm*5μm), a mobile phase of water (0.1% ammonia, v / v) and acetonitrile (acetonitrile volume percentage 46-56%), a flow rate of 25mL / min, and a detection wavelength of 214 / 254nm; preferably, under these conditions, the retention time of the compound that elutes first is 6.88 minutes.

[0745] The compound that elutes later in the chromatogram is selected under the following conditions: a C18 OBD column (19*250mm*5μm), a mobile phase of water (0.1% ammonia, v / v) and acetonitrile (acetonitrile volume percentage 46-56%), a flow rate of 25mL / min, and a detection wavelength of 214 / 254nm; preferably, under these conditions, the retention time of the compound that elutes later is 7.73 minutes.

[0746] The compound that elutes first under the following conditions: a C18 OBD column (19*250mm*5μm), a mobile phase of water (0.1% ammonia, v / v) and acetonitrile (acetonitrile volume percentage 48-52%), a flow rate of 25mL / min, and a detection wavelength of 214 / 254nm; preferably, under these conditions, the retention time of the compound that elutes first is 7.43 minutes.

[0747] The compound that elutes later in the chromatogram is selected under the following conditions: a C18 OBD column (19*250mm*5μm), a mobile phase of water (0.1% ammonia, v / v) and acetonitrile (acetonitrile volume percentage 48-52%), a flow rate of 25mL / min, and a detection wavelength of 214 / 254nm; preferably, under these conditions, the retention time of the compound that elutes later is 9.83 minutes.

[0748] The compound that elutes first under the following conditions: a C18 OBD column (19*250mm*5μm), a mobile phase of water (0.1% formic acid, v / v) and acetonitrile (acetonitrile volume percentage 30-40%), a flow rate of 25mL / min, and a detection wavelength of 214 / 254nm; preferably, under these conditions, the retention time of the compound that elutes first is 7.03 minutes.

[0749] The compound that elutes later in the chromatogram is selected under the following conditions: a C18 OBD column (19*250mm*5μm), a mobile phase of water (0.1% formic acid, v / v) and acetonitrile (acetonitrile volume percentage 30-40%), a flow rate of 25mL / min, and a detection wavelength of 214 / 254nm; preferably, under these conditions, the retention time of the compound that elutes later is 7.97 minutes.

[0750] The compound that elutes first under the following conditions: a C18 OBD column (19*250mm*5μm), a mobile phase of water (0.1% ammonia, v / v) and acetonitrile (acetonitrile volume percentage 70-70%), a flow rate of 25mL / min, and a detection wavelength of 214 / 254nm; preferably, under these conditions, the retention time of the compound that elutes first is 7.43 minutes.

[0751] The compound that elutes later in the chromatogram is selected under the following conditions: a C18 OBD column (19*250mm*5μm), a mobile phase of water (0.1% ammonia, v / v) and acetonitrile (acetonitrile volume percentage 70-70%), a flow rate of 25mL / min, and a detection wavelength of 214 / 254nm; preferably, under these conditions, the retention time of the compound that elutes later is 9.75 minutes.

[0752] The compound that elutes first under the following conditions: a C18 OBD column (19*250mm*5μm), a mobile phase of water (0.1% ammonia, v / v) and acetonitrile (acetonitrile volume percentage 70-70%), a flow rate of 25mL / min, and a detection wavelength of 214 / 254nm; preferably, under these conditions, the retention time of the compound that elutes first is 7.23 minutes.

[0753] The compound that elutes later in the chromatogram is determined under the following conditions: a C18 OBD column (19*250mm*5μm), a mobile phase of water (0.1% ammonia, v / v) and acetonitrile (acetonitrile volume percentage 70-70%), a flow rate of 25mL / min, and a detection wavelength of 214 / 254nm; preferably, under these conditions, the retention time of the compound that elutes later is 9.32 minutes.

[0754] The compound that elutes first under the following conditions: a C18 OBD column (19*250mm*5μm), a mobile phase of water (0.1% ammonia, v / v) and acetonitrile (acetonitrile volume percentage 57%), a flow rate of 25mL / min, and a detection wavelength of 214 / 254nm; preferably, under these conditions, the retention time of the compound that elutes first is 6.29 minutes.

[0755] The compound that elutes later in the chromatogram is determined under the following conditions: a C18 OBD column (19*250mm*5μm), a mobile phase of water (0.1% ammonia, v / v) and acetonitrile (acetonitrile volume percentage 57%), a flow rate of 25mL / min, and a detection wavelength of 214 / 254nm; preferably, under these conditions, the retention time of the compound that elutes later is 7.83 minutes.

[0756] The compound that elutes first under the following conditions: a C18 OBD column (19*250mm*5μm), a mobile phase of water (0.1% ammonia, v / v) and acetonitrile (acetonitrile volume percentage 70-70%), a flow rate of 25mL / min, and a detection wavelength of 214 / 254nm; preferably, under these conditions, the retention time of the compound that elutes first is 7.98 minutes.

[0757] The compound that elutes later in the chromatogram is selected under the following conditions: a C18 OBD column (19*250mm*5μm), a mobile phase of water (0.1% ammonia, v / v) and acetonitrile (acetonitrile volume percentage 70-70%), a flow rate of 25mL / min, and a detection wavelength of 214 / 254nm; preferably, under these conditions, the retention time of the compound that elutes later is 10.25 minutes.

[0758] The present invention also provides a pharmaceutical composition comprising a compound of Formula I as described above, its stereoisomers or pharmaceutically acceptable salts thereof, and pharmaceutical excipients. The compound of Formula I, its stereoisomers or pharmaceutically acceptable salts thereof may be in a therapeutically effective amount.

[0759] The present invention also provides the use of a compound of Formula I as described above, its stereoisomers or pharmaceutically acceptable salts thereof, or a pharmaceutical composition as described above in the preparation of a medicament for treating and / or preventing KRAS-mediated diseases. The KRAS-mediated diseases are preferably cancer.

[0760] The present invention also provides the use of a compound of Formula I as described above, its stereoisomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described above in the preparation of a medicament for treating and / or preventing cancer.

[0761] The present invention also provides the use of a compound of Formula I as described above, its stereoisomers or pharmaceutically acceptable salts thereof, or a pharmaceutical composition as described above in the preparation of a KRAS inhibitor. In the described application, the KRAS inhibitor can be used in mammalian organisms; it can also be used in vitro, primarily for experimental purposes, such as providing a standard or control sample for comparison, or preparing a kit according to conventional methods in the art to provide rapid detection of the effect of KRAS inhibition.

[0762] The present invention also provides a method for inhibiting KRAS, comprising administering to a patient a therapeutically effective amount of a compound of Formula I as described above, its stereoisomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described above.

[0763] 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 as described above, its stereoisomers or pharmaceutically acceptable salts thereof, or a pharmaceutical composition as described above. The KRAS-mediated disease is preferably cancer.

[0764] The present invention also provides a method for treating and / or preventing cancer, comprising administering to a patient a therapeutically effective amount of a compound of Formula I as described above, its stereoisomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described above.

[0765] As mentioned above, KRAS can be mutated, such as KRAS G12C, KRAS G12D, KRAS G12V, KRAS G12A, KRAS G12R, KRAS G12S, KRAS G13C, KRAS G13D, KRAS Q61H, KRAS Q61K or KRAS Q61R mutations, and for example KRAS G12C, KRAS G12D or KRAS G12V mutations.

[0766] As described above, cancer can be associated with at least one of the following mutations: KRAS G12C, KRAS G12D, KRAS G12V, KRAS G12A, KRAS G12R, KRAS G12S, KRAS G13C, KRAS G13D, KRAS Q61H, KRAS Q61K, and KRAS Q61R, particularly with at least one of the following mutations: KRAS G12C, KRAS G12D, and KRAS G12V.

[0767] As described above, the cancer may be 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.

[0768] In some embodiments of the present invention, the lung cancer is non-small cell lung cancer or small cell lung cancer, preferably non-small cell lung cancer.

[0769] In some embodiments of the present invention, the colorectal cancer may be colon cancer or rectal cancer.

[0770] Unless otherwise specified, the following terms have the meanings shown below.

[0771] Certain chemical groups defined in this document are preceded by simplified symbols to indicate the total number of carbon atoms present in the group. For example, C1-C6 alkyl or C 1-6 Alkyl refers to an alkyl group having a total of 1, 2, 3, 4, 5 or 6 carbon atoms as defined below.

[0772] In this paper, the numerical ranges defined in the substituents, such as 0 to 10, 1-6, 1-3, etc., indicate integers within that range. For example, 1-6 means 1, 2, 3, 4, 5, or 6.

[0773] The term "comprising" is an open-ended expression, meaning it includes the contents specified in this invention, but does not exclude other aspects.

[0774] 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.

[0775] 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. For example... R represents 4 The substitution site can be on the thiophene ring (e.g. It can also be applied to cyclopentane (e.g.) ).

[0776] Those skilled in the art will understand that, according to conventions used in the art, the structural formulas of the groups described in this invention are... This refers to the fact that the corresponding group R is linked to other fragments or groups in the compound through this site.

[0777] The terms “part,” “structural unit,” “group,” and “chemical group” used in this article refer to specific segments or functional groups in a molecule.

[0778] 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.

[0779] 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".

[0780] The term "multiple" refers to 2, 3, 4, or 5.

[0781] When the term "one or more" is used to define the number of a certain group, it means 1, 2, 3, 4 or more.

[0782] When the term "one or more" is used to define the number of heteroatom species, it refers to one, two, or three.

[0783] 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.

[0784] Unless otherwise specified, use wedge-shaped solid line keys. and wedge-shaped dashed key The absolute configuration representing the center of a solid.

[0785] In this invention, the asterisk (*) next to a carbon atom in the chemical structural formula indicates that the carbon atom at that position has an R configuration, an S configuration, or a mixture of both.

[0786] The term "stereoisomer" includes conformational isomers and configurational isomers, wherein configurational isomers mainly include cis-trans isomers and optical isomers. The compounds described in this invention can exist in stereoisomer form, and therefore encompass all possible stereoisomer forms, including but not limited to cis-trans isomers, enantiomers, diastereomers, and transisomers. The compounds described in this invention can also exist in any combination or mixture of the aforementioned stereoisomers, such as equal mixtures of meso, racemic, and transisomers, or, for example, a single enantiomer, a single diastereomer or a mixture of more than one, or a single transisomer or a mixture thereof.

[0787] "Halogens" refer to F, Cl, Br, and I.

[0788] 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.

[0789] In this invention, the term "-O-C1-C6 alkyl" 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 including but not limited to -O-methyl, -O-ethyl, -O-n-propyl, -O-isopropyl, -O-n-butyl, -O-tert-butyl, -O-isobutyl, or -O-sec-butyl.

[0790] In this invention, the term "alkenyl" refers to a straight-chain or branched hydrocarbon chain group having at least one double bond, consisting only of carbon and hydrogen atoms, having, for example, 2 to 12 (preferably 2 to 8, more preferably 2 to 6, most preferably 2 to 4) carbon atoms, and connected to the rest of the molecule by single bonds, such as including but not limited to vinyl, 1-propenyl, n-allyl, but-1-enyl, but-2-enyl, pent-1-enyl, or pent-1,4-dienyl, etc.

[0791] The term "alkynyl" refers to a straight-chain or branched hydrocarbon chain group having at least one triple bond, consisting only of carbon and hydrogen atoms, having, for example, 2 to 12 (preferably 2 to 8, more preferably 2 to 6, most preferably 2 to 4) carbon atoms, and being connected to the rest of the molecule by single bonds, such as including but not limited to ethynyl, 1-propynyl, n-propynyl, but-1-alkynyl, but-2-alkynyl, pent-1-alkynyl, or pent-1,4-dialkynyl.

[0792] The term "oxo" refers to =O, where an oxygen atom replaces two hydrogen atoms on the same atom. For example, methylene (-(CH2-)) becomes carbonyl (-C(=O)-) after being oxidized.

[0793] The term "cycloalkyl" refers to a ring with a specified number of carbon atoms (e.g., C3-C6, C3-C4, C8-C9, C3-C8, C7-C6). 15 Or C3-C 12 Cycloalkyl groups are saturated monocyclic or polycyclic (spirocyclic, bridged, or fused) cyclic groups whose ring atoms consist only of carbon atoms; the polycyclic group may be bicyclic or tricyclic. Cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0794] 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. The cycloalkenyl group can form a spirocycle with other parts of the compound. When a spirocycle is formed, exemplary structures of the cycloalkenyl group include, but are not limited to, those shown below.

[0795] In this invention, the term "heterocyclic alkyl" refers to a saturated monovalent group having a specified number of ring atoms (e.g., 3-12, 3-10, 4-6, 7-10, 7-15), a specified number of heteroatoms (e.g., 1, 2, 3, 4, or 5), a specified type of heteroatom (one, two, or more of N, O, and S), and being monocyclic or polycyclic (e.g., 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. Exemplary 4-membered heterocyclic alkyl groups include, but are not limited to, oxocyclic butyl or azacyclic butyl. Exemplary 5-membered heterocyclic alkyl groups include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, and pyrrolidinyl. Isoxazolidinyl Or its isomers and stereoisomers. Exemplary 6-membered heterocyclic alkyl groups include, but are not limited to, piperidinyl, tetrahydropyranyl, sulfide cyclopentyl, morpholinyl, thiomorpholinyl, dithiaalkyl, dioxyl, piperazine, triazinealkyl, etc. Or its isomers and stereoisomers. Exemplary 7-membered heterocyclic alkyl groups include, but are not limited to, Or its isomers and stereoisomers. Exemplary 8-membered heterocyclic alkyl groups include, but are not limited to, (For example ), Or its isomers and stereoisomers. Exemplary 9-membered heterocyclic alkyl groups include, but are not limited to, those shown below. Exemplary 10-membered heterocyclic alkyl groups include, but are not limited to, Exemplary 11-membered heterocyclic alkyl groups include, but are not limited to,

[0796] In this invention, the term "heterocyclic alkenyl" refers to a cyclic, unsaturated group having a specified number of ring atoms (e.g., 3-10, 3-6, 7-15, or 8-0), 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 linked 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, 5,6-dihydro-4H-cyclopentano[b]thiopheneyl, 4,5,6,7-tetrahydrobenzo[b]thiopheneyl, etc. The heterocyclic alkenyl group can form a spirocycle with other parts of the compound. When a spirocycle is formed, exemplary structures of the heterocyclic alkenyl group include, but are not limited to, those shown below.

[0797] 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. Examples of aryl include, but are not limited to, phenyl or naphthyl.

[0798] In this invention, the term "heteroaryl" refers to a cyclic, unsaturated monovalent group having a specified number of ring atoms (e.g., 5-membered, 5-10-membered, 5-6-membered, 9-10-membered), 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 at least one bond, and at least one ring is aromatic. A heteroaryl group can be attached to the rest of the molecule via a carbon atom or a heteroatom. A heteroaryl group can be attached to the rest of the molecule via a ring with heteroatoms or a ring without heteroatoms. A heteroaryl group can be attached to the rest of the molecule via an aromatic ring. Examples of heteroaryl groups include, but are not limited to, thienyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, indazole, 1H-pyrazolo[4,3-c]pyridyl, 1H-imidazo[4,5-c]pyridyl, 1H-pyrazolo[3,4-c]pyridyl, and pyridyl (e.g.) ), pyrimidinyl, pyrazinyl, quinazolinyl, benzoxazole, benzoisoazole, triazolyl, pyridazinyl.

[0799] 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).

[0800] 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. Pharmaceutically acceptable acids include 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.

[0801] 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).

[0802] 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.

[0803] The term "prevention" refers to the reduction of the risk of acquiring or developing a disease or disorder.

[0804] 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.

[0805] Based on common knowledge in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[0806] The reagents and raw materials used in this invention are all commercially available.

[0807] The positive and progressive effects of this invention are as follows: the nitrogen-containing heterocyclic compounds provided by this invention have proliferative inhibitory activity against at least one of NCI-H358, Capan-1 and AsPC-1 cancer cells containing KRAS mutations, while their proliferative inhibitory activity against KRAS wild-type PC-9 cells is relatively weak, exhibiting good selectivity and showing promise for treating and / or preventing KRAS-mediated diseases. Detailed Implementation

[0808] 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.

[0809] I. Examples of Compound Preparation of the Invention

[0810] The structures of the compounds of this invention were determined by nuclear magnetic resonance (NMR) and / or liquid chromatography-mass spectrometry (LCMS). NMR chemical shifts (δ) are given in parts per million (ppm). NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer, with deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), or deuterated methanol (CD3OD) as the solvent, and tetramethylsilane (TMS) as the internal standard. LCMS measurements were performed using an Agilent 6410 Triple Quad LC / MS instrument.

[0811] The compounds of this invention, when purified by preparative high-performance liquid chromatography, have the following separation conditions:

[0812] Pillar: C18 OBD TM 19*250mm*5μm, flow rate 25mL / min. Mobile phase: [A: water (0.1% ammonia, v / v) B: acetonitrile] or [A: water (0.1% formic acid, v / v) B: acetonitrile]; Mobile phase B%: isocratic or gradient elution; Detection wavelength: 214 / 254nm.

[0813] In this invention, room temperature refers to ambient temperature, typically 10-35°C; overnight refers to 8-16 hours. Reflux refers to the solvent reflux temperature under normal pressure.

[0814] The abbreviations in this application are as follows:

[0815] PMB: p-methoxybenzyl; Boc: tert-butyloxycarbonyl; EA: ethyl acetate; SEM: (trimethylsilyl)ethoxymethyl; THF: tetrahydrofuran; TBDPS: tert-butyldiphenylsilyl; Ts: p-toluenesulfonyl; TBS: tert-butyldimethylsilyl.

[0816] Intermediate preparation examples

[0817] Intermediate A1: (1R)-1-(3-{bis[(4-methoxyphenyl)methyl]amino}pyrazin-2-yl)ethyl-1-amine

[0818] Step 1: 1-(3-{bis[(4-methoxyphenyl)methyl]amino}pyrazin-2-yl)ethyl-1-one

[0819] 1-(3-chloropyrazin-2-yl)ethyl-1-one (5 g, 31.93 mmol) and bis[(4-methoxyphenyl)methyl]amine (12.33 g, 47.90 mmol) were dissolved in dimethyl sulfoxide (50 mL), and N,N-diisopropylethylamine (17 mL, 97.59 mmol) was added. The reaction was stirred at 80 °C for 4 hours. The reaction mixture was diluted with ethyl acetate (300 mL), then washed once with water (150 mL), twice with 10% citric acid (150 mL), and once with saturated brine (150 mL). The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated to give the product (12 g, 31.79 mmol, 99.59%) as a brown oil. ESI-MS m / z: 378.1 [M+1] + .

[0820] Step 2: 1-(3-{bis[(4-methoxyphenyl)methyl]amino}pyrazin-2-yl)-N-[(S)-(2-methylpropyl-2-yl)(oxonyl)-λ 4 [-thio]ethaneimine

[0821] 1-(3-{bis[(4-methoxyphenyl)methyl]amino}pyrazin-2-yl)ethyl-1-one (12 g, 31.79 mmol) and S-tert-butylsulfinamide (11.56 g, 95.37 mmol) were dissolved in tetrahydrofuran (20 mL), and tetraethyl titanate (21.76 g, 95.38 mmol) was added. The system was protected with argon and stirred at 85 °C for 8 hours. The reaction was monitored to be essentially complete. The reaction mixture was poured into saturated brine (500 mL). The mixture was filtered, and the filter cake was washed with ethyl acetate (500 mL). The aqueous phase was extracted again with ethyl acetate (200 mL), and the ethyl acetate phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (ethyl acetate-petroleum ether, 0-20% gradient elution) to give the product (12.19 g, 25.36 mmol, 79.78%) as a brown oil. ESI-MS m / z: 481.2 [M+1] + ; 1 H NMR(400MHz, CDCl3)δ8.16(d,J=2.3Hz,1H),7.91(d,J=2.2Hz,1H),7.11-7.03(m, 4H),6.84-6.78(m,4H),4.76-4.66(m,4H),3.78(s,6H),2.45(s,3H),1.23(s,9H).

[0822] Step 3: 3-{bis[(4-methoxyphenyl)methyl]amino}-2-[(1R)-1-{[(2-methylpropyl-2-yl)(oxoyl)-λ 4 [-thio]amino}ethyl]pyrazine

[0823] 1-(3-{bis[(4-methoxyphenyl)methyl]amino}pyrazin-2-yl)-N-[(S)-(2-methylpropyl-2-yl)(oxo-ylidene)-λ 4 [-Thio]ethaneimine (5 g, 10.40 mmol) was dissolved in tetrahydrofuran (50 mL) under argon protection and cooled to -70 °C. A solution of tri-sec-butylborohydride in tetrahydrofuran (30 mL, 30.00 mmol, 1 mol / L) was added dropwise. The reaction was stirred at room temperature for 1.5 h. The reaction mixture was poured into a saturated ammonium chloride solution (100 mL), and the system was extracted twice with ethyl acetate (100 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (methanol-dichloromethane, 0-2% gradient elution) to give the product (1.56 g, 3.23 mmol, 31.08%) as a brown oil. ESI-MS m / z: 483.2 [M+1] + ; 1H NMR (400MHz, DMSO-d6) δ8.24(d,J=2.4Hz,1H),8.16(d,J=2.5Hz,1H),7.21-7.12(m,4H),6.88-6.80(m,4H),5.30(d,J=7.9Hz,1H),5.09 -4.99(m,1H),4.24(s,4H),3.71(s,6H),1.44(d,J=6.5Hz,3H),0.97(s,9H).

[0824] Step 4: (1R)-1-(3-{bis[(4-methoxyphenyl)methyl]amino}pyrazin-2-yl)ethyl-1-amine

[0825] 3-{bis[(4-methoxyphenyl)methyl]amino}-2-[(1R)-1-{[(2-methylpropyl-2-yl)(oxo-ylidene)-λ 4 [Thio]amino]ethyl]pyrazine (1.42 g, 2.94 mmol) was dissolved in a mixed solvent of THF (10 mL) and water (1 mL), and elemental iodine (0.15 g, 0.59 mmol) was added. The system was protected with argon and stirred at 50 °C for 3 hours. The reaction was monitored for completeness. The reaction mixture was diluted with ethyl acetate (30 mL), washed with 10% sodium thiosulfate solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (methanol-dichloromethane, 0-3% gradient elution) to give the product (560 mg, 1.48 mmol, 50.45%) as a brown oil. ESI-MS m / z: 379.2 [M+1] + ; 1 H NMR (400MHz, DMSO-d6) δ8.19(d,J=2.5Hz,1H),8.12(d,J=2.5Hz,1H),7.20-7.09(m,4H),6.92-6.77(m,4H ), 4.45 (q, J = 6.5Hz, 1H), 4.29 (q, J = 14.5Hz, 4H), 3.71 (s, 6H), 2.47-2.17 (bs, 2H), 1.25 (d, J = 6.4Hz, 3H).

[0826] Intermediate A2: 5-[(methylamino)methyl]-1-(3,4,5,6-tetrahydro-2H-pyran-2-yl)pyrazole

[0827] Step 1: 2-(3,4,5,6-tetrahydro-2H-pyran-2-yl)pyrazole-3-carboxaldehyde

[0828] 1-(3,4,5,6-tetrahydro-2H-pyran-2-yl)pyrazole (10 g, 65.70 mmol) was dissolved in tetrahydrofuran (50 mL), cooled to -78 °C, and a solution of n-butyllithium (49.277 mL, 78.84 mmol) was added dropwise. The reaction was maintained at this temperature for 90 minutes. Then, a tetrahydrofuran dilution of N,N-dimethylformamide (6.347 mL, 78.84 mmol) was added dropwise, and the reaction was maintained at this temperature for 90 minutes. After the reaction was complete, the reaction mixture was poured into water, and extracted twice with ethyl acetate (50 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product (11 g, 61.04 mmol, 92.90%), a yellowish oil, which was used directly in the next step. ESI-MS m / z: 203.0 [M+23] +

[0829] Step 2: 5-[(methylamino)methyl]-1-(3,4,5,6-tetrahydro-2H-pyran-2-yl)pyrazole

[0830] 2-(3,4,5,6-tetrahydro-2H-pyran-2-yl)pyrazol-3-carboxaldehyde (4 g, 22.20 mmol) was dissolved in methanol (20 mL), and methylamino alcohol solution (10 mL, 225.05 mmol) was added. The mixture was stirred for 1 hour, and sodium borohydride solid (1.01 g, 26.64 mmol) was added in portions, with stirring for 2 hours each time. After the reaction was complete, the reaction solution was poured into water, extracted with dichloromethane, concentrated, and then evaporated to dryness. The extract was then loaded onto a column for purification (methanol-dichloromethane, 0-2% gradient elution) to give the product (3.2 g, 16.39 mmol, 73.83%), a colorless, transparent liquid. ESI-MS m / z: 196.1 [M+1]+. 1 H NMR(400MHz, CDCl3) δ7.49(d,J=1.8Hz,1H),6.22(d,J=1.8Hz,1H),5.47(dd,J=9.7,2.7Hz,1H),4.1 6–4.01(m,1H),3.85(s,2H),3.74–3.63(m,1H),2.46(s,3H),2.17–1.99(m,2H),1.80–1.57(m,4H).

[0831] Intermediate A3: (3R)-3-amino-3-(2-{bis[(4-methoxyphenyl)methyl]amino}pyridin-3-yl)prop-1-ol

[0832] Step 1: 2-{bis[(4-methoxyphenyl)methyl]amino}pyridine-3-carboxaldehyde

[0833] 2-Fluoropyridine-3-carboxaldehyde (20 g, 159.87 mmol), di[(4-methoxyphenyl)methyl]amine (49.37 g, 191.84 mmol), potassium carbonate (66.28 g, 479.62 mmol), and dimethylformamide (300 mL) were added to a 1 L single-necked flask and reacted at 90 °C for 1 h under nitrogen protection. The reaction solution was filtered, and the filtrate was extracted with water (300 mL) and ethyl acetate (300 x 3 mL). The organic phases were combined, evaporated to dryness, stirred, and eluted with a 0-20% gradient of ethyl acetate-petroleum ether to give a yellow oily product (42 g, 115.88 mmol, 72.49%). ESI-MS m / z: 363.2 [M+1] +

[0834] Step 2: (R,Z)-N-((2-(di(4-methoxybenzyl)amino)pyridin-3-yl)methylene)-2-methylpropane-2-sulfinamide

[0835] 2-{bis[(4-methoxyphenyl)methyl]amino}pyridine-3-carboxaldehyde (21 g, 57.94 mmol) was dissolved in tetrahydrofuran (220 mL), and (S)-2-methylpropane-2-sulfinamide (17.56 g, 144.86 mmol) and tetraethyl titanate (26.43 g, 115.88 mmol) were added. The reaction mixture was reacted at 85 °C for 3 hours. The reaction mixture was quenched with water, extracted with ethyl acetate, and purified by silica gel column chromatography (petroleum ether / ethyl acetate, 0-30% gradient elution) to give a colorless oily product (26.2 g, 56.27 mmol, 97.11%). ESI-MS m / z: 466.2 [M+1] +

[0836] Step 3: (R)-Ethyl 3-(2-(di(4-methoxybenzyl)amino)pyridin-3-yl)-3-((R)-1,1-dimethylethylsulfinylamino)propionate

[0837] (R,Z)-N-((2-(di(4-methoxybenzyl)amino)pyridin-3-yl)methylene)-2-methylpropane-2-sulfinamide (26 g, 55.84 mmol) and tetrahydrofuran (250 mL) were added to a 1 L three-necked flask. The mixture was purged with nitrogen three times. Ethyl acetate (4.67 g, 53.05 mmol) was added, followed by the addition of bis(trimethylsilylamino)lithium (94.929 mL, 94.93 mmol) at -78 °C. The reaction was continued for 30 min. A saturated ammonium chloride solution (100 mL) was added at low temperature, followed by extraction with ethyl acetate (100 x 3 mL). The organic phases were combined, evaporated to dryness, stirred, and purified by silica gel column chromatography (ethyl acetate-petroleum ether, 0-100% gradient elution) to give a yellow oily product (25.1 g, 45.33 mmol, 81.18%). ESI-MS m / z: 554.3 [M+1] +

[0838] Step 4: (R)-N-((R)-1-(2-(di(4-methoxybenzyl)amino)pyridin-3-yl)-3-hydroxypropyl)-2-methylpropane-2-sulfinamide

[0839] (R)-ethyl 3-(2-(di(4-methoxybenzyl)amino)pyridin-3-yl)-3-((R)-1,1-dimethylethylsulfinylamino)propionate (50.2 g, 90.66 mmol) and tetrahydrofuran (450 mL) were added to a 1 L three-necked flask. Lithium aluminum hydride (181.319 mL, 181.32 mmol) was added at 0 °C, and the mixture was reacted at 0 °C for 30 min. Water (50 mL) was added at 0 °C, followed by saturated potassium sodium tartrate solution (1500 mL). The mixture was stirred overnight, extracted with ethyl acetate (200 x 3 mL), and the organic phases were combined, evaporated to dryness, mixed, and purified by silica gel column chromatography (ethyl acetate-petroleum ether, 0-100% gradient elution) to obtain a colorless oily product (44.8 g, 93.68%).

[0840] ESI-MS m / z: 512.3 [M+1] +

[0841] Step 5: (R)-3-amino-3-(2-(di(4-methoxybenzyl)amino)pyridin-3-yl)propane-1-ol

[0842] (R)-N-((R)-1-(2-(di(4-methoxybenzyl)amino)pyridin-3-yl)-3-hydroxypropyl)-2-methylpropane-2-sulfinamide (44.8 g, 84.93 mmol) was dissolved in methanol (400 mL), and dioxane hydrochloride solution (0.016 mL) was added at 0 °C. The reaction mixture was allowed to react at room temperature for 2 hours. The reaction mixture was then adjusted to pH 7-8 by adding saturated sodium bicarbonate solution at 0 °C, evaporated to dryness, mixed, and purified by silica gel column chromatography (methanol-dichloromethane, 0-10% gradient elution) to give a white solid (32.6 g, 80.00 mmol, 94.20%). 1 H NMR(400MHz, CDCl3)δ8.32(dd,J=4.7,1.7Hz,1H),8.01(dd,J=7.8,1.8Hz,1H),7.12–7.06(m,4H),6.79–6.72(m,5H),5.08(dd,J=10.3,2.2 Hz,1H),4.12–3.96(m,4H),3.70(s,6H),3.64–3.55(m,1H),3.27(dd,J=10.0,5.9Hz,1H),1.96–1.82(m,1H),0.83(d,J=14.9Hz,1H).ESI-MS m / z: 408.2[M+1] +

[0843] Intermediate A4: N-methyl-1-(pyridazin-3-yl)methylamine

[0844] Step 1: Pyridazine-3-ylmethylmethanesulfonate

[0845] Pyridazine-3-ylmethanol (1 g, 9.08 mmol) was dissolved in dichloromethane (20 mL), and triethylamine (1.893 mL, 13.62 mmol) was added. Methanesulfonyl chloride (1.054 mL, 13.62 mmol) was added at 0 °C, and the mixture was stirred at 20 °C for 1 hour. The reaction solution was quenched with saturated sodium bicarbonate solution (5 mL), separated, and the organic phase was concentrated and directly added to the next step. ESI-MS m / z: 189.0 [M+H] + .

[0846] Step 2: N-methyl-1-(pyridazin-3-yl)methylamine

[0847] Pyridazine-3-ylmethylmethanesulfonate (1 g, 5.31 mmol) was dissolved in methylamine (8.745 mL, 53.13 mmol) ethanol solution and stirred at 15 °C for 1 hour. The solution was concentrated and separated by column chromatography (dichloromethane / methanol = 10:1) to give 400 mg of a brown solid. ESI-MS m / z: 124.1 [M+H] + .

[0848] Intermediate A5: 1-(1-(4-methoxybenzyl)-5-methyl-1H-1,2,4-triazol-3-yl)-N-methylmethylamine

[0849] Step 1: Ethyl 1-(4-methoxybenzyl)-5-methyl-1H-1,2,4-triazole-3-carboxylic acid ester

[0850] Ethyl 5-methyl-1H-1,2,4-triazol-3-carboxylic acid (2 g, 12.89 mmol) was dissolved in N,N-dimethylformamide (20 mL), and cesium carbonate (6.30 g, 19.33 mmol) and 4-methoxybenzyl chloride (2.42 g, 15.47 mmol) were added. The mixture was stirred at 10 °C for 1 hour. The solution was diluted with water (100 mL), extracted with ethyl acetate (50 mL x 2), and the organic phases were combined. The mixture was washed once with saturated brine (30 mL), dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (petroleum ether / ethyl acetate = 1:1) to give 3.2 g of a clear oil (yield: 90%). ESI-MS m / z: 276.1 [M+H] + .

[0851] Step 2: 1-(4-methoxybenzyl)-5-methyl-1H-1,2,4-triazole-3-carboxaldehyde

[0852] Morpholine (1.565 mL, 17.87 mmol) was dissolved in tetrahydrofuran (20 mL). Diisobutylaluminum hydride (17.435 mL, 17.43 mmol) was slowly added dropwise under an argon atmosphere at 0 °C. The mixture was stirred at 0 °C for 30 minutes. A tetrahydrofuran solution of 1-(4-methoxybenzyl)-5-methyl-1H-1,2,4-triazol-3-carboxylic acid ethyl ester (1.2 g, 4.36 mmol) was slowly added, and the mixture was stirred at 0 °C for 10 minutes. The reaction was quenched with 1 M dilute hydrochloric acid (20 mL), and the mixture was stirred for 10 minutes. The mixture was extracted with ethyl acetate (50 mL x 2). The combined organic phases were washed once with saturated brine (30 mL), dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (petroleum ether / ethyl acetate = 1:1) to give 900 mg of a clear oil (yield: 89%). ESI-MS m / z: 232.0 [M+H] + .

[0853] Step 3: 1-(1-(4-methoxybenzyl)-5-methyl-1H-1,2,4-triazol-3-yl)-N-methylmethylamine

[0854] 1-(4-methoxybenzyl)-5-methyl-1H-1,2,4-triazol-3-carboxaldehyde (800 mg, 3.46 mmol) and methylamine (1.139 mL, 6.92 mmol) were dissolved in methanol (10 mL) and stirred at 15 °C for 1 hour. Sodium borohydride (196.31 mg, 5.19 mmol) was added, and the mixture was stirred at 15 °C for 10 minutes. The pH was adjusted to 1 with 1 M dilute hydrochloric acid, stirred, and then adjusted to 9–10 with saturated sodium carbonate solution. The mixture was extracted with dichloromethane (20 mL), the organic phase was concentrated, and separated by column chromatography (DMC:MeOH = 10:1) to give 400 mg of a colorless, transparent oil (yield: 46%). ESI-MS m / z: 247.1 [M+H] + .

[0855] Intermediate A6: (R)-1-(1-(4-methoxybenzyl)-5-methyl-1H-1,2,4-triazol-3-yl)ethylamine

[0856] Step 1: (R)-tert-butyl(1-(5-methyl-1H-1,2,4-triazol-3-yl)ethyl)carbamate

[0857] Sodium hydroxide (147.61 mg, 3.69 mmol) was added to 10 mL of ethanol containing ethyl imide hydrochloride (456.04 mg, 3.69 mmol), and the mixture was stirred for 15 minutes. Then, (R)-tert-butyl(1-hydrazino-1-oxopropane-2-yl)carbamate (500.00 mg, 2.46 mmol) was added, and the mixture was stirred at 100 °C for 5 hours. The mixture was diluted with water (30 mL), extracted with ethyl acetate (20 mL x 3), washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a colorless colloidal product (520 mg). ESI-MS m / z: 227.1 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ13.23(s,1H),7.09(s,1H),4.68-4.60(m,1H),2.27(s,3H),1.38(s,9H),1.33(d,J=7.0Hz,3H).

[0858] Step 2: (R)-tert-butyl(1-(1-(4-methoxybenzyl)-5-methyl-1H-1,2,4-triazol-3-yl)ethyl)carbamate

[0859] At room temperature, p-methoxybenzyl chloride (359.90 mg, 2.30 mmol) was added to N,N-dimethylformamide (10 mL) containing (R)-tert-butyl(1-(5-methyl-1H-1,2,4-triazol-3-yl)ethyl)carbamate (520 mg, 2.30 mmol) and potassium carbonate (952.77 mg, 6.89 mmol). The mixture was stirred at room temperature for 16 hours. The extract was obtained by diluting ethyl acetate (20 mL x 3) with water (30 mL), washing the organic phase with saturated brine (30 mL x 2), drying the organic phase to anhydrous sodium sulfate, filtering, and concentrating under reduced pressure. The residue was then subjected to silica gel column chromatography (dichloromethane / methanol = 100:2, v / v) to give a colorless oily product (750 mg). ESI-MS m / z: 347.2 [M+1] + .1H NMR (400MHz, DMSO-d6) δ7.19–7.13(m,2H),7.04(d,J=8.4Hz,1H),6.91-6.87(m,2H),5.22( d,J=10.3Hz,2H),3.73(s,3H),2.34(s,3H),1.36(d,J=10.9Hz,9H),1.31(d,J=7.0Hz,3H).

[0860] Step 3: (R)-1-(1-(4-methoxybenzyl)-5-methyl-1H-1,2,4-triazol-3-yl)ethylamine

[0861] To a solution of compound (R)-tert-butyl(1-(1-(4-methoxybenzyl)-5-methyl-1H-1,2,4-triazol-3-yl)ethyl)carbamate (720 mg, 2.08 mmol) in dichloromethane (35 mL), trifluoroacetic acid (3.5 mL, 45.71 mmol) was added. The mixture was stirred at room temperature for 1 hour, and the pH was adjusted to alkaline with solid sodium carbonate. The mixture was then filtered, and the organic phase was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 100:4, v / v) to give 470 mg of a colorless oil. ESI-MS m / z: 247.1 [M+1] + . 1H NMR(400MHz,DMSO-d6)δ8.36(s,2H),7.24–7.19(m,2H),6.93(dd,J=8.8,2.3Hz,2H ),5.29(s,2H),4.48-4.38(m,1H),3.74(s,3H),2.45(s,3H),1.48(d,J=6.9Hz,3H).

[0862] Intermediate A7: (R)-4-(1-aminoethyl)-N,N-bis(4-methoxybenzyl)pyridazine-3-amine

[0863] Step 1: 6-Chloro-4-(1-ethoxyvinyl)pyridazine-3-amine

[0864] 3-Amino-4-bromo-6-chloropyridazine (24.9 g, 119.46 mmol), tributyl(1-ethoxyethylene)tin (43.144 mL, 131.40 mmol), lithium chloride (15.19 g, 358.38 mmol), and palladium dichloride (1.68 g, 2.39 mmol) were dissolved in N,N-dimethylformamide (200 mL). The system was protected with argon and stirred at 100 °C for 16 hours. The reaction mixture was monitored for complete reaction. The reaction solution was poured into an aqueous solution of potassium fluoride (10.41 g, 179.19 mmol) (200 mL), and the reaction was stirred at room temperature for 1 hour. Insoluble matter was removed by filtration. The filter cake was washed with ethyl acetate. Extraction was performed, the ethyl acetate phases were combined, washed four times with water (300 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (ethyl acetate-petroleum ether, 0-50% gradient elution) to give the product (18.88 g, 94.57 mmol, 79.16%) as a yellow solid. ESI-MS m / z: 200.0, 202.0 [M+H] + .

[0865] Step 2: 4-(1-ethoxyvinyl)pyridazine-3-amine

[0866] 6-Chloro-4-(1-ethoxyvinyl)pyridazin-3-amine (18.88 g, 94.57 mmol) was dissolved in tetrahydrofuran (200 mL), and N,N,N',N'-tetramethylethylenediamine (21.98 g, 189.14 mmol) and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloromethane dichloride complex (3.87 g, 4.73 mmol) were added. The system was protected with argon, and sodium borohydride (7.16 g, 189.14 mmol) was added last. The reaction was stirred at 60 °C for 60 h. Product formation was monitored. The reaction mixture was poured into water (200 mL) and stirred for 30 min. It was then extracted twice with ethyl acetate (200 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (tetrahydrofuran-petroleum ether, elution from 0-50% gradient). The product was homogenized with a small amount of ethyl acetate. Filtered. A pure product (7.44 g, 45.04 mmol, 47.63%) was obtained as an off-white solid. ESI-MS m / z: 166.1 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ8.47(d,J=4.8Hz,1H),7.25(d,J=4.7Hz,1H),6.24(s,2 H), 4.56 (dd, J=15.5, 2.9Hz, 2H), 3.89 (q, J=6.9Hz, 2H), 1.31 (t, J=7.0Hz, 3H).

[0867] Step 3: 4-(1-ethoxyvinyl)-N,N-bis(4-methoxybenzyl)pyridazine-3-amine

[0868] 4-(1-ethoxyvinyl)pyridazine-3-amine (8.1 g, 49.03 mmol) was dissolved in dimethyl sulfoxide (50 mL), and 4-methoxybenzyl chloride (9.21 g, 58.84 mmol) was added. Finally, sodium tert-butoxide (5.65 g, 58.84 mmol) was added. The reaction was stirred at room temperature for about 1 hour. The reaction was monitored to be essentially complete. The reaction solution was extracted with ethyl acetate (200 mL) and water (200 mL). The ethyl acetate phase was washed four times with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (ethyl acetate-petroleum ether, 0-25% gradient elution) to give the product (6.46 g, 15.93 mmol, 32.49%) as a brown oil. ESI-MS m / z: 406.2 [M+H] + .

[0869] Step 4: 1-(3-(di(4-methoxybenzyl)amino)pyridazin-4-yl)ethyl ketone

[0870] 4-(1-ethoxyvinyl)-N,N-bis(4-methoxybenzyl)pyridazine-3-amine (6.46 g, 15.93 mmol) was dissolved in acetonitrile (50 mL), and dilute hydrochloric acid (2.0 M, 50 mL) was added. The reaction was stirred at room temperature for about 1 hour.

[0871] The formation of a large amount of product was monitored. Saturated sodium carbonate was added to the reaction solution to adjust the pH to 8-9. The mixture was extracted twice with ethyl acetate (100 mL), and the organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (ethyl acetate-petroleum ether, 0-30% gradient elution) to give the product (2.63 g, 6.97 mmol, 43.76%) as a yellow oil. ESI-MS m / z: 378.2 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ8.80(d,J=4.9Hz,1H),7.56(d,J=4.8Hz,1H),7.13-7.03(m,4H),6.89-6.82(m,4H),4.54(s,4H),3.71(s,6H),2.41(s,3H).

[0872] Step 5: (S)-N-(1-(3-(di(4-methoxybenzyl)amino)pyridazine-4-yl)ethylene)-2-methylpropane-2-sulfinamide

[0873] 1-(3-(di(4-methoxybenzyl)amino)pyridazin-4-yl)acetone (4.25 g, 11.26 mmol) was dissolved in tetrahydrofuran (10 mL), and tetraethyl titanate (7.71 g, 33.78 mmol) and S-tert-butylsulfinamide (4.09 g, 33.78 mmol) were added. The system was protected with argon and stirred at 80 °C for 16 hours. The reaction was monitored to be essentially complete. The reaction mixture was poured into saturated brine (100 mL), stirred, filtered, and the filter cake was washed with ethyl acetate (250 mL). Extraction was performed, the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (ethyl acetate-petroleum ether, 0-50% gradient elution) to give the product (5.05 g, 10.51 mmol, 93.35%) as a brown oil. ESI-MS m / z: 481.2 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ8.85(d,J=4.8Hz,1H),7.41(d,J=4.8Hz,1H),7.08(d,J=8.4Hz,4H),6.86(d,J=8.4 Hz, 4H), 4.53 (d, J = 14.9Hz, 2H), 4.43 (d, J = 15.0Hz, 2H), 3.72 (s, 6H), 2.63-2.50 (m, 3H), 1.19-1.09 (m, 9H).

[0874] Step 6: (S)-N-((R)-1-(3-(di(4-methoxybenzyl)amino)pyridazine-4-yl)ethyl)-2-methylpropane-2-sulfinamide

[0875] (S)-N-(1-(3-(di(4-methoxybenzyl)amino)pyridazin-4-yl)ethylidene)-2-methylpropane-2-sulfinamide (5.53 g, 11.51 mmol) was dissolved in tetrahydrofuran (50 mL), the system was protected with argon, and cooled to -60 °C. A solution of tri-sec-butylborohydride in tetrahydrofuran (1.0 M, 35 mL, 35.00 mmol) was slowly added dropwise. The reaction was continued at -60 °C with stirring for 40 min. The temperature was then raised to 0 °C and stirred for another 30 min. The reaction was monitored for completeness. The reaction was quenched with saturated ammonium chloride, followed by extraction with ethyl acetate (100 mL) and saturated brine (100 mL). The ethyl acetate phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (ethyl acetate-petroleum ether, 0-100% gradient elution) to give a product (2.3 g, 4.77 mmol, 41.44%) as a brown oil. ESI-MS m / z: 483.3 [M+H] + . 1 H NMR(400MHz, DMSO-d6)δ8.90(d,J=5.0Hz,1H),7.66(d,J=5.0Hz,1H),7.23-7.16(m,4H),6.88-6.82(m,4H),5.6 7(d,J=5.8Hz,1H),4.95-4.84(m,1H),4.26(q,J=14.3Hz,4H),3.71(s,6H),1.42(d,J=6.7Hz,3H),1.04(s,9H).

[0876] Step 7: (R)-4-(1-aminoethyl)-N,N-bis(4-methoxybenzyl)pyridazine-3-amine

[0877] (S)-N-((R)-1-(3-(di(4-methoxybenzyl)amino)pyridazin-4-yl)ethyl)-2-methylpropane-2-sulfinamide (1.3 g, 2.69 mmol) was dissolved in a mixed solvent of tetrahydrofuran (10 mL) and water (1 mL), and elemental iodine (0.14 g, 0.54 mmol) was added. The system was protected with argon and stirred at 50 °C for 16 hours.

[0878] The reaction mixture was monitored to be essentially complete. It was diluted with ethyl acetate (40 mL), washed with 10% sodium thiosulfate (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (methanol-dichloromethane, 0-5% gradient elution) to obtain a product (800 mg, 2.11 mmol, 78.43%) as a brown oil. ESI-MS m / z: 379.2 [M+H] + ; 1 H NMR(400MHz, DMSO-d6)δ8.84(d,J=5.0Hz,1H),7.71(d,J=5.0Hz,1H),7.20-7.14(m,4H),6.89-6.81( m, 4H), 4.39-4.33 (m, 3H), 4.22 (d, J = 14.3Hz, 2H), 3.71 (s, 6H), 2.15 (bs, 2H), 1.20 (d, J = 6.5Hz, 3H).

[0879] Intermediate A8: (R)-3-(1-aminoethyl)-5-fluoro-N,N-di(4-methoxybenzyl)pyridine-2-amine

[0880] Step 1: 1-(2-(di(4-methoxybenzyl)amino)-5-fluoropyridin-3-yl)ethyl ketone

[0881] 1-(2-chloro-5-fluoropyridin-3-yl)acetone (4.8 g, 27.65 mmol), bis-(4-methoxybenzyl)-amine (7.83 g, 30.42 mmol), and N,N-diisopropylethylamine (7.15 g, 55.31 mmol) were dissolved in N,N-dimethylformamide (10 mL), and the mixture was heated to 120 °C and stirred for 24 hours. The reaction mixture was poured into water, extracted with ethyl acetate, washed with brine, washed twice with 15% citric acid, dried, concentrated, mixed, and column-sected (ethyl acetate-petroleum ether, 0-10% gradient elution) to give the product (1.78 g, 4.51 mmol, 16.32%). ESI-MS m / z: 394.1 [M+H] + .

[0882] Step 2: (S,E)-N-(1-(2-(di(4-methoxybenzyl)amino)-5-fluoropyridin-3-yl)ethylidene)-2-methylpropane-2-sulfinamide

[0883] 1-(2-(di(4-methoxybenzyl)amino)-5-fluoropyridin-3-yl)acetone (1.78 g, 4.51 mmol), S-tert-butylsulfinamide (0.55 g, 4.51 mmol), and tetraethyl titanate (3.09 g, 13.54 mmol) were dissolved in toluene (10 mL), and the mixture was heated to 110 °C and stirred overnight. The reaction solution was poured into water, stirred, filtered through a diatomaceous earth filter, washed with EA, separated into layers, dried, concentrated, mixed, and subjected to column chromatography (ethyl acetate-petroleum ether, 0-20% gradient elution) to give the product (1.77 g, 3.56 mmol, 79.02%), a yellow oil. ESI-MS m / z: 498.1 [M+H] + .

[0884] Step 3: (S)-N-((R)-1-(2-(di(4-methoxybenzyl)amino)-5-fluoropyridin-3-yl)ethyl)-2-methylpropane-2-sulfinamide

[0885] (S,E)-N-(1-(2-(di(4-methoxybenzyl)amino)-5-fluoropyridin-3-yl)ethylidene)-2-methylpropane-2-sulfinamide (1660 mg, 3.34 mmol) was dissolved in tetrahydrofuran (20 mL). Trisec-butylborohydride (10.007 mL, 10.01 mmol) was added dropwise under ice bath conditions. After addition, the mixture was stirred and kept at this temperature for 2 hours. The reaction mixture was quenched by adding water dropwise, extracted with ethyl acetate (EA), concentrated, and loaded onto a column using a wet column chromatography method (ethyl acetate-dichloromethane, 0-10% gradient elution) to give the product (1.3 g, 2.60 mmol, 77.84%) as a yellow oil. ESI-MS m / z: 500.1 [M+H] + .

[0886] Step 4: (R)-3-(1-aminoethyl)-5-fluoro-N,N-bis(4-methoxybenzyl)pyridine-2-amine

[0887] (S)-N-((R)-1-(2-(di(4-methoxybenzyl)amino)-5-fluoropyridin-3-yl)ethyl)-2-methylpropane-2-sulfinamide (1.3 g, 2.60 mmol) was dissolved in tetrahydrofuran (15 mL) and water (1.5 mL), and iodine (0.13 g, 0.52 mmol) was added. The mixture was heated to 50 °C and stirred for 2 hours. The reaction solution was poured into an aqueous sodium sulfite solution, extracted with EA, washed with salt, dried, concentrated, and wet-processed. The solution was then passed through a column (methanol-dichloromethane, 0-1% gradient elution) to obtain the product (0.70 g, 1.77 mmol, 67.96%), a yellow oil. ESI-MS m / z: 396.1 [M+H] + ;1H NMR(400MHz, CDCl3)δ8.23(d,J=3.0Hz,1H),7.39(dd,J=9.0,3.0Hz,1H),7.15–7.10(m,4H), 6.82–6.78(m,4H),4.17–4.02(m,4H),3.85–3.81(m,1H),3.78(s,6H),1.11(d,J=6.7Hz,3H).

[0888] Intermediate A9: (R)-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-7-yl)ethylamine

[0889] Step 1: N-methoxy-N-methyl-1H-indazole-7-carboxamide

[0890] 1H-indazole-7-carboxylic acid (12.55 g, 77.40 mmol) was dissolved in dichloromethane (250 mL), and dimethylhydroxylamine hydrochloride (9.06 g, 92.88 mmol), N,N-diisopropylethylamine (40.446 mL, 232.19 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethylurea hexafluorophosphate (35.32 g, 92.88 mmol) were added. The reaction was stirred at room temperature for 2 hours. The reaction was monitored for completeness. The reaction mixture was diluted with dichloromethane (250 mL), then washed twice with dilute hydrochloric acid (1.0 M, 250 mL), and once with saturated brine (250 mL). The dichloromethane phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (ethyl acetate-petroleum ether, 0-50% gradient elution) to give a product (15.2 g, 74.07 mmol, 95.70%) as a pale yellow oil-solid mixture. ESI-MS m / z: 206.2 [M+H] + ; 1H NMR (400MHz, CDCl3) δ8.16(dd,J=7.5,0.9Hz,1H),8.14(s,1H),7.93(dd,J=8.0,1.0Hz,1H),7.21(t,J=7.7Hz,1H),3.69(s,3H),3.50(s,3H).

[0891] Step 2: N-methoxy-N-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-7-carboxamide

[0892] N-methoxy-N-methyl-1H-indazole-7-carboxamide (3 g, 14.62 mmol) was dissolved in N,N-dimethylformamide (20 mL). The system was protected with argon and cooled in an ice bath. Sodium hydride (0.88 g, 21.93 mmol) was added. The reaction was stirred in an ice bath for 30 minutes. 2-(trimethylsilyl)ethoxymethyl chloride (2.92 g, 17.54 mmol) was added dropwise. The reaction was stirred in an ice bath for 30 minutes. The reaction was monitored for completeness. The reaction was quenched with saturated ammonium chloride, followed by extraction with ethyl acetate (100 mL) and saturated brine (50 mL). The ethyl acetate phase was washed three times with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (ethyl acetate-petroleum ether, 0-100% gradient elution) to give the product (3.1 g, 9.24 mmol, 63.21%) as a colorless, transparent oil. ESI-MS m / z: 693.2 [2M+Na] + ; 1 H NMR (400MHz, CDCl3) δ8.05(s,1H),7.82(dd,J=8.0,1.1Hz,1H),7.46(s,1H),7.21(dd,J=8.1,7.1Hz,1H),5.81(s,2H),3.58-3.09(m,8H),0.92 -0.70(m,2H),0.00(s,9H).

[0893] Step 3: 1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-7-yl)acetone

[0894] N-methoxy-N-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-7-carboxamide (500 mg, 1.49 mmol) was dissolved in tetrahydrofuran (5 mL) under argon protection and cooled in an ice bath. A tetrahydrofuran solution of methyl magnesium bromide (1.0 M, 4 mL, 4.00 mmol) was added dropwise. The reaction was stirred at room temperature for 16 hours. The reaction was quenched with saturated ammonium chloride, followed by extraction with ethyl acetate (20 mL) and water (20 mL). The ethyl acetate phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (ethyl acetate-petroleum ether, 0-25% gradient elution) to give the product (178 mg, 0.61 mmol, 41.13%) as a colorless oil. 1 H NMR (400MHz, CDCl3) δ8.10(s,1H),7.94(dd,J=8.0,1.1Hz,1H),7.78(dd,J=7.2,1.1Hz,1H),7.26(d d,J=8.0,7.2Hz,1H),5.94(s,2H),3.26-3.18(m,2H),2.73(s,3H),0.79-0.68(m,2H),0.00(s,9H).

[0895] Step 4: (S)-2-methyl-N-(1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-7-yl)ethylene)propane-2-sulfinamide

[0896] 1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-7-yl)acetone (3.8 g, 13.08 mmol) was dissolved in toluene (8 mL). (S)-(-)-tert-butylsulfinamide (3.17 g, 26.17 mmol) and tetraethyl titanate (8.95 g, 39.25 mmol) were added. The system was protected with argon and stirred at 110 °C for 20 hours. The reaction mixture was poured into saturated brine (200 mL), and the insoluble matter was removed by filtration. The filter cake was washed twice with ethyl acetate (100 mL), extracted, and the ethyl acetate phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (ethyl acetate-petroleum ether, 0-30% gradient elution) to give the product (4 g, 10.16 mmol, 77.69%) as a brown oil. 1HNMR(400MHz, CDCl3)δ8.08(s,1H),7.82(dd,J=8.1,1.1Hz,1H),7.40(dd,J=7.2,1.1Hz,1H),7.25-7.21 (m,1H),5.88-5.77(m,2H),3.36-3.21(m,2H),2.87(s,3H),1.28(s,9H),0.85-0.72(m,2H),0.00(s,9H).

[0897] Step 5: (S)-2-methyl-N-((R)-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-7-yl)ethyl)propane-2-sulfinamide

[0898] (S)-2-methyl-N-(1-(1-(((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-7-yl)ethylidene)propane-2-sulfinamide (3.5 g, 8.89 mmol) was dissolved in tetrahydrofuran (50 mL). The system was cooled to -60 °C under nitrogen protection, and a tetrahydrofuran solution of tri-sec-butylborohydride (1.0 M, 26 mL, 26.00 mmol) was added dropwise. The reaction was stirred at -60 °C for 2 h, then at room temperature for 2 h. The starting material was monitored to be substantially completely converted. The reaction was quenched with saturated ammonium chloride, followed by extraction with ethyl acetate and saturated brine. The ethyl acetate phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (ethyl acetate-petroleum ether, 0-75% gradient elution) to give the product (3.03 g, 7.66 mmol, 86.13%) as a colorless, transparent oil. ESI-MS m / z: 395.9 [M+H] + . 1 H NMR (400MHz, CDCl3) δ8.02 (d, J = 1.7Hz, 1H), 7.72-7.70 (m, 1H), 7.61-7.50 (m, 1H), 7.25-7.20 (m, 1H), 6.11 (dd, J = 28.3, 11.7Hz, 1H), 5.79-5. 74(m,1H),5.49-5.38(m,1H),3.74-3.42(m,3H),1.74(dd,J=6.6,4.0Hz,3H),1.19(d,J=9.8Hz,9H),0.94-0.80(m,2H),0.00(d,J=4.1Hz,9H).

[0899] Step 6: (R)-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-7-yl)ethylamine

[0900] (S)-2-methyl-N-((R)-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-7-yl)ethyl)propane-2-sulfinamide (3.03 g, 7.66 mmol) was dissolved in a mixed solvent of tetrahydrofuran (30 mL) and water (6 mL). Iodine (0.78 g, 3.06 mmol) was added. The reaction was stirred at 50 °C for about 4 hours. The starting material was monitored for complete conversion. The reaction mixture was diluted with ethyl acetate (50 mL), washed with saturated sodium sulfite (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (methanol-dichloromethane, 0-5% gradient elution) to give the product (2.2 g, 7.55 mmol, 98.56%) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ8.17(s,1H),7.76(dd,J=8.0,1.0Hz,1H),7.65-7.59(m,1H),7.25(t,J=7.6Hz,1H),6.05(d,J=11.8Hz,1H),5.7 6(d,J=11.8Hz,1H),5.46(bs,2H),4.90(q,J=6.6Hz,1H),3.55-3.40(m,2H),1.54(d,J=6.5Hz,3H),0.82(t,J=8.1Hz,2H),0.00(s,9H).

[0901] Intermediate A10: (R)-3-(1-aminoethyl)-N,N-bis(4-methoxybenzyl)-6-methylpyridine-2-amine

[0902] Step 1: 2-Chloro-N-methoxy-N,6-dimethylnicotinamide

[0903] 2-Chloro-6-methylnicotinic acid (5 g, 29.14 mmol), N,N-diisopropylethylamine (11.30 g, 87.42 mmol), and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (13.30 g, 34.97 mmol) were dissolved in N,N-dimethylformamide (50 mL). Under an argon atmosphere at 0 °C, N,O-dimethylhydroxylamine hydrochloride (3.41 g, 34.97 mmol) was added, and the mixture was stirred at 10 °C for 2 hours. The mixture was diluted with water (300 mL), extracted with ethyl acetate (100 mL x 2), and the organic phases were combined. The mixture was washed once with saturated brine (50 mL), dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (petroleum ether / ethyl acetate = 3:1) to give 2.2 g of a clear oil (yield: 35%). ESI-MS m / z: 215.0 [M+H] + .

[0904] Step 2: 1-(2-chloro-6-methylpyridin-3-yl)acetone

[0905] 2-Chloro-N-methoxy-N,6-dimethylnicotinamide (2.2 g, 10.25 mmol) was dissolved in tetrahydrofuran (10 mL). Lanthanum(III) chloride bis(lithium chloride) complex (25.623 mL, 15.37 mmol) was added under argon atmosphere at 15 °C, and the mixture was stirred for 1 hour. Methyl magnesium bromide solution (25.623 mL, 25.62 mmol) was added dropwise at 0 °C, and the mixture was stirred for 1 hour. The mixture was then stirred at 15 °C for 12 hours. The reaction was quenched with saturated ammonium chloride solution (20 mL), and the mixture was extracted with ethyl acetate (30 mL x 2). The combined organic phases were washed once with saturated brine (30 mL), dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (petroleum ether / ethyl acetate = 3:1) to give 1.68 g of a clear oil (yield: 96%). ESI-MS m / z: 170.0 [M+H] + .

[0906] Step 3: 1-(2-(di(4-methoxybenzyl)amino)-6-methylpyridin-3-yl)acetone

[0907] 1-(2-chloro-6-methylpyridin-3-yl)acetone (1.68 g, 9.91 mmol) and bis(4-methoxybenzyl)amine (5.10 g, 19.81 mmol) were dissolved in N,N-dimethylacetamide (20 mL), and N,N-diisopropylethylamine (3.84 g, 29.72 mmol) was added. The mixture was stirred at 120 °C for 12 hours. The reaction solution was diluted with water (100 mL), extracted with ethyl acetate (50 mL x 2), the organic phases were combined and washed once with saturated brine (50 mL), dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (petroleum ether / ethyl acetate = 5:1) to give 3.3 g of a yellow oil (yield: 85%). ESI-MS m / z: 391.1 [M+H] + .

[0908] Step 4: (R,E)-N-(1-(2-(di(4-methoxybenzyl)amino)-6-methylpyridin-3-yl)ethylene)-2-methylpropane-2-sulfinamide

[0909] 1-(2-(di(4-methoxybenzyl)amino)-6-methylpyridin-3-yl)acetone (3.3 g, 8.45 mmol) and (S)-tert-butylsulfinamide (2.05 g, 16.90 mmol) were dissolved in toluene (30 mL), and tetraethyl titanate (5.78 g, 25.35 mmol) was added. The mixture was stirred at 110 °C for 12 hours under an argon atmosphere. The reaction solution was poured into saturated brine (50 mL), and ethyl acetate (100 mL) was added. The mixture was filtered through diatomaceous earth, and the filtrate was separated. The organic phase was washed once with saturated brine (50 mL), dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (petroleum ether / ethyl acetate = 3:1) to give 2.1 g of crude yellow oil. ESI-MS m / z: 494.1 [M+H] + .

[0910] Step 5: (R)-N-((R)-1-(2-(di(4-methoxybenzyl)amino)-6-methylpyridin-3-yl)ethyl)-2-methylpropane-2-sulfinamide

[0911] (R,E)-N-(1-(2-(di(4-methoxybenzyl)amino)-6-methylpyridin-3-yl)ethylidene)-2-methylpropane-2-sulfinamide (2.1 g, 4.25 mmol) was dissolved in tetrahydrofuran (20 mL). Trisec-butylborohydride (12.762 mL, 12.76 mmol) was added under argon atmosphere and at 0 °C, and the mixture was stirred for 2 hours. The reaction was quenched with saturated ammonium chloride aqueous solution (30 mL), and the mixture was extracted with ethyl acetate (50 mL * 2). The combined organic phases were washed once with saturated brine (50 mL), dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (petroleum ether / ethyl acetate = 2:1) to give 1.9 g of crude yellow oil. ESI-MS m / z: 496.1 [M+H] + .

[0912] Step 6: (R)-3-(1-aminoethyl)-N,N-bis(4-methoxybenzyl)-6-methylpyridin-2-amine

[0913] (R)-N-((R)-1-(2-(di(4-methoxybenzyl)amino)-6-methylpyridin-3-yl)ethyl)-2-methylpropane-2-sulfinamide (1.9 g, 3.83 mmol) was dissolved in tetrahydrofuran (20 mL) and water (2 mL), and iodine (0.39 g, 1.53 mmol) was added. The mixture was stirred at 50 °C for 5 hours under an argon atmosphere. The reaction was quenched with saturated sodium sulfite solution (30 mL), and the pH was adjusted to 9–10 with saturated sodium carbonate solution. The mixture was extracted with ethyl acetate (50 mL * 2), and the organic phases were combined and washed once with saturated brine (50 mL). The mixture was dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (dichloromethane / methanol = 10:1) to give 1 g of a yellow oil. ESI-MS m / z: 392.1 [M+H] + .

[0914] Intermediate A11: (R)-N-(4-methoxybenzyl)-3-(pyrrolidone-2-yl)pyridine-2-amine

[0915] Step 1: 2-(Di(4-methoxybenzyl)amino)pyridine-3-carboxaldehyde

[0916] 2-Fluoropyridine-3-carboxaldehyde (5 g, 39.97 mmol) and bis(4-methoxybenzyl)amine (13.37 g, 51.96 mmol) were dissolved in N,N-dimethylacetamide (80 mL), and potassium carbonate (16.57 g, 119.90 mmol) was added. The mixture was stirred at 90 °C for 1 hour. The reaction solution was diluted with water (500 mL), extracted with ethyl acetate (100 mL x 3), and the organic phases were combined and washed once with saturated brine (100 mL). The mixture was dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (petroleum ether / ethyl acetate = 5:1) to give 12 g of a yellow oil (yield: 82%). ESI-MS m / z: 363.1 [M+H] + .

[0917] Step 2: (R,E)-N-((2-(bis(4-methoxybenzyl)amino)pyridin-3-yl)methylene)-2-tert-butyl-2-sulfinamide

[0918] 2-(bis(4-methoxybenzyl)amino)pyridine-3-carboxaldehyde (12 g, 33.11 mmol) and (R)-tert-butylsulfinamide (4.41 g, 36.42 mmol) were dissolved in dichloromethane (100 mL), and cesium carbonate (12.95 g, 39.73 mmol) was added. The mixture was stirred at 10 °C for 1 hour. The reaction solution was diluted with water (100 mL), separated, and the organic phase was dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (petroleum ether / ethyl acetate = 3 / 1). 15.4 g of a pale yellow oil was obtained (yield: 99%). ESI-MS m / z: 466.2 [M+H] + .

[0919] Step 3: (R)-N-((R)-1-(2-(bis(4-methoxybenzyl)amino)pyridin-3-yl)-3-(1,3-dioxane-2-yl)propyl)-2-tert-butyl-2-sulfinamide

[0920] Magnesium shavings (0.93 g, 38.45 mmol) were dissolved in tetrahydrofuran (50 mL) under an argon atmosphere. A 1 / 5 volume solution of 3-bromopropanol cyclopropane (5 g, 25.63 mmol) in THF (50 mL) was added. Iodine was added and the reaction was initiated by heating. The remaining reactants were then added, and the mixture was stirred at 15 °C for 1 hour. Once the reaction solution ceased to exothermic, it was cooled to 0 °C to prepare the Grignard reagent. (R,E)-N-((2-(di(4-methoxybenzyl)amino)pyridin-3-yl)methylene)-2-tert-butyl-2-sulfinamide (4 g, 8.59 mmol) was dissolved in tetrahydrofuran (40 mL). The prepared Grignard reagent was slowly added under an argon atmosphere at -78 °C, and the mixture was stirred for 30 minutes. The temperature was then raised to 15 °C and stirred for 2 hours. The reaction was quenched by adding saturated ammonium chloride aqueous solution (20 mL), and extracted with ethyl acetate (20 mL * 3). The organic phases were combined, washed once with saturated brine (20 mL), dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (petroleum ether / ethyl acetate = 3:1) to give 4 g of a pale yellow oil (yield: 80%). ESI-MS m / z: 582.3 [M+H] + . 1H NMR(400MHz, DMSO-d6)δ8.17(dd,J=4.7,1.9Hz,1H),7.88(dd,J=7.7,1.9Hz,1H),7.20–7.15(m,4H),7 .07(dd,J=7.7,4.7Hz,1H),6.84–6.80(m,4H),5.54(d,J=9.4Hz,1H),4.81–4.70(m,1H),4.61(t,J=5. 3Hz,0H),4.44–4.40(m,1H),4.15(d,J=13.8Hz,2H),3.99–3.94(m,2H),3.71(s,6H),3.68–3.62(m,2H ),3.43(td,J=6.6,5.2Hz,1H),1.90–1.77(m,2H),1.67–1.60(m,2H),1.35–1.28(m,2H),1.08(s,9H).

[0921] Step 4: (R)-N-(4-methoxybenzyl)-3-(pyrrolidine-2-yl)pyridine-2-amine

[0922] (R)-N-((R)-1-(2-(di(4-methoxybenzyl)amino)pyridin-3-yl)-3-(1,3-dioxane-2-yl)propyl)-2-tert-butyl-2-sulfinamide (1 g, 1.72 mmol) was dissolved in trifluoroacetic acid (5 mL, 65.30 mmol) and water (0.5 mL, 27.66 mmol) and stirred at 15 °C for 1 hour. Triethylsilane (0.959 mL, 6.02 mmol) was added and stirred at 15 °C for 12 hours. The pH was adjusted to 9–10 with saturated sodium carbonate solution, and the mixture was extracted with dichloromethane (20 mL). The organic phase was dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (dichloromethane / methanol = 10 / 1) to obtain 500 mg of a pale yellow oil. The crude product was directly added to the next step. ESI-MS m / z: 284.1 [M+H] + .

[0923] Intermediate A12: (R)-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridin-7-yl)ethylamine

[0924] Step 1: 7-Chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine

[0925] 7-Chloro-1H-pyrazolo[3,4-c]pyridine (1.5 g, 14.62 mmol) was dissolved in tetrahydrofuran (30 mL) under argon protection and cooled in an ice bath. Sodium hydrogen (0.78 g, 19.54 mmol) was added. The reaction was stirred in an ice bath for 30 minutes. 2-(trimethylsilyl)ethoxymethyl chloride (2.45 g, 14.65 mmol) was added dropwise. The reaction was stirred in an ice bath for 30 minutes, then slowly heated overnight, and the reaction was monitored for completeness. The reaction was quenched with saturated ammonium chloride, followed by extraction with ethyl acetate (100 mL) and saturated brine (50 mL). The ethyl acetate phase was washed three times with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (ethyl acetate-petroleum ether, 0-10% gradient elution) to give the product (1.17 g, 4.12 mmol, 42%) as a colorless, transparent oil. ESI-MS m / z: 284.0 [M+H] + ; 1 H NMR (400MHz, CDCl3) δ8.15 -8.11(m,2H),7.60(d,J=5.5Hz,1H),6.08(s,2H),3.66-3.56(m,2H),0.96-0.83(m,2H),0.00(s,9H).

[0926] Step 2: 7-(1-ethoxyvinyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine

[0927] 7-Chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine (1.06 g, 3.73 mmol), tributyl(1-ethoxyethylene)tin (1.48 g, 4.11 mmol), and bis(triphenylphosphine)palladium dichloride (0.26 g, 0.37 mmol) were dissolved in 1,4-dioxane (25 mL). The system was protected with argon and stirred at 100 °C for 16 hours. The reaction mixture was monitored for complete reaction. The reaction solution was poured into an aqueous solution of potassium fluoride (1.08 g, 18.67 mmol) (20 mL), and the reaction was stirred at room temperature for 1 hour. Insoluble matter was removed by filtration. The filter cake was washed with ethyl acetate. Extraction was performed, the ethyl acetate phases were combined, washed four times with water (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (ethyl acetate-petroleum ether, 0-20% gradient elution) to give the product (0.76 g, 2.38 mmol, 64%) as a yellow solid. ESI-MS m / z: 320.2 [M+H] + ; 1H NMR (400MHz, CDCl3) δ8.37(d,J=5.5Hz,1H),8.13(s,1H),7.65(d,J=5.5Hz,1H),5.91(s,2H),4.72(d,J=2.6Hz,1H),4. 64(d,J=2.6Hz,1H),4.09(q,J=7.1Hz,2H),3.52-3.45(m,2H),1.46(t,J=7.0Hz,3H),0.88-0.82(m,2H),-00.00(s,9H).

[0928] Step 3: 1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridin-7-yl)acetone

[0929] 7-(1-ethoxyvinyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine (0.73 g, 2.28 mmol) was dissolved in acetonitrile (6 mL), and dilute hydrochloric acid (1.0 M, 6 mL) was added. The reaction was stirred at room temperature for about 24 hours. A large amount of product was monitored for formation. Saturated sodium carbonate was added to the reaction solution to adjust the pH to 8-9. The reaction mixture was extracted twice with ethyl acetate (20 mL), and the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (ethyl acetate-petroleum ether, 0-30% gradient elution) to give the product (0.53 g, 1.82 mmol, 80%) as a yellow oil. ESI-MS m / z: 292.2 [M+H] + ; 1 H NMR (400MHz, CDCl3) δ8.43(d,J=5.3Hz,1H),8.18(s,1H),7.87(d,J=5.3Hz,1H) ,6.10(s,2H),3.36-3.24(m,2H),2.87(s,3H),0.82-0.73(m,2H),0.00(s,9H).

[0930] Step 4: (S)-2-methyl-N-(1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridin-7-yl)ethylene)propane-2-sulfinamide

[0931] 1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridin-7-yl)acetone (0.53 g, 1.8 mmol) was dissolved in toluene (8 mL). (S)-(-)-tert-butylsulfinamide (0.66 g, 5.4 mmol) and tetraethyl titanate (1.24 g, 5.4 mmol) were added. The system was protected with argon and stirred at 110 °C for 20 hours. The conversion of the starting material was monitored for completeness. The reaction mixture was poured into saturated brine (20 mL) and filtered to remove insoluble matter. The filter cake was washed twice with ethyl acetate (20 mL), extracted, and the ethyl acetate phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (ethyl acetate-petroleum ether, 0-30% gradient elution) to give the product (0.44 g, 1.12 mmol, 61%) as a brown oil. ESI-MS m / z: 395.1 [M+H] +

[0932] Step 5: (S)-2-methyl-N-((R)-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridin-7-yl)ethyl)propane-2-sulfinamide

[0933] (S)-2-methyl-N-(1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridin-7-yl)ethylene)propane-2-sulfinamide (0.44 g, 1.12 mmol) was dissolved in tetrahydrofuran (20 mL). The system was cooled to -60 °C under nitrogen protection, and a tetrahydrofuran solution of tri-sec-butylborohydride (1.0 M, 3.3 mL, 3.3 mmol) was added dropwise. The reaction was stirred at -60 °C for 2 hours and then at room temperature for 2 hours. The starting material was monitored to be substantially completely converted. The reaction was quenched with saturated ammonium chloride, followed by extraction with ethyl acetate and saturated brine. The ethyl acetate phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (ethyl acetate-petroleum ether, 0-75% gradient elution) to give the product (0.4 g, 1.01 mmol, 90%) as a colorless, transparent oil. ESI-MS m / z: 397.1 [M+H] + .

[0934] Step 6: (R)-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridin-7-yl)ethylamine

[0935] (S)-2-methyl-N-((R)-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridin-7-yl)ethyl)propane-2-sulfinamide (0.4 g, 1.01 mmol) was dissolved in a mixed solvent of tetrahydrofuran (5 mL) and water (1 mL). Iodine (0.1 g, 0.4 mmol) was added. The reaction was stirred at 50 °C for about 2 hours. The starting material was monitored for complete conversion. The reaction mixture was diluted with ethyl acetate (25 mL), washed with saturated sodium sulfite (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (methanol-dichloromethane, 0-5% gradient elution) to give the product (0.32 g, 0.98 mmol, 97%) as a colorless oil. ESI-MS m / z: 293.1 [M+H] + .

[0936] Intermediate A13: (1R)-1-(2-{bis[(4-methoxyphenyl)methyl]amino}pyridin-3-yl)(1-deuterated)ethyl-1-amine

[0937] Step 1: 3-[(1R)-1-{[(S)-(2-methylpropyl-2-yl)(oxo-subunit)-λ 4 [-thio]amino}(1-deuterated)ethyl]-2-{bis[(4-methoxyphenyl)methyl]amino}pyridine

[0938] Under nitrogen protection, at -60℃ to -50℃, sodium deuterated borohydride (0.53 g, 12.51 mmol) was slowly added to (R,E)-N-(1-(2-(di(4-methoxybenzyl)amino)pyridin-3-yl)ethylidene)-2-methylpropane-2-sulfinamide (2 g, 4.17 mmol) in tetrahydrofuran (20 mL) and water (5 mL). The reaction mixture was heated to room temperature and stirred for 2 hours. After the reaction was complete, 20 mL of water was added for dilution, followed by extraction with dichloromethane (20 mL x 3), washing with saturated sodium chloride (50 mL x 1) on the organic phase, drying to anhydrous sodium sulfate, and concentrating. The residue was separated by silica gel column chromatography (ethyl acetate-dichloromethane, 0-6% gradient elution) to give a yellow oily product (660 mg, 1.37 mmol, 32.79%). ESI-MS m / z: 482.8 [M+H] + . 1H NMR (400MHz, CDCl3) δ8.35–8.30(m,1H),7.67(s,1H),7.18(d,J=8.2Hz,4H),7.04(t,J=6.2Hz, 1H),6.84–6.77(m,4H),4.21–4.10(m,4H),3.76(s,6H),3.22(s,1H),1.33(s,3H),1.12(s,9H).

[0939] Step 2: (1R)-1-(2-{bis[(4-methoxyphenyl)methyl]amino}pyridin-3-yl)(1-deuterated)ethyl-1-amine

[0940] 3-[(1R)-1-{[(S)-(2-methylpropyl-2-yl)(oxo-ylidene)-λ 4 [-thio]amino}(1-deuterated)ethyl]-2-{bis[(4-methoxyphenyl)methyl]amino}pyridine (300 mg, 0.62 mmol) was dissolved in tetrahydrofuran (5 mL) and water (1 mL), and iodine (47.33 mg, 0.19 mmol) was added. The mixture was heated to 55 °C and stirred for 1 hour. The reaction solution was poured into a saturated sodium sulfite aqueous solution (20 mL), extracted with ethyl acetate (20 mL * 3), washed with saturated sodium chloride (50 mL * 3), dried over anhydrous sodium sulfate, concentrated, and the residue was separated by silica gel column chromatography (methanol-dichloromethane, 0-3% gradient elution) to give the product (200 mg, 0.53 mmol, 85.02%), a yellow oil. ESI-MS m / z: 378.9 [M+H] + ; 1 H NMR(400MHz, CDCl3)δ8.34(dd,J=4.7,1.9Hz,1H),7.66(dd,J=7.7,1.9Hz,1H),7.14–7.09(m,4H ),7.04(dd,J=7.7,4.7Hz,1H),6.81–6.76(m,4H),4.21–4.06(m,4H),3.76(s,6H),1.18(s,3H).

[0941] Intermediate A14: (S)-3-(1-amino-2,2-difluoroethyl)-N,N-bis(4-methoxybenzyl)pyridine-2-amine

[0942] Step 1: 2,2-Difluoro-1-(2-fluoropyridin-3-yl)ethyl ketone

[0943] At -60°C, lithium diisopropylamino (19.714 mL, 39.43 mmol) was added dropwise to tetrahydrofuran (30 mL) containing 2-fluoropyridine (3.48 g, 35.84 mmol). After stirring for 40 minutes, 2,2-difluoro-N-methoxy-N-methylacetamide (5.48 g, 39.43 mmol) was added dropwise and stirring was continued for 1.5 hours. The mixture was then quenched with saturated ammonium chloride (50 mL), extracted with ethyl acetate (50 mL * 2), washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 6.28 g of a yellow oily crude product.

[0944] 1 H NMR (400MHz, CDCl3) δ8.54(ddd,J=4.9,2.1,1.1Hz,1H),8.44(ddd,J=9.3,7.6,2.1Hz,1H),7.46(ddd,J=7.4,4.8,2.2Hz,1H),6.49(td,J=53.1,2.5Hz,1H).

[0945] Step 2: 1-(2-(bis(4-methoxybenzyl)amino)pyridin-3-yl)-2,2-difluoroethyl ketone

[0946] Compounds 2,2-difluoro-1-(2-fluoropyridin-3-yl)ethyl ketone (6.28 g, 35.86 mmol), bis-(4-methoxybenzyl)-amine (11.07 g, 43.04 mmol), and N,N-diisopropylethylamine (6.95 g, 53.79 mmol) in dimethylformamide (30 mL) were stirred at 110 °C for 1 hour, cooled to room temperature, diluted with ethyl acetate (150 mL), washed with water (90 mL x 3), then washed with saturated brine (90 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether / ethyl acetate = 85:15, v / v) to give a yellow oily product (12.9 g). ESI-MS m / z: 413.0 [M+1] + .

[0947] 1 H NMR (400MHz, CDCl3) δ8.43 (dd, J=4.6, 1.9Hz, 1H), 7.95 (dq, J=7.8, 1.5Hz, 1H), 7.05 –6.96(m,4H),6.85–6.78(m,5H),6.14(t,J=53.9Hz,1H),4.51(s,4H),3.79(s,6H).

[0948] Step 3: (S,Z)-N-(1-(2-(di(4-methoxybenzyl)amino)pyridin-3-yl)-2,2-difluoroethylidene)-2-methylpropane-2-sulfinamide

[0949] Compounds 1-(2-(di(4-methoxybenzyl)amino)pyridin-3-yl)-2,2-difluoroethyl ketone (4 g, 9.70 mmol), S-tert-butylsulfinamide (2.35 g, 19.40 mmol), and tetraethyl titanate (6.64 g, 29.10 mmol) in toluene (8 mL) were stirred at 120 °C for 1 hour, then cooled to room temperature. Ethyl acetate (100 mL) and saturated brine (60 mL) were added, and the mixture was stirred for 10 minutes. The mixture was filtered, separated into layers, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether / ethyl acetate = 80:20, v / v) to give a yellow oily product (3.77 g). ESI-MS m / z: 516.1 [M+1] + .

[0950] 1 H NMR (400MHz, CDCl3) δ8.38(s,1H),7.69(s,1H),7.06(d,J=8.3Hz,4H),6.98(d,J=7.1Hz,1H ),6.87–6.79(m,4H),6.38–6.01(m,1H),4.75–3.95(m,4H),3.80(s,6H),1.36-1.18(m,9H).

[0951] Step 4: (S)-N-((S)-1-(2-(di(4-methoxybenzyl)amino)pyridin-3-yl)-2,2-difluoroethyl)-2-methylpropane-2-sulfinamide

[0952] (S,Z)-N-(1-(2-(di(4-methoxybenzyl)amino)pyridin-3-yl)-2,2-difluoroethylidene)-2-methylpropane-2-sulfinamide (3.77 g, 7.31 mmol) was dissolved in tetrahydrofuran (40 mL), and tri-sec-butylborohydride (21.935 mL, 21.93 mmol) was added at -70 °C. The reaction was carried out at room temperature for 0.5 h. The reaction was quenched by slow dropwise addition of water (60 mL), extracted with ethyl acetate (40 mL * 3), washed with saturated brine (60 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether / ethyl acetate = 75:25, v / v) to give a yellow oily product (2.155 g). ESI-MS m / z: 518.1 [M+1] + .

[0953] 1 H NMR (400MHz, CDCl3) δ8.49 (dd, J=4.7, 1.9Hz, 1H), 7.70 (d, J=7.7Hz, 1H), 7.20-7.10 (m, 5H), 6. 88–6.78(m,4H),5.55–5.36(m,2H),4.25–4.04(m,4H),3.83(s,1H),3.79(s,6H),1.17(s,9H).

[0954] Step 5: (S)-3-(1-amino-2,2-difluoroethyl)-N,N-bis(4-methoxybenzyl)pyridine-2-amine

[0955] (S)-N-((S)-1-(2-(di(4-methoxybenzyl)amino)pyridin-3-yl)-2,2-difluoroethyl)-2-methylpropane-2-sulfinamide (2.015 g, 4.01 mmol) was dissolved in a mixed solution of tetrahydrofuran (20 mL) and water (4 mL), and iodine (412.85 mg, 1.63 mmol) was added. The reaction was carried out at 70 °C for 3 hours under argon protection. After cooling to room temperature, the reaction solution was quenched with a saturated sodium thiosulfate solution (30 mL), extracted with ethyl acetate (30 mL x 3), washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether / ethyl acetate = 70:30, v / v) to give a yellow oily product (1.3 g). ESI-MS m / z: 414.1 [M+1] + .

[0956] 1 H NMR(400MHz, CDCl3) δ8.47(dd,J=4.7,1.9Hz,1H),7.68(dd,J=7.7,1.9Hz,1H),7.16–7.08(m,5H),6.84 –6.77(m,4H),5.59–5.26(m,1H),4.81(ddd,J=16.5,10.3,3.4Hz,1H),4.19–4.07(m,4H),3.78(s,6H).

[0957] Intermediate A15: (S)-3-(1-amino-2,2-difluoro(1-deuterated)ethyl)-N,N-di(4-methoxybenzyl)pyridine-2-amine

[0958] Step 1: (R)-N-((S)-1-(2-(di(4-methoxybenzyl)amino)pyridin-3-yl)-2,2-difluoro(1-deuterated)ethyl)-2-methylpropane-2-sulfinamide

[0959] Under nitrogen protection and at 0°C, sodium deuterated borohydride (0.49 g, 11.64 mmol) was added to a solution of (R,Z)-N-(1-(2-(di(4-methoxybenzyl)amino)pyridin-3-yl)-2,2-difluoroethylidene)-2-methylpropane-2-sulfinamide (2 g, 4.17 mmol) in water (5 mL) and tetrahydrofuran (20 mL). The reaction mixture was stirred at room temperature for 10 minutes. After the reaction was complete, the mixture was diluted with saturated brine (20 mL) and extracted with ethyl acetate (3 × 20 mL). The organic phases were combined and washed with saturated brine (1 × 50 mL). The organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-petroleum ether, 0-35% gradient elution) to give the product (1.7 g, 3.28 mmol, 84.51%), a yellowish oil. ESI-MS m / z: 519.1 [M+1] + . 1 H NMR (400MHz, CDCl3) δ8.49 (dd, J=4.8, 1.9Hz, 1H), 7.70 (d, J=7.8Hz, 1H), 7.19–7.11 (m, 5H), 6.88–6.7 8(m,4H),5.38(t,J=55.3Hz,1H),4.20–4.12(m,4H),3.83(d,J=3.6Hz,1H),3.79(s,6H),1.17(s,9H).

[0960] Step 2: (S)-3-(1-amino-2,2-difluoro(1-deuterated)ethyl)-N,N-di(4-methoxybenzyl)pyridine-2-amine

[0961] Under nitrogen protection, iodine (0.25 g, 0.98 mmol) was added to a solution of (R)-N-((S)-1-(2-(di(4-methoxybenzyl)amino)pyridin-3-yl)-2,2-difluoro(1-deuterated)ethyl)-2-methylpropane-2-sulfinamide (1.7 g, 3.28 mmol) in water (4 mL) and tetrahydrofuran (20 mL). The reaction system was stirred at 55 °C for 5 hours. After the reaction was complete, saturated sodium sulfite aqueous solution (50 mL) was added, followed by extraction with ethyl acetate (3 × 30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (ethyl acetate-petroleum ether, 0-30% gradient elution) to give the product (1.05 g, 2.53 mmol, 77.29%), a colorless oil. ESI-MS m / z: 414.8 [M+1] + . 1H NMR (400MHz, CDCl3) δ8.45 (dd, J=4.7, 1.9Hz, 1H), 7.67 (dd, J=7.6, 1.9Hz, 1H), 7.08 (dq, J=7. 8,2.6,2.1Hz,5H),6.81–6.76(m,4H),5.39(t,J=56.2Hz,1H),4.20–4.02(m,4H),3.76(s,6H).

[0962] Intermediate A16: (1R)-1-(2-{bis[(4-methoxyphenyl)methyl]amino}pyridin-3-yl)(1-deuterated)ethyl-1-amine

[0963] Step 1: 3-[(1R)-1-{[(S)-(2-methylpropyl-2-yl)(oxo-subunit)-λ 4 [-thio]amino}(1-deuterated)ethyl]-2-{bis[(4-methoxyphenyl)methyl]amino}pyridine

[0964] Under nitrogen protection, at -60℃ to -50℃, sodium deuterated borohydride (0.53 g, 12.51 mmol) was slowly added to (R,E)-N-(1-(2-(di(4-methoxybenzyl)amino)pyridin-3-yl)ethylidene)-2-methylpropane-2-sulfinamide (2 g, 4.17 mmol) in tetrahydrofuran (20 mL) and water (5 mL). The reaction mixture was heated to room temperature and stirred for 2 hours. After the reaction was complete, 20 mL of water was added for dilution, followed by extraction with dichloromethane (20 mL x 3), washing with saturated sodium chloride (50 mL x 1) on the organic phase, drying to anhydrous sodium sulfate, and concentrating. The residue was separated by silica gel column chromatography (ethyl acetate-dichloromethane, 0-6% gradient elution) to give a yellow oily product (660 mg, 1.37 mmol, 32.79%). ESI-MS m / z: 482.8 [M+1] + . 1 H NMR (400MHz, CDCl3) δ8.35–8.30(m,1H),7.67(s,1H),7.18(d,J=8.2Hz,4H),7.04(t,J=6.2Hz, 1H),6.84–6.77(m,4H),4.21–4.10(m,4H),3.76(s,6H),3.22(s,1H),1.33(s,3H),1.12(s,9H).

[0965] Step 2: (1R)-1-(2-{bis[(4-methoxyphenyl)methyl]amino}pyridin-3-yl)(1-deuterated)ethyl-1-amine

[0966] 3-[(1R)-1-{[(S)-(2-methylpropyl-2-yl)(oxo-ylidene)-λ 4 [-thio]amino}(1-deuterated)ethyl]-2-{bis[(4-methoxyphenyl)methyl]amino}pyridine (300 mg, 0.62 mmol) was dissolved in tetrahydrofuran (5 mL) and water (1 mL), and iodine (47.33 mg, 0.19 mmol) was added. The mixture was heated to 55 °C and stirred for 1 hour. The reaction solution was poured into a saturated sodium sulfite aqueous solution (20 mL), extracted with ethyl acetate (20 mL * 3), washed with saturated sodium chloride (50 mL * 3), dried over anhydrous sodium sulfate, concentrated, and the residue was separated by silica gel column chromatography (methanol-dichloromethane, 0-3% gradient elution) to give the product (200 mg, 0.53 mmol, 85.02%), a yellow oil. ESI-MS m / z: 378.9 [M+1] + ; 1 H NMR(400MHz, CDCl3)δ8.34(dd,J=4.7,1.9Hz,1H),7.66(dd,J=7.7,1.9Hz,1H),7.14–7.09(m,4H ),7.04(dd,J=7.7,4.7Hz,1H),6.81–6.76(m,4H),4.21–4.06(m,4H),3.76(s,6H),1.18(s,3H).

[0967] Intermediate A17: (R)-1(2-{bis[(4-methoxyphenyl)methyl]amino}pyridin-3-yl)(1,2,2,2-tetradeuteryl)ethyl-1-amine

[0968] Step 1: 2-Fluoropyridine-3-deuterated formaldehyde

[0969] Add Dys-Martin oxidant (31.53 g, 74.34 mmol) to a solution of (2-fluoropyridin-3-yl)(dideuterium)methanol (8 g, 61.95 mmol) in dichloromethane (150 mL). Stir the reaction mixture at room temperature for 15 minutes. Extract the reaction mixture with saturated sodium bicarbonate aqueous solution (100 mL) and dichloromethane (30 mL x 3). Combine the organic phases and wash successively with water (200 mL) and saturated brine (200 mL), dry to anhydrous sodium sulfate, filter, and evaporate to dryness to obtain the crude product. Purify the crude product by silica gel column chromatography (petroleum ether / ethyl acetate, 0–10%) to obtain the product (4.8 g, yield: 61%), a colorless oily liquid. MS m / z: 126.9 [M+H] + . 1H NMR (400MHz, CDCl3) δ8.13 (dt, J = 4.9, 1.7Hz, 1H), 7.95-7.88 (m, 1H), 7.25-7.19 (m, 1H).

[0970] Step 2: (2-{bis[(4-methoxyphenyl)methyl]amino}pyridin-3-yl)-deuterated formaldehyde

[0971] To a solution of 2-fluoropyridine-3-deuterated formaldehyde (4.6 g, 36.48 mmol) and N,N-diisopropylethylamine (19.061 mL, 109.43 mmol) in N,N-dimethylacetamide (60 mL), bis(p-methoxybenzyl)amine (18.77 g, 72.95 mmol) was added. The reaction mixture was stirred at 120 °C for 16 hours. The reaction was monitored by LCMS until completion. The reaction mixture was extracted with water (300 mL) and ethyl acetate (50 mL x 3). The organic phases were combined and then mixed with hydrochloric acid aqueous solution (100 mL, 1 M). After stirring, the mixture was filtered. The filtrate was separated, and the organic phase was washed successively with water (200 mL) and saturated brine (200 mL). The mixture was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 0–20%) to obtain the product (12 g, yield: 90%), a colorless oily liquid. MS m / z: 364.0 [M+H] + . 1 H NMR (400MHz, CDCl3) δ8.41 (dd, J=4.7, 2.0Hz, 1H), 8.04 (dd, J=7.6, 2.0Hz, 1H), 7.16–7 .03(m,4H),6.90(dd,J=7.6,4.7Hz,1H),6.87–6.78(m,4H),4.61(s,4H),3.80(s,6H).

[0972] Step 3: (1E)-1-(2-{bis[(4-methoxyphenyl)methyl]amino}pyridin-3-yl)-N-[(S)-(2-methylpropyl-2-yl)(oxonyl)-λ 4 [-thio](deuterated)methaneimine

[0973] Cesium carbonate (5.39 g, 16.55 mmol) was added to a solution of (2-{bis[(4-methoxyphenyl)methyl]amino}pyridin-3-yl)-deuterated formaldehyde (3 g, 8.28 mmol) and (S)-tert-butylsulfinamide (1.15 g, 9.52 mmol) in dichloromethane (60 mL). The reaction mixture was stirred at 50 °C for 12 hours. The mixture was then extracted with water (200 mL) and dichloromethane (50 mL x 2). The combined organic phases were washed successively with water (200 mL) and saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 0–20%) to obtain the product (3.2 g, yield: 83%), a yellow oily liquid. MS m / z: 467.0 [M+H] + . 1 H NMR(400MHz, CDCl3)δ8.38(dd,J=4.8,2.0Hz,1H),8.17(dd,J=7.7,2.0Hz,1H),7.17–7.04(m,4H ),6.97(dd,J=7.7,4.7Hz,1H),6.88–6.76(m,4H),4.49–4.29(m,4H),3.78(s,6H),1.25(s,9H).

[0974] Step 4: 2-{bis[(4-methoxyphenyl)methyl]amino}-3-(1-{[(2-methylpropyl-2-yl)(oxoyl)-λ 4 [-thio]amino}(1,2,2,2-tetradeuteryl)ethyl)pyridine

[0975] Under nitrogen protection at 0℃, the (1E)-1-(2-{bis[(4-methoxyphenyl)methyl]amino}pyridin-3-yl)-N-[(S)-(2-methylpropyl-2-yl)(oxonyl)-λ 4 [-Thio](deuterated)methaneimine (3.2 g, 6.87 mmol) was dissolved in dichloromethane (60 mL), and magnesium iodide diethyl ether solution (13.745 mL, 13.75 mmol, 1 M) was added dropwise. The reaction mixture was stirred at 40 °C for 3 hours. The reaction was monitored by LCMS until completion. The reaction mixture was then extracted with saturated ammonium chloride aqueous solution (100 mL) and dichloromethane (30 mL x 2). The combined organic phases were washed successively with water (200 mL) and saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. The crude product was used directly for the next step without further purification. MS m / z: 486.0 [M+H] + . 1H NMR(400MHz, CDCl3)δ8.34(dd,J=4.8,2.0Hz,1H),7.68(d,J=7.6Hz,1H),7.25–7.12(m,4H),7.0 5(dd,J=7.6,4.7Hz,1H),6.92–6.76(m,4H),4.17(s,4H),3.79(s,6H),3.24(s,1H),1.14(s,9H).

[0976] Step 5: (R)-1-(2-{bis[(4-methoxyphenyl)methyl]amino}pyridin-3-yl)(1,2,2,2-tetradeuteryl)ethyl-1-amine

[0977] Under nitrogen protection, the reaction proceeds to 2-{bis[(4-methoxyphenyl)methyl]amino}-3-(1-{[(2-methylpropyl-2-yl)(oxonyl)-λ 4 Iodine (0.59 g, 2.31 mmol) was added to a solution of (1,2,2,2-tetradeuteryl)ethyl)pyridine (2.8 g, 5.77 mmol) in tetrahydrofuran (50 mL) and water (5 mL). The reaction mixture was stirred at 50 °C for 5 hours. The reaction mixture was quenched with ammonia (1 mL) after adding saturated sodium thiosulfate aqueous solution (50 mL), and extracted with ethyl acetate (30 mL * 2). The organic phases were combined and washed successively with water (100 mL) and saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. The crude product was subjected to silica gel column chromatography (dichloromethane / methanol, 0–5%) to give the product (1.4 g, yield: 68%), a colorless oily liquid. MS m / z: 381.9 [M+H] + . 1 H NMR(400MHz, CDCl3) δ8.34(dd,J=4.7,1.9Hz,1H),7.66(dd,J=7.6,1.9Hz,1H),7.21–7.09( m,4H),7.05(dd,J=7.6,4.7Hz,1H),6.86–6.73(m,4H),4.14(q,J=13.4Hz,4H),3.77(s,6H).

[0978] Intermediate A18: (R)-(2-{bis[(4-methoxyphenyl)methyl]amino}pyridin-3-yl)(cyclopropyl)methaneamine

[0979] Step 1: (1E)-1-(2-{bis[(4-methoxyphenyl)methyl]amino}pyridin-3-yl)-N-[(S)-(2-methylpropyl-2-yl)(oxoyl)-λ 4 [-thio]methaneimine

[0980] Cesium carbonate (8.99 g, 27.59 mmol, 2.0 eq) was added to a solution of 2-{bis[(4-methoxyphenyl)methyl]amino}pyridine-3-carboxaldehyde (5 g, 13.80 mmol) and (S)-tert-butylsulfinamide (2.51 g, 20.69 mmol, 1.5 eq) in dichloromethane (60 mL). The reaction mixture was stirred at 50 °C for 8 hours. The reaction mixture was filtered, and the filtrate was extracted with water (100 mL) and dichloromethane (20 mL x 2). The combined organic phases were washed successively with water (100 mL) and saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 0–30%) to obtain the product (5.8 g, yield: 90%), a yellow oily liquid. MS m / z: 466.0 [M+H] + . 1 H NMR(400MHz, CDCl3)δ8.90(s,1H),8.38(dd,J=4.8,2.0Hz,1H),8.17(dd,J=7.6,2.0Hz,1H),7.19–7.0 3(m,4H),6.97(dd,J=7.7,4.7Hz,1H),6.86–6.73(m,4H),4.49–4.24(m,4H),3.78(s,6H),1.25(s,9H).

[0981] Step 2: 3-[(R)-{[(S)-(2-methylpropyl-2-yl)(oxonyl)-λ 4 [-thio]amino}(cyclopropyl)methyl]-2-{bis[(4-methoxyphenyl)methyl]amino}pyridine

[0982] Under nitrogen protection at 0℃, the (1E)-1-(2-{bis[(4-methoxyphenyl)methyl]amino}pyridin-3-yl)-N-[(S)-(2-methylpropyl-2-yl)(oxonyl)-λ 4 [-Thio]methaneimine (2 g, 4.30 mmol) was dissolved in tetrahydrofuran (40 mL), and a solution of cyclopropylmagnesium bromide in tetrahydrofuran (6.880 mL, 6.88 mmol) was added dropwise. The reaction mixture was stirred at 0 °C for 15 minutes. The reaction mixture was quenched with saturated ammonium chloride aqueous solution (100 mL) and extracted with ethyl acetate (50 mL * 2). The organic phases were combined and washed successively with water (100 mL) and saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 0–40%) to obtain the product (2 g, yield: 92%), a yellow oily liquid. MS m / z: 508.1 [M+H] + .1 H NMR (400MHz, CDCl3) δ8.31(d,J=4.5Hz,1H),7.77(s,1H),7.14(d,J=8.0Hz,4H),7.05(s,1H),6.86–6.77(m,4H),4.41–4.10(m,5H),3.7 8(s,6H),3.56–3.42(m,1H),1.32–1.22(m,1H),1.12(s,9H),0.74–0.60(m,1H),0.39(p,J=5.7,4.9Hz,2H),0.29(q,J=6.0,5.6Hz,1H).

[0983] Step 3: (R)-(2-{bis[(4-methoxyphenyl)methyl]amino}pyridin-3-yl)(cyclopropyl)methaneamine

[0984] Under nitrogen protection, towards 3-[(R)-{[(S)-(2-methylpropyl-2-yl)(oxonyl)-λ 4 Iodine (0.44 g, 1.75 mmol) was added to a solution of 2.0 g (4.33 mmol) of pyridine in water (5 mL) and tetrahydrofuran (50 mL). The reaction mixture was stirred at 50 °C for 2 hours under nitrogen protection. The reaction was monitored by TLC (dichloromethane / methanol = 10:1) until completion. A saturated sodium thiosulfate aqueous solution (20 mL) was added to the reaction mixture, which was quenched with ammonia (1 mL) and extracted with ethyl acetate (10 mL * 3). The organic phase was washed successively with water (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. The crude product was purified by silica gel column chromatography (dichloromethane / methanol, 0–5%) to obtain the product (1.3 g, yield: 74%), a colorless oily liquid. MS m / z: 403.9 [M+H] + . 1 H NMR(400MHz, CDCl3)δ8.42(dd,J=4.7,1.9Hz,1H),7.87(dd,J=7.7,1.9Hz,1H),7.21–6.99(m,5H),6.90–6.64(m,4H),4.28–3 .95(m,6H),3.77(s,6H),3.62(d,J=9.0Hz,1H),1.19–1.06(m,1H),0.72–0.56(m,1H),0.49–0.33(m,2H),0.07–-0.07(m,1H).

[0985] Intermediate A19: (R)-3-(1-aminoprop-2-yn-1-yl)-N,N-bis(4-methoxybenzyl)pyridine-2-amine

[0986] Step 1: 2-(Di(4-methoxybenzyl)amino)pyridine-3-carboxaldehyde

[0987] 2-Fluoropyridine-3-carboxaldehyde (5 g, 39.97 mmol) and bis(4-methoxybenzyl)amine (13.37 g, 51.96 mmol) were dissolved in N,N-dimethylacetamide (80 mL), and potassium carbonate (16.57 g, 119.90 mmol) was added. The mixture was stirred at 90 °C for 1 hour. The reaction solution was diluted with water (500 mL), extracted with ethyl acetate (100 mL x 3), and the organic phases were combined and washed once with saturated brine (100 mL). The mixture was dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (petroleum ether / ethyl acetate = 5:1) to give 12 g of a yellow oil (yield: 82%). ESI-MS m / z: 363.1 [M+H] + .

[0988] Step 2: (S,E)-N-((2-(bis(4-methoxybenzyl)amino)pyridin-3-yl)methylene)-2-tert-butyl-2-sulfinamide

[0989] 2-(di(4-methoxybenzyl)amino)pyridine-3-carboxaldehyde (12 g, 33.11 mmol) and (S)-tert-butylsulfinamide (4.41 g, 36.42 mmol) were dissolved in dichloromethane (100 mL), and cesium carbonate (12.95 g, 39.73 mmol) was added. The mixture was stirred at 10 °C for 1 hour. The reaction solution was diluted with water (100 mL), separated, and the organic phase was dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (petroleum ether / ethyl acetate = 3 / 1). 15.4 g of a pale yellow oil was obtained (yield: 99%). ESI-MS m / z: 466.2 [M+H] + .

[0990] Step 3: (S)-N-((S)-1-(2-(bis(4-methoxybenzyl)amino)pyridin-3-yl)-3-(trimethylsilyl)prop-2-yn-1-yl)-2-methylpropane-2-sulfinamide

[0991] (S,E)-N-((2-(di(4-methoxybenzyl)amino)pyridin-3-yl)methylene)-2-tert-butyl-2-sulfinamide (3 g, 6.44 mmol) was dissolved in dichloromethane (30 mL). The system was protected with argon and cooled to -70 °C. A solution of magnesium chloride tetrahydrofuran (40 mL, 20.00 mmol, 0.5 mmol / mL) was added dropwise. The reaction was stirred at -70 °C for 0.5 h. Subsequently, it was stirred at room temperature for about 6 h. The conversion of the starting material was monitored by LC-MS to ensure complete conversion. The reaction was quenched with saturated ammonium chloride. It was then extracted with dichloromethane (100 mL) and saturated brine (100 mL). The dichloromethane phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (ethyl acetate-petroleum ether, 0-30% gradient elution) to give a product (3 g, 5.32 mmol, 82.58%) as a yellow oil. ESI-MS m / z: 564.3 [M+1] + ; 1 H NMR (400MHz, CDCl3) δ8.31(dd,J=4.9,1.9Hz,1H),7.88(d,J=7.6Hz,1H),7.20(d,J=8.2Hz,4H),7.04(d,J=7.2Hz,1H),6. 87-6.77(m,4H),5.87(d,J=3.0Hz,1H),4.33(d,J=14.0Hz,2H),4.19-4.08(m,2H),3.77(s,6H),1.14(s,9H),0.07(s,9H).

[0992] Step 4: (S)-3-(1-amino-3-(trimethylsilyl)prop-2-yn-1-yl)-N,N-bis(4-methoxybenzyl)pyridine-2-amine

[0993] (S)-N-((S)-1-(2-(di(4-methoxybenzyl)amino)pyridin-3-yl)-3-(trimethylsilyl)prop-2-yn-1-yl)-2-methylpropane-2-sulfinamide (3 g, 5.32 mmol) was dissolved in a mixture of tetrahydrofuran (60 mL) and water (12 mL). Sodium carbonate (2.82 g, 26.60 mmol), 4-dimethylaminopyridine (0.33 g, 2.66 mmol), and iodine (2.70 g, 10.64 mmol) were added. The reaction was stirred at 55 °C for 30 minutes. Iodine (1 g) was added, and the reaction was stirred for another 60 minutes. Iodine (1 g) was added again, and the reaction was stirred for another 60 minutes. The reaction was quenched with 10% sodium thiosulfate, followed by extraction with ethyl acetate (100 mL) and saturated sodium bicarbonate (50 mL). The ethyl acetate phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (ethyl acetate-petroleum ether, 0-25% gradient elution) to give a product (1.17 g, 2.55 mmol, 47.84%) as a brown oil. ESI-MS m / z: 460.2 [M+1] + ; 1 H NMR (400MHz, CDCl3) δ8.34 (dd, J=4.8, 1.9Hz, 1H), 7.90 (dd, J=7.6, 1.9Hz, 1H), 7.19-7.11 (m, 4H), 7.06 (dd, J=7.6, 4.7Hz, 1H), 6.84-6.74 (m, 4H), 5.25 (s, 1H), 4.27 (d, J = 13.7Hz, 2H), 4.14 (d, J = 9.3Hz, 2H), 3.77 (s, 6H), 1.94 (s, 2H), 0.11 (s, 9H).

[0994] Step 5: (R)-3-(1-aminoprop-2-yn-1-yl)-N,N-bis(4-methoxybenzyl)pyridine-2-amine

[0995] (S)-3-(1-amino-3-(trimethylsilyl)prop-2-yn-1-yl)-N,N-bis(4-methoxybenzyl)pyridine-2-amine (1.17 g, 2.55 mmol) was dissolved in tetrahydrofuran (10 mL). A tetrabutylammonium fluoride solution in tetrahydrofuran (1.0 M, 2.545 mL, 2.55 mmol) was added. The reaction was stirred at room temperature for 15 minutes. The reaction mixture was extracted with ethyl acetate (30 mL) and saturated sodium bicarbonate (20 mL). The ethyl acetate phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (ethyl acetate-petroleum ether, 0-50% gradient elution) to give the product (850 mg, 2.19 mmol, 86.19%) as a brown oil. ESI-MS m / z: 388.2 [M+1] + ; 1 H NMR (400MHz, DMSO-d6) δ8.15(dd,J=4.7,1.9Hz,1H),7.99(dd,J=7.6,1.9Hz,1H),7.19-7.12(m,4H),7.06(dd,J=7.6,4. 7Hz,1H),6.86-6.80(m,4H),5.12(d,J=2.4Hz,1H),4.29-4.16(m,4H),3.70(s,6H),3.27(d,J=2.2Hz,1H),2.38(s,2H).

[0996] Intermediate A20: (R)-3-(1-aminopropyl(1-deuterated)-2-yn-1-yl)-N,N-bis(4-methoxybenzyl)pyridine-2-amine

[0997] Step 1: (S)-N-((R)-1-(2-(bis(4-methoxybenzyl)amino)pyridin-3-yl)(1-deuterated)prop-2-yn-1-yl)-2-methylpropane-2-sulfinamide

[0998] Under nitrogen protection and at -70°C to -60°C, acetylated magnesium bromide (90.009 mL, 45.00 mmol) was slowly added to a tetrahydrofuran (20 mL) solution of (S,E)-N-((2-(di(4-methoxybenzyl)amino)pyridin-3-yl)methylene(1-deuterated)methyl)-2-methylpropane-2-sulfinamide (2 g, 4.17 mmol) and the reaction mixture was heated to room temperature and stirred for 4 hours. After the reaction was complete, the reaction mixture was diluted with saturated ammonium chloride (50 mL) and extracted with ethyl acetate (3 × 50 mL). The organic phases were combined and washed with saturated brine (1 × 100 mL). The organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-petroleum ether, 0-19% gradient elution) to give the product (2.3 g, 4.67 mmol, 51.87%), a yellowish oil. ESI-MS m / z: 493.1 [M+1] + . 1 H NMR(400MHz, DMSO-d6)δ8.20(dd,J=4.7,1.9Hz,1H),8.02(dd,J=7.7,1.9Hz,1H),7.20–7.16(m,4H),7.12(dd, J=7.7,4.7Hz,1H),6.85–6.79(m,4H),6.35(s,1H),4.26–4.08(m,4H),3.70(s,6H),3.53(s,1H),1.01(s,9H).

[0999] Step 2: (R)-3-(1-aminopropyl(1-deuterated)-2-yn-1-yl)-N,N-bis(4-methoxybenzyl)pyridine-2-amine

[1000] Under nitrogen protection, iodine (0.36 g, 1.40 mmol) was added to a solution of (S)-N-((R)-1-(2-(di(4-methoxybenzyl)amino)pyridin-3-yl)(1-deuterated)prop-2-yn-1-yl)-2-methylpropane-2-sulfinamide (1.7 g, 3.28 mmol) in water (8 mL) and tetrahydrofuran (40 mL). The reaction system was stirred at 55 °C for 2 hours. After the reaction was complete, saturated sodium sulfite aqueous solution (50 mL) was added, followed by extraction with ethyl acetate (3 × 30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (ethyl acetate-petroleum ether, 0-30% gradient elution) to give the product (1.5 g, 3.86 mmol, 82.70%), a reddish oil. ESI-MS m / z: 389.2 [M+1] + . 1H NMR(400MHz, DMSO-d6)δ8.15(dd,J=4.7,1.9Hz,1H),7.98(dd,J=7.6,1.9Hz,1H),7.18–7.11(m,4H),7. 06(dd,J=7.6,4.7Hz,1H),6.86–6.79(m,4H),4.31–4.17(m,4H),3.70(s,6H),3.27(s,1H),2.38(s,2H).

[1001] Intermediate A21: (1S)-1-(2-{bis[(4-methoxyphenyl)methyl]amino}pyridin-3-yl)(1-deuteryl)but-2-yne-1-amine

[1002] Step 1: 3-[(1S)-1-{[(S)-(2-methylpropyl-2-yl)(oxo-subunit)-λ 4 [-thio]amino}(1-deuteryl)but-2-ynyl]-2-{bis[(4-methoxyphenyl)methyl]amino}pyridine

[1003] (1E)-1-(2-{bis[(4-methoxyphenyl)methyl]amino}pyridin-3-yl)-N-[(S)-(2-methylpropyl-2-yl)(oxoyl)-λ 4 [-Thio]deuterated methaneimine (2.5 g, 5.36 mmol) was dissolved in dichloromethane (30 mL). The system was protected with argon and cooled to -70 °C. A tetrahydrofuran solution of magnesium 1-propyne bromide (0.5 mol / L, 32 mL, 16.00 mmol) was added. The reaction was stirred at -70 °C for 0.5 h. It was then stirred at room temperature for about 2 h. The reaction was quenched with saturated ammonium chloride. Extraction was then performed with dichloromethane (100 mL) and saturated brine (100 mL). The dichloromethane phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (ethyl acetate-petroleum ether, 0-30% gradient elution) to give the product (1.9 g, 3.75 mmol, 70%) as a yellow oil. ESI-MS m / z: 507.2 [M+1] + ;

[1004] 1H NMR(400MHz, DMSO-d6)δ8.13(dd,J=4.7,1.9Hz,1H),7.94(dd,J=7.7,1.9Hz,1H),7.19–7.09(m,4H),7.05(dd, J=7.7,4.7Hz,1H),6.82–6.66(m,4H),6.13(s,1H),4.25–4.02(m,4H),3.66(s,6H),1.73(s,3H),0.96(s,9H).

[1005] Step 2: (1S)-1-(2-{bis[(4-methoxyphenyl)methyl]amino}pyridin-3-yl)(1-deuteryl)but-2-yne-1-amine

[1006] 3-[(1S)-1-{[(S)-(2-methylpropyl-2-yl)(oxo-ylidene)-λ 4 [-thio]amino}(1-deuteryl)but-2-ynyl]-2-{bis[(4-methoxyphenyl)methyl]amino}pyridine (1.9 g, 3.75 mmol) was dissolved in a mixture of tetrahydrofuran (100 mL) and water (10 mL), and iodine (0.38 g, 1.5 mmol) was added. The reaction was stirred at 50 °C for 3 hours. The reaction was quenched with 10% sodium thiosulfate, followed by extraction with ethyl acetate (100 mL) and saturated sodium bicarbonate (50 mL). The ethyl acetate phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (tetrahydrofuran-petroleum ether, 0-40% gradient elution) to give the product (1.46 g, 3.63 mmol, 96.73%) as a brown oil. ESI-MS m / z: 403.2 [M+1] + ; 1 H NMR (400MHz, DMSO-d6) δ8.13(dd,J=4.8,1.9Hz,1H),7.96(dd,J=7.7,1.9Hz,1H),7.15(d,J=8.3Hz,4H),7.0 4(dd,J=7.6,4.7Hz,1H),6.88–6.79(m,4H),4.34–4.18(m,4H),3.70(s,6H),2.33–2.18(m,2H),1.75(s,3H).

[1007] Intermediate B1: [(2R,6S,7aS)-2-fluoro-6-[(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)methyl]-2,3,5,6,7,7a-hexahydro-1H-pyridine-7a-yl]methanol

[1008] Step 1: [(2S,6R,7aS)-7a-(4,4-dimethyl-3,3-diphenyl-2-oxa-3-silaxapran-1-yl)-6-fluoro-2,3,5,6,7,7a-hexahydro-1H-pyridine-2-yl]methanol

[1009] To a solution of (2R,6R,7aS)-7a-(4,4-dimethyl-3,3-diphenyl-2-oxa-3-silazopent-1-yl)-6-fluoro-2-(hydroxymethyl)-2,3,5,6,7,7a-hexahydro-1H-pyridine-3-one (prepared according to the method in patent CN116514847 A, 500 mg, 1.13 mol, 1.0 eq) in tetrahydrofuran (10 mL), borane dimethyl sulfide (11.3 mL, 1 M, 10.0 eq) was added. The reaction mixture was stirred at 40 °C for 30 min. The reaction mixture was quenched with methanol (40 mL), and the solvent was evaporated to dryness. Then, methanol (40 mL) was added, and the reaction mixture was stirred at 60 °C for 1 h. The solvent was evaporated to dryness, and the product was purified by silica gel column chromatography (dichloromethane:methanol = 9:1) to give a colorless oily liquid product (450 mg, yield: 93%). MS m / z: 428.2 [M+H] + . 1 H NMR (400MHz, CDCl3) δ7.81–7.60(m,4H),7.53–7.34(m,6H),5.26(d,J=53.6Hz,1H),3.63(t,J=5.7Hz,2H),3.51(d,J =12.2Hz,1H),3.29(d,J=75.3Hz,3H),2.77(s,1H),2.38(s,1H),2.27–2.01(m,3H),1.36–1.23(m,2H),1.10(s,9H).

[1010] Step 2: (2R,6S,7aS)-7a-(4,4-dimethyl-3,3-diphenyl-2-oxa-3-silazopent-1-yl)-2-fluoro-6-[(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)methyl]-2,3,5,6,7,7a-hexahydro-1H-pyridine

[1011] Add 3,4-dihydro-2H-pyran (904.6 mg, 10.76 mmol, 10.0 eq) to a solution of [(2S,6R,7aS)-7a-(4,4-dimethyl-3,3-diphenyl-2-oxa-3-silazopent-1-yl)-6-fluoro-2,3,5,6,7,7a-hexahydro-1H-pyrrin-2-yl]methanol (460 mg, 1.087 mmol, 1.0 eq) and p-toluenesulfonic acid (279.0 mg, 1.62 mmol, 1.5 eq) in tetrahydrofuran (15 mL). Stir the reaction mixture at room temperature for 30 minutes, quench the reaction mixture with saturated sodium bicarbonate aqueous solution (50 mL), and extract with ethyl acetate (50 mL * 3). The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, evaporated to dryness, and purified by column chromatography (dichloromethane:methanol = 9:1) to give a colorless oily liquid product (520 mg, yield: 94%). MS m / z: 512.3 [M+H] + . 1 H NMR (400MHz, CDCl3) δ7.74–7.63(m,4H),7.48–7.35(m,6H),5.23(d,J=53.6 Hz,1H),4.62–4.54(m,1H),4.10–3.74(m,2H),3.76–3.65(m,1H),3.65–3.4 5(m,3H),3.45–3.27(m,3H),3.24–2.90(m,2H),2.74(s,1H),2.55–2.36(m, 1H),2.26–1.96(m,3H),1.94–1.77(m,2H),1.76–1.61(m,3H),1.08(s,9H).

[1012] Step 3: [(2R,6S,7aS)-2-fluoro-6-[(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)methyl]-2,3,5,6,7,7a-hexahydro-1H-pyridine-7a-yl]methanol

[1013] Potassium fluoride (2.95 g, 50.0 eq) was added to a methanol (10 mL) solution of (2R,6S,7aS)-7a-(4,4-dimethyl-3,3-diphenyl-2-oxa-3-silazopent-1-yl)-2-fluoro-6-[(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)methyl]-2,3,5,6,7,7a-hexahydro-1H-pyridine (520 mg, 1.02 mmol, 1.0 eq). The reaction mixture was stirred at 60 °C for 2 hours. The solvent was evaporated to dryness, and then dichloromethane (50 mL) was added. The mixture was filtered, and the filtrate was evaporated to dryness and purified by silica gel chromatography (dichloromethane:methanol = 9:1, v / v) to give a colorless oily liquid product (100 mg, yield: 36%). MS m / z: 274.2 [M+H] + . 1 H NMR (400MHz, CDCl3) δ5.36–5.16(m,1H),4.57(h,J=1.4Hz,1H),3.83(tt,J=7.6,3.9Hz,1H ),3.74(ddd,J=11.2,9.6,6.7Hz,1H),3.57–3.42(m,2H),3.42–3.34(m,2H),3.31(d,J=10 .7Hz,1H),3.29–3.15(m,1H),3.15–2.95(m,1H),2.79(ddt,J=10.7,9.0,1.5Hz,1H),2.60 –2.51(m,1H),2.18–2.11(m,1H),2.11–1.91(m,2H),1.89–1.66(m,3H),1.64–1.46(m,4H).

[1014] Intermediate B2: [(2R,6R,7aS)-2-fluoro-6-[(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)methyl]-2,3,5,6,7,7a-hexahydro-1H-pyridine-7a-yl]methanol

[1015] Intermediate B2, a colorless oily liquid, was obtained using (2S,6R,7aS)-7a-(4,4-dimethyl-3,3-diphenyl-2-oxa-3-silazopent-1-yl)-6-fluoro-2-(hydroxymethyl)-2,3,5,6,7,7a-hexahydro-1H-pyridine-3-one as a starting material, through a method similar to that used in the synthesis of intermediate B1. MS m / z: 274.2 [M+H] + .

[1016] Intermediate B3: Dideuteryl[(2R,7aS)-5,5-dideuteryl-2-fluoro-2,3,5,6,7,7a-hexahydro-1H-pyridine-7a-yl]methanol

[1017] Step 1: Dideuteryl[(2R,7aS)-5,5-dideuteryl-2-fluoro-2,3,5,6,7,7a-hexahydro-1H-pyridine-7a-yl]methanol

[1018] Methyl (2R,7aS)-2-fluoro-5-oxoylide-2,3,5,6,7,7a-hexahydro-1H-pyridine-7a-carboxylate (200 mg, 0.99 mmol) was dissolved in 2-methyltetrahydrofuran (5 mL). Lithium aluminum deuterate (166.92 mg, 3.98 mmol) was added under ice bath conditions, and the mixture was heated to 90 °C and stirred for 2 hours. Sodium sulfate decahydrate was added to the reaction mixture, and the mixture was filtered and concentrated under reduced pressure. The product, a colorless, transparent liquid (160 mg, yield 98.4%), was obtained. m / z: 164.1 [M+1] + . 1 H NMR (400MHz, CDCl3) δ5.36–5.09(m,1H),3.20–2.99(m,2H),2.14–1.71(m,6H).

[1019] Intermediate B4: ((5S,7aS)-5-(((2S,6R)-2,6-dimethylmorpholino)methyl)-2-methylenehexahydro-1H-pyrrolizin-7a-yl)methanol

[1020] Step 1: (5S)-methyl 5-(((2S,6R)-2,6-dimethylmorpholino)methyl)-2-methylenehexahydro-1H-pyrrolizine-7a-carboxylic acid ester

[1021] At 0 °C, methanesulfonyl chloride (975.88 mg, 8.52 mmol) was added to a solution of (5S)-methyl 5-(hydroxymethyl)-2-methylenehexahydro-1H-pyrrolizin-7a-carboxylic acid ester (900 mg, 4.26 mmol) and triethylamine (1.776 mL, 12.78 mmol) in 10 mL of dichloromethane. The reaction mixture was stirred for 40 minutes. After the reaction was complete, the reaction mixture was diluted with saturated sodium chloride (30 mL), extracted with dichloromethane (3 × 20 mL), and the organic phases were combined and washed with saturated brine (1 × 50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was added to acetonitrile (10 mL), potassium carbonate (2292.59 mg, 16.59 mmol), and (cis)-2,6-dimethylmorpholine (1433.03 mg, 12.44 mmol), and the reaction was stirred at room temperature for 12 hours. After the reaction was complete, the reaction solution was filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (methanol-dichloromethane, 0-4% gradient elution) to give the product (600 mg, 1.95 mmol, 46.91%), a yellowish oil. ESI-MS m / z: 309.2 [M+1] + .

[1022] Step 2: ((5S,7aS)-5-(((2S,6R)-2,6-dimethylmorpholino)methyl)-2-methylenehexahydro-1H-pyrrolizin-7a-yl)methanol

[1023] Under nitrogen protection and at 0 °C, sodium borohydride (110.39 mg, 2.92 mmol) was added to a methanol (5 mL) solution of (5S)-methyl 5-(((2S,6R)-2,6-dimethylmorpholino)methyl)-2-methylenehexahydro-1H-pyrrolizin-7a-carboxylic acid ester (300 mg, 0.67 mmol) and lithium chloride (123.70 mg, 2.92 mmol). The reaction was stirred at 60 °C for 2 hours. After the reaction was complete, the reaction solution was filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (methanol-dichloromethane, 0-4% gradient elution) to give the product (140 mg, 0.50 mmol, 51.33%), which was a colorless oil. ESI-MS m / z: 281.3 [M+1]+.

[1024] Intermediate B5: (S)-(2-methylisoxazolidine-3-yl)methanol

[1025] Step 1: (S)-Ethylisoxazolidine-3-carboxylic acid ester trifluoroacetate

[1026] (S)-2-tert-butyl-3-ethylisoxazolidine-2,3-dicarboxylic acid ester (1 g, 4.08 mmol) was dissolved in dichloromethane (10 mL), and the system was cooled in an ice bath. Trifluoroacetic acid (2.5 mL) was slowly added dropwise. The reaction was then stirred at room temperature for 1 hour. The reaction was monitored for completeness. The reaction solution was directly concentrated, and the residue was used directly in the next reaction. ESI-MS m / z: 146.2 [M+1] + .

[1027] Step 2: (S)-Ethyl 2-methylisoxazolidine-3-carboxylic acid ester

[1028] (S)-ethylisoxazolidine-3-carboxylic acid ester trifluoroacetate (591 mg, 4.07 mmol) was dissolved in tetrahydrofuran (20 mL), and formaldehyde aqueous solution (4.054 mL, 40.71 mmol) was added. The system was protected with argon and stirred at room temperature for 15 minutes. Sodium borohydride acetate (1725 mg, 8.14 mmol) was added. The reaction was stirred at room temperature for 1.5 hours. The starting material was monitored to be almost completely converted. Saturated sodium bicarbonate was added to adjust the pH of the aqueous phase to 8-9. The aqueous phase was extracted twice with ethyl acetate (50 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (ethyl acetate-petroleum ether, 0-50% gradient elution) to give the product (460 mg, 2.89 mmol, 70.77%) as a colorless oil. ESI-MS m / z: 160.2 [M+1] + ; 1 H NMR (400MHz, CDCl3) δ4.23 (q, J = 7.1Hz, 2H), 4.07-3.91 (m, 2H), 3.42-3.41 (m, 1H), 2.77 (s, 3H), 2.60-2.47 (m, 2H), 1.31 (t, J = 7.1Hz, 3H).

[1029] Step 3: (S)-(2-methylisoxazolidine-3-yl)methanol

[1030] (S)-Ethyl 2-methylisoxazolidine-3-carboxylic acid ester (460 mg, 2.89 mmol) was dissolved in methanol (5 mL), and lithium chloride (367 mg, 8.67 mmol) was added. The system was cooled in an ice bath under argon protection. Sodium borohydride (327 mg, 8.67 mmol) was added in portions. The reaction was stirred at room temperature for 3 hours. The reaction was monitored for completeness. The reaction mixture was diluted with dichloromethane, mixed directly, and purified by column chromatography (methanol-dichloromethane, 0-8% gradient elution) to give the product (232 mg, 1.98 mmol, 68.24%) as a colorless oil. ESI-MS m / z: 118.2 [M+1] + ; 1 HNMR(400MHz, CDCl3)δ4.05-3.99(m,1H),3.90-3.84(m,1H),3.54-3.39(m,2H),3 .06-3.02(m,1H),2.76(s,1H),2.68(s,3H),2.46-2.37(m,1H),1.98-1.90(m,1H).

[1031] Intermediate B6: ((3S,6S)-1,1-difluoro-5-methyl-5-azaspiro[2,4]heptane-6-yl)methanol

[1032] At 0-5°C, a tetrahydrofuran solution (1.08 mL, 2.7 mmol) of lithium aluminum hydride in tetrahydrofuran was added dropwise to (150 mg, 0.54 mmol) of (3S,6S)-5-(tert-butoxycarbonyl)-1,1-difluoro-5-azaspiro[2.4]heptane-6-carboxylic acid. After stirring for 30 minutes, the reaction mixture was heated to 70°C and stirred for 7 hours. Finally, sodium sulfate decahydrate was slowly added under ice bath conditions, and stirring was continued for 0.5 hours. The mixture was then filtered through diatomaceous earth, and the filtrate was concentrated to give 110 mg of a pale yellow oily crude product. ESI-MS m / z: 227.1 [M+H] + .

[1033] Intermediate B7: [(2R,7aS)-2-fluoro-2,3,5,6,7,7a-hexahydro(5,5-dideuterated)-1H-pyridine-7a-yl]methanol

[1034] (6R,7aS)-7a-(4,4-dimethyl-3,3-diphenyl-2-oxa-3-silazopent-1-yl)-6-fluoro-2,3,5,6,7,7a-hexahydro-1H-pyrrin-3-one (1 g, 2.43 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL), and lithium aluminum deuterate (0.15 g, 3.64 mmol) was added at 0 °C. The reaction was stirred at 60 °C. After the reaction was complete, sodium sulfate decahydrate was slowly added to quench the reaction. The mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol-dichloromethane, 0-10% gradient elution) to give a colorless oily product (120 mg, 0.74 mmol, 30.6%). ESI-MS m / z: 162.1 [M+H] + . 1 H NMR (400MHz, CDCl3) δ5.28 (ddt, J=4.5, 3.0, 1.5Hz, 1H), 5.17–5.13 (m, 1H), 3.21–3.15(m,2H),3.15–3.09(m,2H),2.19–2.09(m,2H),1.97–1.86(m,4H).

[1035] Intermediate B8: [(2'R,7a'S)-2'-fluoro-1',2',3',6',7',7a'-hexahydrospiro[cyclopropane-1,5'-pyridine]-7a'-yl]methanol

[1036] Step 1: (2'R,7a'S)-7a'-(4,4-dimethyl-3,3-diphenyl-2-oxa-3-silazopent-1-yl)-2'-fluoro-1',2',3',6',7',7a'-hexahydrospiro[cyclopropane-1,5'-pyridine]

[1037] (6R,7aS)-7a-(4,4-dimethyl-3,3-diphenyl-2-oxa-3-silazopent-1-yl)-6-fluoro-2,3,5,6,7,7a-hexahydro-1H-pyrrin-3-one (1 g, 2.43 mmol) and tetraisopropyl titanate (2.07 g, 7.29 mmol) were dissolved in anhydrous tetrahydrofuran (20 mL). Ethyl magnesium bromide (12.15 mL, 12.15 mmol) was added at 0 °C, and the reaction was stirred at room temperature. After the reaction was complete, a saturated ammonium chloride solution was added to quench the reaction. The mixture was extracted with ethyl acetate (3 × 60 mL). The organic phases were combined and washed successively with water and saturated brine. The organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-petroleum ether, 0-30% gradient elution) to give a yellow liquid product (550 mg, 1.30 mmol, 53.40%). MS m / z: 423.9 [M+H]+ . 1 H NMR (400MHz, CDCl3) δ7.75–7.68(m,4H),7.48–7.40(m,4H),7.38(dt,J=6.4,1.7Hz,2H),5.12(d,J=56.0Hz,1H),3.53(d,J=15.5Hz,2H),3 .35–3.00(m,2H),2.38(ddd,J=39.5,14.7,7.7Hz,2H),2.19–2.02(m,1H),1.94(s,2H),1.26(d,J=22.6Hz,1H),1.08(s,9H),0.82(s,1H).

[1038] Step 2: [(2'R,7a'S)-2'-fluoro-1',2',3',6',7',7a'-hexahydrospiro[cyclopropane-1,5'-pyridine]-7a'-yl]methanol

[1039] (2'R,7a'S)-7a'-(4,4-dimethyl-3,3-diphenyl-2-oxa-3-silazopent-1-yl)-2'-fluoro-1',2',3',6',7',7a'-hexahydrospiro[cyclopropane-1,5'-pyridine] (550 mg, 1.30 mmol) was dissolved in methanol (10 mL), and potassium fluoride (3.77 g, 64.91 mmol) was added. The reaction mixture was stirred at 80 °C. After the reaction was complete, the mixture was filtered through diatomaceous earth and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol-dichloromethane, 0-10% gradient elution) to give a yellow oily product (150 mg, 0.81 mmol, 62.5%). MS m / z: 186.1 [M+H] + . 1 H NMR(400MHz, CDCl3)δ5.12(dtt,J=55.3,4.5,2.1Hz,1H),3.47(d,J=10.7Hz,1H),3.41–3.12(m,3H),2.49–2.29(m,2H),2.15–1.93(m,2H),1.80 (ddd,J=13.4,10.6,8.2Hz,1H),1.37–1.25(m,1H),0.88(dt,J=12.2,5.8Hz,1H),0.66(dd,J=11.0,5.2Hz,2H),0.45(dq,J=9.9,5.0,4.0Hz,1H).

[1040] Intermediate B9: [(2R)-2-fluoro-6-methyl-2,3,5,6,7,7a-hexahydro-1H-pyridine-7a-yl]methanol

[1041] Step 1: (4R)-2-[2-(chloromethyl)prop-2-enyl]-4-fluoro-1-{[(2-methylprop-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylic acid methyl ester

[1042] Methyl (2S,4R)-4-fluoro-1-{[(2-methylprop-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylate (1.24 g, 5.01 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL). Bistrimethylsilylaminolithium (10.03 mL, 10.03 mmol) was added at -70 °C, and the mixture was stirred for 15 min. Then, 3-chloro-2-chloromethylpropene was added, and the reaction was continued with stirring for 1 h. After the reaction was complete, a saturated ammonium chloride solution was added to quench the reaction. The mixture was extracted with ethyl acetate (3 × 40 mL). The combined organic phases were washed successively with water and saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-petroleum ether, 0-20% gradient elution) to give a yellow liquid product (1.35 g, 4.02 mmol, 80.4%). MS m / z: 336.1 [M+H] + . 1 H NMR (400MHz, CDCl3) δ5.46(t,J=1.4Hz,1H),5.15(tt,J=4.7,1.9Hz,0.5H),5.11(s,1H),5.02(tt,J=4 .6,1.9Hz,0.5H),4.22–3.83(m,4H),3.77(d,J=6.4Hz,3H),2.86–2.26(m,4H),1.50(d,J=3.3Hz,9H).

[1043] Step 2: (2R)-2-fluoro-6-methyl-2,3,5,6,7,7a-hexahydro-1H-pyridine-7a-carboxylic acid methyl ester

[1044] Methyl (4R)-2-[2-(chloromethyl)prop-2-enyl]-4-fluoro-1-{[(2-methylprop-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylate (1.35 g, 4.02 mmol) was dissolved in acetonitrile (40 mL), and dioxane hydrochloride solution (10 mL) was added under ice bath conditions. The reaction mixture was stirred at room temperature for 1 h. Sodium bicarbonate (16.89 g, 201.01 mmol) was then added, and stirring continued for 1 h. After the reaction was complete, the mixture was filtered through diatomaceous earth and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol-dichloromethane, 0-10% gradient elution) to give a pale yellow oily product (0.78 g, 3.92 mmol, 97.5%). MS m / z: 200.1 [M+H] + .1 H NMR(400MHz, CDCl3) δ5.24(dddt,J=53.4,5.0,4.0,1.1Hz,1H),5.04–4.87(m,2H),3.95–3.84(m,1H),3.77(s,3H),3.60–3.4 5(m,1H),3.24(dq,J=14.8,1.8Hz,1H),2.99–2.77(m,3H),2.54(dq,J=16.2,1.9Hz,1H),2.09(ddd,J=36.9,15.0,4.9Hz,1H).

[1045] Step 3: [(2R)-2-fluoro-6-methyl-2,3,5,6,7,7a-hexahydro-1H-pyridine-7a-yl]methanol

[1046] Methyl (2R)-2-fluoro-6-methyl-2,3,5,6,7,7a-hexahydro-1H-pyridine-7a-carboxylate (730 mg, 3.92 mmol) was dissolved in anhydrous tetrahydrofuran (15 mL). Lithium aluminum hydride (4.70 mL, 4.70 mmol) was added under argon atmosphere in an ice bath, and the reaction was stirred for 0.5 h. After the reaction was complete, sodium sulfate decahydrate was added to quench the reaction, and the mixture was filtered through diatomaceous earth and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol-dichloromethane, 0-10% gradient elution) to give a colorless oily product (550 mg, 3.21 mmol, 82.1%). MS m / z: 172.1 [M+H] + . 1 H NMR (400MHz, CDCl3) δ5.17(dddt,J=54.1,5.5,4.2,1.3Hz,1H),4.91(dp,J=18.9,2.2Hz,2H),3.62(dp,J=15.3,1.8Hz,1H),3.40–3.26(m,3 H),3.19(dq,J=15.2,1.8Hz,1H),2.89–2.72(m,2H),2.48(dp,J=16.3,1.9Hz,1H),2.33–2.19(m,2H),2.03(ddd,J=34.9,15.1,5.7Hz,1H).

[1047] Intermediate B10: [2-(difluoromethyl)-2,3,5,6,7,7a-hexahydro-1H-pyridine-7a-yl]methanol

[1048] Step 1: 3-(difluoromethylene)-1-{[(2-methylprop-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylic acid ethyl ester

[1049] Ethyl 1-{[(2-methylprop-2-yl)oxy]carbonyl}-3-oxomylidene-2-carboxylate (2.6 g, 10.11 mmol) and (triphenylphosphonium)difluoroacetic acid inner salt (10.08 g, 28.29 mmol) were dissolved in anhydrous N,N-dimethylformamide (50 mL). The reaction was carried out under an argon atmosphere at 80 °C with stirring for 2 h. After the reaction was complete, the mixture was extracted with ethyl acetate (3 × 120 mL). The organic phases were combined and washed with water and saturated brine (1 × 200 mL). The organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-petroleum ether, 0-10% gradient elution) to give a yellow oily product (1.8 g, 6.18 mmol, 61.2%). MS m / z: 292.1 [M+H] + . 1 H NMR (400MHz, CDCl3) δ4.86 (dd, J=36.2, 3.1Hz, 1H), 4.31–4.11 (m, 2H), 3.86– 3.48(m,2H),2.63(tq,J=6.9,3.4Hz,2H),1.47(s,9H),1.29(q,J=7.3Hz,3H).

[1050] Step 2: 2-(3-chloropropyl)-3-(difluoromethyl)-1-{[(2-methylpropyl-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylic acid ethyl ester

[1051] Following step 1 of the preparation of intermediate B9, a colorless oily product (1.5, 4.08 mmol, 79.3%) was obtained. MS m / z: 368.1 [M+H] + . 1 H NMR (400MHz, CDCl3) δ4.32–4.08(m,2H),3.80–3.59(m,2H),3.58–3.46(m,2H),2.74–2.47(m,3H),2.34– 2.18(m,1H),1.71(tdd,J=9.4,8.4,6.8,4.3Hz,2H),1.45(d,J=9.3Hz,9H),1.26(dt,J=13.3,7.2Hz,3H).

[1052] Step 3: 2-(difluoromethylene)-2,3,5,6,7,7a-hexahydro-1H-pyridine-7a-carboxylic acid ethyl ester

[1053] Following step 2 of the preparation of intermediate B9, a colorless oil (0.64 g, 2.77 mmol, 68.1%) was obtained. MS m / z: 232.0 [M / 2+H] + .

[1054] Step 4: [2-(difluoromethyl)-2,3,5,6,7,7a-hexahydro-1H-pyridine-7a-yl]methanol

[1055] Following step 3 of the preparation of intermediate B9, a colorless oily product was obtained (0.38 g, 2.01 mmol, 73.1%). MS m / z: 189.9 [M / 2+H] + . 1 H NMR (400MHz, CDCl3) δ3.49–3.35(m,2H),3.11–2.98(m,2H),2.88–2.79(m,1H),2.72–2.59(m,2H),2.53–2.41(m,1H),2.08–1.72(m,4H).

[1056] Intermediate B11: [(2S)-1-methylhexahydropyridin-2-yl]methanol

[1057] Step 1: [(2S)-1-methylhexahydropyridin-2-yl]methanol

[1058] (2S)-1-{[(2-methylpropyl-2-yl)oxy]carbonyl}hexahydropyridine-2-carboxylic acid (2 g, 8.72 mmol) was dissolved in anhydrous tetrahydrofuran (30 mL). Under nitrogen purging protection, a tetrahydrofuran solution of lithium aluminum hydride (34.892 mL, 34.89 mmol, 1 M) was slowly added under an ice-water bath, followed by heating at 70 °C for approximately 3 hours. After the reaction was complete, the mixture was transferred to an ice-water bath, and water (1.5 mL), 15% sodium hydroxide aqueous solution (1.5 mL), and water (4.5 mL) were slowly added dropwise sequentially. After stirring for another hour under an ice-water bath, ethyl acetate (10 mL) and anhydrous sodium sulfate were added. The mixture was filtered, concentrated by vacuum distillation, and the residue was purified by silica gel column chromatography (methanol-dichloromethane, 0-10% gradient elution) to give the product (580 mg, 4.49 mmol, 51.46%), a yellowish oil. ESI-MS m / z: 130.1 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ4.32(t,J=5.6Hz,1H),3.54–3.46(m,1H),3.30(dt,J=10.6,5.0Hz,1H),2.70(dt,J=11.4,3.4Hz,1H),2.17( s,3H),1.95(td,J=11.5,3.0Hz,1H),1.80–1.73(m,1H),1.71–1.58(m,2H),1.54–1.46(m,1H),1.45–1.32(m,1H),1.26–1.09(m,2H).

[1059] Intermediate B12: (1-methyl-2,3,5,6,7,7a-hexahydro-1H-pyridine-7a-yl)methanol

[1060] Step 1: 2-(ethoxycarbonyl)-3-methylpyrrolidine-1-carboxylic acid-2-methylpropyl-2-yl ester

[1061] Methyltriphenylphosphine bromide (10.41 g, 29.15 mmol) was added to tetrahydrofuran (200 mL), cooled to 0 °C, and potassium tert-butoxide (29.150 mL, 29.15 mmol) was added at 0 °C under nitrogen protection. After the addition was complete, the reaction mixture was stirred at room temperature for 1 hour. Ethyl 1-{[(2-methylpropyl-2-yl)oxy]carbonyl}-3-oxomylidene-2-carboxylate (3 g, 11.66 mmol) was dissolved in tetrahydrofuran (10 mL) and slowly added to the above reaction solution under nitrogen atmosphere at room temperature. After the addition was complete, the mixture was stirred at room temperature for 3 hours. Saturated ammonium chloride aqueous solution (30 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (100 mL × 3). The organic phase was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated by silica gel column chromatography (ethyl acetate-petroleum ether, 0-10% gradient elution) to give the product (1.5 g, 5.88 mmol, 50.39%) as a colorless liquid. ESI-MS m / z: 156.1 [M-100+H] + ; 1 H NMR (400MHz, CDCl3) δ5.26–5.16(m,1H),5.07(q,J=2.1Hz,1H),4.74–4.59(m,1H),4.30– 4.08(m,2H),3.68–3.47(m,2H),2.72–2.51(m,2H),1.48–1.39(m,9H),1.29–1.24(m,3H).

[1062] Step 2: 2-(3-chloropropyl)-2-(ethoxycarbonyl)-3-methylpyrrolidine-1-carboxylic acid-2-methylpropyl-2-yl ester

[1063] 2-(ethoxycarbonyl)-3-methylpyrrolidine-1-carboxylic acid-2-methylpropyl-2-yl ester (1.40 g, 5.48 mmol) was dissolved in anhydrous tetrahydrofuran (15 mL) under nitrogen protection. Diisopropylaminolithium (5.484 mL, 10.97 mmol) was slowly added dropwise at -70 °C. After stirring at this temperature for 1 hour, a solution of 1-chloro-3-iodopropane (3.36 g, 16.45 mmol) in anhydrous tetrahydrofuran (10 mL) was slowly added to the above solution. The reaction mixture was stirred at -70 °C for another hour, then slowly raised to room temperature and stirred for another hour. The reaction was quenched at room temperature with saturated ammonium chloride aqueous solution (30 mL), extracted with ethyl acetate (100 mL × 3), and the combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated by vacuum distillation. The crude product was separated by silica gel column chromatography (ethyl acetate-petroleum ether, 0-5% gradient elution) to give the product (1.48 g, 4.46 mmol, 81.33%) as a colorless oil. ESI-MS m / z: 231.9 [M-100+H] + ; 1 H NMR (400MHz, CDCl3) δ5.17–4.97(m,2H),4.24–3.99(m,2H),3.76–3.41(m,4H),2.75–2. 46(m,3H),2.19–2.04(m,1H),1.73–1.58(m,2H),1.48–1.39(m,9H),1.26–1.15(m,3H).

[1064] Step 3: 2-(3-chloropropyl)-3-methylpyrrolidine-2-carboxylic acid ethyl ester

[1065] 2-(3-chloropropyl)-2-(ethoxycarbonyl)-3-methylpyrrolidine-1-carboxylic acid-2-methylpropyl-2-yl ester (1.48 g, 4.46 mmol) was dissolved in acetonitrile (5 mL), and dioxane hydrochloride solution (4 M, 20 mL) was added at room temperature. The mixture was stirred at room temperature for 30 minutes. The solution was concentrated by vacuum distillation, and the crude product was used directly in the next reaction step.

[1066] Step 4: ethyl 1-methyl-2,3,5,6,7,7a-hexahydro-1H-pyridine-7a-carboxylate

[1067] Ethyl 2-(3-chloropropyl)-3-methylpyrrolidine-2-carboxylate (1 g, 4.32 mmol) was dissolved in acetonitrile (30 mL), and sodium bicarbonate (1.81 g, 21.58 mmol) and potassium iodide (0.07 g, 0.43 mmol) were added at room temperature. The mixture was stirred at room temperature for 2 hours. The reaction solution was filtered, the filter cake was washed with acetonitrile, and the filtrate was concentrated by vacuum distillation. The crude product was used directly in the next reaction step.

[1068] Step 5: (1-methyl-2,3,5,6,7,7a-hexahydro-1H-pyridine-7a-yl)methanol

[1069] Ethyl 1-methyl-2,3,5,6,7,7a-hexahydro-1H-pyridine-7a-carboxylate (967 mg, 4.95 mmol) was dissolved in tetrahydrofuran (20 mL) under nitrogen protection. Lithium aluminum hydride (9.905 mL, 9.90 mmol) was added dropwise in an ice-water bath for 1 hour. Then, water (0.15 mL), 15% NaOH aqueous solution (0.15 mL), and water (0.45 mL) were slowly added dropwise in an ice-water bath. After stirring for another 30 minutes in an ice-water bath, tetrahydrofuran and anhydrous sodium sulfate were added. The mixture was filtered, and the filtrate was concentrated by vacuum distillation. The crude product was used directly in the next reaction step. 1 H NMR (400MHz, DMSO-d6) δ4.91(s,1H),4.81(s,1H),4.34(s,1H),3.15(q,J=10.6Hz,2H),2.98–2.90(m ,1H),2.89–2.80(m,1H),2.64–2.54(m,1H),2.53–2.36(m,3H),1.92–1.80(m,1H),1.74–1.51(m,3H).

[1070] Intermediate B13: [(2S,4R)-4-fluoro-1-methylpyrrolidone-2-yl]methanol

[1071] Under nitrogen protection at 0°C, a tetrahydrofuran solution of lithium aluminum hydride (34.299 mL, 1 M, 4.0 eq) in tetrahydrofuran (10 mL) was added dropwise to a solution of (2S,4R)-4-fluoro-1-{[(2-methylprop-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylic acid (2 g, 8.57 mmol, 1.0 eq). The reaction mixture was stirred at 70°C for 2 hours. The reaction was monitored for completion by LC-MS. The reaction mixture was cooled to 0°C, and water (1.5 mL), 15% sodium hydroxide aqueous solution (1.5 mL), and water (4.5 mL) were added dropwise. The mixture was stirred for 1 hour, and ethyl acetate (200 mL) was added. The mixture was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated to obtain the crude product. The crude product was purified by silica gel column chromatography (dichloromethane / methanol = 10:1) to obtain the product (800 mg, yield: 70%), a colorless oily liquid. MS m / z: 134.1 [M+H] + . 1 H NMR (400MHz, CDCl3) δ5.20-5.09(m,1H),3.85-3.70(m,1H),3.63–3.43(m, 2H),2.89–2.78(m,1H),2.76–2.61(m,1H),2.43(s,3H),2.19–2.02(m,2H).

[1072] Intermediate B14: [(2R,6S,7aS)-6-{[(2S,6R)-2,6-dimethyl-1,4-oxazacyclohexyl-4-yl]methyl}-2-fluoro-2,3,5,6,7,7a-hexahydro-1H-pyridine-7a-yl]methanol

[1073] Step 1: 4-Methylbenzenesulfonic acid-[(2S,6R,7aS)-7a-(4,4-dimethyl-3,3-diphenyl-2-oxa-3-silazopent-1-yl)-6-fluoro-3-oxoylide-2,3,5,6,7,7a-hexahydro-1H-pyridine-2-yl]methyl ester

[1074] To a solution of (2S,6R,7aS)-7a-(4,4-dimethyl-3,3-diphenyl-2-oxa-3-silazopent-1-yl)-6-fluoro-2-(hydroxymethyl)-2,3,5,6,7,7a-hexahydro-1H-pyrrin-3-one (2.6 g, 4.71 mmol, 1.0 eq), triethylamine (1.309 mL, 9.42 mmol, 2.0 eq), and 4-dimethylaminopyridine (0.06 g, 0.47 mmol, 0.1 eq) in dichloromethane (25 mL), p-toluenesulfonyl chloride (1.08 g, 5.65 mmol, 1.2 eq) was added dropwise. The reaction mixture was stirred at room temperature for 7 hours. The reaction mixture was quenched with water (20 mL), then extracted with dichloromethane (20 mL * 2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 2:1) to give the product (2.5 g, yield: 89%), a colorless oily liquid. MS m / z: 596.0 [M+H] + . 1 H NMR (400MHz, CDCl3) δ7.74–7.54(m,6H),7.54–7.38(m,6H),7.31–7.27(m,2H),5.42(d ,J=5.2Hz,1H),5.27(q,J=3.6,2.3Hz,1H),4.21(dd,J=9.8,3.9Hz,1H),4.12–4.01(m,2 H),3.60(d,J=10.5Hz,1H),3.40(d,J=10.6Hz,1H),3.35-3.28(m,1H),3.03-2.90(m,1 H),2.60-2.46(m,1H),2.42(s,3H),2.25-2.16(m,1H),1.99–1.78(m,2H),1.07(s,9H).

[1075] Step 2: (2S,6R,7aS)-2-{[(2S,6R)-2,6-dimethyl-1,4-oxazacyclohexyl-4-yl]methyl}-7a-(4,4-dimethyl-3,3-diphenyl-2-oxa-3-silazopent-1-yl)-6-fluoro-2,3,5,6,7,7a-hexahydro-1H-pyridine-3-one

[1076] Under nitrogen protection, (2S,6R,7aS)-7a-(4,4-dimethyl-3,3-diphenyl-2-oxa-3-silazopent-1-yl)-6-fluoro-3-oxoylide-2,3,5,6,7,7a-hexahydro-1H-pyrrin-2-yl)methyl 4-methylbenzenesulfonic acid-[(2S,6R,7aS)-7a-(4,4-dimethyl-3,3-diphenyl-2-oxa-3-silazopent-1-yl)-6-fluoro-3-oxoylide-2,3,5,6,7,7a-hexahydro-1H-pyrrin-2-yl]methyl ester (2.5 g, 4.20 mmol, 1.0 eq) and potassium carbonate (2.32 g, 16.78 mmol, 4.0 eq) in acetonitrile (30 mL) was added. The reaction mixture was incubated at 80 °C for 12 hours. The solvent was removed by rotary evaporation of the reaction solution, followed by dissolution in water (100 mL), extraction with ethyl acetate (30 mL x 3), and the organic phases were combined. The mixture was washed successively with water (100 mL) and saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and rotary evaporated to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain the product (1.45 g, yield: 64%), a colorless oily liquid. MS m / z: 539.1 [M+H] + . 1 H NMR (400MHz, CDCl3) δ7.70-7.59(m,4H),7.55–7.31(m,6H),5.46(s,1H),4.21–4.14(m,1H),3.63–3.42(m,4H),3.38-3.30 (m,1H),2.84(s,1H),2.69–2.32(m,5H),2.14(t,J=11.9Hz,1H),2.05–1.85(m,2H),1.82–1.61(m,2H),1.22–0.98(m,15H).

[1077] Step 3: [(2R,6S,7aS)-6-{[(2S,6R)-2,6-dimethyl-1,4-oxazacyclohexyl-4-yl]methyl}-2-fluoro-2,3,5,6,7,7a-hexahydro-1H-pyridine-7a-yl]methanol

[1078] At 0°C, under nitrogen protection, ((2S,6R,7aS)-2-{[(2S,6R)-2,6-dimethyl-1,4-oxazacyclohexyl-4-yl]methyl}-7a-(4,4-dimethyl-3,3-diphenyl-2-oxa-3-silazopent-1-yl)-6-fluoro-2,3,5,6,7,7a-hexahydro-1H-pyridine-3-one (1.4 g, 2.60 mmol, 1 oz) was added dropwise to a lithium aluminum hydride tetrahydrofuran solution (10.394 mL, 1 M, 4.0 eq) of 1 M. A 0.0 eq) solution of tetrahydrofuran (10 mL) was added. The reaction mixture was stirred at 60 °C for 2 hours. The reaction mixture was then cooled to 0 °C, and water (0.5 mL), 15% sodium hydroxide aqueous solution (0.5 mL), and water (1.5 mL) were added dropwise. The mixture was stirred for 1 hour, and ethyl acetate (100 mL) was added. The mixture was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated to obtain the crude product. The crude product was purified by rapid silica gel column chromatography (dichloromethane / methanol = 10:1) to obtain the product (500 mg, yield: 67%), a colorless oily liquid. MS m / z: 287.1 [M+H] + . 1 H NMR(400MHz, CDCl3)δ5.19-5.10(m,1H),3.74-3.63(m,2H),3.38–3.05(m,5H) ,2.88–2.63(m,4H),2.39–1.98(m,5H),1.79–1.55(m,3H),1.23-1.14(m,6H).

[1079] Intermediate B15: (2,2-Difluoro-2,3,5,6,7,7a-hexahydro-1H-pyridine-7a-yl)methanol

[1080] Step 1: Ethyl 2,2-difluoro-5-oxoylide-2,3,5,6,7,7a-hexahydro-1H-pyridine-7a-carboxylate

[1081] Under nitrogen protection at 0°C, diethylaminosulfur trifluoride (3.753 mL, 28.41 mmol, 3.0 eq) was added dropwise to a solution of ethyl 2,5-dioxane-2,3,5,6,7,7a-hexahydro-1H-pyridine-7a-carboxylate (2 g, 9.47 mmol, 1.0 eq) in dichloromethane (40 mL). The reaction mixture was stirred at 25°C for 16 hours. The reaction mixture was cooled to 0°C, neutralized to pH 10 with saturated sodium bicarbonate solution, and extracted with dichloromethane (20 mL x 2). The organic phases were combined, washed successively with water (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain the product (1.8 g, yield: 81%), a colorless oily liquid. MS m / z: 234.1 [M+H] + . 1 H NMR (400MHz, CDCl3) δ4.33–4.21(m,2H),4.20–4.07(m,1H),3.54-3.46(m,1H),3.05-2.97(m,1H),2.85–2.69(m,1H),2.71-2.60(m 1H),2.50–2.40(m,1H),2.43-2.30(m,1H),2.24-2.17(m,1H),1.36-1.30(m,3H).

[1082] Step 2: (2,2-Difluoro-2,3,5,6,7,7a-hexahydro-1H-pyridine-7a-yl)methanol [108...

Claims

A compound of Formula I, its stereoisomer, or a pharmaceutically acceptable salt thereof. in, X is -C(R) 6 )2-、-NR 7 -, -O-, -S-, -SO- or -SO2-; Y is -NR 8 -、-O-、-S-、-SO-、-NR 8 SO2- or -SO2-; t is 0 or 1; Each R 6 Independently hydrogen, deuterium, halogen, cyano, nitro, -NH2, -OH, -NH (C1-C6 alkyl), -N (C1-C6 alkyl)2, C1-C6 alkyl, or with one or more R 6a Substituted C1-C6 alkyl, -O-C1-C6 alkyl, or substituted with one or more R 6b Substituted -O-C1-C6 alkyl, C2-C6 alkenyl, or with one or more R 6c Substituted C2-C6 alkenyl, C2-C6 alkynyl, or with one or more R 6d Substituted C2-C6 ynyl group, C3-C 12 cycloalkyl, with one or more R 6e Replacement C3-C 12 cycloalkyl, C3-C 12 Cycloalkenyl, with one or more R 6f Replacement C3-C 12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, with one or more R 6g Substituted 3-12-membered heterocyclic alkyl, 3-12-membered heterocyclic alkenyl, or substituted with one or more R 6h Substituted 3-12 membered heterocyclic alkenyl groups, C6-C 10 aryl, with one or more R 6i Replacement C6-C 10 aryl, 5-10 heteroaryl, or with one or more R 6j Substituted 5-10 heteroaryl groups; Each R 6a R 6b R 6c R 6d R 6e R 6f R 6g R 6h R 6i and R 6j Each of the following can be independently represented as deuterium, hydroxyl, halogen, cyano, nitro, oxo, -NH2, -NH (C1-C6 alkyl), -N (C1-C6 alkyl)2, C1-C6 alkyl, -O-C1-C6 alkyl, C3-C 12 Cycloalkyl or C1-C6 alkyl groups substituted with one or more substituents selected from deuterium, hydroxyl and halogen; R 7 It is hydrogen, C1-C6 alkyl, and is formed by one or more R 7a Substituted C1-C6 alkyl, C2-C6 alkenyl, or with one or more R 7b Substituted C2-C6 alkenyl, C2-C6 alkynyl, or with one or more R 7c Substituted C2-C6 ynyl group, C3-C 12 cycloalkyl, with one or more R 7d Replacement C3-C 12 cycloalkyl, C3-C 12 Cycloalkenyl, with one or more R 7e Replacement C3-C 12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, with one or more R 7f Substituted 3-12-membered heterocyclic alkyl, 3-12-membered heterocyclic alkenyl, or substituted with one or more R 7g Substituted 3-12 membered heterocyclic alkenyl groups, C6-C 10 aryl, with one or more R 7h Replacement C6-C 10 aryl, 5-10 heteroaryl, or with one or more R 7i Substituted 5-10 heteroaryl groups; Each R 7a R 7b R 7c R 7d R 7e R 7f R 7g R 7h and R 7i Each of the following can be independently represented as deuterium, hydroxyl, halogen, cyano, nitro, -NH2, -NH (C1-C6 alkyl), -N (C1-C6 alkyl)2, C1-C6 alkyl, -O-C1-C6 alkyl, C3-C 12 Cycloalkyl, or C1-C6 alkyl groups substituted with one or more substituents selected from deuterium, hydroxyl and halogen; R 8 It is hydrogen, C1-C6 alkyl, and is formed by one or more R 8a Substituted C1-C6 alkyl, C2-C6 alkenyl, or with one or more R 8b Substituted C2-C6 alkenyl, C2-C6 alkynyl, or with one or more R 8c Substituted C2-C6 ynyl group, C3-C 12 cycloalkyl, with one or more R 8d Replacement C3-C 12 cycloalkyl, C3-C 12 Cycloalkenyl, with one or more R 8e Replacement C3-C 12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, with one or more R 8f Substituted 3-12-membered heterocyclic alkyl, 3-12-membered heterocyclic alkenyl, or substituted with one or more R 8g Substituted 3-12 membered heterocyclic alkenyl groups, C6-C 10 aryl, with one or more R 8h Replacement C6-C 10 aryl, 5-10 heteroaryl, or with one or more R 8i Substituted 5-10 heteroaryl groups; Each R 8a R 8b R 8c R 8d R 8e R 8f R 8g R 8h and R 8i Each of the following can be independently represented as deuterium, hydroxyl, halogen, cyano, nitro, -NH2, -NH (C1-C6 alkyl), -N (C1-C6 alkyl)2, C1-C6 alkyl, -O-C1-C6 alkyl, C3-C 12 Cycloalkyl or C1-C6 alkyl groups substituted with one or more substituents selected from deuterium, hydroxyl and halogen; R 1 and R 1’ Each is independently hydrogen, deuterium, C1-C6 alkyl, or formed by one or more R 1a Substituted C1-C6 alkyl, C2-C6 alkenyl, or with one or more R 1b Substituted C2-C6 alkenyl, C2-C6 alkynyl, or with one or more R 1c Substituted C2-C6 ynyl group, C3-C 12 cycloalkyl, with one or more R 1d Replacement C3-C 12 cycloalkyl, C3-C 12 Cycloalkenyl, with one or more R 1e Replacement C3-C 12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, with one or more R 1f Substituted 3-12-membered heterocyclic alkyl, 3-12-membered heterocyclic alkenyl, or substituted with one or more R 1g Substituted 3-12 membered heterocyclic alkenyl groups, C6-C 10 aryl, with one or more R 1h Replacement C6-C 10 aryl, 5-10 heteroaryl, or with one or more R 1i Substituted 5-10 heteroaryl groups; Or R 1 and R 1’ Together they form = O; Or, R 1 R 1’ Together with the carbon atoms it is attached to, they form C3-C 12 cycloalkyl or with one or more R 1j Replacement C3-C 12 cycloalkyl; Each R 1a R 1b R 1c R 1d R 1e R 1f R 1g R 1h R 1i and R 1j Each of the following can be independently represented as deuterium, hydroxyl, halogen, cyano, nitro, oxo, -NH2, -NH (C1-C6 alkyl), -N (C1-C6 alkyl)2, C1-C6 alkyl, -O-C1-C6 alkyl, C3-C 12 Cycloalkyl or C1-C6 alkyl groups substituted with one or more halogens; Ring A is C6-C 10 Aryl, 5-10 heteroaryl or C3-C 12 cycloalkyl; Each R 5 Independently deuterium, halogen, cyano, nitro, -OR 9 -SR 9 -N(R) 9 )2、-S(O) 1-2 R 9 -(CH2) m1 C(O)N(R 9 2、-(CH2) m2 OC(O)N(R 9 2、-(CH2) m3 NR 9 C(O)OR 9 -(CH2) m4 NR 9 C(O)N(R 9 2、-(CH2) m5 NR 9 C(O)R 9 -(CH2) m6 NR 9 S(O)2R 9 -(CH2) m7 OC(O)R 9 -(CH2) m8 C(O)R 9 -(CH2) m9 C(O)OR 9 C1-C6 alkyl groups, with one or more R 5a Substituted C1-C6 alkyl, C2-C6 alkenyl, or with one or more R 5b Substituted C2-C6 alkenyl, C2-C6 alkynyl, or with one or more R 5c Substituted C2-C6 ynyl group, C3-C 12 cycloalkyl, with one or more R 5d Replacement C3-C 12 cycloalkyl, C3-C 12 Cycloalkenyl, with one or more R 5e Replacement C3-C 12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, with one or more R 5f Substituted 3-12-membered heterocyclic alkyl, 3-12-membered heterocyclic alkenyl, or substituted with one or more R 5g Substituted 3-12 membered heterocyclic alkenyl groups, C6-C 10 aryl, with one or more R 5h Replacement C6-C 10 aryl, 5-10 heteroaryl, or with one or more R 5i Substituted 5-10 heteroaryl groups; Each R 5a R 5b R 5c R 5d R 5e R 5f R 5g R 5h and R 5i Each can be independently represented by deuterium, hydroxyl, halogen, cyano, nitro, oxo, or -(CH2). m10 NH2、-(CH2) m11 NH (C1-C6 alkyl), -(CH2) m12 N(C1-C6 alkyl)2, -O-C1-C6 alkyl, C3-C 12 Cycloalkyl, C1-C6 alkyl, or C1-C6 alkyl substituted with one or more substituents selected from deuterium, halogens, and hydroxyl groups; m can be 0, 1, 2, 3, 4, or 5; m1, m2, m3, m4, m5, m6, m7, m8, m9, m10, m11 and m12 are each independently 0, 1, 2 or 3; Each R 9 Independently hydrogen, C1-C6 alkyl, and composed of one or more R 9a Substituted C1-C6 alkyl, -O-C1-C6 alkyl, or substituted with one or more R 9b Substituted -O-C1-C6 alkyl, C2-C6 alkenyl, or with one or more R 9c Substituted C2-C6 alkenyl, C2-C6 alkynyl, or with one or more R 9d Substituted C2-C6 ynyl group, C3-C 12 cycloalkyl, with one or more R 9e Replacement C3-C 12 cycloalkyl, C3-C 12 Cycloalkenyl, with one or more R 9f Replacement C3-C 12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, with one or more R 9g Substituted 3-12-membered heterocyclic alkyl, 3-12-membered heterocyclic alkenyl, or substituted with one or more R 9h Substituted 3-12 membered heterocyclic alkenyl groups, C6-C 10 aryl, with one or more R 9i Replacement C6-C 10 aryl, 5-10 heteroaryl, or with one or more R 9j Substituted 5-10 heteroaryl groups; Each R 9a R 9b R 9c R 9d R 9e R 9f R 9g R 9h R 9i and R 9j Each is independently of deuterium, -NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl group, hydroxyl group, halogen group, cyano group, nitro group, oxo group, C1-C6 alkyl group, -O-C1-C6 alkyl group, C3-C 12 Cycloalkyl or C1-C6 alkyl groups substituted with one or more substituents selected from deuterium, hydroxyl and halogen; L is a chemical bond, -O-(CR 10 R 11 ) q1 -, -O-(CR 10 R 11 ) q2 -CR 12 R 13 -(CR 10 R 11 ) q3 -, -S-(CR 10 R 11 ) q4 -, -N(R 14 )-(CR 10 R 11 ) q5 -, -S(O)-(CR 10 R 11 ) q6 - or -S(O)2-(CR 10 R 11 ) q7 -; Each R 10 and R 11 Each of these can be independently hydrogen, deuterium, halogen, cyano, hydroxyl, C1-C6 alkyl, -O-C1-C6 alkyl, or C3-C 12 Cycloalkyl, 5-10-membered heteroaryl, or C1-C6 alkyl group substituted with one or more substituents selected from deuterium, hydroxyl, and halogen; R 12 R 13 Together with the carbon atoms they are connected to, they form C3-C. 12 cycloalkyl or with one or more R 12a Replacement C3-C 12 cycloalkyl; Or, R 12 and R 13 Each of these can be independently hydrogen, deuterium, halogen, cyano, hydroxyl, C1-C6 alkyl, -O-C1-C6 alkyl, or C3-C 12 Cycloalkyl, 5-10-membered heteroaryl, or C1-C6 alkyl group substituted with one or more substituents selected from deuterium, hydroxyl, and halogen; Each R 12a Independently, it can be deuterium, halogen, cyano, hydroxyl, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, or -O-C1-C6 alkyl; R 14 It can be hydrogen, hydroxyl, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C3-C 12 cycloalkyl, C3-C 12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, or 3-12 membered heterocyclic alkenyl; q1, q2, q3, q4, q5, q6, and q7 are each independently 0, 1, 2, or 3; (when 0, it indicates a connection key); R 2 It is hydrogen, C1-C6 alkyl, and is formed by one or more R 2a Substituted C1-C6 alkyl, C3-C 12 cycloalkyl, with one or more R 2b Replacement C3-C 12 cycloalkyl, C3-C 12 Cycloalkenyl, with one or more R 2c Replacement C3-C 12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, with one or more R 2d Substituted 3-12-membered heterocyclic alkyl, 3-12-membered heterocyclic alkenyl, or substituted with one or more R 2e Substituted 3-12 membered heterocyclic alkenyl groups, C6-C 10 aryl, with one or more R 2f Replacement C6-C 10 aryl, 5-10 heteroaryl, with one or more R 2g Substituted 5-10 heteroaryl groups, -C(O)OR 15 -C(O)R 15 -N(R) 15 )2、-NR 15 C(=NR 15 )N(R 15 )2、-C(O)N(R 15 )2 or -NR 15 C(O)R 15 ; Each R 2a R 2b R 2c R 2d R 2e R 2f and R 2g Each can be independently halogenated, deuterated, cyano, oxo, or -OR. 16 -SR 16 -N(R) 16 )2、-S(O) 1-2 R 16 -SO2F, -(CH2) r1 C(O)N(R 16 2、-(CH2) r2 OC(O)N(R 16 2、-(CH2) r3 NR 16 C(O)OR 16 -(CH2) r4 NR 16 C(O)N(R 16 2、-(CH2) r5 NR 16 C(O)R 16 -(CH2) r6 NR 16 S(O)2R 16 -(CH2) r7 OC(O)R 16 -(CH2) r8 C(O)R 16 -(CH2) r9 C(O)OR 16 =CR 2-j R 2-j C1-C6 alkyl groups, with one or more R 2-a Substituted C1-C6 alkyl, C2-C6 alkenyl, or with one or more R 2-b Substituted C2-C6 alkenyl, C2-C6 alkynyl, or with one or more R 2-c Substituted C2-C6 ynyl group, C3-C 12 cycloalkyl, with one or more R 2-d Replacement C3-C 12 cycloalkyl, C3-C 12 Cycloalkenyl, with one or more R 2-e Replacement C3-C 12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, with one or more R 2-f Substituted 3-12-membered heterocyclic alkyl, 3-12-membered heterocyclic alkenyl, or substituted with one or more R 2-g Substituted 3-12 membered heterocyclic alkenyl groups, C6-C 10 aryl, with one or more R 2-h Replacement C6-C 10 aryl, 5-10 heteroaryl, or with one or more R 2-i Substituted 5-10 heteroaryl groups; Each R 2-a R 2-b R 2-c R 2-d R 2-e R 2-f R 2-g R 2-h and R 2-i Each is independently a deuterium, cyano, halogen, or hydroxyl group. C1-C6 alkyl, -O-C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C 12 cycloalkyl, C3-C 12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, 3-12 membered heterocyclic alkenyl, C6-C 10 aryl, 5-10 heteroaryl, or with one or more R 2-a-1 Substituted 3-12 membered heterocyclic alkyl groups; Each R 2-a-1 R 2-a-2 and R 2-a-3 Each can be independently deuterium, cyano, halogen, hydroxyl, C1-C6 alkyl, -O-C1-C6 alkyl, 3-7 membered cycloalkyl-O-, 3-7 membered cycloalkenyl-O-, 4-10 membered heterocycloalkyl-O-, 4-10 membered heterocycloalkenyl-O-, phenyl-O-, phenyl-CH2-O- or 5-6 membered heteroaryl-O-; Each R 2-j Independently, it can be hydrogen, deuterium, cyano, halogen, hydroxyl, C1-C6 alkyl, -O-C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C3-C 12 cycloalkyl, C3-C 12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, 3-12 membered heterocyclic alkenyl, C6-C 10 Aryl or 5-10 heteroaryl groups; Each R 15 and R 16 Each is independently hydrogen, C1-C6 alkyl, and composed of one or more R groups. 15a Substituted C1-C6 alkyl, C3-C 12 cycloalkyl, with one or more R 15b Replacement C3-C 12 cycloalkyl, C3-C 12 Cycloalkenyl, with one or more R 15c Replacement C3-C 12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, with one or more R 15d Substituted 3-12-membered heterocyclic alkyl, 3-12-membered heterocyclic alkenyl, or substituted with one or more R 15e Substituted 3-12 membered heterocyclic alkenyl groups, C6-C 10 aryl, with one or more R 15f Replacement C6-C 10 aryl, 5-10 heteroaryl, or with one or more R 15g Substituted 5-10 heteroaryl groups; Each R 15a R 15b R 15c R 15d R 15e R 15f and R 15g Each can be independently represented as deuterium, halogen, cyano, hydroxyl, oxo, -SO2F, -C(O)H, C1-C6 alkyl, -O-C1-C6 alkyl, C3-C 12 cycloalkyl, C3-C 12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, 3-12 membered heterocyclic alkenyl, C6-C 10 Aryl, 5-10-membered heteroaryl, or C1-C6 alkyl group substituted with one or more substituents selected from deuterium, hydroxyl, and halogen; r1, r2, r3, r4, r5, r6, r7, r8 and r9 are each independently 0, 1, 2 or 3; Each R 3 Independently hydrogen, deuterium, halogen, cyano, nitro, oxo, -N(R) 17 )2、-OR 17 C1-C6 alkyl groups, with one or more R 3a Substituted C1-C6 alkyl, C2-C6 alkenyl, or with one or more R 3b Substituted C2-C6 alkenyl, C2-C6 alkynyl, or with one or more R 3c Substituted C2-C6 ynyl group, C3-C 12 cycloalkyl, with one or more R 3d Replacement C3-C 12 cycloalkyl, C3-C 12 Cycloalkenyl, with one or more R 3e Replacement C3-C 12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, with one or more R 3f Substituted 3-12-membered heterocyclic alkyl, 3-12-membered heterocyclic alkenyl, or substituted with one or more R 3g Substituted 3-12 membered heterocyclic alkenyl groups, C6-C 10 aryl, with one or more R 3h Replacement C6-C 10 aryl, 5-10 heteroaryl, or with one or more R 3i Substituted 5-10 heteroaryl groups; Each R 3a R 3b R 3c R 3d R 3e R 3f R 3g R 3h and R 3i Each of the following can be independently represented as deuterium, hydroxyl, halogen, cyano, nitro, oxo, -NH2, -NH (C1-C6 alkyl), -N (C1-C6 alkyl)2, C1-C6 alkyl, -O-C1-C6 alkyl, C3-C 12 Cycloalkyl or C1-C6 alkyl groups substituted with one or more substituents selected from deuterium, hydroxyl and halogen; Each R 17 Independently hydrogen, C1-C6 alkyl, and composed of one or more R 17a Substituted C1-C6 alkyl, C3-C 12 cycloalkyl, with one or more R 17b Replacement C3-C 12 cycloalkyl, C3-C 12 Cycloalkenyl, with one or more R 17c Replacement C3-C 12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, with one or more R 17d Substituted 3-12-membered heterocyclic alkyl, 3-12-membered heterocyclic alkenyl, or substituted with one or more R 17e Substituted 3-12 membered heterocyclic alkenyl groups, C6-C 10 aryl, with one or more R 17f Replacement C6-C 10 aryl, 5-10 heteroaryl, or with one or more R 17g Substituted 5-10 heteroaryl groups; Each R 17a R 17b R 17c R 17d R 17e R 17f and R 17g Each can be independently deuterium, halogen, cyano, hydroxyl, oxo, C1-C6 alkyl, -O-C1-C6 alkyl, C3-C 12 Cycloalkyl or C1-C6 alkyl groups substituted with one or more substituents selected from deuterium, hydroxyl and halogen; n is 1, 2, 3 or 4; Ring B is C7-C 15 cycloalkyl, C7-C 15 Cycloalkenyl, 7-15 membered heterocyclic alkyl, or 7-15 membered heterocyclic alkenyl; Each R 4 Independently deuterium, halogen, cyano, nitro, oxo, -N(R) 18 2. -B(OR) 18 )2、-OR 18 -SR 18 -S(O) 1-2 R 18 -S(O) 1-2 N(R 18 )2、-NR 18 S(O) 1-2 R 18 -(CH2) p1 C(O)NR 18 OR 18 -(CH2) p2 NR 18 C(O)R 18 -(CH2) p3 NR 18 C(O)N(R 18 2、-(CH2) p4 NR 18 C(O)OR 18 -(CH2) p5 OC(O)N(R 18 2、-(CH2) p6 C(O)N(R 18 2、-(CH2) p7 C(O)R 18 -(CH2) p8 C(O)OR 18 -(CH2) p9 OC(O)R 18 C1-C6 alkyl groups, with one or more R 4a Substituted C1-C6 alkyl, C2-C6 alkenyl, or with one or more R 4b Substituted C2-C6 alkenyl, C2-C6 alkynyl, or with one or more R 4c Substituted C2-C6 ynyl group, C3-C 12 cycloalkyl, with one or more R 4d Replacement C3-C 12 cycloalkyl, C3-C 12 Cycloalkenyl, with one or more R 4e Replacement C3-C 12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, with one or more R 4f Substituted 3-12-membered heterocyclic alkyl, 3-12-membered heterocyclic alkenyl, or substituted with one or more R 4g Substituted 3-12 membered heterocyclic alkenyl groups, C6-C 10 aryl, with one or more R 4h Replacement C6-C 10 aryl, 5-10 heteroaryl, or with one or more R 4i Substituted 5-10 heteroaryl groups; Each R 4a R 4b R 4c R 4d R 4e R 4f R 4g R 4h and R 4i Each independently constitutes deuterium, -N(R) 19 2. Hydroxyl, halogen, cyano, nitro, oxo, thio (=S), C1-C6 alkyl, with one or more R 4-a Substituted C1-C6 alkyl, -O-C1-C6 alkyl, or substituted with one or more R 4-b Substituted -O-C1-C6 alkyl, C2-C6 alkenyl, or with one or more R 4-c Substituted C2-C6 alkenyl, C2-C6 alkynyl, or with one or more R 4-d Substituted C2-C6 ynyl group, C3-C 12 cycloalkyl, with one or more R 4-e Replacement C3-C 12 cycloalkyl, C3-C 12 Cycloalkenyl, with one or more R 4-f Replacement C3-C 12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, with one or more R 4-g Substituted 3-12-membered heterocyclic alkyl, 3-12-membered heterocyclic alkenyl, or substituted with one or more R 4-h Substituted 3-12 membered heterocyclic alkenyl groups, C6-C 10 aryl, with one or more R 4-i Replacement C6-C 10 aryl, 5-10 heteroaryl, or with one or more R 4-j Substituted 5-10 heteroaryl groups; Each R 4-a R 4-b R 4-c R 4-d R 4-e R 4-f R 4-g R 4-h R 4-i and R 4-j Each of the following is independently deuterium, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, hydroxyl, halogen, cyano, nitro, oxo, C1-C6 alkyl, -O-C1-C6 alkyl, or a C1-C6 alkyl group substituted with one or more substituents selected from deuterium, hydroxyl and halogen; Each R 18 and R 19 Each is independently hydrogen, C1-C6 alkyl, and composed of one or more R groups. 18a Substituted C1-C6 alkyl, C3-C 12 cycloalkyl, with one or more R 18b Replacement C3-C 12 cycloalkyl, C3-C 12 Cycloalkenyl, with one or more R 18c Replacement C3-C 12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, with one or more R 18d Substituted 3-12-membered heterocyclic alkyl, 3-12-membered heterocyclic alkenyl, or substituted with one or more R 18e Substituted 3-12 membered heterocyclic alkenyl groups, C6-C 10 aryl, with one or more R 18f Replacement C6-C 10 aryl, 5-10 heteroaryl, or with one or more R 18g Substituted 5-10 heteroaryl groups; Each R 18a R 18b R 18c R 18d R 18e R 18f and R 18g Each can be independently represented as deuterium, halogen, cyano, hydroxyl, oxo, -NH2, -NH (C1-C6 alkyl), -N (C1-C6 alkyl)2, C1-C6 alkyl, -O-C1-C6 alkyl, C3-C 12 Cycloalkyl or C1-C6 alkyl groups substituted with one or more substituents selected from deuterium, hydroxyl and halogen; p is 0, 1, 2, 3, 4, 5, 6, 7 or 8; p1, p2, p3, p4, p5, p6, p7, p8 and p9 are each independently 0, 1, 2 or 3; In each "heterocyclic alkyl", the heteroatom is independently selected from one or more of N, O and S, and the number of heteroatoms is independently 1, 2, 3 or 4. In each "heterocyclic alkenyl", the heteroatom is independently selected from one or more of N, O and S, and the number of heteroatoms is independently 1, 2, 3 or 4. In each "heteroaryl", the heteroatoms are independently selected from one or more of N, O and S, and the number of heteroatoms is independently 1, 2, 3 or 4. The compound of Formula I as claimed in claim 1, its stereoisomers, or pharmaceutically acceptable salts thereof, is characterized in that, R 1 and R 1’ Each is independently hydrogen, deuterium, C1-C6 alkyl, or formed by one or more R 1a Substituted C1-C6 alkyl, C2-C6 alkenyl, or with one or more R 1b Substituted C2-C6 alkenyl, C2-C6 alkynyl, or with one or more R 1c Substituted C2-C6 ynyl group, C3-C 12 cycloalkyl, with one or more R 1d Replacement C3-C 12 cycloalkyl, C3-C 12 Cycloalkenyl, with one or more R 1e Replacement C3-C 12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, with one or more R 1f Substituted 3-12-membered heterocyclic alkyl, 3-12-membered heterocyclic alkenyl, or substituted with one or more R 1g Substituted 3-12 membered heterocyclic alkenyl groups, C6-C 10 aryl, with one or more R 1h Replacement C6-C 10 aryl, 5-10 heteroaryl, or with one or more R 1i Substituted 5-10 heteroaryl groups; Or R 1 and R 1’ Together they form = O; Each R 1a R 1b R 1c R 1d R 1e R 1f R 1g R 1h and R 1i Each of the following can be independently represented as deuterium, hydroxyl, halogen, cyano, nitro, oxo, -NH2, -NH (C1-C6 alkyl), -N (C1-C6 alkyl)2, C1-C6 alkyl, -O-C1-C6 alkyl, C3-C 12 Cycloalkyl or C1-C6 alkyl groups substituted with one or more halogens; Ring A is C6-C 10 Aryl or 5-10 heteroaryl groups; L is -O-(CR 10 R 11 ) q1 -, -O-(CR 10 R 11 ) q2 -CR 12 R 13 -(CR 10 R 11 ) q3 -, -S-(CR 10 R 11 ) q4 -, -N(R 14 )-(CR 10 R 11 ) q5 -, -S(O)-(CR 10 R 11 ) q6 - or -S(O)2-(CR 10 R 11 ) q7 -; Each R 10 and R 11 Each of these can be independently hydrogen, deuterium, halogen, cyano, hydroxyl, C1-C6 alkyl, -O-C1-C6 alkyl, or C3-C 12 Cycloalkyl, 5-10-membered heteroaryl, or C1-C6 alkyl group substituted with one or more substituents selected from deuterium, hydroxyl, and halogen; R 12 R 13 Together with the carbon atoms they are connected to, they form C3-C. 12 cycloalkyl or with one or more R 12a Replacement C3-C 12 cycloalkyl; Each R 12a Independently, it can be deuterium, halogen, cyano, hydroxyl, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, or -O-C1-C6 alkyl; R 14 It can be hydrogen, hydroxyl, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C3-C 12 cycloalkyl, C3-C 12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, or 3-12 membered heterocyclic alkenyl; q1, q2, q3, q4, q5, q6 and q7 are each independently 0, 1, 2 or 3; (when it is 0, it indicates a connection key). The compound of Formula I as claimed in claim 1, its stereoisomers, or pharmaceutically acceptable salts thereof, is characterized in that, R 1 and R 1’ Each is independently hydrogen, deuterium, C1-C6 alkyl, or formed by one or more R 1a Substituted C1-C6 alkyl, C2-C6 alkenyl, or with one or more R 1b Substituted C2-C6 alkenyl, C2-C6 alkynyl, or with one or more R 1c Substituted C2-C6 ynyl group, C3-C 12 cycloalkyl, with one or more R 1d Replacement C3-C 12 cycloalkyl, C3-C 12 Cycloalkenyl, with one or more R 1e Replacement C3-C 12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, with one or more R 1f Substituted 3-12-membered heterocyclic alkyl, 3-12-membered heterocyclic alkenyl, or substituted with one or more R 1g Substituted 3-12 membered heterocyclic alkenyl groups, C6-C 10 aryl, with one or more R 1h Replacement C6-C 10 aryl, 5-10 heteroaryl, or with one or more R 1i Substituted 5-10 heteroaryl groups; Or R 1 and R 1’ Together they form = O; Each R 1a R 1b R 1c R 1d R 1e R 1f R 1g R 1h and R 1i Each of the following can be independently represented as deuterium, hydroxyl, halogen, cyano, nitro, oxo, -NH2, -NH (C1-C6 alkyl), -N (C1-C6 alkyl)2, C1-C6 alkyl, -O-C1-C6 alkyl, C3-C 12 Cycloalkyl or C1-C6 alkyl groups substituted with one or more halogens; Ring A is C6-C 10 Aryl or 5-10 heteroaryl groups; L is -O-(CR 10 R 11 ) q1 -, -O-(CR 10 R 11 ) q2 -CR 12 R 13 -(CR 10 R 11 ) q3 -, -S-(CR 10 R 11 ) q4 -, -N(R 14 )-(CR 10 R 11 ) q5 -, -S(O)-(CR 10 R 11 ) q6 - or -S(O)2-(CR 10 R 11 ) q7 -; Each R 10 and R 11 Each of these can be independently hydrogen, deuterium, halogen, cyano, hydroxyl, C1-C6 alkyl, -O-C1-C6 alkyl, or C3-C 12 Cycloalkyl, 5-10-membered heteroaryl, or C1-C6 alkyl group substituted with one or more substituents selected from deuterium, hydroxyl, and halogen; R 12 R 13 Together with the carbon atoms they are connected to, they form C3-C. 12 cycloalkyl or with one or more R 12a Replacement C3-C 12 cycloalkyl; Each R 12a Independently, it can be deuterium, halogen, cyano, hydroxyl, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, or -O-C1-C6 alkyl; R 14 It can be hydrogen, hydroxyl, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C3-C 12 cycloalkyl, C3-C 12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, or 3-12 membered heterocyclic alkenyl; q1, q2, q3, q4, q5, q6, and q7 are each independently 0, 1, 2, or 3; (when 0, it indicates a connection key); Each R 2-a R 2-b R 2-c R 2-d R 2-e R 2-f R 2-g R 2-h and R 2-i Each can be independently deuterium, cyano, halogen, hydroxyl, C1-C6 alkyl, -O-C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C 12 cycloalkyl, C3-C 12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, 3-12 membered heterocyclic alkenyl, C6-C 10 Aryl or 5-10 heteroaryl compounds. The compound of formula I as claimed in any one of claims 1-3, its stereoisomers, or pharmaceutically acceptable salts thereof, is 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, for example fluorine; (2) Each C1-C6 alkyl group is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, or sec-butyl, for example, methyl; (3) Each -O-C1-C6 alkyl group is independently -O-C1-C4 alkyl group, such as methoxy, ethoxy, n-propoxy or isopropoxy; (4) Each C2-C6 alkenyl group is independently vinyl, propenyl, allyl, or (5) Each C2-C6 ynyl group is independently an ethynyl group. (6) Each C3-C 12 The cycloalkyl group is independently a C3-C8 cycloalkyl group, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; (7) The heteroatom species of each 3-12 membered heterocyclic alkyl group is independently selected from one or two of N, O and S, and the number of heteroatoms is independently 1, 2 or 3; preferably, the heteroatom species is independently N and the number of heteroatoms is independently 1. (8) Each 3-12 membered heterocyclic alkyl group is independently monocyclic or polycyclic; the polycyclic ring may be a bridged ring, a fused ring, or a spirocyclic ring; preferably a fused ring; (9) Each 3-12 membered heterocyclic alkyl group is independently a 4-6 membered monocyclic heterocyclic alkyl group or an 8-12 membered bicyclic heterocyclic alkyl group; preferably tetrahydropyrrole or For example For example (10) Each C3-C 12 The cycloalkenyl group is independently a C5-C6 cycloalkenyl group; (11) Each C3-C 12 The cycloalkenyl group independently contains one or more carbon-carbon sp groups. 2 It has double bonds and is not aromatic; (12) The heteroatoms in each 3-12 membered heterocyclic alkenyl group are each independently selected from one or two of N, O and S, and the number of heteroatoms is 1, 2 or 3. (13) Each 3-12 membered heterocyclic alkenyl group is independently monocyclic or polycyclic; the polycyclic group may be a bridged ring, a fused ring or a spirocyclic ring; the polycyclic group may also be a bicyclic or a tricyclic ring; preferably, each 3-12 membered heterocyclic alkenyl group is independently a 3-6 membered monocyclic heterocyclic alkenyl group or an 8-10 membered bicyclic heterocyclic alkenyl group; (14) Each 3-12 membered heterocyclic alkenyl group independently contains one or more sp atoms. 2 It has double bonds and is not aromatic; (15) Each C6-C 10 The aryl group can be phenyl or naphthyl, for example, phenyl; (16) The heteroatom species in each 5-10 aryl group is independently selected from one or two of N, O and S, and the number of heteroatoms is independently 1, 2 or 3; preferably, the heteroatom species is independently N and the number of heteroatoms is independently 1. (17) Each 5-10 member heteroaryl group is independently monocyclic or bicyclic; preferably, each 5-10 member heteroaryl group is independently a 5-6 member monocyclic heteroaryl group or a 9-10 member bicyclic heteroaryl group; for example, pyridyl; and for example... (18) Each C7-C 15 The cycloalkyl group can be a monocyclic or polycyclic ring, and the polycyclic ring can be a bridged ring, a fused ring, or a spirocyclic ring; (19) Each C7-C 15 The cycloalkyl group is independently C7-C 10 Cycloalkyl groups, preferably C8-C9 cycloalkyl groups; (20) Each C7-C 15 The cycloalkenyl group can be a monocyclic or polycyclic compound, and the polycyclic compound can be a bridged ring, a fused ring, or a spirocyclic compound. The polycyclic compound can also be a bicyclic or a tricyclic compound. (21) Each C7-C 15 The cycloalkenyl group is independently C7-C. 10 Cycloalkenyl groups, preferably C8-C9 cycloalkenyl groups; (22) Each C7-C 15 The cycloalkenyl group independently contains one or more carbon-carbon sp groups. 2 It has double bonds and is not aromatic; (23) The heteroatoms of each 7-15 membered heterocyclic alkyl group are independently selected from one or two of N, O and S, and the number of heteroatoms is independently 1, 2 or 3. (24) Each 7-15 membered heterocyclic alkyl group may be a monocyclic or polycyclic ring, wherein the polycyclic ring may be a bridged ring, a fused ring or a spirocyclic ring, and the polycyclic ring may also be a bicyclic or a tricyclic ring; (25) Each 7-15 membered heterocyclic alkyl group is independently a 7-membered monocyclic heterocyclic alkyl group or an 8-10 membered bicyclic heterocyclic alkyl group; (26) The heteroatom species of each 7-15 member heterocyclic alkenyl group is independently selected from one or two of N, O and S, and the number of heteroatoms is independently 1, 2 or 3; preferably, the heteroatom species is independently S, and the number of heteroatoms is 1. (27) Each 7-15 membered heterocyclic alkenyl group is independently monocyclic or polycyclic, the polycyclic group being a bridged ring, fused ring, or spirocyclic ring, preferably fused ring; the polycyclic group may also be bicyclic or tricyclic; preferably, each 7-15 membered heterocyclic alkenyl group is independently an 8-10 membered bicyclic heterocyclic alkenyl group, such as 5,6-dihydro-4H-cyclopentano[b]thiopheneyl or 4,5,6,7-tetrahydrobenzo[b]thiopheneyl; and (28) Each 7-15 membered heterocyclic alkenyl group independently contains one or more sp ions. 2 Double bonds, preferably containing 2 sp bonds. 2 Double bond. The compound of formula I as claimed in any one of claims 1-3, its stereoisomers, or pharmaceutically acceptable salts thereof, is characterized in that, The compound represented by Formula I satisfies one or more of the following conditions: (1) X is -NR 7 -, -O- or -S-, preferably -NR 7 - or -O-, more preferably -O-; (2) Y is -NR 8 -、-O-、-S- or *-NR 8 SO2-, wherein the * end is connected to the pyrimidine ring in the parent nucleus; preferably -NR. 8 -、-O- or *-NR 8 SO2-, wherein the * end is connected to the pyrimidine ring in the parent nucleus; more preferably -NR 8 -; (3)R 7 It is hydrogen, C1-C6 alkyl, and is formed by one or more R 7a Substituted C1-C6 alkyl, C3-C 12 cycloalkyl or with one or more R 7d Replacement C3-C 12 Cycloalkyl, preferably C1-C6 alkyl or alkylated by one or more R 7a Substituted C1-C6 alkyl groups; (4) Each R 7a and R 7d Each is independently deuterium, halogen, C1-C6 alkyl, -O-C1-C6 alkyl, or C3-C 12 Cycloalkyl groups, preferably deuterium; (5)R 8 It is hydrogen, C1-C6 alkyl, and is formed by one or more R 8a Substituted C1-C6 alkyl, C3-C 12 cycloalkyl or with one or more R 8d Replacement C3-C 12 Cycloalkyl, preferably hydrogen, C1-C6 alkyl, or alkyl grouped by one or more R 8a The substituted C1-C6 alkyl group is more preferably hydrogen or C1-C6 alkyl; (6) Each R 8a and R 8d Each is independently deuterium, hydroxyl, halogen, -O-C1-C6 alkyl or C3-C 12 Cycloalkyl groups, preferably deuterium; (7)R 1 and R 1’ Each is independently hydrogen, deuterium, C1-C6 alkyl, or formed by one or more R 1a Substituted C1-C6 alkyl, C3-C 12 cycloalkyl or with one or more R 1d Replacement C3-C 12 cycloalkyl, or R 1 and R 1’ Together they form = O; preferably, R 1 and R 1’ Each is independently hydrogen or C1-C6 alkyl, or R 1 and R 1’ Together they form = O; more preferably, R 1 and R 1’ Each is independently hydrogen or C1-C6 alkyl; (8) Each R 1a and R 1d Each can be independently deuterated, halogenated, oxo-, or -O-C1-C6 alkyl. (9) Ring A is a 5-10 membered heteroaryl group; (10) Each R 5 Independently deuterium, halogen, cyano, nitro, -OR 9 -SR 9 -N(R) 9 )2、-S(O) 1-2 R 9 C1-C6 alkyl or C3-C 12 Cycloalkyl, preferably -OR 9 -SR 9 -N(R) 9 )2 or C1-C6 alkyl, more preferably -N(R 9 )2; (11) Each R 9 It is independently hydrogen, C1-C6 alkyl, or composed of one or more R 9a Substituted C1-C6 alkyl groups, preferably H; (12) Each R 9a It can be either deuterium or a halogen independently; (13) m can be 0, 1, 2 or 3, preferably 1; (14) L is -O-(CR) 10 R 11 ) q1 - a or -O-(CR) 10 R 11 ) q2 -CR 12 R 13 -(CR 10 R 11 ) q3 - a The a end and R 2 Connection; preferably -O-(CR) 10 R 11 ) q1 - a The a end and R 2 connect; (15) Each R 10 and R 11 Each is independently hydrogen, halogen, or C1-C6 alkyl, preferably hydrogen; (16)R 12 R 13 Together with the carbon atoms they are connected to, they form C3-C. 12 cycloalkyl; (17) q1, q2 and q3 are each independently 1, 2 or 3, preferably 1; (18)R 2 It is a 3-12 membered heterocyclic alkyl group, with one or more R 2d Substituted 3-12-membered heterocyclic alkyl, 3-12-membered heterocyclic alkenyl, or substituted with one or more R 2e The substituted 3-12 membered heterocyclic alkenyl group is preferably replaced by one or more R groups. 2d Substituted 3-12 membered heterocyclic alkyl groups; (19) Each R 2d and R 2e Each is independently a halogen, oxo group, or -OR 16 -SR 16 -N(R) 16 )2、=CR 2-j R 2-j C1-C6 alkyl or containing one or more R 2-a The substituted C1-C6 alkyl group is preferably a halogen or a C1-C6 alkyl group, more preferably a halogen; (20) Each R 2-a It can be independently deuterium, halogen, or -O-C1-C6 alkyl; (21) Each R 2-j Independently hydrogen or halogen; (22) Each R 16 Independently hydrogen or C1-C6 alkyl; (23) Each R 3 It is independently hydrogen, halogen, or C1-C6 alkyl, preferably hydrogen; (24) n is 1 or 2, preferably 1; (25) Cycle B is a 7-15 membered heterocyclic alkyl group or a 7-15 membered heterocyclic alkenyl group, preferably a 7-15 membered heterocyclic alkenyl group. (26) Each R 4 Independently deuterium, halogen, cyano, -N(R) 18 )2、-OR 18 -SR 18 Or C1-C6 alkyl, preferably cyano or -N(R) 18 )2; (27) Each R 18 It is independently hydrogen, C1-C6 alkyl or C3-C 12 Cycloalkyl groups, preferably hydrogen-based; and (28) p is 0, 1, 2 or 3, preferably 2. The compound of formula I as claimed in any one of claims 1-3, its stereoisomers, or pharmaceutically acceptable salts thereof, is characterized in that, The compound represented by Formula I satisfies one or more of the following conditions: (1) Each halogen is independently chlorine; (2) Each C1-C6 alkyl group is independently an ethyl group; (3) Each C7-C 15 The cycloalkenyl group is independently 1,2,3,4-tetrahydronaphthyl, 1,2-dihydronaphthyl, or 3',4'-dihydro-2'H-spiro[cyclopropane-1,1'-naphthyl]; (4) Each C7-C 15 The cycloalkenyl group is independently C 10 -C 12 Cycloalkenyl; (5) Each C7-C 15 The cycloalkenyl group independently contains 3 or 4 sp groups. 2 It has double bonds and is not aromatic; (6) Each 7-15 membered heterocyclic alkenyl group has an independent heteroatom of type O and a heteroatom number of 1. (7) Each 7-15 membered heterocyclic alkenyl group is independently 3,4-dihydro-2H-chromenyl; and (8) Each 7-15 membered heterocyclic alkenyl group independently contains 3 sps 2 Double bond. The compound of formula I as claimed in any one of claims 1-3, its stereoisomers, or pharmaceutically acceptable salts thereof, is characterized in that, The compound represented by Formula I satisfies one or more of the following conditions: (1) Each R 1a and R 1d Each is independently a hydroxyl group; (2) Ring B is C7-C 15 Cycloalkenyl; (3) Each R 4 Independent of an oxo group or by one or more R groups 4a Substituted C1-C6 alkyl groups; (4) Each R 4a Halogens are independent of each other; (5) p is 3, 4, or 5; and (6) Structural Unit for (For example )、 (For example )、 The b end is connected to X. The compound of formula I as claimed in any one of claims 1-3, its stereoisomers, or pharmaceutically acceptable salts thereof, is characterized in that, The compound represented by Formula I satisfies one or more of the following conditions: (1) Each C3-C 12 The cycloalkyl group is independently cyclopropyl; (2) The heteroatoms of each 3-12 membered heterocyclic alkyl group are independently selected from one or two of N and O, and the number of heteroatoms is independently 1 or 2. (3) Each 3-12 membered heterocyclic alkyl group is independently monocyclic or polycyclic, wherein the polycyclic group is bicyclic or tricyclic; (4) Each 3-12 membered heterocyclic alkyl group is independently morpholino, isoxazolyl, piperidinyl, or For example For example (5) The heteroatom in each 5-10 membered heteroaryl group is of the N type, and the number of heteroatoms is independently 1, 2, or 3; and (6) Each 5-10 member heteroaryl group is independently pyrazolyl, 1H-1,2,4-triazolyl, pyridazinyl, pyrazinyl, or pyrimidinyl; for example The compound of formula I as claimed in any one of claims 1-3, its stereoisomers, or pharmaceutically acceptable salts thereof, is characterized in that, The compound represented by Formula I satisfies one or more of the following conditions: (1)R 7 It is a C1-C6 alkyl group; (2)R 8 It is a C1-C6 alkyl group or is composed of one or more R groups. 8a Substituted C1-C6 alkyl groups; (3)R 1 and R 1’ Each is independently hydrogen, C1-C6 alkyl, or composed of one or more R... 1a Substituted C1-C6 alkyl groups, preferably, R 1 For hydrogen, R 1’ It is a C1-C6 alkyl group or is composed of one or more R groups. 1a Substituted C1-C6 alkyl groups; (4) Ring A is a 5-6 membered monocyclic heteroaryl group; (5) Each R 5 Independently -N(R) 9 )2 or C1-C6 alkyl; (6) m is 0 or 1; (7) Each R 10 and R 11 Each is independently a deuterium; (8)R 12 R 13 Together with the carbon atoms they are connected to, they form C3-C8 cycloalkyl groups; (9)R 2 It is a 3-12 membered heterocyclic alkyl group or is composed of one or more R groups. 2d Substituted 3-12 membered heterocyclic alkyl groups; (10) Each R 2d and R 2e Each independently constitutes deuterium, -OR 16 =CR 2-j R 2-j Or by one or more R 2-a Substituted C1-C6 alkyl groups, preferably -OR 16 =CR 2-j R 2-j Or by one or more R 2-a Substituted C1-C6 alkyl groups; (11) Each R 2-a Independently hydroxyl, 3-12 membered heterocyclic alkyl groups or those containing one or more R groups 2-a-1 The substituted 3-12 membered heterocyclic alkyl group is preferably a hydroxyl group; (12) Each R 2-a-1 R 2-a-2 and R 2-a-3 Each is independently deuterium, halogen, hydroxyl or C1-C6 alkyl, preferably hydroxyl or C1-C6 alkyl; (13) Each R 16 Independently C1-C6 alkyl; and (14) Each R 4 Independently halogen, cyano, -N(R) 18 2. C1-C6 alkyl or containing one or more R 4a Substituted C1-C6 alkyl groups. The compound of formula I as claimed in any one of claims 1-3, its stereoisomers, or pharmaceutically acceptable salts thereof, is characterized in that, The compound represented by Formula I satisfies one or more of the following conditions: (1) Each C3-C 12 The cycloalkyl group is independently cyclobutyl; (2) Each 3-12 membered heterocyclic alkyl group is independently an aza-butane, For example (for example) )、 (for example) )、 (for example) )、 (for example) )、 (for example) )、 (3) Each 3-12 membered heterocyclic alkyl group is independently... (For example )、 (For example )、 (For example )、 (4) Each 3-12 membered heterocyclic alkenyl group is independently... and (5) Each 5-10 member heteroaryl group is independently thiazolyl, isothiazolyl, pyrazolyl, oxazolyl, isoxazolyl, indazole, 1H-pyrazolo[4,3-c]pyridyl, 1H-imidazo[4,5-c]pyridyl, or 1H-pyrazolo[3,4-c]pyridyl; for example The compound of formula I as claimed in any one of claims 1-3, its stereoisomers, or pharmaceutically acceptable salts thereof, is characterized in that, The compound represented by Formula I satisfies one or more of the following conditions: (1)R 1 and R 1’ Each is independently a C2-C6 alkynyl group; or R 1 R 1’ Together with the carbon atoms it is attached to, they form C3-C 12 cycloalkyl; (2)R 1 It is deuterium; (3)R 1’ It is a C2-C6 acetylene or C3-C 12 cycloalkyl; (4) Each R 1a It can be either deuterium or a halogen independently; (5) Ring A is C3-C 12 cycloalkyl; (6) Each R 5 Halogens are independent of each other; (7) m is 0, 1 or 2; (8) L is a chemical bond; (9)R 12 and R 13 Each is independently hydrogen, deuterium, halogen, C1-C6 alkyl, C3-C 12 Cycloalkyl, or C1-C6 alkyl substituted with one or more substituents selected from deuterium, hydroxyl and halogen, preferably C1-C6 alkyl; (10) q1, q2 and q3 are each independently 0; (11)R 2 -N(R) 15 )2; (12) Each R 2d and R 2e Each is independently a 3-12 membered heterocyclic alkyl group, C6-C 10 aryl or aryl with one or more R 2-h Replacement C6-C 10 Aryl; (13) Each R 2-h Independently deuterium, halogen, or C1-C6 alkyl; preferably halogen; and (14) Each R 15 It is independently hydrogen or C1-C6 alkyl; preferably C1-C6 alkyl. The compound of formula I as claimed in any one of claims 1-4, its stereoisomers, or pharmaceutically acceptable salts thereof, is characterized in that, The compound represented by Formula I satisfies any of the following schemes: Option 1: X is -NR 7 -、-O- or -S-; Y is -NR 8 -、-O-、-S- or *-NR 8 SO2-, the * end is connected to the pyrimidine ring in the parent nucleus; t is 0 or 1; R 7 It is hydrogen, C1-C6 alkyl, and is formed by one or more R 7a Substituted C1-C6 alkyl, C3-C 12 cycloalkyl or with one or more R 7d Replacement C3-C 12 cycloalkyl; each R 7a and R 7d Each is independently deuterium, halogen, C1-C6 alkyl, -O-C1-C6 alkyl, or C3-C 12 cycloalkyl; R 8 It is hydrogen, C1-C6 alkyl, and is formed by one or more R 8a Substituted C1-C6 alkyl, C3-C 12 cycloalkyl or with one or more R 8d Replacement C3-C 12 cycloalkyl; each R 8a and R 8d Each is independently deuterium, hydroxyl, halogen, -O-C1-C6 alkyl or C3-C 12 cycloalkyl; R 1 and R 1’ Each is independently hydrogen, deuterium, C1-C6 alkyl, or formed by one or more R 1a Substituted C1-C6 alkyl, C3-C 12 cycloalkyl or with one or more R 1d Replacement C3-C 12 cycloalkyl; or, R 1 and R 1’ Together they form = O; Each R 1a and R 1d Each can be independently deuterated, halogenated, oxo-, or -O-C1-C6 alkyl. Ring A is a 5-10 member heteroaryl group; Each R 5 Independently deuterium, halogen, cyano, nitro, -OR 9 -SR 9 -N(R) 9 )2、-S(O) 1-2 R 9 C1-C6 alkyl or C3-C 12 cycloalkyl; Each R 9 It is independently hydrogen, C1-C6 alkyl, or composed of one or more R 9a Substituted C1-C6 alkyl groups; each R 9a It can be either deuterium or a halogen independently; m can be 0, 1, 2, or 3; L is -O-(CR) 10 R 11 ) q1 - a or -O-(CR) 10 R 11 ) q2 -CR 12 R 13 -(CR 10 R 11 ) q3 - a The a end and R 2 connect; Each R 10 and R 11 Each is independently hydrogen, halogen, or C1-C6 alkyl; R 12 R 13 Together with the carbon atoms they are connected to, they form C3-C. 12 cycloalkyl; q1, q2, and q3 are each independently 1, 2, or 3; R 2 It is a 3-12 membered heterocyclic alkyl group, with one or more R 2d Substituted 3-12-membered heterocyclic alkyl, 3-12-membered heterocyclic alkenyl, or substituted with one or more R 2e Substituted 3-12 membered heterocyclic alkenyl groups; Each R 2d and R 2e Each is independently a halogen, oxo group, or -OR 16 -SR 16 -N(R) 16 )2、=CR 2-j R 2-j C1-C6 alkyl or containing one or more R 2-a Substituted C1-C6 alkyl groups; Each R 2-a It can be independently deuterium, halogen, or -O-C1-C6 alkyl; Each R 2-j Independently hydrogen or halogen; Each R 16 Independently hydrogen or C1-C6 alkyl; Each R 3 It is independently hydrogen, halogen, or C1-C6 alkyl; n is 1 or 2; Ring B is a 7-15 membered heterocyclic alkyl or a 7-15 membered heterocyclic alkenyl; Each R 4 Independently deuterium, halogen, cyano, -N(R) 18 )2、-OR 18 -SR 18 Or C1-C6 alkyl; Each R 18 It is independently hydrogen, C1-C6 alkyl or C3-C 12 cycloalkyl; p is 0, 1, 2 or 3; Option 2: X is -NR 7 -or -O-; Y is -NR 8 -、-O- or *-NR 8 SO2-, the * end is connected to the pyrimidine ring in the parent nucleus; t is 0 or 1; R 7 It is a C1-C6 alkyl group or is composed of one or more R groups. 7a Substituted C1-C6 alkyl groups; each R 7a Deuterium is independent of other substances; R 8 It is hydrogen, C1-C6 alkyl, or composed of one or more R 8a Substituted C1-C6 alkyl groups; each R 8a Deuterium is independent of other substances; R 1 and R 1’ Each is independently hydrogen or C1-C6 alkyl; or R 1 and R 1’ Together they form = O; Ring A is a 5-10 member heteroaryl group; Each R 5 Independently -N(R) 9 )2; Each R 9 Independently hydrogen; m is 1; L is -O-(CR) 10 R 11 ) q1 - a The a end and R 2 Connection; each R 10 and R 11 Each is independently hydrogen; q1 is 1; R 2 It is a 3-12 membered heterocyclic alkyl group or is composed of one or more R groups. 2d Substituted 3-12 membered heterocyclic alkyl groups; R 2d It is independently a halogen or a C1-C6 alkyl group; R 3 It is hydrogen; n is 1; Cycle B is a 7-15 membered heterocyclic alkenyl group; Each R 4 Independently cyano or -N(R) 18 )2; Each R 18 Independently hydrogen; p is 2; Option 3: The compound represented by Formula I is the same as the compound represented by Formula I-1. Among them, X, Y, R 1 R 1’ R 2 R 3 R 4 R 5 The definitions of L, ring A, t, m, n and p are as defined in any one of claims 1-3, and y1 is 1 or 2; Option 4: The compound represented by Formula I is the same as the compound represented by Formula I-2. Where X is -NR 7 -or -O-; Y is -NR 8 -or -O-; preferably -NR 8 -; t is 1; R 7 It is a C1-C6 alkyl group or is composed of one or more R groups. 7a Substituted C1-C6 alkyl groups; each R 7a Deuterium is independent of other substances; R 8 It is hydrogen, C1-C6 alkyl, or composed of one or more R 8a Substituted C1-C6 alkyl groups; each R 8a Deuterium is independent of other substances; R 1 and R 1’ Each is independently hydrogen or C1-C6 alkyl; or R 1 and R 1’ Together they form = O; Ring A is a 5-10 member heteroaryl group; Each R 5 Independently -N(R) 9 )2; Each R 9 Independently hydrogen; m is 1; L is -O-(CR) 10 R 11 ) q1 - a The a end and R 2 Connection; each R 10 and R 11 Each is independently hydrogen; q1 is 1; R 2 It is a 3-12 membered heterocyclic alkyl group or is composed of one or more R groups. 2d Substituted 3-12 membered heterocyclic alkyl groups; R 2d It is independently a halogen or a C1-C6 alkyl group; Each R 4 Independently cyano or -N(R) 18 )2; Each R 18 Independently hydrogen; p is 2; y1 is 1 or 2; Option 5: X is -NR 7 -、-O- or -S-; Y is -NR 8 -、-O-、-S- or *-NR 8 SO2-, the * end is connected to the pyrimidine ring in the parent nucleus; t is 0 or 1; R 7 It is hydrogen, C1-C6 alkyl, and is formed by one or more R 7a Substituted C1-C6 alkyl, C3-C 12 cycloalkyl or with one or more R 7d Replacement C3-C 12 cycloalkyl; each R 7a and R 7d Each is independently deuterium, halogen, C1-C6 alkyl, -O-C1-C6 alkyl, or C3-C 12 cycloalkyl; R 8 It is hydrogen, C1-C6 alkyl, and is formed by one or more R 8a Substituted C1-C6 alkyl, C3-C 12 cycloalkyl or with one or more R 8d Replacement C3-C 12 cycloalkyl; each R 8a and R 8d Each is independently deuterium, hydroxyl, halogen, -O-C1-C6 alkyl or C3-C 12 cycloalkyl; R 1 and R 1’ Each is independently hydrogen, deuterium, C1-C6 alkyl, or formed by one or more R 1a Substituted C1-C6 alkyl, C3-C 12 cycloalkyl or with one or more R 1d Replacement C3-C 12 cycloalkyl; or, R 1 and R 1’ Together they form = O; Each R 1a and R 1d Each can be independently deuterium, hydroxyl, halogen, oxo group or -O-C1-C6 alkyl; Ring A is a 5-10 member heteroaryl group; Each R 5 Independently deuterium, halogen, cyano, nitro, -OR 9 -SR 9 -N(R) 9 )2、-S(O) 1-2 R 9 C1-C6 alkyl or C3-C 12 cycloalkyl; Each R 9 It is independently hydrogen, C1-C6 alkyl, or composed of one or more R 9a Substituted C1-C6 alkyl groups; each R 9a It can be either deuterium or a halogen independently; m can be 0, 1, 2, or 3; L is -O-(CR) 10 R 11 ) q1 - a or -O-(CR) 10 R 11 ) q2 -CR 12 R 13 -(CR 10 R 11 ) q3 - a The a end and R 2 connect; Each R 10 and R 11 Each is independently hydrogen, halogen, or C1-C6 alkyl; R 12 R 13 Together with the carbon atoms they are connected to, they form C3-C. 12 cycloalkyl; q1, q2, and q3 are each independently 1, 2, or 3; R 2 It is a 3-12 membered heterocyclic alkyl group, with one or more R 2d Substituted 3-12-membered heterocyclic alkyl, 3-12-membered heterocyclic alkenyl, or substituted with one or more R 2e Substituted 3-12 membered heterocyclic alkenyl groups; Each R 2d and R 2e Each is independently a halogen, oxo group, or -OR 16 -SR 16 -N(R) 16 )2、=CR 2-j R 2-j C1-C6 alkyl or containing one or more R 2-a Substituted C1-C6 alkyl groups; Each R 2-a It can be independently deuterium, halogen, or -O-C1-C6 alkyl; Each R 2-j Independently hydrogen or halogen; Each R 16 Independently hydrogen or C1-C6 alkyl; Each R 3 It is independently hydrogen, halogen, or C1-C6 alkyl; n is 1 or 2; Ring B is a 7-15 membered heterocyclic alkyl group, C7-C 15 Cycloalkenyl or 7-15 membered heterocyclic alkenyl; Each R 4 Independently deuterium, halogen, cyano, oxo, -N(R) 18 )2、-OR 18 -SR 18 C1-C6 alkyl or containing one or more R 4a Substituted C1-C6 alkyl groups; Each R 18 It is independently hydrogen, C1-C6 alkyl or C3-C 12 cycloalkyl; each R 4a Halogens are independent of each other; p is 0, 1, 2, 3, 4 or 5; Option Six: X is -NR 7 -or -O-; Y is -NR 8 -、-O- or *-NR 8 SO2-, the * end is connected to the pyrimidine ring in the parent nucleus; t is 0 or 1; R 7 It is a C1-C6 alkyl group or is composed of one or more R groups. 7a Substituted C1-C6 alkyl groups; each R 7a Deuterium is independent of other substances; R 8 It is hydrogen, C1-C6 alkyl, or composed of one or more R 8a Substituted C1-C6 alkyl groups; each R 8a Deuterium is independent of other substances; R 1 and R 1’ Each is independently hydrogen, C1-C6 alkyl, or composed of one or more R... 1a Substituted C1-C6 alkyl; or R 1 and R 1’ Together form = O; each R 1a Independently, it is a hydroxyl group; Ring A is a 5-10 member heteroaryl group; Each R 5 Independently -N(R) 9 )2; Each R 9 Independently hydrogen; m is 1; L is -O-(CR) 10 R 11 ) q1 - a The a end and R 2 Connection; each R 10 and R 11 Each is independently hydrogen; q1 is 1; R 2 It is a 3-12 membered heterocyclic alkyl group or is composed of one or more R groups. 2d Substituted 3-12 membered heterocyclic alkyl groups; R 2d It is independently a halogen or a C1-C6 alkyl group; R 3 It is hydrogen; n is 1; Ring B is C7-C 15 Cycloalkenyl or 7-15 membered heterocyclic alkenyl; Each R 4 Independently halogen, cyano, oxo, -N(R) 18 2. C1-C6 alkyl or containing one or more R 4a Substituted C1-C6 alkyl groups; each R 18 Independently hydrogen; each R 4a Halogens are independent of each other; p is 2, 3, 4 or 5; Option Seven: The compound represented by Formula I is the same as the compound represented by Formula I-3. Where X is -NR 7 -or -O-; Y is -NR 8 -; t is 1; R 7 It is a C1-C6 alkyl group or is composed of one or more R groups. 7a Substituted C1-C6 alkyl groups; each R 7a Deuterium is independent of other substances; R 8 It is hydrogen, C1-C6 alkyl, or composed of one or more R 8a Substituted C1-C6 alkyl groups; each R 8a Deuterium is independent of other substances; R 1 and R 1’ Each is independently hydrogen or C1-C6 alkyl; or R 1 and R 1’ Together they form = O; Ring A is a 5-10 member heteroaryl group; Each R 5 Independently -N(R) 9 )2; Each R 9 Independently hydrogen; m is 1; L is -O-(CR) 10 R 11 ) q1 - a The a end and R 2 Connection; each R 10 and R 11 Each is independently hydrogen; q1 is 1; R 2 It is a 3-12 membered heterocyclic alkyl group or is composed of one or more R groups. 2d Substituted 3-12 membered heterocyclic alkyl groups; R 2d It is independently a halogen or a C1-C6 alkyl group; R 3 It is hydrogen; n is 1; Each R 4 Independently halogen, cyano, oxo, -N(R) 18 2. C1-C6 alkyl or containing one or more R 4a Substituted C1-C6 alkyl groups; each R 18 Independently hydrogen; each R 4a Halogens are independent of each other; p is 2 or 3; Option 8: The compound represented by Formula I is either Formula I-3A or I-3B. Where X is -NR 7 -or -O-; Y is -NR 8 -; t is 1; R 7 It is a C1-C6 alkyl group or is composed of one or more R groups. 7a Substituted C1-C6 alkyl groups; each R 7a Deuterium is independent of other substances; R 8 It is hydrogen, C1-C6 alkyl, or composed of one or more R 8a Substituted C1-C6 alkyl groups; each R 8a Deuterium is independent of other substances; R 1 and R 1’ Each is independently hydrogen or C1-C6 alkyl; or R 1 and R 1’ Together they form = O; Ring A is a 5-10 member heteroaryl group; Each R 5 Independently -N(R) 9 )2; Each R 9 Independently hydrogen; m is 1; L is -O-(CR) 10 R 11 ) q1 - a The a end and R 2 Connection; each R 10 and R 11 Each is independently hydrogen; q1 is 1; R 2 It is a 3-12 membered heterocyclic alkyl group or is composed of one or more R groups. 2d Substituted 3-12 membered heterocyclic alkyl groups; R 2d It is independently a halogen or a C1-C6 alkyl group; R 3 It is hydrogen; n is 1; Each R 4 Independently halogen, cyano, oxo, -N(R) 18 2. C1-C6 alkyl or containing one or more R 4a Substituted C1-C6 alkyl groups; each R 18 Independently hydrogen; each R 4a Halogens are independent of each other; p is 2 or 3; Option Nine: X is -NR 7 -、-O- or -S-; Y is -NR 8 -、-O-、-S- or *-NR 8 SO2-, the * end is connected to the pyrimidine ring in the parent nucleus; t is 0 or 1; R 7 It is hydrogen, C1-C6 alkyl, and is formed by one or more R 7a Substituted C1-C6 alkyl, C3-C 12 cycloalkyl or with one or more R 7d Replacement C3-C 12 cycloalkyl; each R 7a and R 7d Each is independently deuterium, halogen, C1-C6 alkyl, -O-C1-C6 alkyl, or C3-C 12 cycloalkyl; R 8 It is hydrogen, C1-C6 alkyl, and is formed by one or more R 8a Substituted C1-C6 alkyl, C3-C 12 cycloalkyl or with one or more R 8d Replacement C3-C 12 cycloalkyl; each R 8a and R 8d Each is independently deuterium, hydroxyl, halogen, -O-C1-C6 alkyl or C3-C 12 cycloalkyl; R 1 and R 1’ Each is independently hydrogen, deuterium, C1-C6 alkyl, or formed by one or more R 1a Substituted C1-C6 alkyl, C3-C 12 cycloalkyl or with one or more R 1d Replacement C3-C 12 cycloalkyl; or, R 1 and R 1’ Together they form = O; Each R 1a and R 1d Each can be independently deuterium, hydroxyl, halogen, oxo group or -O-C1-C6 alkyl; Ring A is a 5-10 member heteroaryl group; Each R 5 Independently deuterium, halogen, cyano, nitro, -OR 9 -SR 9 -N(R) 9 )2、-S(O) 1-2 R 9 C1-C6 alkyl or C3-C 12 cycloalkyl; Each R 9 It is independently hydrogen, C1-C6 alkyl, or composed of one or more R 9a Substituted C1-C6 alkyl groups; each R 9a It can be either deuterium or a halogen independently; m can be 0, 1, 2, or 3; L is -O-(CR) 10 R 11 ) q1 - a or -O-(CR) 10 R 11 ) q2 -CR 12 R 13 -(CR 10 R 11 ) q3 - a The a end and R 2 connect; Each R 10 and R 11 Each is independently hydrogen, deuterium, halogen, or C1-C6 alkyl; R 12 R 13 Together with the carbon atoms they are connected to, they form C3-C. 12 cycloalkyl; q1, q2, and q3 are each independently 1, 2, or 3; R 2 It is a 3-12 membered heterocyclic alkyl group, with one or more R 2d Substituted 3-12-membered heterocyclic alkyl, 3-12-membered heterocyclic alkenyl, or substituted with one or more R 2e Substituted 3-12 membered heterocyclic alkenyl groups; Each R 2d and R 2e Each is independently a halogen, deuterium, oxo group, or -OR. 16 -SR 16 -N(R) 16 )2、=CR 2-j R 2-j C1-C6 alkyl or containing one or more R 2-a Substituted C1-C6 alkyl groups; Each R 2-a Independently deuterium, halogen, hydroxyl, 3-12 membered heterocyclic alkyl, -O-C1-C6 alkyl, or with one or more R 2-a-1 Substituted 3-12 membered heterocyclic alkyl groups; Each R 2-j Independently hydrogen or halogen; Each R 2-a-1 R 2-a-2 and R 2-a-3 Each is independently deuterium, halogen, hydroxyl, or C1-C6 alkyl; Each R 16 Independently hydrogen or C1-C6 alkyl; Each R 3 It is independently hydrogen, halogen, or C1-C6 alkyl; n is 1 or 2; Ring B is a 7-15 membered heterocyclic alkyl group, C7-C 15 Cycloalkenyl or 7-15 membered heterocyclic alkenyl; Each R 4 Independently deuterium, halogen, cyano, oxo, -N(R) 18 )2、-OR 18 -SR 18 C1-C6 alkyl or containing one or more R 4a Substituted C1-C6 alkyl groups; Each R 18 It is independently hydrogen, C1-C6 alkyl or C3-C 12 cycloalkyl; each R 4a Halogens are independent of each other; p is 0, 1, 2, 3, 4 or 5; Option 10: X is -NR 7 -or -O-; Y is -NR 8 -、-O- or *-NR 8 SO2-, the * end is connected to the pyrimidine ring in the parent nucleus; t is 0 or 1; R 7 It is a C1-C6 alkyl group or is composed of one or more R groups. 7a Substituted C1-C6 alkyl groups; each R 7a Deuterium is independent of other substances; R 8 It is hydrogen, C1-C6 alkyl, or composed of one or more R 8a Substituted C1-C6 alkyl groups; each R 8a Deuterium is independent of other substances; R 1 and R 1’ Each is independently hydrogen, C1-C6 alkyl, or composed of one or more R... 1a Substituted C1-C6 alkyl; or R 1 and R 1’ Together form = O; each R 1a Independently, it can be deuterium, halogen, or hydroxyl; Ring A is a 5-10 member heteroaryl group; Each R 5 Independently -N(R) 9 )2 or C1-C6 alkyl; each R 9 Independently hydrogen; m is 0 or 1; L is -O-(CR) 10 R 11 ) q1 - a or -O-(CR) 10 R 11 ) q2 -CR 12 R 13 -(CR 10 R 11 ) q3 - a The a end and R 2 Connection; each R 10 and R 11 Each is independently hydrogen, deuterium, or C1-C6 alkyl; q1, q2, and q3 are each independently 1; R 12 R 13 Together with the carbon atoms they are connected to, they form C3-C. 12 cycloalkyl; R 2 It is a 3-12 membered heterocyclic alkyl group or is composed of one or more R groups. 2d Substituted 3-12 membered heterocyclic alkyl groups; R 2d Independent of halogen, deuterium, -OR 16 =CR 2-j R 2-j C1-C6 alkyl or containing one or more R 2-a Substituted C1-C6 alkyl groups; R 16 It is hydrogen or C1-C6 alkyl; Each R 2-j Independently hydrogen or halogen; Each R 2-a Independently, it is deuterium, halogen, hydroxyl, -O-PO(OH)2, 3-12 membered heterocyclic alkyl, -O-C1-C6 alkyl, or is associated with one or more R 2-a-1 Substituted 3-12 membered heterocyclic alkyl groups; Each R 2-a-1 Independently, it is a C1-C6 alkyl group; R 3 It is hydrogen; n is 1; Ring B is C7-C 15 Cycloalkenyl or 7-15 membered heterocyclic alkenyl; Each R 4 Independently halogen, cyano, oxo, -N(R) 18 2. C1-C6 alkyl or containing one or more R 4a Substituted C1-C6 alkyl groups; each R 18 Independently hydrogen; each R 4a Halogens are independent of each other; p is 2, 3, 4 or 5; Option 11: The compound represented by Formula I is the same as the compound represented by Formula I-4. in, It can be a single bond or a double bond; X is -NR 7 -or -O-; Y is -NR 8 -; t is 1; R 7 It is a C1-C6 alkyl group or is composed of one or more R groups. 7a Substituted C1-C6 alkyl groups; each R 7a Deuterium is independent of other substances; R 8 It is hydrogen, C1-C6 alkyl, or composed of one or more R 8a Substituted C1-C6 alkyl groups; each R 8a Deuterium is independent of other substances; R 1 and R 1’ Each is independently hydrogen, C1-C6 alkyl, or composed of one or more R... 1a Substituted C1-C6 alkyl groups; Each R 1a Independently, it can be deuterium, halogen, or hydroxyl; Ring A is a 5-10 member heteroaryl group; Each R 5 Independently -N(R) 9 )2; Each R 9 Independently hydrogen; m is 1; L is -O-(CR) 10 R 11 ) q1 - a or -O-(CR) 10 R 11 ) q2 -CR 12 R 13 -(CR 10 R 11 ) q3 - a The a end and R 2 Connection; each R 10 and R 11 Each is independently hydrogen or deuterium; q1, q2 and q3 are each independently 1; R 12 R 13 Together with the carbon atoms they are connected to, they form C3-C. 12 cycloalkyl; R 2 It is a 3-12 membered heterocyclic alkyl group or is composed of one or more R groups. 2d Substituted 3-12 membered heterocyclic alkyl groups; R 2d Independent of halogen, deuterium, =CR 2- j R 2-j -OR 16 C1-C6 alkyl or containing one or more R 2-a Substituted C1-C6 alkyl groups; Each R 2-j Independently hydrogen or halogen; Each R 2-a Independently, it can be deuterium, halogen, or hydroxyl; R 16 It is hydrogen or C1-C6 alkyl; R 3 It is hydrogen; n is 1; Each R 4 Independently halogen, cyano, oxo, -N(R) 18 2. C1-C6 alkyl or containing one or more R 4a Substituted C1-C6 alkyl groups; each R 18 Independently hydrogen; each R 4a Halogens are independent of each other; p is 2 or 3; Option Twelve: The compound represented by Formula I is either Formula I-4A or I-4B. in, It can be a single bond or a double bond; X is -NR 7 -or -O-; Y is -NR 8 -; t is 1; R 7 It is a C1-C6 alkyl group or is composed of one or more R groups. 7a Substituted C1-C6 alkyl groups; each R 7a Deuterium is independent of other substances; R 8 It is hydrogen, C1-C6 alkyl, or composed of one or more R 8a Substituted C1-C6 alkyl groups; each R 8a Deuterium is independent of other substances; R 1 and R 1’ Each is independently hydrogen, C1-C6 alkyl, or composed of one or more R... 1a Substituted C1-C6 alkyl groups; Each R 1a Independently, it can be deuterium, halogen, or hydroxyl; Ring A is a 5-10 member heteroaryl group; Each R 5 Independently -N(R) 9 )2; Each R 9 Independently hydrogen; m is 1; L is -O-(CR) 10 R 11 ) q1 - a or -O-(CR) 10 R 11 ) q2 -CR 12 R 13 -(CR 10 R 11 ) q3 - a The a end and R 2 Connection; each R 10 and R 11 Each is independently hydrogen or deuterium; q1, q2 and q3 are each independently 1; R 12 R 13 Together with the carbon atoms they are connected to, they form C3-C. 12 cycloalkyl; R 2 It is a 3-12 membered heterocyclic alkyl group or is composed of one or more R groups. 2d Substituted 3-12 membered heterocyclic alkyl groups; R 2d Independent of halogen, deuterium, =CR 2- j R 2-j -OR 16 C1-C6 alkyl or containing one or more R 2-a Substituted C1-C6 alkyl groups; Each R 2-j Independently hydrogen or halogen; Each R 2-a Independently, it can be deuterium, halogen, or hydroxyl; R 16 It is hydrogen or C1-C6 alkyl; R 3 It is hydrogen; n is 1; Each R 4 Independently halogen, cyano, oxo, -N(R) 18 2. C1-C6 alkyl or containing one or more R 4a Substituted C1-C6 alkyl groups; each R 18 Independently hydrogen; each R 4a Halogens are independent of each other; p is 2 or 3; Option Thirteen: The compound represented by Formula I-4 is the same as the compound represented by Formula I-4C. in, It can be a single bond or a double bond; X, Y, L, ring A, R 1’ R 2 R 3 R 4 R 5 The definitions of m, n and p are as described in any one of claims 1-11; Option Fourteen: Formula I-4A is the compound represented by Formula I-4A-1; Formula I-4B is the compound represented by Formula I-4B-1; in, It can be a single bond or a double bond; X, Y, L, ring A, R 1’ R 2 R 3 R 4 R 5 The definitions of m, n and p are as described in any one of claims 1-11; Option Fifteen: X is -NR 7 -、-O- or -S-; Y is -NR 8 -、-O-、-S- or *-NR 8 SO2-, the * end is connected to the pyrimidine ring in the parent nucleus; t is 0 or 1; R 7 It is hydrogen, C1-C6 alkyl, and is formed by one or more R 7a Substituted C1-C6 alkyl, C3-C 12 cycloalkyl or with one or more R 7d Replacement C3-C 12 cycloalkyl; each R 7a and R 7d Each is independently deuterium, halogen, C1-C6 alkyl, -O-C1-C6 alkyl, or C3-C 12 cycloalkyl; R 8 It is hydrogen, C1-C6 alkyl, and is formed by one or more R 8a Substituted C1-C6 alkyl, C3-C 12 cycloalkyl or with one or more R 8d Replacement C3-C 12 cycloalkyl; each R 8a and R 8d Each is independently deuterium, hydroxyl, halogen, -O-C1-C6 alkyl or C3-C 12 cycloalkyl; R 1 and R 1’ Each is independently hydrogen, deuterium, C2-C6 ynyl, C1-C6 alkyl, or formed by one or more R groups. 1a Substituted C1-C6 alkyl, C3-C 12 cycloalkyl or with one or more R 1d Replacement C3-C 12 cycloalkyl; or, R 1 and R 1’ Together they form = O; Or, R 1 R 1’ Together with the carbon atoms it is attached to, they form C3-C 12 cycloalkyl; Each R 1a and R 1d Each can be independently deuterium, hydroxyl, halogen, oxo group or -O-C1-C6 alkyl; Ring A is a 5-10 membered heteroaryl group or a C3-C ring. 12 cycloalkyl; Each R 5 Independently deuterium, halogen, cyano, nitro, -OR 9 -SR 9 -N(R) 9 )2、-S(O) 1-2 R 9 C1-C6 alkyl or C3-C 12 cycloalkyl; Each R 9 It is independently hydrogen, C1-C6 alkyl, or composed of one or more R 9a Substituted C1-C6 alkyl groups; each R 9a It can be either deuterium or a halogen independently; m can be 0, 1, 2, or 3; L represents a chemical bond, -O-(CR) 10 R 11 ) q1 - a or -O-(CR) 10 R 11 ) q2 -CR 12 R 13 -(CR 10 R 11 ) q3 - a The a end and R 2 connect; Each R 10 and R 11 Each is independently hydrogen, deuterium, halogen, or C1-C6 alkyl; R 12 R 13 Together with the carbon atoms they are connected to, they form C3-C. 12 cycloalkyl; Or, R 12 and R 13 Each is independently hydrogen, deuterium, halogen, C1-C6 alkyl, C3-C 12 Cycloalkyl, or C1-C6 alkyl groups substituted with one or more substituents selected from deuterium, hydroxyl and halogen; q1, q2, and q3 are each independently 0, 1, 2, or 3; R 2 -N(R) 15 )2, 3-12 membered heterocyclic alkyl groups, with one or more R 2d Substituted 3-12-membered heterocyclic alkyl, 3-12-membered heterocyclic alkenyl, or substituted with one or more R 2e Substituted 3-12 membered heterocyclic alkenyl groups; Each R 2d and R 2e Each is independently a halogen, deuterium, oxo group, or -OR. 16 -SR 16 -N(R) 16 )2、=CR 2-j R 2-j C1-C6 alkyl, 3-12 membered heterocyclic alkyl, C6-C 10 aryl, with one or more R 2-a Substituted C1-C6 alkyl groups or those with one or more R 2-h Replacement C6-C 10 Aryl; Each R 2-a Independently deuterium, halogen, hydroxyl, 3-12 membered heterocyclic alkyl, -O-C1-C6 alkyl, or with one or more R 2-a-1 Substituted 3-12 membered heterocyclic alkyl groups; Each R 2-h It can be independently deuterium, halogen, or C1-C6 alkyl; Each R 2-j Independently hydrogen or halogen; Each R 2-a-1 R 2-a-2 and R 2-a-3 Each is independently deuterium, halogen, hydroxyl, or C1-C6 alkyl; Each R 15 Independently hydrogen or C1-C6 alkyl; Each R 16 Independently hydrogen or C1-C6 alkyl; Each R 3 It is independently hydrogen, halogen, or C1-C6 alkyl; n is 1 or 2; Ring B is a 7-15 membered heterocyclic alkyl group, C7-C 15 Cycloalkenyl or 7-15 membered heterocyclic alkenyl; Each R 4 Independently deuterium, halogen, cyano, oxo, -N(R) 18 )2、-OR 18 -SR 18 C1-C6 alkyl or containing one or more R 4a Substituted C1-C6 alkyl groups; Each R 18 It is independently hydrogen, C1-C6 alkyl or C3-C 12 cycloalkyl; each R 4a Halogens are independent of each other; p is 0, 1, 2, 3, 4 or 5; Option Sixteen: The compound represented by Formula I is the same as the compound represented by Formula I-5. X is -NR 7 -or -O-; Y is -NR 8 -、-O- or *-NR 8 SO2-, the * end is connected to the pyrimidine ring in the parent nucleus; t is 0 or 1; R 7 It is a C1-C6 alkyl group or is composed of one or more R groups. 7a Substituted C1-C6 alkyl groups; each R 7a Deuterium is independent of other substances; R 8 It is hydrogen, C1-C6 alkyl, or composed of one or more R 8a Substituted C1-C6 alkyl groups; each R 8a Deuterium is independent of other substances; R 1 and R 1’ Each can be independently hydrogen, deuterium, C2-C6 alkynyl, C1-C6 alkyl, or C3-C 12 cycloalkyl or with one or more R 1a Substituted C1-C6 alkyl; or R 1 and R 1’ Together they form = O; or, R 1 R 1’ Together with the carbon atoms it is attached to, they form C3-C 12 cycloalkyl; Each R 1a Independently, it can be deuterium, halogen, or hydroxyl; Ring A is a 5-10 membered heteroaryl group or a C3-C ring. 12 cycloalkyl; Each R 5 Independently halogen, -N(R) 9 )2 or C1-C6 alkyl; each R 9 Independently hydrogen; m is 0, 1, or 2; L represents a chemical bond, -O-(CR) 10 R 11 ) q1 - a or -O-(CR) 10 R 11 ) q2 -CR 12 R 13 -(CR 10 R 11 ) q3 - a The a end and R 2 Connection; each R 10 and R 11 Each is independently hydrogen, deuterium, or C1-C6 alkyl; q1, q2, and q3 are each independently 0 or 1; R 12 R 13 Together with the carbon atoms they are connected to, they form C3-C. 12 cycloalkyl; Or, R 12 and R 13 Each is independently a C1-C6 alkyl group; R 2 -N(R) 15 )2, 3-12 membered heterocyclic alkyl groups, with one or more R 2d Substituted 3-12-membered heterocyclic alkyl, 3-12-membered heterocyclic alkenyl, or substituted with one or more R 2e Substituted 3-12 membered heterocyclic alkenyl groups; Each R 2d and R 2e Each independently constitutes halogen, deuterium, -OR 16 =CR 2-j R 2-j C1-C6 alkyl, 3-12 membered heterocyclic alkyl, C6-C 10 aryl, with one or more R 2-a Substituted C1-C6 alkyl groups or those with one or more R 2-h Replacement C6-C 10 Aryl; Each R 15 Independently, it is a C1-C6 alkyl group; R 16 Independently hydrogen or C1-C6 alkyl; Each R 2-h Halogens are independent of each other; Each R 2-j Independently hydrogen or halogen; Each R 2-a Independently, it is deuterium, halogen, hydroxyl, -O-PO(OH)2, 3-12 membered heterocyclic alkyl, -O-C1-C6 alkyl, or is associated with one or more R 2-a-1 Substituted 3-12 membered heterocyclic alkyl groups; Each R 2-a-1 Independently, it is a C1-C6 alkyl group; Each R 4 Independently halogen, cyano, oxo, -N(R) 18 2. C1-C6 alkyl or containing one or more R 4a Substituted C1-C6 alkyl groups; each R 18 Independently hydrogen; each R 4a Halogens are independent of each other; p is 2, 3, 4 or 5; Option 17: The compound represented by Formula I is the same as the compound represented by Formula I-5. in, It can be a single bond or a double bond; X is -NR 7 -or -O-; Y is -NR 8 -; t is 1; R 7 It is a C1-C6 alkyl group or is composed of one or more R groups. 7a Substituted C1-C6 alkyl groups; each R 7a Deuterium is independent of other substances; R 8 It is hydrogen, C1-C6 alkyl, or composed of one or more R 8a Substituted C1-C6 alkyl groups; each R 8a Deuterium is independent of other substances; R 1 and R 1’ Each of the following is independently hydrogen, deuterium, C1-C6 alkyl, C2-C6 alkynyl, or C3-C 12 cycloalkyl or with one or more R 1a Substituted C1-C6 alkyl groups; Each R 1a Independently, it can be deuterium, halogen, or hydroxyl; Ring A is a 5-10 member heteroaryl group; Each R 5 Independently -N(R) 9 )2 or halogen; each R 9 Independently hydrogen; m is 0, 1, or 2; L is -O-(CR) 10 R 11 ) q1 - a or -O-(CR) 10 R 11 ) q2 -CR 12 R 13 -(CR 10 R 11 ) q3 - a The a end and R 2 connect; Each R 10 and R 11 Each is independently hydrogen or deuterium; q1, q2 and q3 are each independently 1; R 12 R 13 Together with the carbon atoms they are connected to, they form C3-C. 12 cycloalkyl; Or, R 12 and R 13 Each is independently a C1-C6 alkyl group; R 2 -N(R) 15 )2, 3-12 membered heterocyclic alkyl groups, with one or more R 2d Substituted 3-12-membered heterocyclic alkyl, 3-12-membered heterocyclic alkenyl, or substituted with one or more R 2e Substituted 3-12 membered heterocyclic alkenyl groups; Each R 2d and R 2e Each independently constitutes halogen, deuterium, and CR. 2-j R 2-j -OR 16 C1-C6 alkyl, C6-C 10 aryl, with one or more R 2-a Substituted C1-C6 alkyl groups or those with one or more R 2-h Replacement C6-C 10 Aryl; Each R 2-h Halogens are independent of each other; Each R 2-j Independently hydrogen or halogen; Each R 2-a Independently deuterium, halogen, hydroxyl group, or by one or more R 2-a-1 Substituted 3-12 membered heterocyclic alkyl groups; Each R 2-a-1 Independently, it is a C1-C6 alkyl group; Each R 15 Independently, it is a C1-C6 alkyl group; R 16 It is hydrogen or C1-C6 alkyl; Each R 4 Independently halogen, cyano, -N(R) 18 2. C1-C6 alkyl or containing one or more R 4a Substituted C1-C6 alkyl groups; each R 18 Independently hydrogen; each R 4a Halogens are independent of each other; p is 2 or 3; Option 18: The compound represented by Formula I is either Formula I-5A or I-5B. in, It can be a single bond or a double bond; X is -NR 7 -or -O-; Y is -NR 8 -; t is 1; R 7 It is a C1-C6 alkyl group or is composed of one or more R groups. 7a Substituted C1-C6 alkyl groups; each R 7a Deuterium is independent of other substances; R 8 It is hydrogen, C1-C6 alkyl, or composed of one or more R 8a Substituted C1-C6 alkyl groups; each R 8a Deuterium is independent of other substances; R 1 and R 1’ Each of the following is independently hydrogen, deuterium, C1-C6 alkyl, C2-C6 alkynyl, or C3-C 12 cycloalkyl or with one or more R 1a Substituted C1-C6 alkyl groups; and R 1 and R 1’ Different; Each R 1a Independently, it can be deuterium, halogen, or hydroxyl; Ring A is a 5-10 member heteroaryl group; Each R 5 Independently -N(R) 9 )2 or halogen; each R 9 Independently hydrogen; m is 0, 1, or 2; L is -O-(CR) 10 R 11 ) q1 - a or -O-(CR) 10 R 11 ) q2 -CR 12 R 13 -(CR 10 R 11 ) q3 - a The a end and R 2 connect; Each R 10 and R 11 Each is independently hydrogen or deuterium; q1, q2 and q3 are each independently 1; R 12 R 13 Together with the carbon atoms they are connected to, they form C3-C. 12 cycloalkyl; Or, R 12 and R 13 Each is independently a C1-C6 alkyl group; R 2 -N(R) 15 )2, 3-12 membered heterocyclic alkyl groups, with one or more R 2d Substituted 3-12-membered heterocyclic alkyl, 3-12-membered heterocyclic alkenyl, or substituted with one or more R 2e Substituted 3-12 membered heterocyclic alkenyl groups; Each R 2d and R 2e Each independently constitutes halogen, deuterium, and CR. 2-j R 2-j -OR 16 C1-C6 alkyl, C6-C 10 aryl, with one or more R 2-a Substituted C1-C6 alkyl groups or those with one or more R 2-h Replacement C6-C 10 Aryl; Each R 2-h Halogens are independent of each other; Each R 2-j Independently hydrogen or halogen; Each R 2-a Independently deuterium, halogen, hydroxyl group, or by one or more R 2-a-1 Substituted 3-12 membered heterocyclic alkyl groups; Each R 2-a-1 Independently, it is a C1-C6 alkyl group; Each R 15 Independently, it is a C1-C6 alkyl group; R 16 It is hydrogen or C1-C6 alkyl; Each R 4 Independently halogen, cyano, -N(R) 18 2. C1-C6 alkyl or containing one or more R 4a Substituted C1-C6 alkyl groups; each R 18 Independently hydrogen; each R 4a Halogens are independent of each other; p is 2 or 3. The compound of formula I as claimed in any one of claims 1-4, its stereoisomers, or pharmaceutically acceptable salts thereof, is characterized in that, The compound represented by Formula I satisfies one or more of the following conditions: (1) X is -N(CH3)-, -N(CD3)- or -O-; (2) Y is -NH-, -O-, -N(CH3)-, -N(CD3)- or The * end is connected to the pyrimidine ring in the parent nucleus; (3)R 1 and R 1’ Each can be independently H, -CH3, -CH2OH, or -CH2CH2OH; or, R 1 and R 1’ Together they form = O, preferably, R 1 and R 1’ Each is independently hydrogen or -CH3; or, R 1 and R 1’ Together they form = O; (4) Each R 5 Independently -NH2 or -CH3, preferably, each R 5 Independently -NH2; (5) Structural Unit for Preferably, structural unit for (6) L is -OCH2- a , The a end and R 2 Connection, preferably, L is -OCH2- a The a end and R 2 connect; (7)R 2 for Preferably, R 2 for and (8) Structural Unit for Preferred The b end is connected to X. The compound of formula I as claimed in any one of claims 1-3, its stereoisomers, or pharmaceutically acceptable salts thereof, is characterized in that, The compound represented by Formula I satisfies one or two of the following conditions: (1)R 4 It can be -F, -Cl, -CN, -NH2, oxo group, -CH3 or -CF3; (2)R 1 and R 1’ Each can be independently H, -CH2OH, or -CH2CH2OH; and (3) Structural Unit for The b-end is connected to X, preferably, in a structural unit. for The b end is connected to X. The compound of formula I as claimed in any one of claims 1-3, its stereoisomers, or pharmaceutically acceptable salts thereof, is characterized in that, The compound represented by Formula I satisfies one or two of the following conditions: (1) X is -N(CH2CH3)-; (2)R 1 and R 1’ Each independently constitutes deuterium, -CHF2, -CF3, -CH2CHF2, -CH2CH3, -CH2F, -CD3, Or, R 1 R 1’ It forms together with the carbon atoms it is attached to. (3) Each R 5 Independently -F; (4) Structural Unit for (5) L represents a chemical bond, -O-, The a end and R 2 Connection; and (6)R 2 for A compound, its stereoisomer, or a pharmaceutically acceptable salt thereof, characterized in that, The compound is any one of the following compounds: The compound of Formula I as claimed in claim 1, its stereoisomers, or pharmaceutically acceptable salts thereof, is characterized in that, The compound represented by Formula I is any of the following compounds: The compound that elutes first under the following conditions: a C18OBD 19*250mm*5μm column, a mobile phase of water (0.1% formic acid, v / v) and acetonitrile, with acetonitrile comprising 10% by volume, a flow rate of 25mL / min, and a detection wavelength of 214 / 254nm; preferably, under these conditions, the retention time of the compound that elutes first is 4.58 minutes. The compound that elutes later in the chromatogram is determined under the following conditions: a C18OBD column (19*250mm*5μm), a mobile phase of water (0.1% formic acid, v / v) and acetonitrile (acetonitrile volume percentage 10%), a flow rate of 25mL / min, and a detection wavelength of 214 / 254nm; preferably, under these conditions, the retention time of the compound that elutes later is 5.45 minutes. The compound that elutes first under the following conditions: a C18OBD 19*250mm*5μm column, a mobile phase of water (0.1% formic acid, v / v) and acetonitrile, with acetonitrile comprising 10% by volume, a flow rate of 25mL / min, and a detection wavelength of 214 / 254nm; preferably, under these conditions, the retention time of the compound that elutes first is 3.7 minutes. The compound that elutes later in the chromatogram is determined under the following conditions: a C18OBD 19*250mm*5μm column, a mobile phase of water (containing 0.1% formic acid, v / v) and acetonitrile, with acetonitrile comprising 10% by volume, a flow rate of 25mL / min, and a detection wavelength of 214 / 254nm; preferably, under these conditions, the retention time of the compound that elutes later is 7.0 min. The compound that elutes first under the following conditions: a C18OBD 19*250mm*5μm column, a mobile phase of water (0.1% formic acid, v / v) and acetonitrile, with acetonitrile comprising 10% by volume, a flow rate of 25mL / min, and a detection wavelength of 214 / 254nm; preferably, under these conditions, the retention time of the compound that elutes first is 4.5 minutes. The compound that elutes later in the chromatogram is determined under the following conditions: a C18OBD column (19*250mm*5μm), a mobile phase of water (0.1% formic acid, v / v) and acetonitrile (acetonitrile volume percentage 10%), a flow rate of 25mL / min, and a detection wavelength of 214 / 254nm; preferably, under these conditions, the retention time of the compound that elutes later is 6.8 minutes. The compound that elutes first under the following conditions: a C18 OBD column (19*250mm*5μm), a mobile phase of water (0.1% ammonia, v / v) and acetonitrile (acetonitrile volume percentage 55-57%), a flow rate of 25mL / min, and a detection wavelength of 214 / 254nm; preferably, under these conditions, the retention time of the compound that elutes first is 5.47 minutes. The compound that elutes later in the chromatogram is selected under the following conditions: a C18 OBD column (19*250mm*5μm), a mobile phase of water (0.1% ammonia, v / v) and acetonitrile (acetonitrile volume percentage 55-57%), a flow rate of 25mL / min, and a detection wavelength of 214 / 254nm; preferably, under these conditions, the retention time of the compound that elutes later is 7.43 minutes. The compound that elutes first under the following conditions: a C18 OBD column (19*250mm*5μm), a mobile phase of water (0.1% ammonia, v / v) and acetonitrile (acetonitrile volume percentage 50-53%), a flow rate of 25mL / min, and a detection wavelength of 214 / 254nm; preferably, under these conditions, the retention time of the compound that elutes first is 7.37 minutes. The compound that elutes later in the chromatogram is selected under the following conditions: a C18 OBD column (19*250mm*5μm), a mobile phase of water (0.1% ammonia, v / v) and acetonitrile (acetonitrile volume percentage 50-53%), a flow rate of 25mL / min, and a detection wavelength of 214 / 254nm; preferably, under these conditions, the retention time of the compound that elutes later is 9.92 minutes. The compound that elutes first under the following conditions: a C18 OBD column (19*250mm*5μm), a mobile phase of water (0.1% ammonia, v / v) and acetonitrile (acetonitrile volume percentage 45-55%), a flow rate of 25mL / min, and a detection wavelength of 214 / 254nm; preferably, under these conditions, the retention time of the compound that elutes first is 4.71 minutes. The compound that elutes later in the chromatogram is selected under the following conditions: a C18 OBD column (19*250mm*5μm), a mobile phase of water (0.1% ammonia, v / v) and acetonitrile (acetonitrile volume percentage 45-55%), a flow rate of 25mL / min, and a detection wavelength of 214 / 254nm; preferably, under these conditions, the retention time of the compound that elutes later is 6.25 minutes. The compound that elutes first under the following conditions: a C18 OBD column (19*250mm*5μm), a mobile phase of water (0.1% ammonia, v / v) and acetonitrile (acetonitrile volume percentage 45-55%), a flow rate of 25mL / min, and a detection wavelength of 214 / 254nm; preferably, under these conditions, the retention time of the compound that elutes first is 4.74 minutes. The compound that elutes later in the chromatogram is selected under the following conditions: a C18 OBD column (19*250mm*5μm), a mobile phase of water (0.1% ammonia, v / v) and acetonitrile (acetonitrile volume percentage 45-55%), a flow rate of 25mL / min, and a detection wavelength of 214 / 254nm; preferably, under these conditions, the retention time of the compound that elutes later is 6.42 minutes. The compound that elutes first under the following conditions: a C18 OBD column (19*250mm*5μm), a mobile phase of water (0.1% ammonia, v / v) and acetonitrile (acetonitrile volume percentage 55-65%), a flow rate of 25mL / min, and a detection wavelength of 214 / 254nm; preferably, under these conditions, the retention time of the compound that elutes first is 6.22 minutes. The compound that elutes later in the chromatogram is determined under the following conditions: a C18 OBD column (19*250mm*5μm), a mobile phase of water (0.1% ammonia, v / v) and acetonitrile (acetonitrile volume percentage 55-65%), a flow rate of 25mL / min, and a detection wavelength of 214 / 254nm; preferably, under these conditions, the retention time of the compound that elutes later is 8.37 minutes. The compound that elutes first under the following conditions: a C18 OBD column (19*250mm*5μm), a mobile phase of water (0.1% ammonia, v / v) and acetonitrile (acetonitrile volume percentage 53%), a flow rate of 25mL / min, and a detection wavelength of 214 / 254nm; preferably, under these conditions, the retention time of the compound that elutes first is 7.6 minutes. The compound that elutes later in the chromatogram is determined under the following conditions: a C18 OBD column (19*250mm*5μm), a mobile phase of water (0.1% ammonia, v / v) and acetonitrile (acetonitrile volume percentage 53%), a flow rate of 25mL / min, and a detection wavelength of 214 / 254nm; preferably, under these conditions, the retention time of the compound that elutes later is 9.5 minutes. The compound that elutes first under the following conditions: a C18 OBD column (19*250mm*5μm), a mobile phase of water (0.1% formic acid, v / v) and acetonitrile (acetonitrile volume percentage 19%), a flow rate of 25mL / min, and a detection wavelength of 214 / 254nm; preferably, under these conditions, the retention time of the compound that elutes first is 7.58 minutes. The compound that elutes later in the chromatogram is determined under the following conditions: a C18 OBD column (19*250mm*5μm), a mobile phase of water (0.1% formic acid, v / v) and acetonitrile (acetonitrile volume percentage 19%), a flow rate of 25mL / min, and a detection wavelength of 214 / 254nm; preferably, under these conditions, the retention time of the compound that elutes later is 8.35 minutes. The compound that elutes first under the following conditions: a C18 OBD column (19*250mm*5μm), a mobile phase of water (0.1% ammonia, v / v) and acetonitrile (acetonitrile volume percentage 57%), a flow rate of 25mL / min, and a detection wavelength of 214 / 254nm; preferably, under these conditions, the retention time of the compound that elutes first is 6.23 minutes. The compound that elutes later in the chromatogram is determined under the following conditions: a C18 OBD column (19*250mm*5μm), a mobile phase of water (0.1% ammonia, v / v) and acetonitrile (acetonitrile volume percentage 57%), a flow rate of 25mL / min, and a detection wavelength of 214 / 254nm; preferably, under these conditions, the retention time of the compound that elutes later is 8.95 minutes. The compound that elutes first under the following conditions: a C18 OBD column (19*250mm*5μm), a mobile phase of water (0.1% ammonia, v / v) and acetonitrile, with acetonitrile comprising 46-56% by volume, a flow rate of 25mL / min, and a detection wavelength of 214 / 254nm; preferably, under these conditions, the retention time of the compound that elutes first is 5.66 minutes. The compound that elutes later in the chromatogram is determined under the following conditions: a C18 OBD column (19*250mm*5μm), a mobile phase of water (0.1% ammonia, v / v) and acetonitrile (acetonitrile volume percentage 46-56%), a flow rate of 25mL / min, and a detection wavelength of 214 / 254nm; preferably, under these conditions, the retention time of the compound that elutes later is 8.61 minutes. The compound that elutes first under the following conditions: a C18 OBD column (19*250mm*5μm), a mobile phase of water (0.1% ammonia, v / v) and acetonitrile, with acetonitrile comprising 46-56% by volume, a flow rate of 25mL / min, and a detection wavelength of 214 / 254nm; preferably, under these conditions, the retention time of the compound that elutes first is 5.56 minutes. The compound that elutes later in the chromatogram is selected under the following conditions: a C18 OBD column (19*250mm*5μm), a mobile phase of water (0.1% ammonia, v / v) and acetonitrile (acetonitrile volume percentage 46-56%), a flow rate of 25mL / min, and a detection wavelength of 214 / 254nm; preferably, under these conditions, the retention time of the compound that elutes later is 8.59 minutes. The compound that elutes first under the following conditions: a C18 OBD column (19*250mm*5μm), a mobile phase of water (0.1% ammonia, v / v) and acetonitrile (acetonitrile volume percentage 40-60%), a flow rate of 25mL / min, and a detection wavelength of 214 / 254nm; preferably, under these conditions, the retention time of the compound that elutes first is 5.0 min. The compound that elutes later in the chromatogram is selected under the following conditions: a C18 OBD column (19*250mm*5μm), a mobile phase of water (0.1% ammonia, v / v) and acetonitrile (acetonitrile volume percentage 40-60%), a flow rate of 25mL / min, and a detection wavelength of 214 / 254nm; preferably, under these conditions, the retention time of the compound that elutes later is 8.50 min. The compound that elutes first under the following conditions: a C18 OBD column (19*250mm*5μm), a mobile phase of water (0.1% ammonia, v / v) and acetonitrile (acetonitrile volume percentage 46-56%), a flow rate of 25mL / min, and a detection wavelength of 214 / 254nm; preferably, under these conditions, the retention time of the compound that elutes first is 5.5 minutes. The compound that elutes later in the chromatogram is selected under the following conditions: a C18 OBD column (19*250mm*5μm), a mobile phase of water (0.1% ammonia, v / v) and acetonitrile (acetonitrile volume percentage 46-56%), a flow rate of 25mL / min, and a detection wavelength of 214 / 254nm; preferably, under these conditions, the retention time of the compound that elutes later is 7.0 min. The compound that elutes first under the following conditions: a C18 OBD column (19*250mm*5μm), a mobile phase of water (0.1% ammonia, v / v) and acetonitrile (acetonitrile volume percentage 45-55%), a flow rate of 25mL / min, and a detection wavelength of 214 / 254nm; preferably, under these conditions, the retention time of the compound that elutes first is 7.27 minutes. The compound that elutes later in the chromatogram is selected under the following conditions: a C18 OBD column (19*250mm*5μm), a mobile phase of water (0.1% ammonia, v / v) and acetonitrile (acetonitrile volume percentage 45-55%), a flow rate of 25mL / min, and a detection wavelength of 214 / 254nm; preferably, under these conditions, the retention time of the compound that elutes later is 8.83 minutes. The compound that elutes first under the following conditions: a C18 OBD column (19*250mm*5μm), a mobile phase of water (0.1% ammonia, v / v) and acetonitrile (acetonitrile volume percentage 65-80%), a flow rate of 25mL / min, and a detection wavelength of 214 / 254nm; preferably, under these conditions, the retention time of the compound that elutes first is 5.5 minutes. The compound that elutes later in the chromatogram is selected under the following conditions: a C18 OBD column (19*250mm*5μm), a mobile phase of water (0.1% ammonia, v / v) and acetonitrile (acetonitrile volume percentage 65-80%), a flow rate of 25mL / min, and a detection wavelength of 214 / 254nm; preferably, under these conditions, the retention time of the compound that elutes later is 8.5 minutes. The compound that elutes first under the following conditions: a C18 OBD column (19*250mm*5μm), a mobile phase of water (0.1% ammonia, v / v) and acetonitrile (acetonitrile volume percentage 53%), a flow rate of 25mL / min, and a detection wavelength of 214 / 254nm; preferably, under these conditions, the retention time of the compound that elutes first is 7.6 minutes. The compound that elutes later in the chromatogram is determined under the following conditions: a C18 OBD column (19*250mm*5μm), a mobile phase of water (0.1% ammonia, v / v) and acetonitrile (acetonitrile volume percentage 53%), a flow rate of 25mL / min, and a detection wavelength of 214 / 254nm; preferably, under these conditions, the retention time of the compound that elutes later is 9.5 minutes. The compound that elutes first under the following conditions: a C18 OBD column (19*250mm*5μm), a mobile phase of water (0.1% ammonia, v / v) and acetonitrile (acetonitrile volume percentage 10%), a flow rate of 25mL / min, and a detection wavelength of 214 / 254nm; preferably, under these conditions, the retention time of the compound that elutes first is 7.2 minutes. The compound that elutes later in the chromatogram is determined under the following conditions: a C18 OBD column (19*250mm*5μm), a mobile phase of water (0.1% ammonia, v / v) and acetonitrile (acetonitrile volume percentage 10%), a flow rate of 25mL / min, and a detection wavelength of 214 / 254nm; preferably, under these conditions, the retention time of the compound that elutes later is 9.9 minutes. The compound that elutes first under the following conditions: a C18 OBD column (19*250mm*5μm), a mobile phase of water (0.1% ammonia, v / v) and acetonitrile (acetonitrile volume percentage 53%), a flow rate of 25mL / min, and a detection wavelength of 214 / 254nm; preferably, under these conditions, the retention time of the compound that elutes first is 7.6 minutes. The compound that elutes later in the chromatogram is determined under the following conditions: a C18 OBD column (19*250mm*5μm), a mobile phase of water (0.1% ammonia, v / v) and acetonitrile (acetonitrile volume percentage 53%), a flow rate of 25mL / min, and a detection wavelength of 214 / 254nm; preferably, under these conditions, the retention time of the compound that elutes later is 9.5 minutes. The compound that elutes first under the following conditions: a C18 OBD column (19*250mm*5μm), a mobile phase of water (0.1% ammonia, v / v) and acetonitrile (acetonitrile volume percentage 41%), a flow rate of 25mL / min, and a detection wavelength of 214 / 254nm; preferably, under these conditions, the retention time of the compound that elutes first is 7.63 minutes. The compound that elutes later in the chromatogram is determined under the following conditions: a C18 OBD column (19*250mm*5μm), a mobile phase of water (0.1% ammonia, v / v) and acetonitrile (acetonitrile volume percentage 41%), a flow rate of 25mL / min, and a detection wavelength of 214 / 254nm; preferably, under these conditions, the retention time of the compound that elutes later is 8.3 minutes. The compound that elutes first under the following conditions: a C18 OBD column (19*250mm*5μm), a mobile phase of water (0.1% ammonia, v / v) and acetonitrile (acetonitrile volume percentage 45-55%), a flow rate of 25mL / min, and a detection wavelength of 214 / 254nm; preferably, under these conditions, the retention time of the compound that elutes first is 6.08 minutes. The compound that elutes later in the chromatogram is selected under the following conditions: a C18 OBD column (19*250mm*5μm), a mobile phase of water (0.1% ammonia, v / v) and acetonitrile (acetonitrile volume percentage 45-55%), a flow rate of 25mL / min, and a detection wavelength of 214 / 254nm; preferably, under these conditions, the retention time of the compound that elutes later is 8.58 minutes. The compound that elutes first under the following conditions: a C18 OBD column (19*250mm*5μm), a mobile phase of water (0.1% ammonia, v / v) and acetonitrile, with an acetonitrile volume percentage of 38-62%, a flow rate of 25mL / min, and a detection wavelength of 214 / 254nm; preferably, under these conditions, the retention time of the compound that elutes first is 7.5 minutes. The compound that elutes later in the chromatogram is selected under the following conditions: a C18 OBD column (19*250mm*5μm), a mobile phase of water (0.1% ammonia, v / v) and acetonitrile (acetonitrile volume percentage 38-62%), a flow rate of 25mL / min, and a detection wavelength of 214 / 254nm; preferably, under these conditions, the retention time of the compound that elutes later is 11.2 minutes. The compound that elutes first under the following conditions: a C18 OBD column (19*250mm*5μm), a mobile phase of water (0.1% ammonia, v / v) and acetonitrile (acetonitrile volume percentage 51%), a flow rate of 25mL / min, and a detection wavelength of 214 / 254nm; preferably, under these conditions, the retention time of the compound that elutes first is 5.57 minutes. The compound that elutes later in the chromatogram is determined under the following conditions: a C18 OBD column (19*250mm*5μm), a mobile phase of water (0.1% ammonia, v / v) and acetonitrile (acetonitrile volume percentage 51%), a flow rate of 25mL / min, and a detection wavelength of 214 / 254nm; preferably, under these conditions, the retention time of the compound that elutes later is 7.53 minutes. The compound that elutes first under the following conditions: a C18 OBD column (19*250mm*5μm), a mobile phase of water (0.1% ammonia, v / v) and acetonitrile (acetonitrile volume percentage 10%), a flow rate of 25mL / min, and a detection wavelength of 214 / 254nm; preferably, under these conditions, the retention time of the compound that elutes first is 5.9 minutes. The compound that elutes later in the chromatogram is determined under the following conditions: a C18 OBD column (19*250mm*5μm), a mobile phase of water (0.1% ammonia, v / v) and acetonitrile (acetonitrile volume percentage 10%), a flow rate of 25mL / min, and a detection wavelength of 214 / 254nm; preferably, under these conditions, the retention time of the compound that elutes later is 7.3 minutes. The compound that elutes first under the following conditions: a C18 OBD column (19*250mm*5μm), a mobile phase of water (0.1% formic acid, v / v) and acetonitrile (acetonitrile volume percentage 15%), a flow rate of 25mL / min, and a detection wavelength of 214 / 254nm; preferably, under these conditions, the retention time of the compound that elutes first is 6.5 minutes. The compound that elutes later in the chromatogram is determined under the following conditions: a C18 OBD column (19*250mm*5μm), a mobile phase of water (0.1% formic acid, v / v) and acetonitrile (acetonitrile volume percentage 15%), a flow rate of 25mL / min, and a detection wavelength of 214 / 254nm; preferably, under these conditions, the retention time of the compound that elutes later is 7.6 minutes. The compound that elutes first under the following conditions: a C18 OBD column (19*250mm*5μm), a mobile phase of water (0.1% formic acid, v / v) and acetonitrile (acetonitrile volume percentage 15%), a flow rate of 25mL / min, and a detection wavelength of 214 / 254nm; preferably, under these conditions, the retention time of the compound that elutes first is 6.0 min. The compound that elutes later in the chromatogram is determined under the following conditions: a C18 OBD column (19*250mm*5μm), a mobile phase of water (0.1% formic acid, v / v) and acetonitrile (acetonitrile volume percentage 15%), a flow rate of 25mL / min, and a detection wavelength of 214 / 254nm; preferably, under these conditions, the retention time of the compound that elutes later is 7.8 minutes. The compound that elutes first under the following conditions: a C18 OBD column (19*250mm*5μm), a mobile phase of water (0.1% ammonia, v / v) and acetonitrile (acetonitrile volume percentage 46-56%), a flow rate of 25mL / min, and a detection wavelength of 214 / 254nm; preferably, under these conditions, the retention time of the compound that elutes first is 4.6 minutes. The compound that elutes later in the chromatogram is selected under the following conditions: a C18 OBD column (19*250mm*5μm), a mobile phase of water (0.1% ammonia, v / v) and acetonitrile (acetonitrile volume percentage 46-56%), a flow rate of 25mL / min, and a detection wavelength of 214 / 254nm; preferably, under these conditions, the retention time of the compound that elutes later is 6.1 minutes. The compound that elutes first under the following conditions: a C18 OBD column (19*250mm*5μm), a mobile phase of water (0.1% ammonia, v / v) and acetonitrile (acetonitrile volume percentage 45-55%), a flow rate of 25mL / min, and a detection wavelength of 214 / 254nm; preferably, under these conditions, the retention time of the compound that elutes first is 5.3 minutes. The compound that elutes later in the chromatogram is selected under the following conditions: a C18 OBD column (19*250mm*5μm), a mobile phase of water (0.1% ammonia, v / v) and acetonitrile (acetonitrile volume percentage 45-55%), a flow rate of 25mL / min, and a detection wavelength of 214 / 254nm; preferably, under these conditions, the retention time of the compound that elutes later is 6.5 minutes. The compound that elutes first under the following conditions: a C18 OBD column (19*250mm*5μm), a mobile phase of water (0.1% ammonia, v / v) and acetonitrile (acetonitrile volume percentage 46-56%), a flow rate of 25mL / min, and a detection wavelength of 214 / 254nm; preferably, under these conditions, the retention time of the compound that elutes first is 6.47 minutes. The compound that elutes later in the chromatogram is selected under the following conditions: a C18 OBD column (19*250mm*5μm), a mobile phase of water (0.1% ammonia, v / v) and acetonitrile (acetonitrile volume percentage 46-56%), a flow rate of 25mL / min, and a detection wavelength of 214 / 254nm; preferably, under these conditions, the retention time of the compound that elutes later is 7.81 minutes. The compound that elutes first under the following conditions: a C18 OBD column (19*250mm*5μm), a mobile phase of water (0.1% ammonia, v / v) and acetonitrile (acetonitrile volume percentage 46-56%), a flow rate of 25mL / min, and a detection wavelength of 214 / 254nm; preferably, under these conditions, the retention time of the compound that elutes first is 6.88 minutes. The compound that elutes later in the chromatogram is selected under the following conditions: a C18 OBD column (19*250mm*5μm), a mobile phase of water (0.1% ammonia, v / v) and acetonitrile (acetonitrile volume percentage 46-56%), a flow rate of 25mL / min, and a detection wavelength of 214 / 254nm; preferably, under these conditions, the retention time of the compound that elutes later is 7.73 minutes. The compound that elutes first under the following conditions: a C18 OBD column (19*250mm*5μm), a mobile phase of water (0.1% ammonia, v / v) and acetonitrile (acetonitrile volume percentage 48-52%), a flow rate of 25mL / min, and a detection wavelength of 214 / 254nm; preferably, under these conditions, the retention time of the compound that elutes first is 7.43 minutes. The compound that elutes later in the chromatogram is selected under the following conditions: a C18 OBD column (19*250mm*5μm), a mobile phase of water (0.1% ammonia, v / v) and acetonitrile (acetonitrile volume percentage 48-52%), a flow rate of 25mL / min, and a detection wavelength of 214 / 254nm; preferably, under these conditions, the retention time of the compound that elutes later is 9.83 minutes. The compound that elutes first under the following conditions: a C18 OBD column (19*250mm*5μm), a mobile phase of water (0.1% formic acid, v / v) and acetonitrile (acetonitrile volume percentage 30-40%), a flow rate of 25mL / min, and a detection wavelength of 214 / 254nm; preferably, under these conditions, the retention time of the compound that elutes first is 7.03 minutes. The compound that elutes later in the chromatogram is selected under the following conditions: a C18 OBD column (19*250mm*5μm), a mobile phase of water (0.1% formic acid, v / v) and acetonitrile (acetonitrile volume percentage 30-40%), a flow rate of 25mL / min, and a detection wavelength of 214 / 254nm; preferably, under these conditions, the retention time of the compound that elutes later is 7.97 minutes. The compound that elutes first under the following conditions: a C18 OBD column (19*250mm*5μm), a mobile phase of water (0.1% ammonia, v / v) and acetonitrile (acetonitrile volume percentage 70-70%), a flow rate of 25mL / min, and a detection wavelength of 214 / 254nm; preferably, under these conditions, the retention time of the compound that elutes first is 7.43 minutes. The compound that elutes later in the chromatogram is selected under the following conditions: a C18 OBD column (19*250mm*5μm), a mobile phase of water (0.1% ammonia, v / v) and acetonitrile (acetonitrile volume percentage 70-70%), a flow rate of 25mL / min, and a detection wavelength of 214 / 254nm; preferably, under these conditions, the retention time of the compound that elutes later is 9.75 minutes. The compound that elutes first under the following conditions: a C18 OBD column (19*250mm*5μm), a mobile phase of water (0.1% ammonia, v / v) and acetonitrile (acetonitrile volume percentage 70-70%), a flow rate of 25mL / min, and a detection wavelength of 214 / 254nm; preferably, under these conditions, the retention time of the compound that elutes first is 7.23 minutes. The compound that elutes later in the chromatogram is determined under the following conditions: a C18 OBD column (19*250mm*5μm), a mobile phase of water (0.1% ammonia, v / v) and acetonitrile (acetonitrile volume percentage 70-70%), a flow rate of 25mL / min, and a detection wavelength of 214 / 254nm; preferably, under these conditions, the retention time of the compound that elutes later is 9.32 minutes. The compound that elutes first under the following conditions: a C18 OBD column (19*250mm*5μm), a mobile phase of water (0.1% ammonia, v / v) and acetonitrile (acetonitrile volume percentage 57%), a flow rate of 25mL / min, and a detection wavelength of 214 / 254nm; preferably, under these conditions, the retention time of the compound that elutes first is 6.29 minutes. The compound that elutes later in the chromatogram is determined under the following conditions: a C18 OBD column (19*250mm*5μm), a mobile phase of water (0.1% ammonia, v / v) and acetonitrile (acetonitrile volume percentage 57%), a flow rate of 25mL / min, and a detection wavelength of 214 / 254nm; preferably, under these conditions, the retention time of the compound that elutes later is 7.83 minutes. The compound that elutes first under the following conditions: a C18 OBD column (19*250mm*5μm), a mobile phase of water (0.1% ammonia, v / v) and acetonitrile (acetonitrile volume percentage 70-70%), a flow rate of 25mL / min, and a detection wavelength of 214 / 254nm; preferably, under these conditions, the retention time of the compound that elutes first is 7.98 minutes. The compound that elutes later in the chromatogram is selected under the following conditions: a C18 OBD column (19*250mm*5μm), a mobile phase of water (0.1% ammonia, v / v) and acetonitrile (acetonitrile volume percentage 70-70%), a flow rate of 25mL / min, and a detection wavelength of 214 / 254nm; preferably, under these conditions, the retention time of the compound that elutes later is 10.25 minutes. A pharmaceutical composition comprising the compound as described in any one of claims 1-17, its stereoisomer, or a pharmaceutically acceptable salt thereof, and pharmaceutical excipients. The use of a compound as described in any one of claims 1-17, its stereoisomers or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described in claim 18, wherein the use comprises one or more of the following: (1) Prepare a drug for treating and / or preventing diseases mediated by KRAS; wherein the diseases mediated by KRAS are preferably cancer; (2) To prepare medicines for the treatment and / or prevention of cancer; and (3) Preparation of KRAS inhibitors. The application as described in claim 19 is characterized in that, The application meets one or more of the following conditions: (1) The KRAS mentioned is a KRAS mutation, such as KRAS G12C, KRAS G12D, KRAS G12V, KRAS G12A, KRAS G12R, KRAS G12S, KRAS G13C, KRAS G13D, KRAS Q61H, KRAS Q61K or KRAS Q61R mutation, and for example KRAS G12C, KRAS G12D or KRAS G12V mutation; (2) The cancer is associated with at least one of the following mutations: KRAS G12C, KRAS G12D, KRAS G12V, KRAS G12A, KRAS G12R, KRAS G12S, KRAS G13C, KRAS G13D, KRAS Q61H, KRAS Q61K, and KRAS Q61R, for example, with at least one of the following mutations: KRAS G12C, KRAS G12D, and KRAS G12V; and (3) The cancer 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 non-small cell lung cancer or pancreatic cancer.

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