KRAS G12D degrader, its manufacturing method and application

Abstract

The present invention discloses a KRAS G12D degrader and its preparation method and application. The KRAS G12D degrader of the present invention is a compound of Formula I or I', and / or its stereoisomer, enantiomer, diastereoisomer, atropisomer, deuterated product, hydrate, solvate, prodrug, and / or pharmaceutically acceptable salt. The compound described in the present invention can effectively degrade and / or inhibit KRAS G12D protein in cells and can be used to manufacture a medicament for treating and / or preventing related diseases or conditions mediated by KRAS G12D. GLE G'-LE II' [Formula 1] TIFF2025536369001175.tif34169 [C2] TIFF2025536369001176.tif37169

Description

Detailed Description of the Invention

[0001] This application claims priority to Chinese patent application No. 2022112973637, filed October 21, 2022, priority to Chinese patent application No. 2023100563994, filed January 20, 2023, priority to Chinese patent application No. 2023108468752, filed July 11, 2023, priority to Chinese patent application No. 2023108869828, filed July 19, 2023, and priority to Chinese patent application No. 2023113475347, filed October 17, 2023. This application is hereby incorporated by reference in its entirety.

[0002] [Technical field] The present invention belongs to the field of pharmaceutical technology, and specifically relates to a KRAS G12D degrading agent, its preparation method and application.

[0003] [Background technology] RAS (rat sarcoma) is one of the oncogenic genes with the highest mutation rates in tumors, with mutations present in approximately 30% of human malignancies. The RAS family includes KRAS, NRAS, and HRAS. KRAS (kirsten rat sarcoma viral oncogene) is more likely to mutate than the other two RAS subtypes, accounting for approximately 85% of cases, and is particularly common in solid tumors (Cancer Res. 2020, 80, 2969-2974). KRAS gene mutations are present in 30-40% of colorectal cancers, 90% of pancreatic cancers, and 15-20% of lung cancers. Once activated, KRAS regulates cell proliferation, differentiation, and survival through downstream signaling pathways, including RAF-MEK-ERK and PI3K-AKT-mTOR. After KRAS gene mutation, the protein remains persistently activated, leading to sustained activation of downstream signaling pathways and promoting tumorigenesis (Nat. Rev. Cancer 2015, 15, 290-301). Therefore, KRAS is an important target for tumor therapeutic efforts, including targeting the KRAS protein itself, its post-translational modifications, membrane localization, protein-protein interactions, and RAS downstream signaling pathways.

[0004] KRAS binds to GTP or GDP with extremely high affinity (picomolar concentrations), and the surface of the RAS protein is smooth, lacking an ideal small molecule binding site. Therefore, developing a competitive inhibitor that acts directly on the RAS protein is considered extremely difficult (Nat. Rev. Drug Discov. 2020, 19, 533-552).

[0005] Currently, depending on the mode of action of the inhibitor, KRAS inhibitors (Cancer Discov. 2022, 12, 924-937) can be classified as follows: 1) Inhibitors that directly target KRAS, such as inhibitors of KRAS G12C, KRAS G12D, KRAS G12R (J. Am. Chem. Soc. 2022, 144, 35, 15916-15921) and KRAS G12S (Nat. Chem. Biol. 2022, 18, 1177-1183), 2) SHP2 (SHP 099, Nature 2016, 535, 148-152 & J. Med. Chem. 2016, 59, 7773-7782; RMC4550, Nat. Cell Biol. 2018, 20, 1064-1073; TNO155, J. Med. Chem. 2020, 63, 22, 13578-13594; RMC4630, WO 2021142026A1; JAB-3068, WO2017211303A1, etc.), SOS1 inhibitors (Bay-293, Proc. Natl. Acad. Sci. USA 2019, 116, 2551-2560; BI-3406, Cancer Discov. 2021, 11, 142-157; MRTX0902, J. Med. Chem. 2022, 65, 678-9690, etc.) and inhibitors that act indirectly on KRAS, such as KRAS(on) inhibitors (WO2021091982A1, WO2022060836A1).

[0006] In recent years, with the advancement of KRAS research, the research and development of KRAS inhibitors has also made significant progress (Cancer Discov. 2022, 12, 924-937). In the design process of KRAS-G12C inhibitors, the cysteine ​​at codon 12 is primarily used, as it is easy to form covalent bonds. The use of covalent targeting at the cysteine ​​site has been an important breakthrough in KRAS drug development. Shokat discovered a new allosteric binding pocket in Switch-II, called the Switch-II pocket, and developed the first batch of KRAS-G12C covalent inhibitors (Nature 2013, 503, 548-551; Nat. Rev. Drug Discov. 2016, 15, 771-785). On May 28, 2021, the FDA granted accelerated approval to Lumakras (Sotorasib, AMG510), developed by Amgen (Nature 2019, 575, 217-223; J. Med. Chem. 2020, 63, 52-65), for the treatment of patients with non-small cell lung cancer whose tumors harbor the KRAS-G12C mutation (N. Engl. J. Med. 2021, 384, 2371-2381). Currently, various small molecule drugs targeting KRAS-G12C are in clinical trials worldwide. On February 16, 2022, the FDA accepted a new drug application for the second KRAS-G12C inhibitor, Adagrasib (MRTX849), submitted by Mirati Pharmaceuticals, Inc. (Cancer Discov. 2020, 10, 54-71 & J. Med. Chem. 2020, 63, 6679-6693), for the treatment of patients with non-small cell lung cancer (NSCLC) harboring a KRAS G12C mutation who have received at least one prior systemic therapy (N. Engl. J. Med. 2022, 387, 120-131). Adagrasib is expected to become the second KRAS-targeted drug worldwide.

[0007] Unlike KRAS G12C, the most common mutation in non-small cell lung cancer (NSCLC), KRAS G12D is the most common mutation in colorectal and pancreatic cancers. Codon 12 of the KRAS G12C mutant contains a cysteine ​​(Cys), making it amenable to covalent bond formation. This structural feature allows for covalent conjugation of the mutant with small molecule inhibitors. However, codon 12 of the KRAS G12D mutant contains an aspartic acid (Asp), making this strategy unfeasible.

[0008] KRAS-G12D activation is mainly mediated by protein-protein interactions. Considering the lack of a clear binding pocket on the KRAS protein surface and the high binding affinity of cyclic peptides to the protein surface, peptide molecules serve as the optimal choice for targeting KRAS G12D (Biochem. Biophys. Res. Commun. 2017, 484, 605-611; Bioorg. Med. Chem. Lett. 2017, 27, 2757-2761; ACS Med. Chem. Lett. 2017, 8, 732-736; Sci. Rep. 2020, 10, 21671). Several effective cyclic peptides targeting KRAS G12D have been reported (MedChemComm 2013, 4, 378-382; Angew. Chem., Int. Ed. 2015, 54, 7602-7606; J. Med. Chem. 2021, 64, 13038), but they have relatively poor cell membrane permeability. Cellular uptake of peptides depends on the modulation of the cell surface receptor neurofilament protein-1 (NRP1), which is overexpressed on the cell membrane of human lung cancer cells. Therefore, screening for cyclic peptides targeting NRP1 and KRAS G12D revealed that the cyclic peptides not only have relatively high cellular uptake but also act on KRAS G12D to exert antitumor effects (J. Am. Chem. Soc. 2022, 144, 7117-7128).

[0009] On December 10, 2021, Mirati reported MRTX1133, the first non-covalent, potent, and highly selective KRAS-G12D inhibitor (J. Med. Chem. 2022, 65, 3923-3942; WO2021041671A1). MRTX1133 inhibits activated or inactivated KRAS-G12D mutant cells but not wild-type tumor cells, demonstrating over 1000-fold specificity. In vivo tumor models of both pancreatic and colorectal cancer, MRTX1133 demonstrated dose-dependent inhibition.

[0010] Patents such as WO2021041671A1, WO2022015375A1, WO2022031678A1, WO2022066646A1, WO2022098625A1, WO2022192790A1, WO2022192794A1, WO2021106231A1, WO2021107160A1, and WO2022173870A1 disclosed several KRAS G12D inhibitors.

[0011] Targeted protein degraders have become a popular research and development technology worldwide in recent years (Nat. Rev. Drug Discov. 2017, 16, 101-114; Nat. Rev. Drug Discov. 2019, 18, 949-963; Nat. Rev. Drug Discov. 2022, 21, 181-200). This technology has the following characteristics: the development of "druggable" targets has encountered bottlenecks, while the potential of "undruggable" targets is limitless. PROTAC technology is expected to solve the development challenges of "undruggable" targets. PROTAC drugs have advantages such as good drug discovery, high selectivity, the ability to overcome drug resistance, diverse administration routes, low dosages, and low toxicity.

[0012] Thus, there is an unmet clinical need for KRAS G12D targeted protein degraders.

[0013] [Summary of the Invention] The technical problem to be solved by the present invention is to provide a KRAS G12D degrading agent, a method for producing the same, and applications thereof, in order to overcome the drawback of the limited variety of KRAS G12D degrading agents. The compounds provided by the present invention can effectively degrade and / or inhibit KRAS G12D protein in cells.

[0014] The present invention provides compounds of Formula I or I', and / or their stereoisomers, enantiomers, diastereoisomers, atropisomers, deuterated forms, hydrates, solvates, prodrugs, and / or pharmaceutically acceptable salts thereof: GLE G'-LE II' where: G is for G1 [ka] and G' is G1' [ka] and Each Y independently represents a bond, O, —C(R 3a )2 or -NR 3a and Each X1 is independently a bond or -(CH2) m - and each X 1 ' is independently a bond or -C(O)-; Each R 1a are independently -OH, -N(R 3a )2, C3-C 12 a cycloalkyl group or a 3- to 12-membered heterocycloalkyl group, 12 The cycloalkyl group, 3- to 12-membered heterocycloalkyl group may optionally be one or more R a may be substituted with Each R 2aare independently a halogen, deuterium, a cyano group, an amino group, a hydroxy group, a C1-C6 alkyl group, a C1-C6 heteroalkyl group, a C3-C8 cycloalkyl group, a 3- to 8-membered heterocycloalkyl group, -S-C1-C6 alkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a triazolyl group, an -O-C1-C6 alkyl group, an -O-C3-C8 cycloalkyl group, -CH2C(=O)N(R 3a )2, -N(R 3a )2, C1-C3 alkyl-O-C1-C3 alkyl-, HC(=O)-, -CO2R 3a , -CON(R 3a ) a 2- or 5- to 6-membered heteroaryl group, wherein the C1-C6 alkyl group, C1-C6 heteroalkyl group, C3-C8 cycloalkyl group, 3- to 8-membered heterocycloalkyl group, —S—C1-C6 alkyl group, C2-C6 alkenyl group, C2-C6 alkynyl group, O—C1-C6 alkyl group, —O—C3-C8 cycloalkyl group or 5- to 6-membered heteroaryl group is optionally substituted with one or more deuterium atoms, halogen atoms, hydroxy groups, cyano groups, amino groups, nitro groups, C1-C3 alkoxy groups or C1-C3 alkyl groups; Each R 3a are independently H, a C1-C6 alkyl group, a C3-C8 cycloalkyl group, a C3-C6 alkenyl group, or a C3-C6 alkynyl group; Or, two R's 3a together with the atoms to which they are connected form a 4- to 12-membered heterocycloalkyl group, which is optionally substituted with one or more deuterium, halogen, hydroxy, cyano, amino, C1-C3 alkoxy, or C1-C3 alkyl groups; Or, R 1a and R 3a (where R 3a is the -C(R 3a )2 and -NR 3a R in 3a (R 1aand -NR 3a R in 3a form a 4- to 12-membered heterocycloalkyl group together with the atoms to which they are respectively connected, the 4- to 12-membered heterocycloalkyl group contains at least one N atom), and optionally one or more R b is replaced by substitution, each ring A1 is independently absent and is an -L'-6 to 15-membered aryl group, an -L'-5 to 15-membered heteroaryl group, or an -L'-5 to 15-membered heterocycloalkyl group; Each ring B is independently a 6- to 15-membered aryl group, a 5- to 15-membered heteroaryl group, a C5-C 15 a cycloalkyl group or a 5- to 16-membered heterocycloalkyl group, and the 6- to 15-membered aryl group, 5- to 15-membered heteroaryl group, C5-C 15 The cycloalkyl group or 5- to 16-membered heterocycloalkyl group may optionally be one or more R a is replaced by each L' is independently a bond or a C1-C4 alkylene group, wherein the C1-C4 alkylene group is optionally substituted with one or more deuterium, hydroxy, C1-C4 hydroxyalkyl, or 5- to 10-membered heteroaryl groups; Each R a and each R b are independently hydrogen, a hydroxy group, a halogen atom, a cyano group, -N(R 3a )2, -CH2N(R 3a ) 2, 3 to 8-membered heterocycloalkyl group, C1-C6 alkyl group, HC(=O)-, -CO2R 4a , -CO2N(R 4a )2, C1-C3 alkoxy group, (C1-C3 alkoxy)-C1-C3 alkyl-, C1-C3 alkyl-N(R 4a)2, a C2-C4 alkenyl group, a C3-C8 cycloalkyl group, a 3- to 8-membered heterocycloalkyl group, or a 5- to 6-membered heteroaryl group, wherein the C1-C6 alkyl group, C1-C3 alkoxy group, C2-C4 alkenyl group, C3-C8 cycloalkyl group, 3- to 8-membered heterocycloalkyl group, or 5- to 6-membered heteroaryl group is optionally substituted with one or more deuterium atoms, halogen atoms, cyano groups, hydroxy groups, amino groups, nitro groups, C1-C3 alkyl groups, or C1-C3 alkoxy groups; Each R 4a are independently hydrogen, a C1-C3 alkyl group, or a C1-C3 hydroxyalkyl group; Or, two R's 4a together with the atom to which they are attached form a heterocycloalkyl group, said heterocycloalkyl group optionally substituted with one or more deuterium, —OH, —NH, C1-C3 alkyl or C1-C3 alkoxy groups; m is 0, 1, 2, 3 or 4; n is 0, 1, 2, 3 or 4; J1 and J2 are independently CR' or N, provided that J1 and J2 are not simultaneously CR', and R' is hydrogen, halogen, deuterium, cyano, amino, hydroxy, or C1-C6 alkyl; Each R 2a' are independently a halogen, deuterium, a cyano group, an amino group, a hydroxy group, a C1-C6 alkyl group, a C1-C6 heteroalkyl group, a C3-C8 cycloalkyl group, a 3- to 8-membered heterocycloalkyl group, -S-C1-C6 alkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a triazolyl group, an -O-C1-C6 alkyl group, an -O-C3-C8 cycloalkyl group, -CH2C(=O)N(R 3a )2, N(R 3a )2, C1-C3 alkyl-O-C1-C3 alkyl-, HC(=O)-, -CO2R 3a , -CON(R 3a2) a 5- to 6-membered heteroaryl group or an -O-3- to 8-membered heterocycloalkyl group, wherein the C1-C6 alkyl group, C1-C6 heteroalkyl group, C3-C8 cycloalkyl group, 3- to 8-membered heterocycloalkyl group, -S-C1-C6 alkyl group, C2-C6 alkenyl group, C2-C6 alkynyl group, O-C1-C6 alkyl group, -O-C3-C8 cycloalkyl group, 5- to 6-membered heteroaryl group or -O-3- to 8-membered heterocycloalkyl group is optionally substituted with one or more deuterium atoms, halogen atoms, hydroxy groups, cyano groups, amino groups, nitro groups, C1-C3 alkoxy groups or C1-C3 alkyl groups; When J1 and J2 are simultaneously N, at least one R 2a' is an —O-3 to 8-membered heterocycloalkyl group, L is a linking chain that connects G and E via a covalent bond, L is a linking chain that connects G' and E via a covalent bond, wherein each E is independently E1, E2, or E3; [ka] Here, in the above E1, Z' is O, S or CH2; X 2 ' is CH or N, Y 2 ' is CH, N, O or S, Q1, Q2, Q3, Q4 and Q5 are each independently CR 3b or N, R 3beach independently represents hydrogen, deuterium, a hydroxy group, an amino group, a cyano group, a halogen atom, a nitro group, a mercapto group, a C1-C6 alkyl group, a C1-C6 heteroalkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C3-C8 cycloalkyl group, a 3- to 8-membered heterocycloalkyl group, a 6- to 10-membered aryl group, a 5- to 10-membered heteroaryl group, -O-(C1-C6 alkyl), -O-(C1-C6 heteroalkyl), -O-(C3-C8 cycloalkyl), -O-(3- to 8-membered heterocycloalkyl), -S-(C1-C6 alkyl), -S-(C1-C6 heteroalkyl), -S-(C3-C8 cycloalkyl), -S-(3- to 8-membered heterocycloalkyl), -N(C1-C6 alkyl) 1-2 , —N(C1-C6 heteroalkyl) 1-2 , -N(C3-C8 cycloalkyl) 1-2 , -N(3-8 membered heterocycloalkyl) 1-2 , -O-(C6-C 10 aryl), -O-(5- to 10-membered heteroaryl), and the above C1-C6 alkyl group, C1-C6 heteroalkyl group, C2-C6 alkenyl group, C2-C6 alkynyl group, C3-C8 cycloalkyl group, 3- to 8-membered heterocycloalkyl group, C6-C 10 The aryl group and the 5- to 10-membered heteroaryl group may optionally be substituted with deuterium, hydroxyl, halogen, cyano, amino, O(C1-C6 alkyl), O—(C3-C8 cycloalkyl), —O—(3- to 8-membered heterocycloalkyl), N(C1-C6 alkyl) 1-2 , -NH(C3-C8 cycloalkyl), -NH(3- to 8-membered heterocycloalkyl), -O-(C6-C 10 -O-(aryl) and -O-(5- to 10-membered heteroaryl), or two adjacent R 3b together with the atoms to which they are attached form a cycloalkyl group, a heterocycloalkyl group (e.g., a 5-, 6-, 7-, or 8-membered heterocycloalkyl group, where the heteroatoms are one or more of N, S, and O, and may be 1, 2, or 3 in number), a heteroaryl group, or an aryl group; m'' is 1, 2 or 3; R1b are each independently hydrogen, deuterium, a hydroxy group, an amino group, a cyano group, a halogen, a C1-C6 alkyl group, a C1-C6 heteroalkyl group, a C3-C8 cycloalkyl group, a 3- to 8-membered heterocycloalkyl group, a C6-C 10 Aryl group, 5-10 membered heteroaryl group, -O(C1-C6 alkyl), -O-(C3-C8 cycloalkyl), -O-(3-8 membered heterocycloalkyl), -N(C1-C6 alkyl) 1-2 , -NH(C3-C8 cycloalkyl), -NH(3- to 8-membered heterocycloalkyl), -O-(C6-C 10 -O-(aryl) or -O-(5- to 10-membered heteroaryl), wherein the alkyl group, cycloalkyl group, heterocycloalkyl group, aryl group, or heteroaryl group is optionally substituted with 1 to 3 groups independently selected from a hydroxy group, a halogen atom, a cyano group, a hydroxy group, and an amino group; R 2b is absent and is hydrogen, deuterium, a C1-C6 alkyl group, or a C3-C6 cycloalkyl group, and the C1-C6 alkyl group and C3-C6 cycloalkyl group are optionally substituted with 1 to 3 groups independently selected from a hydroxy group, a halogen, a cyano group, a hydroxy group, an amino group, and —OC(O)(C1-C6 alkyl).

[0015] [ka] Here, in the above E2, Q1, Q2, Q3 and Q4 are each independently CR 3b or N, W is CR 1c R 2c , C(S), C(O), SO2, -OC=R 4c -,-SC=R 4c -or-C=R 4c NR 5c - or -N=CA'-, X is CH, O or S; X c is -CH2- or -NG'-, Z is CH, O or S; G' and G'' are each independently hydrogen, deuterium, a C1-C6 alkyl group, OH, a C3-C6 cycloalkyl group, a -CH2-heterocycloalkyl group, or a -CH2-phenyl group, wherein the C1-C6 alkyl group, C3-C6 cycloalkyl group, -CH2-heterocycloalkyl group, or -CH2-phenyl group is optionally substituted with one or more hydroxy groups, halogens, cyano groups, and amino groups; A' is hydrogen, deuterium, a C1-C6 alkyl group, a C3-C8 cycloalkyl group, or halogen; R 1c , R 2c and R 3c are each independently hydrogen, deuterium, a hydroxy group, a halogen, -NH2, or -N(C1-C6 alkyl). 1-2 , C1-C6 alkyl group, C1-C6 alkoxy group, C1-C6 haloalkyl group, -CONR ' R '' , -OR ' , -NR ' R '' , -SR ' , -SO2R ' , -SO2NR ' R '' , -CR ' R '' , -CR ' NR ' R '' , C6-C 10 Aryl group, 5-10 membered heteroaryl group, C3-C8 cycloalkyl group, 3-8 membered heterocycloalkyl group, -P(O)(OR ' )R '' , -P(O)R ' R '' , -OP(O)(OR ' )R '' , CN, -NR ' SO2NR ' R '' , -NR ' C(O)NR ' R '' , -C(O)NR ' C(O)R '' , -NR ' C(=N-CN)NR ' R'' , -C(=N-CN)NR ' R '' , -NR ' C(=N-CN)R '' , -NR ' C(=C-NO2)NR ' R '' , -SO2NR ' COR '' , -NO2, -COR ' , -C(C=N-OR ' )R '' , -CR ' =CR ' R '' , -CCR ' , -S(C=O)(C=NR ' )R '' , -SF5 or -OCF3, R 4c is O or S, R 5c is H, C1-C6 alkyl group, C6-C 10 an aryl group, a 5- to 12-membered heteroaryl group, a C3-C8 cycloalkyl group, or a 3- to 8-membered heterocycloalkyl group; R ' and R '' are each independently a bond, hydrogen, deuterium, a C1-C6 alkyl group, a C3-C8 cycloalkyl group, a C6-C 10 an aryl group, a 5- to 10-membered heteroaryl group, or a 3- to 8-membered heterocycloalkyl group, n '' is 0, 1, 2, 3 or 4, [ka] is a single or double bond, [ka] is a bond, which may be an R stereoisomer, an S stereoisomer, or a non-stereoisomer; [ka] Here, in E3 above, X 1and X 2 are each independently a bond, O, C(O), C(S), or NR 1d or CR 1d R 2d and R 1d and R 2d are each independently H, deuterium, or a C1-C6 alkyl group, wherein the C1-C6 alkyl group is optionally substituted with one or more halogens or C1-C6 alkoxy groups; R P are independently H, deuterium, halogen, —OH, or a C1-C3 alkyl group, wherein the C1-C3 alkyl group is optionally substituted with one or more halogens, hydroxy groups, or C1-C3 alkoxy groups; W 3 is a C1-C6 alkyl group, -TN(R 3d R 4d ), -TN(R 3d R 4d )X 3 , -T-C6-C 10 Aryl group, -T-5 to 10-membered heteroaryl group, -T-3 to 8-membered heterocyclyl group, -NR 5d -T-C6-C 10 Aryl group, -NR 5d -T-5 to 10-membered heteroaryl group or -NR 5d -T- is a 3- to 8-membered heterocyclyl group, and is the C1-C6 alkyl group as defined above, -TN(R 3d R 4d ), -TN(R 3d R 4d )X 3 , -T-C6-C 10 Aryl group, -T-5 to 10-membered heteroaryl group, -T-3 to 8-membered heterocyclyl group, -NR 5d -T-C6-C 10 Aryl group, -NR 5d -T-5 to 10-membered heteroaryl group or -NR 5d -T-3 to 8 membered heterocyclyl group is optionally substituted, X 3 is C(O), R 3d , R 4d or R 5d and R3d , R 4d or R 5d are each independently selected from H, deuterium, and a C1-C6 alkyl group, and the C1-C6 alkyl group optionally contains one or more halogens, —OH, R 1d C(O), R 1d C(S), R 1d SO, R 1d SO2, NR 1d R 2d C(O), NR 1d R 2d C(S), NR 1d R 2d SO or NR 1d R 2d Replaced by SO2, T is a C1-C6 alkyl group or -(CH2) n -, and the above -(CH2) n one or more methylene groups in - are optionally substituted with deuterium, halogen or a C1-C6 alkyl group, and the C1-C6 alkyl group is optionally substituted with a halogen, —OH or amino group; n is 0, 1, 2, 3, 4, 5, or 6; W 4 teeth, [ka] and the above [ka] is optionally replaced, R 6d and R 7d are each independently H, deuterium, a C3-C8 cycloalkyl group, or a C1-C6 alkyl group, wherein the C3-C8 cycloalkyl group or the C1-C6 alkyl group is optionally substituted with a halogen, —OH, CN, NO2, or an amino group; W 5 is a 6- to 10-membered aryl group or a 5- to 10-membered heteroaryl group, R 8d are H, deuterium, halogen, CN, OH, NO2, NR 6d R 7d , OR6d , C.O.R. 6d R 7d , N.R. 6d COR 7d , SO2R 6d R 7d , R 6d SO2R 7d , C1-C6 alkyl group, C1-C6 alkoxy group, C6-C 10 An aryl group, a 5- to 10-membered heteroaryl group, a C3-C8 cycloalkyl group, or a 3- to 8-membered heterocycloalkyl group, wherein the C1-C6 alkyl group and C1-C6 alkoxy group are optionally substituted with deuterium, halogen, —OH, CN, NO2, or an amino group.

[0016] Preferably, in some embodiments of the present invention, in each C1-C6 heteroalkyl group, one, two, three, or four methylene groups are replaced with heteroatoms and / or heteroatom groups, wherein the heteroatoms are one or more of O, S, and N, and the heteroatom groups are one or more of -C(O)-, -S(O)-, -S(O)2-, -C(O)O-, -OC(O)-, -C(O)NH-, and -NHC(O)-.

[0017] Preferably, in some embodiments of the present invention, the heteroatoms or heteroatom groups in the 3- to 8-membered heterocycloalkyl groups, the 4- to 12-membered heterocycloalkyl groups, the 5- to 16-membered heterocycloalkyl groups, and the heterocycloalkyl groups may each independently be one or more of O, S, —S(O)—, —S(O)2—, and N, and the number is 1, 2, 3, 4, or 5. Preferably, when the heteroatom is a nitrogen atom, it is not quaternized or oxidized.

[0018] Preferably, in some embodiments of the present invention, the heteroatoms in each of the 5- to 6-membered heteroaryl groups, each of the 5- to 10-membered heteroaryl groups, each of the 5- to 12-membered heteroaryl groups, each of the 5- to 15-membered heteroaryl groups, and each of the heteroaryl groups may each independently be one or more of O, S, —S(O)—, —S(O)2—, and N, and the number is 1, 2, 3, or 4.

[0019] Preferably, in some embodiments of the present invention, in Formula I, R 2a , R 3a and a C1-C4 alkylene group in L', R a and R b may be further substituted with the following definitions, provided that L is linked to E via -C(O)-; R 2a and R 2a' is independently —O—C1-C6 heteroalkyl group, —NH(C1-C6 heteroalkyl), —N(C1-C6 heteroalkyl)(C1-C6 heteroalkyl), or —C3-C4 alkynyl-N(R 5a' )2, R 2a and R 2a' wherein the hydroxy groups are independently optionally substituted with one or more of deuterium, halogen, hydroxy, cyano, amino, nitro, C1-C3 alkoxy, C1-C3 alkyl, C3-C8 cycloalkyl, -Si-C1-C3 alkyl, 3- to 8-membered heterocycloalkyl, or -CON(R 3a )2, R 2a and R 2a' wherein the C1-C6 alkyl group, C1-C6 heteroalkyl group, C3-C8 cycloalkyl group, 3- to 8-membered heterocycloalkyl group, —S—C1-C6 alkyl group, C2-C6 alkenyl group, C2-C6 alkynyl group, —O—C1-C6 alkyl group, —O—C3-C8 cycloalkyl group and 5- to 6-membered heteroaryl group are independently and optionally selected from one or more C3-C8 cycloalkyl group, —Si—C1-C3 alkyl group, 3- to 8-membered heterocycloalkyl group or —CON(R3a )2, Each R 3a is deuterium, The C1-C4 alkylene group in L' may be further optionally substituted with one or more halogens; R a and R b are independently a bond, deuterium, oxo, cyanomethyl group, -N(R 3a )2, -CH2N(R 3a ) -2 , -O(C1-C6 alkyl), -O(C3-C8 cycloalkyl), -O(C1-C6 heteroalkyl), -O(3- to 8-membered heterocycloalkyl), -S(C1-C6 alkyl), -S(C3-C8 cycloalkyl), -O-phenyl group, -O-pyridyl group, C2-C4 alkynyl group, triazolyl group, -CH2C(=O)N(R 3a )2, -C3-C4 alkynyl-N(R 3a ) may be a 2- or 3- to 8-membered heterocycloalkyl group, Or, two adjacent R a together with the atoms linked thereto, form a 6- to 10-membered aryl group, a 5- to 10-membered heteroaryl group, a 5- to 8-membered cycloalkyl group or a 5- to 8-membered heterocycloalkyl group, wherein the 6- to 10-membered aryl group, the 5- to 10-membered heteroaryl group, the 5- to 8-membered cycloalkyl group or the 5- to 8-membered heterocycloalkyl group is optionally substituted with one or more hydroxy groups, amino groups, halogens, cyano groups or nitro groups; R a and R b wherein the C1-C6 alkyl group, C1-C3 alkoxy group, C2-C4 alkenyl group, C3-C8 cycloalkyl group, 3- to 8-membered heterocycloalkyl group, or 5- to 6-membered heteroaryl group is optionally substituted with one or more C1-C3 haloalkyl groups; R a and R b In the above, the C1-C6 heteroalkyl group, the phenyl group, the pyridyl group, the C2-C4 alkynyl group, the triazolyl group, -CH2C(=O)N(R 3a ) 1-2 or -C3-C4 alkyl-N(R 3a)2 is optionally substituted with one or more deuterium, halogen, cyano, hydroxy, amino, nitro, C1-C3 haloalkyl, C1-C3 alkyl, or C1-C3 alkoxy groups; Each R 4a are independently a C4-C6 alkyl group.

[0020] Preferably, in some embodiments of the present invention, each R 1a In the above C3-C 12 The cycloalkyl group is a C3-C6 cycloalkyl group.

[0021] Preferably, in some embodiments of the present invention, each R 1a In the above, the 3- to 12-membered heterocycloalkyl group is a 5- to 6-membered monocyclic saturated heterocycloalkyl group or a 7-, 8-, or 9-membered bridged heterocycloalkyl group, the heteroatom is N, and the number is 1 or 2, such as a piperidinyl group, [ka] is.

[0022] Preferably, in some embodiments of the present invention, each R 2a and each R 2a' wherein the halogen is F, Cl, Br or I, for example, F or Cl.

[0023] Preferably, in some embodiments of the present invention, each R 2a and each R 2a' wherein the C1-C6 alkyl group, the C1-C6 alkyl group in the -S-C1-C6 alkyl group, and the C1-C6 alkyl group in the -O-C1-C6 alkyl group are independently a C1-C4 alkyl group and may also be a C1-C3 alkyl group, such as a methyl group, an ethyl group, an n-propyl group, or an isopropyl group.

[0024] Preferably, in some embodiments of the present invention, each R 2a and each R 2a'wherein the C1-C6 alkyl group or the —O—C1-C6 alkyl group may optionally be substituted with one or more halogens or C1-C3 alkoxy groups.

[0025] Preferably, in some embodiments of the present invention, each R 2a and each R 2a' In the above, the C1-C6 heteroalkyl group is a C3 heteroalkyl group, and the 2-methylene group in the heteroalkyl group is substituted with O and -C(O)NH-, for example: [ka] is.

[0026] Preferably, in some embodiments of the present invention, each R 2a and each R 2a' In the above, the C3-C8 cycloalkyl group is a C3-C6 cycloalkyl group, for example, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, or a cyclohexyl group.

[0027] Preferably, in some embodiments of the present invention, each R 2a' In the above, the -O-3 to 8-membered heterocycloalkyl group is an -O-3, 4, 5, or 6-membered monocyclic saturated heterocycloalkyl group, the heteroatom is one or more of N, S, and O, and the number is 1, 2, or 3, and for example, [ka] is.

[0028] Preferably, in some embodiments of the present invention, each R 2a and each R 2a' wherein C3-C8 may optionally be substituted with one or more C1-C3 alkyl groups.

[0029] Preferably, in some embodiments of the present invention, each R 2a and each R 2a'In the above, the 3- to 8-membered heterocycloalkyl group is a 3- to 6-membered heterocycloalkyl group, and the heteroatom is one or more of N, S and O, and the number is 1, 2 or 3.

[0030] Preferably, in some embodiments of the present invention, each R 2a and each R 2a' In the above, the C2-C6 alkynyl group is a C2-C4 alkynyl group, for example, an ethynyl group.

[0031] Preferably, in some embodiments of the present invention, each R 2a and each R 2a' is optionally substituted with a substituent, in which the halogen is F, Cl, Br or I, for example F.

[0032] Preferably, in some embodiments of the present invention, each R 2a and each R 2a' is optionally substituted with a substituent, in which the C1-C3 alkoxy group is a methoxy group, an ethoxy group, an n-propoxy group or an isopropoxy group, for example a methoxy group.

[0033] Preferably, in some embodiments of the present invention, each R 2a and each R 2a' is optionally substituted with a substituent, in which the C1-C3 alkyl group is a methyl group, an ethyl group, an n-propyl group or an isopropyl group, for example, a methyl group.

[0034] Preferably, in some embodiments of the present invention, each R 3a wherein the C1-C6 alkyl group, the C1-C6 alkyl group in the -S-C1-C6 alkyl group, and the C1-C6 alkyl group in the -O-C1-C6 alkyl group are independently a C1-C4 alkyl group and may also be a C1-C3 alkyl group, such as a methyl group, an ethyl group, an n-propyl group, or an isopropyl group.

[0035] Preferably, in some embodiments of the present invention, in each ring A1, the 6- to 15-membered aryl group in the -L'-6- to 15-membered aryl group is a 6- to 10-membered aryl group, such as a phenyl group or a naphthyl group.

[0036] Preferably, in some embodiments of the present invention, in each ring A1, the 5- to 15-membered heteroaryl group in the -L'-5- to 15-membered heteroaryl group is a 5- to 10-membered heteroaryl group, and may further be a 6-, 7-, 8-, or 9-membered monocyclic or bicyclic heteroaryl group, in which the heteroatom is one or more of N, S, and O, and the number is 1 or 2, such as a pyridyl group, a 1H-indazolyl group, a phenyl[d]thiazole group, or an oxazolophenyl group.

[0037] Preferably, in some embodiments of the present invention, in each ring A1, the 5- to 15-membered heterocycloalkyl group in the -L'-5- to 15-membered heterocycloalkyl group is a 5- to 10-membered heterocycloalkyl group, and the heteroatom is one or more of N, S, and O, and the number is 1 or 2.

[0038] Preferably, in some embodiments of the present invention, in each ring B, the 6- to 15-membered aryl group is a 6- to 10-membered aryl group, such as a phenyl group or a naphthyl group. Preferably, in some embodiments of the present invention, in each ring B, the 5- to 15-membered heteroaryl group is a 5- to 10-membered heteroaryl group, and may further be a 5- to 6-membered heteroaryl group, in which the heteroatom is N and the number is 1 or 2, for example, a pyridyl group.

[0039] Preferably, in some embodiments of the present invention, in each ring B, the C5-C 15 The cycloalkyl group is a C5-C7 monocyclic saturated cycloalkyl group, a C5-C7 cycloalkenyl group or a C8-C 15 and the like are tricyclic cycloalkyl groups, for example [ka] And " [ka] " represents condensation with the ring to which it is connected via a bond of ".

[0040] Preferably, in some embodiments of the present invention, in each ring B, the 5- to 16-membered heterocycloalkyl group is a 5- to 7-membered monocyclic heterocycloalkyl group, the heteroatom is N and / or O, the number is 1 or 2, and the heteroatom is, for example, a pyrrolidinyl group, a piperidinyl group, or a tetrahydro-2H-pyranyl group.

[0041] Preferably, in some embodiments of the present invention, each R a and each R b wherein the halogen is F, Cl, Br or I, for example F or Cl.

[0042] Preferably, in some embodiments of the present invention, each R a and each R b In the formula (I), the C1-C6 alkyl group is a C1-C3 alkyl group, such as a methyl group, an ethyl group, an n-propyl group, or an isopropyl group.

[0043] Preferably, in some embodiments of the present invention, each R a and each R b wherein the C1-C3 alkoxy group and the C1-C3 alkoxy group in the (C1-C3 alkoxy)-C1-C3 alkyl- are independently a methoxy group, an ethoxy group, an n-propoxy group, or an isopropoxy group.

[0044] Preferably, in some embodiments of the present invention, G1 is G1-I or G1-II; [ka] Here, in the above G1-I, R 1eis a hydroxy group, -N(R a'' )2, C3-C 12 a cycloalkyl group or a 3- to 12-membered heterocycloalkyl group (e.g., a 6-, 7-, 8-, 9-, or 10-membered monocyclic or bridged heterocycloalkyl group, wherein the heteroatom is one or more of N, S, or O, and each digit is 1, 2, or 3), and the C3-C 12 The cycloalkyl group or 3- to 12-membered heterocycloalkyl group may optionally be one or more R x is replaced by X 1e is a bond or a C1-C4 alkylene group, Y 1e is a bond, O or NR a'' and Ring C is C6-C 10 a 5- or 6-membered aryl group (e.g., a phenyl group), a 5- to 10-membered heteroaryl group (e.g., a 5- or 6-membered heteroaryl group, in which the heteroatom is N and each digit is 1 or 2), or a 5- to 10-membered heterocycloalkyl group (e.g., a 5- or 6-membered heterocycloalkyl group, in which the heteroatom is N and each digit is 1 or 2); X' is a bond, C, or N (e.g., X' is a bond, C, or N); Y' is C or N; [ka] is one or more optionally present double bonds, R 2e is H, deuterium, halogen, hydroxy group, amino group, C1-C6 alkyl group, C3-C8 cycloalkyl group, -O(C1-C6 alkyl) or -O(C3-C8 cycloalkyl), R 3eis a bond, H, deuterium, halogen, cyano, oxo, -O(C1-C6 alkyl) (e.g., methoxy or ethoxy), -O(C1-C6 heteroalkyl), -O(C3-C8 cycloalkyl), -O(3- to 8-membered heterocycloalkyl), -S(C1-C6 alkyl), -S(C3-C8 cycloalkyl), -O-phenyl or -O-pyridyl, wherein the phenyl or pyridyl group is optionally substituted with one or more hydroxy, halogen, cyano, amino, C1-C3 haloalkyl, C1-C3 alkyl or C1-C3 alkoxy groups; R 4e is -L1-6 to 10-membered aryl group (e.g., phenyl group or naphthyl group) or -L1-5 to 10-membered heteroaryl group (e.g., 6-, 7-, 8-, or 9-membered monocyclic or bicyclic heteroaryl group, wherein the heteroatom is one or two of N, S, or O, and each digit is 1 or 2), and the 6 to 10-membered aryl group or the 5 to 10-membered heteroaryl group may optionally be one or more R a' is replaced by Or, R 4e is a C8-C bond along with the carbon atoms attached to it. 10 Form an aryl group or an 8- to 10-membered heteroaryl group (i.e., R 4e forms a spiro ring structure together with Y' linked thereto), 10 the aryl or 8- to 10-membered heteroaryl group is optionally substituted with halogen, hydroxy, cyano, —O(C1-C6 alkyl), —S(C1-C6 alkyl), and C1-C6 alkyl; R 5e is hydrogen, deuterium, halogen (e.g., F, Cl, or Br), cyano, C1-C6 alkyl, C3-C8 cycloalkyl, —O(C1-C6 alkyl), or —O(C3-C8 cycloalkyl); L1 is a bond or a C1-C4 alkylene group, the C1-C4 alkylene group being optionally substituted with halogen, deuterium, a hydroxy group, a C1-C4 hydroxyalkyl group or a 5-10 membered heteroaryl group; Each R a'' are independently hydrogen, deuterium, or a C1-C6 alkyl group; Each R x are independently H, deuterium, —OH, halogen, C1-C3 alkyl group (e.g., methyl group), —N(R a'' ) 1-2 (e.g., -N(CH3)2), -CH2N(R a'' ) 1-2 , C1-C3 alkoxy group, (C1-C3 alkoxy)-C1-C3 alkyl group, C1-C3 alkyl-N(R a'' ) 1-2 , cyano group, C2-C4 alkenyl group, HC(=O), -CO2R a'' , -CON(R a'' ) a 2, 3 to 8-membered heterocycloalkyl group or a 5 to 6-membered heteroaryl group, wherein the C1-C3 alkyl group, C1-C3 alkoxy group or C2-C4 alkenyl group is optionally substituted with deuterium, halogen, cyano group, hydroxy group, nitro group or amino group; R a' are independently a halogen (e.g., F or Cl), a cyano group, a hydroxy group, a C1-C6 alkyl group (e.g., a methyl group, an ethyl group, or an isopropyl group), a C1-C6 heteroalkyl group, an —S—C1-C6 alkyl group (e.g., an —S-methyl group), a C2-C6 alkenyl group, a C2-C6 alkynyl group (e.g., an ethynyl group), a triazolyl group, an —O—C1-C6 alkyl group (e.g., an ethoxy group), an —O—C1-C6 heteroalkyl group, or an —N(C1-C6 alkyl) 1-2 , —N(C1-C6 heteroalkyl) 1-2 , -CH2C(=O)N(R 5a' )2, -C3-C4 alkynyl (NR 5a' ) 1-2 , -N(R 5a' ) 1-2 , (C1-C3 alkoxy)C1-C3 alkyl-, a C3-C6 cycloalkyl group (e.g., a cyclopropyl group), or a 3- to 6-membered heterocycloalkyl group, wherein the above-mentioned C1-C6 alkyl group, C1-C6 heteroalkyl group, -S-C1-C6 alkyl group, C2-C6 alkenyl group, C2-C6 alkynyl group, -O-C1-C6 alkyl group, -O-C1-C6 heteroalkyl group, -N(C1-C6 alkyl) 1-2 , —N(C1-C6 heteroalkyl)1-2 , the C3-C6 cycloalkyl group or 3- to 6-membered heterocycloalkyl group is optionally substituted with deuterium, halogen, cyano group, hydroxy group, nitro group, amino group, C1-C3 alkyl group, -O-C1-C3 alkyl group or -Si-C1-C3 alkyl group; Each R 5a' are independently H, deuterium, or a C1-C6 alkyl group.

[0045] [ka] Here, in the above G1-II, Ring D is a 6- to 10-membered heterocycloalkyl group, and the 6- to 10-membered heterocycloalkyl group is optionally R b' and the 6- to 10-membered heterocycloalkyl group contains at least one heteroatom selected from N, S, and O. Ring E is a C5-C7 cycloalkyl group, a 5- to 7-membered heterocycloalkyl group (for example, a 5-membered monocyclic heterocycloalkyl group, in which the heteroatom is N and the number is 1 or 2), a C6-C 10 a 5- to 10-membered aryl group, a 5- to 10-membered heteroaryl group, a C5-C7 cycloalkenyl group, or an 8- to 10-membered spiro ring, which forms a parallel ring between ring E and the pyrimidine ring; and 10 The aryl group, 5- to 10-membered heteroaryl group, C-C cycloalkenyl group, or 8- to 10-membered spiro ring is optionally represented by R b'' and the heterocycloalkyl group contains at least one heteroatom selected from N, S, or O, Y" is a 6- to 10-membered heterocycloalkyl group, a 6- to 10-membered aryl group (e.g., a phenyl group or a naphthyl group), or a 5- to 10-membered heteroaryl group, and the 6- to 10-membered heterocycloalkyl group or the 5- to 10-membered heteroaryl group contains at least one heteroatom selected from N, S, or O, and optionally R b''' is replaced by R b'is a C1-C3 alkyl group, a hydroxy group, -O(C1-C3 alkyl), a cyano group, a halogen, -N(R x' ) 1-2 , -CHN(R x' ) 1-2 , a cyanomethyl group, or a 3- to 8-membered heterocycloalkyl group; R b'' is a halogen (e.g., F), deuterium, cyano group, hydroxy group, C1-C4 alkyl group, -S-C1-C3 alkyl group, C2-C4 alkenyl group, C2-C4 alkynyl group (e.g., ethynyl group), triazolyl group, -O-C1-C3 alkyl group, -CH2C(=O)N(R x' ) 1-2 , -C3-C4 alkynyl (NR x' ) 1-2 , -N(R x' ) 1-2 , -C1-C3 alkoxy-C1-C3 alkyl-, wherein the C1-C4 alkyl group, -S-C1-C3 alkyl group, C2-C4 alkenyl group, C2-C4 alkynyl group, or C1-C3 alkoxy group is optionally substituted with deuterium, halogen, hydroxy group, cyano group, amino group, nitro group, C1-C3 alkoxy group, or C1-C3 alkyl group; R b''' is hydrogen, hydroxy group, halogen, cyano group, C1-C6 alkyl group, C2-C4 alkynyl group, C2-C4 alkenyl group, O(C1-C6 alkyl), HC(=O)-, -CO2R x' , -CO2N(R x' ) a 2- or 5- to 6-membered heteroaryl group, wherein the C1-C6 alkyl group is optionally substituted with a halogen, a hydroxy group, a cyano group, or an amino group; Each R x' are independently H or a C1-C3 alkyl group; p is 0 or 1.

[0046] Preferably, in some embodiments of the present invention, G1 is G1-Ia, G1-Ib, or G1-II-a; [ka] where: r is 1 or 2; t is 1, 2 or 3; W 1 and W 2 form a 6- to 10-membered heterocycloalkyl group together with the N atom linked thereto, and the 6- to 10-membered heterocycloalkyl group contains at least one heteroatom selected from N, S, or O (for example, a 6-, 7-, 8-, 9-, or 10-membered monocyclic or bridged heterocycloalkyl group, wherein the heteroatom is one or more of N, S, or O, and each digit is 1, 2, or 3, and at least one N); wherein the rings C and R of G1-Ia, G1-Ib, or G1-II-a are 1e , R 2e , R 3e , R 4e , R 5e , X', Y', Y'' and p are as defined and described by the present invention.

[0047] Preferably, in some embodiments of the present invention, G1 is G1-I-a1, G1-I-a1', G1-I-a1'', G1-I-a1''', G1-I-a2, G1-I-a2', G1-I-b1, G1-I-b2 or G1-II-a1; [ka] Here, in the above G1-I-a1, G1-I-a1', G1-I-a1'' and G1-I-a1''', R 1a' is hydrogen, a hydroxy group, a halogen, a cyano group, a C1-C6 alkyl group (e.g., a methyl group), a C3-C8 cycloalkyl group, HC(=O)-, -CO2R 5a' , -CO2N(R 5a' ) a 2- or 5- to 6-membered heteroaryl group, wherein the C1-C6 alkyl group or the C3-C8 cycloalkyl group is optionally substituted with a halogen, a hydroxy group, a cyano group, or an amino group; Each R 5a' are independently hydrogen or a C1-C6 alkyl group; where R 3e , R4e , R 5e , X' and Y' are as defined and described by G1-Ia.

[0048] [ka] Here, in the above G1-I-a2 and G1-I-a2', Each R 1a'' are independently hydrogen, a hydroxy group, a halogen atom, a C1-C3 alkyl group, a C1-C3 alkoxy group, (C1-C3 alkoxy)-C1-C3 alkyl-, C1-C3 alkyl-N(R 5a' ) 1-2 , cyano group, C2-C4 alkenyl group, HC(=O)-, -CO2R 5a' or -CO2N(R 5a' ) 2, wherein the C1-C3 alkyl group or the C2-C4 alkenyl group is optionally substituted with a halogen, a hydroxy group, a cyano group, or an amino group; Each R 4a' is a 6- to 10-membered aryl group, a 6- to 10-membered aryl group (e.g., a phenyl group or a naphthyl group), a 5- to 10-membered heteroaryl group, or a 5- to 10-membered heteroaryl group, and the 6- to 10-membered aryl group or the 5- to 10-membered heteroaryl group may optionally be one or more R 8a' may be substituted with each L2 is a C1-C4 alkylene group, the C1-C4 alkylene group being optionally substituted with a hydroxy group, a halogen, a cyano group, an amino group, a C1-C4 hydroxyalkyl group, or a 5- to 10-membered heteroaryl group; Each R 5a' are independently H or a C1-C3 alkyl group; Each R 8a' are independently a halogen, deuterium, a cyano group, a hydroxy group, an amino group, a C1-C6 alkyl group, a C1-C6 heteroalkyl group, a C3-C6 cycloalkyl group, an -S-C1-C3 alkyl group, a C2-C4 alkenyl group, a C2-C4 alkynyl group, a triazolyl group, an -O-C1-C6 alkyl group, an N(R 5a' ) 1-2or an —O—C1-C6 alkyl group, wherein the C1-C6 alkyl group, C1-C6 heteroalkyl group, C3-C6 cycloalkyl group, —S—C1-C3 alkyl group, C2-C4 alkenyl group, C2-C4 alkynyl group, or —O—C1-C6 alkyl group is optionally substituted with a halogen, a hydroxy group, a cyano group, or an amino group; R 3a' is hydrogen or oxo.

[0049] [ka] In the above G1-I-b1, G1-I-b2, and G1-II-a1, where R 1e , R 3e , R 4e , R 5e , t, r, Y″ and p are as defined and described by the present invention.

[0050] Preferably, in some embodiments of the present invention, G1' is G1'-I or G1'-II, [ka] Here, in the above G1'-I, n2 is 1 or 2; J1 and J2 are independently selected from CR' or N, and J1 and J2 are not simultaneously CR'; R' is hydrogen, halogen, deuterium, cyano, amino, hydroxy, or C1-C6 alkyl; R 1e is a hydroxy group, -N(R a'' )2, C3-C 12 a cycloalkyl group or a 3- to 12-membered heterocycloalkyl group, 12 The cycloalkyl group or 3- to 12-membered heterocycloalkyl group may optionally be one or more R x is replaced by X 1e is a bond or a C1-C4 alkylene group, Y 1eis a bond, O or NR a'' and Ring C is C6-C 10 a 5- to 10-membered aryl group, a 5- to 10-membered heteroaryl group, or a 5- to 10-membered heterocycloalkyl group, X' is a bond, O, C or N; Y' is C or N; [ka] is one or more optionally present double bonds, R 2e is H, deuterium, halogen, hydroxy group, amino group, C1-C6 alkyl group, C3-C8 cycloalkyl group, -O(C1-C6 alkyl) or -O(C3-C8 cycloalkyl), R 3e is H, deuterium, halogen, cyano, oxo, -O(C1-C6 alkyl), -O(C1-C6 heteroalkyl), -O(C3-C8 cycloalkyl), -O(3- to 8-membered heterocycloalkyl), -S(C1-C6 alkyl), -S(C3-C8 cycloalkyl), -O-phenyl or -O-pyridyl, wherein the phenyl or pyridyl group is optionally substituted with one or more hydroxy, halogen, cyano, amino, C1-C3 haloalkyl, C1-C3 alkyl or C1-C3 alkoxy groups; R 4e is a 6- to 10-membered aryl group or a 5- to 10-membered heteroaryl group, and the 6- to 10-membered aryl group or the 5- to 10-membered heteroaryl group may optionally be one or more R a' is replaced by Alternatively, if n2 is 2, two R 4e are C8-C together with the carbon atoms connected to them. 10 An aryl group or an 8- to 10-membered heteroaryl group is formed, and the C8-C 10 the aryl or 8- to 10-membered heteroaryl group is optionally substituted with halogen, hydroxy, cyano, —O(C1-C6 alkyl), —S(C1-C6 alkyl) or C1-C6 alkyl; R 5eis hydrogen, deuterium, halogen, cyano, C1-C6 alkyl, C3-C8 cycloalkyl, -O(C1-C6 alkyl) or -O(C3-C8 cycloalkyl), L1 is a bond or a C1-C4 alkylene group, the C1-C4 alkylene group being optionally substituted with halogen, deuterium, a hydroxy group, a C1-C4 hydroxyalkyl group or a 5-10 membered heteroaryl group; Each R a'' are independently hydrogen, deuterium, or a C1-C6 alkyl group; Each R x are independently H, deuterium, -OH, halogen, cyano group, C1-C6 alkyl group, -N(R a'' ) 1-2 , -CHN(R a'' ) 1-2 , C1-C3 alkoxy group, (C1-C3 alkoxy)-C1-C3 alkyl group, C1-C3 alkyl-N(R a'' ) 1-2 , cyano group, C2-C4 alkenyl group, HC(=O), -CO2R a'' , -CON(R a'' 2) a C3-C8 cycloalkyl group, a 3- to 8-membered heterocycloalkyl group, or a 5- to 6-membered heteroaryl group, wherein the C1-C6 alkyl group, C3-C8 cycloalkyl group, C1-C3 alkoxy group, or C2-C4 alkenyl group is optionally substituted with deuterium, halogen, cyano group, hydroxy group, nitro group, or amino group; R a' are independently a halogen, deuterium, a cyano group, a hydroxy group, a C1-C6 alkyl group, a C1-C6 heteroalkyl group, -S-C1-C6 alkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a triazolyl group, -O-C1-C6 alkyl group, -O-C1-C6 heteroalkyl group, -NH(C1-C6 heteroalkyl), -N(C1-C6 heteroalkyl), -CH2C(=O)N(R 5a' )2, -C3-C4 alkynyl (NR 5a' )2, -N(R 5a')2 (for example, -N(C1-C6 alkyl)2, -NH(C1-C6 heteroalkyl)), (C1-C3 alkoxy)C1-C3 alkyl-, a C3-C6 cycloalkyl group or a 3- to 6-membered heterocycloalkyl group, wherein the above-mentioned C1-C6 alkyl group, C1-C6 heteroalkyl group, -S-C1-C6 alkyl group, C2-C6 alkenyl group, C2-C6 alkynyl group, -O-C1-C6 alkyl group, -O-C1-C6 heterocycloalkyl group, the heteroalkyl group, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -NH(C1-C6 heteroalkyl), -N(C1-C6 heteroalkyl)2, -, C3-C6 cycloalkyl group, and 3- to 6-membered heterocycloalkyl group are optionally substituted with deuterium, halogen, cyano group, hydroxy group, nitro group, amino group, C1-C3 alkyl group, -O-C1-C3 alkyl group, or -Si-C1-C3 alkyl group; Each R 5a' are independently H, deuterium, or a C1-C6 alkyl group; [ka] Here, in the above G1'-II, J1 and J2 are independently CR' or N, and J1 and J2 are not simultaneously CR'; R' is hydrogen, halogen, deuterium, cyano, amino, hydroxy, or C1-C6 alkyl; Ring D is a 6- to 10-membered heterocycloalkyl group, and the 6- to 10-membered heterocycloalkyl group is optionally R b' and the 6- to 10-membered heterocycloalkyl group contains at least one heteroatom selected from N, S, and O. Ring E is C5-C 15 Cycloalkyl groups, 5-7 membered heterocycloalkyl groups, C6-C 10 a C5-C7 cycloalkyl group, a 5- to 7-membered heterocycloalkyl group, a C6-C7 cycloalkyl group, a 5- to 10-membered aryl group, a 5- to 10-membered heteroaryl group, or a C5-C7 cycloalkenyl group, an 8- to 10-membered spiro ring; 10 The aryl group, 5- to 10-membered heteroaryl group, C-C cycloalkenyl group, or 8- to 10-membered spiro ring is optionally represented by Rb'' and the heterocycloalkyl group contains at least one heteroatom selected from N, S, or O, Y" is a 6- to 10-membered heterocycloalkyl group, a 6- to 10-membered aryl group, or a 5- to 10-membered heteroaryl group, and the 6- to 10-membered heterocycloalkyl group or the 5- to 10-membered heteroaryl group contains at least one heteroatom selected from N, S, and O, and optionally contains R b''' is replaced by R b' is hydrogen, C1-C6 alkyl group, hydroxy group, -O(C1-C3 alkyl), cyano group, halogen, -N(R x' )2, -CH2N(R x' )2, -CO2R x' , -CO2N(R x' 2) a cyanomethyl group, a 5-6 membered heteroaryl group, or a 3-8 membered heterocycloalkyl group, wherein the C1-C6 alkyl group, C3-C8 cycloalkyl group is optionally substituted with a halogen, a hydroxy group, a cyano group, or an amino group; R b'' is a halogen, deuterium, cyano group, hydroxy group, C1-C4 alkyl group, -S-C1-C3 alkyl group, C2-C4 alkenyl group, C2-C4 alkynyl group, triazolyl group, -O-C1-C3 alkyl group, -CH2C(=O)N(R x' ) -2 , -C3-C4 alkynyl (NR x' )2, -N(R x' )2 or -C1-C3 alkoxy-C1-C3 alkyl-, wherein the C1-C4 alkyl group, -S-C1-C3 alkyl group, C2-C4 alkenyl group, C2-C4 alkynyl group, or C1-C3 alkoxy group is optionally substituted with deuterium, halogen, hydroxy group, cyano group, amino group, nitro group, C1-C3 alkoxy group, or C1-C3 alkyl group; R b''' is hydrogen, hydroxy group, halogen, cyano group, C1-C6 alkyl group, C2-C4 alkynyl group, C2-C4 alkenyl group, O(C1-C6 alkyl), HC(=O)-, -CO2R x' , -CO2N(R x') a 2- or 5- to 6-membered heteroaryl group, wherein the C1-C6 alkyl group is optionally substituted with a halogen, a hydroxy group, a cyano group, or an amino group; Each R x' are independently H or a C1-C6 alkyl group; p is 0 or 1.

[0051] Preferably, in some embodiments of the present invention, G1'-I is G1'-Ia or G1'-Ib, and G1'-II is G1'-II-a; [ka] where: r is 1 or 2; t is 1, 2 or 3; W 1 and W 2 form a 6- to 10-membered heterocycloalkyl group together with the N atom linked thereto, and the 6- to 10-membered heterocycloalkyl group contains at least one heteroatom selected from N, S, and O, wherein the rings C, J1, J2, R of G1'-Ia, G1'-Ib, or G1'-II-a are 1e , R 2e , R 3e , R 4e , R 5e , X', Y', Y'' and p are as defined and described by the present invention.

[0052] Preferably, in some embodiments of the present invention, G1' is G1'-I-a1, G1'-I-a1', G1'-I-a1'', G1'-I-a1''', G1'-I-a2, G1'-I-b1, G1'-I-b2 or G1'-II-a1; [ka] Here, in the above G1'-I-a1, G1'-I-a1', G1'-I-a1'' and G1'-I-a1''', R 1a'is hydrogen, hydroxyl group, halogen, cyano group, C1-C6 alkyl group, C3-C8 cycloalkyl group, HC(=O)-, -CO2R 5a' , -CO2N(R 5a' ) a 2- or 5- to 6-membered heteroaryl group, wherein the C1-C6 alkyl group and the C3-C8 cycloalkyl group are optionally substituted with halogen, hydroxyl, cyano, or amino groups; Each R 5a' are independently hydrogen or a C1-C6 alkyl group; Here, J1, J2, R 3e , R 4e , R 5e , X' and Y' are as defined and described by G1'-Ia of the present invention.

[0053] [ka] Here, in the above G1'-I-a2, J1 and J2 are independently CR' or N, and J1 and J2 are not simultaneously CR'; R' is hydrogen, halogen, deuterium, cyano, amino, hydroxy, or C1-C6 alkyl; t' is 0 or 1, Each R 1a'' are independently hydrogen, a hydroxy group, a halogen atom, a C1-C3 alkyl group, a C1-C3 alkoxy group, -(C1-C3 alkoxy)-C1-C3 alkyl-, -C1-C3 alkyl-N(R 5a' ) -2 , cyano group, C2-C4 alkenyl group, HC(=O)-, -CO2R 5a' or -CO2N(R 5a' ) 2, wherein the C1-C3 alkyl group or the C2-C4 alkenyl group is optionally substituted with a halogen, a hydroxy group, a cyano group, or an amino group; R 4a' is a 6- to 10-membered aryl group, a 6- to 10-membered aryl group, a 5- to 10-membered heteroaryl group, or a 5- to 10-membered heteroaryl group, and the 6- to 10-membered aryl group or the 5- to 10-membered heteroaryl group may optionally be one or more R8a' may be substituted with L2 is a C1-C4 alkylene group, which is optionally substituted with a hydroxy group, a halogen, a cyano group, an amino group, a C1-C4 hydroxyalkyl group, or a 5- to 10-membered heteroaryl group; R 5a' are independently H or a C1-C3 alkyl group; Each R 8a' are independently a halogen, deuterium, a cyano group, a hydroxy group, an amino group, a C1-C6 alkyl group, a C1-C6 heteroalkyl group, a C3-C6 cycloalkyl group, an -S-C1-C3 alkyl group, a C2-C4 alkenyl group, a C2-C4 alkynyl group, a triazolyl group, an -O-C1-C6 alkyl group, an N(R 5a' ) 1-2 or an —O—C1-C6 alkyl group, wherein the C1-C6 alkyl group, C1-C6 heteroalkyl group, C3-C6 cycloalkyl group, —S—C1-C3 alkyl group, C2-C4 alkenyl group, C2-C4 alkynyl group, or —O—C1-C6 alkyl group is optionally substituted with a halogen, a hydroxy group, a cyano group, or an amino group; R 3a' is hydrogen or oxo, [ka] In the above G1'-I-b1, G1'-I-b2 and G1'-II-a1, Here, J1, J2, R 1e , R 3e , R 4e , R 5e , t, r, Y″ and p are as defined and described by the present invention.

[0054] Preferably, in some embodiments of the present invention, in G1': Y1 is a bond, X1 is a bond, and X 1 ' is a bond, R 1arepresents a 3- to 12-membered heterocycloalkyl group, the heteroatom in the 3- to 12-membered heterocycloalkyl group being one or more of O, S and N, and the number of the heteroatoms is 1, 2 or 3; Ring A1 is -L'-6 to 15-membered aryl group, L' is a bond; Ring B is a 5- to 15-membered heteroaryl group, and the heteroatom in the 5- to 15-membered heteroaryl group is one or more of O, S, and N, and the number of heteroatoms is 1, 2, or 3; Each R 2a' are independently a hydroxy group, a C1-C6 alkyl group, a C2-C6 alkynyl group, or an -O-3 to 8-membered heterocycloalkyl group.

[0055] Preferably, G1' is G1'-I-a1 or G1'-III: [ka] is.

[0056] Preferably, in some embodiments of the present invention, each ring B is independently a 6- to 15-membered aryl group, a 5- to 15-membered heteroaryl group, a C5-C 15 is a cycloalkyl group or a 5- to 16-membered heterocycloalkyl group, and each R a are independently a halogen, a hydroxy group, an amino group, a cyano group, a -C1-C6 alkyl group, a -C1-C6 heteroalkyl group, a -C3-C8 cycloalkyl group, a -C2-C6 alkenyl group, a -C2-C6 alkynyl group, a 3- to 8-membered heterocycloalkyl group, -O(C1-C6 alkyl), -O(C3-C8 cycloalkyl), -S(C1-C6 alkyl), -S(C3-C8 cycloalkyl), -NH(C1-C6 alkyl)2-N(C1-C6 alkyl)2, -NH(C3-C8 cycloalkyl) or -N(C3-C8 cycloalkyl)2.

[0057] Preferably, each ring B is independently a 6- to 15-membered aryl group, a 5- to 15-membered heteroaryl group, or a 5- to 16-membered heterocycloalkyl group, and each R aare independently a halogen, a hydroxy group, an amino group, a cyano group, a -C1-C6 alkyl group, a -C1-C6 heteroalkyl group, a -C3-C8 cycloalkyl group, a -C2-C6 alkenyl group, a -C2-C6 alkynyl group, a -C3-C8 heterocycloalkyl group (e.g., a 3- to 8-membered heterocycloalkyl), -O(C1-C6 alkyl), -O(C3-C8 cycloalkyl), -S(C1-C6 alkyl), -S(C3-C8 cycloalkyl), -N(C1-C6 alkyl) 1-2 or -N(C3-C8 cycloalkyl) 1-2 is replaced by

[0058] More preferably, each ring B is independently a 6- to 15-membered aryl group, a 5- to 15-membered heteroaryl group, or a 5- to 16-membered heterocycloalkyl group, and each R a are independently a halogen, a hydroxy group, an amino group, a cyano group, a -C1-C6 alkyl group, a -C1-C6 heteroalkyl group, a -C3-C6 alkenyl group, a -C3-C6 alkynyl group, a -C3-C8 heterocycloalkyl group (e.g., a 3- to 8-membered heterocycloalkyl), -O(C1-C6 alkyl), -S(C1-C6 alkyl), or -N(C1-C6 alkyl). 1-2 It is substituted with (e.g., F, Cl, hydroxyl, cyano, methyl).

[0059] Preferably, in some embodiments of the present invention, the structural unit [ka] teeth, [ka] and the structural unit

[0060] [ka] (i.e., the structural unit defined in this aspect) optionally includes F, Cl, Br, I, a hydroxy group, an amino group, a cyano group, a -C1-C6 alkyl group, a -C1-C6 heteroalkyl group, a -C3-C8 cycloalkyl group, a -C2-C6 alkenyl group, a -C2-C6 alkynyl group, a 3- to 8-membered heterocycloalkyl group, -O(C1-C6 alkyl), -O(C3-C8 cycloalkyl), -S(C1-C6 alkyl), -S(C3-C8 cycloalkyl), -N(C1-C6 alkyl) 1-2 , -N(C3-C8 cycloalkyl) 1-2 is replaced by

[0061] Preferably, in some embodiments of the present invention, wherein the structural unit [ka] teeth, [ka] and the structural unit

[0062] [ka] (i.e., the structural unit defined in this aspect) optionally includes F, Cl, Br, I, a hydroxy group, an amino group, a cyano group, a -C1-C6 alkyl group, a -C1-C6 heteroalkyl group, a -C3-C8 cycloalkyl group, a -C2-C6 alkenyl group, a -C2-C6 alkynyl group, a -C3-C8 heterocycloalkyl group (e.g., a 3- to 8-membered heterocycloalkyl), -O(C1-C6 alkyl), -O(C3-C8 cycloalkyl), -S(C1-C6 alkyl), -S(C3-C8 cycloalkyl), -N(C1-C6 alkyl) 1-2 or -N(C3-C8 cycloalkyl) 1-2 is replaced by

[0063] More preferably, in some embodiments of the present invention, the structural unit [ka] teeth, [ka] and the structural unit

[0064] [ka] (i.e., the structural unit defined in this aspect) optionally includes F, Cl, Br, I, a hydroxy group, an amino group, a cyano group, a -C1-C6 alkyl group, a -C1-C6 heteroalkyl group, a -C3-C6 alkenyl group, a -C3-C6 alkynyl group, a -C3-C8 heterocycloalkyl group (e.g., a 3- to 8-membered heterocycloalkyl), -O(C1-C6 alkyl), -S(C1-C6 alkyl), or -N(C1-C6 alkyl). 1-2 is replaced by

[0065] Preferably, in some embodiments of the present invention, the structural unit [ka] teeth, [ka] is.

[0066] Preferably, in some embodiments of the present invention, the structural unit [ka] teeth, [ka] and the structural unit [ka] is optionally substituted with F, Cl, Br, I, a hydroxy group, an amino group, a cyano group, a -C1-C6 alkyl group, a -C1-C6 heteroalkyl group, a -C3-C8 cycloalkyl group, a -C2-C6 alkenyl group, a -C2-C6 alkynyl group, a 3- to 8-membered heterocycloalkyl group, -O(C1-C6 alkyl), -O(C3-C8 cycloalkyl), -S(C1-C6 alkyl), -S(C3-C8 cycloalkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl), -NH(C3-C8 cycloalkyl), or -N(C3-C8 cycloalkyl).

[0067] Preferably, in some embodiments of the present invention, the structural unit [ka] teeth, [ka] is.

[0068] Preferably, in some embodiments of the present invention, each ring A1 is C6-C 15 an aryl group or a 5- to 15-membered heteroaryl group, and R 2a and R 2a' are independently a hydroxy group, an amino group, a halogen, a C1-C6 alkyl group, a C1-C6 heteroalkyl group, an —S—C1-C6 alkyl group, an —O—C1-C6 alkyl group, a C3-C8 cyclopropyl group, a C2-C6 alkynyl group, or an —O-3 to 8-membered heterocycloalkyl group, and the C1-C6 alkyl group, the —S—C1-C6 alkyl group, and the C3-C8 cyclopropyl group are optionally substituted with a halogen, CN, —OH, —NH2, or a C1-C3 alkyl group.

[0069] Preferably, R 2a and R 2a' are independently a hydroxy group, an amino group, a halogen, a C1-C6 alkyl group, a C1-C6 heteroalkyl group, an -S-C1-C6 alkyl group, an -O-C1-C6 alkyl group, a C3-C8 cyclopropyl group, or a C2-C6 alkynyl group.

[0070] Preferably, in some embodiments of the present invention, each ring A1 is C6-C 15 an aryl group or a 5- to 15-membered heteroaryl group, and 15 The aryl group or 5- to 15-membered heteroaryl group may optionally be selected from the group consisting of -OH, F, Cl, Br, I, CN, -NH2, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2-, -OCH3, OCH2CH3, [ka] or -SCH3, and is substituted with -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2-, [ka] Or -SCH3 is optionally substituted with halogen, CN, -OH, -NH2 or a C1-C3 alkyl group.

[0071] Preferably, R 2a and R 2a' are independently a hydroxy group, an amino group, F, Cl, a methyl group, an ethyl group, an isopropyl group, a trifluoromethyl group, [ka] -SCH3, [ka] cyclopropyl group or [ka] is.

[0072] More preferably, in some embodiments of the present invention, ring A1 is a phenyl group, a pyridyl group, a naphthyl group, [ka] wherein the ring A1 (i.e., the group defined in this aspect) is optionally selected from -OH, F, Cl, Br, I, CN, -NH2, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2-, -OCH3, OCH2CH3, [ka] or -SCH3, and is substituted with -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2-, [ka] Or -SCH3 is optionally substituted with halogen, CN, -OH, -NH2 or a C1-C3 alkyl group.

[0073] Preferably, in some embodiments of the present invention: [ka] does not exist, [ka] The file is TIFF2025536369000057.tif22169.

[0074] Preferably, in some embodiments of the present invention, wherein the structural unit [ka] teeth, [ka] is.

[0075] Preferably, in some embodiments of the present invention, wherein the structural unit [ka] teeth, [ka] and the structural unit

[0076] [ka] (i.e., the structural unit as defined herein) may optionally contain 1, 2, or 3 R a is replaced by

[0077] More preferably, in some embodiments of the present invention, the structural unit [ka] teeth, [ka] and the structural unit

[0078] [ka] (i.e., the structural unit defined in this embodiment) may optionally contain one or two R a is replaced by

[0079] Preferably, in some embodiments of the present invention, wherein the structural unit [ka] teeth, [ka] TIFF2025536369000068.tif141169.

[0080] Preferably, in some embodiments of the present invention, wherein the structural unit [ka] teeth, [ka] is.

[0081] More preferably, in some embodiments of the present invention, the structural unit [ka] teeth, [ka] is.

[0082] Preferably, in some embodiments of the present invention, wherein the structural unit [ka] teeth, [ka] is.

[0083] Preferably, in some embodiments of the present invention, wherein the structural unit [ka] teeth, [ka] TIFF2025536369000077.tif192169TIFF2025536369000078.tif181169TIFF2025536369000079.tif192169TIFF2025536369000080.tif207169TIFF2025536369000081.tif34169, and the above structural units

[0084] [ka] (i.e., the structural unit as defined herein) may optionally contain 1, 2, or 3 R a is replaced by

[0085] Preferably, in some embodiments of the present invention, the structural unit [ka] teeth, [ka] and the structural unit

[0086] [ka] (i.e., the structural unit defined in this embodiment) may optionally contain one or two R a Preferably, R a is a C1-C6 alkyl group optionally substituted with one or more hydroxy groups, for example, —CH2OH.

[0087] Preferably, in some embodiments of the present invention, wherein the structural unit [ka] teeth, [ka] TIFF2025536369000088.tif201169TIFF2025536369000089.tif186169TIFF2025536369000090.tif217169TIFF2025536369000091.tif146169.

[0088] Preferably, in some embodiments of the present invention, the structural unit [ka] teeth, [ka] is.

[0089] Preferably, in some embodiments of the present invention, wherein the structural unit [ka] teeth, [ka] TIFF2025536369000096.tif204169TIFF2025536369000097.tif180169TIFF2025536369000098.tif193169TIFF2025536369000099.tif217169TIFF2025536369000100.tif179169. Preferably, in some embodiments of the present invention, wherein the structural unit [ka] teeth, [ka] and the above [ka] independently and optionally 1, 2 or 3 R a is replaced by

[0090] Preferably, in some embodiments of the present invention, wherein the structural unit [ka] teeth, [ka] is.

[0091] Preferably, in some embodiments of the present invention, the structural unit [ka] teeth, [ka] TIFF2025536369000108.tif199169TIFF2025536369000109.tif97169

[0092] Preferably, in some embodiments of the present invention, wherein the structural unit [ka] teeth, [ka] Preferably, each R 2a' are independently halogen, a C1-C6 alkyl group, a C2-C6 alkynyl group, or an -O-3 to 8-membered heterocycloalkyl group.

[0093] Preferably, in some embodiments of the present invention, wherein the structural unit [ka] teeth, [ka] is.

[0094] Preferably, in certain embodiments of the present invention, L is -(CH2) j -, and the above -(CH2) j One or more methylene groups of - are optionally -NR 3' -, -O-, -CR 1' R 2' -, -C(O)-, -S(O)-, -S(O)2-, -C(O)O-, -OC(O)-, -C(O)NR 3' -, -NR 3' C(O)-, -S(O)NR 3' -, -NR 3'S(O)2-, vinylidene group, ethynylene group, phenyl group, 8-10 membered bicyclic arylene group, 3-7 membered saturated or partially unsaturated cycloalkylene group, 5-11 membered saturated or partially unsaturated spirocycloalkylene group, 5-11 membered saturated or partially unsaturated fused cycloalkylene group, 8-10 membered bicyclic saturated or partially unsaturated cycloalkylene group, 4-7 membered saturated or partially unsaturated heterocycloalkylene group having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur, 5-11 membered saturated or partially unsaturated spiroheterocycloalkylene group having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur, 5-11 membered saturated or partially unsaturated fused heterocycloalkylene group having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur. a 8- to 10-membered bicyclic saturated or partially unsaturated heterocycloalkylene group having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5- to 6-membered heteroarylene group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8- to 10-membered bicyclic heteroaryl group having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and the vinylidene group, ethynylene group, cycloalkylene group, heterocycloalkylene group, phenyl group, spiroheterocycloalkylene group, fused heterocycloalkylene group, spirocycloalkylene group, fused cycloalkylene group, and heteroarylene group are each independently optionally substituted with halogen, oxo, -NR 3' R 4' , -OR 3' , nitro group, -CN, C1-C6 alkyl group, C3-C 10 Cycloalkyl groups, C3-C 10 and heterocycloalkyl groups, wherein the alkyl, cycloalkyl, and heterocycloalkyl groups are optionally substituted with one or more substituents selected from halogen, —OH, —NH, —CN, C1-C4 alkyl groups, and C3-C6 cycloalkyl groups; and R 1' , R 2'are each independently halogen, —OH, —NH, a C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, —O(C1-C4 alkyl), —NH(C1-C4 alkyl), —NH(C1-C4 alkyl), a C3-C6 cycloalkyl group, —O(C3-C6 cycloalkyl), —NH(C3-C6 cycloalkyl), a C3-C6 heterocycloalkyl group, —O(C3-C6 heterocycloalkyl), or —NH(C3-C6 cycloalkyl); R 3' , R 4' are each independently hydrogen, deuterium, a C1-C4 alkyl group, a C3-C6 cycloalkyl group, or a C3-C6 heterocycloalkyl group; and j is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12.

[0095] Preferably, in some embodiments of the present invention, L is [ka] TIFF2025536369000115.tif224169TIFF2025536369000116.tif223169TIFF2025536369000117.tif218169TIFF2025536369000118.tif218169TIFF2025536369000119.tif211169TIFF2025536369000120.tif212169TIFF2025536369000121.tif213169TIFF2025536369000122.tif213169TIFF2025536369000123.tif226169TIFF2025536369000124.tif212169TIFF2025536369000125.tif220169TIFF2025536369000126.tif217169TIFF2025536369000127.tif217169TIFF2025536369000128.tif211169TIFF2025536369000129.tif226169TIFF2025536369000130.tif223169TIFF2025536369000131.tif223169TIFF2025536369000132.tif224169TIFF2025536369000133.tif214169TIFF2025536369000134.tif217169TIFF2025536369000135.tif229169TIFF2025536369000136.tif206169TIFF2025536369000137.tif227169TIFF2025536369000138.tif219169TIFF2025536369000139.tif225169TIFF2025536369000140.tif225169TIFF2025536369000141.tif219169TIFF2025536369000142.tif219169TIFF2025536369000143.tif211169TIFF2025536369000144.tif20169。

[0096] Preferably, in some embodiments of the present invention, the methylene group in L is substituted with a group selected from -O-, C(O)-, a vinylidene group, a 4- to 7-membered saturated or partially unsaturated heterocycloalkylene group having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 11-membered saturated or partially unsaturated spiroheterocycloalkylene group having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0097] Preferably, in some embodiments of the present invention, j is 8.

[0098] Preferably, in some embodiments of the present invention, L is -O-CH2-vinylidene-CH2-, a 4- to 7-membered saturated or partially unsaturated heterocycloalkylene -CH2- having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5- to 11-membered saturated or partially unsaturated spiroheterocycloalkylene group -C(O)- having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, such as [ka] is.

[0099] Preferably, in some embodiments of the invention, L is LA,

[0100] [ka] Here, in the above LA, Case I: Ring U is C3-C 12 a cycloalkylene group or a 3- to 12-membered heterocycloalkylene group containing 1 to 2 heteroatoms selected from N, O, and S, and 12 The cycloalkylene group and the 3- to 12-membered heterocycloalkylene group are optionally substituted with a substituent selected from halogen, oxo, cyano, amino, hydroxy, COBn, C-C alkyl, C-C haloalkyl, C-C hydroxyalkyl, and —O—(C-C alkyl); Ring Y is a bond, C3-C 12 a cycloalkylene group or a 3- to 12-membered heterocycloalkylene group containing 1 to 2 heteroatoms selected from N, O, and S (the heterocycloalkylene group may be a monocyclic heterocycloalkylene group or a bicyclic spiroheterocycloalkylene group), and 12 The cycloalkylene group and the 3- to 12-membered heterocycloalkylene group are optionally substituted with a substituent selected from halogen, oxo, cyano, amino, hydroxy, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, and -O-(C1-C6 alkyl); X'' is a bond, -C(O)-, -NH-, -NCH3-, -O-, -C(CH3)2-, -S-, -C=C-, -C≡C-, -CHF-, -CHCF3-, or -(CH2) q C(O)-, -S(O)-, -S(O)2-, -C(O)O-, -OC(O)-, -(CH2) q -C(O)NH-, -C(O)NCH3-, -NHC(O)-, -NCH3C(O)- or -C(O)CHO-; q is 1 or 2; Lx is -(CH2) v -, and one or two methylene groups in Lx are optionally -O-, -S-, -NH-, -C≡C-, -N(C1-C6 alkyl)-, -N(C1-C6 haloalkyl)-, -C(O)-, -N(C1-C6 hydroxyalkyl)-, -N(C3-C8 cycloalkyl)- or -CR d R e -, and v is 1, 2, 3, 4, 5, 6, or 7; R d , R e are each independently H, —OH, a C1-C6 alkyl group, or a C1-C6 alkoxy group; Or, R d and R e are -C=C(R) together with the C atoms connected to them. f ) 2, forming a C3-C8 cycloalkyl group or a 3- to 8-membered heterocycloalkyl group; R fis hydrogen or a C1-C3 alkyl group, Ly is -(CH2) k -, wherein one or two methylene groups in Ly are optionally substituted with one selected from -O-, -NH-, -C≡C-, -N(C1-C6 alkyl)-, -N(C1-C6 haloalkyl)-, -C(O)-, -N(C1-C6 hydroxyalkyl)-, or -N(C3-C8 cycloalkyl)-; and k is 1, 2, 3, 4, 5, 6, 7, or 8.

[0101] Case II: Ring U is a 3- to 12-membered heterocycloalkylene group containing 1 to 2 heteroatoms selected from N, O, or S (e.g., a 4- to 8-membered saturated monocyclic heterocycloalkylene group containing 1 or 2 nitrogen heteroatoms), and the 3- to 12-membered heterocycloalkylene group is optionally substituted with a C1-C6 alkyl group (e.g., —CH2OH) substituted with 1, 2, or 3 hydroxy groups; Ring Y is a 3- to 12-membered heterocycloalkylene group containing 1 to 2 heteroatoms selected from N, O, and S (e.g., a bicyclic spiroheterocycloalkylene group), X'' is -C(O)-; Lx is -(CH2) v -, and one or two methylene groups in Lx are optionally -O- and -CR d R e -, v is 1, 2, 3, 4, 5, 6, or 7, and R d , R e are each independently H, NH, or a C-C alkyl group substituted with 1, 2, or 3 halogens (e.g., fluorine) (e.g., —CHCHF or —CHCHCF), or R d and R e form a C3-C8 cycloalkyl group together with the C atom to which they are attached, Ly is -(CH2) k-, wherein one or more hydrogen atoms of the methylene group in Ly are optionally replaced with (for example, one or two) deuterium atoms; and each k is independently 1, 2, 3, 4, 5, 6, 7, or 8.

[0102] Preferably, in some embodiments of the invention, L is LA, [ka] Here, in the above LA, Ring U is C3-C 12 a cycloalkylene group or a 3- to 12-membered heterocycloalkylene group containing 1 to 2 heteroatoms selected from N, O, and S, wherein the cycloalkylene group and heterocycloalkylene group are optionally substituted with a substituent selected from halogen, oxo, cyano, amino, hydroxy, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, or -O-(C1-C6 alkyl); Ring Y is a bond, C3-C 12 a cycloalkylene group or a 3- to 12-membered heterocycloalkylene group containing 1 to 2 heteroatoms selected from N, O, and S, wherein the cycloalkylene group and heterocycloalkylene group are optionally substituted with a substituent selected from halogen, oxo, cyano, amino, hydroxy, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, or -O-(C1-C6 alkyl); X'' is a bond, -C(O)-, -NH-, -NCH3-, -O-, -C(CH3)2-, -S-, -C=C-, -C≡C-, -CHF-, -CHCF3-, or -(CH2) q C(O)-, -S(O)-, -S(O)2-, -C(O)O-, -OC(O)-, -(CH2) q -C(O)NH-, -C(O)NCH3-, -NHC(O)-, -NCH3C(O)- or -C(O)CHO-; q is 1 or 2; Lx is -(CH2) v-, and one or two methylene groups in Lx are optionally -O-, -S-, -NH-, -C≡C-, -N(C1-C6 alkyl)-, -N(C1-C6 haloalkyl)-, -C(O)-, -N(C1-C6 hydroxyalkyl)-, -N(C3-C8 cycloalkyl)- or -CR d R e -, and v is 1, 2, 3, 4, 5, 6, or 7; R d , R e are each independently H, —OH, a C1-C6 alkyl group, or a C1-C6 alkoxy group; Or, R d and R e form a C3-C8 cycloalkyl group or a 3- to 8-membered heterocycloalkyl group together with the C atom connected thereto, Ly is -(CH2) k -, wherein one or two methylene groups in Ly are optionally substituted with one selected from -O-, -NH-, -C≡C-, -N(C1-C6 alkyl)-, -N(C1-C6 haloalkyl)-, -C(O)-, -N(C1-C6 hydroxyalkyl)-, or -N(C3-C8 cycloalkyl)-; and k is 1, 2, 3, 4, 5, 6, 7, or 8.

[0103] Preferably, in some embodiments of the present invention, in ring U, the C3-C 12 The cycloalkylene group is a C3-C6 monocyclic saturated cycloalkylene group or a C6-C 10 and a 7-, 8-, or 9-membered (e.g., 7-, 8-, or 9-membered bicyclic bridged ring) bridged ring cycloalkylene group, such as a cyclohexyl alkylene group or a bicyclo[2.2.2]octyl alkylene group.

[0104] Preferably, in some embodiments of the present invention, in ring U, the 3- to 12-membered heterocycloalkylene group is a 3- to 8-membered (e.g., heterocycloalkylene group, 3-, 4-, 5-, or 6-membered) saturated monocyclic heterocycloalkylene group, a 6- to 10-membered (e.g., 7-, 8-, or 9-membered fused ring) fused heterocycloalkylene group, or a 6- to 10-membered (e.g., 7-, 8-, or 9-membered fused ring) bridged cyclic heterocycloalkylene group, in which the heteroatom is N and the number is 1 or 2, such as an azacyclobutylalkylene group, a pyrrolidinylene group, a piperidinylene group, a piperazinylene group, a hexahydro-1H-pyrrolidine group, a 2,5-diazabicyclo[2.2.1]heptylalkylene group, a 3,8-diazabicyclo[3.2.1]octylalkylene group, or a 3,6-diazabicyclo[3.1.1]heptylalkylene group. Alternatively, the 3- to 12-membered heterocycloalkylene group may be further substituted with an 8-, 9-, or 10-membered bridged cyclic heterocycloalkylene group, in which the heteroatom is N and / or O and the number is 1, 2, or 3, for example [ka] is.

[0105] Preferably, in some embodiments of the present invention, the halogen in the substituent of the ring U is F, Cl, Br or I.

[0106] Preferably, in some embodiments of the present invention, in the substituents of Ring U, the C1-C6 alkyl group and the C1-C6 alkyl group in the -O-(C1-C6 alkyl) are independently a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, or a tert-butyl group.

[0107] Preferably, in some embodiments of the present invention, 1, 2, 3, or 4 hydrogen atoms in the U ring are optionally substituted with a substituent selected from halogen, amino, hydroxy, —O—(C1-C6 alkyl), or a C1-C6 alkyl group. Alternatively, 1, 2, 3, or 4 hydrogen atoms in the U ring may be substituted with a C1-C6 alkyl group further substituted with 1, 2, or 3 hydroxy groups.

[0108] More preferably, in some embodiments of the present invention, one, two, three, or four hydrogen atoms in the U ring are optionally substituted with a group selected from F, —OH, —OCH, —NH, or a methyl group, or one, two, three, or four hydrogen atoms in the U ring may be further substituted with —CHOH.

[0109] Preferably, in some embodiments of the present invention, ring U is [ka] Alternatively, preferably, ring U is [ka] is replaced by

[0110] Preferably, in some embodiments of the present invention, in ring Y, the C3-C 12 The cycloalkylene group is a C3-C6 monocyclic cycloalkylene group, for example, a cyclohexylalkylene group.

[0111] Preferably, in some embodiments of the present invention, in ring Y, the 3- to 12-membered heterocycloalkylene group is a 6- to 8-membered (e.g., 6, 7, or 8-membered) monocyclic heterocycloalkylene group, a 7- to 11-membered (e.g., 7, 8, 9, 10, or 11-membered) spiroheterocycloalkylene group, or a 7- to 11-membered (e.g., 7, 8, 9, 10, or 11-membered) fused heterocycloalkylene group, wherein the heteroatom is N and the number is The heterocycloalkylene group may be substituted with a 7-, 8-, 9-, 10-, or 11-membered spiroheterocycloalkylene group, and the heteroatom may be N and / or O, and the number of heteroatoms may be 1 or 2, such as piperidinylene, piperazinylene, 3-azaspiro[5.5]undecane alkylene, 7-azaspiro[3.5]nonyl alkylene, 2,7-diazaspiro[3.5]nonyl alkylene, 3,9-diazaspiro[5.5]undecyl alkylene, 2,6-diazaspiro[3.3]heptyl alkylene, or 2-azaspiro[3.3]heptyl alkylene. Alternatively, the 3- to 12-membered heterocycloalkylene group may be further substituted with a 7-, 8-, 9-, 10-, or 11-membered spiroheterocycloalkylene group, and the heteroatom may be N and / or O, and the number of heteroatoms may be 1 or 2, such as 2-oxa-9-azaspiro[5.5]undecane.

[0112] Preferably, in some embodiments of the present invention, in the substituent of ring Y, the C1-C6 alkyl groups in the -O-(C1-C6 alkyl) are independently a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, or a tert-butyl group.

[0113] Preferably, in some embodiments of the present invention, ring Y is [ka] Alternatively, preferably, ring Y is further [ka] may be replaced by

[0114] Preferably, in some embodiments of the present invention, in L A, the ring U is a 4-8 membered saturated monocyclic heterocycloalkylene group containing one or two nitrogen heteroatoms, a 6-10 membered fused heterocycloalkylene group, a 6-10 membered bridged cyclic heterocycloalkylene group, or a C6-C 10 wherein ring Y is a 6- to 8-membered saturated monocyclic heterocycloalkylene group containing one or two nitrogen heteroatoms, a 7- to 11-membered spiroheterocycloalkylene group or a fused heterocycloalkylene group containing one or two nitrogen heteroatoms, X″ is a bond or —C(O)—, and Lx is —(CH2) v -, v is 1, 2, 3, 4 or 5, and Ly is -(CH2) k - and k is 1, 2, 3, 4, or 5. In LA, the ring Y may be further substituted with a 7-, 8-, 9-, 10-, or 11-membered spiroheterocycloalkylene group, and the heteroatom is N and / or O, and the number is 1 or 2.

[0115] Preferably, in some embodiments of the present invention, in L-A, ring U is a 4- to 8-membered saturated monocyclic heterocycloalkylene group containing one or two nitrogen heteroatoms, or a 6- to 10-membered fused heterocycloalkylene group; ring Y is a 6- to 8-membered saturated monocyclic heterocycloalkylene group containing one or two nitrogen heteroatoms, or a 7- to 11-membered spiroheterocycloalkylene group or fused heterocycloalkylene group containing one or two nitrogen heteroatoms; X″ is a bond or —C(O)—; and Lx is —(CH) v -, v is 1, 2, 3, 4 or 5, and Ly is -(CH2) k - and k is 1, 2, 3, 4, or 5. In LA, the ring Y may be further substituted with a 7-, 8-, 9-, 10-, or 11-membered spiroheterocycloalkylene group, and the heteroatom is N and / or O, and the number is 1 or 2.

[0116] Preferably, in some embodiments of the present invention, LA is LA-1, LA-2, [ka] X″ is —C(O)— or —C(O)NH—; Here, in the above LA-1 and LA-2, ring U, ring Y, Lx, Ly, and q are as defined and described in accordance with the present invention.

[0117] Preferably, in some embodiments of the present invention, wherein LA is LA-3, LA-4, LA-5 or LA-6; [ka] Here, in the above LA-3, Lx is -(CH2) v wherein one or two CH2 contained in Lx are each independently optionally selected from -O-, -S-, -NH-, -NMe-, or -CR d R e - is replaced by -CR d R e -teeth, [ka] -C(CH3)2-, -CH(CH3)-, -CH(OH)-, -CH(OCH3)-, C(CH3)(OH)- or -C=CH2, and v is 1, 2, 3, 4, 5 or 6; Ring U is [ka] wherein the a-terminus is linked to Lx, the b-terminus is linked to Ly, and 1, 2, 3 or 4 hydrogen atoms in the ring U are optionally replaced with F, —OH, —OCH3, —NH2; Ring Y is a bond, [ka] wherein the c-terminus is linked to Ly, the d-terminus is linked to X″, and 1, 2, 3 or 4 hydrogen atoms in the ring Y are optionally replaced with F, —OH, —OCH3; Ly is -(CH2) k-, wherein one or two CH2 contained in Ly are each independently optionally substituted with -O-, -C≡C-, -C(O)- or -N(C1-C6 alkyl)-, and k is 1, 2, 3, 4, 5 or 6; X'' is a bond, -C(O)-, -(CH2) 1-2 C(O)- or -(CH2) 1-2 C(O)NH-, [ka] Here, in the above LA-4, Lx is -(CH2) v wherein one or two CH2 contained in Lx are each independently optionally selected from -O-, -S-, -NH-, or -CR d R e - is replaced by -CR d R e -teeth, [ka] -C(CH3)2-, -CH(CH3)-, -CH(CH3)-, -CH(CH3)-, -CH(OCH3)-, -CH(OH)-, -C(CH3)(OH)- or -C=CH2, and v is 1, 2, 3, 4, 5 or 6; Ring U is [ka] wherein the a-terminus is linked to Lx, the b-terminus is linked to Ly, and 1, 2, 3 or 4 hydrogen atoms in the ring U are optionally replaced with F (e.g., [ka] ), and ring Y is [ka] wherein the c-terminus is linked to Ly, the d-terminus is linked to X″, and 1, 2, 3 or 4 hydrogen atoms in the ring Y are optionally replaced with F; Ly is -(CH2) k-, wherein one or two CH2 contained in Ly are each independently optionally substituted with -O- or -N(C1-C6 alkyl)-, and k is 1, 2, 3, 4, 5, or 6; X'' is -C(O)-; Alternatively, ring Y may further be [ka] may be replaced by Case B: Lx is -(CH2) v wherein one or two CH2 contained in Lx are each independently optionally selected from -O-, -S-, -NH-, or -CR d R e - is replaced by -CR d R e -teeth, [ka] -CH(NH2)-, -CH(CH2CHF2)-, -CH(CH2CH2CF3)-, or -CH(CH3)2-, and v is 1, 2, 3, 4, 5, or 6; Ring U is [ka] and Ring Y is [ka] is.

[0118] Ly is -(CH2) k -, wherein one or more hydrogen atoms in the methylene group of Ly are optionally substituted with deuterium atoms (e.g., one or two), and k is 1, 2, 3, 4, 5, or 6; X'' is -C(O)-; [ka] Here, in the above LA-5, Lx is -(CH2)v -, wherein one or two CH2 contained in Lx are each independently optionally replaced with -O-, and v is 1, 2, 3, or 4; Ring U is [ka] wherein the a-terminus is linked to Lx, the b-terminus is linked to Ly, and 1, 2, 3 or 4 hydrogen atoms in the ring U are optionally replaced with F; Ring Y is a bond; Ly is -(CH2) k wherein one or two CH2 contained in Ly are each independently optionally replaced by -O-, -C(O)- or -NH-; and k is 1, 2, 3, 4, 5, 6, 7 or 8; X″ is —C(O)NH—; [ka] Here, in the above LA-6, Lx is -(CH2) v wherein one or two CH2 contained in Lx are each independently optionally selected from -O- or -CR d R e - is replaced by -CR d R e -teeth, [ka] and v is 1, 2, 3 or 4; Ring U is [ka] or [ka] wherein the a-terminus is linked to Lx and the b-terminus is linked to Ly; Ring Y is [ka] and Ly is -(CH2) k wherein one or two CH2 contained in Ly are each independently optionally replaced with -O-, -C(O)- or -NH-; and k is 1, 2, 3, 4, 5 or 6; X'' is a bond.

[0119] Preferably, LA has the following structure: [ka] is.

[0120] Preferably, each ring U is independently a 4- to 8-membered saturated monocyclic heterocycloalkylene group or a 6- to 10-membered bridged heterocycloalkylene group containing one or two nitrogen heteroatoms; each ring Y is independently a 3- to 12-membered heterocycloalkylene group containing 1 to 2 heteroatoms selected from N, O, or S, and the heterocycloalkyl group is a monocyclic heterocycloalkylene group or a bicyclic spiroheterocycloalkylene group; X'' is -C(O)-.

[0121] Most preferably, LA has one of the following structures: [ka] The file is TIFF2025536369000176.tif11169.

[0122] Preferably, in some embodiments of the present invention, L A has any one of the following structures: [ka] TIFF2025536369000178.tif198169TIFF2025536369000179.tif212169TIFF2025536369000180.tif212169TIFF2025536369000181.tif224169TIFF2025536369000182.tif212169TIFF2025536369000183.tif197169TIFF2025536369000184.tif60169.

[0123] Preferably, in some embodiments of the invention, E1 has a structure of formula E1-1a, E1-1b, E1-1c, E1-1d, E1-1e, E1-1f, E1-1g, E1-1aa, E1-1h, E1-1bb, E1-1cc, E1-1dd, E1-1ee, E1-1ff, E1-1gg, or E1-1hh; [ka] wherein Q1, Q2, Q3, Q4, Q5, R1'', R2'', R3'', and m'' are as defined and described by the present invention.

[0124] Preferably, in some embodiments of the present invention, E1 has a structure of formula E1-1h'', E1-1i', E1-1j', or E1-1h''h'', [ka] where R 3b is as defined and described by the present invention.

[0125] Preferably, in some embodiments of the present invention, R 3b is hydrogen, halogen, cyano group, -OH, -NH2, C1-C6 alkyl group, C3-C8 cycloalkyl group, 3-8 membered heterocycloalkyl group, -O(C1-C6 alkyl), -O(C3-C8 cycloalkyl), -O(3-8 membered heterocycloalkyl), -N(C1-C6 alkyl) 1-2 , -N(C3-C8 cycloalkyl) 1-2or -S(C1-C6 alkyl), and the above C1-C6 alkyl group, C3-C8 cycloalkyl group, 3- to 8-membered heterocycloalkyl group, -O(C1-C6 alkyl), -O(C3-C8 cycloalkyl) or -O(3- to 8-membered heterocycloalkyl), -N(C1-C6 alkyl) 1-2 , -N(C3-C8 cycloalkyl) 1-2 Or, -S(C1-C6 alkyl) is optionally substituted with 1 to 3 halogens, cyano groups, -OH, and -NH2. Alternatively, the above-mentioned C1-C6 alkyl groups, C3-C8 cycloalkyl groups, 3- to 8-membered heterocycloalkyl groups, -O(C1-C6 alkyl), -O(C3-C8 cycloalkyl) or -O(3- to 8-membered heterocycloalkyl), -N(C1-C6 alkyl) 1-2 , -N(C3-C8 cycloalkyl) 1-2 and -S(C1-C6 alkyl) may be further optionally substituted with 1, 2, or 3 deuterium atoms.

[0126] Preferably, in some embodiments of the present invention, E1 is [ka] The file is TIFF2025536369000188.tif96169.

[0127] Preferably, in some embodiments of the invention, E2 has the structure of formula E2-1a, E2-1b, E2-1c, E2-1d, E2-1e, or E2-1f: [ka] and Here, in the above E2-1a, E2-1b, E2-1c, E2-1d, E2-1e, and E2-1f, W is CR 1c R 2c , C(S), C(O) or SO2; X is CH, O or S; Y 2 is NH, -N-C1-C6 alkyl group, -N-C6-C 10an aryl group, an —N-5 to 10-membered heteroaryl group, an —N-C3-C8 cycloalkyl group, an —N-3 to 8-membered heterocycloalkyl group, O, or S; Z is CH, O or S; G" and G' are each independently selected from hydrogen, deuterium, a C1-C6 alkyl group, OH, a C3-C6 cycloalkyl group, a -CH2-heterocycloalkyl group, or a -CH2-phenyl group, and the C1-C6 alkyl group, C3-C6 cycloalkyl group, -CH2-heterocycloalkyl group, or -CH2-phenyl group is optionally substituted with 1 to 3 groups independently selected from a hydroxy group, a halogen atom, a cyano group, and an amino group; Q1, Q2, Q3, and Q4 are each independently CR 3b or N, A' is hydrogen, deuterium, a C1-C6 alkyl group, a C3-C6 cycloalkyl group, or halogen; R 1c , R 2c and R 3c are each independently hydrogen, a hydroxy group, a halogen atom, -NH2, or -N(C1-C6 alkyl). 1-2 , C1-C6 alkyl group, C1-C6 alkoxy group, C1-C6 haloalkyl group, -CONR ' R '' , -OR ' , -NR ' R '' , -SR ' , -SO2R ' , -SO2NR ' R '' , -CR ' R '' , -CR ' NR ' R '' , aryl group, heteroaryl group, C3-C8 cycloalkyl group, 3-8 membered heterocycloalkyl group, -P(O)(OR ' )R '' , -P(O)R ' R '' , -OP(O)(OR ' )R '' , -Cl, -F, -Br, -I, -CF3, -CN, -NR ' SO2NR' R '' , -NR ' C(O)NR ' R '' , -C(O)NR ' C(O)R '' , -NR ' C(=N-CN)NR ' R '' , -C(=N-CN)NR ' R '' , -NR ' C(=N-CN)R '' , -NR ' C(=C-NO2)NR ' R '' , -SO2NR ' COR '' , -NO2, -COR ' , -C(C=N-OR ' )R '' , -CR ' =CR ' R '' , -CCR ' , -S(C=O)(C=NR ' )R '' , -SF5 or -OCF3, R ' and R '' are each independently a bond, hydrogen, deuterium, a C1-C6 alkyl group, a C3-C8 cycloalkyl group, a C6-C 10 an aryl group, a 5- to 10-membered heteroaryl group, or a 3- to 8-membered heterocycloalkyl group, n '' is 0, 1, 2 or 3, [ka] is a bond, which may be an R stereoisomer, an S stereoisomer, or a non-stereoisomer; where R 3b is as described and defined by the present invention.

[0128] Preferably, in some embodiments of the invention, E2 has the structure of formula E2-1bb, E2-1aa, or E2-1cc: [ka] Here, in the above E2-1bb, Q1, Q2, Q3 and Q4 are each independently CR 3b or N, W is C(O) or CH2; A' is hydrogen, deuterium, a C1-C6 alkyl group or halogen; R 3c is hydrogen, deuterium, hydroxyl group, halogen, -NH2, -N(C1-C6 alkyl) 1-2 , a C1-C6 alkyl group, a C1-C6 alkoxy group, or a C1-C6 haloalkyl group; n '' is 0, 1, 2 or 3, [ka] is a bond, which may be an R stereoisomer, an S stereoisomer, or a non-stereoisomer; where R 3b is as described and defined by the present invention; [ka] Here, in the above E2-1aa or E2-1cc, W is CH2 or C(O); A' is hydrogen, a methyl group, Cl or F; R 3c are each independently hydrogen, halogen, cyano, hydroxy, NH, C-C alkyl, or C-C alkoxy; n '' is 0, 1, 2 or 3, [ka] is a bond, which may be the R stereoisomer, the S stereoisomer, or a non-stereoisomer.

[0129] Preferably, in some embodiments of the present invention, E2 is [ka] TIFF2025536369000196.tif214169TIFF2025536369000197.tif197169TIFF2025536369000198.tif198169TIFF2025536369000199.tif194169TIFF2025536369000200.tif225169TIFF2025536369000201.tif79169.

[0130] Preferably, in some embodiments of the present invention, E3 has the structure of formula E3-1: [ka] W 3 is C6-C 10 an aryl group, a 5- to 10-membered heteroaryl group, or [ka] wherein the aryl group and heteroaryl group are optionally substituted; R 9 , R 10 are each independently selected from hydrogen, a C1-C6 alkyl group, a C3-C8 cycloalkyl group, or a 5-10 membered heteroaryl group, and the C1-C6 alkyl group, C3-C8 cycloalkyl group, or 5-10 membered heteroaryl group is optionally substituted with one or more -OH, halogen, or -NH2; Or, R 9 , R 10 together with the carbon atoms to which they are attached form a C3-C8 cycloalkyl group, said C3-C8 cycloalkyl group optionally substituted with -OH, halogen, -NH2 or a C1-C3 alkyl group; R 11 represents a C1-C6 alkyl group, a C1-C6 alkoxy group, a 3- to 8-membered heterocycloalkyl group, a C6-C 10 an aryl group, a 5- to 10-membered heteroaryl group, or [ka] and selected from the above C1-C6 alkyl groups, C1-C6 alkoxy groups, 3- to 8-membered heterocycloalkyl groups, C6-C 10 the aryl group or 5- to 10-membered heteroaryl group is optionally substituted with one or more -OH, halogen, or -NH; R 12 is selected from H, C(O) or a substituted alkyl group; R 13 is selected from H, a C1-C6 alkyl group, -alkylCO-, -(cycloalkyl)alkylCO-, -aralkylCO-, -arylCO-, -(heterocycloalkyl)CO- or an arylalkyl group, wherein said alkyl group, -alkylCO-, -(cycloalkyl)alkylCO-, -aralkylCO-, -arylCO-, -(heterocycloalkyl)CO- or arylalkyl group is optionally substituted; R 16 is H, halogen, —OH, a C1-C6 alkyl group or a C1-C6 alkoxy group, wherein the C1-C6 alkyl group or the C1-C6 alkoxy group is optionally substituted with halogen; o is 1, 2, 3 or 4; where R 8d , R 14a , R 14b , R 15 is as described and defined by the present invention.

[0131] Preferably, in some embodiments of the invention, E3 has the structure of formula E3-1a, E3-1b, or E3-1c: [ka] where: R 1d is H, ethyl, isopropyl, tert-butyl, sec-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, alkyl, hydroxyalkyl, heteroaryl or haloalkyl, wherein the alkyl, hydroxyalkyl or heteroaryl group is optionally substituted; R 6dis H, —CH, —CHF, —CHOH, an ethyl group, an isopropyl group, or a cyclopropyl group, R 8d H, halogen, CN, OH, NO2, C6-C 10 an aryl group, a 5- to 10-membered heteroaryl group, a C1-C6 alkyl group, a C1-C6 alkoxy group, a C3-C8 cycloalkyl group, or a 3- to 8-membered heterocycloalkyl group; 10 the aryl group, the 5- to 10-membered heteroaryl group, the C1-C6 alkyl group, the C1-C6 alkoxy group, the C3-C8 cycloalkyl group or the 3- to 8-membered heterocycloalkyl group is optionally substituted with a halogen, —OH, CN, NO2 or amino group; X d is CH2 or C(O), R d is a 5- to 6-membered heteroaryl group, and the 5- to 6-membered heteroaryl group is optionally substituted.

[0132] Preferably, in some embodiments of the invention, E3 has the structure of formula E3-1aa: [ka] where: R 6d is H, —CH, —CHF, —CHOH, an ethyl group, an isopropyl group, or a cyclopropyl group, R 9 is H, R 10 is H, ethyl, isopropyl, tert-butyl, sec-butyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; R 11 teeth, [ka] or a 5- to 10-membered heteroaryl group, which is optionally substituted with one or more -OH, halogen, or -NH; R 12 is H or C(O), R 13 is H, an alkyl group, -alkylCO-, -(cycloalkyl)alkylCO-, -aralkylCO-, -arylCO-, -(heterocycloalkyl)CO- or an arylalkyl group, wherein said alkyl group, -alkylCO-, -(cycloalkyl)alkylCO-, -aralkylCO-, -arylCO-, -(heterocycloalkyl)CO- or arylalkyl group is optionally substituted; R 8d is H, halogen, CN, OH, NO2, nn, [ka] is.

[0133] More preferably, formula E3-1aa is R 12 Connects to L via

[0134] Preferably, in some embodiments of the present invention, E3 is [ka] The file is TIFF2025536369000210.tif212169.

[0135] Preferably, in some embodiments of the present invention, E3 is [ka] The file is TIFF2025536369000212.tif161169.

[0136] In one preferred embodiment of the present invention, in the compound of formula I or I', G1 is [ka] and G1' is [ka] and L is [ka] and E is independently E1 [ka] and R 1a' , R 3e , R 4e , R 5e , X', Y', each R a , R 2a' , J1, J2, Lx, Ly, Ring U, Ring Y, X'', Q1, Q2, Q3, Q4, Q5, X 2' , Y 2' , R 1b , R 2b , Z′ and m″ are all defined as above.

[0137] In one preferred embodiment of the present invention, In the compounds of formula II or I' above, G1 is [ka] and G1' is [ka] and R 1a teeth, [ka] and L is [ka] and Lx is -(CH2) v -, and the two methylene groups in Lx are -O- and -CR d R e - is replaced by a member selected from R d and R eare each independently H, a C1-C6 alkyl group, a C1-C6 alkoxy group, NH2, or a C1-C6 alkyl group substituted with 1, 2, or 3 halogens, or R d and R e form a C3-C8 cycloalkyl group together with the C atom to which they are attached, v is 1, 2, 3, 4, 5, 6, or 7; Ring U is a 3- to 12-membered heterocycloalkylene group containing 1 to 2 N heteroatoms; Ly is -(CH2) k -, wherein one or two methylene groups in Ly are optionally replaced by -O-, and k is 1, 2, 3, 4, 5, 6, 7, or 8; Ring Y is a 3- to 12-membered heterocycloalkylene group containing 1, 2, or 3 heteroatoms selected from N and O, X'' is -C(O)-; E is [ka] and Each R a , R 2a , R 2a' , J1, J2, n and each R 3b The definition of is as described above.

[0138] Preferably, Each R 2a and R 2a' are independently a halogen, a hydroxy group, a C1-C6 alkyl group, or a C2-C6 alkynyl group; R a is a halogen, L is one of the following structures: [ka] TIFF2025536369000223.tif204169TIFF2025536369000224.tif104169, R 3bis a halogen, a C1-C6 alkyl group or -O-(C1-C6 alkyl), and the C1-C6 alkyl group or -O-(C1-C6 alkyl) is optionally substituted with 1 to 3 independently selected from deuterium or halogen. Preferably, in one preferred embodiment of the present invention, in the compound of formula I or I' above, G1 is [ka] and G1' is [ka] and R 1a teeth, [ka] and L is [ka] and Lx is -(CH2) v -, and the two methylene groups in Lx are -O- and / or -CR d R e - is replaced by a member selected from R d and R e are each independently a C1-C6 alkyl group, or R d and R e form a C3-C8 cycloalkyl group together with the C atom to which they are attached, v is 1, 2, 3, 4, 5, 6, or 7; Ring U is a 3- to 12-membered heterocycloalkylene group containing 1 to 2 N heteroatoms; Ly is -(CH2) k -, wherein one or two methylene groups in Ly are optionally replaced by -O-, and k is 1, 2, 3, 4, 5, 6, 7, or 8; Ring Y is a 3- to 12-membered heterocycloalkylene group containing 1 or 2 heteroatoms selected from N; X'' is -C(O)-; E is [ka] is.

[0139] More preferably, Each R 2a and R 2a' are independently a halogen, a hydroxy group, a C1-C6 alkyl group, or a C2-C6 alkynyl group; R a is a halogen, L is a compound having one of the following structures: [ka] R 3b are each independently hydrogen, a C1-C6 alkyl group, or —O—(C1-C6 alkyl).

[0140] Preferably, in some embodiments of the present invention, the compound of formula I or I' is [ka] TIFF2025536369000232.tif207169TIFF2025536369000233.tif205169TIFF2025536 369000234.tif221169TIFF2025536369000235.tif206169TIFF2025536369000236.ti f218169TIFF2025536369000237.tif224169TIFF2025536369000238.tif211169TIFF2 025536369000239.tif207169TIFF2025536369000240.tif205169TIFF2025536369000 241.tif219169TIFF2025536369000242.tif217169TIFF2025536369000243.tif2181 69TIFF2025536369000244.tif217169TIFF2025536369000245.tif212169TIFF202553 6369000246.tif213169TIFF2025536369000247.tif206169TIFF2025536369000248.tif205169TIFF2025536369000249.tif219169TIFF2025536369000250.tif219169.

[0141] The present invention further provides a compound of formula W-1, W-2, W-3, W-4, W-5, INTA, INTA', INTC or INTC', [ka] Here, rings C and R 2e , R 3e , R 4e , R 5e , R 1b , R 2b , R 3b , W 1 , W 2, X', Y', J1, J2, L and E are as defined and described by the present invention, the definitions of Lx, ring U, Ly and ring Y and the connection relationships therebetween are as defined and described by the present invention, p'' is 1, 2, 3 or 4, and n2 is 1 or 2.

[0142] Preferably, formula W-1 is formula W-1-1, formula W-2 is formula W-2-1, formula W-3 is formula W-3-1, formula W-4 is formula W-4-1, or formula W-5 is formula W-5-1; [ka] Here, rings C and R 2e , R 3e , R 4e , R 5e , R 1b , R 2b , R 3b , W 1 , W 2 , Lx, ring U, Ly and ring Y and p'' are as defined and described by the present invention.

[0143] Preferably, the compound represented by the above formula W-1, W-2, W-3, W-4 or W-5 is [ka] Selected from TIFF2025536369000254.tif206169TIFF2025536369000255.tif87169.

[0144] The present invention further provides a compound of formula II-1, II-2 or II-3: [ka] Here, each R 1a are independently [ka] and each R 19 independently an amino protecting group (e.g., -Boc), and R 17and each R 18 are independently a hydroxy protecting group (e.g., -MOM), and the definitions of J1, J2, L and E are all as described above.

[0145] The compound of formula II-1, II-2 or II-3 above is preferably any one of the following compounds: [ka] TIFF2025536369000259.tif228169TIFF2025536369000260.tif199169TIFF2025536369000261.tif215169TIFF2025536369000262.tif224169TIFF2025536369000263.tif211169TIFF2025536369000264.tif205169TIFF2025536369000265.tif30169

[0146] The present invention provides methods for preparing compounds of Formula I or I', and / or their stereoisomers, enantiomers, diastereoisomers, atropisomers, deuterated forms, hydrates, solvates, metabolites, prodrugs, and / or pharmaceutically acceptable salts thereof.

[0147] The present invention provides pharmaceutical compositions comprising a therapeutically effective amount of a compound of Formula I or I', and / or its stereoisomers, enantiomers, diastereoisomers, atropisomers, deuterated forms, hydrates, solvates, prodrugs, and / or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier, diluent, or excipient.

[0148] The present invention provides a method for degrading KRAS G12D protein, the method comprising contacting a compound of formula I or I', and / or its stereoisomers, enantiomers, diastereoisomers, atropisomers, deuterated forms, hydrates, solvates, metabolites, prodrugs, and / or pharmaceutically acceptable salts thereof, or a pharmaceutical composition thereof, with KRAS G12D protein.

[0149] The present invention provides use of a compound of formula I or I' above, and / or its stereoisomers, enantiomers, diastereoisomers, atropisomers, deuterated forms, hydrates, solvates, metabolites, prodrugs, and / or pharmaceutically acceptable salts thereof, or a pharmaceutical composition thereof, as a drug for treating or preventing a KRAS G12D-mediated disease or condition.

[0150] The present invention provides use of a compound of the above formula I or I', and / or its stereoisomer, enantiomer, diastereoisomer, atropisomer, deuterated form, hydrate, solvate, metabolite, prodrug, and / or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, as a drug for treating or preventing a KRAS mutation-mediated disease or condition.

[0151] The present invention provides the use of the compound of the above formula I or I', and / or its stereoisomer, enantiomer, diastereoisomer, atropisomer, deuterated form, hydrate, solvate, metabolite, prodrug, and / or pharmaceutically acceptable salt thereof, or pharmaceutical composition thereof, in the manufacture of a medicament for treating or preventing a KRAS mutation-mediated disease or condition.

[0152] The present invention provides the use of the compound of the above formula I or I', and / or its stereoisomer, enantiomer, diastereoisomer, atropisomer, deuterated product, hydrate, solvate, metabolite, prodrug, and / or pharmaceutically acceptable salt thereof, or pharmaceutical composition thereof, in the manufacture of a medicament for treating or preventing a disease or condition (cancer) caused by the interaction between KRAS G12D and SOS1 or SHP2 protein.

[0153] The present invention provides the use of a compound of formula I or I', and / or its stereoisomers, enantiomers, diastereoisomers, atropisomers, deuterated forms, hydrates, solvates, metabolites, prodrugs, and / or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, in the manufacture of a medicament for treating or preventing cancer.

[0154] The present invention provides the use of a compound of Formula I or I', and / or a stereoisomer, enantiomer, diastereoisomer, atropisomer, deuteride, hydrate, solvate, metabolite, prodrug, and / or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the manufacture of a medicament for treating or preventing pancreatic cancer, lung cancer, colorectal cancer, cholangiocarcinoma, multiple myeloma, melanoma, uterine cancer, endometrial cancer, thyroid cancer, acute myeloid leukemia, bladder cancer, urothelial cancer, gastric cancer, cervical cancer, head and neck squamous cell carcinoma, diffuse large B-cell lymphoma, esophageal cancer, chronic lymphocytic leukemia, hepatocellular carcinoma, breast cancer, ovarian cancer, prostate cancer, glioblastoma, kidney cancer, and sarcoma (e.g., the above diseases or conditions are caused by the interaction between KRAS G12D and SOS1 or SHP2 protein).

[0155] The present invention provides a method for treating or preventing a KRAS G12D-mediated disease or condition, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula I or I', and / or its stereoisomers, enantiomers, diastereoisomers, atropisomers, deuterated forms, hydrates, solvates, metabolites, prodrugs, and / or pharmaceutically acceptable salts thereof, or a pharmaceutical composition thereof.

[0156] The present invention provides methods for treating or preventing a disease or condition (e.g., cancer) modulated by the interaction of KRAS G12D with SOS1 or SHP2 proteins, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula I or I', and / or its stereoisomers, enantiomers, diastereoisomers, atropisomers, deuterated forms, hydrates, solvates, metabolites, prodrugs, and / or pharmaceutically acceptable salts thereof, or a pharmaceutical composition thereof.

[0157] In certain embodiments of the invention, the cancer is Heart: sarcomas (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma group, Lung: Bronchial carcinoma (squamous cell carcinoma, undifferentiated small cell carcinoma, undifferentiated large cell carcinoma, adenocarcinoma), alveolar carcinoma (bronchiolar carcinoma), bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma, Gastrointestinal tract: esophageal cancer (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, vasoactive intestinal peptide tumor), small intestine (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, fibroneuroma, fibroma), large intestine (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma), Urinary system: kidney (adenocarcinoma, embryonal carcinosarcoma (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratoma, choriocarcinoma, sarcoma, mesenchymal cell carcinoma, fibroma, fibroadenoma, adenomatous tumor, lipoma), Liver: liver cancer (hepatocellular carcinoma), small hepatic bile duct carcinoma, hepatoblastoma, malignant hemangioendothelial tumor, hepatocellular adenoma, hemangioma, Biliary tract: bile duct cancer, gallbladder cancer, ampullary cancer, small hepatic bile duct cancer, Bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor, chordoma, chondroma (osteochondral exogenous bone disease), benign chondroma, chondroblastoma, chondromyxoid fibroma, osteoid osteoma and giant cell tumor, Nervous system: skull (osteoma, hemangioma, granuloma, xanthomas, osteitis teratoides), meninges (meningioma, meningeal sarcoma, glioma), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumor (pineal tumor), glioblastoma multiforme, oligodendroglioma, schwannoma, eye cancer, congenital tumor), spinal cord neurofibroma, meningioma, glioma, sarcoma), Gynecology: Uterus (endometrial cancer (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-theca cell tumor, ovarian Sertoli-Leydig cell tumor, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, carcinoma in situ, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botulinum sarcoma (embryonal rhabdomyosarcoma), fallopian tube (cancer), Hematology: Blood (myeloid leukemia (acute and chronic), acute lymphocytic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelohyperplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma), Skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, dysplastic nevus, lipoma, hemangioma, dermatofibroma, keloid, psoriasis, Adrenal gland: Selected from neuroblastoma.

[0158] In certain embodiments of the invention, the cancer is a KRAS G12D-associated cancer.

[0159] In certain embodiments of the invention, the cancer is non-small cell lung cancer, small cell lung cancer, colorectal cancer, rectal cancer or pancreatic cancer.

[0160] The present invention further provides a compound of the above formula I or I', a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer, or a pharmaceutically acceptable salt of the atropisomer, for treating a disease or condition associated with a KRAS G12D mutant protein.

[0161] The present invention further provides a compound of the above formula I or I', wherein the disease or condition associated with KRAS G12D mutant protein is a cancer associated with KRAS G12D mutant protein.

[0162] In certain embodiments of the invention, the cancer is selected from pancreatic cancer, colorectal cancer, endometrial cancer or lung cancer.

[0163] In certain embodiments of the invention, the lung cancer is selected from non-small cell lung cancer or small cell lung cancer. The present invention provides methods for preparing compounds of Formula I or I', and / or their stereoisomers, enantiomers, diastereoisomers, atropisomers, deuterated forms, hydrates, solvates, metabolites, prodrugs, and / or pharmaceutically acceptable salts thereof.

[0164] G [ka] and L is LA [ka] and ring U contains an NH group, the preparation method may comprise: [ka] and G1' [ka] and L is LA [ka] and ring U contains an NH group, the preparation method may comprise: [ka] and INT-A (INT-A') is subjected to reductive amination with INT-B to obtain the target compound, wherein the reducing reagent for the reductive amination includes, but is not limited to, Pd / C, sodium borohydride, sodium cyanoborohydride, borane, and sodium triacetoxyborohydride. [ka] refers to the ring U containing the NH group, and R 3e , R 4e , R 5e , X', Y', n2, R 1a' is as defined and described by G1-I-a1; [ka] refers to Lx containing an aldehyde group, wherein ring U, ring Y, X″, Lx, Ly are as defined by LA, and E is as defined and described by the present invention, preferably E is E1-1a, E1-1b, E1-1c, E1-1d, E1-1e, E1-1f, E1-1g, E1-1aa, E1-1h, E1-1bb, E1-1cc, E1-1dd, E1-1ee, E1-1ff, E1-1gg or E1-1hh.

[0165] G [ka] and L is LA [ka] and ring Y contains an NH group and X″ is C(O), the preparation method comprises: [ka] and G1' [ka] and L is LA [ka] and ring Y contains an NH group and X″ is C(O), the preparation method comprises: [ka] and INT-C (or INT-C') is subjected to a substitution reaction with INT-D under basic conditions to give the target compound, where the base includes, but is not limited to, triethylamine, N,N-diisopropylethylamine, potassium carbonate, sodium carbonate, and sodium bicarbonate. [ka] refers to the ring Y containing the NH group, and P 100is a pentafluorophenyl group or a p-nitrophenyl group, and R 3e , R 4e , R 5e , X', Y', n2, R 1a' are as defined and described by G1-I-a1, ring U, ring Y, X'', Lx, Ly are as defined by LA, and E is as defined and described by the present invention, preferably E is E1-1a, E1-1b, E1-1c, E1-1d, E1-1e, E1-1f, E1-1g, E1-1aa, E1-1h, E1-1bb, E1-1cc, E1-1dd, E1-1ee, E1-1ff, E1-1gg or E1-1hh.

[0166] G is any other structure in the specification and L is LA [ka] In this case, the manufacturing method is the same as above.

[0167] DETAILED DESCRIPTION: Unless stated to the contrary, the following terms used in the specification and claims have the following meanings.

[0168] The term "alkyl group" refers to a saturated aliphatic hydrocarbon group including a straight-chain or branched-chain alkyl group, for example, a C1-C8 alkyl group refers to an alkyl group containing 1 to 8 carbon atoms, and the C1-C8 alkyl group includes a C1-C2, C1-C3, C1-C4, C1-C5, C2-C3 or C2-C4 alkyl group, such as a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a tert-butyl group, a sec-butyl group, an n-pentyl group, a 1,1-dimethylpropyl group, a 1,2-dimethylpropyl group, a 2,2-dimethylpropyl group, a 1-ethylpropyl group, a 2-methylbutyl group, a 3-methylbutyl group, an n-hexyl group, a 1-ethyl-2-methylpropyl group, a 1,1,2-trimethylpropyl group, a 1,1-dimethylbutyl group, a 1,2-dimethylbutyl group, a 2,2-dimethylbutyl group, a 1,3-dimethylbutyl group, a 2-ethylbutyl group, a 2-methyl ... butyl pentyl group, 3-methylpentyl group, 4-methylpentyl group, 2,3-dimethylbutyl group, n-heptyl group, 2-methylhexyl group, 3-methylhexyl group, 4-methylhexyl group, 5-methylhexyl group, 2,3-dimethylpentyl group, 2,4-dimethylpentyl group, 2,2-dimethylpentyl group, 3,3-dimethylpentyl group, 2-ethylpentyl group, 3-ethylpentyl group, n-octyl group, 2,3-dimethylhexyl group, The alkyl group may be 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, or various branched chain isomers thereof, preferably a C1-C6 alkyl group, more preferably a C1-C4 alkyl group. The alkyl group may be substituted or unsubstituted. In some embodiments, the alkyl group is a C1, C2, C3, C4, C5, C6, C7, or C8 alkyl group.

[0169] "Heteroalkyl group" refers to a saturated aliphatic hydrocarbon group, including a straight-chain or branched-chain heteroalkyl group, in which a methylene group (-CH2-) is replaced with a heteroatom (e.g., O, S, N), a heteroatom group (e.g., -C(O)-, -S(O)-, -S(O)2-, -C(O)O-, -OC(O)-), C(O)NH-, -NHC(O)-, a vinylidene group, or an ethynylene group, and a C1-C8 heteroalkyl group refers to an alkyl group containing 1 to 8 carbon atoms, in which at least one of the methylene groups is replaced with a heteroatom (e.g., O, S, N), a heteroatom group (e.g., -C(O)-, -S(O)-, -S(O)2-, -C(O)O-, -OC(O)-), a C1-C8 heteroalkyl group refers to an alkyl group containing 1 to 8 carbon atoms, in which at least one of the methylene groups is replaced with a heteroatom (e.g., O, S, N), a heteroatom group (e.g., -C(O)-, -S(O)-, -C(O)O-, -OC(O)-), a vinylidene group, or an ethynylene group. is substituted with a heteroatom or heteroatom group, such as -C(O)-CH3, -CH2-O-CH3, -CH2-S-CH3, -CH2-S(O)-CH3, -CH2-S-CH2-CH3, -CH2-O-CH2-CH3, -CH2-O-CH2-CH3, -CH2-S(O)-CH2-CH3, or various branched chain isomers thereof, preferably a C1-C6 heteroalkyl group, more preferably a C1-C4 heteroalkyl group. The heteroalkyl group may be substituted or unsubstituted. In some embodiments, the heteroalkyl group is a C1, C2, C3, C4, C5, C6, C7, or C8 heteroalkyl group.

[0170] Unless otherwise specified, the number of atoms on a ring is usually defined as the number of members in the ring, for example, a "5- to 7-membered ring" refers to a "ring" with 5 to 7 atoms arranged around it.

[0171] Unless otherwise specified, C n-n+m or C n -C n+m includes any one specific situation of n to n+m carbons, for example, C 1-12 are C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 , C 11 , and C 12 and any one of the ranges n to n+m, for example, C 1-12 is C 1-3 , C 1-6 , C 1-9 , C 3-6 , C 3-9 , C 3-12 , C 6-9 , C 6-12, and C 9-12 Similarly, n- to n+m-membered rings means that the number of atoms on the ring is n to n+m. For example, a 3- to 12-membered ring includes a 3-membered ring, a 4-membered ring, a 5-membered ring, a 6-membered ring, a 7-membered ring, an 8-membered ring, a 9-membered ring, a 10-membered ring, an 11-membered ring, and a 12-membered ring, and also includes any one range of n to n+m. For example, a 3- to 12-membered ring includes a 3- to 6-membered ring, a 3- to 9-membered ring, a 5- to 6-membered ring, a 5- to 7-membered ring, a 6- to 7-membered ring, a 6- to 8-membered ring, and a 6- to 10-membered ring.

[0172] "Cycloalkyl group" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, including "C3-C 11 "Cycloalkyl group" refers to a cycloalkyl group containing 3 to 11 carbon atoms, and includes the above C3-C 11 Cycloalkyl groups are C3-C 11 , C3-C 10 , C3-C8, C4-C 11 , C4-C 10 , C4-C8, C4-C7, C4-C6 or C4-C5, etc.; "C3-C8 membered cycloalkyl group" refers to a cycloalkyl group containing 3 to 8 carbon atoms, and the C3-C8 cycloalkyl group includes C3-C8, C3-C6, C3-C5, C4-C8, C4-C7, C4-C6 or C4-C5, etc.; Non-limiting examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentene, cyclohexyl, cyclohexene, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl groups, etc., preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl groups, preferably C3-C8 membered cycloalkyl groups, more preferably C3-C6 membered cycloalkyl groups.

[0173] Polycyclic cycloalkyl groups include spirocyclic, fused-ring, and bridged-ring cycloalkyl groups. "Spirocycloalkyl groups" refer to polycyclic groups in which single rings share one carbon atom (called a spiro atom), which may contain one or more double bonds, but none of the rings has a completely conjugated π-electron system. Depending on the number of spiro atoms shared between the rings, spirocycloalkyl groups are classified as monospirocycloalkyl groups, bisspirocycloalkyl groups, or polyspirocycloalkyl groups, with 7- to 12-membered bisspirocycloalkyl groups being preferred. Non-limiting examples of spirocycloalkyl groups include: [ka] Includes:

[0174] "Fused cycloalkyl group" refers to an all-carbon polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with another ring in the system, where one or more rings may contain one or more double bonds, but no ring has a completely conjugated π-electron system. Depending on the number of rings, fused cycloalkyl groups can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic, with bicyclic fused cycloalkyl groups being preferred. Non-limiting examples of fused cycloalkyl groups include: [ka] Includes:

[0175] "Bridged-ring alkyl group" refers to an all-carbon polycyclic group in which any two rings share two carbon atoms that are not directly connected, and may contain one or more double bonds, but no ring has a completely conjugated π-electron system, and can be classified as a bicyclic, tricyclic, tetracyclic, or polycyclic bridged-ring alkyl group depending on the number of rings it comprises. Non-limiting examples of bridged-ring alkyl groups include: [ka] Includes:

[0176] The cycloalkyl ring may be fused to an aryl group, a heteroaryl group, or a heterocycloalkyl ring, where the ring connected to the parent structure is a cycloalkyl group ring, non-limiting examples include indanyl, tetrahydronaphthyl, benzocycloheptanyl, etc. The cycloalkyl group may be optionally substituted or unsubstituted.

[0177] In some embodiments, the cycloalkyl group is selected from the group consisting of C, ... 10 , C 11 , C 12 Mono- or polycyclic (eg, spirocyclic, fused or bridged) cycloalkyl groups.

[0178] "Heterocycloalkyl group" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent in which one or more (e.g., 2, 3, 4, or 5) ring atoms are nitrogen, oxygen, or S(O). r(where r is an integer 0, 1, or 2), but does not include the ring moieties -OO-, -OS-, or -SS-, and the remaining ring atoms are carbon, wherein the nitrogen atom is optionally quaternized and the nitrogen and sulfur heteroatoms may be optionally oxidized (i.e., NO and S(O)p, where p is 1 or 2). A "3- to 11-membered heterocycloalkyl group" refers to a cyclyl group containing 3 to 11 ring atoms, a "5- to 10-membered heterocycloalkyl group" refers to a cyclyl group containing 5 to 10 ring atoms, and a "3- to 8-membered heterocycloalkyl group" refers to a cyclyl group containing 3 to 8 ring atoms, preferably a "3- to 11-membered heterocycloalkyl group" containing 1 to 2 heteroatoms selected from N, O, or S, and more preferably a 3- to 11-membered heterocycloalkyl group containing 1 or 2 N atoms. For example, a 3- to 10-membered heterocycloalkyl group includes 3- to 8-membered, 3- to 6-membered, 3- to 5-membered, 4- to 6-membered, 5- to 6-membered, 4-membered, 5-membered, and 6-membered heterocycloalkyl groups. Specific examples of the 3- to 10-membered heterocycloalkyl group include an azetidinyl group, an oxetanyl group, a thiacyclobutyl group, a pyrrolidinyl group, a pyrazolyl group, an imidazolidine group, a tetrahydrothiophene group (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl), a tetrahydrofuran group (including tetrahydrofuran-2-yl), a tetrahydropyranyl group, a piperidinyl group (including 1-piperidinyl, 2-piperidinyl, and 3-piperidinyl). 1,2-oxazinyl, 1,2-thiazide, hexahydropyridazinyl, homopiperazinyl, homopiperidinyl, or dioxepane group.

[0179] The monocyclic heterocycloalkyl group is preferably a 3- to 8-membered monocyclic heterocycloalkyl group containing 1 to 2 N heteroatoms, and non-limiting examples of the monocyclic heterocycloalkyl group include a pyrrolidinyl group, a piperidinyl group, a piperazinyl group, a morpholinyl group, a thiomorpholinyl group, a homopiperazinyl group, etc., and preferably a piperidinyl group or a piperazinyl group.

[0180] Polycyclic heterocycloalkyl groups include spirocyclic, fused-ring, and bridged-ring heterocycloalkyl groups. A "spiroheterocycloalkyl group" refers to a polycyclic heterocycloalkyl group that shares one atom (referred to as a spiroatom) between the rings, where one or more ring atoms is nitrogen, oxygen, or S(O). r (where r is an integer selected from 0, 1, and 2), and the remaining ring atoms are carbon. They may contain one or more double bonds, but none of the rings has a completely conjugated π-electron system. Spirocycloalkyl groups are classified as monospiroheterocycloalkyl groups, bisspiroheterocycloalkyl groups, or polyspiroheterocycloalkyl groups depending on the number of spiro atoms shared by the rings. Preferred are saturated "3- to 11-membered bisspiroheterocycloalkyl groups" containing 1 to 2 heteroatoms selected from N, O, or S, and more preferred are saturated "7- to 11-membered bisspiroheterocycloalkyl groups" containing 1 or 2 N atoms. Non-limiting examples of spiroheterocycloalkyl groups include: [ka] Includes:

[0181] "Fused heterocycloalkyl group" refers to a polycyclic heterocycloalkyl group in which each ring in the system shares an adjacent pair of atoms with another ring in the system, one or more rings may contain one or more double bonds, but no ring has a completely conjugated pi-electron system, and wherein one or more ring atoms is nitrogen, oxygen, or S(O) r(where r is an integer selected from 0, 1, and 2), and the remaining ring atoms are carbon. Depending on the number of rings constituting the heterocycloalkyl group, it can be divided into bicyclic, tricyclic, tetracyclic, and polycyclic fused heterocycloalkyl groups, and is preferably a "3- to 11-membered bicyclic fused heterocycloalkyl group" containing 1 to 3 heteroatoms selected from N, O, and S, and more preferably a saturated "3- to 11-membered bicyclic fused heterocycloalkyl group" containing 1 or 2 N atoms. Non-limiting examples of fused heterocycloalkyl groups include: [ka] Includes:

[0182] A "bridged heterocycloalkyl group" refers to a polycyclic heterocycloalkyl group in which any two rings share two atoms that are not directly connected, and may contain one or more double bonds, but no ring has a completely conjugated pi-electron system, and in which one or more ring atoms is not nitrogen, oxygen, or S(O). r (wherein r is an integer selected from 0, 1, and 2), and the remaining ring atoms are carbon. Depending on the number of rings constituting the group, the group can be classified into bicyclic, tricyclic, tetracyclic, or polycyclic bridged ring alkyl groups. Non-limiting examples of bridged heterocycloalkyl groups are: [ka] Includes:

[0183] The heterocycloalkyl group ring may be fused to an aryl group, heteroaryl group, or cycloalkyl group ring, where the ring connected to the parent structure is a heterocycloalkyl group ring, non-limiting examples include: [ka] wherein the heterocycloalkyl group may be optionally substituted or unsubstituted.

[0184] In some embodiments, the heterocycloalkyl group is a 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered monocyclic or polycyclic (e.g., spirocyclic, fused, or bridged) heterocycloalkyl group, wherein the number of heteroatoms can be 1, 2, 3, 4, or 5, and each heteroatom is independently nitrogen, oxygen, or S(O). r (where r is an integer 0, 1, or 2).

[0185] The term "aryl group" refers to an all-carbon monocyclic or fused polycyclic (i.e., rings that share adjacent pairs of carbon atoms) polycyclic group having a conjugated pi-electron system, and includes "C6-C 10 "Aryl group" or "6-10 membered aryl group" refers to an all-carbon aryl group containing 6 to 10 carbons, such as phenyl and naphthyl groups, preferably phenyl. The aryl ring may be fused to a heteroaryl, heterocycloalkyl, or cycloalkyl ring, where the ring connected to the parent structure is an aryl ring; non-limiting examples include: [ka] In some embodiments, the aryl group comprises a C-C 10 It is an aryl group.

[0186] "Heteroaryl group" refers to a heteroaromatic system containing 1 to 4 heteroatoms, where the heteroatoms are nitrogen, oxygen, or S(O). r(where r is an integer 0, 1, or 2), the 5- to 6-membered heteroaryl group is a heteroaromatic system containing 5 to 6 ring atoms, and the 5- to 10-membered heteroaryl group is a heteroaromatic system containing 5 to 10 ring atoms, preferably a 5- to 6-membered heteroaryl group, more preferably a 5- to 6-membered heteroaryl group containing one or two N atoms, non-limiting examples include furan, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidine, pyrazinyl, pyrazole, imidazolyl, triazolyl, tetrazolyl, etc., preferably a pyridyl group. The heteroaryl ring may be fused to an aryl, heterocycloalkyl, or cycloalkyl ring, where the ring connected to the parent structure is a heteroaryl ring, non-limiting examples include [ka] In some embodiments, the heteroaryl group is a 5-, 6-, 7-, 8-, 9-, or 10-membered heteroaryl group, where the number of heteroatoms can be 1, 2, 3, 4, or 5, and each heteroatom is independently nitrogen, oxygen, or sulfur.

[0187] The term "alkenyl group" refers to an alkyl group as defined above that is composed of at least two carbon atoms and at least one carbon-carbon double bond. A "C2-8 alkenyl group" refers to a straight-chain or branched alkenyl group containing 2 to 8 carbon atoms, including, but not limited to, vinyl, 1-propenyl, 2-propenyl, 1-, 2-, or 3-butenyl groups. A "C2-6 alkenyl group" is preferred, and a "C2-4 alkenyl group" is more preferred. The alkenyl group may be substituted or unsubstituted. In some embodiments, the alkenyl group is a C2, C3, C4, C5, C6, C7, or C8 alkenyl group.

[0188] The term "alkynyl group" refers to an alkyl group as defined above that is composed of at least two carbon atoms and at least one carbon-carbon triple bond. A "C2-8 alkynyl group" refers to a straight- or branched-chain alkynyl group containing 2 to 8 carbon atoms, including, but not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-, 2-, or 3-butynyl. A "C2-6 alkynyl group" is preferred, and a "C2-4 alkynyl group" is more preferred. The alkynyl group may be substituted or unsubstituted. In some embodiments, the alkynyl group is a C2, C3, C4, C5, C6, C7, or C8 alkynyl group.

[0189] "Subunit" refers to a divalent group, for example, alkylene group refers to a divalent alkyl group, alkenylene group refers to a divalent alkenyl group, alkynylene group refers to a divalent alkynyl group, cycloalkylene group refers to a divalent cycloalkyl group, heterocycloalkylene group refers to a divalent heterocycloalkyl group, arylene group refers to a divalent aryl group, and heteroarylene group refers to a divalent heteroaryl group, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups are as defined above, and the subunits may be optionally substituted or unsubstituted.

[0190] "Haloalkyl group" refers to an alkyl group optionally substituted with one or more fluorine, chlorine, bromine, or iodine atoms, wherein said alkyl group is as defined above, and non-limiting examples include, but are not limited to, difluoromethyl, dichloromethyl, dibromomethyl, trifluoromethyl, trichloromethyl, tribromomethyl, and the like.

[0191] "Hydroxyalkyl group" refers to an alkyl group optionally substituted with one or more -OH groups, where the alkyl group is as defined above, and non-limiting examples include hydroxymethyl, hydroxyethyl, hydroxypropyl, and hydroxyisopropyl groups.

[0192] "Alkoxy" refers to an --O-alkyl group, wherein said alkyl group is as defined above, and non-limiting examples include methoxy, ethoxy, isopropoxy, tert-butoxy, and the like.

[0193] "Cycloalkoxy" refers to an -O-cycloalkyl group, wherein said cycloalkyl group is as defined above, and non-limiting examples include cyclopropanyloxy, cyclobutanyloxy, cyclopentanyloxy, cyclohexanyloxy, and the like.

[0194] "Heterocycloalkoxy" refers to an -O-heterocycloalkyl group, wherein said heterocycloalkyl group is as defined above, and non-limiting examples include azetidinyloxy, azacyclopentanyloxy, piperidinyloxy, piperazinyloxy, oxolanyloxy, oxanyloxy, and the like.

[0195] "-C(O)C1-C3 alkyl group" refers to -C(O)-CH3, -C(O)-CH2CH3, and the like.

[0196] "Heteroatom or heteroatom group" refers to N, O, S, S(=O)2, S(O), and the like.

[0197] A "cyano group" refers to -CN.

[0198] A "hydroxy group" refers to -OH.

[0199] A "sulfonyl group" refers to -S(O)2-.

[0200] A "carboxy group" or a "carboxylic acid" refers to -COOH.

[0201] "Oxo" refers to the group =O.

[0202] "Halogen" refers to fluorine, chlorine, bromine or iodine.

[0203] "EA or EtOAc" refers to ethyl acetate.

[0204] "THF" refers to tetrahydrofuran.

[0205] "DCM" refers to dichloromethane;

[0206] "cataCXium A Pd-G3" refers to [n-butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate.

[0207] "POCl3" refers to phosphorus oxychloride.

[0208] "NaHCO3" refers to sodium bicarbonate.

[0209] "NaCl" refers to sodium chloride.

[0210] "Na2SO4" refers to sodium sulfate.

[0211] "NH4Cl" refers to ammonium chloride.

[0212] "Cs2CO3" refers to cesium carbonate.

[0213] "NaBH(OAc)3" refers to sodium borohydride acetate.

[0214] "Triton B" refers to benzyltrimethylammonium hydroxide.

[0215] "NaBH3CN" refers to sodium cyanoborohydride.

[0216] "CsF" refers to cesium fluoride.

[0217] "Na2CO3" refers to sodium carbonate.

[0218] "HOAc" refers to acetic acid.

[0219] "TPAP" refers to tetrapropylammonium perruthenate.

[0220] "NMO" refers to N-methylmorpholine oxide.

[0221] "Cs2CO3" refers to cesium carbonate.

[0222] "NaH" refers to sodium hydrogen.

[0223] "i-PrOH" refers to isopropanol.

[0224] "DMF" refers to N,N-dimethylformamide.

[0225] "MeOH" refers to methanol.

[0226] "Pd / C" refers to palladium on carbon.

[0227] "DMSO" refers to dimethyl sulfoxide.

[0228] "TFA" refers to trifluoroacetic acid.

[0229] "DIEA" refers to N,N-diisopropylethylamine.

[0230] "Dess-Martin" refers to the Dess-Martin reagent.

[0231] "PBS" refers to phosphate buffer solution.

[0232] "SDS-PAGE" refers to sodium dodecyl sulfate-polyacrylamide gel electrophoresis.

[0233] "PVDF" refers to polyvinylidene fluoride.

[0234] "PE" refers to petroleum ether.

[0235] "AcOH" refers to acetic acid.

[0236] "HCl" refers to hydrochloric acid.

[0237] "Dioxane" refers to 1,4-dioxane.

[0238] "ACN" refers to acetonitrile.

[0239] "DMP" refers to dimethyl phthalate.

[0240] "Pd-118" refers to 1,1'-bis(di-tert-butylphosphine)ferrocene palladium dichloride.

[0241] "BH3" refers to borane.

[0242] "PdCl2(dtbpf)" refers to [1,1'-bis(di-tert-butylphosphine)ferrocene]palladium dichloride.

[0243] "HATU" refers to 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate.

[0244] "EtOH" refers to ethanol.

[0245] "DMAP" refers to 4-dimethylaminopyridine.

[0246] "TBAF" refers to tetrabutylammonium fluoride.

[0247] "EDCI" refers to 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride.

[0248] "HOBT" refers to 1-hydroxybenzotriazole.

[0249] "LiAlH4" refers to lithium aluminum hydride.

[0250] "RuPhos Pd G3" refers to (2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate.

[0251] "LAH" refers to lithium aluminum hydride.

[0252] "TsCl" refers to p-toluenesulfonyl chloride.

[0253] "Na2S2O3" refers to sodium thiosulfate.

[0254] "NaNO2" refers to sodium nitrite.

[0255] "BBr3" refers to boron tribromide.

[0256] "K3PO4" refers to potassium phosphate.

[0257] "AcOK" refers to potassium acetate.

[0258] "DIBAL-H" refers to diisobutylaluminum hydride.

[0259] "TEA" refers to triethylamine.

[0260] "GTP" refers to guanosine triphosphate.

[0261] "Prep-HPLC" or "pre-HPLC" refers to preparative high performance liquid chromatography.

[0262] "Sat." refers to a saturated solution.

[0263] "aq" refers to an aqueous solution.

[0264] In the chemical structures herein, a bond "-" indicates a single bond, and an "=" indicates a double bond (which may be trans or cis, unless the configuration is limited).

[0265] "Optionally" means that the subsequently described event or circumstance may, but does not necessarily, occur, and the description includes cases where the event or circumstance occurs and cases where it does not. For example, "a heterocycloalkyl group optionally substituted with an alkyl group" means that the alkyl group may, but does not necessarily, be present, and the phrase includes cases where the heterocycloalkyl group is substituted with an alkyl group and cases where the heterocycloalkyl group is not substituted with an alkyl group. The term "substituted" refers to one or more hydrogen atoms in a group, preferably 5 or less, more preferably 1 to 3 hydrogen atoms, being independently replaced with the corresponding number of substituents. Of course, the substituents are located only at their chemically feasible positions, and those skilled in the art can easily determine (by experiment or theory) possible or impossible substitutions. For example, an amino group or a hydroxy group having free hydrogen may be unstable when bonded to a carbon atom having an unsaturated (e.g., olefinic) bond.

[0266] Unless otherwise specified, the term "optionally substituted" as used herein may mean unsubstituted or substituted, and when substituted, the substituents may be independently one or more (e.g., 2, 3, 4, 5, or 6) selected from alkyl groups, alkenyl groups, alkynyl groups, hydroxy groups, hydroxyalkyl groups, haloalkyl groups, alkoxy groups, amino groups, aminoalkyl groups, cyano groups, halogens, oxo, cycloalkyl groups, heterocycloalkyl groups, aryl groups, and heteroaryl groups, and the alkyl groups, alkenyl groups, alkynyl groups, hydroxy groups, hydroxyalkyl groups, haloalkyl groups, alkoxy groups, amino groups, aminoalkyl groups, cyano groups, halogens, oxo, cycloalkyl groups, heterocycloalkyl groups, aryl groups, and heteroaryl groups. The hydroxyalkyl, haloalkyl, alkoxy, amino, and aminoalkyl groups are optionally substituted with one or more (e.g., 2, 3, 4, 5, or 6) cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups, and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups are optionally substituted with one or more groups selected from alkyl, alkenyl, alkynyl, hydroxy, hydroxyalkyl, haloalkyl, alkoxy, amino, aminoalkyl, cyano, halogen, and oxo.

[0267] Unless otherwise stated, the following terms and phrases as used herein are intended to have the following meanings: A particular term or phrase should not be considered indefinite or unclear unless specifically defined, but should be understood in its ordinary sense. When a trade name is mentioned herein, it is intended to refer to the corresponding product or its active ingredient.

[0268] A "pharmaceutical composition" refers to a mixture of one or more compounds described herein or physiologically / pharmaceutically acceptable salts or prodrugs thereof with other chemical components, and other components such as physiologically / pharmaceutically acceptable carriers and excipients. The pharmaceutical composition is intended to facilitate administration to a living body and contribute to the absorption of the active ingredients to further exert their biological activity.

[0269] The present invention further provides pharmaceutically acceptable salts of compounds of formula (I). The term "pharmaceutically acceptable salts" refers to acid or base addition salts of relatively non-toxic compounds of the present invention. Such acid addition salts are salts formed with a compound of formula (I) of the present invention and a suitable inorganic or organic acid. These salts may be prepared during the final isolation and purification process of the compound, or may be prepared by reacting a purified compound of formula (I) in its free base form with a suitable organic or inorganic acid. Representative acid addition salts include hydrochloride, tartrate, hydrobromide, sulfate, bisulfate, sulfite, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, hydrogen phosphate, carbonate, bicarbonate, toluate, citrate, maleate, fumarate, succinate, benzoate, methanesulfonate, p-toluenesulfonate, gluconate, lactobionate, laurylsulfonate, and the like. The base addition salts are salts formed between the compounds of formula (I) and suitable inorganic or organic bases, including salts formed with basic metals, basic earth metals, and quaternary ammonium cations, such as sodium salts, lithium salts, potassium salts, calcium salts, magnesium salts, tetramethylquaternary ammonium salts, and tetraethylquaternary ammonium salts; and amine salts include salts formed with ammonia (NH), primary amines, secondary amines, or tertiary amines, such as methylamine salts, dimethylamine salts, trimethylamine salts, triethylamine salts, and ethylamine salts.

[0270] The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains an acid or base group by conventional chemical methods. Generally, such salts are prepared by reacting the free acid or base form of the compound with the stoichiometrically appropriate base or acid in water or an organic solvent, or a mixture of both.

[0271] The above-mentioned "pharmaceutically acceptable additive" refers to an inert substance that is administered simultaneously with an active ingredient and that aids in the administration of the active ingredient, and includes, but is not limited to, any glidant, sweetener, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersant, disintegrant, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier that is approved by the China Food and Drug Administration for use in humans or animals (e.g., livestock).

[0272] As used herein, and as known in the art, "treatment" or "treating" refers to an approach for obtaining beneficial or desired results (including clinical results). Beneficial or desired clinical results may include, but are not limited to, a decrease in tumor progression, a decrease in tumor size, a decrease in tumor growth rate, a decrease in tumor invasiveness and metastatic potential, alleviation or amelioration of one or more symptoms or conditions, a decrease in the extent of disease, a stabilization of the disease state (i.e., not worsening), prevention of disease spread, a delay or mitigation of disease progression, an improvement or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable. "Treatment" or "treating" may also mean prolonging survival as compared to expected survival in the absence of further treatment.

[0273] The therapeutic dosage of the compounds of the present application can be determined, for example, based on the particular therapeutic use, the manner of administration of the compound, the health and condition of the patient, and the judgment of the prescribing physician. The proportion or concentration of a compound of the present application in a pharmaceutical composition will depend on several factors, including dosage, chemical characteristics (e.g., hydrophobicity), and the route of administration, and may not be fixed.

[0274] In the present invention, -N (group) 1-2 represents an -NH (group) or an -N (group) 2 . The term "treatment" means administering a compound or formulation described herein to ameliorate or eliminate a disease or one or more symptoms associated with said disease, and includes: (i) inhibiting a disease or disease state, i.e., slowing its progression; (ii) remission of the disease or disease state, i.e., regression of the disease or disease state.

[0275] The term "therapeutically effective amount" refers to a dose of a compound of the present application that (i) treats a particular disease, condition, or disorder, (ii) reduces, ameliorates, or eliminates one or more symptoms of a particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of a particular disease, condition, or disorder described herein. The amount of a compound of the present application that constitutes a "therapeutically effective amount" varies depending on the compound, the disease state and its severity, the method of administration, and the age of the mammal being treated, but can be routinely determined by one of ordinary skill in the art using their own knowledge and the present disclosure.

[0276] Unless otherwise required in this application, throughout the specification and the claims that follow, the word "comprise" and its English variants, such as "comprises" and "comprising," are to be interpreted in an open, exhaustive sense, i.e., "including but not limited to."

[0277] References throughout this specification to "some embodiments," or "in an embodiment," or "in another embodiment," or "in a particular embodiment" are meant to include the relevant specific referenced element, structure, or feature described in that embodiment in at least one embodiment. Thus, the appearances of the phrases "some embodiments," or "in an embodiment," or "in another embodiment," or "in a particular embodiment" in different places throughout the specification do not necessarily all refer to the same embodiment. Otherwise, the specific elements, structures, or features may be combined in any suitable manner in one or more embodiments.

[0278] Unless otherwise stated, the term "isomer" is meant to include geometric isomers, cis-trans isomers, stereoisomers, enantiomers, optical isomers, diastereoisomers and tautomers.

[0279] The compounds of the present invention may exist in particular geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereoisomers, (D)-isomers, (L)-isomers, and other mixtures thereof, such as racemic mixtures and enantiomerically or diastereoisomerically enriched mixtures, and all such mixtures are within the scope of the present invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All of these isomers and mixtures thereof are within the scope of the present invention.

[0280] Unless otherwise stated, the terms "enantiomers" or "optical isomers" refer to stereoisomers that are mirror images of one another.

[0281] Unless otherwise stated, the terms "cis-trans isomers" or "geometric isomers" are caused by the inability to freely rotate about a double bond or a single bond of ring-forming carbon atoms.

[0282] Unless otherwise stated, the term "diastereoisomer" refers to stereoisomers whose molecules have two or more centers of chirality and are non-mirror-image related between the molecules.

[0283] Unless otherwise specified, a solid wedge key and a dashed wedge key represent the absolute configuration of a stereo center, a solid straight line key and a dashed straight line key represent the relative configuration of a stereo center, and a wavy line represents a solid wedge key or a dashed wedge key, or a wavy line represents a solid straight line key or a dashed straight line key.

[0284] Unless otherwise stated, the term "diastereoisomer" refers to stereoisomers whose molecules have two or more centers of chirality and are non-mirror-image related between the molecules.

[0285] Unless otherwise stated, "(+)" denotes right-handed, "(-)" denotes left-handed, and "(±)" denotes racemic.

[0286] "Optional" or "optionally" means that the subsequently described event or circumstance may, but does not necessarily, occur, and that the description includes instances where the event or circumstance occurs and instances where the event or circumstance does not occur.

[0287] The term "substituted" means that any one or more hydrogen atoms on a specified atom are replaced with a substituent, and the substituent may include variants of deuterium and hydrogen, so long as the specified valence is correct and the compound after substitution is stable. When the substituent is oxygen (i.e., =0), it means that two hydrogen atoms are replaced. Oxygen substitution does not occur on aromatic groups.

[0288] The term "optionally substituted" means that it may or may not be substituted, and unless otherwise specified, the type and number of substituents may be optional based on what is chemically feasible.

[0289] The term "prodrug" refers to a chemical derivative of a compound of the present invention, which, upon chemical reaction in the body, is converted into a compound of general formula I.

[0290] When any variable (e.g., R) occurs more than one time in a compound composition or structure, its definition at each occurrence is independent. Thus, for example, if a group is substituted with 0 to 2 R, then that group may optionally be substituted with up to 2 R, and each occurrence of R is independently selectable. Otherwise, combinations of substituents and / or variants thereof are permissible only if such combinations result in stable compounds.

[0291] When the number of linking groups is 0, for example, -(CRR)0- indicates that the linking group is a single bond.

[0292] When one of the variables is selected from a single bond, it indicates that the two groups it connects are directly bonded; for example, when L in ALZ is a single bond, it indicates that the structure is actually AZ.

[0293] The absence of a substituent indicates that the substituent is not present, for example, the absence of X in AX indicates that the structure is actually A. If a listed substituent does not specify through which atom it is linked to the substituted group, the substituent can be attached through any atom, for example, a pyridyl group can be linked as a substituent to the substituted group through any carbon atom of the pyridine ring.

[0294] When a recited linking group does not specify the linking direction, the linking direction is arbitrary. For example, when the linking group L is -MW-, -MW- may be formed by linking ring A and ring B in the same direction as the left-to-right reading order of the linking group, or may be formed by linking ring A and ring B in the opposite direction to the left-to-right reading order. Combinations of substituents and / or variants thereof are permissible only if such combinations result in stable compounds.

[0295] Unless otherwise specified, if a group has one or more linkable sites, any one or more of the sites can be bonded to other groups via a chemical bond. If the chemical bond is irregular and a linkable site contains an H atom, the number of H atoms at the site is reduced accordingly depending on the number of chemical bonds connected, resulting in a group with a corresponding valence. The chemical bond connecting the site to another group can be represented by a straight solid line, a straight dashed line, or a wavy line. For example, in -OCH3, the straight solid line indicates that the group is bonded to another group via the oxygen atom in the group, the straight dashed line indicates that the group is bonded to another group via the two ends of the nitrogen atom in the group, and the wavy line indicates that the phenyl group is bonded to another group via the carbon atoms at positions 1 and 2.

[0296] Unless otherwise specified, [ka] teeth, [ka] is used to indicate that a hydrogen atom at any position of the group in may be substituted.

[0297] Unless otherwise stated, the terms "enriched isomer," "enriched isomer," "enantiomerically enriched," or "enantiomerically enriched" mean that the amount of one isomer or enantiomer is less than 100% and that the amount of that isomer or enantiomer is 60% or more, or 70% or more, or 80% or more, or 90% or more, or 95% or more, or 96% or more, or 97% or more, or 98% or more, or 99% or more, or 99.5% or more, or 99.6% or more, or 99.7% or more, or 99.8% or more, or 99.9% or more.

[0298] Unless otherwise stated, the terms "isomeric excess" or "enantiomeric excess" refer to the difference between the relative percentages of two isomers or two enantiomers. For example, if one isomer or enantiomer is present at 90% and the other is present at 10%, the isomeric or enantiomeric excess (ee) is 80%.

[0299] Optically active (R)- and (S)-isomers and D- and L-isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. Enantiomers of certain compounds of the present invention can be prepared by asymmetric synthesis or derivatization with chiral auxiliaries, where the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide the pure desired enantiomer. Alternatively, if the molecule contains a basic (e.g., amino) or acidic (e.g., carboxy) functional group, the salt of the diastereomeric salt can be formed with an appropriate optically active acid or base, and the diastereoisomers can then be resolved and recovered by conventional methods known in the art to provide the pure enantiomers. Separation of enantiomers and diastereoisomers is otherwise typically achieved by chromatography, using a chiral stationary phase and optionally combined with chemical derivatization (e.g., amine to carbamate formation).

[0300] The compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, tritium (3H), iodine-125 ( 125 I) or C-14( 14 Radioisotope-labeled compounds such as benzophenone-3, benzophenone-4, benzophenone-5, benzophenone-6, benzophenone-7, benzophenone-8, benzophenone-9, benzophenone-10, benzophenone-11, benzophenone-12, benzophenone-13, benzophenone-14, benzophenone-15, benzophenone-16, benzophenone-17, benzophenone-18, benzophenone-19, benzophenone-20, benzophenone-21, benzophenone-22, benzophenone-23, benzophenone-24, benzophenone-25, benzophenone-26, benzophenone-27, benzophenone-28, benzophenone-29, benzophenone-30, benzophenone-31, benzophenone-32, benzophenone-33, benzophenone-34, benzophenone-35, benzophenone-36, benzophenone-37, benzophenone-38, benzophenone-39, benzophenone-40, benzophenone-41, benzophenone-42, benzophenone-43, benzophenone-44, benzophenone-45, benzophenone-46, benzophenone-47, benzophenone-48, benzophenone-49 ...

[0301] The compounds of the present invention can be prepared by various synthetic methods known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combination with other chemical synthetic methods, and equivalent substitution forms known to those skilled in the art, and preferred embodiments include, but are not limited to, the examples of the present invention.

[0302] The structure of the compounds of the present invention can be confirmed by conventional methods known to those skilled in the art, and when the present invention relates to the absolute configuration of a compound, the absolute configuration can be confirmed by conventional techniques in the art. For example, single crystal X-ray diffraction (SXRD) is performed by collecting diffraction intensity data on a Bruker D8 venture diffractometer using a CuKα radiation source and scanning method. After collecting relevant data, the crystal structure can be analyzed using a direct method (Shelxs97) to confirm the absolute configuration.

[0303] The compounds of the present invention, or pharmaceutically acceptable salts thereof, can be administered to mammals, including humans, orally, rectally, topically (intravenously, intramuscularly, or subcutaneously), locally (as powders, ointments, or drops), or intratumorally.

[0304] The dosage of the compound of the present invention may be about 0.05 to 300 mg / kg body weight / day, preferably 10 to 300 mg / kg body weight / day, and more preferably 10 to 200 mg / kg body weight / day.

[0305] The compounds of the present invention or pharmaceutically acceptable salts thereof can be formulated into solid dosage forms for oral administration, including, but not limited to, capsules, tablets, pills, powders, granules, etc. In these solid dosage forms, the compounds of formula (I) of the present invention are mixed as an active ingredient with at least one conventional inert excipient (or carrier), for example, sodium citrate or dicalcium phosphate, or the following ingredients: (1) a filler or solubilizer such as starch, lactose, sucrose, glucose, mannitol, and silicic acid, (2) a binder such as hydroxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic, (3) a humectant such as glycerin, and (4) agar. The capsules, tablets, and pills may contain buffering agents, such as (1) disintegrants such as calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate, (2) solubilizers such as paraffin, (3) absorption promoters such as quaternary ammonium compounds, (4) wetting agents such as cetyl alcohol and glyceryl monostearate, (5) adsorbents such as kaolin, and (6) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, and sodium lauryl sulfate, or mixtures thereof.

[0306] The above solid dosage forms, such as tablets, sugar-coated tablets, capsules, pills, and granules, can be coated or microencapsulated with coating and shell materials, such as enteric coatings, and other materials well known in the art. They may also contain opacifying agents, so that the release of the active ingredient in such compositions can be delayed in a specific part of the digestive tract. Examples of embedding materials that can be used include polymeric substances and wax-based materials. If necessary, the active ingredient can be formed into a microencapsulated form with one or more of the above-mentioned excipients.

[0307] The compounds of the present invention or their pharmaceutically acceptable salts can be formulated into liquid dosage forms for oral administration, including, but not limited to, pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and tinctures. In addition to the compound of formula (I) or its pharmaceutically acceptable salt as the active ingredient, the liquid dosage forms may contain inert diluents commonly used in the art, such as water, and other solvents, solubilizers, and emulsifiers, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil, or mixtures of these substances. In addition to these inert diluents, the liquid dosage forms of the present invention may contain conventional auxiliary agents, such as wetting agents, emulsifying and suspending agents, sweeteners, flavoring agents, and fragrances.

[0308] Such suspending agents include ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide, agar, and the like, or mixtures of these substances.

[0309] The compounds of the present invention or their pharmaceutically acceptable salts can be formulated into dosage forms for parenteral injection, including, but not limited to, physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable carriers, diluents, solvents or excipients include water, ethanol, polyols, and suitable mixtures thereof.

[0310] The compound of the present invention or a pharmaceutically acceptable salt thereof can also be formulated into dosage forms for topical administration, including ointments, powders, suppositories, drops, sprays, inhalants, etc. The compound of formula (I) of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and optional preservatives, buffers, or propellants that may be required as needed.

[0311] The present invention further provides a pharmaceutical composition comprising a compound of formula (I) of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient, and a pharmaceutically acceptable carrier, excipient or diluent. When preparing a pharmaceutical composition, the compound of formula (I) of the present invention or a pharmaceutically acceptable salt thereof is generally mixed with a pharmaceutically acceptable carrier, excipient or diluent.

[0312] According to conventional manufacturing methods, the above compositions of the present invention can be prepared into conventional pharmaceutical preparations, such as tablets, pills, capsules, powders, granules, emulsions, suspensions, dispersions, solutions, syrups, elixirs, ointments, drops, suppositories, sprays, propellants, etc.

[0313] The compounds according to the present invention or their pharmaceutically acceptable salts may be administered alone or (if necessary) in combination with other pharmaceutically acceptable therapeutic agents, such as other antitumor agents. The combined components may be administered simultaneously or sequentially in a single formulation or in different formulations. The above combinations may include combinations of the compounds of the present invention with one other active agent, or may include combinations of the compounds of the present invention with two or more other active agents.

[0314] In the present invention, other pharmaceutically acceptable therapeutic agents that can be used together with or in combination with the compound of formula (I) which is a KRAS G12D degrading agent include EGFR and / or mutant inhibitors thereof, ErbB2 (Her2) and / or mutant inhibitors thereof, ALK and / or mutant inhibitors thereof, MEK and / or mutant inhibitors thereof, KRAS and / or mutant inhibitors thereof, BCR-ABL and / or mutant inhibitors thereof, FGFR1 / FGFR2 / FGFR3 and / or mutant inhibitors thereof, ROS1 and / or mutant inhibitors thereof, c-MET and / or mutant inhibitors thereof. The inhibitor may be an antitumor agent, an inhibitor of AXL and / or its mutants, an inhibitor of NTRK1 and / or its mutants, an inhibitor of RET and / or its mutants, a taxane, a platinum-containing compound, an antimetabolite, a mitotic kinase inhibitor, an immunotherapeutic agent, an anti-angiogenic drug, a topoisomerase inhibitor, an inhibitor of A-Raf / B-Raf / C-RAf and / or its mutants, an inhibitor of ERK and / or its mutants, an inhibitor of cell apoptosis, an inhibitor of AKT and / or its mutants, an mTOR inhibitor, an epigenetic modulator, an IGF1 / 2 and / or IGF1-R inhibitor, an inhibitor of Ras GEF and / or its mutants, an inhibitor of SOS1 and / or its mutants, an inhibitor of SHP2 and / or its mutants, an inhibitor of PI3K and / or its mutants, or a PD-1 / PD-L1 inhibitor. Degrading agents for EGFR and / or its mutants, degrading agents for ErbB2 (Her2) and / or its mutants, degrading agents for ALK and / or its mutants, degrading agents for MEK and / or its mutants, degrading agents for KRAS and / or its mutants, degrading agents for BCR-ABL and / or its mutants, degrading agents for FGFR1 / FGFR2 / FGFR3 and / or their mutants, degrading agents for ROS1 and / or its mutants, degrading agents for c-MET and / or its mutants, degrading agents for AXL and / or its mutants, degrading agents for NTRK1 and / or its mutants, degrading agents for RET and / or its mutants, degrading agents for A-Raf / B-Raf / C-RAf and / or their mutants, degrading agents for ERK and / or its mutants, degrading agents for AKT and / or its mutants, degrading agents for IGF1 / 2 and / or IGF1-R, degrading agents for Ras Degrading agents for GEF and / or mutants thereof, degrading agents for SOS1 and / or mutants thereof, degrading agents for SHP2 and / or mutants thereof, degrading agents for PI3K and / or mutants thereof.Monoclonal antibodies against EGFR and / or its mutants, monoclonal antibodies against ErbB2 (Her2) and / or its mutants, PD-1 / PD-L1 monoclonal antibodies, CTLA-4 monoclonal antibodies, PD-L1 / TIGHT bibody, PD-L1 / CTLA-4 bibody, EGFR / MET bibody, EGFR / CD3 bibody, EGFR / 4-IBB bibody, PD-L1 / 4-IBB bibody, HER2 / CD3 bibody.

[0315] In the present invention, other pharmaceutically acceptable therapeutic agents that can be used together with or in combination with the compound of formula (I) which is a KRAS G12D degrading agent include afatinib, erlotinib, gefitinib, lapatinib, cetuximab, panituzumab, osimertinib, olmutinib, EGF-816, trastuzumab, pertuzumab, crizotinib, alectinib, and the like. inib), entrectinib, brigatinib, trametinib, cobimetinib, binimetinib, selumetinib, rifatinib, imatinib, dasatinib, nilotinib, nintedanib, crizotinib, lorlatinib, selenite Litinib (ceritinib), merestinib (merestinib), paclitaxel (paclitaxel), nab-paclitaxel, docetaxel (docetaxel), cisplatin (cisplatin), carboplatin (carboplatin), oxaliplatin (oxaliplatin), 5-fluorouracil, capecitabine (capecitabine), fluoxuridine, cytarabine (cytarabine), gemcitabine (gemcitabine), trifluridine (trifl uridine) and tipiracil combination (=TAS102), palbociclib (palbociclib), ribociclib (ribociclib), abemaciclib (abemaciclib), ipilimumab (ipilimumab), nivolumab (nivolumab), pembrolizumab (pembrolizumab), atezolizumab (atezolizumab), avelumab (avelumab), durvalumab (durvalumab), irinotecan (pidilizumab),It may also be PDR-001 (= spartalizumab), bevacizumab, pidilizumab, liposomal irinotecan, topotecan, ulixertinib, rapamycin, temsirolimus, everolimus, ridaforolimus, JQ-1, GSK 525762, OTX 015 (= MK8628), CPI 0610, TEN-010 (= RO6870810), xentuzumab (antibody 60833 of WO 2010 / 066868) or MEDI-573 (= dusigitumab). ,

[0316] In accordance with common knowledge in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain preferred examples of the present invention.

[0317] All of the reagents and raw materials used in the present invention are commercially available.

[0318] Compounds follow conventional naming principles in the art, and commercially available compounds may use supplier catalog names.

[0319] In the present invention, experiments measuring KRAS G12D kinase activity demonstrated that the compound of formula I described in the present invention can effectively bind to or inhibit KRAS G12D target protein, and Western blot demonstrated that the compound of formula I described in the present invention can effectively and specifically degrade KRAS G12D protein in A427 cells. The compound of formula I described in the present invention, and / or its stereoisomers, enantiomers, diastereoisomers, deuterated compounds, hydrates, solvates, metabolites, prodrugs, and / or pharmaceutically acceptable salts thereof, can effectively degrade KRAS G12D protein, thereby achieving the effects of preventing or treating diseases or conditions related to KRAS G12D or caused by the interaction of KRAS G12D with SOS1 or SHP2 proteins.

[0320] [Mode for Carrying Out the Invention] The present invention will be further explained by the following examples, but the present invention is not limited to the scope of the above examples. In the following examples, experimental methods without specific conditions are selected according to conventional methods and conditions or product instructions.

[0321] The present invention will be described in more detail and comprehensively with reference to the following examples, but the present invention is not limited thereto. The present invention is also not limited to the contents of the examples. The starting materials in the examples of the present invention are known and commercially available, or can be synthesized by methods known in the art. Unless otherwise specified, experimental methods for which specific conditions are not specified in the examples of the present invention generally follow conventional conditions or conditions recommended by the manufacturers of raw materials or products.

[0322] I. Example of compound production Intermediate 1: tert-Butyl 3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((1-(piperazin-1-ylmethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate Step 1: Preparation of 1-((4-benzylpiperazin-1-yl)methyl)cyclopropyl)methanol

[0323] [ka] tert-Butyl piperazine-1-carboxylate (14.7 g, 102.0 mmol) was dissolved in toluene (120 mL) and heated to 120 °C. Methyl 1-(hydroxymethyl)cyclopropane-1-carboxylate (12 g, 68.0 mmol) and phenylsilane (5.5 g, 51.0 mmol) were added. The mixture was reacted at 120 °C for 16 h, and then phenylsilane (14.7 g, 136.0 mmol) and zinc acetate (1.2 g, 6.8 mmol) were added, followed by further reaction for 2 h. After completion of the reaction, the mixture was cooled to room temperature and quenched with 2 M aqueous hydrochloric acid (120 mL). The mixture was extracted with dichloromethane (10 mL × 3). The aqueous phase was adjusted to pH 12 with 4 M sodium hydroxide solution (60 mL) and extracted with dichloromethane (100 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give 1-((4-benzylpiperazin-1-yl)methyl)cyclopropyl)methanol. LC-MS: (ESI, m / z): [M+H] + = 261.2.

[0324] Step 2: Preparation of tert-butyl 3-(2-((1-((4-benzylpiperazin-1-yl)methyl)cyclopropyl)methoxy)-7-chloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0325] [ka] Tert-butyl 3-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (5.00 g, 11.70 mmol) and 1-((4-benzylpiperazin-1-yl)methyl)cyclopropyl)methanol (3.30 g, 12.80 mmol) were dissolved in THF, followed by the addition of cesium carbonate. The mixture was stirred at 90°C for 16 hours. After completion of the reaction, the mixture was cooled to room temperature, quenched by the addition of saturated ammonium chloride solution (100 mL), extracted with ethyl acetate (100 mL x 3), and the combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (PE: EtOAc = 10:1 to 3:1) to give tert-butyl 3-(2-((1-((4-benzylpiperazin-1-yl)methyl)cyclopropyl)methoxy)-7-chloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate. LC-MS: (ESI, m / z): [M+H] + = 652.3.

[0326] Step 3: Preparation of tert-butyl 3-(7-chloro-8-fluoro-2-((1-(piperazin-1-ylmethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0327] [ka] Tert-butyl 3-(2-((1-((4-benzylpiperazin-1-yl)methyl)cyclopropyl)methoxy)-7-chloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.5 g, 2.4 mmol) was dissolved in DCM (15 mL), and 1-chloroethyl chloroformate (1.03 g, 7.2 mmol) and DIEA (0.62 g, 4.8 mmol) were added. The mixture was reacted at room temperature for 30 minutes, concentrated under reduced pressure, and the concentrate was dissolved in MeOH (15 mL) and heated to 50° C. for 30 minutes. After the reaction was completed, the mixture was concentrated and purified by silica gel column chromatography (DCM:MeOH = 100:1 to 10:1) to obtain tert-butyl 3-(7-chloro-8-fluoro-2-((1-(piperazin-1-ylmethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate. LC-MS: (ESI, m / z): [M / 2+H] + = 562.2.

[0328] Step 4: Preparation of tert-butyl 3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((1-(piperazin-1-ylmethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0329] [ka] To a solution of tert-butyl 3-(7-chloro-8-fluoro-2-((1-(piperazin-1-ylmethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.00 g, 1.78 mmol) and ((2-fluoro-6-((methoxymethyl)oxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxybenzofuran-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (1.1 g, 2.14 mmol) in 1,4-dioxane (9 mL) and HO (1 mL) was added cataCXium A Pd-G3 (262 mg, 0.36 mmol) and cesium carbonate (1.74 g, 5.34 mmol). The mixture was reacted at 80 °C for 16 hours under nitrogen gas protection. Water (100 mL) was added to the reaction mixture, which was then extracted with ethyl acetate (100 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The concentrate was purified by column chromatography (DCM:MeOH = 100:1 to 7:1) to give tert-butyl 3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((1-(piperazin-1-ylmethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate). LC-MS: (ESI, m / z): [M+H] + = 912.4. 1H NMR (400 MHz, DMSO-d6) δ 9.17 (s, 1H), 8.11 (dd, J = 9.2 Hz, 6.0 Hz, 1H), 7.75 (d, J = 2.4 Hz, 1H), 7.59-7.53 (m, 1H), 7.33 (d, J = 2.4 Hz, 1H), 5.37 (s, 2H), 4.77-4.70 (d, J = 12 Hz, 1H), 4.40-4.15 (m, 6H), 3.73 (d, J = 11.6 Hz, 1H), 3.43 (s, 1H), 3.38-3.32 (m, 2H), 2.95-2.85 (m, 4H), 2.52-2.51 (m, 2H), 2.47-2.29 (m, 2H), 1.96-1.77 (m, 3H), 1.74-1.57 (m, 2H), 1.46 (s, 9H), 0.81 (t, J = 7.2 Hz, 18H), 0.69-0.60 (m, 2H), 0.53-0.37 (m, 5H).

[0330] Intermediate 2: tert-Butyl 3-(2-(((S)-1-((benzyloxy)carbonyl)pyrrol-2-yl)methoxy)-7-(8-ethyl-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate Step 1: Preparation of 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine

[0331] [ka] 7-Chloro-8-fluoro-1,2,3,4-tetrahydropyrido[4,3-d]pyrimidine-2,4-dione (9.30 g, 43.14 mol) was dissolved in POCl3 (100 mL), cooled to 0 °C, and DIEA (16.69 g, 129.42 mol) was added dropwise with stirring. The reaction mixture was heated to 120 °C and reacted for 16 hours. After completion of the reaction, the reaction mixture was concentrated, diluted with ethyl acetate, and then quenched by slowly pouring into ice water. The mixture was extracted with ethyl acetate (100 mL × 3), and the organic phase was separated. The organic phase was washed successively with cold aqueous NaHCO3 and saturated NaCl solution, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine.

[0332] Step 2: Preparation of tert-butyl 3-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0333] [ka] 2,4,7-Trichloro-8-fluoropyrido[4,3-d]pyrimidine (1.00 g, 3.97 mmol) and TEA (1.20 g, 11.90 mmol) were dissolved in THF (15 mL) and cooled to -60 °C. A solution of tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (0.71 g, 3.37 mmol) in THF (5 mL) was slowly added dropwise and the reaction was allowed to proceed at -60 °C for 30 min. After completion of the reaction, the reaction solution was poured into aqueous NH4Cl (20 mL) and extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated NaCl solution, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated to give the crude product, which was purified by silica gel column (PE: EtOAc = 3:1) to give tert-butyl 3-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate. LC-MS: (ESI, m / z): [M+H]+ = 428.2.

[0334] Step 3: Preparation of tert-butyl 3-(2-(((S)-1-((benzyloxy)carbonyl)pyrrolidin-2-yl)methoxy)-7-chloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0335] [ka] tert-Butyl 3-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.20 g, 3.27 mmol) and (S)-2-(hydroxymethyl)tetrahydropyrrole-1-benzyl formate (1.15 g, 4.91 mmol) were dissolved in THF (25 mL) and CsCO (2.13 g, 6.54 mmol) was added. The reaction mixture was heated to 85 °C and reacted for 16 h. After completion of the reaction, the mixture was cooled to room temperature, water (30 mL) was added, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated NaCl solution, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated to give the crude product, which was purified by silica gel column (DCM:MeOH=100:1) to give tert-butyl 3-(2-(((S)-1-((benzyloxy)carbonyl)pyrrolidin-2-yl)methoxy)-7-chloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate. LC-MS: (ESI, m / z): [M+H] + = 627.2.

[0336] Step 4: Preparation of tert-butyl 3-(2-(((S)-1-((benzyloxy)carbonyl)pyrrol-2-yl)methoxy)-7-(8-ethyl-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0337] [ka] tert-Butyl 3-(2-(((S)-1-((benzyloxy)carbonyl)pyrrolidin-2-yl)methoxy)-7-chloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (540 mg, 0.86 mmol), 2-(8-ethyl-3-((methoxymethyl)oxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (353 mg, 1.03 mmol), and potassium phosphate (364 mg, 1.72 mmol) were added to dioxane / HO (10 mL / 2 mL) and catalyst cataCXium A Pd-G3 (62 mg, 0.086 mmol) was added. The mixture was mixed thoroughly and purged with nitrogen gas three times, and the reaction mixture was heated to 100°C for 16 h. After completion of the reaction, the reaction mixture was concentrated and purified using a silica gel column (DCM:MeOH = 80:1) to obtain tert-butyl 3-(2-(((S)-1-((benzyloxy)carbonyl)pyrrol-2-yl)methoxy)-7-(8-ethyl-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate. LC-MS: (ESI, m / z): [M+H] + = 806.9.

[0338] Intermediate 3: 3-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzoyl)-3-azaspiro[5.5]undecane-9-formaldehyde Step 1: Preparation of 3-azaspiro[5.5]undecane-9-formaldehyde

[0339] [ka] tert-Butyl 9-formyl-3-azaspiro[5.5]undecane-3-carboxylate (400 mg, 1.16 mmol) was dissolved in DCM (4 mL), and then TFA (2 mL) was added. The mixture was stirred at room temperature for 1 hour and concentrated to give 3-azaspiro[5.5]undecane-9-formaldehyde, which was used directly in the next reaction.

[0340] Step 2: Preparation of 3-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzoyl)-3-azaspiro[5.5]undecane-9-formaldehyde

[0341] [ka] To a solution of 3-azaspiro[5.5]undecane-9-formaldehyde (500 mg, 1.87 mmol) in DMSO (5 mL), DIEA (720 mg, 5.61 mmol) and pentafluorophenyl 4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzoate (850 mg, 1.96 mmol) were added, and the reaction mixture was stirred at room temperature for 1 hour. Water was added, and the mixture was extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified using a silica gel column (DCM:MeOH = 100:1 to 5:1) to give 3-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzoyl)-3-azaspiro[5.5]undecane-9-formaldehyde. LC-MS: (ESI, m / z): [M+H] + = 432.0.

[0342] Intermediate 4: tert-butyl 3-(2-((1-((4-((3-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)-3-azaspiro[5.5]undecan-9-yl)methyl)piperazin-1-yl)methyl)cyclopropyl)methoxy)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate Step 1: Preparation of tert-butyl 9-((4-((benzyloxy)carbonyl)piperazin-1-yl)methyl)-3-azaspiro[5.5]undecane-3-carboxylate

[0343] [ka] To a solution of tert-butyl 9-formyl-3-azaspirocyclo[5.5]undecane-3-carboxylate (1.30 g, 4.62 mmol) and tert-butyl piperazine-1-carboxylate (1.82 g, 8.28 mmol) in DCM / MeOH (15 mL / 5 mL) was added AcOH (0.2 mL) and stirred at room temperature for 0.5 h. Next, NaBH(OAc)3 (2.25 g, 10.60 mmol) was added in several portions to the mixture at 0-5 °C and stirred for 0.5 h. The reaction mixture was directly concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (DCM:MeOH = 150:1 to 20:1) to give tert-butyl 9-((4-((benzyloxy)carbonyl)piperazin-1-yl)methyl)-3-azaspiro[5.5]undecane-3-carboxylate). LC-MS: (ESI, m / z): [M+H] + = 486.3.

[0344] Step 2: Preparation of benzyl 4-((3-azaspiro[5.5]undecan-9-yl)methyl)piperazine-1-carboxylate

[0345] [ka] To a solution of tert-butyl 9-((4-((benzyloxy)carbonyl)piperazin-1-yl)methyl)-3-azaspiro[5.5]undecane-3-carboxylate (750 mg, 4.54 mmol) in 1,4-dioxane (5 mL) was added HCl / 1,4-dioxane (6 N, 5 mL). The mixture was stirred at room temperature for 1 hour, and the reaction mixture was directly concentrated under reduced pressure to give benzyl 4-((3-azaspiro[5.5]undecan-9-yl)methyl)piperazine-1-carboxylate. The crude product obtained was used directly in the next reaction without further purification.

[0346] Step 3: Preparation of benzyl 4-((3-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)-3-azaspiro[5.5]undecan-9-yl)methyl)piperazine-1-carboxylate

[0347] [ka] To a solution of benzyl 4-((3-azaspiro[5.5]undecan-9-yl)methyl)piperazine-1-carboxylate (632 mg, crude) in DMSO (10 mL) was added pentafluorophenyl 3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoate (430 mg, 1.00 mmol) and DIEA (516 mg, 4.00 mmol). The mixture was stirred at room temperature for 1 hour and then purified by pre-HPLC to give benzyl 4-((3-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)-3-azaspiro[5.5]undecan-9-yl)methyl)piperazine-1-carboxylate. LC-MS: (ESI, m / z): [M+H] + = 632.3.

[0348] Step 4: Preparation of 1-(2-methoxy-5-(9-(piperazin-1-ylmethyl)-3-azaspiro[5.5]undecane-3-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione

[0349] [ka] To a solution of benzyl 4-((3-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)-3-azaspiro[5.5]undecane-9-yl)methyl)piperazine-1-carboxylate (586 mg, 0.93 mmol) in ethyl acetate (20 mL) was added Pd / C (300 mg) and stirred at room temperature for 16 hours. The reaction mixture was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to give 1-(2-methoxy-5-(9-(piperazin-1-ylmethyl)-3-azaspiro[5.5]undecane-3-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione. LC-MS: (ESI, m / z): [M+H] + = 498.2.

[0350] Step 5: Preparation of tert-butyl 3-(2-((1-((4-((3-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)-3-azaspiro[5.5]undecan-9-yl)methyl)piperazin-1-yl)methyl)cyclopropyl)methoxy)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0351] [ka] To a solution of tert-butyl 3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((1-aldehydecyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (100 mg, 0.114 mmol) in THF (0.8 mL), 1-(2-methoxy-5-(9-(piperazin-1-ylmethyl)-3-azaspiro[5.5]undecane-3-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione (68 mg, 0.17 mmol) and tetraisopropyl titanate (485 mg, 1.71 mmol) were added and stirred at 70 ° C. for 2 hours. Next, MeOH (0.3 mL) was added to the mixture at room temperature, and then NaBH(OAc)3 (72 mg, 0.34 mmol) was added in several portions, followed by stirring for 4 hours. The reaction mixture was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (DCM:MeOH = 100:1 to 20:1) to give tert-butyl 3-(2-((1-((4-((3-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)-3-azaspiro[5.5]undecan-9-yl)methyl)piperazin-1-yl)methyl)cyclopropyl)methoxy)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate. LC-MS: (ESI, m / z): [M / 2+H] + = 662.4.

[0352] Step 6: Preparation of tert-butyl 3-(2-((1-((4-((3-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)-3-azaspiro[5.5]undecan-9-yl)methyl)piperazin-1-yl)methyl)cyclopropyl)methoxy)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0353] [ka] Cesium fluoride (40 mg, 0.27 mmol) was added to a solution of tert-butyl 3-(2-((1-((4-((3-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)-3-azaspiro[5.5]undecan-9-yl)methyl)piperazin-1-yl)methyl)cyclopropyl)methoxy)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (100 mg, 0.0755 mmol) in DMF (3 mL), and the mixture was stirred at room temperature for 30 minutes. Water was added to the mixture, which was then extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure to give tert-butyl 3-(2-((1-((4-((3-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)-3-azaspiro[5.5]undecan-9-yl)methyl)piperazin-1-yl)methyl)cyclopropyl)methoxy)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate. LC-MS: (ESI, m / z): [M+H] + = 1167.3.

[0354] Intermediate 5: tert-Butyl 3-(8-fluoro-2-((1-(hydroxymethyl)cyclopropyl)methoxy)-7-(5-methyl-1H-indazol-4-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0355] [ka] To a solution of tert-butyl 3-(7-chloro-8-fluoro-2-((1-(hydroxymethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (400 mg, 0.81 mmol) in 1,4-dioxane / HO (5.0 mL / 1.0 mL) was added (5-methyl-1H-indazol-4-yl)boronic acid (257 mg, 1.46 mmol), cesium carbonate (792 mg, 2.43 mmol), and 1,1″-bis(di-tert-butylphosphine)ferrocenepalladium dichloride (59 mg, 0.08 mmol), and the mixture was reacted overnight at 75 °C under N-protection. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (MeOH:DCM = 100:1 to 20:1) to give tert-butyl 3-(8-fluoro-2-((1-(hydroxymethyl)cyclopropyl)methoxy)-7-(5-methyl-1H-indazol-4-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate. LC-MS: (ESI, m / z): [M+H] + = 590.2.

[0356] Intermediate 6: tert-Butyl 3-(7-(8-ethyl-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-((1-aldehydecyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate Step 1: Preparation of tert-butyl 3-(7-(8-ethyl-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-((1-(hydroxymethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0357] [ka] To a solution of tert-butyl 3-(7-chloro-8-fluoro-2-((1-(hydroxymethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (500 mg, 1.0 mmol) and 2-(8-ethyl-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (411 mg, 1.2 mmol) in 1,4-dioxane / HO (5 mL / 1 mL) was added cataCXium A Pd-G3 (146 mg, 0.2 mmol) and cesium carbonate (981 mg, 3.0 mmol). The mixture was reacted at 85°C for 16 hours under nitrogen gas protection, water (10 mL) was added to the reaction mixture, and extracted with ethyl acetate (10 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (DCM:MeOH = 50:1) to give tert-butyl 3-(7-(8-ethyl-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-((1-(hydroxymethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate). LC-MS: (ESI, m / z): [M / 2+H] + = 674.2.

[0358] Step 2: Preparation of tert-butyl 3-(7-(8-ethyl-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-((1-aldehydecyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0359] [ka] Dess-Martin oxidant (242 g, 0.57 mmol) was added to a solution of tert-butyl 3-(7-(8-ethyl-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-((1-(hydroxymethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (320 mg, 0.47 mmol) in DCM (5 mL) at 0 °C, and the reaction was allowed to proceed at room temperature for 1 hour. The reaction mixture was quenched by the addition of sodium thiosulfate solution (5 mL) and sodium bicarbonate solution (5 mL), extracted with dichloromethane (5 mL × 3), and the combined organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (DCM:MeOH=30:1) to give tert-butyl 3-(7-(8-ethyl-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-((1-aldehydecyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate. LC-MS: (ESI, m / z): [M / 2+H] + = 672.3.

[0360] Intermediate 7: tert-butyl 3-(2-((1-((4-((3-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methylbenzoyl)-3-azaspiro[5.5]undecan-9-yl)methyl)piperazin-1-yl)methyl)cyclopropanealkyl)methoxy)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate Step 1: Preparation of 4-((3-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methylbenzoyl)-3-azaspiro[5.5]undecan-9-yl)methyl)piperazine-1-carboxylate

[0361] [ka] To a solution of 4-((3-azaspiro[5.5]undecan-9-yl)methyl)piperazine-1-carboxylate hydrochloride (930 mg, 2.2 mmol) in DMSO (20 mL) was added pentafluorophenyl 3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methylbenzoate (921 mg, 2.3 mmol) and DIEA (995 mg, 7.7 mmol). The mixture was stirred at room temperature for 1 hour and purified by pre-HPLC to give 4-((3-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methylbenzoyl)-3-azaspiro[5.5]undecan-9-yl)methyl)piperazine-1-carboxylate. LC-MS: (ESI, m / z): [M+H] + = 616.3.

[0362] Step 2: Preparation of 1-(2-methyl-5-(9-(piperazin-1-ylmethyl)-3-azaspiro[5.5]undecane-3-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione

[0363] [ka] To a solution of 4-((3-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methylbenzoyl)-3-azaspiro[5.5]undecane-9-yl)methyl)piperazine-1-carboxylate (900 mg, 1.46 mmol) in ethyl acetate (20 mL) was added Pd / C (100 mg) and stirred at room temperature for 16 hours. The reaction mixture was filtered through diatomaceous earth, and the filtrate was concentrated to give 1-(2-methyl-5-(9-(piperazin-1-ylmethyl)-3-azaspiro[5.5]undecane-3-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione. LC-MS: (ESI, m / z): [M+H] + = 482.2.

[0364] Step 3: Preparation of tert-butyl 3-(2-((1-((4-((3-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methylbenzoyl)-3-azaspiro[5.5]undecan-9-yl)methyl)piperazin-1-yl)methyl)cyclopropyl)methoxy)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0365] [ka] To a solution of tert-butyl 3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((1-formylcyclopropanealkyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (100 mg, 0.114 mmol) in THF (5 mL), 1-(2-methyl-5-(9-(piperazin-1-ylmethyl)-3-azaspiro[5.5]undecane-3-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione (66 mg, 0.17 mmol) and tetraisopropyl titanate (485 mg, 1.71 mmol) were added and stirred at 70 °C for 2 hours. To the mixture was added MeOH (5 mL) at room temperature, followed by the addition of NaBH(OAc)3 (72 mg, 0.34 mmol) in several portions, and the mixture was stirred for 2 hours. The mixture was concentrated, and the resulting crude product was purified by silica gel column chromatography (DCM:MeOH = 100:1 to 20:1) to give tert-butyl 3-(2-((1-((4-((3-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methylbenzoyl)-3-azaspiro[5.5]undecan-9-yl)methyl)piperazin-1-yl)methyl)cyclopropyl)methoxy)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate. LC-MS: (ESI, m / z): [M / 2+H] + = 654.9.

[0366] Step 4: Preparation of tert-butyl 3-(2-((1-((4-((3-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methylbenzoyl)-3-azaspiro[5.5]undecan-9-yl)methyl)piperazin-1-yl)methyl)cyclopropanealkyl)methoxy)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0367] [ka] Cesium fluoride (40 mg, 0.27 mmol) was added to a solution of tert-butyl 3-(2-((1-((4-((3-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methylbenzoyl)-3-azaspiro[5.5]undecan-9-yl)methyl)piperazin-1-yl)methyl)cyclopropyl)methoxy)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (100 mg, 0.076 mmol) in DMF (3 mL), and the mixture was stirred at room temperature for 30 minutes. Water was added and the mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated to give tert-butyl 3-(2-((1-((4-((3-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methylbenzoyl)-3-azaspiro[5.5]undecan-9-yl)methyl)piperazin-1-yl)methyl)cyclopropanealkyl)methoxy)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate. LC-MS: (ESI, m / z): [M+H] + = 1151.5.

[0368] Intermediate 8: tert-Butyl 3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((1-aldehydecyclopropyl)methyl)amino)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate Step 1: Preparation of tert-butyl 3-(7-chloro-8-fluoro-2-(((1-(hydroxymethyl)cyclopropyl)methyl)amino)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0369] [ka] tert-Butyl 3-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (0.5 g, 1.17 mmol) and 1-(aminomethyl)cyclopropylmethanol (0.16 g, 1.52 mmol) were added to THF (8 mL), followed by the addition of cesium carbonate (0.76 g, 2.34 mmol), and the mixture was reacted at 25° C. for 16 hours. After the reaction was completed, water (30 mL) was added, and the mixture was extracted with ethyl acetate (30 mL × 2). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (PE:EA = 5:1) to give tert-butyl 3-(7-chloro-8-fluoro-2-(((1-(hydroxymethyl)cyclopropyl)methyl)amino)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate. LC-MS: (ESI, m / z): [M+H] + = 493.1. 1H NMR (300 MHz, DMSO-d6) δ 8.65 (d, J = 8.6 Hz, 1H), 7.89 - 7.57 (m, 1H), 4.78 (t, J = 6.0 Hz, 1H), 4.54 - 4.35 (m, 2H), 4.23 (s, 2H), 3.58 - 3.43 (m, 3H), 3.42 - 3.37 (m, 1H), 3.33 - 3.28 (m, 1H), 1.87 -1.65 (m, 4H), 1.49 (s, 9H), 0.52 - 0.35 (m, 4H).

[0370] Step 2: Preparation of tert-butyl 3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((1-(hydroxymethyl)cyclopropyl)methyl)amino)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0371] [ka] To a solution of tert-butyl 3-(7-chloro-8-fluoro-2-(((1-(hydroxymethyl)cyclopropyl)methyl)amino)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (400 mg, 0.81 mmol) and ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (540 mg, 1.05 mmol) in 1,4-dioxane (15 mL) and HO (3 mL) was added cataCXium A Pd G3 (60 mg, 0.081 mmol) and cesium carbonate (660 mg, 2.03 mmol). The mixture was reacted at 85 °C for 6 h under nitrogen gas protection. The reaction mixture was filtered and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (DCM:MeOH=100:1) to give tert-butyl 3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((1-(hydroxymethyl)cyclopropyl)methyl)amino)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate. LC-MS: (ESI, m / z): [M+H] + = 843.4.

[0372] Step 3: Preparation of tert-butyl 3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((1-aldehydecyclopropyl)methyl)amino)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0373] [ka] To a solution of tert-butyl 3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((1-(hydroxymethyl)cyclopropyl)methyl)amino)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (200 mg, 0.24 mmol) in dichloromethane (1 mL) was added Dess-Martin reagent (122 mg, 0.29 mmol). The mixture was stirred at room temperature for 2 hours. After completion of the reaction, the reaction was quenched by the addition of sodium thiosulfate solution (3 mL) and sodium bicarbonate solution (3 mL). The mixture was extracted with dichloromethane (5 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (PE:EA=1:1) to obtain tert-butyl 3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((1-aldehydecyclopropyl)methyl)amino)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate. LC-MS: (ESI, m / z): [M+H] + = 841.4.

[0374] Intermediate 9: tert-butyl 3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(piperidin-4-ylmethoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate Step 1: Preparation of tert-butyl 3-(2-((1-benzylpiperidin-4-yl)methoxy)-7-chloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0375] [ka] tert-Butyl 3-(2,7-dichloro-8-fluoropyridine[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.00 g, 2.33 mmol) and (1-benzylpiperidin-4-yl)methanol (0.96 g, 2.67 mmol) were dissolved in THF (10 mL) and CsCO (2.28 g, 7.00 mmol) was added. The reaction mixture was heated to 90 °C and reacted for 16 h. After completion of the reaction, the mixture was cooled to room temperature, water (50 mL) was added, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated NaCl solution, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated to give the crude product, which was purified by silica gel column chromatography (PE:EA=3:1) to give tert-butyl 3-(2-((1-benzylpiperidin-4-yl)methoxy)-7-chloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate. LC-MS: (ESI, m / z): [M+H] + = 597.3. 1 H NMR (400 MHz, CDCl3) δ 8.71 (s, 1H), 7.36 - 7.26 (m, 5H), 4.53 - 4.25 (m, 6H), 3.77 - 3.57 (m, 2H), 3.51 (s, 2H), 2.95 (d, J = 11.2 Hz, 2H), 2.05 - 1.93 (m, 4H), 1.86 - 1.80 (m, 2H), 1.73 - 1.68 (m, 2H), 1.51 (s, 9H), 1.47 - 1.37 (m, 2H), 1.28 - 1.22 (m, 1H).

[0376] Step 2: Preparation of tert-butyl 3-(7-chloro-8-fluoro-2-(piperidin-4-ylmethoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0377] [ka] Tert-butyl 3-(2-((1-benzylpiperidin-4-yl)methoxy)-7-chloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.02 g, 1.71 mmol) was dissolved in DCM (10 mL), and 1-chloroethyl chloroformate (733 mg, 5.12 mmol) and DIEA (441 mg, 3.42 mmol) were added. The mixture was reacted at room temperature for 1 hour, concentrated under reduced pressure, and the concentrate was dissolved in MeOH (3 mL) and heated to 50°C for 10 minutes. After completion of the reaction, the mixture was concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (DCM:MeOH(NH3) = 7:93) to give tert-butyl 3-(7-chloro-8-fluoro-2-(piperidin-4-ylmethoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate. LC-MS: (ESI, m / z): [M+H] + = 507.0. 1 H NMR (400 MHz, CD3OD) δ 8.86 (s, 1H), 4.61 (d, J = 12.4 Hz, 2H), 4.42 - 4.32 (m, 4H), 3.72 (d, J = 12.4 Hz, 2H), 3.41 (d, J = 12.4 Hz, 2H), 3.03 - 2.90 (m, 2H), 2.19 - 2.16 (m, 1H), 2.06 (d, J = 13.6 Hz, 2H),1.97 - 1.89 (m, 2H), 1.78 - 1.71 (m, 2H), 1.67 - 1.57 (m, 2H), 1.53 (s, 9H), 1.54 - 1.24 (m, 1H).

[0378] Step 3: Preparation of tert-butyl 3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(piperidin-4-ylmethoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0379] [ka] To a solution of tert-butyl 3-(7-chloro-8-fluoro-2-(piperidin-4-ylmethoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (400 mg, 0.79 mmol) and ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (485 mg, 0.95 mmol) in 1,4-dioxane (5 mL) and HO (1 mL) was added cataCXium A Pd G3 (58 mg, 0.08 mmol) and cesium carbonate (771 mg, 2.37 mmol). The mixture was reacted under nitrogen gas protection at 85 °C for 16 hours, quenched by adding water (10 mL), extracted with ethyl acetate (20 mL × 3), and the combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (DCM:MeOH(NH) = 7%) to give tert-butyl 3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(piperidin-4-ylmethoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate. LC-MS: (ESI, m / z): [M / 2+H] + = 429.3.

[0380] Intermediate 10: tert-butyl 3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(2-(piperazin-1-yl)ethoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate Step 1: Preparation of 2-(4-benzylpiperazin-1-yl)ethanol

[0381] [ka] Anhydrous potassium carbonate (1180 mg, 8.510 mmol) was added to a solution of 1-benzylpiperazine (1000 mg, 5.673 mmol) and 2-bromo-1-ol (851 mg, 6.808 mmol) in anhydrous acetonitrile (25 mL) at room temperature, and the mixture was stirred at 90°C for 16 hours. After completion of the reaction, the precipitate was removed by filtration, and the mixture was concentrated under reduced pressure at 40°C. The resulting crude product was purified by silica gel column chromatography (dichloromethane:methanol = 100:1 to 10:1, 0.1% NH3) to give 2-(4-benzylpiperazin-1-yl)ethanol. LC-MS: (ESI, m / z): [M+H] + = 221.2.

[0382] Step 2: Preparation of tert-butyl 3-(2-(2-(4-benzylpiperazin-1-yl)ethoxy)-7-chloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0383] [ka] To a solution of 2-(4-benzylpiperazin-1-yl)ethanol (823 mg, 3.735 mmol) and tert-butyl 3-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (800 mg, 1.868 mmol) in anhydrous acetonitrile (25 mL) at room temperature, anhydrous cesium carbonate (1217 mg, 3.736 mmol) and 1,4-diazabicyclo[2.2.2]octane (105 mg, 0.934 mmol) were added and stirred at 25°C for 4 hours. After the reaction was completed, the reaction mixture was diluted with tetrahydrofuran (50 mL), the solid was removed by filtration, and the filtrate was concentrated under reduced pressure at 40°C. The resulting crude product was purified by silica gel column chromatography (petroleum ether:tetrahydrofuran = 10:1 to 2:1) to give tert-butyl 3-(2-(2-(4-benzylpiperazin-1-yl)ethoxy)-7-chloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate. LC-MS: (ESI, m / z): [M+H] + = 612.1.

[0384] Step 3: Preparation of tert-butyl 3-(7-chloro-8-fluoro-2-(2-(piperazin-1-yl)ethoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0385] [ka] At room temperature, 3-(2-(2-(4-benzylpiperazin-1-yl)ethoxy)-7-chloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate tert-butyl (840 mg, 1.372 mmol) in dichloromethane (40 mL) was added 1-chloroethyl chloroformate (1217 mg, 3.736 mmol) and stirred at 30 ° C. for 1 hour. After completion of the reaction, the mixture was concentrated under reduced pressure at 40 ° C. to obtain 3-(7-chloro-8-fluoro-2-(2-(piperazin-1-yl)ethoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate tert-butyl. LC-MS: (ESI, m / z): [M+H] + = 522.1.

[0386] Step 4: Preparation of tert-butyl 3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(2-(piperazin-1-yl)ethoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0387] [ka] To a solution of tert-butyl 3-(7-chloro-8-fluoro-2-(2-(piperazin-1-yl)ethoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (714 mg, 1.372 mmol) and (2-fluoro-6-methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (845 mg, 1.646 mmol) in 1,4-dioxane (20 mL) and water (4 mL) was added anhydrous cesium carbonate (1608 mg, 4.938 mmol) and cataCXium®A Pd G3 (240 mg, 0.329 mmol) at room temperature. After degassing, the mixture was stirred under nitrogen gas protection at 85°C for 16 hours. After completion of the reaction, the mixture was concentrated under reduced pressure at 40°C. The resulting crude product was purified by silica gel column chromatography (dichloromethane:methanol = 100:1 to 10:1, 0.1% NH3) to obtain tert-butyl 3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(2-(piperazin-1-yl)ethoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate. LC-MS: (ESI, m / z): [M+H] + = 872.2.

[0388] Intermediate 11: 1-(2-Methoxy-5-(3,9-diazaspiro[5.5]undecane-3-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione Step 1: Preparation of tert-butyl 9-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate

[0389] [ka] To a solution of tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate (473 mg, 1.86 mmol) in dimethyl sulfoxide (8 mL) were added DIEA (721 mg, 5.58 mmol) and pentafluorophenyl 3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoate (800 mg, 1.86 mmol). The mixture was stirred at 30 °C for 1 hour. After completion of the reaction, it was extracted with water (10 mL) and ethyl acetate (10 mL × 3). The organic phase was washed with brine (20 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The obtained crude product was purified by silica gel column chromatography (DCM:MeOH=20:1) to give tert-butyl 9-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate. LC-MS: (ESI, m / z): [M-tBu+H] + = 445.1.

[0390] Step 2: Preparation of 1-(2-methoxy-5-(3,9-diazaspiro[5.5]undecane-3-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione

[0391] [ka] To a solution of tert-butyl 9-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate (920 mg, 1.84 mmol) in 1,4-dioxane (4 mL) was added HCl / 1,4-dioxane (2 mL) and stirred at 30° C. for 1 hour. After completion of the reaction, the mixture was concentrated in vacuo to give 1-(2-methoxy-5-(3,9-diazaspiro[5.5]undecane-3-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione. The crude product was used directly in the next step without further purification. LC-MS: (ESI, m / z): [M+H]+ = 401.1.

[0392] Intermediate 12: 1-(2-chloro-5-(9-(piperazin-1-ylmethyl)-3-azaspiro[5.5]undecane-3-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione Step 1: Preparation of tert-butyl 9-((4-benzylpiperazin-1-yl)methyl)-3-azaspiro[5.5]undecane-3-carboxylate

[0393] [ka] To a solution of tert-butyl 9-formyl-3-azaspirocyclo[5.5]undecane-3-carboxylate (0.5 g, 1.77 mmol) and 1-benzylpiperazine (0.38 g, 2.14 mmol) in 1,2-dichloroethane (10 mL) was added acetic acid (0.1 mL). The mixture was stirred at 30 °C for 0.5 h. The mixture was cooled to 0 °C, and NaBH(OAc) (0.75 g, 3.56 mmol) was added. The mixture was then warmed to room temperature and reacted for 3 h. After completion of the reaction, the reaction was quenched by the addition of HO (10 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (DCM / MeOH=20:1) to give tert-butyl 9-((4-benzylpiperazin-1-yl)methyl)-3-azaspiro[5.5]undecane-3-carboxylate. LC-MS: (ESI, m / z): [M+H] + = 442.2.

[0394] Step 2: Preparation of 9-((4-benzylpiperazin-1-yl)methyl)-3-azaspiro[5.5]undecane

[0395] [ka] To a solution of tert-butyl 9-((4-benzylpiperazin-1-yl)methyl)-3-azaspiro[5.5]undecane-3-carboxylate (200 mg, 0.45 mmol) in 1,4-dioxane (3 mL) was added hydrochloric acid / 1,4-dioxane (1 mL). The mixture was stirred at room temperature for 1 hour. The reaction mixture was directly concentrated under reduced pressure to give 9-((4-benzylpiperazin-1-yl)methyl)-3-azaspiro[5.5]undecane, which was used directly in the next reaction without further purification. LC-MS: (ESI, m / z): [M+H] + = 342.3.

[0396] Step 3: Preparation of 1-(5-(9-((4-benzylpiperazin-1-yl)methyl)-3-azaspiro[5.5]undecane-3-carbonyl)-2-chlorophenyl)dihydropyrimidine-2,4(1H,3H)-dione

[0397] [ka] 9-((4-benzylpiperazin-1-yl)methyl)-3-azaspiro[5.5]undecane (150 mg, 0.45 mmol) was dissolved in DMF (3 mL), and 4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)pentafluorophenyl benzoate (205 mg, 0.47 mmol) and DIEA (175 mg, 1.35 mmol) were added. The reaction mixture was stirred at room temperature for 1 hour. Water (20 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (20 mL × 2). The organic phases were combined, washed with saturated brine (30 mL × 3), and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated, and the resulting crude product was purified by silica gel column chromatography (DCM:MeOH = 100:1 to 5:1) to give 1-(5-(9-((4-benzylpiperazin-1-yl)methyl)-3-azaspiro[5.5]undecane-3-carbonyl)-2-chlorophenyl)dihydropyrimidine-2,4(1H,3H)-dione. LC-MS: (ESI, m / z): [M+H] += 592.2.

[0398] Step 4: Preparation of 1-(2-chloro-5-(9-(piperazin-1-ylmethyl)-3-azaspiro[5.5]undecane-3-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione

[0399] [ka] 1-(5-(9-((4-benzylpiperazin-1-yl)methyl)-3-azaspiro[5.5]undecane-3-carbonyl)-2-chlorophenyl)dihydropyrimidine-2,4(1H,3H)-dione (0.16 g, 0.27 mmol) was dissolved in DCM (3 mL), and then 1-chloroethyl chloroformate (77 mg, 0.54 mmol) and DIEA (70 mg, 0.54 mmol) were added. The mixture was reacted at room temperature for 30 minutes, and then MeOH (3 mL) was added, and the reaction mixture was reacted at 50°C for 30 minutes. After the reaction was completed, water was added, and the mixture was extracted with ethyl acetate (50 mL x 3). The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The obtained crude product was purified by silica gel column chromatography (DCM:MeOH=20:1) to give 1-(2-chloro-5-(9-(piperazin-1-ylmethyl)-3-azaspiro[5.5]undecane-3-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione. LC-MS: (ESI, m / z): [M+H] + = 502.2.

[0400] Intermediate 13: 1-(2-chloro-5-(3,9-diazaspiro[5.5]undecane-3-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride Step 1: Preparation of tert-butyl 9-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzoyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate

[0401] [ka] To a solution of tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate (294 mg, 1.16 mmol) in DMF (5 mL), pentafluorophenyl 4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzoate (500 mg, 1.15 mmol) and DIEA (387 mg, 3.00 mmol) were added, and the mixture was allowed to react at room temperature for 2 hours. Water (50 mL) was added to the reaction mixture, which was then extracted with ethyl acetate (30 mL × 2). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified by silica gel column chromatography (DCM:MeOH = 100:1 elution) to give tert-butyl 9-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzoyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate. LC-MS: (ESI, m / z): [M-tBu+H] + = 449.2.

[0402] Step 2: Preparation of 1-(2-chloro-5-(3,9-diazaspiro[5.5]undecane-3-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride

[0403] [ka] To a stirred solution of tert-butyl 9-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzoyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate (400 mg, 0.79 mmol) in 1,4-dioxane (5.0 mL), HCl / 1,4-dioxane (6 N, 5.0 mL) was added and the reaction was allowed to proceed at room temperature for 1 hour. The reaction mixture was concentrated and then directly concentrated under reduced pressure to give 1-(2-chloro-5-(3,9-diazaspiro[5.5]undecane-3-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride. The resulting product was used directly in the next reaction.

[0404] Intermediate 14: tert-Butyl 3-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-((1-formylcyclopropyl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate Step 1: Preparation of tert-butyl 3-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-((1-formylcyclopropyl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0405] [ka] Cesium fluoride (1.35 g, 8.92 mmol) was added to a solution of tert-butyl 3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((1-formylcyclopropyl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.5 g, 1.78 mmol) in DMF (6 mL). The mixture was reacted at 25 °C for 16 hours, quenched by the addition of water (10 mL), extracted with ethyl acetate (10 mL × 3), and the combined organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (DCM:MeOH=30:1) to give tert-butyl 3-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-((1-formylcyclopropyl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate. LC-MS: (ESI, m / z): [M+H] + = 685.3.

[0406] Step 2: Preparation of tert-butyl 3-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-((1-formylcyclopropyl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0407] [ka] 3-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-((1-formylcyclopropyl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate tert-butyl (800 mg, 1.17 mmol) in ethyl acetate (6 mL) was added to Pd / C (124 mg, 0.117 mmol) and reacted at 30 ° C. for 16 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure to give 3-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-((1-formylcyclopropyl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate tert-butyl. LC-MS: (ESI, m / z): [M+H] + = 688.9.

[0408] Intermediate 15: tert-butyl 3-(8-fluoro-2-((1-formylcyclopropyl)methoxy)-7-(3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate Step 1: Preparation of tert-butyl 3-(8-fluoro-2-((1-(hydroxymethyl)cyclopropyl)methoxy)-7-(3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0409] [ka] To a solution of tert-butyl 3-(7-chloro-8-fluoro-2-((1-(hydroxymethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (300 mg, 0.61 mmol) and triisopropyl((6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)silane (361 mg, 0.73 mmol) in 1,4-dioxane (6 mL) and HO (1.2 mL) was added cataCXium A Pd G3 (44 mg, 0.061 mmol) and cesium carbonate (398 mg, 1.22 mmol). The mixture was reacted at 85 °C for 6 h under nitrogen gas protection. The reaction mixture was directly filtered and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (DCM:MeOH=100:1) to give tert-butyl 3-(8-fluoro-2-((1-(hydroxymethyl)cyclopropyl)methoxy)-7-(3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate. LC-MS: (ESI, m / z): [M+H] + = 826.1.

[0410] Step 2: Preparation of tert-butyl 3-(8-fluoro-2-((1-formylcyclopropyl)methoxy)-7-(3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0411] [ka] To a solution of tert-butyl 3-(8-fluoro-2-((1-(hydroxymethyl)cyclopropyl)methoxy)-7-(3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (260 mg, 0.31 mmol) in dichloromethane (5 mL) was added Dess-Martin reagent (200 mg, 0.47 mmol). The mixture was stirred at room temperature for 2 hours. After completion of the reaction, the reaction was quenched by the addition of sodium thiosulfate solution (5 mL) and sodium bicarbonate solution (5 mL). The mixture was extracted with dichloromethane (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (PE:EA=1:1) to give tert-butyl 3-(8-fluoro-2-((1-formylcyclopropyl)methoxy)-7-(3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate. LC-MS: (ESI, m / z): [M+H] + = 824.1.

[0412] Intermediate 16: 1-(2-chloro-5-(4-(2-(methyl(piperidin-4-ylmethyl)amino)ethyl)piperidine-1-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione Step 1: Preparation of 4-(2-oxoethyl)piperidine-1-carboxylate

[0413] [ka] To a solution of 4-(2-hydroxyethyl)piperidine-1-carboxylate (5 g, 18.99 mmol) in DCM (50 mL) was added Dess-Martin oxidant (10.5 g, 24.69 mmol), and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, the reaction was quenched by the addition of sodium thiosulfate solution (50 mL) and sodium bicarbonate solution (50 mL), followed by extraction with dichloromethane (50 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 4-(2-oxoethyl)piperidine-1-carboxylate, which was used directly in the next step.

[0414] Step 2: Preparation of 4-(2-(((1-(tert-butoxycarbonyl)piperidin-4-yl)methyl)(methyl)amino)ethyl)piperidine-1-carboxylate

[0415] [ka] To a solution of 4-(2-oxoethyl)piperidine-1-carboxylate (2.66 g, 10.2 mmol) in DCM / MeOH (30 mL / 15 mL) was added tert-butyl 4-((methylamino)methyl)piperidine-1-carboxylate (2.8 g, 12.3 mmol) and acetic acid (1.5 mL). The mixture was stirred at room temperature for 2 h. Then, at 0 °C, NaBH(OAc) (4.3 g, 20.4 mmol) was added. The mixture was diluted with water (30 mL) and extracted with DCM (30 mL × 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by silica gel column chromatography (DCM:MeOH = 20:1) to give 4-(2-(((1-(tert-butoxycarbonyl)piperidin-4-yl)methyl)(methyl)amino)ethyl)piperidine-1-carboxylate. LC-MS: (ESI, m / z): [M+H] + = 474.1.

[0416] Step 3: Preparation of tert-butyl 4-((methyl(2-(piperidin-4-yl)ethyl)amino)methyl)piperidine-1-carboxylate

[0417] [ka] To a solution of 4-(2-(((1-(tert-butoxycarbonyl)piperidin-4-yl)methyl)(methyl)amino)ethyl)piperidine-1-carboxylate (2 g, 4.2 mmol) in methanol (15 mL) was added Pd / C (447 mg) and stirred at 30° C. for 16 hours under hydrogen balloon protection. The mixture was filtered and concentrated to give tert-butyl 4-((methyl(2-(piperidin-4-yl)ethyl)amino)methyl)piperidine-1-carboxylate. The crude product was used directly in the next step without further purification. LC-MS: (ESI, m / z): [M+H] + = 340.3.

[0418] Step 4: Preparation of tert-butyl 4-(((2-(1-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzoyl)piperidin-4-yl)ethyl)(methyl)amino)methyl)piperidine-1-carboxylate

[0419] [ka] To a solution of tert-butyl 4-((methyl(2-(piperidin-4-yl)ethyl)amino)methyl)piperidine-1-carboxylate (600 mg, crude) in DMF (8 mL) was added pentafluorophenyl 4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzoate (769 mg, 1.77 mmol) and DIEA (686 mg, 5.31 mmol). The mixture was stirred at room temperature for 2 hours. After completion of the reaction, water (10 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phase was dried, concentrated, and purified by silica gel column chromatography (DCM:MeOH = 20:1) to give tert-butyl 4-(((2-(1-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzoyl)piperidin-4-yl)ethyl)(methyl)amino)methyl)piperidine-1-carboxylate. LC-MS: (ESI, m / z): [M+H] + = 590.3.

[0420] Step 5: Preparation of 1-(2-chloro-5-(4-(2-(methyl(piperidin-4-ylmethyl)amino)ethyl)piperidine-1-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione

[0421] [ka] To a solution of tert-butyl 4-(((2-(1-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzoyl)piperidin-4-yl)ethyl)(methyl)amino)methyl)piperidine-1-carboxylate (900 mg, 1.5 mmol) in 1,4-dioxane (3 mL) was added HCl / 1,4-dioxane (2 mL) and stirred at 30° C. for 1 hour. After completion of the reaction, aqueous NaCO (5 mL) was added to adjust the pH to >7, and the mixture was extracted with ethyl acetate (5 mL × 3). The combined organic phase was dried over Na2SO4, filtered, concentrated under reduced pressure and purified by silica gel column chromatography (DCM:MeOH(NH3)=20:1) to give 1-(2-chloro-5-(4-(2-(methyl(piperidin-4-ylmethyl)amino)ethyl)piperidine-1-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione. LC-MS: (ESI, m / z): [M+H] + = 490.3.

[0422] Intermediate 17: tert-butyl 3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((1-formylcyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate Step 1: Preparation of tert-butyl 3-(7-chloro-8-fluoro-2-((1-(hydroxymethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0423] [ka] To a solution of tert-butyl 3-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (4.0 g, 9.35 mmol) and cyclopropane-1,1-diyldimethanol (1.9 g, 18.7 mmol) in THF (50 mL) was added CsCO (9.1 g, 28.0 mmol), and the mixture was stirred at room temperature for 16 h. To the reaction mixture was added HO (50 mL), extracted with EtOAc (50 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (DCM:MeOH = 50:1) to give tert-butyl 3-(7-chloro-8-fluoro-2-((1-(hydroxymethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate. LC-MS: (ESI, m / z): [M+H] + = 494.2.

[0424] Step 2: Preparation of tert-butyl 3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((1-(hydroxymethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0425] [ka] To a solution of tert-butyl 3-(7-chloro-8-fluoro-2-((1-(hydroxymethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (6.0 g, 12.2 mmol) and (2-fluoro-6-(methoxymethyloxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (7.5 g, 14.6 mmol) in 1,4-dioxane (60 mL) and HO (12 mL) was added cataCXium A Pd G3 (1.8 g, 2.4 mmol) and cesium carbonate (11.9 g, 36.4 mmol). The mixture was reacted under nitrogen gas protection at 85 °C for 3 hours, quenched by adding water (100 mL), extracted with ethyl acetate (100 mL × 3), and the combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (DCM:MeOH = 100:1) to give tert-butyl 3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((1-(hydroxymethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate. LC-MS: (ESI, m / z): [M+H] + = 844.4.

[0426] Step 3: Preparation of tert-butyl 3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((1-formylcyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0427] [ka] A solution of tert-butyl 3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((1-(hydroxymethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (4.0 g, 4.7 mmol) in DCM (40 mL) was cooled to 0 ° C., and then Dess-Martin (2.4 g, 5.7 mmol) was added and reacted at room temperature for 0.5 hours. The reaction mixture was quenched by adding water (30 mL), extracted with dichloromethane (30 mL × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (DCM:MeOH(NH3) = 30:1) to give tert-butyl 3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((1-formylcyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate. LC-MS: (ESI, m / z): [M+H] + = 842.4. 1H NMR (400 MHz, CDCl3) δ 9.27 (s, 1H), 9.07 (s, 1H), 7.79 (dd, J = 9.2 Hz, 5.6 Hz, 1H), 7.51 (d, J = 2.8 Hz, 1H), 7.35-7.28 (m, 2H), 5.35 - 5.24 (m, 2H), 4.86 - 4.69 (m, 2H), 4.64 - 4.55 (m, 1H), 4.50 - 4.28 (m, 2H), 4.21 - 4.10 (m, 1H), 3.90 - 3.68 (m, 1H), 3.62 - 3.34 (m, 4H), 2.05 - 1.98 (m, 3H), 1.79 - 1.64 (m, 1H), 1.52 (s, 9H), 1.39 - 1.26 (m, 4H), 0.95 - 0.78 (m, 18H), 0.61 - 0.47 (m, 3H).

[0428] Intermediate 18: 1-(2-chloro-5-(4-(3-(piperazin-1-yl)propyl)piperidine-1-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione Step 1: Preparation of 4-(3-hydroxypropyl)piperidine-1-carboxylate

[0429] [ka] To a solution of 3-(piperidin-4-yl)propan-1-ol (3 g, 20.9 mmol) in tetrahydrofuran (12 mL) was added a solution of sodium bicarbonate (42 mL), cooled to 0 °C, and then benzyl chloroformate (3.9 g, 23.0 mmol) was added dropwise. The mixture was allowed to react at room temperature for 2 hours, and then extracted with ethyl acetate (30 mL × 3). The organic phase was dried and concentrated, and purified by silica gel column chromatography (PE:EA = 30:1) to give 4-(3-hydroxypropyl)piperidine-1-carboxylate. LC-MS: (ESI, m / z): [M+H] + = 278.1.

[0430] Step 2: Preparation of 4-(3-oxopropyl)piperidine-1-carboxylate

[0431] [ka] To a solution of 4-(3-hydroxypropyl)piperidine-1-carboxylate (4 g, 14.4 mmol) in dichloromethane (50 mL) was added Dess-Martin (7 g, 17.3 mmol). The mixture was stirred at room temperature for 2 hours. After completion of the reaction, the reaction was quenched by the addition of sodium thiosulfate solution (50 mL) and sodium bicarbonate solution (50 mL). The mixture was extracted with dichloromethane (50 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (PE:EA = 2:1) to give 4-(3-oxopropyl)piperidine-1-carboxylate. LC-MS: (ESI, m / z): [M+H] + = 276.1.

[0432] Step 3: Preparation of tert-butyl 4-(3-(1-((benzyloxy)carbonyl)piperidin-4-yl)propyl)piperazine-1-carboxylate

[0433] [ka] 4-(3-oxopropyl)piperidine-1-carboxylate (3.3 g, 12.0 mmol) in 1,2-dichloroethane (60 mL) was added with tert-butyl piperazine-1-carboxylate (6.7 g, 36.0 mmol) and acetic acid (2 mL). The mixture was allowed to react at room temperature for 2 hours. After cooling to 0 °C, sodium borohydride acetate (5.3 g, 24.0 mmol) was added slowly and the mixture was allowed to react at room temperature for 16 hours. After completion of the reaction, the reaction was quenched by adding water (60 mL) and extracted with dichloromethane (60 mL × 3). The organic phase was dried, concentrated, and purified by silica gel column chromatography (PE:EA = 1:1) to give tert-butyl 4-(3-(1-((benzyloxy)carbonyl)piperidin-4-yl)propyl)piperazine-1-carboxylate. LC-MS: (ESI, m / z): [M+H] + = 446.2.

[0434] Step 4: Preparation of tert-butyl 4-(3-(piperidin-4-yl)propyl)piperazine-1-carboxylate

[0435] [ka] To a solution of tert-butyl 4-(3-(1-((benzyloxy)carbonyl)piperidin-4-yl)propyl)piperazine-1-carboxylate (2.5 g, 5.6 mmol) in methanol (40 mL) was added Pd / C (597 mg) and stirred at 30° C. for 16 hours. The mixture was filtered and concentrated to give tert-butyl 4-(3-(piperidin-4-yl)propyl)piperazine-1-carboxylate. LC-MS: (ESI, m / z): [M+H] + = 312.2.

[0436] Step 5: Preparation of tert-butyl 4-(3-(1-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzoyl)piperidin-4-yl)propyl)piperazine-1-carboxylate

[0437] [ka] To a solution of tert-butyl 4-(3-(piperidin-4-yl)propyl)piperazine-1-carboxylate (250 mg, 0.8 mmol) in DMF (3 mL) was added 4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)pentafluorophenyl benzoate (348 mg, 0.8 mmol) and DIEA (310 mg, 2.4 mmol). The mixture was stirred at room temperature for 1 hour. After completion of the reaction, water (5 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (5 mL x 3). The organic phase was dried, concentrated, and purified by silica gel column chromatography (DCM:MeOH = 20:1) to give tert-butyl 4-(3-(1-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzoyl)piperidin-4-yl)propyl)piperazine-1-carboxylate. LC-MS: (ESI, m / z): [M+H] + = 562.2.

[0438] Step 6: Preparation of 1-(2-chloro-5-(4-(3-(piperazin-1-yl)propyl)piperidine-1-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione

[0439] [ka] To a solution of tert-butyl 4-(3-(1-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzoyl)piperidin-4-yl)propyl)piperazine-1-carboxylate (400 mg, 0.71 mmol) in 1,4-dioxane (2 mL) was added HCl / 1,4-dioxane (6 N, 1 mL). The mixture was stirred at room temperature for 1 hour, concentrated, and purified by silica gel column chromatography (DCM:MeOH(NH)=20:1) to give 1-(2-chloro-5-(4-(3-(piperazin-1-yl)propyl)piperidine-1-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione. LC-MS: (ESI, m / z): [M+H] + = 462.2.

[0440] Intermediate 19: tert-Butyl 9-(3-hydroxypropyl)-3-azaspiro[5.5]undecane-3-carboxylate

[0441] [ka] It was prepared with reference to Example 21 of patent WO2022223034A1.

[0442] Intermediate 20: tert-Butyl 9-(2-hydroxyethyl)-3-azaspiro[5.5]undecane-3-carboxylate

[0443] [ka] It was prepared with reference to Example 22 of patent WO2022223034A1.

[0444] Intermediate 21: 1-(2-chloro-5-(piperazine-1-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione

[0445] [ka] It was prepared with reference to Example 40 of patent WO2023025159A1.

[0446] Intermediate 22: 3-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methylbenzoyl)-3-azaspiro[5.5]undecane-9-formaldehyde

[0447] [ka] Prepared with reference to intermediate 32 of patent WO2023025159A1.

[0448] Intermediate 23: 1-(2-chloro-5-(3,9-diazaspiro[5.5]undecane-3-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione

[0449] [ka] It was prepared with reference to Example 48 of patent WO2023025159A1.

[0450] Intermediate 24: 3-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)-3-azaspiro[5.5]undecane-9-formaldehyde

[0451] [ka] Refer to the preparation method of intermediate 3.

[0452] Intermediate 25: tert-butyl 3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((R)-2-methyl-3-(piperazin-1-yl)propoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate Step 1: Preparation of methyl (S)-3-((tert-butyldimethylsilyl)oxy)-2-methylpropionate

[0453] [ka] Methyl (S)-3-hydroxy-2-methylpropionate (30 g, 254 mmol) and imidazole (34.5 g, 508 mmol) were dissolved in dichloromethane (120 mL), tert-butyldimethylchlorosilane (46 g, 305 mmol) was added, and the mixture was allowed to react at room temperature for 3 hours. After completion of the reaction, the reaction mixture was poured into saturated aqueous ammonium chloride (20 mL) and extracted with ethyl acetate (200 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The resulting crude product was purified by silica gel column chromatography (PE: EtOAc = 30:1) to give methyl (S)-3-((tert-butyldimethylsilyl)oxy)-2-methylpropionate. 1 H NMR (400 MHz, CDCl3) δ 3.80 - 3.73 (m, 1H), 3.70 - 3.58 (m, 4H), 2.69 - 2.57(m, 1H), 1.14 (d, J = 7.0 Hz, 3H), 0.87 (s, 9H), 0.03 (d, J = 1.4 Hz, 6H).

[0454] Step 2: Preparation of (R)-3-((tert-butyldimethylsilyl)oxy)-2-methylpropan-1-ol

[0455] [ka] Methyl (S)-3-((tert-butyldimethylsilyl)oxy)-2-methylpropionate (49 g, 211 mmol) was dissolved in THF / MeOH (500 mL / 100 mL) and cooled to 0-5°C. Lithium borohydride (7 g, 317 mmol) was added and the mixture was allowed to react at room temperature for 16 h. The reaction was quenched by adding aqueous ammonium chloride solution, followed by extraction with ethyl acetate (200 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give (R)-3-((tert-butyldimethylsilyl)oxy)-2-methylpropan-1-ol, which was used directly in the next reaction. 1 H NMR (400 MHz, CDCl3) δ 3.77 - 3.69 (m, 1H), 3.68 - 3.49 (m, 3H), 2.82 (brs, 1H), 2.00 - 1.87 (m, 1H), 0.89 (s, 9H), 0.83 (d, J = 7.0 Hz, 3H), 0.07 (s, 6H).

[0456] Step 3: Preparation of (S)-3-((tert-butyldimethylsilyl)oxy)-2-methylpropyl methanesulfonate

[0457] [ka] (R)-3-((tert-butyldimethylsilyl)oxy)-2-methylpropan-1-ol (35 g, 172 mmol) and triethylamine (34.7 g, 344 mmol) were dissolved in DCM and cooled to 0-5°C. Methanesulfonyl chloride (23.6 g, 206 mmol) was added and the mixture was allowed to react at room temperature for 2 hours. Aqueous ammonium chloride was added, and the mixture was extracted with DCM. The organic phase was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give crude (S)-3-((tert-butyldimethylsilyl)oxy)-2-methylpropyl methanesulfonate. The crude product was used directly in the next reaction.

[0458] Step 4: Preparation of (R)-1-benzyl-4-(3-((tert-butyldimethylsilyl)oxy)-2-methylpropyl)piperazine

[0459] [ka] (S)-3-((tert-butyldimethylsilyl)oxy)-2-methylpropyl methanesulfonate (48 g, crude product) was added to a mixture of 1-benzylpiperazine hydrochloride (73 g, 344 mmol) and potassium carbonate (95 g, 688 mmol), heated at 60°C, and reacted for 16 hours. The reaction mixture was filtered, and the filtrate was concentrated and purified by column chromatography (PE: EtOAc = 20:1 to 3:1) to give (R)-1-benzyl-4-(3-((tert-butyldimethylsilyl)oxy)-2-methylpropyl)piperazine. LC-MS: (ESI, m / z): [M+H] + = 363.4.

[0460] Step 5: Preparation of (R)-3-(4-benzylpiperazin-1-yl)-2-methylpropan-1-ol

[0461] [ka] (R)-1-Benzyl-4-(3-((tert-butyldimethylsilyl)oxy)-2-methylpropyl)piperazine (22 g, 60 mmol) was dissolved in ethanol (300 mL), cooled to 0-5°C, and concentrated hydrochloric acid (80 mL) was added. The mixture was allowed to react at room temperature for 1 hour. The reaction mixture was concentrated to remove the ethanol. Water (100 mL) was added to the residue, followed by extraction with methyl tert-butyl ether (100 mL). The aqueous phase was adjusted to pH 8-9 with aqueous sodium carbonate and extracted with ethyl acetate (100 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give (R)-3-(4-benzylpiperazin-1-yl)-2-methylpropan-1-ol (ee=98.8%). 1 H NMR (400 MHz, CDCl3) δ 7.34 - 7.28 (m, 4H), 7.27 - 7.22 (m, 1H), 3.70 - 3.59 (m, 1H), 3.54 - 3.39 (m, 3H), 2.86 - 2.25 (m, 10H), 2.18 - 2.10 (m, 1H), 0.73 (d, J = 6.8 Hz, 3H). LC-MS: (ESI, m / z): [M+H] + = 249.2.

[0462] Step 6: Preparation of tert-butyl 3-(2-((R)-3-(4-benzylpiperazin-1-yl)-2-methylpropoxy)-7-chloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-diazabicyclo[3.2.1]octane-8-carboxylate

[0463] [ka] tert-Butyl 3-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-diazabicyclo[3.2.1]octane-8-carboxylate (1.50 g, 3.50 mmol) and (R)-3-(4-benzylpiperazin-1-yl)-2-methylpropan-1-ol (1.30 g, 5.26 mmol) were dissolved in THF (100 mL) and placed in a sealed tube reactor. CsCO (3.42 g, 10.5 mmol) was added. The reaction mixture was heated to 90 °C and allowed to react for 16 h. After completion of the reaction, the mixture was cooled to room temperature, water (30 mL) was added, and the mixture was then extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated NaCl solution, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated. The resulting crude product was purified by silica gel column chromatography (DCM:MeOH=20:1) to give tert-butyl 3-(2-((R)-3-(4-benzylpiperazin-1-yl)-2-methylpropoxy)-7-chloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-diazabicyclo[3.2.1]octane-8-carboxylate. LC-MS: (ESI, m / z): [M+H] + = 640.4.

[0464] Step 7: Preparation of tert-butyl 3-(2-((R)-3-(4-benzylpiperazin-1-yl)-2-methylpropoxy)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-diazabicyclo[3.2.1]octane-8-carboxylate

[0465] [ka] To a solution of tert-butyl 3-(2-((R)-3-(4-benzylpiperazin-1-yl)-2-methylpropoxy)-7-chloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-diazabicyclo[3.2.1]octane-8-carboxylate (1.00 g, 1.56 mmol) and ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (0.96 g, 1.81 mmol) in 1,4-dioxane / water (6 mL / 1.2 mL) was added Ruphos Pd G3 (0.13 g, 0.16 mmol) and potassium phosphate (0.99 g, 4.68 mmol). The mixture was reacted under nitrogen gas protection at 85 °C for 16 hours, water (20 mL) was added, and extracted with ethyl acetate (20 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (DCM:MeOH = 20:1) to give tert-butyl 3-(2-((R)-3-(4-benzylpiperazin-1-yl)-2-methylpropoxy)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-diazabicyclo[3.2.1]octane-8-carboxylate. LC-MS: (ESI, m / z): [M+H] + = 990.6.

[0466] Step 8: Preparation of tert-butyl 3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((R)-2-methyl-3-(piperazin-1-yl)propoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0467] [ka] Tert-butyl 3-(2-((R)-3-(4-benzylpiperazin-1-yl)-2-methylpropoxy)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-diazabicyclo[3.2.1]octane-8-carboxylate (300 mg, 0.30 mmol) was dissolved in DCM (3 mL), and 1-chloroethyl chloroformate (130 mg, 0.91 mmol) and DIEA (117 mg, 0.91 mmol) were added. The mixture was reacted at room temperature for 1 hour, and the reaction solution was directly concentrated under reduced pressure. MeOH (5 mL) was added to the concentrate, which was then heated to 50 °C and reacted for 1 hour. After completion of the reaction, the mixture was concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (DCM:MeOH(NH3) = 20:1) to give tert-butyl 3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((R)-2-methyl-3-(piperazin-1-yl)propoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate. LC-MS: (ESI, m / z): [M+H] + = 900.5.

[0468] Intermediate 26: 3-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-(methyl-d3)benzoyl)-3-azaspiro[5.5]undecane-9-formaldehyde

[0469] [ka] To a solution of 3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-(methyl-d3)benzoic acid (50 mg, 0.2 mmol) in DMF (5 mL), HATU (76 mg, 0.2 mmol) and DIEA (130 mg, 1 mmol) were added, followed by 3-azaspiro[5.5]undecane-9-formaldehyde (47 mg, 0.17 mmol). The mixture was allowed to react at room temperature overnight. After completion of the reaction, HO (15 mL) was added to the reaction mixture, which was then extracted with ethyl acetate (15 mL × 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (DCM:MeOH=20:1) to give 3-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-(methyl-d3)benzoyl)-3-azaspiro[5.5]undecane-9-formaldehyde. LC-MS: (ESI, m / z): [M+H] + = 415.3.

[0470] Intermediate 27: 3-(5-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-2-fluoro-4-methylbenzoyl)-3-azaspiro[5.5]undecane-9-formaldehyde Step 1: Preparation of 5-amino-2-fluoro-4-methylbenzoic acid

[0471] [ka] To a solution of 2-fluoro-4-methyl-5-nitrobenzoic acid (4.8 g, 24.1 mmol) in MeOH (150 mL) was added Pd / C (700 mg, 10%). The mixture was stirred overnight at 50 °C under a H atmosphere. The reaction mixture was filtered through diatomaceous earth, and the filtrate was concentrated to give 5-amino-2-fluoro-4-methylbenzoic acid. LC-MS: (ESI, m / z): [M+H] + = 170.1.

[0472] Step 2: Preparation of 5-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-2-fluoro-4-methylbenzoic acid

[0473] [ka] Acrylic acid (6.6 mL, 7 g, 96.8 mmol) and HOAc (30 mL) were added to 5-amino-2-fluoro-4-methylbenzoic acid (4.1 g, 24.2 mmol) and stirred at 100°C for 3 hours. After the reaction, urea (9 g, 150 mmol) was added and the mixture was stirred at 120°C overnight. The reaction mixture was poured into ice water, concentrated hydrochloric acid was added with stirring, and the mixture was allowed to stand overnight at low temperature. The mixture was then filtered and washed with water. The filter cake was dried to give 5-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-2-fluoro-4-methylbenzoic acid. LC-MS: (ESI, m / z): [M+H] + = 267.1.

[0474] Step 3: Preparation of 3-(5-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-2-fluoro-4-methylbenzoyl)-3-azaspiro[5.5]undecane-9-formaldehyde

[0475] [ka] To a solution of 5-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-2-fluoro-4-methylbenzoic acid (350 mg, 1.3 mmol) in DMF (10 mL) was added HATU (502 mg, 1.3 mmol) and DIEA (430 mg, 3.3 mmol), followed by 3-azaspiro[5.5]undecane-9-formaldehyde (200 mg, 1.1 mmol), and the mixture was stirred at room temperature overnight. After completion of the reaction, HO (50 mL) was added, and the mixture was extracted with ethyl acetate (50 mL × 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure in vacuo. The crude product was purified by silica gel column chromatography (DCM:MeOH=20:1) to give 3-(5-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-2-fluoro-4-methylbenzoyl)-3-azaspiro[5.5]undecane-9-formaldehyde. LC-MS: (ESI, m / z): [M+H] + = 430.2.

[0476] Intermediate 28: tert-butyl 3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((1-formylcyclopropyl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0477] [ka] Refer to the preparation method of intermediate 17.

[0478] Intermediate 29: 3-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-ethylbenzoyl)-3-azaspiro[5.5]undecane-9-formaldehyde

[0479] [ka] Refer to the preparation of intermediate 26.

[0480] Intermediate 30: (R)-3-(4-benzylpiperazin-1-yl)-2-methoxypropan-1-ol Step 1: Preparation of (R)-1-(4-benzylpiperazin-1-yl)-3-((tert-butyldimethylsilyl)oxy)propan-2-ol

[0481] [ka] A mixture of (R)-tert-butyldimethyl(epoxy-2-ylmethoxy)silane (20 g, 106 mmol), N-benzylpiperazine hydrochloride (25 g, 117 mmol), and potassium carbonate (29 g, 212 mmol) in THF (15 mL) was heated to reflux for 3 h. After completion of the reaction, the solid was filtered, and the filtrate was concentrated to give the crude product, which was purified by silica gel column chromatography (PE:EA = 2:1) to give (R)-1-(4-benzylpiperazin-1-yl)-3-((tert-butyldimethylsilyl)oxy)propan-2-ol. LC-MS: (ESI, m / z): [M+H] + = 365.3.

[0482] Step 2: Preparation of (R)-1-benzyl-4-(3-((tert-butyldimethylsilyl)oxy)-2-methoxypropyl)piperazine

[0483] [ka] (R)-1-(4-benzylpiperazin-1-yl)-3-((tert-butyldimethylsilyl)oxy)propan-2-ol (20.0 g, 55 mmol) was dissolved in THF (200 mL). NaH (2.6 g, 110 mmol) was added at 0 °C and the mixture was reacted at 25 °C for 30 min. After cooling to 0 °C, iodomethane (9.7 g, 69 mmol) was added and the mixture was reacted at room temperature for 3 h. After completion of the reaction, the reaction mixture was slowly poured into cooled aqueous NH4Cl (200 mL) and then extracted with ethyl acetate (200 mL × 3). The organic phases were combined, washed with saturated NaCl solution, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated. The resulting crude product was purified by silica gel column chromatography (PE:EA=5:1) to give (R)-1-benzyl-4-(3-((tert-butyldimethylsilyl)oxy)-2-methoxypropyl)piperazine (ee=99.3%).

[0484] Chiral separation: The column was IG 5 μm, the column size was 4.6 × 250 mm, the mobile phase was Hex:EtOH:DEA = 90:2:0.2, the flow rate was 1 mL / min 254 nm, and the column temperature was 30°C. LC-MS: (ESI, m / z): [M+H] + = 379.2.

[0485] Step 3: Preparation of (R)-3-(4-benzylpiperazin-1-yl)-2-methoxypropan-1-ol

[0486] [ka] (R)-1-benzyl-4-(3-((tert-butyldimethylsilyl)oxy)-2-methoxypropyl)piperazine (15.0 g, 40 mmol) was dissolved in ethanol (100 mL) and cooled to 0-5°C. Concentrated hydrochloric acid (40 mL) was added and the mixture was allowed to react at room temperature for 1 hour. After completion of the reaction, the reaction mixture was concentrated to remove the ethanol. Water (100 mL) was added to the concentrate and the mixture was extracted with methyl tert-butyl ether (100 mL). The aqueous phase was adjusted to pH 8-9 with aqueous sodium carbonate and extracted with ethyl acetate (100 mL x 3). The combined EA phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give (R)-3-(4-benzylpiperazin-1-yl)-2-methoxypropan-1-ol, which was used directly in the next reaction.

[0487] Intermediate 31: tert-butyl 3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((R)-2-methoxy-3-(piperazin-1-yl)propoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate Step 1: Preparation of tert-butyl 3-(2-((R)-3-(4-benzylpiperazin-1-yl)-2-methoxypropoxy)-7-chloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0488] [ka] tert-Butyl 3-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.5 g, 3.50 mmol) and (R)-3-(4-benzylpiperazin-1-yl)-2-methoxypropan-1-ol (1.11 g, 4.20 mmol) were dissolved in ACN (15 mL), and CsCO (3.42 g, 10.5 mmol) and DABCO (79 mg, 0.70 mmol) were added. The mixture was allowed to react at room temperature for 1 h. After completion of the reaction, the solid was removed by filtration, the filter cake was washed twice with dichloromethane, the filtrate was concentrated, and the resulting crude product was purified by silica gel column chromatography (PE:EA=2:1) ​​to give tert-butyl 3-(2-((R)-3-(4-benzylpiperazin-1-yl)-2-methoxypropoxy)-7-chloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate. LC-MS: (ESI, m / z): [M+H] + = 656.3.

[0489] Step 2: Preparation of tert-butyl 3-(2-((R)-3-(4-benzylpiperazin-1-yl)-2-methoxypropoxy)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0490] [ka] To a solution of tert-butyl 3-(2-((R)-3-(4-benzylpiperazin-1-yl)-2-methoxypropoxy)-7-chloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.2 g, 1.83 mmol) and ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (1.13 g, 2.20 mmol) in 1,4-dioxane (8 mL) and HO (1.6 mL) was added Cata CXium Pd G3 (267 mg, 0.366 mmol) and cesium carbonate (1.79 g, 5.49 mmol). The mixture was reacted at 85°C for 16 hours under nitrogen gas protection. Water (20 mL) was added to the reaction mixture, which was then extracted with ethyl acetate (30 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (DCM:MeOH = 20:1) to give tert-butyl 3-(2-((R)-3-(4-benzylpiperazin-1-yl)-2-methoxypropoxy)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate.

[0491] LC-MS: (ESI, m / z): [M+H] + = 1006.6.

[0492] Step 3: Preparation of tert-butyl 3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((R)-2-methoxy-3-(piperazin-1-yl)propoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0493] [ka] Tert-butyl 3-(2-((R)-3-(4-benzylpiperazin-1-yl)-2-methoxypropoxy)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.3 g, 1.29 mmol) was dissolved in DCM (5 mL), and then 1-chloroethyl chlorocarbonate (553 mg, 3.87 mmol) and DIEA (500 mg, 3.87 mmol) were added. The mixture was reacted at room temperature for 1 hour, and the reaction solution was directly concentrated under reduced pressure. The concentrate was dissolved in MeOH (5 mL) and then heated to 50 °C for 30 minutes. After completion of the reaction, the mixture was concentrated under reduced pressure, and the concentrate was purified by silica gel column chromatography (DCM:MeOH(NH3) = 15:1) to obtain tert-butyl 3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((R)-2-methoxy-3-(piperazin-1-yl)propoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate.

[0494] LC-MS: (ESI, m / z): [M+H] + = 916.5.

[0495] Intermediate 32: tert-butyl 3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((R)-2-methyl-3-(piperazin-1-yl)propoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate Step 1: Preparation of tert-butyl 3-(7-bromo-2-chloro-8-fluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0496] [ka] To a solution of 7-bromo-2,4-dichloro-8-fluoroquinazoline (5.000 g, 16.896 mmol) in dichloromethane (150 mL) was added triethylamine (5.129 g, 50.689 mmol) and tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (3.659 g, 17.234 mmol) at -50 °C and stirred for 4 hours at -50 °C. Anhydrous tetrahydrofuran (60 mL) was added, and the mixture was stirred for 30 minutes. Insoluble matter was removed by filtration, and the filtrate was concentrated. Petroleum ether / tetrahydrofuran (10 / 1, 50 mL) was added to the concentrate, and the mixture was stirred and filtered to give tert-butyl 3-(7-bromo-2-chloro-8-fluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate. LC-MS: (ESI, m / z): [M+H] + = 471.1.

[0497] Step 2: Preparation of tert-butyl 3-(2-((R)-3-(4-benzylpiperazin-1-yl)-2-methylpropoxy)-7-bromo-8-fluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ka] To a stirred solution of tert-butyl 3-(7-bromo-2-chloro-8-fluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (2.000 g, 4.239 mmol) and (R)-3-(4-benzylpiperazin-1-yl)-2-methylpropan-1-ol (1.369 g, 5.511 mmol) in anhydrous acetonitrile (50 mL) at 25° C., triethylenediamine (0.143 g, 1.272 mmol) and cesium carbonate (4.143 g, 12.717 mmol) were added and the mixture was stirred at 25° C. for 18 hours. After completion of the reaction, the reaction mixture was poured into water (150 mL) and extracted with ethyl acetate (50 mL × 3). The organic phase was washed with saturated brine (150 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (petroleum ether: tetrahydrofuran = 20:1 to 4:1) to give tert-butyl 3-(2-((R)-3-(4-benzylpiperazin-1-yl)-2-methylpropoxy)-7-bromo-8-fluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate. LC-MS: (ESI, m / z): [M+H] + = 683.2.

[0498] Step 3: Preparation of tert-butyl 3-(2-((R)-3-(4-benzylpiperazin-1-yl)-2-methylpropoxy)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0499] [ka] To a solution of tert-butyl 3-(2-((R)-3-(4-benzylpiperazin-1-yl)-2-methylpropoxy)-7-bromo-8-fluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (2.354 g, 3.443 mmol) and ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (2.118 g, 4.132 mmol) in 1,4-dioxane (25 mL) and (5 mL) at 25 °C, cesium carbonate (3.366 g, 10.330 mmol) was added. To the mixture were added 1,1'-bis(di-tert-butylphosphine)ferrocenepalladium dichloride (0.449 g, 0.689 mmol) and 1,1'-bis(di-tert-butylphosphine)ferrocenepalladium dichloride (0.449 g, 0.689 mmol), and the mixture was stirred at 85°C for 16 hours. After the reaction was completed, the reaction mixture was poured into water (100 mL) and extracted with ethyl acetate (20 mL × 3). The organic phase was washed with saturated brine (100 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (dichloromethane: methanol = 600: 1 to 30: 1) to give tert-butyl 3-(2-((R)-3-(4-benzylpiperazin-1-yl)-2-methylpropoxy)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate. LC-MS: (ESI, m / z): [M+H] + = 989.5.

[0500] Step 4: Preparation of tert-butyl 3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((R)-2-methyl-3-(piperazin-1-yl)propoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0501] [ka] At 25 ° C., 3- (2- ((R)-3- (4-benzylpiperazin-1-yl) -2-methylpropoxy) -8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) quinazolin-4-yl) -3,8-diazabicyclo [3.2.1] octane-8-carboxylate tert- butyl (2.767 g, 2.797 mmol) and N, N- diisopropylethylamine (1.085 g, 8.391 mmol) in dichloromethane (80 mL) was stirred, and 1-chloroethyl chloroformate (1.200 g, 8.391 mmol) was added and stirred at 25 ° C. for 1 hour. The mixture was concentrated under reduced pressure, and the concentrate was dissolved in methanol (80 mL) and stirred at 50 ° C. for 1 hour. The crude product was concentrated under reduced pressure again, and purified by silica gel column chromatography (petroleum ether: tetrahydrofuran: methanol = 1:1:0.01 to 1:1:0.1) to give 3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((R)-2-methyl-3-(piperazin-1-yl)propoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester. LC-MS: (ESI, m / z): [M+H] + = 899.4.

[0502] Example 1: 1-(5-(4-(3-((S)-2-(((4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethyl-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)pyrrol-1-yl)propyl)piperidine-1-carbonyl)-2-chlorophenyl)dihydropyrimidine-2,4(1H,3H)-dione Step 1: Preparation of 4-(3-oxopropyl)piperidine-1-carboxylate

[0503] [ka] Dess-Martin reagent (5.5 g, 13.0 mmol) was added in portions to a solution of methyl 4-(3-hydroxypropyl)piperidine-1-carboxylate (3.0 g, 10.8 mmol) in DCM (60 mL) at 0 °C and the reaction mixture was allowed to react for 1 h. After completion of the reaction, the reaction mixture was quenched with saturated aqueous NaSO (50 mL) and aqueous NaHCO (50 mL) and extracted with DCM (100 mL x 3). The combined organic phase was washed with saturated brine (100 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (EA:PE = 3:17 to 3:7) to give 4-(3-oxopropyl)piperidine-1-carboxylate. 1 H NMR (400 MHz, CDCl3) δ 9.78 (s, 1H), 7.38-7.28 (m, 5H), 5.12 (s, 2H), 4.28-4.02 (m, 2H), 2.90-2.65 (m, 2H), 2.51-2.42 (m, 2H), 1.74-1.54 (m, 4H), 1.51-1.37 (m, 1H), 1.21-1.03 (m, 2H).

[0504] Step 2: Preparation of tert-butyl 3-(2-(((S)-1-(3-(1-((benzyloxy)carbonyl)piperidin-4-yl)propyl)pyrrol-2-yl)methoxy)-7-(8-ethyl-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0505] [ka] Tert-butyl 3-(2-(((S)-1-((benzyloxy)carbonyl)pyrrol-2-yl)methoxy)-7-(8-ethyl-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (360 mg, 0.45 mmol) was dissolved in ethanol (10 mL) and acetic acid (1 mL), and palladium on carbon (100 mg) was added. The reaction mixture was purged with a hydrogen balloon three times and reacted at 15°C for 1 hour. After completion of the reaction, it was filtered, and the filtrate was used directly in the next step. The filtrate was cooled to 0-5°C, and NaBH(OAc)3 (243.80 mg, 1.15 mmol) was added, followed by 4-(3-oxopropyl)piperidine-1-carboxylate. The reaction was continued at 15°C for 30 minutes. The mixture was quenched with aqueous sodium bicarbonate and extracted with EtOAc (30 mL × 2). The organic layer was washed with saturated NaCl solution, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated to give the crude product, which was purified by silica gel column chromatography (DCM:MeOH = 80:1) to give tert-butyl 3-(2-(((S)-1-(3-(1-((benzyloxy)carbonyl)piperidin-4-yl)propyl)pyrrol-2-yl)methoxy)-7-(8-ethyl-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate. LC-MS: (ESI, m / z): [M+H] + =932.1.

[0506] Step 3: Preparation of tert-butyl 3-(7-(8-ethyl-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-((((S)-1-(3-(piperidin-4-yl)propyl]pyrrol-2-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0507] [ka] Tert-butyl 3-(2-(((S)-1-(3-(1-((benzyloxy)carbonyl)piperidin-4-yl)propyl)pyrrol-2-yl)methoxy)-7-(8-ethyl-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (230 mg, 0.25 mmol) was dissolved in ethanol (10 mL) and palladium carbon (80 mg) was added. The reaction mixture was purged with hydrogen balloon protection three times and reacted at 15°C for 3 hours. After completion of the reaction, it was filtered, and the filtrate was concentrated under reduced pressure to give tert-butyl 3-(7-(8-ethyl-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-((((S)-1-(3-(piperidin-4-yl)propyl]pyrrol-2-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate, which was used directly in the next reaction without purification. LC-MS: (ESI, m / z): [M+H] + =798.3.

[0508] Step 4: Preparation of tert-butyl 3-(2-(((S)-1-(3-(1-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzoyl)piperidin-4-yl)propyl)pyrrol-2-yl)methoxy)-7-(8-ethyl-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0509] [ka] Tert-butyl 3-(7-(8-ethyl-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-((((S)-1-(3-(piperidin-4-yl)propyl]pyrrol-2-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (160 mg, 0.20 mmol) and DIEA (51.60 mg, 0.40 mmol) were dissolved in DMSO (2 mL), and 4-chloro-3-(2,4-dioxotetrahydropyrimidin-1-yl)benzoic acid pentafluorophenyl ester (87 mg, 0.20 mmol) was added. The mixture was stirred at room temperature for 1 hour. Water (30 mL) was added, and the mixture was extracted with EtOAc (30 mL × 2). The organic phase was separated using saturated NaCl solution (50 The mixture was washed with 1 mL of tert-butyl 3-(2-(((S)-1-(3-(1-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzoyl)piperidin-4-yl)propyl)pyrrol-2-yl)methoxy)-7-(8-ethyl-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate. LC-MS: (ESI, m / z): [M+H] + =1048.6.

[0510] Step 5: Preparation of 1-(5-(4-(3-((S)-2-(((4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethyl-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)pyrrol-1-yl)propyl)piperidine-1-carbonyl)-2-chlorophenyl)dihydropyrimidine-2,4(1H,3H)-dione

[0511] [ka] Tert-butyl 3-(2-(((S)-1-(3-(1-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzoyl)piperidin-4-yl)propyl)pyrrol-2-yl)methoxy)-7-(8-ethyl-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (100 mg, 0.095 mmol) was dissolved in DCM (2 mL), and TFA (1 mL) was added. The reaction mixture was allowed to react at 15°C for 1 hour. The reaction mixture was concentrated, diluted with DCM (20 mL), and the pH was adjusted to >7 with aqueous NaHCO3. The organic phase was separated, washed with saturated NaCl solution, dried over anhydrous NaSO, filtered, and the filtrate was concentrated to give the crude product, which was purified by high-performance liquid preparative chromatography to give 1-(5-(4-(3-((S)-2-(((4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethyl-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)pyrrol-1-yl)propyl)piperidine-1-carbonyl)-2-chlorophenyl)dihydropyrimidine-2,4(1H,3H)-dione. LC-MS: (ESI, m / z): [M+H] + =904.3. 1 H NMR (400 MHz, CD3OD) δ 9.04 (s, 1H), 7.64-7.56 (m, 2H), 7.46 (s, 1H), 7.38-7.31 (m, 2H), 7.27 (s, 1H), 7.15 (d, J= 7.2 Hz, 1H), 7.00 (d, J= 2.8 Hz, 1H), 4.66-4.34 (m, 5H), 3.84-3.59 (m, 7H), 3.20-3.15 (m, 1H), 3.04-2.66 (m, 6H), 2.45-2.20 (m, 4H), 2.09-2.00 (m, 1H), 1.90-1.49 (m, 12H), 1.33-0.98 (m, 4H), 0.89 (t, J = 7.2 Hz, 3h). Example 2: 1-((S)-2-(3-(3-((S)-2-(((4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethyl-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)pyrrol-1-yl)propoxy)propionamido)-3,3-dimethylbutyryl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)phenyl)pyrrole-2-carboxamide Step 1: Preparation of benzyl 3-(3-hydroxypropoxy)propionate

[0512] [ka] Triton B (82.00 g, 0.123 mol, 25% aqueous solution) was added to a solution of benzyl acrylate (20.0 g, 0.123 mol) and propane-1,3-diol (46.89 g, 0.617 mol) in acetonitrile (250 mL) at room temperature. The reaction mixture was stirred overnight at room temperature. The reaction mixture was added to brine and extracted with EtOAc (200 mL × 2). The organic phase was dried over Na2SO4, filtered, and the filtrate was concentrated to give the crude product, which was purified by silica gel column chromatography (DCM:MeOH = 5:1) to give benzyl 3-(3-hydroxypropoxy)propionate. LC-MS: (ESI, m / z): [M+H] + =239.1.

[0513] Step 2: Preparation of benzyl 3-(3-oxopropoxy)propionate

[0514] [ka] A solution of benzyl 3-(3-hydroxypropoxy)propionate (1.90 g, 7.98 mmol) in dichloromethane (30 mL) was cooled to 0-10°C, and Dess-Martin oxidant (4.06 g, 9.58 mmol) was added in several portions. The resulting reaction mixture was stirred at room temperature for 1.5 hours. The mixture was quenched by the addition of aqueous sodium thiosulfate and aqueous sodium bicarbonate, and extracted with dichloromethane (30 mL × 2). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (PE: EtOAc = 5:1) to give benzyl 3-(3-oxopropoxy)propionate. 1 H NMR (400 MHz, CDCl3) δ 9.76 (t, J = 1.6 Hz, 1H), 7.37-7.28 (m, 5H), 4.52 (s, 2H), 4.44 (t, J = 6.0 Hz, 2H), 3.73 (t, J = 6.0 Hz, 2H), 2.79-2.73 (m, 2H), 2.63-2.58 (m, 2H).

[0515] Step 3: Preparation of tert-butyl 3-(2-(((S)-1-(3-(3-(benzyloxy)-3-oxopropoxy)propyl)pyrrol-2-yl)methoxy)-7-(8-ethyl-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0516] [ka] Tert-butyl 3-(2-(((S)-1-((benzyloxy)carbonyl)pyrrol-2-yl)methoxy)-7-(8-ethyl-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (300 mg, 0.37 mmol) was dissolved in ethanol (9 mL) and acetic acid (1 mL), and palladium on carbon (100 mg) was added. The atmosphere was purged with hydrogen gas three times using a balloon and the reaction mixture was allowed to react at 10°C for 1 hour. The reaction mixture was filtered through diatomaceous earth, and the filtrate was used directly in the next step. The filtrate was cooled to 0-5°C, and NaBH(OAc)3 (196.10 mg, 0.93 mmol) was added, followed by benzyl 3-(3-oxopropoxy)propionate (174.64 mg, 0.74 mmol), and the mixture was stirred at 15°C for 30 minutes. After completion of the reaction, aqueous sodium bicarbonate was added, and the mixture was extracted with ethyl acetate (30 mL × 2). The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, and filtered. Concentration under reduced pressure gave the crude product, which was purified by thin-layer preparative plate (DCM:MeOH=10:1) to give tert-butyl 3-(2-(((S)-1-(3-(3-(benzyloxy)-3-oxopropoxy)propyl)pyrrol-2-yl)methoxy)-7-(8-ethyl-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate. LC-MS: (ESI, m / z): [M / 2+H] + =447.3.

[0517] Step 4: Preparation of 3-(3-((S)-2-(((4-(8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethyl-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)pyrrol-1-yl)propoxy)propionic acid

[0518] [ka] Tert-butyl 3-(2-(((S)-1-(3-(3-(benzyloxy)-3-oxopropoxy)propyl)pyrrol-2-yl)methoxy)-7-(8-ethyl-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (50.0 mg, 0.06 mmol) was dissolved in ethyl acetate (3 mL), and palladium on carbon (20 mg) was added. The mixture was purged with hydrogen balloon protection three times and stirred at 30°C for 2 hours. The reaction mixture was filtered through diatomaceous earth, the filtrate was concentrated under reduced pressure, and the resulting crude product was purified by thin-layer preparative plate (DCM:MeOH=5:1) to give 3-(3-((S)-2-(((4-(8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethyl-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)pyrrol-1-yl)propoxy)propionic acid. LC-MS: (ESI, m / z): [M / 2+H] + = 402.3.

[0519] Step 5: Preparation of tert-butyl 3-(7-(8-ethyl-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((S)-1-(3-(3-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)phenyl)carbamoyl)pyrrol-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-3-oxopropoxy)propyl)pyrrol-2-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0520] [ka] 3-(3-((S)-2-(((4-(8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethyl-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)pyrrol-1-yl)propoxy)propionic acid (33 mg, 0.041 mmol) and HATU (18.62 mg, 0.049 mmol) were dissolved in DMF (1 mL), stirred for 3 min, and DIEA (10.58 mg, 0.82 mmol) was obtained. (2S,4R)-1-((S)-2-amino-3,3-dimethylbutyryl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)phenyl)pyrrole-2-carboxamide (21.18 mg, 0.049 mmol) was added sequentially, and the reaction mixture was stirred at 25° C. for 1 hour. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (10 mL × 2). The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting crude product was purified by thin-layer preparative plate (DCM:MeOH=5:1) to give tert-butyl 3-(7-(8-ethyl-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((S)-1-(3-(3-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)phenyl)carbamoyl)pyrrol-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-3-oxopropoxy)propyl)pyrrol-2-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate. LC-MS: (ESI, m / z): [M / 2+H] + = 608.5.

[0521] Step 6: Preparation of 1-((S)-2-(3-(3-((S)-2-(((4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethyl-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)pyrrol-1-yl)propoxy)propionamido)-3,3-dimethylbutyryl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)phenyl)pyrrole-2-carboxamide

[0522] [ka] 3-(7-(8-ethyl-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((S)-1-(3-(3-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)phenyl)carbamoyl)pyrrol-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-3-oxopropoxy)propyl)pyrrol-2-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate tert-butyl ester (30 mg, 0.0247 mmol) was dissolved in DCM (1 mL), TFA (0.5 mL) was added, and the mixture was stirred at 15 ° C. for 1 hour. The reaction mixture was concentrated under reduced pressure, then dissolved in DCM (20 mL), and the pH was adjusted to > 7 with aqueous NaHCO. The organic layer was separated, washed with saturated NaCl, dried over anhydrous NaSO, filtered, and the filtrate was concentrated to give the crude product, which was purified by pre-HPLC to give 1-((S)-2-(3-(3-((S)-2-(((4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethyl-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)pyrrol-1-yl)propoxy)propionamido)-3,3-dimethylbutyryl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)phenyl)pyrrole-2-carboxamide. LC-MS: (ESI, m / z): [M+H]+ =1071.3. 1 H NMR (400 MHz, CD3OD) δ 9.03 (s, 1H), 8.85 (s, 1H), 7.62 (d, J = 8.4 Hz, 1H), 7.47-7.32 (m, 5H), 7.28 (d, J = 2.4 Hz, 1H), 7.15 (d, J = 7.2 Hz, 1H), 7.03-7.00 (m, 1H), 4.65-4.31 (m, 8H), 3.89-3.44 (m, 10H), 3.22-2.99 (m, 3H), 2.56-2.00 (m, 11H), 1.88-1.74 (m, 8H), 1.35-1.27 (m, 3H), 1.00 (s, 9H), 0.88 (J = 7.6 Hz, 3H).

[0523] Example 3: 1-(5-(4-(2-(4-((1-(((4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperazin-1-yl)ethyl)piperidine-1-carbonyl)-2-chlorophenyl)dihydropyrimidine-2,4(1H,3H)-dione Step 1: Preparation of 2-(piperidin-4-yl)acetaldehyde

[0524] [ka] To a solution of tert-butyl 4-(2-oxoethyl)piperidine-1-carboxylate (400 mg, 1.76 mmol) in DCM (4.0 mL) was added TFA (2.0 mL) at 0° C. and stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to give crude 2-(piperidin-4-yl)acetaldehyde, which was used directly in the next step without further purification.

[0525] Step 2: Preparation of 2-(1-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzoyl)piperidin-4-yl)acetaldehyde

[0526] [ka] To a solution of pentafluorophenyl 4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzoate (477 mg, 1.10 mmol) and DIEA (568 mg, 4.40 mmol) in DMF (3 mL) was added 2-(piperidin-4-yl)acetaldehyde (180 mg, 1.41 mmol). The mixture was stirred at room temperature for 1 hour and purified by reverse-phase silica gel column chromatography (C18, ACN:water = 0-100%) to give 2-(1-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzoyl)piperidin-4-yl)acetaldehyde. LC-MS: (ESI, m / z): [M+H] + = 378.1.

[0527] Step 3: Preparation of tert-butyl 3-(2-((1-((4-(2-(1-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzoyl)piperidin-4-yl)ethyl)piperazin-1-yl)methyl)cyclopropyl)methoxy)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0528] [ka] 3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((1-(piperazin-1-ylmethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate tert-butyl ester (62 mg, 0.068 mmol) and 2-(1-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzoyl)piperidin-4-yl)acetaldehyde (51 mg, 0.14 mmol) were dissolved in DCM / MeOH / AcOH (0.3 mL / 0.2 mL / 0.1 mL) and stirred at room temperature for 30 minutes. NaBH(OAc)3 (19 mg, 0.22 mmol) was added and stirred at room temperature for 2 hours. NaHCO3 aqueous solution was added and extracted with DCM (20 mL × 2). The combined organic phase was washed with brine, dried, and concentrated. The crude product was purified by silica gel column (dichloromethane:methanol=20:1) to give tert-butyl 3-(2-((1-((4-(2-(1-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzoyl)piperidin-4-yl)ethyl)piperazin-1-yl)methyl)cyclopropyl)methoxy)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate. LC-MS: (ESI, m / z): [M / 2+H] + = 637.2.

[0529] Step 4: Preparation of 1-(5-(4-(2-(4-((1-(((4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperazin-1-yl)ethyl)piperidine-1-carbonyl)-2-chlorophenyl)dihydropyrimidine-2,4(1H,3H)-dione

[0530] [ka] Tert-butyl 3-(2-((1-((4-(2-(1-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzoyl)piperidin-4-yl)ethyl)piperazin-1-yl)methyl)cyclopropyl)methoxy)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (54 mg, 0.042 mmol) was dissolved in DMF (2 mL) and cesium fluoride (32 mg, 0.21 mmol) was added. The reaction mixture was allowed to react at room temperature for 30 minutes. Water (10 mL) was added and the mixture was extracted with EtOAc (20 mL × 2). The organic phase was washed with brine, dried, and concentrated. The residue was dissolved in 1,4-dioxane (2 mL), and HCl / dioxane solution (6 N, 1 mL) was added. The mixture was stirred at room temperature for 0.5 hours and concentrated under reduced pressure. The resulting crude product was purified by pre-HPLC to give compound 1-(5-(4-(2-(4-((1-(((4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperazin-1-yl)ethyl)piperidine-1-carbonyl)-2-chlorophenyl)dihydropyrimidine-2,4(1H,3H)-dione. LC-MS: (ESI, m / z): [M+H] + = 973.2. 1 H NMR (400 MHz, CD3OD) δ 8.99 (s, 1H), 7.88-7.81 (m, 1H), 7.63 (d, J = 8.4 Hz, 1H), 7.52 (s, 1H), 7.39 (d, J = 8.4 Hz, 1H), 7.36-7.27 (m, 2H), 7.19 (s, 1H), 4.70-4.47 (m, 4H), 4.41-4.32 (m, 1H), 3.81-3.62 (m, 7H), 3.31 (s, 1H), 3.10-3.00 (m, 1H), 2.96-2.73 (m, 4H), 2.67-2.27 (m, 11H), 1.89-1.76 (m, 4H), 1.67-1.54 (m, 2H), 1.49-1.42 (m, 2H), 1.35-1.11 (m, 3H), 0.76-0.66 (m, 2H), 0.55-0.43 (m, 2H).

[0531] Example 4: 1-(5-(4-(3-(4-((1-(((4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperazin-1-yl)propyl)piperidine-1-carbonyl)-2-chlorophenyl)dihydropyrimidine-2,4(1H,3H)-dione Step 1: Preparation of 1-(2-chloro-5-(4-(3-hydroxypropyl)piperidine-1-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione

[0532] [ka] To a solution of 3-(piperidin-4-yl)propan-1-ol (500 mg, 3.49 mmol) in DMSO (5 mL) was added 4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)pentafluorophenyl benzoate (1.6 g, 3.66 mmol) and DIEA (1.35 g, 10.47 mmol). The mixture was stirred at room temperature for 1 hour and purified by pre-HPLC (acetonitrile / water = 0-100%) to give 1-(2-chloro-5-(4-(3-hydroxypropyl)piperidine-1-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione. LC-MS: (ESI, m / z): [M+H] + = 394.0.

[0533] Step 2: Preparation of 3-(1-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzoyl)piperidin-4-yl)propionaldehyde

[0534] [ka] Dess-Martin reagent (452 ​​mg, 1.07 mmol) was added to a DCM (10 mL) solution of 1-(2-chloro-5-(4-(3-hydroxypropyl)piperidine-1-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione (350 mg, 0.89 mmol), and the mixture was allowed to react for 1 hour. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (DCM:MeOH=200:1 to 20:1) to give 3-(1-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzoyl)piperidin-4-yl)propionaldehyde. LC-MS: (ESI, m / z): [M+H] + = 392.0.

[0535] Step 3: Preparation of tert-butyl 3-(2-((1-((4-(3-(1-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzoyl)piperidin-4-yl)propyl)piperazin-1-yl)methyl)cyclopropyl)methoxy)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0536] [ka] 3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((1-(piperazin-1-ylmethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate tert-butyl ester (100 mg, 0.11 mmol) in DCM / MeOH (3 mL / 3 mL) solution, acetic acid (0.1 mL) and 3-(1-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzoyl)piperidin-4-yl)propionaldehyde (65 mg, 0.16 mmol) were added and stirred at room temperature for 0.5 hours. The mixture was added with NaBHCN (19 mg, 0.22 mmol) at room temperature and stirred for 0.5 hours. The mixture was concentrated and purified by silica gel column chromatography (MeOH:DCM = 200:1 to 20:1) to give tert-butyl 3-(2-((1-((4-(3-(1-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzoyl)piperidin-4-yl)propyl)piperazin-1-yl)methyl)cyclopropyl)methoxy)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate). LC-MS: (ESI, m / z): [M / 2+H] + = 644.6.

[0537] Step 4: Preparation of 1-(5-(4-(3-(4-((1-(((4-((3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperazin-1-yl)propyl)piperidine-1-carbonyl)-2-chlorophenyl)dihydropyrimidine-2,4(1H,3H)-dione

[0538] [ka] Cesium fluoride (80 mg, 0.5 mmol) was added to a DMF (3 mL) solution of tert-butyl 3-(2-((1-((4-(3-(1-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzoyl)piperidin-4-yl)propyl)piperazin-1-yl)methyl)cyclopropyl)methoxy)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (130 mg, 0.1 mmol) and the mixture was stirred at room temperature for 30 minutes. After extraction with EA and water, the organic phase was concentrated, and the residue was further added with 1,4-dioxane (2 mL) and a mixture of HCl / 1,4-dioxane (6 N, 1 mL) at room temperature. The mixture was reacted for 0.5 hours and then concentrated under reduced pressure. The resulting crude product was purified by pre-HPLC to give 1-(5-(4-(3-(4-((1-(((4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperazin-1-yl)propyl)piperidine-1-carbonyl)-2-chlorophenyl)dihydropyrimidine-2,4(1H,3H)-dione. LC-MS: (ESI, m / z): [M+H] + = 987.2. 1H NMR (400 MHz, CD3OD) δ 8.99 (s, 1H), 7.85 (dd, J = 9.1, 5.7 Hz, 1H), 7.63 (d, J = 8.2 Hz, 1H), 7.51 (s, 1H), 7.40 (d, J = 8.1 Hz, 1H), 7.34-7.27 (m, 2H), 7.20 (d, J = 2.5 Hz, 1H), 4.69-4.34 (m, 6H), 3.81-3.64 (m, 7H), 3.36 (s, 1H), 3.12-3.00 (m, 1H), 2.90 -2.77 (m, 3H), 2.66-2.35 (m, 9H), 2.32-2.26 (m, 2H), 1.90-1.76 (m, 5H), 1.57-1.47 (m, 3H), 1.30-1.12 (m, 5H), 0.71 (t, J = 5.2 Hz, 2H), 0.49 (t, J = 5.2 Hz, 2H).

[0539] Example 5: 1-(5-(4-(4-(4-((1-(((4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperazin-1-yl)butyl)piperidine-1-carbonyl)-2-chlorophenyl)dihydropyrimidine-2,4(1H,3H)-dione Step 1: Preparation of 4-(piperidin-4-yl)butan-1-ol

[0540] [ka] tert-Butyl 4-(4-hydroxybutyl)piperidine-1-carboxylate (500 mg, 1.94 mmol) was dissolved in a solution of hydrochloric acid / 1,4-dioxane (8 M, 1.5 mL) and stirred at 30° C. for 16 hours. After completion of the reaction, the mixture 4-(piperidin-4-yl)butan-1-ol was concentrated under reduced pressure. The crude product was used directly in the next step without further purification.

[0541] Step 2: Preparation of 1-(2-chloro-5-(4-(4-hydroxybutyl)piperidine-1-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione

[0542] [ka] To a solution of 4-(piperidin-4-yl)butan-1-ol (257 mg, 1.63 mmol) in dimethyl sulfoxide (3 mL) were added DIEA (1.3 mL) and 4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)pentafluorophenyl benzoate (746 mg, 1.72 mmol). The mixture was stirred at 30° C. for 16 hours. After completion of the reaction, the reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (100 mL×3). The organic phase was washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel column (DCM:MeOH(NH3)=20:1) to give 1-(2-chloro-5-(4-(4-hydroxybutyl)piperidine-1-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione. LC-MS: (ESI, m / z): [M+H] + =408.1.

[0543] Step 3: Preparation of 4-(1-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzoyl)piperidin-4-yl)n-butyraldehyde

[0544] [ka] To a solution of 1-(2-chloro-5-(4-(4-hydroxybutyl)piperidine-1-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione (245 mg, 0.60 mmol) in dichloromethane (5 mL) was added Dess Martin reagent (305 mg, 0.72 mmol). The mixture was stirred at 30 °C for 1 hour. After completion of the reaction, the reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (20 mL × 3). The organic phase was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give crude 4-(1-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzoyl)piperidin-4-yl)n-butyraldehyde. The crude product was used in the next step without further purification. LC-MS: (ESI, m / z): [M+H] + = 406.1.

[0545] Step 4: Preparation of tert-butyl 3-(2-((1-((4-(4-(1-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzoyl)piperidin-4-yl)butyl)piperazin-1-yl)methyl)cyclopropyl)methoxy)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0546] [ka] 3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((1-(piperazin-1-ylmethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate tert-butyl ester (100 mg, 0.11 mmol) in 1,2-dichloroethane (0.5 mL) and methanol (5 mL) were added to a mixture of acetic acid (0.01 mL) and 4-(1-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzoyl)piperidin-4-yl)n-butyraldehyde (134 mg, 0.33 mmol). The mixture was stirred at 30 °C for 1 hour, and then NaBHCN (21 mg, 0.33 mmol) was added. After the reaction was completed, H O (10 mL) was added and extracted with ethyl acetate (10 mL × 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by silica gel column chromatography (DCM:MeOH=20:1) to give 3-(2-((1-((4-(4-(1-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzoyl)piperidin-4-yl)butyl)piperazin-1-yl)methyl)cyclopropyl)methoxy)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester. LC-MS: (ESI, m / z): [M / 2+H] + = 651.3.

[0547] Step 5: Preparation of 1-(5-(4-(4-(4-((1-(((4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperazin-1-yl)butyl)piperidine-1-carbonyl)-2-chlorophenyl)dihydropyrimidine-2,4(1H,3H)-dione

[0548] [ka] tert-Butyl 3-(2-((1-((4-(4-(1-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzoyl)piperidin-4-yl)butyl)piperazin-1-yl)methyl)cyclopropyl)methoxy)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (110 mg, 0.08 mmol) was dissolved in DMF (1 mL), and CsF (60 mg, 0.4 mmol) was added. The mixture was allowed to react at room temperature for 2 hours. After completion of the reaction, the mixture was diluted with HO (5 mL) and extracted with ethyl acetate (5 mL × 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. Hydrochloric acid / 1,4-dioxane (8 M, 1 mL) was added to the crude product and stirred at room temperature for 0.5 hours. After the reaction was complete, H2O (5 mL) was added and the pH was adjusted to >7 with aqueous Na2CO3, followed by extraction with ethyl acetate (5 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by pre-HPLC to give 1-(5-(4-(4-(4-((1-(((4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperazin-1-yl)butyl)piperidine-1-carbonyl)-2-chlorophenyl)dihydropyrimidine-2,4(1H,3H)-dione. LC-MS: (ESI, m / z): [M+H] + = 1001.1. 1H NMR (400 MHz, CD3OD) δ 8.99 (s, 1H), 7.85 (dd, J= 9.2, 4.2 Hz, 1H), 7.63 (d, J= 8.4 Hz, 1H), 7.52 (s, 1H), 7.40 (d, J= 8.4 Hz, 1H), 7.35-7.27 (m, 2H), 7.20 (d, J= 2.8 Hz, 1H), 4.71-4.30 (m, 6H), 3.82-3.62 (m, 7H), 3.31 (s, 1H), 3.12-3.03 (m, 1H), 2.91-2.78 (m, 3H), 2.62-2.24 (m, 11H), 1.91-1.74 (m, 5H), 1.66-1.43 (m, 4H), 1.32-1.09 (m, 6H), 0.71 (t, J= 6.0 Hz, 2H), 0.49 (t, J= 6.0 Hz, 2H).

[0549] Example 6: 1-(5-(9-((4-((1-(((4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperazin-1-yl)methyl)-3-azaspiro[5.5]undecane-3-carbonyl)-2-chlorophenyl)dihydropyrimidine-2,4(1H,3H)-dione Step 1: Preparation of tert-butyl 3-(2-((1-((4-((3-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzoyl)-3-azaspiro[5.5]undecan-9-yl)methyl)piperazin-1-yl)methyl)cyclopropyl)methoxy)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0550] [ka] To a solution of tert-butyl 3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((1-(piperazin-1-ylmethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (90 mg, 0.1 mmol) in DCM / methanol (3 mL / 3 mL), HOAc (0.1 mL) and 3-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzoyl)-3-azaspiro[5.5]undecane-9-formaldehyde (64 mg, 0.15 mmol) were added and stirred at room temperature for 0.5 hours. To the mixture was added NaBHCN (13 mg, 0.20 mmol) at 0-5°C and stirred for 0.5 h. The mixture was concentrated and purified by silica gel column chromatography (DCM:MeOH = 100:1 to 5:1) to give tert-butyl 3-(2-((1-((4-((3-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzoyl)-3-azaspiro[5.5]undecan-9-yl)methyl)piperazin-1-yl)methyl)cyclopropyl)methoxy)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate. LC-MS: (ESI, m / z): [M / 2+H] + = 664.2.

[0551] Step 2: Preparation of 1-(5-(9-((4-((1-(((4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperazin-1-yl)methyl)-3-azaspiro[5.5]undecane-3-carbonyl)-2-chlorophenyl)dihydropyrimidine-2,4(1H,3H)-dione

[0552] [ka] CsF (75 mg, 0.49 mmol) was added to a solution of tert-butyl 3-(2-((1-((4-((3-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzoyl)-3-azaspiro[5.5]undecan-9-yl)methyl)piperazin-1-yl)methyl)cyclopropyl)methoxy)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (120 mg, 0.09 mmol) in DMF (3.0 mL), and the mixture was allowed to react at room temperature for 30 minutes. Water (10 mL) was added and the mixture was extracted with ethyl acetate (10 mL × 2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the filtrate was filtered and concentrated to obtain the crude intermediate product. The crude product was dissolved in 1,4-dioxane (2 mL), and HCl / 1,4-dioxane (6 N, 1.0 mL) was added and the mixture was reacted at room temperature for 0.5 hours. Aqueous Na2CO3 was added to the reaction mixture to adjust the pH to > 7, followed by extraction with EtOAc / i-PrOH (v / v = 5 / 1, 10 mL × 2). The organic phase was washed with brine, dried over anhydrous Na2SO4, and concentrated. The crude product was purified by pre-HPLC to give 1-(5-(9-((4-((1-(((4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperazin-1-yl)methyl)-3-azaspiro[5.5]undecane-3-carbonyl)-2-chlorophenyl)dihydropyrimidine-2,4(1H,3H)-dione. LC-MS: (ESI, m / z): [M+H] + = 1027.2. 1H NMR (400 MHz, CD3OD) δ 8.99 (s, 1H), 7.85 (dd, J = 9.2, 5.6 Hz, 1H), 7.63 (d, J = 8.2 Hz, 1H), 7.53 (d, J = 1.6 Hz, 1H), 7.41 (dd, J = 8.2, 2.0 Hz, 1H), 7.36-7.28 (m, 2H), 7.20 (d, J = 2.4 Hz, 1H), 4.85-4.33 (m, 5H), 3.82-3.64 (m, 8H), 3.45-3.34 (m, 3H), 2.88-2.82 (m, 2H), 2.57-2.36 (m, 8H), 2.19-2.11 (m, 2H), 1.91-1.73 (m, 6H), 1.61-1.29 (m, 8H), 1.21-1.04 (m, 4H), 0.75-0.66 (m, 2H), 0.54-0.45 (m, 2H).

[0553] Example 7: 1-(5-(9-(3-(4-((1-(((4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperazin-1-yl)propyl)-3-azaspiro[5.5]undecane-3-carbonyl)-2-chlorophenyl)dihydropyrimidine-2,4(1H,3H)-dione Step 1: Preparation of 3-(3-azaspiro[5.5]undecan-9-yl)propan-1-ol

[0554] [ka] tert-Butyl 9-(3-hydroxypropyl)-3-azaspiro[5.5]undecane-3-carboxylate (360 mg, 1.16 mmol) was dissolved in DCM (4 mL), and then TFA (2 mL) was added. The mixture was stirred at room temperature for 1 hour and concentrated to give 3-(3-azaspiro[5.5]undecan-9-yl)propan-1-ol. The crude product was used directly in the next step without further purification.

[0555] Step 2: Preparation of 1-(2-chloro-5-(9-(3-hydroxypropyl)-3-azaspiro[5.5]undecane-3-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione

[0556] [ka] To a solution of 3-(3-azaspiro[5.5]undecan-9-yl)propan-1-ol (240 mg, 1.14 mmol) in DMF (5 mL), DIEA (736 mg, 5.70 mmol) and 4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)pentafluorophenyl benzoate (496 mg, 1.14 mmol) were added, and the reaction mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The resulting crude product was purified by silica gel column chromatography (DCM:MeOH = 100:1 to 5:1) to give 1-(2-chloro-5-(9-(3-hydroxypropyl)-3-azaspiro[5.5]undecane-3-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione. LC-MS: (ESI, m / z): [M+H] + =462.2.

[0557] Step 3: Preparation of 3-(3-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzoyl)-3-azaspiro[5.5]undecan-9-yl)propionaldehyde

[0558] [ka] To a solution of 1-(2-chloro-5-(9-(3-hydroxypropyl)-3-azaspiro[5.5]undecane-3-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione (200 mg, 0.43 mmol) in DCM (5 mL) were added TPAP (101 mg, 0.87 mmol) and NMO (30 mg, 0.09 mmol), and the reaction mixture was stirred at room temperature for 1 hour. After completion of the reaction, water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The resulting crude product was purified by silica gel column chromatography (DCM:MeOH = 100:1 to 5:1) to give 3-(3-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzoyl)-3-azaspiro[5.5]undecan-9-yl)propionaldehyde. LC-MS: (ESI, m / z): [M+H] + = 460.2.

[0559] Step 4: Preparation of tert-butyl 3-(2-((1-((4-(3-(3-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzoyl)-3-azaspiro[5.5]undecan-9-yl)propyl)piperazin-1-yl)methyl)cyclopropyl)methoxy)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0560] [ka] To a solution of tert-butyl 3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((1-(piperazin-1-ylmethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (100 mg, 0.11 mmol) in ethanol (2 mL), acetic acid (0.1 mL) and 3-(3-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzoyl)-3-azaspiro[5.5]undecan-9-yl)propionaldehyde (76 mg, 0.17 mmol) were added and stirred at room temperature for 15 minutes. To the mixture was added NaBHCN (21 mg, 0.33 mmol) at 0°C to 5°C, followed by stirring for 0.5 hours. The mixture was concentrated, and the resulting crude product was purified by silica gel column chromatography (DCM:MeOH = 100:1 to 5:1) to give tert-butyl 3-(2-((1-((4-(3-(3-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzoyl)-3-azaspiro[5.5]undecan-9-yl)propyl)piperazin-1-yl)methyl)cyclopropyl)methoxy)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate. LC-MS: (ESI, m / z): [M / 2+H] + = 678.7.

[0561] Step 5: Preparation of 1-(5-(9-(3-(4-((1-(((4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperazin-1-yl)propyl)-3-azaspiro[5.5]undecane-3-carbonyl)-2-chlorophenyl)dihydropyrimidine-2,4(1H,3H)-dione

[0562] [ka] CsF (56 mg, 0.37 mmol) was added to a solution of tert-butyl 3-(2-((1-((4-(3-(3-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzoyl)-3-azaspiro[5.5]undecan-9-yl)propyl)piperazin-1-yl)methyl)cyclopropyl)methoxy)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (100 mg, 0.07 mmol) in DMF (2.0 mL), and the mixture was allowed to react at room temperature for 2 hours. Water (10 mL) was added to the reaction mixture, which was then extracted with ethyl acetate (10 mL × 2). The combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. The filtrate was filtered and concentrated to give the crude product. The resulting crude product was dissolved in 1,4-dioxane (2.0 mL), and then HCl / 1,4-dioxane (6 N, 1.0 mL) was added and the mixture was allowed to react at room temperature for 0.5 hours. Aqueous Na2CO3 was added to the reaction mixture to adjust the pH to >7, and the mixture was further extracted with ethyl acetate (10 mL × 2). The organic phase was washed with brine, dried over anhydrous Na2SO4, and concentrated. The crude product was purified by pre-HPLC to give 1-(5-(9-(3-(4-((1-(((4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperazin-1-yl)propyl)-3-azaspiro[5.5]undecane-3-carbonyl)-2-chlorophenyl)dihydropyrimidine-2,4(1H,3H)-dione. LC-MS: (ESI, m / z): [M+H] + = 1055.1. 1H NMR (400 MHz, DMSO-d6) δ 10.51 (s, 1H), 10.23 (s, 1H), 9.02 (s, 1H),7.99 - 7.95 (m, 1H), 7.63 (d, J = 8.0 Hz, 1H), 7.54 - 7.35 (m, 4H), 7.16 (d, J = 2.4 Hz, 1H), 4.48 (d, J = 10.4 Hz, 1H), 4.34 - 4.18 (m, 3H), 3.92 (s, 1H), 3.77 - 3.71 (m, 1H), 3.62 - 3.48 (m, 7H), 3.18 - 3.27 (m, 2H), 2.76 - 2.69 (m, 2H), 2.43 - 2.11 (m, 13H), 1.73 - 1.60 (m, 5H), 1.48 - 0.97 (m, 16H), 0.66 - 0.56 (m, 2H), 0.43 - 0.36 (m, 2H).

[0563] Example 8: 1-(5-(4-(3-(4-((1-(((4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperazin-1-yl)propyl)piperidine-1-carbonyl)-2-methoxyphenyl)dihydropyrimidine-2,4(1H,3H)-dione Step 1: Preparation of 1-(5-(4-(3-hydroxypropyl)piperidine-1-carbonyl)-2-methoxyphenyl)dihydropyrimidine-2,4(1H,3H)-dione

[0564] [ka] To a solution of 3-(piperidin-4-yl)propan-1-ol (300 mg, 2.09 mmol) in DMSO (3 mL) were added pentafluorophenyl 3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoate (0.95 g, 2.20 mmol) and DIEA (0.81 g, 6.27 mmol). The mixture was stirred at room temperature for 1 hour. After the reaction was completed, water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude product was purified on a silica gel column to give 1-(5-(4-(3-hydroxypropyl)piperidine-1-carbonyl)-2-methoxyphenyl)dihydropyrimidine-2,4(1H,3H)-dione. LC-MS: (ESI, m / z): [M+H] + = 390.1.

[0565] Step 2: Preparation of 3-(1-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)piperidin-4-yl)propionaldehyde

[0566] [ka] To a solution of 1-(5-(4-(3-hydroxypropyl)piperidine-1-carbonyl)-2-methoxyphenyl)dihydropyrimidine-2,4(1H,3H)-dione (270 mg, 0.69 m...

Claims

1. A compound of formula I or I', and / or its stereoisomers, enantiomers, diastereoisomers, atropisomers, deuterated forms, hydrates, solvates, prodrugs, and / or pharmaceutically acceptable salts thereof, GLE G'-LE II' where G is G1 【Chemistry 1】 and G' is G1' 【Chemistry 2】 and Each Y 1 are independently a bond, O, C(R 3a ) 2 or NR 3a and each X 1 are independently a bond or -(CH 2 ) m - and each X 1 ' are independently a bond or -C(O)-; Each R 1a are independently -OH, -N(R 3a ) 2 , C 3 -C 12 is a cycloalkyl group or a 3- to 12-membered heterocycloalkyl group, 3 -C 12 The cycloalkyl group, 3- to 12-membered heterocycloalkyl group, optionally may be one or more R a may be substituted with Each R 2a are independently halogen, deuterium, cyano group, amino group, hydroxy group, C 1 -C 6 Alkyl group, C 1 -C 6 Heteroalkyl groups, C 3 -C 8 Cycloalkyl groups, 3- to 8-membered heterocycloalkyl groups, -SC 1 -C 6 Alkyl group, C 2 -C 6 Alkenyl group, C 2 -C 6 Alkynyl group, triazolyl group, -OC 1 -C 6 Alkyl group, -OC 3 -C 8 Cycloalkyl groups, -CH 2 C(=O)N(R 3a ) 2 , N(R 3a ) 2 , C 1 -C 3 Alkyl-OC 1 -C 3 Alkyl-, HC(=O)-, -CO 2 R 3a , -CON(R 3a ) 2 or a 5- to 6-membered heteroaryl group, wherein said C 1 -C 6 Alkyl group, C 1 -C 6 Heteroalkyl groups, C 3 -C 8 Cycloalkyl groups, 3- to 8-membered heterocycloalkyl groups, -SC 1 -C 6 Alkyl group, C 2 -C 6 Alkenyl group, C 2 -C 6 Alkynyl group, OC 1 -C 6 Alkyl group, -OC 3 -C 8 The cycloalkyl group or the 5- to 6-membered heteroaryl group may optionally contain one or more deuterium, halogen, hydroxy, cyano, amino, nitro, C 1 -C 3 Alkoxy group or C 1 -C 3 substituted with an alkyl group, Each R 3a are independently H, C 1 -C 6 Alkyl group, C 3 -C 8 Cycloalkyl groups, C 3 -C 6 Alkenyl group or C 3 -C 6 is an alkynyl group, Or, two R's 3a together with the atom to which they are connected form a 4- to 12-membered heterocycloalkyl group, said 4- to 12-membered heterocycloalkyl group optionally containing one or more deuterium, halogen, hydroxy group, cyano group, amino group, C 1 -C 3 Alkoxy group or C 1 -C 3 substituted with an alkyl group, Or, R 1a and R 3a together with the atoms to which they are respectively connected form a 4- to 12-membered heterocycloalkyl group, said 4- to 12-membered heterocycloalkyl group containing at least one heteroatom selected from N, O or S, and optionally one or more R b is replaced by each ring A1 is independently absent and is -L'-6- to 15-membered aryl group, -L'-5- to 15-membered heteroaryl group, or -L'-5- to 15-membered heterocycloalkyl group; Each ring B is independently a 6- to 15-membered aryl group, a 5- to 15-membered heteroaryl group, C 5 -C 15 a cycloalkyl group or a 5- to 16-membered heterocycloalkyl group, and the 6- to 15-membered aryl group, the 5- to 15-membered heteroaryl group, C 5 -C 15 The cycloalkyl group or 5- to 16-membered heterocycloalkyl group may optionally be one or more R a is replaced by Each L' is independently a bond or C 1 -C 4 is an alkylene group, 1 -C 4 The alkylene group may optionally contain one or more deuterium, hydroxy groups, C 1 -C 4 substituted with a hydroxyalkyl group or a 5- to 10-membered heteroaryl group; Each R a and each R b are independently hydrogen, a hydroxy group, a halogen atom, a cyano group, -N(R 3a ) 2 , -CH 2 N (R 3a ) 2 , 3- to 8-membered heterocycloalkyl group, C 1 -C 6 Alkyl groups, HC(=O)-, -CO 2 R 4a , -CO 2 N (R 4a ) 2 , C 1 -C 3 Alkoxy groups, (C 1 -C 3 Alkoxy)-C 1 -C 3 Alkyl-, C 1 -C 3 Alkyl-N(R 4a ) 2 , C 2 -C 4 Alkenyl group, C 3 -C 8 a cycloalkyl group, a 3- to 8-membered heterocycloalkyl group, or a 5- to 6-membered heteroaryl group, 1 -C 6 Alkyl group, C 1 -C 3 Alkoxy group, C 2 -C 4 Alkenyl group, C 3 -C 8 The cycloalkyl group, 3- to 8-membered heterocycloalkyl group, or 5- to 6-membered heteroaryl group may optionally contain one or more deuterium, halogen, cyano, hydroxy, amino, nitro, C 1 -C 3 Alkyl group or C 1 -C 3 substituted with an alkoxy group, Each R 4a are independently hydrogen, C 1 -C 3 Alkyl group or C 1 -C 3 is a hydroxyalkyl group, Or, two R's 4a together with the atom to which they are attached form a heterocycloalkyl group, said heterocycloalkyl group optionally containing one or more deuterium, —OH, —NH 2 , C 1 -C 3 Alkyl group or C 1 -C 3 substituted with an alkoxy group, m is 0, 1, 2, 3 or 4; n is 0, 1, 2, 3 or 4; J 1 and J 2 are independently CR' or N, provided that J 1 and J 2 is not CR', and R' is hydrogen, halogen, deuterium, cyano group, amino group, hydroxy group or C 1 -C 6 is an alkyl group, Each R 2a' are independently halogen, deuterium, cyano group, amino group, hydroxy group, C 1 -C 6 Alkyl group, C 1 -C 6 Heteroalkyl groups, C 3 -C 8 Cycloalkyl groups, 3- to 8-membered heterocycloalkyl groups, -SC 1 -C 6 Alkyl group, C 2 -C 6 Alkenyl group, C 2 -C 6 Alkynyl group, triazolyl group, -OC 1 -C 6 Alkyl group, -OC 3 -C 8 Cycloalkyl groups, -CH 2 C(=O)N(R 3a ) 2 , N(R 3a ) 2 , C 1 -C 3 Alkyl-OC 1 -C 3 Alkyl-, HC(=O)-, -CO 2 R 3a , -CON(R 3a ) 2 , a 5- to 6-membered heteroaryl group or an —O-3- to 8-membered heterocycloalkyl group, wherein said C 1 -C 6 Alkyl group, C 1 -C 6 Heteroalkyl groups, C 3 -C 8 Cycloalkyl groups, 3- to 8-membered heterocycloalkyl groups, -SC 1 -C 6 Alkyl group, C 2 -C 6 Alkenyl group, C 2 -C 6 Alkynyl group, OC 1 -C 6 Alkyl group, -OC 3 -C 8 The cycloalkyl group, the 5- to 6-membered heteroaryl group, or the -O-3 to 8-membered heterocycloalkyl group may optionally contain one or more deuterium, halogen, hydroxyl, cyano, amino, nitro, C 1 -C 3 Alkoxy group or C 1 -C 3 substituted with an alkyl group, J 1 and J 2 If both are N, then at least one R 2a' is an —O-3 to 8 membered heterocycloalkyl group, L is a linking chain that connects G and E via a covalent bond, L is a linking chain that connects G' and E via a covalent bond, wherein each E is independently E1, E2, or E3; 【Transformation 3】 Here, in the above E1, Z' is O, S or CH 2 and X 2 ' is CH or N, Y 2 ' is CH, N, O or S, Q 1 , Q 2 , Q 3 , Q 4 , Q 5 are each independently CR 3b or N, R 3b are each independently hydrogen, deuterium, a hydroxy group, an amino group, a cyano group, a halogen, a nitro group, a mercapto group, or C 1 -C 6 Alkyl group, C 1 -C 6 Heteroalkyl groups, C 2 -C 6 Alkenyl group, C 2 -C 6 Alkynyl group, C 3 -C 8 Cycloalkyl groups, 3- to 8-membered heterocycloalkyl groups, 6- to 10-membered aryl groups, 5- to 10-membered heteroaryl groups, -O-(C 1 -C 6 alkyl), -O-(C 1 -C 6 heteroalkyl), -O-(C 3 -C 8 cycloalkyl), -O-(3- to 8-membered heterocycloalkyl), -S-(C 1 -C 6 alkyl), -S-(C 1 -C 6 heteroalkyl), -S-(C 3 -C 8 cycloalkyl), -S-(3- to 8-membered heterocycloalkyl), -N(C 1 -C 6 alkyl) 1-2 , -N(C 1 -C 6 Heteroalkyl) 1-2 , -N(C 3 -C 8 cycloalkyl) 1-2 , -N(3- to 8-membered heterocycloalkyl) 1-2 , -O-(C 6 -C 10 aryl), -O- (5- to 10-membered heteroaryl group), 1 -C 6 Alkyl group, C 1 -C 6 Heteroalkyl groups, C 2 -C 6 Alkenyl group, C 2 -C 6 Alkynyl group, C 3 -C 8 Cycloalkyl groups, 3- to 8-membered heterocycloalkyl groups, C 6 -C 10 The aryl group, the 5- to 10-membered heteroaryl group, may optionally contain deuterium, hydroxyl, halogen, cyano, amino, O(C 1 -C 6 alkyl), O-(C 3 -C 8 cycloalkyl), -O-(3- to 8-membered heterocycloalkyl), N(C 1 -C 6 alkyl) 1-2 , -NH(C 3 -C 8 cycloalkyl), -NH(3- to 8-membered heterocycloalkyl), -O-(C 6 -C 10 -O- (5- to 10-membered heteroaryl) or two adjacent R 3b together with the atom to which they are connected form a cycloalkyl group, heterocycloalkyl group, heteroaryl group, or aryl group; m'' is 1, 2 or 3; R 1b are each independently hydrogen, deuterium, a hydroxy group, an amino group, a cyano group, a halogen, or C 1 -C 6 Alkyl group, C 1 -C 6 Heteroalkyl groups, C 3 -C 8 Cycloalkyl groups, 3- to 8-membered heterocycloalkyl groups, C 6 -C 10 Aryl groups, 5- to 10-membered heteroaryl groups, -O(C 1 -C 6 alkyl), -O-(C 3 -C 8 cycloalkyl), -O-(3- to 8-membered heterocycloalkyl), -N(C 1 -C 6 alkyl) 1-2 , -NH(C 3 -C 8 cycloalkyl), -NH(3- to 8-membered heterocycloalkyl), -O-(C 6 -C 10 -O-(5- to 10-membered heteroaryl), wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group is optionally substituted with 1 to 3 groups independently selected from hydroxy, halogen, cyano, hydroxy, and amino; R 2b does not exist, and hydrogen, deuterium, C 1 -C 6 Alkyl group or C 3 -C 6 is a cycloalkyl group, 1 -C 6 Alkyl groups and C 3 -C 6 The cycloalkyl group may optionally be selected from the group consisting of hydroxy, halogen, cyano, hydroxy, amino, and -OC(O)(C 1 -C 6 alkyl), 【Chemistry 4】 Here, in E2, Q 1 , Q 2 , Q 3 and Q 4 are each independently CR 3b or N, W is CR 1c R 2c , C(S), C(O), SO 2 , -OC=R 4c -,-SC=R 4c -or-C=R 4c NR 5c - or -N=CA'-, X is CH 2 , O or S; X c is -CH 2 - or -NG'-, Z is CH 2 , O or S; G' and G'' are each independently hydrogen, deuterium, or C 1 -C 6 Alkyl groups, OH, C 3 -C 6 Cycloalkyl groups, -CH 2 -heterocycloalkyl group or -CH 2 -phenyl group, 1 -C 6 Alkyl group, C 3 -C 6 Cycloalkyl groups, -CH 2 -heterocycloalkyl group or -CH 2 -phenyl groups optionally substituted with one or more hydroxy groups, halogens, cyano groups and amino groups; A' is hydrogen, deuterium, C 1 -C 6 Alkyl group, C 3 -C 8 is a cycloalkyl group or a halogen; R 1c , R 2c and R 3c are each independently hydrogen, deuterium, a hydroxyl group, a halogen, or -NH 2 , -N(C 1 -C 6 alkyl) 1-2 , C 1 -C 6 Alkyl group, C 1 -C 6 Alkoxy group, C 1 -C 6 Haloalkyl group, -CONR ' R '' , -OR ' , -NR ' R '' , -SR ' , -SO 2 R ' , -SO 2 NR ' R '' , -CR ' R '' , -CR ' NR ' R '' , C 6 -C 10 Aryl groups, 5- to 10-membered heteroaryl groups, C 3 -C 8 Cycloalkyl groups, 3- to 8-membered heterocycloalkyl groups, -P(O)(OR ' ) R '' , -P(O)R ' R '' , -OP(O)(OR ' ) R '' , CN, -NR ' SO 2 NR ' R '' , -NR ' C(O)NR ' R '' , -C(O)NR ' C(O)R '' , -NR ' C(=N-CN)NR ' R '' , -C(=N-CN)NR ' R '' , -NR ' C(=N-CN)R '' , -NR ' C(=C-NO 2 ) NR ' R '' , -SO 2 NR ' COR '' , -NO 2 , -COR ' , -C (C=N-OR ' ) R '' , -CR ' =CR ' R '' , -CCR ' , -S(C=O)(C=NR ' ) R '' ,-SCIENCE FICTION 5 or -OCF 3 and R 4c is O or S, R 5c is H, C 1 -C 6 Alkyl group, C 6 -C 10 Aryl groups, 5- to 12-membered heteroaryl groups, C 3 -C 8 a cycloalkyl group or a 3- to 8-membered heterocycloalkyl group, R ' and R '' are independently bond, hydrogen, deuterium, C 1 -C 6 Alkyl group, C 3 -C 8 Cycloalkyl groups, C 6 -C 10 an aryl group, a 5- to 10-membered heteroaryl group, or a 3- to 8-membered heterocycloalkyl group; n '' is 0, 1, 2, 3 or 4, 【Transformation 5】 is a single or double bond, 【Transformation 6】 is a bond, which may be an R stereoisomer, an S stereoisomer, or a non-stereoisomer; 【Transformation 7】 Here, in E3, X 1 and X 2 are each independently a bond, O, C(O), C(S), or NR 1d or CR 1d R 2d and R 1d and R 2d are independently H, deuterium, and C 1 -C 6 is an alkyl group, 1 -C 6 The alkyl group may optionally contain one or more halogens or C 1 -C 6 substituted with an alkoxy group, R P are independently H, deuterium, halogen, -OH, C 1 -C 3 is an alkyl group, 1 -C 3 The alkyl group may optionally contain one or more halogens, hydroxy groups or C 1 -C 3 substituted with an alkoxy group, W 3 is C 1 -C 6 Alkyl group, -TN(R 3d R 4d ), -TN(R 3d R 4d ) X 3 , -TC 6 -C 10 Aryl group, -T-5 to 10-membered heteroaryl group, -T-3 to 8-membered heterocyclyl group, -NR 5d -TC 6 -C 10 Aryl group, -NR 5d -T-5 to 10-membered heteroaryl group or -NR 5d -T-3 to 8-membered heterocyclyl group, 1 -C 6 Alkyl group, -TN(R 3d R 4d ), -TN(R 3d R 4d ) X 3 , -TC 6 -C 10 Aryl group, -T-5 to 10-membered heteroaryl group, -T-3 to 8-membered heterocyclyl group, -NR 5d -TC 6 -C 10 Aryl group, -NR 5d -T-5 to 10-membered heteroaryl group or -NR 5d -T-3 to 8 membered heterocyclyl group is optionally substituted, X 3 is C(O),R 3d , R 4d or R 5d and R 3d , R 4d or R 5d are independently H, deuterium, and C 1 -C 6 alkyl groups, 1 -C 6 The alkyl group may optionally contain one or more halogens, —OH, R 1d C(O), R 1d C(S), R 1d SO, R 1d SO 2 , N.R. 1d R 2d C(O),NR 1d R 2d C(S), NR 1d R 2d SO or NR 1d R 2d SO 2 is replaced by T is C 1 -C 6 Alkyl group or -(CH 2 ) n -, wherein -(CH 2 ) n -, wherein one or more methylene groups are optionally deuterium, halogen or C 1 -C 6 substituted with an alkyl group, 1 -C 6 the alkyl group is optionally substituted with a halogen, —OH or amino group; n is 0, 1, 2, 3, 4, 5, or 6; W 4 teeth, 【Transformation 8】 and 【Chemistry 9】 is optionally replaced, R 6d and R 7d are independently H, deuterium, and C 3 -C 8 Cycloalkyl group or C 1 -C 6 is an alkyl group, 3 -C 8 Cycloalkyl group or C 1 -C 6 The alkyl group may optionally be a halogen, -OH, CN, NO 2 or substituted with an amino group, W 5 is a 6- to 10-membered aryl group or a 5- to 10-membered heteroaryl group, R 8d H, deuterium, halogens, CN, OH, NO 2 , N.R. 6d R 7d , OR 6d , C.O.R. 6d R 7d , N.R. 6d COR 7d , SO 2 R 6d R 7d , R 6d SO 2 R 7d , C 1 -C 6 Alkyl group, C 1 -C 6 Alkoxy group, C 6 -C 10 Aryl groups, 5- to 10-membered heteroaryl groups, C 3 -C 8 is a cycloalkyl group or a 3- to 8-membered heterocycloalkyl group, 1 -C 6 Alkyl group, C 1 -C 6 The alkoxy group may optionally contain deuterium, halogen, -OH, CN, NO 2 or an amino group, and / or its stereoisomers, enantiomers, diastereoisomers, atropisomers, deuterated forms, hydrates, solvates, prodrugs, and / or pharmaceutically acceptable salts thereof.

2. In formula I or I′, R 2a , R 2a' , R 3a , C in L' 1 -C 4 Alkylene group, R a and R b wherein one or more of the definitions of groups in are further substituted with the following definitions, with the proviso that L is linked to E via —C(O)—; R 2a and R 2a' are independently -OC 1 -C 6 Heteroalkyl groups, -NH(C 1 -C 6 heteroalkyl), -N(C 1 -C 6 Heteroalkyl) (C 1 -C 6 heteroalkyl) or -C 3 -C 4 Alkynyl-N(R 5a' ) 2 and R 2a and R 2a' wherein the hydroxy groups are independently optionally substituted with one or more of deuterium, halogen, hydroxy group, cyano group, amino group, nitro group, C 1 -C 3 Alkoxy group, C 1 -C 3 Alkyl group, C 3 -C 8 Cycloalkyl groups, -Si-C 1 -C 3 alkyl group, 3- to 8-membered heterocycloalkyl group, or -CON(R 3a ) 2 is replaced by R 2a and R 2a' In the above, C 1 -C 6 Alkyl group, C 1 -C 6 Heteroalkyl groups, C 3 -C 8 Cycloalkyl groups, 3- to 8-membered heterocycloalkyl groups, -SC 1 -C 6 Alkyl group, C 2 -C 6 Alkenyl group, C 2 -C 6 Alkynyl group, -OC 1 -C 6 Alkyl group, -OC 3 -C 8 The cycloalkyl group and the 5- to 6-membered heteroaryl group independently optionally contain one or more C 3 -C 8 Cycloalkyl groups, -Si-C 1 -C 3 alkyl group, 3- to 8-membered heterocycloalkyl group, or -CON(R 3a ) 2 is replaced by Each R 3a is deuterium, C in L' 1 -C 4 The alkylene group is further optionally substituted with one or more halogens; R a and R b are independently a bond, deuterium, oxo, cyanomethyl group, -N(R 3a ) 2 , -CH 2 N (R 3a ) -2 , -O(C 1 -C 6 alkyl), -O(C 3 -C 8 cycloalkyl), -O(C 1 -C 6 heteroalkyl), -O(3- to 8-membered heterocycloalkyl), -S(C 1 -C 6 alkyl), -S(C 3 -C 8 cycloalkyl), -O-phenyl group, -O-pyridyl group, C 2 -C 4 Alkynyl group, triazolyl group, -CH 2 C(=O)N(R 3a ) 2 , -C 3 -C 4 Alkynyl-N(R 3a ) 2 or a 3- to 8-membered heterocycloalkyl group, Or, two adjacent R a together with the atoms to which they are connected form a 6- to 10-membered aryl group, a 5- to 10-membered heteroaryl group, a 5- to 8-membered cycloalkyl group, or a 5- to 8-membered heterocycloalkyl group, which 6- to 10-membered aryl group, 5- to 10-membered heteroaryl group, 5- to 8-membered cycloalkyl group, or 5- to 8-membered heterocycloalkyl group is optionally substituted with one or more hydroxy groups, amino groups, halogen groups, cyano groups, or nitro groups; R a and R b In the above, C 1 -C 6 Alkyl group, C 1 -C 3 Alkoxy group, C 2 -C 4 Alkenyl group, C 3 -C 8 The cycloalkyl group, 3- to 8-membered heterocycloalkyl group, or 5- to 6-membered heteroaryl group may optionally have one or more C 1 -C 3 substituted with a haloalkyl group; R a and R b In the above, C 1 -C 6 Heteroalkyl groups, phenyl groups, pyridyl groups, C 2 -C 4 Alkynyl group, triazolyl group, -CH 2 C(=O)N(R 3a ) 1-2 or -C 3 -C 4 Alkyl-N(R 3a ) 2 optionally containing one or more deuterium, halogen, cyano group, hydroxy group, amino group, nitro group, C 1 -C 3 Haloalkyl group, C 1 -C 3 Alkyl group or C 1 -C 3 substituted with an alkoxy group, Each R 4a is independently C 4 -C 6 2. The compound of formula I or I' according to claim 1, characterized in that: I is an alkyl group; and / or its stereoisomers, enantiomers, diastereoisomers, atropisomers, deuterated forms, hydrates, solvates, prodrugs, and / or pharmaceutically acceptable salts thereof.

3. (1) Each C 1 -C 6 In a heteroalkyl group, one, two, three, or four methylene groups are replaced with heteroatoms and / or heteroatomic groups, the heteroatoms being one or more of O, S, and N, and the heteroatomic groups are -C(O)-, -S(O)-, -S(O)-, -C ... 2 -, -C(O)O-, -OC(O)-, -C(O)NH- and -NHC(O)-; (2) The heteroatoms or heteroatom groups in the 3- to 8-membered heterocycloalkyl groups, the 4- to 12-membered heterocycloalkyl groups, the 5- to 16-membered heterocycloalkyl groups, the heterocycloalkyl groups, the 5- to 6-membered heteroaryl groups, the 5- to 10-membered heteroaryl groups, the 5- to 12-membered heteroaryl groups, the 5- to 15-membered heteroaryl groups, and the heteroaryl groups are each independently O, S, -S(O)-, -S(O) 2 - and N, the number being 1, 2, 3, 4 or 5; (3) Each R 1a In the above, C 3 -C 12 the cycloalkyl group is a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, or a cyclohexyl group; (4) Each R 1a In the formula (I), the 3- to 12-membered heterocycloalkyl group is a 5- to 6-membered monocyclic saturated heterocycloalkyl group or a 7-, 8-, or 9-membered bridged heterocycloalkyl group, the heteroatom is N, and the number is 1 or 2, such as a piperidinyl group, 【Chemistry 10】 and (5) Each R 2a and each R 2a' wherein the halogen is F, Cl, Br or I, for example, F or Cl; (6) Each R 2a and each R 2a' In the above, C 1 -C 6 alkyl group, the -SC group 1 -C 6 C in alkyl groups 1 -C 6 Alkyl group and the -OC 1 -C 6 C in alkyl groups 1 -C 6 The alkyl groups are independently C 1 -C 4 alkyl group, and further C 1 -C 3 It may be an alkyl group, for example, a methyl group, an ethyl group, an n-propyl group, or an isopropyl group; (7) Each R 2a and each R 2a' In the above, C 1 -C 6 Heteroalkyl groups include C 3 A heteroalkyl group in which 2-methylene groups are replaced by O and -C(O)NH-, for example: 【Chemistry 11】 and (8) Each R 2a and each R 2a' In the above, C 3 -C 8 The cycloalkyl group is C 3 -C 6 a cycloalkyl group, for example, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, or a cyclohexyl group; (9) Each R 2a' In the formula, the -O-3 to 8-membered heterocycloalkyl group is an -O-3, 4, 5, or 6-membered monocyclic saturated heterocycloalkyl group, the heteroatom is one or more of N, S, and O, and the number is 1, 2, or 3, for example 【Chemistry 12】 and (10) Each R 2a and each R 2a' wherein the 3- to 8-membered heterocycloalkyl group is a 3- to 6-membered heterocycloalkyl group, the heteroatom is one or more of N, S and O, and the number is 1, 2 or 3; (11) Each R 2a and each R 2a' In the above, C 2 -C 6 The alkynyl group is C 2 -C 4 an alkynyl group, for example an ethynyl group; (12) Each R 2a and each R 2a' is optionally substituted with a substituent, in which the halogen is F, Cl, Br or I, for example F; (13) Each R 2a and each R 2a' is optionally substituted with a substituent, wherein the C 1 -C 3 an alkoxy group is a methoxy group, an ethoxy group, an n-propoxy group or an isopropoxy group, for example a methoxy group; (14) Each R 2a and each R 2a' is optionally substituted with a substituent, wherein the C 1 -C 3 the alkyl group is a methyl group, an ethyl group, an n-propyl group or an isopropyl group, for example a methyl group; (15) Each R 3a In the above, C 1 -C 6 alkyl group, the -SC group 1 -C 6 C in alkyl groups 1 -C 6 Alkyl group and the -OC 1 -C 6 C in alkyl groups 1 -C 6 The alkyl groups are independently C 1 -C 4 alkyl group, and further C 1 -C 3 It may be an alkyl group, such as a methyl group, an ethyl group, an n-propyl group, or an isopropyl group; (16) In each ring A1, the 6- to 15-membered aryl group in the -L'-6- to 15-membered aryl group is a 6- to 10-membered aryl group, for example, a phenyl group or a naphthyl group; (17) In each ring A1, the 5- to 15-membered heteroaryl group in the -L'-5- to 15-membered heteroaryl group is a 5- to 10-membered heteroaryl group, and may also be a 6-, 7-, 8-, or 9-membered monocyclic or bicyclic heteroaryl group, the heteroatom being one or more of N, S, and O, and the number is 1 or 2, such as a pyridyl group, a 1H-indazolyl group, a phenyl[d]thiazole group, or an oxazolophenyl group; (18) In each ring A1, the 5- to 15-membered heteroaryl group in the -L'-5- to 15-membered heteroaryl group is a 5- to 10-membered heteroaryl group, and may also be a 6-, 7-, 8-, or 9-membered monocyclic or bicyclic heteroaryl group, the heteroatom being one or more of N, S, and O, and the number is 1 or 2, such as a pyridyl group, a 1H-indazolyl group, a phenyl[d]thiazole group, or an oxazolophenyl group; (19) In each ring A1, the 5- to 15-membered heterocycloalkyl group in the -L'-5- to 15-membered heterocycloalkyl group is a 5- to 10-membered heterocycloalkyl group, and the heteroatom is one or more of N, S, and O, and the number is 1 or 2; (20) In each ring B, the 6- to 15-membered aryl group is a 6- to 10-membered aryl group, for example, a phenyl group or a naphthyl group; (21) In each ring B, the 5- to 15-membered heteroaryl group is a 5- to 10-membered heteroaryl group, and may also be a 5- to 6-membered heteroaryl group, and the heteroatom is N, and the number is 1 or 2, such as a pyridyl group; (22) In each ring B, the C 5 -C 15 The cycloalkyl group is C 5 -C 7 Monocyclic saturated cycloalkyl groups, C 5 -C 7 Cycloalkenyl group or C 8 -C 15 and the like are tricyclic cycloalkyl groups, for example 【Chemistry 13】 and (23) In each ring B, the 5- to 16-membered heterocycloalkyl group is a heterocycloalkyl group of a 5- to 7-membered monocyclic heterocycloalkyl group, the heteroatom is N and / or O, the number is 1 or 2, for example, a pyrrolidinyl group, a piperidinyl group, or a tetrahydro-2H-pyranyl group; (24) Each R a and each R b wherein the halogen is F, Cl, Br or I, for example, F or Cl; (25) Each R a and each R b In the above, C 1 -C 6 The alkyl group is C 1 -C 3 an alkyl group, such as a methyl group, an ethyl group, an n-propyl group, or an isopropyl group; (26) Each R a and each R b In the above, C 1 -C 3 Alkoxy groups and the above (C 1 -C 3 Alkoxy)-C 1 -C 3 Alkyl-C 1 -C 3 3. A compound of formula I or I' according to claim 1 or 2, and / or its stereoisomers, enantiomers, diastereoisomers, atropisomers, deuterated forms, hydrates, solvates, prodrugs, and / or pharmaceutically acceptable salts thereof, characterized in that the alkoxy groups are independently methoxy, ethoxy, n-propoxy, or isopropoxy groups.

4. (1) each ring B is independently a 6- to 15-membered aryl group, a 5- to 15-membered heteroaryl group, or a 5- to 16-membered heterocycloalkyl group; and each R a are independently a halogen, a hydroxy group, an amino group, a cyano group, -C 1 -C 6 Alkyl group, -C 1 -C 6 Heteroalkyl groups, -C 3 -C 8 Cycloalkyl groups, -C 2 -C 6 Alkenyl group, -C 2 -C 6 Alkynyl group, -C 3 -C 8 Heterocycloalkyl groups (e.g., 3- to 8-membered heterocycloalkyl groups), -O(C 1 -C 6 alkyl), -O(C 3 -C 8 cycloalkyl), -S(C 1 -C 6 alkyl), -S(C 3 -C 8 cycloalkyl), -N(C 1 -C 6 alkyl) 1-2 or -N(C 3 -C 8 cycloalkyl) 1-2 is replaced by Preferably, each ring B is independently a 6- to 15-membered aryl group, a 5- to 15-membered heteroaryl group, or a 5- to 16-membered heterocycloalkyl group, and each R a are independently a halogen, a hydroxy group, an amino group, a cyano group, -C 1 -C 6 Alkyl group, -C 1 -C 6 Heteroalkyl groups, -C 3 -C 6 Alkenyl group, -C 3 -C 6 Alkynyl group, -C 3 -C 8 Heterocycloalkyl groups (e.g., 3- to 8-membered heterocycloalkyl groups), -O(C 1 -C 6 alkyl), -S(C 1 -C 6 alkyl) or -N(C 1 -C 6 alkyl) 1-2 is replaced by More preferably, R a is F, Cl, a hydroxy group, a cyano group, or a methyl group, (2) Each ring A1 is C 6 -C 15 an aryl group or a 5- to 15-membered heteroaryl group, R 2a and R 2a' are independently a hydroxy group, an amino group, a halogen, or C 1 -C 6 Alkyl group, C 1 -C 6 Heteroalkyl groups, -SC 1 -C 6 Alkyl group, -OC 1 -C 6 Alkyl group, C 3 -C 8 Cyclopropyl group, C 2 -C 6 alkynyl group or -O-3 to 8-membered heterocycloalkyl group, 1 -C 6 alkyl group, the -SC group 1 -C 6 Alkyl groups and the C 3 -C 8 The cyclopropyl group may optionally be substituted with halogen, CN, —OH, —NH 2 or C 1 -C 3 substituted with an alkyl group, Preferably, R 2a and R 2a' are independently a hydroxy group, an amino group, a halogen, or C 1 -C 6 Alkyl group, C 1 -C 6 Heteroalkyl groups, -SC 1 -C 6 Alkyl group, -OC 1 -C 6 Alkyl group, C 3 -C 8 Cyclopropyl group or C 2 -C 6 is an alkynyl group, 1 -C 6 alkyl group, the -SC group 1 -C 6 Alkyl groups and the C 3 -C 8 The cyclopropyl group may optionally be substituted with halogen, CN, —OH, —NH 2 or C 1 -C 3 substituted with an alkyl group, More preferably, R 2a and R 2a' are independently -OH, F, Cl, Br, I, CN, -NH 2 , -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 -, -OCH 3 , OCH 2 CH 3 , 【Chemistry 14】 or -SCH 3 and wherein the —CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 -, 【Chemistry 15】 or -SCH 3 is optionally a halogen, CN, -OH, -NH 2 or C 1 -C 3 substituted with an alkyl group, More preferably, R 2a and R 2a' are independently a hydroxy group, an amino group, F, Cl, a methyl group, an ethyl group, an isopropyl group, a trifluoromethyl group, 【Chemistry 16】 -SCH 3 、 【Chemistry 17】 cyclopropyl group or [Chemistry 18] 3. A compound of formula I or I' according to claim 1 or 2, and / or its stereoisomers, enantiomers, diastereoisomers, atropisomers, deuterated forms, hydrates, solvates, prodrugs, and / or pharmaceutically acceptable salts thereof, which satisfies one or more of the following conditions:

5. (1) Structural units 【Chemistry 19】 teeth, 【Chemistry 20】 and 【Chemistry 21】 are independently optionally selected from F, Cl, Br, I, a hydroxy group, an amino group, a cyano group, -C 1 -C 6 Alkyl group, -C 1 -C 6 Heteroalkyl groups, -C 3 -C 8 Cycloalkyl groups, -C 2 -C 6 Alkenyl group, -C 2 -C 6 Alkynyl group, -3 to 8-membered heterocycloalkyl group, -O(C 1 -C 6 alkyl), -O(C 3 -C 8 cycloalkyl), -S(C 1 -C 6 alkyl), -S(C 3 -C 8 cycloalkyl), -N(C 1 -C 6 alkyl) 1-2 , -N(C 3 -C 8 cycloalkyl) 1-2 is replaced by Structural Unit 【Chemistry 22】 teeth, 【Chemistry 23】 may be 【Chemistry 24】 are independently optionally selected from F, Cl, Br, I, a hydroxy group, an amino group, a cyano group, -C 1 -C 6 Alkyl group, -C 1 -C 6 Heteroalkyl groups, -C 3 -C 8 Cycloalkyl groups, -C 2 -C 6 Alkenyl group, -C 2 -C 6 Alkynyl group, -C 3 -C 8 Heterocycloalkyl groups, -O(C 1 -C 6 alkyl), -O(C 3 -C 8 cycloalkyl), -S(C 1 -C 6 alkyl), -S(C 3 -C 8 cycloalkyl), -N(C 1 -C 6 alkyl) 1-2 or -N(C 3 -C 8 cycloalkyl) 1-2 is replaced by Structural Unit 【Chemistry 25】 is further 【Chemistry 26】 may be 【Chemistry 27】 is optionally F, Cl, Br, I, a hydroxy group, an amino group, a cyano group, -C 1 -C 6 Alkyl group, -C 1 -C 6 Heteroalkyl groups, -C 3 -C 6 Alkenyl group, -C 3 -C 6 Alkynyl group, -C 3 -C 8 Heterocycloalkyl groups (e.g., 3- to 8-membered heterocycloalkyl groups), -O(C 1 -C 6 alkyl), -S(C 1 -C 6 alkyl) or -N(C 1 -C 6 alkyl) 1-2 is replaced by Structural Unit 【Chemistry 28】 is further 【Chemistry 29】 may be (2) Structural units 【Transformation 30】 teeth, 【Chemistry 31】 and the structural unit 【Chemistry 32】 is optionally F, Cl, Br, I, a hydroxy group, an amino group, a cyano group, -C 1 -C 6 Alkyl group, -C 1 -C 6 Heteroalkyl groups, -C 3 -C 8 Cycloalkyl groups, -C 2 -C 6 Alkenyl group, -C 2 -C 6 Alkynyl group, -3 to 8-membered heterocycloalkyl group, -O(C 1 -C 6 alkyl), -O(C 3 -C 8 cycloalkyl), -S(C 1 -C 6 alkyl), -S(C 3 -C 8 cycloalkyl), -NH(C 1 -C 6 alkyl), -N(C 1 -C 6 alkyl) 2 , -NH(C 3 -C 8 cycloalkyl) or -N(C 3 -C 8 cycloalkyl) 2 is replaced by Structural Unit 【Transformation 33】 is further 【Transformation 34】 may be (3) Ring A1 is a phenyl group, a pyridyl group, a naphthyl group, 【Chemistry 35】 and the phenyl group, pyridyl group, naphthyl group, 【Transformation 36】 are independently optionally selected from -OH, F, Cl, Br, I, CN, -NH 2 , -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 -, -OCH 3 , OCH 2 CH 3 , 【Chemistry 37】 or -SCH 3 and wherein the —CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 -, 【Transformation 38】 or -SCH 3 is optionally a halogen, CN, -OH, -NH 2 or C 1 -C 3 5. The compound of formula I or I' according to claim 4, and / or its stereoisomers, enantiomers, diastereoisomers, atropisomers, deuterated forms, hydrates, solvates, prodrugs, and / or pharmaceutically acceptable salts thereof, which satisfy one or more of the conditions:

6. （1） 【Chemistry 39】 does not exist, 【Chemistry 40】 【change】 and (2) Structural units 【Chemistry 41】 teeth, 【Chemistry 42】 and (3) Structural units 【Chemistry 43】 teeth, 【Chemistry 44】 and 【Chemistry 45】 independently and optionally 1, 2 or 3 R a is replaced by Structural Unit 【Chemistry 46】 teeth, 【Chemistry 47】 may be 【Chemistry 48】 independently and optionally, one or two R a is replaced by Structural Unit 【Chemistry 49】 is further [Transformation 50] 【change】 may be For example, structural units 【Chemistry 51】 teeth, 【Chemistry 52】 and For example, the structural unit 【Chemistry 53】 teeth, 【Chemistry 54】 and (4) Structural units 【Transformation 55】 teeth, 【Transformation 56】 and the structural unit 【Chemistry 57】 optionally 1, 2 or 3 R a is replaced by Structural Unit 【Chemistry 58】 is further 【Chemistry 59】 6. The compound of formula I or I' according to claim 5, and / or its stereoisomers, enantiomers, diastereoisomers, atropisomers, deuterated forms, hydrates, solvates, prodrugs, and / or pharmaceutically acceptable salts thereof, which satisfies one or more of the conditions:

7. (1) Structural units 【Transformation 60】 teeth, 【Chemistry 61】 【change】 【change】 【change】 【change】 For example, 【Transformation 62】 and Structural Unit 【Transformation 63】 teeth, 【Chemistry 64】 【change】 【change】 【change】 【change】 may be 【Transformation 65】 【change】 【change】 【change】 【change】 independently and optionally 1, 2 or 3 R a is replaced by Structural Unit 【Chemical 66】 is further 【Transformation 67】 may be 【Transformation 68】 independently and optionally, one or two R a and preferably R a is optionally substituted with one or more hydroxy groups 1 -C 6 is an alkyl group, e.g., -CH 2 OH, Structural Unit 【Transformation 69】 is further 【Transformation 70】 【change】 【change】 【change】 【change】 【change】 may be (2) Structural units 【Chemistry 71】 teeth, 【Chemistry 72】 and Furthermore 【Transformation 73】 3. A compound of formula I or I' according to claim 1 or 2, and / or its stereoisomers, enantiomers, diastereoisomers, atropisomers, deuterated forms, hydrates, solvates, prodrugs, and / or pharmaceutically acceptable salts thereof, which satisfies one or more of the conditions:

8. (1) G1 is G1-I or G1-II, 【Chemistry 74】 Here, in G1-I, R 1e is a hydroxy group, -N(R a'' ) 2 , C 3 -C 12 is a cycloalkyl group or a 3- to 12-membered heterocycloalkyl group, 3 -C 12 The cycloalkyl group or 3- to 12-membered heterocycloalkyl group may optionally be one or more R x is replaced by X 1e is a bond or C 1 -C 4 is an alkylene group, Y 1e is a bond, O or NR a'' and Ring C is C 6 -C 10 a 5- to 10-membered aryl group, a 5- to 10-membered heteroaryl group, or a 5- to 10-membered heterocycloalkyl group; X' is a bond, C or N; Y' is C or N; 【Chemistry 75】 is one or more optionally present double bonds, R 2e is H, deuterium, halogen, hydroxyl group, amino group, C 1 -C 6 Alkyl group, C 3 -C 8 Cycloalkyl groups, -O(C 1 -C 6 alkyl) or -O(C 3 -C 8 cycloalkyl), R 3e represents a bond, H, deuterium, halogen, cyano group, oxo, -O (C 1 -C 6 alkyl), -O(C 1 -C 6 heteroalkyl), -O(C 3 -C 8 cycloalkyl), -O(3- to 8-membered heterocycloalkyl), -S(C 1 -C 6 alkyl), -S(C 3 -C 8 cycloalkyl), -O-phenyl or -O-pyridyl, wherein the phenyl or pyridyl group optionally contains one or more hydroxy groups, halogens, cyano groups, amino groups, C 1 -C 3 Haloalkyl group, C 1 -C 3 Alkyl group or C 1 -C 3 substituted with an alkoxy group, R 4e -L 1 -6 to 10-membered aryl group or -L 1 - a 5- to 10-membered heteroaryl group, wherein the 6- to 10-membered aryl group or the 5- to 10-membered heteroaryl group optionally contains one or more R a' is replaced by Or, R 4e is a C together with the carbon atom connected to it. 8 -C 10 An aryl group or an 8- to 10-membered heteroaryl group is formed, 8 -C 10 The aryl or 8- to 10-membered heteroaryl group may optionally be substituted with halogen, hydroxy, cyano, -O(C 1 -C 6 alkyl), -S(C 1 -C 6 alkyl) and C 1 -C 6 substituted with an alkyl group, R 5e is hydrogen, deuterium, halogen, cyano group, C 1 -C 6 Alkyl group, C 3 -C 8 Cycloalkyl groups, -O(C 1 -C 6 alkyl) or -O(C 3 -C 8 cycloalkyl), L 1 is a bond or C 1 -C 4 is an alkylene group, 1 -C 4 The alkylene group may optionally be substituted with halogen, deuterium, hydroxyl, C 1 -C 4 substituted with a hydroxyalkyl group or a 5- to 10-membered heteroaryl group; Each R a'' are independently hydrogen, deuterium, or C 1 -C 6 is an alkyl group, Each R x are independently H, deuterium, -OH, halogen, C 1 -C 3 Alkyl group, -N(R a'' ) 1-2 , -CH 2 N (R a'' ) 1-2 , C 1 -C 3 Alkoxy groups, (C 1 -C 3 Alkoxy)-C 1 -C 3 Alkyl group, C 1 -C 3 Alkyl-N(R a'' ) 1-2 , cyano group, C 2 -C 4 Alkenyl groups, HC(=O), -CO 2 R a'' , -CON(R a'' ) 2 , a 3- to 8-membered heterocycloalkyl group or a 5- to 6-membered heteroaryl group, 1 -C 3 Alkyl group, C 1 -C 3 Alkoxy group or C 2 -C 4 the alkenyl group is optionally substituted with deuterium, halogen, cyano, hydroxy, nitro, or amino groups; R a' are independently a halogen, a cyano group, a hydroxy group, C 1 -C 6 Alkyl group, C 1 -C 6 Heteroalkyl groups, -SC 1 -C 6 Alkyl group, C 2 -C 6 Alkenyl group, C 2 -C 6 Alkynyl group, triazolyl group, -OC 1 -C 6 Alkyl group, -OC 1 -C 6 Heteroalkyl groups, -N(C 1 -C 6 alkyl) 1-2 , -N(C 1 -C 6 Heteroalkyl) 1-2 , -CH 2 C(=O)N(R 5a' ) 2 , -C 3 -C 4 Alkynyl (NR 5a' ) 1-2 , -N(R 5a' ) 1-2 , (C 1 -C 3 Alkoxy) C 1 -C 3 Alkyl-, C 3 -C 6 a cycloalkyl group or a 3- to 6-membered heterocycloalkyl group, 1 -C 6 Alkyl group, C 1 -C 6 Heteroalkyl groups, -SC 1 -C 6 Alkyl group, C 2 -C 6 Alkenyl group, C 2 -C 6 Alkynyl group, -OC 1 -C 6 Alkyl group, -OC 1 -C 6 Heteroalkyl groups, -N(C 1 -C 6 alkyl) 1-2 , -N(C 1 -C 6 Heteroalkyl) 1-2 , C 3 -C 6 The cycloalkyl group or 3- to 6-membered heterocycloalkyl group may optionally be substituted with deuterium, halogen, cyano, hydroxy, nitro, amino, C 1 -C 3 Alkyl group, -OC 1 -C 3 Alkyl group or -Si-C 1 -C 3 substituted with an alkyl group, Each R 5a' are independently H, deuterium, or C 1 -C 6 is an alkyl group, 【Transformation 76】 Here, in G1-II, Ring D is a 6- to 10-membered heterocycloalkyl group, said 6- to 10-membered heterocycloalkyl group optionally being R b' and the 6- to 10-membered heterocycloalkyl group contains at least one heteroatom selected from N, S, or O; Ring E is C 5 -C 7 Cycloalkyl groups, 5- to 7-membered heterocycloalkyl groups, C 6 -C 10 5- to 10-membered aryl groups, 5- to 10-membered heteroaryl groups, C 5 -C 7 a cycloalkenyl group or an 8- to 10-membered spiro ring, which forms a parallel ring between ring E and the pyrimidine ring; 5 -C 7 Cycloalkyl groups, 5- to 7-membered heterocycloalkyl groups, C 6 -C 10 Aryl groups, 5- to 10-membered heteroaryl groups, C 5 -C 7 The cycloalkenyl group or 8- to 10-membered spiro ring is optionally R b'' and the heterocycloalkyl group contains at least one heteroatom selected from N, S, or O, Y″ is a 6- to 10-membered heterocycloalkyl group, a 6- to 10-membered aryl group, or a 5- to 10-membered heteroaryl group, wherein the 6- to 10-membered heterocycloalkyl group or the 5- to 10-membered heteroaryl group contains at least one heteroatom selected from N, S, or O, and optionally R b''' is replaced by R b' is C 1 -C 3 Alkyl group, hydroxy group, -O(C 1 -C 3 alkyl), cyano group, halogen, -N(R x' ) 1-2 , -CH 2 N (R x' ) 1-2 , a cyanomethyl group, or a 3- to 8-membered heterocycloalkyl group; R b'' is a halogen, deuterium, cyano group, hydroxy group, C 1 -C 4 Alkyl group, -SC 1 -C 3 Alkyl group, C 2 -C 4 Alkenyl group, C 2 -C 4 Alkynyl group, triazolyl group, -OC 1 -C 3 Alkyl group, -CH 2 C(=O)N(R x' ) 1-2 , -C 3 -C 4 Alkynyl (NR x' ) 1-2 , -N(R x' ) 1-2 , -C 1 -C 3 Alkoxy-C 1 -C 3 alkyl-, wherein C 1 -C 4 Alkyl group, -SC 1 -C 3 Alkyl group, C 2 -C 4 Alkenyl group, C 2 -C 4 Alkynyl group, C 1 -C 3 The alkoxy group may optionally be substituted with deuterium, halogen, hydroxy, cyano, amino, nitro, C 1 -C 3 Alkoxy group or C 1 -C 3 substituted with an alkyl group, R b''' is hydrogen, hydroxyl group, halogen, cyano group, C 1 -C 6 Alkyl group, C 2 -C 4 Alkynyl group, C 2 -C 4 Alkenyl group, O(C 1 -C 6 alkyl), HC(=O)-, -CO 2 R x' , -CO 2 N (R x' ) 2 or a 5- to 6-membered heteroaryl group, 1 -C 6 the alkyl group is optionally substituted with a halogen, a hydroxy group, a cyano group, or an amino group; Each R x' are independently H or C 1 -C 3 is an alkyl group, p is 0 or 1; (2) The G1' is G1'-I or G1'-II, 【Chemical Formula 77】 Here, in G1'-I, n2 is 1 or 2; J 1 and J 2 are independently selected from CR′ or N, and J 1 and J 2 is not CR' at the same time, R' is hydrogen, halogen, deuterium, cyano group, amino group, hydroxy group or C 1 -C 6 is an alkyl group, R 1e is a hydroxy group, -N(R a'' ) 2 , C 3 -C 12 is a cycloalkyl group or a 3- to 12-membered heterocycloalkyl group, 3 -C 12 The cycloalkyl group or 3- to 12-membered heterocycloalkyl group may optionally be one or more R x is replaced by X 1e is a bond or C 1 -C 4 is an alkylene group, Y 1e is a bond, O or NR a'' and Ring C is C 6 -C 10 a 5- to 10-membered aryl group, a 5- to 10-membered heteroaryl group, or a 5- to 10-membered heterocycloalkyl group; X' is a bond, O, C or N; Y' is C or N; 【Transformation 78】 is one or more optionally present double bonds, R 2e is H, deuterium, halogen, hydroxyl group, amino group, C 1 -C 6 Alkyl group, C 3 -C 8 Cycloalkyl groups, -O(C 1 -C 6 alkyl) or -O(C 3 -C 8 cycloalkyl), R 3e is H, deuterium, halogen, cyano group, oxo, -O(C 1 -C 6 alkyl), -O(C 1 -C 6 heteroalkyl), -O(C 3 -C 8 cycloalkyl), -O(3- to 8-membered heterocycloalkyl), -S(C 1 -C 6 alkyl), -S(C 3 -C 8 cycloalkyl), -O-phenyl or -O-pyridyl, wherein the phenyl or pyridyl group optionally contains one or more hydroxy groups, halogens, cyano groups, amino groups, C 1 -C 3 Haloalkyl group, C 1 -C 3 Alkyl group or C 1 -C 3 substituted with an alkoxy group, R 4e -L 1 -6 to 10-membered aryl group or -L 1 - a 5- to 10-membered heteroaryl group, wherein the 6- to 10-membered aryl group or the 5- to 10-membered heteroaryl group optionally contains one or more R a' is replaced by Alternatively, if n2 is 2, two R 4e are C together with the carbon atoms connected to them. 8 -C 10 An aryl group or an 8- to 10-membered heteroaryl group is formed, 8 -C 10 The aryl or 8- to 10-membered heteroaryl group may optionally be substituted with halogen, hydroxy, cyano, -O(C 1 -C 6 alkyl), -S(C 1 -C 6 alkyl) or C 1 -C 6 substituted with an alkyl group, R 5e is hydrogen, deuterium, halogen, cyano group, C 1 -C 6 Alkyl group, C 3 -C 8 Cycloalkyl groups, -O(C 1 -C 6 alkyl) or -O(C 3 -C 8 cycloalkyl), L 1 is a bond or C 1 -C 4 is an alkylene group, 1 -C 4 The alkylene group may optionally be substituted with halogen, deuterium, hydroxyl, C 1 -C 4 substituted with a hydroxyalkyl group or a 5- to 10-membered heteroaryl group; Each R a'' are independently hydrogen, deuterium, or C 1 -C 6 is an alkyl group, Each R x are independently H, deuterium, -OH, halogen, cyano group, C 1 -C 6 Alkyl group, -N(R a'' ) 1-2 , -CH 2 N (R a'' ) 1-2 , C 1 -C 3 Alkoxy groups, (C 1 -C 3 Alkoxy)-C 1 -C 3 Alkyl group, C 1 -C 3 Alkyl-N(R a'' ) 1-2 , cyano group, C 2 -C 4 Alkenyl groups, HC(=O), -CO 2 R a'' , -CON(R a'' ) 2 , C 3 -C 8 a cycloalkyl group, a 3- to 8-membered heterocycloalkyl group, or a 5- to 6-membered heteroaryl group, 1 -C 6 Alkyl group, C 3 -C 8 Cycloalkyl groups, C 1 -C 3 Alkoxy group or C 2 -C 4 the alkenyl group is optionally substituted with deuterium, halogen, cyano, hydroxy, nitro, or amino groups; R a' are independently halogen, deuterium, cyano group, hydroxy group, C 1 -C 6 Alkyl group, C 1 -C 6 Heteroalkyl groups, -SC 1 -C 6 Alkyl group, C 2 -C 6 Alkenyl group, C 2 -C 6 Alkynyl group, triazolyl group, -OC 1 -C 6 Alkyl group, -OC 1 -C 6 Heteroalkyl groups, -NH(C 1 -C 6 heteroalkyl), -N(C 1 -C 6 Heteroalkyl) 2 , -CH 2 C(=O)N(R 5a' ) 2 , -C 3 -C 4 Alkynyl (NR 5a' ) 2 , -N(R 5a' ) 2 (e.g. -N(C 1 -C 6 alkyl) 2 , -NH(C 1 -C 6 Heteroalkyl),), (C 1 -C 3 Alkoxy) C 1 -C 3 Alkyl-, C 3 -C 6 a cycloalkyl group or a 3- to 6-membered heterocycloalkyl group, 1 -C 6 Alkyl group, C 1 -C 6 Heteroalkyl groups, -SC 1 -C 6 Alkyl group, C 2 -C 6 Alkenyl group, C 2 -C 6 Alkynyl group, -OC 1 -C 6 Alkyl group, -OC 1 -C 6 Heteroalkyl groups, -NH(C 1 -C 6 alkyl), -N(C 1 -C 6 alkyl) 2 , -NH(C 1 -C 6 heteroalkyl), -N(C 1 -C 6 Heteroalkyl) 2 ,-,C 3 -C 6 The cycloalkyl group and the 3- to 6-membered heterocycloalkyl group may optionally be substituted with deuterium, halogen, cyano, hydroxy, nitro, amino, C 1 -C 3 Alkyl group, -OC 1 -C 3 Alkyl group or -Si-C 1 -C 3 substituted with an alkyl group, Each R 5a' are independently H, deuterium, or C 1 -C 6 is an alkyl group, 【Chemistry 79】 Here, in G1'-II, J 1 and J 2 are independently CR′ or N, and J 1 , J 2 is not CR' at the same time, R' is hydrogen, halogen, deuterium, cyano group, amino group, hydroxy group or C 1 -C 6 is an alkyl group, Ring D is a 6- to 10-membered heterocycloalkyl group, said 6- to 10-membered heterocycloalkyl group optionally being R b' and the 6- to 10-membered heterocycloalkyl group contains at least one heteroatom selected from N, S, or O; Ring E is C 5 -C 15 Cycloalkyl groups, 5- to 7-membered heterocycloalkyl groups, C 6 -C 10 a 5- to 10-membered aryl group, a 5- to 10-membered heteroaryl group, or a C 5 -C 7 cycloalkenyl group, an 8- to 10-membered spiro ring, 5 -C 7 Cycloalkyl groups, 5- to 7-membered heterocycloalkyl groups, C 6 -C 10 Aryl groups, 5- to 10-membered heteroaryl groups, C 5 -C 7 The cycloalkenyl group or 8- to 10-membered spiro ring is optionally R b'' and the heterocycloalkyl group contains at least one heteroatom selected from N, S, or O, Y″ is a 6- to 10-membered heterocycloalkyl group, a 6- to 10-membered aryl group, or a 5- to 10-membered heteroaryl group, wherein the 6- to 10-membered heterocycloalkyl group or the 5- to 10-membered heteroaryl group contains at least one heteroatom selected from N, S, or O, and optionally R b''' is replaced by R b' is hydrogen, C 1 -C 6 Alkyl group, hydroxy group, -O(C 1 -C 3 alkyl), cyano group, halogen, -N(R x' ) 2 , -CH 2 N (R x' ) 2 , -CO 2 R x' , -CO 2 N (R x' ) 2 a cyanomethyl group, a 5- to 6-membered heteroaryl group, or a 3- to 8-membered heterocycloalkyl group; 1 -C 6 Alkyl group, C 3 -C 8 the cycloalkyl group is optionally substituted with a halogen, a hydroxy group, a cyano group, or an amino group; R b'' is a halogen, deuterium, cyano group, hydroxy group, C 1 -C 4 Alkyl group, -SC 1 -C 3 Alkyl group, C 2 -C 4 Alkenyl group, C 2 -C 4 Alkynyl group, triazolyl group, -OC 1 -C 3 Alkyl group, -CH 2 C(=O)N(R x' ) -2 , -C 3 -C 4 Alkynyl (NR x' ) 2 , -N(R x' ) 2 or -C 1 -C 3 Alkoxy-C 1 -C 3 alkyl-, and the C 1 -C 4 Alkyl group, -SC 1 -C 3 Alkyl group, C 2 -C 4 Alkenyl group, C 2 -C 4 Alkynyl group, C 1 -C 3 The alkoxy group may optionally be substituted with deuterium, halogen, hydroxy, cyano, amino, nitro, C 1 -C 3 Alkoxy group or C 1 -C 3 substituted with an alkyl group, R b''' is hydrogen, hydroxyl group, halogen, cyano group, C 1 -C 6 Alkyl group, C 2 -C 4 Alkynyl group, C 2 -C 4 Alkenyl group, O(C 1 -C 6 alkyl), HC(=O)-, -CO 2 R x' , -CO 2 N (R x' ) 2 or a 5- to 6-membered heteroaryl group, 1 -C 6 the alkyl group is optionally substituted with a halogen, a hydroxy group, a cyano group, or an amino group; Each R x' are independently H or C 1 -C 6 is an alkyl group, 3. A compound of formula I or I' according to claim 1 or 2, and / or its stereoisomers, enantiomers, diastereoisomers, atropisomers, deuterated forms, hydrates, solvates, prodrugs, and / or pharmaceutically acceptable salts thereof, characterized in that one or more of the following conditions are met: p is 0 or 1.

9. wherein G1 is G1-Ia, G1-Ib, or G1-II-a; 【Chemistry 80】 where r is 1 or 2, t is 1, 2, or 3; W 1 and W 2 form a 6- to 10-membered heterocycloalkyl group together with the N atom to which they are linked, and the 6- to 10-membered heterocycloalkyl group contains at least one heteroatom selected from N, S, or O; wherein the rings C and R of G1-Ia, G1-Ib, or G1-II-a 1e , R 2e , R 3e , R 4e , R 5e , X', Y', Y'' and p are as defined in claim 8; Preferably, G1 is G1-I-a1, G1-I-a1', G1-I-a1'', G1-I-a1''', G1-I-a2, G1-I-a2', G1-I-b1, G1-I-b2 or G1-II-a1; 【Chemistry 81】 Here, in G1-I-a1, G1-I-a1', G1-I-a1'' and G1-I-a1''', R 1a' is hydrogen, hydroxyl group, halogen, cyano group, C 1 -C 6 Alkyl group, C 3 -C 8 Cycloalkyl groups, HC(=O)-, -CO 2 R 5a' , -CO 2 N (R 5a' ) 2 or a 5- to 6-membered heteroaryl group, 1 -C 6 Alkyl group or C 3 -C 8 the cycloalkyl group is optionally substituted with a halogen, a hydroxy group, a cyano group, or an amino group; Each R 5a' are independently hydrogen or C 1 -C 6 is an alkyl group, where R 3e , R 4e , R 5e , X' and Y' are defined in G1-Ia, each as defined in claim 8; 【Chemistry 82】 Here, in G1-I-a2 and G1-I-a2', Each R 1a'' are independently hydrogen, a hydroxy group, a halogen, or C 1 -C 3 Alkyl group, C 1 -C 3 Alkoxy groups, (C 1 -C 3 Alkoxy)-C 1 -C 3 Alkyl-, C 1 -C 3 Alkyl-N(R 5a' ) 1-2 , cyano group, C 2 -C 4 Alkenyl groups, HC(=O)-, -CO 2 R 5a' or -CO 2 N (R 5a' ) 2 and C 1 -C 3 Alkyl group or C 2 -C 4 the alkenyl group is optionally substituted with a halogen, a hydroxy group, a cyano group, or an amino group; Each R 4a' -L 2 -6 to 10-membered aryl group, 6 to 10-membered aryl group, -L 2 - a 5- to 10-membered heteroaryl group or a 5- to 10-membered heteroaryl group, wherein the 6- to 10-membered aryl group or the 5- to 10-membered heteroaryl group optionally contains one or more R 8a' may be substituted with Each L 2 is C 1 -C 4 is an alkylene group, 1 -C 4 The alkylene group may optionally be substituted with a hydroxy group, a halogen, a cyano group, an amino group, a C 1 -C 4 substituted with a hydroxyalkyl group or a 5- to 10-membered heteroaryl group; Each R 5a' are independently H or C 1 -C 3 is an alkyl group, Each R 8a' are independently halogen, deuterium, cyano group, hydroxy group, amino group, C 1 -C 6 Alkyl group, C 1 -C 6 Heteroalkyl groups, C 3 -C 6 Cycloalkyl groups, -SC 1 -C 3 Alkyl group, C 2 -C 4 Alkenyl group, C 2 -C 4 Alkynyl group, triazolyl group, -OC 1 -C 6 Alkyl groups, N(R 5a' ) 1-2 or -OC 1 -C 6 is an alkyl group, 1 -C 6 Alkyl group, C 1 -C 6 Heteroalkyl groups, C 3 -C 6 Cycloalkyl groups, -SC 1 -C 3 Alkyl group, C 2 -C 4 Alkenyl group, C 2 -C 4 Alkynyl group, -OC 1 -C 6 the alkyl group is optionally substituted with a halogen, a hydroxy group, a cyano group, or an amino group; R 3a' is hydrogen or oxo, 【Chemistry 83】 In G1-I-b1, G1-I-b2 and G1-II-a1, where R 1e , R 3e , R 4e , R 5e , t, r, Y″ and p are all defined as in claim 8; The G1', G1'-Ia, G1'-Ib, or G1'-II-a is 【Chemical 84】 and where r is 1 or 2, t is 1, 2, or 3; W 1 and W 2 form a 6- to 10-membered heterocycloalkyl group together with the N atom to which they are linked, and the 6- to 10-membered heterocycloalkyl group contains at least one heteroatom selected from N, S, or O; wherein the rings C, J of G1'-Ia, G1'-Ib or G1'-II-a 1 , J 2 , R 1e , R 2e , R 3e , R 4e , R 5e , X', Y', Y'' and p are defined as set forth in claim 8; Preferably, G1' is G1'-I-a1, G1'-I-a1', G1'-I-a1'', G1'-I-a1''', G1'-I-a2, G1'-I-b1, G1'-I-b2 or G1'-II-a1; 【Chemical 85】 Here, in the G1'-I-a1, G1'-I-a1', G1'-I-a1'' and G1'-I-a1''', R 1a' is hydrogen, hydroxyl group, halogen, cyano group, C 1 -C 6 Alkyl group, C 3 -C 8 Cycloalkyl groups, HC(=O)-, -CO 2 R 5a' , -CO 2 N (R 5a' ) 2 or a 5- to 6-membered heteroaryl group, 1 -C 6 Alkyl group, C 3 -C 8 the cycloalkyl group is optionally substituted with a halogen, a hydroxy group, a cyano group, or an amino group; Each R 5a' are independently hydrogen or C 1 -C 6 is an alkyl group, Here, J 1 , J 2 , R 3e , R 4e , R 5e , X' and Y' are defined as in claim 8; 【Chemical 86】 Here, in the G1'-I-a2, J 1 and J 2 are independently CR′ or N, and J 1 and J 2 is not CR' at the same time, R' is hydrogen, halogen, deuterium, cyano group, amino group, hydroxy group or C 1 -C 6 is an alkyl group, t' is 0 or 1, Each R 1a'' are independently hydrogen, a hydroxy group, a halogen, or C 1 -C 3 Alkyl group, C 1 -C 3 Alkoxy group, -(C 1 -C 3 Alkoxy)-C 1 -C 3 Alkyl-, -C 1 -C 3 Alkyl-N(R 5a' ) -2 , cyano group, C 2 -C 4 Alkenyl groups, HC(=O)-, -CO 2 R 5a' or -CO 2 N (R 5a' ) 2 and C 1 -C 3 Alkyl group or C 2 -C 4 the alkenyl group is optionally substituted with a halogen, a hydroxy group, a cyano group, or an amino group; R 4a' -L 2 -6 to 10-membered aryl group, 6 to 10-membered aryl group, -L 2 - a 5- to 10-membered heteroaryl group or a 5- to 10-membered heteroaryl group, wherein the 6- to 10-membered aryl group or the 5- to 10-membered heteroaryl group optionally contains one or more R 8a' may be substituted with L 2 is C 1 -C 4 is an alkylene group, 1 -C 4 The alkylene group may optionally be substituted with a hydroxy group, a halogen, a cyano group, an amino group, a C 1 -C 4 substituted with a hydroxyalkyl group or a 5- to 10-membered heteroaryl group; R 5a' are independently H or C 1 -C 3 is an alkyl group, Each R 8a' are independently halogen, deuterium, cyano group, hydroxy group, amino group, C 1 -C 6 Alkyl group, C 1 -C 6 Heteroalkyl groups, C 3 -C 6 Cycloalkyl groups, -SC 1 -C 3 Alkyl group, C 2 -C 4 Alkenyl group, C 2 -C 4 Alkynyl group, triazolyl group, -OC 1 -C 6 Alkyl groups, N(R 5a' ) 1-2 or -OC 1 -C 6 is an alkyl group, 1 -C 6 Alkyl group, C 1 -C 6 Heteroalkyl groups, C 3 -C 6 Cycloalkyl groups, -SC 1 -C 3 Alkyl group, C 2 -C 4 Alkenyl group, C 2 -C 4 Alkynyl group, -OC 1 -C 6 the alkyl group is optionally substituted with a halogen, a hydroxy group, a cyano group, or an amino group; R 3a' is hydrogen or oxo, 【Chemistry 87】 In the above G1'-I-b1, G1'-I-b2, and G1'-II-a1, Here, J 1 , J 2 , R 1e , R 3e , R 4e , R 5e 9. The compound of formula I or I' according to claim 8, and / or its stereoisomers, enantiomers, diastereoisomers, atropisomers, deuterated forms, hydrates, solvates, prodrugs, and / or pharmaceutically acceptable salts thereof, wherein the definitions of t, r, Y'' and p are as set forth in claim 8.

10. L is -(CH 2 ) j - or LA 【Chemical 88】 and Said -(CH 2 ) j One or more methylene groups in - may optionally be -NR 3' -, -O-, -CR 1' R 2' -, -C(O)-, -S(O)-, -S(O) 2 -, -C(O)O-, -OC(O)-, -C(O)NR 3' -, -NR 3' C(O)-, -S(O) 2 NR 3' -, -NR 3' S (O) 2 -, vinylidene group, ethynylene group, phenyl group, 8 to 10-membered bicyclic arylene group, 3 to 7-membered saturated or partially unsaturated cycloalkylene group, 5 to 11-membered saturated or partially unsaturated spirocycloalkylene group, 5 to 11-membered saturated or partially unsaturated fused cycloalkylene group, 8 to 10-membered bicyclic saturated or partially unsaturated cycloalkylene group, 4 to 7-membered saturated or partially unsaturated heterocycloalkylene group having 1 to 2 heteroatoms independently selected from nitrogen, oxygen or sulfur, 5 to 11-membered saturated or partially unsaturated spiroheterocycloalkylene group having 1 to 2 heteroatoms independently selected from nitrogen, oxygen or sulfur, 5 to 11-membered saturated or partially unsaturated fused heterocycloalkylene group having 1 to 2 heteroatoms independently selected from nitrogen, oxygen or sulfur, a 8- to 10-membered bicyclic saturated or partially unsaturated heterocycloalkylene group having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur; a 5- to 6-membered heteroarylene group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or an 8- to 10-membered bicyclic heteroaryl group having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and the vinylidene group, ethynylene group, cycloalkylene group, heterocycloalkylene group, phenyl group, spiroheterocycloalkylene group, fused heterocycloalkylene group, spirocycloalkylene group, fused cycloalkylene group, and heteroarylene group are each independently optionally substituted with halogen, oxo, -NR 3' R 4' , -OR 3' , nitro group, -CN, C 1 -C 6 Alkyl group, C 3 -C 10 Cycloalkyl groups, C 3 -C 10 and heterocycloalkyl groups, wherein the alkyl, cycloalkyl, and heterocycloalkyl groups are optionally substituted with one or more substituents selected from halogen, —OH, —NH 2 , -CN, C 1 -C 4 Alkyl group, C 3 -C 6 cycloalkyl groups, R 1' , R 2' are each independently a halogen, -OH, or -NH 2 , C 1 -C 4 Alkyl group, C 1 -C 4 Chloroalkyl group, C 1 -C 4 Hydroxyalkyl groups, -O(C 1 -C 4 alkyl), -NH(C 1 -C 4 alkyl), -NH(C 1 -C 4 alkyl), C 3 -C 6 Cycloalkyl groups, -O(C 3 -C 6 cycloalkyl), -NH(C 3 -C 6 cycloalkyl), C 3 -C 6 Heterocycloalkyl groups, -O(C 3 -C 6 heterocycloalkyl), -NH(C 3 -C 6 cycloalkyl), and R 3' , R 4' are independently hydrogen, deuterium, and C 1 -C 4 Alkyl group, C 3 -C 6 Cycloalkyl groups, C 3 -C 6 a heterocycloalkyl group, and j is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; The definition of LA is Case I or Case II, Case I: Ring U is C 3 -C 12 a cycloalkylene group or a 3- to 12-membered heterocycloalkylene group containing 1 to 2 heteroatoms selected from N, O, or S, and the cycloalkylene group and heterocycloalkylene group may optionally contain halogen, oxo, cyano, amino, hydroxy, C 1 -C 6 Alkyl group, C 1 -C 6 Haloalkyl group, C 1 -C 6 Hydroxyalkyl group or -O-(C 1 -C 6 alkyl), Ring Y is a bond, C 3 -C 12 A cycloalkylene group or a 3- to 12-membered heterocycloalkylene group containing 1 to 2 heteroatoms selected from N, O, or S, wherein the cycloalkylene group and heterocycloalkylene group are optionally substituted with halogen, oxo, cyano, amino, hydroxy, C 1 -C 6 Alkyl group, C 1 -C 6 Haloalkyl group, C 1 -C 6 Hydroxyalkyl group or -O-(C 1 -C 6 alkyl), X'' is a combination of -C(O)-、-NH-、-NCH 3 -、-O-、-C(CH 3 ) 2 -、-S-、-C=C-、-C≡C-、-CHF-、-CHCF 3 -、-(CH 2 ) q C(O)-、-S(O)-、-S(O) 2 -、-C(O)O-、-OC(O)-、-(CH 2 ) q C(O)NH-,-C(O)NCH 3 -、-NHC(O)-、-NCH 3 C(O)- or -C(O)CH 2 Oh q is 1 or 2; Lx is -(CH 2 ) v -, and one or two methylene groups in Lx are optionally -O-, -S-, -NH-, -C≡C-, -N(C 1 -C 6 alkyl)-, -N(C 1 -C 6 haloalkyl)-, -C(O)-, -N(C 1 -C 6 hydroxyalkyl)-, -N(C 3 -C 8 Cycloalkyl)- or -CR d R e -, and v is 1, 2, 3, 4, 5, 6, or 7; R d , R e are independently H, -OH, C 1 -C 6 Alkyl group or C 1 -C 6 is an alkoxy group, Or, R d and R e are C atoms along with the C atoms that connect them. 3 -C 8 forming a cycloalkyl group or a 3- to 8-membered heterocycloalkyl group, Ly is -(CH 2 ) k -, and one or two methylene groups in Ly are optionally -O-, -NH-, -C≡C-, -N(C 1 -C 6 alkyl)-, -N(C 1 -C 6 haloalkyl)-, -C(O)-, -N(C 1 -C 6 hydroxyalkyl)- or -N(C 3 -C 8 cycloalkyl)-, where k is 1, 2, 3, 4, 5, 6, 7, or 8; Case II: Ring U is a 3- to 12-membered heterocycloalkylene group containing 1 to 2 heteroatoms selected from N, O, or S, and the 3- to 12-membered heterocycloalkylene group is optionally C substituted with 1, 2, or 3 hydroxy groups. 1 -C 6 substituted with a substituent such as an alkyl group, Ring Y is a 3- to 12-membered heterocycloalkylene group containing 1 to 2 heteroatoms selected from N, O, or S; X'' is -C(O)-; Lx is -(CH 2 ) v -, and one or two methylene groups in Lx are optionally -O- and -CR d R e -, v is 1, 2, 3, 4, 5, 6, or 7, and R d , R e are each independently H, NH 2 or C substituted with 1, 2 or 3 halogens 1 -C 6 is an alkyl group, or R d and R e are C atoms along with the C atoms that connect them. 3 -C 8 forming a cycloalkyl group, Ly is -(CH 2 ) k -, wherein one or more hydrogens on the methylene group in Ly are optionally replaced with deuterium, and each k is independently 1, 2, 3, 4, 5, 6, 7, or 8, and / or a stereoisomer, enantiomer, diastereoisomer, atropisomer, deuterated product, hydrate, solvate, prodrug, and / or pharmaceutically acceptable salt thereof.

11. In L, -(CH 2 ) j the methylene group in - is substituted by -O-, C(O)-, a vinylidene group, a 4- to 7-membered saturated or partially unsaturated heterocycloalkylene group having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and a 5- to 11-membered saturated or partially unsaturated spiroheterocycloalkylene group having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur; j is 8; Preferably, -(CH 2 ) j -, -O-CH 2 -vinylidene-CH 2 -, 4- to 7-membered saturated or partially unsaturated heterocycloalkylene -CH having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur 2 -, a 5- to 11-membered saturated or partially unsaturated spiroheterocycloalkylene group -C(O)- having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur; LA is solution 1 or 2 below, Solution 1: In LA, ring U is a 4- to 8-membered saturated monocyclic heterocycloalkylene group containing one or two nitrogen heteroatoms, a 6- to 10-membered fused heterocycloalkylene group, a 6- to 10-membered bridged heterocycloalkylene group, or C 6 -C 10 wherein ring Y is a 6- to 8-membered saturated monocyclic heterocycloalkylene group containing one or two nitrogen heteroatoms, a 7- to 11-membered spiroheterocycloalkylene group or a fused heterocycloalkylene group containing one or two nitrogen heteroatoms, X″ is a bond or —C(O)—, and Lx is —(CH 2 ) v -, v is 1, 2, 3, 4 or 5, and Ly is -(CH 2 ) k -, and k is 1, 2, 3, 4 or 5; or in L A, ring Y may be substituted with a 7-, 8-, 9-, 10- or 11-membered spiroheterocycloalkylene group, the heteroatoms being N and / or O and being 1 or 2 in number; Preferably, in L-A, ring U is a 4- to 8-membered saturated monocyclic heterocycloalkylene group containing one or two nitrogen heteroatoms, or a 6- to 10-membered fused heterocycloalkylene group; ring Y is a 6- to 8-membered saturated monocyclic heterocycloalkylene group containing one or two nitrogen heteroatoms, or a 7- to 11-membered spiroheterocycloalkylene group or a fused heterocycloalkylene group containing one or two nitrogen heteroatoms; X″ is a bond or —C(O)—; Lx is —(CH 2 ) v -, v is 1, 2, 3, 4 or 5, and Ly is -(CH 2 ) k -, and k is 1, 2, 3, 4 or 5; or in L A, ring Y may be substituted with a 7-, 8-, 9-, 10- or 11-membered spiroheterocycloalkylene group, the heteroatoms being N and / or O and being 1 or 2 in number; Solution 2: LA is LA-1, LA-2, 【Chemistry 89】 where X″ is —C(O)— or —C(O)NH—; In the LA-1 and LA-2, the ring U, the ring Y, Lx, Ly, and q are all as defined in claim 10, Preferably, LA is LA-3, [Chemical 90] Here, the definition of LA-3 is any one of the following cases 1 to 5: Case 1: Lx is -(CH 2 ) v -, wherein one or two CH contained in said Lx 2 are each independently optionally -O-, -S-, -NH-, -NMe- or -CR d R e - is replaced by -CR d R e -teeth, 【Chemistry 91】 -C(CH 3 ) 2 -, -CH(CH 3 )-, -CH(OH)-, -CH(OCH 3 )-, C(CH 3 )(OH)- or -C=CH 2 and v is 1, 2, 3, 4, 5 or 6; Ring U is 【Chemistry 92】 wherein the a-terminus is linked to Lx and the b-terminus is linked to Ly, and 1, 2, 3 or 4 hydrogen atoms in the ring U are optionally selected from F, —OH, —OCH 3 , -NH 2 is replaced by Ring Y is a bond, 【Chemistry 93】 wherein the c-terminus is linked to Ly and the d-terminus is linked to X″, and 1, 2, 3 or 4 hydrogen atoms in said ring Y are optionally selected from F, —OH, —OCH 3 is replaced by Ly is -(CH 2 ) k -, wherein one or two CH contained in said Ly 2 are each independently optionally -O-, -C≡C-, -C(O)-, or -N(C 1 -C 6 substituted with (alkyl)-, and k is 1, 2, 3, 4, 5, or 6; X'' is a bond, -C(O)-, -(CH 2 ) 1-2 C(O)- or -(CH 2 ) 1-2 C(O)NH- Case 2: Lx is -(CH 2 ) v -, wherein one or two CH contained in said Lx 2 are each independently optionally -O-, -S-, -NH- or -CR d R e - is replaced by -CR d R e -teeth, 【Chemical 94】 -C(CH 3 ) 2 -, -CH(CH 3 ) -, -CH(CH 3 )-, -CH(OCH 3 )-, -CH(OH)-, -C(CH 3 )(OH)- or -C=CH 2 and v is 1, 2, 3, 4, 5 or 6; Ring U is 【Chemical 95】 wherein the a-terminus is linked to Lx, the b-terminus is linked to Ly, and 1, 2, 3 or 4 hydrogen atoms in the ring U are optionally replaced with F; Ring Y is 【Chemistry 96】 wherein the c-terminus is linked to Ly, the d-terminus is linked to X″, and 1, 2, 3 or 4 hydrogen atoms in said ring Y are optionally replaced with F; Ly is -(CH 2 ) k -, wherein one or two CH contained in said Ly 2 are each independently optionally -O- or -N(C 1 -C 6 substituted with (alkyl)-, and k is 1, 2, 3, 4, 5, or 6; X'' is -C(O)-; Alternatively, the ring Y in case 2 is 【Chemistry 97】 is further replaced by Case 3: Lx is -(CH 2 ) v -, wherein one or two CH contained in said Lx 2 are each independently optionally -O-, -S-, -NH- or -CR d R e - is replaced by -CR d R e -teeth, 【Chem.98】 -CH(NH 2 ) -, -CH(CH 2 CHF 2 ) -, -CH(CH 2 CH 2 CF 3 ) - or -CH(CH 3 ) 2 and v is 1, 2, 3, 4, 5 or 6; Ring U is 【Chem.99】 and Ring Y is 【Chemistry 100】 and Ly is -(CH 2 ) k wherein one or more hydrogen atoms in the methylene group of Ly are optionally replaced with deuterium atoms, and k is 1, 2, 3, 4, 5, or 6; X'' is -C(O)-; Case 4: Lx is -(CH 2 ) v -, wherein one or two CH contained in said Lx 2 are each independently optionally substituted with —O—; and v is 1, 2, 3, or 4; Ring U is 【Chemistry 101】 wherein the a-terminus is linked to Lx, the b-terminus is linked to Ly, and 1, 2, 3 or 4 hydrogen atoms in the ring U are optionally replaced with F; Ring Y is a bond; Ly is -(CH 2 ) k -, wherein one or two CH contained in said Ly 2 are each independently optionally substituted with —O—, —C(O)—, or —NH—; and k is 1, 2, 3, 4, 5, 6, 7, or 8; X'' is -C(O)NH-; Case 5: Lx is -(CH 2 ) v -, wherein one or two CH contained in said Lx 2 are each independently optionally -O- or -CR d R e - is replaced by -CR d R e -teeth, 【Chemical Engineering 102】 and v is 1, 2, 3 or 4; Ring U is 【Chemistry 103】 wherein the a-terminus is linked to Lx and the b-terminus is linked to Ly; Ring Y is 【Chemical 104】 and Ly is -(CH 2 ) k -, wherein one or two CH contained in said Ly 2 are each independently optionally substituted with —O—, —C(O)—, or —NH—; and k is 1, 2, 3, 4, 5, or 6; 11. The compound of formula I or I' according to claim 10, and / or its stereoisomers, enantiomers, diastereoisomers, atropisomers, deuterated forms, hydrates, solvates, prodrugs, and / or pharmaceutically acceptable salts thereof, wherein one or more of the following conditions are met: X'' is a bond.

12. (1) In the ring U in LA, 3 -C 12 The cycloalkylene group is C 3 -C 6 Monocyclic saturated cycloalkylene group or C 6 -C 10 a membered bridged cyclic cycloalkylene group, for example a cyclohexylalkylene group or a bicyclo[2.2.2]octylalkylene group; (2) In the ring U in LA, the 3- to 12-membered heterocycloalkylene group is a 3- to 8-membered saturated monocyclic heterocycloalkylene group, a 6- to 10-membered fused heterocycloalkylene group, or a 6- to 10-membered bridged cyclic heterocycloalkylene group, in which the heteroatom is N and the number is 1 or 2; or the 3- to 12-membered heterocycloalkylene group is an 8-, 9-, or 10-membered bridged cyclic heterocycloalkylene group, in which the heteroatom is N and / or O and the number is 1, 2, or 3; The 3- to 12-membered heterocycloalkylene group is preferably an azacyclobutylalkylene group, a pyrrolidinylene group, a piperidinylene group, a piperazinylene group, a hexahydro-1H-pyrrolidine group, a 2,5-diazabicyclo[2.2.1]heptylalkylene group, a 3,8-diazabicyclo[3.2.1]octylalkylene group, a 3,6-diazabicyclo[3.1.1]heptylalkylene group, or 【Chemistry 105】 and (3) In the substituent of the ring U in L-A, the halogen is F, Cl, Br or I; (4) In the ring U substituent in LA, 1 -C 6 The alkyl group and the —O—(C 1 -C 6 C in alkyl 1 -C 6 the alkyl groups are independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl; (5) In L A, 1, 2, 3 or 4 hydrogen atoms in the ring U are optionally replaced by halogen, amino group, hydroxy group, -O-(C 1 -C 6 alkyl) or C 1 -C 6 or 1, 2, 3 or 4 hydrogen atoms in the ring U are substituted with 1, 2 or 3 C alkyl groups each substituted with a hydroxy group; 1 -C 6 may be further substituted with an alkyl group, Preferably, 1, 2, 3 or 4 hydrogen atoms in the ring U are optionally selected from F, —OH, —OCH 3 , -NH 2 or methyl group, or one, two, three or four hydrogen atoms in the ring U are substituted with -CH 2 is substituted with OH, (6) In the ring Y in LA, 3 -C 12 The cycloalkylene group is C 3 -C 6 a monocyclic cycloalkylene group, such as a cyclohexyl alkylene group; (7) In LA, in the ring Y, the 3- to 12-membered heterocycloalkylene group is a 6- to 8-membered monocyclic heterocycloalkylene group, a 7- to 11-membered spiroheterocycloalkylene group, or a 7- to 11-membered fused heterocycloalkylene group, in which the heteroatom is N and the number is 1 or 2; or the 3- to 12-membered heterocycloalkylene group is a 7-, 8-, 9-, 10-, or 11-membered spiroheterocycloalkylene group, in which the heteroatom is N and / or O and the number is 1 or 2; Preferably, the 3- to 12-membered heterocycloalkylene group is a piperidinylene group, a piperazinylene group, a 3-azaspiro[5.5]undecane alkylene group, a 7-azaspiro[3.5]nonyl alkylene group, a 2,7-diazaspiro[3.5]nonyl alkylene group, a 3,9-diazaspiro[5.5]undecyl alkylene group, a 2,6-diazaspiro[3.3]heptyl alkylene group, a 2-azaspiro[3.3]heptyl alkylene group, or a 2-oxa-9-azaspiro[5.5]undecane; (8) In the substituent of ring Y in LA, the —O—(C 1 -C 6 C in alkyl l -C 6 11. The compound of formula I or I' according to claim 10, and / or its stereoisomers, enantiomers, diastereoisomers, atropisomers, deuterated forms, hydrates, solvates, prodrugs, and / or pharmaceutically acceptable salts thereof, wherein the alkyl groups are independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl.

13. LA has the following structure: 【Chemistry 106】 and Preferably, each ring U is independently a 4- to 8-membered saturated monocyclic heterocycloalkylene group or a 6- to 10-membered bridged heterocycloalkylene group containing one or two nitrogen heteroatoms; each ring Y is independently a 3- to 12-membered heterocycloalkylene group containing one to two heteroatoms selected from N, O, or S, and the heterocycloalkyl group is a monocyclic heterocycloalkylene group or a bicyclic spiroheterocycloalkylene group; X″ is —C(O)—; More preferably, LA has one of the following structures: 【Chemistry 107】 and Most preferably, ring U in LA is 【Chemistry 108】 13. The compound of formula I or I' according to claim 12, wherein:

14. (1) In L, -(CH 2 ) j -teeth, 【Chemistry 109】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 and (2) In L, LA is one of the following structures: 【Chemical 110】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 11. The compound of formula I or I' according to claim 10, and / or its stereoisomers, enantiomers, diastereoisomers, atropisomers, deuterated forms, hydrates, solvates, prodrugs, and / or pharmaceutically acceptable salts thereof, which satisfies one or more of the following conditions:

15. (1) the E1 has a structure of formula E1-1a, E1-1b, E1-1c, E1-1d, E1-1e, E1-1f, E1-1g, E1-1aa, E1-1h, E1-1bb, E1-1cc, E1-1dd, E1-1ee, E1-1ff, E1-1gg, or E1-1hh; 【Chemistry 111】 【change】 Q 1 , Q 2 , Q 3 , Q 4 , Q 5 , R 1 '', R 2 '', R 3 " and m" are defined as in claim 1 or 2, (2) E2 has a structure of formula E2-1a, E2-1b, E2-1c, E2-1d, E2-1e, or E2-1f; 【Chemistry 112】 Here, in E2-1a, E2-1b, E2-1c, E2-1d, E2-1e, and E2-1f, W is CR 1c R 2c , C(S), C(O) or SO 2 and X is CH 2 , O or S; Y 2 -NH, -NC 1 -C 6 Alkyl group, -NC 6 -C 10 Aryl group, -N-5 to 10-membered heteroaryl group, -NC 3 -C 8 cycloalkyl group, -N-3 to 8-membered heterocycloalkyl group, O or S; Z is CH 2 , O or S; G'' and G' are independently hydrogen, deuterium, or C 1 -C 6 Alkyl groups, OH, C 3 -C 6 Cycloalkyl groups, -CH 2 -heterocycloalkyl group or -CH 2 -phenyl group, 1 -C 6 Alkyl group, C 3 -C 6 Cycloalkyl groups, -CH 2 -heterocycloalkyl group or -CH 2 - the phenyl group is optionally substituted with 1 to 3 groups independently selected from hydroxy, halogen, cyano, and amino groups; Q 1 , Q 2 , Q 3 , Q 4 are independently 3b or N and R 3b is defined as in claim 1 or 2, A' is hydrogen, deuterium, C 1 -C 6 Alkyl group, C 3 -C 6 is a cycloalkyl group or a halogen; R 1c , R 2c and R 3c are each independently hydrogen, a hydroxy group, a halogen, or -NH 2 , -N(C 1 -C 6 alkyl) 1-2 , C 1 -C 6 Alkyl group, C 1 -C 6 Alkoxy group, C 1 -C 6 Haloalkyl group, -CONR ' R '' , -OR ' , -NR ' R '' , -SR ' , -SO 2 R ' , -SO 2 NR ' R '' , -CR ' R '' , -CR ' NR ' R '' , aryl group, heteroaryl group, C 3 -C 8 Cycloalkyl groups, 3- to 8-membered heterocycloalkyl groups, -P(O)(OR ' ) R '' , -P(O)R ' R '' , -OP(O)(OR ' ) R '' , -Cl, -F, -Br, -I, -CF 3 , -CN, -NR ' SO 2 NR ' R '' , -NR ' C(O)NR ' R '' , -C(O)NR ' C(O)R '' , -NR ' C(=N-CN)NR ' R '' , -C(=N-CN)NR ' R '' , -NR ' C(=N-CN)R '' , -NR ' C(=C-NO 2 ) NR ' R '' , -SO 2 NR ' COR '' , -NO 2 , -COR ' , -C (C=N-OR ' ) R '' , -CR ' =CR ' R '' , -CCR ' , -S(C=O)(C=NR ' ) R '' ,-SCIENCE FICTION 5 or -OCF 3 Selected from R ' and R '' are independently bond, hydrogen, deuterium, C 1 -C 6 Alkyl group, C 3 -C 8 Cycloalkyl groups, C 6 -C 10 an aryl group, a 5- to 10-membered heteroaryl group, or a 3- to 8-membered heterocycloalkyl group; n '' is 0, 1, 2 or 3, 【Chemistry 113】 is a bond, which may be an R stereoisomer, an S stereoisomer, or a non-stereoisomer; (3) E3 has the structure of formula E3-1: 【Chemical 114】 W 3 is C 6 -C 10 an aryl group, a 5- to 10-membered heteroaryl group, or 【Chemical 115】 wherein the aryl group and heteroaryl group are optionally substituted; R 9 , R 10 are each independently hydrogen, C 1 -C 6 Alkyl group, C 3 -C 8 cycloalkyl group or 5- to 10-membered heteroaryl group, 1 -C 6 Alkyl group, C 3 -C 8 The cycloalkyl group or the 5- to 10-membered heteroaryl group may optionally contain one or more -OH, halogen, or -NH 2 is replaced by Or, R 9 , R 10 are C together with the carbon atoms connected to them. 3 -C 8 Forming a cycloalkyl group, 3 -C 8 The cycloalkyl group may optionally be selected from the group consisting of -OH, halogen, -NH 2 or C 1 -C 3 substituted with an alkyl group, R 11 is C 1 -C 6 Alkyl group, C 1 -C 6 Alkoxy groups, 3- to 8-membered heterocycloalkyl groups, C 6 -C 10 an aryl group, a 5- to 10-membered heteroaryl group, or 【Chemistry 116】 and C 1 -C 6 Alkyl group, C 1 -C 6 Alkoxy groups, 3- to 8-membered heterocycloalkyl groups, C 6 -C 10 The aryl group or 5- to 10-membered heteroaryl group may optionally contain one or more -OH, halogen or -NH 2 is replaced by R 12 is selected from H, C(O) or a substituted alkyl group; R 13 is H, C 1 -C 6 selected from alkyl groups, -alkylCO-, -(cycloalkyl)alkylCO-, -aralkylCO-, -arylCO-, -(heterocycloalkyl)CO- or arylalkyl groups, wherein said alkyl groups, -alkylCO-, -(cycloalkyl)alkylCO-, -aralkylCO-, -arylCO-, -(heterocycloalkyl)CO- or arylalkyl groups are optionally substituted; R 16 is H, halogen, -OH, C 1 -C 6 Alkyl group or C 1 -C 6 is an alkoxy group, 1 -C 6 Alkyl group or C 1 -C 6 the alkoxy group is optionally substituted with a halogen; o is 1, 2, 3 or 4; where R 8d , R 14a , R 14b and R 15 and / or a stereoisomer, enantiomer, diastereoisomer, atropisomer, deuterated product, hydrate, solvate, prodrug, and / or a pharmaceutically acceptable salt thereof, of formula I or I' according to claim 1, characterized in that the definitions of are as set out in claims 1 and 2.

16. (1) E1 has a structure of formula E1-1h'', E1-1i', E1-1j', or E1-1h''h'', 【Chemistry 117】 where R 3b is defined as in claim 1 or 2, Preferably, R 3b are independently hydrogen, halogen, cyano group, -OH, -NH 2 , C 1 -C 6 Alkyl group, C 3 -C 8 Cycloalkyl groups, 3- to 8-membered heterocycloalkyl groups, -O(C 1 -C 6 alkyl), -O(C 3 -C 8 cycloalkyl), -O(3- to 8-membered heterocycloalkyl), -N(C 1 -C 6 alkyl) 1-2 , -N(C 3 -C 8 cycloalkyl) 1-2 or -S(C 1 -C 6 alkyl), Said C 1 -C 6 Alkyl group, C 3 -C 8 Cycloalkyl groups, 3- to 8-membered heterocycloalkyl groups, -O(C 1 -C 6 alkyl), -O(C 3 -C 8 cycloalkyl) or -O(3- to 8-membered heterocycloalkyl), -N(C 1 -C 6 alkyl) 1-2 , -N(C 3 -C 8 cycloalkyl) 1-2 or -S(C 1 -C 6 alkyl) optionally containing 1 to 3 halogen atoms, cyano groups, -OH, -NH 2 is replaced by Or, the above C 1 -C 6 Alkyl group, C 3 -C 8 Cycloalkyl groups, 3- to 8-membered heterocycloalkyl groups, -O(C 1 -C 6 alkyl), -O(C 3 -C 8 cycloalkyl) or -O(3- to 8-membered heterocycloalkyl), -N(C 1 -C 6 alkyl) 1-2 , -N(C 3 -C 8 cycloalkyl) 1-2 and -S(C 1 -C 6 alkyl) is further optionally substituted with 1, 2, or 3 deuterium atoms; (2) E2 has a structure of formula E2-1bb, E2-1aa, or E2-1cc; 【Chemistry 118】 Here, in the E2-1bb, Q 1 , Q 2 , Q 3 and Q 4 are each independently CR 3b or N, W is C(O) or CH 2 and A' is hydrogen, deuterium, C 1 -C 6 an alkyl group or a halogen; R 3c represents hydrogen, deuterium, hydroxyl groups, halogens, -NH 2 , -N(C 1 -C 6 alkyl) 1-2 , C 1 -C 6 Alkyl group, C 1 -C 6 Alkoxy group, C 1 -C 6 is a haloalkyl group, n '' is 0, 1, 2 or 3, 【Chemical 119】 is a bond, which may be an R stereoisomer, an S stereoisomer, or a non-stereoisomer; where R 3b is defined as in claim 1 or 2, 【Chemical 120】 Here, in the E2-1aa or E2-1cc, W is CH 2 or C(O), A' is hydrogen, a methyl group, Cl or F; R 3c are each independently hydrogen, halogen, cyano group, hydroxy group, NH 2 , C 1 -C 6 Alkyl group or C 1 -C 6 is an alkoxy group, n '' is 0, 1, 2 or 3, 【Chemistry 121】 is a bond, which may be an R stereoisomer, an S stereoisomer, or a non-stereoisomer; (3) E3 has the structure of formula E3-1a, E3-1b, or E3-1c, 【Chemistry 122】 where R 1d is H, ethyl, isopropyl, tert-butyl, sec-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, alkyl, hydroxyalkyl, heteroaryl or haloalkyl, wherein the alkyl, hydroxyalkyl or heteroaryl group is optionally substituted; R 6d -H, -CH 3 , -CH 2 F, -CH 2 OH, an ethyl group, an isopropyl group, or a cyclopropyl group; R 8d H, halogen, CN, OH, NO 2 , C 6 -C 10 Aryl groups, 5- to 10-membered heteroaryl groups, C 1 -C 6 Alkyl group, C 1 -C 6 Alkoxy group, C 3 -C 8 is a cycloalkyl group or a 3- to 8-membered heterocycloalkyl group, 6 -C 10 Aryl groups, 5- to 10-membered heteroaryl groups, C 1 -C 6 Alkyl group, C 1 -C 6 Alkoxy group, C 3 -C 8 The cycloalkyl group or 3- to 8-membered heterocycloalkyl group may optionally be selected from the group consisting of halogen, —OH, CN, NO 2 or substituted with an amino group, X d is CH 2 or C(O), R d is a 5- to 6-membered heteroaryl group, said 5- to 6-membered heteroaryl group being optionally substituted; Preferably, E3 has the structure of formula E3-1aa: 【Chemical 123】 where R 6d -H, -CH 3 , -CH 2 F, -CH 2 OH, an ethyl group, an isopropyl group, or a cyclopropyl group; R 9 is H, R 10 is H, ethyl, isopropyl, tert-butyl, sec-butyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; R 11 teeth, 【Chemistry 124】 or a 5- to 10-membered heteroaryl group, said 5- to 10-membered heteroaryl group optionally containing one or more -OH, halogen or -NH 2 is replaced by R 12 is H or C(O), R 13 is H, an alkyl group, -alkylCO-, -(cycloalkyl)alkylCO-, -aralkylCO-, -arylCO-, -(heterocycloalkyl)CO- or an arylalkyl group, wherein said alkyl group, -alkylCO-, -(cycloalkyl)alkylCO-, -aralkylCO-, -arylCO-, -(heterocycloalkyl)CO- or arylalkyl group is optionally substituted; R 8d H, halogen, CN, OH, NO 2 ,nn, 【Chemistry 125】 and More preferably, formula E3-1aa is R 12 and / or a stereoisomer, enantiomer, diastereoisomer, atropisomer, deuterated form, hydrate, solvate, prodrug, and / or pharmaceutically acceptable salt thereof, of formula I or I', according to claim 15, characterized in that it satisfies one or more of the conditions:

17. (1) E1 is 【Chemistry 126】 【change】 and (2) In E, E2 is 【Chemistry 127】 【change】 【change】 【change】 【change】 【change】 【change】 and (3) E3 is 【Chemistry 128】 【change】 17. The compound of formula I or I' according to claim 16, and / or its stereoisomers, enantiomers, diastereoisomers, atropisomers, deuterated forms, hydrates, solvates, prodrugs, and / or pharmaceutically acceptable salts thereof, which satisfies one or more of the following conditions:

18. Solution a, b or c, Solution a: In the compounds of formula I or I', G1 is 【Chemistry 129】 and G1' is 【Chemistry 130】 and L is 【Chemistry 131】 and E is independently E1 【Chemistry 132】 and R 1a ', R 3e , R 4e , R 5e The definitions of X' and Y' are as defined in claim 8 or 9, and each R a , R 2a ', J 1 and J 2 are as defined in any one of claims 1 to 9, the definitions of Lx, Ly, ring U and ring Y are as defined in any one of claims 10 to 14, and X'', Q 1 , Q 2 , Q 3 , Q 4 , Q 5 , X 2' , Y 2' , R 1b , R 2b , Z' and m'' are defined as in any one of claims 1 to 9, Solution b: In the compound of formula II or I', G1 is 【Chemistry 133】 and G1' is 【Chemistry 134】 and R 1a teeth, 【Chemistry 135】 and L is 【Transformation 136】 and Lx is -(CH 2 ) v -, and the two methylene groups in Lx are -O- and -CR d R e - is replaced by a member selected from R d and R e are independently H, C 1 -C 6 Alkyl group, C 1 -C 6 Alkoxy group, NH 2 or C substituted with 1, 2 or 3 halogens 1 -C 6 is an alkyl group, or R d and R e are C atoms along with the C atoms that connect them. 3 -C 8 forming a cycloalkyl group, v is 1, 2, 3, 4, 5, 6, or 7; Ring U is a 3- to 12-membered heterocycloalkylene group containing 1 to 2 N heteroatoms; Ly is -(CH 2 ) k -, wherein one or two methylene groups in Ly are optionally replaced by -O-, and k is 1, 2, 3, 4, 5, 6, 7, or 8; Ring Y is a 3- to 12-membered heterocycloalkylene group containing 1, 2, or 3 heteroatoms selected from N and O; X'' is -C(O)-; E is 【Chemistry 137】 and Each R a , R 2a , R 2a ', J 1 , J 2 and n are defined as in any one of claims 1 to 9, and each R 3b are defined as in any one of claims 1 to 17, Preferably, each R 2a and R 2a' are independently a halogen, a hydroxyl group, C 1 -C 6 Alkyl group or C 2 -C 6 is an alkynyl group, and R a is a halogen, L is one of the following structures: 【Chemistry 138】 【change】 【change】 and R 3b is a halogen, C 1 -C 6 Alkyl group or -O-(C 1 -C 6 alkyl), and 1 -C 6 Alkyl group or -O-(C 1 -C 6 alkyl) is optionally substituted with 1 to 3 independently selected from deuterium or halogen; Solution c: In the compounds of formula II or I', G1 is 【Chemistry 139】 and G1' is [Chemical 140] and R 1a teeth, 【Chemistry 141】 and L is 【Chemistry 142】 and Lx is -(CH 2 ) v -, and the two methylene groups in Lx are -O- and / or -CR d R e - is replaced by a member selected from R d and R e are each independently C 1 -C 6 is an alkyl group, or R d and R e are C atoms along with the C atoms that connect them. 3 -C 8 forming a cycloalkyl group, v is 1, 2, 3, 4, 5, 6, or 7; Ring U is a 3- to 12-membered heterocycloalkylene group containing 1 to 2 N heteroatoms; Ly is -(CH 2 ) k -, wherein one or two methylene groups in Ly are optionally replaced by -O-, and k is 1, 2, 3, 4, 5, 6, 7, or 8; Ring Y is a 3- to 12-membered heterocycloalkylene group containing 1 to 2 heteroatoms selected from N; X'' is -C(O)-; E is 【Chemistry 143】 and Each R a , R 2a , R 2a ', J 1 , J 2 and n are defined as in any one of claims 1 to 9, and each R 3b are defined as in any one of claims 1 to 17, Preferably, each R 2a and R 2a' are independently a halogen, a hydroxyl group, C 1 -C 6 Alkyl group or C 2 -C 6 is an alkynyl group, and R a is a halogen, L is one of the following structures: 【Chemistry 144】 and R 3b are each independently hydrogen, C 1 -C 6 Alkyl group or -O-(C 1 -C 6 3. The compound of formula I or I′ according to claim 1 or 2, characterized in that:

19. Any one of the following compounds: 【Chemistry 145】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 3. The compound of formula I or I' according to claim 1 or 2, characterized in that it is: and / or a stereoisomer, enantiomer, diastereoisomer, atropisomer, deuterated form, hydrate, solvate, prodrug, and / or pharmaceutically acceptable salt thereof.

20. 1. A pharmaceutical composition comprising:

20. A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I or I' according to any one of claims 1 to 19, and / or its stereoisomers, enantiomers, diastereoisomers, atropisomers, deuterated forms, hydrates, solvates, prodrugs, and / or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier, diluent, or excipient.

21. The application of substance X in the manufacture of a drug, the substance X is a compound of formula I or I' according to any one of claims 1 to 19, and / or a stereoisomer, enantiomer, diastereoisomer, atropisomer, deuterated product, hydrate, solvate, prodrug, and / or pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 20, wherein the drug is a drug for treating or preventing a KRAS mutation-mediated disease or condition, or a drug for treating or preventing cancer; Preferably, the KRAS mutation-mediated disease or condition is a disease or condition caused by the interaction of KRAS G12D with SOS1 or SHP2 protein; The cancer is Heart: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma group, Lung: Bronchial carcinoma (squamous cell carcinoma, undifferentiated small cell carcinoma, undifferentiated large cell carcinoma, adenocarcinoma), alveolar carcinoma (bronchiolar carcinoma), bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma, Gastrointestinal tract: esophageal cancer (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, vasoactive intestinal peptide tumor), small intestine (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, fibroneuroma, fibroma), large intestine (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma), Urinary system: kidney (adenocarcinoma, embryonal carcinosarcoma (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratoma, choriocarcinoma, sarcoma, mesenchymal cell carcinoma, fibroma, fibroadenoma, adenomatous tumor, lipoma), Liver: liver cancer (hepatocellular carcinoma), small hepatic bile duct carcinoma, hepatoblastoma, malignant hemangioendothelial tumor, hepatocellular adenoma, hemangioma, Biliary tract: bile duct cancer, gallbladder cancer, ampullary cancer, small hepatic bile duct cancer, Bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor, chordoma, chondroma (osteochondral extrinsic bone disease), benign chondroma, chondroblastoma, chondromyxoid fibroma, osteoid osteoma and giant cell tumor, Nervous system: skull (osteoma, hemangioma, granuloma, xanthomas, osteitis teratoides), meninges (meningioma, meningeal sarcoma, glioma), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumor (pineal tumor), glioblastoma multiforme, oligodendroglioma, schwannoma, eye cancer, congenital tumors), spinal cord neurofibroma, meningioma, glioma, sarcoma) Gynecology: Uterus (endometrial cancer (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-theca cell tumor, ovarian Sertoli-Leydig cell tumor, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, carcinoma in situ, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botulinum sarcoma (embryonal rhabdomyosarcoma), fallopian tube (cancer), Hematology: Blood (myeloid leukemia (acute and chronic), acute lymphocytic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelohyperplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma), Skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, dysplastic nevus, lipoma, hemangioma, dermatofibroma, keloid, psoriasis, Adrenal gland: selected from neuroblastoma, For example, the cancer is 1. The use of the present invention, wherein the cancer is selected from pancreatic cancer, lung cancer, colorectal cancer, cholangiocarcinoma, multiple myeloma, melanoma, uterine cancer, endometrial cancer, thyroid cancer, acute myeloid leukemia, bladder cancer, urothelial carcinoma, gastric cancer, cervical cancer, squamous cell carcinoma of the head and neck, diffuse large B-cell lymphoma, esophageal cancer, chronic lymphocytic leukemia, hepatocellular carcinoma, breast cancer, ovarian cancer, prostate cancer, glioblastoma, renal cancer, and sarcoma.

22. 20. A process for preparing a compound of formula I or I' according to any one of claims 1 to 19, and / or its stereoisomers, enantiomers, diastereoisomers, atropisomers, deuterated forms, hydrates, solvates, metabolites, prodrugs, and / or pharmaceutically acceptable salts thereof, comprising: G 【Chemistry 146】 and L is LA 【Chemistry 147】 and ring U contains an NH group, the preparation method is 【Chemistry 148】 and G1' 【Chemistry 149】 and L is LA [Chemical 150] and ring U contains an NH group, the preparation method is 【Chemistry 151】 and Here, the 【Chemistry 152】 refers to the ring U containing the NH group, R 1a' are defined as in any one of claims 1 to 10, and R 3e , R 4e , R 5e , X', Y' and R 1a' are defined as in any one of claims 8 or 9, 【Chemistry 153】 refers to Lx containing an aldehyde group, the definition of Lx being as defined in any one of claims 10 to 14, The definitions of ring U, ring Y, X″, Lx and Ly are all as described in any one of claims 10 to 14, The definition of E is as defined in any one of claims 1 to 19, G 【Chemistry 154】 and L is LA 【Chemistry 155】 and ring Y contains an NH group and X″ is C(O), the preparation method is 【Chemistry 156】 and G1' 【Chemistry 157】 and L is LA 【Chemistry 158】 and ring Y contains an NH group and X″ is C(O), the preparation method is 【Chemistry 159】 and where: [Chemical 160] refers to the ring Y containing the NH group, P 100 is a pentafluorophenyl group or a p-nitrophenyl group, R 1a' are defined as in any one of claims 1 to 10, and R 3e , R 4e , R 5e , X', Y' and R 1a' are defined as in claim 8 or 9, The definitions of ring U, ring Y, X'', Lx and Ly are all as defined in LA of any one of claims 10 to 14, 19. A method, characterized in that E is defined as in any one of claims 1 to 18.

23. A compound represented by formula W-1, W-2, W-3, W-4, W-5, formula II-1, formula II-2 or formula II-3, 【Chemistry 161】 【change】 Here, each R 1a are independently 【Chemistry 162】 and each R 19 are independently amino protecting groups, and R 17 and each R 18 are independently hydroxy protecting groups, The definitions of J1, J2, L and E are as set forth in any one of claims 1 to 19, Ring C, R 2e , R 3e , R 4e , R 5e , R 1b , R 2b , R 3b , W 1 , W 2 , X' and Y' are defined as in any one of claims 8 to 10; The definitions of ring U, ring Y, X″, Lx and Ly are all as described in any one of claims 10 to 13, p'' is 1, 2, 3 or 4; Preferably, formula W-1 is formula W-1-1, formula W-2 is formula W-2-1, formula W-3 is formula W-3-1, formula W-4 is formula W-4-1, and formula W-5 is formula W-5-1; 【Chemistry 163】 Here, rings C and R 2e , R 3e , R 4e , R 5e , W 1 and W 2 is as defined in any one of claims 8 to 10, and R 1b , R 2b and R 3b are defined as in any one of claims 1 to 16, The definitions of Lx, ring U, Ly, ring Y and p″ are as set forth in any one of claims 10 to 14; More preferably, the compound represented by the formula W-1, W-2, W-3, W-4 or W-5 is 【Chemistry 164】 【change】 【change】 【change】 Selected from The compound represented by formula II-1, formula II-2 or formula II-3 is preferably any one of the following compounds: 【Chemistry 165】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 A compound represented by formula W-1, W-2, W-3, W-4, W-5, formula II-1, formula II-2 or formula II-3, wherein

24. 1. A method for treating or preventing a KRAS G12D mediated disease or condition, comprising:

20. A method for treating a rheumatoid arthritis comprising administering to a patient in need thereof a therapeutically effective amount of a substance X, wherein the substance X is a compound of formula I or I' according to any one of claims 1 to 19, and / or a stereoisomer, enantiomer, diastereoisomer, atropisomer, deuterated form, hydrate, solvate, prodrug, and / or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 20; Preferably, the KRAS G12D mediated disease or condition is any of those described in claim 21.

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