Pan-KRAS decomposing agent, its manufacturing method and application

Abstract

The present invention provides pan-KRAS degrading agents and their preparation methods and applications. Specifically, the present invention discloses small molecule compounds that target the degradation of pan-KRAS protein, as well as their preparation methods and applications as therapeutic agents for preventing and / or treating cancer. The compounds described in the present invention can effectively degrade and / or inhibit pan-KRAS protein in cells and can be used to manufacture drugs for treating and / or preventing related diseases or conditions mediated by pan-KRAS.

Description

[Technical Field]

[0001] This application claims priority from Chinese Patent Application No. 2022112974447 filed on October 21, 2022, Chinese Patent Application No. 2023100790752 filed on January 20, 2023, and Chinese Patent Application No. 2023108419741 filed on July 11, 2023. This application references the above Chinese patent applications in their entireties.

[0002] The present invention belongs to the field of pharmaceutical technology, and specifically, the present invention relates to a pan-KRAS degrading agent, a method for preparing the same, and its application as a therapeutic agent for preventing and / or treating cancer. [Background technology]

[0003] 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:

[0006] 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 Jul 21. doi:10.1038 / s41589-022-01065-9), 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, 9678-9690, etc.) and inhibitors that act indirectly on KRAS, such as KRAS(on) inhibitors (WO2021091982A1, WO2022060836A1).

[0007] In recent years, as KRAS research has progressed, the research and development of KRAS inhibitors has finally made significant progress (Cancer Discov. 2022, 12, 924-937), and firstly, a specific KRAS-G12C inhibitor has been discovered.

[0008] In the design process of KRAS-G12C inhibitors, cysteine ​​at codon 12 is mainly used, as it is easy to form covalent bonds. The use of covalent targeting of 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) (Nature 2019, 575, 217-223; J. Med. Chem. 2020, 63, 52-65), developed by Amgen, 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 approved a new drug application for the second KRAS-G12C inhibitor, Adagrasib (MRTX849), submitted by Mirati Pharmaceuticals (Cancer Discov. 2020, 10, 54-71 & J. Med. Chem. 2020, 63, 6679-6693). Adagrasib was used to treat patients with non-small cell lung cancer harboring KRAS G12C mutations who had received at least one prior systemic therapy (N. Engl. J. Med. 2022, 387, 120-131). Adagrasib is expected to become the second KRAS-targeting drug worldwide.

[0009] 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.

[0010] 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).

[0011] 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.

[0012] Patents such as WO2021041671A1, WO2022015375A1, WO2022031678A1, WO2022066646A1, WO2022098625A1, WO2022192790A1, WO2022192794A1, WO2021106231A1, WO2021107160A1, and WO2022173870A1 disclose several classes of KRAS G12D-specific inhibitors.

[0013] While the above-mentioned inhibitors that directly target KRAS, such as KRAS-G12C and KRAS-G1D inhibitors, are all specific inhibitors, inhibitors that indirectly target KRAS, such as SHP2, SOS1, and KRAS(on) inhibitors, are pan-KRAS inhibitors. When SOS1 inhibitors indirectly target KRAS, they can exert their effects against various KRAS mutants, including KRAS-G12C / G12D / G12V / G13D (BI-3406, Cancer Discov. 2021, 11, 142-157; MRTX0902, J. Med. Chem. 2022, 65, 9678-9690).

[0014] Patents such as WO2022132200A1 and WO2022133038A1 disclose several classes of pan-KRAS inhibitors.

[0015] In recent years, targeted protein degraders have become a popular research and development technology worldwide (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: while the development of "druggable" targets has encountered bottlenecks, the potential of "undruggable" targets is limitless, and 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.

[0016] Thus, there is an unmet clinical need for pan-KRAS targeted protein degraders. Summary of the Invention

[0017] 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:

[0018] [ka] where: K is K1

[0019] [ka] and K' is K2

[0020] [ka] and 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 ) 2- or 5- to 6-membered heteroaryl group, wherein the above-mentioned 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, (NR 3a 2. —O—C3-C8 cycloalkyl or 5-6 membered heteroaryl group is optionally substituted with one or more deuterium, halogen, hydroxyl, cyano, amino, nitro, C1-C3 alkoxy or C1-C3 alkyl groups; Each R 3a are independently selected from 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; Each ring A1 is independently absent and C6-C 10 an aryl group, a 5- to 10-membered heteroaryl group, or a 5- to 10-membered heterocycloalkyl group, Each ring B independently is C6-C 15 Aryl groups, 5-15 membered heteroaryl groups, C5-C 15 a cycloalkyl group or a 5- to 16-membered heterocycloalkyl group, 15Aryl groups, 5-15 membered heteroaryl groups, C5-C 15 The cycloalkyl group or 5- to 16-membered heterocycloalkyl group may optionally be one or more R a is replaced by Ring D is a 4- to 12-membered heterocycloalkyl group, and the 4- to 12-membered heterocycloalkyl group optionally contains one or more R a the 4- to 12-membered heterocycloalkyl group contains at least one heteroatom or heteroatom group selected from N, S, and O; Each R a are independently hydrogen, a hydroxy group, a halogen atom, a cyano group, -N(R 3a ) 1-2 , -CHN(R 3a ) 1-2 , 3-8 membered heterocycloalkyl group, C1-C6 alkyl group, HC(=O)-, -CO2R 4a , -CON(R 4a ) 1-2 , C1-C3 alkoxy group, (C1-C3 alkoxy)-C1-C3 alkyl-, C1-C3 alkyl-N(R 4a ) 1-2 , a C2-C4 alkenyl group, a C2-C6 alkynyl 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-C6 heteroalkyl group, -O(C1-C6 alkyl), -O1-C6 heteroalkyl group, -O(C3-C8 cycloalkyl), -O(3- to 8-membered heterocycloalkyl), -S(C1-C6 alkyl), -S(C3-C8 cycloalkyl), -O-phenyl group, -O-pyridyl group, C1-C3 alkoxy group, C2-C4 alkenyl group, C2-C6 alkynyl 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-C4 alkyl group, or a C1-C3 hydroxyalkyl group; Or, two R's 4atogether with the atom to which they are attached form a heterocycloalkyl group, said heterocycloalkyl group being optionally substituted with one or more deuterium, —OH, —NH, C1-C3 alkyl or C1-C3 alkoxy groups; each X 1 ' is independently a bond or -C(O)-; Each R 1 and each R 2 are independently hydrogen, a C1-C6 alkyl group, a C1-C6 alkoxy group, a C3-C8 cycloalkyl group, or a 3- to 8-membered heterocycloalkyl group, and the C1-C6 alkyl group, C3-C8 cycloalkyl group, or 3- to 8-membered heterocycloalkyl group is optionally substituted with one or more deuterium atoms, halogen atoms, hydroxy groups, amino groups, -C1-C3 alkyl groups, -S-C1-C3 alkyl groups, -O-C1-C3 alkyl groups, or -NH-C1-C3 alkyl groups; n is 0, 1, 2, 3 or 4; L is a linking chain connecting K and E via a covalent bond, L is a linking chain that connects K′ and E via a covalent bond, wherein each E is independently E1, E2, or E3;

[0021] [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 3b are each independently 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 C6-C 10Aryl group, 5-10 membered heteroaryl group, -O-(C1-C6 alkyl), -O-(C1-C6 heteroalkyl), -O-(C3-C8 cycloalkyl), -O-(3-8 membered heterocycloalkyl), -S-(C1-C6 alkyl), -S-(C1-C6 heteroalkyl), -S-(C3-C8 cycloalkyl), -S-(3-8 membered heterocycloalkyl), -N(C1-C6 alkyl) 1-2 , -N(C1-C6 terephthaloalkyl) 1-2 , -N(C3-C8 cycloalkyl) 1-2 , -N(3- to 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), -O-(5- to 10-membered heteroaryl), or R 3b together with the atom to which it is attached 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, a C1-C6 alkyl group, a C1-C6 heteroalkyl group, a C3-C8 cycloalkyl group, a C3-C8 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), -O-(5- to 10-membered heteroaryl), wherein the alkyl group, cycloalkyl group, heterocycloalkyl group, aryl group, and heteroaryl group are 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 the 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, or —OC(O)(C1-C6 alkyl);

[0022] [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 selected from 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, or 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 selected from 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,

[0023] [ka] is a single or double bond, ----- is a bond, which may be an R stereoisomer, an S stereoisomer, or a non-stereoisomer;

[0024] [ka] Here, in E3 above, X 1 , X 2 are each independently a bond, O, C(O), C(S), or NR 1d or CR 1d R 2d and R 1d , R 2dare each independently selected from H, deuterium, and 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 selected from H, deuterium, halogen, —OH, and 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-(5-10 membered) heteroaryl group, -T-(4-12 membered) heterocycloalkyl group, -NR 5d -T-(C6-C 10 ) aryl group, -NR 5d -T-(5- to 10-membered) heteroaryl group or -NR 5d -T-(4-12 membered) heterocycloalkyl group, 3d R 4d ), -TN(R 3d R 4d )X 3 , -T-(C6-C 10 ) aryl group, -T-(5-10 membered) heteroaryl group, -T-(4-12 membered) heterocycloalkyl group, -NR 5d -T-(C6-C 10 ) aryl group, -NR 5d -T-(5- to 10-membered) heteroaryl group or -NR 5d -T-(4- to 12-membered)heterocycloalkyl group is optionally substituted; X 3 is C(O), R 3d , R 4d or R 5d and R 3d , R 4d or R 5dare 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,

[0025] [ka] Selected from the above

[0026] [ka] is optionally replaced, R 6d , R 7d are each independently selected from 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 selected from 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 6dR 7d , OR 6d , 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 or C1-C6 alkoxy group is optionally substituted with deuterium, halogen, —OH, CN, NO2, or an amino group.

[0027] Preferably, in some embodiments of the present invention, in Formula I, R 2a , R 3a , R a and R 4a wherein the definition of one or more groups in is further replaced by the following definitions, with the proviso that L is linked to E via —C(O)—; R 2a represents a mercapto group, (C1-C3 alkoxy)C1-C3 alkyl-, -O-C1-C6 heteroalkyl group, -OCOR 3a , -NH(C1-C6 heteroalkyl), -N(C1-C6 heteroalkyl)(C1-C6 heteroalkyl) or -C3-C4 alkynyl-N(R 5a' )2, R 2a wherein the hydroxy groups are independently optionally substituted with one or more deuterium atoms, a C1-C3 alkoxy group, a C1-C3 alkyl group, a C3-C8 cycloalkyl group, a —Si—C1-C3 alkyl group, a 3- to 8-membered heterocycloalkyl group, or —CON(R 3a )2, R 2awherein 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 heteroalkyl 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(R 3a )2, Each R 3a is deuterium or an —NH—C1-C3 alkyl group, R a are independently a bond, deuterium, oxo, cyanomethyl, C1-C6 heteroalkyl group, -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, triazolyl group, -CH2C(=O)N(R 3a )2 or -C3-C4 alkynyl-N(R 3a )2, Or, two adjacent R a together with the atoms connected 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 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 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(R3a ) 1-2 or -C3-C4 alkynyl-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 C1-C6 alkyl group.

[0028] Preferably, in some embodiments of the present invention, each R 2a In the above, the C1-C6 heteroalkyl group is a C3 heteroalkyl group, and the methylene group in the heteroalkyl group is substituted with -C(O)NH-, for example

[0029] [ka] is.

[0030] Preferably, in some embodiments of the present invention, each R 2a wherein C3-C8 may optionally be substituted with one or more C1-C3 alkyl groups.

[0031] Preferably, in some embodiments of the present invention, each R 2a wherein the C3-C8 cycloalkyl group may be optionally substituted with one or more C1-C3 alkyl groups.

[0032] Preferably, in some embodiments of the present invention, 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.

[0033] Preferably, in some embodiments of the present invention, each R 2a In the above, the C2-C6 alkynyl group is a C2-C4 alkynyl group, for example, an ethynyl group.

[0034] Preferably, in some embodiments of the present invention, each R 2a is optionally substituted with a substituent, in which the halogen is F, Cl, Br or I, for example F.

[0035] Preferably, in some embodiments of the present invention, 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.

[0036] Preferably, in some embodiments of the present invention, 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.

[0037] Preferably, in some embodiments of the present invention, in each ring A1, the C6-C 10 The aryl group is a phenyl group or a naphthyl group.

[0038] Preferably, in some embodiments of the present invention, in each ring A1, the 5- to 15-membered heteroaryl group in the 5- to 15-membered heteroaryl group is a 5- to 10-membered heteroaryl group, which may 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.

[0039] Preferably, in some embodiments of the present invention, in each ring A1, the 5- to 10-membered heteroaryl group is a bicyclic heteroaryl group, and 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.

[0040] In some embodiments of the present invention, in each ring A1, the 5- to 10-membered heterocycloalkyl group preferably has one or more heteroatoms selected from N, S and O, and the number of heteroatoms is 1 or 2.

[0041] Preferably, in some embodiments of the present invention, in each ring B, the C6-C 15 The aryl group is C6-C 10 It is an aryl group, for example a phenyl group or a naphthyl group.

[0042] 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.

[0043] 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, such as

[0044] [ka] and

[0045] [ka] Here, represents condensation with the ring to which it is connected via the bond of.

[0046] 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.

[0047] Preferably, in some embodiments of the present invention, in each ring D, ring D is:

[0048] [ka] isn't it.

[0049] Preferably, in some embodiments of the present invention, in each ring D, the 4- to 12-membered heterocycloalkyl group is a 5- to 7-membered monocyclic saturated heterocycloalkyl group, in which the heteroatom is one or more of N, O, and S (including heteroatom groups formed by each heteroatom, such as -C(O)-, -S(O)-, -S(O)2-, -C(O)O-, -OC(O)-), C(O)NH-, -NHC(O)-), and the number is 1, 2, or 3, for example:

[0050] [ka] is.

[0051] Preferably, in some embodiments of the present invention, in each ring D, the 4- to 12-membered heterocycloalkyl group is an 8-, 9-, or 10-membered bridged heterocycloalkyl group or spiroheterocycloalkyl group, and the heteroatom is one or more of N, O, and S (including heteroatom groups formed by each heteroatom, such as -C(O)-, -S(O)-, -S(O)2-, -C(O)O-, -OC(O)-), C(O)NH-, and -NHC(O)-), and the number is 1, 2, or 3, for example:

[0052] [ka] is.

[0053] Preferably, in some embodiments of the present invention, in Formula I, R 2a , R 3a , a C1-C4 alkylene group in L', R a and R b wherein one or more of the definitions of groups in may be further substituted with the following definitions, with the proviso that L is linked to E via —C(O)—; R 2a is a mercapto group, (C1-C3 alkoxy)C1-C3 alkyl-, -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 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 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 heteroalkyl 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(R 3a )2, Each R 3a is deuterium, R aare independently a bond, deuterium, oxo, cyanomethyl, C1-C6 heteroalkyl group, -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, triazolyl group, -CH2C(=O)N(R 3a )2 or -C3-C4 alkynyl-N(R 3a )2, 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 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 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 alkynyl-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 C1-C6 alkyl group.

[0054] Preferably, in some embodiments of the present invention, K1 is K1-I or K1-II;

[0055] [ka] Here, in the above K1-I, Ring C is C6-C 10 Aryl groups, 5-10 membered heteroaryl groups, C6-C 10 a cycloalkyl group or a 5- to 10-membered heterocycloalkyl group, X' is a bond, C or N; Y' is C or N;

[0056] [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), O(C3-C8 cycloalkyl), R 3e is a bond, 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 Or, R 4e is a C6-C bond along with the carbon atoms attached to it. 12 aryl group, 5- to 12-membered heteroaryl group (i.e., R 4e forms a spiro ring structure together with Y' linked thereto), and 12The aryl group, the 5- to 12-membered heteroaryl group is optionally substituted with H, deuterium, halogen, hydroxy group, amino group, C1-C6 alkyl group, -S(C1-C6 alkyl) or -O(C1-C6 alkyl); R 5e is hydrogen, deuterium, halogen, cyano group, C1-C6 alkyl group, C3-C8 cycloalkyl group, -O(C1-C6 alkyl), -O(C3-C8 cycloalkyl), R a' are independently a halogen, a cyano group, a hydroxy group, a C1-C6 alkyl group, a C1-C6 heteroalkyl group, an -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-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' )2, -N(R 5a' )2, (C1-C3 alkoxy)C1-C3 alkyl-, C3-C6 cycloalkyl group, 3- to 6-membered heterocycloalkyl group, wherein the above-mentioned hydroxy group, 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, the 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)3; Each R 5a' are independently selected from H, deuterium, or a C1-C6 alkyl group; Ring D is defined and described by the present invention;

[0057] [ka] Here, in the above K1-II, Ring E is a C5-C7 cycloalkyl group, a 5- to 7-membered heterocycloalkyl group, a C6-C 10 an 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; 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, 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 contains 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' )2, -CH2N(R x' ) 2, a cyanomethyl group or a 3- to 8-membered heterocycloalkyl 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, a C1-C3 alkoxy group, or -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; Rb''' 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 selected from H or a C1-C3 alkyl group; p is 0 or 1; Ring D is defined and described by the present invention.

[0058] Preferably, in some embodiments of the present invention, K1 is K1-I, K1-II or K2-I;

[0059] [ka] Here, in the above K1-I, Ring C is C6-C 15 Aryl groups, 5-10 membered heteroaryl groups, C6-C 15 a cycloalkyl group or a 5- to 10-membered heterocycloalkyl group, X' is a bond, C, O or N; Y' is C or N;

[0060] [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), O(C3-C8 cycloalkyl), R 3eis a bond, 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 Or, R 4e is a C6-C bond along with the carbon atoms attached to it. 12 Forming an aryl group or a 5- to 12-membered heteroaryl group, the above C6-C 12 The aryl group, the 5- to 12-membered heteroaryl group is optionally substituted with H, deuterium, halogen, hydroxy group, amino group, C1-C6 alkyl group, S(C1-C6 alkyl) or O(C1-C6 alkyl); R 5e is hydrogen, deuterium, halogen, cyano group, C1-C6 alkyl group, C3-C8 cycloalkyl group, O(C1-C6 alkyl), O(C3-C8 cycloalkyl), R a' are independently a halogen, a cyano group, a hydroxy group, a C1-C6 alkyl group, a C1-C6 heteroalkyl group, an -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-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' )2, -N(R 5a')2, (C1-C3 alkoxy)C1-C3 alkyl-, C3-C6 cycloalkyl group, 3- to 6-membered heterocycloalkyl group, wherein the above-mentioned hydroxy group, 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, the 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)3; Each R 5a' are independently selected from H, deuterium, or a C1-C6 alkyl group; Ring D is defined and described by the present invention;

[0061] [ka] Here, in the above K1-II, Ring E is a C5-C7 cycloalkyl group, a 5- to 7-membered heterocycloalkyl group, 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, 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, oxo, halogen, deuterium, cyano group, hydroxy group, amino group, 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, triazolyl group, -O-C1-C6 alkyl group, -CH2C(=O)N(R x' )2, -C3-C4 alkynyl (NR x' )2, -N(R x' )2, -C1-C3 alkoxy-C1-C3 alkyl-, wherein the C1-C6 alkyl group, C1-C6 heteroalkyl group, C3-C6 cycloalkyl group, -O-C1-C6 alkyl group, -S-C1-C3 alkyl group, C2-C4 alkenyl group, C2-C4 alkynyl 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 selected from H or a C1-C3 alkyl group; p is 0 or 1; Ring D is defined and described by the present invention;

[0062] [ka] Here, in the above K2-I, Ring C is C6-C 10 Aryl groups, 5-10 membered heteroaryl groups, C6-C 10 a cycloalkyl group or a 5- to 10-membered heterocycloalkyl group, X' is a bond, C, O or N; Y' is C or N;

[0063] [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), O(C3-C8 cycloalkyl), R 3e is a bond, 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 C6-C 10 an aryl group or a 5- to 10-membered heteroaryl group, and 10 The aryl group or 5- to 10-membered heteroaryl group may optionally be one or more R a' is replaced by Or, R 4e is a C6-C bond along with the carbon atoms attached to it. 12 Forming an aryl group or a 5- to 12-membered heteroaryl group, the above C6-C 12 The aryl group, the 5- to 12-membered heteroaryl group is optionally substituted with H, deuterium, halogen, hydroxy group, amino group, C1-C6 alkyl group, S(C1-C6 alkyl) or O(C1-C6 alkyl); R 5e is hydrogen, deuterium, halogen, cyano group, C1-C6 alkyl group, C3-C8 cycloalkyl group, O(C1-C6 alkyl), O(C3-C8 cycloalkyl), R a'are independently a halogen, a cyano group, a hydroxy group, an amino group, a mercapto group, a C1-C6 alkyl group, a C1-C6 heteroalkyl group, an -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-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' )2, -N(R 5a' )2, (C1-C3 alkoxy)C1-C3 alkyl-, C3-C6 cycloalkyl group, 3- to 6-membered heterocycloalkyl group, wherein the above-mentioned hydroxy group, 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, the 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)3; Each R 5a' are independently selected from H, deuterium, or a C1-C6 alkyl group; R 1 , R 2 is defined and described by the present invention.

[0064] Preferably, in some embodiments of the present invention, K1 is K1-Ia or K1-II-a;

[0065] [ka] where: r is 1 or 2; t is 1, 2 or 3; Here, ring C, ring D, and R of K1-Ia or K1-II-a 2e , R 3e , R 4e , R 5e , Y″ and p are defined and described by the present invention.

[0066] Preferably, in some embodiments of the present invention, K1 is K1-Ia, K1-II-a or K2-Ia;

[0067] [ka] where: r is 1 or 2; t is 1, 2 or 3; Here, ring C, ring D, and R of K1-Ia or K1-II-a 2e , R 3e , R 4e , R 5e , X', Y', R 1 , R 2 , Y″ and p are defined and described by the present invention.

[0068] Preferably, in some embodiments of the present invention, K1 is K1-I-a1, K1-I-a2, K1-I-a3, K1-I-a4, K1-I-a5, K1-I-a6, K1-II-a1, K1-II-a2, K1-II-a3 or K1-II-a4;

[0069] [ka] Here, K1-I-a1, K1-I-a2, K1-I-a3, K1-I-a4, K1-I-a5 or K1-I-a6 is mentioned above, R 1a' is hydrogen, hydroxyl group, halogen, cyano group, C1-C6 alkyl group, C3-C8 cycloalkyl group, HC(=O)-, -CO2R 5a' , -CON(R 5a' ) 1-2or a 5- to 6-membered heteroaryl group, wherein the C1-C6 alkyl group or 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 selected from hydrogen or a C1-C4 alkyl group; Or, two R's 5a' together with the N atom to which they are attached form a 4- to 8-membered heterocycloalkyl group, said 4- to 8-membered heterocycloalkyl group containing one or more N, O, S heteroatoms or heteroatomic groups; W1 is CH2, O, NH or S; m is 0, 1, 2 or 3; R 3e , R 4e , R 5e , X' and Y' are defined and described by the present invention;

[0070] [ka] Here, in the above K1-II-a1, K1-II-a2, K1-II-a3 or K1-II-a4, R 1a' is hydrogen, hydroxyl group, halogen, cyano group, C1-C6 alkyl group, C3-C8 cycloalkyl group, HC(=O)-, -CO2R 5a' , -CON(R 5a' ) 1-2 or a 5- to 6-membered heteroaryl group, wherein the C1-C6 alkyl group or 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 selected from hydrogen or a C1-C6 alkyl group; Or, two R's 5a' together with the N atom to which they are attached form a 4- to 8-membered heterocycloalkyl group, said 4- to 8-membered heterocycloalkyl group containing one or more N, O, S heteroatoms or heteroatomic groups; R 4a'is selected from 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 8a' may be substituted with R 5a' are independently selected from 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.

[0071] Preferably, in some embodiments of the present invention, K1 is K1-I-a1, K1-I-a2, K1-I-a3, K1-I-a4, K1-I-a5, K1-I-a6, K1-I-a7, K1-II-a1, K1-II-a2, K1-II-a3, K1-II-a4, K1-II-a5 or K2-I-a1;

[0072] [ka] Here, in the above K1-I-a1, K1-I-a2, K1-I-a3, K1-I-a4, K1-I-a5, K1-I-a6 or K1-I-a7, R 1a' is hydrogen, hydroxy group, halogen, cyano group, amino group, C1-C6 alkyl group, C3-C8 cycloalkyl group, HC(=O)-, -CO2R 5a' , -CON(R 5a' )1-2 or a 5- to 6-membered heteroaryl group, wherein the C1-C6 alkyl group or 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 selected from hydrogen or a C1-C6 alkyl group; Or, two R's 5a' together with the N atom to which they are attached form a 4- to 8-membered heterocycloalkyl group, said 4- to 8-membered heterocycloalkyl group containing one or more N, O, S heteroatoms or heteroatomic groups; W1 is CH2, O, NH or S; m is 0, 1, 2 or 3; R 3e , R 4e , R 5e , X' and Y' are defined and described by K1-Ia of the present invention;

[0073] [ka] Here, in the above K1-II-a1, K1-II-a2, K1-II-a3, K1-II-a4 or K1-II-a5, R 1a' is hydrogen, hydroxyl group, halogen, cyano group, C1-C6 alkyl group, C3-C8 cycloalkyl group, HC(=O)-, -CO2R 5a' , -CON(R 5a' ) 1-2 or a 5- to 6-membered heteroaryl group, wherein the C1-C6 alkyl group or 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 selected from hydrogen or a C1-C6 alkyl group; Or, two R's 5a' together with the N atom to which they are attached form a 4- to 8-membered heterocycloalkyl group, said 4- to 8-membered heterocycloalkyl group containing one or more N, O, S heteroatoms or heteroatomic groups; R 4a'is selected from 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 8a' may be substituted with R 5a' are independently selected from 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 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, W1 is CH2, O, NH or S; m is 0, 1, 2 or 3; Y″ is defined and described by the present invention;

[0074] [ka] Here, in the above K2-I-a1, R 3e , R 4e , R 5e , X', Y', R 1 and R 2 is defined and described by the present invention.

[0075] Preferably, in some embodiments of the present invention, K1 is K1-I-a1,

[0076] [ka] and where X' is C or N and Y' is C; R 3e is H or absent, R 4e is C6-C 10 an aryl group or a 5- to 10-membered heteroaryl group, and 10 The aryl group or 5- to 10-membered heteroaryl group may optionally be one or more R a' is replaced by R a' are independently selected from halogen, a hydroxy group, a C1-C6 alkyl group, a C2-C6 alkynyl group, or a C3-C6 cycloalkyl group; R 5e is a halogen, R 1a' is hydrogen, a hydroxy group, NH2, a halogen, or a C1-C6 alkyl group, W1 is CH2 or O; m is 0, 1, 2 or 3; The above K2 is K2-I-a1,

[0077] [ka] and where X' is C or N and Y' is C; R 3e is H or absent, R 4e is C6-C 10 an aryl group or a 5- to 10-membered heteroaryl group, and 10 The aryl group or 5- to 10-membered heteroaryl group may optionally be one or more R a' is replaced by R a' are independently selected from halogen, a hydroxy group, a C1-C6 alkyl group, a C2-C6 alkynyl group, or a C3-C6 cycloalkyl group; R 5e is a halogen, R 1 and R 2are independently hydrogen, a C1-C6 alkyl group, or a C3-C8 cycloalkyl group, wherein the C1-C6 alkyl group or the C3-C8 cycloalkyl group is optionally substituted with one or more halogens, hydroxy groups, or amino groups.

[0078] Preferably, in some embodiments of the present invention, K1 is K1-I-a1,

[0079] [ka] and where X' is C or N and Y' is C; R 3e is H or absent, and R 4e is C6-C 10 An aryl group, C6-C 10 The aryl group may optionally be one or more R a' is replaced by R a' are independently selected from halogen, a hydroxy group, a C1-C6 alkyl group, a C2-C6 alkynyl group, or a C3-C6 cycloalkyl group; R 5e is a halogen, R 1a' is hydrogen, a hydroxy group, or a C1-C6 alkyl group, W1 is CH2 or O; m is 1 or 2; The above K2 is K2-I-a1,

[0080] [ka] and where X' is N and Y' is C; R 3e does not exist, R 4e is C6-C 10 An aryl group, C6-C 10 The aryl group may optionally be one or more R a' is replaced by R a' are independently selected from halogen, a hydroxy group, or a C2-C6 alkynyl group; R 5e is a halogen, R 1 and R 2 are independently hydrogen, a C1-C6 alkyl group, or a C3-C8 cycloalkyl group.

[0081] Preferably, in some embodiments of the present invention, wherein the structural unit

[0082] [ka] teeth,

[0083] [ka] and the structural unit

[0084] [ka] is optionally 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

[0085] Preferably, in some embodiments of the present invention, wherein the structural unit

[0086] [ka] teeth,

[0087] [ka] and the structural unit

[0088] [ka] is optionally 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 -C3-C6 alkenyl group, a -C3-C6 alkynyl group, a -C3-C8 heterocycloalkyl group, -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

[0089] More preferably, in some embodiments of the present invention, the structural unit

[0090] [ka] teeth,

[0091] [ka] and the structural unit

[0092] [ka] is optionally 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 -C3-C6 alkenyl group, a -C3-C6 alkynyl group, a -C3-C8 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

[0093] Preferably, in some embodiments of the present invention, 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,

[0094] [ka] or -SCH3, and the above -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2,

[0095] [ka] Or -SCH3 is optionally substituted with halogen, CN, -OH, -NH2 or a C1-C3 alkyl group.

[0096] Preferably, in some embodiments of the present invention, ring A1 is C6-C 10 an aryl group or a 5- to 10-membered heteroaryl group, and 10 The aryl group or 5- to 10-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,

[0097] [ka] or -SCH3, and the above -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2,

[0098] [ka] Or -SCH3 is optionally substituted with halogen, CN, -OH, -NH2 or a C1-C3 alkyl group.

[0099] More preferably, in some embodiments of the present invention, ring A1 is a phenyl group, a pyridyl group, a naphthyl group,

[0100] [ka] and the phenyl group, pyridyl group, naphthyl group,

[0101] [ka] is optionally —OH, F, Cl, Br, I, CN, —NH2, —CH3, —CH2CH3, —CH2CH2CH3, —CH(CH3)2—, —OCH3, OCH2CH3,

[0102] [ka] or -SCH3, and the above -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2,

[0103] [ka] Or -SCH3 is optionally substituted with halogen, CN, -OH, -NH2 or a C1-C3 alkyl group.

[0104] Preferably, in some embodiments of the present invention, wherein the structural unit

[0105] [ka] teeth,

[0106] [ka] and the structural unit

[0107] [ka] optionally 1, 2 or 3 R a is replaced by

[0108] Preferably, in some embodiments of the present invention, wherein the structural unit

[0109] [ka] teeth,

[0110] [ka] and the structural unit

[0111] [ka] optionally 1, 2 or 3 R a is replaced by

[0112] Preferably, in some embodiments of the present invention, wherein the structural unit

[0113] [ka] teeth,

[0114] [ka] and the structural unit

[0115] [ka] optionally 1, 2 or 3 R a is replaced by

[0116] Preferably, in some embodiments of the present invention, wherein the structural unit

[0117] [ka] teeth,

[0118] [ka] TIFF2025537482000063.tif35169, and the above structural unit

[0119] [ka] optionally 1, 2 or 3 R a is replaced by

[0120] More preferably, in some embodiments of the present invention, the structural unit

[0121] [ka] teeth,

[0122] [ka] is.

[0123] More preferably, in some embodiments of the present invention, the structural unit

[0124] [ka] teeth,

[0125] [ka] is.

[0126] More preferably, in some embodiments of the present invention, the structural unit

[0127] [ka] teeth,

[0128] [ka] is.

[0129] Preferably, in some embodiments of the present invention, wherein the structural unit

[0130] [ka] teeth,

[0131] [ka] TIFF2025537482000073.tif130169, and the above structural unit

[0132] [ka] optionally 1, 2 or 3 R a is replaced by

[0133] Preferably, in some embodiments of the present invention, wherein the structural unit

[0134] [ka] teeth,

[0135] [ka] TIFF2025537482000077.tif237169TIFF2025537482000078.tif222169

[0136] Preferably, in some embodiments of the present invention, wherein the structural unit

[0137] [ka] teeth,

[0138] [ka] is.

[0139] Preferably, in some embodiments of the present invention, the structural unit

[0140] [ka] teeth,

[0141] [ka] TIFF2025537482000083.tif216169TIFF2025537482000084.tif230169TIFF2025537482000085.tif210169.

[0142] Preferably, in some embodiments of the present invention, the structural unit

[0143] [ka] teeth,

[0144] [ka] is.

[0145] Preferably, in some embodiments of the present invention, the structural unit

[0146] [ka] teeth,

[0147] [ka] and the structural unit

[0148] [ka] is optionally substituted with one or more deuterium, F, Cl, Br, hydroxy groups, amino groups, -CH3, or -S-CH3.

[0149] Preferably, in some embodiments of the present invention, the structural unit

[0150] [ka] teeth,

[0151] [ka] is.

[0152] Preferably, in some embodiments of the present invention, the structural unit

[0153] [ka] teeth,

[0154] [ka] and the structural unit

[0155] [ka] is optionally substituted with one or more deuterium, F, Cl, Br, hydroxy groups, amino groups, -CH3, or -S-CH3.

[0156] Preferably, in some embodiments of the present invention, the structural unit

[0157] [ka] teeth,

[0158] [ka] is.

[0159] Preferably, in some embodiments of the present invention, L is -(CH) j -, and the above -(CH2) 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)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 heterocycloalkylene group, an 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 chloroalkyl 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.

[0160] Preferably, in some embodiments of the present invention, L is

[0161] [ka] TIFF2025537482000099.tif237169TIFF2025537482000100.tif236169TIFF2025537482000101.tif23 6169TIFF2025537482000102.tif224169TIFF2025537482000103.tif231169TIFF2025537482000104.ti f236169TIFF2025537482000105.tif233169TIFF2025537482000106.tif235169TIFF2025537482000107 .tif235169TIFF2025537482000108.tif242169TIFF2025537482000109.tif242169TIFF2025537482000 110.tif239169TIFF2025537482000111.tif235169TIFF2025537482000112.tif235169TIFF202553748 2000113.tif236169TIFF2025537482000114.tif232169TIFF2025537482000115.tif228169TIFF202553 7482000116.tif235169TIFF2025537482000117.tif218169TIFF2025537482000118.tif230169TIFF2025537482000119.tif224169TIFF2025537482000120.tif218169TIFF2025537482000121.tif116169.

[0162] Preferably, in some embodiments of the invention, L is LA,

[0163] [ka] Here, in the above LA, Ring U is C3-C 12a 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 Re 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.

[0164] Preferably, in some embodiments of the invention, L is LA,

[0165] [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-, -CHF-, -CHCF3-, or -(CH2) qC(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.

[0166] Preferably, in some embodiments of the invention, L is LA,

[0167] [ka] Here, in the above LA, Ring U is C3-C 12a cycloalkylene group or a 3- to 12-membered heterocycloalkylene group containing 1 to 3 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-, -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, —NH, a C1-C6 haloalkyl group, a C1-C6 alkyl group, or a C1-C6 alkoxy group; Or, Rd 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.

[0168] 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.

[0169] 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, a 6- to 10-membered fused heterocycloalkylene group, or a 7- to 11-membered spiroheterocycloalkylene group; 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, —C(O)CHO—, or —C(O)—; Lx is —(CH) v -, v is 1, 2, 3, 4 or 5, and Ly is -(CH2) kand k is 1, 2, 3, 4 or 5.

[0170] Preferably, in some embodiments of the present invention, LA is LA-1, LA-2,

[0171] [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.

[0172] Preferably, in some embodiments of the present invention, LA is LA-1, LA-2,

[0173] [ka] X″ is —C(O)—, —C(O)NH—, or —C(O)CHO—; 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.

[0174] Preferably, in some embodiments of the present invention, wherein LA is LA-3, LA-4, or LA-5;

[0175] [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,

[0176] [ka] , —C(CH3)2, —CH(CH3)—, —CH(OH)—, —CH(OCH3)—, or C(CH3)(OH)—, and v is 1, 2, 3, 4, 5, or 6; Ring U is

[0177] [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,

[0178] [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-, -C≡C- or -N(C1-C6 alkyl)-, and k is 1, 2, 3, 4, 5 or 6; X″ is a bond, —C(O)—, —(CH)C(O)—, or —(CH)C(O)NH—;

[0179] [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,

[0180] [ka] , —C(CH3)2—, —CH(CH3)—, —CH(OCH3)—, —CH(OH)—, or —C(CH3)(OH)—, and v is 1, 2, 3, 4, 5, or 6; Ring U is

[0181] [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

[0182] [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)-;

[0183] [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

[0184] [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—;

[0185] [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

[0186] [ka] and v is 1, 2, 3 or 4; Ring U is

[0187] [ka] wherein the a-terminus is linked to Lx and the b-terminus is linked to Ly; Ring Y is

[0188] [ka] and 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 or 6; X'' is a bond.

[0189] Preferably, in some embodiments of the present invention, wherein LA is LA-3, LA-4, LA-5 or LA-6;

[0190] [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,

[0191] [ka] , —C(CH3)2—, —CH(CH3)—, —CH(OH)—, —CH(OCH3)—, or C(CH3)(OH)—, and v is 1, 2, 3, 4, 5, or 6; Ring U is

[0192] [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,

[0193] [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-, -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)-, -CH2-C≡C-, -C(O)CH2O- or -(CH2) 1-2 C(O)NH-,

[0194] [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,

[0195] [ka] , —C(CH3)2—, —CH(CH3)—, —CH(OCH3)—, —CH(OH)—, or —C(CH3)(OH)—, and v is 1, 2, 3, 4, 5, or 6; Ring U is

[0196] [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

[0197] [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)-;

[0198] [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

[0199] [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—;

[0200] [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 Re - is replaced by -CR d R e -teeth,

[0201] [ka] and v is 1, 2, 3 or 4; Ring U is

[0202] [ka] wherein the a-terminus is linked to Lx and the b-terminus is linked to Ly; Ring Y is

[0203] [ka] and 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 or 6; X'' is a bond.

[0204] Preferably, in some embodiments of the present invention, wherein LA is LA-7 or LA-8;

[0205] [ka] Here, in the above LA-7, 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,

[0206] [ka] , —C(CH3)2—, —CH(CH3)—, —CH(OH)—, —CH(OCH3)—, or C(CH3)(OH)—, and v is 1, 2, 3, 4, 5, or 6; Ring U is

[0207] [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,

[0208] [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-, -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)-, -CH2-C≡C-, -C(O)CH2O- or -(CH2) 1-2 C(O)NH-,

[0209] [ka] Here, in the above LA-8, 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,

[0210] [ka] , —C(CH3)2—, —CH(CH3)—, —CH(OCH3)—, —CH(OH)—, —C(CH3)(OH)—, —CH(CHF2)—, —CH(CH(CH3)2)—, —CH(CH2CF3)—, or —CH(NH2)—, and v is 1, 2, 3, 4, 5, or 6; Ring U is

[0211] [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 selected from F, a cyano group, C 1-6 substituted with an alkyl group or a C1-C6 hydroxyalkyl group; Ring Y is

[0212] [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)-.

[0213] Preferably, in some embodiments of the present invention, wherein LA is LA-9 or LA-10;

[0214] [ka] Here, in the above LA-9, Lx is -(CH2) vwherein 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,

[0215] [ka] and v is 1, 2, 3, 4, 5 or 6; Ring U is

[0216] [ka] wherein the a-terminus is linked to Lx and the b-terminus is linked to Ly; Ring Y is

[0217] [ka] where the c-terminus is linked to Ly and the d-terminus is linked to X″; Ly is -(CH2) k -, wherein one or two CH2 contained in Ly are each independently optionally substituted with -O-, -C≡C- or -N(C1-C6 alkyl)-, and k is 1, 2, 3, 4, 5 or 6; X'' is -C(O)-;

[0218] [ka] Here, in the above LA-10, 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,

[0219] [ka] , —CH(CH3)—, —CH(OCH3)—, —CH(OH)—, or —CH(NH2)—, and v is 1, 2, 3, 4, 5, or 6; Ring U is

[0220] [ka] wherein the a-terminus is linked to Lx and the b-terminus is linked to Ly; Ring Y is

[0221] [ka] where the c-terminus is linked to Ly and the d-terminus is linked to X″; Ly is -(CH2) k and k is 1, 2, 3, 4, 5 or 6; X'' is -C(O)-.

[0222] Preferably, in some embodiments of the present invention, wherein LA is LA-11 or LA-12;

[0223] [ka] Here, in the above LA-11, 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,

[0224] [ka] and v is 1, 2, 3, 4, 5 or 6; Ring U is

[0225] [ka] wherein the a-terminus is linked to Lx and the b-terminus is linked to Ly; Ring Y is

[0226] [ka] where the c-terminus is linked to Ly and the d-terminus is linked to X″; Ly is -(CH2) k wherein one or two CH2 contained in Ly are each independently optionally replaced by -O- or -C≡C-; and k is 1, 2, 3, 4, 5, or 6; X'' is -C(O)-;

[0227] [ka] Here, in the above LA-12, 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,

[0228] [ka] or —CH(CH3)—, where v is 1, 2, 3, 4, 5, or 6; Ring U is

[0229] [ka] wherein the a-terminus is linked to Lx and the b-terminus is linked to Ly; Ring Y is

[0230] [ka] where the c-terminus is linked to Ly and the d-terminus is linked to X″; Ly is -(CH2) k and k is 1, 2, 3, 4, 5 or 6; X'' is -C(O)-.

[0231] Preferably, in some embodiments of the present invention, Lx is

[0232] [ka] is.

[0233] Preferably, in some embodiments of the present invention, Ly is -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-,

[0234] [ka] And.

[0235] Preferably, in some embodiments of the present invention, L A has any one of the following structures:

[0236] [ka] TIFF2025537482000182.tif225169TIFF2025537482000183.tif211169TIFF2025537482000184.tif229169TIFF2025537482000185.tif211169TIFF2025537482000186.tif232169TIFF2025537482000187.tif98169.

[0237] Preferably, in some embodiments of the present invention, L A has any one of the following structures:

[0238] [ka] is.

[0239] Preferably, in some embodiments of the present invention, L A has any one of the following structures:

[0240] [ka] TIFF2025537482000190.tif217169TIFF2025537482000191.tif46169

[0241] 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;

[0242] [ka] wherein Q1, Q2, Q3, Q4, Q5, R1'', R2'', R3'', and m'' are as defined and described by the present invention.

[0243] Preferably, in some embodiments of the present invention, E1 has a structure of formula E1-1h'', E1-1i', E1-1j' or E1-1h'h',

[0244] [ka] where R 3b is as defined and described by the present invention.

[0245] Preferably, in some embodiments of the present invention, R 3bis 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) 1-2 or -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, -NH2.

[0246] Preferably, in some embodiments of the present invention, E1 has the structure of formula E1-1h″:

[0247] [ka] , where R 3b are each independently hydrogen, halogen, a C1-C6 alkyl group, or —O(C1-C6 alkyl), and the C1-C6 alkyl group and —O(C1-C6 alkyl) are optionally substituted with deuterium, halogen, cyano group, —OH, or —NH2, and the number of such substitutions is 1, 2, or 3.

[0248] Preferably, in some embodiments of the present invention, E1 is

[0249] [ka] The file is TIFF2025537482000196.tif64169.

[0250] Preferably, in some embodiments of the present invention, E1 is

[0251] [ka] is.

[0252] Preferably, in some embodiments of the present invention, E1 is

[0253] [ka] is.

[0254] 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:

[0255] [ka] 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, an N-alkyl group, an N-aryl group, an N-heteroaryl group, an N-cycloalkyl group, an N-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 selected from an aryl group, a 5- to 10-membered heteroaryl group, or a 3- to 8-membered heterocycloalkyl group; n '' is 1, 2, 3 or 4, ----- 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; Preferably, in some embodiments of the invention, E2 has the structure of formula E2-1bb or E2-1aa:

[0256] [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, and a C1-C6 haloalkyl group; n '' is 1, 2, 3 or 4, ----- is a bond, which may be an R stereoisomer, an S stereoisomer, or a non-stereoisomer; where R3b is as described and defined by the present invention;

[0257] [ka] Here, the above E2-1aa: W is CH2 or C(O); A' is hydrogen, a methyl group, Cl or F; R 3c are each independently selected from hydrogen, a hydroxy group, NH, a C-C alkyl group, or a C-C alkoxy group; n '' is 1, 2, 3 or 4, ----- is a bond, which may be the R stereoisomer, the S stereoisomer, or a non-stereoisomer.

[0258] Preferably, in some embodiments of the present invention, E2 is

[0259] [ka] TIFF2025537482000203.tif238169TIFF2025537482000204.tif229169TIFF2025537482000205.tif221169TIFF2025537482000206.tif202169.

[0260] Preferably, in some embodiments of the present invention, E2 is

[0261] [ka] is.

[0262] Preferably, in some embodiments of the present invention, E3 has the structure of formula E3-1:

[0263] [ka] W 3 is an aryl group, a heteroaryl group, or

[0264] [ka] wherein the aryl group and heteroaryl group are optionally substituted; R 9 , R 10 are each independently selected from hydrogen, an alkyl group, a C3-C8 cycloalkyl group, or a 5-10 membered heteroaryl group, and the 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

[0265] [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 13is selected from H, an alkyl group, -alkylCO-, -(cycloalkyl)alkylCO-, -aralkylCO-, -arylCO-, -(heterocycloalkyl)CO- or an arylalkyl group, wherein the alkyl group, -alkylCO-, -(cycloalkyl)alkylCO-, -aralkylCO-, -arylCO-, -(heterocycloalkyl)CO- or arylalkyl group is optionally substituted; R 16 is H, halogen, —OH, an alkyl group or an alkoxy group, said alkyl group or alkoxy group being optionally substituted with a 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.

[0266] Preferably, in some embodiments of the invention, E3 has the structure of formula E3-1a, E3-1b, or E3-1c:

[0267] [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 6d is H, —CH, —CHF, —CHOH, an ethyl group, an isopropyl group, or a cyclopropyl group, R 8dis H, halogen, CN, OH, NO, an aryl group, a heteroaryl group, a C1-C6 alkyl group, a C1-C6 alkoxy group, a cycloalkyl group or a heterocycloalkyl group, wherein the aryl group, heteroaryl group, C1-C6 alkyl group, C1-C6 alkoxy group, cycloalkyl group or heterocycloalkyl group is optionally substituted with halogen, —OH, CN, NO or an 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.

[0268] Preferably, in some embodiments of the invention, E3 has the structure of formula E3-1aa:

[0269] [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,

[0270] [ka] or a 5- to 10-membered heteroaryl group, wherein the 5- to 10-membered heteroaryl group is optionally substituted with one or more -OH, halogen, or -NH; R 12 is H or C(O), R 13is 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 are H, halogens, CN, OH, NO2,

[0271] [ka] is.

[0272] Preferably, in some embodiments of the present invention, E3 is

[0273] [ka] The file is TIFF2025537482000216.tif99169.

[0274] Preferably, in some embodiments of the present invention, E3 is

[0275] [ka] The file is TIFF2025537482000218.tif100169.

[0276] Preferably, in some embodiments of the present invention, K is K1-I-a1, or K' is K2-I-a1;

[0277] [ka] and In the above K1-I-a1, X' is C or N, and Y' is C; R 3e is H or absent, R4e is C6-C 10 an aryl group or a 5- to 10-membered heteroaryl group, and 10 The aryl group or 5- to 10-membered heteroaryl group may optionally be one or more R a' is replaced by R a' are independently selected from halogen, a hydroxy group, a C1-C6 alkyl group, a C2-C6 alkynyl group, or a C3-C6 cycloalkyl group; R 5e is a halogen, R 1a' is hydrogen, a hydroxy group, NH2, a halogen, or a C1-C6 alkyl group, W1 is CH2 or O; m is 0, 1, 2 or 3;

[0278] [ka] , In the above K2-I-a1, X' is C or N, and Y' is C; R 3e is H or absent, R 4e is C6-C 10 an aryl group or a 5- to 10-membered heteroaryl group, and 10 The aryl group or 5- to 10-membered heteroaryl group may optionally be one or more R a' is replaced by R a' are independently selected from halogen, a hydroxy group, a C1-C6 alkyl group, a C2-C6 alkynyl group, or a C3-C6 cycloalkyl group; R 5e is a halogen, R 1 and R 2 are independently hydrogen, a C1-C6 alkyl group, or a C3-C8 cycloalkyl group, wherein the C1-C6 alkyl group or the C3-C8 cycloalkyl group is optionally substituted with one or more halogens, hydroxy groups, or amino groups; wherein L is LA-9 or LA-10;

[0279] [ka] Here, in the above LA-9, 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,

[0280] [ka] and v is 1, 2, 3, 4, 5 or 6; Ring U is

[0281] [ka] wherein the a-terminus is linked to Lx and the b-terminus is linked to Ly; Ring Y is

[0282] [ka] where the c-terminus is linked to Ly and the d-terminus is linked to X″; Ly is -(CH2) k -, wherein one or two CH2 contained in Ly are each independently optionally substituted with -O-, -C≡C- or -N(C1-C6 alkyl)-, and k is 1, 2, 3, 4, 5 or 6; X'' is -C(O)-;

[0283] [ka] Here, in the above LA-10, Lx is -(CH2) vwherein 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,

[0284] [ka] , —CH(CH3)—, —CH(OCH3)—, —CH(OH)—, or —CH(NH2)—, and v is 1, 2, 3, 4, 5, or 6; Ring U is

[0285] [ka] wherein the a-terminus is linked to Lx and the b-terminus is linked to Ly; Ring Y is

[0286] [ka] where the c-terminus is linked to Ly and the d-terminus is linked to X″; Ly is -(CH2) k and k is 1, 2, 3, 4, 5 or 6; X'' is -C(O)-; E is E1-1h″ or E2-1aa,

[0287] [ka] , Here, in the above E1-1h'', R 3b are each independently hydrogen, halogen, a C1-C6 alkyl group, or —O(C1-C6 alkyl), and the C1-C6 alkyl group and —O(C1-C6 alkyl) are optionally substituted with deuterium, halogen, cyano group, —OH, or —NH2, and the number of such substitutions is 1, 2, or 3;

[0288] [ka] , Here, in the above E2-1aa, W is CH2 or C(O); A' is hydrogen, a methyl group, Cl or F; R 3c are each independently selected from hydrogen, a hydroxy group, NH, a C-C alkyl group, or a C-C alkoxy group; n '' is 1, 2, 3 or 4, ----- is a bond and is the R stereoisomer, the S stereoisomer or no stereoisomer.

[0289] Preferably, in some embodiments of the present invention, K1 is K1-I-a1, or K2 is K2-I-a1;

[0290] [ka] and In the above K1-I-a1, X' is C or N, and Y' is C; R 3e is H or absent, and R 4e is C6-C 10 An aryl group, C6-C 10 The aryl group may optionally be one or more R a' is replaced by R a' are independently selected from halogen, a hydroxy group, a C1-C6 alkyl group, a C2-C6 alkynyl group, or a C3-C6 cycloalkyl group; R 5e is a halogen, R 1a' is hydrogen, a hydroxy group, or a C1-C6 alkyl group, W1 is CH2 or O; m is 1 or 2;

[0291] [ka] and In the above K2-I-a1, X' is N and Y' is C; R 3e does not exist, R 4e is C6-C 10 An aryl group, C6-C 10 The aryl group may optionally be one or more R a' is replaced by R a' are independently selected from halogen, a hydroxy group, or a C2-C6 alkynyl group; R 5e is a halogen, R 1 and R 2 are independently hydrogen, a C1-C6 alkyl group, or a C3-C8 cycloalkyl group; L is LA-11 or LA-12:

[0292] [ka] Here, in the above LA-11, 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,

[0293] [ka] and v is 1, 2, 3, 4, 5 or 6; Ring U is

[0294] [ka] wherein the a-terminus is linked to Lx and the b-terminus is linked to Ly; Ring Y is

[0295] [ka] where the c-terminus is linked to Ly and the d-terminus is linked to X″; Ly is -(CH2) k wherein one or two CH2 contained in Ly are each independently optionally replaced by -O- or -C≡C-; and k is 1, 2, 3, 4, 5, or 6; X'' is -C(O)-;

[0296] [ka] Here, in the above LA-12, 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,

[0297] [ka] or —CH(CH3)—, where v is 1, 2, 3, 4, 5, or 6; Ring U is

[0298] [ka] wherein the a-terminus is linked to Lx and the b-terminus is linked to Ly; Ring Y is

[0299] [ka] where the c-terminus is linked to Ly and the d-terminus is linked to X″; Ly is -(CH2) k and k is 1, 2, 3, 4, 5 or 6; X'' is -C(O)-; E is E1-1h″,

[0300] [ka] , where R 3b are each independently hydrogen, halogen, a C1-C6 alkyl group, or —O(C1-C6 alkyl), and the C1-C6 alkyl group and —O(C1-C6 alkyl) are optionally substituted with deuterium, halogen, cyano group, —OH, or —NH2, and the number of substitutions is 1, 2, or 3.

[0301] Preferably, in some embodiments of the present invention, the compound of formula I or I' is

[0302] [ka] TIFF2025537482000243.tif217169TIFF2025537482000244.tif212169TIFF2025537482000245.tif230169TIFF202553748200 0246.tif216169TIFF2025537482000247.tif238169TIFF2025537482000248.tif232169TIFF2025537482000249.tif217169TI FF2025537482000250.tif204169TIFF2025537482000251.tif216169TIFF2025537482000252.tif225169TIFF2025537482000253.tif232169TIFF2025537482000254.tif234169TIFF2025537482000255.tif216169TIFF2025537482000256.tif186169.

[0303] The present invention further provides a compound of formula S-1, S-2, S-3 or S-4:

[0304] [ka] Here, ring C, ring D, R 2e , R 3e , R 4e and R 5e are defined and described by the present invention, the definitions of Lx, ring U, Ly and ring Y and the connections between them are all defined and described by the present invention, and p'' is 1, 2, 3 or 4.

[0305] Preferably, formula S-1 is formula S-1-1, formula S-2 is formula S-2-1, formula S-3 is formula S-3-1, and formula S-4 is formula S-4-1;

[0306] [ka] Here, ring C, ring D, R 2e , R 3e , R 4e , R 5e , Lx, ring U, Ly and ring Y and p'' are defined and described by the present invention.

[0307] Preferably, the compound represented by the above formula S-1, S-2, S-3 or S-4 is

[0308] [ka] Selected from.

[0309] 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.

[0310] 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.

[0311] The present invention provides a method for degrading a pan-KRAS protein, 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 the pan-KRAS protein.

[0312] 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 pharmaceutical compositions thereof, as a drug for treating or preventing a pan-KRAS mediated disease or condition.

[0313] 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, as a drug for treating or preventing a disease or condition (cancer) caused by pan-KRAS.

[0314] 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 a pan-KRAS mediated disease or condition (e.g., cancer).

[0315] 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.

[0316] 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 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.

[0317] The present invention provides a method for treating or preventing a pan-KRAS 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.

[0318] The present invention provides methods for treating or preventing a disease or condition modulated by pan-KRAS (e.g., cancer), 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 pharmaceutical compositions thereof.

[0319] In certain embodiments of the invention, the cancer is Heart: the group consisting of sarcomas (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma; Lung: Bronchial cancer (squamous cell carcinoma, undifferentiated small cell carcinoma, undifferentiated large cell carcinoma, adenocarcinoma), alveolar carcinoma (bronchiolar carcinoma), bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma, lung cancer, small cell lung cancer, 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), appendix cancer, gastrointestinal neuroendocrine tumor, esophageal cancer and gastric cancer, anal cancer, gastrointestinal stromal tumor, 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), germ cell tumor, bladder cancer, prostate cancer, 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, bone cancer, 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), cervical cancer, endometrioid carcinoma, 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.

[0320] In certain embodiments of the invention, the cancer is a cancer associated with a KRAS G12A, KRAS G12C, KRAS G12D, KRAS G12R, KRAS G12S, KRAS G12V, KRAS G13D or KRAS Q61H protein mutation.

[0321] In certain embodiments of the invention, the cancer is a KRAS G12A-associated cancer that is non-small cell lung cancer, ovarian cancer, or colorectal cancer.

[0322] In certain embodiments of the invention, the cancer is a KRAS G12C-associated cancer that is non-small cell lung cancer, colorectal cancer or pancreatic cancer.

[0323] In certain embodiments of the invention, the cancer is a KRAS G12D-associated cancer that is biliary tract cancer, endometrial cancer, pancreatic cancer, colorectal cancer, non-small cell lung cancer, ovarian cancer or rectal cancer.

[0324] In certain embodiments of the invention, the cancer is a KRAS G12R-associated cancer that is pancreatic cancer or non-small cell lung cancer.

[0325] In certain embodiments of the invention, the cancer is a KRAS G12S-associated cancer that is rectal cancer, colon adenocarcinoma or colorectal cancer.

[0326] In certain embodiments of the invention, the cancer is a KRAS G12V-associated cancer that is pancreatic cancer, colorectal cancer, non-small cell lung cancer, or ovarian cancer.

[0327] In a particular embodiment of the invention, the cancer is a KRAS G13D-associated cancer that is colorectal cancer.

[0328] 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.

[0329] 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 thereof for treating a disease or condition associated with a pan-KRAS mutant protein.

[0330] The present invention further provides a compound of the above formula I or I', wherein the disease or condition associated with a pan-KRAS mutant protein is a cancer associated with a pan-KRAS mutant protein.

[0331] In certain embodiments of the invention, the cancer is selected from pancreatic cancer, colorectal cancer, endometrial cancer or lung cancer.

[0332] In certain embodiments of the invention, the lung cancer is selected from non-small cell lung cancer or small cell lung cancer.

[0333] 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.

[0334] K is K1-Ia

[0335] [ka] and L is LA

[0336] [ka] and ring U contains an NH group, the preparation method is

[0337] [ka] INT-A is subjected to a reductive amination reaction 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.

[0338] [ka] refers to ring U containing an NH group, and rings C, D, and R 2e , R 3e , R 4e , R 5e , Y″ is defined and described by K1-Ia;

[0339] [ka] refers to Lx containing an aldehyde group, wherein ring U, ring Y, X'', Lx, and Ly are defined by L-A, and E is defined and described by the present invention, preferably 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.

[0340] K is K1-Ia

[0341] [ka] and L is LA

[0342] [ka] and ring Y contains an NH group and X″ is C(O), the preparation method comprises:

[0343] [ka] INT-C is subjected to a substitution reaction with INT-D under basic conditions to obtain the target compound, where the base includes, but is not limited to, triethylamine, N,N-diisopropylethylamine, potassium carbonate, sodium carbonate, and sodium bicarbonate.

[0344] [ka] refers to the ring Y containing the NH group, and P 100 is a pentafluorophenyl group or a p-nitrophenyl group, and rings C, D, and R 2e , R 3e , R 4e , R 5e , Y″ are defined and described by K1-Ia, ring U, ring Y, X″, Lx, Ly are defined by LA, and E is 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.

[0345] DETAILED DESCRIPTION: Unless stated to the contrary, the following terms used in the specification and claims have the following meanings.

[0346] 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-methylbutyl group, a 2-methyl 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.

[0347] "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.

[0348] 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.

[0349] 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.

[0350] "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.

[0351] 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:

[0352] [ka] Includes:

[0353] "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:

[0354] [ka] Selected from.

[0355] "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:

[0356] [ka] .

[0357] 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.

[0358] 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.

[0359] "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.

[0360] 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.

[0361] Polycyclic heterocycloalkyl groups include spirocyclic, fused-ring, and bridged-ring heterocycloalkyl groups. A "spiroheterocycloalkyl group" is a polycyclic heterocycloalkyl group that shares one atom (called 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:

[0362] [ka] etc.

[0363] A "fused heterocycloalkyl group" is 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 in which 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:

[0364] [ka] Includes:

[0365] A "bridged heterocycloalkyl group" is 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:

[0366] [ka] Includes:

[0367] 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:

[0368] [ka] 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).

[0369] An "aryl group" is an all-carbon monocyclic or fused polycyclic (i.e., rings that share adjacent pairs of carbon atoms) polycyclic group having a conjugated π-electron system, and a "6- to 10-membered aryl group" is an all-carbon aryl group containing 6 to 10 carbons, such as phenyl and naphthyl, 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:

[0370] [ka] wherein the aryl group may be optionally substituted or unsubstituted. In some embodiments, the aryl group is a 6- to 10-membered aryl group.

[0371] A "heteroaryl group" is a heteroaromatic system containing 1 to 4 heteroatoms, the heteroatoms being nitrogen, oxygen, or S(O). r(where r is an integer 0, 1, or 2), and 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, and non-limiting examples include

[0372] [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.

[0373] An "alkenyl group" is 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" is 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. Preferably, it is a "C2-6 alkenyl group," and more preferably a "C2-4 alkenyl group." 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.

[0374] 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.

[0375] "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.

[0376] "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.

[0377] "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.

[0378] "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.

[0379] "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.

[0380] "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.

[0381] "-C(O)C1-C3 alkyl group" refers to -C(O)-CH3, -C(O)-CH2CH3, and the like.

[0382] A "cyano group" refers to -CN.

[0383] A "hydroxy group" refers to -OH.

[0384] A "sulfonyl group" refers to -S(O)2-.

[0385] A "carboxy group" or a "carboxylic acid" refers to -COOH.

[0386] "Oxo" refers to the group =O.

[0387] "Halogen" refers to fluorine, chlorine, bromine or iodine.

[0388] "EA or EtOAc" refers to ethyl acetate.

[0389] "THF" refers to tetrahydrofuran.

[0390] "DCM" refers to dichloromethane;

[0391] "cataCXium A Pd-G3" refers to [n-butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate.

[0392] "POCl3" refers to phosphorus oxychloride.

[0393] "NaHCO3" refers to sodium bicarbonate.

[0394] "NaCl" refers to sodium chloride.

[0395] "Na2SO4" refers to sodium sulfate.

[0396] "NH4Cl" refers to ammonium chloride.

[0397] "Cs2CO3" refers to cesium carbonate.

[0398] "NaBH(OAc)3" refers to sodium borohydride acetate.

[0399] "Triton B" refers to benzyltrimethylammonium hydroxide.

[0400] "NaBH3CN" refers to sodium cyanoborohydride.

[0401] "CsF" refers to cesium fluoride.

[0402] "Na2CO3" refers to sodium carbonate.

[0403] "HOAc" refers to acetic acid.

[0404] "TPAP" refers to tetrapropylammonium perruthenate.

[0405] "NMO" refers to N-methylmorpholine oxide.

[0406] "Cs2CO3" refers to cesium carbonate.

[0407] "NaH" refers to sodium hydrogen.

[0408] "i-PrOH" refers to isopropanol.

[0409] "DMF" refers to N,N-dimethylformamide.

[0410] "MeOH" refers to methanol.

[0411] "Pd / C" refers to palladium on carbon.

[0412] "DMSO" refers to dimethyl sulfoxide.

[0413] "TFA" refers to trifluoroacetic acid.

[0414] "DIEA" refers to N,N-diisopropylethylamine.

[0415] "Dess-Martin" refers to the Dess-Martin reagent.

[0416] "PBS" refers to phosphate buffer solution.

[0417] "SDS-PAGE" refers to sodium dodecyl sulfate-polyacrylamide gel electrophoresis.

[0418] "PVDF" refers to polyvinylidene fluoride.

[0419] "PE" refers to petroleum ether.

[0420] "AcOH" refers to acetic acid.

[0421] "HCl" refers to hydrochloric acid.

[0422] "NH3" refers to aqueous ammonia.

[0423] "EDCI" refers to 1-ethyl-(3-dimethylaminopropyl)carbodii hydrochloride.

[0424] "HOBT" refers to 1-hydroxybenzotriazole.

[0425] "HMPA" refers to hexamethylphosphoric triamide.

[0426] "Pd(dppf)Cl2" refers to [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride(II).

[0427] "LAH" refers to lithium aluminum tetrahydride.

[0428] "Prep-HPLC" refers to preparative high performance liquid chromatography.

[0429] "Sat." refers to a saturated solution.

[0430] "aq" refers to an aqueous solution.

[0431] 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).

[0432] "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.

[0433] 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.

[0434] 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.

[0435] 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.

[0436] 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.

[0437] 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.

[0438] 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.

[0439] 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).

[0440] 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.

[0441] 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.

[0442] 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.

[0443] 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.

[0444] 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."

[0445] 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.

[0446] Unless otherwise stated, the term "isomer" is meant to include geometric isomers, cis-trans isomers, stereoisomers, enantiomers, optical isomers, diastereoisomers and tautomers.

[0447] 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.

[0448] Unless otherwise stated, the terms "enantiomers" or "optical isomers" refer to stereoisomers that are mirror images of one another.

[0449] 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.

[0450] 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.

[0451] 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.

[0452] 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.

[0453] Unless otherwise stated, "(+)" denotes right-handed, "(-)" denotes left-handed, and "(±)" denotes racemic.

[0454] "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.

[0455] 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.

[0456] 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.

[0457] 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.

[0458] 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.

[0459] When the number of linking groups is 0, for example, -(CRR)0- indicates that the linking group is a single bond.

[0460] 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.

[0461] 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.

[0462] 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.

[0463] 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.

[0464] Unless otherwise specified,

[0465] [ka] teeth,

[0466] [ka] is used to indicate that a hydrogen atom at any position of the group in may be substituted.

[0467] 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.

[0468] 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%.

[0469] 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).

[0470] 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 ...

[0471] 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.

[0472] 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.

[0473] 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.

[0474] 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.

[0475] 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.

[0476] 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.

[0477] 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.

[0478] 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.

[0479] 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.

[0480] 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.

[0481] 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.

[0482] 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.

[0483] 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.

[0484] Other pharmaceutically acceptable therapeutic agents that can be used in the present invention together with or in combination with the compounds of formula (I) that are pan-KRAS degraders 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, and the like. or inhibitors thereof, AXL and / or mutants thereof inhibitors, NTRK1 and / or mutants thereof inhibitors, RET and / or mutants thereof inhibitors, taxanes, platinum-containing compounds, antimetabolites, mitotic kinase inhibitors, immunotherapeutic drugs, anti-angiogenic drugs, topoisomerase inhibitors, A-Raf / B-Raf / C-RAf and / or mutants thereof inhibitors, ERK and / or mutants thereof inhibitors, apoptosis inhibitors, AKT and / or mutants thereof inhibitors, mTOR inhibitors, epigenetic regulators, IGF1 / 2 and / or IGF1-R inhibitors, Ras GEF and / or mutants thereof inhibitors, SOS1 and / or mutants thereof inhibitors, SHP2 and / or mutants thereof inhibitors, PI3K and / or mutants thereof inhibitors, PD-1 / PD-L1 inhibitors. 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, monoclonal antibodies against PD-1 / PD-L1, monoclonal antibodies against CTLA-4, PD-L1 / TIGHT dual antibodies, PD-L1 / CTLA-4 dual antibodies, EGFR / MET dual antibodies, EGFR / CD3 dual antibodies, EGFR / 4-IBB dual antibodies, PD-L1 / 4-IBB dual antibodies, and HER2 / CD3 dual antibodies.

[0485] In the present invention, other pharmaceutically acceptable therapeutic agents that can be used together with or in combination with the compound of formula (I) that is a pan-KRAS degrading agent include afatinib, erlotinib, gefitinib, lapatinib, cetuximab, panituzumab, osimertinib, olmutinib, EGF-816, trastuzumab, pertuzumab, crizotinib, alkene, and the like. Alectinib, Enrectinib, Brigatinib, Trametinib, Cobimetinib, Binimetinib, Selumetinib, Rifatinib, Imatinib, Dasatinib, Nilotinib, Nintedanib, Crizotinib, Lorlatinib nib), ceritinib, merestinib, paclitaxel, nab-paclitaxel, docetaxel, cisplatin, carboplatin, oxaliplatin, 5-fluorouracil, capecitabine, fluoxuridine, cytarabine, gemcitabine, trifluridine fluridine and tipiracil combination (=TAS102), palbociclib, ribociclib, abemaciclib, ipilimumab, nivolumab, pembrolizumab, atezolizumab, avelumab, durvalumab, pidilizumab,It may be PDR-001 (= spartalizumab), bevacizumab, irinotecan, liposomal irinotecan, topotecan, ulixertinib, rapamycin, temsirolimus, everolimus, ridaforolimus, JQ-1, GSK 525762, OTX 015 (= MK8628), CPI 0610, TEN-010 (= RO6870810), xentuzumab (antibody 60833 of WO2010 / 066868) or MEDI-573 (= dusigitumab).

[0486] 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.

[0487] All of the reagents and raw materials used in the present invention are commercially available.

[0488] Compounds are named according to conventional naming principles in the art or Chemdraw® software; commercially available compounds may use supplier catalog names.

[0489] In the present invention, KRAS G12C, KRAS G12D, or KRAS G12V protein binding activity experiments prove that the compounds of formula I or I' described in the present invention can effectively bind to pan-KRAS target proteins and inhibit the downstream signaling pathway. Western blot analysis proves that the compounds of formula I or I' described in the present invention can effectively degrade KRAS G12C protein in NCI-H358 cells, KRAS G12D protein in A427 cells, KRAS G12D protein in AsPc-1 cells, KRAS G12V protein in SW900 cells, KRAS G12V protein in SW620 cells, KRAS 13D protein in DLD-1 cells, and KRAS WT (amplified) protein in MKN1 cells. The compounds of formula I or I' according to the present invention, and / or their stereoisomers, enantiomers, diastereoisomers, deuterated compounds, hydrates, solvates, metabolites, prodrugs and / or pharmaceutically acceptable salts thereof, can effectively decompose KRAS G12C, KRAS G12D, KRAS G12V, KRAS G13D, KRAS WT (amplified) protein, KRAS G12V, KRAS G12D and KRAS G12C proteins, thereby achieving the effect of preventing or treating diseases or conditions caused by various mutations in KRAS G13D, KRAS WT (amplified) protein, KRAS G12V, KRAS G12D and KRAS G12C. DETAILED DESCRIPTION OF THE INVENTION

[0490] 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.

[0491] I. Example of compound production Intermediate 1: 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine

[0492] [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.

[0493] Intermediate 2: (R)-1-(((8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-4-(3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropane-1-formaldehyde Step 1: Preparation of (R)-1-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol

[0494] [ka] 2,4,7-Trichloro-8-fluoropyrido[4,3-d]pyrimidine (1.9 g, 7.53 mmol) and triethylamine (1.9 g, 18.82 mmol) were dissolved in THF (20 mL) and cooled to -78 °C. (R)-3-methylpiperidin-3-ol hydrochloride (0.9 g, 6.02 mmol) was added and the mixture was allowed to react at -78 °C 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 (30 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 (DCM:MeOH = 100:1 to 50:1) to give (R)-1-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol.

[0495] LC-MS: (ESI, m / z): [M+H] + = 331.1. Step 2: Preparation of (R)-1-(2-((1-(((tert-butyldiphenylsilylalkyl)oxy)methyl)cyclopropyl)methoxy)-7-chloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol

[0496] [ka] (R)-1-(2,7-Dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (971 mg, 2.93 mmol) and (1-(((tert-butyldiphenylsilyl)oxy)methyl)cyclopropyl)methanol (2.0 g, 5.86 mmol) were added to anhydrous acetonitrile (10 mL), followed by the addition of cesium carbonate (1.4 g, 4.40 mmol) and 1,4-diazabicyclo[2.2.2]octane (164 mg, 1.47 mmol). The mixture was stirred at 25 °C for 1 hour. After completion of the reaction, the reaction was quenched by the addition of saturated brine (30 mL). The mixture was then extracted with ethyl acetate (50 mL × 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 (PE:EA=5:1) to give (R)-1-(2-((1-(((tert-butyldiphenylsilylalkyl)oxy)methyl)cyclopropyl)methoxy)-7-chloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol.

[0497] LC-MS: (ESI, m / z): [M+H] + = 635.4. Step 3: Preparation of (R)-1-(7-chloro-8-fluoro-2-((1-(hydroxymethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol

[0498] [ka] (R)-1-(2-((1-(((tert-butyldiphenylsilylalkyl)oxy)methyl)cyclopropyl)methoxy)-7-chloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (988 mg, 1.56 mmol) was dissolved in DMF (10 mL), and cesium fluoride (709 mg, 4.67 mmol) was added. The mixture was heated to 50°C and reacted for 6 hours. After completion of the reaction, the mixture was cooled to room temperature, quenched by adding water (30 mL), and extracted with ethyl acetate (60 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 (DCM:MeOH=98:2) to give (R)-1-(7-chloro-8-fluoro-2-((1-(hydroxymethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol.

[0499] LC-MS: (ESI, m / z): [M+H] + = 397.1. 1 H NMR (400 MHz, CDCl3) δ 8.93 (s, 1H), 4.50 - 4.36 (m, 4H), 3.65 - 3.56 (m, 1H), 3.46 - 3.32 (m, 3H), 3.26 (d, J = 13.6 Hz, 1H), 2.52 - 2.40 (m, 1H), 2.15 - 1.99 (m, 1H), 1.92 - 1.83 (m, 1H), 1.78 - 1.66 (m, 2H), 1.33 (s, 3H), 0.71 - 0.66 (m, 2H), 0.63 - 0.58 (m, 2H). Step 4: Preparation of (R)-1-(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-methylpiperidin-3-ol

[0500] [ka] (R)-1-(7-chloro-8-fluoro-2-((1-(hydroxymethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (85 mg, 0.214 mmol), cesium carbonate (210 mg, 0.642 mmol), ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane, and cataXium A Pd G3 (31 mg, 0.043 mmol) were added to 1,4-dioxane / HO (2.5 mL / 0.5 mL) and reacted overnight at 80 °C under N protection. The mixture was filtered and concentrated, and the resulting crude product was purified by silica gel column chromatography (DCM:MeOH=100:1 to 10:1) to give (R)-1-(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-methylpiperidin-3-ol.

[0501] LC-MS: (ESI, m / z): [M+H] + = 747.4. Step 5: Preparation of (R)-1-(((8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-4-(3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropane-1-formaldehyde

[0502] [ka] A solution of (R)-1-(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-methylpiperidin-3-ol (80 mg, 0.107 mmol) in DCM (2 mL) was cooled to 0 ° C., and then Dess-Martin oxidant (91 mg, 0.214 mmol) was added and reacted at room temperature for 0.5 hours. After completion of the reaction, the reaction was quenched by adding saturated sodium thiosulfate solution (5 mL), and further extracted with dichloromethane (10 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=10:1) to give (R)-1-(((8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-4-(3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropane-1-formaldehyde.

[0503] LC-MS: (ESI, m / z): [M+H] + = 745.4. Intermediate 3: (R)-1-(((7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-4-(3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropane-1-formaldehyde Step 1: Preparation of (R)-1-(((7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-4-(3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropane-1-formaldehyde

[0504] [ka] CsF (143 mg, 0.94 mmol) was added to a solution of (R)-1-(((8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-4-(3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropane-1-formaldehyde (140 mg, 0.188 mmol) in DMF (2 mL) at room temperature, and the mixture was reacted at room temperature for 30 minutes. After the reaction was completed, water was added, the mixture was extracted with ethyl acetate, the organic phase was concentrated, washed with saturated brine, and the crude product was purified by silica gel column chromatography (DCM:MeOH = 50:1 to 10:1) to obtain (R)-1-(((7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-4-(3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropane-1-formaldehyde.

[0505] LC-MS: (ESI, m / z): [M+H] + = 589.2. Step 2: Preparation of (R)-1-(((7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-4-(3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropane-1-formaldehyde

[0506] [ka] To a solution of (R)-1-(((7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-4-(3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropane-1-formaldehyde (95 mg, 0.161 mmol) in MeOH (2 mL) was added Pd / C (50 mg) and stirred at 30° C. for 3 hours. The mixture was filtered and concentrated to give (R)-1-(((7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-4-(3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropane-1-formaldehyde. The crude product was used directly in the next step without purification.

[0507] LC-MS: (ESI, m / z): [M+H] + = 593.2. Intermediate 4: 1-(2-chloro-5-(4-((2-(piperidin-4-yl)ethoxy)methyl)piperidine-1-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione Step 1: Preparation of tert-butyl 4-(2-(pyridin-4-ylmethoxy)ethyl)piperidine-1-carboxylate

[0508] [ka] To a solution of tert-butyl 4-(2-hydroxyethyl)piperidine-1-carboxylate (2 g, 8.72 mmol) in THF (10 mL) was added NaH (1.75 g, 43.6 mmol, 60%) at 0 °C and stirred at room temperature for 0.5 h. Then, 4-(bromomethyl)pyridine (3.4 g, 13.08 mmol) was added. The reaction mixture was stirred at room temperature for 12 h. The reaction mixture was quenched with aqueous ammonium chloride, extracted with ethyl acetate, and the organic phase was dried and concentrated. The crude product was purified by silica gel column chromatography (DCM:MeOH=100:1) to give tert-butyl 4-(2-(pyridin-4-ylmethoxy)ethyl)piperidine-1-carboxylate.

[0509] LC-MS: (ESI, m / z): [M+H] + = 321.2. Step 2: Preparation of tert-butyl 4-(2-(piperidin-4-ylmethoxy)ethyl)piperidine-1-carboxylate

[0510] [ka] To a solution of tert-butyl 4-(2-(pyridin-4-ylmethoxy)ethyl)piperidine-1-carboxylate (2.4 g, 7.49 mmol) in i-PrOH / HO (20 mL / 20 mL) was added Pd / C (500 mg) and the mixture was stirred at 75°C under a hydrogen gas atmosphere for 16 hours. The reaction mixture was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure. The resulting crude product was purified by silica gel chromatography (MeOH:DCM = 0 to 1:4) to give tert-butyl 4-(2-(piperidin-4-ylmethoxy)ethyl)piperidine-1-carboxylate.

[0511] 1H NMR (400 MHz, CDCl3) δ 4.05 (s, 1H), 3.44 (t, J = 6.3 Hz, 2H), 3.23 (d, J = 6.0 Hz, 2H), 3.11 - 3.04 (m, 2H), 2.74 - 2.55 (m, 4H), 1.93 (s, 2H), 1.75 - 1.62 (m, 5H), 1.59 - 1.42 (m, 12H), 1.19 - 1.04 (m, 4H). Step 3: Preparation of tert-butyl 4-(2-((1-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzoyl)piperidin-4-yl)methoxy)ethyl)piperidine-1-carboxylate

[0512] [ka] To a solution of tert-butyl 4-(2-(piperidin-4-ylmethoxy)ethyl)piperidine-1-carboxylate (200 mg, 0.61 mmol) in DMSO (5 mL) was added pentafluorophenyl 4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzoate (0.28 g, 0.64 mmol) and DIEA (0.24 g, 1.84 mmol). The mixture was stirred at room temperature for 1 hour. The crude product was purified by pre-HPLC (CAN: HO = 0% to 100%) to give tert-butyl 4-(2-((1-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzoyl)piperidin-4-yl)methoxy)ethyl)piperidine-1-carboxylate.

[0513] LC-MS: (ESI, m / z): [M+Na] + = 599.2. Step 4: Preparation of 1-(2-chloro-5-(4-((2-(piperidin-4-yl)ethoxy)methyl)piperidine-1-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione

[0514] [ka] To a solution of tert-butyl 4-(2-((1-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzoyl)piperidin-4-yl)methoxy)ethyl)piperidine-1-carboxylate (120 mg, 0.21 mmol) in DCM (4 mL) was added TFA (2 mL). The mixture was stirred at room temperature for 1 hour, and the reaction mixture was directly concentrated under reduced pressure to give 1-(2-chloro-5-(4-((2-(piperidin-4-yl)ethoxy)methyl)piperidine-1-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione. The crude product obtained was used directly in the next reaction.

[0515] LC-MS: (ESI, m / z): [M+H] + = 477.2. Intermediate 5: 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 (9H-fluoren-9-yl)methyl 4-((3-azaspiro[5.5]undecan-9-yl)methyl)piperazine-1-carboxylate

[0516] [ka] A solution of tert-butyl 9-((4-(((9H-fluorenyl-9-yl)methoxy)carbonyl)piperazin-1-yl)methyl)-3-azaspiro[5.5]undecane-3-carboxylate (500 mg, 0.87 mmol) in HCl / 1,4-dioxane (4 M, 3 mL) was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure to give (9H-fluoren-9-yl)methyl 4-((3-azaspiro[5.5]undecan-9-yl)methyl)piperazine-1-carboxylate. The resulting product was used directly in the next reaction.

[0517] LC-MS: (ESI, m / z): [M+H]+ = 474.2. Step 2: Preparation of (9H-fluoren-9-yl)methyl 4-((3-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzoyl)-3-azaspiro[5.5]undecan-9-yl)methyl)piperazine-1-carboxylate

[0518] [ka] (9H-Fluorenyl-9-yl)methyl 4-((3-azaspiro[5.5]undecan-9-yl)methyl)piperazine-1-carboxylate (400 mg, 0.84 mmol) was dissolved in DMSO (4 mL). To the solution was then added 4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)pentafluorophenyl benzoate (367 mg, 0.84 mmol) and DIEA (325 mg, 2.5 mmol). The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was poured into water, extracted with EA (20 mL × 3), dried over anhydrous NaSO, and concentrated under reduced pressure. The obtained crude product was purified by chromatography column (DCM:MeOH=19:1) to give ((9H-fluoren-9-yl)methyl 4-((3-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzoyl)-3-azaspiro[5.5]undecan-9-yl)methyl)piperazine-1-carboxylate.

[0519] LC-MS: (ESI, m / z): [M+H] + = 724.3. Step 3: Preparation of 1-(2-chloro-5-(9-(piperazin-1-ylmethyl)-3-azaspiro[5.5]undecane-3-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione

[0520] [ka] To a solution of ((9H-fluoren-9-yl)methyl 4-((3-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzoyl)-3-azaspiro[5.5]undecan-9-yl)methyl)piperazine-1-carboxylate (500 mg, 0.69 mmol) in DCM (5 mL) was added piperidine (587 mg, 6.9 mmol). The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was poured into water and diluted with DCM (20 The crude product was extracted with 1 mL of hexane (3 mL), dried over anhydrous NaSO, and concentrated under reduced pressure. The crude product was purified by chromatography (DCM:MeOH = 19:1) to give 1-(2-chloro-5-(9-(piperazin-1-ylmethyl)-3-azaspiro[5.5]undecane-3-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione.

[0521] LC-MS: (ESI, m / z): [M+H] + = 502.4. Intermediate 6: 1-(2-Methoxy-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-((benzyloxy)carbonyl)piperazin-1-yl)methyl)-3-azaspiro[5.5]undecane-3-carboxylate

[0522] [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 (MeOH:DCM = 150:1 to 20:1) to give tert-butyl 9-((4-((benzyloxy)carbonyl)piperazin-1-yl)methyl)-3-azaspiro[5.5]undecane-3-carboxylate.

[0523] LC-MS: (ESI, m / z): [M+H] + = 486.3. Step 2: Preparation of benzyl 4-((3-azaspiro[5.5]undecan-9-yl)methyl)piperazine-1-carboxylate

[0524] [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.

[0525] 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

[0526] [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.

[0527] LC-MS: (ESI, m / z): [M+H] + = 632.3. 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

[0528] [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.

[0529] LC-MS: (ESI, m / z): [M+H] + = 498.2. Intermediate 7: 1-(2-chloro-5-(4-(2-(piperidin-4-ylmethoxy)ethyl)piperidine-1-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione Step 1: Preparation of tert-butyl 4-(2-((1-benzylpiperidin-4-yl)methoxy)ethyl)piperidine-1-carboxylate

[0530] [ka] To a mixture of tert-butyl 4-(2-(piperidin-4-ylmethoxy)ethyl)piperidine-1-carboxylate (100 mg, 0.31 mmol) and benzaldehyde (39 mg, 0.37 mmol) in 1,2-dichloroethane / methanol (0.5 mL / 0.5 mL) was added acetic acid (0.01 mL). The mixture was stirred at 30 °C for 1 hour. NaBHCN (39 mg, 0.62 mmol) was added at 0 °C, and the mixture was reacted at room temperature for 2 hours. After completion of the reaction, H2O (10 mL) was added and the mixture was extracted with ethyl acetate (30 mL x 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 tert-butyl 4-(2-((1-benzylpiperidin-4-yl)methoxy)ethyl)piperidine-1-carboxylate.

[0531] LC-MS: (ESI, m / z): [M+H] + = 417.3. Step 2: Preparation of 1-benzyl-4-((2-(piperidin-4-yl)ethoxy)methyl)piperidine

[0532] [ka] To a solution of tert-butyl 4-(2-((1-benzylpiperidin-4-yl)methoxy)ethyl)piperidine-1-carboxylate (100 mg, 0.24 mmol) in DCM (2 mL) was added TFA (1 mL). The mixture was stirred at room temperature for 1 hour, and the reaction mixture was directly concentrated under reduced pressure to give 1-benzyl-4-((2-(piperidin-4-yl)ethoxy)methyl)piperidine, which was used directly in the next reaction.

[0533] Step 3: Preparation of 1-(5-(4-(2-((1-benzylpiperidin-4-yl)methoxy)ethyl)piperidine-1-carbonyl)-2-chlorophenyl)dihydropyrimidine-2,4(1H,3H)-dione

[0534] [ka] 1-Benzyl-4-((2-(piperidin-4-yl)ethoxy)methyl)piperidine (100 mg, 0.32 mmol) was dissolved in DMSO (2 mL), and 4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)pentafluorophenyl benzoate (110 mg, 0.34 mmol) and DIEA (93 mg, 0.96 mmol) were added. The reaction mixture was stirred at room temperature for 2 hours. Water (20 mL) was added, and the mixture was extracted 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 purified by silica gel column chromatography (DCM:MeOH=100:1 to 5:1) to give 1-(5-(4-(2-((1-benzylpiperidin-4-yl)methoxy)ethyl)piperidine-1-carbonyl)-2-chlorophenyl)dihydropyrimidine-2,4(1H,3H)-dione.

[0535] LC-MS: (ESI, m / z): [M+H] + = 567.2. Step 4: Preparation of 1-(2-chloro-5-(4-(2-(piperidin-4-ylmethoxy)ethyl)piperidine-1-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione

[0536] [ka] 1-1-(5-(4-(2-((1-benzylpiperidin-4-yl)methoxy)ethyl)piperidine-1-carbonyl)-2-chlorophenyl)dihydropyrimidine-2,4(1H,3H)-dione (200 mg, 0.35 mmol) was dissolved in DCM (2 mL), and 1-chloroethyl chloroformate (150 mg, 1.05 mmol) and DIEA (90 mg, 0.7 mmol) were added. The mixture was reacted at room temperature for 30 minutes, concentrated under reduced pressure, and the concentrate was dissolved in MeOH (2 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(NH)=100:1 to 9:1) to obtain 1-(2-chloro-5-(4-(2-(piperidin-4-ylmethoxy)ethyl)piperidine-1-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione.

[0537] LC-MS: (ESI, m / z): [M+H] + = 477.3. Intermediate 8: tert-Butyl 4-((1-(hydroxymethyl)cyclopropyl)methyl)piperidine-1-carboxylate Step 1: Preparation of methyl 4-hydroxy-2-methylenebutyrate

[0538] [ka] To a solution of methyl 4-bromo-2-methylenebutyrate (5.00 g, 27.93 mmol) and 37% aqueous formaldehyde (4.53 g, 55.86 mmol) in ethanol (50 mL) and water (50 mL) was added indium powder (3.53 g, 30.74 mmol) at room temperature, and the mixture was stirred at 25°C for 24 hours under nitrogen gas protection. Dichloromethane (200 mL) and water (200 mL) were added to the reaction mixture, and the mixture was stirred for 30 minutes. The mixture was then filtered through diatomaceous earth, the organic phase was washed with saturated brine (100 mL), and the aqueous phase was extracted with dichloromethane (200 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give methyl 4-hydroxy-2-methylenebutyrate.

[0539] LC-MS: (ESI, m / z): [M+H] + =131.2. Step 2: Preparation of methyl 4-chloro-2-methylenebutyrate

[0540] [ka] To a solution of methyl 4-hydroxy-2-methylenebutyrate (3.05 g, 23.46 mmol) in dichloromethane (120 mL) at room temperature, pyridine (2.4 mL) and dichlorosulfoxide (4.5 mL, 59.93 mmol) were added. After degassing, the mixture was stirred at 50 °C for 18 hours under nitrogen gas protection. Petroleum ether (100 mL) was added to the reaction mixture, which was then poured into water (100 mL). The mixture was extracted with dichloromethane (20 mL x 2). The combined organic phase was washed with saturated sodium chloride (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 100:1 to 10:1) to give methyl 4-chloro-2-methylenebutyrate.

[0541] 1 H NMR (400 MHz, CDCl3) δ 6.31 (s, 1H), 5.71 (s, 1H), 3.77 (s, 3H), 3.67 (t, J = 6.8 Hz, 2H), 2.77 (t, J = 6.8 Hz, 2H). Step 3: Preparation of tert-butyl 4-((1-(methoxycarbonyl)cyclopropyl)methyl)piperidine-1-carboxylate

[0542] [ka] Phenyllithium (1.0 M, 10 mL, 10.00 mmol) was added to a solution of tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)piperidine-1-carboxylate (2.87 g, 9.22 mmol) in tetrahydrofuran (30 mL) at 0° C. and stirred for 10 minutes at 25° C. The mixture was then concentrated under reduced pressure, and the residue was dissolved in N,N-dimethylformamide (30 mL). Methyl 4-chloro-2-methylenebutyrate (1.25 g, 8.38 mmol) and 2,4,5,6-tetrakis(9-carbazolyl)-isophthalonitrile (331 mg, 0.42 mmol) were added, and the mixture was stirred at 25° C. for 24 hours under nitrogen gas protection. The reaction mixture was poured into water (300 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic phase was washed with water (100 mL) and saturated sodium chloride (100 mL), respectively. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 100:1 to 10:1) to give tert-butyl 4-((1-(methoxycarbonyl)cyclopropyl)methyl)piperidine-1-carboxylate.

[0543] LC-MS: (ESI, m / z): [M-tBu+H] + = 242.2. Step 4: Preparation of tert-butyl 4-((1-(hydroxymethyl)cyclopropyl)methyl)piperidine-1-carboxylate

[0544] [ka] Lithium aluminum tetrahydride (1.0 M, 7.3 mL, 7.3 mmol) was added to a solution of tert-butyl 4-((1-(methoxycarbonyl)cyclopropyl)methyl)piperidine-1-carboxylate (1.69 mg, 5.69 mmol) in tetrahydrofuran (90 mL) at 0°C. The mixture was stirred at 0°C for 1 hour under nitrogen gas protection. After completion of the reaction, the reaction was quenched by adding saturated sodium potassium tartrate solution (1 mL). The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude tert-butyl 4-((1-(hydroxymethyl)cyclopropyl)methyl)piperidine-1-carboxylate, which was used directly in the next reaction.

[0545] Intermediate 9: (R)-1-(7-bromo-8-fluoro-2-((1-(hydroxymethyl)cyclopropyl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol Step 1: Preparation of (R)-1-(7-bromo-2-chloro-8-fluoroquinazolin-4-yl)-3-methylpiperidin-3-ol

[0546] [ka] TEA (695 mg, 6.87 mmol) was added to a solution of 7-bromo-2,4-dichloro-8-fluoroquinazoline (678 mg, 2.29 mmol) in THF (30 mL) at -50 °C, and (R)-3-methylpiperidin-3-ol hydrochloride (347 mg, 2.29 mmol) was added, followed by stirring for 5 h. HO (50 mL) was added to the reaction mixture, followed by extraction with EtOAc (30 mL × 3). 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 = 5:1) to give (R)-1-(7-bromo-2-chloro-8-fluoroquinazolin-4-yl)-3-methylpiperidin-3-ol.

[0547] LC-MS: (ESI, m / z): [M+H] + = 375.8. Step 2: Preparation of (R)-1-(7-bromo-8-fluoro-2-((1-(hydroxymethyl)cyclopropyl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol

[0548] [ka] To a solution of (R)-1-(7-bromo-2-chloro-8-fluoroquinazolin-4-yl)-3-methylpiperidin-3-ol and cyclopropane-1,1-dimethanol (327 mg, 3.20 mmol) in anhydrous acetonitrile (30 mL), triethylenediamine (90 mg, 0.80 mmol) and anhydrous cesium carbonate (783 mg, 22.40 mmol) were added and stirred for 18 hours at 25 ° C. After completion of the reaction, the mixture was poured into water (100 mL) and extracted with ethyl acetate (20 mL × 2). The organic phases were combined, washed with saturated sodium chloride (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (dichloromethane:methanol=100:1 to 15:1) to obtain (R)-1-(7-bromo-8-fluoro-2-((1-(hydroxymethyl)cyclopropyl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol.

[0549] LC-MS: (ESI, m / z): [M+H] + = 439.8. Intermediate 10: (R)-1-(((8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-4-(3-hydroxy-3-methylpiperidin-1-yl)quinazolin-2-yl)oxy)methyl)cyclopropane-1-formaldehyde Step 1: Preparation of (R)-1-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((1-(hydroxymethyl)cyclopropyl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol

[0550] [ka] To a solution of (R)-1-(7-bromo-8-fluoro-2-((1-(hydroxymethyl)cyclopropyl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol (600 mg, 1362.67 μmol) and ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (838 mg, 1635.21 μmol) in 1,4-dioxane (40 mL) and water (10 mL) was added anhydrous cesium carbonate (1344 mg, 4088.01 μmol) and cataCXium(R)A Pd G3 (149 mg, 204.40 μmol) at room temperature. The mixture was stirred at 75 °C for 18 hours under nitrogen gas protection. The reaction mixture was poured into water (100 mL) and extracted with ethyl acetate (20 mL × 2). The combined organic phase was washed with saturated sodium chloride (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 80:1, 0.1% NH3) to give (R)-1-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((1-(hydroxymethyl)cyclopropyl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol.

[0551] LC-MS: (ESI, m / z): [M+H] + =746.4. Step 2: Preparation of (R)-1-(((8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-4-(3-hydroxy-3-methylpiperidin-1-yl)quinazolin-2-yl)oxy)methyl)cyclopropane-1-formaldehyde

[0552] [ka] At room temperature, (R)-1-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((1-(hydroxymethyl)cyclopropyl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol (752 mg, 1.008 mmol) in dichloromethane (30 mL) was cooled to 0 ° C., Dess-Martin reagent (555 mg, 1.309 mmol) was added, and the mixture was stirred at 25 ° C. for 1 hour. After the reaction was completed, the mixture was poured into saturated aqueous sodium bicarbonate solution (100 mL), extracted with dichloromethane (20 mL × 2), and the combined organic phase was washed with saturated sodium chloride (100 mL), dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate=10:1 to 1 / 1, 0.1% NH3) to give (R)-1-(((8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-4-(3-hydroxy-3-methylpiperidin-1-yl)quinazolin-2-yl)oxy)methyl)cyclopropane-1-formaldehyde.

[0553] LC-MS: (ESI, m / z): [M+H] + =743.9. Intermediate 11: 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

[0554] [ka] tert-Butyl 9-formyl-3-azaspiro[5.5]undecane-3-carboxylate (400 mg, 1.42 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 trifluoroacetate, which was used directly in the next reaction.

[0555] Step 2: Preparation of 3-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzoyl)-3-azaspiro[5.5]undecane-9-formaldehyde

[0556] [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 phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by silica gel column chromatography (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.

[0557] MS(ESI) m / z: [M+H] + = 432.0. Intermediate 12: 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

[0558] [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.

[0559] LC-MS: (ESI, m / z): [M+H] + = 278.1. Step 2: Preparation of 4-(3-oxopropyl)piperidine-1-carboxylate

[0560] [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.

[0561] LC-MS: (ESI, m / z): [M+H] + = 276.1. Step 3: Preparation of tert-butyl 4-(3-(1-((benzyloxy)carbonyl)piperidin-4-yl)propyl)piperazine-1-carboxylate

[0562] [ka] To a solution of 4-(3-oxopropyl)piperidine-1-carboxylate (3.3 g, 12.0 mmol) in 1,2-dichloroethane (60 mL), tert-butyl piperazine-1-carboxylate (6.7 g, 36.0 mmol) and acetic acid (2 mL) were added and 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.

[0563] LC-MS: (ESI, m / z): [M+H] + = 446.2. Step 4: Preparation of tert-butyl 4-(3-(piperidin-4-yl)propyl)piperazine-1-carboxylate

[0564] [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.

[0565] LC-MS: (ESI, m / z): [M+H] + = 312.2. 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

[0566] [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)benzoic acid perfluorophenyl ester (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 × 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.

[0567] LC-MS: (ESI, m / z): [M+H] + = 562.2. Step 6: Preparation of 1-(2-chloro-5-(4-(3-(piperazin-1-yl)propyl)piperidine-1-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione

[0568] [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.

[0569] LC-MS: (ESI, m / z): [M+H] + = 462.2. Intermediate 13: 1-(2-methyl-5-(9-(piperazin-1-ylmethyl)-3-azaspiro[5.5]undecane-3-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione 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

[0570] [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.

[0571] LC-MS: (ESI, m / z): [M+H] + = 616.3. 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

[0572] [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.

[0573] LC-MS: (ESI, m / z): [M+H] + = 482.2. Intermediate 14: tert-Butyl 4-(2-(piperazin-1-yl)ethyl)piperidine-1-carboxylate Step 1: Preparation of 4-(2-(1-(tert-butoxycarbonyl)piperidin-4-yl)ethyl)piperazine-1-carboxylate

[0574] [ka] tert-Butyl 4-(2-oxoethyl)piperidine-1-carboxylate (2 g, 8.8 mmol) was dissolved in 1,2-dichloroethane (30 mL), acetic acid (1 mL) and piperazine-1-carboxylate (5.8 g, 26.4 mmol) were added, and the mixture was stirred at 30 °C for 2 h. NaBHCN (1.1 g, 17.6 mmol) was then added slowly in an ice bath, and the mixture was stirred at 30 °C for 16 h. After completion of the reaction, the mixture was diluted with water (30 mL), extracted with ethyl acetate (50 mL × 3), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (DCM:MeOH = 20:1) to give 4-(2-(1-(tert-butoxycarbonyl)piperidin-4-yl)ethyl)piperazine-1-carboxylate.

[0575] LC-MS: (ESI, m / z): [M+H] + = 432.2. Step 2: Preparation of tert-butyl 4-(2-(piperazin-1-yl)ethyl)piperidine-1-carboxylate

[0576] [ka] To a solution of 4-(2-(1-(tert-butoxycarbonyl)piperidin-4-yl)ethyl)piperazine-1-carboxylate (2 g, 4.6 mmol) in methanol (10 mL) was added Pd / C (490 mg) and stirred under a hydrogen atmosphere at 30° C. for 16 hours. After completion of the reaction, the mixture was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to give tert-butyl 4-(2-(piperazin-1-yl)ethyl)piperidine-1-carboxylate. The crude product was used directly in the next step without further purification.

[0577] Intermediate 15: tert-Butyl 9-(piperazin-1-ylmethyl)-3-azaspiro[5.5]undecane-3-carboxylate Step 1: Preparation of tert-butyl 9-((4-((benzyloxy)carbonyl)piperazin-1-yl)methyl)-3-azaspiro[5.5]undecane-3-carboxylate

[0578] [ka] tert-Butyl 9-aldehyde-3-azaspiro[5.5]undecane-3-carboxylate (300 mg, 1.06 mmol) and piperazine-1-carboxylate (235 mg, 1.06 mmol) were dissolved in tetrahydrofuran (10 mL) and, with stirring, sodium triacetoxyborohydride (674 mg, 3.18 mmol) was added. After stirring at room temperature for 2 hours, water (50 mL) was added, and the mixture was extracted with dichloromethane (30 mL × 3). The organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (methanol:dichloromethane = 1:9) to give tert-butyl 9-((4-((benzyloxy)carbonyl)piperazin-1-yl)methyl)-3-azaspiro[5.5]undecane-3-carboxylate.

[0579] LC-MS: (ESI, m / z): [M+H] + =486.2. Step 2: Preparation of tert-butyl 9-(piperazin-1-ylmethyl)-3-azaspiro[5.5]undecane-3-carboxylate

[0580] [ka] tert-Butyl 9-((4-((benzyloxy)carbonyl)piperazin-1-yl)methyl)-3-azaspiro[5.5]undecane-3-carboxylate (500 mg, 1.02 mmol) was dissolved in ethyl acetate (15 mL), and Pd(OH)2 / C (250 mg, 0.35 mmol) was added. The mixture was heated to 70 °C under a hydrogen gas atmosphere and stirred overnight. The reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure to give tert-butyl 9-(piperazin-1-ylmethyl)-3-azaspiro[5.5]undecane-3-carboxylate. The crude product was used directly in the next reaction without further purification.

[0581] LC-MS: (ESI, m / z): [M+H] + =352.2. Intermediate 16: 2-(3-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzoyl)-3-azaspiro[5.5]undecan-9-yl)acetaldehyde

[0582] [ka] Prepared with reference to Intermediate 11.

[0583] Intermediate 17: 1-(2-chloro-5-(piperazine-1-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione

[0584] [ka] It was prepared with reference to Example 40 of patent WO2023025159A1.

[0585] Intermediate 18: 3-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methylbenzoyl)-3-azaspiro[5.5]undecane-9-formaldehyde

[0586] [ka] Prepared with reference to intermediate 32 of patent WO2023025159A1.

[0587] Intermediate 19: (R)-1-(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-methylpiperidin-3-ol Step 1: Preparation of (R)-1-(2-((R)-3-(4-benzylpiperazin-1-yl)-2-methylpropoxy)-7-chloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol

[0588] [ka] (R)-1-(2,7-Dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (3.6 g, 10.87 mmol) and (R)-3-(4-benzylpiperazin-1-yl)-2-methylpropan-1-ol (5.4 g, 21.74 mmol) were dissolved in THF (50 mL) and added to a sealed tube reactor. CsCO (10.63 g, 32.61 mmol) was added. The reaction was carried out at 90 °C 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. The resulting crude product was purified by silica gel column chromatography (DCM:MeOH=20:1) to give (R)-1-(2-((R)-3-(4-benzylpiperazin-1-yl)-2-methylpropoxy)-7-chloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol.

[0589] LC-MS: (ESI, m / z): [M+H] + = 543.3. Step 2: Preparation of (R)-1-(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)-3-methylpiperidin-3-ol

[0590] [ka] To a solution of (R)-1-(2-((R)-3-(4-benzylpiperazin-1-yl)-2-methylpropoxy)-7-chloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (1 g, 1.84 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, 2.21 mmol) in 1,4-dioxane (6 mL) and HO (1.2 mL) was added CataCXium A Pd G3 (134 mg, 0.18 mmol) and cesium carbonate (1.8 g, 5.52 mmol). The mixture was reacted at 85 °C for 16 hours under nitrogen gas protection, water (10 mL) was added, and extracted with ethyl acetate (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 (DCM:MeOH = 20:1) to give (R)-1-(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)-3-methylpiperidin-3-ol.

[0591] LC-MS: (ESI, m / z): [M+H] + = 893.5. Step 3: Preparation of (R)-1-(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-methylpiperidin-3-ol

[0592] [ka] (R)-1-(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)-3-methylpiperidin-3-ol (1 g, 1.12 mmol) was dissolved in DCM (5 mL), and 1-chloroethyl chloroformate (480 mg, 3.36 mmol) and DIEA (434 mg, 3.36 mmol) were added. The mixture was reacted at room temperature for 1 hour, concentrated under reduced pressure, and MeOH (5 mL) was added to the concentrate, which was heated to 50 °C and reacted 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) = 20:1) to give (R)-1-(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-methylpiperidin-3-ol.

[0593] LC-MS: (ESI, m / z): [M / 2+H] + = 402.3. Intermediate 20: (R)-1-(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-methylpiperidin-3-ol Step 1: Preparation of (R)-1-(2-((R)-3-(4-benzylpiperazin-1-yl)-2-methylpropoxy)-7-bromo-8-fluoroquinazolin-4-yl)-3-methylpiperidin-3-ol

[0594] [ka] (R)-1-(7-Bromo-2-chloro-8-fluoroquinazolin-4-yl)-3-methylpiperidin-3-ol (1.2 g, 3.20 mmol) and (R)-3-(4-benzylpiperazin-1-yl)-2-methylpropan-1-ol (1.03 g, 4.16 mmol) were dissolved in acetonitrile (15 mL), and CsCO (3.13 g, 9.60 mmol) and DABCO (CAS: 280-57-9, 72 mg, 0.64 mmol) were added, followed by reaction at room temperature for 10 hours. After completion of the reaction, the reaction mixture was filtered, and the filtrate was concentrated. The resulting crude product was purified by silica gel column chromatography (DCM:MeOH=20:1) to give (R)-1-(2-((R)-3-(4-benzylpiperazin-1-yl)-2-methylpropoxy)-7-bromo-8-fluoroquinazolin-4-yl)-3-methylpiperidin-3-ol.

[0595] LC-MS: (ESI, m / z): [M+H] + = 586.2. Step 2: Preparation of (R)-1-(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-methylpiperidin-3-ol

[0596] [ka] To a solution of (R)-1-(2-((R)-3-(4-benzylpiperazin-1-yl)-2-methylpropoxy)-7-bromo-8-fluoroquinazolin-4-yl)-3-methylpiperidin-3-ol (1.3 g, 2.22 mmol) and ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (1.37 g, 2.66 mmol) in 1,4-dioxane (10 mL) and HO (2 mL) was added [1,1'-bis(di-tert-butylphosphine)ferrocene]palladium dichloride (289 mg, 0.44 mmol) and cesium carbonate (2.17 g, 6.66 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 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 (R)-1-(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-methylpiperidin-3-ol.

[0597] LC-MS: (ESI, m / z): [M+H] + = 892.5. Step 3: Preparation of (R)-1-(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-methylpiperidin-3-ol

[0598] [ka] (R)-1-(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-methylpiperidin-3-ol (1.5 g, 1.68 mmol) was dissolved in DCM (8 mL), and 1-chloroethyl chlorocarbonate (721 mg, 5.04 mmol) and DIEA (651 mg, 5.04 mmol) were added. The mixture was reacted at room temperature for 1 hour, and the reaction solution was directly concentrated under reduced pressure. MeOH (8 mL) was added to the concentrate, dissolved, and heated to 50 °C for 30 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) = 30:1) to give (R)-1-(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-methylpiperidin-3-ol.

[0599] LC-MS: (ESI, m / z): [M+H] + = 802.5. Intermediate 21: 2,7-dichloro-4-(3,3-difluoropiperidin-1-yl)-8-fluoropyrido[4,3-d]pyrimidine

[0600] [ka] 2,4,7-Trichloro-8-fluoropyrido[4,3-d]pyrimidine (3.0 g, 11.88 mmol) and triethylamine (3.61 g, 35.64 mmol) were dissolved in THF (40 mL) and cooled to -50 °C. 3,3-Difluoropiperidine (1.68 g, 10.69 mmol) was added and the mixture was allowed to react at -50 °C 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 (20 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by silica gel column chromatography (PE: EtOAc = 3:1) to give 2,7-dichloro-4-(3,3-difluoropiperidin-1-yl)-8-fluoropyrido[4,3-d]pyrimidine.

[0601] LC-MS: (ESI, m / z): [M+H] + = 337.1. Intermediate 22: (R)-1-(2-((1-((4-((3-azaspiro[5.5]undecan-9-yl)methyl)piperazin-1-yl)methyl)cyclopropyl)methoxy)-8-fluoro-7-(7-fluoro-3-hydroxy-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol Step 1: Preparation of tert-butyl (R)-9-((4-((1-(((8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-4-(3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperazin-1-yl)methyl)-3-azaspiro[5.5]undecane-3-carboxylate

[0602] [ka] At room temperature, (R)-1-(((8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-4-(3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropane-1-formaldehyde (518 mg, 695.34 μmol) and 9-(piperazin-1-ylmethyl)-3-azaspiro[5.5]undecane-3-carboxylate tert-butyl (566 mg, 1610.80 μmol) in dichloromethane (30 mL) was stirred, and tetraisopropyl titanate (1145 mg, 4027.0 μmol) and glacial acetic acid (0.4 mL) were added and stirred at 25 ° C. for 4 hours. Sodium triacetoxyborohydride (442 mg, 2086.02 μmol) was further added, and the reaction was continued for 4 hours at 25° C. The mixture was concentrated under reduced pressure at 40° C., and the resulting crude product was purified by silica gel column chromatography (dichloromethane:methanol = 100:1 to 10:1) to give (R)-9-((4-((1-(((8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-4-(3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperazin-1-yl)methyl)-3-azaspiro[5.5]undecane-3-carboxylate tert-butyl ester.

[0603] LC-MS: (ESI, m / z): [M+H] + = 1080.6. Step 2: Preparation of (R)-1-(2-((1-((4-((3-azaspiro[5.5]undecan-9-yl)methyl)piperazin-1-yl)methyl)cyclopropyl)methoxy)-8-fluoro-7-(7-fluoro-3-hydroxy-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol

[0604] [ka] At 0 ° C., a 1,4-dioxane solution (2 mL) of crude (R)-9-((4-((1-(((8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-4-(3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperazin-1-yl)methyl)-3-azaspiro[5.5]undecane-3-carboxylate tert-butyl (511.6 mg, 473.49 μmol) was added to a 1,4-dioxane solution (2 mL) of hydrogen chloride / 1,4-dioxane solution (4.0 M, 3 mL), and the mixture was allowed to react at room temperature for 1.5 hours. After completion of the reaction, the mixture was concentrated under reduced pressure at 30°C, and ammonia methanol solution (5 mL) was added to the concentrate, followed by further concentration under reduced pressure at 30°C. (R)-1-(2-((1-((4-((3-azaspiro[5.5]undecan-9-yl)methyl)piperazin-1-yl)methyl)cyclopropyl)methoxy)-8-fluoro-7-(7-fluoro-3-hydroxy-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol was obtained.

[0605] LC-MS: (ESI, m / z): [M+H] + = 936.5. Intermediate 23: tert-butyl (1-(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-methylpiperidin-3-yl)carboxylate Step 1: Preparation of tert-butyl (1-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-yl)carboxylate

[0606] [ka] TEA (2.4 g, 23.7 mmol) was added to a solution of 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (2.0 g, 7.9 mmol) in DCM (20 mL) at -78 °C. After stirring for 30 min, tert-butyl (3-methylpiperidin-3-yl)aminocarboxylate (1.35 g, 2.0 mmol) was added and stirred for 4 h. After completion of the reaction, the mixture was allowed to warm to room temperature, HO (30 mL) was added, and extracted with DCM (30 mL × 3). 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 = 5:1) to give tert-butyl (1-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-yl)carboxylate.

[0607] LC-MS: (ESI, m / z): [M+H]+ = 430.1. Step 2: Preparation of tert-butyl (1-(7-chloro-8-fluoro-2-((1-(hydroxymethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-yl)carboxylate

[0608] [ka] To a solution of tert-butyl (1-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-yl)carboxylate (2.3 g, 5.3 mmol) and cyclopropane-1,1-diyldimethanol (286 mg, 10.6 mmol) in acetonitrile (5 mL) was added CsCO (1.3 g, 4.2 mmol) and DABCO (1.1 g, 0.7 mmol), and the mixture was stirred at room temperature for 30 minutes. After the reaction was completed, water (20 mL) was added, and the mixture was 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 (1-(7-chloro-8-fluoro-2-((1-(hydroxymethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-yl)carboxylate.

[0609] LC-MS: (ESI, m / z): [M+H]+ = 496.1. Step 3: Preparation of tert-butyl (1-(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-methylpiperidin-3-yl)carboxylate

[0610] [ka] To a solution of tert-butyl (1-(7-chloro-8-fluoro-2-((1-(hydroxymethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-yl)carboxylate (400 mg, 0.81 mmol) in 1,4-dioxane (12 mL) and HO (2 mL) was added ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (496 mg, 0.97 mmol), cataCXium A Pd G3 (118 mg, 0.36 mmol), and cesium carbonate (788 mg, 2.42 mmol). The mixture was reacted at 85 °C for 16 h under nitrogen gas protection. After completion of the reaction, water (10 mL) was added to the reaction mixture, which was then extracted with ethyl acetate (10 mL × 3). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (DCM:MeOH = 10:1) to give tert-butyl (1-(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-methylpiperidin-3-yl)carboxylate.

[0611] LC-MS: (ESI, m / z): [M+H]+ = 846.4. Step 4: Preparation of tert-butyl (1-(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-methylpiperidin-3-yl)carboxylate

[0612] [ka] A solution of tert-butyl (1-(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-methylpiperidin-3-yl)carboxylate (500 mg, 0.59 mmol) in DCM (5 mL) was cooled to 0 ° C., Dess-Martin oxidant (501 mg, 1.18 mmol) was added, and the reaction was carried out at room temperature for 1 hour. After completion of the reaction, the reaction was quenched by adding sodium thiosulfate solution (5 mL) and sodium bicarbonate solution (5 mL), extracted with dichloromethane (5 mL × 3), and 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=20:1) to give tert-butyl (1-(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-methylpiperidin-3-yl)carboxylate.

[0613] LC-MS: (ESI, m / z): [M+H]+ = 844.4. Intermediate 24: (R)-1-(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-methylpiperidin-3-ol Step 1: Preparation of (R)-1-(2-((R)-3-(4-benzylpiperazin-1-yl)-2-methoxypropoxy)-7-chloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol

[0614] [ka] (R)-1-(2,7-Dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (1.50 g, 4.53 mmol) and (R)-3-(4-benzylpiperazin-1-yl)-2-methoxypropan-1-ol (2.39 g, 9.06 mmol) were dissolved in acetonitrile (20 mL), and CsCO (2.95 g, 9.06 mmol) and DABCO (51 mg, 0.45 mmol) were added. The mixture was allowed to react at room temperature for 2 hours. 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. The resulting crude product was purified by silica gel column chromatography (DCM:MeOH=20:1) to give (R)-1-(2-((R)-3-(4-benzylpiperazin-1-yl)-2-methoxypropoxy)-7-chloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol.

[0615] LC-MS: (ESI, m / z): [M+H] + = 559.2. Step 2: Preparation of (R)-1-(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-methylpiperidin-3-ol

[0616] [ka] To a solution of (R)-1-(2-((R)-3-(4-benzylpiperazin-1-yl)-2-methoxypropoxy)-7-chloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (1.00 g, 1.80 mmol) and ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (1.20 g, 2.30 mmol) in 1,4-dioxane / water (10 mL / 2 mL) was added Ruphos Pd G3 (130 mg, 0.18 mmol) and cesium carbonate (1.20 g, 3.60 mmol). The mixture was reacted at 85 °C for 16 hours under nitrogen gas protection, 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 (R)-1-(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-methylpiperidin-3-ol.

[0617] LC-MS: (ESI, m / z): [M / 2+H] + = 455.4. Step 3: Preparation of (R)-1-(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-methylpiperidin-3-ol

[0618] [ka] To a stirred solution of (R)-1-(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-methylpiperidin-3-ol (1.000 g, 1.099 mmol) in dichloromethane (30 mL) and N,N-diisopropylethylamine (0.426 g, 3.300 mmol) was added 1-chloroethyl chloroformate (0.472 g, 3.300 mmol) at room temperature. After stirring at 25 °C for 1 hour, the mixture was concentrated under reduced pressure. The concentrate was dissolved in anhydrous methanol (30 mL) and allowed to react at 50° C. for 1 hour, then concentrated under reduced pressure at 40° C. to obtain crude product (R)-1-(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-methylpiperidin-3-ol.

[0619] LC-MS: (ESI, m / z): [M+H] + = 819.4. Intermediate 25: 3-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)-3-azaspiro[5.5]undecane-9-formaldehyde

[0620] [ka] TFA (50 mL) was added to a solution of tert-butyl 9-formyl-3-azaspiro[5.5]undecane-3-carboxylate (10 g, 35.6 mmol) in DCM (200 mL) at 25° C., and the mixture was allowed to react for 1 hour at 25° C. The reaction mixture was concentrated, and the concentrate was dissolved in N,N-dimethylformamide (200 mL). DIEA (46 g, 356 mmol) and pentafluorophenyl 3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoate (18 g, 42.7 mmol) were added, and the mixture was stirred at 25° C. for 16 hours. After the reaction was completed, the reaction mixture was directly purified by high performance liquid separation to obtain 3-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)-3-azaspiro[5.5]undecane-9-formaldehyde.

[0621] LC-MS: (ESI, m / z): [M+H] + = 428.3. Intermediate 26: 1-(2-ethyl-5-(9-(piperazin-1-ylmethyl)-3-azaspiro[5.5]undecane-3-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione

[0622] [ka] Prepared with reference to Intermediate 12.

[0623] Intermediate 27: Pentafluorophenyl 3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-(methyl-d3)benzoate Step 1: Preparation of methyl 3-((tert-butoxycarbonyl)amino)-4-iodobenzoate

[0624] [ka] Methyl 3-amino-4-iodobenzoate (20.0 g, 72.2 mmol) was dissolved in tetrahydrofuran (200 mL), and BocO (47.2 g, 216.6 mmol) and DMAP (0.9 g, 7.22 mmol) were added. The mixture was reacted at 25°C for 5 hours. After the reaction was completed, the reaction mixture was poured into saturated aqueous ammonium chloride solution (100 mL) and extracted with ethyl acetate (100 mL x 2). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude intermediate product. The intermediate was dissolved in DCM (300 mL), and trifluoroacetic acid (10 mL) was added at 0-5°C. The mixture was reacted at 0-5°C for 1 hour. The reaction mixture was slowly added dropwise to sodium carbonate solution at 0-5°C and extracted with ethyl acetate (100 mL x 2). The organic phase was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and concentrated. The resulting crude product was purified by silica gel column chromatography (PE:EA=100:1 to 20:1) to give methyl 3-((tert-butoxycarbonyl)amino)-4-iodobenzoate.

[0625] LC-MS: (ESI, m / z): [M-Boc+H] + = 278.0. Step 2: Preparation of methyl 3-((tert-butoxycarbonyl)amino)-4-(methyl-d3)benzoate

[0626] [ka] Methyl 3-((tert-butoxycarbonyl)amino)-4-iodobenzoate (13.5 g, 35.8 mmol) and deuterated iodomethane (15.6 g, 107.4 mmol) were dissolved in anhydrous THF (150 mL), and sodium iodide (2.7 g, 17.9 mmol), zinc powder (7.0 g, 107.4 mmol), and 1,3-bis(diphenylphosphinopropane)nickel dichloride (1.9 g, 3.58 mmol) were added. The mixture was reacted at 25 °C for 16 h under nitrogen gas protection. After completion of the reaction, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (PE:EA = 200:1 to 50:1) to give methyl 3-((tert-butoxycarbonyl)amino)-4-(methyl-d3)benzoate.

[0627] LC-MS: (ESI, m / z): [M-tBu+H] + = 213.2. Step 3: Preparation of 3-((tert-butoxycarbonyl)amino)-4-(methyl-d3)benzoic acid

[0628] [ka] Methyl 3-((tert-butoxycarbonyl)amino)-4-(methyl-d3)benzoate (2.0 g, 7.46 mmol) was dissolved in THF (15 mL) and HO (15 mL). Lithium hydroxide (1.25 g, 29.9 mmol) was added and the mixture was allowed to react at 25 °C for 3 hours. Methyl tert-butyl ether (20 mL) was added and the mixture was extracted. The aqueous phase was adjusted to pH 4 with dilute hydrochloric acid and extracted with ethyl acetate (30 mL × 2). The combined organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give 3-((tert-butoxycarbonyl)amino)-4-(methyl-d3)benzoic acid.

[0629] LC-MS: (ESI, m / z): [M-tBu+H] + = 199.1. Step 4: Preparation of 3-amino-4-(methyl-d3)benzoic acid

[0630] [ka] 3-((tert-butoxycarbonyl)amino)-4-(methyl-d3)benzoic acid (1.5 g, 5.90 mmol) was dissolved in 1,4-dioxane (10 mL), and HCl / 1,4-dioxane (4 N, 10 mL) was added. The reaction mixture was reacted at 25° C. for 3 hours. The reaction mixture was concentrated to give 3-amino-4-(methyl-d3)benzoic acid, which was used directly in the next reaction.

[0631] Step 5: Preparation of 3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-(methyl-d3)benzoic acid

[0632] [ka] A mixture of 3-amino-4-(methyl-d3)benzoic acid (1.00 g, 6.62 mmol) and acrylic acid (1.4 g, 19.87 mmol) was heated to 100 °C and stirred for 3 hours. After cooling to room temperature, glacial acetic acid (10 mL) was added, the mixture was heated to 100 °C and maintained at this temperature for 10 minutes. Urea (2.38 g, 39.72 mmol) was then added, and the mixture was heated to 120 °C and stirred for 16 hours. After the reaction was complete, the mixture was cooled to room temperature and poured into dilute glacial hydrochloric acid (1 N, 30 mL). A large amount of solid precipitated. The mixture was stirred for 1 hour and filtered to give 3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-(methyl-d3)benzoic acid.

[0633] LC-MS: (ESI, m / z): [M+H] + = 252.1. Step 6: Preparation of pentafluorophenyl 3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-(methyl-d3)benzoate

[0634] [ka] To a solution of 3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-(methyl-d3)benzoic acid (400 mg, 1.59 mmol) and 2,3,4,5,6-pentafluorophenol (351 mg, 1.91 mmol) in DMF (2 mL) was added N,N'-dicyclohexylcarbodiimide (393 mg, 1.91 mmol) and stirred at 25 °C for 3 hours. Water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (DCM / MeOH = 20 / 1 to 10 / 1) to give pentafluorophenyl 3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-(methyl-d3)benzoate.

[0635] LC-MS: (ESI, m / z): [M+H] + = 418.1. Intermediate 28: 3-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-(methyl-d3)benzoyl)-3-azaspiro[5.5]undecane-9-formaldehyde

[0636] [ka] Prepared with reference to Intermediate 11.

[0637] Intermediate 29: 3-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-ethylbenzoyl)-3-azaspiro[5.5]undecane-9-formaldehyde Step 1: Preparation of 3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-ethylbenzoic acid

[0638] [ka] A mixture of 3-amino-4-ethylbenzoic acid (3.00 g, 18.19 mmol) and acrylic acid (3.9 g, 54.55 mmol) was heated to 100°C and stirred for 3 hours. After cooling to room temperature, glacial acetic acid (20 mL) was added, the mixture was heated to 100°C and maintained at this temperature for 10 minutes. Urea (6.5 g, 109.08 mmol) was then added, the mixture was heated to 120°C, and stirred for 16 hours. After the reaction was complete, the mixture was cooled to room temperature and poured into dilute glacial hydrochloric acid (1N, 100 mL). A large amount of solid precipitated. The mixture was stirred for 1 hour and filtered to give 3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-ethylbenzoic acid.

[0639] LC-MS: (ESI, m / z): [M+H] + = 263.1. Step 2: Preparation of pentafluorophenyl 3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-ethylbenzoate

[0640] [ka] To a stirred solution of 3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-ethylbenzoic acid (3.7 g, 14.1 mmol) and pentafluorophenol (3.1 g, 16.92 mmol) in N,N-dimethylformamide (70 mL) at room temperature, N,N'-dicyclohexylcarbodiimide (3.5 g, 16.92 mmol) and DMAP (172 mg, 1.41 mmol) were added, and the mixture was stirred at 25°C for 16 hours. After completion of the reaction, the reaction mixture was poured into water (100 mL) and extracted with ethyl acetate (100 mL × 3). The organic phase was washed with saturated brine (100 mL × 2). 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 (MeOH:DCM = 1:20) to give pentafluorophenyl 3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-ethylbenzoate.

[0641] LC-MS: (ESI, m / z): [M+H] + = 429.1. Step 3: Preparation of 3-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-ethylbenzoyl)-3-azaspiro[5.5]undecane-9-formaldehyde

[0642] [ka] TFA (50 mL) was added to a solution of tert-butyl 9-formyl-3-azaspiro[5.5]undecane-3-formate (2 g, 7.1 mmol) in DCM (200 mL) at 25° C., and the mixture was allowed to react for 1 hour at 25° C. The reaction mixture was concentrated, and the concentrate was dissolved in N,N-dimethylformamide (20 mL). DIEA (4.6 g, 35.6 mmol) and pentafluorophenyl 3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-ethylbenzoate (3.0 g, 7.1 mmol) were added, and the mixture was stirred at 25° C. for 16 hours. After the reaction was completed, the reaction mixture was directly purified using reverse phase chromatography (acetonitrile / water = 5 / 95 to 95 / 95), and the collected solution was freeze-dried to obtain 3-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-ethylbenzoyl)-3-azaspiro[5.5]undecane-9-formaldehyde.

[0643] LC-MS: (ESI, m / z): [M+H] + = 426.3. Intermediate 30: 3-(5-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-2-fluoro-4-methylbenzoyl)-3-azaspiro[5.5]undecane-9-formaldehyde

[0644] [ka] Prepared with reference to Intermediate 11.

[0645] Intermediate 31: 3-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-(methoxy-d3)benzoyl)-3-azaspiro[5.5]undecane-9-formaldehyde Step 1: Preparation of methyl 4-(methoxy-d3)-3-nitrobenzoate

[0646] [ka] Deuterated iodomethane (20.00 g, 137.97 mmol) was added to a solution of methyl 4-hydroxy-3-nitrobenzoate (25.00 g, 126.81 mmol) and anhydrous potassium carbonate (52.58 g, 380.42 mmol) in N,N-dimethylformamide (150 mL) at 25 °C, and the mixture was stirred at 65 °C for 16 hours. After completion of the reaction, the reaction mixture was poured into water (500 mL) and extracted with ethyl acetate (200 mL × 3). The organic phase was washed with saturated brine (500 mL × 2). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was added to petroleum ether / ethyl acetate (20 / 1), stirred, and filtered to give methyl 4-(methoxy-d3)-3-nitrobenzoate.

[0647] LC-MS: (ESI, m / z): [M+H] + = 215.1. Step 2: Preparation of methyl 3-amino-4-(methoxy-d3)benzoate

[0648] [ka] To a stirred solution of methyl 4-(methoxy-d3)-3-nitrobenzoate (25.84 g, 120.626 mmol) in glacial acetic acid (250 mL) at 25 °C, zinc powder (78.87 g, 1206.27 mmol) was added and stirred at 50 °C for 16 h. The insoluble material was removed by filtration through diatomaceous earth, and the filtrate was concentrated under reduced pressure to dryness. The residue was added to saturated aqueous sodium carbonate (200 mL) and extracted with ethyl acetate (100 mL × 3). The organic phase was washed with saturated brine (200 mL). 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 (petroleum ether:ethyl acetate = 20:1 to 1:1) to give methyl 3-amino-4-(methoxy-d3)benzoate.

[0649] LC-MS: (ESI, m / z): [M+H] + = 185.2. Step 3: Preparation of 3-amino-4-(methoxy-d3)benzoic acid

[0650] [ka] Lithium hydroxide (19.70 g, 469.57 mmol) was added to a stirred solution of methyl 3-amino-4-(methoxy-d3)benzoate (17.30 g, 93.92 mmol) in tetrahydrofuran (170 mL) and water (170 mL) at 25° C., and the mixture was stirred for 16 hours at 50° C. The reaction mixture was concentrated under reduced pressure to dryness, and the residue was dissolved in ethyl acetate and dried over anhydrous sodium sulfate. Insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure to give 3-amino-4-(methoxy-d3)benzoic acid.

[0651] LC-MS: (ESI, m / z): [M+H] + = 171.2. Step 4: Preparation of 3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-(methoxy-d3)benzoic acid

[0652] [ka] A mixture of 3-amino-4-(methoxy-d3)benzoic acid (2.00 g, 11.75 mmol) and acrylic acid (3.39 g, 47.01 mmol) was heated to 100 °C and stirred for 3 hours. After cooling to room temperature, glacial acetic acid (14 mL) was added, the mixture was heated to 100 °C and maintained at this temperature for 10 minutes. Urea (4.38 g, 72.86 mmol) was then added, and the mixture was heated to 120 °C and stirred for 16 hours. After the reaction was complete, the mixture was cooled to room temperature and poured into dilute glacial hydrochloric acid (1 N, 150 mL). A large amount of solid precipitated. The mixture was stirred for 1 hour and filtered to give 3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-(methoxy-d3)benzoic acid.

[0653] LC-MS: (ESI, m / z): [M+H] + = 268.1. Step 5: Preparation of methyl 3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-(methoxy-d3)benzoate

[0654] [ka] To a stirred solution of 3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-(methoxy-d3)benzoic acid (1.83 g, 6.84 mmol) and pentafluorophenol (1.39 g, 7.53 mmol) in N,N-dimethylformamide (60 mL) at −10° C., a tetrahydrofuran solution (10 mL) containing N,N′-dicyclohexylcarbodiimide (20.00 g, 137.97 mmol) was added, and the mixture was stirred at 25° C. for 16 hours. After completion of the reaction, the reaction mixture was poured into water (200 mL) and extracted with ethyl acetate (50 mL × 3). The organic phase was washed with saturated brine (200 mL × 2). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was stirred with petroleum ether / tetrahydrofuran (5 / 1) and filtered to obtain methyl 3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-(methoxy-d3)benzoate.

[0655] LC-MS: (ESI, m / z): [M+H] + = 434.1. Step 6: Preparation of 3-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-(methoxy-d3)benzoyl)-3-azaspiro[5.5]undecane-9-formaldehyde

[0656] [ka] TFA (2 mL) was added to a solution of tert-butyl 9-formyl-3-azaspiro[5.5]undecane-3-carboxylate (0.56 g, 2.01 mmol) in DCM (4 mL) at 25° C., and the mixture was allowed to react for 1 hour at 25° C. The reaction mixture was concentrated, and the concentrate was dissolved in N,N-dimethylformamide (10 mL). DIEA (2.98 g, 23.08 mmol) and methyl 3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-(methoxy-d3)benzoate (1.00 g, 2.01 mmol) were added, and the mixture was stirred at 25° C. for 16 hours. After the reaction was completed, the reaction mixture was directly purified by high-performance liquid preparative separation (acetonitrile:water = 5:95 to 95:95) to obtain 3-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-(methoxy-d3)benzoyl)-3-azaspiro[5.5]undecane-9-formaldehyde.

[0657] LC-MS: (ESI, m / z): [M+H] + = 431.3. Intermediate 32: (R)-1-(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-methylpiperidin-3-ol

[0658] [ka] Prepared with reference to Intermediate 11.

[0659] Intermediate 33: (R)-3-(4-benzylpiperazin-1-yl)-2-methylpropan-1-ol Step 1: Preparation of methyl (S)-3-((tert-butyldimethylsilyl)oxy)-2-methylpropionate

[0660] [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.

[0661] 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). Step 2: Preparation of (R)-3-((tert-butyldimethylsilyl)oxy)-2-methylpropan-1-ol

[0662] [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.

[0663] 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). Step 3: Preparation of (S)-3-((tert-butyldimethylsilyl)oxy)-2-methylpropyl methanesulfonate

[0664] [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.

[0665] Step 4: Preparation of (R)-1-benzyl-4-(3-((tert-butyldimethylsilyl)oxy)-2-methylpropyl)piperazine

[0666] [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.

[0667] LC-MS: (ESI, m / z): [M+H] + = 363.4. Step 5: Preparation of (R)-3-(4-benzylpiperazin-1-yl)-2-methylpropan-1-ol

[0668] [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%).

[0669] 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. Intermediate 34: (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

[0670] [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.

[0671] LC-MS: (ESI, m / z): [M+H] + = 365.3. Step 2: Preparation of (R)-1-benzyl-4-(3-((tert-butyldimethylsilyl)oxy)-2-methoxypropyl)piperazine

[0672] [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%).

[0673] 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.

[0674] LC-MS: (ESI, m / z): [M+H] + = 379.2. Step 3: Preparation of (R)-3-(4-benzylpiperazin-1-yl)-2-methoxypropan-1-ol

[0675] [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.

[0676] Intermediate 35: 3-(4-benzylpiperazin-1-yl)-2-methylpropan-1-ol Step 1: Preparation of methyl 3-(4-benzylpiperazin-1-yl)-2-methylpropionate

[0677] [ka] Methyl 3-hydroxy-2-methylpropionate (3.60 g, 30.47 mmol) was dissolved in dichloromethane (35 mL). Triethylamine (9.25 g, 91.42 mmol) and methanesulfonyl chloride (5.24 g, 45.71 mmol) were added at 0 °C, and the mixture was allowed to react for 2 hours. After the reaction was complete, the mixture was warmed to room temperature, water (50 mL) was added, and the mixture was extracted with ethyl acetate (50 mL × 3). The combined organic phase was washed with saturated NaCl solution, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was dissolved in DMF (50 mL), potassium carbonate (12.64 g, 91.42 mmol) and 1-benzylpiperazine (10.74 g, 60.95 mmol) were added, and the reaction mixture was heated to 85 °C and allowed to react for 16 hours. After the reaction was completed, the mixture was cooled to room temperature, water (200 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 mL × 3). The combined organic phase 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 = 20:1) to give methyl 3-(4-benzylpiperazin-1-yl)-2-methylpropionate.

[0678] LC-MS: (ESI, m / z): [M+H] + = 277.3. Step 2: Preparation of 3-(4-benzylpiperazin-1-yl)-2-methylpropan-1-ol

[0679] [ka] Methyl 3-(4-benzylpiperazin-1-yl)-2-methylpropionate (1.17 g, 4.23 mmol) was dissolved in THF (10 mL), and DIBAL-H (12.69 mL, 12.69 mmol, 1 M) was added in an ice bath. The mixture was allowed to react for 3 hours. After completion of the reaction, the mixture was warmed to room temperature, and saturated sodium potassium tartrate solution (100 mL) was added to the reaction mixture. The mixture was then extracted with ethyl acetate (50 mL × 3). The combined organic phase was washed with saturated NaCl solution, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated to give the crude product. The crude product was purified by silica gel column chromatography (DCM:MeOH = 20:1) to give 3-(4-benzylpiperazin-1-yl)-2-methylpropan-1-ol.

[0680] LC-MS: (ESI, m / z): [M+H] + = 249.1. Example 1: (R)-1-(2-chloro-5-(9-((4-((1-(((7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-(3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperazin-1-yl)methyl)-3-azaspiro[5.5]undecane-3-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione Step 1: Preparation of (R)-1-(2-chloro-5-(9-((4-((1-(((8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-4-(3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperazin-1-yl)methyl)-3-azaspiro[5.5]undecane-3-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione

[0681] [ka] To a stirred solution of (R)-1-(((8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-4-(3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropane-1-formaldehyde (60 mg, 0.08 mmol) in DCM (2 mL) was added tetraisopropyl titanate (227 mg, 0.80 mmol) and 1-(2-chloro-5-(9-(piperazin-1-ylmethyl)-3-azaspiro[5.5]undecane-3-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione (48 mg, 0.096 mmol) and stirred at 30 °C for 2 h. To the mixture was added NaBH(OAc)3 (53 mg, 0.24 mmol) at room temperature and 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 15:1) to give (R)-1-(2-chloro-5-(9-(4-((1-(((8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-4-(3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperazin-1-yl)methyl)-3-azaspiro[5.5]undecane-3-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione.

[0682] LC-MS: (ESI, m / z): [M / 2+H] + = 615.9. Step 2: Preparation of (R)-1-(2-chloro-5-(9-((4-((1-(((7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-(3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperazin-1-yl)methyl)-3-azaspiro[5.5]undecane-3-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione

[0683] [ka] Cesium fluoride (21 mg, 0.14 mmol) was added to a solution of (R)-1-(2-chloro-5-(9-((4-((1-(((8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-4-(3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperazin-1-yl)methyl)-3-azaspiro[5.5]undecane-3-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione (35 mg, 0.028 mmol) in DMF (2 mL), followed by stirring at room temperature for 30 minutes. EA and water were added to the reaction mixture, and the organic phase was separated and concentrated under pressure. To the resulting mixture, 1,4-dioxane (1 mL) and a mixture of HCl / 1,4-dioxane (6 N, 0.5 mL) were added at room temperature, and the mixture was allowed to react for 0.5 hours. The reaction mixture was directly concentrated under reduced pressure, and the resulting crude product was purified by pre-HPLC to give (R)-1-(2-chloro-5-(9-(4-((1-(((7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-(3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperazin-1-yl)methyl)-3-azaspiro[5.5]undecane-3-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione.

[0684] LC-MS: (ESI, m / z): [M+H] + = 1030.2. 1H NMR (400 MHz, DMSO-d6) δ 10.51 (s, 1H), 10.16 (s, 1H), 9.23 - 9.01 (m, 1H), 7.97 (dd, J = 9.2, 5.9 Hz, 1H), 7.63 (d, J = 8.2 Hz, 1H), 7.54 (d, J = 1.9 Hz, 1H), 7.49 - 7.43 (m, 1H), 7.41 - 7.35 (m, 2H), 7.25 - 7.15 (m, 1H), 4.74 (d, J = 30.0 Hz, 1H), 4.42 - 4.05 (m, 4H), 3.98 - 3.92 (m, 1H), 3.81-3.69 (m, 1H), 3.66 - 3.49 (m, 4H), 3.29 - 3.18 (m, 2H), 2.78 - 2.65 (m, 2H), 2.45 - 2.16 (m, 9H), 2.13 - 1.90 (m, 4H), 1.76 - 1.59 (m, 5H), 1.57 - 1.38 (m, 5H), 1.34 - 1.21 (m, 3H), 1.20 - 1.12 (m, 3H), 1.11 - 0.92 (m, 4H), 0.66 - 0.57 (m, 2H), 0.45 - 0.40 (m, 2H). Example 2: (R)-1-(2-chloro-5-(9-((4-((1-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-(3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperazin-1-yl)methyl)-3-azaspiro[5.5]undecane-3-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione Step 1: Preparation of (R)-1-(2-chloro-5-(9-((4-((1-(((7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-4-(3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperazin-1-yl)methyl)-3-azaspiro[5.5]undecane-3-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione

[0685] [ka] To a solution of (R)-1-(((7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-4-(3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropane-1-formaldehyde (100 mg, 0.169 mmol) in DCM (2 mL), 1-(2-chloro-5-(9-(piperazin-1-ylmethyl)-3-azaspiro[5.5]undecane-3-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione (102 mg, 0.203 mmol) and tetraisopropyl titanate (480 mg, 1.69 mmol) were added and stirred at room temperature for 2 hours. To the mixture was added NaBH(OAc)3 (113 mg, 0.507 mmol) at 0°C and stirred for 2 hours. The mixture was concentrated and purified by silica gel column chromatography (DCM:MeOH = 100:1 to 9:1) to give (R)-1-(2-chloro-5-(9-((4-((1-(((7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-4-(3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperazin-1-yl)methyl)-3-azaspiro[5.5]undecane-3-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione.

[0686] LC-MS: (ESI, m / z): [M+H] + = 1078.4. Step 2: Preparation of (R)-1-(2-chloro-5-(9-((4-((1-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-(3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperazin-1-yl)methyl)-3-azaspiro[5.5]undecane-3-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione

[0687] [ka] A solution of (R)-1-(2-chloro-5-(9-(4-((1-((7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-4-(3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperazin-1-yl)methyl)-3-azaspiro[5.5]undecane-3-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione (100 mg, 0.093 mmol) in 1,4-dioxane (2.0 mL) was added with HCl / 1,4-dioxane (6 N, 1.0 mL) and reacted at room temperature for 0.5 hours. The reaction mixture was adjusted to pH > 7 by the addition of aqueous NaCO solution and extracted with EtOAc (10 mL × 2). The organic phase was washed with brine, dried over anhydrous Na2SO4, and concentrated. The crude product was purified by preparative high-performance liquid chromatography to give (R)-1-(2-chloro-5-(9-(4-((1-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-(3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperazin-1-yl)methyl)-3-azaspiro[5.5]undecane-3-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione.

[0688] LC-MS: (ESI, m / z): [M+H] + = 1034.1. 1 H NMR (400 MHz, DMSO-d6) δ10.50 (s, 1H), 9.92 (d, J = 3.1 Hz, 1H), 9.21 (s, 1H), 7.79 - 7.73 (m, 1H), 7.63 (d, J = 8.2 Hz, 1H), 7.54 (d, J = 1.9 Hz, 1H), 7.40 - 7.30 (m, 3H), 7.02 (d, J = 2.6 Hz, 1H), 4.73 (d, J = 4.6 Hz, 1H), 4.38 - 4.23 (m, 3H), 4.09 - 3.95 (m, 1H), 3.80 - 3.69 (s, 1H), 3.66 - 3.46 (m, 4H), 3.30 - 3.23 (m, 2H), 2.78-2.65 (m, 2H), 2.46 - 2.14 (m, 12H), 2.07 - 1.97 (m, 3H), 1.74 - 1.60 (m, 5H), 1.55 - 1.22 (m, 8H), 1.16 (d, J = 9.8 Hz, 3H), 1.12 - 0.93 (m, 4H), 0.77 - 0.69 (m, 3H), 0.63 (s, 2H), 0.40 (s, 2H). Example 3: (R)-1-(2-chloro-5-(9-((4-((1-(((7-(8-ethyl-3-hydroxynaphthalen-1-yl)-8-fluoro-4-(3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperazin-1-yl)methyl)-3-azaspiro[5.5]undecane-3-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione Step 1: Preparation of (R)-1-(7-(8-ethyl-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-((1-(hydroxymethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol

[0689] [ka] To a solution of (R)-1-(7-chloro-8-fluoro-2-((1-(hydroxymethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (150 mg, 0.378 mmol) and 2-(8-ethyl-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (155 mg, 0.454 mmol) in 1,4-dioxane / HO (2.5 mL / 0.5 mL) was added cataCXium A Pd G3 (55 mg, 0.076 mmol) and cesium carbonate (370 mg, 1.134 mmol). The mixture was reacted at 80°C for 16 hours under nitrogen gas protection, quenched by adding water (10 mL), extracted with ethyl acetate (20 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 (DCM:MeOH = 10:1) to give (R)-1-(7-(8-ethyl-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-((1-(hydroxymethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol.

[0690] LC-MS: (ESI, m / z): [M+H] + = 577.2. Step 2: Preparation of (R)-1-(((7-(8-ethyl-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-4-(3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropane-1-formaldehyde

[0691] [ka] A solution of (R)-1-(7-(8-ethyl-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-((1-(hydroxymethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (150 mg, 0.26 mmol) in DCM (5 mL) was cooled to 0 ° C., Dess-Martin reagent (221 mg, 0.52 mmol) was added, and the mixture was allowed to react at room temperature for 0.5 hours. After completion of the reaction, the reaction was quenched by adding water (10 mL), extracted with dichloromethane (30 mL × 3), and 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=10:1) to give (R)-1-(((7-(8-ethyl-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-4-(3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropane-1-formaldehyde.

[0692] LC-MS: (ESI, m / z): [M+H] + = 575.2. Step 3: Preparation of (R)-1-(2-chloro-5-(9-((4-((1-(((7-(8-ethyl-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-4-(3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperazin-1-yl)methyl)-3-azaspiro[5.5]undecane-3-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione

[0693] [ka] To a stirred solution of (R)-1-(((7-(8-ethyl-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-4-(3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropane-1-formaldehyde (100 mg, 0.174 mmol) and 1-(2-chloro-5-(9-(piperazin-1-ylmethyl)-3-azaspiro[5.5]undecane-3-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione (105 mg, 0.209 mmol) in DCM (2 mL) was added tetraisopropyl titanate (495 mg, 1.74 mmol) and stirred at 30 °C for 2 h. The mixture was added with NaBH(OAc) (116 mg, 0.522 mmol) at room temperature and stirred for 2 hours. The mixture was concentrated and purified by silica gel column chromatography (MeOH:DCM = 0 to 1:4) to give (R)-1-(2-chloro-5-(9-(4-((1-((7-(8-ethyl-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-4-(3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperazin-1-yl)methyl)-3-azaspiro[5.5]undecane-3-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione.

[0694] LC-MS: (ESI, m / z): [M+H] + = 1060.4. Step 4: Preparation of (R)-1-(2-chloro-5-(9-((4-((1-(((7-(8-ethyl-3-hydroxynaphthalen-1-yl)-8-fluoro-4-(3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperazin-1-yl)methyl)-3-azaspiro[5.5]undecane-3-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione

[0695] [ka] A solution of (R)-1-(2-chloro-5-(9-(4-((1-((7-(8-ethyl-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-4-(3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperazin-1-yl)methyl)-3-azaspiro[5.5]undecane-3-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione (100 mg, 0.094 mmol) in 1,4-dioxane (2.0 mL) was added with HCl / 1,4-dioxane (6 N, 1.0 mL) and reacted at room temperature for 0.5 hours. The reaction mixture was adjusted to pH > 7 by the addition of aqueous NaCO solution and extracted with EtOAc (10 mL × 2). The organic phase was washed with brine, dried over anhydrous NaSO, and concentrated. The crude product was purified by preparative HPLC to give (R)-1-(2-chloro-5-(9-(4-((1-(((7-(8-ethyl-3-hydroxynaphthalen-1-yl)-8-fluoro-4-(3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperazin-1-yl)methyl)-3-azaspiro[5.5]undecane-3-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione.

[0696] LC-MS: (ESI, m / z): [M+H] + = 1016.2. 1H NMR (400 MHz, DMSO-d6) δ10.50 (s, 1H), 9.88 (d, J = 3.0 Hz, 1H), 9.20 (d, J = 6.4 Hz, 1H), 7.69 - 7.56 (m, 2H), 7.54 (d, J = 1.9 Hz, 1H), 7.40 - 7.33 (m, 2H), 7.28 (d, J = 2.5 Hz, 1H), 7.12 (d, J = 7.1 Hz, 1H), 6.97 (d, J = 2.6 Hz, 1H), 4.73 (d, J = 12.9 Hz, 1H), 4.36 - 4.25 (m, 3H), 4.08 - 3.96 (m, 1H), 3.80 - 3.69 (m, 1H), 3.67 - 3.47 (m, 4H), 3.30 - 3.21 (m, 2H), 2.78 - 2.65 (m, 2H), 2.44 - 2.13 (m, 12H), 2.07 - 1.96 (m, 3H), 1.74 - 1.62 (m, 5H), 1.55 - 1.22 (m, 8H), 1.17 (d, J = 11.1 Hz, 3H), 1.11 - 0.93 (m, 4H), 0.85 - 0.78 (m, 3H), 0.63 (s, 2H), 0.40 (s, 2H). Example 4: (R)-1-(2-chloro-5-(4-(3-(4-((1-(((7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-(3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperazin-1-yl)propyl)piperidine-1-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione Step 1: Preparation of (R)-1-(2-chloro-5-(4-(3-(4-((1-(((8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-4-(3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperazin-1-yl)propyl)piperidine-1-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione

[0697] [ka] To a solution of (R)-1-(((8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-4-(3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropane-1-formaldehyde (100 mg, 0.134 mmol) and 1-(2-chloro-5-(4-(3-(piperazin-1-yl)propyl)piperidine-1-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione (74 mg, 0.161 mmol) in DCM / AcOH (1.0 mL / 0.01 mL), tetraisopropyl titanate (190 mg, 0.67 mmol) was added and stirred at room temperature for 2 hours. To the mixture was added NaBH(OAc)3 (89 mg, 0.402 mmol) at 0° C. and stirred for 2 hours. The mixture was concentrated and purified by silica gel column chromatography (DCM:MeOH = 100:1 to 9:1) to give (R)-1-(2-chloro-5-(4-(3-(4-((1-(((8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-4-(3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperazin-1-yl)propyl)piperidine-1-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione.

[0698] LC-MS: (ESI, m / z): [M / 2+H] + = 595.9. Step 2: Preparation of (R)-1-(2-chloro-5-(4-(3-(4-((1-(((7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-(3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperazin-1-yl)propyl)piperidine-1-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione

[0699] [ka] To a stirred solution of (R)-1-(2-chloro-5-(4-(3-(4-((1-(((8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-4-(3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperazin-1-yl)propyl)piperidine-1-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione (70 mg, 0.059 mmol) in DMF (2 mL) was added cesium fluoride (45 mg, 0.295 mmol) and stirred at room temperature for 30 minutes. The mixture was extracted with ethyl acetate and water, and the organic phase was concentrated. The residual mixture was further added to 1,4-dioxane (1 mL) and a mixture of HCl / 1,4-dioxane (6 N, 0.5 mL) at room temperature and reacted for 0.5 h. Aqueous Na2CO3 solution was added to the reaction mixture to adjust the pH to > 7, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phase was washed with brine, dried over anhydrous Na2SO4, and concentrated. The crude product was purified by high performance liquid chromatography to give (R)-1-(2-chloro-5-(4-(3-(4-((1-(((7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-(3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperazin-1-yl)propyl)piperidine-1-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione.

[0700] LC-MS: (ESI, m / z): [M / 2+H] + = 495.7. 1H NMR (400 MHz, DMSO-d6) δ 10.49 (s, 1H), 10.15 (s, 1H), 9.12 (d, J = 66.1 Hz, 1H), 7.97 (dd, J = 9.2, 5.9 Hz, 1H), 7.62 (d, J = 8.2 Hz, 1H), 7.54 (d, J = 2.0 Hz, 1H), 7.46 (t, J = 9.0 Hz, 1H), 7.41 - 7.33 (m, 2H), 7.20 (dd, J = 17.2, 2.5 Hz, 1H), 4.73 (d, J = 30.7 Hz, 1H), 4.46 - 4.17 (m, 4H), 4.12 - 3.92 (m, 2H), 3.81 - 3.70 (m, 1H), 3.65 - 3.50 (m, 3H), 3.00 (s, 1H), 2.84 - 2.62 (m, 4H), 2.42 - 2.14 (m, 11H), 2.08 - 1.96 (m, 1H), 1.76 - 1.36 (m, 9H), 1.24 - 1.13 (m, 5H), 1.11 - 1.00 (m, 2H), 0.63 (s, 2H), 0.40 (s, 2H). Example 5: (R)-1-(2-chloro-5-(4-((2-(1-((1-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-(3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)ethoxy)methyl)piperidine-1-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione Step 1: Preparation of (R)-1-(2-chloro-5-(4-((2-(1-((1-(((7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-4-(3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)ethoxy)methyl)piperidine-1-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione

[0701] [ka] To a solution of (R)-1-(((7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-4-(3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropane-1-formaldehyde (40 mg, 0.067 mmol) and 1-(2-chloro-5-(4-((2-(piperidin-4-yl)ethoxy)methyl)piperidine-1-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione (38 mg, 0.08 mmol) in DCM (1 mL), tetraisopropyl titanate (95 mg, 0.335 mmol) was added and stirred at room temperature for 2 hours. To the mixture was added NaBH(OAc)3 (45 mg, 0.201 mmol) at 0° C. and stirred for 2 hours. The mixture was concentrated and purified by silica gel column chromatography (DCM:MeOH = 100:1 to 9:1) to give (R)-1-(2-chloro-5-(4-((2-(1-((1-(((7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-4-(3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)ethoxy)methyl)piperidine-1-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione.

[0702] LC-MS: (ESI, m / z): [M+H] + = 1053.5. Step 2: Preparation of (R)-1-(2-chloro-5-(4-((2-(1-((1-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-(3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)ethoxy)methyl)piperidine-1-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione

[0703] [ka] To a stirred solution of (R)-1-(2-chloro-5-(4-((2-(1-((1-((7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-4-(3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)ethoxy)methyl)piperidine-1-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione (40 mg, 0.038 mmol) in 1,4-dioxane (1.0 mL) was added HCl / 1,4-dioxane (6 N, 0.5 mL) and the mixture was allowed to react at room temperature for 0.5 hours. Aqueous NaCO solution was added to the reaction mixture, and the mixture was adjusted to pH > 7 and extracted with EtOAc (10 mL × 3). The organic phase was washed with brine, dried over anhydrous NaSO, and concentrated. The crude product was purified by high-performance liquid chromatography to give (R)-1-(2-chloro-5-(4-((2-(1-((1-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-(3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)ethoxy)methyl)piperidine-1-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione.

[0704] LC-MS: (ESI, m / z): [M+H] += 1009.1. 1 H NMR (400 MHz, DMSO-d6) δ 10.51 (s, 1H), 9.93 (s, 1H), 9.21 (s, 1H), 7.76 (dd, J = 9.0, 6.0 Hz, 1H), 7.63 (d, J = 8.2 Hz, 1H), 7.54 (d, J = 1.9 Hz, 1H), 7.38 - 7.31 (m, 3H), 7.02 (d, J = 2.5 Hz, 1H), 4.74 (d, J = 5.0 Hz, 1H), 4.50 - 4.23 (m, 4H), 4.03 (dd, J = 22.0, 13.2 Hz, 1H), 3.79 - 3.71 (m, 1H), 3.66 - 3.48 (m, 3H), 3.43 - 3.34 (m, 3H), 3.20 (d, J = 6.1 Hz, 2H), 3.03 (s, 1H), 2.94 - 2.84 (m, 2H), 2.78 - 2.66 (m, 3H), 2.38 - 1.93 (m, 6H), 1.83 - 1.52 (m, 10H), 1.42 - 1.33 (m, 2H), 1.26 - 1.22 (m, 1H), 1.16 (d, J = 9.8 Hz, 3H), 1.13 - 1.05 (m, 3H), 0.77 -0.68 (m, 3H), 0.67 - 0.59 (m, 2H), 0.44 - 0.34 (m, 2H). Example 6: (R)-1-(5-(9-((4-((1-(((7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-(3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperazin-1-yl)methyl)-3-azaspiro[5.5]undecane-3-carbonyl)-2-methylphenyl)dihydropyrimidine-2,4(1H,3H)-dione Step 1: Preparation of (R)-1-(5-(9-((4-((1-(((8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-4-(3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperazin-1-yl)methyl)-3-azaspiro[5.5]undecane-3-carbonyl)-2-methylphenyl)dihydropyrimidine-2,4(1H,3H)-dione

[0705] [ka] To a solution of (R)-1-(((8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-4-(3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropane-1-formaldehyde (100 mg, 0.134 mmol) and 1-(2-methyl-5-(9-(piperazin-1-ylmethyl)-3-azaspiro[5.5]undecane-3-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione (78 mg, 0.161 mmol) in DCM / AcOH (1.0 mL / 0.01 mL), tetraisopropyl titanate (190 mg, 0.67 mmol) was added and stirred at room temperature for 2 hours. To the mixture was added NaBH(OAc)3 (89 mg, 0.402 mmol) at 0 °C and stirred for 2 hours. The mixture was concentrated and purified by silica gel column chromatography (DCM:MeOH = 100:1 to 9:1) to give (R)-1-(5-(9-((4-((1-(((8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-4-(3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperazin-1-yl)methyl)-3-azaspiro[5.5]undecane-3-carbonyl)-2-methylphenyl)dihydropyrimidine-2,4(1H,3H)-dione.

[0706] LC-MS: (ESI, m / z): [M / 2+H] + = 605.9. Step 2: Preparation of (R)-1-(5-(9-((4-((1-(((7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-(3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperazin-1-yl)methyl)-3-azaspiro[5.5]undecane-3-carbonyl)-2-methylphenyl)dihydropyrimidine-2,4(1H,3H)-dione

[0707] [ka] To a stirred solution of (R)-1-(5-(9-((4-((1-(((8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-4-(3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperazin-1-yl)methyl)-3-azaspiro[5.5]undecane-3-carbonyl)-2-methylphenyl)dihydropyrimidine-2,4(1H,3H)-dione (80 mg, 0.066 mmol) in DMF (2 mL) was added cesium fluoride (58 mg, 0.385 mmol) and stirred at room temperature for 30 minutes. The mixture was extracted with EA and water, and the organic phase was concentrated. The residual mixture was further added to 1,4-dioxane (1 mL) and a mixture of HCl / 1,4-dioxane (6 N, 0.5 mL) at room temperature and reacted for 0.5 h. Aqueous Na2CO3 solution was added to the reaction mixture to adjust the pH to > 7, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phase was washed with brine, dried over anhydrous Na2SO4, and concentrated. The crude product was purified by high performance liquid chromatography to give (R)-1-(5-(9-((4-((1-(((7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-(3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperazin-1-yl)methyl)-3-azaspiro[5.5]undecane-3-carbonyl)-2-methylphenyl)dihydropyrimidine-2,4(1H,3H)-dione.

[0708] LC-MS: (ESI, m / z): [M+H] + = 1010.2. 1H NMR (400 MHz, DMSO-d6) δ 10.39 (s, 1H), 10.18 (s, 1H), 9.12 (d, J = 66.8 Hz, 1H), 7.98 (dd, J = 9.2, 6.0 Hz, 1H), 7.46 (t, J = 9.0 Hz, 1H), 7.39 (s, 1H), 7.35 - 7.28 (m, 2H), 7.26 - 7.17 (m, 2H), 4.76 (d, J = 29.8 Hz, 1H), 4.40 - 4.21 (m, 3H), 4.12 - 3.92 (m, 2H), 3.85 - 3.76 (m, 1H), 3.65 - 3.42 (m, 4H), 3.32 - 3.21 (m, 3H), 2.82 - 2.65 (m, 2H), 2.48 - 2.22 (m, 9H), 2.21 (s, 3H), 2.09 - 1.97 (m, 3H), 1.74 - 1.58 (m, 5H), 1.55 - 1.37 (m, 5H), 1.27 (d, J = 31.2 Hz, 3H), 1.16 (m, 3H), 1.11 - 0.95 (m, 4H), 0.67 - 0.59 (m, 2H), 0.44 - 0.34 (m, 2H). Example 7: (R)-1-(5-(9-((4-((1-(((7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-(3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperazin-1-yl)methyl)-3-azaspiro[5.5]undecane-3-carbonyl)-2-methoxyphenyl)dihydropyrimidine-2,4(1H,3H)-dione Step 1: Preparation of (R)-1-(5-(9-((4-((1-(((8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-4-(3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperazin-1-yl)methyl)-3-azaspiro[5.5]undecane-3-carbonyl)-2-methoxyphenyl)dihydropyrimidine-2,4(1H,3H)-dione

[0709] [ka] To a solution of (R)-1-(((8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-4-(3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropane-1-formaldehyde (100 mg, 0.134 mmol) and 1-(2-methoxy-5-(9-(piperazin-1-ylmethyl)-3-azaspiro[5.5]undecane-3-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione (80 mg, 0.161 mmol) in DCM / AcOH (1.0 mL / 0.01 mL), tetraisopropyl titanate (190 mg, 0.67 mmol) was added and stirred at room temperature for 2 hours. To the mixture was added NaBH(OAc)3 (89 mg, 0.402 mmol) at 0 °C and stirred for 2 hours. The mixture was concentrated and purified by silica gel column chromatography (DCM:MeOH = 100:1 to 9:1) to give (R)-1-(5-(9-((4-((1-(((8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-4-(3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperazin-1-yl)methyl)-3-azaspiro[5.5]undecane-3-carbonyl)-2-methoxyphenyl)dihydropyrimidine-2,4(1H,3H)-dione.

[0710] LC-MS: (ESI, m / z): [M / 2+H] + = 613.9. Step 2: Preparation of (R)-1-(5-(9-((4-((1-(((7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-(3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperazin-1-yl)methyl)-3-azaspiro[5.5]undecane-3-carbonyl)-2-methoxyphenyl)dihydropyrimidine-2,4(1H,3H)-dione

[0711] [ka] To a stirred solution of (R)-1-(5-(9-((4-((1-(((8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-4-(3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperazin-1-yl)methyl)-3-azaspiro[5.5]undecane-3-carbonyl)-2-methoxyphenyl)dihydropyrimidine-2,4(1H,3H)-dione (90 mg, 0.073 mmol) in DMF (2 mL) was added cesium fluoride (55 mg, 0.365 mmol) and stirred at room temperature for 30 minutes. The mixture was extracted with EA and water, and the organic phase was concentrated. The residual mixture was further added to 1,4-dioxane (1 mL) and a mixture of HCl / 1,4-dioxane (6 N, 0.5 mL) at room temperature and reacted for 0.5 h. Aqueous Na2CO3 solution was added to the reaction mixture to adjust the pH to > 7, and the mixture was 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 high performance liquid chromatography to give (R)-1-(5-(9-((4-((1-(((7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-(3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperazin-1-yl)methyl)-3-azaspiro[5.5]undecane-3-carbonyl)-2-methoxyphenyl)dihydropyrimidine-2,4(1H,3H)-dione.

[0712] LC-MS: (ESI, m / z): [M+H] + = 1026.2. 1H NMR (400 MHz, DMSO-d6) δ 10.32 (s, 1H), 10.15 (s, 1H), 9.12 (d, J = 65.7 Hz, 1H), 7.97 (dd, J = 9.2, 5.9 Hz, 1H), 7.46 (t, J = 9.0 Hz, 1H), 7.40 - 7.30 (m, 3H), 7.24 - 7.12 (m, 2H), 4.74 (d, J = 30.2 Hz, 1H), 4.40 - 4.22 (m, 3H), 4.12 - 3.91 (m, 2H), 3.84 (s, 3H), 3.65 - 3.36 (m, 7H), 2.68 (t, J = 6.5 Hz, 2H), 2.45 - 2.12 (m, 10H), 2.07 - 1.96 (m, 3H), 1.73 - 1.60 (m, 5H), 1.55 - 1.39 (m, 5H), 1.35 - 1.21 (m, 3H), 1.17 (d, J = 16.5 Hz, 3H), 1.10 - 0.92 (m, 4H), 0.67 - 0.59 (m, 2H), 0.44 - 0.34 (m, 2H). Example 8: (R)-1-(2-chloro-5-(4-((2-(1-((1-(((7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-(3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)ethoxy)methyl)piperidine-1-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione Step 1: Preparation of (R)-1-(2-chloro-5-(4-((2-(1-((1-(((8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-4-(3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)ethoxy)methyl)piperidine-1-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione

[0713] [ka] To a solution of (R)-1-(((8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-4-(3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropane-1-formaldehyde (100 mg, 0.134 mmol) and 1-(2-chloro-5-(4-((2-(piperidin-4-yl)ethoxy)methyl)piperidine-1-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione (77 mg, 0.161 mmol) in DCM / AcOH (1.0 mL / 0.01 mL), tetraisopropyl titanate (190 mg, 0.67 mmol) was added and stirred at room temperature for 2 hours. To the mixture was added NaBH(OAc)3 (89 mg, 0.402 mmol) at 0° C. and stirred for 2 hours. The mixture was concentrated and purified by silica gel column chromatography (DCM:MeOH = 100:1 to 9:1) to give (R)-1-(2-chloro-5-(4-((2-(1-((1-(((8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-4-(3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)ethoxy)methyl)piperidine-1-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione.

[0714] LC-MS: (ESI, m / z): [M / 2+H] + = 603.4. Step 2: Preparation of (R)-1-(2-chloro-5-(4-((2-(1-((1-(((7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-(3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)ethoxy)methyl)piperidine-1-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione

[0715] [ka] To a stirred solution of (R)-1-(2-chloro-5-(4-((2-(1-((1-(((8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-4-(3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)ethoxy)methyl)piperidine-1-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione (80 mg, 0.066 mmol) in DMF (2 mL) was added cesium fluoride (50 mg, 0.33 mmol) and stirred at room temperature for 30 minutes. The mixture was extracted with ethyl acetate and water, and the organic phase was concentrated. The residual mixture was further added to 1,4-dioxane (1 mL) and a mixture of HCl / 1,4-dioxane (6 N, 0.5 mL) at room temperature and reacted for 0.5 h. Aqueous Na2CO3 solution was added to the reaction mixture to adjust the pH to > 7, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phase was washed with brine, dried over anhydrous Na2SO4, and concentrated. The crude product was purified by high performance liquid chromatography to give (R)-1-(2-chloro-5-(4-((2-(1-((1-(((7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-(3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)ethoxy)methyl)piperidine-1-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione.

[0716] LC-MS: (ESI, m / z): [M+H] + = 1005.1 1H NMR (400 MHz, DMSO-d6) δ10.50 (s, 1H), 10.15 (s, 1H), 9.12 (d, J = 66.1 Hz, 1H), 7.97 (dd, J = 9.2, 5.9 Hz, 1H), 7.63 (d, J = 8.2 Hz, 1H), 7.53 (d, J = 1.9 Hz, 1H), 7.50 - 7.42 (m, 1H), 7.41 - 7.34 (m, 2H), 7.20 (dd, J = 17.0, 2.4 Hz, 1H), 4.74 (d, J = 30.2 Hz, 1H), 4.52 - 4.21 (m, 4H), 4.13 - 3.92 (m, 2H), 3.80 - 3.50 (m, 4H), 3.38 - 3.33 (m, 2H), 3.27 - 3.14 (m, 3H), 3.06 - 2.86 (m, 3H), 2.79 - 2.66 (m, 3H), 2.34 - 2.22 (m, 2H), 2.08 - 1.97 (m, 1H), 1.83 - 1.53 (m, 10H), 1.42 - 1.34 (m, 2H), 1.30 - 1.22(m, 2H), 1.20 - 1.13 (m, 3H), 1.12 - 1.05 (m, 3H), 0.67 - 0.59 (m, 2H), 0.44 - 0.34 (m, 2H). Example 9: (R)-1-(2-chloro-5-(9-(2-(4-((1-(((7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-(3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperazin-1-yl)ethyl)-3-azaspiro[5.5]undecane-3-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione Step 1: Preparation of 2-(3-azaspiro[5.5]undecan-9-yl)acetaldehyde

[0717] [ka] tert-Butyl 9-(2-oxoethyl)-3-azaspiro[5.5]undecane-3-carboxylate (250 mg, 0.85 mmol) was dissolved in DCM (2 mL), and then TFA (1 mL) was added. The mixture was stirred at room temperature for 1 hour. The reaction mixture was directly concentrated under reduced pressure to give 2-(3-azaspiro[5.5]undecan-9-yl)acetaldehyde. The crude product was used directly in the next step without further purification.

[0718] LC-MS: (ESI, m / z): [M+H] + = 196.2. Step 2: Preparation of 2-(3-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzoyl)-3-azaspiro[5.5]undecan-9-yl)acetaldehyde

[0719] [ka] To a solution of 2-(3-azaspiro[5.5]undecan-9-yl)acetaldehyde (150 mg, 0.77 mmol) in DMF (5 mL), DIEA (496 mg, 3.84 mmol) and 4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)pentafluorophenyl benzoate (334 mg, 0.77 mmol) were added, and the reaction mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. 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 (MeOH:DCM = 100:1 to 5:1) to give 2-(3-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzoyl)-3-azaspiro[5.5]undecan-9-yl)acetaldehyde.

[0720] LC-MS: (ESI, m / z): [M+H] + = 446.2. Step 3: Preparation of tert-butyl (R)-4-((1-(((8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-4-(3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperazine-1-carboxylate

[0721] [ka] To a solution of (R)-1-(((8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-4-(3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropane-1-formaldehyde (150 mg, 0.201 mmol) and tert-butyl piperazine-1-carboxylate (45 mg, 0.241 mmol) in DCM / AcOH (2.0 mL / 0.02 mL) was added tetraisopropyl titanate (286 mg, 1.005 mmol) and stirred at room temperature for 2 hours. To the mixture was added NaBH(OAc)3 (134 mg, 0.603 mmol) at 0 °C and stirred for 2 hours. The mixture was concentrated and purified by silica gel column chromatography (DCM:MeOH=100:1 to 9:1) to give tert-butyl (R)-4-((1-(((8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-4-(3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperazine-1-carboxylate.

[0722] LC-MS: (ESI, m / z): [M+H] + = 915.5. Step 4: Preparation of (R)-1-(8-fluoro-7-(7-fluoro-3-hydroxy-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((1-(piperazin-1-ylmethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol

[0723] [ka] To a solution of (R)-4-((1-(((8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-4-(3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperazine-1-carboxylate tert-butyl (120 mg, 0.131 mmol) in 1,4-dioxane (2 mL), a mixture of HCl / 1,4-dioxane (6 N, 1 mL) was added, and the mixture was reacted at room temperature for 1 hour. After completion of the reaction, saturated sodium carbonate solution was added to adjust the pH to >7, followed by extraction with ethyl acetate (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 (DCM:MeOH=9:1) to give (R)-1-(8-fluoro-7-(7-fluoro-3-hydroxy-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((1-(piperazin-1-ylmethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol.

[0724] LC-MS: (ESI, m / z): [M+H] + = 771.5. Step 5: Preparation of (R)-1-(2-chloro-5-(9-(2-(4-((1-(((8-fluoro-7-(7-fluoro-3-hydroxy-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-4-(3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperazin-1-yl)ethyl)-3-azaspiro[5.5]undecane-3-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione

[0725] [ka] To a stirred solution of (R)-1-(8-fluoro-7-(7-fluoro-3-hydroxy-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((1-(piperazin-1-ylmethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (75 mg, 0.097 mmol) and 2-(3-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzoyl)-3-azaspiro[5.5]undecan-9-yl)acetaldehyde (52 mg, 0.1116 mmol) in DCM (1 mL) / AcOH (0.1 mL) was added tetraisopropyl titanate (138 mg, 0.485 mmol) and stirred at 30 °C for 2 h. To the mixture was added NaBH(OAc)3 (65 mg, 0.291 mmol) at room temperature and stirred for 2 hours. After completion of the reaction, the mixture was concentrated and purified by silica gel column chromatography (DCM:MeOH = 1:0 to 4:1) to give (R)-1-(2-chloro-5-(9-(2-(4-((1-(((8-fluoro-7-(7-fluoro-3-hydroxy-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-4-(3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperazin-1-yl)ethyl)-3-azaspiro[5.5]undecane-3-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione.

[0726] LC-MS: (ESI, m / z): [1 / 2M+H] + = 600.9. Step 6: Preparation of (R)-1-(2-chloro-5-(9-(2-(4-((1-(((7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-(3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperazin-1-yl)ethyl)-3-azaspiro[5.5]undecane-3-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione

[0727] [ka] Cesium fluoride (44 mg, 0.29 mmol) was added to a stirred solution of (R)-1-(2-chloro-5-(9-(2-(4-((1-(((8-fluoro-7-(7-fluoro-3-hydroxy-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-4-(3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperazin-1-yl)ethyl)-3-azaspiro[5.5]undecane-3-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione (70 mg, 0.058 mmol) in DMF (2 mL), and the mixture was stirred at 40° C. for 60 minutes. The mixture was extracted with EA and water, and the combined organic phase was washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate and concentrated to give a crude product, which was purified by high-performance liquid chromatography to give (R)-1-(2-chloro-5-(9-(2-(4-((1-(((7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-(3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperazin-1-yl)ethyl)-3-azaspiro[5.5]undecane-3-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione.

[0728] LC-MS: (ESI, m / z): [M+H] + = 1044.2. 1H NMR (400 MHz, DMSO-d6) δ10.50 (s, 1H), 10.15 (s, 1H), 9.12 (d, J = 65.6 Hz, 1H), 7.97 (dd, J = 9.2, 6.0 Hz, 1H), 7.63 (d, J = 8.2 Hz, 1H), 7.54 (d, J = 1.9 Hz, 1H), 7.49 - 7.42 (m, 1H), 7.41 - 7.35 (m, 2H), 7.20 (dd, J = 17.1, 2.4 Hz, 1H), 4.74 (d, J = 30.3 Hz, 1H), 4.40 - 4.21 (m, 3H), 4.12 - 3.92 (m, 2H), 3.80 - 3.70 (m, 1H), 3.68 - 3.46 (m, 4H), 3.42 - 3.32 (m, 1H), 3.29 - 3.18 (m, 2H), 2.77 - 2.66 (m, 2H), 2.45 - 2.16 (m, 11H), 2.07 - 1.96 (m, 1H), 1.75 - 1.57 (m, 5H), 1.53 - 1.37 (s, 4H), 1.39 - 1.12 (m, 9H), 1.11 - 0.95 (m, 4H), 0.67 - 0.59 (m, 2H), 0.44 - 0.37 (m, 2H). Example 10: (R)-1-(2-chloro-5-(4-(2-((1-((1-(((7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-(3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)methoxy)ethyl)piperidine-1-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione Step 1: Preparation of tert-butyl 4-(2-((1-benzylpiperidin-4-yl)methoxy)ethyl)piperidine-1-carboxylate

[0729] [ka] To a mixture of tert-butyl 4-(2-(piperidin-4-ylmethoxy)ethyl)piperidine-1-carboxylate (100 mg, 0.31 mmol) and benzaldehyde (39 mg, 0.37 mmol) in 1,2-dichloroethane / methanol (0.5 mL / 0.5 mL) was added acetic acid (0.01 mL). The mixture was stirred at 30 °C for 1 hour. NaBHCN (39 mg, 0.62 mmol) was added at 0 °C, and the mixture was reacted at room temperature for 2 hours. After completion of the reaction, H2O (10 mL) was added and the mixture was extracted with ethyl acetate (30 mL x 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 tert-butyl 4-(2-((1-benzylpiperidin-4-yl)methoxy)ethyl)piperidine-1-carboxylate.

[0730] LC-MS: (ESI, m / z): [M+H] + = 417.3. Step 2: Preparation of 1-benzyl-4-((2-(piperidin-4-yl)ethoxy)methyl)piperidine

[0731] [ka] To a solution of tert-butyl 4-(2-((1-benzylpiperidin-4-yl)methoxy)ethyl)piperidine-1-carboxylate (100 mg, 0.24 mmol) in DCM (2 mL) was added TFA (1 mL). The mixture was stirred at room temperature for 1 hour, and the reaction mixture was directly concentrated under reduced pressure to give 1-benzyl-4-((2-(piperidin-4-yl)ethoxy)methyl)piperidine, which was used directly in the next reaction.

[0732] Step 3: Preparation of 1-(5-(4-(2-((1-benzylpiperidin-4-yl)methoxy)ethyl)piperidine-1-carbonyl)-2-chlorophenyl)dihydropyrimidine-2,4(1H,3H)-dione

[0733] [ka] 1-Benzyl-4-((2-(piperidin-4-yl)ethoxy)methyl)piperidine (100 mg, 0.32 mmol) was dissolved in DMSO (2 mL), and 4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)pentafluorophenyl benzoate (110 mg, 0.34 mmol) and DIEA (93 mg, 0.96 mmol) were added. The reaction mixture was stirred at room temperature for 2 hours. Water (20 mL) was added, and the mixture was extracted 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 purified by silica gel column chromatography (DCM:MeOH=100:1 to 5:1) to give 1-(5-(4-(2-((1-benzylpiperidin-4-yl)methoxy)ethyl)piperidine-1-carbonyl)-2-chlorophenyl)dihydropyrimidine-2,4(1H,3H)-dione.

[0734] LC-MS: (ESI, m / z): [M+H] + = 567.2. Step 4: Preparation of 1-(2-chloro-5-(4-(2-(piperidin-4-ylmethoxy)ethyl)piperidine-1-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione

[0735] [ka] 1-1-(5-(4-(2-((1-benzylpiperidin-4-yl)methoxy)ethyl)piperidine-1-carbonyl)-2-chlorophenyl)dihydropyrimidine-2,4(1H,3H)-dione (200 mg, 0.35 mmol) was dissolved in DCM (2 mL), and 1-chloroethyl chloroformate (150 mg, 1.05 mmol) and DIEA (90 mg, 0.7 mmol) were added. The mixture was reacted at room temperature for 30 minutes, concentrated under reduced pressure, and the concentrate was dissolved in MeOH (2 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(NH)=100:1 to 9:1) to obtain 1-(2-chloro-5-(4-(2-(piperidin-4-ylmethoxy)ethyl)piperidine-1-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione.

[0736] MS(ESI) m / z: [M+H] + = 477.3. Step 5: Preparation of (R)-1-(2-chloro-5-(4-(2-((1-((1-(((8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-4-(3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)methoxy)ethyl)piperidine-1-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione

[0737] [ka] To a solution of (R)-1-(((8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-4-(3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropane-1-formaldehyde (100 mg, 0.134 mmol) and 1-(2-chloro-5-(4-(2-(piperidin-4-ylmethoxy)ethyl)piperidine-1-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione (77 mg, 0.161 mmol) in DCM / AcOH (1.0 mL / 0.01 mL), tetraisopropyl titanate (190 mg, 0.67 mmol) was added and stirred at room temperature for 2 hours. To the mixture was added NaBH(OAc)3 (89 mg, 0.402 mmol) at 0° C. and stirred for 2 hours. The mixture was concentrated and purified by silica gel column chromatography (DCM:MeOH=100:1 to 9:1) to give (R)-1-(2-chloro-5-(4-(2-((1-((1-(((8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-4-(3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)methoxy)ethyl)piperidine-1-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione.

[0738] LC-MS: (ESI, m / z): [M / 2+H] + = 603.4. Step 6: Preparation of (R)-1-(2-chloro-5-(4-(2-((1-((1-(((7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-(3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)methoxy)ethyl)piperidine-1-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione

[0739] [ka] To a stirred solution of (R)-1-(2-chloro-5-(4-(2-((1-((1-(((8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-4-(3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)methoxy)ethyl)piperidine-1-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione (100 mg, 0.083 mmol) in DMF (2 mL) was added cesium fluoride (58 mg, 0.385 mmol) and stirred at room temperature for 30 minutes. The mixture was extracted with ethyl acetate and water, and the organic phase was concentrated. The residual mixture was further added to 1,4-dioxane (2 mL) and a mixture of HCl / 1,4-dioxane (6 N, 1 mL) at room temperature and reacted for 0.5 h. Aqueous Na2CO3 was added to the reaction mixture to adjust the pH to > 7, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phase was washed with brine, dried over anhydrous Na2SO4, and concentrated. The crude product was purified by high performance liquid chromatography to give (R)-1-(2-chloro-5-(4-(2-((1-((1-(((7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-(3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)methoxy)ethyl)piperidine-1-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione.

[0740] LC-MS: (ESI, m / z): [M / 2+H] + = 1005.1. 1H NMR (400 MHz, DMSO-d6) δ10.50 (s, 1H), 10.15 (s, 1H), 9.12 (d, J = 66.7 Hz, 1H), 7.97 (dd, J = 9.2, 5.9 Hz, 1H), 7.62 (d, J = 8.2 Hz, 1H), 7.53 (d, J = 1.9 Hz, 1H), 7.49 - 7.43 (t, J = 9.1 Hz, 1H), 7.41 - 7.33 (m, 2H), 7.20 (dd, J = 17.4, 2.4 Hz, 1H), 4.74 (d, J = 31.0 Hz, 1H), 4.49 - 4.20 (m, 4H), 4.13 - 3.92 (m, 2H), 3.81 - 3.70 (m, 1H), 3.68 - 3.43 (m, 3H), 3.38 - 3.33 (m, 2H), 3.32 - 3.23 (m, 2H), 3.14 (d, J = 6.1 Hz, 2H), 3.06 - 2.86 (m, 3H), 2.80 - 2.65 (m, 3H), 2.33 - 2.23 (m, 2H), 2.10 - 1.95 (m, 1H), 1.86 - 1.76 (m, 2H), 1.75 - 1.53 (m, 8H), 1.47 - 1.38 (m, 3H), 1.20 - 1.13 (m, 3H), 1.16 (d, J = 16.8 Hz, 3H), 0.69 - 0.56 (m, 2H), 0.43 - 0.34 (m, 2H). Example 11: (R)-1-(2-chloro-5-(9-((4-((1-(((7-(8-ethynyl-3-hydroxynaphthalen-1-yl)-8-fluoro-4-(3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperazin-1-yl)methyl)-3-azaspiro[5.5]undecane-3-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione Step 1: Preparation of (R)-1-(8-fluoro-2-((1-(hydroxymethyl)cyclopropyl)methoxy)-7-(3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol

[0741] [ka] To a solution of (R)-1-(7-chloro-8-fluoro-2-((1-(hydroxymethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (150 mg, 0.378 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, 【Chemistry 1】 where: K is K1 【Chemistry 2】 and K' is K2 【Transformation 3】 and 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, (NR 3a ) 2 , -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 alkynyl groups, 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, Each ring A1 is independently absent and C 6 -C 10 an aryl group, a 5- to 10-membered heteroaryl group, or a 5- to 10-membered heterocycloalkyl group; Each ring B is independently C 6 -C 15 Aryl groups, 5- to 15-membered heteroaryl groups, C 5 -C 15 is a cycloalkyl group or a 5- to 16-membered heterocycloalkyl group, 6 -C 15 Aryl groups, 5- to 15-membered heteroaryl groups, 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 Ring D is a 4- to 12-membered heterocycloalkyl group, said 4- to 12-membered heterocycloalkyl group optionally containing one or more R a and the 4- to 12-membered heterocycloalkyl group contains at least one heteroatom or heteroatom group selected from N, S, or O; Each R a are independently hydrogen, a hydroxy group, a halogen atom, a cyano group, -N(R 3a ) 1-2 , -CH 2 N (R 3a ) 1-2 , 3- to 8-membered heterocycloalkyl group, C 1 -C 6 Alkyl group, HC(=O)-, -CO 2 R 4a , -CON(R 4a ) 1-2 , C 1 -C 3 Alkoxy groups, (C 1 -C 3 Alkoxy)-C 1 -C 3 Alkyl-, C 1 -C 3 Alkyl-N(R 4a ) 1-2 , C 2 -C 4 Alkenyl group, C 2 -C 6 Alkynyl 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 6 Heteroalkyl groups, -O(C 1 -C 6 alkyl), -OC 1 -C 6 Heteroalkyl groups, -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 group, -O-pyridyl group, C 1 -C 3 Alkoxy group, C 2 -C 4 Alkenyl group, C 2 -C 6 Alkynyl 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 4 Alkyl group or C 1 -C 3 hydroxyalkyl groups, 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, each X 1 ' are independently a bond or -C(O)-; Each R 1 and each R 2 are independently hydrogen, 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, 1 -C 6 Alkyl group, C 3 -C 8 The cycloalkyl group or 3- to 8-membered heterocycloalkyl group may optionally contain one or more deuterium, halogen, hydroxy group, amino group, -C 1 -C 3 Alkyl group, -SC 1 -C 3 Alkyl group, -OC 1 -C 3 Alkyl group or -NH-C 1 -C 3 substituted with an alkyl group, n is 0, 1, 2, 3 or 4; L is a linking chain connecting K and E via a covalent bond, L is a linking chain that connects K′ and E via a covalent bond, wherein each E is independently E1, E2, or E3; 【Chemistry 4】 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, C 6 -C 10 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), 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 R 3b together with the atom to which it is attached 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, C 3 -C 8 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 a hydroxy group, a halogen, a cyano group, a hydroxy group, an amino group, or -OC(O)(C 1 -C 6 alkyl), 【Transformation 5】 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 - the phenyl group is optionally substituted with one or more hydroxy groups, halogens, cyano groups, 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 Selected from 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 cycloalkyl groups, 3- to 8-membered heterocycloalkyl groups, R ' and R '' are independently bond, hydrogen, deuterium, C 1 -C 6 Alkyl group, C 3 -C 8 Cycloalkyl groups, C 6 -C 10 selected from 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 6】 is a single or double bond, ----- is a bond, which may be an R stereoisomer, an S stereoisomer, or a non-stereoisomer; 【Transformation 7】 Here, in E3, X 1 , X 2 are each independently a bond, O, C(O), C(S), or NR 1d or CR 1d R 2d and R 1d , R 2d are independently H, deuterium, and C 1 -C 6 alkyl groups, 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 alkyl groups, 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 , -T-(C 6 -C 10 ) aryl group, -T-(5- to 10-membered) heteroaryl group, -T-(4- to 12-membered) heterocycloalkyl group, -NR 5d -T-(C 6 -C 10 ) aryl group, -NR 5d -T-(5- to 10-membered) heteroaryl group or -NR 5d -T-(4- to 12-membered) heterocycloalkyl group, 1 -C 6 Alkyl group, -TN(R 3d R 4d ), -TN(R 3d R 4d ) X 3 , -T-(C 6 -C 10 ) aryl group, -T-(5- to 10-membered) heteroaryl group, -T-(4- to 12-membered) heterocycloalkyl group, -NR 5d -T-(C 6 -C 10 ) aryl group, -NR 5d -T-(5- to 10-membered) heteroaryl group or -NR 5d -T-(4- to 12-membered)heterocycloalkyl 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 alkyl group, and 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】 is optionally replaced, R 6d , 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 substituted with an amino group, Compounds of Formula I or I', and / or their stereoisomers, enantiomers, diastereoisomers, atropisomers, deuterated forms, hydrates, solvates, prodrugs, and / or pharmaceutically acceptable salts thereof.

2. In formula I or I′, R 2a , R 3a , R a and R 4a wherein the definition of one or more groups in is further replaced by the definition below, with the proviso that L is linked to E via —C(O)—; R 2a is a mercapto group, (C 1 -C 3 Alkoxy) C 1 -C 3 Alkyl-, -OC 1 -C 6 Heteroalkyl groups, -OCOR 3a , -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 wherein the hydroxy groups independently optionally contain one or more deuterium 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 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 Heteroalkyl groups, -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 or -NH-C 1 -C 3 is an alkyl group, R a are independently a bond, deuterium, oxo, cyanomethyl group, C 1 -C 6 Heteroalkyl groups, -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, triazolyl group, -CH 2 C(=O)N(R 3a ) 2 or -C 3 -C 4 Alkynyl-N(R 3a ) 2 and 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 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 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 Alkynyl-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 1 -C 6 is an alkyl group, 2. A compound of formula I or I' according to claim 1, and / or its stereoisomers, enantiomers, diastereoisomers, atropisomers, deuterated forms, hydrates, solvates, prodrugs, and / or pharmaceutically acceptable salts thereof.

3. The K1 is K1-I or K1-II, and the K2 is K2-I; 【Chemistry 9】 Here, in the K1-I, Ring C is C 6 -C 15 Aryl groups, 5- to 10-membered heteroaryl groups, C 6 -C 15 a cycloalkyl group or a 5- to 10-membered heterocycloalkyl group, X' is a bond, C, O or N; Y' is C or N; 【Chemistry 10】 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), -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 is C 6 -C 10 an aryl group or a 5- to 10-membered heteroaryl group, 6 -C 10 The aryl group or 5- to 10-membered heteroaryl group may optionally be one or more R a' is replaced by Or, R 4e is a C together with the carbon atom connected to it. 6 -C 12 aryl group, 5- to 12-membered heteroaryl group, 6 -C 12 The aryl group, the 5- to 12-membered heteroaryl group, may optionally be H, deuterium, halogen, hydroxy group, amino group, C 1 -C 6 Alkyl group, S(C 1 -C 6 alkyl) or O(C 1 -C 6 alkyl), 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), -O(C 3 -C 8 cycloalkyl), R a' is a halogen, 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, -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' ) 2 , -N(R 5a' ) 2 , (C 1 -C 3 Alkoxy) C 1 -C 3 Alkyl-, C 3 -C 6 cycloalkyl groups, 3- to 6-membered heterocycloalkyl groups, wherein the hydroxy groups, 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, -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 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 alkyl) 3 is replaced by Each R 5a' are independently H, deuterium, or C 1 -C 6 is an alkyl group, Ring D is defined and described by claim 1 or 2, 【Chemistry 11】 Here, in the K1-II, Ring E is C 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 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'' wherein said heterocycloalkyl group contains at least one heteroatom which is N, S or O; Y″ is a 6- to 10-membered heterocycloalkyl group, C 6 -C 10 an 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 which is N, S, or O, and optionally R b''' is replaced by R b'' is hydrogen, oxo, 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 group, -CH 2 C(=O)N(R x' ) 2 , -C 3 -C 4 Alkynyl (NR x' ) 2 , -N(R x' ) 2 , -C 1 -C 3 Alkoxy-C 1 -C 3 alkyl-, wherein C 1 -C 6 Alkyl group, C 1 -C 6 Heteroalkyl groups, C 3 -C 6 Cycloalkyl groups, -OC 1 -C 6 Alkyl group, -SC 1 -C 3 Alkyl group, C 2 -C 4 Alkenyl group, C 2 -C 4 The alkynyl 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; Ring D is defined and described by claim 1 or 2, 【Chemistry 12】 Here, in the K2-I, Ring C is C 6 -C 10 Aryl groups, 5- to 10-membered heteroaryl groups, C 6 -C 10 a cycloalkyl group or a 5- to 10-membered heterocycloalkyl group, X' is a bond, C, O or N; Y' is C or N; 【Chemistry 13】 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), -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 is C 6 -C 10 an aryl group or a 5- to 10-membered heteroaryl group, 6 -C 10 The aryl group or 5- to 10-membered heteroaryl group may optionally be one or more R a' is replaced by Or, R 4e is a C together with the carbon atom connected to it. 6 -C 12 aryl group, 5- to 12-membered heteroaryl group, 6 -C 12 The aryl group, the 5- to 12-membered heteroaryl group, may optionally be H, deuterium, halogen, hydroxy group, amino group, C 1 -C 6 Alkyl group, -S(C 1 -C 6 alkyl) or -O(C 1 -C 6 alkyl), 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), -O(C 3 -C 8 cycloalkyl), R a' is a halogen, cyano group, hydroxy group, amino group, mercapto 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' ) 2 , -N(R 5a' ) 2 , (C 1 -C 3 Alkoxy) C 1 -C 3 Alkyl-, C 3 -C 6 cycloalkyl groups, 3- to 6-membered heterocycloalkyl groups, wherein the hydroxy groups, 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, -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 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 alkyl) 3 is replaced by Each R 5a' are independently H, deuterium, or C 1 -C 6 is an alkyl group, R 1 , R 2 is defined and described by claim 1, 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.

4. said K1 is K1-Ia or K1-II-a, or said K2 is K2-Ia; 【Chemistry 14】 where: r is 1 or 2; wherein ring C, ring D, and R of K1-Ia or K1-II-a 2e , R 3e , R 4e , R 5e , X', Y', R 1 , R 2 , Y″ and p are defined and described by claim 2; 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.

5. K1 is K1-I-a1, K1-I-a2, K1-I-a3, K1-I-a4, K1-I-a5, K1-I-a6, K1-I-a7, K1-II-a1, K1-II-a2, K1-II-a3, K1-II-a4 or K1-II-a5, or K2 is K2-I-a1; 【Chemistry 15】 Here, in the K1-I-a1, K1-I-a2, K1-I-a3, K1-I-a4, K1-I-a5, K1-I-a6 or K1-I-a7, R 1a' is hydrogen, hydroxyl group, halogen, cyano group, amino group, C 1 -C 6 Alkyl group, C 3 -C 8 Cycloalkyl groups, HC(=O)-, -CO 2 R 5a' , -CON(R 5a' ) 1-2 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, Or, two R's 5a' together with the N atom to which they are attached form a 4- to 8-membered heterocycloalkyl group, said 4- to 8-membered heterocycloalkyl group containing one or more N, O, S heteroatoms or heteroatomic groups; W 1 is CH 2 , O, NH or S; m is 0, 1, 2 or 3; where R 3e , R 4e , R 5e , X' and Y' are defined and described by K1-Ia of claim 3; 【Chemistry 16】 Here, in the above K1-II-a1, K1-II-a2, K1-II-a3, K1-II-a4 or K1-II-a5, 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' , -CON(R 5a' ) 1-2 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, Or, two R's 5a' together with the N atom to which they are attached form a 4- to 8-membered heterocycloalkyl group, said 4- to 8-membered heterocycloalkyl group containing one or more N, O, S heteroatoms or heteroatomic groups; R 4a' 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 optionally contains one or more R 8a' may be substituted with 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, 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, W 1 is CH 2 , O, NH or S; m is 0, 1, 2 or 3; Y'' is defined and described by claim 3; 【Chemistry 17】 Here, in the K2-I-a1, R 3e , R 4e , R 5e , X', Y', R 1 and R 2 is defined and described by claim 3, 5. A 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.

6. said K1 is K1-I-a1, or said K2 is K2-I-a1; [Chemistry 18] 、 wherein in K1-I-a1, X' is C or N, and Y' is C; R 3e is H or absent, R 4e is C 6 -C 10 an aryl group or a 5- to 10-membered heteroaryl group, 6 -C 10 The aryl group or 5- to 10-membered heteroaryl group may optionally be one or more R a' is replaced by R a' are independently a halogen, a hydroxyl group, C 1 -C 6 Alkyl group, C 2 -C 6 Alkynyl group or C 3 -C 6 cycloalkyl groups, R 5e is a halogen, R 1a' is hydrogen, hydroxyl group, NH 2 , halogen or C 1 -C 6 is an alkyl group, W 1 is CH 2 or O, m is 0, 1, 2 or 3; 【Chemistry 19】 、 wherein in K2-I-a1, X' is C or N, and Y' is C; R 3e is H or absent, R 4e is C 6 -C 10 an aryl group or a 5- to 10-membered heteroaryl group, 6 -C 10 The aryl group or 5- to 10-membered heteroaryl group may optionally be one or more R a' is replaced by R a' are independently a halogen, a hydroxyl group, C 1 -C 6 Alkyl group, C 2 -C 6 Alkynyl group or C 3 -C 6 cycloalkyl groups, R 5e is a halogen, R 1 and R 2 are independently hydrogen, C 1 -C 6 Alkyl group or C 3 -C 8 is a cycloalkyl group, 1 -C 6 Alkyl group or C 3 -C 8 The cycloalkyl group is optionally substituted with one or more halogen, hydroxy or amino groups.

6. A 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.

7. Structural Unit 【Chemistry 20】 teeth, 【Chemistry 21】 and the structural unit 【Chemistry 22】 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), -N(C 1 -C 6 alkyl) 1-2 , -N(C 3 -C 8 cycloalkyl) 1-2 is replaced by 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.

8. Ring A1 is C 6 -C 15 an aryl group or a 5- to 15-membered heteroaryl group, 6 -C 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, -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 23】 or -SCH 3 and wherein the —CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , 【Chemistry 24】 or -SCH 3 is optionally a halogen, CN, -OH, -NH 2 or C 1 -C 3 substituted with an alkyl group, 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.

9. Structural Unit 【Chemistry 25】 teeth, 【Chemistry 26】 and the structural unit 【Chemistry 27】 optionally 1, 2 or 3 R a is replaced by 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.

10. Structural Unit 【Chemistry 28】 teeth, 【Chemistry 29】 【change】 and the structural unit 【Transformation 30】 optionally 1, 2 or 3 R a is replaced by 10. A compound of formula I or I' according to claim 9, and / or its stereoisomers, enantiomers, diastereoisomers, atropisomers, deuterated forms, hydrates, solvates, prodrugs, and / or pharmaceutically acceptable salts thereof.

11. Structural Unit 【Chemistry 31】 、 【Chemistry 32】 【change】 and the structural unit 【Transformation 33】 optionally 1, 2 or 3 R a is replaced by 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.

12. Structural Unit 【Transformation 34】 teeth, 【Chemistry 35】 【change】 【change】 That is, 12. A compound of formula I or I' according to claim 11, and / or its stereoisomers, enantiomers, diastereoisomers, atropisomers, deuterated forms, hydrates, solvates, prodrugs, and / or pharmaceutically acceptable salts thereof.

13. Structural Unit 【Transformation 36】 teeth, 【Chemistry 37】 That is, 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.

14. Structural Unit 【Transformation 38】 teeth, 【Chemistry 39】 【change】 【change】 【change】 【change】 That is, 13. A compound of formula I or I' according to claim 12, and / or its stereoisomers, enantiomers, diastereoisomers, atropisomers, deuterated forms, hydrates, solvates, prodrugs, and / or pharmaceutically acceptable salts thereof.

15. Structural Unit 【Chemistry 40】 teeth, 【Chemistry 41】 That is, 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.

16. Structural Unit 【Chemistry 42】 teeth, 【Chemistry 43】 and the structural unit 【Chemistry 44】 optionally one or more of deuterium, F, Cl, Br, a hydroxy group, an amino group, -CH 3 or -S-CH 3 is replaced by 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.

17. Structural Unit 【Chemistry 45】 teeth, 【Chemistry 46】 That is, 17. A 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.

18. Structural Unit 【Chemistry 47】 teeth, 【Chemistry 48】 and the structural unit 【Chemistry 49】 optionally one or more of deuterium, F, Cl, Br, a hydroxy group, an amino group, -CH 3 or -S-CH 3 is replaced by 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.

19. Structural Unit [Transformation 50] teeth, 【Chemistry 51】 That is, 19. A compound of formula I or I' according to claim 18, and / or its stereoisomers, enantiomers, diastereoisomers, atropisomers, deuterated forms, hydrates, solvates, prodrugs, and / or pharmaceutically acceptable salts thereof.

20. wherein L is -(CH 2 ) j -, wherein -(CH 2 ) j One or more methylene groups in - are optionally represented by -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 being nitrogen, oxygen or sulfur, 5 to 11-membered saturated or partially unsaturated spiroheterocycloalkylene group having 1 to 2 heteroatoms independently being nitrogen, oxygen or sulfur, 5 to 11-membered saturated or partially unsaturated fused heterocycloalkylene group having 1 to 2 heteroatoms independently being nitrogen, oxygen or sulfur. a cycloalkylene group, an 8- to 10-membered bicyclic saturated or partially unsaturated heterocycloalkylene group having 1 to 2 heteroatoms independently of each other, nitrogen, oxygen, or sulfur, a 5- to 6-membered heteroarylene group having 1 to 4 heteroatoms independently of each other, nitrogen, oxygen, or sulfur, or an 8- to 10-membered bicyclic heteroaryl group having 1 to 5 heteroatoms independently of each other, nitrogen, oxygen, or sulfur, wherein the vinylidene group, ethynylene group, cycloalkylene group, heterocycloalkylene group, phenyl group, spiroheterocycloalkylene group, fused heterocycloalkylene group, spirocycloalkylene group, fused cycloalkylene group, and heteroarylene group each independently optionally contain one or more halogen atoms, 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 The alkyl, cycloalkyl, and heterocycloalkyl groups are optionally substituted with one or more halogen atoms, -OH, -NH 2 , -CN, C 1 -C 4 Alkyl group, C 3 -C 6 substituted with a substituent that is a cycloalkyl group, 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; 20. 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.

21. The L is 【Chemistry 52】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 That is, 21. A compound of formula I or I' according to claim 20, and / or its stereoisomers, enantiomers, diastereoisomers, atropisomers, deuterated forms, hydrates, solvates, prodrugs, and / or pharmaceutically acceptable salts thereof.

22. wherein L is LA; 【Chemistry 53】 Here, the LA is (1) The ring U is C 3 -C 12 a cycloalkylene group or a 3- to 12-membered heterocycloalkylene group containing 1 to 2 heteroatoms which are N, O or S, and the cycloalkylene and heterocycloalkylene groups 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), 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 which are N, O or S, and the cycloalkylene and heterocycloalkylene groups 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-、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)-, and k is 1, 2, 3, 4, 5, 6, 7, or 8; (2) The ring U is C 3 -C 12 a cycloalkylene group or a 3- to 12-membered heterocycloalkylene group containing 1 to 3 heteroatoms that are N, O, or S, and the cycloalkylene and heterocycloalkylene groups 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), 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 which are N, O or S, and the cycloalkylene and heterocycloalkylene groups 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-、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 each independently H, -OH, or -NH 2 , C 1 -C 6 Haloalkyl group, 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)-, and k is 1, 2, 3, 4, 5, 6, 7, or 8; 20. 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.

23. In the above 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, or a 7- to 11-membered spiroheterocycloalkylene group; 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; and X″ is a bond, —C(O)CH 2 -O- 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; 23. A compound of formula I or I' according to claim 22, and / or its stereoisomers, enantiomers, diastereoisomers, atropisomers, deuterated forms, hydrates, solvates, prodrugs, and / or pharmaceutically acceptable salts thereof.

24. The LA is LA-1 or LA-2, 【Chemistry 54】 X'' is -C(O)-, -C(O)NH- or -C(O)CH 2 O-, wherein in LA-1 and LA-2, the ring U, the ring Y, Lx, Ly, and q are defined and described by claim 22; 23. A compound of formula I or I' according to claim 22, and / or its stereoisomers, enantiomers, diastereoisomers, atropisomers, deuterated forms, hydrates, solvates, prodrugs, and / or pharmaceutically acceptable salts thereof.

25. the LA is LA-3, LA-4, LA-5 or LA-6; 【Transformation 55】 Here, in the LA-3, Lx is a bond, 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, 【Transformation 56】 , -C(CH 3 ) 2 -, -CH(CH 3 )-, -CH(OH)-, -CH(OCH 3 )- or C(CH 3 )(OH)—, and v is 1, 2, 3, 4, 5, or 6; Ring U is 【Chemistry 57】 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, 【Transformation 58】 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 -(CH 2 ) k -, wherein one or two CH contained in said Ly 2 are each independently optionally -O-, -C≡C, 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- 【Chemistry 59】 Here, in the LA-4, 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, 【Transformation 60】 , -C(CH 3 ) 2 -, -CH(CH 3 )-, -CH(OCH 3 )-, -CH(OH)- or -C(CH 3 )(OH)—, and v is 1, 2, 3, 4, 5, or 6; Ring U is 【Chemistry 61】 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 【Transformation 62】 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 -(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)-; 【Transformation 63】 Here, in the LA-5, 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 64】 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-; 【Transformation 65】 Here, in the LA-6, 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 Formula 66】 and v is 1, 2, 3 or 4; Ring U is 【Transformation 67】 wherein the a-terminus is linked to Lx and the b-terminus is linked to Ly; Ring Y is 【Transformation 68】 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; X'' is a bond, 23. A compound of formula I or I' according to claim 22, and / or its stereoisomers, enantiomers, diastereoisomers, atropisomers, deuterated forms, hydrates, solvates, prodrugs, and / or pharmaceutically acceptable salts thereof.

26. the LA is LA-7, LA-8, LA-9, LA-10, LA-11 or LA-12; 【Transformation 69】 Here, in the LA-7, 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, 【Transformation 70】 , -C(CH 3 ) 2 -, -CH(CH 3 )-, -CH(OH)-, -CH(OCH 3 )- or C(CH 3 )(OH)—, and v is 1, 2, 3, 4, 5, or 6; Ring U is 【Chemistry 71】 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, 【Chemistry 72】 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 -(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)-, -CH 2 -C≡C-, -C(O)CH 2 O- or -(CH 2 ) 1-2 C(O)NH- 【Transformation 73】 Here, in the LA-8, 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, 【Chemistry 74】 , -C(CH 3 ) 2 -, -CH(CH 3 )-, -CH(OCH 3 )-, -CH(OH)-, -C(CH 3 )(OH)-, -CH(CHF 2 ) -, -CH(CH(CH 3 ) 2 ) -, -CH(CH 2 CF 3 )- or -CH(NH 2 )-, and v is 1, 2, 3, 4, 5, or 6; Ring U is 【Chemistry 75】 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 selected from F, a cyano group, C 1-6 Alkyl group or C 1 -C 6 substituted with a hydroxyalkyl group, Ring Y is 【Transformation 76】 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 -(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)-; 【Chemical 77】 Here, in the LA-9, 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, 【Transformation 78】 and v is 1, 2, 3, 4, 5 or 6; Ring U is 【Chemistry 79】 wherein the a-terminus is linked to Lx and the b-terminus is linked to Ly; Ring Y is 【Chemistry 80】 where the c-terminus is linked to Ly and the d-terminus is linked to X″; Ly is -(CH 2 ) k -, wherein one or two CH contained in said Ly 2 are each independently optionally -O-, -C≡C- or -N(C 1 -C 6 substituted with (alkyl)-, and k is 1, 2, 3, 4, 5, or 6; X'' is -C(O)-; 【Chemistry 81】 Here, in the LA-10, 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, 【Chemistry 82】 , -CH(CH 3 )-, -CH(OCH 3 )-, -CH(OH)- or -CH(NH 2 )-, and v is 1, 2, 3, 4, 5, or 6; Ring U is 【Chemistry 83】 wherein the a-terminus is linked to Lx and the b-terminus is linked to Ly; Ring Y is 【Chemical 84】 where the c-terminus is linked to Ly and the d-terminus is linked to X″; Ly is -(CH 2 ) k and k is 1, 2, 3, 4, 5 or 6; X'' is -C(O)-; 【Chemical 85】 Here, in the LA-11, 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 86】 and v is 1, 2, 3, 4, 5 or 6; Ring U is 【Transformation 87】 wherein the a-terminus is linked to Lx and the b-terminus is linked to Ly; Ring Y is 【Chemical 88】 where the c-terminus is linked to Ly and the d-terminus is linked to X″; Ly is -(CH 2 ) k -, wherein one or two CH contained in said Ly 2 are each independently optionally substituted with —O— or —C≡C—; and k is 1, 2, 3, 4, 5, or 6; X'' is -C(O)-; 【Chemical 89】 Here, in the LA-12, 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, 【Chemistry 90】 or -CH(CH 3 )-, and v is 1, 2, 3, 4, 5, or 6; Ring U is 【Chemistry 91】 wherein the a-terminus is linked to Lx and the b-terminus is linked to Ly; Ring Y is 【Chemistry 92】 where the c-terminus is linked to Ly and the d-terminus is linked to X″; Ly is -(CH 2 ) k and k is 1, 2, 3, 4, 5 or 6; X'' is -C(O)-; 23. A compound of formula I or I' according to claim 22, and / or its stereoisomers, enantiomers, diastereoisomers, atropisomers, deuterated forms, hydrates, solvates, prodrugs, and / or pharmaceutically acceptable salts thereof.

27. The LA has one of the following structures: 【Chemistry 93】 【change】 【change】 【change】 【change】 【change】 【change】 That is, 26. A compound of formula I or I' according to claim 22 or 25, and / or its stereoisomers, enantiomers, diastereoisomers, atropisomers, deuterated forms, hydrates, solvates, prodrugs, and / or pharmaceutically acceptable salts thereof.

28. The LA has one of the following structures: 【Chemical 94】 【change】 That is, 27. A compound of formula I or I' according to claim 22 or 26, and / or its stereoisomers, enantiomers, diastereoisomers, atropisomers, deuterated forms, hydrates, solvates, prodrugs, and / or pharmaceutically acceptable salts thereof.

29. wherein 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; 【Chemical 95】 Here, the Q 1 , Q 2 , Q 3 , Q 4 , Q 5 , R 1b , R 2b , R 3b , m″ is defined and described by claim 1; 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.

30. wherein E1 has a structure of formula E1-1h'', E1-1i', E1-1j' or E1-1h'h'; 【Chemistry 96】 where R 3b is defined by claim 24, 30. A compound of formula I or I' according to claim 29, and / or its stereoisomers, enantiomers, diastereoisomers, atropisomers, deuterated forms, hydrates, solvates, prodrugs, and / or pharmaceutically acceptable salts thereof.

31. R 3b represents 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), and 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 31. A compound of formula I or I' according to any one of claims 29 or 30, and / or its stereoisomers, enantiomers, diastereoisomers, atropisomers, deuterated forms, hydrates, solvates, prodrugs, and / or pharmaceutically acceptable salts thereof.

32. wherein E1 has the structure of formula E1-1h″; 【Chemistry 97】 、 where R 3b are independently hydrogen, halogen, or C 1 -C 6 Alkyl group or -O(C 1 -C 6 alkyl), and 1 -C 6 Alkyl groups and -O(C 1 -C 6 alkyl) optionally containing deuterium, halogen, cyano group, —OH or —NH 2 and the number of substitutions is 1, 2 or 3.

30. A compound of formula I or I' according to claim 29, and / or its stereoisomers, enantiomers, diastereoisomers, atropisomers, deuterated forms, hydrates, solvates, prodrugs, and / or pharmaceutically acceptable salts thereof.

33. The E1 is 【Chem.98】 【change】 That is, 31. A compound of formula I or I' according to claim 30, and / or its stereoisomers, enantiomers, diastereoisomers, atropisomers, deuterated forms, hydrates, solvates, prodrugs, and / or pharmaceutically acceptable salts thereof.

34. The E1 is 【Chem.99】 That is, 33. A compound of formula I or I' according to claim 32, and / or its stereoisomers, enantiomers, diastereoisomers, atropisomers, deuterated forms, hydrates, solvates, prodrugs, and / or pharmaceutically acceptable salts thereof.

35. wherein E2 has the structure of formula E2-1a, E2-1b, E2-1c, E2-1d, E2-1e, or E2-1f; 【Chemistry 100】 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, N-(C 1 -C 6 ) alkyl group, N-(C 6 -C 10 ) aryl group, N-(5- to 10-membered) heteroaryl group, N-(C 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 each independently CR 3b or N, 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 '' , -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 and 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, ----- is a bond, which may be an R stereoisomer, an S stereoisomer, or a non-stereoisomer; where R 3b is as described or defined by claim 1 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.

36. said E2 having the structure of formula E2-1bb, E2-1aa, or E2-1cc; 【Chemistry 101】 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 group, halogen, cyano group, -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, ----- is a bond, which may be an R stereoisomer, an S stereoisomer, or a non-stereoisomer; where R 3b is described and defined by claim 1, 【Chemical Engineering 102】 Here, the E2-1aa and E2-1aa are W is CH 2 or C(O), A' is hydrogen, a methyl group, Cl or F; R 3c are each independently hydrogen, a hydroxyl group, or NH 2 , C 1 -C 6 Alkyl group or C 1 -C 6 is an alkoxy group, n '' is 0, 1, 2 or 3, ----- is a bond, which may be an R stereoisomer, an S stereoisomer or a non-stereoisomer; 36. A compound of formula I or I' according to claim 35, and / or its stereoisomers, enantiomers, diastereoisomers, atropisomers, deuterated forms, hydrates, solvates, prodrugs, and / or pharmaceutically acceptable salts thereof.

37. The E2 is 【Chemistry 103】 【change】 【change】 【change】 【change】 【change】 That is, 36. A compound of formula I or I' according to claim 35, and / or its stereoisomers, enantiomers, diastereoisomers, atropisomers, deuterated forms, hydrates, solvates, prodrugs, and / or pharmaceutically acceptable salts thereof.

38. wherein E3 has the structure of formula E3-1: 【Chemical 104】 W 3 is C 6 -C 10 an aryl group, a 5- to 10-membered heteroaryl group, or 【Chemistry 105】 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 a cycloalkyl group or a 5- to 10-membered heteroaryl group, 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 106】 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 , R 15 is as described and defined by claim 1, 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.

39. wherein E3 has the structure of formula E3-1a, E3-1b, or E3-1c, 【Chemistry 107】 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; 39. A compound of formula I or I' according to claim 38, and / or its stereoisomers, enantiomers, diastereoisomers, atropisomers, deuterated forms, hydrates, solvates, prodrugs, and / or pharmaceutically acceptable salts thereof.

40. said E3 having the structure of formula E3-1aa: 【Chemistry 108】 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 109】 or a 5- to 10-membered heteroaryl group, said 5- to 10-membered heteroaryl group optionally containing one or more of -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 , 【Chemical 110】 That is, 40. A compound of formula I or I' according to any one of claims 1, 2, 38 or 39, and / or its stereoisomers, enantiomers, diastereoisomers, atropisomers, deuterated forms, hydrates, solvates, prodrugs, and / or pharmaceutically acceptable salts thereof.

41. The E3 is 【Chemistry 111】 【change】 That is, A compound of formula I or I' according to any one of claims 1, 2, 38 to 40, and / or its stereoisomers, enantiomers, diastereoisomers, atropisomers, deuterated forms, hydrates, solvates, prodrugs, and / or pharmaceutically acceptable salts thereof.

42. The E3 is 【Chemistry 112】 【change】 That is, 42. A compound of formula I or I' according to claim 41, and / or its stereoisomers, enantiomers, diastereoisomers, atropisomers, deuterated forms, hydrates, solvates, prodrugs, and / or pharmaceutically acceptable salts thereof.

43. The compound of formula I or I' is (1) K is K1-I-a1, or K' is K2-I-a1; 【Chemistry 113】 、 wherein in K1-I-a1, X' is C or N, and Y' is C; R 3e is H or absent, R 4e is C 6 -C 10 an aryl group or a 5- to 10-membered heteroaryl group, 6 -C 10 The aryl group or 5- to 10-membered heteroaryl group may optionally be one or more R a' is replaced by R a' are independently a halogen, a hydroxyl group, C 1 -C 6 Alkyl group, C 2 -C 6 Alkynyl group or C 3 -C 6 cycloalkyl groups, R 5e is a halogen, R 1a' is hydrogen, hydroxyl group, NH 2 , halogen or C 1 -C 6 is an alkyl group, W 1 is CH 2 or O, m is 0, 1, 2 or 3; 【Chemical 114】 、 wherein in K2-I-a1, X' is C or N, and Y' is C; R 3e is H or absent, R 4e is C 6 -C 10 an aryl group or a 5- to 10-membered heteroaryl group, 6 -C 10 The aryl group or 5- to 10-membered heteroaryl group may optionally be one or more R a' is replaced by R a' are independently a halogen, a hydroxyl group, C 1 -C 6 Alkyl group, C 2 -C 6 Alkynyl group or C 3 -C 6 cycloalkyl groups, R 5e is a halogen, R 1 and R 2 are independently hydrogen, C 1 -C 6 Alkyl group or C 3 -C 8 is a cycloalkyl group, 1 -C 6 Alkyl group or C 3 -C 8 the cycloalkyl group is optionally substituted with one or more halogen, hydroxy or amino groups; L is LA-9 or LA-10, 【Chemical 115】 Here, in the LA-9, 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, 【Chemistry 116】 and v is 1, 2, 3, 4, 5 or 6; Ring U is 【Chemistry 117】 wherein the a-terminus is linked to Lx and the b-terminus is linked to Ly; Ring Y is 【Chemistry 118】 where the c-terminus is linked to Ly and the d-terminus is linked to X″; Ly is -(CH 2 ) k -, wherein one or two CH contained in said Ly 2 are each independently optionally -O-, -C≡C- or -N(C 1 -C 6 substituted with (alkyl)-, and k is 1, 2, 3, 4, 5, or 6; X'' is -C(O)-; 【Chemical 119】 Here, in the LA-10, 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 120】 , -CH(CH 3 )-, -CH(OCH 3 )-, -CH(OH)- or -CH(NH 2 )-, and v is 1, 2, 3, 4, 5, or 6; Ring U is 【Chemistry 121】 wherein the a-terminus is linked to Lx and the b-terminus is linked to Ly; Ring Y is 【Chemistry 122】 where the c-terminus is linked to Ly and the d-terminus is linked to X″; Ly is -(CH 2 ) k and k is 1, 2, 3, 4, 5 or 6; X'' is -C(O)-; E is E1-1h″ or E2-1aa, 【Chemical 123】 、 Here, in the E1-1h″, R 3b are independently hydrogen, halogen, or C 1 -C 6 Alkyl group or -O(C 1 -C 6 alkyl), and 1 -C 6 Alkyl groups and -O(C 1 -C 6 alkyl) optionally containing deuterium, halogen, cyano group, —OH or —NH 2 and the number of substitutions is 1, 2 or 3; 【Chemistry 124】 、 wherein, in said E2-1aa, W is CH 2 or C(O), A' is hydrogen, a methyl group, Cl or F; R 3c are each independently hydrogen, a hydroxyl group, or NH 2 , C 1 -C 6 Alkyl group or C 1 -C 6 selected from alkoxy groups, n '' is 1, 2, 3 or 4, ----- is a bond, which is an R stereoisomer, an S stereoisomer, or a non-stereoisomer; (2) The compound of formula I or I' is the following compound: 【Chemistry 125】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 It satisfies one of the following conditions: 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.

44. 1. A pharmaceutical composition comprising:

44. A compound according to any one of claims 1 to 43, and / or its stereoisomers, enantiomers, diastereoisomers, atropisomers, deuterated forms, hydrates, solvates, prodrugs, and / or pharmaceutically acceptable salts thereof, together with a pharmaceutically acceptable carrier, diluent or excipient. A pharmaceutical composition comprising:

45. The application of substance X in the manufacture of a drug, the substance X is a compound according to any one of claims 1 to 43, and / or a stereoisomer, enantiomer, diastereoisomer, atropisomer, deuterated product, hydrate, solvate, prodrug, and / or pharmaceutically acceptable salt thereof, or the use of a pharmaceutical composition according to claim 44 in the manufacture of a medicament for treating and / or preventing a KRAS-mediated disease or condition, or cancer; An application of substance X characterized by:

46. The cancer is Heart: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma, Lung: Bronchial cancer (squamous cell carcinoma, undifferentiated small cell carcinoma, undifferentiated large cell carcinoma, adenocarcinoma), alveolar carcinoma (bronchiolar carcinoma), bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma, lung cancer, small cell lung cancer, 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), appendix cancer, gastrointestinal neuroendocrine tumor, esophageal cancer and gastric cancer, anal cancer, gastrointestinal stromal tumor, 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), germ cell tumor, bladder cancer, prostate cancer, Liver: liver cancer (hepatocellular carcinoma), small hepatic bile duct carcinoma, hepatoblastoma, malignant hemangioendothelial tumor, hepatocellular adenoma, hemangioma, Biliary tract: cholangiocarcinoma, gallbladder cancer, ampullary cancer, small hepatic bile duct cancer, hepatocholangiocarcinoma, 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, bone cancer, 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), cervical cancer, endometrioid carcinoma, 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, skin cancer, non-melanoma, Adrenal gland: selected from neuroblastoma, 46. ​​The application of claim 45.

47. the cancer is a cancer associated with a KRAS G12A, KRAS G12C, KRAS G12D, KRAS G12R, KRAS G12S, KRAS G12V, KRAS G13D, or KRAS Q61H protein mutation; 46. ​​The application of claim 45.

48. the KRAS G12A-associated cancer is non-small cell lung cancer, ovarian cancer, or colorectal cancer; the KRAS G12C-associated cancer is non-small cell lung cancer, colorectal cancer, or pancreatic cancer; the KRAS G12D-associated cancer is biliary tract cancer, endometrial cancer, pancreatic cancer, colorectal cancer, non-small cell lung cancer, ovarian cancer, or rectal cancer; the KRAS G12R-associated cancer is pancreatic cancer or non-small cell lung cancer; the KRAS G12S-associated cancer is rectal cancer, colon adenocarcinoma, or colorectal cancer; the KRAS G12V-associated cancer is pancreatic cancer, colorectal cancer, non-small cell lung cancer, or ovarian cancer; and the KRAS G13D-associated cancer is colorectal cancer.

48. The application of claim 47.

49. A compound represented by formula S-1, S-2, S-3 or S-4, 【Chemistry 126】 Here, ring C, ring D, R 2e , R 3e , R 4e and R 5e are defined and described by claim 3, and the definitions of Lx, ring U, Ly and ring Y and the connection relationship between them are all described in any one of claims 20 to 28, and p'' is 1, 2, 3 or 4. compound.

50. wherein the formula S-1 is formula S-1-1, the formula S-2 is formula S-2-1, the formula S-3 is formula S-3-1, and the formula S-4 is formula S-4-1; 【Chemistry 127】 Here, ring C, ring D, R 2e , R 3e , R 4e , R 5e , Lx, ring U, Ly, ring Y and p'' are defined and described by claim 49; 50. The compound of claim 49.

51. The compound represented by the formula S-1, S-2, S-3 or S-4 is 【Chemistry 128】 Selected from 50. A compound of formula S-1, S-2, S-3 or S-4 according to claim 49.

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