KRAS g12d degradation agent as well as preparation method therefor and use thereof

Abstract

Disclosed in the present invention are a KRAS G12D degradation agent as well as a preparation method therefor and the use thereof. The present invention provides compounds as shown below, and / or stereoisomers, enantiomers, diastereoisomers, atropisomers, deuterated compounds, hydrates, solvates, prodrugs and / or pharmaceutically acceptable salts thereof. The compounds provided by the present invention can effectively degrade and / or inhibit KRAS G12D protein in cells, and can be used for preparing drugs for treating and / or preventing related diseases or disorders caused by KRAS G12D mediation. G-L-E I

Description

KRAS G12D degraders, methods of making and uses thereof

[0001] This application claims priority to Chinese patent application 2024104786939 with a filing date of 2024 / 4 / 19, Chinese patent application 2024114044653 with a filing date of 2024 / 10 / 10, Chinese patent application 2025100771962 with a filing date of 2025 / 1 / 17, and Chinese patent application 2025104624657 with a filing date of 2025 / 04 / 11. This application incorporates the entire contents of the above-mentioned Chinese patent applications. TECHNICAL FIELD

[0002] The present application belongs to the technical field of medicine, in particular, the present application relates to KRAS G12D degraders, methods of making and uses thereof. BACKGROUND

[0003] RAS (rat sarcoma) is one of the most frequently mutated oncogenes in tumors, with mutations present in approximately 30% of human malignancies. The RAS family includes KRAS, NRAS, and HRAS, of which KRAS (kirsten rat sarcoma viral oncogene) is more prone to mutation than the other two RAS subtypes, accounting for about 85%, and is particularly common in solid tumors (Cancer Res. 2020, 80, 2969-2974). KRAS gene mutations exist in 30-40% of colorectal cancers, 90% of pancreatic cancers, and 15-20% of lung cancers. After KRAS is activated, it regulates cell proliferation, differentiation, and survival functions through downstream signaling pathways such as RAF-MEK-ERK and PI3K-AKT-mTOR. After KRAS gene mutation, the protein remains in an activated state, leading to persistent activation of downstream signaling pathways and promoting tumorigenesis (Nat. Rev. Cancer 2015, 15, 290-301). Therefore, KRAS is an important target for tumor treatment efforts, including targeting KRAS protein itself, or its post-translational modification, membrane localization, protein-protein interaction, and RAS downstream signaling pathway.

[0004] Because KRAS binds to GTP or GDP with ultra-high affinity (picomolar concentration), and the RAS protein surface is smooth, lacking ideal small molecule binding sites, it is considered extremely challenging to develop competitive inhibitors that directly act on the RAS protein (Nat. Rev. Drug Discov. 2020, 19, 533-552).

[0005] Currently, KRAS inhibitors (Cancer Discov. 2022, 12, 924-937) can be divided into:

[0006] 1) inhibitors directly targeting KRAS such as KRAS G12C, KRAS G12D, KRAS G12R (J. Am. Chem. Soc. 2022, 144, 35, 15916-15921) and KRAS G12S (Nat. Chem. Biol. 2022, 18, 1177-1183) and the like;

[0007] 2) inhibitors indirectly acting on KRAS such as 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 and the like), SOS1 inhibitors (Bay-293, Proc. Natl. Acad. Sci. U S A. 2019, 116, 2551-2560; BI-3406, Cancer Discov. 2021, 11, 142-157; MRTX0902, J. Med. Chem. 2022, 65, 678-9690 and the like) and KRAS (on) inhibitors (WO2021091982A1, WO2022060836A1).

[0008] In recent years, with the deepening of the research on KRAS, the development of KRAS inhibitors has finally made significant progress (Cancer Discov. 2022, 12, 924-937). In the design process of KRAS-G12C inhibitors, the cysteine in the 12th codon is easy to form a covalent bond, and covalent targeting of the cysteine site has become an important breakthrough in the development of KRAS drugs. 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 accelerated the approval of Lumakras (Sotorasib, AMG510) developed by Amgen (Nature 2019, 575, 217-223; J. Med. Chem. 2020, 63, 52-65) for the treatment of non-small cell lung cancer patients carrying KRAS-G12C mutations (N. Engl. J. Med. 2021, 384, 2371-2381). Currently, there are several small molecule drugs targeting KRAS-G12C in clinical trials. On February 16, 2022, the FDA accepted the new drug application of the second KRAS-G12C inhibitor Adagrasib (MRTX849) submitted by Mirati (Cancer Discov. 2020, 10, 54-71 & J. Med. Chem. 2020, 63, 6679-6693) for the treatment of non-small cell lung cancer patients carrying KRAS G12C mutations who have received at least one systemic therapy (N. Engl. J. Med. 2022, 387, 120-131). Adagrasib is expected to become the second KRAS-targeted drug in the world.

[0009] Unlike KRAS G12C, which is the most common mutation in non-small cell lung cancer (NSCLC) patients, KRAS G12D is the most common mutation in colorectal and pancreatic cancers. Because the 12th codon of the KRAS G12C mutant has a cysteine (Cys), it is easy to form a covalent bond; with this structural feature, covalent binding of the mutant to small molecule inhibitors can be achieved. But the 12th codon of the KRAS G12D mutant is aspartic acid (Asp), which cannot adopt this strategy.

[0010] The activation of KRAS-G12D is mainly mediated by protein-protein interaction. Considering that the surface of KRAS protein lacks obvious binding pockets, and that cyclic peptides have high binding affinity to protein surfaces, peptide molecules are the first 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 their cell membrane permeability is poor. The ability of cells to uptake peptides depends on the regulation of cell surface receptors, neuropilin-1 (NRP1), and this protein is overexpressed on the cell membrane of human lung cancer cells. Therefore, screening cyclic peptides targeting NRP1 and KRAS G12D not only makes the cyclic peptides have higher cell uptake ability, but also can act on KRAS G12D to exert an anti-tumor effect (J. Am. Chem. Soc. 2022, 144, 7117-7128).

[0011] On December 10, 2021, Mirati reported the first non-covalent, effective and highly selective KRAS-G12D inhibitor MRTX1133 (J. Med. Chem. 2022, 65, 3923-3942; WO2021041671A1). MRTX1133 can inhibit KRAS-G12D mutant cells in activated or inactivated state, but not wild-type tumor cells, with a specificity of more than 1000 times. In the in vivo transplanted tumor models of pancreatic cancer and colorectal cancer, dose-dependent inhibition was shown.

[0012] WO2021041671A1, WO2022015375A1, WO2022031678A1, WO2022066646A1, WO2022098625A1, WO2022192790A1, WO2022192794A1, WO2021106231A1, WO2021107160A1, WO2022173870A1, and the like patents disclose several classes of KRAS G12D inhibitors.

[0013] Targeted protein degradation agents are a hot research and development technology worldwide in recent years (Nat. Rev. Drug Discov. 2017, 16, 101-114; Nat. Rev. Drug Discov. 2019, 18, 949-963; Nat. Rev. Drug Discov. 2022, 21, 181-200). This technology has the following characteristics: the development of "druggable" target points encounters a bottleneck, and the potential of "non-druggable" target points is endless, and the PROTAC technology is expected to solve the development problem of "non-druggable" target points; PROTAC drugs have the advantages of good drugability, high selectivity, overcoming drug resistance, various drug administration routes, small dosage, low toxicity, etc.

[0014] Therefore, there is an unmet clinical need for KRAS G12D targeted protein degradation agents. SUMMARY

[0015] The technical problem to be solved by the present application is to overcome the shortcomings of KRAS G12D inhibitors that are prone to drug resistance and KRAS G12D degradation agents that require injection for administration, and therefore, a KRAS G12D degradation agent, a preparation method and application thereof are provided. The compound provided by the present application can effectively degrade and / or inhibit KRAS G12D protein in cells.

[0016] The present application provides a compound of formula I, and / or its stereoisomer, enantiomer, diastereomer, atropisomer, deuterated compound, hydrate, solvate, prodrug, and / or its pharmaceutically acceptable salt: G-L-E I

[0017] G is G1 or G2

[0018] In G1,

[0019] X is C or N;

[0020] R 1 is H or halogen;

[0021] R 2 is C l -C3 alkyl, C2-C4 alkenyl or C2-C4 alkynyl;

[0022] R a is H, fluorine, C 1-3 alkyl, C 1-3 alkyl-O-C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 alkyl, C 1-3 alkyl-O-C 1-3alkyl, C 2-4 alkenyl, C 2-4 alkynyl optionally substituted with 1 or more halogen, OH, or deuterium;

[0023] R b and R c are independently H, OH, halogen, C 1-3 alkyl, or C 1-3 alkoxy optionally substituted with 1 or more halogen, OH, or deuterium; 1-3 alkyl, or C 1-3 alkoxy optionally substituted with 1 or more halogen, OH, or deuterium;

[0024] wherein in said G2:

[0025] W is N or CRza;

[0026] Rza is hydrogen, halogen, C 1-6 alkyl, or C 1-6 alkoxy;

[0027] Z is N or CRzb;

[0028] Rzb is hydrogen, halogen, C 1-6 alkyl, or C 1-6 alkoxy;

[0029] Rzc is phenyl, naphthyl, quinoline, isoquinoline, benzo[b]thiophene, indole, indazol, or pyridine; said phenyl, naphthyl, quinoline, isoquinoline, benzo[b]thiophene, indole, indazol, or pyridine optionally substituted with 1 or more R 1’ ;

[0030] Rzd is hydrogen, deuterium, methyl, deuterated methyl, halogenated methyl, -CD2F, -CDF2, C 2-6 alkyl, or C 3-6 cycloalkyl, said methyl, C 2-6 alkyl, or C 3-6 cycloalkyl optionally substituted with 1 or more hydroxyl, deuterium, or halogen;

[0031] each R 1’ is independently C 1-6 alkyl, halogen, hydroxyl, cyano, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, NR 21 R 22 , -C(O)NR 23 R 24 , CH2R 25 , N=S(O)(C 1-6 alkyl)2, S(O)C1-6 Alkyl, S(O)2R 26 、-SC 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 2-6 Hydroxyalkynyl, C 1-6 Cyanoalkyl, triazole, -SC 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, CH2C(O)NR 27 R 28 、-C 2- 6-Alkynyl-NR 29 R 30 、C 2-6 Deuterated alkynyl, (C 1-6 Alkoxy) C 1-6 Haloalkyl- or cycloalkyl, wherein the cycloalkyl is optionally substituted by one or more halogen or C 1-6 Alkyl substitution;

[0032] or R 1’ For SF5;

[0033] R 21 For hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl or C(O)C 1-6 alkyl;

[0034] R 22 For hydrogen, C 1-6 Alkyl or C 1-6 alkyl halide;

[0035] or R 21 、R 22 Together with the nitrogen atom to which they are attached, they form a 3-6 membered heterocycloalkyl group, wherein the 3-6 membered heterocycloalkyl group is optionally substituted with one or more halogen, methyl, trifluoromethyl, methoxy or trifluoromethoxy groups;

[0036] R 23 、R 24 Each independently is H, C 1-6 Alkyl or C 1-6 alkyl halide;

[0037] or R 23 、R 24 Together with the nitrogen atom to which they are attached, they form a 3-6 membered heterocycloalkyl group, wherein the 3-6 membered heterocycloalkyl group is optionally substituted with one or more halogen, methyl, trifluoromethyl, methoxy or trifluoromethoxy groups;

[0038] R 25 For hydroxyl, cyano, heterocyclic, NR 25a R25b C(O)NR 25c R 25d SO2C 1-6 alkyl;

[0039] R 25a R 25b R 25c R 25d each independently H or C 1-6 alkyl;

[0040] or R 25a R 25b and the nitrogen atom to which they are attached join to form a 3-6 membered heterocycloalkyl group optionally substituted with one or more halo, methyl, trifluoromethyl, methoxy, or trifluoromethoxy;

[0041] or R 23c R 25d and the nitrogen atom to which they are attached join to form a 3-6 membered heterocycloalkyl group optionally substituted with one or more halo, methyl, trifluoromethyl, methoxy, or trifluoromethoxy;

[0042] R 26 C 1-6 alkyl, C 1-6 haloalkyl, or NR 26a R 26b

[0043] R 26a R 26b each independently H or C 1-6 alkyl;

[0044] or R 26a R 26b and the nitrogen atom to which they are attached join to form a 3-6 membered heterocycloalkyl group optionally substituted with one or more halo, methyl, trifluoromethyl, methoxy, or trifluoromethoxy;

[0045] R 27 R 28 each independently H, C 1-6 alkyl, or C 1-6 haloalkyl;

[0046] or R 27 R 28 and the nitrogen atom to which they are attached join to form a 3-6 membered heterocycloalkyl group optionally substituted with one or more halo, methyl, trifluoromethyl, methoxy, or trifluoromethoxy;

[0047] R 29 R30 Each independently is H, C 1-6 Alkyl or C 1-6 alkyl halide;

[0048] or R 29 、R 30 Together with the nitrogen atom to which they are attached, they form a 3-6 membered heterocycloalkyl group, wherein the 3-6 membered heterocycloalkyl group is optionally substituted with one or more halogen, methyl, trifluoromethyl, methoxy or trifluoromethoxy groups;

[0049] R 3a For hydrogen, halogen, hydroxyl, cyano, C 1-3 Alkyl, C 1-3 Deuterated alkyl or C 1-3 alkyl halide;

[0050] n is 0, 1, 2, 3, 4 or 5;

[0051] L is L is connected to G through A or B;

[0052] E is

[0053] The present invention provides a compound of formula I, and / or its stereoisomers, enantiomers, diastereomers, atropisomers, deuterated forms, hydrates, solvates, prodrugs, and / or pharmaceutically acceptable salts: GLE Ⅰ

[0054] Wherein: G is G1 or G2

[0055] In the G1,

[0056] X is C or N;

[0057] R 1 is H or halogen;

[0058] R 2 C l -C3 alkyl, C2-C4 alkenyl or C2-C4 alkynyl;

[0059] R a H, fluorine, C 1-3 Alkyl, C 1-3 Alkyl-OC 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, the C 1-3 Alkyl, C1-3 alkyl-O-C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl optionally substituted with 1 or more halogen, OH, or deuterium;

[0060] R b and R c are independently H, OH, halogen, C 1-3 alkyl, or C 1-3 alkoxy, said C 1-3 alkyl or C 1-3 alkoxy optionally substituted with 1 or more halogen, OH, or deuterium;

[0061] wherein in said G2:

[0062] W is N or CRza;

[0063] Rza is hydrogen, halogen, C 1-6 alkyl, or C 1-6 alkoxy;

[0064] Z is N or CRzb;

[0065] Rzb is hydrogen, halogen, C 1-6 alkyl, or C 1-6 alkoxy;

[0066] Rzc is phenyl, naphthyl, quinoline, isoquinoline, benzo[b]thiophene, indole, indazol, or pyridine; said phenyl, naphthyl, quinoline, isoquinoline, benzo[b]thiophene, indole, indazol, or pyridine optionally substituted with 1 or more R 1’ ;

[0067] Rzd is hydrogen, deuterium, methyl, deuterated methyl, halogenated methyl, -CD2F, -CDF2, C 2-6 alkyl, or C 3-6 cycloalkyl, said methyl, C 2-6 alkyl, or C 3-6 cycloalkyl optionally substituted with 1 or more hydroxyl, deuterium, or halogen;

[0068] each R 1’ is independently C 1-6 alkyl, halogen, hydroxyl, cyano, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, NR 21 R 22 , -C(O)NR 23 R 24 , CH2R 25 , N=S(O)(C1-6 alkyl)2, S(O)C 1-6 alkyl, S(O)2R 26 , -S-C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 2-6 hydroxyalkynyl, C 1-6 cyanoalkyl, triazolyl, -S-C 1-6 haloalkyl, C 1-6 hydroxyalkyl, CH2C(O)NR 27 R 28 , -C 2- 6alkynyl-NR 29 R 30 , C 2-6 deuterated alkynyl, (C 1-6 alkoxy)C 1-6 haloalkyl- or cycloalkyl, wherein the cycloalkyl is optionally substituted with one or more halogen or C 1-6 alkyl;

[0069] R 21 is hydrogen, C 1-6 alkyl, C 1-6 haloalkyl or C(O)C 1-6 alkyl;

[0070] R 22 is hydrogen, C 1-6 alkyl or C 1-6 haloalkyl;

[0071] or R 21 , R 22 together with the nitrogen atom to which they are attached form a 3-6 membered heterocycloalkyl group, which is optionally substituted with one or more halogen, methyl, trifluoromethyl, methoxy or trifluoromethoxy;

[0072] R 23 , R 24 are each independently H, C 1-6 alkyl or C 1-6 haloalkyl;

[0073] or R 23 , R 24 together with the nitrogen atom to which they are attached form a 3-6 membered heterocycloalkyl group, which is optionally substituted with one or more halogen, methyl, trifluoromethyl, methoxy or trifluoromethoxy;

[0074] R 25 is hydroxy, cyano, heterocyclyl, NR 25a R 25b , C(O)NR 25cR 25d or SO2C 1-6 alkyl;

[0075] R 25a , R 25b , R 25c , R 25d each independently H or C 1-6 alkyl;

[0076] or R 25a , R 25b together with the nitrogen atom to which they are attached form a 3-6 membered heterocycloalkyl group, which is optionally substituted with one or more halogen, methyl, trifluoromethyl, methoxy or trifluoromethoxy;

[0077] or R 23c , R 25d together with the nitrogen atom to which they are attached form a 3-6 membered heterocycloalkyl group, which is optionally substituted with one or more halogen, methyl, trifluoromethyl, methoxy or trifluoromethoxy;

[0078] R 26 is C 1-6 alkyl, C 1-6 haloalkyl or NR 26a R 26b

[0079] R 26a , R 26b each independently H or C 1-6 alkyl;

[0080] or R 26a , R 26b together with the nitrogen atom to which they are attached form a 3-6 membered heterocycloalkyl group, which is optionally substituted with one or more halogen, methyl, trifluoromethyl, methoxy or trifluoromethoxy;

[0081] R 27 , R 28 each independently H, C 1-6 alkyl or C 1-6 haloalkyl;

[0082] or R 27 , R 28 together with the nitrogen atom to which they are attached form a 3-6 membered heterocycloalkyl group, which is optionally substituted with one or more halogen, methyl, trifluoromethyl, methoxy or trifluoromethoxy;

[0083] R 29 , R 30 each independently H, C 1-6 alkyl or C1-6 haloalkyl;

[0084] R 29 , R 30 and the nitrogen atom to which they are attached form a 3-6 membered heterocycloalkyl group, which is optionally substituted with 1 or more halogen, methyl, trifluoromethyl, methoxy or trifluoromethoxy;

[0085] R 3a is hydrogen, halogen, hydroxyl, cyano, C 1-3 alkyl, C 1-3 deuteroalkyl or C 1-3 haloalkyl;

[0086] n is 0, 1, 2, 3, 4 or 5;

[0087] L is L is attached to G through A or B;

[0088] E is

[0089] The present application provides a compound of Formula I, and / or stereoisomers, enantiomers, diastereomers, atropisomers, deuterated forms, hydrates, solvates, prodrugs thereof, and / or pharmaceutically acceptable salts thereof: G-L-E I

[0090] wherein: the G is G1or G2

[0091] in the G1,

[0092] X is C or N;

[0093] R 1 is H or halogen;

[0094] R 2 is C l -C3alkyl, C2-C4alkenyl or C2-C4alkynyl;

[0095] R a is H, C 1-3 alkyl, C 1-3 alkyl-O-C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, the C 1-3 alkyl, C 1-3 alkyl-O-C 1-3 alkyl, C2-4 alkenyl, C 2-4 alkynyl optionally substituted with 1 or more halogen, OH, or deuterium;

[0096] R b and R c are independently H, OH, halogen, C 1-3 alkyl or C 1-3 alkoxy optionally substituted with 1 or more halogen, OH, or deuterium; 1-3 alkyl or C 1-3 alkoxy optionally substituted with 1 or more halogen, OH, or deuterium;

[0097] wherein in said G2:

[0098] W is N or CRza;

[0099] Rza is hydrogen, halogen, C 1-6 alkyl or C 1-6 alkoxy;

[0100] Z is N or CRzb;

[0101] Rzb is hydrogen, halogen, C 1-6 alkyl or C 1-6 alkoxy;

[0102] Rzc is phenyl, naphthyl, quinoline, isoquinoline, benzo[b]thiophene, indole, indazole, or pyridine; said phenyl, naphthyl, quinoline, isoquinoline, benzo[b]thiophene, indole, indazole, or pyridine optionally substituted with 1 or more R 1’ ;

[0103] Rzd is hydrogen, deuterium, methyl, deuterated methyl, halogenated methyl, -CD2F, or -CDF2;

[0104] each R 1’ is independently C 1-6 alkyl, halogen, hydroxyl, cyano, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, NR 21 R 22 , -C(O)NR 23 R 24 , CH2R 25 , N=S(O)(C 1-6 alkyl)2, S(O)C 1-6 alkyl, S(O)2R 26 , -S-C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 2-6 hydroxyalkynyl, C 1-6 cyanoalkyl, triazolyl, -S-C1-6 haloalkyl, C 1-6 hydroxyalkyl, CH2C(O)NR 27 R 28 , -C 2- 6alkynyl-NR 29 R 30 , C 2-6 deuterated alkynyl, (C 1-6 alkoxy)C 1-6 haloalkyl- or cycloalkyl; wherein said cycloalkyl is optionally substituted with one or more halogen or C 1-6 alkyl;

[0105] R 21 is hydrogen, C 1-6 alkyl, C 1-6 haloalkyl or C(O)C 1-6 alkyl;

[0106] R 22 is hydrogen, C 1-6 alkyl or C 1-6 haloalkyl;

[0107] or R 21 , R 22 together with the nitrogen atom to which they are attached form a 3-6 membered heterocycloalkyl group, said 3-6 membered heterocycloalkyl group being optionally substituted with one or more halogen, methyl, trifluoromethyl, methoxy or trifluoromethoxy;

[0108] R 23 , R 24 are each independently H, C 1-6 alkyl or C 1-6 haloalkyl;

[0109] or R 23 , R 24 together with the nitrogen atom to which they are attached form a 3-6 membered heterocycloalkyl group, said 3-6 membered heterocycloalkyl group being optionally substituted with one or more halogen, methyl, trifluoromethyl, methoxy or trifluoromethoxy;

[0110] R 25 is hydroxyl, cyano, heterocyclyl, NR 25a R 25b , C(O)NR 25c R 25d or SO2C 1-6 alkyl;

[0111] R 25a , R 25b , R 25c , R 25d are each independently H or C 1-6 alkyl;

[0112] or R 25a , R 25b form, together with the nitrogen atom to which they are attached, a 3-6 membered heterocycloalkyl group, which is optionally substituted with one or more halogen, methyl, trifluoromethyl, methoxy or trifluoromethoxy;

[0113] or R 23c , R 25d form, together with the nitrogen atom to which they are attached, a 3-6 membered heterocycloalkyl group, which is optionally substituted with one or more halogen, methyl, trifluoromethyl, methoxy or trifluoromethoxy;

[0114] R 26 is C 1-6 alkyl, C 1-6 haloalkyl or NR 26a R 26b

[0115] R 26a , R 26b are each independently H or C 1-6 alkyl;

[0116] or R 26a , R 26b form, together with the nitrogen atom to which they are attached, a 3-6 membered heterocycloalkyl group, which is optionally substituted with one or more halogen, methyl, trifluoromethyl, methoxy or trifluoromethoxy;

[0117] R 27 , R 28 are each independently H, C 1-6 alkyl or C 1-6 haloalkyl;

[0118] or R 27 , R 28 form, together with the nitrogen atom to which they are attached, a 3-6 membered heterocycloalkyl group, which is optionally substituted with one or more halogen, methyl, trifluoromethyl, methoxy or trifluoromethoxy;

[0119] R 29 , R 30 are each independently H, C 1-6 alkyl or C 1-6 haloalkyl;

[0120] or R 29 , R 30 form, together with the nitrogen atom to which they are attached, a 3-6 membered heterocycloalkyl group, which is optionally substituted with one or more halogen, methyl, trifluoromethyl, methoxy or trifluoromethoxy;

[0121] R 3a halogen, hydroxyl, cyano, C 1-3 alkyl, C 1-3 deuteroalkyl or C 1-3 haloalkyl;

[0122] n is 0, 1, 2, 3, 4 or 5;

[0123] L is L is attached to G through A or B;

[0124] E is

[0125] In some preferred embodiments of the present application, the compound of Formula I is not any of the compounds disclosed in WO2024083258A1 (International Application No. PCT / CN2023125979), in particular not any of the compounds disclosed on pages 108-126.

[0126] In some preferred embodiments of the present application, X is N.

[0127] In some preferred embodiments of the present application, R 1 is halogen.

[0128] In some preferred embodiments of the present application, R 2 is C2-C4alkynyl.

[0129] In some preferred embodiments of the present application, R a is fluorine, C 1-3 alkyl, C 1-3 alkyl-O-C 1-3 alkyl, C 2-4 alkenyl, said C 1-3 alkyl, C 1-3 alkyl-O-C 1-3 alkyl or C 2-4 alkenyl is optionally substituted with one or more halogen or deuterium; preferably, R a is C 1-3 alkyl, C 1-3 alkyl-O-C 1-3 alkyl or C 2-4 alkenyl, said C 1-3 alkyl, C 1-3 alkyl-O-C 1-3 alkyl or C 2-4 alkenyl is optionally substituted with one or more halogen or deuterium.

[0130] In some preferred embodiments of the present application, Ra In particular, the C 1-3 alkyl, C 1-3 alkyl-O-C 1-3 alkyl, C 2-4 alkenyl is optionally substituted with one or more deuterium.

[0131] In some preferred embodiments of the application, R b is H.

[0132] In some preferred embodiments of the application, R c is halogen.

[0133] In some preferred embodiments of the application, L is

[0134] In some preferred embodiments of the application, E is More preferably, E is Even more preferably, E is

[0135] In some preferred embodiments of the application, in the compound of formula I,

[0136] G is

[0137] X is CH or N;

[0138] R 1 is H or halogen;

[0139] R 2 is C l -C3 alkyl, C2-C4 alkenyl or C2-C4 alkynyl;

[0140] R a is C 1-3 alkyl, C 1-3 alkyl-O-C 1-3 alkyl, C 2-4 alkenyl, said C 1-3 alkyl, C 1-3 alkyl-O-C 1-3 alkyl, C 2-4 alkenyl is optionally substituted with one or more halogen or deuterium;

[0141] R b and R c are independently H, OH, halogen, C 1-3 alkyl or C 1-3 alkoxy, said C 1-3 alkyl or C 1-3 alkoxy is optionally substituted with one or more halogen, OH or deuterium;

[0142] L is L is attached to G via A;

[0143] E is

[0144] In some preferred embodiments of the application, in the compound of formula I,

[0145] G is

[0146] X is N;

[0147] R 1 is halogen;

[0148] R 2 is C2-C4alkynyl;

[0149] R a is C 1-3 alkyl, C 1-3 alkyl-O-C 1-3 alkyl, C 2-4 alkenyl, said C 1-3 alkyl, C 1-3 alkyl-O-C 1-3 alkyl, C 2-4 alkenyl is optionally substituted with one or more deuterium;

[0150] R b is H;

[0151] R c is halogen;

[0152] L is L is attached to G via A;

[0153] E is

[0154] In some preferred embodiments of the application, in the compound of formula I,

[0155] G is

[0156] X is C or N;

[0157] R 1 is H or halogen;

[0158] R 2 is C l -C3alkyl, C2-C4alkenyl or C2-C4alkynyl;

[0159] R a fluoro, C 1-3 alkyl, C 1-3 alkyl-O-C 1-3 alkyl, C 2-4 alkenyl, said C 1-3 alkyl, C 1-3 alkyl-O-C 1-3 alkyl, C 2-4 alkenyl is optionally substituted with one or more halogen or deuterium;

[0160] R b and R c are independently H, OH, halogen, C 1-3 alkyl or C 1-3 alkoxy, said C 1-3 alkyl or C 1-3 alkoxy is optionally substituted with one or more halogen, OH or deuterium;

[0161] L is L is attached to G via A;

[0162] E is

[0163] In some preferred embodiments of the application, in the compound of formula I,

[0164] G is

[0165] X is N;

[0166] R 1 is halogen;

[0167] R 2 is C2-C4alkynyl;

[0168] R a is fluoro, C 1-3 alkyl, C 1-3 alkyl-O-C 1-3 alkyl, C 2-4 alkenyl, said C 1-3 alkyl, C 1-3 alkyl-O-C 1-3 alkyl, C 2-4 alkenyl is optionally substituted with one or more deuterium;

[0169] R b is H

[0170] R c halogen;

[0171] L is L is attached to G through A;

[0172] E is

[0173] In some preferred embodiments of the application, G is

[0174] In some preferred embodiments of the application, G is

[0175] In some preferred embodiments of the application, G is

[0176] In some preferred embodiments of the application, G is L is

[0177] In some preferred embodiments of the application, G is L is

[0178] In some preferred embodiments of the application, G is L is

[0179] In some preferred embodiments of the application, G is L is

[0180] In some preferred embodiments of the application, G is L is

[0181] In some preferred embodiments of the application, G is L is

[0182] In some preferred embodiments of the application, G is L is

[0183] In some preferred embodiments of the application, G is L is

[0184] In some preferred embodiments of the application, G is L is

[0185] In some preferred embodiments of the application, G is L is

[0186] In some preferred embodiments of the application, G is L is

[0187] In some preferred embodiments of the application, G is L is

[0188] In some preferred embodiments of the application, G is L is

[0189] In some preferred embodiments of the application, G is L is

[0190] In some preferred embodiments of the application, G is L is

[0191] In some preferred embodiments of the application, G is L is

[0192] In some preferred embodiments of the application, G is L is

[0193] In some preferred embodiments of the application, G is L is

[0194] In some preferred embodiments of the application, G is L is

[0195] In some preferred embodiments of the application, G is L is

[0196] In some preferred embodiments of the application, G is L is

[0197] In some preferred embodiments of the application, G is L is

[0198] In some preferred embodiments of the application, G is L is

[0199] In some preferred embodiments of the application, G is L is

[0200] In some preferred embodiments of the application, G is L is

[0201] In some preferred embodiments of the application, G is L is

[0202] In some preferred embodiments of the application, G is L is

[0203] In some preferred embodiments of the application, G is L is

[0204] In some preferred embodiments of the application, G is L is

[0205] In some preferred embodiments of the application, G is E is

[0206] In some preferred embodiments of the application, G is E is

[0207] In some preferred embodiments of the application, G is E is

[0208] In some preferred embodiments of the application, G is E is

[0209] In some preferred embodiments of the application, G is E is

[0210] In some preferred embodiments of the application, G is E is

[0211] In some preferred embodiments of the application, G is E is

[0212] In some preferred embodiments of the application, G is E is

[0213] In some preferred embodiments of the application, G is E is

[0214] In some preferred embodiments of the application, G is E is

[0215] In some preferred embodiments of the application, G is E is

[0216] In some preferred embodiments of the application, G is E is

[0217] In some preferred embodiments of the application, G is E is In some preferred embodiments of the application, G is E is

[0218] In some preferred embodiments of the application, G is E is

[0219] In some preferred embodiments of the application, G is E is

[0220] In some preferred embodiments of the application, G is E is

[0221] In some preferred embodiments of the application, G is E is

[0222] In some preferred embodiments of the application, G is E is

[0223] In some preferred embodiments of the application, G is E is

[0224] In some preferred embodiments of the application, G is E is

[0225] In some preferred embodiments of the application, G is E is

[0226] In some preferred embodiments of the application, G is E is

[0227] In some preferred embodiments of the application, G is E is

[0228] In some preferred embodiments of the application, L is E is

[0229] In some preferred embodiments of the application, L is E is

[0230] In some preferred embodiments of the application, L is E is

[0231] In some preferred embodiments of the application, L is E is

[0232] In some preferred embodiments of the application, L is E is

[0233] In some preferred embodiments of the application, L is E is

[0234] In some preferred embodiments of the application, L is E is

[0235] In some preferred embodiments of the application, L is E is

[0236] In some preferred embodiments of the application, L is E is

[0237] In some preferred embodiments of the application, L is E is

[0238] In some preferred embodiments of the application, L is E is

[0239] In some preferred embodiments of the application, L is E is

[0240] In some preferred embodiments of the application, L is E is

[0241] In some preferred embodiments of the application, L is E is

[0242] In some preferred embodiments of the application, L is E is

[0243] In some preferred embodiments of the application, L is E is

[0244] In some preferred embodiments of the application, L is E is

[0245] In some preferred embodiments of the application, L is E is

[0246] In some preferred embodiments of the application, L is E is

[0247] In some preferred embodiments of the application, L is E is

[0248] In some preferred embodiments of the application, L is E is

[0249] In some preferred embodiments of the application, L is E is

[0250] In some preferred embodiments of the application, L is E is

[0251] In some preferred embodiments of the application, L is E is

[0252] In some preferred embodiments of the application, L is E is

[0253] In some preferred embodiments of the application, L is E is

[0254] In some preferred embodiments of the application, L is E is

[0255] In some preferred embodiments of the application, L is E is

[0256] In some preferred embodiments of the application, L is E is

[0257] In some preferred embodiments of the application, L is E is

[0258] In some preferred embodiments of the application, L is E is

[0259] In some preferred embodiments of the application, L is E is

[0260] In some preferred embodiments of the application, L is E is

[0261] In some preferred embodiments of the application, L is E is

[0262] In some preferred embodiments of the application, L is E is

[0263] In some preferred embodiments of the application, L is E is

[0264] In some preferred embodiments of the application, L is E is

[0265] In some preferred embodiments of the application, L is E is

[0266] In some preferred embodiments of the application, G is L is

[0267] E is

[0268] In some preferred embodiments of the application, G is L is E is

[0269] In some preferred embodiments of the application, G is L is E is

[0270] In some preferred embodiments of the application, G is L is E is

[0271] In some preferred embodiments of the application, G is L is E is

[0272] In some preferred embodiments of the application, G is L is E is

[0273] In some preferred embodiments of the application, G is L is E is

[0274] In some preferred embodiments of the application, G is L is E is

[0275] In some preferred embodiments of the application, G is L is E is

[0276] In some preferred embodiments of the application, G is L is E is Preferably, G is

[0277] In some preferred embodiments of the application, G is L is E is

[0278] In some preferred embodiments of the application, G is L is E is

[0279] In some preferred embodiments of the application, G is L is E is

[0280] In some preferred embodiments of the application, G is L is E is

[0281] In some preferred embodiments of the application, G is L is E is

[0282] In some preferred embodiments of the application, G is L is E is

[0283] In some preferred embodiments of the application, G is L is E is

[0284] In some preferred embodiments of the application, G is L is E is

[0285] In some preferred embodiments of the application, G is L E is

[0286] In some preferred embodiments of the application, G is L is E is

[0287] In some preferred embodiments of the application, G is L is E is

[0288] In some preferred embodiments of the application, G is L is E is

[0289] In some preferred embodiments of the application, G is L is E is

[0290] In some preferred embodiments of the application, G is L is E is Preferably, G is is

[0291] In some preferred embodiments of the application, G is L is E is

[0292] In some preferred embodiments of the application, G is L is E is

[0293] In some preferred embodiments of the application, G is L is E is

[0294] In some preferred embodiments of the application, G is L is E is

[0295] In some preferred embodiments of the application, A in L is attached to G.

[0296] In some preferred embodiments of the application, W is CRza.

[0297] In some preferred embodiments of the application, Rza is H or halo, e.g., halo.

[0298] In some preferred embodiments of the application, Z is N.

[0299] In some preferred embodiments of the application, Rzd is methyl, deuterated methyl, halogenated methyl, -CD2F, -CDF2, or C 2-6 alkyl, said C 2-6The alkyl group is optionally substituted with one or more hydroxyl groups, deuterium or halogen; preferably, Rzd is methyl or deuterated methyl.

[0300] In some preferred embodiments of the present invention, n is 0.

[0301] In some preferred embodiments of the present invention, Rzc is phenyl, naphthyl or benzo[b]thiophene; said phenyl, naphthyl or benzo[b]thiophene is optionally substituted with one or more R 1’ replace.

[0302] In some preferred embodiments of the present invention, the compound of formula I:

[0303] Where: G is

[0304] W is CRza;

[0305] Rza is hydrogen or halogen;

[0306] Z is N;

[0307] Rzc is phenyl, naphthyl, quinoline, isoquinoline, benzo[b]thiophene, indole, indazole or pyridine; said phenyl, naphthyl, quinoline, isoquinoline, benzo[b]thiophene, indole, indazole or pyridine is optionally replaced by one or more R 1’ replace;

[0308] Each R 1’ Independently C 1-6 Alkyl, halogen, hydroxyl, cyano, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy, NR 21 R 22 、C 2-6 Alkenyl, C 2-6 Alkynyl, C 2-6 Deuterated alkynyl or cycloalkyl; (Preferably, the cycloalkyl is C 3-6 cycloalkyl, such as cyclopropyl)

[0309] R 21 is hydrogen;

[0310] R 22 is hydrogen;

[0311] Rzd is hydrogen, deuterium, methyl, deuterated methyl, halomethyl, -CD2F, -CDF2, C 2-6 Alkyl, the C 2-6 The alkyl group is optionally substituted with one or more hydroxyl groups, deuterium or halogen;

[0312] R 3a For hydrogen, halogen, hydroxyl, cyano, C 1-3alkyl, C 1-3 deuteroalkyl or C 1-3 haloalkyl;

[0313] n is 0 or 1 ;

[0314] L is L is attached to G through A;

[0315] E is

[0316] In some preferred embodiments of the application, in the compound of formula I:

[0317] wherein: G is

[0318] W is CRza;

[0319] Rza is halo;

[0320] Z is N;

[0321] Rzc is phenyl, naphthyl or benzo[b]thiophene; said phenyl, naphthyl or benzo[b]thiophene is optionally substituted with one or more R 1’ substituents;

[0322] each R 1’ is independently C 1-6 alkyl, halo, hydroxy, cyano, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, NR 21 R 22 , C 2-6 alkenyl, C 2-6 alkynyl, C 2-6 deuteroalkynyl or cycloalkyl;

[0323] R 21 is hydrogen;

[0324] R 22 is hydrogen;

[0325] Rzd is methyl or deutero-methyl;

[0326] n is 0;

[0327] L is

[0328] E is

[0329] In some preferred embodiments of the application, G2 is G2-1, G2-2, G2-3 or G2-4:

[0330] Wherein, Rzc, Rzd, R 3a and n are as described and defined in the present invention.

[0331] In some preferred embodiments of the present invention, G2 is G2-2-1, G2-2-2 or G2-2-3:

[0332] Among them, Rza, Rzb, Rzc, Rzd, R 3a and n are as described and defined in the present invention.

[0333] In some embodiments of the present invention, for

[0334] In some preferred embodiments of the present invention, G2 is:

[0335] In some preferred embodiments of the present invention, G2 is:

[0336] In some preferred embodiments of the present invention, G2 is: For example

[0337] In some preferred embodiments of the present invention, G2 is:

[0338] In some preferred embodiments of the present invention, G2 is:

[0339] In some preferred embodiments of the present invention, G2 is:

[0340] In some preferred embodiments of the present invention, G2 is:

[0341] In some preferred embodiments of the present invention, G2 is:

[0342] In some preferred embodiments of the present invention, G2 is L is

[0343] In some preferred embodiments of the application, G2 is L is E is

[0344] In some preferred embodiments of the application, G2 is L is E is

[0345] In some preferred embodiments of the application, G2 is L is E is

[0346] In some preferred embodiments of the application, G2 is L is E is

[0347] In some preferred embodiments of the application, G2 is L is E is

[0348] In some preferred embodiments of the application, G2 is L is E is

[0349] In some preferred embodiments of the application, G2 is L is E is

[0350] In some preferred embodiments of the application, G2 is L is E is

[0351] In some preferred embodiments of the application, G2 is L is E is

[0352] In some preferred embodiments of the application, G2 is L is E is

[0353] In some preferred embodiments of the application, G2 is L is E is

[0354] In some preferred embodiments of the application, G2 is L is E is

[0355] In some preferred embodiments of the application, G2 is L is E is

[0356] In some preferred embodiments of the application, Rzc is: More preferably, Rzc is

[0357] In some preferred embodiments of the application, Rzc is

[0358] In some preferred embodiments of the application, Rzc is:

[0359] In some preferred embodiments of the application, Rzc is:

[0360] In some preferred embodiments of the application, Rzc is:

[0361] In some preferred embodiments of the application, the compound of Formula I is any one of the following:

[0362] In some preferred embodiments of the application, the diastereomeric compound has any one of the following structures:

[0363] In some preferred embodiments of the application,

[0364] the compound eluting first under the following chromatographic conditions: column: CHIRALPAK IC (IC00CD-TB016), 0.46 cm x 15 cm I.D., 10 μm; mobile phase: MeOH / ACN (acetonitrile) / DEA (diethanolamine); gradient: MeOH / ACN / DEA 65 / 35 / 0.2 (V / V / V); flow rate: 1 mL / min; column temperature: 35 °C; preferably, the compound eluting first has a retention time of 6.913 min;

[0365] ​the compound that elutes later under the following chromatographic conditions: column: CHIRALPAK IC (IC00CD-TB016), 0.46 cm * 15 cm I.D., 10 μm; mobile phase: MeOH / ACN / DEA; gradient: MeOH / ACN / DEA 65 / 35 / 0.2 (V / V / V); flow rate: 1 mL / min; column temperature: 35 °C; preferably the compound that elutes later has a retention time of 9.062 min.

[0366] In some preferred embodiments of the application, In some preferred embodiments of the application, the configuration of the compound that elutes first under the following chromatographic conditions: column: Daicel chiralpak AD_3, 3*150 mm, 3 μm; mobile phase A: CO2; mobile phase B: MeOH (0.1 % diethanolamine); gradient: mobile phase A / mobile phase B 50 / 50 (V / V) for 6 min; flow rate: 1.5 mL / min; wavelength: 214 nm; column temperature: 37 °C; preferably the compound that elutes first has a retention time of 2.248 min.

[0367] In some preferred embodiments of the application, In some preferred embodiments of the application, the configuration of the compound that elutes later under the following chromatographic conditions: column: Daicel chiralpak AD_3, 3*150 mm, 3 μm; mobile phase A: CO2; mobile phase B: MeOH (0.1 % diethanolamine); gradient: mobile phase A / mobile phase B 50 / 50 (V / V) for 6 min; flow rate: 1.5 mL / min; wavelength: 214 nm; column temperature: 37 °C; preferably the compound that elutes later has a retention time of 2.350 min.

[0368] In some preferred embodiments of the application, In some preferred embodiments of the application, the configuration of the compound eluting first under the following chromatographic conditions: Column: Daicel chiralpak AD_3, 3*150 mm, 3 μm; mobile phase A is CO2; mobile phase B is MeOH (0.1% diethanolamine); gradient: A / B is 80 / 20 (V / V), elution time 6 min; flow rate: 2 mL / min; wavelength: 214 nm; column temperature: 37 °C; preferably the compound eluting first has a retention time of 1.408 min.

[0369] In some preferred embodiments of the application, In some preferred embodiments of the application, the compound eluting second has the same configuration as the compound eluting second under the following chromatographic conditions: Column: chiralpak-IG-3, 150 mm x 3 mm, 3 μm; mobile phase A is CO2; mobile phase B is MeOH (0.1% diethanolamine); gradient: A / B is 90 / 10 (V / V), elution time 6 min; flow rate: 2.0 mL / min; wavelength: 214 nm or 254 nm; column temperature: 37 °C; preferably the compound eluting second has a retention time of 1.357 min.

[0370] In some preferred embodiments of the application, In some preferred embodiments of the application, the compound eluting second has the same configuration as the compound eluting second under the following chromatographic conditions: Column: Daicel CHIRALPAK IB-3, 3*150 mm, 3 um; mobile phase A is CO2; mobile phase B is MeOH; gradient: A / B is 70 / 30 (V / V), elution time 6 min; flow rate: 2.0 mL / min; wavelength: 214 nm or 254 nm; column temperature: 37 °C; preferably the compound eluting second has a retention time of 1.681 min.

[0371] In some preferred embodiments of the application, In some preferred embodiments of the application, the compound eluting second has the same configuration as The compounds that elute first under the following chromatographic conditions have the same configuration, and the chromatographic conditions are as follows: column: Daicel CHIRALPAK IB-3, 3*150mm, 3um; mobile phase A is CO2; mobile phase B is MeOH (0.1% diethanolamine); gradient: A / B is 70 / 30 (V / V), elution time is 6 min; flow rate: 2.0 mL / min; wavelength: 214 nm; column temperature: 37°C; preferably, the retention time of the compound that elutes first is 2.513 min.

[0372] In some preferred embodiments of the present invention, middle The configuration and The compounds that elute first under the following chromatographic conditions have the same configuration: column: Daicel CHIRALCEL OD-3, 150 mm × 3 mm, 3 μm; mobile phase A: CO2; mobile phase B: MeOH (0.1% diethanolamine); gradient: A / B: 60 / 40 (v / v), elution time: 6 min; flow rate: 2.0 mL / min; wavelength: 214 nm; column temperature: 37° C.; preferably, the retention time of the compound that elutes first is 1.693 min;

[0373] Or, with The compounds eluting later under the following chromatographic conditions had the same configuration: column: Daicel CHIRALCEL OD-3, 150 mm × 3 mm, 3 μm; mobile phase A: CO2; mobile phase B: MeOH (0.1% diethanolamine); gradient: A / B: 60 / 40 (v / v), elution time: 6 min; flow rate: 2.0 mL / min; wavelength: 214 nm; column temperature: 37°C. Preferably, the retention time of the compound eluting later was 1.942 min.

[0374] In some preferred embodiments of the present invention, the prodrug of the compound of formula I is as follows:

[0375] The present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I, and / or its stereoisomers, enantiomers, diastereomers, atropisomers, deuterated forms, hydrates, solvates, prodrugs, and / or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier, diluent, or excipient.

[0376] The present application provides a method for degrading KRAS G12D protein, comprising contacting a compound of Formula I, and / or a stereoisomer, enantiomer, diastereomer, atropisomer, deuterated compound, hydrate, solvate, metabolite, prodrug, and / or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof with KRAS G12D protein.

[0377] The present application provides a compound of Formula I, and / or a stereoisomer, enantiomer, diastereomer, atropisomer, deuterated compound, hydrate, solvate, metabolite, prodrug, and / or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for use as a medicament for treating or preventing a KRAS G12D-mediated disease or disorder.

[0378] The present application provides a compound of Formula I, and / or a stereoisomer, enantiomer, diastereomer, atropisomer, deuterated compound, hydrate, solvate, metabolite, prodrug, and / or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for use as a medicament for treating or preventing a KRAS mutation-mediated disease or disorder.

[0379] The present application provides a compound of Formula I, and / or a stereoisomer, enantiomer, diastereomer, atropisomer, deuterated compound, hydrate, solvate, metabolite, prodrug, and / or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for use as a medicament for treating or preventing a KRAS mutation-mediated disease or disorder.

[0380] The present application provides a compound of Formula I, and / or a stereoisomer, enantiomer, diastereomer, atropisomer, deuterated compound, hydrate, solvate, metabolite, prodrug, and / or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for use as a medicament for treating or preventing a KRAS mutation-mediated disease or disorder.

[0381] The present application provides a compound of Formula I, and / or a stereoisomer, enantiomer, diastereomer, atropisomer, deuterated compound, hydrate, solvate, metabolite, prodrug, and / or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for use as a medicament for treating or preventing a KRAS mutation-mediated disease or disorder.

[0382] The present application provides a compound of Formula I, and / or stereoisomers, enantiomers, diastereomers, atropisomers, deuterated compounds, hydrates, solvates, metabolites, prodrugs, and / or pharmaceutically acceptable salts thereof, or a pharmaceutical composition thereof for use in the treatment or prevention of a disease or disorder mediated by KRAS G12D, such as a cancer.

[0383] The present application provides a method for treating or preventing a disease or disorder mediated by KRAS G12D, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula I, and / or stereoisomers, enantiomers, diastereomers, atropisomers, deuterated compounds, hydrates, solvates, metabolites, prodrugs, and / or pharmaceutically acceptable salts thereof, or a pharmaceutical composition thereof.

[0384] The present application provides a method for treating or preventing a disease or disorder (e.g., cancer) regulated by the interaction of KRAS G12D with SOS1 or SHP2 protein, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula I, and / or stereoisomers, enantiomers, diastereomers, atropisomers, deuterated compounds, hydrates, solvates, metabolites, prodrugs, and / or pharmaceutically acceptable salts thereof, or a pharmaceutical composition thereof.

[0385] In certain embodiments of the present application, the cancer is selected from the group consisting of:

[0386] Heart: sarcomas (angiosarcomas, fibrosarcomas, rhabdomyosarcomas, liposarcomas), myxomas, rhabdomyomas, fibromas, lipomas, and teratomas;

[0387] Lung: bronchogenic carinomas (squamous cell carcinoma, undifferentiated small cell carcinoma, undifferentiated large cell carcinoma, adenocarcinoma), alveolar carcinoma (bronchiolar carcinoma), bronchial adenoma, sarcomas, lymphomas, chondromas hamartomas, mesotheliomas;

[0388] Gastrointestinal tract: esophagus (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, fibro-neuroma, fibroma), large intestine (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma);

[0389] Urogenital 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, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumor, lipoma);

[0390] Liver: hepatocarcinoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, malignant hemangioendothelioma, hepatocellular adenoma, hemangioma;

[0391] Biliary tract: cholangiocarcinoma, gallbladder carcinoma, ampullary carcinoma, hepatocellular carcinoma;

[0392] Bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteoma (osteosis), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumor;

[0393] Nervous system: skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma, meningeal sarcoma, glioma), brain (astrocytoma, medulloblastoma, neuroglioma, ependymoma, germ cell tumor (pinealoma), glioblastoma multiforme, oligodendroglioma, schwannoma, eye cancer, congenital tumors), spinal cord neurofibroma, meningioma, glioma, sarcoma);

[0394] Gynecology: uterus (endometrial carcinoma (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-thecal cell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, rhabdomyosarcoma (embryonal type), fallopian tubes (carcinoma);

[0395] Hematology: blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disease, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma);

[0396] Skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, moles dysplastic nevi, lipoma, angioma, dermatofibroma, keloids, psoriasis;

[0397] Adrenal gland: neuroblastoma.

[0398] In certain embodiments of the application, the cancer is a KRAS G12D-associated cancer.

[0399] In certain embodiments of the application, the cancer is non-small cell lung cancer, small cell lung cancer, colorectal cancer, rectal cancer, or pancreatic cancer.

[0400] The present application also provides a compound of Formula I, a stereoisomer thereof, a pharmaceutically acceptable salt of the compound or the stereoisomer thereof, or a pharmaceutically acceptable salt of the atropisomer thereof, for use in the treatment of a disease or disorder associated with a KRAS G12D mutant protein.

[0401] The present application also provides a compound of Formula I, a stereoisomer thereof, a pharmaceutically acceptable salt of the compound or the stereoisomer thereof, or a pharmaceutically acceptable salt of the atropisomer thereof, for use in the treatment of a disease or disorder associated with a KRAS G12D mutant protein.

[0402] In certain embodiments of the application, the cancer is selected from pancreatic cancer, colorectal cancer, endometrial cancer, or lung cancer.

[0403] In certain embodiments of the application, the lung cancer is selected from non-small cell lung cancer or small cell lung cancer.

[0404] In certain embodiments of the application, the cancer and the KRAS mutation-mediated disease or disorder are independently selected from gastric cancer, pancreatic cancer, pancreatic adenocarcinoma, or colon cancer.

[0405] DETAILED DESCRIPTION: Unless otherwise indicated, the following terms used in the specification and claims have the following meanings.

[0406] "Alkyl" refers to a saturated aliphatic hydrocarbon group, including straight-chain or branched alkyl groups; for example, C1-C8 alkyl refers to an alkyl group containing 1 to 8 carbon atoms, and the C1-C8 alkyl group includes C1-C2, C1-C3, C1-C4, C1-C5, C2-C3 or C2-C4 alkyl groups, etc.; for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethyl Butyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 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 C1-C6 alkyl; more preferably C1-C4 alkyl. 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.

[0407] “C 1-3 "Alkyl" refers to a straight or branched saturated hydrocarbon group consisting of 1 to 3 carbon atoms. 1-3 Alkyl groups include C 1- 2 alkyl and C 2-3 Alkyl, etc.; it can be monovalent (such as methyl), divalent (such as methylene) or polyvalent (such as methine). 1-3 Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), and the like.

[0408] "Heteroalkyl" refers to a saturated aliphatic hydrocarbon group in which a methylene (-CH2-) group has been replaced with a heteroatom, such as O, S, N, a heteroatom group, such as -C(O)-, -S(O)-, -S(O)2-, -C(O)O-, -OC(O)-, C(O)NH-, -NHC(O)-, a vinylenyl group, or an ethynyl group, including straight, branched, or cyclic heteroalkyl groups; C1-C8heteroalkyl refers to a heteroatom or heteroatom group replacing at least one methylene group in an alkyl group containing 1-8 carbon atoms, such as -C(O)-CH3, -CH2-O-CH3, -CH2-S-CH3, -CH2-S(O)-CH3, -CH2-S(O)2-CH3, -CH2-S-CH2-CH3, -CH2-O-CH2-CH3, -CH2-O-CH2-CH3, -CH2-S(O)-CH2-CH3, or various branched isomers thereof; preferably C1-C6heteroalkyl; more preferably C1-C4heteroalkyl. The heteroalkyl group can be substituted or unsubstituted. In some embodiments, the heteroalkyl group is a C1, C2, C3, C4, C5, C6, C7, or C8heteroalkyl group.

[0409] "Alkenyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, "C 2-8 Alkenyl" refers to a straight or branched chain alkenyl group containing 2-8 carbons, including but not limited to ethenyl, 1 -propenyl, 2-propenyl, 1 -, 2-, or 3-butenyl, and the like, preferably "C 2-6 Alkenyl", more preferably "C 2-4 Alkenyl". The alkenyl group can be substituted or unsubstituted. In some embodiments, the alkenyl group is a C2, C3, C4, C5, C6, C7, C8alkenyl group.

[0410] "C 2-4 Alkenyl" refers to a straight or branched chain alkenyl group containing 2-8 carbons, including but not limited to ethenyl, 1 -propenyl, 2-propenyl, 1 -, 2-, or 3-butenyl, and the like, preferably "C 2-4 Alkenyl" refers to a straight or branched chain alkenyl group containing 2-8 carbons, including but not limited to ethenyl, 1 -propenyl, 2-propenyl, 1 -, 2-, or 3-butenyl, and the like, preferably "C 2-4 Alkenyl" refers to a straight or branched chain alkenyl group containing 2-8 carbons, including but not limited to ethenyl, 1 -propenyl, 2-propenyl, 1 -, 2-, or 3-butenyl, and the like, preferably "C 2-4 Alkenyl" refers to a straight or branched chain alkenyl group containing 2-8 carbons, including but not limited to ethenyl, 1 -propenyl, 2-propenyl, 1 -, 2-, or 3-butenyl, and the like, preferably "C

[0411] "Akynyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon triple bond, "C 2-8 Akynyl" refers to a straight or branched chain akynyl group containing 2-8 carbons, including but not limited to ethynyl, 1 -propynyl, 2-propynyl, 1 -, 2-, or 3-butynyl, and the like, preferably "C 2-6 Akynyl", more preferably "C2-4 alkynyl. The alkynyl group can be substituted or unsubstituted. In some embodiments, the alkynyl group is C2, C3, C4, C5, C6, C7, C8alkynyl.

[0412] "C 2-4 alkynyl refers to a straight-chain or branched hydrocarbon group consisting of 2 to 4 carbon atoms containing at least one carbon-carbon triple bond. The carbon-carbon triple bond can be located in any position, but is typically between the first and second carbon atom. The C 2-4 alkynyl includes C4alkynyl, C3alkynyl, and C2alkynyl; the C 2-4 alkynyl can be monovalent, divalent, or multivalent. C 2-4 Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl (including 1-, 2-, or 3-butynyl), and the like.

[0413] "alkylene" refers to a divalent group, such as divalent alkyl, divalent alkenyl, divalent alkynyl, divalent cycloalkyl, divalent heterocycloalkyl, divalent aryl, divalent heteroaryl, the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl groups being as defined above, the alkylene group can be optionally substituted or unsubstituted.

[0414] "haloalkyl" refers to an alkyl group optionally substituted with one or more fluorine, chlorine, bromine, or iodine atoms, wherein the alkyl group is as defined above, non-limiting examples include difluoromethyl, dichloromethyl, dibromomethyl, trifluoromethyl, trichloromethyl, tribromomethyl, and the like.

[0415] "hydroxyalkyl" refers to an alkyl group optionally substituted with one or more OH groups, wherein the alkyl group is as defined above, non-limiting examples include hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxyisopropyl.

[0416] "alkoxy" refers to -O-alkyl, wherein the alkyl group is as defined above, non-limiting examples include methoxy, ethoxy, isopropoxy, tert-butoxy, and the like.

[0417] "Heteroalkyl" refers to a saturated aliphatic hydrocarbon group in which a methylene (-CH2-) is replaced with a heteroatom (e.g., O, S, N), a heteroatomic group (e.g., -C(O)-, -S(O)-, -S(O)2-, -C(O)O-, -OC(O)-), C(O)NH-, -NHC(O)-, a vinylene, or an ethynylene group, including straight-chain or branched-chain heteroalkyl groups; C1-C8heteroalkyl refers to a heteroalkyl group containing 1-8 carbon atoms in which at least one methylene group is replaced with a heteroatom or heteroatomic group, such as -C(O)-CH3, -CH2-O-CH3, -CH2-S-CH3, -CH2-S(O)-CH3, -CH2-S(O)2-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 C1-C6heteroalkyl; more preferably C1-C4heteroalkyl. The heteroalkyl group can be substituted or unsubstituted. In some embodiments, the heteroalkyl group is a C1, C2, C3, C4, C5, C6, C7, or C8heteroalkyl group.

[0418] "Cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent; "C3-C8cycloalkyl" refers to a cycloalkyl group including 3 to 8 carbon atoms; "C5-C10cycloalkyl" refers to a cycloalkyl group including 5 to 10 carbon atoms; "C3-C6cycloalkyl" refers to a cycloalkyl group including 3 to 6 carbon atoms; and "C3-C4cycloalkyl" refers to a cycloalkyl group including 3 to 4 carbon atoms. 11 "Cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent; "C3-C8cycloalkyl" refers to a cycloalkyl group including 3 to 8 carbon atoms; "C5-C10cycloalkyl" refers to a cycloalkyl group including 5 to 10 carbon atoms; "C3-C6cycloalkyl" refers to a cycloalkyl group including 3 to 6 carbon atoms; and "C3-C4cycloalkyl" refers to a cycloalkyl group including 3 to 4 carbon atoms. 10 "Cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent; "C3-C8cycloalkyl" refers to a cycloalkyl group including 3 to 8 carbon atoms; "C5-C10cycloalkyl" refers to a cycloalkyl group including 5 to 10 carbon atoms; "C3-C6cycloalkyl" refers to a cycloalkyl group including 3 to 6 carbon atoms; and "C3-C4cycloalkyl" refers to a cycloalkyl group including 3 to 4 carbon atoms.

[0419] Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like, preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; preferably C3-C8cycloalkyl; more preferably C3-C6cycloalkyl.

[0420] Polycyclic cycloalkyl groups include spirocyclic, fused, and bridged cycloalkyl groups. "Spirocycloalkyl" refers to polycyclic groups in which single rings share a carbon atom (referred to as a spiro atom), which can contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system. Spirocycloalkyl groups are classified as mono-, bi-, or polycyclic, depending on the number of spiro atoms shared between rings, preferably 7-12 membered bicyclic spirocycloalkyl groups. Non-limiting examples of spirocycloalkyl groups include:

[0421]

[0422] ​"Condensed ring alkyl" refers to a fully carbon polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more rings can contain one or more double bonds, but no ring has a fully conjugated system of π electrons. Condensed ring alkyl groups can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic, depending on the number of rings comprising the group, with bicyclic condensed ring alkyl groups being preferred. Non-limiting examples of condensed ring alkyl groups include:

[0423] "Bridge ring alkyl" refers to a fully carbon polycyclic group in which any two rings share two non-adjacent carbon atoms, wherein one or more rings can contain one or more double bonds, but no ring has a fully conjugated system of π electrons. Bridge ring alkyl groups can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic, depending on the number of rings comprising the group. Non-limiting examples of bridge ring alkyl groups include:

[0424] and the like.

[0425] The cycloalkyl ring can be condensed on an aryl, heteroaryl, or heterocycloalkyl ring, where the ring that is attached to the parent structure is a cycloalkyl, non-limiting examples including indanyl, tetrahydronaphthyl, benzocycloheptyl, and the like. The cycloalkyl group can be optionally substituted or unsubstituted.

[0426] In some embodiments, the cycloalkyl is a C3, C4, C5, C6, C7, C8, C9, C 10 , C 11 , C 12 monocyclic or polycyclic (e.g., spiro, condensed, or bridged) cycloalkyl group.

[0427] "Cycloalkyl" refers to a saturated or partially unsaturated cyclic hydrocarbon substituent. The cycloalkyl group can be monocyclic or polycyclic (e.g., spiro, condensed, or bridged). Non-limiting examples of cycloalkyl groups include:

[0428] "Heterocycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic ring of hydrocarbon substituent in which one or more (e.g., 2, 3, 4, or 5) ring atoms are selected from nitrogen, oxygen, or S(O) r (where r is an integer of 0, 1, or 2), but not including -O-O-, -O-S-, or -S-S- ring members, with the remaining ring atoms being carbon. "3-11 membered heterocycloalkyl" refers to a ring group containing 3 to 11 ring atoms, "5-10 membered heterocycloalkyl" refers to a ring group containing 5 to 10 ring atoms, and "3-8 membered heterocycloalkyl" refers to a ring group containing 3 to 8 ring atoms, with "3-11 membered heterocycloalkyl" preferably containing 1-2 heteroatoms selected from N, O, or S, and more preferably 3-11 membered heterocycloalkyl containing 1 or 2 N atoms.

[0429] Monocyclic heterocycloalkyl groups are preferably 3-8 membered monocyclic heterocycloalkyl groups containing 1-2 N heteroatoms; non-limiting examples of monocyclic heterocycloalkyl groups include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl and the like, preferably piperidinyl and piperazinyl.

[0430] Polycyclic heterocycloalkyl groups include spirocyclic, fused and bridged heterocycloalkyl groups. "Spiroheterocycloalkyl" refers to polycyclic heterocycloalkyl groups in which the rings share one atom (referred to as a spiro atom) between the rings, wherein one or more of the ring atoms is selected from nitrogen, oxygen or S(O) r (wherein r is an integer 0, 1, 2) and the remaining ring atoms are carbon. They can contain one or more double bonds, but no ring has a fully conjugated pi-electron system. Spirocycloalkyl groups are classified as mono-, bi- or polyspirocycloalkyl groups depending on the number of spiro atoms shared between the rings, preferably "3-11 membered bi-spirocycloalkyl" groups containing 1-2 heteroatoms selected from N, O or S, more preferably "7-11 membered bi-spirocycloalkyl" groups containing 1 or 2 N atoms. Non-limiting examples of spiroheterocycloalkyl groups include:

[0431] and the like.

[0432] "Fused heterocycloalkyl" refers to polycyclic heterocycloalkyl groups in which each ring in the system shares an adjacent pair of atoms with other rings in the system, one or more of the rings can contain one or more double bonds, but no ring has a fully conjugated pi-electron system, wherein one or more of the ring atoms is selected from nitrogen, oxygen or S(O) r (wherein r is an integer 0, 1, 2) and the remaining ring atoms are carbon. Fused heterocycloalkyl groups can be classified as bi-, tri-, tetra- or polycyclic depending on the number of rings, preferably "3-11 membered bi-fused heterocycloalkyl" groups containing 1-3 heteroatoms selected from N, O or S, more preferably "3-11 membered bi-fused heterocycloalkyl" groups containing 1 or 2 N atoms. Non-limiting examples of fused heterocycloalkyl groups include: and the like.

[0433] "Bridged heterocycloalkyl" refers to polycyclic heterocycloalkyl groups in which any two rings share two non-adjacent atoms, they can contain one or more double bonds, but no ring has a fully conjugated pi-electron system, wherein one or more of the ring atoms is selected from nitrogen, oxygen or S(O) r (wherein r is an integer 0, 1, 2) and the remaining ring atoms are carbon. Bridged heterocycloalkyl groups can be classified as bi-, tri-, tetra- or polycyclic, non-limiting examples of bridged heterocycloalkyl groups include:

[0434] and the like.

[0435] The heterocycloalkyl ring can be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring that is attached to the parent structure is a heterocycloalkyl, non-limiting examples include:

[0436] The heterocycloalkyl group can be optionally substituted or unsubstituted. In some embodiments, the heterocycloalkyl group is a 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 membered monocyclic or polycyclic (e.g., spiro, fused or bridged) heterocycloalkyl group, wherein the number of heteroatoms can be 1, 2, 3, 4 or 5, each heteroatom independently being nitrogen, oxygen or S(O) r (wherein r is an integer of 0, 1 or 2).

[0437] "Heterocycloalkyl" refers to a saturated or unsaturated ring radical of up to 10 carbon atoms which contains one or more heteroatoms which are independently nitrogen, oxygen or S(O)

[0438] "Aryl" refers to a carbocyclic, monocyclic or fused polycyclic (i.e., rings which share adjacent pairs of carbon atoms) ring system having a conjugated pi-electron system, "6-10 membered aryl" refers to a carbocyclic aryl group containing 6-10 carbons, such as phenyl and naphthyl; preferably phenyl. The aryl ring can be fused to a heteroaryl, heterocycloalkyl or cycloalkyl ring, wherein the ring that is attached to the parent structure is an aryl ring, non-limiting examples include: The aryl group can be optionally substituted or unsubstituted. In some embodiments, the aryl group is a 6-10 membered aryl.

[0439] "Heteroaryl" refers to a heteroaromatic ring system containing 1 to 4 heteroatoms, which include nitrogen, oxygen or S(O) r (wherein r is an integer of 0, 1, 2), 5-6 membered heteroaryl refers to a heteroaromatic ring system containing 5-6 ring atoms, 5-10 membered heteroaryl refers to a heteroaromatic ring system containing 5-10 ring atoms, preferably 5-6 membered heteroaryl; more preferably 5-6 membered heteroaryl containing 1 or 2 N atoms; non-limiting examples include furanyl, thienyl, pyridyl, pyrrolyl, N-alkyl pyrrolyl, pyrimidinyl, pyrazinyl, pyrazole, imidazolyl, triazolyl, tetrazolyl, etc.; preferably pyridyl. The heteroaryl ring can be fused to an aryl, heterocycloalkyl or cycloalkyl ring, wherein the ring that is attached to the parent structure is a heteroaryl ring, non-limiting examples include: The heteroaryl group can be optionally substituted or unsubstituted. In some embodiments, the heteroaryl group is a 5, 6, 7, 8, 9, 10 membered heteroaryl, wherein the number of heteroatoms can be 1, 2, 3, 4 or 5, each heteroatom independently being nitrogen, oxygen or S.

[0440] "Alkenyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond. 2-8 "Alkenyl" refers to a straight or branched chain alkenyl containing 2 to 8 carbon atoms, including but not limited to vinyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl, etc., preferably "C 2-6 Alkenyl", more preferably "C 2-4 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.

[0441] "Alkynyl" refers to an alkyl group as defined above composed of at least two carbon atoms and at least one carbon-carbon triple bond. 2-8 "Alkynyl" refers to a straight or branched chain alkynyl containing 2 to 8 carbon atoms, including but not limited to ethynyl, 1-propynyl, 2-propynyl, 1-, 2- or 3-butynyl, preferably "C 2-6 Alkynyl", more preferably "C 2-4 The alkynyl group can be substituted or unsubstituted. In some embodiments, the alkynyl group is a C2, C3, C4, C5, C6, C7, or C8 alkynyl group.

[0442] "Ylene" refers to a divalent group, such as alkylene refers to a divalent alkyl group, alkenylene refers to a divalent alkenyl group, alkynylene refers to a divalent alkynyl group, cycloalkylene refers to a divalent cycloalkyl group, heterocycloalkylene refers to a divalent heterocycloalkyl group, arylene refers to a divalent aryl group, and heteroarylene refers to a divalent heteroaryl group. The alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups are as defined above, and the alkylene group may be optionally substituted or unsubstituted.

[0443] "Haloalkyl" refers to an alkyl group optionally substituted with one or more fluorine, chlorine, bromine or iodine atoms, wherein alkyl is as defined above, non-limiting examples of which include difluoromethyl, dichloromethyl, dibromomethyl, trifluoromethyl, trichloromethyl, tribromomethyl and the like.

[0444] "Alkoxy" refers to an -O-alkyl group wherein alkyl is as defined above, non-limiting examples of which include methoxy, ethoxy, isopropoxy, tert-butoxy, and the like.

[0445] In the present invention, "one or more" means one or more under reasonable conditions, such as 2, 3, 4, 5, 6, 7, 8, 9 or 10.

[0446] Unless otherwise specified, as used herein, the point of attachment of a substituent may be from any suitable position of the substituent.

[0447] Also included within the scope of the application are metabolites of the compounds of the application, i.e., substances produced within the body that arise from the administration of a compound of the application. Such products can result, e.g., from oxidation, reduction, hydrolysis, amidation, deamidation, esterification, enzymatic cleavage, and the like. Accordingly, metabolites of the compounds of the application, including those produced by the in vivo chemical transformation of a compound of the application, are within the scope of the application.

[0448] The application further includes within its scope prodrugs of the compounds of the application, which are certain derivatives of the compounds of the application that can have little or no pharmacological activity themselves, but, when administered into or onto the body, are converted by metabolic processes into the compounds of the application that are the pharmacologically active substances. Typically such prodrugs will be functional derivatives of the compounds of the application, which are easily converted by in vivo chemical processes into the desired therapeutically active compounds.

[0449] "Heteroatom or heteroatomic group" means N, O, S, S(=0)2, S(O), and the like.

[0450] "Cyano" means -CN.

[0451] "Hydroxy" means -OH.

[0452] "Sulfonyl" means -S(O)2-.

[0453] "Carboxyl" or "carboxylic acid" means -COOH.

[0454] "Oxo" means =0 group.

[0455] "Halo" means fluorine, chlorine, bromine, or iodine.

[0456] "EA or EtOAc" means ethyl acetate.

[0457] "THF" means tetrahydrofuran.

[0458] "DCM" means dichloromethane.

[0459] "CataCXium A Pd-G3" means [n-Bu2(1-adamantyl)phosphine](2-amino-1,1'- biphenyl-2-yl)palladium(II) mesylate.

[0460] "POCl3" means phosphorous oxychloride.

[0461] "NaHCO3" means sodium bicarbonate.

[0462] "NaCl" means sodium chloride.

[0463] "Na2SO4" means sodium sulfate.

[0464] "NH4Cl" means ammonium chloride.

[0465] "C2CO3" means cesium carbonate.

[0466] "CD3I" means deuterated iodomethane.

[0467] "NaBH(OAc)3" means sodium borohydride acetate.

[0468] "Triton B" means benzyltrimethylammonium hydroxide.

[0469] "NaBH3CN" means sodium cyanoborohydride

[0470] "CsF" means cesium fluoride.

[0471] "Na2CO3" means sodium carbonate.

[0472] "HOAc" means acetic acid.

[0473] "TPAP" means tetrapropylammonium perruthenate.

[0474] "NaH" means sodium hydride.

[0475] "i-PrOH" means isopropyl alcohol.

[0476] "DMF" means N,N-dimethylformamide.

[0477] "MeOH" means methanol.

[0478] "Pd / C" means palladium on carbon.

[0479] "DMSO" means dimethylsulfoxide.

[0480] "TFA" means trifluoroacetic acid.

[0481] "DIEA" means N,N-diisopropylethylamine.

[0482] "Dess-Martin" means Dess-Martin periodinane.

[0483] "PBS" means phosphate buffered saline.

[0484] "SDS-PAGE" means sodium dodecyl sulfate-polyacrylamide gel electrophoresis.

[0485] "PVDF" means polyvinylidene difluoride.

[0486] "PE" means petroleum ether.

[0487] "AcOH" means acetic acid.

[0488] "HCl" means hydrochloric acid.

[0489] "dioxane" means 1,4-dioxane.

[0490] "ACN" means acetonitrile.

[0491] "DMP" means dimethyl phthalate.

[0492] "BH3" means borane.

[0493] "PdCl2(dtbpf)" means [1,1'-bis(di-tert-butylphosphino) ferrocene] palladium dichloride.

[0494] "HATU" means 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate. "EtOH" means ethanol.

[0495] "DMAP" means 4-dimethylaminopyridine.

[0496] "TBAF" means tetra-n-butylammonium fluoride.

[0497] "TMEDA" means tetramethylethylenediamine.

[0498] "s-BuLi" means sec-butyllithium.

[0499] "NaBH4" means sodium borohydride.

[0500] "CH3I" means methyl iodide.

[0501] "DEA" means diethanolamine.

[0502] "EDCI" means 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride.

[0503] "HOBT" means 1-hydroxybenzotriazole.

[0504] "LAH" means lithium aluminum hydride.

[0505] "TsCl" means p-toluenesulfonyl chloride.

[0506] "Na2S2O3" means sodium thiosulfate.

[0507] "NaNO2" means sodium nitrite.

[0508] "BBr3" means boron tribromide.

[0509] "K3PO4" means potassium phosphate.

[0510] "AcOK" means potassium acetate.

[0511] "DIBAL-H" means diisobutylaluminum hydride.

[0512] "TEA" means triethylamine.

[0513] "GTP" means guanosine triphosphate.

[0514] "Prep-HPLC" or "pre-HPLC" means preparative high performance liquid chromatography.

[0515] "NFSI" means N-fluorobenzenesulfonamide.

[0516] "Ti(O-iPr)4" means titanium tetraisopropoxide.

[0517] "Pd(dppf)Cl2" means [l,l-bis(diphenylphosphino) ferrocene] dichloropalladium.

[0518] "t-BuOK" means potassium tert-butoxide.

[0519] "Grubbs II catalyst" means ferrocene dimethylruthenium(II) bis(diisopropylphosphine).

[0520] "Pd(OH)2" means palladium hydroxide.

[0521] "LiAlD4" means lithium aluminum deuteride.

[0522] "CH3MgBr" means methylmagnesium bromide.

[0523] "BOPCl" means bis(2-oxo-3-oxazolidinyl)phosphoryl chloride.

[0524] "m-CPBA" means meta-chloroperoxybenzoic acid.

[0525] "Ti(Oi-Pr)4" means titanium tetraisopropoxide.

[0526] "T3P" means 1-propylphosphonic anhydride.

[0527] "sat." means saturated solution.

[0528] "aq" means aqueous solution.

[0529] In the chemical structures herein, "-" as a bond means single bond, and "=" means double bond (in the case of no configuration is specified, it can be trans or cis).

[0530] In the present invention, the expression -N( group) 1-2 means -NH( group) or -N( group)2.

[0531] "Optional" means that the event or circumstance subsequently described can or can not occur, and this description includes instances where the event or circumstance occurs and instances where it does not. For example, "heterocycloalkyl optionally substituted with alkyl" means that alkyl can or can not be present, and this description includes instances where the heterocycloalkyl group is substituted with alkyl and instances where the heterocycloalkyl group is not substituted with alkyl.

[0532] "Substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3, of a group are independently of each other replaced with a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, which can be determined (experimentally or theoretically) by the person skilled in the art without undue effort, possible or impossible substitutions. For example, an amino group with a free hydrogen or a hydroxyl group can be unstable when bound to a carbon atom with an unsaturated (e.g. olefinic) bond.

[0533] Unless otherwise indicated, the term "optionally substituted" as used herein can be unsubstituted or substituted; when substituted, the substituents can be one or more (e.g. 2, 3, 4, 5, or 6) independently selected from alkyl, alkenyl, alkynyl, hydroxyl, hydroxyalkyl, haloalkyl, alkoxy, amino, aminoalkyl, cyano, halogen, oxo, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, said alkyl, alkenyl, alkynyl, hydroxyl, hydroxyalkyl, haloalkyl, alkoxy, amino, aminoalkyl optionally substituted with one or more (e.g. 2, 3, 4, 5, or 6) cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; said cycloalkyl, heterocycloalkyl, aryl, and heteroaryl optionally substituted with one or more groups selected from alkyl, alkenyl, alkynyl, hydroxyl, hydroxyalkyl, haloalkyl, alkoxy, amino, aminoalkyl, cyano, halogen, oxo.

[0534] Unless otherwise indicated, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be considered indefinite or unclear if it is not specifically defined, but should be construed in accordance with its ordinary meaning. When a trade name appears herein, it is intended to designate the corresponding product or its active ingredient.

[0535] "Pharmaceutical composition" means a mixture containing one or more compounds described herein or a physiologically / pharmaceutically acceptable salt or prodrug thereof, in combination with other chemical components such as carriers and excipients, which are also physiologically / pharmaceutically acceptable. The purpose of a pharmaceutical composition is to facilitate administration to an organism, to facilitate absorption, and to facilitate biological activity.

[0536] The present application also provides pharmaceutically acceptable salts of the compounds of Formula (I). The term "pharmaceutically acceptable salt" means a relatively non-toxic, inorganic or organic acid addition salt of a compound of the present application. The acid addition salts are prepared from a compound of Formula (I) by reaction with a suitable inorganic or organic acid following art-known procedures. Representative salts include the hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, sulfite, acetate, oxalate, valerate, oleate, palmitate, stearate, pantothenate, borate, benzoate, lactate, phosphate, monohydrogenphosphate, carbonate, bicarbonate, toluene-p-sulfonate, citrate, maleate, fumarate, succinate, benzoate, methanesulfonate, p-toluenesulfonate, gluconate, lactobionate, and laurylsulfonate salts, and the like. The base salts are prepared from a compound of Formula (I) by reaction with a suitable inorganic or organic base following art-known procedures. Representative base salts include alkali metal, alkaline earth metal, and basic ammonium salts, including for example sodium, lithium, potassium, calcium, magnesium, tetramethylammonium, tetraethylammonium, and the like; and salts with amines including ammonia (NH3), primary, secondary, and tertiary amines, such as methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like.

[0537] The pharmaceutically acceptable salts of the present application can be synthesized from the parent compound that contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two. Generally, non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred.

[0538] The "pharmaceutically acceptable excipient" means an inert substance used to facilitate administration of an active ingredient to a human or animal (e.g., domesticated animals), including but not limited to any of the following: a binder, a bulking agent, a diluent, a preservative, a dye / colorant, a flavor enhancer, a surface active agent, a wetting agent, a dispersing agent, a disintegrant, a suspending agent, a stabilizer, an isotonic agent, a solvent, or an emulsor, which is approved by the State Food and Drug Administration for use in humans or animals.

[0539] As used herein and as familiar in the art, "treatment" or "treating" is an approach for obtaining beneficial or desired results, including clinical results. Beneficial or desired clinical results can include, but are not limited to, decreasing tumor progression, reducing tumor size, decreasing tumor growth rate, reducing tumor invasion and metastatic potential, relieving or ameliorating one or more symptoms or conditions, decreasing the extent of disease, stabilizing (i.e., not worsening) a disease state, preventing disease progression, delaying or slowing disease progression, ameliorating or palliating a disease state, and remission (whether partial or total), whether or not detectable to the eye. "Treatment" or "treating" can also mean prolonging survival as compared to expected survival if not receiving treatment.

[0540] The therapeutic dosage of the compounds of the present application can be determined by, for example, the particular use for which the treatment is made, 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 can vary depending upon a number of factors, including dosage, chemical characteristics (e.g., hydrophobicity), and the route of administration.

[0541] The term "treatment" means the administration of a compound or formulation described herein to ameliorate or eliminate a disease or one or more symptoms associated with the disease, and includes:

[0542] (i) inhibiting the disease or condition, i.e., arresting its development;

[0543] (ii) relieving the disease or condition, i.e., causing regression of the disease or condition.

[0544] The term "therapeutically effective amount" means an amount 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 as described herein. The amount of a compound of the present application that will constitute a "therapeutically effective amount" will vary depending on the compound, the disease state and its severity, the manner of administration, and the age of the mammal to be treated, but can be routinely determined by the skilled practitioner according to his own knowledge and the disclosure herein.

[0545] Unless otherwise required by context, the word "comprise" and variations such as "comprises" or "comprising" will be understood to imply the inclusion of a stated integer or group of integers but not the exclusion of any other integer or group of integers.

[0546] References in the specification to "in some embodiments" or "in embodiments" or "in another embodiment" or "in certain embodiments" means including the particular feature, structure, or characteristic so described, in at least one embodiment. Thus, appearances of the phrases "in some embodiments" or "in embodiments" or "in another embodiment" or "in certain embodiments" in various places in the specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics can be combined in any suitable manner in one or more embodiments.

[0547] The term "isomer" is intended to encompass geometric isomers, cis / trans isomers, stereoisomers, enantiomers, optical isomers, diastereomers, and tautomers, unless otherwise indicated.

[0548] The compounds of the present application can exist in particular geometric or stereoisomeric forms. The present application contemplates all such compounds, including cis- and trans-isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)- isomers, (L)-isomers, as well as the racemic mixtures and other mixtures of the enantiomers or diastereomers, and all isomeric forms modified by

[0549] The term "enantiomer" or "optical isomer" means a stereoisomer which is a mirror image of the other and which cannot be superimposed on the other.

[0550] The term "cis-trans isomer" or "geometric isomer" is caused by the inability of a double bond or ring-forming carbon atom single bond to rotate freely, unless otherwise indicated.

[0551] The term "diastereomer" means a stereoisomer which has two or more chiral centers and which is not a mirror image of the other and which cannot be superimposed on the other, unless otherwise indicated.

[0552] "(+)" means dextrorotatory, "(-)" means levorotatory, and "(±)" means racemic, unless otherwise indicated.

[0553] The term "prodrug" means a chemical derivative of a compound of the present application which, upon in vivo chemical conversion to the compound of Formula I.

[0554] "Optional" or "optionally" means that the subsequently described event or circumstance can or can not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not.

[0555] The term "substituted" means that any one or more hydrogen atoms on a given atom are replaced with a substituent group, which can include isotopes of hydrogen and variations thereof, as long as the valency of the given atom is not exceeded and the resulting compound is stable. When the substituent group is oxygen (i.e., =0), it means that two hydrogen atoms are replaced. Oxygen substitution does not occur on aromatic groups.

[0556] The term "optionally substituted" means that the group can or can not be substituted and that the types and number of substituents are any that are chemically possible, unless otherwise specified.

[0557] When any variable (e.g., R) occurs more than one time in a compound or substituent, its definition in each instance is independent of the definition of the other instances. Thus, for example, if a group is substituted with 0-2 R groups, then the group can optionally be substituted with up to two R groups, and at each occurrence R is selected independently. In addition, combinations of substituents, and / or variables, are permissible only if such combinations result in stable compounds.

[0558] When the number of occurrences of a linking group is zero, such as -(CRR)0-, it means that the linking group is a single bond.

[0559] When one of the variables is selected from a single bond, it means that the two groups to which it is attached are directly connected, such as when L represents a single bond in A-L-Z, the structure actually is A-Z.

[0560] When a substituent is "null," it means that the substituent is absent, such as when X is null in A-X, the structure actually is A. When a recited substituent does not specify through which atom of the recited substituent it is attached to the substituted group, the substituent can be bonded through any of its atoms, for example, a pyridyl group as a substituent can be attached to the substituted group through any of the carbon atoms of the pyridyl ring.

[0561] When a recited linking group does not specify its direction of attachment, its direction of attachment is arbitrary, for example, when the linking group L is -M-W-, then -M-W- can attach ring A and ring B either in the same direction as the reading order from left to right or in the opposite direction as the reading order from left to right. Combinations of substituents, and / or variables, are permissible only if such combinations result in stable compounds.

[0562] Unless otherwise stated, when a group has one or more connectable sites, any one or more sites of the group can be connected to other groups through chemical bonds. When the chemical bond connection mode is non-positional and there is an H atom at the connectable site, when the chemical bond is connected, the number of H atoms at the site will decrease accordingly with the number of connected chemical bonds, and become a group with a corresponding valence. The chemical bond connecting the site to other groups can be represented by a straight solid bond. Straight dotted key or wavy lines For example, the straight solid bond in -OCH2CH3 indicates that it is connected to other groups through the oxygen atom in the group; The straight dashed bond in the group indicates that the two ends of the sulfur atom in the group are connected to other groups; The wavy line in the phenyl group indicates that it is connected to other groups through the carbon atoms at positions 1 and 2 in the phenyl group; Indicates that any linkable site on the pyrrolidyl group can be connected to other groups through a chemical bond, including at least In these three connection methods, even if an H atom is drawn on -N-, Still includes For groups connected in this way, when one chemical bond is connected, the H at that site will be reduced by one and become a corresponding monovalent pyrrolidyl group.

[0563] Unless otherwise specified, use a solid wedge key. and dotted wedge key To indicate the absolute configuration of a stereocenter, use a straight solid bond and straight dashed key Indicate the relative configuration of stereocenters with a wavy line Indicates a wedge-shaped solid key or dotted wedge key Or use a wavy line Indicates a straight solid bond or straight dashed key like represent represent represent

[0564] Unless otherwise indicated, the absolute configuration of a stereocenter is indicated by a solid wedge and a dashed wedge bond, the relative configuration of a stereocenter is indicated by a solid straight bond and a dashed straight bond, and a solid wedge or a dashed wedge bond or a solid straight bond or a dashed straight bond is indicated by a wavy line.

[0565] Unless otherwise indicated, where a compound contains a double bond, such as a carbon-carbon double bond, a carbon-nitrogen double bond, and a nitrogen-nitrogen double bond, and each atom of the double bond is attached to two different substituents (in the case of a double bond involving a nitrogen atom, a pair of lone electrons on the nitrogen atom is considered to be one substituent), if the atoms of the double bond and their substituents are connected by a wavy line indicates that the compound exists as a single isomer of formula (A-1) or formula (A-2) or as a mixture of both isomers of formula (A-1) and formula (A-2). Formula (B) below indicates that the compound exists as a single isomer of formula (B-1) or formula (B-2) or as a mixture of both isomers of formula (B-1) and formula (B-2). Formula (C) below indicates that the compound exists as a single isomer of formula (C-1) or formula (C-2) or as a mixture of both isomers of formula (C-1) and formula (C-2).

[0566] Unless otherwise indicated, the compounds described herein are intended to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the structure of the present application except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by an isotopically enriched 13 C or 14 C-enriched carbon are within the scope of this disclosure.

[0567] Unless otherwise indicated, in some instances the compounds described herein exist as diastereomers, enantiomers, or other stereoisomers. In the absence of specific indications of absolute stereochemistry, compounds, depicted are meant to include all possible enantiomers, diastereomers and rotamers, and isotopologues thereof. Isomers can be separated by chromatography or by separation of mixtures of diastereomers or enantiomers, or any combination thereof, by recrystallization or chromatography. Isomers can also be obtained by stereoselective synthesis.

[0568] Unless otherwise indicated, the term "atropisomer" (or "atropoisomer") is a stereoisomer having a particular spatial configuration resulting from restricted rotation about a single bond due to large steric hindrance. Certain compounds of the present application can exist as atropisomers. The compounds disclosed herein include all atropisomers, either as pure individual atropisomers, or enriched in one atropisomer, or as non-specific mixtures of each. Isomers can be separated if the potential for rotation about the single bond is sufficiently high and the interconversion between conformations is sufficiently slow to allow separation of the isomers. For example with for a pair of atropisomers, wherein the naphthalene ring is represents that the side view is facing outward, represents that the side view is facing inward.

[0569] Unless otherwise indicated, in some embodiments of the application, as represents represents represents represents represents

[0570] Unless otherwise indicated, in some embodiments of the application, are interchangeable, R are interchangeable, R a and R c as defined and described herein; for example are interchangeable, R represents

[0571] Unless otherwise specified, are interchangeable, R the hydrogen atom at any position within the group can be replaced with a substituent.

[0572] Unless otherwise indicated, the term "enriched in one isomer," "isomerically enriched," "enriched in one enantiomer," or "enantiomerically enriched" means that the content of one isomer or enantiomer is less than 100% and the content of the isomer or enantiomer is greater than or equal to 60%, or greater than or equal to 70%, or greater than or equal to 80%, or greater than or equal to 90%, or greater than or equal to 95%, or greater than or equal to 96%, or greater than or equal to 97%, or greater than or equal to 98%, or greater than or equal to 99%, or greater than or equal to 99.5%, or greater than or equal to 99.6%, or greater than or equal to 99.7%, or greater than or equal to 99.8%, or greater than or equal to 99.9%.

[0573] Unless otherwise indicated, the term "excess of isomer" or "excess of enantiomer" means the difference between the relative percentages of two isomers or two enantiomers. For example, where the content of one isomer or enantiomer is 90% and the content of the other isomer or enantiomer is 10%, the excess of isomer or enantiomer (the ee value) is 80%.

[0574] Optically active (R)- and (S)-isomers and the D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If desired, one enantiomer of a compound of the application can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group cleaved to give the pure desired enantiomer. Alternatively, when a basic functionality (such as an amino group) or an acidic functionality (such as a carboxyl group) is present in the molecule, a diastereomeric salt form of the compound with an appropriate optically active acid or base can be formed, and the diastereomeric salt form separated by conventional means, and the desired enantiomer recovered by cleavage of the bond to the auxiliary group. In addition, separation of the enantiomers and diastereomers is typically accomplished by chromatography using a chiral stationary phase, optionally in combination with chemical derivatization (e.g., formation of a carbamate from an amine).

[0575] The compounds of the present application can contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds can be radiolabeled with radioactive isotopes, such as for example tritium ( 3 H), iodine-125 ( 125 I) or carbon-14 ( 14 C). For example, deuterium can be substituted for hydrogen to form deuterated drugs, which have advantages over non-deuterated drugs, such as reduced toxicity, increased stability, increased efficacy, increased biological half-life, etc. All isotopic variations of the compounds of the present application, whether radioactive or not, are encompassed within the scope of the present application.

[0576] Unless otherwise stated, D as used herein means deuterium ( 2 H).

[0577] Unless otherwise indicated, the term "leaving group" means a functional group or atom which can be displaced by another functional group or atom through a substitution reaction, such as a nucleophilic substitution reaction. For example, representative leaving groups include triflate; chloro, bromo, iodo; sulfonate groups such as mesylate, tosylate, brosylate, p-tosylate, and the like; acyloxy groups such as acetoxy, trifluoroacetoxy, and the like.

[0578] Unless otherwise indicated, the term "protecting group" includes, but is not limited to, "amino protecting group," "hydroxyl protecting group," or "thiol protecting group." The term "amino protecting group" refers to a protecting group suitable for blocking the amino nitrogen from side reactions. Representative amino protecting groups include, but are not limited to: formyl; acyl groups, such as alkanoyl groups (e.g., acetyl, trichloroacetyl or trifluoroacetyl); alkoxycarbonyl groups, such as tert-butoxycarbonyl (Boc); arylmethoxycarbonyl groups, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc); arylmethyl groups, such as benzyl (Bn), trityl (Tr), 1,1-bis-(4'-methoxyphenyl)methyl; silyl groups, such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS), and the like. The term "hydroxyl protecting group" refers to a protecting group suitable for blocking the hydroxyl group from side reactions. Representative hydroxyl protecting groups include, but are not limited to: alkyl groups, such as methyl, ethyl, and tert-butyl; acyl groups, such as alkanoyl groups (e.g., acetyl); arylmethyl groups, such as benzyl (Bn), p-methoxybenzyl (PMB), 9-fluorenylmethyl (Fm), and diphenylmethyl (benzhydryl, DPM); silyl groups, such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS), and the like.

[0579] The compounds of the present application can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments set forth below, embodiments formed by combining other chemical synthetic methods with the embodiments set forth below, and equivalents thereof as appreciated by those skilled in the art, preferred embodiments including, but not limited to, the examples of the present application.

[0580] The compounds of the present application can be confirmed by conventional methods well known to those skilled in the art, and if the present application relates to the absolute configuration of a compound, the absolute configuration can be confirmed by conventional means in the art. For example, single crystal X-ray diffraction (SXRD), the diffraction intensity data of the single crystal grown by a Bruker D8 venture diffractometer is collected, the light source is Cu Kα radiation, the scanning mode is scanning, after collecting the relevant data, the crystal structure is further analyzed by direct method (Shelxs97), and the absolute configuration can be confirmed.

[0581] The compounds of the present application, or a pharmaceutically acceptable salt thereof, can be administered to mammals, including humans, orally, rectally, parenterally (intravenously, intramuscularly, or subcutaneously), topically (as a powder, ointment, or drops), or intratumorally.

[0582] The compounds of the present application can be administered in a dose of about 0.05 to 300 mg / kg body weight / day, preferably 10 to 300 mg / kg body weight / day, more preferably 10 to 200 mg / kg body weight / day.

[0583] The compounds of the present application, or their pharmaceutically acceptable salts, can be formulated into solid dosage forms for oral administration such as, but not limited to, capsules, tablets, pills, powders, and granules. In these solid dosage forms, the compounds of Formula (I) of the present application as the active ingredient are mixed with at least one conventional inert excipient (or carrier) such as sodium citrate or dicalcium phosphate, or with ingredients such as (1) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, and the like; (2) binders such as hydroxymethylcellulose, alginic acid, gelatin, polyvinylpyrrolidone, sucrose, and acacia, and the like; (3) humectants such as glycerol and the like; (4) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate, and the like; (5) solution retarders such as paraffin, and the like; (6) absorption accelerators such as quaternary ammonium compounds, and the like; (7) wetting agents such as cetyl alcohol and glycerol monostearate, and the like; (8) absorbents such as kaolin and the like; and (9) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and the like, or mixtures thereof. Buffers, preservatives, flavoring agents, coloring agents, and the like, can also be incorporated.

[0584] The solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other well-known coatings and shells, and they can contain opacifying agents, and can be of such composition that they release the active ingredient(s) in a certain part of the intestinal tract in a delayed manner. Examples of embedding compositions that can be used are polymeric substances and waxes. The active ingredient(s) can also be in micro-encapsulated form, if desired, with one or more of the excipients described above.

[0585] The compounds of the present application, or their pharmaceutically acceptable salts, can be formulated into liquid dosage forms for oral administration such as, but not limited to, pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs. In addition to the compounds of Formula (I) or their pharmaceutically acceptable salts as the active ingredient, the liquid dosage forms can contain inert diluents such as water and other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, and the like, or mixtures thereof, and the like. Besides such inert diluents, the liquid dosage forms can contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents, and the like.

[0586] The suspending agents include, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan, microcrystalline cellulose, aluminum metahydroxide, and agar-agar, and the like or mixtures thereof.

[0587] The compounds of the present application, or their pharmaceutically acceptable salts, can be formulated into dosage forms for parenteral injection by dissolution or suspension in a physiologically acceptable diluent. Carriers which can be used include water, saline, dextrose / glucose, fructose, maltose, lactose, sucrose, mannose, mannitol, polyols, glycols, and the like, and combinations thereof. Intravenous vehicles include fluid and nutrient replenishers. For oral therapeutic administration, the compounds of the present application, or their pharmaceutically acceptable salts, can be combined with one or more excipients and used in the form of tablets, capsules, ovules, gelcaps, troches or lozenges. Pharmaceutical preparations for oral use can be obtained by mixing the compounds of the present application, or their pharmaceutically acceptable salts, with one or more excipients and / or diluents.

[0588] The compounds of the present application, or their pharmaceutically acceptable salts, can also be formulated into dosage forms for topical administration including, for example, ointments, powders, suppositories, drops, sprays, and inhalers. The compounds of the present application, or their pharmaceutically acceptable salts, as the active ingredient, are mixed under sterile conditions with a pharmaceutically acceptable carrier and optionally buffered, to provide the compositions useful in the methods of treatment of the present application.

[0589] The present application also provides pharmaceutical compositions comprising a compound of Formula (I) of the present application, or a pharmaceutically acceptable salt thereof, as an active ingredient, in combination with a pharmaceutically acceptable carrier, excipient, or diluent. In making the pharmaceutical compositions of the present application, the compounds of Formula (I) of the present application, or their pharmaceutically acceptable salts, are typically mixed with a pharmaceutically acceptable carrier, excipient, or diluent.

[0590] The compositions of the present application can be formulated into conventional pharmaceutical compositions by conventional methods. For example, tablets, pills, capsules, powders, granules, emulsions, suspensions, solutions, syrups, elixirs, ointments, drops, suppositories, inhalers, sprays, and the like can be prepared.

[0591] The compounds of the present application, or their pharmaceutically acceptable salts, can be administered alone or, if desired, in combination with other pharmaceutically acceptable therapeutic agents, such as other anti-neoplastic agents. The components to be combined can be administered simultaneously or sequentially, in either order, in separate compositions or in a unitary composition. The combinations described can include combinations of a compound of the present application and one other active agent, as well as combinations of a compound of the present application and two or more other active agents.

[0592] In the present application, other pharmaceutically acceptable therapeutic agents that can be used together or in combination with the KRAS G12D degrader compound of formula (I) can be: EGFR and / or its mutant inhibitor, ErbB2 (Her2) and / or its mutant inhibitor, ALK and / or its mutant inhibitor, MEK and / or its mutant inhibitor, KRAS and / or its mutant inhibitor, BCR-ABL and / or its mutant inhibitor, FGFR1 / FGFR2 / FGFR3 and / or its mutant inhibitor, ROS1 and / or its mutant inhibitor, c-MET and / or its mutant inhibitor, AXL and / or its mutant inhibitor, NTRK1 and / or its mutant inhibitor, RET and / or its mutant inhibitor, taxane, platinum-containing compound, antimetabolite, mitotic kinase inhibitor, immunotherapeutic agent, anti-angiogenic drug, topoisomerase inhibitor, A-Raf / B-Raf / C-RAf and / or its mutant inhibitor, ERK and / or its mutant inhibitor, apoptosis inhibitor, AKT and / or its mutant inhibitor, mTOR inhibitor, epigenetic regulator, IGF1 / 2 and / or IGF1-R inhibitor, Ras GEF and / or its mutant inhibitor, SOS1 and / or its mutant inhibitor, SHP2 and / or its mutant inhibitor, PI3K and / or its mutant inhibitor, PD-1 / PD-L1 inhibitor. EGFR and / or its mutant degrader, ErbB2 (Her2) and / or its mutant degrader, ALK and / or its mutant degrader, MEK and / or its mutant degrader, KRAS and / or its mutant degrader, BCR-ABL and / or its mutant degrader, FGFR1 / FGFR2 / FGFR3 and / or its mutant degrader, ROS1 and / or its mutant degrader, c-MET and / or its mutant degrader, AXL and / or its mutant degrader, NTRK1 and / or its mutant degrader, RET and / or its mutant degrader, A-Raf / B-Raf / C-RAf and / or its mutant degrader, ERK and / or its mutant degrader, AKT and / or its mutant degrader, IGF1 / 2 and / or IGF1-R degrader, Ras GEF and / or its mutant degrader, SOS1 and / or its mutant degrader, SHP2 and / or its mutant degrader, PI3K and / or its mutant degrader. EGFR and / or its mutant mAb, ErbB2 (Her2) and / or its mutant mAb, PD-1 / PD-L1 mAb, CTLA-4 mAb. PD-L1 / TIGHT bi-mAb, PD-L1 / CTLA-4 bi-mAb, EGFR / MET bi-mAb, EGFR / CD3 bi-mAb, EGFR / 4-IBB bi-mAb, PD-L1 / 4-IBB bi-mAb, HER2 / CD3 bi-mAb.

[0593] In the present application, the other pharmaceutically acceptable therapeutic agent that can be used together or in combination with the KRAS G12D degrader compound of formula (I) can be: afatinib, erlotinib, gefitinib, lapatinib, cetuximab, panitumumab, osimertinib, olmutinib, EGF-816, trastuzumab, pertuzumab, crizotinib, alectinib, entrectinib, brigatinib, trametinib, cobimetinib, binimetinib, selumetinib, refametinib, imatinib, dasatinib, nilotinib, nintedanib, crizotinib, lorlatinib, ceritinib, merestinib, paclitaxel, nab-paclitaxel, docetaxel, cisplatin, carboplatin, oxaliplatin, 5-fluorouracil, capecitabine, floxuridine, cytarabine, gemcitabine, the combination of trifluridine and tipiracil (= TAS102), palbociclib, ribociclib, abemaciclib, ipilimumab, nivolumab, pembrolizumab, atezolizumab, avelumab, durvalumab, pidilizumab, PDR-001 (= spartalizumab), bevacizumab, irinotecan, liposomal irinotecan, topotecan, ulixertinib, rapamycin, temsirolimus, everolimus,Ridaforolimus, JQ-1, GSK 525762, OTX 015 (= MK8628), CPI 0610, TEN-010 (= RO 6870810), xentuzumab (antibody 60833 in WO 2010 / 066868) or MEDI-573 (= dusigitumab).

[0594] The above-mentioned preferred conditions can be combined arbitrarily, i.e. to obtain the preferred embodiments of the present application.

[0595] The reagents and materials used in the present application are commercially available.

[0596] The compounds are named according to the usual rules in the art, and the commercially available compounds can also use the name in the supplier's catalog.

[0597] The present application is proved by KRAS G12D kinase activity test that the compound of formula I can effectively bind to or produce inhibitory effect on KRAS G12D target protein, and Western-Blot proves that the compound of formula I can effectively and specifically degrade KRAS G12D protein in A427 cells. The compound of formula I, and / or its stereoisomer, enantiomer, diastereomer, deuterated compound, hydrate, solvate, metabolite, prodrug and / or pharmaceutically acceptable salt thereof can effectively degrade KRAS G12D protein, so as to achieve the effect of preventing or treating diseases or disorders related to KRAS G12D or caused by the interaction of KRAS G12D with SOS1 or SHP2 protein. DETAILED DESCRIPTION

[0598] The present application will be further described in the following examples, but the present application is not limited in the scope of the examples. The experimental methods in the following examples without specific conditions are selected according to the conventional methods and conditions, or according to the instructions of the commodity.

[0599] The present application will be further described in the following examples, but the present application is not limited in the scope of the examples. The experimental methods in the following examples without specific conditions are selected according to the conventional methods and conditions, or according to the instructions of the commodity.

[0600] Preparation examples of compound I

[0601] Intermediate 1: tert-Butyl 3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- ((trisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((1-(piperazin-1-ylmethyl)cyclopropyl) methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0602] Step 1: Preparation of tert-butyl 3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- ((trisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((1-(piperazin-1-ylmethyl)cyclopropyl) methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0603] Step 1: Preparation of tert-butyl 3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- ((trisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((1-(piperazin-1-ylmethyl)cyclopropyl) methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0604] LC-MS: (ESI, m / z): [M+H] + = 261.2.

[0605] Step 2: Preparation of tert-butyl 3-(2-((1-((4-benzylpiperazin-1-yl)methyl)cyclopropyl) methoxy)-7-chloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate

[0606] tert-Butyl 3-(2-((1-((4-benzylpiperazin-1-yl)methyl)cyclopropyl)methoxy)-7-chloro-8- fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.5 g, 2.4 mmol) was dissolved in DCM (15 mL), 1-chloroethyl chloroformate (1.03 g, 7.2 mmol) and DIEA (0.62 g, 4.8 mmol) were added. The mixture was reacted at room temperature for 30 minutes, concentrated under reduced pressure, the concentrate was dissolved with MeOH (15 mL), heated to 50 °C and reacted for 30 minutes. After the reaction was completed, the mixture was concentrated and purified by silica gel column chromatography (DCM:MeOH = 100:1 ~ 10:1) to obtain tert-butyl 3-(7-chloro-8-fluoro-2-((1-(piperazin-1-ylmethyl)cyclopropyl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate.

[0607] LC-MS: (ESI, m / z): [M+H] + = 652.3.

[0608] Step 3: Preparation of tert-butyl 3-(7-chloro-8-fluoro-2-((1-(piperazin-1-ylmethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0609] tert-Butyl 3-(2-((1-((4-benzylpiperazin-1-yl)methyl)cyclopropyl)methoxy)-7-chloro-8- fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.5 g, 2.4 mmol) was dissolved in DCM (15 mL), 1-chloroethyl chloroformate (1.03 g, 7.2 mmol) and DIEA (0.62 g, 4.8 mmol) were added. The mixture was reacted at room temperature for 30 minutes, concentrated under reduced pressure, the concentrate was dissolved with MeOH (15 mL), heated to 50 °C and reacted for 30 minutes. After the reaction was completed, the mixture was concentrated and purified by silica gel column chromatography (DCM:MeOH = 100:1 ~ 10:1) to obtain tert-butyl 3-(7-chloro-8-fluoro-2-((1-(piperazin-1-ylmethyl)cyclopropyl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate.

[0610] LC-MS: (ESI, m / z): [M / 2+H] + = 562.2.

[0611] Step 4: Preparation of tert-butyl 3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((1-(piperazin-1-ylmethyl)cyclopropyl) methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0612] To a mixture solution of tert-butyl 3-(7-chloro-8-fluoro-2-((1-(piperazin-1-ylmethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (1.00 g, 1.78 mmol) and ((2-fluoro-6-((methoxymethyl)oxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (1.1 g, 2.14 mmol) in dioxane (9 mL) and H2O (1 mL) was added cataCXium A Pd-G3 (262 mg, 0.36 mmol) and cesium carbonate (1.74 g, 5.34 mmol). The mixture was reacted at 80 °C for 16 h under nitrogen protection. Water (100 mL) was added to the reaction solution, and the organic phase was extracted with ethyl acetate (100 mL x 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The concentrate was purified by column chromatography (DCM:MeOH = 100:1 ~ 7:1) to obtain tert-butyl 3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((1-(piperazin-1-ylmethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate.

[0613] LC-MS: (ESI, m / z): [M+H] + = 912.4.

[0614] 1H NMR (400 MHz, DMSO-d6) δ 9.17 (s, 1H), 8.11 (dd, J = 9.2 Hz, 6.0 Hz, 1H), 7.75 (d, J = 2.4 Hz, 1H), 7.59-7.53 (m, 1H), 7.33 (d, J = 2.4 Hz, 1H), 5.37 (s, 2H), 4.77-4.70 (d, J = 12 Hz, 1H), 4.40-4.15 (m, 6H), 3.73 (d, J = 11.6 Hz, 1H), 3.43 (s, 1H), 3.38-3.32 (m, 2H), 2.95-2.85 (m, 4H), 2.52-2.51 (m, 2H), 2.47-2.29 (m, 2H), 1.96-1.77 (m, 3H), 1.74-1.57 (m, 2H), 1.46 (s, 9H), 0.81 (t, J = 7.2 Hz, 18H), 0.69-0.60 (m, 2H), 0.53-0.37 (m, 5H).

[0615] Intermediate 2: Intermediate 2-P1 and Intermediate 2-P2

[0616] Step 1: Preparation of tert-butyl 3-benzyl-l-formyl-3,8-diazabicyclo[3.2.1]octane-8- carboxylate

[0617] tert-Butyl 3-benzyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (9.5 g, 31.4 mmol) and TMEDA (4.1 g, 35.16 mmol) were dissolved in tetrahydrofuran (100 mL), cooled to 0 °C, s-BuLi (36 mL, 47.1 mmol, 1.3 mol / L / n-hexane solution) was added, after reaction at 0 °C for 1 hour, DMF (2.8 g, 37.7 mmol) was added, slowly raised to room temperature for reaction for 10 hours. After the reaction was completed, the reaction liquid was poured into saturated aqueous ammonium chloride solution (100 mL) and extracted with ethyl acetate (100 mL x 2). The organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated to give a crude product, which was purified by silica gel column chromatography (PE:EtOAc = 100:1 ~ 20:1) to give tert-butyl 3-benzyl-l-formyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate.

[0618] LC-MS: (ESI, m / z): [M+H] + = 331.2.

[0619] Step 2: Preparation of tert-butyl 3-benzyl-l-(hydroxymethyl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate

[0620] tert-Butyl 3-benzyl-l-formyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (5.0 g, 15.15 mmol) was dissolved in methanol (500 mL), NaBH4(1.15 g, 30.30 mmol) was added at 0 °C and the reaction was allowed to proceed for 3 h. After the reaction was completed, saturated aqueous ammonium chloride solution (20 mL) was added and extracted with ethyl acetate (60 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give tert-butyl 3-benzyl-l-(hydroxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate.

[0621] LC-MS: (ESI, m / z): [M+H] + = 333.2.

[0622] Step 3: Preparation of tert-butyl 3-benzyl-l-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0623] tert-Butyl 3-benzyl-l-(hydroxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (4.1 g, 12.30 mmol) was dissolved in N,N-dimethylformamide (50 mL) and cooled to 0 °C. NaH (733 mg, 18.45 mmol) was added and the reaction was allowed to proceed for 1 h at 0 °C. CH3I (5.24 g, 36.90 mmol) was added and the reaction was allowed to proceed for 3 h at 25 °C. After the reaction was completed, the reaction solution was poured into saturated aqueous ammonium chloride solution (40 mL) and extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (PE:EA = 4: 1) to give tert-butyl 3-benzyl-l-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate.

[0624] LC-MS: (ESI, m / z): [M+H] + = 347.2.

[0625] Step 5: Preparation of tert-butyl l-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0626] tert-Butyl 3-benzyl-l-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (3.1 g, 8.95 mmol) was dissolved in methanol (30 mL), Pd / C (0.5 g) was added, and the reaction was carried out under hydrogen atmosphere at 25 °C for 16 h. The reaction solution was filtered through celite, and the filtrate was concentrated to give tert-butyl l-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate.

[0627] LC-MS: (ESI, m / z): [M-Boc+H] + = 157.3.

[0628] Step 6: Preparation of Intermediate 2-P1 and Intermediate 2-P2

[0629] tert-Butyl 3-benzyl-l-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (3.1 g, 8.95 mmol) was dissolved in methanol (30 mL), Pd / C (0.5 g) was added, and the reaction was carried out under hydrogen atmosphere at 25 °C for 16 h. The reaction solution was filtered through celite, and the filtrate was concentrated to give tert-butyl l-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate.

[0630] Intermediate 2-P1 (chiral column peak time: 2.248 min). SFC analysis method (column: Daicel chiralpak AD_3, 3*150 mm, 3 pm; mobile phase: CO2 / MeOH (0.1% DEA); gradient: 50 / 50, 6 min; flow rate: 1.5 mL / min; wavelength: 214 nm; column temperature: 37 °C; optical purity: 100%.

[0631] Intermediate 2-P2 (Chiral column retention time: 2.350 min). SFC analysis method (Column: Daicel chiralpak AD_3, 3*150 mm, 3 pm; Mobile phase: CO2 / MeOH (0.1% DEA); Gradient: 50 / 50, 6 min; Flow rate: 1.5 mL / min; Wavelength: 214 nm; Column temperature: 37 °C; Optical purity: 100%.

[0632] LC-MS: (ESI, m / z): [M+H] + = 472.1.

[0633] Intermediate 3: 3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- ((trisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((1-formylcyclopropyl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)-1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

[0634] Step 1: Preparation of 3-(7-chloro-8-fluoro-2-((1-(hydroxymethyl)cyclopropyl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)-1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

[0635] Intermediate 2-P1 (Chiral column retention time: 2.248 min) (400 mg, 0.85 mmol) and cyclopropane-1,1-diyl dimethanol (173 mg, 1.69 mmol) were dissolved in anhydrous acetonitrile (40 mL), cesium carbonate (551 mg, 1.69 mmol) and triethylenediamine (28 mg, 0.25 mmol) were added. The reaction was stirred at 25 °C for 4 h. The reaction was poured into saturated aqueous ammonium chloride solution (150 mL), extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated NaCl solution, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated to give 3-(7-chloro-8-fluoro-2-((1-(hydroxymethyl)cyclopropyl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)-1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester.

[0636] LC-MS: (ESI, m / z): [M+H] + = 538.2.

[0637] Step 2: Preparation of tert-butyl 3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((1-(hydroxymethyl)cyclopropyl)methoxy) pyridino[4,3-d]pyrimidin-4-yl)-1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate

[0638] To a mixture solution of tert-butyl 3-(7-chloro-8-fluoro-2-((1- (hydroxymethyl)cyclopropyl)methoxy)pyridino[4,3-d]pyrimidin-4-yl)-1- (methoxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (482 mg, 0.90 mmol) and ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1- yl)ethynyl)triisopropylsilane (917 mg, 1.79 mmol) in 1,4-dioxane (40 mL) and H2O (10 mL) was added CataCXium A Pd-G3 (130 mg, 0.18 mmol) and cesium carbonate (875 mg, 2.68 mmol). The mixture was reacted at 85 °C for 18 h under nitrogen protection. Water (10 mL) was added to the reaction solution, which was then extracted with ethyl acetate (10 mL x 3), the organic phases were combined and dried over anhydrous sodium sulfate before being concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (DCM:MeOH = 20:1) to obtain tert-butyl 3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((1- (hydroxymethyl)cyclopropyl)methoxy)pyridino[4,3-d]pyrimidin-4-yl)-1-(methoxymethyl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate.

[0639] LC-MS: (ESI, m / z): [M+H] + = 888.3.

[0640] Step 3: Preparation of tert-butyl 3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((1-formylcyclopropyl)methoxy)pyridino[4,3- d]pyrimidin-4-yl)-1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0641] To a solution of 3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((1-(hydroxymethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (656 mg, 0.74 mmol) in dichloromethane (50 mL) was added Dess-Martin Oxidizing reagent (470 mg, 1.11 mmol) and the reaction was stirred at room temperature for 3 hours. The reaction was poured into saturated aqueous sodium carbonate solution (60 mL) and then extracted with ethyl acetate (50 mL x 2). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous Na2SO4, filtered and the filtrate was concentrated to give 3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((1-formylcyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester.

[0642] LC-MS: (ESI, m / z): [M+H] + = 886.3.

[0643] Intermediate 4: 3-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)-3- azaspiro[5.5]undecane-9-carbaldehyde

[0644] 9-Formyl-3-azaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester (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-carbaldehyde which was used directly in the next reaction.

[0645] Step 2: Preparation of 3-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)-3- azaspiro[5.5]undecane-9-carbaldehyde

[0646] To a solution of 3-azaspiro[5.5]undecan-9-carbaldehyde (500 mg, crude) in DMSO (10 mL) was added DIEA (720 mg, 5.61 mmol) and 3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoic acid pentafluorophenyl ester (641 mg, 1.49 mmol), the reaction was stirred at room temperature for 1 hour. Water was added to the reaction and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated and purified by silica gel column chromatography (DCM:MeOH = 100:1 ~ 10:1) to give 3-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)-3-azaspiro[5.5]undecan-9-carbaldehyde.

[0647] LC-MS: (ESI, m / z): [M+H] + = 428.3.

[0648] Intermediate 5: 3-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methylbenzoyl)-3-azaspiro[5.5]undecan-9-carbaldehyde

[0649] Prepared according to the procedure described in WO2023025159A1 for intermediate 32.

[0650] Intermediate 6: 3-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

[0651] Step 1: Preparation of 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine

[0652] 7-chloro-8-fluoro-1,2,3,4-tetrahydropyrido[4,3-d]pyrimidine-2,4-dione (9.30 g, 43.14 mmol) was dissolved in PCl3(100 mL), cooled to 0 °C, and DIEA (16.69 g, 129.42 mmol) was added dropwise slowly with stirring. The reaction was heated to 120 °C for 16 hours. After the reaction was completed, the reaction was concentrated, diluted with ethyl acetate, and then slowly poured into ice water to quench, extracted with ethyl acetate (100 mL x 3), and the organic phase was separated. The organic phase was washed successively with cooled aqueous NaHCO3solution 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.

[0653] Step 2: Preparation of tert-butyl 3-(2,7-dichloro-8-fluoropyrido[4,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0654] To a solution of 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (1.00 g, 3.97 mmol) and TEA (1.20 g, 11.90 mmol) in THF (15 mL) was cooled to -60 °C. A solution of tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (0.71 g, 3.37 mmol) in THF (5 mL) was added dropwise slowly and the reaction was stirred at -60 °C for 30 min. After the reaction was completed, the reaction was poured into aqueous NH4Cl solution (20 mL) and extracted with ethyl acetate (30 mL x 3). The organic phase was combined, washed with saturated NaCl solution, dried over anhydrous Na2SO4, filtered and the filtrate was concentrated to give the crude product which was purified by silica gel column (PE:EtOAc = 3:1) to give tert-butyl 3-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate.

[0655] LC-MS: (ESI, m / z): [M+H] + = 428.2.

[0656] Intermediate 7: 1-(2-methoxy-5-(9-(piperazin-1-ylmethyl)-3-azaspiro[5.5]undecane-3- carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione

[0657] Step 1: Preparation of tert-butyl 9-((4-((benzyloxy)carbonyl)piperazin-1-yl)methyl)-3- azaspiro[5.5]undecane-3-carboxylate

[0658] To a mixture of tert-butyl 9-formyl-3-azaspiro[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. Then NaBH(OAc)3 (2.25 g, 10.60 mmol) was added portionwise to the above mixture at 0-5 °C and the stirring was continued for 0.5 h. The reaction was directly concentrated under reduced pressure and the crude product was purified by silica gel column chromatography (MeOH:DCM = 150:1 ~ 20:1) to give tert-butyl 9-((4-((benzyloxy)carbonyl)piperazin-1-yl)methyl)-3-azaspiro[5.5]undecane-3- carboxylate.

[0659] LC-MS: (ESI, m / z): [M+H] + = 486.3.

[0660] Step 2: Preparation of 4-((3-azaspiro[5.5]undecan-9-yl)methyl)piperazine-1- carboxylic acid benzyl ester

[0661] 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 HC1 / 1,4-dioxane (6 N, 5 mL). The mixture was stirred at room temperature for 1 hour, and the reaction was directly concentrated under reduced pressure to give 4-((3-azaspiro[5.5]undecan-9-yl)methyl)piperazine-1-carboxylic acid benzyl ester. The resulting crude product was used directly in the next step without purification.

[0662] Step 3: Preparation of 4-((3-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4- methoxybenzoyl)-3-azaspiro[5.5]undecan-9-yl)methyl)piperazine-1-carboxylic acid benzyl ester

[0663] To a solution of 4-((3-azaspiro[5.5]undecan-9-yl)methyl)piperazine-1-carboxylic acid benzyl ester (632 mg, crude) in DMSO (10 mL) was added 3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoic acid pentafluorophenyl ester (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 4-((3-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)-3-azaspiro[5.5]undecan-9-yl)methyl)piperazine-1-carboxylic acid benzyl ester.

[0664] LC-MS: (ESI, m / z): [M+H] + = 632.3.

[0665] Step 4: Preparation of 1-(2-methoxy-5-(9-(piperazin-1-ylmethyl)-3-azaspiro[5.5]undecan-3- ylcarbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione

[0666] To a solution of 4-((3-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4- methoxybenzoyl)-3-azaspiro[5.5]undecan-9-yl)methyl)piperazine-1-carboxylic acid benzyl ester (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 was filtered through celite 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.

[0667] LC-MS: (ESI, m / z): [M+H] + = 498.2.

[0668] Intermediate 8: 1-(2-methyl-5-(9-(piperazin-1-ylmethyl)-3-azaspiro[5.5]undecane-3- carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione

[0669] 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-carboxylic acid benzyl ester

[0670] To a solution of 4-((3-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4- methylbenzoyl)-3-azaspiro[5.5]undecan-9-yl)methyl)piperazine-1-carboxylic acid benzyl ester (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 was filtered through celite 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.

[0671] LC-MS: (ESI, m / z): [M+H] + = 616.3.

[0672] 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

[0673] To a solution of 4-((3-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4- methylbenzoyl)-3-azaspiro[5.5]undecan-9-yl)methyl)piperazine-1-carboxylic acid benzyl ester (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 was filtered through celite 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.

[0674] LC-MS: (ESI, m / z): [M+H] + = 482.2.

[0675] Intermediate 9: tert-Butyl 3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((R)-2-methyl-3-(piperazin-1-yl)propoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-ethenyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0676] Step 1: Preparation of tert-Butyl 3-trityl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0677] tert-Butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (11.00 g, 51.57 mmol) and triethylamine (10.44 g, 103.14 mmol) were dissolved in acetonitrile (150 mL), and triphenylmethyl chloride (21.57 g, 77.36 mmol) was added, and the reaction was carried out at room temperature for 18 hours in the dark. After the reaction was completed, petroleum ether (50 mL) was added to the reaction, stirred for 30 minutes, filtered, the filter cake was stirred with water (100 mL) and filtered, repeated twice, and then freeze-dried to remove water to give tert-butyl 3-trityl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate.

[0678] LC-MS: (ESI, m / z): [M+Na] + = 477.2.

[0679] Step 2: Preparation of tert-Butyl 1-formyl-3-trityl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0680] A solution of 3-trityl-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (15 g, 32.9 mmol) in THF (150 mL) was cooled to -78 °C, TMEDA (9.56 g, 82.2 mmol) and s-BuLi (4.22 g, 65.8 mmol) were added slowly under nitrogen protection, after stirring at -78 °C for 2 h, DMF (7.21 g, 98.7 mmol) was added, then warmed to room temperature and stirred for 16 h. The reaction was poured into saturated aqueous ammonium chloride solution (200 mL), extracted with ethyl acetate (200 mL x 3). The organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The obtained crude product was purified by silica gel column chromatography (PE:EA = 10:1) to give 1-formyl-3-trityl-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester.

[0681] LC-MS: (ESI, m / z): [M+Na] + = 505.2.

[0682] Step 3: Preparation of Intermediate 9-P1 and Intermediate 9-P2

[0683] Methyl triphenylphosphonium bromide (18.22 g, 51.0 mmol) was dissolved in THF (80 mL), t-BuOK (5.72 g, 51.0 mmol) was added to the mixture at 0 °C. After 10 min, 1-formyl-3-trityl-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (8.2 g, 17.0 mmol) was added at 0 °C, then the reaction mixture was stirred at 25 °C for 18 h. The reaction was poured into saturated aqueous ammonium chloride solution (200 mL), extracted with ethyl acetate (200 mL x 3). The organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The obtained crude product was purified by silica gel column chromatography (PE:EtOAc = 50:1~5:1) to give 3-trityl-1-vinyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester, the obtained compound was purified by SFC, method: column: chiralpak-IG, 250*30mm, 10um; mobile phase: CO2 / MeOH (0.2% NH3(7M Solution in MeOH; gradient: 90 / 10, 6min; flow rate: 80g / min; wavelength: 214nm; column temperature: 35 °C.

[0684] Intermediate 9-P2 (Chiral column retention time: 1.744 min). SFC analytical method (Column: chiralpak-IG-3, 150 mm x 3 mm, 3 pm); mobile phase: C02 / MeOH (0.1% DEA); gradient: 90 / 10, 6 min; flow rate: 2.0 mL / min; wavelength: 214 nm & 254 nm; column temperature: 37 °C; optical purity: 100%.

[0685] Intermediate 9-P2 (Chiral column retention time: 1.744 min). SFC analytical method (Column: chiralpak-IG-3, 150 mm x 3 mm, 3 pm); mobile phase: C02 / MeOH (0.1% DEA); gradient: 90 / 10, 6 min; flow rate: 2.0 mL / min; wavelength: 214 nm & 254 nm; column temperature: 37 °C; optical purity: 100%.

[0686] LC-MS: (ESI, m / z): [M+Na] + = 503.2.

[0687] Step 4: Preparation of tert-butyl 1-vinyl-3,8-diazabicyclo[3.2.1]octane-8- carboxylate

[0688] Intermediate 9-P1 (1.50 g, 3.11 mmol) was dissolved in DCM (20 mL), AcOH (10 mL) was added, and the reaction was stirred at 45 °C for 4 h. The reaction was directly concentrated, and the obtained crude was purified by silica gel column chromatography (DCM:MeOH(NH3) = 10:1) to give tert-butyl 1-vinyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate.

[0689] LC-MS: (ESI, m / z): [M-56+H] + = 183.2.

[0690] Step 5: Preparation of tert-butyl 3-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)- 1-vinyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0691] Dissolve 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (353 mg, 1.40 mmol) and triethylamine (430 mg, 1.70 mmol) in tetrahydrofuran (6 mL), cool to -50 °C, add tert-butyl 1-vinyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (367 mg, 1.53 mmol), and react at -50 °C for 3 h. Pour the reaction into saturated aqueous ammonium chloride solution (10 mL), and extract with ethyl acetate (20 mL x 3). Combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate. Purify the resulting crude product by silica gel column chromatography (PE:EA = 2:1) to obtain tert-butyl 3-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-1-vinyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate.

[0692] LC-MS: (ESI, m / z): [M+H] + = 454.1.

[0693] Step 6: Preparation of tert-butyl 3-(2-((R)-3-(4-benzylpiperazin-1-yl)-2-methylpropoxy)-7-chloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-1-vinyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0694] Dissolve tert-butyl 3-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-1-vinyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (450 mg, 0.99 mmol) and (R)-3-(4-benzylpiperazin-1-yl)-2-methylpropan-1-ol (370 mg, 1.48 mmol) in THF (8 mL) and add to a sealed tube reactor, add Cs2CO3 (966 mg, 2.96 mmol). React at 90 °C for 16 h. After the reaction is complete, cool to room temperature, add water (10 mL) to the reaction, and extract with ethyl acetate (20 mL x 3). Combine the organic phases, wash with saturated NaCl solution, dry over anhydrous Na2SO4, filter, and concentrate the filtrate. Purify the resulting crude product by silica gel column chromatography (DCM:MeOH = 15:1) to obtain tert-butyl 3-(2-((R)-3-(4-benzylpiperazin-1-yl)-2-methylpropoxy)-7-chloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-1-vinyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate.

[0695] LC-MS: (ESI, m / z): [M+H] + = 666.3.

[0696] Step 7: Preparation of tert-butyl 3-(2-((R)-3-(4-benzylpiperazin-1-yl)-2- methylpropoxy)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-1- ethenyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0697] To a mixture solution of tert-butyl 3-(2-((R)-3-(4-benzylpiperazin-1-yl)-2- methylpropoxy)-7-chloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-1-ethenyl-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (500 mg, 0.75 mmol) and ((2-fluoro-6- (methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl) ethynyl)triisopropylsilane (460 mg, 0.90 mmol) in 1,4-dioxane (5 mL) and H2O (1 mL) was added CataCXium A Pd-G3 (109 mg, 0.15 mmol) and cesium carbonate (731 mg, 2.24 mmol). The mixture was reacted at 85 °C for 16 h under nitrogen protection. Water (15 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (15 mL x 3). The organic phase was combined and dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (DCM:MeOH = 15:1) to give tert-butyl 3-(2-((R)-3-(4-benzylpiperazin-1-yl)-2-methylpropoxy)-8-fluoro-7-(7-fluoro-3- (methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3- d]pyrimidin-4-yl)-1-ethenyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate.

[0698] LC-MS: (ESI, m / z): [M / 2 + H] + = 508.9.

[0699] Step 8: Preparation of tert-butyl 3-(8-fluoro-7-(7-fluoro-3- (methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((R)-2-methyl- 3-(piperazin-1-yl)propoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-ethenyl-3,8- diazabicyclo[3.2.1]octane-8-carboxylate

[0700] Tert-butyl 3-(2-((R)-3-(4-benzylpiperazin-1-yl)-2-methylpropoxy)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-1-vinyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (490 mg, 0.48 mmol) was dissolved in DCM (5 mL), and 1-chloroethyl chloroformate (206 mg, 1.44 mmol) and DIEA (124 mg, 0.96 mmol) were added. The mixture was reacted at room temperature for 1 hour. The reaction solution was directly concentrated under reduced pressure, and MeOH (5 mL) was added to the resulting concentrate, which was then heated to 50°C for 10 minutes. After the reaction was completed, the mixture was concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (DCM:MeOH=10:1) to give tert-butyl 3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((R)-2-methyl-3-(piperazin-1-yl)propoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-vinyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate.

[0701] LC-MS:(ESI,m / z):[M / 2+H] + =463.8.

[0702] Intermediate 10: tert-Butyl 1-ethyl-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((R)-2-methyl-3-(piperazin-1-yl)propoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0703] Step 1: Preparation of tert-butyl 1-vinyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0704] Intermediate 9-P1 (1.50 g, 3.11 mmol) was dissolved in DCM (20 mL) and AcOH (10 mL) was added. The mixture was reacted at 45°C for 4 hours. The reaction solution was concentrated, and the crude product was purified by silica gel column chromatography (DCM:MeOH(NH3) = 10:1) to obtain tert-butyl 1-vinyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate.

[0705] LC-MS: (ESI, m / z): [M-56+H] + =183.2.

[0706] Step 2: Preparation of tert-butyl 1-ethyl-3,8-diazabicyclo[3.2.1]octane-8- carboxylate

[0707] tert-Butyl 1-ethyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (330 mg, 1.38 mmol) was dissolved in MeOH (3 mL), Pd / C (60 mg) was added, and the reaction was stirred at room temperature under a hydrogen atmosphere for 3 hours. After the reaction was completed, it was filtered and concentrated to give crude tert-butyl 1-ethyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate.

[0708] LC-MS: (ESI, m / z): [M+H] + = 241.3.

[0709] Step 3: Preparation of tert-butyl 3-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-1- ethyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0710] tert-Butyl 3-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-1-ethyl-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (250 mg, 0.54 mmol) was dissolved in THF (5 mL), and 2 M NaOH (2 mL) was added. The reaction was stirred at room temperature for 3 hours. After the reaction was completed, it was concentrated, and the residue was dissolved in water (5 mL). The pH was adjusted to 7 with 1 M HCl, and the product was extracted with ethyl acetate (20 mL x 3). The organic phase was combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The obtained crude product was purified by silica gel column chromatography (PE:EA = 3:1) to give tert-butyl 3-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-1-ethyl-3,8- diazabicyclo[3.2.1]octane-8-carboxylate.

[0711] LC-MS: (ESI, m / z): [M+H] + = 456.2.

[0712] Step 4: Preparation of tert-butyl 3-(2-((R)-3-(4-benzylpiperazin-1-yl)-2-methylpropoxy)-7- chloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-1-ethyl-3,8-diazabicyclo[3.2.1]octane-8- carboxylate

[0713] tert-Butyl 3-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-1-ethyl-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (280 mg, 0.61 mmol) and (R)-3-(4- benzylpiperazin-1-yl)-2-methylpropan-1-ol (305 mg, 1.23 mmol) were dissolved in THF (3 mL) and added to a sealed tube reactor, Cs2CO3(600 mg, 1.84 mmol) was added, and the reaction was carried out at 90 °C for 16 h. After cooling to room temperature, water (10 mL) was added to the reaction, and ethyl acetate (10 mL x 3) was used to extract the reaction. The organic phase was 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 obtain tert-butyl 3-(2-((R)-3-(4-benzylpiperazin-1-yl)-2-methylpropoxy)-7-chloro-8- fluoropyrido[4,3-d]pyrimidin-4-yl)-1-ethyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate.

[0714] LC-MS: (ESI, m / z): [M+H] + = 668.3.

[0715] Step 5: Preparation of tert-butyl 3-(2-((R)-3-(4-benzylpiperazin-1-yl)-2- methylpropoxy)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- ((trisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-1-ethyl-3,8- diazabicyclo[3.2.1]octane-8-carboxylate

[0716] To a mixture solution of 3-(2-((R)-3-(4-benzylpiperazin-1-yl)-2-methylpropoxy)-7- chloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-1-ethyl-3,8-diazabicyclo[3.2.1]octane-8- carboxylic acid tert-butyl ester (240 mg, 0.36 mmol) and ((2-fluoro-6- (methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl) triisopropylsilane (239 mg, 0.47 mmol) in 1,4-dioxane (3 mL) and H2O (0.6 mL), CataCXium A Pd-G3 (52 mg, 0.072 mmol) and cesium carbonate (351 mg, 1.08 mmol) were added. The mixture was reacted at 85 °C for 16 h under nitrogen protection. Water (15 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (15 mL x 3). The organic phase was combined and dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (DCM:MeOH = 20:1) to obtain 3-(2-((R)-3-(4-benzylpiperazin-1-yl)-2-methylpropoxy)-8-fluoro-7-(7-fluoro-3- (methoxymethoxy)-8-((trisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-1- ethyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester.

[0717] LC-MS: (ESI, m / z): [M / 2 + H] + = 509.9.

[0718] Step 6: Preparation of 1-ethyl-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- ((trisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((R)-2-methyl-3-(piperazin-1-yl)propoxy)pyrido[4,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

[0719] tert-Butyl 3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((R)-2-methyl-3-(piperazin-1-yl)propoxy)pyrido[4,3-d]pyrimidin-4-yl)-1- ethyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate was prepared from 3-(2-((R)-3-(4- benzylpiperazin-1-yl)-2-methylpropoxy)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-1-ethyl-3,8- diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (255 mg, 0.25 mmol) by dissolving in DCM (2 mL), adding 1-chloroethyl chloroformate (107 mg, 0.75 mmol) and DIEA (97 mg, 0.75 mmol). The mixture was reacted at room temperature for 1 hour, concentrated under reduced pressure, and MeOH (3 mL) was added to the concentrate, which was then heated to 50 °C for 10 minutes. After the reaction was completed, the reaction was concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (DCM:MeOH = 15:1) to give tert-butyl 1-ethyl-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((R)-2-methyl-3-(piperazin-1-yl)propoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate.

[0720] LC-MS: (ESI, m / z): [M / 2 + H] + = 464.9.

[0721] Intermediate 11: Intermediate 11-P1 and Intermediate 11-P2

[0722] Step 1: Preparation of tert-butyl 3-benzyl-1-((methoxy-d3)methyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0723] tert-Butyl 3-benzyl-1-(hydroxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (2.5 g, 7.53 mmol) was dissolved in acetonitrile (30 mL), silver oxide (5.24 g, 22.59 mmol) and CD3I (1.64 g, 11.30 mmol) were added, and the mixture was reacted at room temperature for 72 hours in the dark. After the reaction was completed, the reaction liquid was filtered and purified by silica gel column chromatography (PE:EA = 20:1 ~ 3:1) to give tert-butyl 3-benzyl-1-((methoxy-d3)methyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate.

[0724] LC-MS: (ESI, m / z): [M + H] + = 350.2.

[0725] Step 2: Preparation of tert-butyl 1-((methoxy-d3)methyl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate

[0726] tert-Butyl 3-benzyl-l-((methoxy-d3)methyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (450 mg, 1.29 mmol) was dissolved in methanol (6 mL), Pd / C (300 mg) was added, and the reaction was allowed to proceed at 25 °C for 16 h. The reaction was filtered, and the filtrate was concentrated to give tert-butyl l-((methoxy-d3)methyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate.

[0727] LC-MS: (ESI, m / z): [M-Boc+H] + = 160.3.

[0728] Step 3: Preparation of the preparation of Intermediate 11-P1 and Intermediate 11-P2

[0729] tert-Butyl 3-benzyl-l-((methoxy-d3)methyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (450 mg, 1.29 mmol) was dissolved in methanol (6 mL), Pd / C (300 mg) was added, and the reaction was allowed to proceed at 25 °C for 16 h. The reaction was filtered, and the filtrate was concentrated to give tert-butyl l-((methoxy-d3)methyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate.

[0730] Intermediate 11-P1 (Chiral column retention time: 1.408 min). SFC analysis method (Column: Daicel chiralpak OD_3, 3*150 mm, 3 pm; Mobile phase: CO2 / MeOH (0.1% DEA); Gradient: 80 / 20, 6 min; Flow rate: 2.0 mL / min; Wavelength: 214 nm; Column temperature: 37 °C; Optical purity: 100%.

[0731] Intermediate 11-P2 (Chiral column retention time: 1.753 min). SFC analysis method (Column: Daicel chiralpak OD_3, 3*150 mm, 3 pm; Mobile phase: CO2 / MeOH (0.1% DEA); Gradient: 80 / 20, 6 min; Flow rate: 2.0 mL / min; Wavelength: 214 nm; Column temperature: 37 °C; Optical purity: 100%.

[0732] LC-MS: (ESI, m / z): [M+H] + = 475.2.

[0733] Intermediate 12: 3-(8-Fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- ((trisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((R)-2-methyl-3-(piperazin-1-yl)propoxy)pyrido[4,3- d]pyrimidin-4-yl)-1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

[0734] Step 1: Preparation of 3-(2-((R)-3-(4-benzylpiperazin-1-yl)-2-methylpropoxy)-7- chloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylic acid tert-butyl ester

[0735] Intermediate 2-P1 (chiral column retention time: 2.248 min) (400 mg, 0.85 mmol) and (R)-3-(4-benzylpiperazin-1-yl)-2-methylpropan-1-ol (421 mg, 1.69 mmol) were dissolved in THF (5 mL) and added to a sealed tube reactor, Cs2CO3(828 mg, 2.54 mmol) was added. The reaction was heated at 90 °C for 16 h. The reaction was cooled to room temperature, water (10 mL) was added, and the mixture was extracted with ethyl acetate (10 mL x 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 column chromatography on silica gel (PE:EA = 1:1) to give tert-butyl 3-(2-((R)-3-(4-benzylpiperazin-1-yl)-2-methylpropoxy)-7-chloro-8-fluoropyrido[4,3- d]pyrimidin-4-yl)-1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate.

[0736] LC-MS: (ESI, m / z): [M+H] + = 684.3.

[0737] Step 2: Preparation of tert-butyl 3-(2-((R)-3-(4-benzylpiperazin-1-yl)-2-methylpropoxy)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3- d]pyrimidin-4-yl)-1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0738] To a mixture solution of 3-(2-((R)-3-(4-benzylpiperazin-1-yl)-2-methylpropoxy)-7- chloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-1-(methoxymethyl)-3,8-diazabicyclo[3.2.1] octane-8-carboxylic acid tert-butyl ester (400 mg, 0.58 mmol) and ((2-fluoro-6- (methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl) triisopropylsilane (360 mg, 0.7 mmol) in 1,4-dioxane (3 mL) and H2O (0.6 mL), added CataCXium A Pd-G3 (85 mg, 0.12 mmol) and cesium carbonate (571 mg, 1.75 mmol). The mixture was reacted at 85 °C for 16 hours under nitrogen protection, added water (10 mL), and extracted with ethyl acetate (10 mL x 3), the combined organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (DCM:MeOH = 20:1) to give 3-(2-((R)-3-(4-benzylpiperazin-1-yl)-2-methylpropoxy)-8-fluoro-7-(7-fluoro-3- (methoxymethoxy)-8-((trisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-1- (methoxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester.

[0739] LC-MS: (ESI, m / z): [M / 2 + H] + = 517.9.

[0740] Step 3: Preparation of 3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- ((trisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((R)-2-methyl-3-(piperazin-1-yl)propoxy)pyrido[4,3- d]pyrimidin-4-yl)-1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

[0741] Tert-butyl 3-(2-((R)-3-(4-benzylpiperazin-1-yl)-2-methylpropoxy)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (510 g, 0.49 mmol) was dissolved in DCM (5 mL), followed by the addition of 1-chloroethyl chloroformate (211 mg, 1.48 mmol) and N,N-diisopropylethylamine (191 mg, 1.48 mmol). The mixture was reacted at room temperature for 1 hour, then concentrated under reduced pressure. The concentrate was dissolved in MeOH (5 mL), and the resulting mixture was heated to 50°C for 10 minutes. After completion of the reaction, the mixture was concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (DCM:MeOH=10:1) to give tert-butyl 3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((R)-2-methyl-3-(piperazin-1-yl)propoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate.

[0742] LC-MS:(ESI,m / z):[M / 2+H] + =472.8.

[0743] Intermediate 13: tert-Butyl 3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((1-formylcyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0744] The preparation method refers to the preparation method of intermediate 17 in WO2024083258A1.

[0745] Intermediate 14: Intermediate 14-P1 and Intermediate 14-P2

[0746] Step 1: Preparation of tert-butyl 1-methyl-3-trityl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0747] tert-Butyl 3-trityl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (5.0 g, 10.99 mmol) was dissolved in tetrahydrofuran (30 mL), TMEDA (2.56 g, 21.99 mmol) was added, and s-BuLi (1.41 g, 21.99 mmol) was added dropwise at -30 °C. After the dropwise addition was completed, it was stirred at 0 °C for 30 min, and iodomethane (4.68 g, 31.99 mmol) was added dropwise, and stirring was continued at 0 °C for 15 min. After the reaction was completed, saturated aqueous ammonium chloride solution (30 mL) was added to quench the reaction, and then extracted with ethyl acetate (30 mL x 3). The organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The obtained crude product was purified by silica gel column chromatography (PE:EtOAc = 100:1 ~ 10:1) to obtain tert-butyl 1-methyl-3-trityl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate.

[0748] LC-MS: (ESI, m / z): [M+Na] + = 491.1.

[0749] Step 2: Preparation of tert-butyl 1-methyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0750] tert-Butyl 1-methyl-3-trityl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (3 g, 6.40 mmol) was dissolved in dichloromethane (15 mL), and glacial acetic acid (15 mL) was added, and the reaction was refluxed at 50 °C for 1 hour. After the reaction was completed, the reaction was directly concentrated, and the obtained crude product was purified by silica gel column chromatography (DCM:MeOH(NH3) = 20:1) to obtain tert-butyl 1-methyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate.

[0751] LC-MS: (ESI, m / z): [M+H] + = 227.2.

[0752] Step 3: Preparation of Intermediate 14-P1 and Intermediate 14-P2

[0753] Dissolve 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (1.5 g, 5.94 mmol) and triethylamine (1.8 g, 17.83 mmol) in tetrahydrofuran (20 mL), cool to -50°C, add tert-butyl 1-methyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.2 g, 5.30 mmol), and react at -50°C for 3 hours. After completion of the reaction, pour the reaction solution into saturated aqueous ammonium chloride (50 mL), and extract with ethyl acetate (30 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated. The crude product was purified by silica gel column chromatography (PE:EA = 2:1) to afford tert-butyl 3-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-1-methyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate. The purified racemate was separated by chiral SFC using the following method: column: Daicel CHIRALCEL IB-N, 250 mm x 30 mm, 10 μm; mobile phase: CO2 / MeOH (0.1% DEA); gradient: 70 / 30, 6 min; flow rate: 80 g / min; wavelength: 214 nm; column temperature: 35°C.

[0754] Intermediate 14-P1 (chiral column elution time: 1.252 min). SFC analysis method (column: Daicel CHIRALPAK OD_3, 3*150 mm, 3 μm; mobile phase: CO2 / MeOH (0.1% DEA); gradient: 70 / 30, 6 min; flow rate: 2 mL / min; wavelength: 214 nm; column temperature: 37°C; optical purity: 100%).

[0755] Intermediate 14-P2 (chiral column elution time: 1.663 min). SFC analysis method (column: Daicel CHIRALPAK OD_3, 3*150 mm, 3 μm; mobile phase: CO2 / MeOH (0.1% DEA); gradient: 70 / 30, 6 min; flow rate: 2 mL / min; wavelength: 214 nm; column temperature: 37°C; optical purity: 100%).

[0756] Confirmation of the absolute configuration of intermediate 14-P1:

[0757] Step 4: Preparation of (R)-2-methyl-5-oxopyrrolidine-2-carboxylic acid methyl ester

[0758] (R)-2-methyl-5-oxopyrrolidine-2-carboxylic acid (500 mg, 3.50 mmol) was dissolved in DMF (5 mL), potassium carbonate (966 mg, 7.0 mmol) was added, and the reaction was allowed to proceed at room temperature for 2 hours. After the reaction was completed, the reaction solution was poured into an aqueous solution (20 mL) and extracted with ethyl acetate (3 x 20 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give a crude product, which was purified by column chromatography on silica gel (PE / EA = 20 / 1 to 10 / 1) to give (R)-methyl 2-methyl-5-oxopyrrolidine-2-carboxylate.

[0759] LC-MS: (ESI, m / z): [M+H] + = 158.2.

[0760] Step 5: Preparation of (R)-methyl 1-benzyl-2-methyl-5-oxopyrrolidine-2-carboxylate

[0761] (R)-methyl 2-methyl-5-oxopyrrolidine-2-carboxylate (300 mg, 1.91 mmol) was dissolved in DMF (5 mL), cooled to 0°C, and NaH (90 mg) was added. The mixture was stirred at 0°C for 30 minutes. Then benzyl bromide (488 mg, 2.87 mmol) was added, and the mixture was stirred at 25°C for 30 minutes. After the reaction was completed, saturated aqueous ammonium chloride solution (1 mL) was added dropwise to quench the reaction, and water (20 mL) was added. The mixture was extracted with ethyl acetate (3 x 20 mL). The organic phases were combined, washed with saturated NaCl solution (20 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated to give a crude product, which was purified by column chromatography on silica gel (DCM / MeOH = 100 / 1) to give (R)-methyl 1-benzyl-2-methyl-5-oxopyrrolidine-2-carboxylate.

[0762] LC-MS: (ESI, m / z): [M+H] + = 248.2.

[0763] Step 6: Preparation of (R)-1-benzyl-5-ethoxy-2-(methoxycarbonyl)-2-methyl-3,4-dihydro-2H-pyrrol-1-ium tetrafluoroborate

[0764] (R)-methyl 1-benzyl-2-methyl-5-oxopyrrolidine-2-carboxylate (360 mg, 1.46 mmol) was dissolved in dichloromethane (5 mL), and triethyl oxotetrafluoroborate (554.8 mg, 2.92 mmol) was added at 0°C. The reaction was allowed to proceed at room temperature for 24 hours. After the reaction was completed, the reaction solution was concentrated to give a crude product, (R)-1-benzyl-5-ethoxy-2-(methoxycarbonyl)-2-methyl-3,4-dihydro-2H-pyrrol-1-ium tetrafluoroborate.

[0765] LC-MS: (ESI, m / z): [M] + = 276.2.

[0766] Step 7: Preparation of (R)-methyl 1-benzyl-2-methyl-5-(nitromethyl)pyrrolidine-2- carboxylate

[0767] The crude product (R)-1-benzyl-5-ethoxy-2-(methoxycarbonyl)-2-methyl-3,4- dihydro-2H-pyrrol-1-ium tetrafluoroborate (900 mg, 0.88 mmol) was dissolved in DCM (5 mL), and nitromethane (270 mg, 4.4 mmol) and triethylamine (355.5 mg, 3.52 mmol) were added under ice-bath cooling. The reaction was allowed to proceed at room temperature for 2 hours. After completion of the reaction, the reaction solution was concentrated to obtain the crude product, which was subjected to column chromatography on silica gel (DCM / MeOH = 50 / 1) to obtain (R)-methyl 1-benzyl-2-methyl-5-(nitromethyl)pyrrolidine-2-carboxylate.

[0768] LC-MS: (ESI, m / z): [M+H] + = 291.1.

[0769] Step 8: Preparation of (1R,5S)-1-methyl-3,8-diazabicyclo[3.2.1]octan-2-one

[0770] (R)-methyl 1-benzyl-2-methyl-5-(nitromethyl)pyrrolidine-2-carboxylate (90 mg, 0.31 mmol) was dissolved in MeOH (5 mL), and palladium on carbon (50 mg) was added at room temperature, followed by replacement with a hydrogen balloon three times. The reaction was allowed to proceed at room temperature for 16 hours. After completion of the reaction, the palladium on carbon was filtered off, and the filtrate was concentrated to obtain (1R,5S)-1-methyl-3,8-diazabicyclo[3.2.1]octan-2-one.

[0771] LC-MS: (ESI, m / z): [M+H] + = 141.1.

[0772] Step 9: Preparation of tert-butyl (1R,5S)-1-methyl-2-oxo-3,8-diazabicyclo[3.2.1]octane-8- carboxylate

[0773] The crude product (1R,5S)-1-methyl-3,8-diazabicyclo[3.2.1]octane-2-one (40 mg, 0.31 mmol) was dissolved in MeOH (3 mL), di-tert-butyl dicarbonate (134 mg, 0.62 mmol) was added at room temperature, and the reaction was allowed to proceed at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated to obtain the crude product, which was purified by silica gel column chromatography (DCM / MeOH = 20 / 1) to obtain (1R,5S)-tert-butyl 1-methyl-2-oxo-3,8-diazabicyclo[3.2.1]octane-8-carboxylate.

[0774] LC-MS: (ESI, m / z): [M-56+H] + = 185.2.

[0775] Step 10: Preparation of (1R,5S)-3-benzyl-1-methyl-2-oxo-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

[0776] (1R,5S)-tert-butyl 1-methyl-2-oxo-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (30 mg, 0.125 mmol) was dissolved in DMF (3 mL), cooled to 0°C, and NaH (10 mg) was added. The mixture was stirred at 0°C for 30 minutes. Then benzyl bromide (32.3 mg, 0.19 mmol) was added, and the mixture was stirred at 25°C for 30 minutes. After the reaction was completed, saturated aqueous ammonium chloride solution (0.5 mL) was added dropwise to quench the reaction, and water (10 mL) was added. The mixture was extracted with ethyl acetate (3 x 10 mL). The combined organic phase was washed with saturated NaCl solution (20 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated to obtain the crude product, which was purified by silica gel column chromatography (PE / EA = 20 / 1) to obtain (1R,5S)-3-benzyl-1-methyl-2-oxo-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester.

[0777] LC-MS: (ESI, m / z): [M-56+H] + = 275.1.

[0778] Step 11: Preparation of (1R,5S)-3-benzyl-1-methyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

[0779] (1R,5S)-3-benzyl-1-methyl-2-oxo-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (30 mg, 0.09 mmol) was dissolved in THF (3 mL), 10 M borane dimethyl sulfide (0.18 mL, 1.8 mmol) was added at room temperature, and the reaction was carried out at 50 °C for 2 hours. After the reaction was completed, the reaction solution was concentrated to obtain a crude product, which was purified by silica gel column chromatography (PE / EA = 20 / 1) to obtain (1R,5S)-3-benzyl-1-methyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester.

[0780] LC-MS: (ESI, m / z): [M+H] + = 317.2.

[0781] Step 12: Preparation of (1R,5S)-1-methyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

[0782] (1R,5S)-3-benzyl-1-methyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (20 mg, 0.063 mmol) was dissolved in MeOH (3 mL), palladium on carbon (20 mg) was added at room temperature, and the reaction was carried out at room temperature for 3 hours after replacement with a hydrogen balloon three times. After the reaction was completed, the palladium on carbon was filtered off, and the filtrate was concentrated to obtain a crude product, which was purified by silica gel column chromatography (DCM / 4 M NH3 in MeOH = 30 / 1) to obtain (1R,5S)-1-methyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester.

[0783] LC-MS: (ESI, m / z): [M-56+H] + = 171.2.

[0784] 1H NMR (400 MHz, CDCl3) δ 4.20 (s, 1H), 2.99 (d, J = 10.8 Hz, 2H), 2.56 (dd, J = 32.4, 12.0 Hz, 2H), 2.01-1.92 (m, 2H), 1.74-1.65 (m, 2H), 1.47 (s, 9H), 1.43 (s, 3H).

[0785] Step 13: Preparation of (1R,5S)-3-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-1-methyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

[0786] (1R,5S)-3-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-1-methyl-3,8- diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester eluted at the same time as the chiral resolved intermediate 14-P1 from the chiral column in Step 3. The absolute configuration of intermediate 14-P1 was determined to be (1R,5S) by the method of chiral synthesis.

[0787] Chiral analysis method (column: Daicel CHIRALPAK OD_3, 3*150 mm, 3 μm; mobile phase: CO2 / MeOH (0.1% DEA); gradient: 70 / 30, 6 min; flow rate: 2 mL / min; wavelength: 214 nm; column temperature: 37 °C;

[0788] (1R,5S)-3-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-1-methyl-3,8- diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester eluted at the same time as the chiral resolved intermediate 14-P1 from the chiral column in Step 3. The absolute configuration of intermediate 14-P1 was determined to be (1R,5S) by the method of chiral synthesis.

[0789] Intermediate 15: 3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- ((trisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((1-formylcyclopropyl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)-1-ethenyl-5λ 3 -3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

[0790] Step 1: Preparation of 1-ethenyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

[0791] Intermediate 9-P1 (1.50 g, 3.11 mmol) was dissolved in DCM (20 mL), AcOH (10 mL) was added, and the mixture was reacted at 45 °C for 4 h. The reaction solution was directly concentrated, and the obtained crude product was purified by silica gel column chromatography (DCM:MeOH(NH3)=10:1) to obtain tert-butyl 1-vinyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate.

[0792] LC-MS: (ESI, m / z): [M+H] + = 183.2.

[0793] Step 2: Preparation of tert-butyl 3-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-1- vinyl-5λ 3 -3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0794] To a solution of 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (400 mg, 1.58 mmol) in tetrahydrofuran (6 mL), triethylamine (481 mg, 4.75 mmol) and tert-butyl 1-vinyl-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (341 mg, 1.43 mmol) were added at -50 °C, and the mixture was stirred at -50 °C for 3 h. After the reaction was completed, saturated aqueous ammonium chloride solution (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product, which was purified by silica gel column chromatography (PE:EA=3:1) to obtain tert-butyl 3-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-1-vinyl-5λ 3 -3,8-diazabicyclo[3.2.1]octane-8-carboxylate.

[0795] LC-MS: (ESI, m / z): [M+H] + = 454.1.

[0796] Step 3: Preparation of tert-butyl 3-(7-chloro-8-fluoro-2-((1-(hydroxymethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-vinyl-5λ 3 -3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0797] To a solution of tert-butyl 3-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-1-vinyl-5λ 3A solution of tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (460 mg, 1.01 mmol) and cyclopropane-1,1-dimethyl dimethanol (206 mg, 2.02 mmol) in anhydrous acetonitrile (5 mL) was added triethylenediamine (57 mg, 0.51 mmol) and anhydrous cesium carbonate (987 mg, 3.03 mmol) and reacted at 25 °C for 2 h. After the reaction was completed, the reaction solution was filtered and concentrated to give a crude product, which was purified by silica gel column chromatography (PE:EA = 3:1) to give 3-(7-chloro-8-fluoro-2-((1-(hydroxymethyl)cyclopropyl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)-1-ethenyl-5λ 3 tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate.

[0798] LC-MS: (ESI, m / z): [M+H] + = 520.2.

[0799] Step 4: 3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2- ((1-(hydroxymethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-ethenyl-5λ 3 Preparation of tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0800] To a solution of 3-(7-chloro-8-fluoro-2-((1-(hydroxymethyl)cyclopropyl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)-1-ethenyl-5λ 3A solution of tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (364 mg, 0.70 mmol) and ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (430 mg, 0.84 mmol) in 1,4-dioxane (5 mL) and water (1 mL) was added anhydrous cesium carbonate (683 mg, 2.10 mmol) and cataCXium(R) A Pd G3 (102 mg, 0.14 mmol). After nitrogen substitution, it was stirred at 85 °C for 16 h under nitrogen protection. After reaction, water (10 mL) was added and extracted with ethyl acetate (10 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated to give a crude product, which was purified by silica gel column chromatography (PE:EA = 1:1) to give 3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((1-(hydroxymethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-ethenyl-5λ 3 tert-Butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate.

[0801] LC-MS: (ESI, m / z): [M+H] + = 870.3.

[0802] Step 5: 3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((1-formylcyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-ethenyl-5λ 3 Preparation of tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0803] Step 6: 3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((1-(hydroxymethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-ethenyl-5λ 3A solution of tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (460 mg, 0.53 mmol) in dichloromethane (3 mL) was cooled to 0 °C, and Dess-Martin reagent (448 mg, 1.06 mmol) was added. The reaction was stirred at 25 °C for 2 h. After the reaction was completed, saturated aqueous sodium thiosulfate solution (20 mL) was added and extracted with dichloromethane (20 mL x 3). The combined organic phase was washed with saturated sodium bicarbonate solution and saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The obtained crude was purified by silica gel column chromatography (PE:EA = 1:1) to give 3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((1- formylcyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-ethenyl-5λ 3 tert-Butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate.

[0804] LC-MS: (ESI, m / z): [M+H] + = 868.4.

[0805] Intermediate 16: tert-Butyl 3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((R)-2-methyl-3-(piperazin-1-yl)propoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0806] The preparation method refers to the preparation method of intermediate 25 in WO2024083258A1.

[0807] Intermediate 17: 9-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)-1-oxo-9-azaspiro[5.5]undecane-3-carbaldehyde

[0808] To a solution of 1-oxa-9-azaspiro[5.5]undecan-3-carboxaldehyde (1.94 g, crude) in DMF (20 mL) was added DIEA (6.84 g, 52.95 mmol) and 3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoic acid pentafluorophenyl ester (4.39 g, 10.59 mmol), the reaction was stirred at room temperature for 1 hour. Water was added and extracted with ethyl acetate (200 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated and purified by silica gel column chromatography (DCM:MeOH = 20:1) to give 9-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)-1-oxa-9-azaspiro[5.5]undecan-3-carboxaldehyde.

[0809] LC-MS (ESI) m / z: [M+H] + = 430.2.

[0810] Intermediate 18: 3-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)-3- azaspiro[5.5]undecane-9-carboxaldehyde

[0811] The preparation method refers to the preparation method of intermediate 3 in WO2024083258A1.

[0812] Intermediate 19: 1-(2-methoxy-5-(3-(piperazin-1-ylmethyl)-3λ 3 -1-oxa-9-azaspiro[5.5]undecane-9-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)- dione

[0813] Step 1: Preparation of tert-butyl 4-allyl-4-((2-(methoxycarbonyl)allyl)oxy)piperidine-1- carboxylate

[0814] Tert-butyl 4-allyl-4-hydroxypiperidine-1-carboxylate (9.0 g, 37.29 mmol) was dissolved in DMF (200 mL), NaH (1.79 g, 44.75 mmol) was added at 0 °C, and the reaction was stirred at room temperature for 1 hour. After cooling to 0 °C, methyl 2-(bromomethyl)acrylate (6.68 g, 37.29 mmol) was added, and the reaction was stirred at room temperature for 72 h. After the reaction was completed, NH4Cl (200 mL) was added, and ethyl acetate (200 mL x 3) was extracted. The organic phases were combined, washed with saturated NaCl solution, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated. The obtained crude product was purified by silica gel column chromatography (PE:EA = 5:1) to give tert-butyl 4-allyl-4-((2-(methoxycarbonyl)allyl)oxy)piperidine-1-carboxylate.

[0815] LC-MS: (ESI, m / z): [M+Na] + = 362.2

[0816] Step 2: Preparation of 9-(tert-butyl) 3-methyl 1-oxa-9-azaspiro[5.5]undecane-3,9- dicarboxylate

[0817] tert-Butyl 4-allyl-4-((2-(methoxycarbonyl)allyl)oxy)piperidine-1-carboxylate (3.0 g, 8.84 mmol) was dissolved in DCE (700 mL), Grubbs II catalyst (229 mg, 0.27 mmol) was added, and the reaction was stirred at 90 °C for 16 h. The reaction was cooled to room temperature, filtered, and the filtrate was concentrated. The resulting crude product was purified by silica gel column chromatography (PE:EA = 5:1) to give 9-(tert-butyl) 3-methyl 1-oxa-9-azaspiro[5.5]undecane-3,9-dicarboxylate.

[0818] LC-MS: (ESI, m / z): [M+Na] + = 334.2

[0819] Step 3: Preparation of 9-(tert-butyl) 3-methyl 1-oxa-9-azaspiro[5.5]undecane-3,9- dicarboxylate

[0820] To a solution of 9-(tert-butyl) 3-methyl 1-oxa-9-azaspiro[5.5]undecane-3,9-dicarboxylate (1.3 g, 4.17 mmol) in EtOH (20 mL) was added Pd(OH)2(586 mg, 4.17 mmol) and the reaction was stirred at 50 °C for 16 h under H2atmosphere. The reaction was cooled to room temperature, filtered, and the filtrate was concentrated. The resulting crude product was purified by silica gel column chromatography (PE:EA = 5:1) to give 9-(tert-butyl) 3-methyl 1-oxa-9-azaspiro[5.5]undecane-3,9-dicarboxylate.

[0821] Step 4: Preparation of methyl 1-oxa-9-azaspiro[5.5]undecane-3-carboxylate

[0822] To a solution of 9-(tert-butyl) 3-methyl 1-oxa-9-azaspiro[5.5]undecane-3,9-dicarboxylate (1.386 g, 44.10 mmol) in dichloromethane (100 mL) was added hydrochloric acid / 1,4-dioxane (4.0 M, 50 mL) at 0 °C and stirred at 25 °C for 2 h. The reaction was directly concentrated under reduced pressure at 40 °C to give methyl 1-oxa-9-azaspiro[5.5]undecane-3-carboxylate. It was used directly in the next step.

[0823] LC-MS: (ESI, m / z): [M+H] + = 214.1.

[0824] Step 5: Preparation of methyl 9-benzyl-l-oxo-9-azaspiro[5.5]undecane-3-carboxylate

[0825] To a solution of methyl 1-oxo-9-azaspiro[5.5]undecane-3-carboxylate (8.755 g, crude) in dichloromethane (180 mL) was added benzaldehyde (6.534 g, 61.57 mmol). After reaction at room temperature for 2 hours, sodium triacetylborohydride (17.400 g, 82.10 mmol) was added and the reaction was continued at room temperature for 16 hours. The reaction was poured into saturated aqueous ammonium chloride solution (200 mL) and then extracted with dichloromethane (150 mL x 2). The organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The concentrate was stirred with a mixed solvent of petroleum ether / dichloromethane (10 / 1, 200 mL), filtered, and dried to give methyl 9-benzyl-l-oxo-9-azaspiro[5.5]undecane-3-carboxylate.

[0826] LC-MS: (ESI, m / z): [M+H] + = 304.3.

[0827] Step 6: Preparation of (9-benzyl-l-oxo-9-azaspiro[5.5]undecan-3-yl)methanol

[0828] To a solution of methyl 9-benzyl-l-oxo-9-azaspiro[5.5]undecane-3-carboxylate (11.363 g, 37.33 mmol) in tetrahydrofuran (200 mL) was added lithium aluminum hydride / tetrahydrofuran (1.0 M, 37.3 mL, 37.33 mmol) at 0 °C. The mixture was stirred at 0-25 °C for 2 hours. After the reaction was completed, water (1.4 mL), aqueous sodium hydroxide solution (15% (w / w), 1.4 mL), and water (1.4 mL) were added at intervals of 10 minutes. After stirring for 30 minutes, anhydrous sodium sulfate (10 g) was added, and the stirring was continued for 30 minutes. After filtration, the filtrate was concentrated under reduced pressure to give (9-benzyl-l-oxo-9-azaspiro[5.5]undecan-3-yl)methanol.

[0829] LC-MS: (ESI, m / z): [M+H] + = 276.2.

[0830] Step 7: Preparation of 9-benzyl-l-oxo-9-azaspiro[5.5]undecane-3-carbaldehyde

[0831] Dess-Martin periodinane (22.507 g, 53.06 mmol) was added to a solution of (9-benzyl-l-oxo-9-azaspiro[5.5]undecan-3-yl)methanol (9.778 g, 35.38 mmol) in dichloromethane (180 mL) at 0 °C. The mixture was stirred at 25 °C for 4 h. After the reaction was completed, the reaction solution was poured into saturated aqueous sodium carbonate solution (250 mL) and extracted with ethyl acetate (200 mL x 2). The combined organic phase was washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 9-benzyl-l-oxo-9-azaspiro[5.5]undecan-3- carboxaldehyde.

[0832] LC-MS: (ESI, m / z): [M+H] + = 274.2.

[0833] Step 8: Preparation of 19-P1 and 19-P2

[0834] To a solution of 9-benzyl-l-oxo-9-azaspiro[5.5]undecan-3-carboxaldehyde (9.641 g, 35.14 mmol) in dichloromethane (180 mL) was added tert-butyl piperazine- 1-carboxylate (9.870 g, 52.71 mmol). After the reaction was carried out at room temperature for 2 h, sodium triacetylboration hydride (14.894 g, 70.28 mmol) was added and the reaction was continued at room temperature for 16 h. The reaction solution was poured into saturated aqueous ammonium chloride solution (500 mL) and extracted with ethyl acetate (200 mL x 2). The organic phase was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by silica gel column chromatography (DCM:MeOH = 100:1 ~ 20:1) to give tert-butyl 4-((9-benzyl-l-oxo-9-azaspiro[5.5]undecan-3-yl)methyl)piperazine-l- carboxylate. The obtained compound was purified and resolved by SFC with the following method: Column: Daicel chiralpak IG, 30*250 mm, 10 μm; Mobile phase: CO2 / MeOH (0.2% NH3(7M Solution in MeOH)); Gradient: 65 / 35, 6 min; Flow rate: 100 mL / min; Wavelength: 214 nm; Column temperature: 35 °C.

[0835] 19-P2 (Chiral column retention time: 3.171 min). SFC analytical method (Column: Daicel chiralpak AD_3, 3*150 mm, 3 pm; Mobile phase: C02 / MeOH (0.1% DEA); Gradient: 70 / 30, 6 min; Flow rate: 2.0 mL / min; Wavelength: 214 nm; Column temperature: 37 °C; Optical purity: 100%.

[0836] 1 H NMR (400 MHz, CD3OD) δ 7.39 - 7.36 (m, 5H), 3.85 (s, 2H), 3.78 - 3.73 (m, 1H), 3.50 - 3.35 (m, 4H), 3.31 - 3.27 (m, 4H), 2.90 - 2.60 (m, 4H), 2.40 - 2.25 (m, 4H), 2.25 - 2.15 (m, 2H), 1.85 - 1.50 (m, 6H), 1.45 (s, 9H).

[0837] LC-MS: (ESI, m / z): [M+H] + = 444.3.

[0838] 19-P2 (Chiral column retention time: 3.171 min). SFC analytical method (Column: Daicel chiralpak AD_3, 3*150 mm, 3 pm; Mobile phase: C02 / MeOH (0.1% DEA); Gradient: 70 / 30, 6 min; Flow rate: 2.0 mL / min; Wavelength: 214 nm; Column temperature: 37 °C; Optical purity: 100%.

[0839] 1 H NMR (400 MHz, CD3OD) δ 7.52 - 7.46 (m, 5H), 4.23 (s, 2H), 3.81 - 3.77 (m, 1H), 3.50 - 3.35 (m, 4H), 3.35 - 3.27 (m, 4H), 3.25 - 3.00 (m, 4H), 2.40 - 2.35 (m, 4H), 2.35 - 2.15 (m, 2H), 1.85 - 1.55 (m, 6H), 1.45 (s, 9H).

[0840] LC-MS: (ESI, m / z): [M+H] + = 444.3.

[0841] Step 9: Preparation of tert-butyl 4-((1-oxo-9-azaspiro[5.5]undecan-3- yl)methyl)piperazine-1-carboxylate

[0842] To a solution of 19-P1 (1.10 g, 2.50 mmol) in methanol (10 mL) was added Pd / C (0.20 g), hydrogen balloon was replaced for three times, stirred at 25 °C for 16 h. The reaction was filtered through celite, the filtrate was concentrated to give the crude product 4-((1-oxo-9-azaspiro[5.5]undecan-3-yl)methyl)piperazine-1-carboxylic acid tert-butyl ester, which was used directly in the next step.

[0843] LC-MS: (ESI, m / z): [M+H] + = 354.3.

[0844] Step 10: Preparation of 4-((9-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4- methoxybenzoyl)-1-oxo-9-azaspiro[5.5]undecan-3-yl)methyl)piperazine-1-carboxylic acid tert-butyl ester

[0845] To a solution of 4-((1-oxo-9-azaspiro[5.5]undecan-3-yl)methyl)piperazine-1-carboxylic acid tert-butyl ester (450 mg, 1.27 mmol) in DMF (5 mL) was added DIEA (328 mg, 2.54 mmol) and 3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoate (601 mg, 1.40 mmol), the reaction was stirred at room temperature for 2 h. Water was added and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, the crude was purified by silica gel column chromatography (DCM:MeOH = 100:1 ~ 10:1) to give 4-((9-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)-1-oxo-9-azaspiro[5.5]undecan-3-yl)methyl)piperazine-1-carboxylic acid tert-butyl ester.

[0846] LC-MS: (ESI, m / z): [M+H] + = 600.3.

[0847] Step 11: Preparation of 1-(2-methoxy-5-(3-(piperazin-1-ylmethyl)-1-oxo-9-azaspiro[5.5]undecan-9- carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione

[0848] To a solution of tert-butyl 4-((9-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4- methoxybenzoyl)-1-oxa-9-azaspiro[5.5]undecan-3-yl)methyl)piperazine-1-carboxylate (250 mg, 0.42 mmol) in 1,4-dioxane (3 mL) was added HC1 / 1,4-dioxane (1.5 mL), stirred at 30 °C for 1 h. After the reaction was completed, Na2CO3 (5 mL) aqueous solution was added to adjust pH > 7, and extracted with ethyl acetate (20 mL x 3). The combined organic layer was dried over Na2SO4, filtered and concentrated, the crude product was purified by silica gel column chromatography (DCM:MeOH = 20:1) to give 1-(2-methoxy-5-(3-(piperazin-1-ylmethyl)-1-oxa-9- azaspiro[5.5]undecane-9-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione.

[0849] LC-MS: (ESI, m / z): [M+H] + = 500.3.

[0850] Intermediate 20: 1-(2-methyl-5-(3-(piperazin-1-ylmethyl)-3λ 3 -1-oxa-9-azaspiro[5.5]undecane-9-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)- dione

[0851] Step 1: Preparation of tert-butyl 4-((1-oxa-9-azaspiro[5.5]undecan-3-yl)methyl)piperazine-1- carboxylate

[0852] To a solution of 19-P1 (1.10 g, 2.50 mmol) in methanol (10 mL) was added Pd / C (0.20 g), replaced with hydrogen balloon for three times, stirred at 25 °C for 16 h. The reaction solution was filtered through celite, the filtrate was concentrated to give the crude product tert-butyl 4-((1-oxa-9-azaspiro[5.5]undecan-3-yl)methyl)piperazine-1-carboxylate, which was used directly in the next reaction.

[0853] LC-MS (ESI) m / z: [M+H] + = 354.3.

[0854] Step 2: Preparation of tert-butyl 4-((9-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4- methylbenzoyl)-1-oxa-9-azaspiro[5.5]undecan-3-yl)methyl)piperazine-1-carboxylate

[0855] To a solution of tert-butyl 4-((1-oxa-9-azaspiro[5.5]undecan-3-yl)methyl)piperazine-1- carboxylate (430 mg, 1.21 mmol) in DMF (5 mL) was added DIEA (313 mg, 2.42 mmol) and 3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methylbenzoic acid perfluorophenyl ester (503 mg, 1.21 mmol), and the reaction was stirred at room temperature for 2 hours. Water was added and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated and purified by silica gel column chromatography (DCM:MeOH = 100:1 ~ 10:1) to give tert-butyl 4-((9-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methylbenzoyl)-1-oxa-9- azaspiro[5.5]undecan-3-yl)methyl)piperazine-1-carboxylate.

[0856] LC-MS (ESI) m / z: [M+H] + = 584.3.

[0857] Step 3: Preparation of 1-(2-methyl-5-(3-(piperazin-1-ylmethyl)-3λ 3 -1-oxa-9-azaspiro[5.5]undecane-9-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione

[0858] To a solution of tert-butyl 4-((9-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methylbenzoyl)-1-oxa-9- azaspiro[5.5]undecan-3-yl)methyl)piperazine-1-carboxylate (500 mg, 0.86 mmol) in 1,4-dioxane (5 mL) was added HCl / 1,4-dioxane (5 mL) and stirred at 30 °C for 1 hour. After the reaction was completed, Na2CO3 (5 mL) aqueous solution was added to adjust pH > 7, and extracted with ethyl acetate / isopropanol (20 mL x 3, v / v = 5 / 1). The combined organic phase was dried over Na2SO4, filtered and concentrated to give 1-(2-methyl-5-(3-(piperazin-1-ylmethyl)-3λ 3 -1-oxa-9-azaspiro[5.5]undecane-9-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione.

[0859] LC-MS (ESI) m / z: [M+H] + = 484.3.

[0860] Intermediate 21: (R)-3-(4-benzylpiperazin-1-yl)-2-methylpropan-3,3-d2-1-ol

[0861] Step 1: Preparation of (2S)-methyl 2-methyl-3-((tetrahydro-2H-pyran-2- yl)oxy)propanoate

[0862] Methyl (S)-3-hydroxy-2-methylpropanoate (3.0 g, 25.39 mmol) was dissolved in DCM (60 mL), 3,4-dihydropyran (4.27 g, 50.79 mmol) and p-toluenesulfonic acid pyridine salt (1.91 g, 7.62 mmol) were added, and the reaction was allowed to proceed at room temperature for 2 hours. After the reaction was completed, the reaction solution was poured into an aqueous solution (100 mL), and then extracted with dichloromethane (100 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The resulting crude product was purified by silica gel column chromatography (PE:EA = 100:1 ~ 5:1) to obtain methyl (2S)-2-methyl-3-((tetrahydro-2H-pyran-2-yl)oxy)propanoate.

[0863] 1 H NMR (400 MHz, CDCl3) δ 4.68-4.55 (m, 1H), 3.95-3.73 (m, 2H), 3.69 (s, 3H), 3.63-3.41 (m, 2H), 2.85-2.70 (m, 1H), 1.82-1.48 (m, 6H), 0.65-0.95 (m, 3H).

[0864] Step 2: Preparation of (2R)-2-methyl-3-((tetrahydro-2H-pyran-2-yl)oxy)propan-1,1-d2-1-ol

[0865] Methyl (2S)-2-methyl-3-((tetrahydro-2H-pyran-2-yl)oxy)propanoate (3.0 g, 14.8 mmol) was dissolved in tetrahydrofuran (80 mL), cooled to 0°C, and LiAlD4 (16 mL, 1.0 M / THF, 16 mmol) was added dropwise. The reaction was allowed to proceed at 0°C for 15 minutes. After the reaction was completed, the reaction was quenched by adding sodium sulfate decahydrate (2 g), and then filtered with ethyl acetate (200 mL). The filtrate was concentrated to obtain (2R)-2-methyl-3-((tetrahydro-2H-pyran-2-yl)oxy)propan-1,1-d2-1-ol.

[0866] 1 H NMR (400 MHz, CDCl3) δ 4.58 (t, J = 3.4 Hz, 1H), 3.92-3.62 (m, 2H), 3.60-3.30 (m, 2H), 2.11-1.93 (m, 1H), 1.90-1.68 (m, 2H), 1.62-1.50 (m, 4H), 0.93-0.78 (m, 3H).

[0867] Step 3: Preparation of l-benzyl-4-((2R)-2-methyl-3-((tetrahydro-2H-pyran-2- yl)oxy)propyl-l, 1 -d2)piperazine

[0868] (2R)-2-methyl-3-((tetrahydro-2H-pyran-2-yl)oxy)propan-l, 1 -d2- 1 -ol (2.4 g, 13.62 mmol) was dissolved in dichloromethane (60 mL), triethylamine (4.13 g, 40.85 mmol) and methanesulfonyl chloride (2.34 g, 20.43 mmol) were added at 0 °C, and the reaction was allowed to proceed for 1 h. After the reaction was completed, the reaction was allowed to warm to room temperature, water (100 mL) was added, and extraction was performed with ethyl acetate (60 mL x 3). The combined organic phase was washed with saturated NaCl solution (100 mL), dried over anhydrous Na2S04, filtered, and the filtrate was concentrated. The concentrate was dissolved in DMF (25 mL), potassium carbonate (5.65 g, 40.85 mmol) and l-benzylpiperazine (5.79 g, 27.23 mmol) were added, and the reaction was heated to 60 °C for 16 h. After the reaction was completed, the reaction was cooled to room temperature, water (100 mL) was added, and extraction was performed with ethyl acetate (60 mL x 2). The combined organic phase was washed with saturated NaCl solution (100 mL), dried over anhydrous Na2S04, filtered, and the filtrate was concentrated. The resulting crude product was purified by silica gel column chromatography (DCM:MeOH = 20: 1) to obtain l-benzyl-4-((2R)-2-methyl-3-((tetrahydro-2H-pyran-2-yl)oxy)propyl-l, 1 -d2)piperazine.

[0869] LC-MS: (ESI, m / z): [M+H] + = 335.3.

[0870] Step 4: Preparation of (R)-3-(4-benzylpiperazin-l-yl)-2-methylpropane-3,3-d2- 1 -ol

[0871] l-benzyl-4-((2R)-2-methyl-3-((tetrahydro-2H-pyran-2-yl)oxy)propyl-l, 1 -d2)piperazine (1.5 g, 4.48 mmol) was dissolved in MeOH (14 mL), concentrated hydrochloric acid (3 mL) was added under ice bath, and the reaction was allowed to proceed at room temperature for 1 h. After the reaction was completed, the MeOH and HCl were concentrated, the mixture was adjusted to pH > 7 with an aqueous Na2C03 solution, and extraction was performed with EtOAc (20 mL x 3). The combined organic phase was dried over anhydrous Na2S04, filtered, and the filtrate was concentrated. The resulting crude product was purified by silica gel column chromatography (DCM / MeOH = 20 / 1) to obtain (R)-3-(4-benzylpiperazin-l-yl)-2-methylpropane-3,3-d2- 1 -ol.

[0872] LC-MS: (ESI, m / z): [M+H] + = 251.3.

[0873] Intermediate 22: Intermediate 22-P1 and Intermediate 22-P2

[0874] Step 1: Preparation of tert-butyl 1-(methyl-d3)-3-trityl-3,8-diazabicyclo[3.2.1]octane-8- carboxylate

[0875] tert-Butyl 3-trityl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (11.0 g, 24.2 mmol) was dissolved in tetrahydrofuran (100 mL), TMEDA (5.62 g, 48.4 mmol) was added, and s-BuLi (27.9 mL, 36.3 mmol, 1.3 M / THF) was added dropwise at -30 °C. After the dropwise addition was completed, it was stirred at 0 °C for 30 min, and then deuterated iodomethane (10.52 g, 72.6 mmol) was added dropwise, and stirring was continued at 0 °C for 15 min. After the reaction was completed, saturated aqueous ammonium chloride solution (100 mL) was added to the reaction solution, and extracted with ethyl acetate (100 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The obtained crude product was purified by silica gel column chromatography (PE:EtOAc = 100:1 ~ 10:1) to obtain tert-butyl 1-(methyl-d3)-3-trityl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate.

[0876] LC-MS: (ESI, m / z): [M+Na] + = 494.2.

[0877] Step 2: Preparation of tert-butyl 1-(methyl-d3)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0878] tert-Butyl 1-(methyl-d3)-3-trityl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (9.0 g, 19.1 mmol) was dissolved in dichloromethane (50 mL), and glacial acetic acid (50 mL) was added, and the reaction was refluxed at 50 °C for 1 hour. After the reaction was completed, it was concentrated, and the obtained crude product was purified by silica gel column chromatography (DCM:MeOH(NH3) = 20:1) to obtain tert-butyl 1-(methyl-d3)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate.

[0879] LC-MS: (ESI, m / z): [M+H] + = 230.2.

[0880] Step 3: Preparation of Intermediates 22-P1 and 22-P2

[0881] Dissolve 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (3.0 g, 11.9 mmol) and triethylamine (3.61 g, 35.7 mmol) in tetrahydrofuran (30 mL), cool to -50°C, add tert-butyl 1-(methyl-d3)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (2.46 g, 10.71 mmol), and react at -50°C for 3 hours. After completion of the reaction, pour the reaction solution into saturated aqueous ammonium chloride (50 mL), and then extract with ethyl acetate (50 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated. The crude product was purified by silica gel column chromatography (PE:EA = 2:1) to afford tert-butyl 3-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-1-(methyl-d3)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate. The purified racemate was subjected to chiral SFC separation to afford intermediates 22-P1 and 22-P2. The chiral separation method was as follows: Column: Daicel CHIRALCEL IB-N, 250 mm x 30 mm ID, 10 μm; Mobile phase: CO2 / MeOH [0.2% NH3 (7 M solution in MeOH)]; Gradient: 60 / 40, 6 min; Flow rate: 100 mL / min; Wavelength: 214 nm; Column temperature: 35°C.

[0882] Intermediate 22-P1 (chiral column elution time: 1.260 min). SFC analysis method (column: Daicel CHIRALPAK IB-3, 3*150 mm, 3 μm; mobile phase: CO2 / MeOH; gradient: 70 / 30, 6 min; flow rate: 2 mL / min; wavelength: 214 & 254 nm; column temperature: 37°C; optical purity: 100%).

[0883] Intermediate 22-P2 (chiral column elution time: 1.681 min). SFC analysis method (column: Daicel CHIRALPAK IB-3, 3*150 mm, 3 μm; mobile phase: CO2 / MeOH; gradient: 70 / 30, 6 min; flow rate: 2 mL / min; wavelength: 214 & 254 nm; column temperature: 37°C; optical purity: 100%).

[0884] LC-MS:(ESI,m / z):[M+H] + =445.1.

[0885] Intermediate 23: (R)-3-(4-benzylpiperazin-1-yl)-2-methylpropan-1-ol

[0886] The preparation method refers to the preparation method of intermediate 25 in WO2024083258A1.

[0887] Intermediate 24: 3-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)-3- azaspiro[5.5]undecan-9-carboxaldehyde-d

[0888] Step 1: Preparation of 3-(tert-butoxycarbonyl)-3-azaspiro[5.5]undecane-9-carboxylic acid

[0889] tert-Butyl 9-formyl-3-azaspiro[5.5]undecane-3-carboxylate (2.0 g, 7.11 mmol) was dissolved in tert-butanol (20 mL) and water (10 mL), and 2-methyl-2-butene (1.0 g, 14.22 mmol), sodium chlorite (9.11 g, 21.33 mmol) and sodium phosphate dibasic (3.83 g, 31.95 mmol) were added in turn. After the addition was completed, the mixture was stirred at 25 °C for 2 hours. After the reaction was completed, the reaction solution was filtered, and the filtrate was concentrated. The obtained crude product was purified by reverse silica gel column chromatography (H2O:ACN = 50:1 ~ 1:2) to obtain 3-(tert-butoxycarbonyl)-3-azaspiro[5.5]undecane-9-carboxylic acid.

[0890] LC-MS: (ESI, m / z): [M-H] - = 296.2.

[0891] Step 2: Preparation of tert-butyl 9-(hydroxymethyl-d2)-3-azaspiro[5.5]undecane-3-carboxylate

[0892] 3-(tert-Butoxycarbonyl)-3-azaspiro[5.5]undecane-9-carboxylic acid (1.2 g, 4.035 mmol) was dissolved in tetrahydrofuran (12 mL), and LiAlD4 (6 mL, 1.0 M / THF) was slowly added dropwise at 0 °C, and the reaction was allowed to proceed at room temperature for 2 hours. After the reaction was completed, sodium sulfate decahydrate was added for quenching, and then the mixture was filtered, and the filtrate was concentrated. The obtained crude product was purified by silica gel column chromatography (DCM:MeOH = 15:1) to obtain tert-butyl 9-(hydroxymethyl-d2)-3-azaspiro[5.5]undecane-3-carboxylate.

[0893] LC-MS: (ESI, m / z): [M-56+H] + = 230.2.

[0894] Step 3: Preparation of (3-azaspiro[5.5]undecan-9-yl)methane-d2-ol

[0895] 9-(hydroxymethyl-d2)-3-azaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester (350 mg, 1.23 mmol) was dissolved in DCM (3 mL), TFA (3 mL) was added, and the reaction was allowed to proceed at room temperature for 2 h. After the reaction was completed, the mixture was concentrated under reduced pressure to obtain crude (3-azaspiro[5.5]undecan-9-yl)methane-d2-ol. The crude product was used directly in the next step without further purification.

[0896] LC-MS: (ESI, m / z): [M+H] + = 186.2.

[0897] Step 4: Preparation of 1-(5-(9-(hydroxymethyl-d2)-3-azaspiro[5.5]undecane-3- carbonyl)-2-methoxyphenyl)dihydropyrimidine-2,4(1H,3H)-dione

[0898] The crude (3-azaspiro[5.5]undecan-9-yl)methane-d2-ol (350 mg) was dissolved in DMF (5 mL), and then DIEA (793 mg, 6.15 mmol) and 3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoic acid pentafluorophenyl ester (582 mg, 1.35 mmol) were added at 0°C. The reaction was allowed to proceed at room temperature for 2 h. After the reaction was completed, water (40 mL) was added to the reaction, and extraction was performed with ethyl acetate (30 mL x 3). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (DCM:MeOH = 10:1) to obtain 1-(5-(9-(hydroxymethyl-d2)-3-azaspiro[5.5]undecane-3-carbonyl)-2-methoxyphenyl)dihydropyrimidine-2,4(1H,3H)-dione.

[0899] LC-MS: (ESI, m / z): [M+H] + = 432.2.

[0900] Step 5: Preparation of 3-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)-3-azaspiro[5.5]undecan-9-carbaldehyde-d

[0901] To a solution of 1-(5-(9-(hydroxymethyl-d2)-3-azaspiro[5.5]undecane-3- carbonyl)-2-methoxyphenyl)dihydropyrimidine-2,4(lH,3H)-dione (310 mg, 0.718 mmol) in DCM (5 mL) was cooled to 0 °C, then Dess-Martin reagent (762 mg, 1.796 mmol) was added, and the reaction was stirred at room temperature for 1 h. After the reaction was completed, the reaction was quenched by adding sodium thiosulfate solution (5 mL) and sodium bicarbonate solution (5 mL), and extracted with dichloromethane (10 mL x 3), the organic phases were combined and dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The concentrate was purified by reverse column chromatography (H2O:ACN = 20:1 ~ 1:2) to give 3-(3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)-4-methoxybenzoyl)-3- azaspiro[5.5]undecane-9-carbaldehyde-d.

[0902] LC-MS: (ESI, m / z): [M+H] + = 429.2.

[0903] Intermediate 25: (R)-3-(4-benzylpiperazin-l-yl)-2-methylpropan-l, 1-d2-1-ol

[0904] Refer to the synthesis method of intermediate 25 in WO2024083258A1.

[0905] Intermediate 26: Intermediate 26-P1 and Intermediate 26-P2

[0906] Step 1: Preparation of tert-butyl 3-benzyl-l-fluoro-3,8-diazabicyclo[3.2.1]octane-8- carboxylate

[0907] To a solution of tert-butyl 3-benzyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (4 g, 13.25 mmol) and TMEDA (3.07 g, 26.50 mmol) in THF (50 mL), sec-butyllithium (6.4 mL, 15.90 mmol, 2.5 M / THF) was added at -78 °C, and stirring was continued for 0.5 h, then NFSI (6.27 g, 19.88 mmol) was added at -78 °C and stirred for 1 h. After the reaction was completed, the reaction was poured into saturated ammonium chloride solution (50 mL), extracted with ethyl acetate (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 = 20:1) to give tert-butyl 3-benzyl-l-fluoro-3,8-diazabicyclo[3.2.1]octane-8-carboxylate.

[0908] LC-MS: (ESI, m / z): [M+H] + = 321.3.

[0909] Step 2: Preparation of tert-butyl 1-fluoro-3,8-diazabicyclo[3.2.1]octane-8- carboxylate

[0910] To a solution of tert-butyl 3-benzyl-l-fluoro-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (3.9 g, 12.19 mmol) in methanol (50 mL), Pd / C (2 g) was added and reacted under hydrogen atmosphere at 25 °C for 2 hours. After the reaction was completed, it was filtered, rinsed with ethyl acetate (10 mL), and the filtrate was concentrated under reduced pressure to give tert-butyl 1-fluoro-3,8-diazabicyclo[3.2.1]octane-8-carboxylate.

[0911] LC-MS: (ESI, m / z): [M-56+H] + = 175.3.

[0912] Step 3: Preparation of Intermediate 26-P1 and Intermediate 26-P2

[0913] To a solution of tert-butyl 1-fluoro-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (2.7 g, 11.74 mmol) and triethylamine (2.37 g, 23.48 mmol) in anhydrous tetrahydrofuran (50 mL), 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (2.95 g, 11.74 mmol) was slowly added and stirred at -50 °C for 1 hour. The reaction solution was poured into saturated ammonium chloride solution (50 mL), extracted with ethyl acetate (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 = 10:1) to give racemic tert-butyl 3-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-l-fluoro-5λ 3 -3,8-diazabicyclo[3.2.1]octane-8-carboxylate, which was resolved by chiral SFC to give Intermediate 26-P1 and Intermediate 26-P2. The chiral resolution method was: Column: Daicel CHIRALCEL OD, 250 mm*30 mm I.D., 10 μm; mobile phase: CO2 / MeOH [0.2% NH3(7M / MeOH)]; gradient: 80 / 20; flow rate: 150 mL / min; wavelength: 214 nm; column temperature: 35 °C.

[0914] Intermediate 26-P1 (Chiral column retention time: 1.693 min). SFC analysis method (Column: Daicel CHIRALCEL OD-3, 150 mm x 3 mm, 3 um; Mobile phase: C02 / MeOH (0.1% DEA); Gradient: 60 / 40, 6 min; Flow rate: 2 mL / min; Wavelength: 214 nm; Column temperature: 37 °C; Optical purity: 100%.

[0915] Intermediate 26-P2 (Chiral column retention time: 1.942 min). SFC analysis method (Column: Daicel CHIRALCEL OD-3, 150 mm x 3 mm, 3 um; Mobile phase: C02 / MeOH (0.1% DEA); Gradient: 60 / 40, 6 min; Flow rate: 2 mL / min; Wavelength: 214 nm; Column temperature: 37 °C; Optical purity: 98.34%.

[0916] LC-MS: (ESI, m / z): [M+H] + = 446.0.

[0917] Intermediate 27: tert-butyl (5S,5aS,6S,9R)-2-chloro-1-fluoro-5-methyl-12-((R)-2-methyl-3-(4- triphenylmethylpiperazin-1-yl)propoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14- pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-14-carboxylate

[0918] Step 1: Preparation of 3-benzyl 8-(tert-butyl) (1S,2S,5R)-2-(hydroxymethyl)-3,8- diazabicyclo[3.2.1]octane-3,8-dicarboxylate

[0919] tert-Butyl (1S,2S,5R)-2-(hydroxymethyl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (1.80 g, 3.72 mmol) and sodium bicarbonate (1.87 g, 22.3 mmol) were dissolved in ethyl acetate (20 mL) and water (7 mL), benzyl chloroformate (1.52 g, 8.92 mmol) was added, and the reaction was allowed to proceed at room temperature for 18 hours. After the reaction was completed, the reaction solution was poured into saturated aqueous ammonium chloride solution (30 mL) and extracted with ethyl acetate (30 mL x 3). The organic phases were combined, 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 = 10:1 to 2:1) to obtain 3-benzyl 8-(tert-butyl) (1S,2S,5R)-2-(hydroxymethyl)-3,8-diazabicyclo[3.2.1]octane-3,8-dicarboxylate.

[0920] LC-MS: (ESI, m / z): [M-Boc+H] + = 277.1.

[0921] Step 2: Preparation of 3-benzyl 8-(tert-butyl) (1S,2S,5R)-2-formyl-3,8-diazabicyclo[3.2.1]octane-3,8-dicarboxylate

[0922] DMSO (3.89 g, 49.75 mmol) was added dropwise to a solution of oxalyl chloride (1.37 g, 11.72 mmol) in dichloromethane (20 mL) at -78°C under nitrogen protection. After stirring for 15 minutes while maintaining the temperature, a solution of 3-benzyl 8-(tert-butyl) (1S,2S,5R)-2-(hydroxymethyl)-3,8-diazabicyclo[3.2.1]octane-3,8-dicarboxylate (2.5 g, 6.63 mmol) in DCM (20 mL) was added. After 1 hour of reaction at -78°C, triethylamine (5.37 g, 5.31 mmol) was added, and the reaction was allowed to proceed for 2 hours while maintaining the temperature at -78°C. After the reaction was completed, the reaction solution was poured into saturated aqueous ammonium chloride solution (100 mL) and extracted with ethyl acetate (30 mL x 3). The organic phases were combined, 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 = 10:1 to 2:1) to obtain 3-benzyl 8-(tert-butyl) (1S,2S,5R)-2-formyl-3,8-diazabicyclo[3.2.1]octane-3,8-dicarboxylate.

[0923] LC-MS: (ESI, m / z): [M+H] + = 375.2.

[0924] Step 3: Preparation of 3-benzyl 8-(tert-butyl) (1S,2S,5R)-2-((S)-1- hydroxyethyl)-3,8-diazabicyclo[3.2.1]octane-3,8-dicarboxylate

[0925] To a solution of 3-benzyl 8-(tert-butyl) (1S,2S,5R)-2-formyl-3,8- diazabicyclo[3.2.1]octane-3,8-dicarboxylate (2.03 g, 5.43 mmol) in tetrahydrofuran (20 mL) was added CH3MgBr (2.17 mL, 6.52 mmol, 3.0 M / THF) dropwise at -78 °C. After the addition was completed, the mixture was stirred at -78 °C for 3 h. After the reaction was completed, saturated aqueous ammonium chloride solution (30 mL) was added and extracted with ethyl acetate (30 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated to give a crude product, which was purified by column chromatography on silica gel (PE / EA = 2 / 1) to give 3-benzyl 8-(tert-butyl) (1S,2S,5R)-2-((S)-1-hydroxyethyl)-3,8- diazabicyclo[3.2.1]octane-3,8-dicarboxylate.

[0926] LC-MS: (ESI, m / z): [M-56+H] + = 335.2.

[0927] Step 4: Preparation of tert-butyl (1S,2S,5R)-2-((S)-1-hydroxyethyl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate

[0928] To a solution of 3-benzyl 8-(tert-butyl) (1S,2S,5R)-2-((S)-1-hydroxyethyl)-3,8- diazabicyclo[3.2.1]octane-3,8-dicarboxylate (1.83 g, 4.70 mmol) in methanol (20 mL) was added Pd / C (0.2 g), and the mixture was replaced with hydrogen for three times under hydrogen protection. The reaction was continued at 25 °C for 16 h. After the reaction was completed, the reaction mixture was filtered, and the crude product was concentrated under reduced pressure to give tert-butyl (1S,2S,5R)-2-((S)-1-hydroxyethyl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate, which was used directly in the next step without further purification.

[0929] LC-MS: (ESI, m / z): [M+H] + = 257.2.

[0930] Step 5: Preparation of (1S,2S,5R)-2-((S)-1-((7-chloro-8-fluoro-2-(methylthio)-4-oxo- 3,4-dihydropyrido[4,3-d]pyrimidin-5-yl)oxy)ethyl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylic acid tert-butyl ester

[0931] (1S,2S,5R)-2-((S)-1-hydroxyethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (1.07 g, 4.17 mmol) was dissolved in tetrahydrofuran (20 mL) and cooled to 0 °C, NaH (0.5 g, 12.5 mmol, 60%) was added and the mixture was stirred at 0 °C for 30 minutes, then 5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one (1.28 g, 4.58 mmol) was added and the mixture was stirred at 25 °C for 3 hours. After the reaction was completed, water (10 mL) was added to the reaction mixture, then the tetrahydrofuran in the reaction mixture was distilled off under reduced pressure. Then the mixture was adjusted to pH about 8 with dilute hydrochloric acid (1 M) until precipitate appeared, and the precipitate was filtered and dried to obtain crude (1S,2S,5R)-2-((S)-1-((7-chloro-8-fluoro-2-(methylthio)-4-oxo-3,4- dihydropyrido[4,3-d]pyrimidin-5-yl)oxy)ethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester, which was used in the next step without further purification.

[0932] LC-MS: (ESI, m / z): [M+H] + = 500.1.

[0933] Step 6: Preparation of (5S,5aS,6S,9R)-2-chloro-1-fluoro-5-methyl-12-(methylthio)- 5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8- ab]heptaen-14-carboxylic acid tert-butyl ester

[0934] (1S,2S,5R)-2-((S)-1-((7-chloro-8-fluoro-2-(methylthio)-4-oxo-3,4- dihydropyrido[4,3-d]pyrimidin-5-yl)oxy)ethyl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylic acid tert-butyl ester (1.43 g, 2.87 mmol) and DIEA (0.37 g, 28.7 mmol) were dissolved in DCM (20 mL), then BOPCl (2.19 g, 8.6 mmol) was added to the mixture. The mixture was reacted at 25 °C for 4 h. After the reaction was completed, water (50 mL) was added to the reaction solution, and dichloromethane (50 mL x 3) was extracted. The organic phases were combined, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated. The obtained crude product was purified by silica gel column chromatography (PE:EA = 2:1) to obtain (5S,5aS,6S,9R)-2-chloro-1-fluoro-5-methyl-12-(methylthio)-5a,6,7,8,9,10- hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptene-14- carboxylic acid tert-butyl ester.

[0935] LC-MS: (ESI, m / z): [M+H] + = 482.1.

[0936] Step 7: Preparation of (5S,5aS,6S,9R)-2-chloro-1-fluoro-5-methyl-12-(methylsulfinyl)- 5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8- ab]heptene-14-carboxylic acid tert-butyl ester

[0937] (5S,5aS,6S,9R)-2-chloro-l-fluoro-5-methyl-12-(methylthio)-5a,6,7,8,9,10- hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptene- 14-carboxylic acid tert-butyl ester (0.87 g, 1.8 mmol) was dissolved in dichloromethane (10 mL), m-CPBA (0.47 g, 2.7 mmol) was added, and the reaction was allowed to proceed at room temperature for 2 hours. After the reaction was completed, the reaction solution was poured into saturated aqueous sodium thiosulfate (20 mL), washed with saturated aqueous sodium bicarbonate (10 mL), and then extracted with dichloromethane (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give crude (5S,5aS,6S,9R)-2-chloro-l-fluoro-5-methyl-12-(methylsulfinyl)-5a,6,7,8,9,10- hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptene-14- carboxylic acid tert-butyl ester, which was used directly in the next step without purification.

[0938] LC-MS: (ESI, m / z): [M+H] + = 498.1.

[0939] Step 8: Preparation of (5S,5aS,6S,9R)-2-chloro-l-fluoro-5-methyl-12-((R)-2-methyl-3- (4-tritylpiperazin-l-yl)propoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14- pentaaza-6,9-methanonaphtho[1,8-ab]heptene-14-carboxylic acid tert-butyl ester

[0940] (R)-2-methyl-3-(4-tritylpiperazin-l-yl)propan-l-ol (0.8 g, 2.0 mmol) was dissolved in tetrahydrofuran (20 mL), cooled to 0 °C, NaH (132 mg, 3.3 mmol) was added slowly, reacted at 25 °C for 30 min, then (5S,5aS,6S,9R)-tert-butyl 2-chloro-l-fluoro-5-methyl-12-((R)-2-methyl-3-(4- tritylpiperazin-l-yl)propoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14- pentaaza-6,9-methanonaphtho[l,8-ab]heptene-14-carboxylate (0.83 g, 1.67 mmol) was added, the mixture was reacted at 0 °C for 1 h. After the reaction was completed, saturated aqueous ammonium chloride solution (10 mL) was added, extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with saturated NaCl solution, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated. The obtained crude product was purified by silica gel column chromatography (DCM:MeOH = 15: 1) to obtain (5S,5aS,6S,9R)-tert-butyl 2-chloro-l-fluoro-5-methyl-12-((R)-2-methyl-3-(4- tritylpiperazin-l-yl)propoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14- pentaaza-6,9-methanonaphtho[l,8-ab]heptene-14-carboxylate.

[0941] LC-MS: (ESI, m / z): [M+H] + = 834.3.

[0942] Example 1: l-(5-(9-((4-((2R)-3-((7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-l-yl)-8-fluoro-4-(l- (methoxymethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)-2- methylpropyl)piperazin-l-yl)methyl)-3-azaspiro[5.5]undecane-3-carbonyl)-2- methoxylphenyl)dihydropyrimidine-2,4(lH,3H)-dione

[0943] Step 1: Preparation of 3-(2-((R)-3-(4-((3-(3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)-4- methoxybenzoyl)-3-azaspiro[5.5]undecan-9-yl)methyl)piperazin-l-yl)-2-methylpropoxy)-8- fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-l-yl)- pyrido[4,3-d]pyrimidin-4-yl)-l-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester LC-MS: (ESI, m / z): [M+H]

[0944] To a stirred solution of intermediate 12 (200 mg, 0.21 mmol) and 3-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)-3- azaspiro[5.5]undecan-9-carbaldehyde (100 mg, 0.23 mmol) in DCM / AcOH (2 mL / 0.2 mL) was added tetraisopropyl titanate (0.5 mL) and stirred at 30 °C for 2 h. The mixture was added NaBH(OAc)3 (135 mg, 0.64 mmol) under ice-bath and stirred for 2 h. The mixture was concentrated, and the resulting concentrate was purified by silica gel column chromatography (DCM:MeOH = 100:1 ~ 10:1) to give 3-(2-((R)-3-(4-((3-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4- methoxybenzoyl)-3-azaspiro[5.5]undecan-9-yl)methyl)piperazin-1-yl)-2- methylpropoxy)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- ((trisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-1- (methoxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester.

[0945] LC-MS: (ESI, m / z): [M / 2 + H] + = 678.5.

[0946] Step 2: Preparation of 1-(5-(9-((4-((2R)-3-((7-(8-ethynyl-7-fluoro-3- hydroxynaphthalen-1-yl)-8-fluoro-4-(1-(methoxymethyl)-3,8- diazabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)-2- methylpropyl)piperazin-1-yl)methyl)-3-azaspiro[5.5]undecane-3- carbonyl)-2-methoxyphenyl)dihydropyrimidine-2,4(1H,3H)-dione

[0947] To a stirred solution of tert-butyl 3-(2-((R)-3-(4-((3-(3-(2,4-dioxotetrahydropyrimidin- 1(2H)-yl)-4-methoxybenzoyl)-3-azaspiro[5.5]undecan-9-yl)methyl)piperazin-1-yl)-2- methylpropoxy)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl) naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-1-(methoxymethyl)-3,8-diazabicyclo[3.2.1] octane-8-carboxylate (200 mg, 0.15 mmol) in DMF (2 mL) was added cesium fluoride (336 mg, 2.2 mmol) and stirred at room temperature for 1 h. The reaction was added to water (10 mL) and extracted with ethyl acetate (10 mL x 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated. To a stirred solution of the concentrate in 1,4-dioxane (1.0 mL) was added HCl / dioxane (6 N, 1.0 mL) and the reaction was allowed to proceed at room temperature for 0.5 h. The reaction was added to aqueous Na2CO3 solution to adjust the mixture to pH > 7 and extracted with EtOAc (10 mL x 3). The organic phase was washed with brine, dried over anhydrous Na2SO4 and concentrated. The crude product was purified by high performance liquid preparative chromatography to give 1-(5-(9-((4-((2R)-3-((7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-(1- (methoxymethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)-2- methylpropyl)piperazin-1-yl)methyl)-3-azaspiro[5.5]undecane-3-carbonyl)-2- methoxyphenyl)dihydropyrimidine-2,4(1H,3H)-dione.

[0948] LC-MS: (ESI, m / z): [M / 2 + H] + = 528.6.

[0949] 1H NMR (400 MHz, DMSO-d6) δ 10.33 (s, 1H), 10.15 (s, 1H), 9.02 (s, 1H), 7.98 (dd, J = 9.2, 6.0 Hz, 1H), 7.46 (t, J = 9.0 Hz, 1H), 7.41 - 7.30 (m, 3H), 7.21 - 7.11 (m, 2H), 4.59 - 4.26 (m, 3H), 4.13 - 4.01 (m, 1H), 3.91 (d, J = 29.6 Hz, 1H), 3.84 (s, 3H), 3.69 - 3.52 (m, 5H), 3.51 - 3.35 (m, 6H), 3.33 (s, 4H), 2.71 - 2.65 (m, 2H), 2.46 - 1.98 (m, 12H), 1.78 - 1.62 (m, 5H), 1.56 - 1.38 (m, 6H), 1.36 - 1.16 (m, 3H), 1.11 - 1.00 (m, 4H), 0.97 (d, J = 6.0 Hz, 3H).

[0950] Example 2: l-(5-(9-((4-((2R)-3-((7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-l-yl)-8-fluoro-4-(l- (methoxymethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)-2- methylpropyl)piperazin-l-yl)methyl)-3-azaspiro[5.5]undecane-3-carbonyl)-2- methoxyphenyl)dihydropyrimidine-2,4(lH,3H)-dione

[0951] Step 1: Preparation of tert-butyl 3-(2-((R)-3-(4-benzylpiperazin-l-yl)-2- methylpropoxy)-7-chloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-l-(methoxymethyl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate

[0952] Intermediate 2-P2 (400 mg, 0.85 mmol) and (R)-3-(4-benzylpiperazin-1-yl)-2- methylpropan-1-ol (421 mg, 1.69 mmol) were dissolved in THF (5 mL) and added to a sealed tube reactor, Cs2CO3 (828 mg, 2.54 mmol) was added and the reaction was stirred at 90 °C for 16 h. The reaction was cooled to room temperature, water (10 mL) was added and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, washed with saturated NaCl solution, dried over anhydrous Na2SO4, filtered and the filtrate was concentrated. The resulting crude was purified by column chromatography on silica gel (PE:EtOAc = 1:1) to give tert-butyl 3-(2-((R)-3-(4-benzylpiperazin-1-yl)-2-methylpropoxy)-7-chloro-8- fluoropyrido[4,3-d]pyrimidin-4-yl)-1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate.

[0953] LC-MS: (ESI, m / z): [M+H] + = 684.3.

[0954] Step 2: Preparation of tert-butyl 3-(2-((R)-3-(4-benzylpiperazin-1-yl)-2-methylpropoxy)-8- fluoropyrido[4,3-d]pyrimidin-4-yl)-1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate

[0955] To a mixture solution of 3-(2-((R)-3-(4-benzylpiperazin-1-yl)-2-methylpropoxy)-7- chloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-1-(methoxymethyl)-3,8-diazabicyclo[3.2.1] octane-8-carboxylic acid tert-butyl ester (395 mg, 0.58 mmol) and ((2-fluoro-6- (methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl) triisopropylsilane (360 mg, 0.7 mmol) in 1,4-dioxane (3 mL) and water (0.6 mL), CataCXium A Pd-G3 (85 mg, 0.12 mmol) and cesium carbonate (571 mg, 1.75 mmol) were added. The mixture was reacted at 85 °C for 16 hours under nitrogen protection. Water (10 mL) was added to the reaction solution, and the organic phase was extracted with ethyl acetate (10 mL x 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (DCM:MeOH = 20:1) to obtain 3-(2-((R)-3-(4-benzylpiperazin-1-yl)-2-methylpropoxy)-8-fluoro-7-(7-fluoro-3- (methoxymethoxy)-8-((trisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-1- (methoxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester.

[0956] LC-MS: (ESI, m / z): [M / 2 + H] + = 517.8.

[0957] Step 3: Preparation of 3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- ((trisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((R)-2-methyl-3-(piperazin-1-yl)propoxy)pyrido[4,3- d]pyrimidin-4-yl)-1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

[0958] To a solution of 3-(2-((R)-3-(4-benzylpiperazin-1-yl)-2-methylpropoxy)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (736 mg, 0.71 mmol) in dichloromethane (35 mL) was added 1-chloroethyl chloroformate (206 mg, 1.44 mmol) and N,N-diisopropylethylamine (272 mg, 2.10 mmol). The mixture was reacted at room temperature for 1 hour, concentrated under reduced pressure, and the concentrate was dissolved in methanol (35 mL), and the resulting mixture was heated to 50°C for 30 minutes. After the reaction was completed, it was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 10:1) to obtain 3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((R)-2-methyl-3-(piperazin-1-yl)propoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester.

[0959] LC-MS: (ESI, m / z): [M+H] + = 944.4.

[0960] Step 4: Preparation of 3-(2-((R)-3-(4-((3-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)-3-azaspiro[5.5]undecan-9-yl)methyl)piperazin-1-yl)-2-methylpropoxy)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

[0961] To a mixture solution of 3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((R)-2-methyl-3-(piperazin-1-yl)propoxy) pyridino[4,3-d]pyrimidin-4-yl)-1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylic acid tert-butyl ester (150 mg, 0.16 mmol) and 3-(3-(2,4-dioxotetrahydropyrimidin- 1(2H)-yl)-4-methoxybenzoyl)-3-azaspiro[5.5]undecan-9-carbaldehyde (102 mg, 0.24 mmol) in dichloromethane (2 mL) and glacial acetic acid (0.2 mL) was added tetraisopropyl titanate (226 mg, 0.79 mmol) and stirred at 30 °C for 2 hours. The mixture was added with sodium triacetoxyborohydride (67 mg, 0.32 mmol) under ice-bath and stirred for 2 hours. The mixture was concentrated and the obtained crude was purified by silica gel column chromatography (dichloromethane:methanol = 100:1 ~ 10:1) to give 3-(2-((R)-3-(4-((3-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4- methoxybenzoyl)-3-azaspiro[5.5]undecan-9-yl)methyl)piperazin-1-yl)-2-methylpropoxy)-8- fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl) pyridino[4,3-d]pyrimidin-4-yl)-1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylic acid tert-butyl ester.

[0962] LC-MS: (ESI, m / z): [M / 2 + H] + = 678.5.

[0963] Step 5: Preparation of 1-(5-(9-((4-((2R)-3-((7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-(1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)-2-methylpropyl)piperazin-1-yl)methyl)-3-azaspiro[5.5]undecane-3-carbonyl)-2-methoxyphenyl)dihydropyrimidine-2,4(1H,3H)-dione

[0964] To a stirred solution of tert-butyl 3-(2-((R)-3-(4-((3-(3-(2,4-dioxotetrahydropyrimidin- 1(2H)-yl)-4-methoxybenzoyl)-3-azaspiro[5.5]undecan-9-yl)methyl)piperazin-1-yl)-2- methylpropoxy)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl) naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-1-(methoxymethyl)-3,8-diazabicyclo[3.2.1] octane-8-carboxylate (208 mg, 0.15 mmol) in N,N-dimethylformamide (5 mL) was added cesium fluoride (234 mg, 1.54 mmol) and stirred at room temperature for 1 h. The reaction was added to water (30 mL) and extracted with ethyl acetate (10 mL x 3), the organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated. To a stirred solution of the concentrate in 1,4-dioxane (1.0 mL) was added hydrogen chloride / 1,4 dioxane (6 N, 1.0 mL) and the reaction was stirred at room temperature for 0.5 h. The reaction was added to aqueous Na2CO3 solution to adjust the mixture to pH > 7 and extracted with ethyl acetate (10 mL x 3). The organic phase was washed with brine, dried over anhydrous Na2SO4 and concentrated. The crude product was purified by high performance liquid preparation to give 1-(5-(9-((4-((2R)-3-((7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-(1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)-2-methylpropyl)piperazin-1-yl)methyl)-3-azaspiro[5.5]undecane-3-carbonyl)-2-methoxyphenyl)dihydropyrimidine-2,4(1H,3H)-dione.

[0965] LC-MS: (ESI, m / z): [M / 2 + H] + = 528.3.

[0966] 1H NMR (400 MHz, DMSO-d6) δ 10.33 (s, 1H), 10.15 (s, 1H), 9.02 (s, 1H), 7.98 (dd, J = 9.2, 6.0 Hz, 1H), 7.46 (t, J = 9.2 Hz, 1H), 7.39 (d, J = 2.4 Hz, 1H), 7.36 (dd, J = 8.4, 2.0 Hz, 1H), 7.31 (d, J = 2.0 Hz, 1H), 7.20 - 7.17 (m, 1H), 7.14 (d, J = 8.8 Hz, 2H), 4.54 - 4.32 (m, 3H), 4.08 - 4.02 (m, 1H), 3.94 - 3.87 (m, 1H), 3.84 (s, 3H), 3.64 - 3.55 (m, 5H), 3.55 - 3.41 (m, 6H), 3.40 - 3.34 (m, 4H), 2.69 - 2.66 (m, 2H), 2.32 - 2.05 (m, 12H), 1.75 - 1.65 (m, 5H), 1.54 - 1.38 (m, 6H), 1.38 - 1.19 (m, 3H), 1.15 - 0.97 (m, 4H), 0.97 (d, J = 6.0 Hz, 3H).

[0967] Example 18: 1-(5-(9-((4-((2R)-3-((7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-(1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)-2-methylpropyl)piperazin-1-yl)methyl)-3-azaspiro[5.5]undecane-3-carbonyl)-2-methylphenyl)dihydropyrimidine-2,4(1H,3H)-dione

[0968] Step 1: Preparation of tert-butyl 3-(2-((R)-3-(4-((3-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methylbenzoyl)-3-azaspiro[5.5]undecan-9-yl)methyl)piperazin-1-yl)-2-methylpropoxy)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0969] To a solution of intermediate 12 (200 mg, 0.21 mmol) and 3-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methylbenzoyl)-3-azaspiro[5.5]undecan-9- carbaldehyde (105 mg, 0.25 mmol) in DCM / AcOH (1.5 mL / 0.15 mL) was added tetraisopropyl titanate (301 mg, 1.05 mmol), and the mixture was stirred at 25 °C for 2 h. Then NaBH(OAc)3 (135 mg, 0.64 mmol) was added at 0 °C and stirred for 1 h. The mixture was concentrated and purified by silica gel column chromatography (DCM:MeOH = 100:1 ~ 10:1) to give 3-(2-((R)-3-(4-((3-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methylbenzoyl)-3-azaspiro[5.5]undecan-9-yl)methyl)piperazin-1-yl)-2-methylpropoxy)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester.

[0970] LC-MS: (ESI, m / z): [M / 2 + H] + = 670.5.

[0971] Step 2: Preparation of 1-(5-(9-((4-((2R)-3-((7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-(1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)-2-methylpropyl)piperazin-1-yl)methyl)-3-azaspiro[5.5]undecane-3-carbonyl)-2-methylphenyl)dihydropyrimidine-2,4(1H,3H)-dione

[0972] To a solution of 3-(2-((R)-3-(4-((3-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4- methylbenzoyl)-3-azaspiro[5.5]undecan-9-yl)methyl)piperazin-1-yl)-2-methylpropoxy)-8- fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)- pyrido[4,3-D]pyrimidin-4-yl)-1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (170 mg, 0.13 mmol) in DMF (2 mL) was added cesium fluoride (289 mg, 1.90 mmol) and stirred at 35 °C for 1 h, diluted with H2O (5 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phase was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. To the crude was added 1,4-dioxane (1 mL) and hydrochloric acid / 1,4-dioxane (4 M, 1 mL) and stirred at room temperature for 0.5 h. The reaction mixture was adjusted to pH > 7 with aqueous Na2CO3 solution and extracted with ethyl acetate (15 mL x 3). The combined organic phase was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude was purified by high performance liquid preparation to give 1-(5-(9-((4-((2R)-3-((7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-(1- (methoxymethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)-2- methylpropyl)piperazin-1-yl)methyl)-3-azaspiro[5.5]undecane-3-carbonyl)-2-methylphenyl) dihydropyrimidine-2,4(1H,3H)-dione.

[0973] 1H NMR (400 MHz, DMSO-d6) δ 10.38 (s, 1H), 10.16 (s, 1H), 9.02 (s, 1H), 7.98 (dd, J = 9.1, 6.0 Hz, 1H), 7.52 - 7.42 (m, 1H), 7.39 (d, J = 2.4 Hz, 1H), 7.36 - 7.28 (m, 2H), 7.26 - 7.16 (m, 2H), 4.60 - 4.28 (m, 3H), 4.12 - 4.01 (m, 1H), 3.91 (d, J = 30.0 Hz, 1H), 3.85 - 3.74 (m, 1H), 3.69 - 3.36 (m, 10H), 3.18 - 3.30 (m, 2H), 2.83 - 2.63 (m, 3H), 2.47 - 2.22 (m, 9H), 2.21 (s, 3H), 2.20 - 1.95 (m, 5H), 1.77 - 1.62 (m, 5H), 1.56 - 1.38 (m, 6H), 1.37 - 1.17 (m, 3H), 1.13 - 1.00 (m, 3H), 0.97 (d, J = 6.0 Hz, 3H).

[0974] LC-MS: (ESI, m / z): [M+H] + = 1039.90.

[0975] Example 19: Compound 19-P1 and Compound 19-P2

[0976] Step 1: Preparation of tert-butyl 3-(2-((2R)-3-(4-((9-(3-(2,4-dioxotetrahydropyrimidin- 1 (2H)-yl)-4-methoxybenzoyl)-1-oxo-9-azaspiro[5.5]undecan-3-yl)methyl)piperazin-1-yl)- 2-methylpropoxy)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl) naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0977] To a solution of 3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((R)-2-methyl-3-(piperazin-1-yl)propoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (280 mg, 0.31 mmol) and 9-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)-1-oxo-9-azaspiro[5.5]undecane-3-carbaldehyde (107 mg, 0.26 mmol) in DCM / AcOH (3 mL / 0.3 mL) was added tetraisopropyl titanate (619 mg, 2.18 mmol) and stirred at 25 °C for 2 h. The mixture was added NaBH(OAc)3(110 mg, 0.52 mmol) under ice bath and stirred for 2 h. The mixture was concentrated and purified by silica gel column chromatography (DCM:MeOH = 100:1 ~ 10:1) to give 3-(2-((2R)-3-(4-((9-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)-1-oxo-9-azaspiro[5.5]undecan-3-yl)methyl)piperazin-1-yl)-2-methylpropoxy)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester.

[0978] LC-MS: (ESI, m / z): [M / 2 + H] + = 657.5.

[0979] Step 2: Preparation of compound 19-P1 and compound 19-P2

[0980] To a solution of 3-(2-((2R)-3-(4-((9-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4- methoxybenzoyl)-1-oxo-9-azaspiro[5.5]undecan-3-yl)methyl)piperazin-1-yl)-2- methylpropoxy)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- ((trisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (210 mg, 0.16 mmol) in DMF (3 mL) was added cesium fluoride (121 mg, 0.80 mmol) and stirred at room temperature for 1 hour. The reaction was added to water (10 mL) and extracted with ethyl acetate (10 mL x 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. To a stirred solution of the concentrate in 1,4-dioxane (2.0 mL) was added HCl / 1,4-dioxane (6 N, 2.0 mL) and reacted at room temperature for 0.5 hours. The reaction was added to an aqueous Na2CO3 solution to adjust the mixture to pH > 7 and extracted with EtOAc (20 mL x 3). 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 racemic 1-(5-(3-((4-((R)-3-((4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethynyl-7-fluoro-3- hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)-2-methylpropyl)piperazin-1-yl)methyl)-1-oxo-9-azaspiro[5.5]undecane-9-carbonyl)-2-methoxyphenyl)dihydropyrimidine-2,4(1H,3H)-dione. The purified racemic compound was submitted for SFC resolution by the following method: Column: CHIRALPAK IC (IC00CD-TB016), 0.46 cm * 15 cm I.D., 10 μm; Mobile phase: MeOH / ACN / DEA; Gradient: 65 / 35 / 0.2 (V / V / V); Flow rate: 1 mL / min; Wavelength: 254 nm; Column temperature: 35 °C.

[0981] Compound 19-P1 (Chiral column peak time: 6.913 min). Chiral analysis method Column: CHIRALPAK IC (IC00CD-TB016), 0.46 cm * 15 cm I.D., 10 μm; Mobile phase: MeOH / ACN / DEA; Gradient: 65 / 35 / 0.2 (V / V / V); Flow rate: 1 mL / min; Wavelength: 254 nm; Column temperature: 35 °C. Optical purity: 93%.

[0982] LC-MS: (ESI, m / z): [M+H]+ = 1013.5.

[0983] 1 H NMR (400 MHz, CD3OD) δ 9.01 (s, 1H), 7.86 (dd, J = 9.1, 5.7 Hz, 1H), 7.44 (dd, J = 8.5, 2.0 Hz, 1H), 7.39 (d, J = 2.0 Hz, 1H), 7.37 - 7.29 (m, 2H), 7.24 - 7.13 (m, 2H), 4.71 - 4.49 (m, 4H), 4.39 - 4.13 (m, 2H), 3.92 (s, 3H), 3.84 - 3.55 (m, 8H), 3.37 (s, 1H), 3.35 - 3.31 (m, 2H), 2.80 (t, J = 6.7 Hz, 2H), 2.75 - 2.40 (m, 9H), 2.40 - 2.08 (m, 5H), 1.97 - 1.50 (m, 9H), 1.50 - 1.28 (m, 3H), 1.09 (d, J = 6.0 Hz, 3H).

[0984] Compound 19-P2 (Chiral column peak time: 9.062 min). Chiral analysis method column: CHIRALPAK IC (IC00CD-TB016), 0.46 cm * 15 cm I.D., 10 pm; mobile phase: MeOH / ACN / DEA; gradient: 65 / 35 / 0.2 (V / V / V); flow rate: 1 mL / min; wavelength: 254 nm; column temperature: 35 °C. Optical purity: 97%.

[0985] LC-MS: (ESI, m / z): [M+H] + = 1013.5.

[0986] 1H NMR (400 MHz, CD3OD) δ 9.00 (s, 1H), 7.86 (dd, J = 9.1, 5.7 Hz, 1H), 7.44 (dd, J = 8.5, 2.0 Hz, 1H), 7.39 (d, J = 2.0 Hz, 1H), 7.37 - 7.29 (m, 2H), 7.24 - 7.13 (m, 2H), 4.68 - 4.60 (m, 2H), 4.58 - 4.50 (m, 2H), 4.39 - 4.13 (m, 2H), 3.92 (s, 3H), 3.84 - 3.55 (m, 8H), 3.37 (s, 1H), 3.35 - 3.31 (m, 2H), 2.80 (t, J = 6.7 Hz, 2H), 2.75 - 2.40 (m, 9H), 2.40 - 2.08 (m, 5H), 1.97 - 1.50 (m, 9H), 1.50 - 1.28 (m, 3H), 1.09 (d, J = 6.0 Hz, 3H).

[0987] Example 49: 1-(5-(9-((4-((S)-3-((4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8- ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)- 2-methoxypropyl)piperazin-1-yl)methyl)-3-azaspiro[5.5]undecane-3-carbonyl)-2- methylphenyl)dihydropyrimidine-2,4(1H,3H)-dione

[0988] Step 1: Preparation of (S)-1-(4-benzylpiperazin-1-yl)-3-((tert-butyldimethylsilyl)oxy)propan-2-ol

[0989] A mixture of (S)-tert-butyldimethyl(oxetan-2-ylmethoxy)silane (20 g, 106 mmol), 1-benzylpiperazine hydrochloride (25 g, 117 mmol) and potassium carbonate (29 g, 212 mmol) in THF (15 mL) was heated to reflux for 3 hours. After completion of the reaction, it was filtered and the filtrate was concentrated. The crude product was purified by silica gel column chromatography (PE:EtOAc = 2:1) to give (S)-1-(4-benzylpiperazin-1-yl)-3-((tert-butyldimethylsilyl)oxy)propan-2-ol.

[0990] LC-MS: (ESI, m / z): [M+H] + = 365.3.

[0991] Step 2: Preparation of (S)-1-benzyl-4-(3-((tert-butyldimethylsilyl)oxy)-2- methoxypropyl)piperazine

[0992] (S)-1-(4-benzylpiperazin-1-yl)-3-((tert-butyldimethylsilyl)oxy)propan-2-ol (5.00 g, 13.70 mmol) was dissolved in THF (50 mL), NaH (0.82 g, 20.55 mmol) was added at 0 °C, after reaction at 25 °C for 30 min, it was cooled to 0 °C, iodomethane (2.14 g, 15.07 mmol) was added, and it was reacted at room temperature for 3 h. After the reaction was completed, the reaction solution was slowly poured into a cooled aqueous NH4Cl solution (100 mL), and then extracted with ethyl acetate (50 mL x 2). The combined organic phase was washed with a saturated NaCl solution, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated. The obtained crude product was purified by silica gel column chromatography (PE:EA = 30:1 ~ 5:1) to obtain (S)-1-benzyl-4-(3-((tert-butyldimethylsilyl)oxy)-2-methoxypropyl)piperazine.

[0993] 1 H NMR (400 MHz, CDCl3) δ 7.32-7.28 (m, 4H), 7.26-7.22 (m, 1H), 3.63 (d, J = 5.2 Hz, 2H), 3.50 (s, 2H), 3.42 (s, 3H), 3.35-3.39 (m, 1H), 2.42-2.60 (m, 8H), 0.89 (m, 9H), 0.05 (s, 6H).

[0994] Step 3: Preparation of (S)-3-(4-benzylpiperazin-1-yl)-2-methoxypropan-1-ol

[0995] (S)-1-benzyl-4-(3-((tert-butyldimethylsilyl)oxy)-2-methoxypropyl)piperazine (3.20 g, 8.40 mmol) was dissolved in ethanol (30 mL), cooled to 0-5 °C, concentrated hydrochloric acid (5 mL) was added, and it was reacted at room temperature for 1 h. The reaction solution was concentrated to remove ethanol, and the residue was dissolved in water (100 mL) and extracted with methyl tert-butyl ether (50 mL). The aqueous phase was adjusted to pH = 8-9 with an aqueous Na2CO3 solution, extracted with ethyl acetate (100 mL x 3), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated to obtain (S)-3-(4-benzylpiperazin-1-yl)-2-methoxypropan-1-ol. The obtained product was used directly in the next reaction without purification.

[0996] Step 4: Preparation of 3-(2-((S)-3-(4-benzylpiperazin-1-yl)-2-methoxypropoxy)-7-chloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

[0997] tert-Butyl 3-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (0.70 g, 1.63 mmol) and (S)-3-(4-benzylpiperazin-1-yl)-2-methoxypropan-1-ol (0.65 g, 2.45 mmol) were dissolved in THF (15 mL), Cs2CO3(1.06 g, 3.26 mmol) was added, and the reaction was stirred at 85 °C for 16 h. After the reaction was completed, the mixture was filtered, and the filtrate was concentrated. The resulting crude product was purified by column chromatography on silica gel (PE:EA = 2:1) to give tert-butyl 3-(2-((S)-3-(4-benzylpiperazin-1-yl)-2-methoxypropoxy)-7-chloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate.

[0998] LC-MS: (ESI, m / z): [M+H] + = 656.3.

[0999] Step 5: Preparation of tert-butyl 3-(2-((S)-3-(4-benzylpiperazin-1-yl)-2-methoxypropoxy)-8-fluoro-7-(7-fluoro-3- (methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate

[1000] To a mixture solution of 3-(2-((S)-3-(4-benzylpiperazin-1-yl)-2- methoxypropoxy)-7-chloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1] octane-8-carboxylic acid tert-butyl ester (0.50 g, 0.76 mmol) and ((2-fluoro-6- (methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl) triisopropylsilane (0.51 g, 0.99 mmol) in 1,4-dioxane (6 mL) and H2O (0.8 mL) was added Cata CXium Pd G3 (55 mg, 0.076 mmol) and cesium carbonate (0.49 g, 1.52 mmol). The mixture was reacted at 85 °C for 16 hours under nitrogen protection. Water (20 mL) was added to the reaction solution, which was then extracted with ethyl acetate (20 mL x 3), and the organic phase was combined and dried over anhydrous sodium sulfate before being concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (DCM:MeOH = 20:1) to obtain 3-(2-((S)-3-(4-benzylpiperazin-1-yl)-2-methoxypropoxy)-8-fluoro-7-(7-fluoro-3- (methoxymethoxy)-8-((trisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)- 3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester.

[1001] LC-MS: (ESI, m / z): [M+H] + = 1006.6.

[1002] Step 6: Preparation of 3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- ((trisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((S)-2-methoxy-3-(piperazin-1-yl)propoxy) pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

[1003] tert-Butyl 3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((S)-2-methoxy-3-(piperazin-1-yl)propoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate was prepared from tert-Butyl 3-(2-((S)-3-(4-benzylpiperazin-1-yl)-2-methoxypropoxy)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (0.30 g, 0.30 mmol) by dissolving in DCM (2 mL), adding 1-chloroethyl chloroformate (64 mg, 0.45 mmol) and DIEA (77 mg, 0.60 mmol). The mixture was reacted at room temperature for 1 hour, concentrated under reduced pressure, and the concentrate was dissolved in MeOH (2 mL) and then heated to 50 °C for 30 minutes. After the reaction was completed, it was directly concentrated under reduced pressure to give tert-Butyl 3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((S)-2-methoxy-3-(piperazin-1-yl)propoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate.

[1004] LC-MS: (ESI, m / z): [M+H] + = 916.5.

[1005] Step 7: Preparation of tert-Butyl 3-(2-((S)-3-(4-((3-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methylbenzoyl)-3-azaspiro[5.5]undecan-9-yl)methyl)piperazin-1-yl)-2-methoxypropoxy)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[1006] To a solution of tert-butyl 3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((S)-2-methoxy-3-(piperazin-1- yl)propoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (120 mg, 0.13 mmol) and 3-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)- 4-methylbenzoyl)-3-azaspiro[5.5]undecan-9-carbaldehyde (81 mg, 0.20 mmol) in DCM / AcOH (1.5 mL / 0.1 mL) was added tetraisopropyl titanate (0.5 mL) and stirred at 30 °C for 2 h. The mixture was added NaBH(OAc)3(55 mg, 0.26 mmol) under ice bath and stirred for 2 h. The mixture was concentrated and purified by silica gel column chromatography (DCM:MeOH = 10:1) to give tert-butyl 3-(2-((S)-3-(4-((3-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4- methylbenzoyl)-3-azaspiro[5.5]undecan-9-yl)methyl)piperazin-1-yl)-2-methoxy- propoxy)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl) naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate.

[1007] LC-MS: (ESI, m / z): [M / 2 + H] + = 656.5.

[1008] Step 8: Preparation of 1-(5-(9-((4-((S)-3-((4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2- yl)oxy)-2-methoxypropyl)piperazin-1-yl)methyl)-3-azaspiro[5.5]undecane-3- carbonyl)-2-methylphenyl)dihydropyrimidine-2,4(1H,3H)-dione

[1009] To a solution of tert-butyl 3-(2-((S)-3-(4-((3-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4- methylbenzoyl)-3-azaspiro[5.5]undecan-9-yl)methyl)piperazin-1-yl)-2- methoxypropoxy)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- ((trisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (95 mg, 0.072 mmol) in DMF (1 mL) was added cesium fluoride (55 mg, 0.36 mmol) and stirred at room temperature for 30 min. To the reaction was added water (10 mL) and extracted with ethyl acetate (10 mL x 3). The organic phase was combined and dried over anhydrous sodium sulfate and concentrated under reduced pressure. To a solution of the concentrate in 1,4-dioxane (2 mL) was added HCl / 1,4-dioxane (4 N, 1.0 mL) and reacted at room temperature for 0.5 h. The reaction was adjusted to pH > 7 with aqueous Na2CO3 solution and extracted with EtOAc (20 mL x 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 1-(5-(9-((4-((S)-3-((4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethynyl-7-fluoro-3- hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)-2- methoxypropyl)piperazin-1-yl)methyl)-3-azaspiro[5.5]undecane-3-carbonyl)-2- methylphenyl)dihydropyrimidine-2,4(1H,3H)-dione.

[1010] LC-MS: (ESI, m / z): [M / 2 + H] + = 506.3.

[1011] 1H NMR (400 MHz, DMSO-d6) δ 10.37 (s, 1H), 10.17 (s, 1H), 9.05 (s, 1H), 7.97 (dd, J = 9.2, 6.0 Hz, 1H), 7.46 (t, J = 8.8 Hz, 1H), 7.39 (d, J = 2.4 Hz, 1H), 7.36 - 7.29 (m, 2H), 7.24 (d, J = 7.6 Hz, 1H), 7.18 (d, J = 2.4 Hz, 1H), 4.62 - 4.44 (m, 2H), 4.39 - 4.25 (m, 2H), 3.93 (s, 1H), 3.83 - 3.75 (m, 1H), 3.73 - 3.43 (m, 10H), 3.36 (s, 3H), 2.88 - 2.62 (m, 3H), 2.47 - 2.24 (m, 10H), 2.21 (s, 3H), 2.11 - 1.97 (m, 2H), 1.79 - 1.58 (m, 6H), 1.57 - 1.37 (m, 5H), 1.36 - 1.19 (m, 2H), 1.16 - 0.87 (m, 4H).

[1012] Example 50: 1-(5-(9-((4-((1-(((7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-(1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octan-3-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

[1013] Step 1: Preparation of tert-butyl 3-(2-((1-((4-((3-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)-3-azaspiro[5.5]undecan-9-yl)methyl)piperazin-1-yl)methyl)cyclopropyl)methoxy)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- (trisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[1014] To a stirred solution of Intermediate 3 (200 mg, 0.23 mmol) and 1-(2-methoxy-5-(9-(piperazin-1-ylmethyl)-3-azaspiro[5.5]undecane-3-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione (202 mg, 0.41 mmol) in dichloromethane / acetic acid (10 mL / 0.1 mL) was added tetraisopropyl titanate (320 mg, 1.13 mmol) and stirred at 25 °C for 2 h. The mixture was added sodium triacetoxyborohydride (143 mg, 0.67 mmol) under ice-bath and stirred for 16 h. The mixture was concentrated and purified by silica gel column chromatography (DCM:MeOH = 100:1 ~ 10:1) to give tert-butyl 3-(2-((1-((4-((3-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)-3-azaspiro[5.5]undecan-9-yl)methyl)piperazin-1-yl)methyl)cyclopropyl)methoxy)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate.

[1015] LC-MS: (ESI, m / z): [M / 2 + H] + = 684.5.

[1016] Step 2: Preparation of 1-(5-(9-((4-((1-(((7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-(1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octan-3-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

[1017] To a solution of tert-butyl 3-(2-((1-((4-((3-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4- methoxybenzoyl)-3-azaspiro[5.5]undecan-9-yl)methyl)piperazin-1-yl)methyl)cyclopropyl)methoxy)-8- fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3- d]pyrimidin-4-yl)-1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (45 mg, 0.03 mmol) in N,N-dimethylformamide (5 mL) was added cesium fluoride (50 mg, 0.33 mmol) and stirred at room temperature for 2 hours. The reaction was diluted with water (50 mL x 2) and extracted with ethyl acetate (20 mL x 2), the organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. To a solution of the concentrate in 1,4-dioxane (2.0 mL) was added HCl / 1,4-dioxane (4.0 M, 2.0 mL) at ice water bath condition, and then stirred at room temperature for another 2 hours. The reaction was concentrated under reduced pressure at 30 °C, diluted with ammonium methanol solution (2.0 M, 5 mL), and concentrated to dryness again. The crude product was purified by preparative high performance liquid chromatography to give 1-(5-(9-((4-((1-(((7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-(1- (methoxymethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)- piperazin-1-yl)methyl)-3-azaspiro[5.5]undecane-3-carbonyl)-2-methoxyphenyl)dihydropyrimidine-2,4(1H,3H)- dione.

[1018] LC-MS: (ESI, m / z): [M+H] + = 1067.8.

[1019] 1H NMR (400 MHz, DMSO-d6) δ 8.98 (d, J = 4.2 Hz, 1H), 7.85 (dd, J = 9.2, 6.0 Hz, 1H), 7.43 (dd, J = 8.4, 2.0 Hz, 1H), 7.38 - 7.29 (m, 3H), 7.21 (d, J = 2.4 Hz, 1H), 7.18 (d, J = 8.8 Hz, 1H), 4.68 - 4.53 (m, 4H), 4.38 - 4.35 (m, 1H), 3.92 (s, 3H), 3.72 - 3.53 (m, 9H), 3.47 - 3.33 (m, 6H), 2.82 - 2.78 (m, 2H), 2.55 - 2.35 (m, 7H), 2.22 - 2.13 (m, 2H), 2.05 - 1.85 (m, 2H), 1.78 - 1.41 (m, 13H), 1.25 - 1.08 (m, 4H), 0.75 - 0.65 (m, 2H), 0.55 - 0.45 (m, 2H).

[1020] Example 63: 1-(5-(9-((4-((2R)-3-((7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-(1-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)-2-methylpropyl) piperazin-1-yl)methyl)-3-azaspiro[5.5]undecane-3-carbonyl)-2-methoxyphenyl)dihydropyrimidine- 2,4(1H,3H)-dione

[1021] Step 1: Preparation of tert-butyl 3-(2-((R)-3-(4-benzylpiperazin-1-yl)-2-methylpropoxy)-7- chloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-1-methyl-3,8-diazabicyclo[3.2.1]octane-8- carboxylate

[1022] Intermediate 14-P1 (500 mg, 1.13 mmol) and (R)-3-(4-benzylpiperazin-1-yl)-2- methylpropan-1-ol (562 mg, 2.26 mmol) were dissolved in THF (5 mL) and added to a sealed tube reactor, Cs2CO3 (1102 mg, 3.38 mmol) was added. The reaction was heated at 90 °C for 16 h. After the reaction was completed, it was cooled to room temperature, water (10 mL) was added, and ethyl acetate (10 mL x 3) was extracted. The combined organic phase was 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 = 2:1) to give tert-butyl 3-(2-((R)-3-(4-benzylpiperazin-1-yl)-2-methylpropoxy)-7-chloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-1-methyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate.

[1023] LC-MS: (ESI, m / z): [M+H] + = 654.3.

[1024] Step 2: Preparation of tert-butyl 3-(2-((R)-3-(4-benzylpiperazin-1-yl)-2-methylpropoxy)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-1-methyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[1025] To a mixture solution of 3-(2-((R)-3-(4-benzylpiperazin-1-yl)-2-methylpropoxy)-7- chloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-1-methyl-3,8-diazabicyclo[3.2.1]octane-8- carboxylic acid tert-butyl ester (500 mg, 0.76 mmol) and ((2-fluoro-6- (methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl) triisopropylsilane (469 mg, 0.91 mmol) in 1,4-dioxane (3 mL) and H2O (0.6 mL), added CataCXium A Pd G3 (111 mg, 0.15 mmol) and cesium carbonate (745 mg, 2.29 mmol). The mixture was reacted at 85 °C for 16 hours under nitrogen protection, added water (10 mL), then extracted with ethyl acetate (10 mL x 3), the organic phase was 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 obtain 3-(2-((R)-3-(4-benzylpiperazin-1-yl)-2-methylpropoxy)-8-fluoro-7-(7-fluoro-3- (methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-1- methyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester.

[1026] LC-MS: (ESI, m / z): [M+H] + = 1004.4.

[1027] Step 3: Preparation of 3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((R)-2-methyl-3-(piperazin-1-yl)propoxy)pyrido[4,3- d]pyrimidin-4-yl)-1-methyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

[1028] tert-Butyl 3-(2-((R)-3-(4-benzylpiperazin-1-yl)-2-methylpropoxy)-8-fluoro-7-(7-fluoro-3- (methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-1- methyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (550 g, 0.55 mmol) was dissolved in DCM (5 mL), 1-chloroethyl chloroformate (234 mg, 1.64 mmol) and DIEA (212 mg, 1.64 mmol) were added. The mixture was reacted at room temperature for 1 hour, concentrated under reduced pressure, the concentrate was dissolved in MeOH (5 mL), heated to 50 °C for 10 minutes. After the reaction was completed, it was concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (DCM:MeOH = 10:1) to obtain tert-butyl 3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2- ((R)-2-methyl-3-(piperazin-1-yl)propoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-methyl-3,8-diazabicyclo[3.2.1] octane-8-carboxylate.

[1029] LC-MS: (ESI, m / z): [M+H] + = 914.4.

[1030] Step 4: Preparation of tert-butyl 3-(2-((R)-3-(4-((3-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4- methoxybenzoyl)-3-azaspiro[5.5]undecan-9-yl)methyl)piperazin-1-yl)-2-methylpropoxy)-8-fluoro-7-(7- fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-1- methyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[1031] To a stirred solution of 3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((R)-2-methyl-3-(piperazin-1-yl)propoxy) pyridino[4,3-d]pyrimidin-4-yl)-1-methyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (150 mg, 0.16 mmol) and 3-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4- methoxybenzoyl)-3-azaspiro[5.5]undecan-9-carbaldehyde (84 mg, 0.20 mmol) in DCM / AcOH (2 mL / 0.2 mL) was added tetraisopropyl titanate (0.5 mL) and stirred at 30 °C for 2 h. To the mixture was added NaBH(OAc)3 (104 mg, 0.49 mmol) under ice bath and stirred for 2 h. The mixture was concentrated and purified by silica gel column chromatography (DCM:MeOH = 100:1 ~ 10:1) to give 3-(2-((R)-3-(4-((3-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4- methoxybenzoyl)-3-azaspiro[5.5]undecan-9-yl)methyl)piperazin-1-yl)-2-methylpropoxy)-8- fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl) pyridino[4,3-d]pyrimidin-4-yl)-1-methyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester.

[1032] LC-MS: (ESI, m / z): [M / 2 + H] + = 663.5.

[1033] Step 5: Preparation of 1-(5-(9-((4-((2R)-3-((7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-(1-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)-2-methylpropyl)piperazin-1-yl)methyl)-3-azaspiro[5.5]undecane-3-carbonyl)-2-methoxyphenyl)dihydropyrimidine-2,4(1H,3H)-dione

[1034] To a stirred solution of tert-butyl 3-(2-((R)-3-(4-((3-(3-(2,4-dioxotetrahydropyrimidin- 1(2H)-yl)-4-methoxybenzoyl)-3-azaspiro[5.5]undecan-9-yl)methyl)piperazin-1-yl)-2- methylpropoxy)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl) naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-1-methyl-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (170 mg, 0.13 mmol) in DMF (2 mL) was added cesium fluoride (292 mg, 1.92 mmol) and stirred at room temperature for 1 h. The reaction was added to water (10 mL) and extracted with ethyl acetate (10 mL x 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated. To a stirred solution of the concentrate in 1,4-dioxane (1.0 mL) was added HCl / 1,4-dioxane (6 N, 1.0 mL) and the reaction was allowed to proceed at room temperature for 0.5 h. The reaction was added to aqueous Na2CO3 solution to adjust the mixture to pH > 7 and extracted with EtOAc (10 mL x 3). 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 1-(5-(9-((4-((2R)-3-((7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-(1- methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)-2-methylpropyl) piperazin-1-yl)methyl)-3-azaspiro[5.5]undecane-3-carbonyl)-2-methoxyphenyl)dihydropyrimidine- 2,4(1H,3H)-dione.

[1035] LC-MS: (ESI, m / z): [M / 2 + H] + = 513.3.

[1036] 1H NMR (400 MHz, DMSO-d6) δ 10.33 (s, 1H), 9.04 (d, J = 2.4 Hz, 1H), 7.96 (dd, J = 9.1, 6.0 Hz, 1H), 7.45 (t, J = 9.0 Hz, 1H), 7.39 - 7.33 (m, 2H), 7.32 (d, J = 1.8 Hz, 1H), 7.20 - 7.10 (m, 2H), 4.53 - 4.38 (m, 2H), 4.35 - 4.25 (m, 1H), 4.12 - 4.00 (m, 1H), 3.92 (s, 1H), 3.84 (s, 3H), 3.67 - 3.48 (m, 6H), 3.30 - 3.17 (m, 3H), 2.70 - 2.64 (m, 2H), 2.49 - 2.09 (m, 12H), 2.09 - 2.00 (m, 2H), 1.83 - 1.60 (m, 5H), 1.57 - 1.39 (m, 5H), 1.38 - 1.27 (m, 3H), 1.24 (s, 3H), 1.11 - 0.92 (m, 7H).

[1037] Example 72: 1-(5-(9-((4-((1-(((7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-(1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octan-3-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

[1038] Step 1: Preparation of tert-butyl 3-(2-((1-((4-((3-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methylbenzoyl)-3-azaspiro[5.5]undecan-9-yl)methyl)piperazin-1-yl)methyl)cyclopropyl)methoxy)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[1039] To a solution of Intermediate 3 (200 mg, 0.23 mmol) and 1-(2-methyl-5-(9-(piperazin-1-ylmethyl)-3-azaspiro[5.5]undecane-3-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione (217 mg, 0.45 mmol) in dichloromethane / acetic acid (10 mL / 0.1 mL) was added tetraisopropyl titanate (320 mg, 1.13 mmol) and stirred at 25 °C for 2 hours. The mixture was added with sodium triacetoxyborohydride (143 mg, 0.67 mmol) under ice-bath and stirred for 16 hours. The mixture was concentrated and purified by silica gel column chromatography (DCM:MeOH = 100:1 ~ 10:1) to give tert-butyl 3-(2-((1-((4-((3-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methylbenzoyl)-3-azaspiro[5.5]undecan-9-yl)methyl)piperazin-1-yl)methyl)cyclopropyl)methoxy)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate.

[1040] LC-MS: (ESI, m / z): [M / 2 + H] + = 676.5.

[1041] Step 2: Preparation of 1-(5-(9-((4-((1-(((7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-(1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octan-3-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

[1042] To a solution of tert-butyl 3-(2-((1-((4-((3-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4- methylbenzoyl)-3-azaspiro[5.5]undecan-9-yl)methyl)piperazin-1-yl)methyl)cyclopropyl)- methoxy)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1- yl)pyrido[4,3-d]pyrimidin-4-yl)-1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (118 mg, 0.03 mmol) in N,N-dimethylformamide (5 mL) was added cesium fluoride (133 mg, 0.88 mmol) and stirred at room temperature for 2 hours. To the reaction was added water (2 x 50 mL) and extracted with ethyl acetate (20 mL x 2), the organic phase was combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. To a solution of the concentrate in 1,4-dioxane (2.0 mL) was added HCl / 1,4-dioxane (4.0 M, 2.0 mL) at ice water bath condition and stirred at room temperature for 2 hours. The reaction was concentrated under reduced pressure at 30 °C, diluted with ammonium methanol solution (2.0 M, 5 mL), and concentrated to dryness again. The crude product was purified by preparative high performance liquid chromatography to give 1-(5-(9-((4-((1-(((7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-(1- (methoxymethyl)-3,8-diazabicyclo[3.2.1]octan-3-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.

[1043] LC-MS: (ESI, m / z): [M+H] + = 1051.8.

[1044] 1H NMR (400 MHz, DMSO-d6) δ 8.98 (d, J = 4.2 Hz, 1H), 7.85 (dd, J = 9.2, 6.0 Hz, 1H), 7.39 (d, J = 8.0 Hz, 1H), 7.33 - 7.29 (m, 4H), 7.21 (d, J = 2.4 Hz, 1H), 4.71 - 4.45 (m, 4H), 4.38 - 4.35 (m, 1H), 3.87 - 3.83 (m, 1H), 3.72 - 3.47 (m, 9H), 3.41 - 3.33 (m, 6H), 2.88 - 2.81 (m, 2H), 2.54 - 2.36 (m, 7H), 2.31 (s, 3H), 2.15 - 2.09 (m, 2H), 1.95 - 1.80 (m, 2H), 1.75 - 1.29 (m, 12H), 1.25 - 1.05 (m, 4H), 0.75 - 0.65 (m, 2H), 0.55 - 0.45 (m, 2H).

[1045] Example 88: 1-(5-(9-((4-((2R)-3-((7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-(1-((methoxy-d3)methyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)-2-methylpropyl)piperazin-1-yl)methyl)-3-azaspiro[5.5]undecane-3-carbonyl)-2-methoxyphenyl)dihydropyrimidine-2,4(1H,3H)-dione

[1046] Step 1: Preparation of tert-butyl 3-(2-((R)-3-(4-benzylpiperazin-1-yl)-2-methylpropoxy)-7-chloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-1-((methoxy-d3)methyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[1047] Intermediate 11-P1 (200 mg, 0.42 mmol) and (R)-3-(4-benzylpiperazin-1-yl)-2- methylpropan-1-ol (209 mg, 0.84 mmol) were dissolved in THF (3 mL) to a sealed tube reactor, Cs2CO3 (411 mg, 1.26 mmol) was added, and the reaction was carried out at 90 °C for 16 h. After the reaction was completed, it was cooled to room temperature, water (10 mL) was added, and extraction was performed with ethyl acetate (10 mL x 3). The combined organic phase was washed with a saturated NaCl solution, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated. The resulting crude product was subjected to silica gel column chromatography (DCM:MeOH = 20:1) to obtain 3-(2-((R)-3-(4-benzylpiperazin-1-yl)-2-methylpropoxy)-7-chloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-1-((methoxy-d3)methyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester.

[1048] LC-MS: (ESI, m / z): [M+H] + = 687.4.

[1049] Step 2: Preparation of 3-(2-((R)-3-(4-benzylpiperazin-1-yl)-2-methylpropoxy)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-1-((methoxy-d3)methyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

[1050] To a mixture solution of 3-(2-((R)-3-(4-benzylpiperazin-1-yl)-2-methylpropoxy)-7- chloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-1-((methoxy-d3)methyl)-3,8-diazabicyclo[3.2.1] octane-8-carboxylic acid tert-butyl ester (210 mg, 0.31 mmol) and ((2-fluoro-6- (methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl) triisopropylsilane (188 mg, 0.37 mmol) in 1,4-dioxane (2 mL) and H2O (0.4 mL) was added CataCXium A Pd-G3 (45 mg, 0.06 mmol) and cesium carbonate (299 mg, 0.92 mmol). The mixture was reacted at 85 °C under nitrogen protection for 16 hours, water (10 mL) was added, and the organic phase was extracted with ethyl acetate (10 mL x 3), combined and dried over anhydrous sodium sulfate before being concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (DCM:MeOH = 20:1) to obtain 3-(2-((R)-3-(4-benzylpiperazin-1-yl)-2-methylpropoxy)-8-fluoro-7-(7-fluoro-3- (methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-1- ((methoxy-d3)methyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester.

[1051] LC-MS: (ESI, m / z): [M / 2 + H] + = 519.5.

[1052] Step 3: Preparation of 3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((R)-2-methyl-3-(piperazin-1-yl)propoxy)pyrido[4,3- d]pyrimidin-4-yl)-1-((methoxy-d3)methyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

[1053] tert-Butyl 3-(2-((R)-3-(4-benzylpiperazin-1-yl)-2-methylpropoxy)-8-fluoro-7-(7-fluoro-3- (methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-1- ((methoxy-d3)methyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (100 mg, 0.096 mmol) was dissolved in DCM (1 mL), 1-chloroethyl chloroformate (41 mg, 0.29 mmol) and DIEA (37 mg, 0.29 mmol) were added. The mixture was reacted at room temperature for 1 hour, concentrated under reduced pressure, and the concentrate was dissolved in MeOH (1 mL) and heated to 50 °C for 10 minutes. After the reaction was completed, it was concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (DCM:MeOH = 10:1) to obtain tert-butyl 3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)- 2-((R)-2-methyl-3-(piperazin-1-yl)propoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-((methoxy-d3)methyl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate.

[1054] LC-MS: (ESI, m / z): [M+H] + = 948.5.

[1055] Step 4: Preparation of tert-butyl 3-(2-((R)-3-(4-((3-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4- methoxybenzoyl)-3-azaspiro[5.5]undecan-9-yl)methyl)piperazin-1-yl)-2-methylpropoxy)-8-fluoro-7-(7- fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4- yl)-1-((methoxy-d3)methyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[1056] To a stirred solution of 3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((R)-2-methyl-3-(piperazin-1-yl)propoxy) pyridino[4,3-d]pyrimidin-4-yl)-1-((methoxy-d3)methyl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylic acid tert-butyl ester (60 mg, 0.063 mmol) and 3-(3-(2,4-dioxotetrahydropyrimidin- 1(2H)-yl)-4-methoxybenzoyl)-3-azaspiro[5.5]undecan-9-carbaldehyde (33 mg, 0.076 mmol) in DCM / AcOH (1 mL / 0.1 mL) was added tetraisopropyl titanate (0.25 mL), stirred at 30 °C for 2 h. The mixture was added NaBH(OAc)3(10 mg, 0.19 mmol) under ice bath and stirred for 1 h. The mixture was concentrated and purified by silica gel column chromatography (DCM:MeOH = 100:1 ~ 10:1) to give 3-(2-((R)-3-(4-((3-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4- methoxybenzoyl)-3-azaspiro[5.5]undecan-9-yl)methyl)piperazin-1-yl)-2-methylpropoxy)-8- fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl) pyridino[4,3-d]pyrimidin-4-yl)-1-((methoxy-d3)methyl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylic acid tert-butyl ester.

[1057] LC-MS: (ESI, m / z): [M / 2 + H] + = 680.0.

[1058] Step 5: Preparation of 1-(5-(9-((4-((2R)-3-((7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)- 8-fluoro-4-(1-((methoxy-d3)methyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidin- 2-yl)oxy)-2-methylpropyl)piperazin-1-yl)methyl)-3-azaspiro[5.5]undecane-3-carbonyl)-2- methoxyphenyl)dihydropyrimidine-2,4(1H,3H)-dione

[1059] To a stirred solution of tert-butyl 3-(2-((R)-3-(4-((3-(3-(2,4-dioxotetrahydropyrimidin- 1(2H)-yl)-4-methoxybenzoyl)-3-azaspiro[5.5]undecan-9-yl)methyl)piperazin-1-yl)-2- methylpropoxy)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl) naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-1-((methoxy-d3)methyl)-3,8-diazabicyclo[3.2.1] octane-8-carboxylate (60 mg, 0.044 mmol) in DMF (1 mL) was added cesium fluoride (101 mg, 0.66 mmol) and stirred at room temperature for 1 h. To the reaction was added water (5 mL) and extracted with ethyl acetate (5 mL x 3), the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated. To a stirred solution of the concentrate in 1,4-dioxane (1.0 mL) was added HCl / 1,4-dioxane (4 N, 1.0 mL) and stirred at room temperature for 0.5 h. The reaction was adjusted to pH > 7 with aqueous Na2CO3 solution and extracted with EtOAc (10 mL x 3). The organic phase was washed with brine, dried over anhydrous Na2SO4 and concentrated. The crude was purified by preparative high performance liquid chromatography to give 1-(5-(9-((4-((2R)-3-((7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-(1-((methoxy-d3)methyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)-2-methylpropyl)piperazin-1-yl)methyl)-3-azaspiro[5.5]undecane-3-carbonyl)-2-methoxyphenyl)dihydropyrimidine-2,4(1H,3H)-dione.

[1060] LC-MS: (ESI, m / z): [M / 2 + H] + = 529.8.

[1061] 1H NMR (400 MHz, CD3OD) δ 9.04 (s, 1H), 8.44 (s, 2H), 7.87 (dd, J = 9.0, 5.8 Hz, 1H), 7.46 - 7.31 (m, 4H), 7.23 - 7.16 (m, 2H), 4.83 - 4.52 (m, 4H), 4.36 - 4.20 (m, 1H), 4.08 - 3.98 (m, 1H), 3.92 (s, 3H), 3.88 - 3.61 (m, 8H), 3.54 - 3.38 (m, 3H), 3.22 - 3.00 (m, 4H), 2.99 - 2.63 (m, 9H), 2.55 - 2.45 (m, 1H), 2.41 - 2.29 (m, 1H), 2.19 - 2.05 (m, 1H), 2.04 - 1.91 (m, 2H), 1.86 - 1.33 (m, 10H), 1.28 - 1.13 (m, 4H), 1.10 (d, J = 6.4 Hz, 3H).

[1062] Example 89: 1-(5-(9-((4-((2R)-3-((7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-(1- ethenyl-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)-2-methylpropyl)piperazin-1-yl)methyl)-3- azaspiro[5.5]undecane-3-carbonyl)-2-methoxyphenyl)dihydropyrimidine-2,4(1H,3H)-dione

[1063] Step 1: Preparation of tert-butyl 3-(2-((R)-3-(4-((3-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4- methoxybenzoyl)-3-azaspiro[5.5]undecan-9-yl)methyl)piperazin-1-yl)-2-methylpropoxy)-8-fluoro-7-(7-fluoro-3- (methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-1-ethenyl-3,8- diazabicyclo[3.2.1]octane-8-carboxylate

[1064] To a stirred solution of intermediate 9 (150 mg, 0.16 mmol) and 3-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)-3- azaspiro[5.5]undecan-9-carbaldehyde (83 mg, 0.19 mmol) in DCM / AcOH (1.5 mL / 0.1 mL) was added tetraisopropyl titanate (0.25 mL) and stirred at 30 °C for 2 h. The mixture was added NaBH(OAc)3(107 mg, 0.48 mmol) under ice-bath and stirred for 2 h. The mixture was concentrated and purified by silica gel column chromatography (DCM:MeOH = 100:1 ~ 10:1) to give 3-(2-((R)-3-(4-((3-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4- methoxybenzoyl)-3-azaspiro[5.5]undecan-9-yl)methyl)piperazin-1-yl)-2-methylpropoxy)-8- fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3- d]pyrimidin-4-yl)-1-ethenyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester.

[1065] LC-MS: (ESI, m / z): [M / 2 + H] + = 669.4.

[1066] Step 2: Preparation of 1-(5-(9-((4-((2R)-3-((7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8- fluoro-4-(1-ethenyl-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)-2- methylpropyl)piperazin-1-yl)methyl)-3-azaspiro[5.5]undecane-3-carbonyl)-2-methoxyphenyl) dihydropyrimidine-2,4(1H,3H)-dione

[1067] To a stirred solution of tert-butyl 3-(2-((R)-3-(4-((3-(3-(2,4-dioxotetrahydropyrimidin- 1(2H)-yl)-4-methoxybenzoyl)-3-azaspiro[5.5]undecan-9-yl)methyl)piperazin-1-yl)-2- methylpropoxy)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl) naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-1-ethenyl-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (120 mg, 0.09 mmol) in DMF (1 mL) was added cesium fluoride (68 mg, 0.45 mmol) and stirred at room temperature for 1 h. To the reaction mixture was added water (5 mL) and extracted with ethyl acetate (15 mL x 3), the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated. To a stirred solution of the concentrate in 1,4-dioxane (1.0 mL) was added HCl / dioxane (4 N, 1.0 mL) and stirred at room temperature for 0.5 h. The reaction mixture was adjusted to pH > 7 with aqueous Na2CO3 solution and extracted with EtOAc (10 mL x 3). The organic phase was washed with brine, dried over anhydrous Na2SO4 and concentrated. The resulting crude was purified by preparative HPLC to give 1-(5-(9-((4-((2R)-3-((7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-(1- ethenyl-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)-2-methylpropyl) piperazin-1-yl)methyl)-3-azaspiro[5.5]undecane-3-carbonyl)-2-methoxyphenyl)dihydropyrimidine- 2,4(1H,3H)-dione.

[1068] LC-MS: (ESI, m / z): [M+H] + = 1037.4.

[1069] 1H NMR (400 MHz, DMSO-d6) δ 10.70 - 9.8 (m, 2H), 9.04 (d, J = 2.3 Hz, 1H), 8.06 - 7.86 (m, 1H), 7.50 - 7.27 (m, 4H), 7.20 - 7.11 (m, 2H), 6.08 (dd, J = 17.5, 10.8 Hz, 1H), 5.38 - 5.25 (m, 1H), 5.23 - 5.12 (m, 1H), 4.62 - 4.27 (m, 3H), 4.14 - 4.03 (m, 1H), 3.93 (d, J = 17.5 Hz, 1H), 3.84 (s, 3H), 3.68 - 3.49 (m, 6H), 3.20 - 3.12 (m, 1H), 2.83 - 2.61 (m, 5H), 2.45 - 1.98 (m, 12H), 1.91 - 1.63 (m, 5H), 1.58 - 1.39 (m, 6H), 1.34 - 1.23 (m, 3H), 1.10 - 0.94 (m, 7H).

[1070] Example 90: 1-(5-(9-((4-((2R)-3-((4-(1-ethyl-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)-2-methylpropyl)piperazin-1-yl)methyl)-3-azaspiro[5.5]undecane-3-carbonyl)-2-methylphenyl)dihydropyrimidine-2,4(1H,3H)-dione

[1071] Step 1: Preparation of tert-butyl 3-(2-((R)-3-(4-((3-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methylbenzoyl)-3-azaspiro[5.5]undecan-9-yl)methyl)piperazin-1-yl)-2-methylpropoxy)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-1-ethyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[1072] To a stirred solution of intermediate 10 (100 mg, 0.11 mmol) and 3-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methylbenzoyl)-3- azaspiro[5.5]undecan-9-carbaldehyde (53 mg, 0.13 mmol) in DCM / AcOH (1.5 mL / 0.1 mL) was added tetraisopropyl titanate (0.13 mL) and stirred at 30 °C for 2 h. The mixture was cooled in an ice bath and NaBH(OAc)3 (68 mg, 0.32 mmol) was added and stirred for 2 h. The mixture was concentrated and purified by silica gel column chromatography (DCM:MeOH = 100:1 ~ 10:1) to give 3-(2-((R)-3-(4-((3-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methylbenzoyl)-3- azaspiro[5.5]undecan-9-yl)methyl)piperazin-1-yl)-2-methylpropoxy)-8-fluoro-7-(7-fluoro-3- (methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-1- ethyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester.

[1073] LC-MS: (ESI, m / z): [M / 2 + H] + = 662.5.

[1074] Step 2: Preparation of 1-(5-(9-((4-((2R)-3-((4-(1-ethyl-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8- ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)-2- methylpropyl)piperazin-1-yl)methyl)-3-azaspiro[5.5]undecane-3-carbonyl)-2-methylphenyl) dihydropyrimidine-2,4(1H,3H)-dione

[1075] To a stirred solution of tert-butyl 3-(2-((R)-3-(4-((3-(3-(2,4-dioxotetrahydropyrimidin- 1(2H)-yl)-4-methylbenzoyl)-3-azaspiro[5.5]undecan-9-yl)methyl)piperazin-1-yl)-2- methylpropoxy)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl) naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-1-ethyl-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (80 mg, 0.06 mmol) in DMF (1 mL) was added cesium fluoride (138 mg, 0.91 mmol) and stirred at room temperature for 1 h. To the reaction mixture was added water (5 mL) and extracted with ethyl acetate (5 mL x 3), the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated. To a stirred solution of the concentrate in 1,4-dioxane (1.0 mL) was added HCl / dioxane (4 N, 1.0 mL) and stirred at room temperature for 0.5 h. The reaction mixture was adjusted to pH > 7 with aqueous Na2CO3 solution and extracted with EtOAc (10 mL x 3). The organic phase was washed with brine, dried over anhydrous Na2SO4 and concentrated. The crude was purified by preparative high performance liquid chromatography to give 1-(5-(9-((4-((2R)-3-((4-(1-ethyl-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethynyl-7-fluoro-3- hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)-2-methylpropyl)piperazin-1- yl)methyl)-3-azaspiro[5.5]undecane-3-carbonyl)-2-methylphenyl)dihydropyrimidine-2,4(1H,3H)- dione.

[1076] LC-MS: (ESI, m / z): [M / 2 + H] + = 512.4.

[1077] 1H NMR (400 MHz, DMSO-d6) δ 10.37 (s, 1H), 10.14 (s, 1H), 9.04 (s, 1H), 7.97 (dd, J = 9.2, 6.0 Hz, 1H), 7.46 (t, J = 9.0 Hz, 1H), 7.39 (d, J = 2.4 Hz, 1H), 7.35 - 7.29 (m, 2H), 7.26 - 7.21 (m, 1H), 7.20 - 7.16 (m, 1H), 4.56 - 4.24 (m, 3H), 4.16 - 4.02 (m, 1H), 3.91 (d, J = 16.4 Hz, 1H), 3.86 - 3.74 (m, 1H), 3.67 - 3.46 (m, 5H), 3.30 - 3.22 (m, 2H), 2.87 - 2.62 (m, 3H), 2.45 - 2.24 (m, 8H), 2.21 (s, 3H), 2.19 - 2.10 (m, 2H), 2.05 (s, 2H), 1.85 - 1.16 (m, 17H), 1.12 - 1.01 (m, 3H), 1.00 - 0.90 (m, 7H).

[1078] Example 92: 1-(5-(3-((4-((1-(((7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-(1- ethenyl-5λ 3 -3,8-diazabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperazin-1-yl)methyl)-3λ 3 -1-oxo-9-azaspiro[5.5]undecan-9-carbonyl)-2-methoxyphenyl)dihydropyrimidine-2,4(1H,3H)- dione

[1079] Step 1: 3-(2-((1-((4-((9-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)-3λ 3 -1-oxo-9-azaspiro[5.5]undecan-3-yl)methyl)piperazin-1-yl)methyl)cyclopropyl)methoxy)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-1-ethenyl-5λ 3 Preparation of tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[1080] To a stirred solution of intermediate 15 (150 mg, 0.17 mmol) and intermediate 19 (103 mg, 0.21 mmol) in DCM / AcOH (2 mL / 0.2 mL) was added tetraisopropyl titanate (0.5 mL) and stirred at 30 °C for 2 h. The mixture was cooled in an ice bath and NaBH(OAc)3 (110 mg, 0.52 mmol) was added and stirred for 2 h. The mixture was concentrated and the crude product was purified by column chromatography on silica gel (DCM:MeOH = 100:1 ~ 10:1) to give 3-(2-((1-((4-((9-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)-3λ 3 -1-oxo-9-azaspiro[5.5]undecan-3-yl)methyl)piperazin-1-yl)methyl)cyclopropyl)methoxy)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-1-ethenyl-5λ 3 -3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester.

[1081] LC-MS: (ESI, m / z): [M / 2+H] + = 676.5.

[1082] Step 2: 1-(5-(3-((4-((1-(((7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-(1-ethenyl-5λ 3 -3,8-diazabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperazin-1-yl)methyl)-3λ 3 Preparation of 1-(5-(3-((4-((1-(((7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-(1-ethenyl-5λ

[1083] To a stirred solution of intermediate 15 (150 mg, 0.17 mmol) and intermediate 19 (103 mg, 0.21 mmol) in DCM / AcOH (2 mL / 0.2 mL) was added tetraisopropyl titanate (0.5 mL) and stirred at 30 °C for 2 h. The mixture was cooled in an ice bath and NaBH(OAc)3 (110 mg, 0.52 mmol) was added and stirred for 2 h. The mixture was concentrated and the crude product was purified by column chromatography on silica gel (DCM:MeOH = 100:1 ~ 10:1) to give 3-(2-((1-((4-((9-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)-3λ 3 -1-oxo-9-azaspiro[5.5]undecan-3-yl)methyl)piperazin-1-yl)methyl)cyclopropyl)methoxy)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-1-ethenyl-5λ 3To a solution of tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (182 mg, 0.13 mmol) in DMF (2 mL) was added cesium fluoride (306 mg, 2.02 mmol) and stirred at room temperature for 1 h. The reaction was added water (10 mL) and extracted with ethyl acetate (10 mL x 3), the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated. To a stirred solution of the concentrate in 1,4-dioxane (1.0 mL) was added HC1 / 1,4-dioxane (6 N, 1.0 mL) and the reaction was stirred at room temperature for 0.5 h. The reaction was added aqueous Na2CO3 solution to adjust the mixture to pH > 7 and extracted with EtOAc (10 mL x 3). The organic phase was washed with brine, dried over anhydrous Na2SO4 and concentrated. The crude was purified by preparative high performance liquid chromatography to give 1-(5-(3-((4-((1-(((7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-(1-ethenyl-5λ 3 -3,8-diazabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperazin-1-yl)methyl)-3λ 3 -1-oxo-9-azaspiro[5.5]undecan-9-carbonyl)-2-methoxyphenyl)dihydropyrimidine-2,4(1H,3H)-dione.

[1084] LC-MS: (ESI, m / z): [M / 2 + H] + = 526.3.

[1085] 1H NMR (400 MHz, DMSO-d6) δ 10.33 (s, 1H), 10.15 (s, 1H), 9.04 (d, J = 3.1 Hz, 1H), 7.97 (dd, J = 9.2, 6.0 Hz, 1H), 7.46 (t, J = 9.0 Hz, 1H), 7.41 - 7.35 (m, 2H), 7.34 - 7.31 (m, 1H), 7.19 - 7.13 (m, 2H), 6.18 - 6.02 (m, 1H), 5.35 - 5.27 (m, 1H), 5.20 - 5.14 (m, 1H), 4.63 - 4.24 (m, 4H), 3.92 (d, J = 10.8 Hz, 1H), 3.84 (s, 3H), 3.73 - 3.50 (m, 6H), 3.31 - 3.10 (m, 4H), 2.68 (t, J = 6.5 Hz, 2H), 2.48 - 2.15 (m, 10H), 2.13 - 1.99 (m, 3H), 1.95 - 1.61 (m, 5H), 1.60 - 1.43 (m, 5H), 1.41 - 1.10 (m, 4H), 0.69 - 0.59 (m, 2H), 0.45 - 0.35 (m, 2H).

[1086] Example 95: 1-(5-(3-((4-((1-(((7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-(1- ethenyl-5λ 3 -3,8-diazabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperazin-1-yl)methyl)-3λ 3 -1-oxo-9-azaspiro[5.5]undecan-9-carbonyl)-2-methylphenyl)dihydropyrimidine-2,4(1H,3H)- dione

[1087] Step 1: 3-(2-((1-((4-((9-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methylbenzoyl)-3λ 3 -1-oxo-9-azaspiro[5.5]undecan-3-yl)methyl)piperazin-1-yl)methyl)cyclopropyl)methoxy)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3- d]pyrimidin-4-yl)-1-ethenyl-5λ 3 Preparation of tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[1088] To a stirred solution of intermediate 15 (150 mg, 0.17 mmol) and intermediate 20 (100 mg, 0.21 mmol) in DCM / AcOH (2 mL / 0.2 mL) was added tetraisopropyl titanate (0.5 mL) and stirred at 30 °C for 2 h. The mixture was cooled in an ice bath and NaBH(OAc)3 (110 mg, 0.52 mmol) was added and stirred for 2 h. The mixture was concentrated and the crude product was purified by column chromatography on silica gel (DCM:MeOH = 100:1 ~ 10:1) to give 3-(2-((1-((4-((9-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methylbenzoyl)-3λ 3 -1-oxo-9-azaspiro[5.5]undecan-3-yl)methyl)piperazin-1-yl)methyl)cyclopropyl)methoxy)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-1-ethenyl-5λ 3 -3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester.

[1089] LC-MS: (ESI, m / z): [M+H] + = 1335.5.

[1090] Step 2: 1-(5-(3-((4-((1-(((7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-(1-ethenyl-5λ 3 -3,8-diazabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperazin-1-yl)methyl)-3λ 3 Preparation of 1-(5-(3-((4-((1-(((7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-(1-ethenyl-5λ

[1091] To a stirred solution of intermediate 15 (150 mg, 0.17 mmol) and intermediate 20 (100 mg, 0.21 mmol) in DCM / AcOH (2 mL / 0.2 mL) was added tetraisopropyl titanate (0.5 mL) and stirred at 30 °C for 2 h. The mixture was cooled in an ice bath and NaBH(OAc)3 (110 mg, 0.52 mmol) was added and stirred for 2 h. The mixture was concentrated and the crude product was purified by column chromatography on silica gel (DCM:MeOH = 100:1 ~ 10:1) to give 3-(2-((1-((4-((9-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methylbenzoyl)-3λ 3 -1-oxo-9-azaspiro[5.5]undecan-3-yl)methyl)piperazin-1-yl)methyl)cyclopropyl)methoxy)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-1-ethenyl-5λ 3To a solution of tert-butyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (175 mg, 0.13 mmol) in DMF (2 mL) was added cesium fluoride (298 mg, 1.96 mmol) and stirred at room temperature for 1 hour. Water (10 mL) was added to the reaction solution and extracted with ethyl acetate (10 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. HCl / 1,4-dioxane (6N, 1.0 mL) was added to a stirred solution of the concentrate in 1,4-dioxane (1.0 mL) and allowed to react at room temperature for 0.5 hours. Aqueous Na2CO3 solution was added to the reaction solution to adjust the mixture to pH>7 and extracted with EtOAc (10 mL x 3). The organic phase was washed with brine, dried over anhydrous Na2SO4, and concentrated. The crude product was purified by HPLC to give 1-(5-(3-((4-((1-(((7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-(1-vinyl-5λ 3 3-[(3,8-diazabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperazin-1-yl)methyl)-3λ 3 -1-oxo-9-azaspiro[5.5]undecane-9-carbonyl)-2-methylphenyl)dihydropyrimidine-2,4(1H,3H)-dione.

[1092] LC-MS:(ESI,m / z):[M / 2+H] + =518.3.

[1093] 1H NMR (400 MHz, DMSO-d6) δ 10.37 (s, 1H), 10.22 (s, 1H), 9.04 (d, J = 3.1 Hz, 1H), 7.97 (dd, J = 9.2, 5.9 Hz, 1H), 7.46 (t, J = 9.0 Hz, 1H), 7.38 (d, J = 2.5 Hz, 1H), 7.35 - 7.31 (m, 2H), 7.28 - 7.23 (m, 1H), 7.19 - 7.16 (m, 1H), 6.14 - 6.04 (m, 1H), 5.35 - 5.27 (m, 1H), 5.20 - 5.14 (m, 1H), 4.64 - 4.24 (m, 4H), 4.4.13 - 4.05 (s, 1H), 3.92 (d, J = 2.5 Hz, 1H), 3.85 - 3.76 (m, 1H), 3.68 - 3.50 (m, 4H), 3.29 - 3.05 (m, 4H), 2.79 - 2.66 (m, 3H), 2.49 - 2.23 (m, 9H), 2.21 (s, 3H), 2.15 - 2.01 (m, 3H), 1.94 - 1.62 (m, 5H), 1.60 - 1.43 (m, 5H), 1.42 - 1.13 (m, 4H), 0.67 - 0.59 (m, 2H), 0.44 - 0.35 (m, 2H).

[1094] Example 102: 1-(5-(9-((4-((2R)-3-((4-(1-ethyl-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)-2-methylpropyl)piperazin-1-yl)methyl)-3-azaspiro[5.5]undecane-3-carbonyl)-2-methoxyphenyl)dihydropyrimidine-2,4(1H,3H)-dione

[1095] Step 1: Preparation of tert-butyl 3-(2-((R)-3-(4-((3-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)-3-azaspiro[5.5]undecan-9-yl)methyl)piperazin-1-yl)-2-methylpropoxy)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- (trisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-1-ethyl-3,8- diazabicyclo[3.2.1]octane-8-carboxylate

[1096] To a stirred solution of intermediate 10 (100 mg, 0.11 mmol) and 3-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)-3- azaspiro[5.5]undecan-9-carbaldehyde (55 mg, 0.13 mmol) in DCM / AcOH (1.5 mL / 0.1 mL) was added tetraisopropyl titanate (0.13 mL) and stirred at 30 °C for 2 h. The mixture was cooled in an ice bath and NaBH(OAc)3 (68 mg, 0.32 mmol) was added and stirred for 2 h. The reaction was directly concentrated and the crude obtained was purified by silica gel column chromatography (DCM:MeOH = 100:1 ~ 10:1) to give 3-(2-((R)-3-(4-((3-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4- methoxybenzoyl)-3-azaspiro[5.5]undecan-9-yl)methyl)piperazin-1-yl)-2- methylpropoxy)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- ((trisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-1- ethyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester.

[1097] LC-MS: (ESI, m / z): [M / 2 + H] + = 670.6.

[1098] Step 2: Preparation of 1-(5-(9-((4-((2R)-3-((4-(1-ethyl-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3- d]pyrimidin-2-yl)oxy)-2-methylpropyl)piperazin-1-yl)methyl)-3- azaspiro[5.5]undecane-3-carbonyl)-2-methoxyphenyl)dihydropyrimidine-2,4(1H,3H)- dione

[1099] To a stirred solution of tert-butyl 3-(2-((R)-3-(4-((3-(3-(2,4-dioxotetrahydropyrimidin- 1(2H)-yl)-4-methoxybenzoyl)-3-azaspiro[5.5]undecan-9-yl)methyl)piperazin-1-yl)-2- methylpropoxy)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl) naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-1-ethyl-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (75 mg, 0.056 mmol) in DMF (1 mL) was added cesium fluoride (128 mg, 0.84 mmol) and stirred at room temperature for 1 h. To the reaction mixture was added water (5 mL) and extracted with ethyl acetate (5 mL x 3), the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated. To a stirred solution of the concentrate in 1,4-dioxane (1.0 mL) was added HCl / 1,4-dioxane (4 N, 1.0 mL) and the reaction mixture was stirred at room temperature for 0.5 h. The reaction mixture was adjusted to pH > 7 with aqueous Na2CO3 solution and extracted with EtOAc (10 mL x 3). The organic phase was washed with brine, dried over anhydrous Na2SO4 and concentrated. The crude was purified by preparative high performance liquid chromatography to give 1-(5-(9-((4-((2R)-3-((4-(1-ethyl-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethynyl-7-fluoro-3- hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)-2-methylpropyl)piperazin-1- yl)methyl)-3-azaspiro[5.5]undecane-3-carbonyl)-2-methoxyphenyl)dihydropyrimidine-2,4(1H,3H)- dione.

[1100] LC-MS: (ESI, m / z): [M+H] + = 1039.4.

[1101] 1H NMR (400 MHz, DMSO-d6) δ 10.33 (s, 1H), 10.18 (s, 1H), 9.04 (s, 1H), 7.97 (dd, J = 9.2, 6.0 Hz, 1H), 7.46 (t, J = 9.0 Hz, 1H), 7.39 - 7.34 (m, 2H), 7.33 - 7.30 (m, 1H), 7.18 (t, J = 3.0 Hz, 1H), 7.14 (d, J = 8.8 Hz, 1H), 4.55 - 4.25 (m, 3H), 4.13 - 4.02 (m, 1H), 3.91 (d, J = 16.4 Hz, 1H), 3.84 (s, 3H), 3.68 - 3.40 (m, 7H), 3.30 - 3.22 (m, 2H), 2.68 (t, J = 6.5 Hz, 2H), 2.47 - 2.10 (m, 11H), 2.09 - 1.98 (m, 2H), 1.81 - 1.18 (m, 16H), 1.14 - 0.89 (m, 10H).

[1102] Example 112: 1-(5-(9-((4-((2R)-3-((7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-(1-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)-2-methylpropyl) piperazin-1-yl)methyl)-3-azaspiro[5.5]undecane-3-carbonyl)-2-methoxyphenyl)dihydropyrimidine- 2,4(1H,3H)-dione

[1103] Step 1: Preparation of tert-butyl 3-(2-((R)-3-(4-benzylpiperazin-1-yl)-2-methylpropoxy)-7- chloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-1-methyl-3,8-diazabicyclo[3.2.1]octane-8- carboxylate

[1104] Intermediate 14-P2 (500 mg, 1.13 mmol) and (R)-3-(4-benzylpiperazin-1-yl)-2- methylpropan-1-ol (562 mg, 2.26 mmol) were dissolved in THF (5 mL) and added to a sealed tube reactor, Cs2CO3 (1102 mg, 3.38 mmol) was added. The reaction was heated at 90 °C for 16 h. After the reaction was completed, the reaction was cooled to room temperature, water (10 mL) was added to the reaction, and the mixture was extracted with ethyl acetate (10 mL x 3). The combined organic phase was washed with saturated NaCl solution, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated. The obtained crude product was purified by silica gel column chromatography (PE:EA = 2:1) to give tert-butyl 3-(2-((R)-3-(4-benzylpiperazin-1-yl)-2-methylpropoxy)-7-chloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-1-methyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate.

[1105] LC-MS: (ESI, m / z): [M+H] + = 654.3.

[1106] Step 2: Preparation of tert-butyl 3-(2-((R)-3-(4-benzylpiperazin-1-yl)-2-methylpropoxy)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-1-methyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[1107] To a mixture solution of 3-(2-((R)-3-(4-benzylpiperazin-1-yl)-2-methylpropoxy)-7- chloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-1-methyl-3,8-diazabicyclo[3.2.1]octane-8- carboxylic acid tert-butyl ester (470 mg, 0.72 mmol) and ((2-fluoro-6- (methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl) triisopropylsilane (440 mg, 0.86 mmol) in 1,4-dioxane (3 mL) and H2O (0.6 mL), added CataCXium A Pd G3 (104 mg, 0.14 mmol) and cesium carbonate (700 mg, 2.15 mmol). The mixture was reacted at 85 °C for 16 hours under nitrogen protection, added water (10 mL), then extracted with ethyl acetate (10 mL x 3), the combined organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (DCM:MeOH = 20:1) to give 3-(2-((R)-3-(4-benzylpiperazin-1-yl)-2-methylpropoxy)-8-fluoro-7-(7-fluoro-3- (methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-1- methyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester.

[1108] LC-MS: (ESI, m / z): [M+H] + = 1004.5.

[1109] Step 3: Preparation of 3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((R)-2-methyl-3-(piperazin-1-yl)propoxy)pyrido[4,3- d]pyrimidin-4-yl)-1-methyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

[1110] tert-Butyl 3-(2-((R)-3-(4-benzylpiperazin-1-yl)-2-methylpropoxy)-8-fluoro-7-(7-fluoro-3- (methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-1- methyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (490 g, 0.49 mmol) was dissolved in DCM (5 mL), 1-chloroethyl chloroformate (209 mg, 1.46 mmol) and DIEA (189 mg, 1.46 mmol) were added. The mixture was reacted at room temperature for 1 hour, concentrated under reduced pressure, and the concentrate was dissolved in MeOH (5 mL) and heated to 50 °C for 10 minutes. After the reaction was completed, it was concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (DCM:MeOH = 10:1) to obtain tert-butyl 3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2- ((R)-2-methyl-3-(piperazin-1-yl)propoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-methyl-3,8-diazabicyclo[3.2.1] octane-8-carboxylate.

[1111] LC-MS: (ESI, m / z): [M+H] + = 914.3.

[1112] Step 4: Preparation of tert-butyl 3-(2-((R)-3-(4-((3-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4- methoxybenzoyl)-3-azaspiro[5.5]undecan-9-yl)methyl)piperazin-1-yl)-2-methylpropoxy)-8-fluoro-7-(7- fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-1- methyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[1113] To a stirred solution of 3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((R)-2-methyl-3-(piperazin-1-yl)propoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-methyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (150 mg, 0.16 mmol) and 3-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)-3-azaspiro[5.5]undecan-9- carboxaldehyde (84 mg, 0.20 mmol) in DCM / AcOH (2 mL / 0.2 mL) was added tetraisopropyl titanate (0.5 mL) and stirred at 30 °C for 2 h. The mixture was added NaBH(OAc)3 (104 mg, 0.49 mmol) under ice bath and stirred for 2 h. The mixture was concentrated and the crude product was purified by silica gel column chromatography (DCM:MeOH = 100:1 ~ 10:1) to give 3-(2-((R)-3-(4-((3-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)-3-azaspiro[5.5]undecan-9-yl)methyl)piperazin-1-yl)-2-methylpropoxy)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-1-methyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester.

[1114] LC-MS: (ESI, m / z): [M / 2 + H] + = 663.5.

[1115] Step 5: Preparation of 1-(5-(9-((4-((2R)-3-((7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-(1-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)-2-methylpropyl)piperazin-1-yl)methyl)-3-azaspiro[5.5]undecane-3-carbonyl)-2-methoxyphenyl)dihydropyrimidine-2,4(1H,3H)-dione

[1116] To a stirred solution of tert-butyl 3-(2-((R)-3-(4-((3-(3-(2,4-dioxotetrahydropyrimidin- 1(2H)-yl)-4-methoxybenzoyl)-3-azaspiro[5.5]undecan-9-yl)methyl)piperazin-1-yl)-2- methylpropoxy)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl) naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-1-methyl-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (140 mg, 0.11 mmol) in DMF (2 mL) was added cesium fluoride (241 mg, 1.58 mmol) and stirred at room temperature for 1 h. The reaction was added water (10 mL) and then extracted with ethyl acetate (10 mL x 3), the organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated. To a stirred solution of the concentrate in 1,4-dioxane (1.0 mL) was added HCl / 1,4-dioxane (6 N, 1.0 mL) and the reaction was allowed to proceed at room temperature for 0.5 h. The reaction was adjusted to pH > 7 with aqueous Na2CO3 solution and extracted with EtOAc (10 mL x 3). The organic phase was washed with brine, dried over anhydrous Na2SO4 and concentrated. The crude product was purified by high performance liquid preparation to give 1-(5-(9-((4-((2R)-3-((7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-(1- methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)-2-methylpropy...

Claims

1. A compound of formula I, and / or its stereoisomers, enantiomers, diastereomers, atropisomers, deuterated forms, hydrates, solvates, prodrugs, and / or pharmaceutically acceptable salts: GLE Ⅰ wherein G is G1or G2 In G1: X is C or N; R 1 R is H or halogen; R 2 is C l -C3alkyl, C2-C4alkenyl or C2-C4alkynyl; R a H, fluoro, C 1-3 alkyl, C 1-3 alkyl-O-C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, said C 1-3 alkyl, C 1-3 alkyl-O-C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl is optionally substituted with one or more halogen, OH, or deuterium; R b and R c are independently H, OH, halogen, C 1-3 alkyl or C 1-3 alkoxy, said C 1-3 alkyl or C 1-3 alkoxy is optionally substituted with 1 or more halogen, OH, or deuterium; Among them, G2: W is N or CRza; Rza is hydrogen, halogen, C 1-6 alkyl or C 1-6 alkoxy; Z is N or CRzb; Rzb is hydrogen, halogen, C 1-6 alkyl or C 1-6 alkoxy; Rzc is phenyl, naphthyl, quinoline, isoquinoline, benzo[b]thiophene, indole, indazol, or pyridine; said phenyl, naphthyl, quinoline, isoquinoline, benzo[b]thiophene, indole, indazol, or pyridine is optionally substituted with 1 or more R 1’ substituents; Rzd is hydrogen, deuterium, methyl, deuterated methyl, halogenated methyl, -CD2F, -CDF2, C 2-6 alkyl or C 3-6 cycloalkyl, said methyl, C 2-6 alkyl or C 3-6 cycloalkyl is optionally substituted with 1 or more hydroxyl, deuterium or halogen; each R 1’ independently C 1-6 alkyl, halo, hydroxy, cyano, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, NR 21 R 22 , -C(O)NR 23 R 24 , CH2R 25 , N=S(O)(C 1-6 alkyl)2, S(O)C 1-6 alkyl, S(O)2R 26 , -S-C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 2-6 hydroxyalkynyl, C 1-6 cyanoalkyl, triazolyl, -S-C 1-6 haloalkyl, C 1-6 hydroxyalkyl, CH2C(O)NR 27 R 28 , -C 2- 6alkynyl-NR 29 R 30 , C 2-6 deuterated alkynyl, (C 1-6 alkoxy)C 1-6 haloalkyl- or cycloalkyl, wherein said cycloalkyl is optionally substituted with one or more halo or C 1-6 alkyl; or R 1’ SF5; R 21 is hydrogen, C 1-6 alkyl, C 1-6 haloalkyl or C(O)C 1-6 alkyl; R 22 is hydrogen, C 1-6 alkyl or C 1-6 haloalkyl; or R 21 , R 22 and the nitrogen atom to which they are attached form a 3-6 membered heterocycloalkyl group, which is optionally substituted with 1 or more halogen, methyl, trifluoromethyl, methoxy, or trifluoromethoxy; R 23 , R 24 each independently H, C 1-6 alkyl or C 1-6 haloalkyl; or R 23 , R 24 and the nitrogen atom to which they are attached to form a 3-6 membered heterocycloalkyl group, which is optionally substituted with 1 or more halogen, methyl, trifluoromethyl, methoxy, or trifluoromethoxy; R 25 is hydroxy, cyano, heterocyclyl, NR 25a R 25b , C(O)NR 25c R 25d or SO2C 1-6 alkyl; R 25a , R 25b , R 25c , R 25d each independently H or C 1-6 alkyl; or R 25a , R 25b and the nitrogen atom to which they are attached form a 3-6 membered heterocycloalkyl group, which is optionally substituted with 1 or more halogen, methyl, trifluoromethyl, methoxy, or trifluoromethoxy; or R 23c , R 25d and the nitrogen atom to which they are attached to form a 3-6 membered heterocycloalkyl group, which is optionally substituted with 1 or more halogen, methyl, trifluoromethyl, methoxy, or trifluoromethoxy; R 26 is C 1-6 alkyl, C 1-6 haloalkyl or NR 26a R 26b R 26a , R 26b each independently H or C 1-6 alkyl; or R 26a , R 26b and the nitrogen atom to which they are attached to form a 3-6 membered heterocycloalkyl group, which is optionally substituted with 1 or more halogen, methyl, trifluoromethyl, methoxy, or trifluoromethoxy; R 27 , R 28 each independently H, C 1-6 alkyl or C 1-6 haloalkyl; or R 27 , R 28 and the nitrogen atom to which they are attached form a 3-6 membered heterocycloalkyl group, which is optionally substituted with 1 or more halogen, methyl, trifluoromethyl, methoxy, or trifluoromethoxy; R 29 , R 30 each independently H, C 1-6 alkyl or C 1-6 haloalkyl; or R 29 , R 30 and the nitrogen atom to which they are attached form a 3-6 membered heterocycloalkyl group, which is optionally substituted with 1 or more halogen, methyl, trifluoromethyl, methoxy, or trifluoromethoxy; R 3a is hydrogen, halogen, hydroxyl, cyano, C 1-3 alkyl, C 1-3 deuteroalkyl or C 1-3 haloalkyl; n is 0, 1, 2, 3, 4 or 5; L is L is connected to G through A or B; E is 2. The compound of formula I according to claim 1, and / or a stereoisomer, enantiomer, diastereomer, atropisomer, deuterated compound, hydrate, solvate, prodrug, and / or a pharmaceutically acceptable salt thereof, characterized in that, It meets one or more of the following conditions: (1) X is N; (2) R 1 is halogen; (3) R 2 C2-C4alkynyl; (4) R a is fluorine, C 1-3 alkyl or C 1-3 alkyl-O-C 1-3 alkyl, C 2-4 alkenyl, said C 1-3 alkyl, C 1-3 alkyl-O-C 1-3 alkyl or C 2-4 alkenyl is optionally substituted with one or more halogen or deuterium; preferably, R a is C 1-3 alkyl, C 1-3 alkyl-O-C 1-3 alkyl or C 2-4 alkenyl, said C 1-3 alkyl, C 1-3 alkyl-O-C 1-3 alkyl or C 2-4 alkenyl is optionally substituted with one or more halogen or deuterium; (5) R a In particular, the C 1-3 alkyl, C 1-3 alkyl-O-C 1-3 alkyl, C 2-4 alkenyl is optionally substituted with one or more deuterium; (6) R b is H; (7) R c is halogen; (8) E is (9) A and G in L are connected; (10)W is CRza; (11) Rza is H or halogen, for example halogen; (12) Z is N; (13) Rzd is methyl, deuterated methyl, halogenated methyl, -CD2F, -CDF2, or C 2-6 alkyl, said C 2-6 alkyl is optionally substituted with 1 or more hydroxyl, deuterium, or halogen; preferably, Rzd is methyl or deuterated methyl; (14) n is 0; (15) Rzcis phenyl, naphthyl, or benzo[b]thiophene; said phenyl, naphthyl, or benzo[b]thiophene is optionally substituted with 1 or more R 1’ substituents.

3. The compound of formula I according to claim 1, and / or its stereoisomers, enantiomers, diastereomers, atropisomers, deuterated forms, hydrates, solvates, prodrugs, and / or pharmaceutically acceptable salts thereof, characterized in that, The compound of formula I is selected from any of the following schemes: Scheme 1: In the compound of formula I, G is X is CH or N; R 1 R is H or halogen; R 2 is C l -C3alkyl, C2-C4alkenyl or C2-C4alkynyl; R a is C 1-3 alkyl, C 1-3 alkyl-O-C 1-3 alkyl, C 2-4 alkenyl, said C 1-3 alkyl, C 1-3 alkyl-O-C 1-3 alkyl, C 2-4 alkenyl is optionally substituted with one or more halogen or deuterium; R b and R c independently H, OH, halogen, C 1-3 alkyl or C 1-3 alkoxy, said C 1-3 alkyl or C 1-3 alkoxy is optionally substituted with 1 or more halogen, OH, or deuterium; L is L is connected to G through A; E is Scheme 2: In the compound of formula I, G is X is N; R 1 R is halogen; R 2 is C2-C4alkynyl; R a is C 1-3 alkyl, C 1-3 alkyl-O-C 1-3 alkyl, C 2-4 alkenyl, said C 1-3 alkyl, C 1-3 alkyl-O-C 1-3 alkyl, C 2-4 alkenyl is optionally substituted with one or more deuterium; R b is H; R c R is halogen; L is L is connected to G through A; E is Scheme 3: In the compound of formula I, G is X is C or N; R 1 is H or halogen; R 2 is C l -C3alkyl, C2-C4alkenyl or C2-C4alkynyl; R a fluoro, C 1-3 alkyl, C 1-3 alkyl-O-C 1-3 alkyl, C 2-4 alkenyl, said C 1-3 alkyl, C 1-3 alkyl-O-C 1-3 alkyl, C 2-4 alkenyl is optionally substituted with one or more halogen or deuterium; R b and R c are independently H, OH, halogen, C 1-3 alkyl or C 1-3 alkoxy, said C 1-3 alkyl or C 1-3 alkoxy optionally substituted with 1 or more halogen, OH or deuterium; L is L is connected to G through A; E is Scheme 4: In the compound of formula I, G is X is N; R 1 R is halogen; R 2 C2-C4-alkynyl; R a halogen, C 1-3 alkyl, C 1-3 alkyl-O-C 1-3 alkyl, C 2-4 alkenyl, said C 1-3 alkyl, C 1-3 alkyl-O-C 1-3 alkyl, C 2-4 alkenyl is optionally substituted with one or more deuterium; R b is H R c is halogen; L is L is connected to G through A; E is Scheme 5: In the compound of formula I: wherein: said G is W is CRza; Rza is hydrogen or halogen; Z is N; Rzc is phenyl, naphthyl, quinoline, isoquinoline, benzo[b]thiophene, indole, indazole, or pyridine; said phenyl, naphthyl, quinoline, isoquinoline, benzo[b]thiophene, indole, indazole, or pyridine is optionally substituted with 1 or more Rz 1’ substituents; Each R 1’ Independently C 1-6 Alkyl, halogen, hydroxyl, cyano, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy, NR 21 R 22 、C 2-6 Alkenyl, C 2-6 Alkynyl, C 2-6 deuterated alkynyl or cycloalkyl; R 21 is hydrogen; R 22 is hydrogen; Rzd is hydrogen, deuterium, methyl, deuterated methyl, halogenated methyl, -CD2F, -CDF2, C 2-6 alkyl, said C 2-6 alkyl is optionally substituted with 1 or more hydroxyl, deuterium, or halogen; R 3a is hydrogen, halogen, hydroxyl, cyano, C 1-3 alkyl, C 1-3 deuteroalkyl or C 1-3 haloalkyl; n is 0 or 1; L is L is connected to G through A; E is Scheme 6: In the compound of formula I: wherein: said G is W is CRza; Rza is a halogen; Z is N; Rzc is phenyl, naphthyl, or benzo[b]thiophene; said phenyl, naphthyl, or benzo[b]thiophene is optionally substituted with 1 or more R 1’ substituents; Each R 1’ Independently C 1-6 Alkyl, halogen, hydroxyl, cyano, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy, NR 21 R 22 、C 2-6 Alkenyl, C 2-6 Alkynyl, C 2-6 deuterated alkynyl or cycloalkyl; R 21 is hydrogen; R 22 is hydrogen; Rzd is methyl or deuterated methyl; n is 0; L is E is 4. The compound of claim 1 of formula I, and / or its stereoisomers, enantiomers, diastereomers, atropisomers, deuterated compounds, hydrates, solvates, prodrugs, and / or pharmaceutically acceptable salts thereof, characterized in that, The G is:

5. The compound of formula I according to claim 4, and / or its stereoisomers, enantiomers, diastereomers, atropisomers, deuterated compounds, hydrates, solvates, prodrugs, and / or its pharmaceutically acceptable salts, characterized in that, The compound represented by formula I satisfies one or more of the following conditions: (1) G is L is E is (2) G is L is E is Preferably, G is L is E is More preferably, G is (3) G is L is E is (4) G is L is E is (5) G is L is E is Preferably, G is L is E is More preferably, G is (6) G is L is E is (7) G is L is E is (8) G is L is E is Preferably, G is L is E is (9) G is L is E is Preferably, G is L is E is 6. The compound of claim 1 of formula I, and / or its stereoisomers, enantiomers, diastereomers, atropisomers, deuterated compounds, hydrates, solvates, prodrugs, and / or pharmaceutically acceptable salts thereof, characterized in that, G2 is G2-1, G2-2, G2-3, or G2-4: wherein Z, W, Rzc, Rzd, R 3a and n are as described in any one of claims 1-3.

7. The compound of formula I according to claim 6, and / or its stereoisomers, enantiomers, diastereomers, atropisomers, deuterated forms, hydrates, solvates, prodrugs, and / or pharmaceutically acceptable salts, characterized in that: G2 is G2-2-1, G2-2-2, or G2-2-3: Rza, Rzb, Rzc, Rzd, R in G2-2-1, G2-2-2 or G2-2-3 3a and n are defined as described in claim 1.

8. The compound of formula I according to claim 7, and / or its stereoisomers, enantiomers, diastereomers, atropisomers, deuterated forms, hydrates, solvates, prodrugs, and / or pharmaceutically acceptable salts thereof, wherein G2 is any of the following: Scheme 1: G2 is Scheme 2: G2 is:

9. The compound according to claim 1 of formula I: ###0007### and / or its stereoisomers, enantiomers, diastereomers, atropisomers, deuterated compounds, hydrates, solvates, prodrugs, and / or its pharmaceutically acceptable salts, wherein the compound of formula I is a compound of: ###0008### Prodrugs of the compounds of Formula I are any of the following compounds:

10. The compound of claim 1 of Formula I, and / or its stereoisomers, enantiomers, diastereomers, atropisomers, deuterated isotopologues, hydrates, solvates, prodrugs, and / or pharmaceutically acceptable salts thereof, wherein the diastereomers have any one of the following structures:

11. A pharmaceutical composition, characterized by, It comprises a therapeutically effective amount of a compound of formula I as described in any one of claims 1 to 10, and / or its stereoisomers, enantiomers, diastereomers, atropisomers, deuterated substances, hydrates, solvates, prodrugs, and / or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier, diluent or excipient.

12. Use of a substance X for the manufacture of a medicament, characterized in that The substance X is a compound of formula I according to any one of claims 1 to 10, and / or its stereoisomers, enantiomers, diastereomers, atropisomers, deuterated forms, hydrates, solvates, prodrugs, and / or pharmaceutically acceptable salts, or the pharmaceutical composition according to claim 11; the drug is a drug for treating or preventing a disease or condition mediated by a KRAS mutation, or a drug for treating or preventing cancer; Preferably, the KRAS mutation-mediated disease or condition is a disease or condition caused by the interaction between KRAS G12D and SOS1 or SHP2 protein, or is a disease or condition mediated by KRAS G12D mutation; The KRAS mutation-mediated disease or condition and the cancer are independently selected from: Heart: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma, and teratoma group; Lung: bronchial cancer (squamous cell carcinoma, undifferentiated small cell carcinoma, undifferentiated large cell carcinoma, adenocarcinoma), alveolar carcinoma (bronchiolar carcinoma), bronchial adenoma, sarcoma, lymphoma, enchondroma, hamartoma, mesothelioma; Gastrointestinal tract: esophageal cancer (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, vipoma), small intestine (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); Genitourinary system: kidney (adenocarcinoma, embryonal carcinosarcoma (Wilms tumor), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenomatous tumor, lipoma); Liver: liver cancer (hepatocellular carcinoma), hepatocellular bile duct carcinoma, hepatoblastoma, malignant hemangioma, hepatocellular adenoma, hemangioma; Biliary tract: bile duct cancer, gallbladder cancer, ampullary cancer, and hepatic bile duct cancer; Bone: osteosarcoma, fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell chordoma, enchondroma (osteoechondrosis), benign enchondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma, and giant cell tumor; Nervous system: skull (osteomas, hemangiomas, granulomas, xanthomas, osteitis deformans), meninges (meningiomas, meningeal sarcomas, gliomas), brain (astrocytomas, medulloblastomas, gliomas, ependymomas, germ cell tumors (pinealomas), glioblastomas multiforme, oligodendrogliomas, schwannomas, eye cancers, congenital tumors), spinal neurofibromas, meningiomas, gliomas, sarcomas); Obstetrics and Gynecology: Uterus (endometrial cancer (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-thecal cell tumor, ovarian Selegans cell tumor, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botulinum sarcoma (embryonic rhabdomyosarcoma), fallopian tube (cancer); Hematology: Blood (myeloid leukemia (acute and chronic), acute lymphocytic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma); Skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, nevus dysplasia, lipoma, hemangioma, dermatofibroma, keloid, psoriasis; Adrenal gland: neuroblastoma; For example, the KRAS mutation-mediated disease or condition and the cancer are independently selected from: Pancreatic cancer, lung cancer, colorectal cancer, cholangiocarcinoma, multiple myeloma, melanoma, uterine cancer, endometrial cancer, thyroid cancer, acute myeloid leukemia, bladder cancer, urothelial carcinoma, gastric cancer, cervical cancer, 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; In another example, the cancer and the KRAS mutation-mediated disease or condition are independently selected from gastric cancer, pancreatic cancer, pancreatic adenocarcinoma or colon cancer.

13. A method of treating or preventing a cancer or a disease or disorder mediated by KRAS G12D, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of claims 1-12, or a pharmaceutically acceptable salt thereof. The method comprises administering to a patient in need thereof a therapeutically effective amount of a substance X, wherein the substance X is a compound of formula I according to any one of claims 1 to 10, and / or its stereoisomers, enantiomers, diastereomers, atropisomers, deuterated substances, hydrates, solvates, prodrugs, and / or pharmaceutically acceptable salts thereof, or the pharmaceutical composition according to claim 11; Preferably, the cancer and the disease or disorder mediated by KRAS G12D are as claimed in claim 12.

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