Pan-KRAS targeted protein degradation agent, preparation method therefor, and use thereof

Abstract

The present invention provides a class of small molecule compounds for targeted degradation of a pan-KRAS protein, a preparation method therefor, and use thereof as a therapeutic agent for preventing and / or treating cancer. The compound of the present invention can effectively degrade and / or inhibit the pan-KRAS protein in cells, and can be used for preparing a drug for treating and / or preventing related diseases or disorders caused by pan-KRAS mediation.

Description

Pan-kras-targeting protein degraders, methods of making and uses thereof

[0001] This application claims priority to Chinese patent application 2024104786962 with a filing date of 2024 / 4 / 19 and Chinese patent application 2024114046517 with a filing date of 2024 / 10 / 10. This application incorporates the entirety of the aforementioned Chinese patent applications. TECHNICAL FIELD

[0002] The present application belongs to the technical field of medicine, in particular, the present application relates to pan-KRAS degraders, methods of making and uses thereof as therapeutic agents for preventing and / or treating cancer. 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 likely to mutate 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 surface of the RAS protein 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 targeting KRAS directly, such as KRAS G12C, KRAS G12D, KRAS G12R (J. Am. Chem. Soc. 2022, 144, 35, 15916-15921) and KRAS G12S (Nat. Chem. Biol. 2022 Jul 21. doi: 10.1038 / s41589-022-01065-9) and the like;

[0007] 2) inhibitors acting on KRAS indirectly, 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, 9678-9690 and the like) and KRAS (on) inhibitors (WO2021091982A1, WO2022060836A1).

[0008] In recent years, with the deepening of the research on KRAS, the research and development of KRAS inhibitors have finally made remarkable progress (Cancer Discov. 2022, 12, 924-937), and the first breakthrough is the specific KRAS-G12C inhibitor.

[0009] In the process of KRAS-G12C inhibitor design, the cysteine in the 12th codon is easy to form covalent bonds, and covalent targeting of cysteine sites has become an important breakthrough in the development of KRAS drugs. Shokat discovered a new allosteric binding pocket in Switch-II, called 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) (Cancer Discov. 2020, 10, 54-71 & J. Med. Chem. 2020, 63, 6679-6693) submitted by Mirati 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.

[0010] 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 covalent bonds; 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), and there is no way to adopt this strategy.

[0011] 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 the surface of the protein, 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).

[0012] 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.

[0013] WO2021041671A1, WO2022015375A1, WO2022031678A1, WO2022066646A1, WO2022098625A1, WO2022192790A1, WO2022192794A1, WO2021106231A1, WO2021107160A1, WO2022173870A1, and the like, disclose several classes of KRAS G12D specific inhibitors.

[0014] The above-mentioned inhibitors directly targeting KRAS, such as KRAS = G12C and KRAS-G1D inhibitors, are specific inhibitors, while the inhibitors indirectly targeting KRAS, such as SHP2, SOS1 and KRAS(on) inhibitors, are pan-KRAS inhibitors. When SOS1 inhibitors indirectly target KRAS, they can act on various mutants of KRAS, including KRAS-G12C / G12D / G12V / G13D (BI-3406, Cancer Discov. 2021, 11, 142-157; MRTX0902, J. Med. Chem. 2022, 65, 9678-9690) and the like.

[0015] WO2022132200A1, WO2022133038A1 and the like disclose several types of pan-KRAS inhibitors.

[0016] Targeted protein degradation agents are a popular research and development technology worldwide in recent years (Nat. Rev. Drug Discov. 2017, 16, 101-114; Nat. Rev. Drug Discov. 2019, 18, 949-963; Nat. Rev. Drug Discov. 2022, 21, 181-200). This technology has the following characteristics: the development of "druggable" targets encounters a bottleneck, and the potential of "non-druggable" targets is endless, and the PROTAC technology is expected to solve the development problem of "non-druggable" targets; PROTAC drugs have the advantages of good drugability, high selectivity, overcoming drug resistance, multiple administration routes, small dosage, low toxicity and the like.

[0017] Therefore, there is an unmet clinical need for pan-KRAS targeted protein degradation agents. SUMMARY

[0018] The present application provides a compound of formula I or I', and / or stereoisomers, enantiomers, diastereomers, atropisomers, deuterated compounds, hydrates, solvates, prodrugs thereof, and / or pharmaceutically acceptable salts thereof:

[0019] K-L-E K'-L'-E'

[0020] I I'

[0021] wherein,

[0022] K is

[0023] K' is independently K1 or K2:

[0024] in said K1:

[0025] ring A is a 6-10 membered heterocycloalkyl, said heterocycloalkyl containing at least one heteroatom or heteroatom group selected from N, S or O, and said 6-10 membered heterocycloalkyl being optionally substituted by one or more R2;

[0026] X1is selected from O, S or NR6;

[0027] X2is selected from CR1or N;

[0028] R1is selected from hydrogen, deuterium, halogen, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 alkoxy or C 1-3 haloalkyl;

[0029] R2is selected from hydrogen, deuterium, hydroxyl, cyano, halogen, -NH(C 1-3 alkyl), C 1-6 alkoxy, C 1-6 alkyl, haloC 1-6 alkyl, C 2-6 alkenyl, haloC 2-6 alkenyl, C 2-6 alkynyl or haloC 2-6 alkynyl;

[0030] R s is selected from hydrogen, deuterium, halogen, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 alkoxy or C 1-3 haloalkyl;

[0031] m is selected from 0, 1, 2, 3 or 4;

[0032] n is selected from 0, 1 or 2;

[0033] R4is selected from C 6-10 aryl or 5-10 membered heteroaryl, said C 6-10 aryl or 5-10 membered heteroaryl being optionally substituted by one or more hydroxyl, halogen, deuterium, cyano, amino, C 1-3 alkyl, C 1-3 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 haloalkyl or C 3-6 cycloalkyl;

[0034] R5is selected from hydrogen, deuterium, halogen, C 1-3 alkyl, C2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Alkoxy or C 1-3 alkyl halide;

[0035] R6 is selected from hydrogen or C 1-3 alkyl;

[0036] In the K2:

[0037] A1 is selected from CH or N;

[0038] D1 is selected from -CH2-, -CH2CH2- or -CH(CH2CN)-;

[0039] X 1a Selected from O or S;

[0040] Y″ is selected from -C(CN)- or N;

[0041] G″ is selected from -C(R 3b )-or N;

[0042] Z″ is selected from -C(R 3c )-or N;

[0043] R 1a Selected from H, OH, methoxy, C 1-4 Alkyl, C 2-4 Heteroalkyl, azetidine, N-linked piperazine piperidine or morpholine, the C 1-4 Alkyl, C 2-4 The heteroalkyl, azetidine, piperidine or N-linked piperazine is optionally replaced by amino, hydroxy, halogen, methyl, trideuteromethyl, methoxy, oxetane or C 1-3 one or more substitutions in the alkyl group;

[0044] R 2a is selected from H, halogen or methyl;

[0045] R 3a 、R 3b and R 3c are each independently selected from H, methyl or halogen;

[0046] L is L is connected to K through A or B;

[0047] E is

[0048] L' is a linking chain that connects K' and E' by covalent bonds;

[0049] wherein each E' is independently E1, E2, or E3:

[0050] wherein in said E1:

[0051] Z' is O, S, or CH2;

[0052] X 2 ' is CH or N;

[0053] Y 2 ' is CH, N, O, or S;

[0054] Q1, Q2, Q3, Q4, Q5 are each independently CR 3b or N;

[0055] R 3b is each independently hydrogen, deuterium, hydroxyl, amino, cyano, halogen, nitro, thiol, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, C6-C 10 aryl, 5-10 membered heteroaryl, -O-(C1-C6 alkyl), -O-(C1-C6 heteroalkyl), -O-(C3-C8 cycloalkyl), -O-(3-8 membered heterocycloalkyl), -S-(C1-C6 alkyl), -S-(C1-C6 heteroalkyl), -S-(C3-C8 cycloalkyl), -S-(3-8 membered heterocycloalkyl), -N(C1-C6 alkyl) 1-2 , -N(C1-C6 heteroalkyl) 1-2 , -N(C3-C8 cycloalkyl) 1-2 , -N(3-8 membered heterocycloalkyl) 1-2 , -O-(C6-C 10 aryl), -O-(5-10 membered heteroaryl); said C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, C6-C 10 aryl, 5-10 membered heteroaryl are optionally substituted with 1-3 independent groups selected from deuterium, hydroxyl, halogen, cyano, amino, O(C1-C6 alkyl), O-(C3-C8 cycloalkyl), -O-(3-8 membered heterocycloalkyl), N(C1-C6 alkyl) 1-2 , -NH(C3-C8 cycloalkyl), -NH(3-8 membered heterocycloalkyl), -O-(C6-C 10 aryl), -O-(5-10 membered heteroaryl); or R 3bwith the atom to which it is attached forms a cycloalkyl, heterocycloalkyl, heteroaryl, or aryl group;

[0056] m" is 1, 2, or 3;

[0057] R 1b each independently is hydrogen, deuterium, hydroxyl, amino, cyano, halogen, C1-C6alkyl, C1-C6heteroalkyl, C3-C8cycloalkyl, C3-C8heterocycloalkyl, C6-C 10 aryl, 5-10 membered heteroaryl, -O(C1-C6alkyl), -O-(C3-C8cycloalkyl), -O-(3-8 membered heterocycloalkyl), -N(C1-C6alkyl) 1-2 , -NH(C3-C8cycloalkyl), -NH(3-8 membered heterocycloalkyl), -O-(C6-C 10 aryl), -O-(5-10 membered heteroaryl), said alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl optionally substituted with 1-3 independent groups selected from hydroxyl, halogen, cyano, hydroxyl, amino;

[0058] R 2b is none, hydrogen, deuterium, C1-C6alkyl, or C3-C6cycloalkyl, said C1-C6alkyl and C3-C6cycloalkyl optionally substituted with 1-3 independent groups selected from hydroxyl, halogen, cyano, hydroxyl, amino, or -OC(O)(C1-C6alkyl);

[0059] wherein in said E2:

[0060] Q1, Q2, Q3, and Q4are each independently CR 3b or N;

[0061] W is CR 1c R 2c , C(S), C(O), SO2, -OC=R 4c -, -SC=R 4c -, or -C=R 4c NR 5c -, or -N=CA'-;

[0062] X is CH2, O, or S;

[0063] X c is -CH2- or -NG'-;

[0064] Z is CH2, O, or S;

[0065] G' and G" are each independently selected from hydrogen, deuterium, C1-C6alkyl, OH, C3-C6cycloalkyl, -CH2-heterocycloalkyl, or -CH2-phenyl, said C1-C6alkyl, C3-C6cycloalkyl, -CH2-heterocycloalkyl, or -CH2-phenyl optionally substituted with 1 or more hydroxyl, halogen, cyano, amino;

[0066] A' is hydrogen, deuterium, C1-C6alkyl, C3-C8cycloalkyl, or halogen;

[0067] R 1c , R 2c , and R 3c are each independently selected from hydrogen, deuterium, hydroxyl, halogen, -NH2, -N(C1-C6alkyl) 1-2 , C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, -CONR ′ R ″ , -OR ′ , -NR ′ R ″ , -SR ′ , -SO2R ′ , -SO2NR ′ R ″ , -CR ′ R ″ , -CR ′ NR ′ R ″ , C6-C 10 aryl, 5-10 membered heteroaryl, C3-C8cycloalkyl, 3-8 membered heterocycloalkyl, -P(O)(OR ′ )R ″ , -P(O)R ′ R ″ , -OP(O)(OR ′ )R ″ , -CN, -NR ′ SO2NR ′ R ″ , -NR ′ C(O)NR ′ R ″ , -C(O)NR ′ C(O)R ″ , -NR ′ C(=N-CN)NR ′ R ″ , -C(=N-CN)NR ′ R ″ , -NR ′ C(=N-CN)R ″ , -NR ′ C(=C-NO2)NR′ R ″ , -SO2NR ′ COR ″ , -NO2, -COR ′ , -C(C=N-OR ′ )R ″ , -CR ′ =CR ′ R ″ , -CCR ′ , -S(C=O)(C=N-R ′ )R ″ , -SF5 or -OCF3;

[0068] R 4c is O or S;

[0069] R 5c is H, C1-C6alkyl, C6-C 10 aryl, 5-12 membered heteroaryl, C3-C8cycloalkyl, 3-8 membered heterocycloalkyl;

[0070] R ′ and R ″ are each independently selected from the group consisting of a bond, hydrogen, deuterium, C1-C6alkyl, C3-C8cycloalkyl, C6-C 10 aryl, 5-10 membered heteroaryl, or 3-8 membered heterocycloalkyl;

[0071] n" is 0, 1, 2, 3, or 4;

[0072] is a single or double bond;

[0073] is a bond, which can be the R stereoisomer, the S stereoisomer, or a non-stereoisomer;

[0074] wherein in said E3:

[0075] X 1 , X 2 are each independently a bond, O, C(O), C(S), NR 1d , or CR 1d R 2d ;

[0076] R 1d , R 2d are each independently selected from H, deuterium, C1-C6alkyl optionally substituted with 1 or more halogen or C1-C6alkoxy;

[0077] R Pindependently selected from H, deuterium, halogen, -OH, C1-C3 alkyl, said C1-C3 alkyl being optionally substituted with one or more halogen, hydroxyl, or C1-C3 alkoxy;

[0078] W 3 C1-C6 alkyl, -T-N(R 3d R 4d ), -T-N(R 3d R 4d )X 3 , -T-(C6-C 10 )aryl, -T-(5-10 membered)heteroaryl, -T-(4-12 membered)heterocycloalkyl, -NR 5d -T-(C6-C 10 )aryl, -NR 5d -T-(5-10 membered)heteroaryl, or -NR 5d -T-(4-12 membered)heterocycloalkyl, said C1-C6 alkyl, -T-N(R 3d R 4d ), -T-N(R 3d R 4d )X 3 , -T-(C6-C 10 )aryl, -T-(5-10 membered)heteroaryl, -T-(4-12 membered)heterocycloalkyl, -NR 5d -T-(C6-C 10 )aryl, -NR 5d -T-(5-10 membered)heteroaryl, or -NR 5d -T-(4-12 membered)heterocycloalkyl being optionally substituted;

[0079] X 3 C(O), R 3d , R 4d , or R 5d ;

[0080] R 3d , R 4d , or R 5d each independently selected from H, deuterium, C1-C6 alkyl, said C1-C6 alkyl being optionally substituted with one or more halogen, -OH, R 1d C(O), R 1d C(S), R 1d SO, R 1d SO2, NR 1d R 2d C(O), NR 1d R 2d C(S), NR 1d R 2d SO, or NR 1d R2d SO2;

[0081] T is C 1- C6alkyl or -(CH2) n' -, said -(CH2) n' - wherein one or more methylenes are optionally substituted with deuterium, halogen or C1-C6alkyl optionally substituted with halogen, -OH or amino;

[0082] n' is 0, 1, 2, 3, 4, 5 or 6;

[0083] W 4 is said optionally substituted;

[0084] R 6d , R 7d each independently H, deuterium, C3-C8cycloalkyl or C1-C6alkyl optionally substituted with halogen, -OH, CN, NO2or amino;

[0085] W 5 is 6-10 membered aryl or 5-10 membered heteroaryl;

[0086] R 8d is H, deuterium, halogen, CN, OH, NO2, NR 6d R 7d , OR 6d , COR 6d R 7d , NR 6d COR 7d , SO2R 6d R 7d , R 6d SO2R 7d , C1-C6alkyl, C1-C6alkoxy, C6-C 10 aryl, 5-10 membered heteroaryl, C3-C8cycloalkyl or 3-8 membered heterocycloalkyl, said C1-C6alkyl, C1-C6alkoxy optionally substituted with deuterium, halogen, -OH, CN, NO2or amino.

[0087] The present application provides a compound of Formula I, and / or stereoisomers, enantiomers, diastereomers, atropisomers, deuterated analogs, hydrates, solvates, prodrugs thereof, and / or pharmaceutically acceptable salts thereof:

[0088] K-L-E

[0089] I

[0090] wherein,

[0091] K is

[0092] L is L is attached to K via A or B;

[0093] E is

[0094] In some preferred embodiments of the application, K' is wherein said R s , m, n, X1, X2, R4and R5are as defined and described herein, for example

[0095] In some preferred embodiments of the application, K' is wherein said R s , m, n, X1, X2, R4and R5are as defined and described herein, for example

[0096] In some preferred embodiments of the application, in ring A, the 6-10 membered heterocycloalkyl is a 6, 7, 8, 9 or 10 membered mono-heterocycloalkyl, bridged-heterocycloalkyl or spiro-heterocycloalkyl, the heteroatoms being one or more of N, O and S (including heteroatom groups formed by the heteroatoms, such as -C(O)-, -S(O)-, -S(O)2-, -C(O)O-, -OC(O)-, -C(O)NH-, -NHC(O)-, etc.), for example: said ring A is optionally substituted with one or more R2, for example

[0097] In some preferred embodiments of the application, K' is wherein said R s , m, R4and R5are as defined and described herein; said ring A is optionally substituted with one or more R2, for example

[0098] In some preferred embodiments of the application, K' is wherein said Rs , m, R4and R5are as defined and described herein, and ring A is optionally substituted with one or more R2.

[0099] In some preferred embodiments of the application, K' is wherein said R s , m, R4and R5are as defined and described herein, and ring A is optionally substituted with one or more R2.

[0100] In some preferred embodiments of the application, K' is wherein said R s , m, R4and R5are as defined and described herein, and ring A is optionally substituted with one or more R2.

[0101] In some preferred embodiments of the application, K' is wherein said R s , m, n, R4, R5and R6are as defined and described herein, and ring A is optionally substituted with one or more R2.

[0102] In some preferred embodiments of the application, K' is wherein said R s , m, R4and R5are as defined and described herein, and ring A is optionally substituted with one or more R2.

[0103] In some preferred embodiments of the application, R4is said R4is optionally substituted with one or more hydroxy, halo, deuterium, cyano, amino, C 1-3 alkyl, C 1-3 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl or C 1-3 haloalkyl.

[0104] In some preferred embodiments of the application, R4is

[0105] In some preferred embodiments of the application, R4is

[0106] In some preferred embodiments of the present application, R5 is halogen, preferably F.

[0107] In some preferred embodiments of the present application, the compound of formula I is not any of the compounds disclosed in the patent application file with the application number PCT / CN2023 / 125794 (international publication number WO2024083256A1) (pages 96-109) falling within the scope of the compound of formula I.

[0108] In some preferred embodiments of the present application, in the compound of formula I, K is

[0109] Preferably, K is

[0110] In some preferred embodiments of the present application,

[0111] In some preferred embodiments of the present application,

[0112] In some preferred embodiments of the present application, K is

[0113] In some preferred embodiments of the present application, L is connected to K through A.

[0114] In some preferred embodiments of the present application, L is L is connected to K through A.

[0115] In some preferred embodiments of the present application, E is For example,

[0116] In some preferred embodiments of the present application, K is

[0117] L is L is connected to K through A;

[0118] E is

[0119] In some preferred embodiments of the present application, K is ​​

[0120] L is L is connected to K via A;

[0121] E is

[0122] In some preferred embodiments of the application, K is

[0123] L is L is connected to K via A;

[0124] E is

[0125] In some preferred embodiments of the application, K is L is

[0126] In some preferred embodiments of the application, K is L is

[0127] In some preferred embodiments of the application, K is L is

[0128] In some preferred embodiments of the application, K is L is

[0129] In some preferred embodiments of the application, K is L is

[0130] In some preferred embodiments of the application, K is L is

[0131] In some preferred embodiments of the application, K is L is

[0132] In some preferred embodiments of the application, K is L is

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

[0134] In some preferred embodiments of the application, K is L is

[0135] In some preferred embodiments of the application, K is L is

[0136] In some preferred embodiments of the application, K is L is

[0137] In some preferred embodiments of the application, K is L is

[0138] In some preferred embodiments of the application, K is L is

[0139] In some preferred embodiments of the application, K is L is

[0140] In some preferred embodiments of the application, K is L is

[0141] In some preferred embodiments of the application, K is L is

[0142] In some preferred embodiments of the application, K is L is

[0143] In some preferred embodiments of the application, K is L is

[0144] In some preferred embodiments of the application, K is L is

[0145] In some preferred embodiments of the application, K is L is

[0146] In some preferred embodiments of the application, K is L is

[0147] In some preferred embodiments of the application, K is E is

[0148] In some preferred embodiments of the application, K is E is

[0149] In some preferred embodiments of the application, K is E is

[0150] In some preferred embodiments of the application, K is E is

[0151] In some preferred embodiments of the application, K is E is

[0152] In some preferred embodiments of the application, K is E is

[0153] In some preferred embodiments of the application, K is E is

[0154] In some preferred embodiments of the application, K is E is

[0155] In some preferred embodiments of the application, K is E is

[0156] In some preferred embodiments of the application, K is E is

[0157] In some preferred embodiments of the application, K is E is

[0158] In some preferred embodiments of the application, K is E is

[0159] In some preferred embodiments of the application, K is E is

[0160] In some preferred embodiments of the application, K is E is

[0161] In some preferred embodiments of the application, K is E is

[0162] In some preferred embodiments of the application, K is E is

[0163] In some preferred embodiments of the application, K is E is

[0164] In some preferred embodiments of the application, K is E is

[0165] In some preferred embodiments of the application, L is E is

[0166] In some preferred embodiments of the application, L is E is

[0167] In some preferred embodiments of the application, L is E is

[0168] In some preferred embodiments of the application, L is E is

[0169] In some preferred embodiments of the application, L is E is

[0170] In some preferred embodiments of the application, L is E is

[0171] In some preferred embodiments of the application, L is E is

[0172] In some preferred embodiments of the application, L is E is

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[0209] In some preferred embodiments of the application, K' is L' is E' is

[0210] In some preferred embodiments of the application, K' is L' is E' is

[0211] In some preferred embodiments of the application, K' is L' is E' is

[0212] Preferably, in certain embodiments of the application, L' is -(CH2) j - wherein one or more methylenes of said -(CH2) j - is optionally replaced by a member selected from the group consisting of -NR 3’ -, -O-, -CR 1’ R 2’ -, -C(O)-, -S(O)-, -S(O)2-, -C(O)O-, -OC(O)-, -C(O)NR 3’ -, -NR 3’ C(O)-, -S(O)2NR 3’ -, -NR 3’S(O)2-, ethenylene, ethynylene, phenyl, 8-10 membered bicyclic arylene, 3-7 membered saturated or partially unsaturated cycloalkylene, 5-11 membered saturated or partially unsaturated spirocycloalkylene, 5-11 membered saturated or partially unsaturated fused cycloalkylene, 8-10 membered bicyclic saturated or partially unsaturated cycloalkylene, 4-7 membered saturated or partially unsaturated heterocycloalkylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 5-11 membered saturated or partially unsaturated spiroheterocycloalkylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 5-11 membered saturated or partially unsaturated fused heterocycloalkylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 8-10 membered bicyclic saturated or partially unsaturated heterocycloalkylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 5-6 membered heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 8-10 membered bicyclic heteroarylene having 1-5 heteroatoms selected from nitrogen, oxygen, or sulfur, each of said ethenylene, ethynylene, cycloalkylene, heterocycloalkylene, phenyl, spiroheterocycloalkylene, fused heterocycloalkylene, heteroarylene, bicyclic arylene, spirocycloalkylene, fused cycloalkylene, independently optionally substituted with one or more substituents selected from halogen, oxo, -NR 3’ 4’ 3’ , nitro, -CN, C1-C6 alkyl, C3-C 10 C6 cycloalkyl, C3-C 10 heterocycloalkyl, said alkyl, cycloalkyl, heterocycloalkyl optionally substituted with one or more substituents selected from halogen, -OH, -NH2, -CN, C1-C4 alkyl, C3-C6 cycloalkyl, R 1’ 2’ each independently halogen, -OH, -NH2, C1-C4 alkyl, C1-C4 chloroalkyl, C1-C4 hydroxyalkyl, -O(C1-C4 alkyl), -NH(C1-C4 alkyl), -NH(C1-C4 alkyl), C3-C6 cycloalkyl, -O(C3-C6 cycloalkyl), -NH(C3-C6 cycloalkyl), C3-C6 heterocycloalkyl, -O(C3-C6 heterocycloalkyl), -NH(C3-C6 cycloalkyl); R 3’ 4’ each independently hydrogen, deuterium, C1-C4 alkyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, and j is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12.

[0213] Preferably, in certain embodiments of the application, L' is LA:

[0214] wherein in said LA:

[0215] ring U is C3-C​​​​12 cycloalkylene or 3-12 membered heterocycloalkylene containing 1-2 heteroatoms selected from N, O, or S, said cycloalkylene and heterocycloalkylene optionally substituted with a substituent selected from halogen, oxo, cyano, amino, hydroxyl, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, or -O-(C1-C6alkyl);

[0216] ring Y is a bond, C3-C 12 cycloalkylene or 3-12 membered heterocycloalkylene containing 1-2 heteroatoms selected from N, O, or S, said cycloalkylene and heterocycloalkylene optionally substituted with a substituent selected from halogen, oxo, cyano, amino, hydroxyl, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, or -O-(C1-C6alkyl);

[0217] X" is a bond, -C(O)-, -NH-, -NCH3-, -O-, -C(CH3)2-, -S-, -C=C-, -C≡C-, -CHF-, -CHCF3-, -(CH2) q C(O)-, -S(O)-, -S(O)2-, -C(O)O-, -OC(O)-, -(CH2) q C(O)NH-, -C(O)NCH3-, -NHC(O)-, -NCH3C(O)-, or -C(O)CH2O-;

[0218] q is 1 or 2;

[0219] Lx is -(CH2) v -, one or both methylene groups in said Lx being optionally replaced with a moiety selected from -O-, -S-, -NH-, -C≡C-, -N(C1-C6alkyl)-, -N(C1-C6haloalkyl)-, -C(O)-, -N(C1-C6hydroxyalkyl)-, -N(C3-C8cycloalkyl)-, or -CR d R e v is 1, 2, 3, 4, 5, 6, or 7;

[0220] R d , R e each independently H, -OH, C1-C6alkyl, or C1-C6alkoxy;

[0221] or R d and R e together with the C atom to which they are attached form a C3-C8cycloalkyl or 3-8 membered heterocycloalkyl;

[0222] Ly is -(CH2) k-, one or two methylene groups in Ly are optionally replaced by -O-, -NH-, -C≡C-, -N(C1-C6 alkyl)-, -N(C1-C6 haloalkyl)-, -C(O)-, -N(C1-C6 hydroxyalkyl)- or -N(C3-C8 cycloalkyl)-, and k is 1, 2, 3, 4, 5, 6, 7 or 8.

[0223] Preferably, in certain embodiments of the present invention, L' is LA:

[0224] Among them, LA:

[0225] Ring U is C3-C 12 Cycloalkylene or 3-12 membered heterocycloalkylene containing 1-2 heteroatoms selected from N, O or S, wherein the cycloalkylene and heterocycloalkylene are optionally substituted with substituents selected from halogen, oxo, cyano, amino, hydroxy, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl or -O-(C1-C6 alkyl);

[0226] Ring Y is a bond, C3-C 12 Cycloalkylene or 3-12 membered heterocycloalkylene containing 1-2 heteroatoms selected from N, O or S, wherein the cycloalkylene and heterocycloalkylene are optionally substituted with substituents selected from halogen, oxo, cyano, amino, hydroxy, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl or -O-(C1-C6 alkyl);

[0227] X" is a bond, -C(O)-, -NH-, -NCH3-, -O-, -C(CH3)2-, -S-, -C=C-, -CHF-, -CHCF3-, -(CH2) q C(O)-, -S(O)-, -S(O)2-, -C(O)O-, -OC(O)-, -(CH2) q C(O)NH-, -C(O)NCH3-, -NHC(O)-, -NCH3C(O)- or -C(O)CH2O-;

[0228] q is 1 or 2;

[0229] Lx is -(CH2) v -, one or two methylene groups in Lx are optionally selected from -O-, -S-, -NH-, -C≡C-, -N(C1-C6 alkyl)-, -N(C1-C6 haloalkyl)-, -C(O)-, -N(C1-C6 hydroxyalkyl)-, -N(C3-C8 cycloalkyl)- or -CR d R e - Substitution, v is 1, 2, 3, 4, 5, 6 or 7;

[0230] R d , R e each independently H, -OH, C1-C6 alkyl, or C1-C6 alkoxy;

[0231] or R d and R e together with the C atom to which they are attached form a C3-C8 cycloalkyl or 3-8 membered heterocycloalkyl;

[0232] Ly is -(CH2) k -, one or both methylene groups in said Ly being optionally replaced by a member selected from -0-, -NH-, -C≡C-, -N(C1-C6 alkyl)-, -N(C1-C6 haloalkyl)-, -C(O)-, -N(C1-C6 hydroxyalkyl)-, or -N(C3-C8 cycloalkyl)-, and k is 1, 2, 3, 4, 5, 6, 7, or 8.

[0233] Preferably, in certain embodiments of the application, L' is LA:

[0234] wherein in said LA:

[0235] Ring U is C3-C 12 cycloalkylene or 3-12 membered heterocycloalkylene containing 1-3 heteroatoms selected from N, O, or S, said cycloalkylene and heterocycloalkylene being optionally substituted with a member selected from halo, oxo, cyano, amino, hydroxy, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, or -O-(C1-C6 alkyl);

[0236] Ring Y is a bond, C3-C 12 cycloalkylene or 3-12 membered heterocycloalkylene containing 1-2 heteroatoms selected from N, O, or S, said cycloalkylene and heterocycloalkylene being optionally substituted with a member selected from halo, oxo, cyano, amino, hydroxy, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, or -O-(C1-C6 alkyl);

[0237] X" is a bond, -C(O)-, -NH-, -NCH3-, -O-, -C(CH3)2-, -S-, -C=C-, -CHF-, -CHCF3-, -(CH2) q C(O)-, -S(O)-, -S(O)2-, -C(O)O-, -OC(O)-, -(CH2) q C(O)NH-, -C(O)NCH3-, -NHC(O)-, -NCH3C(O)-, or -C(O)CH2O-;

[0238] q is 1 or 2;

[0239] Lx is -(CH2) v - one or two methylene groups in said Lx are optionally replaced by a member selected from the group consisting of -0-, -S-, -NH-, -C≡C-, -N(Ci-C6alkyl)-, -N(Ci-C6haloalkyl)-, -C(O)-, -N(Ci-C6hydroxyalkyl)-, -N(C3-C8cycloalkyl)-, or -CR d R e - is replaced by v is 1, 2, 3, 4, 5, 6, or 7;

[0240] R d , R e each independently is H, -OH, -NH2, Ci-C6haloalkyl, Ci-C6alkyl, or Ci-C6alkoxy;

[0241] or R d and R e together with the C atom to which they are attached form a C3-C8cycloalkyl or a 3-8 membered heterocycloalkyl;

[0242] Ly is -(CH2) k - one or two methylene groups in said Ly are optionally replaced by a member selected from the group consisting of -0-, -NH-, -C≡C-, -N(Ci-C6alkyl)-, -N(Ci-C6haloalkyl)-, -C(O)-, -N(Ci-C6hydroxyalkyl)-, or -N(C3-C8cycloalkyl)-, k is 1, 2, 3, 4, 5, 6, 7, or 8.

[0243] Preferably, in certain embodiments of the application, ring U in LA is a 4-8 membered saturated monocyclic heterocycloalkylene containing 1 or 2 nitrogen heteroatoms, a 6-10 membered fused heterocycloalkylene, ring Y is a 6-8 membered saturated monocyclic heterocycloalkylene containing 1 or 2 nitrogen heteroatoms, a 7-11 membered spiroheterocycloalkylene or a fused heterocycloalkylene containing 1 or 2 nitrogen heteroatoms, X" is a bond or -C(O)-, Lx is -(CH2) v - v is 1, 2, 3, 4, or 5; Ly is -(CH2) k - k is 1, 2, 3, 4, or 5.

[0244] Preferably, in certain embodiments of the application, ring U in LA is a 4-8 membered saturated monocyclic heterocycloalkylene containing 1 or 2 nitrogen heteroatoms, a 6-10 membered fused heterocycloalkylene or a 7-11 membered spiroheterocycloalkylene, ring Y is a 6-8 membered saturated monocyclic heterocycloalkylene containing 1 or 2 nitrogen heteroatoms, a 7-11 membered spiroheterocycloalkylene or a fused heterocycloalkylene containing 1 or 2 nitrogen heteroatoms, X" is a bond, -C(O)CH2O-, or -C(O)-, Lx is -(CH2) v- v is 1, 2, 3, 4, or 5; Ly is -(CH2) k - k is 1, 2, 3, 4, or 5.

[0245] Preferably, in certain embodiments of the application, LA is LA-1, LA-2:

[0246] X" is -C(O)- or -C(O)NH-;

[0247] wherein, in said LA-1, LA-2, ring U, ring Y, Lx, Ly, q are as defined and described herein.

[0248] Preferably, in certain embodiments of the application, LA is LA-1, LA-2:

[0249] X" is -C(O)-, -C(O)NH- or -C(O)CH2O-;

[0250] wherein, in said LA-1, LA-2, ring U, ring Y, Lx, Ly, q are as defined and described herein.

[0251] Preferably, in certain embodiments of the application, LA is LA-3, LA-4 or LA-5:

[0252] wherein, in said LA-3:

[0253] Lx is -(CH2) v - wherein one or two CH2in said Lx are each independently optionally replaced by -O-, -S-, -NH-, -NMe- or -CR d R e - wherein one or two CH2in said Lx are each independently optionally replaced by -O-, -S-, -NH-, -NMe- or -CR d R e - is - C(CH3)2, -CH(CH3)-, -CH(OH)-, -CH(OCH3)- or C(CH3)(OH)-; v is 1, 2, 3, 4, 5 or 6;

[0254] ring U is wherein a is attached to Lx and b is attached to Ly; 1, 2, 3 or 4 hydrogen atoms in said ring U are optionally replaced by F;

[0255] ring Y is a bond, wherein c is attached to Ly and d is attached to X"; 1, 2, 3 or 4 hydrogen atoms in said ring Y are optionally replaced by F;

[0256] Ly is -(CH2)k -, wherein one or two CH2 contained in the Ly are each independently optionally replaced by -O-, -C≡C- or -N(C1-C6 alkyl)-; k is 1, 2, 3, 4, 5 or 6;

[0257] X″ is a bond, -C(O)-, -(CH2)2C(O)- or -(CH2)2C(O)NH-;

[0258] Wherein said LA-4:

[0259] Lx is -(CH2) v -, wherein one or two CH2 contained in said Lx are each independently optionally replaced by -O-, -S-, -NH- or -CR d R e -Substitute; -CR d R e -for -C(CH3)2-, -CH(CH3)-, -CH(OCH3)-, -CH(OH)- or -C(CH3)(OH)-; v is 1, 2, 3, 4, 5 or 6;

[0260] Ring U is wherein the a-terminal is connected to Lx, and the b-terminal is connected to Ly; 1, 2, 3 or 4 hydrogen atoms in the ring U are optionally replaced by F;

[0261] Ring Y is wherein the c-terminus is connected to Ly, and the d-terminus is connected to X″; 1, 2, 3 or 4 hydrogen atoms in the ring Y are optionally substituted by F;

[0262] Ly is -(CH2) k -, wherein one or two CH2 contained in the Ly are each independently optionally replaced by -O- or -N(C1-C6 alkyl)-; k is 1, 2, 3, 4, 5 or 6;

[0263] X″ is -C(O)-;

[0264] Wherein, in the LA-5:

[0265] Lx is -(CH2) v -, wherein one or two CH2 contained in said Lx are each independently optionally replaced by -O-; v is 1, 2, 3 or 4;

[0266] Ring U is wherein a is attached to Lxand b is attached to Ly; 1, 2, 3, or 4 hydrogen atoms in ring U are optionally replaced with F;

[0267] ring Y is a bond;

[0268] Lyis -(CH2) k - wherein one or two CH2in said Lyare each independently optionally replaced with -0-, -C(O)-, or -NH-; k is 1, 2, 3, 4, 5, 6, 7, or 8;

[0269] X" is -C(O)NH-;

[0270] wherein in said LA-6:

[0271] Lxis -(CH2) v - wherein one or two CH2in said Lxare each independently optionally replaced with -0-, -S-, -NH-, -NMe-, or -CR d R e -; -CR d R e - is v is 1, 2, 3, or 4;

[0272] ring U is wherein a is attached to Lxand b is attached to Ly;

[0273] ring Y is

[0274] Lyis -(CH2) k - wherein one or two CH2in said Lyare each independently optionally replaced with -0-, -C(O)-, or -NH-; k is 1, 2, 3, 4, 5, or 6;

[0275] X" is a bond.

[0276] Preferably, in certain embodiments of the application, wherein LAis LA-3, LA-4, LA-5, or LA-6:

[0277] wherein in said LA-3:

[0278] Lxis -(CH2) v - wherein one or two CH2in said Lxare each independently optionally replaced with -0-, -S-, -NH-, -NMe-, or -CR d R e -; -CR d R e - is -C(CH3)2-, -CH(CH3)-, -CH(OH)-, -CH(OCH3)- or -C(CH3)(OH)-; v is 1, 2, 3, 4, 5 or 6;

[0279] Ring U is wherein the a end is connected to Lxand the b end is connected to Ly; 1, 2, 3 or 4 hydrogen atoms in said ring U are optionally substituted with F;

[0280] Ring Y is a bond, wherein the c end is connected to Lyand the d end is connected to X"; 1, 2, 3 or 4 hydrogen atoms in said ring Y are optionally substituted with F;

[0281] Lyis -(CH2) k , wherein one or two CH2in said Lyare each independently optionally replaced with -0-, -C≡C-, -C(O)- or -N(Ci-C6alkyl)-; k is 1, 2, 3, 4, 5 or 6;

[0282] X" is a bond, -C(O)-, -(CH2) 1-2 C(O)-, -CH2-C≡C-, -C(O)CH2O- or -(CH2) 1-2 C(O)NH-;

[0283] wherein in said LA-4:

[0284] Lxis -(CH2) v , wherein one or two CH2in said Lxare each independently optionally replaced with -0-, -S-, -NH- or -CR d R e -; -CR d R e is -C(CH3)2-, -CH(CH3)-, -CH(OCH3)-, -CH(OH)- or -C(CH3)(OH)-; v is 1, 2, 3, 4, 5 or 6;

[0285] Ring U is wherein the a end is connected to Lxand the b end is connected to Ly; 1, 2, 3 or 4 hydrogen atoms in said ring U are optionally substituted with F;

[0286] Ring Y is wherein the c end is connected to Lyand the d end is connected to X"; 1, 2, 3 or 4 hydrogen atoms in said ring Y are optionally substituted with F;

[0287] Ly is -(CH2) k - wherein one or two CH2in said Ly are each independently optionally replaced with -O- or -N(C1-C6alkyl)-; k is 1, 2, 3, 4, 5, or 6;

[0288] X" is -C(O)-;

[0289] wherein in said LA-5:

[0290] Lx is -(CH2) v - wherein one or two CH2in said Lx are each independently optionally replaced with -O-; v is 1, 2, 3, or 4;

[0291] Ring U is wherein the a end is connected to Lx and the b end is connected to Ly; 1, 2, 3, or 4 hydrogen atoms in said Ring U are optionally replaced with F;

[0292] Ring Y is a bond;

[0293] Ly is -(CH2) k - wherein one or two CH2in said Ly are each independently optionally replaced with -O-, -C(O)-, or -NH-; k is 1, 2, 3, 4, 5, 6, 7, or 8;

[0294] X" is -C(O)NH-;

[0295] wherein in said LA-6:

[0296] Lx is -(CH2) v - wherein one or two CH2in said Lx are each independently optionally replaced with -O- or -CR d R e -; -CR d R e - is v is 1, 2, 3, or 4;

[0297] Ring U is wherein the a end is connected to Lx and the b end is connected to Ly;

[0298] Ring Y is

[0299] Ly is -(CH2) k - wherein one or two CH2in said Ly are each independently optionally replaced with -O-, -C(O)-, or -NH-; k is 1, 2, 3, 4, 5, or 6;

[0300] X" is a bond.

[0301] Preferably, in certain embodiments of the application, wherein LA is LA-7 or LA-8:

[0302] wherein in said LA-7:

[0303] Lx is -(CH2) v wherein one or two CH2in said Lx are each independently optionally replaced with -O-, -S-, -NH-, -NMe- or -CR d R e -; -CR d R e - is -C(CH3)2-, -CH(CH3)-, -CH(OH)-, -CH(OCH3)- or C(CH3)(OH)-; v is 1, 2, 3, 4, 5 or 6;

[0304] Ring U is wherein a is attached to Lx and b is attached to Ly; 1, 2, 3 or 4 hydrogen atoms in said ring U are optionally replaced with F;

[0305] Ring Y is a bond, wherein c is attached to Ly and d is attached to X"; 1, 2, 3 or 4 hydrogen atoms in said ring Y are optionally replaced with F;

[0306] Ly is -(CH2) k wherein one or two CH2in said Ly are each independently optionally replaced with -O-, -C≡C-, -C(O)- or -N(C1-C6 alkyl)-; k is 1, 2, 3, 4, 5 or 6;

[0307] X" is a bond, -C(O)-, -(CH2) 1-2 C(O)-, -CH2-C≡C-, -C(O)CH2O- or -(CH2) 1-2 C(O)NH-;

[0308] wherein in said LA-8:

[0309] Lx is -(CH2) v wherein one or two CH2in said Lx are each independently optionally replaced with -O-, -S-, -NH- or -CR d R e -; -CR d R e - is -C(CH3)2-, -CH(CH3)-, -CH(OCH3)-, -CH(OH)-, -C(CH3)(OH)-, -CH(CHF2)-, -CH(CH(CH3)2)-, -CH(CH2CF3)-, or -CH(NH2)-; v is 1, 2, 3, 4, 5, or 6;

[0310] Ring U is wherein the a end is connected to Lxand the b end is connected to Ly; 1, 2, 3, or 4 hydrogen atoms in said ring U are optionally replaced with F, cyano, C 1-6 alkyl, or C1-C6hydroxyalkyl;

[0311] Ring Y is wherein the c end is connected to Lyand the d end is connected to X"; 1, 2, 3, or 4 hydrogen atoms in said ring Y are optionally replaced with F;

[0312] Lyis -(CH2) k wherein one or two CH2in said Lyare each independently optionally replaced with -O- or -N(C1-C6alkyl)-; k is 1, 2, 3, 4, 5, or 6;

[0313] X" is -C(O)-.

[0314] Preferably, in certain embodiments of the application, wherein LAis LA-9 or LA-10:

[0315] wherein in said LA-9:

[0316] Lxis -(CH2) v wherein one or two CH2in said Lxare each independently optionally replaced with -O- or -CR d R e -; -CR d R e is v is 1, 2, 3, 4, 5, or 6;

[0317] Ring U is wherein the a end is connected to Lxand the b end is connected to Ly;

[0318] Ring Y is wherein the c end is connected to Lyand the d end is connected to X"; 1, 2, 3, or 4 hydrogen atoms in said ring Y are optionally replaced with F;

[0319] Lyis -(CH2) k, wherein one or two CH2in said Ly is each independently optionally replaced with -O-, -C=C-, or -N(Ci-C6alkyl)-; k is 1, 2, 3, 4, 5, or 6;

[0320] X" is -C(O)-;

[0321] wherein in said LA-10:

[0322] Lx is -(CH2) v , wherein one or two CH2in said Lx is each independently optionally replaced with -O-, or -CR d R e -; -CR d R e - is independently -CH(CH3)-, -CH(OCH3)-, -CH(OH)-, or -CH(NH2)-; v is 1, 2, 3, 4, 5, or 6;

[0323] Ring U is wherein the a end is attached to Lx and the b end is attached to Ly;

[0324] Ring Y is wherein the c end is attached to Ly and the d end is attached to X";

[0325] Ly is -(CH2) k , k is 1, 2, 3, 4, 5, or 6;

[0326] X" is -C(O)-.

[0327] In some preferred embodiments of the application, wherein said L' is LA-10:

[0328] Lx is -(CH2) v , wherein one, two, three, or four CH2in said Lx is each independently optionally replaced with -O-, or -CR d R e -; -CR d R e - is independently -CH(CH3)-, -CH(OCH3)-, -CH(OH)-, -CH(NH2)-, -C(=CH2)-, -C(=CHF)-, or CD2; v is 1, 2, 3, 4, 5, or 6;

[0329] Ring U is wherein the a end is attached to Lx and the b end is attached to Ly;

[0330] Ring Y is wherein the a terminus is attached to Lxand the b terminus is attached to Ly;

[0331] Lyis -(CH2) k -, one CH2in said Lybeing optionally replaced by -CD2-; k is 1, 2, 3, 4, 5, or 6;

[0332] X" is -C(O)-.

[0333] In some preferred embodiments of the application, wherein said L' is LA-10:

[0334] Lxis -(CH2) v -, two, three, or four CH2in said Lxbeing each independently optionally replaced by -O- or -CR d R e -; -CR d R e - is independently CH(CH3)-, -C(=CH2)-, -C(=CHF)-, or CD2; v is 1, 2, 3, 4, 5, or 6;

[0335] Ring U is wherein the a terminus is attached to Lxand the b terminus is attached to Ly;

[0336] Ring Y is wherein the c terminus is attached to Lyand the d terminus is attached to X";

[0337] Lyis -(CH2) k -, one CH2in said Lybeing optionally replaced by -CD2-; k is 1, 2, 3, 4, 5, or 6;

[0338] X" is -C(O)-.

[0339] Preferably, in certain embodiments of the application, wherein LAis LA-11or LA-12:

[0340] wherein in said LA-11:

[0341] Lxis -(CH2) v -, one or two CH2in said Lxbeing each independently optionally replaced by -O- or -CR d R e -; -CR d R e - is v is 1, 2, 3, 4, 5, or 6;

[0342] Ring U is wherein the a terminus is attached to Lxand the b terminus is attached to Ly;

[0343] Ring Y is wherein the c terminus is attached to Lyand the d terminus is attached to X";

[0344] Lyis -(CH2) k - wherein one or two CH2in said Lyare each independently optionally replaced with -O- or -C=C-; k is 1, 2, 3, 4, 5, or 6;

[0345] X" is -C(O)-.

[0346] wherein in said LA-12:

[0347] Lxis -(CH2) v - wherein one or two CH2in said Lxare each independently optionally replaced with -O- or -CR d R e -; -CR d R e is or -CH(CH3)-; v is 1, 2, 3, 4, 5, or 6;

[0348] Ring Y is wherein the a terminus is attached to Lxand the b terminus is attached to Ly;

[0349] Ring Y is wherein the c terminus is attached to Lyand the d terminus is attached to X";

[0350] Lyis -(CH2) k -; k is 1, 2, 3, 4, 5, or 6;

[0351] X" is -C(O)-.

[0352] Preferably, in certain embodiments of the application, Lxis

[0353] Preferably, in certain embodiments of the application, Lyis -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-,

[0354] Preferably, in certain embodiments of the application, E1has the structure of Formula E1-1a, E1-1b, E1-1c, E1-1d, E1-1e, E1-1f, E1-1g, E1-1aa, E1-1h, 1-1bb, E1-1cc, E1-1dd, E1-1ee, E1-1ff, E1-1gg, or E1-1hh:

[0355] wherein Q1, Q2, Q3, Q4, Q5, R1", R2", R3", and m" are as defined and described herein.

[0356] Preferably, in certain embodiments of the application, E1has the structure of Formula E1-1h", E1-1i', E1-1j', or E1-1h'h':

[0357] wherein R 3b are as defined and described herein.

[0358] Preferably, in certain embodiments of the application, R 3b is hydrogen, halogen, cyano, -OH, -NH2, C1-C6alkyl, C3-C8cycloalkyl, 3-8 membered 1-2 heterocycloalkyl, -O(C1-C6alkyl), -O(C3-C8cycloalkyl), -O(3-8 membered heterocycloalkyl), -N(C1-C6alkyl) 1-2 , -N(C3-C8cycloalkyl) 1-2 , or -S(C1-C6alkyl), said C1-C6alkyl, C3-C8cycloalkyl, 3-8 membered heterocycloalkyl, -O(C1-C6alkyl), -O(C3-C8cycloalkyl), or -O(3-8 membered heterocycloalkyl), -N(C1-C6alkyl) 1-2 , -N(C3-C8cycloalkyl) , or -S(C1-C6alkyl) is optionally substituted with 1-3 halogen, cyano, -OH, -NH2.

[0359] Preferably, in certain embodiments of the application, E1has the structure of Formula E1-1h":

[0360] wherein R 3b is each independently hydrogen, halogen, C1-C6alkyl, or -O(C1-C6alkyl), said C1-C6alkyl and -O(C1-C6alkyl) is optionally substituted with 1, 2, or 3 deuterium, halogen, cyano, -OH, or -NH2.

[0361] Preferably, in certain embodiments of the application, E1is:

[0362] Preferably, in certain embodiments of the application, E1is

[0363] Preferably, in certain embodiments of the application, E1is

[0364] Preferably, in certain embodiments of the application, E1is

[0365] Preferably, in certain embodiments of the application, E2has the structure of Formula E2-1a, E2-1b, E2-1c, E2-1d, E2-1e, or E2-1f:

[0366] wherein in said E2-1a, E2-1b, E2-1c, E2-1d, E2-1e, and E2-1f:

[0367] W is CR 1c R 2c , C(S), C(O), or SO2;

[0368] X is CH2, O, or S;

[0369] Y 2 is NH, N-alkyl, N-aryl, N-heteroaryl, N-cycloalkyl, N-heterocycloalkyl, O, or S;

[0370] Z is CH2, O, or S;

[0371] G" and G' are each independently selected from hydrogen, deuterium, C1-C6alkyl, OH, C3-C6cycloalkyl, -CH2-heterocycloalkyl, or -CH2-phenyl, said C1-C6alkyl, C3-C6cycloalkyl, -CH2-heterocycloalkyl, or -CH2-phenyl optionally substituted with 1-3 independent groups selected from hydroxyl, halogen, cyano, amino;

[0372] Q1, Q2, Q3, Q4are each independently CR 3b or N;

[0373] A' is hydrogen, deuterium, C1-C6alkyl, C3-C6cycloalkyl, or halogen;

[0374] R 1c , R 2c , and R 3c are each independently selected from hydrogen, hydroxyl, halogen, -NH2, -N(C1-C6alkyl) 1-2 , C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, -CONR′ R ″ , -OR ′ , -NR ′ R ″ , -SR ′ , -SO2R ′ , -SO2NR ′ R ″ , -CR ′ R ″ , -CR ′ NR ′ R ″ , aryl, heteroaryl, C3-C8cycloalkyl, 3-8 membered heterocycloalkyl, -P(O)(OR ′ )R ″ , -P(O)R ′ R ″ , -OP(O)(OR ′ )R ″ , -Cl, -F, -Br, -I, -CF3, -CN, -NR ′ SO2NR ′ R ″ , -NR ′ C(O)NR ′ R ″ , -C(O)NR ′ C(O)R ″ , -NR ′ C(=N-CN)NR ′ R ″ , -C(=N-CN)NR ′ R ″ , -NR ′ C(=N-CN)R ″ , -NR ′ C(=C-NO2)NR ′ R ″ , -SO2NR ′ COR ″ , -NO2, -COR ′ , -C(C=N-OR ′ )R ″ , -CR ′ =CR ′ R ″ , -CCR ′ , -S(C=O)(C=N-R ′ )R ″ , -SF5or -OCF3;

[0375] R ′ and R ″each independently selected from the group consisting of a bond, hydrogen, deuterium, C1-C6alkyl, C3-C8cycloalkyl, C6-C10aryl, 5-10 membered heteroaryl, 3-8 membered heterocycloalkyl, wherein each of the C1-C6alkyl, C3-C8cycloalkyl, C6-C10aryl, 5-10 membered heteroaryl, and 3-8 membered heterocycloalkyl is optionally substituted with one to three substituents independently selected from the group consisting of halogen, -NH2, -N(C1-C6alkyl)2, -OH, -C1-C6alkyl, -C1-C6alkoxy, -C1-C6haloalkyl, and -C3-C8cycloalkyl; 10 aryl, 5-10 membered heteroaryl, or 3-8 membered heterocycloalkyl;

[0376] n" is 1, 2, 3, or 4;

[0377] is a bond, which can be the R stereoisomer, the S stereoisomer, or a non-stereoisomer;

[0378] wherein R 3b as described and defined herein;

[0379] Preferably, in certain embodiments of the application, E2has the structure of Formula E2-1bb or E2-1aa:

[0380] wherein in said E2-1bb:

[0381] Q1, Q2, Q3, and Q4are each independently CR 3b or N;

[0382] W is C(O) or CH2;

[0383] A' is hydrogen, deuterium, C1-C6alkyl, or halogen;

[0384] R 3c is selected from the group consisting of hydrogen, deuterium, hydroxyl, halogen, -NH2, -N(C1-C6alkyl)2, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl; 1-2 C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl;

[0385] n" is 1, 2, 3, or 4;

[0386] is a bond, which can be the R stereoisomer, the S stereoisomer, or a non-stereoisomer;

[0387] wherein R 3b as described and defined herein;

[0388] wherein in said E2-1aa:

[0389] W is CH2or C(O);

[0390] A' is hydrogen, methyl, Cl, or F;

[0391] R 3c each independently selected from the group consisting of hydrogen, hydroxyl, NH2, C1-C6alkyl, or C1-C6alkoxy;

[0392] n" is 1, 2, 3, or 4;

[0393] R is a key, which can be R stereoisomer, S stereoisomer or non-stereoisomer.

[0394] Preferably, in certain embodiments of the application, E2 is:

[0395] Preferably, in certain embodiments of the application, E2 is

[0396] Preferably, in certain embodiments of the application, E3 has the structure of E3-1:

[0397] W 3 R is an aryl, heteroaryl or said aryl, heteroaryl is optionally substituted;

[0398] R is a key, which can be R stereoisomer, S stereoisomer or non-stereoisomer. 9 , R 10 each independently selected from hydrogen, alkyl, C3-C8 cycloalkyl or 5-10 heteroaryl, said alkyl, C3-C8 cycloalkyl or 5-10 heteroaryl optionally substituted with 1 or more -OH, halogen or -NH2;

[0399] or R 9 , R 10 and the carbon atom to which they are attached form a C3-C8 cycloalkyl, said C3-C8 cycloalkyl optionally substituted with -OH, halogen, -NH2 or C1-C3 alkyl;

[0400] R is a key, which can be R stereoisomer, S stereoisomer or non-stereoisomer. 11 selected from C1-C6 alkyl, C1-C6 alkoxy, 3-8 membered heterocycloalkyl, C6-C 10 aryl, 5-10 membered heteroaryl or said C1-C6 alkyl, C1-C6 alkoxy, 3-8 membered heterocycloalkyl, C6-C 10 aryl or 5-10 membered heteroaryl optionally substituted with 1 or more -OH, halogen or -NH2;

[0401] R is a key, which can be R stereoisomer, S stereoisomer or non-stereoisomer. 12 selected from H, C(O) or substituted alkyl;

[0402] R is a key, which can be R stereoisomer, S stereoisomer or non-stereoisomer. 13is selected from H, alkyl, -alkylCO-, -(cycloalkyl)alkylCO-, -aralkylCO-, -arylCO-, -(heterocycloalkyl)CO-, or arylalkyl, said alkyl, -alkylCO-, -(cycloalkyl)alkylCO-, -aralkylCO-, -arylCO-, -(heterocycloalkyl)CO-, or arylalkyl is optionally substituted;

[0403] R 16 is H, halo, -OH, alkyl, or alkoxy, said alkyl or alkoxy is optionally substituted with halo;

[0404] o is 1, 2, 3, or 4,

[0405] wherein, R 8d , R 14a , R 14b , R 15 are as described and defined herein.

[0406] Preferably, in certain embodiments of the application, E3 has the structure of formula E3-1a, E3-1b, or E3-1c:

[0407] wherein,

[0408] R 1d is H, ethyl, isopropyl, t-butyl, sec-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, alkyl, hydroxyalkyl, heteroaryl, or haloalkyl, said alkyl, hydroxyalkyl, heteroaryl is optionally substituted;

[0409] R 6d is H, -CH3, -CH2F, -CH2OH, ethyl, isopropyl, or cyclopropyl;

[0410] R 8d is H, halo, CN, OH, NO2, aryl, heteroaryl, C1-C6 alkyl, C1-C6 alkoxy, cycloalkyl, or heterocycloalkyl, said aryl, heteroaryl, C1-C6 alkyl, C1-C6 alkoxy, cycloalkyl, or heterocycloalkyl is optionally substituted with halo, -OH, CN, NO2, or amino;

[0411] X d is CH2or C(O);

[0412] R d is 5-6 membered heteroaryl, said 5-6 membered heteroaryl is optionally substituted.

[0413] Preferably, in certain embodiments of the application, E3 has the structure of formula E3-1aa:

[0414] wherein,

[0415] R6d H, -CH3, -CH2F, -CH2OH, ethyl, isopropyl, or cyclopropyl;

[0416] R 9 H;

[0417] R 10 H, ethyl, isopropyl, t-butyl, sec-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl;

[0418] R 11 selected from or 5-10 membered heteroaryl optionally substituted with 1 or more -OH, halo, or -NH2;

[0419] R 12 H or C(O);

[0420] R 13 H, alkyl, -alkylCO-, -(cycloalkyl)alkylCO-, -aralkylCO-, -arylCO-, -(heterocycloalkyl)CO-, or arylalkyl, optionally substituted;

[0421] R 8d H, halo, CN, OH, NO2,

[0422] Preferably, in certain embodiments of the application, E3 is:

[0423] Preferably, in certain embodiments of the application, E3 is:

[0424] In some preferred embodiments of the application, in said K1:

[0425] n is selected from 0 or 1;

[0426] R4is selected from C 6-10 aryl or 5-10 membered heteroaryl, said C 6-10 aryl or 5-10 membered heteroaryl optionally substituted with 1 or more hydroxyl, halo, deuterium, cyano, amino, C 1-3 alkyl, C 1-3 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, or C 1-3 haloalkyl.

[0427] In some preferred embodiments of the application, K1is

[0428] In some preferred embodiments of the application, X2is selected from N.

[0429] In some preferred embodiments of the application, X1is selected from O or NR6.

[0430] In some preferred embodiments of the application, R1and R2are independently selected from hydrogen or deuterium.

[0431] In some preferred embodiments of the application, R s is selected from hydrogen, deuterium or C 1-3 alkyl, such as hydrogen or deuterium.

[0432] In some preferred embodiments of the application, m is selected from 0, 1 or 2.

[0433] In some preferred embodiments of the application, R4is said R4is optionally substituted with 1 or more hydroxyl, halogen, deuterium, cyano, amino, C 1-3 alkyl, C 1-3 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 haloalkyl or C 3-6 cycloalkyl;

[0434] In some preferred embodiments of the application, R5is selected from hydrogen, deuterium or halogen.

[0435] In some preferred embodiments of the application, L' is L' is connected to K' through A.

[0436] In some preferred embodiments of the application,

[0437] K' is

[0438] Ring A is a 6-10 membered heterocycloalkyl, said heterocycloalkyl containing at least one heteroatom or heteroatom group selected from N, S or O, and said 6-10 membered heterocycloalkyl is optionally substituted with 1 or more R2;

[0439] R2is selected from hydrogen, deuterium, hydroxyl or C 1-6 alkyl;

[0440] X1is selected from O or NR6;

[0441] X2is selected from N;

[0442] R s selected from hydrogen, deuterium, or C 1-3 alkyl;

[0443] m is selected from 0, 1, or 2;

[0444] n is selected from 0, 1, or 2;

[0445] R4is said R4is optionally substituted with one or more hydroxyl, halogen, deuterium, cyano, amino, C 1-3 alkyl, C 1-3 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 haloalkyl, or C 3-6 cycloalkyl;

[0446] R5is selected from hydrogen, deuterium, or halogen;

[0447] R6is selected from hydrogen or C 1-3 alkyl;

[0448] L' is L' is connected to K' through A.

[0449] E' is

[0450] In some preferred embodiments of the application, K' is

[0451] X2is selected from N;

[0452] X1is selected from O or NR6;

[0453] R6is selected from hydrogen or C 1-3 alkyl;

[0454] R s selected from hydrogen, deuterium, or C 1-3 alkyl;

[0455] R5is selected from hydrogen, deuterium, or halogen;

[0456] m is selected from 0 or 1;

[0457] R4is said R4is optionally substituted with one or more hydroxyl, halogen, deuterium, cyano, amino, C 1-3 alkyl, C 1-3 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C1-3 haloalkyl or C3-6cycloalkyl;

[0458] L' is

[0459] E' is

[0460] In some preferred embodiments of the application, K' is L' is E' is

[0461] In some preferred embodiments of the application, K' is L' is E' is

[0462] In some preferred embodiments of the application, K' is L' is E' is

[0463] In some preferred embodiments of the application, K' is L' is E' is

[0464] In some preferred embodiments of the application, K' is L' is E' is

[0465] In some preferred embodiments of the application, K' is L' is E' is

[0466] In some preferred embodiments of the application, K' is L' is E' is

[0467] In some preferred embodiments of the application, K' is L' is E' is

[0468] In some preferred embodiments of the application, K' is L' is E' is

[0469] In some preferred embodiments of the application, K' is L' is E' is

[0470] In some preferred embodiments of the application, K' is L' is E' is

[0471] In some preferred embodiments of the application, K' is L' is E' is

[0472] In some preferred embodiments of the application, K' is L' is E' is

[0473] In some preferred embodiments of the application, K' is L' is E' is

[0474] In some preferred embodiments of the application, K' is L' is E' is

[0475] In some preferred embodiments of the application, K' is L' is E' is

[0476] In some preferred embodiments of the application, K' is L' is E' is

[0477] In some preferred embodiments of the application, K' is L' is E' is

[0478] In some preferred embodiments of the application, K' is L' is E' is

[0479] In some preferred embodiments of the application, K' is L' is E' is

[0480] In some preferred embodiments of the application, K' is For example, K' is

[0481] In some preferred embodiments of the application, K' is

[0482] In some preferred embodiments of the application, K' is

[0483] In some preferred embodiments of the application, the compound of Formula I or I' is any one of the following:

[0484] In some preferred embodiments of the application, in the configuration of ​the compound eluting first in the following chromatographic conditions: Column: Daicel chiralpak AD 3,3*150mm, 3μm; mobile phase A: CO2, mobile phase B: MeOH (0.1% diethanolamine); gradient: A / B = 70 / 30 (V / V); flow rate: 1.5 mL / min; wavelength: 214 nm; column temperature: 37°C; preferably the compound eluting first has a retention time of 2.267 min.

[0485] In some preferred embodiments of the application, the compound eluting first in the following chromatographic conditions: Column: Daicel chiralpak AD 3,3*150mm, 3μm; mobile phase A: CO2, mobile phase B: MeOH (0.1% diethanolamine); gradient: A / B = 70 / 30 (V / V); flow rate: 1.5 mL / min; wavelength: 214 nm; column temperature: 37°C; preferably the compound eluting first has a retention time of 2.267 min. In some preferred embodiments of the application,

[0486] In some preferred embodiments of the application, the compound eluting first in the following chromatographic conditions: Column: Daicel chiralpak AD 3,3*150mm, 3μm; mobile phase A: CO2, mobile phase B: MeOH (0.1% diethanolamine); gradient: A / B = 70 / 30 (V / V); flow rate: 2.0 mL / min; wavelength: 214 nm; column temperature: 37°C; preferably the compound eluting first has a retention time of 2.513 min. In some preferred embodiments of the application,

[0487] In some preferred embodiments of the application, the compound eluting first in the following chromatographic conditions: Column: Daicel chiralpak AD 3,3*150mm, 3μm; mobile phase A: CO2, mobile phase B: MeOH (0.1% diethanolamine); gradient: A / B = 70 / 30 (V / V); flow rate: 2.0 mL / min; wavelength: 214 nm; column temperature: 37°C; preferably the compound eluting first has a retention time of 2.513 min. In some preferred embodiments of the application,

[0488] ​​​In some preferred embodiments of the application, the configuration of the compound eluting first in the compound eluting second in

[0489] In some preferred embodiments of the application, the configuration of the compound eluting first in the compound eluting second in

[0490] In some preferred embodiments of the application, the configuration of the compound eluting first in the compound eluting second in

[0491] In some preferred embodiments of the application, the configuration of the compound eluting first in ​​​​The configuration of the compound that eluted later under the following chromatographic conditions is the same, and the chromatographic conditions are as follows: column: Daicel chiralcel IH_3, 3*150mm, 3μm; mobile phase A is CO2, mobile phase B is MeOH (0.1% diethanolamine); gradient: A / B=80 / 20 (V / V), flow rate: 2mL / min; wavelength: 214nm; column temperature: 37°C; preferably, the retention time of the compound that eluted later is 2.785min.

[0492] 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, and the chromatographic conditions are as follows: column: Daicel CHIRALCEL IB-N, 250 mm*30 mm ID, 10 μm; mobile phase A is CO2, mobile phase B is MeOH (0.2% NH3 (7 M / MeOH)); gradient: A / B = 50 / 50 (V / V), flow rate: 120 g / min; wavelength: 214 nm; column temperature: 35°C; preferably, the retention time of the compound that elutes first is 1.603 min.

[0493] In some preferred embodiments of the present invention, middle The configuration and The configuration of the compound that eluted later under the following chromatographic conditions is the same, and the chromatographic conditions are as follows: column: Daicel CHIRALCEL IB-N, 250mm*30mm ID, 10μm; mobile phase A is CO2, mobile phase B is MeOH (0.2% NH3 (7M / MeOH)); gradient: A / B=50 / 50 (V / V), flow rate: 120g / min; wavelength: 214nm; column temperature: 35°C; preferably, the retention time of the compound that eluted later is 2.683min.

[0494] The present invention provides a method for preparing a compound of formula I or I', and / or its stereoisomers, enantiomers, diastereomers, atropisomers, deuterated forms, hydrates, solvates, metabolites, prodrugs, and / or pharmaceutically acceptable salts.

[0495] The present application provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I or I', and / or stereoisomer, enantiomer, diastereomer, atropisomer, deuterated compound, hydrate, solvate, metabolite, prodrug, and / or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, or excipient.

[0496] The present application provides a method of degrading pan-KRAS protein comprising contacting a compound of Formula I or I', and / or stereoisomer, enantiomer, diastereomer, atropisomer, deuterated compound, hydrate, solvate, metabolite, prodrug, and / or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, with a pan-KRAS protein.

[0497] The present application provides a use of a compound of Formula I or I', and / or stereoisomer, enantiomer, diastereomer, atropisomer, deuterated compound, hydrate, solvate, metabolite, prodrug, and / or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, as a medicament for treating or preventing a pan-KRAS-mediated disease or disorder.

[0498] The present application provides a use of a compound of Formula I or I', and / or stereoisomer, enantiomer, diastereomer, atropisomer, deuterated compound, hydrate, solvate, metabolite, prodrug, and / or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, as a medicament for treating or preventing a disease or disorder caused by pan-KRAS (cancer).

[0499] The present application provides a use of a compound of Formula I or I', and / or stereoisomer, enantiomer, diastereomer, atropisomer, deuterated compound, hydrate, solvate, metabolite, prodrug, and / or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the manufacture of a medicament for treating or preventing a pan-KRAS-mediated disease or disorder (e.g., cancer).

[0500] The present application provides a use of a compound of Formula I or I', and / or stereoisomer, enantiomer, diastereomer, atropisomer, deuterated compound, hydrate, solvate, metabolite, prodrug, and / or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the manufacture of a medicament for treating or preventing cancer.

[0501] The present application provides a use of a compound of Formula I or I', and / or stereoisomer, enantiomer, diastereomer, atropisomer, deuterated compound, hydrate, solvate, metabolite, prodrug, and / or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the manufacture of a KRAS inhibitor.

[0502] The present application provides a use of a compound of Formula I or I', and / or stereoisomers, enantiomers, diastereomers, atropisomers, deuterated compounds, hydrates, solvates, metabolites, prodrugs, and / or pharmaceutically acceptable salts thereof, or a pharmaceutical composition thereof in the manufacture of a medicament for treating or preventing pancreatic cancer, lung cancer, colorectal cancer, cholangiocytes cancer, multiple myeloma, melanoma, uterine cancer, endometrial cancer, thyroid cancer, acute myeloid leukemia, bladder cancer, urothelial cancer, gastric cancer, cervical cancer, head and neck squamous cell carcinoma, diffuse large B-cell lymphoma, esophageal cancer, chronic lymphocytic leukemia, hepatocellular carcinoma, breast cancer, ovarian cancer, prostate cancer, glioblastoma, renal cancer, and sarcoma.

[0503] The present application provides a method of treating or preventing a disease or disorder mediated by pan-KRAS, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula I or I', and / or stereoisomers, enantiomers, diastereomers, atropisomers, deuterated compounds, hydrates, solvates, metabolites, prodrugs, and / or pharmaceutically acceptable salts thereof, or a pharmaceutical composition thereof.

[0504] The present application provides a method of treating or preventing a disease or disorder (e.g., cancer) modulated by pan-KRAS, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula I or I', and / or stereoisomers, enantiomers, diastereomers, atropisomers, deuterated compounds, hydrates, solvates, metabolites, prodrugs, and / or pharmaceutically acceptable salts thereof, or a pharmaceutical composition thereof.

[0505] In certain embodiments of the present application, the cancer is selected from:

[0506] Heart: sarcomas (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxomas, rhabdomyomas, fibromas, lipomas, and teratomas group;

[0507] Lung: bronchogenic carcinoma (squamous cell carcinoma, undifferentiated small cell carcinoma, undifferentiated large cell carcinoma, adenocarcinoma), alveolar carcinoma (bronchiolar carcinoma), bronchial adenoma, sarcoma, lymphoma, chondroma hamartoma, mesothelioma, lung cancer, small cell lung cancer;

[0508] Gastrointestinal tract: esophageal carcinoma (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, fibronerveoma, fibroma), large intestine (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma), appendix carcinoma, gastrointestinal neuroendocrine tumors, esophagogastric cancer, anal cancer, gastrointestinal stromal tumors;

[0509] Urogenital system: kidney (adenocarcinoma, embryonal carcinosarcoma (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratocarcinoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma), germ cell tumor, bladder cancer, prostate cancer;

[0510] Liver: hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, malignant hemangioendothelioma, hepatocellular adenoma, hemangioma;

[0511] Biliary tract: bile duct cancer, gallbladder cancer, ampullary cancer, liver small bile duct cancer;

[0512] 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 (osteecartilage exostosis), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumor, bone cancer;

[0513] Nervous system: skull (osteoma, hemangioma, granuloma, xanthoma, Paget's disease), meninges (meningioma, meningeal sarcoma, glioma), brain (astrocytoma, medulloblastoma, neuroglioma, ependymoma, germ cell tumor (pinealoma), glioblastoma multiforme, oligodendroglioma, schwannoma, eye cancer, congenital tumor), spinal cord neurofibroma, meningioma, glioma, sarcoma);

[0514] Gynecology and obstetrics: uterus (endometrial cancer (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, botulism sarcoma (embryonic type rhabdomyosarcoma), fallopian tube (carcinoma), cervical cancer, endometrioid carcinoma;

[0515] Hematology: blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphoblastic leukemia, myeloproliferative disease, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma);

[0516] Skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, nevus dysplastic nevus, lipoma, hemangioma, dermatofibroma, keloid, psoriasis;

[0517] Adrenal gland: neuroblastoma.

[0518] In certain embodiments of the application, the pan-KRAS is KRAS, for example KRAS G12A, KRAS G12C, KRAS G12D, KRAS G12R, KRAS G12S, KRAS G12V, KRAS G13D, KRAS Q61H, or KRAS WT, for example KRAS G12D or KRAS G12V.

[0519] In certain embodiments of the application, the cancer is a KRAS G12A, KRAS G12C, KRAS G12D, KRAS G12R, KRAS G12S, KRAS G12V, KRAS G13D, or KRAS Q61H protein mutation associated cancer.

[0520] In certain embodiments of the application, the cancer is a KRAS G12A associated cancer: non-small cell lung cancer, ovarian cancer, or colorectal cancer.

[0521] In certain embodiments of the application, the KRAS G12A mediated disease is multiple myeloma.

[0522] In certain embodiments of the application, the cancer is a KRAS G12C associated cancer: non-small cell lung cancer, colorectal cancer, or pancreatic cancer.

[0523] In certain embodiments of the application, the cancer is a KRAS G12D associated cancer: biliary tract cancer, endometrial cancer, pancreatic cancer, colorectal cancer, non-small cell lung cancer, ovarian cancer, or rectal cancer.

[0524] In certain embodiments of the application, the KRAS G12D mediated disease is colon cancer, metastatic pancreatic cancer, lung cancer, or gastric cancer.

[0525] In certain embodiments of the application, the cancer is a KRAS G12R associated cancer: pancreatic cancer or non-small cell lung cancer.

[0526] In certain embodiments of the application, the cancer is a KRAS G12S associated cancer: rectal cancer, large intestine adenocarcinoma, or colorectal cancer.

[0527] In certain embodiments of the application, the KRAS G12S mediated disease is non-small cell lung cancer.

[0528] In certain embodiments of the application, the cancer is a KRAS G12V associated cancer: pancreatic cancer, colorectal cancer, non-small cell lung cancer, or ovarian cancer.

[0529] In certain embodiments of the application, the KRAS G12V mediated disease is colon cancer, lung cancer, or lung cancer squamous carcinoma.

[0530] In certain embodiments of the application, the cancer is a KRAS G13D associated cancer: colorectal cancer.

[0531] In certain embodiments of the application, the KRAS WT mediated disease is gastric cancer.

[0532] 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.

[0533] In certain embodiments of the application, the cancer is non-small cell lung cancer, ovarian cancer, colorectal cancer, multiple myeloma, pancreatic cancer, biliary tract cancer, endometrial cancer, non-small cell lung cancer, ovarian cancer, rectal cancer, metastatic pancreatic cancer, lung cancer, gastric cancer, rectal cancer, large intestine adenocarcinoma, or lung cancer squamous carcinoma.

[0534] The present application also provides a compound of Formula I or I', a stereoisomer thereof, a pharmaceutically acceptable salt of the compound or the stereoisomer thereof, or a pharmaceutically acceptable salt of the stereoisomer thereof, for use in the treatment of a disease or disorder associated with pan-KRAS mutant protein.

[0535] The present application also provides a compound of Formula I or I', a stereoisomer thereof, a pharmaceutically acceptable salt of the compound or the stereoisomer thereof, or a pharmaceutically acceptable salt of the stereoisomer thereof, for use in the treatment of a disease or disorder associated with pan-KRAS mutant protein.

[0536] In certain embodiments of the application, the cancer is selected from pancreatic cancer, colorectal cancer, endometrial cancer, or lung cancer.

[0537] In certain embodiments of the application, the lung cancer is selected from non-small cell lung cancer or small cell lung cancer.

[0538] DETAILED DESCRIPTION: Unless otherwise indicated, the following terms used in the specification and claims have the following meanings.

[0539] "Alkyl" refers to saturated aliphatic hydrocarbon groups, including straight chain or branched chain alkyl groups; for example, C1-C8alkyl refers to alkyl groups containing from 1 to 8 carbon atoms, including C1-C2, C1-C3, C1-C4, C1-C5, C2-C3, or C2-C4alkyl groups, and the like; for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-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-ethylbutyl, 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 isomers thereof; preferably C1-C6alkyl; more preferably C1-C4alkyl. The alkyl group can be substituted or unsubstituted. In some embodiments, the alkyl group is a C1, C2, C3, C4, C5, C6, C7, or C8alkyl group.

[0540] "Heteroalkyl" refers to saturated aliphatic hydrocarbon groups in which a methylene (-CH2-) is replaced with a heteroatom (such as O, S, N), a heteroatomic group (such as -C(O)-, -S(O)-, -S(O)2-, -C(O)O-, -OC(O)-), C(O)NH-, -NHC(O)-, vinylene, or acetylene; including straight chain or branched chain heteroalkyl groups; C1-C8heteroalkyl refers to alkyl groups containing from 1 to 8 carbon atoms in which at least one methylene is replaced with a heteroatom or heteroatomic group, for example, -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.

[0541] Unless otherwise specified, the number of atoms in a ring is typically defined by the number of members of the ring, e.g., "5-7 membered ring" means a "ring" that has 5-7 atoms arranged around the ring.

[0542] Unless otherwise specified, C n-n+m or C n -C n+m including any one specific instance of n to n+m carbons, e.g., C 1-12 including C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 , C 11 , and C 12 also including any one range of n to n+m, e.g., C 1-12 including C 1-3 , C 1-6 , C 1-9 , C 3-6 , C 3-9 , C 3-12 , C 6-9 , C 6-12 , and C 9-12 etc.; by analogy, n-membered to n+m-membered means the number of atoms in a ring is n to n+m, e.g., 3-12 membered ring includes 3 membered, 4 membered, 5 membered, 6 membered, 7 membered, 8 membered, 9 membered, 10 membered, 11 membered, and 12 membered rings, also including any one range of n to n+m, e.g., 3-12 membered ring includes 3-6 membered, 3-9 membered, 5-6 membered, 5-7 membered, 6-7 membered, 6-8 membered, and 6-10 membered rings, etc.

[0543] "Cycloalkyl" means a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent; "C3-C 11 Cycloalkyl" means a cycloalkyl group including 3 to 11 carbon atoms, said C3-C 11 Cycloalkyl includes C3-C 11 , C3-C 10 , C3-C8, C4-C 11 , C4-C 10 , C4-C8, C4-C7, C4-C6or C4-C5etc.; "C3-C8membered cycloalkyl" means a cycloalkyl group including 3 to 8 carbon atoms, said C3-C8cycloalkyl group including C3-C8, C3-C6, C3-C5, C4-C8, C4-C7, C4-C6or C4-C5etc.;

[0544] Non-limiting examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like, preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; preferably C3-C8membered cycloalkyl; more preferably C3-C6membered cycloalkyl.

[0545] Polycyclic cycloalkyl groups include spirocyclic, fused, and bridged cycloalkyl groups. "Spirocycloalkyl" refers to polycyclic groups in which single rings share one carbon atom (referred to as a spiro atom) between rings, which can contain one or more double bonds, but no ring has a fully conjugated pi-electron system. Spirocycloalkyl groups can be classified as monospirocycloalkyl, dispirocycloalkyl, or polyspirocycloalkyl groups, preferably 7-12 membered dispirocycloalkyl groups, according to the number of spiro atoms shared between rings. Non-limiting examples of spirocycloalkyl groups include:

[0546] and the like.

[0547] "Fused cycloalkyl" refers to all-carbon polycyclic groups in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, in which one or more rings can contain one or more double bonds, but no ring has a fully conjugated pi-electron system. Fused cycloalkyl groups can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic, preferably bicyclic fused cycloalkyl groups, according to the number of rings comprising the group. Non-limiting examples of fused cycloalkyl groups include:

[0548] and the like.

[0549] "Bridged cycloalkyl" refers to all-carbon polycyclic groups in which any two rings share two non-adjacent carbon atoms, which can contain one or more double bonds, but no ring has a fully conjugated pi-electron system, and can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic, according to the number of rings comprising the group. Non-limiting examples of bridged cycloalkyl groups include:

[0550] and the like.

[0551] The cycloalkyl ring can be fused to an aryl, heteroaryl, or heterocycloalkyl ring, wherein the ring attached to the parent structure is a cycloalkyl, non-limiting examples include indanyl, tetrahydronaphthyl, benzocycloheptyl, and the like. The cycloalkyl group can be optionally substituted or unsubstituted.

[0552] In some embodiments, the cycloalkyl group is a C3, C4, C5, C6, C7, C8, C9, C 10 , C 11 , C 12 monocyclic or polycyclic (e.g., spirocyclic, fused, or bridged) cycloalkyl group.

[0553] "Cycloalkyl" refers to a saturated or partially unsaturated cyclic hydrocarbon substituent.

[0554] "Heterocycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic ring-containing cyclic 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 (wherein r is an integer of 0, 1, or 2), but excluding rings containing -O-O-, -O-S-, or -S-S- moieties, the remaining ring atoms being carbon, wherein the nitrogen atoms are optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O)p, p being 1 or 2). "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. Preferably, the "3-11 membered heterocycloalkyl" contains 1-2 heteroatoms selected from N, O, or S. More preferably, the 3-11 membered heterocycloalkyl contains 1 or 2 N atoms. For example, 3-10 membered heterocycloalkyl includes 3-8 membered, 3-6 membered, 3-5 membered, 4-6 membered, 5-6 membered, 4 membered, 5 membered, and 6 membered heterocycloalkyl, and the like. Examples of 3-10 membered heterocycloalkyl include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, and the like), tetrahydrofuranyl (including tetrahydrofuran-2-yl, and the like), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl, and 3-piperidinyl, and the like), piperazinyl (including 1-piperazinyl and 2-piperazinyl, and the like), morpholinyl (including 3-morpholinyl and 4-morpholinyl, and the like), dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiazinyl, hexahydropyridazinyl, homopiperazinyl, homopiperidinyl, dioxepanyl, and the like.

[0555] Monocyclic heterocycloalkyl is preferably 3-8 membered monocyclic heterocycloalkyl containing 1-2 N heteroatoms; non-limiting examples of monocyclic heterocycloalkyl include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like, preferably piperidinyl and piperazinyl.

[0556] Polycyclic heterocycloalkyl includes spirocyclic, fused, and bridged heterocycloalkyl groups. "Spiroheterocycloalkyl" refers to a polycyclic heterocycloalkyl group in which the single rings share a common atom (referred to as a spiro atom), in which one or more ring atoms are 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 completely conjugated pi-electron system. Spiroheterocycloalkyls are classified as mono-, bi- or polyspiroheterocycloalkyls depending on the number of spiro atoms shared between rings, preferably "3-11 membered biheterocycloalkyls" containing 1-2 heteroatoms selected from N, O or S; more preferably "7-11 membered biheterocycloalkyls" containing 1 or 2 N atoms. Non-limiting examples of spiroheterocycloalkyls include:

[0557] and the like.

[0558] "Fused heterocycloalkyl" refers to a polycyclic heterocycloalkyl group in which each ring in the system shares an adjacent pair of atoms with other rings in the system, one or more rings can contain one or more double bonds but no ring has a completely conjugated pi-electron system, wherein one or more ring atoms are 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 completely conjugated pi-electron system. Fused heterocycloalkyls are classified as bicyclic, tricyclic, tetracyclic or polycyclic depending on the number of rings comprising the ring system, preferably "3-11 membered bicyclic fused heterocycloalkyls" containing 1-3 heteroatoms selected from N, O or S; more preferably "3-11 membered bicyclic fused heterocycloalkyls" containing 1 or 2 N atoms. Non-limiting examples of fused heterocycloalkyls include:

[0559] and the like.

[0560] "Bridged heterocycloalkyl" refers to a polycyclic heterocycloalkyl group in which any two rings share two non-adjacent atoms, they can contain one or more double bonds but no ring has a completely conjugated pi-electron system, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O) r (wherein r is an integer 0, 1, 2) and the remaining ring atoms are carbon. Bridged heterocycloalkyls are classified as bicyclic, tricyclic, tetracyclic or polycyclic depending on the number of rings comprising the ring system, non-limiting examples of bridged heterocycloalkyls include:

[0561] and the like.

[0562] 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:

[0563] , 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).

[0564] "Heterocycloalkyl" refers to a saturated or unsaturated ring radical of up to 10 carbon atoms which contains one or more heteroatoms, e.g., 1, 2, 3, 4, or 5 heteroatoms, each heteroatom independently being nitrogen, oxygen, or S(O)

[0565] "Aryl" refers to a carbocyclic, monocyclic or fused polycyclic (i.e., sharing pairs of adjacent carbon atoms of the rings) ring radical 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 the aryl ring, non-limiting examples include:

[0566] , the aryl group can be optionally substituted or unsubstituted. In some embodiments, the aryl group is a 6-10 membered aryl group.

[0567] "Heteroaryl" refers to a heteroaromatic system comprising 1 to 4 heteroatoms, the heteroatoms comprising nitrogen, oxygen, or S(O) r (wherein r is an integer of 0, 1, 2), 5-6 membered heteroaryl refers to a heteroaromatic system containing 5-6 ring atoms, 5-10 membered heteroaryl refers to a heteroaromatic 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, and the like; 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 the heteroaryl ring, non-limiting examples include:

[0568] , 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 group, wherein the number of heteroatoms can be 1, 2, 3, 4, or 5, each heteroatom independently being nitrogen, oxygen, or S.

[0569] "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, 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, C8 alkenyl group.

[0570] "Alkynyl" refers to an alkyl group as defined above containing at least two carbon atoms and at least one carbon-carbon triple bond, "C 2-8 "Alkynyl" refers to a straight or branched chain alkynyl group containing 2-8 carbons, 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 "Alkynyl". The alkynyl group can be substituted or unsubstituted. In some embodiments, the alkynyl group is a C2, C3, C4, C5, C6, C7, C8 alkynyl group.

[0571] "Alkyl" refers to a straight or branched chain alkyl group containing 1-8 carbons, including but not limited to methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like.

[0572] "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.

[0573] "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.

[0574] "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.

[0575] "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.

[0576] "Heteroaralkyloxy" means a group of the formula -O-heteroarylalkyl wherein the heteroarylalkyl is as defined herein. Non-limiting examples include pyridylalkyloxy, thienylalkyloxy, and the like.

[0577] "one or more" as used herein means one or more than one, e.g., two, three, four, five, six, seven, eight, nine, or ten, under reasonable conditions.

[0578] Unless otherwise specified, as used herein, the point of attachment of a substituent can be from any suitable position on the substituent, unless specified otherwise.

[0579] Also included within the scope of the application are metabolites of the compounds of the application, i.e., substances produced through metabolism of a compound of the application in the body. Such products can result, for example, from the oxidation, reduction, hydrolysis, amidation, deamidation, esterification, enzymatic cleavage, and the like, of the administered compound. Accordingly, metabolites of the compounds of the application, including those produced by the in vivo conversion of a compound of the application, are within the scope of the application.

[0580] 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 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 species. Typically such prodrugs will be functional derivatives of the compounds of the application, which are easily converted to the desired therapeutic agent in vivo.

[0581] "Cyano" means -CN.

[0582] "Hydroxy" means -OH.

[0583] "Sulfonyl" means -S(O)2-.

[0584] "Carboxyl" or "carboxylic acid" means -COOH.

[0585] "Oxo" means a =O group.

[0586] "Halo" means fluorine, chlorine, bromine, or iodine.

[0587] "EA or EtOAc" means ethyl acetate.

[0588] "THF" means tetrahydrofuran.

[0589] "DCM" means dichloromethane.

[0590] "cataCXium A Pd-G3" means [n-Bu2(1-adamantyl)phosphine](2-amino-1,1'- biphenyl-2-yl)palladium(II) methanesulfonate.

[0591] "POCl3" means phosphorous oxychloride.

[0592] "NaHCO3" means sodium bicarbonate.

[0593] "NaCl" means sodium chloride.

[0594] "Grubbs II" means 1,3-bis(2,4,6-trimethylphenyl)-2-(imidazolidinylidene)(dichlorobenzylidene)(tricyclohexylphosphine)ruthenium.

[0595] "Na2SO4" means sodium sulfate.

[0596] "NH4Cl" means ammonium chloride.

[0597] "Cs2CO3" means cesium carbonate.

[0598] "NaBH(OAc)3" means sodium borohydride acetate.

[0599] "Triton B" means benzyltrimethylammonium hydroxide.

[0600] "NaBH3CN" means sodium cyanoborohydride

[0601] "CsF" means cesium fluoride.

[0602] "Na2CO3" means sodium carbonate.

[0603] "HOAc" means acetic acid.

[0604] "TPAP" means tetrapropylammonium perruthenate.

[0605] "NMO" means N-methylmorpholine oxide.

[0606] "Cs2CO3" means cesium carbonate.

[0607] "NaH" means sodium hydride.

[0608] "i-PrOH" means isopropyl alcohol.

[0609] "DMF" means N,N-dimethylformamide.

[0610] "MeOH" means methanol.

[0611] "Pd / C" means palladium on carbon.

[0612] "DMSO" means dimethylsulfoxide.

[0613] "TFA" means trifluoroacetic acid.

[0614] "DIEA" means N,N-diisopropylethylamine.

[0615] "Dess-Martin" refers to Dess-Martin reagent.

[0616] "PBS" refers to phosphate buffered saline solution.

[0617] "SDS-PAGE" refers to sodium dodecyl sulfate-polyacrylamide gel electrophoresis.

[0618] "PVDF" refers to polyvinylidene fluoride.

[0619] "PE" refers to petroleum ether.

[0620] "AcOH" refers to acetic acid.

[0621] "HCl" refers to hydrochloric acid.

[0622] "NH3" refers to aqueous ammonia.

[0623] "EDCI" refers to 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride.

[0624] "HOBT" refers to 1-hydroxybenzotriazole.

[0625] "HMPA" refers to hexamethylphosphoric triamide.

[0626] "Pd(dppf)Cl2" refers to [1,1'-bis(diphenylphosphino)ferrocene] palladium(II) dichloride.

[0627] "LAH" refers to lithium aluminum hydride.

[0628] "Prep-HPLC" refers to preparative high performance liquid chromatography.

[0629] "sat." refers to saturated solution.

[0630] "aq" refers to aqueous solution.

[0631] In the chemical structures herein, "-" as a bond means single bond, and "=" means double bond (in the case of no limitation of configuration, it can be trans or cis).

[0632] In the present invention, the expression -N( group) 1-2 means -NH( group) or -N( group)2.

[0633] "Optional" means that the event or circumstance subsequently described can or can not occur, and the description includes the situation in which the event or circumstance occurs and the situation in which it does not occur. For example, "heterocycloalkyl group optionally substituted with alkyl" means that alkyl can or can not be present, and the description includes the case in which the heterocycloalkyl group is substituted with alkyl and the case in which the heterocycloalkyl group is not substituted with alkyl.

[0634] "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 by a corresponding number of substituents. It is understood that substituents are only in their possible chemical positions, which can be determined (experimentally or theoretically) by a person skilled in the art without undue effort, as possible or impossible. For example, an amino or hydroxy group with a free hydrogen can be unstable when bound to a carbon atom with an unsaturated (e.g. olefinic) bond.

[0635] 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, hydroxy, hydroxyalkyl, haloalkyl, alkoxy, amino, aminoalkyl, cyano, halogen, oxo, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, said alkyl, alkenyl, alkynyl, hydroxy, 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, hydroxy, hydroxyalkyl, haloalkyl, alkoxy, amino, aminoalkyl, cyano, halogen, oxo.

[0636] 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 in the present text, it is intended to designate the corresponding commercial product or its active ingredient.

[0637] 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 in the present text, it is intended to designate the corresponding commercial product or its active ingredient.

[0638] "Pharmaceutical composition" means a mixture containing one or more of the compounds described herein or a physiologically / pharmaceutically acceptable salt or prodrug thereof, in combination with other chemical components, such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration of the active ingredient to a subject, to enhance delivery of the active ingredient into or through the subject, and to facilitate or enable the active ingredient to exert its biological activity.

[0639] The present application also provides pharmaceutically acceptable salts of the compounds of Formula I or 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 or 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, laurate, borate, benzoate, lactate, phosphate, bicarbonate, carbonate, p-toluenesulfonate, citrate, maleate, fumarate, succinate, benzoate, mesylate, p-toluenesulfonylate, gluconate, lactobionate, and laurylsulfonylate salts, and the like. The base salts are prepared from a compound of Formula I or I' by reaction with a suitable inorganic or organic base following art-known procedures. Representative bases include alkali metal, alkaline earth metal, quaternary ammonium cations, and the like. Representative alkali and alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further representative salts include ammonium, quaternary ammonium, and amine salts, such as methylamine salts, dimethylamine salts, trimethylamine salts, ethylamine salts, and the like.

[0640] 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.

[0641] The "pharmaceutically acceptable excipient" means an inert substance used to facilitate administration of an active ingredient to an individual, and includes, without limitation, any of the following: a binder, an excipient, a diluent, a preservative, a dye / colorant, a flavor enhancer, a surface active or wetting agent, a dispersing agent, 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 (e.g., domestic animals).

[0642] 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.

[0643] 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.

[0644] 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:

[0645] (i) inhibiting the disease or condition, i.e., arresting its development;

[0646] (ii) relieving the disease or condition, i.e., causing regression of the disease or condition.

[0647] 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.

[0648] 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.

[0649] 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.

[0650] The term "isomer" is intended to encompass geometric isomers, cis and trans isomers, stereoisomers, enantiomeric isomers, optical isomers, diastereomeric isomers, and tautomers, unless otherwise indicated.

[0651] 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, diastereomeric mixtures, (D)- isomers, (L)-isomers, as well as racemic mixtures and other mixtures thereof, and includes any and all tautomers, which possess the same basic chemical structure but differ in the arrangement of atoms. Additional asymmetric carbon atoms can be present in a substituent group. All such isomers, as well as mixtures thereof, are intended to be included in this application.

[0652] The term "enantiomeric isomers" or "optical isomers" means stereoisomers which are mirror images of one another.

[0653] The term "cis-trans isomers" or "geometric isomers" means stereoisomers which differ in the orientation of substituents around a carbon-carbon single bond or a ring atom, as a result of which they are not superimposable on one another.

[0654] The term "diastereomeric isomers" means stereoisomers which have two or more chiral centers and are not mirror images of one another.

[0655] "(+)" means dextrorotary, "(-)" means levorotary, and "(±)" means racemic, unless otherwise indicated.

[0656] 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.

[0657] When any variable (e.g., R) occurs more than one time in a compound, each definition is independent. Thus, if a group is substituted with 0-2 R, it can be optionally substituted with up to two R groups, and at each occurrence R is selected independently. Also, combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0658] When the number of linking groups is 0, such as -(CRR)0-, it indicates that the linking group is a single bond.

[0659] When one of the variables is selected from a single bond, it indicates that the two groups to which it is attached are directly connected, such as when L represents a single bond in A-L-Z, it indicates that the structure is actually A-Z.

[0660] When a substituent is null, it indicates that the substituent is absent, such as when X is null in A-X, it indicates that the structure is actually A. When a recited substituent does not specify through which of the available atoms of the group it is connected to the rest of the molecule, it can be bonded through any of the available atoms, for example, a pyridyl group as a substituent can be bonded to the rest of the molecule through any of the carbon atoms of the pyridyl ring.

[0661] 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-, it can be attached to ring A and ring B to form either A-M-W-B or B-M-W-A. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0662] Unless otherwise specified, when a group has one or more substituents, one or more of the group's substituents can be attached to the rest of the molecule through a chemical bond. When the chemical bond is not specified, and the available site has an H atom, the number of H atoms at the site will correspondingly decrease by the number of chemical bonds formed. The chemical bond by which the site is attached to the rest of the molecule can be represented by a straight, solid line a straight, dashed line or a wavy line. For example, the straight, solid line in -OCH2CH3indicates that the group is attached to the rest of the molecule through the oxygen atom in the group; the straight, dashed line in -SCH2CH3indicates that the group is attached to the rest of the molecule through both ends of the sulfur atom in the group; and the wavy line in -C6H4-1,2indicates that the group is attached to the rest of the molecule through the 1 and 2 carbon atoms in the phenyl group. represents that any connectable site on the pyrrolidinyl group can be connected to other groups by one chemical bond, at least including The three connections, even if H atoms are drawn on the -N-, but still include groups of this connection, only when connected by one chemical bond, the H at this site will correspondingly decrease by one to become the corresponding monovalent pyrrolidinyl group.

[0663] Unless otherwise specified, a wedge-shaped solid line bond and a wedge-shaped dashed line bond represent the absolute configuration of a stereocenter, a straight solid line bond and a straight dashed line bond represent the relative configuration of a stereocenter, a wavy line represents a wedge-shaped solid line bond or a wedge-shaped dashed line bond or a wavy line represents a straight solid line bond or a straight dashed line bond as represents represents represents

[0664] Unless otherwise specified, a wedge-shaped solid line bond and a wedge-shaped dashed line bond represent the absolute configuration of a stereocenter, a straight solid line bond and a straight dashed line bond represent the relative configuration of a stereocenter, a wavy line represents a wedge-shaped solid line bond or a wedge-shaped dashed line bond or a wavy line represents a straight solid line bond or a straight dashed line bond.

[0665] Unless otherwise specified, when there is a double bond structure, such as a carbon-carbon double bond, a carbon-nitrogen double bond, and a nitrogen-nitrogen double bond, in a compound, and each atom on the double bond is connected to two different substituents (in a double bond containing a nitrogen atom, a pair of lone pair electrons on the nitrogen atom is considered as one substituent connected to it), if the atoms on the double bond in the compound are connected to their substituents by a wavy line , it represents the (Z) isomer, the (E) isomer of the compound. For example, the following formula (A) represents that the compound exists in the form of a single isomer of formula (A-1) or formula (A-2), or exists in the form of a mixture of two isomers of formula (A-1) and formula (A-2); the following formula (B) represents that the compound exists in the form of a single isomer of formula (B-1) or formula (B-2), or exists in the form of a mixture of two isomers of formula (B-1) and formula (B-2). The following formula (C) represents that the compound exists in the form of a single isomer of formula (C-1) or formula (C-2), or exists in the form of a mixture of two isomers of formula (C-1) and formula (C-2).

[0666] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. As used herein, the following terms have the following meanings. The hydrogen atoms at any of the available positions of a group designated

[0667] 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 that 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%.

[0668] Unless otherwise indicated, the term "excess of isomer" or "excess of enantiomer" means the difference between the relative percentages of the two isomers or the two enantiomers. For example, where one isomer or enantiomer is present in 90% and the other isomer or enantiomer is present in 10%, the excess of isomer or enantiomer (the ee value) is 80%.

[0669] Optically active (R)- and (S)-isomers and D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the application is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting mixture of diastereomers is separated and the auxiliary group cleaved to provide the pure desired enantiomer. Alternatively, when a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group) is present in the molecule, a diastereomeric salt form of the 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 often accomplished by the use of chromatography with a chiral stationary phase, optionally in combination with chemical derivatization (e.g., formation of a carbamate from an amine).

[0670] The compounds of the application can contain unnatural proportions of atomic isotopes at one or more of the atoms in a compound. For example, the compounds can be radiolabeled with radioactive isotopes such as tritium ( 125 I) or C-14 ( 14C). For example, deuterium can be substituted for hydrogen to form deuterated drugs, which have advantages over non-deuterated drugs, such as reduced toxicity, increased drug stability, increased efficacy, increased drug biohalf-life, etc. All isotopic variations of the compounds of the present application, whether radioactive or not, are included within the scope of the present application.

[0671] Unless otherwise indicated, D as used herein means deuterium. 2 H).

[0672] Unless otherwise indicated, the term "leaving group" refers to a functional group or atom that 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, tosylate, and the like; acyloxy groups such as acetoxy, trifluoroacetoxy, and the like.

[0673] The term "optionally substituted" means that the group in question can or can not be substituted and that the nature and number of substituents, when present, are optional and can be any that are chemically feasible.

[0674] Unless otherwise indicated, the term "protecting group" includes, but is not limited to, an "amino-protecting group," a "hydroxy-protecting group," or a "thiol-protecting group." The term "amino-protecting group" refers to a protecting group suitable for blocking the amino nitrogen against unwanted 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-di-(4'-methoxyphenyl)methyl; silyl groups, such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS), and the like. The term "hydroxy-protecting group" refers to a protecting group suitable for blocking the hydroxyl group against unwanted reactions. Representative hydroxy-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.

[0675] The compounds of the present application can be prepared by a variety of synthetic methods 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 known to those skilled in the art, preferred embodiments including, but not limited to, the examples of the present application.

[0676] The compounds of the present application can be confirmed by conventional methods known to those skilled in the art, and if the present application relates to the absolute configuration of the compounds, the absolute configuration can be confirmed by conventional means in the art. For example, single crystal X-ray diffraction method (SXRD), the single crystal grown is collected by a Bruker D8 venture diffractometer to collect diffraction intensity data, light source is Cu Kα radiation, scanning mode: scanning, after collecting relevant data, further using direct method (Shelxs97) to analyze the crystal structure, the absolute configuration can be confirmed.

[0677] The compounds of the present application or their pharmaceutically acceptable salts can be administered to mammals, including humans, orally, rectally, parenterally (intravenously, intramuscularly or subcutaneously), topically (powder, ointment or drops), or intratumorally.

[0678] The compounds of the present application can be administered in a dose of about 0.05-300 mg / kg body weight / day, preferably 10-300 mg / kg body weight / day, more preferably 10-200 mg / kg body weight / day.

[0679] The compounds of the present application or their pharmaceutically acceptable salts can be formulated into solid dosage forms for oral administration, including, but not limited to, capsules, tablets, pills, powders and granules, etc. In these solid dosage forms, the compounds of the present application or I' as active ingredients are mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (1) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, and silicic acid, etc.; (2) binders, such as hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and gum arabic, etc.; (3) humectants, such as glycerol, etc.; (4) disintegrating agents, such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates and sodium carbonate, etc.; (5) slow-release agents, such as paraffin, etc.; (6) absorption accelerators, such as quaternary ammonium compounds, etc.; (7) wetting agents, such as cetyl alcohol and glycerol monostearate, etc.; (8) adsorbents, such as kaolin, etc.; and (9) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium dodecyl sulfate, etc., or mixtures thereof. Buffering agents can also be included in the capsules, tablets and pills.

[0680] The solid dosage forms such as tablets, sugar-coated tablets, capsules, pills and granules can be coated with or microencapsulated with coating and shell materials such as enteric coatings and other known in the art. They can contain opacifying agents and can be of a composition that they release the active ingredient(s) in a certain part of the digestive 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.

[0681] The compounds of the present application or their pharmaceutically acceptable salts can be formulated into liquid dosage forms for oral administration including, but not limited to, pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs, etc. In addition to the compounds of Formula I or I' or their pharmaceutically acceptable salts as the active ingredient, the liquid dosage forms can contain inert diluents commonly used in the art such as water and other solvents, solubilizing agents and emulsifiers, as for example ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide, and the like, or mixtures thereof, etc. The liquid dosage forms can also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents, etc.

[0682] The suspending agents include, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan, microcrystalline cellulose, aluminum metahydroxide, agar-agar, and the like or mixtures thereof.

[0683] The compounds of the present application or their pharmaceutically acceptable salts can be formulated into dosage forms for parenteral injection including, but not limited to, physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable carriers, diluents, solvents or excipients include water, ethanol, polyol and suitable mixtures thereof.

[0684] 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, etc. The compounds of the present application or their pharmaceutically acceptable salts as the active ingredient are mixed with a sterile, physiologically acceptable carrier and optionally an adjuvant, a buffer, or a propellant, if necessary.

[0685] The present application also provides pharmaceutical compositions containing the compounds of Formula I or I' or their pharmaceutically acceptable salts as the active ingredient, and a pharmaceutically acceptable carrier, excipient or diluent. In making the pharmaceutical compositions of the present application, the compounds of Formula I or I' or their pharmaceutically acceptable salts are typically mixed with a pharmaceutically acceptable carrier, excipient or diluent.

[0686] The compositions of the present application can be formulated in a conventional manner using routine methods, for example, as tablets, pills, capsules, powders, granules, emulsions, suspensions, dispersions, solutions, syrups, elixirs, ointments, drops, suppositories, inhalers, sprays, etc.

[0687] The compounds of the present application, or pharmaceutically acceptable salts thereof, 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 include not only the use of compounds of the present application with one other active agent, but also with two or more other active agents.

[0688] In the present application, other pharmaceutically acceptable therapeutic agents that can be used together or in combination with the pan-KRAS degrader compound of formula I or 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.

[0689] In the present application, other pharmaceutically acceptable therapeutic agents that can be used together or in combination with the pan-KRAS degrader compound of formula I or 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).

[0690] On the basis of common general knowledge in the art, the above-mentioned preferred conditions can be combined arbitrarily, i.e. to obtain preferred embodiments of the present application.

[0691] The reagents and starting materials used in the present application are commercially available.

[0692] The compounds are named according to the principles of nomenclature conventionally used in the art or For commercially available compounds, the name of the supplier's catalogue can also be used.

[0693] The present application is demonstrated by KRAS G12C, KRAS G12D or KRAS G12V protein binding activity test experiment that the compound of formula I or I' described in the present application can effectively bind to pan-KRAS target protein to produce inhibition of downstream pathway effect, and Western-Blot proves that the compound of formula I or I' described in the present application can effectively degrade KRAS G12C protein in NCI-H358 cells, KRAS G12D protein in A427 cells, KRAS G12D protein in AsPc-1 cells, KRAS G12V protein in SW900 cells, KRAS G12V protein in SW620 cells, KRAS13D protein in DLD-1 cells, KRAS WT(amplification) protein in MKN1 cells. The compound of formula I or I' described in the present application, and / or its stereoisomers, enantiomers, diastereomers, deuterated compounds, hydrates, solvates, metabolites, prodrugs and / or pharmaceutically acceptable salts thereof can effectively degrade KRAS G12C, KRAS G12D, KRAS G12V, KRAS G13D, KRAS WT(amplification) protein, KRAS G12V, KRAS G12D and KRAS G12C protein, so as to achieve the effect of preventing or treating diseases or disorders caused by KRAS G13D, KRAS WT(amplification) protein, KRAS G12V, KRAS G12D and KRAS G12C various mutations. DETAILED DESCRIPTION

[0694] The application will be further described in detail below with reference to the examples, but the application is by no means limited to the examples, nor is the application only limited to the contents of the examples. The starting materials in the examples of the application are known and commercially available, or can be synthesized by using or following the methods known in the art. Unless otherwise specified, the experimental methods in the examples of the application not specified with specific conditions are generally carried out according to the conventional conditions, or according to the conditions suggested by the manufacturers of the materials or commodities.

[0695] Preparation examples of compound I

[0696] Intermediate 1: Intermediate 1-P1 and Intermediate 1-P2

[0697] Step 1: Preparation of tert-butyl 4-allyl-4-((2-(methoxycarbonyl)allyl)oxy)piperidine-1-carboxylate

[0698] 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 carried out at room temperature for 1 h, then cooled to 0 °C, and 2-(bromomethyl) methyl acrylate (6.68 g, 37.29 mmol) was added, and the reaction was carried out at room temperature for 72 h. After the reaction was completed, NH4Cl (200 mL) was added, and extraction was carried out with ethyl acetate (200 mL x 3). The combined organic phases were 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 obtain tert-butyl 4-allyl-4-((2-(methoxycarbonyl)allyl)oxy)piperidine-1-carboxylate.

[0699] LC-MS: (ESI, m / z): [M+Na] + = 362.2

[0700] Step 2: Preparation of tert-butyl 9-(tert-butyl) 3-methyl 1-oxa-9-azaspiro[5.5]undecane-3,9- dicarboxylate

[0701] Tert-butyl 4-allyl-4-((2-(methoxycarbonyl)allyl)oxy)piperidine-1-carboxylate (3.0 g, 8.84 mmol) was dissolved in DCE (700 mL), and Grubbs II catalyst (229 mg, 0.27 mmol) was added, and the reaction was carried out at 90 °C for 16 h. The reaction solution was cooled to room temperature, filtered, the filtrate was concentrated, and the obtained crude product was purified by silica gel column chromatography (PE:EA = 5:1) to obtain tert-butyl 9-(tert-butyl) 3-methyl 1-oxa-9-azaspiro[5.5]undecane-3,9-dicarboxylate.

[0702] LC-MS: (ESI, m / z): [M+Na] + = 334.2

[0703] Step 3: Preparation of 9-(tert-butyl) 3-methyl 1-oxo-9-azaspiro[5.5]undecane-3,9- dicarboxylate

[0704] To a solution of 9-(tert-butyl) 3-methyl 1-oxo-9-azaspiro[5.5]undec-3-ene-3,9- dicarboxylate (1.3 g, 4.17 mmol) in EtOH (20 mL) was added Pd(OH)2(586 mg, 4.17 mmol) and 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-oxo-9-azaspiro[5.5]undecane-3,9-dicarboxylate.

[0705] Step 4: Preparation of 1-oxo-9-azaspiro[5.5]undecane-3-carboxylic acid methyl ester

[0706] To a solution of 9-(tert-butyl) 3-methyl 1-oxo-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 1-oxo-9-azaspiro[5.5]undecane-3-carboxylic acid methyl ester. It was used directly in the next step.

[0707] LC-MS: (ESI, m / z): [M+H] + = 214.1.

[0708] Step 5: Preparation of 9-benzyl-1-oxo-9-azaspiro[5.5]undecane-3-carboxylic acid methyl ester

[0709] 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 triacetylboration hydride (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 mixture of petroleum ether / dichloromethane (10 / 1, 200 mL), filtered, and dried to give methyl 9-benzyl-1-oxo-9-azaspiro[5.5]undecane-3-carboxylate.

[0710] LC-MS: (ESI, m / z): [M+H] + = 304.3.

[0711] Step 6: Preparation of (9-benzyl-1-oxo-9-azaspiro[5.5]undecan-3-yl)methanol

[0712] To a solution of methyl 9-benzyl-1-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-1-oxo-9-azaspiro[5.5]undecan-3-yl)methanol.

[0713] LC-MS: (ESI, m / z): [M+H] + = 276.2.

[0714] Step 7: Preparation of 9-benzyl-1-oxo-9-azaspiro[5.5]undecane-3-carbaldehyde

[0715] Dess-Martin periodinane (22.507 g, 53.06 mmol) was added to a solution of (9-benzyl-1-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-1-oxo-9-azaspiro[5.5]undecan-3- carboxaldehyde.

[0716] LC-MS: (ESI, m / z): [M+H] + = 274.2.

[0717] Step 8: Preparation of Intermediate 1-P1 and Intermediate 1-P2 and

[0718] To a solution of 9-benzyl-1-oxo-9-azaspiro[5.5]undecan-3-carboxaldehyde (9.641 g, 35.14 mmol) in dichloromethane (180 mL) was added 1-piperazine tert-butyl carboxylate (9.870 g, 52.71 mmol). After the reaction was carried out at room temperature for 2 h, sodium triacetylborohydride (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 4-((9-benzyl-1-oxo-9-azaspiro[5.5]undecan-3-yl)methyl)piperazine-1-carboxylic acid tert-butyl ester. The obtained compound was purified and separated by SFC with the following method: Column: Daicel chiralpak IG, 30*250mm, 10μm; Mobile phase: CO2 / MeOH (0.2% NH3(7M Solution in MeOH)); Gradient: 65 / 35, 6min; Flow rate: 100 mL / min; Wavelength: 214nm; Column temperature: 35℃.

[0719] Intermediate 1-P1 (retention time: 2.513 min). SFC analysis method (column: Daicel chiralpak AD_3, 3*150mm, 3μm; mobile phase: CO2 / MeOH (0.1% DEA); gradient: 70 / 30, 6min; flow rate: 2.0 mL / min; wavelength: 214nm; column temperature: 37℃; optical purity: 100%.

[0720] 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).

[0721] LC-MS: (ESI, m / z): [M+H] + = 444.3.

[0722] Intermediate 1-P2 (ret. time: 3.171 min). SFC analysis 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%.

[0723] 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).

[0724] LC-MS: (ESI, m / z): [M+H] + = 444.3.

[0725] Intermediate 2: Intermediate 2-P1 and Intermediate 2-P2

[0726] To a solution of 4-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-6-methyl- 1,4-oxazepan-6-ol (1.5 g, 4.32 mmol) and cyclopropane-1,1-dimethyl dimethanol (882 mg, 8.64 mmol) in anhydrous acetonitrile (15 mL), triethylenediamine (97 mg, 0.86 mmol) and anhydrous cesium carbonate (4.22 g, 12.96 mmol) were added, and stirred at 25 °C for 2 hours. After the reaction was completed, saturated brine (30 mL) was added, and extracted with ethyl acetate (30 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (DCM:MeOH = 20:1) to obtain 4-(7-chloro-8-fluoro-2-((1- (hydroxymethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4- oxazepan-6-ol. Method: Column: Daicel chiralpak IE_3,3*150mm,3μm; Mobile phase: CO2 / MeOH(0.1%DEA); Gradient: 55 / 45,6min; Flow rate: 1.5mL / min; Wavelength: 214nm; Column temperature: 37°C.

[0727] Intermediate 2-P1 (retention time: 2.267 min). SFC analysis method (column: Daicel chiralpak AD_3,3*150mm,3μm; mobile phase: CO2 / MeOH(0.1%DEA); gradient: 70 / 30,6min; flow rate: 1.5mL / min; wavelength: 214nm; column temperature: 37°C; optical purity: 100%.

[0728] Intermediate 2-P2 (retention time: 2.752 min). SFC analysis method (column: Daicel chiralpak AD_3,3*150mm,3μm; mobile phase: CO2 / MeOH(0.1%DEA); gradient: 70 / 30,6min; flow rate: 1.5mL / min; wavelength: 214nm; column temperature: 37°C; optical purity: 100%.

[0729] Intermediate 3: Intermediate 3-P1 and Intermediate 3-P2

[0730] To a solution of 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (898 mg, 3.56 mmol) in anhydrous dichloromethane (50 mL) was added triethylamine (1080 mg, 10.68 mmol) and 1,6-diazaspiro[3.5]nonan-2-one (474 mg, 3.38 mmol) at -50 °C, and stirred at -50 °C for 5 hours. After the reaction was completed, poured into water (200 mL), extracted with ethyl acetate (100 mL x 2), the combined organic phase was washed with saturated sodium chloride (100 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. 6-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-1,6-diazaspiro[3.5]nonan-2-one was obtained. Method: Column: Daicel chiralpak OJ 3,3*150mm,3μm; Mobile phase: CO2 / MeOH; Gradient: 60 / 40,6min; Flow rate: 1.5mL / min; Wavelength: 214nm; Column temperature: 37°C.

[0731] Intermediate 3-P1 (retention time: 2.024 min). SFC analysis method (column: Daicel chiralpak OJ 3,3*150mm,3μm; Mobile phase: CO2 / MeOH; Gradient: 60 / 40,6min; Flow rate: 1.5mL / min; Wavelength: 214nm; Column temperature: 37°C; Optical purity: 100%.

[0732] Intermediate 3-P2 (retention time: 2.725 min). SFC analysis method (column: Daicel chiralpak OJ 3,3*150mm,3μm; Mobile phase: CO2 / MeOH; Gradient: 60 / 40,6min; Flow rate: 1.5mL / min; Wavelength: 214nm; Column temperature: 37°C; Optical purity: 100%.

[0733] LC-MS: (ESI, m / z): [M+H] + = 356.0.

[0734] Intermediate 4: Intermediate 4-P1 and Intermediate 4-P2

[0735] Step 1: Preparation of 1-benzyl-3-ethylpiperidin-3-ol

[0736] Dissolve 1-benzylpiperidin-3-one (3.0 g, 15.8 mmol) in THF (20 mL), add ethyl magnesium bromide (24 mL, 1M in THF) to the mixture at -10 °C, stir the mixture at -10 °C for 4 hours. After the reaction is completed, pour the reaction into aqueous NH4Cl solution (30 mL) and extract with ethyl acetate (30 mL x 3). Combine the organic phase, dry over anhydrous Na2SO4, filter, concentrate the filtrate, and purify the resulting crude product by silica gel column chromatography (PE:EtOAc = 10:1) to give 1-benzyl-3-ethylpiperidin-3-ol.

[0737] LC-MS: (ESI, m / z): [M+H] = 220.1. +

[0738] Step 2: Preparation of 3-ethylpiperidin-3-ol

[0739] Dissolve 1-benzyl-3-ethylpiperidin-3-ol (1.5 g, 6.84 mmol) in MeOH (15 mL), add Pd / C (800 mg) with stirring. Replace the reaction with hydrogen gas three times, then react under hydrogen gas for 16 hours. After the reaction is completed, filter the reaction, concentrate the filtrate to give the crude product, and purify the product 3-ethylpiperidin-3-ol by silica gel column chromatography (DCM:MeOH = 8:1).

[0740] LC-MS: (ESI, m / z): [M+H] = 130.1. +

[0741] Step 3: Preparation of 1-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3- ethylpiperidin-3-ol

[0742] ​​To a solution of 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (600 mg, 2.38 mmol) and TEA (721 mg, 7.14 mmol) in THF (10 mL) was cooled to -50 °C, and a solution of 3-ethylpiperidin-3-ol (277 mg, 2.14 mmol) in THF (5 mL) was added dropwise slowly. The reaction was stirred at -50 °C for 2 h. After the reaction was completed, the reaction mixture was poured into aqueous NH4Cl solution (50 mL) and extracted with ethyl acetate (30 mL x 3). The organic phase was combined, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated. The resulting crude product was purified by silica gel column chromatography (PE:EtOAc = 3:1) to give the product 1-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-ethylpiperidin-3-ol. Method: Column: Daicel chiralcel IH, 30*250 mm, 10 µm; mobile phase: CO2 / MeOH (0.1% DEA); gradient: 75 / 25, 6 min; flow rate: 80 g / min; wavelength: 214 nm; column temperature: 35 °C.

[0743] Intermediate 4-P1 (retention time: 1.939 min). SFC analysis method (column: Daicel chiralcel IH_3, 3*150 mm, 3 µm; 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%.

[0744] Intermediate 4-P2 (retention time: 2.785 min). SFC analysis method (column: Daicel chiralcel IH_3, 3*150 mm, 3 µm; 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%.

[0745] LC-MS: (ESI, m / z): [M+H] + = 345.0.

[0746] Intermediate 5: 3-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)-3- azaspiro[5.5]undecane-9-carbaldehyde

[0747] Prepared according to WO2024083256A1, Intermediate 25.

[0748] Intermediate 6: 1-(2-methoxy-5-(9-(piperazin-1-ylmethyl)-3-azaspiro[5.5]undecane-3- carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione

[0749] Refer to WO2024083256A1 for preparation of Intermediate 6.

[0750] Intermediate 7: (S)-(1-(((7-chloro-8-fluoro-4-(1-oxo-6-azaspiro[3.5]non-6-yl)pyrido[4,3- d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methanol

[0751] Step 1: Preparation of (S)-6-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-1-oxo-6- azaspiro[3.5]nonane

[0752] To a solution of 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (700 mg, 2.77 mmol) in THF (10 mL) was added triethylamine (841 mg, 8.31 mmol) and (S)-1-oxa-6-azaspiro[3.5]nonane (317 mg, 2.49 mmol) at -50 °C, and stirring was continued at -50 °C for 5 hours. After the reaction was completed, it was poured into saturated ammonium chloride solution (20 mL), extracted with ethyl acetate (20 mL x 2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (PE:EA = 5:1) to give (S)-6-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-1-oxo-6- azaspiro[3.5]nonane.

[0753] LC-MS: (ESI, m / z): [M+H] + = 343.1.

[0754] Step 2: Preparation of (S)-(1-(((7-chloro-8-fluoro-4-(1-oxo-6-azaspiro[3.5]non-6-yl)pyrido[4,3- d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methanol

[0755] To a solution of (S)-6-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-1-oxa-6- azaspiro[3.5]nonane (460 mg, 1.34 mmol) and cyclopropane-1,1-dimethyl dimethanol (274 mg, 2.68 mmol) in anhydrous acetonitrile (5 mL), triethylenediamine (75 mg, 0.67 mmol) and anhydrous cesium carbonate (1.31 g, 4.02 mmol) were added, and stirred at 25 °C for 2 hours. After the reaction was completed, saturated aqueous sodium 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 concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (DCM:MeOH = 10:1) to obtain (S)-(1-(((7-chloro-8-fluoro-4-(1-oxa-6-azaspiro[3.5]non-6-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methanol.

[0756] LC-MS: (ESI, m / z): [M+H] + = 409.2.

[0757] Intermediate 8: (R)-1-(((8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-4-(3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropane-1-carbaldehyde

[0758] Refer to WO2024083256A1 Intermediate 2 for preparation.

[0759] Intermediate 9: 9-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)-1-oxa-9- azaspiro[5.5]undecane-3-carbaldehyde

[0760] Step 1: Preparation of 1-oxa-9-azaspiro[5.5]undecane-3-carbaldehyde

[0761] Refer to WO2024083258A1 Example 151 for preparation.

[0762] Step 2: Preparation of 9-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)-1-oxa-9- azaspiro[5.5]undecane-3-carbaldehyde

[0763] 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 5-fluorophenyl 3-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-4-methoxybenzoate (4.39 g, 10.59 mmol), the reaction was stirred at room temperature for 1 hour. 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 = 20:1) to give 9-(3-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-4-methoxybenzoyl)-1-oxa-9-azaspiro[5.5]undecan-3-carboxaldehyde.

[0764] LC-MS (ESI) m / z: [M+H] + = 430.2.

[0765] Intermediate 10: (R)-3-(4-benzylpiperazin-1-yl)-2-methylpropan-1-ol

[0766] Prepared according to WO2024083256A1, Intermediate 33.

[0767] Intermediate 11: (5aS)-2-chloro-1-fluoro-12-(methylsulfinyl)-5a,6,9,10-tetrahydro- 5H,8H-4,7-dioxa-3,10a,11,13-tetraazanaphtho[1,8-ab]heptene

[0768] Step 1: Preparation of (S)-5-((1,4-oxazepan-3-yl)methoxy)-7-chloro-8-fluoro-2- (methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one

[0769] (R)-(1,4-oxazepan-3-yl)methanol (2.42 g, 18.48 mmol) was dissolved in tetrahydrofuran (50 mL) and cooled to 0 °C, NaH (1.84 g, 46.2 mmol, 60% in oil) was added, and the mixture was reacted at 0 °C for 30 min, then 5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one (4.30 g, 15.4 mmol) was added, and the mixture was reacted for 3 h. After the reaction was completed, water (30 mL) was added to the reaction solution, and then tetrahydrofuran was removed under reduced pressure. Then the mixture was adjusted to pH of about 8 with dilute hydrochloric acid (1.0 M) until precipitate appeared, and the precipitate was filtered and dried to obtain the crude product (S)-5-((1,4-oxazepan-3-yl)methoxy)-7-chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one, which was used directly in the next step without further purification.

[0770] LC-MS: (ESI, m / z): [M+H] + = 375.1.

[0771] Step 2: Preparation of (S)-2-chloro-1-fluoro-12-(methylthio)-5a,6,9,10-tetrahydro-5H,8H- 4,7-dioxa-3,10a,11,13-tetraazanaphtho[1,8-ab]heptaene

[0772] (S)-5-((1,4-oxazepan-3-yl)methoxy)-7-chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one (4.2 g, 11.2 mmol) and DIEA (14.48 g, 112.0 mmol) were dissolved in DCM (50 mL), and then T3P (50% EtOAc solution) (71.28 g, 112.0 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, and dichloromethane was extracted (100 mL x 3). The organic phases were combined, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated to obtain the crude product, which was purified by silica gel column chromatography (PE:EtOAc = 2:1) to obtain (S)-2-chloro-1-fluoro-12-(methylthio)-5a,6,9,10-tetrahydro-5H,8H-4,7-dioxa-3,10a,11,13-tetraazanaphtho[1,8-ab]heptaene.

[0773] LC-MS: (ESI, m / z): [M+H] + = 357.0.

[0774] Step 3: Preparation of (5aS)-2-chloro-l-fluoro-12-(methylsulfinyl)-5a,6,9,10- tetrahydro-5H,8H-4,7-dioxa-3,10a,11,13-tetraazanaphtho[l,8-ab]heptaene

[0775] (S)-2-chloro-l-fluoro-12-(methylthio)-5a,6,9,10-tetrahydro-5H,8H-4,7-dioxa-3, 10a,11,13-tetraazanaphtho[l,8-ab]heptaene (2.3 g, 6.4 mmol) was dissolved in dichloromethane (30 mL), m-CPBA (1.66 g, 9.6 mmol) was added, and the reaction was allowed to proceed at room temperature for 3 h. After the reaction was completed, the reaction solution was poured into saturated aqueous sodium thiosulfate solution (20 mL) and saturated aqueous sodium bicarbonate solution (30 mL) was added, followed by extraction with dichloromethane (50 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give crude (5aS)-2-chloro-l-fluoro-12-(methylsulfinyl)-5a,6,9,10-tetrahydro-5H,8H-4,7-dioxa-3,10a,11,13-tetraazanaphtho[l,8-ab]heptaene, which was used directly in the next step without purification.

[0776] LC-MS: (ESI, m / z): [M+H] + = 373.0.

[0777] Intermediate 12: (R)-2-((4-benzylpiperazin-l-yl)methyl)-3-methylbutan-l-ol

[0778] Step 1: Preparation of (R)-methyl 2-(aminomethyl)-3-methylbutanoate

[0779] To a solution of (R)-2-(aminomethyl)-3-methylbutanoic acid (6.9 g, 52.60 mmol) in MeOH (70 mL) was added SOCl2(7.63 mL, 105.2 mmol) slowly dropwise at 0 °C. Then the reaction was continued to proceed at 70 °C for 16 h. After the reaction was completed, the reaction solution was directly concentrated to give (R)-methyl 2-(aminomethyl)-3-methylbutanoate.

[0780] LC-MS: (ESI, m / z): [M+H] + = 146.2.

[0781] Step 2: Preparation of (R)-methyl 2-((4-benzylpiperazin-l-yl)methyl)-3- methylbutanoate

[0782] Methyl (R)-2-(aminomethyl)-3-methylbutanoate (7 g, crude) was dissolved in ethanol (70 mL), then DIEA (33.93 g, 263 mmol) and N-benzyl-2-chloro-N-(2-chloroethyl)ethan-1-amine (14.96 g, 57.86 mmol) were added. The mixture was stirred at 90 °C for 1 h and concentrated to get the crude product, which was purified by silica gel column chromatography (PE:EA = 100:1 ~ 4:1) to give methyl (R)-2-((4-benzylpiperazin-1-yl)methyl)-3-methylbutanoate.

[0783] LC-MS (ESI) m / z: [M+H] + = 305.3.

[0784] Step 3: Preparation of (R)-2-((4-benzylpiperazin-1-yl)methyl)-3-methylbutan-1-ol

[0785] Methyl (R)-2-((4-benzylpiperazin-1-yl)methyl)-3-methylbutanoate (5 g, 16.48 mmol) was dissolved in THF (50 mL), cooled to 0-5 °C, and DIBAL-H (24.72 mL, 24.72 mmol) was added dropwise slowly. The mixture was reacted at room temperature for 16 h. After the reaction was completed, sodium sulfate decahydrate was added under ice bath to quench the reaction, filtered, and the filtrate was concentrated to give the crude product. The crude product was purified by silica gel column chromatography (PE:EA = 50:1 ~ 3:1) to give (R)-2-((4-benzylpiperazin-1-yl)methyl)-3-methylbutan-1-ol.

[0786] LC-MS (ESI) m / z: [M+H] + = 277.1.

[0787] Preparation of Intermediate 13: 1-(2-methyl-5-(3-(piperazin-1-ylmethyl)-1-oxa-9- azaspiro[5.5]undecane-9-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione

[0788] Step 1: Preparation of tert-butyl 4-((1-oxa-9-azaspiro[5.5]undecan-3-yl)methyl)piperazine-1- carboxylate

[0789] To a solution of Intermediate 1-P1 (1.10 g, 2.50 mmol) in methanol (10 mL) was added Pd / C (0.20 g), and the mixture was replaced with hydrogen gas for three times, and stirred at 25 °C for 16 h. The reaction solution was filtered through celite, and 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 step.

[0790] LC-MS (ESI) m / z: [M+H] + = 354.3.

[0791] 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

[0792] 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, and the filtrate was concentrated. The resulting crude product was 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.

[0793] LC-MS (ESI) m / z: [M+H] + = 584.3.

[0794] Step 3: Preparation of 1-(2-methyl-5-(3-(piperazin-1-ylmethyl)-1-oxa-9-azaspiro[5.5]undecan-9- yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione

[0795] 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), 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 / isopropanol (20 mL x 3, v / v = 5 / 1). The combined organic layer was dried over Na2SO4, filtered and concentrated to give 1-(2-methyl-5-(3-(piperazin-1-ylmethyl)-1-oxa-9- azaspiro[5.5]undecan-9-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione.

[0796] LC-MS (ESI) m / z: [M+H] + = 484.3.

[0797] Intermediate 14: (R)-1-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3- methylpiperidin-3-ol

[0798] To a solution of 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (1.9 g, 7.53 mmol) and triethylamine (1.9 g, 18.82 mmol) in THF (20 mL) was cooled to -78 °C, and (R)-3- methylpiperidin-3-ol hydrochloride (0.9 g, 6.02 mmol) was added. The reaction was stirred at -78 °C for 3 h. After the reaction was completed, the reaction was poured into saturated aqueous ammonium chloride solution (20 mL), and extracted 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. The resulting crude product was purified by silica gel column chromatography (DCM:MeOH = 100:1 ~ 50:1) to give (R)-1-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3- methylpiperidin-3-ol.

[0799] LC-MS: (ESI, m / z): [M+H] + = 331.1.

[0800] Intermediate 15: 1-(((8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-4-(2-oxo-1,6-diazaspiro[3.5]non-6-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropane-1-carbaldehyde

[0801] Step 1: Preparation of 6-(7-chloro-8-fluoro-2-((1-(hydroxymethyl)cyclopropyl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)-1,6-diazaspiro[3.5]nonan-2-one

[0802] To a solution of intermediate 3-P2 (200 mg, 0.56 mmol) and cyclopropane-1,1-diyl dimethanol (114 mg, 1.12 mmol) in anhydrous acetonitrile (3 mL), triethylenediamine (7 mg, 0.06 mmol) and anhydrous cesium carbonate (548 mg, 1.68 mmol) were added, and stirred at 25 °C for 2 h. The reaction solution was added with saturated brine (10 mL), extracted with ethyl acetate (10 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (DCM:MeOH = 15:1) to obtain 6-(7-chloro-8-fluoro-2-((1-(hydroxymethyl)cyclopropyl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)-1,6-diazaspiro[3.5]nonan-2-one.

[0803] LC-MS: (ESI, m / z): [M+H] + = 422.2.

[0804] Step 2: Preparation of 6-(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)-1,6-diazaspiro[3.5]nonan-2-one

[0805] To a mixture solution of 6-(7-chloro-8-fluoro-2-((1-(hydroxymethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,6-diazaspiro[3.5]nonan-2-one (160 mg, 0.68 mmol) and ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (130 mg, 0.31 mmol) in 1,4-dioxane (3 mL) and H2O (0.6 mL) was added cesium carbonate (303 mg, 0.93 mmol) and cataCXium A Pd-G3 (45 mg, 0.062 mmol) and reacted at 85 °C under N2protection overnight. The reaction mixture was filtered, the filtrate was concentrated, and the concentrate was purified by silica gel column chromatography (DCM:MeOH = 20:1) to give 6-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((trisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((1-(hydroxymethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,6-diazaspiro[3.5]nonan-2-one.

[0806] LC-MS: (ESI, m / z): [M+H] = 772.3. + = 772.3.

[0807] Step 3: Preparation of 1-(((8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((trisopropylsilyl)ethynyl)naphthalen-1-yl)-4-(2-oxo-1,6-diazaspiro[3.5]non-6-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropane-1-carbaldehyde

[0808] A solution of 6-(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)-1,6-diazaspiro[3.5]nonan-2-one (135 mg, 0.17 mmol) in dichloromethane (3 mL) was cooled to 0 °C at room temperature, Dess-Martin reagent (187 mg, 0.44 mmol) was added, and stirred at 25 °C for 2 h. The reaction solution was added with saturated sodium thiosulfate solution (10 mL), and extracted with dichloromethane (10 mL x 3), and the combined organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (DCM:MeOH = 20:1) to obtain 1-(((8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-4-(2-oxo-1,6-diazaspiro[3.5]non-6-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropane-1-carbaldehyde.

[0809] LC-MS: (ESI, m / z): [M+H] + = 770.3.

[0810] Intermediate 16: (S)-1-(((8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-4-(1-oxido-6-azaspiro[3.5]non-6-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropane-1-carbaldehyde

[0811] Step 1: Preparation of (S)-(1-(((8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-4-(1-oxido-6-azaspiro[3.5]non-6-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methanol

[0812] To a mixture solution of (S)-(l-(((7-chloro-8-fluoro-4-(l-oxo-6- azaspiro[3.5]non-6-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methanol (830 mg, 2.03 mmol) and ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)naphthalen-l- yl)ethynyl)triisopropylsilane (1.25 g, 2.44 mmol) in 1,4-dioxane (10 mL) and H2O (2 mL) was added cesium carbonate (1.98 g, 6.09 mmol) and cataCXium A Pd-G3 (296 mg, 0.41 mmol) and the reaction mixture was heated at 85 °C under N2protection overnight. The reaction mixture was filtered, the filtrate was concentrated, and the resulting crude was purified by silica gel column chromatography (DCM:MeOH = 15:1) to give (S)-(l-(((8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-l-yl)-4-(l-oxo-6- azaspiro[3.5]non-6-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methanol.

[0813] LC-MS: (ESI, m / z): [M+H] = 759.3. + = 759.3.

[0814] Step 2: Preparation of (S)-l-(((8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-l-yl)-4-(l-oxo-6- azaspiro[3.5]non-6-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropane-l- carbaldehyde

[0815] A solution of (S)-(1-(((8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- ((trisopropylsilyl)ethynyl)naphthalen-1-yl)-4-(1-oxo-6-azaspiro[3.5]dec-6-yl) pyridino[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropane-1-carbaldehyde (950 mg, 1.25 mmol) in dichloromethane (15 mL) was cooled to 0 °C at room temperature, Dess-Martin reagent (1.33 g, 3.13 mmol) was added, and stirred at 25 °C for 2 h. After the reaction was completed, saturated sodium thiosulfate solution (20 mL) was added, extracted with dichloromethane (20 mL x 3), and the combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (DCM:MeOH = 20:1) to give (S)-1-(((8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- ((trisopropylsilyl)ethynyl)naphthalen-1-yl)-4-(1-oxo-6-azaspiro[3.5]dec-6-yl) pyridino[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropane-1-carbaldehyde.

[0816] LC-MS: (ESI, m / z): [M+H] + = 757.3.

[0817] Intermediate 17: 1-(2-methoxy-5-(3-(piperazin-1-ylmethyl)-1-oxo-9- azaspiro[5.5]undecane-9-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione

[0818] Step 1: Preparation of tert-butyl 4-((1-oxo-9-azaspiro[5.5]undecan-3-yl)methyl)piperazine-1- carboxylate

[0819] To a solution of intermediate 1-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, and stirred at 25 °C for 16 h. The reaction solution was filtered through diatomite, and the filtrate was concentrated to give crude tert-butyl 4-((1-oxo-9-azaspiro[5.5]undecan-3-yl)methyl)piperazine-1-carboxylate, which was used directly in the next reaction.

[0820] LC-MS: (ESI, m / z): [M+H] + = 354.3.

[0821] Step 2: Preparation of tert-butyl 4-((9-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4- methoxybenzoyl)-1-oxo-9-azaspiro[5.5]undecan-3-yl)methyl)piperazine-1-carboxylate

[0822] To a solution of tert-butyl 4-((1-oxo-9-azaspiro[5.5]undecan-3-yl)methyl)piperazine-1- carboxylate (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-methoxy-pentafluorophenyl ester (601 mg, 1.40 mmol), 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, the crude was 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-methoxybenzoyl)-1-oxo-9- azaspiro[5.5]undecan-3-yl)methyl)piperazine-1-carboxylate.

[0823] LC-MS: (ESI, m / z): [M+H] + = 600.3.

[0824] Step 3: 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

[0825] To a solution of tert-butyl 4-((9-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4- methoxybenzoyl)-1-oxo-9-azaspiro[5.5]undecan-3-yl)methyl)piperazine-1-carboxylate (250 mg, 0.42 mmol) in 1,4-dioxane (3 mL) was added HCl / 1,4-dioxane (1.5 mL), 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 (20 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated, the crude was purified by silica gel column chromatography (DCM:MeOH = 20:1) to give 1-(2-methoxy-5-(3-(piperazin-1-ylmethyl)-1-oxo-9- azaspiro[5.5]undecan-9-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione.

[0826] LC-MS: (ESI, m / z): [M+H] + = 500.3.

[0827] Intermediate 18: (R)-3-(4-benzylpiperazin-1-yl)-2-methylpropane-3,3-d2-1-ol

[0828] Step 1: Preparation of (2S)-methyl 2-methyl-3-((tetrahydro-2H-pyran-2- yl)oxy)propanoate

[0829] 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.

[0830] 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).

[0831] Step 2: Preparation of (2R)-2-methyl-3-((tetrahydro-2H-pyran-2-yl)oxy)propane-1,1-d2-1-ol

[0832] 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 in 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)propane-1,1-d2-1-ol.

[0833] 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).

[0834] Step 3: Preparation of 1 -benzyl-4-((2R)-2-methyl-3-((tetrahydro-2H-pyran-2- yl)oxy)propyl-1,1 -d2)piperazine

[0835] (2R)-2-methyl-3-((tetrahydro-2H-pyran-2-yl)oxy)propan-1,1 -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 1 -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 allowed to cool 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 1 -benzyl-4-((2R)-2-methyl-3-((tetrahydro-2H-pyran-2-yl)oxy)propyl-1,1 -d2)piperazine.

[0836] LC-MS: (ESI, m / z): [M+H] + = 335.3.

[0837] Step 4: Preparation of (R)-3-(4-benzylpiperazin-1-yl)-2-methylpropan-3,3-d2-1-ol

[0838] 1 -benzyl-4-((2R)-2-methyl-3-((tetrahydro-2H-pyran-2-yl)oxy)propyl-1,1 -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, 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-1 -yl)-2-methylpropan-3,3-d2-1 -ol.

[0839] LC-MS: (ESI, m / z): [M+H] + = 251.3.

[0840] Intermediate 19: (1-((4-benzylpiperazin-1-yl)methyl-d2)cyclopropyl)methanol

[0841] Step 1: Preparation of ethyl 1-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)cyclopropane-1- carboxylate

[0842] Ethyl 1-(hydroxymethyl)cyclopropane-1-carboxylate (10.0 g, 69.4 mmol) was dissolved in DCM (100 mL), 3,4-dihydropyran (11.7 g, 139.3 mmol) and p-toluenesulfonic acid pyridine salt (5.3 g, 21.1 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 (200 mL) and 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 ~ 20:1) to obtain ethyl 1-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)cyclopropane-1-carboxylate.

[0843] 1 H NMR (400 MHz, CDCl3) δ 4.66 (t, J = 3.6 Hz, 1H), 4.16-4.08 (m, 2H), 3.91-3.85 (m, 1H), 3.75-3.68 (m, 2H), 3.53-3.48 (m, 1H), 1.85-1.67 (m, 2H), 1.62-1.50 (m, 4H), 1.30-1.12 (m, 5H), 0.96-0.86 (m, 2H).

[0844] Step 2: Preparation of (1-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)cyclopropyl)methane-d2-ol

[0845] Ethyl 1-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)cyclopropane-1-carboxylate (15.0 g, 65.8 mmol) was dissolved in tetrahydrofuran (100 mL), cooled to 0 °C, and LiAlD4(73 mL, 73 mmol, 1.0 M in THF) was added dropwise. The reaction was allowed to proceed at 0 °C for 15 minutes. After the reaction was completed, sodium sulfate decahydrate was added to quench and filtered with ethyl acetate (200 mL). The filtrate was concentrated to obtain (1-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)cyclopropyl)methane-d2-ol as a crude product.

[0846] 1 H NMR (400 MHz, CDC13) δ 4.54 (t, J = 4.0 Hz, 1H), 3.83-3.79 (m, 1H), 3.68 (d, J = 8.0 Hz, 1H), 3.47-3.42 (m, 1H), 3.32 (d, J = 8.0 Hz, 1H), 2.47 (br, 1H), 1.78-1.64 (m, 2H), 1.56-1.49 (m, 4H), 0.50-0.41 (m, 4H).

[0847] Step 3: Preparation of l-benzyl-4-((l-(((tetrahydro-2H-pyran-2- yl)oxy)methyl)cyclopropyl)methyl-d2)piperazine

[0848] (1-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)cyclopropyl)methane-d2-ol (3.0 g, 16.0 mmol) was dissolved in dichloromethane (60 mL), triethylamine (4.85 g, 48.0 mmol) and methanesulfonyl chloride (2.75 g, 24.0 mmol) were added at 0 °C, the reaction was carried out for 1 h. After the reaction was completed, it was raised to room temperature, water (100 mL) was added, and ethyl acetate (60 mL x 3) was extracted. The combined organic phase was washed with saturated NaCl solution (100 mL), dried over anhydrous Na2S04, filtered, and the filtrate was concentrated to give the crude product. The crude product was dissolved in DMF (25 mL), potassium carbonate (6.62 g, 48.0 mmol) and l-benzylpiperazine (5.63 g, 32.0 mmol) were added, and the reaction was heated to 80 °C for 16 h. After the reaction was completed, it was cooled to room temperature, water (100 mL) was added, and ethyl acetate was extracted (100 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 obtained crude product was purified by silica gel column chromatography (DCM:MeOH = 20:1) to give l-benzyl-4-((l-(((tetrahydro-2H-pyran-2- yl)oxy)methyl)cyclopropyl)methyl-d2)piperazine.

[0849] LC-MS (ESI) m / z: [M+H] + = 347.2.

[0850] Step 4: Preparation of (l-((4-benzylpiperazin-l-yl)methyl-d2)cyclopropyl)methanol

[0851] Dissolve 1-benzyl-4-((1-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)cyclopropyl)methyl- d2)piperazine (2.2 g, 6.35 mmol) in MeOH (15 mL), add concentrated HCl (5 mL) under ice bath, and react at room temperature for 1 hour. After the reaction is completed, concentrate MeOH and HCl, add aqueous Na2CO3 solution to adjust the mixture to pH > 7, and then extract with EtOAc (40 mL x 3). Dry the combined organic phase over anhydrous Na2SO4, filter, concentrate the filtrate, and purify the obtained crude product by silica gel column chromatography (DCM:MeOH = 20:1) to obtain (1-((4-benzylpiperazin-1-yl)methyl-d2)cyclopropyl)methanol.

[0852] LC-MS (ESI) m / z: [M+H] + = 263.3.

[0853] Intermediate 20: (R)-1-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((R)-2-methyl-3-(piperazin-1-yl)propoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol

[0854] Refer to the preparation of Intermediate 19 in WO2024083256A1.

[0855] Intermediate 21: Preparation of 9-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methylbenzoyl)-1-oxa-9-azaspiro[5.5]undecane-3-carbaldehyde

[0856] Refer to the preparation of Example 151 in WO2024083258A1.

[0857] Intermediate 22: (R)-2-methyl-3-(4-tritylpiperazin-1-yl)propan-1-ol

[0858] Refer to the preparation of Intermediate 10.

[0859] Intermediate 23: (5aS)-2-chloro-1-fluoro-5-methyl-11-((1-((4-tritylpiperazin-1-yl)methyl)cyclopropyl)methoxy)-5a,6,8,9-tetrahydro-4-oxa-3,7,9a,10,12-pentaazabenzo[4,5]cyclohepta[1,2,3-de]naphth-7(5H)-carboxylic acid tert-butyl ester

[0860] Step 1: Preparation of 1-benzyl 4-(tert-butyl) (S)-2-(hydroxymethyl)piperazine-1,4-dicarboxylate

[0861] To a solution of (S)-3-(hydroxymethyl)piperazine-1-carboxylic acid tert-butyl ester (5 g, 23.13 mmol) and sodium bicarbonate (5.83 g, 69.39 mmol) in ethyl acetate (50 mL), water (50 mL) and benzyl chloroformate (12.14 g, 34.69 mmol) were added at 0 °C, and after the addition was completed, it was stirred at 25 °C for 16 hours. After the reaction was completed, it was poured into a saturated ammonium chloride solution (50 mL), extracted with ethyl acetate (50 mL x 3), the organic phases were combined and dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (PE:EA = 15:1) to obtain 1-benzyl 4-(tert-butyl) (S)-2-(hydroxymethyl)piperazine-1,4-dicarboxylate.

[0862] LC-MS: (ESI, m / z): [M-100+H] + = 251.1.

[0863] Step 2: Preparation of 1-benzyl 4-(tert-butyl) (S)-2-formylpiperazine-1,4-dicarboxylate

[0864] To a solution of oxalyl chloride (5.5 g, 43.33 mmol) in dichloromethane (50 mL), anhydrous DMSO (5.08 g, 65.00 mmol) was added at -78 °C, and stirred at -78 °C for 0.5 hours, then a solution of 1-benzyl 4-(tert-butyl) (S)-2-(hydroxymethyl)piperazine-1,4-dicarboxylate (7.6 g, 21.71 mmol) in dichloromethane (50 mL) was added, and after stirring at -78 °C for 1 hour, triethylamine (10.96 g, 108.55 mmol) was slowly added, and after the addition was completed, the reaction solution was raised to 0 °C and stirred for 1 hour. After the reaction was completed, it was poured into a saturated ammonium chloride solution (100 mL), extracted with ethyl acetate (80 mL x 3), the organic phases were combined and dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (PE:EA = 10:1) to obtain 1-benzyl 4-(tert-butyl) (S)-2-formylpiperazine-1,4-dicarboxylate.

[0865] 1 H NMR (400 MHz, CDCl3) δ 9.60 (d, J = 6.4 Hz, 1H), 7.37-7.26 (m, 5H), 5.22-5.14 (m, 2H), 4.72-4.59 (m, 2H), 4.00-3.93 (m, 2H), 3.12-3.06 (m, 2H), 2.85 (s, 1H), 1.42 (s, 9H).

[0866] Step 3: Preparation of 1-benzyl 4-(tert-butyl) (2S)-2-(1-hydroxyethyl)piperazine-1,4- dicarboxylate

[0867] To a solution of 1-benzyl 4-(tert-butyl) (S)-2-formylpiperazine-1,4-dicarboxylate (6 g, 17.24 mmol) in anhydrous tetrahydrofuran (100 mL), MeMgBr (1.0 M, 26 mL, 26 mmol) was added slowly at 0 °C, then stirred at 25 °C for 3 h. After the reaction was completed, the reaction was quenched with saturated aqueous ammonium chloride solution (50 mL) under ice bath until no bubbles were generated. After the quenching was completed, it was extracted with ethyl acetate (80 mL x 3), the organic phase was combined and dried over anhydrous sodium sulfate, then concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (PE:EA = 5:1) to give 1-benzyl 4-(tert-butyl) (2S)-2-(1-hydroxyethyl)piperazine-1,4-dicarboxylate.

[0868] LC-MS: (ESI, m / z): [M-100+H] + = 265.3.

[0869] Step 4: Preparation of tert-butyl (3S)-3-(1-hydroxyethyl)piperazine-1-carboxylate

[0870] 1-benzyl 4-(tert-butyl) (2S)-2-(1-hydroxyethyl)piperazine-1,4-dicarboxylate (4.5 g, 12.33 mmol) was dissolved in MeOH (50 mL) and aqueous ammonia (5 mL), palladium on carbon (2.5 g) was added at room temperature, then replaced with a hydrogen balloon for three times, and reacted at room temperature for 3 h. After the reaction was completed, the palladium on carbon was filtered off, and the filtrate was concentrated to give tert-butyl (3S)-3-(1-hydroxyethyl)piperazine-1-carboxylate.

[0871] LC-MS: (ESI, m / z): [M+H] + = 231.1.

[0872] Step 5: Preparation of tert-butyl (3S)-3-(1-((7-chloro-8-fluoro-4-hydroxy-2- (methylthio)pyrido[4,3-d]pyrimidin-5-yl)oxy)ethyl)piperazine-1-carboxylate

[0873] A solution of tert-butyl (3S)-3-(1-hydroxyethyl)piperazine-1-carboxylate (2.7 g, 11.74 mmol) in tetrahydrofuran (30 mL) was cooled to 0 °C at room temperature, NaH (1.17 g, 29.35 mmol, 60%) was added, and stirred at 25 °C for 0.5 h. Then a solution of 5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-ol (3.93 g, 14.10 mmol) in tetrahydrofuran (10 mL) was added at 0 °C, stirred at 25 °C for 2 h, then saturated aqueous ammonium chloride solution (50 mL) was added, and extracted with ethyl acetate (50 mL x 3), the organic phases were 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 give tert-butyl (3S)-3-(1-((7-chloro-8-fluoro-4-hydroxy-2-(methylthio)pyrido[4,3-d]pyrimidin-5-yl)oxy)ethyl)piperazine-1-carboxylate.

[0874] LC-MS: (ESI, m / z): [M+H] + = 474.2.

[0875] Step 6: Preparation of tert-butyl (5aS)-2-chloro-1-fluoro-5-methyl-11-(methylthio)- 5a,6,8,9-tetrahydro-4-oxa-3,7,9a,10,12-pentaazabenzo[4,5]cyclohepta[1,2,3-de]naphth- 7(5H)-carboxylate

[0876] To a solution of tert-butyl (3S)-3-(1-((7-chloro-8-fluoro-4-hydroxy-2-(methylthio)pyrido[4,3-d]pyrimidin-5-yl)oxy)ethyl)piperazine-1-carboxylate (3.24 g, 6.85 mmol) and DIEA (8.84 g, 68.5 mmol) in DCM (50 mL) was added T4P (7.4 g, 20.55 mmol) at 0 °C, and stirred at 25 °C for 2 h. After the reaction was completed, saturated aqueous ammonium chloride solution (50 mL) was added, and extracted with ethyl acetate (50 mL x 3), the organic phases were combined and dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (PE:EA = 4:1) to give tert-butyl (5aS)-2-chloro-1-fluoro-5-methyl-11-(methylthio)-5a,6,8,9-tetrahydro-4-oxa-3,7,9a,10,12-pentaazabenzo[4,5]cyclohepta[1,2,3-de]naphth-7(5H)-carboxylate.

[0877] LC-MS: (ESI, m / z): [M+H] + = 456.1.

[0878] Step 7: Preparation of tert-butyl (5aS)-2-chloro-l-fluoro-5-methyl-ll- ((l-((4-tritylpiperazin-l-yl)methyl)cyclopropyl)methoxy)-5a,6,8,9-tetrahydro- 4-oxa-3,7,9a,10,12-pentaazabenzo[4,5]cyclohepta[l,2,3-de]naphth-7(5H)- carboxylate

[0879] To a solution of tert-butyl (5aS)-2-chloro-l-fluoro-5-methyl-ll-(methylthio)- 5a,6,8,9-tetrahydro-4-oxa-3,7,9a,10,12-pentaazabenzo[4,5]cyclohepta[l,2,3- de]naphth-7(5H)-carboxylate (1.62 g, 3.56 mmol) in dichloromethane (20 mL) was added m-CPBA (1.54 g, 8.9 mmol) at 25 °C and stirred at 25 °C for 2 h. After completion of the reaction, poured into saturated sodium bicarbonate solution (30 mL) and extracted with dichloromethane (20 mL x 3), combined organic phase was washed with saturated aqueous sodium chloride solution (30 mL) and dried over anhydrous sodium sulfate and concentrated under reduced pressure to get the crude tert-butyl (5aS)-2-chloro-l-fluoro-5-methyl-ll- (methylsulfonyl)-5a,6,8,9-tetrahydro-4-oxa-3,7,9a,10,12-pentaazabenzo[4,5] cyclohepta[l,2,3-de]naphth-7(5H)-carboxylate.

[0880] LC-MS: (ESI, m / z): [M+H] + = 488.1.

[0881] Step 8: Preparation of tert-butyl (5aS)-2-chloro-l-fluoro-5-methyl-ll- ((l-((4-tritylpiperazin-l-yl)methyl)cyclopropyl)methoxy)-5a,6,8,9-tetrahydro- 4-oxa-3,7,9a,10,12-pentaazabenzo[4,5]cyclohepta[l,2,3-de]naphth-7(5H)- carboxylate

[0882] A solution of (1-((4-tritylpiperazin-1-yl)methyl)cyclopropyl)methanol (1.4 g, 3.39 mmol) in tetrahydrofuran (10 mL) was cooled to 0 °C at room temperature, NaH (164 mg, 4.1 mmol) was added, and stirred at 25 °C for 0.5 h. Then a solution of crude (5aS)-2-chloro-1-fluoro-5-methyl-11-(methylsulfonyl)-5a,6,8,9-tetrahydro-4-oxa-3,7,9a,10,12-pentaazabenzo[4,5]cyclohepta[1,2,3-de]naphth-7(5H)-carboxylic acid tert-butyl ester (1.1 g, 2.26 mmol) in tetrahydrofuran (10 mL) was added at 0 °C, stirred at 25 °C for 2 h, then saturated aqueous ammonium chloride solution (30 mL) was added, and extracted with ethyl acetate (50 mL x 3), the organic phases were combined and dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (DCM:MeOH = 50:1) to give (5aS)-2-chloro-1-fluoro-5-methyl-11-((1-((4-tritylpiperazin-1-yl)methyl)cyclopropyl)methoxy)-5a,6,8,9-tetrahydro-4-oxa-3,7,9a,10,12-pentaazabenzo[4,5]cyclohepta[1,2,3-de]naphth-7(5H)-carboxylic acid tert-butyl ester.

[0883] LC-MS: (ESI, m / z): [M+H] + = 820.3.

[0884] Intermediate 24: 2-chloro-1-fluoro-4-methyl-12-(methylthio)-4,5,5a,6,9,10-hexahydro-8H-7-oxa-3,4,10a,11,13-pentaazanaphtho[1,8-ab]heptaene

[0885] Prepared according to the procedure described in Reference Intermediate 11, Step 1 and Step 2.

[0886] Intermediate 25: 4-((1-(((5-chloro-4-fluoro-7-methyl-7a,8,11,12-tetrahydro-7H,10H-9-oxo-1,3,6,7,12a-pentaazacyclohepta[a]phenalen-2-yl)oxy)methyl)cyclopropyl)methyl)piperazine-1-carboxylic acid tert-butyl ester

[0887] Step 1: Preparation of N,N-dibenzyl-3-(2,2-dimethoxyethoxy)propan-1-amine

[0888] N,N-dibenzyl-3-(2,2-dimethoxyethoxy)propan-1-amine was prepared by dissolving 3-(dibenzylamino)propan-1-ol (30.00 g, 117.48 mmol) in super dry N,N-dimethylformamide (50 mL) and anhydrous tetrahydrofuran (250 mL), cooling to 0 °C, adding NaH (60%, 7.05 g, 176.25 mmol), and reacting at 25 °C for 1 h. The above mixture was cooled to 0 °C, a solution of 2-bromo-1,1-dimethoxyethane (39.72 g, 235.00 mmol) in anhydrous N,N-dimethylformamide (100 mL) was added, and then reacted at 25 °C for 18 h. After the reaction was completed, the reaction solution was poured into saturated aqueous ammonium chloride solution (200 mL), extracted with ethyl acetate (200 mL x 2), and then the organic phase was washed with water (200 mL) and saturated brine (200 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 100:1 to 10:1) to obtain N,N-dibenzyl-3-(2,2-dimethoxyethoxy)propan-1-amine.

[0889] LC-MS: (ESI, m / z): [M+H] + = 344.2.

[0890] Step 2: Preparation of 3-(2,2-dimethoxyethoxy)propan-1-amine

[0891] N,N-dibenzyl-3-(2,2-dimethoxyethoxy)propan-1-amine (22.66 g, 65.97 mmol) was dissolved in anhydrous methanol (150 mL) and anhydrous tetrahydrofuran (50 mL), and palladium hydroxide (5.0 g) was added. Hydrogen was replaced 3 times, and reacted at 25 °C for 18 h. After the reaction was completed, it was filtered through diatomite, and the filtrate was concentrated under reduced pressure at 40 °C to obtain 3-(2,2-dimethoxyethoxy)propan-1-amine.

[0892] LC-MS: (ESI, m / z): [M+H] + = 164.2.

[0893] Step 3: Preparation of 5,7-dichloro-N-(3-(2,2-dimethoxyethoxy)propyl)-8-fluoro-2- (methylthio)pyrido[4,3-d]pyrimidin-4-amine

[0894] Dissolve 5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-ol (16.20 g, 57.83 mmol) in anhydrous toluene (210 mL), add N,N-diisopropylethylamine (22.42 g, 173.49 mmol) and phosphorus oxychloride (17.73 g, 115.65 mmol) at 25 °C, heat to 70 °C for 2 hours, then concentrate under reduced pressure. Dissolve the concentrate in anhydrous dichloromethane (160 mL), add N,N-diisopropylethylamine (14.95 g, 115.65 mmol) and a solution of 3-(2,2-dimethoxyethoxy)propan-1-amine (9.44 g, 57.83 mmol) in dichloromethane (80 mL), then react at 25 °C for 18 h. After the reaction is completed, concentrate the reaction solution, and purify the concentrate by silica gel column chromatography (petroleum ether: ethyl acetate = 100:1 to 10:1) to obtain 5,7-dichloro-N-(3-(2,2-dimethoxyethoxy)propyl)-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-amine.

[0895] LC-MS: (ESI, m / z): [M+H] + = 425.0.

[0896] Step 4: Preparation of 7-chloro-N4-(3-(2,2-dimethoxyethoxy)propyl)-8-fluoro-N5-methyl-2-(methylthio)pyrido[4,3-d]pyrimidine-4,5-diamine

[0897] Dissolve 5,7-dichloro-N-(3-(2,2-dimethoxyethoxy)propyl)-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-amine (10.36 g, 24.35 mmol) in anhydrous DMAc (85 mL), add methylamine hydrochloride (7.24 g, 10.72 mmol) and cesium carbonate (7.24 g, 10.72 mmol) at 25 °C, and heat to 100 °C in a stainless steel autoclave for 18 hours. After the reaction is completed, pour the reaction solution into ice water (500 mL), extract with ethyl acetate (200 mL x 2), then wash the organic phase with water (500 mL) and saturated brine (300 mL), respectively, dry the combined organic phase with anhydrous sodium sulfate, filter, and purify by silica gel column chromatography (petroleum ether: ethyl acetate = 1:0 to 0:1) to obtain 7-chloro-N4-(3-(2,2-dimethoxyethoxy)propyl)-8-fluoro-N5-methyl-2-(methylthio)pyrido[4,3-d]pyrimidine-4,5-diamine.

[0898] LC-MS: (ESI, m / z): [M+H] + = 420.1.

[0899] Step 5: Preparation of 5-chloro-4-fluoro-7-methyl-2-(methylthio)- 7a,8,11,12-tetrahydro-7H,10H-9-oxa-1,3,6,7,12a-pentaazacyclohepta[a]phenalen

[0900] To a solution of 7-chloro-N4-(3-(2,2-dimethoxyethoxy)propyl)-8-fluoro-N5- methyl-2-(methylthio)pyrido[4,3-d]pyrimidine-4,5-diamine (8.42 g, 20.05 mmol) in 1,4-dioxane (170 mL) was added p-toluenesulfonic acid (3.81 g, 20.05 mmol). The reaction was stirred at 100 °C for 18 h. The reaction was complete, and the solvent was blown dry with nitrogen to give 5-chloro-4-fluoro-7-methyl-2-(methylthio)- 7a,8,11,12-tetrahydro-7H,10H-9-oxa-1,3,6,7,12a-pentaazacyclohepta[a]phenalen.

[0901] LC-MS: (ESI, m / z): [M+H] + = 356.0.

[0902] Step 6: Preparation of 9-P1 and 9-P2

[0903] The racemic 5-chloro-4-fluoro-7-methyl-2-(methylthio)-7a,8,11,12- tetrahydro-7H,10H-9-oxa-1,3,6,7,12a-pentaazacyclohepta[a]phenalen was chiral resolved to give 9-P1 and 9-P2.

[0904] 9-P1: (R.T. = 1.603 min, e.e. = 100%); 9-P2: (R.T. = 2.683 min, e.e. = 100%).

[0905] SFC resolution method: Column: Daicel CHIRALCEL IB-N, 250 mm*30 mm I.D., 10 μm; CO2 / MeOH [0.2% NH3(7M / MeOH)] = 50 / 50; Flow rate: 120 g / min; Wavelength: 214 nm; Column temperature: 35 °C;

[0906] SFC analysis method: Column: Daicel CHIRALPAK IB N-3, 3 mm*150 mm, 3 μm; CO2 / MeOH (0.1% DEA)] = 50 / 50; Flow rate: 2.0 mL / min; Wavelength: 214 & 254 nm; Column temperature: 37 °C.

[0907] Step 7: Preparation of 5-chloro-4-fluoro-7-methyl-2-(methylsulfonyl)- 7a,8,11,12-tetrahydro-7H,10H-9-oxa-1,3,6,7,12a-pentaazacyclohepta[a]phenalen

[0908] 9-P1 (1.81 g, 5.08 mmol) was dissolved in anhydrous dichloromethane (60 mL), and m-chloroperoxybenzoic acid (2.06 g, 10.16 mmol) was added at 0 °C. The reaction was allowed to react at 25 °C for 18 hours, and after the reaction was completed, the reaction solution was poured into ice saturated aqueous sodium bicarbonate solution (500 mL), and extracted with ethyl acetate (200 mL x 2), and then the organic phase was washed with water (500 mL) and saturated brine (300 mL), respectively, and the combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 5-chloro-4-fluoro-7-methyl-2-(methylsulfonyl)- 7a,8,11,12-tetrahydro-7H,10H-9-oxa-1,3,6,7,12a-pentaazacyclohepta[a]phenalen.

[0909] LC-MS: (ESI, m / z): [M+H] + = 388.1.

[0910] Step 8: Preparation of 4-((1-(((5-chloro-4-fluoro-7-methyl-7a,8,11,12- tetrahydro-7H,10H-9-oxa-1,3,6,7,12a-pentaazacyclohepta[a]phenalen-2-yl)oxy)methyl)cyclopropyl)methyl)piperazine-1-carboxylic acid tert-butyl ester

[0911] tert-Butyl 4-((1-(hydroxymethyl)cyclopropyl)methyl)piperazine-1-carboxylate (105 mg, 0.32 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL), NaH (21 mg, 0.52 mmol) was added at 0 °C, then warmed to 25 °C for 1 h, then cooled to 0 °C, (S)-5-chloro-4-fluoro-7-methyl-2-(methylsulfonyl)-7a,8,11,12-tetrahydro-7H,10H-9-oxa-1,3,6,7,12a-pentaazacyclohepta[a]phenalen (100 mg, 0.26 mmol) was added, then warmed to 25 °C for 18 h. After the reaction was completed, the reaction solution was poured into saturated aqueous ammonium chloride solution (500 mL), extracted with ethyl acetate (200 mL x 2), then the organic phase was washed with water (500 mL) and saturated brine (300 mL) respectively, the combined organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the concentrate was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:0 ~ 0:1) to obtain tert-butyl 4-((1-(((5-chloro-4-fluoro-7-methyl-7a,8,11,12-tetrahydro-7H,10H-9-oxa-1,3,6,7,12a-pentaazacyclohepta[a]phenalen-2-yl)oxy)methyl)cyclopropyl)methyl)piperazine-1-carboxylate.

[0912] LC-MS: (ESI, m / z): [M+H] + = 578.3.

[0913] Intermediate 26: 5-chloro-4-fluoro-7-methyl-2-((1-((4-tritylpiperazin-1-yl)methyl)cyclopropyl)methoxy)-7a,8,11,12-tetrahydro-7H,10H-9-oxa-1,3,6,7,12a-pentaazacyclohepta[a]phenalen

[0914] It was prepared from 9-P1 according to the method described in Intermediate 25.

[0915] Example 1: 1-(5-(9-((4-((R)-2-(((7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)-3-methylbutyl)piperazin-1-yl)methyl)-3-azaspiro[5.5]undecane-3-carbonyl)-2-methoxyphenyl)dihydropyrimidine-2,4(1H,3H)-dione

[0916] Step 1: Preparation of (R)-1-(2-((R)-2-((4-benzylpiperazin-1-yl)methyl)-3-methylbutoxy)-7-chloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol

[0917] (R)-1-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (1.0 g, 3.02 mmol) was dissolved in THF (15 mL), (R)-2-((4-benzylpiperazin-1-yl)methyl)-3-methylbutan-1-ol (1.25 g, 4.53 mmol) and Cs2CO3(2.95 g, 9.06 mmol) were added. The reaction was heated to 90 °C for 16 h. After the reaction was completed, it was cooled to room temperature, water (30 mL) was added, and it was extracted with ethyl acetate (30 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 silica gel column chromatography (PE:EtOAc = 2:1) to give (R)-1-(2-((R)-2-((4-benzylpiperazin-1-yl)methyl)-3-methylbutoxy)-7-chloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol.

[0918] LC-MS: (ESI, m / z): [M+H] + = 571.3.

[0919] Step 2: Preparation of (R)-1-(2-((R)-2-((4-benzylpiperazin-1-yl)methyl)-3-methylbutoxy)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol

[0920] To a mixture solution of (R)-1-(2-((R)-2-((4-benzylpiperazin-1-yl)methyl)-3- methylbutoxy)-7-chloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (500 mg, 0.88 mmol) and ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (538 mg, 1.05 mmol) in 1,4-dioxane (5 mL) and H2O (1 mL) was added Cata CXium Pd G3 (128 mg, 0.17 mmol) and cesium carbonate (861 mg, 2.64 mmol). The reaction was stirred at 85 °C for 16 h under nitrogen protection, quenched by the addition of water (20 mL) and extracted with ethyl acetate (30 mL x 3), 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 (MeOH:DCM = 15:1) to give (R)-1-(2-((R)-2-((4-benzylpiperazin-1-yl)methyl)-3-methylbutoxy)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol.

[0921] LC-MS: (ESI, m / z): [M / 2+H] + = 461.4.

[0922] Step 3: Preparation of (R)-1-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((R)-3-methyl-2-(piperazin-1-ylmethyl)butoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol

[0923] (R)-1-(2-((R)-2-((4-benzylpiperazin-1-yl)methyl)-3-methylbutoxy)-8-fluoro-7-(7-fluoro-3- (methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3- methylpiperidin-3-ol (450 mg, 0.54 mmol) was dissolved in DCM (5 mL), then 1-chloroethyl chloroformate (232 mg, 1.62 mmol) and DIEA (139 mg, 1.08 mmol) were added. The mixture was reacted at room temperature for 1 hour, the reaction solution was concentrated under reduced pressure, the concentrate was dissolved in MeOH (5 mL), then heated to 50 °C for 50 minutes, then directly concentrated under reduced pressure, and the concentrate was purified by silica gel column chromatography (DCM:MeOH(NH3) = 15:1) to obtain (R)-1-(8-fluoro-7-(7-fluoro-3- (methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((R)-3-methyl-2- (piperazin-1-ylmethyl)butoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol.

[0924] LC-MS: (ESI, m / z): [M+H] + = 831.5.

[0925] Step 4: Preparation of 1-(5-(9-((4-((R)-2-(((8-fluoro-7-(7-fluoro-3- (methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-4-((R)-3-hydroxy-3- methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)-3-methylbutyl)piperazin-1-yl)methyl)- 3-azaspiro[5.5]undecane-3-carbonyl)-2-methoxyphenyl)dihydropyrimidine-2,4(1H,3H)-dione

[0926] To a solution of (R)-1-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((R)-3-methyl-2-(piperazin-1-ylmethyl)butyloxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (130 mg, 0.16 mmol) and 3-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)-3-azaspiro[5.5]undecan-9- formaldehyde (80 mg, 0.19 mmol) in DCM / AcOH (2 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 (107 mg, 0.48 mmol) under ice bath and stirred for 2 h. The mixture was concentrated and then purified by silica gel column chromatography (DCM:MeOH = 10:1) to give 1-(5-(9-((4-((R)-2-(((8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)-3-methylbutyl)piperazin-1-yl)methyl)-3-azaspiro[5.5]undecane-3-carbonyl)-2-methoxyphenyl)dihydropyrimidine-2,4(1H,3H)-dione.

[0927] LC-MS: (ESI, m / z): [M / 2 + H] + = 622.0.

[0928] Step 5: Preparation of 1-(5-(9-((4-((R)-2-(((7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)-3-methylbutyl)piperazin-1-yl)methyl)-3-azaspiro[5.5]undecane-3-carbonyl)-2-methoxyphenyl)dihydropyrimidine-2,4(1H,3H)-dione

[0929] To a solution of 1-(5-(9-((4-((R)-2-(((8-fluoro-7-(7-fluoro-3- (methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-4-((R)-3- hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)-3- methylbutyl)piperazin-1-yl)methyl)-3-azaspiro[5.5]undecane-3-carbonyl)-2- methoxyphenyl)dihydropyrimidine-2,4(1H,3H)-dione (130 mg, 0.11 mmol) in DMF (2 mL) was added cesium fluoride (84 mg, 0.55 mmol) and the reaction was stirred at room temperature for 30 min. Water (10 mL) was added to the reaction and the mixture was 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 the resulting reaction was stirred at room temperature for 0.5 h. The reaction was adjusted to pH > 7 with aqueous Na2CO3 solution and then 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-((R)-2-(((7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)-3-methylbutyl)piperazin-1-yl)methyl)-3-azaspiro[5.5]undecane-3-carbonyl)-2-methoxyphenyl)dihydropyrimidine-2,4(1H,3H)-dione.

[0930] LC-MS: (ESI, m / z): [M / 2 + H] + = 521.4.

[0931] 1H NMR (400 MHz, DMSO-d6) δ 10.32 (s, 1H), 10.14 (s, 1H), 9.13 (d, J = 62.8 Hz, 1H), 8.01 - 7.93 (m, 1H), 7.46 (t, J = 9.0 Hz, 1H), 7.41 - 7.29 (m, 3H), 7.25 - 7.12 (m, 2H), 4.73 (d, J = 23.9 Hz, 1H), 4.49 - 4.26 (m, 3H), 4.13 - 4.25 (m, 2H), 3.84 (s, 3H), 3.67 - 3.36 (m, 7H), 2.68 (t, J = 6.6 Hz, 2H), 2.48 - 2.14 (m, 10H), 2.10 - 1.98 (m, 3H), 1.97 - 1.86 (m, 2H), 1.78 - 1.58 (m, 5H), 1.57 - 1.21 (m, 8H), 1.20 - 1.12 (m, 3H), 1.11 - 0.96 (m, 4H), 0.96 - 0.87 (m, 6H).

[0932] Example 5: l-(5-(9-((4-((l-(((7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-l-yl)-8-fluoro-4-(6-hydroxy-6-methyl-l,4-oxazepan-4-yl)pyrido[4,3- d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperazin-l-yl)methyl)-3- azaspiro[5.5]undecane-3-carbonyl)-2-methoxyphenyl)dihydropyrimidine-2,4(lH,3H)- dione

[0933] Step 1: Preparation of 4-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- (trisopropylsilylethynyl)naphthalen-l-yl)-2-((l-(hydroxymethyl)cyclopropyl)methoxy) pyrido[4,3-d]pyrimidin-4-yl)-6-methyl-l,4-oxazepan-6-ol

[0934] To a mixture solution of intermediate 2-P1 (400 mg, 0.97 mmol) and ((2-fluoro-6- (methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl) triisopropylsilane (597 mg, 1.16 mmol) in 1,4-dioxane (5 mL) and H2O (1 mL) was added cesium carbonate (948 mg, 2.91 mmol) and cataCXium A Pd-G3 (67 mg, 0.19 mmol) and reacted at 85 °C under N2protection overnight. The mixture was filtered and concentrated, and the concentrate was purified by silica gel column chromatography (DCM:MeOH = 10:1) to obtain 4-(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)-6-methyl-1,4- oxazepan-6-ol.

[0935] LC-MS: (ESI, m / z): [M+H] + = 763.3.

[0936] Step 2: Preparation of 1-(((8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-4-(6-hydroxy-6-methyl-1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-2- yl)oxy)methyl)cyclopropane-1-carbaldehyde

[0937] A solution of 4-(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)-6-methyl-1,4- oxazepan-6-ol (390 mg, 0.51 mmol) in dichloromethane (3 mL) was cooled to 0 °C at room temperature, Dess-Martin reagent (433 mg, 1.02 mmol) was added, and stirred at 25 °C for 2 hours. After the reaction was completed, saturated sodium thiosulfate solution (10 mL) was added, and extracted with dichloromethane (10 mL x 3), and the combined organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (DCM:MeOH = 10:1) to obtain 1-(((8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-4-(6-hydroxy-6-methyl-1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropane-1- carbaldehyde.

[0938] LC-MS: (ESI, m / z): [M+H] + = 761.3.

[0939] Step 3: Preparation of 1-(5-(9-((4-((1-(((8-fluoro-7-(7-fluoro-3- (methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-4-(6-hydroxy-6- methyl-1,4-oxazepan-4-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

[0940] To a solution of 1-(((8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-1-yl)-4-(6-hydroxy-6-methyl-1,4-oxazepan-4-yl)pyrido[4,3- d]pyrimidin-2-yl)oxy)methyl)cyclopropane-1-carbaldehyde (160 mg, 0.21 mmol) and 1-(2-methoxy-5-(9-(piperazin-1-ylmethyl)-3-azaspiro[5.5]undecane-3-carbonyl)phenyl)dihydropyrimidine- 2,4(1H,3H)-dione (126 mg, 0.25 mmol) in dichloromethane (2 mL) was added tetraisopropyl titanate (298 mg, 1.05 mmol) and glacial acetic acid (0.2 mL) at room temperature, stirred at 25 °C for 2 hours, the mixture was added NaBH(OAc)3(134 mg, 0.63 mmol) under ice bath and stirred for 2 hours. The mixture was concentrated, the concentrate was purified by silica gel column chromatography (DCM:MeOH = 100:1 ~ 5:1) to give 1-(5-(9-((4-((1-(((8-fluoro-7-(7-fluoro-3- (methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-4-(6-hydroxy-6-methyl-1,4- oxazepan-4-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.

[0941] MS (ESI) m / z: [M / 2+H] + = 622.0.

[0942] Step 4: Preparation of 1-(5-(9-((4-((1-(((7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-(6-hydroxy-6-methyl-1,4-oxazepan-4-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

[0943] To a solution of 1-(5-(9-((4-((1-(((8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- ((trisopropylsilyl)ethynyl)naphthalen-1-yl)-4-(6-hydroxy-6-methyl-1,4-oxazepan-4- 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 (79 mg, 0.064 mmol) in DMF (1 mL) was added cesium fluoride (97 mg, 0.64 mmol) and stirred at room temperature for 30 min. The reaction was added to water (10 mL) and extracted with ethyl acetate (10 mL x 3), the organic phases were combined and dried over anhydrous sodium sulfate and concentrated under reduced pressure. To a solution of the concentrate in 1,4-dioxane (1.0 mL) was added HCl / 1,4-dioxane (6 N, 0.5 mL) and reacted at room temperature for 0.5 h. The reaction was added to an aqueous Na2CO3 solution to adjust the mixture to pH > 7 and extracted with EtOAc (10 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-((1-(((7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-(6-hydroxy-6-methyl-1,4-oxazepan-4-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.

[0944] MS (ESI) m / z: [M+H] + = 1042.8.

[0945] 1H NMR (400 MHz, DMSO-d6) δ 10.56 - 9.95 (m, 2H), 9.36 (d, J = 52 Hz, 1H), 7.97 (dd, J = 9.1, 6.0 Hz, 1H), 7.46 (t, J = 9.0 Hz, 1H), 7.41 - 7.30 (m, 3H), 7.22 - 7.12 (m, 2H), 5.17 (d, J = 73.1 Hz, 1H), 4.50 - 3.86 (m, 9H), 3.84 (s, 3H), 3.65 - 3.47 (m, 8H), 2.71 - 2.65 (m, 2H), 2.47 - 2.15 (m, 10H), 2.08 - 2.00 (m, 2H), 1.75 - 1.62 (m, 2H), 1.55 - 1.23 (m, 8H), 1.16 (d, J = 8.4 Hz, 3H), 1.09 - 0.97 (m, 3H), 0.67 - 0.58 (m, 2H), 0.45 - 0.35 (m, 2H).

[0946] Example 24: l-(5-(3-((4-((R)-3-((7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-l-yl)-8-fluoro-4- ((R)-3-hydroxy-3-methylpiperidin-l-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)-2- methylpropyl)piperazin-l-yl)methyl)-l-oxo-9-azaspiro[5.5]undecan-9- yl)-2-methoxyphenyl)dihydropyrimidine-2,4(lH,3H)-dione

[0947] Step 1: Preparation of l-(5-(3-((4-((R)-3-((8-fluoro-7-(7-fluoro-3- (methoxymethoxy)-8-(trisopropylsilyl)ethynyl)naphthalen-l-yl)-4-((R)-3- hydroxy-3-methylpiperidin-l-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)-2- methylpropyl)piperazin-l-yl)methyl)-l-oxo-9-azaspiro[5.5]undecan-9- yl)-2-methoxyphenyl)dihydropyrimidine-2,4(lH,3H)-dione

[0948] To a solution of (R)-1-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((R)-2-methyl-3-(piperazin-1-yl)propoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (350 mg, 0.44 mmol) and 9-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)-1-oxo-9-azaspiro[5.5]undecan-3-carboxaldehyde (225 mg, 0.52 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 (277 mg, 1.31 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 1-(5-(3-((4-((R)-3-((8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)-2-methylpropyl)piperazin-1-yl)methyl)-1-oxo-9-azaspiro[5.5]undecan-9-yl)-2-methoxyphenyl)dihydropyrimidine-2,4(1H,3H)-dione.

[0949] LC-MS: (ESI, m / z): [M / 2 + H] + = 609.0.

[0950] Step 2: Preparation of 1-(5-(3-((4-((R)-3-((7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)-2-methylpropyl)piperazin-1-yl)methyl)-1-oxo-9-azaspiro[5.5]undecan-9-yl)-2-methoxyphenyl)dihydropyrimidine-2,4(1H,3H)-dione

[0951] To a solution of 1-(5-(3-((4-((R)-3-((8-fluoro-7-(7-fluoro-3- (methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-4-((R)-3- hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)-2- methylpropyl)piperazin-1-yl)methyl)-1-oxo-9-azaspiro[5.5]undecan-9- yl)-2-methoxyphenyl)dihydropyrimidine-2,4(1H,3H)-dione (352 mg, 0.29 mmol) in DMF (4 mL) was added cesium fluoride (659 mg, 4.34 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 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 (2.0 mL) was added HCl / 1,4-dioxane (6 N, 2.0 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 (20 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-((R)-3-((7-(8-ethynyl-7-fluoro-3- hydroxynaphthalen-1-yl)-8-fluoro-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3- d]pyrimidin-2-yl)oxy)-2-methylpropyl)piperazin-1-yl)methyl)-1-oxo-9- azaspiro[5.5]undecan-9-yl)-2-methoxyphenyl)dihydropyrimidine-2,4(1H,3H)-dione.

[0952] LC-MS: (ESI, m / z): [M+H] + = 1016.3.

[0953] 1H NMR (400 MHz, DMSO-d6) δ 10.33 (s, 1H), 9.13 (d, J = 60.5 Hz, 1H), 7.98 (dd, J = 9.2, 5.9 Hz, 1H), 7.50 - 7.43 (m, 1H), 7.40 - 7.35 (m, 2H), 7.33 (d, J = 2.0 Hz, 1H), 7.25 - 7.18 (m, 1H), 7.15 (d, J = 8.6 Hz, 1H), 4.83 - 4.64 (m, 1H), 4.52 - 4.43 (m, 1H), 4.40 - 4.28 (m, 1H), 4.13 - 4.03 (m, 2H), 3.96 - 3.93 (m, 1H), 3.84 (s, 3H), 3.68 - 3.54 (m, 5H), 3.27 - 3.00 (m, 5H), 2.71 - 2.65 (m, 2H), 2.45 - 1.90 (m, 15H), 1.72 - 1.62 (m, 4H), 1.59 - 1.41 (m, 4H), 1.38 - 1.24 (m, 3H), 1.16 (d, J = 15.9 Hz, 3H), 0.97 (d, J = 6.0 Hz, 3H).

[0954] Example 28: l-(5-(9-((4-((l-(((7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-l-yl)-8-fluoro-4-(2- oxo-l,6-diazaspiro[3.5]non-6-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperazin-l- yl)methyl)-3-azaspiro[5.5]undecane-3-carbonyl)-2-methoxyphenyl)dihydropyrimidine-2,4(lH,3H)-dione

[0955] Step 1: Preparation of 6-(7-chloro-8-fluoro-2-((l-(hydroxymethyl)cyclopropyl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)-l,6-diazaspiro[3.5]nonan-2-one

[0956] To a solution of intermediate 3-P1 (220 mg, 0.62 mmol) and cyclopropane-1,1-diyldimethanol (126 mg, 1.24 mmol) in anhydrous acetonitrile (3 mL) were added triethylenediamine (35 mg, 0.31 mmol) and anhydrous cesium carbonate (604 mg, 1.85 mmol), and the mixture was stirred at 25°C for 2 hours. After completion of the reaction, saturated brine (10 mL) was added, and the mixture was extracted with ethyl acetate (10 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (DCM:MeOH = 15:1) to obtain 6-(7-chloro-8-fluoro-2-((1-(hydroxymethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,6-diazaspiro[3.5]nonan-2-one.

[0957] LC-MS:(ESI,m / z):[M+H] + =422.2.

[0958] Step 3: Preparation of 6-(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)-1,6-diazaspiro[3.5]nonan-2-one

[0959] To a mixed solution of 6-(7-chloro-8-fluoro-2-((1-(hydroxymethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,6-diazaspiro[3.5]nonan-2-one (160 mg, 0.68 mmol) and ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (233 mg, 0.46 mmol) in 1,4-dioxane (3 mL) and H2O (0.6 mL) were added cesium carbonate (371 mg, 1.14 mmol) and cataCXium A Pd-G3 (55 mg, 0.076 mmol), and the reaction was carried out at 85°C under N2 protection overnight. The mixture was filtered and concentrated, and the concentrate was purified by silica gel column chromatography (DCM:MeOH=20:1) to give 6-(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)-1,6-diazaspiro[3.5]nonan-2-one.

[0960] LC-MS:(ESI,m / z):[M+H] + =772.3.

[0961] Step 4: Preparation of 1-(((8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- ((trisopropylsilyl)ethynyl)naphthalen-1-yl)-4-(2-oxo-1,6-diazaspiro[3.5]non-6- yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropane-1-carbaldehyde

[0962] A solution of 6-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- ((trisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((1-(hydroxymethyl)cyclopropyl)methoxy) pyrido[4,3-d]pyrimidin-4-yl)-1,6-diazaspiro[3.5]nonan-2-one (170 mg, 0.22 mmol) in dichloromethane (3 mL) was cooled to 0 °C at room temperature, Dess-Martin reagent (187 mg, 0.44 mmol) was added, and stirring was performed at 25 °C for 2 h. After the reaction was completed, saturated sodium thiosulfate solution (10 mL) was added, extraction was performed with dichloromethane (10 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (DCM:MeOH = 20:1) to obtain 1-(((8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- ((trisopropylsilyl)ethynyl)naphthalen-1-yl)-4-(2-oxo-1,6-diazaspiro[3.5]non-6-yl)pyrido[4,3- d]pyrimidin-2-yl)oxy)methyl)cyclopropane-1-carbaldehyde.

[0963] LC-MS: (ESI, m / z): [M+H] + = 770.3.

[0964] Step 5: Preparation of 1-(5-(9-((4-((1-(((8-fluoro-7-(7-fluoro-3- (methoxymethoxy)-8-((trisopropylsilyl)ethynyl)naphthalen-1-yl)-4-(2-oxo-1,6- diazaspiro[3.5]non-6-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

[0965] To a solution of 1-(((8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-4-(2-oxo-1,6-diazaspiro[3.5]non-6-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropane-1-carbaldehyde (60 mg, 0.078 mmol) and 1-(2-methoxy-5-(9-(piperazin-1-ylmethyl)-3-azaspiro[5.5]undecane-3-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione (47 mg, 0.094 mmol) in dichloromethane (1 mL) was added tetraisopropyl titanate (111 mg, 0.39 mmol) and glacial acetic acid (0.1 mL) at room temperature and stirred at 25 °C for 2 h. The mixture was added NaBH(OAc)3(50 mg, 0.23 mmol) under ice bath and stirred for 2 h. The mixture was concentrated and the concentrate was purified by silica gel column chromatography (DCM:MeOH = 100:1 ~ 5:1) to give 1-(5-(9-((4-((1-(((8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-4-(2-oxo-1,6-diazaspiro[3.5]non-6-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.

[0966] MS (ESI) m / z: [M / 2 + H] + = 626.5.

[0967] Step 6: Preparation of 1-(5-(9-((4-((1-(((7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-(2-oxo-1,6-diazaspiro[3.5]non-6-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

[0968] To a solution of 1-(5-(9-((4-((1-(((8-fluoro-7-(7-fluoro-3- (methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-4-(2-oxo-1,6- diazaspiro[3.5]non-6-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 (70 mg, 0.056 mmol) in DMF (1 mL) was added cesium fluoride (127 mg, 0.84 mmol) and stirred at room temperature for 30 min. To the reaction mixture was 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. To the solution of the concentrate in DCM (1.0 mL) was added TFA (0.5 mL) and reacted 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 2). The organic phase was washed with brine, dried over anhydrous Na2SO4, and then concentrated under reduced pressure. The crude product was purified by high performance liquid preparative purification to give 1-(5-(9-((4-((1-(((7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-(2-oxo-1,6- diazaspiro[3.5]non-6-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.

[0969] MS (ESI) m / z: [M / 2 + H] + = 526.3.

[0970] 1H NMR (400 MHz, DMSO-d6) δ 10.34 (s, 1H), 10.18 (s, 1H), 9.01 (d, J = 20.8 Hz, 1H), 8.57 (d, J = 8.8 Hz, 1H), 7.98 (dd, J = 9.2, 6.0 Hz, 1H), 7.47 (t, J = 9.0 Hz, 1H), 7.41 - 7.30 (m, 3H), 7.21 - 7.17 (m, 1H), 7.14 (d, J = 8.4 Hz, 1H), 4.30 - 4.20 (m, 3H), 4.10 - 3.98 (m, 1H), 3.95 - 3.85 (m, 2H), 3.84 (s, 3H), 3.81 - 3.71 (m, 1H), 3.59 (t, J = 6.6 Hz, 2H), 3.53 - 3.45 (m, 2H), 2.87 - 2.78 (m, 1H), 2.71 - 2.62 (m, 4H), 2.35 - 2.23 (m, 6H), 2.08 - 1.93 (m, 4H), 1.91 - 1.81 (m, 3H), 1.77 - 1.59 (m, 3H), 1.57 - 1.37 (m, 6H), 1.33 - 1.21 (m, 3H), 1.15 - 0.85 (m, 5H), 0.66 - 0.60 (m, 2H), 0.44 - 0.37 (m, 2H).

[0971] Example 29: l-(5-(9-((4-((l-(((4-(3-ethyl-3-hydroxypiperidin-l-yl)-7-(8-ethynyl-7-fluoro-3- hydroxynaphthalen-l-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperazin-l- yl)methyl)-3-azaspiro[5.5]undecane-3-carbonyl)-2-methoxyphenyl)dihydropyrimidine-2,4(lH,3H)- dione

[0972] Step 3: Preparation of l-(7-chloro-8-fluoro-2-((l-(hydroxymethyl)cyclopropyl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)-3-ethylpiperidin-3-ol

[0973] Intermediate 4-P1 (265 mg, 0.77 mmol) and cyclopropane-1,1-diyl dimethanol (157 mg, 1.54 mmol) were added to anhydrous acetonitrile (5 mL), then cesium carbonate (751 mg, 2.30 mmol) and triethylene diamine (9 mg, 0.08 mmol) were added, and the mixture was stirred at 25 °C for 1 h. After the reaction was completed, saturated brine (15 mL) was added, extracted with ethyl acetate (15 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (DCM:MeOH = 15:1) to give 1-(7-chloro-8-fluoro-2-((1-(hydroxymethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-ethylpiperidin-3-ol.

[0974] LC-MS: (ESI, m / z): [M+H] + = 411.1.

[0975] Step 4: Preparation of 3-ethyl-1-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((1-(hydroxymethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-ol

[0976] To a mixture solution of 1-(7-chloro-8-fluoro-2-((1-(hydroxymethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-ethylpiperidin-3-ol (270 mg, 0.66 mmol) and ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (404 mg, 0.79 mmol) in 1,4-dioxane (3 mL) and H2O (0.5 mL), CataCXium A Pd G3 (96 mg, 0.13 mmol) and cesium carbonate (645 mg, 1.98 mmol) were added. The mixture was reacted at 85 °C for 16 h under nitrogen protection, water (10 mL) was added, extracted with ethyl acetate (10 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (DCM:MeOH = 15:1) to give 3-ethyl-1-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((1-(hydroxymethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-ol.

[0977] LC-MS: (ESI, m / z): [M+H]+ = 761.3.

[0978] Step 5: Preparation of 1-(((4-(3-ethyl-3-hydroxypiperidin-1-yl)-8-fluoro-7-(7-fluoro-3- (methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-2- yl)oxy)methyl)cyclopropane-1-carbaldehyde

[0979] A solution of 3-ethyl-1-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((1-(hydroxymethyl)cyclopropyl)methoxy) pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-ol (320 mg, 0.42 mmol) in DCM (5 mL) was cooled to 0 °C, Dess-Martin oxidant (445 mg, 1.05 mmol) was added, and the reaction was stirred at room temperature for 0.5 h. After the reaction was completed, saturated sodium thiosulfate solution (15 mL) was added, and the mixture was extracted with dichloromethane (30 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (DCM:MeOH = 15:1) to give 1-(((4-(3-ethyl-3-hydroxypiperidin-1-yl)-8-fluoro-7-(7-fluoro-3- (methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-2- yl)oxy)methyl)cyclopropane-1-carbaldehyde.

[0980] LC-MS: (ESI, m / z): [M+H] + = 759.3.

[0981] Step 6: Preparation of 1-(5-(9-((4-((1-(((4-(3-ethyl-3-hydroxypiperidin-1-yl)-8-fluoro-7-(7-fluoro-3- (methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-2- yl)oxy)methyl)cyclopropyl)methyl)piperazin-1-yl)methyl)-3-azaspiro[5.5]undecane-3- carbonyl)-2-methoxyphenyl)dihydropyrimidine-2,4(1H,3H)-dione

[0982] To a solution of 1-(((4-(3-ethyl-3-hydroxypiperidin-1-yl)-8-fluoro-7-(7-fluoro-3- (methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3- d]pyrimidin-2-yl)oxy)methyl)cyclopropane-1-carbaldehyde (150 mg, 0.20 mmol) and 1-(2-methoxy-5-(9-(piperazin-1-ylmethyl)-3-azaspiro[5.5]undecane-3- carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione (118 mg, 0.24 mmol) in DCM / AcOH (2.0 mL / 0.1 mL) was added tetraisopropyl titanate (281 mg, 0.99 mmol), the mixed solution was stirred at 30 °C for 2 h. Then NaBH(OAc)3 (133 mg, 0.60 mmol) was added at room temperature and stirred for 2 h. The mixture was concentrated and purified by silica gel column chromatography (DCM:MeOH = 20:1) to give 1-(5-(9-((4-((1-(((4-(3-ethyl-3-hydroxypiperidin-1-yl)-8-fluoro-7-(7-fluoro-3- (methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3- d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperazin-1-yl)methyl)-3- azaspiro[5.5]undecane-3-carbonyl)-2-methoxyphenyl)dihydropyrimidine-2,4(1H,3H)- dione.

[0983] LC-MS: (ESI, m / z): [M / 2 + H] + = 621.0.

[0984] Step 7: Preparation of 1-(5-(9-((4-((1-(((4-(3-ethyl-3-hydroxypiperidin-1-yl)-7-(8- ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperazin-1-yl)methyl)-3-azaspiro[5.5]undecane-3- carbonyl)-2-methoxyphenyl)dihydropyrimidine-2,4(1H,3H)-dione

[0985] To a stirred solution of 1-(5-(9-((4-((1-(((4-(3-ethyl-3-hydroxypiperidin-1-yl)-8-fluoro-7-(7-fluoro-3- (methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-2- yl)oxy)methyl)cyclopropyl)methyl)piperazin-1-yl)methyl)-3-azaspiro[5.5]undecane-3- carbonyl)-2-methoxyphenyl)dihydropyrimidine-2,4(1H,3H)-dione (126 mg, 0.10 mmol) in DMF (2 mL) was added cesium fluoride (77 mg, 0.50 mmol) and stirred at room temperature for 30 min. After the reaction was completed, ammonium chloride solution (5 mL) was added, extracted with ethyl acetate (10 mL x 3), the organic phase was combined and washed with saturated brine, and the organic phase was concentrated. The mixture was added with 1,4-dioxane (2 mL) and a mixture of HCl / 1,4-dioxane (6 N, 1 mL) at room temperature and reacted for 0.5 h. The reaction solution was adjusted to pH > 7 with aqueous Na2CO3 solution, extracted with ethyl acetate (10 mL x 2). The organic phase was washed with brine, dried over anhydrous Na2SO4, and concentrated. The crude product was purified by high performance liquid chromatography to obtain 1-(5-(9-((4-((1-(((4-(3-ethyl-3-hydroxypiperidin-1-yl)-7-(8-ethynyl-7-fluoro-3- hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl) piperazin-1-yl)methyl)-3-azaspiro[5.5]undecane-3-carbonyl)-2-methoxyphenyl)dihydropyrimidine-2,4(1H,3H)-dione.

[0986] LC-MS: (ESI, m / z): [M+H] + = 1040.4.

[0987] 1H NMR (400 MHz, DMSO-d6) δ 10.33 (s, 1H), 10.16 (s, 1H), 9.14 (d, J = 67.6 Hz, 1H), 8.03-7.93 (m, 1H), 7.46 (t, J = 9.0 Hz, 1H), 7.41-7.31 (m, 3H), 7.24-7.13 (m, 2H), 4.58 (d, J = 29.0 Hz, 1H), 4.49-4.22 (m, 3H), 4.48-4.22 (m, 1H), 3.97-3.92 (m, 1H), 3.84 (s, 3H), 3.62-3.42 (m, 6H), 3.29-3.22 (m, 2H), 2.70-2.64 (m, 2H), 2.36-2.22 (m, 9H), 2.08-2.02 (m, 3H), 1.71-1.61 (m, 5H), 1.53-1.38 (m, 8H), 1.28-1.22 (m, 2H), 1.10-0.98 (m, 4H), 0.91-0.84 (m, 3H), 0.68-0.58 (m, 2H), 0.45-0.35 (m, 2H).

[0988] Example 30: 1-(5-(9-((4-((1-(((4-(3-ethyl-3-hydroxypiperidin-1-yl)-7-(8-ethynyl-7-fluoro-3- hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperazin- 1-yl)methyl)-3-azaspiro[5.5]undecane-3-carbonyl)-2-methoxyphenyl)dihydropyrimidine-2,4(1H,3H)- dione

[0989] Step 1: Preparation of 1-(7-chloro-8-fluoro-2-((1-(hydroxymethyl)cyclopropyl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)-3-ethylpiperidin-3-ol

[0990] Intermediate 4-P2 (330 mg, 0.96 mmol) and cyclopropane-1,1-diyl dimethanol (195 mg, 1.91 mmol) were added to anhydrous acetonitrile (5 mL), then cesium carbonate (935 mg, 2.87 mmol) and triethylenediamine (21 mg, 0.19 mmol) were added, and the mixture was stirred at 25 °C for 1 h. After the reaction was completed, saturated brine (15 mL) was added, extracted with ethyl acetate (15 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 = 1:1) to give 1-(7-chloro-8-fluoro-2-((1-(hydroxymethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3- ethylpiperidin-3-ol.

[0991] LC-MS: (ESI, m / z): [M+H] + = 411.2.

[0992] Step 2: Preparation of 3-ethyl-l-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-l-yl)-2-((l-(hydroxymethyl)cyclopropyl)methoxy) pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-ol

[0993] To a mixture solution of l-(7-chloro-8-fluoro-2-((l-(hydroxymethyl)cyclopropyl)methoxy) pyrido[4,3-d]pyrimidin-4-yl)-3-ethylpiperidin-3-ol (280 mg, 0.68 mmol) and ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)naphthalen-l- yl)ethynyl)triisopropylsilane (419 mg, 0.82 mmol) in 1,4-dioxane (5 mL) and H20 (1 mL) was added CataCXium A Pd G3 (99 mg, 0.14 mmol) and cesium carbonate (666 mg, 2.04 mmol). The mixture was reacted at 85 °C for 16 h under nitrogen protection, water (10 mL) was added, 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 (PE:EtOAc = 1: 1) to give 3-ethyl-l-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-l-yl)-2-((l-(hydroxymethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-ol.

[0994] LC-MS: (ESI, m / z): [M+H] + = 761.4.

[0995] Step 3: Preparation of l-(((4-(3-ethyl-3-hydroxypiperidin-l-yl)-8-fluoro-7-(7-fluoro-3- (methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-l-yl)pyrido[4,3-d]pyrimidin-2- yl)oxy)methyl)cyclopropane-l-carbaldehyde

[0996] A solution of 3-ethyl-l-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-l-yl)-2-((l-(hydroxymethyl)cyclopropyl)methoxy) pyridino[4,3-d]pyrimidin-4-yl)piperidin-3-ol (260 mg, 0.34 mmol) in DCM (3 mL) was cooled to 0 °C, Dess-Martin oxidant (290 mg, 0.68 mmol) was added, and the reaction was stirred at room temperature for 0.5 h. After the reaction was completed, saturated sodium thiosulfate solution (15 mL) was added, and the mixture was extracted with dichloromethane (30 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (DCM:PE = 1:1) to give l-(((4-(3-ethyl-3-hydroxypiperidin-l-yl)-8-fluoro-7-(7-fluoro-3- (methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-l-yl)pyridino[4,3-d]pyrimidin-2- yl)oxy)methyl)cyclopropane-l-carbaldehyde.

[0997] LC-MS: (ESI, m / z): [M+H] + = 759.4.

[0998] Step 4: Preparation of l-(5-(9-((4-((l-(((4-(3-ethyl-3-hydroxypiperidin-l-yl)-8-fluoro-7-(7-fluoro-3- (methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-l-yl)pyridino[4,3-d]pyrimidin-2- yl)oxy)methyl)cyclopropyl)methyl)piperazin-l-yl)methyl)-3-azaspiro[5.5]undecane-3- carbonyl)-2-methoxyphenyl)dihydropyrimidine-2,4(lH,3H)-dione

[0999] To a solution of 1-(((4-(3-ethyl-3-hydroxypiperidin-1-yl)-8-fluoro-7-(7-fluoro-3- (methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3- d]pyrimidin-2-yl)oxy)methyl)cyclopropane-1-carbaldehyde (100 mg, 0.13 mmol) and 1-(2-methoxy-5-(9-(piperazin-1-ylmethyl)-3-azaspiro[5.5]undecane-3- carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione (79 mg, 0.16 mmol) in DCM / AcOH (2.0 mL / 0.1 mL) was added tetraisopropyl titanate (187 mg, 0.66 mmol), the mixed solution was stirred at 30 °C for 2 h. Then NaBH(OAc)3 (84 mg, 0.40 mmol) was added at room temperature and stirred for 2 h. The reaction was directly concentrated, the concentrate was purified by silica gel column chromatography (DCM:MeOH = 10:1) to give 1-(5-(9-((4-((1-(((4-(3-ethyl-3-hydroxypiperidin-1-yl)-8-fluoro-7-(7-fluoro-3- (methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3- d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperazin-1-yl)methyl)-3- azaspiro[5.5]undecane-3-carbonyl)-2-methoxyphenyl)dihydropyrimidine-2,4(1H,3H)- dione.

[1000] LC-MS: (ESI, m / z): [M / 2 + H] + = 621.0.

[1001] Step 5: Preparation of 1-(5-(9-((4-((1-(((4-(3-ethyl-3-hydroxypiperidin-1-yl)-7-(8- ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperazin-1-yl)methyl)-3-azaspiro[5.5]undecane-3- carbonyl)-2-methoxyphenyl)dihydropyrimidine-2,4(1H,3H)-dione

[1002] To a stirred solution of 1-(5-(9-((4-((1-(((4-(3-ethyl-3-hydroxypiperidin-1-yl)-8-fluoro-7-(7-fluoro-3- (methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-2- yl)oxy)methyl)cyclopropyl)methyl)piperazin-1-yl)methyl)-3-azaspiro[5.5]undecane-3- carbonyl)-2-methoxyphenyl)dihydropyrimidine-2,4(1H,3H)-dione (109 mg, 0.088 mmol) in DMF (2 mL) was added cesium fluoride (200 mg, 1.32 mmol) and stirred at room temperature for 30 min. After the reaction was completed, ammonium chloride solution (5 mL) was added, extracted with ethyl acetate (10 mL x 3), the organic phases were combined and washed with saturated brine, and the organic phase was concentrated. The concentrate was re-added with dioxane (2 mL) and a mixture of HCl / dioxane (6N, 1 ml) at room temperature, and the reaction was allowed to proceed for 0.5 h. The reaction solution was adjusted to pH > 7 with aqueous Na2CO3 solution, extracted with ethyl acetate (10 mL x 2). The organic phase was washed with brine, dried over anhydrous Na2SO4 and concentrated. The crude product was purified by high performance liquid chromatography to obtain 1-(5-(9-((4-((1-(((4-(3-ethyl-3-hydroxypiperidin-1-yl)-7-(8-ethynyl-7-fluoro-3- hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl) piperazin-1-yl)methyl)-3-azaspiro[5.5]undecane-3-carbonyl)-2-methoxyphenyl)dihydropyrimidine-2,4(1H,3H)-dione.

[1003] LC-MS: (ESI, m / z): [M / 2 + H] + = 520.9.

[1004] 1H NMR (400 MHz, DMSO-d6) δ 10.33 (s, 1H), 10.16 (d, J = 4.3 Hz, 1H), 9.14 (d, J = 67.7 Hz, 1H), 8.05 - 7.92 (m, 1H), 7.46 (t, J = 9.0 Hz, 1H), 7.41 - 7.30 (m, 3H), 7.24 - 7.12 (m, 2H), 4.58 (d, J = 29.0 Hz, 1H), 4.48 - 4.22 (m, 3H), 4.19 - 3.98 (m, 1H), 3.97 - 3.91 (m, 1H), 3.84 (s, 3H), 3.63 - 3.39 (m, 6H), 3.31 - 3.17 (m, 2H), 2.71 - 2.65 (m, 2H), 2.48 - 2.15 (m, 9H), 2.13 - 1.90 (m, 3H), 1.77 - 1.61 (m, 5H), 1.60 - 1.33 (m, 8H), 1.32 - 1.22 (m, 2H), 1.16 - 0.95 (m, 4H), 0.92 - 0.82 (m, 3H), 0.68 - 0.58 (m, 2H), 0.46 - 0.33 (m, 2H).

[1005] Example 33: l-(5-(3-((4-((l-(((7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-l-yl)-8-fluoro-4- ((R)-3-hydroxy-3-methylpiperidin-l-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperazin-l-yl)methyl)-l-oxo-9-azaspiro[5.5]undecane-9-carbonyl)-2-methylphenyl)dihydropyrimidine-2,4(lH,3H)-dione

[1006] Step 1: Preparation of l-(5-(3-((4-((l-(((8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- ((trisopropylsilyl)ethynyl)naphthalen-l-yl)-4-((R)-3-hydroxy-3-methylpiperidin-l- yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperazin-l-yl)methyl)-l-oxo-9-azaspiro[5.5]undecane-9-carbonyl)-2-methylphenyl)dihydropyrimidine-2,4(lH,3H)-dione

[1007] To a solution of (R)-1-(((8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- ((trisopropylsilyl)ethynyl)naphthalen-1-yl)-4-(3-hydroxy-3-methylpiperidin-1- yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropane-1-carbaldehyde (150 mg, 0.20 mmol) and Intermediate 13 (75 mg, 0.16 mmol) in DCM / AcOH (3 mL / 0.2 mL) was added tetraisopropyl titanate (220 mg, 0.78 mmol) and stirred at 25 °C for 1 h. The mixture was added NaBH(OAc)3(82 mg, 0.39 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 1-(5-(3-((4-((1-(((8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- ((trisopropylsilyl)ethynyl)naphthalen-1-yl)-4-((R)-3-hydroxy-3-methylpiperidin-1- yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperazin-1-yl)methyl)-1- oxo-9-azaspiro[5.5]undecan-9-carbonyl)-2-methylphenyl)dihydropyrimidine-2,4(1H,3H)- dione.

[1008] LC-MS: (ESI, m / z): [M / 2 + H] + = 607.0.

[1009] Step 2: Preparation of 1-(5-(3-((4-((1-(((7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1- yl)-8-fluoro-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2- yl)oxy)methyl)cyclopropyl)methyl)piperazin-1-yl)methyl)-1-oxo-9-azaspiro[5.5]undecan-9- carbonyl)-2-methylphenyl)dihydropyrimidine-2,4(1H,3H)-dione

[1010] To a solution of 1-(5-(3-((4-((1-(((8-fluoro-7-(7-fluoro-3- (methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-4-((R)-3- hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl) methyl)piperazin-1-yl)methyl)-1-oxo-9-azaspiro[5.5]undecane-9-carbonyl)-2- methylphenyl)dihydropyrimidine-2,4(1H,3H)-dione (130 mg, 0.11 mmol) in DMF (2 mL) was added cesium fluoride (81 mg, 0.54 mmol) and stirred at room temperature for 1 h. To the reaction was added water (20 mL) and extracted with ethyl acetate (20 mL x 3), the organic phases were combined and washed with saturated brine, dried over anhydrous Na2SO4, filtered and concentrated. To a stirred solution of the concentrate in dichloromethane (2.0 mL) was added TFA (1.0 mL) and the reaction was stirred at room temperature for 0.5 h. The reaction was adjusted to pH > 7 with aqueous NaHCO3solution and extracted with EtOAc (20 mL x 3). The organic phase was washed with brine, dried over anhydrous Na2SO4and 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-((R)-3- hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl) piperazin-1-yl)methyl)-1-oxo-9-azaspiro[5.5]undecane-9-carbonyl)-2-methylphenyl)dihydropyrimidine-2,4(1H,3H)-dione.

[1011] LC-MS: (ESI, m / z): [M+H] + = 1012.3.

[1012] 1H NMR (400 MHz, DMSO-d6) δ 10.37 (s, 1H), 10.20 (s, 1H), 9.12 (d, J = 66.0 Hz, 1H), 7.97 (dd, J = 9.2, 5.9 Hz, 1H), 7.46 (t, J = 9.1 Hz, 1H), 7.39 (s, 1H), 7.36 - 7.29 (m, 2H), 7.28 - 7.15 (m, 2H), 4.74 (d, J = 29.5 Hz, 1H), 4.40 - 4.21 (m, 3H), 4.12 - 3.92 (m, 3H), 3.82 - 3.75 (m, 1H), 3.69 - 3.50 (m, 5H), 2.81 - 2.65 (m, 3H), 2.43 - 2.16 (m, 12H), 2.16 - 1.86 (m, 5H), 1.80 - 1.42 (m, 9H), 1.37 - 1.23 (m, 3H), 1.17 (d, J = 16.7 Hz, 3H), 0.70 - 0.57 (m, 2H), 0.45 - 0.33 (m, 2H).

[1013] Example 34: l-(5-(3-((4-((R)-3-((7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-l-yl)-8-fluoro-4-((R)-3-hydroxy-3-methylpiperidin-l-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)-2-methylpropyl)piperazin-l-yl)methyl)-l-oxo-9-azaspiro[5.5]undecan-9- carbonyl)-2-methylphenyl)dihydropyrimidine-2,4(lH,3H)-dione

[1014] Step 1: Preparation of l-(5-(3-((4-((R)-3-((8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- (trisopropylsilyl)ethynyl)naphthalen-l-yl)-4-((R)-3-hydroxy-3-methylpiperidin-l- yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)-2-methylpropyl)piperazin-l-yl)methyl)-l-oxo-9- azaspiro[5.5]undecan-9-carbonyl)-2-methylphenyl)dihydropyrimidine-2,4(lH,3H)- dione

[1015] To a solution of (R)-1-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((R)-2-methyl-3-(piperazin-1-yl)propoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (200 mg, 0.25 mmol) and 9-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methylbenzoyl)-1-oxa-9-azaspiro[5.5]undecane-3-carbaldehyde (123 mg, 0.30 mmol) in DCM / AcOH (3 mL / 0.3 mL) was added tetraisopropyl titanate (354 mg, 1.25 mmol) and stirred at 25 °C for 2 h. The mixture was added NaBH(OAc)3(158 mg, 0.75 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 1-(5-(3-((4-((R)-3-((8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)-2-methylpropyl)piperazin-1-yl)methyl)-1-oxa-9-azaspiro[5.5]undecane-9-carbonyl)-2-methylphenyl)dihydropyrimidine-2,4(1H,3H)-dione.

[1016] LC-MS: (ESI, m / z): [M / 2 + H] + = 601.0.

[1017] Step 2: Preparation of 1-(5-(3-((4-((R)-3-((7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)-2-methylpropyl)piperazin-1-yl)methyl)-1-oxa-9-azaspiro[5.5]undecane-9-carbonyl)-2-methylphenyl)dihydropyrimidine-2,4(1H,3H)-dione

[1018] To a solution of 1-(5-(3-((4-((R)-3-((8-fluoro-7-(7-fluoro-3- (methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-4-((R)-3- hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)-2-methylpropyl) piperazin-1-yl)methyl)-1-oxo-9-azaspiro[5.5]undecan-9-carbonyl)-2-methylphenyl) dihydropyrimidine-2,4(1H,3H)-dione (203 mg, 0.17 mmol) in DMF (2 mL) was added cesium fluoride (385 mg, 2.54 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 (2.0 mL) was added HCl / 1,4-dioxane (6 N, 2.0 mL) and the reaction was allowed to proceed at room temperature for 0.5 h. The reaction was added to aqueous Na2CO3solution to adjust the mixture to pH > 7 and extracted with EtOAc (3 x 10 mL). The organic phase was washed with brine, dried over anhydrous Na2SO4and concentrated. The crude product was purified by preparative high-performance liquid chromatography to give 1-(5-(3-((4-((R)-3-((7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)-2-methylpropyl)piperazin-1-yl)methyl)-1-oxo-9-azaspiro[5.5]undecan-9-carbonyl)-2-methylphenyl) dihydropyrimidine-2,4(1H,3H)-dione.

[1019] LC-MS: (ESI, m / z): [M+H] + = 1000.4.

[1020] 1H NMR (400 MHz, DMSO-d6) δ 10.37 (s, 1H), 10.16 (s, 1H), 9.13 (d, J = 60.2 Hz, 1H), 7.97 (dd, J = 9.1, 6.0 Hz, 1H), 7.46 (t, J = 8.8 Hz, 1H), 7.39 (s, 1H), 7.36 - 7.30 (m, 2H), 7.27 - 7.18 (m, 2H), 4.73 (d, J = 19.3 Hz, 1H), 4.52 - 4.28 (m, 2H), 4.18 - 3.98 (m, 3H), 3.94 (d, J = 3.4 Hz, 1H), 3.85 - 3.75 (m, 1H), 3.70 - 3.43 (m, 4H), 3.24 - 3.10 (m, 2H), 2.79 - 2.66 (m, 2H), 2.48 - 2.23 (m, 9H), 2.21 (s, 3H), 2.18 - 1.95 (m, 6H), 1.80 - 1.42 (m, 9H), 1.40 - 1.21 (m, 4H), 1.16 (d, J = 15.8 Hz, 3H), 0.97 (d, J = 5.8 Hz, 3H).

[1021] Example 36: (S)-1-(5-(9-((4-((1-(((7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-(1-oxido-6- azaspiro[3.5]non-6-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

[1022] Step 1: Preparation of (S)-1-(5-(9-((4-((1-(((8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- ((trisopropylsilyl)ethynyl)naphthalen-1-yl)-4-(1-oxido-6-azaspiro[3.5]non-6-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

[1023] To a solution of (S)-1-(((8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- ((trisopropylsilyl)ethynyl)naphthalen-1-yl)-4-(1-oxo-6-azaspiro[3.5]non-6-yl)pyrido[4,3- d]pyrimidin-2-yl)oxy)methyl)cyclopropane-1-carbaldehyde (140 mg, 0.185 mmol) and 1-(2- methoxy-5-(9-(piperazin-1-ylmethyl)-3-azaspiro[5.5]undecane-3-carbonyl)phenyl)dihydropyrimidine- 2,4(1H,3H)-dione (110 mg, 0.222 mmol) in dichloromethane (2 mL) was added tetraisopropyl titanate (263 mg, 0.925 mmol) and glacial acetic acid (0.1 mL) at room temperature and stirred at 25 °C for 2 h. The mixture was added NaBH(OAc)3(118 mg, 0.555 mmol) under ice bath and stirred at room temperature for 2 h. The mixture was concentrated and the resulting crude was purified by silica gel column chromatography (DCM:MeOH = 100:1 ~ 5:1) to give (S)-1-(5-(9-((4-((1-(((8-fluoro-7-(7-fluoro-3- (methoxymethoxy)-8-((trisopropylsilyl)ethynyl)naphthalen-1-yl)-4-(1-oxo-6-azaspiro[3.5]non-6-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.

[1024] LC-MS: (ESI, m / z): [M / 2 + H] + = 620.0.

[1025] Step 2: Preparation of (S)-1-(5-(9-((4-((1-(((7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)- 8-fluoro-4-(1-oxo-6-azaspiro[3.5]non-6-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

[1026] To a solution of (S)-1-(5-(9-((4-((1-(((8-fluoro-7-(7-fluoro-3- (methoxymethoxy)-8-((triisopropylsilyl)ethynyl) naphthalen-1-yl)-4-(1-oxido-6- azaspiro[3.5]non-6-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 (120 mg, 0.097 mmol) in DMF (1 mL) was added cesium fluoride (74 mg, 0.485 mmol) and stirred at room temperature for 30 min. Water (5 mL) was added to the reaction mixture and extracted with ethyl acetate (5 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 DCM (1.0 mL) was added TFA (0.5 mL) and reacted at room temperature for 0.5 h. The reaction mixture was adjusted to pH > 7 with aqueous Na2CO3 solution and extracted with EtOAc (5 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 (S)-1-(5-(9-((4-((1-(((7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-(1-oxido-6- azaspiro[3.5]non-6-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.

[1027] LC-MS: (ESI, m / z): [M+H] + = 1038.3.

[1028] 1H NMR (400 MHz, DMSO-d6) δ 10.33 (s, 1H), 9.13 (d, J = 29.4 Hz, 1H), 7.92 (s, 1H), 7.49 - 2.23 (m, 4H), 7.20 - 7.07 (m, 2H), 4.47 - 4.36 (m, 2H), 4.33 - 4.05 (m, 4H), 3.98 - 3.87 (m, 1H), 3.84 (s, 3H), 3.82 - 3.76 (m, 1H), 3.59 (t, J = 6.4 Hz, 2H), 2.72 - 2.63 (m, 3H), 2.46 - 2.22 (m, 12H), 2.18 - 2.00 (m, 4H), 1.98 - 1.78 (m, 3H), 1.76 - 1.63 (m, 3H), 1.59 - 1.35 (m, 6H), 1.34 - 1.17 (m, 3H), 1.12 - 0.95 (m, 4H), 0.69 - 0.58 (m, 2H), 0.44 - 0.36 (s, 2H).

[1029] Example 39: (S)-1-(5-(3-((4-((1-(((7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-(1-oxo-6-azaspiro[3.5]nonan-6-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

[1030] Step 1: (S)-1-(5-(3-((4-((1-(((8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- ((trisopropylsilyl)ethynyl)naphthalen-1-yl)-4-(1-oxo-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3- d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperazin-1-yl)methyl)-3λ 3 Preparation of (S)-1-(5-(3-((4-((1-(((8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- ((trisopropylsilyl)ethynyl)naphthalen-1-yl)-4-(1-oxo-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3- d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperazin-1-yl)methyl)-3λ

[1031] To a solution of (S)-l-(((8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- ((trisopropylsilyl)ethynyl)naphthalen-l-yl)-4-(l-oxo-6-azaspiro[3.5]dec-6-yl)pyrido[4,3- d]pyrimidin-2-yl)oxy)methyl)cyclopropane-l -carbaldehyde (140 mg, 0.185 mmol) and Intermediate 17 (111 mg, 0.222 mmol) in dichloromethane (2 mL) was added tetraisopropyl titanate (263 mg, 0.925 mmol) and glacial acetic acid (0.1 mL) at room temperature, stirred at 25 °C for 2 h. The mixture was added NaBH(OAc)3(118 mg, 0.555 mmol) under ice-bath and stirred at room temperature for 2 h. The mixture was concentrated and purified by silica gel column chromatography (DCM:MeOH = 100:1 ~ 5:1) to give (S)-l-(5-(3-((4-((l-(((8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- ((trisopropylsilyl)ethynyl)naphthalen-l-yl)-4-(l-oxo-6-azaspiro[3.5]dec-6-yl)pyrido[4,3- d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperazin-l-yl)methyl)-3λ 3 -1-oxo-9-azaspiro[5.5]undecan-9-carbonyl)-2-methoxyphenyl)dihydropyrimidine-2,4(lH,3H)- dione.

[1032] LC-MS: (ESI, m / z): [M / 2 + H] + = 621.0.

[1033] Step 2: Preparation of (S)-l-(5-(3-((4-((l-(((7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-l- yl)-8-fluoro-4-(l-oxo-6-azaspiro[3.5]dec-6-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl) methyl)piperazin-l-yl)methyl)-3λ 3 -1-oxo-9-azaspiro[5.5]undecan-9-carbonyl)-2-methoxyphenyl)dihydropyrimidine-2,4(lH,3H)- dione.

[1034] To a solution of (S)-l-(((8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- ((trisopropylsilyl)ethynyl)naphthalen-l-yl)-4-(l-oxo-6-azaspiro[3.5]dec-6-yl)pyrido[4,3- d]pyrimidin-2-yl)oxy)methyl)cyclopropane-l -carbaldehyde (140 mg, 0.185 mmol) and Intermediate 17 (111 mg, 0.222 mmol) in dichloromethane (2 mL) was added tetraisopropyl titanate (263 mg, 0.925 mmol) and glacial acetic acid (0.1 mL) at room temperature, stirred at 25 °C for 2 h. The mixture was added NaBH(OAc)3(118 mg, 0.555 mmol) under ice-bath and stirred at room temperature for 2 h. The mixture was concentrated and purified by silica gel column chromatography (DCM:MeOH = 100:1 ~ 5:1) to give (S)-l-(5-(3-((4-((l-(((8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- ((trisopropylsilyl)ethynyl)naphthalen-l-yl)-4-(l-oxo-6-azaspiro[3.5]dec-6-yl)pyrido[4,3- d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperazin-l-yl)methyl)-3λ 3To a solution of (S)-1-(5-(3-((4-((1-(((7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-(1-oxido-6-azaspiro[3.5]non-6-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperazin-1-yl)methyl)-3λ 3 -1-oxido-9-azaspiro[5.5]undecane-9-carbonyl)-2-methoxyphenyl)pyrimidine-2,4(1H,3H)-dione.

[1035] LC-MS: (ESI, m / z): [M / 2 + H] + = 520.8.

[1036] 1 H NMR (400 MHz, DMSO-d6) δ 10.33 (s, 1H), 9.13 (d, J = 29.7 Hz, 1H), 7.94 (dd, J = 8.8, 6.0 Hz, 1H), 7.50 - 7.30 (m, 4H), 7.22 - 7.10 (m, 2H), 4.54 - 4.33 (m, 3H), 4.32 - 4.24 (m, 2H), 4.23 - 4.05 (m, 2H), 3.97 (s, 1H), 3.93 - 3.85 (m, 1H), 3.84 (s, 3H), 3.82 - 3.76 (m, 1H), 3.69 - 3.53 (m, 4H), 2.71 - 2.65 (m, 3H), 2.47 - 2.17 (m, 10H), 2.16 - 1.98 (m, 4H), 1.95 - 1.82 (m, 2H), 1.81 - 1.61 (m, 3H), 1.61 - 1.42 (m, 4H), 1.41 - 1.13 (m, 4H), 0.69 - 0.61 (m, 2H), 0.44 - 0.36 (m, 2H).

[1037] Example 43: 1-(5-(3-((4-((1-(((7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-(2-oxo-1,6-diazaspiro[3.5]nonan-6-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-methoxyphenyl)dihydropyrimidine-2,4(1H,3H)-dione

[1038] Step 1: 1-(5-(3-((4-((1-(((8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-4-(2-oxo-1,6-diazaspiro[3.5]nonan-6-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-methoxyphenyl)dihydropyrimidine-2,4(1H,3H)-dione

[1039] To a stirred solution of intermediate 15 (110 mg, 0.14 mmol) and intermediate 17 (86 mg, 0.17 mmol) in DCM / AcOH (1 mL / 0.1 mL) was added tetraisopropyl titanate (203 mg, 0.71 mmol) and stirred at 25 °C for 2 h. The mixture was added with NaBH(OAc)3 (91 mg, 0.43 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 1-(5-(3-((4-((1-(((8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-4-(2-oxo-1,6-diazaspiro[3.5]nonan-6-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-methoxyphenyl)dihydropyrimidine-2,4(1H,3H)-dione.

[1040] LC-MS: (ESI, m / z): [M / 2+H] + = 627.5.

[1041] Step 2: 1-(5-(3-((4-((1-(((7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-(2-oxo-1,6-diazaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperazin-1-yl)methyl)-3λ 3 Preparation of 1-oxo-9-azaspiro[5.5]undecane-9-carbonyl)-2-methoxyphenyl)dihydropyrimidine-2,4(1H,3H)-dione

[1042] 1-(5-(3-((4-((1-(((8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-4-(2-oxo-1,6-diazaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperazin-1-yl)methyl)-3λ 3 To a solution of (1-oxo-9-azaspiro[5.5]undecane-9-carbonyl)-2-methoxyphenyl)dihydropyrimidine-2,4(1H,3H)-dione (100 mg, 0.080 mmol) in DMF (1 mL) was added cesium fluoride (182 mg, 1.20 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 combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated. To a stirred solution of the concentrate in 1,4-dioxane (2.0 mL) was added HCl / 1,4-dioxane (6N, 2.0 mL) and allowed to react at room temperature for 0.5 hour. Aqueous NaCO3 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 NaSO4, 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-(2-oxo-1,6-diazaspiro[3.5]nonan-6-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-methoxyphenyl)dihydropyrimidine-2,4(1H,3H)-dione.

[1043] LC-MS:(ESI,m / z):[M / 2+H] + =527.3.

[1044] 1H NMR (400 MHz, DMSO-d6) δ 10.40 - 10.19 (m, 2H), 9.01 (d, J = 20.8 Hz, 1H), 8.56 (d, J = 8.8 Hz, 1H), 7.97 (dd, J = 9.2, 5.9 Hz, 1H), 7.46 (t, J = 9.0 Hz, 1H), 7.40 - 7.32 (m, 3H), 7.22 - 7.17 (m, 1H), 7.14 (d, J = 8.6 Hz, 1H), 4.30 - 4.20 (m, 3H), 4.07 - 3.99 (m, 1H), 3.95 - 3.85 (m, 2H), 3.84 (s, 3H), 3.77 (d, J = 13.2 Hz, 1H), 3.68 - 3.55 (m, 4H), 3.25 - 3.14 (m, 2H), 2.86 - 2.77 (m, 1H), 2.70 - 2.64 (m, 3H), 2.45 - 2.19 (m, 9H), 2.15 - 1.93 (m, 5H), 1.92 - 1.80 (m, 3H), 1.77 - 1.45 (m, 6H), 1.44 - 1.15 (m, 5H), 0.68 - 0.59 (m, 2H), 0.45 - 0.36 (m, 2H).

[1045] Example 61: 1-(5-(9-((4-((1-(((7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-(2-oxo-1,6-diazaspiro[3.5]non-6-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

[1046] Step 1: Preparation of 6-(7-chloro-8-fluoro-2-((1-(hydroxymethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,6-diazaspiro[3.5]nonan-2-one

[1047] To a solution of 6-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-1,6- diazaspiro[3.5]nonan-2-one (300 mg, 0.84 mmol) and cyclopropane-1,1- diyl dimethanol (172 mg, 1.68 mmol) in anhydrous acetonitrile (3 mL), add triethylene diamine (9 mg, 0.084 mmol) and anhydrous cesium carbonate (822 mg, 2.52 mmol), stir at 25 °C for 2 h. After the reaction is completed, add saturated brine (10 mL), extract with ethyl acetate (10 mL x 3), combine the organic phases, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The concentrate is purified by silica gel column chromatography (DCM:MeOH = 15:1) to give 6-(7-chloro-8-fluoro-2-((1- (hydroxymethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,6- diazaspiro[3.5]nonan-2-one.

[1048] LC-MS: (ESI, m / z): [M+H] + = 422.1.

[1049] Step 2: Preparation of 6-(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)-1,6-diazaspiro[3.5]nonan-2-one

[1050] To a mixture solution of 6-(7-chloro-8-fluoro-2-((1-(hydroxymethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,6-diazaspiro[3.5]nonan-2-one (260 mg, 0.62 mmol) and ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (379 mg, 0.74 mmol) in 1,4-dioxane (3 mL) and H2O (0.6 mL), add cesium carbonate (606 mg, 1.86 mmol) and cataCXium A Pd-G3 (90 mg, 0.12 mmol), react at 85 °C under N2protection overnight. Filter the reaction mixture, concentrate the filtrate, and purify the concentrate by silica gel column chromatography (DCM:MeOH = 20:1) to give 6-(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)-1,6-diazaspiro[3.5]nonan-2-one.

[1051] LC-MS: (ESI, m / z): [M+H] + = 772.3.

[1052] Step 3: Preparation of 1-(((8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- ((trisopropylsilyl)ethynyl)naphthalen-1-yl)-4-(2-oxo-1,6-diazaspiro[3.5]non-6- yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropane-1-carbaldehyde

[1053] A solution of 6-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- ((trisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((1-(hydroxymethyl)cyclopropyl)methoxy) pyrido[4,3-d]pyrimidin-4-yl)-1,6-diazaspiro[3.5]nonan-2-one (230 mg, 0.30 mmol) in dichloromethane (3 mL) was cooled to 0 °C at room temperature, Dess-Martin reagent (316 mg, 0.74 mmol) was added, and stirring was performed at 25 °C for 2 h. After the reaction was completed, saturated sodium thiosulfate solution (10 mL) was added, extracted with dichloromethane (10 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (DCM:MeOH = 20:1) to obtain 1-(((8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- ((trisopropylsilyl)ethynyl)naphthalen-1-yl)-4-(2-oxo-1,6-diazaspiro[3.5]non-6-yl)pyrido[4,3- d]pyrimidin-2-yl)oxy)methyl)cyclopropane-1-carbaldehyde.

[1054] LC-MS: (ESI, m / z): [M+H] + = 770.3.

[1055] Step 4: Preparation of 1-(5-(9-((4-((1-(((8-fluoro-7-(7-fluoro-3- (methoxymethoxy)-8-((trisopropylsilyl)ethynyl)naphthalen-1-yl)-4-(2-oxo-1,6- diazaspiro[3.5]non-6-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

[1056] To a solution of 1-(((8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-4-(2-oxo-1,6-diazaspiro[3.5]non-6-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropane-1-carbaldehyde (80 mg, 0.104 mmol) and 1-(2-methoxy-5-(9-(piperazin-1-ylmethyl)-3-azaspiro[5.5]undecane-3-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione (62 mg, 0.125 mmol) in dichloromethane (1 mL) was added tetraisopropyl titanate (148 mg, 0.52 mmol) and glacial acetic acid (0.1 mL) at room temperature and stirred at 25 °C for 2 h. The mixture was added NaBH(OAc)3(69 mg, 0.31 mmol) under ice bath and stirred for 2 h. The mixture was concentrated, the concentrate was purified by silica gel column chromatography (DCM:MeOH = 100:1 ~ 5:1) to give 1-(5-(9-((4-((1-(((8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-4-(2-oxo-1,6-diazaspiro[3.5]non-6-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.

[1057] LC-MS: (ESI, m / z): [M / 2+H] + = 626.8.

[1058] Step 5: Preparation of 1-(5-(9-((4-((1-(((7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-(2-oxo-1,6-diazaspiro[3.5]non-6-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

[1059] To a solution of 1-(5-(9-((4-((1-(((8-fluoro-7-(7-fluoro-3- (methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-4-(2-oxo-1,6- diazaspiro[3.5]non-6-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 (70 mg, 0.056 mmol) in DMF (1 mL) was added cesium fluoride (43 mg, 0.28 mmol) and stirred at room temperature for 30 min. To the reaction mixture was added water (5 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. To the solution of the concentrate in DCM (1.0 mL) was added TFA (0.5 mL) and reacted at room temperature for 0.5 h. The reaction mixture was adjusted to pH > 7 with aqueous Na2CO3 solution and extracted with EtOAc (5 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 purification to give 1-(5-(9-((4-((1-(((7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-(2-oxo-1,6- diazaspiro[3.5]non-6-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.

[1060] LC-MS: (ESI, m / z): [M / 2 + H] + = 526.6.

[1061] 1H NMR (400 MHz, CD3OD) δ 9.01 (d, J = 7.7 Hz, 1H), 7.84 (dd, J = 9.1, 5.7 Hz, 1H), 7.43 (dd, J = 8.5, 2.0 Hz, 1H), 7.38 (d, J = 1.9 Hz, 1H), 7.35 - 7.27 (m, 2H), 7.25 - 7.15 (m, 2H), 4.53 - 4.15 (m, 2H), 4.08 - 3.97 (m, 1H), 3.92 (s, 3H), 3.87 - 3.39 (m, 10H), 3.38 - 3.32 (m, 2H), 2.93 - 2.72 (m, 4H), 2.70 - 2.30 (m, 9H), 2.19 - 2.02 (m, 4H), 2.01 - 1.90 (m, 2H), 1.82 - 1.69 (m, 2H), 1.68 - 1.00 (m, 13H), 0.75 - 0.65 (m, 2H), 0.55 - 0.45 (m, 2H).

[1062] Example 62: (S)-1-(5-(9-((4-((1-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-(1-oxido-6- azaspiro[3.5]dec-6-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

[1063] Step 1: Preparation of (S)-6-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-1-oxido-6- azaspiro[3.5]decane

[1064] To a solution of 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (700 mg, 2.77 mmol) in THF (10 mL) was added triethylamine (841 mg, 8.31 mmol) and (S)-1-oxa-6-azaspiro[3.5]decane (317 mg, 2.49 mmol) at -50 °C, and stirring was continued at -50 °C for 5 h. After the reaction was completed, it was poured into saturated ammonium chloride solution (20 mL), extracted with ethyl acetate (20 mL x 2), the organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (PE:EA = 5:1) to give (S)-6-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-1-oxido-6-azaspiro[3.5]decane.

[1065] LC-MS: (ESI, m / z): [M+H] += 343.1.

[1066] Step 2: Preparation of (S)-(1-(((7-chloro-8-fluoro-4-(1-oxo-6-azaspiro[3.5]nonan-6- yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methanol

[1067] To a solution of (S)-6-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-1-oxo-6- azaspiro[3.5]nonane (460 mg, 1.34 mmol) and cyclopropane-1,1-dimethyl dimethanol (274 mg, 2.68 mmol) in anhydrous acetonitrile (5 mL), triethylenediamine (75 mg, 0.67 mmol) and anhydrous cesium carbonate (1.31 g, 4.02 mmol) were added, and stirred at 25 °C for 2 hours. After the reaction was completed, saturated aqueous sodium 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 concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (DCM:MeOH = 10:1) to obtain (S)-(1-(((7-chloro-8-fluoro-4-(1-oxo-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-2- yl)oxy)methyl)cyclopropyl)methanol.

[1068] LC-MS: (ESI, m / z): [M+H] + = 409.2.

[1069] Step 3: Preparation of (S)-6-fluoro-4-(8-fluoro-2-((1-(hydroxymethyl)cyclopropyl)methoxy)- 4-(1-oxo-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-7-yl)-5-((triisopropylsilyl)ethynyl) naphthalen-2-ol

[1070] To a mixture solution of (S)-(1-(((7-chloro-8-fluoro-4-(1-oxido-6- azaspiro[3.5]non-6-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methanol (360 mg, 0.88 mmol) and 6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5- ((triisopropylsilyl)ethynyl)naphthalen-2-ol (495 mg, 1.06 mmol) in 1,4-dioxane (3 mL) and H2O (0.6 mL) was added cesium carbonate (861 mg, 2.64 mmol) and cataCXium A Pd-G3 (64 mg, 0.088 mmol), and the reaction mixture was heated at 85 °C under N2protection overnight. The mixture was filtered, and the filtrate was concentrated. The concentrate was purified by silica gel column chromatography (DCM:MeOH = 10:1) to give (S)-6-fluoro-4-(8-fluoro-2-((1- (hydroxymethyl)cyclopropyl)methoxy)-4-(1-oxido-6-azaspiro[3.5]non-6-yl)pyrido[4,3- d]pyrimidin-7-yl)-5-((triisopropylsilyl)ethynyl)naphthalen-2-ol.

[1071] LC-MS: (ESI, m / z): [M+H] = 715.3. + = 715.3.

[1072] Step 4: Preparation of (S)-(1-(((8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)-3- ((2-(trimethylsilyl)ethoxy)methoxy)naphthalen-1-yl)-4-(1-oxido-6-azaspiro[3.5]non-6- yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methanol

[1073] A solution of (S)-6-fluoro-4-(8-fluoro-2-((1-(hydroxymethyl)cyclopropyl)methoxy)- 4-(1-oxido-6-azaspiro[3.5]non-6-yl)pyrido[4,3-d]pyrimidin-7-yl)-5-((triisopropylsilyl)ethynyl)naphthalen-2-ol (445 mg, 0.62 mmol) in dichloromethane (3 mL) was cooled to 0 °C at room temperature, DIEA (161 mg, 1.24 mmol) and SEM-Cl (125 mg, 0.75 mmol) were added, and stirred at 25 °C for 2 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (DCM:MeOH = 15:1) to obtain (S)-(1-(((8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((2- (trimethylsilyl)ethoxy)methoxy)naphthalen-1-yl)-4-(1-oxido-6-azaspiro[3.5]non-6-yl)pyrido[4,3- d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methanol.

[1074] LC-MS: (ESI, m / z): [M+H] = 845.3. + = 845.3.

[1075] Step 5: Preparation of (S)-1-(((8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((2- (trimethylsilyl)ethoxy)methoxy)naphthalen-1-yl)-4-(1-oxido-6-azaspiro[3.5]non-6-yl)pyrido[4,3- d]pyrimidin-2-yl)oxy)methyl)cyclopropane-1-carbaldehyde

[1076] A solution of (S)-(1-(((8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)-3- ((2-(trimethylsilyl)ethoxy)methoxy)naphthalen-1-yl)-4-(1-oxido-6- azaspiro[3.5]non-6-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methanol (400 mg, 0.47 mmol) in dichloromethane (3 mL) was cooled to 0 °C at room temperature, Dess-Martin reagent (401 mg, 0.95 mmol) was added, and stirred at 25 °C for 2 h. After the reaction was completed, saturated sodium thiosulfate solution (10 mL) was added, and extracted with dichloromethane (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 (PE:EA = 50:1 ~ 2:1) to give (S)-1-(((8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((2- (trimethylsilyl)ethoxy)methoxy)naphthalen-1-yl)-4-(1-oxido-6- azaspiro[3.5]non-6-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropane-1- carbaldehyde.

[1077] LC-MS: (ESI, m / z): [M+H] + = 843.3.

[1078] Step 6: Preparation of (S)-6-(2-((1-((4-benzylpiperazin-1-yl)methyl)cyclopropyl)methoxy)- 8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((2- (trimethylsilyl)ethoxy)methoxy)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-1- oxido-6-azaspiro[3.5]nonane

[1079] To a solution of (S)-1-(((8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)-3- ((2-(trimethylsilyl)ethoxy)methoxy)naphthalen-1-yl)-4-(1-oxido-6-azaspiro[3.5]non-6- yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropane-1-carbaldehyde (190 mg, 0.23 mmol) and 1-benzylpiperazine (96 mg, 0.45 mmol) in DCM / AcOH (2.0 mL / 0.2 mL) was added triethylamine (68 mg, 0.68 mmol) and stirred at 30 °C for 2 h. The mixture was added NaBH(OAc)3(143 mg, 0.68 mmol) under ice bath and stirred for 1 h. The reaction mixture was concentrated, and the concentrate was purified by silica gel column chromatography (DCM:MeOH = 100:1 ~ 5:1) to give (S)-6-(2-((1-((4-benzylpiperazin-1-yl)methyl)cyclopropyl)methoxy)-8-fluoro-7-(7- fluoro-8-((triisopropylsilyl)ethynyl)-3-((2-(trimethylsilyl)ethoxy)methoxy)naphthalen-1-yl) pyrido[4,3-d]pyrimidin-4-yl)-1-oxido-6-azaspiro[3.5]nonane.

[1080] LC-MS: (ESI, m / z): [M / 2 + H] + = 502.5.

[1081] Step 7: Preparation of (S)-6-(2-((1-((4-benzylpiperazin-1-yl)methyl)cyclopropyl)methoxy)-7- (8-ethynyl-7-fluoro-3-((2-(trimethylsilyl)ethoxy)methoxy)naphthalen-1-yl)-8-fluoropyrido[4,3- d]pyrimidin-4-yl)-1-oxido-6-azaspiro[3.5]nonane

[1082] (S)-6-(2-((1-((4-benzylpiperazin-1-yl)methyl)cyclopropyl)methoxy)-8-fluoro-7-(7-fluoro-8- ((trisopropylsilyl)ethynyl)-3-((2-(trimethylsilyl)ethoxy)methoxy)naphthalen-1-yl)pyrido[4,3- d]pyrimidin-4-yl)-1-oxo-6-azaspiro[3.5]nonane (150 mg, 0.15 mmol) was dissolved in DMF (1 mL), cesium fluoride (341 mg, 2.24 mmol) was added, and the reaction was allowed to proceed at 25 °C for 30 min. The reaction was added to water (10 mL) and extracted with ethyl acetate (10 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. (S)-6-(2-((1-((4-benzylpiperazin-1-yl)methyl)cyclopropyl)methoxy)-7-(8-ethynyl-7-fluoro-3- ((2-(trimethylsilyl)ethoxy)methoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-1-oxo- 6-azaspiro[3.5]nonane was obtained.

[1083] LC-MS: (ESI, m / z): [M+H] + = 847.3.

[1084] Step 8: Preparation of (S)-6-(7-(8-ethyl-7-fluoro-3-((2-(trimethylsilyl)ethoxy)methoxy)naphthalen-1-yl)-8- fluoro-2-((1-(piperazin-1-ylmethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-oxo-6- azaspiro[3.5]nonane

[1085] To a solution of (S)-6-(2-((1-((4-benzylpiperazin-1-yl)methyl)cyclopropyl)methoxy)-7-(8- ethynyl-7-fluoro-3-((2-(trimethylsilyl)ethoxy)methoxy)naphthalen-1-yl)-8-fluoropyrido[4,3- d]pyrimidin-4-yl)-1-oxo-6-azaspiro[3.5]nonane (103 mg, 0.12 mmol) in methanol (2 mL) was added Pd / C (200 mg), and the reaction was replaced with hydrogen three times. The reaction was allowed to proceed at 25 °C for 4 h, and after the reaction was completed, the reaction was filtered through diatomite, and the filtrate was concentrated. The concentrate was purified by silica gel column chromatography (DCM:MeOH = 100:1 ~ 5:1) to obtain (S)-6-(7-(8-ethyl-7-fluoro-3-((2- (trimethylsilyl)ethoxy)methoxy)naphthalen-1-yl)-8-fluoro-2-((1-(piperazin-1-ylmethyl)cyclopropyl) methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-oxo-6-azaspiro[3.5]nonane.

[1086] LC-MS: (ESI, m / z): [M+H] + = 761.5.

[1087] Step 9: Preparation of (S)-1-(5-(9-((4-((1-(((7-(8-ethyl-7-fluoro-3-((2- (trimethylsilyl)ethoxy)methoxy)naphthalen-1-yl)-8-fluoro-4-(1-oxido-6- azaspiro[3.5]non-6-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

[1088] To a solution of (S)-6-(7-(8-ethyl-7-fluoro-3-((2- (trimethylsilyl)ethoxy)methoxy)naphthalen-1-yl)-8-fluoro-2-((1-(piperazin-1-ylmethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-oxido-6- azaspiro[3.5]nonane (50 mg, 0.066 mmol) and 3-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)-3-azaspiro[5.5]undecane-9-carbaldehyde (37 mg, 0.085 mmol) in dichloromethane (0.4 mL) was added tetraisopropyl titanate (93 mg, 0.33 mmol) and glacial acetic acid (0.01 mL) at room temperature and stirred at 25 °C for 2 h. The mixture was added with NaBH(OAc)3 (134 mg, 0.63 mmol) under ice-bath and stirred for 1 h. The reaction mixture was directly concentrated, and the concentrate was purified by silica gel column chromatography (DCM:MeOH = 100:1 ~ 5:1) to give (S)-1-(5-(9-((4-((1-(((7-(8-ethyl-7-fluoro-3-((2- (trimethylsilyl)ethoxy)methoxy)naphthalen-1-yl)-8-fluoro-4-(1-oxido-6- azaspiro[3.5]non-6-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.

[1089] LC-MS: (ESI, m / z): [M+H] + = 1172.5.

[1090] Step 10: Preparation of (S)-1-(5-(9-((4-((1-(((7-(8-ethyl-7-fluoro-3- hydroxynaphthalen-1-yl)-8-fluoro-4-(1-oxo-6-azaspiro[3.5]dec-6-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

[1091] To a stirred solution of (S)-1-(5-(9-((4-((1-(((7-(8-ethyl-7-fluoro-3-((2- (trimethylsilyl)ethoxy)methoxy)naphthalen-1-yl)-8-fluoro-4-(1-oxo-6- azaspiro[3.5]dec-6-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 (41 mg, 0.035 mmol) in dichloromethane (0.4 mL) was added trifluoroacetic acid (0.2 mmol) at room temperature and stirred for 30 min at room temperature. The reaction was slowly added to NH3 / MeOH solution adjusted to pH > 7 and then concentrated. To the concentrate was added H2O (3 mL) and then extracted with ethyl acetate, the organic phase was washed with saturated aqueous sodium chloride, dried over anhydrous Na2SO4 and concentrated. The crude was purified by high performance liquid preparation to give (S)-1-(5-(9-((4-((1-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-(1-oxo-6-azaspiro[3.5]dec-6-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.

[1092] LC-MS: (ESI, m / z): [M / 2 + H] + = 521.8.

[1093] 1H NMR (400 MHz, CD3OD) δ 9.25 (d, J = 13.4 Hz, 1H), 7.67 (dd, J = 9.0, 5.8 Hz, 1H), 7.43 (dd, J = 8.5, 2.1 Hz, 1H), 7.37 (d, J = 2.1 Hz, 1H), 7.29 (d, J = 2.6 Hz, 1H), 7.24 (t, J = 9.2 Hz, 1H), 7.17 (d, J = 8.6 Hz, 1H), 7.07 (d, J = 2.5 Hz, 1H), 5.33 (t, J = 4.6 Hz, 1H), 4.71 - 4.35 (m, 6H), 3.91 (s, 3H), 3.87 - 3.77 (m, 1H), 3.76 - 3.58 (m, 4H), 3.49 - 3.42 (m, 2H), 2.79 (t, J = 6.7 Hz, 2H), 2.60 - 2.29 (m, 11H), 2.24 - 2.15 (m, 4H), 2.08 - 1.88 (m, 5H), 1.85 - 1.69 (m, 3H), 1.66 - 1.48 (m, 6H), 1.17 - 1.10 (m, 2H), 0.93 - 0.87 (m, 2H), 0.85 - 0.77 (m, 3H), 0.77 - 0.66 (m, 2H), 0.56 - 0.45 (m, 2H).

[1094] Example 66: 1-(5-(9-((4-((1-(((7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-(2-oxo-1,6-diazaspiro[3.5]non-6-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

[1095] Step 1: Preparation of 1-(5-(9-((4-((1-(((8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- ((trisopropylsilyl)ethynyl)naphthalen-1-yl)-4-(2-oxo-1,6-diazaspiro[3.5]non-6-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

[1096] To a solution of intermediate 15 (52 mg, 0.068 mmol) and 1-(2-methoxy-5-(9-(piperazin-1-ylmethyl)-3-azaspiro[5.5]undecane-3-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione (40 mg, 0.081 mmol) in dichloromethane (1 mL) was added tetraisopropyl titanate (97 mg, 0.34 mmol) and glacial acetic acid (0.1 mL) at room temperature, stirred at 25 °C for 2 h. The mixture was added NaBH(OAc)3(45 mg, 0.21 mmol) under ice-bath and stirred for 2 h. The reaction mixture was concentrated, the concentrate was purified by silica gel column chromatography (DCM:MeOH = 100:1 ~ 5:1) to give 1-(5-(9-((4-((1-(((8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-4-(2-oxo-1,6-diazaspiro[3.5]non-6-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.

[1097] LC-MS: (ESI, m / z): [M / 2+H] + = 626.5.

[1098] Step 2: Preparation of 1-(5-(9-((4-((1-(((7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-(2-oxo-1,6-diazaspiro[3.5]non-6-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

[1099] To a solution of 1-(5-(9-((4-((1-(((8-fluoro-7-(7-fluoro-3- (methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-4-(2-oxo-1,6- diazaspiro[3.5]non-6-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 (45 mg, 0.036 mmol) in DMF (1 mL) was added cesium fluoride (27 mg, 0.18 mmol) and stirred at room temperature for 30 min. To the reaction mixture was added water (5 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. To the solution of the concentrate in DCM (1.0 mL) was added TFA (0.5 mL) and reacted at room temperature for 0.5 h. The reaction mixture was adjusted to pH > 7 with aqueous Na2CO3 solution and extracted with EtOAc (5 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 purification to give 1-(5-(9-((4-((1-(((7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-(2-oxo-1,6- diazaspiro[3.5]non-6-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.

[1100] LC-MS: (ESI, m / z): [M / 2 + H] + = 526.3.

[1101] 1H NMR (400 MHz, DMSO-d6) δ 10.24 - 10.48 (m, 2H), 9.01 (d, J = 21.2 Hz, 1H), 8.57 (d, J = 8.4 Hz, 1H),, 8.02 - 7.91 (m, 1H), 7.46 (t, J = 9.0 Hz, 1H), 7.41 - 7.28 (m, 3H), 7.22 - 7.10 (m, 2H), 4.34 - 4.16 (m, 3H), 4.08 - 3.98 (m, 1H), 3.96 - 3.79 (m, 4H), 3.79 - 3.71 (m, 1H), 3.67 - 3.42 (m, 6H), 2.90 - 2.75 (m, 2H), 2.73 - 2.60 (m, 3H), 2.48 - 2.10 (m, 9H), 2.08 - 1.95 (m, 3H), 1.95 - 1.80 (m, 3H), 1.72 - 1.60 (m, 2H), 1.55 - 1.37 (m, 4H), 1.34 - 1.17 (m, 3H), 1.15 - 0.81 (m, 5H), 0.67 - 0.58 (m, 2H), 0.45 - 0.35 (m, 2H).

[1102] Example 164: 1-(5-(3-((4-((1-(((7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperazin-1-yl)methyl)-1-oxo-9-azaspiro[5.5]undecane-9-carbonyl)-2-methoxyphenyl)dihydropyrimidine-2,4(1H,3H)-dione

[1103] Step 1: Preparation of 1-(5-(3-((4-((1-(((8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- ((trisopropylsilyl)ethynyl)naphthalen-1-yl)-4-((R)-3-hydroxy-3-methylpiperidin-1- yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperazin-1-yl)methyl)-1- oxo-9-azaspiro[5.5]undecane-9-carbonyl)-2-methoxyphenyl)dihydropyrimidine-2,4(1H,3H)-dione

[1104] To a solution of intermediate 17 (120 mg, 0.24 mmol) in dichloromethane (2 mL) and acetic acid (0.2 mL) was added (R)-1-(((8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- ((trisopropylsilyl)ethynyl)naphthalen-1-yl)-4-(3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3- d]pyrimidin-2-yl)oxy)methyl)cyclopropane-1-carbaldehyde (150 mg, 0.20 mmol) and titanium(IV) isopropoxide (286 mg, 1.00 mmol), the mixture was stirred at 25 °C for 2 h, then NaBH(OAc)3 (128 mg, 0.60 mmol) was added at 0 °C and stirred for 1 h. After the reaction was completed, the mixture was concentrated, and the crude product was purified by silica gel column chromatography (DCM:MeOH = 100:1 ~ 5:1) to give 1-(5-(3-((4-((1-(((8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- ((trisopropylsilyl)ethynyl)naphthalen-1-yl)-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3- d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperazin-1-yl)methyl)-1-oxo-9-azaspiro[5.5]undecan- 9-yl)-2-methoxyphenyl)dihydropyrimidine-2,4(1H,3H)-dione.

[1105] LC-MS: (ESI, m / z): [M / 2 + H] + = 615.0.

[1106] Step 2: Preparation of 1-(5-(3-((4-((1-(((7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8- fluoro-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl) methyl)piperazin-1-yl)methyl)-1-oxo-9-azaspiro[5.5]undecan-9-yl)-2-methoxyphenyl)dihydropyrimidine- 2,4(1H,3H)-dione

[1107] To a stirred solution of 1-(5-(3-((4-((1-(((8-fluoro-7-(7-fluoro-3- (methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-4-((R)-3- hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl) methyl)piperazin-1-yl)methyl)-1-oxo-9-azaspiro[5.5]undecane-9-carbonyl)-2- methoxyphenyl)dihydropyrimidine-2,4(1H,3H)-dione (185 mg, 0.15 mmol) in DMF (2 mL) was added cesium fluoride (343 mg, 2.26 mmol) and stirred at room temperature for 30 min. The reaction was quenched with water (10 mL) and extracted with ethyl acetate (3 x 10 mL). The organic layers were combined and dried over anhydrous sodium sulfate and concentrated under reduced pressure. To a stirred solution of the concentrate in 1,4-dioxane (2 mL) was added HCl / 1,4-dioxane (6 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 2). The organic layer 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-((R)-3- hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl) methyl)piperazin-1-yl)methyl)-1-oxo-9-azaspiro[5.5]undecane-9-carbonyl)-2- methoxyphenyl)dihydropyrimidine-2,4(1H,3H)-dione.

[1108] LC-MS: (ESI, m / z): [M / 2 + H] + = 514.9.

[1109] 1H NMR (400 MHz, DMSO-d6) δ 10.34 (s, 1H), 10.16 (d, J = 3.6 Hz, 1H), 9.13 (d, J = 66.8 Hz, 1H), 7.98 (dd, J = 9.2, 6.0 Hz, 1H), 7.51 - 7.43 (m, 1H), 7.41 - 7.32 (m, 3H), 7.24 - 7.12 (m, 2H), 4.75 (d, J = 30.0 Hz, 1H), 4.40 - 4.20 (m, 3H), 4.09 (d, J = 13.2 Hz, 1H), 4.03 - 3.87 (m, 2H), 3.84 (s, 3H), 3.77 - 3.44 (m, 5H), 3.33 - 3.11 (m, 4H), 2.68 (t, J = 6.4 Hz, 2H), 2.48 - 2.17 (m, 9H), 2.15 - 1.98 (m, 4H), 1.76 - 1.47 (m, 8H), 1.46 - 1.20 (m, 4H), 1.17 (d, J = 16.8 Hz, 3H), 0.68 - 0.58 (m, 2H), 0.45 - 0.35 (m, 2H).

[1110] Example 167: 1-(5-(3-((4-((1-(((7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4- ((R)-3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperazin-1-yl)methyl)-1-oxo-9-azaspiro[5.5]undecane-9-carbonyl)-2-methoxyphenyl)dihydropyrimidine-2,4(1H,3H)-dione

[1111] Step 1: Preparation of tert-butyl 4-((1-oxo-9-azaspiro[5.5]undecan-3-yl)methyl)piperazine-1-carboxylate

[1112] To a solution of intermediate 1-P2 (0.50 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 hours. The reaction was filtered through celite, the filtrate was concentrated to give the crude product tert-butyl 4-((1-oxo-9-azaspiro[5.5]undecan-3-yl)methyl)piperazine-1-carboxylate, which was used directly in the next reaction.

[1113] LC-MS: (ESI, m / z): [M+H] + = 354.3.

[1114] Step 2: Preparation of tert-butyl 4-((9-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4- methoxybenzoyl)-1-oxo-9-azaspiro[5.5]undecan-3-yl)methyl)piperazine-1-carboxylate

[1115] To a solution of tert-butyl 4-((1-oxo-9-azaspiro[5.5]undecan-3-yl)methyl)piperazine-1- carboxylate (410 mg, 1.16 mmol) in N,N-dimethylformamide (25 mL) was added N,N- diisopropylethylamine (450 mg, 3.48 mmol) and 3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)- 4-methoxybenzoic acid pentafluorophenyl ester (499 mg, 1.16 mmol), and the reaction was stirred at room temperature for 2 hours. After the reaction was completed, the reaction was poured into saturated aqueous sodium carbonate solution (250 mL), and extracted with ethyl acetate (200 mL x 2). The combined organic layer was washed with saturated sodium chloride (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (DCM:MeOH = 100:1 ~ 10:1) to obtain tert-butyl 4-((9-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4- methoxybenzoyl)-1-oxo-9-azaspiro[5.5]undecan-3-yl)methyl)piperazine-1-carboxylate.

[1116] LC-MS: (ESI, m / z): [M+H] + = 600.3.

[1117] Step 3: 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

[1118] To a solution of tert-butyl 4-((9-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4- methoxybenzoyl)-1-oxo-9-azaspiro[5.5]undecan-3-yl)methyl)piperazine-1-carboxylate (270 mg, 0.45 mmol) in 1,4-dioxane (3 mL) was added HCl / 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 (5 mL x 3). The combined organic phase was dried over Na2SO4, filtered and concentrated, and 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-oxo-9-azaspiro[5.5]undecan-9- yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione.

[1119] LC-MS: (ESI, m / z): [M+H] + = 500.3.

[1120] Step 4: Preparation of 1-(5-(3-((4-((1-(((8-fluoro-7-(7-fluoro-3- (methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-4-((R)-3- hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl) methyl)piperazin-1-yl)methyl)-1-oxo-9-azaspiro[5.5]undecan-9-yl)-2- methoxyphenyl)dihydropyrimidine-2,4(1H,3H)-dione

[1121] To a solution 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 (120 mg, 0.24 mmol) in dichloromethane (2 mL) and acetic acid (0.2 mL) was added (R)-1-(((8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-4-(3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropane-1-carbaldehyde (150 mg, 0.20 mmol) and tetraisopropyl titanate (286 mg, 1.00 mmol), the mixture was stirred at 25 °C for 2 hours, then NaBH(OAc)3 (128 mg, 0.60 mmol) was added at 0 °C, and stirred for 1 hour. After the reaction was completed, the mixture was concentrated, and the crude product was purified by silica gel column chromatography (DCM:MeOH = 100:1 ~ 5:1) to obtain 1-(5-(3-((4-((1-(((8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperazin-1-yl)methyl)-1-oxo-9-azaspiro[5.5]undecan-9-carbonyl)-2-methoxyphenyl)dihydropyrimidine-2,4(1H,3H)-dione.

[1122] LC-MS: (ESI, m / z): [M / 2 + H] + = 615.0.

[1123] Step 5: Preparation of 1-(5-(3-((4-((1-(((7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperazin-1-yl)methyl)-1-oxo-9-azaspiro[5.5]undecan-9-carbonyl)-2-methoxyphenyl)dihydropyrimidine-2,4(1H,3H)-dione

[1124] To a stirred solution of 1-(5-(3-((4-((1-(((8-fluoro-7-(7-fluoro-3- (methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-4-((R)-3- hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl) methyl)piperazin-1-yl)methyl)-1-oxo-9-azaspiro[5.5]undecane-9-carbonyl)-2- methoxyphenyl)dihydropyrimidine-2,4(1H,3H)-dione (170 mg, 0.14 mmol) in DMF (2 mL) was added cesium fluoride (105 mg, 0.69 mmol) and stirred at room temperature for 30 min. The reaction was added to water (10 mL) and extracted with ethyl acetate (10 mL x 3), the organic phases were combined and dried over anhydrous sodium sulfate and concentrated under reduced pressure. To a stirred solution of the concentrate in 1,4-dioxane (2 mL) was added HCl / 1,4-dioxane (6 N, 1.0 mL) and reacted 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 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-(3-((4-((1-(((7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-((R)-3- hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl) methyl)piperazin-1-yl)methyl)-1-oxo-9-azaspiro[5.5]undecane-9-carbonyl)-2- methoxyphenyl)dihydropyrimidine-2,4(1H,3H)-dione.

[1125] LC-MS: (ESI, m / z): [M / 2 + H] + = 514.8.

[1126] 1H NMR (400 MHz, DMSO-d6) δ 10.34 (s, 1H), 9.11 (d, J = 64.8 Hz, 1H), 7.95 - 7.84 (m, 1H), 7.44 - 7.27 (m, 4H), 7.23 - 7.10 (m, 2H), 4.85 - 4.58 (m, 1H), 4.41 - 4.22 (m, 3H), 4.09 (d, J = 15.4 Hz, 1H), 4.01 - 3.87 (m, 2H), 3.84 (s, 3H), 3.71 - 3.50 (m, 5H), 3.29 - 3.13 (m, 4H), 2.72 - 2.64 (m, 2H), 2.46 - 2.17 (m, 9H), 2.15 - 1.96 (m, 4H), 1.77 - 1.47 (m, 8H), 1.45 - 1.19 (m, 4H), 1.16 (d, J = 16.4 Hz, 3H), 0.68 - 0.58 (m, 2H), 0.45 - 0.35 (m, 2H).

[1127] Example 168: l-(5-(9-((4-((l-(((7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-l-yl)-8-fluoro-4-(6-hydroxy-6-methyl-l,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperazin-l-yl)methyl)-3- azaspiro[5.5]undecane-3-carbonyl)-2-methoxyphenyl)dihydropyrimidine-2,4(lH,3H)- dione

[1128] Step 1: Preparation of 4-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- (trisopropylsilylethynyl)naphthalen-l-yl)-2-((l-(hydroxymethyl)cyclopropyl)methoxy) pyrido[4,3-d]pyrimidin-4-yl)-6-methyl-l,4-oxazepan-6-ol

[1129] To a mixture solution of Intermediate 2-P2 (200 mg, 0.48 mmol) and ((2-fluoro-6- (methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl) triisopropylsilane (298 mg, 0.58 mmol) in 1,4-dioxane (2 mL) and H2O (0.5 mL) was added cesium carbonate (473 mg, 1.45 mmol) and cataCXium A Pd-G3 (70 mg, 0.097 mmol) and reacted at 85 °C under N2protection overnight. The mixture was filtered and concentrated, and the crude product was purified by silica gel column chromatography (DCM:MeOH = 10:1) to obtain 4-(8-fluoro-7-(7-fluoro-3- (methoxymethoxy)-8-((trisopropylsilyl)ethynyl)naphthalen-1-yl)-2- ((1-(hydroxymethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-methyl- 1,4-oxazepan-6-ol.

[1130] LC-MS: (ESI, m / z): [M+H] + = 763.3.

[1131] Step 2: Preparation of 1-(((8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- ((trisopropylsilyl)ethynyl)naphthalen-1-yl)-4-(6-hydroxy-6-methyl-1,4-oxazepan-4- yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropane-1-carbaldehyde

[1132] A solution of 4-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- ((trisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((1-(hydroxymethyl)cyclopropyl) methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazepan-6-ol (260 mg, 0.34 mmol) in dichloromethane (3 mL) was cooled to 0 °C at room temperature, Dess-Martin reagent (361 mg, 0.85 mmol) was added, and stirred at 25 °C for 2 h. After the reaction was completed, saturated sodium thiosulfate solution (10 mL) was added, and extracted with dichloromethane (10 mL x 3), and the combined organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (DCM:MeOH = 10:1) to obtain 1-(((8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- ((trisopropylsilyl)ethynyl)naphthalen-1-yl)-4-(6-hydroxy-6-methyl-1,4-oxazepan-4- yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropane-1-carbaldehyde.

[1133] LC-MS: (ESI, m / z): [M+H] + = 761.3.

[1134] Step 3: Preparation of 1-(5-(9-((4-((1-(((8-fluoro-7-(7-fluoro-3- (methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-4-(6-hydroxy-6- methyl-1,4-oxazepan-4-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

[1135] To a solution of 1-(((8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-1-yl)-4-(6-hydroxy-6-methyl-1,4-oxazepan-4-yl)pyrido[4,3- d]pyrimidin-2-yl)oxy)methyl)cyclopropane-1-carbaldehyde (160 mg, 0.21 mmol) and 1-(2-methoxy-5-(9-(piperazin-1-ylmethyl)-3-azaspiro[5.5]undecane-3-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione (126 mg, 0.25 mmol) in dichloromethane (2 mL) was added tetraisopropyl titanate (298 mg, 1.05 mmol) and glacial acetic acid (0.1 mL) at room temperature and stirred at 25 °C for 2 h. The mixture was added NaBH(OAc)3(134 mg, 0.63 mmol) under ice-bath and stirred for 2 h. The mixture was concentrated and the crude was purified by silica gel column chromatography (DCM:MeOH = 100:1 ~ 5:1) to give 1-(5-(9-((4-((1-(((8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-1-yl)-4-(6-hydroxy-6-methyl-1,4-oxazepan-4-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.

[1136] LC-MS: (ESI, m / z): [M / 2+H] + = 621.9.

[1137] Step 4: Preparation of 1-(5-(9-((4-((1-(((7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-(6-hydroxy-6-methyl-1,4-oxazepan-4-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

[1138] To a solution of 1-(5-(9-((4-((1-(((8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- ((trisopropylsilyl)ethynyl)naphthalen-1-yl)-4-(6-hydroxy-6-methyl-1,4-oxazepan-4- 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 (100 mg, 0.081 mmol) in DMF (1 mL) was added cesium fluoride (61 mg, 0.40 mmol) and stirred at room temperature for 30 min. The reaction was added to water (10 mL) and extracted with ethyl acetate (10 mL x 3), the organic phases were combined and dried over anhydrous sodium sulfate and concentrated under reduced pressure. To a solution of the concentrate in 1,4-dioxane (1.0 mL) was added HCl / 1,4-dioxane (6 N, 0.5 mL) and reacted at room temperature for 0.5 h. The reaction was added to an aqueous Na2CO3 solution to adjust the mixture to pH > 7 and extracted with EtOAc (10 mL x 2). 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-((1-(((7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-(6-hydroxy-6-methyl-1,4-oxazepan-4-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.

[1139] LC-MS: (ESI, m / z): [M / 2+H] + = 521.8.

[1140] 1H NMR (400 MHz, DMSO-d6) δ 10.32 (s, 1H), 10.15 (s, 1H), 9.36 (d, J = 50.9 Hz, 1H), 8.04 - 7.90 (m, 1H), 7.46 (t, J = 9.0 Hz, 1H), 7.41 - 7.27 (m, 3H), 7.21 - 7.11 (m, 2H), 5.14 (d, J = 72.3 Hz, 1H), 4.48 - 3.87 (m, 9H), 3.84 (s, 3H), 3.66 - 3.39 (m, 8H), 2.73 - 2.63 (m, 3H), 2.45 - 2.17 (m, 9H), 2.10 - 1.98 (m, 2H), 1.74 - 1.61 (m, 2H), 1.53 - 1.23 (m, 8H), 1.16 (d, J = 8.3 Hz, 3H), 1.11 - 0.96 (m, 3H), 0.68 - 0.58 (m, 2H), 0.45 - 0.36 (m, 2H).

[1141] Example 169: (S)-1-(5-(9-((4-((1-(((2-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-1-fluoro- 5a,6,9,10-tetrahydro-5H,8H-4,7-dioxa-3,10a,11,13-tetraazanaphtho[1,8-ab]heptalen-12-yl)oxy)methyl)cyclopropyl)methyl)piperazin-1-yl)methyl)-3-azaspiro[5.5]undecane-3-carbonyl)-2- methoxyphenyl)dihydropyrimidine-2,4(1H,3H)-dione

[1142] Step 1: Preparation of (1-((4-benzylpiperazin-1-yl)methyl)cyclopropyl)methanol

[1143] (1-((4-benzylpiperazin-1-yl)methyl)cyclopropyl)methanol was prepared according to the following procedure. 1-Benzylpiperazine (18.0 g, 102.0 mmol) was dissolved in toluene (120 mL) and warmed to 120 °C, then 1-(hydroxymethyl)cyclopropane-1-carboxylate (12 g, 68.0 mmol) and phenylsilane (5.5 g, 51.0 mmol) were added. The mixture was reacted at 120 °C for 16 h, then phenylsilane (14.7 g, 136.0 mmol) and zinc acetate (1.2 g, 6.8 mmol) were added and the reaction was continued for 2 h. After the reaction was completed, it was cooled to room temperature, quenched with aqueous hydrochloric acid (2 M, 120 mL), then extracted with dichloromethane (10 mL x 3), the aqueous phase was adjusted to pH 12 with sodium oxide solution (4 M, 60 mL) and extracted with dichloromethane (100 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography to give (1-((4-benzylpiperazin-1-yl)methyl)cyclopropyl)methanol.

[1144] LC-MS: (ESI, m / z): [M+H] + = 261.2.

[1145] Step 2: Preparation of (S)-12-((l-((4-benzylpiperazin-l-yl)methyl)cyclopropyl)methoxy)- 2-chloro-l-fluoro-5a,6,9,10-tetrahydro-5H,8H-4,7-dioxa-3,10a,11,13-tetraazanaphtho[l,8- ab]heptaen

[1146] (1-((4-benzylpiperazin-l-yl)methyl)cyclopropyl)methanol (409 mg, 1.07 mmol) was dissolved in tetrahydrofuran (5 mL), cooled to 0 °C, NaH (97 mg, 2.41 mmol) was added slowly, reacted at 25 °C for 30 min, then (5aS)-2-chloro-l-fluoro-12- (methylsulfinyl)-5a,6,9,10-tetrahydro-5H,8H-4,7-dioxa-3,10a,11,13-tetraazanaphtho[l,8-ab]heptaen (450 mg, 1.21 mmol) was added at 0 °C, the mixture was reacted at 25 °C for 1 h. After the reaction was completed, saturated aqueous ammonium chloride solution (20 mL) was added, and ethyl acetate (20 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 obtained crude product was purified by silica gel column chromatography (DCM:MeOH = 15: 1) to obtain (S)-12-((l-((4-benzylpiperazin-l-yl)methyl)cyclopropyl)methoxy)-2-chloro-l-fluoro- 5a,6,9,10-tetrahydro-5H,8H-4,7-dioxa-3,10a,11,13-tetraazanaphtho[l,8-ab]heptaen.

[1147] LC-MS: (ESI, m / z): [M+H] + = 569.2.

[1148] Step 3: Preparation of (S)-4-(12-((l-((4-benzylpiperazin-l-yl)methyl)cyclopropyl)methoxy)-l-fluoro- 5a,6,9,10-tetrahydro-5H,8H-4,7-dioxa-3,10a,11,13-tetraazanaphtho[l,8-ab]heptaen-2-yl)-6-fluoro- 5-((triisopropylsilyl)ethynyl)naphthalen-2-ol

[1149] To a mixture solution of (S)-12-((l-((4-benzylpiperazin-l-yl)methyl)cyclopropyl)methoxy)- 2-chloro-l-fluoro-5a,6,9,10-tetrahydro-5H,8H-4,7-dioxa-3,10a,11,13-tetraazanaphtho[l,8-ab] heptene (170 mg, 0.30 mmol) and 6-fluoro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-5- ((triisopropylsilyl)ethynyl)naphthalen-2-ol (168 mg, 0.36 mmol) in 1,4-dioxane (2 mL) and H2O (0.4 mL) was added cesium carbonate (292 mg, 0.90 mmol) and cataCXium APd-G3 (44 mg, 0.06 mmol) and reacted at 85 °C under N2protection overnight. The mixture was added to water (20 mL) and extracted with ethyl acetate (20 mL x 3), the organic phase was combined and dried over anhydrous sodium sulfate and concentrated under reduced pressure. The concentrate was purified by column chromatography (DCM / MeOH = 10 / 1) to give (S)-4-(12-((l-((4-benzylpiperazin-l-yl)methyl)cyclopropyl)methoxy)-l-fluoro-5a,6,9,10- tetrahydro-5H,8H-4,7-dioxa-3,10a,11,13-tetraazanaphtho[l,8-ab]hepten-2-yl)-6-fluoro-5- ((triisopropylsilyl)ethynyl)naphthalen-2-ol.

[1150] LC-MS: (ESI, m / z): [M+H] + = 875.3.

[1151] Step 4: Preparation of (S)-6-fluoro-4-(l-fluoro-12-((l-(piperazin-l-ylmethyl)cyclopropyl)methoxy)- 5a,6,9,10-tetrahydro-5H,8H-4,7-dioxa-3,10a,11,13-tetraazanaphtho[l,8-ab]hepten-2-yl)-5- ((triisopropylsilyl)ethynyl)naphthalen-2-ol

[1152] (S)-4-(12-((1-((4-benzylpiperazin-1-yl)methyl)cyclopropyl)methoxy)-1-fluoro- 5a,6,9,10-tetrahydro-5H,8H-4,7-dioxa-3,10a,11,13-tetraazanaphtho[1,8-ab]heptalen- 2-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalen-2-ol (85 mg, 0.097 mmol) was dissolved in DCM (2 mL), and 1-chloroethyl chloroformate (42 mg, 0.29 mmol) was added. The mixture was reacted at room temperature for 1 hour, concentrated under reduced pressure, and the concentrate was dissolved in MeOH (2 mL) and heated to 50 °C for 50 minutes. After the reaction was completed, the reaction was concentrated under reduced pressure, and the concentrate was purified by silica gel column chromatography (DCM:MeOH...

Claims

1. A compound of formula I or I', and / or its stereoisomers, enantiomers, diastereomers, atropisomers, deuterated forms, hydrates, solvates, prodrugs, and / or pharmaceutically acceptable salts: wherein, K is K' is independently K1or K2: K1 is selected from the group consisting of: ring A is a 6-10 membered heterocycloalkyl, said heterocycloalkyl containing at least one heteroatom or heteroatom group selected from N, S or O, and said 6-10 membered heterocycloalkyl being optionally substituted with one or more R2; X1 is selected from O, S or NR6; X2 is selected from CR1 or N; R1is selected from hydrogen, deuterium, halogen, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 alkoxy, or C 1-3 haloalkyl; R2is selected from hydrogen, deuterium, hydroxyl, cyano, halogen, -NH(C 1-3 alkyl), C 1-6 alkyl, C 1-6 alkyl, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkenyl, C 2-6 alkynyl, or C 2-6 alkynyl; R s selected from hydrogen, deuterium, halogen, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 alkoxy or C 1-3 haloalkyl; m is selected from 0, 1, 2, 3 or 4; n is selected from 0, 1 or 2; R4is selected from C 6-10 aryl or 5-10 membered heteroaryl, said C 6-10 aryl or 5-10 membered heteroaryl is optionally substituted with 1 or more hydroxy, halo, deuterium, cyano, amino, C 1-3 alkyl, C 1-3 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 haloalkyl or C 3-6 cycloalkyl; R5is selected from hydrogen, deuterium, halogen, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 alkoxy, or C 1-3 haloalkyl; R6is selected from hydrogen or C 1-3 alkyl; K2 is selected from the group consisting of: A1 is selected from CH or N; D1 is selected from -CH2-, -CH2CH2- or -CH(CH2CN)-; X 1a selected from O or S; Y" is selected from -C(CN)- or N; G" is selected from -C(R 3b )- or N; Z" is selected from -C(R 3c )- or N; R 1a selected from H, OH, methoxy, C 1-4 alkyl, C 2-4 heteroalkyl, azetidine, N-linked piperazine, piperidine, or morpholine, said C 1- 4alkyl, C 2-4 heteroalkyl, azetidine, piperidine, or N-linked piperazine is optionally substituted with one or more of amino, hydroxyl, halogen, methyl, trideuteromethyl, methoxy, oxetane, or C 1-3 alkyl; R 2a selected from H, halogen or methyl; R 3a , R 3b and R 3c are each independently selected from H, methyl or halogen; L is L is attached to K via A or B; E is L' is a linking chain which connects K' and E' via covalent bonds; wherein each E' is independently E1, E2, or E3: wherein E1 is selected from the group consisting of: Z' is O, S or CH2; X 2 ' is CH or N; Y 2 is CH, N, O or S; Q1, Q2, Q3, Q4, Q5are each independently CR 3b or N; R 3b Each is independently hydrogen, deuterium, hydroxyl, amino, cyano, halogen, nitro, thiol, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, C6-C 10 Aryl, 5-10 membered heteroaryl, -O-(C1-C6 alkyl), -O-(C1-C6 heteroalkyl), -O-(C3-C8 cycloalkyl), -O-(3-8 membered heterocycloalkyl), -S-(C1-C6 alkyl), -S-(C1-C6 heteroalkyl), -S-(C3-C8 cycloalkyl), -S-(3-8 membered heterocycloalkyl), -N(C1-C6 alkyl) 1-2 、-N(C1-C6 heteroalkyl) 1-2 、-N(C3-C8 cycloalkyl) 1-2 、-N(3-8 membered heterocycloalkyl) 1-2 、-O-(C6-C 10 aryl), -O-(5-10 membered heteroaryl); the C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, C6-C 10 Aryl, 5-10 membered heteroaryl optionally substituted by 1-3 independently selected from deuterium, hydroxyl, halogen, cyano, amino, O (C1-C6 alkyl), O- (C3-C8 cycloalkyl), -O- (3-8 membered heterocycloalkyl), N (C1-C6 alkyl) 1-2 、-NH(C3-C8 cycloalkyl),-NH(3-8 membered heterocycloalkyl),-O-(C6-C 10 aryl), -O-(5-10 membered heteroaryl); or R 3b together with the atoms to which they are attached, form a cycloalkyl, heterocycloalkyl, heteroaryl, or aryl group; m" is 1, 2 or 3; R 1b each independently is hydrogen, deuterium, hydroxyl, amino, cyano, halogen, C1-C6alkyl, C1-C6heteroalkyl, C3-C8cycloalkyl, C3-C8heterocycloalkyl, C6-C10aryl, 5-10 membered heteroaryl, -0(C1-C6alkyl), -0-(C3-C8cycloalkyl), -0-(3-8 membered heterocycloalkyl), -N(C1-C6alkyl) 10 (C6-C10aryl), -0-(5-10 membered heteroaryl), said alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl optionally substituted with 1-3 independent groups selected from hydroxyl, halogen, cyano, hydroxyl, amino; and 1-2 R1is hydrogen, deuterium, halogen, cyano, C1-C6alkyl, C1-C6heteroalkyl, C3-C8cycloalkyl, C3-C8heterocycloalkyl, C6-C10aryl, 5-10 membered heteroaryl, -0(C1-C6alkyl), -0-(C3-C8cycloalkyl), -0-(3-8 membered heterocycloalkyl), -N(C1-C6alkyl) 10 (C6-C10aryl), -0-(5-10 membered heteroaryl), said alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl optionally substituted with 1-3 independent groups selected from hydroxyl, halogen, cyano, hydroxyl, amino; and R 2b is none, hydrogen, deuterium, C1-C6alkyl or C3-C6cycloalkyl, said C1-C6alkyl and C3-C6cycloalkyl optionally substituted with 1-3 groups independently selected from hydroxy, halogen, cyano, hydroxy, amino or -OC(O)(C1-C6alkyl); wherein E2 is selected from the group consisting of: Q1, Q2, Q3, and Q4are each independently CR 3b or N; W is CR 1c R 2c , C(S), C(O), SO2, -OC=R 4c -, -SC=R 4c - or -C=R 4c NR 5c - or -N=CA'-; X is CH2, O or S; X c is -CH2- or -NG'-; Z is CH2, O or S; G' and G" are each independently selected from hydrogen, deuterium, C1-C6 alkyl, OH, C3-C6 cycloalkyl, -CH2-heterocycloalkyl or -CH2-phenyl, said C1-C6 alkyl, C3-C6 cycloalkyl, -CH2-heterocycloalkyl or -CH2-phenyl being optionally substituted with one or more hydroxyl, halogen, cyano, amino; A' is hydrogen, deuterium, C1-C6 alkyl, C3-C8 cycloalkyl or halogen; R 1c 、R 2c and R 3c Each independently selected from hydrogen, deuterium, hydroxyl, halogen, -NH2, -N(C1-C6 alkyl) 1-2 , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, -CONR'R", -OR', -NR'R", -SR', -SO2R', -SO2NR'R", -CR'R", -CR'NR'R", C6-C 10 Aryl, 5-10 membered heteroaryl, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, -P(O)(OR′)R″, -P(O)R′R″, -OP(O)(OR′)R″, -CN, -NR′SO2NR′R″, -NR′C(O)NR′R″, -C(O)NR′C(O)R″, -NR′C(═N—CN)NR′R″, -C(═N—CN)NR′R″, -NR′C(═N—CN)R″, -NR′C(═C—NO2)NR′R″, -SO2NR′COR″, -NO2, -COR′, -C(C═N—OR′)R″, -CR′═CR′R″, -CCR′, -S(C═O)(C═NR′)R″, -SF5, or -OCF3; R 4c is O or S; R 5c H, C1-C6 alkyl, C6-C 10 Aryl, 5-12 membered heteroaryl, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl; R' and R" are each independently selected from the group consisting of a bond, hydrogen, deuterium, Ci-C6alkyl, C3-C8cycloalkyl, C6-Ci0aryl, 5-10 membered heteroaryl, 3-8 membered heterocycloalkyl; wherein each of the alkyl, cycloalkyl, aryl, heteroaryl, and heterocycloalkyl groups is optionally substituted with one or more Rfgroups; 10 aryl, 5-10 membered heteroaryl, or 3-8 membered heterocyc n" is 0, 1, 2, 3 or 4; is a single or double bond; is a bond, which may be an R stereoisomer, an S stereoisomer or a non-stereoisomer; wherein E3 is selected from the group consisting of: X 1 , X 2 each independently is a bond, O, C(O), C(S), NR 1d or CR 1d R 2d ; R 1d , R 2d each independently is selected from H, deuterium, C1-C6alkyl optionally substituted with 1 or more halogen or C1-C6alkoxy; R P independently selected from H, deuterium, halogen, -OH, C1-C3alkyl optionally substituted with 1 or more halogen, hydroxyl, or C1-C3alkoxy; W 3 C1-C6 alkyl, -T-N(R 3d R 4d ), -T-N(R 3d R 4d )X 3 , -T-(C6-C 10 )aryl, -T-(5-10 membered)heteroaryl, -T-(4-12 membered)heterocycloalkyl, -NR 5d -T-(C6-C 10 )aryl, -NR 5d -T-(5-10 membered)heteroaryl, or -NR 5d -T-(4-12 membered)heterocycloalkyl, said C1-C6 alkyl, -T-N(R 3d R 4d ), -T-N(R 3d R 4d )X 3 , -T-(C6-C 10 )aryl, -T-(5-10 membered)heteroaryl, -T-(4-12 membered)heterocycloalkyl, -NR 5d -T-(C6-C 10 )aryl, -NR 5d -T-(5-10 membered)heteroaryl, or -NR 5d -T-(4-12 membered)heterocycloalkyl are optionally substituted; X 3 C(O), R 3d , R 4d or R 5d ; R 3d , R 4d , or R 5d are each independently selected from H, deuterium, C1-C6alkyl optionally substituted with 1 or more halogen, -OH, R 1d C(O), R 1d C(S), R 1d SO, R 1d SO2, NR 1d R 2d C(O), NR 1d R 2d C(S), NR 1d R 2d SO, or NR 1d R 2d SO2; T is C 1- C6alkyl or -(CH2) n' -1 or more methylenes in said -(CH2) n' - are optionally substituted with one or more selected from deuterium, halogen or C1-C6alkyl optionally substituted with halogen, -OH or amino; n' is 0, 1, 2, 3, 4, 5 or 6; W 4 for The is optionally substituted; R 6d , R 7d each independently H, deuterium, C3-C8cycloalkyl, or Ci-C6alkyl optionally substituted with halogen, -OH, CN, NO2, or amino; W 5 R is 6-10 membered aryl or 5-10 membered heteroaryl; R 8d H, deuterium, halogen, CN, OH, NO2, NR 6d R 7d , OR 6d , COR 6d R 7d , NR 6d COR 7d , SO2R 6d R 7d , R 6d SO2R 7d , C1-C6alkyl, C1-C6alkoxy, C6-C 10 aryl, 5-10 membered heteroaryl, C3-C8cycloalkyl, or 3-8 membered heterocycloalkyl, said C1-C6alkyl, C1-C6alkoxy optionally substituted with deuterium, halogen, -OH, CN, NO2, or amino.

2. The compound 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: K is K1 is selected from the group consisting of: n is selected from 0 or 1; R4is selected from C 6-10 aryl or 5-10 membered heteroaryl, said C 6-10 aryl or 5-10 membered heteroaryl is optionally substituted with 1 or more hydroxy, halo, deuterium, cyano, amino, C 1-3 alkyl, C 1-3 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl or C 1-3 haloalkyl.

3. The compound of formula I or 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 or I' satisfies one or more of the following conditions: (1) K is Preferably, For (2) L is attached to K via A; (3) L is L is attached to K via A; (4) E is (5) E1 is For example, E1 is (6) K1 is (7) in ring A, the 6-10 membered heterocycloalkyl is a 6, 7, 8, 9, or 10 membered mono-, bridged-, or spiro-heterocycloalkyl, with the heteroatoms being one or more of N, O, and S, for example: said ring A is optionally substituted with 1 or more R2, for example (8) X2 is selected from N; (9) X1 is selected from O or NR6; (10) R1 and R2 are independently selected from hydrogen or deuterium; (11) R s selected from hydrogen, deuterium or C 1-3 alkyl, for example hydrogen or deuterium; (12) m is selected from 0, 1 or 2; (13) R4 is R4is optionally substituted with 1 or more hydroxyl, halogen, deuterium, cyano, amino, C 1-3 alkyl, C 1-3 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 haloalkyl, or C 3-6 cycloalkyl; (14) R5 is selected from hydrogen, deuterium or halogen; (15) L' is L' is attached to K' via A.

4. The compound of formula I or I' according to claim 1, and / or its stereoisomers, enantiomers, diastereomers, atropisomers, deuterated forms, hydrates, solvates, prodrugs, and / or its pharmaceutically acceptable salts, characterized in that, satisfies any one of the following scenarios: Scenario 1: K is L is L is attached to K via A; E is Scenario 2: K is L is L is attached to K via A; E is Scenario 3: K is L is L is attached to K via A; E is Scenario 4: K' is ring A is a 6-10 membered heterocycloalkyl, said heterocycloalkyl containing at least one heteroatom or heteroatom group selected from N, S or O, and said 6-10 membered heterocycloalkyl being optionally substituted with one or more R2; R2is selected from hydrogen, deuterium, hydroxyl, or C 1-6 alkyl; X1 is selected from O or NR6; X2 is selected from N; R s selected from hydrogen, deuterium or C 1-3 alkyl; m is selected from 0, 1 or 2; n is selected from 0, 1 or 2; R4 is R4is optionally substituted with 1 or more hydroxyl, halogen, deuterium, cyano, amino, C 1-3 alkyl, C 1-3 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 haloalkyl, or C 3-6 cycloalkyl; R5 is selected from hydrogen, deuterium or halogen; R6is selected from hydrogen or C 1-3 alkyl; L' is L' is attached to K' via A. E' is Scenario 5: K' is X2 is selected from N; X1 is selected from O or NR6; R6is selected from hydrogen or C 1-3 alkyl; R s selected from hydrogen, deuterium or C 1-3 alkyl; R5 is selected from hydrogen, deuterium or halogen; m is selected from 0 or 1; R4 is said R4is optionally substituted with 1 or more hydroxyl, halogen, deuterium, cyano, amino, C 1-3 alkyl, C 1-3 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 haloalkyl, or C3-6cycloalkyl; L' is L' is attached to K' via A. E' is 5. The compound of formula I or I' according to claim 1, and / or its stereoisomers, enantiomers, diastereomers, atropisomers, deuterated forms, hydrates, solvates, prodrugs, and / or its pharmaceutically acceptable salts, characterized in that, the compound of formula I or I' satisfies one or more of the following conditions: (1) K is L is E is (2) K is L is E is (3) K is L is E is (4) K is L is E is (5) K is L is E is (6) K is L is E is (7) K is L is E is (8) K is L is E is (9) K is L is E is (10) K is L is E is (11) K is L is E is (12) K is L is E is (13) K is L is E is (14) K is L is E is (15) K is L is E is (16) K is L is E is (17) K is L is E is (18) K is L is E is Preferably L is attached to K via A.

6. The compound of formula I or I' according to claim 1, and / or its stereoisomers, enantiomers, diastereomers, atropisomers, deuterated forms, hydrates, solvates, prodrugs, and / or pharmaceutically acceptable salts thereof, wherein K' is For example, K′ is or; K' is 7. The compound of formula I or I' according to claim 6, and / or its stereoisomers, enantiomers, diastereomers, atropisomers, deuterated forms, hydrates, solvates, prodrugs, and / or its pharmaceutically acceptable salts, characterized in that, the compound of formula I' satisfies one or more of the following conditions: (1) K' is L' is E' is (2) K' is L' is E' is (3) K' is L' is E' is (4) K' is L' is E' is (5) K' is L' is E' is (6) K' is L' is E' is (7) K' is L' is E' is (8) K' is L' is E' is (9) K' is L' is E' is (10) K' is L' is E' is (11) K' is L' is E' is (12) K' is L' is E' is (13) K' is L' is E' is (14) K' is L' is E' is (15) K' is L' is E' is (16) K' is L' is E' is (17) K' is L' is E' is (18) K' is L' is E' is (19) K' is L' is E' is (20) K' is L' is E' is 8. The compound of formula I or I' according to claim 6, and / or its stereoisomers, enantiomers, diastereomers, atropisomers, deuterated forms, hydrates, solvates, prodrugs, and / or its pharmaceutically acceptable salts, characterized in that, the compound of formula I' satisfies one or more of the following conditions: (1) K' is L' is E' is (2) K' is L' is E' is (3) K' is L' is E' is 9. The compound of formula I or I′ according to claim 1, and / or its stereoisomers, enantiomers, diastereomers, atropisomers, deuterated forms, hydrates, solvates, prodrugs, and / or pharmaceutically acceptable salts thereof, wherein the compound of formula I or I′ is:

10. A pharmaceutical composition, characterized by, which comprises a compound according to any one of claims 1 to 9, and / or a stereoisomer, enantiomer, diastereomer, atropisomer, deuterated compound, hydrate, solvate, prodrug, and / or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient.

11. Use of a substance X for the preparation of a medicament or a KRAS inhibitor, characterized in that, said substance X is a compound according to any one of claims 1 to 9, and / or a stereoisomer, enantiomer, diastereomer, atropisomer, deuterated compound, hydrate, solvate, prodrug, and / or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 10, said pharmaceutical being for use in the treatment and / or prevention of a KRAS-mediated disease or disorder, or, said pharmaceutical being for use in the treatment or prevention of a cancer.

12. Use as claimed in claim 11, characterised in that, which fulfils one or more of the following conditions: (1) the KRAS-mediated disease is a cancer; (2) KRAS is KRAS G12A, KRAS G12C, KRAS G12D, KRAS G12R, KRAS G12S, KRAS G12V, KRAS G13D, KRAS Q61H or KRAS WT.

13. Use according to claim 11, wherein said KRAS-mediated disease and said cancer are independently selected from: heart: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma; lung: bronchogenic carcinoma (squamous cell carcinoma, undifferentiated small cell carcinoma, undifferentiated large cell carcinoma, adenocarcinoma), alveolar carcinoma (bronchiolar carcinoma), bronchial adenoma, sarcoma, lymphoma, chondroma hamartoma, mesothelioma, lung cancer, small cell lung cancer; gastrointestinal tract: esophageal carcinoma (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, fibronerveoma, fibroma), large intestine (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma), appendix carcinoma, gastrointestinal neuroendocrine tumor, gastroesophageal carcinoma, anal carcinoma, gastrointestinal stromal tumor; 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), germ cell tumor, bladder cancer, prostate cancer; liver: hepatocarcinoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, malignant hemangioendothelioma, hepatocellular adenoma, hemangioma; biliary tract: bile duct carcinoma, gallbladder carcinoma, ampullary carcinoma, cholangiocarcinoma, hepatobiliary carcinoma; Bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, chondroma (osteecartilage exostosis), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumor, bone cancer; 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 tumor), spinal cord neurofibroma, meningioma, glioma, sarcoma); Gynecology: uterus (endometrial carcinoma (serous cystadenocarcinoma, mucinous cystadenocarcinoma, non-classified 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, botulinum sarcoma (embryonic type rhabdomyosarcoma), fallopian tube (carcinoma), cervical cancer, endometrioid carcinoma; Hematology: blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphoblastic leukemia, myeloproliferative disease, 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 dysplastic nevus, lipoma, hemangioma, dermatofibroma, keloid, psoriasis, skin cancer, non-melanoma; Adrenal gland: neuroblastoma; Preferably, the cancer is non-small cell lung cancer, ovarian cancer, colorectal cancer, multiple myeloma, pancreatic cancer, biliary tract cancer, endometrial cancer, non-small cell lung cancer, ovarian cancer, rectal cancer, metastatic pancreatic cancer, lung cancer, gastric cancer, rectal cancer, large intestine adenocarcinoma or lung cancer squamous carcinoma.

14. The use according to claim 12, wherein the compound is ###00011### or a pharmaceutically acceptable salt thereof. It meets one or more of the following conditions: (1) the KRAS G12A-mediated disease is non-small cell lung cancer, ovarian cancer, colorectal cancer or multiple myeloma; (2) the KRAS G12C-mediated disease is non-small cell lung cancer, colorectal cancer or pancreatic cancer; (3) the KRAS G12D-mediated disease is biliary tract cancer, endometrial cancer, pancreatic cancer, colorectal cancer, non-small cell lung cancer, ovarian cancer, rectal cancer, colon cancer, metastatic pancreatic cancer, lung cancer or gastric cancer; (4) the KRAS G12R-mediated disease is pancreatic cancer or non-small cell lung cancer; (5) the KRAS G12S-mediated disease is rectal cancer, large intestine adenocarcinoma, colorectal cancer or non-small cell lung cancer; (6) the KRAS G12V-mediated disease is pancreatic cancer, colorectal cancer, non-small cell lung cancer, ovarian cancer, colon cancer, lung cancer or lung cancer squamous carcinoma; (7) the KRAS G13D-mediated disease is colorectal cancer; (8) the KRAS WT-mediated disease is gastric cancer.

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