Macrocyclic compound, preparation method therefor and use thereof

Abstract

Disclosed in the present invention are a macrocyclic compound having a structure represented by formula I, a preparation method therefor and a use thereof. The compound has significant inhibitory effects on KRAS and PI3K protein activity, can be used as a KRAS and / or PI3K protein inhibitor, and is used for preparing a drug for treating diseases such as KRAS and / or PI3K protein-mediated cancers. Moreover, the compound of the present invention has an extremely strong inhibitory effect on KRAS G12D inhibitor drug-resistant cancer cells, and has a wide application prospect.

Description

A macrocyclic compound and its preparation method and use

[0001] This application claims priority to Chinese Patent Application No. 202311227517X filed on September 22, 2023, and Chinese Patent Application No. 202410560884X filed on May 8, 2024. The entire contents of the aforementioned Chinese patent applications are incorporated herein by reference. Technical Field

[0002] The present invention relates to the field of medical technology, and in particular to a compound used as a KRAS G12D inhibitor and / or a PI3K protein inhibitor, which has a strong inhibitory effect on cancer cells resistant to multiple KRAS inhibitors. Background Art

[0003] The RAS (rat sarcoma) gene is an important oncogene, with three main subtypes: HRAS, NRAS, and KRAS. KRAS (kirsten rat sarcoma viral oncogene) mutations account for more than 85% of all RAS gene mutations (AT Baines, D. Xu, CJ Der, Future Med. Chem. 2011, 3, 1787-1808). KRAS is also the most commonly mutated gene in various human cancers, with a mutation rate of 96% in pancreatic cancer (Almoguera, C.; Shibata, D.; Forrester, K.; Martin, J.; Arnheim, N.; Perucho, M. Cell 1988, 53(4), 549-54), 54% in colorectal cancer (Bos, JL; Fearon, ER; Hamilton, SR; Verlaan-de Vries, M.; van Boom, JH; van der Eb, AJ; Vogelstein, B. Nature 1987, 327(6120), 293-7), and 39% in lung cancer (Rodenhuis, S.; van de Wetering, ML; Mooi, WJ; Evers, SG; van Zandwijk, N.; Bos, JL New Engl. J. Med. 1987, 317, 929-935).

[0004] The most common KRAS mutations occur at Gly12, Gly13, and Gln61, accounting for approximately 85%-90% of all KRAS mutations. Mutations at G12 predominate, accounting for 83%. Among the numerous KRAS subtypes and mutation types, KRAS G12D mutations are particularly prevalent, particularly in pancreatic and colon cancers. The order of observed KRAS G12 mutations is G12D, G12V, G12C, G12A, G12S, and G12R, with G12D, G12V, and G12C accounting for 41%, 28%, and 14%, respectively. KRAS G12D is the most common KRAS mutation in pancreatic and colorectal cancers, accounting for 47% and 44%, respectively, followed by NSCLC, accounting for 17%. KRAS G12D mutations are found in 25% of all pancreatic cancer patients, 13.3% of all colon cancer patients, 10.1% of rectal cancer patients, 4.1% of non-small cell lung cancer patients, and 1.7% of small cell lung cancer patients (The AACR Project GENIE Consortium, Cancer Discovery 2017, 7, 818-831).

[0005] Due to the special structure of KRAS protein molecules, it has long been considered an undruggable target. Currently, small molecules that directly target KRAS mutations are mainly concentrated in KRAS G12C, such as AMG510 and MTRX849. Although KRAS G12D mutations are more common, due to the special structure and regulatory mechanism of G12D, there are relatively few small molecule inhibitors targeting KRAS G12D that have been disclosed (Vasta, JD, et al, Nat. Chem. Bio., 2022, 18(6), 596; Wang, X., et al, J. Med. Chem., 2022, 65(4), 3123). In recent years, due to the progress of drug development technology and strategies, certain breakthroughs have been made in the development of direct target drugs for KRAS mutations. The development of inhibitors for KRAS G12D has also recently begun to be reported. For example, Jacobio recently disclosed a class of fused ring compounds as G12D selective inhibitors (Han, H.; et al, WO2022188729); Mirati researchers recently reported a class of non-covalent highly selective G12D inhibitors represented by MRTX-1133 (Wang, X.; et al, J. Med. Chem., 2022, 65, 3123-3133).

[0006] PI3K is widely present in human tissues. PI3K is an important part of the PI3K-AKT-mTOR pathway and a key regulator of intracellular function. Structurally, PI3K consists of a catalytic subunit and a regulatory subunit. Based on their structure and substrates, PI3K can be divided into types I, II, and III, with type I being most closely associated with tumors. Based on the differences in their type I catalytic subunits, PI3K can be further subdivided into α, β, δ, and γ types. PI3K expression distribution varies with the catalytic subunits: PI3Kα and PI3Kβ are expressed in a variety of cell types, while PI3Kδ and PI3Kγ are expressed only in the immune system.

[0007] PI3K signaling, acting downstream of tyrosine kinases, G protein-coupled receptors (GPCRs), and GTPases (such as RAS, RAC, and CDC42), regulates a range of cellular activities, including metabolism, proliferation, and migration (Cantley, LC, Science, 2002, 296, 1655-1657). The PI3K signaling pathway is one of the most frequently activated signaling pathways in human cancer, mediating the development of nearly 50% of malignant tumors. Studies have shown that overactive PI3K signaling is significantly correlated with tumor progression, increased tumor microvascular density, and enhanced cancer cell chemotaxis and invasiveness. Currently, PI3K has become an important target for the treatment of various malignancies. Although KRAS-targeted therapies (including G12C inhibitors) are initially very effective in inhibiting tumor growth, the development of resistance to these drugs is almost inevitable. Researchers have found that shortly after drug administration, some cancer cells are rendered quiescent and have reduced KRAS activity, while others bypass this effect to resume proliferation and develop resistance. (XIE, JY; et al, Nature 2020, 577, 421-425). The latest study by Adachi et al. shows that the continuous activation of the PI3K signaling pathway is a key mechanism leading to intrinsic and acquired resistance to KRAS inhibitors. (Adachi, Y., et al Clin Cancer Res 2020, Sep 8. doi: 10.1158 / 1078-0432. CCR-20-2077.). Although other studies have been published on the mechanism of resistance to KRAS inhibitors, there is still no good and practical solution to the problem of resistance to such inhibitors in clinical practice. Therefore, the development of a class of dual inhibitors that can simultaneously inhibit KRAS G12D and PI3K is of great importance and far-reaching significance for the treatment of KRAS G12D resistance-related diseases.

[0008] Summary of the Invention

[0009] The main technical problem solved by the present invention is to provide a pyrimidine aromatic ring compound, which serves as a dual inhibitor of KRAS G12D and PI3K, has high activity and good drugability, especially for G12D resistance-related diseases, and has good potential therapeutic prospects.

[0010] Compound

[0011] To solve the above technical problems, on the one hand, the present invention provides a compound represented by formula IA, or its tautomers, stereoisomers, solvates, metabolites, isotope-labeled substances, pharmaceutically acceptable salts, and cocrystals.

[0012] in,

[0013] W is Among them, the a-terminal is connected to the pyridyl group;

[0014] X1 is N or CR8;

[0015] R8 is selected from hydrogen, amino, halogen, hydroxy, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2, C 3-8 Cycloalkyl, 3-8 membered alicyclic group, C 6-10 Aryl, 5-10 membered heteroaryl; the alkyl group is optionally substituted with one or more selected from -CN, -N(C 1-6 alkyl)2 is substituted with a substituent;

[0016] L1 is selected from a single bond, -O-, -S-, -N(Ra)-;

[0017] L2 is selected from a single bond, C 1-6 Alkylene, the alkylene is optionally substituted by one or more selected from C 1-6 is substituted by an alkyl substituent; L1 and L2 are not single bonds at the same time;

[0018] R a Selected from hydrogen and C 1-6 alkyl;

[0019] A is in, Each is independently selected from a 4- to 10-membered heterocycloalkyl group or a 4- to 10-membered heterocycloalkenyl group, wherein the heterocycloalkyl group or heterocycloalkenyl group is a monocyclic, fused, spirocyclic or bridged ring;

[0020] The condition is that when A is When L2 is connected to any ring atom on the ring; when A is When L2 is connected to A2, or L2 is connected to any ring atom on the ring;

[0021] A1 and A2 are each independently selected from CR7 and N;

[0022] R7 are each independently selected from hydrogen, C 1-6 Alkyl, -C 1-6 Alkyl-OH, -C 1-6 Alkyl-CN, -C 1-6 Alkyl-OC 1-6 alkyl;

[0023] Ring B is selected from 5-7 membered heteroaryl and phenyl, wherein the 5-7 membered heteroaryl or phenyl is optionally substituted with one or more R6;

[0024] R6 are each independently selected from H, halogen, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, -NH-C 1-6 Alkyl, -N(C 1-6 Alkyl)2;

[0025] R1 is selected from hydrogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, alkoxyalkyl, C 1-6 Alkoxy, -(C 1-6 Alkyl)-OH or -(C 1-6 alkyl)-(3-8 membered alicyclic group), wherein the 3-8 membered alicyclic group is optionally substituted by one or more C 1-6 Alkyl substitution;

[0026] R2 is selected from hydrogen, deuterium, amino, halogen, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, -NH-C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered alicyclic group, C 6-10 Aryl, 5-10 membered heteroaryl;

[0027] R3 is selected from hydrogen, halogen, cyano, hydroxy, amino, C 1-6 Alkyl, C 3-8 Cycloalkyl, -NH-C 1-6 Alkyl, 3-8 membered aliphatic heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, C 1-6 Alkoxy, alkoxyalkyl, deuterated C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, -N(C 1-6 Alkyl)2;

[0028] R4 is selected from hydrogen, halogen, cyano, C1-6 Alkyl and C 1-6 alkoxy;

[0029] R5 is selected from C 6-10 Aryl and 5-10 membered heteroaryl, wherein the aryl or heteroaryl is optionally substituted by one or more R b replace;

[0030] R b Each occurrence is independently selected from hydrogen, halogen, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, alkoxyalkyl, halo C 1-6 Alkyl, halogenated C 1-6 Alkoxy, -S(O)2(C 1-6 Alkyl), -(C 1-6 Alkyl)-CN, -C 1-6 Alkyl-N(C 1-6 Alkyl)2, C 3-8 Cycloalkyl, -O-(3-8 membered alicyclic group), -O-(C 3-8 Cycloalkyl), 3-8 membered alicyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, amino, C 1-6 an alkyl-substituted amino group;

[0031] Or, two adjacent R b Together with the ring atoms to which it is connected, it forms a 3-6 membered cycloalkyl group;

[0032] n1 and n2 are each independently selected from 0, 1, 2, 3, and 4; n3 is selected from 0, 1, and 2.

[0033] In some embodiments, the present invention provides a compound of formula I, or a tautomer, stereoisomer, solvate, metabolite, isotope-labeled substance, pharmaceutically acceptable salt, or cocrystal thereof.

[0034] X1 is N or CR8;

[0035] R8 is selected from hydrogen, amino, halogen, hydroxy, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2, C 3-8 Cycloalkyl, 3-8 membered alicyclic group, C 6-10 Aryl, 5-10 membered heteroaryl; the alkyl group is optionally substituted with one or more selected from -CN, -N(C 1-6 alkyl)2 is substituted with a substituent;

[0036] L1 is selected from a single bond, -O-, -S-, -N(Ra)-;

[0037] L2 is selected from a single bond, C 1-6 Alkylene, the alkylene is optionally substituted by one or more selected from C 1-6 substituted by an alkyl substituent;

[0038] R a Selected from hydrogen and C 1-6 alkyl;

[0039] A is in, Each is independently selected from a 4- to 10-membered heterocycloalkyl group or a 4- to 10-membered heterocycloalkenyl group, wherein the heterocycloalkyl group or heterocycloalkenyl group is a monocyclic, fused, spirocyclic or bridged ring;

[0040] The condition is that when A is When L2 is connected to any ring atom on the ring; when A is When L2 is connected to A2, or L2 is connected to any ring atom on the ring;

[0041] A1 and A2 are each independently selected from CR7 and N;

[0042] R7 are each independently selected from hydrogen, C 1-6 Alkyl, -C 1-6 Alkyl-OH, -C 1-6 Alkyl-CN, -C 1-6 Alkyl-OC 1-6 alkyl;

[0043] Ring B is selected from 5-7 membered heteroaryl and phenyl, wherein the 5-7 membered heteroaryl or phenyl is optionally substituted with one or more R6;

[0044] R6 are each independently selected from H, halogen, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, -NH-C 1-6 Alkyl, -N(C 1-6 Alkyl)2;

[0045] R1 is selected from hydrogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, alkoxyalkyl and C 1-6 alkoxy;

[0046] R2 is selected from hydrogen, deuterium, amino, halogen, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, -NH-C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered alicyclic group, C 6-10Aryl, 5-10 membered heteroaryl;

[0047] R3 is selected from hydrogen, halogen, cyano, hydroxy, amino, C 1-6 Alkyl, C 3-8 Cycloalkyl, -NH-C 1-6 Alkyl, 3-8 membered aliphatic heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, -N(C 1-6 Alkyl)2;

[0048] R4 is selected from hydrogen, halogen, cyano, C 1-6 Alkyl and C 1-6 alkoxy;

[0049] R5 is selected from C 6-10 Aryl and 5-10 membered heteroaryl, wherein the aryl or heteroaryl is optionally substituted by one or more R b replace;

[0050] R b Each occurrence is independently selected from hydrogen, halogen, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, -S(O)2(C 1-6 Alkyl), -(C 1-6 Alkyl)-CN, -C 1-6 Alkyl-N(C 1-6 Alkyl)2, C 3-8 Cycloalkyl, 3-8 membered alicyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, amino, C 1-6 an alkyl-substituted amino group;

[0051] Or, two adjacent R b Together with the ring atoms to which it is connected, it forms a 3-6 membered cycloalkyl group;

[0052] n1 and n2 are each independently selected from 0, 1, 2, 3, and 4; n3 is selected from 0, 1, and 2.

[0053] In some embodiments, the present invention provides a compound of formula I, or a tautomer, stereoisomer, solvate, metabolite, isotope-labeled substance, pharmaceutically acceptable salt, or cocrystal thereof.

[0054] in,

[0055] X1 is N or CR8;

[0056] R8 is selected from hydrogen, amino, halogen, hydroxy, cyano, C1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 3-8 membered alicyclic group, C 6-10 Aryl, 5-10 membered heteroaryl;

[0057] L1 is selected from a single bond, -O-, -S-, -N(Ra)-;

[0058] L2 is selected from C 1-6 Alkylene, the alkylene is optionally substituted by one or more selected from C 1-6 substituted by an alkyl substituent;

[0059] R a Selected from hydrogen and C 1-6 alkyl;

[0060] A is in, Each is independently selected from a 4- to 10-membered heterocycloalkyl group or a 4- to 10-membered heterocycloalkenyl group, wherein the heterocycloalkyl group or heterocycloalkenyl group is a monocyclic, fused, spirocyclic or bridged ring;

[0061] The condition is that when A is When , L2 is connected to A2;

[0062] A1 and A2 are each independently selected from CR7 and N;

[0063] R7 are each independently selected from hydrogen, C 1-6 Alkyl, -C 1-6 Alkyl-OH, -C 1-6 Alkyl-CN, -C 1-6 Alkyl-OC 1-6 alkyl;

[0064] Ring B is selected from 5-7 membered heteroaryl and phenyl, wherein the 5-7 membered heteroaryl or phenyl is optionally substituted with one or more R6;

[0065] R6 are each independently selected from H, halogen, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, -NH-C 1-6 Alkyl, -N(C 1-6 Alkyl)2;

[0066] R1 is selected from hydrogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl and C 1-6 alkoxy;

[0067] R2 is selected from hydrogen, deuterium, amino, halogen, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, -NH-C1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered alicyclic group, C 6-10 Aryl, 5-10 membered heteroaryl;

[0068] R3 is selected from hydrogen, halogen, cyano, hydroxy, amino, C 1-6 Alkyl, C 3-8 Cycloalkyl, -NH-C 1-6 Alkyl, 3-8 membered aliphatic heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, C 1-6 alkoxy;

[0069] R4 is selected from hydrogen, halogen, cyano, C 1-6 Alkyl and C 1-6 alkoxy;

[0070] R5 is selected from C 6-10 Aryl and 5-10 membered heteroaryl, wherein the aryl or heteroaryl is optionally substituted by one or more R b replace;

[0071] R b Each occurrence is independently selected from hydrogen, halogen, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 3-8 Cycloalkyl, 3-8 membered alicyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, amino, C 1-6 an alkyl-substituted amino group;

[0072] n1 and n2 are each independently selected from 0, 1, 2, 3, and 4; n3 is selected from 0, 1, and 2.

[0073] In some embodiments, in the compound of formula I, ring B is selected from 6-membered heteroaryl and phenyl.

[0074] In some embodiments, in the compound represented by formula I, R a is selected from hydrogen, methyl, ethyl, propyl and butyl; preferably, R a is selected from hydrogen and methyl; more preferably, R a For hydrogen.

[0075] In some embodiments, in the compound of formula I, R5 is selected from 5-6 membered heteroaryl and phenyl, and the heteroaryl or phenyl is optionally replaced by one or more R b replace.

[0076] In some embodiments, in the compound of formula I, R5 is selected from 6-membered heteroaryl and phenyl, and the heteroaryl or phenyl is optionally replaced by one or more R b replace.

[0077] In some embodiments, the compound provided by the present invention has a structure shown in Formula II or Formula III, or a tautomer, stereoisomer, solvate, metabolite, isotope label, pharmaceutically acceptable salt, or cocrystal thereof.

[0078] in,

[0079] X2 is N or CR6;

[0080] X3, X4, X5, and X6 are each independently selected from N and CR b ;

[0081] In the compound represented by formula II, is a 4-8 membered monocyclic heterocycloalkyl, a 6-8 membered cyclic heterocycloalkyl, a 6-8 membered spirocyclic heterocycloalkyl, a 6-8 membered bridged heterocycloalkyl or a 4-8 membered monocyclic heterocycloalkenyl; preferably a 6 membered monocyclic heterocycloalkyl;

[0082] In the compound represented by formula III, is a 4-6 membered monocyclic heterocycloalkyl group or a 4-6 membered monocyclic heterocycloalkenyl group; preferably a 4-membered monocyclic heterocycloalkyl group or a 6-membered monocyclic heterocycloalkyl group;

[0083] n4 is selected from 0, 1, 2, 3, 4;

[0084] The remaining substituents are as defined in Formula I.

[0085] In some embodiments, in the compound of formula I, R5 is selected from thienyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl and phenyl, and the thienyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl or phenyl is optionally replaced by one or more R b replace.

[0086] In some embodiments, in the compound of formula I, R5 is selected from pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl and phenyl, and the pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl or phenyl is optionally replaced by one or more R b replace.

[0087] In some embodiments, in the compound of formula I, R5 is selected from pyridyl and phenyl, and the pyridyl or phenyl is optionally replaced by one or more R b replace.

[0088] In some embodiments, in the compound of formula I, when R5 is phenyl, it is connected to the remaining groups through positions 1, 2 or positions 1, 4 to form a cyclic compound.

[0089] In some embodiments, in the compound of formula I, when R5 is a pyridyl group, it is connected to the remaining groups through the 2, 3 positions or the 3, 4 positions to form a cyclic compound.

[0090] In some embodiments, the compound provided by the present invention has the structure shown in Formula II-A or Formula III-A, or its tautomers, stereoisomers, solvates, metabolites, isotope labels, pharmaceutically acceptable salts, cocrystals,

[0091] in,

[0092] Each substituent is as defined in Formula I, Formula II or Formula III.

[0093] In some embodiments, in the compound represented by Formula II or Formula II-A, It is a 4-6 membered monocyclic heterocycloalkyl or a 4-6 membered monocyclic heterocycloalkenyl; preferably a 6 membered monocyclic heterocycloalkyl.

[0094] In some embodiments, in the compound represented by Formula III or Formula III-A, It is a 4-6 membered monocyclic heterocycloalkyl group or a 4-6 membered monocyclic heterocycloalkenyl group; preferably a 4-membered monocyclic heterocycloalkyl group or a 6-membered monocyclic heterocycloalkyl group.

[0095] In some embodiments, n3 is selected from 0, 1, and 2.

[0096] In some embodiments, Each independently selected from Among them, the 1-position end is connected to L2, and the 2-position end is connected to the heteroaromatic ring.

[0097] In some embodiments, A is independently selected from Among them, the 1-position end is connected to L2, and the 2-position end is connected to the heteroaromatic ring.

[0098] In some embodiments, the structural fragment Selected from: Among them, the 1 position terminal is connected to W.

[0099] In some embodiments, the compounds provided by the present invention have the structure shown in Formula II-1, Formula II-2, Formula III-1 or Formula III-2, or their tautomers, stereoisomers, solvates, metabolites, isotope labels, pharmaceutically acceptable salts, cocrystals,

[0100] Wherein, each substituent is as defined in Formula I, Formula II or Formula III.

[0101] In some embodiments, the compound provided by the present invention has the structure shown in Formula II-3, or its tautomers, stereoisomers, solvates, metabolites, isotope labels, pharmaceutically acceptable salts, cocrystals,

[0102] Wherein, each substituent is as defined in Formula I, Formula II or Formula III.

[0103] In some embodiments, in the compounds represented by Formula I, Formula II, Formula III, Formula II-A, Formula III-A, Formula II-1, Formula II-2, Formula III-1, Formula III-2 or Formula III-3, L1 is a single bond, -O-, -NH- or -N(C 1-6 alkyl)-.

[0104] In some embodiments, in the compounds represented by Formula I, Formula II, Formula III, Formula II-A, Formula III-A, Formula II-1, Formula II-2, Formula III-1, Formula III-2 or Formula III-3, L1 is a single bond, -O-, -NH- or -N(CH3)-.

[0105] In some embodiments, in the compound represented by Formula I, Formula II, Formula III, Formula II-A, Formula III-A, Formula II-1, Formula II-2, Formula III-1, Formula III-2 or Formula III-3, L1 is a single bond or -O-.

[0106] In some embodiments, in the compound represented by Formula I, Formula II, Formula III, Formula II-A, Formula III-A, Formula II-1, Formula II-2, Formula III-1, Formula III-2 or Formula III-3, L1 is -O-.

[0107] In some embodiments, in the compounds of Formula I, Formula II, Formula III, Formula II-A, Formula III-A, Formula II-1, Formula II-2, Formula III-1, Formula III-2 or Formula III-3, L2 is selected from a single bond and C 1-4 Alkylene, said alkylene being optionally substituted by one or more C 1-6 Alkyl substituted.

[0108] In some embodiments, in the compound represented by Formula I, Formula II, Formula III, Formula II-A, Formula III-A, Formula II-1, Formula II-2, Formula III-1, Formula III-2 or Formula III-3, L2 is selected from C 1-4Alkylene, said alkylene being optionally substituted by one or more C 1-6 Alkyl substituted.

[0109] In some embodiments, in the compounds represented by Formula I, Formula II, Formula III, Formula II-A, Formula III-A, Formula II-1, Formula II-2, Formula III-1, Formula III-2 or Formula III-3, L2 is selected from methylene, ethylene, propylene, butylene, and the methylene, ethylene, propylene, butylene are optionally replaced by one or more C 1-6 Alkyl substituted.

[0110] In some embodiments, in the compounds represented by Formula I, Formula II, Formula III, Formula II-A, Formula III-A, Formula II-1, Formula II-2, Formula III-1, Formula III-2 or Formula III-3, L2 is selected from methylene, ethylene, propylene, butylene; the methylene, ethylene, propylene or butylene is optionally replaced by one or more C 1-4 Alkyl substituted.

[0111] In some embodiments, in the compounds represented by formula I, formula II, formula III, formula II-A, formula III-A, formula II-1, formula II-2, formula III-1, formula III-2 or formula III-3, L2 is selected from methylene, ethylene, propylene, and butylene; and the methylene, ethylene, propylene, or butylene is optionally substituted with one or more substituents selected from methyl and ethyl.

[0112] In some embodiments, the structural fragment Selected from

[0113] In some embodiments, in the compound represented by Formula I, Formula II, Formula III, Formula II-A, Formula III-A, Formula II-1, Formula II-2, Formula III-1, Formula III-2 or Formula III-3, X1 is N or CR8;

[0114] R8 is selected from hydrogen, amino, halogen, hydroxy, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, -NH(C 1-6 Alkyl), -N(C 1-6 alkyl) 2; the alkyl group is optionally substituted by one or more selected from -CN, -N(C 1-6 alkyl)2 is substituted with a substituent.

[0115] In some embodiments, in the compound represented by Formula I, Formula II, Formula III, Formula II-A, Formula III-A, Formula II-1, Formula II-2, Formula III-1, Formula III-2 or Formula III-3, X1 is N or CR8;

[0116] R8 is selected from hydrogen, halogen, cyano, C 1-6 Alkyl, C1-6 Alkoxy, -NH(C 1-6 Alkyl), -N(C 1-6 alkyl) 2; the alkyl group is optionally substituted by one or more selected from -CN, -N(C 1-6 alkyl)2 is substituted with a substituent.

[0117] In some embodiments, in the compound represented by Formula I, Formula II, Formula III, Formula II-A, Formula III-A, Formula II-1, Formula II-2, Formula III-1, Formula III-2 or Formula III-3, X1 is N or CR8; R8 is selected from hydrogen, amino, halogen, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Alkoxy.

[0118] In some embodiments, in the compounds represented by formula I, formula II, formula III, formula II-A, formula III-A, formula II-1, formula II-2, formula III-1, formula III-2 or formula III-3, R8 is selected from H, F, -CN, -CH3, methoxy, -CH2-CN, -CH2-N(CH3)2, -NH(CH3)2 or -N(CH3)2.

[0119] In some embodiments, in the compounds represented by formula I, formula II, formula III, formula II-A, formula III-A, formula II-1, formula II-2, formula III-1, formula III-2 or formula III-3, R8 is selected from H, -CN, -CH3, methoxy, -CH2-CN, -CH2-N(CH3)2, -NH(CH3)2 or -N(CH3)2.

[0120] In some embodiments, in the compounds represented by Formula I, Formula II, Formula III, Formula II-A, Formula III-A, Formula II-1, Formula II-2, Formula III-1, Formula III-2 or Formula III-3, X1 is N, CH or C(CN); preferably, X1 is N.

[0121] In some embodiments, in the compound represented by Formula II, Formula III, Formula II-A, Formula III-A, Formula II-1, Formula II-2, Formula III-1, Formula III-2 or Formula III-3, X2 is N or CR6.

[0122] In some embodiments, in the compound represented by Formula II, Formula III, Formula II-A, Formula III-A, Formula II-1, Formula II-2, Formula III-1, Formula III-2 or Formula III-3, X2 is selected from N, CH and C (halogen).

[0123] In some embodiments, in the compound represented by Formula II, Formula III, Formula II-A, Formula III-A, Formula II-1, Formula II-2, Formula III-1, Formula III-2 or Formula III-3, X2 is selected from N, CH, C(F).

[0124] In some embodiments, R6 is independently selected from H, halogen, cyano, C1-6 Alkyl, C 1-6 Alkoxy, -NH-C 1-6 Alkyl, -N(C 1-6 Alkyl)2.

[0125] In some embodiments, in the compounds of Formula I, Formula II, Formula III, Formula II-A, Formula III-A, Formula II-1, Formula II-2, Formula III-1, Formula III-2 or Formula III-3, R6 is independently selected from H, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, -NH-C 1-6 Alkyl, -N(C 1-6 Alkyl)2.

[0126] In some embodiments, in the compounds of Formula I, Formula II, Formula III, Formula II-A, Formula III-A, Formula II-1, Formula II-2, Formula III-1, Formula III-2 or Formula III-3, R6 is independently selected from H, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, -NH-C 1-6 alkyl.

[0127] In some embodiments, in the compounds of Formula I, Formula II, Formula III, Formula II-A, Formula III-A, Formula II-1, Formula II-2, Formula III-1, Formula III-2 or Formula III-3, R6 is independently selected from H, halogen, C 1-6 Alkyl, C 1-6 Alkoxy.

[0128] In some embodiments, in the compounds represented by Formula I, Formula II, Formula III, Formula II-A, Formula III-A, Formula II-1, Formula II-2, Formula III-1, Formula III-2 or Formula III-3, R6 is independently selected from H, F, Cl, Br, I, CN, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, butoxy, -NH-CH3, N(CH3)2; preferably, R6 is independently selected from H, F, Cl, CN, methyl, methoxy, ethoxy, -NH-CH3; more preferably, R6 is independently selected from H, F, CN, methyl, methoxy, ethoxy, -NH-CH3.

[0129] In some embodiments, in the compounds represented by Formula I, Formula II, Formula III, Formula II-A, Formula III-A, Formula II-1, Formula II-2, Formula III-1, Formula III-2 or Formula III-3, R6 is independently selected from H, F, Cl, Br, I, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, butoxy, -NH-CH3, N(CH3)2; preferably, R6 is independently selected from H, F, methyl, methoxy, ethoxy; more preferably, R6 is independently selected from H, F, methyl and methoxy.

[0130] In some embodiments, in the compound of Formula II or Formula III, one or more of X3, X4, X5, and X6 is N.

[0131] In some embodiments, in the compound of Formula II or Formula III, X3 is N, and X4, X5, and X6 are each independently CR b .

[0132] In some embodiments, in the compound of Formula II or Formula III, X4 is N, and X3, X5, and X6 are each independently CR b .

[0133] In some embodiments, in the compound of Formula II or Formula III, X5 is N, and X3, X4, and X6 are each independently CR b .

[0134] In some embodiments, in the compound of Formula II or Formula III, X6 is N, and X3, X4, and X5 are each independently CR b .

[0135] In some embodiments, in the compound of Formula II or Formula III, X3, X4, X5, and X6 are each independently CR b .

[0136] In some embodiments, in the compound represented by Formula II, Formula III, Formula II-A, Formula III-A, Formula II-1, Formula II-2, Formula III-1, Formula III-2 or Formula III-3, R b Each occurrence is independently selected from hydrogen, halogen, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, -S(O)2(C 1-6 Alkyl), -(C 1-6 Alkyl)-CN, -C 1-6 Alkyl-N(C 1-6 alkyl) 2, 3-8 membered alicyclic group, 5-10 membered heteroaryl, alkoxyalkyl, amino, C 1-6 Alkyl-substituted amino groups.

[0137] In some embodiments, in the compound represented by Formula II, Formula III, Formula II-A, Formula III-A, Formula II-1, Formula II-2, Formula III-1, Formula III-2 or Formula III-3, R b Each occurrence is independently selected from hydrogen, halogen, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C1-6 Alkoxy, amino, C 1-6 Alkyl-substituted amino groups.

[0138] In some embodiments, in the compound represented by Formula II, Formula III, Formula II-A, Formula III-A, Formula II-1, Formula II-2, Formula III-1, Formula III-2 or Formula III-3, R b Each occurrence is independently selected from hydrogen, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, S(O)2(C 1-6 Alkyl), -(C 1-6 Alkyl)-CN, -C 1-6 Alkyl-N(C 1-6 alkyl) 2, 3-8 membered alicyclic group, 5-10 membered heteroaryl, alkoxyalkyl, C 1-6 Alkyl-substituted amino, -O-(4-6 membered heterocycloalkyl) and -O-(C 3-6 (membered cycloalkyl).

[0139] In some embodiments, in the compound represented by Formula II, Formula III, Formula II-A, Formula III-A, Formula II-1, Formula II-2, Formula III-1, Formula III-2 or Formula III-3, R b Each occurrence is independently selected from hydrogen, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, S(O)2(C 1-6 Alkyl), -(C 1-6 Alkyl)-CN, -C 1-6 Alkyl-N(C 1-6 alkyl) 2, 3-8 membered alicyclic group, 5-10 membered heteroaryl, alkoxyalkyl and C 1-6 Alkyl-substituted amino groups.

[0140] In some embodiments, in the compound represented by Formula II, Formula III, Formula II-A, Formula III-A, Formula II-1, Formula II-2, Formula III-1, Formula III-2 or Formula III-3, R b Each occurrence is independently selected from hydrogen, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, S(O)2(C 1-6 Alkyl), -(C 1-6 Alkyl)-CN, -C 1-6 Alkyl-N(C 1-6alkyl) 2, 3-8 membered alicyclic group, 5-10 membered heteroaryl, alkoxyalkyl, C 1-6 Alkyl-substituted amino, -O-(4-6 membered heterocycloalkyl) and -O-(C 3-6 (a) a cycloalkyl group;

[0141] Or, two adjacent R b Together with the ring atoms to which it is connected, it forms a 3-6 membered cycloalkyl group.

[0142] In some embodiments, in the compound represented by Formula II, Formula III, Formula II-A, Formula III-A, Formula II-1, Formula II-2, Formula III-1, Formula III-2 or Formula III-3, R b Each occurrence is independently selected from hydrogen, halogen, cyano, C 1-6 Alkyl, halogenated C 1-6 Alkyl and halogenated C 1-6 Alkoxy.

[0143] In some embodiments, in the compound represented by Formula II, Formula III, Formula II-A, Formula III-A, Formula II-1, Formula II-2, Formula III-1, Formula III-2 or Formula III-3, R b Each occurrence is independently selected from H, F, Cl, Br, I, cyano, methyl, ethyl, propyl, butyl, -OCH3, -OCH2CH3, -S(O)2CH3, furyl, oxetanyl, -CH2CN, -CH2OCH3, -NH(CH3), -N(CH3)2, -CH2N(CH3)2, halo 1-6 Alkyl, halogenated C 1-6 Alkoxy, -O-(4-6 membered heterocycloalkyl) and -O-(C 3-6 (membered cycloalkyl).

[0144] In some embodiments, in the compound represented by Formula II, Formula III, Formula II-A, Formula III-A, Formula II-1, Formula II-2, Formula III-1, Formula III-2 or Formula III-3, R b Each occurrence is independently selected from H, F, Cl, Br, I, cyano, methyl, ethyl, propyl, butyl, -OCH3, -OCH2CH3, -S(O)2CH3, furanyl, oxetanyl, -CH2CN, -CH2OCH3, -NH(CH3), -CH2N(CH3)2, halo 1-6 Alkyl, halogenated C 1-6 Alkoxy.

[0145] In some embodiments, in the compound represented by Formula II, Formula III, Formula II-A, Formula III-A, Formula II-1, Formula II-2, Formula III-1, Formula III-2 or Formula III-3, R bEach occurrence is independently selected from H, F, Cl, Br, I, cyano, methyl, ethyl, propyl, butyl, -OCH3, -OCH2CH3, -S(O)2CH3, furanyl, oxetanyl, -CH2CN, -CH2OCH3, -NH(CH3), -CH2N(CH3)2, trifluoromethyl, trifluoromethoxy, -N(CH3)2, -OCHF2, -O-oxetanyl, -O-oxolanyl and -O-cyclopropyl.

[0146] In some embodiments, in the compound represented by Formula II, Formula III, Formula II-A, Formula III-A, Formula II-1, Formula II-2, Formula III-1, Formula III-2 or Formula III-3, R b Each occurrence is independently selected from H, F, Cl, Br, I, cyano, methyl, ethyl, propyl, butyl, -OCH3, -OCH2CH3, -S(O)2CH3, furanyl, oxetanyl, -CH2CN, -CH2OCH3, -NH(CH3), -CH2N(CH3)2, trifluoromethyl, trifluoromethoxy.

[0147] In some embodiments, in the compound represented by Formula II, Formula III, Formula II-A, Formula III-A, Formula II-1, Formula II-2, Formula III-1, Formula III-2 or Formula III-3, R b Each occurrence is independently selected from H, F, Cl, cyano, methyl, -OCH3, -OCH2CH3, -S(O)2CH3, furanyl, oxetanyl, -CH2CN, -CH2OCH3, -NH(CH3), -CH2N(CH3)2, trifluoromethyl, trifluoromethoxy, -N(CH3)2, -OCHF2, -O-oxetanyl, -O-oxolanyl and -O-cyclopropyl.

[0148] In some embodiments, the structural fragment Selected from Among them, the 1st position terminal is connected to L1.

[0149] In some embodiments, in the compound represented by Formula II, Formula III, Formula II-A, Formula III-A, Formula II-1, Formula II-2, Formula III-1, Formula III-2 or Formula III-3, R b Each occurrence is independently selected from H, F, Cl, Br, I, cyano, methyl, ethyl, propyl, butyl, halo 1-6 Alkyl, halogenated C 1-6 Alkoxy; preferably, R b Each occurrence is independently selected from H, F, Cl, cyano, trifluoromethyl, trifluoromethoxy.

[0150] In some embodiments, in the compounds of Formula I, Formula II, Formula III, Formula II-A, Formula III-A, Formula II-1, Formula II-2, Formula III-1, Formula III-2 or Formula III-3, R1 is hydrogen, alkoxyalkyl, C 1-6 Alkyl, hydroxy substituted C 1-6 Alkyl, -C 1-6 Alkyl-4-6 membered heterocycloalkyl; said heterocycloalkyl is optionally substituted by one or more C 1-6 Alkyl substituted;

[0151] In some embodiments, in the compounds of Formula I, Formula II, Formula III, Formula II-A, Formula III-A, Formula II-1, Formula II-2, Formula III-1, Formula III-2 or Formula III-3, R1 is hydrogen, alkoxyalkyl or C 1-6 alkyl.

[0152] In some embodiments, R1 is H, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, butyl, -CH2OCH3, -(CH2)2OCH3, -CH 2- C(CH3)2-OH, -C(CH3)2-OCH3, -CH2-C(CH3)2-OCH3, -C(CH3)2-OH,

[0153] In some embodiments, R1 is H, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, butyl, -CH2OCH3.

[0154] In some embodiments, in the compounds of Formula I, Formula II, Formula III, Formula II-A, Formula III-A, Formula II-1, Formula II-2, Formula III-1, Formula III-2 or Formula III-3, R1 is hydrogen or C 1-6 Alkyl; preferably, R1 is C 1-6 Alkyl; preferably, R1 is methyl, ethyl, propyl, butyl; more preferably, R1 is methyl or ethyl.

[0155] In some embodiments, R1 is selected from methyl, ethyl, hydrogen,

[0156] In some embodiments, in the compound represented by Formula I, Formula II, Formula III, Formula II-A, Formula III-A, Formula II-1, Formula II-2, Formula III-1, Formula III-2 or Formula III-3, R2 is selected from hydrogen, deuterium, amino, halogen, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 3-8 membered alicyclic group.

[0157] In some embodiments, in the compounds represented by formula I, formula II, formula III, formula II-A, formula III-A, formula II-1, formula II-2, formula III-1, formula III-2 or formula III-3, R2 is selected from hydrogen, deuterium and amino; preferably, R2 is selected from hydrogen and amino; more preferably, R2 is hydrogen.

[0158] In some embodiments, in the compound represented by Formula I, Formula II, Formula III, Formula II-A, Formula III-A, Formula II-1, Formula II-2, Formula III-1, Formula III-2 or Formula III-3, R3 is selected from hydrogen, halogen, cyano, hydroxyl, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 1-6 Alkoxy, alkoxyalkyl, halo C 1-6 Alkoxy and -N(C 1-6 Alkyl)2.

[0159] In some embodiments, in the compounds of Formula I, Formula II, Formula III, Formula II-A, Formula III-A, Formula II-1, Formula II-2, Formula III-1, Formula III-2 or Formula III-3, R3 is selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, alkoxyalkyl, halo C 1-6 Alkoxy and -N(C 1- 6 alkyl) 2, deuterated C 1-6 Alkoxy.

[0160] In some embodiments, in the compounds of Formula I, Formula II, Formula III, Formula II-A, Formula III-A, Formula II-1, Formula II-2, Formula III-1, Formula III-2 or Formula III-3, R3 is selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, alkoxyalkyl, halo C 1-6 Alkoxy and -N(C 1- 6 alkyl)2.

[0161] In some embodiments, in the compound represented by Formula I, Formula II, Formula III, Formula II-A, Formula III-A, Formula II-1, Formula II-2, Formula III-1, Formula III-2 or Formula III-3, R3 is selected from hydrogen, halogen, cyano, hydroxyl, C 1-6 Alkyl, C 3-8 Cycloalkyl and C 1-6 Alkoxy.

[0162] In some embodiments, in the compounds represented by formula I, formula II, formula III, formula II-A, formula III-A, formula II-1, formula II-2, formula III-1, formula III-2 or formula III-3, R3 is selected from hydrogen, F, Cl, Br, I, -CH3, -CH2CH3, -CH2-OCH3, -N(CH3)2, -O-CHF2, methoxy, ethoxy, propoxy and butoxy, -OCD3; preferably, R3 is selected from hydrogen, Cl, -CH3, -CH2CH3, -CH2-OCH3, -N(CH3)2, -O-CHF2, -O-CH3 and -OCD3.

[0163] In some embodiments, in the compounds represented by Formula I, Formula II, Formula III, Formula II-A, Formula III-A, Formula II-1, Formula II-2, Formula III-1, Formula III-2 or Formula III-3, R3 is selected from hydrogen, Cl, -CH3, -CH2CH3, -CH2-OCH3, -N(CH3)2, -O-CHF2 and -O-CH3.

[0164] In some embodiments, in the compounds represented by formula I, formula II, formula III, formula II-A, formula III-A, formula II-1, formula II-2, formula III-1, formula III-2 or formula III-3, R3 is selected from hydrogen, F, Cl, Br, I, methoxy, ethoxy, propoxy and butoxy; preferably, R3 is selected from hydrogen, Cl and methoxy.

[0165] In some embodiments, in the compound represented by Formula I, Formula II, Formula III, Formula II-A, Formula III-A, Formula II-1, Formula II-2, Formula III-1, Formula III-2 or Formula III-3, R4 is selected from hydrogen, halogen, cyano, C 1-4 Alkyl and C 1-4 Alkoxy.

[0166] In some embodiments, in the compound represented by Formula I, Formula II, Formula III, Formula II-A, Formula III-A, Formula II-1, Formula II-2, Formula III-1, Formula III-2 or Formula III-3, R4 is selected from hydrogen, C 1-4 Alkyl and halogen; preferably, R4 is selected from hydrogen, methyl, F, Cl, Br and I; more preferably, R4 is hydrogen and methyl.

[0167] In some embodiments, in the compounds represented by formula I, formula II, formula III, formula II-A, formula III-A, formula II-1, formula II-2, formula III-1, formula III-2 or formula III-3, R4 is selected from hydrogen and halogen; preferably, R4 is selected from hydrogen, F, Cl, Br and I; more preferably, R4 is hydrogen.

[0168] In some embodiments, in the compounds of Formula I, Formula II, Formula III, Formula II-A, Formula III-A, Formula II-1, Formula II-2, Formula III-1, Formula III-2 or Formula III-3, R7 is independently selected from hydrogen, C1-6 Alkyl, -C 1-6 Alkyl-OH, -C 1-6 Alkyl-CN, -CH2-OC 1-6 Preferably, R7 are each independently selected from hydrogen, C 1-6 Alkyl, -CH2-OH, -CH2-CN, -CH2-OC 1-6 Alkyl; preferably, R7 are each independently selected from hydrogen and C 1-6 Alkyl; preferably, R7 is each independently selected from hydrogen, methyl, ethyl, propyl, butyl; more preferably, R7 is each independently selected from hydrogen and methyl; more preferably, R7 is each independently hydrogen.

[0169] In some embodiments, in the compounds represented by Formula I, Formula II, Formula III, Formula II-A, Formula III-A, Formula II-1, Formula II-2, Formula III-1, Formula III-2 or Formula III-3, n1 and n2 are each independently selected from 0, 1, 2 and 3; preferably, n1 and n2 are each independently selected from 0, 1 and 2.

[0170] In some embodiments, in the compounds represented by Formula II, Formula III, Formula II-A, Formula III-A, Formula II-1, Formula II-2, Formula III-1, Formula III-2 or Formula III-3, n4 is selected from 0, 1, 2 and 3; preferably, n4 is selected from 0, 1 and 2.

[0171] In some embodiments, L1 and L2 are not both single bonds.

[0172] In some embodiments, when A is When A2 Connected to the carbonyl group, the A1 end Connected to W.

[0173] In some embodiments, when L2 and A are linked to form a chiral carbon atom, the chirality of the chiral carbon atom is preferably in the R configuration.

[0174] In some embodiments, the halogen is independently selected from fluorine, chlorine, bromine, or iodine.

[0175] In some embodiments, the C1-C6 alkyl group is independently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl or sec-butyl, such as methyl or ethyl.

[0176] In some embodiments, the C1-C6 alkoxy group is independently selected from methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, isobutoxy, or sec-butoxy, such as methoxy or ethoxy.

[0177] In some embodiments, the C3-C8 cycloalkyl group is independently selected from cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0178] In some embodiments, the heteroatom species of the 3-8 membered aliphatic heterocyclic group are independently selected from one or two of N, O and S, and the number of heteroatoms is independently 1, 2 or 3.

[0179] In some embodiments, the 3-8 membered alicyclic heterocyclic group is independently a 3-8 membered heterocycloalkyl group or a 3-8 membered heterocycloalkenyl group, preferably a 4-6 membered heterocycloalkyl group, such as oxetane, tetrahydropyrrole or tetrahydrofuranyl.

[0180] In some embodiments, the C 6-10 Aryl groups are independently selected from phenyl or naphthyl.

[0181] In some embodiments, the heteroatom species of the 5-10 membered heteroaryl group is independently selected from one or two of N, O and S, and the number of heteroatoms is independently 1, 2 or 3; preferably, the heteroatom species is N, and the number of heteroatoms is independently 1 or 2.

[0182] In some embodiments, the 5-10 membered heteroaryl group may independently be a monocyclic or bicyclic ring, and the bicyclic ring is a fused ring; preferably, the 5-10 membered heteroaryl group is independently selected from a 5-6 membered monocyclic heteroaryl group or a 9-10 membered bicyclic heteroaryl group; the 5-10 membered heteroaryl group is, for example, pyridyl, thienyl or furyl.

[0183] In some embodiments, the C1-C6 alkylene group is independently selected from methylene, ethylene, isopropylene or n-isopropylene, such as methylene or ethylene.

[0184] In some embodiments, the heteroatom species of the 4- to 10-membered heterocycloalkyl group is independently selected from one or two of N, O, and S, and the number of heteroatoms is independently 1, 2, or 3; preferably, the heteroatom species is N, and the number of heteroatoms is independently 1 or 2.

[0185] In some embodiments, the 4- to 10-membered heterocycloalkyl group may independently be a monocyclic or polycyclic ring, the polycyclic ring may be a bridged ring, a cyclic ring or a spirocyclic ring, and the polycyclic ring may also be a bicyclic or tricyclic ring; preferably, the 4- to 10-membered heterocycloalkyl group may independently be a 4- to 7-membered monocyclic heterocycloalkyl group or an 8- to 10-membered bicyclic heterocycloalkyl group;

[0186] The 4-7 membered monocyclic heterocycloalkyl group is for example

[0187] The 8-10 membered bicyclic heterocycloalkyl group is for example

[0188] In some embodiments, the heteroatom species of the 4- to 10-membered heterocycloalkenyl group is independently selected from one or two of N, O, and S, and the number of heteroatoms is independently 1, 2, or 3; preferably, the heteroatom species is N, and the number of heteroatoms is independently 1 or 2.

[0189] In some embodiments, the 4- to 10-membered heterocycloalkenyl group may independently be a monocyclic or polycyclic ring, the polycyclic ring may be a bridged ring, a parallel ring or a spiro ring, and the polycyclic ring may also be a bicyclic or tricyclic ring; preferably, the 4- to 10-membered heterocycloalkenyl group may independently be a 4-7-membered monocyclic heteroalkene group or an 8-10-membered bicyclic heterocycloalkenyl group.

[0190] In some embodiments, the 4-10 membered heterocycloalkenyl group independently contains 1 or 2 sp 2 Double bond.

[0191] In some embodiments, the heteroatom species of the 5-7 membered heteroaryl group is independently selected from one or two of N, O and S, and the number of heteroatoms is independently 1, 2 or 3; preferably, the heteroatom species is N, and the number of heteroatoms is independently 1 or 2.

[0192] In some embodiments, the 5-7 membered heteroaryl group is, for example, pyridinyl.

[0193] In some embodiments, the halogenated C 1-6 The alkyl group is selected from -CF3, -C2F5, -CHF2, -CH2F, -CH2CF3, -CH2Cl or -CH2CH2CF3.

[0194] In some embodiments, the alkoxyalkyl group is -C 1-6 Alkyl-C 1-6 Alkoxy, such as -CH2OCH3, -CH2OCH2CH3, Or -CH2OtBu.

[0195] In some embodiments, the deuterated C 1-6 Alkoxy group, for example -OCD3.

[0196] In some embodiments, the halogenated C 1-6 The alkoxy group is selected from -OCF3, -OC2F5, -OCHF2, -OCH2F, -OCH2CF3, -OCH2Cl or -OCH2CH2CF3.

[0197] In some embodiments, the C 1-6 Alkyl-substituted amino groups are selected from -NH(C 1-6 alkyl) or -N(C 1-6 Alkyl)2.

[0198] In some embodiments, the structural fragment Selected from

[0199] In some embodiments, the structural fragment for In some embodiments, the structural fragment for

[0200] In some embodiments, the structural fragment Selected from

[0201] In some embodiments, the structural fragment Selected from

[0202] In some embodiments, the structural fragment Selected from

[0203] In some embodiments, the present invention provides a compound of formula IA, or a tautomer, stereoisomer, solvate, metabolite, isotope-labeled substance, pharmaceutically acceptable salt, or cocrystal thereof.

[0204] in,

[0205] W is Among them, the a-terminal is connected to the pyridyl group;

[0206] X1 is N or CR8;

[0207] R8 is selected from hydrogen, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, -NH(C 1-6 alkyl) or -N(C 1-6 alkyl) 2; the alkyl group is optionally substituted by one or more selected from -CN, -N(C 1-6 alkyl)2 is substituted with a substituent;

[0208] L1 is selected from a single bond, -O- or -N(Ra)-;

[0209] L2 is selected from a single bond or C 1-6 Alkylene, the alkylene is optionally substituted by one or more selected from C 1-6 is substituted by an alkyl substituent; L1 and L2 are not single bonds at the same time;

[0210] R a Selected from hydrogen and C 1-6 alkyl;

[0211] A is in, Each is independently selected from a 4- to 10-membered heterocycloalkyl group, wherein the heterocycloalkyl group is a monocyclic, fused, spirocyclic or bridged ring;

[0212] The condition is that when A is When L2 is connected to any ring atom on the ring; when A is When L2 is connected to A2, or L2 is connected to any ring atom on the ring;

[0213] A1 and A2 are each independently selected from CR7 and N;

[0214] R7 are each independently selected from hydrogen or C 1-6 alkyl;

[0215] Ring B is selected from 5-7 membered heteroaryl and phenyl, wherein the 5-7 membered heteroaryl or phenyl is optionally substituted with one or more R6;

[0216] R6 are each independently selected from H, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy or -NH-C 1-6 alkyl;

[0217] R1 is selected from hydrogen, C 1-6 Alkyl, -C 1-6 Alkyl-C 1-6 Alkoxy, -(C 1-6 Alkyl)-OH or -(C 1-6 alkyl)-(3-8 membered alicyclic group), wherein the 3-8 membered alicyclic group is optionally substituted by one or more C 1-6 Alkyl substitution;

[0218] R2 is selected from hydrogen, deuterium or amino;

[0219] R3 is selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, -C 1-6 Alkyl-C 1-6 Alkoxy, deuterated C 1-6 Alkoxy, halogenated C 1-6 Alkoxy or -N(C 1-6 Alkyl)2;

[0220] R4 is selected from hydrogen, halogen or C 1-6 alkyl;

[0221] R5 is selected from C6-10 Aryl and 5-10 membered heteroaryl, wherein the aryl or heteroaryl is optionally substituted by one or more R b replace;

[0222] R b Each occurrence is independently selected from hydrogen, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, -C 1-6 Alkyl-C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, -S(O)2(C 1-6 Alkyl), -(C 1-6 Alkyl)-CN, -O-(3-8 membered alicyclic), -O-(C 3-8 cycloalkyl), 3-8 membered alicyclic group, 5-10 membered heteroaryl or C 1-6 an alkyl-substituted amino group;

[0223] Or, two adjacent R b Together with the ring atoms to which it is connected, it forms a 3-6 membered cycloalkyl group;

[0224] n1 and n2 are each independently selected from 0, 1, 2 and 3; n3 is selected from 0, 1 and 2.

[0225] In some embodiments, the compound provided by the present invention has the structure shown in Formula IV,

[0226] in,

[0227] X1 is N or CR8

[0228] X2 is N or CR6;

[0229] X3 for N and CR b ;

[0230] R1 is selected from C 1-6 Alkyl, -C 1-6 Alkyl-C 1-6 Alkoxy, -(C 1-6 Alkyl)-OH or -(C 1-6 alkyl)-(3-8 membered alicyclic group), wherein the 3-8 membered alicyclic group is optionally substituted by one or more C 1-6 Alkyl substitution;

[0231] R2 is selected from hydrogen, deuterium or amino;

[0232] R3 is selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, -C 1-6 Alkyl-C1-6 Alkoxy, deuterated C 1-6 Alkoxy, halogenated C 1-6 Alkoxy or -N(C 1-6 Alkyl)2;

[0233] R4 is selected from hydrogen, halogen or C 1-6 alkyl;

[0234] R6 are each independently selected from H, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy or -NH-C 1-6 alkyl;

[0235] R7 are each independently selected from hydrogen or C 1-6 alkyl;

[0236] R8 is selected from hydrogen, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, -NH(C 1-6 alkyl) or -N(C 1-6 alkyl) 2; the alkyl group is optionally substituted by one or more selected from -CN, -N(C 1-6 alkyl)2 is substituted with a substituent;

[0237] R b independently selected from hydrogen, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, -C 1-6 Alkyl-C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, -S(O)2(C 1-6 Alkyl), -(C 1-6 Alkyl)-CN, -O-(3-8 membered alicyclic), -O-(C 3-8 cycloalkyl), 3-8 membered alicyclic group, 5-10 membered heteroaryl or C 1-6 an alkyl-substituted amino group;

[0238] Or, two adjacent R b Together with the ring atoms to which it is connected, it forms a 3-6 membered cycloalkyl group;

[0239] n1, n2 and n4 are each independently selected from 0, 1 and 2.

[0240] In some embodiments, the compound provided by the present invention has the structure shown in Formula V,

[0241] in,

[0242] X1 is N or CR8

[0243] X2 is N or CR6;

[0244] X3 for N and CR b ;

[0245] R1 is selected from C 1-6 alkyl;

[0246] R3 is selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy or -C 1-6 Alkyl-C 1-6 alkoxy;

[0247] R6 are each independently selected from H, halogen or C 1-6 alkyl;

[0248] R8 is selected from hydrogen, halogen, C 1-6 Alkyl or C 1-6 alkoxy;

[0249] R b independently selected from hydrogen, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, -C 1-6 Alkyl-C 1-6 Alkoxy or halogenated C 1-6 alkyl;

[0250] n4 is 0, 1 or 2.

[0251] In some embodiments, the compound of the present invention is selected from:

[0252] In some embodiments, the compound of the present invention is selected from any of the following compounds:

[0253] (1) The compound that elutes first under the following HPLC conditions: HPLC column: Waters Xbridge C18 150 mm*4.6 mm 3.5 μm, mobile phase A: 10 mM NH4HCO3 aqueous solution, mobile phase B: ACN, gradient elution: mobile phase B from 5% to 95% over 15.0 minutes and maintained at 95% for 10 minutes; flow rate: 1.0 mL / min; column temperature: 40°C; preferably, under these conditions, the retention time of the compound that elutes first is 9.36 minutes;

[0254] (2) The compound eluting later under the following conditions: HPLC column: Waters Xbridge C18 150mm*4.6mm 3.5um, mobile phase A: 10mM NH4HCO3 aqueous solution, mobile phase B: ACN, gradient elution: mobile phase B from 5% to 95% over 15.0 minutes and maintained at 95% for 10 minutes; flow rate: 1.0mL / min; column temperature: 40°C; preferably, under the above conditions, the retention time of the compound eluting later is 9.74 minutes;

[0255] (3) The compound that elutes first under the following HPLC conditions: HPLC column: Waters Xbridge C18 150 mm*4.6 mm 3.5 μm, mobile phase A: 10 mM NH4HCO3 aqueous solution, mobile phase B: ACN, gradient elution: mobile phase B from 5% to 95% over 15.0 minutes and maintained at 95% for 10 minutes; flow rate: 1.0 mL / min; column temperature: 40°C; preferably, under these conditions, the retention time of the compound that elutes first is 8.54 minutes;

[0256] (4) The compound eluting later under the following conditions: HPLC column: Waters Xbridge C18 150mm*4.6mm 3.5um, mobile phase A: 10mM NH4HCO3 aqueous solution, mobile phase B: ACN, gradient elution: mobile phase B from 5% to 95% over 15.0 minutes and maintained at 95% for 10 minutes; flow rate: 1.0mL / min; column temperature: 40°C; preferably, under these conditions, the retention time of the compound eluting later is 9.13 minutes;

[0257] (5) The compound that elutes first under the following conditions: HPLC column: Waters ACQUITY UPLC BEH C18 100 mm*3 mm 1.7 μm, mobile phase A: 0.01% TFA in water, mobile phase B: 0.01% TFA in ACN, gradient elution: mobile phase B at 5% for 5 minutes, then from 5% to 95% over 15.0 minutes, and held at 95% for 10 minutes; flow rate: 0.6 mL / min; column temperature: 40°C; preferably, under these conditions, the retention time of the compound that elutes first is 12.28 minutes.

[0258] (6) The compound eluting later under the following conditions: HPLC column: Waters ACQUITY UPLC BEH C18 100 mm*3 mm 1.7 μm, mobile phase A: 0.01% TFA in water, mobile phase B: 0.01% TFA in ACN, gradient elution: mobile phase B at 5% for 5 minutes, 5% to 95% over 15.0 minutes, and hold at 95% for 10 minutes; flow rate: 0.6 mL / min; column temperature: 40°C; preferably, under these conditions, the retention time of the compound eluting later is 13.24 minutes;

[0259] (7) The H NMR spectra of the following compounds are: 1 H NMR(400MHz,DMSO-d6)δppm 10.05(s,1H),8.66(d,J=10.0Hz,1H),8.48(d,J=2.0Hz,0.5H),8.35-8.22(m,3H),8.12-8.06(m,1.5H),7.89(dd,J=8.8Hz,3.2H z,1H),7.58(d,J=11.2Hz,0.5H),7.44(d,J=16.0Hz,0.5H),7.33(dd,J=2.8Hz,10.8Hz,0.5H),7.28-7.15(m,1.5H),6.84(d,J=1 5.6Hz,0.5H),6.67(d,J=15.6Hz,0.5H),5.44(d,J=16.0Hz,1H),5.26-5.20(m,1H),4.92-4.87(m,1H),4.35-4.12(m,3H),3.91( s,1.5H),3.86(s,1.5H),3.63-3.52(m,1H),2.43(s,2H),2.40-2.36(m,2H),2.11(d,J=10.4Hz,0.5H),2.03(d,J=10.4Hz,0.5H);

[0260] (8) The H NMR spectra of the following compounds are: 1 H NMR(400MHz,DMSO-d6)δppm 10.20(s,1H),8.58(s,1H),8.37-8.27(m,4H),8.03-7.99(m,1H),7.84(d,J=8.8Hz,1H),7.39(d,J= 15.6Hz,1H),7.20(d,J=11.2Hz,1H),7.06-7.01(m,1H),6.73(d,J=15.6Hz,1H),5.67(s,1H),5.07( s,1H),4.72(t,J=9.2Hz,1H),4.57(d,J=8.8Hz,1H),4.50(d,J=10.0Hz,1H),4.34(d,J=12.0Hz,1H) ,3.92(s,3H),3.48(d,J=12.0Hz,1H),2.40(s,3H),2.06(d,J=10.4Hz,1H),1.94(d,J=10.0Hz,1H);

[0261] (9) The H NMR spectra of the following compounds are: 1 H NMR(400MHz,DMSO-d6)δppm 10.20(s,1H),8.71(s,1H),8.42-8.19(m,4H),8.05-7.86(m,2H),7.39(d,J=15.6Hz,1H),7.25-7. 09(m,1H),7.07-6.96(m,1H),6.76-6.58(m,1H),5.54(s,1H),5.44-5.24(m,1H),5.18(t,J=10.4H z,1H),4.84(d,J=10.0Hz,1H),4.46-4.33(m,0.21H),4.21-4.08(m,0.79H),3.99-373(m,4H),3.5 9(d,J=12.8Hz,0.81H),3.23-3.15(m,0.19H),2.36(s,2.50H),2.21(s,0.50H),1.97-1.71(m,4H);

[0262] (10) The H NMR spectra of the following compounds are: 1 H NMR (400 MHz, DMSO-d 6)δppm 10.15(s,1H),8.67(s,1H),8.42-8.19(m,4H),8.15-8.03(m,1H),7.88(d,J=8.8Hz,1H), 7.41(d,J=15.6Hz,1H),7.34(d,J=10.0Hz,1H),7.24(t,J=8.8Hz,1H),6.62(d,J=15.6Hz, 1H),5.18-4.89(m,3H),4.60(t,J=9.6Hz,1H),4.53-4.44(m,1H),4.04(d,J=11.2Hz,1H) ,3.94(s,3H),3.60(d,J=12.4Hz,1H),2.36(s,3H),2.18-2.03(m,2H),1.78-1.65(m,2H);

[0263] (11) The H NMR spectra of the following compounds are: 1 H NMR(400MHz,DMSO-d6)δppm 10.04(s,1H),8.63(d,J=9.2Hz,1H),8.49(d,J=2.4Hz,0.5H),8.35-8.22(m,3H),8.14-8.06(m,1.5H),7.88(d,J=6.0Hz,1H),7 .58(d,J=10.8Hz,0.5H),7.44(d,J=16.0Hz,0.5H),7.33(dd,J=2.4Hz,10.8Hz,0.5H),7.28-7.15(m,1.5H),6.84(d,J=15.6Hz, 0.5H),6.67(d,J=15.6Hz,0.5H),5.45-5.41(m,1H),5.26-5.18(m,1H),4.92-4.86(m,1H),4.35-4.12(m,3H),3.92(s,1.5H),3 .87(s,1.5H),3.57(d,J=10.4Hz,1H),2.43(s,2H),2.39-2.33(m,2H),2.10(d,J=10.0Hz,0.5H),2.01(d,J=10.8Hz,0.5H); (12) The H NMR spectra of the following compounds are: 1H NMR(400MHz,DMSO-d6)δppm 10.22(s,1H),8.51(s,1H),8.34-8.28(m,4H),8.02-7.98(m,1H),7.83(d,J=8.8Hz,1H),7.37(d,J =16.0Hz,1H),7.18(d,J=10.8Hz,1H),7.05-7.00(m,1H),6.73(d,J=15.6Hz,1H),5.62(s,1H),5.0 5(s,1H),4.73-4.70(m,1H),4.56(d,J=8.8Hz,1H),4.49(d,J=9.2Hz,1H),4.34(d,J=12.0Hz,1H), 3.91 (s, 3H), 3.43 (d, J = 12.0Hz, 1H), 2.39 (s, 3H), 2.02 (d, J = 10.0Hz, 1H), 2.01 (d, J = 10.4Hz, 1H).

[0264] Preparation method

[0265] The present invention also provides a method for preparing the above compound, comprising the following steps:

[0266] Wherein, L1 is an oxygen atom; R1, R2, R3, R4, R6, R7, R a 、R b , X1, X2, X3, X4, X5, X6, L2, n1, n2, n3, n4 are as defined above.

[0267] Step 1: A-1 and A-2 undergo nucleophilic substitution or Buchwald reaction to obtain compound A-3;

[0268] The reaction is carried out in a suitable solvent. The solvent can be selected from DMF, N,N-dimethylacetamide, N-methylpyrrolidone, 1,4-dioxane, THF, DCM, acetonitrile, EA, toluene, diethyl ether, chloroform, ethylene glycol dimethyl ether, methanol, ethanol, isopropanol, n-butanol, and the like, and any combination thereof. The reaction is carried out at a suitable temperature of -78-160°C. The reaction is carried out for a suitable time, for example, 0.5-120 hours.

[0269] Step 2, compound A-3 and compound A-4 are reacted by Suzuki reaction to obtain compound A-5;

[0270] The reaction is carried out in a suitable solvent. The solvent can be selected from water, DMF, N,N-dimethylacetamide, N-methylpyrrolidone, 1,4-dioxane, THF, acetonitrile, EA, toluene, ethylene glycol dimethyl ether, methanol, ethanol, isopropanol, n-butanol, and any combination thereof. The reaction is carried out at a suitable temperature of 40-140° C. The reaction is carried out for a suitable time, for example, 0.5-120 h.

[0271] Step 3, compound A-5 undergoes Boc removal reaction to obtain compound A-6;

[0272] The reaction is carried out in a suitable solvent. The solvent can be selected from water, chloroform, 1,4-dioxane, THF, DCM, acetonitrile, EA, toluene, diethyl ether, chloroform, ethylene glycol dimethyl ether, methanol, ethanol, isopropanol, n-butanol, TFA, and the like, and any combination thereof. The reaction is carried out at a suitable temperature of -78-120°C. The reaction is carried out for a suitable time, for example, 0.5-120 hours.

[0273] Step 4, compound A-6 undergoes intramolecular ring closure to obtain compound A-7;

[0274] The reaction is carried out in a suitable solvent. The solvent can be selected from DMF, N,N-dimethylacetamide, N-methylpyrrolidone, 1,4-dioxane, THF, toluene, diethyl ether, ethylene glycol dimethyl ether, and any combination thereof. The reaction is carried out at a suitable temperature of -78-160°C. The reaction is carried out for a suitable time, for example, 0.5-120 hours.

[0275] Step 5: Compound A-7 is subjected to condensation reaction with acid A-8 to obtain compound A-9.

[0276] The reaction is carried out in a suitable solvent. The solvent can be selected from DMF, N,N-dimethylacetamide, N-methylpyrrolidone, 1,4-dioxane, THF, DCM, acetonitrile, EA, toluene, diethyl ether, chloroform, ethylene glycol dimethyl ether, methanol, ethanol, isopropanol, n-butanol, and the like, and any combination thereof. The reaction is carried out at a suitable temperature of -78-120°C. The reaction is carried out for a suitable time, for example, 0.5-120 hours.

[0277] The compounds listed in the present invention can be synthesized by multi-step reactions using methods well known in the field of organic chemistry, including but not limited to the synthesis methods listed in the specific embodiments, the embodiments formed by combining them with other chemical synthesis methods, and equivalent substitution methods well known to those skilled in the art.

[0278] Pharmaceutical compositions or preparations

[0279] The present invention also provides a pharmaceutical composition comprising the above compound, or its tautomers, stereoisomers, solvates, metabolites, isotope-labeled substances, pharmaceutically acceptable salts, cocrystals, and pharmaceutically acceptable excipients.

[0280] The term "pharmaceutically acceptable" as used herein includes any substance that does not interfere with the effectiveness of the biological activity of the active ingredient and is non-toxic to the host to which it is administered.

[0281] The pharmaceutically acceptable excipients described in the present invention are a general term for all additional materials in a drug other than the main drug. Excipients should have the following properties: (1) be non-toxic to the human body and have almost no side effects; (2) be chemically stable and not easily affected by temperature, pH, storage time, etc.; (3) have no incompatibility with the main drug and do not affect the efficacy and quality inspection of the main drug; (4) do not interact with the packaging material. Excipients in the pharmaceutical composition of the present invention include, but are not limited to, fillers (diluents), lubricants, dispersants, wetting agents, adhesives, regulators, solubilizers, antioxidants, antibacterial agents, emulsifiers, disintegrants, etc.

[0282] The mode of administration of the compound of the present invention or pharmaceutical composition is not particularly limited, and representative modes of administration include (but are not limited to): oral, parenteral (intravenous, intramuscular or subcutaneous), and topical administration. Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. Compositions for parenteral injection may include physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for redissolving into sterile injectable solutions or dispersions. The dosage forms of the compound of the present invention for topical administration include ointments, powders, patches, sprays and inhalants.

[0283] Treatment methods and uses

[0284] The present invention also provides the use of the above-mentioned compound or its tautomers, stereoisomers, solvates, metabolites, isotope-labeled substances, pharmaceutically acceptable salts, cocrystals, or the above-mentioned pharmaceutical compositions in the preparation of KRAS inhibitors and / or PI3K inhibitors.

[0285] Furthermore, the above-mentioned KRAS inhibitor is selected from KRAS G12C inhibitor, KRAS G12V inhibitor, KRAS G12D inhibitor, KRAS G12S inhibitor; preferably KRAS G12D inhibitor; the PI3K inhibitor is PI3Kα inhibitor and / or PI3Kδ inhibitor.

[0286] The present invention also provides the use of the above-mentioned compound or its tautomers, stereoisomers, solvates, metabolites, isotope-labeled substances, pharmaceutically acceptable salts, cocrystals, or the above-mentioned pharmaceutical compositions in the preparation of drugs for treating diseases mediated by KRAS and / or PI3K.

[0287] The present invention provides use of the above-mentioned compound or its tautomers, stereoisomers, solvates, metabolites, isotope-labeled products, pharmaceutically acceptable salts, cocrystals, or pharmaceutical compositions in the preparation of drugs for treating diseases mediated by one or more of KRAS G12D, PI3Kα, and PI3Kδ.

[0288] The present invention also provides the use of the above-mentioned compound or its tautomers, stereoisomers, solvates, metabolites, isotope-labeled substances, pharmaceutically acceptable salts, cocrystals, or the above-mentioned pharmaceutical compositions in the preparation of drugs for treating diseases associated with KRAS resistance, preferably associated with KRAS G12D resistance.

[0289] In a certain embodiment, the KRAS resistance-related disease is an MRTX1133 resistance-related disease, preferably an MRTX1133 resistance-related cancer.

[0290] The present invention also provides the use of the above-mentioned compound or its tautomers, stereoisomers, solvates, metabolites, isotope-labeled products, pharmaceutically acceptable salts, cocrystals, or the above-mentioned pharmaceutical compositions in the preparation of drugs for treating diseases that cause overexpression of PI3K protein and / or KRAS G12D protein.

[0291] In some embodiments, the disease is cancer or an autoimmune disease.

[0292] In some embodiments, the disease is cancer, and the cancer is selected from lung cancer (e.g., non-small cell lung cancer), pancreatic cancer, ovarian cancer, bladder cancer, prostate cancer, chronic myeloid leukemia, intestinal cancer, brain cancer, liver cancer, kidney cancer, stomach cancer, breast cancer (e.g., triple-negative breast cancer), skin cancer, melanoma, head and neck cancer, bone cancer, cervical cancer, pelvic cancer, vaginal cancer, oral cancer, lymphoma, blood cancer, esophageal cancer, urethra cancer, and nasal cancer;

[0293] Preferably, the cancer is selected from colorectal cancer, pancreatic cancer, gastric cancer, lung cancer (e.g., non-small cell lung cancer) and breast cancer (e.g., triple-negative breast cancer);

[0294] More preferably, the cancer is selected from colorectal cancer, pancreatic cancer, gastric cancer, non-small cell lung cancer and triple-negative breast cancer.

[0295] The present invention also provides the use of the above-mentioned compound or its tautomers, stereoisomers, solvates, metabolites, isotope-labeled substances, pharmaceutically acceptable salts, cocrystals, or the above-mentioned pharmaceutical compositions in the preparation of a medicament for treating a disease resistant to an anticancer agent;

[0296] Preferably, the anticancer agent is MRTX1133.

[0297] The present invention also provides a method for treating diseases mediated by KRAS and / or PI3K, and a method for treating diseases resulting in overexpression of PI3K protein and / or KRAS G12D protein, comprising administering to a subject an effective amount of the above-mentioned compound or its tautomer, stereoisomer, solvate, metabolite, isotope-labeled substance, pharmaceutically acceptable salt, cocrystal, or pharmaceutical composition.

[0298] The present invention also provides a method for treating a disease resistant to KRAS inhibitors, comprising administering to a subject an effective amount of the above-mentioned compound or its tautomer, stereoisomer, solvate, metabolite, isotope-labeled substance, pharmaceutically acceptable salt, cocrystal, or pharmaceutical composition.

[0299] In some embodiments, the KRAS inhibitor is selected from KRAS G12D mutation inhibitors.

[0300] In some embodiments, the KRAS inhibitor is MRTX1133.

[0301] Definitions and terms

[0302] The term "alkyl" refers to a straight or branched saturated aliphatic hydrocarbon group. Typical alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, etc., preferably C 1-6 Alkyl, more preferably C 1-4 Alkyl groups, such as methyl or ethyl.

[0303] As used herein, C 1-n Including C 1-2 、C 1-3 ...C 1-n , n is an integer greater than one; as a prefix of a substituent, it indicates the minimum and maximum number of carbon atoms in the substituent, for example, "C 1-6 "Alkyl" refers to a straight or branched chain alkyl group containing 1 to 6 carbon atoms.

[0304] The term "alkylene" refers to a saturated divalent hydrocarbon group obtained by removing two hydrogen atoms from a straight or branched saturated hydrocarbon group, containing a specified number of carbon atoms. Examples include alkylene groups having 1 to 6 carbon atoms, such as methylene (-CH2-), ethylene (-CH2CH2-), isopropylene (-CH2-CH2-CH2- or -CH(CH3)CH2-), and methylene or ethylene.

[0305] The term "haloalkyl" refers to an alkyl group substituted by one or more (such as 1 to 3) the same or different halogen atoms. 1-6 Alkyl", "halogenated C 1-4 "Alkyl" refers to a halogenated alkyl group having 1 to 6 carbon atoms, 1 to 4 carbon atoms, for example, -CF3, -C2F5, -CHF2, -CH2F, -CH2CF3, -CH2Cl or -CH2CH2CF3, etc.

[0306] The terms "comprises," "comprising," "having," "containing," or "involving," and other variations thereof herein, are inclusive or open-ended and do not exclude additional unrecited elements or method steps.

[0307] "Ring" refers to any covalently closed structure, including, for example, a carbocyclic ring (e.g., an aryl or cycloalkyl group), a heterocyclic ring (e.g., a heteroaryl or heterocycloalkyl group), an aromatic group (e.g., an aryl or heteroaryl group), or a non-aromatic group (e.g., a cycloalkyl or heterocycloalkyl group). The "ring" herein may be a monocyclic ring or a polycyclic ring, and may be a fused ring, a spirocyclic ring, or a bridged ring.

[0308] "Cycloalkyl" refers to a saturated cyclic hydrocarbon group. As used herein, "C 3-8 "Cycloalkyl" refers to a saturated cyclic hydrocarbon group containing 3 to 8 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[0309] "Cycloalkenyl" refers to a cyclic substituent having at least one carbon-carbon double bond in the ring backbone.

[0310] "Heteroatom" refers to a nitrogen (N), oxygen (O) or sulfur (S) atom.

[0311] "Aliphatic heterocyclic group" refers to a saturated or partially unsaturated cyclic substituent group containing 1, 2, 3 or 4 heteroatoms selected from N, O and S in the ring skeleton, and is not aromatic. "Aliphatic heterocyclic group" includes "heterocycloalkyl" and "heterocycloalkenyl". Alternatively, the "aliphatic heterocyclic group" also includes monocyclic, fused or bridged rings. Examples of aliphatic heterocyclic groups include but are not limited to:

[0312] In a preferred embodiment, the heteroatom species of the "3-8 membered alicyclic group" as described herein are independently selected from one or two of N, O and S, and the number of heteroatoms is independently 1, 2 or 3. In a preferred embodiment, the 3-8 membered alicyclic group as described herein is independently a 3-8 membered heterocycloalkyl or a 3-8 membered heterocycloalkenyl, preferably a 4-6 membered heterocycloalkyl, such as oxetane, tetrahydropyrrole or tetrahydrofuranyl.

[0313] "Heterocycloalkyl" refers to a saturated cyclic group containing heteroatoms in the ring backbone. As described herein, a "4-10 membered heterocycloalkyl" refers to a saturated cyclic group containing 4-10 ring atoms, and a "5-10 membered heterocycloalkyl" refers to a saturated cyclic group containing 5-10 ring atoms. The "4-10 membered heterocycloalkyl" or "5-10 membered heterocycloalkyl" group contains 1, 2, 3, or 4 heteroatoms selected from N, O, and S. In a preferred embodiment, the heteroatom species of the 4-10 membered heterocycloalkyl group described herein are each independently selected from one or two of N, O, and S, and the number of heteroatoms is each independently 1, 2, or 3; preferably, the heteroatom species is N, and the number of heteroatoms is each independently 1 or 2. In a preferred embodiment, as described herein, the 4- to 10-membered heterocycloalkyl group may independently be a monocyclic or polycyclic ring, the polycyclic ring may be a bridged ring, a fused ring or a spiro ring, and the polycyclic ring may also be a bicyclic or tricyclic ring; preferably, the 4- to 10-membered heterocycloalkyl group may independently be a 4- to 7-membered monocyclic heterocycloalkyl group or an 8- to 10-membered bicyclic heterocycloalkyl group;

[0314] The 4-7 membered monocyclic heterocycloalkyl group is for example

[0315] The 8-10 membered bicyclic heterocycloalkyl group is for example "Heterocycloalkenyl" refers to a monocyclic or bicyclic ring system of a partially unsaturated alkenyl group containing a heteroatom in the ring skeleton, which has 1, 2, 3 or 4 heteroatoms selected from N, O and S. In a preferred embodiment, the heteroatom species of the 4-10 membered heterocycloalkenyl group as described herein are independently selected from one or two of N, O and S, and the number of heteroatoms is independently 1, 2 or 3; preferably, the heteroatom species is N, and the number of heteroatoms is independently 1 or 2. In a preferred embodiment, the 4-10 membered heterocycloalkenyl group as described herein can independently be monocyclic or polycyclic, and the polycyclic ring can be a bridged ring, a cyclic ring or a spiro ring, and the polycyclic ring can also be bicyclic or tricyclic; preferably, the 4-10 membered heterocycloalkenyl group can independently be a 4-7 membered monocyclic heteroalkene group or an 8-10 membered bicyclic heterocycloalkenyl group. In a preferred embodiment, the 4-10 membered heterocycloalkenyl group as described herein independently contains 1 or 2 sp 2 Double bond.

[0316] "Aryl" refers to a monocyclic or polycyclic group with aromatic properties, whose planar ring has a delocalized π electron system and contains 4n+2 π electrons, where n is an integer; typical aryl groups include but are not limited to phenyl, naphthyl, phenanthrenyl, anthracenyl, fluorenyl and indenyl. In a preferred embodiment, as described herein, C 6-10 Aryl groups are exemplified by phenyl or naphthyl.

[0317] "Heteroaryl" refers to a monocyclic or polycyclic group containing heteroatoms and having aromatic properties, preferably a 5- to 7-membered heteroaryl group having 5, 6 or 7 ring atoms, of which 1, 2 or 3 ring atoms are heteroatoms selected from nitrogen, oxygen or S.

[0318] Typical heteroaryl groups include, but are not limited to:

[0319] In a preferred embodiment, the heteroatom species of the 5-10 membered heteroaryl group described herein are each independently selected from one or two of N, O, and S, and the number of heteroatoms is each independently 1, 2, or 3; preferably, the heteroatom species is N, and the number of heteroatoms is each independently 1 or 2. In a preferred embodiment, the 5-10 membered heteroaryl group described herein may be independently monocyclic or bicyclic, and the bicyclic rings may be fused; preferably, the 5-10 membered heteroaryl group is independently selected from a 5-6 membered monocyclic heteroaryl group or a 9-10 membered bicyclic heteroaryl group; examples of the 5-10 membered heteroaryl group include pyridylthienyl and furyl.

[0320] In a preferred embodiment, the heteroatom species of the 5-7 membered heteroaryl group as described herein is N, and the number of heteroatoms is independently 1 or 2. In a preferred embodiment, the 5-7 membered heteroaryl group as described herein is, for example, pyridyl. The term "alkoxy" refers to -O-(alkyl), wherein alkyl is as defined above, for example, C 1-6 Alkoxy, C 1-4 Alkoxy or C 1-3 Alkoxy. C 1-6 Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, isopropoxy, n-propoxy, n-butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy, and the like, such as methoxy or ethoxy.

[0321] The term "alkoxyalkyl" refers to an alkyl group substituted with one or more alkoxy groups, for example -C 1-6 Alkyl-C 1-6 Alkoxy, wherein alkyl and alkoxy are as defined above, non-limiting examples include: -CH2OCH3, -CH2OCH2CH3 and -CH2OtBu. The alkoxyalkyl group is further exemplified by -CH2OCH3, -CH2OCH2CH3, Or -CH2OtBu.

[0322] The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein the alkoxy group is as defined above. 1-6 Alkyl groups include -CF3, -C2F5, -CHF2, -CH2F, -CH2CF3, -CH2Cl or -CH2CH2CF3.

[0323] The term "deuterated alkoxy" refers to an alkoxy group substituted with one or more deuterium groups, wherein alkoxy is as defined above. 1-6 Alkoxy group, for example -OCD3.

[0324] "Halogen" or "halo" refers to fluorine, chlorine, bromine or iodine.

[0325] "Cyano" refers to -CN.

[0326] "Amino" refers to -NH2.

[0327] "Hydroxyl" refers to -OH.

[0328] "(O)" means =O, such as -C(O)R d means The same applies to other similar situations.

[0329] "Oxo" refers to =0.

[0330] The structural formula of pyridine is

[0331] The structural formula of thiophene is

[0332] The structural formula of pyrrole is

[0333] "1H-1,2,3-triazole" is

[0334] The structural formula of "oxazole" is

[0335] The structural formula of furan is

[0336] MRTX1133:

[0337] "Optionally substituted by one or more..." means that it may be substituted by one or more specified substituents, or it may be unsubstituted; if the "plurality" in "one or more" is not limited, the minimum value is 2, and the maximum value is the value of the substitutable sites of the substituted group.

[0338] If substituents are described as being "individually selected" or "independently selected" from a group, each substituent is selected independently of the other. Thus, each substituent may be the same as or different from another (or other) substituent.

[0339] "Substitution" means that a hydrogen atom in a molecule is replaced by another different group.

[0340] The term "membered" refers to the number of skeletal atoms constituting the ring.

[0341] The "bond" or "single bond" mentioned in the present invention means that there is only one connecting bond, and can also be understood as "none".

[0342] When a bond to a substituent is shown to pass through a bond connecting two atoms in a ring, then such substituent may be bonded to any ring atom in the substitutable ring.

[0343] As used herein, "individual" or "subject" includes humans and non-human animals. Exemplary human individuals include human individuals suffering from a disease (e.g., a disease described herein) (hereinafter referred to as a patient) or normal individuals. "Non-human animals" include all vertebrates, such as non-mammals and mammals, such as non-human primates, livestock, and / or domesticated animals.

[0344] As used herein, an "effective amount" refers to an amount of a compound that, when administered, will relieve to some extent one or more of the symptoms of the disease being treated. Dosage regimens may be adjusted to provide the optimum desired response.

[0345] As used herein, "pharmaceutically acceptable" is meant to include any material that does not interfere with the effectiveness of the biological activity of the active ingredient and is non-toxic to the host to which it is administered.

[0346] The term "pharmaceutically acceptable salt" refers to salts of the compounds of the present invention formed with acids or bases that are suitable for use as pharmaceuticals, including salts of inorganic acids and bases, and organic acids and bases.

[0347] The term "prevention" includes inhibiting and delaying the onset of a disease, and includes not only prevention before the development of a disease but also prevention of recurrence of a disease after treatment.

[0348] The term "treating" includes curing symptoms, ameliorating symptoms, and inhibiting the progression of symptoms.

[0349] The term "tautomer" refers to functional group isomers resulting from the rapid shift of an atom between two positions in a molecule. Tautomeric compounds can exist as two or more interconvertible species. Prototropic tautomers result from the migration of a covalently bonded hydrogen atom between two atoms. Tautomers generally exist in equilibrium, and attempts to isolate individual tautomers usually produce a mixture with physical and chemical properties consistent with a mixture of compounds. The position of equilibrium depends on the chemical properties within the molecule. For example, in many aliphatic aldehydes and ketones, such as acetaldehyde, the keto form predominates, while in phenols, the enol form predominates.

[0350] The term "stereoisomer" refers to isomers that result from differences in the arrangement of atoms in a molecule in space. The compounds of the present invention may contain asymmetric centers or chiral centers and therefore exist in different stereoisomeric forms. It is contemplated that all stereoisomeric forms of the compounds of the present invention, including but not limited to diastereomers, enantiomers and atropisomers, and geometric (or conformational) isomers, and mixtures thereof, such as racemic mixtures, are within the scope of the present invention.

[0351] The term "solvate" refers to a pharmaceutically suitable association formed between one or more solvent molecules and the compound of the present invention. Solvents that form solvates include, but are not limited to, water, methanol, ethanol, isopropanol, EA, THF, DMF, dimethyl sulfoxide, and the like.

[0352] The term "metabolite" refers to a pharmaceutically acceptable metabolic derivative of a compound of the present invention (or a salt thereof).

[0353] The term "co-crystal" refers to a molecular complex of an ionized or non-ionized compound of Formula (I) (or any other compound disclosed herein) and one or more non-ionized co-crystal formers (such as pharmaceutically acceptable salts) linked by non-covalent interactions.

[0354] The term "isotopically labeled" refers to the replacement of one or more atoms in a molecule with an atom having a different atomic mass or mass number. Examples of isotopes that can be incorporated into the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, such as, but not limited to, 2H, 3H, 11C, 13C, 14C, 13N, 15N, 15O, 17O, 18O, 35S, 18F, 36Cl, 123I, and 125I, respectively. Certain isotopically labeled compounds of the invention are useful in drug and / or substrate tissue distribution studies. The radioactive isotopes tritium, i.e., 3H, and carbon-14, i.e., 14C, are particularly useful for this purpose due to their ease of incorporation and convenient means of detection. For example, the compounds of the invention may be enriched by 1%, 2%, 5%, 10%, 25%, 50%, 75%, 90%, 95%, or 99% of a specified isotope. DETAILED DESCRIPTION

[0355] The following is a clear and complete description of the technical solution of the present invention. Obviously, the embodiments described are only some embodiments of the present invention, not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making any creative efforts are within the scope of protection of the present invention.

[0356] The structures of the compounds were determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR chemical shifts (δ) are given in ppm. NMR measurements were performed using an AVANCE NEO 400MHz Bruker instrument, with deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), deuterated methanol (CD3OD) as the solvents, and tetramethylsilane (TMS) as the internal standard. MS measurements were performed using an ISQ-EC Thermo Fisher LC-MS instrument. The instrument used for preparative HPLC was a GX-281 Gilson chromatograph. Preparative separation method 1: Sun Prep C18 OBD™ 5μm, 30 x 150mm Column, 0.06% formic acid / acetonitrile; Preparative Separation Method 2: Prep C18 OBD™ 5μm, 30 x 150mm Column, 10mM NH4HCO3 aqueous solution / acetonitrile.

[0357] Unless otherwise specified in the examples, solution refers to aqueous solution.

[0358] Unless otherwise specified in the examples, the reaction temperature is room temperature, 20°C to 30°C.

[0359] HATU refers to O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate

[0360] DIPEA and DIEA refer to diisopropylethylamine;

[0361] DMSO refers to dimethyl sulfoxide;

[0362] Pd2(dba)3 refers to tris(dibenzylideneacetone)dipalladium;

[0363] DCE refers to 1,2-dichloroethane;

[0364] MTBE refers to methyl tert-butyl ether;

[0365] DCM refers to dichloromethane;

[0366] DMF refers to N,N-dimethylformamide;

[0367] NMP refers to N-methylpyrrolidone;

[0368] TFA refers to trifluoroacetic acid;

[0369] NBS refers to N-bromosuccinimide;

[0370] NIS refers to N-iodosuccinimide;

[0371] EA refers to ethyl acetate;

[0372] ACN refers to acetonitrile;

[0373] PE refers to petroleum ether;

[0374] DIEA refers to N,N-diisopropylethylamine;

[0375] Pd(dppf)Cl2 refers to 1,1'-bis(diphenylphosphinoferrocene)palladium dichloride;

[0376] THF refers to tetrahydrofuran;

[0377] T3P refers to 1-n-propylphosphoric anhydride;

[0378] 1,4-Dioxane refers to 1,4-dioxane.

[0379] TBAF refers to tetrabutylammonium fluoride

[0380] TBSCl refers to tert-butyldimethylsilyl chloride

[0381] Synthesis of Intermediate I 2,4,6-trichloropyrido[3,2-d]pyrimidine

[0382] Step 1. Synthesis of compound b

[0383] Compound a (25.0 g, 146 mmol) was dissolved in anhydrous THF (800 mL), and triphosgene (26.0 g, 87.6 mmol) was added to the reaction solution in portions. The mixture was then heated to 60°C and stirred for 2 h. The reaction was monitored by LCMS until complete. The reaction mixture was cooled to room temperature, filtered, and the filter cake was rinsed with acetonitrile. The solid obtained by filtration was concentrated under reduced pressure to afford compound b (22.2 g, 112 mmol, 77% yield).

[0384] Its structural characterization is as follows: ESI-MS m / z: 198.0 [M+H] + .

[0385] Step 2: Synthesis of 2,4,6-trichloropyrido[3,2-d]pyrimidine

[0386] Compound b (22.2 g, 112 mmol) was dissolved in 150 mL of anhydrous toluene, and DIPEA (57.8 g, 448 mmol) was added dropwise. Phosphorus oxychloride (171 g, 1120 mmol) was then added dropwise. The mixture was heated to 100°C and stirred for 6 h. LCMS confirmed the reaction was complete. The reaction solution was concentrated under reduced pressure to obtain a residue, which was purified by normal phase chromatography to afford 2,4,6-trichloropyrido[3,2-d]pyrimidine (17.8 g, 76.1 mmol, 68% yield).

[0387] Its structural characterization is as follows: ESI-MS m / z: 233.9, 235.9 [M+H] + .

[0388] Synthesis of Intermediate II 2,6-difluoro-N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)benzenesulfonamide

[0389] Compound a (1.00 g, 4.00 mmol) was dissolved in pyridine (15 mL), cooled to 0°C, and compound b (1.02 g, 4.80 mmol) was added. The mixture was stirred at room temperature for 1 h. After completion of the reaction, water (150 mL) was added to quench the mixture. The aqueous phase was extracted with EA, and the organic phases were combined. The organic phases were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to afford 2,6-difluoro-N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)benzenesulfonamide (962 mg, 2.26 mmol, 56% yield).

[0390] Its structural characterization is as follows: ESI-MS m / z: 427.1[M+H] + .

[0391] Intermediate III Synthesis of 2,4-difluoro-N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)benzenesulfonamide.

[0392] Compound a (1.00 g, 4.00 mmol) was dissolved in 15 mL of pyridine, and compound b (1.02 g, 4.80 mmol) was added at 0°C and stirred at room temperature for 1 h. After the reaction, water and EA were added for extraction. The organic phases were combined and dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain 2,4-difluoro-N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)benzenesulfonamide (826 mg, 1.93 mmol, yield 48%).

[0393] Its structural characterization is as follows: ESI-MS m / z: 427.1[M+H] + .

[0394] Intermediate IV Synthesis of 2,4,6-trifluoro-N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)benzenesulfonamide.

[0395] Compound a (1.00 g, 4.00 mmol) was dissolved in pyridine (15 mL) at room temperature, cooled to 0°C, and compound b (1.11 g, 4.80 mmol) was added. The mixture was stirred at room temperature for 1 hour. After completion of the reaction, water (150 mL) was added to quench the mixture. The aqueous phase was extracted with EA, and the organic phases were combined. The organic phases were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to afford 2,4,6-trifluoro-N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)benzenesulfonamide (825 mg, 1.86 mmol, 46% yield).

[0396] Its structural characterization is as follows: ESI-MS m / z: 445.1[M+H] + .

[0397] Synthesis of Intermediate V 6-Bromo-2,4-dichloro-5-fluoroquinazoline

[0398] Step 1. Synthesis of compound b

[0399] Compound a (3.5 g, 16.27 mmol) and potassium carbonate (4.5 g, 32.54 mmol) were dissolved in dimethyl sulfoxide (100 mL) at room temperature. 35% hydrogen peroxide (6.3 mL, 65.08 mmol) was added and stirred at room temperature for 4 h. The reaction solution was poured into 1 L of ice water. Solid precipitated, which was collected by filtration and dried under vacuum to obtain compound b (2.8 g, 12.01 mmol, 74% yield).

[0400] Its structural characterization is as follows: ESI-MS m / z: 232.9, 234.9 [M+H] + .

[0401] Step 2: Synthesis of Compound C

[0402] Compound b (2.8 g, 12.01 mmol) was dissolved in 280 mL of THF, triphosgene (3.5 g, 12.0 mmol) was added, and the mixture was stirred at 60°C for 3 h. The mixture was concentrated under reduced pressure, and the obtained solid was washed three times with EA / PE (1 / 5) to obtain compound c (3.0 g, 11.6 mmol, yield 96%).

[0403] Its structural characterization is as follows: ESI-MS m / z: 258.9, 260.9 [M+H] + .

[0404] Step 3. Synthesis of compound d

[0405] Compound c (3.0 g, 11.6 mmol), phosphorus oxychloride (17.8 g, 115.80 mmol), and DIEA (7.5 g, 57.90 mmol) were dissolved in toluene (100 mL) and reacted at 100°C for 15 h. The mixture was concentrated under reduced pressure and purified on a silica gel column to afford 6-bromo-2,4-dichloro-5-fluoroquinazoline (2.5 g, 8.42 mmol, 73% yield).

[0406] Its structural characterization is as follows: ESI-MS m / z: 296.9, 298.9 [M+H] + .

[0407] Synthesis of Intermediate VI 6-bromo-2,4-dichloro-5,8-difluoroquinazoline

[0408] Step 1: Synthesis of compound b

[0409] Compound a (8.4 g, 40.6 mmol) was dissolved in 80 mL of glacial acetic acid, and NIS (10.4 g, 44.6 mmol) was added. The mixture was allowed to react at room temperature for 3 h. After the reaction, a large amount of water was added, and the mixture was extracted three times with EA. The combined organic phases were washed three times with water and once with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to yield 12 g of crude compound b.

[0410] Its structural characterization is as follows: ESI-MS m / z: 333.9[M+H] + .

[0411] Step 2: Synthesis of compound c

[0412] Compound b (12 g, 36 mmol) was dissolved in 120 mL of NMP, and cuprous cyanide (3.6 g, 39.6 mmol) was added. The mixture was heated to 120° C. for 5 h, and then extracted with water and EA. The mixture was dried over sodium sulfate, filtered, concentrated under reduced pressure, and purified on a silica gel column to obtain compound c (4.5 g, 19.4 mmol, two-step yield 48%).

[0413] Its structural characterization is as follows: ESI-MS m / z: 232.9[M+H] + .

[0414] Step 3. Synthesis of compound d

[0415] Compound c (4.5 g, 19.4 mmol) was dissolved in 50 mL of DMSO, potassium carbonate (8.0 g, 58.2 mmol) was added, and hydrogen peroxide solution (9.4 mL, 35%, 97 mmol) was added dropwise under an ice bath. The mixture was heated to room temperature and reacted for 1 h. After the reaction was completed, water was added to precipitate a large amount of solid, which was filtered and the filter cake was dried to obtain compound d (4.3 g, 17.1 mmol, yield 87%).

[0416] Its structural characterization is as follows: ESI-MS m / z: 251.0 [M+H] + .

[0417] Step 4: Synthesis of 6-bromo-2,4-dichloro-5,8-difluoroquinazoline

[0418] Compound d (4.3 g, 17.1 mmol) was dissolved in 50 mL of THF and triphosgene (2.6 g, 8.6 mmol) was added. The mixture was heated to 60°C and reacted for 6 h. After the disappearance of the starting material by LC-MS monitoring, the mixture was directly filtered and the filter cake was dried to obtain crude compound e (4.6 g, 16.6 mmol, 97% yield).

[0419] Its structural characterization is as follows: ESI-MS m / z: 276.9[M+H] + .

[0420] Step 5. Synthesis of compound f

[0421] Compound e (1 g, 3.6 mmol) was dissolved in 10 mL of toluene, and phosphorus oxychloride (3.4 mL, 36 mmol) and DIPEA (3.2 mL, 18 mmol) were added and heated to 110°C for 12 h. After the reaction was completed, the reaction solution was directly concentrated to dryness under reduced pressure and purified on a silica gel column to obtain compound f (600 mg, 1.9 mmol, yield 60%).

[0422] Its structural characterization is as follows: ESI-MS m / z: 312.9[M+H] + .

[0423] Synthesis of Intermediate VII 6-bromo-2,4-dichloro-3-cyanoquinoline

[0424] Step 1. Synthesis of compound b

[0425] Compound a (10 g, 46.3 mmol) was dissolved in 200 mL of anhydrous methanol and 10 mL of thionyl chloride was slowly added dropwise in an ice bath. The mixture was heated to 60°C and stirred for 5 h. The reaction was monitored by LCMS after completion. The reaction solution was concentrated under reduced pressure to obtain a residue, which was dispersed in aqueous sodium bicarbonate solution, extracted with EA, dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound b (10 g, 43.4 mmol, 94% yield).

[0426] Its structural characterization is as follows: ESI-MS m / z: 229.9, 231.9 [M+H] + .

[0427] Step 2: Synthesis of Compound d

[0428] Compound b (10 g, 43.4 mmol) and compound c (5.5 g, 65.1 mmol) were dissolved in 150 mL of DCM. EDCI (12.5 g, 65.1 mmol) was added portionwise to the reaction mixture at room temperature and stirred for 2 h. After completion of the reaction, as determined by LCMS, the mixture was diluted with water, extracted with DCM, washed repeatedly with dilute hydrochloric acid, and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to yield compound d (11 g, 37.0 mmol, 85% yield).

[0429] Its structural characterization is as follows: ESI-MS m / z: 296.9, 298.9 [M+H] + .

[0430] Step 3. Synthesis of compound e

[0431] Compound d (11 g, 37.0 mmol) was dissolved in 250 mL of anhydrous methanol, and sodium methoxide (8.0 g, 148 mmol) was added portionwise. The mixture was stirred at room temperature for 2 h. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the residue was dissolved in water. The pH was adjusted to 3 with hydrochloric acid. A large amount of solid precipitated, which was filtered to obtain a filter cake. The product was then washed with acetonitrile and water. The filter cake was then concentrated under reduced pressure and dried to obtain compound e (8.6 g, 32.1 mmol, 87% yield).

[0432] Its structural characterization is as follows: ESI-MS m / z: 264.9, 266.9 [M+H] + .

[0433] Step 4: Synthesis of 6-bromo-2,4-dichloro-3-cyanoquinoline

[0434] Compound e (1 g, 3.77 mmol) was dissolved in 10 mL of toluene. DIPEA (2.6 mL, 15 mmol) was added to the reaction mixture at room temperature, followed by the dropwise addition of phosphorus oxychloride (2.3 g, 15.1 mmol). The mixture was heated to 100°C and reacted for 6 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain the residue, which was purified by normal phase purification to yield 6-bromo-2,4-dichloro-3-cyanoquinoline (660 mg, 2.18 mmol, 58% yield).

[0435] Its structural characterization is as follows: ESI-MS m / z: 300.9, 302.9 [M+H] + .

[0436] Intermediate VIII Synthesis of 2-methoxy-5-(4-(2-(trimethylsilyl)ethoxy)quinazolin-6-yl)pyridin-3-amine

[0437] Step 1. Synthesis of compound c

[0438] Compound a (1.0 g, 4.13 mmol) was dissolved in THF (20 mL). Compound b (975 mg, 8.26 mmol) and LiHMDS (8.26 mL, 8.26 mmol, 1 mol / L) were added under ice-cooling. The mixture was stirred at room temperature for 2 h. Extraction was performed with EA and water. The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain compound c (1.23 g, 3.80 mmol, 92% yield).

[0439] Its structural characterization is as follows: ESI-MS m / z: 325.0, 327.0 [M+H] + .

[0440] Step 2: Synthesis of 2-methoxy-5-(4-(2-(trimethylsilyl)ethoxy)quinazoline-6-yl)pyridin-3-amine

[0441] Compound c (1.23 g, 3.80 mmol) was dissolved in 1,4-dioxane (20 mL), and compound d (1.05 g, 4.18 mmol), potassium carbonate (1.05 g, 7.60 mmol), Pd(dppf)Cl2 (278 mg, 0.38 mmol), and water (4 mL) were added. The atmosphere was replaced with nitrogen and stirred at 75°C for 3 h. The mixture was extracted with EA and water, and the combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to afford 2-methoxy-5-(4-(2-(trimethylsilyl)ethoxy)quinazolin-6-yl)pyridin-3-amine (1.20 g, 3.27 mmol, 86% yield).

[0442] Its structural characterization is as follows: ESI-MS m / z: 369.2[M+H] + .

[0443] Synthesis of Intermediate IX 2,4-dichloro-6-(6-methoxy-5-nitropyridin-3-yl)-1,5-naphthyridine

[0444] Step 1. Synthesis of compound b

[0445] Compound a (20 g, 87 mmol) was dissolved in 100 mL of DCM. Pyridine (28 mL, 346 mmol) was added under ice-cooling, followed by the slow dropwise addition of a 20 mL solution of methyl 3-chloro-3-oxopropanoate (14 g, 104 mmol) in DCM. The mixture was allowed to react for 1 h. The reaction mixture was concentrated under reduced pressure and purified by column chromatography to afford solid compound b (26 g, 79 mmol, 92% yield).

[0446] Its structural characterization is as follows: ESI-MS m / z: 331.1[M+H] + .

[0447] Step 2: Synthesis of Compound C

[0448] Compound b (26 g, 79.02 mmol) was dissolved in 100 mL of ethanol, and sodium methoxide (12.8 g, 237.06 mmol) was added portionwise. The mixture was stirred at 60°C for 2 h. After completion of the reaction, the reaction solution was extracted with EA and purified by organic column chromatography to obtain solid compound c (23 g, 77 mmol, 98% yield).

[0449] Its structural characterization is as follows: ESI-MS m / z: 299.1[M+H] + .

[0450] Step 3. Synthesis of compound d

[0451] Compound c (23 g, 77.4 mmol) was dissolved in 100 mL of hydrobromic acid-acetic acid solution at room temperature. The reaction temperature was raised to 90°C and stirred for 4 hours. After the reaction was complete, the reaction solution was allowed to cool to precipitate a solid, which was filtered and dried to obtain compound d (13.6 g, 56.6 mmol, 73% yield).

[0452] Its structural characterization is as follows: ESI-MS m / z: 241.1[M+H] +

[0453] Step 4. Synthesis of compound f

[0454] Compound e (3 g, 10.7 mmol), potassium carbonate (4.4 g, 32.1 mmol), Pd(dppf)Cl2 (725 mg, 1 mmol), and compound d (2.5 g, 10.7 mmol) were dissolved in a mixture of 1,4-dioxane and H2O (30 mL / 6 mL) at room temperature and stirred at 100°C under nitrogen for 5 h. The reaction solution was concentrated under reduced pressure and purified by normal-phase column chromatography to afford solid compound f (2.5 g, 7.9 mmol, 73% yield).

[0455] Its structural characterization is as follows: ESI-MS m / z: 315.2[M+H] + .

[0456] Step 5. Synthesis of compound g

[0457] Compound f (2.5 g, 7.9 mmol) was dissolved in a toluene / DMF (15 mL / 15 mL) mixture at room temperature. Phosphorus oxychloride (6.1 g, 40 mmol) was added and the mixture was allowed to react at 80°C for 2 h. After completion, ice water was poured into the mixture and the reaction mixture was neutralized with NaHCO₃. The mixture was extracted with EA, and the organic phase was concentrated and purified by a forward column chromatography to afford solid compound e (802 mg, 2.3 mmol, 28% yield).

[0458] Its structural characterization is as follows: ESI-MS m / z: 351.2[M+H] + .

[0459] Synthesis of Intermediate X N-(5-bromo-4-fluoro-2-methoxypyridin-3-yl)-N-((2,4-difluorophenyl)sulfonyl)-2,4-difluorobenzenesulfonamide

[0460] Step 1. Synthesis of compound b

[0461] Compound a (1.0 g, 5.21 mmol) was dissolved in 10 mL of DMF, followed by the addition of NIS (1.41 g, 6.25 mmol) and the reaction was allowed to proceed at 70°C for 3 h. After completion, the reaction solution was poured into water and extracted with EA. The combined organic phases were dried over anhydrous sodium sulfate, and concentrated under reduced pressure to yield compound b (1.5 g, 4.73 mmol, 90% yield).

[0462] Its structural characterization is as follows: ESI-MS m / z: 317.8, 319.8 [M+H] +

[0463] Step 2: Synthesis of Compound C

[0464] Compound b (1.4 g, 4.40 mmol) was dissolved in 20 mL of toluene, followed by the addition of AgCO (1.82 g, 6.60 mmol) and iodomethane (1.87 g, 13.2 mmol). After addition, the temperature was raised to 50°C and stirred overnight. After completion of the reaction, the reaction solution was poured into water and extracted with EA. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and then purified by silica gel column chromatography to obtain compound c (0.53 g, 1.6 mmol, 36% yield).

[0465] Its structural characterization is as follows: ESI-MS m / z: 331.9, 333.9 [M+H] + .

[0466] Step 3. Synthesis of compound e

[0467] Compound c (0.48 g, 1.45 mmol), compound d (0.29 g, 1.59 mmol), Pd2(dba)3 (0.10 g, 0.14 mmol), Xantphos (0.17 g, 0.29 mmol), and cesium carbonate (0.94 g, 2.90 mmol) were dissolved in 1,4-dioxane (10 mL). The atmosphere was replaced with nitrogen three times at room temperature, then heated to 80°C and stirred overnight. LC-MS monitoring confirmed the completion of the reaction. The reaction solution was poured into water and extracted with EA. The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and then purified by silica gel column chromatography to afford compound e (0.28 g, 0.73 mmol, 50% yield).

[0468] Its structural characterization is as follows: ESI-MS m / z: 385.0, 387.0 [M+H] + .

[0469] Step 4. Synthesis of compound f

[0470] Compound e (0.28 g, 0.73 mmol) was dissolved in THF (10 mL), followed by the addition of hydrochloric acid (2 mL, 2 M). The mixture was stirred at room temperature for 2 h. LC-MS confirmed the reaction was complete. The reaction solution was poured into saturated sodium bicarbonate and extracted with EA. The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and then purified by silica gel column chromatography to afford compound f (0.12 g, 0.54 mmol, 74% yield).

[0471] Its structural characterization is as follows: ESI-MS m / z: 221.0, 223.0 [M+H] + .

[0472] Step 5. Synthesis of compound h

[0473] Compound f (0.12 g, 0.54 mmol) was dissolved in 3 mL of pyridine, followed by the addition of compound g (0.34 g, 1.62 mmol) and stirring at room temperature overnight. After completion of the reaction, the reaction solution was poured into water and extracted with EA. The combined organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography to afford compound h (0.15 g, 0.26 mmol, 48% yield).

[0474] Its structural characterization is as follows: ESI-MS m / z: 572.9, 574.9 [M+H] + .

[0475] Synthesis of Intermediate XI(S)-tert-Butyl 2-(Hydroxymethyl)-4-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-4-yl)piperidine-1-carboxylate

[0476] Compound a (800 mg, 1.89 mmol), Pd(dppf)Cl2 (139 mg, 0.19 mmol), compound b (960 mg, 3.78 mmol), and KOAc (463 mg, 4.73 mmol) were dissolved in 1,4-dioxane (30 mL) at room temperature, replaced with nitrogen, and stirred at 90°C for 5 h. Water and ethyl acetate were added for separation, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain compound c (522 mg, 1.11 mmol, 59% yield).

[0477] Its structural characterization is as follows: ESI-MS m / z: 471.2[M+H] + .

[0478] Example 1 (E)-1-((1 3 S)-6 4 -Fluoro-3 6 -Methoxy-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinazoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 Synthesis of 1,4-dione-2-pentyl)pent-2-ene

[0479] Step 1. Synthesis of compound c

[0480] Compound a (260 mg, 1.08 mmol) was dissolved in 5 mL of DCM. DIEA (470 μL, 2.70 mmol) and compound b (298 mg, 1.30 mmol) were added and stirred at room temperature for 2 h. After the reaction was complete, the mixture was concentrated under reduced pressure and purified by column chromatography to afford compound c (284 mg, 0.64 mmol, 59% yield).

[0481] Its structural characterization is as follows: ESI-MS m / z: 423.1, 425.1 [M+H] + .

[0482] Step 2: Synthesis of Compound e

[0483] Compound c (284 mg, 0.64 mmol), Pd(dppf)Cl2 (47 mg, 0.06 mmol), compound d (327 mg, 0.77 mmol), and Na2CO3 (170 mg, 1.60 mmol) were dissolved in a mixed solvent of 1,4-dioxane / H2O (4 mL / 1 mL) at room temperature, replaced with nitrogen, and stirred at 80°C for 3 h. After the reaction was complete, water and EA were added for extraction. The aqueous phase was washed twice with EA, and the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain compound e (206 mg, 0.31 mmol, yield 48%).

[0484] Its structural characterization is as follows: ESI-MS m / z: 643.2[M+H] + .

[0485] Step 3. Synthesis of compound f

[0486] Compound e (206 mg, 0.31 mmol) was dissolved in DCM (4 mL), TFA (2 mL) was added, and the mixture was stirred at room temperature for 1 h. After the reaction was complete, the mixture was concentrated under reduced pressure and purified by reverse-phase MPLC to give compound f (56 mg, 0.10 mmol, yield 32%).

[0487] Its structural characterization is as follows: ESI-MS m / z: 543.2[M+H] + .

[0488] Step 4. Synthesis of compound g

[0489] Compound f (56 mg, 0.10 mmol) was dissolved in THF (4 mL), and NaH (11 mg, 0.74 mmol, 60%) was added. The mixture was stirred at 50°C for 12 h. The reaction was then quenched by the addition of saturated ammonium chloride in an ice bath, and extracted with water and EA. The aqueous phase was washed twice with EA, and the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain compound g (25 mg, 0.05 mmol, 50% yield).

[0490] Its structural characterization is as follows: ESI-MS m / z: 523.2[M+H]+.

[0491] Step 5, (E)-1-((1 3 S)-6 4 -Fluoro-3 6 -Methoxy-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinazoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 Synthesis of 1,4-dione-2-pentyl)pent-2-ene

[0492] Compound g (25 mg, 0.05 mmol) was dissolved in 5 mL THF, compound f (88 mg, 0.77 mmol) and DIEA (206 mg, 1.60 mmol) were added, the temperature was lowered to -40°C, T3P (610 mg, 0.96 mmol, 50% EA solution) was added, and the mixture was stirred at -40°C for 2 h. After the reaction was complete, water and EA were added for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and then purified by high pressure liquid chromatography (method 1) to obtain (E)-1-((1 3 S)-6 4 -Fluoro-3 6 -Methoxy-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinazoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 -yl)pent-2-ene-1,4-dione (6 mg, 0.01 mmol, yield 20%).

[0493] Its structural characterization is as follows: 1H NMR(400MHz,DMSO-d6)δppm 10.16(s,1H),8.77(s,1H),8.34-8.21(m,3H),8.10-8.06(m,2H),7.96-7.94(m,1H),7.50(d,J=16.0Hz,1H),7.44 -7.37(m,1H),7.10(t,J=7.6Hz,1H),6.77(d,J=16.0Hz,1H),5.43-5.29 (m,1H),5.10-5.07(m,0.8H),4.85-4.43(m,1.2H),4.61-4.57(m,0.2H), 4.39-4.31(m,1.8H),4.11-3.93(m,1H),3.93(s,3H),3.58-3.64(m,1.0 H),3.22-3.37(m,1H),3.14-3.08(m,1H),2.40(s,2.4H),2.29(s,0.6H).

[0494] ESI-MS m / z:619.2[M+H] + .

[0495] Example 2 (E)-1-((1 3 R)-6 4 -Fluoro-3 6 -Methoxy-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinazoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 Synthesis of (-)pent-2-ene-1,4-dione

[0496] According to the synthetic method from step 1 to step 5 of Example 1, the compound b of Example 1 was replaced by the compound b of Example 2, and the other operations were the same to obtain (E)-1-((1 3 R)-6 4 -Fluoro-3 6 -Methoxy-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinazoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 -yl)pent-2-ene-1,4-dione.

[0497] Its structural characterization is as follows: 1H NMR(400MHz,MeOD-d4)δppm 8.60(s,1H),8.25(brs,1H),8.05-7.91(m,4H),7.81-7.77(m,1H),7.38(d,J=16.0Hz,1H),7.1 1-7.05(m,1H),6.83-6.71(m,2H),5.42-5.37(m,0.4H),5.29-5.12(m,1.6H),4.94-4.92(m,1H ),4.65-4.62(m,0.3H),4.49-4.32(m,1H),4.22-4.19(m,0.7H),4.18-3.87(m,1H),3.87(s,3H ),3.60-3.51(m,0.8H),3.29-3.25(m,1H),3.14-3.03(m,1.2H),2.30(s,2.3H),2.23(s,0.7H).

[0498] ESI-MS m / z:619.2[M+H] + .

[0499] Example 3 (E)-1-(6 4 -Fluoro-3 6 -Methoxy-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinazoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 Synthesis of 1,4-dione-2-pentyl)pent-2-ene

[0500] According to the synthetic method from step 1 to step 5 of Example 1, the compound b of Example 1 was replaced by the compound b of Example 3, and the other operations were the same to obtain (E)-1-(6 4 -Fluoro-3 6 -Methoxy-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinazoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 -yl)pent-2-ene-1,4-dione.

[0501] Its structural characterization is as follows: 1H NMR(400MHz,MeOD-d4)δppm 8.73(s,1H),8.53-8.34(m,1H),8.32-8.08(m,3H),8.08-7.98(m,1H),7.95(d,J=8.8Hz,1H),7.47(d,J=15.6Hz,1H),7.31-7.04 (m,1H),7.02-6.78(m,2H),5.55-5.44(m,0.20H),5.37-5.26(m,1H),5.15-5.00(m,0.8H),4.76-4.65(m,1H),4.58-4.47(m,1H), 4.35-4.09(m,1H),4.08-3.87(m,4H),3.75-3.52(m,1H),3.42-3.35(m,1H),3.25-3.15(m,1H),2.39(s,2.2H),2.33(s,0.8H).

[0502] ESI-MS m / z:619.2[M+H] +

[0503] Example 4 (E)-1-((1 3 R)-6 4 -Fluoro-3 6 -Methoxy-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinazoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclononane-1 4 Synthesis of 1,4-dione-2-pentyl)pent-2-ene

[0504] According to the synthetic method from step 1 to step 5 of Example 1, the compound b of Example 1 was replaced by the compound b of Example 4, and the other operations were the same to obtain (E)-1-((1 3 R)-6 4 -Fluoro-3 6 -Methoxy-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinazoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclononane-1 4 -yl)pent-2-ene-1,4-dione.

[0505] Its structural characterization is as follows: 1H NMR(400MHz,DMSO-d4)δppm 9.64(s,0.3H),9.56(s,0.7H),8.82(s,1H),8.42(s,1H),8.37-8.32(m,2H),8.23(s,0.7H),8.18(s,0.3H),8.00-7.94(m ,2H),7.48(d,J=15.6Hz,1H),7.28-7.26(m,0.3H),7.20-7.17(m,0.7H),7.02-6.97(m,1H),6.7(d,J=15.6Hz,1H),4.81-4 .80(m,0.7H),4.62-4.59(m,0.3H),4.51-4.47(m,1.4H),4.24-4.18(m,2H),4.15-4.06(m,0.6H),4.00-3.96(m,1H),3.9 6(s,3H),3.64-3.58(m,0.8H),3.54-3.52(m,0.2H),3.13-3.08(m,2H),2.72-2.68(m,2H),2.39(s,2.4H),2.38(s,0.6H).

[0506] ESI-MS m / z:633.2[M+H] + .

[0507] Example 5 (E)-1-((1 3 S)-6 4 -Fluoro-3 6 -Methoxy-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinazoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclononane-1 4 -yl)pent-2-ene-1,4-dione

[0508] According to the synthetic method from step 1 to step 5 of Example 1, the compound b of Example 1 was replaced by the compound b of Example 4, and the other operations were the same to obtain (E)-1-((1 3 R)-6 4 -Fluoro-3 6 -Methoxy-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinazoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclononane-1 4 -yl)pent-2-ene-1,4-dione.

[0509] Its structural characterization is as follows: 1H NMR(400MHz,DMSO-d6)δppm 9.64-9.55(m,1H),8.81(s,1H),8.43(s,1H),8.40-8.29(m,2H),8.23-8.18(m,1H),8.03-7.91 (m,2H),7.48(d,J=15.6Hz,1H),7.32-7.15(m,1H),7.04-6.94(m,1H),6.82-6.71(m,1H),4.80( m,0.7H),4.62-4.59(m,0.3H),4.57-4.41(m,1.3H),4.30-4.12(m,2.4H),4.09-4.06(m,0.3H) ,4.00-3.96(m,4H),3.67-3.24(m,1H),3.16-3.03(m,2H),2.81-2.60(m,2H),2.42-2.36(m,3H)

[0510] ESI-MS m / z:633.2[M+H] + .

[0511] Example 6 (E)-1-(((1 3 R)-6 4 -Chloro-3 6 -Methoxy-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinazoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 Synthesis of 1,4-dione-2-pentyl)pent-2-ene

[0512] Step 1. Synthesis of compound c

[0513] Compound a (300 mg, 1.20 mmol) and compound b (330 mg, 1.44 mmol) were dissolved in 8 mL of pyridine at room temperature and stirred for 2 h. After completion of the reaction, the mixture was extracted with water and DCM, washed with 2N hydrochloric acid, and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure and purified by normal phase column chromatography to afford solid compound c (285 mg, 0.63 mmol, 52% yield).

[0514] Its structural characterization is as follows: ESI-MS m / z: 443.1[M+H] + .

[0515] Step 2 to step 5, (E)-1-(((1R)-6-chloro-3-methoxy-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinazoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 Synthesis of 1,4-dione-2-pentyl)pent-2-ene

[0516] According to the synthesis method from step 2 to step 5 of Example 2, the compound d of Example 2 was replaced by the compound c of Example 6, and the other operations were the same to obtain (E)-1-(((1 3 R)-6 4 -Chloro-3 6 -Methoxy-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinazoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 -yl)pent-2-ene-1,4-dione.

[0517] Its structural characterization is as follows: 1 H NMR(400MHz,DMSO-d6)δppm 10.24(s,1H),8.80(s,1H),8.35-8.21(m,3H),8.09(s,1H),8.01(d,J=8.8Hz,1H),7.95(d,J=8.8H z,1H),7.68-7.55(m,1H),7.53-7.44(m,1H),7.36-7.26(m,1H),6.77(d,J=15.6Hz,1H),5.48-5.26 (m,1H),5.09(d,J=10.0Hz,1H),4.87(d,J=13.6Hz,1H),4.47(d,J=13.2Hz,1H),4.33(d,J=13.6Hz ,1H),3.98(d,J=9.6Hz,1H),3.94(s,3H),3.70-3.57(m,1H),3.48-3.10(m,2H),2.42-2.27(m,3H).

[0518] ESI-MS m / z:635.1[M+H] + .

[0519] Example 7 (E)-1-((1 3 S)-6 4 -Chloro-3 6 -Methoxy-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinazoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-14 Synthesis of 1,4-dione-2-pentyl)pent-2-ene

[0520] According to the synthesis method from step 2 to step 5 of Example 1, the compound d of Example 1 was replaced by the compound a of Example 7, and the other operations were the same to obtain (E)-1-((1 3 S)-6 4 -Chloro-3 6 -Methoxy-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinazoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 -yl)pent-2-ene-1,4-dione.

[0521] Its structural characterization is as follows: 1 H NMR(400MHz,DMSO-d6)δppm 10.25(s,1H),8.77(s,1H),8.35-8.29(m,2H),8.24-8.22(m,1H),8.08(s,1H),8.01(d,J=8.8Hz,1H),7.95(d,J=8.8Hz,1H),7.6 6(s,0.2H),7.58(s,0.8H),7.50(d,J=15.6Hz,1H),7.32-7.30(m,1H),6.77(d,J=15.6Hz,1H),5.47-5.32(m,1H),5.09-5.06(m,0 .8H),4.86-4.82(m,0.8H),4.72-4.69(m,0.2H),4.60-4.57(m,0.2H),4.40-4.30(m,1.8H),4.15-4.11(m,0.2H),3.97-3.93(m, 1H),3.93(s,3H)3.66-3.59(m,1H),3.35-3.31(m,1H),3.14-3.08(m,0.8H),3.05-3.97(s,0.2H),2.40(s,2.4H),2.29(s,0.6H).

[0522] ESI-MS m / z:635.1[M+H] + .

[0523] Example 8 (E)-1-((1 3 R)-6 4 -Fluoro-3 6-Methoxy-4-methyl-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinazoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 Synthesis of 1,4-dione-2-pentyl)pent-2-ene

[0524] Step 1. Synthesis of compound b

[0525] Compound a (150 mg, 0.29 mmol), N,N-diisopropylethylamine (112 mg, 0.87 mmol), and di-tert-butyl dicarbonate (76 mg, 0.35 mmol) were dissolved in THF (8 mL) at room temperature and stirred for 5 h. After completion of the reaction, the mixture was extracted with water and EA, dried over anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure and purified by normal phase column chromatography to afford compound b (140 mg, 0.22 mmol, 76% yield).

[0526] Its structural characterization is as follows: ESI-MS m / z: 623.2[M+H] + .

[0527] Step 2: Synthesis of Compound C

[0528] Compound b (140 mg, 0.22 mmol) was dissolved in 5 mL of DMF at room temperature, and NaH (26 mg, 0.66 mmol, 60%) was added. The reaction was allowed to react at room temperature for 1 h. Subsequently, iodomethane (63 mg, 0.44 mmol) was added to the reaction solution and allowed to react at room temperature for 6 h. After the reaction was complete, the solution was diluted with water, extracted with EA, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified on a silica gel column to afford compound c (105 mg, 0.16 mmol, 73% yield).

[0529] Its structural characterization is as follows: ESI-MS m / z: 637.2[M+H] + .

[0530] Step 3. Synthesis of compound d

[0531] Compound c (105 mg, 0.16 mmol) was dissolved in 5 mL DCM at room temperature, 2 mL TFA was added and stirred for 30 min. After the reaction was complete, the mixture was concentrated under reduced pressure at room temperature to give compound d (86 mg, 0.16 mmol, 100% yield).

[0532] Its structural characterization is as follows: ESI-MS m / z: 537.2[M+H] + .

[0533] Step 4, (E)-1-((1 3 R)-64 -Fluoro-3 6 -Methoxy-4-methyl-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinazoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 Synthesis of 1,4-dione-2-pentyl)pent-2-ene

[0534] Compounds d (86 mg, 0.16 mmol) and e (20 mg, 0.18 mmol) were dissolved in 8 mL of THF at room temperature. DIEA (39 mg, 0.30 mmol) was added to the reaction solution, followed by 1-propylphosphonic anhydride (140 mg, 0.22 mmol, 50%). After the reaction was complete, the mixture was concentrated under reduced pressure and then purified by high pressure liquid chromatography (method 1) to give (E)-1-((1 3 R)-6 4 -Fluoro-3 6 -Methoxy-4-methyl-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinazoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 -yl)pent-2-ene-1,4-dione (18 mg, 0.028 mmol, 17% yield).

[0535] Its structural characterization is as follows: 1 H NMR(400MHz,DMSO-d6)δppm 8.81(s,1H),8.61-8.49(m,1H),8.45(d,J=2.0Hz,1H),8.34-8.23(m,1H),8.18(s,1H),8.06-7.93( m,2H),7.67(d,J=10.4Hz,1H),7.55-7.44(m,1H),7.17-7.06(m,1H),6.86-6.68(m,1H),5.35(t,J=1 0.0Hz,1H),5.23-5.14(m,0.8H),4.85-4.54(m,1.2H),4.39-4.24(m,1H),4.22-4.09(m,2H),4.05-3 .93(m,3H),3.62-3.46(m,1H),3.38-3.32(m,1H),3.21-3.03(m,4H),2.40(s,2.4H),2.24(s,0.6H).

[0536] ESI-MS m / z:633.2[M+H] +

[0537] Example 9 (E)-1-(((13 R)-6 4 ,6 6 -Difluoro-3 6 -Methoxy-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinazoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 Synthesis of 1,4-dione-2-pentyl)pent-2-ene

[0538] According to the synthesis method from step 2 to step 5 of Example 2, the compound d of Example 2 was replaced by the compound b of Example 9, and the other operations were the same to obtain (E)-1-(((1 3 R)-6 4 ,6 6 -Difluoro-3 6 -Methoxy-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinazoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 -yl)pent-2-ene-1,4-dione.

[0539] Its structural characterization is as follows: 1 H NMR (400MHz, DMSO-d6) δ (ppm): 10.32-10.29 (m, 1H), 8.80 (s, 1H), 8.29-8.20 (m, 2H), 8.18-8.16 (m, 1H), 8.02-7.84 (m, 2H),7.51(d,J=15.6,1H),7.33-7.23(m,1H),7.17-7.07(m,1H),6.78(d,J=15.6Hz,1H),5.40-5.21(m,1H),5.12-5.09( m,0.8H),4.88-4.80(m,1H),4.68-4.66(m,0.2H),4.61-4.58(m,0.2H),4.43-4.32(m,1.8H),4.14-4.12(m,0.2H),3.9 9-3.89(m,0.8H),3.96(s,3H),3.68-3.50(m,1H),3.43-3.35(m,1H),3.18-2.94(m,1H),2.40(s,2.3H),2.33(s,0.7H).

[0540] ESI-MS m / z:637.2[M+H] + .

[0541] Example 10 (E)-1-((1 3 R)-66 -Fluoro-3 6 -Methoxy-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinazoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 Synthesis of 1,4-dione-2-pentyl)pent-2-ene

[0542] According to the synthesis method from step 2 to step 5 of Example 2, the compound d of Example 2 was replaced by the compound b of Example 10, and the other operations were the same to obtain (E)-1-((1 3 R)-6 6 -Fluoro-3 6 -Methoxy-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinazoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 -yl)pent-2-ene-1,4-dione.

[0543] Its structural characterization is as follows: 1 H NMR(400MHz,DMSO-d6)δppm 10.19-10.16(m,1H),8.78(s,1H),8.31-8.21(m,2H),8.18-8.16(m,1H),8.02-7.88(m,2H),7.65-7.55(m,1H),7.51(d,J=15.6Hz,1H),7.33- 7.22(m,1H),7.07-6.98(m,1H),6.77(d,J=15.6Hz,1H),5.39-5.23(m,1H),5.12-5.06( m,0.8H),4.92-4.84(m,1H),4.69-4.67(m,0.2H),4.61-4.58(m,0.2H),4.45-4.42(m,1 H),4.35-4.32(m,0.8H),4.11-4.09(m,0.2H),3.99-3.87(m,0.8H),3.92(s,3H),3.72- 3.57(m,0.8H),3.45-3.37(m,1.2H),3.18-2.95(m,1H),2.40(s,2.3H),2.32(s,0.7H).

[0544] ESI-MS m / z:619.2[M+H] + .

[0545] Example 11 (E)-1-(((1 3 S)-6 4,6 6 -Difluoro-3 6 -Methoxy-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinazoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 Synthesis of 1,4-dione-2-pentyl)pent-2-ene

[0546] According to the synthesis method from step 2 to step 5 of Example 1, the compound d of Example 1 was replaced by the compound b of Example 11, and the other operations were the same to obtain (E)-1-(((1 3 S)-6 4 ,6 6 -Difluoro-3 6 -Methoxy-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinazoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 -yl)pent-2-ene-1,4-dione.

[0547] Its structural characterization is as follows: 1 H NMR(400MHz,DMSO-d6)δppm 10.32(s,1H),8.77(s,1H),8.23(dd,J=10.4,2.0Hz,2H),8.19-8.16(m,1H),7.95(d,J=8.8Hz,1H),7. 92(s,1H),7.51(d,J=15.6Hz,1H),7.34-7.31(m,0.2H),7.27-7.24(m,0.8H),7.13(t,J=9.6Hz,1H),6. 78(d,J=15.6Hz,1H),5.38-5.36(m,0.2H),5.30-5.25(m,0.8H),5.12-5.09(m,0.8H),4.88-4.85(m,0. 8H),4.67-4.66(m,0.2H),4.62-4.59(m,0.2H),4.41(d,J=12.8Hz,1H),4.34(d,J=13.6Hz,0.8H),4.15 -4.12(m,0.2H),3.96-3.91(m,4H),3.68-3.55(m,1H),3.39-3.36(m,0.8H ),3.14-3.08(m,1H),3.01-2.94(m,0.2H),2.41(s,2.6H),2.33(s,0.4H).

[0548] ESI-MS m / z:637.6[M+H]+ .

[0549] Example 12 (E)-1-((1 3 S)-6 6 -Fluoro-3 6 -Methoxy-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinazoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 Synthesis of 1,4-dione-2-pentyl)pent-2-ene

[0550] According to the synthesis method from step 2 to step 5 of Example 1, the compound d of Example 1 was replaced by the compound b of Example 12, and the other operations were the same to obtain (E)-1-((1 3 S)-6 6 -Fluoro-3 6 -Methoxy-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinazoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 -yl)pent-2-ene-1,4-dione.

[0551] Its structural characterization is as follows: 1 H NMR(400MHz,DMSO-d6)δppm 10.25(s,1H),8.85(s,1H),8.31(d,J=10.8Hz,2H),8.26(d,J=8.4Hz,1H),8.04-8.01(m,1.8H),7.68-7.53(m,2.2H),7.36-7.29(m, 1H),7.18-7.16(m,0.2H),7.11-7.06(m,0.8H),6.84(d,J=15.6Hz,1H),5.49-5.43(m,0.2H),5.36-5.31(m,0.8H),5.20-5.17(m,0. 8H),4.99-4.96(m,0.8H),4.78-4.74(m,0.2H),4.68-4.65(m,0.2H),4.56-4.52(m,1H),4.42-4.39(m,0.8H),4.19-4.16(s,0.2H), 4.00-3.98(m,4H),3.71-3.65(m,1H),3.51-3.47(s,0.7H),3.23-3.17(m,1H),3.11-3.03(s,0.3H),2.46(s,2.5H),2.35(s,0.5H).

[0552] ESI-MS m / z:619.6[M+H] + .

[0553] Example 13 (E)-1-((1 3 R)-6 4 -Cyano-3 6 -Methoxy-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinazoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 Synthesis of 1,4-dione-2-pentyl)pent-2-ene

[0554] According to the synthesis method from step 1 to step 5 of Example 6, the compound a of Example 6 was replaced by the compound a of Example 13, and the other operations were the same to obtain (E)-1-((1 3 R)-6 4 -Cyano-3 6 -Methoxy-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinazoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 -yl)pent-2-ene-1,4-dione.

[0555] Its structural characterization is as follows: 1 H NMR(400MHz,DMSO-d6)δppm 10.52-10.38(m,1H),8.81(s,1H),8.43-8.24(m,3H),8.17(d,J=8.8Hz ,1H),8.07(s,1H),8.01-7.92(m,2H),7.74-7.65(m,1H),7.53-7.43(m, 1H),6.81-6.67(m,1H),5.47-5.31(m,1H),5.15-5.06(m,0.8H),4.86(d,J=14.0H z,0.8H),4.80-4.71(m,0.4H),4.65-4.56(m,0.2H),4.53-4.42(m,1H),4.35(d,J= 12.8Hz,0.8H),4.23-4.15(m,0.2H),4.04(d,J=10.0Hz,0.8H),3.93(s,3H),3.67- 3.57(m,1H),3.49-3.43(m,1H),3.21-3.17(m,1H),2.39(s,2.3H),2.26(s,0.7H).

[0556] ESI-MS m / z:626.2[M+H]+

[0557] Example 14 (E)-1-((1 3 S)-3 6 -methoxy-5,5-dioxo-6 4 -(Trifluoromethyl)-7-oxa-5-thia-4-aza-2(4,6)-quinazoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 Synthesis of 1,4-dione-2-pentyl)pent-2-ene

[0558] Step 1. Synthesis of compound b

[0559] Compound a (500 mg, 2.0 mmol) was dissolved in 25 mL of 1,4-dioxane at room temperature, and Pd2(dba)3 (189 mg, 0.2 mmol), Xantphos (238 mg, 0.4 mmol), DIPEA (645 mg, 5.0 mmol) and benzyl mercaptan (384 mg, 3.0 mmol) were added. 0 After the reaction was complete, the mixture was diluted with water, extracted with EA, dried over sodium sulfate, filtered, concentrated under reduced pressure, and purified on a silica gel column to obtain compound b (520 mg, 1.8 mmol, yield 88%).

[0560] Step 2: Synthesis of Compound C

[0561] Compound b (520 mg, 1.8 mmol) was dissolved in acetonitrile (25 mL) at room temperature. Acetic acid and water (0.5 mL / 0.5 mL) were added dropwise, followed by dichlorohydantoin (1.0 g, 5.5 mmol). The mixture was stirred at room temperature for 2 h. LC-MS monitored the reaction for completion. The mixture was diluted with water, extracted with EA, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified on a silica gel column to afford compound c (400 mg, 1.5 mmol, 84% yield).

[0562] Steps 3 to 7, E)-1-((1 3 S)-3 6 -methoxy-5,5-dioxo-6 4 -(Trifluoromethyl)-7-oxa-5-thia-4-aza-2(4,6)-quinazoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 Synthesis of 1,4-dione-2-pentyl)pent-2-ene

[0563] According to the synthesis method from step 1 to step 5 of Example 6, the compounds a and d of Example 6 were replaced by compounds c and f of Example 14, respectively, and the other operations were the same to obtain (E)-1-((1 3 S)-3 6 -methoxy-5,5-dioxo-6 4 -(Trifluoromethyl)-7-oxa-5-thia-4-aza-2(4,6)-quinazoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 -yl)pent-2-ene-1,4-dione.

[0564] Its structural characterization is as follows: 1 H NMR(400MHz,MeOD-d4)δppm 10.56-10.41(m,1H),8.89(s,1H),8.42-8.29(m,3H),8.23(d,J=8.4Hz,1H),8.18-8.10(m,1H),8.00(d,J =8.8Hz,1H),7.83-7.72(m,1H),7.67-7.58(m,1H),7.54-7.43(m,1H),6.82-6.68(m,1H),5.52-5.36(m,1 H),5.20-5.10(m,0.8H),5.03-4.85(m,1H),4.83-4.62(m,1.2H),4.37(d,J=13.2Hz,0.8H),4.30-4.23(m ,0.2H),4.14-4.05(m,1H),3.94(s,3H),3.73-3.63(m,1H),3.45-3.17(m,2H),2.39(s,2H),2.28(s,1H).

[0565] ESI-MS m / z:669.2[M+H] +

[0566] Example 15 (E)-1-((1 3 R)-3 6 -methoxy-5,5-dioxo-6 4 -(Trifluoromethyl)-7-oxa-5-thia-4-aza-2(4,6)-quinazoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 Synthesis of 1,4-dione-2-pentyl)pent-2-ene

[0567] According to the synthesis method from step 4 to step 7 of Example 14, the compound f of Example 14 was replaced by the compound b of Example 15, and the other operations were the same to obtain (E)-1-((1 3 R)-3 6 -methoxy-5,5-dioxo-6 4 -(Trifluoromethyl)-7-oxa-5-thia-4-aza-2(4,6)-quinazoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 -yl)pent-2-ene-1,4-dione.

[0568] Its structural characterization is as follows: 1 H NMR(400MHz,DMSO-d6)δppm 8.74(s,1H),8.41(s,1H),8.27-8.07(m,4H),7.90(d,J=8.8Hz,1H),7.67-7.58(m,1H ),7.52-7.40(m,2H),6.95-6.80(m,1H),5.57-5.37(m,1H),5.35-5.22(m,1H),5.20-5 .04(m,1H),4.99-4.85(m,1H),4.76-4.67(m,1H),4.37-4.15(m,1H),4.05(d,J=8.8Hz ,1H),3.97(s,3H),3.70(t,J=13.2Hz,1H),3.55(d,J=13.6Hz,1H),2.44-2.28(m,3H).

[0569] ESI-MS m / z:669.2[M+H] +

[0570] Example 16 (E)-1-((1 3 S)-6 3 -Fluoro-3 6 -Methoxy-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinazoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 Synthesis of 1,4-dione-2-pentyl)pent-2-ene

[0571] According to the synthetic method from step 1 to step 5 of Example 6, the compound a of Example 6 was replaced by the compound a of Example 16, and the compound d of Example 6 was replaced by the compound d of Example 16. The other operations were the same to obtain (E)-1-((1 3 S)-63-Fluoro-3 6-Methoxy-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinazoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 -yl)pent-2-ene-1,4-dione.

[0572] Its structural characterization is as follows: 1 H NMR(400MHz,DMSO-d6)δ10.25(s,1H),8.88(s,1H),8.64(s,1H),8.48-8.41(m ,3H),7.87(d,J=8.0Hz,1H),7.88(d,J=8.0Hz,1H),7.67-7.59(m,1H),7.46-7 .43(m,2H),6.70-6.66(m,1H),5.23-5.13(m,1.8H),4.70-4.56(m,2.2H),4.2 9-1.08(m,3H),3.89(s,3H),3.89-3.17(m,2H),2.36(s,2.2H),2.2(s,0.8H).

[0573] ESI-MS m / z:619.2[M+H] +

[0574] Example 17 (E)-1-((1 3 S)-6 5 -Fluoro-3 6 -Methoxy-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinazoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 Synthesis of 1,4-dione-2-pentyl)pent-2-ene

[0575] According to the synthetic method from step 1 to step 5 of Example 6, the compound a of Example 6 was replaced by the compound a of Example 17, and the compound d of Example 6 was replaced by the compound d of Example 17. The other operations were the same to obtain (E)-1-((1 3 S)-6 5 -Fluoro-3 6 -Methoxy-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinazoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 -yl)pent-2-ene-1,4-dione.

[0576] Its structural characterization is as follows: 1H NMR (400MHz, DMSO-d6) δ10.17(s,1H),8.76(s,1H),8.44(s,1H),8.29-8.14(m,3H),7.94(d,J=8.0 Hz,1H),7.86-7.83(m,1H),7.49-7.46(m,3H),6.75-6.71(m,1H),5.31-5.26(m,1H),5.08-5.05(m, 0.8H),4.81-4.73(m,1.2H),4.56-4.53(m,0.2H),4.32-4.28(m,1.8H),3.93(s,3H),3.93-3.84(m ,1H),3.58(t,J=12.0Hz,1H),3.35-3.32(m,1H),3.12-2.99(m,1H),2.37(s,2.3H),2.26(s,0.7H).

[0577] ESI-MS m / z:619.2[M+H] +

[0578] Example 18 (E)-1-((1 3 R)-6 5 -Fluoro-3 6 -Methoxy-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinazoline-1(1,3)-piperazine-3(3,5),6(4,3)-bipyridinecyclooctane-1 4 Synthesis of 1,4-dione-2-pentyl)pent-2-ene

[0579] Step 1. Synthesis of compound b

[0580] Compound a (500 mg, 2.58 mmol) was dissolved in 4 mL of THF. Under nitrogen, n-butyllithium (1.9 mL, 3.10 mmol, 1.6 M in n-hexane) was added dropwise at -70°C. Stirring was continued at -70°C for 0.5 h. Sulfur dioxide gas was then introduced, and the mixture was allowed to return to room temperature for 2 h. The reaction solution was then concentrated under reduced pressure, and the resulting residue was dispersed in 10 mL of DCM. NBS (641 mg, 3.60 mmol) was added to the reaction solution in portions. After completion of the reaction, the mixture was extracted with water and DCM, dried over anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure to yield crude compound b.

[0581] Its structural characterization is as follows: ESI-MS m / z: 257.9 [M+H] + .

[0582] Step 2 to Step 6, (E)-1-((1 3 R)-65 -Fluoro-3 6 -Methoxy-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinazoline-1(1,3)-piperazine-3(3,5),6(4,3)-bipyridinecyclooctane-1 4 Synthesis of 1,4-dione-2-pentyl)pent-2-ene

[0583] According to the synthesis method from step 1 to step 5 of Example 6, the compound a of Example 6 was replaced by the compound b of Example 18, and the other operations were the same to obtain (E)-1-((1 3 R)-6 5 -Fluoro-3 6 -Methoxy-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinazoline-1(1,3)-piperazine-3(3,5),6(4,3)-bipyridinecyclooctane-1 4 -yl)pent-2-ene-1,4-dione.

[0584] Its structural characterization is as follows: 1 H NMR(400MHz,DMSO-d6)δppm 10.75(s,1H),8.72-8.63(m,2H),8.47-8.35(m,1H),8.23-8.12(m,3H),7.95-7.93(m,2H),7.45(d,J= 15.6Hz,1H),6.73(d,J=15.6Hz,1H),5.53-5.31(m,1H),5.08-5.07(m,0.8H),4.93-4.74(m,1H),4.73- 4.61(m,0.2H),4.60-4.49(m,0.2H),4.44-4.32(m,1H),4.31-4.21(m,1H),4.17-4.00(m,0.8H),3.99 -3.84(s,3H),3.61-3.54(m,1H),3.40-3.31(m,1H),3.16-3.05(m,1H),2.37(s,2.5H),2.29(s,0.5H).

[0585] ESI-MS m / z:620.2[M+H] + .

[0586] Example 19 (E)-1-((1 3 R)-3 6 -Methoxy-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinazoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,4)-phenylcyclooctane-1 4Synthesis of 1,4-dione-2-pentyl)pent-2-ene

[0587] According to the synthesis method from step 1 to step 5 of Example 6, the compound a of Example 6 was replaced by the compound a of Example 19, and the other operations were the same to obtain (E)-1-((1 3 R)-3 6 -Methoxy-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinazoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,4)-phenylcyclooctane-1 4 -yl)pent-2-ene-1,4-dione.

[0588] Its structural characterization is as follows: 1 H NMR(400MHz,DMSO-d6)δppm 9.79-9.67(m,1H),8.85(s,1H),8.54(s,1H),8.36(s,1H),7.96-9.87(m,2H),7.60-7.05(m,5H),7.00-6.70(m,2H),5.03-4.67(m,2 H),4.61-4.39(m,1H),4.40-4.13(m,2H),4.03-4.00(m,3H),3.94-3.81(m,2H),3.62-3.58(m,1H),3.11-3.05(m,1H),2.42(s,3H).

[0589] ESI-MS m / z:601.2[M+H] + .

[0590] Example 20 (E)-1-(((1 3 S)-3 6 -methoxy-6 4 -methyl-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinazoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 Synthesis of (-)pent-2-ene-1,4-dione

[0591] According to the synthesis method from step 1 to step 5 of Example 6, the compounds a and d of Example 6 were replaced by compounds a and d of Example 20, respectively, and the other operations were the same to obtain (E)-1-(((1 3 S)-3 6 -methoxy-6 4-methyl-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinazoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 -yl)pent-2-ene-1,4-dione.

[0592] Its structural characterization is as follows: 1H NMR (400 MHz, DMSO-d6) δ ppm 10.00 (s, 1H), 8.77 (s, 1H), 8.38-8.14 (m, 4H), 7.94 (d, J = 8.0 Hz, 1H), 7.85 (d, J = 8.0 Hz, 1H), 7.51-7.47 (m, 1H), 7.30-7.24 (m, 1H), 7.00 (d, J = 8 Hz, 1H), 6.76 (d, J = 16 Hz, 1H), 5.36-5.25 (m, 1H), 5.07 (d, J = 8.0 Hz, 1H), 4.87-4.56 (m, 2H), 4.40-4.30 (m,2H),3.91-3.85(m,4H),3.62(t,J=12Hz,1H),3.11(t,J=12Hz,1H),2.39(s,2.2H),2.28-2.25(m,3.8H).

[0593] ESI-MS m / z:615.2[M+H] + .

[0594] Example 21 (E)-1-((1 3 S)-6 6 -Cyano-3 6 -Methoxy-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinazoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 Synthesis of 1,4-dione-2-pentyl)pent-2-ene

[0595] According to the synthetic method from step 1 to step 7 of Example 14, the compound a in step 1 of Example 14 was replaced by the compound a in Example 21, and the benzyl mercaptan was replaced by 4-methoxybenzyl mercaptan. The other operations were the same to obtain (E)-1-((1 3 S)-6 6 -Cyano-3 6 -Methoxy-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinazoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 -yl)pent-2-ene-1,4-dione.

[0596] Its structural characterization is as follows: 1 H NMR(400MHz,Methanol-d4)δppm 8.79(s,1H),8.37(d,J=2.4Hz,1H),8.28-8.23(m,1H),8.22(s,1H),8.16(s,1H) ,7.97-7.89(m,1H),7.70-7.55(m,3H),7.54-7.42(m,1H),6.99-6.82(m,1H),5.5 3-5.15(m,3H),5.07-4.92(m,1H),4.44-4.32(m,0.7H),4.20(s,0.3H),4.11-4. 04(m,1H),4.02(s,3H),3.86-3.64(m,2H),3.44-3.34(m,1H),2.42-2.35(m,3H).

[0597] ESI-MS m / z:626.2[M+H] + .

[0598] Example 22 (E)-1-((1 3 R)-6 6 -Cyano-3 6 -Methoxy-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinazoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 Synthesis of 1,4-dione-2-pentyl)pent-2-ene

[0599] According to the synthesis method from step 4 to step 7 of Example 21, the compound f in step 1 of Example 21 was replaced by the compound b in Example 22, and the other operations were the same to obtain (E)-1-((1 3 R)-6 6 -Cyano-3 6 -Methoxy-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinazoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 -yl)pent-2-ene-1,4-dione.

[0600] Its structural characterization is as follows: 1H NMR (400 MHz, Methanol-d4) δ ppm 8.82 (s, 1H), 8.37 (d, J = 2.0 Hz, 1H), 8.34-8.27 (m, 1H), 8.25 (s, 1H), 8.17 (s, 1H), 7.96-7.88 (m, 1H), 7.74-7.54 (m, 3H), 7.54-7.38 (m, 1H), 7.01-6.82 (m, 1H), 5.54-5.37 (m, 1H), 5.38-5.24 (m, 1 .8H),5.24-5.10(m,1H),5.07-4.96(m,0.2H),4.48-4.34(m,0.8H),4.29-4.18(m,0.2H),4.15- 4.06(m,1H),4.02(s,3H),3.92-3.81(m,1H),3.81-3.67(m,1H),3.53-3.40(m,1H),2.40(s,3H).

[0601] ESI-MS m / z:626.2[M+H] + .

[0602] Example 23 (E)-1-((1 3 R)-6 5 -Cyano-3 6 -Methoxy-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinazoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 Synthesis of 1,4-dione-2-pentyl)pent-2-ene

[0603] According to the synthetic method from step 1 to step 5 of Example 6, the compound a of Example 6 was replaced by the compound a of Example 23, and the compound d of Example 6 was replaced by the compound d of Example 23. The other operations were the same to obtain (E)-1-((1 3 R)-6 5 -Cyano-3 6 -Methoxy-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinazoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 -yl)pent-2-ene-1,4-dione.

[0604] Its structural characterization is as follows: 1H NMR (400MHz, DMSO-d6) δ10.32(s,1H),8.82(s,1H),8.57-8.48(m,1H),8.37-8.21(m,3H),8.13-8.05(m,1H),8.02(s,1H ),7.96(d,J=8.8Hz,1H),7.71-7.59(m,1H),7.49(d,J=15.6Hz,1H),6.81-6.71(m,1H),5.53-5.32(m,1H),5.15-5.05(m, 0.76H),4.92-4.68(m,1.24H),4.63(d,J=14.8Hz,0.25H),4.51(d,J=12.4Hz,1H),4.36(d,J=13.2Hz,0.75H),4.31-4.23 (m,0.21H),4.12(d,J=9.6Hz,0.79H),3.97(s,3H),3.67-3.47(m,2H),3.21-3.02(m,1H),2.40(s,2.2H),2.30(s,0.8H).

[0605] ESI-MS m / z:626.2[M+H] +

[0606] Example 24 (E)-1-((1 3 S)-6 6 -Trifluoromethyl-3 6 -Methoxy-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinazoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 Synthesis of 1,4-dione-2-pentyl)pent-2-ene

[0607] According to the synthetic method from step 1 to step 7 of Example 14, the compound a in step 1 of Example 14 was replaced by the compound a in Example 24, and the other operations were the same to obtain (E)-1-((1 3 S)-6 6 -Trifluoromethyl-3 6 -Methoxy-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinazoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 -yl)pent-2-ene-1,4-dione.

[0608] Its structural characterization is as follows: 1H NMR (400 MHz, DMSO-d6) δ ppm 9.42(s,1H),8.83(s,1H),8.44(s,1H),8.38-8.23(m,3H),8.03-7.93(m,1H ),7.87-7.65(m,3H),7.53-7.36(m,1H),6.76-6.59(m,1H),5.50-5.33(m,1H ),5.24-5.13(m,0.7H),5.03-4.74(m,1.3H),4.69-4.27(m,2H),3.94-3.79( m,4H),3.65-3.49(m,2H),3.25-3.06(m,1H),2.38(s,2.2H),2.26(s,0.8H).

[0609] ESI-MS m / z:669.2[M+H] + .

[0610] Example 25 (E)-1-((1 3 R)-6 6 -Trifluoromethyl-3 6 -Methoxy-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinazoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 Synthesis of 1,4-dione-2-pentyl)pent-2-ene

[0611] According to the synthesis method from step 4 to step 7 of Example 24, the compound f of step 4 of Example 24 was replaced by the compound b of Example 25, and the other operations were the same to obtain (E)-1-((1 3 R)-6 6 -Trifluoromethyl-3 6 -Methoxy-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinazoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 -yl)pent-2-ene-1,4-dione.

[0612] Its structural characterization is as follows: 1H NMR(400MHz,DMSO-d6)δppm 9.38(s,1H),8.79(s,1H),8.45(s,1H),8.39-8.17(m,3H),8.01-7.92(m, 1H),7.87-7.66(m,3H),7.54-7.35(m,1H),6.78-6.57(m,1H),5.54-5.31 (m,1H),5.23-5.11(m,0.7H),4.97-4.72(m,1H),4.62-4.51(m,0.3H),4.45-4.25(m,1.7H),4.10-3. 98(m,0.3H),3.93-3.79(m,4H),3.65-3.49(m,1H),3.24-2.88(m,2H),2.38(s,2.2H),2.24(s,0.8H).

[0613] ESI-MS m / z:669.2[M+H] +

[0614] Example 26 (E)-1-((1 3 S)-6 4 -Cyano-6 6 -Fluoro-3 6 -Methoxy-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinazoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 Synthesis of 1,4-dione-2-pentyl)pent-2-ene

[0615] Step 1. Synthesis of compound b

[0616] Compound a (200 mg, 1.27 mmol) was dissolved in 5 mL of DMF, and potassium carbonate (351 mg, 2.54 mmol) and 4-methoxybenzylmercaptan (205 mg, 1.33 mmol) were added. The mixture was stirred at room temperature for 6 h. After the reaction was complete, the mixture was concentrated under reduced pressure and purified by silica gel column chromatography to obtain compound c (320 mg, 1.1 mmol, 86% yield).

[0617] Its structural characterization is as follows: ESI-MS m / z: 292.1[M+H] + .

[0618] Steps 2 to 7, (E)-1-((1 3 S)-6 4 -Cyano-6 6 -Fluoro-3 6-Methoxy-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinazoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 Synthesis of 1,4-dione-2-pentyl)pent-2-ene

[0619] According to the synthetic method from step 2 to step 7 of Example 14, the compound b of step 2 of Example was replaced by compound b of Example 26, and the other operations were the same to obtain (E)-1-((1 3 S)-6 4 -Cyano-6 6 -Fluoro-3 6 -Methoxy-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinazoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 -yl)pent-2-ene-1,4-dione.

[0620] Its structural characterization is as follows: 1 H NMR(400MHz,DMSO-d6)δ10.65(s,1H),8.77(s,1H),8.31-8.10(m,3H),8.01-7.88(m,2.2H),7.82(s,0.8H) ,7.67(d,J=10Hz,1H),7.51(d,J=15.6Hz,1H),6.78(d,J=15.6Hz,1H),5.54-5.28(m,1H),5.11(d,J=10.0H z,0.8H),4.95-4.78(m,1H),4.65-4.57(m,0.2H),4.48-4.29(m,1.8H),4.24-4.09(m,0.2H),4.04-3.97(m ,1H),3.93(s,3H),3.69-3.58(m,1H),3.42-3.34(m,1H),3.17-2.93(m,1H),2.41(s,2.3H),2.33(s,0.7H).

[0621] ESI-MS m / z:644.2[M+H] + .

[0622] Example 27 (E)-1-((1 3 S)-6 3 ,6 4 -Difluoro-3 6-Methoxy-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinazoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 Synthesis of (-)pent-2-ene-1,4-dione

[0623] According to the synthesis method from step 1 to step 5 of Example 6, the compounds a and d of Example 6 were replaced by compounds a and d of Example 27, respectively, and the other operations were the same to obtain (E)-1-((1 3 S)-6 3 ,6 4 -Difluoro-3 6 -Methoxy-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinazoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 -yl)pent-2-ene-1,4-dione.

[0624] Its structural characterization is as follows: 1 H NMR(400MHz,DMSO-d6)δppm 10.29(s,1H),8.84(s,1H),8.70-8.65(m,1H),8.42-8.38(m,3H),7.99-7.92(m ,2H),7.68-7.59(s,1H),7.47-7.48-7.37(m,1H),6.71-6.54(m,1H),5.36-5.3 0(m,1H),5.10(d,J=8.0Hz,0.7H),4.64-4.52(m,2H),4.28-4.24(m,1.3H),4.0 3-3.90(m,4H),3.60-3.53(m,1H),3.21-3.01(m,2H),2.36(s,2H),2.23(m,1H).

[0625] ESI-MS m / z:637.2[M+H] + .

[0626] Example 28 (E)-1-((1 3 S)-3 6 -methoxy-5,5-dioxo-6 4 -(Trifluoromethoxy)-7-oxa-5-thia-4-aza-2(4,6)-quinazoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 Synthesis of (-)pent-2-ene-1,4-dione

[0627] According to the synthesis method from step 1 to step 7 of Example 14, the compound a of Example 14 was replaced by compound a, and the other operations were the same to obtain (E)-1-((1 3 S)-3 6 -methoxy-5,5-dioxo-6 4 -(Trifluoromethoxy)-7-oxa-5-thia-4-aza-2(4,6)-quinazoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 -yl)pent-2-ene-1,4-dione.

[0628] Its structural characterization is as follows: 1H NMR (400MHz, DMSO-d6) δppm 10.31 (s, 1H), 8.78 (s, 1H), 8.37-8.23 (m, 3H), 8.17-8.09 (m, 2H), 7.97-7.94 (m, 1H), 7.52-7.46 (m, 2H), 7.27 (d, J = 8 Hz, 1H), 6.77 (d, J = 8 Hz, 1H), 5.46-5.33(m,1H),5.10-5.07(m,1H),4.86-4.58(m,1.7H),4.40-4.31(m,2H),4.16-4.12(m,0. 3H),3.99-3.94(m,4H),3.62(t,J=12Hz,1H),3.15-3.09(m,1H),2.40(s,2.4H),2.28(m,0.6H).

[0629] ESI-MS m / z:685.2[M+H] + .

[0630] Example 29 (S,E)-1-(6 4 -Fluoro-3 6 -Methoxy-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinazoline-1(1,2)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 Synthesis of 1,4-dione-2-pentyl)pent-2-ene

[0631] Step 1. Synthesis of compound b

[0632] Compound a (600 mg, 3.0 mmol) was dissolved in 25 mL of DCM, and DIEA (620 mg, 5.0 mmol) and TBSCl (600 mg, 5.6 mmol) were added. The mixture was allowed to react at room temperature for 1 h. After completion of the reaction, the mixture was extracted with water and DCM, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified on a silica gel column to afford compound b (934 mg, 2.8 mmol, 93% yield).

[0633] Its structural characterization is as follows: ESI-MS m / z: 331.2[M+H] + .

[0634] Step 2: Synthesis of Compound d

[0635] Compound b (600 mg, 2.5 mmol) was dissolved in DCM (25 mL) at room temperature, and DIEA (620 mg, 5.0 mmol) and compound c (935 mg, 2.8 mmol) were added. The mixture was stirred at room temperature for 1 h. After the reaction was complete, water and DCM were added for extraction. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified on a silica gel column to afford compound d (902 mg, 1.7 mmol, 68% yield).

[0636] Its structural characterization is as follows: ESI-MS m / z: 537.2, 539.2 [M+H] + .

[0637] Step 3. Synthesis of compound f

[0638] Compound d (900 mg, 1.7 mmol) and Pd(dppf)Cl2 (122 mg, 0.17 mmol) were dissolved in THF / water (18 mL / 4 mL), and compound e (693 mg, 1.9 mmol) and potassium carbonate (695 mg, 5.1 mmol) were added. Stirring was performed at 80°C for 2 h under nitrogen. After completion of the reaction, the mixture was extracted with water and EA, dried over anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure. Reverse-phase MPLC purification afforded solid compound f (803 mg, 1.1 mmol, 65% yield).

[0639] Its structural characterization is as follows: ESI-MS m / z: 757.3[M+H] + .

[0640] Step 4. Synthesis of compound g

[0641] Compound f (800 mg, 1.1 mmol) was dissolved in 18 mL of THF, and tetrabutylammonium fluoride (820 mg, 3.3 mmol) was added. The mixture was stirred at room temperature for 2 h. After completion of the reaction, the organic phase was concentrated under reduced pressure and purified by column chromatography to afford solid compound g (601 mg, 0.93 mmol, 85% yield).

[0642] Its structural characterization is as follows: ESI-MS m / z: 643.2[M+H] + .

[0643] Step 5. Synthesis of compound h

[0644] Compound g (600 mg, 0.93 mmol) was dissolved in 20 mL of THF, and sodium hydride (150 mg, 3.7 mmol) was added. The mixture was stirred at 50°C for 2 h. The mixture was then quenched with 100 μL of TFA in an ice bath, concentrated under reduced pressure, and purified by column chromatography to afford compound h (299 mg, 0.45 mmol, 55% yield).

[0645] Its structural characterization is as follows: ESI-MS m / z: 623.2[M+H] + .

[0646] Step 6. Synthesis of Compound I

[0647] Compound h (299 mg, 0.45 mmol) was dissolved in DCM (5 mL) at room temperature, TFA (2 mL) was added and stirred for 30 min. After the reaction was complete, the mixture was concentrated under reduced pressure to give crude compound i (251 mg).

[0648] Its structural characterization is as follows: ESI-MS m / z: 523.2[M+H] + .

[0649] Step 7, (S, E)-1-(6 4 -Fluoro-3 6 -Methoxy-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinazoline-1(1,2)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 Synthesis of 1,4-dione-2-pentyl)pent-2-ene

[0650] Crude compounds i (250 mg) and j (53.5 mg, 0.5 mmol) were dissolved in THF (8 mL) at room temperature. DIEA (196.4 mg, 1.75 mmol) was added to the reaction solution, followed by 1-propylphosphoric anhydride (483.6 mg, 0.76 mmol, 50%). After the reaction was complete, the mixture was concentrated under reduced pressure and then purified by high pressure liquid chromatography (method 1) to obtain ((S,E)-1-(6 4 -Fluoro-3 6 -Methoxy-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinazoline-1(1,2)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4-yl)pent-2-ene-1,4-dione (59 mg, 0.11 mmol, 25% yield over two steps).

[0651] Its structural characterization is as follows: 1 H NMR(400MHz,MeOD-d4)δppm 10.11(s,1H),8.67(s,1H),8.50-8.39(m,1H),8.27(s,1H),8.24-8.04(m,3H),7.87(d,J=8.8Hz,1H), 7.51-7.26(m,2H),7.17-7.04(m,1H),6.77(d,J=15.6Hz,0.68H),6.56(d,J=15.6Hz,0.32H),5.22-5. 09(m,1H),5.06-4.78(m,2H),4.74-4.59(m,1H),4.50(d,J=8.8Hz,1H),4.31(d,J=12.0Hz,0.68H),4. 04(d,J=14.8Hz,0.32H),3.94(s,3H),3.73-3.48(m,2H),3.26-3.20(m,1H),2.39(s,2H),1.98(s,1H).

[0652] ESI-MS m / z:619.2[M+H] +

[0653] Example 30 (R,E)-1-(6 4 -Fluoro-3 6 -Methoxy-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinazoline-1(1,2)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 Synthesis of 1,4-dione-2-pentyl)pent-2-ene

[0654] According to the synthetic method from step 1 to step 7 of Example 29, the compound a of Example 29 was replaced by the compound a of Example 30, and the other operations were the same to obtain (R, E)-1-(6 4 -Fluoro-3 6 -Methoxy-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinazoline-1(1,2)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 -yl)pent-2-ene-1,4-dione.

[0655] Its structural characterization is as follows: 1H NMR(400MHz,DMSO-d6)δppm 10.11(s,1H),8.67(s,1H),8.50-8.39(m,1H),8.27(s,1H),8.24-8.04(m,3H),7.87(d,J =8.8Hz,1H),7.51-7.26(m,2H),7.17-7.04(m,1H),6.82-6.50(m,1H),5.22-5.09(m,1H), 5.06-4.78(m,2H),4.74-4.59(m,1H),4.55-4.38(m,1H),4.35-4.21(m,0.7H),4.08-3.99 (m,0.30H),3.94(s,3H),3.78-3.44(m,2H),3.26-3.12(m,1H),2.39(s,2H),1.98(s,1H).

[0656] ESI-MS m / z:619.2[M+H] + .

[0657] Example 31 (E)-1-(6 4 -Fluoro-3 6 -Methoxy-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinazoline-1(1,2)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 Synthesis of 1,4-dione-2-pentyl)pent-2-ene

[0658] According to the synthetic method from step 1 to step 7 of Example 29, the compound a of Example 29 was replaced by the compound a of Example 31, and the other operations were the same to obtain (E)-1-(6 4 -Fluoro-3 6 -Methoxy-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinazoline-1(1,2)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 -yl)pent-2-ene-1,4-dione.

[0659] Its structural characterization is as follows: 1H NMR(400MHz,MeOD-d4)δppm 10.16(s,0.68H),10.09(s,0.32H),8.67(s,1H),8.50-8.39(m,1H),8.27(s,1H),8.24-8.04(m,3H),7.87(d,J=8.8Hz, 1H),7.51-7.26(m,2H),7.17-7.04(m,1H),6.78(d,J=15.6Hz,0.7H),6.57(d,J=15.6Hz,0.3H),5.22-5.09(m,1H),5.05 (d,J=13.6Hz,0.3H),4.99-4.88(m,1H),4.83(t,J=9.6Hz,0.7H),4.74-4.59(m,1H),4.50(d,J=8.8Hz,1H),4.31(d,J= 12.0Hz,0.7H),4.04(d,J=14.8Hz,0.3H),3.94(s,3H),3.73-3.48(m,2H),3.26-3.20(m,1H),2.39(s,2H),1.98(s,1H).

[0660] ESI-MS m / z:619.2[M+H] + .

[0661] Example 32 (R,E)-1-(6 4 -Fluoro-3 6 -Methoxy-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinazoline-1(1,2)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclononane-1 4 Synthesis of 1,4-dione-2-pentyl)pent-2-ene

[0662] According to the synthetic method from step 1 to step 5 of Example 1, the compound b of Example 1 was replaced by the compound b of Example 32, and the other operations were the same to obtain (R, E)-1-(6 4 -Fluoro-3 6 -Methoxy-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinazoline-1(1,2)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclononane-1 4 -yl)pent-2-ene-1,4-dione.

[0663] Its structural characterization is as follows: 1H NMR(400MHz,DMSO-d6)δppm 10.07-10.05(m,1H),8.79(s,1H),8.47-8.41(m,1H),8.39-8.28(m,2H),8.12(s,1H),8.11-8.02(m,1H),7.94-7 .92(m,1H),7.54-7.29(m,2H),7.26-7.13(m,1H),6.79-6.71(m,1H),4.86-4.80(m,1H),4.74-4.70(m,1H),4.62 -4.47(m,1H),4.47-4.32(m,1H),4.31-4.13(m,1.6H),4.11-3.99(m,0.4H),3.93(s,3H),3.72-3.58(m,0.7H),3 .57-3.46(m,1.3H),3.46-3.38(m,1H),2.98-2.81(m,0.7H),2.72-2.57(m,1.3H),2.39(s,1.8H),2.33(s,1.2H).

[0664] ESI-MS m / z:633.2[M+H] + .

[0665] Example 33 (S,E)-1-(6 4 -Fluoro-3 6 -Methoxy-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinazoline-1(1,2)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclononane-1 4 Synthesis of 1,4-dione-2-pentyl)pent-2-ene

[0666] According to the synthetic method from step 1 to step 5 of Example 1, the compound b of Example 1 was replaced by the compound b of Example 33, and the other operations were the same to obtain (S,E)-1-(6 4 -Fluoro-3 6 -Methoxy-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinazoline-1(1,2)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclononane-1 4 -yl)pent-2-ene-1,4-dione.

[0667] Its structural characterization is as follows: 1H NMR(400MHz,DMSO-d6)δppm 10.07-10.04(m,1H),8.75(s,1H),8.49-8.39(m,1H),8.40-8.26(m,2H),8.16-8.03(m,2H),7.96-7.88(m,1H),7.54-7.38 (m,1H),7.38-7.29(m,1H),7.26-7.14(m,1H),6.80-6.68(m,1H),4.84-4.76(m,1H),4.71-4.60(m,1H),4.60-4.46(m,1H), 4.46-4.31(m,1H),4.28-4.13(m,1.7H),4.13-4.01(m,0.3H),3.93(s,3H),3.72-3.58(m,0.7H),3.57-3. 46(m,1.3H),3.46-3.38(m,1H),2.98-2.81(m,0.7H),2.72-2.57(m,1.3H),2.39(s,1.8H),2.33(s,1.2H).

[0668] ESI-MS m / z:633.2[M+H] + .

[0669] Example 34 (E)-1-(5 5 -Fluorine-1 6 -methoxy-6,6-dioxo-6-thia-7-aza-2(6,4)-quinazoline-3(1,3)-piperazine-1(3,5)-pyridine-5(1,2)-phencycloheptan-3 4 Synthesis of 1,4-dione-2-pentyl)pent-2-ene

[0670] Step 1. Synthesis of compound c

[0671] Compound a (5.0 g, 18.9 mmol) was dissolved in THF (100 mL) at room temperature. Water (50 mL), potassium hydroxide (2.36 g, 13.9 mmol), tetrabutylammonium iodide (7.0 g, 18.9 mmol), and compound b (5.6 g, 18.9 mmol) were added under ice-cooling. Stir at room temperature for 5 h. Extraction was performed with EA and water. The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain compound c (6.45 g, 13.4 mmol, 71% yield).

[0672] Its structural characterization is as follows: ESI-MS m / z: 482.1, 484.1 [M+H] + .

[0673] Step 2: Synthesis of Compound d

[0674] Dissolve compound c (6.45 g, 13.4 mmol) in 50 mL of 1,4-dioxane at room temperature. Add 50 mL of 1,4-dioxane hydrochloric acid solution. Heat to 50°C and stir for 4 hours. Concentrate under reduced pressure to obtain the hydrochloride salt of compound d, which is used directly in the next reaction.

[0675] Its structural characterization is as follows: ESI-MS m / z: 262.0, 264.0 [M+H] + .

[0676] Step 3. Synthesis of compound e

[0677] Compound d (3.5 g, 13.4 mmol) was dissolved in 40 mL of THF. Water (20 mL), potassium hydroxide (1.13 g, 20 mmol), and di-tert-butyl dicarbonate (3.51 g, 16.1 mmol) were added under ice-cooling. The mixture was stirred at room temperature for 2 h. The pH was adjusted to approximately 3 with dilute hydrochloric acid. The mixture was extracted with EA and water. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Purification by reverse-phase MPLC afforded compound e (3.43 g, 9.5 mmol, 71% yield over two steps).

[0678] Its structural characterization is as follows: ESI-MS m / z: 362.0, 364.0 [M+H] + .

[0679] Step 4. Synthesis of compound g

[0680] Compound e (3.43 g, 9.5 mmol) was dissolved in DCM (50 mL), and EDCI (2.72 g, 14.3 mmol), HOBT (1.41 g, 10.5 mmol), DIEA (3.68 g, 28.5 mmol), and compound f (1.01 g, 11.4 mmol) were added. The mixture was allowed to react overnight at room temperature. The mixture was extracted with DCM and water, and the combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to afford compound g (2.79 g, 6.46 mmol, 68% yield).

[0681] Its structural characterization is as follows: ESI-MS m / z: 433.1, 435.1 [M+H] + .

[0682] Step 5. Synthesis of compound h

[0683] Dissolve compound g (2.79 g, 6.46 mmol) in DCM (20 mL) at room temperature, add TFA (10 mL), and stir at room temperature for 2 h. Concentrate under reduced pressure to obtain the TFA salt of compound h, which is used directly in the next reaction.

[0684] Its structural characterization is as follows: ESI-MS m / z: 333.0, 335.0 [M+H] + .

[0685] Step 6. Synthesis of Compound I

[0686] Compound h (2.9 g, 6.46 mmol) was dissolved in 1,4-dioxane (40 mL), and water (10 mL) and sodium bicarbonate (2.71 g, 32.3 mmol) were added. The mixture was stirred at 70°C for 5 h. The mixture was extracted with EA and water, and the combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to afford compound i (1.65 g, 5.49 mmol, 85% yield over two steps).

[0687] Its structural characterization is as follows: ESI-MS m / z: 300.1, 302.1 [M+H] + .

[0688] Step 7. Synthesis of Compound J

[0689] Dissolve compound i (1.65 g, 5.49 mmol) in 20 mL of THF and add borane dimethyl sulfide solution (5.49 mL, 54.9 mmol, 10 mol / L). Heat to 70°C and stir for 10 h. Add TFA (10 mL) dropwise in an ice bath and stir at room temperature for 30 minutes. Concentrate under reduced pressure and purify with a reverse-phase column to obtain compound j (1.33 g, 4.89 mmol, 89% yield).

[0690] Its structural characterization is as follows: ESI-MS m / z: 273.0, 275.0 [M+H] + .

[0691] Step 8. Synthesis of Compound K

[0692] Compound j (1.33 g, 4.89 mmol) was dissolved in 20 mL of DCM. Triethylamine (1.49 g, 14.7 mmol) and di-tert-butyl dicarbonate (2.35 g, 10.8 mmol) were added and reacted at room temperature for 2 h. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography to afford compound k (2.15 g, 4.55 mmol, 93% yield).

[0693] Its structural characterization is as follows: ESI-MS m / z: 473.1, 475.1 [M+H] + .

[0694] Step 9. Synthesis of Compound M

[0695] Compound k (1 g, 2.12 mmol) was dissolved in toluene (30 mL), and compound l (392 mg, 2.54 mmol), Xant-Phos (121 mg, 0.21 mmol), Pd2(dba)3 (192 mg, 0.21 mmol), and DIEA (547 mg, 4.24 mmol) were added. The atmosphere was replaced with nitrogen, and the mixture was heated to 100°C and stirred for 20 h. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography to obtain compound m (301 mg, 0.55 mmol, 26% yield).

[0696] Its structural characterization is as follows: ESI-MS m / z: 547.3[M+H] + .

[0697] Step 10. Synthesis of Compound n

[0698] Compound m (301 mg, 0.55 mmol) was dissolved in acetonitrile (20 mL), and glacial acetic acid (0.5 mL), water (0.5 mL), and dichlorohydantoin (163 mg, 0.83 mmol) were added. The mixture was stirred at room temperature for 2 h. Extraction was performed with EA and water. The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to afford compound n (173 mg, 0.35 mmol, 64% yield).

[0699] Its structural characterization is as follows: ESI-MS m / z: 493.2[M+H] + .

[0700] Step 11. Synthesis of Compound O

[0701] Compound S (129 mg, 0.35 mmol) was dissolved in pyridine (5 mL). Compound N (173 mg, 0.35 mmol) was added under ice-cooling and stirred at room temperature for 2 h. The mixture was extracted with EA and water. The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to afford Compound O (150 mg, 0.18 mmol, 52% yield).

[0702] Its structural characterization is as follows: ESI-MS m / z: 825.3[M+H] + .

[0703] Step 12: Synthesis of Compound P

[0704] Compound o (150 mg, 0.18 mmol) was dissolved in DCM (5 mL), and TFA (1 mL) was added. The mixture was stirred at room temperature for 2 h, concentrated under reduced pressure, and purified by reverse-phase MPLC to afford compound p (89 mg, 0.17 mmol, 94% yield).

[0705] Its structural characterization is as follows: ESI-MS m / z: 525.3[M+H] + .

[0706] Step 13. Synthesis of compound q

[0707] Compound p (89 mg, 0.17 mmol) was dissolved in 10 mL of acetonitrile, and DBU (78 mg, 0.51 mmol) and PyBOP (115 mg, 0.22 mmol) were added. The mixture was allowed to react at room temperature for 1 h. The mixture was extracted with EA and water, and the combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by reverse-phase chromatography to afford compound q (19 mg, 0.037 mmol, 22% yield).

[0708] Its structural characterization is as follows: ESI-MS m / z: 507.2[M+H] + .

[0709] Step 14, (E)-1-(5 5 -Fluorine-1 6 -methoxy-6,6-dioxo-6-thia-7-aza-2(6,4)-quinazoline-3(1,3)-piperazine-1(3,5)-pyridine-5(1,2)-phencycloheptan-3 4 Synthesis of 1,4-dione-2-pentyl)pent-2-ene

[0710] Compound q (19 mg, 0.037 mmol) was dissolved in THF (5 mL), and compound r (5 mg, 0.044 mmol) and DIEA (14 mg, 0.11 mmol) were added. The temperature was lowered to -78°C, and T3P (35 mg, 0.056 mmol, 50% EA solution) was added. The mixture was stirred at -78°C for 2 h. Water (15 mL) was added to quench the mixture, and the aqueous phase was extracted with EA. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The mixture was then purified by high pressure liquid chromatography (method 1) to obtain (E)-1-(5 5 -Fluorine-1 6 -methoxy-6,6-dioxo-6-thia-7-aza-2(6,4)-quinazoline-3(1,3)-piperazine-1(3,5)-pyridine-5(1,2)-phencycloheptan-3 4 -yl)pent-2-ene-1,4-dione (2.1 mg, 0.003 mmol, yield 9%).

[0711] Its structural characterization is as follows: 1H NMR(400MHz,MeOD-d4)δppm 8.52(s,1H),8.25(s,1H),8.13(d,J=8.4Hz,1H),8.05-7.95(m,2H),7.84-7.75(m,2H),7.50-7.40(m,2H),7.21(d,J=8.4Hz,1 H),6.86-6.84(m,1H),5.67-5.65(m,1H),4.91-4.86(m,1H),4.10(s,3H),3.97-3.65(m,6H),3.21-3.19(m,1H),2.43(s,3H).

[0712] ESI-MS m / z:603.2[M+H] + .

[0713] Example 35 (E)-1-(6 4 -Fluoro-3 6 -Methoxy-5,5-dioxo-5-thia-4-aza-2(4,6)-quinazoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 Synthesis of 1,4-dione-2-pentyl)pent-2-ene

[0714] Step 1. Synthesis of compound b

[0715] Dissolve compound a (3 g, 11.3 mmol) in toluene (40 mL) and add triphenylphosphine (3.1 g, 11.8 mmol). Heat to 100°C and stir for 12 h. Cool to room temperature, filter, collect the solid, and dry to obtain compound b (4.62 g, 10.3 mmol, 91% yield).

[0716] Its structural characterization is as follows: ESI-MS m / z: 449.1, 451.1 [M+H] + .

[0717] Step 2: Synthesis of Compound d

[0718] Dissolve compound c (2.0 g, 9.26 mmol) in 30 mL of THF. Add water (15 mL), sodium bicarbonate (1.56 g, 18.5 mmol), and benzyl chloroformate (2.36 g, 13.9 mmol) under ice-cooling. Stir at room temperature for 5 h. Extract with EA and water. Combine the organic phases, dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify by silica gel column chromatography to obtain compound d (2.89 g, 8.24 mmol, 89% yield).

[0719] Its structural characterization is as follows: ESI-MS m / z: 351.2[M+H] + .

[0720] Step 3. Synthesis of compound e

[0721] Compound d (2.89 g, 8.24 mmol) was dissolved in 30 mL of DCM and Dess-Martin reagent (5.24 g, 12.4 mmol) was added. Stir at room temperature for 2 h. The mixture was extracted with DCM and water. The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to afford compound e (1.92 g, 5.52 mmol, 67% yield).

[0722] Its structural characterization is as follows: ESI-MS m / z: 349.2[M+H] + .

[0723] Step 4. Synthesis of compound f

[0724] Compound b (2.48 g, 5.52 mmol) was dissolved in 30 mL of THF, and potassium tert-butoxide (742 mg, 6.62 mmol) was added. The mixture was stirred at room temperature for 1 hour under a nitrogen atmosphere. Compound e (1.92 g, 5.52 mmol) was dissolved in 10 mL of THF and added dropwise to the reaction mixture. The mixture was stirred at room temperature for 2 hours. The mixture was extracted with EA and water, and the combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to afford compound f (1.80 g, 3.48 mmol, 63% yield).

[0725] Its structural characterization is as follows: ESI-MS m / z: 519.1, 521.1 [M+H] + .

[0726] Step 5. Synthesis of compound h

[0727] Compound f (1.00 g, 1.93 mmol) was dissolved in toluene (30 mL), and compound g (446 mg, 2.90 mmol), Xant-Phos (110 mg, 0.19 mmol), Pd2(dba)3 (174 mg, 0.19 mmol), and DIEA (498 mg, 3.86 mmol) were added. The atmosphere was replaced with nitrogen, heated to 100°C, and stirred for 20 h. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography to obtain compound h (605 mg, 1.02 mmol, 53% yield).

[0728] Its structural characterization is as follows: ESI-MS m / z: 593.2[M+H] + .

[0729] Step 6. Synthesis of Compound I

[0730] Compound h (605 mg, 1.02 mmol) was dissolved in 20 mL of acetonitrile, and 0.5 mL of glacial acetic acid and 0.5 mL of water were added, along with dichlorohydantoin (301 mg, 1.53 mmol). The mixture was allowed to react at room temperature for 2 h. The mixture was extracted with EA and water, and the combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to afford compound i (335 mg, 0.62 mmol, 61% yield).

[0731] Its structural characterization is as follows: ESI-MS m / z: 539.1[M+H] + .

[0732] Step 7. Synthesis of compound K

[0733] Compound j (228 mg, 0.62 mmol) was dissolved in pyridine (10 mL). Compound i (335 mg, 0.62 mmol) was added under ice-cooling and stirred at room temperature for 2 h. The mixture was extracted with EA and water. The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to afford compound k (297 mg, 0.34 mmol, 55% yield).

[0734] Its structural characterization is as follows: ESI-MS m / z: 871.3[M+H] + .

[0735] Step 8. Synthesis of Compound 1

[0736] Compound k (297 mg, 0.34 mmol) was dissolved in DCM (5 mL), and TFA (1 mL) was added. The mixture was stirred at room temperature for 2 h, concentrated under reduced pressure, and purified by reverse-phase MPLC to afford compound 1 (207 mg, 0.31 mmol, 91% yield).

[0737] Its structural characterization is as follows: ESI-MS m / z: 671.3[M+H] + .

[0738] Step 9. Synthesis of Compound M

[0739] Compound 1 (207 mg, 0.31 mmol) was dissolved in ACN (10 mL), and DBU (141 mg, 0.93 mmol) and PyBOP (210 mg, 0.40 mmol) were added. The mixture was stirred at room temperature for 4 h. Extraction was performed with EA and water. The combined organic phases were filtered, concentrated under reduced pressure, and purified by reverse-phase MPLC to afford compound m (81 mg, 0.12 mmol, 40% yield).

[0740] Its structural characterization is as follows: ESI-MS m / z: 653.2[M+H] + .

[0741] Step 10. Synthesis of Compound n

[0742] Compound m (81 mg, 0.12 mmol) was dissolved in MeOH (10 mL) and 10% palladium on carbon (50 mg) was added. The mixture was replaced with hydrogen and stirred at room temperature for 4 h. The mixture was filtered, and the filtrate was concentrated under reduced pressure. Reverse-phase MPLC was used to purify compound n (56 mg, 0.11 mmol, 90% yield).

[0743] Its structural characterization is as follows: ESI-MS m / z: 521.2[M+H] + .

[0744] Step 11, (E)-1-(6 4 -Fluoro-3 6 -Methoxy-5,5-dioxo-5-thia-4-aza-2(4,6)-quinazoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-benzocyclooctane-1 4 Synthesis of 1,4-dione-2-pentyl)pent-2-ene

[0745] Compound n (56 mg, 0.11 mmol) was dissolved in THF (5 mL), compound o (15 mg, 0.13 mmol) and DIEA (43 mg, 0.33 mmol) were added, the temperature was lowered to -78 ° C, T3P (105 mg, 0.17 mmol, 50% EA solution) was added, and the mixture was stirred at -78 ° C for 2 h. Water (15 mL) was added to quench the mixture, the aqueous phase was extracted with EA, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and then purified by high pressure liquid chromatography to obtain (E)-1-(6 4 -Fluoro-3 6 -Methoxy-5,5-dioxo-5-thia-4-aza-2(4,6)-quinazoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-benzocyclooctane-1 4 -yl)pent-2-ene-1,4-dione (4.6 mg, 0.008 mmol, yield 7%).

[0746] Its structural characterization is as follows: 1H NMR (400 MHz, DMSO-d6) δ ppm 10.64(s,1H),8.74(s,1H),8.28(s,2H),8.05-8.00(m,3H),7.90(d,J=8.8H z,1H),7.52(d,J=16.0Hz,1H),7.41-7.27(m,2H),6.84-6.76(m,1H),5.03-5 .01(m,0.5H),4.67-4.61(m,0.5H),4.50-4.22(m,2H),4.01(s,3H),3.47-3 .29(m,4H),3.16-3.10(m,2H),2.72-2.61(m,2H),2.40(s,2H),2.36(s,1H).

[0747] ESI-MS m / z:617.2[M+H] + .

[0748] Example 36 (E)-1-(6 4 -Fluoro-3 6 -Methoxy-1 3 -methyl-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinazoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 Synthesis of 1,4-dione-2-pentyl)pent-2-ene

[0749] Step 1. Synthesis of compound b

[0750] Compound a (3.8 g, 11 mmol) was dissolved in 40 mL of anhydrous THF at room temperature. LiHMDS (22 mL, 22 mmol) was added at -70°C and stirred for 1 h. Iodomethane (2.06 mL, 33 mmol) was then added at -70°C and allowed to react for 4 h. After completion of the reaction, saturated aqueous ammonium chloride was added to quench the reaction. The mixture was extracted with EA, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified on a silica gel column to afford compound b (2.8 g, 8.1 mmol, 74% yield).

[0751] ESI-MS m / z:359.1[M+H] + .

[0752] Step 2: Synthesis of Compound C

[0753] Compound b (400 mg, 1.12 mmol) was dissolved in 5 mL of methanol at room temperature. Aqueous KOH (189 mg, 3.36 mmol) (5 mL) was added and the mixture was refluxed with stirring for 16 h. After the reaction was complete, the pH was adjusted to 2 with 1 M HCl. The mixture was extracted with EA, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford compound c (366 mg, 3.05 mmol, 95% yield).

[0754] Its structural characterization is as follows: ESI-MS m / z: 345.1[M+H] + .

[0755] Step 3. Synthesis of compound d

[0756] Dissolve compound c (366 mg, 1.05 mmol) in 3 mL of THF, and add borane dimethyl sulfide (900 μL, 15 mmol) to the reaction mixture. Heat to 60°C and stir under nitrogen for 5 h. After the reaction is complete, quench the reaction mixture by adding methanol dropwise over ice. Concentrate under reduced pressure at room temperature to obtain the crude product, which is used directly in the next step.

[0757] Its structural characterization is as follows: ESI-MS m / z: 331.1[M+H] + .

[0758] Step 4. Synthesis of compound e

[0759] Dissolve the crude product from the previous step in 2 mL of methanol, and add 2 mL of 4 M hydrochloric acid (EA) dropwise to the reaction mixture. Allow to react at room temperature for 1 h. Concentrate under reduced pressure at room temperature to obtain the crude product, which is used directly in the next step.

[0760] Its structural characterization is as follows: ESI-MS m / z: 131.1[M+H] + .

[0761] Step 5. Synthesis of compound g

[0762] The crude product from the previous step was dissolved in 2 mL of DCM at room temperature, and DIEA (320 μL, 1.82 mmol) and compound f (244 mg, 1.0 mmol) were added. Stirring was continued at room temperature for 24 hours. After completion of the reaction, the mixture was extracted with water and DCM. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified on a silica gel column to afford compound g (168 mg, 0.50 mmol, 46% yield over three steps).

[0763] Its structural characterization is as follows: ESI-MS m / z: 337.1, 339.1 [M+H] + .

[0764] Step 6. Synthesis of Compound I

[0765] Compound g (168 mg, 0.50 mmol), Pd(dppf)Cl2 (37 mg, 0.050 mmol), compound h (213 mg, 0.50 mmol), and K2CO3 (138 mg, 1.0 mmol) were dissolved in 1,4-dioxane / H2O (8 mL / 2 mL) at room temperature and stirred at 70°C under nitrogen for 4 h. The mixture was diluted with water, extracted with EA, and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure and purified by normal phase column chromatography to afford compound i (86 mg, 0.15 mmol, 30% yield).

[0766] Its structural characterization is as follows: ESI-MS m / z: 557.2[M+H] + .

[0767] Step 7. Synthesis of Compound J

[0768] Compound i (86 mg, 0.15 mmol) was dissolved in 4 mL of DMF at room temperature. Sodium hydride (60 mg, 1.5 mmol, 60%) was added portionwise to the reaction mixture. The mixture was heated to 60°C and stirred for 12 h under nitrogen. After completion, the reaction was quenched with ice water and concentrated under reduced pressure at room temperature to afford the crude product. This crude product was purified by reverse-phase MPLC to afford compound j (33 mg, 0.061 mmol, 41% yield).

[0769] Its structural characterization is as follows: ESI-MS m / z: 537.2[M+H] + .

[0770] Step 8, (E)-1-(6 4 -Fluoro-3 6 -Methoxy-1 3 -methyl-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinazoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 Synthesis of 1,4-dione-2-pentyl)pent-2-ene.

[0771] Compounds j (33 mg, 0.061 mmol) and k (10 mg, 0.088 mmol) were dissolved in pyridine (5 mL) at room temperature. EDCI (190 uL, 0.72 mmol) was added to the reaction solution in batches and stirred at room temperature for 2 h. After the reaction was complete, the mixture was concentrated under reduced pressure at room temperature and then purified by high pressure liquid chromatography (method 2) to obtain (E)-1-(6 4 -Fluoro-3 6 -Methoxy-1 3-methyl-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinazoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 -yl)pent-2-ene-1,4-dione (3 mg, 0.0047 mmol, yield 8%).

[0772] Its structural characterization is as follows: 1 H NMR(400MHz,MeOD-d4)δppm 8.65(s,1H),8.34(s,1H),8.21(s,1H),8.13-8.11(m,2H),8.04-8.00(m ,1H),7.92(d,J=8.8Hz,1H),7.41(d,J=15.6Hz,1H),7.09(d,J=10.0Hz, 1H),6.93-6.88(m,1H),6.80(d,J=16.0Hz,1H),5.12-4.73(m,2H),4.16 -4.07(m,2H),4.00(s,3H),4.00-3.92(m,4H),2.39(s,3H),1.89(s,3H).

[0773] ESI-MS m / z:633.2[M+H] + .

[0774] Example 37 (E)-1-((1 3 R,8R)-6 4 -Fluoro-3 6 -Methoxy-8-methyl-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinazoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 Synthesis of 1,4-dione-2-pentyl)pent-2-ene

[0775] Step 1. Synthesis of compound c

[0776] Compound a (5.0 g, 29.5 mmol) was dissolved in 50 mL of DCM, and a 30 mL aqueous solution of sodium bicarbonate (7.43 g, 88.4 mmol) was added. Compound b (4.33 g, 38.3 mmol) was added in an ice bath and allowed to react at room temperature for 4 h. The mixture was then extracted, and the aqueous phase was washed three times with DCM. The combined organic phases were dried over sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent, yielding the crude compound c, which was used directly in the next step.

[0777] Its structural characterization is as follows: ESI-MS m / z: 210.1[M+H] +

[0778] Step 2: Synthesis of Compound e

[0779] The crude compound c from the previous step was dissolved in 50 mL of n-butanol, and compound d (5.92 g, 35.4 mmol) and triethylamine (12.3 mL, 88.5 mmol, cooled to room temperature) were added. The mixture was stirred at 100°C for 16 h. The mixture was then cooled to room temperature and 100 mL of EA was added. A large amount of white solid precipitated, which was filtered and washed with water. The solid was collected to obtain compound e (5.2 g, 16.8 mmol, 57% yield over two steps).

[0780] Its structural characterization is as follows: ESI-MS m / z: 309.1[M+H] +

[0781] Step 3. Synthesis of compound f

[0782] Compound e (3.6 g, 11.7 mmol) was dissolved in 30 mL of THF at room temperature. Borane dimethyl sulfide (5.4 mL, 90 mmol) was added to the reaction mixture. The mixture was heated to 60°C and stirred for 5 h under nitrogen. After the reaction was complete, the mixture was quenched by adding methanol and concentrated under reduced pressure at room temperature to obtain the crude product, which was used directly in the next step.

[0783] Its structural characterization is as follows: ESI-MS m / z: 281.2[M+H] +

[0784] Step 4. Synthesis of compound g

[0785] The above crude product was dissolved in 30 mL of TFA and refluxed for 2 h. After completion of the reaction, the solvent was removed by concentration under reduced pressure. The residue was extracted with EA and 1 M hydrochloric acid. The aqueous phase was collected and concentrated under reduced pressure to remove the solvent to obtain compound g (564 mg, 4.34 mmol, two-step yield 37%).

[0786] Its structural characterization is as follows: ESI-MS m / z: 131.1[M+H] + .

[0787] Steps 5 to 7: Synthesis of Compound 1

[0788] According to the synthesis method from step 5 to step 7 of Example 36, the compound e of Example 36 was replaced by the compound g of Example 37, and the other operations were the same to obtain compound 1.

[0789] ESI-MS m / z:537.2[M+H] + .

[0790] Step 8. (E)-1-((1 3R,8R)-6 4 -Fluoro-3 6 -Methoxy-8-methyl-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinazoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 Synthesis of 1,4-dione-2-pentyl)pent-2-ene

[0791] According to the synthesis method of step 5 of Example 1, the compound g of Example 1 was replaced by the compound l of Example 37, and the other operations were the same to obtain compound (E)-1-((1 3 R,8R)-6 4 -Fluoro-3 6 -Methoxy-8-methyl-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinazoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 -yl)pent-2-ene-1,4-dione.

[0792] Its structural characterization is as follows: 1 H NMR(400MHz,DMSO-d6)δppm 10.21(s,1H),8.60(s,1H),8.26-8.08(m,5H),7.86(d,J=8.8Hz,1H),7.79-7.77(m,1H),7.54(d,J=15.6Hz,1H),7.10-7.06(m,1H),6.81(d, J=15.6Hz,1H),5.33-4.75(m,2H),4.54-4.41(m,3H),4.05-3.89(m,2H),3.97(s,3H),3.72-3.52(m,1H),2.40(s,3H),1.52(d,J=5.6Hz,1H).

[0793] ESI-MS m / z:633.2[M+H] + .

[0794] Example 38 (E)-1-((1 3 S)-3 4 ,6 4 -Difluoro-3 6 -Methoxy-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinazoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 Synthesis of 1,4-dione-2-pentyl)pent-2-ene

[0795] Step 1. Synthesis of compound b

[0796] Compound a (1 g, 2.37 mmol) was dissolved in 20 mL of 1,4-dioxane, and diboronic acid pinacol ester (662 mg, 2.6 mmol), potassium acetate (697 mg, 7.11 mmol), and Pd(dppf)Cl2 (172 mg, 0.24 mmol) were added. The atmosphere was replaced with nitrogen three times at room temperature, then the temperature was raised to 80°C and stirred for 8 h. LC-MS monitoring confirmed the completion of the reaction. The reaction solution was poured into water and extracted with EA. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to afford intermediate b (800 mg, 1.7 mmol, 72% yield).

[0797] Its structural characterization is as follows: ESI-MS m / z: 471.3[M+H]+.

[0798] Step 2: Synthesis of Compound d

[0799] Compound c (0.15 g, 0.26 mmol), compound b (0.12 g, 0.26 mmol), Pd(dppf)Cl2 (0.018 g, 0.026 mmol), and K2CO3 (0.11 g, 0.78 mmol) were dissolved in a mixture of 1,4-dioxane and water (5 mL / 1 mL). The atmosphere was replaced with nitrogen three times at room temperature, then heated to 80°C for 7 h. The mixture was cooled to room temperature, and sodium hydroxide (0.031 g, 0.68 mmol) was added. The mixture was stirred at room temperature for 2 h. The reaction mixture was poured into saturated ammonium chloride and extracted with EA. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and then purified by silica gel column chromatography to obtain compound d (0.12 g, 0.18 mmol, 70% yield).

[0800] Its structural characterization is as follows: ESI-MS m / z: 661.2[M+H] + .

[0801] Steps 3 to 5, (E)-1-((1 3 S)-3 4 ,6 4 -Difluoro-3 6 -Methoxy-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinazoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 Synthesis of 1,4-dione-2-pentyl)pent-2-ene

[0802] According to the method of step 3 to step 5 of Example 1, the compound e of Example 1 was replaced by the compound d of Example 38, and the other operations were the same to obtain (E)-1-((1 3 S)-3 4 ,6 4 -Difluoro-3 6 -Methoxy-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinazoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 -yl)pent-2-ene-1,4-dione.

[0803] Its structural characterization is as follows: 1 H NMR (400MHz, DMSO-d6) δ9.74 (s, 1H), 8.77 (s, 1H), 8.16 (d, J = 8.4Hz, 1H), 8.04-7.92 (m, 4H), 7.48 (d, J = 15.2Hz, 0.8H), 7.44 -7.40(m,0.2H),7.33-7.30(m,0.8H),7.22-7.19(m,0.2H),7.13-7.06(m,1H),6.74(d,J=15.2Hz,0.8H),6.67-6.60(m,0.2H),5.23 -5.06(m,2H),4.64-4.60(m,1H),4.32-4.23(m,2H),4.09-3.79(m,4H),3.61 -3.52(m,2H),3.25-3.15(m,1H),2.38(s,2.2H),2.26(s,0.8H).

[0804] ESI-MS m / z:637.2[M+H] + .

[0805] Example 39 (E)-1-((1 3 R)-3 6 -6-chloro- 4 -Fluoro-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinazoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 Synthesis of 1,4-dione-2-pentyl)pent-2-ene

[0806] According to the synthetic method from step 1 to step 5 of Example 6, the compound a of Example 6 was replaced by the compound a of Example 39, and the compound b of Example 6 was replaced by the compound b of Example 39. The other operations were the same to obtain (E)-1-((1 3 R)-36 -6-chloro- 4 -Fluoro-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinazoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 -yl)pent-2-ene-1,4-dione.

[0807] Its structural characterization is as follows: 1 H NMR(400MHz,DMSO-d6)δppm 10.54(s,1H),8.82(s,1H),8.55-8.50(m,2H),8.36-8.24(m,1H),8.20-8.16(m,1H),8.10-8.02(m,1H),8. 00(d,J=8.8Hz,1H),7.50(d,J=15.6Hz,1H),7.42-7.37(m,1H),7.20-7.08(m,1H),6.77(d,J=15.6Hz,1H),5 .42-5.25(m,1H),5.10-4.82(m,0.8H),4.85-4.72(m,1.2H),4.62-4.58(m,0.2H),4.46-4.28(m,1.8H),4.1 5-4.13(m,0.2H),4.01-3.98(m,0.8H),3.66-3.53(m,1H),3.45-3.00(m,2H),2.4(s,2.3H),2.24(s,0.7H).

[0808] ESI-MS m / z:623.1[M+H] + .

[0809] Example 40 (E)-1-((1 3 S)-3 6 -6-chloro- 4 -Fluoro-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinazoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 Synthesis of 1,4-dione-2-pentyl)pent-2-ene

[0810] According to the synthesis method from step 1 to step 4 of Example 7, the compound a of Example 7 was replaced by the compound a of Example 40, and the other operations were the same to obtain (E)-1-((1 3 S)-3 6 -6-chloro- 4-Fluoro-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinazoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 -yl)pent-2-ene-1,4-dione.

[0811] Its structural characterization is as follows: 1 H NMR(400MHz,DMSO-d6)δppm 10.55(s,1H),8.82(s,1H),8.62-8.46(m,2H),8.35-8.22(m,1H),8.22-8.11(m,1H),8.10-8.03(m,1H),7 .99(d,J=8.8Hz,1H),7.54-7.44(m,1H),7.44-7.33(m,1H),7.22-7.07(m,1H),6.81-6.65(m,1H),5.45-5 .23(m,1H),5.15-5.01(m,0.8H),4.90-4.66(m,1.2H),4.64-4.54(m,0.2H),4.47-4.27(m,1.8H),4.19-4 .07(m,0.2H),4.04-3.94(m,0.8H),3.65-3.57(m,1H),3.47-2.97(m,2H),2.40(s,2.2H),2.28(s,0.8H).

[0812] ESI-MS m / z:623.1[M+H] + .

[0813] Example 41 (E)-1-((1 3 S)-6 6 -Fluoro-3 6 -methoxy-5,5-dioxol-6- 4 -(Trifluoromethyl)-7-oxa-5-thia-4-aza-2(4,6)-quinazoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 Synthesis of (-yl)pent-2-en-1,4-one

[0814] Step 1. Synthesis of compound b

[0815] Compound a (500 mg, 2.5 mmol) was dissolved in EtOH (20 mL) at room temperature, and p-methoxybenzylmercaptan (462.69 mg, 3.0 mmol) and NaOH (100 mg, 2.5 mmol, dissolved in 1 mL of H2O) were added. The mixture was stirred at room temperature for 2 h, concentrated under reduced pressure, dissolved in water, and extracted with DCM. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified on a silica gel column to afford compound b (480 mg, 1.4 mmol, 57% yield).

[0816] Steps 2 to 7, (E)-1-((1 3 S)-6 6 -Fluoro-3 6 -methoxy-5,5-dioxol-6- 4 -(Trifluoromethyl)-7-oxa-5-thia-4-aza-2(4,6)-quinazoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 Synthesis of 1,4-pentyl)pent-2-en-1,4-one

[0817] According to the synthesis method from step 2 to step 7 of Example 14, the compound b of Example 14 was replaced by the compound b of Example 41, and the other operations were the same to obtain (E)-1-((1 3 S)-6 6 -Fluoro-3 6 -methoxy-5,5-dioxol-6- 4 -(Trifluoromethyl)-7-oxa-5-thia-4-aza-2(4,6)-quinazoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 -yl)pent-2-en-1,4-one.

[0818] Its structural characterization is as follows: 1H NMR (400 MHz, DMSO-d6) δ ppm 10.57 (s, 1H), 8.75 (s, 1H), 8.25-8.15 (m, 3H), 7.94-7.92 (m, 2H), 7.67-7.48 (m, 3H), 6.77 (d, J = 8 Hz, 1H), 5.51-5.38 (m, 1H), 5.12-5.10 (m, 0.7H), 4.91-4.67 (m, 1.3H), 4.61-4.58 ( m,0.3H),4.44-4.31(m,1.7H),4.25-4.23(m,0.2H),4.03(d,J=8Hz,0.8H),3.92(s,3H),3 .65(t,J=12Hz,0.8H),3.46-3.25(m,1.2H),3.13-3.07(m,1H),2.39(s,2H),2.31(m,1H).

[0819] ESI-MS m / z:687.2[M+H] + .

[0820] Example 42 (E)-1-((1 3 S)-3 6 -Methoxy-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinazoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 Synthesis of (-)pent-2-ene-1,4-dione

[0821] According to the synthetic method from step 1 to step 5 of Example 6, the compound a of Example 6 was replaced by the compound a of Example 42, and the compound d of Example 6 was replaced by the compound d of Example 42. The other operations were the same to obtain (E)-1-((1 3 S)-3 6 -Methoxy-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinazoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 -yl)pent-2-ene-1,4-dione.

[0822] Its structural characterization is as follows: 1H NMR (400 MHz, DMSO-d6) δppm 10.11 (s, 1H), 8.77 (s, 1H), 8.42 (s, 1H), 8.26-8.15 (m, 3H), 8.00 (d, J = 8 Hz, 1H), 7.95 (d, J = 8 Hz, 1H), 7.59-7.40 (m, 3H), 7.20 (t, J = 12 Hz, 1H), 6.75 (d, J = 8 Hz, 1H), 5.39-5.28 (m, 1H), 5.10 -5.07(m,1H),4.87-4.73(m,1H),4.59-4.55(m,0.2H),4.38-4.30(m,1.8H),3.91-3.87(m,4H ),3.60(t,J=12Hz,1H),3.36-3.31(m,1H),3.14-3.08(m,1H),2.39(s,2.3H),2.26(m,0.7H).

[0823] ESI-MS m / z:601.2[M+H] + .

[0824] Example 43 (E)-1-((1 3 R)-2 5 ,6 4 -Difluoro-3 6 -Methoxy-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinazoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 Synthesis of 1,4-dione-2-pentyl)pent-2-ene

[0825] Step 1. Synthesis of compound c

[0826] Compound a (200 mg, 0.68 mmol) was dissolved in 3 mL of DCM, and DIEA (240 μL, 1.36 mmol) and compound b (176 mg, 0.81 mmol) were added. The mixture was allowed to react at room temperature for 1 h. The mixture was concentrated under reduced pressure and purified by column chromatography to afford compound c (270 mg, 0.56 mmol, 83% yield).

[0827] Its structural characterization is as follows: ESI-MS m / z: 475.1[M+H] + .

[0828] Step 2: Synthesis of Compound e

[0829] Compound c (270 mg, 0.56 mmol), Pd(dppf)Cl2 (41 mg, 0.056 mmol), compound d (263 mg, 0.62 mmol), and Na2CO3 (119 mg, 1.12 mmol) were dissolved in a mixture of 1,4-dioxane / H2O (4 mL / 1 mL) and heated to 80°C under nitrogen for 6 h. After completion, the reaction solution was concentrated under reduced pressure and purified by silica gel chromatography to obtain compound e (330 mg, 0.47 mmol, 84% yield).

[0830] Its structural characterization is as follows: ESI-MS m / z: 695.2[M+H] + .

[0831] Step 3. Synthesis of compound f

[0832] Compound e (330 mg, 0.47 mmol) and Pd(dppf)Cl2 (21 mg, 0.047 mmol) were dissolved in 4 mL of MeOH, and sodium borohydride (36 mg, 0.94 mmol) was added. The mixture was reacted at room temperature for 1 h, concentrated under reduced pressure, and purified by silica gel chromatography to obtain solid compound f (210 mg, 0.31 mmol, yield 67%).

[0833] Its structural characterization is as follows: ESI-MS m / z: 661.2[M+H] + .

[0834] Step 4 to Step 6, (E)-1-((1 3 R)-2 5 ,6 4 -Difluoro-3 6 -Methoxy-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinazoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 Synthesis of 1,4-dione-2-pentyl)pent-2-ene

[0835] According to the synthesis method from step 3 to step 5 of Example 1, the compound e of Example 1 was replaced by the compound f of Example 43, and the other operations were the same to obtain (E)-1-((1 3 R)-2 5 ,6 4 -Difluoro-3 6 -Methoxy-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinazoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 -yl)pent-2-ene-1,4-dione.

[0836] Its structural characterization is as follows: 1 H NMR(400MHz,DMSO-d6)δppm 10.29(s,1H),8.77(s,1H),8.26(s,1H),8.15-8.04(m,3H),7.78-7.75(m,1H),7.52(d,J=15.6Hz ,1H),7.44-7.28(m,1H),7.07-6.96(m,1H),6.79(d,J=15.6Hz,1H),5.10-4.99(m,1H),4.99-4.84 (m,0.7H),4.63-4.61(m,0.3H),4.49-4.31(m,1.7H),4.26-4.22(m,1H),4.05-4.03(m,0.3H),3.9 6(s,3H),3.92-3.83(m,1H),3.75-3.60(m,1H),3.31-3.02(m,2H),2.41(s,2.3H),2.33(s,0.7H).

[0837] ESI-MS m / z:637.2[M+H] + .

[0838] Example 44 (E)-1-((1 3 S)-2 5 ,6 4 -Difluoro-3 6 -Methoxy-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinazoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 Synthesis of 1,4-dione-2-pentyl)pent-2-ene

[0839] According to the synthetic method from step 1 to step 6 of Example 43, the compound b of Example 43 was replaced by the compound b of Example 44, and the other operations were the same to obtain (E)-1-((1 3 S)-2 5 ,6 4 -Difluoro-3 6 -Methoxy-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinazoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 -yl)pent-2-ene-1,4-dione.

[0840] Its structural characterization is as follows: 1H NMR(400MHz,DMSO-d6)δppm 10.06(s,1H),8.74(s,1H),8.26(s,1H),8.12-8.03(m,3H),7.76(d,J=8.8Hz,1H),7.51(d,J=16.0Hz ,1H),7.35-7.32(m,1H),7.01(t,J=9.2Hz,1H),6.77(d,J=16.0Hz,1H),5.03-4.93(m,1.7H),4.63-4. 60(m,0.3H),4.36-4.33(m,2H),4.23-4.19(m,1H),4.02(d,J=9.2Hz,0.2H),3.95(s,3H),3.86(d,J=8 .8Hz,0.8H),3.68-3.61(m,1H),3.20-3.17(m,1H),3.07-3.01(m,1H),2.40(s,2.4H),2.32(s,0.6H).

[0841] ESI-MS m / z:637.2[M+H] + .

[0842] Example 45 (E)-1-(((1 3 R)-6 4 -Fluoro-3 6 -methoxy-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-pyrido[3,2-d]pyrimidine-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 Synthesis of 1,4-dione-2-pentyl)pent-2-ene

[0843] According to the synthetic method from step 1 to step 6 of Example 43, the compound a of Example 43 was replaced by the compound a of Example 45, and the other operations were the same to obtain (E)-1-((1R)-2,6-difluoro-3-methoxy-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinazoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 -yl)pent-2-ene-1,4-dione.

[0844] Its structural characterization is as follows: 1H NMR(400MHz,DMSO-d6)δppm 9.88-9.86(m,1H),8.73-8.68(m,3H),8.50-8.39(m,1H),8.26-8.24(d,J=8.8Hz,1H),8 .01-7.95(m,1H),7.47(d,J=15.6Hz,0.75H),7.32-7.24(m,1.25H),7.12-7.00(m,1H), 6.72(d,J=15.6Hz,0.75H),6.55(d,J=15.6Hz,0.25H),6.36-6.33(m,0.25H),5.87-5.8 2(m,0.75H),5.16-5.12(m,0.75H),4.99-4.94(m,0.25H),4.80-4.72(m,2H),4.57-4.54 (m,1H),4.39-4.15(m,2H),4.00-3.98(m,3H),3.75 -3.67(m,1.5H),3.34-3.31(m,0.25H),3.21-3.18(m,0.25H),2.38(s,2.2H),2.17(s,0.8H).

[0845] ESI-MS m / z:620.2[M+H] + .

[0846] Example 46 (E)-1-((1 3 S)-6 4 -Fluoro-3 6 -methoxy-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-pyrido[3,2-d]pyrimidine-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 Synthesis of 1,4-dione-2-pentyl)pent-2-ene

[0847] According to the synthesis method from step 1 to step 6 of Example 43, the compounds a and b of Example 43 were replaced by compounds a and b of Example 46, respectively, and the other operations were the same to obtain (E)-1-((1 3 S)-6 4 -Fluoro-3 6 -methoxy-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-pyrido[3,2-d]pyrimidine-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 -yl)pent-2-ene-1,4-dione.

[0848] Its structural characterization is as follows: 1 H NMR(400MHz,DMSO-d6)δppm 9.86(s,1H),8.74-8.64(m,3H),8.50-8.46(m,1H),8.22(d,J=8.8Hz,1H),8.01-7.96(m,1H),7.47(d,J=15.6Hz,1 H),7.32-7.26(m,1H),7.02(t,J=9.2Hz,1H),6.72(d,J=16.0Hz,0.74H),6.55(d,J=15.6Hz,0.26H),6.35(d,J=13 .6Hz,0.26H),5.86(dd,J=14.0Hz,5.2Hz,0.74H),5.14-5.11(m,0.7H),5.00-4.96(m,0.3H),4.81-4.72(m,2H),4 .56-4.54(m,1H),4.39-4.15(m,2H),4.00(s,2H),3.98(s,1H),3.67(d,J=10.4Hz,2H),2.38(s,2H),2.17(s,1H).

[0849] ESI-MS m / z:620.2[M+H] + .

[0850] Example 47 (E)-1-((1 3 R)-6 4 -Fluoro-3 6 -Methoxy-2 3 -cyano-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinazoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 Synthesis of 1,4-dione-2-pentyl)pent-2-ene

[0851] According to the synthetic method from step 1 to step 6 of Example 43, the compound a of Example 43 was replaced by the compound a of Example 47, and the other operations were the same to obtain (E)-1-((1 3 R)-6 4 -Fluoro-3 6 -Methoxy-2 3 -cyano-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinazoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 -yl)pent-2-ene-1,4-dione.

[0852] Its structural characterization is as follows: 1 H NMR(400MHz,DMSO-d6)δppm 9.99(s,1H),8.89(s,1H),8.57-8.23(m,4H),8.14(d,J=8.8Hz,1H),8.11-8.02(m,1H),7.61-7.34(m,2H),7.30-7.08(m,1H),6.8 0-6.62(m,1H),5.32-4.62(m,2H),4.61-4.02(m,3H),4.01-3.81(m,4H),3.80-3.58(m,2H),3.56-3.42(m,1H),2.43-2.22(m,3H).

[0853] ESI-MS m / z:643.2[M+H] +

[0854] Example 48 (E)-1-((1 3 S)-6 4 -Fluoro-3 6 -Methoxy-2 3 -cyano-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinazoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 Synthesis of 1,4-dione-2-pentyl)pent-2-ene

[0855] According to the synthetic method from step 1 to step 6 of Example 1, the compounds a and b of Example 43 were replaced by compounds a and b of Example 48, respectively, and the other operations were the same to obtain (E)-1-((1 3 S)-6 4 -Fluoro-3 6 -Methoxy-2 3 -cyano-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinazoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 -yl)pent-2-ene-1,4-dione.

[0856] Its structural characterization is as follows: 1H NMR (400 MHz, DMSO-d6) δ ppm 9.98(s,1H),8.89(s,1H),8.47(s,1H),8.39(s,2H),8.35-8.26(m,1H),8.1 4(d,J=8.8Hz,1H),8.11-8.02(m,1H),7.61-7.34(m,2H),7.30-7.08(m,1H), 6.83-6.62(m,1H),5.29-5.16(m,1H),5.12-4.78(m,1H),4.64-4.06(m,3H), 4.02-3.81(m,4H),3.80-3.62(m,2H),3.59-3.44(m,1H),2.43-2.24(m,3H).

[0857] ESI-MS m / z:643.2[M+H] +

[0858] Example 49 (E)-1-((1 3 R)-2 5 ,2 8 ,6 4 -Trifluoro-3 6 -Methoxy-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinazoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 Synthesis of 1,4-dione-2-pentyl)pent-2-ene

[0859] According to the synthetic method from step 1 to step 6 of Example 43, the compound a of Example 43 was replaced by the compound a of Example 49, and the other operations were the same to obtain (E)-1-((1 3 R)-2 5 ,2 8 ,6 4 -Trifluoro-3 6 -Methoxy-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinazoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 -yl)pent-2-ene-1,4-dione.

[0860] Its structural characterization is as follows: 1H NMR (400 MHz, MeOD-d4) δ ppm 8.70(s,1H),8.32-8.23(m,1H),7.98(t,J=8.0Hz,1H),7.90(s,1H),7.81- 7.72(m,1H),7.56-7.44(m,1H),7.18-7.04(m,1H),6.97-6.78(m,2H),5.2 9-5.12(m,2H),5.02-4.96(m,1H),4.48-4.39(m,2H),4.36-4.28(m,1H),4 .09-3.85(m,4H),3.72-3.57(m,1H),3.10-3.00(m,1H),2.44-2.32(m,3H).

[0861] ESI-MS m / z:655.1[M+H] + .

[0862] Example 50 (E)-1-((1 3 R)-2 5 ,2 7 ,6 4 -Trifluoro-3 6 -Methoxy-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinazoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 Synthesis of 1,4-dione-2-pentyl)pent-2-ene

[0863] Step 1. Synthesis of compound b

[0864] Compound a (1.0 g, 4.81 mmol) was dissolved in glacial acetic acid (10 mL) and N-iodosuccinimide (1.2 g, 5.29 mmol) was added at room temperature. The mixture was stirred at room temperature for 5 h. After completion of the reaction, the reaction solution was concentrated under reduced pressure. The resulting residue was dispersed in aqueous sodium bicarbonate solution, extracted with EA, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by normal phase chromatography to afford compound b (1.4 g, 4.15 mmol, 86% yield).

[0865] Its structural characterization is as follows: ESI-MS m / z: 333.8, 335.8 [M+H] + .

[0866] Step 2: Synthesis of Compound C

[0867] Compound b (1.4 g, 4.15 mmol), zinc cyanide (1.4 g, 4.2 mmol), 1,1'-bis(diphenylphosphino)ferrocene (1.4 g, 4.2 mmol), and Pd2(dba)3 (5.5 g, 65 mmol) were dissolved in 15 mL of DMF at room temperature. Stirred at 100°C for 3 h under nitrogen. After completion of the reaction, the mixture was extracted with water and EA, dried over anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure. The crude product was purified by column chromatography to afford compound c (851 mg, 3.65 mmol, 88% yield).

[0868] Its structural characterization is as follows: ESI-MS m / z: 232.9, 234.9 [M+H] + .

[0869] Step 3. Synthesis of compound d

[0870] Compound c (851 mg, 3.65 mmol) was dissolved in 10 mL of DMSO, and potassium carbonate (1.51 g, 11.0 mmol) was added. The temperature was cooled to 10°C, and hydrogen peroxide (1.07 g, 11.0 mmol, 35%) was added dropwise. The mixture was returned to room temperature and stirred for 2 h. After completion of the reaction, the mixture was extracted with water and EA, dried over anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure. The resulting crude product was purified by normal phase column chromatography to afford compound d (652 mg, 2.60 mmol, 63% yield).

[0871] Its structural characterization is as follows: ESI-MS m / z: 250.9, 252.9 [M+H] + .

[0872] Step 4. Synthesis of compound e

[0873] Compound d (652 mg, 2.60 mmol) was dissolved in triethyl orthoformate (10 mL) at room temperature and heated to 130°C with stirring for 6 h. After completion of the reaction, the reaction solution was concentrated under reduced pressure by LCMS. The resulting residue was purified by slurrying with methyl tert-butyl ether to afford compound e (578 mg, 2.21 mmol, 85% yield).

[0874] Its structural characterization is as follows: ESI-MS m / z: 260.9, 262.9 [M+H] + .

[0875] Step 5. Synthesis of compound f

[0876] Compound e (200 mg, 0.77 mmol) was dissolved in phosphorus oxychloride (8.0 mL) at room temperature. The mixture was heated to 100°C and stirred for 5 h. LC-MS monitoring revealed a large amount of product. The reaction solution was then concentrated under reduced pressure to afford crude compound f.

[0877] Its structural characterization is as follows: ESI-MS m / z: 278.9, 280.9 [M+H] + .

[0878] Steps 6 to 10, (E)-1-((1 3 R)-2 5 ,2 7 ,6 4 -Trifluoro-3 6 -Methoxy-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinazoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 Synthesis of 1,4-dione-2-pentyl)pent-2-ene

[0879] According to the synthesis method from step 1 to step 5 of Example 1, the compounds a and b of Example 1 were replaced by the compounds f and g of Example 50, respectively, and the other operations were the same to obtain (E)-1-((1 3 R)-2 5 ,2 7 ,6 4 -Trifluoro-3 6 -Methoxy-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinazoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 -yl)pent-2-ene-1,4-dione.

[0880] Its structural characterization is as follows: 1 H NMR(400MHz,DMSO-d6)δppm 10.23(s,1H),8.75(s,1H),8.19(s,1H),8.06-7.96(m,2H),7.66(d,J=10.4Hz,1H),7.49(d,J=15 .8Hz,1H),7.36-7.18(m,1H),7.04-6.95(m,1H),6.84-6.77(m,1H),5.02-4.92(m,1H),4.90-4.7 9(m,0.8H),4.69-4.47(m,0.4H),4.39-4.26(m,1.8H),4.26-4.07(m,1H),3.94(s,3H),3.88-3.7 2(m,1H),3.66-3.54(m,1H),3.24-3.16(m,1H),3.11-2.98(m,1H),2.40(s,2.5H),2.32(s,0.5H).

[0881] ESI-MS m / z:655.2[M+H] +

[0882] Example 51 (E)-1-((1 3 S)-2 7 ,6 4 -Difluoro-3 6 -Methoxy-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinazoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 Synthesis of 1,4-dione-2-pentyl)pent-2-ene

[0883] Step 1. Synthesis of compound b

[0884] Compound a (200 mg, 0.92 mmol) was dissolved in 5 mL of DCM, and DIPEA (325 μL, 1.84 mmol) was added, followed by TBSCl (217 mg, 1.38 mmol). The mixture was allowed to react at room temperature for 2 h. Water and DCM were added for extraction, and the combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to afford compound b (271 mg, 0.82 mmol, 89% yield).

[0885] Its structural characterization is as follows: ESI-MS m / z: 331.2[M+H] + .

[0886] Step 2: Synthesis of Compound d

[0887] Compound c (100 mg, 0.41 mmol) was dissolved in acetonitrile (5 mL), and DBU (93 mg, 0.62 mmol) and compound b (163 mg, 0.49 mmol) were added, followed by PyBOP (322 mg, 0.62 mmol). The mixture was allowed to react at room temperature for 2 h. The mixture was quenched with 10 mL of water and extracted with EA. The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to afford compound d (155 mg, 0.28 mmol, 68% yield).

[0888] Its structural characterization is as follows: ESI-MS m / z: 555.2, 557.2 [M+H] + .

[0889] Step 3. Synthesis of compound f

[0890] Compound d (155 mg, 0.28 mmol), compound e (143 mg, 0.34 mmol), and Pd(dppf)Cl2 (20 mg, 0.028 mmol) were dissolved in 1,4-dioxane (5 mL) and water (1 mL) at room temperature. The atmosphere was replaced with nitrogen and stirred at 90°C for 2 h. The mixture was diluted with water, extracted with EA, and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure and purified by silica gel column chromatography to afford compound f (171 mg, 0.22 mmol, 79% yield) as a solid.

[0891] Its structural characterization is as follows: ESI-MS m / z: 775.3[M+H] + .

[0892] Step 4. Synthesis of compound g

[0893] Compound f (171 mg, 0.22 mmol) was dissolved in 3 mL DCM and 3 mL TFA at room temperature and stirred at 45° C. for 12 h. The mixture was concentrated under reduced pressure and purified on a reverse C18 column to give compound g (102 mg, 0.18 mmol, 82% yield).

[0894] Its structural characterization is as follows: ESI-MS m / z: 561.2[M+H] + .

[0895] Step 5. Synthesis of compound h

[0896] Compound g (102 mg, 0.18 mmol) was dissolved in THF (10 mL) at room temperature, and sodium hydride (30 mg, 0.75 mmol) was added. The mixture was stirred at 50°C for 2 h. The mixture was quenched with saturated aqueous ammonium chloride, extracted with EA, and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to provide compound h (63 mg, 0.12 mmol, 67% yield).

[0897] Its structural characterization is as follows: ESI-MS m / z: 541.2[M+H] + .

[0898] Step 6, (E)-1-((1 3 S)-2 7 ,6 4 -Difluoro-3 6 -Methoxy-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinazoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 Synthesis of 1,4-dione-2-pentyl)pent-2-ene

[0899] Compound h (63 mg, 0.12 mmol) was dissolved in a mixed solvent of THF (2 mL) and DMF (2 mL), and compound i (20 mg, 0.17 mmol) and DIEA (46 mg, 0.36 mmol) were added. The temperature was lowered to -78°C, and T3P (153 μL, 0.24 mmol, 50% EA solution) was added. The mixture was stirred at -78°C for 2 h. 10 mL of water was added to quench the mixture, and the mixture was extracted with EA. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The mixture was then purified by high pressure liquid chromatography (method 1) to obtain compound (E)-1-((1 3 S)-2 7 ,6 4 -Difluoro-3 6 -Methoxy-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinazoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 -yl)pent-2-ene-1,4-dione (35 mg, 0.055 mmol, yield 46%).

[0900] Its structural characterization is as follows: 1 H NMR(400MHz,DMSO-d6)δppm 10.12(s,1H),8.78(s,1H),8.24(d,J=1.6Hz,1H),8.20-8.11(m,1H),8.09-7.92(m,2H),7.78(d,J=11 .2Hz,1H),7.54-7.41(m,1H),7.39-7.22(m,1H),7.16-7.02(m,1H),6.75(d,J=15.6Hz,1H),5.39-5.1 4(m,1H),5.10-4.94(m,0.8H),4.87-4.59(m,1.2H),4.58-4.51(m,0.2H),4.42-4.21(m,1.8H),4.11- 3.91(m,1H),3.91-3.81(m,3H),3.61-3.35(m,2H),3.15-2.95(m,1H),2.38(s,2.3H),2.25(s,0.7H).

[0901] ESI-MS m / z:637.2[M+H] + .

[0902] Example 52 (E)-1-((1 3 R)-2 7 ,6 4 -Difluoro-3 6-Methoxy-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinazoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 Synthesis of 1,4-dione-2-pentyl)pent-2-ene

[0903] According to the synthetic method from step 1 to step 6 of Example 51, the compound a of Example 51 was replaced by the compound a of Example 52, and the other operations were the same to obtain (E)-1-((1 3 R)-2 7 ,6 4 -Difluoro-3 6 -Methoxy-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinazoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 -yl)pent-2-ene-1,4-dione.

[0904] Its structural characterization is as follows: 1 H NMR(400MHz,DMSO-d6)δppm 10.12(s,1H),8.78(s,1H),8.24(d,J=1.6Hz,1H),8.20-8.11(m,1H),8.09-7.92(m,2H),7.78(d,J=11 .2Hz,1H),7.54-7.41(m,1H),7.39-7.22(m,1H),7.16-7.02(m,1H),6.75(d,J=15.6Hz,1H),5.39-5.1 4(m,1H),5.10-4.94(m,0.8H),4.87-4.59(m,1.2H),4.58-4.51(m,0.2H),4.42-4.21(m,1.8H),4.11- 3.91(m,1H),3.91-3.81(m,3H),3.61-3.35(m,2H),3.15-2.95(m,1H),2.38(s,2.3H),2.25(s,0.7H).

[0905] ESI-MS m / z:637.2[M+H] + .

[0906] Example 53 (E)-1-((1 3 R)-6 4 -Fluorine-2 8 ,3 6-Dimethoxy-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinazoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 -yl)pent-2-ene-1,4-dione

[0907] Step 1. Synthesis of compound b

[0908] Compound a (2.0 g, 8.13 mmol) was dissolved in DMF (30 mL), and ammonium chloride (1.7 g, 32.52 mmol) and HATU (4.3 g, 11.38 mmol) were added, followed by DIEA (2.1 g, 16.26 mmol). The reaction was allowed to react at room temperature for 2 h. The mixture was quenched with 200 mL of water, and the aqueous phase was extracted with EA. The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to afford compound b (1.8 g, 7.35 mmol, 90% yield).

[0909] Its structural characterization is as follows: ESI-MS m / z: 245.9, 247.9 [M+H] + .

[0910] Step 2: Synthesis of Compound C

[0911] Compound b (1.8 g, 7.35 mmol) was dissolved in 60 mL of triethyl orthoformate and stirred at 120° C. for 24 h. The mixture was concentrated under reduced pressure and washed three times with EA:petroleum ether (1:1) to obtain compound c (1.4 g, 5.49 mmol, yield 75%).

[0912] Its structural characterization is as follows: ESI-MS m / z: 254.9, 256.9 [M+H] + .

[0913] Steps 3 to 7

[0914] According to the synthetic method from step 2 to step 6 of Example 52, the compound c of Example 52 was replaced by the compound c of Example 53, and the other operations were the same to obtain (E)-1-((1 3 R)-6 4 -Fluorine-2 8 ,3 6 -Dimethoxy-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinazoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 -yl)pent-2-ene-1,4-dione.

[0915] Its structural characterization is as follows: 1H NMR(400MHz,DMSO-d6)δppm 10.18(s,1H),8.76(s,1H),8.45-8.28(m,2H),8.12-8.01(m,1H),7.73-7.54(m,2H),7.5 3-7.31(m,2H),7.17-7.03(m,1H),6.76(d,J=15.6Hz,1H),5.44-5.21(m,1H),5.15-4.98 (m,0.8H),4.91-4.68(m,1.2H),4.63-4.54(m,0.2H),4.47-4.26(m,1.8H),4.06(s,3H), 4.00-3.83(m,4H),3.68-3.55(m,1H),3.18-3.02(m,2H),2.39(s,2.4H),2.29(s,0.6H).

[0916] ESI-MS m / z:649.2[M+H] + .

[0917] Example 54 (E)-1-((1 3 S)-6 4 -Fluorine-2 8 ,3 6 -Dimethoxy-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinazoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 -yl)pent-2-ene-1,4-dione

[0918] According to the synthesis method from step 3 to step 7 of Example 53, the compound d of Example 53 was replaced by the compound b of Example 54, and the other operations were the same to obtain (E)-1-((1 3 S)-6 4 -Fluorine-2 8 ,3 6 -Dimethoxy-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinazoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 -yl)pent-2-ene-1,4-dione.

[0919] Its structural characterization is as follows: 1 H NMR (400 MHz, DMSO-d6) 1H NMR(400MHz,DMSO-d6)δppm 10.18(s,1H),8.76(s,1H),8.45-8.28(m,2H),8.12-8.01(m,1H),7.73-7.54(m,2H),7.5 3-7.31(m,2H),7.17-7.03(m,1H),6.76(d,J=15.6Hz,1H),5.44-5.21(m,1H),5.15-4.98 (m,0.8H),4.91-4.68(m,1.2H),4.63-4.54(m,0.2H),4.47-4.26(m,1.8H),4.06(s,3H), 4.00-3.83(m,4H),3.68-3.55(m,1H),3.18-3.02(m,2H),2.39(s,2.4H),2.29(s,0.72H).

[0920] ESI-MS m / z:649.2[M+H] + .

[0921] Example 55 (E)-1-((1 3 S)-6 4 -Fluoro-3 6 -Methoxy-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 Synthesis of 1,4-dione-2-pentyl)pent-2-ene

[0922] Step 1. Synthesis of compound c

[0923] Compound a (500 mg, 2.06 mmol) was dissolved in 10 mL of DMSO at room temperature. DIEA (1.02 mL, 6.18 mmol) and compound b (665.18 mg, 3.09 mmol) were added and reacted at 105°C for 3 h. After completion of the reaction, the mixture was extracted with EA and water, with the aqueous phase extracted three times with EA. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. Silica gel column chromatography afforded compound c (510 mg, 1.21 mmol, 52% yield) as a yellow oil.

[0924] Its structural characterization is as follows: ESI-MS m / z: 424.0 [M+H] + .

[0925] Steps 2 to 5, (E)-1-((1 3 S)-6 4 -Fluoro-3 6-Methoxy-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 Synthesis of 1,4-dione-2-pentyl)pent-2-ene

[0926] According to the synthesis method from step 2 to step 5 of Example 1, the compound c of Example 1 was replaced by the compound c of Example 55, and the other operations were the same to obtain (E)-1-((1 3 S)-6 4 -Fluoro-3 6 -Methoxy-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 -yl)pent-2-ene-1,4-dione.

[0927] Its structural characterization is as follows: 1 H NMR(400MHz,MeOD-d4)δppm 8.67(d,J=4.0Hz,1H),8.51(s,1H),8.31(s,1H),8.14-8.00(m,4H),7.46(d,J=16.0Hz,1H),7.20- 7.13(m,2H),6.99-6.79(m,2H),5.61-5.48(m,0.3H),5.47(t,J=12.0Hz,0.7H),5.19-5.16(m,0.7 H),4.75-4.55(m,1.6H),4.28(d,J=16.0Hz,0.7H),4.00-3.80(m,1H),3.96(s,3H),3.73(t,J=12. 0Hz,0.7H),3.64-3.55(m,1H),3.37-3.18(m,1.3H),2.99-2.95(m,1H),2.40(s,2H),2.29(s,1H).

[0928] ESI-MS m / z:618.2[M+H] + .

[0929] Example 56 (E)-1-((1 3 R)-6 4 -Fluoro-3 6 -Methoxy-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 Synthesis of 1,4-dione-2-pentyl)pent-2-ene

[0930] According to the synthetic method from step 1 to step 5 of Example 55, the compound b of Example 55 was replaced by the compound b of Example 56, and the other operations were the same to obtain (E)-1-((1 3 R)-6 4 -Fluoro-3 6 -Methoxy-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 -yl)pent-2-ene-1,4-dione.

[0931] Its structural characterization is as follows: 1 H NMR(400MHz,MeOD-d4)δppm 8.67(d,J=4.0Hz,1H),8.51(s,1H),8.31(s,1H),8.13-8.00(m,4H),7.45(d,J=16.0Hz,1H), 7.23-7.13(m,2H),6.99(s,1H),6.92-6.88(m,1H),5.59-5.46(m,1H),5.19-5.16(m,0.7H),4 .74-4.62(m,1.6H),4.30-4.26(m,0.7H),4.00-3.80(m,1H),3.96(s,3H),3.73(t,J=12.0Hz, 0.7H),3.64-3.55(m,1H),3.37-3.18(m,1.3H),2.99-2.95(m,1H),2.40(s,2H),2.29(s,1H).

[0932] ESI-MS m / z:618.2[M+H] +

[0933] Example 57 (E)-1-((1 3 S)-6 6 -Fluoro-3 6 -Methoxy-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 Synthesis of 1,4-dione-2-pentyl)pent-2-ene

[0934] According to the synthetic method from step 1 to step 5 of Example 55, the compound d of Example 55 was replaced by the compound d of Example 57. The final high pressure liquid phase preparation was purified by method 2. The other operations were the same to obtain (E)-1-((1 3 S)-6 6 -Fluoro-3 6 -Methoxy-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 -yl)pent-2-ene-1,4-dione.

[0935] Its structural characterization is as follows: 1 H NMR(400MHz,DMSO-d6)δppm 9.95(s,1H),8.75(d,J=5.2Hz,1H),8.36-8.16(m,2H),8.11-7.87(m,3H),7.65-7.43(m,2H),7.36-7.22(m ,1H),7.18-7.00(m,2H),6.77(d,J=15.6Hz,1H),5.46-5.20(m,1H),5.13-5.03(m,0.75H),4.75-4.64(m,0 .25H),4.63-4.39(m,1.25H),4.32(d,J=13.6Hz,0.75H),4.14-4.04(m,0.23H),3.92(m,3.77H),3.77-3.6 2(m,0.77H),3.55-3.44(m,1H),3.24-3.08(m,1.23H),3.05-2.86(m,1H),2.41(s,2.28H),2.30(s,0.72H).

[0936] ESI-MS m / z:618.2[M+H] + .

[0937] Example 58 (E)-1-((1 3 S)-6 4 ,6 6 -Difluoro-3 6 -Methoxy-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 Synthesis of 1,4-dione-2-pentyl)pent-2-ene

[0938] According to the synthetic method from step 1 to step 5 of Example 55, the compound d of Example 55 was replaced by the compound d of Example 58, and the other operations were the same to obtain (E)-1-((1 3 S)-6 4 ,6 6 -Difluoro-3 6 -Methoxy-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 -yl)pent-2-ene-1,4-dione.

[0939] Its structural characterization is as follows: 1 H NMR(400MHz,DMSO-d6)δppm 10.20(s,1H),8.75(d,J=5.2Hz,1H),8.29-8.13(m,2H),8.08-8.03(m,1H),8.01-7.85(m,2H),7.52(d,J=15 .6Hz,1H),7.41-7.25(m,1H),7.20-7.07(m,2H),6.77(d,J=15.6Hz,1H),5.39-5.20(m,1H),5.11-5.03(m,0. 76H),4.71-4.48(m,1.24H),4.33(d,J=13.2Hz,0.77H),4.17-4.07(m,0.23H),3.99-3.85(m,4H),3.76-3.6 0(m,0.75H),3.55-3.44(m,0.82H),3.25-3.08(m,1.43H),3.04-2.90(m,1H),2.41(s,2.3H),2.32(s,0.7H).

[0940] ESI-MS m / z:636.2[M+H] + .

[0941] Example 59 (E)-1-((1 3 S)-6 4 -Fluoro-3 6 -Methoxy-5,5-dioxo-7-oxa-5-thia-4-aza-2(8,2)-naphthyridine-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 Synthesis of 1,4-dione-2-pentyl)pent-2-ene

[0942] Step 1. Synthesis of compound c

[0943] Compound a (1.3 g, 3.71 mmol) was dissolved in NMP (20 mL) at room temperature, and DIEA (957 mg, 7.42 mmol) and compound b (962 mg, 4.45 mmol) were added. The mixture was heated to 50°C and stirred overnight. LC-MS monitored the reaction for completion. The mixture was diluted with water, extracted with EA, dried over sodium sulfate, filtered, concentrated under reduced pressure, and purified on a silica gel column to afford compound c (688 mg, 1.30 mmol, 35% yield).

[0944] Its structural characterization is as follows: ESI-MS m / z: 531.2[M+H] + .

[0945] Step 2: Synthesis of Compound d

[0946] Compound c (688 mg, 1.30 mmol) was dissolved in methanol (20 mL) at room temperature, and 10% palladium on carbon (200 mg) was added. The mixture was replaced with hydrogen and stirred at room temperature for 5 h. After completion of the reaction, the mixture was filtered, concentrated under reduced pressure, and purified by reverse-phase column chromatography to afford compound d (369 mg, 0.79 mmol, 61% yield).

[0947] Its structural characterization is as follows: ESI-MS m / z: 467.2[M+H] + .

[0948] Step 3. Synthesis of compound f

[0949] Compound d (100 mg, 0.21 mmol) was dissolved in 5 mL of pyridine, and compound e (67 mg, 0.32 mmol) was added. The mixture was stirred at room temperature for 2 h. After completion, the reaction was extracted with water and EA, dried over anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure. The mixture was purified by silica gel column chromatography to afford compound f (90 mg, 0.14 mmol, 67% yield).

[0950] Its structural characterization is as follows: ESI-MS m / z: 643.2[M+H] + .

[0951] Step 4 to Step 6, (E)-1-((1 3 S)-6 4 -Fluoro-3 6 -Methoxy-5,5-dioxo-7-oxa-5-thia-4-aza-2(8,2)-naphthyridine-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 Synthesis of 1,4-dione-2-pentyl)pent-2-ene

[0952] According to the synthesis method from step 3 to step 5 of Example 1, the compound e of Example 1 was replaced by the compound f of Example 59, and the other operations were the same to obtain (E)-1-((1 3 S)-6 4 -Fluoro-3 6 -Methoxy-5,5-dioxo-7-oxa-5-thia-4-aza-2(8,2)-naphthyridine-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 -yl)pent-2-ene-1,4-dione.

[0953] Its structural characterization is as follows: 1 H NMR(400MHz,DMSO-d6)δppm 9.61(s,1H),8.87(s,1H),8.66(s,1.7H),8.60(s,0.3H),8.39-8.30(m,2H),8.00-7.95(m,1H),7.49(d,J=15.6Hz,0.7H),7.28-7. 22(m,1.3H),7.10-6.97(m,2H),6.73(d,J=16.0Hz,0.7H),6.61(d,J=15.6Hz,0.3H),5.49-5.46(m,0.3H),5.31-5.28(m,0.3H),5. 18-5.08(m,1.3H),5.01-4.98(m,0.7H),4.73-4.60(m,1H),4.46(d,J=10.8Hz,0.7H),4.32(d,J=14.0Hz,0.7H),3.99(s,1.90H),3 .97(s,1.10H),3.87(d,J=12.0Hz,0.7H),3.64-3.59(m,2H),3.51d,J=12.0Hz,0.3H),3.18-3.15(m,1H),2.39(s,2H),2.10(s,1H).

[0954] ESI-MS m / z:619.2[M+H] + .

[0955] Example 60 (E)-1-((1 3 S)-6 4 ,6 6 -Difluoro-3 6 -Methoxy-5,5-dioxo-7-oxa-5-thia-4-aza-2(8,2)-naphthyridine-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 Synthesis of 1,4-dione-2-pentyl)pent-2-ene

[0956] According to the synthesis method from step 3 to step 6 of Example 59, the compound e of Example 59 was replaced by the compound b of Example 60, and the other operations were the same to obtain (E)-1-((1 3 S)-6 4 ,6 6 -Difluoro-3 6 -Methoxy-5,5-dioxo-7-oxa-5-thia-4-aza-2(8,2)-naphthyridine-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 -yl)pent-2-ene-1,4-dione.

[0957] Its structural characterization is as follows: 1 H NMR(400MHz,DMSO-d6)δppm 10.00(s,1H),8.67(d,J=9.2Hz,1H),8.55(d,J=2.4Hz,1H),8.52(s,1H),8.36(d,J=8.8Hz,1H),8.24-8.20(m,1H),7.51(d,J=15 .6Hz,0.67H),7.42(d,J=9.2Hz,0.33H),7.13-7.08(m,2H),6.75(d,J=15.6Hz,0.65H),6.68(d,J=16.0Hz,0.35H),5.78-5.69(m ,1H),4.99-4.95(m,1.66H),4.73-4.71(m,0.34H),4.60(d,J=13.6Hz,0.30H),4.52(d,J=6.4Hz,0.30H),4.31(d,J=14.0Hz,0.7 0H), 4.21 (d, J = 8.0Hz, 0.70H), 3.97 (s, 3H), 3.71-3.59 (m, 2H), 3.45-3.42 (m, 1H), 3.25-3.11 (m, 2H), 2.40 (s, 2H), 2.27 (s, 1H).

[0958] ESI-MS m / z:637.2[M+H] + .

[0959] Example 61 (E)-1-((1 3 R)-6 4 -Fluoro-3 6 -Methoxy-5,5-dioxo-7-oxa-5-thia-4-aza-2(8,2)-naphthyridine-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4Synthesis of 1,4-dione-2-pentyl)pent-2-ene

[0960] According to the synthetic method from step 1 to step 6 of Example 59, the compound b of Example 59 was replaced by the compound b of Example 61, and the other operations were the same to obtain (E)-1-((1 3 R)-6 4 -Fluoro-3 6 -Methoxy-5,5-dioxo-7-oxa-5-thia-4-aza-2(8,2)-naphthyridine-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 -yl)pent-2-ene-1,4-dione.

[0961] Its structural characterization is as follows: 1 H NMR(400MHz,DMSO-d6)δppm 9.62(s,1H),8.85(s,1H),8.69-8.62(m,2H),8.39-8.33(m,2H),8.01-7.95(m,1H),7.48(d,J=15.6Hz ,0.7H),7.31-7.21(m,1.3H),7.11-6.98(m,2H),6.72(d,J=15.6Hz,0.7H),6.59(d,J=15.6Hz,0.3H), 5.43-5.39(m,0.2H),5.26-5.22(m,0.2H),5.05-4.97(m,2H),4.73-4.60(m,0.8H),4.43-4.32(m,1.8 H),4.00(s,1.90H),3.97(s,1.10H),3.73-3.65(m,2H),3.25-3.22(m,2H),2.39(s,2H),2.28(s,1H).

[0962] ESI-MS m / z:619.2[M+H] + .

[0963] Example 62 (E)-1-((1 3 S)-6 6 -Fluoro-3 6 -Methoxy-5,5-dioxo-7-oxa-5-thia-4-aza-2(8,2)-naphthyridine-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 Synthesis of 1,4-dione-2-pentyl)pent-2-ene

[0964] According to the synthesis method from step 3 to step 6 of Example 59, the compound e of Example 59 was replaced by the compound b of Example 62, and the other operations were the same to obtain (E)-1-((1 3 S)-6 6 -Fluoro-3 6 -Methoxy-5,5-dioxo-7-oxa-5-thia-4-aza-2(8,2)-naphthyridine-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 -yl)pent-2-ene-1,4-dione.

[0965] Its structural characterization is as follows: 1 H NMR (400 MHz, CDCl3) δ ppm 8.73-8.55(m,3H),8.35-8.32(m,1H),8.02(d,J=8.8Hz,1H),7.69-7.55(m, 1H),7.48-7.42(m,1H),7.12-7.04(m,1H),7.00-6.90(m,3H),5.68-5.66(m ,1H),5.19-4.93(m,2H),4.79-4.58(m,2H),4.19-4.14(m,0.7H),4.08(s,3 H),4.03-4.01(m,0.3H),3.84-3.74(m,1H),3.64-3.37(m,2H),2.40(s,3H).

[0966] ESI-MS m / z:619.2[M+H] + .

[0967] Example 63 (E)-1-((1 3 R)-2 2 -Amino-6 4 -Fluoro-3 6 -Methoxy-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinazoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 Synthesis of 1,4-dione-2-pentyl)pent-2-ene

[0968] Step 1. Synthesis of compound c

[0969] Compound a (300 mg, 1.08 mmol) was dissolved in 8 mL of DCM, and DIEA (421 mg, 3.26 mmol) and compound b (280 mg, 1.30 mmol) were added. The reaction was allowed to react at room temperature for 1 h. After completion, the mixture was extracted with water and DCM, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified on a silica gel column to afford compound c (399 mg, 0.87 mmol, 81% yield).

[0970] Its structural characterization is as follows: ESI-MS m / z: 457.1, 459.1 [M+H] + .

[0971] Step 2: Synthesis of Compound e

[0972] Compound c (399 mg, 0.87 mmol) was dissolved in 10 mL of DMSO, and cesium carbonate (851 mg, 2.61 mmol) and compound d (291 mg, 1.74 mmol) were added. The mixture was stirred at room temperature overnight. After completion, water and EA were added to extract the mixture. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified on a silica gel column to afford compound e (327 mg, 0.56 mmol, 64% yield).

[0973] Its structural characterization is as follows: ESI-MS m / z: 588.2, 590.1 [M+H] + .

[0974] Step 3. Synthesis of compound g

[0975] Compound e (327 mg, 0.56 mmol), Pd(dppf)Cl2 (41 mg, 0.056 mmol), compound f (262 mg, 0.62 mmol), and potassium carbonate (155 mg, 1.12 mmol) were dissolved in 1,4-dioxane / H2O (10 mL / 2 mL) and stirred at 70°C for 4 h under nitrogen. After completion of the reaction, the mixture was extracted with water and EA, dried over anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure and purified by column chromatography to obtain compound g (303 mg, 0.38 mmol, 67% yield).

[0976] Its structural characterization is as follows: ESI-MS m / z: 808.3[M+H] + .

[0977] Step 4. Synthesis of compound h

[0978] Compound g (303 mg, 0.38 mmol) was dissolved in DCM (10 mL) at room temperature, and TFA (2 mL) was added and stirred for 30 min. After the reaction was complete, the mixture was concentrated under reduced pressure and purified by reverse phase column to obtain compound h (197 mg, 0.35 mmol, 93% yield).

[0979] Its structural characterization is as follows: ESI-MS m / z: 558.2[M+H] + .

[0980] Step 5. Synthesis of Compound I

[0981] Compound h (197 mg, 0.35 mmol) was dissolved in THF (15 mL) at room temperature, and sodium hydride (70 mg, 1.75 mmol, 60%) was added portionwise to the reaction mixture. The mixture was heated to 70°C and stirred for 2 h under nitrogen. After completion, the reaction was quenched with ice water and concentrated under reduced pressure at room temperature to afford the crude product, which was then purified by reverse-phase MPLC to afford compound i (160 mg, 0.30 mmol, 85% yield).

[0982] Its structural characterization is as follows: ESI-MS m / z: 538.2[M+H] + .

[0983] Step 6, (E)-1-((1 3 R)-2 2 -Amino-6 4 -Fluoro-3 6 -Methoxy-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinazoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 Synthesis of 1,4-dione-2-pentyl)pent-2-ene

[0984] Compounds i (160 mg, 0.30 mmol) and j (41 mg, 0.36 mmol) were dissolved in THF (10 mL) at room temperature. DIEA (116 mg, 0.90 mmol) was added, followed by 1-propylphosphoric anhydride (286 mg, 0.45 mmol, 50%). After the reaction was complete, the mixture was concentrated under reduced pressure and then purified by high pressure liquid chromatography (method 1) to give (E)-1-((1 3 R)-2 2 -Amino-6 4 -Fluoro-3 6 -Methoxy-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinazoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 -yl)pent-2-ene-1,4-dione (25 mg, 0.038 mmol, 13% yield).

[0985] Its structural characterization is as follows: 1H NMR(400MHz,DMSO-d6)δppm 10.10(s,1H),8.25(s,0.74H),8.17-8.14(m,1.26H),8.10-8.05(m,1H),7.94(d,J=12.8Hz,1H ),7.86(s,1H),7.5-7.35(m,3H),7.11-7.07(m,1H),6.79-6.73(m,3H),5.38-5.23(m,1H),5.0 5(d,J=10.0Hz,0.7H),4.74-4.69(m,1H),4.55(d,J=12.4Hz,0.3H),4.31-4.05(m,2H),3.93-3 .91(m,1H),3.91(s,3H),3.60-3.53(m,1H),3.08-2.93(m,2H),2.39(s,2.2H),2.28(s,0.8H).

[0986] ESI-MS m / z:634.2[M+H] + .

[0987] Example 64 (E)-1-((1 3 S)-2 2 -Amino-6 4 -Fluoro-3 6 -Methoxy-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinazoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 Synthesis of 1,4-dione-2-pentyl)pent-2-ene

[0988] According to the synthetic method from step 1 to step 6 of Example 63, the compound b of Example 63 was replaced by the compound b of Example 64, and the other operations were the same to obtain (E)-1-((1 3 S)-2 2 -Amino-6 4 -Fluoro-3 6 -Methoxy-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinazoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 -yl)pent-2-ene-1,4-dione.

[0989] Its structural characterization is as follows: 1H NMR(400MHz,DMSO-d6)δppm 10.10(s,1H),8.25(s,0.74H),8.20-8.12(m,1.26H),8.10-8.00(m,1H),8.00-7.89(m,1H),7.85(s,1H),7 .55-7.28(m,3H),7.17-7.01(m,1H),6.85-6.67(m,1H),6.66-6.46(m,2H),5.39-5.22(m,1H),5.09-5.00( m,0.74H),4.89-4.63(m,1.26H),4.54(d,J=12.8Hz,0.24H),4.29(d,J=12.8Hz,0.76H),4.17(d,J=12.8Hz ,1H),3.93-3.91(m,1H),3.91(s,3H),3.62-3.51(m,1H),3.19-2.85(m,2H),2.39(s,2.2H),2.28(s,0.8H).

[0990] ESI-MS m / z:634.2[M+H] + .

[0991] Example 65 (E)-1-((1 3 S)-2 8 ,6 4 -Difluoro-3 6 -Methoxy-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinazoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 Synthesis of 1,4-dione-2-pentyl)pent-2-ene

[0992] According to the synthetic method from step 1 to step 7 of Example 53, the compounds a and d of Example 53 were replaced by the compounds a and d of Example 65, respectively, and the other operations were the same to obtain (E)-1-((1 3 S)-2 8 ,6 4 -Difluoro-3 6 -Methoxy-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinazoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 -yl)pent-2-ene-1,4-dione.

[0993] Its structural characterization is as follows: 1H NMR(400MHz,DMSO-d6)δ10.18(s,1H),8.79(s,1H),8.43-8.25(m,2H),8.25-8.11(m,1H),8.11-8.00(m,1H)7.98-7.79(m ,1H),7.53-7.41(m,1.2H),7.38-7.29(m,0.8H),7.17-7.02(m,1H),6.83-6.63(m,1H),5.42-5.21(m,1H),5.16-4.98(m, 0.8H),4.91-4.77(m,0.8H),4.76-4.65(m,0.4H),4.63-4.50(m,0.2H),4.46-4.27(m,1.8H),4.12-3.94(m,0.8H),4.94- 4.91(m,0.2H),4.93(s,3H),3.69-3.52(m,1H),3.30-3.18(m,0.8H),3.17-2.94(m,1.2H),2.39(s,2.4H),2.27(s,0.6H).

[0994] ESI-MS m / z:637.2[M+H] + .

[0995] Example 66 (E)-1-((1 3 R)-2 8 ,6 4 -Difluoro-3 6 -Methoxy-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinazoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 Synthesis of 1,4-dione-2-pentyl)pent-2-ene

[0996] According to the synthetic method from step 1 to step 7 of Example 53, the compound a of Example 53 was replaced by the compound a of Example 66, and the other operations were the same to obtain (E)-1-((1 3 R)-2 8 ,6 4 -Difluoro-3 6 -Methoxy-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinazoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 -yl)pent-2-ene-1,4-dione.

[0997] Its structural characterization is as follows: 1H NMR(400MHz,DMSO-d6)δ10.18(s,1H),8.79(s,1H),8.43-8.25(m,2H),8.25-8.11(m,1H),8.11-8.00(m,1H)7.98-7.79( m,1H),7.53-7.41(m,1.2H),7.38-7.29(m,0.8H),7.17-7.02(m,1H),6.83-6.63(m,1H),5.42-5.21(m,1H),5.16-4.98( m,0.8H),4.91-4.77(m,0.8H),4.76-4.65(m,0.4H),4.63-4.27(m,2H),4.12-3.94(m,0.8H),4.94-4.91(m,0.2H),4.93 (s,3H),3.65-3.53(m,0.8H),3.46-3.35(m,1H),3.25-3.18(m,0.2H),3.17-2.93(m,1H),2.39(s,2.4H),2.27(s,0.6H).

[0998] ESI-MS m / z:637.2[M+H] +

[0999] Example 67 (E)-1-((1 3 S)-6 4 -Fluoro-3 6 -Methoxy-2 8 -methyl-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinazoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 Synthesis of 1,4-dione-2-pentyl)pent-2-ene

[1000] According to the synthetic method from step 1 to step 7 of Example 53, the compounds a and d of Example 53 were replaced by compounds a and d of Example 67, respectively, and the other operations were the same to obtain (E)-1-((1 3 S)-6 4 -Fluoro-3 6 -Methoxy-2 8 -methyl-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinazoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 -yl)pent-2-ene-1,4-dione.

[1001] Its structural characterization is as follows: 1H NMR(400MHz,DMSO-d6)δppm 10.27-10.16(m,1H),8.88(s,1H),8.45-8.30(m,2H),8.26-8.18(m,1H),8.17-8.08(m,1H),8.05-7.9 2(m,1H),7.59-7.51(m,1H),7.50-7.38(m,1H),7.23-7.10(m,1H),6.87-6.72(m,1H),5.50-5.30(m,1 H),5.19-5.07(m,0.77H),4.95-4.74(m,1.23H),4.69-4.60(m,0.25H),4.53-4.34(m,1.7,5H),4.06- 3.95(m,4H),3.73-3.63(m,1H),3.29-3.05(m,2H),2.77-2.72(m,3H),2.45(s,2H),2.40-2.32(m,1H).

[1002] ESI-MS m / z:633.2[M+H] + .

[1003] Example 68 (E)-1-((1 3 R)-6 4 -Fluoro-3 6 -Methoxy-2 8 -methyl-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinazoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 Synthesis of 1,4-dione-2-pentyl)pent-2-ene

[1004] According to the synthetic method from step 1 to step 7 of Example 53, the compound a of Example 53 was replaced by the compound a of Example 68, and the other operations were the same to obtain (E)-1-((1 3 R)-6 4 -Fluoro-3 6 -Methoxy-2 8 -methyl-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinazoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 -yl)pent-2-ene-1,4-dione.

[1005] Its structural characterization is as follows: 1H NMR(400MHz,DMSO-d6)δppm 10.20-10.09(m,1H),8.82(s,1H),8.36-8.24(m,2H),8.19-8.04(m,2H),7.99-7.86(m,1H),7.54 -7.46(m,1H),7.45-7.34(m,1H),7.17-7.06(m,1H),6.80-6.66(m,1H),5.46-5.25(m,1H),5.12- 4.98(m,0.77H),4.87-4.65(m,1.25H),4.63-4.52(m,0.26H),4.43-4.23(m,1.78H),4.13-3.89( m,4H),3.66-3.57(m,1H),3.17-3.01(m,2H),2.73-2.65(m,3H),2.39(s,2H),2.35-2.27(m,1H).

[1006] ESI-MS m / z:633.2[M+H] +

[1007] Example 69 (E)-1-(6 4 -Fluoro-3 6 -methoxy-5,5-dioxo-7-oxa-5-thia-4,11-diaza-2(4,6)-quinazoline-3(3,5)-pyridine-1(1,3)-azetidine-6(1,2)-phencyclodecane-11-yl)pent-2-ene-1,4-dione

[1008] Step 1. Synthesis of compound c

[1009] Compound a (150 mg, 0.62 mmol) was dissolved in 5 mL of DCM at room temperature. DIEA (160 mg, 1.24 mmol) and compound b (128 mg, 0.74 mmol) were added and allowed to react at room temperature for 1 h. The mixture was extracted with water and DCM, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified on a silica gel column to afford compound c (218 mg, 0.57 mmol, 92% yield).

[1010] Its structural characterization is as follows: ESI-MS m / z: 379.1, 381.1 [M+H] + .

[1011] Step 2: Synthesis of Compound e

[1012] Compound c (218 mg, 0.57 mmol) was dissolved in DMF (8 mL) at room temperature, and sodium hydride (91 mg, 2.28 mmol) was added, followed by compound d (721 mg, 2.85 mmol). The mixture was stirred at room temperature for 2 h. The mixture was quenched with saturated aqueous ammonium chloride, extracted with EA, and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure and purified by silica gel column chromatography to afford compound e (213 mg, 0.39 mmol, 68% yield).

[1013] Its structural characterization is as follows: ESI-MS m / z: 551.2, 553.2 [M+H] + .

[1014] Step 3. Synthesis of compound g

[1015] Compound e (213 mg, 0.39 mmol), f (200 mg, 0.47 mmol), NaCO (83 mg, 0.78 mmol), and Pd(dppf)Cl (29 mg, 0.039 mmol) were dissolved in a mixture of 1,4-dioxane (5 mL) and water (1 mL). The atmosphere was replaced with nitrogen and stirred at 90°C for 1 h. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography to afford compound g (121 mg, 0.16 mmol, 41% yield).

[1016] Its structural characterization is as follows: ESI-MS m / z: 771.3[M+H] + .

[1017] Step 4. Synthesis of compound h

[1018] Compound g (121 mg, 0.16 mmol) was dissolved in THF (8 mL) at room temperature, and TBAF (84 mg, 0.32 mmol) was added. The mixture was allowed to react at room temperature for 2 h. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography to obtain compound h (73 mg, 0.11 mmol, 69% yield).

[1019] Its structural characterization is as follows: ESI-MS m / z: 657.2[M+H] + .

[1020] Step 5. Synthesis of Compound I

[1021] Compound h (73 mg, 0.11 mmol) was dissolved in DCM (3 mL) at room temperature, and TFA (1 mL) was added. The mixture was reacted at room temperature for 1 h, concentrated under reduced pressure, and purified on a C18 silica gel column to afford compound i (52 mg, 0.094 mmol, 85% yield).

[1022] Its structural characterization is as follows: ESI-MS m / z: 557.2[M+H] + .

[1023] Step 6. Synthesis of Compound J

[1024] Compound i (52 mg, 0.094 mmol) was dissolved in 8 mL of THF at room temperature, and sodium hydride (15 mg, 0.38 mmol) was added. The mixture was stirred at 50°C for 2 h. The mixture was quenched with saturated aqueous ammonium chloride, extracted with EA, dried over anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure to afford compound j (21 mg, 0.039 mmol, 41% yield).

[1025] Its structural characterization is as follows: ESI-MS m / z: 537.2[M+H] + .

[1026] Step 7, (E)-1-(6 4 -Fluoro-3 6 Synthesis of 1,4-dione-6-methoxy-5,5-dioxo-7-oxa-5-thia-4,11-diaza-2(4,6)-quinazoline-3(3,5)-pyridine-1(1,3)-azetidine-6(1,2)-phencyclodecane-11-yl)pent-2-ene

[1027] Compound j (21 mg, 0.039 mmol) was dissolved in THF (4 mL), and compound k (5 mg, 0.047 mmol) and DIEA (15 mg, 0.12 mmol) were added. The temperature was lowered to -78°C, and T3P (50 μL, 0.078 mmol, 50% EA solution) was added. The mixture was reacted at -78°C for 2 h. 10 mL of water was added to quench the mixture, and the mixture was extracted with EA. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The mixture was then purified by high pressure liquid chromatography (method 1) to obtain (E)-1-(6 4 -Fluoro-3 6 -methoxy-5,5-dioxo-7-oxa-5-thia-4,11-diaza-2(4,6)-quinazoline-3(3,5)-pyridine-1(1,3)-azetidin-6(1,2)-phencyclodecane-11-yl)pent-2-ene-1,4-dione (5 mg, 0.0079 mmol, yield 20%).

[1028] Its structural characterization is as follows: 1H NMR(400MHz,MeOD-d4)δppm 8.50(s,1H),8.15-8.10(m,1H),8.03(s,1H),7.82(s,1H),7.72-7.58(m,2H),7. 54-7.33(m,1H),7.27-7.15(m,1H),7.14-7.05(m,1H),7.04-6.90(m,1H),6.80-6 .63(m,1H),5.53-4.92(m,4H),4.70-4.48(m,1H),4.37-4.25(m,1.7H),4.14-3.9 8(m,4.3H),3.82-3.56(m,1H),2.42(s,2.4H),2.35(s,0.6H),2.24-2.06(m,2H).

[1029] ESI-MS m / z:633.2[M+H] + .

[1030] Example 70 (E)-1-(6 4 -Fluoro-3 6 -methoxy-5,5-dioxo-7-oxa-5-thia-4,10-diaza-2(4,6)-quinazoline-3(3,5)-pyridine-1(1,3)-azetidine-6(1,2)-phencyclodecane-10-yl)pent-2-ene-1,4-dione

[1031] Steps 1 to 5

[1032] According to the synthesis method from step 1 to step 5 of Example 69, the compound d of Example 69 was replaced by the compound d of Example 70, and the other operations were the same to obtain compound i.

[1033] Its structural characterization is as follows: ESI-MS m / z: 543.2[M+H] + .

[1034] Step 6. Synthesis of Compound J

[1035] Compound i (133 mg, 0.24 mmol) was dissolved in 5 mL of DMSO and potassium tert-butoxide (135 mg, 1.20 mmol) was added. The mixture was stirred at room temperature for 2 h. The mixture was quenched with saturated aqueous ammonium chloride and extracted with EA. The organic phase was concentrated under reduced pressure and purified on a C18 column to afford compound j (38 mg, 0.073 mmol, 30% yield).

[1036] Its structural characterization is as follows: ESI-MS m / z: 523.2[M+H] + .

[1037] Step 7, (E)-1-(6 4 -Fluoro-3 6 Synthesis of 1,4-dione-6-methoxy-5,5-dioxo-7-oxa-5-thia-4,10-diaza-2(4,6)-quinazoline-3(3,5)-pyridine-1(1,3)-azetidine-6(1,2)-phencyclodecane-10-yl)pent-2-ene

[1038] Compound j (38 mg, 0.073 mmol) was dissolved in 4 mL of THF, and compound k (10 mg, 0.088 mmol) and DIEA (28 mg, 0.22 mmol) were added. The temperature was lowered to -78°C, and T3P (93 μL, 0.15 mmol, 50% EA solution) was added. The mixture was reacted at -78°C for 2 h. Water (10 mL) was added to quench the mixture and the mixture was extracted with EA. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and then purified by high pressure liquid chromatography (method 1) to obtain compound (E)-1-(6 4 -Fluoro-3 6 -methoxy-5,5-dioxo-7-oxa-5-thia-4,10-diaza-2(4,6)-quinazoline-3(3,5)-pyridine-1(1,3)-azetidine-6(1,2)-phencyclodecane-10-yl)pent-2-ene-1,4-dione (17 mg, 0.027 mmol, yield 37%).

[1039] Its structural characterization is as follows: 1 H NMR(400MHz,DMSO-d6)δppm 10.22(s,1H),8.52(s,1H),8.33(d,J=1.6Hz,1H),8.20-8.06(m,1H),7.84-7.69(m,2H),7.53-7.24(m,2H),7.24-7.05(m,2H),7. 05-6.89(m,1H),6.77(d,J=15.6Hz,1H),5.20-4.74(m,1H),4.73-4.53(m,4H),4.52-4.10(m,3H),4.09-3.76(m,4H),2.39(s,3H).

[1040] ESI-MS m / z:619.2[M+H] + .

[1041] Example 71 (E)-1-(6 4 -Fluoro-3 6Synthesis of 1,4-dione-6-methoxy-5,5-dioxo-7-oxa-5-thia-4,12-diaza-2(4,6)-quinazoline-3(3,5)-pyridine-1(1,3)-azetidine-6(1,2)-benzocyclododecan-12-yl)pent-2-ene-1,4-dione

[1042] Step 1. Synthesis of compound b

[1043] Compound a (1.0 g, 6.5 mmol) was dissolved in 20 mL of DMF, and imidazole (1.1 g, 16.3 mmol) and TBDPSCl (2.3 g, 8.5 mmol) were added. The mixture was allowed to react at room temperature for 2 h. After completion, the reaction was diluted with water, extracted with EA, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified on a silica gel column to afford compound b (2.01 g, 5.0 mmol, 78% yield).

[1044] Step 2 to Step 7, (E)-1-(6 4 -Fluoro-3 6 Synthesis of 1,4-dione-6-methoxy-5,5-dioxo-7-oxa-5-thia-4,12-diaza-2(4,6)-quinazoline-3(3,5)-pyridine-1(1,3)-azetidine-6(1,2)-benzocyclododecan-12-yl)pent-2-ene

[1045] According to the synthesis method from step 2 to step 7 of Example 70, the compound d of Example 70 was replaced by the compound b of Example 71, and the other operation methods were the same to obtain (E)-1-(64-fluoro-36-methoxy-5,5-dioxo-7-oxa-5-thia-4,12-diaza-2(4,6)-quinazoline-3(3,5)-pyridine-1(1,3)-azetidine-6(1,2)-phenylcyclododecanand-12-yl)pent-2-ene-1,4-dione.

[1046] Its structural characterization is as follows: 1 H NMR(400MHz,MeOD)δppm 8.47(s,1H),7.93-7.84(m,3H),7.82-7.75(m,1H),7.56-7.50(m,1H),7.48-7.42(m,1H),7.34(d,J=15.6Hz,1H),6 .97-6.82(m,3H),4.78-4.68(m,5H),4.17(s,2H),4.05(s,3H),3.68-3.56(m,2H),2.36(s,3H),1.84-1.74(m,4H).

[1047] ESI-MS m / z:647.2[M+H]+ .

[1048] Example 72 (E)-1-(6 4 -Fluoro-3 6 Synthesis of 2-methoxy-5,5-dioxo-7-oxa-5-thia-4,11-diaza-2(4,6)-quinazoline-3(3,5)-pyridine-1(1,4)-piperidin-6(1,2)-phenanthene-11-yl)pent-2-ene-1,4-dione

[1049] According to the synthetic method from step 1 to step 6 of Example 69, the compound b of Example 69 was replaced by the compound b of Example 72, and the other operations were the same to obtain (E)-1-(6 4 -Fluoro-3 6 -methoxy-5,5-dioxo-7-oxa-5-thia-4,11-diaza-2(4,6)-quinazoline-3(3,5)-pyridine-1(1,4)-piperidin-6(1,2)-phenanthene-11-yl)pent-2-ene-1,4-dione.

[1050] Its structural characterization is as follows: 1 H NMR(400MHz,DMSO-d6)δ10.50(s,1H),8.70-8.67(m,1H),8.42(s,1H),8.31-8.25(m,1H),8.07-8.01(m,1H ),7.92-7.85(m,2H),7.79-7.70(m,1H),7.55(d,J=12.0Hz,0.6H),7.43(d,J=12.0Hz,0.4H),7.26-7.22(m, 1H),6.91-6.85(m,1H),6.78-6.70(m,1H),4.55-4.53(m,0.4H),4.37-4.18(m,3.6H),4.07-4.04(m,3H),3 .98-3.80(m,2H),3.58-3.51(m,1H),3.11-3.05(m,2H),2.39(m,3H),2.15-2.00(m,5H),1.77-1.74(m,1H).

[1051] ESI-MS m / z:661.2[M+H] + .

[1052] Example 73 (E)-1-((1 3 S)-6 4 ,6 5 -Difluoro-3 6-Methoxy-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinazoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 Synthesis of (-)pent-2-ene-1,4-dione

[1053] According to the synthesis method from step 1 to step 5 of Example 6, the compounds a and d of Example 6 were replaced by compounds a and d of Example 73 respectively. The other operations were the same to obtain (E)-1-((1 3 S)-6 4 ,6 5 -Difluoro-3 6 -Methoxy-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinazoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 -yl)pent-2-ene-1,4-dione.

[1054] Its structural characterization is as follows: 1H NMR (400 MHz, DMSO-d6) δ ppm 10.16 (s, 1H), 8.77 (s, 1H), 8.36-8.24 (m, 3H), 8.14-8.09 (m, 2H), 7.95 (d, J = 8 Hz, 1H), 7.77-7.65 (m, 1H), 7.51-7.44 (m, 1H), 6.77-6.67 (m, 1H), 5.37-5.27 (m, 1H), 5.08-5.05 (m, 0.7H), 4.81-4.7 8(m,1.3H),4.59-4.56(m,0.3H),4.34-4.31(m,1.7H),4.11-4.07(m,0.3H),3.95-3.92(m,3.7H) ,3.58(t,J=12Hz,0.8H),3.40-3.19(m,1.2H),3.13-2.97(m,1H),2.39(s,2.4H),2.28(s,0.6H).

[1055] ESI-MS m / z:637.2[M+H] + .

[1056] Example 74 (E)-1-((1 3 S)-6 4 -Cyano-3 6 -Methoxy-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinazoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4Synthesis of 1,4-dione-2-pentyl)pent-2-ene

[1057] According to the synthetic method from step 1 to step 5 of Example 13, the compound d of Example 13 was replaced by the compound d of Example 74, and the other operations were the same to obtain (E)-1-((1 3 S)-6 4 -Cyano-3 6 -Methoxy-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinazoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 -yl)pent-2-ene-1,4-dione.

[1058] Its structural characterization is as follows: 1 H NMR(400MHz,DMSO-d6)δppm 10.54-10.40(m,1H),8.85(s,1H),8.42-8.25(m,3H),8.18(d,J=8.4Hz,1H),8.14-8.03(m,1.2H),7.99-7.92(m,1 .8H),7.68(d,J=8.4Hz,1H),7.50(d,J=15.6Hz,1H),6.78(d,J=15.6Hz,1H),,5.47-5.30(m,1H),5.16-5.07(m,0. 76H),4.93-4.84(m,0.79H),4.82-4.73(m,0.40H),4.65-4.50(m,1H),4.36(d,J=12.8Hz,0.81H),4.24-4.16(m,0 .27H), 4.06 (d, J = 8.8Hz, 1H), 3.94 (s, 3H), 3.67-3.59 (m, 1H), 3.27-3.17 (m, 2H), 2.40 (s, 2H), 2.34-2.27 (m, 1H).

[1059] ESI-MS m / z:626.2[M+H] +

[1060] Example 75 (E)-1-((1 3 S)-3 6 -6-chloro- 3 -Fluoro-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinazoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 Synthesis of 1,4-dione-2-pentyl)pent-2-ene

[1061] Step 1. Synthesis of compound c

[1062] Compound a (300 mg, 0.71 mmol), Pd(dppf)Cl2 (52 mg, 0.071 mmol), compound b (198 mg, 0.78 mmol), and potassium carbonate (196 mg, 1.42 mmol) were dissolved in a mixture of 1,4-dioxane and H2O (10 mL / 2 mL) at room temperature and reacted at 70°C under nitrogen for 4 h. After completion of the reaction, water was added, the mixture was extracted with EA, and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure and purified by normal phase column chromatography to afford compound c (216 mg, 0.46 mmol, 65% yield).

[1063] Its structural characterization is as follows: ESI-MS m / z: 471.2[M+H] + .

[1064] Step 2: Synthesis of Compound e

[1065] Compound c (216 mg, 0.46 mmol) was dissolved in 10 mL of pyridine at room temperature, and compound d (146 mg, 0.69 mmol) was added. The mixture was stirred at room temperature for 2 h. After completion of the reaction, the mixture was diluted with water, extracted with EA, and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure and purified by normal phase column chromatography to afford solid compound e (155 mg, 0.24 mmol, 54% yield).

[1066] Its structural characterization is as follows: ESI-MS m / z: 647.2[M+H] + .

[1067] Steps 3 to 5, (E)-1-((1 3 S)-3 6 -6-chloro- 3 -Fluoro-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinazoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 Synthesis of 1,4-dione-2-pentyl)pent-2-ene

[1068] According to the synthesis method from step 3 to step 5 of Example 1, the compound e of Example 1 was replaced by the compound e of Example 75, and the other operations were the same to obtain (E)-1-((1 3 S)-3 6 -6-chloro- 3 -Fluoro-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinazoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4-yl)pent-2-ene-1,4-dione.

[1069] Its structural characterization is as follows: 1 H NMR(400MHz,DMSO-d6)δppm 10.50(s,1H),8.88(s,1H),8.74(s,1H),8.66(d,J=2.0Hz,1H),8.52-8.40(m,2H),8.02( d,J=8.8Hz,1H),7.90(d,J=8.4Hz,1H),7.70-7.62(m,1H),7.52-7.43(m,2H),6.70-6.56( m,1H),5.31-5.25(m,1H),5.11-5.08(m,0.65H),4.60-4.57(m,1.35H),4.28-4.12(m,2H) ,3.86-3.65(m,0.7H),3.58-3.54(m,1.3H),3.22-3.18(m,2H),2.36(s,2H),2.23(s,1H).

[1070] ESI-MS m / z:623.1[M+H] + .

[1071] Example 76 (E)-1-((1 3 S)-3 6 -6-chloro- 4 -Fluorine-2 8 -Methoxy-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinazoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 Synthesis of 1,4-dione-2-pentyl)pent-2-ene

[1072] Step 1. Synthesis of compound b

[1073] Compound a (400 mg, 1.57 mmol) was dissolved in 10 mL of phosphorus oxychloride. Stirred at 100°C for 3 h. The mixture was concentrated under reduced pressure. The residue was dissolved in EA, washed with saturated aqueous sodium bicarbonate, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified on a silica gel column to afford compound b (303 mg, 1.11 mmol, 71% yield).

[1074] Its structural characterization is as follows: ESI-MS m / z: 272.9, 274.9 [M+H] + .

[1075] Step 2: Synthesis of Compound d

[1076] Compound b (303 mg, 1.11 mmol) was dissolved in 8 mL of DCM at room temperature. DIEA (580 μL, 3.33 mmol) and compound c (287 mg, 1.33 mmol) were added and allowed to react at room temperature for 3 h. After completion, the mixture was extracted with water and DCM, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified on a silica gel column to afford compound d (371 mg, 0.82 mmol, 74% yield).

[1077] Its structural characterization is as follows: ESI-MS m / z: 453.1, 455.1 [M+H] + .

[1078] Step 3. Synthesis of compound f

[1079] Compound d (371 mg, 0.82 mmol), Pd(dppf)Cl2 (60 mg, 0.082 mmol), compound e (349 mg, 0.82 mmol), and potassium carbonate (226 mg, 1.64 mmol) were dissolved in a mixture of 1,4-dioxane (10 mL) and H2O (2 mL) at room temperature and stirred at 70°C under nitrogen for 4 h. The mixture was diluted with water, extracted with EA, and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure and purified by normal phase column chromatography to afford compound f (352 mg, 0.52 mmol, 64% yield) as a solid.

[1080] Its structural characterization is as follows: ESI-MS m / z: 677.2[M+H] + .

[1081] Step 4. Synthesis of compound g

[1082] Compound f (352 mg, 0.52 mmol) was dissolved in DCM (15 mL) at room temperature, TFA (3 mL) was added and stirred for 30 min. After the reaction was complete, the mixture was concentrated under reduced pressure and purified by reverse phase column to obtain compound g (271 mg, 0.47 mmol, 91% yield).

[1083] Its structural characterization is as follows: ESI-MS m / z: 577.1[M+H] + .

[1084] Step 5. Synthesis of compound h

[1085] Compound g (271 mg, 0.47 mmol) was dissolved in THF / DMF (15 mL / 5 mL) at room temperature, and sodium hydride (188 mg, 4.7 mmol, 60%) was added portionwise to the reaction mixture. The mixture was heated to 70°C and stirred for 2 h under nitrogen. After completion of the reaction, the mixture was quenched with ice water and concentrated under reduced pressure at room temperature to afford the crude product. The crude product was purified by reverse-phase MPLC to afford compound h (212 mg, 0.38 mmol, 81% yield).

[1086] Its structural characterization is as follows: ESI-MS m / z: 557.1[M+H] + .

[1087] Step 6, (E)-1-((1 3 S)-3 6 -6-chloro- 4 -Fluorine-2 8 -Methoxy-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinazoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 Synthesis of 1,4-dione-2-pentyl)pent-2-ene

[1088] Compounds h (212 mg, 0.38 mmol) and i (52 mg, 0.46 mmol) were dissolved in THF (10 mL) at room temperature. DIEA (147 mg, 1.14 mmol) was added to the reaction solution, followed by 1-propylphosphoric anhydride (263 mg, 0.57 mmol, 50%). After the reaction was complete, water and EA were added for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and then purified by high pressure liquid chromatography (method 1) to obtain (E)-1-((1 3 S)-3 6 -6-chloro- 4 -Fluorine-2 8 -Methoxy-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinazoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 -yl)pent-2-ene-1,4-dione (65 mg, 0.1 mmol, 26.3% yield).

[1089] Its structural characterization is as follows: 1H NMR(400MHz,DMSO-d6)δppm 10.60(s,1H),8.79(s,1H),8.64(d,J=2.4Hz,1H),8.55(s,0.2H),8.51(s,0.8H),8.05(dd,J=6.4,8.8Hz,1H),7.71-7.66(m, 2H),7.52-7.38(m,2H),7.16-7.12(m,1H),6.78-6.69(m,1H),5.34(t,J=10.4Hz,0.3H),5.28(t,J=10.4Hz,0.7H),5.07(d,J =10.0Hz,0.7H),4.80(d,J=14.0Hz,0.7H),4.72-4.71(m,0.3H),4.58(d,J=14.0Hz,0.3H),4.32(d,J=12.8Hz,1.7H),4.13-4 .09(m,0.3H),4.06(s,3H),3.98(d,J=9.6Hz,1H),3.58(t,J=12.4Hz,1H),3.18-2.98(m,2H),2.40(s,2.2H),2.28(s,0.8H).

[1090] ESI-MS m / z:653.1[M+H] + .

[1091] Example 77 (E)-1-((1 3 S)-2 8 -ethoxy-6 4 -Fluoro-3 6 -Methoxy-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinazoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 Synthesis of 1,4-dione-2-pentyl)pent-2-ene

[1092] Step 1. Synthesis of compound b

[1093] Compound a (400 mg, 1.65 mmol) was dissolved in THF (10 mL) at room temperature. Ethanol (380 mg, 8.25 mmol) and sodium hydroxide (660 mg, 16.5 mmol, 60%) were added under ice-cooling. The mixture was heated to 70°C and stirred for 3 h. LC-MS monitored the reaction for completion. The solution was concentrated under reduced pressure, an appropriate amount of water was added, and the mixture was stirred for 10 min. The solid was collected by filtration and dried to afford compound b (367 mg, 1.37 mmol, 83% yield).

[1094] Its structural characterization is as follows: ESI-MS m / z: 268.9, 270.9 [M+H] + .

[1095] Steps 2 to 7, (E)-1-((1 3 S)-2 8 -ethoxy-6 4 -Fluoro-3 6 -Methoxy-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinazoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 Synthesis of 1,4-dione-2-pentyl)pent-2-ene

[1096] According to the synthesis method from step 1 to step 6 of Example 76, the compounds a and e of Example 76 were replaced by the compounds b and f of Example 77, respectively, and the other operations were the same to obtain (E)-1-((1 3 S)-2 8 -ethoxy-6 4 -Fluoro-3 6 -Methoxy-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinazoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 -yl)pent-2-ene-1,4-dione.

[1097] Its structural characterization is as follows: 1H NMR(400MHz,DMSO-d6)δppm 10.16(s,1H),8.76(s,1H),8.34(s,2H),8.08(dd,J=6.8,9.2Hz,1H),7.63-7.57(m,2H),7.52-7.47(m,1.2H),7.38(d,J=11.2 Hz,0.8H),7.10(t,J=9.6Hz,1H),6.76(d,J=16.0Hz,1H),5.38(t,J=10.8Hz,0.2H),5.29(t,J=10.0Hz,0.8H),5.08(d,J=10.0 Hz,0.8H),4.83(d,J=13.6Hz,0.8H),4.74-4.71(m,0.2H),4.58(d,J=13.6Hz,0.2H),4.37-4.27(m,4H),4.12-4.08(m,0.2H), 3.94(s,3.8H),3.63-3.57(m,1H),3.25-3.19(m,1H),3.15-3.09(m,1H),2.40(s,2.4H),2.29(s,0.6H),1.46(t,J=6.8Hz,3H).

[1098] ESI-MS m / z:663.2[M+H] + .

[1099] Example 78 (E)-1-((1 3 S)-6 4 -Fluoro-3 6 -Methoxy-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinazoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 Synthesis of 1,4-dione-2-hexane

[1100] According to the synthesis method of step 5 in Example 1, the compound h in Example 1 was replaced by the compound b in Example 78, and the other operations were the same to obtain (E)-1-((1 3 S)-6 4 -Fluoro-3 6 -Methoxy-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinazoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 -yl)hex-2-ene-1,4-dione.

[1101] Its structural characterization is as follows: 1H NMR(400MHz,DMSO-d6)δppm 10.18(s,1H),8.78(s,1H),8.34-8.22(m,3H),8.10-8.05(m,2H),7.95(d,J=8Hz,1H),7.49-7.36(m,2H), 7.10(t,J=8Hz,1H),6.88-6.84(m,1H),5.34-5.29(m,1H),5.10-5.07(m,0.7H),4.85-4.70(m,1.3H),4.6 0-4.57(m,0.3H),4.39-4.29(m,1.7H),4.13-4.10(m,0.3H),3.96-3.93(m,3.7H),3.57(t,J=12Hz,0.8H) ,3.37-3.20(m,1.2H),3.15-2.96(m,1H),2.82-2.77(m,1.6H),2.68-2.63(m,0.4H),1.04-0.96(m,3H)).

[1102] ESI-MS m / z:633.2[M+H] + .

[1103] Example 79 (E)-4-((1 3 S)-6 4 -Fluoro-3 6 -Methoxy-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinazoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 Synthesis of 4-oxobut-2-enal

[1104] Step 1. Synthesis of compound b

[1105] Dissolve compound a (1.5 g, 11.7 mmol) in 20 mL of ethanol. Add triethyl orthoformate (2.1 g, 14.1 mmol) and one drop of concentrated hydrochloric acid under ice-cooling. Stir at room temperature for 5 h. Concentrate under reduced pressure and perform silica gel column chromatography to obtain compound b (2.0 g, 9.9 mmol, 85% yield).

[1106] Its structural characterization is as follows: ESI-MS m / z: 203.1[M+H] + .

[1107] Step 2: Synthesis of Compound C

[1108] Compound b (1.0 g, 4.94 mmol) was dissolved in a mixture of THF / H₂O (10 mL / 5 mL) at room temperature. Sodium hydroxide (240 mg, 6.0 mmol) was added. The mixture was stirred at room temperature for 1 h. The pH was adjusted to a weakly acidic state with dilute hydrochloric acid. The mixture was extracted with EA and water. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by normal phase column chromatography to afford compound c (610 mg, 3.53 mmol, 71% yield).

[1109] Its structural characterization is as follows: ESI-MS m / z: 173.1[MH] - .

[1110] Step 3. Synthesis of compound e

[1111] Compound d (100 mg, 0.19 mmol) was dissolved in THF (8 mL), and compound c (40 mg, 0.23 mmol) and DIEA (74 mg, 0.57 mmol) were added. The temperature was cooled to -78°C, and T3P (242 mg, 0.38 mmol, 50% EA solution) was added. The mixture was stirred at -78°C for 2 h. Extraction was performed with EA and water, and the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by normal phase column chromatography to obtain compound e (81 mg, 0.12 mmol, 63% yield).

[1112] Its structural characterization is as follows: ESI-MS m / z: 679.2[M+H] + .

[1113] Step 4: Compound (E)-4-((1 3 S)-6 4 -Fluoro-3 6 -Methoxy-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinazoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 Synthesis of 4-oxobut-2-enal

[1114] Compound e (81 mg, 0.12 mmol) was dissolved in 5 mL of acetonitrile, TFA / H2O (1 mL / 0.2 mL) was added, and the mixture was stirred at room temperature for 1 h. The mixture was concentrated under reduced pressure and purified by high pressure liquid chromatography (method 1) to obtain (E)-4-((1 3 S)-6 4 -Fluoro-3 6 -Methoxy-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinazoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4-yl)-4-oxobut-2-enal (35 mg, 0.058 mmol, yield 48%).

[1115] Its structural characterization is as follows: 1 H NMR(400MHz,DMSO-d6)δppm 10.23(s,1H),9.79(d,J=8.0Hz,0.8H),9.73(d,J=7.6Hz,0.2H),8.87(s,1H),8.35-8.29(m,3H),8.10-8.07(m,2 H),7.96(d,J=8.8Hz,1H),7.81(d,J=15.2Hz,1H),7.38-7.32(m,1H),7.13-7.08(m,1H),6.74-6.68(m,1H),5.32 -5.27(m,1H),5.15-5.12(m,0.8H),4.94(d,J=14.0Hz,0.8H),4.81-4.74(m,0.4H),4.69-4.66(m,1H),4.32(d,J =14.0Hz,0.8H),4.18-4.12(m,0.2H),4.04(d,J=9.2Hz,1H),3.94(s,3H),3.75-3.64(m,2H),3.31-3.24(m,1H).

[1116] ESI-MS m / z:605.2[M+H] + .

[1117] Example 80 (E)-1-((1 3 S)-6 4 -Fluoro-3 6 -Methoxy-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinazoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 Synthesis of 5-methoxypent-2-ene-1,4-dione

[1118] Step 1. Synthesis of compound b

[1119] Potassium hydroxide (5.7 g, 100 mmol) was added to compound a (10.0 g, 102 mmol). Methyl iodide (15.8 g, 112 mmol) was added dropwise under ice-cooling and stirred for 4 h. The mixture was extracted with methyl tert-butyl ether and water. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Silica gel column chromatography afforded compound b (7.0 g, 62.2 mmol, 61% yield).

[1120] Step 2: Synthesis of Compound C

[1121] Compound b (7.0 g, 62.2 mmol) was dissolved in tert-butanol (70 mL) at room temperature. Sodium dihydrogen phosphate (8.21 g, 68.4 mmol) and water (50 mL) were added under ice-cooling. A solution of sodium chlorite (12.3 g, 136.8 mmol) in water (20 mL) was slowly added dropwise to the reaction mixture, and the mixture was stirred at room temperature for 2 h. 2-Methyl-2-butene (8.7 g, 124.4 mmol) was added dropwise to the reaction mixture, and the mixture was stirred at room temperature for 2 h. The mixture was extracted with DCM and water, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by reverse-phase column chromatography to afford compound c (230 mg, 1.61 mmol, 2.5% yield).

[1122] Its structural characterization is as follows: ESI-MS m / z: 143.0[MH] - .

[1123] Step 3, (E)-1-((1 3 S)-6 4 -Fluoro-3 6 -Methoxy-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinazoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 Synthesis of 5-methoxypent-2-ene-1,4-dione

[1124] Compound d (150 mg, 0.29 mmol) was dissolved in THF (10 mL), and compound c (50 mg, 0.0.35 mmol) and DIEA (187 mg, 1.45 mmol) were added. The temperature was lowered to -78°C, and T3P (369 mg, 0.58 mmol, 50% EA solution) was added. The mixture was reacted at -78°C for 2 h. The mixture was extracted with water and DCM, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and then purified by high pressure liquid chromatography (method 1) to obtain (E)-1-((1 3 S)-6 4 -Fluoro-3 6 -Methoxy-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinazoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 -yl)-5-methoxypent-2-ene-1,4-dione (80 mg, 0.12 mmol, yield 43%).

[1125] Its structural characterization is as follows: 1H NMR(400MHz,DMSO-d6)δppm 8.74-8.72(m,1H),8.30-8.08(m,3H),7.95 -7.81(m,3H),7.24(d,J=7.6Hz,1H),6.97-6.85(m,1.3H),6.77(d,J=12.0Hz,0.7H),6.5 4(d,J=12.0Hz,1H),5.37-5.27(m,1H),5.01(d,J=10.4Hz,0.7H),4.85-4.82(m,1H),4.5 5(d,J=13.2Hz,0.3H),4.35-4.30(m,1H),4.21(s,1H),4.11-4.08(m,0.3H),3.93(d,J=9 .2Hz,0.7H),3.87-3.80(m,4H),3.53-3.47(m,3H),3.26-3.21(m,3H),3.05-2.98(m,1H).

[1126] ESI-MS m / z:649.2[M+H] + .

[1127] Example 81 (E)-1-((1 3 S)-6 4 -Fluoro-3 6 -Methoxy-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinazoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 -yl)-5-methylhex-2-en-1,4-one.

[1128] Step 1. Synthesis of compound c

[1129] Compound a (500 mg, 5.8 mmol), b (1.3 g, 18 mmol), and AcOH (350 mg, 5.83 mmol) were dissolved in 15 mL of MeOH. 500 μL of tetrahydropyrrole was added and the mixture was microwaved at 60°C for 4 h. After completion of the reaction, the mixture was concentrated under reduced pressure and purified by reverse-phase MPLC to afford compound c (220 mg, 1.40 mmol, 27% yield).

[1130] Step 2, (E)-1-((1 3 S)-6 4 -Fluoro-3 6 -Methoxy-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinazoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-14 Synthesis of 5-methylhex-2-en-1,4-one

[1131] According to the synthesis method of step 5 of Example 1, the compound h of Example 1 was replaced by the compound c of Example 81, and the other operations were the same to obtain (E)-1-((1 3 S)-6 4 -Fluoro-3 6 -Methoxy-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinazoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 -yl)-5-methylhex-2-en-1,4-one.

[1132] Its structural characterization is as follows: 1 H NMR(400MHz,DMSO-d6)δppm 10.16(s,1H),8.77(s,1H),8.34-8.21(m,3H),8.10-8.06(m,2H),7.96-7.94(m,1H),7.50(d,J=16.0Hz,1H),7.44 -7.37(m,1H),7.10(t,J=7.6Hz,1H),7.00(d,J=8.0Hz,0.7H),6.88(d,J=8.0Hz,0.3H), 5.43-5.29(m,1H),5.10-5.07(m,0.8H),4.85-4.43(m,1.2H),4.61-4.57(m,0.2H),4.39 -4.31(m,1.8H),4.11-3.93(m,1H),3.93(s,3H),3.59-3.56(m,0.4H),3.16-3.20(m,0. 6H),3.13-3.10(m,2H),2.98-2.91(m,1H),1.07(d,J=8.0Hz,4H),0.98(d,J=8.0Hz,2H).

[1133] ESI-MS m / z:647.2[M+H] + .

[1134] Example 82 (E)-1-(6 4 -Fluoro-3 6 -methoxy-5,5-dioxo-1 1 ,1 2 ,1 3 ,1 3a ,1 4 ,1 5 ,1 6 ,1 6a-Octahydro-7-oxa-5-thia-4-aza-2(4,6)-quinazoline-1(2,3a)-pyrrolo[3,4-c]pyrrolo-3(3,5)-pyrido-6(1,2)-phenylcyclooctane-1 5 Synthesis of 1,4-dione-2-pentyl)pent-2-ene

[1135] Step 1. Synthesis of compound c

[1136] Compound a (1 g, 10.2 mmol) was dissolved in 50 mL of DCM. TFA (220 μL) and compound b (6.04 g, 25.5 mmol) were added and stirred at room temperature for 20 h. After the reaction was complete, the mixture was concentrated under reduced pressure and purified on a silica gel column to afford compound c (781 mg, 2.14 mmol, 21% yield).

[1137] Its structural characterization is as follows: ESI-MS m / z: 365.2[M+H] + .

[1138] Step 2: Synthesis of Compound e

[1139] Compound c (781 mg, 2.14 mmol) was dissolved in 20 mL of DCM. Triethylamine (432 mg, 4.28 mmol) and compound d (365 mg, 2.57 mmol) were added under ice-cooling and stirred at room temperature for 2 h. The reaction was concentrated under reduced pressure, and methanol (20 mL) was added. The mixture was stirred at 60°C for 4 h. After completion of the reaction, the reaction was concentrated under reduced pressure and purified on a silica gel column to afford compound e (214 mg, 1.16 mmol, 54% yield).

[1140] Its structural characterization is as follows: ESI-MS m / z: 185.1[M+H] + .

[1141] Step 3. Synthesis of compound g

[1142] Compound e (214 mg, 1.16 mmol) was dissolved in 10 mL of DCM, and compound f (281 mg, 1.16 mmol) and DIEA (300 mg, 2.32 mmol) were added. Stir at room temperature for 2 h. After completion of the reaction, the mixture was concentrated under reduced pressure and purified by normal phase column chromatography to afford solid compound g (394 mg, 1.01 mmol, 87% yield).

[1143] Its structural characterization is as follows: ESI-MS m / z: 391.1, 393.1 [M+H] + .

[1144] Step 4. Synthesis of compound h

[1145] Compound g (394 mg, 1.01 mmol) was dissolved in 10 mL of methanol, and di-tert-butyl dicarbonate (231 mg, 1.06 mmol) and triethylamine (102 mg, 1.01 mmol) were added. Stir at room temperature for 2 h. After completion of the reaction, the mixture was concentrated under reduced pressure and purified by normal phase column chromatography to obtain solid compound h (460 mg, 0.94 mmol, 93% yield).

[1146] Its structural characterization is as follows: ESI-MS m / z: 491.1, 493.1 [M+H] + .

[1147] Step 5. Synthesis of Compound J

[1148] Compound h (460 mg, 0.94 mmol) was dissolved in a mixture of 1,4-dioxane and water (10 mL / 2 mL). Compound i (400 mg, 0.94 mmol), Pd(dppf)Cl2 (69 mg, 0.094 mmol), and potassium carbonate (259 mg, 1.88 mmol) were added. The mixture was stirred at 80°C under nitrogen for 2 h. After completion, the reaction was concentrated under reduced pressure and purified by normal phase column chromatography to afford solid compound j (527 mg, 0.74 mmol, 79% yield).

[1149] Its structural characterization is as follows: ESI-MS m / z: 711.2[M+H] + .

[1150] Step 6. Synthesis of Compound K

[1151] Compound j (527 mg, 0.74 mmol) was dissolved in 10 mL of methanol, and sodium methoxide (8 mg, 0.15 mmol) and sodium borohydride (82 mg, 2.22 mmol) were added. Stirring was carried out at 40°C under nitrogen for 2 h. After completion of the reaction, water and EA were added for extraction, followed by drying over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure and purified by normal phase column chromatography to afford solid compound k (267 mg, 0.40 mmol, 54% yield).

[1152] Its structural characterization is as follows: ESI-MS m / z: 669.2[M+H] + .

[1153] Steps 7 to 9, (E)-1-(6 4 -Fluoro-3 6 -methoxy-5,5-dioxo-1 1 ,1 2 ,1 3 ,1 3a ,1 4 ,1 5 ,1 6 ,16a -Octahydro-7-oxa-5-thia-4-aza-2(4,6)-quinazoline-1(2,3a)-pyrrolo[3,4-c]pyrrolo-3(3,5)-pyrido-6(1,2)-phenylcyclooctane-1 5 Synthesis of 1,4-dione-2-pentyl)pent-2-ene

[1154] According to the synthesis method from step 3 to step 5 of Example 1, the compound e of Example 1 was replaced by the compound k of Example 82, and the other operations were the same to obtain (E)-1-(6 4 -Fluoro-3 6 -methoxy-5,5-dioxo-1 1 ,1 2 ,1 3 ,1 3a ,1 4 ,1 5 ,1 6 ,1 6a -Octahydro-7-oxa-5-thia-4-aza-2(4,6)-quinazoline-1(2,3a)-pyrrolo[3,4-c]pyrrolo-3(3,5)-pyrido-6(1,2)-phenylcyclooctane-1 5 -yl)pent-2-ene-1,4-dione.

[1155] Its structural characterization is as follows: 1 H NMR(400MHz,DMSO-d6)δppm 10.39(s,1H),8.50(s,1H),8.32-8.31(m,1H),8.13-8.09(m,2H),7.97-7.89(m,2H),7 .73(d,J=8.8Hz,1H),7.22-7.04(m,2H),6.87(t,J=8.4Hz,1H),6.82-6.76(m,1H),4.81 -4.74(m,1H),4.49(d,J=10.0Hz,1H),4.35-4.23(m,2H),4.13-4.02(m,2H),3.93(s,3 H),3.90-3.73(m,3H),3.68-3.58(m,1H),2.90-2.77(m,1H),2.36(s,2H),2.34(s,1H).

[1156] ESI-MS m / z:645.2[M+H] + .

[1157] Example 83 (E)-1-((1 3 S)-6 4 -Fluoro-3 6-methoxy-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-pyrido[3,4-d]pyrimidine-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 Synthesis of 1,4-pentyl)pent-2-en-1,4-one

[1158] According to the synthetic method from step 1 to step 6 of Example 51, the compound c of Example 51 was replaced by the compound c of Example 83, and the other operations were the same to obtain (E)-1-((1 3 S)-6 4 -Fluoro-3 6 -methoxy-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-pyrido[3,4-d]pyrimidine-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 -yl)pent-2-en-1,4-one.

[1159] Its structural characterization is as follows: 1 H NMR(400MHz,DMSO-d6)δppm 10.37(s,1H),9.28(s,1H),8.83(s,1H),8.68-8.60(m,1H),8.33(s,1H),8.17-8.08(m,1H),8.00(s,1H),7.56-7.47(m,1.2H),7 .39(d,J=10.4Hz,0.8H),7.09(t,J=7.6Hz,1H),6.78(d,J=15.6Hz,1H),5.50-5.39(m,0.2H),5.33(d,J=10.0Hz,0.8H),5.18-5. 08(m,0.8H),4.91(d,J=14.0Hz,1H),4.77-4.68(m,0.2H),4.66-4.53(m,1H),4.34(d,J=13.6Hz,0.8H),4.21-4.11(m,0.2H),4. 04-3.93(m,4H),3.68-3.58(m,1H),3.56-3.48(m,1H),3.20-3.08(m,0.8H),3.07-2.95(m,0.2H),2.40(s,2.4H),2.31(s,0.8H).

[1160] ESI-MS m / z:620.2[M+H] +

[1161] Example 84 (E)-1-((1 3 S)-64 -Fluoro-3 6 -Methoxy-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-diaza-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 Synthesis of 1,4-dione-2-pentyl)pent-2-ene

[1162] Step 1. Synthesis of compound c

[1163] Compound a (300 mg, 1.24 mmol) was dissolved in 1,4-dioxane (15 mL) at room temperature, and compound b (321 mg, 1.49 mmol) and DIEA (480 mg, 3.72 mmol) were added. The reaction was stirred at 100°C for 5 h. The mixture was extracted with DCM and water, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain compound c (456 mg, 1.08 mmol, 87% yield).

[1164] Its structural characterization is as follows: ESI-MS m / z: 423.1[M+H] + .

[1165] Steps 2 to 5, (E)-1-((1 3 S)-6 4 -Fluoro-3 6 -Methoxy-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-diaza-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 Synthesis of 1,4-dione-2-pentyl)pent-2-ene

[1166] According to the synthesis method from step 2 to step 5 of Example 1, the compound c of Example 1 was replaced by the compound c of Example 84, and the other operations were the same to obtain (E)-1-((1 3 S)-6 4 -Fluoro-3 6 -Methoxy-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-cinnoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylenediamine-1-carboxylate 4 -yl)pent-2-ene-1,4-dione.

[1167] Its structural characterization is as follows: 1H NMR(400MHz,DMSO-d6)δppm 10.40(s,1H),9.07(d,J=8.0Hz,1H),8.44-8.24(m,4H),8.16-8.04(m,2H),7.55- 7.39(m,2H),7.12-7.10(m,1H),6.75(d,J=15.6Hz,1H),5.38-5.28(m,1H),5.07( d,J=10.4Hz,0.7H),4.85-4.78(m,0.3H),4.56-4.49(m,1H),4.34(d,J=13.2Hz,1 H),3.92(s,4H),3.74-3.63(m,2H),3.15-3.10(m,2H),2.41(s,2H),2.28(s,1H).

[1168] ESI-MS m / z:619.2[M+H] + .

[1169] Example 85 (E)-1-((1 3 S)-6 4 -Fluoro-3 6 -Methoxy-2 3 -methyl-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 -yl)pent-2-ene-1,4-dione

[1170] Step 1. Synthesis of compound c

[1171] Compound a (10 g, 59 mmol) was dissolved in 300 mL of toluene, and compound b (17.8 g, 88.23 mmol) was added. The mixture was heated under reflux for 8 h. The mixture was cooled to room temperature and concentrated under reduced pressure to obtain a crude product of compound c (18.2 g).

[1172] Its structural characterization is as follows: ESI-MS m / z: 356.1, 358.1 [M+H] +.

[1173] Step 2: Synthesis of Compound d

[1174] Disperse the crude product of compound c (18.2 g) in diphenyl ether (500 mL) and stir at 220°C for 6 h. After cooling to room temperature, pour the reaction solution into petroleum ether (2 L). The precipitated solid was collected by filtration and dried to obtain compound d (11.0 g, 35.43 mmol, 60% yield over two steps).

[1175] Its structural characterization is as follows: ESI-MS m / z: 310.0, 312.0 [M+H] +.

[1176] Step 3. Synthesis of compound e

[1177] Compound d (11.0 g, 35.43 mmol) was dissolved in THF (100 mL), and aqueous NaOH (35 mL, 140 mmol, 4 N) was added. The mixture was stirred at 50°C for 2 h. The pH was adjusted to 5 with 12N hydrochloric acid, diluted with water, extracted with EA, and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain solid compound e (9.1 g, 32.25 mmol, 91% yield).

[1178] Its structural characterization is as follows: ESI-MS m / z: 281.9, 283.9 [M+H] +.

[1179] Step 4. Synthesis of compound f

[1180] Compound e (9.1 g, 32.25 mmol) was dispersed in 300 mL of diphenyl ether at room temperature and stirred at 240°C for 36 h. After cooling to room temperature, the reaction mixture was poured into 1 L of petroleum ether to precipitate a solid. The solid was collected by filtration and purified by silica gel column chromatography to afford compound f (3.3 g, 13.9 mmol, 43% yield over two steps).

[1181] Its structural characterization is as follows: ESI-MS m / z: 237.9, 239.9 [M+H] +.

[1182] Step 5. Synthesis of compound g

[1183] Compound f (3.3 g, 13.86 mmol) was dissolved in POCl3 (50 mL) at room temperature and stirred at 80°C for 3 h. The mixture was cooled to room temperature, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain compound g (3.0 g, 11.69 mmol, yield 84%).

[1184] Its structural characterization is as follows: ESI-MS m / z: 255.9, 257.9 [M+H] +.

[1185] Step 6. Synthesis of Compound I

[1186] Compound g (3.0 g, 11.69 mmol) was dissolved in 50 mL of DMSO at room temperature. DIEA (3.0 g, 23.38 mmol) and compound b (3.8 g, 17.54 mmol) were added and stirred at 105°C for 3 days. The mixture was diluted with water, extracted with EA, and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure and purified by silica gel column chromatography to afford compound e (322 mg, 0.74 mmol, 6% yield).

[1187] Its structural characterization is as follows: ESI-MS m / z: 436.2, 438.2 [M+H] + .

[1188] Steps 7 to 10, (E)-1-((1 3 S)-6 4 -Fluoro-3 6 -Methoxy-2 3 -methyl-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 Synthesis of 1,4-dione-2-pentyl)pent-2-ene

[1189] According to the synthesis method from step 2 to step 5 of Example 55, the compound c of Example 55 was replaced by the compound i of Example 85, and the other operations were the same to obtain (E)-1-((1 3 S)-6 4 -Fluoro-3 6 -Methoxy-2 3 -methyl-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 -yl)pent-2-ene-1,4-dione.

[1190] Its structural characterization is as follows: 1 H NMR(400MHz,DMSO-d6)δppm 10.15(brs,1H),8.65(s,1H),8.60-8.48(m,1H),8.48-8.18(m,2H),8.16-7.96( m,3H),7.86-7.21(m,2H)7.20-6.97(m,1H),6.83-6.44(m,1H),5.39-4.97(m,1H ),4.97-4.61(m,1H),4.53-4.34(m,0.8H),4.14-4.07(m,0.2H),3.98(s,3H),3. 68-3.42(m,3H),3.29-3.07(m,3H),2.48(s,3H),2.36(s,1.8H),2.33(s,1.2H).

[1191] ESI-MS m / z:632.2[M+H]+.

[1192] Example 86 (E)-1-((1 3 S)-6 4 -Cyano-3 6 -Methoxy-23 -methyl-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinazoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 Synthesis of 1,4-dione-2-pentyl)pent-2-ene

[1193] According to the synthesis method from step 6 to step 10 of Example 85, the compound j of Example 85 was replaced by the compound d of Example 86, and the other operations were the same to obtain (E)-1-((1 3 S)-6 4 -Cyano-3 6 -Methoxy-2 3 -methyl-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinazoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 -yl)pent-2-ene-1,4-dione.

[1194] Its structural characterization is as follows: 1H NMR (400 MHz, DMSO-d6) δppm 10.26 (brs, 1H), 8.65 (s, 1H), 8.58-8.47 (m, 1H), 8.47-8.22 (m, 2H), 8.21-7.83 (m, 4H), 7.80-7.65 (m, 1H) 7.59-7.35 (m, 1H), 6.79-6.49 (m, 1H), 5.33-5.01 (m, 1H), 5.01-4.9 1(m,0.5H),4.90-4.80(m,0.5H),4.60-4.31(m,1.2H),4.21-4.03(m,0.8H),3.98(s,3 H),3.69-3.53(m,2H),3.53-3.42(m,2H),3.27-3.19(m,1H),2.49(s,3H),2.35(s,3H).

[1195] ESI-MS m / z:639.2[M+H]+.

[1196] Example 87 (E)-1-((1 3 S,Z)-6 4 -Fluoro-3 6 -methoxy-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-pyrrolo[2,1-f][1,2,4]triazine-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 Synthesis of 1,4-dione-2-pentyl)pent-2-ene

[1197] According to the synthetic method from step 1 to step 5 of Example 1, the compound a of Example 1 was replaced by the compound a of Example 87, and the other operations were the same to obtain (E)-1-((1 3 S,Z)-6 4 -Fluoro-3 6 -methoxy-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-pyrrolo[2,1-f][1,2,4]triazine-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 -yl)pent-2-ene-1,4-dione.

[1198] Its structural characterization is as follows: 1 H NMR(400MHz,DMSO-d6)δppm 10.62(s,1H),8.25-8.18(m,1H),8.15(s,1H),8.13-8.09(m,1H),8.08-8.03(m,1H),8.02(s,1H),7.60-7.4 4(m,1H),7.39-7.19(m,2H),7.07-6.97(m,1H),6.85-6.71(m,1H),5.17-4.89(m,2H),4.87-4.74(m,1H),4. 74-4.63(m,1H),4.61-4.49(m,0.2H),4.35-4.20(m,0.8H),4.20-4.11(m,0.2H),3.97(s,0.8H),3.95-3.89 (m,3H),3.76-3.60(m,1H),3.58-3.51(m,0.8H),3.27-3.11(m,1H),3.09-2.97(m,0.2H),2.42-2.32(m,3H).

[1199] ESI-MS m / z:608.2[M+H] + .

[1200] Example 88 (E)-1-((1 3 S)-2 3 -((dimethylamino)methyl)-6-((dimethylamino)methyl)- 4 -Fluoro-3 6 -Methoxy-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 Synthesis of 1,4-dione-2-pentyl)pent-2-ene

[1201] Step 1. Synthesis of compound b

[1202] Compound a (2.0 g, 6.39 mmol) was dissolved in anhydrous THF / anhydrous ethanol (5 mL / 20 mL). Sodium borohydride (728 mg, 19.2 mmol) was added portionwise under ice-cooling and stirred at room temperature for 1 h. After completion of the reaction, saturated aqueous ammonium chloride was added to quench the reaction. The mixture was extracted with EA, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified on a silica gel column to afford compound b (710 mg, 2.62 mmol, 41% yield).

[1203] ESI-MS m / z:271.9,273.9[M+H] + .

[1204] Step 2: Synthesis of Compound C

[1205] Dissolve compound b (710 mg, 2.62 mmol) in 20 mL of chloroform, add one drop of DMF and phosphorus oxychloride (802 mg, 5.24 mmol) under ice-cooling, and stir at room temperature for 5 h. Extract with EA and water, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain crude compound c (689 mg).

[1206] Its structural characterization is as follows: ESI-MS m / z: 289.9, 291.9 [M+H] + .

[1207] Step 3. Synthesis of compound d

[1208] Crude compound c (689 mg) was dissolved in 10 mL of DMF at room temperature, and potassium carbonate (985 mg, 7.14 mmol) and dimethylamine hydrochloride (578 mg, 7.14 mmol) were added. The mixture was stirred at room temperature for 5 h. The mixture was extracted with EA and water, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The mixture was then concentrated under reduced pressure at room temperature and purified on a silica gel column to afford compound d (489 mg, 1.64 mmol, 63% yield over two steps).

[1209] Its structural characterization is as follows: ESI-MS m / z: 299.0, 301.0 [M+H] + .

[1210] Step 4. Synthesis of compound f

[1211] Compound d (489 mg, 1.64 mmol) was dissolved in n-butanol (15 mL) at room temperature, and DIEA (635 mg, 4.92 mmol) and compound e (425 mg, 1.97 mmol) were added. The mixture was stirred at 80°C for 48 h. After completion of the reaction, water and EA were added for extraction. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified on a silica gel column to afford compound f (306 mg, 0.64 mmol, 39% yield).

[1212] Its structural characterization is as follows: ESI-MS m / z: 479.2, 481.2 [M+H] + .

[1213] Steps 5 to 8, (E)-1-((1 3 S)-2 3 -((dimethylamino)methyl)-6-((dimethylamino)methyl)- 4 -Fluoro-3 6 -Methoxy-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 Synthesis of 1,4-dione-2-pentyl)pent-2-ene

[1214] According to the synthesis method from step 2 to step 5 of Example 1, the compound c of Example 1 was replaced by the compound f of Example 88, and the other operations were the same to obtain (E)-1-((1 3 S)-2 3 -((dimethylamino)methyl)-6-((dimethylamino)methyl)- 4 -Fluoro-3 6 -Methoxy-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 -yl)pent-2-ene-1,4-dione.

[1215] Its structural characterization is as follows: 1H NMR(400MHz,DMSO-d6)δppm 10.04(s,1H),8.72(d,J=7.6Hz,1H),8.57(d,J=14.0Hz,1H),8.41-8.33(m,2H),8.1 7-8.12(m,1H),8.09-8.03(m,2H),7.56-7.35(m,2H),7.17-7.07(m,1H),6.69-6.55( m,1H),5.10(s,1H),4.92-4.77(m,1H),4.45-4.38(m,1H),4.16-4.07(m,1H),3.98( s,3H),3.80-3.45(m,6H),3.33-3.25(m,1H),2.36(s,2H),2.32(s,1H),2.16(s,6H).

[1216] ESI-MS m / z:675.2[M+H] + .

[1217] Example 89 (E)-1-((1 3 S)-2 8 -6-chloro- 4 -Fluoro-3 6 -Methoxy-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinazoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 -yl)pent-2-ene-1,4-dione synthesis.

[1218] Step 1. Synthesis of compound b

[1219] Compound a (1.0 g, 4.96 mmol) was dissolved in thionyl chloride (9 mL) at room temperature, heated to 80°C, and stirred for 1 h. The reaction solution was concentrated and DCM (15 mL) was added. Aqueous ammonia (3 mL) was slowly added dropwise at 0°C and stirred for 0.5 h. After completion of the reaction, LCMS was monitored. The product was extracted with EA, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by normal phase purification to afford compound b (960 mg, 4.79 mmol, 96% yield).

[1220] Step 2: Synthesis of Compound C

[1221] Compound b (960 mg, 4.79 mmol) was dissolved in 5 mL HCl / 45 mL EtOH at room temperature, and iron powder (860 mg, 15.33 mmol) was added. The mixture was heated to 90°C and stirred for 1 hour. LCMS monitored the reaction for completion. The reaction solution was cooled to room temperature, the pH adjusted to 8 with saturated NaHCO₃, and 50 mL of EA was added and stirred for 0.5 hour. The suspension was filtered, and the filtrate was extracted with EA, dried over anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure. The crude product was purified by normal phase column chromatography to afford compound c (230 mg, 1.35 mmol, 28% yield).

[1222] Its structural characterization is as follows: ESI-MS m / z: 171.0 [M+H] + .

[1223] Step 3. Synthesis of compound d

[1224] Compound c (200 mg, 1.17 mmol) was dissolved in 5 mL of ACN at room temperature, and NBS (250 mg, 1.4 mmol) was added. The mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated to obtain a crude product. The crude product was purified by normal phase column chromatography to obtain compound c (230 mg, 0.92 mmol, 78% yield).

[1225] Its structural characterization is as follows: ESI-MS m / z: 248.9[M+H] + .

[1226] Steps 4 to 10, (E)-1-((1 3 S)-2 8 -6-chloro- 4 -Fluoro-3 6 -Methoxy-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinazoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 Synthesis of 1,4-dione-2-pentyl)pent-2-ene

[1227] According to the synthesis method from step 4 to step 10 of Example 50, the compounds d and g of Example 50 were replaced by the compounds d and g of Example 89, respectively, and the other operations were the same to obtain (E)-1-((1 3 S)-2 8 -6-chloro- 4 -Fluoro-3 6 -methoxy-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinazoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclohexine-1 4 -yl)pent-2-ene-1,4-dione.

[1228] Its structural characterization is as follows: 1H NMR (400 MHz, DMSO-d6) δ ppm 10.17 (s, 1H), 8.84 (s, 1H), 8.44-8.28 (m, 3H), 8.09-7.97 (m, 2H), 7.51-7.35 (m, 2H), 7.12-7.07 (m, 1H), 6.78-6.68 (m, 1H), 5.38-5.27 (m, 1H), 5.09-5.06 (m, 0.8H), 4.81-4.70 (m, 1.2H), 4.60-4.56 (m, 0.3H), 4.41-4.31 (m, 1.7H), 4.10-4.07 (m, 0.3H), 3.97-3.92 (m,3.7H),3.63-3.56(m,0.8H),3.37-3.31(m,1.2H),3.16-3.00(m,1H),2.39(s,2.3H),2.27(s,0.7H).

[1229] ESI-MS m / z:653.1[M+H] + .

[1230] Example 90 (E)-1-((1 3 S)-6 4 -Fluoro-3 6 -Methoxy-2 8 -cyano-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinazoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 Synthesis of 1,4-dione-2-pentyl)pent-2-ene

[1231] Step 1. Synthesis of compound b

[1232] Compound a (5 g, 23 mmol) was dissolved in 50 mL of DMF, and NIS (6.25 g, 27.8 mmol) was added. The mixture was stirred at room temperature overnight. After completion of the reaction, the reaction solution was poured into water and extracted with EA. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound b (8.5 g, crude product).

[1233] Its structural characterization is as follows: ESI-MS m / z: 341.9, 343.9 [M+H] + .

[1234] Step 2: Synthesis of Compound C

[1235] Crude compound b (8.5 g) was dissolved in DMF (50 mL), and KCO (5.15 g, 37.30 mmol) was slowly added under ice. The mixture was then warmed to room temperature and stirred for 2 h. LC-MS monitoring indicated complete consumption of the starting material. The reaction mixture was poured into water and extracted with EA. The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and then purified by silica gel column chromatography to yield compound c (6.2 g, 17.4 mmol, 75% yield over two steps).

[1236] Its structural characterization is as follows: ESI-MS m / z: 355.9, 357.9 [M+H] + .

[1237] Step 3. Synthesis of compound d

[1238] Compound c (6 g, 16.86 mmol) was dissolved in 60 mL of DMF, followed by the addition of Zn(CN)2 (2.18 g, 18.56 mmol) and Pd(PPh3)4 (0.97 g, 0.83 mmol). The mixture was then reacted at 80°C for 3 h under nitrogen. After completion, the reaction solution was poured into water and extracted with EA. The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and then purified by silica gel column chromatography to afford compound d (2.8 g, 11.0 mmol, 65% yield).

[1239] Its structural characterization is as follows: ESI-MS m / z: 255.0, 257.0 [M+H] + .

[1240] Step 4. Synthesis of compound e

[1241] Compound d (2.5 g, 9.80 mmol) was dissolved in DMF (60 mL), followed by the addition of formamide (15.44 g, 343 mmol) and potassium carbonate (4.06 g, 29.40 mmol). The mixture was heated in a microwave oven at 150°C for 1 h. LC-MS monitoring indicated complete consumption of the starting material. The reaction mixture was poured into water and extracted with EA. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford compound e (1.6 g, crude product).

[1242] Its structural characterization is as follows: ESI-MS m / z: 250.0, 252.0 [M+H] + .

[1243] Steps 5 to 10, (E)-1-((1 3 S)-6 4 -Fluoro-3 6 -Methoxy-2 8-cyano-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinazoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 Synthesis of 1,4-dione-2-pentyl)pent-2-ene

[1244] According to the synthesis method from step 5 to step 10 of Example 50, the compounds e and g of Example 50 were replaced by the compounds e and g of Example 90, respectively, and the other operations were the same to obtain (E)-1-((1 3 S)-6 4 -Fluoro-3 6 -Methoxy-2 8 -cyano-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinazoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 -yl)pent-2-ene-1,4-dione.

[1245] Its structural characterization is as follows: 1 H NMR (400MHz, DMSO) δ10.19(s,1H),8.85(d,J=8.4Hz,2H),8.39-8.28(m,3H),8.07(dd,J=8.8,6.4Hz,1H),7.51-7.46(m,1H),7.42(d,J=10.4Hz,0.2 H),7.34(d,J=10.4Hz,0.8H),7.10(t,J=8.0Hz,1H),6.78-6.69(m,1H),5. 37(t,J=9.6Hz,0.2H),5.30(t,J=9.6Hz,0.8H),5.09(d,J=10.0Hz,0.8H), 4.81(d,J=14.0Hz,0.8H), 4.72(d,J=11.6Hz,0.4H), 4.59(d,J=12.4Hz,0. 2H),4.51(d,J=12.8Hz,1H),4.34(d,J=12.4Hz,0.8H),4.12-4.09(m,0.2H ),3.97-3.94(m,3.8H),3.59(t,J=12.8Hz,0.8H),3.49(d,J=13.6Hz,0.8H ),3.18-3.11(m,1H),3.05-2.99(m,0.4H),2.40(s,2.3H),2.28(s,0.7H).

[1246] ESI-MS m / z:644.2[M+H] + .

[1247] Example 91 (E)-1-((1 3 S)-6 4 -Fluoro-3 6 -Methoxy-2 8 -(Methylamino)-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinazoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 Synthesis of 1,4-dione-2-pentyl)pent-2-ene

[1248] Step 1. Synthesis of compound c

[1249] Compound a (700 mg, 2.89 mmol) was dissolved in 50 mL of NMP, and DIEA (1.86 g, 14.5 mmol) and compound b (1.05 g, 5.78 mmol) were added. The mixture was heated to 130°C and stirred for 10 h. The temperature was cooled to room temperature, and an appropriate amount of water was added. The mixture was stirred for 10 min, filtered, and the solid was collected and dried to obtain compound c (685 mg, 1.71 mmol, 59% yield).

[1250] Its structural characterization is as follows: ESI-MS m / z: 403.1, 405.1 [M+H] + .

[1251] Step 2 to Step 6, (E)-1-((1 3 S)-6 4 -Fluoro-3 6 -Methoxy-2 8 -(Methylamino)-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinazoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 Synthesis of 1,4-dione-2-pentyl)pent-2-ene

[1252] According to the synthesis method from step 3 to step 7 of Example 65, the compound c of Example 65 was replaced by the compound c of Example 91, and the other operations were the same to obtain (E)-1-((1 3 S)-6 4 -Fluoro-3 6 -Methoxy-2 8 -(Methylamino)-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinazoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 -yl)pent-2-ene-1,4-dione.

[1253] Its structural characterization is as follows:1 H NMR(400MHz,DMSO-d6)δppm 10.12(s,1H),8.70(s,1H),8.32-8.29(m,2H),8.10-8.05(m,1H),7.50(d,J=15.6Hz,1H),7.38(d,J=12.0Hz,1H), 7.11-7.06(m,2H),6.93(s,1H),6.78-6.71(m,2H),5.36(t,J=10.4Hz,0.2H),5.26(t,J=10.4Hz,0.8H),5.05(d,J =9.6Hz,0.8H),4.91-4.87(m,1H),4.58(d,J=13.6Hz,0.2H),4.30(d,J=13.6Hz,1.8H),4.11-4.07(m,0.2H),3.93 (s,4H),3.60(t,J=15.6Hz,1H),3.24-3.21(m,1H),3.13-3.06(m,1H),2.95(s,3H),2.40(s,2.3H),2.30(s,0.7H).

[1254] ESI-MS m / z:648.2[M+H] + .

[1255] Example 92 (E)-1-((1 3 S)-6 4 -Cyano-3 6 -Methoxy-2 8 -Methoxy-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinazoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 Synthesis of 1,4-dione-2-pentyl)pent-2-ene

[1256] According to the synthesis method from step 2 to step 5 of Example 54, the compound d of Example 54 was replaced by the compound b of Example 92, and the other operations were the same to obtain (E)-1-((1 3 S)-6 4 -Cyano-3 6 -Methoxy-2 8 -Methoxy-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinazoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 -yl)pent-2-ene-1,4-dione.

[1257] Its structural characterization is as follows:1 H NMR(400MHz,DMSO-d6)δppm 10.62-10.31(m,1H),8.71(s,1H),8.42-8.20(m,2H),8.13(d,J=8.4Hz,1H),7.99-7.83(m,1 H),7.71-7.50(m,3H),7.44(d,J=15.6Hz,1H),6.72(d,J=15.6Hz,1H),5.41-5.20(m,1H),5. 16-5.00(m,0.8H),4.98-4.66(m,1.2H),4.64-4.43(m,1.2H),4.37-4.20(m,0.8H),4.17-3. 98(m,4H),3.90(s,3H),3.63-3.44(m,2H),3.25-3.06(m,1H),2.36(s,2.4H),2.25(s,0.6H).

[1258] ESI-MS m / z:656.2[M+H] +

[1259] Example 93 (E)-1-((1 3 S)-6 4 -Fluorine-2 8 ,3 6 -Dimethoxy-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 Synthesis of 1,4-dione-2-pentyl)pent-2-ene

[1260] Step 1. Synthesis of compound c

[1261] Dissolve compound a (10.0 g, 49.8 mmol) in 100 mL of isopropanol at room temperature. Add compound b (9.72 g, 52.2 mmol), heat to 100°C, and stir for 10 hours. After the reaction is complete, concentrate under reduced pressure and use the residue directly in the next reaction.

[1262] Its structural characterization is as follows: ESI-MS m / z: 356.1, 358.1 [M+H] + .

[1263] Step 2: Synthesis of Compound d

[1264] Heat 500 mL of diphenyl ether to 250°C and add the crude compound b from the previous step in batches. React at 250°C for 3 h. Cool to room temperature, add 1 L of petroleum ether, stir, filter, collect the solid, and dry under reduced pressure to obtain compound d (8.48 g, 33.5 mmol, 67% yield over two steps).

[1265] Its structural characterization is as follows: ESI-MS m / z: 254.0, 256.0 [M+H] + .

[1266] Step 3. Synthesis of compound e

[1267] Compound d (1.0 g, 3.95 mmol) was added to 20 mL of phosphorus oxychloride and stirred at 100°C under nitrogen for 4 h. Water and EA were added for extraction, and the organic phase was washed with saturated sodium bicarbonate and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure and purified by normal phase column chromatography to afford solid compound e (867 mg, 3.20 mmol, 81% yield).

[1268] Its structural characterization is as follows: ESI-MS m / z: 271.9, 273.9 [M+H] + .

[1269] Step 4. Synthesis of compound g

[1270] Compound e (867 mg, 3.20 mmol) was dissolved in 25 mL of NMP at room temperature, and compound f (829 mg, 3.84 mmol) was added. The mixture was stirred at 140°C for 5 h. Water and EA were added for extraction, and the mixture was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure and purified by normal phase column chromatography to afford compound g (1.23 g, 2.72 mmol, 85% yield).

[1271] Its structural characterization is as follows: ESI-MS m / z: 452.1, 454.1 [M+H] + .

[1272] Steps 5 to 8, (E)-1-((1 3 S)-6 4 -Fluorine-2 8 ,3 6 -Dimethoxy-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 Synthesis of 1,4-dione-2-pentyl)pent-2-ene

[1273] According to the synthesis method from step 2 to step 5 of Example 1, the compound c of Example 1 was replaced by the compound g of Example 93, and the other operations were the same to obtain (E)-1-((1 3 S)-6 4 -Fluorine-2 8 ,3 6 -Dimethoxy-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 -yl)pent-2-ene-1,4-dione.

[1274] Its structural characterization is as follows: 1 H NMR(400MHz,DMSO-d6)δppm 10.18(s,1H),8.64(s,1H),8.11-8.05(m,1H),7.90-7.87(m,1H),7.61-7.45 (m,2H),7.29-7.11(m,2H),7.04-6.97(m,1H),6.73(d,J=15.6Hz,1H),6.61- 6.41(m,2H),5.39(t,J=11.2Hz,0.4H),5.27(t,J=10.8Hz,0.6H),5.00-4.97(m,0.6H),4.79-4.77(m,0.4H),4.51-4.20(m ,2H),4.03(s,3H),3.80-3.65(m,4H),3.64-3.62(m,1H),3.19-3.10(m,2H),2.78-2.68(m,1H),2.39(s,2H),2.25(s,1H).

[1275] ESI-MS m / z:648.2[M+H] + .

[1276] Example 94 (E)-1-((1 3 S)-6 4 -Cyano-2 8 ,3 6 -Dimethoxy-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 Synthesis of 1,4-dione-2-pentyl)pent-2-ene

[1277] According to the synthesis method from step 2 to step 5 of Example 1, the compounds c and d of Example 1 were replaced by the compounds a and b of Example 94, respectively, and the other operations were the same to obtain (E)-1-((1 3 S)-6 4 -Cyano-2 8 ,3 6 -Dimethoxy-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 -yl)pent-2-ene-1,4-dione.

[1278] Its structural characterization is as follows: 1 H NMR(400MHz,DMSO-d6)δppm 10.14(s,1H),8.69(d,J=4.8Hz,1H),8.51-8.48(m,0.5H),8.35-8.32(m,1H),8.15-8.11(m,1.5H),8.02(s,1H ),7.79-7.70(m,2H),7.54-7.47(m,2H),7.19-7.14(m,1H),6.83(d,J=16.0Hz,0.3H),6.75(d,J=16.0Hz,0.7H) ,5.41-5.33(m,1H),5.03-5.01(m,0.6H),4.86-4.84(m,0.4H),4.56-4.53(m,0.4H),4.38-4.22(m,1.6H),4.05 -3.95(m,4H),3.90(s,3H),3.69-3.58(m,1H),3.22-3.11(m,2H),2.85-2.82(m,1H),2.40(s,2H),2.27(s,1H).

[1279] ESI-MS m / z:655.2[M+H] + .

[1280] Example 95 (E)-1-((1 3 S)-6 4 -Cyano-3 6 -Methoxy-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 Synthesis of 1,4-dione-2-pentyl)pent-2-ene

[1281] According to the synthetic method from step 1 to step 5 of Example 55, the compound d of Example 55 was replaced by the compound d of Example 95, and the other operations were the same to obtain (E)-1-((1 3 S)-6 4 -Cyano-3 6 -Methoxy-5,5-dioxo-7-oxa-5-thia-4-aza-2(4,6)-quinoline-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 -yl)pent-2-ene-1,4-dione.

[1282] Its structural characterization is as follows: 1 H NMR(400MHz,DMSO-d6)δppm 10.20(s,1H),8.77(d,J=5.6Hz,1H),8.56-8.49(m,0.3H),8.42(s,0.7H),8.35-8.14(m,4H),8.13-8.06(m,1H),8.05-7.95(m,1H ),7.80-7.75(m,0.3H),7.71(t,J=8.4Hz,0.7H),7.46(d,J=15.6Hz,0.7H),7.39(d,J=15.6Hz,0.3H),7.30-7.22(m,1H),6.82-6.7 1(m,0.7H),6.69-6.60(m,0.3H),5.42-5.25(m,1H),5.12-5.00(m,0.7H),4.85-4.73(m,0.3H),4.65-4.50(m,1H),4.49-4.39(m, 0.3H), 4.30 (d, J = 12.4Hz, 0.7H), 4.22-4.00 (m, 1H), 3.90 (s, 3H), 3.63-3.53 (m, 2H), 3.38-3.22 (m, 2H), 2.38 (s, 2H), 2.25 (s, 1H).

[1283] ESI-MS m / z:625.2[M+H] +

[1284] Example 96 (E)-1-((1 3 S)-6 4 -Cyano-3 6 -Methoxy-5,5-dioxo-7-oxa-5-thia-4-aza-2(8,2)-naphthyridine-1(1,3)-piperazine-3(3,5)-pyridine-6(1,2)-phenylcyclooctane-1 4 Synthesis of 1,4-dione-2-pentyl)pent-2-ene

[1285] Step 1. Synthesis of compound c

[1286] Compound a (2.2 g, 8.40 mmol) was dissolved in 20 mL of NMP at room temperature. DIEA (3.25 g, 25.2 mmol) and compound b (2.2 g, 10 mmol) were added and stirred at 120°C for 48 h. The mixture was extracted with EA and water, and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Silica gel column chromatography afforded compound c (2.5 g, 6.68 mmol, 79% yield).

[1287] Its structural characterization is as follows...

Claims

1. A compound of formula IA, or a tautomer, stereoisomer, solvate, metabolite, isotope-labeled substance, pharmaceutically acceptable salt, or cocrystal thereof, in, W is Among them, the a-terminal is connected to the pyridyl group; X1 is N or CR8; R8 is selected from hydrogen, amino, halogen, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2, C 3-8 Cycloalkyl, 3-8 membered alicyclic group, C 6-10 Aryl, 5-10 membered heteroaryl; the alkyl group is optionally substituted with one or more selected from -CN, -N(C 1-6 Alkyl)2 is substituted by a substituent; L1 is selected from a single bond, -O-, -S-, -N(Ra)-; L2 is selected from a single bond, C 1-6 Alkylene, the alkylene is optionally substituted by one or more selected from C 1-6 The alkyl group is substituted by a substituent; L1 and L2 are not single bonds at the same time; R a Selected from hydrogen and C 1-6 alkyl; A is in, Each is independently selected from a 4- to 10-membered heterocycloalkyl group or a 4- to 10-membered heterocycloalkenyl group, wherein the heterocycloalkyl group or heterocycloalkenyl group is a monocyclic, fused, spirocyclic or bridged ring; The condition is that when A is When L2 is connected to any ring atom on the ring; when A is When L2 and A2 is connected, or L2 is connected to any ring atom on the ring; A1 and A2 are each independently selected from CR7 and N; R7 are each independently selected from hydrogen, C 1-6 Alkyl, -C 1-6 Alkyl-OH, -C 1-6 Alkyl-CN, -C 1-6 Alkyl-OC 1-6 alkyl; Ring B is selected from 5-7 membered heteroaryl and phenyl, wherein the 5-7 membered heteroaryl or phenyl is optionally substituted with one or more R6; R6 are each independently selected from H, halogen, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, -NH-C 1-6 Alkyl, -N(C 1-6 Alkyl)2; R1 is selected from hydrogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, alkoxyalkyl, C 1-6 Alkoxy, -(C 1-6 Alkyl)-OH or -(C 1-6 alkyl)-(3-8 membered alicyclic heterocyclic group), wherein the 3-8 membered alicyclic heterocyclic group is optionally substituted by one or more C 1-6 Alkyl substitution; R2 is selected from hydrogen, deuterium, amino, halogen, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, -NH-C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered alicyclic group, C 6-10 Aryl, 5-10 membered heteroaryl; R3 is selected from hydrogen, halogen, cyano, hydroxyl, amino, C 1-6 Alkyl, C 3-8 Cycloalkyl, -NH-C 1-6 Alkyl, 3-8 membered alicyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, C 1-6 Alkoxy, alkoxyalkyl, deuterated C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, -N(C 1-6 Alkyl)2; R4 is selected from hydrogen, halogen, cyano, C 1-6 Alkyl and C 1-6 Alkoxy; R5 is selected from C 6-10 Aryl and 5-10 membered heteroaryl, wherein the aryl or heteroaryl is optionally substituted by one or more R b replace; R b Each occurrence is independently selected from hydrogen, halogen, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, alkoxyalkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, -S(O)2(C 1-6 Alkyl), -(C 1-6 Alkyl)-CN, -C 1-6 Alkyl-N(C 1-6 Alkyl)2, C 3-8 Cycloalkyl, -O-(3-8 membered alicyclic group), -O-(C 3-8 Cycloalkyl), 3-8 membered alicyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, amino, C 1-6 Alkyl substituted amino group; Or, two adjacent R b Together with the ring atoms to which it is connected, it forms a 3-6-membered cycloalkyl group; n1 and n2 are each independently selected from 0, 1, 2, 3, and 4; n3 is selected from 0, 1, and 2.

2. The compound according to claim 1, or its tautomer, stereoisomer, solvate, metabolite, isotope-labeled substance, pharmaceutically acceptable salt, cocrystal, wherein the compound has the structure shown in Formula I: in, X1 is N or CR8; R8 is selected from hydrogen, amino, halogen, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2, C 3-8 Cycloalkyl, 3-8 membered alicyclic group, C 6-10 Aryl, 5-10 membered heteroaryl; the alkyl group is optionally substituted by one or more selected from -CN, - N(C 1-6 Alkyl)2 is substituted by a substituent; L1 is selected from a single bond, -O-, -S-, -N(Ra)-; L2 is selected from a single bond, C 1-6 Alkylene, the alkylene is optionally substituted by one or more selected from C 1-6 substituted by an alkyl substituent; R a Selected from hydrogen and C 1-6 alkyl; A is in, Each is independently selected from a 4- to 10-membered heterocycloalkyl group or a 4- to 10-membered heterocycloalkenyl group, wherein the heterocycloalkyl group or heterocycloalkenyl group is a monocyclic, fused, spirocyclic or bridged ring; The condition is that when A is When L2 is connected to any ring atom on the ring; when A is When , L2 is connected to A2, or L2 is connected to any ring atom on the ring; A1 and A2 are each independently selected from CR7 and N; R7 are each independently selected from hydrogen, C 1-6 Alkyl, -C 1-6 Alkyl-OH, -C 1-6 Alkyl-CN, -C 1-6 Alkyl-OC 1-6 alkyl; Ring B is selected from 5-7 membered heteroaryl and phenyl, wherein the 5-7 membered heteroaryl or phenyl is optionally substituted with one or more R6; R6 are each independently selected from H, halogen, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, -NH-C 1-6 Alkyl, -N(C 1-6 Alkyl)2; R1 is selected from hydrogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, alkoxyalkyl and C 1-6 Alkoxy; R2 is selected from hydrogen, deuterium, amino, halogen, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, -NH-C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered alicyclic group, C 6-10 Aryl, 5-10 membered heteroaryl; R3 is selected from hydrogen, halogen, cyano, hydroxyl, amino, C 1-6 Alkyl, C 3-8 Cycloalkyl, -NH-C 1-6 Alkyl, 3-8 membered alicyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, -N(C 1-6 Alkyl)2; R4 is selected from hydrogen, halogen, cyano, C 1-6 Alkyl and C 1-6 Alkoxy; R5 is selected from C 6-10 Aryl and 5-10 membered heteroaryl, wherein the aryl or heteroaryl is optionally substituted by one or more R b replace; R b Each occurrence is independently selected from hydrogen, halogen, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, -S(O)2(C 1-6 Alkyl), -(C 1-6 Alkyl)-CN, -C 1-6 Alkyl-N(C 1-6 Alkyl)2, C 3-8 Cycloalkyl, 3-8 membered alicyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, amino, C 1-6 Alkyl substituted amino group; Or, two adjacent R b Together with the ring atoms to which it is connected, it forms a 3-6-membered cycloalkyl group; n1 and n2 are each independently selected from 0, 1, 2, 3, and 4; n3 is selected from 0, 1, and 2.

3. The compound according to claim 1 or 2, or a tautomer, stereoisomer, solvate, metabolite, isotope-labeled substance, pharmaceutically acceptable salt, or cocrystal thereof, wherein R5 is selected from a 5-6 membered heteroaryl group and a phenyl group, wherein the heteroaryl group or the phenyl group is optionally replaced by one or more R b replace; Preferably, R5 is selected from 6-membered heteroaryl and phenyl, wherein the heteroaryl or phenyl is optionally replaced by one or more R b replace.

4. The compound according to at least one of claims 1 to 3, or its tautomer, stereoisomer, solvate, metabolite, isotope-labeled substance, pharmaceutically acceptable salt, cocrystal, wherein the compound has a structure shown in Formula II or Formula III: in, X2 is N or CR6; X3, X4, X5, and X6 are each independently selected from N and CR b ; In the compound represented by formula II, is a 4-8 membered monocyclic heterocycloalkyl, a 6-8 membered cyclic heterocycloalkyl, a 6-8 membered spirocyclic heterocycloalkyl, a 6-8 membered bridged heterocycloalkyl or a 4-8 membered monocyclic heterocycloalkenyl; preferably a 6 membered monocyclic heterocycloalkyl; In the compound represented by formula III, is a 4-6 membered monocyclic heterocycloalkyl or a 4-6 membered monocyclic heterocycloalkenyl; preferably a 4-membered monocyclic heterocycloalkyl or a 6-membered monocyclic heterocycloalkyl; n4 is selected from 0, 1, 2, 3, 4; X1, L1, L2, R1, R2, R3, R4, R6, R7, R a , R b , n1, n2, n3 are defined as at least one of claims 1 to 3.

5. The compound according to at least one of claims 1 to 4, or a tautomer, stereoisomer, solvate, metabolite, isotope-labeled substance, pharmaceutically acceptable salt, or cocrystal thereof, wherein the compound has a structure shown in Formula II-A or Formula III-A, in, Each substituent is as defined in at least one of claims 1 to 4; Preferably, in the compound represented by formula II, is a 4-6 membered monocyclic heterocycloalkyl or a 4-6 membered monocyclic heterocycloalkenyl; preferably a 6 membered monocyclic heterocycloalkyl; Preferably, in the compound represented by formula III, It is a 4-6 membered monocyclic heterocycloalkyl or a 4-6 membered monocyclic heterocycloalkenyl; preferably a 4-membered monocyclic heterocycloalkyl or a 6-membered monocyclic heterocycloalkyl.

6. The compound according to at least one of claims 1 to 5, or its tautomer, stereoisomer, solvate, metabolite, isotope-labeled substance, pharmaceutically acceptable salt, cocrystal, wherein the compound has a structure shown in Formula II-1, Formula II-2, Formula II-3, Formula III-1 or Formula III-2, in, X1, X2, X3, L1, L2, R1, R2, R3, R4, R6, R7, R b , n1, n2, n3, n4 are defined as at least one of claims 1 to 5.

7. The compound according to claim 4, or its tautomer, stereoisomer, solvate, metabolite, isotope-labeled substance, pharmaceutically acceptable salt, cocrystal, wherein the compound satisfies one or more of the following conditions (1), (2) and (3): (1) X3, X4, X5, and X6 are each independently N or CR b ; Preferably, X3, X4, X5, and X6 satisfy one of the following schemes 1, 2, 3, or 4: Solution 1: X3 is N, and X4, X5, and X6 are CR independently b ; Solution 2: X4 is N, and X3, X5, and X6 are CR independently b ; Solution 3: X5 is N, and X3, X4, and X6 are CR independently b ; Solution 4: X6 is N, and X3, X4, and X5 are CR independently b ; (2) n4 is selected from 0, 1, 2 and 3; preferably, n4 is selected from 0, 1 and 2; and (3) Each independently selected from in, The 1-position terminal is connected to L2, and the 2-position terminal is connected to the heteroaromatic ring.

8. The compound of at least one of claims 1 to 7, or a tautomer, stereoisomer, solvate, metabolite, isotope-labeled substance, pharmaceutically acceptable salt, cocrystal thereof, which satisfies one or more of the following conditions: (1) L1 is a single bond, -O-, -NH- or -N(C 1-6 Alkyl)-; L2 is selected from a single bond and C 1-4 Alkylene, the alkylene is optionally substituted with One or more C 1-6 Preferably, L1 is a single bond or -O-; L2 is selected from a single bond and C 1-4 Alkylene, the alkylene group is optionally substituted with one or more C 1-6 Alkyl substituted; Preferably, L2 is selected from methylene, ethylene, propylene, butylene, wherein the methylene, ethylene, propylene, butylene are optionally replaced by one or more C 1-6 Alkyl substituted; (2) X1 is N or CR8; R8 is selected from hydrogen, amino, halogen, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, -NH(C 1-6 Alkyl), -N(C 1-6 alkyl)2; the alkyl group is optionally substituted by one or more selected from -CN, -N(C 1-6 Alkyl)2 is substituted by a substituent; Preferably, X1 is N or CR8; R8 is selected from hydrogen, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, -NH(C 1-6 Alkyl), -N(C 1- 6 alkyl) 2; the alkyl group is optionally substituted by one or more selected from -CN, -N(C 1-6 Alkyl)2 is substituted by a substituent; Preferably, R8 is selected from H, F, -CN, -CH3, -OCH3, -CH2CN, -CH2-N(CH3)2, -NH(CH3) or -N(CH3)2; More preferably, R8 is selected from -CN, -CH3, -OCH3, -CH2CN, -CH2-N(CH3)2, -NH(CH3) or -N(CH3)2; Preferably, X1 is N, CH or C-CN; More preferably, X1 is N; (3) X2 is N or CR6; R6 are each independently selected from H, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, -NH-C 1-6 Alkyl, N(C 1-6 Alkyl)2; Preferably, R6 is each independently selected from H, F, Cl, Br, I, CN, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, butoxy, -NH-CH3, -N(CH3)2; Preferably, R6 is each independently selected from H, F, Cl, CN, methyl, methoxy, ethoxy, -NH-CH3; More preferably, R6 is each independently selected from H, F, CN, methyl, methoxy, ethoxy, -NH-CH3; Further preferably, X2 is selected from N, CH and C (halogen); (4)R b Each occurrence is independently selected from hydrogen, halogen, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, -S(O)2(C 1-6 Alkyl), -(C 1-6 Alkyl)-CN, -C 1-6 Alkyl-N(C 1-6 alkyl)2, 3-8 membered alicyclic group, 5-10 membered heteroaryl, alkoxyalkyl, amino, C 1-6 Alkyl-substituted amino, -O-(4-6 membered heterocycloalkyl) and -O-(C 3-6 More preferably, R b Each occurrence is independently selected from hydrogen, halogen, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, -S(O)2(C 1-6 Alkyl), -(C 1-6 Alkyl)-CN, -C 1-6 Alkyl-N(C 1-6 alkyl)2, 3-8 membered alicyclic group, 5-10 membered heteroaryl, alkoxyalkyl, amino, C 1-6 Alkyl-substituted amino; preferably, R b Each occurrence is independently selected from hydrogen, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, -S(O)2(C 1-6 Alkyl), -(C 1-6 Alkyl)-CN, -C 1- 6-Alkyl-N(C 1-6 alkyl)2, 3-8 membered alicyclic group, 5-10 membered heteroaryl, alkoxyalkyl and C 1-6 Alkyl-substituted amino, -O-(4-6 membered heterocycloalkyl) and -O-(C 3-6 More preferably, R b Each occurrence is independently selected from hydrogen, halogen, cyano, C 1-6 Alkyl, C 1- 6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, -S(O)2(C 1-6 Alkyl), -(C 1-6 Alkyl)-CN, -C 1-6 Alkyl-N(C 1-6 alkyl)2, 3-8 membered alicyclic group, 5-10 membered heteroaryl, alkoxyalkyl and C 1-6 Alkyl substituted amino group; More preferably, R b Each occurrence is independently selected from H, F, Cl, Br, I, cyano, methyl, ethyl, propyl, butyl, -OCH3, -OCH2CH3, -S(O)2CH3, furanyl, oxetanyl, -CH2CN, -CH2OCH3, -NH(CH3), -N(CH3)2, -CH2N(CH3)2, haloC 1-6 Alkyl, halogenated C 1-6 Alkoxy, -O-(4-6 membered heterocycloalkyl) and -O-(C 3-6 Preferably, R b Each occurrence is independently selected from H, F, Cl, Br, I, cyano, methyl, ethyl, propyl, butyl, -OCH3, -OCH2CH3, -S(O)2CH3, furanyl, oxetanyl, -CH2CN, -CH2OCH3, -NH(CH3), -CH2N(CH3)2, halo 1-6 Alkyl, halogenated C 1-6 alkyl Oxygen group; More preferably, H, F, Cl, cyano, methyl, -OCH3, -OCH2CH3, -S(O)2CH3, furyl, oxetanyl, -CH2CN, -CH2OCH3, -NH(CH3), -CH2N(CH3)2, trifluoromethyl, trifluoromethoxy, -N(CH3)2, -OCHF2, -O-oxetanyl, -O-oxacyclopentyl, -O-cyclopropyl; (5) R1 is selected from hydrogen, alkoxyalkyl, C 1-6 Alkyl, hydroxy substituted C 1-6 Alkyl, -C 1-6 Alkyl-4-6 membered heterocycloalkyl; the heterocycloalkyl is optionally substituted by one or more C 1-6 Preferably, R1 is selected from hydrogen, alkoxyalkyl or C 1-6 alkyl; Preferably, R1 is H, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, butyl, -CH2OCH3, -(CH2)2OCH3, -CH 2- C(CH3)2-OH, -C(CH3)2-OCH3, -CH2-C(CH3)2-OCH3, -C(CH3)2-OH, Preferably, R1 is H, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, butyl or -CH2OCH3; (6) R2 is selected from hydrogen, deuterium, amino, halogen, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 3-8 membered alicyclic group; preferably, R2 is selected from hydrogen, deuterium and amino; (7) R3 is selected from hydrogen, halogen, cyano, hydroxyl, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 1-6 Alkoxy, alkoxyalkyl, halogenated C 1- 6-alkoxy, -N(C 1-6 Alkyl)2, deuterated C 1-6 Alkoxy; preferably, R3 is selected from hydrogen, halogen, cyano, hydroxyl, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 1-6 Alkoxy, alkoxyalkyl, halogenated C 1-6 Alkoxy, -N(C 1-6 Alkyl)2; Preferably, R3 is selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, alkoxyalkyl, halogenated C 1-6 Alkoxy and -N(C 1-6 Alkyl)2; More preferably, R3 is selected from hydrogen, F, Cl, Br, I, -CH3, -CH2CH3, -CH2-OCH3, -N(CH3)2, -O-CHF2, methoxy, ethoxy, propoxy, butoxy, -OCD3; further preferably, R3 is selected from hydrogen, F, Cl, Br, I, -CH3, -CH2CH3, -CH2-OCH3, -N(CH3)2, -O-CHF2, methoxy, ethoxy, propoxy, butoxy; (8) R4 is selected from hydrogen, halogen, cyano, C 1-4 Alkyl and C 1-4 Alkoxy; preferably, R4 is selected from hydrogen, C 1-4 Alkyl and halogen; (9) R7 are each independently selected from hydrogen, C 1-6 Alkyl, -C 1-6 Alkyl-OH, -C 1-6 Alkyl-CN, -CH2-OC 1-6 Preferably, R7 are each independently selected from hydrogen, C 1-6 Alkyl, -CH2-OH, -CH2-CN, -CH2-OC 1-6 alkyl; and (10) n1 and n2 are each independently selected from 0, 1, 2 and 3; preferably, n1 and n2 are each independently selected from 0, 1 and 2.

9. The compound of claim 1 or 2, or a tautomer, stereoisomer, solvate, metabolite, isotope-labeled substance, pharmaceutically acceptable salt, or cocrystal thereof, wherein the compound satisfies one or more of the following conditions: (1) Structural fragments Selected from in, 1 position terminal is connected to W; (2) Structural fragments Selected from (3) Structural fragments Selected from Among them, the 1st position terminal is connected to L1; (4) Structural fragments Selected from (5) Structural fragments for (6) Structural fragments for (7) Structural fragments Selected from (8) Structural fragments Selected from 10. The compound of claim 1 or 2, or a tautomer, stereoisomer, solvate, metabolite, isotope-labeled substance, pharmaceutically acceptable salt, or cocrystal thereof, wherein the compound satisfies one or more of the following conditions: (1) The halogen is independently selected from fluorine, chlorine, bromine or iodine; (2) the C1-C6 alkyl group is independently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl or sec-butyl, such as methyl or ethyl; (3) the C1-C6 alkoxy group is independently selected from methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, isobutoxy or sec-butoxy, such as methoxy or ethoxy; (4) The C3-C8 cycloalkyl group is independently selected from cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; (5) The heteroatom species of the 3-8 membered aliphatic heterocyclic group are each independently selected from one or two of N, O and S, and the number of heteroatoms is each independently 1, 2 or 3; (6) The 3-8 membered alicyclic group is independently a 3-8 membered heterocycloalkyl or a 3-8 membered heterocycloalkenyl, preferably a 4-6 membered heterocycloalkyl, such as oxetane, tetrahydropyrrole or tetrahydrofuranyl; (7) C 6-10 Aryl is independently selected from phenyl or naphthyl; (8) The heteroatom species of the 5-10 membered heteroaryl group is independently selected from one or two of N, O and S, and the number of heteroatoms is independently 1, 2 or 3; preferably, the heteroatom species is N, and the number of heteroatoms is independently 1 or 2; (9) The 5-10 membered heteroaryl group is independently a monocyclic or bicyclic ring, and the bicyclic ring is a fused ring; preferably, the 5-10 membered heteroaryl group is independently selected from a 5-6 membered monocyclic heteroaryl group or a 9-10 membered bicyclic heteroaryl group; the 5-10 membered heteroaryl group is, for example, pyridyl, thienyl or furyl; (10) The C1-C6 alkylene group is independently selected from methylene, ethylene, isopropylene or n-isopropylidene, such as methylene or ethylene; (11) The heteroatom species of the 4- to 10-membered heterocycloalkyl group is independently selected from one or two of N, O and S, and the number of heteroatoms is independently 1, 2 or 3; preferably, the heteroatom species is N, and the number of heteroatoms is independently 1 or 2; (12) The 4- to 10-membered heterocycloalkyl group is independently a monocyclic or polycyclic ring, the polycyclic ring is a bridged ring, a fused ring or a spiro ring, and the polycyclic ring is also a bicyclic or tricyclic ring; preferably, the 4- to 10-membered heterocycloalkyl group is independently a 4- to 7-membered monocyclic heterocycloalkyl group or an 8- to 10-membered bicyclic heterocycloalkyl group; The 4-7 membered monocyclic heterocycloalkyl group is for example The 8-10 membered bicyclic heterocycloalkyl group is for example (13) The heteroatom species of the 4- to 10-membered heterocycloalkenyl group is independently selected from one or two of N, O and S, and the number of heteroatoms is independently 1, 2 or 3; preferably, the heteroatom species is N, and the number of heteroatoms is independently 1 or 2; (14) The 4- to 10-membered heterocycloalkenyl group is independently a monocyclic or polycyclic ring, the polycyclic ring is a bridged ring, a fused ring or a spiro ring, and the polycyclic ring is also a bicyclic or tricyclic ring; preferably, the 4- to 10-membered heterocycloalkenyl group is independently a 4- to 7-membered monocyclic heterocycloalkenyl group or an 8- to 10-membered bicyclic heterocycloalkenyl group; (15) The 4- to 10-membered heterocycloalkenyl group independently contains 1 or 2 sp 2 Double bond; (16) The heteroatom species of the 5-7 membered heteroaryl group is independently selected from one or two of N, O and S, and the number of heteroatoms is independently 1, 2 or 3; preferably, the heteroatom species is N, and the number of heteroatoms is independently 1 or 2; (17) The 5-7 membered heteroaryl group, for example, pyridyl; (18) The halogenated C 1-6 Alkyl is selected from -CF3, -C2F5, -CHF2, -CH2F, -CH2CF3, -CH2Cl or -CH2CH2CF3; (19) The alkoxyalkyl group is -C 1-6 Alkyl-C 1-6 Alkoxy, such as -CH2OCH3, -CH2OCH2CH3, or -CH2OtBu; (20) The deuterated C 1-6 Alkoxy such as -OCD3; (21) The halogenated C 1-6 Alkoxy is selected from -OCF3, -OC2F5, -OCHF2, -OCH2F, -OCH2CF3, -OCH2Cl or -OCH2CH2CF3; and (22) C 1-6 The alkyl-substituted amino group is selected from -NH(C 1-6 Alkyl) or -N(C 1-6 Alkyl)2.

11. Any of the following compounds, or tautomers, stereoisomers, solvates, metabolites, isotope-labeled substances, pharmaceutically acceptable salts, or cocrystals thereof:

12. A pharmaceutical composition comprising the compound of at least one of claims 1 to 11, or its tautomer, stereoisomer, solvate, metabolite, isotope-labeled product, pharmaceutically acceptable salt, cocrystal, and pharmaceutically acceptable excipients.

13. A use of a compound according to at least one of claims 1 to 11, or a tautomer, stereoisomer, solvate, metabolite, isotope-labeled substance, pharmaceutically acceptable salt, cocrystal thereof, or a pharmaceutical composition according to claim 12, wherein the use comprises one of the following: (1) Use in the preparation of KRAS inhibitors and / or PI3K inhibitors; (2) Use in the preparation of drugs for treating diseases mediated by KRAS and / or PI3K; (3) Use in the preparation of a drug for treating a disease associated with KRAS resistance; preferably, use in the preparation of a drug for treating a disease associated with KRAS G12D resistance; (4) Use in the preparation of drugs for treating diseases associated with overexpression of PI3K protein and / or KRAS G12D protein; and (5) use in the preparation of a drug for treating a disease resistant to an anticancer agent; preferably, the anticancer agent is MRTX1133.

14. The use according to claim 13, wherein the disease is cancer or an autoimmune disease; Preferably, the cancer is selected from lung cancer, pancreatic cancer, ovarian cancer, bladder cancer, prostate cancer, chronic myeloid leukemia, intestinal cancer, brain cancer, liver cancer, kidney cancer, stomach cancer, breast cancer, skin cancer, melanoma, head and neck cancer, bone cancer, cervical cancer, pelvic cancer, vaginal cancer, oral cancer, lymphoma, blood cancer, esophageal cancer, urethral cancer, nasal cancer; More preferably, the cancer is selected from colorectal cancer, pancreatic cancer, gastric cancer, lung cancer and breast cancer.

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