Substituted heterocyclic fused-ring compounds, their preparation methods and pharmaceutical uses

Abstract

This invention discloses a substituted heterocyclic fused-ring compound or its pharmaceutically acceptable salt, stereoisomer, solvate or prodrug, which has selective inhibitory activity against KRAS gene mutations, as shown in formula (I) or formula (IA), wherein the definitions of each group are detailed in the specification. Furthermore, this invention also discloses pharmaceutical compositions comprising this compound and their use in the preparation of cancer drugs.

Description

[0001] This application is a divisional application of the national invention patent application with application number CN202210818001.1, which was filed on October 28, 2020, and is entitled "Substituted heterocyclic fused-ring compounds, their preparation method and pharmaceutical use". Technical Field

[0002] This invention relates to the field of pharmaceutical technology, and in particular to a substituted heterocyclic fused-ring compound, its application as a selective inhibitor of KRAS gene mutations, and pharmaceutical compositions prepared therefrom. Background Technology

[0003] Lung cancer is the most common cancer worldwide. In China, lung cancer has the highest incidence rate among all cancers and is also the cancer with the highest incidence and mortality rate. According to data released by the American Cancer Society in 2016, approximately 1.8 million people worldwide are diagnosed with lung cancer each year, of which nearly 80% are non-small cell lung cancer (NSCLC).

[0004] Reactive Acids (RAS) are a group of closely related, monomeric globular proteins (21 kDa molecular weight) containing 188-189 amino acids and bound to guanosine diphosphate (GDP) or guanosine triphosphate (GTP). RAS subfamily members include HRAS, KRAS, and NRAS. RAS acts as a molecular switch; when RAS contains bound GDP, it is in a dormant or off position and "inactive." When cells are exposed to certain growth-promoting stimuli, RAS is induced to convert its bound GDP to GTP. When bound to GTP, RAS is "on" and can interact with and activate other downstream target proteins. The intrinsic ability of RAS proteins to hydrolyze GTP back to GDP (thus switching themselves back to the off state) is extremely low. Exogenous GTPase activator proteins (GAPs) are required to restore them to the off state; the interaction between GAPs and RAS greatly accelerates the conversion of GTP to GDP. Any mutation in the RAS will affect the interaction between RAS and GAP, as well as the ability of GTP to be converted into GDP. This mutation leads to a prolonged protein activation time, thereby prolonging cell signaling and consequently causing continued cell growth and division. Since this signaling induces cell growth and division, overactivated RAS signaling can ultimately lead to cancer. In lung cancer, mutations in the RAS gene have been confirmed in approximately 32% of lung cancers. Any mutation in any of the three major subtypes of the RAS (HRAS, NRAS, or KRAS) gene can lead to tumorigenesis in humans. It has been reported that the KRAS gene has the highest mutation frequency among RAS genes, with KRAS mutations detected in 25-30% of tumors. In comparison, the rate of oncogenic mutations in members of the NRAS and HRAS families is much lower (8% and 3%, respectively). The most common KRAS mutations are found at residues G12 and G13 in the P-ring and at residue Q61. The G12C mutation is a frequent mutation in the KRAS gene (glycine-12 mutation to cysteine). This mutation has been found in approximately 13% of cancers, about 43% of lung cancers, and almost 100% of MYH-related polyposis (familial colorectal cancer syndrome). Therefore, developing inhibitors that selectively suppress KRAS mutations is a promising direction. To improve the inhibitory activity against KRAS mutations while reducing the inhibitory activity against wild-type KRAS, it is of great significance to develop novel selective inhibitors of RAS mutants with higher activity, better selectivity, and lower toxicity. Summary of the Invention

[0005] This invention provides a novel substituted heterocyclic fused-ring compound that serves as a selective inhibitor of KRAS mutations, exhibiting advantages such as high activity, good selectivity, and low toxicity.

[0006] In one aspect, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof:

[0007]

[0008] In the formula,

[0009] Z is either NC(O)-CR3=CR1R2 or NC(O)-C≡CR4;

[0010] R1 and R2 are independently hydrogen, halogen, cyano, and NR, respectively. a R b -C 1-3 Alkyl, Halogenated C 1-3 Alkyl, -C 1-3 Alkyl-hydroxyl, -C 1-3 Alkyl-cyano, -C 1-3 Alkyl-C 1-3 Alkoxy, -C 1-3 Alkyl-NR a R b -C 1-3 Alkyl-3 to 6-membered heterocyclic alkyl or -C 1-3 Alkyl-5 or 6-membered monocyclic heteroaryl; wherein the 3 to 6-membered heterocyclic alkyl or the 5 or 6-membered monocyclic heteroaryl has 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms;

[0011] R3 represents hydrogen, halogen, or -C. 1-3 Alkyl or -C 1-3 Alkoxy;

[0012] R4 is hydrogen or halogenated C. 1-3 Alkyl, -C 1-3 Alkyl-hydroxyl, -C 1-3 alkyl-cyano or -C 1-3 Alkyl-C 1-3 Alkoxy;

[0013] R 11 R 12 Whether the same or different, each is independently hydrogen, halogen, -C 1-3 Alkyl, -halogenated C 1-3 Alkyl, -C 1-3 Alkyl-hydroxyl, -C 1-3 Alkyl-cyano, -C 1-3 Alkyl-C 1-6 Alkoxy, -C 1-3 Alkyl-halogenated C 1-6 Alkyl or -C 1-3 Alkyl-halogenated C 1-6 Alkoxy;

[0014] R 21 R 22 Whether the same or different, each is independently hydrogen, halogen, -C 1-3 Alkyl, -halogenated C 1-3 Alkyl, -C 1-3 Alkyl-hydroxyl, -C 1-3 Alkyl-cyano, -C 1-3 Alkyl-C 1-6 Alkoxy, -C 1-3 Alkyl-halogenated C 1-6 Alkyl or -C 1-3 Alkyl-halogenated C 1-6 Alkoxy;

[0015] R 31 R 32 Whether the same or different, each is independently hydrogen, halogen, -C 1-3 Alkyl, -halogenated C 1-3 Alkyl, -C 1-3 Alkyl-hydroxyl, -C 1-3 Alkyl-cyano, -C 1-3 Alkyl-C 1-6 Alkoxy, -C 1-3 Alkyl-halogenated C 1-6 Alkyl or -C 1-3 Alkyl-halogenated C 1-6 Alkoxy;

[0016] R 41 Hydrogen, halogen, -C 1-3 Alkyl, -halogenated C 1-3 Alkyl, -C 1-3 Alkyl-hydroxyl, -C 1-3 Alkyl-cyano, -C 1-3 Alkyl-C 1-6 Alkoxy, -C 1-3 Alkyl-halogenated C 1-6 Alkyl or -C 1-3 Alkyl-halogenated C 1-6 Alkoxy;

[0017] when When the dashed line represents a single bond, P is O, NH, or NR. m ;R m -C 1-6 Alkyl, -halogenated C 1-6 Alkyl, -C 1-6 Alkyl-hydroxyl, -C 1-6 Alkyl-cyano, -C 1-6 Alkyl-C 1-6 Alkoxy, -C 1-6 Alkyl-halogenated C 1-6 Alkoxy, -C1-6 Alkyl-C 3-6 cycloalkyl or -C 1-6 Alkyl-3- to 6-membered heterocyclic alkyl; R 42 -(C=O)-, -C 1-3 Alkyl-, -C 1-3 Alkyl (hydroxy) -, -C 1-3 Alkyl (cyano) -, -C 1-3 Alkyl (C) 1-6 alkyl)-, -C 1-3 Alkyl (halogenated C) 1-6 alkyl)-, -C 1-3 Alkyl (C) 1-6 alkyl-hydroxy)-, -C 1-3 Alkyl (C) 1-6 (alkyl-cyano)-, -C 1-3 Alkyl (C) 1-6 alkoxy group (-, or -C) 1-3 Alkyl (halogenated C) 1-6 alkoxy)-;

[0018] Or when When the dashed line in the diagram represents none, P represents hydrogen or halogen; R 42 Hydrogen, halogen, -C 1-3 Alkyl, -halogenated C 1-3 Alkyl, -C 1-3 Alkyl-hydroxyl, -C 1-3 Alkyl-cyano, -C 1-3 Alkyl-C 1-6 Alkoxy, -C 1-3 Alkyl-halogenated C 1-6 Alkyl or -C 1-3 Alkyl-halogenated C 1-6 Alkoxy;

[0019] When Y1 is C; X1 is hydrogen, halogen, cyano, hydroxyl, amino, nitro, -substituted, or unsubstituted C. 1-6 Alkyl, -substituted or unsubstituted C 3-6 Cycloalkyl, -substituted or unsubstituted 3- to 6-membered heterocyclic alkyl, -O-substituted or unsubstituted C 1-6 Alkyl, -O-substituted or unsubstituted C 3-6 Cycloalkyl, -O-substituted or unsubstituted 3- to 6-membered heterocyclic alkyl, -NH-substituted or unsubstituted C 1-6 Alkyl, -N (substituted or unsubstituted C) 1-6 Alkyl)2, -NH-substituted or unsubstituted C 3-6 Cycloalkyl, -NH-substituted or unsubstituted 3- to 6-membered heterocyclic alkyl, -NH(C=O)-substituted or unsubstituted C 1-6 Alkyl group, -NH(C=O)-C3-6 Cycloalkyl, -NH(SO2)-substituted or unsubstituted C 1-6 Alkyl, -NH(SO2)- substituted or unsubstituted C 3-6 Cycloalkyl, -SO2-substituted or unsubstituted C 1-6 Alkyl, -SO2-substituted or unsubstituted C 3-6 cycloalkyl, -(C=O)-NR j R k -、-(C=O)-O- substituted or unsubstituted C 1-6 Alkyl, -(C=O)-O-substituted or unsubstituted C 3-6 cycloalkyl; wherein, R j R k Each is independently hydrogen or C 1-3 Alkyl; or R j R k Together with the attached nitrogen atom, it forms a substituted or unsubstituted 3- to 6-membered nitrogen-containing heterocyclic alkyl group; the 3- to 6-membered heterocyclic alkyl group has 1, 2, or 3 heteroatoms selected from N, O, and S as ring atoms; the 3- to 6-membered nitrogen-containing heterocyclic alkyl group has 3 to 6 ring atoms, one of which is a nitrogen atom, and the remaining 0, 1, or 2 ring atoms are optionally heteroatoms selected from N, O, and S; the term "substitution" refers to 1, 2, 3, or 4 hydrogen atoms in the group being replaced by substituents each independently selected from the S group;

[0020] Or, when Y1 is N, X1 is none;

[0021] The S group substituents are selected from: hydroxyl, halogen, nitro, oxo, -C 1-6 Alkyl, -halogenated C 1-6 Alkyl, hydroxyl substituted C 1-6 Alkyl, benzyl, -(CH2) u -cyano, -(CH2) u -C 1-6 Alkyl group, -(CH2) u - Halogenated C 1-6 Alkyl group, -(CH2) u - Halogenated C 1-6 Alkyl group, -(CH2) u -3 to 6-membered heterocyclic alkyl groups, -(CH2) u -5 or 6-membered monocyclic heteroaryl groups, -(CH2) u -C 3-8 Cycloalkyl, -(CH2) u -O-(CH2) v -C 3-8 Cycloalkyl, -(CH2) u -O-(CH2) v -C1-6 Alkyl group, -(CH2) u -O-(CH2) v OH, -(CH2) u -SO2C 1-6 Alkyl group, -(CH2) u -NR a0 R b0 -(CH2) u -C(O)NR a0 R b0 -(CH2) u -C(O)C 1-6 Alkyl, -C(O)OC 1-6 Alkyl, NR a0 C(O)-(CH2) u -NR a0 R b0 NR a0 C(O)-(CH2) u OH, NR a0 C(O)-halogenated C 1-6 Alkyl group; wherein the 3- to 6-membered heterocyclic alkyl group or the 5- or 6-membered monocyclic heteroaryl group each independently has 1, 2, or 3 heteroatoms selected from N, O, and S as ring atoms; the 3- to 6-membered heterocyclic alkyl group and the 5- or 6-membered monocyclic heteroaryl group are optionally surrounded by 1, 2, or 3 heteroatoms selected from halogen, cyano, -C 1-3 Alkyl, -C 1-3 Alkoxy and C 3-6 Substituents of cycloalkyl groups; u and v are each independently 0, 1, 2, 3, or 4; R a0 R b0 Each is independently hydrogen or C 1-3 alkyl;

[0022] E1 is N or CR5; where R5 is hydrogen, halogen, cyano, or -C. 1-6 Alkyl, -C 1-6 Alkoxy, -halogenated C 1-6 Alkyl, -halogenated C 1-6 Alkoxy, -C 3-6 cycloalkyl, -NR h R i -C 1-4 Alkyl-hydroxyl, -C 1-4 Alkyl-cyano, -C 1-4 Alkyl-C 1-6 Alkoxy, -C 1-4 Alkyl-halogenated C 1-6 Alkyl or -C 1-4 Alkyl-halogenated C 1-6 Alkoxy;

[0023] E2 is N or CR6; where R6 is hydrogen, halogen, cyano, or -C. 1-6 Alkyl, -C 1-6 Alkoxy, -halogenated C 1-6 Alkyl, -halogenated C 1-6 Alkoxy, -C 3-6 cycloalkyl, -NR h R i -C 1-4 Alkyl-hydroxyl, -C 1-4 Alkyl-cyano, -C 1-4 Alkyl-C 1-6 Alkoxy, -C 1-4 Alkyl-halogenated C 1-6 Alkyl or -C 1-4 Alkyl-halogenated C 1-6 Alkoxy;

[0024] The condition is that Y1, E1, and E2 are not all N at the same time;

[0025] Ar is C 6-10 Aryl, 5- or 6-membered monocyclic heteroaryl, or 8- to 10-membered bicyclic heteroaryl; wherein the 5- or 6-membered monocyclic heteroaryl has 1, 2, or 3 heteroatoms selected from N, O, and S as ring atoms; the 8- to 10-membered bicyclic heteroaryl has 1, 2, 3, 4, or 5 heteroatoms selected from N, O, and S as ring atoms; and the C 6-10 The aryl group, the 5- or 6-membered monocyclic heteroaryl group, or the 8- to 10-membered bicyclic heteroaryl group is unsubstituted or is composed of 1, 2, 3, or 4 independently selected from R. s1 Substitution of groups;

[0026] or

[0027] Ar represents the structure shown in equation (B):

[0028]

[0029] Wherein, ring B1 is a benzene ring or a 5- or 6-membered monocyclic heteroaryl ring; ring B2 is a fused 5- or 6-membered monocyclic heterocyclic alkyl ring or a fused 5- or 6-membered monocyclic cycloalkyl ring; wherein the 5- or 6-membered monocyclic heteroaryl ring or the fused 5- or 6-membered monocyclic heterocyclic alkyl ring has 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms;

[0030] (R s1 ) p This indicates that the hydrogen on the B1 ring is replaced by p R atoms. s1 Replacement, p is 0, 1, 2 or 3, each R s1 Same or different;

[0031] (R s2 ) qThis indicates that the hydrogen on ring B2 is replaced by q R atoms. s2 Replacement, where q is 0, 1, 2, or 3, for each R s2 Same or different;

[0032] R s1 R s2 Each is independently a halogen, cyano, nitro, hydroxyl, or -C group. 1-6 Alkyl, -C 1-6 Alkoxy, -halogenated C 1-6 Alkyl, -halogenated C 1-6 Alkoxy, -C 3-6 cycloalkyl, -NR c R d -C(O)NR e R f -SO2C 1-3 Alkyl, -SO2 halogenated C 1-3 Alkyl, -SO2NR e R f -C 1-4 Alkyl-hydroxyl, -C 1-4 Alkyl-cyano, -C 1-4 Alkyl-C 1-6 Alkoxy, -C 1-4 Alkyl-halogenated C 1-6 Alkyl, -C 1-4 Alkyl-halogenated C 1-6 Alkoxy, -C 1-4 Alkyl-3 to 6-membered heterocyclic alkyl, -C 1-4 Alkyl-NR e R f -C 1-4 Alkyl-C(O)NR e R f -C 1-4 Alkyl-SO2C 1-3 Alkyl or C 2-4 Alkyne group; wherein the 3 to 6-membered heterocyclic alkyl group has 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms;

[0033] R0 is -C 1-6 Alkyl, -C 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl, C 6-10 aryl, 5- or 6-membered monocyclic heteroaryl, 8- to 10-membered bicyclic heteroaryl, 7- to 11-membered spirocycloalkyl, -C 1-3 Alkyl-C 6-10 Aryl, -C 1-3 Alkyl-5 or 6-membered monocyclic heteroaryl, -NR g -C 6-10 Aryl, -OC 6-10 Aryl, -C 1-3Alkyl-3 to 6-membered heterocyclic alkyl, -C 1-3 Alkyl-C 3-6 Cycloalkyl groups, wherein the 3- to 6-membered heterocycloalkyl group, the 5- or 6-membered monocyclic heteroaryl group, or the 8- to 10-membered bicyclic heteroaryl group has 1, 2, or 3 heteroatoms selected from N, O, and S as ring atoms; and the C 1-6 Alkyl, C 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl, C 6-10 The aryl, 5- or 6-membered monocyclic heteroaryl, 8- to 10-membered bicyclic heteroaryl, and 7- to 11-membered spirocyclic alkyl groups are unsubstituted or are separated by 1, 2, 3, or 4 independent groups selected from R. s3 The group substitution; the -C 1-3 Alkyl groups are either unsubstituted or composed of 1, 2, 3, or 4 independently selected C14 groups. 1-3 Alkyl substitution;

[0034] or

[0035] R0 is the structure shown in equation (A-1) or equation (A-2):

[0036]

[0037] Wherein, ring A1 is a benzene ring or a 5- or 6-membered monocyclic heteroaryl ring; ring A2 is a fused 5- or 6-membered monocyclic heterocyclic alkyl ring or a fused 5- or 6-membered monocyclic cycloalkyl ring; wherein the 5- or 6-membered monocyclic heteroaryl ring or the fused 5- or 6-membered monocyclic heterocyclic alkyl ring has 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms;

[0038] (R s3 ) t This indicates that the hydrogen on the A1 ring is replaced by t R atoms. s3 Replacement, t is 0, 1, 2 or 3, each R s3 Same or different;

[0039] (R s4 ) s This indicates that the hydrogen on the A2 ring is replaced by s R s4 Replacement, s is 0, 1, 2 or 3, each R s4 Same or different;

[0040] R s3 R s4 Each is independently a halogen, cyano, hydroxyl, or -C group. 1-6 Alkyl, -C 1-6 Alkoxy, -halogenated C 1-6 Alkyl, -halogenated C 1-6 Alkoxy, -C 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl, -NR h R i -C(O)NRe R f -SO2C 1-3 Alkyl, -SO2 halogenated C 1-3 Alkyl, -SO2NR e R f -C 1-3 Alkyl-hydroxyl, -C 1-3 Alkyl-C 2-4 alkynyl group, -C 1-3 Alkyl-cyano, -C 1-3 Alkyl-C 1-6 Alkoxy, -C 1-3 Alkyl-halogenated C 1-6 Alkyl, -C 1-3 Alkyl-halogenated C 1-6 Alkoxy, -C 1-3 Alkyl-3 to 6-membered heterocyclic alkyl, -C 1-3 Alkyl-C 3-6 cycloalkyl, -C 1-3 Alkyl-NR e R f -C 1-3 Alkyl-C(O)NR e R f -C 1-3 Alkyl-SO2C 1-3 Alkyl or C 2-4 Alkyne group; wherein the 3 to 6-membered heterocyclic alkyl group has 1, 2, or 3 heteroatoms selected from N, O, and S as ring atoms; and the C 1-6 Alkyl, -C 1-6 Alkoxy, -C 1-3 Alkyl-, -C 3-6 The cycloalkyl group or 3- to 6-membered heterocycloalkyl group is optionally substituted by 1, 2 or 3 substituents independently selected from halogen, methyl, ethyl, propyl (n-propyl), isopropyl, trifluoromethyl, amino, N(CH3)2, hydroxyl or carboxyl;

[0041] R a R b R e R f R g Each is independently hydrogen or C 1-3 alkyl;

[0042] R c R d R h R i Each is independently hydrogen, -C 1-3 Alkyl, -C(O)C 1-3 Alkyl or -CO2C 1-3 alkyl.

[0043] In one embodiment of the present invention, the compound represented by formula (I) is either the compound of formula (I-1) or the compound of formula (I-2);

[0044]

[0045] In Equation I-1, P is O, NH or NR. m ;R m -C 1-6 Alkyl, -halogenated C 1-6 Alkyl, -C 1-6 Alkyl-hydroxyl, -C 1-6 Alkyl-cyano, -C 1-6 Alkyl-C 1-6 Alkoxy, -C 1-6 Alkyl-halogenated C 1-6 Alkoxy, -C 1-6 Alkyl-C 3-6 cycloalkyl or -C 1-6 Alkyl-3- to 6-membered heterocyclic alkyl; R 42 -(C=O)-, -C 1-3 Alkyl-, -C 1-3 Alkyl (hydroxy) -, -C 1-3 Alkyl (cyano) -, -C 1-3 Alkyl (C) 1-6 alkyl)-, -C 1-3 Alkyl (halogenated C) 1-6 alkyl)-, -C 1-3 Alkyl (C) 1-6 alkyl-hydroxy)-, -C 1-3 Alkyl (C) 1-6 (alkyl-cyano)-, -C 1-3 Alkyl (C) 1-6 alkoxy group (-, or -C) 1-3 Alkyl (halogenated C) 1-6 alkoxy)-; R 11 R 12 R 21 R 22 R 31 R 32 R 41 Z, R0, Ar, E1, E2, X1, Y1 are defined as before;

[0046] In formula I-2, P represents hydrogen or halogen; R 42 Hydrogen, halogen, -C 1-3 Alkyl, -halogenated C 1-3 Alkyl, -C 1-3 Alkyl-hydroxyl, -C 1-3 Alkyl-cyano, -C 1-3 Alkyl-C 1-6 Alkoxy, -C1-3 Alkyl-halogenated C 1-6 Alkyl or -C 1-3 Alkyl-halogenated C 1-6 Alkoxy; R 11 R 12 R 21 R 22 R 31 R 32 R 41 Z, R0, Ar, E1, E2, X1, and Y1 are defined as before.

[0047] In another aspect, the present invention provides a compound of formula (IA) or a tautomer, cis-trans isomer, meso compound, racemic compound, enantiomer, diastereomer, trans-blocker isomer or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof:

[0048]

[0049] In the formula,

[0050] Z is either NC(O)-CR3=CR1R2 or NC(O)-C≡CR4;

[0051] R1 and R2 are independently hydrogen, halogen, cyano, and NR, respectively. a R b -C 1-3 Alkyl, Halogenated C 1-3 Alkyl, -C 1-3 Alkyl-hydroxyl, -C 1-3 Alkyl-cyano, -C 1-3 Alkyl-C 1-3 Alkoxy, -C 1-3 Alkyl-NR a R b -C 1-3 Alkyl-3 to 6-membered heterocyclic alkyl or -C 1-3 Alkyl-5 or 6-membered monocyclic heteroaryl; wherein the 3 to 6-membered heterocyclic alkyl or the 5 or 6-membered monocyclic heteroaryl has 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms;

[0052] R3 represents hydrogen, halogen, or -C. 1-3 Alkyl or -C 1-3 Alkoxy;

[0053] R4 is hydrogen or halogenated C. 1-3 Alkyl, -C 1-3 Alkyl-hydroxyl, -C 1-3 alkyl-cyano or -C 1-3 Alkyl-C 1-3 Alkoxy;

[0054] R 11 R 12 Whether the same or different, each is independently hydrogen, halogen, -C 1-3 Alkyl, -halogenated C 1-3 Alkyl, -C 1-3 Alkyl-hydroxyl, -C 1-3 Alkyl-cyano, -C 1-3 Alkyl-C 1-6 Alkoxy, -C 1-3 Alkyl-halogenated C 1-6 Alkyl or -C 1-3 Alkyl-halogenated C 1-6 Alkoxy;

[0055] R 21 R 22 Whether the same or different, each is independently hydrogen, halogen, -C 1-3 Alkyl, -halogenated C 1-3 Alkyl, -C 1-3 Alkyl-hydroxyl, -C 1-3 Alkyl-cyano, -C 1-3 Alkyl-C 1-6 Alkoxy, -C 1-3 Alkyl-halogenated C 1-6 Alkyl or -C 1-3 Alkyl-halogenated C 1-6 Alkoxy;

[0056] R 31 R 32 Whether the same or different, each is independently hydrogen, halogen, -C 1-3 Alkyl, -halogenated C 1-3 Alkyl, -C 1-3 Alkyl-hydroxyl, -C 1-3 Alkyl-cyano, -C 1-3 Alkyl-C 1-6 Alkoxy, -C 1-3 Alkyl-halogenated C 1-6 Alkyl or -C 1-3 Alkyl-halogenated C 1-6 Alkoxy;

[0057] R 41 Hydrogen, halogen, -C 1-3 Alkyl, -halogenated C 1-3 Alkyl, -C 1-3 Alkyl-hydroxyl, -C 1-3 Alkyl-cyano, -C 1-3 Alkyl-C 1-6 Alkoxy, -C 1-3 Alkyl-halogenated C 1-6 Alkyl or -C 1-3 Alkyl-halogenated C1-6 Alkoxy;

[0058] when When the dashed line represents a single bond, P′ is O, NH, or NR. m′ ;R m′ -deuterated C 1-6 Alkyl, -C 1-6 Alkyl, -halogenated C 1-6 Alkyl, -C 1-6 Alkyl-hydroxyl, -C 1-6 Alkyl-cyano, -C 1-6 Alkyl-C 1-6 Alkoxy, -C 1-6 Alkyl-halogenated C 1-6 Alkoxy, -C 1-6 Alkyl-C 3-6 cycloalkyl or -C 1-6 Alkyl-3- to 6-membered heterocyclic alkyl; R 42 ′ for -C 1-3 Alkyl-(C=O)-, -(C=O)-, -C 1-3 Alkyl-, -C 1-3 Alkyl (hydroxy) -, -C 1-3 Alkyl (cyano) -, -C 1-3 Alkyl (C) 1-6 alkyl)-, -C 1-3 Alkyl (halogenated C) 1-6 alkyl)-, -C 1-3 Alkyl (C) 1-6 alkyl-hydroxy)-, -C 1-3 Alkyl (C) 1-6 (alkyl-cyano)-, -C 1-3 Alkyl (C) 1-6 alkoxy group (-, or -C) 1-3 Alkyl (halogenated C) 1-6 alkoxy)-;

[0059] Or when When the dashed line in the diagram is absent, P′ represents hydrogen or halogen; R 42 ′ represents hydrogen, halogen, -C 1-3 Alkyl, -halogenated C 1-3 Alkyl, -C 1-3 Alkyl-hydroxyl, -C 1-3 Alkyl-cyano, -C 1-3 Alkyl-C 1-6 Alkoxy, -C 1-3 Alkyl-halogenated C 1-6 Alkyl or -C 1-3 Alkyl-halogenated C 1-6 Alkoxy;

[0060] When Y1 is C; X1 is hydrogen, halogen, cyano, hydroxyl, amino, nitro, -substituted, or unsubstituted C. 1-6 Alkyl, -substituted or unsubstituted C 3-6 Cycloalkyl, -substituted or unsubstituted 3- to 6-membered heterocyclic alkyl, -O-substituted or unsubstituted C 1-6 Alkyl, -O-substituted or unsubstituted C 3-6 Cycloalkyl, -O-substituted or unsubstituted 3- to 6-membered heterocyclic alkyl, -NH-substituted or unsubstituted C 1-6 Alkyl, -N (substituted or unsubstituted C) 1-6 Alkyl)2, -NH-substituted or unsubstituted C 3-6 Cycloalkyl, -NH-substituted or unsubstituted 3- to 6-membered heterocyclic alkyl, -NH(C=O)-substituted or unsubstituted C 1-6 Alkyl group, -NH(C=O)-C 3-6 Cycloalkyl, -NH(SO2)-substituted or unsubstituted C 1-6 Alkyl, -NH(SO2)- substituted or unsubstituted C 3-6 Cycloalkyl, -SO2-substituted or unsubstituted C 1-6 Alkyl, -SO2-substituted or unsubstituted C 3-6 cycloalkyl, -(C=O)-NR j R k -、-(C=O)-O- substituted or unsubstituted C 1-6 Alkyl, -(C=O)-O-substituted or unsubstituted C 3-6 cycloalkyl; wherein, R j R k Each is independently hydrogen or C 1-3 Alkyl; or R j R k Together with the attached nitrogen atom, it forms a substituted or unsubstituted 3- to 6-membered nitrogen-containing heterocyclic alkyl group; the 3- to 6-membered heterocyclic alkyl group has 1, 2, or 3 heteroatoms selected from N, O, and S as ring atoms; the 3- to 6-membered nitrogen-containing heterocyclic alkyl group has 3 to 6 ring atoms, one of which is a nitrogen atom, and the remaining 0, 1, or 2 ring atoms are optionally heteroatoms selected from N, O, and S; the term "substitution" refers to 1, 2, 3, or 4 hydrogen atoms in the group being replaced by substituents each independently selected from the S group;

[0061] Or, when Y1 is N, X1 is none;

[0062] The S group substituents are selected from: hydroxyl, halogen, nitro, oxo, -C 1-6 Alkyl, -halogenated C 1-6 Alkyl, hydroxyl substituted C 1-6 Alkyl, benzyl, -(CH2) u-cyano, -(CH2) u -C 1-6 Alkyl group, -(CH2) u - Halogenated C 1-6 Alkyl group, -(CH2) u - Halogenated C 1-6 Alkyl group, -(CH2) u -3 to 6-membered heterocyclic alkyl groups, -(CH2) u -5 or 6-membered monocyclic heteroaryl groups, -(CH2) u -C 3-8 Cycloalkyl, -(CH2) u -O-(CH2) v -C 3-8 Cycloalkyl, -(CH2) u -O-(CH2) v -C 1-6 Alkyl group, -(CH2) u -O-(CH2) v OH, -(CH2) u -SO2C 1-6 Alkyl group, -(CH2) u -NR a0 R b0 -(CH2) u -C(O)NR a0 R b0 -(CH2) u -C(O)C 1-6 Alkyl, -C(O)OC 1-6 Alkyl, NR a0 C(O)-(CH2) u -NR a0 R b0 NR a0 C(O)-(CH2) u OH, NR a0 C(O)-halogenated C 1-6 Alkyl group; wherein the 3- to 6-membered heterocyclic alkyl group or the 5- or 6-membered monocyclic heteroaryl group each independently has 1, 2, or 3 heteroatoms selected from N, O, and S as ring atoms; the 3- to 6-membered heterocyclic alkyl group and the 5- or 6-membered monocyclic heteroaryl group are optionally surrounded by 1, 2, or 3 heteroatoms selected from halogen, cyano, -C 1-3 Alkyl, -C 1-3 Alkoxy and C 3-6 Substituents of cycloalkyl groups; u and v are each independently 0, 1, 2, 3, or 4; R a0 R b0 Each is independently hydrogen or C 1-3 alkyl;

[0063] E1' is N or CR5'; where R5' is hydrogen, halogen, cyano, or -C. 1-6 Alkyl, -C 1-6 Alkoxy, -halogenated C 1-6 Alkyl, -halogenated C 1-6 Alkoxy, -C 3-6 cycloalkyl, -OC 3-6 cycloalkyl, -NR h R i -C 1-4 Alkyl-hydroxyl, -C 1-4 Alkyl-cyano, -C 1-4 Alkyl-C 1-6 Alkoxy, -C 1-4 Alkyl-halogenated C 1-6 Alkyl or -C 1-4 Alkyl-halogenated C 1-6 Alkoxy;

[0064] E2' is N or CR6'; where R6' is hydrogen, halogen, cyano, or -C. 1-6 Alkyl, -C 1-6 Alkoxy, -halogenated C 1-6 Alkyl, -halogenated C 1-6 Alkoxy, -C 3-6 cycloalkyl, -OC 3-6 cycloalkyl, -NR h R i -C 1-4 Alkyl-hydroxyl, -C 1-4 Alkyl-cyano, -C 1-4 Alkyl-C 1-6 Alkoxy, -C 1-4 Alkyl-halogenated C 1-6 Alkyl or -C 1-4 Alkyl-halogenated C 1-6 Alkoxy;

[0065] The condition is that Y1, E1', and E2' are not all N at the same time;

[0066] Ar' is C 6-10 aryl, 5- or 6-membered monocyclic heteroaryl, 8- to 10-membered bicyclic heteroaryl, or pyridinone group; wherein the 5- or 6-membered monocyclic heteroaryl has 1, 2, or 3 heteroatoms selected from N, O, and S as ring atoms; the 8- to 10-membered bicyclic heteroaryl has 1, 2, 3, 4, or 5 heteroatoms selected from N, O, and S as ring atoms; and the C 6-10 The aryl group, the 5- or 6-membered monocyclic heteroaryl group, the 8- to 10-membered bicyclic heteroaryl group, and the pyridone group are unsubstituted or are substituted by 1, 2, 3, or 4 independently selected from R s1 Substitution of groups;

[0067] Alternatively, Ar' can be the structure shown in equation (B):

[0068]

[0069] Wherein, ring B1 is a benzene ring or a 5- or 6-membered monocyclic heteroaryl ring; ring B2 is a fused 5- or 6-membered monocyclic heterocyclic alkyl ring or a fused 5- or 6-membered monocyclic cycloalkyl ring; wherein the 5- or 6-membered monocyclic heteroaryl ring or the fused 5- or 6-membered monocyclic heterocyclic alkyl ring has 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms;

[0070] (R s1 ) p This indicates that the hydrogen on the B1 ring is replaced by p R atoms. s1 Replacement, p is 0, 1, 2 or 3, each R s1 Same or different;

[0071] (R s2 ) q This indicates that the hydrogen on ring B2 is replaced by q R atoms. s2 Replacement, where q is 0, 1, 2, or 3, for each R s2 Same or different;

[0072] R s1 R s2 Each is independently a halogen, cyano, nitro, hydroxyl, or -C group. 1-6 Alkyl, -C 1-6 Alkoxy, -halogenated C 1-6 Alkyl, -halogenated C 1-6 Alkoxy, -C 3-6 cycloalkyl, -NR c R d -C(O)NR e R f -SO2C 1-3 Alkyl, -SO2 halogenated C 1-3 Alkyl, -SO2NR e R f -C 1-4 Alkyl-hydroxyl, -C 1-4 Alkyl-cyano, -C 1-4 Alkyl-C 1-6 Alkoxy, -C 1-4 Alkyl-halogenated C 1-6 Alkyl, -C 1-4 Alkyl-halogenated C 1-6 Alkoxy, -C 1-4 Alkyl-3 to 6-membered heterocyclic alkyl, -C 1-4 Alkyl-NR e R f -C 1-4 Alkyl-C(O)NR eR f -C 1-4 Alkyl-SO2C 1-3 Alkyl or C 2-4 Alkyne group; wherein the 3 to 6-membered heterocyclic alkyl group has 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms;

[0073] R0' is -C 1-6 Alkyl, -C 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl, C 6-10 aryl, 5- or 6-membered monocyclic heteroaryl, 8- to 10-membered bicyclic heteroaryl, 7- to 11-membered spirocycloalkyl, -C 1-3 Alkyl-C 6-10 Aryl, -C 1-3 Alkyl-5 or 6-membered monocyclic heteroaryl, -NR g -C 6-10 Aryl, -OC 6-10 Aryl, -C 1-3 Alkyl-3 to 6-membered heterocyclic alkyl, -C 1-3 Alkyl-C 3-6 Cycloalkyl or pyridinone group, wherein the 3- to 6-membered heterocycloalkyl group, the 5- or 6-membered monocyclic heteroaryl group, or the 8- to 10-membered bicyclic heteroaryl group has 1, 2, or 3 heteroatoms selected from N, O, and S as ring atoms; and the C 1-6 Alkyl, C 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl, C 6-10 The aryl, 5- or 6-membered monocyclic heteroaryl, 8- to 10-membered bicyclic heteroaryl, 7- to 11-membered spirocyclic alkyl, and pyridone groups are unsubstituted or are selected by 1, 2, 3, or 4 independent groups from R s3 The group substitution; the -C 1-3 Alkyl groups are either unsubstituted or composed of 1, 2, 3, or 4 independently selected C14 groups. 1-3 Alkyl substitution;

[0074] Alternatively, R0' can be the structure shown in equation (A-1) or equation (A-2):

[0075]

[0076] Wherein, ring A1 is a benzene ring or a 5- or 6-membered monocyclic heteroaryl ring; ring A2 is a fused 5- or 6-membered monocyclic heterocyclic alkyl ring or a fused 5- or 6-membered monocyclic cycloalkyl ring; wherein the 5- or 6-membered monocyclic heteroaryl ring or the fused 5- or 6-membered monocyclic heterocyclic alkyl ring has 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms;

[0077] (R s3 ) t This indicates that the hydrogen on the A1 ring is replaced by t R atoms. s3Replacement, t is 0, 1, 2 or 3, each R s3 Same or different;

[0078] (R s4 ) s This indicates that the hydrogen on the A2 ring is replaced by s R s4 Replacement, s is 0, 1, 2 or 3, each R s4 Same or different;

[0079] R s3 R s4 Each is independently a halogen, cyano, hydroxyl, or -C group. 1-6 Alkyl, -C 1-6 Alkoxy, -halogenated C 1-6 Alkyl, -halogenated C 1-6 Alkoxy, -C 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl, -NR h R i -C(O)NR e R f -SO2C 1-3 Alkyl, -SO2 halogenated C 1-3 Alkyl, -SO2NR e R f -C 1-3 Alkyl-hydroxyl, -C 1-3 Alkyl-C 2-4 alkynyl group, -C 1-3 Alkyl-cyano, -C 1-3 Alkyl-C 1-6 Alkoxy, -C 1-3 Alkyl-halogenated C 1-6 Alkyl, -C 1-3 Alkyl-halogenated C 1-6 Alkoxy, -C 1-3 Alkyl-3 to 6-membered heterocyclic alkyl, -C 1-3 Alkyl-C 3-6 cycloalkyl, -C 1-3 Alkyl-NR e R f -C 1-3 Alkyl-C(O)NR e R f -C 1-3 Alkyl-SO2C 1-3 Alkyl or C 2-4 Alkyne group; wherein the 3 to 6-membered heterocyclic alkyl group has 1, 2, or 3 heteroatoms selected from N, O, and S as ring atoms; and the C 1-6 Alkyl, -C 1-6 Alkoxy, -C 1-3 Alkyl-, -C 3-6The cycloalkyl group or 3- to 6-membered heterocycloalkyl group is optionally substituted by 1, 2 or 3 substituents independently selected from halogen, methyl, ethyl, propyl (n-propyl), isopropyl, trifluoromethyl, amino, N(CH3)2, hydroxyl or carboxyl;

[0080] R a R b R e R f R g Each is independently hydrogen or C 1-3 alkyl;

[0081] R c R d R h R i Each is independently hydrogen, -C 1-3 Alkyl, -C(O)C 1-3 Alkyl or -CO2C 1-3 alkyl.

[0082] In one embodiment of the present invention, the compound represented by formula (IA) is a compound of formula (IB) or a compound of formula (IC);

[0083]

[0084] In formula IB, P' is O, NH, or NR. m′ ;R m′ -deuterated C 1-6 Alkyl, -C 1-6 Alkyl, -halogenated C 1-6 Alkyl, -C 1-6 Alkyl-hydroxyl, -C 1-6 Alkyl-cyano, -C 1-6 Alkyl-C 1-6 Alkoxy, -C 1-6 Alkyl-halogenated C 1-6 Alkoxy, -C 1-6 Alkyl-C 3-6 cycloalkyl or -C 1-6 Alkyl-3- to 6-membered heterocyclic alkyl; R 42 'for-C 1-3 Alkyl-(C=O)-, -(C=O)-, -C 1-3 Alkyl-, -C 1-3 Alkyl (hydroxy) -, -C 1-3 Alkyl (cyano) -, -C 1-3 Alkyl (C) 1-6 alkyl)-, -C 1-3 Alkyl (halogenated C) 1-6 alkyl)-, -C 1-3 Alkyl (C) 1-6alkyl-hydroxy)-, -C 1-3 Alkyl (C) 1-6 (alkyl-cyano)-, -C 1-3 Alkyl (C) 1-6 alkoxy group (-, or -C) 1-3 Alkyl (halogenated C) 1-6 alkoxy)-; R 11 、R 12 、R 21 、R 22 、R 31 、R 32 、R 41 Z, R0', Ar', E1', E2', X1, and Y1 are defined as before;

[0085] In formula IC, P' is hydrogen or halogen; R 42 'For hydrogen, halogen, -C 1-3 Alkyl, -halogenated C 1-3 Alkyl, -C 1-3 Alkyl-hydroxyl, -C 1-3 Alkyl-cyano, -C 1-3 Alkyl-C 1-6 Alkoxy, -C 1-3 Alkyl-halogenated C 1-6 Alkyl or -C 1-3 Alkyl-halogenated C 1-6 Alkoxy; R 11 、R 12 、R 21 、R 22 、R 31 、R 32 、R 41 The definitions of Z, R0', Ar', E1', E2', X1, and Y1 are the same as before.

[0086] In one embodiment of the present invention, in formula IB, P' is O, NH, or NR. m′ ;R m′ -deuterated C 1-6 Alkyl or -C 1-6 Alkyl; R 42 ′ for -C 1-3 Alkyl-(C=O)-, -(C=O)-, or -C 1-3 alkyl-.

[0087] In one embodiment of the present invention, in formula IB, P' is O, NH, or NR. m′ ;R m′ -deuterated C 1-3 Alkyl or -C 1-3 Alkyl; R 42 'for-C 1-3Alkyl-(C=O)-, -(C=O)-, or -C 1-3 alkyl-.

[0088] In one embodiment of the present invention, in formula IB, P' is O, NH, or NR. m′ ;R m′ It is deuterated methyl, deuterated ethyl, deuterated n-propyl, deuterated isopropyl, methyl, ethyl, n-propyl, or isopropyl; R 42 'It can be -CH2-(C=O)-, -CH2CH2-(C=O)-, -(C=O)-, -CH2-, -CH2CH2- or -CH2CH2CH2-.

[0089] In one embodiment of the present invention, in formula IB, P' is NH or NR. m′ ;R m′ -deuterated C 1-6 Alkyl or -C 1-6 Alkyl; R 42 'for-C 1-3 Alkyl-(C=O)- or -(C=O)-.

[0090] In one embodiment of the present invention, in formula IB, P' is NH or NR. m′ ;R m′ -deuterated C 1-3 Alkyl or -C 1-3 Alkyl; R 42 'for-C 1-3 Alkyl-(C=O)- or -(C=O)-.

[0091] In one embodiment of the present invention, in formula IB, P' is NH or NR. m′ ;R m′ It is a deuterated methyl or methyl group; R 42 ′ can be -CH2-(C=O)-, -CH2CH2-(C=O)-, or -(C=O)-.

[0092] In one embodiment of the present invention, in formula IB, P′ is O; R 42 'for-C 1-3 alkyl-.

[0093] In one embodiment of the present invention, in formula IB, P' is O; R 42 'For -CH2-.

[0094] In one embodiment of the present invention, the compound represented by formula (IB) is a compound of formula (IB-1) or a compound of formula (IB-2);

[0095]

[0096] In equations (IB-1) and (IB-2), R 21 R 22 R 11 R 12 R 31 R 32 R 41 R 42 The definitions of ', Z, P', R0', Ar', E1', E2', X1, and Y1 are the same as before.

[0097] In one embodiment of the present invention, in formula IB-1, P′ is O, NH, or NR. m′ ;R m′ -deuterated C 1-6 Alkyl or -C 1-6 Alkyl; R 42 ′ for -C 1-3 Alkyl-(C=O)-, -(C=O)-, or -C 1-3 alkyl-.

[0098] In one embodiment of the present invention, in formula IB-1, P′ is NH or NR. m′ ;R m′ -deuterated C 1-6 Alkyl or -C 1-6 Alkyl; R 42 'for-C 1-3 Alkyl-(C=O)- or -(C=O)-.

[0099] In one embodiment of the present invention, in formula IB-1, P′ is NH or NR. m′ ;R m′ -deuterated C 1-3 Alkyl or -C 1-3 Alkyl; R 42 'for-C 1-3 Alkyl-(C=O)- or -(C=O)-.

[0100] In one embodiment of the present invention, in formula IB-1, P′ is NH or NR. m′ ;R m′ It is a deuterated methyl or methyl group; R 42 ′ can be -CH2-(C=O)-, -CH2CH2-(C=O)-, or -(C=O)-.

[0101] In one embodiment of the present invention, in formula IB-1, P′ is O; R 42 ′ for -C 1-3 alkyl-.

[0102] In one embodiment of the present invention, in formula IB-1, P′ is O; R 42 ′ is -CH2-.

[0103] In another aspect, the present invention provides a compound of formula (IB-1a) or (IB-2a), or a tautomer, cis-trans isomer, meso compound, racemic compound, enantiomer, diastereomer, trans-blocker isomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof:

[0104]

[0105] Where R1, R2, R3, R 21 R 22 R 12 R 11 R 31 R 32 The definitions of P′, R0′, Ar′, E1′, and X1 are the same as before.

[0106] In one embodiment of the present invention, in formula IB-1a, P′ is NH or NR. m′ ;R m′ -deuterated C 1-6 Alkyl or -C 1-6 alkyl.

[0107] In one embodiment of the present invention, in formula IB-1a, P′ is NH or NR. m′ ;R m′ -deuterated C 1-3 Alkyl or -C 1-3 alkyl.

[0108] In one embodiment of the present invention, in formula IB-1a, P′ is NH or NR. m′ ;R m′ It is a deuterated methyl or methyl group.

[0109] In one embodiment of the present invention, the compound represented by formula (IB-1a) is a compound of formula (IB-1aa), a compound of formula (IB-1ab), a compound of formula (IB-1ac), or a compound of formula (IB-1ad).

[0110]

[0111] In equations (IB-1aa) and (IB-1ab), R 21 'Independently halogen, -C 1-3 Alkyl, -halogenated C 1-3 Alkyl, -C 1-3 Alkyl-hydroxyl, -C 1-3 Alkyl-cyano, -C 1-3 Alkyl-C 1-6 Alkoxy, -C 1-3Alkyl-halogenated C 1-6 Alkyl or -C 1-3 Alkyl-halogenated C 1-6 Alkoxy groups; R1, R2, R3, R 12 R 11 R 31 R 32 The definitions of P', R0', Ar', E1', and X1 are the same as before;

[0112] In equations (IB-1ac) and (IB-1ad), R 12 'Independently halogen, -C 1-3 Alkyl, -halogenated C 1-3 Alkyl, -C 1-3 Alkyl-hydroxyl, -C 1-3 Alkyl-cyano, -C 1-3 Alkyl-C 1-6 Alkoxy, -C 1-3 Alkyl-halogenated C 1-6 Alkyl or -C 1-3 Alkyl-halogenated C 1-6 Alkoxy groups; R1, R2, R3, R 21 R 22 R 31 R 32 The definitions of P′, R0′, Ar′, E1′, and X1 are the same as before.

[0113] In another aspect, the present invention provides a compound of formula (IB-1c) or formula (IB-2c), or a tautomer, cis-trans isomer, meso compound, racemic compound, enantiomer, diastereomer, trans-blocker isomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof:

[0114]

[0115] Where R1, R2, R3, R 21 R 22 R 12 R 11 R 31 R 32 The definitions of P′, R0′, Ar′, E1′, and X1 are the same as before.

[0116] In one embodiment of the present invention, in formula IB-1c, P′ is NH or NR. m′ ;R m′ -deuterated C 1-6 Alkyl or -C 1-6 alkyl.

[0117] In one embodiment of the present invention, in formula IB-1c, P′ is NH or NR.m′ ;R m′ -deuterated C 1-3 Alkyl or -C 1-3 alkyl.

[0118] In one embodiment of the present invention, in formula IB-1c, P′ is NH or NR. m′ ;R m′ It is a deuterated methyl or methyl group.

[0119] In one embodiment of the present invention, the compound represented by formula (IB-1c) is a compound of formula (IB-1ca), a compound of formula (IB-1cb), a compound of formula (IB-1cc), or a compound of formula (IB-1cd).

[0120]

[0121] In equations (IB-1ca) and (IB-1cb), R 21 'Independently halogen, -C 1-3 Alkyl, -halogenated C 1-3 Alkyl, -C 1-3 Alkyl-hydroxyl, -C 1-3 Alkyl-cyano, -C 1-3 Alkyl-C 1-6 Alkoxy, -C 1-3 Alkyl-halogenated C 1-6 Alkyl or -C 1-3 Alkyl-halogenated C 1-6 Alkoxy groups; R1, R2, R3, R 12 R 11 R 31 R 32 The definitions of P′, R0′, Ar′, E1′, and X1 are the same as before;

[0122] In equations (IB-1cc) and (IB-1cd), R 12 'Independently halogen, -C 1-3 Alkyl, -halogenated C 1-3 Alkyl, -C 1-3 Alkyl-hydroxyl, -C 1-3 Alkyl-cyano, -C 1-3 Alkyl-C 1-6 Alkoxy, -C 1-3 Alkyl-halogenated C 1-6 Alkyl or -C 1-3 Alkyl-halogenated C 1-6 Alkoxy groups; R1, R2, R3, R 21 R 22 R 31 R 32The definitions of P′, R0′, Ar′, E1′, and X1 are the same as before.

[0123] In one embodiment of the present invention, in formulas IB-1a, IB-1c, IB-2a, and IB-2c, P′ is independently NH or NR. m′ ;R m′ -deuterated C 1-6 Alkyl or -C 1-6 alkyl.

[0124] In one embodiment of the present invention, in formulas IB-1a, IB-1c, IB-2a, and IB-2c, P′ is independently NH or NR. m′ ;R m′ -deuterated C 1-3 Alkyl or -C 1-3 alkyl.

[0125] In one embodiment of the present invention, in formulas IB-1a, IB-1c, IB-2a, and IB-2c, P' is independently NH or NR. m′ ;R m′ It can be deuterated methyl, deuterated ethyl, deuterated n-propyl, deuterated isopropyl, methyl, ethyl, n-propyl or isopropyl.

[0126] In another aspect, the present invention provides a compound of formula (IB-1b) or (IB-2b), or a tautomer, cis-trans isomer, meso compound, racemic compound, enantiomer, diastereomer, trans-blocker isomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof:

[0127]

[0128] Where R1, R2, R3, R 21 R 22 R 12 R 11 R 31 R 32 The definitions of P′, R0′, Ar′, E1′, and X1 are the same as before.

[0129] In one embodiment of the present invention, the compound represented by formula (IB-1b) is a compound of formula (IB-1ba), a compound of formula (IB-1bb), a compound of formula (IB-1bc), or a compound of formula (IB-1bd).

[0130]

[0131] In equations (IB-1ba) and (IB-1bb), R 21 'Independently halogen, -C1-3 Alkyl, -halogenated C 1-3 Alkyl, -C 1-3 Alkyl-hydroxyl, -C 1-3 Alkyl-cyano, -C 1-3 Alkyl-C 1-6 Alkoxy, -C 1-3 Alkyl-halogenated C 1-6 Alkyl or -C 1-3 Alkyl-halogenated C 1-6 Alkoxy groups; R1, R2, R3, R 12 R 11 R 31 R 32 The definitions of P′, R0′, Ar′, E1′, and X1 are the same as before;

[0132] In equations (IB-1bc) and (IB-1bd), R 12 'Independently halogen, -C 1-3 Alkyl, -halogenated C 1-3 Alkyl, -C 1-3 Alkyl-hydroxyl, -C 1-3 Alkyl-cyano, -C 1-3 Alkyl-C 1-6 Alkoxy, -C 1-3 Alkyl-halogenated C 1-6 Alkyl or -C 1-3 Alkyl-halogenated C 1-6 Alkoxy groups; R1, R2, R3, R 21 R 22 R 31 R 32 The definitions of P′, R0′, Ar′, E1′, and X1 are the same as before.

[0133] In another aspect, the present invention provides a compound of formula (IB-1d) or formula (IB-2d), or a tautomer, cis-trans isomer, meso compound, racemic compound, enantiomer, diastereomer, trans-blocker isomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof:

[0134]

[0135] Where R1, R2, R3, R 21 R 22 R 12 R 11 R 31 R 32 The definitions of P′, R0′, Ar′, E1′, and X1 are the same as before.

[0136] In one embodiment of the present invention, the compound represented by formula (IB-1d) is a compound of formula (IB-1da), a compound of formula (IB-1db), a compound of formula (IB-1dc), or a compound of formula (IB-1dd).

[0137]

[0138] In equations (IB-1da) and (IB-1db), R 21 'Independently halogen, -C 1-3 Alkyl, -halogenated C 1-3 Alkyl, -C 1-3 Alkyl-hydroxyl, -C 1-3 Alkyl-cyano, -C 1-3 Alkyl-C 1-6 Alkoxy, -C 1-3 Alkyl-halogenated C 1-6 Alkyl or -C 1-3 Alkyl-halogenated C 1-6 Alkoxy groups; R1, R2, R3, R 12 R 11 R 31 R 32 The definitions of P′, R0′, Ar′, E1′, and X1 are the same as before;

[0139] In equations (IB-1dc) and (IB-1dd), R 12 'Independently halogen, -C 1-3 Alkyl, -halogenated C 1-3 Alkyl, -C 1-3 Alkyl-hydroxyl, -C 1-3 Alkyl-cyano, -C 1-3 Alkyl-C 1-6 Alkoxy, -C 1-3 Alkyl-halogenated C 1-6 Alkyl or -C 1-3 Alkyl-halogenated C 1-6 Alkoxy groups; R1, R2, R3, R 21 R 22 R 31 R 32 The definitions of P', R0', Ar', E1', and X1 are the same as before.

[0140] In one embodiment of the present invention, in formulas IB-1b, IB-1d, IB-2b, and IB-2d, P′ is independently O.

[0141] In one embodiment of the present invention, R 21 ′、R 12 Each is independent as -C 1-3 Alkyl, -C1-3 Alkyl-hydroxyl, -C 1-3 alkyl-cyano or -C 1-3 Alkyl-C 1-6 Alkyl group.

[0142] In one embodiment of the present invention, R 21 '、R 12 'Each is independent as -C 1-3 Alkyl, -CH2-hydroxy, -CH2-cyano, or -CH2-C 1-3 Alkyl group.

[0143] In one embodiment of the present invention, R 21 '、R 12 Each can be methyl, ethyl, n-propyl or isopropyl.

[0144] In one embodiment of the present invention, X1 is hydrogen, halogen, substituted or unsubstituted C. 1-6 Alkyl, -substituted or unsubstituted C 3-6 Cycloalkyl, or -O-substituted or unsubstituted C 1-6 Alkyl; the term "substitution" refers to the substitution of 1, 2, 3, or 4 hydrogen atoms in a group by substituents selected independently from group S.

[0145] In one embodiment of the present invention, X1 is hydrogen, halogen, or unsubstituted C. 1-3 Alkyl, unsubstituted C 3-6 cycloalkyl or -O-unsubstituted C 1-3 alkyl.

[0146] In one embodiment of the present invention, X1 is hydrogen, fluorine, chlorine, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, n-propoxy, or isopropoxy.

[0147] In one embodiment of the present invention, X1 is fluorine, chlorine, or cyclopropyl.

[0148] In one embodiment of the present invention, Y1 is C; E1' is N or CR5'; E2' is CR6'; R5' and R6' are defined as before.

[0149] In one embodiment of the present invention, Y1 is C; E1' is CR5'; E2' is N; and R5' is defined as before.

[0150] In one embodiment of the present invention, Y1 is C; E1′ is N or CR5'; E2' is CH; R5' is defined as before.

[0151] In one embodiment of the present invention, Y1 is C; E1' is N or CF; and E2' is CH.

[0152] In one embodiment of the invention, Ar' is a phenyl, a 5- or 6-membered monocyclic heteroaryl, or a pyridone group; and the phenyl, 5- or 6-membered monocyclic heteroaryl, and pyridone group are unsubstituted or substituted by 1, 2, 3, or 4 independently selected groups from the following: halogen, cyano, hydroxyl, -C 1-6 Alkyl, -C 1-6 Alkoxy, -NR c R d -C 1-4 Alkyl-NR e R f ;where R e R f Each is independently hydrogen or C 1-3 Alkyl; R c R d Each is independently hydrogen, -C 1-3 Alkyl, -C(O)C 1-3 Alkyl or -CO2C 1-3 alkyl.

[0153] In one embodiment of the invention, Ar' is phenyl or pyridone; and the phenyl and pyridone groups are unsubstituted or substituted by 1, 2, 3 or 4 independently selected groups from the following: fluorine, chlorine, bromine, cyano, hydroxyl, -C 1-3 Alkyl, -C 1-3 Alkoxy, -NH2, -NHCH3, -N(CH3)2, -CH2-NH2, -CH2-NHCH3, -CH2-N(CH3)2.

[0154] In one embodiment of the invention, Ar' is a phenyl group; the phenyl group is selected from R s1 Group substitution; R s1 Halogen, cyano, -C 1-6 Alkyl, -C 1-6 Alkoxy, -halogenated C 1-6 Alkyl, -halogenated C 1-6 alkoxy or -C 3-6 Cycloalkyl.

[0155] In one embodiment of the present invention, Ar' is selected from the following structures: In the formula, R s1 R s2 The definition is the same as before.

[0156] In one embodiment of the present invention, Ar' is selected from the following structures: In the formula, R s1 For hydroxyl group; R s2 Halogen, cyano, -C 1-6 Alkyl, -C 1-6Alkoxy, -halogenated C 1-6 Alkyl, -halogenated C 1-6 alkoxy or -C 3-6 Cycloalkyl. In one embodiment of the invention, the R... s1 Above the plane of the benzene ring.

[0157] In one embodiment of the present invention, Ar' is selected from the following structures: In the formula, R s1 -C 1-6 Alkoxy; R s2 Halogen, cyano, -C 1-6 Alkyl, -C 1-6 Alkoxy, -halogenated C 1-6 Alkyl, -halogenated C 1-6 alkoxy or -C 3-6 Cycloalkyl. In one embodiment of the invention, the R... s1 Above the plane of the benzene ring.

[0158] In one embodiment of the present invention, R0' is a phenyl, a 5- or 6-membered monocyclic heteroaryl, or a pyridone group, wherein the 5- or 6-membered monocyclic heteroaryl has 1, 2, or 3 heteroatoms selected from N, O, and S as ring atoms; and the phenyl, 5- or 6-membered monocyclic heteroaryl, and pyridone group are unsubstituted or surrounded by 1, 2, 3, or 4 independent atoms selected from R0'. s3 Substitution of groups.

[0159] In one embodiment of the present invention, R0' is phenyl, thiazolyl, isothiazolyl, imidazolel, oxazolyl, isoxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, or pyridonel, and the phenyl, thiazolyl, isothiazolyl, imidazolel, oxazolyl, isoxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, and pyridonel groups are unsubstituted or are selected independently by 1, 2, 3, or 4 groups from R0'. s3 Substitution of groups.

[0160] In one embodiment of the present invention, R0' is selected from the following structures:

[0161]

[0162] In the above structures, R s3 'Same or different, each 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 3-6 cycloalkyl, -NR h R i -C(O)NRe R f -C 1-3 alkyl-hydroxyl and -C 1-3 Alkyl-NR e R f ; and the -C mentioned above 3-6 The cycloalkyl group is optionally substituted by one, two, or three substituents independently selected from halogen, methyl, ethyl, propyl (n-propyl), isopropyl, trifluoromethyl, amino, N(CH3)2, hydroxyl, and carboxyl groups; wherein R e R f Each is independently hydrogen or C 1-3 Alkyl; R h R i Each is independently hydrogen, -C 1-3 Alkyl, -C(O)C 1-3 Alkyl or -CO2C 1-3 alkyl;

[0163] In the above structures, R s3 "Whether the same or different, each 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 3-6 cycloalkyl, -NR h R i -C(O)NR e R f -C 1-3 alkyl-hydroxyl and -C 1-3 Alkyl-NR e R f ; and the -C mentioned above 3-6 The cycloalkyl group is optionally substituted by one, two, or three substituents independently selected from halogen, methyl, ethyl, propyl (n-propyl), isopropyl, trifluoromethyl, amino, N(CH3)2, hydroxyl, and carboxyl groups; wherein R e R f Each is independently hydrogen or C 1-3 Alkyl; R h R i Each is independently hydrogen, -C 1-3 Alkyl, -C(O)C 1-3 Alkyl or -CO2C 1-3 alkyl;

[0164] In the above structures, R s3 "The same or different, each is independently selected from hydrogen, -C" 1-6 Alkyl, -halogenated C 1-6 Alkyl, -C 3-6 cycloalkyl, -C1-3 Alkyl-C(O)NR e R f -C(O)NR e R f -C 1-4 alkyl-hydroxyl and -C 1-4 Alkyl-NR e R f ; and the -C mentioned above 3-6 The cycloalkyl group is optionally substituted by one, two, or three substituents independently selected from halogen, methyl, ethyl, propyl (n-propyl), isopropyl, trifluoromethyl, amino, N(CH3)2, hydroxyl, and carboxyl groups; wherein R e R f Each is independently hydrogen or C 1-3 alkyl;

[0165] In the above structures, R s3 Whether the groups are the same or different, they are each independently selected from halogens, cyano groups, hydroxyl groups, and -C groups. 1-6 Alkyl, -C 1-6 Alkoxy, -halogenated C 1-6 Alkyl, -halogenated C 1-6 Alkoxy, -C 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl, -NR h R i -C(O)NR e R f -SO2C 1-3 Alkyl, -SO2 halogenated C 1-3 Alkyl, -SO2NR e R f -C 1-3 Alkyl-hydroxyl, -C 1-3 Alkyl-C 2-4 alkynyl group, -C 1-3 Alkyl-cyano, -C 1-3 Alkyl-C 1-6 Alkoxy, -C 1-3 Alkyl-halogenated C 1-6 Alkyl, -C 1-3 Alkyl-halogenated C 1-6 Alkoxy, -C 1-3 Alkyl-3 to 6-membered heterocyclic alkyl, -C 1-3 Alkyl-C 3-6 cycloalkyl, -C 1-3 Alkyl-NR e R f -C 1-3 Alkyl-C(O)NR e R f -C 1-3 Alkyl-SO2C 1-3Alkyl or C 2-4 Alkyne group; wherein the 3 to 6-membered heterocyclic alkyl group has 1, 2, or 3 heteroatoms selected from N, O, and S as ring atoms; and the C 1-6 Alkyl, -C 1-6 Alkoxy, -C 1-3 Alkyl-, -C 3-6 The cycloalkyl group or 3- to 6-membered heterocycloalkyl group is optionally substituted by 1, 2, or 3 substituents independently selected from halogen, methyl, ethyl, propyl (n-propyl), isopropyl, trifluoromethyl, amino, N(CH3)2, hydroxyl, and carboxyl groups; wherein R h R i Each is independently hydrogen, -C 1-3 Alkyl, -C(O)C 1-3 Alkyl or -CO2C 1-3 Alkyl; R e R f Each is independently hydrogen or C 1-3 alkyl;

[0166] In each of the above structures, n may be the same or different, and each can be 0, 1, 2 or 3 independently.

[0167] In one embodiment of the present invention, R0' is... R s3 'For hydrogen, halogen, cyano, hydroxyl, -C 1-6 Alkyl, -C 1-6 Alkoxy, -halogenated C 1-6 Alkyl, -halogenated C 1-6 Alkoxy, -C 3-6 cycloalkyl, -NR h R i -C(O)NR e R f -C 1-3 alkyl-hydroxyl and -C 1-3 Alkyl-NR e R f ; and the -C mentioned above 3-6 The cycloalkyl group is optionally substituted by one, two, or three substituents independently selected from halogen, methyl, ethyl, propyl (n-propyl), isopropyl, trifluoromethyl, amino, N(CH3)2, hydroxyl, and carboxyl groups; wherein R e R f Each is independently hydrogen or C 1-3 Alkyl; R h R i Each is independently hydrogen, -C 1-3 Alkyl, -C(O)C 1-3 Alkyl or -CO2C 1-3 Alkyl; R s3" is isopropyl; n is 0. In one embodiment, the R s3 "Below the plane of the benzene ring."

[0168] In one embodiment of the present invention, R0' is selected from the following structures: R s3 'For hydrogen, halogen, cyano, hydroxyl, -C 1-6 Alkyl, -C 1-6 Alkoxy, -halogenated C 1-6 Alkyl, -halogenated C 1-6 Alkoxy, -C 3-6 cycloalkyl, -NR h R i -C(O)NR e R f -C 1-3 alkyl-hydroxyl and -C 1-3 Alkyl-NR e R f ; and the -C mentioned above 3-6 The cycloalkyl group is optionally substituted by one, two, or three substituents independently selected from halogen, methyl, ethyl, propyl (n-propyl), isopropyl, trifluoromethyl, amino, N(CH3)2, hydroxyl, and carboxyl groups; wherein R e R f Each is independently hydrogen or C 1-3 Alkyl; R h R i Each is independently hydrogen, -C 1-3 Alkyl, -C(O)C 1-3 Alkyl or -CO2C 1-3 Alkyl; R s3 "Isopropyl; R" s3 -C 1-6 Alkyl; n is 0 or 1. In one embodiment, the R s3 "Below the plane of the pyridine ring."

[0169] In one embodiment of the present invention, R0' is selected from the following structures: R s3 'For hydrogen, halogen, cyano, hydroxyl, -C 1-6 Alkyl, -C 1-6 Alkoxy, -halogenated C 1-6 Alkyl, -halogenated C 1-6 Alkoxy, -C 3-6 cycloalkyl, -NR h R i -C(O)NR e R f -C 1-3 alkyl-hydroxyl and -C 1-3 Alkyl-NRe R f ; and the -C mentioned above 3-6 The cycloalkyl group is optionally substituted by one, two, or three substituents independently selected from halogen, methyl, ethyl, propyl (n-propyl), isopropyl, trifluoromethyl, amino, N(CH3)2, hydroxyl, and carboxyl groups; wherein R e R f Each is independently hydrogen or C 1-3 Alkyl; R h R i Each is independently hydrogen, -C 1-3 Alkyl, -C(O)C 1-3 Alkyl or -CO2C 1-3 Alkyl; R s3 " is isopropyl; n is 0. In one embodiment, the R s3 "Below the plane of the pyrimidine ring."

[0170] In one embodiment of the present invention, R0′ is selected from the following structures: R s3 'For hydrogen, halogen, cyano, hydroxyl, -C 1-6 Alkyl, -C 1-6 Alkoxy, -halogenated C 1-6 Alkyl, -halogenated C 1-6 Alkoxy, -C 3-6 cycloalkyl, -NR h R i -C(O)NR e R f -C 1-3 alkyl-hydroxyl and -C 1-3 Alkyl-NR e R f ; and the -C mentioned above 3-6 The cycloalkyl group is optionally substituted by one, two, or three substituents independently selected from halogen, methyl, ethyl, propyl (n-propyl), isopropyl, trifluoromethyl, amino, N(CH3)2, hydroxyl, and carboxyl groups; wherein R e R f Each is independently hydrogen or C 1-3 Alkyl; R h R i Each is independently hydrogen, -C 1-3 Alkyl, -C(O)C 1-3 Alkyl or -CO2C 1-3 Alkyl; R s3 "' represents isopropyl; n is 0. In one embodiment, the R..." s3 "'Below the plane of the pyrazole ring."

[0171] In one embodiment of the present invention, R0′ is selected from the following structures: R s3 ′ represents isopropyl; n is 0. In one embodiment, the R s3 ′ Below the plane of the pyrazine ring.

[0172] In one embodiment of the present invention, R0′ is selected from the following structures: R s3 ′ represents hydrogen, halogen, cyano, hydroxyl, -C 1-6 Alkyl, -C 1-6 Alkoxy, -halogenated C 1-6 Alkyl, -halogenated C 1-6 Alkoxy, -C 3-6 cycloalkyl, -NR h R i -C(O)NR e R f -C 1-3 alkyl-hydroxyl and -C 1-3 Alkyl-NR e R f ; and the -C mentioned above 3-6 The cycloalkyl group is optionally substituted by one, two, or three substituents independently selected from halogen, methyl, ethyl, propyl (n-propyl), isopropyl, trifluoromethyl, amino, N(CH3)2, hydroxyl, and carboxyl groups; wherein R e R f Each is independently hydrogen or C 1-3 Alkyl; R h R i Each is independently hydrogen, -C 1-3 Alkyl, -C(O)C 1-3 Alkyl or -CO2C 1-3 Alkyl; R s3 "Isopropyl; R" s3 "' is -C 1-6 Alkyl group. In one embodiment, the R... s3 "Below the plane of the pyrazole ring."

[0173] In one embodiment of the present invention, R0′ is selected from the following structures:

[0174]

[0175]

[0176] In another aspect, the present invention provides a compound of formula (II), or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof.

[0177]

[0178] In the formula,

[0179] Z is either NC(O)-CR3=CR1R2 or NC(O)-C≡CR4;

[0180] R1 and R2 are independently hydrogen, halogen, cyano, and NR, respectively. a R b -C 1-3 Alkyl, Halogenated C 1-3 Alkyl, -C 1-3 Alkyl-hydroxyl, -C 1-3 Alkyl-cyano, -C 1-3 Alkyl-C 1-3 Alkoxy, -C 1-3 Alkyl-NR a R b -C 1-3 Alkyl-3 to 6-membered heterocyclic alkyl or -C 1-3 Alkyl-5 or 6-membered monocyclic heteroaryl; wherein the 3 to 6-membered heterocyclic alkyl or the 5 or 6-membered monocyclic heteroaryl has 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms;

[0181] R3 represents hydrogen, halogen, or -C. 1-3 Alkyl or -C 1-3 Alkoxy;

[0182] R4 is hydrogen or halogenated C. 1-3 Alkyl, -C 1-3 Alkyl-hydroxyl, -C 1-3 alkyl-cyano or -C 1-3 Alkyl-C 1-3 Alkoxy;

[0183] R 11 R 12 Whether the same or different, each is independently hydrogen, halogen, -C 1-3 Alkyl, -halogenated C 1-3 Alkyl, -C 1-3 Alkyl-hydroxyl, -C 1-3 Alkyl-cyano, -C 1-3 Alkyl-C 1-6 Alkoxy, -C 1-3 Alkyl-halogenated C 1-6 Alkyl or -C 1-3 Alkyl-halogenated C 1-6 Alkoxy;

[0184] R 21 R 22 Whether the same or different, each is independently hydrogen, halogen, -C 1-3 Alkyl, -halogenated C 1-3 Alkyl, -C 1-3 Alkyl-hydroxyl, -C1-3 Alkyl-cyano, -C 1-3 Alkyl-C 1-6 Alkoxy, -C 1-3 Alkyl-halogenated C 1-6 Alkyl or -C 1-3 Alkyl-halogenated C 1-6 Alkoxy;

[0185] R 31 R 32 Whether the same or different, each is independently hydrogen, halogen, -C 1-3 Alkyl, -halogenated C 1-3 Alkyl, -C 1-3 Alkyl-hydroxyl, -C 1-3 Alkyl-cyano, -C 1-3 Alkyl-C 1-6 Alkoxy, -C 1-3 Alkyl-halogenated C 1-6 Alkyl or -C 1-3 Alkyl-halogenated C 1-6 Alkoxy;

[0186] R 41 Hydrogen, halogen, -C 1-3 Alkyl, -halogenated C 1-3 Alkyl, -C 1-3 Alkyl-hydroxyl, -C 1-3 Alkyl-cyano, -C 1-3 Alkyl-C 1-6 Alkoxy, -C 1-3 Alkyl-halogenated C 1-6 Alkyl or -C 1-3 Alkyl-halogenated C 1-6 Alkoxy;

[0187] P is O, NH or NR m ;R m -C 1-6 Alkyl, -halogenated C 1-6 Alkyl, -C 1-6 Alkyl-hydroxyl, -C 1-6 Alkyl-cyano, -C 1-6 Alkyl-C 1-6 Alkoxy, -C 1-6 Alkyl-halogenated C 1-6 Alkoxy, -C 1-6 Alkyl-C 3-6 cycloalkyl or -C 1-6 Alkyl-3- to 6-membered heterocyclic alkyl groups;

[0188] R 42 -(C=O)-, -C 1-3 Alkyl, -C 1-3Alkyl (hydroxy) -, -C 1-3 Alkyl (cyano) -, -C 1-3 Alkyl (C) 1-6 Alkyl), -C 1-3 Alkyl (halogenated C) 1-6 alkyl)-, -C 1-3 Alkyl (C) 1-6 alkyl-hydroxy)-, -C 1-3 Alkyl (C) 1-6 (alkyl-cyano)-, -C 1-3 Alkyl (C) 1-6 alkoxy group (-, or -C) 1-3 Alkyl (halogenated C) 1-6 alkoxy)-;

[0189] X2 and Y2 may be the same or different, and each can independently be hydrogen, halogen, or -C. 1-3 Alkyl, -halogenated C 1-3 Alkyl, -C 1-3 Alkyl-hydroxyl, -C 1-3 Alkyl-cyano, -C 1-3 Alkyl-C 1-6 Alkoxy, -C 1-3 Alkyl-halogenated C 1-6 Alkyl or -C 1-3 Alkyl-halogenated C 1-6 Alkoxy;

[0190] Alternatively, X2 and Y2 together with their adjacent carbon atoms can form substituted or unsubstituted carbon atoms. 3-6 Cycloalkyl or substituted or unsubstituted 3- to 6-membered heterocyclic alkyl groups; the 3- to 6-membered heterocyclic alkyl groups having 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms; the term "substituted" means that 1, 2, 3 or 4 hydrogen atoms in the group are each independently replaced by substituents selected from the S group;

[0191] E3 is either N or CL-R5; where...

[0192] L represents a key, -CR L1 R L2 -、-O-(CR L1 R L2 ) t1 -or-NH-(CR L3 R L4 ) t2 -; where R L1 R L2 R L3 R L4 Whether the elements are the same or different, each can be independently hydrogen, halogen, hydroxyl, hydroxymethyl, hydroxyethyl, or -C. 1-3Alkyl or oxo group; t1 and t2 are each independently 0, 1, 2, 3 or 4; R L1 With R L2 or R L3 With R L4 In this case, when one of them is an oxygen group, the other is not present;

[0193] R5 is a C that is hydrogen, halogen, hydroxyl, -substituted, or unsubstituted. 1-6 Alkyl, -substituted or unsubstituted C 3-6 Cycloalkyl, -substituted or unsubstituted 3- to 6-membered heterocyclic alkyl, -O-substituted or unsubstituted C 1-6 Alkyl, -O-substituted or unsubstituted C 3-6 Cycloalkyl, -O-substituted or unsubstituted 3- to 6-membered heterocyclic alkyl, -SO2-substituted or unsubstituted C 1-6 Alkyl, -SO2-substituted or unsubstituted C 3-6 Cycloalkyl, -SO2-substituted or unsubstituted 3- to 6-membered heterocyclic alkyl, -substituted or unsubstituted 5- or 6-membered monocyclic heteroaryl or NR 51 R 52 Among them, R 51 R 52 Each is independently hydrogen, substituted or unsubstituted C 1-6 Alkyl, -SO2C 1-6 Alkyl, -SO2C 3-6 Cycloalkyl, -C(O)C 1-6 Alkyl or -C(O) halocarbon 1-6 Alkyl; or R 51 and R 52 Together with the attached nitrogen atom, they form substituted or unsubstituted 3- to 6-membered nitrogen-containing heterocyclic alkyl groups; wherein each of the 3- to 6-membered heterocyclic alkyl groups and the 5- or 6-membered monocyclic heteroaryl groups independently has 1, 2, or 3 heteroatoms selected from N, O, and S as ring atoms; the 3- to 6-membered nitrogen-containing heterocyclic alkyl groups have 3 to 6 ring atoms, one of which is a nitrogen atom, and the remaining 0, 1, or 2 ring atoms are optionally heteroatoms selected from N, O, and S; the term "substitution" refers to the substitution of 1, 2, 3, or 4 hydrogen atoms in the group by substituents independently selected from the S group;

[0194] The S group substituents are selected from: hydroxyl, halogen, nitro, oxo, -C 1-6 Alkyl, -halogenated C 1-6 Alkyl, hydroxyl substituted C 1-6 Alkyl, benzyl, -(CH2) u -cyano, -(CH2) u -C 1-6 Alkyl group, -(CH2) u - Halogenated C 1-6Alkyl group, -(CH2) u - Halogenated C 1-6 Alkyl group, -(CH2) u -3 to 6-membered heterocyclic alkyl groups, -(CH2) u -5 or 6-membered monocyclic heteroaryl groups, -(CH2) u -C 3-8 Cycloalkyl, -(CH2) u -O-(CH2) v -C 3-8 Cycloalkyl, -(CH2) u -O-(CH2) v -C 1-6 Alkyl group, -(CH2) u -O-(CH2) v OH, -(CH2) u -SO2C 1-6 Alkyl group, -(CH2) u -NR a0 R b0 -(CH2) u -C(O)NR a0 R b0 -(CH2) u -C(O)C 1-6 Alkyl, -C(O)OC 1-6 Alkyl, NR a0 C(O)-(CH2) u -NR a0 R b0 NR a0 C(O)-(CH2) u OH, NR a0 C(O)-halogenated C 1-6 Alkyl group; wherein the 3- to 6-membered heterocyclic alkyl group or the 5- or 6-membered monocyclic heteroaryl group each independently has 1, 2, or 3 heteroatoms selected from N, O, and S as ring atoms; the 3- to 6-membered heterocyclic alkyl group and the 5- or 6-membered monocyclic heteroaryl group are optionally surrounded by 1, 2, or 3 heteroatoms selected from halogen, cyano, -C 1-3 Alkyl, -C 1-3 Alkoxy and C 3-6 Substituents of cycloalkyl groups; u and v are each independently 0, 1, 2, 3, or 4; R a0 R b0 Each is independently hydrogen or C 1-3 alkyl;

[0195] E4 is either N or CH;

[0196] Ar is C 6-10Aryl, 5- or 6-membered monocyclic heteroaryl, or 8- to 10-membered bicyclic heteroaryl; wherein the 5- or 6-membered monocyclic heteroaryl has 1, 2, or 3 heteroatoms selected from N, O, and S as ring atoms; the 8- to 10-membered bicyclic heteroaryl has 1, 2, 3, 4, or 5 heteroatoms selected from N, O, and S as ring atoms; and the C 6-10 The aryl group, the 5- or 6-membered monocyclic heteroaryl group, or the 8- to 10-membered bicyclic heteroaryl group is unsubstituted or is composed of 1, 2, 3, or 4 independently selected from R. s1 Substitution of groups;

[0197] or

[0198] Ar represents the structure shown in equation (B):

[0199]

[0200] Wherein, ring B1 is a benzene ring or a 5- or 6-membered monocyclic heteroaryl ring; ring B2 is a fused 5- or 6-membered monocyclic heterocyclic alkyl ring or a fused 5- or 6-membered monocyclic cycloalkyl ring; wherein the 5- or 6-membered monocyclic heteroaryl ring or the fused 5- or 6-membered monocyclic heterocyclic alkyl ring has 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms;

[0201] (R s1 ) p This indicates that the hydrogen on the B1 ring is replaced by p R atoms. s1 Replacement, p is 0, 1, 2 or 3, each R s1 Same or different;

[0202] (R s2 ) q This indicates that the hydrogen on ring B2 is replaced by q R atoms. s2 Replacement, where q is 0, 1, 2, or 3, for each R s2 Same or different;

[0203] R s1 R s2 Each is independently a halogen, cyano, nitro, hydroxyl, or -C group. 1-6 Alkyl, -C 1-6 Alkoxy, -halogenated C 1-6 Alkyl, -halogenated C 1-6 Alkoxy, -C 3-6 cycloalkyl, -NR c R d -C(O)NR e R f -SO2C 1-3 Alkyl, -SO2 halogenated C 1-3 Alkyl, -SO2NR e R f -C 1-4 Alkyl-hydroxyl, -C1-4 Alkyl-cyano, -C 1-4 Alkyl-C 1-6 Alkoxy, -C 1-4 Alkyl-halogenated C 1-6 Alkyl, -C 1-4 Alkyl-halogenated C 1-6 Alkoxy, -C 1-4 Alkyl-3 to 6-membered heterocyclic alkyl, -C 1-4 Alkyl-NR e R f -C 1-4 Alkyl-C(O)NR e R f -C 1-4 Alkyl-SO2C 1-3 Alkyl or C 2-4 Alkyne group; wherein the 3 to 6-membered heterocyclic alkyl group has 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms;

[0204] R a R b R e R f Each is independently hydrogen or C 1-3 alkyl;

[0205] R c R d Each is independently hydrogen, -C 1-3 Alkyl, -C(O)C 1-3 Alkyl, -CO2C 1-3 alkyl.

[0206] In one embodiment of the present invention, R s1 R s2 Each is independently a halogen, cyano, nitro, hydroxyl, or -C group. 1-3 Alkyl, -C 1-3 Alkoxy, halogenated C 1-3 Alkyl, Halogenated C 1-3 Alkoxy, -C 3-6 cycloalkyl, -NR c R d -C(O)NR e R f -SO2C 1-3 Alkyl, -SO2 halogenated C 1-3 Alkyl, -SO2NR e R f -C 1-2 Alkyl-hydroxyl, -C 1-2 Alkyl-cyano, -C 1-2 Alkyl-C 1-3 Alkoxy, -C 1-2Alkyl-halogenated C 1-3 Alkyl, -C 1-2 Alkyl-halogenated C 1-3 Alkoxy, -C 1-2 Alkyl-3 to 6-membered heterocyclic alkyl, -C 1-2 Alkyl-NR e R f -C 1-2 Alkyl-C(O)NR e R f -C 1-2 Alkyl-SO2C 1-3 Alkyl or C 2-4 alkynyl group; wherein, R c R d Each is independently hydrogen, -C 1-3 Alkyl, -C(O)C 1-3 Alkyl, -CO2C 1-3 Alkyl; R e R f Each is independently hydrogen or C 1-3 alkyl.

[0207] In one embodiment of the present invention, R s1 R s2 Each is independently a halogen, cyano, nitro, hydroxyl, or -C group. 1-3 Alkyl, -C 1-3 Alkoxy, halogenated C 1-3 Alkyl, Halogenated C 1-3 Alkoxy, -C 3-6 cycloalkyl, -NR c R d -C(O)NR e R f -SO2C 1-3 Alkyl, -SO2 halogenated C 1-3 Alkyl, -SO2NR e R f -CH2-hydroxy, -CH2-cyano, -CH2-C 1-3 Alkoxy, -CH2-halogenated C 1-3 Alkyl, -CH2-halogenated C 1-3 Alkoxy, -CH2-3 to 6-membered heterocyclic alkyl, -CH2-NR e R f -CH2-C(O)NR e R f -CH2-SO2C 1-3 Alkyl or C 2-4 alkynyl group; wherein, R c For hydrogen, -C 1-3 Alkyl, -C(O)CH3 or -CO2CH3; Re R f R d Each is independently hydrogen or C 1-3 alkyl.

[0208] In one embodiment of the present invention, R s1 R s2 Each is independently a halogen, cyano, nitro, hydroxyl, or -C group. 1-3 Alkyl, -C 1-3 Alkoxy, halogenated C 1-3 Alkyl, Halogenated C 1-3 Alkoxy, -C 3-6 cycloalkyl, -NR c R d -C(O)NR e R f -CH2-hydroxyl, -CH2-cyano; wherein, R c It is hydrogen, -C(O)CH3 or -CO2CH3; R e R f R d Each is independently hydrogen or C 1-3 alkyl.

[0209] In one embodiment of the present invention, R s1 and R s2 In the context, C 3-6 The cycloalkyl group is selected from: cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cyclobutanone, cyclobutane-1,2-dione, cyclopentanone, cyclopentane-1,3-dione, cyclohexanone, cyclohexane-1,3-dione.

[0210] In one embodiment of the present invention, R s1 and R s2 In this context, the 3- to 6-membered heterocyclic alkyl group is selected from: aziridine, ethylene oxide, aziridine butane, oxaziridine, oxazolidinyl, 1,3-dioxolane, imidazoline, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, piperidine, piperazine, morpholine, thiomorpholine, thiomorpholine-1,1-dioxide, tetrahydropyran, 1,3-oxazine, hexahydropyrimidine, and 1,4-dioxane.

[0211] In one embodiment of the present invention, R s1 R s2Each of these can be independently identified as halogen, cyano, nitro, hydroxy, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, propoxy (n-propoxy), isopropoxy, monochloromethyl, dichloromethyl, trichloromethyl, monochloroethyl, 1,2-dichloroethyl, trichloroethyl, monobromoethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, trifluoroethyl, trifluoromethoxy, trifluoroethoxy, monofluoromethoxy, monofluoroethoxy, difluoromethoxy, difluoroethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -NR c R d -C(O)NR e R f -CH2-hydroxyl, -CH2-cyano; wherein, R c It is hydrogen, -C(O)CH3 or -CO2CH3; R e R f R d Each can be independently hydrogen, methyl, or ethyl.

[0212] In one embodiment of the present invention, R s3 R s4 Each is independently a halogen, cyano, hydroxyl, or -C group. 1-6 Alkyl, -C 1-3 Alkoxy, halogenated C 1-3 Alkyl, Halogenated C 1-3 Alkoxy, -C 3-6 Cycloalkyl, 3- to 6-membered heterocyclic alkyl, amino, NHCH3, N(CH3)2, -C(O)NR e R f -SO2C 1-3 Alkyl, -SO2 halogenated C 1-3 Alkyl, -SO2NR e R f -C 1-2 Alkyl-hydroxyl, -C 1-2 alkyl-acetylene, -C 1-2 Alkyl-cyano, -C 1-2 Alkyl-C 1-3 Alkoxy, -C 1-2 Alkyl-halogenated C 1-3 Alkyl, -C 1-2 Alkyl-halogenated C 1-3 Alkoxy, -C 1-2 Alkyl-3 to 6-membered heterocyclic alkyl, -C 1-2 Alkyl-C 3-6 cycloalkyl, -C 1-2 Alkyl-NR e R f -C 1-2 Alkyl-C(O)NR e Rf -C 1-2 Alkyl-SO2C 1-3 Alkyl or ethynyl; wherein, the C 1-6 Alkyl, -C 1-3 Alkoxy, -C 1-2 Alkyl-, -C 3-6 The cycloalkyl group or 3- to 6-membered heterocycloalkyl group is optionally substituted by 1, 2, or 3 substituents independently selected from halogen, methyl, ethyl, propyl (n-propyl), isopropyl, trifluoromethyl, amino, N(CH3)2, hydroxyl, or carboxyl groups; R e R f Each is independently hydrogen or C 1-3 alkyl.

[0213] In one embodiment of the present invention, R s3 R s4 Each is independently a halogen, cyano, hydroxyl, C 1-4 Alkyl, -C 1-3 Alkoxy, halogenated C 1-3 Alkyl, Halogenated C 1-3 Alkoxy, -C 3-6 Cycloalkyl, 3- to 6-membered heterocyclic alkyl, amino, NHCH3, N(CH3)2, -C(O)NR e R f -SO2C 1-3 Alkyl, -SO2 halogenated C 1-3 Alkyl, -SO2NR e R f -CH2-hydroxy, -CH2-ethynyl, -CH2-cyano, -CH2-C 1-3 Alkoxy, -CH2-halogenated C 1-3 Alkyl, -CH2-halogenated C 1-3 Alkoxy, -CH2-3 to 6-membered heterocyclic alkyl, -CH2-C 3-6 cycloalkyl, -CH2-NR e R f -CH2-C(O)NR e R f -CH2-SO2C 1-3 Alkyl or ethynyl; wherein, the C 1-4 Alkyl, -C 1-3 Alkoxy, -CH2-, -C 3-6 The cycloalkyl group or 3- to 6-membered heterocycloalkyl group is optionally substituted by 1, 2, or 3 substituents independently selected from halogen, methyl, ethyl, propyl (n-propyl), isopropyl, trifluoromethyl, amino, N(CH3)2, hydroxyl, or carboxyl groups; R e R f Each is independently hydrogen or C 1-3alkyl.

[0214] In one embodiment of the present invention, R s3 R s4 Each is independently a halogen, cyano, hydroxyl, C 1-4 Alkyl, -C 1-3 Alkoxy, halogenated C 1-3 Alkyl, -C 3-6 Cycloalkyl, 3- to 6-membered heterocyclic alkyl, amino, NHCH3, N(CH3)2, -CH2-hydroxy, -CH2-ethynyl; wherein, the C 1-4 Alkyl, -C 1-3 Alkoxy, -CH2-, -C 3-6 The cycloalkyl group or 3- to 6-membered heterocycloalkyl group is optionally substituted by 1, 2 or 3 substituents independently selected from halogen, methyl, ethyl, propyl (n-propyl), isopropyl, trifluoromethyl, amino, N(CH3)2, hydroxyl or carboxyl.

[0215] In one embodiment of the present invention, R s3 and R s4 In, the C 3-6 The cycloalkyl group is selected from: cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0216] In one embodiment of the present invention, R s3 and R s4 In this context, the 3 to 6-membered heterocyclic alkyl group is selected from: azirron, ethylene oxide, azirrobutane, oxacyclobutane, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, piperidine, piperazine, morpholine, thiomorpholine, thiomorpholine-1,1-dioxide, and tetrahydropyran.

[0217] In one embodiment of the present invention, R s3 R s4Each of these groups independently represents a halogen, cyano, hydroxyl, methyl, ethyl, n-propyl, isopropyl, sec-butyl, methoxy, ethoxy, propoxy (n-propoxy), isopropoxy, monochloromethyl, dichloromethyl, trichloromethyl, monochloroethyl, 1,2-dichloroethyl, trichloroethyl, monobromoethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, ethylene oxide, azacyclobutane, oxacyclobutane, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, piperidine, piperazine, morpholine, thiomorpholine, thiomorpholine-1,1-dioxane. The compounds are: tetrahydropyran, amino, NHCH3, N(CH3)2, -CH2-hydroxy, -CH2-ethynyl; wherein the methyl, ethyl, n-propyl, methoxy, ethoxy, propoxy (n-propoxy), -CH2-, aziridine, oxacyclobutane, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, piperidine, piperazine, morpholine, thiomorpholine, thiomorpholine-1,1-dioxide, and tetrahydropyran are optionally substituted by 1, 2, or 3 substituents independently selected from halogen, methyl, ethyl, propyl (n-propyl), isopropyl, trifluoromethyl, amino, N(CH3)2, hydroxy, and carboxyl groups.

[0218] In one embodiment of the present invention, the S-group substituent is selected from: hydroxyl, halogen, nitro, oxo, -C 1-3 Alkyl, hydroxyl substituted C 1-3 Alkyl, benzyl, -(CH2) u -cyano, -(CH2) u -C 1-3 Alkyl group, -(CH2) u - Halogenated C 1-3 Alkyl group, -(CH2) u - Halogenated C 1-3 Alkyl group, -(CH2) u -3 to 6-membered heterocyclic alkyl groups, -(CH2) u -5 or 6-membered monocyclic heteroaryl groups, -(CH2) u -C 3-6 Cycloalkyl, -(CH2) u -O-(CH2) v -C 3-6 Cycloalkyl, -(CH2) u -O-(CH2) v -C 1-3 Alkyl group, -(CH2) u -O-(CH2) v OH, -(CH2) u -SO2C 1-3 Alkyl group, -(CH2) u -NR a0 R b0-(CH2) u -C(O)NR a0 R b0 -(CH2) u -C(O)C 1-3 Alkyl, -C(O)OC 1-3 Alkyl, NR a0 C(O)-(CH2) u -NR a0 R b0 NR a0 C(O)-(CH2) u OH, NR a0 C(O)-halogenated C 1-3 Alkyl group; wherein the 3- to 6-membered heterocyclic alkyl group and the 5- or 6-membered monocyclic heteroaryl group each independently have 1, 2, or 3 heteroatoms selected from N, O, and S as ring atoms; the 3- to 6-membered heterocyclic alkyl group and the 5- or 6-membered monocyclic heteroaryl group are optionally surrounded by 1, 2, or 3 heteroatoms selected from halogen, cyano, -C 1-3 Alkyl, -C 1-3 Alkoxy and C 3-6 Substituents of cycloalkyl groups; u and v are each independently 0, 1, 2, 3, or 4; R a0 R b0 Each is independently hydrogen or C 1-3 alkyl.

[0219] In one embodiment of the present invention, the S group substituent is a halogen.

[0220] In one embodiment of the present invention, the S group substituents are selected from: C 1-3 Alkyl group, -(CH2) u -3 to 6-membered heterocyclic alkyl groups, -(CH2) u -SO2C 1-3 Alkyl group, -(CH2) u -NR a0 R b0 The 3- to 6-membered heterocyclic alkyl group has 1, 2, or 3 heteroatoms selected from N, O, and S as ring atoms; the 3- to 6-membered heterocyclic alkyl group is optionally surrounded by 1, 2, or 3 heteroatoms selected from halogen, cyano, -C 1-3 Alkyl, -C 1-3 Alkoxy and C 3-6 Substituents of cycloalkyl groups; u is 0, 1, 2, 3 or 4; R a0 R b0 Each is independently hydrogen or C 1-3 alkyl.

[0221] In one embodiment of the present invention, among the above-mentioned groups (e.g., Ar, RO), the C 6-10Each aryl group can be either phenyl or naphthyl.

[0222] In one embodiment of the invention, in the above-mentioned group (e.g., Ar), the C 6-10 When the aryl group is phenyl, it is selected from the following structures:

[0223] In the formula, R s1 R s2 The definition is the same as before.

[0224] In one embodiment of the present invention, the 5- or 6-membered monocyclic heteroaryl group (e.g., Ar, RO) is independently selected from: thiophene, N-alkylcyclopyrrole, furan, thiazole, isothiazole, imidazole, oxazole, pyrrole, pyrazole, triazole, 1,2,3-triazole, 1,2,4-triazole, 1,2,5-triazole, 1,3,4-triazole, tetrazolium, isoxazole, oxadiazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, thiadiazole, pyridine, pyridazine, pyrimidine, pyrazine.

[0225] In one embodiment of the present invention, among the above-mentioned groups (e.g., Ar, RO), each of the 5- or 6-membered monocyclic heteroaryl groups is independently selected from the following structures:

[0226]

[0227] In one embodiment of the present invention, among the above-mentioned groups (e.g., Ar, RO), each of the 8 to 10 membered bicyclic heteroaryl groups is independently a 9 to 10 membered bicyclic heteroaryl group formed by fusion of a benzene ring and a 5 or 6 membered monocyclic heteroaryl ring, or an 8 to 10 membered bicyclic heteroaryl group formed by fusion of a 5 or 6 membered monocyclic heteroaryl ring and a 5 or 6 membered monocyclic heteroaryl ring.

[0228] In one embodiment of the present invention, the 5- or 6-membered monocyclic heteroaryl ring forming a 9- to 10-membered bicyclic heteroaryl or an 8- to 10-membered bicyclic heteroaryl is selected from: thiophene ring, N-alkyl ring, pyrrole ring, furan ring, thiazole ring, isothiazole ring, imidazole ring, oxazole ring, pyrrole ring, pyrazole ring, triazole ring, 1,2,3-triazole ring, 1,2,4-triazole ring, 1,2,5-triazole ring, 1,3,4-triazole ring, tetrazolium ring, isoxazole ring, oxadiazole ring, 1,2,3-oxadiazole ring, 1,2,4-oxadiazole ring, 1,2,5-oxadiazole ring, 1,3,4-oxadiazole ring, thiadiazole ring, pyridine ring, pyridazine ring, pyrimidine ring, or pyrazine ring.

[0229] In one embodiment of the present invention, the 5- or 6-membered monocyclic heteroaryl ring forming a 9- to 10-membered bicyclic heteroaryl or an 8- to 10-membered bicyclic heteroaryl is selected from the following structures:

[0230] in The two ring atoms connected represent adjacent atom pairs shared when fused with other rings.

[0231] In one embodiment of the present invention, in rings B1 and A1, the 5- or 6-membered monocyclic heteroaryl rings are each independently selected from: thiophene ring, N-alkyl ring, pyrrole ring, furan ring, thiazole ring, isothiazole ring, imidazole ring, oxazole ring, pyrrole ring, pyrazole ring, triazole ring, 1,2,3-triazole ring, 1,2,4-triazole ring, 1,2,5-triazole ring, 1,3,4-triazole ring, tetraazole ring, isoxazole ring, oxadiazole ring, 1,2,3-oxadiazole ring, 1,2,4-oxadiazole ring, 1,2,5-oxadiazole ring, 1,3,4-oxadiazole ring, thiadiazole ring, pyridine ring, pyridazine ring, pyrimidine ring, or pyrazine ring.

[0232] In one embodiment of the present invention, in ring B1 and ring A1, the 5- or 6-membered monocyclic heteroaryl rings are each independently selected from the following structures:

[0233] in The two ring atoms connected represent adjacent atom pairs shared when fused with other rings.

[0234] In one embodiment of the present invention, in ring B2 and ring A2, the fused 5- or 6-membered monocyclic cycloalkyl rings are each independently selected from: cyclopentyl ring, cyclopentenyl ring, cyclohexyl ring, cyclohexenyl ring, cyclohexadienyl ring, cyclopentanone, cyclopentane-1,3-dione, cyclohexanone, cyclohexane-1,3-dione.

[0235] In one embodiment of the present invention, in rings B2 and A2, the fused 5- or 6-membered monocyclic heterocyclic alkyl rings are each independently selected from: oxazolidine, pyrrolidine-2-one, pyrrolidine-2,5-dione, 1,3-dioxolane, dihydrofuran-2(3H)-one, dihydrofuran-2,5-dione, piperidin-2-one, piperidin-2,6-dione, tetrahydro-2H-pyran-2-one, imidazoline, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, 1,3-dioxolane-2-one, oxazolidine-2-one, imidazoline-2-one, piperidine, piperazine, piperazine-2-one, morpholine, morpholine-3-one, morpholine-2-one, thiomorpholine-3-one. 1-Dioxide, thiomorpholine, thiomorpholine-1,1-dioxide, tetrahydropyran, 1,2-dihydroazacyclobutadiene, 1,2-dihydrooxocyclobutadiene, 2,5-dihydro-1H-pyrrole, 2,5-dihydrofuran, 2,3-dihydrofuran, 2,3-dihydro-1H-pyrrole, 3,4-dihydro-2H-pyran, 1,2,3,4-tetrahydropyridine, 3,6-dihydro-2H-pyran, 1,2,3,6-tetrahydropyridine, 1,3-oxazine, hexahydropyrimidine, 1,4-dioxane, tetrahydropyrimidine-2(1H)-one, 1,4-dioxane-2-one, 5,6-dihydro-2H-pyran-2-one, 5,6-dioxane Hydropyrimidine-4(3H)-one, 3,4-dihydropyridine-2(1H)-one, 5,6-dihydropyridine-2(1H)-one, 5,6-dihydropyrimidine-4(1H)-one, pyrimidine-4(3H)-one, pyrimidine-4(1H)-one, 4,5-dihydro-1H-imidazolium, 2,3-dihydro-1H-imidazolium, 2,3-dihydrooxazole, 1,3-dioxacyclopentene, 2,3-dihydrothiophene, 2,5-dihydrothiophene, 3,4-dihydro-2H-1,4-oxazine, 3,4-dihydro-2H-1,4-thiazine 1,1-dioxide, 1,2,3,4-tetrahydropyrazine, 1,3-dihydro-2H-pyrrole-2-one, 1,5-Dihydro-2H-pyrrolo-2-one, 1H-pyrrolo-2,5-dione, furan-2(3H)-one, furan-2(5H)-one, 1,3-dioxacyclopenten-2-one, oxazol-2(3H)-one, 1,3-dihydro-2H-imidazol-2-one, furan-2,5-dione, 3,6-dihydropyridin-2(1H)-one, pyridin-2,6-(1H,3H)-dione, 5,6-dihydro-2H-pyrrolo-2-one, 3,6-dihydro-2H-pyrrolo-2-one, 3,4-dihydro-2H-1,3-oxazine, 3,6-dihydro-2H-1,3-oxazine, 1,2,3,4-tetrahydropyrimidine.

[0236] In one embodiment of the present invention, the fused 5- or 6-membered monocyclic heterocyclic alkyl ring is selected from the following structures:

[0237]

[0238] In one embodiment of the present invention, the 8 to 10 membered bicyclic heteroaryl groups (e.g., Ar, RO) are each independently selected from: benzoxazole, benzoisoxazole, benzoimidazole, benzothiazole, benzoisothiazole, benzotriazole, benzofuran, benzothiophene, indole, indazole, isoindole, quinoline, isoquinoline, quinazoline, quinoxaline, cyclophosphine, pyridinidine, and naphthidine.

[0239] In one embodiment of the present invention, the 8 to 10 membered bicyclic heteroaryl groups (e.g., Ar, RO) are each independently selected from: benzo[d]isoxazole, 1H-indole, isoindole, 1H-benzo[d]imidazol, benzo[d]isothiazol, 1H-benzo[d][1,2,3]triazole, benzo[d]oxazole, benzo[d]thiazol, indazole, benzofuran, benzo[b]thiophene, quinoline, isoquinoline, quinazoline, quinoxaline, cycloline, pyrido[3,2-d]pyrimidine, pyrido[2,3-d]pyrimidine, pyrido[3,4-d]pyrimidine, pyrido[4,3-d]pyrimidine, 1,8-naphthidine, 1,7-naphthidine, 1,6-naphthidine, 1,5-naphthidine.

[0240] In one embodiment of the present invention, among the above-mentioned groups (e.g., Ar, RO), each of the 8- to 10-membered bicyclic heteroaryl groups is independently selected from the following structures:

[0241]

[0242] In one embodiment of the present invention, among the above-mentioned groups (e.g., Ar, RO), each of the 8- to 10-membered bicyclic heteroaryl groups is independently selected from the following structures:

[0243]

[0244] In one embodiment of the present invention, among the above-mentioned groups (e.g., Ar, RO), each of the 8- to 10-membered bicyclic heteroaryl groups is independently selected from the following structures:

[0245]

[0246]

[0247] In one embodiment of the present invention Each is independently selected from the following structure:

[0248]

[0249] In one embodiment of the present invention, formulas (B) and (A-1) are each independently selected from the following structures:

[0250]

[0251] In one embodiment of the present invention, Ar and Ar′ are independently selected from the following structures:

[0252]

[0253]

[0254]

[0255] In one embodiment of the invention, in the above-mentioned group (e.g., R0), the C 3-6 The cycloalkyl group is selected from: cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cyclobutanone, cyclobutane-1,2-dione, cyclopentanone, cyclopentane-1,3-dione, cyclohexanone, cyclohexane-1,3-dione.

[0256] In one embodiment of the present invention, the 3 to 6-membered heterocyclic alkyl group (e.g., RO) is selected from: aziridine, ethylene oxide, aziridine butane, oxaziridine, oxazolidine, 1,3-dioxolane, imidazoline, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, piperidine, piperazine, morpholine, thiomorpholine, thiomorpholine-1,1-dioxide, tetrahydropyran, 1,3-oxazine, hexahydropyrimidine, and 1,4-dioxane.

[0257] In one embodiment of the present invention, the 7 to 11-membered spirocyclic alkyl group (e.g., RO) is a monospirocyclic alkyl group containing one spiro atom formed by any two monocyclic alkyl rings selected from cyclopropyl ring, cyclobutyl ring, cyclopentyl ring and cyclohexyl ring.

[0258] In one embodiment of the present invention, R0 is -C 1-6 Alkyl, -C 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, 5- or 6-membered monocyclic heteroaryl, 8- to 10-membered bicyclic heteroaryl, 7- to 11-membered spirocycloalkyl, -CH2-phenyl, -CH(C 1-2 alkyl)-phenyl, -CH2-5 or 6-membered monocyclic heteroaryl, -CH(C 1-2 alkyl)-5 or 6-membered monocyclic heteroaryl, -NH-phenyl, -N(C 1-3 Alkyl)-phenyl, -O-phenyl, -CH2-3 to 6-membered heterocyclic alkyl, -CH2-C 3-6 cycloalkyl, -CH(C) 1-2 alkyl)-C 3-6 cycloalkyl, wherein the C 1-6 Alkyl, C 3-6Cycloalkyl, 3- to 6-membered heterocyclic alkyl, phenyl, 5- or 6-membered monocyclic heteroaryl, 8- to 10-membered bicyclic heteroaryl, 7- to 11-membered spirocyclic alkyl are unsubstituted or are selected by 1, 2, 3 or 4 independently selected from R s3 Substitution of groups.

[0259] In one embodiment of the present invention, R0 is phenyl, cyclopropyl, 5- or 6-membered monocyclic heteroaryl, -CH2-5- or 6-membered monocyclic heteroaryl, -CH2-phenyl, -CH(C 1-2 alkyl)-phenyl, -NH-phenyl, -N(C 1-3 Alkyl)-phenyl, -O-phenyl; wherein the 5 or 6-membered monocyclic heteroaryl group is selected from: thiophene, N-alkylcyclopyrrole, furan, thiazole, isothiazole, imidazole, oxazole, pyrrole, pyrazole, triazole, 1,2,3-triazole, 1,2,4-triazole, 1,2,5-triazole, 1,3,4-triazole, tetrazolium, isoxazole, oxadiazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, thiadiazole, pyridine, pyridazine, pyrimidine, pyrazine; wherein the phenyl, 5 or 6-membered monocyclic heteroaryl group is unsubstituted or is substituted by 1, 2, 3 or 4 independently selected from R s3 Substitution of groups.

[0260] In one embodiment of the present invention, R0 is selected from the following structures:

[0261]

[0262]

[0263] In one embodiment of the present invention, R 11 R 12 Whether the same or different, each is independently hydrogen, halogen, -C 1-3 Alkyl, -CH2-hydroxy, -CH2-cyano, -CH2-C 1-3 Alkoxy, -CH2-halogenated C 1-3 Alkyl or -CH2-halogenated C 1-3 Alkyl group.

[0264] In one embodiment of the present invention, R 11 R 12 They may be the same or different, and each independently represents hydrogen, halogen, methyl, ethyl, n-propyl, isopropyl, -CH2-hydroxy, -CH2-cyano, -CH2-methoxy, -CH2-ethoxy, -CH2-propoxy (n-propoxy), -CH2-isopropoxy, -CH2-trifluoromethyl, -CH2-difluoromethyl, -CH2-difluoroethyl, -CH2-trifluoromethoxy, and -CH2-difluoromethoxy.

[0265] In one embodiment of the present invention, R 11 R 12 Whether they are the same or different, each is independently hydrogen or -C 1-3 alkyl.

[0266] In one embodiment of the present invention, R 11 R 12 Whether they are the same or different, they are each independently hydrogen or methyl.

[0267] In one embodiment of the present invention, R 21 R 22 Whether the same or different, each is independently hydrogen, halogen, -C 1-3 Alkyl, -CH2-hydroxy, -CH2-cyano, -CH2-C 1-3 Alkoxy, -CH2-halogenated C 1-3 Alkyl or -CH2-halogenated C 1-3 Alkyl group.

[0268] In one embodiment of the present invention, R 21 R 22 They may be the same or different, and each independently represents hydrogen, halogen, methyl, ethyl, n-propyl, isopropyl, -CH2-hydroxy, -CH2-cyano, -CH2-methoxy, -CH2-ethoxy, -CH2-propoxy (n-propoxy), -CH2-isopropoxy, -CH2-trifluoromethyl, -CH2-difluoromethyl, -CH2-difluoroethyl, -CH2-trifluoromethoxy, and -CH2-difluoromethoxy.

[0269] In one embodiment of the present invention, R 21 R 22 Whether they are the same or different, each is independently hydrogen or -C 1-3 alkyl.

[0270] In one embodiment of the present invention, R 21 R 22 Whether they are the same or different, they are each independently hydrogen or methyl.

[0271] In one embodiment of the present invention, R 31 R 32 Whether the same or different, each is independently hydrogen, halogen, -C 1-3 Alkyl, -CH2-hydroxy, -CH2-cyano, -CH2-C 1-3 Alkoxy, -CH2-halogenated C 1-3 Alkyl or -CH2-halogenated C 1-3 Alkyl group.

[0272] In one embodiment of the present invention, R 31 R32 They may be the same or different, and each independently represents hydrogen, halogen, methyl, ethyl, n-propyl, isopropyl, -CH2-hydroxy, -CH2-cyano, -CH2-methoxy, -CH2-ethoxy, -CH2-propoxy (n-propoxy), -CH2-isopropoxy, -CH2-trifluoromethyl, -CH2-difluoromethyl, -CH2-difluoroethyl, -CH2-trifluoromethoxy, and -CH2-difluoromethoxy.

[0273] In one embodiment of the present invention, R 31 R 32 Whether they are the same or different, each is independently hydrogen or -C 1-3 alkyl.

[0274] In one embodiment of the present invention, R 31 R 32 Whether they are the same or different, they are each independently hydrogen or methyl.

[0275] In one embodiment of the present invention, R 41 Hydrogen, halogen, -C 1-3 Alkyl, -CH2-hydroxy, -CH2-cyano, -CH2-C 1-3 Alkoxy, -CH2-halogenated C 1-3 Alkyl or -CH2-halogenated C 1-3 Alkyl group.

[0276] In one embodiment of the present invention, R 41 It can be hydrogen, halogen, methyl, ethyl, n-propyl, isopropyl, -CH2-hydroxy, -CH2-cyano, -CH2-methoxy, -CH2-ethoxy, -CH2-propoxy (n-propoxy), -CH2-isopropoxy, -CH2-trifluoromethyl, -CH2-difluoromethyl, -CH2-difluoroethyl, -CH2-trifluoromethoxy, or -CH2-difluoromethoxy.

[0277] In one embodiment of the present invention, R 41 It is hydrogen.

[0278] In one embodiment of the present invention, in formula I, when When the dashed line represents a single bond, P is O; R 42 -C 1-3 Alkyl-, -C 1-3 Alkyl (hydroxy) -, -C 1-3 Alkyl (cyano) -, -C 1-3 Alkyl (C) 1-3 Alkyl), -C 1-3 Alkyl (halogenated C) 1-3 alkyl)-, -C 1-3 Alkyl (C) 1-3alkyl-hydroxy)-, -C 1-3 Alkyl (C) 1-3 (alkyl-cyano)-, -C 1-3 Alkyl (C) 1-3 alkoxy group (-, or -C) 1-3 Alkyl (halogenated C) 1-3 alkoxy)-; where, C 1-3 The alkyl group is methyl, ethyl, or propyl (n-propyl or isopropyl); C 1-3 The alkoxy group can be methoxy, ethoxy, or propoxy (n-propoxy or isopropoxy).

[0279] In one embodiment of the present invention, in formula I, when When the dashed line represents a single bond, P is either NH or NR. m ;R m -C 1-3 Alkyl, -halogenated C 1-3 Alkyl, -C 1-3 Alkyl-hydroxyl, -C 1-3 Alkyl-cyano, -C 1-3 Alkyl-C 1-3 Alkoxy, -C 1-3 Alkyl-halogenated C 1-3 Alkoxy; R 42 -(C=O)-, -C 1-3 Alkyl-, -C 1-3 Alkyl (hydroxy) -, -C 1-3 Alkyl (cyano) -, -C 1-3 Alkyl (C) 1-3 Alkyl), -C 1-3 Alkyl (halogenated C) 1-3 alkyl)-, -C 1-3 Alkyl (C) 1-3 alkyl-hydroxy)-, -C 1-3 Alkyl (C) 1-3 (alkyl-cyano)-, -C 1-3 Alkyl (C) 1-3 alkoxy group (-, or -C) 1-3 Alkyl (halogenated C) 1-3 alkoxy)-; where, C 1-3 The alkyl group is methyl, ethyl, or propyl (n-propyl or isopropyl); C 1-3 The alkoxy group can be methoxy, ethoxy, or propoxy (n-propoxy or isopropoxy).

[0280] In one embodiment of the present invention, in formula I, when When the dashed line represents a single bond, P is O, NH, or NR. m ;R m -C 1-6 Alkyl; R 42-(C=O)- or -C 1-3 alkyl-.

[0281] In one embodiment of the present invention, in formula I, when When the dashed line represents a single bond, P is O, NH, or NR. m ;R m -C 1-3 Alkyl; R 42 -(C=O)- or -C 1-3 alkyl-.

[0282] In one embodiment of the present invention, in formula I, when When the dashed line represents a single bond, P is O, NH, or NR. m ;R m It is methyl, ethyl, n-propyl, or isopropyl; R 42 It can be -(C=O)-, -CH2-, -CH2CH2- or -CH2CH2CH2-.

[0283] In one embodiment of the present invention, in formula I, when When the dashed line in the diagram is absent, P represents hydrogen or a halogen; R 42 Hydrogen, halogen, -C 1-3 Alkyl, -CH2-hydroxy, -CH2-cyano, -CH2-C 1-3 Alkoxy, -CH2-halogenated C 1-3 Alkyl or -CH2-halogenated C 1-3 Alkyl group.

[0284] In one embodiment of the present invention, in formula I, when When the dashed line in the diagram is absent, P represents hydrogen or a halogen; R 42 It can be hydrogen, halogen, methyl, ethyl, n-propyl, isopropyl, -CH2-hydroxy, -CH2-cyano, -CH2-methoxy, -CH2-ethoxy, -CH2-propoxy (n-propoxy), -CH2-isopropoxy, -CH2-trifluoromethyl, -CH2-difluoromethyl, -CH2-difluoroethyl, -CH2-trifluoromethoxy, or -CH2-difluoromethoxy.

[0285] In one embodiment of the present invention, in Formula I, X1 is hydrogen, halogen, cyano, hydroxyl, amino, nitro, substituted or unsubstituted C. 1-3 Alkyl, -substituted or unsubstituted C 3-6 Cycloalkyl, -substituted or unsubstituted 3- to 6-membered heterocyclic alkyl, -O-substituted or unsubstituted C 1-3 Alkyl, -O-substituted or unsubstituted C 3-6 Cycloalkyl, -O-substituted or unsubstituted 3- to 6-membered heterocyclic alkyl, -NH-substituted or unsubstituted C1-3 Alkyl, -N (substituted or unsubstituted C) 1-3 Alkyl)2, -NH-substituted or unsubstituted C 3-6 Cycloalkyl, -NH-substituted or unsubstituted 3- to 6-membered heterocyclic alkyl, -NH(C=O)-substituted or unsubstituted C 1-3 Alkyl group, -NH(C=O)-C 3-6 Cycloalkyl, -NH(SO2)-substituted or unsubstituted C 1-3 Alkyl, -NH(SO2)- substituted or unsubstituted C 3-6 Cycloalkyl, -SO2-substituted or unsubstituted C 1-3 Alkyl, -SO2-substituted or unsubstituted C 3-6 cycloalkyl, -(C=O)-NR j R k -、-(C=O)-O- substituted or unsubstituted C 1-3 Alkyl, -(C=O)-O-substituted or unsubstituted C 3-6 cycloalkyl; wherein, R j R k Each is independently hydrogen or C 1-3 Alkyl; or R j R k Together with the attached nitrogen atom, it forms a substituted or unsubstituted 3- to 6-membered nitrogen-containing heterocyclic alkyl group; the 3- to 6-membered heterocyclic alkyl group has 1, 2, or 3 heteroatoms selected from N, O, and S as ring atoms; the 3- to 6-membered nitrogen-containing heterocyclic alkyl group has 3 to 6 ring atoms, one of which is a nitrogen atom, and the remaining 0, 1, or 2 ring atoms are optionally heteroatoms selected from N, O, and S; the term "substitution" refers to 1, 2, 3, or 4 hydrogen atoms in the group being replaced by substituents each independently selected from the S group; wherein, C 1-3 The alkyl group is methyl, ethyl, or propyl (n-propyl or isopropyl); C 1-3 The alkoxy group can be methoxy, ethoxy, or propoxy (n-propoxy or isopropoxy).

[0286] In one embodiment of the present invention, in Formula I, Y1 is N; E1 is C; and E2 is C.

[0287] In one embodiment of the present invention, in Formula I, Y1 is C; E1 is N; and E2 is C.

[0288] In one embodiment of the present invention, in Formula I, Y1 is C; E1 is C; and E2 is N.

[0289] In one embodiment of the present invention, in formula I, Y1 is C; E1 is N; and E2 is N.

[0290] In one embodiment of the present invention, in formula I, Y1 is N; E1 is N; and E2 is C.

[0291] In one embodiment of the present invention, in formula I, Y1 is N; E1 is N; and E2 is C.

[0292] In one embodiment of the present invention, P is O in Formula II.

[0293] In one embodiment of the present invention, in formula II, P is NH or NR. m ;R m C 1-3 Alkyl, Halogenated C 1-3 Alkyl, -C 1-3 Alkyl-hydroxyl, -C 1-3 Alkyl-cyano, -C 1-3 Alkyl-C 1-3 Alkoxy, -C 1-3 Alkyl-halogenated C 1-3 Alkoxy; wherein, C 1-3 The alkyl group is methyl, ethyl, or propyl (n-propyl or isopropyl); C 1-3 The alkoxy group can be methoxy, ethoxy, or propoxy (n-propoxy or isopropoxy).

[0294] In one embodiment of the present invention, in formula II, R 42 -(C=O)-, -C 1-3 Alkyl, -C 1-3 Alkyl (hydroxy) -, -C 1-3 Alkyl (cyano) -, -C 1-3 Alkyl (C) 1-3 Alkyl), -C 1-3 Alkyl (halogenated C) 1-3 alkyl)-, -C 1-3 Alkyl (C) 1-3 alkyl-hydroxy)-, -C 1-3 Alkyl (C) 1-3 (alkyl-cyano)-, -C 1-3 Alkyl (C) 1-3 alkoxy group (-, or -C) 1-3 Alkyl (halogenated C) 1-3 alkoxy)-; where, C 1-3 The alkyl group is methyl, ethyl, or propyl (n-propyl or isopropyl); C 1-3 The alkoxy group can be methoxy, ethoxy, or propoxy (n-propoxy or isopropoxy).

[0295] In one embodiment of the present invention, in formula II, X2 and Y2 may be the same or different, and each is independently hydrogen, halogen, or -C. 1-3 Alkyl, -C 1-3 Alkyl-hydroxyl, -C1-3 Alkyl-cyano, -C 1-3 Alkyl-C 1-3 Alkoxy, -C 1-3 Alkyl-halogenated C 1-3 Alkyl or -C 1-3 Alkyl-halogenated C 1-3 Alkoxy; wherein, C 1-3 The alkyl group is methyl, ethyl, or propyl (n-propyl or isopropyl); C 1-3 The alkoxy group can be methoxy, ethoxy, or propoxy (n-propoxy or isopropoxy).

[0296] In one embodiment of the present invention, in formula II, X2, Y2, and their adjacent carbon atoms together form substituted or unsubstituted C atoms. 3-6 Cycloalkyl or substituted or unsubstituted 3- to 6-membered heterocyclic alkyl; the 3- to 6-membered heterocyclic alkyl has 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms; the term "substituted" means that 1, 2, 3 or 4 hydrogen atoms in the group are replaced by substituents each independently selected from the S group.

[0297] In one embodiment of the present invention, in formula II, L is a bond.

[0298] In one embodiment of the present invention, in Formula II, R5 is hydrogen, halogen, hydroxyl, -substituted or unsubstituted C. 1-3 Alkyl, -substituted or unsubstituted C 3-6 Cycloalkyl, -substituted or unsubstituted 3- to 6-membered heterocyclic alkyl, -O-substituted or unsubstituted C 1-3 Alkyl, -O-substituted or unsubstituted C 3-6 Cycloalkyl, -O-substituted or unsubstituted 3- to 6-membered heterocyclic alkyl, -SO2-substituted or unsubstituted C 1-3 Alkyl, -SO2-substituted or unsubstituted C 3-6 Cycloalkyl, -SO2-substituted or unsubstituted 3- to 6-membered heterocyclic alkyl, -substituted or unsubstituted 5- or 6-membered monocyclic heteroaryl or NR 51 R 52 Among them, R 51 R 52 Each is independently hydrogen, substituted or unsubstituted C 1-3 Alkyl, -SO2C 1-3 Alkyl, -SO2C 3-6 Cycloalkyl, -C(O)C 1-3 Alkyl or -C(O) halocarbon 1-3 Alkyl; or R 51 and R 52Together with the attached nitrogen atom, they form substituted or unsubstituted 3- to 6-membered nitrogen-containing heterocyclic alkyl groups; wherein each of the 3- to 6-membered heterocyclic alkyl groups and the 5- or 6-membered monocyclic heteroaryl groups independently has 1, 2, or 3 heteroatoms selected from N, O, and S as ring atoms; the 3- to 6-membered nitrogen-containing heterocyclic alkyl groups have 3 to 6 ring atoms, one of which is a nitrogen atom, and the remaining 0, 1, or 2 ring atoms are optionally heteroatoms selected from N, O, and S; the term "substitution" refers to the substitution of 1, 2, 3, or 4 hydrogen atoms in the group by substituents independently selected from the S group; wherein, C 1-3 The alkyl group is methyl, ethyl, or propyl (n-propyl or isopropyl); C 1-3 The alkoxy group can be methoxy, ethoxy, or propoxy (n-propoxy or isopropoxy).

[0299] In one embodiment of the present invention, R1 and R2 are each independently hydrogen, halogen, cyano, amino, NHCH3, N(CH3)2, methyl, ethyl, n-propyl, isopropyl, monochloromethyl, dichloromethyl, trichloromethyl, monochloroethyl, 1,2-dichloroethyl, trichloroethyl, monobromoethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, -CH2-hydroxy, -CH2-cyano, -CH2-methoxy, -CH2-ethoxy, -CH2-propoxy (n-propoxy), -CH2-isopropoxy, -CH2-NH2, -CH2-NHCH3, -CH2-N(CH3)2, -CH2-3 to 6-membered heterocyclic alkyl or -CH2-5 or 6-membered monocyclic heteroaryl; the 3 to 6-membered The heterocyclic alkyl group is selected from: aziridine, ethylene oxide, aziridine, oxacyclobutane, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, piperidine, piperazine, morpholine, thiomorpholine, thiomorpholine-1,1-dioxide, and tetrahydropyrran; the 5 or 6-membered monocyclic heteroaryl group is selected from: thiophene, N-alkylcyclopyrrole, furan, thiazole, isothiazole, imidazole, oxazole, pyrrole, pyrazole, triazole, 1,2,3 -triazole, 1,2,4-triazole, 1,2,5-triazole, 1,3,4-triazole, tetraazole, isoxazole, oxadiazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, thiadiazole, pyridine, pyridazine, pyrimidine, pyrazine; wherein the 3 to 6-membered heterocyclic alkyl group, or the 5 or 6-membered monocyclic heteroaryl group, is optionally surrounded by 1 or 2 halogens or C 1-3 Alkyl substitution.

[0300] In one embodiment of the present invention, R3 is hydrogen, halogen, methoxy, ethoxy, propoxy (n-propoxy), or isopropoxy.

[0301] In one embodiment of the present invention, R4 is hydrogen, monochloromethyl, dichloromethyl, trichloromethyl, monochloroethyl, 1,2-dichloroethyl, trichloroethyl, monobromoethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, -CH2-hydroxy, -CH2-cyano, -CH2-methoxy, -CH2-ethoxy, -CH2-propoxy (n-propoxy), or -CH2-isopropoxy.

[0302] In one embodiment of the present invention, R1, R2, and R3 are hydrogen.

[0303] In one embodiment of the present invention, E1 is N or CR5; wherein R5 is hydrogen.

[0304] In one embodiment of the present invention, E2 is N or CR6; wherein R6 is hydrogen.

[0305] In one embodiment of the invention, in the compound of formula (I), the R... 11 R 12 R 21 R 22 R 31 R 32 R 41 R 42 Z, P, R0, Ar, E1, E2, X1, and Y1 are each independently the corresponding functional groups in the specific compounds in the examples.

[0306] In one embodiment of the present invention, the compound of formula (I) is selected from any one of the compounds Z1, Z3 to Z16 in the examples or their diastereomers.

[0307] In one embodiment of the invention, a representative compound of formula (IA) comprises the structures listed in Table A-1 below, or tautomers, cis-trans isomers, meso compounds, racemic compounds, enantiomers, diastereomers, or transisomers of any structure in Table A-1, or mixtures of the aforementioned isomers, or pharmaceutically acceptable salts, solvates, or prodrugs of the structures in Table A-1 and their aforementioned isomers.

[0308] Table A-1

[0309]

[0310]

[0311]

[0312]

[0313]

[0314]

[0315]

[0316]

[0317]

[0318]

[0319]

[0320]

[0321]

[0322]

[0323] In one embodiment of the invention, representative compounds of formula (IA) include, but are not limited to, the structures listed in Table A-2 below, or pharmaceutically acceptable salts, solvates, or prodrugs of any structure in Table A-2.

[0324] Table A-2

[0325]

[0326]

[0327]

[0328] In one embodiment of the invention, representative formula (IA) compounds include, but are not limited to, any of the compound structures described in Examples 51 to 342, or pharmaceutically acceptable salts, solvates, or prodrugs of such structures.

[0329] In one embodiment of the invention, in the compound of formula (II), the R... 11 R 12 R 21 R 22 R 31 R 32 R 41 R 42 Z, P, Ar, E3, E4, X2, and Y2 are each independent groups in the specific compounds in the examples.

[0330] In one embodiment of the invention, the compound of formula (II) is selected from any one of the compounds Z2, Z17 to Z20 in the examples or their diastereomers.

[0331] In another aspect, the present invention provides a pharmaceutical composition comprising the aforementioned compound or its tautomers, cis-trans isomers, meso compounds, racemates, enantiomers, diastereomers, transisomers, or mixtures thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof; and a pharmaceutically acceptable carrier.

[0332] As used herein, the term "pharmaceutically acceptable carrier" refers to any formulation or carrier medium capable of delivering an effective amount of the active substance of the present invention without interfering with the biological activity of the active substance and without toxic side effects on the host or subject. Representative carriers include water, oils, vegetables and minerals, ointment bases, lotion bases, and ointment bases. These bases include suspending agents, thickeners, transdermal penetration enhancers, etc. Their formulations are well known to those skilled in the art of cosmetics or topical pharmaceuticals.

[0333] In embodiments of the invention, the pharmaceutical composition can be administered in any of the following ways: orally, by spray inhalation, rectal administration, nasal administration, buccal administration, topical administration, parenteral administration, such as subcutaneous, intravenous, intramuscular, intraperitoneal, intrathecal, intraventricular, intrasternal, and intracranial injection or infusion, or via an external implantation device. When administered orally, the compounds of the invention can be formulated into any orally acceptable dosage form, including but not limited to tablets, capsules, aqueous solutions, or aqueous suspensions. Tablets typically use carriers comprising lactose and corn starch, and lubricants such as magnesium stearate may also be added. Capsule formulations typically use diluents comprising lactose and dried corn starch. Aqueous suspension formulations typically involve mixing the active ingredient with suitable emulsifiers and suspending agents. If desired, sweeteners, flavorings, or colorings may also be added to the above oral formulations. When used topically, especially for treating affected areas or organs easily accessible through topical application, such as the eyes, skin, or lower gastrointestinal neurological disorders, the compounds of this invention can be formulated into different topical formulations depending on the affected area or organ. For topical application to the eye, the compounds of this invention can be formulated as a micronized suspension or solution, using an isotonic sterile saline solution of a specific pH as the carrier, with or without preservatives such as benzyl alkyl chloride. For ophthalmic use, the compounds can also be formulated as ointments such as petrolatum. When applied topically to the skin, the compounds of this invention can be formulated as appropriate ointments, lotions, or creams, wherein the active ingredient is suspended or dissolved in one or more carriers. Carriers that can be used in ointment formulations include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyethylene oxide, polypropylene oxide, emulsified wax, and water; carriers that can be used in lotions or creams include, but are not limited to, mineral oil, sorbitan monostearate, Tween 60, hexadecyl ester wax, hexadecene aromatic alcohol, 2-octyldodecyl alcohol, benzyl alcohol, and water. The compounds of this invention can also be administered in sterile injectable formulations, including sterile injectable aqueous or oil suspensions or sterile injectable solutions. Usable carriers and solvents include water, Ringer's solution, and isotonic sodium chloride solution. Furthermore, sterilized non-volatile oils, such as monoglycerides or diglycerides, can also be used as solvents or suspension media.

[0334] In another aspect, the present invention provides the use of the aforementioned compound or its tautomers, cis-trans isomers, meso compounds, racemic compounds, enantiomers, diastereomers, transisomers, or mixtures thereof, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, in the preparation of medicaments for treating and / or preventing KRAS G12C mutation-induced diseases. Preferably, the KRAS G12C mutation-induced disease is cancer.

[0335] In another aspect, the present invention provides the use of the aforementioned compound or its tautomers, cis-trans isomers, meso compounds, racemates, enantiomers, diastereomers, transisomers or mixtures thereof, or pharmaceutically acceptable salts, solvates or prodrugs thereof, in the preparation of medicaments for the treatment and / or prevention of cancer.

[0336] In one embodiment of the present invention, the cancer is pancreatic cancer, colorectal cancer, or lung cancer.

[0337] In one embodiment of the present invention, the cancer is lung cancer, preferably non-small cell lung cancer.

[0338] In another aspect, the present invention provides the use of the aforementioned compound or its tautomers, cis-trans isomers, meso compounds, racemates, enantiomers, diastereomers, transisomers or mixtures thereof, or pharmaceutically acceptable salts, solvates or prodrugs thereof, in the preparation of KRAS mutation inhibitors (preferably, the KRAS mutation is a KRAS G12C mutation).

[0339] In another aspect, the present invention provides a method for treating cancer, comprising administering to a subject in need a therapeutically effective amount of the aforementioned compound or its tautomers, cis-trans isomers, meso compounds, racemic compounds, enantiomers, diastereomers, transisomers, or mixtures thereof, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, or any combination thereof, or the step of administering the aforementioned pharmaceutical composition.

[0340] As used in this article, the term "subject" refers to an animal, particularly a mammal, preferably a human.

[0341] As used herein, the term "effective amount" or "therapeutic effective amount" refers to a sufficient quantity of a drug or agent that is non-toxic but achieves the desired effect. In embodiments of the invention, when treating a patient according to the invention, the amount of a given drug depends on many factors, such as the specific dosing regimen, the type and severity of the disease or condition, and the unique characteristics of the patient or host requiring treatment (e.g., weight). However, depending on the specific surrounding circumstances, including, for example, the specific drug used, the route of administration, the condition being treated, and the patient or host being treated, the dosage can be conventionally determined by methods known in the art. Typically, for adult treatment, the dosage is typically in the range of 0.02-5000 mg / day, for example, about 1-1500 mg / day. This required dosage can conveniently be expressed as a single dose, or concurrent (or over a short period of time) or fractions at appropriate intervals, such as two, three, four, or more doses per day. Those skilled in the art will understand that although the above dosage ranges are given, the specific effective amount can be appropriately adjusted according to the patient's condition and in conjunction with the physician's diagnosis.

[0342] As used herein, the term "pharmaceutically acceptable salt" refers to a salt of the compounds of the present invention that is pharmaceutically acceptable and has the pharmacological activity of the parent compound. Such salts include: salts formed by addition to inorganic acids or acids formed with organic acids, such as nitric acid, phosphoric acid, carbonic acid, etc.; organic acids such as propionic acid, hexanoic acid, cyclopentylpropionic acid, glycolic acid, pyruvic acid, gluconic acid, stearic acid, mucoacinic acid, etc.; or salts formed when an acidic proton present on the parent compound is replaced by a metal ion, such as an alkali metal ion or an alkaline earth metal ion; or coordination compounds formed with an organic base, such as ethanolamine, diethanolamine, triethanolamine, N-methylglucosamine, etc. The pharmaceutically acceptable salts of the present invention can be synthesized from parent compounds containing an acid radical or a base by conventional chemical methods. Generally, such salts are prepared by reacting these compounds in their free acid or base form with a stoichiometric amount of a suitable base or acid in water or an organic solvent or a mixture of both. In addition to salt forms, the compounds provided by the present invention also exist in prodrug forms. The prodrugs of the compounds described herein readily undergo chemical changes under physiological conditions to be converted into the compounds of the present invention. Furthermore, the prodrugs can be converted into the compounds of the present invention in the in vivo environment via chemical or biochemical methods.

[0343] As used herein, the terms "solvent compound" and "solvent" refer to substances formed by combining the compounds of the present invention with pharmaceutically acceptable solvents. Solvent compounds include stoichiometric solvent compounds and non-stoichiometric solvent compounds. Some compounds of the present invention may exist in either a non-solventized or a solvated form. Generally, solvated and non-solventized forms are equivalent and both are included within the scope of the present invention.

[0344] As used herein, the term "stereoisomer" includes conformational isomers and configurational isomers, wherein configurational isomers primarily include cis-trans isomers and optical isomers. The compounds of this invention can exist in stereoisomer form and therefore encompass all possible stereoisomeric forms, including but not limited to cis-trans isomers, tautomers, enantiomers, diastereomers, and rotationally blocked isomers (or may also be called rotational isomers). The compounds of this invention can also exist in any combination or mixture of the aforementioned stereoisomers, such as meso compounds, racemic compounds, and equal mixtures of rotationally blocked isomers. Examples include a single enantiomer, a single diastereomer or a mixture of more than one, or a single rotationally blocked isomer or a mixture thereof. When the compounds of this invention contain an olefinic double bond, unless otherwise specified, they include cis and trans isomers, and any combination thereof. The rotationally blocked isomers of this invention are stereoisomers with axial or planar chirality resulting from restricted intramolecular rotation. The compounds of this invention have two transisomers derived from axis asymmetry, which are restricted to C when the substituent Ar′ or R0′ is C. 6-10 The transisomers of the present invention are generated by the rotation of cyclic groups such as aryl, 5- or 6-membered monocyclic heteroaryl, 8- to 10-membered bicyclic heteroaryl, or pyridone groups, and the bond connection with the substituted naphthidone ring, resulting in steric hindrance. Regarding the transisomers of the present invention, the compounds having the structure of formula (I), formula (IA), or formula (II), or the compounds of formula (I), formula (IA), or formula (II) having isomers derived from asymmetric carbons, etc., represent any one of a pair of transisomers present in each isomer. Furthermore, transisomers with excellent activity are preferred as pharmaceuticals. The compounds of formula (I), formula (IA), or formula (II) have optical isomers derived from asymmetric carbons, axial asymmetry, etc., and if necessary, a single isomer can be obtained by optical resolution. The transisomers of the compounds of the present invention can be represented by P or M configurations, or by other notations commonly known in the art.

[0345] As previously stated, the present invention provides compounds with the structures shown above, or tautomers, cis-trans isomers, meso compounds, racemates, enantiomers, diastereomers, septate isomers, or mixtures thereof, wherein “mixtures thereof” includes any form of mixing between any of the aforementioned stereoisomers (e.g., tautomers, cis-trans isomers, enantiomers, diastereomers, septate isomers) and / or mixtures (meso compounds, racemates), such as mixtures of cis-trans isomers, mixtures of enantiomers and diastereomers, mixtures of diastereomers, mixtures of septate isomers, or mixtures of cis-trans isomers and racemates, mixtures of enantiomers and diastereomers, mixtures of septate isomers and diastereomers, etc.

[0346] As used in this article, the "-" symbol contained in the substituents of each group indicates a bond that connects to other groups or structures.

[0347] As used in this article, the term "fusion" refers to a structure in which two or more rings share one or more bonds.

[0348] As used herein, the term "alkyl" refers to a straight-chain or branched saturated aliphatic hydrocarbon group containing 1 to 20 carbon atoms. 1-10 "Alkyl" refers to a straight-chain or branched alkyl group having 1 to 10 carbon atoms, more preferably a straight-chain or branched alkyl group having 1, 2, 3, 4, 5 or 6 carbon atoms, i.e., C10, C20, C30, C40, C50, C60, C70, C80, C9 ... 1-6 Alkyl, more preferably C 1-4 Alkyl group, most preferably C 1-3 Alkyl groups. Specific examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, and their various branched isomers.

[0349] It should be noted that, unless otherwise specified, if both propyl and isopropyl are present in a list of options, propyl here refers to n-propyl. If only propyl is present in a list of options, propyl here refers to either n-propyl or isopropyl.

[0350] As used in this article, "-C" 1-3 alkyl-" and "C" 1-3 "Alkylene" is used interchangeably to refer to a saturated straight-chain or branched aliphatic hydrocarbon group having two residues derived from the same carbon atom or two different carbon atoms of the parent alkyl group by removing two hydrogen atoms. It is a straight-chain or branched group containing one to three carbon atoms. Non-limiting examples of alkylene include, but are not limited to, methylene (-CH2-), 1,1-ethylene (-CH(CH3)-), 1,2-ethylene (-CH2CH2-), 1,1-propylene (-CH(CH2CH3)-), 1,2-propylene (-CH2CH(CH3)-), 1,3-propylene (-CH2CH2CH2-), etc.

[0351] As used in this article, "-C" 1-3 Alkyl (hydroxy) -, -C 1-3Alkyl (cyano) -, -C 1-3 Alkyl (C) 1-6 alkyl)-, -C 1-3 Alkyl (halogenated C) 1-6 alkyl)-, -C 1-3 Alkyl (C) 1-6 alkyl-hydroxy)-, -C 1-3 Alkyl (C) 1-6 (alkyl-cyano)-, -C 1-3 Alkyl (C) 1-6 Alkoxy)-, -C 1-3 Alkyl (halogenated C) 1-6 Alkoxy)-” respectively refers to “-C 1-3 One or more hydrogen atoms in the alkyl group are respectively converted by hydroxyl, cyano, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, -C 1-6 Alkyl-hydroxyl, -C 1-6 Alkyl-cyano, C 1-6 Alkoxy, halogenated C 1-6 Residues formed by alkoxy substitution. Non-limiting examples include, but are not limited to, -CH(OH)-, -CH2CH(CN)-, -CH2CH(CH2CH3)-, -CH2CH(CF3)-, -CH(CH2OH)-, -CH2CH(CH2CN)-, -CH(OCH3)-, and -CH2CH(OCF3)-.

[0352] As used herein, the term "alkoxy" refers to a group having an -O-alkyl structure, wherein the definition of alkyl is as described above. The term "C" 1-10 "Alkoxy group" refers to an alkoxy group having 1 to 10 carbon atoms, preferably C10. 1-6 Alkyl groups, more preferably C 1-4 Alkyl groups, more preferably C 1-3 Alkoxy groups. Specific examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, isobutoxy, and n-pentoxy.

[0353] It should be noted that, unless otherwise specified, if both propoxy and isopropoxy are present in a list of parallel options, propoxy in that list represents n-propoxy. If only propoxy is present in a list of parallel options, propyl in that list represents either n-propoxy or isopropoxy.

[0354] As used herein, the term "alkathioyl" refers to a group having a -S-alkyl structure, wherein the definition of alkyl is as described above. The term "C 1-10 "Alkylthio" refers to an alkylthio group having 1 to 10 carbon atoms, preferably C10. 1-6 Alkylthio, more preferably C 1-4 Alkylthio, more preferably C1-3 Alkylthio groups. Specific examples of alkylthio groups include, but are not limited to, methylthio, ethylthio, propylthio, isopropylthio, butylthio, tert-butylthio, isobutylthio, pentylthio, etc.

[0355] As used herein, the term "alkenyl" refers to an alkyl group as defined above that has one or more carbon-carbon double bonds at any point in the chain, and the term "C" refers to an alkyl group. 2-8 "Alkenyl" refers to an alkenyl group having 2 to 8 carbon atoms and at least one carbon-carbon double bond, preferably an alkenyl group having 2 to 6 carbon atoms and 1 to 2 carbon-carbon double bonds, i.e., C 2-6 Alkenyl. More preferably, an alkenyl group having 2 to 4 carbon atoms and 1 to 2 carbon-carbon double bonds, i.e., C 2-4 Alkenyl. Specific examples of alkenyl groups include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl, pentenyl, hexenyl, butadienyl, etc.

[0356] As used herein, the term "alkynyl" refers to an alkyl group as defined above that has one or more carbon-carbon triple bonds at any point in the chain, and the term "C" refers to an alkyl group. 2-8 "Alynyl" refers to an alkynyl group having 2 to 8 carbon atoms and at least one carbon-carbon triple bond, preferably an alkynyl group having 2 to 6 carbon atoms and 1 to 2 carbon-carbon triple bonds, i.e., C 2-6 Alkynyl group. More preferably, it is an alkynyl group having 2 to 4 carbon atoms and 1 to 2 carbon-carbon triple bonds, i.e., C 2-4 Alkyne group. Specific examples of alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-, 2-, or 3-butynyl.

[0357] As used in this article, the term "halogen" refers to fluorine, chlorine, bromine, and iodine.

[0358] As used herein, the term "halogenated alkyl" refers to an alkyl group substituted with one or more (e.g., 1, 2, 3, 4, or 5) halogens, wherein the definition of an alkyl group is as described above. The term "halogenated C" 1-10 "Alkyl" refers to a haloalkyl group having 1 to 10 carbon atoms. Haloalkyl is preferred. 1-6 Alkyl, more preferably halogenated C 1-4 Alkyl, more preferably halogenated C 1-3 Alkyl groups. Specific examples of haloalkyl groups include, but are not limited to, monochloromethyl, dichloromethyl, trichloromethyl, monochloroethyl, 1,2-dichloroethyl, trichloroethyl, monobromoethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, and trifluoroethyl.

[0359] As used herein, the term "deuterated alkyl" refers to an alkyl group substituted with one or more (e.g., 1, 2, 3, 4, or 5) deuterium atoms, wherein the definition of alkyl is as described above. The term "deuterated C..." 1-10"Alkyl" refers to a deuterated alkyl group having 1 to 10 carbon atoms. Deuterated C atoms are preferred. 1-6 Alkyl groups, more preferably deuterated C4 groups 1-4 Alkyl groups, more preferably deuterated C4 groups 1-3 Alkyl groups. Specific examples of deuterated alkyl groups include, but are not limited to, monodeuterylmethyl, dideuterylmethyl, trideuterylmethyl, monodeuterylethyl, 1,2-dideuterylethyl, trideuterylethyl, etc.

[0360] As used herein, the term "haloalkoxy" refers to an alkoxy group substituted with one or more (e.g., 1, 2, 3, 4, or 5) halogens, wherein the definition of an alkoxy group is as described above. The term "haloC" refers to an alkoxy group substituted with one or more halogens (e.g., 1, 2, 3, 4, or 5). 1-10 "Alkoxy" refers to a haloalkoxy group having 1 to 10 carbon atoms. Preferably, it is a halo-C group. 1-6 Alkoxy, more preferably halogenated C 1-4 Alkoxy, more preferably halogenated C 1-3 Alkyl groups. Specific examples of haloalkoxy groups include, but are not limited to, trifluoromethoxy, trifluoroethoxy, monofluoromethoxy, monofluoroethoxy, difluoromethoxy, and difluoroethoxy.

[0361] As used herein, the terms "cycloalkyl" and "cycloalkyl ring" are used interchangeably to refer to a saturated monocyclic or polycyclic fused cyclic hydrocarbon group. The term "C" 3-20 "Cycloalkyl" refers to a cycloalkyl group having 3 to 20 carbon atoms, including monocyclic cycloalkyl, spirocyclic cycloalkyl, fused cycloalkyl, and bridged cycloalkyl. Preferably, it has 3 carbon atoms. 3-12 Cycloalkyl groups. The cyclic carbon atoms of the cycloalkyl groups described in this invention may optionally be substituted with one, two, or three oxo groups to form a cyclic ketone structure. The term "C" is used in this context. 3-8 "Monocyclic cycloalkyl" and "C" 3-8 "Cycloalkyl" refers to a saturated monocyclic cyclic hydrocarbon group having 3 to 8 carbon atoms, preferably C12. 3-6 Monocyclic cycloalkyl (i.e., C 3-6 Cycloalkyl groups, more preferably C3, C4, C5 or C6 monocyclic cycloalkyl groups. Specific examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, etc.

[0362] As used herein, the terms "spirocycloalkyl" and "spirocycloalkyl ring" refer to polycyclic cyclic hydrocarbon groups formed by two or more monocyclic rings sharing a single carbon atom (called a spiro atom). Spirocycloalkyl groups are classified into monospirocycloalkyl, bispirocycloalkyl, and polyspirocycloalkyl groups based on the number of shared spiro atoms between the rings. The terms "5 to 20-membered spirocycloalkyl" or "C..." 5-20 "Spirocycloalkyl" refers to a polycyclic cyclic hydrocarbon group having 5 to 20 ring carbon atoms, wherein the monocyclic ring sharing the spiro atom is a 3 to 8-membered monocyclic cycloalkyl ring. Preferably, it is a 6 to 14-membered (C) ring. 6-14Spirocycloalkyl, more preferably 6- to 14-membered monospirocycloalkyl, more preferably 7- to 11-membered (C 7-11 Spirocycloalkyl, more preferably 7- to 11-membered monospirocycloalkyl, most preferably 7-membered (4-membered monocycloalkyl ring / 4-membered monocycloalkyl ring), 8-membered (4-membered monocycloalkyl ring / 5-membered monocycloalkyl ring), 9-membered (4-membered monocycloalkyl ring / 6-membered monocycloalkyl ring, 5-membered monocycloalkyl ring / 5-membered monocycloalkyl ring), 10-membered (5-membered monocycloalkyl ring / 6-membered monocycloalkyl ring), or 11-membered (6-membered monocycloalkyl ring / 6-membered monocycloalkyl ring) monospirocycloalkyl. Specific examples of spirocycloalkyl include, but are not limited to:

[0363]

[0364] The cycloalkyl ring may be fused to an aryl, heteroaryl, or heterocyclic ring, wherein the ring connected to the parent structure is a cycloalkyl ring, and non-limiting examples include indenyl, tetrahydronaphthyl, benzocycloheptyl, etc. In this invention, the above-mentioned cycloalkyl groups may be optionally substituted, and when substituted, the substituents are preferably one or more substituent groups described in this application.

[0365] As used herein, the term "halocycloalkyl" refers to a cycloalkyl group substituted with one or more (e.g., 1, 2, 3, 4, or 5) halogens, wherein the definition of cycloalkyl is as described above. The term "haloC" 3-8 "Cycloalkyl" refers to a halocycloalkyl group having 3 to 8 ring carbon atoms. Preferably, it is a halocarbon group. 3-6 Cycloalkyl, more preferably halogenated C3, halogenated C4, halogenated C5, or halogenated C6 cycloalkyl. Specific examples of halogenated cycloalkyl groups include, but are not limited to, trifluorocyclopropyl, monofluorocyclopropyl, monofluorocyclohexyl, difluorocyclopropyl, and difluorocyclohexyl.

[0366] As used herein, the terms "heterocyclic group" and "heterocyclic ring" are used interchangeably to refer to a saturated or partially unsaturated monocyclic or polycyclic fused cyclic hydrocarbon group. The term "C" is used in conjunction with the meaning of the cyclic group. 3-20 "Heterocyclic group" or "3 to 20-membered heterocyclic group" refers to a saturated or partially unsaturated monocyclic or polycyclic fused cyclic hydrocarbon group having 3 to 20 ring atoms, wherein one or more (preferably 1, 2, 3 or 4) ring atoms are selected from nitrogen, oxygen or S(O). mThe heterocyclic group (where m is an integer from 0 to 2) contains heteroatoms, but excludes the ring portion of -OO-, -OS-, or -SS-, with the remaining ring atoms being carbon. When the ring atom is a nitrogen atom, it can be substituted or unsubstituted (i.e., N or NR, where R is hydrogen or another substituent defined herein). The ring carbon atom of the heterocyclic group described in this invention may optionally be substituted with 1, 2, or 3 oxo groups to form a cyclic ketone, cyclic lactone, or cyclic lactam structure. The 3- to 20-membered heterocyclic groups described in this invention include monocyclic heterocyclic groups, spirocyclic groups, fused heterocyclic groups, and bridged heterocyclic groups.

[0367] As used in this article, the term "C" 3-8 "Monocyclic heterocyclic group", "3- to 8-membered monocyclic heterocyclic group", and "3- to 8-membered monocyclic heterocyclic group ring" refer to groups with 3 to 8 ring atoms, of which 1, 2, or 3 ring atoms are selected from nitrogen, oxygen, or S(O). m (where m is an integer from 0 to 2) saturated or partially unsaturated monocyclic cyclic hydrocarbon groups with heteroatoms. Preferably, they are 3 to 6 membered monocyclic heterocyclic groups (i.e., C16H12 ... 3-6 Monocyclic heterocyclic groups. More preferably, 5- or 6-membered monocyclic heterocyclic groups having 5 or 6 ring atoms, wherein 1 or 2 ring atoms are heteroatoms. When the heteroatom is a nitrogen atom, the nitrogen atom may be substituted or unsubstituted (i.e., N or NR, where R is hydrogen or other substituents already defined herein). When the heteroatom is a sulfur atom, the sulfur atom may optionally be oxidized (i.e., S(O)). m(where m is an integer from 0 to 2). The cyclic carbon atom of the monocyclic heterocyclic group may optionally be replaced by 1, 2, or 3 oxo groups to form a cyclic ketone, cyclic lactone, or cyclic lactam structure. Specific examples of monocyclic heterocyclic groups include, but are not limited to, aziridine, ethylene oxide, aziridine, aziridine-2-one, oxazolidinyl, oxazolidinyl-2-one ... Morpholin-3-one 1,1-dioxide, thiomorpholine, thiomorpholine-1,1-dioxide, tetrahydropyran, 1,2-dihydroazacyclobutadiene, 1,2-dihydrooxocyclobutadiene, 2,5-dihydro-1H-pyrrole, 2,5-dihydrofuran, 2,3-dihydrofuran, 2,3-dihydro-1H-pyrrole, 3,4-dihydro-2H-pyran, 1,2,3,4-tetrahydropyridine, 3,6-dihydro-2H-pyran, 1,2,3,6-tetrahydropyridine, 1,3-oxazine, hexahydropyrimidine, 1,4-dioxane, tetrahydropyrimidine-2(1H)-one, 1,4-dioxane-2-one, 5,6-dihydro-2H-pyran-2-one, 5,6-Dihydropyrimidin-4(3H)-one, 3,4-Dihydropyridin-2(1H)-one, 5,6-Dihydropyridin-2(1H)-one, 5,6-Dihydropyrimidin-4(1H)-one, pyrimidin-4(3H)-one, pyrimidin-4(1H)-one, 4,5-Dihydro-1H-imidazolium, 2,3-Dihydro-1H-imidazolium, 2,3-Dihydrooxazole, 1,3-Dioxacyclopentene, 2,3-Dihydrothiophene, 2,5-Dihydrothiophene, 3,4-Dihydro-2H-1,4-oxazine, 3,4-Dihydro-2H-1,4-thiazine 1,1-dioxide, 1,2,3,4-Tetrahydropyrazine, 1,3-Dihydro-2H-pyrrole-2- Ketones, 1,5-dihydro-2H-pyrrolo-2-one, 1H-pyrrolo-2,5-dione, furan-2(3H)-one, furan-2(5H)-one, 1,3-dioxacyclopenten-2-one, oxazol-2(3H)-one, 1,3-dihydro-2H-imidazol-2-one, furan-2,5-dione, 3,6-dihydropyridin-2(1H)-one, pyridin-2,6-(1H,3H)-dione, 5,6-dihydro-2H-pyran-2-one, 3,6-dihydro-2H-pyran-2-one, 3,4-dihydro-2H-1,3-oxazine, 3,6-dihydro-2H-1,3-oxazine, 1,2,3,4-tetrahydropyrimidine, etc. The term "C" is used in conjunction with these. 3-8"Heterocyclic alkyl" and "3- to 8-membered heterocyclic alkyl" refer to saturated monocyclic cyclic hydrocarbon groups having 3 to 8 ring atoms, wherein 1 or 2 ring atoms are heteroatoms. Preferably, they are 3- to 6-membered heterocyclic alkyl groups having 3 to 6 ring atoms, wherein 1 or 2 ring atoms are heteroatoms. Specific examples of heterocyclic alkyl groups include, but are not limited to, aziridine, ethylene oxide, aziridine, oxaziridine, oxazolidine, 1,3-dioxopentanyl, dioxahexacycloyl, imidazoalkyl, tetrahydrofuranyl, tetrahydrothiophene, tetrahydropyrroleyl, piperidinyl, piperazine, morpholinyl, thiomorpholinyl, thiomorpholin-1,1-dioxide, tetrahydropyranyl, 1,4-oxaziridine, 1,3-oxaziridine, 1,3-oxazinyl, hexahydropyrimidinyl, and 1,4-dioxalyl.

[0368] The two ring atoms attached to the monocyclic heterocyclic group ring, including CC and NC, can optionally be fused with cycloalkyl, heterocyclic, aryl or heteroaryl groups as defined in this invention to form fused polycyclic rings. The two ring atoms attached to the monocyclic heterocyclic group forming the fused ring with other rings are preferably CC.

[0369] As used in this article, the term "C" 6-14 Aryl", "C" 6-14 "Aryl ring" and "C" 6-14 The term "aromatic ring" is used interchangeably and refers to a monocyclic, polycyclic, or fused polycyclic carbon ring with 6 to 14 ring atoms. The ring must be aromatic, meaning it possesses a conjugated π-electron system. C is preferred. 6-10 Aryl. In this invention, C 6-14 Aryl groups include monocyclic aryl, polycyclic aryl, and aromatic fused polycyclic groups, with examples of monocyclic aryl groups including phenyl and examples of polycyclic aryl groups including biphenyl.

[0370] In this invention, C 6-14 When the aryl group is an aromatic fused polycyclic ring, the aromatic fused polycyclic ring can be a polycyclic group formed by the fusion of a monoaryl ring with one or more monoaryl rings, and non-limiting examples include naphthyl, anthracene, etc.

[0371] In some embodiments of the present invention, the aromatic fused polycyclic group may also be a polycyclic group formed by the fusion of a monoaryl ring (such as phenyl) with one or more non-aromatic rings, wherein the ring connected to the parent structure is an aromatic ring or a non-aromatic ring. The non-aromatic ring includes, but is not limited to, 3- to 6-membered monocyclic heterocyclic rings (preferably 5- or 6-membered monocyclic heterocyclic rings, wherein the ring carbon atom of the monocyclic heterocyclic ring may be substituted by 1 to 2 oxo groups to form a cyclic lactam or cyclic lactone structure), and 3- to 6-membered monocyclic cycloalkyl rings (preferably 5- or 6-membered monocyclic cycloalkyl rings, wherein the ring carbon atom of the monocyclic cycloalkyl ring may be substituted by 1 or 2 oxo groups to form a cyclic ketone structure). The above-mentioned polycyclic group fused with a monoaryl ring and one or more non-aromatic rings may be connected to other groups or the parent structure via nitrogen or carbon atoms, wherein the ring connected to the parent structure is a monoaryl ring or a non-aromatic ring.

[0372] In this article, the fusion of a benzene ring with a 5- or 6-membered monocyclic heterocyclic base ring to form a 9- or 10-membered aromatic fused bicycle refers to the formation of a fused 5- or 6-membered monocyclic heterocyclic base ring by two adjacent substituents on the phenyl group and the ring atoms to which they are attached. The 5- or 6-membered monocyclic heterocyclic base ring is as defined above, and the resulting 9- or 10-membered aromatic fused bicycle can also be referred to as a 9- or 10-membered phenyl heterocyclic base ring.

[0373] In this document, the fusion of a benzene ring with a 5- or 6-membered monocyclic cycloalkyl ring to form a 9- or 10-membered aromatic fused bicycle refers to the formation of a fused 5- or 6-membered monocyclic cycloalkyl ring by two adjacent substituents on the phenyl group and the ring atoms to which they are attached. The 5- or 6-membered monocyclic cycloalkyl ring is as defined above. The resulting 9- or 10-membered aromatic fused bicycle can also be referred to as a 9- or 10-membered phenylcycloalkyl ring. Non-limiting examples include:

[0374]

[0375]

[0376] In this invention, the various aryl groups described above can be substituted or unsubstituted. When substituted, the substituent is preferably one or more of the substituent groups described in this application.

[0377] As used herein, the terms "heteroaryl," "heteroaryl ring," and "heteroary ring" are used interchangeably to refer to a monocyclic or fused polycyclic (i.e., sharing adjacent ring atom pairs, which may be CC or NC) group in which the ring atom is substituted by at least one heteroatom independently selected from nitrogen, oxygen, or sulfur, wherein the nitrogen and sulfur atoms may optionally be oxidized, and the nitrogen atom may optionally be quaternized. The heteroaryl group has 6, 10, or 14 shared π electrons, and at least one ring in the group is aromatic. The term "C" is used in conjunction with the term "C" in the original text. 5-14"Heteroaryl" and "5- to 14-membered heteroaryl" refer to heteroaryl groups having 5 to 14 ring atoms, wherein 1, 2, 3, or 4 ring atoms are heteroatoms. Preferably, they are 5- to 10-membered heteroaryl groups having 5 to 10 ring atoms, wherein 1, 2, 3, or 4 ring atoms are heteroatoms. In this invention, C... 5-14 Heteroaryl groups can be mono-heteroaryl, fused bicyclic heteroaryl, or fused tricyclic heteroaryl.

[0378] As used herein, the terms "5- or 6-membered monoheteroaryl" and "5- or 6-membered monocyclic heteroaryl" are used interchangeably, referring to a monocyclic heteroaryl group having 5 or 6 ring atoms, of which 1, 2, or 3 ring atoms are heteroatoms. Specific examples of monoheteroaryl groups include, but are not limited to, thiophene, furan, thiazole, isothiazole, imidazole, oxazole, pyrrole, pyrazole, triazole, 1,2,3-triazole, 1,2,4-triazole, 1,2,5-triazole, 1,3,4-triazole, tetraazole, isoxazole, oxadiazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, thiadiazole, pyridine, pyridazine, pyrimidine, pyrazine, etc.

[0379] As used herein, the terms "8 to 10-membered diheteroaryl" and "8 to 10-membered bicyclic heteroaryl" are used interchangeably, referring to a fused bicyclic heteroaryl having 8 to 10 ring atoms, of which 1, 2, 3, 4, or 5 ring atoms are heteroatoms. The fused bicyclic heteroaryl can be a bicyclic group (preferably a 9 or 10-membered diheteroaryl ring) formed by fusion of a monoaryl ring (such as phenyl) and a monoheteroaryl ring (preferably a 5 or 6-membered monoheteroaryl ring), or a bicyclic group formed by fusion of a monoheteroaryl ring (preferably a 5 or 6-membered monoheteroaryl ring) and another monoheteroaryl ring (preferably a 5 or 6-membered monoheteroaryl ring).

[0380] Any two ring atoms attached to the aforementioned mono-heteroaryl ring, including CC, NC, and NN, can be fused with cycloalkyl, heterocyclic, aryl, or heteroaryl groups, such as monocyclic cycloalkyl rings, monocyclic heterocyclic rings, monoaryl rings, and 5- or 6-membered mono-heteroaryl rings, as defined in this invention, to form fused polycyclic rings. The two ring atoms attached to the mono-heteroaryl ring forming the fused ring with other rings are preferably CC, and non-limitingly include the following forms:

[0381]

[0382] Non-limiting examples of 8- to 10-membered diheteroaryl groups include: benzo[d]isoxazole, 1H-indole, isoindole, 1H-benzo[d]imidazol, benzo[d]isothiazol, 1H-benzo[d][1,2,3]triazole, benzo[d]oxazole, benzo[d]thiazol, indazole, benzofuran, benzo[b]thiophene, quinoline, isoquinoline, quinazoline, quinoxaline, cycloline, pyrido[3,2-d]pyrimidine, pyrido[2,3-d]pyrimidine, pyrido[3,4-d]pyrimidine, pyrido[4,3-d]pyrimidine, 1,8-naphthidine, 1,7-naphthidine, 1,6-naphthidine, 1,5-naphthidine, pyrazolo[1,5-a]pyrimidine, imidazo[1,2-b]pyridazine, etc.

[0383] The aforementioned monoheteroaryl groups, or diheteroaryl groups formed by the fusion of a benzene ring and a monoheteroaryl ring, or diheteroaryl groups formed by the fusion of two monoheteroaryl rings, can be linked to other groups or the parent structure via nitrogen or carbon atoms. When it is a diheteroaryl group, the ring linked to the parent structure is a monoheteroaryl ring or a benzene ring, specific examples of which include, but are not limited to:

[0384]

[0385]

[0386] In some embodiments of the present invention, the fused bicyclic heteroaryl or fused tricyclic heteroaryl can be a polycyclic group formed by fusion of a monocyclic heteroaryl ring (preferably a 5- or 6-membered monocyclic heteroaryl ring) with one or more non-aromatic rings, wherein the ring connected to the parent structure is a monocyclic heteroaryl ring or a non-aromatic ring. The non-aromatic ring includes, but is not limited to, 3- to 6-membered monocyclic heterocyclic rings (preferably 5- or 6-membered monocyclic heterocyclic rings, wherein the ring carbon atom of the monocyclic heterocyclic ring can be replaced by 1 to 2 oxo groups to form a cyclic lactam or cyclic lactone structure), 3- to 6-membered monocyclic cycloalkyl rings (preferably 5- or 6-membered monocyclic cycloalkyl rings, wherein the ring carbon atom of the monocyclic cycloalkyl ring can be replaced by 1 or 2 oxo groups to form a cyclic ketone structure), etc. The polycyclic group formed by fusion of the above-mentioned monocyclic heteroaryl ring with one or more non-aromatic rings can be connected to other groups or the parent structure through nitrogen atoms or carbon atoms, wherein the ring connected to the parent structure is a monocyclic heteroaryl ring or a non-aromatic ring.

[0387] In this article, the fusion of a 5- or 6-membered mono-heteroaryl ring with a 5- or 6-membered monocyclic heterocyclic base ring to form an 8- to 10-membered fused bicyclic heteroaryl ring refers to the formation of a fused 5- or 6-membered monocyclic heterocyclic base ring by two adjacent substituents on a 5- or 6-membered monocyclic heterocyclic ring and the ring atom to which they are attached. The 5- or 6-membered monocyclic heterocyclic base ring is as defined above, and the resulting 8- to 10-membered fused bicyclic heteroaryl ring can also be referred to as an 8- to 10-membered heteroaryl heterocyclic base ring.

[0388] In this document, the fusion of a 5- or 6-membered mono-heteroaryl ring with a 5- or 6-membered monocyclic cycloalkyl ring to form an 8- to 10-membered fused bicyclic heteroaryl ring refers to the formation of a fused 5- or 6-membered monocyclic cycloalkyl ring by two adjacent substituents on a 5- or 6-membered mono-heteroaryl ring and the ring atoms to which they are attached. The 5- or 6-membered monocyclic cycloalkyl ring is as defined above, and the resulting 8- to 10-membered fused bicyclic heteroaryl ring can also be referred to as an 8- to 10-membered heteroaryl cycloalkyl ring. Non-limiting examples include:

[0389]

[0390] In this invention, the various heteroaryl groups described above can be substituted or unsubstituted. When substituted, the substituent is preferably one or more of the substituent groups described in this application.

[0391] As used herein, the term "-alkyl-R" indicates a substituent formed by replacing an alkyl group with one or more R groups, wherein "-alkyl-" indicates an alkylene or trialkylene group formed after substitution. R as described herein can be hydroxyl, cyano, alkoxy, substituted amino, heterocyclic alkyl, heteroaryl, haloalkyl, haloalkoxy, cycloalkyl, alkynyl, etc., and the group represented by R is as defined herein. Preferably -C 1-6 Alkyl-R, more preferably -C 1-4 Alkyl-R, more preferably -C 1-3 Alkyl-R, more preferably -C 1-2 Alkyl-R, such as -CH2-CH(CH3)-R, -CH2-CH2-CH2-R, -CH2-CH2-R, -CH2-R, etc.

[0392] As used in this article, the term "hydroxyl" refers to -OH.

[0393] As used herein, the term "hydroxymethyl" refers to -CH2OH, and "hydroxyethyl" refers to -CH2CH2OH or -CH(OH)CH3.

[0394] As used herein, the term "cyanomethyl" refers to -CH2CN, and "cyanoethyl" refers to -CH2CH2CN or -CHCNCH3.

[0395] As used in this article, the term "amino" refers to -NH2.

[0396] As used in this article, the term "cyano" refers to -CN.

[0397] As used in this article, the term "nitro" refers to -NO2.

[0398] As used in this article, the term "benzyl" refers to -CH2-benzene.

[0399] As used in this article, the term "oxo" refers to =O.

[0400] As used in this article, the term "carboxyl group" refers to -C(O)OH.

[0401] As used herein, the term "carboxylic acid ester group" refers to -C(O)O (alkyl) or -C(O)O (cycloalkyl).

[0402] As used in this article, the term "acetyl" refers to -COCH3.

[0403] In this article, C 1-10 C can be preferred. 1-6 More preferably, C 1-4 More preferably, C 1-3 For example, C 1-10 Alkyl groups can preferably be C10-30 ... 1-6 Alkyl; more preferably C 1-4 Alkyl; more preferably C 1-3 Alkyl group. For example, C 1-10 Alkoxy groups can preferably be C10-3 ... 1-6 Alkyloxy group; more preferably C 1-4 Alkyloxy group; more preferably C 1-3 Alkyl group.

[0404] In this article, C 3-20 C can be preferred. 3-10 More preferably, C 3-8 More preferably, C 3-6 More preferably, C 3-5 For example, C 3-20 Cycloalkyl groups are preferably C16-26-3 ... 3-8 Cycloalkyl; more preferably C 3-6 Cycloalkyl; more preferably C 3-6 Cycloalkyl.

[0405] In one embodiment of the invention, in any group, the C 3-6 The cycloalkyl group is selected from: cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0406] In one embodiment of the present invention, in any one of the groups, the 3 to 6-membered heterocyclic alkyl group is selected from: azirron, ethylene oxide, azirronbutane, oxacyclobutane, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, piperidine, piperazine, morpholine, thiomorpholine, thiomorpholine-1,1-dioxide, and tetrahydropyran.

[0407] In one embodiment of the present invention, in any one of the groups, the 5- or 6-membered monocyclic heteroaryl group is selected from: thiophene, N-alkylcyclopyrrole, furan, thiazole, isothiazole, imidazole, oxazole, pyrrole, pyrazole, triazole, 1,2,3-triazole, 1,2,4-triazole, 1,2,5-triazole, 1,3,4-triazole, tetrazolium, isoxazole, oxadiazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, thiadiazole, pyridine, pyridazine, pyrimidine, pyrazine.

[0408] In one embodiment of the present invention, in any one of the groups, the 8 to 10 membered bicyclic heteroaryl group is selected from: benzoxazole, benzoisoxazole, benzoimidazole, benzothiazole, benzoisothiazole, benzotriazole, benzofuran, benzothiophene, indole, indazole, isoindole, quinoline, isoquinoline, quinazoline, quinoxaline, cyclophosphine, pyridinidine, and naphthidine.

[0409] As used herein, the term "substituted" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, which may include deuterium and hydrogen variants, provided that the valence state of the particular atom is normal and the substituted compound is stable. When the substituent is an oxo group (i.e., =O), it means that two hydrogen atoms are replaced. Oxosubstituted substituents do not occur on aromatic groups. The terms "optionally substituted" or "optionally substituted" mean that it may or may not be substituted, and unless otherwise specified, the type and number of substituents may be arbitrary on a chemically feasible basis.

[0410] When any variable (e.g., R) appears more than once in the composition or structure of a compound, its definition is independent in each case. Thus, for example, if a group is substituted by 0-2 Rs, the group can optionally be substituted by at most two Rs, and the Rs in each case have independent options. Furthermore, combinations of substituents and / or their variants are only permitted if such combinations produce a stable compound.

[0411] The compounds represented by formula (IA) or (IB) of this invention can be prepared using synthetic methods known in the art or in combination with methods known in the art. The solvents, temperatures, and other reaction conditions given in this invention are exemplary and can be varied according to methods well known in the art. The compounds of the examples described in this invention can be synthesized according to the methods described in the examples, depending on their specific structures, using appropriate starting materials, or can be synthesized using methods similar to those described in the examples. The starting materials used to synthesize the compounds of the examples of this invention can be prepared by known synthetic methods or similar methods described in the literature, or obtained from commercial sources. The compounds of the examples can be further resolved to obtain their stereoisomers by methods well known in the art, such as crystallization, chromatography, etc., where the resolution conditions are readily obtained by those skilled in the art through conventional means or limited experimentation.

[0412] As further explanation, the compounds of formula (IB-1′) and formula (IB-2′) of the present invention can be synthesized by the following method, wherein the solvent, temperature and other reaction conditions in each step can be the same or similar to those described in the following examples, or reaction conditions known in the art can be used.

[0413]

[0414] The compounds of formula (IB-1′) and formula (IB-2′) of the present invention can also be synthesized by the following methods, wherein the solvent, temperature and other reaction conditions in each step can be the same or similar to those described in the following examples, or reaction conditions known in the art can be used.

[0415]

[0416] In the preparation routes of compounds of formula (IB-1′) and formula (IB-2′), R in each formula lev Leaving groups well known in the art include, for example, trifluoromethanesulfonates; chlorine, bromine, iodine; sulfonate groups, such as methanesulfonates, toluenesulfonates, p-toluenesulfonates, etc.; acyloxy groups, such as acetoxy, trifluoroacetoxy, etc. In each formula, R... p Amino protecting groups well known in the art, such as formyl; acyl groups, such as alkanoyl groups (e.g., acetyl, trichloroacetyl, or trifluoroacetyl); alkoxycarbonyl groups, such as tert-butoxycarbonyl (Boc); arylmethoxycarbonyl groups, such as benzyloxycarbonyl (Cbz) and 9-fluorenemethoxycarbonyl (Fmoc); arylmethyl groups, such as benzyl (Bn), triphenylmethyl (Tr), 1,1-di-(4'-methoxyphenyl)methyl; silyl groups, such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS), etc. R1, R2, R3, R 21 R 22 R 12 R11 R 31 R 32 R m′ R0′, Ar′, E1′, and X1 are defined as before (e.g., the definitions of the corresponding groups in formula I or formula IA).

[0417] The compounds of formula (IB-1”) and formula (IB-2”) of the present invention can be synthesized by the following method, wherein the solvent, temperature and other reaction conditions in each step can be the same or similar to those described in the following examples, or reaction conditions known in the art can be used.

[0418]

[0419] In the preparation routes of compounds of formula (IB-1”) and formula (IB-2”), R in each formula p Amino protecting groups well known in the art, such as formyl; acyl groups, such as alkanoyl groups (e.g., acetyl, trichloroacetyl, or trifluoroacetyl); alkoxycarbonyl groups, such as tert-butoxycarbonyl (Boc); arylmethoxycarbonyl groups, such as benzyloxycarbonyl (Cbz) and 9-fluorenemethoxycarbonyl (Fmoc); arylmethyl groups, such as benzyl (Bn), triphenylmethyl (Tr), 1,1-di-(4′-methoxyphenyl)methyl; silyl groups, such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS), etc. R1, R2, R3, R 21 R 22 R 12 R 11 R 31 R 32 The definitions of R0', Ar', E1', and X1 are the same as before (e.g., the definitions of the corresponding groups in formula I or formula IA).

[0420] The compound of formula e can also be synthesized by the following methods, wherein the solvent, temperature and other reaction conditions in each step can be the same or similar to those described in the examples below, or reaction conditions known in the art can be used.

[0421]

[0422] In the preparation route of compound e, R lev Leaving groups well known in the art include, for example, trifluoromethanesulfonates; chlorine, bromine, iodine; sulfonate groups, such as methanesulfonates, toluenesulfonates, p-toluenesulfonates, etc.; acyloxy groups, such as acetoxy, trifluoroacetoxy, etc. R0', Ar', E1', X1 are defined as before (e.g., the same as the definitions of the corresponding groups in Formula I or Formula IA). Attached Figure Description

[0423] Figure 1This is the X-ray single-crystal diffraction molecular stereostructure diagram of compound Z25-2.

[0424] Figure 2 This is the X-ray single-crystal diffraction molecular stereostructure diagram of compound Z27-2. Detailed Implementation

[0425] The compounds of this invention can be prepared by various synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthetic methods, and equivalent substitutions well known to those skilled in the art. Preferred embodiments include, but are not limited to, the embodiments of this invention. The invention is described in detail below by way of examples, but this does not imply any adverse limitation on the invention. This document has described the invention in detail, and specific embodiments thereof have also been disclosed. It will be apparent to those skilled in the art that various changes and modifications can be made to the specific embodiments of this invention without departing from the spirit and scope of the invention. Where specific conditions are not specified in the examples, conventional conditions or conditions recommended by the manufacturer are followed. Reagents or instruments whose manufacturers are not specified are all commercially available conventional products.

[0426] The reagents used in the following examples are abbreviated as follows: THF: tetrahydrofuran; DMSO: dimethyl sulfoxide; PE: petroleum ether; EtOAc: ethyl acetate; DCM: dichloromethane; MeOH: methanol; ACN: acetonitrile; IPA: isopropylamine; DMA: dimethylamine; TFA: trifluoroacetic acid; NH4Cl: ammonium chloride; SPhos: 2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl; SPhos-Pd-G2: chloro(2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II); NaHMDS: sodium bis(trimethylsilyl)amino; LiHMDS: lithium bis(trimethylsilyl)amino.

[0427] The preparative HPLC used in the following examples can be performed under the following conditions: column type: Waters XBridge C18, 190*250mm, 5μm; mobile phase system: A: 0.1% ammonium bicarbonate aqueous solution; B: preparative grade acetonitrile; flow rate: 15ml / min; B% = 20%-100%; column temperature: room temperature.

[0428] If isomers are to be detected using analytical HPLC, the following conditions can be used: Column type: XBridge C18, 3.5μm 4.6*150mm; Mobile phase: A: purified water (0.05% TFA); B: preparative grade acetonitrile (0.05% TFA); Gradient: 5%-95% B; Run time: 15min; Flow rate: 1ml / min; Column temperature: 40℃.

[0429] Example 1: Preparation of compounds Z1, Z1-1 and Z1-2

[0430]

[0431] Step 1: 2-Isopropyl-4-methylpyridin-3-amine (582 mg, 3.88 mmol) was dissolved in THF (20 mL). The reaction mixture was cooled to 0 °C, and NaHMDS (5.8 mL, 11.60 mmol, 2 M in THF) was added dropwise. The reaction mixture was stirred for 15 minutes, and then a THF solution (6 mL) of 2,5-difluoro-6-(2-fluoro-6-methoxyphenyl)nicotinic acid (1.0 g, 3.53 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into 30 mL of saturated NH4Cl. The mixture was extracted three times with 40 mL of ethyl acetate. The organic phase was dried and concentrated. The crude product was purified by rapid silica gel column chromatography (0-5% MeOH / DCM) to give 5-fluoro-6-(2-fluoro-6-methoxyphenyl)-2-((2-isopropyl-4-methylpyridin-3-yl)amino)nicotinic acid (850 mg, Y: 58.2%), a yellow solid. ES-API:[M+H] + =414.1

[0432] Step 2: 5-Fluoro-6-(2-fluoro-6-methoxyphenyl)-2-((2-isopropyl-4-methylpyridin-3-yl)amino)nicotinic acid (700 mg, 1.69 mmol) was dissolved in 1,2-dichloroethane (15 mL), and SOCl2 (2.0 g, 16.90 mmol) was added. The reaction was stirred at 80 °C for 2 hours. The reaction was concentrated to give the product 5-fluoro-6-(2-fluoro-6-methoxyphenyl)-2-((2-isopropyl-4-methylpyridin-3-yl)amino)nicotinic acid chloride (721 mg, Y: 100%), which was used directly in the next step without purification.

[0433] Step 3: At 0°C, a 2 mL solution of ethyl nitroacetate (449 mg, 3.38 mmol) in THF was added dropwise to a 25 mL suspension of THF containing NaH (608 mg, 15.21 mmol). The reaction was stirred at 0°C for half an hour. Then, a 15 mL solution of 5-fluoro-6-(2-fluoro-6-methoxyphenyl)-2-((2-isopropyl-4-methylpyridin-3-yl)amino)nicotinic acid chloride (721 mg, 1.69 mmol) in THF was added dropwise. The ice bath was removed, and the reaction mixture was stirred overnight at 70°C. The reaction mixture was then poured into ice water, and the pH was adjusted to 3 with 3.0 M dilute hydrochloric acid. The mixture was extracted three times with ethyl acetate. The organic phase was dried and concentrated to give 1.05 g of crude 6-fluoro-7-(2-fluoro-6-methoxyphenyl)-4-hydroxy-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro-1,8-naphthidium-2(1H)-one, which was directly used in the next reaction. ES-API: [M+H] + =483.1

[0434] Step 4: 6-Fluoro-7-(2-fluoro-6-methoxyphenyl)-4-hydroxy-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro-1,8-naphthidin-2(1H)-one (1.05 g, 1.69 mmol) was dissolved in acetonitrile (25 mL), followed by the addition of POCl3 (1.30 g, 8.45 mmol) and N,N-diisopropylethylamine (1.74 g, 13.52 mmol). The reaction mixture was stirred at 80 °C for 1 hour. The reaction solution was concentrated and washed successively with ice water, water, and saturated brine using ethyl acetate. After drying and concentrating the organic phase, the crude product was purified by rapid silica gel column chromatography (EtOAc / PE: 0-50%) to give 4-chloro-6-fluoro-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro-1,8-naphthidium-2(1H)-one (185 mg, Y: 21.9%), a yellow solid. ES-API: [M+H] + =500.1

[0435] Step 5: 4-Chloro-6-fluoro-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro-1,8-naphthidium-2(1H)-one (175 mg, 0.35 mmol) was dissolved in DMF (6 mL), and (R)-3-(hydroxymethyl)piperazine-1-carboxylic acid tert-butyl ester (454 mg, 2.10 mmol) was added. The reaction mixture was stirred at 80 °C for 18 hours. The reaction solution was then poured into 30 mL of water. The mixture was extracted three times with 20 mL of ethyl acetate. The organic phase was washed three times with saturated brine, dried, and concentrated. The crude product was purified by rapid silica gel column chromatography (EtOAc / PE: 0-70%) to give (3R)-4-(6-fluoro-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro-2-oxo-1,2-dihydro-1,8-naphthidin-4-yl)-3-(hydroxymethyl)piperazine-1-carboxylic acid tert-butyl ester (85 mg, Y: 35.7%), a yellow solid. ES-API: [M+H] + =681.3.

[0436] Step 6: Dissolve (3R)-4-(6-fluoro-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro-2-oxo-1,2-dihydro-1,8-naphthidin-4-yl)-3-(hydroxymethyl)piperazine-1-carboxylic acid tert-butyl ester (73 mg, 0.11 mmol) in DMA (4 mL), add NaH (22 mg, 0.55 mmol), and stir the reaction mixture at 145 °C for 10 hours. Pour the cooled reaction mixture into 15 mL of water. Extract three times with 30 mL of ethyl acetate. The organic phase was washed three times with saturated brine, dried, and concentrated. The crude product was analyzed by thick-layer chromatography (thick-layer chromatography plate, dichloromethane / methanol = 20:1) to give the product (4aR)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-7-oxo-1,2,4a,5,7,8-hexahydropyrazine [1′,2′:4,5][1,4]oxo-2,3-c][1,8]naphthyl-3(4H)-carboxylic acid tert-butyl ester (35 mg, Y: 51.5%), a yellow solid. ES-API: [M+H] + =634.2

[0437] Step 7: Dissolve (4aR)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-7-oxo-1,2,4a,5,7,8-hexahydropyrazine[1',2′:4,5][1,4]oxo-2,3-c][1,8]naphthyl-3(4H)-carboxylic acid tert-butyl ester (35 mg, 0.055 mmol) in dichloromethane (2.5 mL), and add trifluoroacetic acid (0.5 mL). The mixture was stirred at room temperature for 0.5 hours, and the reaction solution was concentrated to obtain the product (4aR)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-1,2,3,4,4a,5-hexahydropyrazine[1',2':4,5][1,4]oxazine[2,3-c][1,8]naphthyl-7(8H)-one (40 mg, crude product), which was directly used in the next reaction. ES-API:[M+H] + =534.3.

[0438] Step 8: (4aR)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-1,2,3,4,4a,5-hexahydropyrazine[1′,2′:4,5][1,4]oxazine[2,3-c][1,8]naphthyl-7(8H)-one (40 mg, 0.055 mmol) was dissolved in dichloromethane (4 mL), and triethylamine (28 mg, 0.28 mmol) was added. The reaction mixture was cooled to 0 °C, and a dichloromethane solution of acrylic anhydride (6 mg, 0.05 mmol) (0.5 mL) was added dropwise to the reaction mixture. The reaction mixture was stirred at 0 °C for 15 minutes. 10 mL of saturated NaHCO3 aqueous solution was added to the reaction mixture, and the mixture was extracted three times with 10 mL of dichloromethane. After drying and concentration of the organic phase, the crude product was analyzed using a thick-layer chromatography plate (dichloromethane / methanol = 10:1) to yield the product (4aR)-3-acryloyl-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-1,2,3,4,4a,5-hexahydropyrazine[1′,2':4,5][1,4]oxazine[2,3-c][1,8]naphthidium-7(8H)-one (17 mg, Y: 52.4%), a pale yellow solid. ES-API: [M+H] + =588.2.

[0439] Step 9: (4aR)-3-acryloyl-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-1,2,3,4,4a,5-hexahydropyrazine[1',2′:4,5][1,4]oxazine[2,3-c][1,8]naphthyl-7(8H)-one (15 mg, 0.025 mmol) was dissolved in dichloromethane (1.5 mL). The reaction mixture was cooled to 0 °C, and a 17% boron tribromide solution in dichloromethane (1 mL) was added dropwise. The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into 20 mL of saturated NaHCO3 aqueous solution and extracted three times with 20 mL of dichloromethane. After drying and concentrating the organic phase, the crude product was purified by preparative HPLC to obtain the product (4aR)-3-acryloyl-11-fluoro-10-(2-fluoro-6-hydroxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-1,2,3,4,4a,5-hexahydropyrazine[1′,2′:4,5][1,4]oxazine[2,3-c][1,8]naphthidium-7(8H)-one (Z1, 10 mg, Y: 68.3%), a white solid. 1 HNMR(500MHz,DMSO-d6)δ9.96(s,1H),8.35(d,J=4.8Hz,1H),7.19-7.14(m,2H),6.8 7-6.75(m,1H),6.64(d,J=8.5Hz,1H),6.59(t,J=8.5Hz,1H),6.12(d,J=15.9Hz,1H) ,5.71-5.67(m,1H),4.39-3.95(m,4H),3.79-3.30(m,4H),3.06-2.98(m,1H),2.56- 2.29(m,1H),1.80-1.73(m,3H),0.99-0.95(m,3H),0.85-0.80(m,3H).ES-API:[M+H] + =574.2.

[0440] Step 10: Compound Z1 was separated by preparative chiral HPLC (column type: Chiralpak IC: 10 μm, 20*250 mm, mobile phase: acetonitrile:isopropanol:ammoniamethanol = 70:30:0.2, flow rate: 15 ml / min, column temperature: room temperature) to obtain: a trans-restricted isomer compound, the structure of which is arbitrarily designated as Z1-1 (75 mg, peak 1, retention time 3.94 min, Y: 15.4%), a pale yellow solid. 1H NMR (400MHz, DMSO-d6) δ10.04(s,1H),8.42(d,J=4.9Hz,1H),8.22(d,J=8.3Hz,1H), 7.28-7.20(m,2H),6.96-6.81(m,1H),6.75–6.58(m,2H),6.18(d,J=17.1Hz,1H),5.8 2–5.69(m,1H),4.49–4.00(m,4H),3.90–3.43(m,4H),3.08(t,J=11.0Hz,1H),2.64-2 .55(m,1H),1.80(s,3H),1.05(d,J=6.7Hz,3H),0.91(d,J=6.7Hz,3H).ES-API:[M+H] + =574.2. And another transisomer compound, the structure of which is arbitrarily designated as Z1-2 (115 mg, peak 2, retention time 5.04 min, Y: 23.6%), a pale yellow solid. 1 H NMR (400MHz, DMSO-d6) δ10.05(s,1H),8.42(d,J=4.8Hz,1H),8.22(d,J=6.9Hz,1H),7. 28-7.20(m,2H),6.96-6.81(m,1H),6.74–6.59(m,2H),6.19(d,J=16.7Hz,1H),5.83–5 .68(m,1H),4.49–4.00(m,4H),3.94–3.44(m,4H),3.08(t,J=11.0Hz,1H),2.49–2.41( m,1H),1.87(s,3H),1.03(dd,J=6.3,3.7Hz,3H),0.88(d,J=6.6Hz,3H).ES-API:[M+H] + =574.2. The isomers were detected by analytical chiral HPLC (column type: Chiralpak IC: 5 μm, 4.6*250 mm, mobile phase: acetonitrile:isopropanol:ammoniamethanol = 70:30:0.2, flow rate: 1 ml / min, column temperature = 30 °C).

[0441] Example 2: Preparation of compound Z2

[0442]

[0443] Step 1: At room temperature, add 5-(methoxymethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (2.9 g, 15.62 mmol) and isopropanol (40 mL) to a 100 mL round-bottom flask. Add 2-chloropyridin-3-amine (2.0 g, 15.62 mmol) in portions. Reflux and stir for 15 minutes. Cool the reaction mixture to room temperature, filter the precipitated solid, wash the filter cake with a small amount of isopropanol, and dry under vacuum to obtain the product 5-((2-chloropyridin-3-yl)amino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (3.90 g, Y: 58.2%), a white solid. ES-API: [M+H] + =283.1

[0444] Step 2: Add 200 mL of diphenyl ether to a 500 mL round-bottom flask, heat to 220 °C, and add 3.9 g (13.83 mmol) of 5-((2-chloropyridin-3-yl)amino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione in portions. Stir the reaction mixture at 220 °C for 20 minutes. Cool the reaction mixture to room temperature, pour it into petroleum ether, filter the precipitated solid, wash the filter cake with petroleum ether, and dry under vacuum to give the product 8-chloro-1,7-naphthyl-4-ol (1.5 g, Y: 60%), a light brown solid. ES-API: [M+H] + =181.0

[0445] Step 3: Add 8-chloro-1,7-naphthidine-4-ol (500 mg, 2.78 mmol), sodium acetate (300 mg, 2.78 mmol), anhydrous ethanol (25 mL), and 5% Pd / C (250 mg) to a 50 mL round-bottom flask. Stir the reaction mixture at room temperature for 3 days under a hydrogen balloon. Filter the reaction solution with diatomaceous earth, concentrate the filtrate, and purify the crude product using a rapid silica gel column chromatography (dichloromethane / methanol: 0-10%) to obtain the product 1,7-naphthidine-4-ol (200 mg, Y: 49.3%), a yellow solid. ES-API: [M+H] + =147.1

[0446] Step 4: Dissolve 1,7-naphthidine-4-ol (550 mg, 3.77 mmol) in concentrated sulfuric acid (4.5 mL), cool to 0°C, and slowly add concentrated nitric acid (1.0 mL, 15.08 mmol). Stir the reaction mixture at 100°C for 1 hour. Pour the cooled reaction solution into ice water, adjust the pH to 6-7 with concentrated ammonia, filter the precipitated solid, and dry under vacuum to give 3-nitro-1,7-naphthidine-4-ol (530 mg, Y: 73.7%), a yellow solid. ES-API: [M+H] + =192.1

[0447] Step 5: Add 3-nitro-1,7-naphthidine-4-ol (480 mg, 2.51 mmol) and phosphorus oxychloride (4.68 mL, 50.20 mmol) to a 20 mL round-bottom flask. Cool to -15 °C, then slowly add triethylamine (1.8 mL, 12.55 mmol). Stir the reaction mixture at room temperature for 1 hour. Pour the reaction mixture into ice water, adjust the pH to 8 with cold saturated sodium bicarbonate solution, and extract three times with dichloromethane. Dry and concentrate the organic phase to give the product 4-chloro-3-nitro-1,7-naphthidine (450 mg, Y: 85.7%), a brown solid. ES-API: [M+H] + =210.1.

[0448] Step 6: 4-Chloro-3-nitro-1,7-naphthidine (450 mg, 2.15 mmol) was dissolved in 1,4-dioxane (15 mL), and (R)-3-(hydroxymethyl)piperazine-1-carboxylic acid tert-butyl ester (1.02 g, 4.73 mmol) and N,N-diisopropylethylamine (832 mg, 6.45 mmol) were added sequentially. The reaction was stirred at 80 °C for 3 hours. The reaction solution was concentrated, and the crude product was purified by rapid silica gel column chromatography (EtOAc / PE: 50-100%) to give (R)-3-(hydroxymethyl)-4-(3-nitro-1,7-naphthidine-4-yl)piperazine-1-carboxylic acid tert-butyl ester (330 mg, Y: 39.4%), a yellow solid. ES-API: [M+H] + =390.2.

[0449] Step 7: Add (R)-3-(hydroxymethyl)-4-(3-nitro-1,7-naphthid-4-yl)piperazine-1-carboxylic acid tert-butyl ester (310 mg, 0.80 mmol), DMF (18 mL), and NaH (96 mg, 2.40 mmol) sequentially to a 50 mL sealed tube. Stir the reaction mixture at 95 °C for 3 days. Pour the cooled reaction solution into water and extract twice with ethyl acetate. Wash the organic phase three times with saturated brine, dry and concentrate. Spectroscopy the crude product using a thick-layer chromatography plate (dichloromethane / methanol = 15:1) to obtain the product (R)-8a,9,11,12-tetrahydropyrazine[1′,2′:4,5][1,4]oxazine[2,3-c][1,7]naphthid-10(8H)-carboxylic acid tert-butyl ester (175 mg, Y: 64%), a yellow solid. ES-API: [M+H] + =343.3

[0450] Step 8: (R)-8a,9,11,12-tetrahydropyrazine[1′,2′:4,5][1,4]oxazine[2,3-c][1,7]naphthyl-10(8H)-carboxylic acid tert-butyl ester (100 mg, 0.29 mmol) was dissolved in acetic acid (4 mL), and sodium cyanoborohydride (73 mg, 1.16 mmol) was added. The reaction mixture was stirred overnight at room temperature. The reaction solution was poured into ice water, the pH was adjusted to 8 with saturated sodium bicarbonate solution, and the mixture was extracted twice with dichloromethane. The organic phase was washed with saturated brine, dried, and concentrated. The crude product was analyzed by thick-layer chromatography (thick-layer chromatography plate, dichloromethane / methanol / ammonia = 100:8:1) to give product (R)-1,2,3,4,8a,9,11,12-octahydropyrazine [1′,2′:4,5][1,4]oxazine [2,3-c][1,7]naphthyl-10(8H)-carboxylic acid tert-butyl ester (50 mg, Y: 49.4%), a pale yellow solid. ES-API: [M+H] + =390.2.

[0451] Step 9: Add (R)-1,2,3,4,8a,9,11,12-octahydropyrazine[1',2′:4,5][1,4]oxazine[2,3-c][1,7]naphthyl-10(8H)-carboxylic acid tert-butyl ester (50 mg, 0.14 mmol), 4-bromo-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (83 mg, 0.28 mmol), cesium carbonate (136 mg, 0.42 mmol), Pd2(dba)3 (51 mg, 0.056 mmol), and Ruphos (26 mg, 0.056 mmol) to a 5 mL microwave tube. 1 mmol) and toluene (6 mL), purged with nitrogen, reacted in a microwave reactor at 120 °C with stirring for 1 hour, cooled to room temperature, filtered, dried and concentrated, the crude product was analyzed by thick-layer chromatography (dichloromethane / methanol / ammonia = 100:5:1) to give (8aR)-3-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-1,2,3,4,8a,9,11,12-octahydropyrazine[1′,2':4,5][1,4]oxazine[2,3-c][1,7]naphthyl-10(8H)-carboxylic acid tert-butyl ester (60 mg, Y: 74.1%). ES-API: [M+H] + =561.3

[0452] Step 10: Dissolve (8aR)-3-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-1,2,3,4,8a,9,11,12-octahydropyrazine[1′,2′:4,5][1,4]oxazine[2,3-c][1,7]naphthyl-10(8H)-carboxylic acid tert-butyl ester (60 mg, 0.11 mmol) in dichloromethane (3 mL), and add trifluoroacetic acid (0.8 mL). The reaction mixture was stirred at room temperature for 1 hour, and then concentrated to give the product (R)-3-(5-methyl-1H-indazol-4-yl)-1,2,3,4,8,8a,9,10,11,12-decahydropyrazine[1′,2′:4,5][1,4]oxazine[2,3-c][1,7]naphthidine (60 mg, crude yield), which could be used directly in the next reaction without purification. ES-API:[M+H] + =377.1.

[0453] Step 11: (R)-3-(5-methyl-1H-indazol-4-yl)-1,2,3,4,8,8a,9,10,11,12-decahydropyrazine[1′,2′:4,5][1,4]oxazine[2,3-c][1,7]naphthylidine (60 mg, 0.11 mmol) and N,N-diisopropylethylamine (71 mg, 0.55 mmol) were dissolved in dichloromethane (5 mL). The reaction mixture was cooled to 0 °C, and a dichloromethane solution (0.5 mL) of acrylic anhydride (13 mg, 0.10 mmol) was added dropwise to the reaction mixture. The reaction mixture was stirred at 0 °C for 10 minutes. 10 mL of saturated NaHCO3 aqueous solution was added to the reaction mixture, and the mixture was extracted three times with 10 mL of dichloromethane. After drying and concentrating the organic phase, the crude product was purified by preparative HPLC to obtain the product (R)-1-(3-(5-methyl-1H-indazol-4-yl)-1,2,3,4,8a,9,11,12-octylhydropyrazine[1′,2′:4,5][1,4]oxazine[2,3-c][1,7]naphthid-10(8H)-yl)propyl-2-en-1-one (Z2, 12 mg, Y: 26.0%), a white solid. 1 HNMR(500MHz,DMSO-d6)δ12.91(s,1H),8.04(s,1H),7.86(s,1H),7.21–7.07(m,2H),6.89–6.64(m,1H),6.09(d,J=16.6Hz,1H),5.67(m,1H),4. 21-4.11(m,3H),3.96(t,J=10.0Hz,1H),3.86-3.53(m,4H),3.45-3.30( m,2H),3.15-3.08(m,1H),2.86-2.75(m,2H),2.28(s,3H).ES-API:[M+H] +=431.2.

[0454] Example 3 Preparation of compounds Z3a and Z3

[0455]

[0456] Step 1: 4-Chloro-6-fluoro-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro-1,8-naphthidium-2(1H)-one (700 mg, 1.40 mmol) was dissolved in DMF (10 mL), and (2R,5R)-5-(hydroxymethyl)-2-methylpiperazine-1-carboxylic acid tert-butyl ester (1.61 g, 7.0 mmol) was added. The reaction mixture was stirred at 80 °C for 1 hour. The reaction solution was then poured into 30 mL of water. The mixture was extracted three times with 20 mL of ethyl acetate. The organic phase was washed three times with saturated brine, dried, and concentrated. The crude product was purified by rapid silica gel column chromatography (EtOAc / PE: 0-70%) to give (2R,5R)-4-(6-fluoro-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro-2-oxo-1,2-dihydro-1,8-naphthidin-4-yl)-5-(hydroxymethyl)-2-methylpiperazine-1-carboxylic acid tert-butyl ester (325 mg, Y: 33.4%), a yellow solid. ES-API: [M+H] + =695.2.

[0457] Step 2: (2R,5R)-4-(6-fluoro-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro-2-oxo-1,2-dihydro-1,8-naphthidin-4-yl)-5-(hydroxymethyl)-2-methylpiperazine-1-carboxylic acid tert-butyl ester (300 mg, 0.44 mmol) was dissolved in DMA (20 mL), and NaH (52 mg, 1.32 mmol) was added. The reaction mixture was stirred at 125 °C for 20 hours. The cooled reaction solution was poured into 15 mL of water. The mixture was extracted three times with 30 mL of ethyl acetate. The organic phase was washed eight times with saturated brine, dried, and concentrated. The crude product was purified by rapid silica gel column chromatography (EtOAc / PE: 0-100%) to give (2R,4aR)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-2-methyl-7-oxo-1,2,4a,5,7,8-hexahydropyrazine[1',2':4,5][1,4]oxazine[2,3-c][1,8]naphthyl-3(4H)-carboxylic acid tert-butyl ester (60 mg, Y: 21.4%), a yellow solid. ES-API: [M+H]+ = 648.3.

[0458] Step 3: Dissolve (2R,4aR)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-2-methyl-7-oxo-1,2,4a,5,7,8-hexahydropyrazine[1',2':4,5][1,4]oxazine[2,3-c][1,8]naphthyl-3(4H)-carboxylic acid tert-butyl ester (60 mg, 0.093 mmol) in dichloromethane (3 mL), and add trifluoroacetic acid (0.7 mL). The reaction mixture was stirred at room temperature for 1 hour, and then concentrated to obtain the product (2R,4aR)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-2-methyl-1,2,3,4,4a,5-hexahydropyrazine[1',2':4,5][1,4]oxazine[2,3-c][1,8]naphthyl-7(8H)-one (61 mg, crude product), which was directly used in the next step of the reaction. ES-API:[M+H] + =548.2.

[0459] Step 4: (2R,4aR)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-2-methyl-1,2,3,4,4a,5-hexahydropyrazine[1',2':4,5][1,4]oxazine[2,3-c][1,8]naphthyl-7(8H)-one (61 mg, 0.093 mmol) was dissolved in dichloromethane (5 mL), and triethylamine (47 mg, 0.46 mmol) was added. The reaction mixture was cooled to 0 °C, and a dichloromethane solution of acrylic anhydride (17 mg, 0.14 mmol) was added dropwise to the reaction mixture (1 mL). The reaction mixture was stirred at 0 °C for 15 minutes. 10 mL of saturated NaHCO3 aqueous solution was added to the reaction mixture, and the mixture was extracted three times with 10 mL of dichloromethane. The organic phase was dried and concentrated. The crude product was analyzed using a thick-layer chromatography plate (dichloromethane / methanol = 10:1) to give the product ((2R,4aR)-3-acryloyl-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-2-methyl-1,2,3,4,4a,5-hexahydropyrazine[1',2':4,5][1,4]oxypyrazine[2,3-c][1,8]naphthidium-7(8H)-one (Z3a, 32 mg, Y: 57.4%), a white solid. ES-API: [M+H] + =602.2. 1H NMR (500MHz, DMSO-d6) δ8.42(d,J=4.1Hz,1H),7.87(d,J=8.8Hz,1H),7.43(dd,J=15. 4,8.3Hz,1H),7.21(d,J=4.8Hz,1H),6.99–6.78(m,3H),6.17(d,J=17.4Hz,1H),5.75( d,J=10.5Hz,1H),4.80-4.15(m,4H),3.94–3.35(m,6H),3.13-2.97(m,1H),2.62-2.4 0(m,1H),1.90-1.73(m,3H),1.66-1.48(m,3H),1.08–0.95(m,3H),0.91–0.77(m,3H).

[0460] Step 5: (6aR,9R)-8-acryloyl-3-fluoro-2-(2-fluoro-6-methoxyphenyl)-13-(2-isopropyl-4-methylpyridin-3-yl)-9-methyl-6,6a,7,8,9,10-hexahydropyrazine[1',2':4,5][1,4]oxypyrazine[3,2-c][1,8]naphthyl-12(13H)-one (32 mg, 0.053 mmol) was dissolved in dichloromethane (1.5 mL). The reaction mixture was cooled to 0 °C, and a 17% boron tribromide solution in dichloromethane (1 mL) was added dropwise. The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into 20 mL of saturated NaHCO3 aqueous solution and extracted three times with 20 mL of dichloromethane. The organic phase was dried and concentrated. The crude product was purified by preparative HPLC to obtain the product (6aR,9R)-8-acryloyl-3-fluoro-2-(2-fluoro-6-hydroxyphenyl)-13-(2-isopropyl-4-methylpyridin-3-yl)-9-methyl-6,6a,7,8,9,10-hexahydropyrazine[1',2':4,5][1,4]oxypyrazine[3,2-c][1,8]naphthidium-12(13H)-one (Z3, 18 mg, Y: 57.6%), a white solid. ES-API: [M+H] + =588.3.

[0461] Example 6 Preparation of compound Z6

[0462]

[0463] Step 1: 1.8 g (3.48 mmol) of 4,6-dichloro-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro-1,8-naphthidium-2(1H)-one was dissolved in DMF (15 mL), and 3 g (13.92 mmol) of (R)-3-(hydroxymethyl)piperazine-1-carboxylic acid tert-butyl ester was added. The reaction mixture was stirred at 80 °C for 2 hours. The reaction mixture was then poured into 30 mL of water. The mixture was extracted three times with 20 mL of ethyl acetate. The organic phase was washed three times with saturated brine, dried, and concentrated. The crude product was purified by rapid silica gel column chromatography (EtOAc / PE: 0-70%) to give (3R)-4-(6-chloro-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro-2-oxo-1,2-dihydro-1,8-naphthidin-4-yl)-3-(hydroxymethyl)piperazine-1-carboxylic acid tert-butyl ester (1.3 g, 54%), a yellow solid. ES-API: [M+H] + =697.2.

[0464] Step 2: (3R)-4-(6-chloro-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro-2-oxo-1,2-dihydro-1,8-naphthidin-4-yl)-3-(hydroxymethyl)piperazine-1-carboxylic acid tert-butyl ester (1.3 g, 1.86 mmol) was dissolved in DMA (10 mL), and LHMDS (5.6 mmol, 5.6 mmol, 1 M tetrahydrofuran solution) was added. The reaction mixture was stirred at 140 °C for 20 hours. The cooled reaction mixture was poured into 15 mL of water. The mixture was extracted three times with 30 mL of ethyl acetate. The organic phase was washed three times with saturated brine, dried, and concentrated. The crude product was purified by rapid silica gel column chromatography (methanol / dichloromethane: 0-10%) to give (4aR)-11-chloro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-7-oxo-1,2,4a,5,7,8-hexahydropyrazino[1',2′:4,5][1,4]oxazino[2,3-c][1,8]naphthyl-3(4H)-carboxylic acid tert-butyl ester (0.24 g, 20%), a yellow solid. ES-API: [M+H] + =650.2.

[0465] Step 3: Dissolve (4aR)-11-chloro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-7-oxo-1,2,4a,5,7,8-hexahydropyrazino[1′,2′:4,5][1,4]oxazino[2,3-c][1,8]naphthyl-3(4H)-carboxylic acid tert-butyl ester (240 mg, 0.37 mmol) in dichloromethane (2 mL), and add trifluoroacetic acid (2 mL). The mixture was stirred at room temperature for 0.5 hours, and the reaction solution was concentrated to obtain the product (4aR)-11-chloro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-1,2,3,4,4a,5-hexahydropyrazino[1',2':4,5][1,4]oxazino[2,3-c][1,8]naphthidium-7(8H)-one (203 mg, crude product), which was directly used in the next reaction. ES-API:[M+H] + =550.1.

[0466] Step 4: (4aR)-11-chloro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-1,2,3,4,4a,5-hexahydropyrazino[1',2':4,5][1,4]oxazino[2,3-c][1,8]naphthyl-7(8H)-one (203 mg, 0.37 mmol) was dissolved in dichloromethane (4 mL), and triethylamine (187 mg, 1.85 mmol) was added. The reaction mixture was cooled to 0 °C, and a dichloromethane solution of acrylic anhydride (37 mg, 0.30 mmol) (0.5 mL) was added dropwise to the reaction mixture. The reaction mixture was stirred at 0 °C for 10 minutes. 10 mL of saturated NaHCO3 aqueous solution was added to the reaction mixture, and the mixture was extracted three times with 10 mL of dichloromethane. The organic phase was dried and concentrated. The crude product was analyzed using a thick-layer chromatography plate (dichloromethane / methanol = 10:1) to give the product (4aR)-3-acryloyl-11-chloro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-1,2,3,4,4a,5-hexahydropyrazino[1',2':4,5][1,4]oxazino[2,3-c][1,8]naphthidium-7(8H)-one (223 mg, crude product), a pale yellow solid. ES-API: [M+H] + =604.2.

[0467] Step 5: (4aR)-3-acryloyl-11-chloro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-1,2,3,4,4a,5-hexahydropyrazino[1',2':4,5][1,4]oxazino[2,3-c][1,8]naphthidium-7(8H)-one (223 mg, 0.37 mmol) was dissolved in dichloromethane (1.5 mL). The reaction mixture was cooled to 0 °C, and a 17% boron tribromide solution in dichloromethane (3 mL) was added dropwise. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into 20 mL of saturated NaHCO3 aqueous solution and extracted three times with 20 mL of dichloromethane. After drying and concentrating the organic phase, the crude product was purified by preparative HPLC to obtain the product (4aR)-3-acryloyl-11-chloro-10-(2-fluoro-6-hydroxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-1,2,3,4,4a,5-hexahydropyrazino[1',2':4,5][1,4]oxazino[2,3-c][1,8]naphthidium-7(8H)-one (Z6, 26.28 mg, 11%), a white solid. 1 H NMR(400MHz,DMSO-d6)δ8.42-8.36(m,2H),7.22-7.18(m,2H),6.68-6.62(m,3H),6.22-6.17(m,1H),5.78-5.77(m,1H),4.46 -3.55(m,8H),3.12-3.10(m,1H),2.52-2.51(m,1H),1.88-1.80(m,3H),1.06-1.04(m,3H),0.89-0.86(m,3H).ES-API:[M+H] + =590.2.

[0468] Example 9 Preparation of compounds Z9, Z9-1 and Z9-2

[0469]

[0470] Step 1: 4-Chloro-6-fluoro-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro-1,8-naphthidium-2(1H)-one (500 mg, 1.00 mmol) was dissolved in N,N-dimethylacetamide (6 mL), and (R)-1-(tert-butyl)3-methylpiperazine-1,3-dicarboxylic acid ester (732 mg, 3.00 mmol) and N,N-diisopropylethylamine (387 mg, 3.00 mmol) were added sequentially. The reaction was stirred at 120 °C for 2 hours. 100 mL of ethyl acetate was added to the reaction solution, and the mixture was washed four times with 30 mL of dilute brine, then washed again with 30 mL of saturated brine. The solution was dried and concentrated. The crude product was purified by rapid silica gel column chromatography (EtOAc / PE: 0-70%) to give (3R)-1-(tert-butyl)-3-methyl-4-(6-fluoro-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro-2-oxo-1,2-dihydro-1,8-naphthidin-4-yl)piperazine-1,3-dicarboxylic acid ester (500 mg, Y: 70.6%), a yellow solid. ES-API: [M+H] + =709.2.

[0471] Step 2: (3R)-1-(tert-butyl)-3-methyl-4-(6-fluoro-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro-2-oxo-1,2-dihydro-1,8-naphthidin-4-yl)piperazine-1,3-dicarboxylic acid ester (500 mg, 0.71 mmol) was dissolved in acetic acid (8 mL), and iron powder (138 mg, 2.47 mmol) was added. The reaction was stirred at 80 °C for 30 minutes. The reaction solution was concentrated, and 50 mL of ethyl acetate and 30 mL of saturated sodium bicarbonate were added sequentially. The suspension was filtered through diatomaceous earth, and the filter cake was washed with ethyl acetate. The organic phase was separated and washed sequentially with 30 mL of saturated sodium bicarbonate aqueous solution and 30 mL of saturated brine. After drying and concentration, the product (4aR)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-5,7-dioxo-1,2,4,4a,5,6,7,8-octahydro-3H-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8]naphthyl-3-carboxylic acid tert-butyl ester (450 mg, Y: 98.6%) was obtained as a pale yellow solid. ES-API: [M+H] + =647.2.

[0472] Step 3: Add (4aR)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-5,7-dioxo-1,2,4,4a,5,6,7,8-octahydro-3H-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8]naphthyl-3-carboxylic acid tert-butyl ester (450 mg, 0.70 mmol), 12 mL acetone, anhydrous potassium carbonate (290 mg, 2.10 mmol), and iodomethane (596 mg, 4.20 mmol) sequentially to a 15 mL sealed tube. Seal the tube and stir the reaction at 50 °C for 20 hours. The reaction solution was concentrated, and 60 mL of ethyl acetate was added. The mixture was washed successively with 30 mL of water and 30 mL of saturated brine. After drying and concentration, the crude product was purified by rapid silica gel column chromatography (EtOAc / PE: 0-70%) to give (4aR)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-6-methyl-5,7-dioxy-1,2,4,4a,5,6,7,8-octahydro-3H-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8]naphthyl-3-carboxylic acid tert-butyl ester (390 mg, Y: 84.8%), an orange solid. ES-API: [M+H] + =661.3.

[0473] Step 4: Dissolve (4aR)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-6-methyl-5,7-dioxy-1,2,4,4a,5,6,7,8-octahydro-3H-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8]naphthyl-3-carboxylic acid tert-butyl ester (940 mg, 1.42 mmol) in dichloromethane (6 mL), and add trifluoroacetic acid (2 mL). The reaction mixture was stirred at room temperature for 2 hours, and then concentrated to obtain the product (4aR)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-6-methyl-2,3,4,4a,6,8-hexahydro-1H-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8]naphthidine-5,7-dione (1.1 g, crude product), which was directly used in the next reaction. ES-API:[M+H] + =561.3.

[0474] Step 5: (4aR)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-6-methyl-2,3,4,4a,6,8-hexahydro-1H-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8]naphthylidine-5,7-dione (1.1 g, crude) was dissolved in dichloromethane (20 mL), and N,N-diisopropylethylamine (916 mg, 7.10 mmol) was added. The reaction was cooled to 0 °C, and acryloyl chloride (256 mg, 2.84 mmol) was added to the reaction solution. The reaction was stirred at 0 °C for 15 minutes. Add 30 mL of dichloromethane to the reaction solution, wash successively with 15 mL of water, 15 mL of saturated NaHCO3 aqueous solution, and 15 mL of saturated brine, dry and concentrate. After drying and concentration, the crude product is purified by rapid silica gel column chromatography (EtOAc / PE: 0-100%) to obtain the product ((4aR)-3-acryloyl-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-6-methyl-2,3,4,4a,6,8-hexahydro-1H-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8]naphthidine-5,7-dione (780 mg, Y: 88.3%), a pale yellow solid. ES-API: [M+H] + =615.3.

[0475] Step 6: (4aR)-3-acryloyl-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-6-methyl-2,3,4,4a,6,8-hexahydro-1H-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8]naphthidine-5,7-dione (390 mg, 0.64 mmol) was dissolved in dichloromethane (9 mL). The reaction mixture was cooled to 0 °C, and a 17% boron tribromide solution in dichloromethane (7 mL) was added dropwise. The reaction mixture was stirred at room temperature for 6 hours. The reaction mixture was poured into 60 mL of saturated NaHCO3 aqueous solution and extracted twice with 80 mL of dichloromethane. The organic phase was washed successively with 50 mL of saturated NaHCO3 aqueous solution and 80 mL of saturated brine, dried, and concentrated to give the product (4aR)-3-acryloyl-11-fluoro-10-(2-fluoro-6-hydroxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-6-methyl-2,3,4,4a,6,8-hexahydro-1H-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8,8]naphthidine-5,7-dione (Z9, 375 mg, Y: 98.4%), a pale yellow solid. ES-API: [M+H] + =601.2.

[0476] Step 7: (4aR)-3-acryloyl-11-fluoro-10-(2-fluoro-6-hydroxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-6-methyl-2,3,4,4a,6,8-hexahydro-1H-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8,8]naphthidine-5,7-dione (750 mg, 1.25 mmol) was purified by preparative HPLC and then resolved by preparative chiral HPLC (column type: IB:10 μm, 30*250 mm, mobile phase: hexane:EtOH=65:35, flow rate: 25 ml / min, column temperature) to obtain: a trans-isomer compound, arbitrarily designated as Z9-1 (250 mg, peak 1, retention time 6.463 min, Y: 33.3%), a pale yellow solid. 1 HNMR(500MHz,DMSO-d6)δ10.11(d,J=1.3Hz,1H),8.46-8.34(m,2H),7.30–7.19(m,2H),7.10–6.7 9(m,1H),6.74–6.62(m,2H),6.15(d,J=16.9Hz,1H),5.75(d,J=12.0Hz,1H),4.73(d,J=13.3Hz,1H ),4.45(d,J=12.7Hz,1H),4.10–3.97(m,1H),3.63-3.47(m,2H),3.39-3.08(m,4H),2.83-2.59(m ,1H),2.48-2.39(m,1H),1.99(s,3H),1.02(d,J=6.7Hz,3H),0.85(d,J=6.7Hz,3H).ES-API:[M+H] + =601.2. And another transisomer compound, the structure of which is arbitrarily designated as Z9-2 (350 mg, peak 2, retention time 8.252 min, Y: 46.7%), a pale yellow solid. 1H NMR (500MHz, DMSO-d6) δ10.14(s,1H),8.44(d,J=4.9Hz,1H),8.38(d,J=9.0Hz,1H),7.29–7.20( m,2H),7.10–6.79(m,1H),6.76–6.59(m,2H),6.15(d,J=16.9Hz,1H),5.75(d,J=11.1Hz,1H),4.7 3(d,J=14.0Hz,1H),4.45(d,J=12.4Hz,1H),4.02–3.89(m,1H),3.62–3.50(m,2H),3.33–3.09(m, 4H),2.88–2.61(m,2H),1.79(s,3H),1.10(d,J=6.7Hz,3H),0.98(d,J=6.7Hz,3H).ES-API:[M+H] + =601.2. The isomers were detected by analytical chiral HPLC (column type: IB: 5 μm, 4.6*250 mm, mobile phase: hexane: EtOH = 65:35, flow rate: 1 ml / min, column temperature = 30 °C).

[0477] Example 10: Preparation of compounds Z10, Z10-1, and Z10-2

[0478]

[0479] Step 1: Add (2R,4aR)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-2-methyl-5,7-dioxo-1,2,4,4a,5,6,7,8-octyl-3H-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8]naphthyl-3-carboxylic acid tert-butyl ester (800 mg, 1.21 mmol), 20 mL acetone, anhydrous potassium carbonate (500 mg, 3.63 mmol), and iodomethane (1.03 g, 7.26 mmol) to a 50 mL sealed tube. Seal the tube and stir the reaction at 50 °C for 18 hours. The reaction solution was concentrated, and 60 mL of ethyl acetate was added. The mixture was washed successively with 20 mL of water and 30 mL of saturated brine. After drying and concentration, the crude product was purified by rapid silica gel column chromatography (EtOAc / PE: 0-70%) to give (2R,4aR)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-2,6-dimethyl-5,7-dioxo-1,2,4,4a,5,6,7,8-octyl-3H-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8]naphthyl-3-carboxylic acid tert-butyl ester (790 mg, Y: 96.7%), an orange solid. ES-API: [M+H]+ =675.3.

[0480] Step 2: Dissolve (2R,4aR)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-2,6-dimethyl-5,7-dioxo-1,2,4,4a,5,6,7,8-octyl-3H-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8]naphthyl-3-carboxylic acid tert-butyl ester (790 mg, 1.42 mmol) in dichloromethane (6 mL), and add trifluoroacetic acid (2 mL). The reaction mixture was stirred at room temperature for 2 hours, and then concentrated to obtain the product (2R,4aR)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-2,6-dimethyl-2,3,4,4a,6,8-hexahydro-1H-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8]naphthidine-5,7-dione (810 mg, crude product), which was directly used in the next step of the reaction. ES-API:[M+H] + =575.2.

[0481] Step 3: (2R,4aR)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-2,6-dimethyl-2,3,4,4a,6,8-hexahydro-1H-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8]naphthyl-5,7-dione (810 mg, crude) was dissolved in dichloromethane (15 mL), and N,N-diisopropylethylamine (755 mg, 5.85 mmol) was added. The reaction was cooled to 0 °C, and acryloyl chloride (211 mg, 2.34 mmol) was added to the reaction solution. The reaction was stirred at 0 °C for 15 minutes. Add 50 mL of dichloromethane to the reaction solution, wash successively with 20 mL of water, 40 mL of saturated NaHCO3 aqueous solution, and 20 mL of saturated saline solution, dry, concentrate, and purify the crude product by rapid silica gel column chromatography (EtOAc / PE: 0-100%) to obtain the product (2R,4aR)-3-acryloyl-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-2,6-dimethyl-2,3,4,4a,6,8-hexahydro-1H-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8]naphthidine-5,7-dione (670 mg, Y: 91.0%), a pale yellow solid. ES-API: [M+H] + =629.2.

[0482] Step 4: (2R,4aR)-3-acryloyl-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-2,6-dimethyl-2,3,4,4a,6,8-hexahydro-1H-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8]naphthyl-5,7-dione (370 mg, 0.59 mmol) was dissolved in dichloromethane (8 mL). The reaction mixture was cooled to 0 °C, and a 17% boron tribromide solution in dichloromethane (7 mL) was added dropwise. The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into 60 mL of saturated NaHCO3 aqueous solution and extracted twice with 80 mL of dichloromethane. The organic phase was washed successively with 50 mL of saturated NaHCO3 aqueous solution and 80 mL of saturated brine, dried, and concentrated. The crude product was purified by preparative HPLC to obtain the product (2R,4aR)-3-acryloyl-11-fluoro-10-(2-fluoro-6-hydroxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-2,6-dimethyl-2,3,4,4a,6-hexahydro-1H-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8,8]naphthidine-5-dione (Z10, 249 mg, Y: 68.7%), a pale yellow solid. ES-API: [M+H] + =615.2.

[0483] Step 5: Compound Z10 (450 mg, 1.06 mmol) was resolved by preparative chiral HPLC (column type: OD-H: 10 μm, 20*250 mm, mobile phase: hexane:EtOH = 80:20, flow rate: 15 ml / min, column temperature) to obtain: a trans-restricted isomer compound, arbitrarily designated as Z10-1 (206 mg, peak 1, retention time 8.321 min, Y: 45.7%), a pale yellow solid. 1HNMR(500MHz,DMSO-d6)δ10.13(d,J=1.3Hz,1H),8.44(d,J=4.9Hz,1H),8.02-7.95(m,1H),7.33–7.20(m, 2H),7.06-6.82(m,1H),6.76–6.63(m,2H),6.24–6.08(m,1H),5.82–5.67(m,1H),5.05–4.73(m,1H),4.63– 4.37(m,1H),4.07-3.97(m,1H),3.73(dd,J=14.1,4.2Hz,1H),3.39-3.20(m,4H),2.94–2.78(m,1H),2.49 -2.39(m,1H),1.99(s,3H),1.61-1.49(m,3H),1.02(d,J=6.7Hz,3H),0.85(d,J=6.7Hz,3H).ES-API:[M+H] + =615.2. And another transisomer compound, the structure of which is arbitrarily designated as Z10-2 (209 mg, peak 2, retention time 10.183 min, Y: 46.4%), a yellow solid. 1 H NMR(500MHz,DMSO-d6)δ10.15(s,1H),8.45(d,J=4.9Hz,1H),8.03-7.95(m,1H),7.30–7.18(m,2H),7.0 6-6.82(m,1H),6.75–6.61(m,2H),6.21–6.09(m,1H),5.80–5.65(m,1H),5.05–4.72(m,1H),4.63–4.37 (m,1H),4.01-3.92(m,1H),3.74(dd,J=14.2,4.2Hz,1H),3.43-3.21(m,4H),2.95–2.82(m,1H),2.80-2 .72(m,1H),1.80(s,3H),1.60-1.48(m,3H),1.11(d,J=6.7Hz,3H),0.98(d,J=6.7Hz,3H).ES-API:[M+H] + =615.2. The isomers were detected by analytical chiral HPLC (column type: OD-H: 5 μm, 4.6*250 mm, mobile phase: hexane:EtOH = 80:20, flow rate: 1 ml / min, column temperature = 30 °C).

[0484] Examples 4 to 5, 7 to 8, 11 to 20

[0485] Compounds Z4 to Z5, Z7 to Z8, and Z11 to Z20 are prepared by a similar method to that of compounds Z1 or Z2. The starting materials for each compound can be prepared by commercially available sources or by existing methods known to those skilled in the art. Similar synthetic methods for intermediates are readily available to those skilled in the art by referring to existing methods.

[0486]

[0487]

[0488]

[0489] Example 21 Preparation of compounds Z21, Z21-1 and Z21-2

[0490]

[0491] Step 1: Add 2 g (5.34 mmol) of 7-chloro-6-fluoro-4-hydroxy-1-(4-isopropyl-6-methylpyrimidin-5-yl)-2-oxo-1,2-dihydro-1,8-naphthidine-3-onitrile, 12 mL of water, and 12 mL of dioxane to a round-bottom flask. After cooling the system to 0 °C, add 12 mL of concentrated sulfuric acid dropwise to the reaction solution. After the addition is complete, stir the reaction at 120 °C for 18 hours. Upon completion of the reaction, a large amount of solid precipitates. Filter the solution, and wash the filter cake three times with water. After drying the filter cake, obtain 1.4 g (75%) of 7-chloro-6-fluoro-4-hydroxy-1-(4-isopropyl-6-methylpyrimidin-5-yl)-1,8-naphthidine-2(1H)-one, a white solid. The crude product is used directly in the next step. ES-API: [M+H] + =349.1.

[0492] Step 2: Add 1.3 g (3.72 mmol) of 7-chloro-6-fluoro-4-hydroxy-1-(4-isopropyl-6-methylpyrimidin-5-yl)-1,8-naphthidine-2(1H)-one, 26 mg (0.37 mmol) of sodium nitrite, and 8 mL of glacial acetic acid to a round-bottom flask. Add concentrated nitric acid (700 mg, 11.1 mmol) dropwise to the reaction mixture. Heat the reaction mixture in an oil bath at 30 °C for 2 hours. Pour the reaction mixture into ice water, and a solid precipitates. Filter the mixture, and wash the filter cake with water. Collect the filter cake and dry it under vacuum to obtain 1.2 g (76% purity) of 7-chloro-6-fluoro-4-hydroxy-1-(4-isopropyl-6-methylpyrimidin-5-yl)-3-nitro-1,8-naphthidine-2(1H)-one, a yellow solid. The crude product is used directly in the next step. ES-API: [M+H] + =394.1.

[0493] Step 3: Add 7-chloro-6-fluoro-4-hydroxy-1-(4-isopropyl-6-methylpyrimidin-5-yl)-3-nitro-1,8-naphthidine-2(1H)-one (1.2 g, 3 mmol), 2-fluoro-6-methoxyphenylboronic acid (2 g, 12 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (123 mg, 0.3 mmol), chloro(2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) (216 mg, 0.3 mmol), potassium phosphate (1.9 g, 9 mmol), 15 mL dioxane, and 3 mL water to the reaction flask. The reaction was carried out under nitrogen protection in a 110°C oil bath with stirring for 1 hour, after which the reaction was stopped. Add 30 mL of 1 M potassium carbonate aqueous solution to the reaction mixture, and extract once with 20 mL of 1:1 ethyl acetate solution to remove impurities. Adjust the pH of the aqueous phase to 4 with 6 M hydrochloric acid aqueous solution. Extract three times with ethyl acetate. Dry the organic phase with sodium sulfate and concentrate to obtain 1.1 g (75%) of 6-fluoro-7-(2-fluoro-6-methoxyphenyl)-4-hydroxy-1-(4-isopropyl-6-methylpyrimidin-5-yl)-3-nitro-1,8-naphthidine-2(1H)-one, a yellow solid. ES-API: [M+H] + =483.1.

[0494] Step 4: Add 1.2 g (2.48 mmol) of 6-fluoro-7-(2-fluoro-6-methoxyphenyl)-4-hydroxy-1-(4-isopropyl-6-methylpyrimidin-5-yl)-3-nitro-1,8-naphthidium-2(1H)-one, 2.48 mmol of diisopropylethylamine, and 20 mL of acetonitrile to a round-bottom flask. Add 2.2 g (14.5 mmol) of phosphorus oxychloride dropwise. Stir the reaction mixture at 85 °C for 1 hour. LC-MS was used to determine the completion of the reaction. The reaction mixture was then poured into ice water and extracted with ethyl acetate. The organic phase was dried over sodium sulfate and concentrated to give 1.1 g of 4-chloro-6-fluoro-7-(2-fluoro-6-methoxyphenyl)-1-(4-isopropyl-6-methylpyrimidin-5-yl)-3-nitro-1,8-naphthidine-2(1H)-one (83% purity). The crude product was used directly in the next reaction. ES-API: [M+H] + =502.1.

[0495] Step 5: Add 4-chloro-6-fluoro-7-(2-fluoro-6-methoxyphenyl)-1-(4-isopropyl-6-methylpyrimidin-5-yl)-3-nitro-1,8-naphthidium-2(1H)-one (1 g, 2 mmol), 1-(tert-butyl)-3-methyl(R)-piperazine-1,3-dicarboxylic acid ester (1.94 g, 8 mmol), N,N-diisopropylethylamine (516 mg, 4 mmol), and N,N-dimethylacetamide (10 mL) to a round-bottom flask. Stir the reaction mixture at 120 °C for 2 hours. The reaction was confirmed to be complete by LC-MS. Pour the reaction mixture into 30 mL of water. Extract three times with ethyl acetate. The organic phase was washed four times with saturated brine / water (v / v, 1:1), dried, and concentrated. The crude product was purified by rapid silica gel column chromatography (EtOAc / PE: 0-40%) to give 1-(tert-butyl)3-methyl(3R)-4-(6-fluoro-7-(2-fluoro-6-methoxyphenyl)-1-(4-isopropyl-6-methylpyrimidin-5-yl)-3-nitro-2-oxo-1,2-dihydro-1,8-naphthidin-4-yl)piperazine-1,3-dicarboxylic acid ester (1 g, purity 82%). ES-API: [M+H] + =710.2.

[0496] Step 6: Add 1-(tert-butyl)3-methyl(3R)-4-(6-fluoro-7-(2-fluoro-6-methoxyphenyl)-1-(4-isopropyl-6-methylpyrimidin-5-yl)-3-nitro-2-oxo-1,2-dihydro-1,8-naphthidin-4-yl)piperazine-1,3-dicarboxylic acid ester (1 g, 1.4 mmol), iron powder (390 mg, 7 mmol), and 15 mL of glacial acetic acid to the reaction flask. Stir the reaction mixture at 80 °C for 1 hour. The reaction was confirmed to be complete by LC-MS. Pour the reaction mixture into 50 mL of sodium bicarbonate aqueous solution and extract three times with 30 mL of ethyl acetate. The organic phase was dried and concentrated to give (4aR)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(4-isopropyl-6-methylpyrimidin-5-yl)-5,7-dioxo-1,2,4,4a,5,6,7,8-octahydro-3H-pyrazino[1',2':4,5]pyrazino[2,3-c][1,8]naphthyl-3-carboxylic acid tert-butyl ester (850 mg, 93%), a yellow solid. ES-API:[M+H] + =648.3.

[0497] Step 7: Add (4aR)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(4-isopropyl-6-methylpyrimidin-5-yl)-5,7-dioxo-1,2,4,4a,5,6,7,8-octahydro-3H-pyrazino[1',2':4,5]pyrazino[2,3-c][1,8]naphthyl-3-carboxylic acid tert-butyl ester (450 mg, 0.69 mmol), methyl iodide (789 mg, 5.55 mmol), potassium carbonate (286 mg, 2.07 mmol), and 10 mL of acetone to a round-bottom flask. Seal the flask and stir at 50 °C for 16 hours. The reaction is complete as detected by LC-MS. Filter the reaction solution through diatomaceous earth. The filtrate was concentrated, and the crude product was purified by rapid silica gel column chromatography (EtOAc / PE: 0-60%) to give (4aR)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(4-isopropyl-6-methylpyrimidin-5-yl)-6-methyl-5,7-dioxo-1,2,4,4a,5,6,7,8-octahydro-3H-pyrazino[1',2':4,5]pyrazino[2,3-c][1,8]naphthyl-3-carboxylic acid tert-butyl ester (260 mg, 57%), a yellow solid. ES-API: [M+H] + =662.2.

[0498] Step 8: Add (4aR)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(4-isopropyl-6-methylpyrimidin-5-yl)-6-methyl-5,7-dioxo-1,2,4,4a,5,6,7,8-octahydro-3H-pyrazino[1',2':4,5]pyrazino[2,3-c][1,8]naphthyl-3-carboxylic acid tert-butyl ester (260 mg, 0.39 mmol), 1 mL of dichloromethane, and 3 mL of trifluoroacetic acid to a round-bottom flask. Stir at room temperature for 1 hour, and the reaction is complete as detected by LC-MS. The reaction solution was concentrated to give (4aR)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(4-isopropyl-6-methylpyrimidin-5-yl)-6-methyl-2,3,4,4a,6,8-hexahydro-1H-pyrazino[1',2':4,5]pyrazino[2,3-c][1,8]naphthidine-5,7-dione (219 mg), a yellow solid. The crude product was used directly in the next step. ES-API:[M+H] + =562.2.

[0499] Step 9: Add (4aR)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(4-isopropyl-6-methylpyrimidin-5-yl)-6-methyl-2,3,4,4a,6,8-hexahydro-1H-pyrazino[1',2':4,5]pyrazino[2,3-c][1,8]naphthyl-5,7-dione (219 mg, 0.39 mmol), 3 mL of dichloromethane, and triethylamine (158 mg, 1.56 mmol) to a 50 mL round-bottom flask. Cool the reaction mixture to 0 °C, and add a dichloromethane solution of acryloyl chloride (71 mg, 0.78 mmol, 0.5 mL) dropwise to the reaction mixture. Stir the reaction mixture at 0 °C for 10 minutes. Add 40 mL of saturated sodium bicarbonate aqueous solution to the reaction mixture, and extract three times with 20 mL of dichloromethane. The organic phase was dried and concentrated to give (4aR)-3-acryloyl-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(4-isopropyl-6-methylpyrimidin-5-yl)-6-methyl-2,3,4,4a,6,8-hexahydro-1H-pyrazino[1',2':4,5]pyrazino[2,3-c][1,8]naphthidine-5,7-dione (240 mg, 87% purity), a yellow solid. The crude product was used directly for the next step. ES-API:[M+H] + =616.3.

[0500] Step 10: Add (4aR)-3-acryloyl-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(4-isopropyl-6-methylpyrimidin-5-yl)-6-methyl-2,3,4,4a,6,8-hexahydro-1H-pyrazino[1',2':4,5]pyrazino[2,3-c][1,8]naphthidine-5,7-dione (240 mg, 0.39 mmol) and 3 mL of dichloromethane to a round-bottom flask. Cool the reaction mixture to 0°C and add dropwise 6 mL of a 17% boron tribromide solution in dichloromethane. After the addition is complete, stir the reaction mixture at room temperature for 2 hours. Pour the reaction mixture into 30 mL of ice-cold saturated NaHCO3 aqueous solution and extract three times with 20 mL of dichloromethane. The organic phase was dried and concentrated. The crude product was purified by preparative HPLC to obtain the product (4aR)-3-acryloyl-11-fluoro-10-(2-fluoro-6-hydroxyphenyl)-8-(4-isopropyl-6-methylpyrimidin-5-yl)-6-methyl-2,3,4,4a,6,8-hexahydro-1H-pyrazino[1',2':4,5]pyrazino[2,3-c][1,8]naphthidine-5,7-dione (Z21, 130 mg, 55%), a yellow solid. ES-API: [M+H] + =602.2.

[0501] Step 11: Compound (4aR)-3-acryloyl-11-fluoro-10-(2-fluoro-6-hydroxyphenyl)-8-(4-isopropyl-6-methylpyrimidin-5-yl)-6-methyl-2,3,4,4a,6,8-hexahydro-1H-pyrazino[1',2':4,5]pyrazino[2,3-c][1,8]naphthidine-5,7-dione (130 mg) was resolved by preparative chiral HPLC (column: Chiralpak IE: 10 μm, 20*250 mm; mobile phase: hexane:ethanol:diethylamine = 70:30:0.2; flow rate: 15 ml / min; column temperature) to give: a trans-isomer compound, arbitrarily designated as Z21-1 (peak 2, retention time: 12.33 min, 47 mg), a yellow solid. ES-API: [M+H] + =602.2. 1 HNMR(500MHz,DMSO-d6):10.17(s,1H),9.03(s,1H),8.41(d,J=9Hz,1H),7.26-7.25(m,1H),7 .08-7.05(m,1H),6.68-6.66(m,2H),6.17-6.14(m,1H),5.77-5.75(m,1H),4.75-4.73(m,1H) ,4.46-4.44 (m, 1H), 4.0-3.95 (m, 1H), 3.55-3.54 (m, 2H), 3.41 (s, 3H), 3.20-3.18 (m, 1H), 2.85-2.83 (m, 1H), 2.68-2.65 (m, 1H), 2.00 (s, 3H), 1.13 (d, J = 6.5 Hz, 3H), 1.06 (d, J = 6.5 Hz, 3H). And another transisomer compound, arbitrarily designated Z21-2 (peak 1, retention time: 10.58 min, 48 mg), yellow solid. ES-API: [M+H] + =602.2. 1HNMR(500MHz,DMSO-d6):10.16(s,1H),9.03(s,1H),8.41(d,J=9Hz,1H),7.26-7.25(m,1H),7 .08-7.05(m,1H),6.68-6.66(m,2H),6.17-6.14(m,1H),5.77-5.75(m,1H),4.75-4.73(m,1H) The isomers were detected by analytical chiral HPLC (column type: Chiralpak IE: 5 μm, 4.6*250 mm; mobile phase: hexane:ethanol:ammoniamethanol = 70:30:0.2; flow rate: 1 ml / min; column temperature: 30 °C). The isomers were 4.46–4.44 (m, 1H), 4.0–3.95 (m, 1H), 3.55–3.54 (m, 2H), 3.41 (s, 3H), 3.20–3.18 (m, 1H), 2.65–2.60 (m, 1H), 2.52–2.51 (m, 1H), 2.20 (s, 3H), 1.06 (d, J = 6.5 Hz, 3H), and 0.86 (d, J = 6.5 Hz, 3H).

[0502] Example 22 Preparation of compound Z22

[0503]

[0504] Step 1: 7-Chloro-6-fluoro-4-hydroxy-1-(3-isopropylpyrazin-2-yl)-1,8-naphthidin-2(1H)-one (2 g, 6 mmol) was dissolved in acetic acid (5 mL), followed by the addition of sodium nitrite (41 mg, 0.6 mmol) and concentrated nitric acid (1.5 g, 24 mmol). The reaction mixture was stirred at room temperature for 30 minutes. The reaction solution was slowly poured into 100 mL of ice water. The precipitated solid was filtered, and the filter cake was washed with 20 mL of ice water and dried under vacuum to obtain the product 7-chloro-6-fluoro-4-hydroxy-1-(3-isopropylpyrazin-2-yl)-3-nitro-1,8-naphthidin-2(1H)-one (1.5 g, 65%), a yellow solid. ES-API: [M+H] + =380.2.

[0505] Step 2: Add 7-chloro-6-fluoro-4-hydroxy-1-(3-isopropylpyrazin-2-yl)-3-nitro-1,8-naphthidine-2(1H)-one (1.5 g, 3.94 mmol), (2-fluoro-6-methoxyphenyl)boronic acid (2.04 g, 12 mmol), chloro(2-dicyclohexylphosphine-2′,6′-dimethoxy-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) (288 mg, 0.4 mmol), 2-dicyclohexylphosphine-2′,6′-dimethoxybiphenyl (164 mg, 0.4 mmol), potassium phosphate (2.5 g, 12 mmol), 10 mL of water, and 40 mL of dioxane to a 100 mL three-necked round-bottom flask. Under nitrogen protection, stir at 100 °C for 2–3 hours. After the reaction was complete, the reaction solution was cooled to room temperature, and 80 mL of water and 100 mL of methyl tert-butyl ether were added for extraction once. The aqueous phase was adjusted to pH 3–5 with 1 M hydrochloric acid solution and extracted with ethyl acetate (200 mL * 2). The ethyl acetate phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was dried under vacuum to give the product 6-fluoro-7-(2-fluoro-6-methoxyphenyl)-4-hydroxy-1-(3-isopropylpyrazin-2-yl)-3-nitro-1,8-naphthidium-2(1H)-one (1.6 g, crude product), a pale yellow solid. ES-API: [M + H] + =470.1.

[0506] Step 3: 6-Fluoro-7-(2-fluoro-6-methoxyphenyl)-4-hydroxy-1-(3-isopropylpyrazin-2-yl)-3-nitro-1,8-naphthidium-2(1H)-one (1.6 g, 3.4 mmol) was dissolved in acetonitrile (30 mL), followed by the addition of phosphorus oxychloride (2.6 g, 17 mmol) and N,N-diisopropylethylamine (3 g, 23.8 mmol). The reaction mixture was gradually heated to 80 °C and stirred for 30 minutes. The reaction solution was concentrated, and 30 mL of cold acetonitrile was added dropwise to 150 mL of saturated sodium bicarbonate solution under an ice-water bath. The mixture was extracted with ethyl acetate (200 mL * 2), and the organic phases were combined and washed once with 200 mL of saturated brine. The product was dried over anhydrous sodium sulfate, filtered, and the organic phase was dried and concentrated. The crude product was purified by rapid silica gel column chromatography (EtOAc / PE: 0-50%) to obtain 4-chloro-6-fluoro-7-(2-fluoro-6-methoxyphenyl)-1-(3-isopropylpyrazin-2-yl)-3-nitro-1,8-naphthidium-2(1H)-one (340 mg, Y: 20%), a yellow solid. ES-API: [M+H] + =488.2.

[0507] Step 4: 4-Chloro-6-fluoro-7-(2-fluoro-6-methoxyphenyl)-1-(3-isopropylpyrazin-2-yl)-3-nitro-1,8-naphthidium-2(1H)-one (310 mg, 0.64 mmol) was dissolved in N,N-dimethylacetamide (5 mL), followed by the sequential addition of 1-(tert-butyl)-3-methyl(3R,6R)-6-methylpiperazine-1,3-dicarboxylic acid (247 mg, 0.96 mmol) and N,N-diisopropylethylamine (250 mg, 1.92 mmol). The reaction mixture was stirred at 120 °C for 2 hours. 50 mL of ethyl acetate was added to the reaction solution, and the mixture was washed three times with 30 mL of saturated brine. The ethyl acetate phase was dried and concentrated. The crude product was purified by rapid silica gel column chromatography (EtOAc / PE: 0-80%) to give 1-(tert-butyl)-3-methyl(3R,6R)-4-(6-fluoro-7-(2-fluoro-6-methoxyphenyl)-1-(3-isopropylpyrazin-2-yl)-3-nitro-2-oxo-1,2-dihydro-1,8-naphthidin-4-yl)-6-methylpiperazine-1,3-dicarboxylic acid ester (317 mg, Y: 70%), a yellow solid. ES-API: [M+H] + =710.2.

[0508] Step 5: 1-(tert-butyl)3-methyl(3R,6R)-4-(6-fluoro-7-(2-fluoro-6-methoxyphenyl)-1-(3-isopropylpyrazin-2-yl)-3-nitro-2-oxo-1,2-dihydro-1,8-naphthidin-4-yl)-6-methylpiperazine-1,3-dicarboxylic acid ester (280 mg, 0.4 mmol) was dissolved in acetic acid (4 mL), and iron powder (78 mg, 1.4 mmol) was added. The reaction was stirred at 80 °C for 30 minutes. The reaction solution was concentrated, and 50 mL of ethyl acetate and 30 mL of saturated sodium bicarbonate were added sequentially. The suspension was filtered through diatomaceous earth, and the filter cake was washed with ethyl acetate. The organic phase was separated and washed sequentially with 100 mL of saturated sodium bicarbonate and 30 mL of saturated brine. After drying and concentration, the product (2R,4aR)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(3-isopropylpyrazin-2-yl)-2-methyl-5,7-dioxo-1,2,4,4a,5,6,7,8-octahydro-3H-pyrazino[1',2':4,5]pyrazino[2,3-c][1,8]naphthyl-3-carboxylic acid tert-butyl ester (312 mg, crude product) was obtained as a yellow solid. ES-API: [M+H]+=648.1.

[0509] Step 6: Add (2R,4aR)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(3-isopropylpyrazin-2-yl)-2-methyl-5,7-dioxo-1,2,4,4a,5,6,7,8-octahydro-3H-pyrazino[1',2':4,5]pyrazino[2,3-c][1,8]naphthyl-3-carboxylic acid tert-butyl ester (295 mg, 0.46 mmol), 3 mL acetone, anhydrous potassium carbonate (1 g, 6.9 mmol), and iodomethane (253 mg, 1.84 mmol) to a 15 mL sealed tube. Seal the tube and stir the reaction at 55 °C for 18 hours. The reaction solution was added to 50 mL of ethyl acetate, washed three times with 20 mL of saturated brine, dried, and concentrated to give the product (2R,4aR)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(3-isopropylpyrazin-2-yl)-2,6-dimethyl-5,7-dioxo-1,2,4,4a,5,6,7,8-octahydro-3H-pyrazino[1',2':4,5]pyrazino[2,3-c][1,8]naphthyl-3-carboxylic acid tert-butyl ester (356 mg, crude product), a yellow solid. ES-API:[M+H] + =662.2.

[0510] Step 7: Dissolve (2R,4aR)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(3-isopropylpyrazin-2-yl)-2,6-dimethyl-5,7-dioxo-1,2,4,4a,5,6,7,8-octahydro-3H-pyrazino[1',2':4,5]pyrazino[2,3-c][1,8]naphthyl-3-carboxylic acid tert-butyl ester (356 mg, 0.54 mmol) in dichloromethane (8 mL), and add trifluoroacetic acid (4 mL). The reaction mixture was stirred at room temperature for 2 hours, and then concentrated to obtain the product (2R,4aR)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(3-isopropylpyrazin-2-yl)-2,6-dimethyl-2,3,4,4a,6,8-hexahydro-1H-pyrazino[1',2':4,5]pyrazino[2,3-c][1,8]naphthidine-5,7-dione (415 mg, crude product), which was directly used in the next step of the reaction. ES-API:[M+H] + =562.2.

[0511] Step 8: (2R,4aR)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(3-isopropylpyrazin-2-yl)-2,6-dimethyl-2,3,4,4a,6,8-hexahydro-1H-pyrazino[1',2':4,5]pyrazino[2,3-c][1,8]naphthidine-5,7-dione (415 mg, 0.74 mmol) was dissolved in dichloromethane (15 mL), and triethylamine (3.0 mL, 21.62 mmol) was added. The reaction was cooled to 0 °C, and acryloyl chloride (115 mg, 1.28 mmol) was added dropwise to the reaction solution. The reaction was stirred at 0 °C for 5 minutes. Add 50 mL of dichloromethane to the reaction solution, wash with 50 mL of saturated NaHCO3 aqueous solution and 80 mL of saturated brine, dry and concentrate. Purify the crude product using a rapid silica gel column chromatography (EtOAc / PE: 0-60%) to obtain the product (2R,4aR)-3-acryloyl-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(3-isopropylpyrazin-2-yl)-2,6-dimethyl-2,3,4,4a,6,8-hexahydro-1H-pyrazino[1',2':4,5]pyrazino[2,3-c][1,8]naphthidine-5,7-dione (201 mg, Y: 44%), a yellow solid. ES-API: [M+H] + =616.2.

[0512] Step 9: Under ice-water bath conditions, (2R,4aR)-3-acryloyl-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(3-isopropylpyrazin-2-yl)-2,6-dimethyl-2,3,4,4a,6,8-hexahydro-1H-pyrazino[1',2':4,5]pyrazino[2,3-c][1,8]naphthidine-5,7-dione (201 mg, 0.33 mmol) was added to dry dichloromethane (3.0 mL), followed by boron tribromide (5.0 mL). The reaction was carried out at room temperature for 30 minutes. Under ice-water bath conditions, the above... The reaction mixture was added dropwise to a saturated sodium bicarbonate solution, extracted twice with dichloromethane (50 mL), dried, concentrated, and the crude product was purified by preparative HPLC to obtain the product (2R,4aR)-3-acryloyl-11-fluoro-10-(2-fluoro-6-hydroxyphenyl)-8-(3-isopropylpyrazin-2-yl)-2,6-dimethyl-2,3,4,4a,6,8-hexahydro-1H-pyrazino[1',2':4,5]pyrazino[2,3-c][1,8]naphthidine-5,7-dione (Z22, 65 mg, Y: 33%). ES-API: [M+H + =602.2. 1H NMR (500MHz, DMSO-d6) δ10.17(s,1H),8.75(dd,J=4.0,2.6Hz,1H),8.55(dd,J=15.5,2.4Hz,1H),8.05-7.98(m,1H),7.2 6(dd,J=15.0,8.2Hz,1H),7.03(dd,J=16.8,10.0Hz,1H),6.73(d,J=8.4Hz,1H),6.67(t,J=8.8Hz,1H),6.16(t,J=12.4Hz ,1H),5.74(dd,J=20.0,11.8Hz,1H),4.78(s,1H),4.65-4.56(m,1H),4.00(t,J=28.0Hz,1H),3.80-3.70(m,1H),3.36(d, J=2.4Hz,3H),3.05-2.62(m,2H),1.63-1.48(m,3H),1.18(d,J=6.8Hz,2H),1.10(d,J=6.8Hz,3H),1.00(d,J=6.7Hz,2H).

[0513] Example 23 Preparation of compound Z23

[0514]

[0515] Step 1: Add 0.8 g (1.46 mmol) of 4-chloro-6-fluoro-7-(2-fluoro-6-methoxyphenyl)-1-(4-isopropyl-6-methylpyrimidin-5-yl)-3-nitro-1,8-naphthidium-2(1H)-one, 1-(tert-butyl)-3-methyl(3R,6R)-6-methylpiperazine-1,3-dicarboxylic acid ester (567 mg, 2.2 mmol), N,N-diisopropylethylamine (565 mg, 4.38 mmol), and N,N-dimethylacetamide (10 mL) to a round-bottom flask. Stir the mixture at 120 °C for 1 hour. The reaction was confirmed to be complete by LC-MS. Pour the reaction mixture into 30 mL of water. Extract three times with ethyl acetate. The organic phase was washed four times with saturated brine / water (v / v, 1:1), dried, and concentrated to give 1-(tert-butyl)-3-methyl(3R,6R)-4-(6-chloro-1-(4,6-diisopropylpyrimidin-5-yl)-7-(2-fluoro-6-methoxyphenyl)-3-nitro-2-oxo-1,2-dihydro-1,8-naphthidin-4-yl)-6-methylpiperazine-1,3-dicarboxylic acid ester (1 g, yield 89%). ES-API:[M+H] + =768.3.

[0516] Step 2: Add 1-(tert-butyl)3-methyl(3R,6R)-4-(6-chloro-1-(4,6-diisopropylpyrimidin-5-yl)-7-(2-fluoro-6-methoxyphenyl)-3-nitro-2-oxo-1,2-dihydro-1,8-naphthidin-4-yl)-6-methylpiperazine-1,3-dicarboxylic acid ester (1 g, 1.3 mmol), iron powder (300 mg, 5.3 mmol), and 8 mL of glacial acetic acid to the reaction flask. Stir the reaction mixture at 80 °C for 0.5 hours. The reaction was confirmed to be complete by LC-MS. Pour the reaction mixture into 50 mL of sodium bicarbonate aqueous solution and extract three times with 30 mL of ethyl acetate. The organic phase was dried and concentrated to give crude (2R,4aR)-11-chloro-8-(4,6-diisopropylpyrimidin-5-yl)-10-(2-fluoro-6-methoxyphenyl)-2-methyl-5,7-dioxo-1,2,4,4a,5,6,7,8-octahydro-3H-pyrazino[1',2':4,5]pyrazino[2,3-c][1,8]naphthyl-3-carboxylic acid tert-butyl ester (761 mg, 83%), a yellow solid. ES-API:[M+H] + =706.3.

[0517] Step 3: Add (2R,4aR)-11-chloro-8-(4,6-diisopropylpyrimidin-5-yl)-10-(2-fluoro-6-methoxyphenyl)-2-methyl-5,7-dioxo-1,2,4,4a,5,6,7,8-octahydro-3H-pyrazino[1',2':4,5]pyrazino[2,3-c][1,8]naphthyl-3-carboxylic acid tert-butyl ester (761 mg, 1.08 mmol), methyl iodide (1.5 g, 10.79 mmol), potassium carbonate (596 mg, 4.32 mmol), and 15 mL of acetone to a round-bottom flask. The reaction mixture was sealed and stirred at 50 °C for 16 hours. The reaction was monitored by LC-MS until complete. The reaction solution was filtered through diatomaceous earth. The filtrate was concentrated to give crude (2R,4aR)-11-chloro-8-(4,6-diisopropylpyrimidin-5-yl)-10-(2-fluoro-6-methoxyphenyl)-2,6-dimethyl-5,7-dioxo-1,2,4,4a,5,6,7,8-octahydro-3H-pyrazino[1',2':4,5]pyro[2,3-c][1,8]naphthyl-3-carboxylic acid tert-butyl ester (738 mg, 95%), a yellow solid. ES-API:[M+H] + =720.3.

[0518] Step 4: Add (2R,4aR)-11-chloro-8-(4,6-diisopropylpyrimidin-5-yl)-10-(2-fluoro-6-methoxyphenyl)-2,6-dimethyl-5,7-dioxo-1,2,4,4a,5,6,7,8-octahydro-3H-pyrazino[1',2':4,5]pyro[2,3-c][1,8]naphthyl-3-carboxylic acid tert-butyl ester (738 mg, 1.02 mmol), 2 mL of dichloromethane, and 5 mL of trifluoroacetic acid to a round-bottom flask. Stir at room temperature for 1 hour, and the reaction is complete as detected by LC-MS. The reaction solution was concentrated to give (2R,4aR)-11-chloro-8-(4,6-diisopropylpyrimidin-5-yl)-10-(2-fluoro-6-methoxyphenyl)-2,6-dimethyl-2,3,4,4a,6,8-hexahydro-1H-pyrazino[1',2':4,5]pyrazino[2,3-c][1,8]naphthidine-5,7-dione (632 mg, 100%), a yellow solid. The crude product was used directly in the next step. ES-API:[M+H] + =620.3.

[0519] Step 5: Add (2R,4aR)-11-chloro-8-(4,6-diisopropylpyrimidin-5-yl)-10-(2-fluoro-6-methoxyphenyl)-2,6-dimethyl-2,3,4,4a,6,8-hexahydro-1H-pyrazino[1',2':4,5]pyrazino[2,3-c][1,8]naphthyl-5,7-dione (632 mg, 1.02 mmol), 3 mL of dichloromethane, and triethylamine (677 mg, 6.7 mmol) to a 50 mL round-bottom flask. Cool the reaction mixture to 0 °C, and add a dichloromethane solution of acryloyl chloride (249 mg, 2.77 mmol, 0.5 mL) dropwise to the reaction mixture. Stir the reaction mixture at 0 °C for 10 minutes. Add 40 mL of saturated sodium bicarbonate aqueous solution to the reaction mixture, and extract three times with 20 mL of dichloromethane. The organic phase was dried and concentrated. The crude product was purified by rapid silica gel column chromatography (EtOAc / PE: 0-60%) to give (2R,4aR)-3-acryloyl-11-chloro-8-(4,6-diisopropylpyrimidin-5-yl)-10-(2-fluoro-6-methoxyphenyl)-2,6-dimethyl-2,3,4,4a,6,8-hexahydro-1H-pyrazino[1',2':4,5]pyrazino[2,3-c][1,8]naphthidine-5,7-dione (500 mg, 72%), a yellow solid. The crude product was used directly for the next step. ES-API: [M+H] + =674.2.

[0520] Step 6: Add (2R,4aR)-3-acryloyl-11-chloro-8-(4,6-diisopropylpyrimidin-5-yl)-10-(2-fluoro-6-methoxyphenyl)-2,6-dimethyl-2,3,4,4a,6,8-hexahydro-1H-pyrazino[1',2':4,5]pyrazino[2,3-c][1,8]naphthidine-5,7-dione (500 mg, 0.74 mmol) and 3 mL of dichloromethane to a round-bottom flask. Cool the reaction solution to 0°C and add dropwise 12 mL of a 17% boron tribromide solution in dichloromethane. After the addition is complete, stir the reaction solution at 25°C for 25 hours. Pour the reaction solution into 30 mL of ice-cold saturated NaHCO3 aqueous solution and extract three times with 20 mL of dichloromethane. After drying and concentrating the organic phase, the crude product was purified by preparative HPLC to obtain the product (2R,4aR)-3-acryloyl-11-chloro-8-(4,6-diisopropylpyrimidin-5-yl)-10-(2-fluoro-6-hydroxyphenyl)-2,6-dimethyl-2,3,4,4a,6,8-hexahydro-1H-pyrazino[1',2':4,5]pyrazino[2,3-c][1,8]naphthidine-5,7-dione (Z23, 200 mg, 40%), a yellow solid. 1 HNMR (500MHz, DMSO-d6): δ10.10-10.5(m,1H),9.11(s,1H),8.25-8.23(m 1H),7.22-7.21(m,1H),6.86-6.74(m,1H),6.67-6.64(m,2H),6.17-6.1 4(m,1H),5.75-5.71(m,1H),5.04-5.01(m,1H),4.62-4.42(m,1H),4.03 -3.98(m,1H),3.74-3.72(m,1H),3.42-3.33(m,5H),2.77-2.64(m,2H), 1.56-1.52(m,3H),1.05-0.97(m,9H),0.86-0.84(m,3H).ES-API:[M+H] + =660.3.

[0521] Example 24 Preparation of compounds Z24, Z24-1 and Z24-2

[0522]

[0523] Step 1: 6,7-Dichloro-4-hydroxy-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthidium-3-carboxynitrile (30.0 g, 77.319 mmol) was suspended in a mixed solution of 1,4-dioxane (120 mL) and water (120 mL), and concentrated sulfuric acid (120 mL) was slowly added. The reaction was stirred at 120 °C for 36 hours. The cooled reaction solution was poured into 200 mL of ice water, the pH was adjusted to 2–3 with sodium carbonate, and the mixture was extracted with ethyl acetate (1000 mL * 2). The ethyl acetate phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was dried under vacuum to obtain the product 6,7-dichloro-4-hydroxy-1-(2-isopropyl-4-methylpyridin-3-yl)-1,8-naphthidium-2(1H)-one (24 g, Y: 85.7%), a light brown solid. ES-API:[M+H] + =364.1.

[0524] Step 2: 6,7-Dichloro-4-hydroxy-1-(2-isopropyl-4-methylpyridin-3-yl)-1,8-naphthidin-2(1H)-one (3.16 g, 8.705 mmol) was dissolved in acetic acid (15 mL), followed by the addition of sodium nitrite (100 mg, 1.58 mmol) and concentrated nitric acid (5.0 mL, 74.52 mmol). The reaction mixture was stirred at room temperature for 30 minutes. The reaction solution was slowly poured into 100 mL of ice water. The precipitated solid was filtered, and the filter cake was washed with 20 mL of ice water and dried under vacuum to obtain the product 6,7-dichloro-4-hydroxy-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro-1,8-naphthidin-2(1H)-one (3.5 g, Y: 92%), a yellow solid. ES-API: [M+H] + =409.1.

[0525] Step 3: Add 3.5 g (8.570 mmol) of 6,7-dichloro-4-hydroxy-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro-1,8-naphthidin-2(1H)-one, (2-fluoro-6-methoxyphenyl)boronic acid (5.8 g, 34.10 mmol), tetrakis(triphenylphosphine)palladium (1.15 g, 0.9956 mmol), sodium carbonate (3.5 g, 33.02 mmol), 10 mL of water, and 40 mL of dioxane to a 100 mL three-necked round-bottom flask. Under nitrogen protection, stir the mixture at 100 °C for 2–3 hours. After the reaction is complete, cool the reaction solution to room temperature, add 80 mL of water and 100 mL of methyl tert-butyl ether, and extract once. The aqueous phase was adjusted to pH 3–5 with 1M hydrochloric acid solution, extracted with ethyl acetate (200 mL * 2), and the ethyl acetate phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was dried under vacuum to give the product 6-chloro-7-(2-fluoro-6-methoxyphenyl)-4-hydroxy-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro-1,8-naphthidium-2(1H)-one (4.5 g, crude product), a pale yellow solid. ES-API: [M + H] + =499.1.

[0526] Step 4: 6-Chloro-7-(2-fluoro-6-methoxyphenyl)-4-hydroxy-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro-1,8-naphthidin-2(1H)-one (4.6 g, 8.57 mmol) was dissolved in acetonitrile (30 mL), followed by the addition of phosphorus oxychloride (7.5 g, 48.92 mmol) and N,N-diisopropylethylamine (10.5 g, 81.24 mmol). The reaction mixture was gradually heated to 80 °C and stirred for 30 minutes. The reaction solution was concentrated, and 30 mL of cold acetonitrile was added dropwise to 150 mL of saturated sodium bicarbonate solution under an ice-water bath. The mixture was extracted with ethyl acetate (200 mL * 2), and the combined ethyl acetate phases were washed once with 200 mL of saturated brine. After drying with anhydrous sodium sulfate and filtering, the organic phase was dried and concentrated. The crude product was purified by rapid silica gel column chromatography (EtOAc / PE: 0-50%) to obtain 4,6-dichloro-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro-1,8-naphthidium-2(1H)-one (3.05 g, Y: 76%), a yellow solid. ES-API: [M+H] + =517.2.

[0527] Step 5: 4,6-Dichloro-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro-1,8-naphthidium-2(1H)-one (2.5 g, 4.843 mmol) was dissolved in N,N-dimethylacetamide (25 mL), followed by the addition of 1-(tert-butyl)-3-methyl(R)-piperazine-1,3-dicarboxylic acid ester (3.5 g, 14.34 mmol) and N,N-diisopropylethylamine (2.0 g, 15.47 mmol). The reaction mixture was stirred at 120 °C for 2 hours. 80 mL of ethyl acetate was added to the reaction solution, and the mixture was washed three times with 80 mL of saturated brine. The ethyl acetate phase was dried and concentrated. The crude product was purified by rapid silica gel column chromatography (EtOAc / PE: 0-80%) to give 1-(tert-butyl)-3-methyl(3R)-4-(6-chloro-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro-2-oxo-1,2-dihydro-1,8-naphthidin-4-yl)piperazine-1,3-dicarboxylic acid ester (2.7 g, Y: 77%), a yellow solid. ES-API: [M+H] + =725.2.

[0528] Step 6: 1-(tert-butyl)3-methyl(3R)-4-(6-chloro-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro-2-oxo-1,2-dihydro-1,8-naphthidin-4-yl)piperazine-1,3-dicarboxylic acid ester (2.7 g, 3.728 mmol) was dissolved in acetic acid (30 mL), and iron powder (835 mg, 14.91 mmol) was added. The reaction was stirred at 80 °C for 30 minutes. The reaction solution was concentrated, and 200 mL of ethyl acetate and 100 mL of saturated sodium bicarbonate were added sequentially. The suspension was filtered through diatomaceous earth, and the filter cake was washed with ethyl acetate. The organic phase was separated and washed sequentially with 100 mL of saturated sodium bicarbonate and 150 mL of saturated brine. After drying and concentration, the product (4aR)-11-chloro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-5,7-dioxo-1,2,4,4a,5,6,7,8-octahydro-3H-pyrazino[1',2':4,5]pyrazino[2,3-c][1,8]naphthyl-3-carboxylic acid tert-butyl ester (2.70 g, crude product) was obtained as a yellow solid. ES-API: [M+H]+=663.2.

[0529] Step 7: Add (4aR)-11-chloro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-5,7-dioxo-1,2,4,4a,5,6,7,8-octahydro-3H-pyrazino[1',2':4,5]pyrazino[2,3-c][1,8]naphthyl-3-carboxylic acid tert-butyl ester (250 mg, 0.3774 mmol) sequentially to a 100 mL single-necked flask. 4 mL of dichloromethane and 4 mL of trifluoroacetic acid were mixed and stirred at room temperature for 2 hours. The reaction solution was concentrated to obtain the product (4aR)-11-chloro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-2,3,4,4a,6,8-hexahydro-1H-pyrazino[1',2':4,5]pyrazino[2,3-c][1,8]naphthidine-5,7-dione (300 mg, crude product), which was directly used in the next step of the reaction. ES-API:[M+H] + =563.2.

[0530] Step 8: (4aR)-11-chloro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-2,3,4,4a,6,8-hexahydro-1H-pyrazino[1',2':4,5]pyrazino[2,3-c][1,8]naphthyl-5,7-dione (300 mg, 0.3774 mmol) was dissolved in dichloromethane (10 mL), and triethylamine (3.0 mL, 21.62 mmol) was added. The reaction was cooled to 0 °C, and acryloyl chloride (50 mg, 0.5524 mmol) was added dropwise to the reaction solution. The reaction was stirred at 0 °C for 15 minutes. Add 80 mL of dichloromethane to the reaction solution, wash with 100 mL of saturated NaHCO3 aqueous solution and 80 mL of saturated brine, dry and concentrate. Purify the crude product using a rapid silica gel column chromatography method (methanol / dichloromethane: 0-20%) to obtain the product (4aR)-3-acryloyl-11-chloro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-2,3,4,4a,6,8-hexahydro-1H-pyrazino[1',2':4,5]pyrazino[2,3-c][1,8]naphthidine-5,7-dione (243 mg, crude product), a yellow solid. ES-API: [M+H] + =617.2.

[0531] Step 9: Under ice-water bath conditions, (4aR)-3-acryloyl-11-chloro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-2,3,4,4a,6,8-hexahydro-1H-pyrazino[1',2':4,5]pyrazino[2,3-c][1,8]naphthidine-5,7-dione (243 mg, 0.3774 mmol) was added to dry dichloromethane (6.0 mL), followed by the addition of boron tribromide (5.0 mL, 5.0 mmol). The mixture was then brought to room temperature and reacted overnight. Under ice-water bath conditions, the above reaction solution was added dropwise to a saturated sodium bicarbonate solution, extracted twice with dichloromethane (80 mL), dried, concentrated, and purified by preparative HPLC to obtain (4aR)-3-acryloyl-11-chloro-10-(2-fluoro-6-hydroxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-2,3,4,4a,6,8-hexahydro-1H-pyrazino[1',2':4,5]pyrazino[2,3-c][1,8]naphthidine-5,7-dione (Z24, 76 mg, Y: 32%). [M+H] + =603.2.

[0532] Step 10: Compound Z24 (76.0 mg, 0.1262 mmol) was resolved by preparative chiral HPLC (column type: IA: 10 μm, 30*250 mm, mobile phase: hexane:EtOH = 40:60, flow rate: 25 mL / min, column temperature) to obtain a trans-restricted isomer compound, arbitrarily designated as Z24-1 (13.7 mg, peak 1, retention time 2.612 min, Y: 18%), ES-API: [M+H + =603.2. And another transisomer compound, structurally arbitrarily designated as Z24-2 (21.4 mg, peak 2, retention time 3.985 min, Y: 28%), ES-API: [M+H] + =603.2. The isomers were detected by analytical chiral HPLC (column type IA: 5 μm, 4.6*150 mm, mobile phase: hexane:EtOH = 40:60, flow rate: 1 ml / min, column temperature = 30 °C).

[0533] Example 25 Preparation of compounds Z25, Z25-1 and Z25-2

[0534]

[0535] Step 1: 6,7-Dichloro-4-hydroxy-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthidium-3-carboxynitrile (30.0 g, 77.319 mmol) was suspended in a mixed solution of 1,4-dioxane (120 mL) and water (120 mL), and concentrated sulfuric acid (120 mL) was slowly added. The reaction was stirred at 120 °C for 36 hours. The cooled reaction solution was poured into 200 mL of ice water, the pH was adjusted to 2–3 with sodium carbonate, and the mixture was extracted with ethyl acetate (1000 mL * 2). The ethyl acetate phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was dried under vacuum to obtain the product 6,7-dichloro-4-hydroxy-1-(2-isopropyl-4-methylpyridin-3-yl)-1,8-naphthidium-2(1H)-one (24 g, Y: 85.7%), a light brown solid. ES-API:[M+H] + =364.1.

[0536] Step 2: 6,7-Dichloro-4-hydroxy-1-(2-isopropyl-4-methylpyridin-3-yl)-1,8-naphthidin-2(1H)-one (3.16 g, 8.705 mmol) was dissolved in acetic acid (15 mL), followed by the addition of sodium nitrite (100 mg, 1.58 mmol) and concentrated nitric acid (5.0 mL, 74.52 mmol). The reaction mixture was stirred at room temperature for 30 minutes. The reaction solution was slowly poured into 100 mL of ice water. The precipitated solid was filtered, and the filter cake was washed with 20 mL of ice water and dried under vacuum to obtain the product 6,7-dichloro-4-hydroxy-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro-1,8-naphthidin-2(1H)-one (3.5 g, Y: 92%), a yellow solid. ES-API: [M+H] + =409.1.

[0537] Step 3: Add 3.5 g (8.570 mmol) of 6,7-dichloro-4-hydroxy-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro-1,8-naphthidin-2(1H)-one, (2-fluoro-6-methoxyphenyl)boronic acid (5.8 g, 34.10 mmol), tetrakis(triphenylphosphine)palladium (1.15 g, 0.9956 mmol), sodium carbonate (3.5 g, 33.02 mmol), 10 mL of water, and 40 mL of dioxane to a 100 mL three-necked round-bottom flask. Under nitrogen protection, stir the mixture at 100 °C for 2–3 hours. After the reaction is complete, cool the reaction solution to room temperature, add 80 mL of water and 100 mL of methyl tert-butyl ether, and extract once. The aqueous phase was adjusted to pH 3–5 with 1M hydrochloric acid solution, extracted with ethyl acetate (200 mL * 2), and the ethyl acetate phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was dried under vacuum to give the product 6-chloro-7-(2-fluoro-6-methoxyphenyl)-4-hydroxy-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro-1,8-naphthidium-2(1H)-one (4.5 g, crude product), a pale yellow solid. ES-API: [M + H] + =499.1.

[0538] Step 4: 6-Chloro-7-(2-fluoro-6-methoxyphenyl)-4-hydroxy-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro-1,8-naphthidin-2(1H)-one (4.6 g, 8.57 mmol) was dissolved in acetonitrile (30 mL), followed by the addition of phosphorus oxychloride (7.5 g, 48.92 mmol) and N,N-diisopropylethylamine (10.5 g, 81.24 mmol). The reaction mixture was gradually heated to 80 °C and stirred for 30 minutes. The reaction solution was concentrated, and 30 mL of cold acetonitrile was added dropwise to 150 mL of saturated sodium bicarbonate solution under an ice-water bath. The mixture was extracted with ethyl acetate (200 mL * 2), and the combined ethyl acetate phases were washed once with 200 mL of saturated brine. The product was dried over anhydrous sodium sulfate, filtered, and the organic phase was dried and concentrated. The crude product was purified by rapid silica gel column chromatography (EtOAc / PE: 0-50%) to obtain 4,6-dichloro-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro-1,8-naphthidium-2(1H)-one (3.05 g, Y: 76%), a yellow solid. ES-API: [M+H] + =517.2.

[0539] Step 5: 4,6-Dichloro-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro-1,8-naphthidium-2(1H)-one (2.5 g, 4.843 mmol) was dissolved in N,N-dimethylacetamide (25 mL), followed by the addition of 1-(tert-butyl)-3-methyl(R)-piperazine-1,3-dicarboxylic acid ester (3.5 g, 14.34 mmol) and N,N-diisopropylethylamine (2.0 g, 15.47 mmol). The reaction mixture was stirred at 120 °C for 2 hours. 80 mL of ethyl acetate was added to the reaction solution, and the mixture was washed three times with 80 mL of saturated brine. The ethyl acetate phase was dried and concentrated. The crude product was purified by rapid silica gel column chromatography (EtOAc / PE: 0-80%) to give 1-(tert-butyl)-3-methyl(3R)-4-(6-chloro-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro-2-oxo-1,2-dihydro-1,8-naphthidin-4-yl)piperazine-1,3-dicarboxylic acid ester (2.7 g, Y: 77%), a yellow solid. ES-API: [M+H] + =725.2.

[0540] Step 6: 1-(tert-butyl)3-methyl(3R)-4-(6-chloro-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro-2-oxo-1,2-dihydro-1,8-naphthidin-4-yl)piperazine-1,3-dicarboxylic acid ester (2.7 g, 3.728 mmol) was dissolved in acetic acid (30 mL), and iron powder (835 mg, 14.91 mmol) was added. The reaction was stirred at 80 °C for 30 minutes. The reaction solution was concentrated, and 200 mL of ethyl acetate and 100 mL of saturated sodium bicarbonate were added sequentially. The suspension was filtered through diatomaceous earth, and the filter cake was washed with ethyl acetate. The organic phase was separated and washed sequentially with 100 mL of saturated sodium bicarbonate and 150 mL of saturated brine. After drying and concentration, the product (4aR)-11-chloro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-5,7-dioxo-1,2,4,4a,5,6,7,8-octahydro-3H-pyrazino[1',2':4,5]pyrazino[2,3-c][1,8]naphthyl-3-carboxylic acid tert-butyl ester (2.70 g, crude product) was obtained as a yellow solid. ES-API: [M+H]+=663.2.

[0541] Step 7: Add (4aR)-11-chloro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-5,7-dioxo-1,2,4,4a,5,6,7,8-octahydro-3H-pyrazino[1',2':4,5]pyrazino[2,3-c][1,8]naphthyl-3-carboxylic acid tert-butyl ester (2.7 g, 3.728 mmol), 30 mL acetone, anhydrous potassium carbonate (2.2 g, 15.94 mmol), and iodomethane (5.4 g, 38.03 mmol) to a 150 mL sealed tube. Seal the tube and stir the reaction at 55 °C for 18 hours. The reaction mixture was added to 150 mL of ethyl acetate, washed three times with 100 mL of saturated brine, dried, and concentrated. The crude product was purified by rapid silica gel column chromatography (EtOAc / PE: 0-80%) to give (4aR)-11-chloro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-6-methyl-5,7-dioxo-1,2,4,4a,5,6,7,8-octahydro-3H-pyrazino[1',2':4,5]pyrazino[2,3-c][1,8]naphthyl-3-carboxylic acid tert-butyl ester (2.2 g, Y: 87%), a yellow solid. ES-API: [M+H] + =677.2.

[0542] Step 8: Dissolve (4aR)-11-chloro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-6-methyl-5,7-dioxo-1,2,4,4a,5,6,7,8-octahydro-3H-pyrazino[1',2':4,5]pyrazino[2,3-c][1,8]naphthyl-3-carboxylic acid tert-butyl ester (517 mg, 0.7549 mmol) in dichloromethane (8 mL), and add trifluoroacetic acid (2 mL). The reaction mixture was stirred at room temperature for 2 hours, and then concentrated to obtain the product (4aR)-11-chloro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-6-methyl-2,3,4,4a,6,8-hexahydro-1H-pyrazino[1',2':4,5]pyrazino[2,3-c][1,8]naphthidine-5,7-dione (530 mg, crude product), which was directly used in the next step of the reaction. ES-API:[M+H] + =577.2.

[0543] Step 9: (4aR)-11-chloro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-6-methyl-2,3,4,4a,6,8-hexahydro-1H-pyrazino[1',2':4,5]pyrazino[2,3-c][1,8]naphthyl-5,7-dione (530 mg, 0.7549 mmol) was dissolved in dichloromethane (15 mL), and triethylamine (3.0 mL, 21.62 mmol) was added. The reaction was cooled to 0 °C, and acryloyl chloride (100 mg, 1.1048 mmol) was added dropwise to the reaction solution. The reaction was stirred at 0 °C for 15 minutes. Add 80 mL of dichloromethane to the reaction solution, wash with 100 mL of saturated NaHCO3 aqueous solution and 80 mL of saturated brine, dry and concentrate. Purify the crude product using a rapid silica gel column chromatography (EtOAc / PE: 0-60%) to obtain the product (4aR)-3-acryloyl-11-chloro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-6-methyl-2,3,4,4a,6,8-hexahydro-1H-pyrazino[1',2':4,5]pyrazino[2,3-c][1,8]naphthidine-5,7-dione (280 mg, Y: 59%), a yellow solid. ES-API: [M+H] + =631.2.

[0544] Step 10: Under ice-water bath conditions, (4aR)-3-acryloyl-11-chloro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-6-methyl-2,3,4,4a,6,8-hexahydro-1H-pyrazino[1',2':4,5]pyrazino[2,3-c][1,8]naphthidine-5,7-dione (280 mg, 0.444 mmol) was added to dry dichloromethane (6.0 mL), followed by boron tribromide (5.0 mL, 5.0 mmol). The mixture was then brought to room temperature and reacted overnight. Under ice-water bath conditions, the above reaction solution was added dropwise to a saturated sodium bicarbonate solution, extracted twice with dichloromethane (80 mL), dried, concentrated, and the crude product was purified by rapid silica gel column chromatography (EtOAc / PE: 0-60%) to obtain the product (4aR)-3-acryloyl-11-chloro-10-(2-fluoro-6-hydroxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-6-methyl-2,3,4,4a,6,8-hexahydro-1H-pyrazino[1',2':4,5]pyrazino[2,3-c][1,8]naphthidine-5,7-dione (Z25, 233 mg, Y: 85%).

[0545] Step 11: Compound Z25 was separated by preparative chiral HPLC (column type: IA: 10 μm, 30*250 mm, mobile phase: hexane: EtOH = 60:40, flow rate: 25 ml / min, column temperature) to obtain: a trans-restricted isomer compound Z25-1 (76.8 mg, peak 1, retention time 2.531 min, Y: 34%). 1 H NMR (500MHz, DMSO-d6) δ10.03(d,J=18.4Hz,1H),8.52(d,J=7.3Hz,1H),8.43(d,J=4.7Hz,1H),7.23(d,J=9.6Hz,2H) ,7.08(dd,J=16.6,10.5Hz,1H),6.74–6.62(m,2H),6.15(d,J=16.8Hz,1H),5.75(d,J=10.7Hz,1H),4.73(d,J=14.2H z,1H),4.46(d,J=12.9Hz,1H),4.00(s,1H),3.61(d,J=10.0Hz,1H),3.51(s,1H),3.34(s,3H),3.22(s,1H),2.64(t, J=11.5Hz,1H),2.48–2.42(m,1H),1.98(d,J=5.1Hz,3H),1.03(t,J=6.9Hz,3H),0.86(t,J=7.9Hz,3H).ES-API:[M+H] + =617.2. And another transisomer compound Z25-2 (70 mg, peak 2, retention time 3.683 min, Y: 31%). 1 H NMR (500MHz, CDCl3) δ8.64–8.59(m,1H),8.35(s,1H),8.07(s,1H),7.27–7.20(m,2H),7.14–7.02(m, 1H),6.75–6.63(m,2H),6.39(dd,J=17.0,2.0Hz,1H),5.88–5.77(m,1H),4.91(d,J=14.0Hz,1H),4.8 3(d,J=13.0Hz,1H),3.72–3.58(m,2H),3.50(s,3H),3.43(d,J=12.0Hz,1H),3.16(t,J=13.0Hz,1H), 2.91(t,J=12.0Hz,1H),2.82-2.73(m,1H),1.93(s,3H),1.24(d,J=7.0Hz,3H),1.12(d,J=7.0Hz,3H). ES-API:[M+H] +=617.2. The isomers were detected by analytical chiral HPLC (column type: IA: 5 μm, 4.6*150 mm, mobile phase: hexane:EtOH = 60:40, flow rate: 1 ml / min, column temperature = 30 °C).

[0546] Example 26 Preparation of compounds Z26, Z26-1 and Z26-2

[0547]

[0548] Step 1: (4aR)-11-chloro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-6-(methyl-d3)-5,7-dioxo-1,2,4,4a,5,6,7,8-octahydro-3H-pyrazino[1',2':4,5]pyrazino[2,3-c][1,8]naphthyl-3-carboxylic acid tert-butyl ester (511 mg, 0.7549 mmol) was dissolved in dichloromethane (8 mL), and trifluoroacetic acid (2 mL) was added. The reaction mixture was stirred at room temperature for 2 hours, and then concentrated to obtain the product (4aR)-11-chloro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-6-(methyl-d3)-2,3,4,4a,6,8-hexahydro-1H-pyrazino[1',2':4,5]pyrazino[2,3-c][1,8]naphthidine-5,7-dione (520 mg, crude product), which was directly used in the next step of the reaction. ES-API:[M+H] + =580.3.

[0549] Step 2: (4aR)-11-chloro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-6-(methyl-d3)-2,3,4,4a,6,8-hexahydro-1H-pyrazino[1',2':4,5]pyrazino[2,3-c][1,8]naphthyl-5,7-dione (520 mg, 0.7549 mmol) was dissolved in dichloromethane (10 mL), and triethylamine (3.0 mL, 21.62 mmol) was added. The reaction was cooled to 0 °C, and acryloyl chloride (100 mg, 1.1048 mmol) was added dropwise to the reaction solution. The reaction was stirred at 0 °C for 15 minutes. Add 80 mL of dichloromethane to the reaction solution, wash with 100 mL of saturated NaHCO3 aqueous solution and 80 mL of saturated brine, dry and concentrate. Purify the crude product using a rapid silica gel column chromatography (EtOAc / PE: 0-60%) to obtain the product (4aR)-3-acryloyl-11-chloro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-6-(methyl-d3)-2,3,4,4a,6,8-hexahydro-1H-pyrazino[1',2':4,5]pyrazino[2,3-c][1,8]naphthidine-5,7-dione (232 mg, Y: 48%), a yellow solid. ES-API: [M+H] + =634.2.

[0550] Step 3: Under ice-water bath conditions, (4aR)-3-acryloyl-11-chloro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-6-(methyl-d3)-2,3,4,4a,6,8-hexahydro-1H-pyrazino[1',2':4,5]pyrazino[2,3-c][1,8]naphthidine-5,7-dione (240 mg, 0.3791 mmol) was added to dry dichloromethane (6.0 mL), followed by boron tribromide (5.0 mL, 5.0 mmol). The mixture was then brought to room temperature and reacted overnight. Under ice-water bath conditions, the above reaction solution was added dropwise to a saturated sodium bicarbonate solution, extracted twice with dichloromethane (80 mL), dried, concentrated, and the crude product was purified by rapid silica gel column chromatography (EtOAc / PE: 0-60%) to give the product (4aR)-3-acryloyl-11-chloro-10-(2-fluoro-6-hydroxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-6-(methyl-d3)-2,3,4,4a,6,8-hexahydro-1H-pyrazino[1',2':4,5]pyrazino[2,3-c][1,8]naphthidine-5,7-dione (Z26, 187 mg, Y: 79%). [M+H] + =620.3.

[0551] Step 4: Compound Z26 (187 mg, 0.302 mmol) was separated by preparative chiral HPLC (column type: IA: 10 μm, 30*250 mm, mobile phase: hexane: EtOH = 60:40, flow rate: 25 ml / min, column temperature) to obtain a trans-restricted isomer compound, the structure of which is arbitrarily designated as Z26-1 (68.8 mg, peak 1, retention time 2.525 min, Y: 36.7%). 1 H NMR (500MHz, DMSO-d6) δ10.03(d,J=17.9Hz,1H),8.51(d,J=7.4Hz,1H),8.43(d,J=4.7Hz,1H),7.29–7.18(m ,2H),7.08(dd,J=17.0,10.6Hz,1H),6.74–6.61(m,2H),6.15(d,J=16.6Hz,1H),5.75(d,J=11.5Hz,1H),4.73 (d,J=13.5Hz,1H),4.46(d,J=12.3Hz,1H),4.00(s,1H),3.61(d,J=10.5Hz,1H),3.50(s,1H),3.22(s,1H),2. 65(t,J=12.5Hz,1H), 2.49–2.42(m,1H), 1.98(d,J=5.0Hz,3H), 1.02(d,J=7.0Hz,3H), 0.86(t,J=7.9Hz,3H). ES-API:[M+H] + =620.3. And another transisomer compound, the structure of which is arbitrarily designated as Z26-2 (63.2 mg, peak 2, retention time 3.683 min, Y: 33.79%). 1 H NMR(400MHz, CDCl3)δ8.62(d,J=4.8Hz,1H),8.35(s,1H),8.07(s,1H),7.24–7.20(m,2H),7.16–7.01(m, 1H),6.74–6.63(m,2H),6.39(dd,J=16.8,2.0Hz,1H),5.82(dd,J=10.4,2.0Hz,1H),4.91(d,J=13.6Hz,1H ),4.83(d,J=13.6Hz,1H),3.71–3.57(m,2H),3.42(d,J=12.0Hz,1H),3.16(t,J=12.8Hz,1H),2.91(t,J= 12.0Hz,1H),2.81-2.70(m,1H),1.92(s,3H),1.22(d,J=6.8Hz,3H),1.10(d,J=6.8Hz,3H).ES-API:[M+H] +=620.3. The isomers were detected by analytical chiral HPLC (column type: IA: 5 μm, 4.6*150 mm, mobile phase: hexane:EtOH = 60:40, flow rate: 1 ml / min, column temperature = 30 °C).

[0552] Example 27 Preparation of compounds Z27, Z27-1 and Z27-2

[0553]

[0554] Step 1: 4,6-Dichloro-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro-1,8-naphthidium-2(1H)-one (500 mg, 0.9686 mmol) was dissolved in N,N-dimethylacetamide (5 mL), followed by the sequential addition of 1-(tert-butyl)-3-methyl(3R,6R)-6-methylpiperazine-1,3-dicarboxylic acid ester (375 mg, 1.452 mmol) and N,N-diisopropylethylamine (375 mg, 2.907 mmol). The reaction mixture was stirred at 120 °C for 2 hours. 80 mL of ethyl acetate was added to the reaction solution, and the mixture was washed three times with 80 mL of saturated brine. The ethyl acetate phase was dried and concentrated. The crude product was purified by rapid silica gel column chromatography (EtOAc / PE: 0-80%) to give 1-(tert-butyl)-3-methyl(3R,6R)-4-(6-chloro-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro-2-oxo-1,2-dihydro-1,8-naphthidin-4-yl)-6-methylpiperazine-1,3-dicarboxylic acid ester (535 mg, Y: 74.5%), a yellow solid. ES-API: [M+H] + =739.2.

[0555] Step 2: 1-(tert-butyl)3-methyl(3R,6R)-4-(6-chloro-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro-2-oxo-1,2-dihydro-1,8-naphthidin-4-yl)-6-methylpiperazine-1,3-dicarboxylic acid ester (530 mg, 0.7179 mmol) was dissolved in acetic acid (6 mL), and iron powder (200 mg, 3.571 mmol) was added. The reaction was stirred at 80 °C for 30 minutes. The reaction solution was concentrated, and 200 mL of ethyl acetate and 100 mL of saturated sodium bicarbonate were added sequentially. The suspension was filtered through diatomaceous earth, and the filter cake was washed with ethyl acetate. The organic phase was separated and washed sequentially with 100 mL of saturated sodium bicarbonate and 150 mL of saturated brine. After drying and concentration, the product (2R,4aR)-11-chloro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-2-methyl-5,7-dioxo-1,2,4,4a,5,6,7,8-octahydro-3H-pyrazino[1',2':4,5]pyro[2,3-c][1,8]naphthyl-3-carboxylic acid tert-butyl ester (452 ​​mg, Y: 92%) was obtained as a yellow solid. ES-API: [M+H] + =677.2.

[0556] Step 3: Add (2R,4aR)-11-chloro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-2-methyl-5,7-dioxo-1,2,4,4a,5,6,7,8-octahydro-3H-pyrazino[1',2':4,5]pyro[2,3-c][1,8]naphthyl-3-carboxylic acid tert-butyl ester (445 mg, 0.6583 mmol), 10 mL acetone, anhydrous potassium carbonate (500 mg, 2.633 mmol), and iodomethane (1.20 g, 6.5828 mmol) to a 150 mL sealed tube. Seal the tube and stir the reaction at 55 °C for 18 hours. The reaction mixture was added to 150 mL of ethyl acetate, washed three times with 100 mL of saturated brine, dried, and concentrated. The crude product was purified by rapid silica gel column chromatography (EtOAc / PE: 0-80%) to give (2R,4aR)-11-chloro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-2,6-dimethyl-5,7-dioxo-1,2,4,4a,5,6,7,8-octahydro-3H-pyrazino[1',2':4,5]pyrazino[2,3-c][1,8]naphthyl-3-carboxylic acid tert-butyl ester (455 mg, crude), a yellow solid. ES-API: [M+H] + =691.3.

[0557] Step 4: Dissolve (2R,4aR)-11-chloro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-2,6-dimethyl-5,7-dioxo-1,2,4,4a,5,6,7,8-octahydro-3H-pyrazino[1',2':4,5]pyrazino[2,3-c][1,8]naphthyl-3-carboxylic acid tert-butyl ester (511 mg, 0.7549 mmol) in dichloromethane (8 mL), and add trifluoroacetic acid (2 mL). The reaction mixture was stirred at room temperature for 2 hours, and then concentrated to obtain the product (2R,4aR)-11-chloro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-2,6-dimethyl-2,3,4,4a,6,8-hexahydro-1H-pyrazino[1',2':4,5]pyrazino[2,3-c][1,8]naphthidine-5,7-dione (462 mg, crude product), which was directly used in the next step of the reaction. ES-API:[M+H] + =591.3.

[0558] Step 5: (2R,4aR)-11-chloro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-2,6-dimethyl-2,3,4,4a,6,8-hexahydro-1H-pyrazino[1',2':4,5]pyrazino[2,3-c][1,8]naphthidine-5,7-dione (462 mg, 0.6283 mmol) was dissolved in dichloromethane (8 mL), and triethylamine (2.0 mL, 14.41 mmol) was added. The reaction was cooled to 0 °C, and acryloyl chloride (100 mg, 1.1048 mmol) was added dropwise to the reaction solution. The reaction was stirred at 0 °C for 15 minutes. Add 80 mL of dichloromethane to the reaction solution, wash with 100 mL of saturated NaHCO3 aqueous solution and 80 mL of saturated brine, dry and concentrate. Purify the crude product using a rapid silica gel column chromatography (EtOAc / PE: 0-60%) to obtain the product (2R,4aR)-3-acryloyl-11-chloro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-2,6-dimethyl-2,3,4,4a,6,8-hexahydro-1H-pyrazino[1',2':4,5]pyrazino[2,3-c][1,8]naphthidine-5,7-dione (290 mg, Y: 68%), a yellow solid. ES-API: [M+H] + =645.2.

[0559] Step 6: Under ice-water bath conditions, (2R,4aR)-3-acryloyl-11-chloro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-2,6-dimethyl-2,3,4,4a,6,8-hexahydro-1H-pyrazino[1',2':4,5]pyrazino[2,3-c][1,8]naphthidine-5,7-dione (290 mg, 0.4503 mmol) was added to dry dichloromethane (6.0 mL), followed by boron tribromide (6.0 mL, 6.0 mmol). The mixture was then brought to room temperature and reacted overnight. Under ice-water bath conditions, the above reaction solution was added dropwise to a saturated sodium bicarbonate solution, extracted twice with dichloromethane (80 mL), dried, concentrated, and the crude product was purified by rapid silica gel column chromatography (EtOAc / PE: 0-60%) to obtain the product (2R,4aR)-3-acryloyl-11-chloro-10-(2-fluoro-6-hydroxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-2,6-dimethyl-2,3,4,4a,6,8-hexahydro-1H-pyrazino[1',2':4,5]pyrazino[2,3-c][1,8]naphthidine-5,7-dione (Z27, 307 mg, crude product). [M+H] + =631.2.

[0560] Step 7: Compound Z27 was separated by preparative chiral HPLC (column type: IA*: 10 μm, 30*250 mm, mobile phase: hexane: EtOH = 60:40, flow rate: 25 ml / min, column temperature) to obtain: a trans-restricted isomer compound Z27-1 (67.7 mg, peak 1, retention time 2.394 min, Y: 23.4%). 1H NMR (500MHz, DMSO-d6) δ10.05(d,J=17.8Hz,1H),8.43(d,J=4.8Hz,1H),8.23(d,J=9.9Hz,1H),7.23(d,J=9.9Hz,2H),7 .02(dd,J=16.8,10.6Hz,1H),6.74–6.63(m,2H),6.15(dd,J=16.8,2.3Hz,1H),5.76(dd,J=10.5,2.3Hz,1H),4.78(s,1 H),4.60(d,J=13.8Hz,1H),4.00(d,J=3.5Hz,1H),3.75(dd,J=14.1,3.9Hz,1H),3.41–3.33(m,1H),3.34(s,3H),2.81( d,J=12.1Hz,1H),2.48–2.42(m,1H),1.98(s,3H),1.53(d,J=6.7Hz,3H),1.03(d,J=5.5Hz,3H),0.85(t,J=6.2Hz,3H). ES-API:[M+H] + =631.2. And another transisomer compound Z27-2 (64.6 mg, peak 2, retention time 3.382 min, Y: 23.2%). 1 H NMR (400MHz, CDCl3) δ8.57(d,J=4.8Hz,1H),8.36(s,1H),8.28(s,1H),7.25–7.15(m,2H),7.03(dd,J=16.8,10.8H z,1H),6.72–6.61(m,2H),6.34(dd,J=16.8,2.0Hz,1H),5.80(dd,J=10.8,2.0Hz,1H),5.11–5.01(m,1H),4.77(d,J =14.0Hz,1H),3.82(dd,J=14.0,4.4Hz,1H),3.61(d,J=4.4Hz,1H),3.49(s,3H),3.30–3.17(m,1H),3.03(dd,J=12. 0,3.6Hz,1H),2.80-2.68(m,1H),1.91(s,3H),1.66(d,J=6.8Hz,3H),1.22(d,J=6.8Hz,3H),1.08(d,J=6.8Hz,3H). ES-API:[M+H] + =631.2. The isomers were detected by analytical chiral HPLC (column type: IA: 5 μm, 4.6*150 mm, mobile phase: hexane:EtOH = 60:40, flow rate: 1 ml / min, column temperature = 30 °C).

[0561] Example 28 Preparation of compound Z28

[0562]

[0563] Step 1: 4-Chloro-6-fluoro-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro-1,8-naphthidium-2(1H)-one (400 mg, 0.80 mmol) was dissolved in DMF (5 mL), and (S)-3-(hydroxymethyl)piperazine-1-carboxylic acid tert-butyl ester (432 mg, 2.00 mmol) and N,N-diisopropylethylamine (310 mg, 2.40 mmol) were added. The reaction was stirred at 75 °C for 2 hours. The reaction solution was diluted with 100 mL of ethyl acetate, washed five times with 40 mL of saturated brine, dried, and concentrated. The crude product was purified by rapid silica gel column chromatography (EtOAc / PE: 0-70%) to give (3S)-4-(6-fluoro-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro-2-oxo-1,2-dihydro-1,8-naphthidin-4-yl)-3-(hydroxymethyl)piperazine-1-carboxylic acid tert-butyl ester (420 mg, Y: 77.2%), a yellow solid. ES-API: [M+H] + =681.3.

[0564] Step 2: (3S)-4-(6-fluoro-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro-2-oxo-1,2-dihydro-1,8-naphthidin-4-yl)-3-(hydroxymethyl)piperazine-1-carboxylic acid tert-butyl ester (420 mg, 0.62 mmol) was dissolved in DMA (20 mL), and LiHMDS (1.55 mL, 1.55 mmol, 1.0 M in THF) was added. The reaction was slowly heated to 140 °C and stirred for 24 hours. The reaction solution was diluted with 100 mL of ethyl acetate, washed four times with 40 mL of dilute saline solution, and once with 40 mL of saturated saline solution. After drying and concentration, the crude product was purified by rapid silica gel column chromatography (EtOAc / PE: 0-100%) to give (4aS)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-7-oxo-1,2,4a,5,7,8-hexahydropyrazine[1',2':4,5][1,4]oxazine[2,3-c][1,8]naphthyl-3(4H)-carboxylic acid tert-butyl ester (180 mg, Y: 46.0%), a yellow solid. ES-API: [M+H]+=634.3.

[0565] Step 3: Dissolve (4aS)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-7-oxo-1,2,4a,5,7,8-hexahydropyrazine[1',2':4,5][1,4]oxo[2,3-c][1,8]naphthyl-3(4H)-carboxylic acid tert-butyl ester (35 mg, 0.055 mmol) in dichloromethane (4 mL), and add trifluoroacetic acid (1 mL). The reaction mixture was stirred at room temperature for 1 hour, and then concentrated to obtain the product (4aS)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-1,2,3,4,4a,5-hexahydropyrazine[1',2':4,5][1,4]oxazine[2,3-c][1,8]naphthyl-7(8H)-one (185 mg, crude product), which was directly used in the next reaction. ES-API:[M+H] + =534.3.

[0566] Step 4: (4aS)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-1,2,3,4,4a,5-hexahydropyrazine[1',2':4,5][1,4]oxazine[2,3-c][1,8]naphthyl-7(8H)-one (185 mg, crude) was dissolved in dichloromethane (6 mL), and N,N-diisopropylethylamine (180 mg, 1.40 mmol) was added. The reaction was cooled to 0 °C, and a dichloromethane solution of acryloyl chloride (50 mg, 0.56 mmol) was added dropwise to the reaction mixture (0.5 mL). The reaction was stirred at 0 °C for 15 minutes. Add 50 mL of dichloromethane to the reaction solution, wash twice successively with 15 mL of water, 15 mL of saturated NaHCO3 aqueous solution, and 15 mL of saturated brine. After drying the organic phase, concentrate to obtain the product (4aS)-3-acryloyl-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-1,2,3,4,4a,5-hexahydropyrazine[1',2':4,5][1,4]oxazine[2,3-c][1,8]naphthidium-7(8H)-one (160 mg, Y: 95.8%), a yellow solid. ES-API: [M+H] + =588.3.

[0567] Step 5: (4aS)-3-acryloyl-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-1,2,3,4,4a,5-hexahydropyrazine[1',2':4,5][1,4]oxazine[2,3-c][1,8]naphthyl-7(8H)-one (160 mg, 0.27 mmol) was dissolved in dichloromethane (4 mL). The reaction mixture was cooled to 0 °C, and a 17% boron tribromide solution in dichloromethane (3 mL) was added dropwise. The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into 25 mL of cold saturated NaHCO3 aqueous solution and extracted with 50 mL of dichloromethane. The organic phase was washed successively with 25 mL of saturated NaHCO3 aqueous solution and 25 mL of saturated saline solution, dried and concentrated. The crude product was purified by preparative HPLC to obtain the product (4aS)-3-acryloyl-11-fluoro-10-(2-fluoro-6-hydroxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-1,2,3,4,4a,5-hexahydropyrazine[1′,2′:4,5][1,4]oxazine[2,3-c][1,8]naphthidium-7(8H)-one (Z28, 90 mg, Y: 57.6%), a pale yellow solid. 1 H NMR (400MHz, DMSO-d6) δ10.04(s,1H),8.42(d,J=4.8Hz,1H),8.22(d,J=7.4Hz,1H) ,7.27-7.17(m,2H),7.01–6.78(m,1H),6.77–6.58(m,2H),6.18(d,J=16.3Hz,1H),5 .87–5.66(m,1H),4.51-3.97(m,4H),3.91–3.39(m,4H),3.14–3.01(m,1H),2.62–2 .41(m,1H),1.91-1.76(m,3H),1.12–0.98(m,3H),0.94-0.83(m,3H).ES-API:[M+H] + =574.2.

[0568] Example 29 Preparation of compound Z29

[0569]

[0570] Step 1: 7-Chloro-6-fluoro-4-hydroxy-1-(2-isopropyl-4-methylpyridin-3-yl)-1,8-naphthidin-2(1H)-one (4.0 g, 11.53 mmol) was dissolved in acetic acid (9 mL), followed by the addition of sodium nitrite (79 mg, 1.15 mmol) and concentrated nitric acid (2.3 mL, 34.6 mmol). The reaction mixture was stirred at room temperature for 30 minutes. The reaction solution was slowly poured into 100 mL of ice water. The precipitated solid was filtered, and the filter cake was washed with 20 mL of ice water and dried under vacuum to obtain the product 7-chloro-6-fluoro-4-hydroxy-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro-1,8-naphthidin-2(1H)-one (3.1 g, Y: 80%), a yellow solid. ES-API: [M+H] + =393.1.

[0571] Step 2: Add 7-chloro-6-fluoro-4-hydroxy-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro-1,8-naphthidin-2(1H)-one (1.0 g, 2.55 mmol), (5-methyl-1H-indazole-4-yl)boronic acid (1.8 g, 10.2 mmol), tetrakis(triphenylphosphine)palladium (589 mg, 0.51 mmol), potassium carbonate (1.76 g, 12.75 mmol), 2 mL of water, and 8 mL of dioxane to a 100 mL three-necked round-bottom flask. Under nitrogen protection, stir at 110 °C for 1 hour. After the reaction is complete, cool the reaction mixture to room temperature, add 80 mL of water and 100 mL of methyl tert-butyl ether, and extract once. The aqueous phase was adjusted to pH 3-4 with 1M hydrochloric acid solution, causing solid precipitation. After filtration, the solid product was dried under vacuum to obtain 0.8 g (50%) of 6-fluoro-7-(5-methyl-1H-indazol-4-yl)-4-hydroxy-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro-1,8-naphthidium-2(1H)-one, a pale yellow solid. ES-API: [M+H] + =489.2.

[0572] Step 3: 6-Fluoro-7-(5-methyl-1H-indazol-4-yl)-4-hydroxy-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro-1,8-naphthidin-2(1H)-one (0.6 g, 1.23 mmol) was dissolved in acetonitrile (20 mL), followed by the addition of phosphorus oxychloride (0.94 g, 6.15 mmol) and N,N-diisopropylethylamine (1.27 g, 9.84 mmol). The reaction mixture was gradually heated to 80 °C and stirred for 24 h. The reaction solution was concentrated, and 30 mL of cold acetonitrile was added dropwise to 30 mL of saturated sodium bicarbonate solution under an ice-water bath. The mixture was extracted with ethyl acetate (200 mL * 2), and the combined ethyl acetate phases were washed once with 50 mL of saturated brine. The product was dried over anhydrous sodium sulfate, filtered, and the organic phase was dried and concentrated. The crude product was purified by rapid silica gel column chromatography (EtOAc / PE: 0-80%) to obtain 4-chloro-6-fluoro-7-(5-methyl-1H-indazol-4-yl)-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro-1,8-naphthidium-2(1H)-one (0.3 g, Y: 50%), a yellow solid. ES-API: [M+H] + =507.0.

[0573] Step 4: 4-Chloro-6-fluoro-7-(5-methyl-1H-indazol-4-yl)-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro-1,8-naphthidin-2(1H)-one (150 mg, 0.296 mmol) was dissolved in N,N-dimethylacetamide (25 mL), followed by the addition of (R)-3-(hydroxymethyl)piperazine-1-carboxylic acid tert-butyl ester (1.48 g, 320 mmol). The reaction mixture was stirred at 80 °C for 1.5 hours. 80 mL of ethyl acetate was added to the reaction solution, and the mixture was washed three times with 80 mL of saturated brine. The ethyl acetate phase was dried and concentrated. The crude product was purified by rapid silica gel column chromatography (EtOAc / PE: 0-80%) to give (3R)-4-(6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)-7-(5-methyl-1H-indazol-4-yl)-3-nitro-2-oxo-1,2-dihydro-1,8-naphthidin-4-yl)-3-(hydroxymethyl)piperazine-1-carboxylic acid tert-butyl ester (10 mg, Y: 40%), a yellow solid. ES-API: [M+H] + =787.3.

[0574] Step 5: Dissolve (3R)-4-(6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)-7-(5-methyl-1H-indazol-4-yl)-3-nitro-2-oxo-1,2-dihydro-1,8-naphthidin-4-yl)-3-(hydroxymethyl)piperazine-1-carboxylic acid tert-butyl ester (90 mg, 0.13 mmol) in N,N-dimethylacetamide (25 mL), add sodium hydride (15.7 mg, 0.39 mmol), and stir the reaction at 130 °C for 18 h. Cool to room temperature, pour into ice water, adjust pH to 7 with 3M hydrochloric acid, add 30 mL of ethyl acetate, separate the organic phase, wash successively with 30 mL of water and 30 mL of saturated brine, dry and concentrate to obtain the product (4aR)-11-fluoro-8-(2-isopropyl-4-methylpyridin-3-yl)-10-(5-methyl-1H-indazol-4-yl)-7-oxo-1,2,4a,5,7,8-hexahydropyrazino[1',2':4,5][1,4]oxazine[2,3-c][1,8]naphthyl-3(4H)-carboxylic acid tert-butyl ester (60 mg, Y: 70%), a yellow solid. ES-API: [M+H] + =640.3.

[0575] Step 6: Dissolve (4aR)-11-fluoro-8-(2-isopropyl-4-methylpyridin-3-yl)-10-(5-methyl-1H-indazol-4-yl)-7-oxo-1,2,4a,5,7,8-hexahydropyrazino[1',2':4,5][1,4]oxazine[2,3-c][1,8]naphthyl-3(4H)-carboxylic acid tert-butyl ester (60 mg, 0.094 mmol) in dichloromethane (4 mL), and add trifluoroacetic acid (2 mL). The reaction mixture was stirred at room temperature for 2 hours, and then concentrated to obtain the product (4aR)-11-fluoro-8-(2-isopropyl-4-methylpyridin-3-yl)-10-(5-methyl-1H-indazol-4-yl)-1,2,3,4,4a,5-hexahydropyrazino[1',2':4,5][1,4]oxazine[2,3-c][1,8]naphthidine7(8H)-one (50 mg, crude product), which was directly used in the next step of the reaction. ES-API:[M+H] + =540.2.

[0576] Step 7: (4aR)-11-fluoro-8-(2-isopropyl-4-methylpyridin-3-yl)-10-(5-methyl-1H-indazol-4-yl)-1,2,3,4,4a,5-hexahydropyrazino[1',2':4,5][1,4]oxazine[2,3-c][1,8]naphthidine 7(8H)-one (50 mg, 0.093 mmol) was dissolved in dichloromethane (5 mL), and triethylamine (60 mg, 0.465 mmol) was added. The reaction was cooled to 0 °C, and acryloyl chloride (10.5 mg, 0.083 mmol) was added dropwise to the reaction solution. The reaction was stirred at 0 °C for 15 minutes. 20 mL of dichloromethane was added to the reaction solution, followed by washing with 20 mL of saturated NaHCO3 aqueous solution and 20 mL of saturated saline solution. After drying and concentration, the product (4aR)-3-acryloyl-11-fluoro-8-(2-isopropyl-4-methylpyridin-3-yl)-10-(5-methyl-1H-indazol-4-yl)-1,2,3,4,4a,5-hexahydropyrazino[1',2':4,5][1,4]oxazine[2,3-c][1,8]naphthidium-7(8H)-one (Z29, 15 mg, Y: 28%). ES-API: [M+H + =594.2. 1 H NMR (500MHz, DMSO-d6) δ13.08(s,1H),8.37(d,J=4.8Hz,1H),8.32(d,J=9.4Hz,1H),7.49(d,J=8.1Hz,2H ),7.24(d,J=8.5Hz,1H),7.20(d,J=5.0Hz,1H),6.90(s,1H),6.20(d,J=16.7Hz,1H),5.78(s,1H),4.45( d,J=46.5Hz,1H),4.35–4.20(m,2H),4.05(s,1H),3.85(d,J=51.4Hz,1H),3.75–3.57(m,2H),3.48(s,1H) ),3.15(s,1H),2.05(s,3H),1.90(d,J=33.7Hz,3H),1.03(t,J=6.7Hz,3H),0.81(dd,J=20.9,6.4Hz,3H).

[0577] Example 30: Preparation of compounds Z30, Z30-1 and Z30-2

[0578]

[0579] Step 1: Add (4aR)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-5,7-dioxo-1,2,4,4a,5,6,7,8-octahydro-3H-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8]naphthyl-3-carboxylic acid tert-butyl ester (310 mg, 0.48 mmol), 10 mL acetone, anhydrous potassium carbonate (265 mg, 1.92 mmol), and iodoethane (599 mg, 3.84 mmol) sequentially to a 15 mL sealed tube. Seal the tube and stir the reaction at 55 °C for 18 hours. The reaction solution was concentrated, and 60 mL of ethyl acetate was added. The mixture was washed successively with 30 mL of water and 30 mL of saturated brine. After drying and concentration, the crude product was purified by rapid silica gel column chromatography (EtOAc / PE: 0-70%) to give (4aR)-6-ethyl-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-5,7-dioxo-1,2,4,4a,5,6,7,8-octyl-3H-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8]naphthyl-3-carboxylic acid tert-butyl ester (290 mg, Y: 89.7%), an orange solid. ES-API: [M+H] + =675.3.

[0580] Step 2: Dissolve (4aR)-6-ethyl-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-5,7-dioxo-1,2,4,4a,5,6,7,8-octyl-3H-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8]naphthyl-3-carboxylic acid tert-butyl ester (290 mg, 0.43 mmol) in dichloromethane (4 mL), and add trifluoroacetic acid (1 mL). The reaction mixture was stirred at room temperature for 2 hours, and then concentrated to obtain the product (4aR)-6-ethyl-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-2,3,4,4a,6,8-hexahydro-1H-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8]naphthidine-5,7-dione (300 mg, crude product), which was directly used in the next reaction. ES-API:[M+H] + =575.2.

[0581] Step 3: (4aR)-6-ethyl-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-2,3,4,4a,6,8-hexahydro-1H-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8]naphthyl-5,7-dione (300 mg, crude) was dissolved in dichloromethane (15 mL), and N,N-diisopropylethylamine (464 mg, 3.60 mmol) was added. The reaction was cooled to 0 °C, and acryloyl chloride (130 mg, 1.44 mmol) was added to the reaction solution. The reaction was stirred at 0 °C for 15 minutes. Add 45 mL of dichloromethane to the reaction solution, wash successively with 25 mL of water, 25 mL of saturated NaHCO3 aqueous solution, and 25 mL of saturated brine, dry and concentrate. After drying and concentration, the crude product is purified by rapid silica gel column chromatography (EtOAc / PE: 0-90%) to obtain the product (4aR)-3-acryloyl-6-ethyl-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-2,3,4,4a,6,8-hexahydro-1H-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8]naphthidine-5,7-dione (2450 mg, Y: 90.7%), a pale yellow solid. ES-API: [M+H] + =615.3.

[0582] Step 4: (4aR)-3-acryloyl-6-ethyl-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-2,3,4,4a,6,8-hexahydro-1H-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8]naphthidine-5,7-dione (245 mg, 0.39 mmol) was dissolved in dichloromethane (5 mL). The reaction mixture was cooled to 0 °C, and a 17% boron tribromide solution in dichloromethane (5 mL) was added dropwise. The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into 60 mL of saturated NaHCO3 aqueous solution and extracted twice with 50 mL of dichloromethane. The organic phase was washed successively with 30 mL of saturated NaHCO3 aqueous solution and 30 mL of saturated brine, dried, and concentrated to give the product (4aR)-3-acryloyl-6-ethyl-11-fluoro-10-(2-fluoro-6-hydroxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-2,3,4,4a,6,8-hexahydro-1H-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8]naphthidine-5,7-dione (Z30, 240 mg, Y: 100%), a pale yellow solid. ES-API: [M+H] + =615.3.

[0583] Step 5: Compound Z30 (240 mg, 0.39 mmol) was purified by preparative HPLC and then resolved by preparative chiral HPLC (column type: IB: 10 μm, 30*250 mm, mobile phase: hexane: EtOH = 70:30, flow rate: 25 ml / min, column temperature) to obtain a trans-restricted isomer compound, arbitrarily designated as Z30-1 (71 mg, peak 1, retention time 6.342 min, Y: 29.6%), a pale yellow solid. 1 H NMR (500MHz, DMSO-d6) δ10.11(d,J=1.1Hz,1H),8.45(d,J=4.9Hz,1H),8.40(d,J=8.8Hz,1H),7.32–7.18 (m,2H),7.12-6.80(m,1H),6.75–6.62(m,2H),6.15(dd,J=16.8,2.0Hz,1H),5.75(d,J=12.2Hz,1H),4.7 2(d,J=13.5Hz,1H),4.46(d,J=11.9Hz,1H),4.18-3.93(m,3H),3.63-3.50(m,2H),3.26-3.06(m,1H),2. 80-2.55(m,1H),2.50-2.39(m,1H),1.97(s,3H),1.10–0.95(m,6H),0.86(d,J=6.7Hz,3H).ES-API:[M+H] + =615.2. And another transisomer compound, the structure of which is arbitrarily designated as Z30-2 (73 mg, peak 2, retention time 7.970 min, Y: 30.5%), a pale yellow solid. 1 H NMR (500MHz, DMSO-d6) δ10.13(s,1H),8.45(d,J=4.9Hz,1H),8.39(d,J=8.8Hz,1H),7.31–7. 19(m,2H),7.12-6.80(m,1H),6.77-6.62(m,2H),6.15(dd,J=16.8,2.1Hz,1H),5.75(d,J=12. 3Hz,1H),4.73(d,J=14.1Hz,1H),4.46(d,J=13.0Hz,1H),4.20–4.02(m,2H),4.00-3.91(m,1H ),3.65-3.53(m,2H),3.26-3.06(m,1H),,2.82-2.58(m,2H),1.80(s,3H),1.15–0.93(m,9H). 1 ES-API:[M+H] +=615.2. The isomers were detected by analytical chiral HPLC (column type: IB: 5 μm, 4.6*250 mm, mobile phase: hexane: EtOH = 70:30, flow rate: 1 ml / min, column temperature = 30 °C).

[0584] Example 31 Preparation of compound 731

[0585]

[0586] Step 1: Add 6-chloro-7-(2-fluoro-6-methoxyphenyl)-4-hydroxy-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro-1,8-naphthidin-2(1H)-one (1.0 g, 2.0 mmol), potassium cyclopropyltrifluoroborate (1.48 g, 10.0 mmol), chloro(2-dicyclohexylphosphine-2′,6′-dimethoxy-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) (144 mg, 0.20 mmol), 2-dicyclohexylphosphine-2′,6′-dimethoxybiphenyl (82 mg, 0.20 mmol), potassium carbonate (1.66 g, 12.0 mmol), 2 mL of water, and 20 mL of toluene to a 250 mL round-bottom flask. The reaction was carried out under nitrogen protection and stirred at 125 °C for 18 hours. The reaction solution was concentrated, 50 mL of water was added, and the pH was adjusted to 3.0 with 3.0 M dilute hydrochloric acid. The mixture was extracted twice with 50 mL of dichloromethane. After drying the organic phase, it was concentrated to give the product 6-cyclopropyl-7-(2-fluoro-6-methoxyphenyl)-4-hydroxy-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro-1,8-naphthidine-2(1H)-one (850 mg, crude product), a brown solid. ES-API: [M+H] + =505.2.

[0587] Step 2: 6-Cyclopropyl-7-(2-fluoro-6-methoxyphenyl)-4-hydroxy-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro-1,8-naphthidin-2(1H)-one (1.6 g, crude) was dissolved in acetonitrile (50 mL), followed by the addition of phosphorus oxychloride (2.43 g, 15.85 mmol) and N,N-diisopropylethylamine (3.27 g, 25.36 mmol). The reaction mixture was stirred at 85 °C for 1 hour. The reaction solution was concentrated, and 120 mL of ethyl acetate was added. The solution was washed twice with 60 mL of water, then 60 mL of saturated sodium bicarbonate, and finally 60 mL of saturated brine. After drying and concentrating the organic phase, the crude product was purified by rapid silica gel column chromatography (EtOAc / PE: 0-35%) to obtain the product 4-chloro-6-cyclopropyl-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro-1,8-naphthidium-2(1H)-one (520 mg, Y: 24.8%), a pale yellow solid. ES-API: [M+H] + =523.2.

[0588] Step 3: 4-Chloro-6-cyclopropyl-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro-1,8-naphthidin-2(1H)-one (490 mg, 0.94 mmol) was dissolved in N,N-dimethylacetamide (6 mL), and (3R,6R)-1-N-BOC-6-methylpiperazine-3-carboxylate (485 mg, 1.88 mmol) and N,N-diisopropylethylamine (364 mg, 2.82 mmol) were added sequentially. The reaction was stirred at 125 °C for 3 hours. 100 mL of ethyl acetate was added to the reaction solution, and the mixture was washed four times with 30 mL of dilute brine, then washed again with 30 mL of saturated brine. The solution was dried and concentrated. The crude product was purified by rapid silica gel column chromatography (EtOAc / PE: 0-50%) to give methyl (3R,6R)-1-N-BOC-4-(6-cyclopropyl-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro-2-oxo-1,2-dihydro-1,8-naphthidin-4-yl)-6-methylpiperazine-3-carboxylate (485 mg, Y: 69.4%), an orange solid. ES-API: [M+H] + =745.3.

[0589] Step 4: Methyl (3R,6R)-1-N-BOC-4-(6-cyclopropyl-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro-2-oxo-1,2-dihydro-1,8-naphthidin-4-yl)-6-methylpiperazine-3-carboxylate (455 mg, 0.61 mmol) was dissolved in acetic acid (8 mL), and iron powder (120 mg, 2.14 mmol) was added. The reaction was stirred at 80 °C for 30 minutes. The reaction solution was concentrated, and 80 mL of ethyl acetate and 50 mL of saturated sodium bicarbonate were added sequentially. The suspension was filtered through diatomaceous earth, and the filter cake was washed with ethyl acetate. The organic phase was separated and washed sequentially with 25 mL of saturated sodium bicarbonate and 25 mL of saturated brine. After drying and concentration, the product (2R,4aR)-11-cyclopropyl-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-2-methyl-5,7-dioxo-1,2,4,4a,5,6,7,8-octyl-3H-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8]naphthyl-3-carboxylic acid tert-butyl ester (415 mg, Y: 99.5%) was obtained as a pale yellow solid. ES-API: [M+H]+=683.3.

[0590] Step 5: Add (2R,4aR)-11-cyclopropyl-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-2-methyl-5,7-dioxo-1,2,4,4a,5,6,7,8-octyl-3H-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8]naphthyl-3-carboxylic acid tert-butyl ester (415 mg, 0.61 mmol), 12 mL acetone, anhydrous potassium carbonate (337 mg, 2.44 mmol), and iodomethane (693 mg, 4.88 mmol) to a 50 mL sealed tube. Seal the tube and stir the reaction at 50 °C for 18 hours. The reaction solution was added to 60 mL of ethyl acetate, washed successively with 15 mL of water and 15 mL of saturated brine, dried and concentrated. The crude product was purified by preparative thin-layer chromatography (dichloromethane / methanol = 25:1) to give the product (2R,4aR)-11-cyclopropyl-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-2,6-dimethyl-5,7-dioxo-1,2,4,4a,5,6,7,8-octyl-3H-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8]naphthyl-3-carboxylic acid tert-butyl ester (160 mg, Y: 37.8%), a pale yellow solid. ES-API: [M+H] + =697.3.

[0591] Step 6: Dissolve (2R,4aR)-11-cyclopropyl-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-2,6-dimethyl-5,7-dioxo-1,2,4,4a,5,6,7,8-octyl-3H-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8]naphthyl-3-carboxylic acid tert-butyl ester (160 mg, 0.23 mmol) in dichloromethane (3.5 mL), and add trifluoroacetic acid (0.8 mL). The reaction mixture was stirred at room temperature for 2 hours, and then concentrated to obtain the product ((2R,4aR)-11-cyclopropyl-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-2,6-dimethyl-1,2,4,4a,6,8-hexahydro-3l2-pyrazine[4',3':4,5]pyrazine[2,3-c][1,8]naphthidine-5,7-dione (165 mg, crude product), which was directly used in the next step of the reaction. ES-API:[M+H] + =597.2.

[0592] Step 7: (2R,4aR)-11-cyclopropyl-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-2,6-dimethyl-1,2,4,4a,6,8-hexahydro-3l2-pyrazine[4',3':4,5]pyrazine[2,3-c][1,8]naphthylidine-5,7-dione (165 mg, crude) was dissolved in dichloromethane (10 mL), and N,N-diisopropylethylamine (148 mg, 1.15 mmol) was added. The reaction was cooled to 0 °C, and acryloyl chloride (41 mg, 0.46 mmol) was added dropwise to the reaction solution. The reaction was stirred at 0 °C for 15 minutes. Add 30 mL of dichloromethane to the reaction solution, wash successively with 15 mL of water, 15 mL of saturated NaHCO3 aqueous solution, and 15 mL of saturated brine, dry and concentrate. After drying and concentration, the crude product is purified by rapid silica gel column chromatography (dichloromethane / methanol: 0-5%) to obtain the product (2R,4aR)-3-acryloyl-11-cyclopropyl-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-2,6-dimethyl-2,3,4,4a,6,8-hexahydro-1H-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8]naphthidine-5,7-dione (140 mg, Y: 93.7%), a pale yellow solid. ES-API: [M+H] + =651.3.

[0593] Step 8: (2R,4aR)-3-acryloyl-11-cyclopropyl-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-2,6-dimethyl-2,3,4,4a,6,8-hexahydro-1H-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8]naphthidine-5,7-dione (130 mg, 0.20 mmol) was dissolved in dichloromethane (3 mL). The reaction mixture was cooled to 0 °C, and a 17% boron tribromide solution in dichloromethane (3 mL) was added dropwise. The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into 40 mL of saturated NaHCO3 aqueous solution and extracted twice with 25 mL of dichloromethane. After drying and concentrating the organic phase, the crude product was purified by preparative HPLC to obtain the product (2R,4aR)-3-acryloyl-11-cyclopropyl-10-(2-fluoro-6-hydroxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-2,6-dimethyl-2,3,4,4a,6,8-hexahydro-1H-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8]naphthidine-5,7-dione (Z31, 65 mg, Y: 51.1%), a white solid. 1 H NMR (500MHz, DMSO-d6) δ9.90 (s, 1H), 8.42 (d, J = 4.8Hz, 1H), 7.75-7.73 (m, 1H), 7.22-7.17 (m, 2H), 7. 03(dd,J=16.8,10.5Hz,1H),6.74–6.60(m,2H),6.22–6.08(m,1H),5.81–5.69(m,1H),5.05-4.81(m,1 H),4.62-4.41(m,1H),4.03-3.90(m,1H),3.75(dd,J=14.1,4.2Hz,1H),3.39-3.25(m,4H),2.83-2.6 7(m,1H),2.48-2.37(m,1H),2.01–1.75(m,3H),1.70–1.46(m,4H),1.14–0.55(m,10H).ES-API:[M+H] + =637.3.

[0594] Example 32 Preparation of compound Z32

[0595]

[0596] Step 1: 4,6-Dicyclopropylpyrimidine-5-amine (742 mg, 4.24 mmol) was dissolved in dry tetrahydrofuran (20 mL). 2M NaHMDS (8.48 mL, 16.96 mmol) was added under ice-water bath conditions, and the mixture was stirred for 20 minutes. 2,5-Difluoro-6-(2-fluoro-6-methoxyphenyl)nicotinic acid (1.2 g, 4.24 mmol) was added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was then slowly poured into 30 mL of ice water. The pH was adjusted to 5-6 with dilute hydrochloric acid (3 M). The mixture was extracted with ethyl acetate and washed once with 50 mL of saturated brine. The product was dried over anhydrous sodium sulfate, filtered, and the organic phase was dried and concentrated. The crude product was purified by rapid silica gel column chromatography (EtOAc / PE: 20-40%) to obtain 2-((4,6-dicyclopropylpyrimidin-5-yl)amino)-5-fluoro-6-(2-fluoro-6-methoxyphenyl)nicotinic acid (1.8 g, Y: 98%), a yellow solid. ES-API: [M+H] + =439.1.

[0597] Step 2: Dissolve 2-((4,6-dicyclopropylpyrimidin-5-yl)amino)-5-fluoro-6-(2-fluoro-6-methoxyphenyl)nicotinic acid (1.5 g, 3.42 mmol) in dichloroethane, and add sulfoxide (4.07 g, 34.2 mmol). Stir the reaction mixture at 80 °C for 2 hours. After the reaction is complete, cool the reaction solution to room temperature, concentrate it, and dry it under vacuum at 50 °C for 4 hours to obtain the product 2-((4,6-dicyclopropylpyrimidin-5-yl)amino)-5-fluoro-6-(2-fluoro-6-methoxyphenyl)nicotinic acid chloride (1.57 g, crude product), a pale yellow solid. Methanol detection: ES-API: [M+H] + =453.2.

[0598] Step 3: Under ice-water bath conditions, sodium hydride (1.97 g, 49.35 mmol) was added to tetrahydrofuran containing ethyl nitrate (1.31 g, 9.86 mmol) and stirred for 30 minutes. Then, 2-((4,6-dicyclopropylpyrimidin-5-yl)amino)-5-fluoro-6-(2-fluoro-6-methoxyphenyl)nicotinic acid chloride (1.57 g, 3.29 mmol) was added and stirred at room temperature for 1 h. The mixture was then heated to 80 °C and reacted for 2 h. The mixture was poured into ice water, the pH was adjusted to 3-4 with 3M hydrochloric acid, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the organic phase was dried and concentrated to obtain the product 1-(4,6-dicyclopropylpyrimidin-5-yl)-6-fluoro-7-(2-fluoro-6-methoxyphenyl)-4-hydroxy-3-nitro-1,8-naphthidine-2(1H)-one (110 mg, Y: 20%). ES-API:[M+H] + =508.1.

[0599] Step 4: 1-(4,6-dicyclopropylpyrimidin-5-yl)-6-fluoro-7-(2-fluoro-6-methoxyphenyl)-4-hydroxy-3-nitro-1,8-naphthidium-2(1H)-one (110 mg, 0.20 mmol) was dissolved in acetonitrile (10 mL), and phosphorus oxychloride (153 mg, 1.0 mmol) and N,N-diisopropylethylamine (77 g, 0.6 mmol) were added sequentially. The reaction was gradually heated to 80 °C and stirred for 3 h. The reaction solution was concentrated, and 30 mL of cold acetonitrile was added dropwise to 30 mL of saturated sodium bicarbonate solution under an ice-water bath. Extraction was performed with ethyl acetate (50 mL * 2). The organic phases were combined, washed with 30 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic phase was dried and concentrated. The crude product was purified by rapid silica gel column chromatography (EtOAc / PE: 0-80%) to obtain 4-chloro-6-fluoro-7-(2-fluoro-6-methoxyphenyl)-1-(4,6-dicyclopropylpyrimidin-5-yl)-3-nitro-1,8-naphthidium-2(1H)-one (110 mg, Y: 68%), a yellow solid. ES-API: [M+H] + =526.2.

[0600] Step 5: 4-Chloro-6-fluoro-7-(2-fluoro-6-methoxyphenyl)-1-(4,6-dicyclopropylpyrimidin-5-yl)-3-nitro-1,8-naphthidium-2(1H)-one (110 mg, 0.296 mmol) was dissolved in N,N-dimethylacetamide (3 mL), followed by the addition of 1-(tert-butyl)-3-methyl(R)-piperazine-1,3-dicarboxylic acid ester (54 mg, 0.22 mmol). The reaction was stirred at 120 °C for 2 hours. After the reaction was complete, 30 mL of ethyl acetate was added, and the mixture was washed three times with 30 mL of saturated brine. The ethyl acetate phase was dried and concentrated to give a crude product, the target product (3R)-1-tert-butyl-3-methyl-4-(1-(4,6-dicyclopropylpyrimidin-5-yl)-6-fluoro-7-(2-fluoro-6-methoxyphenyl)-3-nitro-2-oxo-1,2-dihydro-1,8-naphthidin-4-yl)piperazine-1,3-dione (50 mg, Y: 46%), a yellow solid. ES-API: [M+H] + =734.3.

[0601] Step 6: Dissolve ((3R)-1-tert-butyl-3-methyl-4-(1-(4,6-dicyclopropylpyrimidin-5-yl)-6-fluoro-7-(2-fluoro-6-methoxyphenyl)-3-nitro-2-oxo-1,2-dihydro-1,8-naphthidin-4-yl)piperazine-1,3-dione (50 mg, 0.068 mmol) in acetic acid (25 mL), add iron powder (11.5 mg, 0.204 mmol), and stir the reaction mixture at 80 °C for 30 minutes. Concentrate the reaction mixture, add 30 mL of ethyl acetate and 30 mL of saturated sodium bicarbonate sequentially, and filter the suspension through diatomaceous earth. The filter cake was washed with ethyl acetate, and the organic phase was separated. The mixture was then washed successively with 30 mL of saturated sodium bicarbonate and 30 mL of saturated brine. After drying and concentration, the product (4aR)-8-(4,6-dicyclopropylpyrimidin-5-yl)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-5,7-dioxo-4,4a,5,6,7,8-hexahydro-1H-pyrazino[1',2':4,5]pyrazino[2,3-c][1,8]naphthyl-3(2H)-carboxylic acid tert-butyl ester (40 mg, crude product) was obtained as a yellow solid. ES-API: [M+H]+ = 672.2.

[0602] Step 7: Seal (4aR)-8-(4,6-dicyclopropylpyrimidin-5-yl)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-5,7-dioxo-4,4a,5,6,7,8-hexahydro-1H-pyrazino[1',2':4,5]pyrazino[2,3-c][1,8]naphthyl-3(2H)-carboxylic acid tert-butyl ester (40 mg, 0.059 mmol), 30 mL acetone, anhydrous potassium carbonate (33 mg, 0.24 mmol), and iodomethane (85 mg, 0.59 mmol) in a tube and stir the reaction at 50 °C for 18 hours. The reaction mixture was added to 20 mL of ethyl acetate, washed with 20 mL of saturated brine, dried, and concentrated. The crude product was purified by rapid silica gel column chromatography (EtOAc / PE: 0-80%) to give the product (4aR)-tert-butyl-8-(4,6-dicyclopropylpyrimidin-5-yl)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-6-methyl-5,7-dioxo-4,4a,5,6,7,8-hexahydro-1H-pyrazino[1',2':4,5]pyrazino[2,3-c][1,8]naphthidium-3(2H)-one (40 mg, Y: 90%), a yellow solid. ES-API: [M+H] + =686.2.

[0603] Step 8: Dissolve (4aR)-tert-butyl-8-(4,6-dicyclopropylpyrimidin-5-yl)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-6-methyl-5,7-dioxo-4,4a,5,6,7,8-hexahydro-1H-pyrazino[1',2':4,5]pyrazino[2,3-c][1,8]naphthidium-3(2H)-one (44 mg) in dichloromethane (3 mL), and add trifluoroacetic acid (1 mL). The reaction mixture was stirred at room temperature for 2 hours, and then concentrated to obtain the product (4aR)-8-(4,6-dicyclopropylpyrimidin-5-yl)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-6-methyl-2,3,4,4a-tetrahydro-1H-pyrazino[1',2':4,5]pyrazino[2,3-c][1,8]naphthidine-5,7(6H,8H)-dione (40 mg, crude product), which was directly used in the next step of the reaction. ES-API:[M+H] + =586.2.

[0604] Step 9: (4aR)-8-(4,6-dicyclopropylpyrimidin-5-yl)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-6-methyl-2,3,4,4a-tetrahydro-1H-pyrazino[1',2':4,5]pyrazino[2,3-c][1,8]naphthidine-5,7(6H,8H)-dione (40 mg, 0.068 mmol) was dissolved in dichloromethane (5 mL), and diisopropylethylamine (53 mL, 0.408 mmol) was added. The reaction was cooled to 0 °C, and acryloyl chloride (12.4 mg, 0.137 mmol) was added dropwise to the reaction solution. The reaction was stirred at 0 °C for 15 minutes. Add 20 mL of dichloromethane to the reaction solution, wash with 20 mL of saturated NaHCO3 aqueous solution and 20 mL of saturated brine, dry and concentrate. The crude product is purified by preparative HPLC to obtain the product (4aR)-3-acryloyl-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(4,6-dicyclopropylpyrimidin-5-yl)-6-methyl-2,3,4,4a,6,8-hexahydro-1H-pyrazino[1',2':4,5]pyrazino[2,3-c][1,8]naphthidine-5,7-dione (Z32, 10 mg, Y: 22%), a yellow solid. ES-API: [M+H] + =640.2.

[0605] Example 33 Preparation of compounds Z33, Z33-1 and Z33-2

[0606]

[0607] Step 1: 7-Chloro-6-fluoro-4-hydroxy-1-(1-isopropyl-4-methyl-1H-pyrazol-5-yl)-2-oxo-1,2-dihydro-1,8-naphthidium-3-onitrile (3.6 g, 10.0 mmol) was suspended in a mixed solution of 1,4-dioxane (10 mL) and water (120 mL), and concentrated sulfuric acid (10 mL) was slowly added. The reaction was stirred at 120 °C for 18 hours. The cooled reaction solution was poured into 20 mL of ice water, the pH was adjusted to 2-3 with sodium carbonate, and the mixture was extracted with ethyl acetate (1000 mL * 2). The ethyl acetate phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was dried under vacuum to obtain the product 7-chloro-6-fluoro-4-hydroxy-1-(1-isopropyl-4-methyl-1H-pyrazol-5-yl)-1,8-naphthidium-2(1H)-one (3.36 g, Y: 92%), a light brown solid. ES-API:[M+H] + =337.1.

[0608] Step 2: 7-Chloro-6-fluoro-4-hydroxy-1-(1-isopropyl-4-methyl-1H-pyrazol-5-yl)-1,8-naphthidin-2(1H)-one (3.36 g, 10 mmol) was dissolved in acetic acid (7 mL), followed by the addition of sodium nitrite (69 mg, 1.0 mmol) and concentrated nitric acid (2.0 mL, 30 mmol). The reaction mixture was stirred at room temperature for 30 minutes. The reaction solution was slowly poured into 21 mL of ice water. The precipitated solid was filtered, and the filter cake was washed with 10 mL of ice water and dried under vacuum to obtain the product 7-chloro-6-fluoro-4-hydroxy-1-(1-isopropyl-4-methyl-1H-pyrazol-5-yl)3-nitro-1,8-naphthidin-2(1H)-one (3.0 g, Y: 90%), a yellow solid. ES-API: [M+H] + =382.1.

[0609] Step 3: Add 1.5 g (3.93 mmol) of 7-chloro-6-fluoro-4-hydroxy-1-(1-isopropyl-4-methyl-1H-pyrazol-5-yl)3-nitro-1,8-naphthid-2(1H)-one, 2.67 g (15.72 mmol), 908 mg (0.786 mmol), 2.72 g (19.65 mmol), 4 mL of water, and 20 mL of dioxane to a 100 mL three-necked round-bottom flask. Under nitrogen protection, stir the mixture at 100 °C for 3 hours. After the reaction is complete, cool the reaction mixture to room temperature, add 20 mL of water and 50 mL of methyl tert-butyl ether, and extract once. The aqueous phase was adjusted to pH 3-5 with 1M hydrochloric acid solution, extracted with ethyl acetate (50 mL * 2), and the ethyl acetate phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was dried under vacuum to give the product 6-fluoro-7-(2-fluoro-6-methoxyphenyl)-4-hydroxy-1-(1-isopropyl-4-methyl-1H-pyrazol-5-yl)-3-nitro-1,8-naphthidium-2(1H)-one (1.5 g, crude product), a pale yellow solid. ES-API: [M+H] + =472.1.

[0610] Step 4: 6-Fluoro-7-(2-fluoro-6-methoxyphenyl)-4-hydroxy-1-(1-isopropyl-4-methyl-1H-pyrazol-5-yl)-3-nitro-1,8-naphthidin-2(1H)-one (1.5 g, 3.18 mmol) was dissolved in acetonitrile (15 mL), followed by the addition of phosphorus oxychloride (2.4 mL, 25.5 mmol) and N,N-diisopropylethylamine (2.6 mL, 15.9 mmol). The reaction mixture was gradually heated to 80 °C and stirred for 30 minutes. The reaction solution was concentrated, and 10 mL of cold acetonitrile was added dropwise to 20 mL of saturated sodium bicarbonate solution under an ice-water bath. The mixture was extracted with ethyl acetate (20 mL * 2), and the combined ethyl acetate phases were washed once with 20 mL of saturated brine. After drying with anhydrous sodium sulfate and filtering, the organic phase was dried and concentrated. The crude product was purified by rapid silica gel column chromatography (EtOAc / PE: 0-50%) to obtain 4-chloro-6-fluoro-7-(2-fluoro-6-methoxyphenyl)-1-(1-isopropyl-4-methyl-1H-pyrazol-5-yl)-3-nitro-1,8-naphthidium-2(1H)-one (0.9 g, Y: 65%), a yellow solid. ES-API: [M+H] + =490.1.

[0611] Step 5: 4-Chloro-6-fluoro-7-(2-fluoro-6-methoxyphenyl)-1-(1-isopropyl-4-methyl-1H-pyrazol-5-yl)-3-nitro-1,8-naphthidium-2(1H)-one (490 mg, 1.0 mmol) was dissolved in N,N-dimethylacetamide (5 mL), followed by the sequential addition of (3R,6R)-1-tert-butyl-3-methyl-6-methylpiperazine-1,3-dicarboxylic acid (310 mg, 1.2 mmol) and N,N-diisopropylethylamine (390 mg, 3 mmol). The reaction mixture was stirred at 120 °C for 2 hours. 20 mL of ethyl acetate was added to the reaction solution, and the mixture was washed three times with 20 mL of saturated brine. The ethyl acetate phase was dried and concentrated to give (3R,6R)-1-tert-butyl-3-methyl-4-(6-fluoro-7-(2-fluoro-6-methoxyphenyl)-1-(1-isopropyl-4-methyl-1H-pyrazole-5-yl)-3-nitro-2-oxo-1,2-dihydro-1,8-naphthidin-4-yl)piperazine-1,3-dione (620 mg, crude), a yellow solid. ES-API: [M+H] + =712.2.

[0612] Step 6: Dissolve (3R,6R)-1-tert-butyl-3-methyl-4-(6-fluoro-7-(2-fluoro-6-methoxyphenyl)-1-(1-isopropyl-4-methyl-1H-pyrazole-5-yl)-3-nitro-2-oxo-1,2-dihydro-1,8-naphthidin-4-yl)piperazine-1,3-dione (620 mg, 0.872 mmol) in acetic acid (8 mL), add iron powder (146 mg, 2.62 mmol), and stir the reaction at 80 °C for 30 minutes. The reaction solution was concentrated, and 30 mL of ethyl acetate and 30 mL of saturated sodium bicarbonate were added sequentially. The suspension was filtered through diatomaceous earth, and the filter cake was washed with ethyl acetate. The organic phase was separated and washed sequentially with 30 mL of saturated sodium bicarbonate and 30 mL of saturated brine. After drying and concentration, the product (2R,4aR)-tert-butyl11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(1-isopropyl-4-methyl-1H-pyrazol-5-yl)-2-methyl-5,7-dioxo-4,4a,5,6,7,8-hexahydro-1H-pyrazino[1',2':4,5]pyrazino[2,3-c][1,8]naphthidine-3(2H)-carboxylic acid tert-butyl ester (300 mg, crude product) was obtained as a yellow solid. ES-API: [M+H]+=650.3.

[0613] Step 7: Seal (2R,4aR)-tert-butyl11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(1-isopropyl-4-methyl-1H-pyrazol-5-yl)-2-methyl-5,7-dioxo-4,4a,5,6,7,8-hexahydro-1H-pyrazino[1',2':4,5]pyrazino[2,3-c][1,8]naphthyl-3(2H)-carboxylic acid tert-butyl ester (300 mg, 0.462 mmol), 6 mL acetone, anhydrous potassium carbonate (255 mg, 1.84 mmol), and iodomethane (656 mg, 4.62 mmol) in a tube and stir the reaction at 50 °C for 18 hours. The reaction mixture was added to 20 mL of ethyl acetate, washed with 20 mL of saturated brine, dried, and concentrated. The crude product was purified by rapid silica gel column chromatography (EtOAc / PE: 0-80%) to give (2R,4aR)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(1-isopropyl-4-methyl-1H-pyrazol-5-yl)-2,6-dimethyl-5,7-dioxo-4,4a,5,6,7,8-hexahydro-1H-pyrazino[1',2':4,5]pyrazino[2,3-c][1,8]naphthidine-3(2H)-carboxylic acid tert-butyl ester (350 mg, Y: 95%), a yellow solid. ES-API: [M+H] + =664.3.

[0614] Step 8: Dissolve (2R,4aR)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(1-isopropyl-4-methyl-1H-pyrazol-5-yl)-2,6-dimethyl-5,7-dioxo-4,4a,5,6,7,8-hexahydro-1H-pyrazino[1',2':4,5]pyrazino[2,3-c][1,8]naphthyl-3(2H)-carboxylic acid tert-butyl ester (350 mg) in dichloromethane (4 mL), and add trifluoroacetic acid (2 mL). The reaction mixture was stirred at room temperature for 2 hours, and then concentrated to obtain the product (2R,4aR)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(1-isopropyl-4-methyl-1H-pyrazol-5-yl)-2,6-dimethyl-2,3,4,4a-tetrahydro-1H-pyrazino[1',2':4,5]pyrazino[2,3-c][1,8]naphthidine-5,7(6H,8H)-dione (40 mg, crude product), which was directly used in the next reaction. ES-API:[M+H] + =564.2.

[0615] Step 9: (2R,4aR)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(1-isopropyl-4-methyl-1H-pyrazol-5-yl)-2,6-dimethyl-2,3,4,4a-tetrahydro-1H-pyrazino[1',2':4,5]pyrazino[2,3-c][1,8]naphthidine-5,7(6H,8H)-dione (350 mg, 0.62 mmol) was dissolved in dichloromethane (6 mL), and diisopropylethylamine (480 mg, 3.72 mmol) was added. The reaction was cooled to 0 °C, and acryloyl chloride (112.5 mg, 1.24 mmol) was added dropwise to the reaction solution. The reaction was stirred at 0 °C for 15 minutes. Add 20 mL of dichloromethane to the reaction solution, wash with 20 mL of saturated NaHCO3 aqueous solution and 20 mL of saturated saline solution, dry and concentrate. The crude product is purified by preparative chromatography to obtain the product (2R,4aR)-3-acryloyl-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(1-isopropyl-4-methyl-1H-pyrazol-5-yl)-2,6-dimethyl-2,3,4,4a-tetrahydro-1H-pyrazino[1',2':4,5]pyrazino[2,3-c][1,8]naphthidine-5,7(6H,8H)-dione (250 mg, Y: 60%), a yellow solid. ES-API: [M+H] + =618.3.

[0616] Step 10: Under ice-water bath conditions, (2R,4aR)-3-acryloyl-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(1-isopropyl-4-methyl-1H-pyrazol-5-yl)-2,6-dimethyl-2,3,4,4a-tetrahydro-1H-pyrazino[1',2':4,5]pyrazino[2,3-c][1,8]naphthidine-5,7(6H,8H)-dione (250 mg, 0.405 mmol) was added to dry dichloromethane (6.0 mL), followed by boron tribromide (4.0 mL, 4.0 mmol). The mixture was then brought to room temperature and reacted for 1 h. Under ice-water bath conditions, the above reaction solution was added dropwise to a saturated sodium bicarbonate solution, extracted twice with dichloromethane (30 mL), dried, and concentrated to obtain the product (2R,4aR)-3-acryloyl-11-fluoro-10-(2-fluoro-6-hydroxyphenyl)-8-(1-isopropyl-4-methyl-1H-pyrazol-5-yl)-2,6-dimethyl-2,3,4,4a-tetrahydro-1H-pyrazino[1',2':4,5]pyrazino[2,3-c][1,8]naphthidine-5,7(6H,8H)-dione (Z33).

[0617] Step 11: Compound Z33 was purified by preparative HPLC to obtain a transtransisomer compound, the structure of which was arbitrarily designated as Z33-1 (peak 1, 30 mg, retention time 9.576 min, Y: 50%). 1 H NMR (500MHz, DMSO-d6) δ10.17(s,1H),7.98(dd,J=8.4,5.5Hz,1H),7.40(d,J=5.5Hz,1H),7.29(q,J=7.9Hz,1 H),7.02(dd,J=16.8,10.6Hz,1H),6.81–6.68(m,2H),6.20–6.11(m,1H),5.81–5.69(m,1H),4.77(s,1H),4.61 (d, J = 14.7 Hz, 1H), 4.01–3.83 (m, 2H), 3.73 (dd, J = 14.2, 4.2 Hz, 1H), 3.35 (d, J = 5.8 Hz, 3H), 2.86 (dd, J = 48.2, 12.0 Hz, 1H), 1.76–1.59 (m, 3H), 1.55 (dd, J = 16.6, 6.7 Hz, 3H), 1.26 (dd, J = 32.6, 6.6 Hz, 3H), 1.21–1.10 (m, 3H). And another transisomer compound, arbitrarily designated as Z33-2 (peak 2, 15 mg, retention time 9.663 min, Y: 25%). 1 H NMR (500MHz, DMSO-d6) δ10.17(s,1H),7.96(m,1H),7.40(d,J=5.5Hz,1H),7.29(q,J=7.9Hz,1H),7. 02(m,1H),6.81–6.68(m,2H),6.20–6.11(m,1H),5.81–5.69(m,1H),4.77(s,1H),4.61(d,J=14.7Hz The isomers were detected by analytical HPLC. The isomers were 4.01–3.83 (m, 2H), 3.73 (dd, J = 14.2, 4.2 Hz, 1H), 3.35 (d, J = 5.8 Hz, 3H), 2.86 (m, 1H), 1.76–1.59 (m, 3H), 1.55 (m, 3H), 1.30 (dd, J = 32.6, 6.6 Hz, 3H), and 1.23–1.15 (m, 3H).

[0618] Example 34 Preparation of compounds Z34, Z34-1 and Z34-2

[0619]

[0620] Step 1: Add (2R,4aR)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-2-methyl-5,7-dioxo-1,2,4,4a,5,6,7,8-octyl-3H-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8]naphthyl-3-carboxylic acid tert-butyl ester (115 mg, 0.17 mmol), 4 mL of acetone, anhydrous potassium carbonate (94 mg, 0.68 mmol), and deuterated iodomethane (246 mg, 1.70 mmol) sequentially to a 15 mL sealed tube. Seal the tube and stir the reaction at 50 °C for 18 hours. The reaction solution was added to 30 mL of ethyl acetate, washed successively with 12 mL of water and 15 mL of saturated brine, dried, and concentrated to obtain the product (2R,4aR)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-2-methyl-6-(methyl-d3)-5,7-dioxo-1,2,4,4a,5,6,7,8-octyl-3H-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8]naphthyl-3-carboxylic acid tert-butyl ester (118 mg, Y: 100.0%), a yellow solid. ES-API: [M+H] + =678.3.

[0621] Step 2: Dissolve (2R,4aR)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-2-methyl-6-(methyl-d3)-5,7-dioxo-1,2,4,4a,5,6,7,8-octyl-3H-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8]naphthyl-3-carboxylic acid tert-butyl ester (118 mg, 0.17 mmol) in dichloromethane (3 mL), and add trifluoroacetic acid (0.7 mL). The reaction mixture was stirred at room temperature for 2 hours, and then concentrated to obtain the product (2R,4aR)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-2-methyl-6-(methyl-d3)-2,3,4,4a,6,8-hexahydro-1H-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8]naphthidine-5,7-dione (120 mg, crude product), which was directly used in the next step of the reaction. ES-API:[M+H] + =578.2.

[0622] Step 3: (2R,4aR)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-2-methyl-6-(methyl-d3)-2,3,4,4a,6,8-hexahydro-1H-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8]naphthylidine-5,7-dione (120 mg, crude) was dissolved in dichloromethane (5 mL), and N,N-diisopropylethylamine (110 mg, 0.85 mmol) was added. The reaction was cooled to 0 °C, and acryloyl chloride (31 mg, 0.34 mmol) was added dropwise to the reaction solution. The reaction was stirred at 0 °C for 15 minutes. Add 25 mL of dichloromethane to the reaction solution, wash successively with 15 mL of water, 15 mL of saturated NaHCO3 aqueous solution, and 15 mL of saturated brine, dry and concentrate. After drying and concentration, the crude product is purified by rapid silica gel column chromatography (EtOAc / PE: 0-100%) to obtain the product (2R,4aR)-3-acryloyl-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-2-methyl-6-(methyl-d3)-2,3,4,4a,6,8-hexahydro-1H-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8]naphthidine-5,7-dione (85 mg, Y: 77.3%), a pale yellow solid. ES-API: [M+H] + =632.2.

[0623] Step 4: (2R,4aR)-3-acryloyl-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-2-methyl-6-(methyl-d3)-2,3,4,4a,6,8-hexahydro-1H-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8]naphthidine-5,7-dione (85 mg, 0.13 mmol) was dissolved in dichloromethane (1.5 mL). The reaction mixture was cooled to 0 °C, and a 17% boron tribromide solution in dichloromethane (1.5 mL) was added dropwise. The reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was poured into 40 mL of saturated NaHCO3 aqueous solution and extracted twice with 25 mL of dichloromethane. After drying and concentrating the organic phase, the crude product was purified by preparative HPLC to obtain the product (2R,4aR)-3-acryloyl-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-2-methyl-6-(methyl-d3)-2,3,4,4a,6,8-hexahydro-1H-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8]naphthidine-5,7-dione (Z34).

[0624] Step 5: Compound Z34 was purified by preparative chiral HPLC (column type: OD-H: 10 μm, 20*250 mm, mobile phase: hexane:EtOH = 80:20, flow rate: 15 ml / min, column temperature) to obtain: a trans-restricted isomer compound, arbitrarily designated as Z34-1 (23 mg, peak 1, retention time 11.056 min, Y: 28.7%), a pale yellow solid. 1 H NMR (500MHz, DMSO-d6) δ10.14(s,1H),8.44(d,J=4.9Hz,1H),8.01-7.97(m,1H),7.28–7.23(m,2H),7.05-6.84(m 1H),6.77–6.64(m,2H),6.18–6.13(m,1H),5.77–5.71(m,1H),5.03-4.77( m,1H),4.61-4.41(m,1H),4.06-4.00(m,1H),3.73(dd,J=14.1,4.2Hz,1H), 3.39–3.20(m,1H),2.92–2.79(m,1H),2.47-2.36(m,1H),1.99(s,3H),1.5 8-1.53(m,3H),1.03(d,J=6.7Hz,3H),0.85(d,J=6.7Hz,3H).ES-API:[M+H] + =618.2. And another transisomer compound, the structure of which is arbitrarily designated as Z34-2 (25 mg, peak 2, retention time 14.067 min, Y: 31.2%), a pale yellow solid. 1 H NMR (500MHz, DMSO-d6) δ10.15(s,1H),8.45(d,J=4.9Hz,1H),8.01-7.97(m,1H),7.28–7.23(m,2H),7.05-6.85(m 1H),6.74–6.63(m,2H),6.18–6.13(m,1H),5.77–5.71(m,1H),5.04-4.77( m,1H),4.62-4.41(m,1H),4.00-3.94(m,1H),3.73(dd,J=14.1,4.2Hz,1H), 3.43–3.25(m,1H),2.95–2.83(m,1H),2.79-2.74(m,1H),1.80(s,3H),1.5 8-1.53(m,3H),1.11(d,J=6.7Hz,3H),0.98(d,J=6.7Hz,3H).ES-API:[M+H] +=618.2. The isomers were detected by analytical chiral HPLC (...

Claims

1. A compound of formula (b) or (c) or a transisomer thereof or a pharmaceutically acceptable salt thereof: in, R lev It is a trifluoromethanesulfonate group, chlorine, bromine, iodine, methanesulfonate group, or toluenesulfonate group; X1 is hydrogen, halogen, hydroxyl, C 1-6 Alkyl, C 3-6 cycloalkyl; E1' is N or CR5'; where R5' is hydrogen or halogen; R0' is a 5- or 6-membered monocyclic heteroaryl group, wherein the 5- or 6-membered monocyclic heteroaryl group has 1, 2, or 3 heteroatoms selected from N, O, and S as ring atoms; and the 5- or 6-membered monocyclic heteroaryl group is unsubstituted or has 1, 2, 3, or 4 independent heteroatoms selected from R0'. s3 Substitution of groups; R s3 Halogen, cyano, hydroxyl, -C 1-6 Alkyl, -C 1-6 alkoxy or -C 3-6 cycloalkyl; wherein the C 1-6 Alkyl, -C 1-6 Alkoxy, -C 3-6 The cycloalkyl group is optionally represented by one, two, or three independently selected from halogen, methyl, ethyl, propyl, isopropyl, or trifluoromethyl.

2. The compound of formula (b) or (c) as claimed in claim 1, or a transisomer thereof or a pharmaceutically acceptable salt thereof, wherein, R lev It can be trifluoromethanesulfonate group, chlorine, bromine, iodine, methanesulfonate group or p-toluenesulfonate group.

3. The compound of formula (b) or (c) as claimed in claim 1, or a transisomer thereof or a pharmaceutically acceptable salt thereof, wherein, X1 can be hydrogen, fluorine, chlorine, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

4. The compound of formula (b) or (c) as described in any one of claims 1-3, or its transisomer or a pharmaceutically acceptable salt thereof, wherein, X1 is fluorine, chlorine, or cyclopropyl.

5. The compound of formula (b) or (c) as described in claim 4, or its transisomer or a pharmaceutically acceptable salt thereof, wherein, R0' is a 5- or 6-membered monocyclic heteroaryl group, wherein the 5- or 6-membered monocyclic heteroaryl group has 1, 2, or 3 heteroatoms selected from N and O as ring atoms; and the 5- or 6-membered monocyclic heteroaryl group is unsubstituted or has 1, 2, 3, or 4 independent heteroatoms selected from R0'. s3 Substitution of groups.

6. The compound of formula (b) or (c) as claimed in claim 4, or a transisomer thereof or a pharmaceutically acceptable salt thereof, wherein, R0' is selected from the following structure:

7. The following compounds, or their transisomers, or their pharmaceutically acceptable salts:

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