Substituted heterocyclic ring compound, and preparation method and medical application thereof

Abstract

The invention relates to the technical field of medicines, and relates to a substituted heterocyclic ring compound, and a preparation method and medical application thereof. Specifically, the invention discloses a substituted heterocyclic ring compound having a selective inhibition effect on KRAS gene mutation, or a pharmaceutically acceptable salt, a stereoisomer, a solvate or a prodrug thereof, the substituted heterocyclic ring compound is shown as a formula (I) or a formula (IA), and the definition of each group in the formula is shown in the specification. In addition, the invention further discloses a pharmaceutical composition containing the compound and application of the pharmaceutical composition in preparation of cancer drugs. # imgabs0 #

Description

[0001] This application is a divisional application of the invention patent application with the national application number CN202210818001.1. The application date of this invention patent application is October 28, 2020, and the invention title is "Substituted Heterocyclic Fused Ring Compounds, Their Preparation Methods and Pharmaceutical Uses". Technical Field

[0002] The present invention relates to the field of pharmaceutical technology, and particularly relates to a substituted heterocyclic fused ring compound, its application as a selective inhibitor of KRAS gene mutation, and a pharmaceutical composition prepared therefrom. Background Art

[0004] RAS is a group of closely related monomeric globular proteins (21kDa molecular weight) with 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 closed position and "inactive". When cells are exposed to certain growth-promoting stimuli, RAS is induced to convert its bound GDP into GTP. When bound to GTP, RAS is "switched on" and is able to interact with and activate other downstream target proteins. The inherent ability of RAS protein to hydrolyze GTP and restore it to GDP (thereby converting itself to the closed state) is extremely low. Exogenous protein GTPase activating protein (GAP) is required to restore it to the closed state. The interaction of GAP with RAS greatly accelerates the conversion of GTP to GDP. Any mutation in RAS will affect the interaction of RAS with GAP and the ability to convert GTP to GDP. This mutation will lead to a prolonged protein activation time, thereby prolonging cell signaling, which in turn leads to continued cell growth and division. Since this signaling causes cell growth and division, overactivated RAS signaling can ultimately lead to cancer. In lung cancer, mutations in the RAS gene are confirmed in approximately 32% of lung cancers, and any mutation in the three major subtypes of the RAS (HRAS, NRAS or KRAS) gene can lead to the occurrence of human tumors. 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 NRAS and HRAS family members is much lower (8% and 3%, respectively). The most common KRAS mutations are found on residues G12 and G13 in the P loop and on residue Q61. The G12C mutation is a frequent mutation of the KRAS gene (glycine-12 mutates to cysteine). This mutation has been found in about 13% of cancers, about 43% of lung cancers, and almost 100% of MYH-associated polyposis (familial colon cancer syndrome). Therefore, developing inhibitors that selectively inhibit KRAS mutations is a good direction. In order to improve the inhibitory activity against KRAS mutations while reducing the inhibitory activity against wild-type KRAS, it is of great significance to develop new RAS mutant selective inhibitors with higher activity, better selectivity, and lower toxicity. Summary of the invention

[0005] The present invention provides a novel substituted heterocyclic compound, which serves as a selective inhibitor of KRAS mutation and has the advantages of high activity, good selectivity and low toxicity and side effects.

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

[0007]

[0008] In the formula,

[0009] Z is N-C(O)-CR3=CR1R2 or

[0010] R1 and R2 are each independently hydrogen, halogen, cyano, NR a R b , -C 1-3 alkyl, halo-C 1-3 alkyl, -C 1-3 alkyl-hydroxy, -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 heterocycloalkyl or -C 1-3 alkyl-5- or 6-membered monocyclic heteroaryl; wherein the 3- to 6-membered heterocycloalkyl 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 is hydrogen, halogen, -C 1-3 alkyl or -C 1-3 alkoxy;

[0012] R4 is hydrogen, halo-C 1-3 alkyl, -C 1-3 alkyl-hydroxy, -C 1-3 alkyl-cyano or -C 1-3 alkyl-C 1-3 alkoxy;

[0013] R 11 , R 12 are the same or different and are each independently hydrogen, halogen, -C 1-3 alkyl, -halo-C 1-3 alkyl, -C 1-3 alkyl-hydroxy, -C 1-3 alkyl-cyano, -C 1-3 alkyl-C 1-6 alkoxy, -C 1-3 alkyl-halo-C 1-6 alkyl or -C 1-3 alkyl-halo-C 1-6 alkoxy;

[0014] R 21 、R 22 are the same or different and each independently is hydrogen, halogen, -C 1-3 alkyl, -halo-C 1-3 alkyl, -C 1-3 alkyl-hydroxy, -C 1-3 alkyl-cyano, -C 1-3 alkyl-C 1-6 alkoxy, -C 1-3 alkyl-halo-C 1-6 alkyl or -C 1-3 alkyl-halo-C 1-6 alkoxy;

[0015] R 31 、R 32 are the same or different and each independently is hydrogen, halogen, -C 1-3 alkyl, -halo-C 1-3 alkyl, -C 1-3 alkyl-hydroxy, -C 1-3 alkyl-cyano, -C 1-3 alkyl-C 1-6 alkoxy, -C 1-3 alkyl-halo-C 1-6 alkyl or -C 1-3 alkyl-halo-C 1-6 alkoxy;

[0016] R 41 is hydrogen, halogen, -C 1-3 alkyl, -halo-C 1-3 alkyl, -C 1-3 alkyl-hydroxy, -C 1-3 alkyl-cyano, -C 1-3 alkyl-C 1-6 alkoxy, -C 1-3 alkyl-halo-C 1-6 alkyl or -C 1-3 alkyl-halo-C 1-6 alkoxy;

[0017] R 42

[0018] When the dashed line in P is a single bond, P is O, NH or NR m ; R m is -C 1-6 alkyl, -halo-C 1-6 alkyl, -C 1-6 alkyl-hydroxy, -C 1-6 alkyl-cyano, -C 1-6 alkyl-C 1-6 alkoxy, -C 1-6 alkyl-halo-C1-6 alkoxy, -C 1-6 alkyl-C 3-6 cycloalkyl or -C 1-6 alkyl-3- to 6-membered heterocycloalkyl; R 42 is -(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(halo-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)-, or -C 1-3 alkyl(halo-C 1-6 alkoxy)-;

[0019] R 42

[0020] or when the dashed line in P is absent, P is hydrogen, halogen; R 42 is hydrogen, halogen, -C 1-3 alkyl, -halo-C 1-3 alkyl, -C 1-3 alkyl-hydroxy, -C 1-3 alkyl-cyano, -C 1-3 alkyl-C 1-6 alkoxy, -C 1-3 alkyl-halo-C 1-6 alkyl or -C 1-3 alkyl-halo-C 1-6 alkoxy;

[0021] When Y1 is C; X1 is hydrogen, halogen, cyano, hydroxy, amino, nitro, -substituted or unsubstituted C 1-6 alkyl, -substituted or unsubstituted C 3-6 cycloalkyl, -substituted or unsubstituted 3- to 6-membered heterocycloalkyl, -O-substituted or unsubstituted C 1-6 alkyl, -O-substituted or unsubstituted C 3-6 cycloalkyl, -O-substituted or unsubstituted 3- to 6-membered heterocycloalkyl, -NH-substituted or unsubstituted C 1-6 alkyl, -N(substituted or unsubstituted C 1-6 alkyl)2, -NH-substituted or unsubstituted C 3-6Cycloalkyl, -NH-substituted or unsubstituted 3- to 6-membered heterocycloalkyl, -NH(C=O)-substituted or unsubstituted C 1-6 alkyl, -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 are each independently hydrogen or C 1-3 alkyl; or R j 、R k together with the attached nitrogen atom form a substituted or unsubstituted 3- to 6-membered nitrogen-containing heterocycloalkyl; the 3- to 6-membered heterocycloalkyl has 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms; the 3- to 6-membered nitrogen-containing heterocycloalkyl has 3 to 6 ring atoms and one of the ring atoms is a nitrogen atom, and 0, 1 or 2 of the remaining ring atoms are optionally heteroatoms selected from N, O and S; the "substituted" means that 1, 2, 3 or 4 hydrogen atoms in the group are each independently replaced by substituents selected from group S;

[0022] or when Y1 is N, X1 is absent;

[0023] the group S substituents are selected from: hydroxy, halogen, nitro, oxo, -C 1-6 alkyl, -halo C 1-6 alkyl, hydroxy-substituted C 1-6 alkyl, benzyl, -(CH2) u -cyano, -(CH2) u -C 1-6 alkoxy, -(CH2) u -halo C 1-6 alkoxy, -(CH2) u -halo C 1-6 alkyl, -(CH2) u -3- to 6-membered heterocycloalkyl, -(CH2) u -5- or 6-membered monocyclic heteroaryl, -(CH2) u -C 3-8 cycloalkyl, -(CH2) u -O-(CH2) v-C 3-8 Cycloalkyl, -(CH2) u -O-(CH2) v -C 1-6 Alkoxy, -(CH2) u -O-(CH2) v OH, -(CH2) u -SO2C 1-6 Alkyl, -(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; wherein, the 3- to 6-membered heterocycloalkyl or the 5- or 6-membered monocyclic heteroaryl each independently has 1, 2, or 3 heteroatoms selected from N, O, and S as ring atoms; the 3- to 6-membered heterocycloalkyl, 5- or 6-membered monocyclic heteroaryl is optionally substituted with 1, 2, or 3 substituents selected from halogen, cyano, -C 1-3 Alkyl, -C 1-3 Alkoxy, and C 3-6 Cycloalkyl; u and v are each independently 0, 1, 2, 3, or 4; R a0 、R b0 Are each independently hydrogen or C 1-3 Alkyl;

[0024] E1 is N or CR5; wherein, R5 is hydrogen, halogen, cyano, -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-hydroxy, -C 1-4 Alkyl-cyano, -C 1-4 Alkyl-C 1-6 Alkoxy, -C 1-4 Alkyl-Halogenated C 1-6 Alkyl or -C1-4 alkyl-halo C 1-6 alkoxy;

[0025] E2 is N or CR6; wherein, R6 is hydrogen, halogen, cyano, -C 1-6 alkyl, -C 1-6 alkoxy, -halo C 1-6 alkyl, -halo C 1-6 alkoxy, -C 3-6 cycloalkyl, -NR h R i , -C 1-4 alkyl-hydroxy, -C 1-4 alkyl-cyano, -C 1-4 alkyl-C 1-6 alkoxy, -C 1-4 alkyl-halo C 1-6 alkyl or -C 1-4 alkyl-halo C 1-6 alkoxy;

[0026] provided that Y1, E1, and E2 are not simultaneously N;

[0027] Ar is C 6-10 aryl, a 5- or 6-membered monocyclic heteroaryl, or an 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 aryl, the 5- or 6-membered monocyclic heteroaryl, or the 8- to 10-membered bicyclic heteroaryl is unsubstituted or substituted by 1, 2, 3, or 4 groups independently selected from R s1 ;

[0028] or

[0029] Ar has the structure shown in formula (B):

[0030]

[0031] 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 heterocycloalkyl 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 heterocycloalkyl ring has 1, 2, or 3 heteroatoms selected from N, O, and S as ring atoms;

[0032] (R s1 ) p represents that the hydrogen on ring B1 is substituted by p R s1 , p is 0, 1, 2, or 3, and each R s1 is the same or different;

[0033] (R s2 ) q represents that the hydrogen on the B2 ring is substituted by q Rs, q is 0, 1, 2 or 3, and each R s2 is the same or different; s2

[0034] R s1 , R s2 are each independently halogen, cyano, nitro, hydroxy, -C 1-6 alkyl, -C 1-6 alkoxy, -haloalkyl, -halo 1-6 alkoxy, -C 1-6 cycloalkyl, -NR 3-6 R c R d , -C(O)NR e R f R 1-3 , -SO2C 1-3 alkyl, -SO2halo e alkyl, -SO2NR f R 1-4 , -C 1-4 alkyl-hydroxy, -C 1-4 alkyl-cyano, -C 1-6 alkyl-C 1-4 alkoxy, -C 1-6 alkyl-halo 1-4 alkyl, -C 1-6 alkyl-halo 1-4 alkoxy, -C 1-4 alkyl-3- to 6-membered heterocycloalkyl, -C e alkyl-NR f R 1-4 , -C e alkyl-C(O)NR f R 1-4 , -C 1-3 alkyl-SO2C 2-4 alkyl or C

[0035] 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, -O-C 6-10 aryl, -C 1-3 alkyl-3- to 6-membered heterocycloalkyl, -C 1-3 alkyl-C 3-6 cycloalkyl, wherein the 3- to 6-membered heterocycloalkyl, the 5- or 6-membered monocyclic heteroaryl or the 8- to 10-membered bicyclic heteroaryl 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 aryl, 5- or 6-membered monocyclic heteroaryl, 8- to 10-membered bicyclic heteroaryl, 7- to 11-membered spirocycloalkyl is unsubstituted or substituted by 1, 2, 3 or 4 groups independently selected from R s3 ; the -C 1-3 alkyl- is unsubstituted or substituted by 1, 2, 3 or 4 groups independently selected from C 1-3 alkyl;

[0036] Or

[0037] R0 has the structure shown in formula (A-1) or formula (A-2):

[0038]

[0039] 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 heterocycloalkyl 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 heterocycloalkyl ring has 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms;

[0040] (R s3 ) t represents that the hydrogen on ring A1 is substituted by t R s3 , t is 0, 1, 2 or 3, and each R s3 is the same or different;

[0041] (R s4 ) s represents that the hydrogen on ring A2 is substituted by s R s4 , s is 0, 1, 2 or 3, and each R s4 is the same or different;

[0042] R s3 , R s4 are each independently halogen, cyano, hydroxyl, -C 1-6 alkyl, -C 1-6 alkoxy, -halo C 1-6 alkyl, -halo C 1-6 alkoxy, -C 3-6Cycloalkyl, 3- to 6-membered heterocycloalkyl, -NR h R i 、-C(O)NR e R f 、-SO2C 1-3 alkyl, -SO2 halo C 1-3 alkyl, -SO2NR e R f 、-C 1-3 alkyl-hydroxy, -C 1-3 alkyl-C 2-4 alkynyl, -C 1-3 alkyl-cyano, -C 1-3 alkyl-C 1-6 alkoxy, -C 1-3 alkyl-halo C 1-6 alkyl, -C 1-3 alkyl-halo C 1-6 alkoxy, -C 1-3 alkyl-3- to 6-membered heterocycloalkyl, -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 alkynyl; wherein the 3- to 6-membered heterocycloalkyl 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 cycloalkyl, 3- to 6-membered heterocycloalkyl is optionally substituted with 1, 2 or 3 substituents independently selected from halogen, methyl, ethyl, propyl (n-propyl), isopropyl, trifluoromethyl, amino, N(CH3)2, hydroxy, carboxyl;

[0043] R a 、R b 、R e 、R f 、R g each independently is hydrogen or C 1-3 alkyl;

[0044] R c 、R d 、R h 、R i each independently is hydrogen, -C 1-3 alkyl, -C(O)C1-3 alkyl or -CO2C 1-3 alkyl.

[0045] In one embodiment of the present invention, the compound represented by formula (I) is a compound of formula (I-1) or a compound of formula (I-2);

[0046]

[0047] In formula I-1, P is O, NH or NR m ; R m is -C 1-6 alkyl, -halo C 1-6 alkyl, -C 1-6 alkyl-hydroxy, -C 1-6 alkyl-cyano, -C 1-6 alkyl-C 1-6 alkoxy, -C 1-6 alkyl-halo C 1-6 alkoxy, -C 1-6 alkyl-C 3-6 cycloalkyl or -C 1-6 alkyl-3- to 6-membered heteroalkyl; R 42 is -(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(halo 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)-, or -C 1-3 alkyl(halo 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 as defined above;

[0048] In formula I-2, P is hydrogen, halogen; R 42 is hydrogen, halogen, -C 1-3 alkyl, -halo C 1-3 alkyl, -C 1-3Alkyl-hydroxy, -C 1-3 Alkyl-cyano, -C 1-3 Alkyl-C 1-6 Alkoxy, -C 1-3 Alkyl-haloC 1-6 Alkyl or -C 1-3 Alkyl-haloC 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 as defined above.

[0049] In another aspect, the present invention provides a compound represented by formula (IA) or a tautomer, cis-trans isomer, meso form, racemate, enantiomer, diastereoisomer, atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof:

[0050]

[0051] Wherein,

[0052] Z is N-C(O)-CR3=CR1R2 or

[0053] R1 and R2 are each independently hydrogen, halogen, cyano, NR a R b , -C 1-3 Alkyl, haloC 1-3 , -C 1-3 Alkyl-hydroxy, -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 heterocycloalkyl or -C 1-3 Alkyl-5- or 6-membered monocyclic heteroaryl; wherein, the 3- to 6-membered heterocycloalkyl or the 5- or 6-membered monocyclic heteroaryl has 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms;

[0054] R3 is hydrogen, halogen, -C 1-3 Alkyl or -C 1-3 Alkoxy;

[0055] R4 is hydrogen, haloC 1-3 Alkyl, -C 1-3 Alkyl-hydroxy, -C1-3 alkyl-cyano or -C 1-3 alkyl-C 1-3 alkoxy;

[0056] R 11 、R 12 are the same or different and each independently is hydrogen, halogen, -C 1-3 alkyl, -haloalkyl 1-3 alkyl, -C 1-3 alkyl-hydroxy, -C 1-3 alkyl-cyano, -C 1-3 alkyl-C 1-6 alkoxy, -C 1-3 alkyl-haloalkyl 1-6 alkyl or -C 1-3 alkyl-haloalkyl 1-6 alkoxy;

[0057] R 21 、R 22 are the same or different and each independently is hydrogen, halogen, -C 1-3 alkyl, -haloalkyl 1-3 alkyl, -C 1-3 alkyl-hydroxy, -C 1-3 alkyl-cyano, -C 1-3 alkyl-C 1-6 alkoxy, -C 1-3 alkyl-haloalkyl 1-6 alkyl or -C 1-3 alkyl-haloalkyl 1-6 alkoxy;

[0058] R 31 、R 32 are the same or different and each independently is hydrogen, halogen, -C 1-3 alkyl, -haloalkyl 1-3 alkyl, -C 1-3 alkyl-hydroxy, -C 1-3 alkyl-cyano, -C 1-3 alkyl-C 1-6 alkoxy, -C 1-3 alkyl-haloalkyl 1-6 alkyl or -C 1-3 alkyl-haloalkyl 1-6 alkoxy;

[0059] R 41 is hydrogen, halogen, -C 1-3 alkyl, -haloalkyl 1-3 alkyl, -C 1-3 alkyl-hydroxy, -C 1-3 alkyl-cyano, -C 1-3 alkyl-C 1-6Alkoxy, -C 1-3 Alkyl-halo C 1-6 Alkyl or -C 1-3 Alkyl-halo C 1-6 Alkoxy;

[0060] When the dashed line in m is a single bond, P' is O, NH or NR m '; R 1-6 ' is -deuterated C 1-6 Alkyl, -C 1-6 Alkyl, -halo C 1-6 Alkyl, -C 1-6 Alkyl-hydroxy, -C 1-6 Alkyl-cyano, -C 1-6 Alkyl-C 1-6 Alkoxy, -C 1-6 Alkyl-halo C 1-6 Alkoxy, -C 3-6 Alkyl-C 1-6 Cycloalkyl or -C 42 Alkyl-3- to 6-membered heteroalkyl; R 1-3 ' is -C 1-3 Alkyl-(C=O)-, -(C=O)-, -C 1-3 Alkyl-, -C 1-3 Alkyl(hydroxy)-, -C 1-3 Alkyl(cyano)-, -C 1-6 Alkyl(C 1-3 Alkyl)-, -C 1-6 Alkyl(halo C 1-3 Alkyl)-, -C 1-6 Alkyl(C 1-3 Alkyl-hydroxy)-, -C 1-6 Alkyl(C 1-3 Alkyl-cyano)-, -C 1-6 Alkyl(C 1-3 Alkoxy)-, or -C 1-6 Alkyl(halo C

[0061] Or when the dashed line in 42 is absent, P' is hydrogen, halogen; R 1-3 ' is hydrogen, halogen, -C 1-3 Alkyl, -halo C 1-3 Alkyl, -C 1-3 Alkyl-hydroxy, -C 1-3 Alkyl-cyano, -C 1-6 Alkyl-C 1-3 Alkoxy, -C 1-6 Alkyl or -C 1-3Alkyl-halo C 1-6 Alkoxy;

[0062] When Y1 is C; X1 is hydrogen, halogen, cyano, hydroxy, amino, nitro, -substituted or unsubstituted C 1-6 alkyl, -substituted or unsubstituted C 3-6 cycloalkyl, -substituted or unsubstituted 3- to 6-membered heterocycloalkyl, -O-substituted or unsubstituted C 1-6 alkyl, -O-substituted or unsubstituted C 3-6 cycloalkyl, -O-substituted or unsubstituted 3- to 6-membered heterocycloalkyl, -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 heterocycloalkyl, -NH(C=O)-substituted or unsubstituted C 1-6 alkyl, -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 independently is hydrogen or C 1-3 alkyl; or R j 、R k together with the attached nitrogen atom form a substituted or unsubstituted 3- to 6-membered nitrogen-containing heterocycloalkyl; the 3- to 6-membered heterocycloalkyl has 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms; the 3- to 6-membered nitrogen-containing heterocycloalkyl has 3 to 6 ring atoms and one of the ring atoms is a nitrogen atom, and 0, 1 or 2 of the remaining ring atoms are optionally heteroatoms selected from N, O and S; the "substituted" means that 1, 2, 3 or 4 hydrogen atoms in the group are each independently replaced by substituents selected from group S;

[0063] or when Y1 is N, X1 is absent;

[0064] The group S substituents are selected from: hydroxy, halogen, nitro, oxo, -C 1-6 alkyl, -halo C 1-6Alkyl, hydroxy-substituted C 1-6 Alkyl, benzyl, -(CH2) u -Cyano, -(CH2) u -C 1-6 Alkoxy, -(CH2) u -Halogenated C 1-6 Alkoxy, -(CH2) u -Halogenated C 1-6 Alkyl, -(CH2) u -3- to 6-membered heterocycloalkyl, -(CH2) u -5- or 6-membered monocyclic heteroaryl, -(CH2) u -C 3-8 Cycloalkyl, -(CH2) u -O-(CH2) v -C 3-8 Cycloalkyl, -(CH2) u -O-(CH2) v -C 1-6 Alkoxy, -(CH2) u -O-(CH2) v OH, -(CH2) u -SO2C 1-6 Alkyl, -(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; wherein, the 3- to 6-membered heterocycloalkyl or the 5- or 6-membered monocyclic heteroaryl each independently has 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms; the 3- to 6-membered heterocycloalkyl, 5- or 6-membered monocyclic heteroaryl is optionally substituted by 1, 2 or 3 substituents selected from halogen, cyano, -C 1-3 Alkyl, -C 1-3 Alkoxy and C 3-6 Cycloalkyl; u, v are each independently 0, 1, 2, 3 or 4; R a0 、R b0 Each independently is hydrogen or C1-3 alkyl;

[0065] E1' is N or CR5'; wherein, R5' is hydrogen, halogen, cyano, -C 1-6 alkyl, -C 1-6 alkoxy, -halo-C 1-6 alkyl, -halo-C 1-6 alkoxy, -C 3-6 cycloalkyl, -O-C 3-6 cycloalkyl, -NR h R i , -C 1-4 alkyl-hydroxy, -C 1-4 alkyl-cyano, -C 1-4 alkyl-C 1-6 alkoxy, -C 1-4 alkyl-halo-C 1-6 alkyl or -C 1-4 alkyl-halo-C 1-6 alkoxy;

[0066] E2' is N or CR6'; wherein, R6' is hydrogen, halogen, cyano, -C 1-6 alkyl, -C 1-6 alkoxy, -halo-C 1-6 alkyl, -halo-C 1-6 alkoxy, -C 3-6 cycloalkyl, -O-C 3-6 cycloalkyl, -NR h R i , -C 1-4 alkyl-hydroxy, -C 1-4 alkyl-cyano, -C 1-4 alkyl-C 1-6 alkoxy, -C 1-4 alkyl-halo-C 1-6 alkyl or -C 1-4 alkyl-halo-C 1-6 alkoxy;

[0067] provided that Y1, E1', E2' are not simultaneously N;

[0068] Ar' is C 6-10 aryl, 5- or 6-membered monocyclic heteroaryl, 8- to 10-membered bicyclic heteroaryl or 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; 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 aryl, the 5- or 6-membered monocyclic heteroaryl, the 8- to 10-membered bicyclic heteroaryl and the pyridone group are unsubstituted or substituted by 1, 2, 3 or 4 independently selected from Rs1 substituted by a group;

[0069] or Ar' has the structure shown in formula (B):

[0070]

[0071] 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 heterocycloalkyl 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 heterocycloalkyl ring has 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms;

[0072] (R s1 ) p represents that the hydrogen on ring B1 is substituted by p R s1 groups, p is 0, 1, 2 or 3, and each R s1 is the same or different;

[0073] (R s2 ) q represents that the hydrogen on ring B2 is substituted by q R s2 groups, q is 0, 1, 2 or 3, and each R s2 is the same or different;

[0074] R s1 and R s2 are each independently halogen, cyano, nitro, hydroxy, -C 1-6 alkyl, -C 1-6 alkoxy, -halo-C 1-6 alkyl, -halo-C 1-6 alkoxy, -C 3-6 cycloalkyl, -NR c R d , -C(O)NR e R f , -SO2C 1-3 alkyl, -SO2-halo-C 1-3 alkyl, -SO2NR e R f , -C 1-4 alkyl-hydroxy, -C 1-4 alkyl-cyano, -C 1-4 alkyl-C 1-6 alkoxy, -C 1-4 alkyl-halo-C 1-6 alkyl, -C 1-4 alkyl-halo-C 1-6 alkoxy, -C 1-4 alkyl-3- to 6-membered heterocycloalkyl, -C 1-4 alkyl-NR e Rf , -C 1-4 alkyl - C(O)NR e R f , -C 1-4 alkyl - SO2C 1-3 alkyl or C 2-4 alkynyl; wherein the 3 - to 6 - membered heteroalkyl group has 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms;

[0075] R0' is -C 1-6 alkyl, -C 3-6 cycloalkyl, 3 - to 6 - membered heteroalkyl, C 6-10 aryl, 5 - or 6 - membered monocyclic heteroaryl, 8 - to 10 - membered bicyclic heteroaryl, 7 - to 11 - membered spiroalkyl, -C 1-3 alkyl - C 6-10 aryl, -C 1-3 alkyl - 5 - or 6 - membered monocyclic heteroaryl, -NR g , -C 6-10 aryl, -O - C 6-10 aryl, -C 1-3 alkyl - 3 - to 6 - membered heteroalkyl, -C 1-3 alkyl - C 3-6 cycloalkyl or pyridone group, wherein the 3 - to 6 - membered heteroalkyl 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 heteroalkyl, C 6-10 aryl, 5 - or 6 - membered monocyclic heteroaryl, 8 - to 10 - membered bicyclic heteroaryl, 7 - to 11 - membered spiroalkyl and pyridone group are unsubstituted or substituted by 1, 2, 3 or 4 groups independently selected from R s3 ; the -C 1-3 alkyl - is unsubstituted or substituted by 1, 2, 3 or 4 groups independently selected from C 1-3 alkyl;

[0076] Or R0' is a structure represented by formula (A - 1) or formula (A - 2):

[0077]

[0078] 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 heteroalkyl 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 heteroalkyl ring has 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms;

[0079] (R s3 )t means that the hydrogen on the A1 ring is substituted by t R s3 groups, where t is 0, 1, 2 or 3, and each R s3 is the same or different;

[0080] (R s4 ) s means that the hydrogen on the A2 ring is substituted by s R s4 groups, where s is 0, 1, 2 or 3, and each R s4 is the same or different;

[0081] R s3 and R s4 are each independently halogen, cyano, hydroxy, -C 1-6 alkyl, -C 1-6 alkoxy, -haloalkyl, -halo 1-6 alkyl, -halo 1-6 alkoxy, -C 3-6 cycloalkyl, 3- to 6-membered heteroalkyl, -NR h R i , -C(O)NR e R f , -SO2C 1-3 alkyl, -SO2halo 1-3 alkyl, -SO2NR e R f , -C 1-3 alkyl-hydroxy, -C 1-3 alkyl-C 2-4 alkynyl, -C 1-3 alkyl-cyano, -C 1-3 alkyl-C 1-6 alkoxy, -C 1-3 alkyl-halo 1-6 alkyl, -C 1-3 alkyl-halo 1-6 alkoxy, -C 1-3 alkyl-3- to 6-membered heteroalkyl, -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 alkynyl; wherein the 3- to 6-membered heteroalkyl 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, -C1-3 Alkyl-, -C 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl optionally substituted with 1, 2 or 3 substituents independently selected from halogen, methyl, ethyl, propyl (n-propyl), isopropyl, trifluoromethyl, amino, N(CH3)2, hydroxy, carboxyl;

[0082] R a 、R b 、R e 、R f 、R g Each independently is hydrogen or C 1-3 alkyl;

[0083] R c 、R d 、R h 、R i Each independently is hydrogen, -C 1-3 alkyl, -C(O)C 1-3 alkyl or -CO2C 1-3 alkyl.

[0084] 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);

[0085]

[0086] In formula IB, P' is O, NH or NR m '; R m ' is -deuterated C 1-6 alkyl, -C 1-6 alkyl, -halo C 1-6 alkyl, -C 1-6 alkyl-hydroxy, -C 1-6 alkyl-cyano, -C 1-6 alkyl-C 1-6 alkoxy, -C 1-6 alkyl-halo C 1-6 alkoxy, -C 1-6 alkyl-C 3-6 cycloalkyl or -C 1-6 alkyl-3- to 6-membered heterocycloalkyl; R 42 ' is -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(halo C 1-6 alkyl)-, -C1-3 alkyl(C 1-6 alkyl-hydroxy)-, -C 1-3 alkyl(C 1-6 alkyl-cyano)-, -C 1-3 alkyl(C 1-6 alkoxy)-, or -C 1-3 alkyl(halo-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 as defined above;

[0087] In formula IC, P' is hydrogen or halogen; R 42 ' is hydrogen, halogen, -C 1-3 alkyl, -halo-C 1-3 alkyl, -C 1-3 alkyl-hydroxy, -C 1-3 alkyl-cyano, -C 1-3 alkyl-C 1-6 alkoxy, -C 1-3 alkyl-halo-C 1-6 alkyl or -C 1-3 alkyl-halo-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 as defined above.

[0088] In one embodiment of the present invention, in formula IB, P' is O, NH or NR m '; R m ' is -deuterated C 1-6 alkyl or -C 1-6 alkyl; R 42 ' is -C 1-3 alkyl-(C=O)-, -(C=O)- or -C 1-3 alkyl-.

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

[0090] In one embodiment of the present invention, in formula IB, P' is O, NH, or NR m '; R m ' is deuterated methyl, deuterated ethyl, deuterated n-propyl, deuterated isopropyl, methyl, ethyl, n-propyl, or isopropyl; R 42 ' is -CH2-(C=O)-, -CH2CH2-(C=O)-, -(C=O)-, -CH2-, -CH2CH2-, or -CH2CH2CH2-.

[0091] In one embodiment of the present invention, in formula IB, P' is NH or NR m '; R m ' is -deuterated C 1-6 alkyl or -C 1-6 alkyl; R 42 ' is -C 1-3 alkyl-(C=O)- or -(C=O)-.

[0092] In one embodiment of the present invention, in formula IB, P' is NH or NR m '; R m ' is -deuterated C 1-3 alkyl or -C 1-3 alkyl; R 42 ' is -C 1-3 alkyl-(C=O)- or -(C=O)-.

[0093] In one embodiment of the present invention, in formula IB, P' is NH or NR m '; R m ' is deuterated methyl or methyl; R 42 ' is -CH2-(C=O)-, -CH2CH2-(C=O)-, or -(C=O)-.

[0094] In one embodiment of the present invention, in formula IB, P' is O; R 42 ' is -C 1-3 alkyl-.

[0095] In one embodiment of the present invention, in formula IB, P' is O; R 42 ' is -CH2-.

[0096] 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);

[0097]

[0098] In Formula (IB-1) and Formula (IB-2), R 21 , R 22 , R 11 , R 12 , R 31 , R 32 , R 41 , R 42 ', Z, P', R0', Ar', E1', E2', X1, and Y1 are defined as before.

[0099] In one embodiment of the present invention, in Formula IB-1, P' is O, NH, or NR m '; R m ' is -deuterated C 1-6 alkyl or -C 1-6 alkyl; R 42 ' is -C 1-3 alkyl-(C=O)-, -(C=O)-, or -C 1-3 alkyl-.

[0100] In one embodiment of the present invention, in Formula IB-1, P' is NH or NR m '; R m ' is -deuterated C 1-6 alkyl or -C 1-6 alkyl; R 42 ' is -C 1-3 alkyl-(C=O)- or -(C=O)-.

[0101] In one embodiment of the present invention, in Formula IB-1, P' is NH or NR m '; R m ' is -deuterated C 1-3 alkyl or -C 1-3 alkyl; R 42 ' is -C 1-3 alkyl-(C=O)- or -(C=O)-.

[0102] In one embodiment of the present invention, in Formula IB-1, P' is NH or NR m '; R m ' is deuterated methyl or methyl; R 42 ' is -CH2-(C=O)-, -CH2CH2-(C=O)-, or -(C=O)-.

[0103] In one embodiment of the present invention, in Formula IB-1, P' is O; R 42 ' is -C 1-3 alkyl-.

[0104] In one embodiment of the present invention, in formula IB-1, P' is O; R 42 ' is -CH2-.

[0105] In another aspect, the present invention provides a compound represented by formula (IB-1a) or formula (IB-2a), or a tautomer, cis-trans isomer, meso form, racemate, enantiomer, diastereoisomer, atropisomer or a mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof:

[0106]

[0107] wherein R1, R2, R3, R 21 , R 22 , R 12 , R 11 , R 31 , R 32 , P', R0', Ar', E1', X1 are as defined above.

[0108] In one embodiment of the present invention, in formula IB-1a, P' is NH or NR m '; R m ' is -deuterated C 1-6 alkyl or -C 1-6 alkyl.

[0109] In one embodiment of the present invention, in formula IB-1a, P' is NH or NR m '; R m ' is -deuterated C 1-3 alkyl or -C 1-3 alkyl.

[0110] In one embodiment of the present invention, in formula IB-1a, P' is NH or NR m '; R m ' is deuterated methyl or methyl.

[0111] 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);

[0112]

[0113] wherein in formula (IB-1aa) and formula (IB-1ab), R 21 ' is independently halogen, -C 1-3 alkyl, -halo C 1-3 alkyl, -C 1-3 alkyl-hydroxy, -C 1-3Alkyl-cyano, -C 1-3 Alkyl-C 1-6 Alkoxy, -C 1-3 Alkyl-haloC 1-6 Alkyl or -C 1-3 Alkyl-haloC 1-6 Alkoxy; R1, R2, R3, R 12 , R 11 , R 31 , R 32 , P', R0', Ar', E1', X1 are as defined above;

[0114] In formula (IB-1ac) and formula (IB-1ad), R 12 ' is independently halogen, -C 1-3 Alkyl, -haloC 1-3 Alkyl, -C 1-3 Alkyl-hydroxy, -C 1-3 Alkyl-cyano, -C 1-3 Alkyl-C 1-6 Alkoxy, -C 1-3 Alkyl-haloC 1-6 Alkyl or -C 1-3 Alkyl-haloC 1-6 Alkoxy; R1, R2, R3, R 21 , R 22 , R 31 , R 32 , P', R0', Ar', E1', X1 are as defined above.

[0115] In another aspect, the present invention provides a compound represented by formula (IB-1c) or formula (IB-2c), or a tautomer, cis-trans isomer, meso form, racemate, enantiomer, diastereomer, atropisomer or a mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof:

[0116]

[0117] Wherein R1, R2, R3, R 21 , R 22 , R 12 , R 11 , R 31 , R 32 , P', R0', Ar', E1', X1 are as defined above.

[0118] In one embodiment of the present invention, in formula IB-1c, P' is NH or NR m '; R m ' is -deuterated C 1-6 Alkyl or -C 1-6Alkyl

[0119] In one embodiment of the present invention, in formula IB-1c, P' is NH or NR m '; R m ' is -deuterated C 1-3 alkyl or -C 1-3 alkyl

[0120] In one embodiment of the present invention, in formula IB-1c, P' is NH or NR m '; R m ' is deuterated methyl or methyl

[0121] 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);

[0122]

[0123] wherein in formula (IB-1ca) and formula (IB-1cb), R 21 ' is independently halogen, -C 1-3 alkyl, -halo C 1-3 alkyl, -C 1-3 alkyl-hydroxy, -C 1-3 alkyl-cyano, -C 1-3 alkyl-C 1-6 alkoxy, -C 1-3 alkyl-halo C 1-6 alkyl or -C 1-3 alkyl-halo C 1-6 alkoxy; R1, R2, R3, R 12 , R 11 , R 31 , R 32 , P', R0', Ar', E1', X1 are as defined above;

[0124] In formula (IB-1cc) and formula (IB-1cd), R 12 ' is independently halogen, -C 1-3 alkyl, -halo C 1-3 alkyl, -C 1-3 alkyl-hydroxy, -C 1-3 alkyl-cyano, -C 1-3 alkyl-C 1-6 alkoxy, -C 1-3 alkyl-halo C 1-6 alkyl or -C 1-3 alkyl-halo C 1-6 alkoxy; R1, R2, R3, R 21, R 22 , R 31 , R 32 , P', R0', Ar', E1', X1 are defined as above.

[0125] In one embodiment of the present invention, in formula IB-1a, formula IB-1c, formula IB-2a and formula IB-2c, P' is independently NH or NR m '; R m ' is -deuterated C 1-6 alkyl or -C 1-6 alkyl.

[0126] In one embodiment of the present invention, in formula IB-1a, formula IB-1c, formula IB-2a and formula IB-2c, P' is independently NH or NR m '; R m ' is -deuterated C 1-3 alkyl or -C 1-3 alkyl.

[0127] In one embodiment of the present invention, in formula IB-1a, formula IB-1c, formula IB-2a and formula IB-2c, P' is independently NH or NR m '; R m ' is deuterated methyl, deuterated ethyl, deuterated n-propyl, deuterated isopropyl, methyl, ethyl, n-propyl or isopropyl.

[0128] In another aspect, the present invention provides a compound represented by formula (IB-1b) or formula (IB-2b), or a tautomer, cis-trans isomer, meso form, racemate, enantiomer, diastereoisomer, atropisomer or a mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof:

[0129]

[0130] wherein R1, R2, R3, R 21 , R 22 , R 12 , R 11 , R 31 , R 32 , P', R0', Ar', E1', X1 are defined as above.

[0131] 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);

[0132]

[0133] In formulas (IB-1ba) and (IB-1bb), R 21 ' is independently halogen, -C 1-3 alkyl, -halo-C 1-3 alkyl, -C 1-3 alkyl-hydroxy, -C 1-3 alkyl-cyano, -C 1-3 alkyl-C 1-6 alkoxy, -C 1-3 alkyl-halo-C 1-6 alkyl or -C 1-3 alkyl-halo-C 1-6 alkoxy; R1, R2, R3, R 12 , R 11 , R 31 , R 32 , P', R0', Ar', E1', X1 are as defined above;

[0134] In formulas (IB-1bc) and (IB-1bd), R 12 ' is independently halogen, -C 1-3 alkyl, -halo-C 1-3 alkyl, -C 1-3 alkyl-hydroxy, -C 1-3 alkyl-cyano, -C 1-3 alkyl-C 1-6 alkoxy, -C 1-3 alkyl-halo-C 1-6 alkyl or -C 1-3 alkyl-halo-C 1-6 alkoxy; R1, R2, R3, R 21 , R 22 , R 31 , R 32 , P', R0', Ar', E1', X1 are as defined above.

[0135] In another aspect, the present invention provides a compound represented by formula (IB-1d) or formula (IB-2d), or a tautomer, cis-trans isomer, meso form, racemate, enantiomer, diastereoisomer, atropisomer or a mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof:

[0136]

[0137] Wherein R1, R2, R3, R 21 , R 22 , R 12 , R 11 , R 31 , R 32 , P', R0', Ar', E1', X1 are as defined above.

[0138] 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);

[0139]

[0140] wherein in formula (IB-1da) and formula (IB-1db), R 21 ' is independently halogen, -C 1-3 alkyl, -halo-C 1-3 alkyl, -C 1-3 alkyl-hydroxy, -C 1-3 alkyl-cyano, -C 1-3 alkyl-C 1-6 alkoxy, -C 1-3 alkyl-halo-C 1-6 alkyl or -C 1-3 alkyl-halo-C 1-6 alkoxy; R1, R2, R3, R 12 , R 11 , R 31 , R 32 , P', R0', Ar', E1', X1 are as defined above;

[0141] In formula (IB-1dc) and formula (IB-1dd), R 12 ' is independently halogen, -C 1-3 alkyl, -halo-C 1-3 alkyl, -C 1-3 alkyl-hydroxy, -C 1-3 alkyl-cyano, -C 1-3 alkyl-C 1-6 alkoxy, -C 1-3 alkyl-halo-C 1-6 alkyl or -C 1-3 alkyl-halo-C 1-6 alkoxy; R1, R2, R3, R 21 , R 22 , R 31 , R 32 , P', R0', Ar', E1', X1 are as defined above.

[0142] In one embodiment of the present invention, in formula IB-1b, formula IB-1d, formula IB-2b, and formula IB-2d, P' is independently O.

[0143] In one embodiment of the present invention, R 21 ', R 12 ' are each independently -C1-3 alkyl, -C 1-3 alkyl-hydroxy, -C 1-3 alkyl-cyano or -C 1-3 alkyl-C 1-6 alkoxy.

[0144] In one embodiment of the present invention, R 21 ', R 12 ' are each independently -C 1-3 alkyl, -CH2-hydroxy, -CH2-cyano or -CH2-C 1-3 alkoxy.

[0145] In one embodiment of the present invention, R 21 ', R 12 ' are each independently methyl, ethyl, n-propyl or isopropyl.

[0146] 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 "substituted" means that 1, 2, 3 or 4 hydrogen atoms in the group are each independently replaced by substituents selected from group S.

[0147] In one embodiment of the present invention, X1 is hydrogen, halogen, unsubstituted C 1-3 alkyl, unsubstituted C 3-6 cycloalkyl or -O-unsubstituted C 1-3 alkyl.

[0148] 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.

[0149] In one embodiment of the present invention, X1 is fluorine, chlorine or cyclopropyl.

[0150] In one embodiment of the present invention, Y1 is C; E1' is N or CR5'; E2' is CR6'; R5', R6' are each defined as above.

[0151] In one embodiment of the present invention, Y1 is C; E1' is CR5'; E2' is N; R5' is defined as above.

[0152] In one embodiment of the present invention, Y1 is C; E1' is N or CR5'; E2' is CH; R5' is defined as above.

[0153] In one embodiment of the present invention, Y1 is C; E1' is N or CF; E2' is CH.

[0154] In one embodiment of the present invention, Ar' is phenyl, a 5- or 6-membered monocyclic heteroaryl or pyridone group; and the phenyl, 5- or 6-membered monocyclic heteroaryl and pyridone group are unsubstituted or substituted by 1, 2, 3 or 4 groups independently selected 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 ; wherein R e , R f are each independently hydrogen or C 1-3 alkyl; R c , R d are each independently hydrogen, -C 1-3 alkyl, -C(O)C 1-3 alkyl or -CO2C 1-3 alkyl.

[0155] In one embodiment of the present invention, Ar' is phenyl or pyridone group; and the phenyl and pyridone group are unsubstituted or substituted by 1, 2, 3 or 4 groups independently selected 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.

[0156] In one embodiment of the present invention, Ar' is phenyl; the phenyl is substituted by 1 group selected from R s1 ; R s1 is halogen, cyano, -C 1-6 alkyl, -C 1-6 alkoxy, -halo C 1-6 alkyl, -halo C 1-6 alkoxy or -C 3-6 cycloalkyl.

[0157] In one embodiment of the present invention, Ar' is selected from the following structures: wherein, R s1 , R s2 are as defined above.

[0158] In one embodiment of the present invention, Ar' is selected from the following structures: wherein, R s1 is hydroxyl; R s2is halogen, cyano, -C 1-6 alkyl, -C 1-6 alkoxy, -halo-C 1-6 alkyl, -halo-C 1-6 alkoxy or -C 3-6 cycloalkyl. In one embodiment of the present invention, the R s1 is above the plane of the benzene ring.

[0159] In one embodiment of the present invention, Ar' is selected from the following structures: In the formula, R s1 is -C 1-6 alkoxy; R s2 is halogen, cyano, -C 1-6 alkyl, -C 1-6 alkoxy, -halo-C 1-6 alkyl, -halo-C 1-6 alkoxy or -C 3-6 cycloalkyl. In one embodiment of the present invention, the R s1 is above the plane of the benzene ring.

[0160] In one embodiment of the present invention, R0' is phenyl, a 5- or 6-membered monocyclic heteroaryl or 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 substituted by 1, 2, 3 or 4 groups independently selected from R s3 .

[0161] In one embodiment of the present invention, R0' is phenyl, thiazolyl, isothiazolyl, imidazolyl, oxazolyl, isoxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl or pyridone group, and the phenyl, thiazolyl, isothiazolyl, imidazolyl, oxazolyl, isoxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl and pyridone group are unsubstituted or substituted by 1, 2, 3 or 4 groups independently selected from R s3 .

[0162] In one embodiment of the present invention, R0' is selected from the following structures:

[0163]

[0164] In the above structures, R s3 's are the same or different and are each independently selected from hydrogen, halogen, cyano, hydroxy, -C 1-6 alkyl, -C 1-6 alkoxy, -halo-C 1-6 alkyl, -halo-C 1-6 alkoxy, -C 3-6 cycloalkyl, -NRh R i 、 -C(O)NR e R f 、 -C 1-3 alkyl - hydroxy and -C 1-3 alkyl - NR e R f ; and the -C 3-6 cycloalkyl is optionally substituted with 1, 2 or 3 substituents independently selected from halogen, methyl, ethyl, propyl (n - propyl), isopropyl, trifluoromethyl, amino, N(CH3)2, hydroxy, carboxyl; wherein R e , R f are each independently hydrogen or C 1-3 alkyl; R h , R i are each independently hydrogen, -C 1-3 alkyl, -C(O)C 1-3 alkyl or -CO2C 1-3 alkyl;

[0165] In each of the above structures, R s3 ” is the same or different and is independently selected from hydrogen, halogen, cyano, hydroxy, -C 1-6 alkyl, -C 1-6 alkoxy, -haloalkyl, -haloalkoxy, -C 1-6 alkyl, -haloalkyl, -haloalkoxy, -C 1-6 alkyl, -C 3-6 cycloalkyl, -NR h R i 、 -C(O)NR e R f 、 -C 1-3 alkyl - hydroxy and -C 1-3 alkyl - NR e R f ; and the -C 3-6 cycloalkyl is optionally substituted with 1, 2 or 3 substituents independently selected from halogen, methyl, ethyl, propyl (n - propyl), isopropyl, trifluoromethyl, amino, N(CH3)2, hydroxy, carboxyl; wherein R e 、 R f are each independently hydrogen or C 1-3 alkyl; R h 、 R i are each independently hydrogen, -C 1-3 alkyl, -C(O)C 1-3 alkyl or -CO2C 1-3 alkyl;

[0166] In each of the above structures, R s3 ”' is the same or different and is independently selected from hydrogen, -C 1-6 alkyl, -haloalkyl,1-6 alkyl, -C 3-6 cycloalkyl, -C 1-3 alkyl-C(O)NR e R f 、-C(O)NR e R f 、-C 1-4 alkyl-hydroxy and -C 1-4 alkyl-NR e R f ; and said -C 3-6 cycloalkyl is optionally substituted with 1, 2 or 3 substituents independently selected from halogen, methyl, ethyl, propyl (n-propyl), isopropyl, trifluoromethyl, amino, N(CH3)2, hydroxy, carboxyl; wherein R e 、R f are each independently hydrogen or C 1-3 alkyl;

[0167] In each of the above structures, R s3 are the same or different and are each independently selected from halogen, cyano, hydroxy, -C 1-6 alkyl, -C 1-6 alkoxy, -haloalkyl, -haloalkoxy, -C 1-6 alkyl, -haloalkyl 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, -SO2haloalkyl, -SO2NR 1-3 R e R f 、-C 1-3 alkyl-hydroxy, -C 1-3 alkyl-C 2-4 alkynyl, -C 1-3 alkyl-cyano, -C 1-3 alkyl-C 1-6 alkoxy, -C 1-3 alkyl-haloalkyl, -C 1-6 alkyl, -C 1-3 alkyl-haloalkoxy, -C 1-6 alkyl-3- to 6-membered heterocycloalkyl, -C 1-3 alkyl-C 1-3 cycloalkyl, -C 3-6 alkyl-NR 1-3 R 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 alkynyl; wherein the 3- to 6-membered heterocycloalkyl 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 cycloalkyl, 3- to 6-membered heterocycloalkyl is optionally substituted with 1, 2 or 3 substituents independently selected from halogen, methyl, ethyl, propyl (n-propyl), isopropyl, trifluoromethyl, amino, N(CH3)2, hydroxy, carboxyl; wherein R h , R i are each independently hydrogen, -C 1-3 alkyl, -C(O)C 1-3 alkyl or -CO2C 1-3 alkyl; R e , R f are each independently hydrogen or C 1-3 alkyl;

[0168] In each of the above structures, n is the same or different and is independently 0, 1, 2 or 3.

[0169] In one embodiment of the present invention, R0' is R s3 ' is hydrogen, halogen, cyano, hydroxy, -C 1-6 alkyl, -C 1-6 alkoxy, -haloalkyl, -haloalkoxy, -C 1-6 alkyl, -halo-C 1-6 alkoxy, -C 3-6 cycloalkyl, -NR h R i , -C(O)NR e R f , -C 1-3 alkyl-hydroxy and -C 1-3 alkyl-NR e R f ; and the -C 3-6 cycloalkyl is optionally substituted with 1, 2 or 3 substituents independently selected from halogen, methyl, ethyl, propyl (n-propyl), isopropyl, trifluoromethyl, amino, N(CH3)2, hydroxy, carboxyl; wherein R e , R f are each independently hydrogen or C 1-3 alkyl; R h , R i are each independently hydrogen, -C 1-3 alkyl, -C(O)C 1-3 alkyl or -CO2C 1-3Alkyl; R s3 ” is isopropyl; n is 0. In one embodiment, the R s3 ” is below the plane of the benzene ring.

[0170] In one embodiment of the present invention, R0' is selected from the following structures: R s3 ' is hydrogen, halogen, cyano, hydroxy, -C 1-6 alkyl, -C 1-6 alkoxy, -haloalkyl, -haloalkyl 1-6 alkoxy, -C 1-6 cycloalkyl, -NR 3-6 R h R i 、-C(O)NR e R f 、-C 1-3 alkyl-hydroxy and -C 1-3 alkyl-NR e R f ; and the -C 3-6 cycloalkyl is optionally substituted with 1, 2 or 3 substituents independently selected from halogen, methyl, ethyl, propyl (n-propyl), isopropyl, trifluoromethyl, amino, N(CH3)2, hydroxy, carboxyl; wherein R e 、R f are each independently hydrogen or C 1-3 alkyl; R h 、R i are each independently hydrogen, -C 1-3 alkyl, -C(O)C 1-3 alkyl or -CO2C 1-3 alkyl; R s3 ” is isopropyl; R s3 is -C 1-6 alkyl; n is 0 or 1. In one embodiment, the R s3 ” is below the plane of the pyridine ring.

[0171] In one embodiment of the present invention, R0' is selected from the following structures: R s3 ' is hydrogen, halogen, cyano, hydroxy, -C 1-6 alkyl, -C 1-6 alkoxy, -haloalkyl, -haloalkyl 1-6 alkoxy, -C 1-6 cycloalkyl, -NR 3-6 R h R i 、-C(O)NR e R f 、-C 1-3 alkyl-hydroxy and -C1-3 alkyl-NR e R f ; and said -C 3-6 cycloalkyl is optionally substituted with 1, 2 or 3 substituents independently selected from halogen, methyl, ethyl, propyl (n-propyl), isopropyl, trifluoromethyl, amino, N(CH3)2, hydroxy, carboxy; wherein R e , R f are each independently hydrogen or C 1-3 alkyl; R h , R i are each 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, said R s3 ” is below the plane of the pyrimidine ring.

[0172] In one embodiment of the present invention, R0' is selected from the following structures: R s3 ' is hydrogen, halogen, cyano, hydroxy, -C 1-6 alkyl, -C 1-6 alkoxy, -halo-C 1-6 alkyl, -halo-C 1-6 alkoxy, -C 3-6 cycloalkyl, -NR h R i , -C(O)NR e R f , -C 1-3 alkyl-hydroxy and -C 1-3 alkyl-NR e R f ; and said -C 3-6 cycloalkyl is optionally substituted with 1, 2 or 3 substituents independently selected from halogen, methyl, ethyl, propyl (n-propyl), isopropyl, trifluoromethyl, amino, N(CH3)2, hydroxy, carboxy; wherein R e , R f are each independently hydrogen or C 1-3 alkyl; R h , R i are each 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, said R s3 ”' is below the plane of the pyrazole ring.

[0173] In one embodiment of the present invention, R0' is selected from the following structures: R s3 ' is isopropyl; n is 0. In one embodiment, the R s3 ' is below the plane of the pyrazine ring.

[0174] In one embodiment of the present invention, R0' is selected from the following structures: R s3 ' is hydrogen, halogen, cyano, hydroxy, -C 1-6 alkyl, -C 1-6 alkoxy, -halo C 1-6 alkyl, -halo C 1-6 alkoxy, -C 3-6 cycloalkyl, -NR h R i 、-C(O)NR e R f 、-C 1-3 alkyl-hydroxy and -C 1-3 alkyl-NR e R f ; and the -C 3-6 cycloalkyl is optionally substituted with 1, 2 or 3 substituents independently selected from halogen, methyl, ethyl, propyl (n-propyl), isopropyl, trifluoromethyl, amino, N(CH3)2, hydroxy, carboxyl; wherein R e 、R f are each independently hydrogen or C 1-3 alkyl; R h 、R i are each independently hydrogen, -C 1-3 alkyl, -C(O)C 1-3 alkyl or -CO2C 1-3 alkyl; R s3 ” is isopropyl; R s3 ”' is -C 1-6 alkyl. In one embodiment, the R s3 ” is below the plane of the pyrazole ring.

[0175] In one embodiment of the present invention, R0' is selected from the following structures:

[0176]

[0177]

[0178] In another aspect, the present invention provides a compound of formula (II), or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof,

[0179]

[0180] In the formula,

[0181] Z is N-C(O)-CR3=CR1R2 or

[0182] R1 and R2 are each independently hydrogen, halogen, cyano, NR a R b , -C 1-3 alkyl, halo-C 1-3 alkyl, -C 1-3 alkyl-hydroxy, -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 heterocycloalkyl or -C 1-3 alkyl-5- or 6-membered monocyclic heteroaryl; wherein the 3- to 6-membered heterocycloalkyl or the 5- or 6-membered monocyclic heteroaryl has 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms;

[0183] R3 is hydrogen, halogen, -C 1-3 alkyl or -C 1-3 alkoxy;

[0184] R4 is hydrogen, halo-C 1-3 alkyl, -C 1-3 alkyl-hydroxy, -C 1-3 alkyl-cyano or -C 1-3 alkyl-C 1-3 alkoxy;

[0185] R 11 , R 12 are the same or different and are each independently hydrogen, halogen, -C 1-3 alkyl, -halo-C 1-3 alkyl, -C 1-3 alkyl-hydroxy, -C 1-3 alkyl-cyano, -C 1-3 alkyl-C 1-6 alkoxy, -C 1-3 alkyl-halo-C 1-6 alkyl or -C 1-3 alkyl-halo-C 1-6 alkoxy;

[0186] R 21 , R 22 are the same or different and are each independently hydrogen, halogen, -C 1-3 alkyl, -halo-C 1-3Alkyl, -C 1-3 Alkyl - hydroxy, -C 1-3 Alkyl - cyano, -C 1-3 Alkyl - C 1-6 Alkoxy, -C 1-3 Alkyl - halo C 1-6 Alkyl or -C 1-3 Alkyl - halo C 1-6 Alkoxy;

[0187] R 31 、R 32 are the same or different and each independently is hydrogen, halogen, -C 1-3 alkyl, -halo C 1-3 alkyl, -C 1-3 alkyl - hydroxy, -C 1-3 alkyl - cyano, -C 1-3 alkyl - C 1-6 alkoxy, -C 1-3 alkyl - halo C 1-6 alkyl or -C 1-3 alkyl - halo C 1-6 alkoxy;

[0188] R 41 is hydrogen, halogen, -C 1-3 alkyl, -halo C 1-3 alkyl, -C 1-3 alkyl - hydroxy, -C 1-3 alkyl - cyano, -C 1-3 alkyl - C 1-6 alkoxy, -C 1-3 alkyl - halo C 1-6 alkyl or -C 1-3 alkyl - halo C 1-6 alkoxy;

[0189] P is O, NH or NR m ; R m is -C 1-6 alkyl, -halo C 1-6 alkyl, -C 1-6 alkyl - hydroxy, -C 1-6 alkyl - cyano, -C 1-6 alkyl - C 1-6 alkoxy, -C 1-6 alkyl - halo C 1-6 alkoxy, -C 1-6 alkyl - C 3-6 cycloalkyl or -C 1-6 alkyl - 3 - to 6 - membered heteroalkyl;

[0190] R 42 is -(C=O)-, -C 1-3alkyl, -C 1-3 alkyl(hydroxy)-, -C 1-3 alkyl(cyano)-, -C 1-3 alkyl(C 1-6 alkyl), -C 1-3 alkyl(haloC 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)-, or -C 1-3 alkyl(haloC 1-6 alkoxy)-;

[0191] X2 and Y2 are the same or different and each independently is hydrogen, halogen, -C 1-3 alkyl, -haloC 1-3 alkyl, -C 1-3 alkyl-hydroxy, -C 1-3 alkyl-cyano, -C 1-3 alkyl-C 1-6 alkoxy, -C 1-3 alkyl-haloC 1-6 alkyl or -C 1-3 alkyl-haloC 1-6 alkoxy;

[0192] or X2 and Y2 together with the adjacent carbon atom form a substituted or unsubstituted C 3-6 cycloalkyl or a substituted or unsubstituted 3- to 6-membered heterocycloalkyl; the 3- to 6-membered heterocycloalkyl has 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms; the "substituted" means that 1, 2, 3 or 4 hydrogen atoms in the group are each independently replaced by substituents selected from group S;

[0193] E3 is N or C-L-R5; wherein,

[0194] L is a bond, -CR L1 R L2 -, -O-(CR L1 R L2 ) t1 - or -NH-(CR L3 R L4 ) t2 -; wherein, R L1 , R L2 , R L3 , R L4 are the same or different and each independently is hydrogen, halogen, hydroxy, hydroxymethyl, hydroxyethyl, -C 1-3alkyl or oxo; t1 and t2 are each independently 0, 1, 2, 3 or 4; R L1 With R L2 Medium or R L3 With R L4 When one of them is an oxo group, the other does not exist;

[0195] R5 is hydrogen, halogen, hydroxy, -substituted or unsubstituted C 1-6 Alkyl, -substituted or unsubstituted C 3-6 cycloalkyl, -substituted or unsubstituted 3 to 6 membered heterocycloalkyl, -O-substituted or unsubstituted C 1-6 Alkyl, -O-substituted or unsubstituted C 3-6 Cycloalkyl, -O-substituted or unsubstituted 3- to 6-membered heterocycloalkyl, -SO2-substituted or unsubstituted C 1-6 Alkyl, -SO2-substituted or unsubstituted C 3-6 cycloalkyl, -SO2-substituted or unsubstituted 3 to 6-membered heterocycloalkyl, -substituted or unsubstituted 5 or 6-membered monocyclic heteroaryl or NR 51 R 52 ; Among them, R 51 , R 52 are each 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)halogen 1-6 Alkyl; or R 51 and R 52 Together with the connected nitrogen atom, it forms a substituted or unsubstituted 3- to 6-membered nitrogen-containing heterocycloalkyl group; wherein the 3- to 6-membered heterocycloalkyl 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 nitrogen-containing heterocycloalkyl group has 3 to 6 ring atoms, one of which is a nitrogen atom, and 0, 1 or 2 of the remaining ring atoms are optionally heteroatoms selected from N, O and S; the "substituted" refers to that 1, 2, 3 or 4 hydrogen atoms in the group are replaced by substituents independently selected from Group S;

[0196] The substituents in group S are selected from: hydroxyl, halogen, nitro, oxo, -C 1-6 Alkyl, -halogenated C 1-6 Alkyl, hydroxy substituted C 1-6 Alkyl, benzyl, -(CH2) u -Cyano, -(CH2) u -C 1-6 Alkoxy, -(CH2) u -Halogenated C 1-6Alkoxy, -(CH2) u -Halogenated C 1-6 Alkyl, -(CH2) u -3- to 6-membered heterocycloalkyl, -(CH2) u -5- or 6-membered monocyclic heteroaryl, -(CH2) u -C 3-8 Cycloalkyl, -(CH2) u -O-(CH2) v -C 3-8 Cycloalkyl, -(CH2) u -O-(CH2) v -C 1-6 Alkoxy, -(CH2) u -O-(CH2) v OH, -(CH2) u -SO2C 1-6 Alkyl, -(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; wherein the 3- to 6-membered heterocycloalkyl or the 5- or 6-membered monocyclic heteroaryl each independently has 1, 2, or 3 heteroatoms selected from N, O, and S as ring atoms; the 3- to 6-membered heterocycloalkyl, 5- or 6-membered monocyclic heteroaryl is optionally substituted with 1, 2, or 3 substituents selected from halogen, cyano, -C 1-3 Alkyl, -C 1-3 Alkoxy, and C 3-6 Cycloalkyl; u and v are each independently 0, 1, 2, 3, or 4; R a0 、R b0 Each independently is hydrogen or C 1-3 Alkyl;

[0197] E4 is N or CH;

[0198] Ar is C 6-10an aryl group, a 5- or 6-membered monocyclic heteroaryl group, or an 8- to 10-membered bicyclic 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; the 8- to 10-membered bicyclic heteroaryl group 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 substituted by 1, 2, 3, or 4 groups independently selected from R s1 ;

[0199] or

[0200] Ar has the structure shown in formula (B):

[0201]

[0202] 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 heterocycloalkyl 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 heterocycloalkyl ring has 1, 2, or 3 heteroatoms selected from N, O, and S as ring atoms;

[0203] (R s1 ) p means that the hydrogen on ring B1 is substituted by p R s1 , p is 0, 1, 2, or 3, and each R s1 is the same or different;

[0204] (R s2 ) q means that the hydrogen on ring B2 is substituted by q R s2 , q is 0, 1, 2, or 3, and each R s2 is the same or different;

[0205] R s1 , R s2 are each independently halogen, cyano, nitro, hydroxy, -C 1-6 alkyl, -C 1-6 alkoxy, -halo C 1-6 alkyl, -halo C 1-6 alkoxy, -C 3-6 cycloalkyl, -NR c R d , -C(O)NR e R f , -SO2C 1-3 alkyl, -SO2 halo C 1-3 alkyl, -SO2NR e R f , -C 1-4 alkyl-hydroxy, -C1-4 alkyl-cyano, -C 1-4 alkyl-C 1-6 alkoxy, -C 1-4 alkyl-haloC 1-6 alkyl, -C 1-4 alkyl-haloC 1-6 alkoxy, -C 1-4 alkyl-3- to 6-membered heterocycloalkyl, -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 alkynyl; wherein the 3- to 6-membered heterocycloalkyl has 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms;

[0206] R a 、R b 、R e 、R f are each independently hydrogen or C 1-3 alkyl;

[0207] R c 、R d are each independently hydrogen, -C 1-3 alkyl, -C(O)C 1-3 alkyl, -CO2C 1-3 alkyl.

[0208] In one embodiment of the present invention, R s1 、R s2 are each independently halogen, cyano, nitro, hydroxy, -C 1-3 alkyl, -C 1-3 alkoxy, haloC 1-3 alkyl, haloC 1-3 alkoxy, -C 3-6 cycloalkyl, -NR c R d 、-C(O)NR e R f 、-SO2C 1-3 alkyl, -SO2haloC 1-3 alkyl, -SO2NR e R f 、-C 1-2 alkyl-hydroxy, -C 1-2 alkyl-cyano, -C 1-2 alkyl-C 1-3 alkoxy, -C 1-2Alkyl-halo C 1-3 Alkyl, -C 1-2 Alkyl-halo C 1-3 Alkoxy, -C 1-2 Alkyl-3- to 6-membered heteroalkyl, -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; wherein, R c , R d Each independently is hydrogen, -C 1-3 Alkyl, -C(O)C 1-3 Alkyl, -CO2C 1-3 Alkyl; R e , R f Each independently is hydrogen or C 1-3 Alkyl.

[0209] In one embodiment of the present invention, R s1 , R s2 Each independently is halogen, cyano, nitro, hydroxy, -C 1-3 Alkyl, -C 1-3 Alkoxy, halo C 1-3 Alkyl, halo C 1-3 Alkoxy, -C 3-6 Cycloalkyl, -NR c R d , -C(O)NR e R f , -SO2C 1-3 Alkyl, -SO2 halo C 1-3 Alkyl, -SO2NR e R f , -CH2-hydroxy, -CH2-cyano, -CH2-C 1-3 Alkoxy, -CH2-halo C 1-3 Alkyl, -CH2-halo C 1-3 Alkoxy, -CH2-3- to 6-membered heteroalkyl, -CH2-NR e R f , -CH2-C(O)NR e R f , -CH2-SO2C 1-3 Alkyl or C 2-4 Alkynyl; wherein, R c Is hydrogen, -C 1-3 Alkyl, -C(O)CH3 or -CO2CH3; Re , R f , R d Each independently is hydrogen or C 1-3 alkyl group.

[0210] In one embodiment of the present invention, R s1 , R s2 Each independently is halogen, cyano, nitro, hydroxy, -C 1-3 alkyl group, -C 1-3 alkoxy group, halo C 1-3 alkyl group, halo C 1-3 alkoxy group, -C 3-6 cycloalkyl group, -NR c R d , -C(O)NR e R f , -CH2-hydroxy, -CH2-cyano; wherein, R c is hydrogen, -C(O)CH3 or -CO2CH3; R e , R f , R d Each independently is hydrogen or C 1-3 alkyl group.

[0211] In one embodiment of the present invention, in R s1 and R s2 , the C 3-6 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.

[0212] In one embodiment of the present invention, in R s1 and R s2 , the 3- to 6-membered heterocycloalkyl group is selected from: aziridine, ethylene oxide, azetidine, oxetane, oxazolidine, 1,3-dioxolane, imidazolidine, tetrahydrofuran, tetrahydrothiophene, pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, thiomorpholine-1,1-dioxide, tetrahydropyran, 1,3-oxazinane, hexahydropyrimidine, 1,4-dioxane.

[0213] In one embodiment of the present invention, R s1 , R s2Each independently is halogen, cyano, nitro, hydroxy, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, propoxy (n-propoxy), isopropoxy, chloromethyl, dichloromethyl, trichloromethyl, chloroethyl, 1,2-dichloroethyl, trichloroethyl, bromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, trifluoromethoxy, trifluoroethoxy, fluoromethoxy, fluoroethoxy, difluoromethoxy, difluoroethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -NR c R d 、-C(O)NR e R f 、-CH2-hydroxy, -CH2-cyano; wherein, R c is hydrogen, -C(O)CH3 or -CO2CH3; R e 、R f 、R d Each independently is hydrogen, methyl or ethyl.

[0214] In one embodiment of the present invention, R s3 、R s4 Each independently is halogen, cyano, hydroxy, -C 1-6 alkyl, -C 1-3 alkoxy, halo-C 1-3 alkyl, halo-C 1-3 alkoxy, -C 3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, amino, NHCH3, N(CH3)2, -C(O)NR e R f 、-SO2C 1-3 alkyl, -SO2 halo-C 1-3 alkyl, -SO2NR e R f 、-C 1-2 alkyl-hydroxy, -C 1-2 alkyl-ethynyl, -C 1-2 alkyl-cyano, -C 1-2 alkyl-C 1-3 alkoxy, -C 1-2 alkyl-halo-C 1-3 alkyl, -C 1-2 alkyl-halo-C 1-3 alkoxy, -C 1-2 alkyl-3- to 6-membered heterocycloalkyl, -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 cycloalkyl, 3- to 6-membered heterocycloalkyl optionally substituted with 1, 2 or 3 substituents independently selected from halogen, methyl, ethyl, propyl (n-propyl), isopropyl, trifluoromethyl, amino, N(CH3)2, hydroxy, carboxyl; R e , R f are each independently hydrogen or C 1-3 alkyl.

[0215] In one embodiment of the present invention, R s3 , R s4 are each independently halogen, cyano, hydroxy, C 1-4 alkyl, -C 1-3 alkoxy, halo-C 1-3 alkyl, halo-C 1-3 alkoxy, -C 3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, amino, NHCH3, N(CH3)2, -C(O)NR e R f , -SO2C 1-3 alkyl, -SO2 halo-C 1-3 alkyl, -SO2NR e R f , -CH2-hydroxy, -CH2-ethynyl, -CH2-cyano, -CH2-C 1-3 alkoxy, -CH2-halo-C 1-3 alkyl, -CH2-halo-C 1-3 alkoxy, -CH2-3- to 6-membered heterocycloalkyl, -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 cycloalkyl, 3- to 6-membered heterocycloalkyl optionally substituted with 1, 2 or 3 substituents independently selected from halogen, methyl, ethyl, propyl (n-propyl), isopropyl, trifluoromethyl, amino, N(CH3)2, hydroxy, carboxyl; R e , R f are each independently hydrogen or C 1-3Alkyl group.

[0216] In one embodiment of the present invention, R s3 , R s4 are each independently halogen, cyano, hydroxyl, C 1-4 alkyl, -C 1-3 alkoxy, halo-C 1-3 alkyl, -C 3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, amino, NHCH3, N(CH3)2, -CH2-hydroxy, -CH2-ethynyl; wherein the C 1-4 alkyl, -C 1-3 alkoxy, -CH2-, -C 3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl are optionally substituted with 1, 2 or 3 substituents independently selected from halogen, methyl, ethyl, propyl (n-propyl), isopropyl, trifluoromethyl, amino, N(CH3)2, hydroxyl, carboxyl.

[0217] In one embodiment of the present invention, in R s3 and R s4 , the C 3-6 cycloalkyl is selected from: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.

[0218] In one embodiment of the present invention, in R s3 and R s4 , the 3- to 6-membered heterocycloalkyl is selected from: aziridine, oxirane, azetidine, oxetane, tetrahydrofuran, tetrahydrothiophene, pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, thiomorpholine-1,1-dioxide, tetrahydropyran.

[0219] In one embodiment of the present invention, R s3 , R s4Each is independently a halogen, cyano group, hydroxyl group, methyl group, ethyl group, n-propyl group, isopropyl group, sec-butyl group, methoxy group, ethoxy group, propoxy group (n-propoxy group), isopropoxy group, chloromethyl group, dichloromethyl group, trichloromethyl group, chloroethyl group, 1,2-dichloroethyl group, trichloroethyl group, bromoethyl group, fluoromethyl group, difluoromethyl group, trifluoromethyl group, fluoroethyl group, difluoroethyl group, trifluoroethyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, aziridine, ethylene oxide, azetidine, oxetane, tetrahydrofuran, tetrahydrothiophene, pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, thiomorpholine-1,1-dioxide, tetrahydropyran, amino group, NHCH3, N(CH3)2, -CH2-hydroxy group, -CH2-ethynyl group; wherein the methyl group, ethyl group, n-propyl group, methoxy group, ethoxy group, propoxy group (n-propoxy group), -CH2-, azetidine, oxetane, tetrahydrofuran, tetrahydrothiophene, pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, thiomorpholine-1,1-dioxide, tetrahydropyran are optionally substituted by 1, 2 or 3 substituents independently selected from halogen, methyl group, ethyl group, propyl group (n-propyl group), isopropyl group, trifluoromethyl group, amino group, N(CH3)2, hydroxyl group, carboxyl group.

[0220] In one embodiment of the present invention, the S group substituents are selected from: hydroxyl group, halogen, nitro group, oxo group, -C 1-3 alkyl group, hydroxyl-substituted C 1-3 alkyl group, benzyl group, -(CH2) u -cyano group, -(CH2) u -C 1-3 alkoxy group, -(CH2) u -halo C 1-3 alkoxy group, -(CH2) u -halo C 1-3 alkyl group, -(CH2) u -3- to 6-membered heterocycloalkyl group, -(CH2) u -5- or 6-membered monocyclic heteroaryl group, -(CH2) u -C 3-6 cycloalkyl group, -(CH2) u -O-(CH2) v -C 3-6 cycloalkyl group, -(CH2) u -O-(CH2) v -C 1-3 alkoxy 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)-haloalkyl C 1-3 alkyl; wherein the 3- to 6-membered heteroalkyl, 5- or 6-membered monocyclic heteroaryl each independently has 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms; the 3- to 6-membered heteroalkyl, 5- or 6-membered monocyclic heteroaryl is optionally substituted with 1, 2 or 3 substituents selected from halogen, cyano, -C 1-3 alkyl, -C 1-3 alkoxy and C 3-6 cycloalkyl; u, v are each independently 0, 1, 2, 3 or 4; R a0 , R b0 are each independently hydrogen or C 1-3 alkyl.

[0221] In one embodiment of the present invention, the S group substituent is halogen.

[0222] In one embodiment of the present invention, the S group substituent is selected from: C 1-3 alkyl, -(CH2) u -3- to 6-membered heteroalkyl, -(CH2) u -SO2C 1-3 alkyl, -(CH2) u -NR a0 R b0 ; wherein the 3- to 6-membered heteroalkyl has 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms; the 3- to 6-membered heteroalkyl is optionally substituted with 1, 2 or 3 substituents selected from halogen, cyano, -C 1-3 alkyl, -C 1-3 alkoxy and C 3-6 cycloalkyl; u is 0, 1, 2, 3 or 4; R a0 , R b0 are each independently hydrogen or C 1-3 alkyl.

[0223] In one embodiment of the present invention, among the above groups (such as Ar, R0), the C 6-10Each aryl group is independently phenyl or naphthyl.

[0224] In one embodiment of the present invention, among the above groups (such as Ar), the C 6-10 When the aryl group is phenyl, it is selected from the following structures:

[0225] In the formula, R s1 、R s2 are as defined above.

[0226] In one embodiment of the present invention, among the above groups (such as Ar, R0), each 5- or 6-membered monocyclic heteroaryl group is independently selected from: thiophene, N-alkylpyrrole, furan, thiazole, isothiazole, imidazole, oxazole, pyrrole, pyrazole, triazole, 1,2,3-triazole, 1,2,4-triazole, 1,2,5-triazole, 1,3,4-triazole, tetrazole, isoxazole, oxadiazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, thiadiazole, pyridine, pyridazine, pyrimidine, pyrazine.

[0227] In one embodiment of the present invention, among the above groups (such as Ar, R0), each 5- or 6-membered monocyclic heteroaryl group is independently selected from the following structures:

[0228]

[0229] In one embodiment of the present invention, among the above groups (such as Ar, R0), each 8- to 10-membered bicyclic heteroaryl group is independently a 9- to 10-membered bicyclic heteroaryl group formed by the 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 the fusion of a 5- or 6-membered monocyclic heteroaryl ring and a 5- or 6-membered monocyclic heteroaryl ring.

[0230] In one embodiment of the present invention, the 5- or 6-membered monocyclic heteroaryl ring forming the 9- to 10-membered bicyclic heteroaryl group or the 8- to 10-membered bicyclic heteroaryl group is selected from: thiophene ring, N-alkylpyrrole 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, tetrazole 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.

[0231] In one embodiment of the present invention, the 5- or 6-membered monocyclic heteroaryl ring forming the 9- to 10-membered bicyclic heteroaryl group or the 8- to 10-membered bicyclic heteroaryl group is selected from the following structures:

[0232]

[0233]

[0234] wherein the two ring atoms represented are adjacent atom pairs shared when fused with other rings.

[0235] In one embodiment of the present invention, in the B1 ring and the A1 ring, the 5- or 6-membered monocyclic heteroaryl rings are each independently selected from: thiophene ring, N-alkylpyrrole 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, tetrazole 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.

[0236] In one embodiment of the present invention, in the B1 ring and the A1 ring, the 5- or 6-membered monocyclic heteroaryl rings are each independently selected from the following structures:

[0237]

[0238] wherein the two ring atoms represented are adjacent atom pairs shared when fused with other rings.

[0239] In one embodiment of the present invention, in the B2 ring and the A2 ring, 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.

[0240] In one embodiment of the present invention, in the B2 ring and the A2 ring, each of the fused 5- or 6-membered monocyclic heterocycloalkyl rings is independently selected from: oxazolidine, pyrrolidin-2-one, pyrrolidine-2,5-dione, 1,3-dioxolane, dihydrofuran-2(3H)-one, dihydrofuran-2,5-dione, piperidin-2-one, piperidine-2,6-dione, tetrahydro-2H-pyran-2-one, imidazolidine, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, 1,3-dioxolan-2-one, oxazolidin-2-one, imidazolidin-2-one, piperidine, piperazine, piperazine-2-one, morpholine, morpholin-3-one, morpholin-2-one, thiomorpholin-3-one 1,1-dioxide, thiomorpholine, thiomorpholine-1,1-dioxide, tetrahydropyran, 1,2-dihydroazetidine, 1,2-dihydrooxetene, 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-oxazinane, hexahydropyrimidine, 1,4-dioxane, tetrahydropyrimidin-2(1H)-one, 1,4-dioxan-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-imidazole, 2,3-dihydro-1H-imidazole, 2,3-dihydrooxazole, 1,3-dioxolene, 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-pyrrol-2-one, 1,5-dihydro-2H-pyrrol-2-one, 1H-pyrrole-2,5-dione, furan-2(3H)-one, furan-2(5H)-one, 1,3-dioxolene-2-one, oxazol-2(3H)-one, 1,3-dihydro-2H-imidazol-2-one, furan-2,5-dione, 3,6-dihydropyridin-2(1H)-one, pyridine-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.

[0241] In one embodiment of the present invention, the fused 5- or 6-membered monocyclic heterocycloalkyl ring is selected from the following structures:

[0242]

[0243]

[0244] In one embodiment of the present invention, among the above groups (such as Ar, R0), the 8- to 10-membered bicyclic heteroaryl groups are each independently selected from: benzoxazole, benzisoxazole, benzimidazole, benzothiazole, benzisothiazole, benzotriazole, benzofuran, benzothiophene, indole, indazole, isoindole, quinoline, isoquinoline, quinazoline, quinoxaline, cinnoline, pyridopyrimidine, naphthyridine.

[0245] In one embodiment of the present invention, among the above groups (such as Ar, R0), the 8- to 10-membered bicyclic heteroaryl groups are each independently selected from: benzo[d]isoxazole, 1H-indole, isoindole, 1H-benzo[d]imidazole, benzo[d]isothiazole, 1H-benzo[d][1,2,3]triazole, benzo[d]oxazole, benzo[d]thiazole, indazole, benzofuran, benzo[b]thiophene, quinoline, isoquinoline, quinazoline, quinoxaline, cinnoline, pyrido[3,2-d]pyrimidine, pyrido[2,3-d]pyrimidine, pyrido[3,4-d]pyrimidine, pyrido[4,3-d]pyrimidine, 1,8-naphthyridine, 1,7-naphthyridine, 1,6-naphthyridine, 1,5-naphthyridine.

[0246] In one embodiment of the present invention, among the above groups (such as Ar, R0), the 8- to 10-membered bicyclic heteroaryl groups are each independently selected from the following structures:

[0247]

[0248] In one embodiment of the present invention, among the above groups (such as Ar, R0), the 8- to 10-membered bicyclic heteroaryl groups are each independently selected from the following structures:

[0249]

[0250] In one embodiment of the present invention, among the above groups (such as Ar, R0), the 8- to 10-membered bicyclic heteroaryl groups are each independently selected from the following structures:

[0251]

[0252] In one embodiment of the present invention, are each independently selected from the following structures:

[0253]

[0254] In one embodiment of the present invention, formula (B) and formula (A-1) are each independently selected from the following structures:

[0255]

[0256] In one embodiment of the present invention, Ar and Ar' are independently selected from the following structures:

[0257]

[0258]

[0259]

[0260] In one embodiment of the present invention, in the above groups (such as R0), the C 3-6 Cycloalkyl 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.

[0261] In one embodiment of the present invention, in the above groups (such as R0), the 3- to 6-membered heterocycloalkyl is selected from: aziridine, oxirane, azetidine, oxetane, oxazolidine, 1,3-dioxolane, imidazolidine, tetrahydrofuran, tetrahydrothiophene, pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, thiomorpholine-1,1-dioxide, tetrahydropyran, 1,3-oxazinane, hexahydropyrimidine, 1,4-dioxane.

[0262] In one embodiment of the present invention, in the above groups (such as R0), the 7- to 11-membered spirocycloalkyl is a monospirocycloalkyl containing one spiro atom formed by any two monocyclic cycloalkyl rings selected from cyclopropyl ring, cyclobutyl ring, cyclopentyl ring and cyclohexyl ring.

[0263] 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 heterocycloalkyl, -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 heteroalkyl, phenyl, 5- or 6-membered monocyclic heteroaryl, 8- to 10-membered bicyclic heteroaryl, 7- to 11-membered spiroalkyl are unsubstituted or substituted by 1, 2, 3 or 4 groups independently selected from R s3 as defined below.

[0264] 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 is selected from: thiophene, N-alkylpyrrole, furan, thiazole, isothiazole, imidazole, oxazole, pyrrole, pyrazole, triazole, 1,2,3-triazole, 1,2,4-triazole, 1,2,5-triazole, 1,3,4-triazole, tetrazole, 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 and 5- or 6-membered monocyclic heteroaryl are unsubstituted or substituted by 1, 2, 3 or 4 groups independently selected from R s3 as defined below.

[0265] In one embodiment of the present invention, R0 is selected from the following structures:

[0266]

[0267] In one embodiment of the present invention, R 11 , R 12 are the same or different and each independently is hydrogen, halogen, -C 1-3 alkyl, -CH2-hydroxy, -CH2-cyano, -CH2-C 1-3 alkoxy, -CH2-haloC 1-3 alkyl or -CH2-haloC 1-3 alkoxy.

[0268] In one embodiment of the present invention, R 11 , R 12 are the same or different and each independently is 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, -CH2-difluoromethoxy.

[0269] In one embodiment of the present invention, R 11 , R 12Same or different, each independently is hydrogen or -C 1-3 alkyl group.

[0270] In one embodiment of the present invention, R 11 , R 12 Same or different, each independently is hydrogen or methyl.

[0271] In one embodiment of the present invention, R 21 , R 22 Same or different, each independently is hydrogen, halogen, -C 1-3 alkyl group, -CH2-hydroxy, -CH2-cyano, -CH2-C 1-3 alkoxy group, -CH2-halo C 1-3 alkyl group or -CH2-halo C 1-3 alkoxy group.

[0272] In one embodiment of the present invention, R 21 , R 22 Same or different, each independently is 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, -CH2-difluoromethoxy.

[0273] In one embodiment of the present invention, R 21 , R 22 Same or different, each independently is hydrogen or -C 1-3 alkyl group.

[0274] In one embodiment of the present invention, R 21 , R 22 Same or different, each independently is hydrogen or methyl.

[0275] In one embodiment of the present invention, R 31 , R 32 Same or different, each independently is hydrogen, halogen, -C 1-3 alkyl group, -CH2-hydroxy, -CH2-cyano, -CH2-C 1-3 alkoxy group, -CH2-halo C 1-3 alkyl group or -CH2-halo C 1-3 alkoxy group.

[0276] In one embodiment of the present invention, R 31 , R 32Same or different, each independently being 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, -CH2-difluoromethoxy.

[0277] In one embodiment of the present invention, R 31 , R 32 Same or different, each independently being hydrogen or -C 1-3 alkyl.

[0278] In one embodiment of the present invention, R 31 , R 32 Same or different, each independently being hydrogen or methyl.

[0279] In one embodiment of the present invention, R 41 is hydrogen, halogen, -C 1-3 alkyl, -CH2-hydroxy, -CH2-cyano, -CH2-C 1-3 alkoxy, -CH2-halo C 1-3 alkyl or -CH2-halo C 1-3 alkoxy.

[0280] In one embodiment of the present invention, R 41 is 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, -CH2-difluoromethoxy.

[0281] In one embodiment of the present invention, R 41 is hydrogen.

[0282] In one embodiment of the present invention, in formula I, when the dotted line therein is a single bond, P is O; R 42 is -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(halo C 1-3 alkyl)-, -C 1-3 alkyl(C 1-3 alkyl-hydroxy)-, -C1-3 alkyl (C 1-3 alkyl-cyano)-, -C 1-3 alkyl (C 1-3 alkoxy)-, or -C 1-3 alkyl (halo C 1-3 alkoxy)-; wherein, C 1-3 alkyl is methyl, ethyl or propyl (n-propyl or isopropyl); C 1-3 alkoxy is methoxy, ethoxy or propoxy (n-propoxy or isopropoxy).

[0283] In one embodiment of the present invention, in formula I, when the dotted line in is a single bond, P is NH or NR m ; R m is -C 1-3 alkyl, -halo C 1-3 alkyl, -C 1-3 alkyl-hydroxy, -C 1-3 alkyl-cyano, -C 1-3 alkyl-C 1-3 alkoxy, -C 1-3 alkyl-halo C 1-3 alkoxy; R 42 is -(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 (halo 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)-, or -C 1-3 alkyl (halo C 1-3 alkoxy)-; wherein, C 1-3 alkyl is methyl, ethyl or propyl (n-propyl or isopropyl); C 1-3 alkoxy is methoxy, ethoxy or propoxy (n-propoxy or isopropoxy).

[0284] In one embodiment of the present invention, in formula I, when the dotted line in is a single bond, P is O, NH or NR m ; R m is -C 1-6 alkyl; R 42 is -(C=O)- or -C1-3 -alkyl

[0285] In one embodiment of the present invention, in formula I, when the dotted line in is a single bond, P is O, NH or NR m ; R m is -C 1-3 alkyl; R 42 is -(C=O)- or -C 1-3 alkyl-.

[0286] In one embodiment of the present invention, in formula I, when the dotted line in is a single bond, P is O, NH or NR m ; R m is methyl, ethyl, n-propyl or isopropyl; R 42 is -(C=O)-, -CH2-, -CH2CH2- or -CH2CH2CH2-.

[0287] In one embodiment of the present invention, in formula I, when the dotted line in is absent, P is hydrogen or halogen; R 42 is hydrogen, halogen, -C 1-3 alkyl, -CH2-hydroxy, -CH2-cyano, -CH2-C 1-3 alkoxy, -CH2-haloC 1-3 alkyl or -CH2-haloC 1-3 alkoxy.

[0288] In one embodiment of the present invention, in formula I, when the dotted line in is absent, P is hydrogen or halogen; R 42 is 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, -CH2-difluoromethoxy.

[0289] In one embodiment of the present invention, in formula I, X1 is hydrogen, halogen, cyano, hydroxy, amino, nitro, -substituted or unsubstituted C 1-3 alkyl, -substituted or unsubstituted C 3-6 cycloalkyl, -substituted or unsubstituted 3- to 6-membered heterocycloalkyl, -O-substituted or unsubstituted C 1-3 alkyl, -O-substituted or unsubstituted C 3-6 cycloalkyl, -O-substituted or unsubstituted 3- to 6-membered heterocycloalkyl, -NH-substituted or unsubstituted C 1-3alkyl, -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 heterocycloalkyl, -NH(C=O)-substituted or unsubstituted C 1-3 alkyl, -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 are each independently hydrogen or C 1-3 alkyl; or R j , R k together with the attached nitrogen atom form a substituted or unsubstituted 3- to 6-membered nitrogen-containing heterocycloalkyl; the 3- to 6-membered heterocycloalkyl has 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms; the 3- to 6-membered nitrogen-containing heterocycloalkyl has 3 to 6 ring atoms and one of the ring atoms is a nitrogen atom, and 0, 1 or 2 of the remaining ring atoms are optionally heteroatoms selected from N, O and S; the "substituted" means that 1, 2, 3 or 4 hydrogen atoms in the group are each independently replaced by substituents selected from group S; wherein, C 1-3 alkyl is methyl, ethyl or propyl (n-propyl or isopropyl); C 1-3 alkoxy is methoxy, ethoxy or propoxy (n-propoxy or isopropoxy).

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

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

[0292] In one embodiment of the present invention, in formula I, Y1 is C; E1 is C; E2 is N.

[0293] In one embodiment of the present invention, in formula I, Y1 is C; E1 is N; E2 is N.

[0294] In one embodiment of the present invention, in Formula I, Y1 is N; E1 is N; E2 is C.

[0295] In one embodiment of the present invention, in Formula I, Y1 is N; E1 is N; E2 is C.

[0296] In one embodiment of the present invention, in Formula II, P is O.

[0297] In one embodiment of the present invention, in Formula II, P is NH or NR m ; R m is C 1-3 alkyl, halo C 1-3 alkyl, -C 1-3 alkyl-hydroxy, -C 1-3 alkyl-cyano, -C 1-3 alkyl-C 1-3 alkoxy, -C 1-3 alkyl-halo C 1-3 alkoxy; wherein, C 1-3 alkyl is methyl, ethyl or propyl (n-propyl or isopropyl); C 1-3 alkoxy is methoxy, ethoxy or propoxy (n-propoxy or isopropoxy).

[0298] In one embodiment of the present invention, in Formula II, R 42 is -(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(halo 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)-, or -C 1-3 alkyl(halo C 1-3 alkoxy)-; wherein, C 1-3 alkyl is methyl, ethyl or propyl (n-propyl or isopropyl); C 1-3 alkoxy is methoxy, ethoxy or propoxy (n-propoxy or isopropoxy).

[0299] In one embodiment of the present invention, in Formula II, X2, Y2 are the same or different, and each independently is hydrogen, halogen, -C 1-3 alkyl, -C 1-3 alkyl-hydroxy, -C1-3 alkyl-cyano, -C 1-3 alkyl-C 1-3 alkoxy, -C 1-3 alkyl-haloC 1-3 alkyl or -C 1-3 alkyl-haloC 1-3 alkoxy; wherein, C 1-3 alkyl is methyl, ethyl or propyl (n-propyl or isopropyl); C 1-3 alkoxy is methoxy, ethoxy or propoxy (n-propoxy or isopropoxy).

[0300] In one embodiment of the present invention, in Formula II, X2, Y2 and the adjacent carbon atoms together form a substituted or unsubstituted C 3-6 cycloalkyl or a substituted or unsubstituted 3- to 6-membered heterocycloalkyl; the 3- to 6-membered heterocycloalkyl has 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms; the "substituted" means that 1, 2, 3 or 4 hydrogen atoms in the group are independently replaced by substituents selected from Group S.

[0301] In one embodiment of the present invention, in Formula II, L is a bond.

[0302] In one embodiment of the present invention, in Formula II, R5 is hydrogen, halogen, hydroxy, -substituted or unsubstituted C 1-3 alkyl, -substituted or unsubstituted C 3-6 cycloalkyl, -substituted or unsubstituted 3- to 6-membered heterocycloalkyl, -O-substituted or unsubstituted C 1-3 alkyl, -O-substituted or unsubstituted C 3-6 cycloalkyl, -O-substituted or unsubstituted 3- to 6-membered heterocycloalkyl, -SO2-substituted or unsubstituted C 1-3 alkyl, -SO2-substituted or unsubstituted C 3-6 cycloalkyl, -SO2-substituted or unsubstituted 3- to 6-membered heterocycloalkyl, -substituted or unsubstituted 5- or 6-membered monocyclic heteroaryl or NR 51 R 52 ; wherein, R 51 、R 52 are each 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)haloC 1-3 alkyl; or R 51 and R 52together with the linked nitrogen atom form a substituted or unsubstituted 3- to 6-membered nitrogen-containing heterocycloalkyl; wherein, the 3- to 6-membered heterocycloalkyl and 5- or 6-membered monocyclic heteroaryl each independently have 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms; the 3- to 6-membered nitrogen-containing heterocycloalkyl has 3 to 6 ring atoms and one of the ring atoms is a nitrogen atom, and 0, 1 or 2 of the remaining ring atoms are optionally heteroatoms selected from N, O and S; the "substitution" means that 1, 2, 3 or 4 hydrogen atoms in the group are each independently replaced by substituents selected from group S; wherein, C 1-3 alkyl is methyl, ethyl or propyl (n-propyl or isopropyl); C 1-3 alkoxy is methoxy, ethoxy or propoxy (n-propoxy or isopropoxy).

[0303] 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, chloromethyl, dichloromethyl, trichloromethyl, chloroethyl, 1,2-dichloroethyl, trichloroethyl, bromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, 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 heterocycloalkyl or -CH2-5- or 6-membered monocyclic heteroaryl; the 3- to 6-membered heterocycloalkyl is selected from: aziridine, ethylene oxide, azetidine, oxetane, tetrahydrofuran, tetrahydrothiophene, pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, thiomorpholine-1,1-dioxide, tetrahydropyran; the 5- or 6-membered monocyclic heteroaryl is selected from: thiophene, N-alkylpyrrole, furan, thiazole, isothiazole, imidazole, oxazole, pyrrole, pyrazole, triazole, 1,2,3-triazole, 1,2,4-triazole, 1,2,5-triazole, 1,3,4-triazole, tetrazole, isoxazole, oxadiazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, thiadiazole, pyridine, pyridazine, pyrimidine, pyrazine; the 3- to 6-membered heterocycloalkyl and 5- or 6-membered monocyclic heteroaryl are optionally substituted by 1 or 2 halogens or C 1-3 alkyl.

[0304] In one embodiment of the present invention, R3 is hydrogen, halogen, methoxy, ethoxy, propoxy (n-propoxy) or isopropoxy.

[0305] 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.

[0306] In one embodiment of the present invention, R1, R2, and R3 are hydrogen.

[0307] In one embodiment of the present invention, E1 is N or CR5; wherein, R5 is hydrogen.

[0308] In one embodiment of the present invention, E2 is N or CR6; wherein, R6 is hydrogen.

[0309] In one embodiment of the present invention, in the compound of formula (I), the said R 11 、R 12 、R 21 、R 22 、R 31 、R 32 、R 41 、R 42 、Z, P, R0, Ar, E1, E2, X1, Y1 are each independently the corresponding groups in the specific compounds in the examples.

[0310] 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 its diastereomers.

[0311] In one embodiment of the present invention, the representative compounds of formula (IA) include the structures listed in Table A-1 below, or tautomers, cis-trans isomers, mesomers, racemates, enantiomers, diastereomers or atropisomers 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 the aforementioned isomers thereof,

[0312] Table A-1

[0313]

[0314]

[0315]

[0316]

[0317]

[0318]

[0319]

[0320]

[0321]

[0322]

[0323]

[0324]

[0325]

[0326]

[0327] In one embodiment of the present 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 of the structures in Table A-2.

[0328] Table A-2

[0329]

[0330]

[0331] In one embodiment of the present invention, representative compounds of formula (IA) 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 these structures.

[0332] In one embodiment of the present 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, Y2 are each independently the corresponding groups in the specific compounds in the examples.

[0333] In one embodiment of the present invention, the compounds of formula (II) are selected from any of the compounds Z2, Z17 to Z20 in the examples or their diastereoisomers.

[0334] In another aspect, the present invention provides a pharmaceutical composition comprising the aforementioned compound or its tautomer, cis-trans isomer, meso form, racemate, enantiomer, diastereoisomer, atropisomer or a mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof; and a pharmaceutically acceptable carrier.

[0335] As used herein, the term "pharmaceutically acceptable carrier" refers to any formulation or carrier medium that can deliver an effective amount of the active substance of the present invention, does not interfere with the biological activity of the active substance and is non-toxic and side-effect free to the host or subject. Representative carriers include water, oils, vegetables and minerals, paste bases, lotion bases, ointment bases, etc. These bases include suspending agents, thickening agents, transdermal promoters, etc. Their formulations are well known to those skilled in the art of the cosmetic field or the topical drug field.

[0336] In an embodiment of the present invention, the pharmaceutical composition can be administered in any of the following ways: orally, by spray inhalation, rectally, nasally, buccally, topically, parenterally, such as subcutaneous, intravenous, intramuscular, intraperitoneal, intrathecal, intraventricular, intrasternal and intracranial injection or infusion, or by means of an implant reservoir. When administered orally, the compounds of the present invention can be made into any orally acceptable formulation, including but not limited to tablets, capsules, aqueous solutions or aqueous suspensions. Carriers used for tablets generally include lactose and corn starch, and lubricants such as magnesium stearate can also be added. Diluents used for capsule formulations generally include lactose and dried corn starch. Aqueous suspension formulations usually involve mixing the active ingredient with suitable emulsifiers and suspending agents. If necessary, some sweeteners, flavoring agents or coloring agents can also be added to the above oral formulations. When administered topically, especially for treating affected surfaces or organs that are easily accessible by topical application, such as the eyes, skin or lower intestinal neurological diseases, the compounds of the present invention can be made into different topical formulations according to different affected surfaces or organs. When topically administered to the eyes, the compounds of the present invention can be formulated into a micronized suspension or solution, and the carrier used is sterile saline of a certain pH that is isotonic, and a preservative such as benzalkonium chloride can be added or not. For ophthalmic use, the compound can also be made into an ointment form such as petrolatum ointment. When topically administered to the skin, the compounds of the present invention can be made into appropriate ointment, lotion or cream formulations, in which the active ingredient is suspended or dissolved in one or more carriers. Carriers that can be used for ointment formulations include but are not limited to: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyethylene oxide, polypropylene oxide, emulsifying wax and water; carriers that can be used for lotion or cream formulations include but are not limited to: mineral oil, sorbitan monostearate, Tween 60, cetyl ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water. The compounds of the present invention can also be administered in the form of a sterile injection preparation, including a sterile aqueous or oily suspension or a sterile injection solution. Carriers and solvents that can be used include water, Ringer's solution and isotonic sodium chloride solution. In addition, sterilized non-volatile oils can also be used as solvents or suspending media, such as monoglycerides or diglycerides.

[0337] In another aspect, the present invention provides the use of the aforementioned compound or its tautomer, cis-trans isomer, meso form, racemate, enantiomer, diastereomer, atropisomer or a mixture thereof, or its pharmaceutically acceptable salt, solvate or prodrug in the preparation of a drug for treating and / or preventing diseases induced by KRAS G12C mutation. Preferably, the diseases induced by KRAS G12C mutation are cancers.

[0338] In another aspect, the present invention provides the use of the foregoing compound, or a tautomer, cis-trans isomer, meso form, racemate, enantiomer, diastereoisomer, atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, in the preparation of a medicament for treating and / or preventing cancer.

[0339] In one embodiment of the present invention, the cancer is pancreatic cancer, colorectal cancer or lung cancer.

[0340] In one embodiment of the present invention, the cancer is lung cancer, preferably non-small cell lung cancer.

[0341] In another aspect, the present invention provides the use of the foregoing compound, or a tautomer, cis-trans isomer, meso form, racemate, enantiomer, diastereoisomer, atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, in the preparation of a KRAS mutation inhibitor, (preferably, the KRAS mutation is a KRAS G12C mutation).

[0342] In another aspect, the present invention provides a method for treating cancer, which comprises administering to a subject in need thereof a therapeutically effective amount of the foregoing compound, or a tautomer, cis-trans isomer, meso form, racemate, enantiomer, diastereoisomer, atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, or any combination of the above, or administering the above pharmaceutical composition.

[0343] As used herein, the term "subject" refers to an animal, particularly a mammal, preferably a human.

[0344] As used herein, the term "effective amount" or "therapeutically effective amount" refers to a sufficient amount of a drug or agent that is non-toxic but capable of achieving the desired effect. In embodiments of the present invention, when treating a patient according to the present invention, the amount of a given drug depends on a number of factors, such as the specific dosing regimen, the type and severity of the disease or disorder, the uniqueness of the subject or host to be treated (e.g., body weight), however, depending on the specific circumstances involved, including for example the specific drug employed, the route of administration, the disorder being treated, and the subject or host being treated, the dosage to be administered can be routinely determined by methods known in the art. Generally, in terms of the dosage used for adult treatment, the dosage typically ranges from 0.02 - 5000 mg / day, for example about 1 - 1500 mg / day. The required dosage can conveniently be presented as a single dose, or as divided doses administered simultaneously (or within a short period of time) or at appropriate intervals, such as two, three, four or more divided 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 circumstances of the patient in combination with the physician's diagnosis.

[0345] As used herein, the term "pharmaceutically acceptable salt" refers to salts of the compounds of the present invention that are pharmaceutically acceptable and have the pharmacological activity of the parent compound. Such salts include: acid addition salts formed with inorganic acids or with organic acids, such as nitric acid, phosphoric acid, carbonic acid, etc.; such as propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, gluconic acid, stearic acid, mucic 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 organic bases, such as ethanolamine, diethanolamine, triethanolamine, N-methylglucosamine, etc. The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compounds containing acid or base groups by conventional chemical methods. In general, the method for preparing such salts is to react these compounds in the form of the free acid or base with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or a mixture of both. In addition to the salt form, 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 convert into the compounds of the present invention. In addition, the prodrugs can be converted into the compounds of the present invention by chemical or biochemical methods in the in vivo environment.

[0346] As used herein, the terms "solvate compound" and "solvate" refer to substances formed by the combination of the compounds of the present invention with pharmaceutically acceptable solvents. Solvate compounds include stoichiometric solvate compounds and non-stoichiometric solvate compounds. Some compounds of the present invention can exist in non-solvated form or in solvated form. Generally, the solvated form and the non-solvated form are equivalent and are both included within the scope of the present invention.

[0347] As used herein, the term "stereoisomer" includes conformational isomers and configurational isomers, and the configurational isomers mainly include cis-trans isomers and optical isomers. The compounds of the present invention may exist in the form of stereoisomers and thus cover all possible stereoisomeric forms, including but not limited to cis-trans isomers, tautomers, enantiomers, diastereomers, atropisomers (or may also be referred to as rotational isomers), etc. The compounds of the present invention may also exist in any combination or any mixture of the aforementioned stereoisomers, such as meso forms, racemates, equimolar mixtures of atropisomers, etc. For example, a single enantiomer, a single diastereomer or a mixture thereof, or a single atropisomer or a mixture thereof. When the compounds of the present invention contain an olefinic double bond, unless otherwise specified, it includes cis isomers and trans isomers, and any combination thereof. The atropisomers of the present invention are stereoisomers with axial or planar chirality resulting from restricted intramolecular rotation. The compounds of the present invention have two atropisomers derived from axial asymmetry, which are caused by restricting the rotation of the bond connecting the substituted naphthyridone ring when the substituent Ar' or R0' is a cyclic group such as an aryl group, a 5- or 6-membered monocyclic heteroaryl group, an 8- to 10-membered bicyclic heteroaryl group or a pyridone group, etc., to form steric hindrance. Regarding the atropisomers of the present invention, where the compound has the structure of formula (I), formula (IA) or formula (II), or the compounds of formula (I), formula (IA) or formula (II) have isomers generated by asymmetric carbon, etc., it represents any one of a pair of atropisomers present in each isomeric compound. And as a drug, the atropisomer with excellent activity is preferred. The compounds of formula (I), formula (IA) or formula (II) have optical isomers derived from asymmetric carbon, axial asymmetry, etc., and when necessary, the single isomer can be obtained by optical resolution. The atropisomers of the compounds of the present invention can be represented in the P or M configuration, or can also be labeled and represented in other common ways well-known in the art. 6-10 As described above, the present invention provides the compounds shown in the above various structures, or their tautomers, cis-trans isomers, meso forms, racemates, enantiomers, diastereomers, atropisomers or mixtures thereof, where "mixtures thereof" includes any form of mixing between any of the aforementioned stereoisomers (such as tautomers, cis-trans isomers, enantiomers, diastereomers, atropisomers) and / or mixtures (meso forms, racemates), such as mixtures of cis-trans isomers, mixtures of enantiomers and diastereomers, mixtures of diastereomers, mixtures of atropisomers, or mixtures of cis-trans isomers and racemates, mixtures of mixtures of enantiomers and diastereomers, mixtures of mixtures of atropisomers and diastereomers, etc.

[0348] As described above, the present invention provides the compounds shown in the above various structures, or their tautomers, cis-trans isomers, meso forms, racemates, enantiomers, diastereomers, atropisomers or mixtures thereof, where "mixtures thereof" includes any form of mixing between any of the aforementioned stereoisomers (such as tautomers, cis-trans isomers, enantiomers, diastereomers, atropisomers) and / or mixtures (meso forms, racemates), such as mixtures of cis-trans isomers, mixtures of enantiomers and diastereomers, mixtures of diastereomers, mixtures of atropisomers, or mixtures of cis-trans isomers and racemates, mixtures of mixtures of enantiomers and diastereomers, mixtures of mixtures of atropisomers and diastereomers, etc.

[0349] As used herein, the "-" symbol contained in the substituents of each group represents a bond connecting to other groups or structures.

[0350] As used herein, the term "fused" refers to a structure in which two or more rings share one or more bonds.

[0351] As used herein, the term "alkyl" refers to a straight-chain or branched-chain saturated aliphatic hydrocarbon group containing 1 to 20 carbon atoms. The term "C 1-10 alkyl" refers to a straight-chain or branched-chain alkyl group having 1 to 10 carbon atoms, more preferably a straight-chain or branched-chain alkyl group having 1, 2, 3, 4, 5, or 6 carbon atoms, that is, C 1-6 alkyl, more preferably C 1-4 alkyl, and most preferably C 1-3 alkyl. Specific examples of alkyl 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 various branched isomers thereof, etc.

[0352] It should be noted that, unless otherwise specified, if both propyl and isopropyl are present in the alternative options, the propyl here represents n-propyl. If only propyl is present in the alternative options, the propyl here represents n-propyl or isopropyl.

[0353] As used herein, "-C 1-3 alkyl-" and "C 1-3 alkylene" are used interchangeably and refer to a saturated straight-chain or branched-chain aliphatic hydrocarbon group having two residues derived from removing two hydrogen atoms from the same carbon atom or two different carbon atoms of the parent alkyl group, and it is a straight-chain or branched-chain group containing 1 to 3 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.

[0354] As used herein, "-C 1-3 alkyl(hydroxy)-, -C 1-3alkyl(cyano)-, -C 1-3 alkyl(C 1-6 alkyl)-, -C 1-3 alkyl(halo 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(halo C 1-6 alkoxy)-” respectively refer to residues formed by substitution of one or more hydrogen atoms in “-C 1-3 alkyl-” with hydroxyl, cyano, C 1-6 alkyl, halo C 1-6 alkyl, -C 1-6 alkyl-hydroxy, -C 1-6 alkyl-cyano, C 1-6 alkoxy, halo C 1-6 alkoxy. Non-limiting examples include, but are not limited to, -CH(OH)-, -CH2CH(CN)-, -CH2CH(CH2CH3)-, -CH2CH(CF3)-, -CH(CH2OH)-, -CH2CH(CH2CN)-, -CH(OCH3)-, -CH2CH(OCF3)-.

[0355] As used herein, the term “alkoxy” refers to a group having an -O-alkyl structure, where alkyl is defined as above. The term “C 1-10 alkoxy” refers to an alkoxy having 1 to 10 carbon atoms, preferably C 1-6 alkoxy, more preferably C 1-4 alkoxy, more preferably C 1-3 alkoxy. Specific examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, isobutoxy, n-pentyloxy, etc.

[0356] It should be noted that, unless otherwise specified, if n-propoxy and isopropoxy are both present in a list of alternatives, n-propoxy at that position means normal propoxy. If only n-propoxy is present in a list of alternatives, propyl at that position means normal propoxy or isopropoxy.

[0357] As used herein, the term “alkylthio” refers to a group having an -S-alkyl structure, where alkyl is defined as above. The term “C 1-10 alkylthio” refers to an alkylthio having 1 to 10 carbon atoms, preferably C 1-6 alkylthio, more preferably C 1-4 alkylthio, more preferably C1-3 Alkylthio group. Specific examples of the alkylthio group include, but are not limited to, methylthio, ethylthio, propylthio, isopropylthio, butylthio, tert - butylthio, isobutylthio, pentylthio, and the like.

[0358] As used herein, the term "alkenyl" refers to an alkyl group as defined above having one or more carbon - carbon double bonds at any position in the chain, and the term "C 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, it is 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 the alkenyl group include, but are not limited to, vinyl, 1 - propenyl, 2 - propenyl, 1 -, 2 - or 3 - butenyl, pentenyl, hexenyl, butadienyl, and the like.

[0359] As used herein, the term "alkynyl" refers to an alkyl group as defined above having one or more carbon - carbon triple bonds at any position in the chain, and the term "C 2-8 alkynyl" 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. 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 alkynyl. Specific examples of the alkynyl group include, but are not limited to, ethynyl, 1 - propynyl, 2 - propynyl, 1 -, 2 - or 3 - butynyl, and the like.

[0360] As used herein, the term "halogen" refers to fluorine, chlorine, bromine, and iodine.

[0361] As used herein, the term "haloalkyl" refers to an alkyl group substituted by one or more (such as 1, 2, 3, 4, or 5) halogen atoms, wherein the alkyl group is defined as above. The term "halo C 1-10 alkyl" refers to a haloalkyl group having 1 to 10 carbon atoms. Preferably, it is halo C 1-6 alkyl, more preferably halo C 1-4 alkyl, more preferably halo C 1-3 alkyl. Specific examples of the haloalkyl group include, but are not limited to, chloromethyl, dichloromethyl, trichloromethyl, chloroethyl, 1,2 - dichloroethyl, trichloroethyl, bromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, and the like.

[0362] As used herein, the term "deuterated alkyl" refers to an alkyl group substituted by one or more (such as 1, 2, 3, 4, or 5) deuterium atoms, wherein the alkyl group is defined as above. The term "deuterated C 1-10"Alkyl" refers to a deuterated alkyl group having 1 to 10 carbon atoms. Preferably it is deuterated C 1-6 alkyl, more preferably deuterated C 1-4 alkyl, more preferably deuterated C 1-3 alkyl. Specific examples of deuterated alkyl groups include, but are not limited to, monodeuteriomethyl, dideuteriomethyl, trideuteriomethyl, monodeuteroethyl, 1,2-dideuteroethyl, trideuteroethyl, and the like.

[0363] As used herein, the term "haloalkoxy" refers to an alkoxy group substituted with one or more (such as 1, 2, 3, 4, or 5) halogen atoms, wherein the definition of alkoxy is as described above. The term "halo-C 1-10 alkoxy" refers to a haloalkoxy group having 1 to 10 carbon atoms. Preferably it is halo-C 1-6 alkoxy, more preferably halo-C 1-4 alkoxy, more preferably halo-C 1-3 alkoxy. Specific examples of haloalkoxy groups include, but are not limited to, trifluoromethoxy, trifluoroethoxy, monofluoromethoxy, monofluoroethoxy, difluoromethoxy, difluoroethoxy, and the like.

[0364] As used herein, the terms "cycloalkyl" and "cycloalkyl ring" are used interchangeably and 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, spirocycloalkyl, fused cycloalkyl, and bridged cycloalkyl. Preferably it is C 3-12 cycloalkyl. The ring carbon atoms of the cycloalkyl group described in the present invention may optionally be substituted with 1, 2, or 3 oxo groups to form a cyclohexanone structure. The terms "C 3-8 monocyclic cycloalkyl" and "C 3-8 cycloalkyl" refer to a saturated monocyclic cyclic hydrocarbon group having 3 to 8 carbon atoms, preferably C 3-6 monocyclic cycloalkyl (i.e., C 3-6 cycloalkyl), more preferably C3, C4, C5, or C6 monocyclic cycloalkyl. Specific examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like.

[0365] As used herein, the terms "spirocycloalkyl" and "spirocycloalkyl ring" refer to a polycyclic cyclic hydrocarbon group formed by sharing a carbon atom (referred to as a spiro atom) between two or more monocyclic rings. Spirocycloalkyl groups are classified into monospirocycloalkyl, bisspirocycloalkyl, and polyspirocycloalkyl according to the number of spiro atoms shared between the rings. The term "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 6 to 14-membered (C 6-14) Spiroalkyl group, more preferably a 6- to 14-membered monospiroalkyl group, more preferably a 7- to 11-membered (C 7-11 ) Spiroalkyl group, more preferably a 7- to 11-membered monospiroalkyl group, most preferably a 7-membered (4-membered monocyclic cycloalkyl ring / 4-membered monocyclic cycloalkyl ring), 8-membered (4-membered monocyclic cycloalkyl ring / 5-membered monocyclic cycloalkyl ring), 9-membered (4-membered monocyclic cycloalkyl ring / 6-membered monocyclic cycloalkyl ring, 5-membered monocyclic cycloalkyl ring / 5-membered monocyclic cycloalkyl ring), 10-membered (5-membered monocyclic cycloalkyl ring / 6-membered monocyclic cycloalkyl ring) or 11-membered (6-membered monocyclic cycloalkyl ring / 6-membered monocyclic cycloalkyl ring) monospiroalkyl group. Specific examples of the spiroalkyl group include, but are not limited to:

[0366]

[0367] The cycloalkyl ring may be fused to an aryl, heteroaryl or heterocyclic ring, where the ring connected to the parent structure is the cycloalkyl ring. Non-limiting examples include indanyl, tetrahydronaphthyl, benzocycloheptyl, etc. In the present invention, the above various cycloalkyl groups may be optionally substituted, and when substituted, the substituents are preferably one or more of the substitution groups described in the present application.

[0368] As used herein, the term "halocycloalkyl" refers to a cycloalkyl group substituted with one or more (such as 1, 2, 3, 4 or 5) halogens, where the definition of the cycloalkyl group is as described above. The term "halo C 3-8 cycloalkyl" refers to a halocycloalkyl group having 3 to 8 ring carbon atoms. It is preferably a halo C 3-6 cycloalkyl, more preferably a halocyclopropyl, halocyclobutyl, halocyclopentyl or halocyclohexyl group. Specific examples of the halocycloalkyl group include, but are not limited to, trifluorocyclopropyl, fluorocyclopropyl, fluorocyclohexyl, difluorocyclopropyl, difluorocyclohexyl, etc.

[0369] As used herein, the terms "heterocyclic group" and "heterocyclic ring" are used interchangeably and refer to a saturated or partially unsaturated monocyclic or polycyclic fused cyclic hydrocarbon group. The term "C 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, where one or more (preferably 1, 2, 3 or 4) ring atoms are selected from nitrogen, oxygen or S(O) mheteroatoms (where m is an integer from 0 to 2), but excluding ring moieties of -O-O-, -O-S- or -S-S-, and the remaining ring atoms are 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 other substituents defined herein). In the present invention, the ring carbon atoms of the heterocyclic group can optionally be substituted by 1, 2 or 3 oxo groups to form a cyclic ketone, cyclic lactone or cyclic amide structure. The 3- to 20-membered heterocyclic groups described in the present invention include monocyclic heterocyclic groups, spiro heterocyclic groups, fused heterocyclic groups and bridged heterocyclic groups.

[0370] As used herein, the term "C" 3-8 "monocyclic heterocyclic group", "3- to 8-membered monocyclic heterocyclic group" and "3- to 8-membered monocyclic heterocyclic ring" refer to a saturated or partially unsaturated monocyclic hydrocarbon group having 3 to 8 ring atoms, wherein 1, 2 or 3 ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) m (where m is an integer from 0 to 2). Preferably, it is a 3- to 6-membered monocyclic heterocyclic group having 3 to 6 ring atoms, wherein 1 or 2 ring atoms are heteroatoms (i.e., C 3-6 monocyclic heterocyclic group). More preferably, it is a 5- or 6-membered monocyclic heterocyclic group having 5 or 6 ring atoms, wherein 1 or 2 ring atoms are heteroatoms. When the heteroatom is a nitrogen atom, the nitrogen atom can be substituted or unsubstituted (i.e., N or NR, where R is hydrogen or other substituents defined herein). When the heteroatom is a sulfur atom, the sulfur atom can optionally be oxidized (i.e., S(O) m, where m is an integer from 0 to 2). The ring carbon atoms of the monocyclic heterocyclic group may optionally be substituted by 1, 2 or 3 oxo groups to form a cyclic ketone, cyclic lactone or cyclic amide structure. Specific examples of the monocyclic heterocyclic group include, but are not limited to, aziridine, ethylene oxide, azetidine, azetidin-2-one, oxetane, oxetane-2-one, oxazolidine, pyrrolidin-2-one, pyrrolidine-2,5-dione, 1,3-dioxolane, dihydrofuran-2(3H)-one, dihydrofuran-2,5-dione, piperidin-2-one, piperidine-2,6-dione, tetrahydro-2H-pyran-2-one, imidazolidine, tetrahydrofuran, tetrahydrothiophene, pyrrolidine, 1,3-dioxolane-2-one, oxazolidin-2-one, imidazolidin-2-one, piperidine, piperazine, piperazine-2-one, morpholine, morpholin-3-one, morpholin-2-one, thiomorpholin-3-one 1,1-dioxide, thiomorpholine, thiomorpholine-1,1-dioxide, tetrahydropyran, 1,2-dihydroazetadiene, 1,2-dihydrooxetadiene, 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-oxazinane, hexahydropyrimidine, 1,4-dioxane, tetrahydropyrimidin-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-imidazole, 2,3-dihydro-1H-imidazole, 2,3-dihydrooxazole, 1,3-dioxolene, 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-pyrrol-2-one, 1,5-dihydro-2H-pyrrol-2-one, 1H-pyrrole-2,5-dione, furan-2(3H)-one, furan-2(5H)-one, 1,3-dioxolene-2-one, oxazole-2(3H)-one, 1,3-dihydro-2H-imidazol-2-one, furan-2,5-dione, 3,6-dihydropyridin-2(1H)-one, pyridine-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 3-8"Heterocycloalkyl" and "3- to 8-membered heterocycloalkyl" refer to saturated monocyclic cyclic hydrocarbon groups having 3 to 8 ring atoms, where 1 or 2 ring atoms are heteroatoms. Preferably, they are 3- to 6-membered heterocycloalkyl groups having 3 to 6 ring atoms, where 1 or 2 ring atoms are heteroatoms. Specific examples of heterocycloalkyl include, but are not limited to, aziridinyl, oxiranyl, azetidinyl, oxetanyl, oxazolidinyl, 1,3-dioxolanyl, dioxanyl, imidazolidinyl, tetrahydrofuryl, tetrahydrothienyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiomorpholine-1,1-dioxide, tetrahydropyranyl, 1,4-oxazepanyl, 1,3-oxazepanyl, 1,3-oxazinyl, hexahydropyrimidinyl, 1,4-dioxanyl.

[0371] For the 2 ring atoms connected to the above-mentioned monocyclic heterocyclic group ring, including C-C and N-C, they can optionally be fused with a monocyclic cycloalkyl ring, a monocyclic heterocyclic group ring, a monoaryl ring, a 5- or 6-membered monoheteroaryl ring, etc., defined in the present invention, such as cycloalkyl, heterocyclic group, aryl or heteroaryl, to form a fused polycyclic ring. The 2 ring atoms connected to the monocyclic heterocyclic group forming a fused ring with other rings are preferably C-C.

[0372] As used herein, the term "C 6-14 aryl", "C 6-14 aryl ring" and "C 6-14 aromatic ring" can be used interchangeably and refer to a fully carbon monocyclic ring, a fully carbon polycyclic ring (rings are connected by covalent bonds, non-fused) or a fully carbon fused polycyclic ring (that is, rings sharing adjacent carbon atom pairs) group having 6 to 14 ring atoms, and at least one ring in the group is aromatic, that is, having a conjugated π electron system. Preferably, it is C 6-10 aryl. The C 6-14 aryl in the present invention includes monocyclic aryl, polycyclic aryl and aromatic fused polycyclic rings. Examples of monocyclic aryl include phenyl, and examples of polycyclic aryl include biphenyl, etc.

[0373] In the present invention, when the C 6-14 aryl is an aromatic fused polycyclic ring, the aromatic fused polycyclic ring can be a polycyclic group formed by fusing a monoaryl ring with one or more monoaryl rings. Non-limiting examples thereof include naphthyl, anthracenyl, etc.

[0374] In some embodiments of the present invention, the aromatic fused polycycle may also be a polycyclic group formed by the fusion of a monoaryl ring (such as a phenyl ring) 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 rings include, but are not limited to, 3- to 6-membered monocyclic heterocyclic rings (preferably 5- or 6-membered monocyclic heterocyclic rings, and the ring carbon atoms of the monocyclic heterocyclic rings may be substituted by 1 to 2 oxo groups to form an intramolecular amide or lactone structure), and 3- to 6-membered monocyclic cycloalkyl rings (preferably 5- or 6-membered monocyclic cycloalkyl rings, and the ring carbon atoms of the monocyclic cycloalkyl rings may be substituted by 1 or 2 oxo groups to form a cyclohexanone structure). The above polycyclic group formed by the fusion of a monoaryl ring with one or more non-aromatic rings may be connected to other groups or the parent structure through a nitrogen atom or a carbon atom, and the ring connected to the parent structure is a monoaryl ring or a non-aromatic ring.

[0375] As used herein, the fusion of a benzene ring with a 5- or 6-membered monocyclic heterocyclic ring to form a 9- or 10-membered aromatic fused bicyclic ring means that two adjacent substituents on the phenyl ring and the ring atoms to which they are attached form a fused 5- or 6-membered monocyclic heterocyclic ring, and the 5- or 6-membered monocyclic heterocyclic ring is as defined above. The formed 9- or 10-membered aromatic fused bicyclic ring may also be referred to as a 9- or 10-membered phenylheterocyclic ring.

[0376] As used herein, the fusion of a benzene ring with a 5- or 6-membered monocyclic cycloalkyl ring to form a 9- or 10-membered aromatic fused bicyclic ring means that two adjacent substituents on the phenyl ring and the ring atoms to which they are attached form a fused 5- or 6-membered monocyclic cycloalkyl ring, and the 5- or 6-membered monocyclic cycloalkyl ring is as defined above. The formed 9- or 10-membered aromatic fused bicyclic ring may also be referred to as a 9- or 10-membered phenylcycloalkyl ring. Non-limiting examples thereof include:

[0377]

[0378] In the present invention, the above-mentioned various aryl groups may be substituted or unsubstituted. When substituted, the substituents are preferably one or more of the substituents described in the present application.

[0379] As used herein, the terms "heteroaryl", "heteroaryl ring" and "heteroaromatic ring" may be used interchangeably and refer to a monocyclic or fused polycyclic (i.e., sharing adjacent pairs of ring atoms, and the shared adjacent pairs of ring atoms may be C-C or N-C) group in which the ring atoms are substituted by at least one heteroatom independently selected from nitrogen, oxygen or sulfur, wherein the nitrogen and sulfur atoms may be optionally oxidized and the nitrogen atoms may be optionally quaternized. The heteroaryl has 6, 10 or 14 shared π electrons, and at least one ring in the group is aromatic. The term "C 5-14"Heteroaryl" and "5- to 14-membered heteroaryl" refer to heteroaryl having 5 to 14 ring atoms, where 1, 2, 3, or 4 ring atoms are heteroatoms. Preferably, it is a 5- to 10-membered heteroaryl having 5 to 10 ring atoms, where 1, 2, 3, or 4 ring atoms are heteroatoms. In the present invention, C 5-14 The heteroaryl can be a monoheteroaryl, a fused bicyclic heteroaryl, or a fused tricyclic heteroaryl.

[0380] As used herein, the terms "5- or 6-membered monoheteroaryl" and "5- or 6-membered monocyclic heteroaryl" are used interchangeably and refer to a monocyclic heteroaryl having 5 or 6 ring atoms, where 1, 2, or 3 ring atoms are heteroatoms. Specific examples of the monoheteroaryl 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, tetrazole, isoxazole, oxadiazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, thiadiazole, pyridine, pyridazine, pyrimidine, pyrazine, etc.

[0381] As used herein, the terms "8- to 10-membered biheteroaryl" and "8- to 10-membered bicyclic heteroaryl" are used interchangeably and refer to a fused bicyclic heteroaryl having 8 to 10 ring atoms, where 1, 2, 3, 4, or 5 ring atoms are heteroatoms. The fused bicyclic heteroaryl can be either a bicyclic group (preferably a 9- or 10-membered biheteroaryl ring) formed by the fusion of a monoaryl ring (such as a phenyl ring) and a monoheteroaryl ring (preferably a 5- or 6-membered monoheteroaryl ring), or a bicyclic group formed by the fusion of a monoheteroaryl ring (preferably a 5- or 6-membered monoheteroaryl ring) and a monoheteroaryl ring (preferably a 5- or 6-membered monoheteroaryl ring).

[0382] Any two adjacent ring atoms on the above-mentioned monoheteroaryl ring, including C-C, N-C, and N-N, can be fused with a cycloalkyl ring, a heterocyclic ring, an aryl ring, a 5- or 6-membered monoheteroaryl ring, etc. defined in the present invention to form a fused polycyclic ring. The two adjacent ring atoms on the monoheteroaryl ring that form a fused ring with other rings are preferably C-C, and non-limitingly include the following forms:

[0383]

[0384] Non-limiting examples of 8- to 10-membered biheteroaryls include: benz[d]isoxazole, 1H-indole, isoindole, 1H-benzo[d]imidazole, benz[d]isothiazole, 1H-benzo[d][1,2,3]triazole, benz[d]oxazole, benz[d]thiazole, indazole, benzofuran, benzo[b]thiophene, quinoline, isoquinoline, quinazoline, quinoxaline, cinnoline, pyrido[3,2-d]pyrimidine, pyrido[2,3-d]pyrimidine, pyrido[3,4-d]pyrimidine, pyrido[4,3-d]pyrimidine, 1,8-naphthyridine, 1,7-naphthyridine, 1,6-naphthyridine, 1,5-naphthyridine, pyrazolo[1,5-a]pyrimidine, imidazo[1,2-b]pyridazine, and the like.

[0385] The above-mentioned monoheteroaryl, or biheteroaryl formed by the fusion of a benzene ring and a monoheteroaryl ring, or biheteroaryl formed by the fusion of a monoheteroaryl ring and a monoheteroaryl ring can be connected to other groups or the parent structure through a nitrogen atom or a carbon atom. When it is a biheteroaryl, the ring connected to the parent structure is a monoheteroaryl ring or a benzene ring, and specific examples thereof include but are not limited to:

[0386]

[0387] In some embodiments of the present invention, the fused bicyclic heteroaryl or fused tricyclic heteroaryl can be a polycyclic group formed by the fusion of a monoheteroaryl ring (preferably a 5- or 6-membered monoheteroaryl ring) and one or more non-aromatic rings, wherein the ring connected to the parent structure is a monoheteroaryl ring or a non-aromatic ring. The non-aromatic rings include but are not limited to 3- to 6-membered monocyclic heterocyclic rings (preferably 5- or 6-membered monocyclic heterocyclic rings, and the ring carbon atoms of the monocyclic heterocyclic rings can be substituted by 1 to 2 oxo groups to form an intramolecular amide or lactone structure), 3- to 6-membered monocyclic cycloalkyl rings (preferably 5- or 6-membered monocyclic cycloalkyl rings, and the ring carbon atoms of the monocyclic cycloalkyl rings can be substituted by 1 or 2 oxo groups to form a cyclic ketone structure), and the like. The above-mentioned polycyclic group formed by the fusion of a monoheteroaryl ring and one or more non-aromatic rings can be connected to other groups or the parent structure through a nitrogen atom or a carbon atom, and the ring connected to the parent structure is a monoheteroaryl ring or a non-aromatic ring.

[0388] In this article, the fusion of a 5- or 6-membered monoheteroaryl ring and a 5- or 6-membered monocyclic heterocyclic ring to form an 8- to 10-membered fused bicyclic heteroaryl means that two adjacent substituents on the 5- or 6-membered monoheteroaryl and the ring atoms to which they are attached form a fused 5- or 6-membered monocyclic heterocyclic ring, and the 5- or 6-membered monocyclic heterocyclic ring is as defined above. The formed 8- to 10-membered fused bicyclic heteroaryl can also be called an 8- to 10-membered heteroaryl heterocyclic ring.

[0389] As used herein, the fusion of a 5- or 6-membered monocyclic heteroaryl ring with a 5- or 6-membered monocyclic cycloalkyl ring to form an 8- to 10-membered fused bicyclic heteroaryl means that two adjacent substituents on the 5- or 6-membered monocyclic heteroaryl and the ring atoms to which they are attached form a fused 5- or 6-membered monocyclic cycloalkyl ring, and the 5- or 6-membered monocyclic cycloalkyl ring is as defined above. The resulting 8- to 10-membered fused bicyclic heteroaryl may also be referred to as an 8- to 10-membered heteroaryl cycloalkyl ring. Non-limiting examples thereof include:

[0390]

[0391]

[0392] In the present invention, the above-mentioned various heteroaryls may be substituted or unsubstituted. When substituted, the substituents are preferably one or more of the substituents described in the present application.

[0393] As used herein, the term "-alkyl-R" represents a substituent formed by substituting an alkyl group with one or more R groups, wherein "-alkyl-" represents the alkylene or sub-alkylene group formed after substitution. R as described herein may be hydroxyl, cyano, alkoxy, substituted amino, heterocycloalkyl, heteroaryl, haloalkyl, haloalkoxy, cycloalkyl, alkynyl, etc., and the groups represented by R are 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.

[0394] As used herein, the term "hydroxyl" refers to -OH.

[0395] As used herein, the term "hydroxymethyl" refers to -CH2OH, and "hydroxyethyl" refers to -CH2CH2OH or -CH(OH)CH3.

[0396] As used herein, the term "cyanomethyl" refers to -CH2CN, and "cyanoethyl" refers to -CH2CH2CN or -CHCNCH3.

[0397] As used herein, the term "amino" refers to -NH2.

[0398] As used herein, the term "cyano" refers to -CN.

[0399] As used herein, the term "nitro" refers to -NO2.

[0400] As used herein, the term "benzyl" refers to -CH2-benzene.

[0401] As used herein, the term "oxo group" refers to =O.

[0402] As used herein, the term "carboxyl group" refers to -C(O)OH.

[0403] As used herein, the term "carboxylate group" refers to -C(O)O(alkyl) or -C(O)O(cycloalkyl).

[0404] As used herein, the term "acetyl group" refers to -COCH3.

[0405] In the present invention, C 1-10 may preferably be C 1-6 ; more preferably C 1-4 ; even more preferably C 1-3 . For example, C 1-10 alkyl may preferably be C 1-6 alkyl; more preferably C 1-4 alkyl; even more preferably C 1-3 alkyl. For example, C 1-10 alkoxy may preferably be C 1-6 alkoxy; more preferably C 1-4 alkoxy; even more preferably C 1-3 alkoxy.

[0406] In the present invention, C 3-20 may preferably be C 3-10 ; more preferably C 3-8 ; even more preferably C 3-6 ; even more preferably C 3-5 . For example, C 3-20 cycloalkyl may preferably be C 3-8 cycloalkyl; more preferably C 3-6 cycloalkyl; even more preferably C 3-6 cycloalkyl.

[0407] In one embodiment of the present invention, in any group, the C 3-6 cycloalkyl is selected from: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.

[0408] In one embodiment of the present invention, in any group, the 3- to 6-membered heterocycloalkyl is selected from: aziridine, ethylene oxide, azetidine, oxetane, tetrahydrofuran, tetrahydrothiophene, pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, thiomorpholine-1,1-dioxide, tetrahydropyran.

[0409] In one embodiment of the present invention, in any group, the 5- or 6-membered monocyclic heteroaryl is selected from: thiophene, N-alkylpyrrole, furan, thiazole, isothiazole, imidazole, oxazole, pyrrole, pyrazole, triazole, 1,2,3-triazole, 1,2,4-triazole, 1,2,5-triazole, 1,3,4-triazole, tetrazole, isoxazole, oxadiazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, thiadiazole, pyridine, pyridazine, pyrimidine, pyrazine.

[0410] In one embodiment of the present invention, in any group, the 8- to 10-membered bicyclic heteroaryl is selected from: benzoxazole, benzisoxazole, benzimidazole, benzothiazole, benzisothiazole, benzotriazole, benzofuran, benzothiophene, indole, indazole, isoindole, quinoline, isoquinoline, quinazoline, quinoxaline, cinnoline, pyridopyrimidine, naphthyridine.

[0411] 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 variants of hydrogen, provided that the valence state of the particular atom is normal and the resulting compound is stable. When the substituent is an oxo group (i.e., =O), it means that two hydrogen atoms are replaced. Oxo substitution does not occur on aromatic groups. The term "optionally substituted" or "optionally substituted with" means that it may or may not be substituted, and unless otherwise specified, the type and number of substituents may be arbitrary based on what is chemically achievable.

[0412] 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 with 0 - 2 R's, the group may optionally be substituted with up to two R's, and each R has independent options in each case. In addition, combinations of substituents and / or their variants are permitted only if such combinations result in a stable compound.

[0413] The compounds represented by formula (IA) or formula (IB) of the present invention can be prepared by using synthetic methods known in the art or by combining methods known in the art with the methods described in the present invention. The solvents, temperatures and other reaction conditions given in the present invention are all exemplary and can be varied according to methods well known in the art. The exemplified compounds of the present invention can be synthesized according to their specific structures by using appropriate starting materials according to the methods described in the examples, or can also be synthesized by using similar methods described in the examples. The starting materials used for synthesizing the exemplified compounds of the present invention can be prepared by known synthetic methods or similar methods described in the literature or obtained from commercial sources. The exemplified compounds can be further resolved into their stereoisomers by methods well known in the art, such as crystallization, chromatography, etc. The resolution conditions are easily obtained by those skilled in the art through conventional means or limited experiments.

[0414] As a further illustration, the compounds of formula (IB-1') and formula (IB-2') of the present invention can be synthesized by the following methods, wherein the solvents, temperatures and other reaction conditions in each step can be the same as or similar to those described in the following examples, or reaction conditions known in the art are used;

[0415]

[0416]

[0417] The compounds of formula (IB-1') and formula (IB-2') of the present invention can also be synthesized by the following methods, wherein the solvents, temperatures and other reaction conditions in each step can be the same as or similar to those described in the following examples, or reaction conditions known in the art are used;

[0418]

[0419]

[0420] In the preparation routes of the compounds of formula (IB-1') and formula (IB-2'), in each formula, R lev is a leaving group well known in the art, such as trifluoromethanesulfonate; chlorine, bromine, iodine; sulfonate groups, such as mesylate, tosylate, p-toluenesulfonate, etc.; acyloxy groups, such as acetoxy, trifluoroacetoxy, etc. In each formula, R pAmino protecting groups well-known in the art, such as formyl; acyl groups, such as alkanoyl groups (such as acetyl, trichloroacetyl or trifluoroacetyl); alkoxycarbonyl groups, such as tert-butoxycarbonyl (Boc); arylmethoxycarbonyl groups, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc); arylmethyl groups, such as benzyl (Bn), trityl (Tr), 1,1-di-(4'-methoxyphenyl)methyl; silyl groups, such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS), etc. R1, R2, R3, R 21 、R 22 、R 12 、R 11 、R 31 、R 32 、R m ', R0', Ar', E1', X1 are defined as before (for example, the definitions of the corresponding groups in Formula I or Formula IA).

[0421] The compounds of Formula (IB-1”) and Formula (IB-2”) of the present invention can be synthesized by the following methods, where the solvents, temperatures and other reaction conditions in each step can be the same as or similar to those described in the following examples, or reaction conditions known in the art can be used;

[0422]

[0423]

[0424] In the preparation routes of the compounds of Formula (IB-1”) and Formula (IB-2”), in each formula, R p is an amino protecting group well-known in the art, such as formyl; acyl groups, such as alkanoyl groups (such as acetyl, trichloroacetyl or trifluoroacetyl); alkoxycarbonyl groups, such as tert-butoxycarbonyl (Boc); arylmethoxycarbonyl groups, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc); arylmethyl groups, such as benzyl (Bn), trityl (Tr), 1,1-di-(4'-methoxyphenyl)methyl; silyl groups, such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS), etc. R1, R2, R3, R 21 、R 22 、R 12 、R 11 、R 31 、R 32 、R0', Ar', E1', X1 are defined as before (for example, the definitions of the corresponding groups in Formula I or Formula IA).

[0425] Among them, the compound of Formula e can also be synthesized by the following method, where the solvents, temperatures and other reaction conditions in each step can be the same as or similar to those described in the following examples, or reaction conditions known in the art can be used;

[0426]

[0427] In the preparation route of the compound of formula e, R lev is a leaving group well-known in the art, such as trifluoromethanesulfonate; chlorine, bromine, iodine; sulfonate groups, such as methanesulfonate, toluenesulfonate, p-toluenesulfonate, etc.; acyloxy groups, such as acetoxy, trifluoroacetoxy, and so on. R0', Ar', E1', and X1 are defined as before (for example, the definitions of the corresponding groups in formula I or formula IA). Description of the Drawings

[0428] Figure 1 is the X-ray single crystal diffraction molecular three-dimensional structure diagram of compound Z25-2.

[0429] Figure 2 is the X-ray single crystal diffraction molecular three-dimensional structure diagram of compound Z27-2. Detailed Description of the Invention

[0430] The compounds of the present invention can be prepared by a variety of synthetic methods well-known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by their combination with other chemical synthesis methods, and the equivalent substitution methods well-known to those skilled in the art. Preferred embodiments include, but are not limited to, the examples of the present invention. The present invention is described in detail below by way of examples, but this does not mean any adverse limitation to the present invention. The present invention has been described in detail herein, and specific embodiments thereof have also been disclosed. It will be obvious to those skilled in the art that various changes and improvements can be made to the specific embodiments of the present invention without departing from the spirit and scope of the present invention. For those conditions not specified in the examples, they are carried out according to conventional conditions or the conditions recommended by the manufacturer. For those reagents or instruments without indicating the manufacturer, they are all conventional products that can be obtained through commercial purchase.

[0431] The abbreviations of the reagents used in the following examples are as follows: THF: tetrahydrofuran; DMSO: dimethyl sulfoxide; PE: petroleum ether; EtOAc: ethyl acetate; DCM: dichloromethane; MeOH: methanol; ACN is acetonitrile; IPA is isopropylamine; DMA is dimethylamine; TFA is trifluoroacetic acid; NH4Cl is ammonium chloride; SPhos is 2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl; SPhos-Pd-G2 is chloro(2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II); NaHMDS is sodium bis(trimethylsilyl)amide; LiHMDS is lithium bis(trimethylsilyl)amide.

[0432] For the preparation of HPLC used in the following examples, the following conditions can be adopted: Column type: Waters XBridge C18, 190*250mm, 5μm; Mobile phase system: A: 0.1% ammonium bicarbonate aqueous solution; B: Preparation-grade acetonitrile; Flow rate: 15 ml / min; B% = 20% - 100%; Column temperature: Room temperature.

[0433] If isomeric compounds are detected by analytical HPLC method, the following conditions can be adopted: Column type: XBridge C18, 3.5μm 4.6*150mm, Mobile phase: A: Purified water (0.05% TFA); B: Preparation-grade acetonitrile (0.05% TFA), Gradient: 5% - 95% B, Run time: 15 min, Flow rate: 1 ml / min, Column temperature = 40°C.

[0434] Example 1 Preparation of Compounds Z1, Z1-1 and Z1-2

[0435]

[0436] Step 1: 2-Isopropyl-4-methylpyridin-3-amine (582 mg, 3.88 mmol) was dissolved in THF (20 mL). The reaction was cooled to 0°C, and NaHMDS (5.8 mL, 11.60 mmol, 2M in THF) was added dropwise. The reaction was stirred for 15 minutes, and 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 was stirred at room temperature for 3 hours. The reaction solution was poured into 30 mL of saturated NH4Cl. It was extracted 3 times with 40 mL of ethyl acetate. After drying, the organic phase was concentrated, and the crude product was purified by flash silica gel column (0 - 5% MeOH / DCM) to obtain the product 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

[0437] 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 obtain the product 5-fluoro-6-(2-fluoro-6-methoxyphenyl)-2-((2-isopropyl-4-methylpyridin-3-yl)amino)nicotinoyl chloride (721 mg, Y: 100%), which was used directly in the next step without purification.

[0438] Step 3: At 0 °C, a solution of ethyl nitroacetate (449 mg, 3.38 mmol) in THF (2 ml) was added dropwise to a suspension of NaH (608 mg, 15.21 mmol) in THF (25 mL). The reaction was stirred at zero degree for half an hour, and then a solution of 5-fluoro-6-(2-fluoro-6-methoxyphenyl)-2-((2-isopropyl-4-methylpyridin-3-yl)amino)nicotinoyl chloride (721 mg, 1.69 mmol) in THF (15 mL) was added dropwise. The ice bath was removed, and the reaction mixture was stirred at 70 °C overnight. The reaction mixture was poured into ice water, and the pH was adjusted to 3 with 3.0 M dilute hydrochloric acid. The mixture was extracted with ethyl acetate three times. After drying, the organic phase was concentrated to obtain the product 6-fluoro-7-(2-fluoro-6-methoxyphenyl)-4-hydroxy-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro-1,8-naphthyridin-2(1H)-one (1.05 g, crude product), which was directly used in the next step reaction. ES-API: [M+H] + = 483.1

[0439] Step 4: 6-Fluoro-7-(2-fluoro-6-methoxyphenyl)-4-hydroxy-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro-1,8-naphthyridin-2(1H)-one (1.05 g, 1.69 mmol) was dissolved in acetonitrile (25 mL). POCl3 (1.30 g, 8.45 mmol) and N,N-diisopropylethylamine (1.74 g, 13.52 mmol) were added successively. The reaction was stirred at 80 °C for 1 hour. The reaction mixture was concentrated, and ethyl acetate was added. The mixture was washed with ice water, water, and saturated brine successively. After drying and concentrating the organic phase, the crude product was purified by flash silica gel column (EtOAc / PE: 0 - 50%) to obtain the product 4-chloro-6-fluoro-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro-1,8-naphthyridin-2(1H)-one (185 mg, Y: 21.9%), a yellow solid. ES-API: [M+H] + = 500.1

[0440] Step 5: 4-Chloro-6-fluoro-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro-1,8-naphthyridin-2(1H)-one (175 mg, 0.35 mmol) was dissolved in DMF (6 mL), (R)-tert-butyl 3-(hydroxymethyl)piperazine-1-carboxylate (454 mg, 2.10 mmol) was added, and the reaction was stirred at 80 °C for 18 h. The reaction solution was poured into 30 mL of water. It was extracted 3 times with 20 mL of ethyl acetate. The organic phase was washed 3 times with saturated brine, dried and concentrated, and the crude product was purified by flash silica gel column (EtOAc / PE: 0 - 70%) to obtain the product (3R)-tert-butyl 4-(6-fluoro-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro-2-oxo-1,2-dihydro-1,8-naphthyridin-4-yl)-3-(hydroxymethyl)piperazine-1-carboxylate (85 mg, Y: 35.7%), a yellow solid. ES-API: [M+H] + = 681.3.

[0441] Step 6: (3R)-tert-butyl 4-(6-fluoro-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro-2-oxo-1,2-dihydro-1,8-naphthyridin-4-yl)-3-(hydroxymethyl)piperazine-1-carboxylate (73 mg, 0.11 mmol) was dissolved in DMA (4 mL), NaH (22 mg, 0.55 mmol) was added, and the reaction was stirred at 145 °C for 10 h. The cooled reaction solution was poured into 15 mL of water. It was extracted 3 times with 30 mL of ethyl acetate. The organic phase was washed 3 times with saturated brine, dried and concentrated, and the crude product was purified by thick TLC plate (dichloromethane / methanol = 20:1) to obtain the product (4aR)-tert-butyl 11-fluoro-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]naphthyridine-3(4H)-carboxylate (35 mg, Y: 51.5%), a yellow solid. ES-API: [M+H] + = 634.2

[0442] Step 7: tert-Butyl (4aR)-11-fluoro-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]naphthalene-3(4H)-carboxylate (35 mg, 0.055 mmol) was dissolved in dichloromethane (2.5 mL), and trifluoroacetic acid (0.5 mL) was added. The mixture was stirred at room temperature for 0.5 h, 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-hexahydropyrazino[1',2':4,5][1,4]oxazino[2,3-c][1,8]naphthalen-7(8H)-one (40 mg, crude product), which was directly used in the next step. ES-API: [M+H] + = 534.3.

[0443] Step 8: (4aR)-11-fluoro-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]naphthalen-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 was cooled to 0 °C, and a solution of acrylic anhydride (6 mg, 0.05 mmol) in dichloromethane (0.5 mL) was added dropwise to the reaction solution. The reaction was stirred at 0 °C for 15 min. 10 mL of saturated aqueous NaHCO3 was added to the reaction solution, and the mixture was extracted with 10 mL of dichloromethane three times. The organic phase was dried and concentrated, and the crude product was purified by preparative TLC plate (dichloromethane / methanol = 10:1) to obtain 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-hexahydropyrazino[1',2':4,5][1,4]oxazino[2,3-c][1,8]naphthalen-7(8H)-one (17 mg, Y: 52.4%), a pale yellow solid. ES-API: [M+H] + = 588.2.

[0444] 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-hexahydropyrazino[1',2':4,5][1,4]oxazino[2,3-c][1,8]naphthalen-7(8H)-one (15 mg, 0.025 mmol) was dissolved in dichloromethane (1.5 mL). The reaction was cooled to 0 °C, and a solution of 17% boron tribromide in dichloromethane (1 mL) was added dropwise thereto. The reaction was stirred at room temperature for 3 h. The reaction solution was poured into 20 mL of saturated aqueous NaHCO3, and extracted with 20 mL of dichloromethane three times. After drying, the organic phase was concentrated, and 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-hexahydropyrazino[1',2':4,5][1,4]oxazino[2,3-c][1,8]naphthalen-7(8H)-one (Z1, 10 mg, Y: 68.3%), a white solid. 1 H NMR (500 MHz, DMSO-d6) δ 9.96 (s, 1H), 8.35 (d, J = 4.8 Hz, 1H), 7.19 - 7.14 (m, 2H), 6.87 - 6.75 (m, 1H), 6.64 (d, J = 8.5 Hz, 1H), 6.59 (t, J = 8.5 Hz, 1H), 6.12 (d, J = 15.9 Hz, 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.

[0445] Step 10: Compound Z1 was resolved by preparative chiral HPLC (column type: Chiralpak IC: 10 μm, 20 * 250 mm, mobile phase: acetonitrile: isopropanol: ammonia methanol = 70:30:0.2, flow rate: 15 ml / min, column temperature: room temperature) to obtain: a atropisomer compound, arbitrarily designated as Z1-1 (75 mg, peak 1, retention time 3.94 min, Y: 15.4%), a pale yellow solid. 11H NMR (400 MHz, DMSO-d6) δ 10.04 (s, 1H), 8.42 (d, J = 4.9 Hz, 1H), 8.22 (d, J = 8.3 Hz, 1H), 7.28 - 7.20 (m, 2H), 6.96 - 6.81 (m, 1H), 6.75–6.58 (m, 2H), 6.18 (d, J = 17.1 Hz, 1H), 5.82–5.69 (m, 1H), 4.49–4.00 (m, 4H), 3.90–3.43 (m, 4H), 3.08 (t, J = 11.0 Hz, 1H), 2.64 - 2.55 (m, 1H), 1.80 (s, 3H), 1.05 (d, J = 6.7 Hz, 3H), 0.91 (d, J = 6.7 Hz, 3H). ES-API: [M+H] + = 574.2. And another atropisomer compound, arbitrarily designated as Z1-2 (115 mg, peak 2, retention time 5.04 min, Y: 23.6%), pale yellow solid. 1 1H NMR (400 MHz, DMSO-d6) δ 10.05 (s, 1H), 8.42 (d, J = 4.8 Hz, 1H), 8.22 (d, J = 6.9 Hz, 1H), 7.28 - 7.20 (m, 2H), 6.96 - 6.81 (m, 1H), 6.74–6.59 (m, 2H), 6.19 (d, J = 16.7 Hz, 1H), 5.83–5.68 (m, 1H), 4.49–4.00 (m, 4H), 3.94–3.44 (m, 4H), 3.08 (t, J = 11.0 Hz, 1H), 2.49–2.41 (m, 1H), 1.87 (s, 3H), 1.03 (dd, J = 6.3, 3.7 Hz, 3H), 0.88 (d, J = 6.6 Hz, 3H). ES-API: [M+H] + = 574.2. The isomer compound was detected by an analytical chiral HPLC method (column type: Chiralpak IC: 5 μm, 4.6 * 250 mm, mobile phase: acetonitrile: isopropanol: ammonia methanol = 70:30:0.2, flow rate: 1 ml / min, column temperature = 30 °C).

[0446] Example 2 Preparation of Compound Z2

[0447]

[0448] 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. 2-Chloropyridin-3-amine (2.0 g, 15.62 mmol) is added in portions. The reaction is stirred under reflux for 15 minutes. The reaction solution is cooled to room temperature, and the precipitated solid is filtered. The filter cake is washed with a small amount of isopropanol and dried in vacuo 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

[0449] Step 2: Add 200 mL of diphenyl ether to a 500 mL round-bottom flask and heat to 220 °C. 5-((2-chloropyridin-3-yl)amino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (3.9 g, 13.83 mmol) is added in portions. The reaction is stirred at 220 °C for 20 minutes. The reaction solution is cooled to room temperature, poured into petroleum ether, and the precipitated solid is filtered. The filter cake is washed with petroleum ether and dried in vacuo to obtain the product 8-chloro-1,7-naphthyridin-4-ol (1.5 g, Y: 60%), a light brown solid. ES-API: [M+H] + = 181.0

[0450] Step 3: Add 8-chloro-1,7-naphthyridin-4-ol (500 mg, 2.78 mmol), sodium acetate (300 mg, 2.78 mmol), absolute ethanol (25 mL), and 5% Pd / C (250 mg) to a 50 mL round-bottom flask. The reaction is stirred at room temperature under a hydrogen balloon for 3 days. The reaction solution is filtered through diatomaceous earth, the filtrate is concentrated, and the crude product is purified by flash silica gel column (dichloromethane / methanol: 0 - 10%) to obtain the product 1,7-naphthyridin-4-ol (200 mg, Y: 49.3%), a yellow solid. ES-API: [M+H] + = 147.1

[0451] Step 4: 1,7-Naphthyridin-4-ol (550 mg, 3.77 mmol) is dissolved in concentrated sulfuric acid (4.5 mL), cooled to 0 °C, and concentrated nitric acid (1.0 mL, 15.08 mmol) is slowly added dropwise. The reaction is stirred at 100 °C for 1 hour. The cooled reaction solution is poured into ice water, and the pH is adjusted to 6 - 7 with concentrated ammonia water. The precipitated solid is filtered and dried in vacuo to obtain the product 3-nitro-1,7-naphthyridin-4-ol (530 mg, Y: 73.7%), a yellow solid. ES-API: [M+H] + = 192.1

[0452] Step 5: Add 3-nitro-1,7-naphthyridin-4-ol (480 mg, 2.51 mmol) and phosphorus oxychloride (4.68 mL, 50.20 mmol) into a 20 mL round-bottom flask, cool to -15 °C, and slowly add triethylamine (1.8 mL, 12.55 mmol). Stir the reaction at room temperature for 1 hour. Pour the reaction solution into ice water, adjust the pH to 8 with cold saturated sodium bicarbonate solution, and extract with dichloromethane three times. Dry and concentrate the organic phase to obtain the product 4-chloro-3-nitro-1,7-naphthyridine (450 mg, Y: 85.7%), a brown solid. ES-API: [M+H] + = 210.1.

[0453] Step 6: Dissolve 4-chloro-3-nitro-1,7-naphthyridine (450 mg, 2.15 mmol) in 1,4-dioxane (15 mL), and successively add (R)-tert-butyl 3-(hydroxymethyl)piperazine-1-carboxylate (1.02 g, 4.73 mmol) and N,N-diisopropylethylamine (832 mg, 6.45 mmol). Stir the reaction at 80 °C for 3 hours. Concentrate the reaction solution, and purify the crude product by flash silica gel column (EtOAc / PE: 50 - 100%) to obtain the product (R)-tert-butyl 3-(hydroxymethyl)-4-(3-nitro-1,7-naphthyridin-4-yl)piperazine-1-carboxylate (330 mg, Y: 39.4%), a yellow solid. ES-API: [M+H] + = 390.2.

[0454] Step 7: Add (R)-tert-butyl 3-(hydroxymethyl)-4-(3-nitro-1,7-naphthyridin-4-yl)piperazine-1-carboxylate (310 mg, 0.80 mmol), DMF (18 mL), and NaH (96 mg, 2.40 mmol) into a 50 mL sealed tube successively. Stir the reaction at 95 °C for 3 days. Pour the cooled reaction solution into water, and extract with ethyl acetate twice. Wash the organic phase with saturated brine three times, dry and concentrate. Purify the crude product with a thick TLC plate (dichloromethane / methanol = 15:1) to obtain the product (R)-tert-butyl 8a,9,11,12-tetrahydropyrazino[1',2':4,5][1,4]oxazino[2,3-c][1,7]naphthyridine-10(8H)-carboxylate (175 mg, Y: 64%), a yellow solid. ES-API: [M+H] + = 343.3

[0455] Step 8: tert-Butyl (R)-8a,9,11,12-tetrahydropyrazino[1',2':4,5][1,4]oxazino[2,3-c][1,7]naphthalen-10(8H)-carboxylate (100 mg, 0.29 mmol) was dissolved in acetic acid (4 mL), sodium cyanoborohydride (73 mg, 1.16 mmol) was added, and the reaction mixture was stirred at room temperature overnight. The reaction solution was poured into ice water, and the pH was adjusted to 8 with saturated sodium bicarbonate solution. The mixture was extracted twice with dichloromethane. The organic phase was washed with saturated brine, dried and concentrated. The crude product was purified by preparative TLC (dichloromethane / methanol / ammonia water = 100:8:1) to obtain tert-butyl (R)-1,2,3,4,8a,9,11,12-octahydropyrazino[1',2':4,5][1,4]oxazino[2,3-c][1,7]naphthalen-10(8H)-carboxylate (50 mg, Y: 49.4%), a pale yellow solid. ES-API: [M+H] + = 390.2.

[0456] Step 9: To a 5 mL microwave tube were added tert-butyl (R)-1,2,3,4,8a,9,11,12-octahydropyrazino[1',2':4,5][1,4]oxazino[2,3-c][1,7]naphthalen-10(8H)-carboxylate (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), Ruphos (26 mg, 0.056 mmol) and toluene (6 mL). The tube was purged with nitrogen, and the reaction was stirred at 120 °C for 1 hour using a microwave reactor. After cooling to room temperature, the mixture was filtered, and the filtrate was dried and concentrated. The crude product was purified by preparative TLC (dichloromethane / methanol / ammonia water = 100:5:1) to obtain tert-butyl (8aR)-3-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-1,2,3,4,8a,9,11,12-octahydropyrazino[1',2':4,5][1,4]oxazino[2,3-c][1,7]naphthalen-10(8H)-carboxylate (60 mg, Y: 74.1%). ES-API: [M+H] + = 561.3

[0457] Step 10: tert-Butyl (8aR)-3-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-4-yl)-1,2,3,4,8a,9,11,12-octahydropyrazino[1',2':4,5][1,4]oxazino[2,3-c][1,7]naphthalen-10(8H)-carboxylate (60 mg, 0.11 mmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (0.8 mL) was added. The mixture was stirred at room temperature for 1 hour, and the reaction solution was concentrated to obtain the product (R)-3-(5-methyl-1H-indazole-4-yl)-1,2,3,4,8,8a,9,10,11,12-decahydropyrazino[1',2':4,5][1,4]oxazino[2,3-c][1,7]naphthalene (60 mg, crude yield), which was used directly in the next step without purification. ES-API: [M+H] + = 377.1.

[0458] Step 11: (R)-3-(5-methyl-1H-indazole-4-yl)-1,2,3,4,8,8a,9,10,11,12-decahydropyrazino[1',2':4,5][1,4]oxazino[2,3-c][1,7]naphthalene (60 mg, 0.11 mmol) and N,N-diisopropylethylamine (71 mg, 0.55 mmol) were dissolved in dichloromethane (5 mL). The reaction was cooled to 0 °C, and a solution of acrylic anhydride (13 mg, 0.10 mmol) in dichloromethane (0.5 mL) was added dropwise to the reaction solution. The reaction was stirred at 0 °C for 10 minutes. 10 mL of saturated aqueous NaHCO3 was added to the reaction solution, and the mixture was extracted with 10 mL of dichloromethane three times. The organic phase was dried and concentrated, and the crude product was purified by preparative HPLC to obtain the product (R)-1-(3-(5-methyl-1H-indazole-4-yl)-1,2,3,4,8a,9,11,12-octahydropyrazino[1',2':4,5][1,4]oxazino[2,3-c][1,7]naphthalen-10(8H)-yl)prop-2-en-1-one (Z2, 12 mg, Y: 26.0%), a white solid. 1 HNMR (500 MHz, DMSO-d6) δ 12.91 (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 = 16.6 Hz, 1H), 5.67 (m, 1H), 4.21 - 4.11 (m, 3H), 3.96 (t, J = 10.0 Hz, 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。

[0459] Example 3 Preparation of Compounds Z3a and Z3

[0460]

[0461] Step 1: 4-Chloro-6-fluoro-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro-1,8-naphthyridin-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 was stirred at 80 °C for 1 hour. The reaction solution was poured into 30 mL of water. It was extracted 3 times with 20 mL of ethyl acetate. The organic phase was washed 3 times with saturated brine, dried and concentrated. The crude product was purified by flash silica gel column (EtOAc / PE: 0 - 70%) to obtain the product (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-naphthyridin-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。

[0462] 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-naphthyridin-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 was stirred at 125 °C for 20 hours. The cooled reaction solution was poured into 15 mL of water. It was extracted 3 times with 30 mL of ethyl acetate. The organic phase was washed 8 times with saturated brine, dried and concentrated. The crude product was purified by flash silica gel column (EtOAc / PE: 0 - 100%) to obtain the product (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-hexahydropyrazino[1’,2’:4,5][1,4]oxazino[2,3-c][1,8]naphthyridine-3(4H)-carboxylic acid tert-butyl ester (60 mg, Y: 21.4%), a yellow solid. ES-API: [M+H]+ = 648.3。

[0463] Step 3: tert-Butyl (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-hexahydropyrazino[1’,2’:4,5][1,4]oxazino[2,3-c][1,8]naphthalene-3(4H)-carboxylate (60 mg, 0.093 mmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (0.7 mL) was added. The mixture was stirred at room temperature for 1 hour, and the reaction solution was 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-hexahydropyrazino[1’,2’:4,5][1,4]oxazino[2,3-c][1,8]naphthalen-7(8H)-one (61 mg, crude product), which was directly used in the next step reaction. ES-API: [M+H] + = 548.2.

[0464] 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-hexahydropyrazino[1’,2’:4,5][1,4]oxazino[2,3-c][1,8]naphthalen-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 was cooled to 0 °C, and a solution of acrylic anhydride (17 mg, 0.14 mmol) in dichloromethane (1 mL) was added dropwise to the reaction solution. The reaction was stirred at 0 °C for 15 minutes. 10 mL of saturated aqueous NaHCO3 solution was added to the reaction solution, and the mixture was extracted with 10 mL of dichloromethane three times. After drying the organic phase and concentrating, the crude product was purified by preparative TLC plate (dichloromethane / methanol = 10:1) to obtain 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-hexahydropyrazino[1’,2’:4,5][1,4]oxazino[2,3-c][1,8]naphthalen-7(8H)-one (Z3a, 32 mg, Y: 57.4%), a white solid. ES-API: [M+H] + = 602.2. 11H NMR (500 MHz, DMSO-d6) δ 8.42 (d, J = 4.1 Hz, 1H), 7.87 (d, J = 8.8 Hz, 1H), 7.43 (dd, J = 15.4, 8.3 Hz, 1H), 7.21 (d, J = 4.8 Hz, 1H), 6.99–6.78 (m, 3H), 6.17 (d, J = 17.4 Hz, 1H), 5.75 (d, J = 10.5 Hz, 1H), 4.80 - 4.15 (m, 4H), 3.94–3.35 (m, 6H), 3.13 - 2.97 (m, 1H), 2.62 - 2.40 (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).

[0465] 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-hexahydropyrazino[1’,2’:4,5][1,4]oxazino[3,2-c][1,8]naphthyridin-12(13H)-one (32 mg, 0.053 mmol) was dissolved in dichloromethane (1.5 mL). The reaction was cooled to 0 °C, and a solution of 17% boron tribromide in dichloromethane (1 mL) was added dropwise thereto. The reaction was stirred at room temperature for 3 hours. The reaction solution was poured into 20 mL of saturated aqueous NaHCO3, and extracted with 20 mL of dichloromethane three times. After drying the organic phase and concentrating, 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-hexahydropyrazino[1’,2’:4,5][1,4]oxazino[3,2-c][1,8]naphthyridin-12(13H)-one (Z3, 18 mg, Y: 57.6%), a white solid. ES-API: [M+H] + = 588.3.

[0466] Example 6 Preparation of Compound Z6

[0467]

[0468] Step 1: 4,6-Dichloro-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro-1,8-naphthyridin-2(1H)-one (1.8 g, 3.48 mmol) was dissolved in DMF (15 mL), (R)-tert-butyl 3-(hydroxymethyl)piperazine-1-carboxylate (3 g, 13.92 mmol) was added, and the reaction was stirred at 80 °C for 2 h. The reaction solution was poured into 30 mL of water. It was extracted 3 times with 20 mL of ethyl acetate. The organic phase was washed 3 times with saturated brine, dried and concentrated, and the crude product was purified by flash silica gel column (EtOAc / PE: 0 - 70%) to obtain the product (3R)-tert-butyl 4-(6-chloro-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro-2-oxo-1,2-dihydro-1,8-naphthyridin-4-yl)-3-(hydroxymethyl)piperazine-1-carboxylate (1.3 g, 54%), a yellow solid. ES-API: [M+H] + = 697.2.

[0469] Step 2: (3R)-tert-butyl 4-(6-chloro-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro-2-oxo-1,2-dihydro-1,8-naphthyridin-4-yl)-3-(hydroxymethyl)piperazine-1-carboxylate (1.3 g, 1.86 mmol) was dissolved in DMA (10 mL), LHMDS (5.6 mmol, 5.6 mmol, 1 M solution in tetrahydrofuran) was added, and the reaction was stirred at 140 °C for 20 h. The cooled reaction solution was poured into 15 mL of water. It was extracted 3 times with 30 mL of ethyl acetate. The organic phase was washed 3 times with saturated brine, dried and concentrated, and the crude product was purified by flash silica gel column (methanol / dichloromethane: 0 - 10%) to obtain (4aR)-tert-butyl 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]naphthyridine-3(4H)-carboxylate (0.24 g, 20%), a yellow solid. ES-API: [M+H] + = 650.2.

[0470] Step 3: tert-Butyl (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]naphthalene-3(4H)-carboxylate (240 mg, 0.37 mmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (2 mL) was added. The mixture was stirred at room temperature for 0.5 h, 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]naphthalen-7(8H)-one (203 mg, crude), which was directly used in the next step reaction. ES-API: [M+H] + = 550.1.

[0471] 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]naphthalen-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 was cooled to 0 °C, and a dichloromethane solution (0.5 mL) of acrylic anhydride (37 mg, 0.30 mmol) was added dropwise to the reaction solution. The reaction was stirred at 0 °C for 10 min. 10 mL of saturated aqueous NaHCO3 was added to the reaction solution, and the mixture was extracted 3 times with 10 mL of dichloromethane. The organic phase was dried and concentrated, and the crude product was purified by preparative TLC plate (dichloromethane / methanol = 10:1) to obtain 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]naphthalen-7(8H)-one (223 mg, crude), a pale yellow solid. ES-API: [M+H] + = 604.2.

[0472] 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]naphthalen-7(8H)-one (223 mg, 0.37 mmol) was dissolved in dichloromethane (1.5 mL). The reaction was cooled to 0 °C, and a solution of 17% boron tribromide in dichloromethane (3 mL) was added dropwise thereto. The reaction was stirred at room temperature for 1 hour. The reaction solution was poured into 20 mL of saturated aqueous NaHCO3, and extracted with 20 mL of dichloromethane three times. After drying the organic phase and concentrating, 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]naphthalen-7(8H)-one (Z6, 26.28 mg, 11%), a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.42 - 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.

[0473] Example 9 Preparation of Compounds Z9, Z9-1 and Z9-2

[0474]

[0475] Step 1: 4-Chloro-6-fluoro-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro-1,8-naphthyridin-2(1H)-one (500 mg, 1.00 mmol) was dissolved in N,N-dimethylacetamide (6 mL). (R)-1-(tert-Butyl) 3-methyl-piperazine-1,3-dicarboxylate (732 mg, 3.00 mmol) and N,N-diisopropylethylamine (387 mg, 3.00 mmol) were added successively. The reaction was stirred at 120 °C for 2 h. 100 mL of ethyl acetate was added to the reaction solution, and it was washed 4 times with 30 mL of dilute brine and then with 30 mL of saturated brine, dried and concentrated. The crude product was purified by flash silica gel column (EtOAc / PE: 0 - 70%) to obtain the product (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-naphthyridin-4-yl)piperazine-1,3-dicarboxylate (500 mg, Y: 70.6%), a yellow solid. ES-API: [M+H] + = 709.2.

[0476] 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-naphthyridin-4-yl)piperazine-1,3-dicarboxylate (500 mg, 0.71 mmol) was dissolved in acetic acid (8 mL). Iron powder (138 mg, 2.47 mmol) was added, and the reaction was stirred at 80 °C for 30 min. The reaction solution was concentrated. 50 mL of ethyl acetate and 30 mL of saturated sodium bicarbonate were added successively. The suspension was filtered through diatomaceous earth, and the filter cake was washed with ethyl acetate. The organic phase was separated and washed successively with 30 mL of saturated aqueous sodium bicarbonate and 30 mL of saturated brine, dried and concentrated to obtain the product tert-butyl (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-pyrazino[1’,2’:4,5]pyrazino[2,3-c][1,8]naphthyridine-3-carboxylate (450 mg, Y: 98.6%), a pale yellow solid. ES-API: [M+H] + = 647.2.

[0477] Step 3: Add tert-butyl (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-pyrazino[1’,2’:4,5]pyrazino[2,3-c][1,8]naphthyridine-3-carboxylate (450 mg, 0.70 mmol), 12 mL of acetone, potassium carbonate anhydrous (290 mg, 2.10 mmol), and methyl iodide (596 mg, 4.20 mmol) successively into a 15 mL sealed tube. Seal the tube and stir the reaction at 50 °C for 20 hours. Concentrate the reaction solution, add 60 mL of ethyl acetate, wash it successively with 30 mL of water and 30 mL of saturated brine, dry and concentrate it. Purify the crude product by flash silica gel column (EtOAc / PE: 0 - 70%) to obtain the product tert-butyl (4aR)-11-fluoro-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]naphthyridine-3-carboxylate (390 mg, Y: 84.8%), an orange solid. ES-API: [M+H] + = 661.3.

[0478] Step 4: Dissolve tert-butyl (4aR)-11-fluoro-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]naphthyridine-3-carboxylate (940 mg, 1.42 mmol) in dichloromethane (6 mL), and add trifluoroacetic acid (2 mL). Stir at room temperature for 2 hours, concentrate the reaction solution 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-pyrazino[1’,2’:4,5]pyrazino[2,3-c][1,8]naphthyridine-5,7-dione (1.1 g, crude product), which is directly used in the next step reaction. ES-API: [M+H] + = 561.3.

[0479] 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-pyrazino[1’,2’:4,5]pyrazino[2,3-c][1,8]naphthyridine-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. 30 mL of dichloromethane was added to the reaction solution, and it was washed successively with 15 mL of water, 15 mL of saturated NaHCO3 aqueous solution, and 15 mL of saturated brine, dried and concentrated. After drying, it was concentrated, and the crude product was purified by flash silica gel column (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-pyrazino[1’,2’:4,5]pyrazino[2,3-c][1,8]naphthyridine-5,7-dione (780 mg, Y: 88.3%), a pale yellow solid. ES-API: [M+H] + = 615.3.

[0480] 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-pyrazino[1’,2’:4,5]pyrazino[2,3-c][1,8]naphthyridine-5,7-dione (390 mg, 0.64 mmol) was dissolved in dichloromethane (9 mL). The reaction was cooled to 0 °C, and a dichloromethane solution of 17% boron tribromide (7 mL) was added dropwise thereto. The reaction was stirred at room temperature for 6 hours. The reaction solution 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, and concentrated after drying to obtain 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-pyrazino[1’,2’:4,5]pyrazino[2,3-c][1,8,8]naphthyridine-5,7-dione (Z9, 375 mg, Y: 98.4%), a pale yellow solid. ES-API: [M+H] + = 601.2.

[0481] 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-pyrazino[1’,2’:4,5]pyrazino[2,3-c][1,8,8]naphthyridine-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: room temperature) to obtain: a atropisomer compound, arbitrarily designated as Z9-1 (250 mg, peak 1, retention time 6.463 min, Y: 33.3%), pale yellow solid. 1 HNMR (500 MHz, DMSO-d6) δ 10.11 (d, J = 1.3 Hz, 1H), 8.46–8.34 (m, 2H), 7.30–7.19 (m, 2H), 7.10–6.79 (m, 1H), 6.74–6.62 (m, 2H), 6.15 (d, J = 16.9 Hz, 1H), 5.75 (d, J = 12.0 Hz, 1H), 4.73 (d, J = 13.3 Hz, 1H), 4.45 (d, J = 12.7 Hz, 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 = 6.7 Hz, 3H), 0.85 (d, J = 6.7 Hz, 3H). ES-API: [M + H] + = 601.2. And another atropisomer compound, arbitrarily designated as Z9-2 (350 mg, peak 2, retention time 8.252 min, Y: 46.7%), pale yellow solid. 11H NMR (500 MHz, DMSO-d6) δ 10.14 (s, 1H), 8.44 (d, J = 4.9 Hz, 1H), 8.38 (d, J = 9.0 Hz, 1H), 7.29–7.20 (m, 2H), 7.10–6.79 (m, 1H), 6.76–6.59 (m, 2H), 6.15 (d, J = 16.9 Hz, 1H), 5.75 (d, J = 11.1 Hz, 1H), 4.73 (d, J = 14.0 Hz, 1H), 4.45 (d, J = 12.4 Hz, 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 = 6.7 Hz, 3H), 0.98 (d, J = 6.7 Hz, 3H). ES-API: [M+H] + = 601.2. The isomeric compounds were detected by analytical chiral HPLC method (column type: IB: 5 μm, 4.6 * 250 mm, mobile phase: hexane: EtOH = 65:35, flow rate: 1 ml / min, column temperature = 30 °C).

[0482] Example 10 Preparation of Compounds Z10, Z10-1 and Z10-2

[0483]

[0484] Step 1: To a 50 mL sealed tube were successively added tert-butyl (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-octahydro-3H-pyrazino[1’,2’:4,5]pyrazino[2,3-c][1,8]naphthyridine-3-carboxylate (800 mg, 1.21 mmol), 20 mL of acetone, potassium carbonate anhydrous (500 mg, 3.63 mmol), and methyl iodide (1.03 g, 7.26 mmol). The sealed tube was sealed and the reaction was stirred at 50 °C for 18 hours. The reaction solution was concentrated, 60 mL of ethyl acetate was added, and it was successively washed with 20 mL of water and 30 mL of saturated brine, dried and concentrated. The crude product was purified by flash silica gel column (EtOAc / PE: 0 - 70%) to obtain the product tert-butyl (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-octahydro-3H-pyrazino[1’,2’:4,5]pyrazino[2,3-c][1,8]naphthyridine-3-carboxylate (790 mg, Y: 96.7%), an orange solid. ES-API: [M+H]+ = 675.3.

[0485] Step 2: (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-octahydro-3H-pyrazino[1’,2’:4,5]pyrazino[2,3-c][1,8]naphthyridine-3-carboxylic acid tert-butyl ester (790 mg, 1.42 mmol) was dissolved in dichloromethane (6 mL), and trifluoroacetic acid (2 mL) was added. The mixture was stirred at room temperature for 2 h, and the reaction solution was 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-pyrazino[1’,2’:4,5]pyrazino[2,3-c][1,8]naphthyridine-5,7-dione (810 mg, crude product), which was directly used in the next step. ES-API: [M+H] + = 575.2.

[0486] 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-pyrazino[1’,2’:4,5]pyrazino[2,3-c][1,8]naphthyridine-5,7-dione (810 mg, crude product) was dissolved in dichloromethane (15 mL), and N,N-diisopropylethylamine (755 mg, 5.85 mmol) was added. The reaction was cooled to 0 °C, acryloyl chloride (211 mg, 2.34 mmol) was added to the reaction solution, and the reaction was stirred at 0 °C for 15 min. 50 mL of dichloromethane was added to the reaction solution, and the mixture was washed successively with 20 mL of water, 40 mL of saturated NaHCO3 aqueous solution, and 20 mL of saturated brine, dried and concentrated. The crude product was purified by flash silica gel column (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-pyrazino[1’,2’:4,5]pyrazino[2,3-c][1,8]naphthyridine-5,7-dione (670 mg, Y: 91.0%), a pale yellow solid. ES-API: [M+H] + = 629.2.

[0487] 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-pyrazino[1’,2’:4,5]pyrazino[2,3-c][1,8]naphthyridine-5,7-dione (370 mg, 0.59 mmol) was dissolved in dichloromethane (8 mL). The reaction was cooled to 0 °C, and a solution of 17% boron tribromide in dichloromethane (7 mL) was added dropwise thereto. The reaction was stirred at room temperature for 3 hours. The reaction solution was poured into 60 mL of saturated aqueous NaHCO3, and extracted twice with 80 mL of dichloromethane. The organic phase was washed successively with 50 mL of saturated aqueous NaHCO3 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-pyrazino[1’,2’:4,5]pyrazino[2,3-c][1,8,8]naphthyridin-5-one (Z10, 249 mg, Y: 68.7%), a pale yellow solid. ES-API: [M+H] + = 615.2.

[0488] 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: room temperature) to obtain: a atropisomer compound, arbitrarily designated as Z10-1 (206 mg, peak 1, retention time 8.321 min, Y: 45.7%), a pale yellow solid. 1HNMR(500 MHz, DMSO-d6) δ 10.13 (d, J = 1.3 Hz, 1H), 8.44 (d, J = 4.9 Hz, 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, 4.2 Hz, 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 = 6.7 Hz, 3H), 0.85 (d, J = 6.7 Hz, 3H). ES-API: [M+H] + = 615.2. And another atropisomer compound, arbitrarily designated as Z10-2 (209 mg, peak 2, retention time 10.183 min, Y: 46.4%), yellow solid. 1 H NMR(500 MHz, DMSO-d6) δ 10.15 (s, 1H), 8.45 (d, J = 4.9 Hz, 1H), 8.03 - 7.95 (m, 1H), 7.30 – 7.18 (m, 2H), 7.06 - 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, 4.2 Hz, 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 = 6.7 Hz, 3H), 0.98 (d, J = 6.7 Hz, 3H). ES-API: [M+H] + = 615.2. The isomer compound was detected by an analytical chiral HPLC method (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).

[0489] Examples 4 to 5, 7 to 8, 11 to 20

[0490] Compounds Z4 to Z5, Z7 to Z8, Z11 to Z20 are prepared by a similar method to that of reference compound Z1 or Z2, where the starting materials of each compound can be commercially purchased or prepared by referring to the existing methods well-known to those skilled in the art, and the similar synthetic methods of the intermediates can be easily obtained by those skilled in the art by referring to the existing methods.

[0491]

[0492]

[0493]

[0494] Example 21 Preparation of Compounds Z21, Z21-1 and Z21-2

[0495]

[0496] Step 1: Add 7-chloro-6-fluoro-4-hydroxy-1-(4-isopropyl-6-methylpyrimidin-5-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile (2 g, 5.34 mmol), 12 mL of water and 12 mL of dioxane to a round-bottom flask. After the system is cooled to 0 °C, 12 mL of concentrated sulfuric acid is added dropwise to the reaction solution. After the addition is complete, the reaction is stirred at 120 °C for 18 hours. After the reaction is complete, a large amount of solid precipitates. Filter, and wash the filter cake with water three times. After drying the filter cake, 7-chloro-6-fluoro-4-hydroxy-1-(4-isopropyl-6-methylpyrimidin-5-yl)-1,8-naphthyridin-2(1H)-one (1.4 g, 75%) is obtained as a white solid. The crude product is directly used in the next step. ES-API: [M+H] + = 349.1.

[0497] Step 2: Add 7-chloro-6-fluoro-4-hydroxy-1-(4-isopropyl-6-methylpyrimidin-5-yl)-1,8-naphthyridin-2(1H)-one (1.3 g, 3.72 mmol), sodium nitrite (26 mg, 0.37 mmol) and 8 mL of glacial acetic acid to a round-bottom flask. Concentrated nitric acid (700 mg, 11.1 mmol) is added dropwise to the reaction solution. The reaction is heated in an oil bath at 30 °C for 2 hours. The reaction solution is poured into ice water, and a solid precipitates. Filter, and wash the filter cake with water. Collect the filter cake and dry it under vacuum to obtain 7-chloro-6-fluoro-4-hydroxy-1-(4-isopropyl-6-methylpyrimidin-5-yl)-3-nitro-1,8-naphthyridin-2(1H)-one (1.2 g, purity 76%) as a yellow solid. The crude product is directly used in the next step. ES-API: [M+H] + = 394.1.

[0498] Step 3: Add 7-chloro-6-fluoro-4-hydroxy-1-(4-isopropyl-6-methylpyrimidin-5-yl)-3-nitro-1,8-naphthyridin-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 of dioxane and 3 mL of water into the reaction flask. The reaction was stirred in an oil bath at 110 °C for 1 hour under nitrogen protection and then stopped. Add 1 M aqueous potassium carbonate solution (30 mL) to the reaction solution and extract once with 20 mL of EtOAc / PE (1:1) to remove impurities. Adjust the pH of the aqueous phase to 4 with 6 M aqueous hydrochloric acid solution. Extract three times with ethyl acetate. Dry the organic phase with sodium sulfate and concentrate to obtain 6-fluoro-7-(2-fluoro-6-methoxyphenyl)-4-hydroxy-1-(4-isopropyl-6-methylpyrimidin-5-yl)-3-nitro-1,8-naphthyridin-2(1H)-one (1.1 g, 75%), a yellow solid. ES-API: [M+H] + = 483.1.

[0499] Step 4: Add 6-fluoro-7-(2-fluoro-6-methoxyphenyl)-4-hydroxy-1-(4-isopropyl-6-methylpyrimidin-5-yl)-3-nitro-1,8-naphthyridin-2(1H)-one (1.2 g, 2.48 mmol), diisopropylethylamine (3 g, 23.1 mmol), and acetonitrile (20 mL) into a round-bottom flask. Dropwise add phosphorus oxychloride (2.2 g, 14.5 mmol) thereto. The reaction was stirred at 85 °C for 1 hour. The completion of the reaction was detected by LC-MS. Pour the reaction solution into ice water and extract with ethyl acetate. Dry the organic phase with sodium sulfate and concentrate to obtain 4-chloro-6-fluoro-7-(2-fluoro-6-methoxyphenyl)-1-(4-isopropyl-6-methylpyrimidin-5-yl)-3-nitro-1,8-naphthyridin-2(1H)-one (1.1 g, purity 83%), and the crude product was directly used for the next reaction. ES-API: [M+H] + = 502.1.

[0500] Step 5: Add 4-chloro-6-fluoro-7-(2-fluoro-6-methoxyphenyl)-1-(4-isopropyl-6-methylpyrimidin-5-yl)-3-nitro-1,8-naphthyridin-2(1H)-one (1 g, 2 mmol), 1-(tert-butyl) 3-methyl (R)-piperazine-1,3-dicarboxylate (1.94 g, 8 mmol), N,N-diisopropylethylamine (516 mg, 4 mmol) and N,N-dimethylacetamide (10 mL) into a round-bottom flask. The reaction is stirred at 120 °C for 2 hours. The completion of the reaction is detected by LC-MS. Pour the reaction solution into 30 mL of water. Extract with ethyl acetate three times. Wash the organic phase four times with saturated brine / water (v / v, 1:1), dry and concentrate. Purify the crude product by flash silica gel column (EtOAc / PE: 0 - 40%) to obtain 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-naphthyridin-4-yl)piperazine-1,3-dicarboxylate (1 g, purity 82%). ES-API: [M+H] + = 710.2.

[0501] 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-naphthyridin-4-yl)piperazine-1,3-dicarboxylate (1 g, 1.4 mmol), iron powder (390 mg, 7 mmol) and 15 mL of glacial acetic acid into a reaction flask. The reaction is stirred at 80 °C for 1 hour. The completion of the reaction is detected by LC-MS. Pour the reaction solution into 50 mL of aqueous sodium bicarbonate solution. Extract with 30 mL of ethyl acetate three times. Dry and concentrate the organic phase to obtain tert-butyl (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]naphthyridine-3-carboxylate (850 mg, 93%), a yellow solid. ES-API: [M+H] + = 648.3.

[0502] Step 7: Add tert-butyl (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]naphthyridine-3-carboxylate (450 mg, 0.69 mmol), methyl iodide (789 mg, 5.55 mmol), potassium carbonate (286 mg, 2.07 mmol) and 10 mL of acetone into a round-bottom flask. The reaction was stirred in a sealed tube at 50 °C for 16 h, and the reaction was completed as detected by LC-MS. The reaction solution was filtered through diatomaceous earth. The filtrate was concentrated, and the crude product was purified by flash silica gel column (EtOAc / PE: 0 - 60%) to obtain tert-butyl (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]naphthyridine-3-carboxylate (260 mg, 57%), a yellow solid. ES-API: [M+H] + = 662.2.

[0503] Step 8: Add tert-butyl (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]naphthyridine-3-carboxylate (260 mg, 0.39 mmol), 1 mL of dichloromethane and 3 mL of trifluoroacetic acid into a round-bottom flask. Stir at room temperature for 1 h, and the reaction was completed as detected by LC-MS. The reaction solution was concentrated to obtain (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]naphthyridine-5,7-dione (219 mg), a yellow solid. The crude product was directly used for the next step. ES-API: [M+H] + = 562.2.

[0504] 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]naphthyridine-5,7-dione (219 mg, 0.39 mmol), 3 mL of dichloromethane and triethylamine (158 mg, 1.56 mmol) into a 50 mL round-bottom flask. Cool the reaction to 0 °C, and dropwise add a dichloromethane solution of acryloyl chloride (71 mg, 0.78 mmol, 0.5 mL) to the reaction solution. Stir the reaction at 0 °C for 10 minutes. Add 40 mL of saturated aqueous sodium bicarbonate to the reaction solution, and extract it 3 times with 20 mL of dichloromethane. After drying the organic phase and concentrating it, (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]naphthyridine-5,7-dione (240 mg, 87% purity), a yellow solid, is obtained. The crude product is directly used for the next step. ES-API: [M+H] + = 616.3.

[0505] 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]naphthyridine-5,7-dione (240 mg, 0.39 mmol) and 3 mL of dichloromethane into a round-bottom flask. Cool the reaction solution to 0 °C, and dropwise add a dichloromethane solution of 17% boron tribromide (6 mL) to it. After the addition is complete, stir the reaction at room temperature for 2 hours. Pour the reaction solution into 30 mL of ice-cold saturated aqueous NaHCO3, and extract it 3 times with 20 mL of dichloromethane. After drying the organic phase and concentrating it, the crude product is 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]naphthyridine-5,7-dione (Z21, 130 mg, 55%), a yellow solid. ES-API: [M+H] + = 602.2.

[0506] Step 11: The 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]naphthyridine-5,7-dione (130 mg) was resolved by preparative chiral HPLC (column type: Chiralpak IE: 10 μm, 20*250 mm; mobile phase: hexane:ethanol:diethylamine = 70:30:0.2; flow rate: 15 ml / min; column temperature: room temperature) to obtain: a atropisomer compound, arbitrarily designated as Z21-1 in structure (peak 2, retention time: 12.33 min, 47 mg), a yellow solid. ES-API: [M+H] + = 602.2. 1 1H NMR (500 MHz, DMSO-d6): 10.17 (s, 1H), 9.03 (s, 1H), 8.41 (d, J = 9 Hz, 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 atropisomer compound, arbitrarily designated as Z21-2 in structure (peak 1, retention time: 10.58 min, 48 mg), a yellow solid. ES-API: [M+H] + = 602.2. 11H NMR (500 MHz, DMSO-d6): 10.16 (s, 1H), 9.03 (s, 1H), 8.41 (d, J = 9 Hz, 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), 2.65 - 2.60 (m, 1H), 2.52 - 2.51 (m, 1H), 2.20 (s, 3H), 1.06 (d, J = 6.5 Hz, 3H), 0.86 (d, J = 6.5 Hz, 3H). The isomeric compounds were detected by analytical chiral HPLC method (column type: Chiralpak IE: 5 μm, 4.6 * 250 mm; mobile phase: hexane: ethanol: ammonia methanol = 70:30:0.2; flow rate: 1 ml / min; column temperature = 30 °C).

[0507] Example 22 Preparation of Compound Z22

[0508]

[0509] Step 1: 7-Chloro-6-fluoro-4-hydroxy-1-(3-isopropylpyrazin-2-yl)-1,8-naphthyridin-2(1H)-one (2 g, 6 mmol) was dissolved in acetic acid (5 mL). Sodium nitrite (41 mg, 0.6 mmol) and concentrated nitric acid (1.5 g, 24 mmol) were added successively, and the reaction was stirred at room temperature for 30 minutes. The reaction solution was slowly poured into 100 mL of ice water, and the precipitated solid was filtered. 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-naphthyridin-2(1H)-one (1.5 g, 65%), a yellow solid. ES-API: [M + H] + = 380.2.

[0510] Step 2: Add 7-chloro-6-fluoro-4-hydroxy-1-(3-isopropylpyrazin-2-yl)-3-nitro-1,8-naphthyridin-2(1H)-one (1.5 g, 3.94 mmol), (2-fluoro-6-methoxyphenyl)boronic acid (2.04 g, 12 mmol), chloro(2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) (288 mg, 0.4 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (164 mg, 0.4 mmol), potassium phosphate (2.5 g, 12 mmol), 10 mL of water and 40 mL of dioxane into a 100 mL three-necked round-bottom flask. Under nitrogen protection, the reaction is stirred at 100 °C for 2 - 3 hours. After the reaction is completed, the reaction solution is cooled to room temperature, 80 mL of water and 100 mL of methyl tert-butyl ether are added, and extraction is carried out once. The aqueous phase is adjusted to pH 3 - 5 with 1 M hydrochloric acid solution, and extracted with ethyl acetate (200 mL * 2). The ethyl acetate phases are combined, dried over anhydrous sodium sulfate, filtered, and the filtrate is dried in vacuo to obtain the product 6-fluoro-7-(2-fluoro-6-methoxyphenyl)-4-hydroxy-1-(3-isopropylpyrazin-2-yl)-3-nitro-1,8-naphthyridin-2(1H)-one (1.6 g, crude product), a pale yellow solid. ES-API: [M+H] + = 470.1.

[0511] Step 3: Dissolve 6-fluoro-7-(2-fluoro-6-methoxyphenyl)-4-hydroxy-1-(3-isopropylpyrazin-2-yl)-3-nitro-1,8-naphthyridin-2(1H)-one (1.6 g, 3.4 mmol) in acetonitrile (30 mL), and successively add phosphorus oxychloride (2.6 g, 17 mmol) and N,N-diisopropylethylamine (3 g, 23.8 mmol). The reaction gradually rises to 80 °C and is stirred for 30 minutes. The reaction solution is concentrated, 30 mL of cold acetonitrile is added, and the mixture is added dropwise to 150 mL of saturated sodium bicarbonate solution under an ice-water bath. It is extracted with ethyl acetate (200 mL * 2), the organic phases are combined, and washed once with 200 mL of saturated brine. After drying over anhydrous sodium sulfate, filtering, and concentrating the organic phase, the crude product is purified by flash silica gel column (EtOAc / PE: 0 - 50%) to obtain 4-chloro-6-fluoro-7-(2-fluoro-6-methoxyphenyl)-1-(3-isopropylpyrazin-2-yl)-3-nitro-1,8-naphthyridin-2(1H)-one (340 mg, Y: 20%), a yellow solid. ES-API: [M+H] + = 488.2.

[0512] Step 4: 4-Chloro-6-fluoro-7-(2-fluoro-6-methoxyphenyl)-1-(3-isopropylpyrazin-2-yl)-3-nitro-1,8-naphthyridin-2(1H)-one (310 mg, 0.64 mmol) was dissolved in N,N-dimethylacetamide (5 mL). 1-(tert-Butyl) 3-methyl (3R,6R)-6-methylpiperazine-1,3-dicarboxylate (247 mg, 0.96 mmol) and N,N-diisopropylethylamine (250 mg, 1.92 mmol) were added successively. The reaction was stirred at 120 °C for 2 h. 50 mL of ethyl acetate was added to the reaction solution, and it was washed three times with 30 mL of saturated brine. The ethyl acetate phase was dried and concentrated, and the crude product was purified by flash silica gel column (EtOAc / PE: 0 - 80%) to obtain the product 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-naphthyridin-4-yl)-6-methylpiperazine-1,3-dicarboxylate (317 mg, Y: 70%), a yellow solid. ES-API: [M+H] + = 710.2.

[0513] 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-naphthyridin-4-yl)-6-methylpiperazine-1,3-dicarboxylate (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 min. The reaction solution was concentrated, 50 mL of ethyl acetate and 30 mL of saturated sodium bicarbonate were added successively. The suspension was filtered through diatomaceous earth, and the filter cake was washed with ethyl acetate. The organic phase was separated and washed successively with 100 mL of saturated sodium bicarbonate and 30 mL of saturated brine, dried and concentrated to obtain 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]naphthyridine-3-carboxylic acid tert-butyl ester (312 mg, crude product), a yellow solid. ES-API: [M+H]+ = 648.1.

[0514] Step 6: Add tert-butyl (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]naphthalene-3-carboxylate (295 mg, 0.46 mmol), 3 mL of acetone, potassium carbonate anhydrous (1 g, 6.9 mmol), and methyl iodide (253 mg, 1.84 mmol) into a 15 mL sealed tube in sequence. Seal the sealed tube and stir the reaction at 55 °C for 18 hours. Add 50 mL of ethyl acetate to the reaction solution, wash it 3 times with 20 mL of saturated brine, dry and concentrate to obtain the product tert-butyl (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]naphthalene-3-carboxylate (356 mg, crude product), a yellow solid. ES-API: [M+H] + = 662.2.

[0515] Step 7: Dissolve tert-butyl (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]naphthalene-3-carboxylate (356 mg, 0.54 mmol) in dichloromethane (8 mL), and add trifluoroacetic acid (4 mL). Stir at room temperature for 2 hours, and concentrate the reaction solution 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]naphthalene-5,7-dione (415 mg, crude product), which is directly used for the next step of the reaction. ES-API: [M+H] + = 562.2.

[0516] 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]naphthyridine-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. 50 mL of dichloromethane was added to the reaction solution, and it was washed with 50 mL of saturated aqueous NaHCO3 and 80 mL of saturated brine, dried and concentrated. The crude product was purified by flash silica gel column (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]naphthyridine-5,7-dione (201 mg, Y: 44%), a yellow solid. ES-API: [M+H] + = 616.2.

[0517] 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]naphthyridine-5,7-dione (201 mg, 0.33 mmol) was added to dry dichloromethane (3.0 mL), and boron tribromide (5.0 mL) was added. The reaction was carried out at room temperature for 30 minutes. Under ice-water bath conditions, the above reaction solution was added dropwise to saturated sodium bicarbonate solution. It was extracted twice with dichloromethane (50 mL), 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-(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]naphthyridine-5,7-dione (Z22, 65 mg, Y: 33%) ES-API: [M+H] + = 602.2. 11H NMR (500 MHz, DMSO-d6) δ 10.17 (s, 1H), 8.75 (dd, J = 4.0, 2.6 Hz, 1H), 8.55 (dd, J = 15.5, 2.4 Hz, 1H), 8.05 - 7.98 (m, 1H), 7.26 (dd, J = 15.0, 8.2 Hz, 1H), 7.03 (dd, J = 16.8, 10.0 Hz, 1H), 6.73 (d, J = 8.4 Hz, 1H), 6.67 (t, J = 8.8 Hz, 1H), 6.16 (t, J = 12.4 Hz, 1H), 5.74 (dd, J = 20.0, 11.8 Hz, 1H), 4.78 (s, 1H), 4.65 - 4.56 (m, 1H), 4.00 (t, J = 28.0 Hz, 1H), 3.80 - 3.70 (m, 1H), 3.36 (d, J = 2.4 Hz, 3H), 3.05 - 2.62 (m, 2H), 1.63 - 1.48 (m, 3H), 1.18 (d, J = 6.8 Hz, 2H), 1.10 (d, J = 6.8 Hz, 3H), 1.00 (d, J = 6.7 Hz, 2H).

[0518] Example 23 Preparation of Compound Z23

[0519]

[0520] Step 1: Add 4-chloro-6-fluoro-7-(2-fluoro-6-methoxyphenyl)-1-(4-isopropyl-6-methylpyrimidin-5-yl)-3-nitro-1,8-naphthyridin-2(1H)-one (0.8 g, 1.46 mmol), 1-(tert-butyl) 3-methyl (3R,6R)-6-methylpiperazine-1,3-dicarboxylate (567 mg, 2.2 mmol), N,N-diisopropylethylamine (565 mg, 4.38 mmol) and N,N-dimethylacetamide (10 mL) to a round-bottom flask, and stir the reaction at 120 °C for 1 hour. The reaction was monitored by LC-MS until completion. Pour the reaction solution into 30 mL of water. Extract with ethyl acetate three times. Wash the organic phase four times with saturated brine / water (v / v, 1:1), dry and concentrate to obtain 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-naphthyridin-4-yl)-6-methylpiperazine-1,3-dicarboxylate (1 g, yield 89%). ES-API: [M+H] + = 768.3.

[0521] 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-naphthyridin-4-yl)-6-methylpiperazine-1,3-dicarboxylate (1 g, 1.3 mmol), iron powder (300 mg, 5.3 mmol), and 8 mL of glacial acetic acid into a reaction flask. The reaction is stirred at 80 °C for 0.5 h. The reaction completion is detected by LC-MS. Pour the reaction solution into 50 mL of aqueous sodium bicarbonate solution, and extract it 3 times with 30 mL of ethyl acetate. After drying the organic phase and concentrating it, the crude product (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]naphthyridine-3-carboxylic acid tert-butyl ester (761 mg, 83%) is obtained as a yellow solid. ES-API: [M+H] + = 706.3.

[0522] 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]naphthyridine-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 into a round-bottom flask. The reaction is stirred in a sealed tube at 50 °C for 16 h, and the reaction completion is detected by LC-MS. Filter the reaction solution through diatomaceous earth. Concentrate the filtrate to obtain the crude product (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]pyrido[2,3-c][1,8]naphthyridine-3-carboxylic acid tert-butyl ester (738 mg, 95%) as a yellow solid. ES-API: [M+H] + = 720.3.

[0523] Step 4: Add tert-butyl (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]pyrido[2,3-c][1,8]naphthyridine-3-carboxylate (738 mg, 1.02 mmol), 2 mL of dichloromethane and 5 mL of trifluoroacetic acid into a round-bottom flask. Stir at room temperature for 1 hour, and detect the completion of the reaction by LC-MS. Concentrate the reaction solution to obtain (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]pyrido[2,3-c][1,8]naphthyridine-5,7-dione (632 mg, 100%), a yellow solid. The crude product is directly used for the next step. ES-API: [M+H] + = 620.3.

[0524] 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]pyrido[2,3-c][1,8]naphthyridine-5,7-dione (632 mg, 1.02 mmol), 3 mL of dichloromethane and triethylamine (677 mg, 6.7 mmol) into a 50 mL round-bottom flask. Cool the reaction to 0 °C, and add dropwise a dichloromethane solution of acryloyl chloride (249 mg, 2.77 mmol, 0.5 mL) to the reaction solution. Stir the reaction at 0 °C for 10 minutes. Add 40 mL of saturated aqueous sodium bicarbonate solution to the reaction solution, and extract with 20 mL of dichloromethane for 3 times. After drying the organic phase and concentrating, purify the crude product by flash silica gel column (EtOAc / PE: 0 - 60%) to obtain (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]pyrido[2,3-c][1,8]naphthyridine-5,7-dione (500 mg, 72%), a yellow solid. The crude product is directly used for the next step. ES-API: [M+H] + = 674.2.

[0525] 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]naphthyridine-5,7-dione (500 mg, 0.74 mmol) and 3 mL of dichloromethane into a round-bottom flask. Cool the reaction solution to 0 °C, and dropwise add a dichloromethane solution of 17% boron tribromide (12 mL) thereto. After the addition is completed, stir the reaction at 25 °C for 25 hours. Pour the reaction solution into 30 mL of ice-cold saturated aqueous NaHCO3 solution, and extract it 3 times with 20 mL of dichloromethane. After drying the organic phase and concentrating it, purify the crude product 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]naphthyridine-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),6.17-6.14(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.

[0526] Example 24 Preparation of Compounds Z24, Z24-1 and Z24-2

[0527]

[0528] Step 1: Suspend 6,7-dichloro-4-hydroxy-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile (30.0 g, 77.319 mmol) in a mixed solution of 1,4-dioxane (120 mL) and water (120 mL), and slowly add concentrated sulfuric acid (120 mL). Stir the reaction at 120 °C for 36 hours. Pour the cooled reaction solution into 200 mL of ice water, adjust the pH to 2 - 3 with sodium carbonate, extract with ethyl acetate (1000 mL × 2), combine the ethyl acetate phases, dry over anhydrous sodium sulfate, filter, and dry the filtrate under vacuum to obtain the product 6,7-dichloro-4-hydroxy-1-(2-isopropyl-4-methylpyridin-3-yl)-1,8-naphthyridin-2(1H)-one (24 g, Y: 85.7%), a light brown solid. ES-API: [M+H] + = 364.1.

[0529] Step 2: Dissolve 6,7-dichloro-4-hydroxy-1-(2-isopropyl-4-methylpyridin-3-yl)-1,8-naphthyridin-2(1H)-one (3.16 g, 8.705 mmol) in acetic acid (15 mL), successively add sodium nitrite (100 mg, 1.58 mmol) and concentrated nitric acid (5.0 mL, 74.52 mmol), and stir the reaction at room temperature for 30 minutes. Slowly pour the reaction solution into 100 mL of ice water, filter the precipitated solid, wash the filter cake with 20 mL of ice water, and dry under vacuum to obtain the product 6,7-dichloro-4-hydroxy-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro-1,8-naphthyridin-2(1H)-one (3.5 g, Y: 92%), a yellow solid. ES-API: [M+H] + = 409.1.

[0530] Step 3: Add 6,7-dichloro-4-hydroxy-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro-1,8-naphthyridin-2(1H)-one (3.5 g, 8.570 mmol), (2-fluoro-6-methoxyphenyl)boronic acid (5.8 g, 34.10 mmol), tetrakis(triphenylphosphine)palladium(0) (1.15 g, 0.9956 mmol), sodium carbonate (3.5 g, 33.02 mmol), 10 mL of water and 40 mL of dioxane into a 100 mL three-necked round-bottom flask. Under nitrogen protection, the reaction is stirred at 100 °C for 2 - 3 hours. After the reaction is completed, the reaction solution is cooled to room temperature, 80 mL of water and 100 mL of methyl tert-butyl ether are added, and extraction is carried out once. The aqueous phase is adjusted to pH 3 - 5 with 1 M hydrochloric acid solution, and extracted with ethyl acetate (200 mL × 2). The ethyl acetate phases are combined, dried over anhydrous sodium sulfate, filtered, and the filtrate is dried under vacuum to obtain the product 6-chloro-7-(2-fluoro-6-methoxyphenyl)-4-hydroxy-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro-1,8-naphthyridin-2(1H)-one (4.5 g, crude product), a pale yellow solid. ES-API: [M+H] + = 499.1.

[0531] Step 4: 6-Chloro-7-(2-fluoro-6-methoxyphenyl)-4-hydroxy-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro-1,8-naphthyridin-2(1H)-one (4.6 g, 8.57 mmol) is dissolved in acetonitrile (30 mL), phosphorus oxychloride (7.5 g, 48.92 mmol) and N,N-diisopropylethylamine (10.5 g, 81.24 mmol) are added successively. The reaction gradually rises to 80 °C and is stirred for 30 minutes. The reaction solution is concentrated, 30 mL of cold acetonitrile is added, and the mixture is added dropwise to 150 mL of saturated sodium bicarbonate solution under an ice-water bath. It is extracted with ethyl acetate (200 mL × 2), the ethyl acetate phases are combined, and washed once with 200 mL of saturated brine. After drying over anhydrous sodium sulfate, filtering, and concentrating the organic phase, the crude product is purified by flash silica gel column (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-naphthyridin-2(1H)-one (3.05 g, Y: 76%), a yellow solid. ES-API: [M+H] + = 517.2.

[0532] Step 5: 4,6-Dichloro-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro-1,8-naphthyridin-2(1H)-one (2.5 g, 4.843 mmol) was dissolved in N,N-dimethylacetamide (25 mL). 1-(tert-Butyl) 3-methyl (R)-piperazine-1,3-dicarboxylate (3.5 g, 14.34 mmol) and N,N-diisopropylethylamine (2.0 g, 15.47 mmol) were added successively. The reaction was stirred at 120 °C for 2 h. 80 mL of ethyl acetate was added to the reaction solution, and it was washed three times with 80 mL of saturated brine. The ethyl acetate phase was dried and concentrated. The crude product was purified by flash silica gel column (EtOAc / PE: 0 - 80%) to obtain the product 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-naphthyridin-4-yl)piperazine-1,3-dicarboxylate (2.7 g, Y: 77%), a yellow solid. ES-API: [M+H] + = 725.2.

[0533] 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-naphthyridin-4-yl)piperazine-1,3-dicarboxylate (2.7 g, 3.728 mmol) was dissolved in acetic acid (30 mL). Iron powder (835 mg, 14.91 mmol) was added. The reaction was stirred at 80 °C for 30 min. The reaction solution was concentrated. 200 mL of ethyl acetate and 100 mL of saturated sodium bicarbonate were added successively. The suspension was filtered through diatomaceous earth, and the filter cake was washed with ethyl acetate. The organic phase was separated and washed successively with 100 mL of saturated sodium bicarbonate and 150 mL of saturated brine, dried and concentrated to obtain the product tert-butyl (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]naphthyridine-3-carboxylate (2.70 g, crude product), a yellow solid. ES-API: [M+H]+ = 663.2.

[0534] Step 7: Add tert-butyl (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]naphthyridine-3-carboxylate (250 mg, 0.3774 mmol), 4 mL of dichloromethane, and 4 mL of trifluoroacetic acid into a 100 mL single-necked flask in sequence. Stir at room temperature for 2 hours. Concentrate the reaction solution 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]naphthyridine-5,7-dione (300 mg, crude product), which is directly used for the next reaction. ES-API: [M+H] + = 563.2.

[0535] Step 8: Dissolve (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]naphthyridine-5,7-dione (300 mg, 0.3774 mmol) in dichloromethane (10 mL), and add triethylamine (3.0 mL, 21.62 mmol). Cool the reaction to 0 °C, and dropwise add acryloyl chloride (50 mg, 0.5524 mmol) to the reaction solution. Stir the reaction at 0 °C for 15 minutes. Add 80 mL of dichloromethane to the reaction solution, wash it with 100 mL of saturated aqueous NaHCO3 solution and 80 mL of saturated brine, concentrate after drying, and purify the crude product by flash silica gel column (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]naphthyridine-5,7-dione (243 mg, crude product), a yellow solid. ES-API: [M+H] + = 617.2.

[0536] Step 9: Under ice-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]naphthyridine-5,7-dione (243 mg, 0.3774 mmol) was added to dry dichloromethane (6.0 mL), and then boron tribromide (5.0 mL, 5.0 mmol) was added. The mixture was warmed to room temperature and reacted overnight. Under ice-bath conditions, the above reaction solution was added dropwise to saturated sodium bicarbonate solution, and 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]naphthyridine-5,7-dione (Z24, 76 mg, Y: 32%). [M+H] + = 603.2.

[0537] 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: room temperature) to obtain: a atropisomer 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 atropisomer compound, arbitrarily designated as Z24-2 (21.4 mg, peak 2, retention time 3.985 min, Y: 28%), ES-API: [M+H] + = 603.2. The isomer compounds 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).

[0538] Example 25 Preparation of Compounds Z25, Z25-1 and Z25-2

[0539]

[0540] Step 1: Suspend 6,7-dichloro-4-hydroxy-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile (30.0 g, 77.319 mmol) in a mixed solution of 1,4-dioxane (120 mL) and water (120 mL), and slowly add concentrated sulfuric acid (120 mL). Stir the reaction at 120 °C for 36 hours. Pour the cooled reaction solution into 200 mL of ice water, adjust the pH to 2 - 3 with sodium carbonate, extract with ethyl acetate (1000 mL × 2), combine the ethyl acetate phases, dry over anhydrous sodium sulfate, filter, and dry the filtrate under vacuum to obtain the product 6,7-dichloro-4-hydroxy-1-(2-isopropyl-4-methylpyridin-3-yl)-1,8-naphthyridin-2(1H)-one (24 g, Y: 85.7%), a light brown solid. ES-API: [M+H] + = 364.1.

[0541] Step 2: Dissolve 6,7-dichloro-4-hydroxy-1-(2-isopropyl-4-methylpyridin-3-yl)-1,8-naphthyridin-2(1H)-one (3.16 g, 8.705 mmol) in acetic acid (15 mL), and successively add sodium nitrite (100 mg, 1.58 mmol) and concentrated nitric acid (5.0 mL, 74.52 mmol). Stir the reaction at room temperature for 30 minutes. Slowly pour the reaction solution into 100 mL of ice water, filter the precipitated solid, wash the filter cake with 20 mL of ice water, and dry under vacuum to obtain the product 6,7-dichloro-4-hydroxy-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro-1,8-naphthyridin-2(1H)-one (3.5 g, Y: 92%), a yellow solid. ES-API: [M+H] + = 409.1.

[0542] Step 3: Add 6,7-dichloro-4-hydroxy-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro-1,8-naphthyridin-2(1H)-one (3.5 g, 8.570 mmol), (2-fluoro-6-methoxyphenyl)boronic acid (5.8 g, 34.10 mmol), tetrakis(triphenylphosphine)palladium(0) (1.15 g, 0.9956 mmol), sodium carbonate (3.5 g, 33.02 mmol), 10 mL of water and 40 mL of dioxane into a 100 mL three-necked round-bottom flask. Under nitrogen protection, the reaction is stirred at 100 °C for 2 - 3 hours. After the reaction is completed, the reaction solution is cooled to room temperature, 80 mL of water and 100 mL of methyl tert-butyl ether are added, and extraction is carried out once. The aqueous phase is adjusted to pH 3 - 5 with 1 M hydrochloric acid solution, and extracted with ethyl acetate (200 mL × 2). The ethyl acetate phases are combined, dried over anhydrous sodium sulfate, filtered, and the filtrate is dried under vacuum to obtain the product 6-chloro-7-(2-fluoro-6-methoxyphenyl)-4-hydroxy-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro-1,8-naphthyridin-2(1H)-one (4.5 g, crude product), a pale yellow solid. ES-API: [M+H] + = 499.1.

[0543] Step 4: Dissolve 6-chloro-7-(2-fluoro-6-methoxyphenyl)-4-hydroxy-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro-1,8-naphthyridin-2(1H)-one (4.6 g, 8.57 mmol) in acetonitrile (30 mL), and successively add phosphorus oxychloride (7.5 g, 48.92 mmol) and N,N-diisopropylethylamine (10.5 g, 81.24 mmol). The reaction is gradually heated to 80 °C and stirred for 30 minutes. The reaction solution is concentrated, 30 mL of cold acetonitrile is added, and the mixture is added dropwise to 150 mL of saturated sodium bicarbonate solution under an ice-water bath. It is extracted with ethyl acetate (200 mL × 2), the ethyl acetate phases are combined, and washed once with 200 mL of saturated brine. After drying over anhydrous sodium sulfate, filtering, and concentrating the organic phase, the crude product is purified by flash silica gel column (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-naphthyridin-2(1H)-one (3.05 g, Y: 76%), a yellow solid. ES-API: [M+H] + = 517.2.

[0544] Step 5: 4,6-Dichloro-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro-1,8-naphthyridin-2(1H)-one (2.5 g, 4.843 mmol) was dissolved in N,N-dimethylacetamide (25 mL). 1-(tert-Butyl) 3-methyl (R)-piperazine-1,3-dicarboxylate (3.5 g, 14.34 mmol) and N,N-diisopropylethylamine (2.0 g, 15.47 mmol) were added successively. The reaction was stirred at 120 °C for 2 h. 80 mL of ethyl acetate was added to the reaction solution, and it was washed three times with 80 mL of saturated brine. The ethyl acetate phase was dried and concentrated. The crude product was purified by flash silica gel column (EtOAc / PE: 0-80%) to obtain the product 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-naphthyridin-4-yl)piperazine-1,3-dicarboxylate (2.7 g, Y: 77%), a yellow solid. ES-API: [M+H] + = 725.2.

[0545] 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-naphthyridin-4-yl)piperazine-1,3-dicarboxylate (2.7 g, 3.728 mmol) was dissolved in acetic acid (30 mL). Iron powder (835 mg, 14.91 mmol) was added. The reaction was stirred at 80 °C for 30 min. The reaction solution was concentrated. 200 mL of ethyl acetate and 100 mL of saturated sodium bicarbonate were added successively. The suspension was filtered through diatomaceous earth. The filter cake was washed with ethyl acetate. The organic phase was separated and washed successively with 100 mL of saturated sodium bicarbonate and 150 mL of saturated brine, dried and concentrated to obtain the product tert-butyl (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]naphthyridine-3-carboxylate (2.70 g, crude product), a yellow solid. ES-API: [M+H]+ = 663.2.

[0546] Step 7: Add tert-butyl (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]naphthyridine-3-carboxylate (2.7 g, 3.728 mmol), 30 mL of acetone, potassium carbonate anhydrous (2.2 g, 15.94 mmol), and methyl iodide (5.4 g, 38.03 mmol) into a 150 mL sealed tube in sequence. Seal the tube and stir the reaction at 55 °C for 18 hours. Add 150 mL of ethyl acetate to the reaction solution, wash it three times with 100 mL of saturated brine, dry and concentrate it. Purify the crude product by flash silica gel column (EtOAc / PE: 0 - 80%) to obtain the product tert-butyl (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]naphthyridine-3-carboxylate (2.2 g, Y: 87%), a yellow solid. ES-API: [M+H] + = 677.2.

[0547] Step 8: Dissolve tert-butyl (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]naphthyridine-3-carboxylate (517 mg, 0.7549 mmol) in dichloromethane (8 mL), and add trifluoroacetic acid (2 mL). Stir at room temperature for 2 hours, and concentrate the reaction solution 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]naphthyridine-5,7-dione (530 mg, crude product), which is directly used in the next step. ES-API: [M+H] + = 577.2.

[0548] 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]naphthyridine-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. 80 mL of dichloromethane was added to the reaction solution, and it was washed with 100 mL of saturated aqueous NaHCO3 solution and 80 mL of saturated brine, dried and concentrated. The crude product was purified by flash silica gel column (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]naphthyridine-5,7-dione (280 mg, Y: 59%), a yellow solid. ES-API: [M+H] + = 631.2.

[0549] 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]naphthyridine-5,7-dione (280 mg, 0.444 mmol) was added to dry dichloromethane (6.0 mL), and boron tribromide (5.0 mL, 5.0 mmol) was added. The temperature was raised to room temperature, and the reaction was carried out overnight. Under ice-water bath conditions, the above reaction solution was added dropwise to saturated sodium bicarbonate saturated solution, and extracted twice with dichloromethane (80 mL), dried, concentrated. The crude product was purified by flash silica gel column (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]naphthyridine-5,7-dione (Z25, 233 mg, Y: 85%).

[0550] Step 11: Compound Z25 was resolved 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: room temperature) to obtain: a atropisomer compound Z25-1 (76.8 mg, peak 1, retention time 2.531 min, Y: 34%). 1 H NMR (500 MHz, DMSO-d6) δ 10.03 (d, J = 18.4 Hz, 1H), 8.52 (d, J = 7.3 Hz, 1H), 8.43 (d, J = 4.7 Hz, 1H), 7.23 (d, J = 9.6 Hz, 2H), 7.08 (dd, J = 16.6, 10.5 Hz, 1H), 6.74–6.62 (m, 2H), 6.15 (d, J = 16.8 Hz, 1H), 5.75 (d, J = 10.7 Hz, 1H), 4.73 (d, J = 14.2 Hz, 1H), 4.46 (d, J = 12.9 Hz, 1H), 4.00 (s, 1H), 3.61 (d, J = 10.0 Hz, 1H), 3.51 (s, 1H), 3.34 (s, 3H), 3.22 (s, 1H), 2.64 (t, J = 11.5 Hz, 1H), 2.48–2.42 (m, 1H), 1.98 (d, J = 5.1 Hz, 3H), 1.03 (t, J = 6.9 Hz, 3H), 0.86 (t, J = 7.9 Hz, 3H). ES-API: [M+H] + = 617.2. And another atropisomer compound Z25-2 (70 mg, peak 2, retention time 3.683 min, Y: 31%). 1 H NMR (500 MHz, CDCl3) δ 8.64–8.59 (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, 2.0 Hz, 1H), 5.88–5.77 (m, 1H), 4.91 (d, J = 14.0 Hz, 1H), 4.83 (d, J = 13.0 Hz, 1H), 3.72–3.58 (m, 2H), 3.50 (s, 3H), 3.43 (d, J = 12.0 Hz, 1H), 3.16 (t, J = 13.0 Hz, 1H), 2.91 (t, J = 12.0 Hz, 1H), 2.82 - 2.73 (m, 1H), 1.93 (s, 3H), 1.24 (d, J = 7.0 Hz, 3H), 1.12 (d, J = 7.0 Hz, 3H). ES-API: [M+H] += 617.2. The isomeric compounds were detected by an analytical chiral HPLC method (column type: IA: 5 μm, 4.6 * 150 mm, mobile phase: hexane: EtOH = 60:40, flow rate: 1 ml / min, column temperature = 30 °C).

[0551] Example 26 Preparation of Compounds Z26, Z26-1 and Z26-2

[0552]

[0553] 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]naphthyridine-3-carboxylic acid tert-butyl ester (511 mg, 0.7549 mmol) was dissolved in dichloromethane (8 mL), and trifluoroacetic acid (2 mL) was added. Stirred at room temperature for 2 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)-6-(methyl-d3)-2,3,4,4a,6,8-hexahydro-1H-pyrazino[1’,2’:4,5]pyrazino[2,3-c][1,8]naphthyridine-5,7-dione (520 mg, crude product), which was directly used in the next step. ES-API: [M+H] + = 580.3.

[0554] 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]naphthyridine-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. 80 mL of dichloromethane was added to the reaction solution, and it was washed with 100 mL of saturated aqueous NaHCO3 solution and 80 mL of saturated brine, dried and concentrated. The crude product was purified by flash silica gel column (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]naphthyridine-5,7-dione (232 mg, Y: 48%), a yellow solid. ES-API: [M+H] + = 634.2.

[0555] 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]naphthyridine-5,7-dione (240 mg, 0.3791 mmol) was added to dry dichloromethane (6.0 mL), and boron tribromide (5.0 mL, 5.0 mmol) was added. The temperature was raised to room temperature, and the reaction was carried out overnight. Under ice-water bath conditions, the above reaction solution was added dropwise to saturated sodium bicarbonate saturated solution, and extracted twice with dichloromethane (80 mL), dried and concentrated. The crude product was purified by flash silica gel column (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-d3)-2,3,4,4a,6,8-hexahydro-1H-pyrazino[1’,2’:4,5]pyrazino[2,3-c][1,8]naphthyridine-5,7-dione (Z26, 187 mg, Y: 79%). [M+H] + = 620.3.

[0556] Step 4: The compound Z26 (187 mg, 0.302 mmol) was resolved 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: room temperature) to obtain: a atropisomer compound, arbitrarily designated as Z26-1 (68.8 mg, peak 1, retention time 2.525 min, Y: 36.7%). 1 H NMR (500 MHz, DMSO-d6) δ 10.03 (d, J = 17.9 Hz, 1H), 8.51 (d, J = 7.4 Hz, 1H), 8.43 (d, J = 4.7 Hz, 1H), 7.29–7.18 (m, 2H), 7.08 (dd, J = 17.0, 10.6 Hz, 1H), 6.74–6.61 (m, 2H), 6.15 (d, J = 16.6 Hz, 1H), 5.75 (d, J = 11.5 Hz, 1H), 4.73 (d, J = 13.5 Hz, 1H), 4.46 (d, J = 12.3 Hz, 1H), 4.00 (s, 1H), 3.61 (d, J = 10.5 Hz, 1H), 3.50 (s, 1H), 3.22 (s, 1H), 2.65 (t, J = 12.5 Hz, 1H), 2.49–2.42 (m, 1H), 1.98 (d, J = 5.0 Hz, 3H), 1.02 (d, J = 7.0 Hz, 3H), 0.86 (t, J = 7.9 Hz, 3H). ES-API: [M+H] + = 620.3. And another atropisomer compound, arbitrarily designated as Z26-2 (63.2 mg, peak 2, retention time 3.683 min, Y: 33.79%). 1 H NMR (400 MHz, CDCl3) δ 8.62 (d, J = 4.8 Hz, 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, 2.0 Hz, 1H), 5.82 (dd, J = 10.4, 2.0 Hz, 1H), 4.91 (d, J = 13.6 Hz, 1H), 4.83 (d, J = 13.6 Hz, 1H), 3.71–3.57 (m, 2H), 3.42 (d, J = 12.0 Hz, 1H), 3.16 (t, J = 12.8 Hz, 1H), 2.91 (t, J = 12.0 Hz, 1H), 2.81 - 2.70 (m, 1H), 1.92 (s, 3H), 1.22 (d, J = 6.8 Hz, 3H), 1.10 (d, J = 6.8 Hz, 3H). ES-API: [M+H] += 620.3. The isomeric compounds were detected by an analytical chiral HPLC method (column type: IA: 5 μm, 4.6 * 150 mm, mobile phase: hexane: EtOH = 60:40, flow rate: 1 ml / min, column temperature = 30 °C).

[0557] Example 27 Preparation of Compounds Z27, Z27-1 and Z27-2

[0558]

[0559] Step 1: 4,6-Dichloro-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro-1,8-naphthyridin-2(1H)-one (500 mg, 0.9686 mmol) was dissolved in N,N-dimethylacetamide (5 mL). 1-(tert-Butyl) 3-methyl (3R,6R)-6-methylpiperazine-1,3-dicarboxylate (375 mg, 1.452 mmol) and N,N-diisopropylethylamine (375 mg, 2.907 mmol) were added successively. The reaction was stirred at 120 °C for 2 hours. 80 mL of ethyl acetate was added to the reaction solution, and it was washed three times with 80 mL of saturated brine. The ethyl acetate phase was dried and concentrated, and the crude product was purified by flash silica gel column (EtOAc / PE: 0 - 80%) to obtain the product 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-naphthyridin-4-yl)-6-methylpiperazine-1,3-dicarboxylate (535 mg, Y: 74.5%), a yellow solid. ES-API: [M+H] + = 739.2.

[0560] 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-naphthyridin-4-yl)-6-methylpiperazine-1,3-dicarboxylate (530 mg, 0.7179 mmol) was dissolved in acetic acid (6 mL), iron powder (200 mg, 3.571 mmol) was added, and the reaction was stirred at 80 °C for 30 minutes. The reaction solution was concentrated, 200 mL of ethyl acetate and 100 mL of saturated sodium bicarbonate were added successively. The suspension was filtered through diatomaceous earth, the filter cake was washed with ethyl acetate, the organic phase was separated, and it was washed successively with 100 mL of saturated sodium bicarbonate and 150 mL of saturated brine, dried and concentrated to obtain the product tert-butyl (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]pyrido[2,3-c][1,8]naphthalene-3-carboxylate (452 mg, Y: 92%), a yellow solid. ES-API: [M+H] + = 677.2.

[0561] Step 3: (2R,4aR)-tert-Butyl 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]pyrido[2,3-c][1,8]naphthalene-3-carboxylate (445 mg, 0.6583 mmol), 10 mL of acetone, potassium carbonate anhydrous (500 mg, 2.633 mmol), and methyl iodide (1.20 g, 6.5828 mmol) were successively added to a 150 mL sealed tube. The sealed tube was sealed, and the reaction was stirred at 55 °C for 18 hours. The reaction solution was added with 150 mL of ethyl acetate, washed 3 times with 100 mL of saturated brine, dried and concentrated, and the crude product was purified by flash silica gel column (EtOAc / PE: 0 - 80%) to obtain the product tert-butyl (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]pyrido[2,3-c][1,8]naphthalene-3-carboxylate (455 mg, crude), a yellow solid. ES-API: [M+H] + = 691.3.

[0562] Step 4: tert-Butyl (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]naphthalene-3-carboxylate (511 mg, 0.7549 mmol) was dissolved in dichloromethane (8 mL), and trifluoroacetic acid (2 mL) was added. The mixture was stirred at room temperature for 2 h, and the reaction solution was 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]naphthalene-5,7-dione (462 mg, crude product), which was directly used in the next step. ES-API: [M+H] + = 591.3.

[0563] 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]naphthalene-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 min. 80 mL of dichloromethane was added to the reaction solution, and the mixture was washed with 100 mL of saturated aqueous NaHCO3 solution and 80 mL of saturated brine, dried and concentrated. The crude product was purified by flash silica gel column (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]naphthalene-5,7-dione (290 mg, Y: 68%), a yellow solid. ES-API: [M+H] + = 645.2.

[0564] Step 6: Under ice-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]naphthyridine-5,7-dione (290 mg, 0.4503 mmol) was added to dry dichloromethane (6.0 mL), and then boron tribromide (6.0 mL, 6.0 mmol) was added. The mixture was warmed to room temperature and reacted overnight. Under ice-bath conditions, the above reaction solution was dropped into saturated sodium bicarbonate solution, and extracted twice with dichloromethane (80 mL), dried, concentrated, and the crude product was purified by flash silica gel column (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]naphthyridine-5,7-dione (Z27, 307 mg, crude product). [M+H] + = 631.2.

[0565] Step 7: Compound Z27 was resolved 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: room temperature) to obtain: one atropisomer compound Z27-1 (67.7 mg, peak 1, retention time 2.394 min, Y: 23.4%). 11H NMR (500 MHz, DMSO-d6) δ 10.05 (d, J = 17.8 Hz, 1H), 8.43 (d, J = 4.8 Hz, 1H), 8.23 (d, J = 9.9 Hz, 1H), 7.23 (d, J = 9.9 Hz, 2H), 7.02 (dd, J = 16.8, 10.6 Hz, 1H), 6.74–6.63 (m, 2H), 6.15 (dd, J = 16.8, 2.3 Hz, 1H), 5.76 (dd, J = 10.5, 2.3 Hz, 1H), 4.78 (s, 1H), 4.60 (d, J = 13.8 Hz, 1H), 4.00 (d, J = 3.5 Hz, 1H), 3.75 (dd, J = 14.1, 3.9 Hz, 1H), 3.41–3.33 (m, 1H), 3.34 (s, 3H), 2.81 (d, J = 12.1 Hz, 1H), 2.48–2.42 (m, 1H), 1.98 (s, 3H), 1.53 (d, J = 6.7 Hz, 3H), 1.03 (d, J = 5.5 Hz, 3H), 0.85 (t, J = 6.2 Hz, 3H). ES-API: [M+H] + = 631.2. And another atropisomer compound Z27-2 (64.6 mg, peak 2, retention time 3.382 min, Y: 23.2%). 1 1H NMR (400 MHz, CDCl3) δ 8.57 (d, J = 4.8 Hz, 1H), 8.36 (s, 1H), 8.28 (s, 1H), 7.25–7.15 (m, 2H), 7.03 (dd, J = 16.8, 10.8 Hz, 1H), 6.72–6.61 (m, 2H), 6.34 (dd, J = 16.8, 2.0 Hz, 1H), 5.80 (dd, J = 10.8, 2.0 Hz, 1H), 5.11–5.01 (m, 1H), 4.77 (d, J = 14.0 Hz, 1H), 3.82 (dd, J = 14.0, 4.4 Hz, 1H), 3.61 (d, J = 4.4 Hz, 1H), 3.49 (s, 3H), 3.30–3.17 (m, 1H), 3.03 (dd, J = 12.0, 3.6 Hz, 1H), 2.80 - 2.68 (m, 1H), 1.91 (s, 3H), 1.66 (d, J = 6.8 Hz, 3H), 1.22 (d, J = 6.8 Hz, 3H), 1.08 (d, J = 6.8 Hz, 3H). ES-API: [M+H] + = 631.2. The isomer compounds were detected by an analytical chiral HPLC method (column type: IA: 5 μm, 4.6 * 150 mm, mobile phase: hexane: EtOH = 60:40, flow rate: 1 ml / min, column temperature = 30 °C).

[0566] Example 28 Preparation of Compound Z28

[0567]

[0568] Step 1: 4-Chloro-6-fluoro-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro-1,8-naphthyridin-2(1H)-one (400 mg, 0.80 mmol) was dissolved in DMF (5 mL), (S)-tert-Butyl 3-(hydroxymethyl)piperazine-1-carboxylate (432 mg, 2.00 mmol) and N,N-diisopropylethylamine (310 mg, 2.40 mmol) were added, and the reaction was stirred at 75 °C for 2 h. The reaction solution was diluted with 100 mL of ethyl acetate, washed 5 times with 40 mL of saturated brine, dried and concentrated. The crude product was purified by flash silica gel column (EtOAc / PE: 0 - 70%) to obtain the product (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-naphthyridin-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. + = 681.3.

[0569] 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-naphthyridin-4-yl)-3-(hydroxymethyl)piperazine-1-carboxylic acid tert-butyl ester (420 mg, 0.62 mmol) was dissolved in DMA (20 mL), LiHMDS (1.55 mL, 1.55 mmol, 1.0 M in THF) was added, and the reaction was slowly heated to 140 °C and stirred for 24 h. The reaction solution was diluted with 100 mL of ethyl acetate, washed 4 times with 40 mL of dilute brine and 1 time with 40 mL of saturated brine, dried and concentrated. The crude product was purified by flash silica gel column (EtOAc / PE: 0 - 100%) to obtain the product (4aS)-11-Fluoro-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]naphthyridine-3(4H)-carboxylic acid tert-butyl ester (180 mg, Y: 46.0%), a yellow solid. ES-API: [M+H]+ = 634.3.

[0570] Step 3: tert-Butyl (4aS)-11-fluoro-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]naphthalene-3(4H)-carboxylate (35 mg, 0.055 mmol) was dissolved in dichloromethane (4 mL), and trifluoroacetic acid (1 mL) was added. The mixture was stirred at room temperature for 1 hour, and the reaction solution was 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-hexahydropyrazino[1’,2’:4,5][1,4]oxazino[2,3-c][1,8]naphthalen-7(8H)-one (185 mg, crude product), which was directly used in the next step. ES-API: [M+H] + = 534.3.

[0571] Step 4: (4aS)-11-fluoro-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]naphthalen-7(8H)-one (185 mg, crude product) 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 solution of acryloyl chloride (50 mg, 0.56 mmol) in dichloromethane (0.5 mL) was added dropwise to the reaction solution. The reaction was stirred at 0 °C for 15 minutes. 50 mL of dichloromethane was added to the reaction solution, and the mixture was washed successively with 15 mL of water, 15 mL of saturated aqueous NaHCO3 solution twice, and 15 mL of saturated brine. The organic phase was dried and concentrated 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-hexahydropyrazino[1’,2’:4,5][1,4]oxazino[2,3-c][1,8]naphthalen-7(8H)-one (160 mg, Y: 95.8%), a yellow solid. ES-API: [M+H] + = 588.3.

[0572] 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-hexahydropyrazino[1’,2’:4,5][1,4]oxazino[2,3-c][1,8]naphthalen-7(8H)-one (160 mg, 0.27 mmol) was dissolved in dichloromethane (4 mL). The reaction was cooled to 0 °C, and a solution of 17% boron tribromide in dichloromethane (3 mL) was added dropwise thereto. The reaction was stirred at room temperature for 3 hours. The reaction solution was poured into 25 mL of cold saturated aqueous NaHCO3, and extracted with 50 mL of dichloromethane. The organic phase was washed successively with 25 mL of saturated aqueous NaHCO3 and 25 mL of saturated brine, dried and concentrated. The crude product was purified by preparative HPLC to give 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-hexahydropyrazino[1',2':4,5][1,4]oxazino[2,3-c][1,8]naphthalen-7(8H)-one (Z28, 90 mg, Y: 57.6%), a pale yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 10.04 (s, 1H), 8.42 (d, J = 4.8 Hz, 1H), 8.22 (d, J = 7.4 Hz, 1H), 7.27 - 7.17 (m, 2H), 7.01–6.78 (m, 1H), 6.77–6.58 (m, 2H), 6.18 (d, J = 16.3 Hz, 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.

[0573] Example 29 Preparation of Compound Z29

[0574]

[0575] Step 1: 7-Chloro-6-fluoro-4-hydroxy-1-(2-isopropyl-4-methylpyridin-3-yl)-1,8-naphthyridin-2(1H)-one (4.0 g, 11.53 mmol) was dissolved in acetic acid (9 mL). Sodium nitrite (79 mg, 1.15 mmol) and concentrated nitric acid (2.3 mL, 34.6 mmol) were added successively, and the reaction was stirred at room temperature for 30 minutes. The reaction solution was slowly poured into 100 mL of ice water, and the precipitated solid was filtered. 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-naphthyridin-2(1H)-one (3.1 g, Y: 80%), a yellow solid. ES-API: [M+H] + = 393.1.

[0576] Step 2: 7-Chloro-6-fluoro-4-hydroxy-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro-1,8-naphthyridin-2(1H)-one (1.0 g, 2.55 mmol), (5-methyl-1H-indazol-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 were added to a 100 mL three-necked round-bottom flask. Under nitrogen protection, the reaction was stirred at 110 °C for 1 hour. After the reaction was completed, the reaction solution was cooled to room temperature, 80 mL of water and 100 mL of methyl tert-butyl ether were added, and extraction was carried out once. The aqueous phase was adjusted to pH 3 - 4 with 1 M hydrochloric acid solution, and a solid precipitated. After filtration, the solid product was dried under vacuum to obtain the product 6-fluoro-7-(5-methyl-1H-indazol-4-yl)-4-hydroxy-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro-1,8-naphthyridin-2(1H)-one (0.8 g, 50%), a pale yellow solid. ES-API: [M+H] + = 489.2.

[0577] Step 3: 6-Fluoro-7-(5-methyl-1H-indazol-4-yl)-4-hydroxy-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro-1,8-naphthyridin-2(1H)-one (0.6 g, 1.23 mmol) was dissolved in acetonitrile (20 mL). Phosphorus oxychloride (0.94 g, 6.15 mmol) and N,N-diisopropylethylamine (1.27 g, 9.84 mmol) were added successively. The reaction was gradually heated to 80 °C and stirred for 24 h. The reaction solution was concentrated, 30 mL of cold acetonitrile was added, and the mixture was added dropwise to 30 mL of saturated sodium bicarbonate solution under an ice-water bath. It was extracted with ethyl acetate (200 mL × 2). The ethyl acetate phases were combined and washed once with 50 mL of saturated brine. After drying over anhydrous sodium sulfate, filtration, and concentration of the organic phase, the crude product was purified by flash silica gel column (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-naphthyridin-2(1H)-one (0.3 g, Y: 50%), a yellow solid. ES-API: [M+H] + = 507.0.

[0578] Step 4: 4-Chloro-6-fluoro-7-(5-methyl-1H-indazol-4-yl)-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro-1,8-naphthyridin-2(1H)-one (150 mg, 0.296 mmol) was dissolved in N,N-dimethylacetamide (25 mL). (R)-tert-Butyl 3-(hydroxymethyl)piperazine-1-carboxylate (1.48 g, 3.20 mmol) was added successively. The reaction was stirred at 80 °C for 1.5 h. 80 mL of ethyl acetate was added to the reaction solution, and it was washed three times with 80 mL of saturated brine. The ethyl acetate phase was dried and concentrated. The crude product was purified by flash silica gel column (EtOAc / PE: 0 - 80%) to obtain the product (3R)-tert-butyl 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-naphthyridin-4-yl)-3-(hydroxymethyl)piperazine-1-carboxylate (10 mg, Y: 40%), a yellow solid. ES-API: [M+H] + = 787.3.

[0579] Step 5: (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-naphthyridin-4-yl)-3-(hydroxymethyl)piperazine-1-carboxylic acid tert-butyl ester (90 mg, 0.13 mmol) was dissolved in N,N-dimethylacetamide (25 mL), sodium hydride (15.7 mg, 0.39 mmol) was added, and the reaction was stirred at 130 °C for 18 h. After cooling to room temperature, it was poured into ice water, adjusted to pH = 7 with 3 M hydrochloric acid, 30 mL of ethyl acetate was added, the organic phase was separated, washed successively with 30 mL of water and 30 mL of saturated brine, dried and concentrated 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]oxazino[2,3-c][1,8]naphthyridine-3(4H)-carboxylic acid tert-butyl ester (60 mg, Y: 70%), a yellow solid. ES-API: [M+H] + = 640.3.

[0580] Step 6: (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]oxazino[2,3-c][1,8]naphthyridine-3(4H)-carboxylic acid tert-butyl ester (60 mg, 0.094 mmol) was dissolved in dichloromethane (4 mL), and trifluoroacetic acid (2 mL) was added. The reaction was stirred at room temperature for 2 h, and the reaction solution was 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]oxazino[2,3-c][1,8]naphthyridin-7(8H)-one (50 mg, crude product), which was directly used in the next step. ES-API: [M+H] + = 540.2.

[0581] 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]oxazino[2,3-c][1,8]naphthalen-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, and it was washed with 20 mL of saturated aqueous NaHCO3 and 20 mL of saturated brine, dried and concentrated, and purified by preparative HPLC to obtain 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]oxazino[2,3-c][1,8]naphthalen-7(8H)-one (Z29, 15 mg, Y: 28%). ES-API: [M+H] + = 594.2. 1 H NMR (500 MHz, DMSO-d6) δ 13.08 (s, 1H), 8.37 (d, J = 4.8 Hz, 1H), 8.32 (d, J = 9.4 Hz, 1H), 7.49 (d, J = 8.1 Hz, 2H), 7.24 (d, J = 8.5 Hz, 1H), 7.20 (d, J = 5.0 Hz, 1H), 6.90 (s, 1H), 6.20 (d, J = 16.7 Hz, 1H), 5.78 (s, 1H), 4.45 (d, J = 46.5 Hz, 1H), 4.35–4.20 (m, 2H), 4.05 (s, 1H), 3.85 (d, J = 51.4 Hz, 1H), 3.75–3.57 (m, 2H), 3.48 (s, 1H), 3.15 (s, 1H), 2.05 (s, 3H), 1.90 (d, J = 33.7 Hz, 3H), 1.03 (t, J = 6.7 Hz, 3H), 0.81 (dd, J = 20.9, 6.4 Hz, 3H).

[0582] Example 30 Preparation of Compounds Z30, Z30-1 and Z30-2

[0583]

[0584] Step 1: Add tert-butyl (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-pyrazino[1’,2’:4,5]pyrazino[2,3-c][1,8]naphthalene-3-carboxylate (310 mg, 0.48 mmol), 10 mL of acetone, potassium carbonate anhydrous (265 mg, 1.92 mmol), and iodoethane (599 mg, 3.84 mmol) successively into a 15 mL sealed tube. Seal the tube and stir the reaction at 55 °C for 18 h. Concentrate the reaction solution, add 60 mL of ethyl acetate, wash successively with 30 mL of water and 30 mL of saturated brine, dry and concentrate. Purify the crude product by flash silica gel column (EtOAc / PE: 0 - 70%) to obtain the product tert-butyl (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-pyrazino[1’,2’:4,5]pyrazino[2,3-c][1,8]naphthalene-3-carboxylate (290 mg, Y: 89.7%), an orange solid. ES-API: [M+H] + = 675.3.

[0585] Step 2: Dissolve tert-butyl (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-pyrazino[1’,2’:4,5]pyrazino[2,3-c][1,8]naphthalene-3-carboxylate (290 mg, 0.43 mmol) in dichloromethane (4 mL), and add trifluoroacetic acid (1 mL). Stir at room temperature for 2 h, concentrate the reaction solution 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-pyrazino[1’,2’:4,5]pyrazino[2,3-c][1,8]naphthalene-5,7-dione (300 mg, crude product), which is directly used in the next step reaction. ES-API: [M+H] + = 575.2.

[0586] 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-pyrazino[1’,2’:4,5]pyrazino[2,3-c][1,8]naphthyridine-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. 45 mL of dichloromethane was added to the reaction solution, and it was washed successively with 25 mL of water, 25 mL of saturated NaHCO3 aqueous solution, and 25 mL of saturated brine, dried and concentrated. After drying, it was concentrated, and the crude product was purified by flash silica gel column (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-pyrazino[1’,2’:4,5]pyrazino[2,3-c][1,8]naphthyridine-5,7-dione (245 mg, Y: 90.7%), a pale yellow solid. ES-API: [M+H] + = 615.3.

[0587] 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-pyrazino[1’,2’:4,5]pyrazino[2,3-c][1,8]naphthyridine-5,7-dione (245 mg, 0.39 mmol) was dissolved in dichloromethane (5 mL). The reaction was cooled to 0 °C, and a dichloromethane solution of 17% boron tribromide (5 mL) was added dropwise thereto. The reaction was stirred at room temperature for 3 hours. The reaction solution 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 obtain 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-pyrazino[1’,2’:4,5]pyrazino[2,3-c][1,8]naphthyridine-5,7-dione (Z30, 240 mg, Y: 100%), a pale yellow solid. ES-API: [M+H] + = 615.3.

[0588] 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: room temperature) to obtain: a atropisomer 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 (500 MHz, DMSO-d6) δ 10.11 (d, J = 1.1 Hz, 1H), 8.45 (d, J = 4.9 Hz, 1H), 8.40 (d, J = 8.8 Hz, 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, 2.0 Hz, 1H), 5.75 (d, J = 12.2 Hz, 1H), 4.72 (d, J = 13.5 Hz, 1H), 4.46 (d, J = 11.9 Hz, 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 = 6.7 Hz, 3H). ES-API: [M+H] + = 615.2. And another atropisomer compound, arbitrarily designated as Z30-2 (73 mg, peak 2, retention time 7.970 min, Y: 30.5%), a pale yellow solid. 1 H NMR (500 MHz, DMSO-d6) δ 10.13 (s, 1H), 8.45 (d, J = 4.9 Hz, 1H), 8.39 (d, J = 8.8 Hz, 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, 2.1 Hz, 1H), 5.75 (d, J = 12.3 Hz, 1H), 4.73 (d, J = 14.1 Hz, 1H), 4.46 (d, J = 13.0 Hz, 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 isomeric compounds were detected by an analytical chiral HPLC method (column type: IB: 5 μm, 4.6 * 250 mm, mobile phase: hexane: EtOH = 70:30, flow rate: 1 ml / min, column temperature = 30 °C).

[0589] Example 31 Preparation of Compound Z31

[0590]

[0591] Step 1: Add 6-chloro-7-(2-fluoro-6-methoxyphenyl)-4-hydroxy-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro-1,8-naphthyridin-2(1H)-one (1.0 g, 2.0 mmol), potassium cyclopropyltrifluoroborate (1.48 g, 10.0 mmol), chloro(2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) (144 mg, 0.20 mmol), 2-dicyclohexylphosphino-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. Under nitrogen protection, the reaction was stirred at 125 °C for 18 hours. The reaction solution was concentrated, 50 mL of water was added, the pH was adjusted to 3.0 with 3.0 M dilute hydrochloric acid, and the mixture was extracted twice with 50 mL of dichloromethane. After drying the organic phase and concentrating, the product 6-cyclopropyl-7-(2-fluoro-6-methoxyphenyl)-4-hydroxy-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro-1,8-naphthyridin-2(1H)-one (850 mg, crude product), a brown solid, was obtained. ES-API: [M+H] + = 505.2.

[0592] Step 2: 6-Cyclopropyl-7-(2-fluoro-6-methoxyphenyl)-4-hydroxy-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro-1,8-naphthyridin-2(1H)-one (1.6 g, crude) was dissolved in acetonitrile (50 mL). Phosphorus oxychloride (2.43 g, 15.85 mmol) and N,N-diisopropylethylamine (3.27 g, 25.36 mmol) were added successively. The reaction was stirred at 85 °C for 1 hour. The reaction solution was concentrated, and 120 mL of ethyl acetate was added. It was washed successively with 60 mL of water, 60 mL of saturated sodium bicarbonate twice, and 60 mL of saturated brine. After the organic phase was dried and concentrated, the crude product was purified by flash silica gel column (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-naphthyridin-2(1H)-one (520 mg, Y: 24.8%), a pale yellow solid. ES-API: [M+H] + = 523.2.

[0593] Step 3: 4-Chloro-6-cyclopropyl-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro-1,8-naphthyridin-2(1H)-one (490 mg, 0.94 mmol) was dissolved in N,N-dimethylacetamide (6 mL). (3R,6R)-1-N-BOC-6-methylpiperazine-3-carboxylic acid methyl ester (485 mg, 1.88 mmol) and N,N-diisopropylethylamine (364 mg, 2.82 mmol) were added successively. The reaction was stirred at 125 °C for 3 hours. 100 mL of ethyl acetate was added to the reaction solution, and it was washed 4 times with 30 mL of dilute brine and 30 mL of saturated brine, dried and concentrated. The crude product was purified by flash silica gel column (EtOAc / PE: 0 - 50%) to obtain the product (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-naphthyridin-4-yl)-6-methylpiperazine-3-carboxylic acid methyl ester (485 mg, Y: 69.4%), an orange solid. ES-API: [M+H] + = 745.3.

[0594] 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-naphthyridin-4-yl)-6-methylpiperazine-3-carboxylate (455 mg, 0.61 mmol) was dissolved in acetic acid (8 mL), iron powder (120 mg, 2.14 mmol) was added, and the reaction was stirred at 80 °C for 30 minutes. The reaction solution was concentrated, 80 mL of ethyl acetate and 50 mL of saturated sodium bicarbonate were added successively. The suspension was filtered through diatomaceous earth, the filter cake was washed with ethyl acetate, the organic phase was separated, and it was washed successively with 25 mL of saturated sodium bicarbonate and 25 mL of saturated brine, dried and concentrated to obtain the product tert-butyl (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-octahydro-3H-pyrazino[1’,2’:4,5]pyrazino[2,3-c][1,8]naphthalene-3-carboxylate (415 mg, Y: 99.5%), a pale yellow solid. ES-API: [M+H]+ = 683.3.

[0595] Step 5: Into a 50 mL sealed tube were successively added tert-butyl (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-octahydro-3H-pyrazino[1’,2’:4,5]pyrazino[2,3-c][1,8]naphthalene-3-carboxylate (415 mg, 0.61 mmol), 12 mL of acetone, potassium carbonate anhydrous (337 mg, 2.44 mmol), and methyl iodide (693 mg, 4.88 mmol). The sealed tube was sealed and the reaction was stirred at 50 °C for 18 hours. The reaction solution was added with 60 mL of ethyl acetate and 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 plate (dichloromethane / methanol = 25:1) to obtain the product tert-butyl (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-octahydro-3H-pyrazino[1’,2’:4,5]pyrazino[2,3-c][1,8]naphthalene-3-carboxylate (160 mg, Y: 37.8%), a pale yellow solid. ES-API: [M+H] + = 697.3.

[0596] Step 6: tert-Butyl (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-octahydro-3H-pyrazino[1’,2’:4,5]pyrazino[2,3-c][1,8]naphthalene-3-carboxylate (160 mg, 0.23 mmol) was dissolved in dichloromethane (3.5 mL), and trifluoroacetic acid (0.8 mL) was added. The mixture was stirred at room temperature for 2 hours, and the reaction solution was 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-3H-pyrazino[4',3':4,5]pyrazino[2,3-c][1,8]naphthalene-5,7-dione (165 mg, crude product), which was directly used in the next step reaction. ES-API: [M+H] + = 597.2.

[0597] 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-3H-pyrazino[4',3':4,5]pyrazino[2,3-c][1,8]naphthalene-5,7-dione (165 mg, crude product) 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. 30 mL of dichloromethane was added to the reaction solution, and it was washed successively with 15 mL of water, 15 mL of saturated aqueous NaHCO3 solution, and 15 mL of saturated brine, dried and concentrated. After drying, it was concentrated, and the crude product was purified by flash silica gel column (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-pyrazino[1’,2’:4,5]pyrazino[2,3-c][1,8]naphthalene-5,7-dione (140 mg, Y: 93.7%), a pale yellow solid. ES-API: [M+H] + = 651.3.

[0598] 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-pyrazino[1’,2’:4,5]pyrazino[2,3-c][1,8]naphthyridine-5,7-dione (130 mg, 0.20 mmol) was dissolved in dichloromethane (3 mL). The reaction was cooled to 0 °C, and a dichloromethane solution (3 mL) of 17% boron tribromide was added dropwise thereto. The reaction was stirred at room temperature for 3 hours. The reaction solution was poured into 40 mL of saturated aqueous NaHCO3, and extracted twice with 25 mL of dichloromethane. After drying the organic phase and concentrating, 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-pyrazino[1’,2’:4,5]pyrazino[2,3-c][1,8]naphthyridine-5,7-dione (Z31, 65 mg, Y: 51.1%), a white solid. 1 H NMR (500 MHz, DMSO-d6) δ 9.90 (s, 1H), 8.42 (d, J = 4.8 Hz, 1H), 7.75 - 7.73 (m, 1H), 7.22 - 7.17 (m, 2H), 7.03 (dd, J = 16.8, 10.5 Hz, 1H), 6.74–6.60 (m, 2H), 6.22–6.08 (m, 1H), 5.81–5.69 (m, 1H), 5.05 - 4.81 (m, 1H), 4.62 - 4.41 (m, 1H), 4.03 - 3.90 (m, 1H), 3.75 (dd, J = 14.1, 4.2 Hz, 1H), 3.39 - 3.25 (m, 4H), 2.83 - 2.67 (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.

[0599] Example 32 Preparation of Compound Z32

[0600]

[0601] Step 1: 4,6-Dicyclopropylpyrimidin-5-amine (742 mg, 4.24 mmol) was dissolved in dry tetrahydrofuran (20 mL). Under ice-water bath conditions, 2 M NaHMDS (8.48 mL, 16.96 mmol) was added, and the mixture was stirred for 20 minutes under ice-water bath conditions. 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 h. The reaction solution was slowly poured into 30 mL of ice water, and the pH was adjusted to 5 - 6 with dilute hydrochloric acid (3 M). It was extracted with ethyl acetate and washed once with 50 mL of saturated brine. Dried over anhydrous sodium sulfate, filtered, and after drying and concentrating the organic phase, the crude product was purified by flash silica gel column (EtOAc / PE: 20 - 40%) to obtain the product 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.

[0602] Step 2: 2-((4,6-Dicyclopropylpyrimidin-5-yl)amino)-5-fluoro-6-(2-fluoro-6-methoxyphenyl)nicotinic acid (1.5 g, 3.42 mmol) was dissolved in dichloroethane, and thionyl chloride (4.07 g, 34.2 mmol) was added. The reaction was stirred at 80 °C for 2 h. After the reaction was completed, the reaction solution was cooled to room temperature, concentrated, and dried under reduced pressure at 50 °C for 4 h to obtain the product 2-((4,6-dicyclopropylpyrimidin-5-yl)amino)-5-fluoro-6-(2-fluoro-6-methoxyphenyl)nicotinoyl chloride (1.57 g, crude product), a pale yellow solid. ES-API detected with methanol: [M + H] + = 453.2.

[0603] Step 3: Under ice-water bath conditions, sodium hydride (1.97 g, 49.35 mmol) was added to ethyl nitrate acetate (1.31 g, 9.86 mmol) in tetrahydrofuran, and the mixture was stirred for 30 minutes. Subsequently, 2-((4,6-dicyclopropylpyrimidin-5-yl)amino)-5-fluoro-6-(2-fluoro-6-methoxyphenyl)nicotinoyl chloride (1.57 g, 3.29 mmol) was added and stirred at room temperature for 1 h, then heated to 80 °C and reacted for 2 h. Poured into ice water, the pH was adjusted to 3 - 4 with 3 M hydrochloric acid, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and after drying and concentrating the organic phase, the product 1-(4,6-dicyclopropylpyrimidin-5-yl)-6-fluoro-7-(2-fluoro-6-methoxyphenyl)-4-hydroxy-3-nitro-1,8-naphthyridin-2(1H)-one (110 mg, Y: 20%) was obtained. ES-API: [M + H] + = 508.1.

[0604] Step 4: 1-(4,6-Dicyclopropylpyrimidin-5-yl)-6-fluoro-7-(2-fluoro-6-methoxyphenyl)-4-hydroxy-3-nitro-1,8-naphthyridin-2(1H)-one (110 mg, 0.20 mmol) was dissolved in acetonitrile (10 mL). Phosphorus oxychloride (153 mg, 1.0 mmol) and N,N-diisopropylethylamine (77 g, 0.6 mmol) were added successively. The reaction was gradually heated to 80 °C and stirred for 3 h. The reaction solution was concentrated, 30 mL of cold acetonitrile was added, and the mixture was added dropwise to 30 mL of saturated sodium bicarbonate solution under an ice-water bath. It was extracted 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 concentrated after drying. The crude product was purified by flash silica gel column (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-naphthyridin-2(1H)-one (110 mg, Y: 68%), a yellow solid. ES-API: [M+H] + = 526.2.

[0605] Step 5: 4-Chloro-6-fluoro-7-(2-fluoro-6-methoxyphenyl)-1-(4,6-dicyclopropylpyrimidin-5-yl)-3-nitro-1,8-naphthyridin-2(1H)-one (110 mg, 0.296 mmol) was dissolved in N,N-dimethylacetamide (3 mL). 1-(tert-Butyl) 3-methyl (R)-piperazine-1,3-dicarboxylate (54 mg, 0.22 mmol) was added successively. The reaction was stirred at 120 °C for 2 h. After the reaction was completed, 30 mL of ethyl acetate was added, and it was washed three times with 30 mL of saturated brine. The ethyl acetate phase was concentrated after drying to obtain the 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-naphthyridin-4-yl)piperazine-1,3-dione (50 mg, Y: 46%), a yellow solid. ES-API: [M+H] + = 734.3.

[0606] Step 6: ((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-naphthyridin-4-yl)piperazine-1,3-dione (50 mg, 0.068 mmol) was dissolved in acetic acid (25 mL), iron powder (11.5 mg, 0.204 mmol) was added, and the reaction was stirred at 80 °C for 30 minutes. The reaction solution was concentrated, 30 mL of ethyl acetate and 30 mL of saturated sodium bicarbonate were added successively. The suspension was filtered through diatomaceous earth, the filter cake was washed with ethyl acetate, the organic phase was separated, and it was washed successively with 30 mL of saturated sodium bicarbonate and 30 mL of saturated brine, dried and concentrated to obtain the product tert-butyl (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]naphthyridine-3(2H)-carboxylate (40 mg, crude product), a yellow solid. ES-API: [M+H]+ = 672.2.

[0607] Step 7: tert-Butyl (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]naphthyridine-3(2H)-carboxylate (40 mg, 0.059 mmol), 30 mL of acetone, potassium carbonate anhydrous (33 mg, 0.24 mmol), and methyl iodide (85 mg, 0.59 mmol) were sealed in a sealed tube, and the reaction was stirred at 50 °C for 18 hours. The reaction solution was added with 20 mL of ethyl acetate, washed with 20 mL of saturated brine, dried and concentrated, and the crude product was purified by flash silica gel column (EtOAc / PE: 0 - 80%) to obtain the product tert-butyl (4aR)-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]naphthyridin-3(2H)-one (40 mg, Y: 90%), a yellow solid. ES-API: [M+H] + = 686.2.

[0608] Step 8: (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]naphthyridin-3(2H)-one (44 mg) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (1 mL) was added. The mixture was stirred at room temperature for 2 hours, and the reaction solution was 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]naphthyridine-5,7(6H,8H)-dione (40 mg, crude product), which was directly used in the next step reaction. ES-API: [M+H] + = 586.2.

[0609] 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]naphthyridine-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. 20 mL of dichloromethane was added to the reaction solution, and the mixture was washed with 20 mL of saturated aqueous NaHCO3 and 20 mL of saturated brine, dried and concentrated. The crude product was 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]naphthyridine-5,7-dione (Z32, 10 mg, Y: 22%), a yellow solid. ES-API: [M+H] + = 640.2.

[0610] Example 33 Preparation of Compounds Z33, Z33-1 and Z33-2

[0611]

[0612] Step 1: Suspend 7-chloro-6-fluoro-4-hydroxy-1-(1-isopropyl-4-methyl-1H-pyrazol-5-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile (3.6 g, 10.0 mmol) in a mixed solution of 1,4-dioxane (10 mL) and water (120 mL), and slowly add concentrated sulfuric acid (10 mL). Stir the reaction at 120 °C for 18 hours. Pour the cooled reaction solution into 20 mL of ice water, adjust the pH to 2 - 3 with sodium carbonate, extract with ethyl acetate (1000 mL * 2), combine the ethyl acetate phases, dry over anhydrous sodium sulfate, filter, and dry the filtrate under vacuum to obtain the product 7-chloro-6-fluoro-4-hydroxy-1-(1-isopropyl-4-methyl-1H-pyrazol-5-yl)-1,8-naphthyridin-2(1H)-one (3.36 g, Y: 92%), a light brown solid. ES-API: [M + H] + = 337.1.

[0613] Step 2: Dissolve 7-chloro-6-fluoro-4-hydroxy-1-(1-isopropyl-4-methyl-1H-pyrazol-5-yl)-1,8-naphthyridin-2(1H)-one (3.36 g, 10 mmol) in acetic acid (7 mL), and successively add sodium nitrite (69 mg, 1.0 mmol) and concentrated nitric acid (2.0 mL, 30 mmol). Stir the reaction at room temperature for 30 minutes. Slowly pour the reaction solution into 21 mL of ice water, filter the precipitated solid, wash the filter cake with 10 mL of ice water, and dry 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-naphthyridin-2(1H)-one (3.0 g, Y: 90%), a yellow solid. ES-API: [M + H] + = 382.1.

[0614] Step 3: Add 7-chloro-6-fluoro-4-hydroxy-1-(1-isopropyl-4-methyl-1H-pyrazol-5-yl)-3-nitro-1,8-naphthyridin-2(1H)-one (1.5 g, 3.93 mmol), (2-fluoro-6-methoxyphenyl)boronic acid (2.67 g, 15.72 mmol), tetrakis(triphenylphosphine)palladium (908 mg, 0.786 mmol), potassium carbonate (2.72 g, 19.65 mmol), 4 mL of water and 20 mL of dioxane into a 100 mL three-necked round-bottom flask. Under nitrogen protection, the reaction is stirred at 100 °C for 3 hours. After the reaction is completed, the reaction solution is cooled to room temperature, 20 mL of water and 50 mL of methyl tert-butyl ether are added, and extraction is carried out once. The aqueous phase is adjusted to pH 3-5 with 1 M hydrochloric acid solution and extracted with ethyl acetate (50 mL × 2). The ethyl acetate phases are combined, dried over anhydrous sodium sulfate, filtered, and the filtrate is dried in vacuo to obtain the product 6-fluoro-7-(2-fluoro-6-methoxyphenyl)-4-hydroxy-1-(1-isopropyl-4-methyl-1H-pyrazol-5-yl)-3-nitro-1,8-naphthyridin-2(1H)-one (1.5 g, crude product), a pale yellow solid. ES-API: [M+H] + = 472.1.

[0615] Step 4: 6-Fluoro-7-(2-fluoro-6-methoxyphenyl)-4-hydroxy-1-(1-isopropyl-4-methyl-1H-pyrazol-5-yl)-3-nitro-1,8-naphthyridin-2(1H)-one (1.5 g, 3.18 mmol) is dissolved in acetonitrile (15 mL), phosphorus oxychloride (2.4 ml, 25.5 mmol) and N,N-diisopropylethylamine (2.6 ml, 15.9 mmol) are added successively. The reaction gradually rises to 80 °C and is stirred for 30 minutes. The reaction solution is concentrated, 10 mL of cold acetonitrile is added, and the mixture is added dropwise to 20 mL of saturated sodium bicarbonate solution under an ice-water bath. It is extracted with ethyl acetate (20 mL × 2). The ethyl acetate phases are combined and washed once with 20 mL of saturated brine. After drying over anhydrous sodium sulfate and filtering, the organic phase is concentrated by drying. The crude product is purified by flash silica gel column (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-naphthyridin-2(1H)-one (0.9 g, Y: 65%), a yellow solid. ES-API: [M+H] + = 490.1.

[0616] Step 5: 4-Chloro-6-fluoro-7-(2-fluoro-6-methoxyphenyl)-1-(1-isopropyl-4-methyl-1H-pyrazol-5-yl)-3-nitro-1,8-naphthyridin-2(1H)-one (490 mg, 1.0 mmol) was dissolved in N,N-dimethylacetamide (5 mL). (3R,6R)-1-tert-Butyl 3-methyl 6-methylpiperazine-1,3-dicarboxylate (310 mg, 1.2 mmol) and N,N-diisopropylethylamine (390 mg, 3 mmol) were added successively. The reaction was stirred at 120 °C for 2 h. 20 mL of ethyl acetate was added to the reaction solution, and it was washed three times with 20 mL of saturated brine. The ethyl acetate phase was dried and concentrated to obtain the product (3R,6R)-1-tert-butyl-3-methyl 4-(6-fluoro-7-(2-fluoro-6-methoxyphenyl)-1-(1-isopropyl-4-methyl-1H-pyrazol-5-yl)-3-nitro-2-oxo-1,2-dihydro-1,8-naphthyridin-4-yl)piperazine-1,3-dione (620 mg, crude product), a yellow solid. ES-API: [M+H] + = 712.2.

[0617] Step 6: (3R,6R)-1-tert-Butyl-3-methyl 4-(6-fluoro-7-(2-fluoro-6-methoxyphenyl)-1-(1-isopropyl-4-methyl-1H-pyrazol-5-yl)-3-nitro-2-oxo-1,2-dihydro-1,8-naphthyridin-4-yl)piperazine-1,3-dione (620 mg, 0.872 mmol) was dissolved in acetic acid (8 mL). Iron powder (146 mg, 2.62 mmol) was added. The reaction was stirred at 80 °C for 30 min. The reaction solution was concentrated. 30 mL of ethyl acetate and 30 mL of saturated sodium bicarbonate were added successively. The suspension was filtered through diatomaceous earth, and the filter cake was washed with ethyl acetate. The organic phase was separated and washed successively with 30 mL of saturated sodium bicarbonate and 30 mL of saturated brine, then dried and concentrated to obtain the product tert-butyl (2R,4aR)-11-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]naphthyridine-3(2H)-carboxylate (300 mg, crude product), a yellow solid. ES-API: [M+H]+ = 650.3.

[0618] Step 7: (2R,4aR)-tert-Butyl 11-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]naphthyridine-3(2H)-carboxylate (300 mg, 0.462 mmol), 6 mL of acetone, potassium carbonate anhydrous (255 mg, 1.84 mmol), and methyl iodide (656 mg, 4.62 mmol) were sealed in a tube, and the reaction was stirred at 50 °C for 18 h. The reaction mixture was added with 20 mL of ethyl acetate, washed with 20 mL of saturated brine, dried and concentrated. The crude product was purified by flash silica gel column (EtOAc / PE: 0 - 80%) 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-5,7-dioxo-4,4a,5,6,7,8-hexahydro-1H-pyrazino[1’,2’:4,5]pyrazino[2,3-c][1,8]naphthyridine-3(2H)-carboxylate (350 mg, Y: 95%), a yellow solid. ES-API: [M+H] + = 664.3.

[0619] Step 8: (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]naphthyridine-3(2H)-carboxylate (350 mg) was dissolved in dichloromethane (4 mL), and trifluoroacetic acid (2 mL) was added. The mixture was stirred at room temperature for 2 h, and the reaction mixture was 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]naphthyridine-5,7(6H,8H)-dione (40 mg, crude), which was directly used in the next step reaction. ES-API: [M+H] + = 564.2.

[0620] 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]naphthyridine-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. 20 mL of dichloromethane was added to the reaction solution, and it was washed with 20 mL of saturated NaHCO3 aqueous solution and 20 mL of saturated brine, dried and concentrated. The crude product was 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]naphthyridine-5,7(6H,8H)-dione (250 mg, Y: 60%), a yellow solid. ES-API: [M+H] + = 618.3.

[0621] 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]naphthyridine-5,7(6H,8H)-dione (250 mg, 0.405 mmol) was added to dry dichloromethane (6.0 mL), and boron tribromide (4.0 mL, 4.0 mmol) was added. The temperature was raised to room temperature, and the reaction was carried out for 1 h. Under ice-water bath conditions, the above reaction solution was added dropwise to saturated sodium bicarbonate saturated solution, and 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]naphthyridine-5,7(6H,8H)-dione (Z33).

[0622] Step 11: The compound Z33 was purified by preparative HPLC to obtain: a atropisomer compound, arbitrarily designated as Z33-1 in structure (Peak 1, 30 mg, retention time 9.576 min, Y: 50%). 1 H NMR (500 MHz, DMSO-d6) δ 10.17 (s, 1H), 7.98 (dd, J = 8.4, 5.5 Hz, 1H), 7.40 (d, J = 5.5 Hz, 1H), 7.29 (q, J = 7.9 Hz, 1H), 7.02 (dd, J = 16.8, 10.6 Hz, 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 atropisomer compound, arbitrarily designated as Z33-2 in structure (Peak 2, 15 mg, retention time 9.663 min, Y: 25%). 1 H NMR (500 MHz, DMSO-d6) δ 10.17 (s, 1H), 7.96 (m, 1H), 7.40 (d, J = 5.5 Hz, 1H), 7.29 (q, J = 7.9 Hz, 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 = 14.7 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 (m, 1H), 1.76–1.59 (m, 3H), 1.55 (m, 3H), 1.30 (dd, J = 32.6, 6.6 Hz, 3H), 1.23–1.15 (m, 3H). The isomer compounds were detected by analytical HPLC method.

[0623] Example 34 Preparation of Compounds Z34, Z34-1 and Z34-2

[0624]

[0625] Step 1: Add tert-butyl (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-octahydro-3H-pyrazino[1’,2’:4,5]pyrazino[2,3-c][1,8]naphthalene-3-carboxylate (115 mg, 0.17 mmol), 4 mL of acetone, potassium carbonate anhydrous (94 mg, 0.68 mmol), and iodomethane-d3 (246 mg, 1.70 mmol) into a 15 mL sealed tube in sequence. Seal the sealed tube and stir the reaction at 50 °C for 18 hours. Add 30 mL of ethyl acetate to the reaction solution, wash it successively with 12 mL of water and 15 mL of saturated brine, dry and concentrate to obtain the product tert-butyl (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-octahydro-3H-pyrazino[1’,2’:4,5]pyrazino[2,3-c][1,8]naphthalene-3-carboxylate (118 mg, Y: 100.0%), a yellow solid. ES-API: [M+H] + = 678.3.

[0626] Step 2: Dissolve tert-butyl (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-octahydro-3H-pyrazino[1’,2’:4,5]pyrazino[2,3-c][1,8]naphthalene-3-carboxylate (118 mg, 0.17 mmol) in dichloromethane (3 mL), and add trifluoroacetic acid (0.7 mL). Stir at room temperature for 2 hours, concentrate the reaction solution 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-pyrazino[1’,2’:4,5]pyrazino[2,3-c][1,8]naphthalene-5,7-dione (120 mg, crude product), which is directly used for the next step reaction. ES-API: [M+H] + = 578.2.

[0627] 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-pyrazino[1’,2’:4,5]pyrazino[2,3-c][1,8]naphthyridine-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. 25 mL of dichloromethane was added to the reaction solution, and it was washed successively with 15 mL of water, 15 mL of saturated NaHCO3 aqueous solution, and 15 mL of saturated brine, dried and concentrated. After drying, it was concentrated, and the crude product was purified by flash silica gel column (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-pyrazino[1’,2’:4,5]pyrazino[2,3-c][1,8]naphthyridine-5,7-dione (85 mg, Y: 77.3%), a pale yellow solid. ES-API: [M+H] + = 632.2.

[0628] 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-pyrazino[1’,2’:4,5]pyrazino[2,3-c][1,8]naphthyridine-5,7-dione (85 mg, 0.13 mmol) was dissolved in dichloromethane (1.5 mL). The reaction was cooled to 0 °C, and a dichloromethane solution of 17% boron tribromide (1.5 mL) was added dropwise thereto. The reaction was stirred at room temperature for 4 hours. The reaction solution was poured into 40 mL of saturated NaHCO3 aqueous solution and extracted twice with 25 mL of dichloromethane. The organic phase was dried and concentrated, and 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-pyrazino[1’,2’:4,5]pyrazino[2,3-c][1,8]naphthyridine-5,7-dione (Z34).

[0629] Step 5: The compound Z34 was purified by preparative chiral HPLC separation (column type: OD-H: 10 μm, 20 * 250 mm, mobile phase: hexane: EtOH = 80:20, flow rate: 15 ml / min, column temperature: room temperature) to obtain: a atropisomer compound, arbitrarily designated as Z34-1 in structure (23 mg, peak 1, retention time 11.056 min, Y: 28.7%), a pale yellow solid. 1 H NMR (500 MHz, DMSO-d6) δ 10.14 (s, 1H), 8.44 (d, J = 4.9 Hz, 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, 4.2 Hz, 1H), 3.39–3.20 (m, 1H), 2.92–2.79 (m, 1H), 2.47 - 2.36 (m, 1H), 1.99 (s, 3H), 1.58 - 1.53 (m, 3H), 1.03 (d, J = 6.7 Hz, 3H), 0.85 (d, J = 6.7 Hz, 3H). ES-API: [M + H] + = 618.2. And another atropisomer compound, arbitrarily designated as Z34-2 in structure (25 mg, peak 2, retention time 14.067 min, Y: 31.2%), a pale yellow solid. 1 H NMR (500 MHz, DMSO-d6) δ 10.15 (s, 1H), 8.45 (d, J = 4.9 Hz, 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, 4.2 Hz, 1H), 3.43–3.25 (m, 1H), 2.95–2.83 (m, 1H), 2.79 - 2.74 (m, 1H), 1.80 (s, 3H), 1.58 - 1.53 (m, 3H), 1.11 (d, J = 6.7 Hz, 3H), 0.98 (d, J = 6.7 Hz, 3H). ES-API: [M + H] += 618.2. The isomeric compounds were detected by an analytical chiral HPLC method (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).

[0630] Example 35 Preparation of Compounds Z35, Z35-1 and Z35-2

[0631]

[0632] Step 1: (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-octahydro-3H-pyrazino[1’,2’:4,5]pyrazino[2,3-c][1,8]naphthyridine-3-carboxylic acid tert-butyl ester (200 mg, 0.30 mmol) was dissolved in dichloromethane (4 mL), and trifluoroacetic acid (1 mL) was added. Stirred at room temperature for 2 hours, and the reaction solution was concentrated to obtain the product (2R,4aR)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-2-methyl-2,3,4,4a,6,8-hexahydro-1H-pyrazino[1’,2’:4,5]pyrazino[2,3-c][1,8]naphthyridine-5,7-dione (210 mg, crude product), which was directly used in the next step. ES-API: [M+H] + = 561.3.

[0633] Step 2: (2R,4aR)-11-Fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-2-methyl-2,3,4,4a,6,8-hexahydro-1H-pyrazino[1’,2’:4,5]pyrazino[2,3-c][1,8]naphthyridine-5,7-dione (210 mg, crude) was dissolved in dichloromethane (10 mL), and N,N-diisopropylethylamine (194 mg, 1.50 mmol) was added. The reaction was cooled to 0 °C, and acryloyl chloride (54 mg, 0.60 mmol) was added dropwise to the reaction solution. The reaction was stirred at 0 °C for 15 minutes. 30 mL of dichloromethane was added to the reaction solution, and it was washed successively with 15 mL of water, 15 mL of saturated NaHCO3 aqueous solution, and 15 mL of saturated brine. After drying, it was concentrated to obtain the product (2R,4aR)-3-acryloyl-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-2-methyl-2,3,4,4a,6,8-hexahydro-1H-pyrazino[1’,2’:4,5]pyrazino[2,3-c][1,8]naphthyridine-5,7-dione (175 mg, Y: 95.0%), a pale yellow solid. ES-API: [M+H] + = 615.3.

[0634] Step 3: (2R,4aR)-3-Acryloyl-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-2-methyl-2,3,4,4a,6,8-hexahydro-1H-pyrazino[1’,2’:4,5]pyrazino[2,3-c][1,8]naphthyridine-5,7-dione (175 mg, 0.28 mmol) was dissolved in dichloromethane (4 mL). The reaction was cooled to 0 °C, and a dichloromethane solution of 17% boron tribromide (4 mL) was added dropwise thereto. The reaction was stirred at room temperature for 3 hours. The reaction solution was poured into 80 mL of saturated NaHCO3 aqueous solution, and extracted twice with 30 mL of dichloromethane. After drying the organic phase, it was concentrated to obtain the product (2R,4aR)-3-acryloyl-11-fluoro-10-(2-fluoro-6-hydroxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-2-methyl-2,3,4,4a,6,8-hexahydro-1H-pyrazino[1',2':4]pyrazino[2,3,3-c][1,8,8]naphthyridin-5-one (Z35, 170 mg, Y: 99.4%), a pale yellow solid. ES-API: [M+H] + = 601.2.

[0635] Step 4: Compound Z35 (170 mg, 0.28 mmol) was purified by preparative HPLC and then 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: room temperature) to obtain: a atropisomer compound, arbitrarily designated as Z35-1 (19 mg, peak 1, retention time 2.905 min, Y: 11.1%), a pale yellow solid. 1 H NMR (500 MHz, DMSO-d6) δ 10.60 - 10.46 (m, 1H), 10.12 (s, 1H), 8.45 (d, J = 4.8 Hz, 1H), 8.01 - 7.91 (m, 1H), 7.31–7.18 (m, 2H), 7.03 - 6.82 (m, 1H), 6.75–6.63 (m, 2H), 6.20–6.10 (m, 1H), 5.79–5.70 (m, 1H), 5.08–4.70 (m, 1H), 4.67 - 4.39 (m, 1H), 4.09 - 3.97 (m, 1H), 3.72 (dd, J = 14.1, 4.0 Hz, 1H), 3.31–3.18 (m, 1H), 3.02–2.87 (m, 1H), 2.57 - 2.50 (m, 1H), 1.89 (s, 3H), 1.58 - 1.44 (m, 3H), 1.05 (d, J = 6.7 Hz, 3H), 0.89 (d, J = 6.7 Hz, 3H). ES-API: [M+H] + = 601.2. And another atropisomer compound, arbitrarily designated as Z35-2 (19 mg, peak 2, retention time 8.769 min, Y: 11.1%), a pale yellow solid. 11H NMR (500 MHz, DMSO-d6) δ 10.60 - 10.46 (m, 1H), 10.12 (s, 1H), 8.45 (d, J = 4.9 Hz, 1H), 8.01 - 7.91 (m, 1H), 7.31–7.18 (m, 2H), 7.03 - 6.82 (m, 1H), 6.75–6.63 (m, 2H), 6.20–6.08 (m, 1H), 5.78–5.67 (m, 1H), 5.10–4.70 (m, 1H), 4.67 - 4.39 (m, 1H), 4.09 - 3.97 (m, 1H), 3.72 (dd, J = 14.1, 3.8 Hz, 1H), 3.31–3.18 (m, 1H), 3.06–2.92 (m, 1H), 2.66 - 2.57 (m, 1H), 1.83 (s, 3H), 1.58 - 1.44 (m, 3H), 1.08 (d, J = 6.7 Hz, 3H), 0.91 (d, J = 6.7 Hz, 3H). ES-API: [M+H] + = 6...

Claims

1. A compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, wherein, Z is N-C(O)-CR3=CR1R2 or N-C(O)-C≡CR4; R1 and R2 are each independently hydrogen, halogen, cyano, -NR a R b , -C 1-3 alkyl, -halo-C 1-3 alkyl, -C 1-3 alkyl-hydroxy, -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 heteroalkyl or -C 1-3 alkyl-5- or 6-membered monocyclic heteroaryl; wherein, the 3- to 6-membered heterocycloalkyl or the 5- or 6-membered monocyclic heteroaryl has 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms; R3 is hydrogen, halogen, -C 1-3 alkyl or -C 1-3 alkoxy; R4 is hydrogen, -halo C 1-3 alkyl, -C 1-3 alkyl-hydroxy, -C 1-3 alkyl-cyano or -C 1-3 alkyl-C 1-3 alkoxy; R 11 and R 12 are the same or different and each independently is hydrogen, halogen, -C 1-3 alkyl, -halo-C 1-3 alkyl, -C 1-3 alkyl-hydroxy, -C 1-3 alkyl-cyano, -C 1-3 alkyl-C 1-6 alkoxy, -C 1-3 alkyl-halo-C 1-6 alkyl or -C 1-3 alkyl-halo-C 1-6 alkoxy; R 21 and R 22 are the same or different and each independently is hydrogen, halogen, -C 1-3 alkyl, -halo-C 1-3 alkyl, -C 1-3 alkyl-hydroxy, -C 1-3 alkyl-cyano, -C 1-3 alkyl-C 1-6 alkoxy, -C 1-3 alkyl-halo-C 1-6 alkyl or -C 1-3 alkyl-halo-C 1-6 alkoxy; R 31 、R 32 are the same or different and each independently is hydrogen, halogen, -C 1-3 alkyl, -halo-C 1-3 alkyl, -C 1-3 alkyl-hydroxy, -C 1-3 alkyl-cyano, -C 1-3 alkyl-C 1-6 alkoxy, -C 1-3 alkyl-halo-C 1-6 alkyl or -C 1-3 alkyl-halo-C 1-6 alkoxy; R 41 is hydrogen, halogen, -C 1-3 alkyl, -halo-C 1-3 alkyl, -C 1-3 alkyl-hydroxy, -C 1-3 alkyl-cyano, -C 1-3 alkyl-C 1-6 alkoxy, -C 1-3 alkyl-halo-C 1-6 alkyl or -C 1-3 alkyl-halo-C 1-6 alkoxy; When the dashed line in is a single bond, P is O, NH or NR m ; R m is a substituted or unsubstituted C 1-6 alkyl; R 42 is -(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(halo 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)-, or -C 1-3 alkyl(halo C 1-6 alkoxy)-; or when the dotted line in 42 is absent, P is hydrogen or halogen; R 1-3 is hydrogen, halogen, -C 1-3 alkyl, -halo-C 1-3 alkyl, -C 1-3 alkyl-hydroxy, -C 1-3 alkyl-cyano, -C 1-6 alkyl-C 1-3 alkoxy, -C 1-6 alkyl-halo-C 1-3 alkyl or -C 1-6 alkyl-halo-alkoxy; When Y1 is C; X1 is hydrogen, halogen, cyano, hydroxy, amino, nitro, -substituted or unsubstituted C 1-6 alkyl, -substituted or unsubstituted C 3-6 cycloalkyl, -substituted or unsubstituted 3- to 6-membered heterocycloalkyl, -O-substituted or unsubstituted C 1-6 alkyl, -O-substituted or unsubstituted C 3-6 cycloalkyl, -O-substituted or unsubstituted 3- to 6-membered heterocycloalkyl, -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 heterocycloalkyl, -NH(C=O)-substituted or unsubstituted C 1-6 alkyl, -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 independently is hydrogen or C 1-3 alkyl; or R j 、R k together with the attached nitrogen atom form a substituted or unsubstituted 3- to 6-membered nitrogen-containing heterocycloalkyl; the 3- to 6-membered heterocycloalkyl has 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms; the 3- to 6-membered nitrogen-containing heterocycloalkyl has 3 to 6 ring atoms and one of the ring atoms is a nitrogen atom, and 0, 1 or 2 of the remaining ring atoms are optionally heteroatoms selected from N, O and S; the "substituted" means that 1, 2, 3 or 4 hydrogen atoms in the group are each independently replaced by substituents selected from group S; or when Y1 is N, X1 is absent; The S group substituents are selected from: hydroxy, halogen, nitro, oxo group, -C 1-6 alkyl, -halo C 1-6 alkyl, hydroxy-substituted C 1-6 alkyl, benzyl, -(CH2) u -cyano, -(CH2) u -C 1-6 alkoxy, -(CH2) u -halo C 1-6 alkoxy, -(CH2) u -halo C 1-6 alkyl, -(CH2) u -3- to 6-membered heterocycloalkyl, -(CH2) u -5- or 6-membered monocyclic heteroaryl, -(CH2) u -C 3-8 cycloalkyl, -(CH2) u -O-(CH2) v -C 3-8 cycloalkyl, -(CH2) u -O-(CH2) v -C 1-6 alkoxy, -(CH2) u -O-(CH2) v OH, -(CH2) u -SO2C 1-6 alkyl, -(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)-halo C 1-6 alkyl; wherein, the 3- to 6-membered heterocycloalkyl or the 5- or 6-membered monocyclic heteroaryl each independently has 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms; the 3- to 6-membered heterocycloalkyl, 5- or 6-membered monocyclic heteroaryl is optionally substituted with 1, 2 or 3 substituents selected from halogen, cyano, -C 1-3 alkyl, -C 1-3 alkoxy and -C 3-6 Substituted by a substituent of a cycloalkyl group; u and v are each independently 0, 1, 2, 3 or 4; R a0 , R b0 are each independently hydrogen or C 1-3 alkyl; E1 is N or CR5; wherein, R5 is hydrogen, halogen, cyano, -C 1-6 alkyl, -C 1-6 alkoxy, -halo-C 1-6 alkyl, -halo-C 1-6 alkoxy, -C 3-6 cycloalkyl, -NR h R i 、-C 1-4 alkyl-hydroxy, -C 1-4 alkyl-cyano, -C 1-4 alkyl-C 1-6 alkoxy, -C 1-4 alkyl-halo-C 1-6 alkyl or -C 1-4 alkyl-halo-C 1-6 alkoxy; E2 is N or CR6; wherein, R6 is hydrogen, halogen, cyano, -C 1-6 alkyl, -C 1-6 alkoxy, -halo-C 1-6 alkyl, -halo-C 1-6 alkoxy, -C 3-6 cycloalkyl, -NR h R i 、-C 1-4 alkyl-hydroxy, -C 1-4 alkyl-cyano, -C 1-4 alkyl-C 1-6 alkoxy, -C 1-4 alkyl-halo-C 1-6 alkyl or -C 1-4 alkyl-halo-C 1-6 alkoxy; provided that Y1, E1, E2 are not simultaneously N; 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 aryl, the 5- or 6-membered monocyclic heteroaryl or the 8- to 10-membered bicyclic heteroaryl is unsubstituted or substituted by 1, 2, 3 or 4 groups independently selected from R s1 groups; or Ar has the structure shown in formula (B): 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 heterocycloalkyl 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 heterocycloalkyl ring has 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms; (R s1 ) p represents that the hydrogen on the B1 ring is substituted by p R s1 groups, where p is 0, 1, 2 or 3, and each R s1 is the same or different; (R s2 ) q means that the hydrogen on the B2 ring is substituted by q R s2 groups, where q is 0, 1, 2 or 3, and each R s2 is the same or different; R s1 and R s2 are each independently a halogen, cyano, nitro, hydroxy, -C 1-6 alkyl, -C 1-6 alkoxy, -halo-C 1-6 alkyl, -halo-C 1-6 alkoxy, -C 3-6 cycloalkyl, -NR c R d , -C(O)NR e R f , -SO2-C 1-3 alkyl, -SO2-halo-C 1-3 alkyl, -SO2NR e R f , -C 1-4 alkyl-hydroxy, -C 1-4 alkyl-cyano, -C 1-4 alkyl-C 1-6 alkoxy, -C 1-4 alkyl-halo-C 1-6 alkyl, -C 1-4 alkyl-halo-C 1-6 alkoxy, -C 1-4 alkyl-3- to 6-membered heteroalkyl, -C 1-4 alkyl-NR e R f , -C 1-4 alkyl-C(O)NR e R f , -C 1-4 alkyl-SO2-C 1-3 alkyl or C 2-4 alkynyl; wherein the 3- to 6-membered heteroalkyl has 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms; R0 is -C 1-6 alkyl, -C 3-6 cycloalkyl, 3- to 6-membered heteroalkyl, C 6-10 aryl, 5- or 6-membered monocyclic heteroaryl, 8- to 10-membered bicyclic heteroaryl, 7- to 11-membered spiroalkyl, -C 1-3 alkyl-C 6-10 aryl, -C 1-3 alkyl-5- or 6-membered monocyclic heteroaryl, -NR g -C 6-10 aryl, -O-C 6-10 aryl, -C 1-3 alkyl-3- to 6-membered heteroalkyl, -C 1-3 alkyl-C 3-6 cycloalkyl; wherein, the 3- to 6-membered heteroalkyl, the 5- or 6-membered monocyclic heteroaryl or the 8- to 10-membered bicyclic heteroaryl 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 heteroalkyl, C 6-10 aryl, 5- or 6-membered monocyclic heteroaryl, 8- to 10-membered bicyclic heteroaryl, 7- to 11-membered spiroalkyl is unsubstituted or substituted by 1, 2, 3 or 4 groups independently selected from R s3 ; the -C 1-3 alkyl- is unsubstituted or substituted by 1, 2, 3 or 4 groups independently selected from C 1-3 alkyl; or R0 has the structure shown in formula (A-1) or formula (A-2): 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 heterocycloalkyl 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 heterocycloalkyl ring has 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms; (R s3 ) t represents that the hydrogen on the A1 ring is substituted by t Rs s3 , where t is 0, 1, 2 or 3, and each R s3 is the same or different; (R s4 ) s represents that the hydrogen on the A2 ring is substituted by s Rs s4 , where s is 0, 1, 2 or 3, and each R s4 is the same or different; R s3 and R s4 each independently represents halogen, cyano, hydroxy, -C 1-6 alkyl, -C 1-6 alkoxy, -halo-C 1-6 alkyl, -halo-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-halo-C 1-3 alkyl, -SO2NR e R f -, -C 1-3 alkyl-hydroxy, -C 1-3 alkyl-C 2-4 alkynyl, -C 1-3 alkyl-cyano, -C 1-3 alkyl-C 1-6 alkoxy, -C 1-3 alkyl-halo-C 1-6 alkyl, -C 1-3 alkyl-halo-C 1-6 alkoxy, -C 1-3 alkyl-3- to 6-membered heterocycloalkyl, -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 alkynyl; wherein the 3- to 6-membered heterocycloalkyl 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 cycloalkyl, 3- to 6-membered heterocycloalkyl is optionally substituted with 1, 2 or 3 substituents independently selected from halogen, methyl, ethyl, propyl, isopropyl, trifluoromethyl, amino, N(CH3)2, hydroxy and carboxyl; R a 、R b 、R e 、R f 、R g Each independently is hydrogen or a C 1-3 alkyl group; R c 、R d 、R h 、R i each independently is hydrogen, -C 1-3 alkyl, -C(O)C 1-3 alkyl or -CO2C 1-3 alkyl.

2. A compound of formula (II), or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, wherein, Z is N-C(O)-CR3=CR1R2 or N-C(O)-C≡CR4; R1 and R2 are each independently hydrogen, halogen, cyano, NR a R b 、-C 1-3 alkyl, halo-C 1-3 alkyl, -C 1-3 alkyl-hydroxy, -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 heteroalkyl or -C 1-3 alkyl-5- or 6-membered monocyclic heteroaryl; wherein, the 3- to 6-membered heterocycloalkyl or the 5- or 6-membered monocyclic heteroaryl has 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms; R3 is hydrogen, halogen, -C 1-3 alkyl or -C 1-3 alkoxy; R4 is hydrogen, halogenated C 1-3 alkyl, -C 1-3 alkyl-hydroxy, -C 1-3 alkyl-cyano or -C 1-3 alkyl-C 1-3 alkoxy; R 11 、R 12 are the same or different and each independently is hydrogen, halogen, -C 1-3 alkyl, -halo-C 1-3 alkyl, -C 1-3 alkyl-hydroxy, -C 1-3 alkyl-cyano, -C 1-3 alkyl-C 1-6 alkoxy, -C 1-3 alkyl-halo-C 1-6 alkyl or -C 1-3 alkyl-halo-C 1-6 alkoxy; R 21 and R 22 are the same or different and each independently is hydrogen, halogen, -C 1-3 alkyl, -halo-C 1-3 alkyl, -C 1-3 alkyl-hydroxy, -C 1-3 alkyl-cyano, -C 1-3 alkyl-C 1-6 alkoxy, -C 1-3 alkyl-halo-C 1-6 alkyl or -C 1-3 alkyl-halo-C 1-6 alkoxy; R 31 、R 32 are the same or different and each independently is hydrogen, halogen, -C 1-3 alkyl, -halo-C 1-3 alkyl, -C 1-3 alkyl-hydroxy, -C 1-3 alkyl-cyano, -C 1-3 alkyl-C 1-6 alkoxy, -C 1-3 alkyl-halo-C 1-6 alkyl or -C 1-3 alkyl-halo-C 1-6 alkoxy; R 41 is hydrogen, halogen, -C 1-3 alkyl, -halo-C 1-3 alkyl, -C 1-3 alkyl-hydroxy, -C 1-3 alkyl-cyano, -C 1-3 alkyl-C 1-6 alkoxy, -C 1-3 alkyl-halo-C 1-6 alkyl or -C 1-3 alkyl-halo-C 1-6 alkoxy; P is O, NH or NR m ; R m is -C 1-6 alkyl, -halo-C 1-6 alkyl, -C 1-6 alkyl-hydroxy, -C 1-6 alkyl-cyano, -C 1-6 alkyl-C 1-6 alkoxy, -C 1-6 alkyl-halo-C 1-6 alkoxy, -C 1-6 alkyl-C 3-6 cycloalkyl or -C 1-6 alkyl-3-to 6-membered heteroalkyl; R 42 is -(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(halo 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)-, or -C 1-3 alkyl(halo C 1-6 alkoxy)-; X2 and Y2 are the same or different and each independently is hydrogen, halogen, -C 1-3 alkyl, -halo C 1-3 alkyl, -C 1-3 alkyl-hydroxy, -C 1-3 alkyl-cyano, -C 1-3 alkyl-C 1-6 alkoxy, -C 1-3 alkyl-halo C 1-6 alkyl or -C 1-3 alkyl-halo C 1-6 alkoxy; or X2, Y2 together with the adjacent carbon atom form a substituted or unsubstituted C 3-6 cycloalkyl or a substituted or unsubstituted 3- to 6-membered heterocycloalkyl; the 3- to 6-membered heterocycloalkyl having 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms; the "substituted" means that 1, 2, 3 or 4 hydrogen atoms in the group are each independently replaced by substituents selected from group S; E3 is N or C-L-R5; wherein, L is a key, -CR L1 R L2 -, -O-(CR L1 R L2 ) t1 - or -NH-(CR L3 R L4 ) t2 -; wherein, R L1 , R L2 , R L3 , R L4 are the same or different and each independently is hydrogen, halogen, hydroxyl, hydroxymethyl, hydroxyethyl, -C 1-3 alkyl or oxo group; t1 and t2 are each independently 0, 1, 2, 3 or 4; R L1 and R L2 in or R L3 and R L4 in, when one of them is an oxo group, the other does not exist; R5 is hydrogen, halogen, hydroxy, -substituted or unsubstituted C 1-6 Alkyl, -substituted or unsubstituted C 3-6 cycloalkyl, -substituted or unsubstituted 3 to 6 membered heterocycloalkyl, -O-substituted or unsubstituted C 1-6 Alkyl, -O-substituted or unsubstituted C 3-6 Cycloalkyl, -O-substituted or unsubstituted 3- to 6-membered heterocycloalkyl, -SO2-substituted or unsubstituted C 1-6 Alkyl, -SO2-substituted or unsubstituted C 3-6 cycloalkyl, -SO2-substituted or unsubstituted 3 to 6-membered heterocycloalkyl, -substituted or unsubstituted 5 or 6-membered monocyclic heteroaryl or NR 51 R 52 ; Among them, R 51 , R 52 are each 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)halogen 1-6 Alkyl; or R 51 and R 52 Together with the connected nitrogen atom, it forms a substituted or unsubstituted 3- to 6-membered nitrogen-containing heterocycloalkyl group; wherein the 3- to 6-membered heterocycloalkyl 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 nitrogen-containing heterocycloalkyl group has 3 to 6 ring atoms, one of which is a nitrogen atom, and 0, 1 or 2 of the remaining ring atoms are optionally heteroatoms selected from N, O and S; the "substituted" refers to that 1, 2, 3 or 4 hydrogen atoms in the group are replaced by substituents independently selected from Group S; The S group substituents are selected from: hydroxyl, halogen, nitro, oxo group, -C 1-6 alkyl, -halo C 1-6 alkyl, hydroxyl-substituted C 1-6 alkyl, benzyl, -(CH2) u -cyano, -(CH2) u -C 1-6 alkoxy, -(CH2) u -halo C 1-6 alkoxy, -(CH2) u -halo C 1-6 alkyl, -(CH2) u -3- to 6-membered heterocycloalkyl, -(CH2) u -5- or 6-membered monocyclic heteroaryl, -(CH2) u -C 3-8 cycloalkyl, -(CH2) u -O-(CH2) v -C 3-8 cycloalkyl, -(CH2) u -O-(CH2) v -C 1-6 alkoxy, -(CH2) u -O-(CH2) v OH, -(CH2) u -SO2C 1-6 alkyl, -(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)-halo C 1-6 alkyl; wherein, the 3- to 6-membered heterocycloalkyl or the 5- or 6-membered monocyclic heteroaryl each independently has 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms; the 3- to 6-membered heterocycloalkyl, 5- or 6-membered monocyclic heteroaryl is optionally substituted with 1, 2 or 3 substituents selected from halogen, cyano, -C 1-3 alkyl, -C 1-3 alkoxy and C 3-6 Substituted with a cycloalkyl substituent; u and v are each independently 0, 1, 2, 3, or 4; R a0 , R b0 are each independently hydrogen or C 1-3 alkyl; E4 is N or CH; Ar is C 6-10 aryl, a 5- or 6-membered monocyclic heteroaryl or an 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 aryl, the 5- or 6-membered monocyclic heteroaryl or the 8- to 10-membered bicyclic heteroaryl is unsubstituted or substituted by 1, 2, 3 or 4 groups independently selected from R s1 groups; or Ar has the structure shown in formula (B): 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 heterocycloalkyl 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 heterocycloalkyl ring has 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms; (R s1 ) p represents that the hydrogen on the B1 ring is substituted by p Rs s1 , where p is 0, 1, 2 or 3, and each R s1 is the same or different; (R s2 ) q represents that the hydrogen on the B2 ring is substituted by q Rs s2 , where q is 0, 1, 2 or 3, and each R s2 is the same or different; R s1 and R s2 are each independently a halogen, cyano, nitro, hydroxy, -C 1-6 alkyl, -C 1-6 alkoxy, -halo-C 1-6 alkyl, -halo-C 1-6 alkoxy, -C 3-6 cycloalkyl, -NR c R d , -C(O)NR e R f , -SO2C 1-3 alkyl, -SO2-halo-C 1-3 alkyl, -SO2NR e R f , -C 1-4 alkyl-hydroxy, -C 1-4 alkyl-cyano, -C 1-4 alkyl-C 1-6 alkoxy, -C 1-4 alkyl-halo-C 1-6 alkyl, -C 1-4 alkyl-halo-C 1-6 alkoxy, -C 1-4 alkyl-3- to 6-membered heterocycloalkyl, -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 alkynyl; wherein the 3- to 6-membered heterocycloalkyl has 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms; R a 、R b 、R e 、R f each independently represents hydrogen or -C 1-3 alkyl; R c 、R d each independently is hydrogen, -C 1-3 alkyl, -C(O)C 1-3 alkyl, -CO2C 1-3 alkyl.

3. A compound of formula (IA) or a tautomer, cis-trans isomer, meso form, racemate, enantiomer, diastereoisomer, atropisomer or a mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof: wherein, Z is N-C(O)-CR3=CR1R2 or N-C(O)-C≡CR4; R1 and R2 are each independently hydrogen, halogen, cyano, NR a R b , -C 1-3 alkyl, halo-C 1-3 alkyl, -C 1-3 alkyl-hydroxy, -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 heteroalkyl or -C 1-3 alkyl-5- or 6-membered monocyclic heteroaryl; wherein, the 3- to 6-membered heterocycloalkyl or the 5- or 6-membered monocyclic heteroaryl has 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms; R3 is hydrogen, halogen, -C 1-3 alkyl or -C 1-3 alkoxy; R4 is hydrogen, halogenated C 1-3 alkyl, -C 1-3 alkyl-hydroxy, -C 1-3 alkyl-cyano or -C 1-3 alkyl-C 1-3 alkoxy; R 11 、R 12 are the same or different and each independently is hydrogen, halogen, -C 1-3 alkyl, -halo-C 1-3 alkyl, -C 1-3 alkyl-hydroxy, -C 1-3 alkyl-cyano, -C 1-3 alkyl-C 1-6 alkoxy, -C 1-3 alkyl-halo-C 1-6 alkyl or -C 1-3 alkyl-halo-C 1-6 alkoxy; R 21 、R 22 are the same or different and each independently is hydrogen, halogen, -C 1-3 alkyl, -halo-C 1-3 alkyl, -C 1-3 alkyl-hydroxy, -C 1-3 alkyl-cyano, -C 1-3 alkyl-C 1-6 alkoxy, -C 1-3 alkyl-halo-C 1-6 alkyl or -C 1-3 alkyl-halo-C 1-6 alkoxy; R 31 、R 32 are the same or different and each independently is hydrogen, halogen, -C 1-3 alkyl, -halo-C 1-3 alkyl, -C 1-3 alkyl-hydroxy, -C 1-3 alkyl-cyano, -C 1-3 alkyl-C 1-6 alkoxy, -C 1-3 alkyl-halo-C 1-6 alkyl or -C 1-3 alkyl-halo-C 1-6 alkoxy; R 41 is hydrogen, halogen, -C 1-3 alkyl, -halo-C 1-3 alkyl, -C 1-3 alkyl-hydroxy, -C 1-3 alkyl-cyano, -C 1-3 alkyl-C 1-6 alkoxy, -C 1-3 alkyl-halo-C 1-6 alkyl or -C 1-3 alkyl-halo-C 1-6 alkoxy; When the dotted line in is a single bond, P' is O, NH or NR m '; R m ' is a substituted or unsubstituted C 1-6 alkyl; R 42 ' is -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(halo 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)-, or -C 1-3 alkyl(halo C 1-6 alkoxy)-; or when the dotted line in 42 is absent, P' is hydrogen or halogen; R 42 ' is hydrogen, halogen, -C 1-3 alkyl, -halo-C 1-3 alkyl, -C 1-3 alkyl-hydroxy, -C 1-3 alkyl-cyano, -C 1-3 alkyl-C 1-6 alkoxy, -C 1-3 alkyl-halo-C 1-6 alkyl or -C 1-3 alkyl-halo-C 1-6 alkoxy; When Y1 is C; X1 is hydrogen, halogen, cyano, hydroxy, amino, nitro, -substituted or unsubstituted C 1-6 alkyl, -substituted or unsubstituted C 3-6 cycloalkyl, -substituted or unsubstituted 3- to 6-membered heterocycloalkyl, -O-substituted or unsubstituted C 1-6 alkyl, -O-substituted or unsubstituted C 3-6 cycloalkyl, -O-substituted or unsubstituted 3- to 6-membered heterocycloalkyl, -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 heterocycloalkyl, -NH(C=O)-substituted or unsubstituted C 1-6 alkyl, -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 are each independently hydrogen or C 1-3 alkyl; or R j 、R k together with the attached nitrogen atom form a substituted or unsubstituted 3- to 6-membered nitrogen-containing heterocycloalkyl; the 3- to 6-membered heterocycloalkyl has 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms; the 3- to 6-membered nitrogen-containing heterocycloalkyl has 3 to 6 ring atoms and one of the ring atoms is a nitrogen atom, and 0, 1 or 2 of the remaining ring atoms are optionally heteroatoms selected from N, O and S; the "substituted" means that 1, 2, 3 or 4 hydrogen atoms in the group are each independently replaced by substituents selected from group S; or when Y1 is N, X1 is absent; The S group substituents are selected from: hydroxyl, halogen, nitro, oxo group, -C 1-6 alkyl, -halo C 1-6 alkyl, hydroxyl-substituted C 1-6 alkyl, benzyl, -(CH2) u -cyano, -(CH2) u -C 1-6 alkoxy, -(CH2) u -halo C 1-6 alkoxy, -(CH2) u -halo C 1-6 alkyl, -(CH2) u -3- to 6-membered heterocycloalkyl, -(CH2) u -5- or 6-membered monocyclic heteroaryl, -(CH2) u -C 3-8 cycloalkyl, -(CH2) u -O-(CH2) v -C 3-8 cycloalkyl, -(CH2) u -O-(CH2) v -C 1-6 alkoxy, -(CH2) u -O-(CH2) v OH, -(CH2) u -SO2C 1-6 alkyl, -(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)-halo C 1-6 alkyl; wherein, the 3- to 6-membered heterocycloalkyl or the 5- or 6-membered monocyclic heteroaryl each independently has 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms; the 3- to 6-membered heterocycloalkyl, 5- or 6-membered monocyclic heteroaryl is optionally substituted with 1, 2 or 3 substituents selected from halogen, cyano, -C 1-3 alkyl, -C 1-3 alkoxy and C 3-6 Substituted by a substituent of a cycloalkyl group; u and v are each independently 0, 1, 2, 3 or 4; R a0 , R b0 are each independently hydrogen or C 1-3 alkyl; E1' is N or CR5'; wherein, R5' is hydrogen, halogen, cyano, -C 1-6 alkyl, -C 1-6 alkoxy, -halo-C 1-6 alkyl, -halo-C 1-6 alkoxy, -C 3-6 cycloalkyl, -O-C 3-6 cycloalkyl, -NR h R i 、-C 1-4 alkyl-hydroxy, -C 1-4 alkyl-cyano, -C 1-4 alkyl-C 1-6 alkoxy, -C 1-4 alkyl-halo-C 1-6 alkyl or -C 1-4 alkyl-halo-C 1-6 alkoxy; E2' is N or CR6'; wherein, R6' is hydrogen, halogen, cyano, -C 1-6 alkyl, -C 1-6 alkoxy, -halo-C 1-6 alkyl, -halo-C 1-6 alkoxy, -C 3-6 cycloalkyl, -O-C 3-6 cycloalkyl, -NR h R i 、-C 1-4 alkyl-hydroxy, -C 1-4 alkyl-cyano, -C 1-4 alkyl-C 1-6 alkoxy, -C 1-4 alkyl-halo-C 1-6 alkyl or -C 1-4 alkyl-halo-C 1-6 alkoxy; provided that Y1, E1', E2' are not simultaneously N; Ar' is C 6-10 aryl, 5- or 6-membered monocyclic heteroaryl, 8- to 10-membered bicyclic heteroaryl or 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; 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 aryl, the 5- or 6-membered monocyclic heteroaryl, the 8- to 10-membered bicyclic heteroaryl and the pyridone group are unsubstituted or substituted by 1, 2, 3 or 4 groups independently selected from R s1 groups; or Ar' has the structure shown in formula (B): Among them, 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 heterocycloalkyl ring or a fused 5- or 6-membered monocyclic cycloalkyl ring; among them, the 5- or 6-membered monocyclic heteroaryl ring or the fused 5- or 6-membered monocyclic heterocycloalkyl ring has 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms; (R s1 ) p represents that the hydrogen on the B1 ring is substituted by p Rs s1 , where p is 0, 1, 2 or 3, and each R s1 is the same or different; (R s2 ) q represents that the hydrogen on the B2 ring is substituted by q R's s2 , where q is 0, 1, 2 or 3, and each R s2 is the same or different; R s1 and R s2 are each independently a halogen, cyano, nitro, hydroxy, -C 1-6 alkyl, -C 1-6 alkoxy, -halo-C 1-6 alkyl, -halo-C 1-6 alkoxy, -C 3-6 cycloalkyl, -NR c R d , -C(O)NR e R f , -SO2-C 1-3 alkyl, -SO2-halo-C 1-3 alkyl, -SO2NR e R f , -C 1-4 alkyl-hydroxy, -C 1-4 alkyl-cyano, -C 1-4 alkyl-C 1-6 alkoxy, -C 1-4 alkyl-halo-C 1-6 alkyl, -C 1-4 alkyl-halo-C 1-6 alkoxy, -C 1-4 alkyl-3- to 6-membered heteroalkyl, -C 1-4 alkyl-NR e R f , -C 1-4 alkyl-C(O)NR e R f , -C 1-4 alkyl-SO2-C 1-3 alkyl or C 2-4 alkynyl; wherein the 3- to 6-membered heteroalkyl has 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms; R0' is -C 1-6 alkyl, -C 3-6 cycloalkyl, 3- to 6-membered heteroalkyl, C 6-10 aryl, 5- or 6-membered monocyclic heteroaryl, 8- to 10-membered bicyclic heteroaryl, 7- to 11-membered spiroalkyl, -C 1-3 alkyl-C 6-10 aryl, -C 1-3 alkyl-5- or 6-membered monocyclic heteroaryl, -NR g -C 6-10 aryl, -O-C 6-10 aryl, -C 1-3 alkyl-3- to 6-membered heteroalkyl, -C 1-3 alkyl-C 3-6 cycloalkyl or pyridone group, wherein the 3- to 6-membered heteroalkyl, the 5- or 6-membered monocyclic heteroaryl or the 8- to 10-membered bicyclic heteroaryl 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 heteroalkyl, C 6-10 aryl, 5- or 6-membered monocyclic heteroaryl, 8- to 10-membered bicyclic heteroaryl, 7- to 11-membered spiroalkyl and pyridone group are unsubstituted or substituted by 1, 2, 3 or 4 groups independently selected from R s3 ; the -C 1-3 alkyl- is unsubstituted or substituted by 1, 2, 3 or 4 groups independently selected from C 1-3 alkyl; Or R0' has the structure shown in formula (A-1) or formula (A-2): Among them, 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 heterocycloalkyl ring or a fused 5- or 6-membered monocyclic cycloalkyl ring; among them, the 5- or 6-membered monocyclic heteroaryl ring or the fused 5- or 6-membered monocyclic heterocycloalkyl ring has 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms; (R s3 ) t represents that the hydrogen on the A1 ring is substituted by t R s3 , where t is 0, 1, 2 or 3, and each R s3 is the same or different; (R s4 ) s means that the hydrogen on the A2 ring is substituted by s R s4 groups, where s is 0, 1, 2 or 3, and each R s4 group is the same or different; R s3 and R s4 are each independently a halogen, cyano, hydroxy, -C 1-6 alkyl, -C 1-6 alkoxy, -halo-C 1-6 alkyl, -halo-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-halo-C 1-3 alkyl, -SO2NR e R f , -C 1-3 alkyl-hydroxy, -C 1-3 alkyl-C 2-4 alkynyl, -C 1-3 alkyl-cyano, -C 1-3 alkyl-C 1-6 alkoxy, -C 1-3 alkyl-halo-C 1-6 alkyl, -C 1-3 alkyl-halo-C 1-6 alkoxy, -C 1-3 alkyl-3- to 6-membered heterocycloalkyl, -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 alkynyl; wherein the 3- to 6-membered heterocycloalkyl 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 cycloalkyl, 3- to 6-membered heterocycloalkyl is optionally substituted with 1, 2 or 3 substituents independently selected from halogen, methyl, ethyl, propyl, isopropyl, trifluoromethyl, amino, N(CH3)2, hydroxy, carboxyl; R a 、R b 、R e 、R f 、R g are each independently hydrogen or C 1-3 alkyl; R c 、R d 、R h 、R i Each independently is hydrogen, -C 1-3 alkyl, -C(O)C 1-3 alkyl or -CO2C 1-3 alkyl.

4. The compound or its tautomer, cis-trans isomer, meso form, racemate, enantiomer, diastereoisomer, atropisomer or its mixture form as claimed in claim 3, or its pharmaceutically acceptable salt, solvate or prodrug, characterized in that, The compound shown in formula (IA) is a compound of formula (IB) or a compound of formula (IC); In formula IB, P' is O, NH or NR m '; R m ' is a substituted or unsubstituted C 1-6 alkyl; R 42 ' is -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(halo 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)-, or -C 1-3 alkyl(halo 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 as defined in claim 3; In the formula IC, P' is hydrogen or halogen; R 42 ' is hydrogen, halogen, -C 1-3 alkyl, -halo-C 1-3 alkyl, -C 1-3 alkyl-hydroxy, -C 1-3 alkyl-cyano, -C 1-3 alkyl-C 1-6 alkoxy, -C 1-3 alkyl-halo-C 1-6 alkyl or -C 1-3 alkyl-halo-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 as defined in claim 3.

5. The compound or its tautomer, cis-trans isomer, meso form, racemate, enantiomer, diastereoisomer, atropisomer or mixture thereof, or its pharmaceutically acceptable salt, solvate or prodrug according to claim 4, characterized in that, The compound shown in formula (IB) is a compound of formula (IB-1) or a compound of formula (IB-2); In Formula (IB-1) and Formula (IB-2), R 21 , R 22 , R 11 , R 12 , R 31 , R 32 , R 41 , R 42 ', Z, P', R0', Ar', E1', E2', X1, Y1 are as defined in claim 4.

6. The compound or its tautomer, cis-trans isomer, meso form, racemate, enantiomer, diastereoisomer, atropisomer or mixture thereof as claimed in claim 4, or its pharmaceutically acceptable salt, solvate or prodrug, characterized in that, The compound shown in formula (IB) is a compound of formula (IB-1a) or a compound of formula (IB-2a); wherein R1, R2, R3, R 21 , R 22 , R 12 , R 11 , R 31 , R 32 , P', R0', Ar', E1', X1 are as defined in claim 4.

7. The compound according to claim 6, or a tautomer, cis-trans isomer, meso form, racemate, enantiomer, diastereoisomer, atropisomer or a mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, characterized in that, The compound shown in 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); In formula (IB-1aa) and formula (IB-1ab), R 21 ' is independently halogen, -C 1-3 alkyl, -halo-C 1-3 alkyl, -C 1-3 alkyl-hydroxy, -C 1-3 alkyl-cyano, -C 1-3 alkyl-C 1-6 alkoxy, -C 1-3 alkyl-halo-C 1-6 alkyl or -C 1-3 alkyl-halo-C 1-6 alkoxy; R1, R2, R3, R 12 、R 11 、R 31 、R 32 、P', R0', Ar', E1', X1 are as defined in claim 4; In formula (IB-1ac) and formula (IB-1ad), R 12 ' is independently halogen, -C 1-3 alkyl, -halo-C 1-3 alkyl, -C 1-3 alkyl-hydroxy, -C 1-3 alkyl-cyano, -C 1-3 alkyl-C 1-6 alkoxy, -C 1-3 alkyl-halo-C 1-6 alkyl or -C 1-3 alkyl-halo-C 1-6 alkoxy; R1, R2, R3, R 21 、R 22 、R 31 、R 32 、P', R0', Ar', E1', X1 are as defined in claim 4.

8. The compound according to claim 4, or a tautomer, cis-trans isomer, meso form, racemate, enantiomer, diastereoisomer, atropisomer or a mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, characterized in that, The compound shown in formula (IB) is a compound of formula (IB-1c) or a compound of formula (IB-2c); wherein R1, R2, R3, R 21 , R 22 , R 12 , R 11 , R 31 , R 32 , P', R0', Ar', E1', X1 are as defined in claim 4.

9. The compound or its tautomer, cis-trans isomer, meso form, racemate, enantiomer, diastereoisomer, atropisomer or mixture thereof as claimed in claim 8, or its pharmaceutically acceptable salt, solvate or prodrug, characterized in that, The compound shown in 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); In formula (IB-1ca) and formula (IB-1cb), R 21 ' is independently halogen, -C 1-3 alkyl, -halo-C 1-3 alkyl, -C 1-3 alkyl-hydroxy, -C 1-3 alkyl-cyano, -C 1-3 alkyl-C 1-6 alkoxy, -C 1-3 alkyl-halo-C 1-6 alkyl or -C 1-3 alkyl-halo-C 1-6 alkoxy; R1, R2, R3, R 12 、R 11 、R 31 、R 32 、P', R0', Ar', E1', X1 are as defined in claim 4; In formula (IB-1cc) and formula (IB-1cd), R 12 ' independently represents halogen, -C 1-3 alkyl, -halo-C 1-3 alkyl, -C 1-3 alkyl-hydroxy, -C 1-3 alkyl-cyano, -C 1-3 alkyl-C 1-6 alkoxy, -C 1-3 alkyl-halo-C 1-6 alkyl or -C 1-3 alkyl-halo-C 1-6 alkoxy; R1, R2, R3, R 21 , R 22 , R 31 , R 32 , P', R0', Ar', E1', X1 are as defined in claim 4.

10. The compound according to claim 4, or a tautomer, cis-trans isomer, meso form, racemate, enantiomer, diastereoisomer, atropisomer or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, characterized in that, The compound shown in formula (IB) is a compound of formula (IB-1b) or a compound of formula (IB-2b); wherein R1, R2, R3, R 21 , R 22 , R 12 , R 11 , R 31 , R 32 , P', R0', Ar', E1', X1 are as defined in claim 4.

11. The compound according to claim 10, or a tautomer, cis-trans isomer, meso form, racemate, enantiomer, diastereoisomer, atropisomer or a mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, characterized in that, The compound shown in 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); Among formula (IB-1ba) and formula (IB-1bb), R 21 ' is independently halogen, -C 1-3 alkyl, -halo-C 1-3 alkyl, -C 1-3 alkyl-hydroxy, -C 1-3 alkyl-cyano, -C 1-3 alkyl-C 1-6 alkoxy, -C 1-3 alkyl-halo-C 1-6 alkyl or -C 1-3 alkyl-halo-C 1-6 alkoxy; R1, R2, R3, R 12 , R 11 , R 31 , R 32 , P', R0', Ar', E1', X1 are as defined in claim 4; In formula (IB-1bc) and formula (IB-1bd), R 12 ' is independently halogen, -C 1-3 alkyl, -halo-C 1-3 alkyl, -C 1-3 alkyl-hydroxy, -C 1-3 alkyl-cyano, -C 1-3 alkyl-C 1-6 alkoxy, -C 1-3 alkyl-halo-C 1-6 alkyl or -C 1-3 alkyl-halo-C 1-6 alkoxy; R1, R2, R3, R 21 、R 22 、R 31 、R 32 、P', R0', Ar', E1', X1 are as defined in claim 4.

12. The compound or its tautomer, cis-trans isomer, meso form, racemate, enantiomer, diastereomer, atropisomer or mixture thereof as claimed in claim 4, or its pharmaceutically acceptable salt, solvate or prodrug, characterized in that, The compound shown in formula (IB) is a compound of formula (IB-1d) or a compound of formula (IB-2d); wherein R1, R2, R3, R 21 , R 22 , R 12 , R 11 , R 31 , R 32 , P', R0', Ar', E1', X1 are as defined in claim 4.

13. The compound according to claim 12, or a tautomer, cis-trans isomer, meso form, racemate, enantiomer, diastereoisomer, atropisomer or a mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, characterized in that, The compound shown in 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); In formula (IB-1da) and formula (IB-1db), R 21 ' is independently halogen, -C 1-3 alkyl, -halo-C 1-3 alkyl, -C 1-3 alkyl-hydroxy, -C 1-3 alkyl-cyano, -C 1-3 alkyl-C 1-6 alkoxy, -C 1-3 alkyl-halo-C 1-6 alkyl or -C 1-3 alkyl-halo-C 1-6 alkoxy; R1, R2, R3, R 12 、R 11 、R 31 、R 32 、P', R0', Ar', E1', X1 are as defined in claim 4; In formula (IB-1dc) and formula (IB-1dd), R 12 ' is independently halogen, -C 1-3 alkyl, -halo-C 1-3 alkyl, -C 1-3 alkyl-hydroxy, -C 1-3 alkyl-cyano, -C 1-3 alkyl-C 1-6 alkoxy, -C 1-3 alkyl-halo-C 1-6 alkyl or -C 1-3 alkyl-halo-C 1-6 alkoxy; R1, R2, R3, R 21 、R 22 、R 31 、R 32 、P', R0', Ar', E1', X1 are as defined in claim 4.

14. A compound or a tautomer, cis-trans isomer, meso form, racemate, enantiomer, diastereoisomer, atropisomer or a mixture thereof as claimed in claim 7, 9, 11 or 13, or a pharmaceutically acceptable salt, solvate or prodrug thereof, characterized in that, R 21 ', R 12 ' are each independently -C 1-3 alkyl, -C 1-3 alkyl-hydroxy, -C 1-3 alkyl-cyano or -C 1-3 alkyl-C 1-6 alkoxy.

15. The compound according to claim 3, or a tautomer, cis-trans isomer, meso form, racemate, enantiomer, diastereoisomer, atropisomer or a mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, characterized in that, 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; said "substituted" means that 1, 2, 3 or 4 hydrogen atoms in the group are each independently replaced by substituents selected from group S.

16. The compound according to claim 3, or a tautomer, cis-trans isomer, meso form, racemate, enantiomer, diastereoisomer, atropisomer or a mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, characterized in that, Ar' is phenyl, a 5- or 6-membered monocyclic heteroaryl or pyridone group; and said phenyl, 5- or 6-membered monocyclic heteroaryl and pyridone group are unsubstituted or substituted by 1, 2, 3 or 4 groups independently selected from the following: halogen, cyano, hydroxy, -C 1-6 alkyl, -C 1-6 alkoxy, -NR c R d 、-C 1-4 alkyl-NR e R f ; wherein R e 、R f are each independently hydrogen or C 1-3 alkyl; R c 、R d are each independently hydrogen, -C 1-3 alkyl, -C(O)C 1-3 alkyl or -CO2C 1-3 alkyl.

17. The compound according to claim 3, or a tautomer, cis-trans isomer, meso form, racemate, enantiomer, diastereoisomer, atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, characterized in that, Ar' is selected from the following structures: In the formula, R s1 , R s2 is defined as in claim 3.

18. The compound according to claim 3, or a tautomer, cis-trans isomer, meso form, racemate, enantiomer, diastereoisomer, atropisomer or a mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, characterized in that, R0' is phenyl, a 5- or 6-membered monocyclic heteroaryl or 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 substituted by 1, 2, 3 or 4 groups independently selected from R s3 groups.

19. The compound according to claim 3, or a tautomer, cis-trans isomer, meso form, racemate, enantiomer, diastereoisomer, atropisomer or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, characterized in that, R1 and R2 are each independently hydrogen, halogen, cyano, amino, NHCH3, N(CH3)2, methyl, ethyl, n-propyl, isopropyl, chloromethyl, dichloromethyl, trichloromethyl, chloroethyl, 1,2-dichloroethyl, trichloroethyl, bromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, -CH2-hydroxy, -CH2-cyano, -CH2-methoxy, -CH2-ethoxy, -CH2-propoxy, -CH2-isopropoxy, -CH2-NH2, -CH2-NHCH3, -CH2-N(CH3)2, -CH2-3- to 6-membered heterocycloalkyl or -CH2-5- or 6-membered monocyclic heteroaryl; the 3- to 6-membered heterocycloalkyl is selected from: aziridine, ethylene oxide, azetidine, oxetane, tetrahydrofuran, tetrahydrothiophene, pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, thiomorpholine-1,1-dioxide, tetrahydropyran; the 5- or 6-membered monocyclic heteroaryl is selected from: thiophene, N-alkylpyrrole, furan, thiazole, isothiazole, imidazole, oxazole, pyrrole, pyrazole, triazole, 1,2,3-triazole, 1,2,4-triazole, 1,2,5-triazole, 1,3,4-triazole, tetrazole, isoxazole, oxadiazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, thiadiazole, pyridine, pyridazine, pyrimidine, pyrazine; the 3- to 6-membered heterocycloalkyl and 5- or 6-membered monocyclic heteroaryl are optionally substituted by 1 or 2 halogens or C 1-3 alkyl substituents.

20. The compound according to claim 3, or a tautomer, cis-trans isomer, meso form, racemate, enantiomer, diastereoisomer, atropisomer or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, characterized in that, R3 is hydrogen, halogen, methoxy, ethoxy, propoxy or isopropoxy.

21. The compound according to claim 3, or a tautomer, cis-trans isomer, meso form, racemate, enantiomer, diastereoisomer, atropisomer or a mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, characterized in that, R4 is hydrogen, chloromethyl, dichloromethyl, trichloromethyl, chloroethyl, 1,2-dichloroethyl, trichloroethyl, bromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, -CH2-hydroxy, -CH2-cyano, -CH2-methoxy, -CH2-ethoxy, -CH2-propoxy or -CH2-isopropoxy.

22. The compound according to claim 1, or a tautomer, cis-trans isomer, meso form, racemate, enantiomer, diastereoisomer, atropisomer or a mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, characterized in that, P is O, NH or NR m ; R m is -C 1-6 alkyl, -halo-C 1-6 alkyl, -C 1-6 alkyl-hydroxy, -C 1-6 alkyl-cyano, -C 1-6 alkyl-C 1-6 alkoxy, -C 1-6 alkyl-halo-C 1-6 alkoxy, -C 1-6 alkyl-C 3-6 cycloalkyl or -C 1-6 alkyl-3-to 6-membered heteroalkyl.

23. The compound or its tautomer, cis-trans isomer, meso form, racemate, enantiomer, diastereoisomer, atropisomer or mixture thereof as claimed in claim 3 or 4, or its pharmaceutically acceptable salt, solvate or prodrug, characterized in that, P' is O, NH or NR m '; R m ' is -deuterated C 1-6 alkyl, -C 1-6 alkyl, -halo-C 1-6 alkyl, -C 1-6 alkyl-hydroxy, -C 1-6 alkyl-cyano, -C 1-6 alkyl-C 1-6 alkoxy, -C 1-6 alkyl-halo-C 1-6 alkoxy, -C 1-6 alkyl-C 3-6 cycloalkyl or -C 1-6 alkyl-3- to 6-membered heterocycloalkyl; preferably, R m ' is -deuterated C 1-6 alkyl or -C 1-6 alkyl; R 42 ' is -C 1-3 alkyl-(C=O)-, -(C=O)- or -C 1-3 alkyl-.

24. The compound according to claim 3, or a tautomer, cis-trans isomer, meso form, racemate, enantiomer, diastereoisomer, atropisomer thereof or a mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, characterized in that, The compound of formula (ⅠA) is selected from Table A-1 or Table A-2.

25. A pharmaceutical composition, which comprises the compound according to any one of claims 1 to 24 or its tautomer, cis-trans isomer, meso form, racemate, enantiomer, diastereoisomer, atropisomer or a mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof; and a pharmaceutically acceptable carrier.

26. A compound represented by formula (b), formula (c), formula (d), formula (e), formula (g-1), formula (i-1), formula (j-1) or its tautomer, cis-trans isomer, meso form, racemate, enantiomer, diastereoisomer, atropisomer or a mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof: Wherein, R lev is trifluoromethanesulfonate, chlorine, bromine, iodine, methanesulfonate, toluenesulfonate or p-toluenesulfonate; X1 is hydrogen, halogen, cyano, hydroxy, amino, nitro, -substituted or unsubstituted C 1-6 alkyl, -substituted or unsubstituted C 3-6 cycloalkyl, -substituted or unsubstituted 3- to 6-membered heterocycloalkyl, -O-substituted or unsubstituted C 1-6 alkyl, -O-substituted or unsubstituted C 3-6 cycloalkyl, -O-substituted or unsubstituted 3- to 6-membered heterocycloalkyl, -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 heterocycloalkyl, -NH(C=O)-substituted or unsubstituted C 1-6 alkyl, -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 are each independently hydrogen or C 1-3 alkyl; or R j 、R k together with the attached nitrogen atom form a substituted or unsubstituted 3- to 6-membered nitrogen-containing heterocycloalkyl; the 3- to 6-membered heterocycloalkyl has 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms; the 3- to 6-membered nitrogen-containing heterocycloalkyl has 3 to 6 ring atoms and one of the ring atoms is a nitrogen atom, and 0, 1 or 2 of the remaining ring atoms are optionally heteroatoms selected from N, O and S; the "substituted" means that 1, 2, 3 or 4 hydrogen atoms in the group are each independently replaced by substituents selected from group S; The S group substituents are selected from: hydroxy, halogen, nitro, oxo group, -C 1-6 alkyl, -halo C 1-6 alkyl, hydroxy-substituted C 1-6 alkyl, benzyl, -(CH2) u -cyano, -(CH2) u -C 1-6 alkoxy, -(CH2) u -halo C 1-6 alkoxy, -(CH2) u -halo C 1-6 alkyl, -(CH2) u -3- to 6-membered heterocycloalkyl, -(CH2) u -5- or 6-membered monocyclic heteroaryl, -(CH2) u -C 3-8 cycloalkyl, -(CH2) u -O-(CH2) v -C 3-8 cycloalkyl, -(CH2) u -O-(CH2) v -C 1-6 alkoxy, -(CH2) u -O-(CH2) v OH, -(CH2) u -SO2C 1-6 alkyl, -(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)-halo C 1-6 alkyl; wherein, the 3- to 6-membered heterocycloalkyl or the 5- or 6-membered monocyclic heteroaryl each independently has 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms; the 3- to 6-membered heterocycloalkyl, 5- or 6-membered monocyclic heteroaryl is optionally substituted with 1, 2 or 3 substituents selected from halogen, cyano, -C 1-3 alkyl, -C 1-3 alkoxy and C 3-6 Substituted by a substituent of a cycloalkyl group; u and v are each independently 0, 1, 2, 3 or 4; R a0 , R b0 are each independently hydrogen or C 1-3 alkyl; E1' is N or CR5'; wherein, R5' is hydrogen, halogen, cyano, -C 1-6 alkyl, -C 1-6 alkoxy, -halo-C 1-6 alkyl, -halo-C 1-6 alkoxy, -C 3-6 cycloalkyl, -O-C 3-6 cycloalkyl, -NR h R i 、-C 1-4 alkyl-hydroxy, -C 1-4 alkyl-cyano, -C 1-4 alkyl-C 1-6 alkoxy, -C 1-4 alkyl-halo-C 1-6 alkyl or -C 1-4 alkyl-halo-C 1-6 alkoxy; Ar' is C 6-10 aryl, 5- or 6-membered monocyclic heteroaryl, 8- to 10-membered bicyclic heteroaryl or 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; 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 aryl, the 5- or 6-membered monocyclic heteroaryl, the 8- to 10-membered bicyclic heteroaryl and the pyridone group are unsubstituted or substituted by 1, 2, 3 or 4 groups independently selected from R s1 groups; Or Ar' is a structure represented by formula (B): 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 heterocycloalkyl 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 heterocycloalkyl ring has 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms; (R s1 ) p represents that the hydrogen on the B1 ring is substituted by p Rs s1 , where p is 0, 1, 2 or 3, and each R s1 is the same or different; (R s2 ) q means that the hydrogen on the B2 ring is substituted by q Rs s2 , where q is 0, 1, 2 or 3, and each R s2 is the same or different; R s1 、R s2 each independently is halogen, cyano, nitro, hydroxy, -C 1-6 alkyl, -C 1-6 alkoxy, -halo-C 1-6 alkyl, -halo-C 1-6 alkoxy, -C 3-6 cycloalkyl, -NR c R d 、-C(O)NR e R f 、-SO2C 1-3 alkyl, -SO2-halo-C 1-3 alkyl, -SO2NR e R f 、-C 1-4 alkyl-hydroxy, -C 1-4 alkyl-cyano, -C 1-4 alkyl-C 1-6 alkoxy, -C 1-4 alkyl-halo-C 1-6 alkyl, -C 1-4 alkyl-halo-C 1-6 alkoxy, -C 1-4 alkyl-3- to 6-membered heterocycloalkyl, -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 alkynyl; wherein, the 3- to 6-membered heterocycloalkyl has 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms; 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, -O-C 6-10 aryl, -C 1-3 alkyl-3- to 6-membered heterocycloalkyl, -C 1-3 alkyl-C 3-6 cycloalkyl or pyridone group, wherein the 3- to 6-membered heterocycloalkyl, the 5- or 6-membered monocyclic heteroaryl or the 8- to 10-membered bicyclic heteroaryl 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 aryl, 5- or 6-membered monocyclic heteroaryl, 8- to 10-membered bicyclic heteroaryl, 7- to 11-membered spirocycloalkyl and pyridone group are unsubstituted or substituted by 1, 2, 3 or 4 groups independently selected from R s3 ; the -C 1-3 alkyl- is unsubstituted or substituted by 1, 2, 3 or 4 groups independently selected from C 1-3 alkyl; Or R0' is a structure represented by formula (A-1) or formula (A-2): 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 heterocycloalkyl 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 heterocycloalkyl ring has 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms; (R s3 ) t represents that the hydrogen on the A1 ring is substituted by t Rs s3 , where t is 0, 1, 2 or 3, and each R s3 is the same or different; (R s4 ) s represents that the hydrogen on the A2 ring is substituted by s R s4 groups, where s is 0, 1, 2 or 3, and each R s4 is the same or different; R s3 and R s4 are each independently a halogen, cyano group, hydroxyl group, -C 1-6 alkyl, -C 1-6 alkoxy, -halo-C 1-6 alkyl, -halo-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-halo-C 1-3 alkyl, -SO2NR e R f , -C 1-3 alkyl-hydroxy, -C 1-3 alkyl-C 2-4 alkynyl, -C 1-3 alkyl-cyano, -C 1-3 alkyl-C 1-6 alkoxy, -C 1-3 alkyl-halo-C 1-6 alkyl, -C 1-3 alkyl-halo-C 1-6 alkoxy, -C 1-3 alkyl-3- to 6-membered heterocycloalkyl, -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 alkynyl; wherein the 3- to 6-membered heterocycloalkyl 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 cycloalkyl, 3- to 6-membered heterocycloalkyl is optionally substituted with 1, 2 or 3 substituents independently selected from halogen, methyl, ethyl, propyl, isopropyl, trifluoromethyl, amino, N(CH3)2, hydroxyl, carboxyl; R p is formyl, acyl, acetyl, trichloroacetyl, trifluoroacetyl, tert-butoxycarbonyl, benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl, benzyl, trityl, 1,1-bis-(4'-methoxyphenyl)methyl, trimethylsilyl, tert-butyldimethylsilyl; R 11 and R 12 are the same or different and each independently is hydrogen, halogen, -C 1-3 alkyl, -halo-C 1-3 alkyl, -C 1-3 alkyl-hydroxy, -C 1-3 alkyl-cyano, -C 1-3 alkyl-C 1-6 alkoxy, -C 1-3 alkyl-halo-C 1-6 alkyl or -C 1-3 alkyl-halo-C 1-6 alkoxy; R 21 and R 22 are the same or different and each independently is hydrogen, halogen, -C 1-3 alkyl, -halo-C 1-3 alkyl, -C 1-3 alkyl-hydroxy, -C 1-3 alkyl-cyano, -C 1-3 alkyl-C 1-6 alkoxy, -C 1-3 alkyl-halo-C 1-6 alkyl or -C 1-3 alkyl-halo-C 1-6 alkoxy; R 31 、R 32 are the same or different and each independently is hydrogen, halogen, -C 1-3 alkyl, -halo-C 1-3 alkyl, -C 1-3 alkyl-hydroxy, -C 1-3 alkyl-cyano, -C 1-3 alkyl-C 1-6 alkoxy, -C 1-3 alkyl-halo-C 1-6 alkyl or -C 1-3 alkyl-halo-C 1-6 alkoxy; R m 'is a substituted or unsubstituted C 1-6 alkyl group; R e 、R f 、R g are each independently hydrogen or C 1-3 alkyl; R c 、R d 、R h 、R i Each independently is hydrogen, -C 1-3 alkyl, -C(O)C 1-3 alkyl or -CO2C 1-3 alkyl.

27. The compound represented by formula (b), formula (c), formula (d), formula (e), formula (g-1), formula (i-1), formula (j-1) as claimed in claim 26, or its tautomer, cis-trans isomer, meso form, racemate, enantiomer, diastereoisomer, atropisomer or a mixture thereof, or its pharmaceutically acceptable salt, solvate or prodrug, wherein, 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; said "substituted" means that 1, 2, 3 or 4 hydrogen atoms in the group are each independently replaced by substituents selected from group S.

28. A compound represented by formula (b), formula (c), formula (d), formula (e), formula (g-1), formula (i-1), or formula (j-1) as claimed in claim 26, or a tautomer, cis-trans isomer, meso form, racemate, enantiomer, diastereoisomer, atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein, Ar' is phenyl, a 5- or 6-membered monocyclic heteroaryl or pyridone group; and said phenyl, 5- or 6-membered monocyclic heteroaryl and pyridone group are unsubstituted or substituted by 1, 2, 3 or 4 groups independently selected from the following: halogen, cyano, hydroxy, -C 1-6 alkyl, -C 1-6 alkoxy, -NR c R d 、-C 1-4 alkyl-NR e R f ; wherein R e 、R f are each independently hydrogen or C 1-3 alkyl; R c 、R d are each independently hydrogen, -C 1-3 alkyl, -C(O)C 1-3 alkyl or -CO2C 1-3 alkyl; Preferably, Ar' is selected from the following structures: In the formula, R s1 , R s2 are defined as in claim 26; Preferably, R0' is phenyl, a 5- or 6-membered monocyclic heteroaryl or 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 substituted by 1, 2, 3 or 4 groups independently selected from R s3 groups.

29. A compound or a tautomer, cis-trans isomer, meso form, racemate, enantiomer, diastereoisomer, atropisomer or a mixture thereof as claimed in any one of claims 26-28, or a pharmaceutically acceptable salt, solvate or prodrug thereof, characterized in that, R m '-deuterated C 1-6 alkyl, -C 1-6 alkyl, -halo-C 1-6 alkyl, -C 1-6 alkyl-hydroxy, -C 1-6 alkyl-cyano, -C 1-6 alkyl-C 1-6 alkoxy, -C 1-6 alkyl-halo-C 1-6 alkoxy, -C 1-6 alkyl-C 3-6 cycloalkyl or -C 1-6 alkyl-3- to 6-membered heteroalkyl.

30. The following compound or its tautomer, cis-trans isomer, meso form, racemate, enantiomer, diastereoisomer, atropisomer or a mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof:

31. The compound according to any one of claims 1 to 24, 26 - 30 or its tautomer, cis-trans isomer, meso form, racemate, enantiomer, diastereoisomer, atropisomer or a mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, or the use of the pharmaceutical composition according to claim 25 in the preparation of a drug for preventing and / or treating a disease induced by KRAS G12C mutation.

32. The use according to claim 31, characterized in that, The disease induced by KRAS G12C mutation is cancer.

33. The use according to claim 32, characterized in that, The cancer is pancreatic cancer, colorectal cancer or lung cancer.

34. The use according to claim 32, characterized in that, The cancer is non-small cell lung cancer.

35. The compound according to any one of claims 1 to 24, 26 - 30 or its tautomer, cis-trans isomer, meso form, racemate, enantiomer, diastereoisomer, atropisomer or a mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, or the use of the pharmaceutical composition according to claim 25 in the preparation of a KRAS mutation inhibitor; the KRAS mutation is KRAS G12C mutation.

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