Substituted heterocyclic compounds, their preparation and medical use

Abstract

A substituted heterocyclic compound having a selective inhibitory effect on KRAS gene mutation as shown in formula (I) or formula (IA) or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, a pharmaceutical composition comprising the compound and use thereof in the preparation of cancer drugs.

Description

Technical Field

[0001] The present invention relates to the field of medical technology, and in particular to a substituted heterocyclic compound, its use as a selective inhibitor of KRAS gene mutation, and a pharmaceutical composition prepared therefrom. Background Art

[0002] Lung cancer is the most common cancer worldwide. In China, its incidence ranks first among all cancers and it also has the highest incidence and mortality rate in China. According to data released by the American Cancer Society in 2016, approximately 1.8 million people worldwide are diagnosed with lung cancer each year, of which nearly 80% are non-small cell lung cancer (NSCLC).

[0003] RAS is a group of closely related monomeric globular proteins (21kDa molecular weight) with 188-189 amino acids and is bound to guanosine diphosphate (GDP) or guanosine triphosphate (GTP). Members of the RAS subfamily 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 is "inactive." When cells are exposed to certain growth-promoting stimuli, RAS is induced to convert the GDP it binds to 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 the RAS protein to hydrolyze GTP and return 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 its interaction with GAP and its ability to convert GTP to GDP. This mutation will prolong protein activation, thereby prolonging cell signaling and, in turn, leading to continued cell growth and division. Because this signaling drives cell growth and division, overactive RAS signaling can ultimately lead to cancer. Mutations in the RAS gene have been identified in approximately 32% of lung cancers. Mutations in any of the three major isoforms of RAS (HRAS, NRAS, or KRAS) can lead to human tumorigenesis. Reports indicate that KRAS is the most frequently mutated RAS gene, with KRAS mutations detected in 25-30% of tumors. In comparison, the incidence of oncogenic mutations in NRAS and HRAS family members is much lower (8% and 3%, respectively). The most common KRAS mutations are found at residues G12 and G13 in the P-loop and at residue Q61. The G12C mutation (glycine-12 to cysteine) is a frequent mutation in the KRAS gene. This mutation has been found in approximately 13% of cancers, approximately 43% of lung cancers, and almost 100% of MYH-associated polyposis (FAPS) cases. Therefore, developing inhibitors that selectively inhibit KRAS mutations is a promising approach. To enhance inhibitory activity against KRAS mutations while simultaneously reducing inhibitory activity against wild-type KRAS, developing novel RAS mutant-selective inhibitors with enhanced activity, better selectivity, and lower toxicity is of great significance. Summary of the Invention

[0004] 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.

[0005] In one aspect, the present invention provides a compound as shown in formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof:

[0006]

[0007] Where,

[0008] Z is NC(O)-CR3=CR1R2 or NC(O)-C≡CR4;

[0009] R1 and R2 are each independently hydrogen, halogen, cyano, NR a R b 、-C 1-3 Alkyl, halogenated C 1-3 Alkyl, -C 1-3 Alkyl-hydroxyl, -C 1-3 Alkyl-cyano, -C 1-3 Alkyl-C 1-3 Alkoxy, -C 1-3 Alkyl-NR a R b 、-C 1-3 alkyl-3 to 6 membered 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;

[0010] R3 is hydrogen, halogen, -C 1-3 Alkyl or -C 1-3 alkoxy;

[0011] R4 is hydrogen, halogenated C 1-3 Alkyl, -C 1-3 Alkyl-hydroxyl, -C 1-3 Alkyl-cyano or -C 1-3 Alkyl-C 1-3 alkoxy;

[0012] R 11 、R 12 The same or different, each independently hydrogen, halogen, -C 1-3 Alkyl, -halogenated C 1-3 Alkyl, -C 1-3 Alkyl-hydroxyl, -C 1-3 Alkyl-cyano, -C 1-3 Alkyl-C 1-6 Alkoxy, -C 1-3 Alkyl-halide C 1-6 Alkyl or -C 1-3 Alkyl-halide C 1-6 alkoxy;

[0013] R 21 、R 22 The same or different, each independently hydrogen, halogen, -C 1-3 Alkyl, -halogenated C 1-3 Alkyl, -C 1-3 Alkyl-hydroxyl, -C 1-3 Alkyl-cyano, -C 1-3 Alkyl-C 1-6 Alkoxy, -C 1-3 Alkyl-halide C 1-6 Alkyl or -C 1-3 Alkyl-halide C 1-6 alkoxy;

[0014] R 31 、R 32 The same or different, each independently hydrogen, halogen, -C 1-3 Alkyl, -halogenated C 1-3 Alkyl, -C 1-3 Alkyl-hydroxyl, -C 1-3 Alkyl-cyano, -C 1-3 Alkyl-C 1-6 Alkoxy, -C 1-3 Alkyl-halide C 1-6 Alkyl or -C 1-3 Alkyl-halide C 1-6 alkoxy;

[0015] R 41 For hydrogen, halogen, -C 1-3 Alkyl, -halogenated C 1-3 Alkyl, -C 1-3 Alkyl-hydroxyl, -C 1-3 Alkyl-cyano, -C 1-3 Alkyl-C 1-6 Alkoxy, -C 1-3 Alkyl-halide C 1-6 Alkyl or -C 1-3 Alkyl-halide C 1-6 alkoxy;

[0016] when When the dotted line in the figure is a single bond, P is O, NH or NR m ; R m -C 1-6 Alkyl, -halogenated C 1-6 Alkyl, -C 1-6 Alkyl-hydroxyl, -C 1-6 Alkyl-cyano, -C 1-6 Alkyl-C 1-6 Alkoxy, -C 1-6 Alkyl-halogenated C1-6 alkoxy, -C 1-6 Alkyl-C3-6 Cycloalkyl or -C 1-6 Alkyl-3-membered to 6-membered heterocycloalkyl; R 42 -(C=O)-, -C 1-3 Alkyl-, -C 1-3 Alkyl (hydroxy) -, -C 1-3 Alkyl (cyano)-, -C 1-3 Alkyl (C 1-6 Alkyl)-, -C 1-3 Alkyl (halogenated C 1-6 Alkyl)-, -C 1-3 Alkyl (C 1-6 Alkyl-hydroxy)-, -C 1-3 Alkyl (C 1-6 Alkyl-cyano)-, -C 1-3 Alkyl (C 1-6 Alkoxy)-, or -C 1-3 Alkyl (halogenated C 1-6 Alkoxy)-;

[0017] or when When the dotted line is absent, P is hydrogen or halogen; R 42 For hydrogen, halogen, -C 1-3 Alkyl, -halogenated C 1-3 Alkyl, -C 1-3 Alkyl-hydroxyl, -C 1-3 Alkyl-cyano, -C 1-3 Alkyl-C 1-6 Alkoxy, -C 1-3 Alkyl-halide C 1-6 Alkyl or -C 1-3 Alkyl-halide C 1-6 alkoxy;

[0018] When Y1 is C; X1 is hydrogen, halogen, cyano, hydroxyl, amino, nitro, -substituted or unsubstituted C 1-6 Alkyl, -substituted or unsubstituted C 3-6 Cycloalkyl, -substituted or unsubstituted 3 to 6 membered 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 3-6Cycloalkyl, -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 connected nitrogen atom, it forms a substituted or unsubstituted 3- to 6-membered nitrogen-containing heterocycloalkyl group; the 3- to 6-membered heterocycloalkyl group has 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 1, 2, 3 or 4 hydrogen atoms in the group being replaced by substituents independently selected from Group S;

[0019] Or when Y1 is N, X1 is none;

[0020] 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 1-6 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 1-6Alkoxy, -(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 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 heteroatoms selected from halogen, cyano, -C 1-3 Alkyl, -C 1-3 Alkoxy and C 3-6 The cycloalkyl group is substituted by a 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;

[0021] 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-hydroxyl, -C 1-4 Alkyl-cyano, -C 1-4 Alkyl-C 1-6 Alkoxy, -C 1-4 Alkyl-halide C 1-6 Alkyl or -C 1-4 Alkyl-halide C 1-6 alkoxy;

[0022] E2 is N or CR6; wherein R6 is hydrogen, halogen, cyano, -C 1-6 Alkyl, -C 1-6 Alkoxy, -halogenated C 1-6 Alkyl, -halogenated C 1-6 Alkoxy, -C3-6 cycloalkyl, -NR h R i 、-C 1-4 Alkyl-hydroxyl, -C 1-4 Alkyl-cyano, -C 1-4 Alkyl-C 1-6 Alkoxy, -C 1-4 Alkyl-halide C 1-6 Alkyl or -C 1-4 Alkyl-halide C 1-6 alkoxy;

[0023] The condition is that Y1, E1, and E2 are not N at the same time;

[0024] Ar is C 6-10 aryl, 5- or 6-membered monocyclic heteroaryl or 8- to 10-membered bicyclic heteroaryl; wherein the 5- or 6-membered monocyclic heteroaryl has 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms; the 8- to 10-membered bicyclic heteroaryl has 1, 2, 3, 4 or 5 heteroatoms selected from N, O and S as ring atoms; and the C 6-10 The aryl group, the 5- or 6-membered monocyclic heteroaryl group or the 8- to 10-membered bicyclic heteroaryl group is unsubstituted or substituted by 1, 2, 3 or 4 groups independently selected from R s1 The group substitution;

[0025] or

[0026] Ar is a structure represented by formula (B):

[0027]

[0028] wherein the B1 ring is a benzene ring or a 5- or 6-membered monocyclic heteroaryl ring; the B2 ring 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;

[0029] (R s1 ) p Indicates that the hydrogen on the B1 ring is replaced by p R s1 Substitution, p is 0, 1, 2 or 3, each R s1 Same or different;

[0030] (R s2 ) q Indicates that the hydrogen on the B2 ring is replaced by q Rs2 substituted, q is 0, 1, 2 or 3, each R s2 Same or different;

[0031] R s1 、R s2 are independently halogen, cyano, nitro, hydroxyl, -C 1-6 Alkyl, -C 1-6 Alkoxy, -halogenated C 1-6 Alkyl, -halogenated C 1-6 Alkoxy, -C 3-6 Cycloalkyl, -NR c R d 、-C(O)NR e R f 、-SO2C 1-3 Alkyl, -SO2 haloC 1-3 Alkyl, -SO2NR e R f 、-C 1-4 Alkyl-hydroxyl, -C 1-4 Alkyl-cyano, -C 1-4 Alkyl-C 1-6 Alkoxy, -C 1-4 Alkyl-halide C 1-6 Alkyl, -C 1-4 Alkyl-halide 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 wherein the 3- to 6-membered heterocycloalkyl group has 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms;

[0032] R0 is -C 1-6 Alkyl, -C 3-6 Cycloalkyl, 3 to 6 membered heterocycloalkyl, C 6-10 Aryl, 5- or 6-membered monocyclic heteroaryl, 8- to 10-membered bicyclic heteroaryl, 7- to 11-membered spirocycloalkyl, -C 1-3 Alkyl-C 6-10 Aryl, -C 1-3 Alkyl-5 or 6-membered monocyclic heteroaryl, -NR g -C 6-10 Aryl, -OC 6-10 Aryl, -C 1-3Alkyl-3 to 6-membered 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 group substituted; the -C 1-3 Alkyl- is unsubstituted or substituted by 1, 2, 3 or 4 groups independently selected from C 1-3 Alkyl substitution;

[0033] or

[0034] R0 is a structure represented by formula (A-1) or formula (A-2):

[0035]

[0036] wherein the A1 ring is a benzene ring or a 5- or 6-membered monocyclic heteroaryl ring; the A2 ring 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;

[0037] (R s3 ) t Indicates that the hydrogen on the A1 ring is replaced by t R s3 Substitution, t is 0, 1, 2 or 3, each R s3 Same or different;

[0038] (R s4 ) s Indicates that the hydrogen on the A2 ring is replaced by s R s4 Substitution, s is 0, 1, 2 or 3, each R s4 Same or different;

[0039] R s3 、R s4 are independently halogen, cyano, hydroxyl, -C 1-6 Alkyl, -C 1-6 Alkoxy, -halogenated C 1-6 Alkyl, -halogenated C 1-6 Alkoxy, -C 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl, -NR h R i 、-C(O)NRe R f 、-SO2C 1-3 Alkyl, -SO2 haloC 1-3 Alkyl, -SO2NR e R f 、-C 1-3 Alkyl-hydroxyl, -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-halide C 1-6 Alkyl, -C 1-3 Alkyl-halide 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 wherein the 3- to 6-membered heterocycloalkyl group has 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms; and the C 1-6 Alkyl, -C 1-6 Alkoxy, -C 1-3 Alkyl-, -C 3-6 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;

[0040] R a 、R b 、R e 、R f 、R g are each independently hydrogen or C 1-3 alkyl;

[0041] R c 、R d 、R h 、R i are independently hydrogen, -C 1-3 Alkyl, -C(O)C 1-3 Alkyl or -CO2C 1-3 alkyl.

[0042] 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);

[0043]

[0044] In formula I-1, P is O, NH or NR m ; R m -C 1-6 Alkyl, -halogenated C 1-6 Alkyl, -C 1-6 Alkyl-hydroxyl, -C 1-6 Alkyl-cyano, -C 1-6 Alkyl-C 1-6 Alkoxy, -C 1-6 Alkyl-halide C 1-6 Alkoxy, -C 1-6 Alkyl-C 3-6 Cycloalkyl or -C 1-6 Alkyl-3-membered to 6-membered heterocycloalkyl; R 42 -(C=O)-, -C 1-3 Alkyl-, -C 1-3 Alkyl (hydroxy) -, -C 1-3 Alkyl (cyano)-, -C 1-3 Alkyl (C 1-6 Alkyl)-, -C 1-3 Alkyl (halogenated C 1-6 Alkyl)-, -C 1-3 Alkyl (C 1-6 Alkyl-hydroxy)-, -C 1-3 Alkyl (C 1-6 Alkyl-cyano)-, -C 1-3 Alkyl (C 1-6 Alkoxy)-, or -C 1-3 Alkyl (halogenated C 1-6 Alkoxy)-; R 11 、R 12 、R 21 、R 22 、R 31 、R 32 、R 41 , Z, R0, Ar, E1, E2, X1, Y1 are as defined above;

[0045] In formula I-2, P is hydrogen or halogen; R 42 For hydrogen, halogen, -C 1-3 Alkyl, -halogenated C 1-3 Alkyl, -C 1-3 Alkyl-hydroxyl, -C 1-3 Alkyl-cyano, -C 1-3 Alkyl-C 1-6 Alkoxy, -C1-3 Alkyl-halide C 1-6 Alkyl or -C 1-3 Alkyl-halide C 1-6 Alkoxy; R 11 、R 12 、R 21 、R 22 、R 31 、R 32 、R 41 , Z, R0, Ar, E1, E2, X1, and Y1 are defined as before.

[0046] In another aspect, the present invention provides a compound as shown in formula (IA) or its tautomer, cis-trans isomer, meso-isomer, racemate, enantiomer, diastereomer, atropisomer or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof:

[0047]

[0048] Where,

[0049] Z is NC(O)-CR3=CR1R2 or NC(O)-C≡CR4;

[0050] R1 and R2 are each independently hydrogen, halogen, cyano, NR a R b 、-C 1-3 Alkyl, halogenated C 1-3 Alkyl, -C 1-3 Alkyl-hydroxyl, -C 1-3 Alkyl-cyano, -C 1-3 Alkyl-C 1-3 Alkoxy, -C 1-3 Alkyl-NR a R b 、-C 1-3 alkyl-3 to 6 membered 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;

[0051] R3 is hydrogen, halogen, -C 1-3 Alkyl or -C 1-3 alkoxy;

[0052] R4 is hydrogen, halogenated C 1-3 Alkyl, -C 1-3 Alkyl-hydroxyl, -C 1-3 Alkyl-cyano or -C 1-3 Alkyl-C 1-3 alkoxy;

[0053] R 11 、R 12 The same or different, each independently hydrogen, halogen, -C 1-3 Alkyl, -halogenated C 1-3 Alkyl, -C 1-3 Alkyl-hydroxyl, -C 1-3 Alkyl-cyano, -C 1-3 Alkyl-C 1-6 Alkoxy, -C 1-3 Alkyl-halide C 1-6 Alkyl or -C 1-3 Alkyl-halide C 1-6 alkoxy;

[0054] R 21 、R 22 The same or different, each independently hydrogen, halogen, -C 1-3 Alkyl, -halogenated C 1-3 Alkyl, -C 1-3 Alkyl-hydroxyl, -C 1-3 Alkyl-cyano, -C 1-3 Alkyl-C 1-6 Alkoxy, -C 1-3 Alkyl-halide C 1-6 Alkyl or -C 1-3 Alkyl-halide C 1-6 alkoxy;

[0055] R 31 、R 32 The same or different, each independently hydrogen, halogen, -C 1-3 Alkyl, -halogenated C 1-3 Alkyl, -C 1-3 Alkyl-hydroxyl, -C 1-3 Alkyl-cyano, -C 1-3 Alkyl-C 1-6 Alkoxy, -C 1-3 Alkyl-halide C 1-6 Alkyl or -C 1-3 Alkyl-halide C 1-6 alkoxy;

[0056] R 41 For hydrogen, halogen, -C 1-3 Alkyl, -halogenated C1-3 alkyl, -C 1-3 Alkyl-hydroxyl, -C 1-3 Alkyl-cyano, -C 1-3 Alkyl-C 1-6 Alkoxy, -C 1-3 Alkyl-halide C 1-6 Alkyl or -C 1-3 Alkyl-halide C 1-6alkoxy;

[0057] when When the dotted line in the figure is a single bond, P′ is O, NH or NR m ′;R m ' is deuterated C 1-6 Alkyl, -C 1-6 Alkyl, -halogenated C 1-6 Alkyl, -C 1-6 Alkyl-hydroxyl, -C 1-6 Alkyl-cyano, -C 1-6 Alkyl-C 1-6 Alkoxy, -C 1-6 Alkyl-halide C 1-6 Alkoxy, -C 1-6 Alkyl-C 3-6 Cycloalkyl or -C 1-6 Alkyl-3-membered 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 (halogenated C 1-6 Alkyl)-, -C 1-3 Alkyl (C 1-6 Alkyl-hydroxy)-, -C 1-3 Alkyl (C 1-6 Alkyl-cyano)-, -C 1-3 Alkyl (C 1-6 Alkoxy)-, or -C 1-3 Alkyl (halogenated C 1-6 Alkoxy)-;

[0058] or when When the dashed line is absent, P′ is hydrogen or halogen; R 42 ' is hydrogen, halogen, -C 1-3 Alkyl, -halogenated C 1-3 Alkyl, -C 1-3 Alkyl-hydroxyl, -C 1-3 Alkyl-cyano, -C 1-3 Alkyl-C 1-6 Alkoxy, -C 1-3 Alkyl-halide C 1-6 Alkyl or -C 1-3 Alkyl-halide C 1-6 alkoxy;

[0059] When Y1 is C; X1 is hydrogen, halogen, cyano, hydroxyl, amino, nitro, -substituted or unsubstituted C 1-6 Alkyl, -substituted or unsubstituted C 3-6 Cycloalkyl, -substituted or unsubstituted 3 to 6 membered 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 connected nitrogen atom, it forms a substituted or unsubstituted 3- to 6-membered nitrogen-containing heterocycloalkyl group; the 3- to 6-membered heterocycloalkyl group has 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 1, 2, 3 or 4 hydrogen atoms in the group being replaced by substituents independently selected from Group S;

[0060] Or when Y1 is N, X1 is none;

[0061] 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 1-6 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 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 heteroatoms selected from halogen, cyano, -C 1-3 Alkyl, -C 1-3 Alkoxy and C 3-6 The cycloalkyl group is substituted by a 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;

[0062] 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, -OC 3-6 Cycloalkyl, -NR h R i 、-C 1-4 Alkyl-hydroxyl, -C 1-4 Alkyl-cyano, -C 1-4 Alkyl-C 1-6 Alkoxy, -C 1-4 Alkyl-halide C 1-6 Alkyl or -C 1-4 Alkyl-halide C 1-6 alkoxy;

[0063] E2′ is N or CR6′; wherein R6′ 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, -OC 3-6 Cycloalkyl, -NR h R i 、-C 1-4 Alkyl-hydroxyl, -C 1-4 Alkyl-cyano, -C 1-4 Alkyl-C 1-6 Alkoxy, -C 1-4 Alkyl-halide C 1-6 Alkyl or -C 1-4 Alkyl-halide C 1-6 alkoxy;

[0064] The condition is that Y1, E1′, and E2′ are not N at the same time;

[0065] Ar′ is C 6-10 aryl, 5- or 6-membered monocyclic heteroaryl, 8- to 10-membered bicyclic heteroaryl or pyridinone; wherein the 5- or 6-membered monocyclic heteroaryl has 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms; the 8- to 10-membered bicyclic heteroaryl has 1, 2, 3, 4 or 5 heteroatoms selected from N, O and S as ring atoms; and the C 6-10 The aryl group, the 5- or 6-membered monocyclic heteroaryl group, the 8- to 10-membered bicyclic heteroaryl group and the pyridinone group are unsubstituted or substituted by 1, 2, 3 or 4 groups independently selected from R s1 The group substitution;

[0066] Or Ar' is a structure represented by formula (B):

[0067]

[0068] wherein the B1 ring is a benzene ring or a 5- or 6-membered monocyclic heteroaryl ring; the B2 ring 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;

[0069] (R s1 ) p Indicates that the hydrogen on the B1 ring is replaced by p R s1 Substitution, p is 0, 1, 2 or 3, each R s1 Same or different;

[0070] (R s2 ) q Indicates that the hydrogen on the B2 ring is replaced by q R s2 substituted, q is 0, 1, 2 or 3, each R s2 Same or different;

[0071] R s1 、R s2 are independently halogen, cyano, nitro, hydroxyl, -C 1-6 Alkyl, -C 1-6 Alkoxy, -halogenated C 1-6 Alkyl, -halogenated C 1-6 Alkoxy, -C 3-6 Cycloalkyl, -NR c R d 、-C(O)NR e R f 、-SO2C 1-3 Alkyl, -SO2 haloC 1-3 Alkyl, -SO2NR e R f 、-C 1-4 Alkyl-hydroxyl, -C 1-4 Alkyl-cyano, -C 1-4 Alkyl-C 1-6 Alkoxy, -C 1-4 Alkyl-halide C 1-6 Alkyl, -C 1-4 Alkyl-halide 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 eR f 、-C 1-4 Alkyl-SO2C 1-3 Alkyl or C 2-4 wherein the 3- to 6-membered heterocycloalkyl group has 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms;

[0072] R0′ is -C 1-6 Alkyl, -C 3-6 Cycloalkyl, 3 to 6 membered heterocycloalkyl, C 6-10 Aryl, 5- or 6-membered monocyclic heteroaryl, 8- to 10-membered bicyclic heteroaryl, 7- to 11-membered spirocycloalkyl, -C 1-3 Alkyl-C 6-10 Aryl, -C 1-3 Alkyl-5 or 6-membered monocyclic heteroaryl, -NR g -C 6-10 Aryl, -OC 6-10 Aryl, -C 1-3 Alkyl-3 to 6-membered heterocycloalkyl, -C 1-3 Alkyl-C 3-6 Cycloalkyl or pyridone, 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 pyridinone are unsubstituted or substituted by 1, 2, 3 or 4 groups independently selected from R s3 The group substituted; the -C 1-3 Alkyl- is unsubstituted or substituted by 1, 2, 3 or 4 groups independently selected from C 1-3 Alkyl substitution;

[0073] Or R0′ is a structure represented by formula (A-1) or formula (A-2):

[0074]

[0075] wherein the A1 ring is a benzene ring or a 5- or 6-membered monocyclic heteroaryl ring; the A2 ring 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;

[0076] (R s3 ) t Indicates that the hydrogen on the A1 ring is replaced by t R s3Substitution, t is 0, 1, 2 or 3, each R s3 Same or different;

[0077] (R s4 ) s Indicates that the hydrogen on the A2 ring is replaced by s R s4 Substitution, s is 0, 1, 2 or 3, each R s4 Same or different;

[0078] R s3 、R s4 are independently halogen, cyano, hydroxyl, -C 1-6 Alkyl, -C 1-6 Alkoxy, -halogenated C 1-6 Alkyl, -halogenated C 1-6 Alkoxy, -C 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl, -NR h R i 、-C(O)NR e R f 、-SO2C 1-3 Alkyl, -SO2 haloC 1-3 Alkyl, -SO2NR e R f 、-C 1-3 Alkyl-hydroxyl, -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-halide C 1-6 Alkyl, -C 1-3 Alkyl-halide 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 wherein the 3- to 6-membered heterocycloalkyl group has 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms; and the C 1-6 Alkyl, -C 1-6 Alkoxy, -C 1-3 Alkyl-, -C 3-6Cycloalkyl, 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;

[0079] R a 、R b 、R e 、R f 、R g are each independently hydrogen or C 1-3 alkyl;

[0080] R c 、R d 、R h 、R i are independently hydrogen, -C 1-3 Alkyl, -C(O)C 1-3 Alkyl or -CO2C 1-3 alkyl.

[0081] 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);

[0082]

[0083] In formula IB, P' is O, NH or NR m ′;R m ' is deuterated C 1-6 Alkyl, -C 1-6 Alkyl, -halogenated C 1-6 Alkyl, -C 1-6 Alkyl-hydroxyl, -C 1-6 Alkyl-cyano, -C 1-6 Alkyl-C 1-6 Alkoxy, -C 1-6 Alkyl-halide C 1-6 Alkoxy, -C 1-6 Alkyl-C 3-6 Cycloalkyl or -C 1-6 Alkyl-3-membered 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 (halogenated C 1-6 Alkyl)-, -C 1-3 Alkyl (C 1-6Alkyl-hydroxy)-, -C 1-3 Alkyl (C 1-6 Alkyl-cyano)-, -C 1-3 Alkyl (C 1-6 Alkoxy)-, or -C 1-3 Alkyl (halogenated C 1-6 Alkoxy)-; R 11 、R 12 、R 21 、R 22 、R 31 、R 32 、R 41 , Z, R0′, Ar′, E1′, E2′, X1, and Y1 are as defined above;

[0084] In formula IC, P' is hydrogen or halogen; R 42 ' is hydrogen, halogen, -C 1-3 Alkyl, -halogenated C 1-3 Alkyl, -C 1-3 Alkyl-hydroxyl, -C 1-3 Alkyl-cyano, -C 1-3 Alkyl-C 1-6 Alkoxy, -C 1-3 Alkyl-halide C 1-6 Alkyl or -C 1-3 Alkyl-halide C 1-6 Alkoxy; R 11 、R 12 、R 21 、R 22 、R 31 、R 32 、R 41 , Z, R0′, Ar′, E1′, E2′, X1, and Y1 are defined as before.

[0085] In 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-.

[0086] 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 ′ is -C 1-3Alkyl-(C=O)-, -(C=O)- or -C 1-3 alkyl-.

[0087] In one embodiment of the present invention, in Formula IB, P' is O, NH or NR m ′;R m ' 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-.

[0088] 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)-.

[0089] 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)-.

[0090] In one embodiment of the present invention, in Formula IB, P' is NH or NR m ′;R m ' is a deuterated methyl group or a methyl group; R 42 ' is -CH2-(C=O)-, -CH2CH2-(C=O)- or -(C=O)-.

[0091] In one embodiment of the present invention, in Formula IB, P′ is O; R 42 ′ is -C 1-3 alkyl-.

[0092] In one embodiment of the present invention, in Formula IB, P′ is O; R 42 ' is -CH2-.

[0093] 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);

[0094]

[0095] 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 as defined above.

[0096] 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-.

[0097] 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)-.

[0098] 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)-.

[0099] In one embodiment of the present invention, in formula IB-1, P' is NH or NR m ′;R m ' is a deuterated methyl group or a methyl group; R 42 ' is -CH2-(C=O)-, -CH2CH2-(C=O)- or -(C=O)-.

[0100] In one embodiment of the present invention, in formula IB-1, P′ is O; R 42 ′ is -C 1-3 alkyl-.

[0101] In one embodiment of the present invention, in formula IB-1, P′ is O; R42 ' is -CH2-.

[0102] 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-isomer, racemate, enantiomer, diastereomer, atropisomer or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof:

[0103]

[0104] Among them, R1, R2, R3, R 21 、R 22 、R 12 、R 11 、R 31 、R 32 , P′, R0′, Ar′, E1′, and X1 are defined as before.

[0105] 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.

[0106] 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.

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

[0108] 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);

[0109]

[0110] In formula (IB-1aa) and formula (IB-1ab), R 21 ' is independently halogen, -C 1-3 Alkyl, -halogenated C 1-3 Alkyl, -C 1-3 Alkyl-hydroxyl, -C 1-3 Alkyl-cyano, -C 1-3 Alkyl-C1-6 Alkoxy, -C 1-3 Alkyl-halide C 1-6 Alkyl or -C 1-3 Alkyl-halide C 1-6 Alkoxy; R1, R2, R3, R 12 、R 11 、R 31 、R 32 , P′, R0′, Ar′, E1′, X1 are as defined above;

[0111] In formula (IB-1ac) and formula (IB-1ad), R 12 ' is independently halogen, -C 1-3 Alkyl, -halogenated C 1-3 Alkyl, -C 1-3 Alkyl-hydroxyl, -C 1-3 Alkyl-cyano, -C 1-3 Alkyl-C 1-6 Alkoxy, -C 1-3 Alkyl-halide C 1-6 Alkyl or -C 1-3 Alkyl-halide C 1-6 Alkoxy; R1, R2, R3, R 21 、R 22 、R 31 、R 32 , P′, R0′, Ar′, E1′, and X1 are defined as before.

[0112] 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-isomer, racemate, enantiomer, diastereomer, atropisomer or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof:

[0113]

[0114] Among them, R1, R2, R3, R 21 、R 22 、R 12 、R 11 、R 31 、R 32 , P′, R0′, Ar′, E1′, and X1 are defined as before.

[0115] 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 1-6 alkyl.

[0116] 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.

[0117] In one embodiment of the present invention, in formula IB-1c, P' is NH or NR m ′;R m ' is a deuterated methyl group or a methyl group.

[0118] 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);

[0119]

[0120] In formula (IB-1ca) and formula (IB-1cb), R 21 ' is independently halogen, -C 1-3 Alkyl, -halogenated C 1-3 Alkyl, -C 1-3 Alkyl-hydroxyl, -C 1-3 Alkyl-cyano, -C 1-3 Alkyl-C 1-6 Alkoxy, -C 1-3 Alkyl-halide C 1-6 Alkyl or -C 1-3 Alkyl-halide C 1-6 Alkoxy; R1, R2, R3, R 12 、R 11 、R 31 、R 32 , P′, R0′, Ar′, E1′, X1 are as defined above;

[0121] In formula (IB-1cc) and formula (IB-1cd), R 12 ' is independently halogen, -C 1-3 Alkyl, -halogenated C 1-3 Alkyl, -C 1-3 Alkyl-hydroxyl, -C 1-3 Alkyl-cyano, -C 1-3 Alkyl-C 1-6 Alkoxy, -C 1-3 Alkyl-halide C 1-6 Alkyl or -C 1-3 Alkyl-halide C 1-6 Alkoxy; R1, R2, R3, R 21 、R 22 、R 31、R 32 , P′, R0′, Ar′, E1′, and X1 are defined as before.

[0122] 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.

[0123] 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.

[0124] 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.

[0125] 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-isomer, racemate, enantiomer, diastereomer, atropisomer or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof:

[0126]

[0127] Among them, R1, R2, R3, R 21 、R 22 、R 12 、R 11 、R 31 、R 32 , P′, R0′, Ar′, E1′, and X1 are defined as before.

[0128] 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);

[0129]

[0130] In formula (IB-1ba) and formula (IB-1bb), R21 ' is independently halogen, -C 1-3 Alkyl, -halogenated C 1-3 Alkyl, -C 1-3 Alkyl-hydroxyl, -C 1-3 Alkyl-cyano, -C 1-3 Alkyl-C 1-6 Alkoxy, -C 1-3 Alkyl-halide C 1-6 Alkyl or -C 1-3 Alkyl-halide C 1-6 Alkoxy; R1, R2, R3, R 12 、R 11 、R 31 、R 32 , P′, R0′, Ar′, E1′, X1 are as defined above;

[0131] In formula (IB-1bc) and formula (IB-1bd), R 12 ' is independently halogen, -C 1-3 Alkyl, -halogenated C 1-3 Alkyl, -C 1-3 Alkyl-hydroxyl, -C 1-3 Alkyl-cyano, -C 1-3 Alkyl-C 1-6 Alkoxy, -C 1-3 Alkyl-halide C 1-6 Alkyl or -C 1-3 Alkyl-halide C 1-6 Alkoxy; R1, R2, R3, R 21 、R 22 、R 31 、R 32 , P′, R0′, Ar′, E1′, and X1 are defined as before.

[0132] 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-isomer, racemate, enantiomer, diastereomer, atropisomer or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof:

[0133]

[0134] Among them, R1, R2, R3, R 21 、R 22 、R 12 、R 11 、R 31 、R 32 , P′, R0′, Ar′, E1′, and X1 are defined as before.

[0135] 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);

[0136]

[0137] In formula (IB-1da) and formula (IB-1db), R 21 ' is independently halogen, -C 1-3 Alkyl, -halogenated C 1-3 Alkyl, -C 1-3 Alkyl-hydroxyl, -C 1-3 Alkyl-cyano, -C 1-3 Alkyl-C 1-6 Alkoxy, -C 1-3 Alkyl-halide C 1-6 Alkyl or -C 1-3 Alkyl-halide C 1-6 Alkoxy; R1, R2, R3, R 12 、R 11 、R 31 、R 32 , P′, R0′, Ar′, E1′, X1 are as defined above;

[0138] In formula (IB-1dc) and formula (IB-1dd), R 12 ' is independently halogen, -C 1-3 Alkyl, -halogenated C 1-3 Alkyl, -C 1-3 Alkyl-hydroxyl, -C 1-3 Alkyl-cyano, -C 1-3 Alkyl-C 1-6 Alkoxy, -C 1-3 Alkyl-halide C 1-6 Alkyl or -C 1-3 Alkyl-halide C 1-6 Alkoxy; R1, R2, R3, R 21 、R 22 、R 31 、R 32 , P′, R0′, Ar′, E1′, and X1 are defined as before.

[0139] In one embodiment of the present invention, in Formula IB-1b, Formula IB-1d, Formula IB-2b, Formula IB-2d, P' is independently O.

[0140] In one embodiment of the present invention, R 21 ′、R 12 ' are each independently -C 1-3 Alkyl, -C1-3 Alkyl-hydroxyl, -C 1-3 Alkyl-cyano or -C 1-3 Alkyl-C 1-6 Alkoxy.

[0141] 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.

[0142] In one embodiment of the present invention, R 21 ′、R 12 ' are each independently methyl, ethyl, n-propyl or isopropyl.

[0143] 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" refers to 1, 2, 3 or 4 hydrogen atoms in the group are replaced by substituents independently selected from Group S.

[0144] 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.

[0145] 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.

[0146] In one embodiment of the present invention, X1 is fluoro, chloro or cyclopropyl.

[0147] In one embodiment of the present invention, Y1 is C; E1′ is N or CR5′; E2′ is CR6′; and R5′ and R6′ are each as defined above.

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

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

[0150] In one embodiment of the present invention, Y1 is C; E1' is N or CF; and E2' is CH.

[0151] In one embodiment of the present invention, Ar' is phenyl, 5 or 6-membered monocyclic heteroaryl or pyridinone; and the phenyl, 5 or 6-membered monocyclic heteroaryl and pyridinone are unsubstituted or substituted by 1, 2, 3 or 4 groups independently selected from the following groups: halogen, cyano, hydroxyl, -C 1-6 Alkyl, -C 1-6 Alkoxy, -NR c R d 、-C 1-4 Alkyl-NR e R f ; where R e 、R f are each independently hydrogen or C 1-3 Alkyl; R c 、R d are independently hydrogen, -C 1-3 Alkyl, -C(O)C 1-3 Alkyl or -CO2C 1-3 alkyl.

[0152] In one embodiment of the present invention, Ar' is phenyl or pyridonyl; and the phenyl and pyridonyl are unsubstituted or substituted by 1, 2, 3 or 4 groups independently selected from the following groups: fluoro, chloro, bromo, cyano, hydroxy, -C 1-3 Alkyl, -C 1-3 Alkoxy, -NH2, -NHCH3, -N(CH3)2, -CH2-NH2, -CH2-NHCH3, -CH2-N(CH3)2.

[0153] In one embodiment of the present invention, Ar' is phenyl; said phenyl is substituted by one selected from R s1 The group substituted; R s1 Halogen, cyano, -C 1-6 Alkyl, -C 1-6 Alkoxy, -halogenated C 1-6 Alkyl, -halogenated C 1-6 Alkoxy or -C 3-6 Cycloalkyl.

[0154] In one embodiment of the present invention, Ar' is selected from the following structures: Where R s1 、R s2 Same definition as above.

[0155] In one embodiment of the present invention, Ar' is selected from the following structures: Where R s1 is hydroxyl; R s2 Halogen, cyano, -C 1-6 Alkyl, -C 1-6Alkoxy, -halogenated C 1-6 Alkyl, -halogenated C 1-6 Alkoxy or -C 3-6 In one embodiment of the present invention, the R s1 Above the plane of the benzene ring.

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

[0157] In one embodiment of the present invention, R0′ is phenyl, 5- or 6-membered monocyclic heteroaryl or pyridinone, 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 pyridinone are unsubstituted or replaced by 1, 2, 3 or 4 independently selected from R s3 substituted by a group.

[0158] In one embodiment of the present invention, R0′ is phenyl, thiazolyl, isothiazolyl, imidazolyl, oxazolyl, isoxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl or pyridonyl, and the phenyl, thiazolyl, isothiazolyl, imidazolyl, oxazolyl, isoxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl and pyridonyl groups are unsubstituted or substituted by 1, 2, 3 or 4 groups independently selected from R s3 substituted by a group.

[0159] In one embodiment of the present invention, R0′ is selected from the following structures:

[0160]

[0161] In the above structures, R s3 ' are the same or different, each independently selected from hydrogen, halogen, cyano, hydroxyl, -C 1-6 Alkyl, -C 1-6 Alkoxy, -halogenated C 1-6 Alkyl, -halogenated C 1-6 Alkoxy, -C 3-6 Cycloalkyl, -NR h R i 、-C(O)NRe R f 、-C 1-3 Alkyl-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, hydroxyl, carboxyl; wherein R e 、R f are each independently hydrogen or C 1-3 Alkyl; R h 、R i are independently hydrogen, -C 1-3 Alkyl, -C(O)C 1-3 Alkyl or -CO2C 1-3 alkyl;

[0162] In the above structures, R s3 "same or different, each independently selected from hydrogen, halogen, cyano, hydroxyl, -C 1-6 Alkyl, -C 1-6 Alkoxy, -halogenated C 1-6 Alkyl, -halogenated C 1-6 Alkoxy, -C 3-6 Cycloalkyl, -NR h R i 、-C(O)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, hydroxyl, carboxyl; wherein R e 、R f are each independently hydrogen or C 1-3 Alkyl; R h 、R i are independently hydrogen, -C 1-3 Alkyl, -C(O)C 1-3 Alkyl or -CO2C 1-3 alkyl;

[0163] In the above structures, R s3 ' are the same or different and are independently selected from hydrogen, -C 1-6 Alkyl, -halogenated C 1-6 Alkyl, -C 3-6 Cycloalkyl, -C1-3 Alkyl-C(O)NR e R f 、-C(O)NR e R f 、-C 1-4 Alkyl-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, hydroxyl, carboxyl; wherein R e 、R f are each independently hydrogen or C 1-3 alkyl;

[0164] In the above structures, R s3 The same or different, each independently selected from halogen, cyano, hydroxyl, -C 1-6 Alkyl, -C 1-6 Alkoxy, -halogenated C 1-6 Alkyl, -halogenated C 1-6 Alkoxy, -C 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl, -NR h R i 、-C(O)NR e R f 、-SO2C 1-3 Alkyl, -SO2 haloC 1-3 Alkyl, -SO2NR e R f 、-C 1-3 Alkyl-hydroxyl, -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-halide C 1-6 Alkyl, -C 1-3 Alkyl-halide 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 1-3Alkyl or C 2-4 wherein the 3- to 6-membered heterocycloalkyl group has 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms; and the C 1-6 Alkyl, -C 1-6 Alkoxy, -C 1-3 Alkyl-, -C 3-6 Cycloalkyl, 3 to 6 membered heterocycloalkyl are optionally substituted by 1, 2 or 3 substituents independently selected from halogen, methyl, ethyl, propyl (n-propyl), isopropyl, trifluoromethyl, amino, N(CH3)2, hydroxyl, carboxyl; wherein R h 、R i are 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;

[0165] In the above structures, n is the same or different and is independently 0, 1, 2 or 3.

[0166] In one embodiment of the present invention, R0′ is R s3 ' is hydrogen, halogen, cyano, hydroxyl, -C 1-6 Alkyl, -C 1-6 Alkoxy, -halogenated C 1-6 Alkyl, -halogenated C 1-6 Alkoxy, -C 3-6 Cycloalkyl, -NR h R i 、-C(O)NR e R f 、-C 1-3 Alkyl-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, hydroxyl, carboxyl; wherein R e 、R f are each independently hydrogen or C 1-3 Alkyl; R h 、R i are independently hydrogen, -C 1-3 Alkyl, -C(O)C 1-3 Alkyl or -CO2C 1-3 Alkyl; R s3" is isopropyl; n is 0. In one embodiment, the R s3 ″ is below the plane of the benzene ring.

[0167] In one embodiment of the present invention, R0′ is selected from the following structures: R s3 ' is hydrogen, halogen, cyano, hydroxyl, -C 1-6 Alkyl, -C 1-6 Alkoxy, -halogenated C 1-6 Alkyl, -halogenated C 1-6 Alkoxy, -C 3-6 Cycloalkyl, -NR h R i 、-C(O)NR e R f 、-C 1-3 Alkyl-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, hydroxyl, carboxyl; wherein R e 、R f are each independently hydrogen or C 1-3 Alkyl; R h 、R i are independently hydrogen, -C 1-3 Alkyl, -C(O)C 1-3 Alkyl or -CO2C 1-3 Alkyl; R s3 ″ is isopropyl; R s3 -C 1-6 Alkyl; n is 0 or 1. In one embodiment, the R s3 " is below the plane of the pyridine ring.

[0168] In one embodiment of the present invention, R0′ is selected from the following structures: R s3 ' is hydrogen, halogen, cyano, hydroxyl, -C 1-6 Alkyl, -C 1-6 Alkoxy, -halogenated C 1-6 Alkyl, -halogenated C 1-6 Alkoxy, -C 3-6 Cycloalkyl, -NR h R i 、-C(O)NR e R f 、-C 1-3 Alkyl-hydroxy and -C 1-3 Alkyl-NRe 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, hydroxyl, carboxyl; wherein R e 、R f are each independently hydrogen or C 1-3 Alkyl; R h 、R i are independently hydrogen, -C 1-3 Alkyl, -C(O)C 1-3 Alkyl or -CO2C 1-3 Alkyl; R s3 " is isopropyl; n is 0. In one embodiment, the R s3 " is below the plane of the pyrimidine ring.

[0169] In one embodiment of the present invention, R0′ is selected from the following structures: R s3 ' is hydrogen, halogen, cyano, hydroxyl, -C 1-6 Alkyl, -C 1-6 Alkoxy, -halogenated C 1-6 Alkyl, -halogenated C 1-6 Alkoxy, -C 3-6 Cycloalkyl, -NR h R i 、-C(O)NR e R f 、-C 1-3 Alkyl-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, hydroxyl, carboxyl; wherein R e 、R f are each independently hydrogen or C 1-3 Alkyl; R h 、R i are independently hydrogen, -C 1-3 Alkyl, -C(O)C 1-3 Alkyl or -CO2C 1-3 Alkyl; R s3 ' is isopropyl; n is 0. In one embodiment, the R s3 ″′ is below the plane of the pyrazole ring.

[0170] 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.

[0171] In one embodiment of the present invention, R0′ is selected from the following structures: R s3 ' is hydrogen, halogen, cyano, hydroxyl, -C 1-6 Alkyl, -C 1-6 Alkoxy, -halogenated C 1-6 Alkyl, -halogenated C 1-6 Alkoxy, -C 3-6 Cycloalkyl, -NR h R i 、-C(O)NR e R f 、-C 1-3 Alkyl-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, hydroxyl, carboxyl; wherein R e 、R f are each independently hydrogen or C 1-3 Alkyl; R h 、R i are 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 In one embodiment, the R s3 " is below the plane of the pyrazole ring.

[0172] In one embodiment of the present invention, R0′ is selected from the following structures:

[0173]

[0174]

[0175] In another aspect, the present invention provides a compound represented by formula (II), or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof,

[0176]

[0177] Where,

[0178] Z is NC(O)-CR3=CR1R2 or NC(O)-C≡CR4;

[0179] R1 and R2 are each independently hydrogen, halogen, cyano, NR a R b 、-C 1-3 Alkyl, halogenated C 1-3 Alkyl, -C 1-3 Alkyl-hydroxyl, -C 1-3 Alkyl-cyano, -C 1-3 Alkyl-C 1-3 Alkoxy, -C 1-3 Alkyl-NR a R b 、-C 1-3 alkyl-3 to 6 membered 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;

[0180] R3 is hydrogen, halogen, -C 1-3 Alkyl or -C 1-3 alkoxy;

[0181] R4 is hydrogen, halogenated C 1-3 Alkyl, -C 1-3 Alkyl-hydroxyl, -C 1-3 Alkyl-cyano or -C 1-3 Alkyl-C 1-3 alkoxy;

[0182] R 11 、R 12 The same or different, each independently hydrogen, halogen, -C 1-3 Alkyl, -halogenated C 1-3 Alkyl, -C 1-3 Alkyl-hydroxyl, -C 1-3 Alkyl-cyano, -C 1-3 Alkyl-C 1-6 Alkoxy, -C 1-3 Alkyl-halide C 1-6 Alkyl or -C 1-3 Alkyl-halide C 1-6 alkoxy;

[0183] R 21 、R 22 The same or different, each independently hydrogen, halogen, -C 1-3 Alkyl, -halogenated C 1-3 Alkyl, -C 1-3 Alkyl-hydroxyl, -C1-3 Alkyl-cyano, -C 1-3 Alkyl-C 1-6 Alkoxy, -C 1-3 Alkyl-halide C 1-6 Alkyl or -C 1-3 Alkyl-halide C 1-6 alkoxy;

[0184] R 31 、R 32 The same or different, each independently hydrogen, halogen, -C 1-3 Alkyl, -halogenated C 1-3 Alkyl, -C 1-3 Alkyl-hydroxyl, -C 1-3 Alkyl-cyano, -C 1-3 Alkyl-C 1-6 Alkoxy, -C 1-3 Alkyl-halide C 1-6 Alkyl or -C 1-3 Alkyl-halide C 1-6 alkoxy;

[0185] R 41 For hydrogen, halogen, -C 1-3 Alkyl, -halogenated C 1-3 Alkyl, -C 1-3 Alkyl-hydroxyl, -C 1-3 Alkyl-cyano, -C 1-3 Alkyl-C 1-6 Alkoxy, -C 1-3 Alkyl-halide C 1-6 Alkyl or -C 1-3 Alkyl-halide C 1-6 alkoxy;

[0186] P is O, NH or NR m ; R m -C 1-6 Alkyl, -halogenated C 1-6 Alkyl, -C 1-6 Alkyl-hydroxyl, -C 1-6 Alkyl-cyano, -C 1-6 Alkyl-C 1-6 Alkoxy, -C 1-6 Alkyl-halide C 1-6 Alkoxy, -C 1-6 Alkyl-C 3-6 Cycloalkyl or -C 1-6 Alkyl-3- to 6-membered heterocycloalkyl;

[0187] R 42 -(C=O)-, -C 1-3 Alkyl, -C 1-3Alkyl (hydroxy) -, -C 1-3 Alkyl (cyano)-, -C 1-3 Alkyl (C 1-6 Alkyl), -C 1-3 Alkyl (halogenated C 1-6 Alkyl)-, -C 1-3 Alkyl (C 1-6 Alkyl-hydroxy)-, -C 1-3 Alkyl (C 1-6 Alkyl-cyano)-, -C 1-3 Alkyl (C 1-6 Alkoxy)-, or -C 1-3 Alkyl (halogenated C 1-6 Alkoxy)-;

[0188] X2 and Y2 are the same or different and are independently hydrogen, halogen, -C 1-3 Alkyl, -halogenated C 1-3 Alkyl, -C 1-3 Alkyl-hydroxyl, -C 1-3 Alkyl-cyano, -C 1-3 Alkyl-C 1-6 Alkoxy, -C 1-3 Alkyl-halide C 1-6 Alkyl or -C 1-3 Alkyl-halide C 1-6 alkoxy;

[0189] Or X2, Y2 and their adjacent carbon atoms together form a substituted or unsubstituted C 3-6 Cycloalkyl or 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 replaced by substituents independently selected from Group S;

[0190] E3 is N or CL-R5; wherein,

[0191] L is a key, -CR L1 R L2 -、-O-(CR L1 R L2 ) t1 -or-NH-(CR L3 R L4 ) t2 -; among them, R L1 、R L2 、R L3 、R L4 The same or different, each independently hydrogen, halogen, hydroxyl, 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;

[0192] 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)halogenated C 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 each independently selected from Group S;

[0193] 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 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 heteroatoms selected from halogen, cyano, -C 1-3 Alkyl, -C 1-3 Alkoxy and C 3-6 The substituent of the cycloalkyl group is substituted; 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;

[0194] E4 is N or CH;

[0195] Ar is C 6-10aryl, 5- or 6-membered monocyclic heteroaryl or 8- to 10-membered bicyclic heteroaryl; wherein the 5- or 6-membered monocyclic heteroaryl has 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms; the 8- to 10-membered bicyclic heteroaryl has 1, 2, 3, 4 or 5 heteroatoms selected from N, O and S as ring atoms; and the C 6-10 The aryl group, the 5- or 6-membered monocyclic heteroaryl group or the 8- to 10-membered bicyclic heteroaryl group is unsubstituted or substituted by 1, 2, 3 or 4 groups independently selected from R s1 The group substitution;

[0196] or

[0197] Ar is a structure represented by formula (B):

[0198]

[0199] wherein the B1 ring is a benzene ring or a 5- or 6-membered monocyclic heteroaryl ring; the B2 ring 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;

[0200] (R s1 ) p Indicates that the hydrogen on the B1 ring is replaced by p R s1 Substitution, p is 0, 1, 2 or 3, each R s1 Same or different;

[0201] (R s2 ) q Indicates that the hydrogen on the B2 ring is replaced by q R s2 substituted, q is 0, 1, 2 or 3, each R s2 Same or different;

[0202] R s1 、R s2 are independently halogen, cyano, nitro, hydroxyl, -C 1-6 Alkyl, -C 1-6 Alkoxy, -halogenated C 1-6 Alkyl, -halogenated C 1-6 Alkoxy, -C 3-6 Cycloalkyl, -NR c R d 、-C(O)NR e R f 、-SO2C 1-3 Alkyl, -SO2 haloC 1-3 Alkyl, -SO2NR e R f 、-C 1-4 Alkyl-hydroxyl, -C1-4 Alkyl-cyano, -C 1-4 Alkyl-C 1-6 Alkoxy, -C 1-4 Alkyl-halide C 1-6 Alkyl, -C 1-4 Alkyl-halide 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 wherein the 3- to 6-membered heterocycloalkyl group has 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms;

[0203] R a 、R b 、R e 、R f are each independently hydrogen or C 1-3 alkyl;

[0204] R c 、R d are independently hydrogen, -C 1-3 Alkyl, -C(O)C 1-3 Alkyl, -CO2C 1-3 alkyl.

[0205] In one embodiment of the present invention, R s1 、R s2 are independently halogen, cyano, nitro, hydroxyl, -C 1-3 Alkyl, -C 1-3 Alkoxy, halogenated C 1-3 Alkyl, halogenated C 1-3 Alkoxy, -C 3-6 Cycloalkyl, -NR c R d 、-C(O)NR e R f 、-SO2C 1-3 Alkyl, -SO2 haloC 1-3 Alkyl, -SO2NR e R f 、-C 1-2 Alkyl-hydroxyl, -C 1-2 Alkyl-cyano, -C 1-2 Alkyl-C 1-3 Alkoxy, -C 1-2Alkyl-halide C 1-3 Alkyl, -C 1-2 Alkyl-halide C 1-3 Alkoxy, -C 1-2 Alkyl-3 to 6-membered heterocycloalkyl, -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 are independently hydrogen, -C 1-3 Alkyl, -C(O)C 1-3 Alkyl, -CO2C 1-3 Alkyl; R e 、R f are each independently hydrogen or C 1-3 alkyl.

[0206] In one embodiment of the present invention, R s1 、R s2 are independently halogen, cyano, nitro, hydroxyl, -C 1-3 Alkyl, -C 1-3 Alkoxy, halogenated C 1-3 Alkyl, halogenated C 1-3 Alkoxy, -C 3-6 Cycloalkyl, -NR c R d 、-C(O)NR e R f 、-SO2C 1-3 Alkyl, -SO2 haloC 1-3 Alkyl, -SO2NR e R f , -CH2-hydroxy, -CH2-cyano, -CH2-C 1-3 Alkoxy, -CH2-halogenated C 1-3 Alkyl, -CH2-halogenated C 1-3 Alkoxy, -CH2-3 to 6-membered heterocycloalkyl, -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 For hydrogen, -C 1-3 Alkyl, -C(O)CH3 or -CO2CH3; Re 、R f 、R d are each independently hydrogen or C 1-3 alkyl.

[0207] In one embodiment of the present invention, R s1 、R s2 are independently halogen, cyano, nitro, hydroxyl, -C 1-3 Alkyl, -C 1-3 Alkoxy, halogenated C1-3 alkyl, halogenated C 1-3 Alkoxy, -C 3-6 Cycloalkyl, -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 are each independently hydrogen or C 1-3 alkyl.

[0208] In one embodiment of the present invention, R s1 and R s2 In the C 3-6 Cycloalkyl is selected from the group consisting of: cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cyclobutanone, cyclobutane-1,2-dione, cyclopentanone, cyclopentane-1,3-dione, cyclohexanone, cyclohexane-1,3-dione.

[0209] In one embodiment of the present invention, R s1 and R s2 wherein the 3- to 6-membered heterocycloalkyl group is selected from the group consisting of aziridine, ethylene oxide, azetidine, oxetane, oxazolidine, 1,3-dioxolane, imidazolidine, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, piperidine, piperazine, morpholine, thiomorpholine, thiomorpholine-1,1-dioxide, tetrahydropyran, 1,3-oxazinane, hexahydropyrimidine, and 1,4-dioxane.

[0210] In one embodiment of the present invention, R s1 、R s2Each is independently halogen, cyano, nitro, hydroxy, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, propoxy (n-propoxy), isopropoxy, monochloromethyl, dichloromethyl, trichloromethyl, monochloroethyl, 1,2-dichloroethyl, trichloroethyl, monobromoethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, trifluoromethoxy, trifluoroethoxy, monofluoromethoxy, monofluoroethoxy, 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 is independently hydrogen, methyl or ethyl.

[0211] In one embodiment of the present invention, R s3 、R s4 are independently halogen, cyano, hydroxyl, -C 1-6 Alkyl, -C 1-3 Alkoxy, halogenated C 1-3 Alkyl, halogenated C 1-3 Alkoxy, -C 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl, amino, NHCH3, N(CH3)2, -C(O)NR e R f 、-SO2C 1-3 Alkyl, -SO2 haloC 1-3 Alkyl, -SO2NR e R f 、-C 1-2 Alkyl-hydroxyl, -C 1-2 Alkyl-ethynyl, -C 1-2 Alkyl-cyano, -C 1-2 Alkyl-C 1-3 Alkoxy, -C 1-2 Alkyl-halide C 1-3 Alkyl, -C 1-2 Alkyl-halide 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 are optionally substituted by 1, 2 or 3 substituents independently selected from halogen, methyl, ethyl, propyl (n-propyl), isopropyl, trifluoromethyl, amino, N(CH3)2, hydroxyl, carboxyl; R e 、R f are each independently hydrogen or C 1-3 alkyl.

[0212] In one embodiment of the present invention, R s3 、R s4 are independently halogen, cyano, hydroxyl, C 1-4 Alkyl, -C 1-3 Alkoxy, halogenated C 1-3 Alkyl, halogenated C 1-3 Alkoxy, -C 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl, amino, NHCH3, N(CH3)2, -C(O)NR e R f 、-SO2C 1-3 Alkyl, -SO2 haloC 1-3 Alkyl, -SO2NR e R f , -CH2-hydroxy, -CH2-ethynyl, -CH2-cyano, -CH2-C 1-3 Alkoxy, -CH2-halogenated C 1-3 Alkyl, -CH2-halogenated C 1-3 Alkoxy, -CH2-3 to 6-membered 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 are optionally substituted by 1, 2 or 3 substituents independently selected from halogen, methyl, ethyl, propyl (n-propyl), isopropyl, trifluoromethyl, amino, N(CH3)2, hydroxyl, carboxyl; R e 、R f are each independently hydrogen or C 1-3alkyl.

[0213] In one embodiment of the present invention, R s3 、R s4 are independently halogen, cyano, hydroxyl, C 1-4 Alkyl, -C 1-3 Alkoxy, halogenated C 1-3 Alkyl, -C 3-6 Cycloalkyl, 3 to 6 membered heterocycloalkyl, amino, NHCH3, N(CH3)2, -CH2-hydroxyl, -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.

[0214] In one embodiment of the present invention, R s3 and R s4 In the C 3-6 The cycloalkyl group is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

[0215] In one embodiment of the present invention, R s3 and R s4 wherein the 3- to 6-membered heterocycloalkyl group is selected from the group consisting of aziridine, ethylene oxide, azetidine, oxetane, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, piperidine, piperazine, morpholine, thiomorpholine, thiomorpholine-1,1-dioxide, and tetrahydropyran.

[0216] In one embodiment of the present invention, R s3 、R s4Each is independently halogen, cyano, hydroxy, methyl, ethyl, n-propyl, isopropyl, sec-butyl, methoxy, ethoxy, propoxy (n-propoxy), isopropoxy, monochloromethyl, dichloromethyl, trichloromethyl, monochloroethyl, 1,2-dichloroethyl, trichloroethyl, monobromoethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, oxirane, azetidine, oxetane, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, piperidine, piperazine, morpholine, thiomorpholine, thiomorpholine-1,1-dioxolane, Compound, tetrahydropyran, amino, NHCH3, N(CH3)2, -CH2-hydroxy, -CH2-ethynyl; wherein the methyl, ethyl, n-propyl, methoxy, ethoxy, propoxy (n-propyloxy), -CH2-, azetidine, oxetane, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, piperidine, piperazine, morpholine, thiomorpholine, thiomorpholine-1,1-dioxide, tetrahydropyran are 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.

[0217] In one embodiment of the present invention, the substituents in group S are selected from the group consisting of: hydroxyl, halogen, nitro, oxo, -C 1-3 Alkyl, hydroxy substituted C 1-3 Alkyl, benzyl, -(CH2) u -cyano, -(CH2) u -C 1-3 Alkoxy, -(CH2) u -Halogenated C 1-3 Alkoxy, -(CH2) u -Halogenated C 1-3 Alkyl, -(CH2) u -3 to 6-membered heterocycloalkyl, -(CH2) u -5 or 6-membered monocyclic heteroaryl, -(CH2) u -C 3-6 Cycloalkyl, -(CH2) u -O-(CH2) v -C 3-6 Cycloalkyl, -(CH2) u -O-(CH2) v -C 1-3 Alkoxy, -(CH2) u -O-(CH2) v OH, -(CH2) u -SO2C 1-3 Alkyl, -(CH2) u -NR a0 R b0、-(CH2) u -C(O)NR a0 R b0 、-(CH2) u -C(O)C 1-3 Alkyl, -C(O)OC 1-3 Alkyl, NR a0 C(O)-(CH2) u -NR a0 R b0 NR a0 C(O)-(CH2) u OH, NR a0 C(O)-halogenated C 1-3 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 heterocycloalkyl group and the 5- or 6-membered monocyclic heteroaryl group are optionally substituted by 1, 2 or 3 heteroatoms selected from halogen, cyano, -C 1-3 Alkyl, -C 1-3 Alkoxy and C 3-6 The substituent of the cycloalkyl group is substituted; 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.

[0218] In one embodiment of the present invention, the substituent group S is halogen.

[0219] In one embodiment of the present invention, the S group of substituents is selected from: C 1-3 Alkyl, -(CH2) u -3 to 6-membered heterocycloalkyl, -(CH2) u -SO2C 1-3 Alkyl, -(CH2) u -NR a0 R b0 wherein the 3- to 6-membered heterocycloalkyl group has 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms; the 3- to 6-membered heterocycloalkyl group is optionally substituted by 1, 2 or 3 heteroatoms selected from halogen, cyano, -C 1-3 Alkyl, -C 1-3 Alkoxy and C 3-6 The cycloalkyl group is substituted by a substituent; u is 0, 1, 2, 3 or 4; R a0 、R b0 are each independently hydrogen or C 1-3 alkyl.

[0220] In one embodiment of the present invention, in the above groups (eg, Ar, R0), the C 6-10Each aryl group is independently phenyl or naphthyl.

[0221] In one embodiment of the present invention, in the above groups (eg Ar), the C 6-10 When the aryl group is a phenyl group, it is selected from the following structures:

[0222] Where R s1 、R s2 Same definition as above.

[0223] In one embodiment of the present invention, in the above-mentioned groups (e.g., Ar, R0), the 5- or 6-membered monocyclic heteroaryl groups are each independently selected from the group consisting of thiophene, N-alkyl ring pyrrole, 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, and pyrazine.

[0224] In one embodiment of the present invention, in the above groups (e.g., Ar, R0), the 5- or 6-membered monocyclic heteroaryl groups are each independently selected from the following structures:

[0225]

[0226] In one embodiment of the present invention, in the above groups (e.g., Ar, R0), the 8- to 10-membered bicyclic heteroaryl groups are each independently a 9- to 10-membered bicyclic heteroaryl group formed by condensing a benzene ring with a 5- or 6-membered monocyclic heteroaryl ring, or an 8- to 10-membered bicyclic heteroaryl group formed by condensing a 5- or 6-membered monocyclic heteroaryl ring with a 5- or 6-membered monocyclic heteroaryl ring.

[0227] In one embodiment of the present invention, the 5- or 6-membered monocyclic heteroaryl ring forming the 9- to 10-membered bicyclic heteroaryl or the 8- to 10-membered bicyclic heteroaryl is selected from the group consisting of a thiophene ring, an N-alkyl ring, a pyrrole ring, a furan ring, a thiazole ring, an isothiazole ring, an imidazole ring, an oxazole ring, a pyrrole ring, a pyrazole ring, a triazole ring, a 1,2,3-triazole ring, a 1,2,4-triazole ring, a 1,2,5-triazole ring, a 1,3,4-triazole ring, a tetrazole ring, an isoxazole ring, an oxadiazole ring, a 1,2,3-oxadiazole ring, a 1,2,4-oxadiazole ring, a 1,2,5-oxadiazole ring, a 1,3,4-oxadiazole ring, a thiadiazole ring, a pyridine ring, a pyridazine ring, a pyrimidine ring or a pyrazine ring.

[0228] In one embodiment of the present invention, the 5- or 6-membered monocyclic heteroaryl ring forming the 9- to 10-membered bicyclic heteroaryl or the 8- to 10-membered bicyclic heteroaryl is selected from the following structures:

[0229] in The two ring atoms represented as being connected are adjacent pairs of atoms that are shared when fused to other rings.

[0230] In one embodiment of the present invention, in the B1 ring and the A1 ring, the 5- or 6-membered monocyclic heteroaryl ring is independently selected from the group consisting of a thiophene ring, an N-alkyl ring, a pyrrole ring, a furan ring, a thiazole ring, an isothiazole ring, an imidazole ring, an oxazole ring, a pyrrole ring, a pyrazole ring, a triazole ring, a 1,2,3-triazole ring, a 1,2,4-triazole ring, a 1,2,5-triazole ring, a 1,3,4-triazole ring, a tetrazole ring, an isoxazole ring, an oxadiazole ring, a 1,2,3-oxadiazole ring, a 1,2,4-oxadiazole ring, a 1,2,5-oxadiazole ring, a 1,3,4-oxadiazole ring, a thiadiazole ring, a pyridine ring, a pyridazine ring, a pyrimidine ring or a pyrazine ring.

[0231] In one embodiment of the present invention, in the B1 ring and the A1 ring, the 5- or 6-membered monocyclic heteroaryl ring is independently selected from the following structures:

[0232] in The two ring atoms represented as being connected are adjacent pairs of atoms that are shared when fused to other rings.

[0233] In one embodiment of the present invention, in the B2 ring and the A2 ring, the fused 5- or 6-membered monocyclic cycloalkyl ring is independently selected from the group consisting of: cyclopentyl ring, cyclopentenyl ring, cyclohexyl ring, cyclohexenyl ring, cyclohexadienyl ring, cyclopentanone, cyclopentane-1,3-dione, cyclohexanone, and cyclohexane-1,3-dione.

[0234] In one embodiment of the present invention, in the B2 ring and the A2 ring, the fused 5- or 6-membered monocyclic heterocycloalkyl ring is independently selected from the group consisting of oxazolidine, pyrrolidone, pyrrolidine-2,5-dione, 1,3-dioxolane, dihydrofuran-2(3H)-one, dihydrofuran-2,5-dione, piperidine-2-one, piperidine-2,6-dione, tetrahydro-2H-pyran-2-one, imidazolidine, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, 1,3-dioxolane-2-one, oxazolidin-2-one, imidazolidin-2-one, piperidine, piperazine, piperazin-2-one, morpholine, morpholine-3-one, morpholine-2-one, thiomorpholine-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-dihydro- pyrimidin-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-dioxole, 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-dioxol-2-one, oxazol-2(3H)-one, 1,3-dihydro-2H-imidazole-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.

[0235] In one embodiment of the present invention, the fused 5- or 6-membered monocyclic heterocycloalkyl ring is selected from the following structures:

[0236]

[0237] In one embodiment of the present invention, in the above-mentioned groups (e.g., Ar, R0), the 8- to 10-membered bicyclic heteroaryl groups are each independently selected from the group consisting of benzoxazole, benzisoxazole, benzimidazole, benzothiazole, benzisothiazole, benzotriazole, benzofuran, benzothiophene, indole, indazole, isoindole, quinoline, isoquinoline, quinazoline, quinoxaline, cinnoline, pyridopyrimidine, and naphthyridine.

[0238] In one embodiment of the present invention, in the above groups (e.g., Ar, R0), the 8- to 10-membered bicyclic heteroaryl groups are each independently selected from the group consisting of 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, and 1,5-naphthyridine.

[0239] In one embodiment of the present invention, in the above groups (eg, Ar, R0), the 8- to 10-membered bicyclic heteroaryl groups are each independently selected from the following structures:

[0240]

[0241] In one embodiment of the present invention, in the above groups (eg, Ar, R0), the 8- to 10-membered bicyclic heteroaryl groups are each independently selected from the following structures:

[0242]

[0243] In one embodiment of the present invention, in the above groups (eg, Ar, R0), the 8- to 10-membered bicyclic heteroaryl groups are each independently selected from the following structures:

[0244]

[0245] In one embodiment of the present invention, Each is independently selected from the following structures:

[0246]

[0247] In one embodiment of the present invention, formula (B) and formula (A-1) are each independently selected from the following structures:

[0248]

[0249] In one embodiment of the present invention, Ar and Ar' are independently selected from the following structures:

[0250]

[0251]

[0252]

[0253] In one embodiment of the present invention, in the above groups (eg R0), the C 3-6 Cycloalkyl is selected from the group consisting of: cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cyclobutanone, cyclobutane-1,2-dione, cyclopentanone, cyclopentane-1,3-dione, cyclohexanone, cyclohexane-1,3-dione.

[0254] In one embodiment of the present invention, in the above groups (e.g., R0), the 3- to 6-membered heterocycloalkyl group is selected from the group consisting of aziridine, oxirane, azetidine, oxetane, oxazolidine, 1,3-dioxolane, imidazolidine, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, piperidine, piperazine, morpholine, thiomorpholine, thiomorpholine-1,1-dioxide, tetrahydropyran, 1,3-oxazinane, hexahydropyrimidine, and 1,4-dioxane.

[0255] In one embodiment of the present invention, in the above-mentioned groups (e.g., R0), the 7- to 11-membered spirocycloalkyl group is a monospirocycloalkyl group containing one spiro atom formed by any two monocyclic cycloalkyl rings selected from a cyclopropyl ring, a cyclobutyl ring, a cyclopentyl ring, and a cyclohexyl ring.

[0256] 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 heterocycloalkyl, phenyl, 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 substituted by a group.

[0257] 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 wherein the 5- or 6-membered monocyclic heteroaryl is selected from the group consisting of thiophene, N-alkyl ring pyrrole, 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, 5- or 6-membered monocyclic heteroaryl is unsubstituted or substituted by 1, 2, 3 or 4 independently selected R s3 substituted by a group.

[0258] In one embodiment of the present invention, R0 is selected from the following structures:

[0259]

[0260]

[0261] In one embodiment of the present invention, R 11 、R 12 The same or different, each independently hydrogen, halogen, -C 1-3 Alkyl, -CH2-hydroxy, -CH2-cyano, -CH2-C 1-3 Alkoxy, -CH2-halogenated C 1-3 Alkyl or -CH2-halogenated C 1-3 Alkoxy.

[0262] In one embodiment of the present invention, R 11 、R 12 The same or different, each independently represents hydrogen, halogen, methyl, ethyl, n-propyl, isopropyl, -CH2-hydroxy, -CH2-cyano, -CH2-methoxy, -CH2-ethoxy, -CH2-propoxy (n-propoxy), -CH2-isopropoxy, -CH2-trifluoromethyl, -CH2-difluoromethyl, -CH2-difluoroethyl, -CH2-trifluoromethoxy, -CH2-difluoromethoxy.

[0263] In one embodiment of the present invention, R 11 、R 12 The same or different, each independently hydrogen or -C 1-3 alkyl.

[0264] In one embodiment of the present invention, R 11 、R 12 The same or different, each independently represents hydrogen or methyl.

[0265] In one embodiment of the present invention, R 21 、R 22 The same or different, each independently hydrogen, halogen, -C 1-3 Alkyl, -CH2-hydroxy, -CH2-cyano, -CH2-C 1-3 Alkoxy, -CH2-halogenated C 1-3 Alkyl or -CH2-halogenated C 1-3 Alkoxy.

[0266] In one embodiment of the present invention, R 21 、R 22 The same or different, each independently represents hydrogen, halogen, methyl, ethyl, n-propyl, isopropyl, -CH2-hydroxy, -CH2-cyano, -CH2-methoxy, -CH2-ethoxy, -CH2-propoxy (n-propoxy), -CH2-isopropoxy, -CH2-trifluoromethyl, -CH2-difluoromethyl, -CH2-difluoroethyl, -CH2-trifluoromethoxy, -CH2-difluoromethoxy.

[0267] In one embodiment of the present invention, R 21 、R 22 The same or different, each independently hydrogen or -C 1-3 alkyl.

[0268] In one embodiment of the present invention, R 21 、R 22 The same or different, each independently represents hydrogen or methyl.

[0269] In one embodiment of the present invention, R 31 、R 32 The same or different, each independently hydrogen, halogen, -C 1-3 Alkyl, -CH2-hydroxy, -CH2-cyano, -CH2-C 1-3 Alkoxy, -CH2-halogenated C 1-3 Alkyl or -CH2-halogenated C 1-3 Alkoxy.

[0270] In one embodiment of the present invention, R 31 、R32 The same or different, each independently represents hydrogen, halogen, methyl, ethyl, n-propyl, isopropyl, -CH2-hydroxy, -CH2-cyano, -CH2-methoxy, -CH2-ethoxy, -CH2-propoxy (n-propoxy), -CH2-isopropoxy, -CH2-trifluoromethyl, -CH2-difluoromethyl, -CH2-difluoroethyl, -CH2-trifluoromethoxy, -CH2-difluoromethoxy.

[0271] In one embodiment of the present invention, R 31 、R 32 The same or different, each independently hydrogen or -C 1-3 alkyl.

[0272] In one embodiment of the present invention, R 31 、R 32 The same or different, each independently represents hydrogen or methyl.

[0273] In one embodiment of the present invention, R 41 For hydrogen, halogen, -C 1-3 Alkyl, -CH2-hydroxy, -CH2-cyano, -CH2-C 1-3 Alkoxy, -CH2-halogenated C 1-3 Alkyl or -CH2-halogenated C 1-3 Alkoxy.

[0274] In one embodiment of the present invention, R 41 It 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.

[0275] In one embodiment of the present invention, R 41 For hydrogen.

[0276] In one embodiment of the present invention, in Formula I, when When the dotted line in the figure is a single bond, P is O; R 42 -C 1-3 Alkyl-, -C 1-3 Alkyl (hydroxy) -, -C 1-3 Alkyl (cyano)-, -C 1-3 Alkyl (C 1-3 Alkyl), -C 1-3 Alkyl (halogenated C 1-3 Alkyl)-, -C 1-3 Alkyl (C 1-3Alkyl-hydroxy)-, -C 1-3 Alkyl (C 1-3 Alkyl-cyano)-, -C 1-3 Alkyl (C 1-3 Alkoxy)-, or -C 1-3 Alkyl (halogenated 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).

[0277] In one embodiment of the present invention, in Formula I, when When the dotted line in the figure is a single bond, P is NH or NR m ; R m -C 1-3 Alkyl, -halogenated C 1-3 Alkyl, -C 1-3 Alkyl-hydroxyl, -C 1-3 Alkyl-cyano, -C 1-3 Alkyl-C 1-3 Alkoxy, -C 1-3 Alkyl-halide C 1-3 Alkoxy; R 42 -(C=O)-, -C 1-3 Alkyl-, -C 1-3 Alkyl (hydroxy) -, -C 1-3 Alkyl (cyano)-, -C 1-3 Alkyl (C 1-3 Alkyl), -C 1-3 Alkyl (halogenated C 1-3 Alkyl)-, -C 1-3 Alkyl (C 1-3 Alkyl-hydroxy)-, -C 1-3 Alkyl (C 1-3 Alkyl-cyano)-, -C 1-3 Alkyl (C 1-3 Alkoxy)-, or -C 1-3 Alkyl (halogenated 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).

[0278] In one embodiment of the present invention, in Formula I, when When the dotted line in the figure is a single bond, P is O, NH or NR m ; R m -C 1-6 Alkyl; R 42is -(C=O)- or -C 1-3 alkyl-.

[0279] In one embodiment of the present invention, in Formula I, when When the dotted line in the figure is a single bond, P is O, NH or NR m ; R m -C 1-3 Alkyl; R 42 is -(C=O)- or -C 1-3 alkyl-.

[0280] In one embodiment of the present invention, in Formula I, when When the dotted line in the figure is a single bond, P is O, NH or NR m ; R m is methyl, ethyl, n-propyl or isopropyl; R 42 It is -(C=O)-, -CH2-, -CH2CH2- or -CH2CH2CH2-.

[0281] In one embodiment of the present invention, in Formula I, when When the dashed line is absent, P is hydrogen or halogen; R 42 For hydrogen, halogen, -C 1-3 Alkyl, -CH2-hydroxy, -CH2-cyano, -CH2-C 1-3 Alkoxy, -CH2-halogenated C 1-3 Alkyl or -CH2-halogenated C 1-3 Alkoxy.

[0282] In one embodiment of the present invention, in Formula I, when When the dashed line is absent, P is hydrogen or halogen; R 42 It 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.

[0283] 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 C1-3 Alkyl, -N(substituted or unsubstituted C 1-3 Alkyl)2, -NH-substituted or unsubstituted C 3-6 Cycloalkyl, -NH-substituted or unsubstituted 3 to 6 membered 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 connected nitrogen atom, it forms a substituted or unsubstituted 3- to 6-membered nitrogen-containing heterocycloalkyl group; the 3- to 6-membered nitrogen-containing heterocycloalkyl group has 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 1, 2, 3 or 4 hydrogen atoms in the group being replaced by substituents independently 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).

[0284] In one embodiment of the present invention, in Formula I, Y1 is N; E1 is C; and E2 is C.

[0285] In one embodiment of the present invention, in Formula I, Y1 is C; E1 is N; and E2 is C.

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

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

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

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

[0290] In one embodiment of the present invention, in Formula II, P is O.

[0291] In one embodiment of the present invention, in formula II, P is NH or NR m ; R m C 1-3 Alkyl, halogenated C 1-3 Alkyl, -C 1-3 Alkyl-hydroxyl, -C 1-3 Alkyl-cyano, -C 1-3 Alkyl-C 1-3 Alkoxy, -C 1-3 Alkyl-halide 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).

[0292] In one embodiment of the present invention, in Formula II, R 42 -(C=O)-, -C 1-3 Alkyl, -C 1-3 Alkyl (hydroxy) -, -C 1-3 Alkyl (cyano)-, -C 1-3 Alkyl (C 1-3 Alkyl), -C 1-3 Alkyl (halogenated C 1-3 Alkyl)-, -C 1-3 Alkyl (C 1-3 Alkyl-hydroxy)-, -C 1-3 Alkyl (C 1-3 Alkyl-cyano)-, -C 1-3 Alkyl (C 1-3 Alkoxy)-, or -C 1-3 Alkyl (halogenated 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).

[0293] In one embodiment of the present invention, in Formula II, X2 and Y2 are the same or different and are independently hydrogen, halogen, -C 1-3 Alkyl, -C 1-3 Alkyl-hydroxyl, -C1-3 Alkyl-cyano, -C 1-3 Alkyl-C 1-3 Alkoxy, -C 1-3 Alkyl-halide C 1-3 Alkyl or -C 1-3 Alkyl-halide 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).

[0294] In one embodiment of the present invention, in Formula II, X2, Y2 and their adjacent carbon atoms together form a substituted or unsubstituted C 3-6 Cycloalkyl or 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 replaced by substituents independently selected from Group S.

[0295] In one embodiment of the present invention, in Formula II, L is a bond.

[0296] 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 ; Among them, 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)halogenated C 1-3 Alkyl; or R 51 and R 52Together 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 ring atoms of the remaining ring atoms are optionally heteroatoms selected from N, O and S; the "substituted" refers to 1, 2, 3 or 4 hydrogen atoms in the group being replaced by substituents each independently selected from the S group; wherein, C 1-3 Alkyl is methyl, ethyl or propyl (n-propyl or isopropyl); C 1-3 Alkoxy is methoxy, ethoxy or propoxy (n-propoxy or isopropoxy).

[0297] In one embodiment of the present invention, R1 and R2 are each independently hydrogen, halogen, cyano, amino, NHCH3, N(CH3)2, methyl, ethyl, n-propyl, isopropyl, monochloromethyl, dichloromethyl, trichloromethyl, monochloroethyl, 1,2-dichloroethyl, trichloroethyl, monobromoethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, -CH2-hydroxy, -CH2-cyano, -CH2-methoxy, -CH2-ethoxy, -CH2-propoxy(n-propoxy), -CH2-isopropoxy, -CH2-NH2, -CH2-NHCH3, -CH2-N(CH3)2, -CH2-3 to 6 membered heterocycloalkyl or -CH2-5 or 6 membered monocyclic heteroaryl; said 3 to 6 membered The heterocycloalkyl group is selected from the group consisting of aziridine, oxirane, azetidine, oxetane, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, piperidine, piperazine, morpholine, thiomorpholine, thiomorpholine-1,1-dioxide, and tetrahydropyran; the 5- or 6-membered monocyclic heteroaryl group is selected from the group consisting of thiophene, N-alkyl pyrrole, 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, 5 or 6 membered monocyclic heteroaryl are optionally substituted by 1 or 2 halogen or C 1-3 Alkyl substitution.

[0298] In one embodiment of the present invention, R3 is hydrogen, halogen, methoxy, ethoxy, propoxy (n-propoxy) or isopropoxy.

[0299] 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.

[0300] In one embodiment of the present invention, R1, R2, and R3 are hydrogen.

[0301] In one embodiment of the present invention, E1 is N or CR5; wherein R5 is hydrogen.

[0302] In one embodiment of the present invention, E2 is N or CR6; wherein R6 is hydrogen.

[0303] In one embodiment of the present invention, in the compound of formula (I), said R 11 、R 12 、R 21 、R 22 、R 31 、R 32 、R 41 、R 42 , Z, P, R0, Ar, E1, E2, X1, and Y1 are each independently the corresponding group in each specific compound in the examples.

[0304] In one embodiment of the present invention, the compound of formula (I) is selected from any one of compounds Z1, Z3 to Z16 in the Examples or a diastereoisomer thereof.

[0305] In one embodiment of the present invention, representative compounds of formula (IA) include the structures listed in Table A-1 below, or tautomers, cis-trans isomers, meso-isomers, 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,

[0306] Table A-1

[0307]

[0308]

[0309]

[0310]

[0311]

[0312]

[0313]

[0314]

[0315]

[0316]

[0317]

[0318]

[0319]

[0320]

[0321]

[0322] 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 structure in Table A-2,

[0323] Table A-2

[0324]

[0325]

[0326]

[0327] In one embodiment of the present invention, representative compounds of formula (IA) include but are not limited to any one of the compound structures described in Examples 51 to 342, or pharmaceutically acceptable salts, solvates or prodrugs of these structures.

[0328] In one embodiment of the present invention, in the compound of formula (II), said R 11 、R 12 、R 21 、R 22 、R 31 、R 32 、R 41 、R 42 , Z, P, Ar, E3, E4, X2, and Y2 are each independently the corresponding group in each specific compound in the examples.

[0329] In one embodiment of the present invention, the compound of formula (II) is selected from any one of compounds Z2, Z17 to Z20 in the Examples or a diastereomer thereof.

[0330] In another aspect, the present invention provides a pharmaceutical composition comprising the aforementioned compound or its tautomers, cis-trans isomers, meso-isomers, racemates, enantiomers, diastereomers, atropisomers or mixtures thereof, or pharmaceutically acceptable salts, solvates or prodrugs thereof; and a pharmaceutically acceptable carrier.

[0331] 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 has no toxic side effects on the host or subject. Representative carriers include water, oils, vegetables and minerals, cream bases, lotion bases, ointment bases, etc. These bases include suspending agents, viscosity increasing agents, transdermal enhancers, etc. Their preparations are well known to those skilled in the field of cosmetics or topical medicine.

[0332] In an embodiment of the present invention, the pharmaceutical composition can be administered in any of the following ways: orally, by spray inhalation, rectal administration, nasal administration, buccal administration, topical administration, parenteral administration, such as subcutaneous, intravenous, intramuscular, intraperitoneal, intrathecal, intraventricular, intrasternal and intracranial injection or infusion, or by means of an explanted reservoir. When administered orally, the compound of the present invention can be prepared into any orally acceptable dosage form, including but not limited to tablets, capsules, aqueous solutions or aqueous suspensions. The carriers used for tablets generally include lactose and corn starch, and lubricants such as magnesium stearate may also be added. The diluents used for capsule preparations generally include lactose and dry corn starch. Aqueous suspension preparations are usually prepared by mixing the active ingredient with a suitable emulsifier and suspending agent. If necessary, some sweeteners, flavorings or coloring agents may also be added to the above oral dosage forms. For topical administration, particularly for the treatment of affected areas or organs readily accessible by topical application, such as the eyes, skin, or lower intestinal neurological disorders, the compounds of the present invention can be formulated into different topical formulations depending on the affected area or organ. For topical ophthalmic administration, the compounds of the present invention can be formulated into a micronized suspension or solution in an isotonic, sterile saline solution at a specific pH, with or without a preservative such as benzyl chloride. For ophthalmic administration, the compounds can also be formulated into an ointment such as vaseline. For topical skin administration, the compounds of the present invention can be formulated into a suitable ointment, lotion, or cream formulation, wherein the active ingredient is suspended or dissolved in one or more carriers. Carriers that can be used for ointment preparations 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 lotions or creams include, but are not limited to, mineral oil, sorbitan monostearate, Tween 60, cetyl esters wax, hexadecene aryl alcohol, 2-octyldodecanol, benzyl alcohol, and water. The compounds of the present invention can also be administered in the form of sterile injectable preparations, including sterile water for injection or oil suspensions or sterile injectable solutions. Useful carriers and solvents include water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils such as monoglycerides or diglycerides can also be used as solvents or suspending media.

[0333] In another aspect, the present invention provides the use of the aforementioned compound, or its tautomers, cis-trans isomers, meso-isomers, racemates, enantiomers, diastereomers, atropisomers, or mixtures thereof, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, in the preparation of a medicament for treating and / or preventing a disease induced by the KRAS G12C mutation. Preferably, the KRAS G12C mutation-induced disease is cancer.

[0334] In another aspect, the present invention provides the use of the aforementioned compound or its tautomers, cis-trans isomers, meso-isomers, racemates, enantiomers, diastereomers, atropisomers or mixtures thereof, or pharmaceutically acceptable salts, solvates or prodrugs thereof in the preparation of drugs for treating and / or preventing cancer.

[0335] In one embodiment of the invention, the cancer is pancreatic cancer, colorectal cancer or lung cancer.

[0336] In one embodiment of the present invention, the cancer is lung cancer, preferably non-small cell lung cancer.

[0337] In another aspect, the present invention provides the use of the aforementioned compound or its tautomer, cis-trans isomer, meso-isomer, racemate, enantiomer, diastereomer, atropisomer or mixture thereof, or its pharmaceutically acceptable salt, solvate or prodrug in the preparation of a KRAS mutation inhibitor (preferably, the KRAS mutation is a KRASG12C mutation).

[0338] In another aspect, the present invention provides a method for treating cancer, comprising administering to a subject in need thereof a therapeutically effective amount of the aforementioned compound or its tautomer, cis-trans isomer, meso-isomer, racemate, enantiomer, diastereomer, atropisomer or a mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, or any combination thereof, or the step of administering the aforementioned pharmaceutical composition.

[0339] As used herein, the term "subject" refers to an animal, particularly a mammal, preferably a human.

[0340] As used herein, the term "effective amount" or "therapeutically effective amount" refers to a non-toxic but sufficient amount of a drug or medicament that can achieve the desired effect. In embodiments of the present invention, when a patient is treated according to the present invention, the amount of a given drug depends on many factors, such as specific dosing regimen, disease or condition type and severity thereof, the uniqueness (e.g., body weight) of the patient or host in need of treatment, but, according to specific surrounding circumstances, including, for example, the specific drug, route of administration, condition for treatment, and the patient or host for treatment, the dosage can be conventionally determined by methods known in the art. Typically, for adult treatment, the dosage is typically in the range of 0.02-5000 mg / day, such as about 1-1500 mg / day. The desired dose can be conveniently expressed as one dose, or simultaneously administered (or in a short period of time) or in divided doses at appropriate intervals, such as two, three, four, or more divided doses per day. It will be appreciated by those skilled in the art that, although the above-mentioned dosage range has been provided, the specific effective amount can be appropriately adjusted according to the patient's situation and in conjunction with the physician's diagnosis.

[0341] As used herein, the term "pharmaceutically acceptable salt" refers to a salt of a compound of the present invention that is pharmaceutically acceptable and possesses the pharmacological activity of the parent compound. Such salts include: acid addition salts formed with inorganic or organic acids, such as nitric, phosphoric, and carbonic acids; organic acids, such as propionic, hexanoic, cyclopentylpropionic, glycolic, pyruvic, gluconic, stearic, and muconic acids; salts formed when an acidic proton present in the parent compound is replaced by a metal ion, such as an alkali metal or alkaline earth metal ion; or coordination compounds formed with organic bases, such as ethanolamine, diethanolamine, triethanolamine, and N-methylglucamine. Pharmaceutically acceptable salts of the present invention can be synthesized from parent compounds containing acid or base groups by conventional chemical methods. Generally, such salts are prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of an appropriate base or acid in water, an organic solvent, or a mixture of both. In addition to salt forms, the compounds provided herein also exist in prodrug form. Prodrugs of the compounds described herein readily undergo chemical changes under physiological conditions to convert to the compounds of the invention. Additionally, prodrugs can be converted to the compounds of the invention by chemical or biochemical methods in an in vivo environment.

[0342] As used herein, the terms "solvate" and "solvate" refer to a compound of the present invention in combination with a pharmaceutically acceptable solvent. Solvates include both stoichiometric and non-stoichiometric solvents. Certain compounds of the present invention may exist in unsolvated or solvated forms. Generally speaking, solvated forms are equivalent to unsolvated forms and are encompassed within the scope of the present invention.

[0343] As used herein, the term "stereoisomer" includes conformational isomers and configurational isomers, wherein configurational isomers mainly include cis-trans isomers and optical isomers. The compound of the present invention can exist in the form of stereoisomers, and therefore covers 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 compound of the present invention can also exist in the form of any combination or any mixture of the aforementioned stereoisomers, such as mesomorphs, racemates, equal 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 compound of the present invention contains an olefin double bond, unless otherwise stated, it includes cis-isomers and trans-isomers, and any combination thereof. The atropisomer of the present invention is a stereoisomer of axial or planar chirality produced based on restricted intramolecular rotation. The compounds of the present invention have two atropisomers due to axial asymmetry, which are limited to when the substituent Ar' or R0' is C 6-10 When 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 pyridinone group is connected to a substituted naphthyridinone ring and rotates, a steric hindrance is formed. Regarding the atropisomers of the present invention, wherein the compound has a structure of formula (I), formula (IA) or formula (II), or the compound of formula (I), formula (IA) or formula (II) has an isomer produced by an asymmetric carbon, etc., it represents any one of a pair of atropisomers present in each isomeric compound. And as a drug, atropisomers with excellent activity are preferred. The compound of formula (I), formula (IA) or formula (II) has optical isomers derived from an asymmetric carbon, axial asymmetry, etc., and a single isomer can be obtained by optical resolution if necessary. The atropisomers of the compounds of the present invention can be represented by P or M configuration, or can be represented by other commonly used marking methods known in the art.

[0344] As mentioned above, the present invention provides compounds represented by the above-mentioned various structures, or their tautomers, cis-trans isomers, meso-isomers, racemates, enantiomers, diastereomers, atropisomers or mixtures thereof, wherein "their mixtures" include any form of mixtures between any of the aforementioned stereoisomers (e.g., tautomers, cis-trans isomers, enantiomers, diastereomers, atropisomers) and / or mixtures (meso-isomers, 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 enantiomers and diastereomer mixtures, mixtures of atropisomers and diastereomer mixtures, etc.

[0345] As used herein, the "-" symbol contained in a substituent in each group represents a bond to another group or structure.

[0346] As used herein, the term "fused" refers to a structure in which two or more rings share one or more bonds.

[0347] As used herein, the term "alkyl" refers to a straight or branched chain saturated aliphatic hydrocarbon group containing 1 to 20 carbon atoms. 1-10 "Alkyl" refers to a straight or branched chain alkyl group having 1 to 10 carbon atoms, more preferably a straight or branched chain alkyl group having 1, 2, 3, 4, 5 or 6 carbon atoms, i.e., C 1-6 Alkyl, more preferably C 1-4 Alkyl, 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 chain isomers thereof.

[0348] It should be noted that, unless otherwise specified, if both propyl and isopropyl are present in the parallel options, the propyl group in that case refers to n-propyl. If only propyl is present in the parallel options, the propyl group in that case refers to n-propyl or isopropyl.

[0349] As used herein, "-C 1-3 Alkyl-" and "C 1-3 “Alkylene” is used interchangeably to refer to a saturated straight or branched chain aliphatic hydrocarbon radical having two residues derived from the same carbon atom or two different carbon atoms of a parent alkyl group by removing two hydrogen atoms, which is a straight or branched chain radical containing from 1 to 3 carbon atoms. Non-limiting examples of alkylene include, but are not limited to, methylene (—CH—), 1,1-ethylene (—CH(CH)—), 1,2-ethylene (—CHCH—), 1,1-propylene (—CH(CHCH)—), 1,2-propylene (—CHCH(CH)—), 1,3-propylene (—CHCHCHCH—), and the like.

[0350] As used herein, "-C 1-3 Alkyl (hydroxy) -, -C 1-3 Alkyl (cyano)-, -C 1-3 Alkyl (C1-6 Alkyl)-, -C 1-3 Alkyl (halogenated C 1-6 Alkyl)-, -C 1-3 Alkyl (C 1-6 Alkyl-hydroxy)-, -C 1-3 Alkyl (C 1-6 Alkyl-cyano)-, -C 1-3 Alkyl (C 1-6 Alkoxy)-, -C 1-3 Alkyl (halogenated C 1-6 Alkoxy)-" refers to "-C 1-3 One or more hydrogen atoms in the "alkyl-" group are replaced by hydroxyl, cyano, C 1-6 Alkyl, halogenated C 1-6 Alkyl, -C 1-6 Alkyl-hydroxyl, -C 1-6 Alkyl-cyano, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy substitution residues are formed. 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)-.

[0351] As used herein, the term "alkoxy" refers to a group having the structure -O-alkyl, wherein alkyl is as defined above. 1-10 "Alkoxy" refers to an alkoxy group 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-pentoxy, and the like.

[0352] It should be noted that, unless otherwise specified, if both propoxy and isopropoxy are present in the parallel options, the propoxy group in that case represents n-propoxy. If only propoxy is present in the parallel options, the propyl group in that case represents n-propoxy or isopropoxy.

[0353] As used herein, the term "alkylthio" refers to a group having the structure -S-alkyl, wherein alkyl is as defined above. 1-10 "Alkylthio" refers to an alkylthio group having 1 to 10 carbon atoms, preferably C 1-6 Alkylthio, more preferably C 1-4 Alkylthio, more preferably C 1-3Alkylthio. Specific examples of alkylthio include, but are not limited to, methylthio, ethylthio, propylthio, isopropylthio, butylthio, tert-butylthio, isobutylthio, pentylthio, and the like.

[0354] 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 of the chain. 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 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 Specific examples of alkenyl groups include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl, pentenyl, hexenyl, butadienyl, and the like.

[0355] 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 of the chain. 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 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 alkynyl include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-, 2- or 3-butynyl, and the like.

[0356] As used herein, the term "halogen" refers to fluorine, chlorine, bromine, and iodine.

[0357] As used herein, the term "haloalkyl" refers to an alkyl group substituted with one or more (e.g., 1, 2, 3, 4, or 5) halogens, wherein alkyl is as defined above. 1-10 "Alkyl" refers to a halogenated alkyl group having 1 to 10 carbon atoms. Preferably, the halogenated C 1-6 Alkyl, more preferably halogenated C 1-4 Alkyl, more preferably halogenated C 1-3 Specific examples of haloalkyl include, but are not limited to, monochloromethyl, dichloromethyl, trichloromethyl, monochloroethyl, 1,2-dichloroethyl, trichloroethyl, monobromoethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, and the like.

[0358] As used herein, the term "deuterated alkyl" refers to an alkyl group substituted with one or more (e.g., 1, 2, 3, 4, or 5) deuterium atoms, wherein alkyl is as defined above. 1-10"Alkyl" refers to a deuterated alkyl group having 1 to 10 carbon atoms. Preferably, it is a deuterated C 1-6 Alkyl, more preferably deuterated C 1-4 Alkyl, more preferably deuterated C 1-3 Specific examples of deuterated alkyl groups include, but are not limited to, monodeuteriomethyl, dideuteriomethyl, trideuteriomethyl, monodeuterioethyl, 1,2-dideuterioethyl, trideuterioethyl, and the like.

[0359] As used herein, the term "haloalkoxy" refers to an alkoxy group substituted by one or more (eg, 1, 2, 3, 4, or 5) halogen groups, wherein the definition of alkoxy is as described above. 1-10 "Alkoxy" refers to a halogenated alkoxy group having 1 to 10 carbon atoms. Preferably, the halogenated C 1-6 Alkoxy, more preferably halogenated C 1-4 Alkoxy, more preferably halogenated C 1-3 Specific examples of haloalkoxy include, but are not limited to, trifluoromethoxy, trifluoroethoxy, monofluoromethoxy, monofluoroethoxy, difluoromethoxy, difluoroethoxy, and the like.

[0360] As used herein, the terms "cycloalkyl" and "cycloalkyl ring" are used interchangeably to refer to a saturated monocyclic or polycyclic fused cyclic hydrocarbon group. 3-20 "Cycloalkyl" refers to a cycloalkyl group having 3 to 20 carbon atoms, including monocyclic cycloalkyl, spirocyclic alkyl, fused cycloalkyl and bridged cycloalkyl. Preferably, C 3-12 Cycloalkyl. The ring carbon atoms of the cycloalkyl group in the present invention may be optionally substituted by 1, 2 or 3 oxo groups to form a cyclic ketone structure. 3-8 Monocyclic cycloalkyl" and "C 3-8 "Cycloalkyl" refers to a saturated monocyclic hydrocarbon group having 3 to 8 carbon atoms, preferably C 3-6 Monocyclic cycloalkyl (ie, C 3-6 The cycloalkyl group is preferably a C3, C4, C5 or C6 monocyclic cycloalkyl group. Specific examples of the monocyclic cycloalkyl group include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, etc.

[0361] As used herein, the terms "spiroalkyl" and "spiroalkyl ring" refer to a polycyclic hydrocarbon group formed by two or more monocyclic rings sharing a carbon atom (called a spiro atom). Spiroalkyl groups are divided into monospiroalkyl, dispiroalkyl and polyspiroalkyl groups according to the number of spiro atoms shared between the rings. The terms "5- to 20-membered spiroalkyl" or "C 5-20 Spiroalkyl refers to a polycyclic 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, the 6 to 14-membered (C 6-14) spirocycloalkyl, more preferably 6 to 14-membered monospirocycloalkyl, more preferably 7 to 11-membered (C 7-11 ) spirocycloalkyl, more preferably 7 to 11-membered monospirocycloalkyl, most preferably 7-membered (4-membered 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) monospirocycloalkyl. Specific examples of spirocycloalkyl include, but are not limited to:

[0362]

[0363] The cycloalkyl ring may be fused to an aryl, heteroaryl or heterocyclyl ring, wherein the ring connected to the parent structure is a cycloalkyl ring, non-limiting examples of which include indanyl, tetrahydronaphthyl, benzocycloheptanyl, etc. In the present invention, the above-mentioned cycloalkyl groups may be optionally substituted, and when substituted, the substituent is preferably one or more of the substituent groups described in this application.

[0364] As used herein, the term "halocycloalkyl" refers to a cycloalkyl group substituted with one or more (e.g., 1, 2, 3, 4, or 5) halogens, wherein cycloalkyl is as defined above. 3-8 "Cycloalkyl" refers to a halogenated cycloalkyl group having 3 to 8 ring carbon atoms. Preferably, the halogenated C 3-6 Cycloalkyl is more preferably halogenated C3, halogenated C4, halogenated C5 or halogenated C6 cycloalkyl. Specific examples of halogenated cycloalkyl include, but are not limited to, trifluorocyclopropyl, monofluorocyclopropyl, monofluorocyclohexyl, difluorocyclopropyl, difluorocyclohexyl, and the like.

[0365] As used herein, the terms "heterocyclyl" and "heterocyclyl ring" are used interchangeably to refer to a saturated or partially unsaturated monocyclic or polycyclic fused cyclic hydrocarbon group. 3-20 "Heterocyclyl" or "3- to 20-membered heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic fused cyclic hydrocarbon group having 3 to 20 ring atoms, wherein one or more (preferably 1, 2, 3 or 4) ring atoms are selected from nitrogen, oxygen or S(O) m(wherein m is an integer from 0 to 2) heteroatoms, but excluding the ring portion of -OO-, -OS- or -SS-, the remaining ring atoms are carbon. Wherein the ring atom is a nitrogen atom, it can be substituted or unsubstituted (i.e. N or NR, R is hydrogen or other substituents defined herein). In the present invention, the ring carbon atoms of the heterocyclic group can be optionally substituted with 1, 2 or 3 oxo groups to form cyclic ketones, cyclic lactones or cyclic lactam structures. The 3 to 20 membered heterocyclic groups of the present invention include monocyclic heterocyclic groups, spiro heterocyclic groups, fused heterocyclic groups and bridged heterocyclic groups.

[0366] As used herein, the term “C 3-8 "monocyclic heterocyclyl", "3- to 8-membered monocyclic heterocyclyl" and "3- to 8-membered monocyclic heterocyclyl ring" refer to a group having 3 to 8 ring atoms, wherein 1, 2 or 3 of the ring atoms are selected from nitrogen, oxygen or S(O) m (wherein m is an integer from 0 to 2) is a saturated or partially unsaturated monocyclic hydrocarbon group containing 3 to 6 ring atoms, of which 1 or 2 ring atoms are heteroatoms. 3-6 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 may be substituted or unsubstituted (i.e., N or NR, R is hydrogen or other substituents as defined herein). When the heteroatom is a sulfur atom, the sulfur atom may be optionally oxidized (i.e., S(O) m, m is an integer from 0 to 2). The ring carbon atoms of the monocyclic heterocyclic group may be optionally substituted by 1, 2 or 3 oxo groups to form a cyclic ketone, cyclic lactone or cyclic lactam structure. Specific examples of monocyclic heterocyclic groups include, but are not limited to, aziridine, oxirane, azetidine, azetidine-2-one, oxetane, oxetane-2-one, oxazolidine, pyrrolidone, pyrrolidine-2,5-dione, 1,3-dioxolane, dihydrofuran-2(3H)-one, dihydrofuran-2,5-dione, piperidine-2-one, piperidine-2,6-dione, tetrahydro-2H-pyran-2-one, imidazolidine, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, 1,3-dioxolane-2-one, oxazolidin-2-one, imidazolidin-2-one, piperidine, piperazine, piperazin-2-one, morpholine, morpholin-3-one, morpholin-2-one, thiophene ... Morpholin-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-dioxole, 2,3-dihydrothiophene, 2,5-dihydrothiophene, 3,4-dihydro-2H-1,4-oxazine, 3,4-dihydro-2H-1,4-thiazine 1,1-dioxide, 1,2,3,4-tetrahydropyrazine, 1,3-dihydro-2H-pyrrole-2- ketone, 1,5-dihydro-2H-pyrrole-2-one, 1H-pyrrole-2,5-dione, furan-2(3H)-one, furan-2(5H)-one, 1,3-dioxol-2-one, oxazole-2(3H)-one, 1,3-dihydro-2H-imidazole-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, 1 or 2 of which are heteroatoms. Preferred are 3- to 6-membered heterocycloalkyl groups having 3 to 6 ring atoms, 1 or 2 of which are heteroatoms. Specific examples of heterocycloalkyl include, but are not limited to, aziridine, oxiranyl, azetidinyl, oxetanyl, oxazolidinyl, 1,3-dioxolanyl, dioxane, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiomorpholine-1,1-dioxide, tetrahydropyranyl, 1,4-oxazepanyl, 1,3-oxazinyl, hexahydropyrimidinyl, and 1,4-dioxanyl.

[0367] The two ring atoms connected to the monocyclic heterocyclyl ring, including CC and NC, may be optionally fused with a cycloalkyl, heterocyclyl, aryl or heteroaryl group such as a monocyclic cycloalkyl ring, a monocyclic heterocyclyl ring, a monoaryl ring, a 5- or 6-membered monoheteroaryl ring as defined in the present invention to form a fused polycyclic ring. The two ring atoms connected to the monocyclic heterocyclyl that forms a fused ring with other rings are preferably CC.

[0368] As used herein, the term “C 6-14 Aryl", "C 6-14 Aryl ring" and "C 6-14 "Aromatic ring" is used interchangeably to refer to an all-carbon monocyclic, all-carbon polycyclic (rings are connected by covalent bonds and are not fused) or all-carbon fused polycyclic (i.e., rings that share adjacent pairs of carbon atoms) group having 6 to 14 ring atoms, wherein at least one ring in the group is aromatic, i.e., has a conjugated π electron system. Preferably, C 6-10 Aryl. In the present invention, C 6-14 The aryl group includes a monocyclic aryl group, a polycyclic aryl group, and an aromatic condensed polycyclic group. Examples of the monocyclic aryl group include a phenyl group, and examples of the polycyclic aryl group include a biphenyl group.

[0369] In the present invention, C 6-14 When the aryl group is an aromatic fused polycyclic ring, the aromatic fused polycyclic ring may be a polycyclic group formed by condensing a single aryl ring with one or more single aryl rings, and non-limiting examples thereof include naphthyl, anthracenyl, and the like.

[0370] In some embodiments of the present invention, the aromatic fused polycyclic ring may also be a polycyclic group formed by the fusion of a single aromatic ring (such as a phenyl group) and one or more non-aromatic rings, wherein the ring connected to the parent structure is an aromatic ring or a non-aromatic ring. The non-aromatic ring includes but is not limited to a 3- to 6-membered monocyclic heterocyclic ring (preferably a 5- or 6-membered monocyclic heterocyclic ring, the ring carbon atoms of which may be substituted by 1 to 2 oxo groups to form a cyclic lactam or cyclic lactone structure), a 3- to 6-membered monocyclic cycloalkyl ring (preferably a 5- or 6-membered monocyclic cycloalkyl ring, the ring carbon atoms of which may be substituted by 1 or 2 oxo groups to form a cyclic ketone structure). The polycyclic group in which the above-mentioned single aromatic ring is fused to one or more non-aromatic rings may be connected to other groups or the parent structure through nitrogen atoms or carbon atoms, and the ring connected to the parent structure is a single aromatic ring or a non-aromatic ring.

[0371] Herein, a benzene ring fused with a 5- or 6-membered monocyclic heterocyclyl ring to form a 9- or 10-membered aromatic fused bicyclic ring refers to a fused 5- or 6-membered monocyclic heterocyclyl ring formed by two adjacent substituent groups on the phenyl group and the ring atoms to which they are attached, wherein the 5- or 6-membered monocyclic heterocyclyl ring is as defined above, and the formed 9- or 10-membered aromatic fused bicyclic ring may also be referred to as a 9- or 10-membered phenyl heterocyclyl ring.

[0372] As used herein, a 9- or 10-membered aromatic fused bicyclic ring formed by the fusion of a benzene ring with a 5- or 6-membered monocyclic cycloalkyl ring refers to a 5- or 6-membered monocyclic cycloalkyl ring formed by two adjacent substituent groups on the phenyl group and the ring atoms to which they are attached. The 5- or 6-membered monocyclic cycloalkyl ring is as defined above. The resulting 9- or 10-membered aromatic fused bicyclic ring may also be referred to as a 9- or 10-membered phenylcycloalkyl ring. Non-limiting examples include:

[0373]

[0374] In the present invention, the above-mentioned various aryl groups may be substituted or unsubstituted. When substituted, the substituent is preferably one or more substituent groups described in this application.

[0375] As used herein, the terms "heteroaryl", "heteroaryl ring" and "heteroaromatic ring" are used interchangeably and refer to a monocyclic or fused polycyclic (i.e., sharing adjacent pairs of ring atoms, where the shared adjacent pairs of ring atoms may be CC or NC) 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 atom may be optionally quaternized. The heteroaryl group has 6, 10 or 14 shared π electrons and at least one ring in the group is aromatic. The term "C 5-14"Heteroaryl" and "5- to 14-membered heteroaryl" refer to heteroaryl groups having 5 to 14 ring atoms, of which 1, 2, 3 or 4 ring atoms are heteroatoms. Preferably, the heteroaryl group is a 5- to 10-membered heteroaryl group having 5 to 10 ring atoms, of which 1, 2, 3 or 4 ring atoms are heteroatoms. In the present invention, C 5-14 The heteroaryl group can be a monoheteroaryl group, a fused bicyclic heteroaryl group, or a fused tricyclic heteroaryl group.

[0376] As used herein, the term "5- or 6-membered monoheteroaryl" is used interchangeably with "5- or 6-membered monocyclic heteroaryl" and refers to a monocyclic heteroaryl group having 5 or 6 ring atoms, wherein 1, 2 or 3 of the ring atoms are heteroatoms. Specific examples of monoheteroaryl groups include, but are not limited to, thiophene, furan, thiazole, isothiazole, imidazole, oxazole, pyrrole, pyrazole, triazole, 1,2,3-triazole, 1,2,4-triazole, 1,2,5-triazole, 1,3,4-triazole, tetrazole, isoxazole, oxadiazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, thiadiazole, pyridine, pyridazine, pyrimidine, pyrazine, and the like.

[0377] 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 group having 8 to 10 ring atoms, wherein 1, 2, 3, 4 or 5 of the ring atoms are heteroatoms. The fused bicyclic heteroaryl group can be a bicyclic group (preferably a 9- or 10-membered biheteroaryl ring) formed by the fusion of a monoaryl ring (such as phenyl) and a monoheteroaryl ring (preferably a 5- or 6-membered monoheteroaryl ring), or a bicyclic group (preferably a 5- or 6-membered monoheteroaryl ring) and a monoheteroaryl ring (preferably a 5- or 6-membered monoheteroaryl ring).

[0378] Any two connected ring atoms on the above-mentioned monoheteroaryl ring, including CC, NC, and NN, can be fused with a cycloalkyl, heterocyclyl, aryl, or heteroaryl group, such as a monocyclic cycloalkyl ring, a monocyclic heterocyclyl ring, a monoaryl ring, a 5- or 6-membered monoheteroaryl ring, to form a fused polycyclic ring. The two connected ring atoms on the monoheteroaryl ring forming a fused ring with another ring are preferably CC, including, but not limited to, the following forms:

[0379]

[0380] Non-limiting examples of 8- to 10-membered biheteroaryls include 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, pyrazolo[1,5-a]pyrimidine, imidazo[1,2-b]pyridazine, and the like.

[0381] The above-mentioned monoheteroaryl group, or a biheteroaryl group formed by fusion of a benzene ring and a monoheteroaryl ring, or a biheteroaryl group formed by fusion of a monoheteroaryl ring and a monoheteroaryl ring, can be connected to other groups or parent structures through nitrogen atoms or carbon atoms. In the case of a biheteroaryl group, 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:

[0382]

[0383] 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 single heteroaryl ring (preferably a 5- or 6-membered single heteroaryl ring) and one or more non-aromatic rings, wherein the ring connected to the parent structure is a single heteroaryl ring or a non-aromatic ring. The non-aromatic ring includes but is not limited to a 3- to 6-membered monocyclic heterocyclyl ring (preferably a 5- or 6-membered monocyclic heterocyclyl ring, the ring carbon atoms of the monocyclic heterocyclyl ring may be substituted by 1 to 2 oxo groups to form a cyclic lactam or cyclic lactone structure), a 3- to 6-membered monocyclic cycloalkyl ring (preferably a 5- or 6-membered monocyclic cycloalkyl ring, the ring carbon atoms of the monocyclic cycloalkyl ring may be substituted by 1 or 2 oxo groups to form a cyclic ketone structure), etc. The polycyclic group formed by the fusion of the above-mentioned single heteroaryl ring and one or more non-aromatic rings can be connected to other groups or the parent structure through nitrogen atoms or carbon atoms, and the ring connected to the parent structure is a single heteroaryl ring or a non-aromatic ring.

[0384] As used herein, a 5- or 6-membered monoheteroaryl ring fused to a 5- or 6-membered monocyclic heterocyclyl ring to form an 8- to 10-membered fused bicyclic heteroaryl refers to a fused 5- or 6-membered monocyclic heterocyclyl ring formed by two adjacent substituent groups on the 5- or 6-membered monoheteroaryl and the ring atoms to which they are attached, wherein the 5- or 6-membered monocyclic heterocyclyl ring is as defined above, and the formed 8- to 10-membered fused bicyclic heteroaryl may also be referred to as an 8- to 10-membered heteroarylheterocyclyl ring.

[0385] As used herein, a 5- or 6-membered monocyclic heteroaryl ring fused to a 5- or 6-membered monocyclic cycloalkyl ring to form an 8- to 10-membered fused bicyclic heteroaryl group refers to a 5- or 6-membered monocyclic cycloalkyl ring formed by two adjacent substituent groups on the 5- or 6-membered monocyclic heteroaryl group and the ring atoms to which they are attached, wherein the 5- or 6-membered monocyclic cycloalkyl ring is as defined above. The resulting 8- to 10-membered fused bicyclic heteroaryl group may also be referred to as an 8- to 10-membered heteroarylcycloalkyl ring. Non-limiting examples thereof include:

[0386]

[0387] In the present invention, the various heteroaryl groups mentioned above may be substituted or unsubstituted. When substituted, the substituents are preferably one or more substituent groups described in this application.

[0388] As used herein, the term "-alkyl-R" refers to a substituent formed by replacing an alkyl group with one or more R groups, wherein "-alkyl-" refers to an alkylene group or an alkylidene group formed after substitution. As described herein, R can be hydroxy, cyano, alkoxy, substituted amino, heterocycloalkyl, heteroaryl, haloalkyl, haloalkoxy, cycloalkyl, alkynyl, etc., and the group represented by R is as defined herein. Preferably -C 1-6 Alkyl-R, more preferably -C 1-4 Alkyl-R, more preferably -C 1-3 Alkyl-R, more preferably -C 1-2 Alkyl-R, for example, -CH2-CH(CH3)-R, -CH2-CH2-CH2-R, -CH2-CH2-R, -CH2-R, etc.

[0389] As used herein, the term "hydroxy" refers to -OH.

[0390] As used herein, the term "hydroxymethyl" refers to -CH2OH, and "hydroxyethyl" refers to -CH2CH2OH or -CH(OH)CH3.

[0391] As used herein, the term "cyanomethyl" refers to -CH2CN, and "cyanoethyl" refers to -CH2CH2CN or -CHCNCH3.

[0392] As used herein, the term "amino" refers to -NH2.

[0393] As used herein, the term "cyano" refers to -CN.

[0394] As used herein, the term "nitro" refers to -NO2.

[0395] As used herein, the term "benzyl" refers to -CH2-benzene.

[0396] As used herein, the term "oxo" refers to =0.

[0397] As used herein, the term "carboxy" refers to -C(O)OH.

[0398] As used herein, the term "carboxylate" refers to -C(O)O(alkyl) or -C(O)O(cycloalkyl).

[0399] As used herein, the term "acetyl" refers to -COCH3.

[0400] In this paper, C 1-10 It can be preferably C 1-6 More preferably C 1-4 More preferably C 1-3 For example, C 1-10 The alkyl group may preferably be C 1-6 Alkyl; more preferably C 1-4 Alkyl; more preferably C 1-3 Alkyl. For example, C 1-10 The alkoxy group may preferably be C 1-6 Alkoxy; more preferably C 1-4 Alkoxy; more preferably C 1-3 Alkoxy.

[0401] In this paper, C 3-20 It can be preferably C 3-10 More preferably C 3-8 More preferably C 3-6 More preferably C 3-5 For example, C 3-20 The cycloalkyl group may preferably be C 3-8 Cycloalkyl; more preferably C 3-6 Cycloalkyl; more preferably C 3-6 Cycloalkyl.

[0402] In one embodiment of the present invention, in any group, the C 3-6 The cycloalkyl group is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

[0403] In one embodiment of the present invention, in any group, the 3- to 6-membered heterocycloalkyl group is selected from the group consisting of aziridine, oxirane, azetidine, oxetane, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, piperidine, piperazine, morpholine, thiomorpholine, thiomorpholine-1,1-dioxide, and tetrahydropyran.

[0404] In one embodiment of the present invention, in any group, the 5- or 6-membered monocyclic heteroaryl is selected from the group consisting of thiophene, N-alkyl ring pyrrole, 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.

[0405] In one embodiment of the present invention, in any group, the 8- to 10-membered bicyclic heteroaryl is selected from the group consisting of benzoxazole, benzisoxazole, benzimidazole, benzothiazole, benzisothiazole, benzotriazole, benzofuran, benzothiophene, indole, indazole, isoindole, quinoline, isoquinoline, quinazoline, quinoxaline, cinnoline, pyridopyrimidine, and naphthyridine.

[0406] As used herein, the term "substituted" refers to any one or more hydrogen atoms on a particular atom being replaced by a substituent, which may include variants of deuterium and hydrogen, as long as the valence of the particular atom is normal and the substituted compound is stable. When the substituent is an oxo group (i.e., =O), it means that two hydrogen atoms are replaced. Oxo substitution does not occur on aromatic groups. The term "optionally substituted" or "optionally substituted" means that it may or may not be substituted, and unless otherwise specified, the type and number of the substituents may be arbitrary on a chemically feasible basis.

[0407] When any variable (e.g., R) occurs more than once in a compound's composition or structure, its definition at each occurrence is independent. Thus, for example, if a group is substituted with 0-2 Rs, the group may be optionally substituted with up to two Rs, with each occurrence of R being an independent choice. Furthermore, combinations of substituents and / or their variants are permissible only if such combinations result in stable compounds.

[0408] The compounds represented by formula (IA) or (IB) of the present invention can be prepared using synthetic methods known in the art or using methods known in the art in combination with the methods described in the present invention. The solvents, temperatures and other reaction conditions given in the present invention are exemplary and can be varied according to methods well known in the art. The embodiment compounds described in the present invention can be synthesized according to the methods described in the embodiments using appropriate starting materials according to their specific structures, or can be synthesized using methods similar to those described in the embodiments. The starting materials for synthesizing the embodiment 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 embodiment compounds can be further split by methods well known in the art, such as crystallization, chromatography, etc., as needed to obtain their stereoisomers, and the splitting conditions are easily obtained by those skilled in the art through conventional means or limited experiments.

[0409] As a further illustration, the compounds of formula (IB-1′) and formula (IB-2′) of the present invention can be synthesized by the following method, wherein the solvent, temperature and other reaction conditions in each step can be the same or similar to those described in the following examples, or reaction conditions known in the art can be used;

[0410]

[0411]

[0412] The compounds of formula (IB-1′) and formula (IB-2′) of the present invention can also be synthesized by the following method, wherein the solvent, temperature 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;

[0413]

[0414]

[0415] 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 methanesulfonate, toluenesulfonate, p-toluenesulfonate, etc.; acyloxy groups, such as acetoxy, trifluoroacetoxy, etc. In each formula, R pIt is an amino protecting group well known in the art, such as formyl; acyl, such as alkanoyl (such as acetyl, trichloroacetyl or trifluoroacetyl); alkoxycarbonyl, such as tert-butyloxycarbonyl (Boc); arylmethoxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc); arylmethyl, such as benzyl (Bn), trityl (Tr), 1,1-bis-(4′-methoxyphenyl)methyl; silyl, 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', and X1 are as defined above (eg, the same as the definitions of the corresponding groups in Formula I or Formula IA).

[0416] The compounds of formula (IB-1″) and formula (IB-2″) of the present invention can be synthesized by the following method, wherein the solvent, temperature and other reaction conditions in each step can be the same as or similar to those described in the following examples, or reaction conditions known in the art can be used;

[0417]

[0418]

[0419] In the preparation routes of the compounds of formula (IB-1″) and formula (IB-2″), in each formula, R p It is an amino protecting group well known in the art, such as formyl; acyl, such as alkanoyl (such as acetyl, trichloroacetyl or trifluoroacetyl); alkoxycarbonyl, such as tert-butyloxycarbonyl (Boc); arylmethoxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc); arylmethyl, such as benzyl (Bn), trityl (Tr), 1,1-bis-(4′-methoxyphenyl)methyl; silyl, 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′, and X1 are as defined above (eg, the same as the definitions of the corresponding groups in Formula I or Formula IA).

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

[0421]

[0422] In the preparation route of the compound of formula e, R lev are leaving groups 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, etc. R0', Ar', E1', and X1 are as defined above (e.g., the same as the definitions of the corresponding groups in Formula I or Formula IA). BRIEF DESCRIPTION OF THE DRAWINGS

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

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

[0425] 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, embodiments formed by combining them with other chemical synthesis methods, and equivalent replacement methods well known to those skilled in the art. Preferred embodiments include, but are not limited to, examples of the present invention. The present invention is described in detail below by way of examples, but this does not imply any adverse limitations on the present invention. The present invention has been described in detail herein, with specific embodiments thereof disclosed therein. It will be apparent to those skilled in the art that various changes and modifications will be made to the specific embodiments of the present invention without departing from the spirit and scope of the present invention. Where specific conditions are not specified in the examples, the conditions are carried out according to conventional conditions or the conditions recommended by the manufacturer. Where the reagents or instruments used are not specified by the manufacturer, they are all conventional products that can be obtained commercially.

[0426] 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.

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

[0428] If isomeric compounds are detected by analytical HPLC, the following conditions can be used: column type: XBridge C18, 3.5μm 4.6*150mm, mobile phase: A: purified water (0.05% TFA); B: preparative grade acetonitrile (0.05% TFA), gradient: 5%-95% B, run time: 15 min, flow rate: 1 ml / min, column temperature = 40°C.

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

[0430]

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

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

[0433] 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 0°C for half an hour. 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 then 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, adjusted to pH 3 with 3.0 M dilute hydrochloric acid, and extracted three times with ethyl acetate. The organic phase was dried and concentrated to give 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 used directly in the next reaction. ES-API: [M+H] + =483.1

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

[0435] Step 5: Dissolve 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) in DMF (6 mL). Add (R)-tert-butyl 3-(hydroxymethyl)piperazine-1-carboxylate (454 mg, 2.10 mmol) and stir at 80°C for 18 hours. Pour the reaction mixture into 30 mL of water and extract three times with 20 mL of ethyl acetate. The organic phase was washed three times with saturated brine, dried, and concentrated. The crude product was purified on a flash silica gel column (EtOAc / PE: 0-70%) to obtain (3R)-4-(6-fluoro-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro-2-oxo-1,2-dihydro-1,8-naphthyridin-4-yl)-3-(hydroxymethyl)piperazine-1-carboxylic acid tert-butyl ester (85 mg, Y: 35.7%) as a yellow solid. ES-API: [M+H] + =681.3.

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

[0437] Step 7: (4aR)-11-Fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-7-oxo-1,2,4a,5,7,8-hexahydropyrazine[1′,2′:4,5][1,4]oxo-2,3-c][1,8]naphthyridine-3(4H)-carboxylic acid tert-butyl ester (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 hours, and the reaction solution was concentrated to give the product (4aR)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-1,2,3,4,4a,5-hexahydropyrazine[1′,2′:4,5][1,4]oxazine[2,3-c][1,8]naphthyridin-7(8H)-one (40 mg, crude product), which was used directly in the next reaction. ES-API: [M+H] + =534.3.

[0438] Step 8: (4aR)-11-Fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-1,2,3,4,4a,5-hexahydropyrazino[1′,2′:4,5][1,4]oxazin[2,3-c][1,8]naphthyridin-7(8H)-one (40 mg, 0.055 mmol) was dissolved in dichloromethane (4 mL) and triethylamine (28 mg, 0.28 mmol) was added. The reaction mixture was cooled to 0°C and a solution of acrylic anhydride (6 mg, 0.05 mmol) in dichloromethane (0.5 mL) was added dropwise. The reaction mixture was stirred at 0°C for 15 minutes. 10 mL of saturated aqueous NaHCO₃ was added to the reaction mixture and the mixture was extracted three times with 10 mL of dichloromethane. The organic phase was dried and concentrated, and the crude product was purified by thick-thin-layer chromatography (dichloromethane / methanol = 10:1) to give (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]naphthyridin-7(8H)-one (17 mg, Y: 52.4%) as a pale yellow solid. ES-API: [M+H] + =588.2.

[0439] Step 9: (4aR)-3-Acryloyl-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-1,2,3,4,4a,5-hexahydropyrazino[1′,2′:4,5][1,4]oxazin[2,3-c][1,8]naphthyridin-7(8H)-one (15 mg, 0.025 mmol) was dissolved in dichloromethane (1.5 mL). The reaction mixture was cooled to 0°C and a 17% solution of boron tribromide in dichloromethane (1 mL) was added dropwise. The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into 20 mL of saturated aqueous NaHCO₃ and extracted three times with 20 mL of dichloromethane. The organic phase was dried and concentrated, and the crude product was purified by preparative HPLC to give the product (4aR)-3-acryloyl-11-fluoro-10-(2-fluoro-6-hydroxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-1,2,3,4,4a,5-hexahydropyrazine[1′,2′:4,5][1,4]oxazine[2,3-c][1,8]naphthyridine-7(8H)-one (Z1, 10 mg, Y: 68.3%) as a white solid. 1 HNMR (500MHz, DMSO-d6) δ9.96 (s, 1H), 8.35 (d, J=4.8Hz, 1H), 7.19-7.14 (m, 2H), 6.8 7-6.75 (m, 1H), 6.64 (d, J = 8.5Hz, 1H), 6.59 (t, J = 8.5Hz, 1H), 6.12 (d, J = 15.9Hz, 1H) ,5.71-5.67(m,1H),4.39-3.95(m,4H),3.79-3.30(m,4H),3.06-2.98(m,1H),2.56- 2.29 (m, 1H), 1.80-1.73 (m, 3H), 0.99-0.95 (m, 3H), 0.85-0.80 (m, 3H). ES-API: [M+H] + =574.2.

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

[0441] Example 2 Preparation of Compound Z2

[0442]

[0443] Step 1: To a 100 mL round-bottom flask at room temperature, 5-(methoxymethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (2.9 g, 15.62 mmol) and isopropanol (40 mL) were added in portions. 2-chloropyridin-3-amine (2.0 g, 15.62 mmol) was added. The reaction was stirred at reflux for 15 minutes. The reaction mixture was cooled to room temperature, the precipitated solid was filtered, the filter cake was washed with a small amount of isopropanol, and vacuum dried 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%) as a white solid. ES-API: [M+H] + =283.1

[0444] Step 2: Add 200 mL of diphenyl ether to a 500 mL round-bottom flask, heat to 220°C, and add 5-((2-chloropyridin-3-yl)amino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (3.9 g, 13.83 mmol) portionwise. Stir the reaction at 220°C for 20 minutes. The reaction solution was cooled to room temperature and poured into petroleum ether. The precipitated solid was filtered, the filter cake was washed with petroleum ether, and vacuum dried to obtain the product, 8-chloro-1,7-naphthyridin-4-ol (1.5 g, Y: 60%), as a light brown solid. ES-API: [M+H] + =181.0

[0445] Step 3: To a 50 mL round-bottom flask was added 8-chloro-1,7-naphthyridin-4-ol (500 mg, 2.78 mmol), sodium acetate (300 mg, 2.78 mmol), anhydrous ethanol (25 mL), and 5% Pd / C (250 mg). The reaction was stirred at room temperature under a hydrogen balloon for 3 days. The reaction solution was filtered through celite, the filtrate was concentrated, and the crude product was purified by flash silica gel column chromatography (dichloromethane / methanol: 0-10%) to give the product 1,7-naphthyridin-4-ol (200 mg, Y: 49.3%) as a yellow solid. ES-API: [M+H] + =147.1

[0446] Step 4: 1,7-naphthyridin-4-ol (550 mg, 3.77 mmol) was dissolved in concentrated sulfuric acid (4.5 mL), cooled to 0°C, and concentrated nitric acid (1.0 mL, 15.08 mmol) was slowly added dropwise. The reaction was stirred at 100°C for 1 hour. The cooled reaction solution was poured into ice water and the pH was adjusted to 6-7 with concentrated aqueous ammonia. The precipitated solid was filtered and dried under vacuum to obtain 3-nitro-1,7-naphthyridin-4-ol (530 mg, Y: 73.7%) as a yellow solid. ES-API: [M+H] + =192.1

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

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

[0449] Step 7: To a 50 mL sealed tube were added (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) in sequence. The reaction was stirred at 95°C for 3 days. The cooled reaction solution was poured into water and extracted twice with ethyl acetate. The organic phase was washed three times with saturated brine, dried, and concentrated. The crude product was purified by thick-layer chromatography (dichloromethane / methanol = 15:1) to give (R)-8a,9,11,12-tetrahydropyrazine[1′,2′:4,5][1,4]oxazine[2,3-c][1,7]naphthyridine-10(8H)-carboxylate (175 mg, Y: 64%) as a yellow solid. ES-API: [M+H] + =343.3

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

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

[0452] Step 10: (8aR)-3-(5-Methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-1,2,3,4,8a,9,11,12-octahydropyrazine[1′,2′:4,5][1,4]oxazine[2,3-c][1,7]naphthyridine-10(8H)-carboxylic acid tert-butyl ester (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 give the product (R)-3-(5-methyl-1H-indazol-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]naphthyridine (60 mg, crude yield), which was used directly in the next reaction without purification. ES-API: [M+H] + =377.1.

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

[0454] Example 3 Preparation of Compounds Z3a and Z3

[0455]

[0456] Step 1: Dissolve 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) in DMF (10 mL). Add tert-butyl (2R,5R)-5-(hydroxymethyl)-2-methylpiperazine-1-carboxylate (1.61 g, 7.0 mmol). Stir the reaction at 80°C for 1 hour. Pour the reaction mixture into 30 mL of water. Extract with 20 mL of ethyl acetate three times. The organic phase was washed three times with saturated brine, dried, and concentrated. The crude product was purified on a flash silica gel column (EtOAc / PE: 0-70%) to obtain (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%) as a yellow solid. ES-API: [M+H] + =695.2.

[0457] Step 2: Tert-butyl (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-carboxylate (300 mg, 0.44 mmol) was dissolved in DMA (20 mL). NaH (52 mg, 1.32 mmol) was added and the reaction was stirred at 125°C for 20 hours. The cooled reaction solution was poured into 15 mL of water. The product was extracted three times with 30 mL of ethyl acetate. The organic phase was washed eight times with saturated brine, dried, and concentrated. The crude product was purified on a flash silica gel column (EtOAc / PE: 0-100%) to give (2R,4aR)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-2-methyl-7-oxo-1,2,4a,5,7,8-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%) as a yellow solid. ES-API: [M+H]+ = 648.3.

[0458] Step 3: (2R,4aR)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-2-methyl-7-oxo-1,2,4a,5,7,8-hexahydropyrazine[1',2':4,5][1,4]oxazine[2,3-c][1,8]naphthyridine-3(4H)-carboxylic acid tert-butyl ester (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 give 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]oxazin[2,3-c][1,8]naphthyridin-7(8H)-one (61 mg, crude product), which was used directly in the next reaction. ES-API: [M+H] + =548.2.

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

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

[0461] Example 6 Preparation of Compound Z6

[0462]

[0463] Step 1: Dissolve 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) in DMF (15 mL). Add (R)-tert-butyl 3-(hydroxymethyl)piperazine-1-carboxylate (3 g, 13.92 mmol). Stir the reaction at 80°C for 2 hours. Pour the reaction mixture into 30 mL of water. Extract with 20 mL of ethyl acetate three times. The organic phase was washed three times with saturated brine, dried, and concentrated. The crude product was purified on a flash silica gel column (EtOAc / PE: 0-70%) to obtain tert-butyl (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)-3-(hydroxymethyl)piperazine-1-carboxylate (1.3 g, 54%) as a yellow solid. ES-API: [M+H] + =697.2.

[0464] Step 2: Dissolve tert-butyl (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)-3-(hydroxymethyl)piperazine-1-carboxylate (1.3 g, 1.86 mmol) in DMA (10 mL). Add LHMDS (5.6 mmol, 5.6 mmol, 1 M in tetrahydrofuran) and stir at 140°C for 20 hours. Pour the cooled reaction mixture into 15 mL of water and extract three times with 30 mL of ethyl acetate. The organic phase was washed three times with saturated brine, dried, and concentrated. The crude product was purified on a flash silica gel column (methanol / dichloromethane: 0-10%) to give (4aR)-11-chloro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-7-oxo-1,2,4a,5,7,8-hexahydropyrazino[1′,2′:4,5][1,4]oxazino[2,3-c][1,8]naphthyridine-3(4H)-carboxylic acid tert-butyl ester (0.24 g, 20%) as a yellow solid. ES-API: [M+H] + =650.2.

[0465] Step 3: (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]naphthyridine-3(4H)-carboxylic acid tert-butyl ester (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 hours, and the reaction solution was concentrated to give 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]naphthyridin-7(8H)-one (203 mg, crude product), which was used directly in the next reaction. ES-API: [M+H] + =550.1.

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

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

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

[0469]

[0470] Step 1: 4-Chloro-6-fluoro-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro-1,8-naphthyridine-2(1H)-one (500 mg, 1.00 mmol) was dissolved in N,N-dimethylacetamide (6 mL), and (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 in sequence, and the reaction was stirred at 120°C for 2 hours. 100 mL of ethyl acetate was added to the reaction mixture, and the mixture was washed four times with 30 mL of dilute brine and then with 30 mL of saturated brine. The mixture was dried and concentrated, and the crude product was purified on a flash silica gel column (EtOAc / PE: 0-70%) to obtain (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%) as a yellow solid. ES-API: [M+H] + =709.2.

[0471] Step 2: (3R)-1-(tert-Butyl)-3-methyl-4-(6-fluoro-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro-2-oxo-1,2-dihydro-1,8-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 minutes. The reaction mixture was concentrated, and 50 mL of ethyl acetate and 30 mL of saturated sodium bicarbonate were added sequentially. The suspension was filtered through celite, and the filter cake was washed with ethyl acetate. The organic phase was separated and washed sequentially with 30 mL of saturated aqueous sodium bicarbonate solution and 30 mL of saturated brine. The product was dried and concentrated to give (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-carboxylic acid tert-butyl ester (450 mg, Y: 98.6%) as a light yellow solid. ES-API: [M+H] + =647.2.

[0472] Step 3: To a 15 mL sealed tube, 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, anhydrous potassium carbonate (290 mg, 2.10 mmol), and iodomethane (596 mg, 4.20 mmol) were added in sequence. The tube was sealed and the reaction was stirred at 50°C for 20 hours. The reaction mixture was concentrated, 60 mL of ethyl acetate was added, and the mixture was washed sequentially with 30 mL of water and 30 mL of saturated brine, dried, and concentrated. The crude product was purified on a flash silica gel column (EtOAc / PE: 0-70%) to obtain (4aR)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-6-methyl-5,7-dioxy-1,2,4,4a,5,6,7,8-octahydro-3H-pyrazino[1',2':4,5]pyrazino[2,3-c][1,8]naphthyridine-3-carboxylic acid tert-butyl ester (390 mg, Y: 84.8%) as an orange solid. ES-API: [M+H] + =661.3.

[0473] Step 4: (4aR)-11-Fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-6-methyl-5,7-dioxy-1,2,4,4a,5,6,7,8-octahydro-3H-pyrazino[1',2':4,5]pyrazino[2,3-c][1,8]naphthyridine-3-carboxylic acid tert-butyl ester (940 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 hours, and the reaction solution was concentrated to give 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 was used directly in the next reaction. ES-API: [M+H] + =561.3.

[0474] Step 5: (4aR)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-6-methyl-2,3,4,4a,6,8-hexahydro-1H-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 mixture was cooled to 0°C and acryloyl chloride (256 mg, 2.84 mmol) was added to the reaction mixture. The reaction was stirred at 0°C for 15 minutes. 30 mL of dichloromethane was added to the reaction solution, and the mixture was washed sequentially with 15 mL of water, 15 mL of saturated aqueous NaHCO3 solution, and 15 mL of saturated brine, dried, and concentrated. The crude product was purified by flash silica gel column chromatography (EtOAc / PE: 0-100%) to give ((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%) as a light yellow solid. ES-API: [M+H] + =615.3.

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

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

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

[0478]

[0479] Step 1: To a 50 mL sealed tube, 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-octyl-3H-pyrazino[1',2':4,5]pyrazino[2,3-c][1,8]naphthyridine-3-carboxylate (800 mg, 1.21 mmol), 20 mL of acetone, anhydrous potassium carbonate (500 mg, 3.63 mmol), and iodomethane (1.03 g, 7.26 mmol) were added in sequence. The tube was sealed and the reaction was stirred at 50°C for 18 hours. The reaction mixture was concentrated, 60 mL of ethyl acetate was added, and the mixture was washed sequentially with 20 mL of water and 30 mL of saturated brine, dried, and concentrated. The crude product was purified on a flash silica gel column (EtOAc / PE: 0-70%) to obtain (2R,4aR)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-2,6-dimethyl-5,7-dioxo-1,2,4,4a,5,6,7,8-octyl-3H-pyrazino[1',2':4,5]pyrazino[2,3-c][1,8]naphthyridine-3-carboxylic acid tert-butyl ester (790 mg, Y: 96.7%) as an orange solid. ES-API: [M+H]+ =675.3.

[0480] Step 2: 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-octyl-3H-pyrazino[1',2':4,5]pyrazino[2,3-c][1,8]naphthyridine-3-carboxylate (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 hours, and the reaction solution was concentrated to give 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 used directly in the next reaction. ES-API: [M+H] + =575.2.

[0481] Step 3: (2R,4aR)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-2,6-dimethyl-2,3,4,4a,6,8-hexahydro-1H-pyrazino[1',2':4,5]pyrazino[2,3-c][1,8]naphthyridine-5,7-dione (810 mg, crude) was dissolved in dichloromethane (15 mL) and N,N-diisopropylethylamine (755 mg, 5.85 mmol) was added. The reaction mixture was cooled to 0°C and acryloyl chloride (211 mg, 2.34 mmol) was added to the reaction mixture. The reaction mixture was stirred at 0°C for 15 minutes. 50 mL of dichloromethane was added to the reaction solution, which was then washed sequentially with 20 mL of water, 40 mL of saturated aqueous NaHCO₃, and 20 mL of saturated brine. The mixture was dried and concentrated, and the crude product was purified by flash silica gel column chromatography (EtOAc / PE: 0-100%) to obtain (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%) as a light yellow solid. ES-API: [M+H] + =629.2.

[0482] Step 4: (2R,4aR)-3-Acryloyl-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-2,6-dimethyl-2,3,4,4a,6,8-hexahydro-1H-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 mixture was cooled to 0°C and a 17% solution of boron tribromide in dichloromethane (7 mL) was added dropwise. The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into 60 mL of saturated aqueous NaHCO3 and extracted twice with 80 mL of dichloromethane. The organic phase was washed sequentially 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 give (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]naphthyridine-5-dione (Z10, 249 mg, Y: 68.7%) as a light yellow solid. ES-API: [M+H] + =615.2.

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

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

[0485] Compounds Z4 to Z5, Z7 to Z8, and Z11 to Z20 are prepared by methods similar to those of compound Z1 or Z2, wherein the starting materials of each compound can be purchased commercially or prepared by methods known to those skilled in the art. Similar synthetic methods for the intermediates are easily obtained by those skilled in the art by reference to existing methods.

[0486]

[0487]

[0488]

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

[0490]

[0491] 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 was cooled to 0°C, 12 mL of concentrated sulfuric acid was added dropwise to the reaction solution. After the addition was complete, the reaction was stirred at 120°C for 18 hours. After the reaction was completed, a large amount of solid precipitated. Filter and wash the filter cake three times with water. After drying the filter cake, 7-chloro-6-fluoro-4-hydroxy-1-(4-isopropyl-6-methylpyrimidin-5-yl)-1,8-naphthyridine-2(1H)-one (1.4 g, 75%) was obtained as a white solid. The crude product was used directly in the next step. ES-API: [M+H] + =349.1.

[0492] Step 2: To a round-bottom flask was added 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. Concentrated nitric acid (700 mg, 11.1 mmol) was added dropwise to the reaction mixture. The reaction mixture was heated in an oil bath at 30°C for 2 hours. The reaction mixture was poured into ice water, and solid precipitated. The mixture was filtered and the filter cake was washed with water. The filter cake was collected and dried under vacuum to give 7-chloro-6-fluoro-4-hydroxy-1-(4-isopropyl-6-methylpyrimidin-5-yl)-3-nitro-1,8-naphthyridin-2(1H)-one (1.2 g, 76% purity) as a yellow solid. The crude product was used directly in the next step. ES-API: [M+H] + =394.1.

[0493] Step 3: To a reaction flask, 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 were added. The reaction was stirred in an oil bath at 110°C under nitrogen for 1 hour, after which the reaction was stopped. To the reaction mixture was added 1 M aqueous potassium carbonate solution (30 mL), and the mixture was extracted once with 20 mL EtOAc / PE (1:1) to remove impurities. The aqueous phase was then adjusted to pH 4 with 6 M aqueous hydrochloric acid. The mixture was extracted three times with ethyl acetate. The organic phase was dried over sodium sulfate and concentrated to afford 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%) as a yellow solid. ES-API: [M+H] + =483.1.

[0494] 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) to a round-bottom flask. Add phosphorus oxychloride (2.2 g, 14.5 mmol) dropwise. Stir the reaction at 85°C for 1 hour. LC-MS indicates the reaction is complete. Pour the reaction solution into ice water and extract with ethyl acetate. The organic phase was dried over sodium sulfate and concentrated to give 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%). The crude product was used directly in the next reaction. ES-API: [M+H] + =502.1.

[0495] Step 5: To a round-bottom flask, 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). Stir the mixture at 120°C for 2 hours. LC-MS indicates the reaction is complete. Pour the reaction mixture into 30 mL of water. Extract with ethyl acetate three times. The organic phase was washed four times with saturated brine / water (v / v, 1:1), dried and concentrated, and the crude product was purified by flash silica gel column chromatography (EtOAc / PE: 0-40%) to give 1-(tert-butyl)3-methyl(3R)-4-(6-fluoro-7-(2-fluoro-6-methoxyphenyl)-1-(4-isopropyl-6-methylpyrimidin-5-yl)-3-nitro-2-oxo-1,2-dihydro-1,8-naphthyridin-4-yl)piperazine-1,3-dicarboxylate (1 g, purity 82%). ES-API: [M+H] + =710.2.

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

[0497] Step 7: To a round-bottom flask was added 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), iodomethane (789 mg, 5.55 mmol), potassium carbonate (286 mg, 2.07 mmol), and 10 mL of acetone. The reaction mixture was sealed and stirred at 50°C for 16 hours. The reaction was complete by LC-MS. The reaction mixture was filtered through celite. The filtrate was concentrated, and the crude product was purified on a flash silica gel column (EtOAc / PE: 0-60%) to give (4aR)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(4-isopropyl-6-methylpyrimidin-5-yl)-6-methyl-5,7-dioxo-1,2,4,4a,5,6,7,8-octahydro-3H-pyrazino[1',2':4,5]pyrazino[2,3-c][1,8]naphthyridine-3-carboxylic acid tert-butyl ester (260 mg, 57%) as a yellow solid. ES-API: [M+H] + =662.2.

[0498] Step 8: To a round-bottom flask was added 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. The mixture was stirred at room temperature for 1 hour. The reaction was complete after LC-MS. The reaction mixture was concentrated to give (4aR)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(4-isopropyl-6-methylpyrimidin-5-yl)-6-methyl-2,3,4,4a,6,8-hexahydro-1H-pyrazino[1',2':4,5]pyrazino[2,3-c][1,8]naphthyridine-5,7-dione (219 mg) as a yellow solid. The crude product was used directly in the next step. ES-API: [M+H] + =562.2.

[0499] Step 9: To a 50 mL round-bottom flask was added (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). The reaction mixture was cooled to 0°C and a solution of acryloyl chloride in dichloromethane (71 mg, 0.78 mmol, 0.5 mL) was added dropwise. The reaction mixture was stirred at 0°C for 10 minutes. 40 mL of saturated aqueous sodium bicarbonate solution was added to the reaction mixture and the mixture was extracted three times with 20 mL of dichloromethane. The organic phase was dried and concentrated to afford (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) as a yellow solid. The crude product was used directly in the next step. ES-API: [M+H] + =616.3.

[0500] Step 10: To a round-bottom flask, 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. The reaction mixture was cooled to 0°C and a 17% solution of boron tribromide in dichloromethane (6 mL) was added dropwise. After the addition was complete, the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into 30 mL of ice-cold saturated aqueous NaHCO₃ and extracted three times with 20 mL of dichloromethane. The organic phase was dried and concentrated, and the crude product was purified by preparative HPLC to give (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%) as a yellow solid. ES-API: [M+H] + =602.2.

[0501] Step 11: Compound (4aR)-3-acryloyl-11-fluoro-10-(2-fluoro-6-hydroxyphenyl)-8-(4-isopropyl-6-methylpyrimidin-5-yl)-6-methyl-2,3,4,4a,6,8-hexahydro-1H-pyrazino[1',2':4,5]pyrazino[2,3-c][1,8]naphthyridine-5,7-dione (130 mg) was subjected to preparative chiral HPLC (column: Chiralpak IE: 10 μm, 20*250 mm; mobile phase: hexane:ethanol:diethylamine = 70:30:0.2; flow rate: 15 ml / min; column temperature) to give an atropisomer, arbitrarily designated Z21-1 (peak 2, retention time: 12.33 min, 47 mg), as a yellow solid. ES-API: [M+H] + =602.2. 1 HNMR (500MHz, DMSO-d6): 10.17 (s, 1H), 9.03 (s, 1H), 8.41 (d, J=9Hz, 1H), 7.26-7.25 (m, 1H), 7 .08-7.05(m, 1H), 6.68-6.66(m, 2H), 6.17-6.14(m, 1H), 5.77-5.75(m, 1H), 4.75-4.73(m, 1H) δ 4.5-5.7 (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, the structure of which was arbitrarily designated as Z21-2 (peak 1, retention time: 10.58 min, 48 mg), was obtained as a yellow solid. ES-API: [M+H] + =602.2. 1HNMR (500MHz, DMSO-d6): 10.16 (s, 1H), 9.03 (s, 1H), 8.41 (d, J=9Hz, 1H), 7.26-7.25 (m, 1H), 7 .08-7.05(m, 1H), 6.68-6.66(m, 2H), 6.17-6.14(m, 1H), 5.77-5.75(m, 1H), 4.75-4.73(m, 1H) , 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 (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).

[0502] Example 22 Preparation of Compound Z22

[0503]

[0504] 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 sequentially. The reaction was stirred at room temperature for 30 minutes. The reaction solution was slowly poured into 100 mL of ice water. The precipitated solid was filtered, the filter cake was washed with 20 mL of ice water, and dried under vacuum to give 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%) as a yellow solid. ES-API: [M+H] + =380.2.

[0505] Step 2: To a 100 mL three-necked round-bottom flask was added 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. The reaction was stirred at 100° C. under nitrogen for 2-3 hours. After the reaction was complete, the reaction mixture was cooled to room temperature, and 80 mL of water and 100 mL of methyl tert-butyl ether were added and extracted once. The aqueous phase was adjusted to pH 3-5 with 1 M hydrochloric acid solution and extracted with ethyl acetate (200 mL*2). The ethyl acetate phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was dried under vacuum to 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) as a light yellow solid. ES-API: [M+H] + =470.1.

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

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

[0508] Step 5: 1-(tert-Butyl)3-methyl(3R,6R)-4-(6-fluoro-7-(2-fluoro-6-methoxyphenyl)-1-(3-isopropylpyrazin-2-yl)-3-nitro-2-oxo-1,2-dihydro-1,8-naphthyridin-4-yl)-6-methylpiperazine-1,3-dicarboxylate (280 mg, 0.4 mmol) was dissolved in acetic acid (4 mL), iron powder (78 mg, 1.4 mmol) was added, and the reaction was stirred at 80°C for 30 minutes. The reaction mixture was concentrated, and 50 mL of ethyl acetate and 30 mL of saturated sodium bicarbonate were added sequentially. The suspension was filtered through celite, and the filter cake was washed with ethyl acetate. The organic phase was separated and washed sequentially with 100 mL of saturated sodium bicarbonate and 30 mL of saturated brine, then dried and concentrated to give (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) as a yellow solid. ES-API: [M+H]+ = 648.1.

[0509] Step 6: To a 15 mL sealed tube, 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]naphthyridine-3-carboxylate (295 mg, 0.46 mmol), 3 mL of acetone, anhydrous potassium carbonate (1 g, 6.9 mmol), and iodomethane (253 mg, 1.84 mmol) were added in sequence. The tube was sealed and the reaction was stirred at 55° C. for 18 hours. The reaction mixture was added with 50 mL of ethyl acetate, washed three times with 20 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)-2,6-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 (356 mg, crude) as a yellow solid. ES-API: [M+H] + =662.2.

[0510] Step 7: (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]naphthyridine-3-carboxylic acid tert-butyl ester (356 mg, 0.54 mmol) was dissolved in dichloromethane (8 mL) and trifluoroacetic acid (4 mL) was added. The mixture was stirred at room temperature for 2 hours, and the reaction solution was concentrated to give 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]naphthyridine-5,7-dione (415 mg, crude product), which was used directly in the next reaction. ES-API: [M+H] + =562.2.

[0511] Step 8: (2R,4aR)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(3-isopropylpyrazin-2-yl)-2,6-dimethyl-2,3,4,4a,6,8-hexahydro-1H-pyrazino[1',2':4,5]pyrazino[2,3-c][1,8]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 mixture was cooled to 0°C and acryloyl chloride (115 mg, 1.28 mmol) was added dropwise. The reaction mixture was stirred at 0°C for 5 minutes. 50 mL of dichloromethane was added to the reaction solution, and the mixture was washed with 50 mL of saturated aqueous NaHCO₃ and 80 mL of saturated brine, dried, and concentrated. The crude product was purified on a flash silica gel column (EtOAc / PE: 0-60%) to obtain (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%) as a yellow solid. ES-API: [M+H] + =616.2.

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

[0513] Example 23 Preparation of Compound Z23

[0514]

[0515] Step 1: To a round-bottom flask, 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). Stir at 120°C for 1 hour. LC-MS indicates the reaction is complete. Pour the reaction mixture into 30 mL of water. Extract three times with ethyl acetate. The organic phase was washed four times with saturated brine / water (v / v, 1:1), dried and concentrated to give 1-(tert-butyl)-3-methyl-(3R,6R)-4-(6-chloro-1-(4,6-diisopropylpyrimidin-5-yl)-7-(2-fluoro-6-methoxyphenyl)-3-nitro-2-oxo-1,2-dihydro-1,8-naphthyridin-4-yl)-6-methylpiperazine-1,3-dicarboxylate (1 g, yield 89%). ES-API: [M+H] + =768.3.

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

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

[0518] Step 4: To a round-bottom flask was added 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]pyro[2,3-c][1,8]naphthyridine-3-carboxylate (738 mg, 1.02 mmol), 2 mL of dichloromethane, and 5 mL of trifluoroacetic acid. The mixture was stirred at room temperature for 1 hour. The reaction was complete after LC-MS. The reaction mixture was concentrated to give (2R,4aR)-11-chloro-8-(4,6-diisopropylpyrimidin-5-yl)-10-(2-fluoro-6-methoxyphenyl)-2,6-dimethyl-2,3,4,4a,6,8-hexahydro-1H-pyrazino[1',2':4,5]pyrazino[2,3-c][1,8]naphthyridine-5,7-dione (632 mg, 100%) as a yellow solid. The crude product was used directly in the next step. ES-API: [M+H] + =620.3.

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

[0520] Step 6: To a round-bottom flask, 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. Cool the reaction mixture to 0°C and add 17% boron tribromide in dichloromethane (12 mL) dropwise. After the addition is complete, stir the reaction mixture at 25°C for 25 hours. Pour the reaction mixture into 30 mL of ice-cold saturated aqueous NaHCO3 and extract three times with 20 mL of dichloromethane. The organic phase was dried and concentrated, and the crude product was purified by preparative HPLC to give 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%) as a yellow solid. 1 HNMR (500MHz, DMSO-d6): δ10.10-10.5(m, 1H), 9.11(s, 1H), 8.25-8.23(m 1H), 7.22-7.21(m, 1H), 6.86-6.74(m, 1H), 6.67-6.64(m, 2H), 6.17-6.1 4(m, 1H), 5.75-5.71(m, 1H), 5.04-5.01(m, 1H), 4.62-4.42(m, 1H), 4.03 -3.98(m, 1H), 3.74-3.72(m, 1H), 3.42-3.33(m, 5H), 2.77-2.64(m, 2H), 1.56-1.52(m, 3H), 1.05-0.97(m, 9H), 0.86-0.84(m, 3H).ES-API: [M+H] + =660.3.

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

[0522]

[0523] Step 1: 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 mixture of 1,4-dioxane (120 mL) and water (120 mL). Slowly add concentrated sulfuric acid (120 mL). Stir at 120°C for 36 hours. Pour the cooled reaction mixture into 200 mL of ice water, adjust the pH to 2-3 with sodium carbonate, and extract with ethyl acetate (1000 mL x 2). Combine the ethyl acetate phases, dry over anhydrous sodium sulfate, filter, and vacuum-dry the filtrate to obtain 6,7-dichloro-4-hydroxy-1-(2-isopropyl-4-methylpyridin-3-yl)-1,8-naphthyridine-2(1H)-one (24 g, Y: 85.7%) as a light brown solid. ES-API: [M+H] + =364.1.

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

[0525] Step 3: To a 100 mL three-necked round-bottom flask, 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), tetrakistriphenylphosphine palladium (1.15 g, 0.9956 mmol), sodium carbonate (3.5 g, 33.02 mmol), 10 mL of water, and 40 mL of dioxane. Under nitrogen, stir at 100°C for 2-3 hours. After completion of the reaction, cool the reaction mixture to room temperature, add 80 mL of water and 100 mL of methyl tert-butyl ether, and extract once. The aqueous phase was adjusted to pH 3-5 with 1M hydrochloric acid solution and extracted with ethyl acetate (200 mL x 2). The ethyl acetate phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was dried under vacuum to obtain the product, 6-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), as a light yellow solid. ES-API: [M+H] + =499.1.

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

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

[0528] Step 6: 1-(tert-Butyl)3-methyl(3R)-4-(6-chloro-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro-2-oxo-1,2-dihydro-1,8-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, and the reaction was stirred at 80°C for 30 minutes. The reaction mixture was concentrated, and 200 mL of ethyl acetate and 100 mL of saturated sodium bicarbonate were added sequentially. The suspension was filtered through celite, and the filter cake was washed with ethyl acetate. The organic phase was separated and washed sequentially with 100 mL of saturated sodium bicarbonate and 150 mL of saturated brine, then dried and concentrated to give (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-carboxylic acid tert-butyl ester (2.70 g, crude) as a yellow solid. ES-API: [M+H]+ = 663.2.

[0529] Step 7: To a 100 mL single-necked flask were added sequentially 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 were 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)-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 was used directly in the next reaction. ES-API: [M+H] + =563.2.

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

[0531] Step 9: Under ice-water bath conditions, (4aR)-3-acryloyl-11-chloro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-2,3,4,4a,6,8-hexahydro-1H-pyrazino[1',2':4,5]pyrazino[2,3-c][1,8]naphthyridine-5,7-dione (243 mg, 0.3774 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 allowed to react overnight. Under ice-water bath conditions, the reaction solution was added dropwise to a saturated sodium bicarbonate solution, extracted twice with dichloromethane (80 mL), dried, concentrated, and purified by preparative HPLC to give (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.

[0532] Step 10: Compound Z24 (76.0 mg, 0.1262 mmol) was separated by preparative chiral HPLC (column type: IA: 10 μm, 30*250 mm, mobile phase: hexane: EtOH = 40:60, flow rate: 25 ml / min, column temperature) to give: an atropisomer compound, the structure of which was 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, the structure of which was arbitrarily designated as Z24-2 (21.4 mg, peak 2, retention time 3.985 min, Y: 28%), ES-API: [M+H] + = 603.2. The isomers were detected by analytical chiral HPLC (column type IA: 5 μm, 4.6*150 mm, mobile phase: hexane: EtOH = 40:60, flow rate: 1 ml / min, column temperature = 30°C).

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

[0534]

[0535] Step 1: 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 mixture of 1,4-dioxane (120 mL) and water (120 mL). Slowly add concentrated sulfuric acid (120 mL). Stir at 120°C for 36 hours. Pour the cooled reaction mixture into 200 mL of ice water, adjust the pH to 2-3 with sodium carbonate, and extract with ethyl acetate (1000 mL x 2). Combine the ethyl acetate phases, dry over anhydrous sodium sulfate, filter, and vacuum-dry the filtrate to obtain 6,7-dichloro-4-hydroxy-1-(2-isopropyl-4-methylpyridin-3-yl)-1,8-naphthyridine-2(1H)-one (24 g, Y: 85.7%) as a light brown solid. ES-API: [M+H] + =364.1.

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

[0537] Step 3: To a 100 mL three-necked round-bottom flask, 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), tetrakistriphenylphosphine palladium (1.15 g, 0.9956 mmol), sodium carbonate (3.5 g, 33.02 mmol), 10 mL of water, and 40 mL of dioxane. Under nitrogen, stir at 100°C for 2-3 hours. After completion of the reaction, cool the reaction mixture to room temperature, add 80 mL of water and 100 mL of methyl tert-butyl ether, and extract once. The aqueous phase was adjusted to pH 3-5 with 1M hydrochloric acid solution and extracted with ethyl acetate (200 mL x 2). The ethyl acetate phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was dried under vacuum to obtain the product, 6-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), as a light yellow solid. ES-API: [M+H] + =499.1.

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

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

[0540] Step 6: 1-(tert-Butyl)3-methyl(3R)-4-(6-chloro-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro-2-oxo-1,2-dihydro-1,8-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, and the reaction was stirred at 80°C for 30 minutes. The reaction mixture was concentrated, and 200 mL of ethyl acetate and 100 mL of saturated sodium bicarbonate were added sequentially. The suspension was filtered through celite, and the filter cake was washed with ethyl acetate. The organic phase was separated and washed sequentially with 100 mL of saturated sodium bicarbonate and 150 mL of saturated brine, then dried and concentrated to give (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-carboxylic acid tert-butyl ester (2.70 g, crude) as a yellow solid. ES-API: [M+H]+ = 663.2.

[0541] Step 7: To a 150 mL sealed tube, 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, anhydrous potassium carbonate (2.2 g, 15.94 mmol), and iodomethane (5.4 g, 38.03 mmol) were added in sequence. The tube was sealed and the reaction was stirred at 55° C. for 18 hours. The reaction mixture was added with 150 mL of ethyl acetate, washed three times with 100 mL of saturated brine, dried, and concentrated. The crude product was purified on a flash silica gel column (EtOAc / PE: 0-80%) to obtain (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-carboxylic acid tert-butyl ester (2.2 g, Y: 87%) as a yellow solid. ES-API: [M+H] + =677.2.

[0542] Step 8: (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-carboxylic acid tert-butyl ester (517 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 hours, and the reaction solution was concentrated to give 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 was used directly in the next reaction. ES-API: [M+H] + =577.2.

[0543] Step 9: (4aR)-11-chloro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-6-methyl-2,3,4,4a,6,8-hexahydro-1H-pyrazino[1',2':4,5]pyrazino[2,3-c][1,8]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 mixture was cooled to 0°C and acryloyl chloride (100 mg, 1.1048 mmol) was added dropwise. The reaction was stirred at 0°C for 15 minutes. 80 mL of dichloromethane was added to the reaction solution, and the mixture was washed with 100 mL of saturated aqueous NaHCO₃ and 80 mL of saturated brine, dried, and concentrated. The crude product was purified on a flash silica gel column (EtOAc / PE: 0-60%) to obtain (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%) as a yellow solid. ES-API: [M+H] + =631.2.

[0544] Step 10: Under ice-water bath conditions, (4aR)-3-acryloyl-11-chloro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-6-methyl-2,3,4,4a,6,8-hexahydro-1H-pyrazino[1',2':4,5]pyrazino[2,3-c][1,8]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 mixture was warmed to room temperature and reacted overnight. Under ice-water bath conditions, the reaction solution was added dropwise to a saturated sodium bicarbonate solution, extracted twice with dichloromethane (80 mL), dried, and concentrated. The crude product was purified by flash silica gel column chromatography (EtOAc / PE: 0-60%) to give (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%).

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

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

[0547]

[0548] Step 1: (4aR)-11-chloro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-6-(methyl-d3)-5,7-dioxo-1,2,4,4a,5,6,7,8-octahydro-3H-pyrazino[1',2':4,5]pyrazino[2,3-c][1,8]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. The mixture was stirred at room temperature for 2 hours, and the reaction solution was concentrated to give 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 used directly in the next reaction. ES-API: [M+H] + =580.3.

[0549] Step 2: (4aR)-11-chloro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-6-(methyl-d3)-2,3,4,4a,6,8-hexahydro-1H-pyrazino[1',2':4,5]pyrazino[2,3-c][1,8]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 mixture was cooled to 0°C and acryloyl chloride (100 mg, 1.1048 mmol) was added dropwise. The reaction was stirred at 0°C for 15 minutes. 80 mL of dichloromethane was added to the reaction solution, and the mixture was washed with 100 mL of saturated aqueous NaHCO₃ and 80 mL of saturated brine, dried, and concentrated. The crude product was purified on a flash silica gel column (EtOAc / PE: 0-60%) to obtain (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%) as a yellow solid. ES-API: [M+H] + =634.2.

[0550] Step 3: Under ice-water bath conditions, (4aR)-3-acryloyl-11-chloro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-6-(methyl-d3)-2,3,4,4a,6,8-hexahydro-1H-pyrazino[1',2':4,5]pyrazino[2,3-c][1,8]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 allowed to react overnight. Under ice-water bath conditions, the reaction solution was added dropwise to a saturated sodium bicarbonate solution, extracted twice with dichloromethane (80 mL), dried, and concentrated. The crude product was purified by flash silica gel column chromatography (EtOAc / PE: 0-60%) to give (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.

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

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

[0553]

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

[0555] Step 2: 1-(tert-Butyl)3-methyl(3R,6R)-4-(6-chloro-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro-2-oxo-1,2-dihydro-1,8-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, and 200 mL of ethyl acetate and 100 mL of saturated sodium bicarbonate were added sequentially. The suspension was filtered through celite, and the filter cake was washed with ethyl acetate. The organic phase was separated and washed sequentially with 100 mL of saturated sodium bicarbonate and 150 mL of saturated brine, and then dried and concentrated to give the product (2R,4aR)-11-chloro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-2-methyl-5,7-dioxo-1,2,4,4a,5,6,7,8-octahydro-3H-pyrazino[1',2':4,5]pyro[2,3-c][1,8]naphthyridine-3-carboxylic acid tert-butyl ester (452 ​​mg, Y: 92%) as a yellow solid. ES-API: [M+H] + =677.2.

[0556] Step 3: To a 150 mL sealed tube, 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]pyro[2,3-c][1,8]naphthyridine-3-carboxylate (445 mg, 0.6583 mmol), 10 mL of acetone, anhydrous potassium carbonate (500 mg, 2.633 mmol), and iodomethane (1.20 g, 6.5828 mmol) were added in sequence. The tube was sealed and the reaction was stirred at 55° C. for 18 hours. The reaction mixture was added with 150 mL of ethyl acetate, washed three times with 100 mL of saturated brine, dried, and concentrated. The crude product was purified on a flash silica gel column (EtOAc / PE: 0-80%) to obtain (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]naphthyridine-3-carboxylic acid tert-butyl ester (455 mg, crude) as a yellow solid. ES-API: [M+H] + =691.3.

[0557] 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]naphthyridine-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 hours, and the reaction solution was concentrated to give (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]naphthyridine-5,7-dione (462 mg, crude product), which was used directly in the next reaction. ES-API: [M+H] + =591.3.

[0558] Step 5: (2R,4aR)-11-chloro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-2,6-dimethyl-2,3,4,4a,6,8-hexahydro-1H-pyrazino[1',2':4,5]pyrazino[2,3-c][1,8]naphthyridine-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 mixture was cooled to 0°C and acryloyl chloride (100 mg, 1.1048 mmol) was added dropwise. The reaction mixture was stirred at 0°C for 15 minutes. 80 mL of dichloromethane was added to the reaction solution, and the mixture was washed with 100 mL of saturated aqueous NaHCO3 and 80 mL of saturated brine, dried, and concentrated. The crude product was purified on a flash silica gel column (EtOAc / PE: 0-60%) to obtain (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, Y: 68%) as a yellow solid. ES-API: [M+H] + =645.2.

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

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

[0561] Example 28 Preparation of Compound Z28

[0562]

[0563] Step 1: 4-Chloro-6-fluoro-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro-1,8-naphthyridine-2(1H)-one (400 mg, 0.80 mmol) was dissolved in DMF (5 mL), and (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 hours. The reaction mixture was diluted with 100 mL of ethyl acetate, washed five times with 40 mL of saturated brine, dried, and concentrated. The crude product was purified on a flash silica gel column (EtOAc / PE: 0-70%) to obtain (3S)-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 (420 mg, Y: 77.2%) as a yellow solid. ES-API: [M+H] + =681.3.

[0564] Step 2: Tert-butyl (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-carboxylate (420 mg, 0.62 mmol) was dissolved in DMA (20 mL) and LiHMDS (1.55 mL, 1.55 mmol, 1.0 M in THF) was added. The reaction was slowly heated to 140°C with stirring for 24 h. The reaction mixture was diluted with 100 mL of ethyl acetate, washed four times with 40 mL of dilute brine and once with 40 mL of saturated brine, dried, and concentrated. The crude product was purified on a flash silica gel column (EtOAc / PE: 0-100%) to obtain (4aS)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-7-oxo-1,2,4a,5,7,8-hexahydropyrazine[1',2':4,5][1,4]oxazine[2,3-c][1,8]naphthyridine-3(4H)-carboxylic acid tert-butyl ester (180 mg, Y: 46.0%) as a yellow solid. ES-API: [M+H]+ = 634.3.

[0565] Step 3: (4aS)-11-Fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-7-oxo-1,2,4a,5,7,8-hexahydropyrazine[1',2':4,5][1,4]oxo[2,3-c][1,8]naphthyridine-3(4H)-carboxylic acid tert-butyl ester (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 give 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]naphthyridin-7(8H)-one (185 mg, crude product), which was used directly in the next reaction. ES-API: [M+H] + =534.3.

[0566] Step 4: (4aS)-11-Fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-1,2,3,4,4a,5-hexahydropyrazino[1',2':4,5][1,4]oxazin[2,3-c][1,8]naphthyridin-7(8H)-one (185 mg, crude) was dissolved in dichloromethane (6 mL) and N,N-diisopropylethylamine (180 mg, 1.40 mmol) was added. The reaction mixture was cooled to 0°C and a solution of acryloyl chloride (50 mg, 0.56 mmol) in dichloromethane (0.5 mL) was added dropwise. 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 sequentially 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]naphthyridin-7(8H)-one (160 mg, Y: 95.8%) as a yellow solid. ES-API: [M+H] + =588.3.

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

[0568] Example 29 Preparation of Compound Z29

[0569]

[0570] Step 1: 7-Chloro-6-fluoro-4-hydroxy-1-(2-isopropyl-4-methylpyridin-3-yl)-1,8-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 sequentially. The reaction was stirred at room temperature for 30 minutes. The reaction solution was slowly poured into 100 mL of ice water. The precipitated solid was filtered, and the filter cake was washed with 20 mL of ice water and dried under vacuum to give 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%), as a yellow solid. ES-API: [M+H] + =393.1.

[0571] Step 2: To a 100 mL three-necked round-bottom flask, add 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), tetrakistriphenylphosphine palladium (589 mg, 0.51 mmol), potassium carbonate (1.76 g, 12.75 mmol), 2 mL of water, and 8 mL of dioxane. Under nitrogen, stir at 110°C for 1 hour. After completion of the reaction, cool the reaction mixture to room temperature, add 80 mL of water and 100 mL of methyl tert-butyl ether, and extract once. The aqueous phase was adjusted to pH 3-4 with 1M hydrochloric acid solution. The precipitated solid was filtered and dried under vacuum to give 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%) as a light yellow solid. ES-API: [M+H] + =489.2.

[0572] Step 3: 6-Fluoro-7-(5-methyl-1H-indazol-4-yl)-4-hydroxy-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro-1,8-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 sequentially. The temperature was gradually raised 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. The mixture was extracted with ethyl acetate (200 mL x 2). The ethyl acetate phases were combined and washed once with 50 mL of saturated brine. The reaction mixture was dried over anhydrous sodium sulfate, filtered, and the organic phase was dried and concentrated. The crude product was then purified by flash silica gel column chromatography (EtOAc / PE: 0-80%) to give 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%) as a yellow solid. ES-API: [M+H] + =507.0.

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

[0574] 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. The mixture was cooled to room temperature, poured into ice water, and adjusted to pH 7 with 3M hydrochloric acid. 30 mL of ethyl acetate was added, and the organic phase was separated and washed with 30 mL of water and 30 mL of saturated brine, respectively. The mixture was dried and concentrated to give (4aR)-11-fluoro-8-(2-isopropyl-4-methylpyridin-3-yl)-10-(5-methyl-1H-indazol-4-yl)-7-oxo-1,2,4a,5,7,8-hexahydropyrazino[1',2':4,5][1,4]oxazine[2,3-c][1,8]naphthyridine-3(4H)-carboxylic acid tert-butyl ester (60 mg, Y: 70%) as a yellow solid. ES-API: [M+H] + =640.3.

[0575] 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]oxazine[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 mixture was stirred at room temperature for 2 hours, and the reaction solution was concentrated to give 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]oxazin[2,3-c][1,8]naphthyridine-7(8H)-one (50 mg, crude product), which was used directly in the next reaction. ES-API: [M+H] + =540.2.

[0576] Step 7: (4aR)-11-Fluoro-8-(2-isopropyl-4-methylpyridin-3-yl)-10-(5-methyl-1H-indazol-4-yl)-1,2,3,4,4a,5-hexahydropyrazino[1',2':4,5][1,4]oxazin[2,3-c][1,8]naphthyridin-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 mixture was cooled to 0°C and acryloyl chloride (10.5 mg, 0.083 mmol) was added dropwise. The reaction was stirred at 0°C for 15 minutes. The reaction solution was added with 20 mL of dichloromethane, washed with 20 mL of saturated NaHCO3 aqueous solution and 20 mL of saturated brine, dried and concentrated, and purified by preparative HPLC to give 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]oxazin[2,3-c][1,8]naphthyridin-7(8H)-one (Z29, 15 mg, Y: 28%). ES-API: [M+H] + =594.2. 1 H NMR (500MHz, DMSO-d6) δ13.08 (s, 1H), 8.37 (d, J = 4.8Hz, 1H), 8.32 (d, J = 9.4Hz, 1H), 7.49 (d, J = 8.1Hz, 2H ), 7.24 (d, J = 8.5Hz, 1H), 7.20 (d, J = 5.0Hz, 1H), 6.90 (s, 1H), 6.20 (d, J = 16.7Hz, 1H), 5.78 (s, 1H), 4.45 ( d, J=46.5Hz, 1H), 4.35-4.20 (m, 2H), 4.05 (s, 1H), 3.85 (d, J=51.4Hz, 1H), 3.75-3.57 (m, 2H), 3.48 (s, 1H) ), 3.15 (s, 1H), 2.05 (s, 3H), 1.90 (d, J = 33.7Hz, 3H), 1.03 (t, J = 6.7Hz, 3H), 0.81 (dd, J = 20.9, 6.4Hz, 3H).

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

[0578]

[0579] Step 1: To a 15 mL sealed tube, 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 (310 mg, 0.48 mmol), 10 mL of acetone, anhydrous potassium carbonate (265 mg, 1.92 mmol), and iodoethane (599 mg, 3.84 mmol) were added in sequence. The tube was sealed and the reaction was stirred at 55°C for 18 hours. The reaction mixture was concentrated, 60 mL of ethyl acetate was added, and the mixture was washed sequentially with 30 mL of water and 30 mL of saturated brine, dried, and concentrated. The crude product was purified on a flash silica gel column (EtOAc / PE: 0-70%) to obtain (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]naphthyridine-3-carboxylic acid tert-butyl ester (290 mg, Y: 89.7%) as an orange solid. ES-API: [M+H] + =675.3.

[0580] Step 2: (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]naphthyridine-3-carboxylic acid tert-butyl ester (290 mg, 0.43 mmol) was dissolved in dichloromethane (4 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 give 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]naphthyridine-5,7-dione (300 mg, crude product), which was used directly in the next reaction. ES-API: [M+H] + =575.2.

[0581] Step 3: (4aR)-6-Ethyl-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-2,3,4,4a,6,8-hexahydro-1H-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 mixture was cooled to 0°C and acryloyl chloride (130 mg, 1.44 mmol) was added to the reaction mixture. The reaction was stirred at 0°C for 15 minutes. 45 mL of dichloromethane was added to the reaction solution, and the mixture was washed sequentially with 25 mL of water, 25 mL of saturated aqueous NaHCO₃, and 25 mL of saturated brine, dried, and concentrated. The crude product was purified by flash silica gel column chromatography (EtOAc / PE: 0-90%) to obtain (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 (2450 mg, Y: 90.7%) as a light yellow solid. ES-API: [M+H] + =615.3.

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

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

[0584] Example 31 Preparation of Compound Z31

[0585]

[0586] Step 1: To a 250 mL round-bottom flask was added 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. The reaction was stirred at 125° C. under nitrogen for 18 hours. The reaction mixture was concentrated, 50 mL of water was added, and the pH was adjusted to 3.0 with 3.0 M dilute hydrochloric acid. The mixture was extracted twice with 50 mL of dichloromethane. The organic phase was dried and concentrated to give the product 6-cyclopropyl-7-(2-fluoro-6-methoxyphenyl)-4-hydroxy-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro-1,8-naphthyridin-2(1H)-one (850 mg, crude) as a brown solid. ES-API: [M+H] + =505.2.

[0587] Step 2: 6-cyclopropyl-7-(2-fluoro-6-methoxyphenyl)-4-hydroxy-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro-1,8-naphthyridin-2(1H)-one (1.6 g, crude product) was dissolved in acetonitrile (50 mL), and phosphorus oxychloride (2.43 g, 15.85 mmol) and N,N-diisopropylethylamine (3.27 g, 25.36 mmol) were added in sequence. The reaction was stirred at 85°C for 1 hour. The reaction solution was concentrated, 120 mL of ethyl acetate was added, and the mixture was washed with 60 mL of water, 60 mL of saturated sodium bicarbonate twice, and 60 mL of saturated brine. The organic phase was dried and concentrated, and the crude product was purified by flash silica gel column chromatography (EtOAc / PE: 0-35%) to give 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%) as a light yellow solid. ES-API: [M+H] + =523.2.

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

[0589] Step 4: (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 (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 mixture was concentrated, and 80 mL of ethyl acetate and 50 mL of saturated sodium bicarbonate were added sequentially. The suspension was filtered through celite, and the filter cake was washed with ethyl acetate. The organic phase was separated and washed sequentially with 25 mL of saturated sodium bicarbonate and 25 mL of saturated brine, then dried and concentrated to give the product (2R,4aR)-11-cyclopropyl-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-2-methyl-5,7-dioxo-1,2,4,4a,5,6,7,8-octyl-3H-pyrazino[1',2':4,5]pyrazino[2,3-c][1,8]naphthyridine-3-carboxylic acid tert-butyl ester (415 mg, Y: 99.5%) as a light yellow solid. ES-API: [M+H]+ = 683.3.

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

[0591] 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-octyl-3H-pyrazino[1',2':4,5]pyrazino[2,3-c][1,8]naphthyridine-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 give 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-3,1-pyrazino[4′,3′:4,5]pyrazino[2,3-c][1,8]naphthyridine-5,7-dione) (165 mg, crude product), which was used directly in the next reaction. ES-API: [M+H] + =597.2.

[0592] Step 7: (2R,4aR)-11-cyclopropyl-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-2,6-dimethyl-1,2,4,4a,6,8-hexahydro-3,1,2-pyrazino[4′,3′:4,5]pyrazino[2,3-c][1,8]naphthyridine-5,7-dione (165 mg, crude) was dissolved in dichloromethane (10 mL) and N,N-diisopropylethylamine (148 mg, 1.15 mmol) was added. The reaction mixture was cooled to 0°C and acryloyl chloride (41 mg, 0.46 mmol) was added dropwise. The reaction mixture was stirred at 0°C for 15 minutes. 30 mL of dichloromethane was added to the reaction solution, and the mixture was washed sequentially with 15 mL of water, 15 mL of saturated aqueous NaHCO₃, and 15 mL of saturated brine, dried, and concentrated. The crude product was purified by flash silica gel column chromatography (dichloromethane / methanol: 0-5%) to obtain (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 (140 mg, Y: 93.7%) as a light yellow solid. ES-API: [M+H] + =651.3.

[0593] Step 8: (2R,4aR)-3-Acryloyl-11-cyclopropyl-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-2,6-dimethyl-2,3,4,4a,6,8-hexahydro-1H-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 mixture was cooled to 0°C and a 17% solution of boron tribromide in dichloromethane (3 mL) was added dropwise. The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into 40 mL of saturated aqueous NaHCO3 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 give 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%) as a white solid. 1 H NMR (500MHz, DMSO-d6) δ9.90 (s, 1H), 8.42 (d, J=4.8Hz, 1H), 7.75-7.73 (m, 1H), 7.22-7.17 (m, 2H), 7. 03(dd, J=16.8, 10.5Hz, 1H), 6.74-6.60(m, 2H), 6.22-6.08(m, 1H), 5.81-5.69(m, 1H), 5.05-4.81(m, 1 H), 4.62-4.41 (m, 1H), 4.03-3.90 (m, 1H), 3.75 (dd, J=14.1, 4.2Hz, 1H), 3.39-3.25 (m, 4H), 2.83-2.6 7(m, 1H), 2.48-2.37(m, 1H), 2.01-1.75(m, 3H), 1.70-1.46(m, 4H), 1.14-0.55(m, 10H).ES-API: [M+H] + =637.3.

[0594] Example 32 Preparation of Compound Z32

[0595]

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

[0597] Step 2: Dissolve 2-((4,6-dicyclopropylpyrimidin-5-yl)amino)-5-fluoro-6-(2-fluoro-6-methoxyphenyl)nicotinic acid (1.5 g, 3.42 mmol) in dichloroethane and add thionyl chloride (4.07 g, 34.2 mmol). The reaction was stirred at 80°C for 2 hours. After the reaction was completed, the reaction solution was cooled to room temperature, concentrated, and dried under vacuum at 50 degrees for 4 hours to obtain the product 2-((4,6-dicyclopropylpyrimidin-5-yl)amino)-5-fluoro-6-(2-fluoro-6-methoxyphenyl)nicotinyl chloride (1.57 g, crude product) as a light yellow solid. Methanol detection ES-API: [M+H] + =453.2.

[0598] Step 3: Sodium hydride (1.97 g, 49.35 mmol) was added to a solution of ethyl nitrate (1.31 g, 9.86 mmol) in tetrahydrofuran under an ice-water bath. The mixture was stirred for 30 minutes, followed by the addition of 2-((4,6-dicyclopropylpyrimidin-5-yl)amino)-5-fluoro-6-(2-fluoro-6-methoxyphenyl)nicotinoyl chloride (1.57 g, 3.29 mmol). The mixture was stirred at room temperature for 1 hour, and then heated to 80°C for 2 hours. The mixture was poured into ice-water, and the pH was adjusted to 3-4 with 3M hydrochloric acid. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the organic phase was dried and concentrated to afford 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%). ES-API: [M+H] + =508.1.

[0599] Step 4: 1-(4,6-dicyclopropylpyrimidin-5-yl)-6-fluoro-7-(2-fluoro-6-methoxyphenyl)-4-hydroxy-3-nitro-1,8-naphthyridine-2(1H)-one (110 mg, 0.20 mmol) was dissolved in acetonitrile (10 mL), and phosphorus oxychloride (153 mg, 1.0 mmol) and N,N-diisopropylethylamine (77 g, 0.6 mmol) were added in sequence. The reaction temperature was gradually raised to 80°C and stirred for 3 h. The reaction mixture 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. The mixture was extracted with ethyl acetate (50 mL x 2). The organic phases were combined, washed with 30 mL of saturated brine, dried over anhydrous sodium sulfate, and filtered. The organic phase was dried and concentrated, and the crude product was purified on a flash silica gel column (EtOAc / PE: 0-80%) to give 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%) as a yellow solid. ES-API: [M+H] + =526.2.

[0600] Step 5: 4-Chloro-6-fluoro-7-(2-fluoro-6-methoxyphenyl)-1-(4,6-dicyclopropylpyrimidin-5-yl)-3-nitro-1,8-naphthyridin-2(1H)-one (110 mg, 0.296 mmol) was dissolved in N,N-dimethylacetamide (3 mL), and 1-(tert-butyl)-3-methyl(R)-piperazine-1,3-dicarboxylate (54 mg, 0.22 mmol) was added sequentially. The reaction was stirred at 120°C for 2 hours. After the reaction was completed, 30 mL of ethyl acetate was added, and the mixture was washed three times with 30 mL of saturated brine. The ethyl acetate phase was dried and concentrated to give 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%), as a yellow solid. ES-API: [M+H] + =734.3.

[0601] 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 in sequence, and the suspension was filtered through celite. The filter cake was washed with ethyl acetate, and the organic phase was separated and washed sequentially with 30 mL of saturated sodium bicarbonate and 30 mL of saturated brine, then dried and concentrated to afford 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) as a yellow solid. ES-API: [M+H]+ = 672.2.

[0602] Step 7: Add (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)-carboxylic acid tert-butyl ester (40 mg, 0.059 mmol), 30 mL of acetone, anhydrous potassium carbonate (33 mg, 0.24 mmol) and iodomethane (85 mg, 0.59 mmol) in a sealed tube and stir the reaction at 50°C for 18 hours. 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 on a flash silica gel column (EtOAc / PE: 0-80%) to obtain (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 (40 mg, Y: 90%) as a yellow solid. ES-API: [M+H] + =686.2.

[0603] 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]naphthyridine-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 give 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 used directly in the next reaction. ES-API: [M+H] + =586.2.

[0604] Step 9: (4aR)-8-(4,6-dicyclopropylpyrimidin-5-yl)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-6-methyl-2,3,4,4a-tetrahydro-1H-pyrazino[1',2':4,5]pyrazino[2,3-c][1,8]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 mixture was cooled to 0°C and acryloyl chloride (12.4 mg, 0.137 mmol) was added dropwise. 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 solution and 20 mL of saturated brine, dried, and concentrated. The crude product was purified by preparative HPLC to give (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%) as a yellow solid. ES-API: [M+H] + =640.2.

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

[0606]

[0607] Step 1: 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 mixture of 1,4-dioxane (10 mL) and water (120 mL). Slowly add concentrated sulfuric acid (10 mL). Stir the mixture at 120°C for 18 hours. Pour the cooled reaction mixture into 20 mL of ice water, adjust the pH to 2-3 with sodium carbonate, and extract with ethyl acetate (1000 mL x 2). Combine the ethyl acetate phases, dry over anhydrous sodium sulfate, filter, and vacuum-dry the filtrate to obtain 7-chloro-6-fluoro-4-hydroxy-1-(1-isopropyl-4-methyl-1H-pyrazol-5-yl)-1,8-naphthyridine-2(1H)-one (3.36 g, Y: 92%) as a light brown solid. ES-API: [M+H] + =337.1.

[0608] Step 2: 7-Chloro-6-fluoro-4-hydroxy-1-(1-isopropyl-4-methyl-1H-pyrazol-5-yl)-1,8-naphthyridin-2(1H)-one (3.36 g, 10 mmol) was dissolved in acetic acid (7 mL). Sodium nitrite (69 mg, 1.0 mmol) and concentrated nitric acid (2.0 mL, 30 mmol) were added sequentially. The reaction was stirred at room temperature for 30 minutes. The reaction solution was slowly poured into 21 mL of ice water. The precipitated solid was filtered, and the filter cake was washed with 10 mL of ice water and dried under vacuum to give 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%), as a yellow solid. ES-API: [M+H] + =382.1.

[0609] Step 3: To a 100 mL three-necked round-bottom flask was added 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), tetrakistriphenylphosphine palladium (908 mg, 0.786 mmol), potassium carbonate (2.72 g, 19.65 mmol), 4 mL of water, and 20 mL of dioxane. Under nitrogen, the reaction mixture was stirred at 100°C for 3 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, and 20 mL of water and 50 mL of methyl tert-butyl ether were added and extracted once. The aqueous phase was adjusted to pH 3-5 with 1M hydrochloric acid solution and extracted with ethyl acetate (50 mL x 2). The ethyl acetate phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was dried under vacuum to obtain the product, 6-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), as a light yellow solid. ES-API: [M+H] + =472.1.

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

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

[0612] 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, and the reaction was stirred at 80°C for 30 minutes. The reaction mixture was concentrated, and 30 mL of ethyl acetate and 30 mL of saturated sodium bicarbonate were added sequentially. The suspension was filtered through celite, and the filter cake was washed with ethyl acetate. The organic phase was separated and washed sequentially with 30 mL of saturated sodium bicarbonate and 30 mL of saturated brine, then dried and concentrated to give the product (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, crude) as a yellow solid. ES-API: [M+H]+ = 650.3.

[0613] Step 7: Add (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, anhydrous potassium carbonate (255 mg, 1.84 mmol) and iodomethane (656 mg, 4.62 mmol) in a sealed tube and stir the reaction at 50°C for 18 hours. 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 on a flash silica gel column (EtOAc / PE: 0-80%) to obtain (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)-carboxylic acid tert-butyl ester (350 mg, Y: 95%) as a yellow solid. ES-API: [M+H] + =664.3.

[0614] 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)-carboxylic acid tert-butyl ester (350 mg) was dissolved in dichloromethane (4 mL) and trifluoroacetic acid (2 mL) was added. The mixture was stirred at room temperature for 2 hours, and the reaction solution was concentrated to give 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 product), which was used directly in the next reaction. ES-API: [M+H] + =564.2.

[0615] Step 9: (2R,4aR)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(1-isopropyl-4-methyl-1H-pyrazol-5-yl)-2,6-dimethyl-2,3,4,4a-tetrahydro-1H-pyrazino[1',2':4,5]pyrazino[2,3-c][1,8]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 mixture was cooled to 0°C and acryloyl chloride (112.5 mg, 1.24 mmol) was added dropwise. 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 solution and 20 mL of saturated brine, dried, and concentrated. The crude product was purified by preparative chromatography to give (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%) as a yellow solid. ES-API: [M+H] + =618.3.

[0616] Step 10: Under ice-water bath conditions, (2R,4aR)-3-acryloyl-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(1-isopropyl-4-methyl-1H-pyrazol-5-yl)-2,6-dimethyl-2,3,4,4a-tetrahydro-1H-pyrazino[1',2':4,5]pyrazino[2,3-c][1,8]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 reaction solution was added dropwise to a saturated sodium bicarbonate solution, extracted twice with dichloromethane (30 mL), dried, and concentrated to give 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).

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

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

[0619]

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

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

[0622] Step 3: (2R,4aR)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-2-methyl-6-(methyl-d3)-2,3,4,4a,6,8-hexahydro-1H-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 mixture was cooled to 0°C and acryloyl chloride (31 mg, 0.34 mmol) was added dropwise. The reaction mixture was stirred at 0°C for 15 minutes. 25 mL of dichloromethane was added to the reaction solution, which was then washed sequentially with 15 mL of water, 15 mL of saturated aqueous NaHCO₃, and 15 mL of saturated brine, dried, and concentrated. The crude product was purified by flash silica gel column chromatography (EtOAc / PE: 0-100%) to obtain (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%) as a light yellow solid. ES-API: [M+H] + =632.2.

[0623] Step 4: (2R,4aR)-3-Acryloyl-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-2-methyl-6-(methyl-d3)-2,3,4,4a,6,8-hexahydro-1H-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 mixture was cooled to 0°C and a 17% solution of boron tribromide in dichloromethane (1.5 mL) was added dropwise. The reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was poured into 40 mL of saturated aqueous NaHCO3 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 give 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).

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

[0625] Example 35 Preparation of Compounds Z35, Z35-1 and Z35-2

[0626]

[0627] Step 1: 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-octyl-3H-pyrazino[1',2':4,5]pyrazino[2,3-c][1,8]naphthyridine-3-carboxylate (200 mg, 0.30 mmol) was dissolved in dichloromethane (4 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 give 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 used directly in the next reaction. ES-API: [M+H] + =561.3.

[0628] 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 mixture was cooled to 0°C and acryloyl chloride (54 mg, 0.60 mmol) was added dropwise. The reaction mixture was stirred at 0°C for 15 minutes. 30 mL of dichloromethane was added to the reaction solution, which was then washed sequentially with 15 mL of water, 15 mL of saturated aqueous NaHCO₃, and 15 mL of saturated brine. After drying and concentration, 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%) was obtained as a light yellow solid. ES-API: [M+H] + =615.3.

[0629] 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 mixture was cooled to 0°C and a 17% solution of boron tribromide in dichloromethane (4 mL) was added dropwise. The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into 80 mL of saturated aqueous NaHCO3 and extracted twice with 30 mL of dichloromethane. The organic phase was dried and concentrated to give 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]naphthyridine-5-dione (Z35, 170 mg, Y: 99.4%) as a light yellow solid. ES-API: [M+H] + =601.2.

[0630] Step 4: Compound Z35 (170 mg, 0.28 mmol) was purif...

Claims

1. A compound represented by formula (I) or a pharmaceutically acceptable salt thereof: In the formula, Z is NC(O)-CR3=CR1R2; R1 and R2 are each independently hydrogen or halogen; R3 is hydrogen or halogen; R 11 , R 12 are the same or different and are each independently hydrogen, halogen or -C 1-3 alkyl; R 21 , R 22 are the same or different and are each independently hydrogen, halogen or -C 1-3 alkyl; R 31 , R 32 are the same or different and are each independently hydrogen, halogen or -C 1-3 alkyl; R 41 is hydrogen; The dashed line in the figure is a single bond, and P is O, NH, or NR m ; R m For -C 1-6 Alkyl; R 42 -(C=O)-, -C 1-3 Alkyl-(C=O)- or -C 1-3 alkyl-; When Y1 is C; X1 is hydrogen, halogen, hydroxyl, -C 1-6 Alkyl or C 3-6 Cycloalkyl; E1 is N or CR5; Among them, R 5 is hydrogen or halogen; E2 is CR6; wherein R6 is hydrogen or halogen; Ar is C 6-10 aryl, 5- or 6-membered monocyclic heteroaryl or wherein the 5- or 6-membered monocyclic heteroaryl group has 1, 2 or 3 heteroatoms selected from N and O as ring atoms; and the C 6-10 Aryl or 5 or 6 membered monocyclic heteroaryl is unsubstituted or substituted by 1, 2, 3 or 4 groups independently selected from R s1 The group substituted; is unsubstituted or substituted with 1, 2, 3 or 4 -C 1-6 Alkyl substitution; R s1 Halogen, cyano, hydroxyl, -C 1-6 Alkyl, -C 1-6 Alkoxy, -halogenated C 1-6 Alkyl, -halogenated C 1-6 Alkoxy, -C 3-6 Cycloalkyl, -NR c R d 、-C(O)NR e R f , -C 1-4 Alkyl-hydroxyl, -C 1-4 Alkyl-cyano or -C 1-4 Alkyl-NR e R f ; R0 is a 5- or 6-membered monocyclic heteroaryl group; wherein the 5- or 6-membered monocyclic heteroaryl group has 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms; and the 5- or 6-membered monocyclic heteroaryl group is unsubstituted or substituted by 1, 2, 3 or 4 independently selected from R s3 The group substitution; R s3 Halogen, cyano, hydroxyl, -C 1-6 Alkyl, -C 1-6 Alkoxy or -C 3-6 Cycloalkyl; wherein the C 1-6 Alkyl, -C 1-6 Alkoxy or -C 3-6 Cycloalkyl is optionally substituted with 1, 2 or 3 substituents independently selected from halogen, methyl, ethyl, propyl, isopropyl or trifluoromethyl; R e , R f are independently hydrogen or C 1-3 alkyl; R c , R d are independently hydrogen, -C 1-3 Alkyl, -C(O)C 1-3 Alkyl or -CO2C 1-3 alkyl; Provided that the compound of formula (I) does not include:

2. A compound represented by formula (IA) or its racemate or a pharmaceutically acceptable salt thereof: In the formula, Z is NC(O)-CR3=CR1R2; R1 and R2 are each independently hydrogen or halogen; R3 is hydrogen or halogen; R 11 , R 12 are the same or different and are each independently hydrogen, halogen or -C 1-3 alkyl; R 21 , R 22 are the same or different and are each independently hydrogen, halogen or -C 1-3 alkyl; R 31 , R 32 are the same or different and are each independently hydrogen, halogen or -C 1-3 alkyl; R 41 is hydrogen; The dashed line in the figure is a single bond, and P' is O, NH or NR m ';R m ' is - deuterated C 1-6 Alkyl or -C 1-6 Alkyl; R 42 'For -C 1-3 Alkyl-(C=O)-, -(C=O)- or -C 1-3 alkyl-; Y1 is C; X1 is hydrogen, halogen, hydroxyl, -C 1-6 Alkyl or -C 3-6 Cycloalkyl; E1' is N or CR5'; wherein, R5' is hydrogen or halogen; E2' is CR6'; wherein R6' is hydrogen or halogen; Ar' is C 6-10 aryl, 5- or 6-membered monocyclic heteroaryl or wherein the 5- or 6-membered monocyclic heteroaryl group has 1, 2 or 3 heteroatoms selected from N and O as ring atoms; and the C 6-10 Aryl or 5 or 6 membered monocyclic heteroaryl is unsubstituted or substituted by 1, 2, 3 or 4 groups independently selected from R s1 The group substituted; is unsubstituted or substituted with 1, 2, 3 or 4 -C 1-6 Alkyl substitution; R s1 Halogen, cyano, hydroxyl, -C 1-6 Alkyl, -C 1-6 Alkoxy, -halogenated C 1-6 Alkyl, -halogenated C 1-6 Alkoxy, -C 3-6 Cycloalkyl, -NR c R d 、-C(O)NR e R f , -C 1-4 Alkyl-hydroxyl, -C 1-4 Alkyl-cyano or -C 1-4 Alkyl-NR e R f ; R0' is a 5- or 6-membered monocyclic heteroaryl group, wherein the 5- or 6-membered monocyclic heteroaryl group has 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms; and the 5- or 6-membered monocyclic heteroaryl group is unsubstituted or substituted by 1, 2, 3 or 4 independently selected from R s3 The group substitution; R s3 Halogen, cyano, hydroxyl, -C 1-6 Alkyl, -C 1-6 Alkoxy or -C 3-6 Cycloalkyl; wherein the C 1-6 Alkyl, -C 1-6 Alkoxy, -C 3-6 Cycloalkyl is optionally substituted with 1, 2 or 3 substituents independently selected from halogen, methyl, ethyl, propyl, isopropyl or trifluoromethyl; R e , R f are independently hydrogen or C 1-3 alkyl; R c , R d are independently hydrogen, -C 1-3 Alkyl, -C(O)C 1-3 Alkyl or -CO2C 1-3 alkyl; Provided that the compound of formula (IA) does not include:

3. The compound according to claim 2, or its racemate, or a pharmaceutically acceptable salt thereof, characterized in that: The compound represented by formula (IA) is a compound represented by formula (IB): In formula IB, P' is O, NH or NR m ';R m ' is - deuterated C 1-6 Alkyl or -C 1-6 Alkyl; 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 2.

4. The compound according to claim 3, or its racemate, or a pharmaceutically acceptable salt thereof, characterized in that: The compound represented by formula (IB) is a compound represented by formula (IB-1) or a compound represented by 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 3.

5. The compound according to claim 3, or its racemate, or a pharmaceutically acceptable salt thereof, characterized in that: The compound represented by formula (IB) is a compound represented by formula (IB-1a) or a compound represented by formula (IB-2a): Among them, 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 3.

6. The compound according to claim 5, or its racemate, or a pharmaceutically acceptable salt thereof, characterized in that: The compound represented by formula (IB-1a) is a compound represented by formula (IB-1aa), a compound represented by formula (IB-1ab), a compound represented by formula (IB-1ac) or a compound represented by formula (IB-1ad): In formula (IB-1aa) and formula (IB-1ab), R 21 ' is halogen or -C 1-3 Alkyl; R1, R2, R3, R 12 , R 11 , R 31 , R 32 , P', R0', Ar', E1', X1 as defined in claim 5; In formula (IB-1ac) and formula (IB-1ad), R 12 ' is halogen or -C 1-3 Alkyl; R1, R2, R3, R 21 , R 22 , R 31 , R 32 , P', R0', Ar', E1', X1 are as defined in claim 5.

7. The compound according to claim 3, or its racemate, or a pharmaceutically acceptable salt thereof, characterized in that: The compound represented by formula (IB) is a compound represented by formula (IB-1c) or a compound represented by formula (IB-2c): Among them, 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 3.

8. The compound according to claim 7, or its racemate, or a pharmaceutically acceptable salt thereof, characterized in that: 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): In formula (IB-1ca) and formula (IB-1cb), R 21 ' is halogen or -C 1-3 Alkyl; R1, R2, R3, R 12 , R 11 , R 31 , R 32 , P', R0', Ar', E1', X1 as defined in claim 7; In the formula (IB-1cc) and the formula (IB-1cd), R 12 ' is halogen or -C 1-3 Alkyl; R1, R2, R3, R 21 , R 22 , R 31 , R 32 , P', R0', Ar', E1', X1 are as defined in claim 7.

9. The compound according to claim 3, or its racemate, or a pharmaceutically acceptable salt thereof, characterized in that: The compound represented by formula (IB) is a compound represented by formula (IB-1b) or a compound represented by formula (IB-2b): Among them, 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 3.

10. The compound according to claim 9, or its racemate, or a pharmaceutically acceptable salt thereof, characterized in that: The compound represented by formula (IB-1b) is a compound represented by formula (IB-1ba), a compound represented by formula (IB-1bb), a compound represented by formula (IB-1bc), or a compound represented by formula (IB-1bd): In the formula (IB-1ba) and the formula (IB-1bb), R 21 ' is halogen or -C 1-3 Alkyl; R1, R2, R3, R 12 , R 11 , R 31 , R 32 , P', R0', Ar', E1', X1 as defined in claim 9; In the formula (IB-1bc) and the formula (IB-1bd), R 12 ' is halogen or -C 1-3 Alkyl; R1, R2, R3, R 21 , R 22 , R 31 , R 32 , P', R0', Ar', E1', X1 are as defined in claim 9.

11. The compound according to claim 3, or its racemate, or a pharmaceutically acceptable salt thereof, characterized in that: The compound represented by formula (IB) is a compound represented by formula (IB-1d) or a compound represented by formula (IB-2d): Among them, 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 3.

12. The compound according to claim 11, or its racemate, or a pharmaceutically acceptable salt thereof, characterized in that: The compound represented by formula (IB-1d) is a compound represented by formula (IB-1da), a compound represented by formula (IB-1db), a compound represented by formula (IB-1dc) or a compound represented by formula (IB-1dd): In formula (IB-1da) and formula (IB-1db), R 21 ' is halogen or -C 1-3 Alkyl; R1, R2, R3, R 12 , R 11 , R 31 , R 32 , P', R0', Ar', E1', X1 as defined in claim 11; In the formula (IB-1dc) and the formula (IB-1dd), R 12 ' is halogen or -C 1-3 Alkyl; R1, R2, R3, R 21 , R 22 , R 31 , R 32 , P', R0', Ar', E1', X1 are as defined in claim 11.

13. The compound or racemate thereof or pharmaceutically acceptable salt thereof according to any one of claims 6, 8, 10 or 12, characterized in that: R 21 '、R 12 'Each independently -C 1-3 alkyl.

14. The compound according to claim 2, or its racemate, or a pharmaceutically acceptable salt thereof, characterized in that: X1 is hydrogen, halogen, -C 1-6 Alkyl or -C 3-6 Cycloalkyl.

15. The compound according to claim 2, or its racemate, or a pharmaceutically acceptable salt thereof, characterized in that: X1 is hydrogen, fluorine, chlorine, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

16. The compound according to claim 2, or its racemate, or a pharmaceutically acceptable salt thereof, characterized in that: Ar' is phenyl or 5 or 6-membered monocyclic heteroaryl; and the phenyl or 5 or 6-membered monocyclic heteroaryl is unsubstituted or substituted by 1, 2, 3 or 4 groups independently selected from the following groups: halogen, cyano, hydroxyl, -C 1-6 Alkyl, -C 1-6 Alkoxy, -NR c R d or -C 1-4 Alkyl-NR e R f ; where R e , R f are independently hydrogen or C 1-3 Alkyl; R c , R d are independently hydrogen, -C 1-3 Alkyl, -C(O)C 1-3 Alkyl or -CO2C 1-3 alkyl.

17. The compound according to claim 2, or its racemate, or a pharmaceutically acceptable salt thereof, wherein: Ar' is selected from the following structures: In the formula, R s1 As defined in claim 2.

18. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein Ar is selected from the following structures:

19. The compound according to claim 2, or its racemate, or a pharmaceutically acceptable salt thereof, characterized in that: Ar' is selected from the following structures:

20. The compound according to claim 2, or its racemate, or a pharmaceutically acceptable salt thereof, characterized in that: R0' is a 5- or 6-membered monocyclic heteroaryl group, wherein the 5- or 6-membered monocyclic heteroaryl group has 1, 2 or 3 heteroatoms selected from N and O as ring atoms; and the 5- or 6-membered monocyclic heteroaryl group is unsubstituted or substituted by 1, 2, 3 or 4 independently selected from R s3 The group is substituted.

21. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R0 is selected from the following structures:

22. The compound according to claim 2, or its racemate, or a pharmaceutically acceptable salt thereof, characterized in that: R0' is selected from the following structures:

23. The following compound or a pharmaceutically acceptable salt thereof:

24. The following compound or a pharmaceutically acceptable salt thereof:

25. A pharmaceutical composition comprising a compound or a racemate or a pharmaceutically acceptable salt thereof as described in any one of claims 2-17, 19-20, and 22, or a compound or a pharmaceutically acceptable salt thereof as described in any one of claims 1, 18, 21, and 23-24, and a pharmaceutically acceptable carrier.

26. A compound represented by formula (j-1) or a pharmaceutically acceptable salt thereof: in, X1 is hydrogen, halogen, hydroxyl, -C 1-6 Alkyl or -C 3-6 Cycloalkyl; E1' is N or CR5'; R5' is hydrogen or halogen; Ar' is C 6-10 aryl, 5- or 6-membered monocyclic heteroaryl or wherein the 5- or 6-membered monocyclic heteroaryl group has 1, 2 or 3 heteroatoms selected from N and O as ring atoms; and the C 6-10 Aryl or 5 or 6 membered monocyclic heteroaryl is unsubstituted or substituted by 1, 2, 3 or 4 groups independently selected from R s1 The group substituted; is unsubstituted or substituted with 1, 2, 3 or 4 -C 1-6 Alkyl substitution; R s1 Halogen, cyano, hydroxyl, -C 1-6 Alkyl, -C 1-6 Alkoxy, -halogenated C 1-6 Alkyl, -halogenated C 1-6 Alkoxy, -C 3-6 Cycloalkyl, -NR c R d 、-C(O)NR e R f , -C 1-4 Alkyl-hydroxyl, -C 1-4 Alkyl-cyano or -C 1-4 Alkyl-NR e R f ; R0' is a 5- or 6-membered monocyclic heteroaryl group, wherein the 5- or 6-membered monocyclic heteroaryl group has 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms; and the 5- or 6-membered monocyclic heteroaryl group is unsubstituted or substituted by 1, 2, 3 or 4 independently selected from R s3 The group substitution; R s3 Halogen, cyano, hydroxyl, -C 1-6 Alkyl, -C 1-6 Alkoxy or -C 3-6 Cycloalkyl; wherein the C 1-6 Alkyl, -C 1-6 Alkoxy or -C 3-6 Cycloalkyl is optionally substituted with 1, 2 or 3 substituents independently selected from halogen, methyl, ethyl, propyl, isopropyl or trifluoromethyl; R 11 , R 12 are the same or different and are each independently hydrogen, halogen or -C 1-3 alkyl; R 21 , R 22 are the same or different and are each independently hydrogen, halogen or -C 1-3 alkyl; R 31 , R 32 are the same or different and are each independently hydrogen, halogen or -C 1-3 alkyl; R e , R f are independently hydrogen or C 1-3 alkyl; R c , R d are independently hydrogen, -C 1-3 Alkyl, -C(O)C 1-3 Alkyl or -CO2C 1-3 alkyl.

27. The compound according to claim 26 or a pharmaceutically acceptable salt thereof, characterized in that X1 is hydrogen, fluorine, chlorine, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

28. The compound according to claim 26 or a pharmaceutically acceptable salt thereof, characterized in that Ar' is selected from the following structures:

29. The compound according to claim 26 or a pharmaceutically acceptable salt thereof, characterized in that R0' is selected from the following structures:

30. The compound according to claim 26 or a pharmaceutically acceptable salt thereof, wherein: Ar' is phenyl or 5 or 6-membered monocyclic heteroaryl; and the phenyl or 5 or 6-membered monocyclic heteroaryl is unsubstituted or substituted by 1, 2, 3 or 4 groups independently selected from the following groups: halogen, cyano, hydroxyl, -C 1-6 Alkyl or -C 1-6 Alkoxy.

31. The compound according to claim 26 or a pharmaceutically acceptable salt thereof, wherein: Ar' is selected from the following structures: In the formula, R s1 As defined in claim 26.

32. The compound of claim 26 or a pharmaceutically acceptable salt thereof, wherein: R0' is a 5- or 6-membered monocyclic heteroaryl group, wherein the 5- or 6-membered monocyclic heteroaryl group has 1, 2 or 3 heteroatoms selected from N and O as ring atoms; and the 5- or 6-membered monocyclic heteroaryl group is unsubstituted or substituted by 1, 2, 3 or 4 independently selected from R s3 The group is substituted.

33. The following compound or a pharmaceutically acceptable salt thereof:

34. Use of a compound or a racemate or a pharmaceutically acceptable salt thereof as described in any one of claims 2-17, 19-20, 22, or a compound or a pharmaceutically acceptable salt thereof as described in any one of claims 1, 18, 21, 23-24, 26-33, or a pharmaceutical composition as described in claim 25 in the preparation of a medicament for preventing and / or treating a KRAS G12C mutation-induced disease.

35. The use according to claim 34, wherein The KRAS G12C mutation-induced disease is cancer.

36. The use according to claim 35, characterized in that The cancer is pancreatic cancer, colorectal cancer or lung cancer.

37. The use according to claim 35, characterized in that The cancer is non-small cell lung cancer.

38. Use of a compound or a racemate or a pharmaceutically acceptable salt thereof as described in any one of claims 2-17, 19-20, 22, or a compound or a pharmaceutically acceptable salt thereof as described in any one of claims 1, 18, 21, 23-24, 26-33, or a pharmaceutical composition as described in claim 25 in the preparation of a KRAS mutation inhibitor; the KRAS mutation is a KRAS G12C mutation.

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