Substituted heterocyclic-ring system compound, preparation method therefor, and pharmaceutical application thereof

Abstract

To provide a substituted composite ring-ring system compound having a new structure and having advantages such as high activity and high selectivity as a selective inhibitor of KRAS mutation and low toxicity and side effects.SOLUTION: The present invention relates to a substituted heterocyclic-cyclic compound having a selective inhibitory effect on KRAS gene mutations as shown in formula (I) or formula (IA), a pharmaceutically acceptable salt, a stereoisomer, a solvate or a prodrug thereof, a pharmaceutical composition comprising the compound, and use thereof in the preparation of drugs for treating cancer.SELECTED DRAWING: None

Description

[Technical Field]

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

[0002] Lung cancer has the highest incidence rate of any cancer in the world, and in China it ranks first among all cancers, and is also the cancer with the highest incidence rate and mortality rate in China. According to data disclosed by the American Cancer Society in 2016, approximately 1.8 million people worldwide were diagnosed with lung cancer in 2015, of which nearly 80% were non-small cell lung cancer (NSCLC).

[0003] RASs are a series of closely related monomeric globular proteins (21 kDa molecular weight) containing 188–189 amino acids that bind guanosine diphosphate (GDP) or guanosine triphosphate (GTP). The RAS subfamily includes HRAS, KRAS, and NRAS. RASs function as molecular switches; when RAS contains bound GDP, it is in a resting or off state and is "inactive." When cells are exposed to certain growth-inhibitory stimuli, RASs are induced to convert their bound GDP to GTP. When bound to GTP, RASs are "on" and interact with and activate other downstream target proteins. RAS proteins themselves have a very low intrinsic ability to hydrolyze GTP back to GDP (returning themselves to the off state). To restore the off state, exogenous proteins, GTPase-activating proteins (GAPs), are required. The synergistic effect of GAPs and RASs can significantly accelerate the conversion of GTP to GDP. Any mutation in RAS affects the synergistic effect of RAS and GAP and the ability to convert GTP to GDP. Such mutations prolong the protein's activation time, thereby prolonging cell signaling and promoting cell proliferation and division. Because such signaling leads to cell proliferation and division, excessive RAS signaling can ultimately lead to cancer. RAS gene mutations are identified in approximately 32% of lung cancers, and mutations in any of the three major subtypes of RAS (HRAS, NRAS, or KRAS) genes can cause human tumor development. The most common RAS gene mutation is the KRAS gene, with KRAS mutations reported in 25-30% of tumors. In contrast, the incidence of oncogenic mutations in the NRAS and HRAS families is very low (8% and 3%, respectively). The most common KRAS mutations occur at residues G12, G13, and Q61 in the P ring. The G12C mutation is a frequent mutation in the KRAS gene (glycine-12 to cysteine).This mutation is found in approximately 13% of cancers, approximately 43% of lung cancers, and nearly 100% of MYH-associated polyposis (familial adenomatous polyposis). Therefore, inhibitors that selectively inhibit KRAS mutations are expected. In order to improve the inhibitory activity against KRAS mutations and reduce the inhibitory activity against wild-type KRAS, the development of novel RAS mutant-selective inhibitors with higher activity, higher selectivity, and lower toxicity is of great importance. Summary of the Invention

[0004] The present invention provides substituted heterocyclic ring-based compounds with novel structures that have advantages such as high activity and selectivity as selective inhibitors of KRAS mutations, as well as low toxicity and side effects.

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

[0006] [ka]

[0007] (In Formula I, Z is NC(O)-CR═CR═R or NC(O)-C≡CR, R1 and R2 are each independently hydrogen, halogen, cyano, or NR a R b , -C 1-3 Alkyl, halogenated C 1-3 Alkyl, -C 1-3 Alkyl-hydroxy, -C 1-3 Alkyl-cyano, -C 1-3 Alkyl-C 1-3 Alkoxy, -C 1-3 Alkyl-NR a R b , -C 1-3 alkyl-3 to 6-membered heterocycloalkyl or -C 1-3alkyl-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-forming atoms; R3 is hydrogen, halogen, -C 1-3 Alkyl or -C 1-3 is an alkoxy; R4 is hydrogen, halogenated C 1-3 Alkyl, -C 1-3 Alkyl-hydroxy, -C 1-3 Alkyl-cyano or -C 1-3 Alkyl-C 1-3 is an alkoxy, R 11 , R 12 may be the same or different, and each independently represents hydrogen, halogen, or -C 1-3 Alkyl, -halogenated C 1-3 Alkyl, -C 1-3 Alkyl-hydroxy, -C 1-3 Alkyl-cyano, -C 1-3 Alkyl-C 1-6 Alkoxy, -C 1-3 Alkyl-halogenated C 1-6 Alkyl or -C 1-3 Alkyl-halogenated C 1-6 is an alkoxy; R 21 , R 22 may be the same or different, and each independently represents hydrogen, halogen, or -C 1-3 Alkyl, -halogenated C 1-3 Alkyl, -C 1-3 Alkyl-hydroxy, -C 1-3 Alkyl-cyano, -C 1-3 Alkyl-C 1-6 Alkoxy, -C 1-3 Alkyl-halogenated C 1-6 Alkyl or -C 1-3 Alkyl-halogenated C 1-6 is an alkoxy, R 31 , R 32may be the same or different, and each independently represents hydrogen, halogen, or -C 1-3 Alkyl, -halogenated C 1-3 Alkyl, -C 1-3 Alkyl-hydroxy, -C 1-3 Alkyl-cyano, -C 1-3 Alkyl-C 1-6 Alkoxy, -C 1-3 Alkyl-halogenated C 1-6 Alkyl or -C 1-3 Alkyl-halogenated C 1-6 is an alkoxy, R 41 is hydrogen, halogen, -C 1-3 Alkyl, -halogenated C 1-3 Alkyl, -C 1-3 Alkyl-hydroxy, -C 1-3 Alkyl-cyano, -C 1-3 Alkyl-C 1-6 Alkoxy, -C 1-3 Alkyl-halogenated C 1-6 Alkyl or -C 1-3 Alkyl-halogenated C 1-6 is an alkoxy,

[0008] [ka]

[0009] When the dashed line in is a single bond, P is O, NH, or NR m and R m -C 1-6 Alkyl, -halogenated C 1-6 Alkyl, -C 1-6 Alkyl-hydroxy, -C 1-6 Alkyl-cyano, -C 1-6 Alkyl-C 1-6 Alkoxy, -C 1-6 Alkyl-halogenated C 1-6 Alkoxy, -C 1-6 Alkyl-C 3-6 Cycloalkyl or -C 1-6 alkyl-3- 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)-, Or,

[0010] [ka]

[0011] If there is no dashed line, P is hydrogen, halogen, and R 42 is hydrogen, halogen, -C 1-3 Alkyl, -halogenated C 1-3 Alkyl, -C 1-3 Alkyl-hydroxy, -C 1-3 Alkyl-cyano, -C 1-3 Alkyl-C 1-6 Alkoxy, -C 1-3 Alkyl-halogenated C 1-6 Alkyl or -C 1-3 Alkyl-halogenated C 1-6 is an alkoxy, When Y1 is C, X1 is hydrogen, halogen, cyano, hydroxy, amino, nitro, optionally substituted C 1-6 Alkyl, optionally -substituted C 3-6 Cycloalkyl, optionally substituted 3- to 6-membered heterocycloalkyl, -O- optionally substituted C 1-6 Alkyl, -O-optionally substituted C 3-6Cycloalkyl, -O-optionally substituted 3- to 6-membered heterocycloalkyl, -NH-optionally substituted C 1-6 Alkyl, -N(optionally substituted C 1-6 alkyl)2, -NH- optionally substituted C 3-6 Cycloalkyl, -NH- optionally substituted 3- to 6-membered heterocycloalkyl, -NH(C=O)- optionally substituted C 1-6 Alkyl, -NH(C=O)-C 3-6 Cycloalkyl, -NH(SO2)- optionally substituted C 1-6 Alkyl, -NH(SO2)- optionally substituted C 3-6 Cycloalkyl, -SO2- optionally substituted C 1-6 Alkyl, -SO2- optionally substituted C 3-6 Cycloalkyl, -(C=O)-NR j R k -, -(C=O)-O-Optionally substituted C 1-6 Alkyl, -(C=O)-O- optionally substituted C 3-6 is cycloalkyl, and R j , R k are each independently hydrogen or C 1-3 alkyl, or R j , R k form an optionally substituted 3- to 6-membered nitrogen-containing heterocycloalkyl together with the nitrogen atom to which it is connected, the 3- to 6-membered heterocycloalkyl having 1, 2 or 3 heteroatoms selected from N, O and S as ring-forming atoms, the 3- to 6-membered nitrogen-containing heterocycloalkyl having 3 to 6 ring-forming atoms, one of which is a nitrogen atom, and zero, one or two of the remaining ring-forming atoms may optionally be heteroatoms selected from N, O and S, and the "substituted" refers to 1, 2, 3 or 4 hydrogen atoms in the group being substituted with substituents each independently selected from the S group, Or, if Y1 is N, then X1 is none; The S group substituents include hydroxy, halogen, nitro, oxo, -C 1-6 Alkyl, -halogenated C 1-6Alkyl, hydroxy substituted C 1-6 Alkyl, benzyl, -(CH2) u -cyano, -(CH2) u -C 1-6 Alkoxy, -(CH2) u -Halogenated C 1-6 Alkoxy, -(CH2) u -Halogenated C 1-6 Alkyl, -(CH2) u -3 to 6-membered heterocycloalkyl, -(CH2) u -5- or 6-membered monocyclic heteroaryl, -(CH2) u -C 3-8 Cycloalkyl, -(CH2) u -O-(CH2) v -C 3-8 Cycloalkyl, -(CH2) u -O-(CH2) v -C 1-6 Alkoxy, -(CH2) u -O-(CH2) v OH, -(CH2) u -SO2C 1-6 Alkyl, -(CH2) u -NR a0 R b0 , -(CH2) u -C(O)NR a0 R b0 , -(CH2) u -C(O)C 1-6 Alkyl, -C(O)OC 1-6 Alkyl, NR a0 C(O)-(CH2) u -NR a0 R b0 , N.R. a0 C(O)-(CH2) u OH, NR a0 C(O)-halogenated C 1-6alkyl, wherein the 3- to 6-membered heterocycloalkyl or the 5- or 6-membered monocyclic heteroaryl has 1, 2 or 3 heteroatoms each independently selected from N, O and S as ring-forming atoms, the 3- to 6-membered heterocycloalkyl or the 5- or 6-membered monocyclic heteroaryl is optionally substituted by 1, 2 or 3 substituents selected from halogen, cyano, -C1-3 alkyl, -C1-3 alkoxy and C3-6 cycloalkyl, u and v are each independently 0, 1, 2, 3 or 4, and R a0 , R b0 are each independently hydrogen or C 1-3 is alkyl, E1 is N or CR5, and R5 is hydrogen, halogen, cyano, -C 1-6 Alkyl, -C 1-6 Alkoxy, -halogenated C 1-6 Alkyl, -halogenated C 1-6 Alkoxy, -C 3-6 Cycloalkyl, -NR h R i , -C 1-4 Alkyl-hydroxy, -C 1-4 Alkyl-cyano, -C 1-4 Alkyl-C 1-6 Alkoxy, -C 1-4 Alkyl-halogenated C 1-6 Alkyl or -C 1-4 Alkyl-halogenated C 1-6 is an alkoxy, E2 is N or CR6, and 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, -NR h R i , -C 1-4 Alkyl-hydroxy, -C 1-4 Alkyl-cyano, -C 1-4 Alkyl-C 1-6 Alkoxy, -C 1-4 Alkyl-halogenated C 1-6 Alkyl or -C1-4 Alkyl-halogenated C 1-6 is an alkoxy, However, Y1, E1, and E2 are not N at the same time, 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 group has 1, 2, or 3 heteroatoms selected from N, O, and S as ring-forming atoms, and the 8- to 10-membered bicyclic heteroaryl group has 1, 2, 3, 4, or 5 heteroatoms selected from N, O, and S as ring-forming 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 independently R s1 and is substituted with 1, 2, 3 or 4 groups selected from Alternatively, Ar is a structure represented by formula (B):

[0012] [ka]

[0013] In formula (B), ring B1 is a benzene ring or a 5- or 6-membered monocyclic heteroaryl ring, ring B2 is a fused 5- or 6-membered monocyclic heterocycloalkyl ring or a fused 5- or 6-membered monocyclic cycloalkyl ring, and 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-forming atoms; (R s1 ) p The hydrogen atoms of the B1 ring are p R s1 where p is 0, 1, 2, or 3, and each R s1 may be the same or different, (R s2 ) q The hydrogen atoms of the B2 ring are q R s2 q is 0, 1, 2, or 3; and each R s2may be the same or different, R s1 , R s2 are each independently halogen, cyano, nitro, hydroxy, -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 halogenated C 1-3 Alkyl, -SO2NR e R f , -C 1-4 Alkyl-hydroxy, -C 1-4 Alkyl-cyano, -C 1-4 Alkyl-C 1-6 Alkoxy, -C 1-4 Alkyl-halogenated C 1-6 Alkyl, -C 1-4 Alkyl-halogenated C 1-6 Alkoxy, -C 1-4 Alkyl-3 to 6-membered heterocycloalkyl, -C 1-4 Alkyl-NR e R f , -C 1-4 Alkyl-C(O)NR e R f , -C 1-4 Alkyl-SO2C 1-3 Alkyl or C 2-4 alkynyl, wherein the 3- to 6-membered heterocycloalkyl has 1, 2, or 3 heteroatoms selected from N, O, and S as ring-forming atoms; R0 is -C 1-6 Alkyl, -C 3-6 Cycloalkyl, 3-6 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 1-3alkyl-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 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-forming atoms, and the C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6-10 Aryl, 5- or 6-membered monocyclic heteroaryl, 8- to 10-membered bicyclic heteroaryl, and 7- to 11-membered spirocycloalkyl are unsubstituted or independently R s3 and wherein the -C is substituted with 1, 2, 3 or 4 groups selected from 1-3 Alkyl- is unsubstituted or independently C 1-3 substituted with 1, 2, 3 or 4 groups selected from alkyl; Alternatively, R0 is a structure represented by formula (A-1) or formula (A-2),

[0014] [ka]

[0015] In formula (A-1) or formula (A-2), ring A1 is a benzene ring or a 5- or 6-membered monocyclic heteroaryl ring, ring A2 is a fused 5- or 6-membered monocyclic heterocycloalkyl ring or a fused 5- or 6-membered monocyclic cycloalkyl ring, and 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-forming atoms; (R s3 ) t The hydrogen atoms of the A1 ring are R s3 where t is 0, 1, 2, or 3, and each Rs3 may be the same or different, (R s4 ) s The hydrogen atoms of the A2 ring are s R s4 where s is 0, 1, 2, or 3, and each R s4 may be the same or different, R s3 , R s4 are each independently halogen, cyano, hydroxy, -C 1-6 Alkyl, -C 1-6 Alkoxy, -halogenated C 1-6 Alkyl, -halogenated C 1-6 Alkoxy, -C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, -NR h R i , -C(O)NR e R f , -SO2C 1-3 Alkyl, -SO2 halogenated C 1-3 Alkyl, -SO2NR e R f , -C 1-3 Alkyl-hydroxy, -C 1-3 Alkyl-C 2-4 Alkynyl, -C 1-3 Alkyl-cyano, -C 1-3 Alkyl-C 1-6 Alkoxy, -C 1-3 Alkyl-halogenated C 1-6 Alkyl, -C 1-3 Alkyl-halogenated 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 2-4alkynyl, wherein the 3- to 6-membered heterocycloalkyl has 1, 2 or 3 heteroatoms selected from N, O and S as ring-forming atoms, and the C 1-6 Alkyl, -C 1-6 Alkoxy, -C 1-3 Alkyl-, -C 3-6 The cycloalkyl, 3- to 6-membered heterocycloalkyl may be optionally substituted with 1, 2, or 3 substituents independently selected from halogen, methyl, ethyl, propyl (n-propyl), isopropyl, trifluoromethyl, amino, N(CH3)2, hydroxy, and carboxyl; R a , R b , R e , R f , R g are each independently hydrogen or C 1-3 is an alkyl group, and R c , R d , R h , R i are each independently hydrogen, -C 1-3 Alkyl, -C(O)C 1-3 Alkyl or -CO2C 1-3 It is alkyl.

[0016] 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).

[0017] [ka]

[0018] (In formula (I-1), P is O, NH or NR m and R m -C 1-6 Alkyl, -halogenated C 1-6 Alkyl, -C 1-6 Alkyl-hydroxy, -C 1-6 Alkyl-cyano, -C 1-6 Alkyl-C 1-6 Alkoxy, -C 1-6 Alkyl-halogenated C 1-6Alkoxy, -C 1-6 Alkyl-C 3-6 Cycloalkyl or -C 1-6 alkyl-3- to 6-membered heterocycloalkyl, R 42 is -(C=O)-, -C 1-3 Alkyl-, -C 1-3 Alkyl(hydroxy)-, -C 1-3 Alkyl(cyano)-, -C 1-3 Alkyl (C 1-6 alkyl)-, -C 1-3 Alkyl (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)-, and 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 above, In formula (I-2), P is hydrogen or halogen, and R 42 is hydrogen, halogen, -C 1-3 Alkyl, -halogenated C 1-3 Alkyl, -C 1-3 Alkyl-hydroxy, -C 1-3 Alkyl-cyano, -C 1-3 Alkyl-C 1-6 Alkoxy, -C 1-3 Alkyl-halogenated C 1-6 Alkyl or -C 1-3 Alkyl-halogenated C 1-6 is alkoxy, and 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 above.)

[0019] In another aspect, the present invention provides a compound of formula (IA) or a tautomer, cis-trans isomer, mesomers, racemates, enantiomers, diastereomers, atropisomers or mixtures thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof.

[0020] [ka]

[0021] (In formula (IA), Z is NC(O)-CR═CR═R or NC(O)-C≡CR, R1 and R2 are each independently hydrogen, halogen, cyano, or NR a R b , -C 1-3 Alkyl, halogenated C 1-3 Alkyl, -C 1-3 Alkyl-hydroxy, -C 1-3 Alkyl-cyano, -C 1-3 Alkyl-C 1-3 Alkoxy, -C 1-3 Alkyl-NR a R b , -C 1-3 alkyl-3 to 6-membered heterocycloalkyl or -C 1-3 alkyl-5- or 6-membered monocyclic heteroaryl, wherein the 3- to 6-membered heterocycloalkyl or the 5- or 6-membered monocyclic heteroaryl has 1, 2, or 3 heteroatoms selected from N, O, and S as ring-forming atoms; R3 is hydrogen, halogen, -C 1-3 Alkyl or -C 1-3 is an alkoxy, R4 is hydrogen, halogenated C 1-3 Alkyl, -C 1-3 Alkyl-hydroxy, -C 1-3 Alkyl-cyano or -C 1-3 Alkyl-C 1-3 is an alkoxy, R 11 , R 12 may be the same or different, and each independently represents hydrogen, halogen, or -C 1-3 Alkyl, -halogenated C 1-3 Alkyl, -C 1-3 Alkyl-hydroxy, -C 1-3 Alkyl-cyano, -C 1-3 Alkyl-C 1-6 Alkoxy, -C 1-3 Alkyl-halogenated C 1-6 Alkyl or -C 1-3 Alkyl-halogenated C 1-6 is an alkoxy, R 21 , R 22 may be the same or different, and each independently represents hydrogen, halogen, or -C 1-3 Alkyl, -halogenated C 1-3 Alkyl, -C 1-3 Alkyl-hydroxy, -C 1-3 Alkyl-cyano, -C 1-3 Alkyl-C 1-6 Alkoxy, -C 1-3 Alkyl-halogenated C 1-6 Alkyl or -C 1-3 Alkyl-halogenated C 1-6 is an alkoxy, R 31 , R 32 may be the same or different, and each independently represents hydrogen, halogen, or -C 1-3 Alkyl, -halogenated C 1-3 Alkyl, -C 1-3 Alkyl-hydroxy, -C 1-3 Alkyl-cyano, -C 1-3 Alkyl-C 1-6 Alkoxy, -C 1-3 Alkyl-halogenated C 1-6 Alkyl or -C 1-3 Alkyl-halogenated C 1-6 is an alkoxy, R 41 is hydrogen, halogen, -C 1-3 Alkyl, -halogenated C 1-3Alkyl, -C 1-3 Alkyl-hydroxy, -C 1-3 Alkyl-cyano, -C 1-3 Alkyl-C 1-6 Alkoxy, -C 1-3 Alkyl-halogenated C 1-6 Alkyl or -C 1-3 Alkyl-halogenated C 1-6 is an alkoxy,

[0022] [ka]

[0023] When the dashed line in is a single bond, P' is O, NH or NR m ' and R m '-deuterated C 1-6 Alkyl, -C 1-6 Alkyl, -halogenated C 1-6 Alkyl, -C 1-6 Alkyl-hydroxy, -C 1-6 Alkyl-cyano, -C 1-6 Alkyl-C 1-6 Alkoxy, -C 1-6 Alkyl-halogenated C 1-6 Alkoxy, -C 1-6 Alkyl-C 3-6 Cycloalkyl or -C 1-6 alkyl-3- to 6-membered heterocycloalkyl, R 42 ′ is -C 1-3 Alkyl-(C=O)-, -(C=O)-, -C 1-3 Alkyl-, -C 1-3 Alkyl(hydroxy)-, -C 1-3 Alkyl(cyano)-, -C 1-3 Alkyl (C 1-6 alkyl)-, -C 1-3 Alkyl (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 (C1-6 Alkoxy)- or -C 1-3 Alkyl (halogenated C 1-6 alkoxy)-, Or,

[0024] JPEG2026010039000009.jpg2111

[0025] If there is no dashed line, P' is hydrogen, halogen, and R 42 ' is hydrogen, halogen, -C 1-3 Alkyl, -halogenated C 1-3 Alkyl, -C 1-3 Alkyl-hydroxy, -C 1-3 Alkyl-cyano, -C 1-3 Alkyl-C 1-6 Alkoxy, -C 1-3 Alkyl-halogenated C 1-6 Alkyl or -C 1-3 Alkyl-halogenated C 1-6 is an alkoxy, When Y1 is C, X1 is hydrogen, halogen, cyano, hydroxy, amino, nitro, optionally substituted C 1-6 Alkyl, optionally -substituted C 3-6 Cycloalkyl, optionally substituted 3- to 6-membered heterocycloalkyl, -O- optionally substituted C 1-6 Alkyl, -O-optionally substituted C 3-6 Cycloalkyl, -O-optionally substituted 3- to 6-membered heterocycloalkyl, -NH-optionally substituted C 1-6 Alkyl, -N(optionally substituted C 1-6 alkyl)2, -NH- optionally substituted C 3-6 Cycloalkyl, -NH- optionally substituted 3- to 6-membered heterocycloalkyl, -NH(C=O)- optionally substituted C 1-6 Alkyl, -NH(C=O)-C 3-6 Cycloalkyl, -NH(SO2)- optionally substituted C 1-6 Alkyl, -NH(SO2)- optionally substituted C 3-6Cycloalkyl, -SO2- optionally substituted C 1-6 Alkyl, -SO2- optionally substituted C 3-6 Cycloalkyl, -(C=O)-NR j R k -, -(C=O)-O-Optionally substituted C 1-6 Alkyl, -(C=O)-O- optionally substituted C 3-6 cycloalkyl, and R j , R k are each independently hydrogen or C 1-3 alkyl, or j , R k form an optionally substituted 3- to 6-membered nitrogen-containing heterocycloalkyl together with the nitrogen atom to which it is connected, wherein the 3- to 6-membered heterocycloalkyl has 1, 2 or 3 heteroatoms selected from N, O and S as ring-forming atoms, the 3- to 6-membered nitrogen-containing heterocycloalkyl has 3 to 6 ring-forming atoms, one of which is a nitrogen atom and 0, 1 or 2 of the remaining ring-forming atoms are optionally any heteroatom selected from N, O and S, and the "substituted" refers to 1, 2, 3 or 4 hydrogen atoms in the group being each independently substituted with any substituent selected from the S group, Or, if Y1 is N, then X1 is none; The S group substituents include hydroxy, 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 3-8Cycloalkyl, -(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 , N.R. a0 C(O)-(CH2) u OH, NR a0 C(O)-halogenated C 1-6 alkyl, wherein the 3- to 6-membered heterocycloalkyl or the 5- or 6-membered monocyclic heteroaryl has 1, 2, or 3 heteroatoms independently selected from N, O, and S as ring-forming atoms, and the 3- to 6-membered heterocycloalkyl and the 5- or 6-membered monocyclic heteroaryl are selected from halogen, cyano, -C 1-3 Alkyl, -C 1-3 Alkoxy and C 3-6 cycloalkyl, u and v are each independently 0, 1, 2, 3 or 4; R a0 , R b0 are each independently hydrogen or C 1-3 is alkyl, 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 C1-6 Alkoxy, -C 3-6 Cycloalkyl, -OC 3-6 Cycloalkyl, -NR h R i , -C 1-4 Alkyl-hydroxy, -C 1-4 Alkyl-cyano, -C 1-4 Alkyl-C 1-6 Alkoxy, -C 1-4 Alkyl-halogenated C 1-6 Alkyl or -C 1-4 Alkyl-halogenated C 1-6 is an alkoxy, 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-hydroxy, -C 1-4 Alkyl-cyano, -C 1-4 Alkyl-C 1-6 Alkoxy, -C 1-4 Alkyl-halogenated C 1-6 Alkyl or -C 1-4 Alkyl-halogenated C 1-6 is an alkoxy, However, Y1, E1', and E2' are not N at the same time, Ar' is C 6-10 aryl, 5- or 6-membered monocyclic heteroaryl, 8- to 10-membered bicyclic heteroaryl or pyridone group, wherein the 5- or 6-membered monocyclic heteroaryl has 1, 2 or 3 heteroatoms selected from N, O and S as ring-forming atoms, and the 8- to 10-membered bicyclic heteroaryl has 1, 2, 3, 4 or 5 heteroatoms selected from N, O and S as ring-forming atoms, and the C 6-10the aryl, the 5- or 6-membered monocyclic heteroaryl, the 8- to 10-membered bicyclic heteroaryl, and the pyridone group are unsubstituted or substituted with 1, 2, 3, or 4 groups independently selected from Rs1; Alternatively, Ar' is a structure represented by formula (B):

[0026] [ka]

[0027] In formula (B), ring B1 is a benzene ring or a 5- or 6-membered monocyclic heteroaryl ring, ring B2 is a fused 5- or 6-membered monocyclic heterocycloalkyl ring or a fused 5- or 6-membered monocyclic cycloalkyl ring, and 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-forming atoms; (R s1 ) p The hydrogen atoms of the B1 ring are p R s1 where p is 0, 1, 2, or 3, and each R s1 may be the same or different, (R s2 ) q The hydrogen atoms of the B2 ring are q R s2 q is 0, 1, 2, or 3; and each R s2 may be the same or different, R s1 , R s2 are each independently halogen, cyano, nitro, hydroxy, -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 halogenated C1-3 Alkyl, -SO2NR e R f , -C 1-4 Alkyl-hydroxy, -C 1-4 Alkyl-cyano, -C 1-4 Alkyl-C 1-6 Alkoxy, -C 1-4 Alkyl-halogenated C 1-6 Alkyl, -C 1-4 Alkyl-halogenated C 1-6 Alkoxy, -C 1-4 Alkyl-3 to 6-membered heterocycloalkyl, -C 1-4 Alkyl-NR e R f , -C 1-4 Alkyl-C(O)NR e R f , -C 1-4 Alkyl-SO2C 1-3 Alkyl or C 2-4 alkynyl, wherein the 3- to 6-membered heterocycloalkyl group has 1, 2, or 3 heteroatoms selected from N, O, and S as ring-forming atoms; R0' is -C 1-6 Alkyl, -C 3-6 Cycloalkyl, 3-6 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 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-forming atoms, and the C 1-6 Alkyl, C 3-6Cycloalkyl, 3-6 membered heterocycloalkyl, C 6-10 The aryl, 5- or 6-membered monocyclic heteroaryl, 8- to 10-membered bicyclic heteroaryl, 7- to 11-membered spirocycloalkyl, and pyridone groups are unsubstituted or substituted with 1, 2, 3, or 4 groups independently selected from Rs3, and the -C 1-3 Alkyl- is unsubstituted or independently C 1-3 substituted with 1, 2, 3 or 4 groups selected from alkyl; Alternatively, R0' is a structure represented by formula (A-1) or formula (A-2),

[0028] [ka]

[0029] In formula (A-1) or formula (A-2), ring A1 is a benzene ring or a 5- or 6-membered monocyclic heteroaryl ring, ring A2 is a fused 5- or 6-membered monocyclic heterocycloalkyl ring or a fused 5- or 6-membered monocyclic cycloalkyl ring, and 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-forming atoms; (R s3 ) t The hydrogen atoms of the A1 ring are R s3 where t is 0, 1, 2, or 3, and each R s3 may be the same or different, (R s4 ) s The hydrogen atoms of the A2 ring are s R s 4 where s is 0, 1, 2, or 3, and each R s4 may be the same or different, R s3 , R s4 are each independently halogen, cyano, hydroxy, -C 1-6 Alkyl, -C 1-6 Alkoxy, -halogenated C 1-6 Alkyl, -halogenated C1-6 Alkoxy, -C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, -NR h R i , -C(O)NR e R f , -SO2C 1-3 Alkyl, -SO2 halogenated C 1-3 Alkyl, -SO2NR e R f , -C 1-3 Alkyl-hydroxy, -C 1-3 Alkyl-C 2-4 Alkynyl, -C 1-3 Alkyl-cyano, -C 1-3 Alkyl-C 1-6 Alkoxy, -C 1-3 Alkyl-halogenated C 1-6 Alkyl, -C 1-3 Alkyl-halogenated C 1-6 Alkoxy, -C 1-3 Alkyl-3 to 6-membered heterocycloalkyl, -C 1-3 Alkyl-C 3-6 Cycloalkyl, -C 1-3 Alkyl-NR e R f , -C 1-3 Alkyl-C(O)NR e R f , -C 1-3 Alkyl-SO2C 1-3 Alkyl or C 2-4 alkynyl, wherein the 3- to 6-membered heterocycloalkyl group has 1, 2 or 3 heteroatoms selected from N, O and S as ring-forming atoms, and the C 1-6 Alkyl group, -C 1-6 Alkoxy group, -C 1-3 Alkyl-, -C 3-6 The cycloalkyl and 3- to 6-membered heterocycloalkyl may be optionally substituted with 1, 2, or 3 substituents independently selected from halogen, methyl, ethyl, propyl (n-propyl), isopropyl, trifluoromethyl, amino, N(CH3)2, hydroxy, and carboxyl; R a , R b , R e , Rf , R g are each independently hydrogen or C 1-3 is an alkyl group, and R c , R d , R h , R i are each independently hydrogen, -C 1-3 Alkyl, -C(O)C 1-3 Alkyl or -CO2C 1-3 It is alkyl.

[0030] In one embodiment of the present invention, the compound of formula (IA) is a compound of formula (IB) or a compound of formula (IC).

[0031] [ka]

[0032] (In formula (IB), P' is O, NH or NR m '. R m '-deuterated C 1-6 Alkyl, -C 1-6 Alkyl, -halogenated C 1-6 Alkyl, -C 1-6 Alkyl-hydroxy, -C 1-6 Alkyl-cyano, -C 1-6 Alkyl-C 1-6 Alkoxy, -C 1-6 Alkyl-halogenated C 1-6 Alkoxy, -C 1-6 Alkyl-C 3-6 Cycloalkyl or -C 1-6 alkyl-3- to 6-membered heterocycloalkyl, and 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)-, -C1-3 Alkyl (C 1-6 Alkyl-hydroxy)-, -C 1-3 Alkyl (C 1-6 Alkyl-cyano)-, -C 1-3 Alkyl (C 1-6 Alkoxy)- or -C 1-3 Alkyl (halogenated C 1-6 alkoxy)-, and 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 above.) (In formula (IC), P' is hydrogen or halogen, and R 42 ' is hydrogen, halogen, -C 1-3 Alkyl, -halogenated C 1-3 Alkyl, -C 1-3 Alkyl-hydroxy, -C 1-3 Alkyl-cyano, -C 1-3 Alkyl-C 1-6 Alkoxy, -C 1-3 Alkyl-halogenated C 1-6 Alkyl or -C 1-3 Alkyl-halogenated C 1-6 is alkoxy, and 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 above.)

[0033] In one embodiment of the present invention, in formula (IB), P' is O, NH or NR m '. R m '-deuterated C 1-6 Alkyl or -C 1-6 It is alkyl. R 42 '-C 1-3 Alkyl-(C=O)-, -(C=O)- or -C 1-3 It is alkyl.

[0034] In one embodiment of the present invention, in formula IB, P' is O, NH or NR m ' and R m '-deuterated C 1-3 Alkyl or -C 1-3 alkyl, and R 42 '-C 1-3 Alkyl-(C=O)-, -(C=O)- or -C 1-3 It is alkyl.

[0035] In one embodiment of the present invention, in formula IB, P' is O, NH or NR m ' and 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-.

[0036] In one embodiment of the present invention, in formula IB, P' is NH or NR m ' and R m '-deuterated C 1-6 Alkyl or -C 1-6 alkyl, and R 42 '-C 1-3 Alkyl-(C=O)- or -(C=O)-R m ' is.

[0037] In one embodiment of the present invention, in formula IB, P' is NH or NR m ' and R m '-deuterated C 1-3 Alkyl or -C 1-3 alkyl, and R 42 '-C 1-3 It is alkyl-(C=O)- or -(C=O)-.

[0038] In one embodiment of the present invention, in formula IB, P' is NH or NRm '. R m ' is a deuterated methyl or methyl, and R 42 ' is -CH2-(C=O)-, -CH2CH2-(C=O)- or -(C=O)-.

[0039] In one embodiment of the present invention, in formula IB, P' is O and R 42 '-C 1-3 It is alkyl.

[0040] In one embodiment of the present invention, in formula IB, P' is O and R 42 ' is -CH2-.

[0041] According to one embodiment of the present invention, the compound represented by (IB) is a compound represented by formula (IB-1) or a compound represented by formula (IB-2).

[0042] [ka]

[0043] (In formula (IB-1) and formula (IB-2), R 21 , R 22 , R 11 , R 12 , R 31 , R 32 , R 41 , R 42 The definitions of ', Z, P', R0', Ar', E1', E2', X1, and Y1 are the same as above.)

[0044] In one embodiment of the present invention, in formula IB-1, P' is O, NH or NR m ' and R m '-deuterated C 1-6 Alkyl or -C 1-6 alkyl, and R 42 '-C 1-3 Alkyl-(C=O)-, -(C=O)- or -C 1-3 It is alkyl-.

[0045] In one embodiment of the present invention, in formula IB-1, P' is NH or NR m ' and R m '-deuterated C 1-6 Alkyl or -C 1-6 alkyl, and R 42 '-C 1-3 It is alkyl-(C=O)- or -(C=O)-.

[0046] In one embodiment of the present invention, in formula IB-1, P' is NH or NR m ' and R m '-deuterated C 1-3 Alkyl or -C 1-3 alkyl, and R 42 '-C 1-3 It is alkyl-(C=O)- or -(C=O)-.

[0047] In one embodiment of the present invention, in formula IB-1, P' is NH or NR m ' and R m ' is a deuterated methyl or methyl, and R 42 ' is -CH2-(C=O)-, -CH2CH2-(C=O)- or -(C=O)-.

[0048] In one embodiment of the present invention, in formula IB-1, P' is O and R 42 '-C 1-3 It is alkyl.

[0049] In one embodiment of the present invention, in formula IB-1, P' is O and R 42 ' is -CH2-.

[0050] In another aspect, the present invention provides a compound represented by formula (IB-1a) or formula (IB-2a), or a tautomer, cis-trans isomer, mesomers, racemates, enantiomers, diastereomers, atropisomers, or mixtures thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0051] [ka]

[0052] (In formula (IB-1a) or formula (IB-2a), R1, R2, R3, R 21 , R 22 , R 12 , R 11 , R 31 , R 32 The definitions of P', R0', Ar', E1', and X1 are the same as above.)

[0053] In one embodiment of the present invention, in formula IB-1a, P' is NH or NR m ' and R m '-deuterated C 1-6 Alkyl or -C 1-6 It is alkyl.

[0054] In one embodiment of the present invention, in formula IB-1a, P' is NH or NR m ' and R m '-deuterated C 1-3 Alkyl or -C 1-3 It is alkyl.

[0055] In one embodiment of the present invention, in formula IB-1a, P' is NH or NR m ' and R m ' is a deuterated methyl or methyl.

[0056] According to one embodiment of the present invention, 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).

[0057] [ka]

[0058] (In formula (IB-1aa) and formula (IB-1ab), R21 ' are independently halogen, -C 1-3 Alkyl, -halogenated C 1-3 Alkyl, -C 1-3 Alkyl-hydroxy, -C 1-3 Alkyl-cyano, -C 1-3 Alkyl-C 1-6 Alkoxy, -C 1-3 Alkyl-halogenated C 1-6 Alkyl or -C 1-3 Alkyl-halogenated C 1-6 Alkoxy, and R1, R2, R3, R 12 , R 11 , R 31 , R 32 , P', R0', Ar', E1', and X1 are defined as above. In formula (IB-1ac) and formula (IB-1ad), R 12 ' are independently halogen, -C 1-3 Alkyl, -halogenated C 1-3 Alkyl, -C 1-3 Alkyl-hydroxy, -C 1-3 Alkyl-cyano, -C 1-3 Alkyl-C 1-6 Alkoxy, -C 1-3 Alkyl-halogenated C 1-6 Alkyl or -C 1-3 Alkyl-halogenated C 1-6 Alkoxy, and R1, R2, R3, R 21 , R 22 , R 31 , R 32 The definitions of P', R0', Ar', E1', and X1 are the same as above.)

[0059] In another aspect, the present invention provides a compound represented by formula (IB-1c) or formula (IB-2c), or a tautomer, cis-trans isomer, mesomers, racemates, enantiomers, diastereomers, atropisomers, or mixtures thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0060] [ka]

[0061] (In formula (IB-1c) or formula (IB-2c), R1, R2, R3, R 21 , R 22 , R 12 , R 11 , R 31 , R 32 The definitions of P', R0', Ar', E1', and X1 are the same as above.)

[0062] In one embodiment of the present invention, in formula IB-1c, P' is NH or NR m ' and R m '-deuterated C 1-6 Alkyl or -C 1-6 It is alkyl.

[0063] In one embodiment of the present invention, in formula IB-1c, P' is NH or NR m ' and R m '-deuterated C 1-3 Alkyl or -C 1-3 It is alkyl.

[0064] In one embodiment of the present invention, in formula IB-1c, P' is NH or NR m ' and R m ' is a deuterated methyl or methyl.

[0065] According to one embodiment of the present invention, the compound represented by formula (IB-1c) is a compound represented by formula (IB-1ca), a compound represented by formula (IB-1cb), a compound represented by formula (IB-1cc), or a compound represented by formula (IB-1cd).

[0066] [ka]

[0067] (In formula (IB-1ca) and formula (IB-1cb), R 21 ' are independently halogen, -C 1-3 Alkyl, -halogenated C1-3 Alkyl, -C 1-3 Alkyl-hydroxy, -C 1-3 Alkyl-cyano, -C 1-3 Alkyl-C 1-6 Alkoxy, -C 1-3 Alkyl-halogenated C 1-6 Alkyl or -C 1-3 Alkyl-halogenated C 1-6 Alkoxy, and R1, R2, R3, R 12 , R 11 , R 31 , R 32 , P', R0', Ar', E1', and X1 are defined as above. In formula (IB-1cc) and formula (IB-1cd), R 12 ' are independently halogen, -C 1-3 Alkyl, -halogenated C 1-3 Alkyl, -C 1-3 Alkyl-hydroxy, -C 1-3 Alkyl-cyano, -C 1-3 Alkyl-C 1-6 Alkoxy, -C 1-3 Alkyl-halogenated C 1-6 Alkyl or -C 1-3 Alkyl-halogenated C 1-6 Alkoxy, and R1, R2, R3, R 21 , R 22 , R 31 , R 32 The definitions of P', R0', Ar', E1', and X1 are the same as above.)

[0068] 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 ' and R m '-deuterated C 1-6 Alkyl or -C 1-6 It is alkyl.

[0069] 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 ' and R m'-deuterated C 1-3 Alkyl or -C 1-3 It is alkyl.

[0070] 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 ' and R m ' is deuterated methyl, deuterated ethyl, deuterated n-propyl, deuterated isopropyl, methyl, ethyl, n-propyl or isopropyl.

[0071] In another aspect, the present invention provides a compound represented by formula (IB-1b) or formula (IB-2b), or a tautomer, cis-trans isomer, mesomers, racemates, enantiomers, diastereomers, atropisomers, or mixtures thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0072] [ka]

[0073] (In formula (IB-1b) or formula (IB-2b), R1, R2, R3, R 21 , R 22 , R 12 , R 11 , R 31 , R 32 , P', R0', Ar', E1', X1 are defined as (The same as above.)

[0074] According to one embodiment of the present invention, 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).

[0075] [ka]

[0076] (In formula (IB-1ba) and formula (IB-1bb), R 21 ' are independently halogen, -C 1-3 Alkyl, -halogenated C 1-3 Alkyl, -C 1-3 Alkyl-hydroxy, -C 1-3 Alkyl-cyano, -C 1-3 Alkyl-C 1-6 Alkoxy, -C 1-3 Alkyl-halogenated C 1-6 Alkyl or -C 1-3 Alkyl-halogenated C 1-6 Alkoxy, and R1, R2, R3, R 12 , R 11 , R 31 , R 32 , P', R0', Ar', E1', and X1 are defined as above. In formula (IB-1bc) and formula (IB-1bd), R 12 ' are independently halogen, -C 1-3 Alkyl, -halogenated C 1-3 Alkyl, -C 1-3 Alkyl-hydroxy, -C 1-3 Alkyl-cyano, -C 1-3 Alkyl-C 1-6 Alkoxy, -C 1-3 Alkyl-halogenated C 1-6 Alkyl or -C 1-3 Alkyl-halogenated C 1-6 Alkoxy, and R1, R2, R3, R 21 , R 22 , R 31 , R 32 The definitions of P', R0', Ar', E1', and X1 are the same as above.)

[0077] In another aspect, the present invention provides a compound represented by formula (IB-1d) or formula (IB-2d), or a tautomer, cis-trans isomer, mesomers, racemates, enantiomers, diastereomers, atropisomers, or mixtures thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0078] [ka]

[0079] (In formula (IB-1d) or formula (IB-2d), R1, R2, R3, R 21 , R 22 , R 12 , R 11 , R 31 , R 32 The definitions of P', R0', Ar', E1', and X1 are the same as above.)

[0080] According to one embodiment of the present invention, 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).

[0081] [ka]

[0082] (In formula (IB-1da) and formula (IB-1db), R 21 ' are independently halogen, -C 1-3 Alkyl, -halogenated C 1-3 Alkyl, -C 1-3 Alkyl-hydroxy, -C 1-3 Alkyl-cyano, -C 1-3 Alkyl-C 1-6 Alkoxy, -C 1-3 Alkyl-halogenated C 1-6 Alkyl or -C 1-3 Alkyl-halogenated C 1-6 Alkoxy, and R1, R2, R3, R 12 , R 11 , R 31 , R 32 , P', R0', Ar', E1', and X1 are defined as above. In formula (IB-1dc) and formula (IB-1dd), R 12 ' are independently halogen, -C 1-3 Alkyl, -halogenated C1-3 Alkyl, -C 1-3 Alkyl-hydroxy, -C 1-3 Alkyl-cyano, -C 1-3 Alkyl-C 1-6 Alkoxy, -C 1-3 Alkyl-halogenated C 1-6 Alkyl or -C 1-3 Alkyl-halogenated C 1-6 Alkoxy, and R1, R2, R3, R 21 , R 22 , R 31 , R 32 The definitions of P', R0', Ar', E1', and X1 are the same as above.)

[0083] According to one embodiment of the present invention, in formula IB-1b, IB-1d, IB-2b, and IB-2d, P' is independently O.

[0084] In one embodiment of the present invention, R 21 ', R 12 ' are each independently -C 1-3 Alkyl, -C 1-3 Alkyl-hydroxy, -C 1-3 Alkyl-cyano or -C 1-3 Alkyl-C 1-6 It is an alkoxy.

[0085] 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 It is an alkoxy.

[0086] In one embodiment of the present invention, R 21 ', R 12 Each ' is independently methyl, ethyl, n-propyl or isopropyl.

[0087] In one embodiment of the present invention, X is hydrogen, halogen, optionally substituted C 1-6 Alkyl, optionally -substituted C 3-6cycloalkyl, or -O- optionally substituted C 1-6 The term "substituted" refers to 1, 2, 3, or 4 hydrogen atoms in the group being each independently replaced with a substituent selected from the S group.

[0088] 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 It is alkyl.

[0089] According to 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.

[0090] In one embodiment of the present invention, X1 is fluorine, chlorine or cyclopropyl.

[0091] In one embodiment of the present invention, Y1 is C, E1' is N or CR5', and E2' is CR6'. The definitions of R5' and R6' are the same as above.

[0092] In one embodiment of the present invention, Y1 is C, E1' is CR5', and E2' is N. R5 is as defined above.

[0093] In one embodiment of the present invention, Y1 is C, E1' is N or CR5', and E2' is CH. R5' is as defined above.

[0094] In one embodiment of the present invention, Y1 is C, E1' is N or CF, and E2' is CH.

[0095] In one embodiment of the present invention, Ar' is a phenyl, 5- or 6-membered monocyclic heteroaryl, or pyridone group, and the phenyl, 5- or 6-membered monocyclic heteroaryl, and pyridone groups are unsubstituted or independently selected from halogen, cyano, hydroxy, -C 1-6 Alkyl, -C 1-6 Alkoxy, -NR c R d , -C 1-4 Alkyl-NR e R f The R e , R f are each independently hydrogen or C 1-3 It is alkyl. R c , R d are each independently hydrogen, -C 1-3 Alkyl, -C(O)C 1-3 Alkyl or -CO2C 1-3 It is alkyl.

[0096] According to one embodiment of the present invention, Ar' is a phenyl or pyridone group, and the phenyl and pyridone groups are unsubstituted or independently selected from fluorine, chlorine, bromine, cyano, hydroxy, -C 1-3 Alkyl, -C 1-3 It is substituted with 1, 2, 3 or 4 groups selected from alkoxy, -NH2, -NHCH3, -N(CH3)2, -CH2-NH2, -CH2-NHCH3, -CH2-N(CH3)2.

[0097] In one embodiment of the present invention, Ar' is phenyl. The phenyl is R s1 R is substituted with one group selected from s1 is halogen, cyano, -C 1-6 Alkyl, -C 1-6 Alkoxy, -halogenated C 1-6 Alkyl, -halogenated C 1-6 Alkoxy or -C 3-6 It is cycloalkyl.

[0098] In one embodiment of the present invention, Ar' is selected from the following structures:

[0099] [ka]

[0100] (In the formula, R s1 , R s2 The definitions are the same as above.)

[0101] In one embodiment of the present invention, Ar' is selected from the following structures:

[0102] [ka]

[0103] (In the formula, R s1 is hydroxy and R s2 is 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, R s1 is above the plane of the benzene ring.

[0104] In one embodiment of the present invention, Ar' is selected from the following structures:

[0105] [ka]

[0106] (In the formula, R s1 -C 1-6 Alkoxy. R s2 is halogen, cyano, -C 1-6 Alkyl, -C 1-6 Alkoxy, -halogenated C 1-6Alkyl, -halogenated C 1-6 Alkoxy or -C 3-6 In one embodiment of the present invention, R s1 is above the plane of the benzene ring.

[0107] According to one embodiment of the present invention, R is a phenyl, a 5- or 6-membered monocyclic heteroaryl, or a pyridone group. The 5- or 6-membered monocyclic heteroaryl has 1, 2, or 3 heteroatoms selected from N, O, and S as ring-forming atoms. The phenyl, 5- or 6-membered monocyclic heteroaryl, and pyridone group may be unsubstituted or independently R s3 is substituted with 1, 2, 3 or 4 groups selected from

[0108] In one embodiment of the present invention, R is a phenyl, thiazolyl, isothiazolyl, imidazolyl, oxazolyl, isoxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, or pyridone group, and the phenyl, thiazolyl, isothiazolyl, imidazolyl, oxazolyl, isoxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, and pyridone groups are unsubstituted or independently R s3 and substituted with 1, 2, 3 or 4 groups selected from:

[0109] In one embodiment of the present invention, R0' is selected from the following structures:

[0110] [ka]

[0111] In each of the above structures, R s3 ' may be the same or different and each independently represents hydrogen, halogen, cyano, hydroxy, -C 1-6 Alkyl, -C 1-6 Alkoxy, -halogenated C 1-6 Alkyl, -halogenated C 1-6 Alkoxy, -C 3-6Cycloalkyl, -NR h R i , -C(O)NR e R f , -C 1-3 Alkyl-hydroxy and -C 1-3 Alkyl-NR e R f In addition, the -C 3-6 The cycloalkyl is substituted with one, two, or three substituents independently selected from halogen, methyl, ethyl, propyl (n-propyl), isopropyl, trifluoromethyl, amino, N(CH3)2, hydroxy, and carboxyl. e , R f are each independently hydrogen or C 1-3 It is alkyl. R h , R i are each independently hydrogen, -C 1-3 Alkyl, -C(O)C 1-3 Alkyl or -CO2C 1-3 It is alkyl. In each of the above structures, R s3 '' may be the same or different and each independently represents hydrogen, halogen, cyano, hydroxy, -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 wherein -C 3-6 The cycloalkyl is optionally substituted with one, two, or three substituents independently selected from halogen, methyl, ethyl, propyl (n-propyl), isopropyl, trifluoromethyl, amino, N(CH3)2, hydroxy, and carboxyl. e , R f are each independently hydrogen or C1-3 It is alkyl. R h , R i are each independently hydrogen, -C 1-3 Alkyl, -C(O)C 1-3 Alkyl or -CO2C 1-3 It is alkyl. In each of the above structures, R s3 "" may be the same or different and each independently represents hydrogen, -C 1-6 Alkyl, -halogenated C 1-6 Alkyl, -C 3-6 Cycloalkyl, -C 1-3 Alkyl-C(O)NR e R f , -C(O)NR e R f , -C 1-4 Alkyl-hydroxy and -C 1-4 Alkyl-NR e R f and wherein -C 3-6 The cycloalkyl is optionally substituted with one, two, or three substituents independently selected from halogen, methyl, ethyl, propyl (n-propyl), isopropyl, trifluoromethyl, amino, N(CH3)2, hydroxy, and carboxyl. e , R f are each independently hydrogen or C 1-3 It is alkyl. In each of the above structures, R s3 may be the same or different, and each independently represents halogen, cyano, hydroxy, -C 1-6 Alkyl, -C 1-6 Alkoxy, -halogenated C 1-6 Alkyl, -halogenated C 1-6 Alkoxy, -C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, -NR h R i , -C(O)NR e R f , -SO2C 1-3 Alkyl, -SO2 halogenated C 1-3 Alkyl, -SO2NR e Rf , -C 1-3 Alkyl-hydroxy, -C 1-3 Alkyl-C 2-4 Alkynyl, -C 1-3 Alkyl-cyano, -C 1-3 Alkyl-C 1-6 Alkoxy, -C 1-3 Alkyl-halogenated C 1-6 Alkyl, -C 1-3 Alkyl-halogenated 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 The 3- to 6-membered heterocycloalkyl has 1, 2 or 3 heteroatoms selected from N, O and S as ring-forming atoms, and the C 1-6 Alkyl, -C 1-6 Alkoxy, -C 1-3 Alkyl-, -C 3-6 The cycloalkyl and 3- to 6-membered heterocycloalkyl may be optionally substituted with 1, 2, or 3 substituents independently selected from halogen, methyl, ethyl, propyl (n-propyl), isopropyl, trifluoromethyl, amino, N(CH3)2, hydroxy, and carboxyl. h , R i are each independently hydrogen, -C 1-3 Alkyl, -C(O)C 1-3 Alkyl or -CO2C 1-3 It is alkyl. R e , R f are each independently hydrogen or C 1-3 It is an alkyl group. In each of the above structures, n may be the same or different and each independently represents 0, 1, 2, or 3.

[0112] In one embodiment of the present invention, R0' has the following structure:

[0113] [ka]

[0114] (In the formula, R s3 ' is hydrogen, halogen, cyano, hydroxy, -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 the -C 3-6 The cycloalkyl may be optionally substituted with one, two, or three substituents independently selected from halogen, methyl, ethyl, propyl (n-propyl), isopropyl, trifluoromethyl, amino, N(CH), hydroxy, and carboxyl. e , R f are each independently hydrogen or C 1-3 It is alkyl. R h , R i are each independently hydrogen, -C 1-3 Alkyl, -C(O)C 1-3 Alkyl or -CO2C 1-3 It is alkyl. R s3 " is isopropyl. n is 0. In one embodiment, R s3 '' is below the plane of the benzene ring.

[0115] In one embodiment of the present invention, R0' is selected from the following structures:

[0116] [ka]

[0117] (In the formula, R s3 ' is hydrogen, halogen, cyano, hydroxy, -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 In addition, the -C 3-6 The cycloalkyl may be optionally substituted with one, two, or three substituents independently selected from halogen, methyl, ethyl, propyl (n-propyl), isopropyl, trifluoromethyl, amino, N(CH), hydroxy, and carboxyl. e , R f are each independently hydrogen or C 1-3 It is alkyl. R h , R i are each independently hydrogen, -C 1-3 Alkyl, -C(O)C 1-3 Alkyl or -CO2C 1-3 It is alkyl. R s3 '' is isopropyl. s3 -C 1-6 n is 0 or 1. In one embodiment, R s3 '' is below the plane of the pyridine ring.

[0118] In one embodiment of the present invention, R0' is selected from the following structures:

[0119] [ka]

[0120] (In the formula, R s3 ' is hydrogen, halogen, cyano, hydroxy, -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 the -C 3-6 The cycloalkyl may be optionally substituted with one, two, or three substituents independently selected from halogen, methyl, ethyl, propyl (n-propyl), isopropyl, trifluoromethyl, amino, N(CH), hydroxy, and carboxyl. e , R f are each independently hydrogen or C 1-3 It is alkyl. R h , R i are each independently hydrogen, -C 1-3 Alkyl, -C(O)C 1-3 Alkyl or -CO2C 1-3 It is alkyl. R s3 " is isopropyl. n is 0. In one embodiment, R s3 '' is below the plane of the pyrimidine ring.

[0121] In one embodiment of the present invention, R0' is selected from the following structures:

[0122] [ka]

[0123] (In the formula, R s3 ' is hydrogen, halogen, cyano, hydroxy, -C1-6 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 In addition, the -C 3-6 The cycloalkyl may be optionally substituted with one, two, or three substituents independently selected from halogen, methyl, ethyl, propyl (n-propyl), isopropyl, trifluoromethyl, amino, N(CH), hydroxy, and carboxyl. e , R f are each independently hydrogen or C 1-3 It is alkyl. R h , R i are each independently hydrogen, -C 1-3 Alkyl, -C(O)C 1-3 Alkyl or -CO2C 1-3 It is alkyl. R s3 "'' is isopropyl. n is 0. In one embodiment, R s3 ''' is below the plane of the pyrazole ring.

[0124] In one embodiment of the present invention, R0' is selected from the following structures:

[0125] [ka]

[0126] (In the formula, R s3 In one embodiment, R s3 ' is below the plane of the pyrazine ring.

[0127] In one embodiment of the present invention, R0' is selected from the following structures:

[0128] [ka]

[0129] (In the formula, R s3 ' is hydrogen, halogen, cyano, hydroxy, -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 In addition, the -C 3-6 Cycloalkyl may be optionally substituted with one, two, or three substituents independently selected from halogen, methyl, ethyl, propyl (n-propyl), isopropyl, trifluoromethyl, amino, N(CH3)2, hydroxy, and carboxyl, where R e , R f are each independently hydrogen or C 1-3 It is alkyl. R h , R i are each independently hydrogen, -C 1-3 Alkyl, -C(O)C 1-3 Alkyl or -CO2C 1-3 It is alkyl. R s3 '' is isopropyl. s3 ''' means -C 1-6 In one embodiment, the R s 3 '' is below the plane of the pyrazole ring.

[0130] This is called one embodiment of the present invention and is selected from the structures below R0'.

[0131] [ka]

[0132] [ka]

[0133] [ka]

[0134] [ka]

[0135] In another aspect, the present invention provides a compound represented by formula (II), or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof:

[0136] [ka]

[0137] (wherein Z is NC(O)-CR═CR═R or NC(O)-C≡CR═ R1 and R2 are each independently hydrogen, halogen, cyano, or NR a R b , -C 1-3 Alkyl, halogenated C 1-3 Alkyl, -C 1-3 Alkyl-hydroxy, -C 1-3 Alkyl-cyano, -C 1-3 Alkyl-C 1-3 Alkoxy, -C 1-3 Alkyl-NR a R b , -C 1-3 alkyl-3 to 6-membered heterocycloalkyl or -C 1-3Alkyl-5- or 6-membered monocyclic heteroaryl. 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-forming atoms. R3 is hydrogen, halogen, -C 1-3 Alkyl or -C 1-3 It is an alkoxy. R4 is hydrogen, halogenated C 1-3 Alkyl, -C 1-3 Alkyl-hydroxy, -C 1-3 Alkyl-cyano or -C 1-3 Alkyl-C 1-3 It is an alkoxy. R 11 , R 12 may be the same or different, and each independently represents hydrogen, halogen, or -C 1-3 Alkyl, -halogenated C 1-3 Alkyl, -C 1-3 Alkyl-hydroxy, -C 1-3 Alkyl-cyano, -C 1-3 Alkyl-C 1-6 Alkoxy, -C 1-3 Alkyl-halogenated C 1-6 Alkyl or -C 1-3 Alkyl-halogenated C 1-6 It is an alkoxy. R 21 , R 22 may be the same or different, and each independently represents hydrogen, halogen, or -C 1-3 Alkyl, -halogenated C 1-3 Alkyl, -C 1-3 Alkyl-hydroxy, -C 1-3 Alkyl-cyano, -C 1-3 Alkyl-C 1-6 Alkoxy, -C 1-3 Alkyl-halogenated C 1-6 Alkyl or -C 1-3 Alkyl-halogenated C 1-6 It is an alkoxy. R 31 , R 32may be the same or different, and each independently represents hydrogen, halogen, or -C 1-3 Alkyl, -halogenated C 1-3 Alkyl, -C 1-3 Alkyl-hydroxy, -C 1-3 Alkyl-cyano, -C 1-3 Alkyl-C 1-6 Alkoxy, -C 1-3 Alkyl-halogenated C 1-6 Alkyl or -C 1-3 Alkyl-halogenated C 1-6 It is an alkoxy. R 41 is hydrogen, halogen, -C 1-3 Alkyl, -halogenated C 1-3 Alkyl, -C 1-3 Alkyl-hydroxy, -C 1-3 Alkyl-cyano, -C 1-3 Alkyl-C 1-6 Alkoxy, -C 1-3 Alkyl-halogenated C 1-6 Alkyl or -C 1-3 Alkyl-halogenated C 1-6 It is an alkoxy. P is O, NH, or NR m R m -C 1-6 Alkyl, -halogenated C 1-6 Alkyl, -C 1-6 Alkyl-hydroxy, -C 1-6 Alkyl-cyano, -C 1-6 Alkyl-C 1-6 Alkoxy, -C 1-6 Alkyl-halogenated C 1-6 Alkoxy, -C 1-6 Alkyl-C 3-6 Cycloalkyl or -C 1-6 alkyl-3 to 6 membered heterocycloalkyl; R 42 is -(C=O)-, -C 1-3 Alkyl-, -C 1-3 Alkyl(hydroxy)-, -C 1-3 Alkyl(cyano)-, -C 1-3 Alkyl (C 1-6alkyl)-, -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)-. X2 and Y2 may be the same or different, and each independently represents hydrogen, halogen, -C 1-3 Alkyl, -halogenated C 1-3 Alkyl, -C 1-3 Alkyl-hydroxy, -C 1-3 Alkyl-cyano, -C 1-3 Alkyl-C 1-6 Alkoxy, -C 1-3 Alkyl-halogenated C 1-6 Alkyl or -C 1-3 Alkyl-halogenated C 1-6 It is an alkoxy. Alternatively, X and Y may be C, which may be substituted together with the adjacent carbon atoms. 3-6 The cycloalkyl or the optionally substituted 3- to 6-membered heterocycloalkyl has 1, 2, or 3 heteroatoms selected from N, O, and S as ring-forming atoms. The "substituted" refers to 1, 2, 3, or 4 hydrogen atoms in the group being each independently substituted with a substituent selected from the S group. E3 is N or CL-R5. The L is a single bond, -CR L1 R L2 -, -O-(CR L1 R L2 ) t1 - or -NH-(CR L3 R L4 ) t2 -R L1 , R L2 , R L3 , R L4may be the same or different, and each independently represents hydrogen, halogen, hydroxy, hydroxymethyl, hydroxyethyl, -C 1-3 alkyl or oxo. t1 and t2 are each independently 0, 1, 2, 3, or 4. R L1 and R L2 In or R L3 and R L4 In the above formula, when one of them is oxo, the other one is absent. R5 is hydrogen, halogen, hydroxy, optionally substituted C 1-6 Alkyl, optionally -substituted C 3-6 Cycloalkyl, -optionally substituted 3-6 membered heterocycloalkyl, -O-optionally substituted C 1-6 Alkyl, -O- optionally substituted C 3-6 Cycloalkyl, -O-optionally substituted 3-6 membered heterocycloalkyl, -SO2-optionally substituted C 1-6 Alkyl, -SO2- optionally substituted C 3-6 Cycloalkyl, -SO2- optionally substituted 3- to 6-membered heterocycloalkyl, - optionally substituted 5- or 6-membered monocyclic heteroaryl or NR 51 R 52 The above R 51 , R 52 are each independently hydrogen, optionally substituted 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 52form an optionally substituted 3- to 6-membered nitrogen-containing heterocycloalkyl group together with the nitrogen atom to which it is connected. The 3- to 6-membered heterocycloalkyl and 5- or 6-membered monocyclic heteroaryl each have 1, 2, or 3 heteroatoms independently selected from N, O, and S as ring-forming atoms. The 3- to 6-membered nitrogen-containing heterocycloalkyl has 3 to 6 ring-forming atoms, one of which may be a nitrogen atom, and none, one, or two of the remaining ring-forming atoms may be heteroatoms selected from N, O, and S. The "substituted" refers to 1, 2, 3, or 4 hydrogen atoms in the group being independently substituted with substituents independently selected from the S group. The S group substituents include hydroxy, 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 Rb0 , -(CH2) u -C(O)C 1-6 Alkyl, -C(O)OC 1-6 Alkyl, NR a0 C(O)-(CH2) u -NR a0 R b0 , N.R. a0 C(O)-(CH2) u OH and NR a0 C(O)-halogenated C 1-6 The 3- to 6-membered heterocycloalkyl or the 5- or 6-membered monocyclic heteroaryl has 1, 2, or 3 heteroatoms independently selected from N, O, and S as ring-forming atoms. The 3- to 6-membered heterocycloalkyl or the 5- or 6-membered monocyclic heteroaryl may be substituted with 1, 2, or 3 substituents selected from halogen, cyano, -C1-3 alkyl, -C1-3 alkoxy, and C3-6 cycloalkyl. u and v are independently 0, 1, 2, 3, or 4. R a0 , R b0 are each independently hydrogen or C 1-3 It is alkyl. E4 is N or CH. Ar is C 6-10 The C is an aryl, a 5- or 6-membered monocyclic heteroaryl, or an 8- to 10-membered bicyclic heteroaryl. The 5- or 6-membered monocyclic heteroaryl has 1, 2, or 3 heteroatoms selected from N, O, and S as ring-forming atoms. The 8- to 10-membered bicyclic heteroaryl has 1, 2, 3, 4, or 5 heteroatoms selected from N, O, and S as ring-forming atoms. 6-10 The aryl, the 5- or 6-membered monocyclic heteroaryl, or the 8- to 10-membered bicyclic heteroaryl is unsubstituted or independently R s1 is substituted with 1, 2, 3 or 4 groups selected from Alternatively, Ar is a structure represented by formula (B).

[0138] [ka]

[0139] In formula (B), ring B1 is a benzene ring or a 5- or 6-membered monocyclic heteroaryl ring. Ring B2 is a fused 5- or 6-membered monocyclic heterocycloalkyl ring or a fused 5- or 6-membered monocyclic cycloalkyl ring, wherein the 5- or 6-membered monocyclic heteroaryl ring or the fused 5- or 6-membered monocyclic heterocycloalkyl ring has 1, 2, or 3 heteroatoms selected from N, O, and S as ring-forming atoms. (R s1 ) p The hydrogen atoms of the B1 ring are p R s1 where p is 0, 1, 2, or 3, and each R s1 may be the same or different. (R s2 ) q The hydrogen atoms of the B2 ring are q R s2 q is 0, 1, 2, or 3; and each R s2 may be the same or different. R s1 , R s2 are each independently halogen, cyano, nitro, hydroxy, -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 halogenated C 1-3 Alkyl, -SO2NR e R f , -C 1-4 Alkyl-hydroxy, -C 1-4 Alkyl-cyano, -C 1-4 Alkyl-C 1-6 Alkoxy, -C 1-4 Alkyl-halogenated C 1-6 Alkyl, -C 1-4 Alkyl-halogenated C1-6 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 The 3- to 6-membered heterocycloalkyl has 1, 2 or 3 heteroatoms selected from N, O and S as ring-forming atoms. R a , R b , R e , R f are each independently hydrogen or C 1-3 It is an alkyl group. R c , R d are each independently hydrogen, -C 1-3 Alkyl, -C(O)C 1-3 Alkyl or -CO2C 1-3 It is alkyl.

[0140] In one embodiment of the present invention, R s1 , R s2 are each independently halogen, cyano, nitro, hydroxy, -C 1-3 Alkyl, -C 1-3 Alkoxy, halogenated C 1-3 Alkyl, halogenated C 1-3 Alkoxy, -C 3-6 Cycloalkyl, -NR c R d , -C(O)NR e R f , -SO2C 1-3 Alkyl, -SO2 halogenated C 1-3 Alkyl, -SO2NR e R f , -C 1-2 Alkyl-hydroxy, -C 1-2 Alkyl-cyano, -C 1-2 Alkyl-C 1-3 Alkoxy, -C 1-2Alkyl-halogenated C 1-3 Alkyl, -C 1-2 Alkyl-halogenated C 1-3 Alkoxy, -C 1-2 alkyl-3-6 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. c , R d are each independently hydrogen, -C 1-3 Alkyl, -C(O)C 1-3 Alkyl or -CO2C 1-3 It is alkyl. R e , R f are each independently hydrogen or C 1-3 It is alkyl.

[0141] In one embodiment of the present invention, R s1 , R s2 are each independently halogen, cyano, nitro, hydroxy, -C 1-3 Alkyl, -C 1-3 Alkoxy, halogenated C 1-3 Alkyl, halogenated C 1-3 Alkoxy, -C 3-6 Cycloalkyl, -NR c R d , -C(O)NR e R f , -SO2C 1-3 Alkyl, -SO2 halogenated C 1-3 Alkyl, -SO2NR e R f , -CH2-hydroxy, -CH2-cyano, -CH2-C 1-3 Alkoxy, -CH2-Halogenated C 1-3 Alkyl, -CH2-Halogenated C 1-3 Alkoxy, -CH2-3 to 6-membered heterocycloalkyl, -CH2-NR e R f, -CH2-C(O)NR e R f , -CH2-SO2C 1-3 Alkyl or C 2-4 alkynyl. c is hydrogen, -C 1-3 alkyl, -C(O)CH3 or -CO2CH3. R e , R f , R d are each independently hydrogen or C 1-3 It is alkyl.

[0142] In one embodiment of the present invention, R s1 , R s2 are each independently halogen, cyano, nitro, hydroxy, -C 1-3 Alkyl, -C 1-3 Alkoxy, halogenated C 1-3 Alkyl, halogenated C 1-3 Alkoxy, -C 3-6 Cycloalkyl, -NR c R d , -C(O)NR e R f , -CH2-hydroxy, -CH2-cyano. c is hydrogen, -C(O)CH3 or -CO2CH3. e , R f , R d are each independently hydrogen or C 1-3 It is alkyl.

[0143] In one embodiment of the present invention, R s1 and R s2 In the above, C 3-6 Cycloalkyl is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cyclobutanone, cyclobutane-1,2-dione, cyclopentanone, cyclopentane-1,3-dione, cyclohexanone, cyclohexane-1,3-dione.

[0144] In one embodiment of the present invention, R s1 and Rs2 wherein the 3- to 6-membered heterocycloalkyl is selected from aziridine, ethylene oxide, azetidine, oxetane, oxazolidine, 1,3-dioxolane, imidazolidine, tetrahydrofuran, tetrahydrothiophene, pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, thiomorpholine-1,1-dioxide, tetrahydropyran, 1,3-oxazinane, hexahydropyrimidine, and 1,4-dioxane.

[0145] In one embodiment of the present invention, R s1 , R s2 are each 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. c is hydrogen, -C(O)CH3 or -CO2CH3. e , R f , R d are each independently hydrogen, methyl or ethyl.

[0146] In one embodiment of the present invention, R s3 , R s4 are each independently halogen, cyano, hydroxy, -C 1-6 Alkyl, -C 1-3 Alkoxy, halogenated C 1-3 Alkyl, halogenated C 1-3 Alkoxy, -C3-6 Cycloalkyl, 3-6 membered heterocycloalkyl groups, amino, NHCH3, N(CH3)2, -C(O)NR e R f , -SO2C 1-3 Alkyl, -SO2 halogenated C 1-3 Alkyl, -SO2NR e R f , -C 1-2 Alkyl-hydroxy, -C 1-2 Alkyl-ethynyl, -C 1-2 Alkyl-cyano, -C 1-2 Alkyl-C 1-3 Alkoxy, -C 1-2 Alkyl-halogenated C 1-3 Alkyl, -C 1-2 Alkyl-halogenated C 1-3 Alkoxy, -C 1-2 alkyl-3-6 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 R f , -C 1-2 Alkyl-SO2C 1-3 alkyl or ethynyl. 1-6 Alkyl, -C 1-3 Alkoxy, -C 1-2 Alkyl-, -C 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl may be optionally substituted with 1, 2, or 3 substituents independently selected from halogen, methyl, ethyl, propyl (n-propyl), isopropyl, trifluoromethyl, amino, N(CH3)2, hydroxy, and carboxyl. R e , R f are each independently hydrogen or C 1-3 It is an alkyl group.

[0147] In one embodiment of the present invention, R s3 , R s4 are each independently a halogen, a cyano, a hydroxy, or a C 1-4Alkyl, -C 1-3 Alkoxy, halogenated C 1-3 Alkyl, halogenated C 1-3 Alkoxy, -C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, amino, NHCH3, N(CH3)2, -C(O)NR e R f , -SO2C 1-3 Alkyl, -SO2 halogenated C 1-3 Alkyl, -SO2NR e R f , -CH2-hydroxy, -CH2-ethynyl, -CH2-cyano, -CH2-C 1-3 Alkoxy, -CH2-Halogenated C 1-3 Alkyl, -CH2-Halogenated C 1-3 Alkoxy, -CH2-3 to 6-membered 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. 1-4 Alkyl, -C 1-3 Alkoxy, -CH2-, -C 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl may be optionally substituted with 1, 2, or 3 substituents independently selected from halogen, methyl, ethyl, propyl (n-propyl), isopropyl, trifluoromethyl, amino, N(CH3)2, hydroxy, and carboxyl. R e , R f are each independently hydrogen or C 1-3 It is alkyl.

[0148] In one embodiment of the present invention, R s3 , R s4 are each independently a halogen, a cyano, a hydroxy, or a C 1-4 Alkyl, -C 1-3 Alkoxy, halogenated C 1-3 Alkyl, -C 3-6cycloalkyl, 3-6 membered heterocycloalkyl, amino, NHCH3, N(CH3)2, -CH2-hydroxy, -CH2-ethynyl. 1-4 Alkyl, -C 1-3 Alkoxy, -CH2-, -C 3-6 The cycloalkyl, 3- to 6-membered heterocycloalkyl may be optionally substituted with 1, 2, or 3 substituents independently selected from halogen, methyl, ethyl, propyl (n-propyl), isopropyl, trifluoromethyl, amino, N(CH3)2, hydroxy, and carboxyl.

[0149] In one embodiment of the present invention, R s3 and R s4 In the above, C 3-6 Cycloalkyl is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.

[0150] In one embodiment of the present invention, R s3 and R s4 wherein the 3- to 6-membered heterocycloalkyl is selected from aziridine, ethylene oxide, azetidine, oxetane, tetrahydrofuran, tetrahydrothiophene, pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, thiomorpholine-1,1-dioxide, and tetrahydropyran.

[0151] In one embodiment of the present invention, R s3 , R s4are each 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, ethylene oxide, azetidine, oxetane, tetrahydrofuran, tetrahydrothiophene, pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, thiomorpholine-1,1-dioxide, tetrahydropyran, amino, NHCH, N(CH), -CH-hydroxy, or -CH-ethynyl. The methyl, ethyl, n-propyl, methoxy, ethoxy, propoxy (n-propoxy), -CH2-, azetidine, oxetane, tetrahydrofuran, tetrahydrothiophene, pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, thiomorpholine-1,1-dioxide, and tetrahydropyran may be optionally substituted with one, two, or three substituents independently selected from halogen, methyl, ethyl, propyl (n-propyl), isopropyl, trifluoromethyl, amino, N(CH3)2, hydroxy, and carboxyl.

[0152] In one embodiment of the present invention, the S group substituents are hydroxy, 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 a 0 C(O)-(CH2) u -NR a0 R b0 , N.R. a0 C(O)-(CH2) u OH, NR a0 C(O)-halogenated C 1-3 The 3- to 6-membered heterocycloalkyl and 5- or 6-membered monocyclic heteroaryl each have 1, 2, or 3 heteroatoms independently selected from N, O, and S as ring-forming atoms. The 3- to 6-membered heterocycloalkyl and 5- or 6-membered monocyclic heteroaryl may be optionally substituted with 1, 2, or 3 substituents selected from halogen, cyano, -C1-3 alkyl, -C1-3 alkoxy, and C3-6 cycloalkyl. u and v each independently represent 0, 1, 2, 3, or 4. R a0 , R b0 are each independently hydrogen or C 1-3 It is alkyl.

[0153] In one embodiment of the present invention, the S group substituent is halogen.

[0154] In one embodiment of the present invention, the S group substituent is C 1-3 Alkyl, -(CH2) u -3 to 6-membered heterocycloalkyl, -(CH2) u -SO2C 1-3 Alkyl, -(CH2) u -NR a0 R b0 The 3- to 6-membered heterocycloalkyl has 1, 2, or 3 heteroatoms selected from N, O, and S as ring-forming atoms. The 3- to 6-membered heterocycloalkyl may be optionally substituted with 1, 2, or 3 substituents selected from halogen, cyano, -C1-3 alkyl, -C1-3 alkoxy, and C3-6 cycloalkyl. u is 0, 1, 2, 3, or 4. R a0 , R b0 are each independently hydrogen or C 1-3 It is an alkyl group.

[0155] In one embodiment of the present invention, in the group (e.g., Ar, R), 6-10 Each aryl is independently phenyl or naphthyl.

[0156] In one embodiment of the present invention, in the group (e.g., Ar), 6-10 When aryl is phenyl, it is selected from the following structures:

[0157] [ka]

[0158] (In the formula, R s1 , R s2 The definitions are the same as above.)

[0159] According to one embodiment of the present invention, in the group (e.g., Ar, R), the 5- or 6-membered monocyclic heteroaryl is independently selected from thiophene, N-alkylcyclopyrrole, furan, thiazole, isothiazole, imidazole, oxazole, pyrrole, pyrazole, triazole, 1,2,3-triazole, 1,2,4-triazole, 1,2,5-triazole, 1,3,4-triazole, 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.

[0160] According to one embodiment of the present invention, in the group (eg, Ar, R0), the 5- or 6-membered monocyclic heteroaryl is independently selected from the following structures:

[0161] [ka]

[0162] According to one embodiment of the present invention, in the group (e.g., Ar, R), the 8-10 membered bicyclic heteroaryl is independently a 9-10 membered bicyclic heteroaryl formed by fusing a benzene ring with a 5- or 6-membered monocyclic heteroaryl ring, or an 8-10 membered bicyclic heteroaryl group formed by fusing a 5- or 6-membered monocyclic heteroaryl ring with a 5- or 6-membered monocyclic heteroaryl ring.

[0163] According to one embodiment of the present invention, the 5- or 6-membered monocyclic heteroaryl ring forming the 9- to 10-membered bicyclic heteroaryl or 8- to 10-membered bicyclic heteroaryl group is selected from a thiophene ring, an N-alkylcyclopyrrole 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, and a pyrazine ring.

[0164] According to one embodiment of the present invention, the 5- or 6-membered monocyclic heteroaryl ring forming the 9-10 membered bicyclic heteroaryl or 8-10 membered bicyclic heteroaryl group is selected from the following structures:

[0165] [ka]

[0166] where:

[0167] [ka]

[0168] represents a pair of adjacent atoms that are shared when the two connected ring-forming atoms are fused to another ring.

[0169] According to one embodiment of the present invention, in ring B1 and ring A1, the 5- or 6-membered monocyclic heteroaryl ring is independently selected from a thiophene ring, an N-alkylcyclopyrrole 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, and a pyrazine ring.

[0170] According to one embodiment of the present invention, in ring B1 and ring A1, the 5- or 6-membered monocyclic heteroaryl ring is independently selected from the following structures:

[0171] [ka] where:

[0172] [ka]

[0173] represents a pair of adjacent atoms that are shared when the two connected ring-forming atoms are fused to another ring.

[0174] According to one embodiment of the present invention, in the ring B2 and the ring A2, the fused 5- or 6-membered monocyclic cycloalkyl is independently selected from a cyclopentyl ring, a cyclopentenyl ring, a cyclohexyl ring, a cyclohexenyl ring, a cyclohexadiene ring, cyclopentanone, cyclopentane-1,3-dione, cyclohexanone, and cyclohexane-1,3-dione.

[0175] According to one embodiment of the present invention, in the ring B2 and the ring A2, the fused 5- or 6-membered monocyclic heterocycloalkyl is each independently oxazolidine, pyrrolidin-2-one, pyrrolidine-2,5-dione, 1,3-dioxolane, dihydrofuran-2(3H)-one, dihydrofuran-2,5-dione, piperidin-2-one, piperidine-2,6-dione, tetrahydro-2H-pyran-2-one, imidazolidine, tetrahydrofuran, tetrahydrothiophene, piperidin-2,6-dione, tetrahydro-2H-pyran-2-one, tetrahydrofuran, tetrahydrothiophene, tetrahydro-2H-pyran-2-one ... loridine, 1,3-dioxolan-2-one, oxazolidin-2-one, imidazolidin-2-one, piperidine, piperazine, piperazin-2-one, morpholine, morpholin-3-one, morpholin-2-one, thiomorpholin-3-one-1,1-dioxide, thiomorpholine, thiomorpholine-1,1-dioxide, tetrahydropyran, 1,2-dihydroazacyclobutadiene, 1,2-dihydrooxacyclobutadiene, 2,5-dihydro-1H-pyrrole, 2,5-Dihydrofuran, 2,3-Dihydrofuran, 2,3-Dihydro-1H-pyrrole, 3,4-Dihydro-2H-pyran, 1,2,3,4-Tetrahydropyridine, 3,6-Dihydro-2H-pyran, 1,2,3,6-Tetrahydropyridine, 1,3-Oxazine, Hexahydropyrimidine, 1,4-Dioxane, Tetrahydropyrimidin-2(1H)-one, 1,4-Dioxan-2-one, 5,6-Dihydro-2H-pyran-2-one, 5,6-Dihydropyrimidine -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 -imidazol-2-one, furan-2,5-dione, 3,6-dihydropyridin-2(1H)-one, pyridine-2,6-(1H,3H)-dione, 5,6-dihydro-2H-pyran-2-one, 3,6-dihydro-2H-pyran-2-one, 3,4-dihydro-2H-1,3-oxazine, 3,6-dihydro-2H-1,3-oxazine, and 1,2,3,4-tetrahydropyrimidine.

[0176] According to one embodiment of the present invention, the fused 5- or 6-membered monocyclic heterocycloalkyl ring is selected from the following structures:

[0177] [ka]

[0178] According to one embodiment of the present invention, in the group (e.g., Ar, R), the 8-10 membered bicyclic heteroaryl is independently selected from benzoxazole, benzisoxazole, benzimidazole, benzothiazole, benzisothiazole, benzotriazole, benzofuran, benzothiophene, indole, indazole, isoindole, quinoline, isoquinoline, quinazoline, quinoxaline, cinnoline, pyridopyrimidine, and naphthyridine.

[0179] According to one embodiment of the present invention, in the group (e.g., Ar, R), each of the 8-10 membered bicyclic heteroaryls is independently selected from benzo[d]isoxazole, 1H-indole, isoindole, 1H-benzo[d]imidazole, benzo[d]isothiazole, 1H-benzo[d][1,2,3]triazole, benzo[d]oxazole, benzo[d]thiazole, indazole, benzofuran, benzo[b]thiophene, quinoline, isoquinoline, quinazoline, quinoxaline, cinnoline, pyrido[3,2-d]pyrimidine, pyrido[2,3-d]pyrimidine, pyrido[3,4-d]pyrimidine, pyrido[4,3-d]pyrimidine, 1,8-naphthyridine, 1,7-naphthyridine, 1,6-naphthyridine, and 1,5-naphthyridine.

[0180] According to one embodiment of the present invention, in the group (eg, Ar, R0), the 8-10 membered bicyclic heteroaryl is independently selected from the following structures:

[0181] [ka]

[0182] According to one embodiment of the present invention, in the group (eg, Ar, R0), the 8-10 membered bicyclic heteroaryl is independently selected from the following structures:

[0183] [ka]

[0184] According to one embodiment of the present invention, in the group (eg, Ar, R0), the 8-10 membered bicyclic heteroaryl groups are each independently selected from the following structures:

[0185] [ka]

[0186] In one embodiment of the present invention,

[0187] [ka]

[0188] are each independently selected from the following structures:

[0189] [ka]

[0190] According to one embodiment of the present invention, formula (B) and formula (A-1) are each independently selected from the following structures:

[0191] [ka]

[0192] In one embodiment of the present invention, Ar and Ar' are each independently selected from the following structures:

[0193] [ka]

[0194] [ka]

[0195] [ka]

[0196] [ka]

[0197] [ka]

[0198] In one embodiment of the present invention, in the above group (e.g., R0), 3-6 Cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclo It is selected from hexyl, cyclohexenyl, cyclohexadienyl, cyclobutanone, cyclobutane-1,2-dione, cyclopentanone, cyclopentane-1,3-dione, cyclohexanone, and cyclohexane-1,3-dione.

[0199] According to one embodiment of the present invention, in the above group (e.g., R), the 3- to 6-membered heterocycloalkyl is selected from aziridine, ethylene oxide, azetidine, oxetane, oxazolidine, 1,3-dioxolane, imidazolidine, tetrahydrofuran, tetrahydrothiophene, pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, thiomorpholine-1,1-dioxide, tetrahydropyran, 1,3-oxazine, hexahydropyrimidine, and 1,4-dioxane.

[0200] According to one embodiment of the present invention, in the above group (e.g., R), the 7-11-membered spirocycloalkyl is a monospirocycloalkyl 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.

[0201] 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 1-2alkyl)-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 is cycloalkyl. 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, and 7- to 11-membered spirocycloalkyl are unsubstituted or independently selected from R s3 and substituted with 1, 2, 3 or 4 groups selected from:

[0202] According to one embodiment of the present invention, R is phenyl, cyclopropyl, 5- or 6-membered monocyclic heteroaryl, -CH-5- or 6-membered monocyclic heteroaryl, -CH-phenyl, -CH(C 1-2 alkyl)-phenyl, -NH-phenyl, -N(C 1-3 The 5- or 6-membered monocyclic heteroaryl is selected from thiophene, N-alkylcyclopyrrole, furan, thiazole, isothiazole, imidazole, oxazole, pyrrole, pyrazole, triazole, 1,2,3-triazole, 1,2,4-triazole, 1,2,5-triazole, 1,3,4-triazole, 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. The phenyl, 5- or 6-membered monocyclic heteroaryl is unsubstituted or independently selected from R s3 and substituted with 1, 2, 3 or 4 groups selected from:

[0203] In one embodiment of the present invention, R0 is selected from the following structures:

[0204] [ka]

[0205] [ka]

[0206] [ka]

[0207] In one embodiment of the present invention, R 11 , R 12 may be the same or different, and each independently represents hydrogen, halogen, or -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 It is an alkoxy.

[0208] In one embodiment of the present invention, R 11 , R 12 may be the same or different and each independently represent hydrogen, halogen, methyl, ethyl, n-propyl, isopropyl, -CH-hydroxy, -CH-cyano, -CH-methoxy, -CH-ethoxy, -CH-propoxy (n-propoxy), -CH-isopropoxy, -CH-trifluoromethyl, -CH-difluoromethyl, -CH-difluoroethyl, -CH-trifluoromethoxy, or -CH-difluoromethoxy.

[0209] In one embodiment of the present invention, R 11 , R 12 may be the same or different, and each independently represents hydrogen or -C 1-3 It is alkyl.

[0210] In one embodiment of the present invention, R 11 , R 12may be the same or different and each independently represents hydrogen or methyl.

[0211] In one embodiment of the present invention, R 21 , R 22 may be the same or different, and each independently represents hydrogen, halogen, or -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 It is an alkoxy.

[0212] In one embodiment of the present invention, R 21 , R 22 may be the same or different and each independently represent hydrogen, halogen, methyl, ethyl, n-propyl, isopropyl, -CH-hydroxy, -CH-cyano, -CH-methoxy, -CH-ethoxy, -CH-propoxy (n-propoxy), -CH-isopropoxy, -CH-trifluoromethyl, -CH-difluoromethyl, -CH-difluoroethyl, -CH-trifluoromethoxy, or -CH-difluoromethoxy.

[0213] In one embodiment of the present invention, R 21 , R 22 may be the same or different, and each independently represents hydrogen or -C 1-3 It is alkyl.

[0214] In one embodiment of the present invention, R 21 , R 22 may be the same or different and each independently represents hydrogen or methyl.

[0215] In one embodiment of the present invention, R 31 , R 32 may be the same or different, and each independently represents hydrogen, halogen, or -C 1-3Alkyl, -CH2-hydroxy, -CH2-cyano, -CH2-C 1-3 Alkoxy, -CH2-Halogenated C 1-3 Alkyl or -CH2-halogenated C 1-3 It is an alkoxy.

[0216] In one embodiment of the present invention, R 31 , R 32 may be the same or different and each independently represent hydrogen, halogen, methyl, ethyl, n-propyl, isopropyl, -CH-hydroxy, -CH-cyano, -CH-methoxy, -CH-ethoxy, -CH-propoxy (n-propoxy), -CH-isopropoxy, -CH-trifluoromethyl, -CH-difluoromethyl, -CH-difluoroethyl, -CH-trifluoromethoxy, or -CH-difluoromethoxy.

[0217] In one embodiment of the present invention, R 31 , R 32 may be the same or different, and each independently represents hydrogen or -C 1-3 It is alkyl.

[0218] In one embodiment of the present invention, R 31 , R 32 may be the same or different and each independently represents hydrogen or methyl.

[0219] In one embodiment of the present invention, R 41 is hydrogen, halogen, -C 1-3 Alkyl, -CH2-hydroxy, -CH2-cyano, -CH2-C 1-3 Alkoxy, -CH2-Halogenated C 1-3 Alkyl or -CH2-halogenated C 1-3 It is an alkoxy.

[0220] In one embodiment of the present invention, R 41is 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.

[0221] In one embodiment of the present invention, R 41 is hydrogen.

[0222] In one embodiment of the present invention, in formula I:

[0223] [ka]

[0224] If the dashed line in is a single bond, P is O. 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 1-3 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)-. 1-3 Alkyl is methyl, ethyl or propyl (n-propyl or isopropyl). 1-3 Alkoxy is methoxy, ethoxy or propoxy (n-propoxy or isopropoxy).

[0225] In one embodiment of the present invention, in Formula I:

[0226] [ka]

[0227] If the dashed line in 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-hydroxy, -C 1-3 Alkyl-cyano, -C 1-3 Alkyl-C 1-3 Alkoxy, -C 1-3 Alkyl-halogenated C 1-3 Alkoxy. R 42 is -(C=O)-, -C 1-3 Alkyl-, -C 1-3 Alkyl(hydroxy)-, -C 1-3 Alkyl(cyano)-, -C 1-3 Alkyl (C 1-3 alkyl), -C 1-3 Alkyl (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)-. 1-3 Alkyl is methyl, ethyl or propyl (n-propyl or isopropyl). 1-3 Alkoxy is methoxy, ethoxy or propoxy (n-propoxy or isopropoxy).

[0228] In one embodiment of the present invention, in Formula I:

[0229] [ka]

[0230] If the dashed line in is a single bond, -P is O, NH, or NR m R m -C 1-6 It is alkyl. R 42 is -(C=O)- or -C 1-3 It is alkyl.

[0231] In one embodiment of the present invention, in Formula I:

[0232] [ka]

[0233] When the dashed line in is a single bond, P is O, NH, or NR m R m -C 1-3 It is alkyl. R 42 is -(C=O)- or -C 1-3 It is alkyl.

[0234] In one embodiment of the present invention, in Formula I:

[0235] [ka]

[0236] When the dashed line in is a single bond, P is O, NH, or NR m R m is methyl, ethyl, n-propyl or isopropyl. 42 is —(C═O)—, —CH—, —CHCH— or —CHCHCH—.

[0237] In one embodiment of the present invention, in Formula I:

[0238] [ka]

[0239] If there is no dashed line in R, P is hydrogen or halogen. 42 is 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 It is an alkoxy.

[0240] In one embodiment of the present invention, in Formula I:

[0241] [ka]

[0242] If there is no dashed line in R, P is hydrogen or halogen. 42 is hydrogen, halogen, methyl, ethyl, n-propyl, isopropyl, -CH2-hydroxy, -CH2-cyano, -CH2-methoxy, -CH2-ethoxy, -CH2-propoxy (n-propoxy), -CH2-isopropoxy, -CH2-trifluoromethyl, -CH2-difluoromethyl, -CH2-difluoroethyl, -CH2-trifluoromethoxy, -CH2-difluoromethoxy.

[0243] According to one embodiment of the present invention, in formula I, X is hydrogen, halogen, cyano, hydroxy, amino, nitro, optionally substituted C 1-3 Alkyl, optionally -substituted C 3-6 Cycloalkyl, -optionally substituted 3-6 membered heterocycloalkyl, -O-optionally substituted C 1-3 Alkyl, -O- optionally substituted C 3-6 Cycloalkyl, -O-optionally substituted 3-6 membered heterocycloalkyl, -NH-optionally substituted C 1-3 Alkyl, -N(optionally substituted C 1-3 alkyl)2, -NH- optionally substituted C 3-6Cycloalkyl, -NH- optionally substituted 3-6 membered heterocycloalkyl, -NH(C=O)- optionally substituted C 1-3 Alkyl, -NH(C=O)-C 3-6 Cycloalkyl, -NH(SO2)- optionally substituted C 1-3 Alkyl, -NH(SO2)- optionally substituted C 3-6 Cycloalkyl, -SO2- optionally substituted C 1-3 Alkyl, -SO2- optionally substituted C 3-6 Cycloalkyl, -(C=O)-NR j R k -, -(C=O)-O-optionally substituted C 1-3 Alkyl, -(C=O)-O- optionally substituted C 3-6 is cycloalkyl. j , R k are each independently hydrogen or C 1-3 alkyl, or j , R k together with the nitrogen atom to which it is connected, form an optionally substituted 3- to 6-membered nitrogen-containing heterocycloalkyl. The 3- to 6-membered heterocycloalkyl has 1, 2 or 3 heteroatoms selected from N, O and S as ring-forming atoms. The 3- to 6-membered nitrogen-containing heterocycloalkyl group is The "substituted" group has ring-forming atoms, one of which is a nitrogen atom, and 0, 1, or 2 of the remaining ring-forming atoms may be heteroatoms selected from N, O, and S. The "substituted" group has 1, 2, 3, or 4 hydrogen atoms each independently substituted with a substituent selected from the S group. 1-3 Alkyl is methyl, ethyl or propyl (n-propyl or isopropyl). 1-3 Alkoxy is methoxy, ethoxy or propoxy (n-propoxy or isopropoxy).

[0244] According to one embodiment of the present invention, in formula I, Y1 is N, E1 is C, and E2 is C.

[0245] According to one embodiment of the present invention, in formula I, Y 1 is C, E 1 is N, and E 2 is C.

[0246] According to one embodiment of the present invention, in formula I, Y 1 is C, E 1 is C, and E 2 is N.

[0247] According to one embodiment of the present invention, in formula I, Y 1 is C, E 1 is N, and E 2 is N.

[0248] According to one embodiment of the present invention, in formula I, Y1 is N, E1 is N, and E2 is C.

[0249] According to one embodiment of the present invention, in formula I, Y1 is N, E1 is N, and E2 is C.

[0250] In one embodiment of the present invention, in formula II, P is O.

[0251] In one embodiment of the present invention, in formula II, P is NH or NR m and R m is C 1-3 Alkyl, halogenated C 1-3 Alkyl, -C 1-3 Alkyl-hydroxy, -C 1-3 Alkyl-cyano, -C 1-3 Alkyl-C 1-3 Alkoxy, -C 1-3 Alkyl-halogenated C 1-3 Alkoxy, where C 1-3 Alkyl is methyl, ethyl or propyl (n-propyl or isopropyl). 1-3 Alkoxy is methoxy, ethoxy or propoxy (n-propoxy or isopropoxy).

[0252] In one embodiment of the present invention, in formula II, R 42 is -(C=O)-, -C 1-3 Alkyl, -C 1-3 Alkyl(hydroxy)-, -C1-3 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)-. 1-3 Alkyl is methyl, ethyl or propyl (n-propyl or isopropyl). 1-3 Alkoxy is methoxy, ethoxy or propoxy (n-propoxy or isopropoxy).

[0253] In one embodiment of the present invention, in Formula II, X and Y may be the same or different and each independently represent hydrogen, halogen, -C 1-3 Alkyl, -C 1-3 Alkyl-hydroxy, -C 1-3 Alkyl-cyano, -C 1-3 Alkyl-C 1-3 Alkoxy, -C 1-3 Alkyl-halogenated C 1-3 Alkyl or -C 1-3 Alkyl-halogenated C 1-3 The C is an alkoxy. 1-3 Alkyl is methyl, ethyl or propyl (n-propyl or isopropyl). 1-3 Alkoxy is methoxy, ethoxy or propoxy (n-propoxy or isopropoxy).

[0254] According to one embodiment of the present invention, in formula II, X and Y are each an optionally substituted C 3-6The cycloalkyl or optionally substituted 3- to 6-membered heterocycloalkyl group has 1, 2, or 3 heteroatoms selected from N, O, and S as ring-forming atoms. The "substituted" refers to 1, 2, 3, or 4 hydrogen atoms in the group being each independently substituted with a substituent selected from the S group.

[0255] In one embodiment of the present invention, in formula II, L is a single bond.

[0256] According to one embodiment of the present invention, in formula II, R5 is hydrogen, halogen, hydroxy, optionally substituted C 1-3 Alkyl, optionally -substituted C 3-6 Cycloalkyl, -optionally substituted 3-6 membered heterocycloalkyl, -O-optionally substituted C 1-3 Alkyl, -O- optionally substituted C 3-6 Cycloalkyl, -O-optionally substituted 3-6 membered heterocycloalkyl, -SO2-optionally substituted C 1-3 Alkyl, -SO2- optionally substituted C 3-6 Cycloalkyl, -SO2- optionally substituted 3- to 6-membered heterocycloalkyl, - optionally substituted 5- or 6-membered monocyclic heteroaryl group or NR 51 R 52 The above R 51 , R 52 are each independently hydrogen, optionally substituted 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 52form an optionally substituted 3- to 6-membered nitrogen-containing heterocycloalkyl together with the nitrogen atom to which it is connected. The 3- to 6-membered heterocycloalkyl and 5- or 6-membered monocyclic heteroaryl each have 1, 2, or 3 heteroatoms independently selected from N, O, and S as ring-forming atoms. The 3- to 6-membered nitrogen-containing heterocycloalkyl has 3 to 6 ring-forming atoms, one of which is a nitrogen atom, and 0, 1, or 2 of the remaining ring-forming atoms may optionally be heteroatoms selected from N, O, and S. The "substituted" refers to 1, 2, 3, or 4 hydrogen atoms in the group being independently substituted with substituents independently selected from the S group. The C 1-3 Alkyl is methyl, ethyl or propyl (n-propyl or isopropyl). 1-3 Alkoxy is methoxy, ethoxy or propoxy (n-propoxy or isopropoxy).

[0257] According to 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. The 3- to 6-membered heterocycloalkyl is selected from aziridine, ethylene oxide, azetidine, oxetane, tetrahydrofuran, tetrahydrothiophene, pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, thiomorpholine-1,1-dioxide, and tetrahydropyran. The 5- or 6-membered monocyclic heteroaryl is selected from thiophene, N-alkylcyclopyrrole, furan, thiazole, isothiazole, imidazole, oxazole, pyrrole, pyrazole, triazole, 1,2,3-triazole, 1,2,4-triazole, 1,2,5-triazole, 1,3,4-triazole, 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. The 3- to 6-membered heterocycloalkyl, 5- or 6-membered monocyclic heteroaryl may optionally contain 1 or 2 halogen atoms or C 1-3 It may be substituted with alkyl.

[0258] According to one embodiment of the present invention, R3 is hydrogen, halogen, methoxy, ethoxy, propoxy (n-propoxy) or isopropoxy.

[0259] According to 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.

[0260] In one embodiment of the present invention, R1, R2, and R3 are hydrogen.

[0261] According to one embodiment of the present invention, E1 is N or CR5, wherein R5 is hydrogen.

[0262] According to one embodiment of the present invention, E2 is N or CR6, wherein R6 is hydrogen.

[0263] In one embodiment of the present invention, in the compound represented by formula (I), 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 groups corresponding to each specific compound in the Examples.

[0264] According to one embodiment of the present invention, the compound represented by formula (I) is any compound selected from compounds Z1 and Z3 to Z16 according to the examples, or a diastereomer thereof.

[0265] According to one embodiment of the present invention, representative compounds of formula (IA) include the structures shown in Table A-1 below, tautomers, cis-trans isomers, mesomers, racemates, enantiomers, diastereomers, or atropisomers of any of the structures in Table A-1, or mixtures of such isomers, or pharmaceutically acceptable salts, solvates, or prodrugs of the structures shown in Table A-1 and the isomers.

[0266] [Table A-1]

[0267] [Table 1]

[0268] [Table 2]

[0269] [Table 3]

[0270] [Table 4]

[0271] [Table 5]

[0272] [Table 6]

[0273] [Table 7]

[0274] [Table 8]

[0275] Table 9

[0276] Table 10

[0277] Table 11

[0278] Table 12

[0279] Table 13

[0280] Table 14

[0281] Table 15

[0282] Table 16

[0283] Table 17

[0284] Table 18

[0285] Table 19

[0286] [Table 20]

[0287] [Table 21]

[0288] According to one embodiment of the present invention, representative compounds of formula (IA) include, but are not limited to, the structures shown in Table A-2 below, or pharmaceutically acceptable salts, solvates, or prodrugs of any of the structures shown in Table A-2.

[0289] [Table 22]

[0290] [Table 23]

[0291] [Table 24]

[0292] According to one embodiment of the present invention, representative compounds represented by formula (IA) include, but are not limited to, any of the compound structures set forth in Examples 51 to 342, or pharmaceutically acceptable salts, solvates, or prodrugs of these structures.

[0293] In one embodiment of the present invention, in the compound represented by formula (II), 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 groups corresponding to each specific compound according to the Examples.

[0294] According to one embodiment of the present invention, the compound represented by formula (II) is any one of compounds Z2, Z17 to Z20 selected from the examples, or a diastereomer thereof.

[0295] In another aspect, the present invention provides a pharmaceutical composition comprising the compound or a tautomer, cis-trans isomer, mesomers, racemates, enantiomers, diastereomers, atropisomers, or mixtures thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, and a pharmaceutically acceptable carrier.

[0296] The term "pharmaceutically acceptable carrier" as used herein refers to any formulation or carrier medium that can carry an effective amount of an active agent according to the present invention, does not impair the biological activity of the active agent, and is not toxic or has any adverse effects on the host or subject, and includes water, oil, vegetable and mineral substances, ointment bases, lotion bases, ointment bases, etc. These bases may contain suspending agents, thickeners, transdermal enhancers, etc. These formulations are well known to those skilled in the art of cosmetics or topical medicines.

[0297] In an embodiment of the present invention, the pharmaceutical composition can be administered orally, by aerosol inhalation, rectal administration, nasal administration, buccal administration, topical administration, or parenteral administration, such as subcutaneous, intravenous, intramuscular, intraperitoneal, intrathecal, intraventricular, intrasternal, or intracranial injection or delivery, or via external storage. When administered orally, the compounds of the present invention can be prepared in any orally administrable dosage form, including, but not limited to, tablets, capsules, aqueous solutions, or aqueous suspensions. Carriers used for tablets typically include lactose and cornstarch, and lubricants such as magnesium stearate may also be added. Diluents used for capsules typically include lactose and dried cornstarch. Aqueous suspension formulations are generally prepared by mixing the active ingredient with suitable emulsifiers and suspending agents. If desired, the above oral dosage forms can further contain several sweeteners, flavors, or colorants. For topical administration, particularly for treating neurological disorders of the eye, skin, or lower intestine, where topical application is readily achieved, the compounds of the present invention can be formulated into different topical formulations depending on the affected area or organ. For topical administration to the eye, the compounds of the present invention can be formulated into a micronized suspension or solution, with the carrier being isotonic sterile saline with a specific pH, with or without the addition of a preservative, such as benzyl alkoxide chloride. For administration to the eye, the compounds can also be formulated into a paste, such as petrolatum paste. For topical administration to the skin, the compounds of the present invention can be formulated into a suitable ointment, lotion, or cream, with the active ingredient suspended or dissolved in one or more carriers. Carriers that can be used for ointment formulations include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene, emulsifying wax, and water. Carriers that can be used in lotions or creams include, but are not limited to, mineral oil, sorbitan monostearate, Tween 60, cetyl esters wax, hexadecene aromatic alcohol, 2-octyldodecanol, benzyl alcohol and water.The compounds of the present invention can also be administered in sterile injectable preparations, including sterile injectable aqueous or oil suspensions or sterile injectable solutions. Usable carriers and solvents include water, Ringer's solution, and isotonic sodium chloride solution. Sterile non-volatile oils (e.g., monoglycerides or diglycerides) can also be used as solvents or suspending media.

[0298] In another aspect, the present invention provides an application of the compound or a tautomer, cis-trans isomer, mesomers, racemate, enantiomer, diastereomer, atropisomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, in the preparation of a medicament for treating and / or preventing a KRAS G12C mutation-induced disease, wherein the KRAS G12C mutation-induced disease is preferably cancer.

[0299] In another aspect, the present invention provides the application of the above compound or its tautomer, cis-trans isomer, mesomers, racemates, enantiomers, diastereomers, atropisomers or mixtures thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof in the preparation of a medicament for treating and / or preventing cancer.

[0300] In one embodiment of the present invention, the cancer is pancreatic cancer, colorectal cancer or lung cancer.

[0301] In one embodiment of the present invention, the cancer is lung cancer, preferably non-small cell lung cancer.

[0302] In another aspect, the present invention provides an application of the above-mentioned compound or a tautomer, cis-trans isomer, mesomers, racemate, enantiomer, diastereomer, atropisomer or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof in the preparation of a KRAS mutation inhibitor, wherein the KRAS mutation is preferably a KRAS G12C mutation.

[0303] In another aspect, the present invention provides a method for treating cancer, comprising the step of administering to a subject in need of treatment a therapeutically effective amount of the aforementioned compound, or a tautomer, cis-trans isomer, mesomers, racemates, enantiomers, diastereomers, atropisomers, or mixtures thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, or any combination thereof, or a pharmaceutical composition as described above.

[0304] As used herein, the term "subject" refers to animals, particularly mammals. Humans are preferred.

[0305] As used herein, the term "effective amount" or "therapeutically effective amount" refers to a sufficient amount of a drug or agent to achieve the desired effect without toxicity. In an embodiment of the present invention, when treating a patient according to the present invention, the amount of a given drug will depend on many factors, such as the specific administration method, the type and severity of the disease or condition, and the specific characteristics (e.g., body weight) of the patient or host to be treated. However, depending on the specific circumstances, including, for example, the specific drug employed, the route of administration, the condition being treated, and the patient or host being treated, the dosage can generally be determined by methods known in the art. Generally, for dosages used in adult treatment, dosages typically range from 0.02 to 5000 mg / day, e.g., about 1 to 1500 mg / day. The required dosage may be one agent, or may be administered simultaneously (or shortly thereafter) or at appropriate intervals, e.g., two, three, four, or more agents per day. As will be understood by those skilled in the art, although the above dosage ranges are given, the specific effective amount can be appropriately adjusted according to the physician's diagnosis, depending on the patient's circumstances.

[0306] 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 acid, phosphoric acid, or carbonic acid, and organic acids such as propionic acid, caproic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, gluconic acid, stearic acid, or muconic acid; salts formed by replacing an acidic proton in the parent compound with a metal ion, such as an alkali metal ion or an alkaline earth metal ion; or coordination compounds formed with organic bases, such as ethanolamine, diethanolamine, triethanolamine, or N-methylglucamine. The pharmaceutically acceptable salts of the present invention can be synthesized from a parent compound containing an acid or base by conventional methods. Generally, such salts are prepared by reacting the compounds as free acids or bases with an appropriate stoichiometric amount of base or acid in water, an organic solvent, or a mixture of both. In addition to salts, the compounds provided by the present invention may also exist as prodrugs. Prodrugs of the compounds described herein are easily converted into the compounds of the present invention by chemical or biochemical methods in the body's environment.

[0307] The term "solvate" as used herein refers to a substance formed by combining a compound of the present invention with a pharmaceutically acceptable solvent. Solvates include stoichiometric and non-stoichiometric solvates. Some compounds of the present invention may exist in a non-solvated or solvated form. Generally, no distinction is made between solvated and non-solvated forms, and both are considered to be within the scope of the present invention.

[0308] As used herein, the term "stereoisomer" includes conformational isomers and configurational isomers, with configurational isomers primarily including cis-trans isomers and optical isomers. The compounds of the present invention can exist as stereoisomers and, as such, include all possible stereoisomers, including, but not limited to, cis-trans isomers, tautomers, enantiomers, diastereomers, atropisomers (also sometimes called rotational isomers), and the like. The compounds of the present invention may exist as any combination or mixture of the above stereoisomers, such as mesomers, racemates, or equal mixtures of atropisomers. For example, the compounds of the present invention may exist as a single enantiomer, a single diastereomer, or a mixture thereof, or a single atropisomer or a mixture thereof. When the compounds of the present invention contain olefinic double bonds, they include cis- and trans-isomers, and any combination thereof, unless otherwise specified. The atropisomers of the present invention are stereoisomers in which intramolecular rotation is restricted, resulting in axial or planar chirality. The compounds of the present invention include two types of atropisomers resulting from axial asymmetry. This is because the substituent Ar' or R0' is C 6-10 In the case of a cyclic group such as an aryl, a 5- or 6-membered monocyclic heteroaryl, an 8- to 10-membered bicyclic heteroaryl, or a pyridone group, the bond to the substituted naphthyridinone ring is rotated to form steric hindrance. Regarding the atropisomers of the present invention, the compounds have a structure represented by Formula (I), Formula (IA), or Formula (II). Alternatively, the compounds represented by Formula (I), Formula (IA), and Formula (II) have isomers generated by asymmetric carbons, etc., and each isomer represents one of a pair of atropisomers present in the isomeric compound. Furthermore, as a drug, atropisomers with excellent activity are preferred. The compounds represented by Formula (I), Formula (IA), or Formula (II) include optical isomers derived from asymmetric carbons, axial asymmetry, etc., and a single isomer can be obtained by optical resolution, if necessary. The atropisomers of the compounds of the present invention may be represented as P or M configurations, or may be represented by other common methods known in the art.

[0309] As described above, the present invention provides compounds represented by the above structures, or tautomers, cis / trans isomers, mesomers, racemates, enantiomers, diastereomers, atropisomers, or mixtures thereof. The "mixtures thereof" include any combination of any of the stereoisomers (e.g., tautomers, cis / trans isomers, enantiomers, diastereomers, atropisomers) and / or mixtures (mesomers, racemates) of the above, such as a mixture of cis / trans isomers, a mixture of enantiomers and diastereomers, a mixture of diastereomers, a mixture of atropisomers, a mixture of cis / trans isomers and a racemate, a mixture of enantiomers and diastereomers, a mixture of atropisomers and diastereomers, etc.

[0310] As used herein, the symbol "-" contained in a substituent in each group represents a bond connected to another group or structure.

[0311] As used herein, the term "fused" refers to a structure in which two or more rings share one or more bonds.

[0312] The term "alkyl" as used herein refers to a straight-chain or branched-chain saturated aliphatic hydrocarbon group containing 1-20 carbon atoms. 1-10 The term "alkyl" refers to a straight or branched chain alkyl having 1-10 carbon atoms. 1-6 Alkyl is preferred. 1-4 Alkyl is more preferred. 1-3Alkyl is most preferred. Specific examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, and various branched isomers thereof. Unless otherwise specified, when propyl and isopropyl are present simultaneously in a parallel option, the propyl indicates n-propyl. When only propyl is present in a parallel option, the propyl indicates n-propyl or isopropyl.

[0313] As used herein, "-C" 1-3 Alkyl- and C 1-3 The term "alkylene" is commonly used and refers to a saturated, straight-chain or branched-chain aliphatic hydrocarbon group, with the residue derived by removing two hydrogen atoms from the same carbon atom or two different carbon atoms of two parent alkyls, and is a straight-chain or branched group containing 1-3 carbon atoms. Specific examples of alkylene groups 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 (-CHCHCH-), and the like.

[0314] As used herein, "-C" 1-3 Alkyl(hydroxy)-, -C 1-3 Alkyl(cyano)-, -C 1-3 Alkyl (C 1-6 alkyl)-, -C 1-3 Alkyl (halogenated C 1-6alkyl)-, -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)-" are "-C 1-3 One or more hydrogen atoms in "alkyl-" may be hydroxy, cyano, C 1-6 Alkyl, halogenated C 1-6 Alkyl, -C 1-6 Alkyl-hydroxy, -C 1-6 Alkyl-cyano, C 1-6 Alkoxy, halogenated C 1-6 It refers to a residue formed by substitution with alkoxy. Specific examples include, but are not limited to, -CH(OH)-, -CHCH(CN)-, -CHCH(CHCH)-, -CHCH(CF)-, -CH(CHOH)-, -CHCH(CHCN)-, -CH(OCH)-, and -CHCH(OCF)-.

[0315] The term "alkoxy," as used herein, refers to a group having the structure -O-alkyl, where alkyl is as defined above. 1-10 "Alkoxy" is 1 -alkoxy having 10 carbon atoms, C 1-6 Alkoxy is preferred, C 1-4 Alkoxy is more preferred, C 1-3 Alkoxy is more preferred. Specific examples of the alkoxy group include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, isobutoxy, n-pentyloxy, and the like. Unless otherwise specified, when propyl and isopropyl are present simultaneously in a parallel option, the propyl indicates n-propyl. When only propyl is present in a parallel option, the propyl indicates n-propyl or isopropyl.

[0316] The term "alkylthio," as used herein, refers to a group having the structure -S-alkyl, where alkyl is as defined above. 1-10 "Alkylthio" refers to alkylthio having 1-10 carbon atoms, C 1-6 Alkylthio is preferred, C 1-4 Alkylthio is more preferred, C 1-3 Specific examples of the alkylthio group include, but are not limited to, methylthio, ethylthio, propylthio, isopropylthio, butylthio, tert-butylthio, isobutylthio, and pentylthio.

[0317] The term "alkenyl" as used herein refers to an alkyl as defined above having one or more carbon-carbon double bonds at any point in the chain, and includes "C 2-8 The term "alkenyl" refers to an alkenyl having 2-8 carbon atoms and at least one carbon-carbon double bond. An alkenyl having 2-6 carbon atoms and 1-2 carbon-carbon double bonds, i.e., C 2-6 Alkenyl is preferred. Alkenyl having 2-4 carbon atoms and 1-2 carbon-carbon double bonds, i.e., C 2-4 Alkenyl is more preferred. Specific examples of the alkenyl group include, but are not limited to, a vinyl group, a 1-propenyl group, a 2-propenyl group, a 1-, 2- or 3-butenyl group, a pentenyl group, a hexenyl group, and a butadienyl group.

[0318] The term "alkynyl" as used herein is an alkyl as defined above having one or more carbon-carbon triple bonds at any point along the chain. 2-8 An "alkynyl group" refers to an alkynyl having 2-8 carbon atoms and at least one carbon-carbon triple bond. An alkynyl having 2-6 carbon atoms and 1-2 carbon-carbon triple bonds, i.e., C 2-6Alkynyl is preferred. Alkynyl having 2-4 carbon atoms and 1-2 carbon-carbon triple bonds, i.e., C 2-4 Alkynyl is more preferred. Specific examples of alkynyl include, but are not limited to, an ethynyl group, a 1-propynyl group, a 2-propynyl group, and a 1-, 2-, or 3-butynyl group.

[0319] As used herein, the term "halogen" refers to fluorine, chlorine, bromine and iodine.

[0320] As used herein, the term "halogenated alkyl" refers to an alkyl substituted with one or more (e.g., 1, 2, 3, 4, or 5) halogens, where alkyl is as defined above. 1-10 The term "alkyl group" refers to a halogenated alkyl group having 1 to 10 carbon atoms. 1-6 Alkyl is preferred. Halogenated C 1-4 Alkyl is more preferred. Halogenated C 1-3 Specific examples of alkyl halides include, but are not limited to, chloromethyl, dichloromethyl, trichloromethyl, monochloroethyl, 1,2-dichloroethyl, trichloroethyl, bromoethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, and the like.

[0321] As used herein, the term "deuterated alkyl" refers to an alkyl substituted with one or more (e.g., 1, 2, 3, 4, or 5) deuterium atoms, as defined above. 1-10 "Alkyl" refers to a deuterated alkyl having 1-10 carbon atoms. 1-6 Alkyl is preferred. Deuterated C 1-4 Alkyl is more preferred. Deuterated C 1-3Alkyl is more preferred. Specific examples of deuterated alkyl include, but are not limited to, deuterated methyl, methyl-D2, methyl-D3, deuterated ethyl, 1,2-deuterated ethyl, ethyl-D3, and the like.

[0322] The term "halogenated alkoxy" as used herein refers to an alkoxy substituted with one or more (e.g., 1, 2, 3, 4, or 5) halogens, the definition of which is as set forth above. 1-10 "Alkoxy" refers to a halogenated alkoxy having 1 to 10 carbon atoms. 1-6 Alkoxy is preferred. Halogenated C 1-4 Alkoxy is more preferred. Halogenated C 1-3 Alkoxy is more preferred. Specific examples of halogenated alkoxy groups include, but are not limited to, trifluoromethoxy, trifluoroethoxy, monofluoromethoxy, monofluoroethoxy, difluoromethoxy, and difluoroethoxy groups.

[0323] As used herein, the terms "cycloalkyl" and "cycloalkyl ring" can be used interchangeably and refer to a saturated monocyclic or polycyclic fused cyclic hydrocarbon group. 3-20 "Cycloalkyl" refers to a cycloalkyl group having 3-20 carbon atoms, including monocyclic cycloalkyls, spirocycloalkyls, fused cycloalkyls, and bridged cycloalkyls. 3-12 Cycloalkyl is preferred. In the present invention, the ring-forming carbon atoms of the cycloalkyl may be substituted with one, two or three oxo atoms to form a cyclic ketone structure. 3-8 Monocyclic cycloalkyl" and "C 3-8 "Cycloalkyl" refers to a saturated monocyclic hydrocarbon group having 3-8 carbon atoms, 3-6 Monocyclic cycloalkyl (i.e., C 3-6C3, C4, C5 or C6 monocyclic cycloalkyl is preferred. Specific examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, etc.

[0324] The terms "spirocycloalkyl" and "spirocycloalkyl ring" as used herein refer to a polycyclic hydrocarbon group formed by two or more monocyclic rings sharing one carbon atom (referred to as a spiro atom) between them. Depending on the number of spiro atoms shared between the monocyclic rings, spirocycloalkyls are divided into monospirocycloalkyls, bisspirocycloalkyls, and polyspirocycloalkyls. The terms "5-20 membered spirocycloalkyl" or "C 5-20 "Spirocycloalkyl" refers to a polycyclic cyclic hydrocarbon group having 5-20 ring carbon atoms, and the monocyclic rings sharing the spiro atom are 3-8 membered monocyclic cycloalkyl rings. 6-14 ) spiroalkyl is preferred. 6-14 membered monospirocycloalkyl is more preferred. 7-11 membered (C 7-11 ) spiroalkyl is more preferred. 7- to 11-membered monospirocycloalkyl is more preferred. 7-membered (4-membered monocycloalkyl / 4-membered monocycloalkyl ring), 8-membered (4-membered monocycloalkyl ring / 5-membered monocycloalkyl ring), 9-membered (4-membered monocycloalkyl ring / 6-membered monocycloalkyl ring, 5-membered monocycloalkyl ring / 5-membered monocycloalkyl ring), 10-membered (5-membered monocyclic cycloalkyl ring / 6-membered monocyclic cycloalkyl), or 11-membered (6-membered monocycloalkyl ring / 6-membered monocycloalkyl) monospirocycloalkyl is most preferred. Specific examples of spiroalkyl include, but are not limited to, the following structures:

[0325] [ka]

[0326] The cycloalkyl ring may be fused to an aryl, heteroaryl, or heterocyclyl ring, and the ring connected to the parent structure is a cycloalkyl ring, and specific examples include, but are not limited to, indane, tetrahydronaphthyl, benzocycloheptyl, etc. In the present invention, each of the above types of cycloalkyl may be substituted. When substituted, the substituents are preferably one or more of the substituents described herein.

[0327] As used herein, the term "halogenated cycloalkyl" refers to a cycloalkyl group substituted with one or more (e.g., 1, 2, 3, 4, or 5) halogens, where cycloalkyl is defined above. 3-8 "Cycloalkyl" refers to a halogenated cycloalkyl having 3-8 carbon atoms. 3-6 Cycloalkyl is preferred. A halogenated C3 cycloalkyl, a halogenated C4 cycloalkyl, a halogenated C5 cycloalkyl, or a halogenated C6 cycloalkyl is more preferred. Specific examples of halogenated cycloalkyl groups include, but are not limited to, trifluorocyclopropyl, monofluorocyclopropyl, monofluorocyclohexyl, difluorocyclopropyl, difluorocyclohexyl, etc.

[0328] As used herein, the terms "heterocyclyl" and "heterocyclyl ring" may be used interchangeably and refer to saturated or partially unsaturated monocyclic or polycyclic fused ring hydrocarbon groups, including "C 3-20 The term "heterocyclyl" or "3- to 20-membered heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic fused ring hydrocarbon group having 3-20 ring-forming atoms, one or more (preferably 1, 2, 3, or 4) of which ring-forming atoms are nitrogen, oxygen, or S(O). m(where m is an integer of 0-2), but does not include the ring moiety of -OO-, -OS-, or -SS-, and the other ring-forming atoms are carbon. When a ring-forming atom is a nitrogen atom, it may be substituted (i.e., N or NR, where R is hydrogen or another substituent as defined herein). In the present invention, the carbon atoms of the heterocyclyl may be optionally substituted with 1, 2, or 3 oxo to form a cyclic ketone, cyclic lactone, or cyclic lactam structure. In the present invention, the 3- to 20-membered heterocyclyl group includes a monocyclic heterocyclyl group, a spiroheterocyclyl group, a fused heterocyclyl group, and a bridged heterocyclyl group.

[0329] As used herein, "C 3-8 The terms "monocyclic heterocyclyl group," "3- to 8-membered monocyclic heterocyclyl group," and "3- to 8-membered monocyclic heterocyclyl ring" refer to a group having 3-8 ring-forming atoms, where 1, 2, or 3 of the ring-forming atoms are nitrogen, oxygen, or S(O). m (wherein m is an integer of 0 to 2). A 3- to 6-membered monocyclic heterocyclyl (i.e., C 3-6 Monocyclic heterocyclyl) is preferred. Five- or six-membered monocyclic heterocyclyl groups having five or six ring-forming atoms, one or two of which are heteroatoms, are more preferred. When the heteroatom is a nitrogen atom, the nitrogen atom may be substituted (i.e., N or NR, where R is hydrogen or another substituent as defined herein). When the heteroatom is a sulfur atom, the sulfur atom may be oxidized (i.e., S(O) m, m is an integer of 0-2). The ring-forming carbon atoms of the monocyclic heterocyclyl group may be optionally substituted with 1, 2, or 3 oxo groups to form a cyclic ketone, cyclic lactone, or cyclic lactam structure. Specific examples of monocyclic heterocyclyl groups include aziridine, ethylene oxide, azetidine, azetidin-2-one, oxetane, oxetan-2-one, oxazolidine, pyrrolidin-2-one, pyrrolidine-2,5-dione, 1,3-dioxolane, dihydrofuran-2(3H)-one, dihydrofuran-2,5-dione, piperidin-2-one, piperidin-2,6-dione, tetrahydro-2H-pyran-2-one, imidazolidine, tetrahydrofuran, tetrahydrothiophene, Pyrrolidine, 1,3-dioxolan-2-one, oxazolidin-2-one, imidazolidin-2-one, piperidine, piperazine, piperazin-2-one, morpholine, morpholin-3-one, morpholin-2-one, thiomorpholin-3-one-1,1-dioxide, thiomorpholine, thiomorpholine-1,1-dioxide, tetrahydropyran, 1,2-dihydroazacyclobutadiene, 1,2-dihydrooxacyclobutadiene, 2,5-dihydro-1H-pyrrole, 2,5-dihydro- Dorofuran, 2,3-dihydrofuran, 2,3-dihydro-1H-pyrrole, 3,4-dihydro-2H-pyran, 1,2,3,4-tetrahydropyridine, 3,6-dihydro-2H-pyran, 1,2,3,6-tetrahydropyridine, 1,3-oxazine, hexahydropyrimidine, 1,4-dioxane, tetrahydropyrimidine-2(1H)-ketone, 1,4-dioxan-2-one, 5,6-dihydro-2H-pyran-2-one, 5,6-dihydropyrimidin-4(3H)-one, 3, 4-Dihydropyridin-2(1H)-one, 5,6-dihydropyridin-2(1H)-one, 5,6-dihydropyrimidin-4(1H)-one, pyrimidin-4(3H)-one, pyrimidin-4(1H)-one, 4,5-dihydro-1H-imidazole, 2,3-dihydro-1H-imidazole, 2,3-dihydrooxazole, 1,3-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-imidazol-2-one, furan Examples of suitable amines include, but are not limited to, 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, and the like. 3-8 "Heterocycloalkyl" and "3- to 8-membered monocyclic heterocyclyl" are saturated monocyclic hydrocarbon groups having 3 to 8 ring atoms, one or two of which are heteroatoms. 3- to 6-membered heterocycloalkyls having 3 to 6 ring atoms, one or two of which are heteroatoms, are preferred. Specific examples of heterocycloalkyl include, but are not limited to, aziridine, oxirane, azetidine, oxetanyl, oxazolidinyl, 1,3-dioxolanyl, dioxane, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyrrolyl, piperidyl, piperazinyl, morpholino, thiomorpholinyl, thiomorpholine-1,1-dioxide, tetrahydropyranyl, 1,4-oxazepane, 1,3-oxazepane, 1,3-oxazine, hexahydropyrimidinyl, and 1,4-dioxane.

[0330] Two ring-forming atoms connected to the monocyclic heterocyclyl ring, for example, CC and NC, may be fused with a cycloalkyl, heterocyclic group, aryl or heteroaryl such as a monocyclic cycloalkyl ring, a monocyclic heterocyclyl ring, a monoaryl ring or a 5- or 6-membered monoheteroaryl ring defined in the present invention to form a fused polycycle, and the two ring-forming atoms connected to a monocyclic heterocyclyl group that forms a fused ring with another ring are preferably CC.

[0331] As used herein, "C 6-14 aryl," "C 6-14 aryl ring" and "C 6-14 The term "aromatic ring" may be used interchangeably and refers to an all-carbon monocyclic, all-carbon polycyclic (the rings are covalently connected and not fused), or all-carbon fused polycyclic (i.e., rings that share adjacent pairs of carbon atoms) group having 6-14 ring-forming atoms, in which at least one ring in the group is aromatic, i.e., has a conjugated π-electron system. 6-10 Aryl is preferred. 6-14 The aryl includes monocyclic aryl, polycyclic aryl and aromatic fused polycyclic, specific examples of the monocyclic aryl include phenyl, and specific examples of the polycyclic aryl include biphenyl and the like.

[0332] In the present invention, C 6-14 When the aryl is an aromatic fused polycycle, the aromatic fused polycycle may be a polycyclic group formed by condensing a monoaryl ring with one or more monoaryl rings, and specific examples thereof include, but are not limited to, naphthyl, anthranyl, etc.

[0333] In some embodiments of the present invention, the aromatic fused polycyclic ring may be a polycyclic group formed by condensing a monoaryl ring (e.g., phenyl) with one or more non-aromatic rings, and 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 heterocyclyl ring (preferably a 5- or 6-membered monocyclic heterocyclyl ring in which ring-forming carbon atoms are optionally substituted with 1 or 2 oxygen atoms to form a cyclic lactam or cyclic lactone structure) and a 3- to 6-membered monocyclic cycloalkyl ring (preferably a 5- or 6-membered monocyclic cycloalkyl ring in which ring-forming carbon atoms are optionally substituted with 1 or 2 oxo atoms to form a cyclic ketone structure). The polycyclic group formed by condensing a monoaryl ring with one or more non-aromatic rings is connected to another group or the parent structure by a nitrogen atom or a carbon atom, and the ring connected to the parent structure is a monoaryl ring or a non-aromatic ring.

[0334] In this specification, the fusion of a benzene ring with a 5- or 6-membered monocyclic heterocyclyl ring to form a 9- or 10-membered aromatic fused bicyclic ring refers to the fusion of two adjacent phenyl substituents with the ring-forming atoms connected thereto to form a 5- or 6-membered monocyclic heterocyclyl ring, the 5- or 6-membered monocyclic heterocyclyl ring being as defined above, and the formed 9- or 10-membered aromatic fused bicyclic ring is also referred to as a 9- or 10-membered phenylheterocyclyl ring.

[0335] In this specification, the condensation of a benzene ring with one 5- or 6-membered monocyclic cycloalkyl to form a 9- or 10-membered aromatic fused bicyclic ring refers to the condensation of two adjacent phenyl substituents with the ring-forming atoms connected thereto to form a 5- or 6-membered monocyclic cycloalkyl ring, and the 5- or 6-membered monocyclic cycloalkyl is defined as above, and the formed 9- or 10-membered aromatic fused bicyclic ring is also called a 9- or 10-membered phenylcycloalkyl ring. Specific examples include, but are not limited to, the following structures:

[0336] [ka]

[0337] In the present invention, each of the above types of aryl may be substituted, and when substituted, the substituents are preferably one or more of the substituents described herein.

[0338] As used herein, the terms "heteroaryl," "heteroaryl ring," and "heteroaromatic ring" may be used interchangeably and refer to a monocyclic or fused polycyclic ring (i.e., adjacent pairs of ring-forming atoms are shared. The shared adjacent pairs of ring-forming atoms may be CC or NC) in which ring-forming atoms are independently substituted with at least one heteroatom selected from nitrogen, oxygen, or sulfur, and the nitrogen and sulfur atoms may be oxidized, and the nitrogen atom may be ammoniumated. The heteroaryl has 6, 10, or 14 shared π electrons, and at least one ring in the group is aromatic. "C 5-14 The terms "heteroaryl" and "5- to 14-membered heteroaryl group" refer to heteroaryl groups having 5-14 ring atoms, with 1, 2, 3, or 4 ring atoms being heteroatoms. 5- to 10-membered heteroaryl groups having 5-10 ring atoms, with 1, 2, 3, or 4 ring atoms being heteroatoms, are preferred. In the present invention, C 5-14 The heteroaryl group may be a monoheteroaryl group, a fused bicyclic heteroaryl group, or a fused tricyclic heteroaryl group.

[0339] As used herein, the terms "5- or 6-membered monoheteroaryl group" and "5- or 6-membered monocyclic heteroaryl group" may be used interchangeably and refer to a monocyclic heteroaryl having 5 or 6 ring-forming atoms, of which 1, 2, or 3 ring-forming 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, and pyrazine.

[0340] As used herein, the terms "8- to 10-membered bisheteroaryl" and "8- to 10-membered bicyclic heteroaryl" may be used interchangeably and refer to a fused bicyclic heteroaryl group having 8 to 10 ring atoms, of which 1, 2, 3, 4, or 5 ring atoms are heteroatoms. The fused bicyclic heteroaryl may be a biscyclo group (preferably a 9- or 10-membered bisheteroaryl ring) formed by fusing a monoaryl ring (e.g., phenyl) with a monoheteroaryl ring (preferably a 5- or 6-membered monoheteroaryl ring), or a biscyclo group (preferably a 5- or 6-membered monoheteroaryl ring) with a monoheteroaryl ring (preferably a 5- or 6-membered monoheteroaryl ring). Any two adjacent ring-forming atoms of the monoheteroaryl ring, such as CC, NC, or NN, can be fused with a cycloalkyl, heterocyclic group, aryl, or heteroaryl, such as a monocyclic cycloalkyl ring, a monocyclic heterocyclyl ring, a monoaryl ring, or a 5- or 6-membered monoheteroaryl ring, as defined in the present invention, to form a fused polycycle. The two adjacent ring-forming atoms in the monoheteroaryl ring that forms a fused polycycle with another ring are preferably CC. Specific examples include, but are not limited to, the following structures:

[0341] [ka]

[0342] Illustrative examples of 8-10 membered bisheteroaryl groups include, but are not limited to, 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. The above-mentioned monoheteroaryl, bisheteroaryl formed by fusing a benzene ring and a monoheteroaryl ring, or bisheteroaryl formed by fusing a monoheteroaryl ring and a monoheteroaryl ring may be connected to another group or a parent structure by a nitrogen atom or a carbon atom. In the case of a bisheteroaryl, 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, the following structures:

[0343] [ka]

[0344] In some embodiments of the present invention, the fused bicyclic heteroaryl group or fused trisheteroaryl group may be a polycyclic group formed by fusing a monoheteroaryl ring (preferably a 5- or 6-membered monoheteroaryl ring) with one or more non-aromatic rings, where the ring connected to the parent structure is a monoheteroaryl ring or a non-aromatic ring. Examples of the non-aromatic ring include, but are not limited to, a 3- to 6-membered monocyclic heterocyclyl ring (preferably a 5- or 6-membered monocyclic heterocyclyl ring. The monocyclic heterocyclyl ring may have one or two oxo-substituted ring carbon atoms 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 monocyclic cycloalkyl ring may have one or two oxo-substituted ring carbon atoms to form a cyclic ketone structure), and the like. The polycyclic group formed by condensing the monoheteroaryl ring with one or more non-aromatic rings may be connected to another group or to a parent structure by a nitrogen atom or a carbon atom, and the ring connected to the parent structure is a monoheteroaryl ring or a non-aromatic ring.

[0345] As used herein, the fusion of a 5- or 6-membered monoheteroaryl ring with a 5- or 6-membered monocyclic heterocyclyl ring to form an 8- to 10-membered fused bicyclic heteroaryl group refers to the fusion of adjacent two substituents of the 5- or 6-membered monocyclic heteroaryl group with the ring-forming atoms connected thereto to form a 5- or 6-membered monocyclic heterocyclyl ring, where the 5- or 6-membered monocyclic heterocyclyl ring is defined as above, and the formed 8- to 10-membered fused bicyclic heteroaryl group is also referred to as an 8- to 10-membered heteroaryl heterocyclyl ring.

[0346] In this specification, when a 5- or 6-membered monoheteroaryl ring is fused with one 5- or 6-membered monocyclic cycloalkyl ring to form an 8- to 10-membered fused bicyclic heteroaryl, it means that two adjacent substituents of the 5- or 6-membered monoheteroaryl and the ring-forming atoms connected thereto are fused to form a 5- or 6-membered monocyclic cycloalkyl ring, where the 5- or 6-membered monocyclic cycloalkyl is defined as above, and the formed 8- to 10-membered fused bicyclic heteroaryl is also called an 8- to 10-membered heteroarylcycloalkyl ring. Specific examples include, but are not limited to, the following structures:

[0347] [ka]

[0348] In the present invention, each of the above-mentioned heteroaryls may be substituted, and when substituted, the substituents are preferably one or more of the substituents described herein.

[0349] As used herein, the term "-alkyl-R" refers to a substituent formed when an alkyl group is substituted with one or more R groups, and "-alkyl-" refers to the alkylene or alkylidene group formed after substitution. As described herein, R can be hydroxy, cyano, alkoxy, substituted amino, heterocycloalkyl, heteroaryl, halogenated alkyl, halogenated alkoxy, cycloalkyl, alkynyl, etc., and the groups represented by R are as defined herein. -C 1-6 Alkyl-R is preferred. 1-4 Alkyl-R is more preferred. 1-3 Alkyl-R is more preferred. 1-2 Alkyl-R is more preferred, for example, -CH2-CH(CH3)-R, -CH2-CH2-CH2-R, -CH2-CH2-R, -CH2-R, and the like.

[0350] The term "hydroxy" as used herein refers to --OH.

[0351] As used herein, the term "hydroxymethyl" refers to -CHOH. "Hydroxyethyl" refers to -CHCHOH or -CH(OH)CH.

[0352] As used herein, the term "cyanomethyl" refers to -CHCN. "Cyanoethyl" refers to -CHCHCN or -CHCNCH.

[0353] The term "amino" as used herein refers to --NH.sub.2.

[0354] As used herein, the term "cyano" refers to --CN.

[0355] The term "nitro" as used herein refers to -NO2.

[0356] The term "benzyl" as used herein refers to -CH2-benzene.

[0357] The term "oxo" as used herein refers to =O.

[0358] As used herein, the term "carboxyl" refers to --C(O)OH.

[0359] As used herein, the term "carboxylic acid ester" refers to -C(O)O(alkyl) or -C(O)O(cycloalkyl).

[0360] The term "acetyl" as used herein refers to -COCH3.

[0361] In this specification, C 1-10 is C 1-6 is preferred, and C 1-4 is more preferred, and C 1-3 is more preferable. For example, C 1-10 The alkyl group is C 1-6 Alkyl groups are preferred, and C 1-4 Alkyl groups are more preferred, and C 1-3Alkyl groups are more preferred. For example, C 1-10 Alkoxy groups are C 1-6 Alkoxy groups are preferred, C 1-4 Alkoxy groups are more preferred, C 1-3 Alkoxy groups are more preferred.

[0362] In this specification, C 3-20 is C 3-10 is preferred, and C 3-8 is more preferred, and C 3-6 is more preferred, and C 3-5 is more preferable. For example, C 3-20 The cycloalkyl group is C 3-8 Cycloalkyl groups are preferred, C 3-6 Cycloalkyl groups are more preferred, C 3-6 Cycloalkyl groups are more preferred.

[0363] In one embodiment of the present invention, in any group, 3-6 The cycloalkyl group is selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0364] According to one embodiment of the present invention, in any of the groups, the 3- to 6-membered heterocycloalkyl is selected from aziridine, ethylene oxide, azetidine, oxetane, tetrahydrofuran, tetrahydrothiophene, pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, thiomorpholine-1,1-dioxide, and tetrahydropyran.

[0365] According to one embodiment of the present invention, in any of the groups, the 5- or 6-membered monoheteroaryl is selected from thiophene, N-alkylcyclopyrrole, furan, thiazole, isothiazole, imidazole, oxazole, pyrrole, pyrazole, triazole, 1,2,3-triazole, 1,2,4-triazole, 1,2,5-triazole, 1,3,4-triazole, 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.

[0366] According to one embodiment of the present invention, in any of the groups, the 8-10 membered bicyclic heteroaryl group is selected from benzoxazole, benzisoxazole, benzimidazole, benzothiazole, benzisothiazole, benzotriazole, benzofuran, benzothiophene, indole, indazole, isoindole, quinoline, isoquinoline, quinazoline, quinoxaline, cinnoline, pyridopyrimidine, and naphthyridine.

[0367] The term "substituted" as used herein refers to the replacement of any one or more hydrogen atoms connected to a particular atom with a substituent, and may include deuterium and hydrogen variants, provided that the valence of the particular atom is normal and the substituted compound is stable. When a substituent is an oxo group (i.e., =O), this means that two hydrogen atoms are replaced. Oxo group substitution does not occur in aromatic groups. The terms "optionally substituted" or "optionally substituted" refer to either substituted or unsubstituted, and unless otherwise specified, the type and number of substituents may be any that are chemically feasible.

[0368] When any variable (e.g., R) occurs more than one time in a compound composition or structure, its definition at each occurrence is independent. Thus, for example, if a group is substituted with 0-2 R, then said group may be optionally substituted with up to 2 R, and each occurrence of R is independently selected. Also, combinations of substituents and / or variants thereof are permissible only if such combinations result in stable compounds.

[0369] The compounds of formula (IA) and formula (IB) according to the present invention can be prepared using synthetic methods known in the art or a combination of methods known in the art and the methods described in the present invention. The solvents, temperatures, and other reaction conditions provided in the present invention are all exemplary and may be modified based on methods known in the art. The compounds of the Examples described in the present invention may be synthesized using appropriate starting materials according to their specific structures using methods described in the Examples, or may be obtained by synthesis using methods similar to those described in the Examples. The starting materials for synthesizing the compounds of the Examples of the present invention can be prepared by known synthetic methods or similar methods described in the literature, or can be commercially available. The compounds of the Examples can be further resolved, if necessary, to obtain their stereoisomers by methods known in the art, such as crystallization or chromatography, and the resolution conditions can be easily obtained by those skilled in the art through known means or limited experimentation.

[0370] The compounds represented by formula (IB-1') and formula (IB-2') according to the present invention can be synthesized by the following method, and the solvent, temperature, and other reaction conditions in each step may be the same as or similar to those described in the following examples, or reaction conditions known in the art may be used.

[0371] [ka]

[0372] The compounds represented by formula (IB-1') and formula (IB-2') according to the present invention can also be synthesized by the following method, and the solvent, temperature and other reaction conditions in each step may be the same as or similar to those described in the following examples, or reaction conditions known in the art may be used.

[0373] [ka]

[0374] In the preparation scheme of the compounds represented by formula (IB-1′) and formula (IB-2′), R lev is a leaving group well known to those skilled in the art, such as a trifluoromethanesulfonate group, chlorine, bromine, iodine, a sulfonate group such as methanesulfonate, toluenesulfonate, p-toluenesulfonate, etc., and an acyloxy group such as acetoxy, trifluoroacetoxy, etc. In each formula, R p are amino-protecting groups well known in the art, such as formyl, acyl such as alkanoyl (e.g., acetyl, trichloroacetyl, or trifluoroacetyl), alkoxycarbonyl such as tert-butoxycarbonyl (Boc), arylmethoxycarbonyl such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethyloxycarbonyl (Fmoc), arylmethyl such as benzyl (Bn), trityl group (Tr), 1,1-di-(4'-methoxyphenyl)methyl, silyl such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS), and the like. 21 , R 22 , R 12 , R 11 , R 31 , R 32 , R m The definitions of R', R0', Ar', E1', and X1 are the same as above (for example, the definitions of the corresponding groups in Formula I are the same as those in Formula IA).

[0375] The compounds of formula (IB-1″) and formula (IB-2″) according to the present invention can be synthesized by the following methods, and the solvents, temperatures and other reaction conditions in each step may be the same as or similar to those described in the following examples, or reaction conditions known in the art may be used.

[0376] [ka]

[0377] In the preparation scheme of the compounds of formula (IB-1″) and formula (IB-2″), in each formula, R p are amino-protecting groups well known in the art, such as formyl, acyl, e.g., alkanoyl (e.g., acetyl, trichloroacetyl, or trifluoroacetyl), alkoxycarbonyl, e.g., tert-butoxycarbonyl (Boc), arylmethoxycarbonyl, e.g., benzyloxycarbonyl (Cbz) and 9-fluorenylmethyloxycarbonyl (Fmoc), arylmethyl, e.g., benzyl (Bn), trityl group (Tr), 1,1-di-(4′-methoxyphenyl)methyl, silyl, e.g., 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 defined as above (for example, the definitions of the corresponding groups in Formula I are the same as those in Formula IA).

[0378] The compound of formula e can be further synthesized by the following methods, and the solvent, temperature and other reaction conditions in each step may be the same as or similar to those described in the following examples, or may be reaction conditions known in the art.

[0379] [ka]

[0380] In the preparation scheme of the compound represented by formula e, R lev is a leaving group well known to those skilled in the art, and examples thereof include a trifluoromethanesulfonate group, chlorine, bromine, iodine, a sulfonate group such as methanesulfonate, toluenesulfonate, or p-toluenesulfonate, and an acyloxy group such as acetoxy or trifluoroacetoxy. The definitions of R0', Ar', E1', and X1 are the same as those described above (e.g., the same as the definitions of the corresponding groups in Formula I and Formula IA). [Brief explanation of the drawings]

[0381] [Figure 1] FIG. 1 is a diagram of the molecular three-dimensional structure of compound Z25-2 by single crystal X-ray diffraction. [Figure 2] FIG. 1 is a diagram of the molecular three-dimensional structure of compound Z27-2 by single crystal X-ray diffraction. DETAILED DESCRIPTION OF THE INVENTION

[0382] The compounds according to the present invention can be prepared by various synthetic methods known to those skilled in the art, including the specific embodiments listed below, embodiments obtained by combining them with other chemical synthetic methods, and equivalent substitution methods known to those skilled in the art. Preferred embodiments include, but are not limited to, the examples of the present invention. The present invention will be described in detail below using examples, but this does not imply any adverse limitations on the present invention. This specification describes the present invention in detail, but specific examples thereof are disclosed, and it is obvious to those skilled in the art that various modifications and improvements can be made to the specific embodiments of the present invention without departing from the spirit and scope of the present invention. Specific conditions not specified in the examples are carried out under standard conditions or conditions provided by the manufacturer. Unless the manufacturer is specified, the reagents or equipment used are all commercially available and commonly available products.

[0383] The abbreviations for 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: acetonitrile, IPA: isopropylamine, DMA: dimethylamine, TFA: trifluoroacetic acid, NHCl: ammonium chloride, SPhos: 2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl, SPhos-Pd-G2: chloro(2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II), NaHMDS: sodium bis(trimethylsilyl)amide, LiHMDS: lithium bis(trimethylsilyl)amide.

[0384] The preparative HPLC used in the following examples can employ the following conditions. Column: Waters XAFSC18, 190*250 mm, 5 μm Mobile phase: A: 0.1% ammonium bicarbonate aqueous solution B: Acetonitrile (preparative grade) Flow rate: 15ml / min;B%=20%-100%; Column temperature: room temperature

[0385] When an analytical HPLC method is used to detect isomeric compounds, the following conditions can be employed. Column: XBridge C18, 3.5μm 4.6*150mm Mobile phase: A: Purified water (0.05%TFA) B: Acetonitrile (preparative grade) (0.05% TFA) Gradient: 5%-95%B, Runtime: 15min, Flow rate: 1ml / min Column temperature: 40°C.

[0386] Example 1 Preparation of Compounds Z1, Z1-1 and Z1-2

[0387] [ka]

[0388] 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 and 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 added dropwise. The mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into 30 mL of saturated NH4Cl. The mixture was extracted three times with 40 mL of ethyl acetate. The organic layer was dried and concentrated. The crude product was purified using a high-performance silica gel column (0-5% MeOH / DCM) to give the product as a yellow solid: 5-fluoro-6-(2-fluoro-6-methoxyphenyl)-2-((2-isopropyl-4-methylpyridin-3-yl)amino)nicotinic acid (850 mg, Y: 58.2%). ES-API: [M+H] + =414.1 Step 2: 5-Fluoro-6-(2-fluoro-6-methoxyphenyl)-2-((2-isopropyl-4-methylpyridin-3-yl)amino)nicotinic acid (700 mg, 1.69 mmol) was dissolved in 1,2-dichloroethane (15 mL), and SOCl (2.0 g, 16.90 mmol) was added and stirred at 80 °C for 2 hours. After concentration, the product 5-fluoro-6-(2-fluoro-6-methoxyphenyl)-2-((2-isopropyl-4-methylpyridin-3-yl)amino)nicotinic acid chloride was obtained (721 mg, Y: 100%), which was used directly in the next reaction without any need for purification. Step 3: At 0°C, a solution of ethyl nitroacetate (449 mg, 3.38 mmol) in 2 mL of THF was added dropwise to a suspension of NaH (608 mg, 15.21 mmol) in 25 mL of THF and stirred at 0°C for 0.5 hours. A solution of 5-fluoro-6-(2-fluoro-6-methoxyphenyl)-2-((2-isopropyl-4-methylpyridin-3-yl)amino)nicotinic acid chloride (721 mg, 1.69 mmol) in 15 mL of THF was added dropwise. The ice bath was removed, and the reaction mixture was stirred at 70°C overnight. The reaction mixture was poured into ice water, adjusted to pH 3 with 3.0 M dilute hydrochloric acid, and extracted three times with ethyl acetate. The organic layer 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 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, followed by stirring at 80 °C for 1 hour. The reaction mixture was concentrated, and then ethyl acetate was added. The mixture was washed sequentially with ice water, water, and saturated brine. The organic layer was dried and concentrated, and the crude product was purified by high-performance silica gel column chromatography (EtOAc / PE: 0-50%) to give the product as a yellow solid: 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%). ES-API: [M+H] + =500.1 Step 5: 4-Chloro-6-fluoro-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro-1,8-naphthyridin-2(1H)-one (175 mg, 0.35 mmol) was dissolved in DMF (6 mL), and (R)-3-(hydroxymethyl)piperazine-1-carboxylic acid tert-butyl ester (454 mg, 2.10 mmol) was added and stirred at 80° C. for 18 hours. The reaction mixture was poured into 30 mL of water and extracted three times with 20 mL of ethyl acetate. The organic layer was washed three times with saturated brine, dried, and concentrated. The crude product was then purified using a high-performance silica gel column (EtOAc / PE: 0-70%) to obtain the yellow solid product (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%). ES-API: [M+H] + =681.3. Step 6: (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 (73 mg, 0.11 mmol) was dissolved in DMA (4 mL), NaH (22 mg, 0.55 mmol) was added, and the mixture was stirred at 145° C. for 10 hours. The cooled reaction mixture was poured into 15 mL of water and extracted three times with 30 mL of ethyl acetate. The organic layer was washed three times with saturated brine, dried, and concentrated. The crude product was purified by thin-layer chromatography (dichloromethane / methanol = 20:1) to obtain the yellow solid product (4aR)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-7-oxo-1,2,4a,5,7,8-hexahydropyrazine[1',2':4,5][1,4]oxo-2,3-c][1,8]naphthyridine-3(4H)-carboxylic acid tert-butyl ester (35 mg, Y: 51.5%). ES-API: [M+H] + =634.2 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), trifluoroacetic acid (0.5 mL) was added, and the mixture was stirred at room temperature for 0.5 hours. The reaction mixture was concentrated to give (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. Step 8: 4aR)-11-Fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-1,2,3,4,4a,5-hexahydropyrazine[1',2':4,5][1,4]oxazine[2,3-c][1,8]naphthyridin-7(8H)-one (40 mg, 0.055 mmol) was dissolved in dichloromethane (4 mL), triethylamine (28 mg, 0.28 mmol) was added, the reaction mixture was cooled to 0 °C, and a dichloromethane solution (0.5 mL) of acrylic anhydride (6 mg, 0.05 mmol) was added dropwise to the reaction mixture. The mixture was stirred at 0 °C for 15 min. 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 layer was dried and concentrated. The crude product was purified by thin-layer chromatography (dichloromethane / methanol = 10:1) to give the product, (4aR)-3-acryloyl-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-1,2,3,4,4a,5-hexahydropyrazine[1',2':4,5][1,4]oxazine[2,3-c][1,8]naphthyridin-7(8H)-one, as a pale yellow solid. ES-API: [M+H] + =588.2. Step 9: (4aR)-3-Acryloyl-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-1,2,3,4,4a,5-hexahydropyrazine[1',2':4,5][1,4]oxazine[2,3-c][1,8]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 mixture was stirred at room temperature for 3 hours. 20 mL of saturated aqueous NaHCO3 was added to the reaction mixture, which was then extracted three times with 20 mL of dichloromethane. The organic layer was dried and concentrated. 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]naphthyridin-7(8H)-one (Z1: 10 mg, Y: 68.3%), as a white solid. 1 H NMR (500MHz, DMSO-d6) δ9.96(s, 1H), 8.35(d, J=4.8Hz, 1H), 7.19-7.14(m, 2H), 6.87-6.75(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. Step 10: Compound Z1 was separated by chiral preparative HPLC (column: Chiralpak IC: 10 μm, 20*250 mm, mobile phase: acetonitrile:isopropyl alcohol:aminomethanol=70:30:0.2, flow rate: 15 ml / min, column temperature: room temperature) to give a pale yellow solid atropisomeric compound, the structure of which was assigned to Z1-1 (75 mg, peak 1, retention time 3.94 min, Y: 15.4%). 1 H 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), 5.82-5.69(m, 1H), 4.49-4.00(m, 4H), 3.90-3.43(m, 4H), 3.08(t, J=11.0 Hz, 1H), 2.64-2.55(m, 1H), 1.80(s, 3H), 1.05(d, J=6.7Hz, 3H), 0.91(d, J=6.7Hz, 3H).ES-API:[M+H] + =574.2. Another atropisomer compound obtained was a pale yellow solid, and its structure was designated as Z1-2 (115 mg, peak 2, retention time: 5.04 min, Y: 23.6%). 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 isomeric compounds were detected by analytical chiral HPLC (column: Chiralpak IC: 5 μm, 4.6 * 250 mm, mobile phase: acetonitrile: isopropyl alcohol: aminomethanol = 70:30:0.2, flow rate: 1 ml / min, column temperature: 30 ° C.).

[0389] Example 2 Preparation of Compound Z2

[0390] [ka]

[0391] Step 1: At room temperature, 5-(methoxymethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (2.9 g, 15.62 mmol) and isopropyl alcohol (40 mL) were added to a 100 mL flask, and 2-chloropyridin-3-amine (2.0 g, 15.62 mmol) was added batchwise. The mixture was refluxed and stirred for 15 minutes. The reaction mixture was cooled to room temperature. The precipitated solid was filtered, and the filter cake was washed with a small amount of isopropyl alcohol. The mixture was dried in vacuo to obtain the product as a white solid: 5-((2-chloropyridin-3-yl)amino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (3.90 g, Y: 58.2%). ES-API: [M+H] + =283.1 Step 2: 200 mL of diphenyl ether was added to a 500 mL flask and heated to 220 °C. 5-((2-chloropyridin-3-yl)amino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (3.9 g, 13.83 mmol) was added batchwise and stirred at 220 °C for 20 minutes. The reaction mixture was cooled to room temperature and then poured into petroleum ether. The precipitated solid was filtered and washed with petroleum ether. The product was dried in vacuo to give 8-chloro-1,7-naphthyridin-4-ol (1.5 g, Y: 60%) as a light brown solid. ES-API: [M+H] + =181.0 Step 3: A 50 mL flask was charged with 8-chloro-1,7-naphthyridin-4-ol (500 mg, 2.78 mmol), sodium acetate (300 mg, 2.78 mmol), absolute ethanol (25 mL), and 5% Pd / C (250 mg). The mixture was stirred at room temperature under a hydrogen atmosphere for 3 days. The reaction mixture was filtered through diatomaceous earth, and the filtrate was concentrated. The crude product was then purified using a high-performance silica gel column (dichloromethane / methanol: 0-10%) to obtain the product as a yellow solid, 1,7-naphthyridin-4-ol (200 mg, Y: 49.3%). ES-API: [M+H] + =147.1 Step 4: 1,7-Naphthyridin-4-ol (550 mg, 3.77 mmol) was dissolved in concentrated sulfuric acid (4.5 mL) and cooled to 0°C. Concentrated nitric acid (1.0 mL, 15.08 mmol) was slowly added dropwise, and the mixture was stirred at 100°C for 1 hour. The cooled reaction mixture was poured into ice water. The pH was adjusted to 6-7 with concentrated aqueous ammonia, and the precipitated solid was filtered. The product was dried in vacuo to give 3-nitro-1,7-naphthyridin-4-ol (530 mg, Y: 73.7%) as a yellow solid. ES-API: [M+H] + =192.1 Step 5: A 20 mL flask was charged with 3-nitro-1,7-naphthyridin-4-ol (480 mg, 2.51 mmol) and phosphorus oxychloride (4.68 mL, 50.20 mmol) and cooled to -15 °C. Triethylamine (1.8 mL, 12.55 mmol) was slowly added dropwise and stirred at room temperature for 1 hour. The reaction mixture was poured into ice water, adjusted to pH 8 with cold saturated sodium bicarbonate solution, and extracted three times with dichloromethane. The organic layer was 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. Step 6: 4-Chloro-3-nitro-1,7-naphthyridine (450 mg, 2.15 mmol) was dissolved in 1,4-dioxane (15 mL), and (R)-3-(hydroxymethyl)piperazine-1-carboxylic acid tert-butyl ester (1.02 g, 4.73 mmol) and N,N-diisopropylethylamine (832 mg, 6.45 mmol) were added sequentially. The mixture was stirred at 80 °C for 3 h. The reaction mixture was concentrated, and the crude product was purified using a high-performance silica gel column (EtOAc / PE: 50-100%) to give the product as a yellow solid (330 mg, Y: 39.4%). ES-API: [M+H] + =390.2. Step 7: (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) were added to a 50 mL tube and stirred at 95 °C for 3 days. The cooled reaction mixture was poured into water and extracted twice with ethyl acetate. The organic layer was washed three times with saturated brine, dried, and concentrated. The crude product was purified by thin-layer chromatography (dichloromethane / methanol = 15:1) to give (R)-tert-butyl 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 Step 8: (R)-8a,9,11,12-tetrahydropyrazine[1',2':4,5][1,4]oxazine[2,3-c][1,7]naphthyridine-10(8H)-tert-butyl carboxylate (100 mg, 0.29 mmol) was dissolved in acetic acid (4 mL), sodium cyanoborohydride (73 mg, 1.16 mmol) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was poured into ice water, adjusted to pH 8 with saturated sodium bicarbonate solution, and extracted twice with dichloromethane. The organic layer was washed with saturated brine. After drying and concentration, the crude product was purified by thin-layer chromatography (dichloromethane / methanol / aqueous ammonia = 100:8:1) to give the product as a pale yellow solid (50 mg, Y: 49.4%): (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)-tert-butyl carboxylate. ES-API: [M+H] + =390.2. Step 9: To a 5 mL microtube, add (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)-tert-butyl carboxylate (50 mg, 0.14 mmol), 4-bromo-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (83 mg, 0.28 mmol), cesium carbonate (136 mg, 0.42 mmol), Pd(dba) (51 mg, 0.056 mmol), Ruphos (26 mg, 0.056 mmol), and toluene (6 mL). The atmosphere was replaced with nitrogen gas, and the mixture was heated for 120 min in a microwave reactor. oThe mixture was stirred at RT for 1 hour. The mixture was cooled to room temperature, filtered, and the filtrate was dried and concentrated. The crude product was purified by thin-layer chromatography (dichloromethane / methanol / aqueous ammonia = 100:5:1) to give (8aR)-3-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-1,2,3,4,8a,9,11,12-octahydropyrazine[1',2':4,5][1,4]oxazine[2,3-c][1,7]naphthyridine-10(8H)-carboxylate tert-butyl ester (60 mg, Y: 74.1%). ES-API: [M+H] + =561.3 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)-carboxylate tert-butyl (60 mg, 0.11 mmol) was dissolved in dichloromethane (3 mL) and trifluoroacetic acid (0.8 mL) was added. After stirring at room temperature for 1 hour, the reaction mixture was concentrated to give the product (R)-3-(5-methyl-1H-indazol-4-yl)-1,2,3,4,8,8a,9,10,11,12-decahydropyrazine[1',2':4,5][1,4]oxazine[2,3-c][1,7]naphthyridine) (60 mg, crude yield). No purification was required, and the product was used directly in the next reaction. ES-API: [M+H] + =377.1. Step 11: (R)-3-(5-methyl-1H-indazol-4-yl)-1,2,3,4,8,8a,9,10,11,12-decahydropyrazine[1',2':4,5][1,4]oxazine[2,3-c][1,7]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 dichloromethane solution (0.5 mL) of acrylic anhydride (13 mg, 0.10 mmol) was added dropwise to the reaction mixture. The mixture was stirred at 0 °C for 10 min. 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 layer was dried and concentrated. 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-octahydropyrazine[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 H NMR (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.

[0392] Example 3 Preparation of Compounds Z3a and Z3

[0393] [ka]

[0394] Step 1: 4-Chloro-6-fluoro-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro-1,8-naphthyridin-2(1H)-one (700 mg, 1.40 mmol) was dissolved in DMF (10 mL), and tert-butyl (2R,5R)-5-(hydroxymethyl)-2-methylpiperazine-1-carboxylate (1.61 g, 7.0 mmol) was added and stirred at 80 ° C for 1 hour. The reaction mixture was poured into 30 mL of water and extracted three times with 20 mL of ethyl acetate. The organic layer was washed three times with saturated brine, dried and concentrated, and then the crude product was purified using a high-performance silica gel column (EtOAc / PE: 0-70%) to obtain the product, 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 (325 mg, Y: 33.4%), as a yellow solid. ES-API: [M+H] + =695.2. Step 2: (2R,5R)-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)-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 mixture was stirred at 125 °C for 20 h. The cooled reaction mixture was poured into 15 mL of water and extracted three times with 30 mL of ethyl acetate. The organic layer was washed eight times with saturated brine. After drying and concentration, the crude product was purified on a high-performance silica gel column (EtOAc / PE: 0-100%) to give the yellow solid product (2R,4aR)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-2-methyl-7-oxo-1,2,4a,5,7,8-hexahydropyrazine[1',2':4,5][1,4]oxydine[2,3-c][1,8]naphthyridine-3(4H)-carboxylate tert-butyl ester (60 mg, Y: 21.4%). ES-API: [M+H]+ = 648.3. 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]oxydine[2,3-c][1,8]naphthyridine-3(4H)-carboxylate tert-butyl (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. The reaction mixture was concentrated to give (2R,4aR)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-2-methyl-1,2,3,4,4a,5-hexahydropyrazine[1',2':4,5][1,4]oxazine[2,3-c][1,8]naphthyridin-7(8H)-one (61 mg, crude product), which was used directly in the next reaction. ES-API: [M+H] + =548.2. Step 4: (2R,4aR)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-2-methyl-1,2,3,4,4a,5-hexahydropyrazine[1',2':4,5][1,4]oxazine[2,3-c][1,8]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 was cooled to 0 °C and a dichloromethane solution (1 mL) of acrylic anhydride (17 mg, 0.14 mmol) was added dropwise to the reaction mixture. The mixture was stirred at 0 °C for 15 min. 10 mL of saturated aqueous NaHCO3 solution was added to the reaction mixture and extracted three times with 10 mL of dichloromethane. The organic layer was dried and concentrated. The crude product was purified by thin-layer chromatography (dichloromethane / methanol = 10:1). The product was a white solid: ((2R,4aR)-3-acryloyl-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-2-methyl-1,2,3,4,4a,5-hexahydropyrazine[1',2':4,5][1,4]oxydin[2,3-c][1,8]naphthyridin-7(8H)-one (Z3a, 32 mg, Y: 57.4%). ES-API: [M+H] + =602.2. 1 H 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), 2.62-2.40(m, 1H), 1.90-1.73(m, 3H), 1.66-1.48(m, 3H), 1.08-0.95(m, 3H), 0.91-0.77(m, 3H). Step 5: (6aR,9R)-8-Acryloyl-3-fluoro-2-(2-fluoro-6-methoxyphenyl)-13-(2-isopropyl-4-methylpyridin-3-yl)-9-methyl-6,6a,7,8,9,10-hexahydropyrazine[1',2':4,5][1,4]oxydine[3,2-c][1,8]naphthyridin-12(cyclohexyl)-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 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 layer was dried and concentrated. The crude product was purified by preparative HPLC to give the product (6aR,9R)-8-acryloyl-3-fluoro-2-(2-fluoro-6-hydroxyphenyl)-13-(2-isopropyl-4-methylpyridin-3-yl)-9-methyl-6,6a,7,8,9,10-hexahydropyrazine[1',2':4,5][1,4]oxidineoxazin[3,2-c][1,8]naphthyridin-12(cyclohexyl)-one (Z3, 18 mg, Y: 57.6%) as a white solid. ES-API: [M+H] + =588.3.

[0395] Example 6 Preparation of Compound Z6

[0396] [ka]

[0397] Step 1: 4,6-Dichloro-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro-1,8-naphthyridin-2(1H)-one (1.8 g, 3.48 mmol) was dissolved in DMF (15 mL), (R)-3-(hydroxymethyl)piperazine-1-carboxylic acid tert-butyl ester (3 g, 13.92 mmol) was added, and the mixture was stirred at 80° C. for 2 hours. The reaction mixture was poured into 30 mL of water and extracted three times with 20 mL of ethyl acetate. The organic layer was washed three times with saturated brine, dried and concentrated, and then the crude product was purified using a high-performance silica gel column (EtOAc / PE: 0-70%) to obtain the product as a yellow solid: 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%). ES-API: [M+H] + =697.2. Step 2: (3R)-tert-Butyl 4-(6-chloro-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro-2-oxo-1,2-dihydro-1,8-naphthyridin-4-yl)-3-(hydroxymethyl)piperazine-1-carboxylate (1.3 g, 1.86 mmol) was dissolved in DMA (10 mL), LHMDS (5.6 mmol, 5.6 mmol, 1 M solution in tetrahydrofuran) was added, and the mixture was stirred at 140° C. for 20 hours. The cooled reaction mixture was poured into 15 mL of water and extracted three times with 30 mL of ethyl acetate. The organic layer was washed three times with saturated brine, dried, and concentrated. The crude product was purified using a high-performance silica gel column (methanol / dichloromethane: 0-10%) to give a yellow solid: (4aR)-11-chloro-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)-carboxylate (0.24 g, 20%). ES-API: [M+H] + =650.2. 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-hexahydropyrazine-[1',2':4,5][1,4]oxazine-[2,3-c][1,8]naphthyridine-3(4H)-carboxylate tert-butyl (240 mg, 0.37 mmol) was dissolved in dichloromethane (2 mL) and trifluoroacetic acid (2 mL) was added. The mixture was stirred at room temperature for 0.5 h. The reaction mixture was concentrated to give (4aR)-11-chloro-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]oxazin-[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. Step 4: (4aR)-11-chloro-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]oxazin-[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 dichloromethane solution (0.5 mL) of acrylic anhydride (37 mg, 0.30 mmol) was added dropwise to the reaction mixture. The mixture was stirred at 0 °C for 10 min. 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 layer was dried and concentrated. The crude product was purified by thin-layer chromatography (dichloromethane / methanol = 10:1) to give a pale yellow solid, (4aR)-3-acryloyl-11-chloro-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]oxazin-[2,3-c][1,8]naphthyridin-7(8H)-one (223 mg, crude product). ES-API: [M+H] + =604.2. 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-hexahydropyrazine-[1',2':4,5][1,4]oxazine-[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 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 layer was dried and concentrated. 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-hexahydropyrazine-[1',2':4,5][1,4]oxazin-[2,3-c][1,8]naphthyridin-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.

[0398] Example 9 Preparation of Compounds Z9, Z9-1 and Z9-2

[0399] [ka]

[0400] Step 1: 4-chloro-6-fluoro-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro-1,8-naphthyridin-2(1H)-one (500 mg, 1.00 mmol) was dissolved in N,N-dimethylacetamide (6 mL) and (R)-1-(tert-butyl-3-methyl-piperazine-1,3-dicarboxylic acid ester (732 N,N-diisopropylethylamine (387 mg, 3.00 mmol) and N,N-diisopropylethylamine (387 mg, 3.00 mmol) were added in that order, and the mixture was stirred at 120°C for 2 hours. 100 mL of ethyl acetate was added to the reaction mixture, and the mixture was washed with 30 mL of diluted brine four times. After washing with 30 mL of saturated brine and concentrating to dryness, the crude product was purified using a high-performance silica gel column (EtOAc / PE: 0-70%) to obtain the product, (3R)-1-(tert-butyl)-3-methyl-4-(6-fluoro-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro-2-oxo-1,2-dihydro-1,8-naphthyridin-4-yl)piperazine-1,3-dicarboxylic acid ester (500 mg, Y: 70.6%) as a yellow solid. ES-API: [M+H] + =709.2. 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-dicarboxylic acid ester (500 mg, 0.71 mmol) was dissolved in acetic acid (8 mL), iron powder (138 mg, 2.47 mmol) was added, and the mixture was stirred at 80 °C for 30 minutes. After concentrating the reaction mixture, 50 mL of ethyl acetate and 30 mL of saturated sodium bicarbonate were added sequentially. The suspension was filtered through diatomaceous earth, and the filter cake was washed with ethyl acetate. The organic layer was separated and washed sequentially with 30 mL of saturated aqueous sodium bicarbonate and 30 mL of saturated brine. The product was dried and concentrated to give a pale yellow solid: (4aR)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-5,7-dioxo-1,2,4,4a,5,6,7,8-octahydro-3H-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8]naphthyridine-3-carboxylate tert-butyl ester (450 mg, Y: 98.6%). ES-API: [M+H] + =647.2. Step 3: To a 15 mL tube was added (4aR)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-5,7-dioxo-1,2,4,4a,5,6,7,8-octahydro-3H-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8]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), in that order. The tube was sealed and stirred at 50 °C for 20 h. The reaction mixture was concentrated, followed by addition of 60 mL of ethyl acetate and washing with 30 mL of water and 30 mL of saturated brine. After drying and concentration, the crude product was purified on a high-performance silica gel column (EtOAc / PE: 0-70%) to obtain the orange solid product (4aR)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-6-methyl-5,7-dioxy-1,2,4,4a,5,6,7,8-octahydro-3H-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8]naphthyridine-3-carboxylate tert-butyl ester (390 mg, Y: 84.8%). ES-API: [M+H] + =661.3. 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-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8]naphthyridine-3-carboxylate tert-Butyl ester (940 mg, 1.42 mmol) was dissolved in dichloromethane (6 mL) and trifluoroacetic acid (2 mL) was added. The reaction mixture was stirred at room temperature for 2 hours, and then concentrated to give (4aR)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-6-methyl-2,3,4,4a,6,8-hexahydro-1H-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8]naphthyridine-5,7-dione (1.1 g, crude product), which was used directly in the next reaction. ES-API: [M+H] + =561.3. Step 5: (4aR)-11-Fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-6-methyl-2,3,4,4a,6,8-hexahydro-1H-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8]naphthyridine-5,7-dione (1.1 g, crude product) 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 acrylic acid chloride (256 mg, 2.84 mmol) was added to the reaction mixture and stirred at 0 °C for 15 min. 30 mL of dichloromethane was added to the reaction mixture and washed sequentially with 15 mL of water, 15 mL of saturated aqueous NaHCO3, and 15 mL of saturated brine. After drying and concentration, the crude product was purified on a high-performance silica gel column (EtOAc / PE: 0-100%) to obtain the product (4aR)-3-acryloyl-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-6-methyl-2,3,4,4a,6,8-hexahydro-1H-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8]naphthyridine-5,7-dione (780 mg, Y: 88.3%) as a pale yellow solid. ES-API: [M+H] + =615.3. Step 6: (4aR)-3-Acryloyl-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-6-methyl-2,3,4,4a,6,8-hexahydro-1H-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8]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 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 layer was washed sequentially with 50 mL of saturated aqueous NaHCO3 and 80 mL of saturated brine. After drying and concentration, the product was obtained as a pale yellow solid: (4aR)-3-acryloyl-11-fluoro-10-(2-fluoro-6-hydroxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-6-methyl-2,3,4,4a,6,8-hexahydro-1H-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8,8]naphthyridine-5,7-dione (Z9: 375 mg, Y: 98.4%). ES-API: [M+H] + =601.2. Step 7: (4aR)-3-Acryloyl-11-fluoro-10-(2-fluoro-6-hydroxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-6-methyl-2,3,4,4a,6,8-hexahydro-1H-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8,8]naphthyridine-5,7-dione (750 mg, 1.25 mmol) was purified by preparative HPLC. This was then further separated by preparative chiral HPLC (column: IB: 10 μm, 30*250 mm, mobile phase: hexane:EtOH=65:35, flow rate: 25 ml / min, column temperature: room temperature). One atropisomer compound was obtained as a pale yellow solid, and its structure was designated as Z9-1 (250 mg, peak 1, retention time: 6.463 min, Y: 33.3%). 1H NMR (500MHz, DMSO-d6) δ10.11 (d, J =1.3Hz, 1H), 8.46-8.34 (m, 2H), 7.30-7.19 (m, 2H), 7.10-6.79 (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. Another atropisomer compound obtained was a pale yellow solid, and its structure was designated as Z9-2 (350 mg, peak 2, retention time 8.252 min, Y: 46.7%). 1 H 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=16.9 Hz, 1H), 5.75(d, J=11.1Hz, 1H), 4.73(d, J=14.0Hz, 1H), 4.45(d, J=12.4Hz, 1H), 4.02-3.89(m, 1H), 3.62-3.50(m, 2) ES-API:[M+H] + = 601.2. The isomeric compounds were detected by analytical chiral HPLC (column: IB: 5 μm, 4.6 * 250 mm, mobile phase: hexane:EtOH = 65:35, flow rate: 1 ml / min, column temperature: 30 °C).

[0401] Example 10 Preparation of Compounds Z10, Z10-1 and Z10-2

[0402] [ka]

[0403] Step 1: To a 50 mL tube was added (2R,4aR)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-2-methyl-5,7-dioxo-1,2,4,4a,5,6,7,8-octyl-3H-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8]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), in that order. The tube was sealed and stirred at 50 °C for 18 h. The reaction mixture was concentrated, followed by addition of 60 mL of ethyl acetate and washing with 20 mL of water and 30 mL of saturated brine. After drying and concentration, the crude product was purified on a high-performance silica gel column (EtOAc / PE: 0-70%) to obtain the orange solid product (2R,4aR)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-2,6-dimethyl-5,7-dioxo-1,2,4,4a,5,6,7,8-octyl-3H-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8]naphthyridine-3-carboxylate tert-butyl ester (790 mg, Y: 96.7%). ES-API: [M+H] + =675.3. Step 2: (2R,4aR)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-2,6-dimethyl-5,7-dioxo-1,2,4,4a,5,6,7,8-octyl-3H-pyrazine[1',2':4,5]pyrazine[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. The reaction mixture was concentrated to give (2R,4aR)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-2,6-dimethyl-2,3,4,4a,6,8-hexahydro-1H-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8]naphthyridine-5,7-dione (810 mg, crude product), which was used directly in the next reaction. ES-API: [M+H] + =575.2. Step 3: (2R,4aR)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-2,6-dimethyl-2,3,4,4a,6,8-hexahydro-1H-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8]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 acrylic acid chloride (211 mg, 2.34 mmol) was added to the reaction mixture and stirred at 0 °C for 15 min. 50 mL of dichloromethane was added to the reaction mixture and washed sequentially with 20 mL of water, 40 mL of saturated aqueous NaHCO3, and 20 mL of saturated brine. After drying and concentration, the crude product was purified by high-performance silica gel column chromatography (EtOAc / PE: 0-100%) to obtain a pale yellow solid product, (2R,4aR)-3-acryloyl-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-2,6-dimethyl-2,3,4,4a,6,8-hexahydro-1H-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8]naphthyridine-5,7-dione (670 mg, Y: 91.0%). ES-API: [M+H] + =629.2. Step 4: (2R,4aR)-3-Acryloyl-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-2,6-dimethyl-2,3,4,4a,6,8-hexahydro-1H-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8]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 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 layer was washed sequentially with 50 mL of saturated aqueous NaHCO3 and 80 mL of saturated brine. After drying and concentration, the crude product was purified by preparative HPLC to obtain the product (2R,4aR)-3-acryloyl-11-fluoro-10-(2-fluoro-6-hydroxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-2,6-dimethyl-2,3,4,4a,6-hexahydro-1H-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8,8]naphthyridine-5-dione (Z10, 249 mg, Y: 68.7%) as a pale yellow solid. ES-API: [M+H] + =615.2. Step 5: Compound Z10 (450 mg, 1.06 mmol) was separated by preparative chiral HPLC (column: OD-H: 10 μm, 20*250 mm, mobile phase: hexane:EtOH = 80:20, flow rate: 15 ml / min, column temperature: room temperature). One atropisomeric compound was obtained as a pale yellow solid, and its structure was designated Z10-1 (206 mg, peak 1, retention time: 8.321 min, Y: 45.7%). 1H NMR (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), 2.9 4-2.78(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. Another atropisomer compound obtained was a yellow solid, and its structure was designated as Z10-2 (209 mg, peak 2, retention time: 10.183 min, Y: 46.4%). 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), 7.06-6.82(m, 1H), 6.75-6.61(m , 2H), 6.21-6.09(m, 1H), 5.80-5.65(m, 1H), 5.05-4.72(m, 1H), 4.63-4.37(m, 1H), 4.01-3.92 (m, 1H), 3.74(dd, J=14.2, 4.2Hz, 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 isomeric compounds were detected by analytical chiral HPLC (column: OD-H: 5 μm, 4.6*250 mm, mobile phase: hexane:EtOH=80:20, flow rate: 1 ml / min, column temperature: 30°C).

[0404] Examples 4-5, 7-8, 11-20

[0405] Compounds Z4 to Z144, Z7 to Z8, and Z11 to Z20 are prepared by methods similar to those used to prepare compounds Z1 or Z2. The starting materials for each compound are commercially available or can be prepared by conventional methods well known to those skilled in the art. The analogous synthetic methods for the intermediates can be easily obtained by those skilled in the art by referring to conventional methods.

[0406] [Table 25]

[0407] [Table 26]

[0408] [Table 27]

[0409] [Table 28]

[0410] Example 21 Preparation of Compounds Z21, Z21-1 and Z21-2

[0411] [ka]

[0412] Step 1: A flask was charged with 7-chloro-6-fluoro-4-hydroxy-1-(4-isopropyl-6-methylpyrimidin-5-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-nitrile (2 g, 5.34 mmol), 12 mL of water, and 12 mL of dioxane. The reaction mixture was cooled to 0°C, and 12 mL of concentrated sulfuric acid was added dropwise to the reaction mixture. After the addition was complete, the mixture was stirred at 120°C for 18 hours. Upon completion of the reaction, a large amount of solid precipitated. The mixture was filtered, and the filter cake was washed three times with water. The filter cake was dried to obtain 7-chloro-6-fluoro-4-hydroxy-1-(4-isopropyl-6-methylpyrimidin-5-yl)-1,8-naphthyridin-2(1H)-one (1.4 g, 75%) as a white solid. The crude product was used directly in the next step. ES-API:[M+H] + =349.1. Step 2: A flask was charged with 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 placed in a 30°C oil bath and heated for 2 hours. The reaction mixture was poured into ice water, and a 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. Step 3: A reaction flask was charged with 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. The mixture was stirred under nitrogen atmosphere in a 110 °C oil bath for 1 hour to complete the reaction. The reaction mixture was added with 1M aqueous potassium carbonate (30 mL) and extracted once with 20 mL of EtOAc / PE (1:1) to remove impurities. The aqueous layer was further adjusted to pH 4 with 6M aqueous hydrochloric acid. Extraction was performed three times with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated. 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%) was obtained as a yellow solid. ES-API: [M+H] + =483.1. Step 4: A flask was charged with 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). Phosphorus oxychloride (2.2 g, 14.5 mmol) was added dropwise to the flask. The mixture was stirred at 85°C for 1 hour. The completion of the reaction was confirmed by LC-MS. The reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated. 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, 83% purity) was obtained, and the crude product was used directly in the next reaction. ES-API: [M+H] + =502.1. Step 5: 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-dicarboxylic acid ester (1.94 g, 8 mmol), N,N-diisopropylethylamine (516 mg, 4 mmol), and N,N-dimethylacetamide (10 mL) were added to a flask and stirred at 120° C. for 2 hours. The completion of the reaction was confirmed by LC-MS. The reaction solution was stirred for 30 minutes. The mixture was poured into mL of water and extracted three times with ethyl acetate. The organic layer was washed four times with saturated brine / water (v / v, 1:1). After drying and concentration, the crude product was purified on a high-performance silica gel column (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-dicarboxylic acid ester (1 g, purity 82%). ES-API: [M+H] + =710.2. Step 6: A reaction flask was charged with 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-dicarboxylic acid ester (1 g, 1.4 mmol), iron powder (390 mg, 7 mmol), and 15 mL of glacial acetic acid. The mixture was stirred at 80 °C for 1 hour. Completion of the reaction was confirmed by LC-MS. The reaction mixture was poured into 50 mL of aqueous sodium bicarbonate solution and extracted three times with 30 mL of ethyl acetate. The organic layer was dried and concentrated to give a yellow solid: 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-pyrazylo[1',2':4,5]pyrazylo[2,3-c][1,8]naphthyridine-3-carboxylate (850 mg, 93%). ES-API: [M+H] + = 648.3. Step 7: (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-pyrazylo[1',2':4,5]pyrazylo[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 were added to a flask. The reaction was stirred at 50 °C for 16 hours, and the completion of the reaction was monitored by LC-MS. The reaction mixture was filtered through diatomaceous earth, the filtrate was concentrated, and the crude product was purified using a high-performance silica gel column (EtOAc / PE: 0-60%) to give a yellow solid: (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-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8]naphthyridine-3-carboxylate tert-butyl ester (260 mg, 57%). ES-API: [M+H] + =662.2. Step 8: (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-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8]naphthyridine-3-carboxylate (260 mg, 0.39 mmol), 1 mL of dichloromethane, and 3 mL of trifluoroacetic acid were added to a flask. The mixture was stirred at room temperature for 1 hour, and the completion of the reaction was confirmed by LC-MS. The reaction mixture was concentrated to give a yellow solid, (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-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8]naphthyridine-5,7-dione (219 mg). The crude product was used directly in the next step. ES-API: [M+H] + =562.2. Step 9: To a 50 mL 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-pyrazine[1',2':4,5]pyrazine[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 dichloromethane solution of acrylic acid chloride (71 mg, 0.78 mmol, 0.5 mL) was added dropwise. The mixture was stirred at 0 °C for 10 min. 40 mL of saturated aqueous sodium bicarbonate was added to the reaction mixture, and the mixture was extracted three times with 20 mL of dichloromethane. The organic layer was dried and concentrated to give a yellow solid, (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-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8]naphthyridine-5,7-dione (240 mg, 87% purity). The crude product was used directly in the next step. ES-API: [M+H] + =616.3. Step 10: (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-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8]naphthyridine-5,7-dione (240 mg, 0.39 mmol) and 3 mL of dichloromethane were added to a flask. The reaction mixture was cooled to 0 °C, and 6 mL of a 17% solution of boron tribromide in dichloromethane was added dropwise. After the addition was complete, the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into 30 mL of cooled saturated aqueous NaHCO3 and extracted three times with 20 mL of dichloromethane. The organic layer was dried and concentrated. The crude product was purified by preparative HPLC to give the product, (4aR)-3-acryloyl-11-fluoro-10-(2-fluoro-6-hydroxyphenyl)-8-(4-isopropyl-6-methylpyrimidin-5-yl)-6-methyl-2,3,4,4a,6,8-hexahydro-1H-pyrazylo[1',2':4,5]pyrazylo[2,3-c][1,8]naphthyridine-5,7-dione (Z21, 130 mg, 55%), as a yellow solid. ES-API: [M+H] + =602.2. 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-pyrazylo[1',2':4,5]pyrazylo[2,3-c][1,8]naphthyridine-5,7-dione (130 mg) was separated by preparative chiral HPLC (column: Chiralpak IE: 10 μm, 20*250 mm; mobile phase: hexane:ethanol:diethylamine=70:30:0.2; flow rate: 15 ml / min; column temperature: room temperature). The resulting atropisomeric compound was a yellow solid, designated Z21-1 (peak 2, retention time: 12.33 min, 47 mg). ES-API:[M+H] + =602.2. 1HNMR (500MHz, DMSO-d6): 10.17 (s, 1H), 9.03 (s, 1H), 8.41 (d, J=9Hz, 1H), 7.26-7.25 (m, 1H), 7.08-7.05 (m, 1H), 6.68-6.66(m, 2H), 6.17-6.14(m, 1H), 5.77-5.75(m, 1H), 4.75-4.73(m, 1H), 4.46-4.44(m, 1H), 4.0-3.95(m, 1H), 3.55-3.54 (m, 2H), 3.41 (s, 3H), 3.20-3.18 (m, 1H), 2.85-2.83 (m, 1H), 2.68-2.65 (m, 1H), 2.00 (s, 3H), 1.13 (d, J = 6.5 Hz, 3H), 1.06 (d, J = 6.5 Hz, 3H). Another atropisomeric compound was obtained as a yellow solid, and its structure was assigned to Z21-2 (peak 1, retention time: 10.58 min, 48 mg). ES-API: [M+H] + =602.2. 1 HNMR (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 analyzed by chiral HPLC (column: Chiralpak IE: 5 μm, 4.6*250 mm; mobile phase: hexane:ethanol:aminomethanol = 70:30:0.2; flow rate: 1 ml / min; column temperature: 30 o C).

[0413] Example 22 Preparation of Compound Z22

[0414] [ka]

[0415] 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), and sodium nitrite (41 mg, 0.6 mmol) and concentrated nitric acid (1.5 g, 24 mmol) were added sequentially. The mixture was stirred at room temperature for 30 minutes. The reaction mixture was slowly poured into 100 mL of ice water, and the precipitated solid was filtered. The filter cake was washed with 20 mL of ice water and dried under vacuum to 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. Step 2: A 100 mL three-neck flask was charged with 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)borate (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 mixture was stirred at 100 °C under a nitrogen atmosphere for 2–3 h. After the reaction was complete, the reaction mixture was cooled to room temperature. 80 mL of water and 100 mL of methyl tert-butyl ether were added and extracted once. The aqueous layer was adjusted to pH 3-5 with 1 M hydrochloric acid solution and extracted with ethyl acetate (200 mL * 2). The ethyl acetate layers were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under vacuum to give the product as a pale yellow solid: 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). ES-API: [M+H] + =470.1. 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), and phosphorus oxychloride (2.6 g, 17 mmol) and N,N-diisopropylethylamine (3 g, 23.8 mmol) were added, sequentially. The reaction temperature was gradually raised to 80 °C while stirring for 30 minutes. After concentrating the reaction solution, 30 mL of cold acetonitrile was added, and the mixture was added dropwise to 150 mL of saturated sodium bicarbonate solution in an ice-water bath. The mixture was extracted with ethyl acetate (200 mL). The organic layers were combined and washed once with 200 mL of saturated brine. After drying over anhydrous sodium sulfate, filtration, and concentration of the organic layer, the crude product was purified by high-performance silica gel column chromatography (EtOAc / PE: 0-50%) to give a yellow solid, 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%). ES-API: [M+H] + =488.2. 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 that order, and the mixture was stirred at 120° C. for 2 hours. 50 mL of ethyl acetate was added to the reaction mixture. The mixture was washed three times with 30 mL of saturated brine. The ethyl acetate layer was dried and concentrated, and the crude product was purified using a high-performance silica gel column (EtOAc / PE: 0-80%) to obtain the product, 1-(tert-butyl-3-methyl(3R,6R)-4-(6-fluoro-7-(2-fluoro-6-methoxyphenyl)-1-(3-isopropylpyrazin-2-yl)-3-nitro-2-oxo-1,2-dihydro-1,8-naphthyridin-4-yl)-6-methylpiperazine-1,3-dicarboxylic acid ester (317 mg, Y: 70%) as a yellow solid. ES-API: [M+H] + =710.2. 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-dicarboxylic acid ester (280 mg, 0.4 mmol) was dissolved in acetic acid (4 mL), iron powder (78 mg, 1.4 mmol) was added, and the mixture was stirred at 80° C. for 30 minutes. The reaction mixture was concentrated, and then 50 mL of ethyl acetate and 30 mL of saturated sodium bicarbonate were added sequentially. The suspension was filtered through diatomaceous earth, the filter cake was washed with ethyl acetate, the organic layer was separated, and 100 mL of saturated sodium bicarbonate, 30 mL of ethyl acetate, and the mixture was stirred at 80° C. for 30 minutes. The mixture was washed with 1 mL of saturated aqueous sodium chloride solution, dried, and concentrated to give a yellow solid: (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-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8]naphthyridine-3-carboxylate (312 mg, crude product). ES-API: [M+H]+ = 648.1. Step 6: (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-pyrazine[1',2':4,5]pyrazine[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 to a 15 mL tube, sealed, and stirred at 55 °C for 18 h. 50 mL of ethyl acetate was added to the reaction mixture, which was then washed three times with 20 mL of saturated brine. The product was dried and concentrated to give a yellow solid, tert-butyl (2R,4aR)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(3-isopropylpyrazin-2-yl)-2,6-dimethyl-5,7-dioxo-1,2,4,4a,5,6,7,8-octahydro-3H-pyrazylo[1',2':4,5]pyrazylo[2,3-c][1,8]naphthyridine-3-carboxylate (356 mg, crude). ES-API: [M+H] + =662.2. 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-pyrazylo[1',2':4,5]pyrazylo[2,3-c][1,8]naphthyridine-3-carboxylate tert-butyl (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 mixture was concentrated to give (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-pyrazine[1',2':4,5]pyrazine[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. 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-pyrazylo[1',2':4,5]pyrazylo[2,3-c][1,8]naphthyridine-5,7-dione (415 mg, 0.74 mmol) was dissolved in dichloromethane (15 mL), 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 to the reaction mixture. The mixture was stirred at 0 °C for 5 min. 50 mL of dichloromethane was added to the reaction mixture, which was then washed with 50 mL of saturated aqueous NaHCO3 and 80 mL of saturated brine. After drying and concentration, the crude product was purified by high-performance silica gel column chromatography (EtOAc / PE: 0-60%) to obtain the yellow solid product (2R,4aR)-3-acryloyl-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(3-isopropylpyrazin-2-yl)-2,6-dimethyl-2,3,4,4a,6,8-hexahydro-1H-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8]naphthyridine-5,7-dione (201 mg, Y: 44%). ES-API: [M+H] + =616.2. Step 9: ((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-pyrazylo[1',2':4,5]pyrazylo[2,3-c][1,8]naphthyridine-5,7-dione (201 mg, 0.33 mmol) was added to dry dichloromethane (3.0 mL) under ice-water bath conditions, and boron tribromide (5.0 mL) was added. The reaction mixture was reacted at room temperature for 30 minutes, and then the reaction mixture was heated to 100°C under ice-water bath conditions. The mixture was added dropwise to a saturated solution of sodium hydrogen carbonate and extracted twice with dichloromethane (50 mL). After drying and concentration, the crude product was purified by preparative HPLC to obtain the product (2R,4aR)-3-acryloyl-11-fluoro-10-(2-fluoro-6-hydroxyphenyl)-8-(3-isopropylpyrazin-2-yl)-2,6-dimethyl-2,3,4,4a,6,8-hexahydro-1H-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8]naphthyridine-5,7-dione (Z22, 65 mg, Y: 33%). ES-API: [M+H] + =602.2. 1 H 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), 7.26(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=28.0 Hz, 1H), 3.80-3.70(m, 1H), 3.36(d, J=2.4 Hz, 3H), 3.05-2.62(m, 2H), 1.63-1.48(m, 3H), 1.18(d, J=6.8Hz, 2H), 1.10(d, J=6.8Hz, 3H), 1.00(d, J=6.7Hz, 2H).

[0416] Example 23 Preparation of Compound Z23

[0417] [ka]

[0418] Step 1: 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-dicarboxylic acid ester (567 mg, 2.2 mmol), N,N-diisopropylethylamine (565 mg, 4.38 mmol), and N,N-dimethylacetamide (10 mL) were added to a flask and stirred at 120 °C for 1 hour. Completion of the reaction was confirmed by LC-MS. 30 mL of water was added to the reaction mixture and extracted three times with ethyl acetate. The organic layer 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-dicarboxylic acid ester (1 g, 89% yield). ES-API: [M+H] +=768.3. Step 2: 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-dicarboxylic acid ester (1 g, 1.3 mmol), iron powder (300 mg, 5.3 mmol), and 8 mL of glacial acetic acid were added to a reaction flask and stirred at 80°C for 0.5 hours. The completion of the reaction was detected by LC-MS. The reaction solution was poured into 50 mL of aqueous sodium bicarbonate solution and extracted three times with 30 mL of ethyl acetate. The organic layer was dried and concentrated to give the crude product as a yellow solid: 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-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8]naphthyridine-3-carboxylate (761 mg, 83%). ES-API: [M+H] + =706.3. Step 3: To a flask was added (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-pyrazine[1',2':4,5]pyrazine[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 was sealed and stirred at 50 °C for 16 hours. Completion of the reaction was confirmed by LC-MS. The reaction mixture was filtered through diatomaceous earth, and the filtrate was concentrated to give a crude yellow solid: (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-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8]naphthyridine-3-carboxylate (738 mg, 95%). ES-API: [M+H] + =720.3. Step 4: (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-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8]naphthyridine-3-carboxylate (738 mg, 1.02 mmol), 2 mL of dichloromethane, and 5 mL of trifluoroacetic acid were added to a flask. The mixture was stirred at room temperature for 1 hour, and the completion of the reaction was detected by LC-MS. After concentrating the reaction mixture, a yellow solid (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-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8]naphthyridine-5,7-dione (632 mg, 100%) was obtained. The crude product was used directly in the next step. ES-API: [M+H] + =620.3. Step 5: To a 50 mL 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-pyrazine[1',2':4,5]pyrazine[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 dichloromethane solution of acrylic acid chloride (249 mg, 2.77 mmol, 0.5 mL) was added dropwise and stirred at 0 °C for 10 min. 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 layer was dried and concentrated. The crude product was purified by high-performance silica gel column chromatography (EtOAc / PE: 0-60%) to give a yellow solid, (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-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8]naphthyridine-5,7-dione (500 mg, 72%). The crude product was used directly in the next step. ES-API: [M+H] + =674.2. Step 6: (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-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8]naphthyridine-5,7-dione (500 mg, 0.74 mmol) and 3 mL of dichloromethane were added to a flask. The reaction mixture was cooled to 0 °C, and 12 mL of a 17% solution of boron tribromide in dichloromethane was added dropwise. After the addition was complete, the mixture was stirred at 25 °C for 25 hours. The reaction mixture was poured into 30 mL of cooled saturated aqueous NaHCO3 and extracted three times with 20 mL of dichloromethane. The organic layer was dried and concentrated. The crude product was purified by preparative HPLC to give (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-pyrazine[1',2':4,5]pyrazine[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), 6.17-6.14(m, 1H), 5.75-5.71(m, 1H) , 5.04-5.01(m, 1H), 4.62-4.42(m, 1H), 4.03-3.98(m, 1H), 3.74-3.72(m, 1H), 3.42-3. 33(m, 5H), 2.77-2.64(m, 2H), 1.56-1.52(m, 3H), 1.05-0.97(m, 9H), 0.86-0.84(m, 3H). ES-API:[M+H] + =660.3.

[0419] Example 24 Preparation of Compounds Z24, Z24-1 and Z24-2

[0420] [ka]

[0421] Step 1: 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) was suspended in a mixture of 1,4-dioxane (120 mL) and water (120 mL), and concentrated sulfuric acid (120 mL) was added slowly. The mixture was stirred at 120° C. for 36 hours. The cooled reaction mixture was poured into 200 mL of ice water, adjusted to pH 2-3 with sodium carbonate, and extracted with ethyl acetate (1000 mL * 2). The ethyl acetate layers were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was dried under vacuum to give the product as a light brown solid: 6,7-dichloro-4-hydroxy-1-(2-isopropyl-4-methylpyridin-3-yl)-1,8-naphthyridin-2(1H)-one (24 g, Y: 85.7%). ES-API: [M+H] + =364.1. 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), and sodium nitrite (100 mg, 1.58 mmol) and concentrated nitric acid (5.0 mL, 74.52 mmol) were added sequentially. The mixture was stirred at room temperature for 30 minutes. The reaction mixture was slowly poured into 100 mL of ice water, and the precipitated solid was filtered. The filter cake was washed with 20 mL of ice water. The mixture was dried in vacuo 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. Step 3: A 100 mL three-neck flask was charged with 6,7-dichloro-4-hydroxy-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro-1,8-naphthyridin-2(1H)-one (3.5 g, 8.570 mmol), (2-fluoro-6-methoxyphenyl)boronic acid (5.8 g, 34.10 mmol), tetrakis(triphenylphosphine)palladium (1.15 g, 0.9956 mmol), sodium carbonate (3.5 g, 33.02 mmol), 10 mL of water, and 40 mL of dioxane. The mixture was stirred at 100 °C under a nitrogen atmosphere for 2–3 h. After the reaction was complete, the reaction mixture was cooled to room temperature and extracted once with 80 mL of water and 100 mL of methyl tert-butyl ether. The aqueous layer was adjusted to pH 3-5 with 1M hydrochloric acid solution and extracted with ethyl acetate (200 mL * 2). The ethyl acetate layers were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was dried under vacuum to give the product as a pale yellow solid: 6-chloro-7-(2-fluoro-6-methoxyphenyl)-4-hydroxy-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro-1,8-naphthyridin-2(1H)-one (4.5 g, crude product). ES-API: [M+H] + =499.1. 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), and phosphorus oxychloride (7.5 g, 48.92 mmol) and N,N-diisopropylethylamine (10.5 g, 81.24 mmol) were added sequentially. The mixture was gradually heated to 80 °C and stirred for 30 minutes. The reaction mixture was concentrated, and then 30 mL of cold acetonitrile was added. The mixture was added dropwise to 150 mL of saturated sodium bicarbonate solution in an ice-water bath. The mixture was extracted with ethyl acetate (200 mL). The ethyl acetate layers were combined and washed once with 200 mL of saturated brine. After drying over anhydrous sodium sulfate and filtration, the organic layer was dried and concentrated, and the crude product was purified by high-performance silica gel column (EtOAc / PE: 0-50%) to give a yellow solid, 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%). ES-API: [M+H] + =517.2. 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 that order, and the mixture was stirred at 120 °C for 2 hours. 80 mL of ethyl acetate was added to the reaction mixture. The mixture was added with ethanol and washed three times with 80 mL of saturated brine. The ethyl acetate layer was dried and concentrated, and the crude product was purified on a high-performance silica gel column (EtOAc / PE: 0-80%) to obtain the product, 1-(tert-butyl)-3-methyl(3R)-4-(6-chloro-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro-2-oxo-1,2-dihydro-1,8-naphthyridin-4-yl)piperazine-1,3-dicarboxylic acid ester (2.7 g, Y: 77%), as a yellow solid. ES-API: [M+H] + =725.2. 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-dicarboxylic acid ester (2.7 g, 3.728 mmol) was dissolved in acetic acid (30 mL), iron powder (835 mg, 14.91 mmol) was added, and the mixture was stirred at 80 °C for 30 minutes. After concentrating the reaction mixture, 200 mL of ethyl acetate and 100 mL of saturated sodium bicarbonate were added sequentially. The suspension was filtered through diatomaceous earth, the filter cake was washed with ethyl acetate, and the organic layer was separated and washed sequentially with 100 mL of saturated sodium bicarbonate and 150 mL of saturated brine. Drying and concentration gave a yellow solid product, tert-butyl (4aR)-11-chloro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-5,7-dioxo-1,2,4,4a,5,6,7,8-octahydro-3H-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8]naphthyridine-3-carboxylate (2.70 g, crude product). ES-API: [M+H]+ = 663.2. Step 7: In a 100 mL flask, add tert-butyl (4aR)-11-chloro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-5,7-dioxo-1,2,4,4a,5,6,7,8-octahydro-3H-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8]naphthyridine-3-carboxylate (250 mg, 0.3774 mmol), 4 mL of dichloromethane, and 4 mL of tert-butyl 4 1 mL of trifluoroacetic acid was added in turn, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated to give 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-pyrazine[1',2':4,5]pyrazine[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. 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-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8]naphthyridine-5,7-dione (300 mg, 0.3774 mmol) was dissolved in dichloromethane (10 mL), triethylamine (3.0 mL, 21.62 mmol) was added, the reaction mixture was cooled to 0 °C, acrylic acid chloride (50 mg, 0.5524 mmol) was added dropwise to the reaction mixture, and the mixture was stirred at 0 °C for 15 min. 80 mL of dichloromethane was added to the reaction mixture, which was then washed with 100 mL of saturated aqueous NaHCO3 and 80 mL of saturated brine. After drying and concentration, the crude product was purified on a high-performance silica gel column (methanol / dichloromethane: 0-20%) to obtain the yellow solid product (4aR)-3-acryloyl-11-chloro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-2,3,4,4a,6,8-hexahydro-1H-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8]naphthyridine-5,7-dione (243 mg, crude product). ES-API: [M+H] + =617.2. Step 9: (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-pyrazine[1',2':4,5]pyrazine[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 under ice-water bath conditions. The mixture was warmed to room temperature and reacted overnight. The reaction mixture was added dropwise to saturated sodium bicarbonate solution under ice-water bath conditions and extracted twice with dichloromethane (80 mL). After drying and concentration, the residue was 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-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8]naphthyridine-5,7-dione (Z24, 76 mg, Y: 32%). [M+H] + =603.2. Step 10: Compound Z24 (76.0 mg, 0.1262 mmol) was separated by preparative chiral HPLC (column: IA: 10 μm, 30*250 mm, mobile phase: hexane:EtOH=40:60, flow rate: 25 ml / min, column temperature: room temperature). One atropisomeric compound was obtained, and its structure was designated Z24-1 (13.7 mg, peak 1, retention time: 2.612 min, Y: 18%). ES-API: [M+H] + = 603.2. The structure of another atropisomeric compound obtained was designated Z24-2 (21.4 mg, peak 2, retention time 3.985 min, Y: 28%). ES-API: [M+H] + = 603.2. The isomeric compounds were detected by analytical chiral HPLC (column: IA: 5 μm, 4.6*150 mm, mobile phase: hexane:EtOH=40:60, flow rate: 1 ml / min, column temperature: 30°C).

[0422] Example 25 Preparation of Compounds Z25, Z25-1 and Z25-2

[0423] [ka]

[0424] Step 1: 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) was suspended in a mixture of 1,4-dioxane (120 mL) and water (120 mL), concentrated sulfuric acid (120 mL) was added slowly, and the mixture was stirred at 120 °C for 36 h. The cooled reaction mixture was poured into 200 mL of ice water, adjusted to pH 2-3 with sodium carbonate, and extracted with ethyl acetate (1000 mL * 2). The ethyl acetate layers were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was dried under vacuum to give the product, 6,7-dichloro-4-hydroxy-1-(2-isopropyl-4-methylpyridin-3-yl)-1,8-naphthyridin-2(1H)-one (24 g, Y: 85.7%), as a light brown solid. ES-API: [M+H] + =364.1. 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), and sodium nitrite (100 mg, 1.58 mmol) and concentrated nitric acid (5.0 mL, 74.52 mmol) were added sequentially. The mixture was stirred at room temperature for 30 minutes. The reaction mixture 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 as a yellow solid: 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%). ES-API: [M+H] + =409.1. Step 3: A 100 mL three-neck flask was charged with 6,7-dichloro-4-hydroxy-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro-1,8-naphthyridin-2(1H)-one (3.5 g, 8.570 mmol), (2-fluoro-6-methoxyphenyl)boronic acid (5.8 g, 34.10 mmol), tetrakis(triphenylphosphine)palladium (1.15 g, 0.9956 mmol), sodium carbonate (3.5 g, 33.02 mmol), 10 mL water, and 40 mL dioxane. The mixture was stirred at 100 °C under a nitrogen atmosphere for 2–3 h. After the reaction was complete, the reaction mixture was cooled to room temperature. 80 mL water and 100 mL methyl tert-butyl ether were added and extracted once. The aqueous layer was adjusted to pH 3–5 with 1 M hydrochloric acid solution and extracted with ethyl acetate (200 mL). The ethyl acetate layers were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under vacuum to give the product, 6-chloro-7-(2-fluoro-6-methoxyphenyl)-4-hydroxy-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro-1,8-naphthyridin-2(1H)-one (4.5 g, crude product) as a pale yellow solid. ES-API: [M+H] + =499.1. 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), and phosphorus oxychloride (7.5 g, 48.92 mmol) and N,N-diisopropylethylamine (10.5 g, 81.24 mmol) were added sequentially. The mixture was stirred for 30 minutes while gradually increasing the temperature to 80 °C. After concentrating the reaction mixture, 30 mL of cold acetonitrile was added, and the mixture was added dropwise to 150 mL of saturated sodium bicarbonate solution in an ice-water bath. The mixture was extracted with ethyl acetate (200 mL). The ethyl acetate layers were combined and washed once with 200 mL of saturated brine. After drying over anhydrous sodium sulfate, filtration, and concentration of the organic layer, the crude product was purified by high-performance silica gel column chromatography (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. 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-dicarboxylic acid ester (3.5 g, 14.34 mmol) and N,N-diisopropylethylamine (2.0 g, 15.47 mmol) were added in that order, and the mixture was stirred at 120 °C for 2 hours. 80 mL of acetic acid was added to the reaction mixture. Ethyl acetate was added and washed three times with 80 mL of saturated brine. After drying and concentrating the ethyl acetate layer, the crude product was purified using a high-performance silica gel column (EtOAc / PE: 0-80%) to obtain the product as a yellow solid: 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-dicarboxylic acid ester (2.7 g, Y: 77%). ES-API: [M+H] +=725.2. 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 mixture was stirred at 80 °C for 30 minutes. After concentrating the reaction mixture, 200 mL of ethyl acetate and 100 mL of saturated sodium bicarbonate were added, successively. The suspension was filtered through diatomaceous earth, and the filter cake was washed with ethyl acetate. The organic layer was separated and washed successively with 100 mL of saturated sodium bicarbonate and 150 mL of saturated brine. Drying and concentration gave a yellow solid product, tert-butyl (4aR)-11-chloro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-5,7-dioxo-1,2,4,4a,5,6,7,8-octahydro-3H-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8]naphthyridine-3-carboxylate (2.70 g, crude product). ES-API: [M+H]+ = 663.2. Step 7: (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-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8]naphthyridine-3-carboxylate (2.7 g, 3.728 mmol), 30 mL acetone, anhydrous potassium carbonate (2.2 g, 15.94 mmol), and iodomethane (5.4 g, 38.03 mmol) were added to a 150 mL tube, sealed, and stirred at 55 °C for 18 h. 150 mL of ethyl acetate was added to the reaction mixture, which was then washed three times with 100 mL of saturated brine. After drying and concentration, the crude product was purified on a high-performance silica gel column (EtOAc / PE: 0-80%) to obtain the yellow solid product (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-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8]naphthyridine-3-carboxylate tert-butyl ester (2.2 g, Y: 87%). ES-API: [M+H] + =677.2. 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-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8]naphthyridine-3-carboxylate 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 mixture was concentrated to give (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-pyrazine[1',2':4,5]pyrazine[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. 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-pyrazine[1',2':4,5]pyrazine[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 acrylic acid chloride (100 mg, 1.1048 mmol) was added dropwise to the reaction mixture. The mixture was stirred at 0 °C for 15 minutes. 80 mL of dichloromethane was added to the reaction mixture and washed with 100 mL of saturated aqueous NaHCO3 and 80 mL of saturated brine. After drying and concentration, the crude product was purified on a high-performance silica gel column (EtOAc / PE: 0-60%) to obtain the yellow solid product (4aR)-3-acryloyl-11-chloro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-6-methyl-2,3,4,4a,6,8-hexahydro-1H-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8]naphthyridine-5,7-dione (280 mg, Y: 59%). ES-API: [M+H] + =631.2. Step 10: (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-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8]naphthyridine-5,7-dione (280 mg, 0.444 mmol) was added to dry dichloromethane (6.0 mL) under ice-water bath conditions, and boron tribromide (5.0 mL, 5.0 mmol) was added. The mixture was warmed to room temperature and reacted overnight. The reaction mixture was added dropwise to saturated sodium bicarbonate solution under ice-water bath conditions, and extracted twice with dichloromethane (80 mL). After drying and concentration, the crude product was purified by high-performance silica gel column (EtOAc / PE: 0-60%) to give the product (4aR)-3-acryloyl-11-chloro-10-(2-fluoro-6-hydroxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-6-methyl-2,3,4,4a,6,8-hexahydro-1H-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8]naphthyridine-5,7-dione (Z25, 233 mg, Y: 85%). Step 11: Compound Z25 was separated by preparative chiral HPLC (column: IA: 10 μm, 30*250 mm, mobile phase: hexane:EtOH=60:40, flow rate: 25 ml / min, column temperature: room temperature) to obtain one atropisomeric compound, Z25-1 (76.8 mg, peak 1, retention time: 2.531 min, Y: 34%). 1HNMR (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, ES-API:[M+H] + =617.2. Another atropisomer compound obtained was Z25-2 (70 mg, peak 2, retention time: 3.683 min, Y: 31%). 1 HNMR (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 isomeric compounds were detected by analytical chiral HPLC (column: IA: 5 μm, 4.6 * 150 mm, mobile phase: hexane:EtOH = 60:40, flow rate: 1 ml / min, column temperature: 30 °C).

[0425] Example 26 Preparation of Compounds Z26, Z26-1 and Z26-2

[0426] [ka]

[0427] 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-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8]naphthyridine-3-carboxylate tert-Butyl (511 mg, 0.7549 mmol) in dichloromethane (8 The resulting solution was dissolved in 1 mL of HCl, trifluoroacetic acid (2 mL) was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated to give (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-pyrazine[1',2':4,5]pyrazine[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. 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-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8]naphthyridine-5,7-dione (520 mg, 0.7549 mmol) was dissolved in dichloromethane (10 mL), triethylamine (3.0 mL, 21.62 mmol) was added, the reaction mixture was cooled to 0 °C, and acrylic acid chloride (100 mg, 1.1048 mmol) was added dropwise to the reaction mixture. The mixture was stirred at 0 °C for 15 min. 80 mL of dichloromethane was added to the reaction mixture, which was then washed with 100 mL of saturated aqueous NaHCO3 and 80 mL of saturated brine. After drying and concentration, the crude product was purified on a high-performance silica gel column (EtOAc / PE: 0-60%) to obtain the yellow solid product (4aR)-3-acryloyl-11-chloro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-6-(methyl-d3)-2,3,4,4a,6,8-hexahydro-1H-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8]naphthyridine-5,7-dione (232 mg, Y: 48%). ES-API: [M+H] + =634.2. Step 3: (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-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8]naphthyridine-5,7-dione (240 mg, 0.3791 mmol) was added to dry dichloromethane (6.0 mL) under ice-water bath conditions, and boron tribromide (5.0 mL, 5.0 mmol) was added. The mixture was warmed to room temperature and reacted overnight. The reaction mixture was added dropwise to saturated sodium bicarbonate solution under ice-water bath conditions and extracted twice with dichloromethane (80 mL). After drying and concentration, the crude product was purified using a high-performance silica gel column (EtOAc / PE: 0-60%) to obtain the product (4aR)-3-acryloyl-11-chloro-10-(2-fluoro-6-hydroxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-6-(methyl-d3)-2,3,4,4a,6,8-hexahydro-1H-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8]naphthyridine-5,7-dione (Z26, 187 mg, Y: 79%). [M+H] + =620.3. Step 4: Compound Z26 (187 mg, 0.302 mmol) was separated by preparative chiral HPLC (column: IA: 10 μm, 30*250 mm, mobile phase: hexane:EtOH=60:40, flow rate: 25 ml / min, column temperature: room temperature), and one atropisomeric compound obtained was designated as Z26-1 (68.8 mg, peak: 1, retention time: 2.525 min, Y: 36.7%). 1HNMR (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. The structure of another atropisomer compound obtained was designated as Z26-2 (63.2 mg, peak: 2, retention time: 3.683 min, Y: 33.79%). 1 HNMR (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=12.8 Hz, 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 isomeric compounds were detected by analytical chiral HPLC (column: IA: 5 μm, 4.6 * 150 mm, mobile phase: hexane:EtOH = 60:40, flow rate: 1 ml / min, column temperature = 30 ° C.).

[0428] Example 27 Preparation of Compounds Z27, Z27-1 and Z27-2

[0429] [ka]

[0430] 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-dicarboxylic acid ester (375 mg, 1.452 mmol) and N,N-diisopropylethylamine (375 mg, 2.907 mmol) were added in that order, and the reaction mixture was stirred at 120 °C for 2 hours. 80 mL of ethyl acetate was added to the reaction solution, and the mixture was washed three times with 80 mL of saturated brine. The ethyl acetate layer was dried and concentrated, and the crude product was purified using a high-performance silica gel column (EtOAc / PE: 0-80%) to obtain the product, a yellow solid: 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-dicarboxylic acid ester (535 mg, Y: 74.5%). ES-API: [M+H] + =739.2. 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-dicarboxylic acid ester (530 mg, 0.7179 mmol) was dissolved in acetic acid (6 mL), iron powder (200 mg, 3.571 mmol) was added, and the mixture was stirred at 80 °C for 30 minutes. After concentrating the reaction mixture, 200 mL of ethyl acetate and 100 mL of saturated sodium bicarbonate were added, successively. The suspension was filtered through diatomaceous earth, and the filter cake was washed with ethyl acetate. The organic layer was separated and washed successively with 100 mL of saturated sodium bicarbonate and 150 mL of saturated brine. The mixture was dried and concentrated to give a yellow solid 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-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8]naphthyridine-3-carboxylate tert-butyl ester (452 ​​mg, Y: 92%). ES-API: [M+H] + =677.2. Step 3: (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-pyrazine[1',2':4,5]pyrazine[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 to a 150 mL tube, sealed, and stirred at 55 °C for 18 h. 150 mL of ethyl acetate was added to the reaction mixture, which was then washed three times with 100 mL of saturated brine. After drying and concentration, the crude product was purified on a high-performance silica gel column (EtOAc / PE: 0-80%) to obtain a yellow solid product, (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-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8]naphthyridine-3-carboxylate tert-butyl ester (455 mg, crude product). ES-API: [M+H] + =691.3. Step 4: (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-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8]naphthyridine-3-carboxylate (511 mg, 0.7549 mmol) was dissolved in dichloromethane (8 mL) and triflate was added. Fluoroacetic acid (2 mL) was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture 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-pyrazine[1',2':4,5]pyrazine[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. 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-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8]naphthyridine-5,7-dione (462 mg, 0.6283 mmol) was dissolved in dichloromethane (8 mL), triethylamine (2.0 mL, 14.41 mmol) was added, the reaction mixture was cooled to 0 °C, and acrylic acid chloride (100 mg, 1.1048 mmol) was added dropwise to the reaction mixture. The mixture was stirred at 0 °C for 15 min. 80 mL of dichloromethane was added to the reaction mixture, which was then washed with 100 mL of saturated aqueous NaHCO3 and 80 mL of saturated brine. After drying and concentration, the crude product was purified on a high-performance silica gel column (EtOAc / PE: 0-60%) to obtain the yellow solid product (2R,4aR)-3-acryloyl-11-chloro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-2,6-dimethyl-2,3,4,4a,6,8-hexahydro-1H-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8]naphthyridine-5,7-dione (290 mg, Y: 68%). ES-API: [M+H] + =645.2. Step 6: (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-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8]naphthyridine-5,7-dione (290 mg, 0.4503 mmol) was added to dry dichloromethane (6.0 mL) under ice-water bath conditions, and boron tribromide (6.0 mL, 6.0 mmol) was added. The mixture was warmed to room temperature and reacted overnight. The reaction mixture was added dropwise to saturated sodium bicarbonate solution under ice-water bath conditions and extracted twice with dichloromethane (80 mL). After drying and concentration, the crude product was purified using a high-performance silica gel column (EtOAc / PE: 0-60%) to obtain the product (2R,4aR)-3-acryloyl-11-chloro-10-(2-fluoro-6-hydroxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-2,6-dimethyl-2,3,4,4a,6,8-hexahydro-1H-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8]naphthyridine-5,7-dione (Z27, 307 mg, crude product). [M+H] + =631.2. Step 7: Compound Z27 was separated by preparative chiral HPLC (column: IA*: 10 μm, 30*250 mm, mobile phase: hexane:EtOH=60:40, flow rate: 25 ml / min, column temperature: room temperature) to obtain one atropisomeric 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、1H)4.6 0(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=12.1H). z、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 In addition to this, one of the snowflakes is the Z27-2( 64.6mg ピーク2 has a range of 3.382min and 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、10.8Hz、1 H)、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=14.0H). z、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、1 H)、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 isomeric compounds were detected by analytical chiral HPLC (column: IA: 5 μm, 4.6*150 mm, mobile phase: hexane:EtOH = 60:40, flow rate: 1 ml / min, column temperature = 30°C).

[0431] Example 28 Preparation of Compound Z28

[0432] [ka]

[0433] Step 1: 4-Chloro-6-fluoro-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro-1,8-naphthyridin-2(1H)-one (400 mg, 0.80 mmol) was dissolved in DMF (5 mL), 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 stirred at 75 °C for 2 hours. The reaction mixture was diluted with 100 mL of ethyl acetate and washed five times with 40 mL of saturated brine. After drying and concentration, the crude product was purified on a high-performance silica gel column (EtOAc / PE: 0-70%) to obtain the product, 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, Y: 77.2%), as a yellow solid. ES-API: [M+H] + =681.3. Step 2: (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, 0.62 mmol) was dissolved in DMA (20 mL), LiHMDS (1.55 mL, 1.55 mmol, 1.0 M in THF) was added, and the mixture was slowly heated to 140 °C and stirred for 24 h. The reaction mixture was diluted with 100 mL of ethyl acetate and washed four times with 40 mL of dilute brine. The mixture was washed once with 40 mL of saturated brine. After drying and concentration, the crude product was purified by high-performance silica gel column chromatography (EtOAc / PE: 0-100%) to give the yellow solid product (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)-carboxylate tert-butyl ester (180 mg, Y: 46.0%). ES-API: [M+H]+ = 634.3. 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]oxazine[2,3-c][1,8]naphthyridine-3(4H)-carboxylate tert-butyl (35 mg, 0.055 mmol) was dissolved in dichloromethane (4 mL), trifluoroacetic acid (1 mL) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated to give (4aS)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-1,2,3,4,4a,5-hexahydropyrazine[1',2':4,5][1,4]oxazine[2,3-c][1,8]naphthyridin-7(8H)-one (185 mg, crude product), which was used directly in the next reaction. ES-API: [M+H] + =534.3. Step 4: (4aS)-11-Fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-1,2,3,4,4a,5-hexahydropyrazine[1',2':4,5][1,4]oxazine[2,3-c][1,8]naphthyridin-7(8H)-one (185 mg, crude product) was dissolved in dichloromethane (6 mL), N,N-diisopropylethylamine (180 mg, 1.40 mmol) was added, the reaction mixture was cooled to 0 °C, and a dichloromethane solution (0.5 mL) of acrylic acid chloride (50 mg, 0.56 mmol) was added dropwise to the reaction mixture. The mixture was stirred at 0 °C for 15 min. The reaction mixture was added with 50 mL of dichloromethane and washed twice with 15 mL of water, 15 mL of saturated aqueous NaHCO3, and 15 mL of saturated brine. The organic layer was dried and concentrated to give the product, a yellow solid: (4aS)-3-acryloyl-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-1,2,3,4,4a,5-hexahydropyrazine[1',2':4,5][1,4]oxazine[2,3-c][1,8]naphthyridin-7(8H)-one (160 mg, Y: 95.8%). ES-API: [M+H] + =588.3. Step 5: (4aS)-3-Acryloyl-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-1,2,3,4,4a,5-hexahydropyrazine[1',2':4,5][1,4]oxazine[2,3-c][1,8]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 chilled saturated aqueous NaHCO3 and extracted with 50 mL of dichloromethane. The organic layer was washed sequentially with 25 mL of saturated aqueous NaHCO3 and 25 mL of saturated brine, dried, and concentrated. The crude product was purified by preparative HPLC to give a pale yellow solid 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]naphthyridin-7(8H)-one (Z28,90 mg, Y: 57.6%). 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.

[0434] Example 29 Preparation of Compound Z29

[0435] [ka]

[0436] 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), and sodium nitrite (79 mg, 1.15 mmol) and concentrated nitric acid (2.3 mL, 34.6 mmol) were added sequentially. The mixture was stirred at room temperature for 30 minutes. The reaction mixture was slowly poured into 100 mL of ice water, and the precipitated solid was filtered. The filter cake was washed with 20 mL of ice water and dried under vacuum to 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. Step 2: A 100 mL three-neck flask was charged with 7-chloro-6-fluoro-4-hydroxy-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro-1,8-naphthyridin-2(1H)-one (1.0 g, 2.55 mmol), (5-methyl-1H-indazol-4-yl)boronic acid (1.8 g, 10.2 mmol), tetrakis(triphenylphosphine)palladium (589 mg, 0.51 mmol), potassium carbonate (1.76 g, 12.75 mmol), 2 mL of water, and 8 mL of dioxane, and the mixture was stirred at 110 °C for 1 hour under a nitrogen atmosphere. After the reaction was complete, the reaction mixture was cooled to room temperature and extracted once with 80 mL of water and 100 mL of methyl tert-butyl ether. The aqueous layer was adjusted to pH 3-4 with 1M hydrochloric acid solution, and a solid precipitated. The precipitate was filtered and the resulting solid product was dried under vacuum to give a pale yellow solid product, 6-fluoro-7-(5-methyl-1H-indazol-4-yl)-4-hydroxy-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro-1,8-naphthyridin-2(1H)-one (0.8 g, 50%). ES-API: [M+H] + =489.2. 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, and the mixture was stirred for 24 hours while gradually increasing the temperature to 80 °C. After concentrating the reaction mixture, 30 mL of cold acetonitrile was added, and the mixture was added dropwise to 30 mL of saturated sodium bicarbonate solution in an ice-water bath. The mixture was extracted with ethyl acetate (200 mL * 2). The ethyl acetate layers were combined and washed once with 50 mL of saturated brine. After drying over anhydrous sodium sulfate and filtration, the organic layer was dried and concentrated. The crude product was purified on a high-performance silica gel column (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. 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)-3-(hydroxymethyl)piperazine-1-carboxylate (1.48 g, 320 mmol) was added in sequence and 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 layer was dried and concentrated, and the crude product was purified using a high-performance silica gel column (EtOAc / PE: 0-80%) to obtain the product as a yellow solid: tert-butyl (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-carboxylate (10 mg, Y: 40%). ES-API: [M+H] + =787.3. Step 5: tert-Butyl 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-carboxylate (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 mixture was stirred at 130 °C for 18 hours. The mixture was cooled to room temperature, poured into ice water, and adjusted to pH = 7 with 3 M hydrochloric acid. 30 mL of ethyl acetate was added, and the organic layer was separated and washed sequentially with 30 mL of water and 30 mL of saturated brine. The product was dried and concentrated to give a yellow solid: (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-hexahydropyrazine-[1',2':4,5][1,4]oxazine[2,3-c][1,8]naphthyridine-3(4H)-carboxylate tert-butyl ester (60 mg, Y: 70%). ES-API: [M+H] + =640.3. 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-hexahydropyrazine-[1',2':4,5][1,4]oxazine[2,3-c][1,8]naphthyridine-3(4H)-carboxylate tert-butyl (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 mixture was concentrated to give the product ((4aR)-11-fluoro-8-(2-isopropyl-4-methylpyridin-3-yl)-10-(5-methyl-1H-indazol-4-yl)-7-oxo-1,2,4a,5,7,8-hexahydropyrazine-[1',2':4,5][1,4]oxazine[2,3-c][1,8]naphthyridine-3(4H)-carboxylate tert-butyl ester (50 mg, crude product), which was used directly in the next reaction. ES-API: [M+H] + =540.2. Step 7: (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-hexahydropyrazine-[1',2':4,5][1,4]oxazine[2,3-c][1,8]naphthyridine-3(4H)-carboxylate tert-butyl (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 acrylic acid chloride (10.5 mg, 0.083 mmol) was added dropwise to the reaction mixture. The mixture was stirred at 0 °C for 15 min. The reaction mixture was added with 20 mL of dichloromethane and washed with 20 mL of saturated aqueous NaHCO3 and 20 mL of saturated brine. After drying and concentration, the mixture was 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-hexahydropyrazine-[1',2':4,5][1,4]oxazine[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=51.4 Hz, 1H), 3.75-3.57(m, 2H), 3.48(s, 1H), 3.15(s, 1H), 2.05(s, 3H), 1.90(d, J=33.7Hz, 3H), 1.03(t, J=6.7Hz, 3H), 0.81(dd, J=20.9, 6.4Hz, 3H).

[0437] Example 30 Preparation of Compounds Z30, Z30-1 and Z30-2

[0438] [ka]

[0439] Step 1: To a 15 mL tube was added (4aR)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-5,7-dioxo-1,2,4,4a,5,6,7,8-octahydro-3H-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8]naphthyridine-3-carboxylate (tert-butyl ester, 310 mg, 0.48 mmol), 10 mL of acetone, anhydrous potassium carbonate (265 mg, 1.92 mmol), and iodoethane (599 mg, 3.84 mmol), in that order. The tube was sealed and stirred at 55 °C for 18 h. The reaction mixture was concentrated, followed by addition of 60 mL of ethyl acetate and washing with 30 mL of water and 30 mL of saturated brine. After drying and concentration, the crude product was purified on a high-performance silica gel column (EtOAc / PE: 0-70%) to obtain the orange solid product (4aR)-6-ethyl-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-5,7-dioxo-1,2,4,4a,5,6,7,8-octyl-3H-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8]naphthyridine-3-carboxylate tert-butyl ester (290 mg, Y: 89.7%). ES-API: [M+H] + =675.3. 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-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8]naphthyridine-3-carboxylate (290 mg, 0.43 mmol) was dissolved in dichloromethane (4 mL) and treated with trifluoromethane. Acetic acid (1 mL) was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated to give (4aR)-6-ethyl-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-2,3,4,4a,6,8-hexahydro-1H-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8]naphthyridine-5,7-dione (300 mg, crude product), which was used directly in the next reaction. ES-API: [M+H] + =575.2. Step 3: (4aR)-6-Ethyl-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-2,3,4,4a,6,8-hexahydro-1H-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8]naphthyridine-5,7-dione (300 mg, crude product) was dissolved in dichloromethane (15 mL), N,N-diisopropylethylamine (464 mg, 3.60 mmol) was added, the reaction mixture was cooled to 0 °C, acrylic acid chloride (130 mg, 1.44 mmol) was added, and the mixture was stirred at 0 °C for 15 min. 45 mL of dichloromethane was added to the reaction mixture, which was then washed sequentially with 25 mL of water, 25 mL of saturated aqueous NaHCO3, and 25 mL of saturated brine. After drying and concentration, the crude product was purified on a high-performance silica gel column (EtOAc / PE: 0-90%) to obtain the product (4aR)-3-acryloyl-6-ethyl-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-2,3,4,4a,6,8-hexahydro-1H-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8]naphthyridine-5,7-dione (2450 mg, Y: 90.7%) as a pale yellow solid. ES-API: [M+H] + =615.3. Step 4: (4aR)-3-Acryloyl-6-ethyl-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-2,3,4,4a,6,8-hexahydro-1H-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8]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 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 layer was washed sequentially with 30 mL of saturated aqueous NaHCO3 and 30 mL of saturated brine. The mixture was dried and concentrated to give the product, (4aR)-3-acryloyl-6-ethyl-11-fluoro-10-(2-fluoro-6-hydroxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-2,3,4,4a,6,8-hexahydro-1H-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8]naphthyridine-5,7-dione (Z30, 240 mg, Y: 100%), as a pale yellow solid. ES-API: [M+H] + =615.3. Step 5: Compound Z30 (240 mg, 0.39 mmol) was purified by preparative HPLC and then separated by preparative chiral HPLC (column: IB: 10 μm, 30*250 mm, mobile phase: hexane:EtOH=70:30, flow rate: 25 ml / min, column temperature: room temperature). One atropisomeric compound was obtained as a pale yellow solid, and its structure was designated as Z30-1 (71 mg, peak: 1, retention time: 6.342 min, Y: 29.6%). 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), 4.72(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( ES-API:[M+H] + =615.2. Another atropisomer compound obtained was a pale yellow solid, and its structure was designated as Z30-2 (73 mg, peak: 2, retention time: 7.970 min, Y: 30.5%). 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, 1 H), 3.65-3.53(m, 2H), 3.26-3.06(m, 1H), 2.82-2.58(m, 2H), 1.80(s, 3H), 1.15-0.93(m, 9H). 1 ES-API:[M+H] + = 615.2. The isomeric compounds were detected by analytical chiral HPLC (column: IB: 5 μm, 4.6*250 mm, mobile phase: hexane:EtOH=70:30, flow rate: 1 ml / min, column temperature: 30°C).

[0440] Example 31: Preparation of compound Z31

[0441] [ka]

[0442] Step 1: To a 250 mL 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 a nitrogen atmosphere for 18 hours. After concentrating the reaction mixture, 50 mL of water was added, the pH was adjusted to 3.0 with 3.0M dilute hydrochloric acid, and the mixture was extracted twice with 50 mL of dichloromethane. The organic layer was dried and concentrated to give the product as a brown solid: 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). ES-API: [M+H] + =505.2. 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 that order, followed by stirring at 85° C. for 1 hour. The reaction mixture was concentrated, and then 120 mL of ethyl acetate was added. The mixture was washed with 60 mL of water, 60 mL of saturated sodium bicarbonate twice, and then 60 mL of saturated brine. The organic layer was dried and concentrated, and the crude product was purified by high-performance silica gel column chromatography (EtOAc / PE: 0-35%) to obtain the product, 4-chloro-6-cyclopropyl-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro-1,8-naphthyridin-2(1H)-one (520 mg, Y: 24.8%), as a pale yellow solid. ES-API: [M+H] + =523.2. Step 3: 4-Chloro-6-cyclopropyl-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro-1,8-naphthyridin-2(1H)-one (490 mg, 0.94 mmol) was dissolved in N,N-dimethylacetamide (6 mL), and (3R,6R)-1-N-BOC-6-methylpiperazine-3-carboxylate (485 mg, 1.88 mmol) and N,N-diisopropylethylamine (364 mg, 2.82 mmol) were added sequentially and stirred at 125 °C for 3 hours. 100 mL of ethyl acetate was added to the reaction mixture, which was then washed with 30 mL of diluted brine four times and 30 mL of saturated brine. After drying and concentration, the crude product was purified on a high-performance silica gel column (EtOAc / PE: 0-50%) to obtain the product as an orange solid, methyl (3R,6R)-1-N-BOC-4-(6-cyclopropyl-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro-2-oxo-1,2-dihydro-1,8-naphthyridin-4-yl)-6-methylpiperazine-3-carboxylate (485 mg, Y: 69.4%). ES-API: [M+H] + =745.3. 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-carboxylate (455 mg, 0.61 mmol) was dissolved in acetic acid (8 mL), iron powder (120 mg, 2.14 mmol) was added, and the mixture was stirred at 80 °C for 30 minutes. After concentrating the reaction mixture, 80 mL of ethyl acetate and 50 mL of saturated sodium bicarbonate were added sequentially. The suspension was filtered through diatomaceous earth, and the filter cake was washed with ethyl acetate. The organic layer was separated, washed sequentially with 25 mL of saturated sodium bicarbonate and 25 mL of saturated brine, dried, and concentrated to give the product as a pale yellow solid: (2R,4aR)-11-cyclopropyl-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-2-methyl-5,7-dioxo-1,2,4,4a,5,6,7,8-octyl-3H-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8]naphthyridine-3-carboxylate (415 mg, Y: 99.5%). ES-API: [M+H]+ = 683.3. Step 5: To a 50 mL tube was added (2R,4aR)-11-cyclopropyl-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-2-methyl-5,7-dioxo-1,2,4,4a,5,6,7,8-octyl-3H-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8]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), in that order. The tube was sealed and stirred at 50 °C for 18 h. 60 mL of ethyl acetate was added to the reaction mixture, which was then washed with 15 mL of water and 15 mL of saturated brine. After drying and concentration, the crude product was purified by preparative thin-layer chromatography (dichloromethane / methanol = 25:1) to obtain the product (2R,4aR)-11-cyclopropyl-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-2,6-dimethyl-5,7-dioxo-1,2,4,4a,5,6,7,8-octyl-3H-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8]naphthyridine-3-carboxylate tert-butyl ester (160 mg, Y: 37.8%) as a pale yellow solid. ES-API: [M+H] + =697.3. Step 6: (2R,4aR)-11-cyclopropyl-10-(2-fluoro-6-methyl)- (2-isopropyl-4-methylpyridin-3-yl)-2,6-trimethylphenyl tert-Butyl tert-dimethyl-5,7-dioxo-1,2,4,4a,5,6,7,8-octyl-3H-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8]naphthyridine-3-carboxylate (160 mg, 0.23 mmol) was dissolved in dichloromethane (3.5 mL), trifluoroacetic acid (0.8 mL) was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture 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-312-pyrazine[4',3':4,5]pyrazine[2,3-c][1,8]naphthyridine-5,7-dione (165 mg, crude product) was obtained and used directly in the next reaction. ES-API: [M+H] + =597.2. Step 7: (2R,4aR)-11-Cyclopropyl-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-2,6-dimethyl-1,2,4,4a,6,8-hexahydro-3l2-pyrazine[4',3':4,5]pyrazine[2,3-c][1,8]naphthyridine-5,7-dione (165 mg, crude product) was dissolved in dichloromethane (10 mL) and N,N-diisopropylethylamine (148 mg, 1.15 mmol) was added. The reaction mixture was cooled to 0 °C and acrylic acid chloride (41 mg, 0.46 mmol) was added dropwise to the reaction mixture. The mixture was stirred at 0 °C for 15 min. The reaction mixture was added with 30 mL of dichloromethane and washed sequentially with 15 mL of water, 15 mL of saturated aqueous NaHCO3, and 15 mL of saturated brine. After drying and concentration, the crude product was purified using a high-performance silica gel column (dichloromethane / methanol: 0-5%) to obtain the pale yellow solid product (2R,4aR)-3-acryloyl-11-cyclopropyl-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-2,6-dimethyl-2,3,4,4a,6,8-hexahydro-1H-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8]naphthyridine-5,7-dione (140 mg, Y: 93.7%). ES-API: [M+H]+ =651.3. Step 8: (2R,4aR)-3-Acryloyl-11-cyclopropyl-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-2,6-dimethyl-2,3,4,4a,6,8-hexahydro-1H-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8]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 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 layer was dried and concentrated, and the crude product was purified by preparative HPLC to obtain the product, (2R,4aR)-3-acryloyl-11-cyclopropyl-10-(2-fluoro-6-hydroxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-2,6-dimethyl-2,3,4,4a,6,8-hexahydro-1H-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8]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.

[0443] Example 32 Preparation of Compound Z32

[0444] [ka]

[0445] Step 1: 4,6-Dicyclopropylpyrimidin-5-amine (742 mg, 4.24 mmol) was dissolved in dry tetrahydrofuran (20 mL). 2 M 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 then slowly poured into 30 mL of ice-water, adjusted to pH 5-6 with dilute hydrochloric acid (3 M), and extracted with ethyl acetate. The mixture was washed once with 50 mL of saturated brine. After drying over anhydrous sodium sulfate and filtration, the organic layer was dried and concentrated. The crude product was purified on a high-performance silica gel column (EtOAc / PE: 20-40%) to obtain the product as a yellow solid, 2-((4,6-dicyclopropylpyrimidin-5-yl)amino)-5-fluoro-6-(2-fluoro-6-methoxyphenyl)nicotinic acid (1.8 g, Y: 98%). ES-API: [M+H] + =439.1. Step 2: 2-((4,6-dicyclopropylpyrimidin-5-yl)amino)-5-fluoro-6-(2-fluoro-6-methoxyphenyl)nicotinic acid (1.5 g, 3.42 mmol) was dissolved in dichloroethane, and thionyl chloride (4.07 g, 34.2 mmol) was added. The mixture was stirred at 80°C for 2 hours. After the reaction was completed, the reaction solution was cooled to room temperature. The mixture was concentrated and then dried under vacuum at 50°C for 4 hours to obtain the product, 2-((4,6-dicyclopropylpyrimidin-5-yl)amino)-5-fluoro-6-(2-fluoro-6-methoxyphenyl)nicotinic acid chloride (1.57 g, crude product), as a pale yellow solid. Methanol detection ES-API: [M+H] + =453.2. Step 3: Sodium hydride (1.97 g, 49.35 mmol) was added to ethyl nitroacetate (1.31 g, 9.86 mmol) in tetrahydrofuran under ice-water bath conditions and stirred for 30 minutes. Then, 2-((4,6-dicyclopropylpyrimidin-5-yl)amino)-5-fluoro-6-(2-fluoro-6-methoxyphenyl)nicotinic acid chloride (1.57 g, 3.29 mmol) was added and stirred at room temperature for 1 hour, and then the temperature was raised to 80 °C and the reaction was continued for 2 hours. The mixture was poured into ice water, adjusted to pH 3-4 with 3M hydrochloric acid, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the organic layer was dried and concentrated to give the product 1-(4,6-dicyclopropylpyrimidin-5-yl)-6-fluoro-7-(2-fluoro-6-methoxyphenyl)-4-hydroxy-3-nitro-1,8-naphthyridin-2(1H)-one (110 mg, Y: 20%). ES-API: [M+H] + =508.1. Step 4: 1-(4,6-Dicyclopropylpyrimidin-5-yl)-6-fluoro-7-(2-fluoro-6-methoxyphenyl)-4-hydroxy-3-nitro-1,8-naphthyridin-2(1H)-one (110 mg, 0.20 mmol) was dissolved in acetonitrile (10 mL), phosphorus oxychloride (153 mg, 1.0 mmol) and N,N-diisopropylethylamine (77 g, 0.6 mmol) were added sequentially, and the mixture was stirred for 3 hours while gradually raising the temperature to 80 °C. After concentrating the reaction mixture, 30 mL of cold acetonitrile was added, and the mixture was added dropwise to 30 mL of saturated sodium bicarbonate solution in an ice-water bath. The mixture was extracted with ethyl acetate (50 mL * 2). The organic layers were combined and washed with 30 mL of saturated brine. After drying over anhydrous sodium sulfate and filtration, the organic layer was dried and concentrated, and the crude product was purified on a high-performance silica gel column (EtOAc / PE: 0-80%) to give a yellow solid: 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%). ES-API: [M+H] + =526.2. 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-dicarboxylic acid ester (54 mg, 0.22 mmol) was added in this order and stirred at 120 °C for 2 hours. After the reaction was completed, acetic acid 30 mL of ethyl acetate was added, and the mixture was washed three times with 30 mL of saturated brine. The ethyl acetate layer was dried and concentrated to obtain the crude product, the target product (3R)-1-tert-butyl-3-methyl-4-(1-(4,6-dicyclopropylpyrimidin-5-yl)-6-fluoro-7-(2-fluoro-6-methoxyphenyl)-3-nitro-2-oxo-1,2-dihydro-1,8-naphthyridin-4-yl)piperazine-1,3-dione (50 mg, Y: 46%), as a yellow solid. ES-API: [M+H] + =734.3. 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 mixture was stirred at 80°C for 30 minutes. After concentrating the reaction mixture, 30 mL of ethyl acetate and 30 mL of saturated sodium bicarbonate were added in that order, and the suspension was filtered through diatomaceous earth. The filter cake was washed with ethyl acetate, and the organic layer was separated and washed sequentially with 30 mL of saturated sodium bicarbonate and 30 mL of saturated brine. The mixture was dried and concentrated to give a yellow solid: (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-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8]naphthyridine-3(2H)-carboxylate (40 mg, crude product). ES-API: [M+H]+ = 672.2. Step 7: (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-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8]naphthyridine-3(2H)-carboxylate (40 mg, 0.059 mmol), 30 mL of acetone, anhydrous potassium carbonate (33 mg, 0.24 mmol), and iodomethane (85 mg, 0.59 mmol) were placed in a sealed tube and stirred at 50 °C for 18 hours. 20 mL of ethyl acetate was added to the reaction mixture, washed with 20 mL of saturated brine, dried, and concentrated. The crude product was purified using a high-performance silica gel column (EtOAc / PE: 0-80%) to obtain the yellow solid product (4aR)-tert-methyl-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-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8]naphthyridin-3(2H)-one (40 mg, Y: 90%). ES-API: [M+H] + =686.2. Step 8: (4aR)-tert-Methyl-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-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8]naphthyridin-3(2H)-one (44 mg) was dissolved in dichloromethane (3 mL) and trifluoroacetic acid (1 mL) was added. The reaction mixture was stirred at room temperature for 2 hours, and then concentrated to give (4aR)-8-(4,6-dicyclopropylpyrimidin-5-yl)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-6-methyl-2,3,4,4a-tetrahydro-1H-pyrazine[1',2':4,5]pyrazine[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. Step 9: (4aR)-8-(4,6-Dicyclopropylpyrimidin-5-yl)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-6-methyl-2,3,4,4a-tetrahydro-1H-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8]naphthyridine-5,7(6H,8H)-dione (40 mg, 0.068 mmol) was dissolved in dichloromethane (5 mL), diisopropylethylamine (53 mL, 0.408 mmol) was added, the reaction mixture was cooled to 0 °C, and acrylic acid chloride (12.4 mg, 0.137 mmol) was added dropwise to the reaction mixture. The mixture was stirred at 0 °C for 15 min. 20 mL of dichloromethane was added to the reaction mixture, which was then washed with 20 mL of saturated aqueous NaHCO3 and 20 mL of saturated brine. After drying and concentration, the crude product was purified by preparative HPLC to give the product (4aR)-3-acryloyl-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(4,6-dicyclopropylpyrimidin-5-yl)-6-methyl-2,3,4,4a,6,8-hexahydro-1H-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8]naphthyridine-5,7-dione (Z32, 10 mg, Y: 22%) as a yellow solid. ES-API: [M+H] + =640.2.

[0446] Example 33 Preparation of Compounds Z33, Z33-1 and Z33-2

[0447] [ka]

[0448] Step 1: 7-Chloro-6-fluoro-4-hydroxy-1-(1-isopropyl-4-methyl-1H-pyrazol-5-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-nitrile (3.6 g, 10.0 mmol) was suspended in a mixture of 1,4-dioxane (10 mL) and water (120 mL), concentrated sulfuric acid (10 mL) was added slowly, and the mixture was stirred at 120 °C for 18 hours. The cooled reaction mixture was poured into 20 mL of ice water, adjusted to pH 2-3 with sodium carbonate, and extracted with ethyl acetate (1000 mL * 2). The ethyl acetate layers were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was dried under vacuum to give the product, a light brown solid: 7-chloro-6-fluoro-4-hydroxy-1-(1-isopropyl-4-methyl-1H-pyrazol-5-yl)-1,8-naphthyridin-2(1H)-one (3.36 g, Y: 92%). ES-API: [M+H] + =337.1. 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), and sodium nitrite (69 mg, 1.0 mmol) and concentrated nitric acid (2.0 mL, 30 mmol) were added sequentially. The mixture was stirred at room temperature for 30 minutes. The reaction mixture was slowly poured into 21 mL of ice water, and the precipitated solid was filtered. The filter cake was washed with 10 mL of ice water. After drying under vacuum, the product was obtained as a yellow solid: 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%). ES-API: [M+H] + =382.1. Step 3: A 100 mL three-neck flask was charged with 7-chloro-6-fluoro-4-hydroxy-1-(1-isopropyl-4-methyl-1H-pyrazol-5-yl)3-nitro-1,8-naphthyridin-2(1H)-one (1.5 g, 3.93 mmol), (2-fluoro-6-methoxyphenyl)boronic acid (2.67 g, 15.72 mmol), tetrakis(triphenylphosphine)palladium (908 mg, 0.786 mmol), potassium carbonate (2.72 g, 19.65 mmol), 4 mL of water, and 20 mL of dioxane. The mixture was stirred at 100 °C for 3 hours under a nitrogen atmosphere. After the reaction was complete, the reaction mixture was cooled to room temperature and extracted once with 20 mL of water and 50 mL of methyl tert-butyl ether. The aqueous layer was adjusted to pH 3-5 with 1M hydrochloric acid solution and extracted with ethyl acetate (50 mL * 2). The ethyl acetate layers were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was dried under vacuum to give the product, 6-fluoro-7-(2-fluoro-6-methoxyphenyl)-4-hydroxy-1-(1-isopropyl-4-methyl-1H-pyrazol-5-yl)-3-nitro-1,8-naphthyridin-2(1H)-one (1.5 g, crude product) as a pale yellow solid. ES-API: [M+H] + =472.1. 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), and phosphorus oxychloride (2.4 mL, 25.5 mmol) and N,N-diisopropylethylamine (2.6 mL, 15.9 mmol) were added sequentially. The mixture was gradually heated to 80 °C and stirred for 30 min. The reaction mixture was concentrated, and then 10 mL of cold acetonitrile was added. The mixture was added dropwise to 20 mL of saturated sodium bicarbonate solution in an ice-water bath and extracted with ethyl acetate (20 mL). The ethyl acetate layers were combined and washed once with 20 mL of saturated brine. After drying over anhydrous sodium sulfate and filtration, the organic layer was dried and concentrated, and the crude product was purified on a high-performance silica gel column (EtOAc / PE: 0-50%) to give a yellow solid: 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%). ES-API: [M+H] + =490.1. 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,N-diisopropylethylamine (390 mg, 3 mmol) were added sequentially and stirred at 120 °C for 2 hours. 20 mL of ethyl acetate was added to the reaction mixture, which was then washed three times with 20 mL of saturated brine. The ethyl acetate layer was dried and concentrated to give the product (3R,6R)-1-tert-butyl-3-methyl-4-(6-fluoro-7-(2-fluoro-6-methoxyphenyl)-1-(1-isopropyl-4-methyl-1H-pyrazol-5-yl)-3-nitro-2-oxo-1,2-dihydro-1,8-naphthyridin-4-yl)piperazine-1,3-dione (620 mg, crude product) as a yellow solid. ES-API: [M+H] + =712.2. 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 mixture was stirred at 80 °C for 30 minutes. After concentrating the reaction mixture, 30 mL of ethyl acetate and 30 mL of saturated sodium bicarbonate were added sequentially. The suspension was filtered through diatomaceous earth, and the filter cake was washed with ethyl acetate. The organic layer was separated and washed sequentially with 30 mL of saturated sodium bicarbonate and 30 mL of saturated brine. Concentration to dryness afforded a yellow solid 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-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8]naphthyridine-3(2H)-carboxylate (300 mg, crude). ES-API: [M+H]+ = 650.3. Step 7: (2R,4aR)-tert-butyl 11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(1-isopropyl-4-methyl-1H-pyrazol-5-yl)-2-methyl-5,7-dioxo-4,4a,5,6,7,8-hexahydro-1H-pyrazine[1',2':4,5]pyrazine[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) were placed in a sealed tube and stirred at 50 °C for 18 hours. 20 mL of ethyl acetate was added to the reaction mixture, which was then washed with 20 mL of saturated brine. After drying and concentration, the crude product was purified on a high-performance silica gel column (EtOAc / PE: 0-80%) to obtain the yellow solid product (2R,4aR)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(1-isopropyl-4-methyl-1H-pyrazol-5-yl)-2,6-dimethyl-5,7-dioxo-4,4a,5,6,7,8-hexahydro-1H-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8]naphthyridine-3(2H)-carboxylate tert-butyl ester (350 mg, Y: 95%). ES-API: [M+H] + =664.3. 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-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8]naphthyridine-3(2H)-carboxylate tert-Butyl ester (350 mg) was dissolved in dichloromethane (4 mL) and trifluoroacetic acid (2 mL) was added. The reaction mixture was stirred at room temperature for 2 hours, and then concentrated to give (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-pyrazine[1',2':4,5]pyrazine[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. 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-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8]naphthyridine-5,7(6H,8H)-dione (350 mg, 0.62 mmol) was dissolved in dichloromethane (6 mL), diisopropylethylamine (480 mg, 3.72 mmol) was added, the reaction mixture was cooled to 0 °C, and acrylic acid chloride (112.5 mg, 1.24 mmol) was added dropwise to the reaction mixture. The mixture was stirred at 0 °C for 15 minutes. 20 mL of dichloromethane was added to the reaction mixture, which was then washed with 20 mL of saturated aqueous NaHCO3 and 20 mL of saturated brine. After drying and concentration, the crude product was purified by preparative chromatography to give the product (2R,4aR)-3-acryloyl-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(1-isopropyl-4-methyl-1H-pyrazol-5-yl)-2,6-dimethyl-2,3,4,4a-tetrahydro-1H-pyrazine[1',2':4,5]pyrazine[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. Step 10: (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-pyrazine[1',2':4,5]pyrazine[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 mixture was warmed to room temperature and reacted for 1 hour. The reaction mixture was added dropwise to saturated sodium bicarbonate solution in an ice-water bath and extracted twice with dichloromethane (30 mL). The mixture was 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-pyrazine[1′,2′:4,5]pyrazine[2,3-c][1,8]naphthyridine-5,7(6H,8H)-dione (Z33). Step 11: Compound Z33 was purified by preparative HPLC to obtain one atropisomeric compound, whose structure was designated as Z33-1 (peak: 1, 30 mg, retention time: 9.576 min, Y: 50%). 1H 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, 1H), 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=14.7Hz, 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 (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). Another atropisomeric compound was obtained, and its structure was assigned to Z33-2 (peak: 2, 15 mg, retention time: 9.663 min, Y: 25%). 1 H NMR (500MHz, DMSO-d6) δ10.17(s1H), 7.96(m, 1H), 7.40(d, J=5.5Hz, 1H), 7.29(q, J=7.9Hz, 1H), 7.0 2(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, 1 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). Isomeric compounds were detected by analytical HPLC methods.

[0449] Example 34 Preparation of compounds Z34, Z34-1 and Z34-2

[0450] [ka]

[0451] Step 1: To a 15 mL tube, (2R,4aR)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-2-methyl-5,7-dioxo-1,2,4,4a,5,6,7,8-octyl-3H-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8]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 that order. The tube was sealed and stirred at 50 °C for 18 h. 30 mL of ethyl acetate was added to the reaction mixture, which was then washed with 12 mL of water and 15 mL of saturated brine, dried, and concentrated to give the yellow solid product (2R,4aR)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-2-methyl-6-(methyl-d3)-5,7-dioxo-1,2,4,4a,5,6,7,8-octyl-3H-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8]naphthyridine-3-carboxylate tert-butyl ester (118 mg, Y: 100.0%). ES-API: [M+H] + =678.3. 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-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8]naphthyridine-3-carboxylate (118 mg, 0.17 mmol) was dissolved in dichloromethane (3 mL) and trifluoromethylpyridine-3-carboxylate was added. Acetic acid (0.7 mL) was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated to give (2R,4aR)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-2-methyl-6-(methyl-d3)-2,3,4,4a,6,8-hexahydro-1H-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8]naphthyridine-5,7-dione (120 mg, crude product), which was used directly in the next reaction. ES-API: [M+H] + =578.2. Step 3: (2R,4aR)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-2-methyl-6-(methyl-d3)-2,3,4,4a,6,8-hexahydro-1H-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8]naphthyridine-5,7-dione (120 mg, crude product) 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 acrylic acid chloride (31 mg, 0.34 mmol) was added dropwise to the reaction mixture. The mixture was stirred at 0 °C for 15 min. The reaction mixture was added with 25 mL of dichloromethane and washed sequentially with 15 mL of water, 15 mL of saturated aqueous NaHCO3, and 15 mL of saturated brine. After drying and concentration, the crude product was purified using a high-performance silica gel column (EtOAc / PE: 0-100%) to obtain the pale yellow solid product (2R,4aR)-3-acryloyl-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-2-methyl-6-(methyl-d3)-2,3,4,4a,6,8-hexahydro-1H-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8]naphthyridine-5,7-dione (85 mg, Y: 77.3%). ES-API: [M+H] + =632.2. Step 4: (2R,4aR)-3-Acryloyl-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-2-methyl-6-(methyl-d3)-2,3,4,4a,6,8-hexahydro-1H-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8]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 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 layer was dried and concentrated, and the crude product was purified by preparative HPLC 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-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8]naphthyridine-5,7-dione (Z34). Step 5: Compound Z34 was separated and purified by preparative chiral HPLC (column: OD-H: 10 μm, 20*250 mm, mobile phase: hexane:EtOH=80:20, flow rate: 15 ml / min, column temperature: room temperature). One atropisomeric compound was obtained as a pale yellow solid, and its structure was designated as Z34-1 (23 mg, peak: 1, retention time: 11.056 min, Y: 28.7%). 1H 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), 7.0 5-6.84(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), 1.58-1.53(m, 3H), 1.03(d, J=6.7Hz, 3H), 0.85(d, J=6.7Hz, 3H).ES-API:[M+H] + =618.2. Another atropisomer compound obtained was a pale yellow solid, and its structure was designated as Z34-2 (25 mg, peak: 2, retention time: 14.067 min, Y: 31.2%). 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), 7.0 5-6.85(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), 1.58-1.53(m, 3H), 1.11(d, J=6.7Hz, 3H), 0.98(d, J=6.7Hz, 3H).ES-API:[M+H] + = 618.2. The isomeric compounds were detected by analytical chiral HPLC (column: OD-H: 5 μm, 4.6 * 250 mm, mobile phase: hexane:EtOH = 80:20, flow rate: 1 ml / min, column temperature = 30 °C).

[0452] Example 35 Preparation of Compounds Z35, Z35-1 and Z35-2

[0453] [ka]

[0454] Step 1: (2...

Claims

1. A compound represented by formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof: 【Chemistry 1】 (In Formula I, Z is N—C(O)—CR ３ =CR １ R ２ or N—C(O)—C≡CR ４ and R １ , R ２ are each independently hydrogen, halogen, cyano, or NR ａ R ｂ , -C １－３ Alkyl, halogenated C １－３ Alkyl, —C １－３ Alkyl-hydroxy, -C １－３ Alkyl-cyano, -C １－３ Alkyl-C １－３ Alkoxy, -C １－３ Alkyl-NR ａ R ｂ , -C １－３ alkyl-3 to 6-membered heterocycloalkyl or -C １－３ alkyl-5- or 6-membered monocyclic heteroaryl, wherein the 3- to 6-membered heterocycloalkyl or the 5- or 6-membered monocyclic heteroaryl has 1, 2, or 3 heteroatoms selected from N, O, and S as ring-forming atoms; R ３ is hydrogen, halogen, -C １－３ Alkyl or -C １－３ is an alkoxy; R ４ is hydrogen, halogenated C １－３ Alkyl, —C １－３ Alkyl-hydroxy, -C １－３ Alkyl-cyano or -C １－３ Alkyl-C １－３ is an alkoxy; R １１ , R １２ may be the same or different, and each independently represents hydrogen, halogen, or —C １－３ Alkyl, -halogenated C １－３ Alkyl, —C １－３ Alkyl-hydroxy, -C １－３ Alkyl-cyano, -C １－３ Alkyl-C １－６ Alkoxy, -C １－３ Alkyl-halogenated C １－６ Alkyl or -C １－３ Alkyl-halogenated C １－６ is an alkoxy; R ２１ , R ２２ may be the same or different, and each independently represents hydrogen, halogen, or —C １－３ Alkyl, -halogenated C １－３ Alkyl, —C １－３ Alkyl-hydroxy, -C １－３ Alkyl-cyano, -C １－３ Alkyl-C １－６ Alkoxy, -C １－３ Alkyl-halogenated C １－６ Alkyl or -C １－３ Alkyl-halogenated C １－６ is an alkoxy; R ３１ , R ３２ may be the same or different, and each independently represents hydrogen, halogen, or —C １－３ Alkyl, -halogenated C １－３ Alkyl, —C １－３ Alkyl-hydroxy, -C １－３ Alkyl-cyano, -C １－３ Alkyl-C １－６ Alkoxy, -C １－３ Alkyl-halogenated C １－６ Alkyl or -C １－３ Alkyl-halogenated C １－６ is an alkoxy; R ４１ is hydrogen, halogen, -C １－３ Alkyl, -halogenated C １－３ Alkyl, —C １－３ Alkyl-hydroxy, -C １－３ Alkyl-cyano, -C １－３ Alkyl-C １－６ Alkoxy, -C １－３ Alkyl-halogenated C １－６ Alkyl or -C １－３ a Alkyl-Halogenated C １－６ is an alkoxy; 【Chemistry 2】 When the dashed line in is a single bond, P is O, NH or NR ｍ and R ｍ is optionally substituted -C １－６ alkyl, and R ４２ is -(C=O)-, -C １－３ Alkyl-, -C １－３ Alkyl(hydroxy)-, -C １－３ Alkyl(cyano)-, -C １－３ Alkyl (C １－６ alkyl)-, -C １－３ Alkyl (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)-, Or, 【Transformation 3】 If there is no dashed line in ４２ is hydrogen, halogen, -C １－３ Alkyl, -halogenated C １－３ Alkyl, —C １－３ Alkyl-hydroxy, -C １－３ Alkyl-cyano, -C １－３ Alkyl-C １－６ Alkoxy, -C １－３ Alkyl-halogenated C １－６ Alkyl or -C １－３ Alkyl-halogenated C １－６ is an alkoxy; Y １ If C, then X １ is hydrogen, halogen, cyano, hydroxy, amino, nitro, optionally substituted C １－６ alkyl, optionally substituted C ３－６ cycloalkyl, -optionally substituted 3- to 6-membered heterocycloalkyl, -O-optionally substituted C １－６ alkyl, —O-optionally substituted C ３－６ Cycloalkyl, —O-optionally substituted 3- to 6-membered heterocycloalkyl, —NH-optionally substituted C １－６ alkyl, —N(optionally substituted C １－６ alkyl) ２ , —NH-optionally substituted C ３－６ Cycloalkyl, —NH-optionally substituted 3- to 6-membered heterocycloalkyl, —NH(C═O)-optionally substituted C １－６ Alkyl, —NH(C═O)—C ３－６ Cycloalkyl, —NH(SO ２ )-optionally substituted C １－６ Alkyl, -NH(SO ２ )-optionally substituted C ３－６ Cycloalkyl, —SO ２ -Optionally substituted C １－６ Alkyl, —SO ２ -Optionally substituted C ３－６ cycloalkyl, —(C═O)—NR ｊ R ｋ -, -(C=O)-O-optionally substituted C １－６ alkyl, —(C═O)—O- optionally substituted C ３－６ cycloalkyl, and the R ｊ , R ｋ are each independently hydrogen or C １－３ alkyl or is the R ｊ , R ｋ together with the nitrogen atom to which it is connected, form an optionally substituted 3- to 6-membered nitrogen-containing heterocycloalkyl, wherein the 3- to 6-membered heterocycloalkyl has 1, 2 or 3 heteroatoms selected from N, O and S as ring-forming atoms, the 3- to 6-membered nitrogen-containing heterocycloalkyl has 3-6 ring-forming atoms, one of which is a nitrogen atom, and 0, 1 or 2 of the remaining ring-forming atoms may be heteroatoms selected from N, O and S, and the "substituted" refers to 1, 2, 3 or 4 hydrogen atoms in the group being each independently substituted with a substituent selected from the S group, Or, Y １ If N, then X １ story, The S group substituents include hydroxy, halogen, nitro, oxo, -C １－６ Alkyl, -halogenated C １－６ Alkyl, hydroxy-substituted C １－６ Alkyl, benzyl, -(CH ２ ) ｕ -cyano, -(CH ２ ) ｕ -C １－６ Alkoxy, -(CH ２ ) ｕ -Halogenated C １－６ Alkoxy, -(CH ２ ) ｕ -Halogenated C １－６ Alkyl, -(CH ２ ) ｕ -3 to 6-membered heterocycloalkyl, -(CH ２ ) ｕ -5- or 6-membered monocyclic heteroaryl, -(CH ２ ) ｕ -C ３－８ Cycloalkyl, -(CH ２ ) ｕ -O-(CH ２ ) ｖ -C ３－８ Cycloalkyl, -(CH ２ ) ｕ -O-(CH ２ ) ｖ -C １－６ Alkoxy, -(CH ２ ) ｕ -O-(CH ２ ) ｖ OH, -(CH ２ ) ｕ -SO ２ C １－６ Alkyl, -(CH ２ ) ｕ -NR ａ０ R ｂ０ , -(CH ２ ) ｕ -C(O)NR ａ０ R ｂ０ , -(CH ２ ) ｕ -C(O)C １－６ Alkyl, —C(O)OC １－６ Alkyl, NR ａ ０ C(O)-(CH ２ ) ｕ -NR ａ０ R ｂ０ , N.R. ａ０ C(O)-(CH ２ ) ｕ OH, NR ａ０ C(O)-halogenated C １－６ alkyl, wherein the 3- to 6-membered heterocycloalkyl or the 5- or 6-membered monocyclic heteroaryl has 1, 2, or 3 heteroatoms independently selected from N, O, and S as ring-forming atoms, and the 3- to 6-membered heterocycloalkyl and the 5- or 6-membered monocyclic heteroaryl are selected from halogen, cyano, -C １－３ Alkyl, —C １－３ Alkoxy and C ３－６ cycloalkyl, u and v are each independently 0, 1, 2, 3 or 4; R ａ０ , R ｂ０ are each independently hydrogen or C １－３ is alkyl, E １ is N or CR ５ and R ５ is hydrogen, halogen, cyano, -C １－６ Alkyl, —C １－６ Alkoxy, -halogenated C １－６ Alkyl, -halogenated C １－６ Alkoxy, -C ３－６ Cycloalkyl, —NR ｈ R ｉ , -C １－４ Alkyl-hydroxy, -C １－４ Alkyl-cyano, -C １－４ Alkyl-C １－６ Alkoxy, -C １－４ Alkyl-halogenated C １－６ Alkyl or -C １－４ Alkyl-halogenated C １－６ is an alkoxy; E ２ is N or CR ６ and R ６ is hydrogen, halogen, cyano, -C １－６ Alkyl, —C １－６ Alkoxy, -halogenated C １－６ Alkyl, -halogenated C １－６ Alkoxy, -C ３－６ Cycloalkyl, —NR ｈ R ｉ , -C １－４ Alkyl-hydroxy, -C １－４ Alkyl-cyano, -C １－４ Alkyl-C １－６ Alkoxy, -C １－４ Alkyl-halogenated C １－６ Alkyl or -C １－４ Alkyl-halogenated C １－６ is an alkoxy; However, Y １ , E １ , E ２ But at the same time, it is not N, Ar is C ６－１０ aryl, 5- or 6-membered monocyclic heteroaryl, or 8- to 10-membered bicyclic heteroaryl, wherein the 5- or 6-membered monocyclic heteroaryl group has 1, 2, or 3 heteroatoms selected from N, O, and S as ring-forming atoms, and the 8- to 10-membered bicyclic heteroaryl has 1, 2, 3, 4, or 5 heteroatoms selected from N, O, and S as ring-forming atoms, and the C ６－１０ The aryl, the 5- or 6-membered monocyclic heteroaryl, or the 8- to 10-membered bicyclic heteroaryl group is unsubstituted or independently R ｓ１ and is substituted with 1, 2, 3 or 4 groups selected from Alternatively, Ar is a structure represented by formula (B): 【Chemistry 4】 In formula (B), ring B1 is a benzene ring or a 5- or 6-membered monocyclic heteroaryl ring, ring B2 is a fused 5- or 6-membered monocyclic heterocycloalkyl ring or a fused 5- or 6-membered monocyclic cycloalkyl ring, and 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-forming atoms; (R ｓ１ ) ｐ The hydrogen atoms of the B1 ring are p R ｓ１ where p is 0, 1, 2, or 3, and each R ｓ１ may be the same or different, (R ｓ２ ) ｑ The hydrogen atoms of the B2 ring are q R ｓ２ q is 0, 1, 2, or 3; and each R ｓ２ may be the same or different, R ｓ１ , R ｓ２ are each independently halogen, cyano, nitro, hydroxy, -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 , -SO ２ C １－３ Alkyl, —SO ２ Halide C １－３ Alkyl, —SO ２ NR ｅ R ｆ , -C １－４ Alkyl-hydroxy, -C １－４ Alkyl-cyano, -C １－４ Alkyl-C １－６ Alkoxy, -C １－４ Alkyl-halogenated C １－６ Alkyl, —C １－４ Alkyl-halogenated 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-SO ２ C １－３ Alkyl or C ２－４ alkynyl, wherein the 3- to 6-membered heterocycloalkyl group has 1, 2, or 3 heteroatoms selected from N, O, and S as ring-forming atoms; R ０ is -C １－６ Alkyl, —C ３－６ cycloalkyl, 3- to 6-membered heterocycloalkyl, C ６－１０ Aryl, 5- or 6-membered monocyclic heteroaryl, 8- to 10-membered bicyclic heteroaryl, 7- to 11-membered spirocycloalkyl, -C １－３ Alkyl-C ６－１０ Aryl, —C １－３ alkyl-5 or 6-membered monocyclic heteroaryl, —NR ｇ -C ６－１０ Aryl, —O—C ６－１０ Aryl, —C １－３ alkyl-3 to 6-membered heterocycloalkyl, —C １－３ Alkyl-C ３－６ 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-forming 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 are unsubstituted or independently R ｓ３ and wherein the —C １－３ Alkyl- is unsubstituted or contains 1, 2, 3 or 4 independently C １－３ substituted with a group selected from alkyl; Or, R ０ is a structure represented by formula (A-1) or formula (A-2), 【Transformation 5】 In formula (A-1) or formula (A-2), ring A1 is a benzene ring or a 5- or 6-membered monocyclic heteroaryl ring, ring A2 is a fused 5- or 6-membered monocyclic heterocycloalkyl ring or a fused 5- or 6-membered monocyclic cycloalkyl ring, and 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-forming atoms; (R ｓ３ ) ｔ The hydrogen atoms of the A1 ring are t R ｓ３ where t is 0, 1, 2, or 3, and each R ｓ３ may be the same or different, (R ｓ４ ) ｓ The hydrogen atoms of the A2 ring are s R ｓ４ where s is 0, 1, 2, or 3, and each R ｓ４ may be the same or different, R ｓ３ , R ｓ４ are each independently a halogen, a cyano, a hydroxy, or —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 , -SO ２ C １－３ Alkyl, —SO ２ Halide C １－３ Alkyl, —SO ２ NR ｅ R ｆ , -C １－３ Alkyl-hydroxy, -C １－３ Alkyl-C ２－４ Alkynyl, —C １－３ Alkyl-cyano, -C １－３ Alkyl-C １－６ Alkoxy, -C １－３ Alkyl-halogenated C １－６ Alkyl, —C １－３ Alkyl-halogenated 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-SO ２ C １－３ Alkyl or C ２－４ alkynyl, wherein the 3- to 6-membered heterocycloalkyl has 1, 2, or 3 heteroatoms selected from N, O, and S as ring-forming atoms, and the C １－６ Alkyl, —C １－６ Alkoxy, -C １－３ Alkyl-, -C ３－６ Cycloalkyl and 3- to 6-membered heterocycloalkyl include halogen, methyl, ethyl, propyl, isopropyl, trifluoromethyl, amino, N(CH ３ ) ２ , hydroxy, carboxyl; R ａ , R ｂ , R ｅ , R ｆ , R ｇ are each independently hydrogen or C １－３ is alkyl, R ｃ , R ｄ , R ｈ , R ｉ are each independently hydrogen, —C １－３ Alkyl, —C(O)C １－３ Alkyl or —CO ２ C １－３ It is alkyl.)

2. A compound represented by formula (II), or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof: 【Transformation 6】 (In Formula II, Z is N—C(O)—CR ３ =CR １ R ２ or N—C(O)—C≡CR ４ and R １ , R ２ are each independently hydrogen, halogen, cyano, or NR ａ R ｂ , -C １－３ Alkyl, halogenated C １－３ Alkyl, —C １－３ Alkyl-hydroxy, -C １－３ Alkyl-cyano, -C １－３ Alkyl-C １－３ Alkoxy, -C １－３ Alkyl-NR ａ R ｂ , -C １－３ alkyl-3 to 6-membered heterocycloalkyl, or —C １－３ alkyl-5- or 6-membered monocyclic heteroaryl, wherein said 3- to 6-membered heterocycloalkyl or said 5- or 6-membered monocyclic heteroaryl has 1, 2, or 3 heteroatoms selected from N, O, and S as ring-forming atoms; R ３ is hydrogen, halogen, -C １－３ Alkyl or -C １－３ is an alkoxy; R ４ is hydrogen, halogenated C １－３ Alkyl, —C １－３ Alkyl-hydroxy, -C １－３ Alkyl-cyano or -C １－３ Alkyl-C １－３ is an alkoxy; R １１ , R １２ may be the same or different, and each independently represents hydrogen, halogen, or —C １－３ Alkyl, -halogenated C １－３ Alkyl, —C １－３ Alkyl-hydroxy, -C １－３ Alkyl-cyano, -C １－３ Alkyl-C １－６ Alkoxy, -C １－３ Alkyl-halogenated C １－６ Alkyl or -C １－３ Alkyl-halogenated C １－６ is an alkoxy; R ２１ , R ２２ may be the same or different, and each independently represents hydrogen, halogen, or —C １－３ Alkyl, -halogenated C １－３ Alkyl, —C １－３ Alkyl-hydroxy, -C １－３ Alkyl-cyano, -C １－３ Alkyl-C １－６ Alkoxy, -C １－３ Alkyl-halogenated C １－６ Alkyl or -C １－３ Alkyl-halogenated C １－６ is an alkoxy; R ３１ , R ３２ may be the same or different, and each independently represents hydrogen, halogen, or —C １－３ Alkyl, -halogenated C １－３ Alkyl, —C １－３ Alkyl-hydroxy, -C １－３ Alkyl-cyano, -C １－３ Alkyl-C １－６ Alkoxy, -C １－３ Alkyl-halogenated C １－６ Alkyl or -C １－３ Alkyl-halogenated C １－６ is an alkoxy; R ４１ is hydrogen, halogen, -C １－３ Alkyl, -halogenated C １－３ Alkyl, —C １－３ Alkyl-hydroxy, -C １－３ Alkyl-cyano, -C １－３ Alkyl-C １－６ Alkoxy, -C １－３ Alkyl-halogenated C １－６ Alkyl or -C １－３ Alkyl-halogenated C １－６ is an alkoxy; P is O, NH or NR ｍ and R ｍ is -C １－６ Alkyl, -halogenated C １－６ Alkyl, —C １－６ Alkyl-hydroxy, -C １－６ Alkyl-cyano, -C １－ ６ Alkyl-C １－６ Alkoxy, -C １－６ Alkyl-halogenated C １－６ Alkoxy, -C １－６ Alkyl-C ３－６ cycloalkyl, or —C １－６ alkyl-3- to 6-membered heterocycloalkyl; R ４２ is -(C=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)-, X ２ , Y ２ may be the same or different, and each independently represents hydrogen, halogen, or —C １－３ Alkyl, -halogenated C １－３ Alkyl, —C １－３ Alkyl-hydroxy, -C １－３ Alkyl-cyano, -C １－３ Alkyl-C １－６ Alkoxy, -C １－３ Alkyl-halogenated C １－６ Alkyl or -C １－３ Alkyl-halogenated C １－６ is an alkoxy; Or, X ２ , Y ２ optionally substituted together with the adjacent carbon atom ３－６ a cycloalkyl or an optionally substituted 3- to 6-membered heterocycloalkyl is formed, wherein the 3- to 6-membered heterocycloalkyl has 1, 2, or 3 heteroatoms selected from N, O, and S as ring-forming atoms, and the "substituted" refers to 1, 2, 3, or 4 hydrogen atoms in the group being each independently substituted with a substituent selected from the S group; E ３ is N or C-L-R ５ and The L is a single bond, —CR Ｌ１ R Ｌ２ -, -O-(CR Ｌ１ R Ｌ２ ) ｔ１ -, or -NH-(CR Ｌ３ R Ｌ４ ) ｔ２ - and R Ｌ１ , R Ｌ２ , R Ｌ３ , R Ｌ４ may be the same or different, and each independently represents hydrogen, halogen, hydroxy, hydroxymethyl, hydroxyethyl, -C １－３ alkyl or oxo, t1 and t2 are each independently 0, 1, 2, 3, or 4, and R Ｌ１ and R Ｌ２ In or R Ｌ３ and R Ｌ４ In the formula, if one of them is oxo, the other is absent, R ５ is hydrogen, halogen, hydroxy, optionally substituted C １－６ alkyl, optionally substituted C ３－６ cycloalkyl, -optionally substituted 3-6 membered heterocycloalkyl, -O-optionally substituted C １－６ alkyl, —O-optionally substituted C ３－６ Cycloalkyl, —O-optionally substituted 3- to 6-membered heterocycloalkyl, —SO ２ -Optionally substituted C １－６ Alkyl, —SO ２ -Optionally substituted C ３－６ Cycloalkyl, —SO ２ - an optionally substituted 3- to 6-membered heterocycloalkyl, - an optionally substituted 5- or 6-membered monocyclic heteroaryl group or NR ５１ R ５２ and R ５１ , R ５２ are each independently hydrogen, optionally substituted C １－６ Alkyl, —SO ２ C １－６ Alkyl, —SO ２ C ３－６ Cycloalkyl, —C(O)C １－６ Alkyl or -C(O) halogenated C １－６ alkyl, or R ５１ and R ５２ form an optionally substituted 3- to 6-membered nitrogen-containing heterocycloalkyl together with the nitrogen atom to which it is connected, and the 3- to 6-membered heterocycloalkyl and the 5- or 6-membered monocyclic heteroaryl each have 1, 2 or 3 heteroatoms independently selected from N, O and S as ring-forming atoms, the 3- to 6-membered nitrogen-containing heterocycloalkyl has 3 to 6 ring-forming atoms, one of which is a nitrogen atom, and none, one or two of the remaining ring-forming atoms may be a heteroatom independently selected from N, O and S, and the "substituted" refers to 1, 2, 3 or 4 hydrogen atoms in the group being substituted with substituents independently selected from the S group, The S group substituents include hydroxy, halogen, nitro, oxo, -C １－６ Alkyl, -halogenated C １－６ Alkyl, hydroxy-substituted C １－６ Alkyl, benzyl, -(CH ２ ) ｕ -cyano, -(CH ２ ) ｕ -C １－６ Alkoxy, -(CH ２ ) ｕ -Halogenated C １－６ Alkoxy, -(CH ２ ) ｕ -Halogenated C １－６ Alkyl, -(CH ２ ) ｕ -3 to 6-membered heterocycloalkyl, -(CH ２ ) ｕ - 5- or 6-membered monocyclic heteroaryl, (CH ２ ) ｕ -C ３－８ Cycloalkyl, -(CH ２ ) ｕ -O-(CH ２ ) ｖ -C ３－８ Cycloalkyl, -(CH ２ ) ｕ -O-(CH ２ ) ｖ -C １－６ Alkoxy, -(CH ２ ) ｕ -O-(CH ２ ) ｖ OH, -(CH ２ ) ｕ -SO ２ C １－６ Alkyl, -(CH ２ ) ｕ -NR ａ０ R ｂ０ , -(CH ２ ) ｕ -C(O)NR ａ０ R ｂ０ , -(CH ２ ) ｕ -C(O)C １－６ Alkyl, —C(O)OC １－６ Alkyl, NR ａ ０ C(O)-(CH ２ ) ｕ -NR ａ０ R ｂ０ , N.R. ａ０ C(O)-(CH ２ ) ｕ OH, NR ａ０ C(O)-halogenated C １－６ alkyl, wherein the 3- to 6-membered heterocycloalkyl or the 5- or 6-membered monocyclic heteroaryl each independently has 1, 2, or 3 heteroatoms selected from N, O, and S as ring-forming atoms, and the 3- to 6-membered heterocycloalkyl and the 5- or 6-membered monocyclic heteroaryl are each independently selected from halogen, cyano, —C １－３ Alkyl, —C １－３ Alkoxy and C ３－６ cycloalkyl, u and v are each independently 0, 1, 2, 3 or 4; R ａ０ , R ｂ０ are each independently hydrogen or C １－３ is alkyl, E ４ is N or CH, Ar is C ６－１０ an aryl, a 5- or 6-membered monocyclic heteroaryl, or an 8- to 10-membered bicyclic heteroaryl group, wherein the 5- or 6-membered monocyclic heteroaryl group has 1, 2, or 3 heteroatoms selected from N, O, and S as ring-forming atoms, and the 8- to 10-membered bicyclic heteroaryl group has 1, 2, 3, 4, or 5 heteroatoms selected from N, O, and S as ring-forming atoms; and ６－１０ The aryl, the 5- or 6-membered monocyclic heteroaryl, or the 8- to 10-membered bicyclic heteroaryl is unsubstituted or independently R ｓ１ and is substituted with 1, 2, 3 or 4 groups selected from Alternatively, Ar is a structure represented by formula (B): 【Transformation 7】 In formula (B), ring B1 is a benzene ring or a 5- or 6-membered monocyclic heteroaryl ring, ring B2 is a fused 5- or 6-membered monocyclic heterocycloalkyl ring or a fused 5- or 6-membered monocyclic cycloalkyl ring, and 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-forming atoms; (R ｓ１ ) ｐ The hydrogen atoms of the B1 ring are p R ｓ１ where p is 0, 1, 2, or 3, and each R ｓ１ may be the same or different, (R ｓ２ ) ｑ The hydrogen atoms of the B2 ring are q R ｓ２ q is 0, 1, 2, or 3; and each R ｓ２ may be the same or different, R ｓ１ , R ｓ２ are each independently halogen, cyano, nitro, hydroxy, -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 , -SO ２ C １－３ Alkyl, —SO ２ Halide C １－３ Alkyl, —SO ２ NR ｅ R ｆ , -C １－４ Alkyl-hydroxy, -C １－４ Alkyl-cyano, -C １－４ Alkyl-C １－６ Alkoxy, -C １－４ Alkyl-halogenated C １－６ Alkyl, —C １－４ Alkyl-halogenated 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-SO ２ C １－３ Alkyl or C ２－４ alkynyl, wherein the 3- to 6-membered heterocycloalkyl has 1, 2, or 3 heteroatoms selected from N, O, and S as ring-forming atoms; R ａ , R ｂ , R ｅ , R ｆ are each independently hydrogen or —C １－３ is an alkyl group, R ｃ , R ｄ are each independently hydrogen, —C １－３ Alkyl, —C(O)C １－３ Alkyl or —CO ２ C １－３ It is alkyl.)

3. A compound represented by formula (IA) or a tautomer, cis-trans isomer, mesomers, racemates, enantiomers, diastereomers, atropisomers or mixtures thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof. 【Transformation 8】 (In Formula IA, Z is N—C(O)—CR ３ =CR １ R ２ or N—C(O)—C≡CR ４ and R １ , R ２ are each independently hydrogen, halogen, cyano, or NR ａ R ｂ , -C １－３ Alkyl, halogenated C １－３ Alkyl, —C １－３ Alkyl-hydroxy, -C １－３ Alkyl-cyano, -C １－３ Alkyl-C １－３ Alkoxy, -C １－３ Alkyl-NR ａ R ｂ , -C １－３ alkyl-3 to 6-membered heterocycloalkyl or -C １－３ alkyl-5- or 6-membered monocyclic heteroaryl, wherein the 3- to 6-membered heterocycloalkyl or the 5- or 6-membered monocyclic heteroaryl has 1, 2, or 3 heteroatoms selected from N, O, and S as ring-forming atoms; R ３ is hydrogen, halogen, -C １－３ Alkyl or -C １－３ is an alkoxy; R ４ is hydrogen, halogenated C １－３ Alkyl, —C １－３ Alkyl-hydroxy, -C １－３ Alkyl-cyano or -C １－３ Alkyl-C １－３ is an alkoxy; R １１ , R １２ may be the same or different, and each independently represents hydrogen, halogen, or —C １－３ Alkyl, -halogenated C １－３ Alkyl, —C １－３ Alkyl- Hydroxy, -C １－３ Alkyl-cyano, -C １－３ Alkyl-C １－６ Alkoxy, -C １－３ Alkyl-halogenated C １－６ Alkyl or -C １－３ Alkyl-halogenated C １－６ is an alkoxy; R ２１ , R ２２ may be the same or different, and each independently represents hydrogen, halogen, or —C １－３ Alkyl, -halogenated C １－３ Alkyl, —C １－３ Alkyl-hydroxy, -C １－３ Alkyl-cyano, -C １－３ Alkyl-C １－６ Alkoxy, -C １－３ Alkyl-halogenated C １－６ Alkyl or -C １－３ Alkyl-halogenated C １－６ is an alkoxy; R ３１ , R ３２ may be the same or different, and each independently represents hydrogen, halogen, or —C １－３ Alkyl, -halogenated C １－３ Alkyl, —C １－３ Alkyl-hydroxy, -C １－３ Alkyl-cyano, -C １－３ Alkyl-C １－６ Alkoxy, -C １－３ Alkyl-halogenated C １－６ Alkyl or -C １－３ Alkyl-halogenated C １－６ is an alkoxy; R ４１ is hydrogen, halogen, -C １－３ Alkyl, -halogenated C １－３ Alkyl, —C １－３ Alkyl-hydroxy, -C １－３ Alkyl-cyano, -C １－３ Alkyl-C １－６ Alkoxy, -C １－３ Alkyl-halogenated C １－６ Alkyl or -C １－３ Alkyl-halogenated C １－６ is an alkoxy; 【Chemistry 9】 When the dashed line in is a single bond, P′ is O, NH, or NR ｍ ' and R ｍ ' is an optionally substituted C １－６ alkyl, and 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)-, Or, 【Chemistry 10】 If there is no dashed line in ４２ ' is hydrogen, halo Gen, -C １－３ Alkyl, -halogenated C １－３ Alkyl, —C １－３ Alkyl-hydroxy, -C １－３ Alkyl-cyano, -C １－３ Alkyl-C １－６ Alkoxy, -C1 －３ Alkyl-halogenated C １－６ Alkyl or -C １－３ Alkyl-halogenated C １－６ is an alkoxy; Y １ If C, then X １ is hydrogen, halogen, cyano, hydroxy, amino, nitro, optionally substituted C １－６ alkyl, optionally substituted C ３－６ cycloalkyl, -optionally substituted 3- to 6-membered heterocycloalkyl, -O-optionally substituted C １－６ alkyl, —O-optionally substituted C ３－６ Cycloalkyl, —O-optionally substituted 3- to 6-membered heterocycloalkyl, —NH-optionally substituted C １－６ alkyl group, -N(optionally substituted C １－６ alkyl) ２ , —NH-optionally substituted C ３－６ Cycloalkyl, —NH-optionally substituted 3- to 6-membered heterocycloalkyl, —NH(C═O)-optionally substituted C １－６ Alkyl, —NH(C═O)—C ３－６ Cycloalkyl, —NH(SO ２ )-optionally substituted C １－６ Alkyl, -NH(SO ２ )-optionally substituted C ３－６ Cycloalkyl, —SO ２ -Optionally substituted C １－６ Alkyl, —SO ２ -Optionally substituted C ３－６ cycloalkyl, —(C═O)—NR ｊ R ｋ -, -(C=O)-O-optionally substituted C １－６ alkyl, —(C═O)—O- optionally substituted C ３－６ cycloalkyl, and the R ｊ , R ｋ are each independently hydrogen or C １－３ is an alkyl group, or ｊ , R ｋ is connected to a nitrogen atom to form an optionally substituted 3- to 6-membered nitrogen-containing heterocycloalkyl, wherein the 3- to 6-membered heterocycloalkyl has 1, 2, or 3 heteroatoms selected from N, O, and S as ring-forming atoms, the 3- to 6-membered nitrogen-containing heterocycloalkyl has 3 to 6 ring-forming atoms, one of which is a nitrogen atom, and 0, 1, or 2 of the remaining ring-forming atoms may be heteroatoms selected from N, O, and S, and the "substituted" refers to 1, 2, 3, or 4 hydrogen atoms in the group being each independently substituted with a substituent selected from the S group, Or, Y １ If N, then X １ story, The S group substituents include hydroxy, halogen, nitro, oxo, -C １－６ Alkyl, -halogenated C １－６ Alkyl, hydroxy-substituted C １－６ Alkyl, benzyl, -(CH ２ ) ｕ -cyano, -(CH ２ ) ｕ -C １－６ Alkoxy, -(CH ２ ) ｕ -Halogenated C １－６ Alkoxy, -(CH ２ ) ｕ -Halogenated C １－６ Alkyl, -(CH ２ ) ｕ -3 to 6-membered heterocycloalkyl, -(CH ２ ) ｕ -5- or 6-membered monocyclic heteroaryl, -(CH ２ ) ｕ -C ３－８ Cycloalkyl, -(CH ２ ) ｕ -O-(CH ２ ) ｖ -C ３－８ Cycloalkyl, -(CH ２ ) ｕ -O-(CH ２ ) ｖ -C １－６ Alkoxy, -(CH ２ ) ｕ -O-(CH ２ ) ｖ OH, -(CH ２ ) ｕ -SO ２ C １－６ Alkyl, -(CH ２ ) ｕ -NR ａ０ R ｂ０ , -(CH ２ ) ｕ -C(O)NR ａ０ R ｂ０ , -(CH ２ ) ｕ -C(O)C １－６ Alkyl, —C(O)OC １－６ Alkyl, NR ａ ０ C(O)-(CH ２ ) ｕ -NR ａ０ R ｂ０ , N.R. ａ０ C(O)-(CH ２ ) ｕ OH, NR ａ０ C(O)-halogenated C １－６ alkyl, wherein the 3- to 6-membered heterocycloalkyl or the 5- or 6-membered monocyclic heteroaryl has 1, 2, or 3 heteroatoms each independently selected from N, O, and S as ring-forming atoms, and the 3- to 6-membered heterocycloalkyl and the 5- or 6-membered monocyclic heteroaryl are selected from halogen, cyano, —C １－３ Alkyl, —C １－３ Alkoxy and C ３－６ cycloalkyl, u and v are each independently 0, 1, 2, 3 or 4; R ａ０ , R ｂ０ are each independently hydrogen or C １－３ is alkyl, E １ ' is N or CR ５ ', and said R ５ ' 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, —O—C ３－６ Cycloalkyl, —NR ｈ R ｉ , -C １－４ Alkyl-hydroxy, -C １－４ Alkyl-cyano, -C １－４ Alkyl-C １－６ Alkoxy, -C １－４ Alkyl-halogenated C １－６ Alkyl or -C １－４ Alkyl-halogenated C １－６ is an alkoxy; E ２ ' is N or CR ６ ', and said R ６ ' 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, —O—C ３－６ Cycloalkyl, —NR ｈ R ｉ , -C １－４ Alkyl-hydroxy, -C １－４ Alkyl-cyano, -C １－４ Alkyl-C １－６ Alkoxy, -C １－４ Alkyl-halogenated C １－６ Alkyl or -C １－４ Alkyl-halogenated C １－６ is an alkoxy; However, Y １ , E １ ', E ２ ' is not N at the same time, Ar' is C ６－１０ aryl, 5- or 6-membered monocyclic heteroaryl, 8- to 10-membered bicyclic heteroaryl or pyridone group, wherein the 5- or 6-membered monocyclic heteroaryl has 1, 2 or 3 heteroatoms selected from N, O and S as ring-forming atoms, and the 8- to 10-membered bicyclic heteroaryl has 1, 2, 3, 4 or 5 heteroatoms selected from N, O and S as ring-forming atoms, and the C ６－１０ The aryl, the 5- or 6-membered monocyclic heteroaryl, the 8- to 10-membered bicyclic heteroaryl, and the pyridone group are unsubstituted or independently represented by R ｓ１ and is substituted with 1, 2, 3 or 4 groups selected from Alternatively, Ar' is a structure represented by formula (B): 【Chemistry 11】 In formula (B), ring B1 is a benzene ring or a 5- or 6-membered monocyclic heteroaryl ring, ring B2 is a fused 5- or 6-membered monocyclic heterocycloalkyl ring or a fused 5- or 6-membered monocyclic cycloalkyl ring, and 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-forming atoms; (R ｓ１ ) ｐ The hydrogen atoms of the B1 ring are p R ｓ１ where p is 0, 1, 2, or 3, and each R ｓ１ may be the same or different, (R ｓ２ ) ｑ The hydrogen atoms of the B2 ring are q R ｓ２ q is 0, 1, 2, or 3; and each R ｓ２ may be the same or different, R ｓ１ , R ｓ２ are each independently halogen, cyano, nitro, hydroxy, -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 , -SO ２ C １－３ Alkyl, —SO ２ Halide C １－３ Alkyl, —SO ２ NR ｅ R ｆ , -C １－４ Alkyl-hydroxy, -C １－４ Alkyl-cyano, -C １－４ Alkyl-C １－６ Alkoxy, -C １－４ Alkyl-halogenated C １－６ Alkyl, —C １－４ Alkyl-halogenated 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-SO ２ C １－３ Alkyl or C ２－４ alkynyl, a 6-membered heterocycloalkyl group has 1, 2, or 3 heteroatoms selected from N, O, and S as ring-forming atoms; R ０ ' is -C １－６ Alkyl, —C ３－６ cycloalkyl, 3- to 6-membered heterocycloalkyl, C ６－１０ Aryl, 5- or 6-membered monocyclic heteroaryl, 8- to 10-membered bicyclic heteroaryl, 7- to 11-membered spirocycloalkyl, -C １－３ Alkyl-C ６－１０ Aryl, —C １－３ alkyl-5 or 6-membered monocyclic heteroaryl, —NR ｇ -C ６－１０ Aryl, —O—C ６－１０ Aryl, —C １－３ alkyl-3 to 6-membered heterocycloalkyl, —C １－３ Alkyl-C ３－６ a cycloalkyl or pyridone group, wherein the 3- to 6-membered heterocycloalkyl, the 5- or 6-membered monocyclic heteroaryl, or the 8- to 10-membered bicyclic heteroaryl has 1, 2, or 3 heteroatoms selected from N, O, and S as ring-forming atoms; and １－６ Alkyl, C ３－６ cycloalkyl, 3- to 6-membered heterocycloalkyl, C ６－１０ The aryl, 5- or 6-membered monocyclic heteroaryl, 8- to 10-membered bicyclic heteroaryl, 7- to 11-membered spirocycloalkyl, and pyridone groups are unsubstituted or independently R ｓ３ and wherein the —C １－３ Alkyl- is unsubstituted or independently C １－３ substituted with 1, 2, 3 or 4 groups selected from alkyl; Or, R ０ ' is a structure represented by formula (A-1) or formula (A-2), 【Chemistry 12】 In formula (A-1) or formula (A-2), ring A1 is a benzene ring or a 5- or 6-membered monocyclic heteroaryl ring, ring A2 is a fused 5- or 6-membered monocyclic heterocycloalkyl ring or a fused 5- or 6-membered monocyclic cycloalkyl ring, and 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-forming atoms; (R ｓ３ ) ｔ The hydrogen atoms of the A1 ring are t R ｓ３ where t is 0, 1, 2, or 3, and each R ｓ３ may be the same or different, (R ｓ４ ) ｓ The hydrogen atoms of the A2 ring are s R ｓ４ where s is 0, 1, 2, or 3, and each R ｓ４ may be the same or different, R ｓ３ , R ｓ４ are each independently a halogen, a cyano, a hydroxy, or —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 , -SO ２ C １－３ Alkyl, —SO ２ Halide C １－３ Alkyl, —SO ２ NR ｅ R ｆ , -C １－３ Alkyl-hydroxy, -C １－３ Alkyl-C ２－４ Alkynyl, —C １－３ Alkyl-cyano, -C １－３ Alkyl-C １－６ Alkoxy, -C １－３ Alkyl-halogenated C １－６ Alkyl, —C １－３ Alkyl-halogenated 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-SO ２ C １－３ Alkyl or C ２－４ alkynyl, wherein the 3- to 6-membered heterocycloalkyl has 1, 2, or 3 heteroatoms selected from N, O, and S as ring-forming atoms, and the C １－６ Al Kill, -C １－６ Alkoxy, -C １－３ Alkyl-, -C ３－６ Cycloalkyl, 3- to 6-membered heterocycloalkyl are optionally independently selected from halogen, methyl, ethyl, propyl, isopropyl, trifluoromethyl, amino, N(CH ３ ) ２ , hydroxy, carboxyl; R ａ , R ｂ , R ｅ , R ｆ , R ｇ are each independently hydrogen or C １－３ is an alkyl group, R ｃ , R ｄ , R ｈ , R ｉ are each independently hydrogen, —C １－３ Alkyl, —C(O)C １－３ Alkyl or —CO ２ C １－３ It is alkyl.)

4. The compound according to claim 3, characterized in that the compound represented by formula (IA) is a compound represented by formula (IB) or a compound represented by formula (IC), or a tautomer, cis-trans isomer, mesomers, racemates, enantiomers, diastereomers, atropisomers or mixtures thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof. 【Chemistry 13】 (In formula IB, P′ is O, NH, or NR ｍ ', and said R ｍ ' is an optionally substituted -C １－６ alkyl, and 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 C1-6 alkoxy)-, R １１ , R １２ , R ２１ , R ２２ , R ３１ , R ３２ , R ４１ , Z, R ０ ', Ar', E １ ', E ２ ', X １ , Y １ is defined as in claim 3, In formula IC, P′ is hydrogen or halogen, and R ４２ ' is hydrogen, halogen, -C １－３ Alkyl, -halogenated C １－３ Alkyl, —C １－３ Alkyl-hydroxy, -C １－３ Alkyl-cyano, -C １－３ Alkyl-C １－６ Alkoxy, -C １－３ Alkyl-halogenated C １－６ Alkyl or -C １－３ Alkyl-halogenated C １－６ is alkoxy, and R １１ , R １２ , R ２１ , R ２２ , R ３１ , R ３２ , R ４１ , Z, R ０ ', Ar', E １ ', E ２ ', X １ , Y １ is defined as in claim 3.)

5. The compound represented by formula (IB) is a compound represented by formula (IB-1) or a compound represented by formula (IB-2), a compound represented by formula (IB-1a), a compound represented by formula (IB-2a), a compound represented by formula (IB-1c), a compound represented by formula (IB-2c), a compound represented by formula (IB-1b), a compound represented by formula (IB-2b), a compound represented by formula (IB-1d), or a compound represented by formula (IB-2d). Claim 4 or a tautomer, cis-trans isomer, mesomers, racemates, enantiomers, diastereomers, atropisomers or mixtures thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof. 【Chemistry 14】 (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', R ０ ', Ar', E １ ', E ２ ', X １ , Y １ is defined as in claim 4.) 【Chemistry 15】 (In formula (IB-1a) or formula (IB-2a), R １ , R ２ , R ３ , R ２１ , R ２２ , R １２ , R １１ , R ３１ , R ３２ , P', R ０ ', Ar', E １ ', X １ is defined as in claim 4.) 【Chemistry 16】 (In formula (IB-1c) or formula (IB-2c), R １ , R ２ , R ３ , R ２１ , R ２２ , R １２ , R １１ , R ３１ , R ３２ , P', R ０ ', Ar', E １ ', X １ is defined as in claim 4.) 【Chemistry 17】 (In formula (IB-1b) or formula (IB-2b), R １ , R ２ , R ３ , R ２１ , R ２２ , R １２ , R １１ , R ３１ , R ３２ , P', R ０ ', Ar', E １ ', X １ is defined as in claim 4.) [Chemistry 18] (In formula (IB-1d) or formula (IB-2d), R １ , R ２ , R ３ , R ２１ , R ２２ , R １２ , R １１ , R ３１ , R ３２ , P', R ０ ', Ar', E １ ', X １ is defined as in claim 4.)

6. 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), The compound represented by formula (IB-1c) is a compound represented by formula (IB-1ca), a compound represented by formula (IB-1cb), a compound represented by formula (IB-1cc), or a compound represented by formula (IB-1cd), 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), The compound according to claim 5, 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), or a tautomer, cis-trans isomer, mesomers, racemates, enantiomers, diastereomers, atropisomers, or mixtures thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof. 【Chemistry 19】 (In formula (IB-1aa) and formula (IB-1ab), R ２１ ' are independently halogen, -C １－３ Alkyl, -halogenated C １－３ Alkyl, —C １－３ Alkyl-hydroxy, -C １－３ Alkyl-cyano, -C １－３ Alkyl-C １－６ Alkoxy, -C １－３ Alkyl-halogenated C １－６ Alkyl or -C １－３ Alkyl-halogenated C １－６ is alkoxy, and R １ , R ２ , R ３ , R １２ , R １１ , R ３１ , R ３２ , P', R ０ ', Ar', E １ ', X １ is defined as in claim 4, In formula (IB-1ac) and formula (IB-1ad), R １２ ' are independently halogen, -C １－３ Alkyl, -halogenated C １－３ Alkyl, —C １－３ Alkyl-hydroxy, -C １－３ Alkyl-cyano, -C １－３ Alkyl-C １－６ Alkoxy, -C １－３ Alkyl-halogenated C １－６ Alkyl or -C １－３ Alkyl-halogenated C １－６ is alkoxy, and R １ , R ２ , R ３ , R ２１ , R ２２ , R ３１ , R ３２ , P', R ０ ', Ar', E １ ', X １ is defined as in claim 4.) 【Chemistry 20】 (In formula (IB-1ca) and formula (IB-1cb), R ２１ ' are independently halogen, -C １－３ Alkyl, -halogenated C １－３ Alkyl, —C １－３ Alkyl-hydroxy, -C １－３ Alkyl-cyano, -C １－３ Alkyl-C １－６ Alkoxy, -C １－３ Alkyl-halogenated C １－６ Alkyl or -C １－３ Alkyl-halogenated C １－６ is alkoxy, and R １ , R ２ , R ３ , R １２ , R １１ , R ３１ , R ３２ , P', R ０ ', Ar', E １ ', X １ is defined as in claim 4, In formula (IB-1cc) and formula (IB-1cd), R １２ ' are independently halogen, -C １－３ Alkyl, -halogenated C １－３ Alkyl, —C １－３ Alkyl-hydroxy, -C １－３ Alkyl-cyano, -C １－３ Alkyl-C １－６ Alkoxy, -C １－３ Alkyl-halogenated C １－６ Alkyl or -C １－３ Alkyl-halogenated C １－６ is alkoxy, and R １ , R ２ , R ３ , R ２１ , R ２２ , R ３１ , R ３２ , P', R ０ ', Ar', E １ ', X １ is defined as in claim 4.) 【Chemistry 21】 (In formula (IB-1ba) and formula (IB-1bb), R ２１ ' are independently halogen, -C １－３ Alkyl, -halogenated C １－３ Alkyl, —C １－３ Alkyl-hydroxy, -C １－３ Alkyl-cyano, -C １－３ Alkyl-C １－６ Alkoxy, -C １－３ Alkyl-halogenated C １－６ Alkyl or -C １－３ Alkyl-halogenated C １－６ is alkoxy, and R １ , R ２ , R ３ , R １２ , R １１ , R ３１ , R ３２ , P', R ０ ', Ar', E １ ', X １ is defined as in claim 4, In formula (IB-1bc) and formula (IB-1bd), R １２ ' are independently halogen, -C １－３ Alkyl, -halogenated C １－３ Alkyl, —C １－３ Alkyl-hydroxy, -C １－３ Alkyl-cyano, -C １－３ Alkyl-C １－６ Alkoxy, -C １－３ Alkyl-halogenated C １－６ Alkyl or -C １－３ Alkyl-halogenated C １－６ is alkoxy, and R １ , R ２ , R ３ , R ２１ , R ２２ , R ３１ , R ３２ , P', R ０ ', Ar', E １ ', X １ is defined as in claim 4.) 【Chemistry 22】 (In formula (IB-1da) and formula (IB-1db), R ２１ ' are independently halogen, -C １－３ Alkyl, -halogenated C １－３ Alkyl, —C １－３ Alkyl-hydroxy, -C １－３ Alkyl-cyano, -C １－３ Alkyl-C １－６ Alkoxy, -C １－３ Alkyl-halogenated C １－６ Alkyl or -C １－３ Alkyl-halogenated C １－６ is alkoxy, and R １ , R ２ , R ３ , R １２ , R １１ , R ３１ , R ３２ , P', R ０ ', Ar', E １ ', X １ is defined as in claim 4, In formula (IB-1dc) and formula (IB-1dd), R １２ ' are independently halogen, -C １－３ Alkyl, -halogenated C １－３ Alkyl, —C １－３ Alkyl-hydroxy, -C １－３ Alkyl-cyano, -C １－３ Alkyl-C １－６ Alkoxy, -C １－３ Alkyl-halogenated C １－６ Alkyl or -C １－３ Alkyl-halogenated C １－６ Al Koxi and R １ , R ２ , R ３ , R ２１ , R ２２ , R ３１ , R ３２ , P', R ０ ', Ar', E １ ', X １ is defined as in claim 4.)

7. R ２１ ', R １２ ' are each independently -C １－３ Alkyl, —C １－３ Alkyl-hydroxy, -C １－３ Alkyl-cyano or -C １－３ Alkyl-C １－６ 7. The compound according to claim 6, wherein the compound is alkoxy, or a tautomer, cis-trans isomer, mesomers, racemate, enantiomer, diastereomer, atropisomer or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof.

8. X １ is hydrogen, halogen, optionally substituted C １－６ alkyl group, optionally substituted C ３－６ a cycloalkyl group, or an optionally -O-substituted C １－６ The compound according to claim 3, wherein the compound is an alkyl group, and the "substituted" refers to one, two, three, or four hydrogen atoms in the group being each independently replaced with a substituent selected from the S group, or a tautomer, cis-trans isomer, mesomers, racemates, enantiomers, diastereomers, atropisomers, or a mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

9. Ar′ is a phenyl group, a 5- or 6-membered monocyclic heteroaryl group, or a pyridone group, and the phenyl group, the 5- or 6-membered monocyclic heteroaryl group, and the pyridone group are unsubstituted or independently selected from halogen, cyano, hydroxy, —C １－６ Alkyl, —C １－６ Alkoxy, —NR ｃ R ｄ , -C １－４ Alkyl-NR ｅ R ｆ and R ｅ , R ｆ are each independently hydrogen or C １－３ alkyl, and the R ｃ , R ｄ are each independently hydrogen, —C １－３ Alkyl, —C(O)C １－３ Alkyl or —CO ２ C １－３ The compound of claim 3, characterized in that Ar' is alkyl, and preferably Ar' is selected from the following structures: or a tautomer, cis-trans isomer, mesomers, racemates, enantiomers, diastereomers, atropisomers or mixtures thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof. 【Chemistry 23】 (In the formula, R ｓ１ , R ｓ２ is defined as in claim 3.)

10. R ０ ' is a phenyl group, a 5- or 6-membered monocyclic heteroaryl group, or a pyridone group, and the 5- or 6-membered monocyclic heteroaryl group has 1, 2, or 3 heteroatoms selected from N, O, and S as ring-forming atoms, and the phenyl group, the 5- or 6-membered monocyclic heteroaryl group, or the pyridone group is unsubstituted or independently selected from R ｓ３ or a tautomer, cis-trans isomer, mesomers, racemates, enantiomers, diastereomers, atropisomers or mixtures thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, of the compound according to claim 3, characterized in that it is substituted with 1, 2, 3 or 4 groups selected from

11. R １ , R ２ are each independently hydrogen, halogen, cyano, amino, NHCH ３ , N(C H ３ ) ２ , methyl, ethyl, n-propyl, isopropyl, monochloromethyl, dichloromethyl, trichloromethyl, monochloroethyl, 1,2-dichloroethyl, trichloroethyl, monobromoethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, -CH ２ -hydroxy, -CH ２ -cyano, -CH ２ -Methoxy, -CH ２ -ethoxy, -CH ２ -propoxy, -CH ２ -isopropoxy, -CH ２ -NH ２ , -CH ２ -NHCH ３ , -CH ２ -N(CH ３ ) ２ , -CH ２ -3 to 6-membered heterocycloalkyl or -CH ２ - 5- or 6-membered monocyclic heteroaryl; the 3- to 6-membered heterocycloalkyl is selected from aziridine, ethylene oxide, azetidine, oxetane, tetrahydrofuran, tetrahydrothiophene, pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, thiomorpholine-1,1-dioxide, and tetrahydropyran; the 5- or 6-membered monocyclic heteroaryl is selected from thiophene, N-alkylcyclopyrrole, furan, thiazole, isothiazole, imidazole, oxazole, pyrrole, pyrazole, triazole, 1,2,3-triazole, 1,2,4-triazole, 1,2,5-triazole, 1,3,4-triazole, 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; The 3- to 6-membered heterocycloalkyl, 5- or 6-membered monocyclic heteroaryl may optionally contain 1 or 2 halogen atoms or C １－３ The compound according to claim 3, characterized in that it is substituted with alkyl, or a tautomer, cis-trans isomer, mesomers, racemates, enantiomers, diastereomers, atropisomers or mixtures thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof.

12. R ３ is hydrogen, halogen, methoxy, ethoxy, propoxy or isopropoxy, or a tautomer, cis-trans isomer, mesomers, racemates, enantiomers, diastereomers, atropisomers or mixtures thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof.

13. R ４ is hydrogen, monochloromethyl, dichloromethyl, trichloromethyl, monochloroethyl, 1,2-dichloroethyl, trichloroethyl, monobromoethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, —CH ２ -hydroxy, -CH ２ -cyano, -CH ２ -Methoxy, -CH ２ -ethoxy, -CH ２ -propoxy or -CH ２ -isopropoxy, or a tautomer, cis-trans isomer, mesomers, racemates, enantiomers, diastereomers, atropisomers or mixtures thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof.

14. P is O, NH or NR ｍ and R ｍ is -C １－６ Alkyl, -halogenated C １－６ Alkyl, —C １－６ Alkyl-hydroxy, -C １－６ Alkyl-cyano, -C １－６ Alkyl-C １－６ Alkoxy, -C １－６ Alkyl-halogenated C １－６ Alkoxy, -C １－６ Alkyl-C ３－６ Cycloalkyl or -C １－６ The compound of claim 1, which is alkyl-3- to 6-membered heterocycloalkyl, or a tautomer, cis-trans isomer, mesomers, racemates, enantiomers, diastereomers, atropisomers or mixtures thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof.

15. P' is O, NH or NR ｍ ' and R ｍ ' is -deuterated C １－６ Alkyl, —C １－６ Alkyl, -halogenated C １－６ Alkyl, —C １－６ Alkyl-hydroxy, -C １－６ Alkyl-cyano, -C １－６ Alkyl-C １－６ Alkoxy, -C １－６ Al Chloride-halogenated C １－６ Alkoxy, -C １－６ Alkyl-C ３－６ Cycloalkyl or -C １－６ alkyl-3- to 6-membered heterocycloalkyl, preferably R ｍ ' is -deuterated C １－６ Alkyl or -C １－６ alkyl, and R ４２ ' is -C １－３ Alkyl-(C═O), —(C═O)— or —C １－３ The compound according to claim 3 or 4, characterized in that it is alkyl-, or a tautomer, cis-trans isomer, mesomers, racemates, enantiomers, diastereomers, atropisomers or mixtures thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof.

16. The compound of claim 3, wherein the compound of formula (IA) is selected from Tables A-1 and A-2, or a tautomer, cis-trans isomer, mesomers, racemates, enantiomers, diastereomers, atropisomers, or mixtures thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

17. A pharmaceutical composition comprising the compound according to any one of claims 1 to 16, or a tautomer, cis-trans isomer, mesomers, racemate, enantiomer, diastereomer, atropisomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, and a pharmaceutically acceptable carrier.

18. A compound represented by formula (b), a compound represented by formula (c), a compound represented by formula (d), a compound represented by formula (e), a compound represented by formula (g-1), a compound represented by formula (i-1), or a compound represented by formula (j-1), or a tautomer, cis-trans isomer, mesomers, racemates, enantiomers, diastereomers, atropisomers, or mixtures thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof. 【Chemistry 24】 (In each formula, R ｌｅｖ is a trifluoromethanesulfonate group, chlorine, bromine, iodine, methanesulfonate, toluenesulfonate or p-toluenesulfonate. X １ is hydrogen, halogen, cyano, hydroxy, amino, nitro, optionally substituted C １－６ alkyl, optionally substituted C ３－６ cycloalkyl, -optionally substituted 3- to 6-membered heterocycloalkyl, -O-optionally substituted C １－６ alkyl, —O-optionally substituted C ３－６ Cycloalkyl, —O-optionally substituted 3- to 6-membered heterocycloalkyl, —NH-optionally substituted C １－６ alkyl, —N(optionally substituted C １－６ alkyl) ２ , —NH-optionally substituted C ３－６ Cycloalkyl, —NH-optionally substituted 3- to 6-membered heterocycloalkyl, —NH(C═O)-optionally substituted C １－６ Alkyl, —NH(C═O)—C ３－６ Cycloalkyl, —NH(SO ２ )-optionally substituted C １－６ Alkyl, —NH (SO ２ )-optionally substituted C ３－６ Cycloalkyl, —SO ２ -Optionally substituted C １－６ Alkyl, —SO ２ -Optionally substituted C ３－６ cycloalkyl, —(C═O)—NR ｊ R ｋ -, -(C=O)-O-optionally substituted C １－６ alkyl, —(C═O)—O- optionally substituted C ３－６ cycloalkyl, and the R ｊ , R ｋ are each independently hydrogen or C １－３ alkyl, or ｊ , R ｋ together with the nitrogen atom to which it is connected, form an optionally substituted 3- to 6-membered nitrogen-containing heterocycloalkyl, wherein the 3- to 6-membered heterocycloalkyl has 1, 2 or 3 heteroatoms selected from N, O and S as ring-forming atoms, the 3- to 6-membered nitrogen-containing heterocycloalkyl has 3-6 ring-forming atoms, one of which is a nitrogen atom, and 0, 1 or 2 of the remaining ring-forming atoms may be heteroatoms selected from N, O and S, and the "substituted" refers to 1, 2, 3 or 4 hydrogen atoms in the group being each independently substituted with a substituent selected from the S group, The S group substituents include hydroxy, halogen, nitro, oxo, -C １－６ Alkyl, -halogenated C １－６ Alkyl, hydroxy-substituted C １－６ Alkyl, benzyl, -(CH ２ ) ｕ -cyano, -(CH ２ ) ｕ -C １－６ Alkoxy, -(CH ２ ) ｕ -Halogenated C １－６ Alkoxy, -(CH ２ ) ｕ -Halogenated C １－６ Alkyl, -(CH ２ ) ｕ -3 to 6-membered heterocycloalkyl, -(CH ２ ) ｕ -5- or 6-membered monocyclic heteroaryl, -(CH ２ ) ｕ -C ３－８ Cycloalkyl, -(CH ２ ) ｕ -O-(CH ２ ) ｖ -C ３－８ Cycloalkyl, -(CH ２ ) ｕ -O-(CH ２ ) ｖ -C １－６ Alkoxy, -(CH ２ ) ｕ -O-(CH ２ ) ｖ OH, -(CH ２ ) ｕ -SO ２ C １－６ Alkyl, -(CH ２ ) ｕ -NR ａ０ R ｂ０ , -(CH ２ ) ｕ -C(O)NR ａ０ R ｂ０ , -(CH ２ ) ｕ -C(O)C １－６ Alkyl, —C(O)OC １－６ Alkyl, NR ａ０ C(O)-(CH ２ ) ｕ -NR ａ０ R ｂ０ , N.R. ａ０ C(O)-(CH ２ ) ｕ OH, NR ａ０ C(O)-halogenated C １－６ alkyl, wherein the 3- to 6-membered heterocycloalkyl or the 5- or 6-membered monocyclic heteroaryl has 1, 2, or 3 heteroatoms independently selected from N, O, and S as ring-forming atoms, and the 3- to 6-membered heterocycloalkyl and the 5- or 6-membered monocyclic heteroaryl are selected from halogen, cyano, -C １－３ Alkyl, —C １－３ Alkoxy and C ３－６ cycloalkyl, u and v are each independently 0, 1, 2, 3 or 4; R ａ０ , R ｂ０ are each independently hydrogen or C １－３ is alkyl, E1' is N or CR ５ ', and said R ５ ' is hydrogen, halogen, cyano, -C １－６ Alkyl, —C １－６ Alkoxy, -halogenated C １－６ Alkyl, -halogenated C １－６ Alkoxy, -C ３－６ Cycloalkyl, —NR ｈ R ｉ , -C １－４ Alkyl-hydroxy, -C １－４ Alkyl-cyano, -C １－４ Alkyl-C １－６ Alkoxy, -C １－４ Alkyl-halogenated C １－６ Alkyl or -C １－４ Alkyl-halogenated C １－６ is an alkoxy; 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 group has 1, 2, or 3 heteroatoms selected from N, O, and S as ring-forming atoms, and the 8- to 10-membered bicyclic heteroaryl has 1, 2, 3, 4, or 5 heteroatoms selected from N, O, and S as ring-forming atoms, and the C ６－１０ The aryl, the 5- or 6-membered monocyclic heteroaryl, or the 8- to 10-membered bicyclic heteroaryl group is unsubstituted or independently R ｓ１ and is substituted with 1, 2, 3 or 4 groups selected from Alternatively, Ar' is a structure represented by formula (B): 【Chemistry 25】 In formula (B), ring B1 is a benzene ring or a 5- or 6-membered monocyclic heteroaryl ring, ring B2 is a fused 5- or 6-membered monocyclic heterocycloalkyl ring or a fused 5- or 6-membered monocyclic cycloalkyl ring, and 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-forming atoms; (R ｓ１ ) ｐ The hydrogen atoms of the B1 ring are p R ｓ１ where p is 0, 1, 2, or 3, and each R ｓ１ may be the same or different, (R ｓ２ ) ｑ The hydrogen atoms of the B2 ring are q R ｓ２ q is 0, 1, 2, or 3; and each R ｓ２ may be the same or different, R ｓ１ , R ｓ２ are each independently halogen, cyano, nitro, hydroxy, -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 , -SO ２ C １－３ Alkyl, —SO ２ Halide C １－３ Alkyl, —SO ２ NR ｅ R ｆ , -C １－４ Alkyl-hydroxy, -C １－４ Alkyl-cyano, -C １－４ Alkyl-C １－６ Alkoxy, -C １－４ Alkyl-halogenated C １－６ Alkyl, —C １－４ Alkyl-halogenated 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-SO ２ C １－３ Alkyl or C ２－４ alkynyl, wherein the 3- to 6-membered heterocycloalkyl group has 1, 2, or 3 heteroatoms selected from N, O, and S as ring-forming atoms; R ０ ' is -C １－６ Alkyl, —C ３－６ cycloalkyl, 3- to 6-membered heterocycloalkyl, C ６－１０ Aryl, 5- or 6-membered monocyclic heteroaryl, 8- to 10-membered bicyclic heteroaryl, 7- to 11-membered spirocycloalkyl, -C １－３ Alkyl-C ６－１０ Aryl, —C １－３ alkyl-5 or 6-membered monocyclic heteroaryl, —NR ｇ -C ６－１０ Aryl, —O—C ６－１０ Aryl, —C １－３ alkyl-3 to 6-membered heterocycloalkyl, —C １－３ Alkyl-C ３－６ 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-forming 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, and 7- to 11-membered spirocycloalkyl are unsubstituted or independently R ｓ３ and wherein the —C １－３ Alkyl- is unsubstituted or contains 1, 2, 3 or 4 independently C １－３ substituted with a group selected from alkyl; Or, R ０ ' is a structure represented by formula (A-1) or formula (A-2), 【Chemistry 26】 In formula (A-1) or formula (A-2), ring A1 is a benzene ring or a 5- or 6-membered monocyclic heteroaryl ring, ring A2 is a fused 5- or 6-membered monocyclic heterocycloalkyl ring or a fused 5- or 6-membered monocyclic cycloalkyl ring, and 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-forming atoms; (R ｓ３ ) ｔ The hydrogen atoms of the A1 ring are t R ｓ３ where t is 0, 1, 2, or 3, and each R ｓ３ may be the same or different, (R ｓ４ ) ｓ The hydrogen atoms of the A2 ring are s R ｓ４ where s is 0, 1, 2, or 3, and each R ｓ４ may be the same or different, R ｓ３ , R ｓ４ are each independently a halogen, a cyano, a hydroxy, or —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 , -SO ２ C １－３ Alkyl, —SO ２ Halide C １－３ Alkyl, —SO ２ NR ｅ R ｆ , -C １－３ Alkyl-hydroxy, -C １－３ Alkyl-C ２－４ Alkynyl, —C １－３ Alkyl-cyano, -C １－３ Alkyl-C １－６ Alkoxy, -C １－３ Alkyl-halogenated C １－６ Alkyl, —C １－３ Alkyl-halogenated 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-SO ２ C １－３ Alkyl or C ２－４ alkynyl, wherein the 3- to 6-membered heterocycloalkyl has 1, 2, or 3 heteroatoms selected from N, O, and S as ring-forming atoms, and the C １－６ Alkyl, —C １－６ Alkoxy, -C １－３ Alkyl-, -C ３－６ Cycloalkyl and 3- to 6-membered heterocycloalkyl include halogen, methyl, ethyl, propyl, isopropyl, trifluoromethyl, amino, N(CH ３ ) ２ , hydroxy, carboxyl; R ｐ is formyl, acyl, acetyl, trichloroacetyl, trifluoroacetyl, tert-butoxycarbonyl, benzyloxycarbonyl, 9-fluorenylmethyloxycarbonyl, benzyl, trityl group, 1,1-di-(4'-methoxyphenyl)methyl, trimethylsilyl or tert-butyldimethylsilyl. R １１ , R １２ may be the same or different, and each independently represents hydrogen, halogen, or —C １－３ Alkyl, -halogenated C １－３ Alkyl, —C １－３ Alkyl-hydroxy, -C １－３ Alkyl-cyano, -C １－３ Alkyl-C １－６ Alkoxy, -C １－３ Alkyl-halogenated C １－６ Alkyl or -C １－３ Alkyl-halogenated C １－６ is an alkoxy; R ２１ , R ２２ may be the same or different, and each independently represents hydrogen, halogen, or —C １－３ Alkyl, -halogenated C １－３ Alkyl, —C １－３ Alkyl-hydroxy, -C １－３ Alkyl-cyano, -C １－３ Alkyl-C １－６ Alkoxy, -C １－３ Alkyl-halogenated C １－６ Alkyl or -C １－３ Alkyl-halogenated C １－６ is an alkoxy; R ３１ , R ３２ may be the same or different, and each independently represents hydrogen, Halogen, -C １－３ Alkyl, -halogenated C １－３ Alkyl, —C １－３ Alkyl-hydroxy, -C １－３ Alkyl-cyano, -C １－３ Alkyl-C １－６ Alkoxy, -C １－３ Alkyl-halogenated C １－６ Alkyl or -C １－３ Alkyl-halogenated C １－６ is an alkoxy; R ｍ ' is an optionally substituted -C １－６ is alkyl, R ｅ , R ｆ , R ｇ are each independently hydrogen or C １－３ is alkyl, R ｃ , R ｄ , R ｈ , R ｉ are each independently hydrogen, —C １－３ Alkyl, —C(O)C １－３ Alkyl or —CO ２ C １－３ It is alkyl.)

19. X １ is hydrogen, halogen, optionally substituted C １－６ alkyl group, optionally substituted C ３－６ a cycloalkyl group, or an optionally -O-substituted C １－６ The compound represented by formula (b), the compound represented by formula (c), the compound represented by formula (d), the compound represented by formula (e), the compound represented by formula (g-1), the compound represented by formula (i-1) or the compound represented by formula (j-1) according to claim 18, wherein the compound represented by formula (b) is an alkyl group, and the "substituted" refers to 1, 2, 3 or 4 hydrogen atoms in the group being substituted with substituents each independently selected from Group S. Or a tautomer, cis-trans isomer, mesomer, racemic mixture, enantiomer, diastereomer, atropisomer or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof.

20. Ar′ is a phenyl group, a 5- or 6-membered monocyclic heteroaryl group, or a pyridone group, and the phenyl group, the 5- or 6-membered monocyclic heteroaryl group, and the pyridone group are unsubstituted or independently selected from halogen, cyano, hydroxy, —C １－６ Alkyl, —C １－６ Alkoxy, —NR ｃ R ｄ , -C １－４ Alkyl-NR ｅ R ｆ and R ｅ , R ｆ are each independently hydrogen or C １－３ alkyl, and the R ｃ , R ｄ are each independently hydrogen, —C １－３ Alkyl, —C(O)C １－３ Alkyl or —CO ２ C １－３ alkyl, preferably Ar' is selected from the following structures: 【Chemistry 27】 (In the formula, R ｓ１ , R ｓ２ is defined as in claim 18.) Preferably, R ０ ' is a phenyl group, a 5- or 6-membered monocyclic heteroaryl group, or a pyridone group, and the 5- or 6-membered monocyclic heteroaryl group has 1, 2, or 3 heteroatoms selected from N, O, and S as ring-forming atoms, and the phenyl group, the 5- or 6-membered monocyclic heteroaryl group, or the pyridone group is unsubstituted or independently selected from R ｓ３ A compound represented by formula (b), a compound represented by formula (c), a compound represented by formula (d), a compound represented by formula (e), a compound represented by formula (g-1), a compound represented by formula (i-1), or a compound represented by formula (j-1), or a tautomer, cis-trans isomer, mesomers, racemates, enantiomers, diastereomers, atropisomers, or mixtures thereof, or a pharmaceutical composition thereof, characterized in that the compound represented by formula (b), a compound represented by formula (c), a compound represented by formula (d), a compound represented by formula (e), a compound represented by formula (g-1), a compound represented by formula (i-1), or a compound represented by formula (j-1), ... or a A commercially available commercially acceptable salt, solvate or prodrug thereof.

21. The R ｍ ' is -deuterated C １－６ Alkyl, —C １－６ Alkyl, -halogenated C １－６ Alkyl, —C １－６ Alkyl-hydroxy, -C １－６ Alkyl-cyano, -C １－６ Alkyl-C １－６ Alkoxy, -C １－６ Alkyl-halogenated C １－６ Alkoxy, -C １－６ Alkyl-C ３－６ Cycloalkyl or -C １－６ The compound represented by formula (b), the compound represented by formula (c), the compound represented by formula (d), the compound represented by formula (e), the compound represented by formula (g-1), the compound represented by formula (i-1), or the compound represented by formula (j-1) according to claim 18, which is alkyl-3- to 6-membered heterocycloalkyl, or a tautomer, cis-trans isomer, mesomers, racemates, enantiomers, diastereomers, atropisomers, or mixtures thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

22. A compound represented by the following formula: or a tautomer, cis-trans isomer, mesomers, racemate, enantiomer, diastereomer, atropisomer or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof: 【Chemistry 28】

23. The compound according to any one of claims 1 to 16, or a tautomer, cis-trans isomer, mesomers, racemates, enantiomers, diastereomers, atropisomers, or mixtures thereof, or a pharmaceutically acceptable salt or solvate thereof, or the pharmaceutical composition according to claim 17, for use as a drug for treating and / or preventing a KRAS G12C mutation-induced disease.

24. The compound according to any one of claims 1 to 16, or a tautomer, cis-trans isomer, mesomers, racemates, enantiomers, diastereomers, atropisomers, or mixtures thereof, or a pharmaceutically acceptable salt or solvate thereof, for use as a drug for treating and / or preventing cancer, or the pharmaceutical composition according to claim 17.

25. A compound according to any one of claims 1 to 16, or a tautomer, cis-trans isomer, mesomers, racemates, enantiomers, diastereomers, atropisomers or mixtures thereof, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to claim 17, for use as a drug for treating and / or preventing pancreatic cancer, colorectal cancer or lung cancer.

26. for use as a medicament for treating and / or preventing non-small cell lung cancer (NSCLC), The compound according to any one of claims 1 to 16, or a tautomer, cis-trans isomer, mesomers, racemates, enantiomers, diastereomers, atropisomers, or mixtures thereof, or a pharmaceutically acceptable salt or solvate thereof, or the pharmaceutical composition according to claim 17.

27. 19. The compound according to any one of claims 1 to 16, or a tautomer, cis / trans isomer, mesomer, racemate, enantiomer, diastereomer, atropisomer, or a mixture thereof, or a pharmaceutically acceptable salt or solvate thereof, for use as a KRAS mutation inhibitor; or the pharmaceutical composition according to claim 17, wherein the KRAS mutation is a KRAS G12C mutation.

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