Substituted heterocyclic-ring compounds, their preparation and pharmaceutical applications

Abstract

The present invention relates to a substituted heterocyclic-ring compound having selective inhibitory activity against KRAS gene mutations represented by formula (I) or formula (IA), its pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, a pharmaceutical composition containing the compound, and its application to the preparation of a cancer therapeutic drug. JPEG2023502891000253.jpg54150

Description

[Technical field]

[0001] The present invention relates to the pharmaceutical technical field, in particular to a substituted complex ring-ring system 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 all cancers in the world, and in China it ranks first in incidence rate 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] RAS is a series of closely related monomeric globular proteins (21 kDa molecular weight) that have 188-189 amino acids and bind guanosine diphosphate GDP or guanosine triphosphate GTP. The RAS subfamily includes HRAS, KRAS, and NRAS. RAS acts as a molecular switch; 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, RAS is induced to convert its bound GDP to GTP, and when bound to GTP, RAS is "on" and interacts with and activates other downstream target proteins. RAS protein itself has a very low intrinsic ability to hydrolyze GTP back to GDP (converting itself to the off state). It requires the exogenous protein GTPase-activating protein (GAP) to restore it to the off state, and the synergistic effect of GAP and RAS can greatly 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, and such mutations result in an extended activation time of the protein, thereby extending cell signaling and causing cells to continue to grow and divide. Since such signaling causes cell growth and division, the transmission of overly activated RAS signals may ultimately cause cancer. In lung cancer, mutations in the RAS gene have been identified in approximately 32% of lung cancers, and any mutation in the three major subtypes of RAS (HRAS, NRAS, or KRAS) genes may cause the development of human tumors. The most frequent mutation in the RAS gene is the KRAS gene, and it has been reported that KRAS mutations are detected 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 are expressed 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 about 13% of cancers, about 43% of lung cancers, and almost 100% of MYH-associated polyposis (familial adenomatous polyposis). Therefore, an inhibitor that selectively inhibits KRAS mutations is expected. In order to improve the inhibitory activity against KRAS mutations and to reduce the inhibitory activity against wild-type KRAS, it is important to develop a novel RAS mutant selective inhibitor with higher activity, higher selectivity, and lower toxicity. Summary of the Invention

[0004] The present invention provides substituted heterocyclic ring-based compounds having novel structures that have the advantages of being highly active and highly selective as selective inhibitors of KRAS mutations, as well as having low toxicity and side effects.

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

[0006] [ka]

[0007] (In formula I, Z is NC(O)-CR 3 =CR 1 R 2 or NC(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 -C1-3 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, -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, -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, -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; 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 C3-6 Cycloalkyl, -O-optionally substituted 3-6 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 3-6 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, R j , R k are each independently hydrogen or C 1-3 alkyl, or R j , R k form an optionally substituted 3-6 membered nitrogen-containing heterocycloalkyl together with the nitrogen atom connected thereto, the 3-6 membered heterocycloalkyl having 1, 2 or 3 heteroatoms selected from N, O and S as ring-forming atoms, the 3-6 membered nitrogen-containing heterocycloalkyl having 3-6 ring-forming atoms, one of which is a nitrogen atom, and 0, 1 or 2 of the other ring-forming atoms may be a heteroatom selected from N, O and S, and the "substitution" refers to 1, 2, 3 or 4 hydrogen atoms in the group being substituted with a substituent each independently selected from the S group, Or Y 1 If N, then X1 story, The S group substituents are 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 1-6Alkyl, NR a0 C(O)-(CH 2 ) u -NR a0 R b0 , N.R. a0 C(O)-(CH 2 ) u O.H., N.R. a0 C(O)-Halogenated C 1-6 alkyl, wherein the 3-6 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 3-6 membered heterocycloalkyl, 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 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 1-6Alkoxy, -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 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 represented by R s1 and is substituted with 1, 2, 3 or 4 groups selected from Or, 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 atom of ring B1 is p R s1 p is 0, 1, 2 or 3, and each R s1 may be the same or different, (R s2 ) q The hydrogen atom of ring B2 is R s2 q is 0, 1, 2 or 3; 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 1-6Alkoxy, -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 3-6 membered heterocycloalkyl has 1, 2 or 3 heteroatoms selected from N, O and S as ring-forming atoms; R 0 -C 1-6 Alkyl, -C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6-10 Aryl, 5- or 6-membered monocyclic heteroaryl, 8-10-membered bicyclic heteroaryl, 7-11-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 3-6 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 1-3 Alkyl- is unsubstituted or independently C 1-3substituted 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),

[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 atom of the A1 ring is 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 atom of the A2 ring is 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 , -SO 2 C 1-3 Alkyl, -SO2 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, the 3-6 membered heterocycloalkyl having 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, 3-6 membered heterocycloalkyl are optionally independently selected from halogen, methyl, ethyl, propyl (n-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 , Rd , 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 an alkyl group.

[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 1-6 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 1-6Alkoxy)- 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, R 0 , Ar, E 1 , E 2 , X 1 , Y 1 The definition of is the same as above, In formula (I-2), P is hydrogen or halogen; 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 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 The definitions are the same 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 pharma- ceutically acceptable salt, solvate, or prodrug thereof.

[0020] [ka]

[0021] (In formula (IA), Z is NC(O)-CR 3 =CR 1 R 2 or NC(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, -C 1-3 Alkyl, -Halogenated C 1-3 Alkyl, -C 1-3 Alkyl-hydroxy, -C 1-3 Alkyl-cyano, -C 1-3 Alkyl-C1-6 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, -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 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;

[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(C 1-6 Alkoxy)- or -C 1-3 Alkyl (halogenated C 1-6 alkoxy)-, Or,

[0024] JPEG0007601869000009.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; 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 3-6 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 3-6 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, wherein R j , R k are each independently hydrogen or C 1-3 alkyl, or j , R k forms an optionally substituted 3-6 membered nitrogen-containing heterocycloalkyl together with the nitrogen atom connected thereto, the 3-6 membered heterocycloalkyl having 1, 2 or 3 heteroatoms selected from N, O and S as ring-forming atoms, the 3-6 membered nitrogen-containing heterocycloalkyl having 3-6 ring-forming atoms, one of which is a nitrogen atom, and 0, 1 or 2 of the other ring-forming atoms are any heteroatom selected from N, O and S, and the "substitution" 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 Y 1 If N, then X 1 story, The S group substituents are 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 3-8Cycloalkyl, -(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 O.H., N.R. a0 C(O)-Halogenated C 1-6 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, and the 3- to 6-membered heterocycloalkyl and the 5- or 6-membered monocyclic heteroaryl each have 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 b0are 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, -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; 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, -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, Y 1 , E 1 ', E 2 ' but 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, 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 substituted with 1, 2, 3 or 4 groups independently selected from Rs1; Or, 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 atom of ring B1 is p R s1 p is 0, 1, 2 or 3, and each R s1 may be the same or different, (R s2 ) q The hydrogen atom of ring B2 is R s2 q is 0, 1, 2 or 3; s2 may be the same or different, R s1 , R s2 are each independently halogen, cyano, nitro, hydroxy, -C1-6 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 3-6 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, 3-6 membered heterocycloalkyl, C 6-10 Aryl, 5- or 6-membered monocyclic heteroaryl, 8-10-membered bicyclic heteroaryl, 7-11-membered spirocycloalkyl, -C 1-3 Alkyl-C 6-10 Aryl, -C 1-3 Alkyl-5 or 6 membered monocyclic heteroaryl, -NRg -C 6-10 Aryl, -OC 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 the C 1-6 Alkyl, C 3-6 Cycloalkyl, 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; Or, R 0 ' 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 atom of the A1 ring is R s3 where t is 0, 1, 2, or 3, and each R s3may be the same or different, (R s4 ) s The hydrogen atom of the A2 ring is 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 C 1-6 Alkoxy, -C 3-6 Cycloalkyl, 3-6 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 C2-4 alkynyl, the 3-6 membered heterocycloalkyl group having 1, 2 or 3 heteroatoms selected from N, O and S as ring-forming atoms, and 1-6 Alkyl group, -C 1-6 Alkoxy group, -C 1-3 Alkyl-, -C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl are independently selected from halogen, methyl, ethyl, propyl (n-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 an alkyl group.

[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 1-6Alkyl-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(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, R 0 ', Ar', E 1 ', E 2 ', X 1 , Y 1 The definitions are the same 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 1-3Alkyl-halogenated C 1-6 Alkyl or -C 1-3 Alkyl-halogenated C 1-6 Alkoxy, R 11 , R 12 , R 21 , R 22 , R 31 , R 32 , R 41 , Z, R 0 ', Ar', E 1 ', E 2 ', X 1 , Y 1 The definitions are the same as above.)

[0033] According to 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 an alkyl group. 42 ', -C 1-3 Alkyl-(C=O)-, -(C=O)- or -C 1-3 It is an alkyl.

[0034] According to 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 is alkyl, R 42 ', -C 1-3 Alkyl-(C=O)-, -(C=O)- or -C 1-3 It is an alkyl.

[0035] According to one embodiment of the present invention, in formula IB, P' is O, NH or NR m ' and R m R′ is deuterated methyl, deuterated ethyl, deuterated n-propyl, deuterated isopropyl, methyl, ethyl, n-propyl or isopropyl; 42 ′ is -CH 2 -(C=O)-, -CH 2 CH 2-(C=O)-, -(C=O)-, -CH 2 -, -CH 2 CH 2 -or-CH 2 CH 2 CH 2 -It is.

[0036] According to 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 is alkyl, R 42 ', -C 1-3 Alkyl-(C=O)- or -(C=O)-R m ' is.

[0037] According to 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 is alkyl, R 42 ', -C 1-3 Alkyl-(C=O)- or -(C=O)-.

[0038] According to one embodiment of the present invention, in formula IB, P' is NH or NR m '. R m ' is deuterated methyl or methyl, R 42 '-CH 2 -(C=O)-, -CH 2 CH 2 -(C=O)- or -(C=O)-.

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

[0040] According to one embodiment of the present invention, in formula IB, P' is O and R 42 '-CH 2 -It is.

[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 ', Z, P', R 0 ', Ar', E 1 ', E 2 ', X 1 , Y 1 The definitions are the same as above.)

[0044] According to 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 is alkyl, R 42 ', -C 1-3 Alkyl-(C=O)-, -(C=O)- or -C 1-3 It is alkyl-.

[0045] According to 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 is alkyl, R 42 ', -C 1-3 Alkyl-(C=O)- or -(C=O)-.

[0046] According to 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 is alkyl, R 42 ', -C 1-3 Alkyl-(C=O)- or -(C=O)-.

[0047] According to one embodiment of the present invention, in formula IB-1, P' is NH or NR m ' and R m ' is deuterated methyl or methyl, R 42 '-CH 2 -(C=O)-, -CH 2 CH 2 -(C=O)- or -(C=O)-.

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

[0049] According to one embodiment of the present invention, in formula IB-1, P' is O and R 42 '-CH 2 -It is.

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

[0051] [ka]

[0052] (In the formula (IB-1a) or (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 The definitions are the same as above.)

[0053] According to 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 an alkyl.

[0054] According to 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 an alkyl.

[0055] According to one embodiment of the present invention, in formula IB-1a, P' is NH or NR m ' and R m ' is 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), 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 1-6Alkoxy, -C 1-3 Alkyl-halogenated C 1-6 Alkyl or -C 1-3 Alkyl-halogenated C 1-6 Alkoxy, R 1 , R 2 , R 3 , R 12 , R 11 , R 31 , R 32 , P', R 0 ', Ar', E 1 ', X 1 The definition is the same 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, R 1 , R 2 , R 3 , R 21 , R 22 , R 31 , R 32 , P', R 0 ', Ar', E 1 ', X 1 The definitions are the same as above.)

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

[0060] [ka]

[0061] (In the formula (IB-1c) or (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 The definitions are the same as above.)

[0062] According to 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 an alkyl.

[0063] According to 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 an alkyl.

[0064] According to one embodiment of the present invention, in formula IB-1c, P' is NH or NR m ' and R m ' is 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 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, R 1 , R 2 , R 3 , R 12 , R 11 , R 31 , R 32 , P', R 0 ', Ar', E 1 ', X 1 The definition is the same 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, R 1 , R 2 , R 3 , R 21 , R 22 , R 31 , R 32 , P', R 0 ', Ar', E 1 ', X 1 The definitions are the same as above.)

[0068] According to one embodiment of the present invention, in formula IB-1a, IB-1c, IB-2a and IB-2c, P' is independently NH or NR m ' and R m '-deuterated C 1-6 Alkyl or -C 1-6 It is an alkyl.

[0069] According to one embodiment of the present invention, in formula IB-1a, IB-1c, IB-2a and IB-2c, P' is independently NH or NR m ' and R m '-deuterated C 1-3 Alkyl or -C 1-3 It is an alkyl.

[0070] According to one embodiment of the present invention, in formula IB-1a, IB-1c, IB-2a and 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 of formula (IB-1b) or (IB-2b), or a tautomer, cis-trans isomer, mesomers, racemates, enantiomers, diastereomers, atropisomers, or mixtures thereof, or a pharma- ceutically acceptable salt, solvate, or prodrug thereof.

[0072] [ka]

[0073] (In the formula (IB-1b) or (IB-2b), R 1 , R 2 , R 3 , R 21 , R 22 , R 12 , R 11 , R 31 , R 32 , P', R0 ', Ar', E 1 ', X 1 The definitions are 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, R 1 , R 2 , R 3 , R 12 , R 11 , R 31 , R 32 , P', R 0 ', Ar', E 1 ', X 1 The definition is the same 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, -C1-3 Alkyl-halogenated C 1-6 Alkyl or -C 1-3 Alkyl-halogenated C 1-6 Alkoxy, R 1 , R 2 , R 3 , R 21 , R 22 , R 31 , R 32 , P', R 0 ', Ar', E 1 ', X 1 The definitions are the same as above.)

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

[0078] [ka]

[0079] (In the formula (IB-1d) or (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 The definitions 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, R 1 , R 2 , R 3 , R 12 , R 11 , R 31 , R 32 , P', R 0 ', Ar', E 1 ', X 1 The definition is the same as above. 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 Alkoxy, R 1 , R 2 , R 3 , R 21 , R 22 , R 31 , R 32 , P', R 0 ', Ar', E 1 ', X 1 The definitions 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, -CH 2 -Hydroxy, -CH 2 -cyano or -CH 2 -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, 1 is hydrogen, halogen, optionally -substituted C 1-6 Alkyl, optionally -substituted C 3-6 Cycloalkyl, or -O-optionally substituted C 1-6 The "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, 1 is hydrogen, halogen, unsubstituted C 1-3 Alkyl, unsubstituted C 3-6 Cycloalkyl or -O-unsubstituted C 1-3 It is an alkyl.

[0089] In one embodiment of the present invention, 1 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, 1 is fluorine, chlorine or cyclopropyl.

[0091] In one embodiment of the present invention, 1 is C and E 1 ' is N or CR 5 ′ and E 2 ′ is CR 6 '. R 5 ', R 6 'The respective definitions are the same as above.

[0092] In one embodiment of the present invention, 1 is C and E 1 ′ is CR 5 ′ and E 2 ' is N. R 5 The definition of is the same as above.

[0093] In one embodiment of the present invention, 1 is C and E 1 ' is N or CR 5 ′ and E 2 ' is CH. R 5 The definition of "" is the same as above.

[0094] In one embodiment of the present invention, 1 is C and E 1 ' is N or CF, E 2 ' is CH.

[0095] According to 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 substituted with 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 an alkyl group. 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 an 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 substituted with fluorine, chlorine, bromine, cyano, hydroxy, —C 1-3 Alkyl, -C 1-3 Alkoxy, -NH 2 , -NHCH 3 , -N(CH 3 ) 2 , -CH 2 -NH 2 , -CH 2 -NHCH 3 , -CH 2 -N(CH 3 ) 2 is substituted with 1, 2, 3 or 4 groups selected from

[0097] According to 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 C1-6 Alkyl, -Halogenated C 1-6 Alkoxy or -C 3-6 It is cycloalkyl.

[0098] According to 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] According to 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 According to one embodiment of the present invention, R s1 is above the plane of the benzene ring.

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

[0105] [ka]

[0106] (In the formula, R s1 -C1-6 Alkoxy. 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 According to one embodiment of the present invention, R s1 is above the plane of the benzene ring.

[0107] In one embodiment of the present invention, R 0 ' 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 are unsubstituted or independently selected from R s3 is substituted with 1, 2, 3 or 4 groups selected from

[0108] In one embodiment of the present invention, R 0 ' is a phenyl, thiazolyl, isothiazolyl, imidazolyl, oxazolyl, isoxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl or pyridone group. The phenyl, thiazolyl, isothiazolyl, imidazolyl, oxazolyl, isoxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl and pyridone groups are unsubstituted or independently R s3 and is substituted with 1, 2, 3 or 4 groups selected from:

[0109] In one embodiment of the present invention, R 0 ' 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 3-6 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 is independently selected from halogen, methyl, ethyl, propyl (n-propyl), isopropyl, trifluoromethyl, amino, N(CH 3 ) 2 , hydroxyl, and carboxyl. e , R f are each independently hydrogen or C 1-3 It is an alkyl group. 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 an 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 fand wherein said -C 3-6 Cycloalkyl is optionally independently selected from halogen, methyl, ethyl, propyl (n-propyl), isopropyl, trifluoromethyl, amino, N(CH 3 ) 2 , hydroxyl, and carboxyl. e , R f are each independently hydrogen or C 1-3 It is an alkyl group. 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 an 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 said -C 3-6 Cycloalkyl is optionally independently selected from halogen, methyl, ethyl, propyl (n-propyl), isopropyl, trifluoromethyl, amino, N(CH 3 ) 2 , hydroxyl, and carboxyl. e , R f are each independently hydrogen or C 1-3 It is an 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, -C1-6 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 , -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 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 3-6Cycloalkyl, 3-6 membered heterocycloalkyl are optionally independently selected from halogen, methyl, ethyl, propyl (n-propyl), isopropyl, trifluoromethyl, amino, N(CH 3 ) 2 , hydroxy, and carboxyl. 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 an alkyl group. 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 is 0, 1, 2, or 3.

[0112] In one embodiment of the present invention, R 0 ' 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 3-6Cycloalkyl is optionally independently selected from halogen, methyl, ethyl, propyl (n-propyl), isopropyl, trifluoromethyl, amino, N(CH 3 ) 2 R may be substituted with one, two or three substituents selected from the group consisting of hydroxyl, carboxyl, and aryl. e , R f are each independently hydrogen or C 1-3 It is an alkyl group. 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 an alkyl group. 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, R 0 ' 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 3-6Cycloalkyl is optionally independently selected from halogen, methyl, ethyl, propyl (n-propyl), isopropyl, trifluoromethyl, amino, N(CH 3 ) 2 R may be substituted with one, two or three substituents selected from the group consisting of hydroxyl, carboxyl, and aryl. e , R f are each independently hydrogen or C 1-3 It is an alkyl group. 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 an alkyl group. 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, R 0 ' 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 3-6Cycloalkyl is optionally independently selected from halogen, methyl, ethyl, propyl (n-propyl), isopropyl, trifluoromethyl, amino, N(CH 3 ) 2 R may be substituted with one, two or three substituents selected from the group consisting of hydroxyl, carboxyl, and aryl. e , R f are each independently hydrogen or C 1-3 It is an alkyl group. 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 an alkyl group. 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, R 0 ' is selected from the following structures:

[0122] [ka]

[0123] (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 3-6Cycloalkyl is optionally independently selected from halogen, methyl, ethyl, propyl (n-propyl), isopropyl, trifluoromethyl, amino, N(CH 3 ) 2 R may be substituted with one, two or three substituents selected from the group consisting of hydroxyl, carboxyl, and aryl. e , R f are each independently hydrogen or C 1-3 It is an alkyl group. 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 an alkyl group. 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, R 0 ' is selected from the following structures:

[0125] [ka]

[0126] (In the formula, R s3 In one embodiment, R′ is isopropyl. n is 0. s3 ' is below the plane of the pyrazine ring.

[0127] In one embodiment of the present invention, R 0 ' is selected from the following structures:

[0128] [ka]

[0129] (In the formula, R s3 ' is hydrogen, halogen, cyano, hydroxy, -C 1-6 Alkyl, -C1-6 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 is optionally independently selected from halogen, methyl, ethyl, propyl (n-propyl), isopropyl, trifluoromethyl, amino, N(CH 3 ) 2 , hydroxy, and carboxyl, where R e , R f are each independently hydrogen or C 1-3 It is an alkyl group. 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 an alkyl group. s3 '' is isopropyl. s3 ''' means -C 1-6 In one embodiment, R s 3 '' is below the plane of the pyrazole ring.

[0130] In one embodiment of the present invention, R 0 ' is selected from the following structures:

[0131] [ka]

[0132] [ka]

[0133] [ka]

[0134] [ka]

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

[0136] [ka]

[0137] (wherein Z is NC(O)-CR 3 =CR 1 R 2 or NC(O)-C≡CR 4 It is. 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. The 3-6 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 -C1-3 It 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 It is an alkoxy. R 11 , R 12 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. R 21 , R 22 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. 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, -C1-3 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 1-6 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 1-6Alkoxy)- 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, -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. Or X 2 , Y 2 may be substituted together with its adjacent carbon atom 3-6 The cycloalkyl or 3- to 6-membered heterocycloalkyl which may be substituted is formed. The 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 substituted with substituents each independently selected from the S group. E 3 N or CLR 5 It is. The L is a single bond, -CR L1 R L2 -, -O-(CR L1 R L2 ) t1 - or -NH-(CR L3 R L4 ) t2 -It is. 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. RL1 and R L2 In or R L3 and R L4 When 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 3-6 membered heterocycloalkyl, -SO 2 -C which may be substituted 1-6 Alkyl, -SO 2 -C which may be substituted 3-6 Cycloalkyl, -SO 2 -Optionally substituted 3-6 membered heterocycloalkyl, -Optionally substituted 5- or 6-membered monocyclic heteroaryl or NR 51 R 52 The above R 51 , R 52 each independently represents hydrogen or 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 52form an optionally substituted 3- to 6-membered nitrogen-containing heterocycloalkyl group together with the nitrogen atom connected thereto. 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 may be a nitrogen atom, and 0, 1 or 2 of the other ring-forming atoms may be heteroatoms selected from N, O and S. The "substitution" refers to 1, 2, 3 or 4 hydrogen atoms in the group each independently being substituted with a substituent selected from the S group. The S group substituents are 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 and NR a0 C(O)-Halogenated C 1-6 The 3-6 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 3-6 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 an alkyl. E 4 is N or CH. Ar is C 6-10The aryl, 5- or 6-membered monocyclic heteroaryl, or 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. In addition, the C 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 atom of ring B1 is p R s1 p is 0, 1, 2 or 3, and each R s1 may be the same or different. (R s2 ) q The hydrogen atom of ring B2 is R s2 q is 0, 1, 2 or 3; s2 may be the same or different. R s1 , R s2 are each independently halogen, cyano, nitro, hydroxy, -C 1-6 Alkyl, -C1-6 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 The 3-6 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 -CO 2 C 1-3 It is an alkyl group.

[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 , -SO 2 C 1-3 Alkyl, -SO 2 Halide C 1-3 Alkyl, -SO 2 NR e R f , -C 1-2 Alkyl-hydroxy, -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-NR e R f , -C 1-2 Alkyl-C(O)NR e R f , -C 1-2 Alkyl-SO 2 C 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 -CO 2 C 1-3 It is an alkyl group. e , R f are each independently hydrogen or C 1-3 It is an 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 , -SO 2 C 1-3 Alkyl, -SO 2 Halide C 1-3 Alkyl, -SO 2 NR e R f , -CH 2 -Hydroxy, -CH 2 -Cyano, -CH 2 -C 1-3 Alkoxy, -CH 2 -Halogenated C 1-3 Alkyl, -CH 2 -Halogenated C 1-3 Alkoxy, -CH 2 -3 to 6 membered heterocycloalkyl, -CH 2 -NR e R f , -CH 2 -C(O)NR e R f , -CH 2 -SO 2 C 1-3 Alkyl or C 2-4 alkynyl. c is hydrogen, -C 1-3 Alkyl, -C(O)CH 3 or -CO 2 CH 3 R e , R f , R d are each independently hydrogen or C 1-3 It is an alkyl.

[0142] In one embodiment of the present invention, Rs1 , 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 , -CH 2 -Hydroxy, -CH 2 -cyano. c is hydrogen, -C(O)CH 3 or -CO 2 CH 3 R e , R f , R d are each independently hydrogen or C 1-3 It is an alkyl.

[0143] In one embodiment of the present invention, R s1 and R s2 In the above, 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 R s2 wherein the 3-6 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 each independently represents 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 , -CH 2 -Hydroxy, -CH 2 -cyano. c is hydrogen, -C(O)CH 3 or -CO 2 CH 3 R e , R f , R d are each independently hydrogen, methyl or ethyl.

[0146] In one embodiment of the present invention, R s3 , R s4 each independently represents halogen, cyano, hydroxy, -C 1-6 Alkyl, -C 1-3 Alkoxy, halogenated C 1-3 Alkyl, halogenated C 1-3 Alkoxy, -C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl groups, amino, NHCH 3 , N(CH 3 ) 2 , -C(O)NR e R f , -SO 2 C 1-3 Alkyl, -SO2 Halide C 1-3 Alkyl, -SO 2 NR 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-SO 2 C 1-3 The C is alkyl or ethynyl. 1-6 Alkyl, -C 1-3 Alkoxy, -C 1-2 Alkyl-, -C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl are optionally independently selected from halogen, methyl, ethyl, propyl (n-propyl), isopropyl, trifluoromethyl, amino, N(CH 3 ) 2 R may be substituted with one, two or three substituents selected from the group consisting of hydroxyl, carboxyl, and aryl. 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 hydroxyl, or a C 1-4 Alkyl, -C 1-3 Alkoxy, halogenated C 1-3 Alkyl, halogenated C1-3 Alkoxy, -C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, amino, NHCH 3 , N(CH 3 ) 2 , -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 , -CH 2 -Hydroxy, -CH 2 -ethynyl, -CH 2 -Cyano, -CH 2 -C 1-3 Alkoxy, -CH 2 -Halogenated C 1-3 Alkyl, -CH 2 -Halogenated C 1-3 Alkoxy, -CH 2 -3 to 6 membered heterocycloalkyl, -CH 2 -C 3-6 Cycloalkyl, -CH 2 -NR e R f , -CH 2 -C(O)NR e R f , -CH 2 -SO 2 C 1-3 The C is alkyl or ethynyl. 1-4 Alkyl, -C 1-3 Alkoxy, -CH 2 -, -C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl are optionally independently selected from halogen, methyl, ethyl, propyl (n-propyl), isopropyl, trifluoromethyl, amino, N(CH 3 ) 2 R may be substituted with one, two or three substituents selected from the group consisting of hydroxyl, carboxyl, and aryl. e , R f are each independently hydrogen or C 1-3 It is an alkyl.

[0148] In one embodiment of the present invention, R s3 , R s4 are each independently a halogen, a cyano, a hydroxyl, or a C 1-4 Alkyl, -C 1-3 Alkoxy, halogenated C 1-3 Alkyl, -C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, amino, NHCH 3 , N(CH 3 ) 2 , -CH 2 -Hydroxy, -CH 2 -ethynyl. 1-4 Alkyl, -C 1-3 Alkoxy, -CH 2 -, -C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl are optionally independently selected from halogen, methyl, ethyl, propyl (n-propyl), isopropyl, trifluoromethyl, amino, N(CH 3 ) 2 , hydroxy, carboxyl.

[0149] In one embodiment of the present invention, R s3 and R s4 In the above, 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 3-6 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 3 , N(CH 3 ) 2 , -CH 2 -Hydroxy, -CH 2 -ethynyl. The methyl, ethyl, n-propyl, methoxy, ethoxy, propoxy (n-propoxy), -CH 2 -, azetidine, oxetane, tetrahydrofuran, tetrahydrothiophene, pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, thiomorpholine-1,1-dioxide, tetrahydropyran, optionally independently selected from halogen, methyl, ethyl, propyl (n-propyl), isopropyl, trifluoromethyl, amino, N(CH 3 ) 2 , hydroxy, carboxyl.

[0152] According to 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, -(CH 2 ) u -Cyano, -(CH 2 ) u -C 1-3 Alkoxy, -(CH 2 ) u -Halogenated C1-3 Alkoxy, -(CH 2 ) u -Halogenated C 1-3 Alkyl, -(CH 2 ) u -3 to 6 membered heterocycloalkyl, -(CH 2 ) u -5 or 6 membered monocyclic heteroaryl, -(CH 2 ) u -C 3-6 Cycloalkyl, -(CH 2 ) u -O-(CH 2 ) v -C 3-6 Cycloalkyl, -(CH 2 ) u -O-(CH 2 ) v -C 1-3 Alkoxy, -(CH 2 ) u -O-(CH 2 ) v OH, -(CH 2 ) u -SO 2 C 1-3 Alkyl, -(CH 2 ) u -NR a0 R b0 , -(CH 2 ) u -C(O)NR a0 R b0 , -(CH 2 ) u -C(O)C 1-3 Alkyl, -C(O)OC 1-3 Alkyl, NR a 0 C(O)-(CH 2 ) u -NR a0 R b0 , N.R. a0 C(O)-(CH 2 ) u O.H., N.R. a0 C(O)-Halogenated C 1-3The 3-6 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 3-6 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 an alkyl.

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

[0154] According to one embodiment of the present invention, the S group substituent is C 1-3 Alkyl, -(CH 2 ) u -3 to 6 membered heterocycloalkyl, -(CH 2 ) u -SO 2 C 1-3 Alkyl, -(CH 2 ) u -NR a0 R b0 The 3-6 membered heterocycloalkyl has 1, 2 or 3 heteroatoms selected from N, O and S as ring-forming atoms. The 3-6 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] According to one embodiment of the present invention, the groups (e.g., Ar, R 0 ) in the above C 6-10 Each aryl is independently phenyl or naphthyl.

[0156] According to 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, the groups (e.g., Ar, R 0 ), each of the 5- or 6-membered monocyclic heteroaryls 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, the groups (e.g., Ar, R 0 ), wherein the 5- or 6-membered monocyclic heteroaryls are each independently selected from the following structures:

[0161] [ka]

[0162] According to one embodiment of the present invention, the groups (e.g., Ar, R 0), the 8-10 membered bicyclic heteroaryls are each independently a 9-10 membered bicyclic heteroaryl formed by condensing a benzene ring and a 5- or 6-membered monocyclic heteroaryl ring, or an 8-10 membered bicyclic heteroaryl group formed by condensing a 5- or 6-membered monocyclic heteroaryl ring and 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 9-10 membered bicyclic heteroaryl or 8-10 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 or 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 an adjacent pair of 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 an adjacent pair of 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 independently selected from oxazolidine, pyrrolidin-2-one, pyrrolidine-2,5-dione, 1,3-dioxolane, dihydrofuran-2(3H)-one, dihydrofuran-2,5-dione, piperidine-2-one, piperidine-2,6-dione, tetrahydro-2H-pyran-2-one, imidazolidine, tetrahydrofuran, tetrahydrothiophene, piperidine-2,6-dione, tetrahydro-2H-pyran-2-one, tetrahydrofuran, tetrahydrothiophene, tetrahydrofuran ... rolidine, 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, 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, the groups (e.g., Ar, R 0 ), wherein the 8-10 membered bicyclic heteroaryls are each 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, the groups (e.g., Ar, R 0), wherein the 8-10 membered bicyclic heteroaryls are each independently selected from benzo[d]isoxazole, 1H-indole, isoindole, 1H-benzo[d]imidazole, benzo[d]isothiazole, 1H-benzo[d][1,2,3]triazole, benzo[d]oxazole, benzo[d]thiazole, indazole, benzofuran, benzo[b]thiophene, quinoline, isoquinoline, quinazoline, quinoxaline, cinnoline, pyrido[3,2-d]pyrimidine, pyrido[2,3-d]pyrimidine, pyrido[3,4-d]pyrimidine, pyrido[4,3-d]pyrimidine, 1,8-naphthyridine, 1,7-naphthyridine, 1,6-naphthyridine, and 1,5-naphthyridine.

[0180] According to one embodiment of the present invention, the groups (e.g., Ar, R 0 ), wherein the 8-10 membered bicyclic heteroaryls are each independently selected from the following structures:

[0181] [ka]

[0182] According to one embodiment of the present invention, the groups (e.g., Ar, R 0 ), wherein the 8-10 membered bicyclic heteroaryls are each independently selected from the following structures:

[0183] [ka]

[0184] According to one embodiment of the present invention, the groups (e.g., Ar, R 0 ), wherein 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] According to 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] According to one embodiment of the present invention, the above group (e.g., R 0 ) 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.

[0199] According to one embodiment of the present invention, the above group (e.g., R 0 ), the 3-6 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, the above group (e.g., R 0 In the above formula (I), 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, R 0 -C 1-6 Alkyl, -C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, 5- or 6-membered monocyclic heteroaryl, 8- to 10-membered bicyclic heteroaryl, 7- to 11-membered spirocycloalkyl, -CH 2 -phenyl, -CH(C 1-2 alkyl)-phenyl, -CH2 -5 or 6 membered monocyclic heteroaryl, -CH(C 1-2 alkyl)-5 or 6 membered monocyclic heteroaryl, -NH-phenyl, -N(C 1-3 alkyl)-phenyl, -O-phenyl, -CH 2 -3 to 6 membered heterocycloalkyl, -CH 2 -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 is substituted with 1, 2, 3 or 4 groups selected from:

[0202] In one embodiment of the present invention, R 0 is phenyl, cyclopropyl, 5- or 6-membered monocyclic heteroaryl, -CH 2 -5 or 6 membered monocyclic heteroaryl, -CH 2 -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 is substituted with 1, 2, 3 or 4 groups selected from:

[0203] In one embodiment of the present invention, R 0 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, -C 1-3 Alkyl, -CH 2 -Hydroxy, -CH 2 -Cyano, -CH 2 -C 1-3 Alkoxy, -CH 2 -Halogenated C 1-3 Alkyl or -CH 2 -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 represents hydrogen, halogen, methyl, ethyl, n-propyl, isopropyl, -CH 2 -Hydroxy, -CH 2 -Cyano, -CH 2 -Methoxy, -CH 2 -ethoxy, -CH 2 -propoxy (n-propoxy), -CH 2 -isopropoxy, -CH 2 -trifluoromethyl, -CH 2-Difluoromethyl, -CH 2 -Difluoroethyl, -CH 2 -trifluoromethoxy or -CH 2 -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 an alkyl.

[0210] In one embodiment of the present invention, R 11 , R 12 may be the same or different and each independently is 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, -C 1-3 Alkyl, -CH 2 -Hydroxy, -CH 2 -Cyano, -CH 2 -C 1-3 Alkoxy, -CH 2 -Halogenated C 1-3 Alkyl or -CH 2 -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 represents hydrogen, halogen, methyl, ethyl, n-propyl, isopropyl, -CH 2 -Hydroxy, -CH 2 -Cyano, -CH 2 -Methoxy, -CH 2 -ethoxy, -CH 2 -propoxy (n-propoxy), -CH 2 -isopropoxy, -CH 2 -trifluoromethyl, -CH 2-Difluoromethyl, -CH 2 -Difluoroethyl, -CH 2 -trifluoromethoxy, -CH 2 -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 an alkyl.

[0214] In one embodiment of the present invention, R 21 , R 22 may be the same or different and each independently is 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, -C 1-3 Alkyl, -CH 2 -Hydroxy, -CH 2 -Cyano, -CH 2 -C 1-3 Alkoxy, -CH 2 -Halogenated C 1-3 Alkyl or -CH 2 -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 represents hydrogen, halogen, methyl, ethyl, n-propyl, isopropyl, -CH 2 -Hydroxy, -CH 2 -Cyano, -CH 2 -Methoxy, -CH 2 -ethoxy, -CH 2 -propoxy (n-propoxy), -CH 2 -isopropoxy, -CH 2 -trifluoromethyl, -CH 2-Difluoromethyl, -CH 2 -Difluoroethyl, -CH 2 -trifluoromethoxy, -CH 2 -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 an alkyl.

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

[0219] In one embodiment of the present invention, R 41 is hydrogen, halogen, -C 1-3 Alkyl, -CH 2 -Hydroxy, -CH 2 -Cyano, -CH 2 -C 1-3 Alkoxy, -CH 2 -Halogenated C 1-3 Alkyl or -CH 2 -Halogenated C 1-3 It is an alkoxy.

[0220] In one embodiment of the present invention, R 41 is hydrogen, halogen, methyl, ethyl, n-propyl, isopropyl, -CH 2 -Hydroxy, -CH 2 -Cyano, -CH 2 -Methoxy, -CH 2 -ethoxy, -CH 2 -propoxy (n-propoxy), -CH 2 -isopropoxy, -CH 2 -trifluoromethyl, -CH 2 -Difluoromethyl, -CH 2 -Difluoroethyl, -CH 2 -trifluoromethoxy, -CH 2 -difluoromethoxy.

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

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

[0223] [ka]

[0224] When 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] According to one embodiment of the present invention, in formula I:

[0226] [ka]

[0227] When the dashed line in is a single bond, P is NH or NR mR 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] According to one embodiment of the present invention, in formula I:

[0229] [ka]

[0230] When the dashed line in is a single bond, -P is O, NH, or NR m R m -C 1-6 It is an alkyl group. 42 is -(C=O)- or -C1-3 It is an alkyl.

[0231] According to 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 an alkyl group. 42 is -(C=O)- or -C 1-3 It is an alkyl.

[0234] According to 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 2 -, -CH 2 CH 2 -or-CH 2 CH 2 CH 2 -It is.

[0237] According to 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 1-3Alkyl, -CH 2 -Hydroxy, -CH 2 -Cyano, -CH 2 -C 1-3 Alkoxy, -CH 2 -Halogenated C 1-3 Alkyl or -CH 2 -Halogenated C 1-3 It is an alkoxy.

[0240] According to 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, -CH 2 -Hydroxy, -CH 2 -Cyano, -CH 2 -Methoxy, -CH 2 -ethoxy, -CH 2 -propoxy (n-propoxy), -CH 2 -isopropoxy, -CH 2 -trifluoromethyl, -CH 2 -Difluoromethyl, -CH 2 -Difluoroethyl, -CH 2 -trifluoromethoxy, -CH 2 -difluoromethoxy.

[0243] According to one embodiment of the present invention, in formula I, X 1 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 3-6Cycloalkyl, -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 3-6 Cycloalkyl, -NH-optionally substituted 3-6 membered heterocycloalkyl, -NH(C=O)-optionally substituted C 1-3 Alkyl, -NH(C=O)-C 3-6 Cycloalkyl, -NH(SO 2 )-Optionally substituted C 1-3 Alkyl, -NH(SO 2 )-Optionally substituted C 3-6 Cycloalkyl, -SO 2 -C which may be substituted 1-3 Alkyl, -SO 2 -C which may be substituted 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 forms an optionally substituted 3- to 6-membered nitrogen-containing heterocycloalkyl together with the nitrogen atom connected thereto. 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 has 3 to 6 ring-forming atoms, one of which may be a nitrogen atom, and 0, 1 or 2 of the other ring-forming atoms may be heteroatoms selected from N, O and S. The "substituted" group means that 1, 2, 3 or 4 hydrogen atoms are each independently substituted with a substituent selected from the S group. The C 1-3 Alkyl is methyl, ethyl or propyl (n-propyl or isopropyl). 1-3Alkoxy is methoxy, ethoxy or propoxy (n-propoxy or isopropoxy).

[0244] According to one embodiment of the present invention, in formula I, Y 1 is N and E 1 is C and E 2 is C.

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

[0248] According to one embodiment of the present invention, in formula I, Y 1 is N and E 1 is N and E 2 is C.

[0249] According to one embodiment of the present invention, in formula I, Y 1 is N and E 1 is N and E 2 is C.

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

[0251] According to 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, -C1-3 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] According to one embodiment of the present invention, in formula II, R 42 is -(C=O)-, -C 1-3 Alkyl, -C 1-3 Alkyl(hydroxy)-, -C 1-3 Alkyl(cyano)-, -C 1-3 Alkyl(C 1-3 alkyl), -C 1-3 Alkyl (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] According to one embodiment of the present invention, in formula II, X 2 , Y 2 may be the same or different, and each independently represents hydrogen, halogen, -C 1-3 Alkyl, -C 1-3 Alkyl-hydroxy, -C 1-3 Alkyl-cyano, -C1-3 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 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).

[0254] According to one embodiment of the present invention, in formula II, X 2 , Y 2 may be substituted together with its adjacent carbon atom 3-6 The cycloalkyl or 3- to 6-membered heterocycloalkyl group which may be substituted is formed. The 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 substituted with substituents each independently selected from the S group.

[0255] According to 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, R 5 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, -SO 2 -C which may be substituted 1-3 Alkyl, -SO 2 -C which may be substituted 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 The above R 51 , R 52 each independently represents hydrogen or optionally substituted C 1-3 Alkyl, -SO 2 C 1-3 Alkyl, -SO 2 C 3-6 Cycloalkyl, -C(O)C 1-3 Alkyl or -C(O) halogenated C 1-3 alkyl, or R 51 and R 52 form an optionally substituted 3-6 membered nitrogen-containing heterocycloalkyl together with the nitrogen atom connected thereto. The 3-6 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 3-6 membered nitrogen-containing heterocycloalkyl has 3-6 ring-forming atoms, one of which is a nitrogen atom, and 0, 1 or 2 of the other ring-forming atoms may be heteroatoms optionally selected from N, O and S. The "substitution" refers to 1, 2, 3 or 4 hydrogen atoms in the group being independently substituted with a substituent 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] In one embodiment of the present invention, R 1 , R 2 are each independently hydrogen, halogen, cyano, amino, NHCH 3 , N(CH 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 (n-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, 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. 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 is optionally selected from 1 or 2 halogens or C 1-3 It may be substituted with alkyl.

[0258] In one embodiment of the present invention, R 3 is hydrogen, halogen, methoxy, ethoxy, propoxy (n-propoxy) or isopropoxy.

[0259] In one embodiment of the present invention, 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 (n-propoxy) or -CH 2 -isopropoxy.

[0260] In one embodiment of the present invention, R 1 , R 2 , R 3 is hydrogen.

[0261] According to one embodiment of the present invention, E1 is N or CR 5 The above R 5 is hydrogen.

[0262] According to one embodiment of the present invention, E2 is N or CR 6 The above R 6 is hydrogen.

[0263] According to 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, R 0 , Ar, E 1 , E 2 , X 1 , Y1 are each independently a group 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, Z3 to Z16 according to the Examples, or a diastereomer thereof.

[0265] According to one embodiment of the present invention, representative compounds represented by 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 said isomers, or pharma- ceutically acceptable salts, solvates or prodrugs of the structures and isomers shown in Table A-1.

[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 represented by formula (IA) include, but are not limited to, the structures shown in Table A-2 below, or pharma- ceutically 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 pharma- ceutically acceptable salts, solvates, or prodrugs of these structures.

[0293] According to 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, E 3 , E 4 , X 2 , Y 2 are each independently a group 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 pharma- ceutically acceptable salt, solvate or prodrug thereof, and a pharma- ceutically 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 has no toxic or adverse effects on the host or subject, including water, oils, vegetable and mineral substances, paste bases, lotion bases, ointment bases, etc. These bases include suspending agents, thickening agents, 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, parenteral administration, such as subcutaneous, intravenous, intramuscular, intraperitoneal, intrathecal, intraventricular, intrasternal and intracranial injection or delivery, or via external storage. When administered orally, the compound according to the present invention can be in any orally administrable formulation, including, but not limited to, tablets, capsules, aqueous solutions or aqueous suspensions. Carriers used for tablets generally include lactose and cornstarch, and lubricants such as magnesium stearate may also be added. Diluents used for capsules generally include lactose and dried cornstarch. Aqueous suspension formulations are generally used by mixing the active ingredient with suitable emulsifiers and suspending agents. If necessary, some sweeteners, flavors or colorants may be added to the above oral formulations. For topical administration, the compounds of the present invention can be prepared into different topical formulations according to different affected areas or organs, especially when treating neurological diseases of the eye, skin or lower intestine where topical application is easily achieved. For topical administration to the eye, the compounds of the present invention can be prepared into a micronized suspension or solution formulation, and the carrier used is an isotonic sterile saline solution with a specific pH, with or without the addition of a preservative, such as benzyl chloride alkoxide. For topical administration to the eye, the compounds can also be prepared into a paste, such as petrolatum paste. For topical administration to the skin, the compounds of the present invention can be made 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 compound of the present invention can also be administered in a sterile injection preparation, including a sterile water or oil suspension for injection or a sterile injection solution. Usable carriers and solvents include water, Ringer's solution and isotonic sodium chloride solution. Sterile non-volatile oils (such as monoglycerides or diglycerides) can also be used as a solvent or suspension medium.

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

[0299] In another aspect, the present invention provides the application of said compound or its tautomers, cis-trans isomers, mesomers, racemates, enantiomers, diastereomers, atropisomers or mixtures thereof, or its pharma-ceutically acceptable salts, solvates or prodrugs, in the preparation of a medicament for treating and / or preventing cancer.

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

[0301] According to 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 the application of said compound or its tautomers, cis-trans isomers, mesomers, racemates, enantiomers, diastereomers, atropisomers or mixtures thereof, or a pharma-ceutically acceptable salt, solvate or prodrug thereof, in the preparation of a KRAS mutation inhibitor, wherein said 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, mesomeric, racemic, enantiomer, diastereomer, atropisomer or mixtures thereof, or a pharma- ceutically 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, with humans being preferred.

[0305] The term "effective amount" or "therapeutically effective amount" as used herein refers to a sufficient amount of a drug or agent to achieve a 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 of disease or condition and its severity, the specific characteristics of the patient or host that needs to be treated (e.g., body weight), but 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 are typically in the range of 0.02-5000 mg / day, for example, about 1-1500 mg / day. The required dosage may be one agent, or dosages administered simultaneously (or briefly) or at appropriate intervals, for example, 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 doctor's diagnosis depending on the patient's circumstances.

[0306] The term "pharmaceutically acceptable salt" as used herein refers to a salt of the compound of the present invention that is pharmaceutically acceptable and has 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, carbonic acid, and the like, and the organic acid, such as propionic acid, caproic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, gluconic acid, stearic acid, muconic acid, and the like, or salts formed by replacing an acidic proton present 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 an organic base, such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, and the like. The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound containing an acid group or base by conventional methods. Generally, such salts are prepared by reacting these compounds as free acids or bases with a suitable stoichiometric base or acid in water or 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 changes under physiological conditions. Prodrugs can also be converted into the compounds of the present invention by chemical or biochemical methods in the body environment.

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

[0308] The term "stereoisomer" as used herein includes conformational and configurational isomers, the configurational isomers including primarily cis-trans isomers and optical isomers. The compounds of the present invention can exist as stereoisomers, and therefore 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 be any combination or any mixture of the above stereoisomers, such as mesomers, racemates, equal mixtures of atropisomers, and the like. For example, a single enantiomer, a single diastereomer or mixtures thereof, or a single atropisomer or mixtures thereof. The compounds of the present invention, when they contain olefinic double bonds, include cis- and trans-isomers, and any combinations thereof, unless otherwise stated. Atropisomers according to the present invention are stereoisomers in which the intramolecular rotation is restricted, resulting in axial or planar chirality. The compounds according to the present invention include two types of atropisomers resulting from axial asymmetry. This is because the substituents Ar′ or R 0 ' 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 a steric hindrance. Regarding the atropisomer according to the present invention, the compound has a structure represented by formula (I), formula (IA) or formula (II), or the compounds represented by formula (I), formula (IA) and formula (II) have isomers generated by asymmetric carbons, etc., and represent one of a pair of atropisomers present in each isomeric compound. In addition, as a drug, an atropisomer having excellent activity is preferable. 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 as necessary. The atropisomers of the compounds according to the present invention may be represented in P or M configuration, or may be represented in other general ways well known in the art.

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

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

[0311] The term "fused" as used herein 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 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, and 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" may be used interchangeably to refer to a saturated linear or branched aliphatic hydrocarbon group having a residue derived by removing two hydrogen atoms from the same or two different carbon atoms of two parent alkyl groups, and is a linear or branched group containing 1-3 carbon atoms. Specific examples of alkylene groups include methylene (-CH 2 -), 1,1-ethylene (-CH(CH 3 )-), 1,2-ethylene (-CH 2 CH 2 -), 1,1-propylene (-CH(CH 2 CH 3 )-), 1,2-propylene (-CH 2 CH(CH 3 )-), 1,3-propylene (-CH 2 CH 2 CH 2 -), but are not limited to these.

[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 1-6 Alkyl)-, -C 1-3 Alkyl(C 1-6 Alkyl-hydroxy)-, -C 1-3 Alkyl(C 1-6 Alkyl-cyano)-, -C 1-3 Alkyl(C 1-6 Alkoxy)-, -C 1-3 Alkyl (halogenated C 1-6 Alkoxy)-" are "-C 1-3 One or more hydrogen atoms in "alkyl-" are 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 the residue formed by substituting an alkoxy group. Examples include -CH(OH)-, -CH 2 CH(CN)-, -CH 2 CH(CH 2 CH 3 )-, -CH 2 CH(CF 3 )-, -CH(CH 2 OH)-, -CH 2 CH(CH 2 CN)-, -CH(OCH 3 )-, -CH 2 CH(OCF 3 )-, but are not limited to these.

[0315] The term "alkoxy," as used herein, refers to a group having the structure -O-alkyl, where alkyl is defined above. 1-10 "Alkoxy" is an alkoxy having 1-10 carbon atoms, C 1-6 Alkoxy is preferred, C1-4 Alkoxy is more preferred, C 1-3 Alkoxy is more preferred. Specific examples of alkoxy groups 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 defined above. 1-10 "Alkylthio" refers to an alkylthio having 1-10 carbon atoms, 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 site 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 2-4Alkenyl 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 refers to an alkyl as defined above having one or more carbon-carbon triple bonds at any site 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 2-6 Alkynyl 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] The term "halogenated alkyl" as used herein refers to an alkyl substituted with one or more (e.g., 1, 2, 3, 4, or 5) halogens, the alkyl being 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 1-3Alkyl is more preferred. Specific examples of halogenated alkyl 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] The term "deuterated alkyl" as used herein 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 1-3 Alkyl 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 alkoxy being as defined above. 1-10 "Alkoxy" refers to 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" may 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 cycloalkyl, spirocycloalkyl, fused cycloalkyl, and bridged cycloalkyl. 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 to form a cyclic ketone structure. 3-8 Monocyclic cycloalkyl" and "C 3-8 "Cycloalkyl" refers to a saturated monocyclic cyclic hydrocarbon group having 3-8 carbon atoms, C 3-6 Monocyclic cycloalkyl (i.e., C 3-6 Cycloalkyl) is preferred. 3 , C 4 , C 5 Or C 6 Monocyclic cycloalkyl is more preferred. Specific examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like.

[0324] The terms "spirocycloalkyl" and "spirocycloalkyl ring" as used herein refer to a polycyclic cyclic hydrocarbon group formed by sharing one carbon atom (called a spiro atom) between two or more monocyclic rings. 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, with the monocyclic ring sharing the spiro atom being a 3- to 8-membered monocyclic cycloalkyl ring. 6-14 ) spiroalkyl is preferred. 6-14 membered monospirocycloalkyl is more preferred. 7-11 membered (C 7-11) spiroalkyl is more preferred. 7-11 membered monospirocycloalkyl is more preferred. 7-membered (4-membered monocycloalkyl / 4-membered monocycloalkyl ring), 8-membered (4-membered monocycloalkyl / 5-membered monocycloalkyl ring), 9-membered (4-membered monocycloalkyl / 6-membered monocycloalkyl ring, 5-membered monocycloalkyl / 5-membered monocycloalkyl ring), 10-membered (5-membered monocyclic cycloalkyl / 6-membered monocyclic cycloalkyl) or 11-membered (6-membered monocycloalkyl / 6-membered monocycloalkyl) monospirocycloalkyl is most preferred. Specific examples of spiroalkyl include, but are not limited to, the following structures.

[0325] [ka]

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

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

[0328] The terms "heterocyclyl" and "heterocyclyl ring" as used herein may be used interchangeably and refer to a saturated or partially unsaturated monocyclic or polycyclic fused cyclic hydrocarbon group, including "C 3-20 The term "heterocyclyl" or "3- to 20-membered heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic fused cyclic hydrocarbon group having 3-20 ring-forming atoms, one or more (preferably 1, 2, 3 or 4) of which are nitrogen, oxygen or S(O) m (wherein 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 other substituents 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 3-20 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 heterocyclic ring having 3-8 ring atoms, where 1, 2 or 3 of the ring atoms are nitrogen, oxygen or S(O). m (wherein m is an integer of 0 to 2). A 3-6 membered monocyclic heterocyclyl (i.e., C 3-6Monocyclic heterocyclyl) is preferred. Five- or six-membered monocyclic heterocyclyl groups having 5 or 6 ring-forming atoms, of which one or two ring-forming atoms 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 previously defined herein). When the heteroatom is a sulfur atom, the sulfur atom may be oxidized (i.e., S(O) m and m is an integer from 0 to 2. The ring carbon atoms of the monocyclic heterocyclyl group may be optionally substituted with 1, 2 or 3 oxo 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, piperidine-2,6-dione, tetrahydro-2H-pyran-2-one, imidazolidine, tetrahydrofuran, tetrahydrothiophene, pyrrolidine, 1,3-dioxolan-2-one, oxazo Lisin-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-di Hydrofuran, 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-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-imidazo Examples of the compound include, but are not limited to, furan-2-one, furan-2,5-dione, 3,6-dihydropyridin-2(1H)-one, pyridine-2,6-(1H,3H)-dione, 5,6-dihydro-2H-pyran-2-one, 3,6-dihydro-2H-pyran-2-one, 3,4-dihydro-2H-1,3-oxazine, 3,6-dihydro-2H-1,3-oxazine, 1,2,3,4-tetrahydropyrimidine, and the like. 3-8 "Heterocycloalkyl" and "3-8 membered monocyclic heterocyclyl" are saturated monocyclic cyclic hydrocarbon groups having 3-8 ring atoms, one or two of which are heteroatoms. 3-6 membered heterocycloalkyls having 3-6 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, e.g., CC and NC, may be fused to 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 polycyclic ring, and the two ring-forming atoms connected to the 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 to refer to an all-carbon monocyclic, all-carbon polycyclic (wherein the rings are connected by covalent bonds and are not fused) or all-carbon fused polycyclic (i.e., rings which share adjacent pairs of carbon atoms) group having 6-14 ring-forming atoms, in which at least one ring is aromatic, i.e., has a conjugated pi-electron system. 6-10 Aryl is preferred. 6-14 The aryl includes monocyclic aryl, polycyclic aryl and aromatic condensed 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 polycyclic ring, the aromatic fused polycyclic ring 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, and the like.

[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 the ring-forming carbon atoms may be substituted with 1-2 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 the ring-forming carbon atoms may be substituted with 1 or 2 oxo atoms to form a cyclic ketone structure). The polycyclic group formed by condensing the monoaryl ring with one or more non-aromatic rings is connected to another group or 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 condensation 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 condensation of two adjacent substituents in a phenyl ring 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 benzene ring and one 5- or 6-membered monocyclic cycloalkyl are condensed to form a 9- or 10-membered aromatic condensed bicyclic ring, which means that two adjacent substituents of phenyl are condensed to 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 condensed bicyclic ring is also called a 9- or 10-membered phenylcycloalkyl ring. Specific examples thereof 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 pi 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. 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, with 1, 2 or 3 ring-forming atoms being heteroatoms. Specific examples of monoheteroaryl groups include, but are not limited to, thiophene, furan, thiazole, isothiazole, imidazole, oxazole, pyrrole, pyrazole, triazole, 1,2,3-triazole, 1,2,4-triazole, 1,2,5-triazole, 1,3,4-triazole, tetrazole, isoxazole, oxadiazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, thiadiazole, pyridine, pyridazine, pyrimidine, pyrazine, and the like.

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

[0341] [ka]

[0342] Specific 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 monoheteroaryl, or the bisheteroaryl formed by condensing a benzene ring and a monoheteroaryl ring, or the bisheteroaryl group formed by condensing 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 the fused tris heteroaryl group may be a polycyclic group formed by condensing a monoheteroaryl ring (preferably a 5- or 6-membered monoheteroaryl ring) with one or more non-aromatic rings, and the ring connected to the parent structure is a monoheteroaryl ring or a non-aromatic ring. The non-aromatic ring includes, but is not limited to, a 3- to 6-membered monocyclic heterocyclyl ring (preferably a 5- or 6-membered monocyclic heterocyclyl ring. The 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] In this specification, 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, the 5- or 6-membered monocyclic heterocyclyl ring being as defined 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 the present specification, the fusion of a 5- or 6-membered monoheteroaryl ring with one 5- or 6-membered monocyclic cycloalkyl ring to form an 8-10-membered fused bicyclic heteroaryl refers to the fusion of adjacent two substituents of the 5- or 6-membered monoheteroaryl with the ring-forming atoms connected thereto to form a 5- or 6-membered monocyclic cycloalkyl ring, the 5- or 6-membered monocyclic cycloalkyl being defined as above, and the formed 8- to 10-membered fused bicyclic heteroaryl is also called an 8- to 10-membered heteroaryl cycloalkyl ring. Specific examples include, but are not limited to, the following structures:

[0347] [ka]

[0348] In the present invention, each of the above types of heteroaryl 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, with "-alkyl-" referring to the alkylene or alkylidene group formed after substitution. R as described herein can be hydroxy, cyano, alkoxy, substituted amino, heterocycloalkyl, heteroaryl, halogenated alkyl, halogenated alkoxy, cycloalkyl, alkynyl, and the like, with the groups represented by R being as defined herein. 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, -CH 2 -CH(CH 3 )-R, -CH 2 -CH 2 -CH 2 -R, -CH 2 -CH 2 -R, -CH 2 -R, etc.

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

[0351] As used herein, the term "hydroxymethyl" refers to -CH 2 "Hydroxyethyl" refers to -CH 2 CH 2 OH or-CH(OH)CH 3 Refers to...

[0352] As used herein, the term "cyanomethyl" refers to -CH 2 "Cyanoethyl" refers to -CH 2 CH 2 CN or -CHCNCH 3 Refers to...

[0353] As used herein, the term "amino" refers to -NH 2 Refers to...

[0354] The term "cyano" as used herein refers to --CN.

[0355] As used herein, the term "nitro" refers to -NO 2 Refers to...

[0356] As used herein, the term "benzyl" refers to -CH 2 -Refers to benzene.

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

[0358] The term "carboxyl" as used herein refers to -C(O)OH.

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

[0360] As used herein, the term "acetyl" refers to -COCH3 Refers to...

[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, C 1-4 Alkyl groups are more preferred, C 1-3 Alkyl 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, C 3-5 is more preferable. For example, C 3-20 Cycloalkyl groups are C 3-8 Cycloalkyl groups are preferred, C 3-6 Cycloalkyl groups are more preferred, C 3-6 Cycloalkyl groups are more preferred.

[0363] According to one embodiment of the present invention, in any group, 3-6 The cycloalkyl groups are selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.

[0364] According to one embodiment of the present invention, in any of the groups, the 3-6 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 any one or more hydrogen atoms connected to a particular atom being replaced 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), it means that two hydrogen atoms are replaced. Oxo group substitution does not occur in aromatic groups. The term "optionally substituted" or "optionally substituted" refers to whether or not substitution is possible, and unless otherwise specified, the type and number of substituents may be any as long as it is chemically feasible.

[0368] When any variable (e.g., R) occurs more than one time in a composition or structure of a compound, 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. Additionally, 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 by 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 by the methods described in the examples using appropriate starting materials according to their specific structures, 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 obtained commercially. The compounds of the examples can be further resolved, if necessary, by methods known in the art, such as crystallization, chromatography, etc. to obtain their stereoisomers, and the resolution conditions can be easily obtained by those skilled in the art through known means or limited testing.

[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 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, and the like, and an acyloxy group such as acetoxy, trifluoroacetoxy, and the like. p R is an amino protecting group well known in the art, and includes, for example, formyl, acyl such as, for example, alkanoyl (e.g., acetyl, trichloroacetyl or trifluoroacetyl), alkoxycarbonyl such as, for example, tert-butoxycarbonyl (Boc), arylmethoxycarbonyl such as, for example, benzyloxycarbonyl (Cbz) and 9-fluorenylmethyloxycarbonyl (Fmoc), arylmethyl such as, for example, benzyl (Bn), trityl group (Tr), 1,1-di-(4′-methoxyphenyl)methyl, silyl such as, for example, trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS), and the like. 1 , R 2 , R 3 , R 21 , R 22 , R 12 , R 11 , R 31 , R 32 , R m ', R 0 ', Ar', E 1 ', X 1 The definitions of are the same as above (for example, Formula I is the same as the definitions of each corresponding group 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 solvent, temperature and other reaction conditions in each step may be the same 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″), R p is an amino protecting group 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), and the like. R 1 , R 2 , R 3 , R 21 , R 22 , R 12 , R 11 , R 31 , R 32 , R 0 ', Ar', E 1 ', X 1 The definitions of are the same as above (for example, Formula I is the same as the definitions of each corresponding group in Formula IA).

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

[0379] [ka]

[0380] In the preparation scheme of the compound represented by formula e, R lev R 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, and an acyloxy group, such as acetoxy, trifluoroacetoxy, and the like. 0 ', Ar', E 1 ', X 1 The definitions of are the same as those described above (for example, the same as the definitions of the corresponding groups in formula I and formula IA). [Brief description of the drawings]

[0381] [Figure 1] FIG. 2 is a diagram of the molecular conformation of compound Z25-2 by single crystal X-ray diffraction. [Diagram 2] FIG. 2 is a diagram of the molecular conformation of compound Z27-2 by single crystal X-ray diffraction. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0382] The compounds according to the present invention can be prepared by various synthetic methods well 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 well known to those skilled in the art, and preferred embodiments include, but are not limited to, the examples of the present invention. The present invention will be described in detail below by examples, but this does not mean any adverse restrictions on the present invention. This specification describes the present invention in detail, but the specific examples 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 performed under normal conditions or conditions provided by the manufacturer. Unless the manufacturer is specified, the reagents or equipment used are all common products obtained from commercial sources.

[0383] The abbreviations for the reagents used in the following examples are as follows: THF: tetrahydrofuran, DMSO: dimethylsulfoxide, PE: petroleum ether, EtOAc: ethyl acetate, DCM: dichloromethane, MeOH: methanol, ACN: acetonitrile, IPA: isopropylamine, DMA: dimethylamine, TFA: trifluoroacetic acid, NH 4 Cl: 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, 5μm 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 system was cooled to 0° C., NaHMDS (5.8 mL, 11.60 mmol, 2 M in THF) was added dropwise, and the mixture was stirred for 15 minutes. A solution of 2,5-difluoro-6-(2-fluoro-6-methoxyphenyl)nicotinic acid (1.0 g, 3.53 mmol) dissolved in THF (6 mL) was added dropwise. The mixture was stirred at room temperature for 3 hours. The reaction solution was diluted with saturated NH 4 The mixture was poured into 30 mL of Cl. It was extracted three times with 40 mL of ethyl acetate. The organic layer was dried and concentrated. The crude product was purified by high-performance silica gel column (0-5% MeOH / DCM) to give the product 5-fluoro-6-(2-fluoro-6-methoxyphenyl)-2-((2-isopropyl-4-methylpyridin-3-yl)amino)nicotinic acid as a yellow solid (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 dissolved in SOCl. 2 (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 did not need to be purified and was used directly in the next reaction. Step 3: At 0° C., a solution of ethyl nitroacetate (449 mg, 3.38 mmol) in THF (2 ml) was added dropwise to a suspension of NaH (608 mg, 15.21 mmol) in THF (25 mL) and stirred at 0° C. for 0.5 h. 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 THF (15 mL) was added dropwise. The ice bath was removed and the reaction was stirred at 70° C. overnight. The reaction 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 then 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 POCl 3(1.30g, 8.45mmol) and N,N-diisopropylethylamine (1.74g, 13.52mmol) were added in that order, and the mixture was stirred at 80°C for 1 hour. The reaction mixture was concentrated, and then ethyl acetate was added, and the mixture was washed with ice water, water, and saturated saline in that order. The organic layer was dried and concentrated, and the crude product was purified using a high-performance silica gel column (EtOAc / PE: 0-50%) to obtain the product 4-chloro-6-fluoro-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro-1,8-naphthyridin-2(1H)-one (185mg, Y: 21.9%) as a yellow solid. 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), (R)-3-(hydroxymethyl)piperazine-1-carboxylic acid-tert-butyl ester (454 mg, 2.10 mmol) was added, and the mixture was stirred for 18 hours at 80° C. The reaction solution 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 saline, dried, and concentrated, and the crude product was purified using a high-performance silica gel column (EtOAc / PE: 0-70%) to obtain the 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%) as a yellow solid. 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 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 saline, dried and concentrated, and the crude product was purified by thin layer chromatography (dichloromethane / methanol = 20:1) to obtain the product, yellow solid (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 h. The reaction mixture was concentrated to give the product (4aR)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-1,2,3,4,4a,5-hexahydropyrazine[1',2':4,5][1,4]oxazine[2,3-c][1,8]naphthyridin-7(8H)-one (40 mg, crude product), which was used directly in the next reaction. ES-API: [M+H] + =534.3. 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 (40mg, 0.055mmol) was dissolved in dichloromethane (4mL), triethylamine (28mg, 0.28mmol) was added, the reaction system was cooled to 0°C, and a dichloromethane solution (0.5mL) of acrylic anhydride (6mg, 0.05mmol) was added dropwise to the reaction solution. Stirred at 0°C for 15 minutes. Saturated NaHCO 3 10 mL of aqueous solution was added, and extracted three times with 10 mL of dichloromethane. The organic layer was dried and then concentrated. The crude product was purified by thin layer chromatography (dichloromethane / methanol = 10:1) to obtain the product (4aR)-3-acryloyl-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-1,2,3,4,4a,5-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 (15mg, 0.025mmol) was dissolved in dichloromethane (1.5mL), the reaction system was cooled to 0°C, and 17% boron tribromide in dichloromethane solution (1mL) was added dropwise to it. The mixture was stirred at room temperature for 3 hours. 20mL of saturated NaHCO 3Aqueous solution was added and extracted with 20 mL of dichloromethane three times. 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 (500 MHz, DMSO-d 6 )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 as Z1-1 (75 mg, peak 1, retention time 3.94 min, Y: 15.4%). 1 H NMR (400MHz, DMSO-d 6). 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. And another atropisomer compound was obtained as a pale yellow solid, whose structure was designated as Z1-2 (115 mg, peak 2, retention time: 5.04 min, Y: 23.6%). 1 H NMR (400 MHz, DMSO-d 6 ) 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 stirred at reflux 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 vacuum to obtain a white solid product, 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: 200mL diphenyl ether was added to a 500mL flask and heated to 220℃, 5-((2-chloropyridin-3-yl)amino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (3.9g, 13.83mmol) was added batchwise and stirred at 220℃ for 20 minutes. The reaction solution was cooled to room temperature. It was then poured into petroleum ether, the precipitated solid was filtered, and the filter cake was washed with petroleum ether. It was dried in vacuum to obtain the product 8-chloro-1,7-naphthyridin-4-ol (1.5g, Y: 60%) as a light brown solid. ES-API: [M+H] + =181.0 Step 3: 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) were added to a 50 mL flask and stirred at room temperature for 3 days under hydrogen atmosphere. The reaction solution 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 stirred at 100°C for 1 hour. The cooled reaction solution 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 vacuum to obtain a yellow solid 3-nitro-1,7-naphthyridin-4-ol (530 mg, Y: 73.7%). ES-API: [M+H] + =192.1 Step 5: 3-nitro-1,7-naphthyridin-4-ol (480 mg, 2.51 mmol) and phosphorus oxychloride (4.68 mL, 50.20 mmol) were added to a 20 mL flask 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 solution 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-naphthyridin (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), (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 in sequence, and the mixture was stirred at 80 ° C for 3 hours. After concentrating the reaction solution, the crude product was purified by a high-performance silica gel column (EtOAc / PE: 50-100%) to obtain the product as a yellow solid (R)-3-(hydroxymethyl)-4-(3-nitro-1,7-naphthyridine-4-yl)piperazine-1-carboxylate tert-butyl (330 mg, Y: 39.4%). ES-API: [M + H] + =390.2. Step 7: (R)-3-(hydroxymethyl)-4-(3-nitro-1,7-naphthyridin-4-yl)piperazine-1-carboxylate tert-butyl (310 mg, 0.80 mmol), DMF (18 mL) and NaH (96 mg, 2.40 mmol) were added in sequence to a 50 mL tube and stirred at 95 °C for 3 days. The cooled reaction solution was poured into water and extracted twice with ethyl acetate. The organic layer was washed three times with saturated saline, dried and concentrated, and the crude product was purified by thin layer chromatography (dichloromethane / methanol = 15:1) to obtain the product as a yellow solid (R)-8a,9,11,12-tetrahydropyrazine[1',2':4,5][1,4]oxazine[2,3-c][1,7]naphthyridin-10(8H)-carboxylate tert-butyl (175 mg, Y: 64%). 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 saline. After drying and concentration, the crude product was purified by thin layer chromatography (dichloromethane / methanol / aqueous ammonia = 100:8:1) to obtain a pale yellow solid product (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)-carboxylate tert-butyl (50 mg, Y: 49.4%). ES-API: [M+H] + =390.2. Step 9: In a 5 mL microtube, add tert-butyl (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)-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), and Pd 2 (dba) 3 (51 mg, 0.056 mmol), Ruphos (26 mg, 0.056 mmol) and toluene (6 mL) were added, the atmosphere was replaced with nitrogen gas, and the mixture was heated for 120 o C for 1 hour. The mixture was cooled to room temperature, filtered, and the filtrate was dried and then concentrated. The crude product was purified by thin layer chromatography (dichloromethane / methanol / aqueous ammonia = 100:5:1) to obtain (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, 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)-tert-butyl carboxylate (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 (60mg, 0.11mmol) and N,N-diisopropylethylamine (71mg, 0.55mmol) were dissolved in dichloromethane (5mL), the reaction system was cooled to 0°C, and a dichloromethane solution (0.5mL) of acrylic anhydride (13mg, 0.10mmol) was added dropwise to the reaction solution. The mixture was stirred at 0°C for 10 minutes. Saturated NaHCO 3 Aqueous solution (10 mL) was added and extracted with 10 mL of dichloromethane three times. 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 (500 MHz, DMSO-d 6)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=16.6 Hz, 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), (2R,5R)-5-(hydroxymethyl)-2-methylpiperazine-1-carboxylate tert-butyl (1.61 g, 7.0 mmol) was added, and the mixture was stirred at 80° C. for 1 hour. The reaction solution was poured into 30 mL water and extracted three times with 20 mL of ethyl acetate. The organic layer was washed three times with saturated saline, dried and concentrated, and the crude product was purified using a high-performance silica gel column (EtOAc / PE: 0-70%) to obtain the product, yellow solid (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 tert-butyl (325 mg, Y: 33.4%). 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) and NaH (52 mg, 1.32 mmol) was added and stirred at 125 °C for 20 h. The cooled reaction was poured into 15 mL water and extracted three times with 30 mL ethyl acetate. The organic layer was washed eight times with saturated brine. After drying and concentrating, the crude product was purified by high-performance silica gel column (EtOAc / PE: 0-100%) to obtain the product (2R, 4aR)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-2-methyl-7-oxo-1,2,4a,5,7,8-hexahydropyrazine[1',2':4,5][1,4]oxydine[2,3-c][1,8]naphthyridine-3(4H)-carboxylate tert-butyl (60 mg, Y: 21.4%) as a yellow solid. 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 h. 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) as the 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 (61mg, 0.093mmol) was dissolved in dichloromethane (5mL) and triethylamine (47mg, 0.46mmol) was added. The reaction system was cooled to 0°C, and acrylic anhydride (17mg, 0.14mmol) in dichloromethane (1mL) was added dropwise to the reaction solution. The mixture was stirred at 0°C for 15 minutes. The reaction solution was added with saturated NaHCO 3 10 mL of aqueous solution was added, and extracted three times with 10 mL of dichloromethane. The organic layer was dried and then concentrated. The crude product was purified by thin layer chromatography (dichloromethane / methanol = 10:1). The product was obtained as 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]oxydine[2,3-c][1,8]naphthyridin-7(8H)-one (Z3a, 32 mg, Y: 57.4%). ES-API: [M+H] + =602.2. 1 H NMR (500 MHz, DMSO-d 6 )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 (32mg, 0.053mmol) was dissolved in dichloromethane (1.5mL), the reaction system was cooled to 0°C, and 17% boron tribromide in dichloromethane solution (1mL) was added dropwise to it. The reaction solution was stirred at room temperature for 3 hours. The reaction solution was dissolved in 20mL of saturated NaHCO 3 The mixture was poured into an aqueous solution and extracted three times with 20 mL of dichloromethane. The organic layer was dried and then 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]oxidineoxazine[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 for 2 h at 80° C. The reaction solution 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 saline, dried and concentrated, and the crude product was purified using a high-performance silica gel column (EtOAc / PE: 0-70%) to obtain the product as a yellow solid (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 tert-butyl (1.3 g, 54%). ES-API: [M+H] + =697.2. Step 2: (3R)-4-(6-chloro-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro-2-oxo-1,2-dihydro-1,8-naphthyridin-4-yl)-3-(hydroxymethyl)piperazine-1-carboxylate tert-butyl (1.3 g, 1.86 mmol) was dissolved in DMA (10 mL) and LHMDS (5.6 mmol, 5.6 mmol, 1 M solution in tetrahydrofuran) was added and stirred at 140° C. for 20 hours. The cooled reaction 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 saline, dried and concentrated, and the crude product was purified using a high-performance silica gel column (methanol / dichloromethane: 0-10%) to obtain a yellow solid product, (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 (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. After concentrating the reaction solution, (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]oxazine-[2,3-c][1,8]naphthyridin-7(8H)-one (203 mg, crude product) was obtained as the 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]oxazine-[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 system was cooled to 0 ° C. and a dichloromethane solution (0.5 mL) of acrylic anhydride (37 mg, 0.30 mmol) was added dropwise to the reaction solution. The mixture was stirred at 0 ° C. for 10 minutes. The reaction solution was diluted with saturated NaHCO 3 10 mL of aqueous solution was added, and extracted with 10 mL of dichloromethane three times. The organic layer was dried and then concentrated. The crude product was purified by thin layer chromatography (dichloromethane / methanol = 10:1) to obtain the product (4aR)-3-acryloyl-11-chloro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-1,2,3,4,4a,5-hexahydropyrazine-[1',2':4,5][1,4]oxazine-[2,3-c][1,8]naphthyridin-7(8H)-one (223 mg, crude product) as a pale yellow solid. 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 (223mg, 0.37mmol) was dissolved in dichloromethane (1.5mL), the reaction system was cooled to 0°C, and a 17% dichloromethane solution of boron tribromide (3mL) was added dropwise to it. The reaction solution was stirred at room temperature for 1 hour. The reaction solution was dissolved in 20mL of saturated NaHCO 3The mixture was poured into an aqueous solution and extracted three times with 20 mL of dichloromethane. The organic layer was dried and then 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]oxazine-[2,3-c][1,8]naphthyridin-7(8H)-one (Z6, 26.28 mg, 11%) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 )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-dicarboxylate (732 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 solution, and the mixture was washed with 30 mL of diluted saline solution four times. After washing with 30 mL of saturated saline solution and drying and concentrating, the crude product was purified with 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-dicarboxylate (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-dicarboxylate (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 solution, 50 mL of ethyl acetate and 30 mL of saturated sodium bicarbonate were added in that order, the suspension was filtered through diatomaceous earth, and the filter cake was washed with ethyl acetate. The organic layer was separated and washed with 30 mL of saturated aqueous sodium bicarbonate and 30 mL of saturated saline in that order. Drying and concentration gave the product (4aR)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-5,7-dioxo-1,2,4,4a,5,6,7,8-octahydro-3H-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8]naphthyridine-3-carboxylate tert-butyl (450 mg, Y: 98.6%) as a pale yellow solid. ES-API: [M+H] + =647.2. Step 3: (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 (450 mg, 0.70 mmol), 12 mL of acetone, anhydrous potassium carbonate (290 mg, 2.10 mmol), and iodomethane (596 mg, 4.20 mmol) were added in sequence to a 15 mL tube. The tube was sealed and stirred at 50 °C for 20 hours. After concentrating the reaction solution, 60 mL of ethyl acetate was added and washed with 30 mL of water and 30 mL of saturated saline in sequence. After drying and concentration, the crude product was purified by high-performance silica gel column (EtOAc / PE: 0-70%) to obtain the 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 (390 mg, Y: 84.8%) as an orange solid. 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 (940 mg, 1.42 mmol) was dissolved in dichloromethane (6 mL) and trifluoroacetic acid (2 mL) was added. The mixture was stirred at room temperature for 2 hours, and the reaction mixture was concentrated to give the product (4aR)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-6-methyl-2,3,4,4a,6,8-hexahydro-1H-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8]naphthyridine-5,7-dione (1.1 g, crude product), which was used as is 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 was cooled to 0 ° C., acrylic acid chloride (256 mg, 2.84 mmol) was added to the reaction solution, and the mixture was stirred at 0 ° C. for 15 minutes. 30 mL of dichloromethane was added to the reaction solution, 15 mL of water, 15 mL of saturated NaHCO 3The mixture was washed with 15 mL of aqueous solution and 15 mL of saturated saline solution in sequence. After drying and concentration, the crude product was purified with 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 system was cooled to 0 ° C, and a 17% dichloromethane solution of boron tribromide (7 mL) was added dropwise to it. The reaction solution was stirred at room temperature for 6 hours. The reaction solution was dissolved in 60 mL of saturated NaHCO 3 The organic layer was poured into a 50 mL aqueous solution of saturated NaHCO 3 The mixture was washed with 80 mL of aqueous solution and 80 mL of saturated aqueous solution of sodium chloride in that order. After drying and concentration, a pale yellow solid product, (4aR)-3-acryloyl-11-fluoro-10-(2-fluoro-6-hydroxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-6-methyl-2,3,4,4a,6,8-hexahydro-1H-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8,8]naphthyridine-5,7-dione (Z9: 375 mg, Y: 98.4%), was obtained. 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. Then, it was 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) to obtain one atropisomer compound, which was a light yellow solid, and its structure was designated as Z9-1 (250 mg, peak 1, retention time: 6.463 min, Y: 33.3%). 1 H NMR (500 MHz, DMSO-d 6 )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. And another atropisomer compound was obtained as a pale yellow solid, whose structure was designated as Z9-2 (350 mg, peak 2, retention time 8.252 min, Y: 46.7%). 1 H NMR (500 MHz, DMSO-d 6)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: (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 tert-butyl (800 mg, 1.21 mmol), 20 mL of acetone, anhydrous potassium carbonate (500 mg, 3.63 mmol), and iodomethane (1.03 g, 7.26 mmol) were added in sequence to a 50 mL tube. The tube was sealed and stirred at 50 °C for 18 hours. After concentrating the reaction solution, 60 mL of ethyl acetate was added and washed in sequence with 20 mL of water and 30 mL of saturated saline. After drying and concentration, the crude product was purified by high-performance silica gel column (EtOAc / PE: 0-70%) to obtain the 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 (790 mg, Y: 96.7%) as an orange solid. 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 tert-butyl (790 mg, 1.42 mmol) was dissolved in dichloromethane (6 mL) and trifluoroacetic acid (2 mL) was added. The mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated to obtain the product (2R,4aR)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-2,6-dimethyl-2,3,4,4a,6,8-hexahydro-1H-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 product) was dissolved in dichloromethane (15 mL) and N,N-diisopropylethylamine (755 mg, 5.85 mmol) was added. The reaction was cooled to 0 ° C., acrylic acid chloride (211 mg, 2.34 mmol) was added to the reaction solution, and the mixture was stirred at 0 ° C. for 15 minutes. 50 mL of dichloromethane was added to the reaction solution, 20 mL of water, 40 mL of saturated NaHCO 3The mixture was washed with 20 mL of aqueous solution and 20 mL of saturated aqueous solution of sodium chloride in sequence. After drying and concentration, the crude product was purified with a high-performance silica gel column (EtOAc / PE: 0-100%) to obtain the product (2R, 4aR)-3-acryloyl-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-2,6-dimethyl-2,3,4,4a,6,8-hexahydro-1H-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8]naphthyridine-5,7-dione (670 mg, Y: 91.0%) as a pale yellow solid. 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 system was cooled to 0 ° C, and a 17% dichloromethane solution of boron tribromide (7 mL) was added dropwise to it. The reaction solution was stirred at room temperature for 3 hours. The reaction solution was dissolved in 60 mL of saturated NaHCO 3 The organic layer was poured into a 50 mL aqueous solution of saturated NaHCO 3 The mixture was washed with 80 mL of aqueous solution and 80 mL of saturated aqueous solution of sodium chloride in sequence. 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) to obtain one atropisomer compound, which was a light yellow solid, and its structure was designated as Z10-1 (206 mg, peak 1, retention time: 8.321 min, Y: 45.7%). 1 H NMR (500 MHz, DMSO-d 6 )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), 4.6 3-4.37(m, 1H), 4.07-3.97(m, 1H), 3.73(dd, J=14.1, 4.2Hz, 1H), 3.39-3.20(m, 4H), 2.94-2.7 8(m, 1H), 2.49-2.39(m, 1H), 1.99(s, 3H), 1.61-1.49(m, 3H), 1.02(d, J=6.7Hz, 3H), 0.85(d, J =6.7Hz, 3H).ES-API:[M+H] + = 615.2. And another atropisomer compound was obtained as 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 (500 MHz, DMSO-d 6)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 to 5, 7 to 8, 11 to 20

[0405] Compounds Z4 to Z144, Z7 to Z8, and Z11 to Z20 are prepared by referring to a method similar to the preparation method of compound Z1 or Z2. The starting materials of each compound are commercially available or can be prepared by conventional methods well known to those skilled in the art. The similar synthetic methods of 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: 7-chloro-6-fluoro-4-hydroxy-1-(4-isopropyl-6-methylpyrimidin-5-yl)-2-oxo-1,2-dihydro-1,8-naphthyridin-3-nitrile (2 g, 5.34 mmol), 12 mL of water, and 12 mL of dioxane were added to a flask. The reaction system was cooled to 0° C., and 12 mL of concentrated sulfuric acid was added dropwise to the reaction solution. After the addition was completed, the mixture was stirred at 120° C. for 18 hours. After the reaction was completed, a large amount of solid matter was precipitated. The mixture was filtered and the filter cake was washed three times with water. The filter cake was dried to obtain a white solid product, 7-chloro-6-fluoro-4-hydroxy-1-(4-isopropyl-6-methylpyrimidin-5-yl)-1,8-naphthyridin-2(1H)-one (1.4 g, 75%). The crude product was used as it was 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 glacial acetic acid. Concentrated nitric acid (700 mg, 11.1 mmol) was added dropwise to the reaction. The reaction was placed in a 30° C. oil bath and heated for 2 hours. The reaction was poured into ice water and a solid precipitated. It 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% pure) 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 reaction was quenched by stirring in a nitrogen atmosphere at 110° C. oil bath for 1 hour. The reaction mixture was added with 1M aqueous potassium carbonate (30 mL) and extracted once with 20 mL 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 thereto. The mixture was stirred at 85° C. for 1 hour. The completion of the reaction was confirmed by LC-MS. The reaction solution 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-dicarboxylate (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 1 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-dicarboxylate (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-dicarboxylate (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. The completion of the reaction was confirmed by LC-MS. The reaction solution was poured into 50 mL of aqueous sodium bicarbonate and extracted three times with 30 mL of ethyl acetate. The organic layer was dried and then concentrated to give a yellow solid, (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 tert-butyl ester (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 tert-butyl (450mg, 0.69mmol), iodomethane (789mg, 5.55mmol), potassium carbonate (286mg, 2.07mmol) and 10mL of acetone were added to a flask. The reaction was carried out in a tube and stirred at 50°C for 16 hours, and the completion of the reaction was detected by LC-MS. The reaction mixture was filtered through diatomaceous earth, the filtrate was concentrated, and the crude product was purified by high-performance silica gel column (EtOAc / PE: 0-60%) to obtain 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 (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 tert-butyl (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. After concentrating the reaction mixture, 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) was obtained. The crude product was used directly in the next step. ES-API: [M+H] + =562.2. Step 9: (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 dichloromethane and triethylamine (158 mg, 1.56 mmol) were added to a 50 mL flask, the reaction system was cooled to 0 ° C, and a dichloromethane solution of acrylic acid chloride (71 mg, 0.78 mmol, 0.5 mL) was added dropwise to the reaction solution. Stirred at 0 ° C for 10 minutes. 40 mL of saturated aqueous sodium bicarbonate was added to the reaction solution, and it 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), 3 mL dichloromethane was added to the flask, the reaction solution was cooled to 0°C, and 17% boron tribromide in dichloromethane (6 mL) was added dropwise to it. After the addition was completed, the mixture was stirred at room temperature for 2 hours. The reaction solution was cooled to 0°C and stirred for 2 hours at room temperature ... 3The mixture was poured into an aqueous solution and extracted three times with 20 mL of dichloromethane. The organic layer was dried and then 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: 10μm, 20*250mm; mobile phase: hexane:ethanol:diethylamine=70:30:0.2; flow rate: 15ml / min; column temperature: room temperature) to obtain one atropisomer compound, which was a yellow solid and was assigned the structure Z21-1 (peak 2, retention time: 12.33 min, 47 mg). ES-API:[M+H] + =602.2. 1 HNMR (500 MHz, DMSO-d 6):10.17(s, 1H), 9.03(s, 1H), 8.41(d, J=9Hz, 1H), 7.26-7.25(m, 1H), 7.08-7.05(m, 1H), 6.68-6.66(m, 2H), 6.17-6.14(m, 1H), 5.77-5.75(m, 1H), 4.75-4.73(m, 1H), 4.46-4.44(m, 1H), 4.0-3.95(m, 1H), 3.55-3.54 (m, 2H), 3.41 (s, 3H), 3.20-3.18 (m, 1H), 2.85-2.83 (m, 1H), 2.68-2.65 (m, 1H), 2.00 (s, 3H), 1.13 (d, J = 6.5 Hz, 3H), 1.06 (d, J = 6.5 Hz, 3H). And another atropisomeric compound was obtained as a yellow solid, and its structure was assigned as Z21-2 (peak 1, retention time: 10.58 min, 48 mg). ES-API: [M+H] + =602.2. 1 HNMR (500 MHz, DMSO-d 6 ):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), 4.46-4.4 4 (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), sodium nitrite (41 mg, 0.6 mmol) and concentrated nitric acid (1.5 g, 24 mmol) were added in sequence, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was slowly poured into 100 mL of ice water, the precipitated solid was filtered, the filter cake was washed with 20 ml of ice water, and the product was obtained as a yellow solid 7-chloro-6-fluoro-4-hydroxy-1-(3-isopropylpyrazin-2-yl)-3-nitro-1,8-naphthyridin-2(1H)-one (1.5 g, 65%) after drying. ES-API: [M+H] + =380.2. Step 2: In a 100 mL three-neck flask, 7-chloro-6-fluoro-4-hydroxy-1-(3-isopropylpyrazin-2-yl)-3-nitro-1,8-naphthyridin-2(1H)-one (1.5 g, 3.94 mmol), (2-fluoro-6-methoxyphenyl)boronic acid (2.04 g, 12 mmol), chloro(2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (288 mg, 0.4 mmol), 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (164 mg, 0.4 mmol), potassium phosphate (2.5 g, 12 mmol), 10 mL of water, and 40 mL of dioxane were added and stirred at 100 °C for 2 to 3 hours under nitrogen atmosphere. After the reaction was completed, the reaction solution was cooled to room temperature. 80mL of water and 100mL of methyl tert-butyl ether were added and extracted once. The aqueous layer was adjusted to pH 3-5 with 1M hydrochloric acid solution and extracted with ethyl acetate (200mL*2). The ethyl acetate layers were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was dried in vacuum to obtain the product, a light yellow solid 6-fluoro-7-(2-fluoro-6-methoxyphenyl)-4-hydroxy-1-(3-isopropylpyrazin-2-yl)-3-nitro-1,8-naphthyridin-2(1H)-one (1.6g, 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 (1.6g, 3.4mmol) was dissolved in acetonitrile (30 mL), phosphorus oxychloride (2.6g, 17mmol) and N,N-diisopropylethylamine (3g, 23.8mmol) were added in sequence, and the reaction temperature was gradually raised to 80°C while stirring for 30 minutes. After concentrating the reaction solution, 30mL of cold acetonitrile was added, and the mixture was added dropwise to 150mL of saturated sodium bicarbonate solution in an ice-water bath, and extracted with ethyl acetate (200mL*2). The organic layers were combined and washed once with 200mL of saturated saline. After drying over anhydrous sodium sulfate, filtration, and drying and concentrating the organic layer, the crude product was purified by high-performance silica gel column (EtOAc / PE: 0-50%) to give a yellow solid of 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 solution. was added and washed three times with 30 mL of saturated saline. 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,6R)-4-(6-fluoro-7-(2-fluoro-6-methoxyphenyl)-1-(3-isopropylpyrazin-2-yl)-3-nitro-2-oxo-1,2-dihydro-1,8-naphthyridin-4-yl)-6-methylpiperazine-1,3-dicarboxylate (317 mg, Y: 70%) as a yellow solid. ES-API: [M+H] + =710.2. Step 5: 1-(tert-butyl-3-methyl(3R,6R)-4-(6-fluoro-7-(2-fluoro-6-methoxyphenyl)-1-(3-isopropylpyrazin-2-yl)-3-nitro-2-oxo-1,2-dihydro-1,8-naphthyridin-4-yl)-6-methylpiperazine-1,3-dicarboxylate (280 mg, 0.4 mmol) was dissolved in acetic acid (4 mL), iron powder (78 mg, 1.4 mmol) was added, and the mixture was stirred at 80° C. for 30 minutes. After concentrating the reaction solution, 50 mL of ethyl acetate and 30 mL of saturated sodium bicarbonate were added in sequence, 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 in turn. The mixture was dried and concentrated to give a yellow solid product, (2R,4aR)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(3-isopropylpyrazin-2-yl)-2-methyl-5,7-dioxo-1,2,4,4a,5,6,7,8-octahydro-3H-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8]naphthyridine-3-carboxylate tert-butyl (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 tert-butyl (295 mg, 0.46 mmol) was added to a 15 mL tube, 3 mL of acetone, anhydrous potassium carbonate (1 g, 6.9 mmol), and iodomethane (253 mg, 1.84 mmol) were added in that order, the tube was sealed, and the mixture was stirred at 55 ° C for 18 hours. 50 mL of ethyl acetate was added to the reaction solution, and the mixture was washed three times with 20 mL of saturated saline. After drying and concentration, the product was obtained as a yellow solid (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 ester (356 mg, crude product). 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 the product (2R,4aR)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(3-isopropylpyrazin-2-yl)-2,6-dimethyl-2,3,4,4a,6,8-hexahydro-1H-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 system was cooled to 0 ° C, and acrylic acid chloride (115 mg, 1.28 mmol) was added dropwise to the reaction solution. Stirred at 0 ° C for 5 minutes. 50 mL of dichloromethane was added to the reaction solution, and 50 mL of saturated NaHCO 3 The mixture was washed with aqueous solution and 80 mL of saturated saline. After drying and concentration, the crude product was purified by high-performance silica gel column (EtOAc / PE: 0-60%) to obtain the product (2R, 4aR)-3-acryloyl-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(3-isopropylpyrazin-2-yl)-2,6-dimethyl-2,3,4,4a,6,8-hexahydro-1H-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8]naphthyridine-5,7-dione (201 mg, Y: 44%) as a yellow solid. 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 further added, and the reaction was allowed to proceed at room temperature for 30 minutes. The reaction solution was then heated to 100° C. for 30 minutes 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 (500 MHz, DMSO-d 6 )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, 1 H), 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-dicarboxylate (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. The completion of the reaction was confirmed by LC-MS. 30 mL of water was poured into the reaction solution and extracted with ethyl acetate three times. The organic layer was washed four times with saturated saline / water (v / v, 1:1), dried and concentrated to give 1-(tert-butyl)-3-methyl(3R,6R)-4-(6-chloro-1-(4,6-diisopropylpyrimidin-5-yl)-7-(2-fluoro-6-methoxyphenyl)-3-nitro-2-oxo-1,2-dihydro-1,8-naphthyridin-4-yl)-6-methylpiperazine-1,3-dicarboxylate (1g, yield 89%). 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-dicarboxylate (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 a crude product as a yellow solid (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 tert-butyl ester (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 tert-butyl (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, and 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 yellow solid of (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 tert-butyl ester (738 mg, 95%) as a crude product. 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 tert-butyl (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: (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) were added to a 50 mL flask, the reaction system was cooled to 0 ° C., and a dichloromethane solution of acrylic acid chloride (249 mg, 2.77 mmol, 0.5 mL) was added dropwise to the reaction solution, and the mixture was stirred at 0 ° C. for 10 minutes. 40 mL of saturated aqueous sodium bicarbonate was added to the reaction solution, 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 (EtOAc / PE: 0-60%) to give (2R,4aR)-3-acryloyl-11-chloro-8-(4,6-diisopropylpyrimidin-5-yl)-10-(2-fluoro-6-methoxyphenyl)-2,6-dimethyl-2,3,4,4a,6,8-hexahydro-1H-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8]naphthyridine-5,7-dione (500 mg, 72%) as a yellow solid. The crude product was used directly in the next step. ES-API: [M+H] + =674.2. 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 dichloromethane were added to the flask, the reaction solution was cooled to 0° C., and 17% boron tribromide in dichloromethane (12 mL) was added dropwise to it. After the addition was completed, the mixture was stirred at 25° C. for 25 hours. The reaction solution was cooled to 0° C. and stirred for 25 hours at 25° C. with 30 mL of cooled saturated NaHCO 3 3The mixture was poured into an aqueous solution and extracted three times with 20 mL of dichloromethane. The organic layer was dried and then concentrated. The crude product was purified by preparative HPLC to give the product (2R,4aR)-3-acryloyl-11-chloro-8-(4,6-diisopropylpyrimidin-5-yl)-10-(2-fluoro-6-hydroxyphenyl)-2,6-dimethyl-2,3,4,4a,6,8-hexahydro-1H-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-d 6 ):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), 5.04-5.0 1(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 and stirred at 120 °C for 36 hours. The cooled reaction solution was poured into 200mL of ice water, adjusted to pH 2-3 with sodium carbonate, extracted with ethyl acetate (1000mL*2), the ethyl acetate layers were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was dried under vacuum to obtain the product, a light brown solid, 6,7-dichloro-4-hydroxy-1-(2-isopropyl-4-methylpyridin-3-yl)-1,8-naphthyridin-2(1H)-one (24g, 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), sodium nitrite (100 mg, 1.58 mmol) and concentrated nitric acid (5.0 mL, 74.52 mmol) were added in sequence, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was slowly poured into 100 mL of ice water, the precipitated solid was filtered, and the filter cake was washed with 20 ml of ice water. The mixture was dried in vacuum to obtain the product, 6,7-dichloro-4-hydroxy-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro-1,8-naphthyridin-2(1H)-one (3.5 g, Y: 92%) as a yellow solid. ES-API: [M+H] + =409.1. Step 3: 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 were added to a 100 mL three-neck flask and stirred at 100 °C for 2 to 3 hours in a nitrogen atmosphere. After the reaction was completed, the reaction solution was cooled to room temperature, and 80 mL of water and 100 mL of methyl-tert-butyl ether were added and extracted once. The aqueous layer was adjusted to pH 3-5 with 1M hydrochloric acid solution, extracted with ethyl acetate (200mL*2), the ethyl acetate layers were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was dried under vacuum to obtain the product, 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 (4.5g, 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), phosphorus oxychloride (7.5 g, 48.92 mmol) and N,N-diisopropylethylamine (10.5 g, 81.24 mmol) were added in sequence, and the mixture was stirred for 30 minutes while gradually increasing the temperature to 80 ° C. After concentrating the reaction solution, 30 mL of cold acetonitrile was added, and the mixture was dropped into 150 mL of saturated sodium bicarbonate solution in an ice-water bath, extracted with ethyl acetate (200 mL * 2), and the ethyl acetate layer was combined and washed once with 200 mL of saturated saline. After drying over anhydrous sodium sulfate, filtration, and drying and concentrating the organic layer, the crude product was purified by high-performance silica gel column (EtOAc / PE: 0-50%) to obtain a yellow solid of 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 solution. The mixture was added with 1,2-dichloro-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-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 solution, 200 mL of ethyl acetate and 100 mL of saturated sodium bicarbonate were added in turn, the suspension was filtered through diatomaceous earth, the filter cake was washed with ethyl acetate, the organic layer was separated, and the organic layer was washed in turn with 100 mL of saturated sodium bicarbonate and 150 mL of saturated saline. Drying and concentration gave the product (4aR)-11-chloro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-5,7-dioxo-1,2,4,4a,5,6,7,8-octahydro-3H-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8]naphthyridine-3-carboxylate tert-butyl ester (2.70 g, crude product) as a yellow solid. ES-API: [M+H]+=663.2. Step 7: Add tert-butyl (4aR)-11-chloro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-5,7-dioxo-1,2,4,4a,5,6,7,8-octahydro-3H-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8]naphthyridine-3-carboxylate (250 mg, 0.3774 mmol) to a 100 mL flask, 4 mL of dichloromethane, and 4 mL of tert-butyl ether. 1 mL of trifluoroacetic acid was added in sequence, stirred at room temperature for 2 hours, and the reaction solution was concentrated to obtain the product (4aR)-11-chloro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-2,3,4,4a,6,8-hexahydro-1H-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 system was cooled to 0 ° C., acrylic acid chloride (50 mg, 0.5524 mmol) was added dropwise to the reaction solution, and the mixture was stirred at 0 ° C. for 15 minutes. 80 mL of dichloromethane was added to the reaction solution, and 100 mL of saturated NaHCO 3 The mixture was washed with 80 mL of saturated aqueous sodium chloride solution. After drying and concentration, the crude product was purified with a high-performance silica gel column (methanol / dichloromethane: 0-20%) to obtain the product, (4aR)-3-acryloyl-11-chloro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-2,3,4,4a,6,8-hexahydro-1H-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8]naphthyridine-5,7-dione (243 mg, crude product) as a yellow solid. ES-API: [M+H] + =617.2. Step 9: Under ice-water bath conditions, (4aR)-3-acryloyl-11-chloro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-2,3,4,4a,6,8-hexahydro-1H-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, and the mixture was warmed to room temperature and reacted overnight. Under ice-water bath conditions, the reaction solution was added dropwise to a saturated sodium bicarbonate solution and extracted twice with dichloromethane (80 mL). After drying and concentration, the mixture 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 (Z24,76mg, 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), and one atropisomer compound was obtained, whose structure was assigned as Z24-1 (13.7 mg, peak 1, retention time: 2.612 min, Y: 18%). ES-API: [M+H] + = 603.2. And the structure of another atropisomer compound obtained was assigned as 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 hours. The cooled reaction solution 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), sodium nitrite (100 mg, 1.58 mmol) and concentrated nitric acid (5.0 mL, 74.52 mmol) were added in sequence, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was slowly poured into 100 mL of ice water, the precipitated solid was filtered, the filter cake was washed with 20 ml of ice water, and dried in vacuum to obtain the product 6,7-dichloro-4-hydroxy-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro-1,8-naphthyridin-2(1H)-one (3.5 g, Y: 92%) as a yellow solid. ES-API: [M+H] + =409.1. Step 3: 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 were added to a 100 mL three-neck flask and stirred at 100 °C for 2-3 hours under nitrogen atmosphere. After the reaction was completed, the reaction solution 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 * 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-chloro-7-(2-fluoro-6-methoxyphenyl)-4-hydroxy-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro-1,8-naphthyridin-2(1H)-one (4.5 g, crude) as a 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), phosphorus oxychloride (7.5 g, 48.92 mmol), and N,N-diisopropylethylamine (10.5 g, 81.24 mmol) were added in sequence, and the mixture was stirred for 30 minutes while gradually increasing the temperature to 80 ° C. After concentrating the reaction solution, 30 mL cold acetonitrile was added, and the mixture was dropped into 150 mL of saturated sodium bicarbonate solution in an ice-water bath, and extracted with ethyl acetate (200 mL * 2). The ethyl acetate layers were combined and washed once with 200 mL of saturated saline. After drying over anhydrous sodium sulfate, filtration, and drying and concentrating the organic layer, the crude product was purified by high-performance silica gel column (EtOAc / PE: 0-50%) to give 4,6-dichloro-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro-1,8-naphthyridin-2(1H)-one (3.05 g, Y: 76%) as a yellow solid. ES-API: [M+H] + =517.2. 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 acetic acid was added to the reaction solution. Ethyl was added and washed with 80 mL of saturated saline three times. After drying and concentrating the ethyl acetate layer, the crude product was purified with 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-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 solution, 200 mL of ethyl acetate and 100 mL of saturated sodium bicarbonate were added in that order, the suspension was filtered through diatomaceous earth, and the filter cake was washed with ethyl acetate. The organic layer was separated and washed with 100 mL of saturated sodium bicarbonate and 150 mL of saturated saline in that order. Drying and concentration gave the product (4aR)-11-chloro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-5,7-dioxo-1,2,4,4a,5,6,7,8-octahydro-3H-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8]naphthyridine-3-carboxylate tert-butyl ester (2.70 g, crude product) as a yellow solid. 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 tert-butyl (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 in order to a 150 mL tube, the tube was sealed, and the mixture was stirred at 55 ° C for 18 hours. 150 mL of ethyl acetate was added to the reaction solution, and the mixture was washed three times with 100 mL of saturated saline. After drying and concentration, the crude product was purified by high-performance silica gel column (EtOAc / PE: 0-80%) to obtain the 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 (2.2 g, Y: 87%) as a yellow solid. 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 (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 the product (4aR)-11-chloro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-6-methyl-2,3,4,4a,6,8-hexahydro-1H-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 system was cooled to 0 ° C. and acrylic acid chloride (100 mg, 1.1048 mmol) was added dropwise to the reaction solution. The mixture was stirred at 0 ° C. for 15 minutes. 80 mL of dichloromethane was added to the reaction solution and 100 mL of saturated NaHCO 3The aqueous solution was washed with 80 mL of saturated saline. After drying and concentration, the crude product was purified with a high-performance silica gel column (EtOAc / PE: 0-60%) to obtain the product (4aR)-3-acryloyl-11-chloro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-6-methyl-2,3,4,4a,6,8-hexahydro-1H-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8]naphthyridine-5,7-dione (280 mg, Y: 59%) as a yellow solid. ES-API: [M+H] + =631.2. Step 10: Under ice-water bath conditions, (4aR)-3-acryloyl-11-chloro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-6-methyl-2,3,4,4a,6,8-hexahydro-1H-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), boron tribromide (5.0 mL, 5.0 mmol) was further added, the mixture was warmed to room temperature, and reacted overnight. Under ice-water bath conditions, the reaction solution was added dropwise to a saturated sodium bicarbonate solution 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 obtain the product (4aR)-3-acryloyl-11-chloro-10-(2-fluoro-6-hydroxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-6-methyl-2,3,4,4a,6,8-hexahydro-1H-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), and one atropisomer compound was obtained, Z25-1 (76.8 mg, peak 1, retention time: 2.531 min, Y: 34%). 1HNMR (500 MHz, DMSO-d 6 )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=14.2Hz, 1H), 4.4 6(d, J=12.9Hz, 1H), 4.00(s, 1H), 3.61(d, J=10.0Hz, 1H), 3.51(s, 1H), 3.34(s, 3H), 3.22(s, 1H), 2.64(t, J=11. 5Hz, 1H), 2.48-2.42(m, 1H), 1.98(d, J=5.1Hz, 3H), 1.03(t, J=6.9Hz, 3H), 0.86(t, J=7.9Hz, 3H).ES-API:[M+H] + = 617.2. And another atropisomer compound obtained was Z25-2 (70 mg, peak 2, retention time: 3.683 min, Y: 31%). 1 HNMR (500 MHz, CDCl 3 )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), 6.75-6.6 3(m, 2H), 6.39(dd, J=17.0, 2.0Hz, 1H), 5.88-5.77(m, 1H), 4.91(d, J=14.0Hz, 1H), 4.83(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 mixture was dissolved in 1 mL of 1, trifluoroacetic acid (2 mL) was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated to obtain the product (4aR)-11-chloro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-6-(methyl-d3)-2,3,4,4a,6,8-hexahydro-1H-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 system was cooled to 0 ° C., and acrylic acid chloride (100 mg, 1.1048 mmol) was added dropwise to the reaction solution. Stirred at 0 ° C. for 15 minutes. 80 mL of dichloromethane was added to the reaction solution, and 100 mL of saturated NaHCO 3The solution was washed with 80 mL of saturated aqueous sodium chloride solution. After drying and concentration, the crude product was purified with a high-performance silica gel column (EtOAc / PE: 0-60%) to obtain the product (4aR)-3-acryloyl-11-chloro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-6-(methyl-d3)-2,3,4,4a,6,8-hexahydro-1H-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8]naphthyridine-5,7-dione (232 mg, Y: 48%) as a yellow solid. ES-API: [M+H] + =634.2. Step 3: Under ice-water bath conditions, (4aR)-3-acryloyl-11-chloro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-6-(methyl-d3)-2,3,4,4a,6,8-hexahydro-1H-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8]naphthyridine-5,7-dione (240mg, 0.3791mmol) was added to dry dichloromethane (6.0mL), boron tribromide (5.0mL, 5.0mmol) was further added, the mixture was warmed to room temperature, and reacted overnight. Under ice-water bath conditions, the reaction solution was added dropwise to a saturated sodium bicarbonate solution and extracted twice with dichloromethane (80mL). After drying and concentration, the crude product was purified by 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 atropisomer compound was obtained, whose structure was designated as Z26-1 (68.8 mg, peak: 1, retention time: 2.525 min, Y: 36.7%). 1 HNMR (500 MHz, DMSO-d 6 )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), 3.5 0(s, 1H), 3.22(s, 1H), 2.65(t, J=12.5Hz, 1H), 2.49-2.42(m, 1H), 1.98(d, J=5.0Hz, 3H), 1.02 (d, J=7.0Hz, 3H), 0.86(t, J=7.9Hz, 3H). ES-API:[M+H] + = 620.3. And, 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 (400 MHz, CDCl 3)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-dicarboxylate (375 mg, 1.452 mmol) and N,N-diisopropylethylamine (375 mg, 2.907 mmol) were added in that order, and the reaction was stirred at 120 °C for 2 hours. 80mL of ethyl acetate was added to the reaction solution, and the mixture was washed with 80mL of saturated saline three times. 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 a yellow solid product, 1-(tert-butyl)-3-methyl(3R,6R)-4-(6-chloro-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro-2-oxo-1,2-dihydro-1,8-naphthyridin-4-yl)-6-methylpiperazine-1,3-dicarboxylic acid ester (535mg, 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-dicarboxylate (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 solution, 200 mL of ethyl acetate and 100 mL of saturated sodium bicarbonate were added in turn, the suspension was filtered through diatomaceous earth, and the filter cake was washed with ethyl acetate. The organic layer was separated and washed with 100 mL of saturated sodium bicarbonate and 150 mL of saturated saline in turn. The product was dried and concentrated to give a yellow solid (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 tert-butyl (445 mg, 0.6583 mmol), 10 mL of acetone, anhydrous potassium carbonate (500 mg, 2.633 mmol), and iodomethane (1.20 g, 6.5828 mmol) were added in order to a 150 mL tube, the tube was sealed, and the mixture was stirred at 55 ° C for 18 hours. 150 mL of ethyl acetate was added to the reaction solution, and the mixture was washed three times with 100 mL of saturated saline. After drying and concentration, the crude product was purified by high-performance silica gel column (EtOAc / PE: 0-80%) to obtain the 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 (455 mg, crude product) as a yellow solid. 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 tert-butyl (511 mg, 0.7549 mmol) was dissolved in dichloromethane (8 mL) and trifluoroacetate was added. Fluoroacetic acid (2 mL) was added, the mixture was stirred at room temperature for 2 hours, and the reaction mixture was concentrated to obtain the product (2R,4aR)-11-chloro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-2,6-dimethyl-2,3,4,4a,6,8-hexahydro-1H-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 system was cooled to 0 ° C, and acrylic acid chloride (100 mg, 1.1048 mmol) was added dropwise to the reaction solution. Stirred at 0 ° C for 15 minutes. 80 mL of dichloromethane was added to the reaction solution, and 100 mL of saturated NaHCO 3The solution was washed with 80 mL of saturated aqueous sodium chloride solution. After drying and concentration, the crude product was purified with a high-performance silica gel column (EtOAc / PE: 0-60%) to obtain the product (2R,4aR)-3-acryloyl-11-chloro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-2,6-dimethyl-2,3,4,4a,6,8-hexahydro-1H-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8]naphthyridine-5,7-dione (290 mg, Y: 68%) as a yellow solid. 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 (290mg, 0.4503mmol) was added to dry dichloromethane (6.0mL) under ice-water bath conditions, boron tribromide (6.0mL, 6.0mmol) was further added, the mixture was warmed to room temperature, and reacted overnight. Under ice-water bath conditions, the above reaction solution was added dropwise to a saturated sodium bicarbonate solution and extracted twice with dichloromethane (80mL). After drying and concentrating, the crude product was purified by 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 atropisomer compound, Z27-1 (67.7 mg, peak: 1, retention time: 2.394 min, Y: 23.4%). 1 H NMR (500 MHz, DMSO-d 6 )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), 4.60(d , J=13.8Hz, 1H), 4.00(d, J=3.5Hz, 1H), 3.75(dd, J=14.1, 3.9Hz, 1H), 3.41-3.33(m, 1H), 3.34(s, 3H), 2.81(d, J= 12.1Hz, 1H), 2.48-2.42(m, 1H), 1.98(s, 3H), 1.53(d, J=6.7Hz, 3H), 1.03(d, J=5.5Hz, 3H), 0.85(t, J=6.2Hz, 3H). ES-API:[M+H] + = 631.2. And another atropisomer compound obtained was Z27-2 (64.6 mg, peak 2, retention time 3.382 min, Y: 23.2%). 1 H NMR (400 MHz, CDCl 3)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, 1H), 6.72-6 .61(m, 2H), 6.34(dd, J=16.8, 2.0Hz, 1H), 5.80(dd, J=10.8, 2.0Hz, 1H), 5.11-5.01(m, 1H), 4.77(d, J=14.0Hz, 1H), 3.82(dd, J=14.0, 4.4Hz, 1H), 3.61(d, J=4.4Hz, 1H), 3.49(s, 3H), 3.30-3.17(m, 1H), 3.03(dd, J=12.0, 3. 6Hz, 1H), 2.80-2.68(m, 1H), 1.91(s, 3H), 1.66(d, J=6.8Hz, 3H), 1.22(d, J=6.8Hz, 3H), 1.08(d, J=6.8Hz, 3H). ES-API:[M+H] + = 631.2. The 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), (S)-3-(hydroxymethyl)piperazine-1-carboxylate tert-butyl (432 mg, 2.00 mmol), N,N-diisopropylethylamine (310 mg, 2.40 mmol) were added, and the mixture was stirred at 75 ° C for 2 hours. The reaction solution was diluted with 100 mL of ethyl acetate and washed five times with 40 mL of saturated saline. After drying and concentration, the crude product was purified by 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 hours. The reaction solution was diluted with 100 mL of ethyl acetate and washed four times with 40 mL of diluted saline. The mixture was washed once with 40 mL of saturated saline. After drying and concentrating, the crude product was purified by high-performance silica gel column (EtOAc / PE: 0-100%) to obtain the product (4aS)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-7-oxo-1,2,4a,5,7,8-hexahydropyrazine[1',2':4,5][1,4]oxazine[2,3-c][1,8]naphthyridine-3(4H)-carboxylate tert-butyl (180 mg, Y: 46.0%) as a yellow solid. 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 h. The reaction mixture was concentrated to give the product (4aS)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-1,2,3,4,4a,5-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 system 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 solution. Stirred at 0 ° C. for 15 minutes. 50 mL of dichloromethane was added to the reaction solution, 15 mL of water, 15 mL of saturated NaHCO 3 The organic layer was dried and concentrated to give the product, 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 (160mg, 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 was cooled to 0° C., and a 17% solution of boron tribromide in dichloromethane (3 mL) was added dropwise to the reaction. The reaction was stirred at room temperature for 3 hours. The reaction was diluted with 25 mL of chilled saturated NaHCO 3 The organic layer was poured into a 50 mL aqueous solution of dichloromethane and extracted with 50 mL of dichloromethane. 3The mixture was washed with 25 mL of saturated aqueous sodium chloride solution, dried, and then concentrated. The crude product was purified by preparative HPLC to obtain 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 (400 MHz, DMSO-d 6 )δ10.04(s, 1H), 8.42(d, J=4.8Hz, 1H), 8.22(d, J=7.4Hz, 1H), 7.27-7.17(m, 2 H), 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), sodium nitrite (79 mg, 1.15 mmol) and concentrated nitric acid (2.3 mL, 34.6 mmol) were added in sequence, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was slowly poured into 100 mL of ice water, the precipitated solid was filtered, the filter cake was washed with 20 ml of ice water, and dried in vacuum to obtain the product 7-chloro-6-fluoro-4-hydroxy-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro-1,8-naphthyridin-2(1H)-one (3.1 g, Y: 80%) as a yellow solid. ES-API: [M+H] + =393.1. Step 2: 7-chloro-6-fluoro-4-hydroxy-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro-1,8-naphthyridin-2(1H)-one (1.0 g, 2.55 mmol), (5-methyl-1H-indazol-4-yl)boric acid (1.8 g, 10.2 mmol), tetrakis(triphenylphosphine)palladium (589 mg, 0.51 mmol), potassium carbonate (1.76 g, 12.75 mmol), 2 mL of water and 8 mL of dioxane were added to a 100 mL three-neck flask and stirred at 110 ° C. for 1 hour under nitrogen atmosphere. After the reaction was completed, the reaction solution was cooled to room temperature, and 80 mL of water and 100 mL of methyl-tert-butyl ether were added and extracted once. The aqueous layer was adjusted to pH 3-4 with 1M hydrochloric acid solution, and a solid precipitated out, which was filtered and the resulting solid product was dried in vacuum to obtain 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 in sequence, and the mixture was stirred for 24 hours while gradually increasing the temperature to 80 ° C. After concentrating the reaction solution, 30 mL of cold acetonitrile was added, and the mixture was dropped into 30 mL of saturated sodium bicarbonate solution in an ice-water bath, and extracted with ethyl acetate (200 mL * 2), the ethyl acetate layer was combined, and washed once with 50 mL of saturated saline. After drying over anhydrous sodium sulfate, filtration, and drying and concentrating the organic layer, the crude product was purified by high-performance silica gel column (EtOAc / PE: 0-80%) to obtain 4-chloro-6-fluoro-7-(5-methyl-1H-indazol-4-yl)-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro-1,8-naphthyridin-2(1H)-one (0.3 g, Y: 50%) 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), (R)-3-(hydroxymethyl)piperazine-1-carboxylate tert-butyl (1.48 g, 320 mmol) was added in sequence, and the mixture was stirred at 80 ° C. for 1.5 hours. 80 mL of ethyl acetate was added to the reaction solution, and the mixture was washed with 80 mL of saturated saline three times. After drying and concentrating the ethyl acetate layer, the crude product was purified by a high-performance silica gel column (EtOAc / PE: 0-80%) to obtain the product as a yellow solid (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 tert-butyl (10 mg, Y: 40%). ES-API: [M+H] + =787.3. Step 5: 3R)-4-(6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)-7-(5-methyl-1H-indazol-4-yl)-3-nitro-2-oxo-1,2-dihydro-1,8-naphthyridin-4-yl)-3-(hydroxymethyl)piperazine-1-carboxylate tert-butyl (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, adjusted to pH = 7 with 3M hydrochloric acid, 30 mL of ethyl acetate was added, and the organic layer was separated and washed with 30 mL of water and 30 mL of saturated saline in sequence. Drying and concentration gave the product, 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 (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)-tert-butyl carboxylate (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 system was cooled to 0 ° C. and acrylic acid chloride (10.5 mg, 0.083 mmol) was added dropwise to the reaction solution. The mixture was stirred at 0 ° C. for 15 minutes. 20 mL of dichloromethane was added to the reaction solution and 20 mL of saturated NaHCO 3 The solution was washed with 20 mL of saturated aqueous sodium chloride. After drying and concentration, it was purified by preparative HPLC to obtain the product (4aR)-3-acryloyl-11-fluoro-8-(2-isopropyl-4-methylpyridin-3-yl)-10-(5-methyl-1H-indazol-4-yl)-1,2,3,4,4a,5-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-d 6 )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: (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 (310 mg, 0.48 mmol), 10 mL of acetone, anhydrous potassium carbonate (265 mg, 1.92 mmol), and iodoethane (599 mg, 3.84 mmol) were added in order to a 15 mL tube, the tube was sealed, and the mixture was stirred at 55 ° C for 18 hours. After concentrating the reaction solution, 60 mL of ethyl acetate was added, and the mixture was washed with 30 mL of water and 30 mL of saturated saline in order. After drying and concentration, the crude product was purified by high-performance silica gel column (EtOAc / PE: 0-70%) to obtain the 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 (290 mg, Y: 89.7%) as an orange solid. 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 tert-butyl (290 mg, 0.43 mmol) was dissolved in dichloromethane (4 mL) and trifluoroacetate was added. Acetic acid (1 mL) was added and stirred at room temperature for 2 hours. The reaction mixture was concentrated to give the product (4aR)-6-ethyl-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-2,3,4,4a,6,8-hexahydro-1H-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 system was cooled to 0 ° C., acrylic acid chloride (130 mg, 1.44 mmol) was added to the reaction solution, and the mixture was stirred at 0 ° C. for 15 minutes. 45 mL of dichloromethane was added to the reaction solution, 25 mL of water, 25 mL of saturated NaHCO 3The mixture was washed with 25 mL of aqueous solution and 25 mL of saturated saline solution in sequence. After drying and concentration, the crude product was purified with 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 system was cooled to 0 ° C, and a 17% dichloromethane solution of boron tribromide (5 mL) was added dropwise to it. The reaction solution was stirred at room temperature for 3 hours. The reaction solution was dissolved in 60 mL of saturated NaHCO 3 The organic layer was poured into a 50 mL aqueous solution of dichloromethane and extracted twice with 50 mL of dichloromethane. 3 The mixture was washed with 30 mL of aqueous solution and 30 mL of saturated aqueous solution of sodium chloride in sequence. The mixture was dried and concentrated to obtain a pale yellow solid 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%). ES-API: [M+H] + =615.3. Step 5: Compound Z30 (240mg, 0.39mmol) was purified by preparative HPLC, and then separated by preparative chiral HPLC (column: IB: 10μm, 30*250mm, mobile phase: hexane:EtOH=70:30, flow rate: 25ml / min, column temperature: room temperature) to obtain one atropisomer compound, which was a light yellow solid, and its structure was designated as Z30-1 (71mg, peak: 1, retention time: 6.342min, Y: 29.6%). 1 H NMR (500 MHz, DMSO-d 6 )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(m, 1H), 2.50-2.39(m, 1H), 1.97(s, 3H), 1.10-0.95(m, 6H), 0.86(d, J=6.7Hz, 3H).ES-API:[M+H] + = 615.2. And another atropisomer compound was obtained, which 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 (500 MHz, DMSO-d 6)δ10.13(s, 1H), 8.45(d, J=4.9Hz, 1H), 8.39(d, J=8.8Hz, 1H), 7.31-7.19(m, 2H), 7.12- 6.80(m, 1H), 6.77-6.62(m, 2H), 6.15(dd, J=16.8, 2.1Hz, 1H), 5.75(d, J=12.3Hz, 1H), 4 .73(d, J=14.1Hz, 1H), 4.46(d, J=13.0Hz, 1H), 4.20-4.02(m, 2H), 4.00-3.91(m, 1H), 3. 65-3.53(m, 2H), 3.26-3.06(m, 1H), 2.82-2.58(m, 2H), 1.80(s, 3H), 1.15-0.93(m, 9H). 1 ES-API:[M+H] + = 615.2. The 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. for 18 hours under nitrogen atmosphere. After concentrating the reaction, 50 mL of water was added, the pH was adjusted to 3.0 with 3.0 M dilute hydrochloric acid, and extracted twice with 50 mL of dichloromethane. The organic layer was dried and concentrated to give the product 6-cyclopropyl-7-(2-fluoro-6-methoxyphenyl)-4-hydroxy-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro-1,8-naphthyridin-2(1H)-one (850 mg, crude) as a maroon solid. 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), phosphorus oxychloride (2.43 g, 15.85 mmol) and N,N-diisopropylethylamine (3.27 g, 25.36 mmol) were added in that order, and the mixture was stirred at 85° C. for 1 hour. After concentrating the reaction solution, 120 mL of ethyl acetate was added, and the mixture was washed twice with 60 mL of water and 60 mL of saturated sodium bicarbonate, and then washed with 60 mL of saturated saline. After the organic layer was dried and concentrated, the crude product was purified by a high-performance silica gel column (EtOAc / PE: 0-35%) to obtain the product 4-chloro-6-cyclopropyl-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro-1,8-naphthyridin-2(1H)-one (520 mg, Y: 24.8%) 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), (3R,6R)-1-N-BOC-6-methylpiperazine-3-carboxylate methyl (485 mg, 1.88 mmol) and N,N-diisopropylethylamine (364 mg, 2.82 mmol) were added in sequence, and the mixture was stirred at 125 ° C for 3 hours. 100 mL of ethyl acetate was added to the reaction solution, and the mixture was washed with 30 mL of diluted saline four times and 30 mL of saturated saline. After drying and concentration, the crude product was purified by high-performance silica gel column (EtOAc / PE: 0-50%) to obtain the product (3R,6R)-1-N-BOC-4-(6-cyclopropyl-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro-2-oxo-1,2-dihydro-1,8-naphthyridin-4-yl)-6-methylpiperazine-3-carboxylate methyl (485 mg, Y: 69.4%) as an orange solid. 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-methylcarboxylate (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 solution, 80 mL of ethyl acetate and 50 mL of saturated sodium bicarbonate were added in that order, and the suspension was filtered through diatomaceous earth, and the filter cake was washed with ethyl acetate. The organic layer was separated, washed with 25 mL of saturated sodium bicarbonate and 25 mL of saturated saline, dried and concentrated to obtain the product (2R,4aR)-11-cyclopropyl-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-2-methyl-5,7-dioxo-1,2,4,4a,5,6,7,8-octyl-3H-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8]naphthyridine-3-carboxylate tert-butyl (415 mg, Y:99.5%) as a pale yellow solid. ES-API: [M+H]+=683.3. Step 5: (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 tert-butyl (415 mg, 0.61 mmol), 12 mL of acetone, anhydrous potassium carbonate (337 mg, 2.44 mmol), and iodomethane (693 mg, 4.88 mmol) were added in sequence to a 50 mL tube. The tube was sealed and stirred at 50 °C for 18 hours. 60 mL of ethyl acetate was added to the reaction solution, which was then washed with 15 mL of water and 15 mL of saturated saline. 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 (160 mg, Y: 37.8%) as a light yellow solid. ES-API: [M+H] + =697.3. Step 6: (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 (160 mg, 0.23 mmol) was dissolved in dichloromethane (3.5 mL) and trifluoroacetic acid (0.8 mL) was added and stirred at room temperature for 2 hours. The reaction mixture was concentrated to obtain the product ((2R,4aR)-11-cyclopropyl-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-2,6-dimethyl-1,2,4,4a,6,8-hexahydro-312-pyrazine[4',3':4,5]pyrazine[2,3-c][1,8]naphthyridine-5,7-dione (165 mg, crude product), which was used directly in the next reaction. ES-API: [M+H] + =597.2. 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 was cooled to 0 ° C. and acrylic acid chloride (41 mg, 0.46 mmol) was added dropwise to the reaction solution. The mixture was stirred at 0 ° C. for 15 minutes. 30 mL of dichloromethane was added to the reaction solution, 15 mL of water, 15 mL of saturated NaHCO 3The mixture was washed with 15 mL of aqueous solution and 15 mL of saturated saline solution in sequence. After drying and concentration, the crude product was purified with a high-performance silica gel column (dichloromethane / methanol: 0-5%) to obtain the product (2R,4aR)-3-acryloyl-11-cyclopropyl-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-2,6-dimethyl-2,3,4,4a,6,8-hexahydro-1H-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8]naphthyridine-5,7-dione (140 mg, Y: 93.7%) as a light yellow solid. ES-API: [M+H] + =651.3. 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 system was cooled to 0 ° C, and a 17% dichloromethane solution of boron tribromide (3 mL) was added dropwise to it. The reaction solution was stirred at room temperature for 3 hours. The reaction solution was dissolved in 40 mL of saturated NaHCO 3 The mixture was poured into an aqueous solution 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 (500 MHz, DMSO-d 6)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, 1 0.5Hz, 1H), 6.74-6.60(m, 2H), 6.22-6.08(m, 1H), 5.81-5.69(m, 1H), 5.05-4.81(m, 1H), 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), 2.83-2.67(m, 1 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), and 2M NaHMDS (8.48 mL, 16.96 mmol) was added under ice-water bath conditions, and the mixture was stirred for 20 minutes under ice-water bath conditions. 2,5-Difluoro-6-(2-fluoro-6-methoxyphenyl)nicotinic acid (1.2 g, 4.24 mmol) was added, and the mixture was stirred at room temperature for 3 hours. The reaction solution was 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 saline. After drying over anhydrous sodium sulfate, filtration, and drying and concentrating the organic layer, the crude product was purified by high-performance silica gel column (EtOAc / PE: 20-40%) to obtain the product 2-((4,6-dicyclopropylpyrimidin-5-yl)amino)-5-fluoro-6-(2-fluoro-6-methoxyphenyl)nicotinic acid (1.8 g, Y: 98%) as a yellow solid. 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, thionyl chloride (4.07 g, 34.2 mmol) was added, and the mixture was stirred at 80° C. for 2 hours. After the reaction was completed, the reaction solution was cooled to room temperature. After concentration, the mixture was dried at 50° C. under vacuum reduced pressure for 4 hours to obtain a pale yellow solid product, 2-((4,6-dicyclopropylpyrimidin-5-yl)amino)-5-fluoro-6-(2-fluoro-6-methoxyphenyl)nicotinic acid chloride (1.57 g, crude product). Methanol detection ES-API: [M+H] + =453.2. Step 3: Under ice-water bath conditions, sodium hydride (1.97 g, 49.35 mmol) was added to ethyl nitroacetate (1.31 g, 9.86 mmol) in tetrahydrofuran 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 mixture was heated to 80° C. and reacted 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 in sequence, and the mixture was stirred for 3 hours while gradually increasing the temperature to 80 ° C. After concentrating the reaction solution, 30 mL of cold acetonitrile was added, and the mixture was dropped into 30 mL of saturated sodium bicarbonate solution in an ice-water bath, extracted with ethyl acetate (50 mL * 2), and the organic layer was combined and washed with 30 mL of saturated saline. After drying over anhydrous sodium sulfate, filtration, and drying and concentrating the organic layer, the crude product was purified by high-performance silica gel column (EtOAc / PE: 0-80%) to obtain a yellow solid of 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-dicarboxylate (54 mg, 0.22 mmol) was added in sequence and stirred at 120 °C for 2 hours. After the reaction was completed, acetic acid was added. 30 mL of ethyl acetate was added, and the mixture was washed with 30 mL of saturated saline three times. The ethyl acetate layer was dried and concentrated to obtain the crude product, which was 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 solution, 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 with 30 mL of saturated sodium bicarbonate and 30 mL of saturated saline in that order. The mixture was dried and concentrated to give the product (4aR)-8-(4,6-dicyclopropylpyrimidin-5-yl)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-5,7-dioxo-4,4a,5,6,7,8-hexahydro-1H-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8]naphthyridine-3(2H)-carboxylate tert-butyl (40 mg, crude product) as a yellow solid. 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)-tert-butyl carboxylate (40 mg, 0.059 mmol), 30 mL of acetone, anhydrous potassium carbonate (33 mg, 0.24 mmol), iodomethane (85 mg, 0.59 mmol) were taken in a tube, sealed and stirred at 50 °C for 18 h. 20 mL of ethyl acetate was added to the reaction solution, washed with 20 mL of saturated saline, dried, and concentrated, and the crude product was purified using a high-performance silica gel column (EtOAc / PE: 0-80%) to obtain the product, yellow solid (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 mixture was stirred at room temperature for 2 hours, and the reaction mixture was concentrated to give the product (4aR)-8-(4,6-dicyclopropylpyrimidin-5-yl)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-6-methyl-2,3,4,4a-tetrahydro-1H-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 system was cooled to 0 ° C., and acrylic acid chloride (12.4 mg, 0.137 mmol) was added dropwise to the reaction solution. Stirred at 0 ° C. for 15 minutes. 20 mL of dichloromethane was added to the reaction solution, and 20 mL of saturated NaHCO 3 The solution was washed with 20 mL of saturated aqueous sodium chloride solution. After drying and concentration, the crude product was purified by preparative HPLC to obtain the product (4aR)-3-acryloyl-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(4,6-dicyclopropylpyrimidin-5-yl)-6-methyl-2,3,4,4a,6,8-hexahydro-1H-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 solution 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 obtain the product, 7-chloro-6-fluoro-4-hydroxy-1-(1-isopropyl-4-methyl-1H-pyrazol-5-yl)-1,8-naphthyridin-2(1H)-one (3.36 g, Y: 92%), as a light brown solid. 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), sodium nitrite (69 mg, 1.0 mmol) and concentrated nitric acid (2.0 mL, 30 mmol) were added in sequence, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was slowly poured into 21 mL of ice water, the precipitated solid was filtered, and the filter cake was washed with 10 ml of ice water. After drying in 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: 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 were added to a 100 mL three-neck flask. The mixture was stirred at 100 °C for 3 hours under nitrogen atmosphere. After the reaction was completed, the reaction solution was cooled to room temperature and 20 mL of water and 50 mL of methyl-tert-butyl ether were added and extracted once. The aqueous layer was adjusted to pH 3-5 with 1M hydrochloric acid solution, extracted with ethyl acetate (50mL*2), the ethyl acetate layers were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was dried under vacuum to obtain the product 6-fluoro-7-(2-fluoro-6-methoxyphenyl)-4-hydroxy-1-(1-isopropyl-4-methyl-1H-pyrazol-5-yl)-3-nitro-1,8-naphthyridin-2(1H)-one (1.5g, crude product) as a light 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 (1.5g, 3.18 mmol) was dissolved in acetonitrile (15mL), phosphorus oxychloride (2.4ml, 25.5mmol) and N,N-diisopropylethylamine (2.6ml, 15.9mmol) were added in sequence, and the mixture was stirred for 30 minutes while gradually increasing the temperature to 80°C. After concentrating the reaction solution, 10mL of cold acetonitrile was added, and the mixture was dropped into 20mL of saturated sodium bicarbonate solution in an ice-water bath, and extracted with ethyl acetate (20mL*2). The ethyl acetate layers were combined and washed once with 20mL of saturated saline. After drying over anhydrous sodium sulfate, filtration, and drying and concentrating the organic layer, the crude product was purified by high-performance silica gel column (EtOAc / PE: 0-50%) to obtain a yellow solid of 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), (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 in order, and the mixture was stirred at 120 ° C. for 2 hours. 20 mL of ethyl acetate was added to the reaction solution, and the mixture was washed with 20 mL of saturated saline three times. 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 solution, 30 mL of ethyl acetate and 30 mL of saturated sodium bicarbonate were added in turn, the suspension was filtered through diatomaceous earth, and the filter cake was washed with ethyl acetate. The organic layer was separated and washed with 30 mL of saturated sodium bicarbonate and 30 mL of saturated saline in turn. Concentration to dryness gave the product (2R,4aR)-tert-butyl 11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(1-isopropyl-4-methyl-1H-pyrazol-5-yl)-2-methyl-5,7-dioxo-4,4a,5,6,7,8-hexahydro-1H-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8]naphthyridine-3(2H)-carboxylate tert-butyl (300 mg, crude product) as a yellow solid. 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 tert-butyl (300 mg, 0.462 mmol), 6 mL of acetone, anhydrous potassium carbonate (255 mg, 1.84 mmol), iodomethane (656 mg, 4.62 mmol) were taken, sealed in a tube, and stirred at 50 ° C. for 18 hours. 20 mL of ethyl acetate was added to the reaction solution, and it was washed with 20 mL of saturated saline. After drying and concentration, the crude product was purified by high-performance silica gel column (EtOAc / PE: 0-80%) to obtain the product (2R,4aR)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(1-isopropyl-4-methyl-1H-pyrazol-5-yl)-2,6-dimethyl-5,7-dioxo-4,4a,5,6,7,8-hexahydro-1H-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8]naphthyridine-3(2H)-carboxylate tert-butyl (350 mg, Y: 95%) as a yellow solid. 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 (350 mg) was dissolved in dichloromethane (4 mL) and trifluoroacetic acid (2 mL) was added. The mixture was stirred at room temperature for 2 hours, and the reaction mixture was concentrated to obtain the product (2R,4aR)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(1-isopropyl-4-methyl-1H-pyrazol-5-yl)-2,6-dimethyl-2,3,4,4a-tetrahydro-1H-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 system was cooled to 0 ° C., and acrylic acid chloride (112.5 mg, 1.24 mmol) was added dropwise to the reaction solution. Stirred at 0 ° C. for 15 minutes. 20 mL of dichloromethane was added to the reaction solution, and 20 mL of saturated NaHCO 3The aqueous solution was washed with 20 mL of saturated saline. After drying and concentration, the crude product was purified by preparative chromatography to obtain the product (2R,4aR)-3-acryloyl-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(1-isopropyl-4-methyl-1H-pyrazol-5-yl)-2,6-dimethyl-2,3,4,4a-tetrahydro-1H-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: Under ice-water bath conditions, (2R,4aR)-3-acryloyl-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(1-isopropyl-4-methyl-1H-pyrazol-5-yl)-2,6-dimethyl-2,3,4,4a-tetrahydro-1H-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8]naphthyridine-5,7(6H,8H)-dione (250mg, 0.405mmol) was added to dry dichloromethane (6.0mL), boron tribromide (4.0mL, 4.0mmol) was further added, the temperature was raised to room temperature, and the reaction was carried out for 1 hour. Under ice-water bath conditions, the above reaction solution was dropped into a saturated sodium bicarbonate saturated solution and extracted twice with dichloromethane (30mL). Drying and concentration gave 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%). 1 H NMR (500 MHz, DMSO-d 6)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, 4.2Hz, 1H), 3.35(d, J=5.8Hz, 3H), 2.86(dd, J=48.2, 12.0Hz, 1H), 1.76-1.59(m, 3H), 1.55(dd, J=16.6, 6.7Hz, 3H), 1.26(dd, J=32.6, 6.6Hz, 3H), 1.21-1.10(m, 3H). Another atropisomeric compound was also obtained, whose structure was assigned as Z33-2 (peak: 2, 15mg, retention time: 9.663min, Y: 25%). 1 H NMR (500 MHz, DMSO-d 6 )δ10.17(s1H), 7.96(m, 1H), 7.40(d, J=5.5Hz, 1H), 7.29(q, J=7.9Hz, 1H), 7.02(m, 1H), 6.81-6 .68(m, 2H), 6.20-6.11(m, 1H), 5.81-5.69(m, 1H), 4.77(s, 1H), 4.61(d, J=14.7Hz, 1H), 4.01-3 .83 (m, 2H), 3.73 (dd, J=14.2, 4.2Hz, 1H), 3.35 (d, J=5.8Hz, 3H), 2.86 (m, 1H), 1.76-1.59 (m, 3H), 1.55 (m, 3H), 1.30 (dd, J=32.6, 6.6Hz, 3H), 1.23-1.15 (m, 3H). Isomeric compounds were detected by analytical HPLC method.

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

[0450] [ka]

[0451] Step 1: In 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 tert-butyl (115 mg, 0.17 mmol), 4 mL of acetone, anhydrous potassium carbonate (94 mg, 0.68 mmol), and deuterated iodomethane (246 mg, 1.70 mmol) were added in sequence, the tube was sealed, and the mixture was stirred at 50 °C for 18 h. 30 mL of ethyl acetate was added to the reaction solution, which was then washed with 12 mL of water and 15 mL of saturated saline, dried and concentrated to obtain the product (2R,4aR)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-2-methyl-6-(methyl-d3)-5,7-dioxo-1,2,4,4a,5,6,7,8-octyl-3H-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8]naphthyridine-3-carboxylate tert-butyl (118 mg, Y: 100.0%) as a yellow solid. 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 tert-butyl (118 mg, 0.17 mmol) was dissolved in dichloromethane (3 mL) and trifluoroacetate was added. Acetic acid (0.7 mL) was added, the mixture was stirred at room temperature for 2 hours, and the reaction mixture was con...

Claims

1. A compound represented by formula (I) or a pharma- ceutically acceptable salt, stereoisomer, or solvate 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 a 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, -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, -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 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 2】 The dashed line in represents a single bond, and P represents 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)-, 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 3-6 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 3-6 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 R ｊ , R ｋ are each independently hydrogen or C １－３ alkyl, or ｊ , R ｋ form an optionally substituted 3-6 membered nitrogen-containing heterocycloalkyl together with the nitrogen atom to which it is connected, the 3-6 membered heterocycloalkyl having 1, 2 or 3 heteroatoms selected from N, O and S as ring-forming atoms, the 3-6 membered nitrogen-containing heterocycloalkyl having 3-6 ring-forming atoms, one of which is a nitrogen atom, and 0, 1 or 2 of the other ring-forming atoms may be heteroatoms selected from N, O and S, the "substitution" refers to 1, 2, 3 or 4 hydrogen atoms in the group being independently substituted with a substituent selected from the S group, Or, Y １ If N, then X １ story, The S group substituents are 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 O.H., N.R. ａ０ C(O)-Halogenated C １－６ alkyl, wherein the 3- to 6-membered heterocycloalkyl or the 5- or 6-membered monocyclic heteroaryl has, as ring-forming atoms, 1, 2 or 3 heteroatoms each independently selected from N, O and S, and the 3- to 6-membered heterocycloalkyl, the 5- or 6-membered monocyclic heteroaryl is 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 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, 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 3】 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 atom of the B1 ring is p R ｓ１ p is 0, 1, 2 or 3; each R ｓ１ may be the same or different, (R ｓ２ ) ｑ The hydrogen atom of ring B2 is q R ｓ２ q is 0, 1, 2 or 3; each R ｓ２ may be the same or different, R ｓ１ , R ｓ２ each independently represents a halogen atom, a cyano atom, a nitro atom, a hydroxyl group, or -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 N.R. 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, 3-6 membered heterocycloalkyl, C ６－１０ Aryl, 5- or 6-membered monocyclic heteroaryl, 8- to 10-membered bicyclic heteroaryl, 7- to 11-membered spirocycloalkyl, -C １－３ Alkyl-C ６－１０ Aryl, -C １－３ alkyl-5 or 6 membered monocyclic heteroaryl, -NR ｇ -C ６－１０ Aryl, —O—C ６－１０ Aryl, -C １－３ alkyl-3 to 6 membered heterocycloalkyl, -C １－３ Alkyl-C ３－６ Cycloalkyl, wherein the 3- to 6-membered heterocycloalkyl, the 5- or 6-membered monocyclic heteroaryl, or the 8- to 10-membered bicyclic heteroaryl has 1, 2, or 3 heteroatoms selected from N, O, and S as ring-forming atoms, and the C １－６ Alkyl, C ３－６ Cycloalkyl, 3-6 membered heptane Cycloalkyl, 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 selected from R ｓ３ and wherein the -C １－３ Alkyl- is unsubstituted or has 1, 2, 3 or 4 independently C １－３ alkyl; or R ０ is a structure represented by formula (A-1) or formula (A-2), 【Chemistry 4】 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 atom of the A1 ring is R ｓ３ t is 0, 1, 2, or 3; ｓ３ may be the same or different, (R ｓ４ ) ｓ The hydrogen atom of the A2 ring is s R ｓ４ s is 0, 1, 2, or 3; ｓ４ may be the same or different, R ｓ３ , R ｓ４ each independently represents a halogen atom, a cyano atom, a hydroxyl group, or -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 , -SO ２ C １－３ Alkyl, -SO ２ Halide C １－３ Alkyl, -SO ２ N.R. ｅ R ｆ , -C １－３ Alkyl-hydroxy, -C １－３ Alkyl-C ２－４ Alkynyl, -C １－３ Alkyl-cyano, -C １－３ Alkyl-C １－６ Alkoxy, -C １－３ Alkyl-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, said 3-6 membered heterocycloalkyl having 1, 2 or 3 heteroatoms selected from N, O and S as ring-forming atoms, and said C １－６ Alkyl, -C １－６ Alkoxy, -C １－３ Alkyl-, -C ３－６ Cycloalkyl, 3- to 6-membered heterocycloalkyl are 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 an alkyl group. The compounds represented by formula (I) do not include any of the following compounds: 【Chemistry 5】

2. A compound represented by formula (II) or a pharma- ceutically acceptable salt, stereoisomer, or solvate thereof. 【Chemistry 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, -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, -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 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, -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 C, which may be substituted together with its adjacent carbon atom ３－６ A cycloalkyl or an optionally substituted 3- to 6-membered heterocycloalkyl is formed, the 3- to 6-membered heterocycloalkyl having 1, 2 or 3 heteroatoms selected from N, O and S as ring-forming atoms, and the "substitution" 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, R Ｌ１ and R Ｌ２ In or R Ｌ３ and R Ｌ４ When 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 3-6 membered heterocycloalkyl, -SO ２ - optionally substituted C １－６ Alkyl, -SO ２ - optionally substituted C ３－６ Cycloalkyl, -SO ２ -Optionally substituted 3-6 membered heterocycloalkyl; -Optionally substituted 5 or 6-membered monocyclic heteroaryl group or NR ５１ R ５２ and R ５１ , R ５２ Each independently represents hydrogen or 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 forms an optionally substituted 3-6 membered nitrogen-containing heterocycloalkyl together with the nitrogen atom connected thereto, the 3-6 membered heterocycloalkyl and the 5- or 6-membered monocyclic heteroaryl each having 1, 2 or 3 heteroatoms independently selected from N, O and S as ring-forming atoms, the 3-6 membered nitrogen-containing heterocycloalkyl has 3-6 ring-forming atoms, one of which is a nitrogen atom, and 0, 1 or 2 of the other ring-forming atoms may be a heteroatom optionally selected from N, O and S, and the "substitution" refers to 1, 2, 3 or 4 hydrogen atoms in the group being independently substituted with a substituent selected from the S group, The S group substituents are 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 O.H., N.R. ａ０ C(O)-Halogenated C １－６ alkyl, wherein the 3- to 6-membered heterocycloalkyl or the 5- or 6-membered monocyclic heteroaryl each have, as ring-forming atoms, 1, 2 or 3 heteroatoms independently selected from N, O and S, and the 3- to 6-membered heterocycloalkyl and the 5- or 6-membered monocyclic heteroaryl each have, as ring-forming atoms, 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 aryl, 5- or 6-membered monocyclic heteroaryl or 8- to 10-membered bicyclic heteroaryl group, the 5- or 6-membered monocyclic heteroaryl group having 1, 2 or 3 heteroatoms selected from N, O and S as ring-forming atoms, the 8- to 10-membered bicyclic heteroaryl group having 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 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 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 atom of the B1 ring is p R ｓ１ p is 0, 1, 2 or 3; each R ｓ１ may be the same or different, (R ｓ２ ) ｑ The hydrogen atom of ring B2 is q R ｓ２ q is 0, 1, 2 or 3; each R ｓ２ may be the same or different, R ｓ１ , R ｓ２ each independently represents a halogen atom, a cyano atom, a nitro atom, a hydroxyl group, or -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 N.R. 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 an alkyl group.

3. A compound represented by formula (IA) or a tautomer, cis-trans isomer, mesomers, racemates, enantiomers, diastereomers, atropisomers or mixtures thereof, or a pharma- ceutically acceptable salt or solvate thereof. 【Chemistry 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 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, -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, -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, halo, Rogen, -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】 The dashed line in represents a single bond, and P′ represents 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 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 (C １－６ Alkoxy)- or -C １－３ Alkyl (halogenated C １－６ 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 3-6 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 R ｊ , R ｋ are each independently hydrogen or C １－３ an alkyl group, or ｊ , R ｋ is formed, which may be substituted together with the nitrogen atom to which it is attached, and the 3-6 membered heterocycloalkyl has 1, 2 or 3 heteroatoms selected from N, O and S as ring-forming atoms, the 3-6 membered nitrogen-containing heterocycloalkyl has 3-6 ring-forming atoms, one of which is a nitrogen atom, and 0, 1 or 2 of the other ring-forming atoms may be heteroatoms selected from N, O and S, and the "substitution" is , wherein 1, 2, 3 or 4 hydrogen atoms in the group are each independently replaced with a substituent selected from the S group; Or, Y １ If N, then X １ story, The S group substituents are 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 O.H., N.R. 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, the 5- or 6-membered monocyclic heteroaryl is 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, —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 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 10】 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 atom of the B1 ring is p R ｓ１ p is 0, 1, 2 or 3; each R ｓ１ may be the same or different, (R ｓ２ ) ｑ The hydrogen atom of ring B2 is q R ｓ２ q is 0, 1, 2 or 3; each R ｓ２ may be the same or different, R ｓ１ , R ｓ２ each independently represents a halogen atom, a cyano atom, a nitro atom, a hydroxyl group, or -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 N.R. 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, 3-6 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, 3-6 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 selected from 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 11】 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, and (R ｓ３ ) ｔ The hydrogen atom of the A1 ring is R ｓ３ t is 0, 1, 2, or 3; ｓ３ may be the same or different, (R ｓ４ ) ｓ The hydrogen atom of the A2 ring is s R ｓ４ s is 0, 1, 2, or 3; ｓ４ may be the same or different, R ｓ３ , R ｓ４ each independently represents a halogen atom, a cyano atom, a hydroxyl group, or -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 , -SO ２ C １－３ Alkyl, -SO ２ Halide C １－３ Alkyl, -SO ２ N.R. ｅ R ｆ , -C １－３ Alkyl-hydroxy, -C １－３ Alkyl-C ２－４ Alkynyl, -C １－３ Alkyl-cyano, -C １－３ Alkyl-C １－６ Alkoxy, -C １－３ Alkyl-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, said 3-6 membered heterocycloalkyl having 1, 2 or 3 heteroatoms selected from N, O and S as ring-forming atoms, and said C １－６ Alkyl, -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 an alkyl group. Compounds of formula (IA) do not include any of the following compounds: 【Chemistry 12】 【Chemistry 13】 【Chemistry 14】 【Chemistry 15】 【Chemistry 16】 【Chemistry 17】 【Chemistry 18】 【Chemistry 19】 【Chemistry 20】 【Chemistry 21】 【Chemical 22】 【Chemistry 23】 【Chemistry 24】 【Chemistry 25】 【Chemistry 26】 【Chemical 27】 【Chemistry 28】 【Chemical 29】 【Chemistry 30】 【Chemistry 31】 【Chemistry 32】 【Chemical Formula 33】 【Chemical 34】 【Chemistry 35】 【Chemical Formula 36】 【Chemical 37】 【Chemical 38】 【Chemical 39】 【Chemistry 40】 【Chemistry 41】 【Chemistry 42】 【Chemistry 43】 【Chemistry 44】 【Chemistry 45】 【Chemistry 46】

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 tautomer, cis-trans isomer, mesomeric isomer, racemic isomer, enantiomer, diastereomer, atropisomer, or mixture thereof, or a pharmaceutical composition thereof. Pharmaceutically acceptable salts, solvates. 【Chemistry 47】 In formula IB, 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 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 (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.)

5. The compound according to claim 4, characterized in that the compound represented by formula (IB) is a compound represented by formula (IB-1) or a compound represented by formula (IB-2), or a tautomer, cis-trans isomer, mesomers, racemates, enantiomers, diastereomers, atropisomers, or mixtures thereof, or a pharma-ceutically acceptable salt or solvate thereof. 【Chemistry 48】 (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.)

6. The compound according to claim 4, characterized in that the compound represented by formula (IB) is a compound represented by formula (IB-1a) or a compound represented by formula (IB-2a), or a tautomer, cis-trans isomer, mesomers, racemates, enantiomers, diastereomers, atropisomers, or mixtures thereof, or a pharma-ceutically acceptable salt or solvate thereof. 【Chemistry 49】 (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.)

7. The compound according to claim 6, characterized in that the compound represented by formula (IB-1a) is a compound represented by formula (IB-1aa), a compound represented by formula (IB-1ab), a compound represented by formula (IB-1ac), or a compound represented by formula (IB-1ad), or a tautomer, cis-trans isomer, mesomers, racemates, enantiomers, diastereomers, atropisomers, or mixtures thereof, or a pharma-ceutically acceptable salt or solvate thereof. 【Chemistry 50】 (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 Alkoxy, 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 Alkoxy, 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.)

8. The compound according to claim 4, characterized in that the compound represented by formula (IB) is a compound represented by formula (IB-1c) or a compound represented by formula (IB-2c), or a tautomer, cis-trans isomer, mesomers, racemates, enantiomers, diastereomers, atropisomers, or mixtures thereof, or a pharma- ceutically acceptable salt or solvate thereof. 【Chemistry 51】 (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.)

9. 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 according to claim 8, or a tautomer, cis-trans isomer, mesomers, racemates, enantiomers, diastereomers, atropisomers, or mixtures thereof, or a pharma-ceutically acceptable salt or solvate thereof. 【Chemistry 52】 (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 Alkoxy, R １ , R ２ , R ３ , R １２ , R １１ , R ３１ , R ３２ , P', R ０ ', A r', 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 Alkoxy, 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.)

10. The compound according to claim 4, characterized in that the compound represented by formula (IB) is a compound represented by formula (IB-1b) or a compound represented by formula (IB-2b), or a tautomer, cis-trans isomer, mesomers, racemates, enantiomers, diastereomers, atropisomers, or mixtures thereof, or a pharma- ceutically acceptable salt or solvate thereof. 【Chemistry 53】 (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.)

11. The compound according to claim 10, characterized in that the compound represented by formula (IB-1b) is a compound represented by formula (IB-1ba), a compound represented by formula (IB-1bb), a compound represented by formula (IB-1bc), or a compound represented by formula (IB-1bd), or a tautomer, cis-trans isomer, mesomers, racemates, enantiomers, diastereomers, atropisomers, or mixtures thereof, or a pharma-ceutically acceptable salt or solvate thereof. 【Chemical 54】 (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, 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 Alkoxy, 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.)

12. The compound according to claim 4, characterized in that the compound represented by formula (IB) is a compound represented by formula (IB-1d) or a compound represented by formula (IB-2d), or a tautomer, cis-trans isomer, mesomers, racemates, enantiomers, diastereomers, atropisomers, or mixtures thereof, or a pharma- ceutically acceptable salt or solvate thereof. 【Chemistry 55】 (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.)

13. The compound according to claim 12, 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 pharma-ceutically acceptable salt or solvate thereof. 【Chemistry 56】 (In formula (IB-1da) and formula (IB-1db), R ２１ ' is independently halogen, - C １－３ Alkyl, -halogenated C １－３ Alkyl, -C １－３ Alkyl-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, 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 Alkoxy, 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.)

14. 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 14. The compound according to claim 7, 9, 11 or 13, characterized in that it is an alkoxy, or a tautomer, cis-trans isomer, mesomers, racemates, enantiomers, diastereomers, atropisomers or mixtures thereof, or a pharma- ceutically acceptable salt or solvate thereof.

15. X １ is hydrogen, halogen, optionally substituted C １－６ Alkyl group, optionally substituted C ３－６ A cycloalkyl group or an -O-optionally substituted C １－６ The compound according to claim 3, wherein the compound is an alkyl group, and the "substitution" refers to one, two, three or four hydrogen atoms in the group being independently replaced with a substituent selected from the S group. The compound according to claim 3, wherein the compound is a tautomer, a cis-trans isomer, a mesomeric isomer, a racemic isomer, an enantiomer, a diastereomer, an atropisomer or a mixture thereof, or a pharma- ceutically acceptable salt or solvate thereof.

16. 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 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 according to claim 3, characterized in that it is an alkyl group, or a tautomer, cis-trans isomer, mesomers, racemates, enantiomers, diastereomers, atropisomers or mixtures thereof, or a pharma- ceutically acceptable salt or solvate thereof.

17. The compound according to claim 3, characterized in that Ar' is selected from the following structures: or a tautomer, cis-trans isomer, mesomers, racemates, enantiomers, diastereomers, atropisomers or mixtures thereof, or a pharma- ceutically acceptable salt or solvate thereof. 【Chemistry 57】 (In the formula, R ｓ１ , R ｓ２ is defined as in claim 3.)

18. R ０ ' is a phenyl group, a 5- or 6-membered monocyclic heteroaryl group, or a pyridone group, the 5- or 6-membered monocyclic heteroaryl group having 1, 2, or 3 heteroatoms selected from N, O, and S as ring-forming atoms, the phenyl group, the 5- or 6-membered monocyclic heteroaryl group, or the pyridone group being unsubstituted or independently selected from R ｓ３ or a tautomer, cis-trans isomer, mesomers, racemates, enantiomers, diastereomers, atropisomers or mixtures thereof, or a pharma- ceutically acceptable salt or solvate thereof, of the compound according to claim 3, characterized in that it is substituted with one, two, three or four groups selected from the group consisting of:

19. R １ , R ２ are each independently hydrogen, halogen, cyano, amino, NHCH ３ , N(CH 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 3-6 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, pyrazine; The 3- to 6-membered heterocycloalkyl, 5- or 6-membered monocyclic heteroaryl may optionally contain 1 or 2 halogens 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 pharma- ceutically acceptable salt or solvate thereof.

20. 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 pharma- ceutically acceptable salt or solvate thereof.

21. 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 pharma- ceutically acceptable salt or solvate thereof.

22. P' is O, NH or NR ｍ ' and R ｍ ' is -deuterated C １－６ Alkyl or -C １－６ alkyl, R ４２ ' is -C １－３ Alkyl-(C=O), -(C=O)- or -C １－３ 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 pharma- ceutically acceptable salt or solvate thereof.

23. A compound selected from Tables A-1 to A-21, or a tautomer, cis-trans isomer, mesomers, racemates, enantiomers, diastereomers, atropisomers, or mixtures thereof, or a pharma-ceutically acceptable salt or solvate thereof. [Table A-1] 【Table 1】 [Table A-2] 【Table 2】 [Table A-3] 【Table 3】 [Table A-4] 【Table 4】 [Table A-5] 【Table 5】 [Table A-6] 【Table 6】 [Table A-7] 【Table 7】 [Table A-8] 【Table 8】 [Table A-9] 【Table 9】 [Table A-10] 【Table 10】 [Table A-11] 【Table 11】 [Table A-12] 【Table 12】 [Table A-13] 【Table 13】 [Table A-14] 【Table 14】 [Table A-15] 【Table 15】 [Table A-16] 【Table 16】 [Table A-17] 【Table 17】 [Table A-18] 【Table 18】 [Table A-19] 【Table 19】 [Table A-20] 【Table 20】 [Table A-21] 【Table 21】

24. The compound according to claim 3, wherein the compound of formula (IA) is selected from Tables A-22 to A-24, or a tautomer, cis-trans isomer, mesomers, racemates, enantiomers, diastereomers, atropisomers, or mixtures thereof, or a pharma-ceutically acceptable salt or solvate thereof. [Table A-22] 【Table 22】 [Table A-23] 【Table 23】 [Table A-24] 【Table 24】

25. A pharmaceutical composition comprising the compound according to any one of claims 1 to 24, or a tautomer, cis-trans isomer, mesomers, racemates, enantiomers, diastereomers, atropisomers, or mixtures thereof, or a pharma- ceutically acceptable salt or solvate thereof, and a pharma- ceutically acceptable carrier.

26. The pharmaceutical composition according to claim 25 for use in the treatment and / or prevention of a KRAS G12C mutation-induced disease.

27. 26. The pharmaceutical composition according to claim 25, for use in inhibiting a KRAS G12C mutation-induced disease, wherein the KRAS mutation is a KRAS G12C mutation.

28. The pharmaceutical composition according to claim 26 or 27, wherein the KRAS G12C mutation-induced disease is cancer.

29. 29. The pharmaceutical composition of claim 28, wherein the cancer is pancreatic cancer, colorectal cancer or lung cancer.

30. 29. The pharmaceutical composition of claim 28, wherein the cancer is non-small cell lung cancer.

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