Substituted heterocyclic-cyclic compounds, methods for their preparation, and their applications in pharmaceuticals.

Abstract

To provide a substituted heterocyclic fused cyclic compound having a novel structure, which is used as a selective inhibitor for KRAS mutations and has the advantages of high activity, good selectivity, low toxicity and side effects, etc.SOLUTION: The present invention relates to a substituted heterocyclic fused cyclic compound as represented by formula (I) or formula (IA) and having a selective inhibitory effect on KRAS gene mutation, or a pharmaceutically-acceptable salt, a stereoisomer, a solvate or a prodrug thereof, a pharmaceutical composition containing the compound, and an application thereof to the preparation of cancer drugs.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to the pharmaceutical technology, and more particularly to substituted complex ring-ring compounds, their application as selective inhibitors of KRAS gene mutations, and pharmaceutical compositions prepared therefrom. [Background technology]

[0002] Lung cancer is the most common cancer worldwide, ranking first in incidence among all cancers in China, and also the cancer with the highest incidence and mortality rates in China. According to data released to the American Cancer Society in 2016, approximately 1.8 million people worldwide were diagnosed with lung cancer in 2015, with nearly 80% of those being non-small cell lung cancer (NSCLC).

[0003] RAS is a closely related series of monomeric globular proteins (21 kDa molecular weight) having 188-189 amino acids and binding to guanosine diphosphate (GDP) or guanosine triphosphate (GTP). The RAS subfamily includes HRAS, KRAS, and NRAS. RAS acts as a molecular switch; when RAS is bound to GDP, it is in a resting or off state and "inactive." When cells are exposed to a growth-inhibiting stimuli, RAS is induced to convert the GDP bound to it to GTP, and when bound to GTP, RAS is "on" and interacts with and activates other downstream target proteins. The RAS protein itself has very little intrinsic ability to hydrolyze GTP back to GDP (convert itself to the off state). Exogenous protein GTP enzyme-activated protein (GAP) is required to convert it to the off state, and the synergistic effect of GAP and RAS can significantly accelerate the conversion from GTP to GDP. Any mutation in the RAS gene affects the synergistic effect of RAS and GAP, as well as the ability to convert GTP to GDP. Such mutations lead to an extension of the protein's activation time, thereby prolonging cell signaling and allowing cells to continue proliferating and dividing. Because such signaling causes cell proliferation and division, excessive activation of the RAS signaling pathway can ultimately lead to cancer. In lung cancer, mutations in the RAS gene have been identified in approximately 32% of lung cancers, and mutations in any of the three main subtypes of the RAS (HRAS, NRAS, or KRAS) gene can cause the development of human tumors. The KRAS gene has the highest mutation frequency in the RAS gene, with KRAS mutations reported to be 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 (a mutation from glycine-12 to cysteine).This mutation has been found in approximately 13% of cancers, approximately 43% of lung cancers, and almost 100% of MYH - associated polyposis (familial adenomatous polyposis). Therefore, inhibitors that selectively inhibit KRAS mutations are expected. To improve the KRAS mutation inhibitory activity and reduce the inhibitory activity against wild - type KRAS, the development of novel RAS mutant - selective inhibitors with higher activity, higher selectivity, and lower toxicity has important significance.

Summary of the Invention

[0004] The present invention provides a substituted bicyclic - cyclic compound having a novel structure, which has advantages such as high activity as a selective inhibitor of KRAS mutations, high selectivity, and low toxicity and side effects.

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

[0006]

Chemical formula

[0007] (In formula I, Z is N - C(O)-CR3 = CR1R2 or N - C(O)-C≡CR4, R1 and R2 are each independently hydrogen, halogen, cyano, NR a R b 、-C 1-3 alkyl, 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 1-3The alkyl-5 or 6-membered monocyclic heteroaryl, wherein 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. R3 is hydrogen, halogen, -C 1-3 Alkyl or -C 1-3 It is an alkoxy, R4 is hydrogen, halogenated carbon 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 These may be the same or different, and each may independently be hydrogen, halogen, and -C. 1-3 Alkyl, C-halogenated 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 These may be the same or different, and each may independently be hydrogen, halogen, and -C. 1-3 Alkyl, C-halogenated 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 32These may be the same or different, and each may independently be hydrogen, halogen, and -C. 1-3 Alkyl, C-halogenated 1-3 Alkyl, -C 1-3 Alkyl-hydroxy, -C 1-3 Alkyl-cyano, -C 1-3 Alkyl-C 1-6 Alkoxy, -C 1-3 Alkyl-halogenated C 1-6 Alkyl or -C 1-3 Alkyl-halogenated C 1-6 It is an alkoxy, R 41 Hydrogen, halogen, -C 1-3 Alkyl, C-halogenated 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,

[0008] [ka]

[0009] If the dashed line in the diagram represents a single bond, then P is O, NH, or NR. m And R m is -C 1-6 Alkyl, C-halogenated 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 42is -(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 or

[0010]

Chemical formula

[0011] when there is no dashed line in , P is hydrogen, 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, and when Y1 is C, X1 is hydrogen, halogen, cyano, hydroxy, amino, nitro, -optionally substituted C 1-6 alkyl, -optionally substituted C 3-6 cycloalkyl, -optionally substituted 3-6 membered heterocycloalkyl, -O-optionally substituted C 1-6 alkyl, -O-optionally substituted C 3-6Cycloalkyl, 3- to 6-membered heterocycloalkyl, possibly -O-substituted, and possibly -NH-substituted C 1-6 Alkyl, -N (may be substituted C) 1-6 C may be alkyl)2,-NH-substituted. 3-6 Cycloalkyl groups, 3- to 6-membered heterocycloalkyl groups which may be -NH-substituted, and C groups which may be -NH(C=O)-substituted. 1-6 Alkyl, -NH(C=O)-C 3-6 C may be cycloalkyl or -NH(SO2)-substituted. 1-6 C may be alkyl or -NH(SO2)-substituted. 3-6 C may be cycloalkyl or -SO2-substituted. 1-6 C may be alkyl or -SO2-substituted. 3-6 Cycloalkyl, -(C=O)-NR j R k -, -(C=O)-O- may be substituted C 1-6 C may be alkyl or -(C=O)-O-substituted. 3-6 It is cycloalkyl, R j , R k Each is independently hydrogen or C 1-3 Alkyl, or R j , R k This forms a 3-6 member nitrogen-containing heterocycloalkyl group which may be substituted with the connected nitrogen atom, and the 3-6 member heterocycloalkyl group has 1, 2, or 3 heteroatoms selected from N, O, and S as ring-forming atoms, and the 3-6 member nitrogen-containing heterocycloalkyl group has 3-6 ring-forming atoms, of which one ring-forming atom is a nitrogen atom, and 0, 1, or 2 of the other ring-forming atoms may be heteroatoms arbitrarily selected from N, O, and S, and the "substitution" refers to the substitution of 1, 2, 3, or 4 hydrogen atoms in the group with substituents each independently selected from the S group. Alternatively, if Y1 is N, then X1 is none. The S group substituents are hydroxy, halogen, nitro, oxo, and -C. 1-6 Alkyl, C-halogenated 1-6C substituted with alkyl or hydroxyl 1-6 Alkyl, benzyl, -(CH2) u -Cyano, -(CH2) u -C 1-6 Alkoxy, -(CH2) u -Halogenated C 1-6 Alkoxy, -(CH2) u -Halogenated C 1-6 Alkyl, -(CH2) u -3-6 member heterocycloalkyl groups, -(CH2) u -5 or 6-membered monocyclic heteroaryl, -(CH2) u -C 3-8 Cycloalkyl, -(CH2) u -O-(CH2) v -C 3-8 Cycloalkyl, -(CH2) u -O-(CH2) v -C 1-6 Alkoxy, -(CH2) u -O-(CH2) v OH, -(CH2) u -SO2C 1-6 Alkyl, -(CH2) u -NR a0 R b0 ,-(CH2) u -C(O)NR a0 R b0 ,-(CH2) u -C(O)C 1-6 Alkyl, -C(O)OC 1-6 Alkyl, NR a0 C(O)-(CH2) u -NR a0 R b0 , NR a0 C(O)-(CH2) u OH, NR a0 C(O)-halogenated C 1-6The alkyl group is selected from alkyl groups, and the 3-6 membered heterocycloalkyl group or the 5 or 6 membered monocyclic heteroaryl group each has 1, 2, or 3 heteroatoms independently selected from N, O, and S as ring-forming atoms, and the 3-6 membered heterocycloalkyl group or the 5 or 6 membered monocyclic heteroaryl group may be substituted with 1, 2, or 3 substituents selected from halogens, cyano, -C1-3 alkyl, -C1-3 alkoxy, and C3-6 cycloalkyl groups, and u and v are independently 0, 1, 2, 3, or 4, and R a0 , R b0 Each is independently hydrogen or C 1-3 It is alkyl, E1 is N or CR5, and R5 is hydrogen, halogen, cyano, -C 1-6 Alkyl, -C 1-6 Alkoxy, -halogenated C 1-6 Alkyl, C-halogenated 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 It is an alkoxy, E2 is N or CR6, and R6 is hydrogen, halogen, cyano, -C 1-6 Alkyl, -C 1-6 Alkoxy, -halogenated C 1-6 Alkyl, C-halogenated 1-6 Alkoxy, -C 3-6 Cycloalkyl, -NR h R i , -C 1-4 Alkyl-hydroxy, -C 1-4 Alkyl-cyano, -C 1-4 Alkyl-C 1-6 Alkoxy, -C 1-4 Alkyl-halogenated C 1-6 Alkyl or -C1-4 Alkyl-halogenated C 1-6 It is an alkoxy, However, Y1, E1, and E2 are not N at the same time. Ar is C 6-10 The group is an aryl, a 5- or 6-membered monocyclic heteroaryl, or an 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 also C 6-10 The aryl group, the 5- or 6-membered monocyclic heteroaryl group, or the 8- to 10-membered bicyclic heteroaryl group may be unsubstituted or independently R s1 Substituted with 1, 2, 3, or 4 selected from: Alternatively, Ar is a structure represented by equation (B),

[0012] [ka]

[0013] In formula (B), the B1 ring is a benzene ring or a 5- or 6-membered monocyclic heteroaryl ring, and the B2 ring is a fused 5- or 6-membered monocyclic heterocycloalkyl ring or a fused 5- or 6-membered monocyclic cycloalkyl ring, wherein the 5- or 6-membered monocyclic heteroaryl ring or the fused 5- or 6-membered monocyclic heterocycloalkyl ring has 1, 2, or 3 heteroatoms selected from N, O, and S as ring-forming atoms. (R s1 ) p In this case, the B1 ring has p hydrogen atoms. s1 This indicates that it is replaced by p, where p is 0, 1, 2, or 3, and each R s1 They may be the same or they may be different. (R s2 ) q This is a B2 ring with q hydrogen atoms. s2 This indicates that it is replaced by q, where q is 0, 1, 2, or 3, and each R s2They may be the same or they may be different. R s1 , R s2 These are, independently, halogen, cyano, nitro, hydroxy, and -C. 1-6 Alkyl, -C 1-6 Alkoxy, -halogenated C 1-6 Alkyl, C-halogenated 1-6 Alkoxy, -C 3-6 Cycloalkyl, -NR c R d -C(O)NR e R f , -SO2C 1-3 Alkyl, -SO2 halogenated C 1-3 Alkyl, -SO2NR e R f , -C 1-4 Alkyl-hydroxy, -C 1-4 Alkyl-cyano, -C 1-4 Alkyl-C 1-6 Alkoxy, -C 1-4 Alkyl-halogenated C 1-6 Alkyl, -C 1-4 Alkyl-halogenated C 1-6 Alkoxy, -C 1-4 Alkyl-3 to 6-membered heterocycloalkyl, -C 1-4 Alkyl-NR e R f , -C 1-4 Alkyl-C(O)NR e R f , -C 1-4 Alkyl-SO2C 1-3 Alkyl or C 2-4 The alkynyl group is a 3-6 member heterocycloalkyl group having 1, 2, or 3 heteroatoms selected from N, O, and S as ring-forming atoms. R0 is -C 1-6 Alkyl, -C 3-6 Cycloalkyl, 3-6 member 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 Ariel, -C 1-3Alkyl-5 or 6-membered monocyclic heteroaryl, -NR g -C 6-10 Ariel, -OC 6-10 Ariel, -C 1-3 Alkyl-3 to 6-membered heterocycloalkyl, -C 1-3 Alkyl-C 3-6 The cycloalkyl group, the 3-6 membered heterocycloalkyl group, the 5 or 6 membered monocyclic heteroaryl group, or the 8-10 membered bicyclic heteroaryl group, has 1, 2, or 3 heteroatoms selected from N, O, and S as ring-forming atoms, and also has C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6 member heterocycloalkyl, C 6-10 Aryls, 5- or 6-membered monocyclic heteroaryls, 8- to 10-membered bicyclic heteroaryls, and 7- to 11-membered spirocycloalkyls are unsubstituted or independently R s3 Substituted with 1, 2, 3, or 4 groups selected from, and the -C 1-3 Alkyl- is either unsubstituted or independently C 1-3 Substituted with 1, 2, 3, or 4 groups selected from alkyl groups, Alternatively, R0 is a structure represented by equation (A-1) or equation (A-2),

[0014] [ka]

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

[0016] In one embodiment of the present invention, the compound represented by formula (I) is the compound of formula (I-1) or the compound of formula (I-2).

[0017] [ka]

[0018] (In formula (I-1), P is O, NH, or NR) m And R m is -C 1-6 Alkyl, C-halogenated 1-6 Alkyl, -C 1-6 Alkyl-hydroxy, -C 1-6 Alkyl-cyano, -C 1-6 Alkyl-C 1-6 Alkoxy, -C 1-6 Alkyl-halogenated C 1-6Alkoxy, -C 1-6 Alkyl-C 3-6 Cycloalkyl or -C 1-6 Alkyl-3 to 6-membered heterocycloalkyl, R 42 is -(C=O)-, -C 1-3 Alkyl-, -C 1-3 Alkyl(hydroxy)-, -C 1-3 Alkyl(cyano)-, -C 1-3 Alkyl (C 1-6 Alkyl)-, -C 1-3 Alkyl (halogenated C 1-6 Alkyl)-, -C 1-3 Alkyl (C 1-6 Alkyl-hydroxy)-,-C 1-3 Alkyl (C 1-6 Alkyl-cyano)-,-C 1-3 Alkyl (C 1-6 Alkoxy)-, or -C 1-3 Alkyl (halogenated C 1-6 It is alkoxy)- and R 11 , R 12 , R 21 , R 22 , R 31 , R 32 , R 41 The definitions of Z, R0, Ar, E1, E2, X1, and Y1 are the same as above. In equation (I-2), P is hydrogen, halogen, and R 42 Hydrogen, halogen, -C 1-3 Alkyl, C-halogenated 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 11 , R 12 , R 21 , R 22 , R 31 , R 32 , R 41The definitions of Z, R0, Ar, E1, E2, X1, and Y1 are the same as above.

[0019] In another aspect, the present invention provides compounds represented by formula (IA) or their tautomers, cis-trans isomers, mesomers, racemates, enantiomers, diastereomers, atrop isomers or mixtures thereof, or pharmaceutically acceptable salts, solvates or prodrugs thereof.

[0020] [ka]

[0021] (In equation (IA), Z is either NC(O)-CR3=CR1R2 or NC(O)-C≡CR4, R1 and R2 are independently hydrogen, halogen, cyanoacrylate, and 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 The alkyl-5 or 6-membered monocyclic heteroaryl, wherein 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. R3 is hydrogen, halogen, -C 1-3 Alkyl or -C 1-3 It is an alkoxy, R4 is hydrogen, halogenated carbon 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 These may be the same or different, and each may independently be hydrogen, halogen, and -C. 1-3 Alkyl, C-halogenated 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 These may be the same or different, and each may independently be hydrogen, halogen, and -C. 1-3 Alkyl, C-halogenated 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 These may be the same or different, and each may independently be hydrogen, halogen, and -C. 1-3 Alkyl, C-halogenated 1-3 Alkyl, -C 1-3 Alkyl-hydroxy, -C 1-3 Alkyl-cyano, -C 1-3 Alkyl-C 1-6 Alkoxy, -C 1-3 Alkyl-halogenated C 1-6 Alkyl or -C 1-3 Alkyl-halogenated C 1-6 It is an alkoxy, R 41 Hydrogen, halogen, -C 1-3 Alkyl, C-halogenated 1-3Alkyl, -C 1-3 Alkyl-hydroxy, -C 1-3 Alkyl-cyano, -C 1-3 Alkyl-C 1-6 Alkoxy, -C 1-3 Alkyl-halogenated C 1-6 Alkyl or -C 1-3 Alkyl-halogenated C 1-6 It is an alkoxy,

[0022] [ka]

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

[0024] JPEG0007830406000009.jpg2111

[0025] If there is no dashed line in the diagram, P' is hydrogen, halogen, and R 42 ' is hydrogen, halogen, -C 1-3 Alkyl, C-halogenated 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, If Y1 is C, then X1 may be C which is substituted with hydrogen, halogen, cyano, hydroxy, amino, nitro, or - 1-6 Alkyl, possibly substituted C 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl, or -O-substituted C 1-6 C may be alkyl or -O-substituted. 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl, possibly -O-substituted, and possibly -NH-substituted C 1-6 Alkyl, -N (may be substituted C) 1-6 C may be alkyl)2,-NH-substituted. 3-6 Cycloalkyl groups, 3- to 6-membered heterocycloalkyl groups which may be -NH-substituted, and C groups which may be -NH(C=O)-substituted. 1-6 Alkyl, -NH(C=O)-C 3-6 C may be cycloalkyl or -NH(SO2)-substituted. 1-6 C may be alkyl or -NH(SO2)-substituted. 3-6C may be cycloalkyl or -SO2-substituted. 1-6 C may be alkyl or -SO2-substituted. 3-6 Cycloalkyl, -(C=O)-NR j R k -, -(C=O)-O- may be substituted C 1-6 C may be alkyl or -(C=O)-O-substituted. 3-6 It is cycloalkyl, and the R j , R k Each is independently hydrogen or C 1-3 Alkyl, or the R j , R k The group forms a 3-6 member nitrogen-containing heterocycloalkyl group which may be substituted with the connected nitrogen atom, and the 3-6 member heterocycloalkyl group has 1, 2, or 3 heteroatoms selected from N, O, and S as ring-forming atoms, and the 3-6 member nitrogen-containing heterocycloalkyl group has 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 heteroatoms selected from N, O, and S, and the "substitution" means that 1, 2, 3, or 4 hydrogen atoms in the group are each independently substituted with a substituent selected from the S group. Alternatively, if Y1 is N, then X1 is none. The S group substituents are hydroxy, halogen, nitro, oxo, and -C. 1-6 Alkyl, C-halogenated 1-6 Alkyl, hydroxysubstituted C 1-6 Alkyl, benzyl, -(CH2) u -Cyano, -(CH2) u -C 1-6 Alkoxy, -(CH2) u -Halogenated C 1-6 Alkoxy, -(CH2) u -Halogenated C 1-6 Alkyl, -(CH2) u -3-6 member heterocycloalkyl groups, -(CH2) u -5 or 6-membered monocyclic heteroaryl, -(CH2) u -C 3-8Cycloalkyl, -(CH2) u -O-(CH2) v -C 3-8 Cycloalkyl, -(CH2) u -O-(CH2) v -C 1-6 Alkoxy, -(CH2) u -O-(CH2) v OH, -(CH2) u -SO2C 1-6 Alkyl, -(CH2) u -NR a0 R b0 ,-(CH2) u -C(O)NR a0 R b0 ,-(CH2) u -C(O)C 1-6 Alkyl, -C(O)OC 1-6 Alkyl, NR a0 C(O)-(CH2) u -NR a0 R b0 , NR a0 C(O)-(CH2) u OH, NR a0 C(O)-halogenated C 1-6 Selected from alkyl groups, the 3-6 membered heterocycloalkyl group or the 5 or 6 membered monocyclic heteroaryl group each independently has one, two or three heteroatoms selected from N, O and S as ring-forming atoms, and the 3-6 membered heterocycloalkyl group or the 5 or 6 membered monocyclic heteroaryl group may contain halogens, cyanonucleotides, or C-C 1-3 Alkyl, -C 1-3 Alkoxy and C 3-6 It may be substituted with one, two, or three substituents selected from cycloalkyl groups, where u and v are independently 0, 1, 2, 3, or 4, and R a0 , R b0 Each is independently hydrogen or C 1-3 It is alkyl, E1' is N or CR5', and R5' is hydrogen, halogen, cyano, -C 1-6 Alkyl, -C 1-6 Alkoxy, -halogenated C 1-6 Alkyl, C-halogenated1-6 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 It is an alkoxy, E2' is N or CR6', and R6' is hydrogen, halogen, cyano, -C 1-6 Alkyl, -C 1-6 Alkoxy, -halogenated C 1-6 Alkyl, C-halogenated 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 It is an alkoxy, However, Y1, E1', and E2' are not N at the same time. Ar' is C 6-10 The group is an aryl, a 5- or 6-membered monocyclic heteroaryl, an 8- to 10-membered bicyclic heteroaryl, or a pyridone group, wherein the 5- or 6-membered monocyclic heteroaryl has 1, 2, or 3 heteroatoms selected from N, O, and S as ring-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 also C 6-10The aryl group, the 5- or 6-membered monocyclic heteroaryl group, the 8- to 10-membered bicyclic heteroaryl group, and the pyridone group are either unsubstituted or substituted with 1, 2, 3, or 4 groups independently selected from Rs1. Alternatively, Ar' is a structure represented by equation (B),

[0026] [ka]

[0027] In formula (B), the B1 ring is a benzene ring or a 5- or 6-membered monocyclic heteroaryl ring, and the B2 ring is a fused 5- or 6-membered monocyclic heterocycloalkyl ring or a fused 5- or 6-membered monocyclic cycloalkyl ring, wherein the 5- or 6-membered monocyclic heteroaryl ring or the fused 5- or 6-membered monocyclic heterocycloalkyl ring has 1, 2, or 3 heteroatoms selected from N, O, and S as ring-forming atoms. (R s1 ) p In this case, the B1 ring has p hydrogen atoms. s1 This indicates that it is replaced by p, where p is 0, 1, 2, or 3, and each R s1 They may be the same or they may be different. (R s2 ) q This is a B2 ring with q hydrogen atoms. s2 This indicates that it is replaced by q, where q is 0, 1, 2, or 3, and each R s2 They may be the same or they may be different. R s1 , R s2 These are, independently, halogen, cyano, nitro, hydroxy, and -C. 1-6 Alkyl, -C 1-6 Alkoxy, -halogenated C 1-6 Alkyl, C-halogenated 1-6 Alkoxy, -C 3-6 Cycloalkyl, -NR c R d -C(O)NR e R f , -SO2C 1-3 Alkyl, -SO2 halogenated C1-3 Alkyl, -SO2NR e R f , -C 1-4 Alkyl-hydroxy, -C 1-4 Alkyl-cyano, -C 1-4 Alkyl-C 1-6 Alkoxy, -C 1-4 Alkyl-halogenated C 1-6 Alkyl, -C 1-4 Alkyl-halogenated C 1-6 Alkoxy, -C 1-4 Alkyl-3 to 6-membered heterocycloalkyl, -C 1-4 Alkyl-NR e R f , -C 1-4 Alkyl-C(O)NR e R f , -C 1-4 Alkyl-SO2C 1-3 Alkyl or C 2-4 The alkynyl is such that the 3-6 membered heterocycloalkyl group has 1, 2, or 3 heteroatoms selected from N, O, and S as ring-forming atoms. R0′ is -C 1-6 Alkyl, -C 3-6 Cycloalkyl, 3-6 member 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 Ariel, -C 1-3 Alkyl-5 or 6-membered monocyclic heteroaryl, -NR g -C 6-10 Ariel, -OC 6-10 Ariel, -C 1-3 Alkyl-3 to 6-membered heterocycloalkyl, -C 1-3 Alkyl-C 3-6 The cycloalkyl or pyridone group, wherein the 3-6 membered heterocycloalkyl, the 5 or 6 membered monocyclic heteroaryl, or the 8-10 membered bicyclic heteroaryl has 1, 2, or 3 heteroatoms selected from N, O, and S as ring-forming atoms, and also C 1-6 Alkyl, C 3-6Cycloalkyl, 3-6 member 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 either unsubstituted or substituted with 1, 2, 3, or 4 groups independently selected from Rs3, and the -C 1-3 Alkyl- is either unsubstituted or independently C 1-3 Substituted with 1, 2, 3, or 4 groups selected from alkyl groups, Alternatively, R0' is a structure represented by equation (A-1) or equation (A-2),

[0028] [ka]

[0029] In formula (A-1) or formula (A-2), the A1 ring is a benzene ring or a 5- or 6-membered monocyclic heteroaryl ring, and the A2 ring is a fused 5- or 6-membered monocyclic heterocycloalkyl ring or a fused 5- or 6-membered monocyclic cycloalkyl ring, wherein the 5- or 6-membered monocyclic heteroaryl ring or the fused 5- or 6-membered monocyclic heterocycloalkyl ring has 1, 2, or 3 heteroatoms selected from N, O, and S as ring-forming atoms. (R s3 ) t In this case, the A1 ring has t hydrogen atoms. s3 This indicates that it is replaced by t, where t is 0, 1, 2, or 3, and each R s3 They may be the same or they may be different. (R s4 ) s This is where the A2 ring has s hydrogen atoms. s 4 This indicates that it is replaced by s, where s is 0, 1, 2, or 3, and each R s4 They may be the same or they may be different. R s3 , R s4 These are, independently, halogen, cyano, hydroxy, and -C. 1-6 Alkyl, -C 1-6 Alkoxy, -halogenated C 1-6 Alkyl, C-halogenated1-6 Alkoxy, -C 3-6 Cycloalkyl, 3-6 member heterocycloalkyl, -NR h R i -C(O)NR e R f , -SO2C 1-3 Alkyl, -SO2 halogenated C 1-3 Alkyl, -SO2NR e R f , -C 1-3 Alkyl-hydroxy, -C 1-3 Alkyl-C 2-4 Alkinyl, -C 1-3 Alkyl-cyano, -C 1-3 Alkyl-C 1-6 Alkoxy, -C 1-3 Alkyl-halogenated C 1-6 Alkyl, -C 1-3 Alkyl-halogenated C 1-6 Alkoxy, -C 1-3 Alkyl-3 to 6-membered heterocycloalkyl, -C 1-3 Alkyl-C 3-6 Cycloalkyl, -C 1-3 Alkyl-NR e R f , -C 1-3 Alkyl-C(O)NR e R f , -C 1-3 Alkyl-SO2C 1-3 Alkyl or C 2-4 The alkynyl group is characterized by having 1, 2, or 3 heteroatoms selected from N, O, and S as ring-forming atoms, and the C 1-6 Alkyl alkyl group, -C 1-6 Alkoxy group, -C 1-3 Alkyl-, -C 3-6 Cycloalkyls and 3-6 membered heterocycloalkyls may be independently substituted with 1, 2, or 3 substituents selected from halogens, methyl, ethyl, propyl (n-propyl), isopropyl, trifluoromethyl, amino, N(CH3)2, hydroxy, and carboxyl. R a , R b , R e , Rf , R g Each is independently hydrogen or C 1-3 It is an alkyl group, R c , R d , R h , R i These are hydrogen and -C, respectively, independently. 1-3 Alkyl, -C(O)C 1-3 Alkyl or -CO2C 1-3 It is alkyl.

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

[0031] [ka]

[0032] (In formula (IB), P' is O, NH, or NR) m ' is R m ' is -deuterated C 1-6 Alkyl, -C 1-6 Alkyl, C-halogenated 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)-, -C1-3 Alkyl (C 1-6 Alkyl-hydroxy)-,-C 1-3 Alkyl (C 1-6 Alkyl-cyano)-,-C 1-3 Alkyl (C 1-6 Alkoxy)-, or -C 1-3 Alkyl (halogenated C 1-6 It is alkoxy)- and R 11 , R 12 , R 21 , R 22 , R 31 , R 32 , R 41 The definitions of Z, R0', Ar', E1', E2', X1, and Y1 are the same as above. (In formula (IC), P' is hydrogen or halogen, and R 42 ' is hydrogen, halogen, -C 1-3 Alkyl, C-halogenated 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 11 , R 12 , R 21 , R 22 , R 31 , R 32 , R 41 The definitions of Z, R0', Ar', E1', E2', X1, and Y1 are the same as above.

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

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

[0035] This is called one embodiment of the present invention, in formula IB, where P' is O, NH, or NR m ' and R m ' is methyl deuterated, ethyl deuterated, n-propyl deuterated, isopropyl deuterated, methyl, ethyl, n-propyl, or isopropyl, R 42 ′ is -CH2-(C=O)-, -CH2CH2-(C=O)-, -(C=O)-, -CH2-, -CH2CH2-, or -CH2CH2CH2-.

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

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

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

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

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

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

[0042] [ka]

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

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

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

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

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

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

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

[0050] In another embodiment, the present invention provides compounds represented by formula (IB-1a) or formula (IB-2a), or tautomers, cis-trans isomers, mesomers, racemates, enantiomers, diastereomers, atrop isomers or mixtures thereof, or pharmaceutically acceptable salts, solvates or prodrugs thereof.

[0051] [ka]

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

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

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

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

[0056] One embodiment of the present invention, 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 equations (IB-1aa) and (IB-1ab), R21 ' is independently halogen, -C 1-3 Alkyl, C-halogenated 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, R1, R2, R3, R 12 , R 11 , R 31 , R 32 The definitions of P', R0', Ar', E1', and X1 are the same as above. In equations (IB-1ac) and (IB-1ad), R 12 ' is independently halogen, -C 1-3 Alkyl, C-halogenated 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, R1, R2, R3, R 21 , R 22 , R 31 , R 32 The definitions of P', R0', Ar', E1', and X1 are the same as above.

[0059] In another embodiment, the present invention provides compounds represented by formula (IB-1c) or formula (IB-2c), or tautomers, cis-trans isomers, mesomers, racemates, enantiomers, diastereomers, atrop isomers or mixtures thereof, or pharmaceutically acceptable salts, solvates or prodrugs thereof.

[0060] [ka]

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

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

[0063] According to one embodiment of the present invention, in formula IB-1c, P’ is NH or NR m ’, and R m ’ is -deuterated C 1-3 alkyl or -C 1-3 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] [[ID=​​​​​​​​​​​​​​​​1-3 Alkyl, -C 1-3 Alkyl-hydroxy, -C 1-3 Alkyl-cyano, -C 1-3 Alkyl-C 1-6 Alkoxy, -C 1-3 Alkyl-halogenated C 1-6 Alkyl or -C 1-3 Alkyl-halogenated C 1-6 Is alkoxy, and the definitions of R1, R2, R3, R 12 , R 11 , R 31 , R 32 , P’, R0’, Ar’, E1’, X1 are the same as defined above. In formula (IB-1cc) and formula (IB-1cd), R 12 ’ is independently halogen, -C 1-3 Alkyl, -halogenated C 1-3 Alkyl, -C 1-3 Alkyl-hydroxy, -C 1-3 Alkyl-cyano, -C 1-3 Alkyl-C 1-6 Is alkoxy, and the definitions of R1, R2, R3, R 1-3 Alkyl-halogenated C 1-6 Alkyl or -C 1-3 Alkyl-halogenated C 1-6 Is alkoxy, and the definitions of R1, R2, R3, R 21 , R 22 , R 31 , R 32 , P’, R0’, Ar’, E1’, X1 are the same as defined above.)

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

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

[0070] This is referred to as one embodiment of the present invention, in formulas IB-1a, IB-1c, IB-2a, and IB-2c, where P' is independently NH or NR m ' and R m ' is methyl deuterated, ethyl deuterated, n-propyl deuterated, isopropyl deuterated, methyl, ethyl, n-propyl, or isopropyl.

[0071] In another embodiment, the present invention provides compounds represented by formula (IB-1b) or formula (IB-2b), or tautomers, cis-trans isomers, mesomers, racemates, enantiomers, diastereomers, atrop isomers or mixtures thereof, or pharmaceutically acceptable salts, solvates or prodrugs thereof.

[0072] [ka]

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

[0074] One embodiment of the present invention, 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 ’ 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, and the definitions of R1, R2, R3, R 12 , R 11 , R 31 , R 32 , P’, R0’, Ar’, E1’, X1 are the same as described above. In formula (IB-1bc) and formula (IB-1bd), R 12 ’ is independently halogen, -C 1-3 alkyl, -halogenated C 1-3 alkyl, -C 1-3 alkyl-hydroxy, -C 1-3 alkyl-cyano, -C 1-3 alkyl-C 1-6 alkoxy, -C 1-3 alkyl-halogenated C 1-6 alkyl or -C 1-3 alkyl-halogenated C 1-6 alkoxy, and the definitions of R1, R2, R3, R 21 , R 22 , R 31 , R 32 , P’, R0’, Ar’, E1’, X1 are the same as described above.)

[0077] In another aspect, the present invention provides a compound represented by formula (IB-1d) or formula (IB-2d), or a tautomer, cis-trans isomer, mesomer, racemate, enantiomer, diastereomer, atropisomer or a mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof.

[0078] [Chemical formula]

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

[0080] 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 equations (IB-1da) and (IB-1db), R 21 ' is independently halogen, -C 1-3 Alkyl, C-halogenated 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, R1, R2, R3, R 12 , R 11 , R 31 , R 32 The definitions of P', R0', Ar', E1', and X1 are the same as above. In equations (IB-1dc) and (IB-1dd), R 12 ' is independently halogen, -C 1-3 Alkyl, C-halogenated 1-3 Alkyl, -C1-3 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, R1, R2, R3, R 21 , R 22 , R 31 , R 32 The definitions of P', R0', Ar', E1', and X1 are the same as above.

[0083] This is called one embodiment of the present invention, in formulas IB-1b, IB-1d, IB-2b, and IB-2d, where P' is independently O.

[0084] One embodiment of the present invention is called R 21 ', R 12 ' is -C each independently 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] One embodiment of the present invention is called R 21 ', R 12 ' is -C each independently 1-3 Alkyl, -CH2-hydroxy, -CH2-cyano, or -CH2-C 1-3 It is an alkoxy.

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

[0087] In one embodiment of the present invention, X1 is hydrogen, halogen, or C which may be substituted. 1-6 Alkyl, may be substituted C 3-6Cycloalkyl or -O-substituted C 1-6 It is alkyl. The term "substitution" refers to the substitution of one, two, three, or four hydrogen atoms in the group with substituents independently selected from the S group.

[0088] In one embodiment of the present invention, X1 is hydrogen, halogen, and unsubstituted C 1-3 alkyl, unsubstituted C 3-6 Cycloalkyl or -O-unsubstituted C 1-3 It is alkyl.

[0089] This is referred to as one embodiment of the present invention, where X1 is hydrogen, fluorine, chlorine, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, n-propoxy, or isopropoxy.

[0090] This is referred to as one embodiment of the present invention, where X1 is fluorine, chlorine, or cyclopropyl.

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

[0092] This is referred to as one embodiment of the present invention, where Y1 is C, E1' is CR5', and E2' is N. The definition of R5 is the same as described above.

[0093] This is referred to as one embodiment of the present invention, where Y1 is C, E1' is N or CR5', and E2' is CH. The definition of R5' is the same as above.

[0094] This is referred to as one embodiment of the present invention, where Y1 is C, E1' is N or CF, and E2' is CH.

[0095] This is referred to as one embodiment of the present invention, where Ar' is a phenyl, a 5- or 6-membered monocyclic heteroaryl, or a pyridone group. The phenyl, 5- or 6-membered monocyclic heteroaryl, and pyridone groups may be unsubstituted or independently a halogen, cyano, hydroxy, or -C 1-6 Alkyl, -C 1-6 Alkoxy, -NR c R d , -C 1-4 Alkyl-NR e R f The R is replaced by one, two, three, or four groups selected from the above. e , R f Each is independently hydrogen or C 1-3 It is alkyl. c , R d These are hydrogen and -C, respectively, independently. 1-3 Alkyl, -C(O)C 1-3 Alkyl or -CO2C 1-3 It is alkyl.

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

[0097] This is called one embodiment of the present invention, where Ar' is phenyl. The phenyl is R s1 It is replaced by one of the groups selected from R. s1 These are halogen, cyano, -C 1-6 Alkyl, -C 1-6 Alkoxy, -halogenated C 1-6 Alkyl, C-halogenated 1-6 Alkoxy or -C 3-6 It is a cycloalkyl group.

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

[0099] [ka]

[0100] (In the formula, R s1 , R s2 The definition is the same as above.

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

[0102] [ka]

[0103] (In the formula, R s1 It is hydroxyl, and R s2 These are halogen, cyano, -C 1-6 Alkyl, -C 1-6 Alkoxy, -halogenated C 1-6 Alkyl, C-halogenated 1-6 Alkoxy or -C 3-6 It is a cycloalkyl compound. This is called one embodiment of the present invention, and the R s1 (It is located above the benzene ring plane.)

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

[0105] [ka]

[0106] (In the formula, R s1 is -C 1-6 It is an alkoxy. s2 These are halogen, cyano, -C 1-6 Alkyl, -C 1-6 Alkoxy, -halogenated C 1-6Alkyl, C-halogenated 1-6 Alkoxy or -C 3-6 It is a cycloalkyl compound. This is called one embodiment of the present invention, and the R s1 (It is located above the benzene ring plane.)

[0107] In one embodiment of the present invention, R0' 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 either unsubstituted or independently R s3 It is replaced by 1, 2, 3, or 4 selected groups.

[0108] In one embodiment of the present invention, R0' is a phenyl, thiazolyl, isothiazolyl, imidazolyl, oxazolyl, isoxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, or pyridone group. Furthermore, the phenyl, thiazolyl, isothiazolyl, imidazolyl, oxazolyl, isoxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, and pyridone groups may be unsubstituted or independently R s3 It is replaced by one, two, three, or four selected groups.

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

[0110] [ka]

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

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

[0113] [ka]

[0114] (In the formula, R s3 ' is hydrogen, halogen, cyano, hydroxy, -C 1-6 Alkyl, -C 1-6 Alkoxy, -halogenated C 1-6 Alkyl, C-halogenated 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 above-C 3-6 The cycloalkyl group may optionally be independently substituted with one, two, or three substituents selected from halogen, methyl, ethyl, propyl (n-propyl), isopropyl, trifluoromethyl, amino, N(CH3)2, hydroxy, or carboxyl. e , R f Each is independently hydrogen or C 1-3 It is alkyl. h , R i These are hydrogen and -C, respectively, independently. 1-3 Alkyl, -C(O)C 1-3 Alkyl or -CO2C 1-3 It is alkyl. s3 '' is isopropyl. n is 0. In one embodiment, the R s3 '' is located below the plane of the benzene ring.

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

[0116] [ka]

[0117] (In the formula, R s3 ' is hydrogen, halogen, cyano, hydroxy, -C 1-6 Alkyl, -C 1-6 Alkoxy, -halogenated C 1-6 Alkyl, C-halogenated 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 Furthermore, the above-C 3-6 The cycloalkyl group may optionally be independently substituted with one, two, or three substituents selected from halogen, methyl, ethyl, propyl (n-propyl), isopropyl, trifluoromethyl, amino, N(CH3)2, hydroxy, or carboxyl. e , R f Each is independently hydrogen or C 1-3 It is alkyl. h , R i These are hydrogen and -C, respectively, independently. 1-3 Alkyl, -C(O)C 1-3 Alkyl or -CO2C 1-3 It is alkyl. s3 '' is isopropyl. s3 is -C 1-6 It is alkyl. n is 0 or 1. In one embodiment, the R s3 '' is located below the pyridine ring plane.

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

[0119] [ka]

[0120] (In the formula, R s3 ' is hydrogen, halogen, cyano, hydroxy, -C 1-6 Alkyl, -C 1-6 Alkoxy, -halogenated C 1-6 Alkyl, C-halogenated 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 above-C 3-6 The cycloalkyl group may optionally be independently substituted with one, two, or three substituents selected from halogen, methyl, ethyl, propyl (n-propyl), isopropyl, trifluoromethyl, amino, N(CH3)2, hydroxy, or carboxyl. e , R f Each is independently hydrogen or C 1-3 It is alkyl. h , R i These are hydrogen and -C, respectively, independently. 1-3 Alkyl, -C(O)C 1-3 Alkyl or -CO2C 1-3 It is alkyl. s3 '' is isopropyl. n is 0. In one embodiment, the R s3 '' is located below the pyrimidine ring plane.

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

[0122] [ka]

[0123] (In the formula, R s3 ' is hydrogen, halogen, cyano, hydroxy, -C1-6 Alkyl, -C 1-6 Alkoxy, -halogenated C 1-6 Alkyl, C-halogenated 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 Furthermore, the above-C 3-6 The cycloalkyl group may optionally be independently substituted with one, two, or three substituents selected from halogen, methyl, ethyl, propyl (n-propyl), isopropyl, trifluoromethyl, amino, N(CH3)2, hydroxy, or carboxyl. e , R f Each is independently hydrogen or C 1-3 It is alkyl. h , R i These are hydrogen and -C, respectively, independently. 1-3 Alkyl, -C(O)C 1-3 Alkyl or -CO2C 1-3 It is alkyl. s3 ''' is isopropyl. n is 0. In one embodiment, the R s3 ''' is below the pyrazole ring plane.

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

[0125] [ka]

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

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

[0128] [ka]

[0129] (In the formula, R s3 ' is hydrogen, halogen, cyano, hydroxy, -C 1-6 Alkyl, -C 1-6 Alkoxy, -halogenated C 1-6 Alkyl, C-halogenated 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 It is selected from the above-C. 3-6 The cycloalkyl group may optionally be independently substituted with one, two, or three substituents selected from halogen, methyl, ethyl, propyl (n-propyl), isopropyl, trifluoromethyl, amino, N(CH3)2, hydroxy, or carboxyl. Here, R e , R f Each is independently hydrogen or C 1-3 It is alkyl. h , R i These are hydrogen and -C, respectively, independently. 1-3 Alkyl, -C(O)C 1-3 Alkyl or -CO2C 1-3 It is alkyl. s3 '' is isopropyl. s3 ''' is -C 1-6 It is an alkyl group. In one embodiment, the R s 3 '' is located below the pyrazole ring plane.

[0130] This is referred to as one embodiment of the present invention, and is selected from the structures below R0'.

[0131] [ka]

[0132] [ka]

[0133] [ka]

[0134] [ka]

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

[0136] [ka]

[0137] (In the equation, Z is either NC(O)-CR3=CR1R2 or NC(O)-C≡CR4.) R1 and R2 are independently hydrogen, halogen, cyanoacrylate, and 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 1-3It is an alkyl-5 or 6-membered monocyclic heteroaryl. The 3- to 6-membered heterocycloalkyl or the 5 or 6-membered monocyclic heteroaryl has 1, 2, or 3 heteroatoms selected from N, O, and S as ring-forming atoms. R3 is hydrogen, halogen, -C 1-3 Alkyl or -C 1-3 It is an alkoxy. R4 is hydrogen, halogenated carbon 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 These may be the same or different, and each may independently be hydrogen, halogen, and -C. 1-3 Alkyl, C-halogenated 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 These may be the same or different, and each may independently be hydrogen, halogen, and -C. 1-3 Alkyl, C-halogenated 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 32These may be the same or different, and each may independently be hydrogen, halogen, and -C. 1-3 Alkyl, C-halogenated 1-3 Alkyl, -C 1-3 Alkyl-hydroxy, -C 1-3 Alkyl-cyano, -C 1-3 Alkyl-C 1-6 Alkoxy, -C 1-3 Alkyl-halogenated C 1-6 Alkyl or -C 1-3 Alkyl-halogenated C 1-6 It is an alkoxy. R 41 is hydrogen, halogen, -C 1-3 Alkyl, C-halogenated 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 That is. R m is -C 1-6 Alkyl, C-halogenated 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 It is an alkyl-3 to 6-membered heterocycloalkyl group. R 42 is -(C=O)-, -C 1-3 Alkyl-, -C 1-3 Alkyl(hydroxy)-, -C 1-3 Alkyl(cyano)-, -C 1-3 Alkyl (C 1-6Alkyl)-, -C 1-3 Alkyl (halogenated C 1-6 Alkyl)-, -C 1-3 Alkyl (C 1-6 Alkyl-hydroxy)-,-C 1-3 Alkyl (C 1-6 Alkyl-cyano)-,-C 1-3 Alkyl (C 1-6 Alkoxy)-, or -C 1-3 Alkyl (halogenated C 1-6 It is an alkoxy. X2 and Y2 may be the same or different, and each may independently represent hydrogen, halogen, and -C. 1-3 Alkyl, C-halogenated 1-3 Alkyl, -C 1-3 Alkyl-hydroxy, -C 1-3 Alkyl-cyano, -C 1-3 Alkyl-C 1-6 Alkoxy, -C 1-3 Alkyl-halogenated C 1-6 Alkyl or -C 1-3 Alkyl-halogenated C 1-6 It is an alkoxy. Alternatively, X2 and Y2 may be substituted together with their adjacent carbon atoms. 3-6 The group forms a cycloalkyl group or a substituted 3-6 member heterocycloalkyl group. The 3-6 member heterocycloalkyl group has 1, 2, or 3 heteroatoms selected from N, O, and S as ring-forming atoms. The term "substitution" refers to the substitution of 1, 2, 3, or 4 hydrogen atoms in the group with substituents selected independently from the S group. E3 is either N or CL-R5. The aforementioned L is a single bond, -CR L1 R L2 -, -O-(CR L1 R L2 ) t1 -or-NH-(CR L3 R L4 ) t2 - is R L1 , R L2 , R L3 , R L4These may be the same or different, and each may independently be hydrogen, halogen, hydroxyl, hydroxymethyl, hydroxyethyl, and -C. 1-3 It is alkyl or oxo. t1 and t2 are independently 0, 1, 2, 3, or 4. R L1 and R L2 In or R L3 and R L4 In this case, if one of them is oxo, the other does not exist. R5 may be hydrogen, halogen, hydroxyl, or C substituted. 1-6 Alkyl, may be substituted C 3-6 Cycloalkyl, 3-6 member heterocycloalkyl, which may be substituted, and C which may be substituted. 1-6 C may be alkyl or -O-substituted. 3-6 Cycloalkyl, 3-6 member heterocycloalkyl, possibly -O-substituted, possibly -SO2-substituted C 1-6 C may be alkyl or -SO2-substituted. 3-6 Cycloalkyl, 3-6 member heterocycloalkyl, possibly -SO2-substituted, 5 or 6 member monocyclic heteroaryl, or NR 51 R 52 The above R 51 , R 52 These are, independently, hydrogen and C which may be substituted. 1-6 Alkyl, -SO2C 1-6 Alkyl, -SO2C 3-6 Cycloalkyl, -C(O)C 1-6 Alkyl or -C(O)halogenated C 1-6 Alkyl, or R 51 and R 52This forms a 3- to 6-membered nitrogen-containing heterocycloalkyl group, which may be substituted together with the connected nitrogen atom. The 3- to 6-membered heterocycloalkyl group and the 5 or 6-membered monocyclic heteroaryl group 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 group has 3 to 6 ring-forming atoms, of which one ring-forming atom 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 the substitution of 1, 2, 3, or 4 hydrogen atoms in the group with substituents independently selected from the S group. The S group substituents are hydroxy, halogen, nitro, oxo, and -C. 1-6 Alkyl, C-halogenated 1-6 Alkyl, hydroxysubstituted C 1-6 Alkyl, benzyl, -(CH2) u -Cyano, -(CH2) u -C 1-6 Alkoxy, -(CH2) u -Halogenated C 1-6 Alkoxy, -(CH2) u -Halogenated C 1-6 Alkyl, -(CH2) u -3-6 member heterocycloalkyl groups, -(CH2) u -5 or 6-membered monocyclic heteroaryl, -(CH2) u -C 3-8 Cycloalkyl, -(CH2) u -O-(CH2) v -C 3-8 Cycloalkyl, -(CH2) u -O-(CH2) v -C 1-6 Alkoxy, -(CH2) u -O-(CH2) v OH, -(CH2) u -SO2C 1-6 Alkyl, -(CH2) u -NR a0 R b0 ,-(CH2) u -C(O)NR a0 Rb0 ,-(CH2) u -C(O)C 1-6 Alkyl, -C(O)OC 1-6 Alkyl, NR a0 C(O)-(CH2) u -NR a0 R b0 , NR a0 C(O)-(CH2) u OH, and NR a0 C(O)-halogenated C 1-6 The alkyl group is selected from alkyl groups. The 3-6 membered heterocycloalkyl group or the 5 or 6 membered monocyclic heteroaryl group each has 1, 2, or 3 heteroatoms independently selected from N, O, and S as ring-forming atoms. The 3-6 membered heterocycloalkyl group or the 5 or 6 membered monocyclic heteroaryl group may be substituted with 1, 2, or 3 substituents selected from halogens, cyano groups, -C1-3 alkyl groups, -C1-3 alkoxy groups, and C3-6 cycloalkyl groups. u and v are each independently 0, 1, 2, 3, or 4. a0 , R b0 Each is independently hydrogen or C 1-3 It is alkyl. E4 is either N or CH. Ar is C 6-10 The compound is an aryl, a 5- or 6-membered monocyclic heteroaryl, or an 8- to 10-membered bicyclic heteroaryl. The 5- or 6-membered monocyclic heteroaryl has 1, 2, or 3 heteroatoms selected from N, O, and S as ring-forming atoms. The 8- to 10-membered bicyclic heteroaryl has 1, 2, 3, 4, or 5 heteroatoms selected from N, O, and S as ring-forming atoms. Also, the C 6-10 The aryl, the 5- or 6-membered monocyclic heteroaryl, or the 8- to 10-membered bicyclic heteroaryl may be unsubstituted or independently R s1 It is replaced by 1, 2, 3, or 4 selected from the set. Alternatively, Ar is a structure represented by equation (B).

[0138] [ka]

[0139] In formula (B), the B1 ring is a benzene ring or a 5- or 6-membered monocyclic heteroaryl ring. The B2 ring is a fused 5- or 6-membered monocyclic heterocycloalkyl ring or a fused 5- or 6-membered monocyclic cycloalkyl ring. Here, 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 In this case, the B1 ring has p hydrogen atoms. s1 This indicates that it is replaced by p, where p is 0, 1, 2, or 3, and each R s1 They may be the same or they may be different. (R s2 ) q This is where the B2 ring has q hydrogen atoms. s2 This indicates that it is replaced by q, where q is 0, 1, 2, or 3, and each R s2 They may be the same or they may be different. R s1 , R s2 These are, independently, halogen, cyano, nitro, hydroxy, and -C. 1-6 Alkyl, -C 1-6 Alkoxy, -halogenated C 1-6 Alkyl, C-halogenated 1-6 Alkoxy, -C 3-6 Cycloalkyl, -NR c R d -C(O)NR e R f , -SO2C 1-3 Alkyl, -SO2 halogenated C 1-3 Alkyl, -SO2NR e R f , -C 1-4 Alkyl-hydroxy, -C 1-4 Alkyl-cyano, -C 1-4 Alkyl-C 1-6 Alkoxy, -C 1-4 Alkyl-halogenated C 1-6 Alkyl, -C 1-4 Alkyl-halogenated C1-6 Alkoxy, -C 1-4 Alkyl-3 to 6-membered heterocycloalkyl, -C 1-4 Alkyl-NR e R f , -C 1-4 Alkyl-C(O)NR e R f , -C 1-4 Alkyl-SO2C 1-3 Alkyl or C 2-4 It is an alkynyl. 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 Each is independently hydrogen or C 1-3 It is an alkyl group. R c , R d These are hydrogen and -C, respectively, independently. 1-3 Alkyl, -C(O)C 1-3 Alkyl or -CO2C 1-3 It is alkyl.

[0140] One embodiment of the present invention is called R s1 , R s2 These are, independently, halogen, cyano, nitro, hydroxy, and -C. 1-3 Alkyl, -C 1-3 Alkoxy, C halogenated 1-3 Alkyl, halogenated C 1-3 Alkoxy, -C 3-6 Cycloalkyl, -NR c R d -C(O)NR e R f , -SO2C 1-3 Alkyl, -SO2 halogenated C 1-3 Alkyl, -SO2NR e R f , -C 1-2 Alkyl-hydroxy, -C 1-2 Alkyl-cyano, -C 1-2 Alkyl-C 1-3 Alkoxy, -C 1-2Alkyl-halogenated C 1-3 Alkyl, -C 1-2 Alkyl-halogenated C 1-3 Alkoxy, -C 1-2 Alkyl-3-6 member heterocycloalkyl, -C 1-2 Alkyl-NR e R f , -C 1-2 Alkyl-C(O)NR e R f , -C 1-2 Alkyl-SO2C 1-3 Alkyl or C 2-4 It is alkynyl. c , R d These are hydrogen and -C, respectively, independently. 1-3 Alkyl, -C(O)C 1-3 Alkyl or -CO2C 1-3 It is alkyl. e , R f Each is independently hydrogen or C 1-3 It is alkyl.

[0141] One embodiment of the present invention is called R s1 , R s2 These are, independently, halogen, cyano, nitro, hydroxy, and -C. 1-3 Alkyl, -C 1-3 Alkoxy, C halogenated 1-3 Alkyl, halogenated C 1-3 Alkoxy, -C 3-6 Cycloalkyl, -NR c R d -C(O)NR e R f , -SO2C 1-3 Alkyl, -SO2 halogenated C 1-3 Alkyl, -SO2NR e R f -CH2-hydroxy, -CH2-cyano, -CH2-C 1-3 Alkoxy, -CH2-halogenated C 1-3 Alkyl, -CH2-halogenated C 1-3 Alkoxy, -CH2-3~6 member heterocycloalkyl, -CH2-NR e R f-CH2-C(O)NR e R f -CH2-SO2C 1-3 Alkyl or C 2-4 It is alkynyl. c is hydrogen, -C 1-3 It is alkyl, -C(O)CH3, or -CO2CH3. e , R f , R d Each is independently hydrogen or C 1-3 It is alkyl.

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

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

[0144] One embodiment of the present invention is called R s1 and Rs2 In this, the 3-6 member 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] One embodiment of the present invention is called R s1 , R s2 These are, independently, halogen, cyano, nitro, hydroxy, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, propoxy (n-propoxy), isopropoxy, monochloromethyl, dichloromethyl, trichloromethyl, monochloroethyl, 1,2-dichloroethyl, trichloroethyl, monobromoethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, trifluoromethoxy, trifluoroethoxy, monofluoromethoxy, monofluoroethoxy, difluoromethoxy, difluoroethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -NR c R d -C(O)NR e R f The R is -CH2-hydroxy and -CH2-cyano. c R is hydrogen, -C(O)CH3, or -CO2CH3. e , R f , R d These are, independently, hydrogen, methyl, or ethyl.

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

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

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

[0149] One embodiment of the present invention is called R s3 and R s4 In the case of C 3-6 The cycloalkyl group is selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

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

[0151] One embodiment of the present invention is called R s3 , R s4These are, 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, NHCH3, N(CH3)2,-CH2-hydroxy,-CH2-ethynyl. The methyl, ethyl, n-propyl, methoxy, ethoxy, propoxy(n-propoxy), -CH2-, azetidine, oxetane, tetrahydrofuran, tetrahydrothiophene, pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, thiomorpholine-1,1-dioxide, and tetrahydropyran may optionally and independently be substituted with one, two, or three substituents selected from halogen, methyl, ethyl, propyl(n-propyl), isopropyl, trifluoromethyl, amino, N(CH3)2, hydroxy, and carboxyl.

[0152] This is called one embodiment of the present invention, wherein the S group substituents are hydroxy, halogen, nitro, oxo, and -C. 1-3 Alkyl, hydroxysubstituted C 1-3 Alkyl, benzyl, -(CH2) u -Cyano, -(CH2) u -C 1-3 Alkoxy, -(CH2) u -Halogenated C 1-3 Alkoxy, -(CH2) u -Halogenated C 1-3 Alkyl, -(CH2) u -3-6 member heterocycloalkyl, -(CH2) u-5 or 6-membered monocyclic heteroaryl, -(CH2) u -C 3-6 Cycloalkyl, -(CH2) u -O-(CH2) v -C 3-6 Cycloalkyl, -(CH2) u -O-(CH2) v -C 1-3 Alkoxy, -(CH2) u -O-(CH2) v OH, -(CH2) u -SO2C 1-3 Alkyl, -(CH2) u -NR a0 R b0 ,-(CH2) u -C(O)NR a0 R b0 ,-(CH2) u -C(O)C 1-3 Alkyl, -C(O)OC 1-3 Alkyl, NR a 0 C(O)-(CH2) u -NR a0 R b0 , NR a0 C(O)-(CH2) u OH, NR a0 C(O)-halogenated C 1-3 The alkyl group is selected from alkyl groups. The 3-6 membered heterocycloalkyl group and the 5 or 6 membered monocyclic heteroaryl group each have 1, 2, or 3 heteroatoms independently selected from N, O, and S as ring-forming atoms. The 3-6 membered heterocycloalkyl group and the 5 or 6 membered monocyclic heteroaryl group may optionally be substituted with 1, 2, or 3 substituents selected from halogens, cyano, -C1-3 alkyl, -C1-3 alkoxy, and C3-6 cycloalkyl groups. u and v are each independently 0, 1, 2, 3, or 4. R a0 , R b0 Each is independently hydrogen or C 1-3 It is alkyl.

[0153] This is called one embodiment of the present invention, in which the S group substituent is a halogen.

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

[0155] This is called one embodiment of the present invention, in which the group (for example, Ar, R0) is C 6-10 Each aryl group is independently either phenyl or naphthyl.

[0156] This is called one embodiment of the present invention, wherein in the group (for example, Ar), the C 6-10 If the aryl group is phenyl, it is selected from the following structures:

[0157] [ka]

[0158] (In the formula, R s1 , R s2 The definition is the same as above.

[0159] This is referred to as the present invention, wherein in the group (e.g., Ar, R0), the 5 or 6-membered monocyclic heteroaryl is independently selected from thiophene, N-alkylcyclopyrrole, furan, thiazole, isothiazole, imidazole, oxazole, pyrrole, pyrazole, triazole, 1,2,3-triazole, 1,2,4-triazole, 1,2,5-triazole, 1,3,4-triazole, tetrazole, isoxazole, oxadiazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, thiadiazole, pyridine, pyridazine, pyrimidine, and pyrazine.

[0160] In one embodiment of the present invention, the group (e.g., Ar, R0) is such that the 5 or 6-membered monocyclic heteroaryl is independently selected from the following structures.

[0161] [ka]

[0162] This is referred to as one embodiment of the present invention, in which the group (e.g., Ar, R0) is a 9-10 membered bicyclic heteroaryl formed by the condensation of a benzene ring and a 5 or 6 membered monocyclic heteroaryl ring, or an 8-10 membered bicyclic heteroaryl group formed by the condensation of a 5 or 6 membered monocyclic heteroaryl ring and a 5 or 6 membered monocyclic heteroaryl ring.

[0163] In one embodiment of the present invention, the 5 or 6-membered monocyclic heteroaryl ring that forms a 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 thiadiazole ring, a pyridine ring, a pyridazine ring, a pyrimidine ring, or a pyrazine ring.

[0164] One embodiment of the present invention, a 5 or 6-membered monocyclic heteroaryl ring forming a 9-10-membered bicyclic heteroaryl or an 8-10-membered bicyclic heteroaryl group, is selected from the following structures.

[0165] [ka]

[0166] Here,

[0167] [ka]

[0168] This represents a pair of neighboring atoms shared when two connected ring-forming atoms condense with another ring.

[0169] This invention is referred to as the present invention, in the B1 ring and A1 ring, 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 thiadiazole ring, a pyridine ring, a pyridazine ring, a pyrimidine ring, or a pyrazine ring.

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

[0171] [ka] Here,

[0172] [ka]

[0173] This represents a pair of neighboring atoms shared when two connected ring-forming atoms condense with another ring.

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

[0175] In one embodiment of the present invention, the condensed 5 or 6-membered monocyclic heterocycloalkyl groups in the B2 ring and A2 ring are independently oxazolidine, pyrrolidine-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, and pi Roridine, 1,3-dioxolan-2-one, oxazolidine-2-one, imidazolidine-2-one, piperidine, piperazine, piperazine-2-one, morpholine, morpholine-3-one, morpholine-2-one, thiomorpholine-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, tetrahydropyrimidine-2(1H)-one, 1,4-dioxane-2-one, 5,6-dihydro-2H-pyran-2-one, 5,6-dihydropyrimidine -4(3H)-one, 3,4-dihydropyridine-2(1H)-one, 5,6-dihydropyridine-2(1H)-one, 5,6-dihydropyrimidine-4(1H)-one, pyrimidine-4(3H)-one, pyrimidine-4(1H)-one, 4,5-dihydro-1H-imidazole, 2,3-dihydro-1H-imidazole, 2,3-dihydroxazole, 1,3-dioxol, 2,3-dihydrothiophene, 2,5-dihydrothiophene, 3,4-dihydro-2H-1,4-Oxazine, 3,4-dihydro-2H-1,4-thiaidine 1,1-dioxide, 1,2,3,4-tetrahydropyrazine, 1,3-dihydro-2H-pyrrole-2-one, 1,5-dihydro-2H-pyrrole-2-one, 1H-pyrrole-2,5-dione, furan-2(3H)-one, furan-2(5H)-one, 1,3-dioxol-2-one, oxazole-2(3H)-one, 1,3-dihydro-2H - Selected from imidazole-2-one, furan-2,5-dione, 3,6-dihydropyridine-2(1H)-one, pyridine-2,6-(1H,3H)-dione, 5,6-dihydro-2H-pyran-2-one, 3,6-dihydro-2H-pyran-2-one, 3,4-dihydro-2H-1,3-oxazine, 3,6-dihydro-2H-1,3-oxazine, and 1,2,3,4-tetrahydropyrimidine.

[0176] This is referred to as one embodiment of the present invention, in which the condensed 5 or 6-membered monocyclic heterocycloalkyl ring is selected from the following structures.

[0177] [ka]

[0178] This is referred to as one embodiment of the present invention, in which the group (e.g., Ar, R0) is such that the 8-10 membered bicyclic heteroaryl is independently selected from benzoxazole, benzoisoxazole, benzimidazole, benzothiazole, benzisothiazole, benzotriazole, benzofuran, benzothiophene, indole, indazole, isoindole, quinoline, isoquinoline, quinazoline, quinoxaline, cinnoline, pyridopyrimidine, and naphthyridine.

[0179] This is referred to as one embodiment of the present invention, wherein the group (e.g., Ar, R0) is independently selected from benzo[d]isoxazole, 1H-indole, isoindole, 1H-benzo[d]imidazole, benzo[d]isothiazole, 1H-benzo[d][1,2,3]triazole, benzo[d]xazole, 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-naphthiridine, 1,7-naphthiridine, 1,6-naphthiridine, and 1,5-naphthiridine.

[0180] In one embodiment of the present invention, the 8-10 membered bicyclic heteroaryl group in the group (e.g., Ar, R0) is independently selected from the following structures.

[0181] [ka]

[0182] In one embodiment of the present invention, the 8-10 membered bicyclic heteroaryl group in the group (e.g., Ar, R0) is independently selected from the following structures.

[0183] [ka]

[0184] This is referred to as one embodiment of the present invention, in which the 8-10 membered bicyclic heteroaryl group in the group (e.g., Ar, R0) is independently selected from the following structures.

[0185] [ka]

[0186] One embodiment of the present invention is called

[0187] [ka]

[0188] These are each independently selected from the following structures.

[0189] [ka]

[0190] This is referred to as one embodiment of the present invention, where formula (B) and formula (A-1) are independently selected from the following structures.

[0191] [ka]

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

[0193] [ka]

[0194] [ka]

[0195] [ka]

[0196] [ka]

[0197] [ka]

[0198] This is called one embodiment of the present invention, in which the above base (for example, R0), the C 3-6 Cycloalkyls are selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cyclobutanone, cyclobutane-1,2-dione, cyclopentanone, cyclopentane-1,3-dione, cyclohexanone, and cyclohexane-1,3-dione.

[0199] This is referred to as one embodiment of the present invention, in which the above group (for example, R0) 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] This is referred to as one embodiment of the present invention, wherein in the above group (e.g., R0), the 7-11 membered spirocycloalkyl is a single spiroatom-containing monospirocycloalkyl formed of any two monocyclic cycloalkyl rings selected from a cyclopropyl ring, a cyclobutyl ring, a cyclopentyl ring, and a cyclohexyl ring.

[0201] One embodiment of the present invention is called, where R0 is -C 1-6 Alkyl, -C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, 5 or 6 membered monocyclic heteroaryl, 8-10 membered bicyclic heteroaryl, 7-11 membered spirocycloalkyl, -CH2-phenyl, -CH(C 1-2 Alkyl)-phenyl, -CH2-5 or 6-membered monocyclic heteroaryl, -CH(C 1-2Alkyl)-5 or 6-membered monocyclic heteroaryl, -NH-phenyl, -N(C 1-3 Alkyl)-phenyl, -O-phenyl, -CH2-3~6 member heterocycloalkyl, -CH2-C 3-6 Cycloalkyl, -CH(C 1-2 Alkyl)-C 3-6 It is a cycloalkyl. 1-6 Alkyl, C 3-6 Cycloalkyls, 3-6 membered heterocycloalkyls, phenyls, 5 or 6 membered monocyclic heteroaryls, 8-10 membered bicyclic heteroaryls, and 7-11 membered spirocycloalkyls are either unsubstituted or independently R s3 It is replaced by one, two, three, or four selected groups.

[0202] One embodiment of the present invention is called, where R0 is phenyl, cyclopropyl, a 5 or 6-membered monocyclic heteroaryl, -CH2-5 or 6-membered monocyclic heteroaryl, -CH2-phenyl, -CH(C 1-2 Alkyl)-phenyl, -NH-phenyl, -N(C 1-3 The alkyl)-phenyl and -O-phenyl are 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 and 5- or 6-membered monocyclic heteroaryl are unsubstituted or independently R s3 It is replaced by one, two, three, or four selected groups.

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

[0204] [ka]

[0205] [ka]

[0206] [ka]

[0207] One embodiment of the present invention is called R 11 , R 12 These may be the same or different, and each may independently be hydrogen, halogen, and -C. 1-3 Alkyl, -CH2-hydroxy, -CH2-cyano, -CH2-C 1-3 Alkoxy, -CH2-halogenated C 1-3 Alkyl or -CH2-halogenated C 1-3 It is an alkoxy.

[0208] One embodiment of the present invention is called R 11 , R 12 These may be the same or different, and each may independently be hydrogen, halogen, methyl, ethyl, n-propyl, isopropyl, -CH2-hydroxy, -CH2-cyano, -CH2-methoxy, -CH2-ethoxy, -CH2-propoxy (n-propoxy), -CH2-isopropoxy, -CH2-trifluoromethyl, -CH2-difluoromethyl, -CH2-difluoroethyl, -CH2-trifluoromethoxy, or -CH2-difluoromethoxy.

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

[0210] One embodiment of the present invention is called R 11 , R 12These may be the same or different, and each is independently hydrogen or methyl.

[0211] One embodiment of the present invention is called R 21 , R 22 These may be the same or different, and each may independently be hydrogen, halogen, and -C. 1-3 Alkyl, -CH2-hydroxy, -CH2-cyano, -CH2-C 1-3 Alkoxy, -CH2-halogenated C 1-3 Alkyl or -CH2-halogenated C 1-3 It is an alkoxy.

[0212] One embodiment of the present invention is called R 21 , R 22 These may be the same or different, and each is independently hydrogen, halogen, methyl, ethyl, n-propyl, isopropyl, -CH2-hydroxy, -CH2-cyano, -CH2-methoxy, -CH2-ethoxy, -CH2-propoxy (n-propoxy), -CH2-isopropoxy, -CH2-trifluoromethyl, -CH2-difluoromethyl, -CH2-difluoroethyl, -CH2-trifluoromethoxy, and -CH2-difluoromethoxy.

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

[0214] One embodiment of the present invention is called R 21 , R 22 These may be the same or different, and each is independently hydrogen or methyl.

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

[0216] One embodiment of the present invention is called R 31 , R 32 These may be the same or different, and each is independently hydrogen, halogen, methyl, ethyl, n-propyl, isopropyl, -CH2-hydroxy, -CH2-cyano, -CH2-methoxy, -CH2-ethoxy, -CH2-propoxy (n-propoxy), -CH2-isopropoxy, -CH2-trifluoromethyl, -CH2-difluoromethyl, -CH2-difluoroethyl, -CH2-trifluoromethoxy, and -CH2-difluoromethoxy.

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

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

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

[0220] One embodiment of the present invention is called R 41These are hydrogen, halogen, methyl, ethyl, n-propyl, isopropyl, -CH2-hydroxy, -CH2-cyano, -CH2-methoxy, -CH2-ethoxy, -CH2-propoxy(n-propoxy), -CH2-isopropoxy, -CH2-trifluoromethyl, -CH2-difluoromethyl, -CH2-difluoroethyl, -CH2-trifluoromethoxy, and -CH2-difluoromethoxy.

[0221] One embodiment of the present invention is called R 41 It is hydrogen.

[0222] This is called one embodiment of the present invention, in which, in formula I,

[0223] [ka]

[0224] If the dashed line in R represents a single bond, then P is O. 42 is -C 1-3 Alkyl-, -C 1-3 Alkyl(hydroxy)-, -C 1-3 Alkyl(cyano)-, -C 1-3 Alkyl (C 1-3 Alkyl), -C 1-3 Alkyl (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 It is alkoxy. The above C 1-3 The alkyl group is methyl, ethyl, or propyl (n-propyl or isopropyl). 1-3 Alkoxys are methoxy, ethoxy, or propoxy (n-propoxy or isopropoxy).

[0225] This is called one embodiment of the present invention, and in formula I,

[0226] [ka]

[0227] If the dashed line in the diagram represents a single bond, then P is either NH or NR. m That is. R m is -C 1-3 Alkyl, C-halogenated 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 It is an alkoxy. 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 It is alkoxy. The above C 1-3 The alkyl group is methyl, ethyl, or propyl (n-propyl or isopropyl). 1-3 Alkoxys are methoxy, ethoxy, or propoxy (n-propoxy or isopropoxy).

[0228] This is called one embodiment of the present invention, and in formula I,

[0229] [ka]

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

[0231] This is called one embodiment of the present invention, and in formula I,

[0232] [ka]

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

[0234] This is called one embodiment of the present invention, and in formula I,

[0235] [ka]

[0236] If the dashed line in the diagram represents a single bond, then P is O, NH, or NR m That is. R m R is methyl, ethyl, n-propyl, or isopropyl. 42 These are -(C=O)-, -CH2-, -CH2CH2-, or -CH2CH2CH2-.

[0237] This is called one embodiment of the present invention, and in formula I,

[0238] [ka]

[0239] If there is no dashed line in the diagram, P is hydrogen or a halogen. 42 is hydrogen, halogen, -C 1-3 Alkyl, -CH2-hydroxy, -CH2-cyano, -CH2-C 1-3 Alkoxy, -CH2-halogenated C 1-3 Alkyl or -CH2-halogenated C 1-3 It is an alkoxy.

[0240] This is called one embodiment of the present invention, and in formula I,

[0241] [ka]

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

[0243] One embodiment of the present invention, in formula I, X1 is hydrogen, halogen, cyano, hydroxy, amino, nitro, or C which may be substituted. 1-3 Alkyl, may be substituted C 3-6 Cycloalkyl, 3-6 member heterocycloalkyl, which may be substituted, and C which may be substituted. 1-3 C may be alkyl or -O-substituted. 3-6 Cycloalkyl, 3-6 member heterocycloalkyl, possibly -O-substituted, possibly -NH-substituted C 1-3 Alkyl, -N (may be substituted C) 1-3 C (alkyl)2, may be substituted with -NH- 3-6Cycloalkyl, 3-6 member heterocycloalkyl, possibly -NH-substituted, possibly -NH(C=O)-substituted C 1-3 Alkyl, -NH(C=O)-C 3-6 C may be cycloalkyl or -NH(SO2)-substituted. 1-3 C may be alkyl or -NH(SO2)-substituted. 3-6 Cycloalkyl, C may be -SO2-substituted. 1-3 C may be alkyl or -SO2-substituted. 3-6 Cycloalkyl, -(C=O)-NR j R k -, -(C=O)-O- substitution is acceptable. 1-3 Alkyl, -(C=O)-O- substituted C 3-6 It is cycloalkyl. j , R k Each is independently hydrogen or C 1-3 Alkyl, or the aforementioned R j , R k This forms a 3-6 member nitrogen-containing heterocycloalkyl group, which may be substituted together with the connected nitrogen atom. The 3-6 member heterocycloalkyl group has 1, 2, or 3 heteroatoms selected from N, O, and S as ring-forming atoms. The 3-6 member nitrogen-containing heterocycloalkyl group 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. This refers to the substitution of 1, 2, 3, or 4 hydrogen atoms in the "substituted" group, each independently substituted with substituents selected from the S group. 1-3 Alkyl is methyl, ethyl, or propyl (n-propyl or isopropyl). 1-3 Alkoxys are methoxy, ethoxy, or propoxy (n-propoxy or isopropoxy).

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

[0245] This is called one embodiment of the present invention, in formula I, where Y1 is C, E1 is N, and E2 is C.

[0246] This is called one embodiment of the present invention, in formula I, where Y1 is C, E1 is C, and E2 is N.

[0247] This is referred to as one embodiment of the present invention, in formula I, Y1 is C, E1 is N, and E2 is N.

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

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

[0250] This is called one embodiment of the present invention, in equation II, where P is O.

[0251] This is called one embodiment of the present invention, in formula II, where P is NH or NR m And R m C 1-3 Alkyl, halogenated C 1-3 Alkyl, -C 1-3 Alkyl-hydroxy, -C 1-3 Alkyl-cyano, -C 1-3 Alkyl-C 1-3 Alkoxy, -C 1-3 Alkyl-halogenated C 1-3 It is an alkoxy. Here, C 1-3 Alkyl is methyl, ethyl, or propyl (n-propyl or isopropyl). 1-3 Alkoxys are methoxy, ethoxy, or propoxy (n-propoxy or isopropoxy).

[0252] This is called one embodiment of the present invention, in equation II, R 42 is -(C=O)-, -C 1-3 Alkyl, -C 1-3 Alkyl(hydroxy)-, -C1-3 Alkyl(cyano)-, -C 1-3 Alkyl (C 1-3 Alkyl), -C 1-3 Alkyl (halogenated C 1-3 Alkyl), -C 1-3 Alkyl (C 1-3 Alkyl-hydroxy)-,-C 1-3 Alkyl (C 1-3 Alkyl-cyano)-,-C 1-3 Alkyl (C 1-3 Alkoxy)-, or -C 1-3 Alkyl (halogenated C 1-3 It is alkoxy. The above C 1-3 The alkyl group is methyl, ethyl, or propyl (n-propyl or isopropyl). 1-3 Alkoxys are methoxy, ethoxy, or propoxy (n-propoxy or isopropoxy).

[0253] This is called one embodiment of the present invention, in formula II, where X2 and Y2 may be the same or different, and each may independently be hydrogen, halogen, and -C 1-3 Alkyl, -C 1-3 Alkyl-hydroxy, -C 1-3 Alkyl-cyano, -C 1-3 Alkyl-C 1-3 Alkoxy, -C 1-3 Alkyl-halogenated C 1-3 Alkyl or -C 1-3 Alkyl-halogenated C 1-3 It is an alkoxy. 1-3 The alkyl group is methyl, ethyl, or propyl (n-propyl or isopropyl). 1-3 Alkoxys are methoxy, ethoxy, or propoxy (n-propoxy or isopropoxy).

[0254] This is called one embodiment of the present invention, in formula II, where X2 and Y2 may be substituted together with their adjacent carbon atoms. 3-6It forms a cycloalkyl or a substituted 3-6 member heterocycloalkyl group. The 3-6 member heterocycloalkyl group has 1, 2, or 3 heteroatoms selected from N, O, and S as ring-forming atoms. The "substitution" refers to the substitution of 1, 2, 3, or 4 hydrogen atoms in the group with substituents selected from the S group, each independently.

[0255] This is called one embodiment of the present invention, in equation II, where L is a single bond.

[0256] One embodiment of the present invention, in formula II, R5 is hydrogen, halogen, hydroxyl, or C which may be substituted. 1-3 Alkyl, may be substituted C 3-6 Cycloalkyl, 3-6 member heterocycloalkyl, which may be substituted, and C which may be substituted. 1-3 C may be alkyl or -O-substituted. 3-6 Cycloalkyl, 3-6 member heterocycloalkyl, possibly -O-substituted, possibly -SO2-substituted C 1-3 C may be alkyl or -SO2-substituted. 3-6 Cycloalkyl groups, 3-6 membered heterocycloalkyl groups which may be -SO2-substituted, 5 or 6 membered monocyclic heteroaryl groups which may be -substituted, or NR 51 R 52 The above R 51 , R 52 These are, independently, hydrogen and C which may be substituted. 1-3 Alkyl, -SO2C 1-3 Alkyl, -SO2C 3-6 Cycloalkyl, -C(O)C 1-3 Alkyl or -C(O)halogenated C 1-3 Alkyl, or R 51 and R 52This forms a 3- to 6-membered nitrogen-containing heterocycloalkyl group, which may be substituted together with the connected nitrogen atom. The 3- to 6-membered heterocycloalkyl group and the 5 or 6-membered monocyclic heteroaryl group 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 group 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 arbitrarily selected from N, O, and S. The "substitution" refers to the substitution of 1, 2, 3, or 4 hydrogen atoms in the group with substituents independently selected from the S group. 1-3 The alkyl group is methyl, ethyl, or propyl (n-propyl or isopropyl). 1-3 Alkoxys are methoxy, ethoxy, or propoxy (n-propoxy or isopropoxy).

[0257] This is referred to as one embodiment of the present invention, in which R1 and R2 are each independently hydrogen, halogen, cyano, amino, NHCH3, N(CH3)2, methyl, ethyl, n-propyl, isopropyl, monochloromethyl, dichloromethyl, trichloromethyl, monochloroethyl, 1,2-dichloroethyl, trichloroethyl, monobromoethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, -CH2-hydroxy, -CH2-cyano, -CH2-methoxy, -CH2-ethoxy, -CH2-propoxy (n-propoxy), -CH2-isopropoxy, -CH2-NH2, -CH2-NHCH3, -CH2-N(CH3)2, -CH2-3 to 6-membered heterocycloalkyl or -CH2-5 or 6-membered monocyclic heteroaryl. The 3-6 member heterocycloalkyl group 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 member monocyclic heteroaryl group is selected from thiophene, N-alkylcyclopyrrole, furan, thiazole, isothiazole, imidazole, oxazole, pyrrole, pyrazole, triazole, 1,2,3-triazole, 1,2,4-triazole, 1,2,5-triazole, 1,3,4-triazole, 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 aforementioned 3-6 member heterocycloalkyl or 5 or 6 member monocyclic heteroaryl may optionally contain 1 or 2 halogens or C 1-3 It can be substituted with alkyl.

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

[0259] This is referred to as one embodiment of the present invention, where R4 is hydrogen, monochloromethyl, dichloromethyl, trichloromethyl, monochloroethyl, 1,2-dichloroethyl, trichloroethyl, monobromoethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, -CH2-hydroxy, -CH2-cyano, -CH2-methoxy, -CH2-ethoxy, -CH2-propoxy (n-propoxy), or -CH2-isopropoxy.

[0260] This is called one embodiment of the present invention, where R1, R2, and R3 are hydrogen.

[0261] This is referred to as one embodiment of the present invention, where E1 is N or CR5, and R5 is hydrogen.

[0262] This is referred to as one embodiment of the present invention, where E2 is N or CR6, and R6 is hydrogen.

[0263] In a compound represented by formula (I), referred to as one embodiment of the present invention, the R 11 , R 12 , R 21 , R 22 , R 31 , R 32 , R 41 , R 42 Z, P, R0, Ar, E1, E2, X1, and Y1 are groups that independently correspond to each specific compound in the examples.

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

[0265] A compound referred to as one embodiment of the present invention, represented by a typical formula (IA), includes the structure shown in Table A-1 below, tautomers, cis-trans isomers, mesomers, racemates, enantiomers, diastereomers or atrop isomers of any of the structures in Table A-1, or mixtures of the isomers, or the structure shown in Table A-1 and pharmaceutically acceptable salts, solvates or prodrugs of the isomers.

[0266] [Table A-1]

[0267] [Table 1]

[0268] [Table 2]

[0269] [Table 3]

[0270] [Table 4]

[0271] [Table 5]

[0272] [Table 6]

[0273] [Table 7]

[0274] [Table 8]

[0275] Table 9

[0276] Table 10

[0277] Table 11

[0278] Table 12

[0279] Table 13

[0280] Table 14

[0281] Table 15

[0282] Table 16

[0283] Table 17

[0284] Table 18

[0285] Table 19

[0286] [Table 20]

[0287] [Table 21]

[0288] A compound referred to as one embodiment of the present invention, represented by a typical formula (IA), includes, but is not limited to, the structure shown in Table A-2 below, or a pharmaceutically acceptable salt, solvate, or prodrug of any of the structures shown in Table A-2.

[0289] [Table 22]

[0290] [Table 23]

[0291] [Table 24]

[0292] A compound referred to as one embodiment of the present invention, represented by a typical formula (IA), includes, but is not limited to, any of the compound structures described in Examples 51 to 342, or pharmaceutically acceptable salts, solvates, or prodrugs of these structures.

[0293] One embodiment of the present invention, in a compound represented by formula (II), the R 11 , R 12 , R 21 , R 22 , R 31 , R 32 , R 41 , R 42Z, P, Ar, E3, E4, X2, and Y2 are groups that independently correspond to each specific compound in the examples.

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

[0295] In another embodiment, the present invention provides a pharmaceutical composition comprising the compound or its tautomers, cis-trans isomers, mesomers, racemates, enantiomers, diastereomers, atrop isomers or mixtures thereof, or pharmaceutically acceptable salts, solvates or prodrugs thereof, and a pharmaceutically acceptable carrier.

[0296] As used herein, the term “pharmaceutically acceptable carrier” refers to a representative carrier of any formulation or carrier medium that can deliver an effective amount of the active substance according to the present invention, does not impair the biological activity of the active substance, and does not cause toxicity or adverse effects to the host or subject, and includes water, oil, vegetables and minerals, ointment substrates, lotion bases, ointment substrates, etc. These bases include suspending agents, thickeners, transdermal accelerators, etc. These formulations are well known to those skilled in the art in the fields of cosmetics or topical drugs.

[0297] In embodiments of the present invention, the pharmaceutical composition can be administered by any method selected from oral administration, spray inhalation, rectal administration, nasal administration, cheek administration, topical administration, parenteral administration, such as injection / delivery subcutaneously, intramuscularly, intraperitoneally, intrameningally, intraventricularly, intrasternally and intracranially, or administration via external storage. When administered orally, the compound according to the present invention can be in any orally administerable formulation form, including but not limited to tablets, capsules, aqueous solutions, or aqueous suspensions. The carrier used for tablets generally contains lactose and corn starch, and may also contain a lubricant such as magnesium stearate. The diluent used for capsules generally contains lactose and dried corn starch. Aqueous suspension formulations are generally used by mixing the active ingredient with a suitable emulsifier and suspension agent. If necessary, several sweeteners, flavorings, or colorings may be added to the above oral formulation forms. For topical administration, particularly when treating neurological disorders of the affected area / organ where topical application is easily achieved, such as the eyes, skin, or lower intestines, the compounds according to the present invention can be prepared into different topical formulations depending on the affected area or organ. When administered topically to the eye, the compounds according to the present invention can be prepared into a micronized suspension or solution formulation, and the carrier used is an isotonic sterile physiological saline having a specific pH, and preservatives such as benzyl alkoxide chloride may or may not be added. When administered to the eye, the compounds can also be prepared into a paste such as petrolatum paste. When administered topically to the skin, the compounds according to the present invention can be made into a suitable ointment, lotion, or cream, suspending or dissolving the active ingredient in one or more carriers. Carriers usable in ointment formulations include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene, emulsifying wax, and water. Carriers usable in lotions or creams include, but are not limited to, mineral oil, sorbitan monostearate, Tween 60, cetyl ester wax, hexadecene aromatic alcohol, 2-octyldodecanol, benzyl alcohol, and water.The compounds according to the present invention can be further administered by sterile injection formulations, which include sterile water for injection, oil suspensions, or sterile injection solutions. Usable carriers and solvents include water, Ringer's solution, and isotonic sodium chloride solution. Sterilized non-volatile oils (e.g., monoglycerides or diglycerides) may also be used as solvents or suspension media.

[0298] In another embodiment, the present invention provides applications of the compound or its tautomers, cis-trans isomers, mesomers, racemates, enantiomers, diastereomers, atrop isomers or mixtures thereof, or pharmaceutically acceptable salts, solvates or prodrugs thereof, in the preparation of drugs for the treatment and / or prevention of KRAS G12C mutagenic diseases. The KRAS G12C mutagenic disease is preferably cancer.

[0299] In another embodiment, the present invention provides applications of the compound or its tautomers, cis-trans isomers, mesomers, racemates, enantiomers, diastereomers, atrop isomers or mixtures thereof, or pharmaceutically acceptable salts, solvates or prodrugs thereof, in the preparation of drugs for the treatment and / or prevention of cancer.

[0300] This is referred to as one embodiment of the present invention, wherein the cancer is pancreatic cancer, colorectal cancer, or lung cancer.

[0301] This is referred to as one embodiment of the present invention, in which the cancer is lung cancer, and non-small cell lung cancer is preferred.

[0302] In another embodiment, the present invention provides applications in the preparation of KRAS mutation inhibitors (where the KRAS mutation is preferably the KRAS G12C mutation) of the compound or its tautomers, cis-trans isomers, mesomers, racemates, enantiomers, diastereomers, atrop isomers or mixtures thereof, or pharmaceutically acceptable salts, solvates or prodrugs thereof.

[0303] In another embodiment, 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 its tautomers, cis-trans isomers, mesomers, racemates, enantiomers, diastereomers, atrop isomers or mixtures thereof, or pharmaceutically acceptable salts, solvates or prodrugs thereof, or any combination thereof, or the pharmaceutical composition described above.

[0304] As used herein, the term “subject” refers to an animal, in particular a mammal. Humans are preferred.

[0305] As used herein, the terms “effective dose” or “therapeutic effective dose” refer to a sufficient amount of a drug or agent that is non-toxic but capable of achieving the desired effect. In embodiments of the present invention, when treating a patient according to the present invention, the amount of a given drug is determined by many factors, such as the specific administration method, the type and severity of the disease or condition, and the specific characteristics of the person or host being treated (e.g., body weight). However, depending on the specific circumstances, including the specific drug employed, the route of administration, the condition treated, and the person or host being treated, the dose can generally be determined by methods known in the art. Generally, for doses used in the treatment of adults, the dose is typically in the range of 0.02–5000 mg / day, for example, about 1–1500 mg / day. The required dose may be one drug, or a dose administered simultaneously (or for a short period of time) or at appropriate intervals, for example, two, three, four drugs or more drugs per day. As will be understood by those skilled in the art, although the above dose range is given, the specific effective dose can be appropriately adjusted according to the patient's condition and in accordance with the physician's diagnosis.

[0306] As used herein, the term “pharmaceutically acceptable salt” refers to a salt of a compound according to the present invention that is pharmaceutically acceptable and has the pharmacological activity of the parent compound. Such salts include acid addition salts formed with an inorganic acid or an organic acid, wherein the inorganic acid is, for example, nitric acid, phosphoric acid, carbonic acid, etc., and the organic acid is, for example, propionic acid, caproic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, gluconic acid, stearic acid, muconic acid, etc.; or salts formed by substituting an acidic proton present in the parent compound with a metal ion, for example, an alkali metal ion or an alkaline earth metal ion; or coordination compounds formed with an organic base, wherein the organic base is, for example, ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, etc. The pharmaceutically acceptable salts of the present invention can be synthesized from a parent compound containing an acid group or a base by conventional methods. Generally, one method for preparing such salts involves reacting these compounds, as free acids or bases, with a stoichiometrically appropriate base or acid in water, an organic solvent, or a mixture thereof. In addition to salts, the compounds provided by the present invention may also exist as prodrugs. Prodrugs of the compounds described herein readily undergo chemical changes under physiological conditions to convert them into the compounds according to the present invention. Furthermore, prodrugs can be converted into the compounds according to the present invention by chemical or biochemical methods in the internal environment of the body.

[0307] As used herein, the term “solvate” refers to a substance formed by the combination of a compound according to the present invention with a pharmaceutically acceptable solvent. Solvates include stoichiometric amounts of solvates and non-stoichiometric amounts of solvates. Some of the compounds of the present invention may exist in non-solubilized or solvated forms. Generally, solvated and non-solubilized forms are considered indistinguishable and both fall within the scope of the present invention.

[0308] As used herein, the term “stereoisomer” includes conformational isomers and configurational isomers, wherein configurational isomers mainly include cis-trans isomers and optical isomers. Compounds according to the present invention may exist as stereoisomers and, therefore, include, but are not limited to, all possible stereoisomers, including cis-trans isomers, tautomers, enantiomers, diastereomers, atropisomers (sometimes also called rotational isomers), etc. Compounds according to the present invention may be any combination or mixture of the above stereoisomers, for example, mesomers, racemates, equimolar mixtures of atropisomers, etc. For example, there may be a single enantiomer, a single diastereomer or a mixture thereof, or a single atropisomer or a mixture thereof. If a compound according to the present invention contains an olefin double bond, unless otherwise specified, it includes cis-isomers and trans isomers, and any combination thereof. The atropisomers according to the present invention are stereoisomers whose intramolecular rotation is restricted, resulting in axial chirality or planar chirality. The compounds according to the present invention include two types of atropisomers derived from axial asymmetry. These are those in which the substituent Ar' or R0' is C 6-10 In the case of aryl groups, 5- or 6-membered monocyclic heteroaryl groups, 8- to 10-membered bicyclic heteroaryl groups, or cyclic groups such as pyridone groups, the isomers are limited to those formed by rotation of the bond to the substituted naphthyridine-one ring, creating steric hindrance. Regarding the atrop isomers of the present invention, the compounds have structures 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 chiral carbons, etc., and represent one of the pair of atrop isomers present in each isomeric compound. Furthermore, as drugs, atrop isomers with excellent activity are preferred. The compounds represented by formula (I), formula (IA), or formula (II) include optical isomers derived from asymmetric carbons, axial asymmetry, etc., and individual isomers can be obtained by optical resolution as needed. The atrop isomers of the compounds of the present invention may be represented in P or M configuration, or in other common forms well known in the art.

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

[0310] In this specification, the "-" sign in substituents of each group indicates a bond linked to another group or structure.

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

[0312] As used herein, the term "alkyl" refers to a linear or branched saturated aliphatic hydrocarbon group containing 1 to 20 carbon atoms. 1-10 The term "alkyl" refers to linear or branched alkyl groups having 1 to 10 carbon atoms. It also refers to linear or branched alkyl groups having 1, 2, 3, 4, 5, or 6 carbon atoms, i.e., C 1-6 Alkyl is preferred. 1-4 Alkyl is more preferred. C 1-3Alkyl groups are most preferred. Specific examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl group, 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, if both propyl and isopropyl are present in the parallel options, the propyl indicates n-propyl. If only propyl is present in the parallel options, the propyl indicates either n-propyl or isopropyl.

[0313] The term "-C" used in this specification 1-3 "Alkyl-" and "C 1-3 The term "alkylene" can be used in common and refers to a saturated linear or branched aliphatic hydrocarbon group having residues derived by removing two hydrogen atoms from the same carbon atom or two different carbon atoms of two parent alkyl groups, and is a linear or branched group containing 1 to 3 carbon atoms. Specific examples of alkylene groups include, but are not limited to, methylene (-CH2-), 1,1-ethylene (-CH(CH3)-), 1,2-ethylene (-CH2CH2-), 1,1-propylene (-CH(CH2CH3)-), 1,2-propylene (-CH2CH(CH3)-), and 1,3-propylene (-CH2CH2CH2-).

[0314] The term "-C" used in this specification 1-3 Alkyl(hydroxy)-, -C 1-3 Alkyl(cyano)-, -C 1-3 Alkyl (C 1-6 Alkyl)-, -C 1-3 Alkyl (halogenated C 1-6Alkyl)-, -C 1-3 Alkyl (C 1-6 Alkyl-hydroxy)-,-C 1-3 Alkyl (C 1-6 Alkyl-cyano)-,-C 1-3 Alkyl (C 1-6 Alkoxy)-, -C 1-3 Alkyl (halogenated C 1-6 "-alkoxy)" is equivalent to "-C" 1-3 In "alkyl-", one or more hydrogen atoms are hydroxy, cyano, and C, respectively. 1-6 Alkyl, halogenated C 1-6 Alkyl, -C 1-6 Alkyl-hydroxy, -C 1-6 Alkyl-cyano, C 1-6 Alkoxy, C halogenated 1-6 This refers to residues formed by substitution with alkoxy groups. Specific examples include, but are not limited to, -CH(OH)-, -CH2CH(CN)-, -CH2CH(CH2CH3)-, -CH2CH(CF3)-, -CH(CH2OH)-, -CH2CH(CH2CN)-, -CH(OCH3)-, and -CH2CH(OCF3)-.

[0315] As used herein, the term "alkoxy" refers to a group having an -O-alkyl structure, and the definition of alkyl is as described above. 1-10 "Alkoxy" is an alkoxy having 1 to 10 carbon atoms, C 1-6 Alkoxy is preferred, C 1-4 Alkoxy is more preferred, C 1-3 Alkoxy groups are more preferred. Specific examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, isobutoxy, and n-pentyloxy. Unless otherwise specified, if both propyl and isopropyl are present in the parallel options, the propyl indicates n-propyl. If only propyl is present in the parallel options, the propyl indicates either n-propyl or isopropyl.

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

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

[0318] As used herein, the term "alkynyl" refers to an alkyl group having one or more carbon-carbon triple bonds at any site in the chain, as defined above. 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 Alkynnyls are preferred. Alkynnyls having 2-4 carbon atoms and 1-2 carbon-carbon triple bonds, i.e., C2-4 Alkynnyl groups are more preferred. Specific examples of alkynyl groups include, but are not limited to, ethynyl groups, 1-propynyl groups, 2-propynyl groups, and 1-, 2-, or 3-butynyl groups.

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

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

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

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

[0323] As used herein, the terms "cycloalkyl" and "cycloalkyl ring" can be used interchangeably and refer to a cyclic hydrocarbon group formed by the condensation of a saturated monocyclic or polycyclic ring. 3-20 "Cycloalkyl" refers to a cycloalkyl group having 3 to 20 carbon atoms, and includes monocyclic cycloalkyls, spirocycloalkyls, condensed cycloalkyls, and crosslinked cycloalkyls. 3-12 Cycloalkyls are preferred. In the present invention, the ring-forming carbon atoms of the cycloalkyl may be substituted with 1, 2, or 3 oxos to form a cyclic ketone structure. 3-8 "Monocyclic cycloalkyl" and "C 3-8 "Cycloalkyl" refers to a saturated monocyclic hydrocarbon group having 3-8 carbon atoms. 3-6 Monocyclic cycloalkyl (i.e., C 3-6 Cycloalkyl groups are preferred. C3, C4, C5, or C6 monocyclic cycloalkyl groups are more preferred. Specific examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

[0324] As used herein, the terms “spirocycloalkyl” and “spirocycloalkyl ring” 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 classified into monospirocycloalkyl, bisspirocycloalkyl, and polyspirocycloalkyl. The term “5-20 membered spirocycloalkyl” or “C 5-20 "Spirocycloalkyl" refers to a polycyclic cyclic hydrocarbon group having 5-20 ring carbon atoms, and the monocyclic ring sharing the spiro atom is a monocyclic cycloalkyl ring with 3-8 members. 6-14 members (C 6-14 Spiroalkyl groups of ) are preferred. Monospirocycloalkyl groups of 6-14 members are more preferred. 7-11 member (C 7-11 ) spiroalkyls are more preferred. 7-11 member monospirocycloalkyls are more preferred. 7-member (4-member monocycloalkyl / 4-member monocycloalkyl ring), 8-member (4-member monocycloalkyl ring / 5-member monocycloalkyl ring), 9-member (4-member monocycloalkyl ring / 6-member monocycloalkyl ring, 5-member monocycloalkyl ring / 5-member monocycloalkyl ring), 10-member (5-member monocyclic cycloalkyl ring / 6-member monocyclic cycloalkyl), or 11-member (6-member monocycloalkyl ring / 6-member monocycloalkyl) monospirocycloalkyls are most preferred. Specific examples of spiroalkyls include, but are not limited to, the following structures.

[0325] [ka]

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

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

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

[0329] The term "C" used in this specification 3-8 The terms "monocyclic heterocyclyl group," "3-8 membered monocyclic heterocyclyl group," and "3-8 membered monocyclic heterocyclyl ring" refer to a group having 3-8 ring-forming atoms, where 1, 2, or 3 ring-forming atoms are nitrogen, oxygen, or S(O). m A monocyclic cyclic hydrocarbon group that is saturated or partially unsaturated, having a heteroatom selected from (where m is an integer between 0 and 2). A 3-6 member monocyclic heterocycline (i.e., C) having 3-6 ring-forming atoms, of which 1 or 2 are heteroatoms. 3-6 Monocyclic heterocyclyl groups are preferred. More preferred are 5 or 6-membered monocyclic heterocyclyl groups having 5 or 6 ring-forming atoms, of which 1 or 2 are heteroatoms. If the heteroatom is a nitrogen atom, the nitrogen atom may be substituted (i.e., N or NR, where R is hydrogen or another substituent already defined herein). If the heteroatom is a sulfur atom, the sulfur atom may be oxidized (i.e., S(O) m(where m is an integer between 0 and 2). The ring-forming carbon atoms of the monocyclic heterocyclyl group may be optionally substituted with 1, 2, or 3 oxo atoms to form a cyclic ketone, cyclic lactone, or cyclic lactam structure. Specific examples of monocyclic heterocyclyl groups include aziridine, ethylene oxide, azetidine, azetidine-2-one, oxetane, oxetane-2-one, oxazolidine, pyrrolidine-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, and tetrahydrodi Ofen, pyrrolidine, 1,3-dioxolan-2-one, oxazolidine-2-one, imidazolidine-2-one, piperidine, piperazine, piperazine-2-one, morpholine, morpholine-3-one, morpholine-2-one, thiomorpholine-3-one-1,1-dioxide, thiomorpholine, thiomorpholine-1,1-dioxide, tetrahydropyran, 1,2-dihydroazacyclobutadiene, 1,2-dihydrooxacyclobutadiene, 2,5-dihydro-1H-pyran Rol, 2,5-dihydrofuran, 2,3-dihydrofuran, 2,3-dihydro-1H-pyrrole, 3,4-dihydro-2H-pyran, 1,2,3,4-tetrahydropyridine, 3,6-dihydro-2H-pyran, 1,2,3,6-tetrahydropyridine, 1,3-oxazine, hexahydropyrimidine, 1,4-dioxane, tetrahydropyrimidine-2(1H)-ketone, 1,4-dioxan-2-one, 5,6-dihydro-2H-pyran-2-one, 5,6-dihydropyrimidine Midine-4(3H)-one, 3,4-dihydropyridine-2(1H)-one, 5,6-dihydropyridine-2(1H)-one, 5,6-dihydropyrimidine-4(1H)-one, pyrimidine-4(3H)-one, pyrimidine-4(1H)-one, 4,5-dihydro-1H-imidazole, 2,3-dihydro-1H-imidazole, 2,3-dihydroxazole, 1,3-dioxol, 2,3-dihydrothiophene, 2,5-dihydrothiophene, 3,4-dihydro-2H-1,4-Oxazine, 3,4-dihydro-2H-1,4-thiaazine 1,1-dioxide, 1,2,3,4-tetrahydropyrazine, 1,3-dihydro-2H-pyrrole-2-one, 1,5-dihydro-2H-pyrrole-2-one, 1H-pyrrole-2,5-dione, furan-2(3H)-one, furan-2(5H)-one, 1,3-dioxol-2-one, oxazole-2(3H)-one, 1,3-dihydro-2H-imidazo Examples include, but are not limited to, ru-2-one, furan-2,5-dione, 3,6-dihydropyridine-2(1H)-one, pyridine-2,6-(1H,3H)-dione, 5,6-dihydro-2H-pyran-2-one, 3,6-dihydro-2H-pyran-2-one, 3,4-dihydro-2H-1,3-oxazine, 3,6-dihydro-2H-1,3-oxazine, 1,2,3,4-tetrahydropyrimidine, etc. Term "C, 3-8 "Heterocycloalkyl" and "3-8 membered monocyclic heterocyclyl" are saturated monocyclic hydrocarbon groups having 3-8 ring-forming atoms, of which 1 or 2 are heteroatoms. 3-6 membered heterocycloalkyls having 3-6 ring-forming atoms, of which 1 or 2 are heteroatoms, are preferred. Specific examples of heterocycloalkyl groups include, but are not limited to, aziridine groups, oxirane groups, azetidine groups, oxetanyl, oxazolidinyl, 1,3-dioxolanyl, dioxane groups, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyrrolyl, piperidyl, piperazinyl, morpholino, thiomorpholinyl, thiomorpholine-1,1-dioxide group, tetrahydropyranyl, 1,4-oxazepane group, 1,3-oxazepane group, 1,3-oxazine group, hexahydropyrimidinyl, and 1,4-dioxane groups.

[0330] The two ring-forming atoms connected to the monocyclic heterocyclyl group described above, for example CC and NC, may both condense with a cycloalkyl, heterocyclic group, aryl, or heteroaryl group, such as a monocyclic cycloalkyl ring, monocyclic heterocyclyl ring, monoaryl ring, or 5- or 6-membered monoheteroaryl ring, as defined in the present invention, to form a fused polycycle. CC is preferred as the two ring-forming atoms connected to the monocyclic heterocyclyl group that forms a fused ring with other rings.

[0331] The term "C" used in this specification 6-14 "Aryl", "C 6-14 "Aryl ring" and "C 6-14 The term "aromatic ring" may be used in common to refer to an all-carbon monocyclic, all-carbon polycyclic (rings connected by covalent bonds and not fused) or all-carbon fused polycyclic (i.e., rings sharing adjacent pairs of carbon atoms) group having 6-14 ring-forming atoms, wherein at least one ring in the group is aromatic, i.e., has a conjugated π-electron system. 6-10 Aryl is preferred. In the present invention, C 6-14 Aryls include monocyclic aryls, polycyclic aryls, and aromatic condensed polycyclics. Specific examples of monocyclic aryls include phenyl, and specific examples of polycyclic aryls include biphenyl, etc.

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

[0333] In some embodiments of the present invention, the aromatic condensed polycyclic group may be a polycyclic group formed by condensation of a monoaryl ring (e.g., phenyl) with one or more non-aromatic rings, wherein the ring connected to the parent structure is either an aromatic or non-aromatic ring. The non-aromatic ring includes, but is not limited to, a 3-6 member monocyclic heterocyclyl group ring (preferably a 5 or 6 member monocyclic heterocyclyl group ring, where the ring-forming carbon atoms may be substituted with 1-2 oxygen atoms to form a cyclic lactam or cyclic lactone structure) or a 3-6 member monocyclic cycloalkyl ring (preferably a 5 or 6 member monocyclic cycloalkyl ring, where the ring-forming carbon atoms may be substituted with 1 or 2 oxos to form a cyclic ketone structure). The polycyclic group formed by condensation of the monoaryl ring with one or more non-aromatic rings is connected to another group or parent structure by a nitrogen atom or carbon atom, wherein the ring connected to the parent structure is either 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 condensed dicycle means that two adjacent substituents in phenyl condense with the ring-forming atom to which they are attached 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 condensed dicycle is also called a 9 or 10-membered phenyl heterocyclyl ring.

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

[0336] [ka]

[0337] In the present invention, each of the above types of aryls may be substituted, and if substituted, one or more substituents described in this application are preferred.

[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., sharing an adjacent pair of ring-forming atoms, which may be CC or NC) in which the ring-forming atoms are independently substituted with at least one heteroatom selected from nitrogen, oxygen, or sulfur, wherein the nitrogen and sulfur atoms may be oxidized, and the nitrogen atom may be ammoniumlated. The heteroaryl has 6, 10, or 14 shared π electrons, and at least one ring in the group is aromatic. 5-14 The terms "heteroaryl" and "5-14 membered heteroaryl group" refer to heteroaryls having 5-14 ring-forming atoms, with 1, 2, 3, or 4 ring-forming atoms being heteroatoms. A 5-10 membered heteroaryl group having 5-10 ring-forming atoms, with 1, 2, 3, or 4 ring-forming atoms being heteroatoms, is preferred. In the present invention, C 5-14 The heteroaryl group may be a monoheteroaryl group, a fused bicyclic heteroaryl group, or a fused tricyclic heteroaryl group.

[0339] As used herein, the terms “5 or 6-membered monoheteroaryl group” and “5 or 6-membered monocyclic heteroaryl group” may be used interchangeably and refer to a monocyclic heteroaryl having 5 or 6 ring-forming atoms, 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, and pyrazine.

[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-forming atoms, wherein 1, 2, 3, 4, or 5 ring-forming atoms are heteroatoms. The fused bicyclic heteroaryl may be a biscyclo group (preferably a 9 or 10 membered bisheteroaryl ring) formed by the condensation of a monoaryl ring (e.g., phenyl) and a monoheteroaryl ring (preferably a 5 or 6 membered monoheteroaryl ring), or a biscyclo group formed by the condensation of a monoheteroaryl ring (preferably a 5 or 6 membered monoheteroaryl ring) and a monoheteroaryl ring (preferably a 5 or 6 membered monoheteroaryl ring). Any two ring-forming atoms adjacent to the monoheteroaryl ring, for example CC, NC, and NN, can condense with a cycloalkyl, heterocyclic group, aryl, or heteroaryl group, such as a monocyclic cycloalkyl ring, monocyclic heterocyclyl ring, monoaryl ring, or 5- or 6-membered monoheteroaryl ring, as defined in the present invention, to form a fused polycycle. In a monoheteroaryl ring forming a fused polycycle with another ring, CC is preferred as the two adjacent ring-forming atoms. Specific examples 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, sinnoline, pyrido[3,2-d]pyrimidine, pyrido[2,3-d]pyrimidine, pyrido[3,4-d]pyrimidine, pyrido[4,3-d]pyrimidine, 1,8-naphthiridine, 1,7-naphthiridine, 1,6-naphthiridine, 1,5-naphthiridine, pyrazolo[1,5-a]pyrimidine, imidazo[1,2-b]pyridazine, etc. The above-mentioned monoheteroaryl, or bisheteroaryl formed by the condensation of a benzene ring and a monoheteroaryl ring, or bisheteroaryl group formed by the condensation of two monoheteroaryl rings, may be connected to other groups or the 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 include, but are not limited to, the following structures.

[0343] [ka]

[0344] In some embodiments of the present invention, the fused bicyclic heteroaryl group or fused tris heteroaryl group may be a polycyclic group formed by condensation of a monoheteroaryl ring (preferably a 5- or 6-membered monoheteroaryl ring) with one or more non-aromatic rings, wherein the ring connected to the parent structure is a monoheteroaryl ring or a non-aromatic ring. The non-aromatic 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 be substituted with 1-2 oxos 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 be substituted with 1 or 2 oxos to form a cyclic ketone structure), etc. The polycyclic group formed by the condensation of the above monoheteroaryl ring with one or more non-aromatic rings may be connected to other groups or the parent structure by a nitrogen atom or a carbon atom, and the ring connected to the parent structure is either a monoheteroaryl ring or a non-aromatic ring.

[0345] In this specification, the condensation of a 5- or 6-membered monoheteroaryl ring and a 5- or 6-membered monocyclic heterocyclyl group to form an 8-10-membered fused bicyclic heteroaryl group means that two adjacent substituents of a 5- or 6-membered monocyclic heteroaryl group and the ring-forming atoms connected to them condense to form a 5- or 6-membered monocyclic heterocyclyl group, the 5- or 6-membered monocyclic heterocyclyl group is defined as described above, and the formed 8-10-membered fused bicyclic heteroaryl group is also called an 8-10-membered heteroaryl heterocyclyl group.

[0346] In this specification, the condensation of a 5- or 6-membered monoheteroaryl ring and a 5- or 6-membered monocyclic cycloalkyl ring to form an 8-10-membered condensed bicyclic heteroaryl is defined as the condensation of two adjacent substituents of a 5- or 6-membered monoheteroaryl ring and the ring-forming atom connected to them to form a 5- or 6-membered monocyclic cycloalkyl ring, the 5- or 6-membered monocyclic cycloalkyl ring being defined as described above, and the formed 8-10-membered condensed bicyclic heteroaryl is also called an 8-10-membered heteroarylcycloalkyl ring. Specific examples include, but are not limited to, the following structures.

[0347] [ka]

[0348] In the present invention, each of the above types of heteroaryls may be substituted, and if substituted, one or more substituents described in this application are preferred.

[0349] As used herein, the term "-alkyl-R" refers to a substituent formed by substituting one or more R groups with an alkyl group, and "-alkyl-" refers to an alkylene or alkylidene group formed after substitution. The R groups as used herein may include hydroxy, cyano, alkoxy, substituted amino, heterocycloalkyl, heteroaryl, alkyl halide, alkoxy halide, cycloalkyl, and alkynyl groups, and the groups represented by R are as defined herein. -C 1-6 Alkyl-R is preferred. -C 1-4 Alkyl-R is more preferred. -C 1-3 Alkyl-R is more preferred. -C 1-2 Alkyl-R is more preferred. Examples include -CH2-CH(CH3)-R, -CH2-CH2-CH2-R, -CH2-CH2-R, and -CH2-R.

[0350] As used herein, the term "hydroxy" refers to the -OH group.

[0351] As used herein, the term "hydroxymethyl" refers to -CH2OH. "Hydroxyethyl" refers to -CH2CH2OH or -CH(OH)CH3.

[0352] As used herein, the term "cyanomethyl" refers to -CH2CN. "Cyanoethyl" refers to -CH2CH2CN or -CHCNCH3.

[0353] As used herein, the term "amino" refers to -NH2.

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

[0355] As used herein, the term "nitro" refers to -NO2.

[0356] As used herein, the term "benzyl" refers to -CH2-benzene.

[0357] As used herein, the term "oxo" refers to =O.

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

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

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

[0361] In this specification, C 1-10 C 1-6 C is preferred. 1-4 More preferably, C 1-3 This is more preferable. For example, C 1-10 Alkyl groups are C 1-6 Alkyl alkyl groups are preferred, C 1-4 Alkyl alkyl groups are more preferred, C 1-3Alkyl alkyl groups are even more preferred. For example, C 1-10 The alcoholic group is C 1-6 Alcochyl group is preferred, C 1-4 Alcochyl group is more preferred, C 1-3 Alcocyl groups are even more preferred.

[0362] In this specification, C 3-20 C 3-10 C is preferred. 3-8 More preferably, C 3-6 More preferably, C 3-5 This 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 even more preferred.

[0363] This is called one embodiment of the present invention, in which any of the groups, the C 3-6 The cycloalkyl groups are selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

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

[0365] This is referred to as the present invention, in which 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] This is referred to as one embodiment of the present invention, in which any of the groups, the 8-10 membered bicyclic heteroaryl group is selected from benzoxazole, benzoisoxazole, benzimidazole, benzothiazole, benzisothiazole, benzotriazole, benzofuran, benzothiophene, indole, indazole, isoindole, quinoline, isoquinoline, quinazoline, quinoxaline, cinnoline, pyridopyrimidine, and naphthiridine.

[0367] As used herein, the term “substitution” refers to the substitution of one or more hydrogen atoms attached to a particular atom with a substituent, and may include deuterium and hydrogen variants, provided that the valence of the particular atom is normal and the substituted compound is stable. When the substituent is an oxo group (i.e., =O), it means that two hydrogen atoms are substituted. Oxo group substitution does not occur in aromatic groups. The terms “may be substituted” or “may be substituted” mean that substitution may or may not occur, and unless otherwise specified, the type and number of substituents may be arbitrary as long as they are chemically realized.

[0368] Any variable (e.g., R) that appears once or more in the composition or structure of a compound has an independent definition in each case. Therefore, for example, if a group is substituted with 0-2 Rs, that group may be substituted with 2 or fewer Rs, and each case has an independent selection of Rs. Furthermore, combinations of substituents and / or their variants are permitted only if such combinations produce a stable compound.

[0369] The compounds represented by formulas (IA) and (IB) according to the present invention can be prepared using synthetic methods known in the art, or combinations of synthetic methods known in the art and the methods of the present invention. The solvents, temperatures, and other reaction conditions provided by the present invention are all illustrative and may be modified based on well-known methods in the art. The compounds of the examples described in the present invention may be synthesized using appropriate starting materials by the methods of the examples, depending on their specific structure, or may be obtained by methods similar to those of 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 divided by well-known methods in the art, such as crystallization or chromatography, to obtain their stereoisomers, and the conditions for such division can be easily obtained by means known to those skilled in the art or by limited testing.

[0370] The compounds represented by formulas (IB-1') and (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 known reaction conditions in the art may be used.

[0371] [ka]

[0372] The compounds represented by formulas (IB-1') and (IB-2') according to the present invention can also be synthesized by the following method, wherein 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 known reaction conditions in the art may be used.

[0373] [ka]

[0374] In the preparation schemes for the compounds represented by formulas (IB-1') and (IB-2'), in each formula, R lev R is a leaving group well known to those skilled in the art, and includes, for example, trifluoromethanesulfonic acid ester group, chlorine, bromine, iodine, sulfonic acid ester groups such as methanesulfonic acid ester, toluenesulfonic acid ester, p-toluenesulfonic acid ester, and acyloxy groups such as acetoxy and trifluoroacetoxy. In each formula, R p R1, R2, R3, R 21 , R 22 , R 12 , R 11 , R 31 , R 32 , R m The definitions of ', R0', Ar', E1', and X1 are the same as above (for example, formula I is the same as the definition 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 method, wherein 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 known reaction conditions in the art may be used.

[0376] [ka]

[0377] In the preparation schemes for compounds of formula (IB-1'') and formula (IB-2''), in each formula, R p R1, R2, R3, R 21 , R 22 , R 12 , R 11 , R 31 , R 32 The definitions of R0', Ar', E1', and X1 are the same as above (for example, equation I is the same as the definition of each corresponding group in equation IA).

[0378] Of these, the compound of formula e can be further synthesized by the following method, where 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 known reaction conditions in the art may be used.

[0379] [ka]

[0380] In the preparation scheme for the compound represented by formula e, R lev R0' is a leaving group well known to those skilled in the art, and includes, for example, trifluoromethanesulfonic acid ester groups, chlorine, bromine, iodine, sulfonic acid ester groups such as methanesulfonic acid ester, toluenesulfonic acid ester, and p-toluenesulfonic acid ester, and acyloxy groups such as acetoxy and trifluoroacetoxy. The definitions of R0', Ar', E1', and X1 are the same as described above (for example, the same as the definitions of the corresponding groups in formulas I and IA). [Brief explanation of the drawing]

[0381] [Figure 1] This is a molecular structure diagram of compound Z25-2 obtained by single-crystal X-ray diffraction. [Figure 2] This is a molecular structure diagram of compound Z27-2 obtained by single-crystal X-ray diffraction. [Modes for carrying out the invention]

[0382] The compounds according to the present invention can be prepared by various synthesis methods well known to those skilled in the art, including, but are not limited to, the specific embodiments listed below, embodiments obtained by combining them with other chemical synthesis methods, and equivalent substitution methods well known to those skilled in the art. Preferred embodiments include, but are not limited to, the examples of the present invention. The present invention will be described in detail below with reference to examples, but this does not mean any unfavorable limitations on the present invention. This specification has described the present invention in detail, but the forms of the specific examples are disclosed, and it will be obvious to those skilled in the art that various changes and improvements can be made to the specific embodiments of the present invention without departing from the spirit and scope of the present invention. Specific conditions not specified in the examples are carried out under normal conditions or conditions presented by the manufacturer. Unless the manufacturer is specified, the reagents or equipment used are all common commercially available products.

[0383] The abbreviations for the reagents used in the following examples are as follows: THF: Tetrahydrofuran, DMSO: Dimethyl sulfoxide, PE: Petroleum ether, siRNA: Ethyl acetate, DCM: Dichloromethane, MeOH: Methanol, ACN: Acetonitrile, IPA: Isopropylamine, DMA: Dimethylamine, TFA: Trifluoroacetic acid, NH4Cl: Ammonium chloride, SPhos: 2-Dicyclohexylphosphino-2',6'-Dimethoxy-1,1'-Biphenyl, SPhos-Pd-G2: Chloro(2-Dicyclohexylphosphino-2',6'-Dimethoxy-1,1'-Biphenyl)[2-(2'-Amino-1,1'-Biphenyl)] Palladium(II), NaHMDS: Sodium bis(trimethylsilyl)amide, LiHMDS: Lithium bis(trimethylsilyl)amide.

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

[0385] When detecting isomer compounds using analytical HPLC methods, the following conditions can be adopted. 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: 15 min, 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: Dissolve 2-isopropyl-4-methylpyridine-3-amine (582 mg, 3.88 mmol) in THF (20 mL), cool the reaction system to 0°C, add NaHMDS (5.8 mL, 11.60 mmol, 2 M in THF) dropwise, and stir for 15 minutes. Add a solution of 2,5-difluoro-6-(2-fluoro-6-methoxyphenyl)nicotinic acid (1.0 g, 3.53 mmol) dissolved in THF (6 mL) dropwise. Stir at room temperature for 3 hours. Place the reaction mixture in 30 mL of saturated NH4Cl. Extract three times with 40 mL of ethyl acetate. After drying the organic layer, concentrate it. The crude product was purified using a high-speed silica gel column (0-5% MeOH / DCM) to obtain 5-fluoro-6-(2-fluoro-6-methoxyphenyl)-2-((2-isopropyl-4-methylpyridine-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-methylpyridine-3-yl)amino)nicotinic acid (700 mg, 1.69 mmol) was dissolved in 1,2-dichloroethane (15 mL), SOCl2 (2.0 g, 16.90 mmol) was added, and the mixture was stirred at 80°C for 2 hours. After concentration, the product 5-Fluoro-6-(2-Fluoro-6-methoxyphenyl)-2-((2-isopropyl-4-methylpyridine-3-yl)amino)nicotinic acid chloride was obtained (721 mg, Y: 100%), which did not require purification and was used directly in the next reaction. Step 3: At 0°C, a solution of ethyl nitro(449 mg, 3.38 mmol) in THF (2 ml) was added dropwise to a suspension of THF (25 mL) containing NaH (608 mg, 15.21 mmol), and the mixture was stirred at 0°C for 0.5 hours. A solution of 5-fluoro-6-(2-fluoro-6-methoxyphenyl)-2-((2-isopropyl-4-methylpyridine-3-yl)aminonicotinate chloride (721 mg, 1.69 mmol) in THF (15 mL) was added dropwise. The ice bath was removed, and the reaction mixture was stirred at 70°C overnight. The reaction mixture was poured into ice water, the pH was adjusted to 3 with 3.0 M dilute hydrochloric acid, and the mixture was extracted three times with ethyl acetate. After drying the organic layer, it was concentrated to obtain 6-fluoro-7-(2-fluoro-6-methoxyphenyl)-4-hydroxy-1-(2-isopropyl-4-methylpyridine-3-yl)-3-nitro-1,8-naphthyridine-2(1H)-one (1.05 g, crude product) as the product, which was then used directly in the next reaction. ES-API:[M+H] + =483.1 Step 4: Dissolve 6-fluoro-7-(2-fluoro-6-methoxyphenyl)-4-hydroxy-1-(2-isopropyl-4-methylpyridine-3-yl)-3-nitro-1,8-naphthyridine-2(1H)-one (1.05 g, 1.69 mmol) in acetonitrile (25 mL), then add POCl3 (1.30 g, 8.45 mmol) and N,N-diisopropylethylamine (1.74 g, 13.52 mmol) in sequence, and stir at 80°C for 1 hour. After concentrating the reaction mixture, add ethyl acetate and wash sequentially with ice water, water, and saturated saline solution. The organic layer was dried and concentrated, and the crude product was purified by high-speed silica gel column (Âti / PE: 0-50%) to obtain 4-chloro-6-fluoro-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropyl-4-methylpyridine-3-yl)-3-nitro-1,8-naphthyrizin-2(1H)-one as a yellow solid (185 mg, Y: 21.9%). ES-API:[M+H] + = 500.1 Step 5: Dissolve 4-chloro-6-fluoro-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropyl-4-methylpyridine-3-yl)-3-nitro-1,8-naphthyridine-2(1H)-one (175 mg, 0.35 mmol) in DMF (6 mL), add (R)-3-(hydroxymethyl)piperazine-1-carboxylic acid-tert-butyl ester (454 mg, 2.10 mmol), and stir at 80°C for 18 hours. Pour the reaction mixture into 30 mL of water and extract three times with 20 mL of ethyl acetate. The organic layer was washed three times with saturated saline solution, dried, and concentrated. The crude product was then purified by high-performance silica gel column (siRNA / PE: 0-70%) to obtain the yellow solid (3R)-4-(6-fluoro-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropyl-4-methylpyridine-3-yl)-3-nitro-2-oxo-1,2-dihydro-1,8-naphthyridine-4-yl)-3-(hydroxymethyl)piperazine-1-carboxylic acid-tert-butyl ester (85 mg, Y: 35.7%). ES-API:[M+H] + = 681.3. Step 6: (3R)-4-(6-fluoro-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropyl-4-methylpyridine-3-yl)-3-nitro-2-oxo-1,2-dihydro-1,8-naphthyridine-4-yl)-3-(hydroxymethyl)piperazine-1-carboxylic acid-tert-butyl ester (73 mg, 0.11 mmol) was dissolved in DMA (4 mL), NaH (22 mg, 0.55 mmol) was added, and the mixture was stirred at 145°C for 10 hours. The cooled reaction mixture was poured into 15 mL of water and extracted three times with 30 mL of ethyl acetate. The organic layer was washed three times with saturated saline solution, dried, and concentrated. The crude product was then purified by thin-layer chromatography (dichloromethane / methanol = 20:1) to obtain the yellow solid (4aR)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridine-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-methylpyridine-3-yl)-7-oxo-1,2,4a,5,7,8-hexahydropyrazine[1',2':4,5][1,4]oxo-2,3-c][1,8]naphthyridine-3(4H)-carboxylic acid-tert-butyl ester (35 mg, 0.055 mmol) was dissolved in dichloromethane (2.5 mL), trifluoroacetic acid (0.5 mL) was added, and the mixture was stirred at room temperature for 0.5 hours. The reaction mixture was concentrated to obtain (4aR)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridine-3-yl)-1,2,3,4,4a,5-hexahydropyrazine[1',2':4,5][1,4]oxazine[2,3-c][1,8]naphthyridine-7(8H)-one (40 mg, crude product) as the product, which was used directly in the next reaction. ES-API:[M+H] + = 534.3. Step 8: Dissolve 4aR)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridine-3-yl)-1,2,3,4,4a,5-hexahydropyrazine[1',2':4,5][1,4]oxazin[2,3-c][1,8]naphthyridine-7(8H)-one (40 mg, 0.055 mmol) in dichloromethane (4 mL), add triethylamine (28 mg, 0.28 mmol), cool the reaction system to 0°C, and add a 0.5 mL solution of acrylic anhydride (6 mg, 0.05 mmol) in dichloromethane dropwise to the reaction mixture. Stir at 0°C for 15 minutes. Add 10 mL of saturated NaHCO3 aqueous solution to the reaction mixture and extract three times with 10 mL of dichloromethane. After drying the organic layer, concentrate it. The crude product was purified by thin-layer chromatography (dichloromethane / methanol = 10:1) to obtain (4aR)-3-acryloyl-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridine-3-yl)-1,2,3,4,4a,5-hexahydropyrazine[1',2':4,5][1,4]oxazine[2,3-c][1,8]naphthyridine-7(8H)-one 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-methylpyridine-3-yl)-1,2,3,4,4a,5-hexahydropyrazine[1',2':4,5][1,4]oxazine[2,3-c][1,8]naphthyridine-7(8H)-one (15 mg, 0.025 mmol) was dissolved in dichloromethane (1.5 mL), the reaction system was cooled to 0°C, and a 17% solution of boron tribromide in dichloromethane (1 mL) was added dropwise. The mixture was stirred at room temperature for 3 hours. 20 mL of saturated aqueous NaHCO3 solution was added to the reaction mixture 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 obtain (4aR)-3-acryloyl-11-fluoro-10-(2-fluoro-6-hydroxyphenyl)-8-(2-isopropyl-4-methylpyridine-3-yl)-1,2,3,4,4a,5-hexahydropyrazine[1',2':4,5][1,4]oxazine[2,3-c][1,8]naphthirizine-7(8H)-one (Z1:10 mg, Y:68.3%) as a white solid. 1 H NMR (500MHz, DMSO-d6) δ9.96(s, 1H), 8.35(d, J=4.8Hz, 1H), 7.19-7.14(m, 2H), 6.87-6.75(m, 1H), 6.64(d, J=8.5Hz, 1H), 6.59(t, J=8.5Hz, 1H), 6.12(d, J=15.9Hz, 1H), 5.71-5.67(m, 1H), 4.39-3.95(m, 4H), 3.79-3.30(m, 4H), 3.06-2.98(m, 1H), 2.56-2.29(m, 1H), 1.80-1.73(m, 3H), 0.99-0.95(m, 3H), 0.85-0.80(m, 3H).ES-API:[M+H] + = 574.2. Step 10: Compound Z1 was divided 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 obtain a pale yellow solid atropisomer compound, whose structure was designated as Z1-1 (75 mg, peak 1, retention time 3.94 min, Y: 15.4%). 1 H NMR (400MHz, DMSO-d6). δ10.04(s, 1H), 8.42(d, J=4.9Hz, 1H), 8.22(d, J= 8.3Hz, 1H), 7.28-7.20(m, 2H), 6.96-6.81(m, 1H), 6.75-6.58(m, 2H), 6.18(d, J=17.1Hz, 1H), 5.82-5.69(m, 1H), 4.49-4.00(m, 4H), 3.90-3.43(m, 4H), 3.08(t, J=11.0 Hz, 1H), 2.64-2.55(m, 1H), 1.80(s, 3H), 1.05(d, J=6.7Hz, 3H), 0.91(d, J=6.7Hz, 3H).ES-API:[M+H] + =574.2. In addition, the other atropisomer compound obtained was a pale yellow solid, and its structure was designated as Z1-2 (115 mg, peak 2, retention time: 5.04 min, Y: 23.6%). 1 H NMR (400MHz, DMSO-d6) δ10.05(s, 1H), 8.42(d, J=4.8Hz, 1H), 8.22(d, J=6.9Hz, 1H), 7.28-7.20(m, 2H), 6.96-6.81(m, 1H), 6.74-6.59(m, 2H), 6.19(d, J=16.7Hz, 1H), 5.83-5.68(m, 1H), 4.49-4.00(m, 4H), 3.94-3.44(m, 4H), 3.08(t, J=11.0Hz, 1H), 2.49-2.41(m, 1H), 1.87(s, 3H), 1.03(dd, J=6.3, 3.7Hz, 3H), 0.88(d, J=6.6Hz, 3H).ES-API:[M+H] += 574.2. The isomer compounds were detected by analytical chiral HPLC (column: Chiralpak IC: 5 μm, 4.6 x 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-dioxan-4,6-dione (2.9 g, 15.62 mmol) and isopropyl alcohol (40 mL) were added to a 100 mL flask, and 2-pyridine-3-amine chloride (2.0 g, 15.62 mmol) was added batchwise. The mixture was stirred under 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. After vacuum drying, the product was obtained as a white solid, 5-((2-chloropyridine-3-yl)amino)methylene)-2,2-dimethyl-1,3-dioxan-4,6-dione (3.90 g, Y: 58.2%). ES-API:[M+H] + =283.1 Step 2: Add 200 mL of diphenyl ether to a 500 mL flask and heat to 220 °C. Add 5-((2-chloropyridine-3-yl)amino)methylene)-2,2-dimethyl-1,3-dioxan-4,6-dione (3.9 g, 13.83 mmol) in a batch manner and stir at 220 °C for 20 minutes. Cool the reaction mixture to room temperature. Then, pour into petroleum ether, filter the precipitated solid, and wash the filter cake with petroleum ether. Vacuum dry to obtain 8-chloro-1,7-naphthyridine-4-ol (1.5 g, Y:60%) as a light brown solid. ES-API:[M+H] + =181.0 Step 3: Add 8-chloro-1,7-naphthirizin-4-ol (500 mg, 2.78 mmol), sodium acetate (300 mg, 2.78 mmol), anhydrous ethanol (25 mL), and 5% Pd / C (250 mg) to a 50 mL flask and stir at room temperature under a hydrogen atmosphere for 3 days. Filter the reaction mixture through diatomaceous earth and concentrate the filtrate. Then, purify the crude product using a high-performance silica gel column (dichloromethane / methanol: 0-10%) to obtain 1,7-naphthirizin-4-ol (200 mg, Y: 49.3%) as a yellow solid. ES-API:[M+H] + =147.1 Step 4: 1,7-Naphthyridine-4-ol (550 mg, 3.77 mmol) was dissolved in concentrated sulfuric acid (4.5 mL) and cooled to 0°C. Concentrated nitric acid (1.0 mL, 15.08 mmol) was slowly added dropwise, and the mixture was stirred at 100°C for 1 hour. The cooled reaction mixture was poured into ice water. The pH was adjusted to 6-7 with concentrated ammonia water, and the precipitated solid was filtered. Vacuum drying was performed to obtain the product as a yellow solid, 3-nitro-1,7-naphthyridine-4-ol (530 mg, Y: 73.7%). ES-API:[M+H] + =192.1 Step 5: Add 3-nitro-1,7-naphthirizine-4-ol (480 mg, 2.51 mmol) and phosphorus oxychloride (4.68 mL, 50.20 mmol) to a 20 mL flask and cool to -15°C. Slowly add triethylamine (1.8 mL, 12.55 mmol) dropwise and stir at room temperature for 1 hour. Pour the reaction mixture into ice water and adjust the pH to 8 with cold saturated sodium bicarbonate solution, then extract three times with dichloromethane. The organic layer was dried and concentrated to obtain the brown solid 4-chloro-3-nitro-1,7-naphthirizine (450 mg, Y: 85.7%) as the product. ES-API:[M+H] + = 210.1. Step 6: 4-chloro-3-nitro-1,7-naphthiridine (450 mg, 2.15 mmol) was dissolved in 1,4-dioxane (15 mL), and (R)-3-(hydroxymethyl)piperazine-1-carboxylic acid-tert-butyl ester (1.02 g, 4.73 mmol) and N,N-diisopropylethylamine (832 mg, 6.45 mmol) were added sequentially. The mixture was stirred at 80°C for 3 hours. After concentrating the reaction mixture, the crude product was purified using a high-performance silica gel column (siRNA / PE: 50-100%) to obtain the yellow solid (R)-3-(hydroxymethyl)-4-(3-nitro-1,7-naphthiridine-4-yl)piperazine-1-carboxylic acid-tert-butyl (330 mg, Y: 39.4%) as the product. ES-API: [M+H] + = 390.2. Step 7: (R)-3-(hydroxymethyl)-4-(3-nitro-1,7-naphthirizine-4-yl)piperazine-1-carboxylate tert-butyl (310 mg, 0.80 mmol), DMF (18 mL), and NaH (96 mg, 2.40 mmol) were added sequentially to a 50 mL tube, and the mixture was stirred at 95 °C for 3 days. The cooled reaction mixture was poured into water and extracted twice with ethyl acetate. The organic layer was washed three times with saturated brine, dried and concentrated, and the crude product was purified by thin-layer chromatography (dichloromethane / methanol = 15:1) to obtain the yellow solid (R)-8a,9,11,12-tetrahydropyrazine[1',2':4,5][1,4]oxazine[2,3-c][1,7]naphthirizine-10(8H)-carboxylate tert-butyl (175 mg, Y:64%) as the product. ES-API: [M+H] + =343.3 Step 8: Dissolve (R)-8a,9,11,12-tetrahydropyrazine[1',2':4,5][1,4]oxazine[2,3-c][1,7]naphthyridine-10(8H)-carboxylate tert-butyl (100 mg, 0.29 mmol) in acetic acid (4 mL), add sodium borohydride cyanohydride (73 mg, 1.16 mmol), and stir overnight at room temperature. Pour the reaction mixture into ice water, adjust the pH to 8 with saturated sodium bicarbonate solution, and extract twice with dichloromethane. Wash the organic layer with saturated saline solution. After drying and concentration, the crude product was purified by thin-layer chromatography (dichloromethane / methanol / aqueous ammonia = 100:8:1) to obtain (R)-1,2,3,4,8a,9,11,12-octahydropyrazine[1',2':4,5][1,4]oxazine[2,3-c][1,7]naphthirizine-10(8H)-carboxylate tert-butyl (50 mg, Y: 49.4%) as a pale yellow solid. ES-API: [M+H] + = 390.2. Step 9: Add (R)-1,2,3,4,8a,9,11,12-octahydropyrazine[1',2':4,5][1,4]oxazine[2,3-c][1,7]naphthiridine-10(8H)-carboxylate tert-butyl (50 mg, 0.14 mmol), 4-bromo-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (83 mg, 0.28 mmol), cesium carbonate (136 mg, 0.42 mmol), Pd2(dba)3 (51 mg, 0.056 mmol), Ruphos (26 mg, 0.056 mmol), and toluene (6 mL) to a 5 mL microtube, replace the atmosphere with nitrogen gas, and then microwave at 120°C. oThe mixture was stirred in 1°C for 1 hour. After cooling to room temperature, it was filtered, dried, and 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-indazole-4-yl)-1,2,3,4,8a,9,11,12-octahydropyrazine[1',2':4,5][1,4]oxazine[2,3-c][1,7]naphthirizine-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-indazole-4-yl)-1,2,3,4,8a,9,11,12-octahydropyrazine[1',2':4,5][1,4]oxazine[2,3-c][1,7]naphthirizine-10(8H)-carboxylate tert-butyl (60 mg, 0.11 mmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (0.8 mL) was added. The mixture was stirred at room temperature for 1 hour, and the reaction solution was concentrated to obtain (R)-3-(5-methyl-1H-indazole-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]naphthirizine) (60 mg, crude yield) as the product. Purification was not necessary, and it was used directly in the next reaction. ES-API:[M+H] + = 377.1. Step 11: (R)-3-(5-methyl-1H-indazole-4-yl)-1,2,3,4,8,8a,9,10,11,12-decahydropyrazine[1',2':4,5][1,4]oxazine[2,3-c][1,7]naphthyridine (60 mg, 0.11 mmol) and N,N-diisopropylethylamine (71 mg, 0.55 mmol) were dissolved in dichloromethane (5 mL), the reaction system was cooled to 0°C, and a solution of acrylic anhydride (13 mg, 0.10 mmol) in dichloromethane (0.5 mL) was added dropwise to the reaction mixture. The mixture was stirred at 0°C for 10 minutes. 10 mL of saturated aqueous NaHCO3 was added to the reaction mixture and extracted three times with 10 mL of dichloromethane. The organic layer was dried and then concentrated. The crude product was purified by preparative HPLC to obtain (R)-1-(3-(5-methyl-1H-indazole-4-yl)-1,2,3,4,8a,9,11,12-octahydropyrazine[1',2':4,5][1,4]oxazine[2,3-c][1,7]naphthirizine-10(8H)-yl)propyl-2-en-1-one (Z2, 12 mg, Y: 26.0%) as a white solid. 1 H NMR (500MHz, DMSO-d6) δ12.91(s, 1H), 8.04(s, 1H), 7.86(s, 1H), 7.21-7.07(m, 2H), 6.89-6.64(m, 1H), 6.09 (d, J=16.6Hz, 1H), 5.67(m, 1H), 4.21-4.11(m, 3H), 3.96(t, J=10.0Hz, 1H), 3.86-3.53(m, 4H), 3.45-3.30(m, 2H), 3.15-3.08(m, 1H), 2.86-2.75 (m, 2H), 2.28(s, 3H).ES-API:[M+H] + = 431.2.

[0392] Example 3: Preparation of compounds Z3a and Z3

[0393] [ka]

[0394] Step 1: Dissolve 4-chloro-6-fluoro-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropyl-4-methylpyridine-3-yl)-3-nitro-1,8-naphthyridine-2(1H)-one (700 mg, 1.40 mmol) in DMF (10 mL), add (2R,5R)-5-(hydroxymethyl)-2-methylpiperazine-1-carboxylate tert-butyl (1.61 g, 7.0 mmol), and stir at 80°C for 1 hour. Inject the reaction mixture into 30 mL of water and extract three times with 20 mL of ethyl acetate. The organic layer was washed three times with saturated saline solution, dried, and concentrated. The crude product was then purified by high-speed silica gel column (siRNA / PE: 0-70%) to obtain the yellow solid (2R, 5R)-4-(6-fluoro-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropyl-4-methylpyridine-3-yl)-3-nitro-2-oxo-1,2-dihydro-1,8-naphthyridine-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)-4-(6-fluoro-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropyl-4-methylpyridine-3-yl)-3-nitro-2-oxo-1,2-dihydro-1,8-naphthyridine-4-yl)-5-(hydroxymethyl)-2-methylpiperazine-1-carboxylate tert-butyl (300 mg, 0.44 mmol) was dissolved in DMA (20 mL), NaH (52 mg, 1.32 mmol) was added, and the mixture was stirred at 125 °C for 20 hours. The cooled reaction mixture was poured into 15 mL of water and extracted three times with 30 mL of ethyl acetate. The organic layer was washed eight times with saturated saline solution. After drying and concentration, the crude product was purified by high-speed silica gel column (siRNA / PE: 0-100%) to obtain (2R, 4aR)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridine-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 the yellow solid product. ES-API:[M+H]+=648.3. Step 3: (2R, 4aR)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridine-3-yl)-2-methyl-7-oxo-1,2,4a,5,7,8-hexahydropyrazine[1',2':4,5][1,4]oxydine[2,3-c][1,8]naphthyridine-3(4H)-carboxylate tert-butyl (60 mg, 0.093 mmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (0.7 mL) was added. The mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated to obtain (2R,4aR)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridine-3-yl)-2-methyl-1,2,3,4,4a,5-hexahydropyrazine[1',2':4,5][1,4]oxazine[2,3-c][1,8]naphthyridine-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, 4 aR)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridine-3-yl)-2-methyl-1,2,3,4,4a,5-hexahydropyrazine[1',2':4,5][1,4]oxazine[2,3-c][1,8]naphthyridine-7(8H)-one (61 mg, 0.093 mmol) was dissolved in dichloromethane (5 mL), and triethylamine (47 mg, 0.46 mmol) was added. The reaction system was cooled to 0°C, and a dichloromethane solution of acrylic anhydride (17 mg, 0.14 mmol) (1 mL) was added dropwise to the reaction mixture. The mixture was stirred at 0°C for 15 minutes. 10 mL of saturated NaHCO3 aqueous solution was added to the reaction mixture, and it was 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 obtained was a white solid ((2R,4aR)-3-acryloyl-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridine-3-yl)-2-methyl-1,2,3,4,4a,5-hexahydropyrazine[1',2':4,5][1,4]oxyzine[2,3-c][1,8]naphthyridine-7(8H)-one (Z3a, 32 mg, Y: 57.4%). ES-API:[M+H] + = 602.2. 1 H NMR (500MHz, DMSO-d6) δ8.42 (d, J = 4.1Hz, 1H), 7.87 (d, J = 8.8Hz, 1H), 7.43 (dd, J = 15.4, 8.3Hz, 1H), 7.21 (d, J=4.8Hz, 1H), 6.99-6.78(m, 3H), 6.17(d, J=17.4Hz, 1H), 5.75(d, J=10.5Hz, 1H), 4.80-4.15(m, 4H), 3.94-3.35(m, 6H) ), 3.13-2.97(m, 1H), 2.62-2.40(m, 1H), 1.90-1.73(m, 3H), 1.66-1.48(m, 3H), 1.08-0.95(m, 3H), 0.91-0.77(m, 3H). Step 5: (6aR,9R)-8-acryloyl-3-fluoro-2-(2-fluoro-6-methoxyphenyl)-13-(2-isopropyl-4-methylpyridine-3-yl)-9-methyl-6,6a,7,8,9,10-hexahydropyrazine[1',2':4,5][1,4]oxydine[3,2-c][1,8]naphthyrizine-12(cyclohexyl)-one (32 mg, 0.053 mmol) was dissolved in dichloromethane (1.5 mL), the reaction system was cooled to 0°C, and a 17% boron tribromide solution in dichloromethane (1 mL) was added dropwise. The mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into 20 mL of saturated NaHCO3 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 obtain the white solid (6aR,9R)-8-acryloyl-3-fluoro-2-(2-fluoro-6-hydroxyphenyl)-13-(2-isopropyl-4-methylpyridine-3-yl)-9-methyl-6,6a,7,8,9,10-hexahydropyrazine[1',2':4,5][1,4]oxyzineoxazine[3,2-c][1,8]naphthyridine-12(cyclohexyl)-one (Z3, 18 mg, Y: 57.6%). ES-API:[M+H] + = 588.3.

[0395] Example 6 Preparation of Compound Z6

[0396] [ka]

[0397] Step 1: Dissolve 4,6-dichloro-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropyl-4-methylpyridine-3-yl)-3-nitro-1,8-naphthyridine-2(1H)-one (1.8g, 3.48 mmol) in DMF (15 mL), add (R)-3-(hydroxymethyl)piperazine-1-carboxylic acid-tert-butyl ester (3 g, 13.92 mmol), and stir at 80°C for 2 hours. Inject the reaction mixture into 30 mL of water and extract three times with 20 mL of ethyl acetate. The organic layer was washed three times with saturated saline solution, dried, and concentrated. The crude product was then purified by high-performance silica gel column (siRNA / PE: 0-70%) to obtain the yellow solid (3R)-4-(6-chloro-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropyl-4-methylpyridine-3-yl)-3-nitro-2-oxo-1,2-dihydro-1,8-naphthyridine-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-methylpyridine-3-yl)-3-nitro-2-oxo-1,2-dihydro-1,8-naphthyridine-4-yl)-3-(hydroxymethyl)piperazine-1-carboxylate tert-butyl (1.3g, 1.86 mmol) was dissolved in DMA (10 mL), LHMDS (5.6 mmol, 5.6 mmol, 1 M tetrahydrofuran solution) was added, and the mixture was stirred at 140°C for 20 hours. The cooled reaction mixture was poured into 15 mL of water and extracted three times with 30 mL of ethyl acetate. The organic layer was washed three times with saturated saline solution, dried, and concentrated. The crude product was then purified by high-performance silica gel column chromatography (methanol / dichloromethane: 0-10%) to obtain the yellow solid (4aR)-11-chloro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridine-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-methylpyridine-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 hours. After concentrating the reaction mixture, the product obtained was (4aR)-11-chloro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridine-3-yl)-1,2,3,4,4a,5-hexahydropyrazine-[1',2':4,5][1,4]oxazine-[2,3-c][1,8]naphthyridine-7(8H)-one (203 mg, crude product), which was used directly in the next reaction. ES-API:[M+H] + = 550.1. Step 4: (4aR)-11-chloro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridine-3-yl)-1,2,3,4,4a,5-hexahydropyrazine-[1',2':4,5][1,4]oxazin-[2,3-c][1,8]naphthyridine-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 solution of acrylic anhydride (37 mg, 0.30 mmol) in dichloromethane (0.5 mL) was added dropwise to the reaction mixture. The mixture was stirred at 0°C for 10 minutes. 10 mL of saturated aqueous NaHCO3 was added to the reaction mixture, and the mixture was extracted three times with 10 mL of dichloromethane. The organic layer was dried and then concentrated. The crude product was purified by thin-layer chromatography (dichloromethane / methanol = 10:1) to obtain (4aR)-3-acryloyl-11-chloro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridine-3-yl)-1,2,3,4,4a,5-hexahydropyrazine-[1',2':4,5][1,4]oxazine-[2,3-c][1,8]naphthyridine-7(8H)-one (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-methylpyridine-3-yl)-1,2,3,4,4a,5-hexahydropyrazine-[1',2':4,5][1,4]oxazin-[2,3-c][1,8]naphthyridine-7(8H)-one (223 mg, 0.37 mmol) was dissolved in dichloromethane (1.5 mL), the reaction system was cooled to 0°C, and a 17% boron tribromide solution in dichloromethane (3 mL) was added dropwise. The mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into 20 mL of saturated NaHCO3 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 obtain (4aR)-3-acryloyl-11-chloro-10-(2-fluoro-6-hydroxyphenyl)-8-(2-isopropyl-4-methylpyridine-3-yl)-1,2,3,4,4a,5-hexahydropyrazine-[1',2':4,5][1,4]oxazine-[2,3-c][1,8]naphthyridine-7(8H)-one (Z6, 26.28 mg, 11%) as the white solid product. 1 H NMR (400MHz, DMSO-d6) δ8.42-8.36(m, 2H), 7.22-7.18 (m, 2H), 6.68-6.62(m, 3H), 6.22-6.17(m, 1H), 5.78-5.77(m, 1H), 4.46-3.55(m, 8H), 3.12-3.10(m, 1H), 2.52-2.51(m, 1H), 1.88-1.80(m, 3H), 1.06-1.04(m, 3H), 0.89-0.86(m, 3H).ES-API:[M+H] + = 590.2.

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

[0399] [ka]

[0400] Step 1: Dissolve 4-chloro-6-fluoro-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropyl-4-methylpyridine-3-yl)-3-nitro-1,8-naphthyridine-2(1H)-one (500 mg, 1.00 mmol) in N,N-dimethylacetamide (6 mL) and (R)-1-(tert-butyl-3-methyl-piperazine-1,3-dicarboxylic acid ester (732 (387 mg, 3.00 mmol) and N,N-diisopropylethylamine (387 mg, 3.00 mmol) were added sequentially, and the mixture was stirred at 120°C for 2 hours. 100 mL of ethyl acetate was added to the reaction mixture, and it was washed four times with 30 mL of dilute saline. After washing with 30 mL of saturated saline, the mixture was dried and concentrated, and the crude product was purified by high-performance silica gel column (siRNA / PE: 0-70%) to obtain the yellow solid (3R)-1-(tert-butyl)-3-methyl-4-(6-fluoro-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropyl-4-methylpyridine-3-yl)-3-nitro-2-oxo-1,2-dihydro-1,8-naphthyridine-4-yl)piperazine-1,3-dicarboxylic acid ester (500 mg, Y: 70.6%). 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-methylpyridine-3-yl)-3-nitro-2-oxo-1,2-dihydro-1,8-naphthyridine-4-yl)piperazine-1,3-dicarboxylic acid ester (500 mg, 0.71 mmol) was dissolved in acetic acid (8 mL), iron powder (138 mg, 2.47 mmol) was added, and the mixture was stirred at 80°C for 30 minutes. After concentrating the reaction mixture, 50 mL of ethyl acetate and 30 mL of saturated sodium bicarbonate were added in sequence, the suspension was filtered through diatomaceous earth, and the filter cake was washed with ethyl acetate. The organic layer was separated and washed in sequence with 30 mL of saturated sodium bicarbonate aqueous solution and 30 mL of saturated saline solution. The mixture was dried and concentrated to obtain (4aR)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridine-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 product. ES-API:[M+H] + = 647.2. Step 3: (4aR)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridine-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]naphthyrizine-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 sequentially to a 15 mL tube. The tube was sealed and stirred at 50°C for 20 hours. After concentrating the reaction mixture, 60 mL of ethyl acetate was added, and the mixture was washed sequentially with 30 mL of water and 30 mL of saturated saline. After drying and concentration, the crude product was purified by high-speed silica gel column (siRNA / PE: 0-70%) to obtain the orange solid (4aR)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridine-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%). ES-API:[M+H] + = 661.3. Step 4: (4aR)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridine-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 solution was concentrated to obtain (4aR)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridine-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 (1.1g, crude product), which was then used directly in the next reaction. ES-API:[M+H] + = 561.3. Step 5: (4aR)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridine-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 system was cooled to 0°C, acrylate chloride (256 mg, 2.84 mmol) was added to the reaction mixture, and the mixture was stirred at 0°C for 15 minutes. 30 mL of dichloromethane was added to the reaction mixture, and the mixture was washed sequentially with 15 mL of water, 15 mL of saturated NaHCO3 aqueous solution, and 15 mL of saturated saline solution. After drying and concentration, the crude product was purified by high-speed silica gel column (siRNA / PE: 0-100%) to obtain (4aR)-3-acryloyl-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridine-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-methylpyridine-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% boron tribromide solution in dichloromethane (7 mL) was added dropwise. The mixture was stirred at room temperature for 6 hours. The reaction mixture was poured into 60 mL of saturated NaHCO3 aqueous solution and extracted twice with 80 mL of dichloromethane. The organic layer was washed sequentially with 50 mL of saturated NaHCO3 aqueous solution and then with 80 mL of saturated saline solution. After drying, the mixture was concentrated to obtain (4aR)-3-acryloyl-11-fluoro-10-(2-fluoro-6-hydroxyphenyl)-8-(2-isopropyl-4-methylpyridine-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 (Z9:375mg, Y:98.4%) as a pale yellow solid product. ES-API:[M+H] + = 601.2. Step 7: (4aR)-3-acryloyl-11-fluoro-10-(2-fluoro-6-hydroxyphenyl)-8-(2-isopropyl-4-methylpyridine-3-yl)-6-methyl-2,3,4,4a,6,8-hexahydro-1H-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8,8]naphthirizine-5,7-dione (750 mg, 1.25 mmol) was purified by preparative HPLC. Subsequently, the mixture 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). One atropisomer compound was obtained, which was a pale yellow solid, and its structure was designated as Z9-1 (250 mg, peak 1, retention time: 6.463 min, Y: 33.3%). 1H NMR (500MHz, DMSO-d6) δ10.11 (d, J =1.3Hz, 1H), 8.46-8.34 (m, 2H), 7.30-7.19 (m, 2H), 7.10-6.79 (m, 1H), 6.74-6.62(m, 2H), 6.15(d, J=16.9Hz, 1H), 5.75(d, J =12.0Hz, 1H), 4.73(d, J=13.3Hz, 1H), 4.45(d, J=12.7Hz, 1H), 4.10-3.97(m, 1H), 3.63-3.47(m, 2H), 3.39-3.08(m, 4H), 2.83-2.59(m, 1H), 2.48-2.39(m, 1H), 1.99(s, 3H), 1.02(d, J=6.7Hz, 3H), 0.85(d, J=6.7Hz, 3H).ES-API:[M+H] + =601.2. In addition, the other atropisomer compound obtained was a pale yellow solid, and its structure was designated as Z9-2 (350 mg, peak 2, retention time 8.252 min, Y: 46.7%). 1 H NMR (500MHz, DMSO-d6) δ10.14(s, 1H), 8.44(d, J=4.9Hz, 1H), 8.38(d, J=9.0Hz , 1H), 7.29-7.20(m, 2H), 7.10-6.79(m, 1H), 6.76-6.59(m, 2H), 6.15(d, J=16.9 Hz, 1H), 5.75(d, J=11.1Hz, 1H), 4.73(d, J=14.0Hz, 1H), 4.45(d, J=12.4Hz, 1H), 4.02-3.89(m, 1H), 3.62-3.50(m, 2) ES-API:[M+H] + =601.2. The isomer compounds were detected by analytical chiral HPLC (column: IB: 5 μm, 4.6 x 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-methylpyridine-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 mixture, 60 mL of ethyl acetate was added, and the mixture was washed sequentially with 20 mL of water and 30 mL of saturated saline solution. After drying and concentration, the crude product was purified by high-speed silica gel column (siRNA / PE: 0-70%) to obtain the orange solid (2R, 4aR)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridine-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%). ES-API:[M+H] + = 675.3. Step 2: (2R, 4aR)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridine-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 hours. The reaction mixture was concentrated to obtain (2R,4 aR)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridine-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) as the 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-methylpyridine-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 system was cooled to 0°C, acrylate chloride (211 mg, 2.34 mmol) was added to the reaction mixture, and the mixture was stirred at 0°C for 15 minutes. 50 mL of dichloromethane was added to the reaction mixture, and the mixture was washed sequentially with 20 mL of water, 40 mL of saturated NaHCO3 aqueous solution, and 20 mL of saturated saline solution. After drying and concentration, the crude product was purified by high-speed silica gel column (siRNA / PE: 0-100%) to obtain (2R,4aR)-3-acryloyl-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridine-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-methylpyridine-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% boron tribromide solution in dichloromethane (7 mL) was added dropwise. The mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into 60 mL of saturated NaHCO3 aqueous solution and extracted twice with 80 mL of dichloromethane. The organic layer was washed sequentially with 50 mL of saturated NaHCO3 aqueous solution and then with 80 mL of saturated saline solution. After drying and concentration, the crude product was purified by preparative HPLC to obtain (2R,4aR)-3-acryloyl-11-fluoro-10-(2-fluoro-6-hydroxyphenyl)-8-(2-isopropyl-4-methylpyridine-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 divided by preparative chiral HPLC (column: OD-H: 10 μm, 20 * 250 mm, mobile phase: hexane:EtOH = 80:20, flow rate: 15 ml / min, column temperature: room temperature). One atropisomer compound was obtained, which was a pale yellow solid, and its structure was designated as Z10-1 (206 mg, peak 1, retention time: 8.321 min, Y: 45.7%). 1H NMR (500MHz, DMSO-d6) δ10.13(d, J=1.3Hz, 1H), 8.44(d, J=4.9Hz, 1H), 8.02-7.95(m, 1H), 7.33-7. 20(m, 2H), 7.06-6.82(m, 1H), 6.76-6.63(m, 2H), 6.24-6.08(m, 1H), 5.82-5.67(m, 1H), 5.05-4.73( m, 1H), 4.63-4.37(m, 1H), 4.07-3.97(m, 1H), 3.73(dd, J=14.1, 4.2Hz, 1H), 3.39-3.20(m, 4H), 2.9 4-2.78(m, 1H), 2.49-2.39(m, 1H), 1.99(s, 3H), 1.61-1.49(m, 3H), 1.02(d, J=6.7Hz, 3H), 0.85(d, J =6.7Hz, 3H).ES-API:[M+H] + =615.2. In addition, the other atropisomer compound obtained was a yellow solid, and its structure was specified as Z10-2 (209 mg, peak 2, retention time: 10.183 min, Y: 46.4%). 1 H NMR (500MHz, DMSO-d6) δ10.15(s, 1H), 8.45(d, J=4.9Hz, 1H), 8.03-7.95(m, 1H), 7.30-7.18(m, 2H), 7.06-6.82(m, 1H), 6.75-6.61(m , 2H), 6.21-6.09(m, 1H), 5.80-5.65(m, 1H), 5.05-4.72(m, 1H), 4.63-4.37(m, 1H), 4.01-3.92 (m, 1H), 3.74(dd, J=14.2, 4.2Hz, 1H), 3.43-3.21(m, 4H), 2.95- 2.82(m, 1H), 2.80-2.72(m, 1H), 1.80(s, 3H), 1.60-1.48(m, 3H), 1.11(d, J=6.7Hz, 3H), 0.98(d, J=6.7Hz, 3H).ES-API:[M+H] + =615.2. The isomer compounds were detected by analytical chiral HPLC (column: OD-H: 5 μm, 4.6 x 250 mm, mobile phase: hexane:EtOH = 80:20, flow rate: 1 ml / min, column temperature: 30°C).

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

[0405] Compounds Z4-144, Z7-Z8, and Z11-Z20 are prepared by a method similar to the preparation method for compound Z1 or Z2. The starting materials for each compound can be prepared by commercially available or conventional methods well known to those skilled in the art, and similar synthesis methods for 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: 12 mL of water and 12 mL of dioxane were added to a flask containing 7-chloro-6-fluoro-4-hydroxy-1-(4-isopropyl-6-methylpyrimidine-5-yl)-2-oxo-1,2-dihydro-1,8-naphthirizine-3-nitrile (2 g, 5.34 mmol). After cooling the reaction system to 0°C, 12 mL of concentrated sulfuric acid was added dropwise to the reaction mixture. After the addition was complete, the mixture was stirred at 120°C for 18 hours. After the reaction was complete, a large amount of solid precipitated. The mixture was filtered, and the filter cake was washed three times with water. The filter cake was dried to obtain a white solid, 7-chloro-6-fluoro-4-hydroxy-1-(4-isopropyl-6-methylpyrimidine-5-yl)-1,8-naphthirizine-2(1H)-one (1.4 g, 75%). The crude product was used directly in the next step. ES-API:[M+H] + =349.1. Step 2: 7-chloro-6-fluoro-4-hydroxy-1-(4-isopropyl-6-methylpyrimidine-5-yl)-3-nitro-1,8-naphthirizine-2(1H)-one (1.3 g, 3.72 mmol), sodium nitrite (26 mg, 0.37 mmol), and 8 mL of glacial acetic acid were added to a flask. Concentrated nitric acid (700 mg, 11.1 mmol) was added dropwise to the reaction mixture. The reaction system was placed in a 30°C oil bath and heated for 2 hours. The reaction mixture was poured into ice water, and solid matter precipitated. The mixture was filtered, and the filtered cake was washed with water. The filtered cake was collected and vacuum-dried to obtain a yellow solid, 7-chloro-6-fluoro-4-hydroxy-1-(4-isopropyl-6-methylpyrimidine-5-yl)-3-nitro-1,8-naphthirizine-2(1H)-one (1.2 g, purity 76%). The crude product was used directly in the next step. ES-API:[M+H] + =394.1. Step 3: 7-chloro-6-fluoro-4-hydroxy-1-(4-isopropyl-6-methylpyrimidine-5-yl)-3-nitro-1,8-naphthyrizin-2(1H)-one (1.2 g, 3 mmol), 2-fluoro-6-methoxyphenylboric acid (2 g, 12 mmol), 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (123 mg, 0.3 mmol), chloro(2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (216 mg, 0.3 mmol), potassium phosphate (1.9 g, 9 mmol), 15 mL of dioxane, and 3 mL of water were added to the reaction flask. The mixture was stirred in a 110°C oil bath under a nitrogen atmosphere for 1 hour to terminate the reaction. 30 mL of 1 M potassium carbonate aqueous solution was added to the reaction mixture, and the mixture was extracted once with 20 mL of ELISA / PE (1:1) to remove impurities. The aqueous layer was further adjusted to pH 4 with 6 M hydrochloric acid aqueous solution. It was extracted three times with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated. The yellow solid yielded 6-fluoro-7-(2-fluoro-6-methoxyphenyl)-4-hydroxy-1-(4-isopropyl-6-methylpyrimidine-5-yl)-3-nitro-1,8-naphthyrizin-2(1H)-one (1.1 g, 75%). ES-API:[M+H] + = 483.1. Step 4: 6-Fluoro-7-(2-Fluoro-6-methoxyphenyl)-4-hydroxy-1-(4-isopropyl-6-methylpyrimidine-5-yl)-3-nitro-1,8-naphthyrizine-2(1H)-one (1.2 g, 2.48 mmol), diisopropylethylamine (3 g, 23.1 mmol), and acetonitrile (20 mL) were added to the flask. Phosphorus oxychloride (2.2 g, 14.5 mmol) was added dropwise. The mixture was stirred at 85°C for 1 hour. The completion of the reaction was confirmed by LC-MS. The reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated. 4-Chloro-6-fluoro-7-(2-fluoro-6-methoxyphenyl)-1-(4-isopropyl-6-methylpyrimidine-5-yl)-3-nitro-1,8-naphthyridine-2(1H)-one (1.1g, purity 83%) was obtained, and the crude product was used directly in the next reaction. ES-API:[M+H] + = 502.1. Step 5: Add 4-chloro-6-fluoro-7-(2-fluoro-6-methoxyphenyl)-1-(4-isopropyl-6-methylpyrimidine-5-yl)-3-nitro-1,8-naphthyridine-2(1H)-one (1 g, 2 mmol), 1-(tert-butyl-3-methyl(R)-piperazine-1,3-dicarboxylic acid ester (1.94 g, 8 mmol), N,N-diisopropylethylamine (516 mg, 4 mmol), and N,N-dimethylacetamide (10 mL) to the flask and stir at 120°C for 2 hours. The completion of the reaction was confirmed by LC-MS. 30 The mixture was injected into mL of water and extracted three times with ethyl acetate. The organic layer was washed four times with saturated saline / water (v / v, 1:1). After drying and concentration, the crude product was purified by high-performance silica gel column (siRNA / PE: 0-40%) to obtain 1-(tert-butyl)-3-methyl(3R)-4-(6-fluoro-7-(2-fluoro-6-methoxyphenyl)-1-(4-isopropyl-6-methylpyrimidine-5-yl)-3-nitro-2-oxo-1,2-dihydro-1,8-naphthyridine-4-yl)piperazine-1,3-dicarboxylic acid ester (1 g, purity 82%). ES-API:[M+H] + = 710.2. Step 6: 1-(tert-butyl)-3-methyl(3R)-4-(6-fluoro-7-(2-fluoro-6-methoxyphenyl)-1-(4-isopropyl-6-methylpyrimidine-5-yl)-3-nitro-2-oxo-1,2-dihydro-1,8-naphthyridine-4-yl)piperazine-1,3-dicarboxylic acid ester (1 g, 1.4 mmol), iron powder (390 mg, 7 mmol), and 15 mL of glacial acetic acid were added to the reaction flask. 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 solution and extracted three times with 30 mL of ethyl acetate. After drying the organic layer, it was concentrated to obtain the yellow solid (4aR)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(4-isopropyl-6-methylpyrimidine-5-yl)-5,7-dioxo-1,2,4,4a,5,6,7,8-octahydro-3H-pyradylo[1',2':4,5]pyradylo[2,3-c][1,8]naphthyrizine-3-carboxylate tert-butyl (850 mg, 93%). ES-API:[M+H] + = 648.3. Step 7: (4aR)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(4-isopropyl-6-methylpyrimidine-5-yl)-5,7-dioxo-1,2,4,4a,5,6,7,8-octahydro-3H-pyradylo[1',2':4,5]pyradylo[2,3-c][1,8]naphthyrizine-3-carboxylate tert-butyl (450 mg, 0.69 mmol), iodomethane (789 mg, 5.55 mmol), potassium carbonate (286 mg, 2.07 mmol), and 10 mL of acetone were added to the flask. The mixture was reacted in a tube and stirred at 50°C for 16 hours. 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-speed silica gel column (siRNA / PE: 0-60%) to obtain the yellow solid (4aR)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(4-isopropyl-6-methylpyrimidine-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]naphthyrizine-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-methylpyrimidine-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]naphthyrizine-3-carboxylate tert-butyl (260 mg, 0.39 mmol), 1 mL of dichloromethane, and 3 mL of trifluoroacetic acid were added to the 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, the yellow solid (4aR)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(4-isopropyl-6-methylpyrimidine-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: Add (4aR)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(4-isopropyl-6-methylpyrimidine-5-yl)-6-methyl-2,3,4,4a,6,8-hexahydro-1H-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8]naphthyrizine-5,7-dione (219 mg, 0.39 mmol), 3 mL of dichloromethane, and triethylamine (158 mg, 1.56 mmol) to a 50 mL flask. Cool the reaction system to 0°C, and add a dichloromethane solution of acrylate chloride (71 mg, 0.78 mmol, 0.5 mL) dropwise to the reaction mixture. Stir at 0°C for 10 minutes. Add 40 mL of saturated sodium bicarbonate aqueous solution to the reaction mixture and extract three times with 20 mL of dichloromethane. After drying the organic layer, it was concentrated to obtain the yellow solid (4aR)-3-acryloyl-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(4-isopropyl-6-methylpyrimidine-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: Add (4aR)-3-acryloyl-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(4-isopropyl-6-methylpyrimidine-5-yl)-6-methyl-2,3,4,4a,6,8-hexahydro-1H-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8]naphthyrizine-5,7-dione (240 mg, 0.39 mmol) and 3 mL of dichloromethane to a flask. Cool the reaction mixture to 0°C, and add 6 mL of a 17% boron tribromide solution in dichloromethane dropwise. After the addition was complete, stir at room temperature for 2 hours. Inject the reaction mixture into 30 mL of cooled saturated NaHCO3 aqueous solution and extract three times with 20 mL of dichloromethane. After drying the organic layer, concentrate it. The crude product was purified by preparative HPLC to obtain the yellow solid (4aR)-3-acryloyl-11-fluoro-10-(2-fluoro-6-hydroxyphenyl)-8-(4-isopropyl-6-methylpyrimidine-5-yl)-6-methyl-2,3,4,4a,6,8-hexahydro-1H-pyradylo[1',2':4,5]pyradylo[2,3-c][1,8]naphthyridine-5,7-dione (Z21, 130 mg, 55%). ES-API:[M+H] + = 602.2. Step 11: Compound (4aR)-3-acryloyl-11-fluoro-10-(2-fluoro-6-hydroxyphenyl)-8-(4-isopropyl-6-methylpyrimidine-5-yl)-6-methyl-2,3,4,4a,6,8-hexahydro-1H-pyradylo[1',2':4,5]pyradylo[2,3-c][1,8]naphthyrizine-5,7-dione (130 mg) was separated by preparative chiral HPLC (column: Chiralpak IE: 10 μm, 20*250 mm; mobile phase: hexane:ethanol:diethylamine = 70:30:0.2; flow rate: 15 ml / min; column temperature: room temperature). One atropisomer compound obtained was a yellow solid, and its structure was designated as Z21-1 (peak 2, retention time: 12.33 min, 47 mg). ES-API:[M+H] + = 602.2. 1HNMR (500MHz, DMSO-d6): 10.17 (s, 1H), 9.03 (s, 1H), 8.41 (d, J=9Hz, 1H), 7.26-7.25 (m, 1H), 7.08-7.05 (m, 1H), 6.68-6.66(m, 2H), 6.17-6.14(m, 1H), 5.77-5.75(m, 1H), 4.75-4.73(m, 1H), 4.46-4.44(m, 1H), 4.0-3.95(m, 1H), 3.55-3.54 (m, 2H), 3.41 (s, 3H), 3.20-3.18 (m, 1H), 2.85-2.83 (m, 1H), 2.68-2.65 (m, 1H), 2.00 (s, 3H), 1.13 (d, J=6.5Hz, 3H), 1.06 (d, J=6.5Hz, 3H). Additionally, another atropisomer compound was obtained, a yellow solid, with its structure designated as Z21-2 (peak 1, retention time: 10.58 min, 48 mg). ES-API:[M+H] + = 602.2. 1 HNMR (500MHz, DMSO-d6): 10.16 (s, 1H), 9.03 (s, 1H), 8.41 (d, J=9Hz, 1H), 7.26-7.25 (m, 1H), 7 .08-7.05(m, 1H), 6.68-6.66(m, 2H), 6.17-6.14(m, 1H), 5.77-5.75(m, 1H), 4.75-4.73(m, 1H) 4.46-4.44 (m, 1H), 4.0-3.95 (m, 1H), 3.55-3.54 (m, 2H), 3.41 (s, 3H), 3.20-3.18 (m, 1H), 2.65-2.60 (m, 1H), 2.52-2.51 (m, 1H), 2.20 (s, 3H), 1.06 (d, J=6.5Hz, 3H), 0.86 (d, J=6.5Hz, 3H). Isomer compounds were analyzed using chiral HPLC (column: Chiralpak IE: 5μm, 4.6*250mm; mobile phase: hexane:ethanol:aminomethanol = 70:30:0.2; flow rate: 1ml / min; column temperature: 30 o Detected in C).

[0413] Example 22: Preparation of Compound Z22

[0414] [ka]

[0415] Step 1: Dissolve 7-chloro-6-fluoro-4-hydroxy-1-(3-isopropylpyrazine-2-yl)-1,8-naphthirizine-2(1H)-one (2 g, 6 mmol) in acetic acid (5 mL), and sequentially add sodium nitrite (41 mg, 0.6 mmol) and concentrated nitric acid (1.5 g, 24 mmol). Stir at room temperature for 30 minutes. Slowly pour the reaction mixture into 100 mL of ice water, filter the precipitated solid, wash the filter cake with 20 mL of ice water, and dry under vacuum to obtain 7-chloro-6-fluoro-4-hydroxy-1-(3-isopropylpyrazine-2-yl)-3-nitro-1,8-naphthirizine-2(1H)-one (1.5 g, 65%) as a yellow solid. ES-API:[M+H] + = 380.2. Step 2: Add 7-chloro-6-fluoro-4-hydroxy-1-(3-isopropylpyrazine-2-yl)-3-nitro-1,8-naphthyrizine-2(1H)-one (1.5g, 3.94 mmol), (2-fluoro-6-methoxyphenyl)boric acid (2.04g, 12 mmol), chloro(2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (288mg, 0.4 mmol), 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (164mg, 0.4 mmol), potassium phosphate (2.5g, 12 mmol), 10 mL of water, and 40 mL of dioxane to a 100 mL three-necked flask and stir at 100°C for 2-3 hours under a nitrogen atmosphere. After the reaction was complete, the reaction mixture was cooled to room temperature. 80 mL of water and 100 mL of methyl-tert-butyl ether were added, and the mixture was extracted once. The aqueous layer was adjusted to pH 3-5 with 1 M hydrochloric acid solution and extracted with ethyl acetate (200 mL x 2). The ethyl acetate layer was combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was vacuum-dried to obtain the pale yellow solid 6-fluoro-7-(2-fluoro-6-methoxyphenyl)-4-hydroxy-1-(3-isopropylpyrazine-2-yl)-3-nitro-1,8-naphthyridine-2(1H)-one (1.6 g, crude product) as the product. ES-API:[M+H] + = 470.1. Step 3: 6-Fluoro-7-(2-Fluoro-6-methoxyphenyl)-4-hydroxy-1-(3-isopropylpyrazine-2-yl)-3-nitro-1,8-naphthyridine-2(1H)-one (1.6 g, 3.4 mmol) was dissolved in acetonitrile (30 mL), and phosphorus oxychloride (2.6 g, 17 mmol) and N,N-diisopropylethylamine (3 g, 23.8 mmol) were added in sequence, and the mixture was stirred for 30 minutes while gradually raising the reaction temperature to 80°C. After concentrating the reaction mixture, 30 mL of cold acetonitrile was added, and the mixture was added dropwise to 150 mL of saturated sodium bicarbonate solution in an ice bath, and extracted with ethyl acetate (200 mL x 2). The organic layers were combined and washed once with 200 mL of saturated saline solution. The mixture was dried over anhydrous sodium sulfate, filtered, and the organic layer was dried and concentrated. The crude product was then purified by high-performance silica gel column (Âti / PE: 0-50%) to obtain 4-chloro-6-fluoro-7-(2-fluoro-6-methoxyphenyl)-1-(3-isopropylpyrazine-2-yl)-3-nitro-1,8-naphthyrizin-2(1H)-one (340 mg, Y: 20%) as a yellow solid. ES-API:[M+H] + = 488.2. Step 4: Dissolve 4-chloro-6-fluoro-7-(2-fluoro-6-methoxyphenyl)-1-(3-isopropylpyrazine-2-yl)-3-nitro-1,8-naphthyridine-2(1H)-one (310 mg, 0.64 mmol) in N,N-dimethylacetamide (5 mL), then sequentially add 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), and stir at 120°C for 2 hours. Add 50 mL of ethyl acetate to the reaction mixture. The ethyl acetate layer was added and washed three times with 30 mL of saturated saline solution. After drying and concentrating the ethyl acetate layer, the crude product was purified by high-performance silica gel column (siRNA / PE: 0-80%) to obtain the yellow solid 1-(tert-butyl-3-methyl(3R,6R)-4-(6-fluoro-7-(2-fluoro-6-methoxyphenyl)-1-(3-isopropylpyrazine-2-yl)-3-nitro-2-oxo-1,2-dihydro-1,8-naphthyridine-4-yl)-6-methylpiperazine-1,3-dicarboxylic acid ester (317 mg, Y: 70%). 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-isopropylpyrazine-2-yl)-3-nitro-2-oxo-1,2-dihydro-1,8-naphthyridine-4-yl)-6-methylpiperazine-1,3-dicarboxylic acid ester (280 mg, 0.4 mmol) was dissolved in acetic acid (4 mL), iron powder (78 mg, 1.4 mmol) was added, and the mixture was stirred at 80°C for 30 minutes. After concentrating the reaction mixture, 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 was added, 30 The mixture was sequentially washed with mL of saturated saline solution. After drying and concentration, the product was a yellow solid (2R,4aR)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(3-isopropylpyrazine-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-isopropylpyrazine-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]naphthyrizine-3-carboxylate tert-butyl (295 mg, 0.46 mmol), 3 mL of acetone, anhydrous potassium carbonate (1 g, 6.9 mmol), and iodomethane (253 mg, 1.84 mmol) were added in order to a 15 mL tube. The tube was sealed and stirred at 55°C for 18 hours. 50 mL of ethyl acetate was added to the reaction mixture, and it was washed three times with 20 mL of saturated saline solution. The mixture was dried and concentrated to obtain the yellow solid (2R,4aR)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(3-isopropylpyrazine-2-yl)-2,6-dimethyl-5,7-dioxo-1,2,4,4a,5,6,7,8-octahydro-3H-pyradylo[1',2':4,5]pyradylo[2,3-c][1,8]naphthyrizine-3-carboxylate tert-butyl (356 mg, crude product). ES-API:[M+H] + = 662.2. Step 7: (2R, 4aR)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(3-isopropylpyrazine-2-yl)-2,6-dimethyl-5,7-dioxo-1,2,4,4a,5,6,7,8-octahydro-3H-pyradylo[1',2':4,5]pyradylo[2,3-c][1,8]naphthyrizine-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 solution was concentrated to obtain (2R,4aR)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(3-isopropylpyrazine-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) as the 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-isopropylpyrazine-2-yl)-2,6-dimethyl-2,3,4,4a,6,8-hexahydro-1H-pyradylo[1',2':4,5]pyradylo[2,3-c][1,8]naphthyrizine-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 acrylate chloride (115 mg, 1.28 mmol) was added dropwise to the reaction mixture. The mixture was stirred at 0°C for 5 minutes. 50 mL of dichloromethane was added to the reaction mixture, and the mixture was washed with 50 mL of saturated NaHCO3 aqueous solution and 80 mL of saturated saline solution. After drying and concentration, the crude product was purified by high-speed silica gel column (siRNA / PE: 0-60%) to obtain (2R,4aR)-3-acryloyl-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(3-isopropylpyrazine-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: Under ice bath conditions, add ((2R,4aR)-3-acryloyl-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(3-isopropylpyrazine-2-yl)-2,6-dimethyl-2,3,4,4a,6,8-hexahydro-1H-pyradylo[1',2':4,5]pyradylo[2,3-c][1,8]naphthyrizine-5,7-dione (201 mg, 0.33 mmol) to dry dichloromethane (3.0 mL), then add boron tribromide (5.0 mL), and react at room temperature for 30 minutes. Under ice bath conditions, char the reaction solution. The solution was added dropwise to a saturated sodium hydrogen oxyphosphate solution and extracted twice with dichloromethane (50 mL). After drying and concentration, the crude product was purified by preparative HPLC to obtain (2R,4aR)-3-acryloyl-11-fluoro-10-(2-fluoro-6-hydroxyphenyl)-8-(3-isopropylpyrazine-2-yl)-2,6-dimethyl-2,3,4,4a,6,8-hexahydro-1H-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8]naphthyridine-5,7-dione (Z22, 65 mg, Y:33%). ES-API:[M+H] + = 602.2. 1 H NMR (500MHz, DMSO-d6) δ10.17(s, 1H), 8.75(dd, J=4.0, 2.6Hz, 1H), 8.55(dd, J=15 .5, 2.4Hz, 1H), 8.05-7.98(m, 1H), 7.26(dd, J=15.0, 8.2Hz, 1H), 7.03(dd, J=16.8 , 10.0Hz, 1H), 6.73(d, J=8.4Hz, 1H), 6.67(t, J=8.8Hz, 1H), 6.16(t, J=12.4Hz, 1H ), 5.74(dd, J=20.0, 11.8Hz, 1H), 4.78(s, 1H), 4.65-4.56(m, 1H), 4.00(t, J=28.0 Hz, 1H), 3.80-3.70(m, 1H), 3.36(d, J=2.4 Hz, 3H), 3.05-2.62(m, 2H), 1.63-1.48(m, 3H), 1.18(d, J=6.8Hz, 2H), 1.10(d, J=6.8Hz, 3H), 1.00(d, J=6.7Hz, 2H).

[0416] Example 23: Preparation of Compound Z23

[0417] [ka]

[0418] Step 1: Add 4-chloro-6-fluoro-7-(2-fluoro-6-methoxyphenyl)-1-(4-isopropyl-6-methylpyrimidine-5-yl)-3-nitro-1,8-naphthyridine-2(1H)-one (0.8g, 1.46 mmol), 1-(tert-butyl)-3-methyl(3R,6R)-6-methylpiperazine-1,3-dicarboxylic acid ester (567 mg, 2.2 mmol), N,N-diisopropylethylamine (565 mg, 4.38 mmol), and N,N-dimethylacetamide (10 mL) to a flask and stir at 120°C for 1 hour. The completion of the reaction was confirmed by LC-MS. 30 mL of water was added to the reaction mixture and extracted three times with ethyl acetate. The organic layer was washed four times with saturated saline / water (v / v, 1:1), dried, and concentrated to obtain 1-(tert-butyl)-3-methyl(3R,6R)-4-(6-chloro-1-(4,6-diisopropylpyrimidine-5-yl)-7-(2-fluoro-6-methoxyphenyl)-3-nitro-2-oxo-1,2-dihydro-1,8-naphthyridine-4-yl)-6-methylpiperazine-1,3-dicarboxylic acid ester (1g, yield 89%). ES-API:[M+H] + = 768.3. Step 2: 1-(tert-butyl)-3-methyl(3R,6R)-4-(6-chloro-1-(4,6-diisopropylpyrimidine-5-yl)-7-(2-fluoro-6-methoxyphenyl)-3-nitro-2-oxo-1,2-dihydro-1,8-naphthyridine-4-yl)-6-methylpiperazine-1,3-dicarboxylic acid ester (1 g, 1.3 mmol), iron powder (300 mg, 5.3 mmol), and 8 mL of glacial acetic acid were added to the 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 obtain the crude product, a yellow solid (2R,4aR)-11-chloro-8-(4,6-diisopropylpyrimidine-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]naphthyrizine-3-carboxylate tert-butyl (761 mg, 83%). ES-API:[M+H] + = 706.3. Step 3: (2R,4aR)-11-chloro-8-(4,6-diisopropylpyrimidine-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]naphthyrizine-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 were added to the flask. The reaction was carried out by stirring at 50°C for 16 hours in a sealed container, and the completion of the reaction was confirmed by LC-MS. The reaction mixture was filtered through diatomaceous earth, and the filtrate was concentrated to obtain the crude product, a yellow solid (2R,4aR)-11-chloro-8-(4,6-diisopropylpyrimidine-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]naphthyrizine-3-carboxylate tert-butyl (738 mg, 95%). ES-API:[M+H] + = 720.3. Step 4: (2R,4aR)-11-chloro-8-(4,6-diisopropylpyrimidine-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]naphthyrizine-3-carboxylate tert-butyl (738 mg, 1.02 mmol), 2 mL of dichloromethane, and 5 mL of trifluoroacetic acid were added to the 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-diisopropylpyrimidine-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]naphthyrizine-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: Add (2R,4aR)-11-chloro-8-(4,6-diisopropylpyrimidine-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]naphthyrizine-5,7-dione (632 mg, 1.02 mmol), 3 mL of dichloromethane, and triethylamine (677 mg, 6.7 mmol) to a 50 mL flask. Cool the reaction system to 0°C, add a dichloromethane solution of acrylate chloride (249 mg, 2.77 mmol, 0.5 mL) dropwise to the reaction mixture, and stir at 0°C for 10 minutes. Add 40 mL of saturated sodium bicarbonate aqueous solution to the reaction mixture and extract three times with 20 mL of dichloromethane. The organic layer was dried and concentrated. The crude product was purified by high-performance silica gel column (siRNA / PE: 0-60%) to obtain the yellow solid (2R,4aR)-3-acryloyl-11-chloro-8-(4,6-diisopropylpyrimidine-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]naphthyrizine-5,7-dione (500 mg, 72%). The crude product was used directly in the next step. ES-API:[M+H] + = 674.2. Step 6: Add (2R,4aR)-3-acryloyl-11-chloro-8-(4,6-diisopropylpyrimidine-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]naphthyrizine-5,7-dione (500 mg, 0.74 mmol) and 3 mL of dichloromethane to a flask. Cool the reaction mixture to 0°C, and add 12 mL of a 17% boron tribromide solution in dichloromethane dropwise. After the addition is complete, stir at 25°C for 25 hours. Inject the reaction mixture into 30 mL of cooled saturated NaHCO3 aqueous solution and extract three times with 20 mL of dichloromethane. The organic layer is dried and then concentrated. The crude product was purified by preparative HPLC to obtain (2R,4aR)-3-acryloyl-11-chloro-8-(4,6-diisopropylpyrimidine-5-yl)-10-(2-fluoro-6-hydroxyphenyl)-2,6-dimethyl-2,3,4,4a,6,8-hexahydro-1H-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8]naphthyridine-5,7-dione (Z23, 200 mg, 40%) as a yellow solid. 1 HNMR (500MHz, DMSO-d6): δ10.10-10.5(m, 1H), 9.11(s, 1H), 8.25-8.23(m, 1H), 7.22-7 .21(m, 1H), 6.86-6.74(m, 1H), 6.67-6.64(m, 2H), 6.17-6.14(m, 1H), 5.75-5.71(m, 1H) , 5.04-5.01(m, 1H), 4.62-4.42(m, 1H), 4.03-3.98(m, 1H), 3.74-3.72(m, 1H), 3.42-3. 33(m, 5H), 2.77-2.64(m, 2H), 1.56-1.52(m, 3H), 1.05-0.97(m, 9H), 0.86-0.84(m, 3H). ES-API:[M+H] + = 660.3.

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

[0420] [ka]

[0421] Step 1: 6,7-dichloro-4-hydroxy-1-(2-isopropyl-4-methylpyridine-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyrizine-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 slowly added. The mixture was stirred at 120°C for 36 hours. The cooled reaction solution was poured into 200 mL of ice water, the pH was adjusted to 2-3 with sodium carbonate, extracted with ethyl acetate (1000 mL x 2), the ethyl acetate layer was combined, dried with anhydrous sodium sulfate, filtered, and the filtrate was vacuum-dried to obtain 6,7-dichloro-4-hydroxy-1-(2-isopropyl-4-methylpyridine-3-yl)-1,8-naphthyridine-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-methylpyridine-3-yl)-1,8-naphthirizine-2(1H)-one (3.16 g, 8.705 mmol) was dissolved in acetic acid (15 mL), and sodium nitrite (100 mg, 1.58 mmol) and concentrated nitric acid (5.0 mL, 74.52 mmol) were added in sequence. The mixture was stirred at room temperature for 30 minutes. The reaction mixture was slowly poured into 100 mL of ice water, the precipitated solid was filtered, and the filtered cake was washed with 20 mL of ice water. After vacuum drying, the product obtained was a yellow solid, 6,7-Dichloro-4-hydroxy-1-(2-isopropyl-4-methylpyridine-3-yl)-3-nitro-1,8-naphthirizine-2(1H)-one (3.5 g, Y: 92%). ES-API:[M+H] + = 409.1. Step 3: Add 6,7-dichloro-4-hydroxy-1-(2-isopropyl-4-methylpyridine-3-yl)-3-nitro-1,8-naphthyridine-2(1H)-one (3.5g, 8.570 mmol), (2-fluoro-6-methoxyphenyl)boric acid (5.8g, 34.10 mmol), tetrakis(triphenylphosphine)palladium (1.15g, 0.9956 mmol), sodium carbonate (3.5g, 33.02 mmol), 10 mL of water, and 40 mL of dioxane to a 100 mL three-necked flask and stir at 100°C for 2-3 hours under a nitrogen atmosphere. After the reaction is complete, cool the reaction mixture to room temperature, add 80 mL of water and 100 mL of methyl-tert-butyl ether, and extract once. The aqueous layer was adjusted to pH 3-5 with 1M hydrochloric acid solution, extracted with ethyl acetate (200 mL x 2), the ethyl acetate layer was combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was vacuum-dried to obtain the pale yellow solid 6-chloro-7-(2-fluoro-6-methoxyphenyl)-4-hydroxy-1-(2-isopropyl-4-methylpyridine-3-yl)-3-nitro-1,8-naphthyridine-2(1H)-one (4.5 g, crude product) as the product. ES-API:[M+H] + = 499.1. Step 4: 6-chloro-7-(2-fluoro-6-methoxyphenyl)-4-hydroxy-1-(2-isopropyl-4-methylpyridine-3-yl)-3-nitro-1,8-naphthyridine-2(1H)-one (4.6 g, 8.57 mmol) was dissolved in acetonitrile (30 mL), and phosphorus oxychloride (7.5 g, 48.92 mmol) and N,N-diisopropylethylamine (10.5 g, 81.24 mmol) were added in sequence, and the mixture was stirred for 30 minutes while gradually increasing the temperature to 80°C. After concentrating the reaction mixture, 30 mL of cold acetonitrile was added, and the mixture was added dropwise to 150 mL of saturated sodium bicarbonate solution in an ice bath. The mixture was extracted with ethyl acetate (200 mL x 2), the ethyl acetate layer was combined, and the mixture was washed once with 200 mL of saturated saline solution. The mixture was dried over anhydrous sodium sulfate, filtered, and the organic layer was dried and concentrated. The crude product was then purified by high-performance silica gel column (Âti / PE: 0-50%) to obtain the yellow solid 4,6-dichloro-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropyl-4-methylpyridine-3-yl)-3-nitro-1,8-naphthyridine-2(1H)-one (3.05 g, Y: 76%). ES-API:[M+H] + = 517.2. Step 5: Dissolve 4,6-dichloro-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropyl-4-methylpyridine-3-yl)-3-nitro-1,8-naphthyridine-2(1H)-one (2.5 g, 4.843 mmol) in N,N-dimethylacetamide (25 mL), then sequentially add 1-(tert-butyl-3-methyl(R)-piperazine-1,3-dicarboxylic acid ester (3.5 g, 14.34 mmol) and N,N-diisopropylethylamine (2.0 g, 15.47 mmol), and stir at 120°C for 2 hours. Add 80 mL of ethyl acetate to the reaction mixture. The ethyl acetate layer was added and washed three times with 80 mL of saturated saline solution. After drying and concentrating the ethyl acetate layer, the crude product was purified by high-performance silica gel column chromatography (siRNA / PE: 0-80%) to obtain 1-(tert-butyl)-3-methyl(3R)-4-(6-chloro-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropyl-4-methylpyridine-3-yl)-3-nitro-2-oxo-1,2-dihydro-1,8-naphthyridine-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-methylpyridine-3-yl)-3-nitro-2-oxo-1,2-dihydro-1,8-naphthyridine-4-yl)piperazine-1,3-dicarboxylic acid ester (2.7 g, 3.728 mmol) was dissolved in acetic acid (30 mL), iron powder (835 mg, 14.91 mmol) was added, and the mixture was stirred at 80°C for 30 minutes. After concentrating the reaction mixture, 200 mL of ethyl acetate and 100 mL of saturated sodium bicarbonate were added in sequence, the suspension was filtered through diatomaceous earth, the filter cake was washed with ethyl acetate, the organic layer was separated, and washed in sequence with 100 mL of saturated sodium bicarbonate and 150 mL of saturated saline solution. The mixture was dried and concentrated to obtain the yellow solid (4aR)-11-chloro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridine-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 (2.70 g, crude product). ES-API:[M+H]+=663.2. Step 7: Put (4aR)-11-chloro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridine-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]naphthyrizine-3-carboxylate tert-butyl (250 mg, 0.3774 mmol), 4 mL of dichloromethane into a 100 mL flask. mL of trifluoroacetic acid was added sequentially, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated to obtain (4aR)-11-chloro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridine-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) as the product, which was then used in the next reaction. ES-API:[M+H] + = 563.2. Step 8: (4aR)-11-chloro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridine-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, acrylate chloride (50 mg, 0.5524 mmol) was added dropwise to the reaction mixture, and the mixture was stirred at 0°C for 15 minutes. 80 mL of dichloromethane was added to the reaction mixture, and the mixture was washed with 100 mL of saturated NaHCO3 aqueous solution and 80 mL of saturated saline solution. After drying and concentration, the crude product was purified by high-speed silica gel column (methanol / dichloromethane: 0-20%) to obtain the yellow solid (4aR)-3-acryloyl-11-chloro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridine-3-yl)-2,3,4,4a,6,8-hexahydro-1H-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8]naphthyridine-5,7-dione (243 mg, crude product). ES-API:[M+H] + = 617.2. Step 9: Under ice bath conditions, (4aR)-3-acryloyl-11-chloro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridine-3-yl)-2,3,4,4a,6,8-hexahydro-1H-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8]naphthyrizine-5,7-dione (243 mg, 0.3774 mmol) was added to dry dichloromethane (6.0 mL), and then boron tribromide (5.0 mL, 5.0 mmol) was added. The mixture was then heated to room temperature and allowed to react overnight. Under ice bath conditions, the reaction solution was added dropwise to saturated sodium bicarbonate solution and extracted twice with dichloromethane (80 mL). After drying and concentration, the solution was purified by preparative HPLC to obtain (4aR)-3-acryloyl-11-chloro-10-(2-fluoro-6-hydroxyphenyl)-8-(2-isopropyl-4-methylpyridine-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 (Z 24,76 mg, Y: 32%). [M+H] + = 603.2. Step 10: Compound Z24 (76.0 mg, 0.1262 mmol) was divided by preparative chiral HPLC (column: IA: 10 μm, 30*250 mm, mobile phase: hexane:EtOH = 40:60, flow rate: 25 ml / min, column temperature: room temperature). One atropisomer compound obtained was designated as Z24-1 (13.7 mg, peak 1, retention time: 2.612 min, Y: 18%). ES-API:[M+H] + =603.2. Furthermore, the other atropisomer compound obtained was designated as Z24-2 (21.4 mg, peak 2, retention time 3.985 min, Y: 28%). ES-API:[M+H] + =603.2. The isomer compounds were detected by analytical chiral HPLC (column: IA: 5 μm, 4.6 x 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-methylpyridine-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyrizine-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 slowly added. The mixture was stirred at 120°C for 36 hours. The cooled reaction solution was poured into 200 mL of ice water, the pH was adjusted to 2-3 with sodium carbonate, and the mixture was extracted with ethyl acetate (1000 mL x 2). The ethyl acetate layer was combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was vacuum-dried to obtain 6,7-dichloro-4-hydroxy-1-(2-isopropyl-4-methylpyridine-3-yl)-1,8-naphthyridine-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-methylpyridine-3-yl)-1,8-naphthirizine-2(1H)-one (3.16 g, 8.705 mmol) was dissolved in acetic acid (15 mL), and sodium nitrite (100 mg, 1.58 mmol) and concentrated nitric acid (5.0 mL, 74.52 mmol) were added in sequence. The mixture was stirred at room temperature for 30 minutes. The reaction mixture was slowly poured into 100 mL of ice water, the precipitated solid was filtered, the filtered cake was washed with 20 mL of ice water, and vacuum-dried to obtain the yellow solid 6,7-dichloro-4-hydroxy-1-(2-isopropyl-4-methylpyridine-3-yl)-3-nitro-1,8-naphthirizine-2(1H)-one (3.5 g, Y: 92%) as the product. ES-API:[M+H] + = 409.1. Step 3: Add 6,7-dichloro-4-hydroxy-1-(2-isopropyl-4-methylpyridine-3-yl)-3-nitro-1,8-naphthyridine-2(1H)-one (3.5g, 8.570 mmol), (2-fluoro-6-methoxyphenyl)boric acid (5.8g, 34.10 mmol), tetrakis(triphenylphosphine)palladium (1.15g, 0.9956 mmol), sodium carbonate (3.5g, 33.02 mmol), 10 mL of water, and 40 mL of dioxane to a 100 mL three-necked flask and stir at 100 °C for 2-3 hours under a nitrogen atmosphere. After the reaction was complete, the reaction mixture was cooled to room temperature. Add 80 mL of water and 100 mL of methyl-tert-butyl ether and extract once. Adjust the pH of the aqueous layer to 3-5 with 1 M hydrochloric acid solution and extract with ethyl acetate (200 mL x 2). The ethyl acetate layer was combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was vacuum-dried to obtain the pale yellow solid 6-chloro-7-(2-fluoro-6-methoxyphenyl)-4-hydroxy-1-(2-isopropyl-4-methylpyridine-3-yl)-3-nitro-1,8-naphthyridine-2(1H)-one (4.5 g, crude product) as the product. ES-API:[M+H] + = 499.1. Step 4: 6-chloro-7-(2-fluoro-6-methoxyphenyl)-4-hydroxy-1-(2-isopropyl-4-methylpyridine-3-yl)-3-nitro-1,8-naphthyridine-2(1H)-one (4.6 g, 8.57 mmol) was dissolved in acetonitrile (30 mL), and phosphorus oxychloride (7.5 g, 48.92 mmol) and N,N-diisopropylethylamine (10.5 g, 81.24 mmol) were added in sequence, and the mixture was stirred for 30 minutes while gradually increasing the temperature to 80°C. After concentrating the reaction mixture, 30 mL of cold acetonitrile was added, and the mixture was added dropwise to 150 mL of saturated sodium bicarbonate solution in an ice bath and extracted with ethyl acetate (200 mL x 2). The ethyl acetate layer was combined and washed once with 200 mL of saturated saline solution. The mixture was dried over anhydrous sodium sulfate, filtered, and the organic layer was dried and concentrated. The crude product was then purified by high-performance silica gel column (Âti / PE: 0-50%) to obtain 4,6-dichloro-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropyl-4-methylpyridine-3-yl)-3-nitro-1,8-naphthyridine-2(1H)-one (3.05 g, Y: 76%) as a yellow solid. ES-API:[M+H] + = 517.2. Step 5: Dissolve 4,6-dichloro-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropyl-4-methylpyridine-3-yl)-3-nitro-1,8-naphthyridine-2(1H)-one (2.5 g, 4.843 mmol) in N,N-dimethylacetamide (25 mL), then sequentially add 1-(tert-butyl-3-methyl(R)-piperazine-1,3-dicarboxylic acid ester (3.5 g, 14.34 mmol) and N,N-diisopropylethylamine (2.0 g, 15.47 mmol), and stir at 120°C for 2 hours. Add 80 mL of acetic acid to the reaction mixture. Ethyl acetate was added, and the mixture was washed three times with 80 mL of saturated saline solution. After drying and concentrating the ethyl acetate layer, the crude product was purified by high-performance silica gel column (siRNA / PE: 0-80%) to obtain 1-(tert-butyl)-3-methyl(3R)-4-(6-chloro-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropyl-4-methylpyridine-3-yl)-3-nitro-2-oxo-1,2-dihydro-1,8-naphthyridine-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-methylpyridine-3-yl)-3-nitro-2-oxo-1,2-dihydro-1,8-naphthyridine-4-yl)piperazine-1,3-dicarboxylic acid ester (2.7 g, 3.728 mmol) was dissolved in acetic acid (30 mL), iron powder (835 mg, 14.91 mmol) was added, and the mixture was stirred at 80°C for 30 minutes. After concentrating the reaction mixture, 200 mL of ethyl acetate and 100 mL of saturated sodium bicarbonate were added in sequence, the suspension was filtered through diatomaceous earth, and the filter cake was washed with ethyl acetate. The organic layer was separated and washed in sequence with 100 mL of saturated sodium bicarbonate and 150 mL of saturated saline solution. The mixture was dried and concentrated to obtain the yellow solid (4aR)-11-chloro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridine-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 (2.70 g, crude product). ES-API:[M+H]+=663.2. Step 7: (4aR)-11-chloro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridine-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 (2.7g, 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 mixture, and the mixture was washed three times with 100 mL of saturated saline solution. After drying and concentration, the crude product was purified by high-speed silica gel column (siRNA / PE: 0-80%) to obtain the yellow solid (4aR)-11-chloro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridine-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 (2.2g, Y: 87%). ES-API:[M+H] + = 677.2. Step 8: (4aR)-11-chloro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridine-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]naphthyrizine-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 solution was concentrated to obtain (4aR)-11-chloro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridine-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) as the 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-methylpyridine-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 acrylate chloride (100 mg, 1.1048 mmol) was added dropwise to the reaction mixture. The mixture was stirred at 0°C for 15 minutes. 80 mL of dichloromethane was added to the reaction mixture, and it was washed with 100 mL of saturated NaHCO3 aqueous solution and 80 mL of saturated saline solution. After drying and concentration, the crude product was purified by high-speed silica gel column (siRNA / PE: 0-60%) to obtain the yellow solid (4aR)-3-acryloyl-11-chloro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridine-3-yl)-6-methyl-2,3,4,4a,6,8-hexahydro-1H-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8]naphthyridine-5,7-dione (280 mg, Y: 59%). ES-API:[M+H] + = 631.2. Step 10: Under ice bath conditions, (4aR)-3-acryloyl-11-chloro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridine-3-yl)-6-methyl-2,3,4,4a,6,8-hexahydro-1H-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8]naphthyrizine-5,7-dione (280 mg, 0.444 mmol) was added to dry dichloromethane (6.0 mL), and boron tribromide (5.0 mL, 5.0 mmol) was further added. The mixture was then heated to room temperature and allowed to react overnight. Under ice bath conditions, the reaction solution was added dropwise to saturated sodium bicarbonate solution and extracted twice with dichloromethane (80 mL). After drying and concentration, the crude product was purified by high-speed silica gel column (siRNA / PE: 0-60%) to obtain (4aR)-3-acryloyl-11-chloro-10-(2-fluoro-6-hydroxyphenyl)-8-(2-isopropyl-4-methylpyridine-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 divided 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 obtained was Z25-1 (76.8 mg, peak 1, retention time: 2.531 min, Y: 34%). 1HNMR (500MHz, DMSO-d6) δ10.03(d, J=18.4Hz, 1H), 8.52(d, J=7.3Hz, 1H), 8.43(d, J=4.7Hz, 1H), 7.23(d, J=9.6Hz, 2H ), 7.08(dd, J=16.6, 10.5Hz, 1H), 6.74-6.62(m, 2H), 6.15(d, J=16.8Hz, 1H), 5.75(d, J=10.7Hz, 1H), 4.73(d, J=14.2H) z, 1H), 4.46(d, J=12.9Hz, 1H), 4.00(s, 1H), 3.61(d, J=10.0Hz, 1H), 3.51(s, 1H), 3.34(s, 3H), 3.22(s, 1H), 2.64(t, ES-API:[M+H] + =617.2. In addition, the other atropisomer compound obtained was Z25-2 (70 mg, peak 2, retention time: 3.683 min, Y: 31%). 1 HNMR (500MHz, CDCl3) δ8.64-8.59(m, 1H), 8.35(s, 1H), 8.07(s, 1H), 7.27-7.20(m, 2H), 7.14-7.02(m , 1H), 6.75-6.63(m, 2H), 6.39(dd, J=17.0, 2.0Hz, 1H), 5.88-5.77(m, 1H), 4.91(d, J=14.0Hz, 1H), 4.8 3(d, J=13.0Hz, 1H), 3.72-3.58(m, 2H), 3.50(s, 3H), 3.43(d, J=12.0Hz, 1H), 3.16(t, J=13.0Hz, 1H), 2.91(t, J=12.0Hz, 1H), 2.82-2.73(m, 1H), 1.93(s, 3H), 1.24(d, J=7.0Hz, 3H), 1.12(d, J=7.0Hz, 3H). ES-API:[M+H] + =617.2. The isomer compounds were detected by analytical chiral HPLC (column: IA: 5 μm, 4.6 x 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-methylpyridine-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]naphthyrizine-3-carboxylate tert-butyl (511 mg, 0.7549 mmol) to dichloromethane (8 Dissolve in (mL), add trifluoroacetic acid (2mL), stir at room temperature for 2 hours, concentrate the reaction mixture to obtain (4aR)-11-chloro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridine-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) as the 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-methylpyridine-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 acrylate chloride (100 mg, 1.1048 mmol) was added dropwise to the reaction mixture. The mixture was stirred at 0°C for 15 minutes. 80 mL of dichloromethane was added to the reaction mixture, and the mixture was washed with 100 mL of saturated NaHCO3 aqueous solution and 80 mL of saturated saline solution. After drying and concentration, the crude product was purified by high-speed silica gel column (siRNA / PE: 0-60%) to obtain the yellow solid (4aR)-3-acryloyl-11-chloro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridine-3-yl)-6-(methyl-d3)-2,3,4,4a,6,8-hexahydro-1H-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8]naphthyridine-5,7-dione (232 mg, Y: 48%). ES-API:[M+H] + = 634.2. Step 3: Under ice bath conditions, (4aR)-3-acryloyl-11-chloro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridine-3-yl)-6-(methyl-d3)-2,3,4,4a,6,8-hexahydro-1H-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8]naphthyrizine-5,7-dione (240 mg, 0.3791 mmol) was added to dry dichloromethane (6.0 mL), and boron tribromide (5.0 mL, 5.0 mmol) was further added. The mixture was then heated to room temperature and allowed to react overnight. Under ice bath conditions, the reaction solution was added dropwise to saturated sodium bicarbonate solution and extracted twice with dichloromethane (80 mL). After drying and concentration, the crude product was purified by high-speed silica gel column (SiO2 / PE: 0-60%) to obtain (4aR)-3-acryloyl-11-chloro-10-(2-fluoro-6-hydroxyphenyl)-8-(2-isopropyl-4-methylpyridine-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 divided 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). One atropisomer compound obtained was designated as Z26-1 (68.8 mg, peak: 1, retention time: 2.525 min, Y: 36.7%). 1HNMR (500MHz, DMSO-d6) δ10.03 (d, J=17.9Hz, 1H), 8.51 (d, J=7.4Hz, 1H), 8.43 (d, J=4.7Hz, 1H), 7. 29-7.18(m, 2H), 7.08(dd, J=17.0, 10.6Hz, 1H), 6.74-6.61(m, 2H), 6.15(d, J=16.6Hz, 1H), 5.75(d, J=11.5Hz, 1H), 4.73(d, J=13.5Hz, 1H), 4.46(d, J=12.3Hz, 1H), 4.00(s, 1H), 3.61(d, J=10.5Hz, 1H) ), 3.50(s, 1H), 3.22(s, 1H), 2.65(t, J=12.5Hz, 1H), 2.49-2.42(m, 1H), 1.98(d, J=5.0Hz, 3H), 1.02 (d, J=7.0Hz, 3H), 0.86(t, J=7.9Hz, 3H). ES-API:[M+H] + =620.3. In addition, the other atropisomer compound obtained was designated as Z26-2 (63.2 mg, peak: 2, retention time: 3.683 min, Y: 33.79%). 1 HNMR (400MHz, CDCl3) δ8.62(d, J=4.8Hz, 1H), 8.35(s, 1H), 8.07(s, 1H), 7.24-7.20(m, 2H), 7.16-7.01(m, 1H), 6.74-6.63(m, 2H), 6.39(dd, J=16.8, 2.0Hz, 1H), 5.82(dd, J=10.4, 2.0Hz, 1H), 4.91(d, J=13.6Hz, 1H), 4.83(d, J=13.6Hz, 1H), 3.71-3.57(m, 2H), 3.42(d, J=12.0Hz, 1H), 3.16(t, J=12.8 Hz, 1H), 2.91(t, J=12.0Hz, 1H), 2.81-2.70(m, 1H), 1.92(s, 3H), 1.22(d, J=6.8Hz, 3H), 1.10(d, J=6.8Hz, 3H).ES-API:[M+H] + =620.3. The isomer compound was detected by analytical chiral HPLC (column: IA: 5 μm, 4.6 x 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: Dissolve 4,6-dichloro-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropyl-4-methylpyridine-3-yl)-3-nitro-1,8-naphthyridine-2(1H)-one (500 mg, 0.9686 mmol) in N,N-dimethylacetamide (5 mL), then add 1-(tert-butyl-3-methyl(3R,6R)-6-methylpiperazine-1,3-dicarboxylic acid ester (375 mg, 1.452 mmol) and N,N-diisopropylethylamine (375 mg, 2.907 mmol) in sequence, and stir at 120°C for 2 hours. 80 mL of ethyl acetate was added to the solution and washed three times with 80 mL of saturated saline. The ethyl acetate layer was dried and concentrated, and the crude product was purified by high-performance silica gel column (siRNA / PE: 0-80%) to obtain 1-(tert-butyl)-3-methyl(3R,6R)-4-(6-chloro-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropyl-4-methylpyridine-3-yl)-3-nitro-2-oxo-1,2-dihydro-1,8-naphthyridine-4-yl)-6-methylpiperazine-1,3-dicarboxylic acid ester (535 mg, Y: 74.5%) as a yellow solid. 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-methylpyridine-3-yl)-3-nitro-2-oxo-1,2-dihydro-1,8-naphthyridine-4-yl)-6-methylpiperazine-1,3-dicarboxylic acid ester (530 mg, 0.7179 mmol) was dissolved in acetic acid (6 mL), iron powder (200 mg, 3.571 mmol) was added, and the mixture was stirred at 80°C for 30 minutes. After concentrating the reaction mixture, 200 mL of ethyl acetate and 100 mL of saturated sodium bicarbonate were added in sequence, the suspension was filtered through diatomaceous earth, and the filter cake was washed with ethyl acetate. The organic layer was separated and washed in sequence with 100 mL of saturated sodium bicarbonate and 150 mL of saturated saline solution. The mixture was dried and concentrated to obtain the yellow solid (2R,4aR)-11-chloro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridine-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 (452 ​​mg, Y:92%) as the product. ES-API:[M+H] + = 677.2. Step 3: (2R,4aR)-11-chloro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridine-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]naphthyrizine-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 stirred at 55°C for 18 hours. 150 mL of ethyl acetate was added to the reaction mixture and washed three times with 100 mL of saturated saline solution. After drying and concentration, the crude product was purified by high-speed silica gel column (siRNA / PE: 0-80%) to obtain the yellow solid (2R,4aR)-11-chloro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridine-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). ES-API:[M+H] + = 691.3. Step 4: Dissolve (2R,4aR)-11-chloro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridine-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]naphthyrizine-3-carboxylate tert-butyl (511 mg, 0.7549 mmol) in dichloromethane (8 mL) and prepare the truffle Luoroacetate (2 mL) was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated to obtain (2R,4aR)-11-chloro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridine-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) as the product, which was then used 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-methylpyridine-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 acrylate chloride (100 mg, 1.1048 mmol) was added dropwise to the reaction mixture. The mixture was stirred at 0°C for 15 minutes. 80 mL of dichloromethane was added to the reaction mixture, and the mixture was washed with 100 mL of saturated NaHCO3 aqueous solution and 80 mL of saturated saline solution. After drying and concentration, the crude product was purified by high-speed silica gel column (siRNA / PE: 0-60%) to obtain the yellow solid (2R,4aR)-3-acryloyl-11-chloro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridine-3-yl)-2,6-dimethyl-2,3,4,4a,6,8-hexahydro-1H-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8]naphthyridine-5,7-dione (290 mg, Y: 68%). ES-API:[M+H] + = 645.2. Step 6: Under ice bath conditions, (2R,4aR)-3-acryloyl-11-chloro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridine-3-yl)-2,6-dimethyl-2,3,4,4a,6,8-hexahydro-1H-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8]naphthyridine-5,7-dione (290 mg, 0.4503 mmol) was added to dry dichloromethane (6.0 mL), and boron tribromide (6.0 mL, 6.0 mmol) was further added. The mixture was then heated to room temperature and allowed to react overnight. Under ice bath conditions, the reaction solution was added dropwise to saturated sodium bicarbonate solution and extracted twice with dichloromethane (80 mL). After drying and concentration, the crude product was purified by high-speed silica gel column (siRNA / PE: 0-60%) to obtain (2R,4aR)-3-acryloyl-11-chloro-10-(2-fluoro-6-hydroxyphenyl)-8-(2-isopropyl-4-methylpyridine-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 divided 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 obtained was Z27-1 (67.7 mg, peak: 1, retention time: 2.394 min, Y: 23.4%). 1 H NMR(500MHz、DMSO-d6)δ10.05(d、J=17.8Hz、1H)、8.43(d、J=4 .8Hz、1H)、8.23(d、J=9.9Hz、1H)、7.23(d、J=9.9Hz、2H)、7.02 (dd、J=16.8;10.6Hz、1H)、6.74-6.63(m、2H)、6.15(dd、J=16. 8、2.3Hz、1H)、5.76(dd、J=10.5、2.3Hz、1H)、4.78(s、1H)4.6 0(d、J=13.8Hz、1H)、4.00(d、J=3.5Hz、1H)、3.75(dd、J=14.1); 3.9Hz、1H)、3.41-3.33(m、1H)、3.34(s、3H)、2.81(d、J=12.1H). z、1H)、2.48-2.42(m、1H)、1.98(s、3H)、1.53(d、J=6.7Hz、3H) 1.03(d、J=5.5Hz、3H)、0.85(t、J=6.2Hz、3H) ES-API:[M+H] + =631.2 In addition to this, one of the snowflakes is the Z27-2( 64.6mg ピーク2 has a range of 3.382min and Y:23.2%). 1 H NMR(400MHz、CDCl3)δ8.57(d、J=4.8Hz、1H)、8.36(s、1H)、8 .28(s、1H)、7.25-7.15(m、2H)、7.03(dd、J=16.8、10.8Hz、1 H)、6.72-6.61(m、2H)、6.34(dd、J=16.8、2.0Hz、1H)、5.80( dd、J=10.8、2.0Hz、1H)、5.11-5.01(m、1H)、4.77(d、J=14.0H). z、1H)、3.82(dd、J=14.0、4.4Hz、1H)、3.61(d、J=4.4Hz、1H) 3.49(s、3H)、3.30-3.17(m、1H)、3.03(dd、J=12.0、3.6Hz、1 H)、2.80-2.68(m、1H)、1.91(s、3H)、1.66(d、J=6.8Hz、3H) 1.22(d、J=6.8Hz、3H)、1.08(d、J=6.8Hz、3H) ES-API:[M+H] +=631.2. The isomer compounds were detected by analytical chiral HPLC (column: IA: 5 μm, 4.6 x 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: Dissolve 4-chloro-6-fluoro-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropyl-4-methylpyridine-3-yl)-3-nitro-1,8-naphthyridine-2(1H)-one (400 mg, 0.80 mmol) in DMF (5 mL), add (S)-3-(hydroxymethyl)piperazine-1-carboxylate tert-butyl (432 mg, 2.00 mmol) and N,N-diisopropylethylamine (310 mg, 2.40 mmol), and stir at 75°C for 2 hours. Dilute the reaction mixture with 100 mL of ethyl acetate and wash five times with 40 mL of saturated saline solution. After drying and concentration, the crude product was purified by high-speed silica gel column (siRNA / PE: 0-70%) to obtain the yellow solid (3S)-4-(6-fluoro-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropyl-4-methylpyridine-3-yl)-3-nitro-2-oxo-1,2-dihydro-1,8-naphthyridine-4-yl)-3-(hydroxymethyl)piperazine-1-carboxylate tert-butyl (420 mg, Y: 77.2%). ES-API:[M+H] + = 681.3. Step 2: (3S)-4-(6-fluoro-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropyl-4-methylpyridine-3-yl)-3-nitro-2-oxo-1,2-dihydro-1,8-naphthyridine-4-yl)-3-(hydroxymethyl)piperazine-1-carboxylate tert-butyl (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 mixture was diluted with 100 mL of ethyl acetate and washed four times with 40 mL of dilute saline. A final wash was made with 40 mL of saturated saline. After drying and concentration, the crude product was purified by high-speed silica gel column (siRNA / PE: 0-100%) to obtain (4aS)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridine-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 the yellow solid product. ES-API:[M+H]+=634.3. Step 3: (4aS)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridine-3-yl)-7-oxo-1,2,4a,5,7,8-hexahydropyrazine[1',2':4,5][1,4]oxazine[2,3-c][1,8]naphthyridine-3(4H)-carboxylate tert-butyl (35 mg, 0.055 mmol) was dissolved in dichloromethane (4 mL), trifluoroacetic acid (1 mL) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated to obtain (4aS)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridine-3-yl)-1,2,3,4,4a,5-hexahydropyrazine[1',2':4,5][1,4]oxazine[2,3-c][1,8]naphthyridine-7(8H)-one (185 mg, crude product) as the 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-methylpyridine-3-yl)-1,2,3,4,4a,5-hexahydropyrazine[1',2':4,5][1,4]oxazine[2,3-c][1,8]naphthyridine-7(8H)-one (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 of acrylate chloride (50 mg, 0.56 mmol) (0.5 mL) was added dropwise to the reaction mixture. The mixture was stirred at 0°C for 15 minutes. 50 mL of dichloromethane was added to the reaction mixture, and the mixture was washed twice in sequence with 15 mL of water and 15 mL of saturated NaHCO3 aqueous solution, followed by washing with 15 mL of saturated saline solution. After drying the organic layer, it was concentrated to obtain the yellow solid (4aS)-3-acryloyl-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridine-3-yl)-1,2,3,4,4a,5-hexahydropyrazine[1',2':4,5][1,4]oxazine[2,3-c][1,8]naphthyridine-7(8H)-one (160 mg, Y:95.8%) as the product. ES-API:[M+H] + = 588.3. Step 5: (4aS)-3-acryloyl-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridine-3-yl)-1,2,3,4,4a,5-hexahydropyrazine[1',2':4,5][1,4]oxazine[2,3-c][1,8]naphthyridine-7(8H)-one (160 mg, 0.27 mmol) was dissolved in dichloromethane (4 mL), the reaction system was cooled to 0°C, and a 17% boron tribromide solution in dichloromethane (3 mL) was added dropwise. The reaction was stirred at room temperature for 3 hours. The reaction mixture was poured into 25 mL of cooled saturated NaHCO3 aqueous solution and extracted with 50 mL of dichloromethane. The organic layer was washed sequentially with 25 mL of saturated NaHCO3 aqueous solution and 25 mL of saturated saline solution, dried, and concentrated. The crude product was purified by preparative HPLC to obtain (4aS)-3-acryloyl-11-fluoro-10-(2-fluoro-6-hydroxyphenyl)-8-(2-isopropyl-4-methylpyridine-3-yl)-1,2,3,4,4a,5-hexahydropyrazine[1',2':4,5][1,4]oxazine[2,3-c][1,8]naphthyridine-7(8H)-one (Z: 28,90 mg, Y: 57.6%) as a pale yellow solid. 1 H NMR (400MHz, DMSO-d6) δ10.04(s, 1H), 8.42(d, J=4.8Hz, 1H), 8.22(d, J=7.4Hz, 1H) , 7.27-7.17(m, 2H), 7.01-6.78(m, 1H), 6.77-6.58(m, 2H), 6.18(d, J=16.3Hz, 1H), 5 .87-5.66(m, 1H), 4.51-3.97(m, 4H), 3.91-3.39(m, 4H), 3.14-3.01(m, 1H), 2.62-2 .41(m, 1H), 1.91-1.76(m, 3H), 1.12-0.98(m, 3H), 0.94-0.83(m, 3H).ES-API:[M+H] + = 574.2.

[0434] Example 29 Preparation of Compound Z29

[0435] [ka]

[0436] Step 1: Dissolve 7-chloro-6-fluoro-4-hydroxy-1-(2-isopropyl-4-methylpyridine-3-yl)-1,8-naphthirizine-2(1H)-one (4.0 g, 11.53 mmol) in acetic acid (9 mL), and sequentially add sodium nitrite (79 mg, 1.15 mmol) and concentrated nitric acid (2.3 mL, 34.6 mmol). Stir at room temperature for 30 minutes. Slowly pour the reaction mixture into 100 mL of ice water, filter the precipitated solid, wash the filter cake with 20 mL of ice water, and vacuum dry to obtain 7-chloro-6-fluoro-4-hydroxy-1-(2-isopropyl-4-methylpyridine-3-yl)-3-nitro-1,8-naphthirizine-2(1H)-one (3.1 g, Y: 80%) as a yellow solid. ES-API:[M+H] + =393.1. Step 2: Add 7-chloro-6-fluoro-4-hydroxy-1-(2-isopropyl-4-methylpyridine-3-yl)-3-nitro-1,8-naphthyrizine-2(1H)-one (1.0 g, 2.55 mmol), (5-methyl-1H-indazole-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 to a 100 mL three-necked flask and stir at 110 °C for 1 hour under a nitrogen atmosphere. After the reaction is complete, cool the reaction mixture to room temperature, add 80 mL of water and 100 mL of methyl-tert-butyl ether, and extract once. The aqueous layer was adjusted to pH 3-4 with a 1M hydrochloric acid solution, causing solid matter to precipitate. This precipitate was filtered, and the resulting solid product was vacuum-dried to obtain a pale yellow solid, 6-fluoro-7-(5-methyl-1H-indazole-4-yl)-4-hydroxy-1-(2-isopropyl-4-methylpyridine-3-yl)-3-nitro-1,8-naphthyridine-2(1H)-one (0.8g, 50%). ES-API:[M+H] + = 489.2. Step 3: 6-Fluoro-7-(5-methyl-1H-indazole-4-yl)-4-hydroxy-1-(2-isopropyl-4-methylpyridine-3-yl)-3-nitro-1,8-naphthyrizine-2(1H)-one (0.6 g, 1.23 mmol) was dissolved in acetonitrile (20 mL), and 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 mixture, 30 mL of cold acetonitrile was added, and the mixture was added dropwise to 30 mL of saturated sodium bicarbonate solution in an ice bath and extracted with ethyl acetate (200 mL * 2). The ethyl acetate layer was combined and washed once with 50 mL of saturated saline solution. The mixture was dried over anhydrous sodium sulfate, filtered, and the organic layer was dried and concentrated. The crude product was then purified by high-speed silica gel column (Âti / PE: 0-80%) to obtain 4-chloro-6-fluoro-7-(5-methyl-1H-indazole-4-yl)-1-(2-isopropyl-4-methylpyridine-3-yl)-3-nitro-1,8-naphthyridine-2(1H)-one (0.3 g, Y: 50%) as a yellow solid. ES-API:[M+H] + = 507.0. Step 4: Dissolve 4-chloro-6-fluoro-7-(5-methyl-1H-indazole-4-yl)-1-(2-isopropyl-4-methylpyridine-3-yl)-3-nitro-1,8-naphthyridine-2(1H)-one (150 mg, 0.296 mmol) in N,N-dimethylacetamide (25 mL), and sequentially add (R)-3-(hydroxymethyl)piperazine-1-carboxylate tert-butyl (1.48 g, 320 mmol). Stir at 80°C for 1.5 hours. Add 80 mL of ethyl acetate to the reaction mixture and wash three times with 80 mL of saturated saline solution. After drying and concentrating the ethyl acetate layer, the crude product was purified using a high-speed silica gel column (siRNA / PE: 0-80%) to obtain the yellow solid (3R)-4-(6-fluoro-1-(2-isopropyl-4-methylpyridine-3-yl)-7-(5-methyl-1H-indazole-4-yl)-3-nitro-2-oxo-1,2-dihydro-1,8-naphthyridine-4-yl)-3-(hydroxymethyl)piperazine-1-carboxylate tert-butyl (10 mg, Y: 40%). ES-API:[M+H] + = 787.3. Step 5: Dissolve 3R)-4-(6-fluoro-1-(2-isopropyl-4-methylpyridine-3-yl)-7-(5-methyl-1H-indazole-4-yl)-3-nitro-2-oxo-1,2-dihydro-1,8-naphthyridine-4-yl)-3-(hydroxymethyl)piperazine-1-carboxylate tert-butyl (90 mg, 0.13 mmol) in N,N-dimethylacetamide (25 mL), add sodium hydride (15.7 mg, 0.39 mmol), and stir at 130°C for 18 hours. Cool to room temperature, pour into ice water, adjust pH to 7 with 3M hydrochloric acid, add 30 mL of ethyl acetate, separate the organic layer, and wash sequentially with 30 mL of water and 30 mL of saturated saline solution. The mixture was dried and concentrated to obtain (4aR)-11-fluoro-8-(2-isopropyl-4-methylpyridine-3-yl)-10-(5-methyl-1H-indazole-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%) as a yellow solid product. ES-API:[M+H] + = 640.3. Step 6: (4aR)-11-fluoro-8-(2-isopropyl-4-methylpyridine-3-yl)-10-(5-methyl-1H-indazole-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 solution was concentrated to obtain ((4aR)-11-fluoro-8-(2-isopropyl-4-methylpyridine-3-yl)-10-(5-methyl-1H-indazole-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, crude product), which was then used directly in the next reaction. ES-API:[M+H] + = 540.2. Step 7: (4aR)-11-fluoro-8-(2-isopropyl-4-methylpyridine-3-yl)-10-(5-methyl-1H-indazole-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 acrylate chloride (10.5 mg, 0.083 mmol) was added dropwise to the reaction mixture. The mixture was stirred at 0°C for 15 minutes. 20 mL of dichloromethane was added to the reaction mixture, and it was washed with 20 mL of saturated NaHCO3 aqueous solution and 20 mL of saturated saline solution. After drying and concentration, the mixture was purified by preparative HPLC to obtain (4aR)-3-acryloyl-11-fluoro-8-(2-isopropyl-4-methylpyridine-3-yl)-10-(5-methyl-1H-indazole-4-yl)-1,2,3,4,4a,5-hexahydropyrazine-[1',2':4,5][1,4]oxazine[2,3-c][1,8]naphthyridine-7(8H)-one (Z29, 15 mg, Y:28%). ES-API:[M+H] + = 594.2. 1 H-NMR (500MHz, DMSO-d6) δ13.08(s, 1H), 8.37(d, J=4.8Hz, 1H), 8.32(d, J=9.4Hz, 1H), 7.49(d, J=8.1Hz, 2H), 7.24(d, J=8.5Hz, 1H), 7.20(d, J =5.0Hz, 1H), 6.90(s, 1H), 6.20(d, J=16.7Hz, 1H), 5.78(s, 1H), 4.45(d, J=46.5Hz, 1H), 4.35-4.20(m, 2H), 4.05(s, 1H), 3.85(d, J=51.4 Hz, 1H), 3.75-3.57(m, 2H), 3.48(s, 1H), 3.15(s, 1H), 2.05(s, 3H), 1.90(d, J=33.7Hz, 3H), 1.03(t, J=6.7Hz, 3H), 0.81(dd, J=20.9, 6.4Hz, 3H).

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

[0438] [ka]

[0439] Step 1: (4aR)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridine-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]naphthyrizine-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 sequence to a 15 mL tube. The tube was sealed and stirred at 55°C for 18 hours. After concentrating the reaction mixture, 60 mL of ethyl acetate was added, and the mixture was washed sequentially with 30 mL of water and 30 mL of saturated saline. After drying and concentration, the crude product was purified by high-speed silica gel column (siRNA / PE: 0-70%) to obtain the orange solid (4aR)-6-ethyl-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridine-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%). ES-API:[M+H] + = 675.3. Step 2: Dissolve (4aR)-6-ethyl-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridine-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) in dichloromethane (4 mL) and trifluor. 1 mL of chloroacetic acid was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated to obtain (4aR)-6-ethyl-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridine-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) as the product, which was then used 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-methylpyridine-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, acrylate chloride (130 mg, 1.44 mmol) was added to the reaction mixture, and the mixture was stirred at 0°C for 15 minutes. 45 mL of dichloromethane was added to the reaction mixture, and the mixture was washed sequentially with 25 mL of water, 25 mL of saturated NaHCO3 aqueous solution, and 25 mL of saturated saline solution. After drying and concentration, the crude product was purified by high-speed silica gel column (siRNA / PE: 0-90%) to obtain (4aR)-3-acryloyl-6-ethyl-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridine-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-methylpyridine-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% boron tribromide solution in dichloromethane (5 mL) was added dropwise. The mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into 60 mL of saturated NaHCO3 aqueous solution and extracted twice with 50 mL of dichloromethane. The organic layer was washed sequentially with 30 mL of saturated NaHCO3 aqueous solution and 30 mL of saturated saline solution. The mixture was dried and concentrated to obtain (4aR)-3-acryloyl-6-ethyl-11-fluoro-10-(2-fluoro-6-hydroxyphenyl)-8-(2-isopropyl-4-methylpyridine-3-yl)-2,3,4,4a,6,8-hexahydro-1H-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8]naphthyridine-5,7-dione (Z30, 240 mg, Y:100%) as a pale yellow solid product. ES-API:[M+H] + = 615.3. Step 5: Compound Z30 (240 mg, 0.39 mmol) was purified by preparative HPLC, and then separated by preparative chiral HPLC (column: IB: 10 μm, 30 * 250 mm, mobile phase: hexane: EtOH = 70:30, flow rate: 25 ml / min, column temperature: room temperature). One atropisomer compound was obtained, which was a pale yellow solid, and its structure was designated as Z30-1 (71 mg, peak: 1, retention time: 6.342 min, Y: 29.6%). 1H NMR (500MHz, DMSO-d6) δ10.11(d, J=1.1Hz, 1H), 8.45(d, J=4.9Hz, 1H), 8.40(d, J=8.8Hz, 1H), 7.32-7.18 (m, 2H), 7.12-6.80(m, 1H), 6.75-6.62(m, 2H), 6.15(dd, J=16.8, 2.0Hz, 1H), 5.75(d, J=12.2Hz, 1H), 4.7 2(d, J=13.5Hz, 1H), 4.46(d, J=11.9Hz, 1H), 4.18-3.93(m, 3H), 3.63-3.50(m, 2H), 3.26-3.06(m, 1H), 2. 80-2.55(m, 1H), 2.50-2.39(m, 1H), 1.97(s, 3H), 1.10-0.95(m, 6H), 0.86(d, J=6.7Hz, 3H).ES-API:[M+H] + =615.2. In addition, the other atropisomer compound obtained was a pale yellow solid, and its structure was designated as Z30-2 (73 mg, peak: 2, retention time: 7.970 min, Y: 30.5%). 1 H NMR (500MHz, DMSO-d6) δ10.13(s, 1H), 8.45(d, J=4.9Hz, 1H), 8.39(d, J=8.8Hz, 1H), 7.31-7. 19(m, 2H), 7.12-6.80(m, 1H), 6.77-6.62(m, 2H), 6.15(dd, J=16.8, 2.1Hz, 1H), 5.75(d, J=12. 3Hz, 1H), 4.73(d, J=14.1Hz, 1H), 4.46(d, J=13.0Hz, 1H), 4.20-4.02(m, 2H), 4.00-3.91(m, 1 H), 3.65-3.53(m, 2H), 3.26-3.06(m, 1H), 2.82-2.58(m, 2H), 1.80(s, 3H), 1.15-0.93(m, 9H). 1 ES-API:[M+H] + =615.2. The isomer compounds were detected by analytical chiral HPLC (column: IB: 5 μm, 4.6 x 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: Add 6-chloro-7-(2-fluoro-6-methoxyphenyl)-4-hydroxy-1-(2-isopropyl-4-methylpyridine-3-yl)-3-nitro-1,8-naphthyrizine-2(1H)-one (1.0 g, 2.0 mmol), potassium cyclopropyltrifluoroborate (1.48 g, 10.0 mmol), chloro(2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (144 mg, 0.20 mmol), 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (82 mg, 0.20 mmol), potassium carbonate (1.66 g, 12.0 mmol), 2 mL of water, and 20 mL of toluene to a 250 mL flask. The reaction was stirred at 125°C for 18 hours under a nitrogen atmosphere. After concentrating the reaction mixture, 50 mL of water was added, and the pH was adjusted to 3.0 with 3.0 M dilute hydrochloric acid. The mixture was extracted twice with 50 mL of dichloromethane. The organic layer was dried and concentrated to obtain the brown solid 6-cyclopropyl-7-(2-fluoro-6-methoxyphenyl)-4-hydroxy-1-(2-isopropyl-4-methylpyridine-3-yl)-3-nitro-1,8-naphthyrizine-2(1H)-one (850 mg, crude product) as the product. ES-API:[M+H] + = 505.2. Step 2: 6-Cyclopropyl-7-(2-Fluoro-6-methoxyphenyl)-4-Hydroxy-1-(2-Isopropyl-4-methylpyridine-3-yl)-3-Nitro-1,8-Naphthyridine-2(1H)-one (1.6 g, crude product) was dissolved in acetonitrile (50 mL), and phosphorus oxychloride (2.43 g, 15.85 mmol) and N,N-diisopropylethylamine (3.27 g, 25.36 mmol) were added in sequence, and the mixture was stirred at 85°C for 1 hour. After concentrating the reaction mixture, 120 mL of ethyl acetate was added, and the mixture was washed twice in sequence with 60 mL of water and 60 mL of saturated sodium bicarbonate, followed by washing with 60 mL of saturated saline solution. After drying and concentrating the organic layer, the crude product was purified by high-speed silica gel column (Âti / PE: 0-35%) to obtain 4-chloro-6-cyclopropyl-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropyl-4-methylpyridine-3-yl)-3-nitro-1,8-naphthyrizine-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-methylpyridine-3-yl)-3-nitro-1,8-naphthyridine-2(1H)-one (490 mg, 0.94 mmol) was dissolved in N,N-dimethylacetamide (6 mL), and (3R,6R)-1-N-BOC-6-methylpiperazine-3-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 mixture, and the mixture was washed four times with 30 mL of dilute saline solution, followed by washing with 30 mL of saturated saline solution. After drying and concentration, the crude product was purified by high-speed silica gel column (siRNA / PE: 0-50%) to obtain the orange solid (3R,6R)-1-N-BOC-4-(6-cyclopropyl-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropyl-4-methylpyridine-3-yl)-3-nitro-2-oxo-1,2-dihydro-1,8-naphthyridine-4-yl)-6-methylpiperazine-3-carboxylate methyl (485 mg, Y: 69.4%). ES-API:[M+H] + = 745.3. Step 4: (3R,6R)-1-N-BOC-4-(6-cyclopropyl-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropyl-4-methylpyridine-3-yl)-3-nitro-2-oxo-1,2-dihydro-1,8-naphthyridine-4-yl)-6-methylpiperazine-3-carboxylate methyl (455 mg, 0.61 mmol) was dissolved in acetic acid (8 mL), iron powder (120 mg, 2.14 mmol) was added, and the mixture was stirred at 80°C for 30 minutes. After concentrating the reaction mixture, 80 mL of ethyl acetate and 50 mL of saturated sodium bicarbonate were added in sequence, the suspension was filtered through diatomaceous earth, and the filter cake was washed with ethyl acetate. The organic layer was separated and washed sequentially with 25 mL of saturated sodium bicarbonate and 25 mL of saturated saline solution. The mixture was dried and concentrated to obtain (2R,4aR)-11-cyclopropyl-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridine-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-methylpyridine-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]naphthyrizine-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 mixture, and it was washed sequentially with 15 mL of water and 15 mL of saturated saline solution. After drying and concentration, the crude product was purified by preparative thin-layer chromatography (dichloromethane / methanol = 25:1) to obtain (2R,4aR)-11-cyclopropyl-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridine-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 pale yellow solid. ES-API:[M+H] + = 697.3. Step 6: Dissolve (2R,4aR)-11-cyclopropyl-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridine-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]naphthyrizine-3-carboxylate tert-butyl (160 mg, 0.23 mmol) in dichloromethane (3.5 mL) and add trifluoroacetic acid (0.8 (mL) was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated to obtain ((2R,4aR)-11-cyclopropyl-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridine-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) as the product, which was then used 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-methylpyridine-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 system was cooled to 0°C, and acrylate chloride (41 mg, 0.46 mmol) was added dropwise to the reaction mixture. The mixture was stirred at 0°C for 15 minutes. 30 mL of dichloromethane was added to the reaction mixture, and the mixture was washed sequentially with 15 mL of water, 15 mL of saturated NaHCO3 aqueous solution, and 15 mL of saturated saline solution. After drying and concentration, the crude product was purified by high-performance silica gel column (dichloromethane / methanol: 0-5%) to obtain a pale yellow solid (2R,4aR)-3-acryloyl-11-cyclopropyl-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridine-3-yl)-2,6-dimethyl-2,3,4,4a,6,8-hexahydro-1H-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8]naphthyridine-5,7-dione (140 mg, Y: 93.7%). ES-API:[M+H] + = 651.3. Step 8: (2R,4aR)-3-acryloyl-11-cyclopropyl-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridine-3-yl)-2,6-dimethyl-2,3,4,4a,6,8-hexahydro-1H-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8]naphthyrizine-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% boron tribromide solution in dichloromethane (3 mL) was added dropwise. The mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into 40 mL of saturated NaHCO3 aqueous solution and extracted twice with 25 mL of dichloromethane. After drying and concentrating the organic layer, the crude product was purified by preparative HPLC to obtain the white solid (2R,4aR)-3-acryloyl-11-cyclopropyl-10-(2-fluoro-6-hydroxyphenyl)-8-(2-isopropyl-4-methylpyridine-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%). 1 H NMR (500MHz, DMSO-d6) δ9.90(s, 1H), 8.42(d, J=4.8Hz, 1H), 7.75-7.73(m, 1H), 7.22-7.17(m, 2H), 7. 03(dd, J=16.8, 10.5Hz, 1H), 6.74-6.60(m, 2H), 6.22-6.08(m, 1H), 5.81-5.69(m, 1H), 5.05-4.81(m, 1 H), 4.62-4.41(m, 1H), 4.03-3.90(m, 1H), 3.75(dd, J=14.1, 4.2Hz, 1H), 3.39-3.25(m, 4H), 2.83-2.6 7(m, 1H), 2.48-2.37(m, 1H), 2.01-1.75(m, 3H), 1.70-1.46(m, 4H), 1.14-0.55(m, 10H).ES-API:[M+H] + = 637.3.

[0443] Example 32 Preparation of compound Z32

[0444] [ka]

[0445] Step 1: Dissolve 4,6-dicyclopropylpyrimidine-5-amine (742 mg, 4.24 mmol) in dry tetrahydrofuran (20 mL), add 2 M NaHMDS (8.48 mL, 16.96 mmol) under ice bath conditions, and stir for 20 minutes under ice bath conditions. Add 2,5-difluoro-6-(2-fluoro-6-methoxyphenyl)nicotinic acid (1.2 g, 4.24 mmol), stir at room temperature for 3 hours, slowly pour the reaction mixture into 30 mL of ice water, adjust the pH to 5-6 with dilute hydrochloric acid (3 M), and extract with ethyl acetate. Wash once with 50 mL of saturated saline. The mixture was dried over anhydrous sodium sulfate, filtered, and the organic layer was dried and concentrated. The crude product was then purified by high-performance silica gel column (Âti / PE: 20-40%) to obtain 2-((4,6-dicyclopropylpyrimidine-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-dicyclopropylpyrimidine-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 complete, the reaction mixture was cooled to room temperature. After concentration, it was dried at 50°C under vacuum for 4 hours to obtain 2-((4,6-dicyclopropylpyrimidine-5-yl)amino)-5-fluoro-6-(2-fluoro-6-methoxyphenyl)nicotinic acid chloride (1.57 g, crude product), a pale yellow solid, as the product. Methanol detection ES-API: [M+H] + = 453.2. Step 3: Under ice bath conditions, sodium hydride (1.97 g, 49.35 mmol) was added to tetrahydrofuran nitroacetate ethyl (1.31 g, 9.86 mmol) and stirred for 30 minutes. Then, 2-((4,6-dicyclopropylpyrimidine-5-yl)amino)-5-fluoro-6-(2-fluoro-6-methoxyphenyl)nicotinate chloride (1.57 g, 3.29 mmol) was added and stirred at room temperature for 1 hour, and then reacted for 2 hours while raising the temperature to 80°C. The solution was poured into ice water, the pH was adjusted to 3-4 with 3M hydrochloric acid, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the organic layer was dried and concentrated to obtain 1-(4,6-dicyclopropylpyrimidine-5-yl)-6-fluoro-7-(2-fluoro-6-methoxyphenyl)-4-hydroxy-3-nitro-1,8-naphthyrizine-2(1H)-one (110 mg, Y: 20%) as the product. ES-API:[M+H] + = 508.1. Step 4: 1-(4,6-dicyclopropylpyrimidine-5-yl)-6-fluoro-7-(2-fluoro-6-methoxyphenyl)-4-hydroxy-3-nitro-1,8-naphthyrizine-2(1H)-one (110 mg, 0.20 mmol) was dissolved in acetonitrile (10 mL), and phosphorus oxychloride (153 mg, 1.0 mmol) and N,N-diisopropylethylamine (77 g, 0.6 mmol) were added in sequence, and the mixture was stirred for 3 hours while gradually increasing the temperature to 80°C. After concentrating the reaction mixture, 30 mL of cold acetonitrile was added, and the mixture was added dropwise to 30 mL of saturated sodium bicarbonate solution in an ice bath. The mixture was extracted with ethyl acetate (50 mL x 2), the organic layers were combined, and the mixture was washed with 30 mL of saturated brine. The mixture was dried over anhydrous sodium sulfate, filtered, and the organic layer was dried and concentrated. The crude product was then purified by high-speed silica gel column (Âti / PE: 0-80%) to obtain the yellow solid 4-chloro-6-fluoro-7-(2-fluoro-6-methoxyphenyl)-1-(4,6-dicyclopropylpyrimidine-5-yl)-3-nitro-1,8-naphthyrizine-2(1H)-one (110 mg, Y: 68%). ES-API:[M+H] + = 526.2. Step 5: Dissolve 4-chloro-6-fluoro-7-(2-fluoro-6-methoxyphenyl)-1-(4,6-dicyclopropylpyrimidine-5-yl)-3-nitro-1,8-naphthyrizine-2(1H)-one (110 mg, 0.296 mmol) in N,N-dimethylacetamide (3 mL), and sequentially add 1-(tert-butyl-3-methyl(R)-piperazine-1,3-dicarboxylic acid ester (54 mg, 0.22 mmol), stirring at 120°C for 2 hours. After the reaction is complete, acetic acid 30 mL of ethyl acetate was added, and the mixture was washed three times with 30 mL of saturated saline solution. The ethyl acetate layer was dried and concentrated to obtain the target product, a yellow solid (3R)-1-tert-butyl-3-methyl-4-(1-(4,6-dicyclopropylpyrimidine-5-yl)-6-fluoro-7-(2-fluoro-6-methoxyphenyl)-3-nitro-2-oxo-1,2-dihydro-1,8-naphthyridine-4-yl)piperazine-1,3-dione (50 mg, Y: 46%), as the crude product. ES-API:[M+H] + = 734.3. Step 6: Dissolve ((3R)-1-tert-butyl-3-methyl-4-(1-(4,6-dicyclopropylpyrimidine-5-yl)-6-fluoro-7-(2-fluoro-6-methoxyphenyl)-3-nitro-2-oxo-1,2-dihydro-1,8-naphthyridine-4-yl)piperazine-1,3-dione (50 mg, 0.068 mmol) in acetic acid (25 mL), add iron powder (11.5 mg, 0.204 mmol), and stir at 80°C for 30 minutes. After concentrating the reaction mixture, add 30 mL of ethyl acetate and 30 mL of saturated sodium bicarbonate in sequence, filter the suspension through diatomaceous earth, and filter. The percake was washed with ethyl acetate, and the organic layer was separated and washed sequentially with 30 mL of saturated sodium bicarbonate and 30 mL of saturated saline solution. The mixture was dried and concentrated to obtain the yellow solid (4aR)-8-(4,6-dicyclopropylpyrimidine-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 the product. ES-API:[M+H]+=672.2. Step 7: Take (4aR)-8-(4,6-dicyclopropylpyrimidine-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]naphthirizine-3(2H)-carboxylate tert-butyl (40 mg, 0.059 mmol), 30 mL of acetone, anhydrous potassium carbonate (33 mg, 0.24 mmol), and iodomethane (85 mg, 0.59 mmol), seal the mixture in a tube, and stir at 50°C for 18 hours. 20 mL of ethyl acetate was added to the reaction mixture, washed with 20 mL of saturated saline solution, dried, and concentrated. The crude product was then purified by high-performance silica gel column (siRNA / PE: 0-80%) to obtain (4aR)-tert-methyl-8-(4,6-dicyclopropylpyrimidine-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]naphthyrizine-3(2H)-one (40 mg, Y: 90%) as the yellow solid. ES-API:[M+H] + = 686.2. Step 8: (4aR)-tert-methyl-8-(4,6-dicyclopropylpyrimidine-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]naphthyrizine-3(2H)-one (44 mg) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (1 mL) was added. The mixture was stirred at room temperature for 2 hours, and the reaction solution was concentrated to obtain (4aR)-8-(4,6-dicyclopropylpyrimidine-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 then used in the next reaction. ES-API:[M+H] + = 586.2. Step 9: (4aR)-8-(4,6-dicyclopropylpyrimidine-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]naphthyrizine-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 acrylate chloride (12.4 mg, 0.137 mmol) was added dropwise to the reaction mixture. The mixture was stirred at 0°C for 15 minutes. 20 mL of dichloromethane was added to the reaction mixture, and the mixture was washed with 20 mL of saturated NaHCO3 aqueous solution and 20 mL of saturated saline solution. After drying and concentration, the crude product was purified by preparative HPLC to obtain the yellow solid (4aR)-3-acryloyl-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(4,6-dicyclopropylpyrimidine-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%). 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-pyrazole-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), and concentrated sulfuric acid (10 mL) was slowly added. The mixture was stirred at 120 °C for 18 hours. The cooled reaction solution was poured into 20 mL of ice water, the pH was adjusted to 2-3 with sodium carbonate, and the mixture was extracted with ethyl acetate (1000 mL x 2). The ethyl acetate layer was combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was vacuum-dried to obtain the product 7-chloro-6-fluoro-4-hydroxy-1-(1-isopropyl-4-methyl-1H-pyrazole-5-yl)-1,8-naphthirizine-2(1H)-one (3.36 g, Y: 92%), a pale brown solid. ES-API:[M+H] + = 337.1. Step 2: 7-Chloro-6-fluoro-4-hydroxy-1-(1-isopropyl-4-methyl-1H-pyrazole-5-yl)-1,8-naphthirizine-2(1H)-one (3.36 g, 10 mmol) was dissolved in acetic acid (7 mL), and sodium nitrite (69 mg, 1.0 mmol) and concentrated nitric acid (2.0 mL, 30 mmol) were added in sequence. The mixture was stirred at room temperature for 30 minutes. The reaction mixture was slowly poured into 21 mL of ice water, the precipitated solid was filtered, and the filtered cake was washed with 10 mL of ice water. After vacuum drying, the product was a yellow solid, yielding 7-chloro-6-fluoro-4-hydroxy-1-(1-isopropyl-4-methyl-1H-pyrazole-5-yl)3-nitro-1,8-naphthirizine-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-pyrazole-5-yl)3-nitro-1,8-naphthyrizine-2(1H)-one (1.5 g, 3.93 mmol), (2-fluoro-6-methoxyphenyl)boric 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-necked flask. The mixture was stirred at 100 °C for 3 hours under a nitrogen atmosphere. After the reaction was complete, the reaction mixture was cooled to room temperature, and 20 mL of water and 50 mL of methyl-tert-butyl ether were added, followed by a single extraction. The aqueous layer was adjusted to pH 3-5 with 1M hydrochloric acid solution, extracted with ethyl acetate (50 mL x 2), the ethyl acetate layer was combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was vacuum-dried to obtain 6-fluoro-7-(2-fluoro-6-methoxyphenyl)-4-hydroxy-1-(1-isopropyl-4-methyl-1H-pyrazole-5-yl)-3-nitro-1,8-naphthyrizine-2(1H)-one (1.5 g, crude product) as a pale yellow solid. ES-API:[M+H] + = 472.1. Step 4: 6-Fluoro-7-(2-Fluoro-6-methoxyphenyl)-4-hydroxy-1-(1-isopropyl-4-methyl-1H-pyrazole-5-yl)-3-nitro-1,8-naphthyrizine-2(1H)-one (1.5 g, 3.18 mmol) was dissolved in acetonitrile (15 mL), and phosphorus oxychloride (2.4 mL, 25.5 mmol) and N,N-diisopropylethylamine (2.6 mL, 15.9 mmol) were added in sequence, and the mixture was stirred for 30 minutes while gradually increasing the temperature to 80°C. After concentrating the reaction mixture, 10 mL of cold acetonitrile was added, and the mixture was added dropwise to 20 mL of saturated sodium bicarbonate solution in an ice bath and extracted with ethyl acetate (20 mL x 2). The ethyl acetate layer was combined and washed once with 20 mL of saturated saline. The mixture was dried over anhydrous sodium sulfate, filtered, and the organic layer was dried and concentrated. The crude product was then purified by high-performance silica gel column (Âti / PE: 0-50%) to obtain the yellow solid 4-chloro-6-fluoro-7-(2-fluoro-6-methoxyphenyl)-1-(1-isopropyl-4-methyl-1H-pyrazole-5-yl)-3-nitro-1,8-naphthyrizine-2(1H)-one (0.9 g, Y: 65%). ES-API:[M+H] + = 490.1. Step 5: Dissolve 4-chloro-6-fluoro-7-(2-fluoro-6-methoxyphenyl)-1-(1-isopropyl-4-methyl-1H-pyrazole-5-yl)-3-nitro-1,8-naphthyridine-2(1H)-one (490 mg, 1.0 mmol) in N,N-dimethylacetamide (5 mL), and sequentially add (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). Stir at 120°C for 2 hours. Add 20 mL of ethyl acetate to the reaction mixture and wash three times with 20 mL of saturated saline solution. The ethyl acetate layer was dried and concentrated to obtain the yellow solid (3R,6R)-1-tert-butyl-3-methyl-4-(6-fluoro-7-(2-fluoro-6-methoxyphenyl)-1-(1-isopropyl-4-methyl-1H-pyrazole-5-yl)-3-nitro-2-oxo-1,2-dihydro-1,8-naphthyridine-4-yl)piperazine-1,3-dione (620 mg, crude product). 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-pyrazole-5-yl)-3-nitro-2-oxo-1,2-dihydro-1,8-naphthyridine-4-yl)piperazine-1,3-dione (620 mg, 0.872 mmol) was dissolved in acetic acid (8 mL), iron powder (146 mg, 2.62 mmol) was added, and the mixture was stirred at 80°C for 30 minutes. After concentrating the reaction mixture, 30 mL of ethyl acetate and 30 mL of saturated sodium bicarbonate were added in sequence, the suspension was filtered through diatomaceous earth, and the filter cake was washed with ethyl acetate. The organic layer was separated and washed in sequence with 30 mL of saturated sodium bicarbonate and 30 mL of saturated saline solution. The mixture was dried and concentrated to obtain the yellow solid (2R,4aR)-tert-butyl11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(1-isopropyl-4-methyl-1H-pyrazole-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]naphthiridine-3(2H)-carboxylate tert-butyl (300 mg, crude product). ES-API:[M+H]+=650.3. Step 7: (2R,4aR)-tert-butyl11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(1-isopropyl-4-methyl-1H-pyrazole-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), and 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 mixture and washed with 20 mL of saturated saline solution. After drying and concentration, the crude product was purified by high-speed silica gel column (siRNA / PE: 0-80%) to obtain the yellow solid (2R,4aR)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(1-isopropyl-4-methyl-1H-pyrazole-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]naphthirizine-3(2H)-carboxylate tert-butyl (350 mg, Y: 95%). ES-API:[M+H] + = 664.3. Step 8: (2R,4aR)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(1-isopropyl-4-methyl-1H-pyrazole-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 solution was concentrated to obtain (2R,4aR)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(1-isopropyl-4-methyl-1H-pyrazole-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) as the 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-pyrazole-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 acrylate chloride (112.5 mg, 1.24 mmol) was added dropwise to the reaction mixture. The mixture was stirred at 0°C for 15 minutes. 20 mL of dichloromethane was added to the reaction mixture, and the mixture was washed with 20 mL of saturated NaHCO3 aqueous solution and 20 mL of saturated saline solution. After drying and concentration, the crude product was purified by preparation chromatography to obtain the yellow solid (2R,4aR)-3-acryloyl-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(1-isopropyl-4-methyl-1H-pyrazole-5-yl)-2,6-dimethyl-2,3,4,4a-tetrahydro-1H-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8]naphthirizine-5,7(6H,8H)-dione (250 mg, Y:60%). ES-API:[M+H] + = 618.3. Step 10: Under ice bath conditions, (2R,4aR)-3-acryloyl-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(1-isopropyl-4-methyl-1H-pyrazole-5-yl)-2,6-dimethyl-2,3,4,4a-tetrahydro-1H-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8]naphthyrizine-5,7(6H,8H)-dione (250 mg, 0.405 mmol) was added to dry dichloromethane (6.0 mL), and boron tribromide (4.0 mL, 4.0 mmol) was further added. The mixture was heated to room temperature and reacted for 1 hour. Under ice bath conditions, the reaction solution was added dropwise to a saturated sodium bicarbonate solution and extracted twice with dichloromethane (30 mL). The mixture was dried and concentrated to obtain (2R,4aR)-3-acryloyl-11-fluoro-10-(2-fluoro-6-hydroxyphenyl)-8-(1-isopropyl-4-methyl-1H-pyrazole-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) as the product. Step 11: Compound Z33 was purified by preparative HPLC, and one atropisomer compound was obtained, whose structure is Z33-1 (peak: 1, 30 mg, retention time: 9.576). I specified min, Y:50%). 1H NMR (500MHz, DMSO-d6) δ10.17(s, 1H), 7.98(dd, J=8.4, 5.5Hz, 1H), 7.40(d, J=5.5Hz, 1H), 7.29(q, J=7.9Hz, 1H), 7.02(dd, J=16.8, 10.6Hz , 1H), 6.81-6.68(m, 2H), 6.20-6.11(m, 1H), 5.81-5.69(m, 1H), 4.77(s, 1H), 4.61(d, J=14.7Hz, 1H), 4.01-3.83(m, 2H), 3.73(dd, J=14.2, 4.2Hz, 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). In addition, the structure of the other atropisomer compound obtained was specified as Z33-2 (peak: 2, 15 mg, retention time: 9.663 min, Y: 25%). 1 H NMR (500MHz, DMSO-d6) δ10.17(s1H), 7.96(m, 1H), 7.40(d, J=5.5Hz, 1H), 7.29(q, J=7.9Hz, 1H), 7.0 2(m, 1H), 6.81-6.68(m, 2H), 6.20-6.11(m, 1H), 5.81-5.69(m, 1H), 4.77(s, 1H), 4.61(d, J=14.7Hz, 1 H), 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). Isomer compounds were detected by analytical HPLC.

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

[0450] [ka]

[0451] Step 1: (2R, 4aR)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridine-3-yl)-2-methyl-5,7-dioxo-...

Claims

1. A compound represented by formula (I), or a pharmaceutically 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 and R ２ are each independently hydrogen, halogen, cyano, 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 It is an alkoxy, R ４ is hydrogen, halogen 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 These may be the same or different, and each may independently be hydrogen, halogen, and -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 These may be the same or different, and each may independently be hydrogen, halogen, and -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 These may be the same or different, and each may independently be hydrogen, halogen, and -C. １－３ Alkyl, -halogenated C １－３ Alkyl, -C １－３ Alkyl-hydroxy, -C １－３ Alkyl-cyano, -C １－３ Alkyl-C １－６ Alkoxy, -C １－３ Alkyl-halogenated C １－６ Alkyl or -C １－３ Alkyl-halogenated C １－６ It is an alkoxy, R ４１ is hydrogen, halogen, -C １－３ Alkyl, -halogenated C １－３ Alkyl, -C １－３ Alkyl-hydroxy, -C １－３ Alkyl-cyano, -C １－３ Alkyl-C １－６ Alkoxy, -C １－３ Alkyl-halogenated C １－６ Alkyl or -C １－３ Alkyl-halogenated C １－６ It is an alkoxy, 【Chemistry 2】 The dashed line in is a single bond, and P is O, NH or NR ｍ where R ｍ is optionally substituted -C １－６ alkyl, and R ４２ is -(C=O)-, -C １－３ alkyl-, -C １－３ alkyl(hydroxy)-, -C １－３ alkyl(cyano)-, -C １－３ alkyl(C １－６ alkyl)-, -C １－３ alkyl(halogenated C １－６ alkyl)-, -C １－３ alkyl(C １－６ alkyl-hydroxy)-, -C １－３ alkyl(C １－６ alkyl-cyano)-, -C １－３ alkyl(C １－６ alkoxy)-, or -C １－３ alkyl(halogenated C １－６ alkoxy)-, and When Y1 is C, X １ is hydrogen, halogen, cyano, hydroxy, amino, nitro, - 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, - 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 the said R ｊ , R ｋ are each independently hydrogen or C １－３ alkyl, or alternatively, the said R ｊ , R ｋ This forms a 3-6 member nitrogen-containing heterocycloalkyl group which may be substituted together with the connected nitrogen atom, and the 3-6 member heterocycloalkyl group has 1, 2, or 3 heteroatoms selected from N, O, and S as ring-forming atoms, and the 3-6 member nitrogen-containing heterocycloalkyl group 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" refers to the substitution of 1, 2, 3, or 4 hydrogen atoms in the group with substituents selected from the S group, Alternatively, Y １ If X is N, １ It does not exist. The aforementioned S group substituents are hydroxy, halogen, nitro, oxo, and -C. １－６ Alkyl, -halogenated C １－６ Alkyl, hydroxysubstituted 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 groups, -(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 , NR ａ０ C(O)-(CH ２ ) ｕ OH, NR ａ０ C(O)-halogenated C １－６ Selected from alkyl groups, the 3-6 membered heterocycloalkyl group or the 5 or 6 membered monocyclic heteroaryl group each has one, two or three heteroatoms independently selected from N, O and S as ring-forming atoms, and the 3-6 membered heterocycloalkyl group or the 5 or 6 membered monocyclic heteroaryl group may contain halogens, cyanonucleotides, or -C １－３ Alkyl, -C １－３ Alkoxy and C ３－６ It may be substituted with one, two, or three substituents selected from cycloalkyl groups, where u and v are independently 0, 1, 2, 3, or 4, and R ａ０ , R ｂ０ Each is independently hydrogen or C １－３ It is alkyl, E １ is N or CR ５ And the 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 It is an alkoxy, E ２ is N or CR ６ And the 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 It is an alkoxy, However, Y １ , E １ , E ２ However, not N at the same time Ar is C ６－１０ The aryl group is a 5- or 6-membered monocyclic heteroaryl group or an 8- to 10-membered bicyclic heteroaryl group, wherein the 5- or 6-membered monocyclic heteroaryl group has 1, 2, or 3 heteroatoms selected from N, O, and S as ring-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 may be unsubstituted or independently R ｓ１ Substituted with 1, 2, 3, or 4 groups selected from, Alternatively, Ar is a structure represented by formula (B), 【Transformation 3】 In formula (B), the B1 ring is a benzene ring or a 5- or 6-membered monocyclic heteroaryl ring, and the B2 ring is a fused 5- or 6-membered monocyclic heterocycloalkyl ring or a fused 5- or 6-membered monocyclic cycloalkyl ring, wherein the 5- or 6-membered monocyclic heteroaryl ring or the fused 5- or 6-membered monocyclic heterocycloalkyl ring has 1, 2, or 3 heteroatoms selected from N, O, and S as ring-forming atoms. (R ｓ１ ) ｐ In this case, the B1 ring has p hydrogen atoms. ｓ１ This indicates that it is replaced by p, where p is 0, 1, 2, or 3, and each R ｓ１ They may be the same or they may be different. (R ｓ２ ) ｑ This is where the B2 ring has q hydrogen atoms. ｓ２ This indicates that it is replaced by q, where q is 0, 1, 2, or 3, and each R ｓ２ They may be the same or they may be different. R ｓ１ , R ｓ２ These are, independently, halogen, cyano, nitro, hydroxy, and -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 C halogenated 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 alkynyl group is a 3-6 member heterocycloalkyl group having 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 member 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 Ariel, -C １－３ Alkyl-5 or 6-membered monocyclic heteroaryl, -NR ｇ -C ６－１０ Ariel, -O-C ６－１０ Ariel, -C １－３ Alkyl-3 to 6-membered heterocycloalkyl, -C １－３ Alkyl-C ３－６ The cycloalkyl group, the 3-6 membered heterocycloalkyl group, the 5 or 6 membered monocyclic heteroaryl group, or the 8-10 membered bicyclic heteroaryl group, has 1, 2, or 3 heteroatoms selected from N, O, and S as ring-forming atoms, and also has C １－６ Alkyl, C ３－６ Cycloalkyl, 3-6 member heterocycloalkyl, C ６－１０ Aryls, 5- or 6-membered monocyclic heteroaryls, 8- to 10-membered bicyclic heteroaryls, and 7- to 11-membered spirocycloalkyls are unsubstituted or independently R ｓ３ Substituted with 1, 2, 3, or 4 groups selected from, and the -C １－３ Alkyl- is either unsubstituted or has 1, 2, 3, or 4 independently formed C atoms. １－３ Substituted with a group selected from alkyl groups, Or, R ０ This is a structure represented by formula (A-1) or formula (A-2), 【Chemistry 4】 In formula (A-1) or formula (A-2), the A1 ring is a benzene ring or a 5- or 6-membered monocyclic heteroaryl ring, and the A2 ring is a fused 5- or 6-membered monocyclic heterocycloalkyl ring or a fused 5- or 6-membered monocyclic cycloalkyl ring, wherein the 5- or 6-membered monocyclic heteroaryl ring or the fused 5- or 6-membered monocyclic heterocycloalkyl ring has 1, 2, or 3 heteroatoms selected from N, O, and S as ring-forming atoms. (R ｓ３ ) ｔ In this case, the A1 ring has t hydrogen atoms. ｓ３ This indicates that it is replaced by t, where t is 0, 1, 2, or 3, and each R ｓ３ They may be the same or they may be different. (R ｓ４ ) ｓ This is where the A2 ring has s hydrogen atoms. ｓ４ This indicates that it is replaced by s, where s is 0, 1, 2, or 3, and each R ｓ４ They may be the same or they may be different. R ｓ３ , R ｓ４ These are, independently, halogen, cyano, hydroxy, and -C. １－６ Alkyl, -C １－６ Alkoxy, -halogenated C １－６ Alkyl, -halogenated C １－６ Alkoxy, -C ３－６ Cycloalkyl, 3-6 member heterocycloalkyl, -NR ｈ R ｉ , -C(O)NR ｅ R ｆ , -SO ２ C １－３ Alkyl, -SO ２ C halogenated １－３ Alkyl, -SO ２ NR ｅ R ｆ , -C １－３ Alkyl-hydroxy, -C １－３ Alkyl-C ２－４ Alkinyl, -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 alkynyl group is characterized by having one, two, or three 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 Cycloalkyls and 3-6 member heterocycloalkyls include halogens, methyl, ethyl, propyl, isopropyl, trifluoromethyl, amino, and N(CH4). ３ ) ２ It may be substituted with one, two, or three substituents selected from hydroxyl and carboxyl. R ａ , R ｂ , R ｅ , R ｆ , R ｇ Each is independently hydrogen or C １－３ It is alkyl, R ｃ , R ｄ , R ｈ , R ｉ These are hydrogen and -C, respectively, independently. １－３ Alkyl, -C(O)C １－３ Alkyl or -CO ２ C １－３ It is alkyl, However, the following structures are excluded from the compounds represented by formula (I): 【Transformation 5】 。）

2. 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 A compound according to claim 1, or a tautomer, cis-trans isomer, mesomer, racemic mixture, enantiomer, diastereomer, atrop isomer or mixture thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, which is an alkyl-3-membered to 6-membered heterocycloalkyl compound.

3. A pharmaceutical composition comprising a compound according to claim 1 or claim 2, or a tautomer, cis-trans isomer, mesomer, racemic mixture, enantiomer, diastereomer, atrop isomer, or mixture thereof, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.

4. Compounds represented by the following formulas, or their tautomers, cis-trans isomers, mesomers, racemates, enantiomers, diastereomers, atrop isomers or mixtures thereof, or pharmaceutically acceptable salts thereof, or solvates thereof. 【Transformation 6】

5. A compound according to any one of claims 1, 2, and 4, or a tautomer, cis-trans isomer, mesomer, racemic mixture, enantiomer, diastereomer, atrop isomer or mixture thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, for use as a drug for treating and / or preventing KRAS G12C mutagenic disease.

6. The pharmaceutical composition according to claim 3, for use as a drug for treating and / or preventing KRAS G12C mutagenic disease.

7. A compound according to any one of claims 1, 2, and 4, or a tautomer, cis-trans isomer, mesomer, racemic mixture, enantiomer, diastereomer, atrop isomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, for use as a drug for treating and / or preventing cancer.

8. The pharmaceutical composition according to claim 3, for use as a drug for treating and / or preventing cancer.

9. A compound according to any one of claims 1, 2, and 4, or a tautomer, cis-trans isomer, mesomer, racemic mixture, enantiomer, diastereomer, atrop isomer or mixture thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, for use as a drug for treating and / or preventing pancreatic cancer, colorectal cancer, or lung cancer.

10. The pharmaceutical composition according to claim 3, for use as a drug for treating and / or preventing pancreatic cancer, colorectal cancer, or lung cancer.

11. A compound according to any one of claims 1, 2, and 4, or a tautomer, cis-trans isomer, mesomer, racemic mixture, enantiomer, diastereomer, atrop isomer or mixture thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, for use as a drug for treating and / or preventing non-small cell lung cancer (NSCLC).

12. The pharmaceutical composition according to claim 3, for use as a drug for treating and / or preventing non-small cell lung cancer (NSCLC).

13. A compound according to any one of claims 1, 2, and 4, or a tautomer, cis-trans isomer, mesomer, racemic, enantiomer, diastereomer, atrop isomer or mixture thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, for use as a KRAS mutation inhibitor, wherein the KRAS mutation is the KRAS G12C mutation.

14. A pharmaceutical composition according to claim 3 for use as a KRAS mutation inhibitor, wherein the KRAS mutation is a KRAS G12C mutation.

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