Nitrogen-containing heteroaromatic ring compound, preparation method therefor and use thereof

Abstract

The present disclosure relates to a nitrogen-containing heteroaromatic ring compound, a preparation method therefor and the use thereof. In particular, the present disclosure relates to a compound as represented by formula (I), a preparation method therefor, and the use of the nitrogen-containing heteroaromatic ring compound as a κ receptor antagonist in the preparation of a drug for preventing and / or treating κ receptor-mediated diseases.

Description

Nitrogen-containing heterocyclic aromatic compounds, their preparation methods and applications

[0001] Citation of relevant applications

[0002] This disclosure claims priority to the following invention patent applications filed with the State Intellectual Property Office on March 28, 2025, application number 202510389604.8, entitled "Nitrogen-containing heteroaromatic compounds and their preparation methods and applications"; filed with the State Intellectual Property Office on April 9, 2025, application number 202510443268.0, entitled "Nitrogen-containing heteroaromatic compounds and their preparation methods and applications"; filed with the State Intellectual Property Office on July 18, 2025, application number 202510998223.X, entitled "Nitrogen-containing heteroaromatic compounds and their preparation methods and applications"; and filed with the State Intellectual Property Office on November 14, 2025, application number 202511675987.1, entitled "Nitrogen-containing heteroaromatic compounds and their preparation methods and applications", the entire contents of which are incorporated herein by reference. Technical Field

[0003] This disclosure pertains to the field of drug synthesis, specifically relating to a nitrogen-containing heterocyclic aromatic derivative, its preparation method, and its applications. Background Technology

[0004] Opioid receptors are a class of G protein-coupled receptors (GPCRs) primarily expressed in the central and peripheral nervous systems. They regulate physiological processes such as pain, mood, reward, and addiction by binding to endogenous opioid peptides (e.g., endorphins, enkephalins, and dynorphins) or exogenous opioid drugs (e.g., morphine and fentanyl). Opioid receptors are mainly divided into three subtypes: μ receptors (MOR): closely associated with analgesia, euphoria, and respiratory depression, and are the primary targets of most opioid drugs; δ receptors (DOR): involved in analgesia and mood regulation; and κ receptors (KOR): associated with analgesia, sedation, and agitation, and activation may produce aversion. In addition, there is a NOP receptor (Nociceptin / Orphanin FQ receptor), structurally similar to opioid receptors, but which does not bind to classic opioid drugs.

[0005] The κ receptor (KOR) belongs to the GPCR family and has a seven-transmembrane structure, mediating signal transduction through Gi / o proteins. Currently, no functional subtype has been clearly cloned, but splicing variants or differentially modified post-translational forms may exist. In the central nervous system, KOR receptors are mainly distributed in the amygdala (emotion regulation), nucleus accumbens (reward pathway), hypothalamus (stress response), periaqueductal gray matter (pain regulation), and dorsal horn neurons (inhibition of pain signal transmission); they are also distributed in peripheral tissues such as the gastrointestinal tract, immune cells, and skin. Dynorphin is the main endogenous ligand of KOR and is closely related to stress and negative emotions. For exogenous ligands, U-50488 and U-69593 are two commonly used agonists; Nor-BNI, JDTIc, and AZ-MTAB are long-acting antagonists. When KOR receptors are activated by agonists, they can inhibit downstream adenylate cyclase, thereby reducing cAMP levels, activating the MAPK pathway, regulating ion channels, and also being accompanied by the activation of the β-arrestin pathway.

[0006] In recent years, KOR agonists have been shown to induce depression, anhedonia, or irritability in numerous preclinical and human models; systemic administration of KOR antagonists can block depressive-like behaviors induced by social stress failure or reduce immobility time in mice during forced swimming tests. These results suggest that KOR antagonists have great potential to be developed into antidepressants with novel mechanisms of action.

[0007] Several long-acting KOR antagonists (such as nor-BNI, JDTI, and 5-GNTI) were developed in the early stages, which could remain in the brain for several weeks with sustained KOR antagonistic effects after a single dose. However, the development of these long-acting antagonists was terminated due to serious safety issues. Therefore, the development of effective and safe short-acting KOR antagonists has great market demand and clinical value. Summary of the Invention

[0008] The purpose of this disclosure is to provide a compound of general formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope label, metabolite, or prodrug thereof:

[0009] Among them, X a1 Selected from CR a1 and N; X a2 Selected from CR a2 and N; X a3 Selected from CR a3 and N; X a4 Selected from CR a4 and N; X a5 Selected from CR a5 and N;

[0010] U is selected from

[0011] X u1 and X u4 Each independently selected from CR u1 and N;

[0012] X u2 X u3 X u5 X u6 and X u7 Each is independently selected from chemical bonds, O, S, Se, S(O), S(O)2, C(O), CR u2 R u3 and NR u4 Preferred chemical bonds include O, S, S(O), S(O)2, C(O), and CR. u2 R u3 and NR u4 Or, X u1 X u2 X u3 X u4 X u5 X u6 and X u7 Any two rings in the group combine to form C 3-10 Cycloalkyl or 3-10 membered heterocyclic groups, wherein the C 3-10 Cycloalkyl or 3-10-membered heterocyclic groups are optionally separated by one or more independently selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl groups and C 1-6 Substituents of haloalkoxy groups;

[0013] Or, any two adjacent X u1 X u2 X u3 X u4 X u5 X u6 and X u7 Formation of double bonds;

[0014] Or R u2 and R u3 C forms with the carbon atoms that are bonded together. 3-10 Cycloalkyl or 3-10 membered heterocyclic groups, wherein the C 3-10 Cycloalkyl or 3-10-membered heterocyclic groups are optionally separated by one or more independently selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl groups and C 1-6Substituents of haloalkoxy groups;

[0015] Y u1 Y u3 Y u6 and Y u8 Each independently selected from CR u5 and N;

[0016] Y u2 Y u4 Y u5 Y u7 Y u9 and Y u10 Each is independently selected from chemical bonds, O, S, Se, S(O), S(O)2, C(O), CR u6 R u7 and NR u8 Preferred chemical bonds include O, S, S(O), S(O)2, C(O), and CR. u6 R u7 and NR u8 ;

[0017] Z u1 and Z u6 Each independently selected from CR u9 and N;

[0018] Z u2 Z u3 Z u4 Z u5 Z u7 Z u8 Z u9 and Z u10 Each is independently selected from chemical bonds, O, S, Se, S(O), S(O)2, C(O), CR u10 R u11 and NR u12 Preferred chemical bonds include O, S, S(O), S(O)2, C(O), and CR. u10 R u11 and NR u12 ;

[0019] G is

[0020] X g1 Selected from CR g1 and N;

[0021] X g2 X g3 X g4 X g5 X g6 X g7 and X g8Each is independently selected from chemical bonds, O, S, Se, S(O), S(O)2, S(O)(=NR) g2 ), C(O), CR g3 R g4 NR g5 Si(R) g6 2. P(O)R g7 and C (=CR) g8 R g9 Preferred chemical bonds include O, S, S(O), S(O)2, and S(O) (=NR). g2 ), C(O), CR g3 R g4 NR g5 Si(R) g6 2. P(O)R g7 and C (=CR) g8 R g9 );

[0022] Or, X g1 X g2 X g3 X g4 X g5 X g6 X g7 and X g8 Any two rings in the group combine to form C 3-10 Cycloalkyl, 3-10 membered heterocyclic or 5-6 membered heteroaryl, wherein the C 3-10 Cycloalkyl, 3-10-membered heterocyclic or 5-6-membered heteroaryl groups are optionally surrounded by one or more groups independently selected from hydrogen, halogen, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups and C(O)R 43 Substituents, preferably hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl groups and C 1-6 Halogenated alkoxy groups;

[0023] Or R g3 and R g4 C forms with the carbon atoms that are bonded together. 3-10 Cycloalkyl or 3-10 membered heterocyclic groups, wherein the C 3-10 Cycloalkyl or 3-10 membered heterocyclic groups are optionally surrounded by one or more groups independently selected from hydrogen, halogen, oxo group, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6Halogenated alkoxy groups, C(O)R 43 and S(O)2R 52 Substituents, preferably hydrogen, halogen, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups and C(O)R 43 More preferably hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl groups and C 1-6 Halogenated alkoxy groups;

[0024] Or, any two adjacent X g1 X g2 X g3 X g4 X g5 X g6 X g7 and X g8 Double bonds can be formed;

[0025] E is

[0026] X e1 X e2 X e3 and X e4 Each is independently selected from O, S, Se, N, and CR. e1 and NR e2 O, S, N, and CR are preferred. e1 and NR e2 ;

[0027] Or X e1 X e2 X e3 and X e4 The two adjacent rings in the middle form C 3-10 Cycloalkyl, 3-10-membered heterocyclic or 5-10-membered heteroaryl, wherein the C 3-10 Cycloalkyl, 3-10 heterocyclic or 5-10 heteroaryl groups are optionally separated by one or more elements independently selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl groups and C 1-6 Substituents of haloalkoxy groups;

[0028] L is selected from chemical bonds, -O-, -S-, -Se-, -S(O)-, -S(O)2-, -C(O)-, -C 1-6 alkylene-, -C 1-6 Alkylene -O-, -C1-6 Alkylene -C(O)-, -C 1-6 Alkylene-S(O)-, -C 1-6 Alkylene -S(O)2-, -C 1-6 Alkylene-NR 1 -、-NR 1 -、-N(C(O)R 2 )-、-NR 3 C(O)- and -NR 4 SO2-, preferably chemical bonds, -O-, -S-, -S(O)-, -S(O)2-, -C(O)-, -C 1-6 alkylene-, -C 1-6 Alkylene -O-, -C 1-6 Alkylene -C(O)-, -C 1-6 Alkylene-S(O)-, -C 1-6 Alkylene -S(O)2-, -C 1-6 Alkylene-NR 1 -、-NR 1 -、-N(C(O)R 2 )-、-NR 3 C(O)- and -NR 4 SO2-, more preferably chemical bonds, -O-, -S-, -S(O)-, -S(O)2-, -C(O)-, -C 1-6 alkylene-, -C 1-6 Alkylene -O-, -C 1-6 Alkylene -C(O)-, -C 1-6 Alkylene-S(O)-, -C 1-6 Alkylene-S(O)2-, -NR 1 -、-N(C(O)R 2 )-、-NR 3 C(O)- and -NR 4 SO2-; The L mentioned above has no fixed connection order with the U on the left and the G on the right;

[0029] R a1 R a2 R a3 R a4 R a5 R e1 and R e2 Each is independently selected from hydrogen, deuterium, halogens, NO2, OH, CN, C(O)R 5 C(O)OR 6 C(O)NR 7 R 8 NR 9 R 10 NR 11C(O)R 12 S(O)R 13 S(O)2R 14 S(O)2NR 15 R 16 NR 17 S(O)R 18 NR 19 S(O)2R 20 SF5, SCN, Si(R) 21 3. P(O)R 22 R 23 B(OR) 24 2. C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkyl selenyl, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 cycloalkyl, 4-7 membered heterocyclic, C 6-10 aryl and 5-10 heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkyl selenyl, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 Cycloalkyl, 4-7 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl groups are optionally selected by one or more independently chosen from hydrogen, deuterium, halogen, NO2, OH, CN, C(O)R 25 C(O)OR 26 C(O)NR 27 R 28 NR 29 R 30 NR 31 C(O)R 32 S(O)R 33 S(O)2R 34 SO2NR 35 R 36 NR 37 S(O)R 38 NR 39 S(O)2R 40 C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C1-6 Halogenated alkoxy groups and C 1-6 The substituent is replaced by a thioalkoxy group; preferably, R a1 R a2 R a3 R a4 R a5 R e1 and R e2 Each is independently selected from hydrogen, deuterium, halogens, NO2, OH, CN, C(O)R 5 C(O)OR 6 C(O)NR 7 R 8 NR 9 R 10 NR 11 C(O)R 12 S(O)R 13 S(O)2R 14 S(O)2NR 15 R 16 NR 17 S(O)R 18 NR 19 S(O)2R 20 SF5, SCN, Si(R) 21 3. P(O)R 22 R 23 B(OR) 24 2. C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 Cycloalkyl, 4-7 membered heterocyclic groups, C 6-10 aryl and 5-10 heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 Cycloalkyl, 4-7 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl groups are optionally selected by one or more independently chosen from hydrogen, deuterium, halogen, NO2, OH, CN, C(O)R 25 C(O)OR 26 C(O)NR 27 R 28 NR29 R 30 NR 31 C(O)R 32 S(O)R 33 S(O)2R 34 SO2NR 35 R 36 NR 37 S(O)R 38 NR 39 S(O)2R 40 C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups and C 1-6 Substituents of thioalkoxy groups;

[0030] R u1 R u2 R u3 R u4 R u5 R u6 R u7 R u8 R u9 R u10 R u11 R u12 R g1 R g2 R g3 R g4 R g5 R g6 R g7 R g8 and R g9 Each is independently selected from hydrogen, deuterium, halogens, NO2, OH, CN, and NR. 41 R 42 C(O)R 43 -C 1-6 Alkylene-R 43 C(O)OR 44 C(O)NR 45 R 46 C(=NR) 49 )NR 45 R 46 NR 49 C(O)R 50 S(O)R 51 S(O)2R 52 SO2NR 53 R 54 NR 55 S(O)R 56 NR57 S(O)2R 58 C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 Cycloalkyl, 4-7 membered heterocyclic groups, C 6-10 aryl and 5-10 heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Alkylene, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 Cycloalkyl, 4-7 membered heterocyclic groups, C 6-10 The aryl or 5-10 heteroaryl group is optionally surrounded by one or more independently selected groups: hydrogen, deuterium, halogen, oxo group, NO2, OH, CN, C(O)R. 43 C(O)OR 44 C(O)NR 45 R 46 NR 47 R 48 NR 49 C(O)R 50 S(O)R 51 S(O)2R 52 SO2NR 53 R 54 NR 55 S(O)R 56 NR 57 S(O)2R 58 C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Thioalkoxy, C 6-10 Substituents of aryl and 5-10 heteroaryl groups; preferably, R u1 R u2 R u3 R u4 R u5 R u6 R u7 R u8 R u9 R u10 R u11 R u12 Rg1 R g2 R g3 R g4 R g5 R g6 R g7 R g8 and R g9 Each is independently selected from hydrogen, deuterium, halogens, NO2, OH, CN, and NR. 41 R 42 C(O)R 43 C(O)OR 44 C(O)NR 45 R 46 NR 49 C(O)R 50 S(O)R 51 S(O)2R 52 SO2NR 53 R 54 NR 55 S(O)R 56 NR 57 S(O)2R 58 C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 cycloalkyl and 4-7 membered heterocyclic groups, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 The cycloalkyl or 4-7 membered heterocyclic group is optionally selected by one or more independently chosen from hydrogen, deuterium, halogen, NO2, OH, CN, C(O)R. 43 C(O)OR 44 C(O)NR 45 R 46 NR 47 R 48 NR 49 C(O)R 50 S(O)R 51 S(O)2R 52 SO2NR 53 R 54 NR 55 S(O)R 56 NR 57 S(O)2R58 C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups and C 1-6 Substituents of thioalkoxy groups;

[0031] R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11 R 12 R 13 R 14 R 15 R 16 R 17 R 18 R 19 R 20 R 21 R 22 R 23 R 24 R 25 R 26 R 27 R 28 R 29 R 30 R 31 R 32 R 33 R 34 R 35 R 36 R 37 R 38 R 39 R 40 R 41 R 42 R 43 R 44 R 45 R 46 R 47 R 48 R 49 R 50 R 51 R 52 R 53 R 54 R 55 R 56 R 57 and R58 Each is independently selected from hydrogen and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 3-7 Cycloalkyl, 4-7 membered heterocyclic groups, C 6-10 Aryl, 5-10 membered heteroaryl and NR 59 C(O)R 60 The C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 3-7 Cycloalkyl, 4-7 membered heterocyclic groups, C 6-10 The aryl or 5-10 heteroaryl group is optionally surrounded by one or more independently selected from hydrogen, deuterium, halogen, oxo group, NO2, OH, CN, C. 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups and C 1-6 Substituents of thioalkoxy groups; preferably, R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11 R 12 R 13 R 14 R 15 R 16 R 17 R 18 R 19 R 20 R 21 R 22 R 23 R 24 R 25 R 26 R 27 R 28 R 29 R 30 R 31 R 32 R 33 R34 R 35 R 36 R 37 R 38 R 39 R 40 R 41 R 42 R 43 R 44 R 45 R 46 R 47 R 48 R 49 R 50 R 51 R 52 R 53 R 54 R 55 R 56 R 57 and R 58 Each is independently selected from hydrogen and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 3-7 Cycloalkyl, 4-7 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl, the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 3-7 Cycloalkyl, 4-7 membered heterocyclic groups, C 6-10 The aryl or 5-10 heteroaryl group is optionally selected by one or more independently chosen from hydrogen, deuterium, halogen, NO2, OH, CN, C. 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups and C 1-6 Substituents of thioalkoxy groups; more preferably, R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11 R 12 R13 R 14 R 15 R 16 R 17 R 18 R 19 R 20 R 21 R 22 R 23 R 24 R 25 R 26 R 27 R 28 R 29 R 30 R 31 R 32 R 33 R 34 R 35 R 36 R 37 R 38 R 39 R 40 R 41 R 42 R 43 R 44 R 45 R 46 R 47 R 48 R 49 R 50 R 51 R 52 R 53 R 54 R 55 R 56 R 57 and R 58 Each is independently selected from hydrogen and C. 1-6 Alkyl and C 1-6 Halogenated alkyl; or two R 24 The atoms bonded to it together form a 4-7 membered heterocyclic group, which is optionally composed of one or more elements independently selected from hydrogen, halogen, and C. 1-6 Alkyl substituents;

[0032] R 59 and R 60 Each is independently selected from hydrogen and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 3-7 Cycloalkyl, 4-7 membered heterocyclic groups, C6-10 Aryl and 5-10 heteroaryl, the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 3-7 Cycloalkyl, 4-7 membered heterocyclic groups, C 6-10 The aryl or 5-10 heteroaryl group is optionally selected by one or more independently chosen from hydrogen, deuterium, halogen, NO2, OH, CN, C. 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups and C 1-6 Substituents of thioalkoxy groups;

[0033] Where X a1 X a2 X a3 and X a4 None of them are N, and U is selected from: At that time, R a1 R a2 R a3 R a4 R a5 Each is independently selected from SF5, SCN, and Si(R) 21 3. P(O)R 22 R 23 and B(OR) 24 )2; and / or R u1 R u2 and R u3 Each is independently selected from NO2, CN, and NR. 41 R 42 C(O)R 43 C(O)OR 44 C(O)NR 45 R 46 NR 49 C(O)R 50 S(O)R 51 S(O)2R 52 SO2NR 53 R 54 NR 55 S(O)R 56 NR 57 S(O)2R 58 C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6alkynyl group, C 3-7 cycloalkyl and 4-7 membered heterocyclic groups, wherein the C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 The cycloalkyl or 4-7 membered heterocyclic group is optionally selected by one or more independently chosen from hydrogen, deuterium, halogen, NO2, OH, CN, C(O)R. 43 C(O)OR 44 C(O)NR 45 R 46 NR 47 R 48 NR 49 C(O)R 50 S(O)R 51 S(O)2R 52 SO2NR 53 R 54 NR 55 S(O)R 56 NR 57 S(O)2R 58 C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups and C 1-6 Substituents of thioalkoxy groups, or R u2 and R u3 Forming 3-10 membered heterocyclic groups with the commonly linked carbon atoms; and / or R e1 and R e2 Each is independently selected from deuterium, halogens, NO2, OH, CN, C(O)R 5 C(O)NR 7 R 8 NR 9 R 10 NR 11 C(O)R 12 S(O)R 13 S(O)2R 14 S(O)2NR 15 R 16 NR 17 S(O)R 18 NR 19 S(O)2R 20 SF5, SCN, Si(R) 21 3. P(O)R 22 R 23 B(OR) 24 2. C 1-6Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-10 aryl and 5-10 heteroaryl, wherein the C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-10 Aryl or 5-10 heteroaryl groups are optionally selected by one or more independently chosen from hydrogen, deuterium, halogen, NO2, OH, CN, C(O)R 25 C(O)OR 26 C(O)NR 27 R 28 NR 29 R 30 NR 31 C(O)R 32 S(O)R 33 S(O)2R 34 SO2NR 35 R 36 NR 37 S(O)R 38 NR 39 S(O)2R 40 C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups and C 1-6 The substituent is thioalkoxy; and / or L is selected from -O-, -S-, -S(O)-, -S(O)2-, -C 1-6 Alkylene-O-, -N(C(O)R 2 )- and -NR 4 SO2-; and / or U selected from and / or X g1 X g2 X g3 X g4 X g5 X g6 X g7 and X g8 Any two rings in the group can be combined to form a 3-10 membered heterocyclic group or a 5-6 membered heteroaryl group, wherein the 3-10 membered heterocyclic group or the 5-6 membered heteroaryl group is optionally surrounded by one or more elements independently selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl groups and C 1-6Substituents of haloalkoxy groups; and / or R g3 and R g4 C forms with the carbon atoms that are bonded together. 3-10 cycloalkyl, the C 3-10 The cycloalkyl group is optionally surrounded by one or more elements independently selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl groups and C 1-6 Substituents of haloalkoxy groups; and / or any two adjacent X groups. g1 X g2 X g3 X g4 X g5 X g6 X g7 and X g8 It can form at most one double bond; and / or X g2 X g3 X g4 X g5 X g6 X g7 and X g8 At least one of them is selected from S(O)(=NR) g2 ), NR g5 Si(R) g6 )2 and P(O)R g7 And R g5 Selected from C(O)R 43 and C 3-7 cycloalkyl; and / or G selected from

[0034] On the other hand, this disclosure provides a pharmaceutical composition comprising a preventive and / or therapeutically effective amount of the compound of this disclosure or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope label, metabolite or prodrug, and one or more pharmaceutically acceptable carriers.

[0035] On the other hand, this disclosure provides a kit containing a compound of the disclosure or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope label, metabolite or prodrug, or a pharmaceutical composition comprising the disclosure.

[0036] On the other hand, this disclosure provides the use of the compounds of this disclosure or their pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotope labels, metabolites or prodrugs, or pharmaceutical compositions of this disclosure, or the kits of this disclosure in the preparation of a medicament, preferably the medicament for antagonizing κ receptors, or for the prevention and / or treatment of κ receptor-mediated diseases.

[0037] On the other hand, this disclosure provides the use of the compounds of this disclosure or their pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotope labels, metabolites, or prodrugs, or pharmaceutical compositions of this disclosure, in the preparation of κ-receptor antagonists.

[0038] On the other hand, this disclosure provides a method for preparing the compounds disclosed herein.

[0039] On the other hand, this disclosure provides intermediates for preparing the compounds of this disclosure. Detailed Implementation

[0040] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains. In case of any conflict, the definitions provided in this disclosure shall prevail. When trade names appear herein, they are intended to refer to the corresponding product or its active ingredient. All patents, published patent publications, and publications cited herein are incorporated herein by reference.

[0041] definition

[0042] The term "alkyl" refers to a saturated, straight-chain or branched aliphatic hydrocarbon group having 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) carbon atoms, i.e., "C". 1-20 Alkyl group. The alkyl group is preferably an alkyl group having 1 to 12 carbon atoms (i.e., C12). 1-12 Alkyl groups, more preferably alkyl groups having 1 to 8 carbon atoms (i.e., C14-C ... 1-8 Alkyl groups, more preferably alkyl groups having 1 to 6 carbon atoms (i.e., C14-C6 ... 1-6 Alkyl groups, most preferably alkyl groups having 1 to 3 carbon atoms (i.e., C14-C ... 1-3Alkyl groups). Non-limiting examples of the aforementioned alkyl groups include: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl 2,3-Dimethylpentyl, 2,4-Dimethylpentyl, 2,2-Dimethylpentyl, 3,3-Dimethylpentyl, 2-Ethylpentyl, 3-Ethylpentyl, n-Octyl, 2,3-Dimethylhexyl, 2,4-Dimethylhexyl, 2,5-Dimethylhexyl, 2,2-Dimethylhexyl, 3,3-Dimethylhexyl, 4,4-Dimethylhexyl, 2-Ethylhexyl, 3-Ethylhexyl, 4-Ethylhexyl, 2-Methyl-2-Ethylpentyl, 2-Methyl-3-Ethylpentyl, n-Nonyl, 2-Methyl-2-Ethylhexyl, 2-Methyl-3-Ethylhexyl, 2,2-Diethylpentyl, n-Decyl, 3,3-Diethylhexyl, 2,2-Diethylhexyl, and their various branched isomers, etc.

[0043] The term "alkylene" refers to a divalent alkyl group, wherein the alkyl group, as defined above, has 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) carbon atoms (i.e., C2). 1-20 Alkylene). "C 0-12 "Alkylene" refers to an alkylene group having 0-12 carbon atoms (e.g., 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 carbon atoms), such as C 1-12 Alkylene, C 0-6 Alkylene, C 1-6 Alkylene, C 0-3 Alkylene, C 1-2 Alkylenes, etc. Among them, C0 alkylenes with 0 carbon atoms refer to chemical bonds. 0-12 Non-limiting examples of alkylene groups include: bond, -CH2-, -CH(CH3)-, -C(CH3)2-, -CH2CH2-, -CH(CH2CH3)-, -CH2CH(CH3)-, -CH2C(CH3)2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, -(CH2)8-, -(CH2) 11 -wait.

[0044] The term "alkenyl" refers to an alkyl group in which the molecule contains at least one carbon-carbon double bond, wherein the alkyl group, as defined above, has 2 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12) carbon atoms (i.e., C atoms). 2-12 Alkenyl). The alkenyl group is preferably an alkenyl group having 2 to 6 carbon atoms (i.e., C). 2-6 Alkenyl). Non-limiting examples of the aforementioned alkenyl groups include: vinyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl, etc.

[0045] The term "alkenyl" refers to a divalent alkenyl group, where the alkenyl group is as defined above.

[0046] The term "alkynyl" refers to an alkyl group in a molecule that contains at least one carbon-carbon triple bond, wherein the alkyl group, as defined above, has 2 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12) carbon atoms (i.e., C atoms). 2-12 The alkynyl group is preferably an alkynyl group having 2 to 6 carbon atoms (i.e., C64). 2-6 Alkyne group). Non-limiting examples of the aforementioned alkynyl groups include: ethynyl, propynyl, butynyl, penynyl, hexynyl, etc.

[0047] The term "ethynyl" refers to a divalent ethynyl group, where the ethynyl group is as defined above.

[0048] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic cyclic hydrocarbon substituent (i.e., monocyclic cycloalkyl) or polycyclic cyclic hydrocarbon substituent (i.e., polycyclic cycloalkyl) having 3 to 20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) carbon atoms, i.e., C64. 3-20 Cycloalkyl group. The cycloalkyl group is preferably a cycloalkyl group having 3 to 10 carbon atoms (i.e., C10). 3-10 cycloalkyl groups, more preferably cycloalkyl groups having 3 to 7 carbon atoms (i.e., C14-C ... 3-7 Cycloalkyl groups, more preferably cycloalkyl groups having 3 to 6 carbon atoms (i.e., C164-C ... 3-6 (Cycloalkyl). Non-limiting examples of said cycloalkyl groups include: cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl (e.g.) ), cyclohexadienyl, cycloheptyl, cycloheptanetrienyl, cyclooctyl Examples of polycyclic alkyl groups include spirocyclic alkyl groups, fused cyclic alkyl groups, and bridged cyclic alkyl groups.

[0049] The term "heterocyclic group" refers to a saturated or partially unsaturated monocyclic heterocyclic hydrocarbon substituent (i.e., monocyclic heterocyclic group) or polycyclic heterocyclic hydrocarbon substituent (i.e., polycyclic heterocyclic group) having 3 to 20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 3-20 membered heterocyclic group), wherein one or more (e.g., 1, 2, 3, or 4) ring atoms are selected from nitrogen, oxygen, silicon, and P(O). m S(O) n Se(O) n The heterocyclic group contains heteroatoms of S (=O)(=NH) (where m and n are integers from 0 to 2), but does not include the ring portion of -OO-, -OS-, or -SS-, and the remaining ring atoms are carbon. The heterocyclic group preferably has 3 to 10 ring atoms (i.e., 3-10 membered heterocyclic group) or 4 to 7 ring atoms (i.e., 4-7 membered heterocyclic group), wherein it contains 1 to 4 heteroatoms selected from N, O, S, Se, Si, P (=O), S (=O)(=NH) atoms. Non-limiting examples of the heterocyclic groups include: azirrobutyl, oxacyclobutyl, thiohexacyclobutyl, pyrrolyl, imidazoalkyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, dihydropyranyl, dihydroimidazoyl, dihydrofuranyl, dihydropyrazolyl, dihydropyridyl, piperidinyl, piperazinyl, morpholinyl, 1,3-dioxacyclopentyl, 1,3-dioxacyclopentenyl, 2,2-difluoro-1,3-dioxacyclopentyl, cyclopentanone, 2,2-difluorocyclopentanone, piperidinone, azirroheptanyl, oxacyclopentyl, azirropentyl, benzodihydropyranyl, oxazolyl (e.g., 1,3-oxazolyl) Examples of non-limiting examples of polycyclic heterocyclic groups include spirocyclic, fused heterocyclic, and bridged heterocyclic groups. Heterocyclic groups include nitrogen-containing heterocyclic groups, oxygen-containing heterocyclic groups, sulfur-containing heterocyclic groups, etc. In addition to containing nitrogen, oxygen, and sulfur, the nitrogen / oxygen / sulfur-containing heterocyclic group may optionally contain 1-3 heteroatoms selected from N, O, Se, and S atoms. Non-limiting examples of nitrogen-containing monocyclic heterocyclic groups (e.g., 4-11 member nitrogen-containing monocyclic heterocyclic groups) include: aziridine, pyrrolidinyl, imidazoalkyl, dihydroimidazolyl, dihydropyrazolyl, dihydropyridyl, piperidinyl, piperazinyl, aziridine-heptyl, 1,4-diazaheptanyl, etc.

[0050] The term "spiroheterocyclic group" refers to a polycyclic heterocyclic group that shares a single atom (called a spiro atom) between monocyclic rings. It has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 5-20 membered spiroheterocyclic groups), where one or more (e.g., 1, 2, 3, or 4) ring atoms are selected from nitrogen, oxygen, silicon, and P(O). mS(O) n Se(O) n The spiroheterocyclic group contains heteroatoms of S (=O)(=NH) (where m and n are integers from 0 to 2), but does not include the ring portion of -OO-, -OS-, or -SS-, and the remaining ring atoms are carbon. It may contain one or more double bonds. The spiroheterocyclic group is preferably a spiroheterocyclic group having 5 to 11 ring atoms (i.e., a 5-11 member spiroheterocyclic group). The spirocyclic groups are classified into monospirocyclic, bispirocyclic, or multispirocyclic groups based on the number of shared spiro atoms between the rings. Monospirocyclic or bispirocyclic groups are preferred, and more preferably, 3-membered / 4-membered, 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 3-membered, 5-membered / 4-membered, 5-membered / 5-membered, 5-membered / 6-membered, 5-membered / 7-membered, 6-membered / 3-membered, 6-membered / 4-membered, 6-membered / 5-membered, 6-membered / 6-membered, 6-membered / 7-membered, 7-membered / 5-membered, or 7-membered / 6-membered monospirocyclic groups. Non-limiting examples of nitrogen-containing spirocyclic groups (e.g., 5-11 member nitrogen-containing spirocyclic groups) include... Where n1, n2, n3, and n4 are each independently selected from 0, 1, and 2, for example... Other non-limiting examples of spiroheterocyclic groups include

[0051] The term "fused heterocyclic group" refers to a polycyclic heterocyclic group in which each ring in a system shares an adjacent pair of atoms with other rings in the system. It has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., a 5-20 membered fused heterocyclic group), wherein one or more (e.g., 1, 2, 3, or 4) ring atoms are selected from nitrogen, oxygen, silicon, and P(O). m S(O) n Se(O) n The fused heterocyclic group contains heteroatoms of S (=O)(=NH) (where m and n are integers from 0 to 2), but does not include the ring portion of -OO-, -OS-, or -SS-, and the remaining ring atoms are carbon. It may contain one or more double bonds. The fused heterocyclic group is preferably a fused heterocyclic group having 5 to 11 ring atoms (i.e., a 5-11 member fused heterocyclic group). Based on the number of constituent rings, they are classified into bicyclic, tricyclic, tetracyclic, or polycyclic fused heterocyclic groups, with bicyclic or tricyclic fused heterocyclic groups being preferred. More preferably, they are 3-membered / 4-membered, 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 3-membered, 5-membered / 4-membered, 5-membered / 5-membered, 5-membered / 6-membered, 5-membered / 7-membered, 6-membered / 3-membered, 6-membered / 4-membered, 6-membered / 5-membered, 6-membered / 6-membered, 6-membered / 7-membered, 7-membered / 5-membered, or 7-membered / 6-membered bicyclic fused heterocyclic groups, or 6-membered / 5-membered / 6-membered tricyclic fused heterocyclic groups. Non-limiting examples of nitrogen-containing fused heterocyclic groups (e.g., 5-11-membered nitrogen-containing fused heterocyclic groups) include: Where n5 and n6 are each independently 1 or 2. Other non-limiting examples of fused heterocyclic groups include

[0052] The term "bridged heterocyclic group" refers to a polycyclic heterocyclic group in which any two rings share two non-directly connected atoms, having 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 5-20 membered bridged heterocyclic groups), wherein one or more (e.g., 1, 2, 3, or 4) ring atoms are selected from nitrogen, oxygen, silicon, and P(O). m S(O) n Se(O) n The bridged heterocyclic group consists of heteroatoms of S (=O)(=NH) (where m and n are integers from 0 to 2), but excludes the ring portion of -OO-, -OS-, or -SS-, with the remaining ring atoms being carbon. It may contain one or more double bonds. The bridged heterocyclic group is preferably a bridged heterocyclic group having 5 to 11 ring atoms (i.e., a 5-11 member bridged heterocyclic group). It is classified as bicyclic, tricyclic, tetracyclic, or polycyclic bridged heterocyclic groups according to the number of constituent rings, with bicyclic or tricyclic bridged heterocyclic groups being preferred. Non-limiting examples of nitrogen-containing bridged heterocyclic groups (e.g., 5-11 member nitrogen-containing bridged heterocyclic groups) include: Other non-limiting examples of bridged heterocyclic groups include

[0053] The term "aryl" refers to an all-carbon monocyclic group (i.e., monocyclic aryl) or a fused polycyclic group (i.e., polycyclic aryl) having a conjugated π-electron system, having 6 to 14 (e.g., 6, 7, 8, 9, 10, 11, 12, 13, or 14) carbon atoms (i.e., C atoms). 6-14 Aryl group). The aryl group is preferably an aryl group having 6 to 10 carbon atoms (i.e., C64). 6-10 Aryl), further preferably phenyl or naphthyl, most preferably phenyl. The monocyclic aryl group is, for example, phenyl. Non-limiting examples of the polycyclic aryl group include: naphthyl, anthracene, phenanthryl, etc.

[0054] The term "heteroaryl" refers to a monocyclic heteroaryl group (i.e., monocyclic heteroaryl) or a fused polycyclic heteroaryl group (i.e., polycyclic heteroaryl) having a conjugated π-electron system, having 5 to 14 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14) ring atoms (i.e., 5-14 membered heteroaryl), wherein one or more (e.g., 1, 2, 3, or 4) ring atoms are selected from nitrogen, oxygen, and P(O). m Se(O) n and S(O) nThe heteroatom (where m and n are integers from 0 to 2) is preferably selected from nitrogen, oxygen, sulfur, or selenium, but does not include the ring portion of -OO-, -OS-, or -SS-, and the remaining ring atoms are carbon. The heteroaryl group is preferably a heteroaryl group having 5 to 10 ring atoms (i.e., a 5-10 membered heteroaryl group). The monocyclic heteroaryl group is preferably a heteroaryl group having 5 to 6 ring atoms (i.e., a 5-6 membered heteroaryl group), and non-limiting examples include: furanyl, pyranyl, thiophene, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, imidazole, pyrazolyl, triazolyl, tetrazolyl, pyrroleyl, pyridinyl, pyrimidinyl, pyridoneyl, pyrazinyl, pyridazinyl, etc. The polycyclic heteroaryl group is preferably a 5-6 member heteroaryl-5-6 member heteroaryl or a 5-10 member heteroaryl-C 6-10 Aryl or C 6-10 The aryl group comprises 5-10 heteroaryl groups, with 5-6 heteroaryl groups, 5-6 heteroaryl groups, or phenyl groups comprising 5-6 heteroaryl groups. Non-limiting examples include: indolyl, inzolyl, quinolinyl, isoquinolinyl, quinoxalinyl, phthalazinyl, benzimidazolyl, benzothiophenyl, thiophene, quinazolinyl, benzothiazolyl, carbazole, thiophenepyridyl, pyridinothiophenyl, pyridinopyrroleyl, benzoxazolyl, benzopyrazolyl, etc.

[0055] The term "alkoxy" refers to -O- (alkyl) or -O- (unsubstituted cycloalkyl), wherein alkyl and cycloalkyl are defined as above, having 1 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12) carbon atoms (i.e., C). 1-12 Alkoxy group). The alkoxy group is preferably an alkoxy group having 1 to 8 carbon atoms (i.e., C14). 1-8 Alkoxy groups, more preferably alkoxy groups having 1 to 6 carbon atoms (i.e., C14-C6 ... 1-6 Alkoxy groups, preferably alkoxy groups having 1 to 3 carbon atoms (i.e., C14-C ... 1-3 Alkoxy groups). Non-limiting examples of the aforementioned alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexyloxy, etc.

[0056] The term "alkylamino" refers to -N-(alkyl) or -N-(unsubstituted cycloalkyl), wherein alkyl and cycloalkyl are defined as described above, having 1 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12) carbon atoms (i.e., C12). 1-12 Alkylamino group). The alkylamino group is preferably an alkylamino group having 1 to 8 carbon atoms (i.e., C12). 1-8 Alkylamino groups, more preferably alkylamino groups having 1 to 6 carbon atoms (i.e., C42-C ... 1-6Alkylamino groups, preferably alkylamino groups having 1 to 3 carbon atoms (i.e., C42-C ... 1-3 Alkylamino groups). Non-limiting examples of the aforementioned alkylamino groups include: methylamino, ethylamino, propylamino, butylamino, cyclopropylamino, cyclobutylamino, cyclopentamino, cyclohexylamino, etc.

[0057] The term "alkathioyl" refers to -S- (alkyl) or -S- (unsubstituted cycloalkyl), wherein alkyl and cycloalkyl are defined as above, having 1 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12) carbon atoms (i.e., C2). 1-12 Alkylthio group). The alkylthio group is preferably an alkylthio group having 1 to 8 carbon atoms (i.e., C12). 1-8 Alkylthioyl), more preferably alkylthioyl groups having 1 to 6 carbon atoms (i.e., C14-C ... 1-6 Alkylthio group), preferably alkylthio group with 1 to 3 carbon atoms (i.e., C12-C ... 1-3 Alkylthio groups). Non-limiting examples of the aforementioned alkylthio groups include: methylthio, ethylthio, propylthio, butylthio, cyclopropylthio, cyclobutylthio, cyclopentylthio, cyclohexylthio, etc.

[0058] The term "alkylselenyl" refers to -Se- (alkyl) or -Se- (unsubstituted cycloalkyl), wherein the alkyl and cycloalkyl groups are defined as described above and have 1 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12) carbon atoms (i.e., C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C12, C13, C13, C14 ...4, C13, C14, C14, C14, C14, C14, C14, C14, C14, C14, C14, C 1-12 Alkylselenyl group). The alkylselenyl group is preferably an alkylselenyl group having 1 to 8 carbon atoms (i.e., C16). 1-8 Alkyl selenyl), more preferably alkyl selenyl having 1 to 6 carbon atoms (i.e., C16). 1-6 Alkyl selenyl), preferably alkyl selenyl with 1 to 3 carbon atoms (i.e., C12-C ... 1-3 Alkylselenyl). Non-limiting examples of the aforementioned alkylselenyl groups include: methylselenyl, ethenylselenyl, propenylselenyl, butenylselenyl, cyclopropenylselenyl, cyclobutenylselenyl, cyclopentenylselenyl, cyclohexylselenyl, etc.

[0059] The terms “halogen” or “halogenated” should be understood to refer to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I) atoms, preferably fluorine, chlorine or bromine atoms.

[0060] The term "halogenated alkyl" refers to an alkyl group substituted with one or more halogens, wherein the alkyl group is as defined above. Non-limiting examples include: fluoromethyl, chloromethyl, bromomethyl, iodomethyl, difluoromethyl, chlorofluoromethyl, dichloromethyl, bromofluoromethyl, trifluoromethyl, chlorodifluoromethyl, dichlorofluoromethyl, trichloromethyl, bromodifluoromethyl, bromochlorofluoromethyl, dibromofluoromethyl, 2-fluoroethyl, 2-chloroethyl, 2-bromoethyl, 2,2-difluoroethyl, 2-chloro-2-fluoroethyl, 2,2-dichloroethyl, 2-bromo-2-fluoroethyl, 2,2,2-trifluoroethyl, 2-chloro-2,2-difluoroethyl, 2,2-dichloro-2-fluoroethyl, 2,2-dichloro-2-fluoroethyl, 2, 2,2-Trichloroethyl, 2-bromo-2,2-difluoroethyl, 2-bromo-2-chloro-2-fluoroethyl, 2-bromo-2,2-dichloroethyl, 1,1,2,2-tetrafluoroethyl, pentafluoroethyl, 1-chloro-1,2,2,2-tetrafluoroethyl, 2-chloro-1,1,2,2-tetrafluoroethyl, 1,2-dichloro-1,2,2-trifluoroethyl, 2-bromo-1,1,2,2-tetrafluoroethyl, etc., preferably fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2-chloroethyl, 2-bromoethyl, 2,2-difluoroethyl.

[0061] The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein the alkoxy group is as defined above. Non-limiting examples include: fluoromethoxy, chloromethoxy, bromomethoxy, iodomethoxy, difluoromethoxy, chlorofluoromethoxy, dichloromethoxy, bromofluoromethoxy, trifluoromethoxy, chlorodifluoromethoxy, dichlorofluoromethoxy, trichloromethoxy, bromodifluoromethoxy, bromochlorofluoromethoxy, dibromofluoromethoxy, etc.; preferably fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2-fluoroethoxy, 2-chloroethoxy, 2-bromoethoxy, 2,2-difluoroethoxy, 2-chloro-2-fluoroethoxy, 2,2-dichloroethoxy, 2-bromo-2-fluoroethoxy, 2,2,2-trifluoroethoxy, 2-chloro-2,2-difluoroethoxy, 2 2-Dichloro-2-fluoroethoxy, 2,2,2-trichloroethoxy, 2-bromo-2,2-difluoroethoxy, 2-bromo-2-chloro-2-fluoroethoxy, 2-bromo-2,2-dichloroethoxy, 1,1,2,2-tetrafluoroethoxy, pentafluoroethoxy, 1-chloro-1,2,2,2-tetrafluoroethoxy, 2-chloro-1,1,2,2-tetrafluoroethoxy, 1,2-dichloro-1,2,2-trifluoroethoxy, 2-bromo-1,1,2,2-tetrafluoroethoxy, preferably fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2-fluoroethoxy, 2-chloroethoxy, 2-bromoethoxy, 2,2-difluoroethoxy.

[0062] The term "thiol" refers to -SH.

[0063] The term "hydroxyl group" refers to -OH.

[0064] The term "nitro" refers to -NO2.

[0065] The term "amino" refers to -NH2.

[0066] The term "cyano" refers to -CN.

[0067] The term "carboxyl group" refers to -C(O)OH.

[0068] The term "oxo" or "oxo group" refers to =O.

[0069] The term "carbonyl" refers to C=O.

[0070] The term "hydroxyalkyl" refers to an alkyl group that is substituted with one or more hydroxyl groups, wherein the alkyl group is as defined above.

[0071] The terms “comprising,” “including,” “having,” “containing,” or “involving,” and their other variations herein, are inclusive or open-ended and do not exclude other elements or method steps not listed. Those skilled in the art will understand that the foregoing term “comprising” encompasses the meaning of “consisting of.”

[0072] The term "one or more species" or similar expression "at least one species" can mean, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more species.

[0073] When the lower and upper limits of a numerical range are disclosed, any numerical value falling within that range and any included range are specifically disclosed. In particular, each range of values ​​disclosed herein should be understood as representing each numerical value and range encompassed within a wider range.

[0074] In this article, "Z" and "-Z-" both refer to the same specific group and can be used interchangeably.

[0075] The expression "mn" used in this paper refers to the range from m to n, the subrange consisting of the individual point values ​​within it, and the individual point values ​​themselves. For example, the expression "C2-C6" or "C 2-6 "Covering a range of 2-6 carbon atoms, and should be understood to also include any subranges within this range and each point value, such as C2-C3, C2-C4, C2-C5, C3-C4, C2-C6, C3-C6, C4-C6, etc., and C2, C3, C4, C5, C6, etc. For example, the expression "C5-C..." 10 "or "C 5-10 "It should also be understood in a similar way, for example, it can cover any subrange and point value contained therein, such as C3-C9, C6-C9, C6-C8, C6-C7, C7-C..." 10 C7-C9, C7-C8, C8-C9, etc., as well as C3, C4, C5, C6, C7, C8, C9, C 10For example, stating "C1-C6" or "C..." 1-6 "The range encompasses 1-6 carbon atoms, and should be understood to also include any subranges within this range and each point value, such as C2-C5, C3-C4, C1-C2, C1-C3, C1-C4, C1-C5, C1-C6, and C1, C2, C3, C4, C5, C6, etc. Similarly, the expression "4-14 elements" should be understood to include any subrange within this range and each point value, such as 4-8 elements, 6-14 elements, 5-6 elements, and 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, etc. Other similar expressions in this document should also be understood in a similar manner."

[0076] The different expressions used in this article, such as "X is selected from A, B or C", "X is selected from A, B and C", "X is A, B or C", and "X is A, B and C", all express the same meaning, that is, X can be any one or more of A, B, and C.

[0077] The terms “optional” or “optionally” mean that an event or condition described below may or may not occur, including both the occurrence and non-occurrence of the event or condition. For example, “optionally (al) alkyl-substituted cycloalkyl” means that an alkyl group may but is not required to be present, and this description includes cases where the cycloalkyl group is substituted with an alkyl group and cases where the cycloalkyl group is not substituted with an alkyl group.

[0078] The terms "substitution" and "substituted" refer to the selective replacement of one or more (e.g., one, two, three, or four) hydrogen atoms on a specified atom by a chosen substituent from the indicated group, provided that the substitution does not exceed the normal valence of the specified atom in the present case and that the substitution forms a stable compound. Combinations of substituents and / or variables are permitted only if such combinations form a stable compound. When describing the absence of a substituent, it should be understood that the substituent can be one or more hydrogen atoms, provided that the structure allows the compound to reach a stable state. When describing the optional substitution of each carbon atom in a group with a heteroatom, the condition is that the substitution does not exceed the normal valence of all atoms in the group in the present case and that a stable compound is formed.

[0079] If a substituent is described as "optionally...substituted," the substituent may be unsubstituted or substituted. If an atom or group is described as being optionally substituted by one or more of the substituents in the list, one or more hydrogen atoms on that atom or group may be replaced by independently selected, optional substituents. When the substituent is oxo (i.e., =O), it means that two hydrogen atoms are substituted. When the substituent is hydrogen, this may also indicate that the corresponding group is "unsubstituted" or "unsubstituted." Unless otherwise specified, as used herein, the connection point of a substituent may be derived from any suitable position of the substituent.

[0080] When the bond of a substituent is such that it passes through the ring and connects two atoms, then such a substituent can be bonded to any cyclic atom in the substituted ring.

[0081] Regardless of whether the groups exemplified in the definition section of this disclosure are shown by wavy lines at their connection positions, those skilled in the art should understand that such groups can be connected to other parts of the compound at any one or more locations (not limited to those shown by wavy lines).

[0082] When any variable (e.g., R), and labeled variables (e.g., R1, R2, R3, R4, R5, R6, R7, etc.) appear more than once in the composition or structure of a compound, their definition is independent for each occurrence in each case. For example, if a group is substituted by 0, 1, 2, 3, or 4 R substituents, the group may optionally be substituted by up to four R substituents, and the options for each R substituent in each case are independent of each other.

[0083] This disclosure also includes all pharmaceutically acceptable isotopically labeled compounds identical to those of this disclosure, except that one or more atoms are replaced by atoms having the same atomic number but with an atomic mass or mass number different from the dominant atomic mass or mass number in nature. Examples of isotopes suitable for inclusion in the compounds of this disclosure include, but are not limited to, isotopes of hydrogen (e.g., 2 H, 3 H, deuterium (D), tritium (T); carbon isotopes (e.g., H, deuterium (D), tritium (T)); 11 C 13 C and 14 C); isotopes of chlorine (e.g.) 37 Cl); isotopes of fluorine (e.g., Cl); 18 F); isotopes of iodine (e.g., F); 123 I and 125 I); nitrogen isotopes (e.g.) 13 N and 15 N); isotopes of oxygen (e.g., N); 15 O、 17 O and 18 O); isotopes of phosphorus (e.g., O); phosphorus isotopes (e.g., O); 32 P); and isotopes of sulfur (e.g. 35 S). Certain isotope-labeled compounds of this disclosure (e.g., those doped with radioisotopes) can be used in drug and / or substrate tissue distribution studies (e.g., analysis). Radioisotope tritium (i.e. 3 H) and carbon-14 (i.e. 14 C) It is particularly suitable for this purpose due to its ease of incorporation and detection. Using positron-emitting isotopes (e.g.) 11 C 18 F,15 O and 13 Substitution of N) can be used in positron emission tomography (PET) studies to examine substrate acceptor occupancy. Isotopically labeled compounds of this disclosure can be prepared by methods similar to those described in the accompanying routes and / or examples and preparations, by replacing previously used unlabeled reagents with appropriate isotopically labeled reagents. Pharmaceutically acceptable solvates of this disclosure include those in which the crystallization solvent can be isotopically substituted, for example, D2O, acetone-d6, or DMSO-d6.

[0084] The term "stereoisomer" refers to an isomer formed due to at least one asymmetric center. In compounds having one or more (e.g., 1, 2, 3, or 4) asymmetric centers, racemic mixtures, single enantiomers, diastereomer mixtures, and individual diastereomers can be produced. Specific individual molecules may also exist as geometric isomers (cis / trans). Similarly, the compounds of this disclosure can exist as mixtures of two or more structurally different forms in rapid equilibrium (commonly referred to as tautomers). Representative examples of tautomers include keto-enol tautomers, phenol-keto tautomers, nitroso-oxime tautomers, imine-enamine tautomers, etc. It is to be understood that the scope of this disclosure covers all such isomers or mixtures thereof in any proportion (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%).

[0085] This disclosure covers all possible crystalline forms or polymorphs of the compounds disclosed herein, which may be a single polymorph or a mixture of more than one polymorph in any proportion.

[0086] It should also be understood that certain compounds of this disclosure may exist in their free form for therapeutic purposes, or, where appropriate, in their pharmaceutically acceptable derivative forms. In this disclosure, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, solvates, metabolites, or prodrugs that, upon administration to a patient in need, can directly or indirectly provide the compounds of this disclosure or their metabolites or residues. Therefore, when referring herein to “compounds of this disclosure,” it is also intended to encompass the various derivative forms of the compounds described above.

[0087] Pharmaceutically acceptable salts of the compounds disclosed herein include their acid addition salts and base addition salts. Suitable acid addition salts are formed by acids that form pharmaceutically acceptable salts. Suitable base addition salts are formed by bases that form pharmaceutically acceptable salts. A review of suitable salts can be found in Stahl and Wermuth's "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" (Wiley-VCH, 2002). Methods for preparing pharmaceutically acceptable salts of the compounds disclosed herein are known to those skilled in the art.

[0088] The compounds disclosed herein may exist as solvates (preferably hydrates), wherein the compounds contain a polar solvent, particularly, for example, water, methanol, or ethanol, as a structural element of the compound's crystal lattice. The amount of the polar solvent, particularly water, may be stoichiometric or non-stoichiometric.

[0089] Those skilled in the art will understand that not all nitrogen-containing heterocycles can form N-oxides because nitrogen requires available lone pairs of electrons to be oxidized into oxides; those skilled in the art will identify nitrogen-containing heterocycles that can form N-oxides. Those skilled in the art will also recognize that tertiary amines can form N-oxides. Synthetic methods for preparing N-oxides of heterocycles and tertiary amines are well known to those skilled in the art, including the oxidation of heterocycles and tertiary amines with peroxy acids such as peracetic acid and m-chloroperoxybenzoic acid (MCPBA), hydrogen peroxide, alkyl peroxides such as tert-butyl peroxide, sodium perborate, and dioxiranes such as dimethyldioxirane. These methods for preparing N-oxides have been extensively described and reviewed in the literature, see, for example: T.L. Gilchrist, Comprehensive Organic Synthesis, vol. 7, pp. 748-750; A.R. Katritzky and A.J. Boulton, Eds., Academic Press; and G.W. H. Heeseman and E.S. G. Wierstiuk, Advances in Heterocyclic Chemistry, vol. 22, pp. 390-392, A.R. Katritzky and A.J. Boulton, Eds., Academic Press.

[0090] The scope of this disclosure also includes metabolites of the compounds of this disclosure, i.e., substances formed in the body upon administration of the compounds of this disclosure. Such products can be generated, for example, by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, enzymatic hydrolysis, etc., of the administered compound. Therefore, this disclosure includes metabolites of the compounds of this disclosure, including compounds prepared by methods that expose the compounds of this disclosure to mammals for a time sufficient to produce their metabolites.

[0091] This disclosure further includes, within its scope, prodrugs of the compounds of this disclosure, which are certain derivatives of the compounds of this disclosure that may themselves have little or no pharmacological activity, and which, when administered to or onto the body, can be converted, for example, by hydrolysis and cleavage into the compounds of this disclosure having the desired activity. Typically, such prodrugs are functional group derivatives of the compounds that are readily converted in vivo into the compounds with the desired therapeutic activity. Further information regarding the use of prodrugs can be found in “Pro-drugs as Novel Delivery Systems,” Vol. 14, ACS Symposium Series (T. Higuchi and V. Stella) and “Bioreversible Carriers in Drug Design,” Pergamon Press, 1987 (EB Roche, editor, American Pharmaceutical Association). Prodrugs of this disclosure can be prepared, for example, by replacing suitable functional groups present in the compounds of this disclosure with certain portions known to those skilled in the art as “pro-moiety” (e.g., as described in “Design of Prodrugs,” H. Bundgaard (Elsevier, 1985)).

[0092] This disclosure also covers compounds of this disclosure containing protecting groups. In any process of preparing the compounds of this disclosure, protection of sensitive or reactive groups on any relevant molecule may be necessary and / or desired, thereby forming a form of chemical protection for the compounds of this disclosure. This can be achieved by conventional protecting groups, for example, those described in *Protective Groups in Organic Chemistry*, ed. J.F.W. McOmie, Plenum Press, 1973; and T.W. Greene & P. ​​G.W. M. Uts, *Protective Groups in Organic Synthesis*, John Wiley & Sons, 1991, which are incorporated herein by reference. Protecting groups can be removed at appropriate subsequent stages using methods known in the art.

[0093] Unless otherwise specified, all numerical values ​​in this disclosure are modified by the term "about". The term "about" means within ±20%, preferably ±10%, more preferably ±5%, and even more preferably ±2% of the stated numerical value.

[0094] The term "pharmaceutical composition" refers to a composition containing one or more compounds described herein or their physiologically / pharmaceutically acceptable salts or prodrugs, as well as other components such as physiologically / pharmaceutically acceptable carriers or excipients. The purpose of a pharmaceutical composition is to facilitate administration to a living organism, thereby promoting the absorption of the active ingredient and the exertment of its biological activity.

[0095] In this disclosure, "pharmaceuticalally acceptable carrier" means a diluent, excipient, vehicle, or mediator that is administered co-administered with a therapeutic agent and is suitable, to the extent of reasonable medical judgment, for contact with human and / or other animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications commensurate with a reasonable benefit / risk ratio. "Pharmaceuticalally acceptable carrier" includes, but is not limited to, glidants, sweeteners, diluents, preservatives, dyes / colorants, flavoring agents, surfactants, wetting agents, dispersants, disintegrants, stabilizers, solvents, or emulsifiers.

[0096] The terms "administration" or "giving" refer to methods that enable the delivery of a compound or composition to a desired biological site of action. These methods include, but are not limited to, oral or parenteral administration (including intraventricular, intravenous, subcutaneous, intraperitoneal, intramuscular, and intravascular injection or infusion), local administration, and rectal administration. In particular, injection or oral administration.

[0097] As used in this article, the term "prevention" includes suppressing and delaying the onset of disease, and includes not only prevention before the development of disease, but also prevention of recurrence of disease after treatment.

[0098] As used in this article, the term “treatment” means to reverse, alleviate or eliminate the progression of one or more symptoms of a condition or illness to which such term is applied.

[0099] The terms “active ingredient,” “therapeutic agent,” “active substance,” or “active agent” refer to a chemical entity that can effectively treat or prevent a target disorder, disease, or symptom.

[0100] For the purposes of pharmaceuticals, pharmaceutical units, or active ingredients, the terms "effective amount," "therapeutic effective amount," or "preventive effective amount" refer to a sufficient quantity of a drug or agent that provides acceptable side effects while achieving the desired therapeutic effect. The determination of the effective amount varies from person to person, depending on the individual's age and general condition, as well as the specific active substance. The appropriate effective amount in a given case can be determined by a person skilled in the art based on routine testing.

[0101] As used herein, “individual” includes both human and non-human animals. Exemplary human individuals include human individuals suffering from a disease (such as the disease described herein) (referred to as patients) or normal individuals. In this disclosure, “non-human animals” includes all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles) and mammals, such as non-human primates, livestock, and / or domesticated animals (e.g., sheep, dogs, cats, cows, pigs, etc.).

[0102] The term "room temperature" refers to a temperature ranging from 10°C to 40°C. In some embodiments, "room temperature" refers to a temperature ranging from 15°C to 30°C; in other embodiments, "room temperature" refers to a temperature ranging from 18°C ​​to 25°C.

[0103] "Equivalent" or its abbreviation "eq" is the equivalent amount of other raw materials required based on the equivalence relationship of a chemical reaction, with the basic raw material used in each step as the benchmark (1 equivalent).

[0104] The abbreviations “Int” or “int” mentioned in this article refer to intermediates. “NaH” refers to sodium hydride. “DMF” refers to N,N-dimethylformamide. “THF” refers to tetrahydrofuran. “TFA” refers to trifluoroacetic acid. “DCM” refers to dichloromethane. “TMSI” refers to trimethyl sulfoxide. “NaOH” refers to sodium hydroxide. “K2CO3” refers to potassium carbonate. “TEA” refers to triethylamine. “NaOtBu” refers to sodium tert-butoxide. “TTZ” refers to tetrazolium. “MSA” is mesylate. “(Ms)2O” is mesylate anhydride. “MTBE” refers to methyl tert-butyl ether. “Pd(dppf)Cl2” refers to [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride. “Pd / C” refers to palladium on carbon. “Pd2(dba)3” refers to tris(dibenzylacetone)dipalladium. “BINAP” refers to S-(-)-1,1'-binaphthyl-2,2'-bis(diphenylphosphine). “Tol” refers to toluene. “Na(OAc)3BH” refers to sodium triacetylborohydride. “AcOH” refers to acetic acid. “(PPh3)2PdCl2” refers to palladium dichloride bis(triphenylphosphine). “Na2CO3” refers to sodium carbonate. “MeCN” refers to acetonitrile. “PPh3” refers to triphenylphosphine. “DIAD” refers to diisopropyl azodicarbonate. “NMP” refers to N-methylpyrrolidone. “EtOH” refers to ethanol. “Boc” refers to tert-butyloxycarbonyl.

[0105] This article mentions "X" g2 X g3 X g4 X g5 X g6 X g7 and X g8 Each is independently selected from...C (=CR) g8R g9 ")" refers to X g2 X g3 X g4 X g5 X g6 X g7 and X g8 Each can be selected independently.

[0106] The following detailed description is intended to illustrate non-limiting embodiments, enabling other skilled in the art to more fully understand the technical solutions, principles, and practical applications of this disclosure, so that other skilled in the art can modify and implement this disclosure in many forms to best suit the requirements of a particular application.

[0107] compound

[0108] This disclosure provides compounds of formula (I) or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotope labels, metabolites, or prodrugs thereof:

[0109] Among them, X a1 Selected from CR a1 and N; X a2 Selected from CR a2 and N; X a3 Selected from CR a3 and N; X a4 Selected from CR a4 and N; X a5 Selected from CR a5 and N;

[0110] U is selected from

[0111] X u1 and X u4 Each independently selected from CR u1 and N;

[0112] X u2 X u3 X u5 X u6 and X u7 Each is independently selected from chemical bonds, O, S, Se, S(O), S(O)2, C(O), CR u2 R u3 and NR u4 Preferred chemical bonds include O, S, S(O), S(O)2, C(O), and CR. u2 R u3 and NR u4 Or, X u1 Xu2 X u3 X u4 X u5 X u6 and X u7 Any two rings in the group combine to form C 3-10 Cycloalkyl or 3-10 membered heterocyclic groups, wherein the C 3-10 Cycloalkyl or 3-10-membered heterocyclic groups are optionally separated by one or more independently selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl groups and C 1-6 Substituents of haloalkoxy groups;

[0113] Or, any two adjacent X u1 X u2 X u3 X u4 X u5 X u6 and X u7 Formation of double bonds;

[0114] Or R u2 and R u3 C forms with the carbon atoms that are bonded together. 3-10 Cycloalkyl or 3-10 membered heterocyclic groups, wherein the C 3-10 Cycloalkyl or 3-10-membered heterocyclic groups are optionally separated by one or more independently selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl groups and C 1-6 Substituents of haloalkoxy groups;

[0115] Y u1 Y u3 Y u6 and Y u8 Each independently selected from CR u5 and N;

[0116] Y u2 Y u4 Y u5 Y u7 Y u9 and Y u10 Each is independently selected from chemical bonds, O, S, Se, S(O), S(O)2, C(O), CR u6 R u7 and NR u8 Preferred chemical bonds include O, S, S(O), S(O)2, C(O), and CR. u6 R u7 and NR u8 ;

[0117] Z u1 and Z u6 Each independently selected from CR u9 and N;

[0118] Z u2 Z u3 Z u4 Z u5 Z u7 Z u8 Z u9 and Z u10 Each is independently selected from chemical bonds, O, S, Se, S(O), S(O)2, C(O), CR u10 R u11 and NR u12 Preferred chemical bonds include O, S, S(O), S(O)2, C(O), and CR. u10 R u11 and NR u12 ;

[0119] G is

[0120] X g1 Selected from CR g1 and N;

[0121] X g2 X g3 X g4 X g5 X g6 X g7 and X g8 Each is independently selected from chemical bonds, O, S, Se, S(O), S(O)2, S(O)(=NR) g2 ), C(O), CR g3 R g4 NR g5 Si(R) g6 2. P(O)R g7 and C (=CR) g8 R g9 Preferred chemical bonds include O, S, S(O), S(O)2, and S(O) (=NR). g2 ), C(O), CR g3 R g4 NR g5 Si(R) g6 2. P(O)R g7 and C (=CR) g8 R g9 );

[0122] Or, X g1 Xg2 X g3 X g4 X g5 X g6 X g7 and X g8 Any two rings in the group combine to form C 3-10 Cycloalkyl, 3-10 membered heterocyclic or 5-6 membered heteroaryl, wherein the C 3-10 Cycloalkyl, 3-10-membered heterocyclic or 5-6-membered heteroaryl groups are optionally surrounded by one or more groups independently selected from hydrogen, halogen, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups and C(O)R 43 Substituents, preferably hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl groups and C 1-6 Halogenated alkoxy groups;

[0123] Or R g3 and R g4 C forms with the carbon atoms that are bonded together. 3-10 Cycloalkyl or 3-10 membered heterocyclic groups, wherein the C 3-10 Cycloalkyl or 3-10 membered heterocyclic groups are optionally surrounded by one or more groups independently selected from hydrogen, halogen, oxo group, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C(O)R 43 and S(O)2R 52 Substituents, preferably hydrogen, halogen, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups and C(O)R 43 More preferably hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl groups and C 1-6 Halogenated alkoxy groups;

[0124] Or, any two adjacent X g1 X g2 X g3 X g4 X g5 X g6 X g7 and X g8 Double bonds can be formed;

[0125] E is

[0126] X e1 X e2 X e3 and X e4 Each is independently selected from O, S, Se, N, and CR. e1 and NR e2 O, S, N, and CR are preferred. e1 and NR e2 ;

[0127] Or X e1 X e2 X e3 and X e4 The two adjacent rings in the middle form C 3-10 Cycloalkyl, 3-10-membered heterocyclic or 5-10-membered heteroaryl, wherein the C 3-10 Cycloalkyl, 3-10 heterocyclic or 5-10 heteroaryl groups are optionally separated by one or more elements independently selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl groups and C 1-6 Substituents of haloalkoxy groups;

[0128] L is selected from chemical bonds, -O-, -S-, -Se-, -S(O)-, -S(O)2-, -C(O)-, -C 1-6 alkylene-, -C 1-6 Alkylene -O-, -C 1-6 Alkylene -C(O)-, -C 1-6 Alkylene-S(O)-, -C 1-6 Alkylene -S(O)2-, -C 1-6 Alkylene-NR 1 -、-NR 1 -、-N(C(O)R 2 )-、-NR 3 C(O)- and -NR 4 SO2-, preferably chemical bonds, -O-, -S-, -S(O)-, -S(O)2-, -C(O)-, -C 1-6 alkylene-, -C 1-6 Alkylene -O-, -C 1-6 Alkylene -C(O)-, -C 1-6 Alkylene-S(O)-, -C 1-6 Alkylene -S(O)2-, -C 1-6 Alkylene-NR 1 -、-NR 1-、-N(C(O)R 2 )-、-NR 3 C(O)- and -NR 4 SO2-, more preferably chemical bonds, -O-, -S-, -S(O)-, -S(O)2-, -C(O)-, -C 1-6 alkylene-, -C 1-6 Alkylene -O-, -C 1-6 Alkylene -C(O)-, -C 1-6 Alkylene-S(O)-, -C 1-6 Alkylene-S(O)2-, -NR 1 -、-N(C(O)R 2 )-、-NR 3 C(O)- and -NR 4 SO2-; The L mentioned above has no fixed connection order with the U on the left and the G on the right;

[0129] R a1 R a2 R a3 R a4 R a5 R e1 and R e2 Each is independently selected from hydrogen, deuterium, halogens, NO2, OH, CN, C(O)R 5 C(O)OR 6 C(O)NR 7 R 8 NR 9 R 10 NR 11 C(O)R 12 S(O)R 13 S(O)2R 14 S(O)2NR 15 R 16 NR 17 S(O)R 18 NR 19 S(O)2R 20 SF5, SCN, Si(R) 21 3. P(O)R 22 R 23 B(OR) 24 2. C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkyl selenyl, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C3-7 Cycloalkyl, 4-7 membered heterocyclic groups, C 6-10 aryl and 5-10 heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkyl selenyl, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 Cycloalkyl, 4-7 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl groups are optionally selected by one or more independently chosen from hydrogen, deuterium, halogen, NO2, OH, CN, C(O)R 25 C(O)OR 26 C(O)NR 27 R 28 NR 29 R 30 NR 31 C(O)R 32 S(O)R 33 S(O)2R 34 SO2NR 35 R 36 NR 37 S(O)R 38 NR 39 S(O)2R 40 C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups and C 1-6 The substituent is replaced by a thioalkoxy group; preferably, R a1 R a2 R a3 R a4 R a5 R e1 and R e2 Each is independently selected from hydrogen, deuterium, halogens, NO2, OH, CN, C(O)R 5 C(O)OR 6 C(O)NR 7 R 8 NR 9 R 10 NR 11 C(O)R 12 S(O)R 13 S(O)2R 14 S(O)2NR 15 R 16 NR17 S(O)R 18 NR 19 S(O)2R 20 SF5, SCN, Si(R) 21 3. P(O)R 22 R 23 B(OR) 24 2. C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 Cycloalkyl, 4-7 membered heterocyclic groups, C 6-10 aryl and 5-10 heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 Cycloalkyl, 4-7 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl groups are optionally selected by one or more independently chosen from hydrogen, deuterium, halogen, NO2, OH, CN, C(O)R 25 C(O)OR 26 C(O)NR 27 R 28 NR 29 R 30 NR 31 C(O)R 32 S(O)R 33 S(O)2R 34 SO2NR 35 R 36 NR 37 S(O)R 38 NR 39 S(O)2R 40 C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups and C 1-6 Substituents of thioalkoxy groups;

[0130] R u1 R u2 R u3 R u4 Ru5 R u6 R u7 R u8 R u9 R u10 R u11 R u12 R g1 R g2 R g3 R g4 R g5 R g6 R g7 R g8 and R g9 Each is independently selected from hydrogen, deuterium, halogens, NO2, OH, CN, and NR. 41 R 42 C(O)R 43 -C 1-6 Alkylene-R 43 C(O)OR 44 C(O)NR 45 R 46 C(=NR) 49 )NR 45 R 46 NR 49 C(O)R 50 S(O)R 51 S(O)2R 52 SO2NR 53 R 54 NR 55 S(O)R 56 NR 57 S(O)2R 58 C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 Cycloalkyl, 4-7 membered heterocyclic groups, C 6-10 aryl and 5-10 heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Alkylene, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 Cycloalkyl, 4-7 membered heterocyclic groups, C 6-10The aryl or 5-10 heteroaryl group is optionally surrounded by one or more independently selected groups: hydrogen, deuterium, halogen, oxo group, NO2, OH, CN, C(O)R. 43 C(O)OR 44 C(O)NR 45 R 46 NR 47 R 48 NR 49 C(O)R 50 S(O)R 51 S(O)2R 52 SO2NR 53 R 54 NR 55 S(O)R 56 NR 57 S(O)2R 58 C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Thioalkoxy, C 6-10 Substituents of aryl and 5-10 heteroaryl groups; preferably, R u1 R u2 R u3 R u4 R u5 R u6 R u7 R u8 R u9 R u10 R u11 R u12 R g1 R g2 R g3 R g4 R g5 R g6 R g7 R g8 and R g9 Each is independently selected from hydrogen, deuterium, halogens, NO2, OH, CN, and NR. 41 R 42 C(O)R 43 C(O)OR 44 C(O)NR 45 R 46 NR 49 C(O)R 50 S(O)R 51 S(O)2R 52 SO2NR 53 R 54NR 55 S(O)R 56 NR 57 S(O)2R 58 C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 cycloalkyl and 4-7 membered heterocyclic groups, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 The cycloalkyl or 4-7 membered heterocyclic group is optionally selected by one or more independently chosen from hydrogen, deuterium, halogen, NO2, OH, CN, C(O)R. 43 C(O)OR 44 C(O)NR 45 R 46 NR 47 R 48 NR 49 C(O)R 50 S(O)R 51 S(O)2R 52 SO2NR 53 R 54 NR 55 S(O)R 56 NR 57 S(O)2R 58 C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups and C 1-6 Substituents of thioalkoxy groups;

[0131] R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11 R 12 R 13 R 14 R 15 R16 R 17 R 18 R 19 R 20 R 21 R 22 R 23 R 24 R 25 R 26 R 27 R 28 R 29 R 30 R 31 R 32 R 33 R 34 R 35 R 36 R 37 R 38 R 39 R 40 R 41 R 42 R 43 R 44 R 45 R 46 R 47 R 48 R 49 R 50 R 51 R 52 R 53 R 54 R 55 R 56 R 57 and R 58 Each is independently selected from hydrogen and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 3-7 Cycloalkyl, 4-7 membered heterocyclic groups, C 6-10 Aryl, 5-10 membered heteroaryl and NR 59 C(O)R 60 The C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 3-7 Cycloalkyl, 4-7 membered heterocyclic groups, C 6-10The aryl or 5-10 heteroaryl group is optionally surrounded by one or more independently selected from hydrogen, deuterium, halogen, oxo group, NO2, OH, CN, C. 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups and C 1-6 Substituents of thioalkoxy groups; preferably, R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11 R 12 R 13 R 14 R 15 R 16 R 17 R 18 R 19 R 20 R 21 R 22 R 23 R 24 R 25 R 26 R 27 R 28 R 29 R 30 R 31 R 32 R 33 R 34 R 35 R 36 R 37 R 38 R 39 R 40 R 41 R 42 R 43 R 44 R 45 R 46 R 47 R 48 R 49 R 50 R 51 R 52 R 53 R 54 R 55 R56 R 57 and R 58 Each is independently selected from hydrogen and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 3-7 Cycloalkyl, 4-7 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl, the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 3-7 Cycloalkyl, 4-7 membered heterocyclic groups, C 6-10 The aryl or 5-10 heteroaryl group is optionally selected by one or more independently chosen from hydrogen, deuterium, halogen, NO2, OH, CN, C. 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups and C 1-6 Substituents of thioalkoxy groups; more preferably, R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11 R 12 R 13 R 14 R 15 R 16 R 17 R 18 R 19 R 20 R 21 R 22 R 23 R 24 R 25 R 26 R 27 R 28 R 29 R 30 R 31 R 32 R 33 R 34 R35 R 36 R 37 R 38 R 39 R 40 R 41 R 42 R 43 R 44 R 45 R 46 R 47 R 48 R 49 R 50 R 51 R 52 R 53 R 54 R 55 R 56 R 57 and R 58 Each is independently selected from hydrogen and C. 1-6 Alkyl and C 1-6 Halogenated alkyl; or two R 24 The atoms bonded to it together form a 4-7 membered heterocyclic group, which is optionally composed of one or more elements independently selected from hydrogen, halogen, and C. 1-6 Alkyl substituents;

[0132] R 59 and R 60 Each is independently selected from hydrogen and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 3-7 Cycloalkyl, 4-7 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl, the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 3-7 Cycloalkyl, 4-7 membered heterocyclic groups, C 6-10 The aryl or 5-10 heteroaryl group is optionally selected by one or more independently chosen from hydrogen, deuterium, halogen, NO2, OH, CN, C. 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups and C 1-6 Substituents of thioalkoxy groups;

[0133] Where X a1 X a2 X a3 and X a4 None of them are N, and U is selected from: At that time, R a1 R a2 R a3 R a4 R a5 Each is independently selected from SF5, SCN, and Si(R) 21 3. P(O)R 22 R 23 and B(OR) 24 )2; and / or R u1 R u2 and R u3 Each is independently selected from NO2, CN, and NR. 41 R 42 C(O)R 43 C(O)OR 44 C(O)NR 45 R 46 NR 49 C(O)R 50 S(O)R 51 S(O)2R 52 SO2NR 53 R 54 NR 55 S(O)R 56 NR 57 S(O)2R 58 C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 cycloalkyl and 4-7 membered heterocyclic groups, wherein the C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 The cycloalkyl or 4-7 membered heterocyclic group is optionally selected by one or more independently chosen from hydrogen, deuterium, halogen, NO2, OH, CN, C(O)R. 43 C(O)OR 44 C(O)NR 45 R 46 NR 47 R 48 NR 49 C(O)R 50 S(O)R 51 S(O)2R52 SO2NR 53 R 54 NR 55 S(O)R 56 NR 57 S(O)2R 58 C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups and C 1-6 Substituents of thioalkoxy groups, or R u2 and R u3 Forming 3-10 membered heterocyclic groups with the commonly linked carbon atoms; and / or R e1 and R e2 Each is independently selected from deuterium, halogens, NO2, OH, CN, C(O)R 5 C(O)NR 7 R 8 NR 9 R 10 NR 11 C(O)R 12 S(O)R 13 S(O)2R 14 S(O)2NR 15 R 16 NR 17 S(O)R 18 NR 19 S(O)2R 20 SF5, SCN, Si(R) 21 3. P(O)R 22 R 23 B(OR) 24 2. C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-10 aryl and 5-10 heteroaryl, wherein the C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-10 Aryl or 5-10 heteroaryl groups are optionally selected by one or more independently chosen from hydrogen, deuterium, halogen, NO2, OH, CN, C(O)R 25 C(O)OR 26 C(O)NR 27 R 28 NR29 R 30 NR 31 C(O)R 32 S(O)R 33 S(O)2R 34 SO2NR 35 R 36 NR 37 S(O)R 38 NR 39 S(O)2R 40 C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups and C 1-6 The substituent is thioalkoxy; and / or L is selected from -O-, -S-, -S(O)-, -S(O)2-, -C 1-6 Alkylene-O-, -N(C(O)R 2 )- and -NR 4 SO2-; and / or U selected from and / or X g1 X g2 X g3 X g4 X g5 X g6 X g7 and X g8 Any two rings in the group can be combined to form a 3-10 membered heterocyclic group or a 5-6 membered heteroaryl group, wherein the 3-10 membered heterocyclic group or the 5-6 membered heteroaryl group is optionally surrounded by one or more elements independently selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl groups and C 1-6 Substituents of haloalkoxy groups; and / or R g3 and R g4 C forms with the carbon atoms that are bonded together. 3-10 cycloalkyl, the C 3-10 The cycloalkyl group is optionally surrounded by one or more elements independently selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl groups and C 1-6 Substituents of haloalkoxy groups; and / or any two adjacent X groups. g1 X g2 X g3 X g4 X g5 X g6 X g7 and X g8It can form at most one double bond; and / or X g2 X g3 X g4 X g5 X g6 X g7 and X g8 At least one of them is selected from S(O)(=NR) g2 ), NR g5 Si(R) g6 )2 and P(O)R g7 And R g5 Selected from C(O)R 43 and C 3-7 cycloalkyl; and / or G selected from

[0134] In some embodiments of equation (I), X a1 Selected from CR a1 and N; X a2 Selected from CR a2 and N; X a3 Selected from CR a3 and N; X a4 Selected from CR a4 and N; X a5 Selected from CR a5 and N;

[0135] U is selected from

[0136] X u1 and X u4 Each independently selected from CR u1 and N;

[0137] X u2 X u3 X u5 X u6 and X u7 Each is independently selected from chemical bonds, O, S, S(O), S(O)2, C(O), CR u2 R u3 and NR u4 ;

[0138] Or, X u1 X u2 X u3 X u4 X u5 X u6 and X u7 Any two rings in the group combine to form C 3-10 Cycloalkyl or 3-10 membered heterocyclic groups, wherein the C 3-10Cycloalkyl or 3-10-membered heterocyclic groups are optionally separated by one or more independently selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl groups and C 1-6 Substituents of haloalkoxy groups;

[0139] Or, any two adjacent X u1 X u2 X u3 X u4 X u5 X u6 and X u7 Formation of double bonds;

[0140] Or R u2 and R u3 C forms with the carbon atoms that are bonded together. 3-10 Cycloalkyl or 3-10 membered heterocyclic groups, wherein the C 3-10 Cycloalkyl or 3-10-membered heterocyclic groups are optionally separated by one or more independently selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl groups and C 1-6 Substituents of haloalkoxy groups;

[0141] Y u1 Y u3 Y u6 and Y u8 Each independently selected from CR u5 and N;

[0142] Y u2 Y u4 Y u5 Y u7 Y u9 and Y u10 Each is independently selected from chemical bonds, O, S, S(O), S(O)2, C(O), CR u6 R u7 and NR u8 ;

[0143] Z u1 and Z u6 Each independently selected from CR u9 and N;

[0144] Z u2 Z u3 Z u4 Z u5 Z u7 Z u8 Z u9 and Zu10 Each is independently selected from chemical bonds, O, S, S(O), S(O)2, C(O), CR u10 R u11 and NR u12 ;

[0145] G is

[0146] X g1 Selected from CR g1 and N;

[0147] X g2 X g3 X g4 X g5 X g6 X g7 and X g8 Each is independently selected from chemical bonds, O, S, S(O), S(O)2, S(O)(=NR) g2 ), C(O), CR g3 R g4 NR g5 Si(R) g6 2. P(O)R g7 and C (=CR) g8 R g9 );

[0148] Or, X g1 X g2 X g3 X g4 X g5 X g6 X g7 and X g8 Any two rings in the group combine to form C 3-10 Cycloalkyl, 3-10 membered heterocyclic or 5-6 membered heteroaryl, wherein the C 3-10 Cycloalkyl, 3-10-membered heterocyclic or 5-6-membered heteroaryl groups are optionally surrounded by one or more groups independently selected from hydrogen, halogen, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups and C(O)R 43 Substituents of the substituents;

[0149] Or R g3 and R g4 C forms with the carbon atoms that are bonded together. 3-10 Cycloalkyl or 3-10 membered heterocyclic groups, wherein the C 3-10 Cycloalkyl or 3-10 membered heterocyclic groups are optionally surrounded by one or more groups independently selected from hydrogen, halogen, oxo group, C1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups and C(O)R 43 Substituents of the substituents;

[0150] Or, any two adjacent X g1 X g2 X g3 X g4 X g5 X g6 X g7 and X g8 Double bonds can be formed;

[0151] E is

[0152] X e1 X e2 X e3 and X e4 Each is independently selected from O, S, N, CR e1 and NR e2 ;

[0153] Or X e1 X e2 X e3 and X e4 The two adjacent rings in the middle form C 3-10 Cycloalkyl, 3-10-membered heterocyclic or 5-10-membered heteroaryl, wherein the C 3-10 Cycloalkyl, 3-10 heterocyclic or 5-10 heteroaryl groups are optionally separated by one or more elements independently selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl groups and C 1-6 Substituents of haloalkoxy groups;

[0154] L is selected from chemical bonds, -O-, -S-, -S(O)-, -S(O)2-, -C(O)-, -C 1-6 alkylene-, -C 1-6 Alkylene -O-, -C 1-6 Alkylene -C(O)-, -C 1-6 Alkylene-S(O)-, -C 1-6 Alkylene -S(O)2-, -C 1-6 Alkylene-NR 1 -、-NR 1 -、-N(C(O)R 2 )-、-NR 3 C(O)- and -NR 4SO2-; The L mentioned above has no fixed connection order with the U on the left and the G on the right;

[0155] R a1 R a2 R a3 R a4 R a5 R e1 and R e2 Each is independently selected from hydrogen, deuterium, halogens, NO2, OH, CN, C(O)R 5 C(O)OR 6 C(O)NR 7 R 8 NR 9 R 10 NR 11 C(O)R 12 S(O)R 13 S(O)2R 14 S(O)2NR 15 R 16 NR 17 S(O)R 18 NR 19 S(O)2R 20 SF5, SCN, Si(R) 21 3. P(O)R 22 R 23 B(OR) 24 2. C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 Cycloalkyl, 4-7 membered heterocyclic groups, C 6-10 aryl and 5-10 heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 Cycloalkyl, 4-7 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl groups are optionally selected by one or more independently chosen from hydrogen, deuterium, halogen, NO2, OH, CN, C(O)R 25 C(O)OR 26 C(O)NR 27 R 28NR 29 R 30 NR 31 C(O)R 32 S(O)R 33 S(O)2R 34 SO2NR 35 R 36 NR 37 S(O)R 38 NR 39 S(O)2R 40 C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups and C 1-6 Substituents of thioalkoxy groups;

[0156] R u1 R u2 R u3 R u4 R u5 R u6 R u7 R u8 R u9 R u10 R u11 R u12 R g1 R g2 R g3 R g4 R g5 R g6 R g7 R g8 and R g9 Each is independently selected from hydrogen, deuterium, halogens, NO2, OH, CN, and NR. 41 R 42 C(O)R 43 -C 1-6 Alkylene-R 43 C(O)OR 44 C(O)NR 45 R 46 C(=NR) 49 )NR 45 R 46 NR 49 C(O)R 50 S(O)R 51 S(O)2R 52 SO2NR 53 R 54 NR 55 S(O)R 56 NR57 S(O)2R 58 C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 Cycloalkyl, 4-7 membered heterocyclic groups, C 6-10 aryl and 5-10 heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Alkylene, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 Cycloalkyl, 4-7 membered heterocyclic groups, C 6-10 The aryl or 5-10 heteroaryl group is optionally surrounded by one or more independently selected groups: hydrogen, deuterium, halogen, oxo group, NO2, OH, CN, C(O)R. 43 C(O)OR 44 C(O)NR 45 R 46 NR 47 R 48 NR 49 C(O)R 50 S(O)R 51 S(O)2R 52 SO2NR 53 R 54 NR 55 S(O)R 56 NR 57 S(O)2R 58 C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Thioalkoxy, C 6-10 Substituents of aryl and 5-10 heteroaryl groups;

[0157] R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11R 12 R 13 R 14 R 15 R 16 R 17 R 18 R 19 R 20 R 21 R 22 R 23 R 24 R 25 R 26 R 27 R 28 R 29 R 30 R 31 R 32 R 33 R 34 R 35 R 36 R 37 R 38 R 39 R 40 R 41 R 42 R 43 R 44 R 45 R 46 R 47 R 48 R 49 R 50 R 51 R 52 R 53 R 54 R 55 R 56 R 57 and R 58 Each is independently selected from hydrogen and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 3-7 Cycloalkyl, 4-7 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl, the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 3-7 Cycloalkyl, 4-7 membered heterocyclic groups, C 6-10The aryl or 5-10 heteroaryl group is optionally selected by one or more independently chosen from hydrogen, deuterium, halogen, NO2, OH, CN, C. 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups and C 1-6 Substitution of thioalkoxy groups; or two R groups 24 The atoms bonded to it together form a 4-7 membered heterocyclic group, which is optionally composed of one or more elements independently selected from hydrogen, halogen, and C. 1-6 Alkyl substituents;

[0158] Where X a1 X a2 X a3 and X a4 None of them are N, and U is selected from: At that time, R a1 R a2 R a3 R a4 R a5 Each is independently selected from SF5, SCN, and Si(R) 21 3. P(O)R 22 R 23 and B(OR) 24 )2; and / or R u1 R u2 and R u3 Each is independently selected from NO2, CN, and NR. 41 R 42 C(O)R 43 C(O)OR 44 C(O)NR 45 R 46 NR 49 C(O)R 50 S(O)R 51 S(O)2R 52 SO2NR 53 R 54 NR 55 S(O)R 56 NR 57 S(O)2R 58 C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 cycloalkyl and 4-7 membered heterocyclic groups, wherein the C 1-6 Haloalkyl, C 1-6Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 The cycloalkyl or 4-7 membered heterocyclic group is optionally selected by one or more independently chosen from hydrogen, deuterium, halogen, NO2, OH, CN, C(O)R. 43 C(O)OR 44 C(O)NR 45 R 46 NR 47 R 48 NR 49 C(O)R 50 S(O)R 51 S(O)2R 52 SO2NR 53 R 54 NR 55 S(O)R 56 NR 57 S(O)2R 58 C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups and C 1-6 Substituents of thioalkoxy groups, or R u2 and R u3 Forming 3-10 membered heterocyclic groups with the commonly linked carbon atoms; and / or R e1 and R e2 Each is independently selected from deuterium, halogens, NO2, OH, CN, C(O)R 5 C(O)NR 7 R 8 NR 9 R 10 NR 11 C(O)R 12 S(O)R 13 S(O)2R 14 S(O)2NR 15 R 16 NR 17 S(O)R 18 NR 19 S(O)2R 20 SF5, SCN, Si(R) 21 3. P(O)R 22 R 23 B(OR) 24 2. C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C2-6 alkynyl group, C 6-10 aryl and 5-10 heteroaryl, wherein the C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-10 Aryl or 5-10 heteroaryl groups are optionally selected by one or more independently chosen from hydrogen, deuterium, halogen, NO2, OH, CN, C(O)R 25 C(O)OR 26 C(O)NR 27 R 28 NR 29 R 30 NR 31 C(O)R 32 S(O)R 33 S(O)2R 34 SO2NR 35 R 36 NR 37 S(O)R 38 NR 39 S(O)2R 40 C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups and C 1-6 The substituent is thioalkoxy; and / or L is selected from -O-, -S-, -S(O)-, -S(O)2-, -C 1-6 Alkylene-O-, -N(C(O)R 2 )- and -NR 4 SO2-; and / or U selected from and / or X g1 X g2 X g3 X g4 X g5 X g6 X g7 and X g8 Any two rings in the group can be combined to form a 3-10 membered heterocyclic group or a 5-6 membered heteroaryl group, wherein the 3-10 membered heterocyclic group or the 5-6 membered heteroaryl group is optionally surrounded by one or more elements independently selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl groups and C 1-6 Substituents of haloalkoxy groups; and / or R g3 and R g4 C forms with the carbon atoms that are bonded together.3-10 cycloalkyl, the C 3-10 The cycloalkyl group is optionally surrounded by one or more elements independently selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl groups and C 1-6 Substituents of haloalkoxy groups; and / or any two adjacent X groups. g1 X g2 X g3 X g4 X g5 X g6 X g7 and X g8 It can form at most one double bond; and / or X g2 X g3 X g4 X g5 X g6 X g7 and X g8 At least one of them is selected from S(O)(=NR) g2 ), NR g5 Si(R) g6 )2 and P(O)R g7 And R g5 Selected from C(O)R 43 and C 3-7 cycloalkyl; and / or G selected from

[0159] In some embodiments of equation (I), X a1 Selected from CR a1 and N; X a2 Selected from CR a2 and N; X a3 Selected from CR a3 and N; X a4 Selected from CR a4 and N; X a5 Selected from CR a5 and N;

[0160] U is selected from

[0161] X u1 and X u4 Each independently selected from CR u1 and N;

[0162] X u2 X u3 X u5 X u6 and X u7Each is independently selected from chemical bonds, O, S, S(O), S(O)2, C(O), CR u2 R u3 and NR u4 ;

[0163] Or, X u1 X u2 X u3 X u4 X u5 X u6 and X u7 Any two rings in the group combine to form C 3-10 Cycloalkyl or 3-10 membered heterocyclic groups, wherein the C 3-10 Cycloalkyl or 3-10-membered heterocyclic groups are optionally separated by one or more independently selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl groups and C 1-6 Substituents of haloalkoxy groups;

[0164] Or, any two adjacent X u1 X u2 X u3 X u4 X u5 X u6 and X u7 Formation of double bonds;

[0165] Or R u2 and R u3 C forms with the carbon atoms that are bonded together. 3-10 Cycloalkyl or 3-10 membered heterocyclic groups, wherein the C 3-10 Cycloalkyl or 3-10-membered heterocyclic groups are optionally separated by one or more independently selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl groups and C 1-6 Substituents of haloalkoxy groups;

[0166] Y u1 Y u3 Y u6 and Y u8 Each independently selected from CR u5 and N;

[0167] Y u2 Y u4 Y u5 Y u7 Y u9 and Y u10 Each is independently selected from chemical bonds, O, S, S(O), S(O)2, C(O), CRu6 R u7 and NR u8 ;

[0168] Z u1 and Z u6 Each independently selected from CR u9 and N;

[0169] Z u2 Z u3 Z u4 Z u5 Z u7 Z u8 Z u9 and Z u10 Each is independently selected from chemical bonds, O, S, S(O), S(O)2, C(O), CR u10 R u11 and NR u12 ;

[0170] G is

[0171] X g1 Selected from CR g1 and N;

[0172] X g2 X g3 X g4 X g5 X g6 X g7 and X g8 Each is independently selected from chemical bonds, O, S, S(O), S(O)2, S(O)(=NR) g2 ), C(O), CR g3 R g4 NR g5 Si(R) g6 2. P(O)R g7 and C (=CR) g8 R g9 );

[0173] Or, X g1 X g2 X g3 X g4 X g5 X g6 X g7 and X g8 Any two rings in the group combine to form C 3-10 Cycloalkyl, 3-10 membered heterocyclic or 5-6 membered heteroaryl, wherein the C 3-10 Cycloalkyl, 3-10-membered heterocyclic or 5-6-membered heteroaryl groups are optionally separated by one or more independently selected from hydrogen, halogen, C1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl groups and C 1-6 Substituents of haloalkoxy groups;

[0174] Or R g3 and R g4 C forms with the carbon atoms that are bonded together. 3-10 Cycloalkyl or 3-10 membered heterocyclic groups, wherein the C 3-10 Cycloalkyl or 3-10-membered heterocyclic groups are optionally separated by one or more independently selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl groups and C 1-6 Substituents of haloalkoxy groups;

[0175] Or, any two adjacent X g1 X g2 X g3 X g4 X g5 X g6 X g7 and X g8 It can form at most one double bond;

[0176] E is

[0177] X e1 X e2 X e3 and X e4 Each is independently selected from O, S, N, CR e1 and NR e2 ;

[0178] L is selected from chemical bonds, -O-, -S-, -S(O)-, -S(O)2-, -C(O)-, -C 1-6 alkylene-, -C 1-6 Alkylene -O-, -C 1-6 Alkylene -C(O)-, -C 1-6 Alkylene-S(O)-, -C 1-6 Alkylene-S(O)2-, -NR 1 -、-N(C(O)R 2 )-、-NR 3 C(O)- and -NR 4 SO2-; The L mentioned above has no fixed connection order with the U on the left and the G on the right;

[0179] R a1 R a2 R a3 Ra4 R a5 R e1 and R e2 Each is independently selected from hydrogen, deuterium, halogens, NO2, OH, CN, C(O)R 5 C(O)OR 6 C(O)NR 7 R 8 NR 9 R 10 NR 11 C(O)R 12 S(O)R 13 S(O)2R 14 S(O)2NR 15 R 16 NR 17 S(O)R 18 NR 19 S(O)2R 20 SF5, SCN, Si(R) 21 3. P(O)R 22 R 23 B(OR) 24 2. C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 Cycloalkyl, 4-7 membered heterocyclic groups, C 6-10 aryl and 5-10 heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 Cycloalkyl, 4-7 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl groups are optionally selected by one or more independently chosen from hydrogen, deuterium, halogen, NO2, OH, CN, C(O)R 25 C(O)OR 26 C(O)NR 27 R 28 NR 29 R 30 NR 31 C(O)R 32 S(O)R 33 S(O)2R34 SO2NR 35 R 36 NR 37 S(O)R 38 NR 39 S(O)2R 40 C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups and C 1-6 Substituents of thioalkoxy groups;

[0180] R u1 R u2 R u3 R u4 R u5 R u6 R u7 R u8 R u9 R u10 R u11 R u12 R g1 R g2 R g3 R g4 R g5 R g6 R g7 R g8 and R g9 Each is independently selected from hydrogen, deuterium, halogens, NO2, OH, CN, and NR. 41 R 42 C(O)R 43 C(O)OR 44 C(O)NR 45 R 46 NR 49 C(O)R 50 S(O)R 51 S(O)2R 52 SO2NR 53 R 54 NR 55 S(O)R 56 NR 57 S(O)2R 58 C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 cycloalkyl and 4-7 membered heterocyclic groups, wherein the C1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 The cycloalkyl or 4-7 membered heterocyclic group is optionally selected by one or more independently chosen from hydrogen, deuterium, halogen, NO2, OH, CN, C(O)R. 43 C(O)OR 44 C(O)NR 45 R 46 NR 47 R 48 NR 49 C(O)R 50 S(O)R 51 S(O)2R 52 SO2NR 53 R 54 NR 55 S(O)R 56 NR 57 S(O)2R 58 C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups and C 1-6 Substituents of thioalkoxy groups;

[0181] R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11 R 12 R 13 R 14 R 15 R 16 R 17 R 18 R 19 R 20 R 21 R 22 R 23 R 24 R 25 R 26 R 27 R 28 R 29 R30 R 31 R 32 R 33 R 34 R 35 R 36 R 37 R 38 R 39 R 40 R 41 R 42 R 43 R 44 R 45 R 46 R 47 R 48 R 49 R 50 R 51 R 52 R 53 R 54 R 55 R 56 R 57 and R 58 Each is independently selected from hydrogen and C. 1-6 Alkyl and C 1-6 Halogenated alkyl; or two R 24 The atoms bonded to it together form a 4-7 membered heterocyclic group, which is optionally composed of one or more elements independently selected from hydrogen, halogen, and C. 1-6 Alkyl substituents;

[0182] Where X a1 X a2 X a3 and X a4 None of them are N, and U is selected from: At that time, R a1 R a2 R a3 R a4 R a5 Each is independently selected from SF5, SCN, and Si(R) 21 3. P(O)R 22 R 23 B(OR) 24 )2; and / or R u1 R u2 and R u3 Each is independently selected from NO2, CN, and NR. 41 R 42 C(O)R 43 C(O)OR 44 C(O)NR 45 R 46NR 49 C(O)R 50 S(O)R 51 S(O)2R 52 SO2NR 53 R 54 NR 55 S(O)R 56 NR 57 S(O)2R 58 C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 cycloalkyl and 4-7 membered heterocyclic groups, wherein the C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 The cycloalkyl or 4-7 membered heterocyclic group is optionally selected by one or more independently chosen from hydrogen, deuterium, halogen, NO2, OH, CN, C(O)R. 43 C(O)OR 44 C(O)NR 45 R 46 NR 47 R 48 NR 49 C(O)R 50 S(O)R 51 S(O)2R 52 SO2NR 53 R 54 NR 55 S(O)R 56 NR 57 S(O)2R 58 C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups and C 1-6 Substituents of thioalkoxy groups, or R u2 and R u3 Forming 3-10 membered heterocyclic groups with the commonly linked carbon atoms; and / or R e1 and R e2 Each is independently selected from deuterium, halogens, NO2, OH, CN, C(O)R 5 C(O)NR 7 R 8 NR 9 R 10 NR 11 C(O)R12 S(O)R 13 S(O)2R 14 S(O)2NR 15 R 16 NR 17 S(O)R 18 NR 19 S(O)2R 20 SF5, SCN, Si(R) 21 3. P(O)R 22 R 23 B(OR) 24 2. C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-10 aryl and 5-10 heteroaryl, wherein the C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-10 Aryl or 5-10 heteroaryl groups are optionally selected by one or more independently chosen from hydrogen, deuterium, halogen, NO2, OH, CN, C(O)R 25 C(O)OR 26 C(O)NR 27 R 28 NR 29 R 30 NR 31 C(O)R 32 S(O)R 33 S(O)2R 34 SO2NR 35 R 36 NR 37 S(O)R 38 NR 39 S(O)2R 40 C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups and C 1-6 The substituent is thioalkoxy; and / or L is selected from -O-, -S-, -S(O)-, -S(O)2-, -C 1-6 Alkylene-O-, -N(C(O)R 2 )- and -NR 4 SO2-; and / or U selected from and / or Xg1 X g2 X g3 X g4 X g5 X g6 X g7 and X g8 Any two rings in the group can be combined to form a 3-10 membered heterocyclic group or a 5-6 membered heteroaryl group, wherein the 3-10 membered heterocyclic group or the 5-6 membered heteroaryl group is optionally surrounded by one or more elements independently selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl groups and C 1-6 Substituents of haloalkoxy groups; and / or R g3 and R g4 C forms with the carbon atoms that are bonded together. 3-10 cycloalkyl, the C 3-10 The cycloalkyl group is optionally surrounded by one or more elements independently selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl groups and C 1-6 Substituents of haloalkoxy groups; and / or any two adjacent X groups. g1 X g2 X g3 X g4 X g5 X g6 X g7 and X g8 It can form at most one double bond; and / or X g2 X g3 X g4 X g5 X g6 X g7 and X g8 At least one of them is selected from S(O)(=NR) g2 ), NR g5 Si(R) g6 )2 and P(O)R g7 And R g5 Selected from C(O)R 43 and C 3-7 cycloalkyl; and / or G selected from

[0183] In some implementations, X a1 X a2 X a3 and X a4 At least one of them is N.

[0184] In some implementations, Xa1 Let N be the number of elements in the array.

[0185] In some implementations, X a2 Let N be the number of elements in the array.

[0186] In some implementations, X a3 For N

[0187] In some implementations, X a4 Let N be the number of elements in the array.

[0188] In some implementations, X a5 Let N be the number of elements in the array.

[0189] In some implementations, X a1 Let N, X a2 X a3 X a4 and X a5 Not N.

[0190] In some implementations, X a2 Let N, X a1 X a3 X a4 and X a5 Not N.

[0191] In some implementations, X a3 Let N, X a1 X a2 X a4 and X a5 Not N.

[0192] In some implementations, X a4 Let N, X a1 X a2 X a3 and X a5 Not N.

[0193] In some implementations, X a5 Let N, X a1 X a2 X a3 and X a4 Not N.

[0194] In some implementations, X a1 and X a2 Let N, X a3 X a4 and X a5 Not N.

[0195] In some implementations, X a1 and X a4 Let N, X a2 Xa3 and X a5 Not N.

[0196] In some implementations, X a1 and X a5 Let N, X a2 X a3 and X a4 Not N.

[0197] In some implementations, X a1 X a2 X a3 X a4 and X a5 None of them are N.

[0198] In some implementations, R a1 R a2 R a3 R a4 R a5 Each is independently selected from hydrogen, halogen, C(O)R 5 C(O)NR 7 R 8 NR 9 R 10 NR 11 C(O)R 12 S(O)2NR 15 R 16 SF5, SCN, Si(R) 21 3. P(O)R 22 R 23 B(OR) 24 2. C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkyl selenyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 Cycloalkyl, 4-7-membered heterocyclic and 5-10-membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkyl selenyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 Cycloalkyl, 4-7-membered heterocyclic or 5-10-membered heteroaryl groups are optionally selected by one or more independently chosen from hydrogen, deuterium, halogen, NO2, OH, CN, C(O)R 25 C(O)OR 26C(O)NR 27 R 28 NR 29 R 30 NR 31 C(O)R 32 S(O)R 33 S(O)2R 34 SO2NR 35 R 36 NR 37 S(O)R 38 NR 39 S(O)2R 40 C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups and C 1-6 The substituents of the thioalkoxy group are replaced.

[0199] In some implementations, R a1 R a2 R a3 R a4 R a5 Each is independently selected from hydrogen, halogen, C(O)R 5 C(O)NR 7 R 8 NR 9 R 10 NR 11 C(O)R 12 S(O)2NR 15 R 16 SF5, SCN, Si(R) 21 3. P(O)R 22 R 23 B(OR) 24 2. C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 Cycloalkyl, 4-7-membered heterocyclic and 5-10-membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7Cycloalkyl, 4-7-membered heterocyclic or 5-10-membered heteroaryl groups are optionally selected by one or more independently chosen from hydrogen, deuterium, halogen, NO2, OH, CN, C(O)R 25 C(O)OR 26 C(O)NR 27 R 28 NR 29 R 30 NR 31 C(O)R 32 S(O)R 33 S(O)2R 34 SO2NR 35 R 36 NR 37 S(O)R 38 NR 39 S(O)2R 40 C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups and C 1-6 The substituents of the thioalkoxy group are replaced.

[0200] In some implementations, R a1 R a2 R a3 R a4 R a5 Each is independently selected from hydrogen, halogen, C(O)R 5 C(O)NR 7 R 8 NR 9 R 10 S(O)2NR 15 R 16 SF5, SCN, Si(R) 21 3. P(O)R 22 R 23 B(OR) 24 2. C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkyl selenyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 Cycloalkyl, 4-7-membered heterocyclic and 5-10-membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkyl selenyl, C 1-6Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 Cycloalkyl, 4-7-membered heterocyclic or 5-10-membered heteroaryl groups are optionally selected by one or more independently chosen from hydrogen, deuterium, halogen, NO2, OH, CN, C(O)R 25 C(O)OR 26 C(O)NR 27 R 28 NR 29 R 30 NR 31 C(O)R 32 S(O)R 33 S(O)2R 34 SO2NR 35 R 36 NR 37 S(O)R 38 NR 39 S(O)2R 40 C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups and C 1-6 The substituents of the thioalkoxy group are replaced.

[0201] In some implementations, R a1 R a2 R a3 R a4 R a5 Each is independently selected from hydrogen, halogen, C(O)R 5 C(O)NR 7 R 8 NR 9 R 10 S(O)2NR 15 R 16 SF5, SCN, Si(R) 21 3. P(O)R 22 R 23 B(OR) 24 2. C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 Cycloalkyl, 4-7-membered heterocyclic and 5-10-membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 Cycloalkyl, 4-7-membered heterocyclic or 5-10-membered heteroaryl groups are optionally selected by one or more independently chosen from hydrogen, deuterium, halogen, NO2, OH, CN, C(O)R 25 C(O)OR 26 C(O)NR 27 R 28 NR 29 R 30 NR 31 C(O)R 32 S(O)R 33 S(O)2R 34 SO2NR 35 R 36 NR 37 S(O)R 38 NR 39 S(O)2R 40 C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups and C 1-6 The substituents of the thioalkoxy group are replaced.

[0202] In some implementations, R a1 R a2 R a3 R a4 R a5 Each is independently selected from hydrogen, halogen, C(O)R 5 C(O)NR 7 R 8 NR 9 R 10 S(O)2NR 15 R 16 SF5, SCN, Si(R) 21 3. P(O)R 22 R 23 B(OR) 24 2. C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 Cycloalkyl, 4-7 membered heterocyclic and 5-10 membered heteroaryl.

[0203] In some implementations, R a1R a2 R a3 R a4 R a5 Each is independently selected from hydrogen, fluorine, methyl, ethyl, vinyl, ethynyl, SF5, SCN, methyl carbonyl, CH3CF2-, methoxy, methylthio, methylselenyl (CH3-Se-), oxetyl (e.g., ) ), carbamoyl, cyclopropyl, thiazolyl (e.g., carbamoyl, cyclopropyl, thiazolyl) ), methylamino, pyridyl (e.g., ), Trimethylsilyl methyl-substituted pyrazolyl (e.g.) ),

[0204] In some implementations, R a1 R a2 R a3 R a4 R a5 Each is independently selected from hydrogen, fluorine, methyl, ethyl, vinyl, ethynyl, SF5, SCN, methyl carbonyl, CH3CF2-, methoxy, methyl thio, oxetyl (e.g., ) ), carbamoyl, cyclopropyl, thiazolyl (e.g., carbamoyl, cyclopropyl, thiazolyl) ), methylamino, pyridyl (e.g., ), Trimethylsilyl methyl-substituted pyrazolyl (e.g.) ),

[0205] In some implementations, R a1 R a2 R a3 R a4 R a5 Each is independently selected from hydrogen, fluorine, methyl, ethyl, vinyl, ethynyl, SF5, SCN, methyl carbonyl, CH3CF2-, methoxy, methyl thio, oxetyl (e.g., ) ), carbamoyl, cyclopropyl, thiazolyl (e.g., carbamoyl, cyclopropyl, thiazolyl) ), methylamino, pyridyl (e.g., ), Trimethylsilyl

[0206] In some implementations, X u1 Let N, X u4 For CR u1.

[0207] In some implementations, X u1 Let N, X u4 For CH.

[0208] In some implementations, X u2 X u3 X u5 X u6 and X u7 Each is independently selected from chemical bonds and CR u2 R u3 .

[0209] In some implementations, X u2 and X u3 Cyclolysis forms 3-10 membered heterocyclic groups, for example

[0210] In some implementations, Y u3 and Y u8 Each independently selected from CR u5 .

[0211] In some implementations, Y u2 Y u4 Y u5 Y u7 Y u9 and Y u10 Each is independently selected from chemical bonds and CR u6 R u7 .

[0212] In some implementations, Z u2 Z u3 Z u4 Z u5 Z u7 Z u8 Z u9 and Z u10 Each is independently selected from chemical bonds and CR u10 R u11 .

[0213] In some implementations, U is selected from: C 3-7 cycloalkyl, n1, n2, n3 and n4 are each independently selected from 0, 1 and 2, respectively, and n5 and n6 are each independently selected from 1 or 2.

[0214] In some implementations, U is selected from: C 3-7 cycloalkyl, Wherein n1, n2, n3, and n4 are each independently selected from 0, 1, and 2, respectively, and n5 and n6 are each independently selected from 1 or 2. In some embodiments, U is connected to a nitrogen-containing heteroaromatic ring core on its left side and to L on its right side.

[0215] In some implementations, R u1 R u2 R u3 R u4 R u5 R u6 R u7 R u8 R u9 R u10 R u11 R u12 Each is independently selected from hydrogen, deuterium, halogen, OH, CN, and NR. 41 R 42 C(O)OR 44 C(O)NR 45 R 46 C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl groups and C 3-7 cycloalkyl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl or C 3-7 The cycloalkyl group is optionally separated by one or more elements independently selected from hydrogen, deuterium, halogen, NO2, OH, CN, C(O)R. 43 C(O)OR 44 C(O)NR 45 R 46 NR 47 R 48 NR 49 C(O)R 50 S(O)R 51 S(O)2R 52 SO2NR 53 R 54 NR 55 S(O)R 56 NR 57 S(O)2R 58 C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups and C 1-6 The substituents of the thioalkoxy group are replaced.

[0216] In some implementations, R u1Each is independently selected from hydrogen, deuterium, halogens, and C(O)OR. 44 C(O)NR 45 R 46 C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and C 3-7 cycloalkyl, wherein the C 1-6 Alkyl, C 1-6 Halogenated alkyl or C 3-7 The cycloalkyl group is optionally separated by one or more elements independently selected from hydrogen, deuterium, halogen, NO2, OH, CN, C(O)R. 43 C(O)OR 44 C(O)NR 45 R 46 NR 47 R 48 NR 49 C(O)R 50 S(O)R 51 S(O)2R 52 SO2NR 53 R 54 NR 55 S(O)R 56 NR 57 S(O)2R 58 C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups and C 1-6 The substituents of the thioalkoxy group are replaced.

[0217] In some implementations, R u1 Each is independently selected from hydrogen, deuterium, F, methyl, CF3, -CH2OH, cyclopropyl, carbamoyl and CH3CH2OC(O)-.

[0218] In some implementations, R u2 and R u3 Each is independently selected from hydrogen, halogen, OH, CN, NR. 41 R 42 C(O)OR 44 C(O)NR 45 R 46 C 1-6 Alkyl and C 1-6 Alkoxy, wherein the C 1-6 Alkyl or C 1-6 The alkoxy group is optionally selected by one or more independently chosen from hydrogen, deuterium, halogen, NO2, OH, CN, C(O)R 43 C(O)OR 44 C(O)NR45 R 46 NR 47 R 48 NR 49 C(O)R 50 S(O)R 51 S(O)2R 52 SO2NR 53 R 54 NR 55 S(O)R 56 NR 57 S(O)2R 58 C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups and C 1-6 The substituents of the thioalkoxy group are replaced.

[0219] In some implementations, R u2 and R u3 Each is independently selected from hydrogen, F, OH, amino, CN, methyl, methoxy, methylamino, carbamoyl, CH3CH2OC(O)-, -CH2OH and -CH2CN.

[0220] In some implementations, R u2 and R u3 With the carbon atom that is connected to each other in the form of C 3-10 Cycloalkyl (e.g., cyclopropyl) or 3-10 membered heterocyclic groups (e.g., oxobutyl).

[0221] In some implementations, R u4 R u5 R u6 R u7 R u8 R u9 R u10 R u11 and R u12 It is hydrogen.

[0222] In some implementations, U is selected from (For example ), (For example ), (For example ), (For example ), (For example ), (For example ), (For example ), (For example ), (For example ), (For example )and (For example ); where n1, n2, n3, and n4 are each independently selected from 0, 1, and 2, and n5 and n6 are each independently selected from 1 or 2. In some embodiments, U is connected to a nitrogen-containing heteroaromatic ring core on the left and L on the right.

[0223] In some implementations, U is selected from (For example ), (For example ), (For example ), (For example ), (For example ), (For example ), (For example ), Wherein n1, n2, n3, and n4 are each independently selected from 0, 1, and 2, and n5 and n6 are each independently selected from 1 or 2. In some embodiments, U is connected to a nitrogen-containing heteroaromatic ring core on the left and L on the right.

[0224] In some implementations, U is selected from (For example ), (For example ), (For example ), (For example ), (For example ), (For example ), Wherein n1, n2, n3, and n4 are each independently selected from 0, 1, and 2, and n5 and n6 are each independently selected from 1 or 2. In some embodiments, U is connected to a nitrogen-containing heteroaromatic ring core on the left and L on the right.

[0225] In some embodiments, L is selected from chemical bonds, -O-, -S-, -S(O)2-, -C(O)-, -C 1-6 alkylene-, -C 1-6 Alkylene-NR 1 -、-NR 1 -and-N(C(O)R 2 In some implementations, R 1 and R 2 Each is independently selected from hydrogen and C. 1-6 Alkyl and C 1-6 Halogenated alkyl groups.

[0226] In some embodiments, L is selected from chemical bonds, -O-, -S-, -S(O)2-, -C(O)-, -C 1-6 Alkylene-, -NR 1 -and-N(C(O)R 2 )-.

[0227] In some embodiments, L is selected from chemical bonds, -NH-, -NH-CH2-, -CH2-, -O-, -S-, -C(O)-, -S(O)2- and -N(C(O)CH3)-.

[0228] In some embodiments, L is selected from chemical bonds, -NH-, -CH2-, -O-, -S-, -C(O)-, -S(O)2- and -N(C(O)CH3)-.

[0229] In some implementations, X g2 X g3 X g4 X g5 X g6 X g7 and X g8 Each is independently selected from chemical bonds, O, Se, S(O)2, S(O)(=NR) g2 ), C(O), CR g3 R g4 NR g5 Si(R) g6 2. P(O)R g7 and C (=CR) g8 R g9 ).

[0230] In some implementations, X g2 X g3 X g4 X g5 X g6 X g7 and X g8 Each is independently selected from chemical bonds, O, S(O)2, S(O)(=NR) g2 ), C(O), CR g3 R g4 NR g5 Si(R) g6 2. P(O)R g7 and C (=CR) g8 R g9 ).

[0231] In some implementations, X g1 X g2 X g3 X g4 X g5 X g6 X g7 and X g8 Any two rings in the group combine to form C 3-10 Cycloalkyl, 3-10 membered heterocyclic or 5-6 membered heteroaryl, wherein the C 3-10 Cycloalkyl, 3-10-membered heterocyclic or 5-6-membered heteroaryl groups are optionally surrounded by one or more groups independently selected from hydrogen, halogen, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups and C(O)R 43 Substituents are substituted.

[0232] In some implementations, X g1 X g2 X g3 X g4 X g5 X g6 X g7 and X g8 Any two rings in the group combine to form C 3-10 Cycloalkyl, 3-10 membered heterocyclic or 5-6 membered heteroaryl, wherein the C 3-10 Cycloalkyl, 3-10-membered heterocyclic or 5-6-membered heteroaryl groups are optionally separated by one or more independently selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl groups and C 1-6 Substituents of haloalkoxy groups.

[0233] In some implementations, any two adjacent X g1 X g2 X g3 X g4 X g5 X g6 X g7 and X g8 Double bonds can be formed, such as carbon-carbon double bonds. The maximum number of double bonds formed is one.

[0234] In some implementations, R g1 R g2 R g3 R g4 R g5 R g6 R g7 R g8 and R g9 Each is independently selected from hydrogen, halogen, OH, CN, NR. 41 R 42 C(O)R 43 -C 1-6 Alkylene-R 43 C(O)OR 44 C(O)NR 45 R 46 C(=NR) 49 )NR 45 R 46 S(O)R 51 S(O)2R 52 C 1-6 Alkyl, C 1-6 Alkoxy, C 3-7 Cycloalkyl, 4-7 membered heterocyclic groups, C 6-10 aryl and 5-10 heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Alkylene, C 1-6 Alkoxy, C 3-7 Cycloalkyl, 4-7 membered heterocyclic groups, C 6-10 The aryl or 5-10 heteroaryl group is optionally surrounded by one or more independently selected groups: hydrogen, deuterium, halogen, oxo group, NO2, OH, CN, C(O)R. 43 C(O)OR 44 C(O)NR 45 R 46 NR 47 R 48 NR 49 C(O)R 50 S(O)R 51 S(O)2R 52SO2NR 53 R 54 NR 55 S(O)R 56 NR 57 S(O)2R 58 C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Thioalkoxy, C 6-10 Substituents of aryl and 5-10 heteroaryl groups.

[0235] In some implementations, R g1 R g2 R g3 R g4 R g5 R g6 R g7 R g8 and R g9 Each is independently selected from hydrogen, halogen, OH, C(O)R 43 C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and C 3-7 cycloalkyl, or R g3 and R g4 C forms with the carbon atoms that are bonded together. 3-10 Cycloalkyl or 3-10 membered heterocyclic groups.

[0236] In some implementations, R g1 It is hydrogen.

[0237] In some implementations, R g2 R g6 and R g7 Each is independently selected from hydrogen and C. 1-6 alkyl.

[0238] In some implementations, R g5 Each is independently selected from hydrogen, CN, and C. 1-6 Alkyl, C(O)R 43 -C 1-6 Alkylene-R 43 C(O)OR 44 C(O)NR 45 R 46 C(=NR) 49 )NR 45 R 46 S(O)R 51 S(O)2R 52 C 3-7Cycloalkyl, 4-7 membered heterocyclic groups, C 6-10 aryl and 5-10 heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Alkylene, C 3-7 Cycloalkyl, 4-7 membered heterocyclic groups, C 6-10 The aryl or 5-10 heteroaryl group is optionally surrounded by one or more independently selected groups: hydrogen, deuterium, halogen, oxo group, NO2, OH, CN, C(O)R. 43 C(O)OR 44 C(O)NR 45 R 46 NR 47 R 48 NR 49 C(O)R 50 S(O)R 51 S(O)2R 52 SO2NR 53 R 54 NR 55 S(O)R 56 NR 57 S(O)2R 58 C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Thioalkoxy, C 6-10 Substituents of aryl and 5-10 heteroaryl groups.

[0239] In some implementations, R g5 Each is independently selected from hydrogen and C. 1-6 Alkyl, C(O)R 43 and C 3-7 Cycloalkyl.

[0240] In some implementations, R 43 Selected from hydrogen, C 1-6 Alkyl, C 3-7 Cycloalkyl, 4-7 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl, the C 1-6 Alkyl, C 3-7 Cycloalkyl, 4-7 membered heterocyclic groups, C 6-10 The aryl or 5-10 heteroaryl group is optionally selected by one or more independently chosen from hydrogen, deuterium, halogen, NO2, OH, CN, C. 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups and C1-6 Substituents of thioalkoxy groups.

[0241] In some implementations, R g3 and R g4 Each is independently selected from hydrogen, halogen, OH, NR. 41 R 42 C(O)OR 44 C(O)NR 45 R 46 C 1-6 Alkyl, C 1-6 alkoxy and 5-10 heteroaryl groups, the C 1-6 Alkyl, C 1-6 The alkoxy or 5-10 heteroaryl group is optionally surrounded by one or more groups independently selected from hydrogen, deuterium, halogen, oxo group, NO2, OH, CN, C(O)R. 43 C(O)OR 44 C(O)NR 45 R 46 NR 47 R 48 NR 49 C(O)R 50 S(O)R 51 S(O)2R 52 SO2NR 53 R 54 NR 55 S(O)R 56 NR 57 S(O)2R 58 C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Thioalkoxy, C 6-10 Substituents of aryl and 5-10 heteroaryl groups.

[0242] In some implementations, R g3 and R g4 C forms with the carbon atoms that are bonded together. 3-10 Cycloalkyl or 3-10 membered heterocyclic groups, wherein the C 3-10 Cycloalkyl or 3-10 membered heterocyclic groups are optionally surrounded by one or more groups independently selected from hydrogen, halogen, oxo group, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups and C(O)R 43 Substituents are substituted.

[0243] In some implementations, R g3 and R g4 Each is independently selected from hydrogen, halogen, OH, and C. 1-6 Alkyl, or R g3 and R g4 C forms with the carbon atoms that are bonded together. 3-10 Cycloalkyl (e.g., cyclopropyl) or 3-10 membered heterocyclic groups (e.g., oxobutyl, tetrahydropyranyl).

[0244] In some implementations, R g8 and R g9 Each is independently selected from hydrogen and halogens.

[0245] In some implementations, G is selected from: (For example Or selected from cyclopentyl, cyclohexyl, (For example ), (For example ), (For example

[0246] In some embodiments, G is selected from: cyclopentyl, cyclohexyl, (For example ),

[0247] In some embodiments, G is selected from: cyclopentyl, cyclohexyl,

[0248] In some implementations, R e1 Each is independently selected from hydrogen, halogen, OH, C(O)NR 7 R 8 NR 9 R 10 C 1-6 Alkyl and C 1-6 Halogenated alkyl groups. In some embodiments, R 7 R 8 R 9 and R 10Each is independently selected from hydrogen and C. 1-6 Alkyl and C 1-6 Halogenated alkyl groups.

[0249] In some implementations, R e1 Each is independently selected from hydrogen, halogen, and NR. 9 R 10 C 1-6 Alkyl and C 1-6 Halogenated alkyl groups.

[0250] In some implementations, R e2 For H.

[0251] In some implementations, E is selected from

[0252] In some implementations, E is selected from In some implementations, E is selected from In some implementations, E is selected from:

[0253] In some implementations, E is selected from:

[0254] In some implementations, E is selected from:

[0255] In some embodiments, formula (I) is selected from formulas (II-A), (II-B), (II-C), and (II-D):

[0256] Among them, X a1 X a2 X a3 X a4 X a5 E, U, L and G are as defined in any of the preceding embodiments.

[0257] In some implementations, equation (I) is equivalent to equation (II-A):

[0258] Among them, X a2 X a3 X a4 X a5 E, U, L and G are as defined in any of the preceding embodiments.

[0259] In some embodiments, formula (I) is selected from formulas (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), and (III-G):

[0260] Among them, R a1 R a2 R a3 R a4 R a5 E, U, L and G are as defined in any of the preceding embodiments.

[0261] In some implementations, equation (I) is equation (III-A):

[0262] Where R a2 R a3 R a4 R a5 E, U, L and G are as defined in any of the preceding embodiments.

[0263] In some embodiments, formula (I) is formula (III-A-1) or formula (III-A-2):

[0264] in,

[0265] R a3 Selected from hydrogen, deuterium, halogens, NO2, OH, CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkyl selenyl, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 Cycloalkyl, 4-7 membered heterocyclic groups, C 6-10 Aryl and 5-10 quinone heteroaryl groups, preferably hydrogen, deuterium, halogen, NO2, OH, CN, or C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl groups and C 3-7 Cycloalkyl, more preferably ethyl and cyclopropyl;

[0266] E is selected from

[0267] R e1 Each is independently selected from hydrogen, halogen, OH, C(O)NR 7 R 8 NR9 R 10 C 1-6 Alkyl and C 1-6 Haloalkyl groups, preferably hydrogen, halogen, OH, C(O)NH2, NH2, C 1-4 Alkyl and C 1-4 Haloalkyl, more preferably hydrogen, halogen, OH, C(O)NH2, NH2, methyl and trifluoromethyl;

[0268] Preferably, E is selected from

[0269] More preferably, E is selected from

[0270] U is selected from (For example ), (For example ), (For example ), (For example ), (For example ), (For example ), (For example ), Or selected from (For example ), Or selected from (For example ), (For example ) (For example ); where n1, n2, n3 and n4 are each independently selected from 0, 1 and 2, and n5 and n6 are each independently selected from 1 or 2;

[0271] Preferably, U is selected from Or for (For example ); or selected from (For example )and (For example );

[0272] More preferably, U is selected from Or for (For example ); or selected from (For example )and (For example );

[0273] L is selected from chemical bonds, -O-, -S-, -S(O)2-, -C(O)-, -C 1-6 alkylene-, -C 1-6 Alkylene-NR 1 -、-NR 1 -and-N(C(O)R 2 -, preferably chemical bonds, -NH-, -NH-CH2-, -CH2-, -O-, -S-, -C(O)-, -S(O)2- and -N(C(O)CH3)-, more preferably chemical bonds, -NH- and -NH-CH2-, and even more preferably chemical bonds and -NH-;

[0274] G is selected from (For example ), Or selected from cyclopentyl, cyclohexyl, Or selected from (For example ), Or selected from (For example ), (For example ),

[0275] Preferably, G is Or selected from Or selected from (For example ), Or selected from

[0276] More preferably, G is selected from Or selected from (For example ), Or for

[0277] In some embodiments, formula (I) is formula (IV-A) or formula (IV-B):

[0278] Among them, R a1 R a2 R a3 R a4 R a5 E, U, L, and G are as defined in any of the preceding embodiments, provided that U is selected from: When one or more of the following conditions are met:

[0279] (1)R a1 R a2 R a3 R a4 R a5 Each is independently selected from SF5, SCN, and Si(R) 21 3. P(O)R 22 R 23 and B(OR) 24 )2;

[0280] (2)R u1 R u2 and R u3 Each is independently selected from NO2, CN, and NR. 41 R 42 C(O)R 43 C(O)OR 44 C(O)NR 45 R 46 NR 49 C(O)R 50 S(O)R 51 S(O)2R 52 SO2NR 53 R 54 NR 55 S(O)R 56 NR 57 S(O)2R 58 C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 cycloalkyl and 4-7 membered heterocyclic groups, wherein the C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C3-7 The cycloalkyl or 4-7 membered heterocyclic group is optionally selected by one or more independently chosen from hydrogen, deuterium, halogen, NO2, OH, CN, C(O)R. 43 C(O)OR 44 C(O)NR 45 R 46 NR 47 R 48 NR 49 C(O)R 50 S(O)R 51 S(O)2R 52 SO2NR 53 R 54 NR 55 S(O)R 56 NR 57 S(O)2R 58 C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups and C 1-6 Substituents of thioalkoxy groups, or R u2 and R u3 It forms 3-10 membered heterocyclic groups with the carbon atoms it connects to;

[0281] (3)R e1 and R e2 Each is independently selected from deuterium, halogens, NO2, OH, CN, C(O)R 5 C(O)NR 7 R 8 NR 9 R 10 NR 11 C(O)R 12 S(O)R 13 S(O)2R 14 S(O)2NR 15 R 16 NR 17 S(O)R 18 NR 19 S(O)2R 20 SF5, SCN, Si(R) 21 3. P(O)R 22 R 23 B(OR) 24 2. C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C6-10 aryl and 5-10 heteroaryl, wherein the C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-10 Aryl or 5-10 heteroaryl groups are optionally selected by one or more independently chosen from hydrogen, deuterium, halogen, NO2, OH, CN, C(O)R 25 C(O)OR 26 C(O)NR 27 R 28 NR 29 R 30 NR 31 C(O)R 32 S(O)R 33 S(O)2R 34 SO2NR 35 R 36 NR 37 S(O)R 38 NR 39 S(O)2R 40 C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups and C 1-6 Substituents of thioalkoxy groups;

[0282] (4) L is selected from -O-, -S-, -S(O)-, -S(O)2-, -C 1-6 Alkylene-O-, -N(C(O)R 2 )- and -NR 4 SO2-;

[0283] (5) U is selected from

[0284] (6)X g1 X g2 X g3 X g4 X g5 X g6 X g7 and X g8 Any two rings in the group can be combined to form a 3-10 membered heterocyclic group or a 5-6 membered heteroaryl group, wherein the 3-10 membered heterocyclic group or the 5-6 membered heteroaryl group is optionally surrounded by one or more elements independently selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl groups and C 1-6Substituents of haloalkoxy groups;

[0285] (7)R g3 and R g4 C forms with the carbon atoms that are bonded together. 3-10 cycloalkyl, the C 3-10 The cycloalkyl group is optionally surrounded by one or more elements independently selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl groups and C 1-6 Substituents of haloalkoxy groups.

[0286] (8) Any two adjacent X g1 X g2 X g3 X g4 X g5 X g6 X g7 and X g8 It can form at most one double bond; and / or X g2 X g3 X g4 X g5 X g6 X g7 and X g8 At least one of them is selected from S(O)(=NR) g2 ), NR g5 Si(R) g6 )2 and P(O)R g7 And R g5 Selected from C(O)R 43 and C 3-7 cycloalkyl;

[0287] In some embodiments, the compound represented by formula (I) is selected from the following compounds:

[0288] The compounds disclosed herein may optionally be substituted at the positions where substitution is possible by suitable substituents, such suitable substituents being selected, for example, from: deuterium, halogen, hydroxyl, cyano, amino, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkyl selenyl, C 1-6 Alkylamino, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl compounds.

[0289] This disclosure covers compounds obtained by any combination of various embodiments / implementations. Embodiments / implementations obtained by combining technical features or preferred technical features of one embodiment / implementation with technical features or preferred technical features of another embodiment / implementation are also included within the scope of this disclosure.

[0290] Preparation method

[0291] In some embodiments, a method for preparing the compound of formula (I) is provided, comprising the following steps:

[0292] Among them, X a1 X a2 X a3 X a4 X a5 E, U, L and G are as defined in any of the preceding embodiments;

[0293] Y is a halogen, such as chlorine.

[0294] In some embodiments, the compound of formula (I-1) and the compound of formula (I-2) are reacted under basic conditions via a nucleophilic substitution reaction to obtain the compound of formula (I).

[0295] In some embodiments, a method for preparing the compound of formula (I) is provided, comprising one or more of the following steps:

[0296] Where X a1 X a2 X a3X a4 X a5 R u2 R u3 U, L, G, and Y are as defined in any of the preceding embodiments;

[0297] Step 1: The compound of formula I-1 reacts with the compound of formula Ia-1 to generate the compound of formula Ia-2;

[0298] Step 2: The compound of formula Ia-2 reacts to form the compound of formula Ia-3;

[0299] Step 3: The compound of formula Ia-3 reacts with the compound of formula Ia-4 to generate the compound of formula Ia.

[0300] In some embodiments, the compound of formula I-1 and the compound of formula Ia-1 undergo a nucleophilic substitution reaction by heating under basic conditions (such as DIPEA, TEA, etc.) to generate the compound of formula Ia-2.

[0301] In some embodiments, the compound of formula Ia-2 is deprotected under acidic conditions (such as HCl) to generate the compound of formula Ia-3.

[0302] In some embodiments, the compound of formula Ia-3 undergoes a reductive amination reaction with the compound of formula Ia-4 to generate the compound of formula Ia.

[0303] The above preparation method can be used to synthesize commercially available raw materials using known methods. The reaction conditions for each step can be those conventional for such reactions in the art.

[0304] intermediate

[0305] In some embodiments, compounds shown below, or salts thereof, stereoisomers, tautomers, polymorphs, solvates, N-oxides, or isotopically labeled compounds are provided:

[0306] Among them, X a1 X a2 X a3 X a4 X a5 E, R u2 R u3 U, L, G and Y are as defined in any of the preceding embodiments.

[0307] The compounds shown above, or their salts, stereoisomers, tautomers, polymorphs, solvates, N-oxides, or isotopically labeled compounds, can be used to prepare the compounds shown in the general formula herein, or their pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites, or prodrugs.

[0308] Pharmaceutical Compositions and Kits

[0309] Another aspect of this disclosure provides a pharmaceutical composition comprising a preventatively and / or therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope label, metabolite, or prodrug thereof, and one or more pharmaceutically acceptable carriers. Optionally, the pharmaceutical composition may further comprise one or more other therapeutic agents.

[0310] Another aspect of this disclosure provides a kit comprising a compound of the disclosure or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope label, metabolite or prodrug, or a pharmaceutical composition of the disclosure.

[0311] In some embodiments, the kit may further comprise instructions for administering the compound of the present disclosure or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope label, metabolite, or prodrug, or a pharmaceutical composition of the present disclosure.

[0312] In some embodiments, the pharmaceutical composition may be in the form of, for example, a solid dosage form, a semi-solid dosage form, a liquid dosage form, or a gaseous dosage form. The solid dosage form may be, for example, a tablet, capsule, powder, granule, or suppository, and the liquid dosage form may be, for example, a solution, suspension, or injection. The composition may also be in the form of liposomes, microspheres, or other dosage forms.

[0313] The pharmaceutical compositions disclosed herein can act systemically and / or locally. For this purpose, they can be administered via suitable routes, such as by injection (e.g., intravenous, intra-arterial, subcutaneous, intraperitoneal, intramuscular injection, including infusion) or transdermal administration; or by oral, sublingual, nasal, transmucosal, topical, ophthalmic formulations or by inhalation.

[0314] In some embodiments, the pharmaceutical composition may include 0.01-1000 mg of the compound disclosed herein or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope label, metabolite or prodrug, and one or more pharmaceutically acceptable carriers.

[0315] In some embodiments, this disclosure provides a method for preparing a pharmaceutical composition of the present disclosure, the method comprising combining a compound of the present disclosure or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope label, metabolite, or prodrug thereof with one or more pharmaceutically acceptable carriers.

[0316] Treatment methods and uses

[0317] Another aspect of this disclosure provides compounds of the disclosure or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotope labels, metabolites or prodrugs thereof, or pharmaceutical compositions of the disclosure, for antagonizing κ receptors or for the prevention and / or treatment of diseases, particularly κ receptor-mediated diseases.

[0318] Another aspect of this disclosure provides the use of the compounds of this disclosure or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotope labels, metabolites, or prodrugs, or pharmaceutical compositions of this disclosure, in the preparation of a medicament, preferably for antagonizing κ receptors, or for the prevention and / or treatment of κ receptor-mediated diseases.

[0319] Another aspect of this disclosure provides the use of the compounds of this disclosure or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotope labels, metabolites, or prodrugs, or pharmaceutical compositions of this disclosure, in the preparation of κ receptor antagonists.

[0320] Another aspect of this disclosure provides a method for preventing and / or treating κ receptor-mediated diseases, comprising administering to an individual in need a preventive or therapeutically effective amount of a compound of this disclosure or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope label, metabolite, or prodrug, or a pharmaceutical composition of this disclosure.

[0321] In some embodiments, the κ receptor-mediated diseases are selected from addiction disorders including conditions associated with substance abuse or addiction; anxiety disorders; depressive disorders; mood disorders; schizophrenia or affective schizophrenia; stress-related disorders; obesity and eating disorders; migraines; postpartum depression; neurodegenerative diseases or conditions, including mood and behavioral disorders associated with neurodegenerative diseases; postpartum depression; epilepsy; status epilepticus; and seizures. Beneficial effects

[0322] The compound shown in this study has one or more of the following beneficial effects:

[0323] (1) It has a good antagonistic effect on κ receptors;

[0324] (2) It has good selectivity for κ receptors;

[0325] (3) It has high safety (e.g., low degree of hERG channel inhibition);

[0326] (4) It has improved pharmacokinetic properties (e.g., suitable half-life, improved hepatic microsomal metabolic stability);

[0327] (5) It has good antidepressant activity.

[0328] Example

[0329] To make the objectives and technical solutions of this disclosure clearer, the embodiments of this disclosure are described in detail below. However, those skilled in the art will understand that the following embodiments are for illustrative purposes only and should not be considered as limiting the scope of this disclosure. Unless otherwise specified, specific conditions in the embodiments are performed under conventional conditions or conditions recommended by the manufacturer. Reagents or instruments whose manufacturers are not specified are all commercially available conventional products.

[0330] The structures of the compounds in all embodiments were determined by nuclear magnetic resonance (NMR). 1 Recorded by H-NMR using a Vian Mercury 400 NMR spectrometer; chemical shifts are expressed as δ (ppm).

[0331] The following abbreviations are used in this disclosure: room temperature (RT, rt); aqueous solution (aq.); petroleum ether (PE); ethyl acetate (EA); dichloromethane (DCM); methanol (MeOH); methyl tert-butyl ether (MTBE); ethanol (EtOH); trifluoroacetic acid (TFA); equivalent (eq); g / mg; mol / mmol; L / mL; min(s); h, hr, hrs; nitrogen (N2); nuclear magnetic resonance (NMR); liquid chromatography-mass spectrometry (LC-MS); thin layer chromatography (TLC); preparative liquid chromatography (Pre-HPLC); tetrahydrofuran (THF); formic acid (FA).

[0332] Preparation method of high performance liquid chromatograph:

[0333] Instrument model: Agilent 1260; Column: Waters SunFire Prep C18 OBD (19mm×150mm×5.0μm); Column temperature: 25℃; Flow rate: 20.0mL / min; Detection wavelength: 214nm; Elution gradient: (0min: 10%A, 90%B; 16.0min: 90%A, 10%B); Mobile phase A: Acetonitrile; Mobile phase B: 0.05% formic acid aqueous solution or 0.05% ammonium bicarbonate aqueous solution.

[0334] The thin-layer chromatography silica gel plates (TLC) used were Merck aluminum plates (20×20cm), and the TLC separation and purification used Yantai-made GF 254 (1mm) plates.

[0335] The reaction was monitored using thin-layer chromatography (TLC) or LC-MS. The developing solvent systems used included dichloromethane and methanol, n-hexane and ethyl acetate, and petroleum ether and ethyl acetate. The volume ratio of the solvent was adjusted according to the polarity of the compound or by adding triethylamine, etc.

[0336] The microwave reaction was performed using a Biotage Initiator+ (400W, RT~300℃) microwave reactor.

[0337] Column chromatography typically uses 200-300 mesh silica gel as the support. Eluent systems include dichloromethane and methanol systems, and petroleum ether and ethyl acetate systems. The volume ratio of the solvents is adjusted according to the polarity of the compounds, and small amounts of triethylamine or formic acid can also be added for adjustment.

[0338] Unless otherwise specified in the examples, the reaction temperature is room temperature (20℃~35℃);

[0339] The reagents used in this disclosure were purchased from Acros Organics, Aldrich Chemical Company, TEB Chemicals, and other companies.

[0340] Those skilled in the art will understand that the following examples only exemplify the synthesis of some compounds of this disclosure, and other compounds of this disclosure can be synthesized similarly with reference to the following examples.

[0341] Example 1: Synthesis of 1-(6-ethyl-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)-1,5-naphthidin-2-yl)-N-(tetrahydro-2H-pyran-4-yl)piperidin-4-amine (compound 1)

[0342] Step 1: Synthesis of 1-(3-amino-6-chloropyridin-2-yl)ethane-1-one (compounds 1-2)

[0343] 3-Amino-6-chloropyrimidin-2-acrylonitrile (compound 1-1) (1.3 g, 8.47 mmol) was added to a three-necked flask and dissolved in anhydrous tetrahydrofuran (30 mL). Methyl Grignard reagent (29.65 mmol, 9.88 mL) was slowly added dropwise under nitrogen protection at 0 °C. After the addition was complete, the reaction was carried out at 0 °C for 3 h. The reaction was quenched by adding saturated ammonium chloride solution (30 mL) at 0 °C, followed by stirring for 0.5 h after adding 1 N HCl (30 mL). The mixture was concentrated, extracted with ethyl acetate (100 mL x 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain the target compound (compound 1-2) (700.00 mg, 4.1 mmol, yield: 48.47%). MS: m / z = 171.2 [M+H] + .

[0344] Step 2: Synthesis of 1-(3-amino-6-ethylpyridin-2-yl)ethane-1-one (compounds 1-3)

[0345] 1-(3-amino-6-chloropyridin-2-yl)ethane-1-one (compound 1-2) (700.00 mg, 4.10 mmol), ethylboronic acid (606.35 mg, 8.21 mmol), 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (300.24 mg, 0.41 mmol), potassium carbonate (1.7 g, 12.31 mmol), and water (740 mg, 41.00 mmol) were added to a reaction flask, followed by toluene (20 mL). The mixture was heated to 100 °C in an oil bath under nitrogen protection and reacted for 12 h. After cooling to room temperature, the reaction solution was filtered through diatomaceous earth. The filter cake was washed with ethyl acetate, and the filtrate was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain the target compound (compound 1-3) (400 mg, 2.44 mmol, yield 59.37%). MS: m / z = 165.3 [M+H] + .

[0346] Step 3: Synthesis of 5-(2-chloro-6-ethyl-4-methyl-1,5-naphthid-3-yl)-3-methyl-1,2,4-oxadiazole (compounds 1-4)

[0347] 1-(3-amino-6-ethylpyridin-2-yl)ethane-1-one (compounds 1-3) (500 mg, 3.04 mmol) and 2-(3-methyl-1,2,4-oxadiazol-5-yl)acetic acid (476 mg, 3.35 mmol) were added to a round-bottom flask and dissolved in phosphorus oxychloride (5 mL). The mixture was reacted in an oil bath at 110 °C for 1 h. The reaction solution was concentrated and added dropwise to a saturated sodium bicarbonate solution under ice bath conditions with vigorous stirring. The solution was extracted with ethyl acetate (100 mL x 3), and the organic phases were combined. The organic phases were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain the target compounds (compounds 1-4) (410 mg, 1.42 mmol, yield: 46.63%). MS: m / z = 289.3 [M+H] + .

[0348] Step 4: Synthesis of 8-(6-ethyl-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)-1,5-naphthid-2-yl)-1,4-dioxa-8-azaspiro[4.5]decane (compounds 1-5)

[0349] 5-(2-chloro-6-ethyl-4-methyl-1,5-naphthid-3-yl)-3-methyl-1,2,4-oxadiazole (compounds 1-4) (380 mg, 1.32 mmol), 4-piperidinone ethylene glycol (226.13 mg, 1.58 mmol), and N,N-diisopropylethylamine (510.29 mg, 3.95 mmol) were added to a round-bottom flask and dissolved in dimethyl sulfoxide (5 mL). The mixture was reacted in an oil bath at 120 °C for 12 h. After cooling to room temperature, a saturated ammonium chloride solution (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the target compounds (compounds 1-5), which were used directly in the next step without purification. MS: m / z = 396.2 [M+H] + .

[0350] Step 5: Synthesis of 1-(6-ethyl-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)-1,5-naphthidin-2-yl)piperidin-4-one (compounds 1-6)

[0351] 8-(6-ethyl-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)-1,5-naphthid-2-yl)-1,4-dioxa-8-azaspiro[4.5]decane (compounds 1-5) (330 mg, 0.83 mmol) was dissolved in tetrahydrofuran (5 mL), and 3N HCl (2.78 mL, 8.34 mmol) was added with stirring at room temperature. The reaction solution was reacted at 60 °C for 3 h. After cooling to room temperature, the reaction solution was concentrated, water (20 mL) was added, and the pH was adjusted to 7-8 with saturated sodium carbonate solution. The solution was extracted with ethyl acetate (50 mL x 3), and the organic phases were combined. The organic phases were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain the target compounds (compounds 1-6) (190 mg, 0.29 mmol, yield: 64.79%). MS: m / z = 352.2 [M+H] + .

[0352] Step Six: Synthesis of 1-(6-ethyl-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)-1,5-naphthidin-2-yl)-N-(tetrahydro-2H-pyran-4-yl)piperidin-4-amine (Compound 1)

[0353] 1-(6-ethyl-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)-1,5-naphthidin-2-yl)piperidin-4-one (compounds 1-6) (190 mg, 0.54 mmol) and 4-aminotetrahydropyran (65.63 mg, 0.65 mmol) were dissolved in methanol (2 mL). Acetic acid (6.5 mg, 0.11 mmol) was added with stirring at room temperature. After stirring for 0.5 h, sodium cyanoborocyanide (101.93 mg, 1.62 mmol) was added, and the reaction was carried out at room temperature for 3 h. The reaction solution was concentrated and extracted with water (50 mL) and ethyl acetate (50 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by preparative column chromatography to obtain the title compound (compound 1) (60 mg, 0.137 mmol, yield: 25.42%). MS: m / z = 437.3 [M+H] + .

[0354] 1H NMR (400MHz, CDCl3) δ8.01(d,J=8.6Hz,1H),7.49(d,J=8.6Hz,1H),4.04-3.97(m,2H),3.62(d,J=13.2Hz,2H),3.43(td,J=1 1.7,1.7Hz,2H),3.02(q,J=7.6Hz,2H),2.95-2.75(m,4H),2.72(s,3H),2.60(s,3H),1.90-1.80(m,4H),1.47-1.28(m,8H).

[0355] Example 2: Preparation of 1-(6-ethyl-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)-1,8-naphthidin-2-yl)-N-(tetrahydro-2H-pyran-4-yl)piperidin-4-amine (compound 2)

[0356] Step 1: Synthesis of 1-(2-amino-5-bromopyridin-3-yl)acetone (compound 2-2)

[0357] 2-Amino-3-acetylpyridine (compound 2-1) (10.0 g, 73.52 mmol) was dissolved in anhydrous acetonitrile (80 mL), and N-bromosuccinimide (13.72 g, 73.44 mmol) was added. The mixture was stirred at room temperature for 1 h. Water (100 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (100 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to give the title compound (compound 2-2) (10.0 g, 46.50 mmol, yield 63.25%), MS: m / z = 215.1 [M+H]. + .

[0358] Step 2: Synthesis of 1-(2-amino-5-ethylpyridin-3-yl)acetone (compounds 2-3)

[0359] 1-(2-amino-5-bromopyridin-3-yl) ethyl ketone (compound 2-2) (3.0 g, 13.95 mmol), ethylboronic acid (2.06 g, 27.90 mmol), potassium carbonate (5.78 g, 41.85 mmol), 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride (II) (1.02 g, 1.40 mmol) and water (2.51 g, 139.5 mmol) were added to a reaction flask, followed by 40 mL of 1,4-dioxane. The mixture was heated to 100 °C in an oil bath under nitrogen protection and reacted for 12 h. After the reaction solution was cooled to room temperature, it was filtered through diatomaceous earth. The filter cake was washed with ethyl acetate, and the filtrate was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain the target compounds (compounds 2-3) (1.0 g, 6.09 mmol, yield 43.65%), MS: m / z = 165.1 [M+H]. + .

[0360] Step 3: Synthesis of 5-(2-chloro-6-ethyl-4-methyl-1,8-naphthid-3-yl)-3-methyl-1,2,4-oxadiazole (compounds 2-4)

[0361] 1-(2-amino-5-ethylpyridin-3-yl)acetone (compound 2-3) (700 mg, 4.26 mmol) and 2-(3-methyl-1,2,4-oxadiazol-5-yl)acetic acid (604 mg, 4.26 mmol) were added to a reaction flask, dissolved in phosphorus oxychloride (6 mL), and reacted in an oil bath at 110 °C for 12 h. The reaction mixture was concentrated and extracted at 0 °C with saturated sodium bicarbonate solution (30 mL) and ethyl acetate (30 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to give the title compound (compound 2-4) (250 mg, 0.87 mmol, yield 20.33%), MS: m / z = 289.1 [M+H]. + .

[0362] Step 4: Synthesis of 8-(6-ethyl-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)-1,8-naphthidin-2-yl)-1,4-dioxa-8-azaspiro[4.5]decane (compounds 2-5)

[0363] 5-(2-chloro-6-ethyl-4-methyl-1,8-naphthid-3-yl)-3-methyl-1,2,4-oxadiazole (compound 2-4) (250 mg, 0.87 mmol) was dissolved in N,N-dimethylformamide (4 mL). 4-piperidinone ethylene glycol (124 mg, 0.87 mmol) and N,N-diisopropylethylamine (337.32 mg, 2.61 mmol) were added sequentially with stirring at room temperature. After the additions were complete, the reaction mixture was reacted in an oil bath at 110 °C for 2 h. The reaction solution was cooled to room temperature, and a saturated ammonium chloride solution (50 mL) was added. The mixture was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain the title compound (compound 2-5) (300 mg, 0.76 mmol, yield 87.6%), MS: m / z = 396.2 [M+H]+.

[0364] Step 5: Synthesis of 1-(6-ethyl-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)-1,8-naphthidin-2-yl)piperidin-4-one (compounds 2-6)

[0365] 8-(6-ethyl-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)-1,8-naphthid-2-yl)-1,4-dioxa-8-azaspiro[4.5]decane (compound 2-5) (300 mg, 0.76 mmol) was dissolved in tetrahydrofuran (3 mL), and 3M HCl (2.53 mL, 7.58 mmol) was added. The reaction mixture was reacted at room temperature for 12 h. The reaction solution was concentrated, and water (20 mL) was added. The pH was adjusted to 7-8 with saturated sodium carbonate solution. The mixture was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain the target compound (compound 2-6) (200 mg, 0.57 mmol, yield 75.0%), MS: m / z = 352.2 [M+H]. + .

[0366] Step Six: Synthesis of 1-(6-ethyl-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)-1,8-naphthidin-2-yl)-N-(tetrahydro-2H-pyran-4-yl)piperidin-4-amine (Compound 2)

[0367] 1-(6-ethyl-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)-1,8-naphthidin-2-yl)piperidin-4-one (compound 2-6) (70.0 mg, 0.2 mmol) was dissolved in methanol (3 mL). 4-aminotetrahydropyran (30.2 mg, 0.3 mmol) and sodium cyanoborohydride (37.6 mg, 0.6 mmol) were added sequentially at room temperature, and the reaction was carried out for 12 h at room temperature. The reaction was quenched with saturated sodium carbonate solution (20 mL), extracted with ethyl acetate (20 mL × 3), and the organic phases were combined. The organic phases were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by preparative column chromatography to obtain the target compound (20 mg, 0.046 mmol, yield 22.9%), MS: m / z = 437.3 [M+H]. + .

[0368] 1 H NMR (400MHz, CDCl3) δ8.85(s,1H),8.01(s,1H),3.96(d,J=10.9Hz,2H),3.70(d,J=13.4Hz,2H),3.40(t,J=11.6Hz ,2H),2.92(t,J=11.8Hz,2H),2.86-2.76(m,4H),2.56(s,3H),2.54(s,3H),1.90-1.72(m,4H),1.40-1.27(m,8H).

[0369] Example 3: Synthesis of 1-(6-ethyl-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)-1,8-naphthidin-2-yl)-4-methyl-N-(tetrahydro-2H-pyran-4-yl)piperidin-4-amine (compound 3)

[0370] Step 1: Synthesis of tert-butyl 4-methyl-4-((tetrahydro-2H-pyran-4-yl)amino)piperidine-1-carboxylate (compound 3-2)

[0371] 4-Amino-4-methylpiperidin-1-carboxylic acid tert-butyl ester (compound 3-1) (300 mg, 1.40 mmol) and dihydro-2H-pyran-4(3H)-one (420 mg, 4.20 mmol) were dissolved in anhydrous methanol (4 mL). Tetraisopropyl titanate (796 mg, 2.80 mmol) and sodium cyanoborohydride (176 mg, 2.80 mmol) were added sequentially at 0 °C. After the addition was complete, the mixture was allowed to react at room temperature for 12 h. The reaction solution was filtered through diatomaceous earth, the filter cake was washed with ethyl acetate, the organic phases were combined, concentrated under reduced pressure, and purified by column chromatography to obtain the target compound (compound 3-2) (98 mg, 0.34 mmol, yield 23.94%).

[0372] MS: m / z = 299.4 [M+H] + .

[0373] Step 2: Synthesis of 4-methyl-N-(tetrahydro-2H-pyran-4-yl)piperidine-4-amine hydrochloride (compound 3-3)

[0374] 4-Methyl-4-((tetrahydro-2H-pyran-4-yl)amino)piperidine-1-carboxylic acid tert-butyl ester (compound 3-2) (98 mg, 0.34 mmol) was dissolved in anhydrous dichloromethane (4 mL), and hydrochloric acid / 1,4-dioxane solution (0.5 mL) was added. The mixture was stirred at room temperature for 12 h, and the solution was concentrated under reduced pressure to obtain the target compound (compound 3-3), which was directly used in the next step of the reaction.

[0375] Step 3: Preparation of (6-ethyl-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)-1,8-naphthidin-2-yl)-N-(tetrahydro-2H-pyran-4-yl)piperidin-4-amine (compound 3)

[0376] 5-(2-chloro-6-ethyl-4-methyl-1,8-naphthid-3-yl)-3-methyl-1,2,4-oxadiazole (compound 2-4) (30 mg, 0.10 mmol), 4-methyl-N-(tetrahydro-2H-pyran-4-yl)piperidine-4-amine hydrochloride (compound 3-3) (81.4 mg, 0.30 mmol), and potassium fluoride (12 mg, 0.20 mmol) were dissolved in dimethyl sulfoxide (3 mL). N,N-diisopropylethylamine (64.62 mg, 0.5 mmol) was added, and the mixture was stirred in an oil bath at 120 °C for 12 h. After cooling the reaction solution to room temperature, 30 mL of water was added, and the mixture was extracted with ethyl acetate (30 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by preparative column chromatography to obtain the target compound (compound 3) (15.6 mg, 0.03 mmol, two-step yield 33.32%). MS: m / z = 451.4 [M+H] + .

[0377] 1H NMR (400MHz, CDCl3) δ8.75(d,J=2.3Hz,1H),7.93(d,J=2.2Hz,1H),3.82(t,J =11.1Hz,2H),3.38-3.26(m,4H),3.21-3.11(m,2H),2.74(q,J=7.6Hz,2H),2. 69-2.60(m,1H),2.48(s,3H),2.47(s,3H),1.64-1.56(m,2H),1.47-1.40(m,4 H),1.40-1.31(m,2H),1.26(t,J=7.6Hz,3H),1.21-1.15(m,1H),1.04(s,3H).

[0378] Example 4: Synthesis of 1-(4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)-6-vinyl-1,7-naphthidin-2-yl)-N-(tetrahydro-2H-pyran-4-yl)piperidin-4-amine (compound 4)

[0379] Step 1: Preparation of 5-amino-2-bromo-N-methoxy-N-methylisonicotinamide (compound 4-2)

[0380] 5-Amino-2-bromo-4-pyridinecarboxylic acid (4.0 g, 18.43 mmol) and dimethylhydroxylamine hydrochloride (1.80 g, 18.43 mmol) were dissolved in anhydrous N,N-dimethylformamide (50 mL). Under nitrogen protection, 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (10.51 g, 27.65 mmol) and N,N-diisopropylethylamine (7.13 g, 55.29 mmol) were added sequentially, and the reaction was carried out at room temperature for 16 h. A saturated ammonium chloride solution (500 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (500 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by preparative column chromatography to obtain the target compound (compound 4-2) (4.68 g, 17.99 mmol, yield 97.62%). MS: m / z = 260.4 [M+H] + .

[0381] Step 2: Preparation of 1-(5-amino-2-bromopyridin-4-yl)acetone (compound 4-3)

[0382] 5-Amino-2-bromo-N-methoxy-N-methylisonicotinamide (compound 4-2) (4.68 g, 17.99 mmol) was dissolved in tetrahydrofuran (50 mL), and the solution was cooled to 0 °C. Methyl magnesium bromide solution (7.19 mL, 21.59 mmol) was slowly added dropwise under nitrogen protection. The mixture was then slowly heated to room temperature and reacted for 1 h. Ice water (100 mL) was added to the reaction solution at 0 °C, and the mixture was concentrated and extracted with ethyl acetate (100 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by preparative column chromatography to obtain the target compound (compound 4-3) (2.78 g, 12.93 mmol, yield 71.87%). MS: m / z = 215.5 [M+H] + .

[0383] Step 3: Preparation of 1-(5-amino-2-vinylpyridin-4-yl)ethyl-1-one (compound 4-4)

[0384] 1-(5-amino-2-bromopyridin-4-yl)acetone (compound 4-3) (2.78 g, 12.93 mmol), pinacol vinylborate (2.99 g, 19.39 mmol), potassium carbonate (3.57 g, 25.86 mmol), and 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (1.80 g, 2.46 mmol) were dissolved in 1,4-dioxane (50 mL) and water (10 mL). The reaction mixture was reacted in an oil bath at 100 °C for 16 h under nitrogen protection. After cooling to room temperature, the reaction mixture was filtered through diatomaceous earth. The filter cake was washed with ethyl acetate, the filtrate was concentrated, and water (100 mL) was added. The mixture was extracted with ethyl acetate (100 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by preparative column chromatography to obtain the target compound (compound 4-4) (880 mg, 5.43 mmol, yield 41.99%). MS: m / z = 163.4 [M+H] + .

[0385] Step 4: Preparation of 5-(2-chloro-4-methyl-6-vinyl-1,7-naphthid-3-yl)-3-methyl-1,2,4-oxadiazole (compounds 4-5)

[0386] 1-(5-amino-2-vinylpyridin-4-yl)acetone (compound 4-4) (500 mg, 3.09 mmol) and 2-(3-methyl-1,2,4-oxadiazol-5-yl)acetic acid (438.78 mg, 3.09 mmol) were dissolved in phosphorus oxychloride (10 mL), and the mixture was reacted in an oil bath at 90 °C for 2 h. The reaction solution was concentrated, and saturated sodium bicarbonate solution (30 mL) was added at 0 °C. Extraction was performed with ethyl acetate (30 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to give the title compound (compound 4-5) (505 mg, 1.77 mmol, yield 57.14%). MS: m / z = 287.2 [M+H] + .

[0387] Step 5: Synthesis of 1-(4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)-6-vinyl-1,7-naphthidin-2-yl)-N-(tetrahydro-2H-pyran-4-yl)piperidin-4-amine (compound 4)

[0388] 5-(2-chloro-4-methyl-6-vinyl-1,7-naphthid-3-yl)-3-methyl-1,2,4-oxadiazole (compound 4-5) (100 mg, 349.65 μmol), N-(tetrahydro-2H-pyran-4-yl)piperidin-4-amine (64.27 mg, 349.65 μmol) and potassium fluoride (40.53 mg, 699.30 μmol) were dissolved in dimethyl sulfoxide (2 mL), and N,N-diisopropylethylamine (90.15 mg, 699.30 μmol) was added. The mixture was then stirred in an oil bath at 120 °C for 12 h. After cooling the reaction solution to room temperature, 30 ml of water was added, and the mixture was extracted with ethyl acetate (30 ml x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by preparative column chromatography to obtain the target compound (compound 4) (16.2 mg, 37.28 μmol, yield 10.66%). MS: m / z = 435.6 [M+H] + .

[0389] 1H NMR (400MHz, CDCl3) δ9.16 (s, 1H), 7.57 (s, 1H), 6.93 (dd, J = 17.2, 10.7Hz, 1H), 6.34 (d, J = 17.1Hz, 1H), 5.49(d,J=11.3Hz,1H),4.02(d,J=10.6Hz,2H),3.67(d,J=12.8Hz,2H),3.39(t,J=11.3Hz,2H),3.13(br s,1H),2.89(t,J=12.0Hz,2H),2.57(s,3H),2.50(s,3H),2.12-1.82(m,5H),1.75-1.40(m,5H).

[0390] Example 5: Synthesis of 1-(6-ethyl-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)-1,7-naphthidin-2-yl)-N-(tetrahydro-2H-pyran-4-yl)piperidin-4-amine (compound 5)

[0391] Step 1: Synthesis of 1-(5-amino-2-ethylpyridin-4-yl)acetone (compound 5-1)

[0392] 1-(5-amino-2-vinylpyridin-4-yl)acetone (compound 4-4) (500 mg, 3.08 mmol) was dissolved in anhydrous tetrahydrofuran (5 mL), 100 mg of palladium on carbon was added, and the mixture was purged with hydrogen and reacted at room temperature for 12 hours. The reaction solution was filtered through diatomaceous earth, the filter cake was washed with ethyl acetate, and the filtrate was concentrated and purified by silica gel column chromatography to obtain the target compound (compound 5-1) (282.00 mg, 1.72 mmol, yield: 55.76%). MS: m / z = 165.2 [M+H] + .

[0393] Step 2: Synthesis of 5-(2-chloro-6-ethyl-4-methyl-1,7-naphthid-3-yl)-3-methyl-1,2,4-oxadiazole (compound 5-2)

[0394] 1-(5-amino-2-ethylpyridin-4-yl)acetone (compound 5-1) (282.00 mg, 1.72 mmol) was dissolved in phosphorus oxychloride (4 mL), and 2-(3-methyl-1,2,4-oxadiazol-5-yl)acetic acid (244.43 mg, 1.72 mmol) was added. The mixture was heated to 90 °C for 1 hour under nitrogen protection. The reaction solution was concentrated and added dropwise to a saturated sodium bicarbonate solution under ice bath conditions with vigorous stirring. The mixture was extracted with ethyl acetate (50 mL x 3), and the organic phases were combined. The organic phases were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain the target compound (compound 5-2) (210 mg, 0.73 mmol, yield: 42.28%). MS: m / z = 289.2 [M+H] + .

[0395] Step 3: Synthesis of 1-(6-ethyl-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)-1,7-naphthidin-2-yl)-N-(tetrahydro-2H-pyran-4-yl)piperidin-4-amine (compound 5)

[0396] 5-(2-chloro-6-ethyl-4-methyl-1,7-naphthid-3-yl)-3-methyl-1,2,4-oxadiazole (compound 5-2) (200 mg, 0.68 mmol) was dissolved in dimethyl sulfoxide (2 mL). N-(tetrahydro-2H-pyran-4-yl)piperidin-4-amine (124.6 mg, 0.68 mmol), N,N-diisopropylethylamine (175.77 mg, 1.36 mmol), and potassium fluoride (118.52 mg, 2.04 mmol) were added sequentially to the reaction mixture. The mixture was heated to 120 °C under nitrogen protection and stirred for 12 h. After the reaction solution was cooled to room temperature, a saturated ammonium chloride solution (30 mL) was added, followed by extraction with ethyl acetate (10 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by preparative column chromatography to obtain the title compound (compound 5) (28 mg, 0.06 mmol, yield 9.44%). MS: m / z = 437.6 [M+H] + .

[0397] 1 H NMR (400MHz, CDCl3) δ9.17(s,1H),7.48(s,1H),4.00(d,J=11.4Hz,2H),3.62(d,J=13.3Hz,2H),3.39(t,J=11.3H z,2H),3.05-2.82(m,6H),2.56(s,3H),2.49(s,3H),1.99-1.85(m,4H),1.70-1.44(m,5H),1.39(t,J=7.6Hz,3H).

[0398] Example 6: Synthesis of 2-(6-ethyl-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)-1,8-naphthidin-2-yl)-N-(tetrahydro-2H-pyran-4-yl)-2-azaspiro[3.3]heptane-6-amine (compound 6)

[0399] Step 1: Synthesis of 6-(((tetrahydro-2H-pyran-4-yl)amino)-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (compound 6-2)

[0400] 6-oxo-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (compound 6-1) (210 mg, 1.00 mmol) and tetrahydro-2H-pyran-4-amine (101 mg, 1.00 mmol) were dissolved in anhydrous methanol (4 mL). The mixture was cooled to 0 °C, and 1 drop of trifluoroacetic acid and sodium cyanoborohydride (126 mg, 2.00 mmol) were added. The mixture was stirred at room temperature for 12 h. The reaction solution was filtered through diatomaceous earth, the filter cake was washed with ethyl acetate, the filtrate was concentrated, and 30 mL of water was added. The mixture was extracted with ethyl acetate (30 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain the target compound (compound 6-2) (91.3 mg, 0.31 mmol, yield 30.75%). MS: m / z = 297.4 [M+H] + .

[0401] Step 2: Synthesis of N-(tetrahydro-2H-pyran-4-yl)-2-azaspiro[3.3]heptane-6-amine trifluoroacetate (compound 6-3)

[0402] 6-(((tetrahydro-2H-pyran-4-yl)amino)-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (compound 6-2) (91.3 mg, 0.31 mmol) was dissolved in anhydrous dichloromethane (3 mL), and trifluoroacetic acid (1 mL) was added. The mixture was stirred at room temperature for 2 h. The reaction solution was concentrated under reduced pressure to obtain the target compound (compound 6-3), which was directly used in the next step of the reaction.

[0403] Step 3: Synthesis of 2-(6-ethyl-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)-1,8-naphthid-2-yl)-N-(tetrahydro-2H-pyran-4-yl)-2-azaspiro[3.3]heptane-6-amine (compound 6)

[0404] 5-(2-chloro-6-ethyl-4-methyl-1,8-naphthid-3-yl)-3-methyl-1,2,4-oxadiazole (compound 2-4) (40 mg, 0.14 mmol), N-(tetrahydro-2H-pyran-4-yl)-2-azaspiro[3.3]heptane-6-amine trifluoroacetate (compound 6-3) (118.73 mg, 0.28 mmol), and potassium fluoride (16 mg, 0.28 mmol) were dissolved in dimethyl sulfoxide (1 mL), and N,N-diisopropylethylamine (72.37 mg, 0.56 mmol) was added. The mixture was stirred at 120 °C for 12 h. After cooling the reaction solution to room temperature, 10 mL of saturated ammonium chloride solution was added, and the mixture was extracted with ethyl acetate (10 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by preparative column chromatography to obtain the target compound (compound 6) (18.3 mg, 0.40 mmol, yield 28.97%). MS: m / z = 449.6 [M+H] + .

[0405] 1 H NMR (400MHz, CDCl3) δ8.71 (d, J = 1.3Hz, 1H), 7.89 (s, 1H), 3.98-3.85 (m, 4H), 3.75-3.65 (m, 2H), 3.43-3.25 (m, 3H), 2.78-2.65 (m, 3H), 2 .57-2.48(m,4H),2.46-2.38(m,2H),2.36(s,3H),2.12-1.95(m,2H),1.75(d,J=11.7Hz,2H),1.50-1.34(m,2H),1.26(t,J=7.6Hz,3H).

[0406] Example 7: Synthesis of 2-(6-ethyl-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)-1,8-naphthidin-2-yl)-N-(tetrahydro-2H-pyran-4-yl)-2-azaspiro[3.3]heptane-6-amine (compound 10)

[0407] Step 1: Synthesis of 6-(tetrahydro-2H-pyran-4-yl)-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (compound 10-2)

[0408] 2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (200 mg, 1.00 mmol) and dihydro-2H-pyran-4(3H)-one (101 mg, 1.00 mmol) were dissolved in anhydrous methanol (4 mL). The mixture was cooled to 0 °C, and 1 drop of trifluoroacetic acid and sodium cyanoborohydride (126 mg, 2.00 mmol) were added. The mixture was stirred at room temperature for 12 h. The reaction mixture was monitored by LC-MS to ensure complete reaction of the starting material. The reaction solution was filtered through diatomaceous earth, the filter cake was washed with ethyl acetate, the filtrate was concentrated, and 30 mL of water was added. The mixture was extracted with ethyl acetate (30 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then subjected to column chromatography to obtain the target compound (compound 10-2) (173 mg, 0.61 mmol, yield 67.3%). MS: m / z = 282.4 [M+H] + .

[0409] Step 2: Synthesis of 2-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane trifluoroacetate (compound 10-3)

[0410] 6-(tetrahydro-2H-pyran-4-yl)-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (compound 10-2) (173 mg, 0.61 mmol) was dissolved in anhydrous dichloromethane (3 mL), and trifluoroacetic acid (0.5 mL) was added. The mixture was stirred at room temperature for 2 h. After concentration under reduced pressure, the target compound (compound 10-3) was obtained and used directly in the next step of the reaction.

[0411] Step 3: Preparation of 2-(6-ethyl-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)-1,8-naphthidin-2-yl)-N-(tetrahydro-2H-pyran-4-yl)-2-azaspiro[3.3]heptane-6-amine (compound 10)

[0412] 5-(2-chloro-6-ethyl-4-methyl-1,8-naphthid-3-yl)-3-methyl-1,2,4-oxadiazole (compound 2-4) (40 mg, 0.14 mmol), 2-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane trifluoroacetate (181 mg, 0.61 mmol), and potassium fluoride (16 mg, 0.28 mmol) were dissolved in dimethyl sulfoxide (3 mL). N,N-diisopropylethylamine (116 mg, 0.84 mmol) was added, and the mixture was stirred at 120 °C for 12 h. After the reaction solution was cooled to room temperature, 30 mL of water was added, and the mixture was extracted with ethyl acetate (30 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by preparative column chromatography to obtain the target compound (compound 10) (21 mg, 0.048 mmol). MS: m / z = 435.5 [M+H]+ .

[0413] 1 H NMR(400MHz, CDCl3)δ8.80(s,1H),7.95(s,1H),3.98(s,3H),3.96-3.92(m,1H),3.39-3.24(m,6H), 2.80(q,J=7.6Hz,2H),2.57(s,3H),2.43(s,3H),2.13(m,1H),1.68-1.55(m,4H),1.36-1.22(m,5H).

[0414] Example 8: Synthesis of 2-(6-ethyl-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)-1,8-naphthidin-2-yl)-N-(tetrahydro-2H-pyran-4-yl)-2-azaspiro[3.4]octyl-6-amine (compound 11)

[0415] Step 1: Synthesis of 2-azaspiro[3.4]oct-6-one trifluoroacetate (compound 11-2)

[0416] 6-oxo-2-azaspiro[3.4]octane-2-carboxylic acid tert-butyl ester (compound 11-1) (225 mg, 1.00 mmol) was dissolved in anhydrous dichloromethane (5 mL), and trifluoroacetic acid (1 mL) was added at room temperature. The mixture was stirred at room temperature for 2 h. The reaction solution was concentrated under reduced pressure to obtain the target compound (compound 11-2), which was then used directly in the next step.

[0417] Step 2: Synthesis of 2-(6-ethyl-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)-1,8-naphthidin-2-yl)-2-azaspiro[3.4]octane-6-one (compound 11-3)

[0418] 5-(2-chloro-6-ethyl-4-methyl-1,8-naphthid-3-yl)-3-methyl-1,2,4-oxadiazole (compound 2-4) (115 mg, 0.4 mmol), 2-azaspiro[3.4]oct-6-one trifluoroacetate (compound 11-2) (191 mg, 0.8 mmol), and potassium fluoride (46 mg, 0.80 mmol) were dissolved in dimethyl sulfoxide (3 mL). N,N-diisopropylethylamine (310 mg, 2.40 mmol) was added, and the mixture was stirred at 100 °C for 5 h. After cooling the reaction solution to room temperature, 30 mL of water was added, and the mixture was extracted with ethyl acetate (30 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then subjected to column chromatography to obtain the target compound (compound 11-3) (132 mg, 0.35 mmol). MS: m / z = 378.2 [M+H]+ .

[0419] Step 3: Synthesis of 2-(6-ethyl-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)-1,8-naphthid-2-yl)-N-(tetrahydro-2H-pyran-4-yl)-2-azaspiro[3.4]octyl-6-amine (compound 11)

[0420] 2-(6-ethyl-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)-1,8-naphthidin-2-yl)-2-azaspiro[3,4]octane-6-one (50 mg, 0.13 mmol) and tetrahydro-2H-pyran-4-amine (27 mg, 0.26 mmol) were dissolved in anhydrous methanol (3 mL). After cooling to 0 °C, 1 drop of trifluoroacetic acid and sodium cyanoborohydride (17 mg, 0.26 mmol) were added, and the mixture was stirred at room temperature for 12 h. The reaction solution was filtered through diatomaceous earth, the filter cake was washed with ethyl acetate, the filtrate was concentrated, and 30 mL of water was added. The mixture was extracted with ethyl acetate (30 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by preparative column chromatography to obtain the target compound (compound 11) (0.6 mg, 0.001 mmol). MS: m / z = 463.4 [M+H] + .

[0421] 1 H NMR (400MHz, CDCl3) δ8.78(s,1H),7.94(d,J=1.8Hz,1H),3.96(d,J=10.5H z,2H),3.85-3.70(m,3H),3.37(t,J=11.6Hz,2H),3.33-3.23(m,1H),2.79( q,J=7.6Hz,2H),2.72-2.60(m,1H),2.56(s,3H),2.41(s,3H),2.10(dd,J= 12.9,6.7Hz,1H),2.02-1.72(m,6H),1.70-1.45(m,2H),1.42-1.28(m,6H).

[0422] Example 9: Synthesis of 5-(6-ethyl-4-methyl-2-(7-((tetrahydro-2H-pyran-4-yl)methyl)-2,7-diazaspiro[3.5]non-2-yl)-1,8-naphthid-3-yl)-3-methyl-1,2,4-oxadiazole (compound 12)

[0423] Step 1: Synthesis of 7-((tetrahydro-2H-pyran-4-yl)methyl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (compound 12-2)

[0424] Formic acid (2 mg, 0.044 mmol) was added to a methanol (2 mL) solution of 2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (compound 12-1) (100 mg, 0.44 mmol) and tetrahydropyran-4-carboxaldehyde (50 mg, 0.44 mmol). After stirring at room temperature for 0.5 h, sodium cyanoborohydride (56 mg, 0.88 mmol) was added, and the reaction was stirred at room temperature for 8 h. The reaction solution was filtered through diatomaceous earth, the filter cake was washed with ethyl acetate, the filtrate was concentrated, and 30 mL of water was added. The solution was extracted with ethyl acetate (30 mL x 3). The organic phases were combined and dried over anhydrous sodium sulfate. The organic phase was concentrated and purified by silica gel column chromatography to obtain the target compound (compound 12-2) (118 mg, 0.36 mmol). MS: m / z = 325.5 [M+H] + .

[0425] Step 2: Synthesis of 7-((tetrahydro-2H-pyran-4-yl)methyl)-2,7-diazaspiro[3.5]nonane trifluoroacetate (compound 12-3)

[0426] Trifluoroacetic acid (0.5 mL) was added to a 2 mL solution of 201 mg (0.62 mmol) of 7-(tetrahydropyran-4-ylmethyl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (compound 12-2) in dichloromethane. After the addition was complete, the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure to obtain the target compound (compound 12-3), which was directly used in the next step of the reaction.

[0427] Step 3: Synthesis of 5-(6-ethyl-4-methyl-2-(7-((tetrahydro-2H-pyran-4-yl)methyl)-2,7-diazaspiro[3.5]non-2-yl)-1,8-naphthid-3-yl)-3-methyl-1,2,4-oxadiazole (compound 12)

[0428] 5-(2-chloro-6-ethyl-4-methyl-1,8-naphthid-3-yl)-3-methyl-1,2,4-oxadiazole (compound 2-4) (101 mg, 0.35 mol), 7-(tetrahydropyran-4-ylmethyl)-2,7-diazaspiro[3.5]nonane trifluoroacetate (117 mg, 0.35 mmol), and potassium fluoride (40.08 mg, 0.69 mmol) were dissolved in dimethyl sulfoxide (2 mL). N,N-diisopropylethylamine (178.86 mg, 1.38 mmol) was added, and the mixture was reacted at 115 °C for 4 hours. After cooling to room temperature, 30 mL of water was added, and the mixture was extracted with ethyl acetate (30 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by preparative column chromatography to obtain the target compound (compound 12) (80 mg, 167.85 μmol). MS: m / z = 477.2 [M+H] + .

[0429] 1 H NMR (400MHz, CDCl3) δ8.76(s,1H),7.92(s,1H),3.92(d,J=9.2Hz,2H),3.58(s,4H),3.34(t,J=11.4Hz,2H),2.77(q,J=7.1Hz,2H) ,2.55(s,3H),2.40(s,3H),2.32-2.18(m,4H),2.11(d,J=4.8Hz,2H),1.75-1.58(m,7H),1.31(t,J=7.2Hz,3H),1.25-1.15(m,2H).

[0430] Example 10: Synthesis of 5-(6-ethyl-4-methyl-2-(6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.4]oct-2-yl)-1,8-naphthid-3-yl)-3-methyl-1,2,4-oxadiazole (compound 14)

[0431] Step 1: Synthesis of 6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.4]octane-2-carboxylic acid tert-butyl ester (compound 14-2)

[0432] Formic acid (2 mg, 0.047 mmol) was added to a methanol (3 mL) solution of 2,7-diazaspiro[3.4]octane-2-carboxylic acid tert-butyl ester (compound 14-1) (100 mg, 471.06 μmol) and tetrahydropyran-4-one (94 mg, 0.94 mmol). After stirring at room temperature for 0.5 h, sodium cyanoborohydride (89 mg, 1.41 mmol) was added, and the reaction was stirred at room temperature for 12 h. The reaction solution was filtered through diatomaceous earth, the filter cake was washed with ethyl acetate, the filtrate was concentrated, and 30 mL of water was added. The solution was extracted with ethyl acetate (30 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, and the organic phase was concentrated and purified by silica gel column chromatography to obtain the target compound (compound 14-2) (89 mg, 0.3 mmol). MS: m / z = 297.5 [M+H] + .

[0433] Step 2: Synthesis of 6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.4]octane trifluoroacetate (compound 14-3)

[0434] Trifluoroacetic acid (0.5 mL) was added to a 2 mL solution of 7-tetrahydropyran-4-yl-2,7-diazaspiro[3.4]octane-2-carboxylic acid tert-butyl ester (compound 14-2) (89 mg, 0.3 mmol) in dichloromethane. After the addition was complete, the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure to obtain the target compound (compound 14-3), which was directly used in the next step of the reaction.

[0435] Step 3: Preparation of 5-(6-ethyl-4-methyl-2-(6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.4]oct-2-yl)-1,8-naphthid-3-yl)-3-methyl-1,2,4-oxadiazole (compound 14)

[0436] To a solution of 5-(2-chloro-6-ethyl-4-methyl-1,8-naphthid-3-yl)-3-methyl-1,2,4-oxadiazole (43 mg, 0.15 mmol) and 6-tetrahydropyran-4-yl-2,6-diazaspiro[3.4]octanetrifluoroacetate (93 mg, 0.3 mmol) in dimethyl sulfoxide (2 mL), potassium fluoride (17.5 mg, 0.3 mmol) and N,N-diisopropylethylamine (77.5 mg, 0.6 mmol) were added. After the addition was complete, the reaction mixture was reacted at 115 °C for 4 hours. After the reaction mixture was cooled to room temperature, 30 mL of water was added, and the mixture was extracted with ethyl acetate (30 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by preparative column chromatography to obtain the target compound (compound 14) (18 mg, 0.04 mmol). MS: m / z = 449.3 [M+H] + .

[0437] 1 H NMR (400MHz, CDCl3) δ8.78(d,J=2.3Hz,1H),7.93(d,J=2.1Hz,1H),3.95(d, J=9.7Hz,2H),3.83(s,4H),3.40-3.31(m,2H),2.82-2.75(m,4H),2.59(t,J =7.0Hz,2H),2.55(s,3H),2.41(s,3H),2.18(t,J=10.7Hz,1H),2.03(t,J=7 .0Hz,2H),1.74(d,J=11.2Hz,2H),1.58-1.46(m,2H),1.32(t,J=7.6Hz,3H).

[0438] Example 11: Synthesis of 8-(6-ethyl-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)-1,7-naphthidin-2-yl)-N-(tetrahydro-2H-pyran-4-yl)-8-azabicyclo[3.2.1]octyl-3-amine (compound 18)

[0439] Step 1: Synthesis of 3-(((tetrahydro-2H-pyran-4-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (compound 18-2)

[0440] A methanol (10 mL) solution of 3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (compound 18-1) (1 g, 4.44 mmol) and tetrahydro-2H-pyran-4-amine (898.2 mg, 8.88 mmol) was reacted with trifluoroacetic acid (51 mg, 0.44 mmol) at room temperature for 0.5 h, followed by the addition of sodium cyanoborohydride (335 mg, 5.33 mmol) and stirring at room temperature for 8 h. The reaction mixture was filtered through diatomaceous earth, the filter cake was washed with ethyl acetate, the filtrate was concentrated, and 100 mL of water was added. The mixture was extracted with ethyl acetate (100 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography to obtain the target compound (compound 18-2) (0.68 g, 2.19 mmol). MS: m / z = 311.4 [M+H] + .

[0441] Step 2: Synthesis of N-(tetrahydro-2H-pyran-4-yl)-8-azabicyclo[3.2.1]oct-3-amine trifluoroacetate (compound 18-3)

[0442] A solution of 500 mg (1.61 mmol) of tert-butyl 3-(tetrahydropyran-4-ylamino)-8-azabicyclo[3.2.1]octane-8-carboxylic acid (compound 18-2) in dichloromethane (5 mL) was added to trifluoroacetic acid (2.5 mL). After the addition was complete, the mixture was stirred at room temperature for 4 hours. The reaction solution was concentrated to obtain the target compound (compound 18-3), which was directly used in the next step of the reaction.

[0443] Step 3: Synthesis of 8-(6-ethyl-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)-1,7-naphthid-2-yl)-N-(tetrahydro-2H-pyran-4-yl)-8-azabicyclo[3.2.1]octyl-3-amine (compound 18)

[0444] To a solution of 5-(2-chloro-6-ethyl-4-methyl-1,8-naphthid-3-yl)-3-methyl-1,2,4-oxadiazole (compound 2-4) (50 mg, 0.17 mmol) and N-tetrahydropyran-4-yl-8-azabicyclo[3.2.1]octyl-3-amine trifluoroacetate (compound 18-3) (76 mg, 0.17 mmol) in dimethyl sulfoxide (2.0 mL), potassium fluoride (20 mg, 0.34 mmol) and N,N-diisopropylethylamine (67 mg, 0.52 mmol) were added. After the addition was complete, the mixture was stirred at 115 °C for 8 hours. After the reaction solution was cooled to room temperature, 30 mL of water was added, and the mixture was extracted with ethyl acetate (30 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by preparative column chromatography to obtain the target compound (compound 18) (18 mg, 0.39 mmol). MS: m / z = 463.5 [M+H] + .

[0445] 1 H NMR (400MHz, CDCl3) δ8.81 (d, J = 2.1Hz, 1H), 7.97 (s, 1H), 4.10 (s, 2H), 3.94 (s, 2H), 3.40-3.32 (m, 2H), 3.20-3.07 (m, 1H), 2 .86-2.76(m,3H),2.57(s,3H),2.47(s,3H),2.30-2.15(m,2H),2.01-1.75(m,7H),1.65-1.62(m,4H),1.33(t,J=7.6Hz,3H).

[0446] Example 12: Synthesis of 1-(6-ethyl-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)-1,7-naphthid-2-yl)-N-(tetrahydro-2H-pyran-4-yl)azacycloheptane-4-amine (compound 20)

[0447] Step 1: Synthesis of 4-((tetrahydro-2H-pyran-4-yl)amino)azacycloheptan-1-carboxylic acid tert-butyl ester (compound 20-2)

[0448] A solution of tert-butyl 4-oxozyracycloheptan-1-carboxylate (compound 20-1) (1.07 g, 5.0 mmol) and tetrahydro-2H-pyran-4-amine (1.01 g, 10.0 mmol) in dichloromethane (15 mL) was reacted with acetic acid (120 mg, 5.0 mmol) at room temperature for 0.5 h, followed by the addition of sodium cyanoborohydride (628 mg, 10.0 mmol) and stirring at room temperature for 12 h. The reaction mixture was filtered through diatomaceous earth, the filter cake was washed with dichloromethane, the filtrate was concentrated, and 30 mL of water was added. The mixture was extracted with ethyl acetate (40 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain the target compound (compound 20-2) (0.9 g, 3.02 mmol). MS: m / z = 299.4 [M+H] + .

[0449] Step 2: Synthesis of N-(tetrahydro-2H-pyran-4-yl)azacycloheptan-4-amine hydrochloride (compound 20-3)

[0450] Hydrochloric acid / 1,4-dioxane (12.08 mmol, 3.02 mL) was added to a solution of 0.9 g (3.02 mmol) of 4-((tetrahydro-2H-pyran-4-yl)amino)azacycloheptan-1-carboxylic acid tert-butyl ester (compound 20-2) in dichloromethane (10 mL). After the addition was complete, the mixture was stirred at room temperature for 4 hours. The reaction solution was concentrated to obtain the target compound (compound 20-3), which was directly used in the next step of the reaction.

[0451] Step 3: Synthesis of 1-(6-ethyl-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)-1,7-naphthid-2-yl)-N-(tetrahydro-2H-pyran-4-yl)azacycloheptane-4-amine (compound 20)

[0452] Potassium fluoride (12.88 mg, 0.22 mmol) and N,N-diisopropylethylamine (57.30 mg, 0.44 mmol) were added to a solution of 5-(2-chloro-6-ethyl-4-methyl-1,8-naphthid-3-yl)-3-methyl-1,2,4-oxadiazole (compound 2-4) (32 mg, 0.11 mmol) and N-(tetrahydro-2H-pyran-4-yl)azacycloheptane-4-amine hydrochloride (compound 20-3) (60.12 mg, 0.22 mmol) in dimethyl sulfoxide (1.0 mL). After the addition was complete, the mixture was stirred at 115 °C for 12 hours. After the reaction solution was cooled to room temperature, 30 mL of water was added, and the mixture was extracted with ethyl acetate (30 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by preparative column chromatography to obtain the target compound (compound 20) (15 mg, 0.033 mmol). MS: m / z = 451.5 [M+H] + .

[0453] 1 H NMR (400MHz, CDCl3) δ8.80(d,J=1.9Hz,1H),7.95(d,J=1.5Hz,1H),3.93(d,J=10.8Hz,2H),3.72-3.64(m,1H),3.47-3.27(m,4H),3.24-3 .14(m,1H),2.80(q,J=7.4Hz,3H),2.74-2.66(m,1H),2.54(s,3H),2.46(s,3H),2.02-1.93(m,1H),1.80-1.65(m,6H),1.39-1.30(m,7H).

[0454] Example 13: Synthesis of 1-(6-ethyl-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)-1,8-naphthidin-2-yl)-3,3-difluoro-N-(tetrahydro-2H-pyran-4-yl)piperidin-4-amine (compound 23)

[0455] Step 1: Synthesis of tert-butyl 3,3-difluoro-4-((tetrahydro-2H-pyran-4-yl)amino)piperidine-1-carboxylate (compound 23-2)

[0456] 4-Aminotetrahydropyran (1.29 g, 12.8 mmol) and tert-butyl 3,3-difluoro-4-oxopiperidin-1-carboxylate (compound 23-1) (300 mg, 1.28 mmol) were dissolved in anhydrous methanol (20 mL). Tetraisopropyl titanate (1.09 g, 3.83 mmol) and sodium cyanoborohydride (160 mg, 2.55 mmol) were added sequentially, and the mixture was stirred at 85 °C for 12 h. After cooling to room temperature, the reaction mixture was filtered through diatomaceous earth. The filter cake was washed with ethyl acetate, and the filtrate was concentrated. 50 mL of water was added, and the mixture was extracted with ethyl acetate (50 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and then subjected to column chromatography to obtain the target compound (compound 23-2) (250 mg, 0.78 mmol). MS: m / z = 321.4 [M+H] + .

[0457] Step 2: Synthesis of 3,3-difluoro-N-(tetrahydro-2H-pyran-4-yl)piperidine-4-amine hydrochloride (compound 23-3)

[0458] 3,3-Difluoro-4-((tetrahydro-2H-pyran-4-yl)amino)piperidine-1-carboxylic acid tert-butyl ester (compound 23-2) (200 mg, 0.64 mmol) was dissolved in anhydrous dichloromethane (3 mL), and hydrochloric acid / dioxane (4 mmol, 1 mL) was added. The mixture was stirred at room temperature for 2 h. The reaction solution was concentrated under reduced pressure to obtain the target compound (compound 23-3), which was directly used in the next step of the reaction.

[0459] Step 3: Synthesis of 1-(6-ethyl-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)-1,8-naphthidin-2-yl)-3,3-difluoro-N-(tetrahydro-2H-pyran-4-yl)piperidin-4-amine (compound 23)

[0460] 5-(2-chloro-6-ethyl-4-methyl-1,8-naphthid-3-yl)-3-methyl-1,2,4-oxadiazole (121 mg, 0.42 mmol), 3,3-difluoro-N-(tetrahydro-2H-pyran-4-yl)piperidine-4-amine hydrochloride (246 mg, 0.84 mmol), and potassium fluoride (98 mg, 1.68 mmol) were dissolved in dimethyl sulfoxide (3 mL), and N,N-diisopropylethylamine (326 mg, 2.52 mmol) was added. The mixture was stirred at 90 °C for 12 h. After cooling the reaction solution to room temperature, 30 mL of water was added, and the mixture was extracted with ethyl acetate (30 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by preparative column chromatography to obtain the target compound (compound 23) (33.0 mg, 0.07 mmol). MS: m / z = 473.2 [M+H] + .

[0461] 1 H NMR(400MHz, CDCl3)δ8.90(d,J=2.2Hz,1H),8.06(d,J=2.1Hz,1H),4.01-3.84(m,3H),3 .62(d,J=13.8Hz,1H),3.39(dt,J=11.5,5.8Hz,2H),3.26-3.12(m,1H),3.11-3.00(m,2 H),2.99-2.90(m,1H),2.86(q,J=7.6Hz,2H),2.56(s,3H),2.55(s,3H),2.02-1.91(m,1 H),1.82(t,J=11.2Hz,2H),1.70-1.58(m,2H),1.47-1.38(m,2H),1.36(t,J=7.6Hz,3H).

[0462] Example 14: Synthesis of 1-(6-ethyl-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)-1,8-naphthidin-2-yl)-3,3-dimethyl-N-(tetrahydro-2H-pyran-4-yl)piperidin-4-amine (compound 24)

[0463] Step 1: Synthesis of tert-butyl 3,3-dimethyl-4-((tetrahydro-2H-pyran-4-yl)amino)piperidine-1-carboxylate (compound 24-2)

[0464] 4-Aminotetrahydropyran (1.33 g, 13.2 mmol) and tert-butyl 3,3-dimethyl-4-oxopiperidin-1-carboxylate (compound 24-1) (300 mg, 1.32 mmol) were dissolved in anhydrous methanol (20 mL). Tetraisopropyl titanate (1.13 g, 3.96 mmol) and sodium cyanoborohydride (165 mg, 2.64 mmol) were added, and the mixture was stirred at 85 °C for 12 h. After cooling to room temperature, the reaction solution was filtered through diatomaceous earth, the filter cake was washed with ethyl acetate, the filtrate was concentrated, and 30 mL of water was added. The mixture was extracted with ethyl acetate (30 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain the target compound (compound 24-2) (300 mg, 0.96 mmol). MS: m / z = 313.2 [M+H] + .

[0465] Step 2: Synthesis of 3,3-dimethyl-N-(tetrahydro-2H-pyran-4-yl)piperidine-4-amine acid (compound 24-3)

[0466] 3,3-Dimethyl-4-((tetrahydro-2H-pyran-4-yl)amino)piperidine-1-carboxylic acid tert-butyl ester (compound 24-2) (300 mg, 0.96 mmol) was dissolved in anhydrous dichloromethane (3 mL), and hydrochloric acid / 1,4-dioxane (4 mmol, 1 mL) was added. The mixture was stirred at room temperature for 2 h. The reaction solution was concentrated under reduced pressure to obtain the target compound (compound 24-3), which was directly used in the next step of the reaction.

[0467] Step 3: Synthesis of 1-(6-ethyl-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)-1,8-naphthidin-2-yl)-3,3-dimethyl-N-(tetrahydro-2H-pyran-4-yl)piperidin-4-amine (compound 24)

[0468] 5-(2-chloro-6-ethyl-4-methyl-1,8-naphthid-3-yl)-3-methyl-1,2,4-oxadiazole (80 mg, 0.28 mmol), 3,3-dimethyl-N-(tetrahydro-2H-pyran-4-yl)piperidine-4-amine hydrochloride (160 mg, 0.56 mmol), and potassium fluoride (65 mg, 1.12 mmol) were dissolved in dimethyl sulfoxide (3 mL), and N,N-diisopropylethylamine (217 mg, 1.68 mmol) was added. The mixture was stirred at 100 °C for 12 h. After cooling the reaction solution to room temperature, 40 mL of water was added, and the mixture was extracted with ethyl acetate (40 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by preparative column chromatography to obtain the target compound (compound 24) (20.0 mg, 0.07 mmol). MS: m / z = 465.2 [M+H] + .

[0469] 1 H NMR (400MHz, CDCl3) δ8.89(d,J=2.1Hz,1H),8.05(d,J=2.0Hz,1H),3.99(d,J=11.4Hz,2H),3.67-3.49(m,2H),3.49-3.34(m,2H),2.94-2.8 1(m,3H),2.78-2.64(m,2H),2.60(s,3H),2.55(s,3H),2.38-2.27(m, 1H),1.91-1.69(m,3H),1.52-1.28(m,7H),0.96(s,3H),0.83(s,3H).

[0470] Example 15: Synthesis of N-(4-(6-ethyl-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)-1,8-naphthidin-2-yl)cyclohex-3-en-1-yl)tetrahydro-2H-pyran-4-amine (compound 34)

[0471] Step 1: Synthesis of tert-butyl carbamate (compound 34-1)

[0472] Pd(dppf)Cl2 (152 mg, 0.21 mmol) and potassium carbonate (287 mg, 2.08 mmol) were added to a mixed solution of 5-(2-chloro-6-ethyl-4-methyl-1,8-naphthid-3-yl)-3-methyl-1,2,4-oxadiazole (compound 2-4) (300 mg, 1.04 mmol), (4-((tert-butoxycarbonyl)amino)cyclohexyl-1-en-1-yl)boronic acid (376 mg, 1.56 mmol) in 1,4-dioxane (2.0 mL) and water (0.4 mL). The mixture was reacted in an oil bath at 100 °C for 4 hours under nitrogen protection. After the reaction solution was cooled to room temperature, it was filtered through diatomaceous earth. The filter cake was washed with ethyl acetate, and the filtrate was concentrated. After concentration, 30 mL of water was added, and the mixture was extracted with ethyl acetate (30 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain the target compound (193 mg, 0.43 mmol). MS: m / z = 450.4 [M+H] + .

[0473] Step 2: Synthesis of 4-(6-ethyl-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)-1,8-naphthid-2-yl)cyclohexyl-3-en-1-amine trifluoroacetate (compound 34-2)

[0474] TFA (0.5 mL) was added to a solution of N-[4-[6-ethyl-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)-1,8-naphthid-2-yl]cyclohex-3-en-1-yl]tert-butyl carbamate (121 mg, 0.27 mol) in dichloromethane (2 mL), and the mixture was stirred at room temperature for 8 hours. The reaction solution was concentrated under reduced pressure to obtain the target compound (compound 34-2), which was directly used in the next step of the reaction.

[0475] Step 3: Synthesis of N-(4-(6-ethyl-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)-1,8-naphthidin-2-yl)cyclohexyl-3-en-1-yl)tetrahydro-2H-pyran-4-amine (compound 34)

[0476] 0.1 mL of formic acid was added to a methanol (2 mL) solution of 4-[6-ethyl-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)-1,8-naphthid-2-yl]cyclohexyl-3-en-1-amine trifluoroacetate (65 mg, 0.14 mmol) and tetrahydropyran-4-one (14 mg, 0.14 mmol). The mixture was stirred at room temperature for 0.5 h, followed by the addition of sodium cyanoborohydride (18 mg, 0.29 mmol). After the addition was complete, the mixture was stirred at room temperature for 8 h. 30 mL of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by preparative column chromatography to obtain the target compound (compound 34) (36 mg, 0.083 mmol). MS: m / z = 434.3 [M+H] + .

[0477] 1 H NMR(400MHz, CDCl3) δ9.05(d,J=2.3Hz,1H),8.17(d,J=2.3Hz,1H),5.58(s, 1H),3.99(d,J=10.4Hz,2H),3.41(t,J=11.5Hz,2H),3.06-2.99(m,1H),2.9 6-2.84(m,3H),2.73-2.60(m,5H),2.53(s,3H),2.31(d,J=18.0Hz,1H),2.0 1-1.79(m,5H),1.67-1.57(m,2H),1.48-1.43(m,1H),1.39(t,J=7.6Hz,3H).

[0478] Example 16: Synthesis of N-(4-(6-ethyl-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)-1,8-naphthidin-2-yl)cyclohex-3-en-1-yl)tetrahydro-2H-pyran-4-amine (compound 35)

[0479] Step 1: Synthesis of tert-butyl 4-(spiro[2.5]oct-6-ylamino)piperidine-1-carboxylate (compound 35-2)

[0480] Spiro[2.5]octyl-6-amine (400 mg, 3.2 mmol) and tert-butyl 4-oxopiperidinium-1-carboxylate (636 mg, 3.2 mmol) were dissolved in anhydrous methanol (6 mL), and acetic acid (1 drop) and sodium cyanoborohydride (400 mg, 6.4 mmol) were added. The mixture was stirred at room temperature for 12 h. The reaction solution was filtered through diatomaceous earth, the filter cake was washed with ethyl acetate, the filtrate was concentrated, and 30 mL of water was added. The solution was extracted with ethyl acetate (30 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then subjected to column chromatography to obtain the target compound (compound 35-2) (300 mg, 0.5 mmol). MS: m / z = 309.3 [M+H] + .

[0481] Step 2: Synthesis of N-(spiro[2.5]oct-6-yl)piperidine-4-amine hydrochloride (compound 35-3)

[0482] 300 mg (0.5 mmol) of tert-butyl 4-(spiro[2.5]oct-6-ylamino)piperidine-1-carboxylate (compound 35-2) was dissolved in anhydrous dichloromethane (3 mL), and hydrochloric acid / 1,4-dioxane (5 mmol, 1.25 mL) was added. The mixture was stirred at room temperature for 2 h. The reaction solution was concentrated under reduced pressure to obtain the target compound (compound 35-3), which was directly used in the next step of the reaction.

[0483] Step 3: Synthesis of 1-(6-ethyl-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)-1,8-naphthidin-2-yl)-N-(spiro[2.5]oct-6-yl)piperidine-4-amine (compound 35)

[0484] 5-(2-chloro-6-ethyl-4-methyl-1,8-naphthid-3-yl)-3-methyl-1,2,4-oxadiazole (compound 2-4) (124 mg, 0.43 mmol), N-(spiro[2.5]oct-6-yl)piperidine-4-amine hydrochloride (121 mg, 0.43 mmol), and potassium fluoride (100 mg, 1.72 mmol) were dissolved in dimethyl sulfoxide (3 mL), and N,N-diisopropylethylamine (333 mg, 2.58 mmol) was added. The mixture was stirred at 90 °C for 12 h. After cooling the reaction solution to room temperature, 30 mL of water was added, and the mixture was extracted with ethyl acetate (30 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by preparative column chromatography to obtain the target compound (compound 35) (10.0 mg, 0.02 mmol). MS: m / z = 461.3 [M+H] + .

[0485] 1H NMR (400MHz, CDCl3) δ8.85(d,J=2.2Hz,1H),8.00(d,J=2.1Hz,1H),3.72(d,J=13.3Hz,2H),2.95-2.78(m,5H),2.76-2. 67(m,1H),2.55(s,3H),2.53(s,3H),1.97-1.81(m,4H),1.73-1.66(m,3H),1.37-1.27(m,7H),0.96-0.88(m,2H),0.32 -0.24(m,2H),0.23-0.15(m,2H).

[0486] Example 17: Synthesis of N-(4-(difluoromethylene)cyclohexyl)-1-(6-ethyl-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)-1,8-naphthidin-2-yl)piperidine-4-amine (compound 36)

[0487] Step 1: Synthesis of tert-butyl 4-((4-(difluoromethylene)cyclohexyl)amino)piperidine-1-carboxylate (compound 36-2)

[0488] 4-(difluoromethylene)cyclohexyl-1-amine (compound 36-1) (600 mg, 4.08 mmol) and tert-butyl 4-oxopiperidin-1-carboxylate (810 mg, 4.08 mmol) were dissolved in anhydrous methanol (6 mL), and acetic acid (1 drop) and sodium triacetylborohydride (1.73 g, 8.16 mmol) were added. The mixture was stirred at room temperature for 12 h. The reaction solution was filtered through diatomaceous earth, the filter cake was washed with ethyl acetate, the filtrate was concentrated, and 50 mL of water was added. The mixture was extracted with ethyl acetate (50 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and then subjected to column chromatography to obtain the target compound (compound 36-2) (120 mg, 0.36 mmol). MS: m / z = 331.2 [M+H] + .

[0489] Step 2: Synthesis of N-(4-(difluoromethylene)cyclohexyl)piperidine-4-amine hydrochloride (compound 36-3)

[0490] 4-((4-(difluoromethylene)cyclohexyl)amino)piperidine-1-carboxylic acid tert-butyl ester (compound 36-2) (120 mg, 0.36 mmol) was dissolved in anhydrous dichloromethane (2 mL), and hydrochloric acid / 1,4-dioxane (3.6 mmol, 0.9 mL) was added. The mixture was stirred at room temperature for 2 h. The reaction solution was concentrated under reduced pressure to obtain the target compound (compound 36-3), which was directly used in the next step of the reaction.

[0491] Step 3: Synthesis of N-(4-(difluoromethylene)cyclohexyl)-1-(6-ethyl-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)-1,8-naphthidin-2-yl)piperidine-4-amine (compound 36)

[0492] 5-(2-chloro-6-ethyl-4-methyl-1,8-naphthid-3-yl)-3-methyl-1,2,4-oxadiazole (compound 2-4) (80 mg, 0.28 mmol), N-(4-(difluoromethylene)cyclohexyl)piperidine-4-amine hydrochloride (85 mg, 0.28 mmol), and potassium fluoride (65 mg, 1.12 mmol) were dissolved in dimethyl sulfoxide (3 mL), and N,N-diisopropylethylamine (217 mg, 1.68 mmol) was added. The mixture was stirred at 90 °C for 12 h. After cooling the reaction solution to room temperature, 30 mL of water was added, and the mixture was extracted with ethyl acetate (30 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by preparative column chromatography to obtain the target compound (compound 36) (24.0 mg, 0.05 mmol). MS: m / z = 483.2 [M+H] + .

[0493] 1 H NMR (400MHz, CDCl3) δ8.84(d,J=2.0Hz,1H),8.00(d,J=1.5Hz,1H),3.69(d,J=13.4Hz,2H),2.96-2.86(m,2H),2.82(q,J=7.6Hz ,2H),2.77-2.66(m,2H),2.55(s,3H),2.53(s,3H),2.48-2.37(m,2H),1.93-1.78(m,6H),1.37-1.24(m,6H),1.19-1.06(m,2H).

[0494] Example 18: Synthesis of N-(adamantane-1-yl)-1-(6-ethyl-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)-1,8-naphthidin-2-yl)piperidine-4-amine (compound 37)

[0495] Step 1: Synthesis of tert-butyl 4-(adamantane-1-ylamino)piperidine-1-carboxylate (compound 37-2)

[0496] Amantadine (compound 37-1) (296 mg, 1.96 mmol) and tert-butyl 4-oxopiperidinium-1-carboxylate (300 mg, 1.51 mmol) were dissolved in anhydrous methanol (6 mL). Tetraisopropyl titanate (1.28 g, 4.52 mmol) and sodium cyanoborohydride (189 mg, 3.01 mmol) were added, and the mixture was stirred at 85 °C for 12 h. After cooling to room temperature, the reaction solution was filtered through diatomaceous earth. The filter cake was washed with ethyl acetate, and the filtrate was concentrated. 30 mL of water was added, and the mixture was extracted with ethyl acetate (30 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then subjected to column chromatography to obtain the target compound (compound 37-2) (125 mg, 0.37 mmol). MS: m / z = 335.2 [M+H] + .

[0497] Step 2: Synthesis of N-(adamantane-1-yl)piperidine-4-amine hydrochloride (compound 37-3)

[0498] 4-(adamantane-1-ylamino)piperidine-1-carboxylic acid tert-butyl ester (compound 37-2) (125 mg, 0.37 mmol) was dissolved in anhydrous dichloromethane (3 mL), and hydrochloric acid / 1,4-dioxane (4 mmol, 1 mL) was added. The mixture was stirred at room temperature for 2 h. The reaction solution was concentrated under reduced pressure to obtain the target compound (compound 37-3), which was directly used in the next step of the reaction.

[0499] Step 3: Synthesis of N-(adamantane-1-yl)-1-(6-ethyl-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)-1,8-naphthidin-2-yl)piperidine-4-amine (compound 37)

[0500] 5-(2-chloro-6-ethyl-4-methyl-1,8-naphthid-3-yl)-3-methyl-1,2,4-oxadiazole (compound 2-4) (50 mg, 0.17 mmol), N-(adamantane-1-yl)piperidin-4-amine hydrochloride (105 mg, 0.34 mmol), and potassium fluoride (40.2 mg, 0.69 mmol) were dissolved in dimethyl sulfoxide (2 mL), and N,N-diisopropylethylamine (131.8 mg, 1.02 mmol) was added. The mixture was stirred at 90 °C for 12 h. After cooling the reaction solution to room temperature, 30 mL of water was added, and the mixture was extracted with ethyl acetate (30 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by preparative column chromatography to obtain the target compound (compound 37) (4.9 mg, 0.01 mmol). MS: m / z = 487.3 [M+H] + .

[0501] 1H NMR (400MHz, CDCl3) δ8.84(d,J=2.3Hz,1H),7.99(d,J=2.2Hz,1H),3.66(d,J=13.4Hz,2H),2.91(t,J=11.8Hz,2 H),2.82(q,J=7.6Hz,3H),2.55(s,3H),2.51(s,3H),2.08-2.02(m,3H),1.77-1.55(m,15H),1.42-1.30(m,5H).

[0502] Example 19: Synthesis of 5-(6-ethyl-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)-1,8-naphthidin-2-yl)-N-(tetrahydro-2H-pyran-4-yl)-5-azaspiro[2.5]octane-8-amine (compound 39)

[0503] Step 1: Synthesis of 8-(((tetrahydro-2H-pyran-4-yl)amino)-5-azaspiro[2.5]octane-5-carboxylic acid tert-butyl ester (compound 39-2)

[0504] 8-oxo-5-azaspiro[2.5]octane-5-carboxylic acid tert-butyl ester (compound 39-1) (200 mg, 0.88 mmol) and 4-aminotetrahydropyran (135 mg, 1.33 mmol) were dissolved in anhydrous methanol (4 mL), and tetraisopropyl titanate (505 mg, 1.78 mmol) and sodium cyanoborohydride (167 mg, 2.66 mmol) were added. The mixture was stirred at 85 °C for 12 h. After cooling to room temperature, the reaction solution was filtered through diatomaceous earth. The filter cake was washed with ethyl acetate, and the filtrate was concentrated. 30 mL of water was added, and the mixture was extracted with ethyl acetate (30 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then subjected to column chromatography to obtain the target compound (compound 39-2) (140 mg, 0.45 mmol). MS: m / z = 311.3 [M+H] + .

[0505] Step 2: Synthesis of N-(tetrahydro-2H-pyran-4-yl)-5-azaspiro[2.5]octane-8-amine hydrochloride (compound 39-3)

[0506] 8-(((tetrahydro-2H-pyran-4-yl)amino)-5-azaspiro[2.5]octane-5-carboxylic acid tert-butyl ester (140 mg, 0.45 mmol) was dissolved in anhydrous dichloromethane (3 mL), and hydrochloric acid / 1,4-dioxane (4.5 mmol, 1.1 mL) was added. The mixture was stirred at room temperature for 2 h. The reaction solution was concentrated under reduced pressure to obtain the target compound (compound 39-3), which was directly used in the next step of the reaction.

[0507] Step 3: Synthesis of 5-(6-ethyl-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)-1,8-naphthidin-2-yl)-N-(tetrahydro-2H-pyran-4-yl)-5-azaspiro[2.5]octane-8-amine (compound 39)

[0508] 5-(2-chloro-6-ethyl-4-methyl-1,8-naphthid-3-yl)-3-methyl-1,2,4-oxadiazole (compound 2-4) (70 mg, 0.24 mmol), N-(tetrahydro-2H-pyran-4-yl)-5-azaspiro[2.5]octane-8-amine hydrochloride (127 mg, 0.45 mmol), and potassium fluoride (56 mg, 0.97 mmol) were dissolved in dimethyl sulfoxide (2 mL), and N,N-diisopropylethylamine (188 mg, 1.45 mmol) was added. The mixture was stirred at 90 °C for 12 h. After cooling the reaction solution to room temperature, 30 mL of water was added, and the mixture was extracted with ethyl acetate (30 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by preparative column chromatography to obtain the target compound (compound 39) (10.0 mg, 0.022 mmol). MS: m / z = 463.3 [M+H] + .

[0509] 1 H NMR (400MHz, CDCl3) δ8.83(d,J=2.2Hz,1H),7.98(d,J=2.1Hz,1H),3.94(d,J=11.5Hz,2H),3.59-3.43(m,2H),3.41-3.28(m,3H),2.87-2 .79(m,3H),2.72-2.62(m,1H),2.55(s,3H),2.50(s,3H),2.41-2.32(m,1H),1.95-1.49(m,7H),1.33(t,J=7.6Hz,3H),0.40-0.25(m,4H).

[0510] Example 20: Synthesis of 5-(6-ethyl-4-methyl-2-(7-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[3.5]non-2-yl)-1,8-naphthid-3-yl)-3-methyl-1,2,4-oxadiazole (compound 44)

[0511] Step 1: Synthesis of 7-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (compound 44-2)

[0512] Formic acid (0.1 mL) was added to a methanol (2 mL) solution of 2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (compound 44-1) (100 mg, 0.44 mmol) and tetrahydropyran-4-one (44 mg, 0.44 mmol). After stirring at room temperature for 0.5 h, sodium cyanoborohydride (56 mg, 0.88 mmol) was added, and the mixture was stirred at room temperature for 8 h after the addition was complete. The reaction solution was filtered through diatomaceous earth, the filter cake was washed with ethyl acetate, the filtrate was concentrated, and 30 mL of water was added. The solution was extracted with ethyl acetate (30 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then subjected to column chromatography to obtain the target compound (compound 44-2) (110 mg, 0.35 mmol). MS: m / z = 311.4 [M+H] + .

[0513] Step 2: Synthesis of 7-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[3.5]nonane trifluoroacetate (compound 44-3)

[0514] Trifluoroacetic acid (0.5 mL) was added to a solution of 99 mg (0.32 mmol) of tert-butyl 7-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid (tert-butyl ester) in dichloromethane (2 mL). The reaction mixture was stirred at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure to obtain the target compound (compound 44-3), which was used directly in the next step. MS: m / z = 211.3 [M+H] + .

[0515] Step 3: Synthesis of 5-(6-ethyl-4-methyl-2-(7-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[3.5]non-2-yl)-1,8-naphthid-3-yl)-3-methyl-1,2,4-oxadiazole (compound 44)

[0516] To a DMSO (2 mL) solution of 5-(2-chloro-6-ethyl-4-methyl-1,8-naphthid-3-yl)-3-methyl-1,2,4-oxadiazole (compound 2-4) (50 mg, 0.17 mmol), 7-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[3.5]nonane trifluoroacetate (76 mg, 0.17 mmol), potassium fluoride (20 mg, 0.35 mmol) and N,N-diisopropylethylamine (90 mg, 0.69 mmol) were added sequentially. After the addition was complete, the mixture was stirred at 115 °C for 8 hours. After the reaction solution was cooled to room temperature, 30 mL of water was added, and the mixture was extracted with ethyl acetate (30 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by preparative column chromatography to obtain the target compound (compound 44) ​​(42 mg, 0.091 mmol). MS: m / z = 463.4 [M+H] + .

[0517] 1 H NMR (400MHz, CDCl3) δ8.78(d,J=2.3Hz,1H),7.93(d,J=2.1Hz,1H),4.01(dd,J=11.1,3.6Hz,2H),3.63-3.58(m,3H),3.35(t,J =11.2Hz,2H),2.85-2.75(m,2H),2.57(s,3H),2.49-2.39(m,7H),1.82-1.66(m,8H),1.63-1.52(m,2H),1.33(t,J=7.6Hz,3H).

[0518] Example 21: Synthesis of 1-(6-ethyl-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)-1,8-naphthidin-2-yl)-N-(tetrahydro-2H-pyran-4-yl)-4-(trifluoromethyl)piperidin-4-amine (compound 45)

[0519] Step 1: Synthesis of tert-butyl 4-((tetrahydro-2H-pyran-4-yl)imino)piperidine-1-carboxylate (compound 45-1)

[0520] 4-O-piperidine-1-carboxylic acid tert-butyl ester (199 mg, 1.00 mmol) and tetrahydro-2H-pyran-4-amine (252 mg, 2.50 mmol) were dissolved in anhydrous toluene (10 mL), and the mixture was heated to 120 °C and stirred for 5 h. The reaction solution was concentrated under reduced pressure to obtain the target compound (compound 45-1), which was directly used in the next step of the reaction.

[0521] Step 2: Synthesis of tert-butyl 4-((tetrahydro-2H-pyran-4-yl)amino)-4-(trifluoromethyl)piperidine-1-carboxylate (compound 45-2)

[0522] 4-((tetrahydro-2H-pyran-4-yl)imino)piperidin-1-carboxylic acid tert-butyl ester (compound 45-1) (282 mg, 1.0 mmol) was dissolved in anhydrous acetonitrile (3 mL). N,N-dimethylformamide (73 mg, 3.00 mmol) and potassium hydrofluoric acid (58 mg, 0.75 mmol) were added at room temperature. The mixture was cooled to 0 °C, and trifluoroacetic acid (142 mg, 1.25 mmol) and (trifluoromethyl)trimethylsilane (213 mg, 2.00 mmol) were added. The mixture was then brought back to room temperature and stirred for 12 h. The reaction solution was filtered through diatomaceous earth, the filter cake was washed with ethyl acetate, the filtrate was concentrated, and 30 mL of water was added. The mixture was extracted with ethyl acetate (30 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then subjected to column chromatography to obtain the target compound (225 mg, 0.64 mmol). MS: m / z = 297.1 [M-56+H] +

[0523] Step 3: Synthesis of N-(tetrahydro-2H-pyran-4-yl)-4-(trifluoromethyl)piperidine-4-amine hydrochloride (compound 45-3)

[0524] 4-((tetrahydro-2H-pyran-4-yl)amino)-4-(trifluoromethyl)piperidine-1-carboxylic acid tert-butyl ester (225.5 mg, 0.64 mmol) was dissolved in anhydrous dichloromethane (2 mL), and hydrochloric acid / 1,4-dioxane (6.4 mmol, 1.6 mL) was added. The mixture was stirred at room temperature for 2 h. The reaction solution was concentrated under reduced pressure to obtain the target compound (compound 45-3), which was directly used in the next step of the reaction.

[0525] Step 4: Synthesis of 1-(6-ethyl-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)-1,8-naphthidin-2-yl)-N-(tetrahydro-2H-pyran-4-yl)-4-(trifluoromethyl)piperidin-4-amine (compound 45)

[0526] 5-(2-chloro-6-ethyl-4-methyl-1,8-naphthid-3-yl)-3-methyl-1,2,4-oxadiazole (compound 2-4) (40 mg, 0.14 mmol), N-(tetrahydro-2H-pyran-4-yl)-4-(trifluoromethyl)piperidine-4-amine hydrochloride (91 mg, 0.28 mmol), and potassium fluoride (16 mg, 0.28 mmol) were dissolved in dimethyl sulfoxide (3 mL). N,N-diisopropylethylamine (116 mg, 0.84 mmol) was added, and the mixture was stirred at 120 °C for 12 h. After cooling to room temperature, 30 mL of water was added, and the mixture was extracted with ethyl acetate (30 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by preparative column chromatography to obtain the target compound (compound 45) (13.8 mg, 0.03 mmol). MS: m / z = 505.5 [M+H] + .

[0527] 1H NMR (400MHz, CDCl3) δ8.91(d,J=2.2Hz,1H),8.10(s,1H),3.96(d,J=11.6Hz,2H),3.58(d,J=12.5Hz,2H),3.47–3.32(m,4H), 3.08-2.93(m,1H),2.89(q,J=7.6Hz,2H),2.56(s,3H),2.55(s,3H),1.93-1.74(m,4H),1.65-1.55(m,3H),1.50-1.37(m,5H).

[0528] Example 22: Synthesis of 1-(6-ethyl-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)-1,8-naphthidin-2-yl)-N-(tetrahydro-2H-pyran-4-yl)piperidin-4-deuterium-4-amine (compound 46)

[0529] Step 1: Synthesis of 8-(((tetrahydro-2H-pyran-4-yl)amino)-5-azaspiro[2.5]octane-5-carboxylic acid tert-butyl ester (compound 46-1)

[0530] N-tert-Butoxycarbonyl-4-piperidinone (199 mg, 1.0 mmol) and 4-aminotetrahydropyran (202 mg, 2.0 mmol) were dissolved in anhydrous dichloromethane (5 mL). Acetic acid (120.1 mg, 2.0 mmol) was added, and the mixture was stirred at room temperature for 0.5 h. Sodium deuterated borohydride (167 mg, 2.66 mmol) was added, and the reaction was allowed to proceed for 12 h at room temperature after the addition was complete. 30 mL of water was added to the reaction mixture, and the mixture was extracted with dichloromethane (30 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then subjected to column chromatography to obtain the target compound (compound 46-1) (160 mg, 0.56 mmol). MS: m / z = 286.5 [M+H] + .

[0531] Step 2: Synthesis of N-(tetrahydro-2H-pyran-4-yl)piperidine-4-deuter-4-amine hydrochloride (compound 46-2)

[0532] 8-(((tetrahydro-2H-pyran-4-yl)amino)-5-azaspiro[2.5]octane-5-carboxylic acid tert-butyl ester (compound 46-1) (160 mg, 0.56 mmol) was dissolved in anhydrous dichloromethane (2 mL), and hydrochloric acid / 1,4-dioxane (5.6 mmol, 1.4 mL) was added. The mixture was stirred at room temperature for 4 h. The reaction solution was concentrated under reduced pressure to obtain the target compound (compound 46-2), which was directly used in the next step of the reaction.

[0533] Step 3: Synthesis of 1-(6-ethyl-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)-1,8-naphthidin-2-yl)-N-(tetrahydro-2H-pyran-4-yl)piperidin-4-deuterium-4-amine (compound 46)

[0534] 5-(2-chloro-6-ethyl-4-methyl-1,8-naphthid-3-yl)-3-methyl-1,2,4-oxadiazole (compound 2-4) (32 mg, 0.11 mmol), N-(tetrahydro-2H-pyran-4-yl)piperidin-4-deuterium-4-amine hydrochloride (compound 46-2) (57.23 mg, 0.22 mmol), and potassium fluoride (12.88 mg, 0.22 mmol) were dissolved in dimethyl sulfoxide (1 mL), and N,N-diisopropylethylamine (57.23 mg, 0.22 mmol) was added. The mixture was stirred at 115 °C for 12 h. After cooling the reaction solution to room temperature, 20 mL of water was added, and the mixture was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by preparative column chromatography to obtain the target compound (compound 46) (12.0 mg, 0.027 mmol). MS: m / z = 438.3 [M+H] + .

[0535] 1 H NMR (400MHz, CDCl3) δ8.84(d,J=2.3Hz,1H),8.00(d,J=2.2Hz,1H),3.96(d,J=10.7Hz,2H),3.69(d,J=13.4Hz,2H),3.38(td,J=11 .7,1.7Hz,2H),2.95-2.89(m,2H),2.86-2.78(m,3H),2.55(s,3H),2.53(s,3H),1.82(dd,J=20.5,12.9Hz,4H),1.45-1.30(m,8H).

[0536] Example 23: Synthesis of ethyl 1-(6-ethyl-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)-1,8-naphthidin-2-yl)-4-((tetrahydro-2H-pyran-4-yl)amino)piperidine-4-carboxylate (compound 51)

[0537] Step 1: Synthesis of 1-(tert-butyl)-4-ethyl-4-((tetrahydro-2H-pyran-4-yl)amino)piperidine-1,4-dicarboxylate (compound 51-2)

[0538] Formic acid (0.1 mL) was added to a methanol (2.00 mL) solution of ethyl 1-(tert-butyl)-4-aminopiperidine-1,4-dicarboxylate (compound 51-1) (100 mg, 367 μmol) and tetrahydropyran-4-one (37 mg, 367 μmol). After stirring at room temperature for 0.5 h, sodium cyanoborohydride (28 mg, 440 μmol) was added, and the reaction was stirred at room temperature for 8 h after the addition was complete. The reaction solution was filtered through diatomaceous earth, the filter cake was washed with ethyl acetate, the filtrate was concentrated, 30 mL of water was added, and the solution was extracted with ethyl acetate (30 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then subjected to column chromatography to obtain the target compound (compound 51-2) (88 mg, 247 μmol). MS: m / z = 357.5 [M+H] + .

[0539] Step 2: Synthesis of ethyl 4-((tetrahydro-2H-pyran-4-yl)amino)piperidine-4-carboxylic acid trifluoroacetate (compound 51-3)

[0540] TFA (0.5 mL) was added to a 2 mL solution of 1-(tert-butyl)-4-ethyl-4-((tetrahydro-2H-pyran-4-yl)amino)piperidine-1,4-dicarboxylate (compound 51-2) (240 mg, 675 μmol) in dichloromethane. After the addition was complete, the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure to obtain the target compound (compound 51-3), which was directly used in the next step of the reaction. MS: m / z = 257.3 [M+H] + .

[0541] Step 3: Synthesis of ethyl 1-(6-ethyl-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)-1,8-naphthidin-2-yl)-4-((tetrahydro-2H-pyran-4-yl)amino)piperidine-4-carboxylate (compound 51)

[0542] To a DMSO (2 mL) solution of 5-(2-chloro-6-ethyl-4-methyl-1,8-naphthid-3-yl)-3-methyl-1,2,4-oxadiazole (compound 2-4) (50 mg, 173 μmol), 4-((tetrahydro-2H-pyran-4-yl)amino)piperidin-4-carboxylic acid ethyl ester trifluoroacetate (compound 51-3) (84 mg, 173 μmol), potassium fluoride (20 mg, 346 μmol) and N,N-diisopropylethylamine (89 mg, 692 μmol) were added. After the addition was complete, the mixture was stirred at 115 °C for 8 hours. After the reaction solution was cooled to room temperature, 20 mL of water was added, and the mixture was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by preparative column chromatography to obtain the target compound (compound 51) (18 mg, 35 μmol). MS: m / z = 509.1 [M+H] + .

[0543] 1 H NMR (400MHz, CDCl3) δ8.85(d,J=2.3Hz,1H),8.03(s,1H),4.15(q,J=7.1Hz,2H),3.92-3.85(m,2H),3.52-3.44(m,2H),3.38-3.25(m,4H),2.83(dd ,J=15.4,7.8Hz,2H),2.66-2.58(m,1H),2.56(s,3H),2.54(s,3H),2.04- 1.96(m,2H),1.73-1.61(m,5H),1.43-1.32(m,5H),1.27(t,J=7.1Hz,3H).

[0544] Example 24: Synthesis of N-(4,4-difluorocyclohexyl)-1-(6-ethyl-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)-1,8-naphthidin-2-yl)piperidine-4-amine (compound 55)

[0545] Step 1: Synthesis of tert-butyl 4-(4,4-difluorocyclohexyl)amino)piperidine-1-carboxylate (compound 55-2)

[0546] A solution of 4,4-difluorocyclohexane-1-amine (compound 55-1) (450 mg, 3.33 mmol) and tert-butyl 4-oxopiperidinium-1-carboxylate (442 mg, 2.22 mmol) in anhydrous methanol (6 mL) was reacted with acetic acid (1 drop) at room temperature for 0.5 h, followed by the addition of sodium cyanoborohydride (189 mg, 3.01 mmol) and stirring at room temperature for 12 h. The reaction mixture was filtered through diatomaceous earth, the filter cake was washed with ethyl acetate, the filtrate was concentrated, and 30 mL of water was added. The mixture was extracted with ethyl acetate (30 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and then subjected to column chromatography to obtain the target compound (compound 55-2) (200 mg, 0.63 mmol). MS: m / z = 319.2 [M+H] + .

[0547] Step 2: Synthesis of N-(4,4-difluorocyclohexyl)piperidine-4-amine hydrochloride (compound 55-3)

[0548] To anhydrous dichloromethane (3 mL), 200 mg (0.63 mmol) of tert-butyl 4-(4,4-difluorocyclohexyl)amino)piperidine-1-carboxylate (compound 55-2) was added, along with 1,4-dioxane (4.00 mmol, 1.00 mL), and the mixture was stirred at room temperature for 2 h. The reaction solution was concentrated under reduced pressure to obtain the target compound (compound 55-3), which was directly used in the next step of the reaction.

[0549] Step 3: Synthesis of N-(4,4-difluorocyclohexyl)-1-(6-ethyl-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)-1,8-naphthidin-2-yl)piperidine-4-amine (compound 55)

[0550] Potassium fluoride (64.3 mg, 1.12 mmol) and N,N-diisopropylethylamine (214 mg, 1.68 mmol) were added to a solution of 5-(2-chloro-6-ethyl-4-methyl-1,8-naphthid-3-yl)-3-methyl-1,2,4-oxadiazole (compound 2-4) (80 mg, 0.28 mmol) and N-(4,4-difluorocyclohexyl)piperidine-4-amine hydrochloride (compound 55-3) (122 mg, 0.42 mmol) in dimethyl sulfoxide (3 mL). After the addition was complete, the mixture was stirred at 90 °C for 12 h. After the reaction solution was cooled to room temperature, 20 mL of water was added, and the mixture was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by preparative column chromatography to obtain the target compound (compound 55) (54.0 mg, 0.11 mmol). MS: m / z = 471.3 [M+H] + .

[0551] 1 H NMR (400MHz, CDCl3) δ8.85(d,J=2.2Hz,1H),8.01(d,J=2.1Hz,1H),3.70(d,J=13.3Hz,2H),2.92(t,J=12.5Hz,2H),2.8 6-2.72(m,4H),2.55(s,3H),2.54(s,3H),2.18-2.04(m,2H),1.94-1.66(m,7H),1.53-1.43(m,2H),1.37-1.29(m,5H).

[0552] Example 25: Synthesis of N-(1,1-dimethylsilyl-4-yl)-1-(6-ethyl-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)-1,8-naphthidin-2-yl)piperidine-4-amine (compound 57)

[0553] Step 1: Synthesis of tert-butyl 4-((1,1-dimethylsilane-4-yl)amino)piperidine-1-carboxylate (compound 57-2)

[0554] To a solution of 1,1-dimethylsilane-4-amine (compound 57-1) (400 mg, 2.79 mmol) and tert-butyl 4-oxopiperidinium-1-carboxylate (371 mg, 1.86 mmol) in anhydrous methanol (10 mL), tetraisopropyl titanate (1.06 g, 3.72 mmol) was added. After stirring at room temperature for 0.5 h, sodium cyanoborohydride (350.8 mg, 5.58 mmol) was added, and the reaction mixture was stirred at 85 °C for 12 h. The reaction solution was cooled to room temperature and filtered through diatomaceous earth. The filter cake was washed with ethyl acetate, the filtrate was concentrated, and 30 mL of water was added. The mixture was extracted with ethyl acetate (30 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then subjected to column chromatography to obtain the target compound (compound 57-2) (150 mg, 0.45 mmol). MS: m / z = 327.2 [M+H] + .

[0555] Step 2: Synthesis of N-(1,1-dimethylsilyl-4-yl)piperidine-4-amine hydrochloride (compound 57-3)

[0556] Hydrochloric acid / 1,4-dioxane (4.00 mmol, 1.00 mL) was added to anhydrous dichloromethane (3 mL) containing 150 mg (150 mg, 0.45 mmol) of tert-butyl 4-((1,1-dimethylsilyl-4-yl)amino)piperidine-1-carboxylate (compound 57-2). The mixture was stirred at room temperature for 2 h. The reaction solution was concentrated under reduced pressure to obtain the target compound (compound 57-3), which was directly used in the next step of the reaction.

[0557] Step 3: Synthesis of N-(1,1-dimethylsilyl-4-yl)-1-(6-ethyl-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)-1,8-naphthidin-2-yl)piperidine-4-amine (compound 57)

[0558] Potassium fluoride (102 mg, 1.76 mmol) and N,N-diisopropylethylamine (342 mg, 2.64 mmol) were added to a solution of 5-(2-chloro-6-ethyl-4-methyl-1,8-naphthid-3-yl)-3-methyl-1,2,4-oxadiazole (compound 2-4) (127 mg, 0.44 mmol) in dimethyl sulfoxide (3 mL). After the addition was complete, the mixture was stirred at 90 °C for 12 h. After the reaction solution was cooled to room temperature, 20 mL of water was added, and the mixture was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by preparative column chromatography to obtain the target compound (compound 57) (67 mg, 0.14 mmol). MS: m / z = 479.3 [M+H]+ .

[0559] 1 H NMR (400MHz, CDCl3) δ8.84(d,J=2.4Hz,1H),8.00(d,J=2.3Hz,1H),3.70(d,J=13.4 Hz,2H),2.91(t,J=11.7Hz,2H),2.82(q,J=7.6Hz,2H),2.77-2.67(m,1H),2.55(s, 3H),2.53(s,3H),2.52-2.46(m,1H),1.98-1.91(m,2H),1.85(d,J=11.4Hz,2H),1. 44-1.27(m,8H),0.76-0.68(m,2H),0.56-0.42(m,2H),0.02(s,3H),-0.01(s,3H).

[0560] Example 26: Synthesis of 1-(4-(1-(6-ethyl-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)-1,8-naphthidin-2-yl)piperidin-4-yl)amino)piperidin-1-yl)ethyl-1-one (compound 71)

[0561] Step 1: Synthesis of 4-((1-acetylpiperidin-4-yl)amino)piperidin-1-carboxylic acid tert-butyl ester (compound 71-2)

[0562] 1-Acetylpiperidin-4-amine (compound 71-1) (200 mg, 1.41 mmol) and tert-butyl 4-oxopiperidin-1-carboxylate (280 mg, 1.41 mmol) were dissolved in anhydrous dichloromethane (3 mL). The mixture was cooled to 0 °C, and acetic acid (1 mL) and sodium cyanoborohydride (177 mg, 2.82 mmol) were added sequentially. The mixture was stirred at room temperature for 12 h. The reaction solution was filtered through diatomaceous earth, the filter cake was washed with ethyl acetate, the filtrate was concentrated, and 30 mL of water was added. The mixture was extracted with ethyl acetate (30 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then subjected to column chromatography to obtain the target compound (compound 71-2) (278 mg, 0.85 mmol). MS: m / z = 326.3 [M+H] + .

[0563] Step 2: Synthesis of 1-(4-(piperidin-4-ylamino)piperidin-1-yl)ethyl-1-one hydrochloride (compound 71-3)

[0564] 4-((1-acetylpiperidin-4-yl)amino)piperidin-1-carboxylic acid tert-butyl ester (compound 71-2) (278 mg, 0.85 mmol) was dissolved in anhydrous dichloromethane (2 mL), and hydrochloric acid / 1,4-dioxane (8 mmol, 2 mL) was added. The mixture was stirred at room temperature for 2 h. The reaction solution was concentrated under reduced pressure to obtain the target compound (compound 71-3), which was directly used in the next step of the reaction.

[0565] Step 3: Synthesis of 1-(4-(1-(6-ethyl-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)-1,8-naphthidin-2-yl)piperidin-4-yl)amino)piperidin-1-yl)ethyl-1-one (compound 71)

[0566] 5-(2-chloro-6-ethyl-4-methyl-1,8-naphthid-3-yl)-3-methyl-1,2,4-oxadiazole (compound 2-4) (50 mg, 0.17 mmol), 1-(4-(piperidin-4-ylamino)piperidin-1-yl)ethyl-1-one hydrochloride (compound 71-3) (101.4 mg, 0.34 mmol), and potassium fluoride (20 mg, 0.34 mmol) were dissolved in dimethyl sulfoxide (3 mL). N,N-diisopropylethylamine (131.8 mg, 1.02 mmol) was added, and the mixture was stirred at 95 °C for 12 h. After cooling to room temperature, 20 mL of water was added, and the mixture was extracted with ethyl acetate (20 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by preparative column chromatography to obtain the target compound (compound 71) (9.5 mg, 0.02 mmol). MS: m / z = 478.4 [M+H] + .

[0567] 1 H NMR (400MHz, CDCl3) δ8.82(d,J=2.0Hz,1H),7.99(d,J=1.9Hz,1H),4.40(m,1H),3.81-3.58(m,3H),3.12-2.98(m, 1H),2.96-2.63(m,7H),2.53(s,3H),2.51(s,3H),2.05(s,3H),1.90-1.76(m,4H),1.61(s,1H),1.36-1.13(m,7H).

[0568] Example 27: Synthesis of 1-cyclopropyl-N-(1-(6-ethyl-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)-1,8-naphthidin-2-yl)piperidin-4-yl)piperidin-4-amine (compound 72)

[0569] Step 1: Synthesis of tert-butyl 4-((1-cyclopropylpiperidin-4-yl)amino)piperidin-1-carboxylate (compound 72-2)

[0570] Formic acid (0.1 mL) was added to a methanol (2 mL) solution of tert-butyl 4-oxopiperidin-1-carboxylate (284 mg, 1.43 mmol) and 1-cyclopropylpiperidin-4-amine (compound 72-1) (200 mg, 1.43 mmol). The mixture was stirred at room temperature for 0.5 h, followed by the addition of sodium cyanoborohydride (180 mg, 2.85 mmol). The reaction mixture was stirred at room temperature for 12 h. The reaction solution was filtered through diatomaceous earth, the filter cake was washed with ethyl acetate, the filtrate was concentrated, and 30 mL of water was added. The mixture was extracted with ethyl acetate (30 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then subjected to column chromatography to obtain the target compound (compound 72-2) (280 mg, 0.87 mmol). MS: m / z = 324.5 [M+H] + .

[0571] Step 2: Synthesis of 1-cyclopropyl-N-(piperidin-4-yl)piperidin-4-amine trifluoroacetate (compound 72-3)

[0572] Trifluoroacetic acid (0.5 mL) was added to a solution of tert-butyl 4-((1-cyclopropyl-4-piperidinyl)amino)piperidine-1-carboxylate (280 mg, 0.87 mmol) in dichloromethane (3 mL), and the mixture was stirred at 25 °C for 4 hours. The reaction solution was concentrated under reduced pressure to obtain the target compound (compound 72-3), which was directly used in the next step of the reaction.

[0573] Step 3: Synthesis of 1-cyclopropyl-N-(1-(6-ethyl-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)-1,8-naphthidin-2-yl)piperidin-4-yl)piperidin-4-amine (compound 72)

[0574] To a solution of 5-(2-chloro-6-ethyl-4-methyl-1,7-naphthid-3-yl)-3-methyl-1,2,4-oxadiazole (compound 2-4) (50 mg, 0.17 mmol), 1-cyclopropyl-N-(4-piperidinyl)piperidin-4-amine trifluoroacetate (compound 72-3) (153 mg, 0.34 mmol) in DMSO (2 mL), potassium fluoride (20 mg, 0.34 mmol) and N,N-diisopropylethylamine (112 mg, 0.87 mmol) were added. After the addition was complete, the mixture was stirred at 115 °C for 2 hours. After the reaction solution was cooled to room temperature, 30 mL of water was added, and the mixture was extracted with ethyl acetate (30 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by preparative column chromatography to obtain the target compound (compound 72) (89 mg, 0.19 mmol). MS: m / z = 476.4 [M+H] + .

[0575] 1 H NMR (400MHz, CDCl3) δ8.84(d,J=2.3Hz,1H),8.00(d,J=2.2Hz,1H),3.69(d,J=13.4Hz,2H),3.02-2.73(m,8H),2.66-2.57(m,1H) ,2.55(s,3H),2.52(s,3H),2.22(t,J=11.0Hz,2H),1.86-1.80(m,4H),1.59-1.55(m,1H),1.38-1.28(m,7H),0.45-0.39(m,4H).

[0576] Example 28: Synthesis of N-(cyclohexyl-3-en-1-yl)-1-(6-ethyl-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)-1,8-naphthidin-2-yl)piperidine-4-amine (compound 74)

[0577] Step 1: Synthesis of tert-butyl 4-(cyclohexyl-3-en-1-ylamino)piperidine-1-carboxylate (compound 74-2)

[0578] Cyclohexyl-3-en-1-amine (compound 74-1) (200 mg, 2.26 mmol) and tert-butyl 4-oxopiperidinium-1-carboxylate (441 mg, 2.26 mmol) were added to anhydrous methanol (5 mL), and acetic acid (1 drop) was added. The mixture was stirred at room temperature for 0.5 h. Then, sodium triacetylborohydride (959 mg, 4.53 mmol) was added, and the mixture was stirred at room temperature for 12 h. The reaction solution was filtered through diatomaceous earth, the filter cake was washed with dichloromethane, the filtrate was concentrated, and 30 mL of water was added. The mixture was extracted with ethyl acetate (30 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and then subjected to column chromatography to obtain the target compound (compound 74-2) (70 mg, 0.25 mmol). MS: m / z = 281.2 [M+H]+.

[0579] Step 2: Synthesis of N-(cyclohexyl-3-en-1-yl)piperidine-4-amine hydrochloride (compound 74-3)

[0580] 70 mg (0.25 mmol) of tert-butyl 4-(cyclohexyl-3-en-1-ylamino)piperidin-1-carboxylate (compound 74-2) was added to 3 mL of anhydrous dichloromethane and the mixture was stirred at room temperature for 2 h. The reaction solution was concentrated under reduced pressure to obtain the target compound (compound 74-3), which was directly used in the next step. MS: m / z = 181.2 [M+H]+.

[0581] Step 3: Synthesis of N-(cyclohexyl-3-en-1-yl)-1-(6-ethyl-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)-1,8-naphthidin-2-yl)piperidine-4-amine (compound 74)

[0582] Potassium fluoride (64.3 mg, 1.12 mmol) and N,N-diisopropylethylamine (214 mg, 1.68 mmol) were added to a solution of 5-(2-chloro-6-ethyl-4-methyl-1,8-naphthid-3-yl)-3-methyl-1,2,4-oxadiazole (compound 2-4) (80 mg, 0.28 mmol) and N-(cyclohex-3-en-1-yl)piperidin-4-amine hydrochloride (compound 74-3) (63 mg, 0.25 mmol) in dimethyl sulfoxide (3 mL). After the addition was complete, the mixture was stirred at 90 °C for 12 h. After the reaction solution was cooled to room temperature, 30 mL of water was added, and the mixture was extracted with ethyl acetate (30 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by preparative column chromatography to obtain the target compound (compound 74) (34.0 mg, 0.079 mmol). MS: m / z = 433.3 [M+H] + .

[0583] 1 H NMR (400MHz, CDCl3) δ8.84(s,1H),8.00(d,J=1.9Hz,1H),5.71-5.52(m,2H),3.70(d,J=13.5Hz,2H),2.92(t,J=11.7Hz,3H) ,2.86-2.78(m,3H),2.55(s,3H),2.53(s,3H),2.30-2.21(m,1H),2.14-2.05(m,2H),1.92-1.78(m,4H),1.46-1.29(m,7H).

[0584] Example 29: Synthesis of N-(1-(6-ethyl-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)-1,8-naphthidin-2-yl)piperidin-4-yl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-7-amine (compound 79)

[0585] Step 1: Synthesis of tert-butyl 4-((5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-7-yl)amino)piperidine-1-carboxylate (compound 79-2)

[0586] Formic acid (0.1 mL) was added to a methanol (5.0 mL) solution of 5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-7-amine (compound 79-1) (200 mg, 1.46 mmol) and tert-butyl 4-oxopiperidinium-1-carboxylate (290 mg, 1.46 mmol). The mixture was stirred at room temperature for 0.5 h, followed by the addition of sodium cyanoborohydride (110 mg, 1.75 mmol). After the addition was complete, the mixture was stirred at room temperature for 12 h. The reaction solution was filtered through diatomaceous earth, the filter cake was washed with ethyl acetate, the filtrate was concentrated, and 30 mL of water was added. The mixture was extracted with ethyl acetate (30 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and then subjected to column chromatography to obtain the target compound (compound 79-2) (380 mg, 1.19 mmol). MS: m / z = 321.4 [M+H] + .

[0587] Step 2: Synthesis of N-(piperidin-4-yl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-7-amine trifluoroacetate (compound 79-3)

[0588] Trifluoroacetic acid (0.5 mL) was added to a 2 mL solution of 4-(5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-7-ylamino)piperidine-1-carboxylic acid tert-butyl ester (compound 79-2) (99 mg, 0.31 mmol). After the addition was complete, the mixture was stirred at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure to obtain the target compound (compound 79-3), which was directly used in the next step of the reaction.

[0589] Step 3: Synthesis of N-(1-(6-ethyl-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)-1,8-naphthidin-2-yl)piperidin-4-yl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-7-amine (compound 79)

[0590] To a DMSO (2 mL) solution of 5-(2-chloro-6-ethyl-4-methyl-1,8-naphthid-3-yl)-3-methyl-1,2,4-oxadiazole (compound 2-4) (49 mg, 0.17 mmol), N-(4-piperidinyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-7-amine trifluoroacetate (compound 79-3) (76 mg, 0.17 mmol), potassium fluoride (20 mg, 0.35 mmol) and N,N-diisopropylethylamine (67 mg, 0.52 mmol) were added sequentially. After cooling to room temperature, 30 mL of water was added, and the mixture was extracted with ethyl acetate (30 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by preparative column chromatography to obtain the target compound (compound 79) (18 mg, 0.038 mmol). MS: m / z = 473.3 [M+H] + .

[0591] 1 H NMR(400MHz, CDCl3)δ8.85(s,1H),8.01(s,1H),7.01(s,1H),6.80(s,1H),4.16 -4.05(m,1H),3.96-3.87(m,1H),3.70(t,J=12.4Hz,2H),3.38-3.30(m,1H),3.2 4-3.14(m,1H),2.98-2.89(m,2H),2.85-2.77(m,3H),2.55(s,3H),2.54(s,3H), 2.17-2.07(m,2H),2.05-1.96(m,2H),1.92-1.83(m,4H),1.35(t,J=7.5Hz,3H).

[0592] Example 30: Synthesis of N-(1-(6-ethyl-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)-1,8-naphthidin-2-yl)piperidin-4-yl)-3-(trifluoromethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-5-amine (compound 82)

[0593] Step 1: Synthesis of tert-butyl 4-((3-(trifluoromethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-5-yl)amino)piperidine-1-carboxylate (compound 82-2)

[0594] To a solution of 3-(trifluoromethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-5-amine (compound 81-1) (113 mg, 0.55 mmol) and tert-butyl 4-oxopiperidinium-1-carboxylate (100 mg, 0.50 mmol) in anhydrous methanol (3 mL), tetraisopropyl titanate (285 mg, 1.00 mmol) was added and the mixture was stirred at room temperature for 0.5 h. Sodium cyanoborohydride (63 mg, 1.0 mmol) was then added, and the mixture was stirred at 85 °C for 12 h. The reaction mixture was filtered through diatomaceous earth, the filter cake was washed with ethyl acetate, the filtrate was concentrated, and 30 mL of water was added. The mixture was extracted with ethyl acetate (30 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then subjected to column chromatography to obtain the target compound (compound 82-2) (125 mg, 0.32 mmol). MS: m / z = 389.4 [M+H] + .

[0595] Step 2: Synthesis of N-(piperidin-4-yl)-3-(trifluoromethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-5-amine hydrochloride (compound 82-3)

[0596] To a solution of 125 mg (0.32 mmol) of tert-butyl piperidine-1-carboxylate (compound 82-2) in anhydrous dichloromethane (3 mL), hydrochloric acid / 1,4-dioxane (4.00 mmol, 1 mL) was added, and the mixture was stirred at room temperature for 2 h. The reaction solution was then concentrated under reduced pressure to obtain the target compound (compound 82-3), which was directly used in the next step of the reaction.

[0597] Step 3: Synthesis of N-(1-(6-ethyl-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)-1,8-naphthidin-2-yl)piperidin-4-yl)-3-(trifluoromethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-5-amine (compound 82)

[0598] Potassium fluoride (56 mg, 0.96 mmol) and N,N-diisopropylethylamine (188 mg, 1.44 mmol) were added to a solution of 5-(2-chloro-6-ethyl-4-methyl-1,8-naphthid-3-yl)-3-methyl-1,2,4-oxadiazole (compound 2-4) (70 mg, 0.24 mmol) and N-(piperidin-4-yl)-3-(trifluoromethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-5-amine hydrochloride (compound 82-3) (115 mg, 0.32 mmol) in dimethyl sulfoxide (3 mL). After the addition was complete, the mixture was stirred at 90 °C for 12 h. After cooling the reaction solution to room temperature, 30 mL of water was added, and the mixture was extracted with ethyl acetate (30 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by preparative column chromatography to obtain the target compound (compound 82) (6.0 mg, 0.011 mmol). MS: m / z = 541.2 [M+H] + .

[0599] 1 H NMR(400MHz, CDCl3) δ8.85(d,J=2.3Hz,1H),8.02(d,J=2.2Hz,1H),7.63(s,1H ),4.42-4.32(m,1H),4.18-4.06(m,1H),3.73(d,J=12.9Hz,2H),3.45-3.31(m ,1H),3.25-3.15(m,1H),3.00-2.91(m,2H),2.87-2.78(m,3H),2.55(s,6H),2 .37-2.18(m,1H),2.10-1.86(m,3H),1.73-1.53(m,4H),1.35(t,J=7.6Hz,3H).

[0600] Example 31: Synthesis of N-(8-oxabicyclo[3.2.1]oct-3-yl)-1-(6-ethyl-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)-1,8-naphthid-2-yl)piperidine-4-amine (compound 86)

[0601] Step 1: Synthesis of tert-butyl 4-((8-oxabicyclo[3.2.1]oct-3-yl)amino)piperidine-1-carboxylate (compound 86-2)

[0602] Acetic acid (118 mg, 1.96 mmol) was added to a 4 mL solution of 8-oxabicyclo[3.2.1]octyl-3-amine (compound 86-1) (249 mg, 1.96 mmol) and tert-butyl 4-oxopiperidinium-1-carboxylate (195 mg, 0.98 mmol) in anhydrous dichloromethane, and the mixture was stirred at room temperature for 0.5 h. Sodium cyanoborohydride (123 mg, 1.96 mmol) was then added, and the mixture was stirred at room temperature for 12 h. The reaction mixture was filtered through diatomaceous earth, the filter cake was washed with ethyl acetate, the filtrate was concentrated, and 30 mL of water was added. The mixture was extracted with ethyl acetate (30 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then subjected to column chromatography to obtain the target compound (compound 86-2) (280 mg, 0.9 mmol). MS: m / z = 311.5 [M+H] + .

[0603] Step 2: Synthesis of N-(8-oxabicyclo[3.2.1]oct-3-yl)piperidine-4-amine hydrochloride (compound 86-3)

[0604] To a solution of tert-butyl 4-((8-oxabicyclo[3.2.1]oct-3-yl)amino)piperidin-1-carboxylate (compound 86-2) (280 mg, 0.9 mmol) in anhydrous dichloromethane (4 mL), hydrochloric acid / 1,4-dioxane (9 mmol, 2.25 mL) was added, and the mixture was stirred at room temperature for 4 h. The reaction solution was concentrated under reduced pressure to obtain the target compound (compound 86-3), which was directly used in the next step. MS: m / z = 289.4 [M+H] + .

[0605] Step 3: Synthesis of N-(8-oxabicyclo[3.2.1]oct-3-yl)-1-(6-ethyl-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)-1,8-naphthidin-2-yl)piperidin-4-amine (compound 86)

[0606] To a solution of 5-(2-chloro-6-ethyl-4-methyl-1,8-naphthid-3-yl)-3-methyl-1,2,4-oxadiazole (compound 2-4) (200 mg, 0.69 mmol), N-(8-oxabicyclo[3.2.1]oct-3-yl)piperidine-4-amine hydrochloride (compound 86-3) (395 mg, 1.39 mmol) in dimethyl sulfoxide (3 mL), potassium fluoride (80 mg, 1.39 mmol) and N,N-diisopropylethylamine (537 mg, 4.16 mmol) were added. After the addition was complete, the mixture was stirred at 110 °C for 12 h. After the reaction solution was cooled to room temperature, 30 mL of water was added, and the mixture was extracted with ethyl acetate (30 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by preparative column chromatography to obtain the target compound (compound 86) (75 mg, 0.16 mmol). MS: m / z = 463.4 [M+H] + .

[0607] 1 H NMR(400MHz, CDCl3)δ8.82(d,J=2.3Hz,1H),7.99(d,J=2.1Hz,1H),4.33-4.26(m,2H) ,3.66(d,J=13.3Hz,2H),3.10(t,J=5.8Hz,1H),2.93-2.85(m,2H),2.81(q,J=7.6Hz,2 H),2.67-2.58(m,1H),2.54(s,3H),2.52(s,3H),2.13-2.08(m,2H),2.07-1.99(m,2H) ,1.90-1.74(m,5H),1.40(d,J=14.4Hz,2H),1.33(t,J=7.6Hz,3H),1.28-1.17(m,2H).

[0608] Example 32: Synthesis of 1-(6-cyclopropyl-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)-1,8-naphthidin-2-yl)-N-(tetrahydro-2H-pyran-4-yl)piperidin-4-amine (compound 95)

[0609] Step 1: Synthesis of 5-(6-bromo-2-chloro-4-methyl-1,8-naphthid-3-yl)-3-methyl-1,2,4-oxadiazole (Compound 95-1)

[0610] 2-(3-methyl-1,2,4-oxadiazol-5-yl)acetic acid (1.32 g, 9.30 mmol) was added to a phosphorus oxychloride (20 mL) solution of 1-(2-amino-5-bromo-3-pyridyl)acetone (compound 2-2) (2 g, 9.30 mmol). After the addition was complete, the mixture was stirred at 90 °C for 8 hours. The reaction solution was cooled to room temperature and added dropwise to ice water. The pH was adjusted to 7-8 with saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate (100 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then subjected to column chromatography to obtain the target compound (compound 95-1) (1.2 g, 3.53 mmol). MS: m / z = 340.4 [M+H] + .

[0611] Step 2: Synthesis of 1-(6-bromo-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)-1,8-naphthidin-2-yl)-N-(tetrahydro-2H-pyran-4-yl)piperidin-4-amine (compound 95-2)

[0612] To a DMSO (2 mL) solution of 5-(6-bromo-2-chloro-4-methyl-1,8-naphthid-3-yl)-3-methyl-1,2,4-oxadiazole (compound 95-1) (98 mg, 0.29 mmol), N-(tetrahydro-2H-pyran-4-yl)piperidin-4-amine (54 mg, 0.29 mmol), potassium fluoride (34 mg, 0.59 mmol) and N,N-diisopropylethylamine (76 mg, 0.59 mmol) were added. After the addition was complete, the mixture was stirred at 115 °C for 8 hours. The reaction solution was cooled to room temperature, and 30 mL of water was added. The mixture was extracted with ethyl acetate (30 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by preparative column chromatography to obtain the target compound (compound 95-2) (88 mg, 0.18 mmol). MS: m / z = 488.2 [M+H] + .

[0613] Step 3: Synthesis of 1-(6-cyclopropyl-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)-1,8-naphthidin-2-yl)-N-(tetrahydro-2H-pyran-4-yl)piperidin-4-amine (compound 95)

[0614] To a mixed solution of 1-(6-bromo-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)-1,8-naphthidin-2-yl)-N-(tetrahydro-2H-pyran-4-yl)piperidin-4-amine (compound 95-2) (78 mg, 0.16 mmol) and pinacol cyclopropylborate (42 mg, 0.25 mmol) in 1,4-dioxane (2 mL) and water (0.4 mL), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloromethane dichloride complex (27 mg, 0.033 mmol) and potassium carbonate (68 mg, 0.49 mmol) were added, and the mixture was stirred at 100 °C for 2 hours under nitrogen protection. After cooling the reaction solution to room temperature, it was filtered through diatomaceous earth. The filter cake was washed with ethyl acetate, the filtrate was concentrated, and water (100 mL) was added. The mixture was extracted with ethyl acetate (100 mL x 3), and the combined organic phases were dried over anhydrous sodium sulfate. The mixture was filtered, concentrated under reduced pressure, and purified by preparative column chromatography to obtain the target compound (compound 95) (30 mg, 0.067 mmol). MS: m / z = 449.3 [M+H] + .

[0615] 1 H NMR (400MHz, CDCl3) δ8.78(d,J=2.4Hz,1H),7.83(d,J=2.3Hz,1H),3.96(d,J= 10.8Hz,2H),3.69(d,J=13.3Hz,2H),3.38(dd,J=11.7,10.1Hz,2H),2.91(t,J =12.5Hz,2H),2.86-2.76(m,2H),2.55(s,3H),2.51(s,3H),2.11-2.02(m,1H) ,1.90-1.74(m,5H),1.44-1.31(m,4H),1.14-1.05(m,2H),0.86-0.74(m,2H).

[0616] Example 33: Synthesis of 1-(3-ethyl-5-methyl-6-(3-methyl-1,2,4-oxadiazol-5-yl)pyrido[2,3-c]pyridazin-7-yl)-N-(tetrahydro-2H-pyran-4-yl)piperidin-4-amine (compound 108)

[0617] Step 1: Synthesis of 3-ethyl-5-methyl-6-(3-methyl-1,2,4-oxadiazol-5-yl)pyrido[2,3-c]pyridazin-7-ol (compound 108-2)

[0618] Under ice bath conditions, N-methylimidazolium (1.04 g, 12.72 mmol) and N,N,N',N'-tetramethylchloroformamide hexafluorophosphate (1.78 g, 6.36 mmol) were added sequentially to a solution of 1-(3-amino-6-ethylpyridazin-4-yl) ketone (compound 108-1) (700 mg, 4.24 mmol) and 2-(3-methyl-1,2,4-oxadiazol-5-yl)acetic acid (903 mg, 6.36 mmol) in N,N-dimethylformamide (10 mL). The mixture was stirred at room temperature for 8 hours after the addition was complete. 100 mL of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by preparative column chromatography to obtain the target compound (compound 108-2) (420 mg, 1.55 mmol). MS: m / z = 272.2 [M+H] + .

[0619] Step 2: Synthesis of 5-(7-chloro-3-ethyl-5-methylpyridano[2,3-c]pyridazin-6-yl)-3-methyl-1,2,4-oxadiazole (compound 108-3)

[0620] 3-Ethyl-5-methyl-6-(3-methyl-1,2,4-oxadiazol-5-yl)pyrido[2,3-c]pyridazin-7-ol (compound 108-2) (118 mg, 0.43 mmol) was dissolved in phosphorus oxychloride (2 mL) and reacted at 80 °C with stirring for 4 hours. After cooling the reaction solution to room temperature, it was slowly added dropwise to ice water and extracted with ethyl acetate (100 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by preparative column chromatography to obtain the target compound (compound 108-3) (38 mg, 0.13 mmol). MS: m / z = 290.3 [M+H] + .

[0621] Step 3: Synthesis of 1-(3-ethyl-5-methyl-6-(3-methyl-1,2,4-oxadiazol-5-yl)pyrido[2,3-c]pyridazin-7-yl)-N-(tetrahydro-2H-pyran-4-yl)piperidin-4-amine (compound 108)

[0622] Potassium fluoride (14 mg, 0.24 mmol) and N,N-diisopropylethylamine (31 mg, 0.24 mmol) were added to a solution of 5-(7-chloro-3-ethyl-5-methylpyridino[2,3-c]pyridazin-6-yl)-3-methyl-1,2,4-oxadiazole (35 mg, 0.12 mmol), N-tetrahydropyran-4-ylpiperidin-4-amine (22 mg, 0.12 mmol) in dimethyl sulfoxide (2.0 mL). After the addition was complete, the mixture was stirred at 115 °C for 2 hours. After the reaction solution was cooled to room temperature, it was filtered through diatomaceous earth. The filter cake was washed with ethyl acetate, the filtrate was concentrated, and water (100 mL) was added. The mixture was extracted with ethyl acetate (100 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by preparative column chromatography to obtain the target compound (compound 108) (18 mg, 41.14 μmol). MS: m / z = 438.3 [M+H] + .

[0623] 1 H NMR (400MHz, CDCl3) δ7.64(s,1H),3.96(d,J=11.1Hz,2H),3.79(d,J=13.4Hz,2H),3.44-3.35(m,2H),3.25(q,J=7.6Hz,2H),2.99(t,J= 11.6Hz,2H),2.86-2.77(m,2H),2.61-2.57(m,1H),2.56(s,3H),2.54(s,3H),1.91-1.83(m,3H),1.81-1.76(m,3H),1.49-1.43(m,5H).

[0624] Example 34: Synthesis of (3R,4S)-1-(6-ethyl-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)-1,8-naphthidin-2-yl)-3-methoxy-N-(tetrahydro-2H-pyran-4-yl)piperidine-4-amine (compound 159)

[0625] Step 1: Synthesis of (3R,4S)-3-methoxy-4-((tetrahydro-2H-pyran-4-yl)amino)piperidine-1-carboxylic acid tert-butyl ester (compound 159-2)

[0626] Acetic acid (1 drop) was added to a solution of (3R,4S)-4-amino-3-methoxypiperidine-1-carboxylic acid tert-butyl ester (200 mg, 0.87 mmol) and tetrahydropyranone (121 mg, 1.22 mmol) in anhydrous methanol (6 mL). The mixture was stirred at room temperature for 0.5 h, followed by the addition of sodium cyanoborohydride (109 mg, 1.74 mmol), and the reaction was stirred at room temperature for 12 h. The reaction solution was filtered through diatomaceous earth, the filter cake was washed with ethyl acetate, the filtrate was concentrated, and 30 mL of water was added. The mixture was extracted with ethyl acetate (30 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then subjected to column chromatography to obtain the target compound (compound 159-2) (80 mg, 0.25 mmol). MS: m / z = 315.3 [M+H] + .

[0627] Step 2: Synthesis of (3R,4S)-3-methoxy-N-(tetrahydro-2H-pyran-4-yl)piperidine-4-amine hydrochloride (compound 159-3)

[0628] To anhydrous dichloromethane (3 mL), 80 mg of (3R,4S)-3-methoxy-4-((tetrahydro-2H-pyran-4-yl)amino)piperidine-1-carboxylic acid tert-butyl ester (compound 159-2) was added to 1,4-dioxane (4.0 mmol, 1.0 mL), and the mixture was stirred at room temperature for 2 h. The reaction solution was concentrated under reduced pressure to obtain the target compound (compound 159-3), which was directly used in the next step of the reaction.

[0629] Step 3: Synthesis of (3R,4S)-1-(6-ethyl-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)-1,8-naphthidin-2-yl)-3-methoxy-N-(tetrahydro-2H-pyran-4-yl)piperidine-4-amine (compound 159)

[0630] Potassium fluoride (58 mg, 1.0 mmol) and N,N-diisopropylethylamine (194 mg, 1.5 mmol) were added to 3 mL of dimethyl sulfoxide of 5-(2-chloro-6-ethyl-4-methyl-1,8-naphthid-3-yl)-3-methyl-1,2,4-oxadiazole (compound 2-4) (72 mg, 0.33 mmol) and (3R,4S)-3-methoxy-N-(tetrahydro-2H-pyran-4-yl)piperidine-4-amine hydrochloride (compound 159-3) (72 mg, 0.25 mmol). After the addition was complete, the mixture was stirred at 90 °C for 12 h. After cooling the reaction solution to room temperature, it was filtered through diatomaceous earth. The filter cake was washed with ethyl acetate, the filtrate was concentrated, and water (100 mL) was added. Extraction was performed with ethyl acetate (100 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by preparative column chromatography to obtain the target compound (compound 159) (30.0 mg, 0.064 mmol). MS: m / z = 467.3 [M+H] + .

[0631] 1 H NMR (400MHz, CDCl3) δ8.84(d,J=2.4Hz,1H),8.00(d,J=2.3Hz,1H),3.96(d,J=11.5Hz,2H),3.84-3.77(m,1H),3.73-3.62(m,1H),3.47-3.32(m, 3H),3.28(s,3H),3.12-3.06(m,1H),3.04-2.96(m,2H),2.86-2.69(m,3 H),2.55(s,3H),2.54(s,3H),1.83-1.57(m,7H),1.34(t,J=7.6Hz,3H).

[0632] Example 35: Synthesis of (3S,4R)-1-(6-ethyl-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)-1,8-naphthidin-2-yl)-3-methoxy-N-(tetrahydro-2H-pyran-4-yl)piperidine-4-amine (compound 160)

[0633] Step 1: Synthesis of (3S,4R)-3-methoxy-4-((tetrahydro-2H-pyran-4-yl)amino)piperidine-1-carboxylic acid tert-butyl ester (compound 160-2)

[0634] Acetic acid (1 drop) was added to a solution of (3S,4R)-4-amino-3-methoxypiperidine-1-carboxylic acid tert-butyl ester (200 mg, 0.87 mmol) and tetrahydropyranone (121 mg, 1.22 mmol) in anhydrous methanol (6 mL). The mixture was stirred at room temperature for 0.5 h, followed by the addition of sodium cyanoborohydride (109 mg, 1.74 mmol). The reaction mixture was stirred at room temperature for 12 h. The reaction solution was filtered through diatomaceous earth, the filter cake was washed with ethyl acetate, the filtrate was concentrated, and 20 mL of water was added. The mixture was extracted with ethyl acetate (20 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then subjected to column chromatography to obtain the target compound (compound 160-2) (157 mg, 0.50 mmol). MS: m / z = 315.3 [M+H] + .

[0635] Step 2: Synthesis of (3S,4R)-3-methoxy-N-(tetrahydro-2H-pyran-4-yl)piperidine-4-amine hydrochloride (compound 160-3):

[0636] To anhydrous dichloromethane (3 mL), tert-butyl hydrochloride / 1,4-dioxane (5.00 mmol, 1.25 mL) of (3S,4R)-3-methoxy-4-((tetrahydro-2H-pyran-4-yl)amino)piperidine-1-carboxylic acid (compound 160-2) (157 mg, 0.50 mmol) was added, and the mixture was stirred at room temperature for 2 h. The reaction solution was concentrated under reduced pressure to obtain the target compound (compound 160-3), which was directly used in the next step of the reaction.

[0637] Step 3: Synthesis of (3S,4R)-1-(6-ethyl-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)-1,8-naphthidin-2-yl)-3-methoxy-N-(tetrahydro-2H-pyran-4-yl)piperidine-4-amine (compound 160)

[0638] Potassium fluoride (80 mg, 1.40 mmol) and N,N-diisopropylethylamine (268 mg, 2.10 mmol) were added to 3 mL of dimethyl sulfoxide of 5-(2-chloro-6-ethyl-4-methyl-1,8-naphthid-3-yl)-3-methyl-1,2,4-oxadiazole (compound 2-4) (100 mg, 0.35 mmol) and (3S,4R)-3-methoxy-N-(tetrahydro-2H-pyran-4-yl)piperidine-4-amine hydrochloride (compound 160-3) (140 mg, 0.49 mmol). After the addition was complete, the mixture was stirred at 90 °C for 12 h. After cooling the reaction solution to room temperature, it was filtered through diatomaceous earth. The filter cake was washed with ethyl acetate, the filtrate was concentrated, and water (100 mL) was added. The solution was extracted with ethyl acetate (100 mL x 3), and the combined organic phases were dried over anhydrous sodium sulfate. The mixture was filtered, concentrated under reduced pressure, and purified by preparative column chromatography to obtain the target compound (compound 160) (80.0 mg, 0.17 mmol). MS: m / z = 467.3 [M+H] + .

[0639] 1 H NMR (400MHz, CDCl3) δ8.84(d,J=2.3Hz,1H),8.00(d,J=2.2Hz,1H),3.96(d,J=11.4Hz,2H),3.85-3.76(m,1H),3.75-3.67(m,1H),3.42-3.34(m, 3H),3.28(s,3H),3.12-.036(m,1H),3.05-2.95(m,2H),2.86-2.74(m,3 H),2.56(s,3H),2.54(s,3H),1.84-1.54(m,7H),1.34(t,J=7.6Hz,3H).

[0640] Example 36: Synthesis of N-(6,6-difluorobicyclo[3.1.0]hexane-3-yl)-1-(6-ethyl-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)-1,8-naphthidin-2-yl)piperidine-4-amine (compound 161)

[0641] Step 1: Synthesis of tert-butyl 4-((6,6-difluorobicyclo[3.1.0]hexane-3-yl)amino)piperidine-1-carboxylate (compound 161-2)

[0642] To a solution of 6,6-difluorobicyclo[3.1.0]hexyl-3-amine (compound 161-1) (73 mg, 0.55 mmol) and tert-butyl 4-oxopiperidinium-1-carboxylate (100 mg, 0.50 mmol) in anhydrous methanol (6 mL), tetraisopropyl titanate (286 mg, 1.00 mmol) was added, and the mixture was stirred at room temperature for 0.5 h. Sodium cyanoborohydride (94 mg, 1.50 mmol) was then added, and the mixture was stirred at 85 °C for 12 h. The reaction mixture was filtered through diatomaceous earth, the filter cake was washed with ethyl acetate, the filtrate was concentrated, and 20 mL of water was added. The mixture was extracted with ethyl acetate (20 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then subjected to column chromatography to obtain the target compound (compound 161-2) (100 mg, 0.32 mmol). MS: m / z = 317.3 [M+H] + .

[0643] Step 2: Synthesis of N-(6,6-difluorobicyclo[3.1.0]hexane-3-yl)piperidine-4-amine hydrochloride (compound 161-3)

[0644] Hydrochloric acid / 1,4-dioxane (3.2 mmol, 0.8 mL) was added to anhydrous dichloromethane (3 mL) containing 100 mg (100 mg, 0.32 mmol) of tert-butyl piperidine-1-carboxylate (compound 161-2). The mixture was stirred at room temperature for 2 h. The reaction solution was concentrated under reduced pressure to obtain the target compound (compound 161-3), which was directly used in the next step of the reaction.

[0645] Step 3: Synthesis of N-(6,6-difluorobicyclo[3.1.0]hexane-3-yl)-1-(6-ethyl-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)-1,8-naphthidin-2-yl)piperidine-4-amine (compound 161)

[0646] Potassium fluoride (40 mg, 0.68 mmol) and N,N-diisopropylethylamine (134 mg, 1.02 mmol) were added to dimethyl sulfoxide (3 mL) of 5-(2-chloro-6-ethyl-4-methyl-1,8-naphthid-3-yl)-3-methyl-1,2,4-oxadiazole (compound 2-4) (49 mg, 0.17 mmol) and N-(6,6-difluorobicyclo[3.1.0]hexane-3-yl)piperidine-4-amine hydrochloride (compound 161-3) (98 mg, 0.34 mmol), and the mixture was stirred at 90 °C for 12 h. After cooling the reaction solution to room temperature, it was filtered through diatomaceous earth. The filter cake was washed with ethyl acetate, the filtrate was concentrated, and water (100 mL) was added. The mixture was extracted with ethyl acetate (100 mL x 3), and the combined organic phases were dried over anhydrous sodium sulfate. The mixture was filtered, concentrated under reduced pressure, and purified by preparative column chromatography to obtain the target compound (compound 161) (10.0 mg, 0.021 mmol). MS: m / z = 469.2 [M+H] + .

[0647] 1 H NMR (400MHz, CDCl3) δ8.85(d,J=2.2Hz,1H),8.01(d,J=2.2Hz,1H),3.70(d,J=13.0Hz,2H),3.36-3.24(m,1H),2.90(t,J=11.7Hz,2H),2.83(q,J= 7.6Hz,2H),2.72-2.60(m,1H),2.55(s,3H),2.53(s,3H),2.29(dd,J=13 .1,7.2Hz,2H),1.99-1.74(m,7H),1.62-1.57(m,1H),1.42-1.32(m,4H).

[0648] Example 37: Synthesis of (3S,4S)-1-(6-ethyl-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)-1,8-naphthidin-2-yl)-3-methoxy-N-(tetrahydro-2H-pyran-4-yl)piperidine-4-amine (compound 162)

[0649] Step 1: Synthesis of (3S,4S)-3-methoxy-4-((tetrahydro-2H-pyran-4-yl)amino)piperidine-1-carboxylic acid tert-butyl ester (compound 162-2)

[0650] A solution of (3S,4S)-4-amino-3-methoxypiperidine-1-carboxylic acid tert-butyl ester (compound 162-1) (200 mg, 0.87 mmol) and tetrahydropyranone (121 mg, 1.22 mmol) in anhydrous methanol (6 mL) was reacted with acetic acid (1 drop) at room temperature for 0.5 h, followed by the addition of sodium cyanoborohydride (109 mg, 1.74 mmol) and stirring at room temperature for 12 h. The reaction mixture was filtered through diatomaceous earth, the filter cake was washed with dichloromethane, the filtrate was concentrated, and 30 mL of water was added. The mixture was extracted with ethyl acetate (30 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and then subjected to column chromatography to obtain the target compound (compound 162-2) (200 mg, 0.64 mmol). MS: m / z = 315.3 [M+H] + .

[0651] Step 2: Synthesis of (3S,4S)-3-methoxy-N-(tetrahydro-2H-pyran-4-yl)piperidine-4-amine hydrochloride (compound 162-3)

[0652] To anhydrous dichloromethane (3 mL), tert-butyl hydrochloride / 1,4-dioxane (6.4 mmol, 1.6 mL) of (3S,4S)-3-methoxy-4-((tetrahydro-2H-pyran-4-yl)amino)piperidine-1-carboxylic acid (compound 162-2) (200 mg, 0.64 mmol) was added to tert-butyl hydrochloride (compound 162-2) and the mixture was stirred at room temperature for 2 h. The reaction solution was concentrated under reduced pressure to obtain the target compound (compound 162-3), which was directly used in the next step of the reaction.

[0653] Step 3: Synthesis of (3S,4S)-1-(6-ethyl-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)-1,8-naphthidin-2-yl)-3-methoxy-N-(tetrahydro-2H-pyran-4-yl)piperidine-4-amine (compound 162)

[0654] Potassium fluoride (80 mg, 1.4 mmol) and N,N-diisopropylethylamine (268 mg, 2.1 mmol) were added to a solution of 5-(2-chloro-6-ethyl-4-methyl-1,8-naphthid-3-yl)-3-methyl-1,2,4-oxadiazole (compound 2-4) (100 mg, 0.35 mmol) and (3S,4S)-3-methoxy-N-(tetrahydro-2H-pyran-4-yl)piperidine-4-amine hydrochloride (compound 162-3) (141 mg, 0.49 mmol) in dimethyl sulfoxide (3 mL). After the addition was complete, the mixture was stirred at 90 °C for 12 h. After cooling the reaction solution to room temperature, it was filtered through diatomaceous earth. The filter cake was washed with ethyl acetate, the filtrate was concentrated, and water (30 mL) was added. The mixture was extracted with ethyl acetate (30 mL x 3), and the combined organic phases were dried over anhydrous sodium sulfate. The mixture was filtered, concentrated under reduced pressure, and purified by preparative column chromatography to obtain the target compound (compound 162) (30.0 mg, 0.06 mmol). MS: m / z = 467.3 [M+H] + .

[0655] 1 H NMR (400MHz, CDCl3) δ8.84(d,J=2.2Hz,1H),8.00(d,J=2.2Hz,1H),3.96(d,J=11.5Hz,2H),3 .80(dd,J=13.8,5.6Hz,1H),3.72-3.63(m,1H),3.47-3.33(m,3H),3.28(s,3H),3.09(dd,J= 13.7,1.9Hz,1H),3.05-2.94(m,2H),2.82(q,J=7.6Hz,2H),2.78-2.71(m,1H),2.55(s,3H), 2.53(s,3H),1.82-1.67(m,4H),1.65-1.61(m,1H),1.53-1.38(m,2H),1.34(t,J=7.6Hz,3H).

[0656] Example 38: Synthesis of 1-(6-ethyl-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)-1,8-naphthidin-2-yl)-N-(1-methyl-1H-pyrazol-4-yl)piperidine-4-amine (compound 163)

[0657] Step 1: Synthesis of tert-butyl 4-((1-methyl-1H-pyrazol-4-yl)amino)piperidine-1-carboxylate (compound 163-2)

[0658] 1-Methyl-1H-pyrazole-4-amine (compound 163-1) (97 mg, 1.00 mmol) and tert-butyl 4-oxopiperidinium-1-carboxylate (199 mg, 1.00 mmol) were dissolved in anhydrous methanol (3 mL). The solution was cooled to 0 °C, and 1 drop of trifluoroacetic acid and 126 mg of sodium cyanoborohydride (2.00 mmol) were added. After the addition was complete, the mixture was transferred to room temperature and stirred for 12 h. The reaction solution was filtered through diatomaceous earth, the filter cake was washed with ethyl acetate, the filtrate was concentrated, and 30 mL of water was added. The solution was extracted with ethyl acetate (30 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain the target compound (compound 163-2) (147 mg, 0.53 mmol). MS: m / z = 225.2 [M+H] + .

[0659] Step 2: Synthesis of N-(1-methyl-1H-pyrazol-4-yl)piperidine-4-amine hydrochloride (compound 163-3)

[0660] 4-((1-methyl-1H-pyrazol-4-yl)amino)piperidine-1-carboxylic acid tert-butyl ester (compound 163-2) (147 mg, 0.53 mmol) was dissolved in anhydrous dichloromethane (2 mL), and hydrochloric acid / 1,4-dioxane (5.2 mmol, 1.3 mL) was added. The mixture was stirred at room temperature for 2 h. The reaction solution was concentrated under reduced pressure to obtain the target compound (compound 163-3), which was directly used in the next step of the reaction.

[0661] Step 3: Synthesis of 1-(6-ethyl-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)-1,8-naphthidin-2-yl)-N-(1-methyl-1H-pyrazol-4-yl)piperidine-4-amine (compound 163)

[0662] 5-(2-chloro-6-ethyl-4-methyl-1,8-naphthid-3-yl)-3-methyl-1,2,4-oxadiazole (compound 2-4) (50 mg, 0.17 mmol), N-(1-methyl-1H-pyrazol-4-yl)piperidine-4-amine hydrochloride (compound 163-3) (86.1 mg, 0.34 mmol) and potassium fluoride (20 mg, 0.36 mmol) were dissolved in dimethyl sulfoxide (3 mL), and N,N-diisopropylethylamine (134 mg, 1.04 mmol) was added. After the addition was complete, the mixture was stirred at 95 °C for 12 h. After cooling the reaction solution to room temperature, it was filtered through diatomaceous earth. The filter cake was washed with ethyl acetate, the filtrate was concentrated, and water (100 mL) was added. Extraction was performed with ethyl acetate (100 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by preparative column chromatography to obtain the target compound (compound 163) (24.3 mg, 0.05 mmol). MS: m / z = 432.35 [M+H] + .

[0663] 1 H NMR (400MHz, CDCl3) δ8.84(s,1H),8.01(d,J=1.7Hz,1H),7.09(s,1H),6.91(s,1H),3.78(s, 3H),3.68(d,J=13.5Hz,2H),3.05-2.90(m,3H),2.82(q,J=7.6Hz,2H),2.54(s,6H),2.18(br s,1H),2.02-1.97(m,2H),1.45-1.30(m,5H).

[0664] Example 39: Synthesis of N-(3-oxabicyclo[3.1.0]hexane-6-yl)-1-(6-ethyl-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)-1,8-naphthidin-2-yl)piperidine-4-amine (compound 164)

[0665] Step 1: Synthesis of tert-butyl 4-((3-oxabicyclo[3.1.0]hexane-6-yl)amino)piperidine-1-carboxylate (compound 164-2)

[0666] Acetic acid (84 mg, 2.0 mmol) was added to a solution of 3-oxabicyclo[3.1.0]hexane-6-amine (399 mg, 2.0 mmol) and tetrahydropyranone (397 mg, 4.0 mmol) in anhydrous dichloromethane (5 mL). After stirring at room temperature for 0.5 h, sodium cyanoborohydride (251 mg, 4.0 mmol) was added, and the reaction was stirred at room temperature for 12 h. The reaction solution was filtered through diatomaceous earth, the filter cake was washed with ethyl acetate, the filtrate was concentrated, 30 mL of water was added, and the solution was extracted with ethyl acetate (30 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then subjected to column chromatography to obtain the target compound (compound 164-2) (450 mg, 1.59 mmol). MS: m / z = 283.2 [M+H] + .

[0667] Step 2: Synthesis of N-(3-oxabicyclo[3.1.0]hexane-6-yl)piperidine-4-amine hydrochloride (compound 164-3)

[0668] Hydrochloric acid / 1,4-dioxane (16.0 mmol, 4.0 mL) was added to anhydrous dichloromethane (5 mL) containing 4-((3-oxabicyclo[3.1.0]hexan-6-yl)amino)piperidine-1-carboxylic acid tert-butyl ester (compound 164-2) (450 mg, 1.59 mmol), and the mixture was stirred at room temperature for 2 h. The reaction solution was concentrated under reduced pressure to obtain the target compound (compound 164-3), which was directly used in the next step of the reaction.

[0669] Step 3: Synthesis of N-(3-oxabicyclo[3.1.0]hexane-6-yl)-1-(6-ethyl-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)-1,8-naphthidin-2-yl)piperidine-4-amine (compound 164)

[0670] Potassium fluoride (29 mg, 0.5 mmol) and N,N-diisopropylethylamine (129 mg, 1.0 mmol) were added to a solution of 5-(2-chloro-6-ethyl-4-methyl-1,8-naphthid-3-yl)-3-methyl-1,2,4-oxadiazole (compound 2-4) (72 mg, 0.25 mmol), N-(3-oxadicyclo[3.1.0]hexane-6-yl)piperidine-4-amine hydrochloride (compound 164-3) (128 mg, 0.5 mmol) in dimethyl sulfoxide (2 mL). After the addition was complete, the mixture was stirred at 110 °C for 12 h. After cooling the reaction solution to room temperature, it was filtered through diatomaceous earth. The filter cake was washed with ethyl acetate, the filtrate was concentrated, and water (20 mL) was added. The mixture was extracted with ethyl acetate (20 mL x 3), and the combined organic phases were dried over anhydrous sodium sulfate. The mixture was filtered, concentrated under reduced pressure, and purified by preparative column chromatography to obtain the target compound (compound 164) (25.0 mg, 0.58 mmol). MS: m / z = 435.35 [M+H] + .

[0671] 1 H NMR (400MHz, DMSO) δ8.85(d,J=2.3Hz,1H),8.29(d,J=2.3Hz,1H),3.73(d,J=8.2Hz,2H),3.57(d,J=8.1Hz,2H),3.54-3.47(m,2H),2.91-2.79(m,4H), 2.68-2.60(m,1H),2.55(s,3H),2.53-2.51(m,4H),1.87-1.83(m,1H),1.83 -1.74(m,2H),1.59-1.53(m,2H),1.31(t,J=7.6Hz,3H),1.27-1.15(m,2H).

[0672] Example 40: Synthesis of N-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-(6-ethyl-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)-1,8-naphthid-2-yl)piperidine-4-amine (compound 165)

[0673] Step 1: Synthesis of tert-butyl 4-(2,2-dimethyltetrahydro-2H-pyran-4-yl)amino)piperidine-1-carboxylate (compound 165-2)

[0674] Formic acid (0.1 mL) was added to a methanol (5 mL) solution of tert-butyl 4-oxopiperidin-1-carboxylate (500 mg, 2.51 mmol) and 2,2-dimethyltetrahydropyran-4-amine (compound 165-1) (324 mg, 2.51 mol). After stirring at room temperature for 0.5 h, sodium cyanoborohydride (315 mg, 5.02 mmol) was added, and the reaction mixture was stirred at room temperature for 12 h. The reaction solution was filtered through diatomaceous earth, the filter cake was washed with ethyl acetate, the filtrate was concentrated, and 20 mL of water was added. The mixture was extracted with ethyl acetate (20 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then subjected to column chromatography to obtain the target compound (compound 165-2) (660 mg, 2.11 mmol). MS: m / z = 313.4 [M+H] + .

[0675] Step 2: Synthesis of N-(2,2-dimethyltetrahydro-2H-pyran-4-yl)piperidin-4-amine trifluoroacetate (compound 165-3)

[0676] Trifluoroacetic acid (0.5 mL) was added to a solution of tert-butyl 4-(2,2-dimethyltetrahydro-2H-pyran-4-yl)amino)piperidine-1-carboxylate (660 mg, 2.11 mmol) in dichloromethane (5 mL). After the addition was complete, the mixture was stirred at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure to obtain the target compound (compound 165-3), which was directly used in the next step of the reaction.

[0677] Step 3: Synthesis of N-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-(6-ethyl-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)-1,8-naphthidin-2-yl)piperidine-4-amine (compound 165)

[0678] Potassium fluoride (40 mg, 0.69 mmol) and N,N-diisopropylethylamine (90 mg, 0.69 mmol) were added to a solution of 5-(2-chloro-6-ethyl-4-methyl-1,8-naphthid-3-yl)-3-methyl-1,2,4-oxadiazole (compound 2-4) (100 mg, 0.35 mmol), N-(2,2-dimethyltetrahydropyran-4-yl)piperidin-4-amine trifluoroacetate (compound 165-3) (185 mg, 0.42 mmol) in dimethyl sulfoxide (2 mL). After the addition was complete, the mixture was stirred at 115 °C for 4 hours. After cooling the reaction solution to room temperature, it was filtered through diatomaceous earth. The filter cake was washed with ethyl acetate, the filtrate was concentrated, and water (20 mL) was added. The mixture was extracted with ethyl acetate (20 mL x 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by preparative column chromatography to obtain the target compound (compound 165) (89 mg, 191.56 μmol). MS: m / z = 465.35 [M+H] + .

[0679] 1 H NMR (400MHz, CDCl3) δ8.84(d,J=2.4Hz,1H),8.00(d,J=2.3Hz,1H),3.79-3.59(m,4H),3.02-2.87(m,3H) ,2.87-2.76(m,3H),2.55(s,3H),2.53(s,3H),1.86-1.72(m,5H),1.37-1.31(m,5H),1.25-1.13(m,8H).

[0680] Example 41: Synthesis of 1-(6-ethyl-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)-1,8-naphthidin-2-yl)-N-(1-(methanesulfonyl)piperidin-4-yl)piperidin-4-amine (compound 177)

[0681] Step 1: Synthesis of tert-butyl 4-((1-(methylsulfonyl)piperidin-4-yl)amino)piperidin-1-carboxylate (compound 177-2)

[0682] A solution of 1-(methanesulfonyl)piperidin-4-amine (compound 177-1) (267 mg, 1.50 mmol) and tert-butyl 4-oxopiperidin-1-carboxylate (200 mg, 1.00 mmol) in anhydrous methanol (10 mL) was reacted with acetic acid (1 drop) at room temperature for 0.5 h, followed by the addition of sodium cyanoborohydride (189 mg, 3.00 mmol) and stirring at room temperature for 12 h. The reaction mixture was filtered through diatomaceous earth, the filter cake was washed with ethyl acetate, the filtrate was concentrated, and 30 mL of water was added. The mixture was extracted with ethyl acetate (30 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then subjected to column chromatography to obtain the target compound (compound 177-2) (80 mg, 0.22 mmol). MS: m / z = 362.4 [M+H] + .

[0683] Step 2: Synthesis of 1-(methylsulfonyl)-N-(piperidin-4-yl)piperidin-4-amine hydrochloride (compound 177-3)

[0684] Hydrochloric acid / 1,4-dioxane (4.0 mmol, 1.0 mL) was added to a solution of tert-butyl 4-(1-(methanesulfonyl)piperidin-4-yl)amino)piperidin-1-carboxylic acid (tert-butyl ester) (compound 177-2) (80 mg, 0.22 mmol) in anhydrous dichloromethane (3 mL), and the mixture was stirred at room temperature for 2 h. The reaction solution was concentrated under reduced pressure to obtain the target compound (compound 177-3), which was directly used in the next step of the reaction.

[0685] Step 3: Synthesis of 1-(6-ethyl-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)-1,8-naphthidin-2-yl)-N-(1-(methanesulfonyl)piperidin-4-yl)piperidin-4-amine (compound 177)

[0686] Potassium fluoride (40 mg, 0.68 mmol) and N,N-diisopropylethylamine (135 mg, 1.02 mmol) were added to dimethyl sulfoxide (3 mL) of 5-(2-chloro-6-ethyl-4-methyl-1,8-naphthid-3-yl)-3-methyl-1,2,4-oxadiazole (compound 2-4) (50 mg, 0.17 mmol) and 1-(methanesulfonyl)-N-(piperidin-4-yl)piperidin-4-amine hydrochloride (compound 177-3) (87 mg, 0.26 mmol). After the addition was complete, the mixture was stirred at 90 °C for 12 h. After cooling the reaction solution to room temperature, it was filtered through diatomaceous earth. The filter cake was washed with ethyl acetate, the filtrate was concentrated, and water (30 mL) was added. The mixture was extracted with ethyl acetate (30 mL x 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by preparative column chromatography to obtain the target compound (compound 177) (25.0 mg, 0.049 mmol). MS: m / z = 514.2 [M+H] + .

[0687] 1 H NMR (400MHz, CDCl3) δ8.85(d,J=2.1Hz,1H),8.02(d,J=1.8Hz,1H),3.78-3.66(m,4H),2.92(t,J=12.6Hz,2H),2.87-2.81(m,5H ),2.80-2.74(m,4H),2.55(s,3H),2.54(s,3H),2.00-1.84(m,5H),1.59-1.48(m,2H),1.45-1.36(m,2H),1.34(t,J=7.6Hz,3H).

[0688] Example 42: Synthesis of 1-(6-ethyl-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)-1,8-naphthidin-2-yl)-N-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methyl)piperidin-4-amine (compound 181)

[0689] Step 1: Synthesis of ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methylethanesulfonate (compound 181-2)

[0690] ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (compound 181-1) (200 mg, 1.26 mmol) and triethylamine (381 mg, 3.77 mmol) were dissolved in anhydrous dichloromethane (3 mL), cooled to 0 °C, and ethylsulfonyl chloride (178 mg, 1.36 mmol) was added. After the addition was complete, the mixture was stirred at room temperature for 2 h. The reaction solution was then concentrated and proceeded directly to the next step of the reaction.

[0691] Step 2: Synthesis of tert-butyl 4-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methyl)amino)piperidine-1-carboxylate (compound 181-3)

[0692] The ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methyl ethanesulfonate (compound 181-2) (317 mg, 1.26 mmol) and tert-butyl 4-aminopiperidine-1-carboxylate (251 mg, 1.25 mmol) obtained in the previous step were dissolved in anhydrous acetonitrile (3 mL), and the mixture was stirred at 80 °C for 12 h. After cooling the reaction solution to room temperature, it was concentrated under reduced pressure and then subjected to column chromatography to obtain the target compound (compound 181-3) (235 mg, 0.69 mmol). MS: m / z = 342.2 [M+H] + .

[0693] Step 3: Synthesis of N-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methyl)piperidine-4-amine trifluoroacetate (compound 181-4)

[0694] 350 mg (1.08 mmol) of tert-butyl 4-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methyl)amino)piperidine-1-carboxylic acid (compound 181-3) was dissolved in anhydrous dichloromethane (3 mL), and 0.5 mL of trifluoroacetic acid was added. The mixture was stirred at room temperature for 2 h. The reaction solution was concentrated under reduced pressure to obtain the target compound (compound 181-4), which was directly used in the next step of the reaction.

[0695] Step 4: Synthesis of 1-(6-ethyl-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)-1,8-naphthidin-2-yl)-N-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methyl)piperidin-4-amine (compound 181)

[0696] 5-(2-chloro-6-ethyl-4-methyl-1,8-naphthid-3-yl)-3-methyl-1,2,4-oxadiazole (compound 2-4) (70 mg, 0.24 mmol), N-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methyl)piperidin-4-amine trifluoroacetate (225 mg, 0.48 mmol) and potassium fluoride (28 mg, 0.48 mmol) were dissolved in dimethyl sulfoxide (3 mL), and N,N-diisopropylethylamine (186 mg, 1.44 mmol) was added. The mixture was stirred at 95 °C for 12 h. After cooling the reaction solution to room temperature, it was filtered through diatomaceous earth. The filter cake was washed with ethyl acetate, the filtrate was concentrated, and water (30 mL) was added. The mixture was extracted with ethyl acetate (30 mL x 3), and the combined organic phases were dried over anhydrous sodium sulfate. The mixture was filtered, concentrated under reduced pressure, and purified by preparative column chromatography to obtain the target compound (compound 181) (14 mg, 0.03 mmol). MS: m / z = 494.3 [M+H] + .

[0697] 1 H NMR (400MHz, CDCl3) δ8.82(d,J=2.1Hz,1H),7.98(d,J=1.8Hz,1H),5.17(d,J=54.1Hz,1H),3.67-3.58(m,2H),3.19-2.85(m,6 H),2.80(q,J=7.6Hz,2H),2.60-2.48(m,8H),2.43(t,J=13.4Hz,2H),2.28-1.91(m,3H),1.90-1.70(m,5H),1.40-1.25(m,5H).

[0698] Example 43: Synthesis of 1-(6-ethyl-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)-1,8-naphthidin-2-yl)-N-(7-oxaspiro[3.5]non-2-yl)piperidine-4-amine (compound 182)

[0699] Step 1: Synthesis of tert-butyl 4-((7-oxaspiro[3.5]non-2-yl)amino)piperidine-1-carboxylate (compound 182-2)

[0700] A solution of 7-oxaspiro[3.5]non-2-one (compound 182-1) (245 mg, 1.75 mmol) and tert-butyl 4-aminopiperidine-1-carboxylate (250 mg, 1.25 mmol) in anhydrous methanol (4 mL) was reacted with tetraisopropyl titanate (710 mg, 2.50 mmol) at room temperature for 0.5 h, followed by the addition of sodium cyanoborohydride (236 mg, 3.75 mmol) and stirring at 85 °C for 12 h. The reaction mixture was filtered through diatomaceous earth, the filter cake was washed with dichloromethane, the filtrate was concentrated, and 30 mL of water was added. The mixture was extracted with ethyl acetate (30 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and then subjected to column chromatography to obtain the target compound (compound 182-2) (87 mg, 0.27 mmol). MS: m / z = 325.2 [M+H] + .

[0701] Step 2: Synthesis of N-(7-oxaspiro[3.5]non-2-yl)piperidine-4-amine hydrochloride (compound 182-3)

[0702] To anhydrous dichloromethane (3 mL), 87 mg (0.27 mmol) of tert-butyl 4-((7-oxaspiro[3.5]non-2-yl)amino)piperidin-1-carboxylic acid (compound 182-2) was added to 1,4-dioxane (4.00 mmol, 1.00 mL), and the mixture was stirred at room temperature for 2 h. The reaction solution was concentrated under reduced pressure to obtain the target compound (compound 182-3), which was directly used in the next step of the reaction.

[0703] Step 3: Synthesis of 1-(6-ethyl-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)-1,8-naphthidin-2-yl)-N-(7-oxaspiro[3.5]non-2-yl)piperidine-4-amine (compound 182)

[0704] Potassium fluoride (40 mg, 0.68 mmol) and N,N-diisopropylethylamine (134 mg, 1.02 mmol) were added to a solution of 5-(2-chloro-6-ethyl-4-methyl-1,8-naphthid-3-yl)-3-methyl-1,2,4-oxadiazole (compound 2-4) (50 mg, 0.17 mmol), N-(7-oxaspiro[3.5]non-2-yl)piperidine-4-amine hydrochloride (compound 182-3) (101 mg, 0.34 mmol) in dimethyl sulfoxide (3 mL). After the addition was complete, the mixture was stirred at 90 °C for 12 h. After cooling the reaction solution to room temperature, it was filtered through diatomaceous earth. The filter cake was washed with ethyl acetate, the filtrate was concentrated, and water (30 mL) was added. The mixture was extracted with ethyl acetate (30 mL x 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by preparative column chromatography to obtain the target compound (compound 182) (23.0 mg, 0.04 mmol). MS: m / z = 477.3 [M+H] + .

[0705] 1 H NMR (400MHz, CDCl3) δ8.84(d,J=2.4Hz,1H),8.01(d,J=2.3Hz,1H),3.69(d,J=13.3Hz ,2H),3.64-3.58(m,2H),3.56-3.50(m,2H),3.44-3.33(m,1H),2.90(t,J=11.7Hz,2H ),2.83(q,J=7.6Hz,2H),2.73-2.62(m,1H),2.55(s,3H),2.53(s,3H),2.28-2.18(m, 2H),1.90-1.76(m,3H),1.64-1.51(m,6H),1.45-1.37(m,2H),1.34(t,J=7.6Hz,3H).

[0706] Example 44: Synthesis of 5-benzyl-N-(1-(6-ethyl-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)-1,8-naphthidin-2-yl)piperidin-4-yl)-5-azaspiro[2.4]heptane-7-amine (compound 183)

[0707] Step 1: Synthesis of tert-butyl 4-((5-benzyl-5-azaspiro[2,4]heptane-7-yl)amino)piperidine-1-carboxylate (compound 183-2)

[0708] 5-Benzyl-5-azaspiro[2.4]heptane-7-amine (compound 183-1) (203 mg, 1.0 mmol) and tert-butyl 4-oxopiperidinium-1-carboxylate (199 mg, 1.0 mmol) were dissolved in anhydrous methanol (3 mL). After cooling to 0 °C, trifluoroacetic acid (1 drop) and sodium cyanoborohydride (126 mg, 2.0 mmol) were added. The mixture was stirred at room temperature for 12 h. The reaction solution was filtered through diatomaceous earth, the filter cake was washed with ethyl acetate, the filtrate was concentrated, and 30 mL of water was added. The mixture was extracted with ethyl acetate (30 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then subjected to column chromatography to obtain the target compound (compound 183-2) (235 mg, 0.61 mmol). MS: m / z = 386.5 [M+H] + .

[0709] Step 2: Synthesis of 5-benzyl-N-(piperidin-4-yl)-5-azaspiro[2.4]heptane-7-aminetrifluoroacetic acid (compound 183-3)

[0710] 4-((5-benzyl-5-azaspiro[2.4]heptane-7-yl)amino)piperidine-1-carboxylic acid tert-butyl ester (183-2) (235 mg, 0.61 mmol) was dissolved in anhydrous dichloromethane (4 mL), and trifluoroacetic acid (1 mL) was added. The mixture was stirred at room temperature for 2 h. The reaction solution was concentrated under reduced pressure to obtain the target compound (compound 183-3), which was directly used in the next step of the reaction.

[0711] Step 3: Synthesis of 5-benzyl-N-(1-(6-ethyl-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)-1,8-naphthidin-2-yl)piperidin-4-yl)-5-azaspiro[2.4]heptane-7-amine (compound 183)

[0712] 5-(2-chloro-6-ethyl-4-methyl-1,8-naphthid-3-yl)-3-methyl-1,2,4-oxadiazole (compound 2-4) (70 mg, 0.24 mmol), 5-benzyl-N-(piperidin-4-yl)-5-azaspiro[2.4]heptane-7-amine trifluoroacetate (246 mg, 0.48 mmol) and potassium fluoride (28 mg, 0.48 mmol) were dissolved in dimethyl sulfoxide (3 mL), and N,N-diisopropylethylamine (186 mg, 1.44 mmol) was added. The mixture was stirred at 95 °C for 12 h. After cooling the reaction solution to room temperature, it was filtered through diatomaceous earth. The filter cake was washed with ethyl acetate, the filtrate was concentrated, and water (30 mL) was added. The mixture was extracted with ethyl acetate (30 mL x 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by preparative column chromatography to obtain the target compound (compound 183) (8 mg, 0.02 mmol). MS: m / z = 538.4 [M+H] + .

[0713] 1 H NMR (400MHz, CDCl3) δ8.83(d,J=2.2Hz,1H),7.99(d,J=2.1Hz,1H),7.34-7.29(m,4H),7. 25-7.21(m,1H),3.67-3.55(m,4H),3.11-3.03(m,2H),2.95-2.77(m,4H),2.61-2.45(m,1 0H),2.41-2.33(m,1H),1.79-1.66(m,3H),1.36-1.32(m,4H),0.78(dt,J=10.1,5.2Hz,1H ),0.59(dt,J=9.8,5.0Hz,1H),0.49(dt,J=10.1,5.2Hz,1H),0.32(dt,J=9.8,5.0Hz,1H).

[0714] Example 45: Synthesis of cyclopropyl(4-(1-(6-ethyl-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)-1,8-naphthidin-2-yl)piperidin-4-yl)amino)piperidin-1-yl)methyl ketone (compound 194)

[0715] Step 1: Synthesis of benzyl 4-(1-(tert-Butoxycarbonyl)piperidin-4-yl)amino)piperidin-1-carboxylate (compound 194-1)

[0716] 1-Benzyloxycarbonyl-4-piperidinone (10 g, 42.87 mmol) and 4-amino-1-tert-butyloxycarbonylpiperidin (8.76 g, 43.73 mmol) were added to a reaction flask, dissolved in 140 mL of methanol, and then acetic acid (12.87 g, 214.35 mmol) was added. The reaction system was cooled to 5 °C, and sodium triacetoxyborohydride (8.08 g, 128.61 mmol) was added in portions. After the addition was complete, the mixture was brought to room temperature and stirred for 4 h. The pH was adjusted to approximately 8 by adding saturated sodium carbonate aqueous solution under ice bath conditions. The methanol was removed by concentration, and the mixture was extracted with dichloromethane (200 mL x 3). The organic phases were combined, washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the target compound (compound 194-1) (17.5 g, 41.91 mmol). MS: m / z = 417.9 [M+H] + .

[0717] Step 2: Synthesis of tert-butyl 4-(piperidin-4-ylamino)piperidin-1-carboxylate (compound 194-2)

[0718] Benzyl 4-(1-(tert-Butoxycarbonyl)piperidin-4-yl)amino)piperidin-1-carboxylate (compound 194-1) (50 g, 119.9 mmol) was placed in an autoclave, and 500 mL of methanol was added. The mixture was stirred at 60 °C for 24 h under a hydrogen atmosphere (3 MPa). The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The solid was then slurried with 100 mL of ethyl acetate and filtered to obtain the target compound (compound 194-2) (26.92 g, 94.98 mmol). MS: m / z = 284.0 [M+H] + .

[0719] Step 3: Synthesis of tert-butyl 4-((1-(cyclopropanecarbonyl)piperidin-4-yl)amino)piperidin-1-carboxylate (compound 194-3)

[0720] 4-(piperidin-4-ylamino)piperidin-1-carboxylic acid tert-butyl ester (compound 194-2) (4 g, 14.11 mmol) was dissolved in dichloromethane (40 mL) in a reaction flask. After purging with nitrogen, triethylamine (2.14 g, 21.17 mmol) was added. After the addition was complete, the reaction mixture was placed in an ice bath, and cyclopropionyl chloride (1.62 g, 15.52 mmol) was slowly added dropwise. After the addition was complete, the mixture was transferred to room temperature and stirred. LC-MS analysis was performed. After the reaction was complete, water (100 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (100 mL x 3). The organic phases were combined, washed with water, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain the target compound (compound 194-3) (2.1 g, 5.97 mmol). MS: m / z = 352.0 [M+H] + .

[0721] Step 4: Synthesis of cyclopropyl (4-(piperidin-4-ylamino)piperidin-1-yl)methyl ketone hydrochloride (compound 194-4)

[0722] 2 g (5.7 mmol) of tert-butyl 4-((1-(cyclopropanecarbonyl)piperidin-4-yl)amino)piperidin-1-carboxylic acid (compound 194-3) was added to a reaction flask and dissolved in ethyl acetate (10 mL). 4 M hydrochloric acid / ethyl acetate (40 mmol, 10 mL) was slowly added dropwise under ice bath conditions. After the addition was complete, the mixture was moved to room temperature and stirred for 12 h. The solid was then concentrated under reduced pressure after filtration to obtain the target compound (compound 194-4) (1.7 g, 5.25 mmol). MS: m / z = 252.0 [M+H] + .

[0723] Step 5: Synthesis of cyclopropyl(4-(1-(6-ethyl-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)-1,8-naphthidin-2-yl)piperidin-4-yl)amino)piperidin-1-yl)methyl ketone (compound 194)

[0724] 5-(2-chloro-6-ethyl-4-methyl-1,8-naphthid-3-yl)-3-methyl-1,2,4-oxadiazole (compound 2-4) (80 mg, 0.28 mmol) and cyclopropyl(4-(piperidin-4-ylamino)piperidin-1-yl) methyl ketone hydrochloride (compound 194-4) (135 mg, 0.42 mmol) were dissolved in DMSO (4 mL), and N,N-diisopropylethylamine (220 mg, 1.70 mmol) and potassium fluoride (65 mg, 1.12 mmol) were added. The mixture was heated to 100 °C and reacted for 4 hours. After cooling the reaction solution to room temperature, it was filtered through diatomaceous earth. The filter cake was washed with ethyl acetate, the filtrate was concentrated, and water (30 mL) was added. The mixture was extracted with ethyl acetate (30 mL x 3), and the combined organic phases were dried over anhydrous sodium sulfate. The mixture was filtered, concentrated under reduced pressure, and purified by preparative column chromatography to obtain the target compound (compound 194) (55 mg, 0.11 mmol). MS: m / z = 504.3 [M+H] + .

[0725] 1H NMR (400MHz, CDCl3) δ8.85(d,J=2.2Hz,1H),8.01(d,J=2.0Hz,1H),4.47(d,J=11 .5Hz,1H),4.16(d,J=12.8Hz,1H),3.70(d,J=13.2Hz,2H),3.15(t,J=12.5Hz,1H ),2.98-2.66(m,7H),2.55(s,3H),2.54(s,3H),1.98-1.83(m,4H),1.74(ddd,J= 12.8,8.2,4.7Hz,1H),1.42-1.18(m,8H),0.99-0.92(m,2H),0.78-0.67(m,2H).

[0726] Example 46: Synthesis of 4-(1-(6-ethyl-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)-1,8-naphthidin-2-yl)piperidin-4-yl)amino)-N,N-dimethylpiperidin-1-carboxamide (compound 195)

[0727] Step 1: Synthesis of tert-butyl 4-((1-(dimethylcarbamoyl)piperidin-4-yl)amino)piperidin-1-carboxylate (compound 195-1)

[0728] 4-(piperidin-4-ylamino)piperidin-1-carboxylic acid tert-butyl ester (compound 194-2) (4 g, 14.11 mmol) was dissolved in dichloromethane (40 mL) in a reaction flask. After purging with nitrogen, triethylamine (2.14 g, 21.17 mmol) was added. After the addition was complete, the reaction mixture was placed in an ice bath, and dimethylcarbamoyl chloride (1.67 g, 15.52 mmol) was slowly added dropwise. After the addition was complete, the mixture was transferred to room temperature and stirred. LC-MS analysis was performed. After the reaction was complete, water (100 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (100 mL x 3). The organic phases were combined, washed with water, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain the target compound (compound 195-1) (4.2 g, 11.85 mmol). MS: m / z = 355.0 [M+H] + .

[0729] Step 2: Synthesis of N,N-dimethyl-4-(piperidin-4-ylamino)piperidin-1-carboxamide hydrochloride (compound 195-2)

[0730] 4-((1-(dimethylcarbamoyl)piperidin-4-yl)amino)piperidin-1-carboxylic acid tert-butyl ester (compound 195-1) (4.2 g, 11.85 mmol) was added to a reaction flask and dissolved in ethyl acetate (20 mL). 4M hydrochloric acid / ethyl acetate (80 mmol, 20 mL) was slowly added dropwise under ice bath conditions. After the addition was complete, the mixture was moved to room temperature and stirred for 12 h. The solid was then concentrated under reduced pressure after filtration to obtain the target compound (compound 195-2) (3.42 g, 10.45 mmol). MS: m / z = 255.0 [M+H] + .

[0731] Step 3: Synthesis of 4-(1-(6-ethyl-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)-1,8-naphthidin-2-yl)piperidin-4-yl)amino)-N,N-dimethylpiperidin-1-carboxamide (compound 195)

[0732] 5-(2-chloro-6-ethyl-4-methyl-1,8-naphthid-3-yl)-3-methyl-1,2,4-oxadiazole (compound 2-4) (80 mg, 0.28 mmol) and N,N-dimethyl-4-(piperidin-4-ylamino)piperidin-1-carboxamide hydrochloride (compound 195-2) (137 mg, 0.42 mmol) were dissolved in DMSO (4 mL), and N,N-diisopropylethylamine (220 mg, 1.70 mmol) and potassium fluoride (65 mg, 1.12 mmol) were added. The mixture was heated to 100 °C and reacted for 4 hours. After cooling the reaction solution to room temperature, it was filtered through diatomaceous earth. The filter cake was washed with ethyl acetate, the filtrate was concentrated, and water (30 mL) was added. The mixture was extracted with ethyl acetate (30 mL x 3), and the combined organic phases were dried over anhydrous sodium sulfate. The mixture was filtered, concentrated under reduced pressure, and purified by preparative column chromatography to obtain the target compound (compound 195) (20 mg, 39.48 μmol). MS: m / z = 507.3 [M+H] + .

[0733] 1 H NMR (400MHz, CDCl3) δ8.84(d,J=2.3Hz,1H),8.01(d,J=2.2Hz,1H),3.73-3.57(m,4H),2.91(t,J= 11.7Hz,2H),2.86-2.71(m,13H),2.55(s,3H),2.53(s,3H),1.89-1.80(m,4H),1.38-1.27(m,7H).

[0734] Example 47: Synthesis of (4-(1-(6-ethyl-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)-1,8-naphthidin-2-yl)piperidin-4-yl)amino)piperidin-1-yl)(1-methyl-1H-imidazol-2-yl)methyl ketone (compound 196)

[0735] Step 1: Synthesis of tert-butyl 4-(1-(1-methyl-1H-imidazol-2-carbonyl)piperidin-4-yl)amino)piperidin-1-carboxylate (compound 196-1)

[0736] 4-(piperidin-4-ylamino)piperidin-1-carboxylic acid tert-butyl ester (compound 194-2) (4 g, 14.11 mmol), 1-methyl-1H-imidazolium-2-carboxylic acid (1.78 g, 14.11 mmol), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (5.9 g, 15.52 mmol) were dissolved in dichloromethane (40 mL) in a reaction flask. After purging with nitrogen, N,N-diisopropylethylamine (3.65 g, 28.23 mmol) was added. The reaction was stirred at room temperature after the addition was complete. After the reaction was completed, water (100 mL) was added to the reaction solution, followed by extraction with dichloromethane (100 mL x 3). The organic phases were combined, washed with water, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain the target compound (compound 196-1) (2.3 g, 5.87 mmol). MS: m / z = 391.9 [M+H] + .

[0737] Step 2: Synthesis of (1-methyl-1H-imidazol-2-yl)(4-(piperidin-4-ylamino)piperidin-1-yl)methyl ketone (compound 196-2)

[0738] 4-(1-(1-methyl-1H-imidazol-2-carbonyl)piperidin-4-yl)amino)piperidin-1-carboxylic acid tert-butyl ester (compound 196-1) (2.3 g, 5.87 mmol) was added to a reaction flask and dissolved in dichloromethane (10 mL). Trifluoroacetic acid (4 mL) was slowly added dropwise under ice bath conditions. After the addition was complete, the mixture was moved to room temperature and stirred for 12 h. Water (50 mL) was added to the reaction solution, and dichloromethane (20 mL x 3) was back-extracted three times. The pH of the aqueous phase was adjusted to ~8 with potassium carbonate aqueous solution, and the solid was concentrated under reduced pressure. The solid was dissolved in 25 mL of purified water, passed through a methanesulfonic acid exchange resin, washed with purified water to remove inorganic salts, washed with methylamine aqueous solution, and concentrated under reduced pressure to obtain the target compound (compound 196-2) (1.74 g, 5.97 mmol). MS: m / z = 292.0 [M+H] + .

[0739] Step 3: Synthesis of (4-(1-(6-ethyl-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)-1,8-naphthidin-2-yl)piperidin-4-yl)amino)piperidin-1-yl)(1-methyl-1H-imidazol-2-yl)methyl ketone (compound 196) (compound 196)

[0740] 5-(2-chloro-6-ethyl-4-methyl-1,8-naphthid-3-yl)-3-methyl-1,2,4-oxadiazole (compound 2-4) (80 mg, 0.28 mmol) and (1-methyl-1H-imidazol-2-yl)(4-(piperidin-4-ylamino)piperidin-1-yl) methyl ketone (compound 196-2) (125 mg, 0.43 mmol) were dissolved in DMSO (4 mL), and N,N-diisopropylethylamine (220 mg, 1.70 mmol) and potassium fluoride (65 mg, 1.12 mmol) were added. The mixture was heated to 100 °C and reacted for 4 hours. After cooling the reaction solution to room temperature, it was filtered through diatomaceous earth. The filter cake was washed with ethyl acetate, the filtrate was concentrated, and water (30 mL) was added. The mixture was extracted with ethyl acetate (30 mL x 3), and the combined organic phases were dried over anhydrous sodium sulfate. The mixture was filtered, concentrated under reduced pressure, and purified by preparative column chromatography to obtain the target compound (compound 196) (40 mg, 0.74 mmol). MS: m / z = 544.3 [M+H] + .

[0741] 1 H NMR (400MHz, CDCl3) δ8.85(d,J=2.3Hz,1H),8.01(d,J=2.3Hz,1H),7.02(d,J=0.8 Hz,1H),6.91(d,J=0.5Hz,1H),4.71(d,J=13.0Hz,1H),4.55(d,J=12.8Hz,1H),3.8 4(s,3H),3.70(d,J=13.3Hz,2H),3.26(t,J=11.5Hz,1H),2.92(t,J=11.7Hz,4H),2 .87-2.74(m,3H),2.55(s,3H),2.53(s,3H),2.01-1.81(m,4H),1.41-1.29(m,7H).

[0742] Example 48: Synthesis of 1-(4-(1-(6-ethyl-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)-1,8-naphthidin-2-yl)piperidin-4-yl)amino)piperidin-1-yl)-2,2-difluoroethane-1-one (compound 197)

[0743] Step 1: Synthesis of tert-butyl 4-(1-(2,2-difluoroacetyl)piperidin-4-yl)amino)piperidin-1-carboxylate (compound 197-1)

[0744] 4-(piperidin-4-ylamino)piperidin-1-carboxylic acid tert-butyl ester (compound 194-2) (4 g, 14.11 mmol), difluoroacetic acid (1.49 g, 15.52 mmol), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (5.9 g, 15...

Claims

1. The compound of formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope label, metabolite, or prodrug thereof: in, X a1 Selected from CR a1 and N; X a2 Selected from CR a2 and N; X a3 Selected from CR a3 and N; X a4 Selected from CR a4 and N; X a5 Selected from CR a5 and N; U is selected from X u1 and X u4 Each independently selected from CR u1 and N; X u2 X u3 X u5 X u6 and X u7 Each is independently selected from chemical bonds, O, S, Se, S(O), S(O)2, C(O), CR u2 R u3 and NR u4 Preferred chemical bonds include O, S, S(O), S(O)2, C(O), and CR. u2 R u3 and NR u4 Or, X u1 X u2 X u3 X u4 X u5 X u6 and X u7 Any two rings in the chain combine to form C 3-10 Cycloalkyl or 3-10 membered heterocyclic groups, wherein the C 3-10 Cycloalkyl or 3-10-membered heterocyclic groups are optionally separated by one or more independently selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl groups and C 1-6 Substituents of haloalkoxy groups; Or, any two adjacent X u1 X u2 X u3 X u4 X u5 X u6 and X u7 Formation of double bonds; Or R u2 and R u3 C forms with the carbon atoms that are bonded together. 3-10 Cycloalkyl or 3-10 membered heterocyclic groups, wherein the C 3-10 Cycloalkyl or 3-10-membered heterocyclic groups are optionally separated by one or more independently selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl groups and C 1-6 Substituents of haloalkoxy groups; Y u1 Y u3 Y u6 and Y u8 Each independently selected from CR u5 and N; Y u2 Y u4 Y u5 Y u7 Y u9 and Y u10 Each is independently selected from chemical bonds, O, S, Se, S(O), S(O)2, C(O), CR u6 R u7 and NR u8 Preferred chemical bonds include O, S, S(O), S(O)2, C(O), and CR. u6 R u7 and NR u8 ; Z u1 and Z u6 Each independently selected from CR u9 and N; Z u2 Z u3 Z u4 Z u5 Z u7 Z u8 Z u9 and Z u10 Each is independently selected from chemical bonds, O, S, Se, S(O), S(O)2, C(O), CR u10 R u11 and NR u12 Preferred chemical bonds include O, S, S(O), S(O)2, C(O), and CR. u10 R u11 and NR u12 ; G is X g1 Selected from CR g1 and N; X g2 X g3 X g4 X g5 X g6 X g7 and X g8 Each is independently selected from chemical bonds, O, S, Se, S(O), S(O)2, S(O)(=NR) g2 ), C(O), CR g3 R g4 NR g5 Si(R) g6 2. P(O)R g7 and C (=CR) g8 R g9 Preferred chemical bonds include O, S, S(O), S(O)2, and S(O) (=NR). g2 ), C(O), CR g3 R g4 NR g5 Si(R) g6 2. P(O)R g7 and C (=CR) g8 R g9 ); Or, X g1 X g2 X g3 X g4 X g5 X g6 X g7 and X g8 Any two rings in the chain combine to form C 3-10 Cycloalkyl, 3-10 membered heterocyclic or 5-6 membered heteroaryl, wherein the C 3-10 Cycloalkyl, 3-10-membered heterocyclic or 5-6-membered heteroaryl groups are optionally surrounded by one or more groups independently selected from hydrogen, halogen, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups and C(O)R 43 Substituents, preferably hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl groups and C 1-6 Halogenated alkoxy groups; Or R g3 and R g4 C forms with the carbon atoms that are bonded together. 3-10 Cycloalkyl or 3-10 membered heterocyclic groups, wherein the C 3-10 Cycloalkyl or 3-10 membered heterocyclic groups are optionally surrounded by one or more groups independently selected from hydrogen, halogen, oxo group, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C(O)R 43 and S(O)2R 52 Substituents, preferably hydrogen, halogen, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups and C(O)R 43 More preferably hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl groups and C 1-6 Halogenated alkoxy groups; Or, any two adjacent X g1 X g2 X g3 X g4 X g5 X g6 X g7 and X g8 Double bonds can be formed; E is X e1 X e2 X e3 and X e4 Each is independently selected from O, S, Se, N, and CR. e1 and NR e2 O, S, N, and CR are preferred. e1 and NR e2 ; Or X e1 X e2 X e3 and X e4 The two adjacent rings in the middle form C 3-10 Cycloalkyl, 3-10-membered heterocyclic or 5-10-membered heteroaryl, wherein the C 3-10 Cycloalkyl, 3-10 heterocyclic or 5-10 heteroaryl groups are optionally separated by one or more elements independently selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl groups and C 1-6 Substituents of haloalkoxy groups; L is selected from chemical bonds, -O-, -S-, -Se-, -S(O)-, -S(O)2-, -C(O)-, -C 1-6 alkylene-, -C 1-6 Alkylene -O-, -C 1-6 Alkylene -C(O)-, -C 1-6 Alkylene-S(O)-, -C 1-6 Alkylene -S(O)2-, -C 1-6 Alkylene-NR 1 -、-NR 1 -、-N(C(O)R 2 )-、-NR 3 C(O)- and -NR 4 SO2-, preferably chemical bonds, -O-, -S-, -S(O)-, -S(O)2-, -C(O)-, -C 1-6 alkylene-, -C 1-6 Alkylene -O-, -C 1-6 Alkylene -C(O)-, -C 1-6 Alkylene-S(O)-, -C 1-6 Alkylene -S(O)2-, -C 1-6 Alkylene-NR 1 -、-NR 1 -、-N(C(O)R 2 )-、-NR 3 C(O)- and -NR 4 SO2-, more preferably chemical bonds, -O-, -S-, -S(O)-, -S(O)2-, -C(O)-, -C 1-6 alkylene-, -C 1-6 Alkylene -O-, -C 1-6 Alkylene -C(O)-, -C 1-6 Alkylene-S(O)-, -C 1-6 Alkylene-S(O)2-, -NR 1 -、-N(C(O)R 2 )-、-NR 3 C(O)- and -NR 4 SO2-; The L mentioned above has no fixed connection order with the U on the left and the G on the right; R a1 R a2 R a3 R a4 R a5 R e1 and R e2 Each is independently selected from hydrogen, deuterium, halogens, NO2, OH, CN, C(O)R 5 C(O)OR 6 C(O)NR 7 R 8 NR 9 R 10 NR 11 C(O)R 12 S(O)R 13 S(O)2R 14 S(O)2NR 15 R 16 NR 17 S(O)R 18 NR 19 S(O)2R 20 SF5, SCN, Si(R) 21 3. P(O)R 22 R 23 B(OR) 24 2. C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkyl selenyl, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 cycloalkyl, 4-7 membered heterocyclic, C 6-10 aryl and 5-10 heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkyl selenyl, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 cycloalkyl, 4-7 membered heterocyclic, C 6-10 Aryl or 5-10 heteroaryl groups are optionally selected by one or more independently chosen from hydrogen, deuterium, halogen, NO2, OH, CN, C(O)R 25 C(O)OR 26 C(O)NR 27 R 28 NR 29 R 30 NR 31 C(O)R 32 S(O)R 33 S(O)2R 34 SO2NR 35 R 36 NR 37 S(O)R 38 NR 39 S(O)2R 40 C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups and C 1-6 The substituent is replaced by a thioalkoxy group; preferably, R a1 R a2 R a3 R a4 R a5 R e1 and R e2 Each is independently selected from hydrogen, deuterium, halogens, NO2, OH, CN, C(O)R 5 C(O)OR 6 C(O)NR 7 R 8 NR 9 R 10 NR 11 C(O)R 12 S(O)R 13 S(O)2R 14 S(O)2NR 15 R 16 NR 17 S(O)R 18 NR 19 S(O)2R 20 SF5, SCN, Si(R) 21 3. P(O)R 22 R 23 B(OR) 24 2. C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 cycloalkyl, 4-7 membered heterocyclic, C 6-10 aryl and 5-10 heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 cycloalkyl, 4-7 membered heterocyclic, C 6-10 Aryl or 5-10 heteroaryl groups are optionally selected by one or more independently chosen from hydrogen, deuterium, halogen, NO2, OH, CN, C(O)R 25 C(O)OR 26 C(O)NR 27 R 28 NR 29 R 30 NR 31 C(O)R 32 S(O)R 33 S(O)2R 34 SO2NR 35 R 36 NR 37 S(O)R 38 NR 39 S(O)2R 40 C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups and C 1-6 Substituents of thioalkoxy groups; R u1 R u2 R u3 R u4 R u5 R u6 R u7 R u8 R u9 R u10 R u11 R u12 R g1 R g2 R g3 R g4 R g5 R g6 R g7 R g8 and R g9 Each is independently selected from hydrogen, deuterium, halogens, NO2, OH, CN, and NR. 41 R 42 C(O)R 43 -C 1-6 Alkylene-R 43 C(O)OR 44 C(O)NR 45 R 46 C(=NR) 49 )NR 45 R 46 NR 49 C(O)R 50 S(O)R 51 S(O)2R 52 SO2NR 53 R 54 NR 55 S(O)R 56 NR 57 S(O)2R 58 C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 cycloalkyl, 4-7 membered heterocyclic, C 6-10 aryl and 5-10 heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Alkylene, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 cycloalkyl, 4-7 membered heterocyclic, C 6-10 The aryl or 5-10 heteroaryl group is optionally surrounded by one or more independently selected groups: hydrogen, deuterium, halogen, oxo group, NO2, OH, CN, C(O)R. 43 C(O)OR 44 C(O)NR 45 R 46 NR 47 R 48 NR 49 C(O)R 50 S(O)R 51 S(O)2R 52 SO2NR 53 R 54 NR 55 S(O)R 56 NR 57 S(O)2R 58 C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Thioalkoxy, C 6-10 Substituents of aryl and 5-10 heteroaryl groups; preferably, R u1 R u2 R u3 R u4 R u5 R u6 R u7 R u8 R u9 R u10 R u11 R u12 R g1 R g2 R g3 R g4 R g5 R g6 R g7 R g8 and R g9 Each is independently selected from hydrogen, deuterium, halogens, NO2, OH, CN, and NR. 41 R 42 C(O)R 43 C(O)OR 44 C(O)NR 45 R 46 NR 49 C(O)R 50 S(O)R 51 S(O)2R 52 SO2NR 53 R 54 NR 55 S(O)R 56 NR 57 S(O)2R 58 C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 cycloalkyl and 4-7 membered heterocyclic groups, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 The cycloalkyl or 4-7 membered heterocyclic group is optionally selected by one or more independently chosen from hydrogen, deuterium, halogen, NO2, OH, CN, C(O)R. 43 C(O)OR 44 C(O)NR 45 R 46 NR 47 R 48 NR 49 C(O)R 50 S(O)R 51 S(O)2R 52 SO2NR 53 R 54 NR 55 S(O)R 56 NR 57 S(O)2R 58 C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups and C 1-6 Substituents of thioalkoxy groups; R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11 R 12 R 13 R 14 R 15 R 16 R 17 R 18 R 19 R 20 R 21 R 22 R 23 R 24 R 25 R 26 R 27 R 28 R 29 R 30 R 31 R 32 R 33 R 34 R 35 R 36 R 37 R 38 R 39 R 40 R 41 R 42 R 43 R 44 R 45 R 46 R 47 R 48 R 49 R 50 R 51 R 52 R 53 R 54 R 55 R 56 R 57 and R 58 Each is independently selected from hydrogen and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 3-7 cycloalkyl, 4-7 membered heterocyclic, C 6-10 Aryl, 5-10 membered heteroaryl and NR 59 C(O)R 60 The C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 3-7 cycloalkyl, 4-7 membered heterocyclic, C 6-10 The aryl or 5-10 heteroaryl group is optionally surrounded by one or more independently selected from hydrogen, deuterium, halogen, oxo group, NO2, OH, CN, C. 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups and C 1-6 Substituents of thioalkoxy groups; preferably, R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11 R 12 R 13 R 14 R 15 R 16 R 17 R 18 R 19 R 20 R 21 R 22 R 23 R 24 R 25 R 26 R 27 R 28 R 29 R 30 R 31 R 32 R 33 R 34 R 35 R 36 R 37 R 38 R 39 R 40 R 41 R 42 R 43 R 44 R 45 R 46 R 47 R 48 R 49 R 50 R 51 R 52 R 53 R 54 R 55 R 56 R 57 and R 58 Each is independently selected from hydrogen and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 3-7 cycloalkyl, 4-7 membered heterocyclic, C 6-10 Aryl and 5-10 heteroaryl, the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 3-7 cycloalkyl, 4-7 membered heterocyclic, C 6-10 The aryl or 5-10 heteroaryl group is optionally selected by one or more independently chosen from hydrogen, deuterium, halogen, NO2, OH, CN, C. 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups and C 1-6 Substituents of thioalkoxy groups; more preferably, R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11 R 12 R 13 R 14 R 15 R 16 R 17 R 18 R 19 R 20 R 21 R 22 R 23 R 24 R 25 R 26 R 27 R 28 R 29 R 30 R 31 R 32 R 33 R 34 R 35 R 36 R 37 R 38 R 39 R 40 R 41 R 42 R 43 R 44 R 45 R 46 R 47 R 48 R 49 R 50 R 51 R 52 R 53 R 54 R 55 R 56 R 57 and R 58 Each is independently selected from hydrogen and C. 1-6 Alkyl and C 1-6 Halogenated alkyl; or two R 24 The atoms bonded to it together form a 4-7 membered heterocyclic group, wherein the 4-7 membered heterocyclic group is optionally composed of one or more elements independently selected from hydrogen, halogen, and C. 1-6 Alkyl substituents; R 59 and R 60 Each is independently selected from hydrogen and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 3-7 cycloalkyl, 4-7 membered heterocyclic, C 6-10 Aryl and 5-10 heteroaryl, the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 3-7 cycloalkyl, 4-7 membered heterocyclic, C 6-10 The aryl or 5-10 heteroaryl group is optionally selected by one or more independently chosen from hydrogen, deuterium, halogen, NO2, OH, CN, C. 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups and C 1-6 Substituents of thioalkoxy groups; wherein, when X a1 X a2 X a3 and X a4 None of them are N, and U is selected from: At that time, R a1 R a2 R a3 R a4 R a5 Each is independently selected from SF5, SCN, and Si(R) 21 3. P(O)R 22 R 23 and B(OR) 24 )2; and / or R u1 R u2 and R u3 Each is independently selected from NO2, CN, and NR. 41 R 42 C(O)R 43 C(O)OR 44 C(O)NR 45 R 46 NR 49 C(O)R 50 S(O)R 51 S(O)2R 52 SO2NR 53 R 54 NR 55 S(O)R 56 NR 57 S(O)2R 58 C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 cycloalkyl and 4-7 membered heterocyclic groups, wherein the C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 The cycloalkyl or 4-7 membered heterocyclic group is optionally selected by one or more independently chosen from hydrogen, deuterium, halogen, NO2, OH, CN, C(O)R. 43 C(O)OR 44 C(O)NR 45 R 46 NR 47 R 48 NR 49 C(O)R 50 S(O)R 51 S(O)2R 52 SO2NR 53 R 54 NR 55 S(O)R 56 NR 57 S(O)2R 58 C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups and C 1-6 Substituents of thioalkoxy groups, or R u2 and R u3 Forming 3-10 membered heterocyclic groups with the commonly linked carbon atoms; and / or R e1 and R e2 Each is independently selected from deuterium, halogens, NO2, OH, CN, C(O)R 5 C(O)NR 7 R 8 NR 9 R 10 NR 11 C(O)R 12 S(O)R 13 S(O)2R 14 S(O)2NR 15 R 16 NR 17 S(O)R 18 NR 19 S(O)2R 20 SF5, SCN, Si(R) 21 3. P(O)R 22 R 23 B(OR) 24 2. C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-10 aryl and 5-10 heteroaryl, wherein the C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-10 Aryl or 5-10 heteroaryl groups are optionally selected by one or more independently chosen from hydrogen, deuterium, halogen, NO2, OH, CN, C(O)R 25 C(O)OR 26 C(O)NR 27 R 28 NR 29 R 30 NR 31 C(O)R 32 S(O)R 33 S(O)2R 34 SO2NR 35 R 36 NR 37 S(O)R 38 NR 39 S(O)2R 40 C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups and C 1-6 The substituent is thioalkoxy; and / or L is selected from -O-, -S-, -S(O)-, -S(O)2-, -C 1-6 Alkylene-O-, -N(C(O)R 2 )- and -NR 4 SO2-; and / or U selected from and / or X g1 X g2 X g3 X g4 X g5 X g6 X g7 and X g8 Any two rings in the group can be combined to form a 3-10 membered heterocyclic group or a 5-6 membered heteroaryl group, wherein the 3-10 membered heterocyclic group or the 5-6 membered heteroaryl group is optionally surrounded by one or more elements independently selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl groups and C 1-6 Substituents of haloalkoxy groups; and / or R g3 and R g4 C forms with the carbon atoms that are bonded together. 3-10 cycloalkyl, the C 3-10 The cycloalkyl group is optionally surrounded by one or more elements independently selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl groups and C 1-6 Substituents of haloalkoxy groups; and / or any two adjacent X groups. g1 X g2 X g3 X g4 X g5 X g6 X g7 and X g8 It can form at most one double bond; and / or X g2 X g3 X g4 X g5 X g6 X g7 and X g8 At least one of them is selected from S(O)(=NR) g2 ), NR g5 Si(R) g6 )2 and P(O)R g7 And R g5 Selected from C(O)R 43 and C 3-7 cycloalkyl; and / or G selected from 2. The compound of claim 1 or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope label, metabolite, or prodrug thereof, wherein X a1 X a2 X a3 and X a4 At least one of them is N; Preferably, X a1 For N; and / or X a2 For N; and / or X a3 For N; and / or X a4 Let N be the number of elements in the array.

3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope label, metabolite, or prodrug thereof, wherein... R a1 R a2 R a3 R a4 R a5 Each is independently selected from hydrogen, halogen, C(O)R 5 C(O)NR 7 R 8 NR 9 R 10 NR 11 C(O)R 12 S(O)2NR 15 R 16 SF5, SCN, Si(R) 21 3. P(O)R 22 R 23 B(OR) 24 2. C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 Cycloalkyl, 4-7-membered heterocyclic and 5-10-membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 Cycloalkyl, 4-7-membered heterocyclic or 5-10-membered heteroaryl groups are optionally selected by one or more independently chosen from hydrogen, deuterium, halogen, NO2, OH, CN, C(O)R 25 C(O)OR 26 C(O)NR 27 R 28 NR 29 R 30 NR 31 C(O)R 32 S(O)R 33 S(O)2R 34 SO2NR 35 R 36 NR 37 S(O)R 38 NR 39 S(O)2R 40 C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups and C 1-6 Substituents of thioalkoxy groups; Preferably, R a1 R a2 R a3 R a4 R a5 Each is independently selected from hydrogen, halogen, C(O)R 5 C(O)NR 7 R 8 NR 9 R 10 S(O)2NR 15 R 16 SF5, SCN, Si(R) 21 3. P(O)R 22 R 23 B(OR) 24 2. C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 Cycloalkyl, 4-7-membered heterocyclic and 5-10-membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 Cycloalkyl, 4-7-membered heterocyclic or 5-10-membered heteroaryl groups are optionally selected by one or more independently chosen from hydrogen, deuterium, halogen, NO2, OH, CN, C(O)R 25 C(O)OR 26 C(O)NR 27 R 28 NR 29 R 30 NR 31 C(O)R 32 S(O)R 33 S(O)2R 34 SO2NR 35 R 36 NR 37 S(O)R 38 NR 39 S(O)2R 40 C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups and C 1-6 The substituents of the thioalkoxy group are replaced.

4. The compound of any one of claims 1-3 or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope label, metabolite, or prodrug thereof, wherein formula (I) is selected from formulas (II-A), (II-B), (II-C), and (II-D), preferably formula (II-A): Preferably, formula (I) is selected from formulas (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), and (III-G), with formula (III-A) being the most preferred: in, X a1 X a2 X a3 X a4 X a5 R a1 R a2 R a3 R a4 R a5 E, U, L and G are as defined in any one of claims 1-3.

5. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope label, metabolite, or prodrug thereof, wherein... U is selected from C 3-7 cycloalkyl, Preferred C 3-7 cycloalkyl, n1, n2, n3 and n4 are each independently selected from 0, 1 and 2, respectively, and n5 and n6 are each independently selected from 1 or 2.

6. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope label, metabolite, or prodrug thereof, wherein... R u1 R u2 R u3 R u4 R u5 R u6 R u7 R u8 R u9 R u10 R u11 R u12 Each is independently selected from hydrogen, deuterium, halogens, NO2, OH, CN, and NR. 41 R 42 C(O)R 43 C(O)OR 44 C(O)NR 45 R 46 NR 49 C(O)R 50 S(O)R 51 S(O)2R 52 SO2NR 53 R 54 NR 55 S(O)R 56 NR 57 S(O)2R 58 C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 cycloalkyl and 4-7 membered heterocyclic groups, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 The cycloalkyl or 4-7 membered heterocyclic group is optionally selected by one or more independently chosen from hydrogen, deuterium, halogen, NO2, OH, CN, C(O)R. 43 C(O)OR 44 C(O)NR 45 R 46 NR 47 R 48 NR 49 C(O)R 50 S(O)R 51 S(O)2R 52 SO2NR 53 R 54 NR 55 S(O)R 56 NR 57 S(O)2R 58 C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups and C 1-6 Substituents of thioalkoxy groups; Preferably, R u1 R u2 R u3 R u4 R u5 R u6 R u7 R u8 R u9 R u10 R u11 R u12 Each is independently selected from hydrogen, deuterium, halogen, OH, CN, and NR. 41 R 42 C(O)OR 44 C(O)NR 45 R 46 C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl groups and C 3-7 cycloalkyl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl or C 3-7 The cycloalkyl group is optionally separated by one or more elements independently selected from hydrogen, deuterium, halogen, NO2, OH, CN, C(O)R. 43 C(O)OR 44 C(O)NR 45 R 46 NR 47 R 48 NR 49 C(O)R 50 S(O)R 51 S(O)2R 52 SO2NR 53 R 54 NR 55 S(O)R 56 NR 57 S(O)2R 58 C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups and C 1-6 Substituents of thioalkoxy groups; Or R u2 and R u3 C forms with the carbon atoms that are bonded together. 3-10 Cycloalkyl (e.g., cyclopropyl) or 3-10 membered heterocyclic groups (e.g., oxobutyl); More preferably, U is selected from (For example )、 (For example )、 (For example )、 (For example )、 (For example )、 (For example )、 (For example )、 Or selected from (For example )、 Or selected from (For example )、 (For example )and (For example ); where n1, n2, n3 and n4 are each independently selected from 0, 1 and 2, and n5 and n6 are each independently selected from 1 or 2.

7. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope label, metabolite, or prodrug thereof, wherein: L is selected from chemical bonds, -O-, -S-, -S(O)-, -S(O)2-, -C(O)-, -C 1-6 alkylene-, -C 1-6 Alkylene -O-, -C 1-6 Alkylene -C(O)-, -C 1-6 Alkylene-S(O)-, -C 1-6 Alkylene-S(O)2-, -NR 1 -、-N(C(O)R 2 )-、-NR 3 C(O)- and -NR 4 SO2-; preferably, L is selected from chemical bonds, -O-, -S-, -S(O)2-, -C(O)-, -C 1-6 Alkylene-, -NR 1 -and-N(C(O)R 2 )-; Alternatively, L can be selected from chemical bonds, -O-, -S-, -S(O)2-, -C(O)-, -C 1-6 alkylene-, -C 1-6 Alkylene-NR 1 -、-NR 1 -and-N(C(O)R 2 -; preferably, L is selected from chemical bonds, -NH-, -NH-CH2-, -CH2-, -O-, -S-, -C(O)-, -S(O)2- and -N(C(O)CH3)-; more preferably, L is selected from chemical bonds, -NH-, -CH2-, -O-, -S-, -C(O)-, -S(O)2- and -N(C(O)CH3)-.

8. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope label, metabolite, or prodrug thereof, wherein: E is selected from Preferably, E is selected from More preferably, E is selected from and / or R e1 Each is independently selected from hydrogen, halogen, OH, C(O)NR 7 R 8 NR 9 R 10 C 1-6 Alkyl and C 1-6 Halogenated alkyl; preferably, R e1 Each is independently selected from hydrogen, halogen, and NR. 9 R 10 C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; Preferably, E is selected from: More preferably, E is selected from: More preferably, E is selected from:

9. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope label, metabolite, or prodrug thereof, wherein: R g1 R g2 R g3 R g4 R g5 R g6 R g7 R g8 and R g9 Each is independently selected from hydrogen, deuterium, halogens, NO2, OH, CN, and NR. 41 R 42 C(O)R 43 C(O)OR 44 C(O)NR 45 R 46 NR 49 C(O)R 50 S(O)R 51 S(O)2R 52 SO2NR 53 R 54 NR 55 S(O)R 56 NR 57 S(O)2R 58 C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 cycloalkyl and 4-7 membered heterocyclic groups, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 The cycloalkyl or 4-7 membered heterocyclic group is optionally selected by one or more independently chosen from hydrogen, deuterium, halogen, NO2, OH, CN, C(O)R. 43 C(O)OR 44 C(O)NR 45 R 46 NR 47 R 48 NR 49 C(O)R 50 S(O)R 51 S(O)2R 52 SO2NR 53 R 54 NR 55 S(O)R 56 NR 57 S(O)2R 58 C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups and C 1-6 Substituents of thioalkoxy groups; Preferably, R g1 R g2 R g3 R g4 R g5 R g6 R g7 R g8 and R g9 Each is independently selected from hydrogen, halogen, OH, C(O)R 43 C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and C 3-7 cycloalkyl; Or, R g1 R g2 R g3 R g4 R g5 R g6 R g7 R g8 and R g9 Each is independently selected from hydrogen, halogen, OH, CN, NR. 41 R 42 C(O)R 43 -C 1-6 Alkylene-R 43 C(O)OR 44 C(O)NR 45 R 46 C(=NR) 49 )NR 45 R 46 S(O)R 51 S(O)2R 52 C 1-6 Alkyl, C 1-6 Alkoxy, C 3-7 cycloalkyl, 4-7 membered heterocyclic, C 6-10 aryl and 5-10 heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Alkylene, C 1-6 Alkoxy, C 3-7 cycloalkyl, 4-7 membered heterocyclic, C 6-10 The aryl or 5-10 heteroaryl group is optionally surrounded by one or more independently selected groups: hydrogen, deuterium, halogen, oxo group, NO2, OH, CN, C(O)R. 43 C(O)OR 44 C(O)NR 45 R 46 NR 47 R 48 NR 49 C(O)R 50 S(O)R 51 S(O)2R 52 SO2NR 53 R 54 NR 55 S(O)R 56 NR 57 S(O)2R 58 C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Thioalkoxy, C 6-10 Substituents of aryl and 5-10 heteroaryl groups; Or R g3 and R g4 C forms with the carbon atoms that are bonded together. 3-10 Cycloalkyl or 3-10 membered heterocyclic groups, wherein the C 3-10 Cycloalkyl or 3-10 membered heterocyclic groups are optionally surrounded by one or more groups independently selected from hydrogen, halogen, oxo group, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C(O)R 43 and S(O)2R 52 Substituents, preferably hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl groups and C 1-6 Halogenated alkoxy group; preferably, R g3 and R g4 C forms with the carbon atoms that are bonded together. 3-10 Cycloalkyl or 3-10 membered heterocyclic groups; Or, X g1 X g2 X g3 X g4 X g5 X g6 X g7 and X g8 Any two rings in the chain combine to form C 3-10 Cycloalkyl, 3-10 membered heterocyclic or 5-6 membered heteroaryl, wherein the C 3-10 Cycloalkyl, 3-10-membered heterocyclic or 5-6-membered heteroaryl groups are optionally separated by one or more elements independently selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl groups and C 1-6 Substituents of haloalkoxy groups; Or, any two adjacent X g1 X g2 X g3 X g4 X g5 X g6 X g7 and X g8 It can form at most one double bond; Preferably, G is selected from: (For example )、 Or selected from cyclopentyl, cyclohexyl, Or selected from (For example )、 Or selected from (For example )、 (For example )、 10. The compound of any one of claims 1-9 or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope label, metabolite, or prodrug thereof, wherein formula (I) is (IV-A) or (IV-B): Where U is selected from: When one or more of the following conditions are met: (1)R a1 R a2 R a3 R a4 R a5 Each is independently selected from SF5, SCN, and Si(R) 21 3. P(O)R 22 R 23 and B(OR) 24 )2; (2)R u1 R u2 and R u3 Each is independently selected from NO2, CN, and NR. 41 R 42 C(O)R 43 C(O)OR 44 C(O)NR 45 R 46 NR 49 C(O)R 50 S(O)R 51 S(O)2R 52 SO2NR 53 R 54 NR 55 S(O)R 56 NR 57 S(O)2R 58 C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 cycloalkyl and 4-7 membered heterocyclic groups, wherein the C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 The cycloalkyl or 4-7 membered heterocyclic group is optionally selected by one or more independently chosen from hydrogen, deuterium, halogen, NO2, OH, CN, C(O)R. 43 C(O)OR 44 C(O)NR 45 R 46 NR 47 R 48 NR 49 C(O)R 50 S(O)R 51 S(O)2R 52 SO2NR 53 R 54 NR 55 S(O)R 56 NR 57 S(O)2R 58 C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups and C 1-6 Substituents of thioalkoxy groups, or R u2 and R u3 It forms 3-10 membered heterocyclic groups with the carbon atoms it connects to; (3)R e1 and R e2 Each is independently selected from deuterium, halogens, NO2, OH, CN, C(O)R 5 C(O)NR 7 R 8 NR 9 R 10 NR 11 C(O)R 12 S(O)R 13 S(O)2R 14 S(O)2NR 15 R 16 NR 17 S(O)R 18 NR 19 S(O)2R 20 SF5, SCN, Si(R) 21 3. P(O)R 22 R 23 B(OR) 24 2. C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-10 aryl and 5-10 heteroaryl, wherein the C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-10 Aryl or 5-10 heteroaryl groups are optionally selected by one or more independently chosen from hydrogen, deuterium, halogen, NO2, OH, CN, C(O)R 25 C(O)OR 26 C(O)NR 27 R 28 NR 29 R 30 NR 31 C(O)R 32 S(O)R 33 S(O)2R 34 SO2NR 35 R 36 NR 37 S(O)R 38 NR 39 S(O)2R 40 C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups and C 1-6 Substituents of thioalkoxy groups; (4) L is selected from -O-, -S-, -S(O)-, -S(O)2-, -C 1-6 Alkylene-O-, -N(C(O)R 2 )- and -NR 4 SO2-; (5) U is selected from (6)X g1 X g2 X g3 X g4 X g5 X g6 X g7 and X g8 Any two rings in the group can be combined to form a 3-10 membered heterocyclic group or a 5-6 membered heteroaryl group, wherein the 3-10 membered heterocyclic group or the 5-6 membered heteroaryl group is optionally surrounded by one or more elements independently selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl groups and C 1-6 Substituents of haloalkoxy groups; (7)R g3 and R g4 C forms with the carbon atoms that are bonded together. 3-10 cycloalkyl, the C 3-10 The cycloalkyl group is optionally surrounded by one or more elements independently selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl groups and C 1-6 Substituents of haloalkoxy groups; (8) Any two adjacent X g1 X g2 X g3 X g4 X g5 X g6 X g7 and X g8 It can form at most one double bond; and / or X g2 X g3 X g4 X g5 X g6 X g7 and X g8 At least one of them is selected from S(O)(=NR) g2 ), NR g5 Si(R) g6 )2 and P(O)R g7 And R g5 Selected from C(O)R 43 and C 3-7 cycloalkyl; (9) G is selected from 11. The compound of any one of claims 1-10, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope label, metabolite, or prodrug thereof, wherein the compound is selected from...

12. A pharmaceutical composition comprising a preventive and / or therapeutically effective amount of the compound of any one of claims 1-11 or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope label, metabolite or prodrug, and one or more pharmaceutically acceptable carriers.

13. A pharmaceutical kit comprising any one of the compounds of claims 1-11 or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope label, metabolite or prodrug, or the pharmaceutical composition of claim 12.

14. The use of any compound of claims 1-11 or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope label, metabolite or prodrug of claim 12, or the use of the cassette of claim 13 in the preparation of a κ receptor antagonist.

15. The use of the compound of any one of claims 1-11 or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope label, metabolite or prodrug thereof, or the pharmaceutical composition of claim 12, or the use of the cassette of claim 13 in the preparation of a medicament, preferably the medicament being used to antagonize a κ receptor, or for the prevention and / or treatment of κ receptor-mediated diseases.

16. The use as claimed in claim 15, wherein the κ receptor-mediated disease is selected from addiction disorders including conditions related to substance abuse or addiction; anxiety disorders; depressive disorders; mood disorders; schizophrenia or affective schizophrenia; stress-related disorders; obesity and eating disorders; migraines; postpartum depression; neurodegenerative diseases or conditions, including mood and behavioral disorders related to neurodegenerative diseases; postpartum depression; epilepsy; status epilepticus; and seizures.

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