Heterocyclic aryl or heteroaryl-heteroaryl derivatives and uses thereof

Abstract

The invention discloses a heterocyclic aryl or heteroaryl-heteroaryl derivative and application of the heterocyclic aryl or heteroaryl-heteroaryl derivative. The heterocyclic aryl or heteroaryl-heteroaryl derivative of the present invention is a compound of formula (I), a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of a stereoisomer thereof, a pharmaceutically acceptable salt of an isomer thereof, a solvate thereof or a pharmaceutically acceptable salt of a solvate thereof. The compound disclosed by the invention has good inhibitory activity on a 20-hydroxyeicosatetraenoic acid (20-HETE) signal channel, and has a good medicinal prospect. # imgabs0 #

Description

[0001] This application claims priority to the following international application: International Application PCT / CN2024 / 086486 with a filing date of April 8, 2024. This application incorporates the entire text of the above international application by reference. Technical Field

[0002] The present invention relates to compounds that can be used to treat diseases or disorders related to the 20 - hydroxy - eicosatetraenoic acid (20 - HETE) signaling pathway, compositions comprising these compounds, and methods of using these compounds. Background Art

[0003] 20 - Hydroxy - eicosatetraenoic acid (20 - HETE) is a metabolite of arachidonic acid and is synthesized through the catalytic action of cytochrome P450 enzymes (especially the CYP4A and CYP4F families). In the human body, CYP4A11 and CYP4F2 are the main enzymes responsible for this synthesis, and they are highly expressed in the kidneys, liver, and other organs.

[0004] 20 - HETE is involved in multiple biological functions. In various chronic diseases, including hypertension, stroke, chronic kidney disease, coronary artery disease, myocardial infarction, acute renal failure, polycystic kidney, tumor growth and metastasis, and in situations involving visceral injury and fibrosis, the level of 20 - HETE will increase significantly. In addition, 20 - HETE also plays an important role in the development of obesity and metabolic disorders. Both in - vivo and in - vitro studies have demonstrated the correlation between 20 - HETE levels and weight gain. It has been proven that the deletion of the 20 - HETE receptor GPR75 can inhibit the occurrence of obesity and improve diabetes parameters, providing a treatment strategy for treating obesity and related diseases.

[0005] Considering the important role of the 20 - HETE / GPR75 pathway, 20 - HETE ligand - generating inhibitors or GPR75 receptor antagonists may provide potential options for treating obesity, diabetes, and other metabolic diseases. Although in these diseases, some inhibitors have achieved non - clinical proof - of - concept for inhibiting the 20 - HETE / GPR75 pathway, small - molecule drugs with good pharmacokinetic and pharmacodynamic properties are still needed to translate them into clinical applications and further commercialization. Summary of the Invention

[0006] The present invention provides a 20 - hydroxy - eicosatetraenoic acid inhibitor that is completely different from the existing ones. The compounds of the present invention have good inhibitory activity against 20 - hydroxy - eicosatetraenoic acid. The present invention provides a compound of formula (I), its stereoisomers, its atropisomers, its pharmaceutically acceptable salts, pharmaceutically acceptable salts of its stereoisomers, pharmaceutically acceptable salts of its atropisomers, its solvates, or pharmaceutically acceptable salts of its solvates:

[0007]

[0008] X1 is selected from N or CR1;

[0009] X2 is selected from N or CR2;

[0010] X3 is selected from N or CR3;

[0011] X4 is selected from N or CR4;

[0012] Y1, each occurrence thereof, is selected from nothing, -C(R Y1A )2-, -C(R Y1A )=C(R Y1A )-, -C≡C-, -O-, -S-, -N(R Y1B ), -C(=O)-, -S(=O)-, -S(=O)2-, -C(=O)O-, -S(=O)O-, -S(=O)2O-, -N(R Y1B ), -C(=O)-, -N(R Y1B ), -N(R Y1B )S(=O)2-;

[0013] n Y1 is selected from 0, 1, 2, 3, 4, 5 or 6;

[0014] Y2, each occurrence thereof, is selected from nothing, -C(R Y2A )2-, -C(R Y2A )=C(R Y2A ), -C≡C-, -O-, -S-, -N(R Y2B ), -C(=O)-, -S(=O)-, -S(=O)2-, -C(=O)O-, -S(=O)O-, -S(=O)2O-, -N(R Y2B ), -C(=O)-, -N(R Y2B ), -N(R Y2B )S(=O)2-;

[0015] n Y2 is selected from 0, 1, 2, 3, 4, 5 or 6;

[0016] is selected from

[0017] When is ;

[0018] X5 is selected from N or CR5;

[0019] X6 is selected from -C(R 6A )2-、-NR 6B -, -O-, -S-, -C(=O)-, -S(=O)-, -S(=O)2-, -C(=O)-NR 6B -、-C(=O)-NR 6B -C(=O)-, -S(=O)-NR 6B -or-S(=O)2-NR 6B -;

[0020] n1, n2, n3, n4, n5, n6, n7 and n8 are independently selected from 0, 1, 2, 3, 4, 5 or 6 in each instance;

[0021] Optionally, R5 and (R2 or R4) together with the atoms to which they are respectively attached form a ring C; the ring C is selected from a 3-8 membered carbocyclic ring or a 3-8 membered heterocyclic ring; the heterocyclic ring optionally further comprises 1, 2 or 3 heteroatoms selected from N, O or S; the ring C is independently optionally substituted by n ringC R ringC replace;

[0022] when for hour;

[0023] X7 is selected from N or CR7;

[0024] X8 is selected from N or CR8;

[0025] X9 is selected from N or CR9;

[0026] X 10 Selected from -C(R 10A )2-、-NR 10B -, -O-, -S-, -C(=O)-, -S(=O)-, -S(=O)2-, -C(=O)-NR 10B -、-C(=O)-NR 10B -C(=O)-, -S(=O)-NR 10B -or-S(=O)2-NR 10B -;

[0027] n9、n 10 、n 11 、n 12 、n 13 、n 14 、n 15 and n 16 In each instance, independently selected from 0, 1, 2, 3, 4, 5 or 6;

[0028] Optionally, R7 and (R2 or R4) together with the atoms to which they are respectively attached form ring D; said ring D is selected from 3- to 8-membered carbocyclic rings or 3- to 8-membered heterocyclic rings; said heterocyclic rings optionally further contain 1, 2 or 3 heteroatoms selected from N, O or S; said ring D is independently optionally substituted by n ringD R ringD substituents;

[0029] When is ;

[0030] X 14 is selected from N or CR 14 ;

[0031] X 15 is selected from -C(R 15A )2-, -NR 15B -, -O-, -S-, -C(=O)-, -S(=O)-, -S(=O)2-, -C(=O)-NR 15B -, -C(=O)-NR 15B -C(=O)-, -S(=O)-NR 15B - or -S(=O)2-NR 15B -;

[0032] n 17 n 18 n 19 and n 20 in each case are independently optionally selected from 0, 1, 2, 3, 4, 5 or 6;

[0033] Optionally, R 14 and (R2 or R4) together with the atoms to which they are respectively attached form ring E; said ring E is selected from 3- to 8-membered carbocyclic rings or 3- to 8-membered heterocyclic rings; said heterocyclic rings optionally further contain 1, 2 or 3 heteroatoms selected from N, O or S; said ring E is independently optionally substituted by n ringE R ringE substituents;

[0034] When is ;

[0035] n 25 is selected from 0, 1, 2, 3, 4, 5 or 6;

[0036] n 26 is selected from 0, 1, 2, 3, 4, 5 or 6;

[0037] Optionally, R 17 and R 18Together with the atoms to which they are attached respectively, they form ring F; the ring F is selected from a 3-8 membered carbocyclic ring, a 3-8 membered heterocyclic ring, a phenyl ring or a 5-6 membered heteroaryl ring; the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S; the heteroaryl ring may optionally further contain 1, 2 or 3 heteroatoms selected from N, O or S; the ring F is independently optionally substituted by n ringF R ringF replace;

[0038] R1, R2, R3, R4, R5, R 6A , R7, R8, R9, R 10A , R 14 , R 17 , R 18 , R 15A , R Y1A or R Y2A independently selected from hydrogen, halogen, -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -halogenated C 1-6 Alkyl, -O-CH3, -C 2-6 Alkoxy, -CN, -COOH, -NH2, -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2, -OH, -O(C 1-6 alkyl), -SH, -S(C 1-6 alkyl), -C(=O)(C 1-6 alkyl), -S(=O)(C 1-6 alkyl), -S(=O)2(C 1-6 alkyl), -C(=O)NH2, -C(=O ) NH(C 1-6 alkyl), -C(=O ) N(C 1-6 alkyl) ( -NHC(=O)(C 1-6 Alkyl), -N(C 1-6 alkyl)C(=O)(C 1-6 alkyl), -C(=O)O(C 1-6 alkyl), -OC(=O)(C 1-6 alkyl), -S(=O)NH2, -S(=O)NH(C 1-6 alkyl), -S(=O)N(C 1-6 Alkyl)2, -NHS(=O)(C 1-6 Alkyl), -N(C 1-6 alkyl)S(=O)(C 1-6 alkyl), -S(=O)2NH2, -S(=O)2NH(C1-6 alkyl), -S ( =O)2N(C 1-6 alkyl)2, -NHS(=O)2(C 1-6 alkyl), -N(C 1-6 alkyl)S ( =O)2(C 1-6 alkyl), 3 - 10 membered carbocyclic group, 3 - 10 membered heterocyclic group, 6 - 10 membered aryl group or 5 - 10 membered heteroaryl group; wherein, said R1, R2, R3, R4, R5, R7, R8, R9, R 6A , R 10A , R 14 , R 15A , R Y1A or R Y2A are independently optionally substituted by one or more substituents selected from halogen, halo C 1-6 alkyl, -CN, -NH2, -C (1-6) alkyl - C 1-6 alkenyl, -C 1-6 alkynyl, -halo C 1-6 alkyl, -O - CH3, -C 2-6 alkoxy, -CN, -COOH, -NH2, -NH(C 1-6 alkyl), -N(C 1-6 alkyl)2, -OH, -O(C 1-6 alkyl), -SH, -S(C 1-6 alkyl), -C(=O)(C 1-6 alkyl), -S(=O)2(C 1-6 alkyl), -C(=O)NH2, -C(=O)NH(C 1-6 alkyl), -C(=O)N(C 1-6 alkyl)2, -NHC(=O)(C 1-6 alkyl), -N(C 1-6 alkyl)C(=O)(C 1-6 alkyl), -C(=O)O(C 1-6 alkyl), -O - C(=O)(C 1-6 alkyl), -S(=O)NH2, -S(=O)NH(C 1-6 alkyl), -S(=O)N(C 1-6 alkyl)2, -NHS(=O)(C 1-6 alkyl), -N(C 1-6 alkyl)S(=O)(C 1-6 alkyl), -S(=O)2NH2, -S(=O)2NH(C 1-6 alkyl), -S ( =O)2N(C1-6 Alkyl)2, -NHS(=O)2(C 1-6 Alkyl), -N(C 1-6 Alkyl)S ( =O)2(C 1-6 alkyl), 3-10-membered carbocyclyl, 3-10-membered heterocyclyl, 6-10-membered aryl or 5-10-membered heteroaryl;

[0039] R 6B , R 10B , R 15B , R Y1B or R Y2B Selected from hydrogen, -C 1-6 Alkyl, -C 2-6 Alkenyl, -C2-6 alkynyl, -halogenated C 1- 6-alkyl, -O-CH3, -C 2-6 Alkoxy, -C(=O)(C 1-6 alkyl), -C(=O)NH2, -C(=O)NH(C 1-6 alkyl), -C(=O)N(C 1-6 Alkyl)2, -S(=O)(C 1-6 alkyl), -S(=O)2(C 1-6 Alkyl), -(C 0-6 alkenyl)-(3-14 membered carbocyclic group), -(C 0-6 alkenyl)-(3-14 membered heterocyclic group), -(C 0-6 alkenyl)-(phenyl) or -(C 0-6 alkenyl)-(5-14 membered heteroaryl); said R 6B , R 10B , R 15B , R Y1B or R Y2B are independently optionally substituted by 1, 2, 3, 4, 5 or 6 substituents selected from the group consisting of halogen, -C 1-6 Alkyl, -halogenated C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -CN, oxo, -NH2 substituted, -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2-OH, -O(C 1-6 Alkyl), -O(halogenated C 1-6 alkyl), -SH, -S(C 1-6 alkyl), -S(=O)(C 1-6 alkyl), -S(=O)2(C 1-6 alkyl), -C(=O)(C 1-6alkyl), -C(=O)OH, -C(=O)(OC 1-6 Alkyl), -OC ( =O)(C 1-6 alkyl)-C(=O)NH2, -C(=O)NH(C 1-6 alkyl), -C(=O)N(C 1-6 Alkyl)2, -NHC(=O)(C 1-6 alkyl), -S(=O)(OC 1-6 alkyl), -OS(=O)(C 1-6 alkyl), -S(=O)NH2, -S(=O)NH(C 1-6 alkyl), -S(=O)N(C 1-6 Alkyl)2, -NHS(=O)(C 1-6 Alkyl), -S(=O)2(OC 1-6 Alkyl), -S(=O)2(OC 1-6 alkyl), -OS(=O)2(OC 1-6 alkyl), -S(=O)2NH2, -S ( =O)2N(C 1-6 Alkyl)2, -NHS(=O)2(C 1-6 alkyl), 3-10 membered carbocyclyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl;

[0040] Ring A is selected from a 3-14 membered heterocyclic ring or a 5-14 membered heteroaromatic ring; the heterocyclic ring optionally further contains 1, 2, 3, 4, 5 or 6 heteroatoms selected from N, O or S; the heteroaromatic ring optionally further contains 1, 2, 3, 4, 5 or 6 heteroatoms selected from N, O or S;

[0041] R S1 , R S2 , R S3 , R ringC , R ringD , R ringE or R ringF Selected from halogen, -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, -CN, -NO2, -N3, oxo, -NH2, -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2, -OH, -O(C 1-6 alkyl), -SH, -S(C 1-6 alkyl), -S(=O)(C1-6 alkyl), -S(=O)2(C 1-6 alkyl), -C(=O)(C 1-6 alkyl), -C(=O)NH2-C(=O)NH(C 1-6 alkyl), -C(=O)N(C 1-6 alkyl )2 , -NHC(=O)(C 1-6 alkyl), -N(C 1-6 alkyl)C(=O)(C 1-6 alkyl), -OC(=O)O(C 1-6 alkyl), -NHC(=O)(OC 1-6 alkyl), -N(C 1-6 alkyl)C(=O)(OC 1-6 alkyl), -OC(=O)NH(C 1-6 alkyl), -OC(=O)N(C 1-6 alkyl)2, -NHC(=O)NH2, -NHC(=O ) N(C 1-6 alkyl), -N(C 1-6 alkyl)C(=O)NH2, -N(C 1-6 alkyl)C(=O)NH(C 1-6 alkyl), -N(C 1-6 alkyl)C(=O)N(C 1-6 alkyl)2, -S(=O)(OC 1-6 alkyl), -OS(=O)(C 1-6 alkyl), -S(=O)NH2, -S(=O)NH(C 1-6 alkyl), -S(=O)N(C 1-6 alkyl )2 , -NHS(=O)(C 1-6 alkyl), -N(C 1-6 alkyl)S(=O)(C 1-6 alkyl), -S(=O)2(OC 1-6 alkyl), -OS(=O)2(C 1-6 alkyl), -S(=O)2NH2, -S(=O)2NH(C 1-6 alkyl), -S(=O)2N(C 1-6 alkyl)2, -NHS(=O)2(C 1-6 alkyl), -N(C 1-6 alkyl)S(=O)2(C 1-6 alkyl), -OS(=O)2O(C 1-6 alkyl), -NHS(=O)2O(C 1-6 alkyl), -N(C1-6 Alkyl)S(=O)2O(C 1-6 alkyl), -OS(=O)2NH2, -OS(=O)2NH(C 1-6 alkyl), -OS(=O)2N(C 1-6 Alkyl)2, -NHS(=O)2NH2, -NHS(=O)2NH(C 1-6 alkyl), -NHS(=O)2N(C 1-6 alkyl )2 、-N(C 1-6 Alkyl)S(=O)2NH2, -N(C 1-6 Alkyl)S(=O)2NH(C 1-6 Alkyl), -N(C 1-6 alkyl)S(=O )2 N(C 1-6 Alkyl)2, -PH(C 1-6 Alkyl), -P(C 1-6 Alkyl)2, -P(=O)H(C 1-6 alkyl), -P(=O ) (C 1-6 alkyl) 2, 3-7 membered carbocyclyl, 3-7 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl;

[0042] n S1 、n S2 、n S3 、n ringC 、n ringD 、n ringE and n ringF In each instance, independently selected from 0, 1, 2, 3, 4, 5 or 6;

[0043] Each heterocyclic ring contains independently at each occurrence 1, 2, 3, 4, 5 or 6 heteroatoms selected from N, O or S;

[0044] Each heteroaryl group independently contains 1, 2, 3, 4, 5 or 6 heteroatoms selected from N, O or S at each occurrence.

[0045] In the present invention, the compound of formula (I), its stereoisomers, its atropisomers, its pharmaceutically acceptable salts, its pharmaceutically acceptable salts of stereoisomers, its pharmaceutically acceptable salts of atropisomers, its solvates or its pharmaceutically acceptable salts of solvates, the definitions of certain substituents may be as described below, and the definitions of substituents not mentioned are as described in any scheme of the present invention (hereinafter referred to as "in a certain technical scheme"):

[0046] In a certain technical solution, Selected from Preferably

[0047] * indicates the connection point of the molecule.

[0048] In a certain technical solution, each occurrence of R1, R2, R3, R4 or R5 is independently selected from -H, -Cl, -F, -Br, -I, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, oxo group, -CN, -NH2, -NH(CH3), -NH(CH2CH3), -NH(CH2CH2CH3), -NH(CH(CH3)2), -N(CH3)2, -OH, -O-CH3, -O-CH2CH3, -O-CH2CH2CH3, -O-CH(CH3)2, -SH, -S-CH3, -S-CH2CH3, -S-CH2CH2CH3, -S-CH(CH3)2, -C(=O)CH3, -C(=O)(CH2CH3), -C(=O)(CH2CH2CH3), -C(=O)(CH(CH3)2), -S(=O)CH3, -S(=O)(CH2CH3), -S(=O)(CH2CH2CH3), -S(=O)(CH(CH3)2), -S(=O)2CH3, -S(=O)2(CH2CH3), -S(=O)2(CH2CH2CH3), -S(=O)2(CH(CH3)2), -COOH, -C(=O)NH2, -C(=O)NH(CH3), -C(=O)NH(CH2CH3), -C(=O)NH(CH2CH2CH3), -C(=O)NH(CH(CH3)2), -C(=O)N(CH3)2, -S(=O)2NH2, -S(=O)2NH(CH3), -S(=O)2NH(CH2CH3), -S(=O)2NH(CH2CH2CH3), -S(=O)2NH(CH(CH3)2), -S(=O)2N(CH3)2, -cyclopropyl, -cyclobutyl, -cyclopentyl or -cyclohexyl; wherein, the R1, R2, R3, R4 or R5 are independently optionally substituted by 1, 2 or 3 substituents selected from the following: -Cl, -F, -Br, -I, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CN, oxo, -NH2, -NH(CH3), -NH(CH2CH3), -NH(CH2CH2CH3), -NH(CH(CH3)2), -N(CH3)2, -OH, -O-CH3, -O-CH2CH3, -O-CH2CH2CH3, -O-CH(CH3)2, -SH, -S-CH3, -S-CH2CH3, -S-CH2CH2CH3 or -S-CH(CH3)2;

[0049] Further preferably, each occurrence of R1, R2, R3, R4 or R5 is independently selected from -H.

[0050] In a certain technical solution, selected from preferably

[0051] * indicates for connection

[0052] In a certain technical solution, Y1 is selected from none, -C(=O)N(R( Y1B ))-, N(R( Y1B) )C(=O)-**, -C(R Y1A )=C(R( Y1A ))- or -C≡C-; preferably, Y1 is selected from none or -C≡C-;

[0053] ** indicates for connection

[0054] In a certain technical solution, each occurrence of R Y1A is independently selected from -H, -Cl, -F, -Br, -I, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, oxo, -CN, -NH2, -NH(CH3), -NH(CH2CH3), -NH(CH2CH2CH3), -NH(CH(CH3)2), -N(CH3)2, -OH, -O-CH3, -O-CH2CH3, -O-CH2CH2CH3, -O-CH(CH3)2, -SH, -S-CH3, -S-CH2CH3, -S-CH2CH2CH3, -S-CH(CH3)2, -C(=O)CH3, -C(=O)(CH2CH3), -C(=O)(CH2CH2CH3), -C(=O)(CH(CH3)2), -S(=O)CH3, -S(=O)(CH2CH3), -S(=O)(CH2CH2CH3), -S(=O)(CH(CH3)2), -S(=O)2CH3, -S(=O)2(CH2CH3), -S(=O)2(CH2CH2CH3), -S(=O)2(CH(CH3)2), -COOH, -C(=O)NH2, -C(=O)NH(CH3), -C(=O)NH(CH2CH3), -C(=O)NH(CH2CH2CH3), -C(=O)NH(CH(CH3)2), -C(=O)N(CH3)2, -S(=O)2NH2, -S(=O)2NH(CH3), -S(=O)2NH(CH2CH3), -S(=O)2NH(CH2CH2CH3), -S(=O)2NH(CH(CH3)2), -S(=O)2N(CH3)2, -cyclopropyl, -cyclobutyl, -cyclopentyl or -cyclohexyl; wherein, the RY1A is independently optionally substituted by one, two or three substituents selected from the following: -Cl, -F, -Br, -I, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CN, oxo -NH2, -NH(CH3), -NH(CH2CH3), -NH(CH2CH2CH3), -NH(CH(CH3)2), -N(CH3)2, -OH, -O-CH3, -O-CH2CH3, -O-CH2CH2CH3, -O-CH(CH3)2, -SH, -S-CH3, -S-CH2CH3, -S-CH2CH2CH3 or -S-CH(CH3)2;

[0055] More preferably, R Y1A is independently selected from -H at each occurrence point.

[0056] In one technical solution, each occurrence of R Y1B is independently selected from -H, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -C(=O)(CH3), -C(=O)(CH2CH3), -C(=O)(CH2CH2CH3), -C(=O)(CH(CH3)2), -S(=O)CH3, -S(=O)(CH2CH3), -S(=O)(CH2CH2CH3), -S(=O)(CH(CH3)2), -S(=O)2CH3, -S(=O)2(CH2CH3), -S(=O)2(CH2CH2CH3), -S(=O)2(CH(CH3)2), cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;

[0057] Even more preferably, R Y1B is selected from -H or -CH3.

[0058] In one technical solution, Y1 is selected from none, -C(=O)NH-**,** -C(=O)NH-, -CH=CH- or -C≡C-; preferably, Y1 is selected from none or -C≡C-;

[0059] ** represents the attachment point of the molecule.

[0060] In one technical solution,

[0061] n Y1 is selected from 0, 1 or 2; preferably, n Y1 is selected from 0 or 1.

[0062] In a certain technical solution, in ring A, the 5- to 14-membered heteroaromatic ring is a 5- or 6-membered monocyclic heteroaromatic ring or a 9- or 10-membered bicyclic heteroaromatic ring, and the number of heteroatoms is 1, 2, or 3, preferably 1H-pyrazolyl or 1H-indazolyl.

[0063] In a certain technical solution, Selected from

[0064] X 11 Or X 12 Is selected from CH or N;

[0065] X 13 Is selected from O or S;

[0066] R7 is selected from H or -C 1-6 Alkyl.

[0067] In a certain technical solution, From

[0068] Preferably, Selected from

[0069] More preferably, Selected from

[0070] In a certain technical solution, Selected from:

[0071]

[0072] Preferably, Selected from:

[0073] More preferably, it is

[0074] In a certain technical solution, each occurrence of Y2 is selected from absent, -C(R Y2A )2-, -O-, -S-, or -N(R Y2B ).

[0075] Preferably, each occurrence of R Y2AIndependently selected from -H, -Cl, -F, -Br, -I, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, oxo, -CN, -NH2, -NH(CH3), -NH(CH2CH3), -NH(CH2CH2CH3), -NH(CH(CH3)2), -N(CH3)2, -OH, -O-CH3, -O-CH2CH3, -O-CH2CH2CH3, -O-CH(CH3)2, -SH, -S-CH3, -S-CH2CH3, -S-CH2CH2CH3, -S-CH(CH3)2, -C(=O)CH3, -C(=O)(CH2CH3), -C(=O)(CH2CH2CH3), -C(=O)(CH(CH3)2), -S(=O)CH3, -S(=O)(CH2CH3), -S(=O)(CH2CH2CH3), -S(=O)(CH(CH3)2), -S(=O)2CH3, -S(=O)2(CH2CH3), -S(=O)2(CH2CH2CH3), -S(=O)2(CH(CH3)2), -COOH, -C(=O)NH2, -C(=O)NH(CH3), -C(=O)NH(CH2CH3), -C(=O)NH(CH2CH2CH3), -C(=O)NH(CH(CH3)2), -C(=O)N(CH3)2, -S(=O)2NH2, -S(=O)2NH(CH3), -S(=O)2NH(CH2CH3), -S(=O)2NH(CH2CH2CH3), -S(=O)2NH(CH(CH3)2), -S(=O)2N(CH3)2, -cyclopropyl, -cyclobutyl, -cyclopentyl or -cyclohexyl; wherein said R Y2A is independently optionally substituted by 1, 2 or 3 substituents selected from: -Cl, -F, -Br, -I, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CN, oxo, -NH2, -NH(CH3), -NH(CH2CH3), -NH(CH2CH2CH3), -NH(CH(CH3)2), -N(CH3)2, -OH, -O-CH3, -O-CH2CH3, -O-CH2CH2CH3, -O-CH(CH3)2, -SH, -S-CH3, -S-CH2CH3, -S-CH2CH2CH3 or -S-CH(CH3)2.

[0076] Preferably, R Y2A is independently selected from -H each time it appears.

[0077] In one technical solution, R that appears each time Y2BIndependently selected from -H, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -C(=O)(CH3), -C(=O)(CH2CH3), -C(=O)(CH2CH2CH3), -C(=O)(CH(CH3)2), -S(=O)CH3, -S(=O)(CH2CH3), -S(=O)(CH2CH2CH3), -S(=O)(CH(CH3)2), -S(=O)2CH3, -S(=O)2(CH2CH3), -S(=O)2(CH2CH2CH3), -S(=O)2(CH(CH3)2), -(CH2) 0-2 -(cyclopropyl), -(CH2) 0-2 -(cyclobutyl), -(CH2) 0-2 -(cyclopentyl), -(CH2) 0-2 -(cyclohexyl), -(CH2) 0-2 -(phenyl);

[0078] Preferably, each occurrence of R Y2B is independently selected from -H, -CH3, -CH2CH3, -CH2CH2CH3 or -CH(CH3)2.

[0079] In one technical solution, n Y2 is selected from 0, 1 or 2.

[0080] In one technical solution, each occurrence of Y2 is selected from none, -CH2-, -O-, -S- or -NH; preferably, each occurrence of Y2 is selected from none or -O-.

[0081] In one technical solution, the compound of formula (I) is a compound of formula (II):

[0082]

[0083] X5 is selected from N or CR5;

[0084] Optionally, R5 and (R2 or R4) together with the atoms to which they are respectively attached form a ring C; the ring C is selected from a 4- to 7-membered carbocyclic ring or a 4- to 7-membered heterocyclic ring; the heterocyclic ring optionally further contains 1, 2 or 3 heteroatoms selected from N, O or S; the ring C is independently optionally substituted by 1, 2, 3, 4, 5 or 6 R ringC substituted.

[0085] In one technical solution, the compound of formula (II) is a compound of formula (II-1):

[0086]

[0087] In a certain technical solution, the compound of formula (II-1) is formula (II-1A) or formula (II-1B):

[0088]

[0089] Preferably, each occurrence of R5 is independently selected from -H, -Cl, -F, -Br, -I, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, oxo, -CN, -NH2, -NH(CH3), -NH(CH2CH3), -NH(CH2CH2CH3), -NH(CH(CH3)2), -N(CH3)2, -OH, -O-CH3, -O-CH2CH3, -O-CH2CH2CH3, -O-CH(CH3)2, -SH, -S-CH3, -S-CH2CH3, -S-CH2CH2CH3, -S-CH(CH3)2, -C(=O)CH3, -C(=O)(CH2CH3), -C(=O)(CH2CH2CH3), -C(=O)(CH(CH3)2), -S(=O)CH3, -S(=O)(CH2CH3), -S(=O)(CH2CH2CH3), -S(=O)(CH(CH3)2), -S(=O)2CH3, -S(=O)2(CH2CH3), -S(=O)2(CH2CH2CH3), -S(=O)2(CH(CH3)2), -COOH, -C(=O)NH2, -C(=O)NH(CH3), -C(=O)NH(CH2CH3), -C(=O)NH(CH2CH2CH3), -C(=O)NH(CH(CH3)2), -C(=O)N(CH3)2, -S(=O)2NH2, -S(=O)2NH(CH3), -S(=O)2NH(CH2CH3), -S(=O)2NH(CH2CH2CH3), -S(=O)2NH(CH(CH3)2), -S(=O)2N(CH3)2, -cyclopropyl, -cyclobutyl, -cyclopentyl or -cyclohexyl; wherein, the R5 is independently optionally substituted by 1, 2 or 3 substituents selected from the following: -Cl, -F, -Br, -I, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CN, oxo, -NH2, -NH(CH3), -NH(CH2CH3), -NH(CH2CH2CH3), -NH(CH(CH3)2), -N(CH3)2, -OH, -O-CH3, -O-CH2CH3, -O-CH2CH2CH3, -O-CH(CH3)2, -SH, -S-CH3, -S-CH2CH3, -S-CH2CH2CH3 or -S-CH(CH3)2;

[0090] More preferably, each occurrence of R5 is independently selected from -H.

[0091] In one technical solution, the compound of formula (I) is a compound of formula (II-2)

[0092]

[0093] n 21 is selected from 0, 1, 2 or 3;

[0094] n 22 is selected from 0, 1, 2 or 3.

[0095] In one technical solution, the compound of formula (II-2) is a compound of formula (Ⅱ-2A) or formula (Ⅱ-2B):

[0096]

[0097] n 21 is selected from 0, 1, 2 or 3;

[0098] n 22 is selected from 0, 1, 2 or 3.

[0099] In one technical solution, in the compounds of formula (Ⅱ-2), formula (Ⅱ-2A) and formula (Ⅱ-2B):

[0100] Each occurrence of Y2 is selected from none, -CH2-, -O-, -S- or -NH; preferably, each occurrence of Y2 is selected from none or -O-.

[0101] In one technical solution, the compound of formula (II-2) is a compound of formula (Ⅱ-2A-1) or formula (Ⅱ-2B-1):

[0102]

[0103] n 21 is selected from 0, 1, 2 or 3;

[0104] n 22 is selected from 0, 1, 2 or 3.

[0105] In one technical solution, in formula (Ⅱ), formula (Ⅱ-1), formula (Ⅱ-1A), (Ⅱ-1B), formula (Ⅱ-2), formula (Ⅱ-2A) and formula (Ⅱ-2B),

[0106] X6 is selected from -C(R( 6A) )2-, -O-, -S-, -NR 6B -, -S(=O)2-, -C(=O)-NR 6B - or -C(=O)-NR 6B- C(=O)-;

[0107] Preferably, X6 is selected from -S(=O)2- or -C(=O)-NR 6B -.

[0108] In a certain technical solution, in formula (II), formula (II-1), formula (II-1A), formula (II-1B), formula (II-2), formula (II-2A) and formula (II-2B),

[0109] R 6B is selected from -H, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -C(=O)(CH 3) , -C(=O)(CH2CH 3) , -

[0110] C(=O)(CH2CH2CH3), -C(=O)(CH3)2), -S(=O)CH3, -S(=O)(CH2CH3), -S(=O)(CH3)2, -S(=O)2CH3,

[0111] -S(=O)2CH2CH3), -S(=O)2CH2CH2CH3, -S(=O)2CH(CH3)2, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl or benzofuryl; the R 6B is independently optionally substituted by 1, 2 or 3 substituents selected from the following: -Cl, -F, -Br, -I, -CH3, -CH2CH3, - CH2CH2CH3, -CH(CH3)2, CH2F, -CH F2 , -CF3,

[0112] -CH2CH2F, -CH2CH F2 , -CH2CF3, -CHFCH3, -CF2CH3, -CN, oxo, -NH2, -NH(CH3), -NH(CH2CH3),

[0113] -NH(CH2CH2CH3), -NH(CH3)2, -N(CH3)2, -OH, -O-CH3, -O-CH2CH3, -O-CH(CH3)2, -O-CH2F,

[0114] -O-CHF2, -O-CF3, -O-CH2CH2F, -O-CH2CHF2, -O-CH2CF3, -O-CHFCH3, -O-CF2CH3, -OH, -S-CH3, -S-

[0115] CH2CH3, -S-CH2CH2CH3 or -S-CH(CH3)2;

[0116] Preferably, R 6B is selected from -CH3 or -C(=O)CH3.

[0117] In a certain technical solution, each occurrence of R in formula (II), formula (II-1), formula (II-1A), (II-1B), formula (II-2), formula (II-2A) and formula (II-2B) 6A is independently selected from -H, -Cl, -F, -Br, -I, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, oxo, -CN, -NH2, -NH(CH3), -NH(CH2CH3), -NH(CH2CH2CH3), -NH(CH(CH3)2), -N(CH3)2, -OH, -O-CH3, -O-CH2CH3, -O-CH2CH2CH3, -O-CH(CH3)2, -SH, -S-CH3, -S-CH2CH3, -S-CH2CH2CH3, -S-CH(CH3)2, -C(=O)CH3, -C(=O)(CH2CH3), -C(=O)(CH2CH2CH3), -C(=O)(CH(CH3)2), -S(=O)CH3, -S(=O)(CH2CH3), -S(=O)(CH2CH2CH3), -S(=O)(CH(CH3)2), -S(=O)2CH3, -S(=O)2(CH2CH3), -S(=O)2(CH2CH2CH3), -S(=O)2(CH(CH3)2), -COOH, -C(=O)NH2, -C(=O)NH(CH3), -C(=O)NH(CH2CH3), -C(=O)NH(CH2CH2CH3), -C(=O)NH(CH(CH3)2), -C(=O)N(CH3)2, -S(=O)2NH2, -S(=O)2NH(CH3), -S(=O)2NH(CH2CH3), -S(=O)2NH(CH2CH2CH3), -S(=O)2NH(CH(CH3)2), -S(=O)2N(CH3)2, -cyclopropyl, -cyclobutyl, -cyclopentyl or -cyclohexyl; wherein, said R 6AIndependently and optionally substituted by one, two or three substituents selected from the following: -Cl, -F, -Br, -I, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CN, oxo, -NH2, -NH(CH3), -NH(CH2CH3), -NH(CH2CH2CH3), -NH(CH(CH3)2), -N(CH3)2, -OH, -O-CH3, -O-CH2CH3, -O-CH2CH2CH3, -O-CH(CH3)2, -SH, -S-CH3, -S-CH2CH3, -S-CH2CH2CH3 or -S-CH(CH3)2;

[0118] More preferably, R 6A Is independently selected from -H each time it appears.

[0119] In one technical solution, X6 is selected from -CH2-, -O-, -S-, -S(=O)2-, -C(=O)-N(CH3)- or -C(=O)-N(CH3)-C(=O)-;

[0120] Preferably, X6 is selected from -S(=O)2- or -C(=O)-N(CH3)-.

[0121] In one technical solution, in formula (II), formula (II-1), formula (II-1A), (II-1B), formula (II-2), formula (II-2A) and formula (II-2B),

[0122] n1 is 1, n2 is 1, n3 is 1, n4 is 1, n5 is 1, n6 is 1, n7 is 1, n8 is 1; or

[0123] n1 is 1, n2 is 0, n3 is 1, n4 is 1, n5 is 1, n6 is 1, n7 is 1, n8 is 1; or

[0124] n1 is 1, n2 is 0, n3 is 1, n4 is 0, n5 is 1, n6 is 1, n7 is 1, n8 is 1; or

[0125] n1 is 1, n2 is 1, n3 is 1, n4 is 1, n5 is 1, n6 is 0, n7 is 1, n8 is 0; or

[0126] n1 is 1, n2 is 0, n3 is 1, n4 is 1, n5 is 1, n6 is 0, n7 is 1, n8 is 1; or

[0127] n1 is 1, n2 is 0, n3 is 1, n4 is 0, n5 is 1, n6 is 0, n7 is 1, n8 is 0; or

[0128] n1 is 1, n2 is 1, n3 is 1, n4 is 1, n5 is 1, n6 is 1, n7 is 0, n8 is 0; or

[0129] n1 is 1, n2 is 0, n3 is 1, n4 is 1, n5 is 1, n6 is 0, n7 is 1, n8 is 0; or

[0130] n1 is 1, n2 is 0, n3 is 1, n4 is 0, n5 is 1, n6 is 1, n7 is 1, n8 is 0; or

[0131] n1 is 1, n2 is 1, n3 is 1, n4 is 1, n5 is 1, n6 is 0, n7 is 1 ， n8 is 1; or

[0132] n1 is 2, n2 is 1, n3 is 1, n4 is 0, n5 is 0, n6 is 0, n7 is 1 ， n8 is 1; or

[0133] n1 is 2, n2 is 1, n3 is 1, n4 is 0, n5 is 0, n6 is 0, n7 is 1, n8 is 0; or

[0134] n1 is 1, n2 is 1, n3 is 1, n4 is 1, n5 is 1, n6 is 0, n7 is 1, n8 is 0; or

[0135] n1 is 1, n2 is 1, n3 is 1, n4 is 1, n5 is 2, n6 is 1, n7 is 0, n8 is 0; or

[0136] n1 is 1, n2 is 1, n3 is 1, n4 is 1, n5 is 0, n6 is 0, n7 is 1, n8 is 0; or

[0137] n1 is 1, n2 is 0, n3 is 1, n4 is 1, n5 is 1, n6 is 0, n7 is 1, n8 is 0; or

[0138] n1 is 1, n2 is 0, n3 is 1, n4 is 0, n5 is 1, n6 is 0, n7 is 1, n8 is 0.

[0139] In a certain technical solution, Selected from:

[0140] More preferably, Selected from

[0141] In certain embodiments, Selected from In certain embodiments, Selected from In a certain technical solution, Selected from:

[0142] In a certain technical solution, Selected from:

[0143]

[0144] In a certain technical solution, in formula (II), formula (II-2), formula (II-2A) and formula (II-2B),

[0145] n 21 is 0, n 22 is 0; or

[0146] n 21 is 1, n 22 is 0; or

[0147] n 21 is 1, n 22 is 1; or

[0148] n 21 is 1, n 22 is 2.

[0149] In a certain technical solution, Selected from:

[0150]

[0151]

[0152] In a certain technical solution, each occurrence of R 11 is selected from -CH3, -CH2CH3, -CH2CH2CH3 or -CH(CH3)2;

[0153] In a certain technical solution, each occurrence of Y2 is selected from none, -CH2-, -O-, -S- or -NH; preferably, each occurrence of Y2 is selected from none or -O-.

[0154] Preferably selected from:

[0155] In a certain solution, the compound of formula (I) is a compound of formula (III):

[0156]

[0157] In a certain solution, the compound of formula (I) is a compound of formula (III-1):

[0158]

[0159] In one embodiment, the compound of formula (I) is a compound of formula (III-1A) or formula (III-1B):

[0160]

[0161] In one embodiment, in formula (III), formula (III-1), formula (III-1A) and formula (III-1B),

[0162] X7 is selected from N or CR7;

[0163] X8 is selected from N or CR8;

[0164] X9 is selected from N or CR9;

[0165] X 10 is selected from -C(R 10A )2-, -NR 10B -, -O-, -S-, -C(=O)-, -S(=O)-, -S(=O)2-, -C(=O)-NR 10B -, -C(=O)-NR 10B -C(=O)-, -S(=O)-NR 10B - or -S(=O)2-NR 10B

[0166] In one technical solution, in the compounds of formula (III), formula (III-1), formula (III-1A) and formula (III-1B), X7 is selected from CR7;

[0167] Preferably, each occurrence of R7 is independently selected from -H, -Cl, -F, -Br, -I, -CH3, -CH2CH2CH3, -CH(CH3)2, oxo, -CN, -NH2, -NH(CH3), -NH(CH2CH3), -NH(CH2CH2CH3), -NH(CH(CH3)2), -N(CH3)2, -OH, -O-CH3, -O-CH2CH3, -O-CH2CH2CH3, -O-CH(CH3)2, -SH, -S-CH3, -S-CH2CH3, -S-CH2CH2CH3, -S-CH(CH3)2, -C(=O)CH3, -C(=O)(CH2CH3), -C(=O)(CH2CH2CH3), -C(=O)(CH(CH3)2), -S(=O)CH3, -S(=O)(CH2CH3), -S(=O)(CH2CH2CH3), -S(=O)(CH(CH3)2), -S(=O)2CH3, -S(=O)2(CH2CH3), -S(=O)2(CH2CH2CH3), -S(=O)2(CH(CH3)2), -COOH, -C(=O)NH2, -C(=O)NH(CH3), -C(=O)NH(CH2CH3), -C(=O)NH(CH2CH2CH3), -C(=O)NH(CH(CH3)2), -C(=O)N(CH3)2, -S(=O)2NH2, -S(=O)2NH(CH3), -S(=O)2NH(CH2CH3), -S(=O)2NH(CH2CH2CH3), -S(=O)2NH(CH(CH3)2), -S(=O)2N(CH3)2, -cyclopropyl, -cyclobutyl, -cyclopentyl or -cyclohexyl; wherein, said R7 is independently optionally substituted with 1, 2 or 3 substituents selected from the following: -Cl, -F, -Br, -I, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CN, oxo, -NH2, -NH(CH3), -NH(CH2CH3), -NH(CH2CH2CH3), -NH(CH(CH3)2), -N(CH3)2, -OH, -O-CH3, -O-CH2CH3, -O-CH2CH2CH3, -O-CH(CH3)2, -SH, -S-CH3, -S-CH2CH3, -S-CH2CH2CH3 or -S-CH(CH3)2;

[0168] Preferably, R7 is independently selected from -H at each occurrence.

[0169] In a certain technical solution, in formula (III), formula (III-1), formula (III-1A) and formula (III-1B), X7 is selected from CH.

[0170] In a certain technical solution, in formula (III), formula (III-1), formula (III-1A) and formula (III-1B), X8 is selected from N or CR8;

[0171] Preferably, each occurrence of R8 is independently selected from -H, -Cl, -F, -Br, -I, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, oxo, -CN, -NH2, -NH(CH3), -NH(CH2CH3), -NH(CH2CH2CH3), -NH(CH(CH3)2), -N(CH3)2, -OH, -O-CH3, -O-CH2CH3, -O-CH2CH2CH3, -O-CH(CH3)2, -SH, -S-CH3, -S-CH2CH3, -S-CH2CH2CH3, -S-CH(CH3)2, -C(=O)CH3, -C(=O)(CH2CH3), -C(=O)(CH2CH2CH3), -C(=O)(CH(CH3)2), -S(=O)CH3, -S(=O)(CH2CH3), -S(=O)(CH2CH2CH3), -S(=O)(CH(CH3)2), -S(=O)2CH3, -S(=O)2(CH2CH3), -S(=O)2(CH2CH2CH3), -S(=O)2(CH(CH3)2), -COOH, -C(=O)NH2, -C(=O)NH(CH3), -C(=O)NH(CH2CH3), -C(=O)NH(CH2CH2CH3), -C(=O)NH(CH(CH3)2), -C(=O)N(CH3)2, -S(=O)2NH2, -S(=O)2NH(CH3), -S(=O)2NH(CH2CH3), -S(=O)2NH(CH2CH2CH3), -S(=O)2NH(CH(CH3)2), -S(=O)2N(CH3)2, -cyclopropyl, -cyclobutyl, -cyclopentyl or -cyclohexyl; wherein, the R8 is independently optionally substituted by 1, 2 or 3 substituents selected from the following: -Cl, -F, -Br, -I, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CN, oxo, -NH2, -NH(CH3), -NH(CH2CH3), -NH(CH2CH2CH3), -NH(CH(CH3)2), -N(CH3)2, -OH, -O-CH3, -O-CH2CH3, -O-CH2CH2CH3, -O-CH(CH3)2, -SH, -S-CH3, -S-CH2CH3, -S-CH2CH2CH3 or -S-CH(CH3)2;

[0172] More preferably, R8 is independently selected from -H at each occurrence point.

[0173] In a certain technical solution, in formula (III), formula (III-1), formula (III-1A) and formula (III-1B), X8 is selected from N or CH.

[0174] In a certain technical solution, in formula (III), formula (III-1), formula (III-1A) and formula (III-1B), X9 is selected from N or CR9;

[0175] Preferably, each occurrence of R9 is independently selected from -H, -Cl, -F, -Br, -I, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, oxo, -CN, -NH2, -NH(CH3), -NH(CH2CH3), -NH(CH2CH2CH3), -NH(CH(CH3)2), -N(CH3)2, -OH, -O-CH3, -O-CH2CH3, -O-CH2CH2CH3, -O-CH(CH3)2, -SH, -S-CH3, -S-CH2CH3, -S-CH2CH2CH3, -S-CH(CH3)2, -C(=O)CH3, -C(=O)(CH2CH3), -C(=O)(CH2CH2CH3), -C(=O)(CH(CH3)2), -S(=O)CH3, -S(=O)(CH2CH3), -S(=O)(CH2CH2CH3), -S(=O)(CH(CH3)2), -S(=O)2CH3, -S(=O)2(CH2CH3), -S(=O)2(CH2CH2CH3), -S(=O)2(CH(CH3)2), -COOH, -C(=O)NH2, -C(=O)NH(CH3), -C(=O)NH(CH2CH3), -C(=O)NH(CH2CH2CH3), -C(=O)NH(CH(CH3)2), -C(=O)N(CH3)2, -S(=O)2NH2, -S(=O)2NH(CH3), -S(=O)2NH(CH2CH3), -S(=O)2NH(CH2CH2CH3), -S(=O)2NH(CH(CH3)2), -S(=O)2N(CH3)2, -cyclopropyl, -cyclobutyl, -cyclopentyl or -cyclohexyl; wherein, the R9 is independently optionally substituted by 1, 2 or 3 substituents selected from the following: -Cl, -F, -Br, -I, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CN, oxo, -NH2, -NH(CH3), -NH(CH2CH3), -NH(CH2CH2CH3), -NH(CH(CH3)2), -N(CH3)2, -OH, -O-CH3, -O-CH2CH3, -O-CH2CH2CH3, -O-CH(CH3)2, -SH, -S-CH3, -S-CH2CH3, -S-CH2CH2CH3 or -S-CH(CH3)2;

[0176] More preferably, each occurrence of R9 is independently selected from -H.

[0177] In a certain technical solution, in formula (III), formula (III-1), formula (III-1A) and formula (III-1B), X9 is N or CH.

[0178] In a certain technical solution, in formula (III), formula (III-1), formula (III-1A) and formula (III-1B),

[0179] X 10 is selected from -C(R( 10A ) 2- , -O-, -S-, -NR 10B -, -S(=O)2-, -C(=O)-NR 10B - or -C(=O)-NR 10B -C(=O)-.

[0180] In a certain technical solution, in formula (III), formula (III-1), formula (III-1A) and formula (III-1B),

[0181] R 10B is selected from -H, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -C(=O)(CH3), -C(=O)(CH2CH3), -C(=O)(CH2CH2CH3), -C(=O)(CH(CH3)2), -S(=O)CH3, -S(=O)(CH2CH3), -S(=O)(CH2CH2CH3), -S(=O)(CH(CH3)2), -S(=O)2CH3, -S(=O)2(CH2CH3), -S(=O)2(CH2CH2CH3), -S(=O)2(CH(CH3)2), -(CH2) (0-2) -(cyclopropyl), -(CH2) (0-2) -(cyclobutyl), -(CH2) (0-2 )-(cyclopentyl), -(CH2) (0-2) -(cyclohexyl), -(CH2) (0-2) -(phenyl), -(CH2) (0-2) -(pyrrolyl), -(CH2) (0-2) -(furyl), -(CH2) (0-2) -(thienyl)-(CH2 )(0-2) -(imidazolyl), -(CH2) (0-2) -(oxazolyl), -(CH2) (0-2) -(isoxazolyl), -(CH2) (0-2)-( thiazolyl), -(CH2) (0-2) -(isothiazolyl), -(CH2) (0-2) -(pyrazolyl), -(CH2) (0-2) -(pyridyl), -(CH2) (0-2) -(pyrimidinyl), -(CH2 ) ( 0-2)-(pyrazinyl), -(CH2) (0-2) -(indolyl), -(CH2) (0-2) -(isoindolyl) or -(CH2) (0-2) -(benzofuranyl); said R 10B is independently optionally substituted by 1, 2 or 3 substituents selected from the following: -Cl, -F, -Br, -I, -CH 3) , -CH2CH3, -CH2CH2CH3, -CH(CH3)2, CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CHFCH3, -CF2CH3, -CN, oxo, -NH2, -NH(CH3), -NH(CH2CH3), -NH(CH2CH2CH3), -NH(CH(CH3)2), -N(CH3)2, -OH, -O-CH3, -O-CH2CH3, -O-CH2CH2CH3, -O-CH(CH3)2, -O-CH2F, -O-CHF2, -O-CF3, -O-CH2CH2F, -O-CH2CHF2, -O-CH2CF3, -O-CHFCH3, -O-CF2CH3, -OH, -S-CH3, -S-CH2CH3, -S-CH2CH2CH3 or -S-CH(CH3)2;

[0182] Preferably, R 10B is selected from -C(=O)(CH3), -C(=O)(CH2CH3), -S(=O)2CH3, phenyl or -CH2-phenyl.

[0183] In a certain technical solution, in formula (Ⅲ), formula (Ⅲ-1), formula (Ⅲ-1A) and formula (Ⅲ-1B), X 10 is selected from -NR 10B -.

[0184] In a certain technical solution, in formula (Ⅲ), formula (Ⅲ-1), formula (Ⅲ-1A) and formula (Ⅲ-1B), R 10B is selected from -C(=O)(CH3), -C(=O)(CH2CH3), -C(=O)(CH2CH2CH3), -C(=O)(CH(CH3)2), -S(=O)CH3, -S(=O)(CH2CH3), -S(=O)(CH2CH2CH3), -S(=O)(CH(CH3)2), -S(=O)2CH3, -S(=O)2(CH2CH3), -S(=O)2(CH2CH2CH3), -S(=O)2(CH(CH3)2), phenyl, -CH2-phenyl, -CH2CH2-phenyl or -CH(CH3)-phenyl;

[0185] Preferably, R 10B is selected from -C(=O)CH3, -C(=O)(CH2CH3), -S(=O)2CH3, phenyl or -CH2-phenyl.

[0186] In a certain technical solution, in formula (III), formula (III-1), formula (III-1A) and formula (III-1B),

[0187] X7 is selected from -N-; X8 is selected from -CR8-; X9 is selected from -CR9-; X 10 is selected from -NR 10B -; Preferably, X7 is selected from -N-; X8 is selected from -CH-; X9 is selected from -CH-; X 10 is selected from -NR 10B -.

[0188] In a certain technical solution, the general formula of the compound of formula (I) is formula (III), formula (III-1), formula (III-1A) or formula (III-1B):

[0189]

[0190] In a certain technical solution, in formula (III), formula (III-1), formula (III-1A) or formula (III-1B),

[0191] n9 is 1, n 10 is 0, n 11 is 1, n 12 is 0, n 13 is 1, n 14 is 0, n 15 is 1, n 16 is 0; or

[0192] n9 is 1, n 10 is 1, n 11 is 1, n 12 is 0, n 13 is 1, n 14 is 0, n 15 is 1, n 16 is 0; or

[0193] n9 is 1, n 10 is 0, n 11 is 1, n 12 is 0, n 13 is 1, n 14 is 1, n 15 is 1, n 16 is 0; or

[0194] n9 is 1, n 10 is 1, n 11 is 1, n 12 is 0, n13 is 1, n 14 is 1, n 15 is 1, n 16 is 0; or

[0195] n9 is 1, n 10 is 1, n 11 is 1, n 12 is 1, n 13 is 1, n 14 is 0, n 15 is 1, n 16 is 0; or

[0196] n9 is 1, n 10 is 0, n 11 is 1, n 12 is 0, n 13 is 1, n 14 is 1, n 15 is 1, n 16 is 1; or n9 is 1, n 10 is 1, n 11 is 1, n 12 is 1, n 13 is 1, n 14 is 1, n 15 is 1, n 16 is 0; or n9 is 1, n 10 is 1, n 11 is 1, n 12 is 0, n 13 is 1, n 14 is 1, n 15 is 1, n 16 is 1; or n9 is 1, n 10 is 1, n 11 is 1, n 12 is 0, n 13 is 1, n 14 is 1, n 15 is 1, n 16 is 1; or n9 is 1, n 10 is 1, n 11 is 1, n 12 is 1, n 13 is 1, n 14 is 1, n 15 is 1, n 16 is 1; or n9 is 1, n 10 is 2, n 11 is 2, n 12 is 0, n 13 is 1, n 14 is 0, n 15 is 1, n 16 is 0; or n9 is 1, n10 is 0, n 11 is 1, n 12 is 0, n 13 is 1, n 14 is 2, n 15 is 2, n 16 is 0; or n9 is 1, n 10 is 2, n 11 is 2, n 12 is 0, n 13 is 1, n 14 is 1, n 15 is 1, n 16 is 0; or n9 is 1, n 10 is 1, n 11 is 1, n 12 is 0, n 13 is 1, n 14 is 2, n 15 is 2, n 16 is 0; or n9 is 1, n 10 is 2, n 11 2, n 12 is 0, n 13 is 1, n 14 is 1, n 15 is 1, n 16 is 1; or

[0197] n9 is 1, n 10 is 1, n 11 is 1, n 12 is 1, n 13 is 1, n 14 is 2, n 15 is 2, n 16 is 0.

[0198] In a certain technical solution, in formula (III), formula (III-1), formula (III-1A) and formula (III-1B),

[0199] is selected from

[0200] More preferably,[[]] is selected from

[0201] In a certain technical solution, in formula (III), formula (III-1), formula (III-1A) and formula (III-1B),

[0202] is selected from:

[0203] Preferably,[[]] is selected from

[0204] In one technical solution, in formula (III), formula (III-1), formula (III-1A) and formula (III-1B),

[0205] selected from:

[0206] In one technical solution, the compound of formula (I) is the compound of formula (IV)

[0207]

[0208] X 14 selected from N or CR 14 ;

[0209] Each occurrence of ring E is independently selected from a 4- to 7-membered carbocyclic ring or a 4- to 7-membered heterocyclic ring; the heterocyclic ring may optionally further contain 1, 2 or 3 heteroatoms selected from N, O or S; each occurrence of ring E is independently optionally substituted with 1, 2, 3, 4, 5 or 6 R ringE substituted Each occurrence of ring E is independently selected from a 4- to 7-membered carbocyclic ring or a 4- to 7-membered heterocyclic ring; the heterocyclic ring may optionally further contain 1, 2 or 3 heteroatoms selected from N, O or S; each occurrence of ring E is independently optionally substituted with 1, 2, 3, 4, 5 or 6 R ringE substituted.

[0210] In one technical solution, the compound of formula (V) is the compound of formula (IV-1):

[0211]

[0212] In one technical solution, the compound of formula (V) is formula (IV-1A) or formula (IV-1B):

[0213]

[0214] In one technical solution, in formula (IV), formula (IV-1), formula (IV-1A) and formula (IV-1B),

[0215] Each occurrence of Y2 is selected from absent, -C(R Y2A )2-, -O-, -S- or -N(R Y2B );

[0216] Preferably, each occurrence of R Y2AIndependently selected from -H, -Cl, -F, -Br, -I, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, oxo, -CN, -NH2, -NH(CH3), -NH(CH2CH3), -NH(CH(CH3)2), -N(CH3)2, -OH, -O-CH3, -O-CH2CH3, -O-CH(CH3)2, -SH, -S-CH3, -S-CH2CH3, -S-CH(CH3)2, -C(=O)CH3, -C(=O)(CH2CH3), -C(=O)(CH(CH3)2), -S(=O)CH3, -S(=O)(CH2CH3), -S(=O)(CH(CH3)2), -S(=O)2CH3, -S(=O)2(CH2CH3), -S(=O)2(CH(CH3)2), -COOH, -C(=O)NH2, -C(=O)NH(CH3), -C(=O)NH(CH2CH3), -C(=O)NH(CH(CH3)2), -C(=O)N(CH3)2, -S(=O)2NH2, -S(=O)2NH(CH3), -S(=O)2NH(CH2CH3), -S(=O)2NH(CH(CH3)2), -S(=O)2N(CH3)2, -cyclopropyl, -cyclobutyl, -cyclopentyl or -cyclohexyl;

[0217] More preferably, R Y2A Is independently selected from -H each time it appears.

[0218] In a certain technical solution, R Y2B Is selected from -H, -CH3, -CH2CH3, -CH(CH3)2, -C(=O)(CH3), -C(=O)(CH2CH3)2, -S(=O)CH3, -S ( =O)(CH2CH3), -S(=O)CH(CH3)2, -S(=O)2CH2CH3, -S(=O)2CH(CH3)2, -(CH2 )(0-2) -(cyclopropyl), -(CH2) (0-2) -(cyclobutyl), -(CH2) (0-2) -(cyclopentyl), -(CH2) (0-2) -(cyclohexyl), -(CH2) (0-2) -(phenyl); more preferably, R Y2B Is selected from -H, -CH3, -CH2CH3 or -CH(CH3)2;

[0219] More preferably, R Y2B Is selected from -H;

[0220] nY2 Selected from 0, 1 or 2; preferably, n Y2 Selected from 0 or 1.

[0221] In a certain technical solution, among the compounds of formula (IV), formula (IV-1), formula (IV-1A) and formula (IV-1B),

[0222] Each occurrence of Y2 is selected from none, -CH2-, -O-, -S- or -NH; preferably, each occurrence of Y2 is selected from -O-;

[0223] n Y2 Selected from 0 or 1.

[0224] In a certain technical solution, the general formula of the compound of formula (IV) is formula (IV-1A-1) or formula (IV-1B-1):

[0225]

[0226] In a certain technical solution, the compound of formula (IV) is a compound of formula (IV-2):

[0227]

[0228] n 23 Selected from 0, 1, 2 or 3;

[0229] n 24 Selected from 0, 1, 2 or 3.

[0230] In a certain technical solution, the formula (IV) is formula (IV-2A) or formula (IV-2B):

[0231]

[0232] n 23 Selected from 0, 1, 2 or 3;

[0233] n 24 Selected from 0, 1, 2 or 3.

[0234] In a certain technical solution, the formula (IV) is formula (IV-2A-1) or formula (IV-2B-1):

[0235]

[0236] n 23 Selected from 0, 1, 2 or 3;

[0237] n 24 Selected from 0, 1, 2 or 3.

[0238] In a certain technical solution, in formula (IV), formula (IV-1), formula (IV-1A), formula (IV-1B), formula (IV-1A-1) and formula (IV-1B-1),

[0239] X 14 is selected from CR 14 ;

[0240] R 14 is independently selected from -H, -Cl, -F, -Br, -I, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, oxo, -CN, -NH2, -NH(CH3), -NH(CH2CH3), -NH(CH2CH2CH3), -NH(CH(CH3)2), -N(CH3)2, -OH, -O-CH3, -O-CH2CH3, -O-CH2CH2CH3, -O-CH(CH3)2, -SH, -S-CH3, -S-CH2CH3, -S-CH2CH2CH3, -S-CH(CH3)2, -C(=O)CH3, -C(=O)(CH2CH3), -C(=O)(CH2CH2CH3), -C(=O)(CH(CH3)2), -S(=O)CH3, -S(=O)(CH2CH3), -S(=O)(CH2CH2CH3), -S(=O)(CH(CH3)2), -S(=O)2CH3, -S(=O)2(CH2CH3), -S(=O)2(CH2CH2CH3), -S(=O)2(CH(CH3)2), -COOH, -C(=O)NH2, -C(=O)NH(CH3), -C(=O)NH(CH2CH3), -C(=O)NH(CH2CH2CH3), -C(=O)NH(CH(CH3)2), -C(=O)N(CH3)2, -S(=O)2NH2, -S(=O)2NH(CH3), -S(=O)2NH(CH2CH3), -S(=O)2NH(CH2CH2CH3), -S(=O)2NH(CH(CH3)2), -S(=O)2N(CH3)2, -cyclopropyl, -cyclobutyl, -cyclopentyl, -cyclohexyl;

[0241] Preferably, R 14 is independently selected from -H at each occurrence point.

[0242] In a certain technical solution, in formula (IV), formula (IV-1), formula (IV-1A), formula (IV-1B), formula (IV-1A-1) and formula (IV-1B-1), X 14 is selected from -CH-.

[0243] In a certain technical solution, among the compounds of formula (IV), formula (IV-1), formula (IV-1A), formula (IV-1B), formula (IV-1A-1), formula (IV-1B-1), formula (IV-2), formula (IV-2A), formula (IV-2B), formula (IV-2A-1) and formula (IV-2B-1)

[0244] X 15 is selected from -O-, -S- or -NR 15B -;

[0245] Preferably, X 15 is selected from -NR 15B -.

[0246] In a certain technical solution, among the compounds of formula (IV), formula (IV-1), formula (IV-1A), formula (IV-1B), formula (IV-1A-1), formula (IV-1B-1), formula (IV-2), formula (IV-2A), formula (IV-2B), formula (IV-2A-1) and formula (IV-2B-1),

[0247] Preferably, R 15B is selected from -H, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -C(=O)(CH3), -C(=O)(CH2CH3), -C(=O)(CH2CH2CH3), -C(=O)(CH(CH3)2), -S(=O)CH3, -S(=O)(CH2CH3), -S(=O)(CH2CH2CH3), -S(=O)(CH(CH3)2), -S(=O)2CH3, -S(=O)2(CH2CH3), -S(=O)2(CH2CH2CH3), -S(=O)2(CH(CH3)2), cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl or benzofuryl; said R 15BIndependently and optionally substituted by 1, 2 or 3 substituents selected from the following: -Cl, -F, -Br, -I, CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CHFCH3, -CF2CH3, -CN, oxo, -NH2, -NH(CH3), -NH(CH2CH3), -NH(CH2CH2CH3), -NH(CH(CH3)2), -N(CH3)2, -OH, -O-CH3, -O-CH2CH3, -O-CH2CH2CH3, -O-CH(CH3)2, -O-CH2F, -O-CHF2, -O-CF3, -O-CH2CH2F, -O-CH2CHF2, -O-CH2CF3, -O-CHFCH3, -O-CF2CH3, -OH, -S-CH3, -S-CH2CH3, -S-CH2CH2CH3 or -S-CH(CH3)2;

[0248] Preferably, R 15B is selected from -CH3 or -C(=O)CH3.

[0249] In one technical solution, in the compounds of formula (IV), formula (IV-1), formula (IV-1A), formula (IV-1B), formula (IV-1A-1), formula (IV-1B-1), formula (IV-2), formula (IV-2A), formula (IV-2B), formula (IV-2A-1) and formula (IV-2B-1),

[0250] n 17 is 1, n 18 is 0, n 19 is 1, n 20 is 0; or

[0251] n 17 is 1, n 18 is 1, n 19 is 1, n 20 is 1; or

[0252] n 17 is 1, n 18 is 0, n 19 is 1, n 20 is 1; or

[0253] n 17 is 1, n 18 is 1, n 19 is 1, n 20 is 0; or

[0254] n 17 is 2, n 18 is 1, n19 is 1, n 20 is 1; or

[0255] n 17 is 1, n 18 is 1, n 19 is 2, n 20 is 1; or

[0256] n 17 is 2, n 18 is 1, n 19 is 1, n 20 is 0; or

[0257] n 17 is 1, n 18 is 0, n 19 is 2, n 20 is 1; or

[0258] n 17 is 1, n 18 is 1, n 19 is 0, n 20 is 0; or

[0259] n 17 is 0, n 18 is 0, n 19 is 1, n 20 is 1.

[0260] In a certain technical solution, in formula (IV), formula (IV-1), formula (IV-1A), formula (IV-1B), formula (IV-1A-1) and formula (IV-1B-1),

[0261] is selected from:

[0262] In a certain technical solution, in formula (IV), formula (IV-1), formula (IV-1A), formula (IV-1B), formula (IV-1A-1) and formula (IV-1B-1),

[0263] is selected from:

[0264] In a certain technical solution, in formula (IV), formula (IV-1), formula (IV-1A), formula (IV-1B), formula (IV-1A-1) and formula (IV-1B-1), is selected from:

[0265] In a certain technical solution, in formula (IV), formula (IV-2), formula (IV-2A), formula (IV-2B), formula (IV-2A-1) and formula (IV-2B-1),

[0266] selected from

[0267] wherein,

[0268] X1 is CR1, X3 is CR3, X4 is CR4; or

[0269] X1 is N, X3 is CR3, X4 is CR4; or

[0270] X1 is CR1, X3 is N, X4 is CR4; or

[0271] X1 is CR1, X3 is CR3, X4 is N; or

[0272] X1 is N, X3 is N, X4 is CR4; or

[0273] X1 is N, X3 is CR3, X4 is N; or

[0274] X1 is CR1, X3 is N, X4 is N.

[0275] In a certain technical solution, in formula (IV), formula (IV-2), formula (IV-2A), formula (IV-2B), formula (IV-2A-1) and formula (IV-2B-1),

[0276] n 23 is 0, n 24 is 0; or

[0277] n 23 is 1, n 24 is 0; or

[0278] n 23 is 1, n 24 is 1; or

[0279] n 23 is 1, n 24 is 2.

[0280] In a certain technical solution, in formula (IV), formula (IV-2), formula (IV-2A), formula (IV-2B), formula (IV-2A-1) and formula (IV-2B-1),

[0281] selected from:

[0282] Each occurrence of R12 selected from -CH3, -CH2CH3, -CH2CH2CH3 or -CH(CH3)2;

[0283] Each occurrence of Y2 is selected from -CH2-, -O-, -S- or -NH; preferably, each occurrence of Y2 is selected from none or -O-.

[0284] In one technical solution, in formula (IV), formula (IV-2), formula (IV-2A), formula (IV-2B), formula (IV-2A-1) and formula (IV-2B-1),

[0285] selected from:

[0286] preferably is

[0287] In one technical solution, the compound of formula (I) is a compound of formula (V):

[0288]

[0289] Optionally, R 17 and R 18 together with the atoms to which they are respectively attached form ring F; the ring F is selected from a phenyl ring or a 5- or 6-membered heteroaryl ring; the ring F is independently optionally substituted by 1, 2, 3, 4, 5 or 6 R ringF substituents; the heteroaryl ring optionally further contains 1, 2 or 3 heteroatoms selected from N, O or S.

[0290] In one technical solution, in the compound of formula (V),

[0291] R 17 or R 18Independently selected from -H, -Cl, -F, -Br, -I, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, oxo, -CN, -NH2, -NH(CH3), -NH(CH2CH3), -NH(CH2CH2CH3), -NH(CH(CH3)2), -N(CH3)2, -OH, -O-CH3, -O-CH2CH3, -O-CH2CH2CH3, -O-CH(CH3)2, -SH, -S-CH3, -S-CH2CH3, -S-CH2CH2CH3, -S-CH(CH3)2, -C(=O)CH3, -C(=O)(CH2CH3), -C(=O)(CH2CH2CH3), -C(=O)(CH(CH3)2), -S(=O)CH3, -S(=O)(CH2CH3), -S(=O)(CH2CH2CH3), -S(=O)(CH(CH3)2), -S(=O)2CH3, -S(=O)2(CH2CH3), -S(=O)2(CH2CH2CH3), -S(=O)2(CH(CH3)2), -COOH, -C(=O)NH2, -C(=O)NH(CH3), -C(=O)NH(CH2CH3), -C(=O)NH(CH2CH2CH3), -C(=O)NH(CH(CH3)2), -C(=O)N(CH3)2, -S(=O)2NH2, -S(=O)2NH(CH3), -S(=O)2NH(CH2CH3), -S(=O)2NH(CH2CH2CH3), -S(=O)2NH(CH(CH3)2), -S(=O)2N(CH3)2, -cyclopropyl, -cyclobutyl, -cyclopentyl or -cyclohexyl; wherein said R 17 or R 18 is independently optionally substituted by 1, 2 or 3 substituents selected from: -Cl, -F, -Br, -I, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CN, oxo, -NH2, -NH(CH3), -NH(CH2CH3), -NH(CH2CH2CH3), -NH(CH(CH3)2), -N(CH3)2, -OH, -O-CH3, -O-CH2CH3, -O-CH2CH2CH3, -O-CH(CH3)2, -SH, -S-CH3, -S-CH2CH3, -S-CH2CH2CH3 or -S-CH(CH3)2;

[0292] More preferably, R 17 or R 18 is independently selected from -H each time it appears.

[0293] In a certain technical solution, the formula (V) is formula (Ⅴ-1):

[0294]

[0295] In a certain technical solution, the formula (V) is formula (Ⅴ-2):

[0296]

[0297] In a certain technical solution, in formula (Ⅴ) and formula (Ⅴ-2),

[0298] ring F is selected from a phenyl ring, a 5-membered heteroaryl ring or a 6-membered heteroaryl ring; the heteroaryl ring contains 1, 2 or 3 heteroatoms selected from N, O or S;

[0299] Ring F is preferably a phenyl ring.

[0300] In a certain technical solution, the formula (V) is formula (Ⅴ-2A):

[0301]

[0302] In a certain technical solution, in formula (Ⅴ), formula (Ⅴ-1), formula (Ⅴ-2) and formula (Ⅴ-2A),

[0303] each occurrence of Y2 is selected from none, -CH2-, -O-, -S- or -NH; preferably, each occurrence of Y2 is selected from none or -CH2-.

[0304] In a certain technical solution, in formula (Ⅴ), formula (Ⅴ-1), formula (Ⅴ-2) and formula (Ⅴ-2A),

[0305] Y1 is selected from none, -CH=CH-, -C≡C-, -C(=O)NH-** or NHC(=O)-** each time it occurs;

[0306] Preferably, each occurrence of Y1 is selected from none or -C≡C-, -C(=O)NH-** or -NHC(=O)-**;

[0307] ** represents the attachment point of the molecule.

[0308] In a certain technical solution, the formula (V) is formula (Ⅴ-1A), formula (Ⅴ-1B), (Ⅴ-1C), formula (Ⅴ-1D), (Ⅴ-1E) or formula (Ⅴ-1F):

[0309]

[0310] In a certain technical solution, the formula (V) is formula (V-2A-1), formula (V-2B-2), formula (V-1C-1), formula (V-1D-1), formula (V-1E-1) or formula (V-1F-1):

[0311]

[0312]

[0313] In a certain technical solution, in formula (Ⅴ), formula (Ⅴ-1), formula (Ⅴ-1A), formula (Ⅴ-1B), Ⅴ-1C), formula (Ⅴ-1D), (Ⅴ-1E), formula (Ⅴ-1F), formula (Ⅴ-2), formula (Ⅴ-2A), formula (Ⅴ-2A-1), formula (Ⅴ-2A-2), formula(V-2B-2), formula(V-1C-1), formula(V-1D-1), formula(V-1E-1) and formula(V-1F-1),

[0314] n 25 is 0, n 26 is 0; or

[0315] n 25 is 0, n 26 is 1; or

[0316] n 25 is 0, n 26 is 2; or

[0317] n 25 is 0, n 26 is 3; or

[0318] n 25 is 1, n 26 is 0; or

[0319] n 25 is 1, n 26 is 1; or

[0320] n 25 is 1, n 26 is 2; or

[0321] n 25 is 2, n 26 is 0; or

[0322] n 25 is 2, n 26 is 1.

[0323] In a certain technical solution, in formula (Ⅴ), formula (Ⅴ-1), formula (Ⅴ-1A), formula (Ⅴ-1B), (Ⅴ-1C), formula (Ⅴ-1D), (Ⅴ-1E) and formula (Ⅴ-1F),

[0324] Selected from:

[0325] In one technical solution, in formula (V), formula (V-2), formula (V-2A), formula (V-2A-1), formula (V-2B-2), formula (V-1C-1), formula (V-1D-1), formula (V-1E-1) and formula (V-1F-1),

[0326] Selected from:

[0327] In one technical solution, the compound of formula (I), its stereoisomers, its atropisomers, its pharmaceutically acceptable salts, the pharmaceutically acceptable salts of its stereoisomers, the pharmaceutically acceptable salts of its atropisomers, its solvates or the pharmaceutically acceptable salts of its solvates, wherein the compound is any one of the following formulas:

[0328]

[0329]

[0330] In one technical solution, one or more atoms in the compound of the present invention exist in the form of non-natural abundance, or all atoms in the compound such as I exist in the form of natural abundance.

[0331] The present invention also provides a pharmaceutical composition, which comprises the compound of any one of the above, its stereoisomers, its atropisomers, its pharmaceutically acceptable salts, the pharmaceutically acceptable salts of its stereoisomers, the pharmaceutically acceptable salts of its atropisomers, its solvates or the pharmaceutically acceptable salts of its solvates, and at least one pharmaceutically acceptable excipient.

[0332] The present invention also provides a compound of any one of the solutions of the present invention, its stereoisomers, its atropisomers, its pharmaceutically acceptable salts, the pharmaceutically acceptable salts of its stereoisomers, the pharmaceutically acceptable salts of its atropisomers, its solvates or the pharmaceutically acceptable salts of its solvates; or the use of the pharmaceutical composition described above in the preparation of a drug for treating a disease or disorder related to the 20-hydroxyeicosatetraenoic acid (20-HETE) signaling pathway.

[0333] The use according to claim, wherein the disease or disorder associated with the 20-hydroxyeicosatetraenoic acid (20-HETE) signaling pathway is preferably obesity, metabolic syndrome, dyslipidemia, diabetes, diabetic retinopathy, cerebrovascular changes caused by diabetes, diabetic neuropathy, insulin resistance, hyperglycemic state, hyperlipidemia, kidney complications caused by diabetes, elevated blood pressure, lens opacity, decreased bone density, elevated serum uric acid, infections caused by diabetes, hepatic steatosis without alcohol influence, inflammatory hepatic steatosis without alcohol influence, tissue fibrosis, heart disease, cerebrovascular accident, cirrhosis, metabolic acidosis, ketosis, discomfort related to the cardiovascular system, seizure, arteriosclerotic lesion, Parkinson's syndrome, myocardial infarction, acute renal insufficiency, chronic kidney disease, renal cyst, neoplastic disease, terminal organ damage, and Alzheimer's disease.

[0334] The use according to claim, wherein the diabetes includes but is not limited to type 1 diabetes, type 2 diabetes, maturity-onset diabetes of the young (MODY), idiopathic type 1 diabetes, early-onset type 2 diabetes, young adult-onset diabetes, juvenile atypical diabetes, malnutrition-related diabetes, and latent autoimmune diabetes in adults (LADA).

[0335] Definition

[0336] Unless otherwise specified, "halogen" or "halo" are used interchangeably herein and refer to fluorine, chlorine, bromine, or iodine. Preferred halogen groups include -F, -Cl, and -Br.

[0337] Unless otherwise specified, the term "alkyl" as used herein includes saturated monovalent hydrocarbon groups having straight or branched chains. For example, alkyl includes methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 3-(2-methyl)butyl, 2-pentyl, 2-methylbutyl, neopentyl, n-hexyl, 2-hexyl, and 2-methylpentyl. In -C 1-6 The definition in alkyl refers to a group having a straight or branched chain arrangement of 1, 2, 3, 4, 5, or 6 carbon atoms.

[0338] Unless otherwise specified, the term "haloalkyl" as used herein refers to the above alkyl groups substituted with one or more (1, 2, 3, 4, 5, or 6) halogens (-F, -Cl, or -Br). In certain embodiments, haloalkyl is interchangeable with -C 1-6 haloalkyl or halo-C 1-6 alkyl, wherein, -C 1-6 haloalkyl or halo-C 1-6 The C in haloalkyl or halo-C 1-6 represents that the total number of carbon atoms in the alkyl is 1 to 6. In certain embodiments, -C 1-6 haloalkyl is -C 1-3Halogenated alkyl. In certain embodiments, -C 1-3 The halogenated alkyl is (methyl, ethyl, propyl or isopropyl) substituted with 1, 2, 3, 4, 5 or 6 -F; preferably, -C 1-3 The halogenated alkyl is -CF3.

[0339] The term "alkylene" refers to a difunctional group obtained by removing an additional hydrogen atom from the alkyl group defined above. For example, methylene (i.e., -CH2-), ethylene (i.e., -CH2-CH2- or -CH(CH3)-), and propylene (i.e., -CH2-CH2-CH2-, -CH(-CH2-CH3)- or -CH2-CH(CH3)-).

[0340] The term "alkenyl" refers to a straight-chain or branched-chain hydrocarbon group containing one or more double bonds, usually having a length of 2 to 20 carbon atoms. For example, "-C 2-6 alkenyl" contains 2 to 6 carbon atoms. Alkenyl includes but is not limited to vinyl, propenyl, butenyl, 2-methyl-2-buten-1-yl, heptenyl, octenyl, etc.

[0341] The term "alkynyl" includes straight-chain or branched-chain hydrocarbon groups containing one or more triple bonds, usually having a length of 2 to 20 carbon atoms. For example, "C 2-6 alkynyl" contains 2 to 6 carbon atoms. Representative alkynyls include but are not limited to ethynyl, 1-propynyl, 1-butynyl, heptynyl, octynyl, etc.

[0342] The term "alkoxy" group is an oxygen ether formed from the alkyl groups described above. Alkoxy refers to an alkyl group substituted with -O-alkyl, including but not limited to -CH2-O-CH3, -CH2CH2-O-CH3, -CH2-O-CH2CH3, -CH(CH3)-O-CH3, and -CH2CH2-O-CH2CH2.

[0343] As used herein, the term "haloalkoxy", unless otherwise specified, refers to the above alkoxy substituted with one or more (1, 2, 3, 4, 5 or 6) halogens (-F, -Cl or -Br). In certain embodiments, the haloalkoxy is interchangeably -C 1-6 haloalkoxy or halo-C (1-6) alkoxy, wherein, -C (1-6) haloalkoxy or halo-C (1-6) The C in alkoxy 1-6 indicates that the total number of carbon atoms in the alkoxy is 1 to 6. In certain embodiments, -C 1-6 haloalkoxy is -C 1-3 haloalkoxy. In certain embodiments, -C 1-3The haloalkoxy group is (methoxy, ethoxy, propoxy or isopropoxy) substituted with 1, 2, 3, 4, 5 or 6 -F; preferably, -C 1-3 The haloalkoxy group is -OCF3.

[0344] Unless otherwise specified, the term "aryl" as used herein refers to an unsubstituted or substituted monocyclic or polycyclic aromatic ring system containing carbocyclic atoms. Phenyl and naphthyl are preferred aryl groups.

[0345] Unless otherwise specified, the interchangeable terms "heterocyclic group" or "heterocycle" as used herein refer to an unsubstituted and substituted monocyclic or polycyclic non - aromatic ring system containing one or more heteroatoms, including monocyclic heterocycles, bicyclic heterocycles, bridged heterocycles, fused heterocycles or spiro heterocycles. Preferred heteroatoms include N, O and S, including N - oxides, S - oxides and sulfoxides. The ring is preferably three to ten members and is fully saturated or has one or more degrees of unsaturation. Multiple degrees of substitution, preferably one, two or three, are also included in this definition. Examples of such heterocyclic groups include, but are not limited to, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxopiperazinyl, piperidinyl N - oxide, oxoazacyclopentyl, azacyclohexyl, tetrahydrofuranyl, dioxolanyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydrooxazolyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone and oxadiazolyl.

[0346] The interchangeable terms "heteroaryl" or "heteroaryl ring" as used herein, unless otherwise specified, represent an aromatic ring system containing carbon and at least one heteroatom. "Heteroaryl" or "heteroaryl ring" can be monocyclic or polycyclic, substituted or unsubstituted. The ring of a monocyclic heteroaryl can contain 1 to 4 heteroatoms, while a polycyclic heteroaryl can contain 1 to 10 heteroatoms. A polycyclic heteroaryl ring can contain fused rings, spiro rings or bridged ring linkages, for example, bicyclopentaryl is a polycyclic heteroaryl. A bicyclic heteroaryl ring can contain 8 to 12 atoms. A monocyclic heteroaryl ring can contain 5 to 8 atoms (nuclear atoms and heteroatoms). Examples of heteroaryl include, but are not limited to, thienyl, furyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiadiazolyl, triazolyl, pyridyl, pyridazinyl, indolyl, indazolyl, azaindolyl, benzimidazolyl, benzofuranyl, benzothienyl, benzisoxazolyl, benzoxazolyl, benzopyrazolyl, benzothiadiazolyl, benzotriazolyl, quinolinyl or isoquinolinyl.

[0347] The term "carbocyclic ring" refers to a substituted or unsubstituted monocyclic, bicyclic, bridged, fused, spiro, etc. non-aromatic ring system containing only carbon atoms. The ring is preferably three to ten members, either fully saturated or having one or more degrees of unsaturation. Multiple degrees of substitution, preferably one, two or three, are also included in this definition. Carbocyclic rings include, but are not limited to, cycloalkyl, cycloalkenyl and cycloalkynyl. Typical "cycloalkyl" groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.

[0348] The term "one or more" means one or more than one. In certain embodiments, "one or more" means 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.

[0349] In the present invention, when one or more substituents are substituted on a ring, this means that each substituent can be independently substituted on each ring atom of the ring, including but not limited to ring carbon atoms or ring nitrogen atoms. In addition, when the ring is a polycyclic ring, such as a fused ring, a linked ring or a spiro ring, each substituent can be independently substituted on each ring atom of the polycyclic ring.

[0350] The term "carbonyl group" means a group formed by an oxygen atom together with the connected carbon atom

[0351] As used herein, the term "composition" is intended to include a product containing specified ingredients in specified amounts, and any product directly or indirectly formed by the combination of specified amounts of specified ingredients. Thus, a pharmaceutical composition containing a compound of the present invention as an active ingredient and a method for preparing a compound of the present invention are also part of the present invention. In addition, certain crystalline forms of compounds may exist in polymorphic forms and are thus also included in the present invention. In addition, certain compounds can form solvates (i.e., hydrates) with water or common organic solvents, and such solvates are also within the scope of the present invention.

[0352] The term "pharmaceutically acceptable salt" refers to a salt prepared from a pharmaceutically acceptable non-toxic base or acid. When the compound of the present invention is acidic, its corresponding salt can be conveniently prepared from a pharmaceutically acceptable non-toxic base (including inorganic bases and organic bases). When the compound of the present invention is basic, its corresponding salt can be conveniently prepared from a pharmaceutically acceptable non-toxic acid (including inorganic acids and organic acids). Since the compounds in the present invention are used in pharmaceuticals, they are preferably provided in a substantially pure form, for example, at least 60% purity, more suitably at least 75% purity, especially at least 98% purity (% is based on weight ratio). The term "solvate" refers to a substance formed by the combination of a compound with a solvent (including but not limited to: water, methanol, ethanol, etc.). Solvates are divided into stoichiometric solvates and non-stoichiometric solvates. Solvates include, but are not limited to: monohydrates.

[0353] The compounds included in the present invention may contain one or more asymmetric centers and thus can give rise to diastereoisomers and optical isomers. The present invention includes all such possible diastereoisomers and their racemic mixtures, their substantially pure resolved enantiomers, all possible geometric isomers, and their pharmaceutically acceptable salts.

[0354] The present invention includes all stereoisomers of the compounds and their pharmaceutically acceptable salts. In addition, mixtures of stereoisomers and isolated specific stereoisomers are also included. In the synthetic processes used to prepare such compounds, or when using racemization or epimerization procedures known to those skilled in the art, the products of such procedures can be mixtures of stereoisomers.

[0355] The term "stereoisomer" as used in the present invention refers to isomers in which the order of connection of atoms or groups of atoms in the molecule is the same but the spatial arrangement is different, including configurational isomers and conformational isomers. Configurational isomers include geometric isomers and optical isomers, and optical isomers mainly include enantiomers and diastereomers. The present invention includes all possible stereoisomers of the compounds.

[0356] Certain compounds provided herein may exist in the form of atropisomers, which are a type of conformational stereoisomer that appears when the rotation of a single bond in the molecule is blocked or greatly slowed down due to steric interactions with other parts of the molecule. The compounds provided herein include all atropisomers, either as pure single atropisomer preparations, or as enriched preparations of each atropisomer, or as non-specific mixtures of each atropisomer. If the rotational barrier of the single bond is high enough and the interconversion between conformations is slow enough, the isomers can be isolated.

[0357] The present invention is intended to include all atomic isotopes present in the compounds of the present invention. Isotopes include atoms with the same atomic number but different mass numbers. For example, isotopes of hydrogen include deuterium and tritium. Isotopes of hydrogen can be represented as 1 H (hydrogen), 2 H (deuterium), and 3 H (tritium). Deuterium is usually represented by D, and tritium by T. In applications, CD3 represents a methyl group in which all hydrogen atoms are deuterium. Isotopes of carbon include 13 C and 14 C. The isotopically labeled compounds of the present invention can generally be prepared by conventional techniques known to those skilled in the art or by methods similar to those described herein, using appropriate isotopically labeled reagents in place of unlabeled reagents.

[0358] Unless otherwise specified, the term "deuterated derivative" as used herein refers to a compound having the same chemical structure as a reference compound, but with one or more hydrogen atoms replaced by deuterium atoms ("D"). Certain variations in the natural isotope abundances in synthetic compounds depend on the source of the chemical materials used in the synthesis. Despite such variations, the concentration of the naturally abundant stable hydrogen isotopes is small and insignificant compared to the degree of stable isotope substitution in the deuterated derivatives described herein. Accordingly, unless otherwise specified, when referring to a "tritiated derivative" of a compound of the present disclosure, at least one hydrogen is replaced by deuterium, and the abundance of deuterium is much higher than its natural isotope abundance (usually about 0.015%). In certain embodiments, the isotopic enrichment factor for each deuterium atom of the tritiated derivatives of the present disclosure is at least 3500 (52.5%), at least 4500 (67.5%), at least 5000 (75%), at least 5500 (82.5%), at least 6000 (90%), at least 6333.3 (95%), at least 6466.7 (97%) or at least 6600 (99%).

[0359] When homologs of the compounds of the present invention exist, unless otherwise specifically stated, the present invention includes any possible homologs and their pharmaceutically acceptable salts, as well as mixtures thereof.

[0360] In practice, the compounds of the present invention, or their prodrugs or metabolites or their pharmaceutically acceptable salts, can be intimately admixed with a pharmaceutical carrier in accordance with conventional pharmaceutical formulation techniques. The carrier can take a wide variety of forms depending on the desired mode of administration, such as oral or parenteral (including intravenous). Accordingly, the pharmaceutical compositions of the present invention can be discrete units suitable for oral administration, such as capsules, extended-release tablets or tablets, each containing a predetermined amount of the active ingredient. In addition, the compositions of the present invention can also be in the form of powders, granules, solutions, aqueous suspensions, non-aqueous suspensions, water-in-oil emulsions or oil-in-water emulsions. In addition to the above common dosage forms, the compounds represented by Formula I or their pharmaceutically acceptable salts can also be administered by controlled release means and / or delivery devices.

[0361] Accordingly, the pharmaceutical compositions of the present invention can include a pharmaceutically acceptable carrier and a compound or a pharmaceutically acceptable salt. The compounds of Formula I or their pharmaceutically acceptable salts can also be incorporated into the pharmaceutical composition in combination with one or more other therapeutically active compounds.

[0362] For example, the pharmaceutical carrier used can be solid, liquid or gas. Examples of solid carriers include lactose, kaolin, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate and stearic acid. Examples of liquid carriers are syrup, peanut oil, olive oil and water. Examples of gas carriers include carbon dioxide and nitrogen. When preparing an oral dosage form composition, any convenient pharmaceutical medium can be used. For example, water, ethylene glycol, oil, alcohol, flavoring agent, preservative, coloring agent, etc. can be used to form oral liquid preparations such as suspensions, elixirs and solutions; while carriers such as starch, sugar, microcrystalline cellulose, diluent, granulating agent, lubricant, binder, disintegrating agent, etc. can be used to form oral solid preparations such as powders, capsules and tablets. Due to ease of administration, tablets and capsules are the preferred oral dosage forms using solid pharmaceutical carriers. Tablets can be optionally coated using standard aqueous or non-aqueous techniques.

[0363] Tablets containing the composition of the present invention can be prepared by compression or molding methods, and one or more auxiliary ingredients or adjuvants can also be optionally added. The preparation method of compressed tablets is to compress the active ingredient in a free-flowing form such as powder or granules in a suitable machine, and it can be optionally mixed with a binder, a lubricant, an inert diluent, a surfactant or a dispersant. Molded tablets can be prepared by molding the powdered compound mixed with an inert liquid diluent in a suitable machine. Each tablet preferably contains about 0.05 mg to about 5 g of the active ingredient, and each sustained-release tablet or capsule preferably contains about 0.05 mg to about 5 g of the active ingredient. For example, a preparation for human oral administration may contain about 0.5 mg to about 5 g of the active ingredient and be compounded with an appropriate and convenient amount of carrier material, and the carrier material may account for about 0.05% to about 95% of the total composition. The unit dosage form generally contains about 0.01 mg to about 2 g of the active ingredient, usually 0.01 mg, 0.02 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg, 1000 mg, 1500 mg or 2000 mg.

[0364] The pharmaceutical composition suitable for parenteral administration of the present invention can be prepared as a solution or suspension of the active compound in water. Appropriate surfactants can be added, such as hydroxypropyl cellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycol and their mixtures in oil. In addition, preservatives can be added to prevent the harmful growth of microorganisms.

[0365] The pharmaceutical composition suitable for injection use according to the present invention comprises a sterile aqueous solution or dispersion. In addition, the composition of the present invention may also be in the form of a sterile powder for the extemporaneous preparation of such sterile injection solutions or dispersions. In any case, the final injectable form must be sterile and must have effective fluidity for ease of injection. The pharmaceutical composition must be stable under the production and storage conditions; thus, it is preferably to prevent the contamination effects of microorganisms such as bacteria and fungi. The carrier may be a solvent or a dispersion medium, such as water, ethanol, polyols (such as glycerol, propylene glycol and liquid polyethylene glycol), vegetable oils and suitable mixtures thereof.

[0366] The pharmaceutical composition of the present invention may be in a form suitable for topical use, such as an aerosol, cream, ointment, lotion, powder or similar preparations. In addition, the composition of the present invention may also be in a form suitable for use in a transdermal device. These preparations can be prepared by conventional processing methods using the compound represented by Formula I of the present invention or a pharmaceutically acceptable salt thereof. For example, a cream or ointment having a desired consistency is prepared by mixing a hydrophilic material and water with about 0.05 wt% to about 10 wt% of the compound.

[0367] The pharmaceutical composition of the present invention may be in a form suitable for rectal administration, wherein the carrier is a solid. The mixture preferably forms a unit dose suppository. Suitable carriers include cocoa butter and other materials commonly used in the industry. The suppository can be conveniently formed by first mixing the composition with the softened or melted carrier and then cooling and molding in a mold.

[0368] In addition to the above carrier components, the above pharmaceutical preparations may optionally include one or more additional carrier components, such as diluents, buffers, flavoring agents, binders, surfactants, thickeners, lubricants, preservatives (including antioxidants), etc. In addition, other adjuvants may be added to make the preparation isotonic with the blood of the target recipient. The composition containing the compound represented by Formula I or a pharmaceutically acceptable salt thereof may also be prepared in the form of a powder or a liquid concentrate.

[0369] Generally, a dosage level of about 0.001 mg / kg to about 150 mg / kg per day based on body weight can be used to treat the above-mentioned diseases, or a dosage level of about 0.05 mg to about 7 g per patient per day can be used to treat the above-mentioned diseases. For example, inflammation, cancer, psoriasis, allergy / asthma, diseases and disorders of the immune system, diseases and disorders of the central nervous system (CNS) can be effectively treated by administering about 0.001 to 50 mg of the compound per kilogram of body weight per day or about 0.05 mg to about 3.5 g of the compound per patient per day.

[0370] However, the specific dosage level for any particular patient depends on a variety of factors, including age, weight, general health, gender, diet, time of administration, route of administration, rate of excretion, drug combination, and the severity of the particular disease being treated.

[0371] Unless the context otherwise requires, when a value is expressed as "about" X or "approximately" X, the value of X will be understood to be accurate to ±10%, preferably ±5%, ±2%.

[0372] These and other aspects will become apparent from the following written description of the invention.

[0373] Based on the common general knowledge in the art, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[0374] The reagents and raw materials used in the present invention are all commercially available.

[0375] The positive and progressive effects of the present invention are as follows: The compounds of the present invention have good inhibitory effects on 20-HETE, and in particular, they also have excellent pharmacokinetic properties. BRIEF DESCRIPTION OF THE DRAWINGS

[0376] Figure 1 Content of 20-HETE in the kidney and brain 8 hours after a single oral administration of the test compound to ICR mice.

[0377] Figure 2 Content of 20-HETE in the kidney and brain 8 hours after a single oral administration of the test compound to BALB / c mice. DETAILED DESCRIPTION OF THE INVENTION

[0378] Pretreatment method

[0379] The compounds of the present invention can be synthesized from commercially available reagents using the synthetic methods and reaction schemes described herein. The following examples and general schemes outlining specific synthetic routes are intended to provide guidance to a generally skilled synthetic chemist, who will readily understand that solvents, concentrations, reagents, protecting groups, order of synthetic steps, time, temperature, etc. can be modified as needed, all within the scope of the skills and judgment of a generally skilled artisan.

[0380] Examples

[0381] To better illustrate the present invention, the following examples are provided. Unless otherwise specified, all parts and percentages are by weight, and all temperatures are in degrees Celsius. The following abbreviations are used in the examples:

[0382]

[0383]

[0384] Preparation of Intermediate

[0385] Intermediate 1 (INT 1)

[0386]

[0387] A solution of tert-butyl [3,3'-diazabicyclobutane]-1-carboxylate pentaester (1.0 g, 4.71 mmol), (4-iodophenyl)boronic acid (1.642 g, 9.42 mmol), Cu(OAc)2 (795 mg, 15.652 mmol) and Et3N (1.85 mL, 18.84 mmol) in DCM (15 mL) was stirred at 20 °C under an O2 atmosphere for 16 hours and then filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (eluted with V (DCM) / V (MeOH) = 1:20), to obtain INT 1-1 (650 mg, yield 33.3%) as a solid. LCMS: m / z = 415.1 [M+H] + .

[0388] At 20 °C, AcOH (5 mL) was added dropwise to a solution of INT 1-1 (650 mg, 1.57 mmol) in DCM (10 mL). The mixture was stirred at 20 °C under a N2 atmosphere for 4 hours and then concentrated. The residue was purified by preparative liquid chromatography (C18 column, eluted with H2O / MeOH of NH4HCO3), to obtain INT 1 (490 mg, yield 99.1%) as a solid. LCMS: m / z = 315.0 [M+H] + .

[0389] Intermediate 2 (INT 2)

[0390]

[0391] A mixture of 1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (4.44 g, 15.96 mmol), 4-iodophenol (3.52 g, 17.556 mmol), Pd(dppf)Cl2 . DCM (1.3 g, 3.192 mmol) and CsF (7.32 g, 47.88 mmol) in 1,4-dioxane (40 mL) and H2O (10.0 mL) was stirred at 110 °C under a N2 atmosphere for 16 hours and then filtered. The filtrate was purified by preparative liquid chromatography (C18 column, eluted with H2O / CH3CN), to obtain INT 2-1 (2.372 g, yield 60.8%) as a solid. LCMS: m / z = 245.1 [M+H]+ .

[0392] To a solution of INT 2 - 1 (2.128 g, 8.72 mmol), Et3N (4.8 mL), and 4 - dimethylaminopyridine (107 mg, 0.872 mmol) in dichloromethane (50.0 mL) was added dropwise a solution of 1,1,1 - trifluoro - N - phenyl - N - ((trifluoromethyl)sulfonyl)methanesulfonamide (3.93 g, 10.464 mmol) in dichloromethane (50.0 mL) at 0 °C. The mixture was stirred overnight at 20 °C, quenched with water (10 mL) at 0, and then extracted with DCM (100 mL x 3). The combined organic layers were washed with brine (50 mL x 2), dried over Na2SO4, and then concentrated under reduced pressure to give a residue, which was purified by preparative liquid chromatography (C18 column, eluted with H2O / CH3CN) to give INT 2 (2.186 g, yield 66.6%), as an oil. LCMS: m / z = 377.1 [M + H] + .

[0393] Intermediate 3 (INT 3)

[0394]

[0395] Under a nitrogen atmosphere, Pd(dppf)Cl2 (132 mg, 0.018 mmol) was added to a solution of 4 - iodo - 1 - (xanthen - 2 - yl) - 1H - pyrazole (500 mg, 0.18 mmol), (4 - bromophenyl)boronic acid (539 mg, 0.27 mmol), and Na2CO3 (572 mg, 0.54 mmol) in 1,4 - dioxane / H2O (10 / 1, 10 mL). The reaction mixture was stirred at 90 °C for 2 hours and then filtered. The filtrate was concentrated and extracted with EA (50 mL x 3). The organic layer was washed with brine, dried over Na2SO4, and then concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography (V PE / V EA = 4 / 1) to give INT 3 (32 mg, yield 48.8%), as a yellow oil. LCMS: m / z = 307.0 [M + H]+.

[0396] Example 1

[0397]

[0398] To a solution of tert-butyl [3,3'-diazabicyclobutane]-1-carboxylate hydrochloride (745 mg, 3.51 mmol) and DIPEA (4.2 mL, 28.08 mmol) in DCM (20.0 mL) was added dropwise acetyl chloride (340 μL, 4.212 mmol) at 0 °C. The mixture was stirred overnight at 20 °C, quenched with water (10 mL) at 0 °C, and then extracted with DCM (10 mL x 3). The combined organic layers were washed with brine (10 mL x 2), dried over Na2SO4, and then concentrated under reduced pressure to give a residue, which was purified by preparative HPLC (C18 column, eluting with H2O / CH3CN) to afford compound 1-1 (659.5 mg, 73.9% yield) as a solid. LCMS: m / z = 277.2 [M+Na] + . At 0 °C, trans fatty acid (3.0 mL) was added dropwise to a solution of compound 1-1 (1.0 g, 3.93 mmol) in DCM (10.0 mL). The solution was stirred overnight at 20 °C and then concentrated under reduced pressure to give a residue, which was purified by preparative liquid chromatography (C18 column, eluting with H2O / CH3CN) to afford compound 1-2 (512 mg, 84.5% yield) as a solid. LCMS: m / z = 155.1 [M+H] +

[0399] A mixture of compound 1-2 (462 mg, 2.998 mmol), INT 2 (1.24 g, 3.298 mmol), BrettPhosG3 Pd (544 mg, 0.5996 mmol) and t-BuONa (866 mg, 8.994 mmol) in 1,4-dioxane (5.0 mL) and DMF (5.0 mL) was stirred at 110 °C under N2 atmosphere for 16 h and then filtered. The filtrate was purified by preparative liquid chromatography (C18 column, eluting with H2O / CH3CN) to afford compound 1-3 (117 mg, 10.3% yield) as a solid. LCMS: m / z = 381.2 [M+H] + . At 0 °C, trans fatty acid (1.0 mL) was added dropwise to a solution of compound 1-3 (117 mg, 0.31 mmol) in DCM (10.0 mL). The solution was stirred at 20 °C for 1 h and then concentrated under reduced pressure to give a residue, which was purified by preparative liquid chromatography (C18 column, eluting with H2O / CH3CN) to afford compound 1 (11.2 mg, 12.3% yield) as a solid. LCMS: m / z = 297.2 [M+H] +

[0400] 11H NMR (400 MHz, DMSO-d6): δ 7.88 (s, 2H), 7.39 (d, J = 8.0 Hz, 2H), 6.42 (d, J = 8.1 Hz, 2H), 3.99 - 3.77 (m, 4H), 3.56 - 3.47 (m, 2H), 2.99 - 2.82 (m, 2H), 1.73 (s, 3H), 1.23 (s, 2H).

[0401] Example 2

[0402]

[0403] A solution of INT 2 (752 mg, 1.99 mmol), 1-(2,6-diazaspiro[3.3]heptan-2-yl)ethanone 2,2,2-trifluoroacetate (610 mg, 2.388 mmol), BrettPhos G3 Pd (362 mg, 0.398 mmol) and t-BuONa (578 mg, 5.97 mmol) in toluene (10.0 mL) was stirred at 110 °C under N (2) atmosphere for 4 h and then filtered. The filtrate was purified by preparative liquid chromatography (C18 column, eluted with H2O / CH3CN) to give compound 2-1 (282 mg, yield 38.5%), a solid. LCMS: m / z = 367.2 [M+H] + .

[0404] To a solution of compound 2-1 (282 mg, 0.77 mmol) in DCM (5.0 mL) was added dropwise trans fatty acid (1.0 mL) at 0 °C. The solution was stirred at 20 °C for 16 h and then concentrated under reduced pressure to give a residue, which was purified by preparative liquid chromatography (C18 column, eluted with H2O / CH3CN) to give solid compound 2 (115 mg, yield 52.9%). LCMS: m / z = 283.2 [M+H] +

[0405] 1 1H NMR (400 MHz, DMSO-d6): δ 7.88 (s, 2H), 7.47 - 7.32 (m, 2H), 6.48 - 6.39 (m, 2H), 4.28 (s, 2H), 4.00 (s, 2H), 3.92 (s, 4H), 1.75 (s, 3H)

[0406] Example 3

[0407]

[0408] To a solution of INT 1 (110 mg, 0.344 mmol) and Et3N (200 μL, 4.0 eq) in DCM (5.0 mL) at 0 °C was added propionyl chloride (46 μL, 0.516 mmol). The mixture was stirred overnight at 20 °C, quenched with water (10 mL) at 0 °C, and then extracted with DCM (10 mL x 3). The combined organic layers were washed with brine (10 mL x 2), dried over Na2SO4, and then concentrated under reduced pressure to give a residue, which was purified by preparative HPLC (C18 column, eluting with H2O / CH3CN) to afford compound 3-1 (126 mg, yield 97.5%) as a solid. LCMS: m / z = 371.1 [M+H] + .

[0409] To a solution of compound 3-1 (139 mg, 0.37 mmol), 1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (115 mg, 0.74 mmol), Pd(dppf)Cl2 . DCM (60 mg, 0.074 mmol) and CsF (156 mg, 1.11 mmol) in 1,4-dioxane (5.0 mL) and H2O (1.0 mL) was stirred at 110 °C under an atmosphere of N2 for 16 h and then filtered. The filtrate was purified by preparative HPLC (C18 column, eluting with H2O / CH3CN) to afford compound 3-2 (60 mg, yield 40.6%) as a solid. LCMS: m / z = 395.2 [M+H] + .

[0410] A solution of compound 3-2 (60 mg, 0.15 mmol) in trans fatty acid (3.0 mL) was stirred at 20 °C for 4 h and then concentrated under reduced pressure to give a residue, which was purified by preparative liquid chromatography (C18 column, eluting with H2O / CH3CN) to afford compound 3 (26.6 mg, yield 56.1%) as a solid. LCMS: m / z = 311.2 [M+H] + .

[0411] 1 H NMR (400 MHz, DMSO-d6) δ 7.92 (s, 2H), 7.46 - 7.30 (m, 2H), 6.68 - 6.37 (m, 2H), 4.39 - 4.03 (m, 2H), 3.92 (q, J = 8.3, 7.4 Hz, 2H), 3.56 - 3.38 (m, 2H), 3.16 - 2.87 (m, 2H), 2.12 - 1.86 (m, 3H), 1.23 (s, 1H), 1.05 - 0.86 (m, 3H).

[0412] Example 4

[0413]

[0414] To a solution of INT 1 (126 mg, 0.4 mmol) and Et3N (210 μL, 2 mmol) in DCM (10.0 mL) was added methanesulfonyl chloride (60 μL, 0.6 mmol). The mixture was stirred overnight at 20 °C, quenched with water (10 mL) at 0 °C, and then extracted with DCM (10 mL x 3). The combined organic layers were washed with brine (10 mL x 2), dried over Na2SO4, and then concentrated under reduced pressure to give a residue, which was purified by preparative HPLC (C18 column, eluted with H2O / CH3CN) to give compound 4-1 (139 mg, yield 88.4%) as a solid. LCMS: m / z = 393.0 [M+H] +

[0415] Compound 4-1 (139 mg, 0.355 mmol), 1-tert-butoxycarbonylpyrazole-4-boronic acid pinacol ester (212 mg, 0.71 mmol), 1,1'-bis(di-tert-butylphosphino)ferrocene dichloropalladium (48 mg, 0.071 mmol) and Cs2CO3 (366 mg, 1.775 mmol) were stirred in 1,4-dioxane (5.0 mL) and H2O (1.0 mL) at 110 °C under an atmosphere of N2 for 16 h, and then filtered. The filtrate was purified by preparative liquid chromatography (C18 column, eluted with H2O / CH3CN) to give compound 4 (31.2 mg, yield 26.5%) as a solid. LCMS: m / z = 333.1 [M+H] + .

[0416] 1 H NMR (400 MHz, DMSO-d6): δ 12.75 (s, 1H), 7.87 (s, 2H), 7.40 (d, J = 8.0 Hz, 2H), 6.42 (d, J = 8.1 Hz, 2H), 4.02 - 3.94 (m, 2H), 3.93 - 3.86 (m, 2H), 3.65 - 3.58 (m, 2H), 3.56 - 3.46 (m, 2H), 3.00 (s, 3H), 2.97 - 2.87 (m, 2H)

[0417] Example 5

[0418]

[0419] A solution of INT 1 (96 mg, 0.306 mmol), (4-iodophenyl)boronic acid (74 mg, 0.612 mmol), Cu(OAc)2 (92 mg, 0.459 mmol) and Et3N (0.90 mL, 7.344 mmol) in DCM (15 mL) was stirred at 20 °C under an O2 atmosphere for 16 h, then filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (eluting with V (DCM) / V (MeOH) = 20:1), to give the solid compound 5-1 (81 mg, yield 67.9%). LCMS: m / z = 391.1 [M+H]+.

[0420] A solution of compound 5-1 (81 mg, 0.208 mmol), 1-tert-butoxycarbonylpyrazole-4-boronic acid pinacol ester (123 mg, 0.416 mmol), 1,1'-bis(di-tert-butylphosphino)ferrocene dichloropalladium (28 mg, 0.0416 mmol) and Cs2CO3 (338 mg, 1.04 mmol) in 1,4-dioxane (5.0 mL) and H2O (1.0 mL) was stirred at 110 °C under an N2 atmosphere for 16 h, then filtered. The filtrate was purified by preparative liquid chromatography (C18 column, eluting with H2O / CH3CN) to give compound 5 (4.4 mg, yield 6.42%), a solid. LCMS: m / z = 331.2 [M+H] + .

[0421] 1 1H NMR (400 MHz, DMSO-d6) δ 12.74 (s, 1H), 7.87 (s, 2H), 7.39 (d, J = 8.0 Hz, 2H), 7.26 - 7.05 (m, 2H), 6.77 - 6.55 (m, 1H), 6.42 (d, J = 7.9 Hz, 4H), 3.95 - 3.89 (m, 2H), 3.54 (s, 2H), 3.01 (s, 2H).

[0422] Example 6

[0423]

[0424] To a solution of INT 1 (50 mg, 0.159 mmol) and benzaldehyde (34 mg, 0.318 mmol) in 1,2-dichloroethane (5.0 mL) was added DIPEA (0.2 mL). After stirring for 1 h at 20 °C, NaBH3CN (102 mg, 0.477 mmol) was added. The mixture was stirred overnight at 20 °C, quenched with water (10 mL) at 0, and then extracted with DCM (10 mL x 3). The combined organic layers were washed with brine (10 mL x 2), dried over Na2SO4, and then concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography, eluting with V DCM / V MeOH = 20:1 to give compound 6-1 (22.0 mg, yield 34.2%) as a solid. LCMS: m / z = 405.1 [M+H]+.

[0425] A solution of compound 6-1 (22 mg, 0.054 mmol), 1-tert-butoxycarbonylpyrazole-4-boronic acid pinacol ester (50 mg, 0.162), 1,1'-bis(di-tert-butylphosphino)ferrocene dichloropalladium (7 mg, 0.0108 mmol), and Cs2CO3 (90 mg, 0.27 mmol) in 1,4-dioxane (2.0 mL) and H2O (0.5 mL) was stirred at 110 °C under N2 atmosphere for 16 h and then filtered. The filtrate was purified by preparative high performance liquid chromatography (C18 column, eluting with H2O / CH3CN) to give solid compound 6 (5.5 mg, yield 29.4%). LCMS: m / z = 345.2 [M+H]+.

[0426] 1 1H NMR (400 MHz, DMSO-d6) δ 7.86 (s, 2H), 7.44 - 7.36 (m, 2H), 7.34 - 7.18 (m, 5H), 6.43 - 6.35 (m, 2H), 3.91 - 3.83 (m, 2H), 3.55 (s, 2H), 3.52 - 3.47 (m, 2H), 3.29 (d, J = 14.4 Hz, 2H), 2.96 - 2.82 (m, 3H), 2.74 - 2.65 (m, 1H).

[0427] Example 7

[0428]

[0429] 3λ-Thia-9-azaspiro[5.5]undecane-3,3-dione hydrochloride (100 mg, 0.418 mmol), (4-iodophenyl)boronic acid (245 mg, 0.836 mmol), Cu(OAc)2 (148 mg, 0.627 mmol) and Et3N (1.65 mL, 10.032 mmol) were added to DCM (15 mL), and the mixture was stirred at 20 °C under an O2 atmosphere for 16 h, then filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography, eluting with V (DCM) / V (MeOH) = 20:1 to give the solid compound 7-1 (86 mg, 50.6% yield). LCMS: m / z = 406.0 [M+H] + 。

[0430] Compound 7-1 (86 mg, 0.212 mmol), 1-tert-butoxycarbonylpyrazole-4-boronic acid pinacol ester (125 mg, 0.424 mmol), 1,1'-bis(di-tert-butylphosphino)ferrocene dichloropalladium (30 mg, 0.0424 mmol) and Cs2CO3 (343 mg, 1.06 mmol) were stirred in 1,4-dioxane (5.0 mL) and H2O (1.0 mL) at 110 °C under a N2 atmosphere for 16 h, then filtered. The filtrate was purified by preparative liquid chromatography (C18 column, eluting with H2O / CH3CN) to give compound 7 (24.5 mg, 33.4% yield), a solid. LCMS: m / z = 346.2 [M+H] + 。

[0431] 1 H NMR (400 MHz, DMSO-d6) δ 7.94 (s, 2H), 7.55 - 7.39 (m, 2H), 6.99 (s, 2H), 3.08 - 3.01 (m, 4H), 1.98 - 1.84 (m, 4H), 1.66 (s, 4H).

[0432] Example 8

[0433]

[0434] To a solution of pyrrolidin-2-one (8.5 g, 100.05 mmol) in DMF (100 mL) was added NaH (4.8 g, 60% purity, 120.06 mmol) over 30 minutes at 20 °C, and then a solution of methyl 2-(bromomethyl)benzoate (9.92 g, 40.02 mmol) in DMF (10.0 mL) was added dropwise at 20 °C. The resulting mixture was stirred at 20 °C for 16 h, quenched with water (700 mL) at 0 °C, and then extracted with EtOAc (250 mL x 3, 150 mL x 3). The combined organic layers were washed with brine (500 mL x 2), dried over Na2SO4, and then concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography (eluted with petroleum ether / ethyl acetate) to give compound 8-1 (10.0 g, yield 98.8%) as a solid. LCMS: m / z = 254.0 / 255.9 (bromine isotope, [M+H] + ).

[0435] Under a N2 atmosphere, compound 8-1 (253 mg, 1.0 mmol), 4-ethynyl-1H-pyrazole (102 mg, 1.1 mmol), Pd(PPh3)2Cl2 (140 mg, 0.2 mmol), CuI (58 mg, 0.3 mmol), and DIPEA (1.1 mL, 6.0 mmol) were successively added to DMF (2.0 mL) at 20 °C. The reaction mixture was stirred at 40 °C under a N2 atmosphere for 16 h and then filtered. The filtrate was purified by preparative liquid chromatography (C18 column, eluted with H2O / CH3CN) to give compound 8 (3.4 mg, yield 1.28%) as a solid. LCMS: m / z = 266.1 [M+H] + 。

[0436] 1 H NMR (400 MHz, DMSO-d6) δ 8.28 - 7.91 (m, 2H), 7.45 (d, J = 8.1 Hz, 2H), 7.23 (d, J = 8.1 Hz, 2H), 4.38 (s, 2H), 3.27 - 3.21 (m, 2H), 2.35 - 2.26 (m, 2H), 2.03 - 1.88 (m, 2H).

[0437] Example 9

[0438]

[0439] At 90 °C, Cs2CO3 (3.52 g, 10.548 mmol) was added to a solution of 4-bromophenol (620 mg, 3.516 mmol) in DMF (10 mL), and then the mixture was stirred for 2 h. A solution of tert-butyl 6-((methylsulfonyl)oxy)-2-azaspiro[3.3]heptane-2-carboxylate (854 mg, 2.93 mmol) in DMF (1.0 mL) was added dropwise at 90 °C. The resulting mixture was stirred at 90 °C for 16 h, quenched with water (50 mL) at 0 °C, and then extracted with DCM (50 mL x 3). The combined organic layers were washed with brine (50 mL x 4), dried over Na2SO4, and then concentrated under reduced pressure to give a residue, which was purified by preparative liquid chromatography (C18 column, eluted with H2O / CH3CN) to give compound 9-1 (720 mg, yield 66.9%) as a solid. LCMS: m / z = 312.1, 314.1 (bromine isotope, [M+1-56] + ).

[0440] Trimethylsilyl trifluoromethanesulfonate (550 μL, 3.3 mmol) was added to a solution of compound 9-1 (404 mg, 1.1 mmol) in DCM (10 mL). The mixture was stirred overnight at 20 °C and then concentrated under reduced pressure to give a residue, which was purified by preparative liquid chromatography (C18 column, eluted with H2O / CH3CN) to give compound 9-2 (293 mg, yield 99.7%) as a solid. LCMS: m / z = 268.0, 270.0 (bromine isotope, [M+H] + ).

[0441] Acetic anhydride (148 μL, 1.575 mmol) was added dropwise at 0 °C to a solution of compound 9-2 (280 mg, 1.05 mmol) and Et3N (876 μL, 6.3 mmol) in DCM (10.0 mL). The mixture was stirred overnight at 20 °C, quenched with water (5 mL) at 0 °C, and then extracted with DCM (10 mL x 3). The combined organic layers were washed with brine (10 mL x 2), dried over Na2SO4, and then concentrated under reduced pressure to give a residue, which was purified by preparative high performance liquid chromatography (C18 column, eluted with H2O / CH3CN) to give compound 9-3 (303 mg, yield 93.5%) as a solid. LCMS: m / z = 310.0, 312.1 (bromine isotope, [M+H] + .

[0442] Compound 9-3 (303 mg, 0.98 mmol), 1-tert-butoxycarbonylpyrazole-4-boronic acid pinacol ester (588 mg, 1.96 mmol), 1,1'-bis(di-tert-butylphosphino)ferrocene dichloropalladium (130 mg, 0.196 mmol) and Cs2CO3 (1.63 g, 4.9 mmol) were stirred in 1,4-dioxane (5.0 mL) and H2O (1.0 mL) at 110 °C under an atmosphere of N2 for 16 h, and then filtered. The filtrate was purified by preparative high performance liquid chromatography (C18 column, eluted with H2O / CH3CN) to give the solid compound 9 (116.9 mg, yield 40.1%). LCMS: m / z = 298.2 [M+H]+.

[0443] 1 H NMR (400 MHz, DMSO-d6) δ 12.83 (s, 1H), 8.20 - 7.69 (m, 2H), 7.60 - 7.36 (m, 2H), 6.91 - 6.71 (m, 2H), 4.69 - 4.58 (m, 1H), 4.17 (s, 1H), 4.09 (s, 1H), 3.89 (s, 1H), 3.81 (s, 1H), 2.79 - 2.67 (m, 2H), 2.28 - 2.18 (m, 2H), 1.72 (d, J = 7.6 Hz, 3H)

[0444] Example 10

[0445]

[0446] A mixture of methyl 2-(bromomethyl)benzoate (1.14 g, 5.0 mmol), (4-bromophenyl)methanamine (0.93 g, 5.0 mmol) and K2CO3 (2.07 g, 15.0 mmol) in MeOH (50 mL) was stirred at 90 °C for 12 h, cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure to give a residue, which was purified by column chromatography (SiO2, eluted with petroleum ether / ethyl acetate) to give compound 10-1 (0.429 g, 1.505 mmol) as a solid. LCMS: m / z = 302.0, 304.0 (bromine isotope, [M+H] + )

[0447] Under an atmosphere of N2, at 20 °C, compound 10-1 (330 mg, 1.1 mmol), 4-ethynyl-1H-pyrazole (92 mg, 1.0 mmol), Pd(PPh3)2Cl2 (70 mg, 0.1 mmol), CuI (38 mg, 0.2 mmol) and DIPEA (1.1 mL, 6.0 mmol) were successively added to DMF (2.0 mL). The reaction mixture was at 40 °C in N (2)Stir for 16 h under an atmosphere, then filter. The filtrate was purified by preparative liquid chromatography (C18 column, eluted with 1% FA in H2O / CH3CN) to give Compound 10 (155.6 mg, yield 43.3%), as a solid. LCMS: m / z = 314.1 [M+H]+.

[0448] 1 1H NMR (400 MHz, DMSO-d6) δ 13.18 (s, 1H), 8.24 - 7.97 (m, 1H), 7.74 (d, J = 7.6 Hz, 2H), 7.64 - 7.54 (m, 2H), 7.53 - 7.41 (m, 3H), 7.28 (d, J = 7.9 Hz, 2H), 4.75 (s, 2H), 4.39 (s, 2H).

[0449] Example 11

[0450]

[0451] A solution of 3,9-diazaspiro[5.5]undecan-2-one (504 mg, 3.0 mmol), (4-iodophenyl)boronic acid (1.488 g, 6.0 mmol), Cu(OAc)2 (900 mg, 4.5 mmol) and Et3N (1.02 mL, 7.2 mmol) in DCM (50 mL) was stirred at 20 °C under an O2 atmosphere for 16 h, then filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (eluted with V (DCM) / V (MeOH) = 20:1) to give Compound 11-1 (481 mg, yield 43.3%), as a solid. LCMS: m / z = 371.1 [M+H]+.

[0452] To a solution of Compound 11-1 (444 mg, 1.2 mmol) in DMF (10 mL) at 20 °C was added NaH (43 mg, 60% purity, 1.44 mmol), and then a solution of iodomethane (150 μL, 2.4 mmol) in DMF (1.0 mL) was added dropwise at 20 °C. The resulting mixture was stirred at 20 °C for 16 h, quenched with water (50 mL) at 0 °C, and then extracted with DCM (50 mL x 3). The combined organic layers were washed with brine (50 mL x 4), dried over Na2SO4, and then concentrated under reduced pressure to give a residue, which was purified by preparative high performance liquid chromatography (C18 column, eluted with H2O / CH3CN) to give Compound 11-2 (195.7 mg, yield 42.5%), as a solid. LCMS: m / z = 385.1 [M+H]+.

[0453] Compound 11-2 (195.7 mg, 0.56 mmol), 1-tert-butoxycarbonylpyrazole-4-boronic acid pinacol ester (306 mg, 1.12 mmol), 1,1'-bis(di-tert-butylphosphino)ferrocene dichloropalladium (67 mg, 0.112 mmol) and Cs2CO3 (848 mg, 2.8 mmol) were stirred in 1,4-dioxane (5.0 mL) and H2O (1.0 mL) at 110 °C under a N2 atmosphere for 16 h, then filtered. The filtrate was purified by preparative liquid chromatography (C18 column, eluted with H2O / CH3CN) to give Compound 11 (67.0 mg, yield 40.6%), a solid. LCMS: m / z = 325.2 [M+H] +

[0454] 1 1H NMR (400 MHz, DMSO-d6) δ 12.78 (s, 1H), 7.90 (s, 2H), 7.42 (d, J = 8.4 Hz, 2H), 6.92 (d, J = 8.4 Hz, 2H), 3.27 (t, J = 6.4 Hz, 2H), 3.20 - 3.06 (m, 4H), 2.80 (s, 3H), 2.15 (s, 2H), 1.71 (t, J = 6.4 Hz, 2H), 1.60 - 1.43 (m, 4H).

[0455] Example 12

[0456]

[0457] Under a nitrogen atmosphere, to INT 3 (50 mg, 0.16 mmol), 2λ 6 -thia-7-azaspiro[3.5]nonane 2,2-dioxide hydrochloride (42.9 mg, 0.24 mmol) and t-BuONa (47.1 mg, 0.48 mmol) in 1,4-dioxane (2 mL) were added Pd2(dba)3 (14.96 mg, 0.016 mmol) and Xphos (15.6 mg, 0.032 mmol). The reaction mixture was stirred at 100 °C for 2 h, then filtered. The filtrate was concentrated and extracted with EA (50 mL x 3). The organic layer was washed with brine, dried over Na2SO4, then concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography (V (PE) / V EA = 4 / 1) to give Compound 12-2 as a yellow oil (32 mg, yield 48.8%). LCMS: m / z = 402.2 [M+H]+.

[0458] Under a nitrogen atmosphere, TsOH (41.2 mg, 0.24 mmol) was added to a mixture of compound 12-2 (32 mg, 0.08 mmol) in anhydrous THF (3 mL). The reaction mixture was stirred at 60 °C for 2 h, cooled to room temperature, and then filtered. The filtrate was concentrated and extracted with EA (50 mL x 3). The organic layer was washed with brine, dried over Na2SO 4, and then concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography (Combi-Flash (80 g), eluting with V PE / V EA = 1 / 2 to 1 / 5), to afford compound 12 as a white solid (4.29 mg, yield 16.96%). LCMS: m / z = 318.1 [M+H]+.

[0459] Example 13

[0460]

[0461] Under a nitrogen atmosphere, to INT 3 (50 mg, 0.16 mmol), 2λ 6 -thia-7-azaspiro[4.4]nonane 2,2-dioxide hydrochloride (42.9 mg, 0.24 mmol) and t-BuONa (47.1 mg, 0.48 mmol) in 1,4-dioxane (2 mL) were added Pd2(dba)3 (14.96 mg, 0.016 mmol) and Xphos (15.6 mg, 0.032 mmol). The reaction mixture was stirred at 100 °C for 2 h and then filtered. The filtrate was concentrated and extracted with EA (20 mL x 3). The organic layer was washed with brine, dried over Na2SO 4, and then concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography (V (PE) / V EA = 4 / 1), to afford compound 13-1 as a yellow oil (35 mg, yield 53.4%). LCMS: m / z = 402.2 [M+H]+.

[0462] Under a nitrogen atmosphere, TsOH (45.1 mg, 0.261 mmol) was added to a mixture of compound 13-1 (35 mg, 0.087 mmol) in anhydrous THF (3 mL). The reaction mixture was stirred at 60 °C for 2 h, cooled to room temperature, and then filtered. The filtrate was concentrated and extracted with EA (20 mL x 3). The organic layer was washed with brine, dried over Na2SO4, and then concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography (Combi-Flash (80 g), eluting with V PE / V EA(eluted with 1 / 2 to 1 / 5), to obtain the white solid compound 13 (6.3 mg, yield 22.8%). LCMS: m / z = 318.1 [M+H]+.

[0463] Example 14

[0464]

[0465] Under a nitrogen atmosphere, Pd2(dba)3 (14.96 mg, 0.016 mmol) and Xphos (15.6 mg, 0.032 mmol) were added to a solution of INT 3 (50 mg, 0.16 mmol), 3-azaspiro[5.5]undecane (37.5 mg, 0.24 mmol), and t-BuONa (47.1 mg, 0.48 mmol) in 1,4-dioxane (2 mL). The reaction mixture was stirred at 100 °C for 1 hour and then filtered. The filtrate was concentrated and extracted with EA (20 mL x 3). The organic layer was washed with brine, dried over Na2SO 4, dried, and then concentrated under reduced pressure to obtain a residue, which was purified by silica gel column chromatography (V (PE) / V EA = 4 / 1), to obtain the yellow oil compound 14-1 (35 mg, yield 56.5%). LCMS: m / z = 380.3 [M+H]+.

[0466] Under a nitrogen atmosphere, TsOH (47.7 mg, 0.276 mmol) was added to a mixture of compound 14-1 (35 mg, 0.092 mmol) in anhydrous THF (3 mL). The reaction mixture was stirred at 60 °C for 2 hours, cooled to room temperature, and then filtered. The filtrate was concentrated and extracted with EA (20 mL x 3). The organic layer was washed with brine, dried over Na2SO4, and then concentrated under reduced pressure to obtain a residue, which was purified by silica gel column chromatography (Combi-Flash (80 g), V PE / V EA = 1 / 3 elution), to obtain compound 14 (8.76 mg, yield 32.2%), a white solid. LCMS: m / z = 296.2 [M+H]+.

[0467] Example 15

[0468]

[0469] Under a nitrogen atmosphere, to a solution of INT 3 (50 mg, 0.16 mmol), 7λ6-2-aza-7-thiaspiro[3.5]nonane-7,7-dione (42.9 mg, 0.24 mmol) and t-BuONa (47.1 mg, 0.48 mmol) in 1,4-dioxane (2 mL) were added Pd2(dba)3 (14.96 mg, 0.016 mmol) and Xphos (15.6 mg, 0.032 mmol). The reaction mixture was stirred at 100 °C for 1 h and then filtered. The filtrate was concentrated and extracted with EA (20 mL x 3). The organic layer was washed with brine, dried over Na2SO4, and then concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography (V PE / V EA = 4 / 1) to afford compound 15-1 as a yellow oil (20 mg, yield 30.5%). LCMS: m / z = 402.2 [M+H]+.

[0470] Under a nitrogen atmosphere, to a mixture of compound 15-1 (20 mg, 0.05 mmol) in anhydrous THF (1 mL) was added TsOH (25.8 mg, 0.15 mmol). The reaction mixture was stirred at 60 °C for 2 h, cooled to room temperature, and then filtered. The filtrate was concentrated and extracted with EA (20 mL x 3). The organic layer was washed with brine, dried over Na2SO4, and then concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography (Combi-Flash (80 g), eluting with V PE / V EA = 1 / 3) to afford compound 15 as a white solid (12.15 mg, yield 76.9%). LCMS: m / z = 318.1 [M+H]+.

[0471] Example 16

[0472]

[0473] Under a nitrogen atmosphere, to a solution of INT 3 (100 mg, 0.33 mmol), 2λ6-6-aza-2-thiaspiro[3.4]octane-2,2-dione (78.97 mg, 0.495 mmol) and t-BuONa (94.2 mg, 0.99 mmol) were added Pd2(dba)3 (29.9 mg, 0.033 mmol) and Xphos (31.2 mg, 0.066 mmol). The reaction mixture was stirred at 100 °C for 1 h and then filtered. The filtrate was concentrated and extracted with EA (50 mL x 3). The organic layer was washed with brine, dried over Na2SO4, and then concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography (V (PE) / V EA=(4 / 1), a yellow oily compound 16-1 (20 mg, yield 15.8%) was obtained. LCMS: m / z = 388.2 [M+H]+.

[0474] Under a nitrogen atmosphere, TsOH (26.7 mg, 0.156 mmol) was added to a mixture of compound 16-1 (20 mg, 0.052 mmol) in anhydrous THF (3 mL). The reaction mixture was stirred at 60 °C for 2 hours, cooled to room temperature, and then filtered. The filtrate was concentrated and extracted with EA (20 mL x 3). The organic layer was washed with brine, dried over Na2SO4, and then concentrated under reduced pressure to obtain a residue, which was purified by silica gel column chromatography (Combi-Flash (80 g), eluted with V PE / V EA = 1 / 3), to obtain a white solid compound 16 (2.07 mg, yield 13.2%). LCMS: m / z = 304.1 [M+H]+.

[0475] Example 17

[0476]

[0477] Under a nitrogen atmosphere, Pd2(dba)3 (14.96 mg, 0.016 mmol) and Xphos (15.6 mg, 0.032 mmol) were added to a mixture of INT 3 (50 mg, 0.16 mmol), 6λ6-2-aza-6-thiaspiro[3.4]octane-6,6-dione (39.5 mg, 0.24 mmol) and t-BuONa (47.1 mg, 0.48 mmol) in 1,4-dioxane (2 mL). The reaction mixture was stirred at 100 °C for 1 hour, and then filtered. The filtrate was concentrated and extracted with EA (20 mL x 3). The organic layer was washed with brine, dried over Na2SO4, and then concentrated under reduced pressure to obtain a residue, and the residue was purified by silica gel column chromatography (V (PE) / V EA = 4 / 1), to obtain a yellow oily compound 17-1 (25 mg, yield 39.5%). LCMS: m / z = 388.2 [M+H]+.

[0478] Under a nitrogen atmosphere, TsOH (33.4 mg, 0.195 mmol) was added to a mixture of compound 17-1 (25 mg, 0.065 mmol) in anhydrous THF (3 mL). The reaction mixture was stirred at 60 °C for 2 hours, cooled to room temperature, and then filtered. The filtrate was concentrated and extracted with EA (20 mL x 3). The organic layer was washed with brine, dried over Na2SO4, and then concentrated under reduced pressure to obtain a residue, which was purified by silica gel column chromatography (Combi-Flash (80 g), eluted with V PE / VEA (= 1 / 3 elution), a white solid compound 17 (6.04 mg, yield 32.2%) was obtained. LCMS: m / z = 304.1 [M+H]+.

[0479] Example 18

[0480]

[0481] Under a nitrogen atmosphere, to INT 3 (50 mg, 0.16 mmol), 2λ6-6-aza-2-thiaspiro[3.3]heptane-2,2-dione (36 mg, 0.24 mmol) and t-BuONa (47.1 mg, 0.48 mmol), Pd2(dba)3 (14.96 mg, 0.016 mmol) and Xphos (15.6 mg, 0.032 mmol) were added. The reaction mixture was stirred at 100 °C for 1 hour and then filtered. The filtrate was concentrated and extracted with EA (20 mL x 3). The organic layer was washed with brine, dried over Na2SO4, and then concentrated under reduced pressure to obtain a residue, which was purified by silica gel column chromatography (V PE / V EA = 4 / 1), to obtain a yellow oil compound 18-1 (25 mg, yield 41%). LCMS: m / z = 374.2 [M+H]+.

[0482] Under a nitrogen atmosphere, TsOH (34.6 mg, 0.201 mmol) was added to a mixture of compound 18-1 (25 mg, 0.067 mmol) in anhydrous THF (3 mL). The reaction mixture was stirred at 60 °C for 2 hours, cooled to room temperature, and then filtered. The filtrate was concentrated and extracted with EA (20 mL x 3). The organic layer was washed with brine, dried over Na2SO4, and then concentrated under reduced pressure to obtain a residue, which was purified by silica gel column chromatography (Combi-Flash (80 g), eluted with V PE / V EA = 1 / 3), to obtain a white solid compound 18 (2.57 mg, yield 13.3%). LCMS: m / z = 290.1 [M+H]+.

[0483] Example 19

[0484]

[0485] At 0 °C, NaH (39.3 mg, 1.185 mmol, 60% by weight) was added portionwise to a mixture of 2-(tert-butyl)-1-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate (200 mg, 0.79 mmol) in THF (anhydrous, 5 mL). After stirring for 30 minutes, a solution of CH3I (167.6 mg, 1.185 mmol) in THF (1 mL) was added slowly. The reaction mixture was stirred at a constant temperature for 2 hours, quenched with water (4 mL) at 0 °C, and then concentrated under reduced pressure to obtain the crude product Compound 19-1 (250 mg), which was directly carried on to the next step. LCMS: m / z = 269.2 [M+H] + .

[0486] A solution of Compound 19-1 (250 mg, 0.93 mmol) in hydrochloric acid / 1,4-dioxane (4 M, 5.0 mL) was stirred at a constant temperature for 16 hours, then concentrated under reduced pressure, and water was added. The pH of the mixture was adjusted to about 8 with saturated NaHCO3, and then extracted with EtOAc (50 mL x 3). The organic layer was dried over Na2SO4 and concentrated under reduced pressure to obtain the crude product Compound 19-2 (300 mg) as an orange oil. LCMS: m / z = 169.1 [M+H]+.

[0487] Under a nitrogen atmosphere, Pd2(dba)3 (54.5 mg, 0.059 mmol) and Xphos (56.7 mg, 0.118 mmol) were added to a solution of Compound 19-2 (150 mg, 0.885 mmol), INT 3 (182 mg, 0.59 mmol) and t-BuONa (171.5 mg, 1.77 mmol) in 1,4-dioxane (5 mL). The reaction mixture was stirred at 100 °C for 1 hour, then filtered. The filtrate was concentrated and extracted with EA (50 mL x 3). The organic layer was washed with brine, dried over Na2SO4, and then concentrated under reduced pressure to obtain a residue, which was purified by silica gel column chromatography (V (PE) / V EA = 4 / 1) to obtain Compound 19-3 (50 mg, yield 14.2%) as a yellow oil. LCMS: m / z = 395.2 [M+H]+.

[0488] Under a nitrogen atmosphere, hydrochloric acid (4 M, 2 mL) was added to a mixture of Compound 19-3 (50 mg, 0.13 mmol) in EA (3 mL). The reaction mixture was stirred at 60 °C for 2 hours, cooled to room temperature, and then filtered. The filtrate was concentrated and extracted with EA (20 mL x 3). The organic layer was washed with brine, dried over Na2SO4, and then concentrated under reduced pressure to obtain a residue, which was purified by silica gel column chromatography (Combi-Flash (80 g), using VPE / V EA (elution with 1 / 3), a white solid compound 19 (12.67 mg, yield 32.2%) was obtained. LCMS: m / z = 311.2 [M+H]+.

[0489] Example 20

[0490]

[0491] At 0 °C, NaH (44.8 mg, 1.125 mmol, 60% (weight)) was added portionwise to a mixture of 2-methylpropan-2-yl 1-oxo-2,9-diazaspiro[5.5]undecane-9-carboxylate (200 mg, 0.75 mmol) in THF (anhydrous, 5 mL). After stirring for 30 minutes, a solution of CH3I (158.8 mg, 1.185 mmol) in THF (1 mL) was slowly added. The reaction mixture was stirred at r.t. for 2 hours, quenched with water (4 mL) at 0 °C, and concentrated under reduced pressure to obtain the crude product Compound 20-1 (265 mg), which was directly carried on to the next step. LCMS: m / z = 283.2 [M+H]+.

[0492] A solution of compound 20-1 (265 mg, 0.939 mmol) in hydrochloric acid / 1,4-dioxane (4 M, 5.0 mL) was stirred under thermostatic conditions for 16 hours, then concentrated under reduced pressure, and water was added thereafter. The pH of the mixture was adjusted to about 8 with saturated NaHCO3, and then extracted with EtOAc (50 mL x 3). The organic layer was dried over Na2SO4 and concentrated under reduced pressure to obtain the crude compound 20-2 (330 mg) as an orange oil. LCMS: m / z = 183.1 [M+H]+.

[0493] Under a nitrogen atmosphere, Pd2(dba)3 (50.3 mg, 0.0549 mmol) and Xphos (52.3 mg, 0.1098 mmol) were added to a solution of compound 20-2 (150 mg, 0.8235 mmol), INT 3 (168 mg, 0.549 mmol) and t-BuONa (158.3 mg, 1.647 mmol) in 1,4-dioxane (5 mL). The reaction mixture was stirred at 100 °C for 1 hour, and then filtered. The filtrate was concentrated and extracted with EA (50 mL x 3). The organic layer was washed with brine, dried over Na2SO4, and then concentrated under reduced pressure to obtain a residue, which was purified by silica gel column chromatography (V (PE) / V EA = 4 / 1), to obtain the yellow oil compound 20-3 (45 mg, yield 13.4%). LCMS: m / z = 409.3 [M+H]+.

[0494] Under a nitrogen atmosphere, hydrochloric acid (4 M, 2 mL) was added to a mixture of Compound 20-3 (45 mg, 0.11 mmol) in EA (3 mL). The reaction mixture was stirred at 60 °C for 2 hours, cooled to room temperature, and then filtered. After concentration of the filtrate, it was extracted with EA (20 mL x 3). The organic layer was washed with brine, dried over Na2SO4, and then concentrated under reduced pressure to obtain a residue, which was purified by silica gel column chromatography (Combi-Flash (80 g), eluted with VPE / VEA = 1 / 3) to give Compound 20 as a white solid (16.05 mg, yield 44.9%). LCMS: m / z = 325.2 [M+H]+.

[0495] Example 21

[0496]

[0497] At 0 °C, NaH (22.3 mg, 0.5595 mmol, 60% (weight)) was added portionwise to a mixture of 2-methylpropan-2-yl 3-oxo-2,9-diazaspiro[5.5]undecane-9-carboxylate (100 mg, 0.373 mmol) in anhydrous THF (3 mL). After stirring for 30 minutes, a solution of CH3I (79.4 mg, 0.5595 mmol) in THF (1 mL) was added dropwise. The reaction mixture was stirred under constant temperature for 2 hours, quenched with water (4 mL) at 0 °C, and then concentrated under reduced pressure to obtain crude Compound 21-1 (125 mg), which was directly used in the next step. LCMS: m / z = 283.2 [M+H]+.

[0498] A solution of Compound 21-1 (125 mg, 0.443 mmol) in hydrochloric acid / 1,4-dioxane (4 M, 2.0 mL) was stirred under constant temperature for 16 hours, then concentrated under reduced pressure, and water was added. The pH of the resulting mixture was adjusted to about 8 with saturated NaHCO3 solution, and then extracted with EtOAc (20 mL x 3). The organic layer was dried over Na2SO4 and concentrated under reduced pressure to obtain crude Compound 21-2 (105 mg) as an orange oil. LCMS: m / z = 183.1 [M+H]+.

[0499] Under a nitrogen atmosphere, Pd2(dba)3 (35.2 mg, 0.0384 mmol) and Xphos (36.64 mg, 0.0768 mmol) were added to a solution of compound 21-2 (105 mg, 0.576 mmol), INT 3 (117.6 mg, 0.384 mmol), and t-BuONa (110.8 mg, 1.152 mmol) in 1,4-dioxane (5 mL). The reaction mixture was stirred at 100 °C for 1 h and then filtered. The filtrate was concentrated and extracted with EA (50 mL x 3). The organic layer was washed with brine, dried over Na2SO4, and then concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography (V (PE) / V EA = 4 / 1) to afford compound 21-3 as a yellow oil (50 mg, yield 21.2%). LCMS: m / z = 409.3 [M+H]+.

[0500] Under a nitrogen atmosphere, hydrochloric acid (4 M, 2 mL) was added to a mixture of compound 21-3 (50 mg, 0.122 mmol) in EA (3 mL). The reaction mixture was stirred at 60 °C for 2 h, cooled to room temperature, and then filtered. The filtrate was concentrated and extracted with EA (20 mL x 3). The organic layer was washed with brine, dried over Na2SO4, and then concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography (Combi-Flash (80 g), eluted with VPE / VEA = 1 / 3) to afford compound 21 as a white solid (14.07 mg, yield 35.4%). LCMS: m / z = 325.2 [M+H]+.

[0501] Example 22

[0502]

[0503] Pyrrolidine (826.8 mg, 11.6 mmol) was carefully added to a mixture of 1-(5-bromo-2-hydroxyphenyl)ethan-1-one (1.0 g, 4.65 mmol) and tert-butyl 4-oxopiperidine-1-carboxylate (926.5 mg, 4.65 mmol) in MeOH (20 mL). The reaction was stirred at 70 °C for 16 h. Then, the reactants were concentrated. The crude product was purified by Combi-Flash (25 g, eluted with V PE / V EA = 5 / 1) to afford compound 22-1 as a yellow solid (1.6 g, 82.5%). LCMS: m / z = 340.0 [M-55]+.

[0504] A solution of compound 22-1 (1.6 g, 4.04 mmol) in EtOH (20 mL) was cooled to 0 °C, and NaBH4 (305.5 mg, 8.08 mmol) was added. The mixture was stirred at 0 °C for 2 h. It was quenched with an aqueous NH4Cl solution (30 mL). It was extracted with EA (50 mL x 2). The combined EA layers were washed with brine and dried over Na2SO4. It was filtered and concentrated to give yellow solid compound 22-2 (1.45 g, 85.7%). LCMS: m / z = 420.0 [M+Na]+.

[0505] To a solution of compound 22-2 (1.45 g, 3.64 mmol) in DCM (10 mL) were added TFA (5 mL) and Et3SiH (2.5 mL). The mixture was stirred at 25 °C for 16 h. The mixture was concentrated under reduced pressure. The pH was adjusted to 12 with NH3-H2O at 0 °C. It was extracted with dichloromethane (50 mL x 3). The combined DCM layers were washed with brine and dried over Na2SO4. It was filtered and concentrated. The residue was purified by FCC (V DCM / V MeOH = 10 / 1) to give yellow solid compound 22-3 (650 mg, 60.1%). LCMS: m / z = 282.0 [M+1]+.

[0506] To a solution of compound 22-3 (650 mg, 2.30 mmol) in DCM (10 mL) was added DIPEA (595.4 mg, 4.61 mmol). The mixture was cooled to 0 °C. Acetyl chloride (216.9 mg, 2.76 mmol) was added. The mixture was stirred at 0 °C for 1 h. The mixture was concentrated. The residue was purified by FCC (V DCM / V MeOH = 20 / 1) to give yellow solid compound 22-4 (600 mg, 74%). LCMS: m / z = 324.1

[0507] Compound 22-4 (600 mg, 1.85 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (718.1 mg, 3.70 mmol), Pd(dppf)Cl2 (135.4 mg, 0.18 mmol) and K2CO 33 (383.7 mg, 2.78 mmol) in 1,4-dioxane (10 mL) and H2O (2 mL) were heated to 100 °C under N2 and stirred for 24 h. The mixture was cooled to 25 °C and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by FCC (V DCM / V MeOH= 20 / 1) Purification afforded the yellow solid compound 22 (255 mg, 42.0%). LC-MS: m / z = 312.1 [M+H]+.

[0508] 1H NMR (400 MHz, DMSO) δ 12.78 (s, 1H), 7.91 (s, 2H), 7.31 - 7.29 (m, 2H), 6.77 (d, J = 8.1 Hz, 1H), 4.12 - 4.06 (m, 1H), 3.62 (d, J = 13.5 Hz, 1H), 3.39 (d, J = 11.5 Hz, 1H), 3.03 - 3.29 (m, 1H), 2.77 - 2.73 (m, 2H), 2.01 (s, 3H), 1.81 - 1.78 (m, 2H), 1.72 - 1.57 (m, 3H), 1.51 - 1.43 (m, 1H).

[0509] Example 23

[0510]

[0511] To a mixture of 1-(5-bromo-2-hydroxyphenyl)ethan-1-one (1.5 g, 6.98 mmol) and tert-butyl 6-oxo-2-azaspiro[3.3]heptane-2-carboxylate (1.77 g, 8.37 mmol) in MeOH (30 mL) was carefully added pyrrolidine (1.24 g, 17.4 mmol). The reaction was stirred at 70 °C for 16 h. Then the reactants were concentrated. The crude product was purified by Combi-Flash (25 g, V PE / V EA = 5 / 1 elution), affording the yellow solid compound 23-1 (2.2 g, 73.2%). LCMS: m / z = 430.0 [M+Na]+.

[0512] A solution of compound 23-1 (2.20 g, 5.38 mmol) in EtOH (20 mL) was cooled to 0 °C, and NaBH4 (610 mg, 16.1 mmol) was added. The mixture was stirred at 0 °C for 2 h. It was quenched with aqueous NH4Cl solution (30 mL). Extraction was carried out with EA (40 mL x 2). The combined EA layers were washed with brine and dried over Na2SO4. Filtration and concentration gave the yellow solid compound 23-2 (1.60 g, 72%). LCMS: m / z = 354.0 [M - 55]+.

[0513] To a solution of Compound 23-2 (1.60 g, 3.90 mmol) in DCM (10 mL) were added TFA (4 mL) and Et3SiH (4 mL). The mixture was stirred at 25 °C for 16 h. The mixture was concentrated under reduced pressure. The pH was adjusted to 12 with NH3-H2O at 0 °C. The mixture was extracted with dichloromethane (20 mL x 3). The combined DCM layers were washed with brine and dried over Na2SO4. The mixture was filtered and concentrated. The residue was purified by FCC (V DCM / V MeOH = 20 / 1) to give Compound 23-3 as a yellow solid (900 mg, 79%). LCMS: m / z = 294.1 [M+1]+.

[0514] To a solution of Compound 23-3 (820 mg, 2.79 mmol) in DCM (8 mL) was added DIPEA (1.44 g, 11.1 mmol). The mixture was cooled to 0 °C. Acetyl chloride (263 mg, 3.35 mmol) was added. The mixture was stirred at 25 °C for 3 h. The mixture was concentrated. The residue was purified by FCC (V PE / V EA = 2 / 1) to give Compound 23-4 as a yellow solid (700 mg, 74%). LCMS: m / z = 336.1

[0515] A mixture of Compound 23-4 (700 mg, 2.08 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (808 mg, 4.16 mmol), Pd(dppf)Cl2 (152 mg, 0.21 mmol) and K2CO3 (432 mg, 3.12 mmol) in 1,4-dioxane (5 mL) and H2O (1 mL) was heated to 100 °C under N2 and stirred for 24 h. The mixture was cooled to 25 °C and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by preparative liquid chromatography (ACN--H2O (0.1% FA), ACN content from 10% to 90%) to give Compound 23 as a white solid (85.2 mg, 12.66%). LCMS: m / z = 324.2 [M+H]+.

[0516] 1H NMR (400 MHz, DMSO-d6) δ 12.76 (s, 1H), 7.90 (s, 2H), 7.31 - 7.23 (m, 2H), 6.69 (d, J = 8.2 Hz, 1H), 4.16 (d, J = 13.6 Hz, 2H), 3.87 (d, J = 13.4 Hz, 2H), 2.76 (t, J = 6.1 Hz, 2H), 2.41 - 2.30 (m, 4H), 1.82 (t, J = 6.4 Hz, 2H), 1.75 - 1.68 (m, 3H).

[0517] Example 24

[0518]

[0519] To a mixture of 2-methylpropan-2-yl 4-[(4-bromophenyl)oxy]piperidine-1-carboxylate (500 mg, 1.4 mmol) in DCM (2 mL) was carefully added HCl / EA (2 mL, 4 M). The reaction was stirred at 20 °C for 2 h. Then the reaction mixture was concentrated to afford a yellow solid compound 24-1 (400 mg, 1.3 mmol, yield 92.5%, purity 95%). LCMS: m / z = 256.0 [M+H]+.

[0520] To a mixture of compound 24-1 (400 mg, 1.30 mmol) and DIPEA (883 mg, 6.83 mmol) in DCM (10 mL) was carefully added acetyl chloride (128.8 mg, 1.64 mmol). The reaction was stirred at 0 °C for 1 h. Then the reaction mixture was concentrated. The crude product was purified by Combi-Flash (10 g, eluted with V (DCM) / V (MeOH) = 20 / 1) to afford a yellow solid compound 24-2 (400 mg, 1.27 mmol, yield 93.2%, purity 95%). LCMS: m / z = 298.0 [M+H]+.

[0521] To a mixture of compound 24-2 (400 mg, 1.27 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (520.6 mg, 2. In dioxane (10 mL) and H2O (2 mL) were carefully added Pd(dppf)Cl2 (98.2 mg, 0.13 mmol) and K2CO 33 (370.8 mg, 2.68 mmol). The reaction was stirred at 100 °C under N2 for 24 h. Then the reaction mixture was concentrated. The crude product was purified by Combi-Flash (12 g, V DCM / V MeOH = 20 / 1) to afford a light brown solid compound 24 (240 mg, 0.8 mmol, yield 59.56%, purity 97.4%). LCMS: m / z = 286.2 [M+H]+.

[0522] 1H NMR (400 MHz, DMSO) δ 12.80 (s, 1H), 7.95 (s, 2H), 7.50 (d, J = 8.5 Hz, 2H), 6.97 (d, J = 8.5 Hz, 2H), 4.65 - 4.55 (m, 1H), 3.89 - 3.78 (m, 1H), 3.74 - 3.61 (m, 1H), 3.36 - 3.32 (m, 1H), 3.26 - 3.21 (m, 1H), 2.01 (s, 3H), 1.95 - 1.87 (m, 1H), 1.67 - 1.55 (m, 1H), 1.55 - 1.44 (m, 1H).

[0523] Example 25

[0524]

[0525] To a mixture of 2-pyrrolidone (1.2 g, 0.014 mmol) in DMF (20 mL) was carefully added NaOH (0.9 g, 0.023 mmol) and 4-(bromomethyl)benzoic acid (2.5 g, 0.011 mmol). The reaction was stirred at 25 °C for 2 h. Then the reactants were concentrated. The reactants were diluted with EA (50 mL). The organic layer was washed with saturated NH4Cl solution and brine. The organic layer was dried over Na2SO4, filtered, and the filtrate was concentrated. The crude product was purified by Combi-Flash (130 g, V PE / V EA = 1 / 5 elution) to give the yellow solid compound 25-1 (1.2 g, 49.8%). LCMS: m / z = 220.1 [M+H]+.

[0526] To a mixture of compound 25-1 (0.89 g, 4.06 mmol) and 1-BOC-5-amino-1H-imidazole (1.1 g, 4.8 mmol) in DMF (10 mL) was carefully added DIEA (1.57 g, 17.55 mmol) and HATU (2.3 g, 8.77 mmol). The reaction was stirred at 25 °C for 15 h. The reactants were diluted with EA (30 mL). The organic layer was washed with saturated NH(4)Cl NH4Cl solution and brine. The organic layer was dried over Na2SO4, filtered, and the filtrate was concentrated. The crude product was purified by Combi-Flash method (80 g, V DCM / V MeOH = 30 / 1 elution) to give the yellow solid compound 25-2 (0.6 g, 34.0%). LCMS: m / z = 435.2 [M+H]+.

[0527] A mixture of compound 25-2 (300 mg, 0.69 mmol) in hydrochloric acid (6 mL) was stirred at 25 °C for 2 h. After concentration of the reaction mixture under reduced pressure, a residue was obtained. The residue was purified by preparative liquid chromatography (column: Waters Xbridge Prep OB column): Waters Xbridge Prep OBD C18 150x 40mm x 10um; mobile phase: H2O-MeOH; gradient: 10%-55% B, 8.0 min), to give white solid compound 25 (39.5 mg, 11.8%). LCMS: m / z = 335.2 [M+H]+.

[0528] 1 H NMR (400 MHz, DMSO-d6) δ 13.01 (s, 1H), 10.24 (s, 1H), 8.26 - 8.21 (m, 1H), 8.06 (s, 1H), 7.99 - 7.92 (m, 2H), 7.67 - 7.60 (m, 1H), 7.56 - 7.49 (m, 1H), 7.41 - 7.34 (m, 2H), 4.46 (s, 2H), 3.31 - 3.23 (m, 2H), 2.37 - 2.28 (m, 2H), 2.06 - 1.90 (m, 2H).

[0529] Example 26

[0530]

[0531] Phenylsilane (2.14 g, 19.86 mmol) was carefully added to a mixture of 4-nitrobenzaldehyde (1 g, 6.62 mmol) and 4-aminobutyric acid (0.81 g, 7.94 mmol) in EtOH (10 mL). The mixture was stirred at 40 °C for 3 h. The reaction mixture was diluted with EA (30 mL). The organic layer was washed with saturated NH4Cl solution and brine. The organic layer was dried over Na2SO4, filtered, and the filtrate was concentrated. The crude product was purified by Combi-Flash (130 g, eluted with PE / EA = 1 / 4), to give yellow solid compound 26-1 (1 g, 68.6%). LCMS: m / z = 221.0 [M+H]+.

[0532] NH4Cl (2.89 g, 54.09 mmol) and Fe (1.51 g, 27.04 mmol) were carefully added to a mixture of compound 26-1 (0.85 g, 3.86 mmol) in MeOH (15 mL) and H2O (3 mL). The reaction mixture was stirred at 80 °C for 1 h, cooled to room temperature, and then filtered. After concentration of the filtrate, it was extracted with EA (50 mL x 3). The organic layer was washed with brine, Na2SO 4,Dry, then concentrate under reduced pressure to obtain a residue, which is purified by silica gel column chromatography (Combi-Flash (130 g), eluted with V PE / V EA = 1 / 2 to 1 / 7), to obtain the yellow solid compound 26-2 (0.5 g, yield 68.1%). LCMS: m / z = 191.1 [M+H]+.

[0533] To a mixture of compound 26-2 (0.3 g, 1.57 mmol) and 5-carboxyindazole hydrochloride (306.9 mg, 1.89 mmol) in DMF (5 mL), DIEA (611.05 mg, 4.73 mmol) and HATU (899.9 mg, 2.36 mmol) were carefully added. The reaction was stirred at 25 °C for 2 h. The reaction mixture was diluted with EA (50 mL). The organic layer was washed with saturated NH4Cl solution and brine. The organic layer was dried over Na2SO4, filtered, and the filtrate was concentrated. The crude product was purified by preparative high performance liquid chromatography (column: Waters Xbridge Prep OB-XPLC, HPLC, HPLC): Waters Xbridge Prep OBD C18 150x 40mm x 10um; mobile phase: H2O-MeOH; gradient: 10%-55% B, 8.0 min), to obtain the white solid compound 26 (50.1 mg, 9.5%). LCMS: m / z = 335.1 [M+H]+.

[0534] 1 H NMR (400 MHz, DMSO-d6) δ 13.34 (s, 1H), 10.27 (s, 1H), 8.50 - 8.45 (m, 1H), 8.27 (s, 1H), 7.99 - 7.91 (m, 1H), 7.81 - 7.73 (m, 2H), 7.68 - 7.61 (m, 1H), 7.24 - 7.18 (m, 2H), 4.34 (s, 2H), 3.28 - 3.20 (m, 2H), 2.34 - 2.26 (m, 2H), 1.99 - 1.87 (m, 2H).

[0535] Pharmacological experiments

[0536] 1. In vitro 20-HETE inhibitory effect

[0537] To determine the inhibitory effect on 20-HETE formation, compounds that inhibit rCYP4F2 or rCYP4A11 were screened using HLM or recombinant enzyme culture medium. Arachidonic acid was dissolved in 100% acetonitrile (ACN) to obtain a 20 mM stock solution. Each test compound was dissolved in DMSO to obtain a sample solution (50 μM, 10 μM, 2 μM).

[0538] The HLM culture medium (180 μL) contains liver microsomes (20 mg / ml, 2 μL), substrate (20 mM, 1 μL), phosphate buffered saline (100 mM, 176 μL), and 1 μL of test compounds at different concentrations. The recombinant enzyme incubation system contains rCYP4F2 or rCYP4A11 (20 mg / ml, 2 μL), arachidonic acid (10 mM, 1 μL), potassium dihydrogen phosphate buffer (100 mM, 176 μL), and 1 μL of test compounds at different concentrations. The HLM culture medium / recombinant enzyme incubation system was pre-incubated for 10 minutes, NADPH (10 mM, 20 μl) was added, and then incubated with shaking at 37 °C for 90 minutes. The incubation plate was placed on ice to stop the reaction, 400 μl of ACN containing an internal standard was added, and then mixed evenly. After centrifugation at 4700 rpm for 15 minutes at 4 °C, 150 μl of the supernatant was transferred to a new 96-well plate, then 150 μl of ddH2O was added and mixed well for LC-MS / MS analysis.

[0539] 20-HETE was separated on a 2.5 μm (50 × 3 mm) polar reversed-phase chromatography column (UPLC Synergi TM Polar) (Phenomenex) with the following chromatographic conditions: the column temperature was 40 °C; the mobile phase consisted of deionized water (mobile phase A) and 0.1% formic acid acetonitrile (mobile phase B), and the total flow rate was 1.0 mL / min. The composition of the initial mobile phase B was gradually increased to 95% B within 1.2 minutes, then maintained at 95% B for 0.8 minutes, and finally restored to the initial state of 30% B within 0.8 minutes, and then maintained for another 0.5 minutes. The injection volume was 20 μl. Mass spectrometry analysis was performed on a QTRAP 4500 LC-MS / MS (AB Sciex) using electrospray ionization (ESI) technology. The mass spectrometer was operated in the negative multiple reaction monitoring (MRM) mode. The analysis data was acquired and analyzed by the Analyst 1.7.2 system (AB Sciex).

[0540] The formation of 20-HETE was quantified using a well-established UPLC-MS / MS analytical method. Each compound had two to three replicates (n = 2 - 3). The blank group was used as a control, and the percentage of 20-HETE formation rate was calculated. Then, the inhibition rate data was fitted to a four-parameter logistic model using GraphPad Prism 8.0, and the IC 50 value was calculated according to the following equation: Y: inhibition rate; X: logarithm of inhibitor concentration; Bottom: minimum inhibition rate; Top: maximum inhibition rate;

[0541] Tables 1 and 2 list the results of the test compounds, the percentage of inhibition at 250 nM, 50 nM or 10 nM, and the calculated IC 50 value:

[0542] Table 1

[0543]

[0544]

[0545] As can be seen from Table 1, the representative compounds of the present invention have good inhibitory effects on the production of 20-HETE in HLM with high expression of CYP4A11 and CYP4F2.

[0546] Table 2

[0547]

[0548]

[0549] As can be seen from Table 2, the representative compounds of the present invention have good inhibitory effects on the production of 20-HETE by CYP4A11 or CYP4F2.

[0550] 2. Inhibitory effect of 20-HETE in vivo

[0551] The effects of the test compounds on the 20-HETE synthase activity in the kidneys and brains of male mice were detected. Male BALB / c or ICR mice aged 7-8 weeks were randomly divided into several groups and orally administered 50 mg / kg of the compound or the control solvent (10% β-Cyclodextrin and 2% DMSO). Eight hours after administration, the mice were euthanized, and their kidneys and brains were collected to measure the content of 20-HETE. All samples were stored at -80 °C until the concentrations of 20-HETE and the test compounds were quantitatively evaluated.

[0552] The kidney and brain samples were homogenized in methanol four times their weight, which contained 100 μM triphenylphosphine (100:1) and internal standards (250 nM imipramine hydrochloride, 500 nM labetalol hydrochloride, 100 ng / mL dexamethasone). Then all homogenized samples were frozen at 4 °C for 2 hours for sufficient extraction. After centrifugation (4 °C, 4700 rmp, 15 minutes), the supernatant was transferred to a sample plate, diluted with the same volume of ddH2O, and then the concentration of 20-HETE was determined by LC-MS / MS. LC-MS / MS analysis was carried out according to the above method. The content of 20-HETE was expressed as ng / g tissue weight. The lower limit of quantification (LLOQ) of the analysis was 0.2 ng / g.

[0553] Figure 1 and 2 showed the effects of the test compounds on 20-HETE production in the kidneys and brains of mice. All the test compounds significantly reduced 20-HETE production in the kidneys and brains of mice, indicating their potential application value in treating related diseases.

[0554] 3. Mouse Pharmacokinetics Study

[0555] This study aimed to evaluate the pharmacokinetic properties of the compounds in ICR male mice after a single-dose administration. Three mice were required for each compound. The mice were treated with a single 50 mg / kg dose of the compound (orally), and blood samples were collected at 0.5, 1, 2, 4, and 8 hours after dosing. The blood samples were placed on ice until plasma samples were obtained by centrifugation. The plasma samples were stored at -80 °C until analysis. The compound concentrations in the plasma samples were determined by LC-MS / MS method.

[0556] The results are shown in Table 3 below:

[0557] Table 3

[0558]

[0559]

[0560] As can be seen from Table 3, the representative compounds of the present invention have good pharmacokinetic properties.

[0561] It should be understood that if any prior art publications are cited herein, such citation does not constitute an admission that such publication forms part of the common general knowledge in any country.

[0562] The entire disclosures of all publications, patents, patent applications, and published patent applications mentioned herein by means of identifying citations are hereby incorporated herein by reference in their entirety.

[0563] Although the above invention has been described in some detail by way of illustration and example for the purpose of facilitating understanding, it will be apparent to those skilled in the art that certain minor changes and modifications can be made. Therefore, this description and the examples should not be construed as limiting the scope of the present invention.

Claims

1. A compound of formula (I), its stereoisomers, its atropisomers, its pharmaceutically acceptable salts, pharmaceutically acceptable salts of its stereoisomers, pharmaceutically acceptable salts of its isomers, its solvates or pharmaceutically acceptable salts of its solvates: X1 is selected from N or CR1; X2 is selected from N or CR2; X3 is selected from N or CR3; X4 is selected from N or CR4; Y1 is independently selected from none, -C(R Y1A )2-, -C(R Y1A )=C(R Y1A )-, -C≡C-, -O-, -S-, -N(R Y1B ), -C(=O)-, -S(=O)-, -S(=O)2-, -C(=O)O-, -S(=O)O-, -S(=O)2O-, -N(R Y1B )C(=O)-, -N(R Y1B )S(=O)- or -N(R Y1B )S(=O)2-; n Y1 selected from 0, 1, 2, 3, 4, 5 or 6; Each occurrence of Y2 is selected from none, -C(R Y2A )2-, -C(R Y2A )=C(R Y2A )-, -C≡C-, -O-, -S-, -N(R Y2B ), -C(=O)-, -S(=O)-, -S(=O)2-, -C(=O)O-, -S(=O)O-, -S(=O)2O-, -N(R Y2B )C(=O)-, -N(R Y2B )S(=O)- or -N(R Y2B )S(=O)2-; n Y2 selected from 0, 1, 2, 3, 4, 5 or 6; Selected from When is ; X5 is selected from N or CR5; X6 is selected from -C(R 6A )2-, -NR 6B -, -O-, -S-, -C(=O)-, -S(=O)-, -S(=O)2-, -C(=O)-NR 6B -, -C(=O)-NR 6B - C(=O)-, -S(=O)-NR 6B - or -S(=O)2-NR 6B -; n1, n2, n3, n4, n5, n6, n7 and n8 are each independently optionally selected from 0, 1, 2, 3, 4, 5 or 6; Optionally, R5 and (R2 or R4) together with the atoms to which they are respectively attached form ring C; the ring C is selected from 3- to 8-membered carbocyclic rings or 3- to 8-membered heterocyclic rings; the heterocyclic rings optionally further contain 1, 2 or 3 heteroatoms selected from N, O or S; the ring C is independently optionally substituted by n ringC R ringC substituents; When is ; X7 is selected from N or CR7; X8 is selected from N or CR8; X9 is selected from N or CR9; X 10 Selected from -C(R 10A )2-, -NR 10B -, -O-, -S-, -C(=O)-, -S(=O)-, -S(=O)2-, -C(=O)-NR 10B -, -C(=O)-NR 10B - C(=O)-, -S(=O)-NR 10B - or -S(=O)2-NR 10B -; Optionally, R7 and (R2 or R4) together with the atoms to which they are respectively attached form ring D; ring D is selected from 3- to 8-membered carbocyclic rings or 3- to 8-membered heterocyclic rings; the heterocyclic ring optionally further contains 1, 2 or 3 heteroatoms selected from N, O or S; ring D is independently optionally substituted by n ringD R ringD substituents; When is ; X 14 selected from N or CR 14 ; X 15 Selected from -C(R 15A )2-, -NR 15B -, -O-, -S-, -C(=O)-, -S(=O)-, -S(=O)2-, -C(=O)-NR 15B -, -C(=O)-NR 15B - C(=O)-, -S(=O)-NR 15B - or -S(=O)2-NR 15B -; n 17 、n 18 、n 19 and n 20 at each occurrence independently selected from 0, 1, 2, 3, 4, 5 or 6; Optionally, R 14 and (R2 or R4) together with the atoms to which they are respectively attached form ring E; said ring E is selected from 3- to 8-membered carbocyclic rings or 3- to 8-membered heterocyclic rings; said heterocyclic rings optionally further contain 1, 2 or 3 heteroatoms selected from N, O or S; said ring E is independently optionally substituted by n ringE R ringE substituents; When is ; n 25 selected from 0, 1, 2, 3, 4, 5 or 6; n 26 selected from 0, 1, 2, 3, 4, 5 or 6; Optionally, R 17 and R 18 together with the atoms to which they are respectively attached form ring F; said ring F is selected from 3- to 8-membered carbocyclic rings, 3- to 8-membered heterocyclic rings, phenyl rings or 5- to 6-membered heteroaryl rings; said heterocyclic rings contain 1, 2 or 3 heteroatoms selected from N, O or S; said heteroaryl rings may optionally further contain 1, 2 or 3 heteroatoms selected from N, O or S; said ring F is independently optionally substituted by n ringF R ringF substituents; R1, R2, R3, R4, R5, R 6a , R7, R8, R9, R 10a , R 14 , R 17 , R 18 , R 15a , R Y1A or R Y2A is independently selected from hydrogen, halogen, -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -halo-C 1-6 alkyl, -O-CH3, -C 2-6 alkoxy, -CN, -COOH, -NH2, -NH(C 1-6 alkyl), -N(C 1-6 alkyl)2, -OH, -O(C 1-6 alkyl), -SH, -S(C 1-6 alkyl), -C(=O)(C 1-6 alkyl), -S(=O)(C 1-6 alkyl), -S(=O)2(C 1-6 alkyl), -C(=O ) NH2, -C(=O ) NH(C 1-6 alkyl), -C(=O ) N(C 1-6 alkyl)2-NHC(=O)(C 1-6 alkyl), -N(C 1-6 alkyl)C(=O)(C 1-6 alkyl), -C(=O)O(C 1-6 alkyl), -O-C(=O)(C 1-6 alkyl), -S(=O)NH2, -S(=O)NH(C 1-6 alkyl), -S(=O)N(C 1-6 alkyl)2, -NHS(=O)(C 1-6 alkyl), -N(C 1-6 alkyl)S(=O)(C 1-6 alkyl), -S(=O)2NH2, -S(=O)2NH(C 1-6 alkyl), -S ( =O)2N(C 1-6 alkyl)2, -NHS(=O)2(C 1-6 alkyl), -N(C 1-6 alkyl)S(=O)2(C 1-6 alkyl), 3-10-membered carbocyclic group, 3-10-membered heterocyclic group, 6-10-membered aryl group or 5-10-membered heteroaryl group; wherein, The R1, R2, R3, R4, R5, R7, R8, R9, R 6A , R 10A , R 14 , R 15A , R Y1A or R Y2A is independently optionally substituted by one or more substituents selected from halogen, halo-C 1-6 alkyl, -CN, -NH2, -C 1-6 alkyl-C 1-6 alkenyl, -C 1-6 alkynyl, -halo-C 1-6 alkyl, -O-CH3, -C 2-6 alkoxy, -CN, -COOH, -NH2, -NH(C 1-6 alkyl), -N(C 1-6 alkyl)2, -OH, -O(C 1-6 alkyl), -SH, -S(C 1-6 alkyl), -C(=O)(C 1-6 alkyl), -S(=O)2(C 1-6 alkyl), -C(=O)NH2, -C(=O)NH(C 1-6 alkyl), -C(=O)N(C 1-6 alkyl)2, -NHC(=O)(C 1-6 alkyl), -N(C 1-6 alkyl)C(=O)(C 1-6 alkyl), -C(=O)O(C 1-6 alkyl), -O-C(=O)(C 1-6 alkyl), -S(=O)NH2, -S(=O)NH(C 1-6 alkyl), -S(=O)N(C 1-6 alkyl)2, -NHS(=O)(C 1-6 alkyl), -N(C 1-6 alkyl)S(=O)(C 1-6 alkyl), -S(=O)2NH2, -S(=O)2NH(C 1-6 alkyl), -S ( =O)2N(C 1-6 alkyl)2, -NHS(=O)2(C 1-6 alkyl), -N(C 1-6 alkyl)S ( =O)2(C 1-6 alkyl), a 3- to 10-membered carbocyclic group, a 3- to 10-membered heterocyclic group, a 6- to 10-membered aryl group or a 5- to 10-membered heteroaryl group; R 6B 、R 10B 、R 15B 、R Y1B or R Y2B is selected from hydrogen, -C 1-6 alkyl, -C 2-6 alkenyl, -C2-6 alkynyl, -halo-C 1- 6 alkyl, -O-CH3, -C 2-6 alkoxy, -C(=O)(C 1-6 alkyl), -C(=O)NH2, -C(=O)NH(C 1-6 alkyl), -C(=O)N(C 1-6 alkyl)2, -S(=O)(C 1-6 alkyl), -S(=O)2(C 1-6 alkyl), -(C 0-6 alkenyl)-(3-14 membered carbocyclic group), -(C 0-6 alkenyl)-(3-14 membered heterocyclic group), -(C 0-6 alkenyl)-(phenyl) or -(C 0-6 alkenyl)-(5-14 membered heteroaryl); said R 6B 、R 10B 、R 15B 、R Y1B or R Y2B is independently optionally substituted with 1, 2, 3, 4, 5 or 6 substituents selected from the following: halogen, -C (1-6) alkyl, -halo-C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -CN, oxo, -NH2, -NH(C 1-6 alkyl), -N(C 1-6 alkyl)2-OH, -O(C 1-6 alkyl), -O(halo-C 1-6 alkyl), -SH, -S(C 1-6 alkyl), -S(=O)(C 1-6 alkyl), -S(=O)2(C 1-6 alkyl), -C(=O)(C 1-6 alkyl), -C(=O)OH, -C(=O)(OC 1-6 alkyl), -OC ( =O)(C 1-6 alkyl)-C(=O)NH2, -C(=O)NH(C 1-6 alkyl), -C(=O)N(C 1-6 alkyl)2, -NHC(=O)(C 1-6 alkyl), -S(=O)(OC 1-6 (alkyl), -OS(=O)(C 1-6 (alkyl), -S(=O)NH2, -S(=O)NH(C 1-6 (alkyl), -S(=O)N(C 1-6 (alkyl)2, -NHS(=O)(C 1-6 (alkyl), -S(=O)2(OC 1-6 (alkyl), -S(=O)2(OC 1-6 (alkyl), -OS(=O)2(OC 1-6 (alkyl), -S(=O)2NH2, -S ( (=O)2N(C 1-6 (alkyl)2, -NHS(=O)2(C 1-6 (alkyl), a 3- to 10-membered carbocyclic group, a 3- to 10-membered heterocyclic group, a 6- to 10-membered aryl group or a 5- to 10-membered heteroaryl group; Ring A is selected from 3- to 14-membered heterocyclic or 5- to 14-membered heteroaryl rings; the heterocyclic ring may optionally further contain 1, 2, 3, 4, 5 or 6 heteroatoms selected from N, O or S; the heteroaryl ring may optionally further contain 1, 2, 3, 4, 5 or 6 heteroatoms selected from N, O or S; R S1 、R S2 、R S3 、RringC、R ringD 、R ringE or R ringF is selected from halogen, -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 1-6 alkoxy, halo-C 1-6 alkyl, halo-C 1-6 alkoxy, -CN, -NO2, -N3, oxo, -NH2, -NH(C 1-6 alkyl), -N(C 1-6 alkyl)2, -OH, -O(C 1-6 alkyl), -SH, -S(C 1-6 alkyl), -S(=O)(C 1-6 alkyl), -S(=O)2(C 1-6 alkyl), -C(=O)(C 1-6 alkyl), -C(=O)NH2, -C(=O)NH(C 1-6 alkyl), -C(=O)N(C 1-6 alkyl)2, -NHC(=O)(C 1-6 alkyl), --N(C 1-6 alkyl)C(=O)(C 1-6 alkyl), -OC(=O)O(C 1-6 alkyl), -NHC(=O)(OC 1-6 alkyl), -N(C 1-6 alkyl)C(=O)(OC 1-6 alkyl), -OC(=O)NH(C 1-6 alkyl), -OC(=O)N(C 1-6 alkyl)2, -NHC(=O ) NH2, -NHC(=O)N(C 1-6 alkyl), -N(C 1-6 alkyl alkyl)C(=O)NH2, -N(C 1-6 alkyl)C(=O)NH(C 1-6 alkyl), -N(C 1-6 alkyl)C(=O)N(C 1-6 alkyl)2, -S(=O)(OC 1-6 alkyl), -OS(=O)(C 1-6 alkyl), -S(=O)NH2, -S(=O)NH(C 1-6 alkyl), -S(=O)N(C 1-6 alkyl)2, -NHS(=O)(C 1-6 alkyl), -N(C 1-6 alkyl)S(=O)(C 1-6 alkyl), -S(=O)2(OC 1-6 alkyl), -OS(=O)2(C 1-6 alkyl), -S(=O)2NH2, -S(=O)2NH(C 1-6 alkyl), -S(=O)2N(C 1-6 alkyl)2, -NHS(=O)2(C 1-6 alkyl), -N(C 1-6 alkyl)S(=O)2(C 1-6 alkyl), -OS(=O)2O(C 1-6 alkyl), -NHS(=O)2O(C 1-6 alkyl), -N(C 1-6 alkyl ) S(=O)2O(C 1-6 alkyl), -OS(=O)2NH2, -OS(=O)2NH(C 1-6 alkyl), -OS(=O)2N(C 1-6 alkyl)2, -NHS(=O)2NH2, -NHS(=O)2NH(C 1-6 alkyl), -NHS(=O)2N(C 1-6 alkyl)2, -N(C 1-6 alkyl)S(=O)2NH2, -N(C 1-6 alkyl)S(=O)2NH(C 1-6 alkyl), -N(C 1-6 alkyl)S(=O )2 N(C 1-6 alkyl)2, -PH(C 1-6 alkylalkyl), -P(C 1-6 alkyl)2, -P(=O)H(C 1-6 alkylalkyl), -P(=O)(C 1-6 alkyl)2, 3-7 membered carbocyclic group, 3-7 membered heterocyclic group, 6-10 aryl or 5-10 membered heteroaryl; n S1 、n S2 、n S3 、n ringC 、n ringD 、n ringE and n ringF are each independently selected from 0, 1, 2, 3, 4, 5 or 6 in each instance; Each heterocyclic group independently contains 1, 2, 3, 4, 5 or 6 heteroatoms selected from N, O or S each time it appears; Each heteroaryl group independently contains 1, 2, 3, 4, 5 or 6 heteroatoms selected from N, O or S each time it appears.

2. The compound of formula (I), its stereoisomers, its atropisomers, its pharmaceutically acceptable salts, pharmaceutically acceptable salts of its stereoisomers, pharmaceutically acceptable salts of its isomers, its solvates or pharmaceutically acceptable salts of its solvates according to claim 1, characterized in that, It satisfies one or more of the following conditions: (1) Each occurrence of R1, R2, R3, R4 or R5 is independently selected from -H, -Cl, -F, -Br, -I, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, oxo, -CN, -NH2, -NH(CH3), -NH(CH2CH3), -NH(CH2CH2CH3), -NH(CH(CH3)2), -N(CH3)2, -OH, -O-CH3, -O-CH2CH3, -O-CH2CH2CH3, -O-CH(CH3)2, -SH, -S-CH3, -S-CH2CH3, -S-CH2CH2CH3, -S-CH(CH3)2, -C(=O)CH3, -C(=O)(CH2CH3), -C(=O)(CH2CH2CH3), -C(=O)(CH(CH3)2), -S(=O)CH3, -S(=O)(CH2CH3), -S(=O)(CH2CH2CH3), -S(=O)(CH(CH3)2), -S(=O)2CH3, -S(=O)2(CH2CH3), -S(=O)2(CH2CH2CH3), -S(=O)2(CH(CH3)2), -COOH, -C(=O)NH2, -C(=O)NH(CH3), -C(=O)NH(CH2CH3), -C(=O)NH(CH2CH2CH3), -C(=O)NH(CH(CH3)2), -C(=O)N(CH3)2, -S(=O)2NH2, -S(=O)2NH(CH3), -S(=O)2NH(CH2CH3), -S(=O)2NH(CH2CH2CH3), -S(=O)2NH(CH(CH3)2), -S(=O)2N(CH3)2, -cyclopropyl, -cyclobutyl, -cyclopentyl or -cyclohexyl; wherein said R1, R2, R3, R4 or R5 is independently optionally substituted by 1, 2 or 3 substituents selected from: -Cl, -F, -Br, -I, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CN, oxo, -NH2, -NH(CH3), -NH(CH2CH3), -NH(CH2CH2CH3), -NH(CH(CH3)2), -N(CH3)2, -OH, -O-CH3, -O-CH2CH3, -O-CH2CH2CH3, -O-CH(CH3)2, -SH, -S-CH3, -S-CH2CH3, -S-CH2CH2CH3 or -S-CH(CH3)2; Preferably, R1, R2, R3, R4 or R5 is selected from -H; (2) Each occurrence of R Y1A and R Y1B are independently selected from -H, -Cl, -F, -Br, -I, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, oxo, -CN, -NH2, -NH(CH3), -NH(CH2CH3), -NH(CH2CH2CH3), -NH(CH(CH3)2), -N(CH3)2, -OH, -O-CH3, -O-CH2CH3, -O-CH2CH2CH3, -O-CH(CH3)2, -SH, -S-CH3, -S-CH2CH3, -S-CH2CH2CH3, -S-CH(CH3)2, -C(=O)CH3, -C(=O)(CH2CH3), -C(=O)(CH2CH2CH3), -C(=O)(CH(CH3)2), -S(=O)CH3, -S(=O)(CH2CH3), -S(=O)(CH2CH2CH3), -S(=O)(CH(CH3)2), -S(=O)2CH3, -S(=O)2(CH2CH3), -S(=O)2(CH2CH2CH3), -S(=O)2(CH(CH3)2), -COOH, -C(=O)NH2, -C(=O)NH(CH3), -C(=O)NH(CH2CH3), -C(=O)NH(CH2CH2CH3), -C(=O)NH(CH(CH3)2), -C(=O)N(CH3)2, -S(=O)2NH2, -S(=O)2NH(CH3), -S(=O)2NH(CH2CH3), -S(=O)2NH(CH2CH2CH3), -S(=O)2NH(CH(CH3)2), -S(=O)2N(CH3)2, -cyclopropyl, -cyclobutyl, -cyclopentyl or -cyclohexyl; wherein said R Y1A is independently optionally substituted by 1, 2 or 3 substituents selected from: -Cl, -F, -Br, -I, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CN, oxo, -NH2, -NH(CH3), -NH(CH2CH3), -NH(CH2CH2CH3), -NH(CH(CH3)2), -N(CH3)2, -OH, -O-CH3, -O-CH2CH3, -O-CH2CH2CH3, -O-CH(CH3)2, -SH, -S-CH3, -S-CH2CH3, -S-CH2CH2CH3 or -S-CH(CH3)2; (3) Each occurrence of R Y2B and R Y2B is independently selected from -H, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -C(=O)(CH3), -C(=O)(CH2CH3), -C(=O)(CH2CH2CH3), -C(=O)(CH(CH3)2), -S(=O)CH3, -S(=O)(CH2CH3), -S(=O)(CH2CH2CH3), -S(=O)(CH(CH3)2), -S(=O)2CH3, -S(=O)2(CH2CH3), -S(=O)2(CH2CH2CH3), -S(=O)2(CH(CH3)2), cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; Preferably, each occurrence of R Y2B and R Y2B is selected from -H or -CH3; (4) Each occurrence of R 6A is independently selected from -H, -Cl, -F, -Br, -I, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, oxo, -CN, -NH2, -NH(CH3), -NH(CH2CH3), -NH(CH2CH2CH3), -NH(CH(CH3)2), -N(CH3)2, -OH, -O-CH3, -O-CH2CH3, -O-CH2CH2CH3, -O-CH(CH3)2, -SH, -S-CH3, -S-CH2CH3, -S-CH2CH2CH3, -S-CH(CH3)2, -C(=O)CH3, -C(=O)(CH2CH3), -C(=O)(CH2CH2CH3), -C(=O)(CH(CH3)2), -S(=O)CH3, -S(=O)(CH2CH3), -S(=O)(CH2CH2CH3), -S(=O)(CH(CH3)2), -S(=O)2CH3, -S(=O)2(CH2CH3), -S(=O)2(CH2CH2CH3), -S(=O)2(CH(CH3)2), -COOH, -C(=O)NH2, -C(=O)NH(CH3), -C(=O)NH(CH2CH3), -C(=O)NH(CH2CH2CH3), -C(=O)NH(CH(CH3)2), -C(=O)N(CH3)2, -S(=O)2NH2, -S(=O)2NH(CH3), -S(=O)2NH(CH2CH3), -S(=O)2NH(CH2CH2CH3), -S(=O)2NH(CH(CH3)2), -S(=O)2N(CH3)2, -cyclopropyl, -cyclobutyl, -cyclopentyl or -cyclohexyl; wherein R 6A is independently optionally substituted with 1, 2 or 3 substituents selected from: -Cl, -F, -Br, -I, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CN, oxo, -NH2, -NH(CH3), -NH(CH2CH3), -NH(CH2CH2CH3), -NH(CH(CH3)2), -N(CH3)2, -OH, -O-CH3, -O-CH2CH3, -O-CH2CH2CH3, -O-CH(CH3)2, -SH, -S-CH3, -S-CH2CH3, -S-CH2CH2CH3 or -S-CH(CH3)2; Preferably, each occurrence of R 6A is independently selected from -H; (5) Each occurrence of R 6B is independently selected from -H, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -C(=O)(CH3), -C(=O)(CH2CH3), -C(=O)(CH2CH2CH3), -C(=O)(CH(CH3)2), -S(=O)CH3, -S(=O)(CH2CH3), -S(=O)(CH2CH2CH3), -S(=O)(CH(CH3)2), -S(=O)2CH3, -S(=O)2(CH2CH3), -S(=O)2(CH2CH2CH3), -S(=O)2(CH(CH3)2), cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl or benzofuranyl; said R 6B is independently optionally substituted with 1, 2 or 3 substituents selected from: -Cl, -F, -Br, -I, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CHFCH3, -CF2CH3, -CN, oxo, -NH2, -NH(CH3), -NH(CH2CH3), -NH(CH2CH2CH3), -NH(CH(CH3)2), -N(CH3)2, -OH, -O-CH3, -O-CH2CH3, -O-CH2CH2CH3, -O-CH(CH3)2, -O-CH2F, -O-CHF2, -O-CF3, -O-CH2CH2F, -O-CH2CHF2, -O-CH2CF3, -O-CHFCH3, -O-CF2CH3, -OH, -S-CH3, -S-CH2CH3, -S-CH2CH2CH3 or -S-CH(CH3)2; Preferably, R 6B is selected from -CH3 or -C(=O)CH3; (6) Each occurrence of ring C, ring D, and ring E is independently selected from 4- to 7-membered carbocyclic rings or 4- to 7-membered heterocyclic rings; said heterocyclic rings may optionally further contain 1, 2, or 3 heteroatoms selected from N, O, or S; said rings C, D, and E are independently optionally substituted with 1, 2, 3, 4, 5, or 6 R ringC , R ringD or R ringE substituents; Preferably, each occurrence of ring C, ring D and ring E is independently selected from tetrahydro-2H-pyran ring; (7) Each occurrence of R7, R8, and R9 is independently selected from -H, -Cl, -F, -Br, -I, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, oxo, -CN, -NH2, -NH(CH3), -NH(CH2CH3), -NH(CH2CH2CH3), -NH(CH(CH3)2), -N(CH3)2, -OH, -O-CH3, -O-CH2CH3, -O-CH2CH2CH3, -O-CH(CH3)2, -SH, -S-CH3, -S-CH2CH3, -S-CH2CH2CH3, -S-CH(CH3)2, -C(=O)CH3, -C(=O)(CH2CH3), -C(=O)(CH2CH2CH3), -C(=O)(CH(CH3)2), -S(=O)CH3, -S(=O)(CH2CH3), -S(=O)(CH2CH2CH3), -S(=O)(CH(CH3)2), -S(=O)2CH3, -S(=O)2(CH2CH3), -S(=O)2(CH2CH2CH3), -S(=O)2(CH(CH3)2), -COOH, -C(=O)NH2, -C(=O)NH(CH3), -C(=O)NH(CH2CH3), -C(=O)NH(CH2CH2CH3), -C(=O)NH(CH(CH3)2), -C(=O)N(CH3)2, -S(=O)2NH2, -S(=O)2NH(CH3), -S(=O)2NH(CH2CH3), -S(=O)2NH(CH2CH2CH3), -S(=O)2NH(CH(CH3)2), -S(=O)2N(CH3)2, -cyclopropyl, -cyclobutyl, -cyclopentyl or -cyclohexyl; wherein said R7 is independently optionally substituted by 1, 2 or 3 substituents selected from: -Cl, -F, -Br, -I, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CN, oxo, -NH2, -NH(CH3), -NH(CH2CH3), -NH(CH2CH2CH3), -NH(CH(CH3)2), -N(CH3)2, -OH, -O-CH3, -O-CH2CH3, -O-CH2CH2CH3, -O-CH(CH3)2, -SH, -S-CH3, -S-CH2CH3, -S-CH2CH2CH3 or -S-CH(CH3)2; Preferably, each occurrence of R7 is independently selected from -H; (8) Each occurrence of R 10B is independently selected from -H, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -C(=O)(CH3), -C(=O)(CH2CH3), -C(=O)(CH2CH2CH3), -C(=O)(CH(CH3)2), -S(=O)CH3, -S(=O)(CH2CH3), -S(=O)(CH2CH2CH3), -S(=O)(CH(CH3)2), -S(=O)2CH3, -S(=O)2(CH2CH3), -S(=O)2(CH2CH2CH3), -S(=O)2(CH(CH3)2), -(CH2) 0-2 -(cyclopropyl), -(CH2) 0-2 -(cyclobutyl), -(CH2) 0-2 -(cyclopentyl), -(CH2) 0-2 -(cyclohexyl), -(CH2)0-2-(phenyl), -(CH2) 0-2 -(pyrrolyl), -(CH2) 0-2 -(furyl), -(CH2) 0-2 -(thienyl)-(CH2) 0-2 -(imidazolyl), -(CH2) 0-2 -(oxazolyl), -(CH2) 0-2 -(isoxazolyl), -(CH2) 0-2 -(thiazolyl), -(CH2) 0-2 -(isothiazolyl), -(CH2) 0-2 -(pyrazolyl), -(CH2) 0-2 -(pyridyl), -(CH2) 0-2 -(pyrimidinyl), -(CH2) 0-2 -(pyrazinyl), -(CH2) 0-2 -(indolyl), -(CH2) 0-2 -(isoindolyl) or -(CH2) 0-2 -(benzofuryl); said R 10B Independently optionally substituted with 1, 2 or 3 substituents selected from the following: -Cl, -F, -Br, -I, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CHFCH3, -CF2CH3, -CN, oxo, -NH2, -NH(CH3), -NH(CH2CH3), -NH(CH2CH2CH3), -NH(CH(CH3)2), -N(CH3)2, -OH, -O-CH3, -O-CH2CH3, -O-CH2CH2CH3, -O-CH(CH3)2, -O-CH2F, -O-CHF2, -O-CF3, -O-CH2CH2F, -O-CH2CHF2, -O-CH2CF3, -O-CHFCH3, -O-CF2CH3, -OH, -S-CH3, -S-CH2CH3, -S-CH2CH2CH3 or -S-CH(CH3)2; Preferably, each occurrence of R 10B is independently selected from -C(=O)(CH3), -C(=O)(CH2CH3), -S(=O)2CH3, phenyl or -CH2-phenyl; (9) Each occurrence of R 14 is independently selected from -H, -Cl, -F, -Br, -I, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, oxo, -CN, -NH2, -NH(CH3), -NH(CH2CH3), -NH(CH2CH2CH3), -NH(CH(CH3)2), -N(CH3)2, -OH, -O-CH3, -O-CH2CH3, -O-CH2CH2CH3, -O-CH(CH3)2, -SH, -S-CH3, -S-CH2CH3, -S-CH2CH2CH3, -S-CH(CH3)2, -C(=O)CH3, -C(=O)(CH2CH3), -C(=O)(CH2CH2CH3), -C(=O)(CH(CH3)2), -S(=O)CH3, -S(=O)(CH2CH3), -S(=O)(CH2CH2CH3), -S(=O)(CH(CH3)2), -S(=O)2CH3, -S(=O)2(CH2CH3), -S(=O)2(CH2CH2CH3), -S(=O)2(CH(CH3)2), -COOH, -C(=O)NH2, -C(=O)NH(CH3), -C(=O)NH(CH2CH3), -C(=O)NH(CH2CH2CH3), -C(=O)NH(CH(CH3)2), -C(=O)N(CH3)2, -S(=O)2NH2, -S(=O)2NH(CH3), -S(=O)2NH(CH2CH3), -S(=O)2NH(CH2CH2CH3), -S(=O)2NH(CH(CH3)2), -S(=O)2N(CH3)2, -cyclopropyl, -cyclobutyl, -cyclopentyl or -cyclohexyl; Preferably, each occurrence of R 14 is selected from -H; (10) Each occurrence of R 15B is independently selected from -H, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -C(=O)(CH3), -C(=O)(CH2CH3), -C(=O)(CH2CH2CH3), -C(=O)(CH(CH3)2), -S(=O)CH3, -S(=O)(CH2CH3), -S(=O)(CH2CH2CH3), -S(=O)(CH(CH3)2), -S(=O)2CH3, -S(=O)2(CH2CH3), -S(=O)2(CH2CH2CH3), -S(=O)2(CH(CH3)2), cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl or benzofuranyl; said R 15B is independently optionally substituted by 1, 2 or 3 substituents selected from: -Cl, -F, -Br, -I, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CHFCH3, -CF2CH3, -CN, oxo, -NH2, -NH(CH3), -NH(CH2CH3), -NH(CH2CH2CH3), -NH(CH(CH3)2), -N(CH3)2, -OH, -O-CH3, -O-CH2CH3, -O-CH2CH2CH3, -O-CH(CH3)2, -O-CH2F, -O-CHF2, -O-CF3, -O-CH2CH2F, -O-CH2CHF2, -O-CH2CF3, -O-CHFCH3, -O-CF2CH3, -OH, -S-CH3, -S-CH2CH3, -S-CH2CH2CH3 or -S-CH(CH3)2; Preferably, each occurrence of R 15B is independently selected from -CH3 or -C(=O)CH3; (11) Each occurrence of R 17 and R 18 are independently selected from -H, -Cl, -F, -Br, -I, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, oxo, -CN, -NH2, -NH(CH3), -NH(CH2CH3), -NH(CH2CH2CH3), -NH(CH(CH3)2), -N(CH3)2, -OH, -O-CH3, -O-CH2CH3, -O-CH2CH2CH3, -O-CH(CH3)2, -SH, -S-CH3, -S-CH2CH3, -S-CH2CH2CH3, -S-CH(CH3)2, -C(=O)CH3, -C(=O)(CH2CH3), -C(=O)(CH2CH2CH3), -C(=O)(CH(CH3)2), -S(=O)CH3, -S(=O)(CH2CH3), -S(=O)(CH2CH2CH3), -S(=O)(CH(CH3)2), -S(=O)2CH3, -S(=O)2(CH2CH3), -S(=O)2(CH2CH2CH3), -S(=O)2(CH(CH3)2), -COOH, -C(=O)NH2, -C(=O)NH(CH3), -C(=O)NH(CH2CH3), -C(=O)NH(CH2CH2CH3), -C(=O)NH(CH(CH3)2), -C(=O)N(CH3)2, -S(=O)2NH2, -S(=O)2NH(CH3), -S(=O)2NH(CH2CH3), -S(=O)2NH(CH2CH2CH3), -S(=O)2NH(CH(CH3)2), -S(=O)2N(CH3)2, -cyclopropyl, -cyclobutyl, -cyclopentyl or -cyclohexyl; wherein said R 17 or R 18 is independently optionally substituted with 1, 2 or 3 substituents selected from: -Cl, -F, -Br, -I, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CN, oxo, -NH2, -NH(CH3), -NH(CH2CH3), -NH(CH2CH2CH3), -NH(CH(CH3)2), -N(CH3)2, -OH, -O-CH3, -O-CH2CH3, -O-CH2CH2CH3, -O-CH(CH3)2, -SH, -S-CH3, -S-CH2CH3, -S-CH2CH2CH3 or -S-CH(CH3)2; Preferably, each occurrence of R 17 and R 18 is independently selected from -H; (12) Each occurrence of ring F is selected from a phenyl ring or a 5- or 6-membered heteroaryl ring; said ring F is independently optionally substituted with 1, 2, 3, 4, 5 or 6 Rs ringF ; said heteroaryl ring is optionally further comprised of 1, 2 or 3 heteroatoms selected from N, O or S; Preferably, each occurrence of ring F is selected from benzene rings; and, (13) each occurrence of ring A is selected from a 5- to 6-membered monocyclic heteroaromatic ring or a 9- to 10-membered bicyclic heteroaromatic ring, and the number of heteroatoms is 1, 2 or 3; Preferably, each occurrence of ring A is 1H-pyrazolyl or 1H-indazolyl.

3. The compound of formula (I), its stereoisomers, its atropisomers, its pharmaceutically acceptable salts, pharmaceutically acceptable salts of its stereoisomers, pharmaceutically acceptable salts of its isomers, its solvates or pharmaceutically acceptable salts of its solvates according to claim 1, characterized in that, It satisfies one or more of the following conditions: (1) Selected from: Preferably, more preferably selected from *Indicates Attachment point of the molecule; (2)-(Y1) n1 - wherein, Y1 is selected from none, -C(=O)N(R Y1B )-, -N(R Y1B )C(=O)-**,** -N(R Y1B )C(=O)-, -C(R Y1A )=C(R Y1A )-, or -C≡C-, n1 is 0 or 1; preferably, -(Y1)n1- is selected from none, -C(=O)NH- or -C≡C-; ** represents the attachment point of the molecule; (3)n Y1 selected from 0, 1 or 2; preferably, n Y1 is selected from 0 or 1; (4) selected from X 11 or X 12 selected from C, H or N; X 13 selected from O or S; R7 is selected from H or -C 1-6 alkyl; (5)-(Y2) n2 - wherein, Y2 is selected from nothing, -C(R Y2A )2-, -O-, -S- or -N(R Y2B ), n Y2 is selected from 0 or 1; Preferably, -(Y2) n2 - is selected from none, -CH2-, -O-, -S- or -NH-; more preferably none or -O-; (6)n Y12 selected from 0, 1 or 2; preferably, n Y12 is selected from 0 or 1; (7) selected from Preferably selected from (8) Selected from Preferably selected from and, (9) selected from Preferably selected from 4. The compound of formula (I), its stereoisomers, its atropisomers, its pharmaceutically acceptable salts, pharmaceutically acceptable salts of its stereoisomers, pharmaceutically acceptable salts of its isomers, its solvates or pharmaceutically acceptable salts of its solvates according to claim 1, characterized in that, It satisfies one or more of the following conditions: Selected from (2) selected from 5. The compound of formula (I) as described in any one of claims 1-4, its stereoisomers, its atropisomers, its pharmaceutically acceptable salts, the pharmaceutically acceptable salts of its stereoisomers, the pharmaceutically acceptable salts of its isomers, its solvates or its solvates pharmaceutically acceptable salts thereof, characterized in that, The general formula of the compound of formula (I) is formula (II), (II-1), formula (II-1A), formula (II-1B), formula (II-1C), formula (II-1D), formula (II-2), formula (II-2A), formula (II-2B), formula (II-2A-1) or formula (II-2B-1): In formula (II), X5 is selected from N or CR5; Optionally, R5 and (R2 or R4) together with the atoms to which they are respectively attached form ring C; the ring C is selected from 4- to 7-membered carbocyclic rings or 4- to 7-membered heterocyclic rings; the heterocyclic rings optionally further contain 1, 2 or 3 heteroatoms selected from N, O or S; the ring C is independently optionally substituted by 1, 2, 3, 4, 5 or 6 R ringC substituted; In Formula (II), Formula (II-1), Formula (II-1A), Formula (II-1B), Formula (II-2), Formula (II-2A), Formula (II-2B), Formula (II-2A-1) and Formula (II-2B-1), n 21 is selected from 0, 1, 2 or 3; n 22 is selected from 0, 1, 2 or 3.

6. The compound of formula (I), its stereoisomers, its atropisomers, its pharmaceutically acceptable salts, pharmaceutically acceptable salts of its stereoisomers, pharmaceutically acceptable salts of its isomers, its solvates or pharmaceutically acceptable salts of its solvates according to claim 5, characterized in that, It satisfies one or more of the following conditions: (1) In formula (II), formula (II-1), formula (II-1A) or formula (II-1B), X5 is selected from N or CR5, preferably N or CH; (2) In formula (II-1) and formula (II-2), X5 is selected from CR5; Preferably, X5 is selected from CH; (3) In formula (II), formula (II-2), formula (II-2A) and formula (II-2B), each occurrence of Y2 is selected from none, -CH2-, -O-, -S- or -NH; preferably, each occurrence of Y2 is selected from none or -O-; (4) The compound of formula (II) is selected from (II-1), formula (II-1A), formula (II-1B), (II-2), (II-2A), (II-2B), (II-2A-1) and (II-2B-1): X6 is selected from -C(R 6A )2-, -O-, -S-, -NR 6B -, -S(=O)2-, -C(=O)-NR 6B - or -C(=O)-NR 6B -C(=O)-; R 6B is selected from -C(=O)(C 1-3 alkyl), -S(=O)(C 1-3 alkyl) or -S(=O)2(C 1-3 alkyl); Preferably, in formula (II), formula (II-1), formula (II-1A), formula (II-1B), formula (II-2), formula (II-2A), formula (II-2B), formula (II-2A-1) and formula (II-2B-1), X6 is selected from -CH2-, -O-, -S-, -S(=O)2-, -C(=O)-N(CH3)- or -C(=O)-N(CH3)-C(=O)-; And, (5) In formula (II), (II-1), formula (II-1A), formula (II-1B), formula (II-2), formula (II-2A) and formula (II-2B): n1 to n8 are the following combinations: n1 is 1, n2 is 1, n3 is 1, n4 is 1, n5 is 1, n6 is 1, n7 is 1, n8 is 1; or n1 is 1, n2 is 0, n3 is 1, n4 is 1, n5 is 1, n6 is 1, n7 is 1, n8 is 1; or n1 is 1, n2 is 0, n3 is 1, n4 is 0, n5 is 1, n6 is 1, n7 is 1, n8 is 1; or n1 is 1, n2 is 1, n3 is 1, n4 is 1, n5 is 1, n6 is 0, n7 is 1, n8 is 0; or n1 is 1, n2 is 0, n3 is 1, n4 is 1, n5 is 1, n6 is 0, n7 is 1, n8 is 1; or n1 is 1, n2 is 0, n3 is 1, n4 is 0, n5 is 1, n6 is 0, n7 is 1, n8 is 0; or n1 is 1, n2 is 1, n3 is 1, n4 is 1, n5 is 1, n6 is 1, n7 is 0, n8 is 0; or n1 is 1, n2 is 0, n3 is 1, n4 is 1, n5 is 1, n6 is 0, n7 is 1, n8 is 0; or n1 is 1, n2 is 0, n3 is 1, n4 is 0, n5 is 1, n6 is 1, n7 is 1, n8 is 0; or n1 is 1, n2 is 1, n3 is 1, n4 is 1, n5 is 1, n6 is 0, n7 is 1, n8 is 1; or n1 is 2, n2 is 1, n3 is 1, n4 is 0, n5 is 0, n6 is 0, n7 is 1, n8 is 1; or n1 is 2, n2 is 1, n3 is 1, n4 is 0, n5 is 0, n6 is 0, n7 is 1, n8 is 0; or n1 is 1, n2 is 1, n3 is 1, n4 is 1, n5 is 1, n6 is 0, n7 is 1, n8 is 0; or n1 is 1, n2 is 1, n3 is 1, n4 is 1, n5 is 2, n6 is 1, n7 is 0, n8 is 0; or n1 is 1, n2 is 1, n3 is 1, n4 is 1, n5 is 0, n6 is 0, n7 is 1, n8 is 0; or n1 is 1, n2 is 0, n3 is 1, n4 is 1, n5 is 1, n6 is 0, n7 is 1, n8 is 0; or n1 is 1, n2 is 0, n3 is 1, n4 is 0, n5 is 1, n6 is 0, n7 is 1, n8 is 0.

7. The compound of formula (I), its stereoisomers, its atropisomers, its pharmaceutically acceptable salts, pharmaceutically acceptable salts of its stereoisomers, pharmaceutically acceptable salts of its isomers, its solvates or pharmaceutically acceptable salts of its solvates, as described in any one of claims 1-4, characterized in that, The general formula of the compound of formula (I) is formula (III), formula (III-1), formula (III-1A), formula (III-1B), formula (III-1A-1), formula (III-1B-1), formula (III-1A-2) or formula (III-1B-2); 8. The compound of formula (I), its stereoisomers, its atropisomers, its pharmaceutically acceptable salts, pharmaceutically acceptable salts of its stereoisomers, pharmaceutically acceptable salts of its isomers, its solvates or pharmaceutically acceptable salts of its solvates according to claim 7, characterized in that, It satisfies one or more of the following conditions: (1) In formula (III), formula (III-1), formula (III-1A) and formula (III-1B), X 10 is selected from -C(R 10A )2-, -NR 10B -, -O-, -S-, -C(=O)-, -S(=O)-, -S(=O)2-, -C(=O)-NR 10B -, -C(=O)-NR 10B -C(=O)-, -S(=O)-NR 10B - or -S(=O)2-NR 10B ; Preferably, X 10 is selected from -CH2-, -C(=O)-N(CH3)-, -C(=O)-N(CH2CH3)-, -N(-S(=O)2CH3)-, -N(phenyl)- or -N(CH2phenyl)-; (2) In formula (III), formula (III-1), formula (III-1A) and formula (III-1B), X9 is selected from N or CR7; Preferably, X9 is selected from CH; (3) In formula (III), formula (III-1), formula (III-1A) and formula (III-1B), X8 is selected from N or CR8; Preferably, X8 is selected from N or CH; (4) In formula (III), formula (III-1), formula (III-1A) and formula (III-1B), X7 is selected from N or CR7; Preferably, X7 is selected from N or CH; and, in formula (III), formula (III-1), formula (III-1A), formula (III-1B), formula (III-1A-1) and formula (III-1B-1), n9 to n 15 is any one of the following combinations: n9 is 1, n 10 is 0, n 11 is 1, n 12 is 0, n 13 is 1, n 14 is 0, n 15 is 1, n 16 is 0; or n9 is 1, n 10 is 1, n 11 is 1, n 12 is 0, n 13 is 1, n 14 is 0, n 15 is 1, n 16 is 0; or n9 is 1, n 10 is 0, n 11 is 1, n 12 is 0, n 13 is 1, n 14 is 1, n 15 is 1, n 16 is 0; or n9 is 1, n 10 is 1, n 11 is 1, n 12 is 0, n 13 is 1, n 14 is 1, n 15 is 1, n 16 is 0; or n9 is 1, n 10 is 1, n 11 is 1, n 12 is 1, n 13 is 1, n 14 is 0, n 15 is 1, n 16 is 0; or n9 is 1, n 10 is 0, n 11 is 1, n 12 is 0, n 13 is 1, n 14 is 1, n 15 is 1, n 16 is 1; or n9 is 1, n 10 is 1, n 11 is 1, n 12 is 1, n 13 is 1, n 14 is 1, n 15 is 1, n 16 is 0; or n9 is 1, n 10 is 1, n 11 is 1, n 12 is 0, n 13 is 1, n 14 is 1, n 15 is 1, n 16 is 1; or n9 is 1, n 10 is 1, n 11 is 1, n 12 is 0, n 13 is 1, n 14 is 1, n 15 is 1, n 16 is 1; or n9 is 1, n 10 is 1, n 11 is 1, n 12 is 1, n 13 is 1, n 14 is 1, n 15 is 1, n 16 is 1; or n9 is 1, n 10 is 2, n 11 is 2, n 12 is 0, n 13 is 1, n 14 is 0, n 15 is 1, n 16 is 0; or n9 is 1, n 10 is 0, n 11 is 1, n 12 is 0, n 13 is 1, n 14 is 2, n 15 is 2, n 16 is 0; or n9 is 1, n 10 is 2, n 11 is 2, n 12 is 0, n 13 is 1, n 14 is 1, n 15 is 1, n 16 is 0; or n9 is 1, n 10 is 1, n 11 is 1, n 12 is 0, n 13 is 1, n 14 is 2, n 15 is 2, n 16 is 0; or n9 is 1, n 10 is 2, n 11 2, n 12 is 0, n 13 is 1, n 14 is 1, n 15 is 1, n 16 is 1; or n9 is 1, n 10 is 1, n 11 is 1, n 12 is 1, n 13 is 1, n 14 is 2, n 15 is 2, n 16 is 0.

9. The compound of formula (I), its stereoisomers, its atropisomers, its pharmaceutically acceptable salts, pharmaceutically acceptable salts of its stereoisomers, pharmaceutically acceptable salts of its isomers, its solvates or pharmaceutically acceptable salts of its solvates according to any one of claims 1-4, characterized in that, The general formula of the compound of formula (I) is formula (IV), formula (IV-1), (IV-1A), formula (IV-1B), (IV-1A-1), formula (IV-1B-1), formula (IV-2), (IV-2A), formula (IV-2B), (IV-2A-1) or formula (IV-2B-1): In formula (IV), X 14 is selected from N or CR 14 ; Optionally, R 14 and (R2 or R4) together with the atoms to which they are respectively attached form ring E; said ring E is selected from 4- to 7-membered carbocyclic rings or 4- to 7-membered heterocyclic rings; said heterocyclic ring optionally further contains 1, 2 or 3 heteroatoms selected from N, O or S; said ring E is independently optionally substituted by 1, 2, 3, 4, 5 or 6 R ringE substituents; In formula (IV-2), (IV-2A), formula (IV-2B), (IV-2A-1) and formula (IV-2B-1), n 23 is selected from 0, 1, 2 or 3; n 24 is selected from 0, 1, 2 or 3.

10. The compound of formula (I), its stereoisomers, its atropisomers, its pharmaceutically acceptable salts, pharmaceutically acceptable salts of its stereoisomers, pharmaceutically acceptable salts of its isomers, its solvates or pharmaceutically acceptable salts of its solvates according to claim 9, characterized in that, It satisfies one or more of the following conditions: (1) In formula (IV), formula (IV-1), formula (IV-1A), formula (IV-1B), formula (IV-1A-1) and formula (IV-1B-1), X 14 is selected from N or CR 14 ; preferably, X 14 is selected from N or CH; (2) In formula (IV), formula (IV-1), formula (IV-1A), formula (IV-1B), formula (IV-1A-1), formula (IV-1B-1), formula (IV-2), formula (IV-2A), formula (IV-2B), formula (IV-2A-1) and formula (IV-2B-1), X 15 is selected from -O-, -S- or -NR 15B -; preferably R 15B is selected from -CH3 or -C(=O)(CH3); (3) In formula (IV), formula (IV-1), (IV-1A), formula (IV-1B), (IV-1A-1), formula (IV-1B-1), formula (IV-2), (IV-2A), formula (IV-2B), (IV-2A-1) and formula (IV-2B-1), n 17 to n 20 is any one of the following combinations: n 17 is 1, n 18 is 0, n 19 is 1, n 20 is 0; or n 17 is 1, n 18 is 1, n 19 is 1, n 20 is 1; or n 17 is 1, n 18 is 0, n 19 is 1, n 20 is 1; or n 17 is 1, n 18 is 1, n 19 is 1, n 20 is 0; or n 17 is 2, n 18 is 1, n 19 is 1, n 20 is 1; or n 17 is 1, n 18 is 1, n 19 is 2, n 20 is 1; or n 17 is 2, n 18 is 1, n 19 is 1, n 20 is 0; or n 17 is 1, n 18 is 0, n 19 is 2, n 20 is 1; or n 17 is 1, n 18 is 1, n 19 is 0, n 20 is 0; or n 17 is 0, n 18 is 0, n 19 is 1, n 20 is 1; and, in formula (IV-2), formula (IV-2A), formula (IV-2B), formula (IV-2A-1) and formula (IV-2B-1), n 23 to n 24 is any one of the following combinations: n 23 is 0, n 24 is 0; or n 23 is 1, n 24 is 0; or n 23 is 1, n 24 is 1; or n 23 is 1, n 24 is 2.

11. The compound of formula (I), its stereoisomers, its atropisomers, its pharmaceutically acceptable salts, pharmaceutically acceptable salts of its stereoisomers, pharmaceutically acceptable salts of its isomers, its solvates or pharmaceutically acceptable salts of its solvates according to any one of claims 1-4, characterized in that, The general formula of the compound of formula (I) is formula (V), formula (V-1), formula (V-2), formula (V-2A), formula (V-1A), formula (V-1B), formula (V-1C), formula (V-1D), formula (V-1E), formula (V-1F), formula (V-2A-1), formula (V-2A-2), formula (V-1C-1), formula (V-1D-1), formula (V-1E-1) or formula (V-1D-1): In formula (V): Optionally, R 17 and R 18 together with the atoms to which they are respectively attached form ring F; said ring F is selected from a phenyl ring or a 5- to 6-membered heteroaryl ring; said ring F is independently optionally substituted by 1, 2, 3, 4, 5 or 6 R ringF ; said heteroaryl ring optionally further contains 1, 2 or 3 heteroatoms selected from N, O or S; 12. The compound of formula (I), its stereoisomers, its atropisomers, its pharmaceutically acceptable salts, pharmaceutically acceptable salts of its stereoisomers, pharmaceutically acceptable salts of its isomers, its solvates or pharmaceutically acceptable salts of its solvates as claimed in claim 11, characterized in that, It satisfies one or more of the following conditions: (1) In formula (V) and formula (V-2), ring F is selected from a phenyl ring, a 5- or 6-membered heteroaryl ring; the heteroaryl ring contains 1, 2 or 3 heteroatoms selected from N, O or S; Preferably, ring F is selected from a phenyl ring; (2) In formula (V), formula (V-1), formula (V-2) and formula (V-2A), each occurrence of Y2 is selected from none, -CH2-, -O-, -S- or -NH; preferably, each occurrence of Y2 is selected from none or -CH2-; (3) In formula (V), formula (V-1), formula (V-2) and formula (V-2A), each occurrence of Y1 is selected from none, -CH=CH-, -C≡C-, -C(=O)NH- **or NHC(=O)-**; **Indicates Attachment point of the molecule; and, in formula (V), formula (V-1), formula (V-1A), formula (V-1B), formula (V-2), formula (V-2A), formula (V-2A-1) and formula (V-2A-2), n 25 and n 26 is any one of the following combinations: n 25 is 0, n 26 is 0; or n 25 is 0, n 26 is 1; or n 25 is 0, n 26 is 2; or n 25 is 0, n 26 is 3; or n 25 is 1, n 26 is 0; or n 25 is 1, n 26 is 1; or n 25 is 1, n 26 is 2; or n 25 is 2, n 26 is 0; or n 25 is 2, n 26 is 1.

13. The compound of formula (I), its stereoisomers, its atropisomers, its pharmaceutically acceptable salts, pharmaceutically acceptable salts of its stereoisomers, pharmaceutically acceptable salts of its isomers, its solvates or pharmaceutically acceptable salts of its solvates according to claim 1, characterized in that, wherein, the compound is any one of the following formulas:

14. A pharmaceutical composition, characterized in that, It comprises the compound of formula (I) according to any one of claims 1 to 13, its stereoisomers, its atropisomers, its pharmaceutically acceptable salts, pharmaceutically acceptable salts of its stereoisomers, pharmaceutically acceptable salts of its isomers, its solvates or pharmaceutically acceptable salts of its solvates, and at least one pharmaceutically acceptable excipient.

15. Use of a compound of formula (I) according to any one of claims 1 to 13, its stereoisomers, its atropisomers, its pharmaceutically acceptable salts, pharmaceutically acceptable salts of its stereoisomers, pharmaceutically acceptable salts of its isomers, its solvates, pharmaceutically acceptable salts of its solvates or the pharmaceutical composition according to claim 14 for the manufacture of a medicament for treating a disease or disorder associated with the 20-hydroxyeicosatetraenoic acid signaling pathway.

16. The use according to claim 15, characterized in that, Diseases or disorders associated with the 20-hydroxyeicosatetraenoic acid signaling pathway are selected from obesity, metabolic syndrome, dyslipidemia, diabetes, diabetic retinopathy, cerebrovascular alterations caused by diabetes, diabetic neuropathy, insulin resistance, hyperglycemic state, hyperlipidemia, renal complications caused by diabetes, elevated blood pressure, lens opacity, reduced bone density, increased insulin resistance, diabetic neuropathy, insulin resistance, hyperglycemia, hyperlipidemia, renal complications caused by diabetes, elevated blood pressure, lens opacification, reduced bone density, elevated serum uric acid, infections caused by diabetes, non-alcoholic hepatic steatosis, non-alcoholic inflammatory hepatic steatosis, tissue fibrosis, heart disease, cerebrovascular accident, cirrhosis, metabolic acidosis, ketosis, discomfort related to the cardiovascular system, seizures, atherosclerotic lesions, Parkinson's syndrome, myocardial infarction, acute renal insufficiency, chronic renal disease, renal cysts, neoplastic diseases, end-organ damage and Alzheimer's disease; The diabetes preferably includes but is not limited to type 1 diabetes, type 2 diabetes, maturity-onset diabetes of the young, idiopathic type 1 diabetes, early-onset type 2 diabetes, adolescent-onset type 2 diabetes, juvenile atypical diabetes, malnutrition-related diabetes and latent autoimmune diabetes in adults.

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