Small molecule compounds having naphthylamine structure and application thereof

Abstract

The present application discloses small molecule compounds having a naphthylamine structure and an application thereof. In the present application, the structure of a compound having a structure as shown in general formula (I) is as shown in the drawing. The compound and the pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof that are provided by the present application or the pharmaceutical composition provided by the present application can selectively induce autophagy in damaged mitochondria without affecting or only weakly affecting normal mitochondria, and further have superior metabolic stability and pharmacokinetic properties, lower toxicity, and better druggability.

Description

A class of small molecule compounds with naphthylamine structure and their applications

[0001] Cross-reference to related applications

[0002] This patent application claims priority to the Chinese patent application filed on September 22, 2021, with application number 2021111084176 and invention name “A class of small molecule compounds with naphthylamine structure and their applications”. The full text of the above application is incorporated herein by reference. Technical Field

[0003] The present invention relates to the field of chemical medicines, and in particular to a class of small molecule compounds with a naphthylamine structure and applications thereof. Background Art

[0004] Mitochondria, a type of cellular target-specific autophagy, primarily identify and eliminate dysfunctional mitochondria. Because mitochondria play a central role in energy supply through oxidative phosphorylation, along with other important functions including energy metabolism, amino acid production, lipid synthesis, and ion homeostasis, they are crucial for maintaining the function of aerobic cell types such as neurons, muscle cells, and liver cells. Mitochondria biogenesis and the homeostatic regulation of autophagy are crucial for maintaining cellular function. Dysfunction of mitophagy leads to the accumulation of damaged mitochondria, a decrease in their ability to synthesize ATP+, and the production of large amounts of peroxides, which in turn alter cellular intermediate metabolites and trigger a range of pathological consequences. Enhancing mitophagy to eliminate aging or dysfunctional mitochondria could protect cells.

[0005] In the prior art, Chinese patent application number 201910386493.X describes the compound UMI-77 as a mitophagy inducer. However, the inventors discovered in their research that UMI-77, as a mitophagy inducer, cannot selectively induce autophagy in damaged mitochondria. Therefore, during treatment, it also causes autophagy in normal mitochondria, resulting in adverse reactions. In addition, UMI-77 has poor metabolic stability and is rapidly eliminated in in vitro metabolic stability experiments and mouse PK experiments, significantly affecting its drugability. Therefore, developing a mitophagy inducer that can effectively induce autophagy in damaged mitochondria, especially selectively induce autophagy in damaged mitochondria, and has good metabolic stability is crucial for inhibiting or alleviating various acute and chronic diseases caused by mitophagy dysfunction.

[0006] Summary of the Invention

[0007] To solve the above problems, the purpose of the present invention is to provide a class of small molecule compounds with a naphthylamine structure and their applications, which can selectively induce autophagy of damaged mitochondria without affecting normal mitochondria as mitochondrial autophagy inducers, and have better metabolic stability and higher bioavailability.

[0008] The first aspect of the present invention provides a compound having a structure represented by general formula (I) and a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof,

[0009]

[0010] Among them, Z is

[0011] R 1 is hydrogen or C 1～6 alkyl;

[0012] R 2 For hydrogen, C 1～6 Alkyl, three to six-membered cycloalkyl, three to six-membered epoxyalkyl, phenyl or C 1～6 Alkyl-substituted phenyl groups;

[0013] R 3 for

[0014] Among them, R 3-1 For hydrogen, hydroxyl, C 1～6 Alkyl, C 1～6 Alkoxy, three to six-membered cycloalkyl, three to six-membered epoxyalkyl, amino, C 1～6 Amine, -CH2C(O)R 3-2 、-CH2C(O)OR 3-2 or -CH2C(O)N(R 3-2 R 3-2a ),

[0015] R 3-2 and R 3-2a are independently hydrogen, C 1～6 an alkyl group or a three- to six-membered cycloalkyl group,

[0016] Ar is phenyl, paraphenyl, 5- or 6-membered monocyclic heteroaryl, 8- to 10-membered fused bicyclic heteroaryl, at least one hydrogen atom replaced by R 3-3 substituted 5- or 6-membered monocyclic heteroaryl, at least one hydrogen atom is replaced by R 3-3 substituted 8- to 10-membered fused bicyclic heteroaryl, wherein R 3-3 For hydrogen, halogen, C 1～6 Alkyl, three to six-membered cycloalkyl, hydroxyl, C 1～6 Alkoxy, three to six-membered epoxyalkyl, C 1～6 Halogenated alkyl, C2～6 Alkenyl, C 2～6 Alkynyl, -N(R 3-3a R 3-3b ) or phenyl,

[0017] R 3-3a and R 3-3b are independently hydrogen, C 1～6 Alkyl or three to six-membered cycloalkyl;

[0018] R 4 for

[0019] Among them, R 4-1 is phenyl, paraphenyl, at least one hydrogen atom is replaced by R 4-11 Substituted phenyl, 5- or 6-membered monocyclic heteroaryl, at least one hydrogen atom replaced by R 4-11 substituted 5- or 6-membered monocyclic heteroaryl, 8- to 10-membered fused bicyclic heteroaryl, or at least one hydrogen atom replaced by R 4-11 substituted 8- to 10-membered fused bicyclic heteroaryl, wherein R 4-11 For hydrogen, halogen, nitro, nitrile, hydroxyl, C 1～6 Alkyl, three to six-membered cycloalkyl, C 1～6 Alkoxy, -N(R 4-1a R 4-1b ), phenyl, C 1～6 Halogenated alkyl, C 1～6 Haloalkoxy, -C(O)OR 4-12 、-C(O)R 4-12 、-C(O)N(R 4-1a R 4-1b )、-S(O)2R 4-12 、-S(O)R 4-12 、-OC(O)R 4-12 、-OC(O)OR 4-12 or R 4-12 、R 4-1a and R 4-1b are independently hydrogen, C 1～6 Alkyl, three to six-membered cycloalkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, C in which at least one hydrogen is replaced by halogen 1～6 Alkyl, C in which at least one hydrogen is replaced by halogen 2～6 alkenyl, a three- to six-membered cycloalkyl group in which at least one hydrogen is replaced by a halogen, or a C 2～6 Alkynyl, and R 4-1a and R 4-1b Can bond to each other to form a ring,

[0020] R 4-2For hydrogen, C 1～6 Alkyl or three to six-membered cycloalkyl, or when R 2 C 1～6 When alkyl, R 4-2 With R 2 bonded to form a 4- to 8-membered (e.g., 5- to 6-membered) ring,

[0021] R 4-3 For hydrogen, C 1～6 Alkyl or C 1～6 alkoxy;

[0022] In the general formulas and contexts of this specification, unless explicitly stated otherwise, R 5 It may not exist (i.e., 0), or it may exist one or more at the same time if the valence bond rules allow. Therefore, R 5 The number of can be, for example, 0 to 5, preferably 0 to 4, more preferably 0 to 2 or 0 to 1. 5 When the number is not 0, each is independently selected from halogen, nitro, nitrile, -N + (R 5-1 )3. C 1～6 Haloalkyl, -C(O)OR 5-1 、-C(O)R 5-1 、-C(O)N(R 5-1 R 5-1a )、-S(O)2R 5-1 、-S(O)R 5-1 、-S(O)2N(R 5-1 R 5-1a )、-S(O)N(R 5-1 R 5-1a ),-N=C(R 5-1 R 5-1a ), hydroxyl, C 1～6 Alkyl, phenyl, at least one hydrogen is replaced by R 5-1 Substituted phenyl, C 1～6 Alkoxy, -N(R 5-1 R 5-1a )、-N(R 5-1 )C(O)R 5-1a 、-N(R 5-1 )C(O)OR 5-1a 、-N(R 5-1 )C(O)N(R 5-1a R 5-1b ),-OC(O)R 5-1 、-OC(O)OR 5-1 、 -OC(O)N(R 5-1 R 5-1a ) or -SR 5-1 , where R 5-1、R 5-1a and R 5-1b are independently hydrogen, C 1～6 Alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, C in which at least one hydrogen is replaced by halogen 1～6 Alkyl, C in which at least one hydrogen is replaced by halogen 2～6 Alkenyl and C in which at least one hydrogen is replaced by halogen 2～6 Alkynyl.

[0023] In some preferred embodiments, Z is

[0024] R 1 is hydrogen or C 1～4 alkyl;

[0025] R 2 For hydrogen, C 1～4 Alkyl, three- to six-membered cycloalkyl, or four- to six-membered epoxyalkyl;

[0026] R 3 for

[0027] Among them, R 3-1 For hydrogen, hydroxyl, C 1～4 Alkyl, C 1～4 Alkoxy, three to six-membered cycloalkyl, three to six-membered epoxyalkyl,

[0028] -N(R 3-2 R 3-2a )、-CH2C(O)R 3-2 、-CH2C(O)OR 3-2 or -CH2C(O)NR 3-2 R 3-2a ,

[0029] R 3-2 and R 3-2a are independently hydrogen, C 1～4 an alkyl group or a three- to six-membered cycloalkyl group,

[0030] Ar is phenyl, 5- or 6-membered monocyclic heteroaryl, at least one hydrogen atom of which is replaced by R 3-3 substituted 5- or 6-membered monocyclic heteroaryl, wherein R 3-3 For hydrogen, halogen, C 1～4 Alkyl, three to six-membered cycloalkyl, hydroxyl, C 1～4 Alkoxy, three to six-membered epoxyalkyl, C 1～4 Halogenated alkyl, C 2～4 Alkenyl, C 2～4 Alkynyl, -N(R 3-3a R3-3b ) or phenyl,

[0031] R 3-3a and R 3-3b are independently hydrogen, C 1～4 Alkyl or three to six-membered cycloalkyl;

[0032] R 4 for

[0033] Among them, R 4-1 is a phenyl group, at least one hydrogen atom is replaced by R 4-11 Substituted phenyl, 5- or 6-membered monocyclic heteroaryl, at least one hydrogen atom replaced by R 4-11 substituted 5- or 6-membered monocyclic heteroaryl, 8- to 10-membered fused bicyclic heteroaryl, or at least one hydrogen atom replaced by R 4-11 substituted 8- to 10-membered fused bicyclic heteroaryl, wherein R 4-11 For hydrogen, halogen, nitro, C 1～4 Alkyl, three to six-membered cycloalkyl, C 1～4 Alkoxy, -N(R 4-1a R 4-1b ), phenyl, C 1～4 Halogenated alkyl, C 1～4 Haloalkoxy or R 4-1a and R 4-1b are independently hydrogen, C 1～4 alkyl or three to six-membered cycloalkyl, and R 4-1a and R 4-1b Can bond to each other to form a ring,

[0034] R 4-2 C 1～4 Alkyl or three to six-membered cycloalkyl, or when R 2 C 1～4 When alkyl, R 4-2 With R 2 Bonded to form a 4- to 8-membered ring,

[0035] R 4-3 C 1～4 Alkyl or C 1～4 alkoxy;

[0036] R 5 When the number is not 0, each is independently halogen, nitro, nitrile, -N + (R 5-1 )3. C 1～4 Haloalkyl, -C(O)OR 5-1 、-C(O)R 5-1 、-C(O)N(R 5-1 R 5-1a)、-S(O)2R 5-1 、-S(O)R 5-1 、-N=C(R 5-1 R 5-1a ), hydroxyl, C 1～4 Alkyl, phenyl, at least one hydrogen is replaced by R 5-1 Substituted phenyl, C 1～4 Alkoxy, -N(R 5-1 R 5-1a )、-N(R 5-1 )C(O)R 5-1a 、-OC(O)R 5-1 、-OC(O)N(R 5-1 R 5-1a ) or -SR 5-1 , where R 5-1 、R 5-1a and R 5-1b are independently hydrogen, C 1～4 Alkyl, C 2～4 Alkenyl, C 2～4 Alkynyl, C in which at least one hydrogen is replaced by halogen 1～4 Alkyl, C in which at least one hydrogen is replaced by halogen 2～4 Alkenyl or C in which at least one hydrogen is replaced by halogen 2～4 Alkynyl.

[0037] In some preferred embodiments, Z is

[0038] R 1 is hydrogen or C 1～4 alkyl;

[0039] R 2 For hydrogen, C 1～4 Alkyl, three- to six-membered cycloalkyl, or four- to six-membered epoxyalkyl;

[0040] R 3 for

[0041] Among them, R 3-1 For hydrogen, hydroxyl, C 1～4 Alkyl, C 1～4 Alkoxy or -N(R 3-2 R 3-2a ),

[0042] R 3-2 and R 3-2a are independently hydrogen or C 1～4 alkyl,

[0043] Ar is phenyl, 5- or 6-membered monocyclic heteroaryl, at least one hydrogen atom of which is replaced by R 3-3substituted 5- or 6-membered monocyclic heteroaryl, wherein R 3-3 For hydrogen, halogen, C 1～4 Alkyl, hydroxyl, C 1～4 Alkoxy, C 1～4 Haloalkyl or -N(R 3-3a R 3-3b ),

[0044] R 3-3a and R 3-3b are independently hydrogen or C 1～4 alkyl;

[0045] R 4 for

[0046] Among them, R 4-1 is a phenyl group, at least one hydrogen atom is replaced by R 4-11 Substituted phenyl, 5- or 6-membered monocyclic heteroaryl, at least one hydrogen atom replaced by R 4-11 substituted 5- or 6-membered monocyclic heteroaryl, wherein R 4-11 For hydrogen, halogen, nitro, C 1～4 Alkyl, three to six-membered cycloalkyl, C 1～4 Alkoxy, -N(R 4-1a R 4-1b ), phenyl, C 1～4 Halogenated alkyl, C 1～4 Haloalkoxy or R 4-1a and R 4-1b are independently hydrogen, C 1～4 alkyl or three to six-membered cycloalkyl, and R 4-1a and R 4-1b Can bond to each other to form a ring,

[0047] R 4-2 C 1～4 Alkyl or three to six-membered cycloalkyl, or when R 2 C 1～4 When alkyl, R 4-2 With R 2 Bonded to form a 4- to 8-membered ring,

[0048] R 4-3 C 1～4 Alkyl or C 1～4 alkoxy;

[0049] R 5 When the number is not 0, each is independently halogen, nitro, nitrile, -N + (R 5-1 )3. C 1～4 Halogenated alkyl,

[0050] -C(O)OR5-1 、-C(O)R 5-1 、-C(O)N(R 5-1 R 5-1a )、-S(O)2R 5-1 、-S(O)R 5-1 、-N=C(R 5-1 R 5-1a ), hydroxyl, C 1～4 Alkyl, phenyl, at least one hydrogen is replaced by R 5-1 Substituted phenyl, C 1～4 Alkoxy, -N(R 5-1 R 5-1a )、-N(R 5-1 )C(O)R 5-1a or -OC(O)R 5-1 , where R 5-1 、R 5-1a and R 5-1b are independently hydrogen, C 1～4 Alkyl or C in which at least one hydrogen is replaced by halogen 1～4 alkyl.

[0051] In some preferred embodiments, Z is

[0052] R 1 is hydrogen;

[0053] R 2 is hydrogen, methyl, ethyl, n-propyl, isopropyl,

[0054] R 3 for

[0055] Among them, R 3-1 is hydrogen, hydroxy, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy or isobutoxy,

[0056] Ar is phenyl, 5- or 6-membered nitrogen-containing monocyclic heteroaryl;

[0057] R 4 for

[0058] Among them, R 4-1 is a phenyl group, at least one hydrogen atom is replaced by R 4-11 Substituted phenyl, 5- or 6-membered monocyclic heteroaryl, at least one hydrogen atom replaced by R 4-11 substituted 5- or 6-membered monocyclic heteroaryl, 8- to 10-membered fused bicyclic heteroaryl, or at least one hydrogen atom replaced by R4-11 substituted 8- to 10-membered fused bicyclic heteroaryl, wherein R 4-11 is hydrogen, halogen, nitro, methyl, ethyl, n-propyl, isopropyl, fluoromethyl, fluoroethyl, fluoro-n-propyl, fluoroisopropyl, chloromethyl, chloroethyl, chloro-n-propyl, chloroisopropyl, bromomethyl, bromoethyl, bromo-n-propyl, bromoisopropyl, iodomethyl, iodoethyl, iodo-n-propyl, iodoisopropyl, fluoromethoxy, fluoroethoxy, fluoro-n-propoxy, fluoroisopropoxy, chloromethoxy, chloroethoxy, chloro-n-propoxy, chloroisopropoxy, bromomethoxy, bromoethoxy, bromo-n-propoxy, bromoisopropoxy, iodooxymethyl, iodoethoxy, iodo-n-propoxy, iodoisopropoxy or

[0059] R 4-2 is methyl, ethyl, n-propyl or isopropyl, or, when R 2 When R is methyl, ethyl or n-propyl, 4-2 With R 2 Bonded to form a 4- to 8-membered ring,

[0060] R 4-3 is methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy or isopropoxy;

[0061] R 5 When the number is not 0, each is independently selected from halogen, nitro, nitrile, -N + (R 5-1 )3, fluoromethyl, fluoroethyl, fluoro-n-propyl, fluoro-isopropyl, chloromethyl, chloroethyl, chloro-n-propyl, chloro-isopropyl, bromomethyl, bromoethyl, bromo-n-propyl, bromo-isopropyl, -C(O)OR 5-1 、-C(O)R 5-1 、-C(O)N(R 5-1 R 5-1a )、-S(O)2R 5-1 、

[0062] -S(O)R 5-1 、-N=C(R 5-1 R 5-1a ), hydroxyl, methyl, ethyl, n-propyl, isopropyl, phenyl, at least one hydrogen is replaced by R 5-1 Substituted phenyl, methoxy, ethoxy, n-propoxy, isopropoxy, -N(R 5-1 R 5-1a )、-N(R 5-1 )C(O)R 5-1a 、

[0063] -OC(O)R 5-1 , where R 5-1 、R 5-1a and R 5-1b and 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66

[0064] In some more preferred embodiments, the compound represented by the general formula (I) is selected from any one of the following compounds:

[0065]

[0066]

[0067]

[0068]

[0069]

[0070]

[0071]

[0072]

[0073]

[0074]

[0075]

[0076]

[0077] The inventors of the present invention unexpectedly discovered that when Z is When the phosphodiesterase inhibitor is phosphodiesterase inhibitor, the selectivity of inducing autophagy in damaged mitochondria can be significantly improved, and the metabolic stability can be significantly improved. Therefore, in some more preferred embodiments of the present invention, Z is selected from For example, Z is

[0078] In some preferred embodiments, Z is

[0079] R 1 is hydrogen or C 1～6 alkyl;

[0080] R 2 For hydrogen, C 1～6 Alkyl, three to six-membered cycloalkyl, three to six-membered epoxyalkyl, phenyl or C 1～6 Alkyl-substituted phenyl groups;

[0081] R 3 for

[0082] Among them, R 3-1 For hydrogen, hydroxyl, C 1～6 Alkyl, C 1～6 Alkoxy, three to six-membered cycloalkyl, three to six-membered epoxyalkyl, amino, C 1～6 Amine, -CH2C(O)R 3-2 、-CH2C(O)OR 3-2 or -CH2C(O)N(R 3-2 R 3-2a ),

[0083] R 3-2 and R 3-2a are independently hydrogen, C 1～6 an alkyl group or a three- to six-membered cycloalkyl group,

[0084] Ar is phenyl, paraphenyl, 5- or 6-membered monocyclic heteroaryl, 8- to 10-membered fused bicyclic heteroaryl, at least one hydrogen atom replaced by R 3-3 Substituted phenyl, at least one hydrogen atom is replaced by R 3-3 Substituted phenyl, at least one hydrogen atom is replaced by R 3-3 substituted 5- or 6-membered monocyclic heteroaryl, at least one hydrogen atom is replaced by R 3-3 substituted 8- to 10-membered fused bicyclic heteroaryl, wherein R 3-3 For hydrogen, halogen, C 1～6 Alkyl, three to six-membered cycloalkyl, hydroxyl, C 1～6 Alkoxy, three to six-membered epoxyalkyl, C 1～6 Halogenated alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, -N(R 3-3a R 3-3b ) or phenyl,

[0085] R 3-3a and R 3-3b are independently hydrogen, C 1～6 Alkyl or three to six-membered cycloalkyl;

[0086] R 4 for

[0087] Among them, R 4-1 is phenyl, paraphenyl, at least one hydrogen atom is replaced by R4-11 Substituted phenyl, 5- or 6-membered monocyclic heteroaryl, at least one hydrogen atom replaced by R 4-11 substituted 5- or 6-membered monocyclic heteroaryl, 8- to 10-membered fused bicyclic heteroaryl, or at least one hydrogen atom replaced by R 4-11 substituted 8- to 10-membered fused bicyclic heteroaryl, wherein R 4-11 For hydrogen, halogen, nitro, nitrile, hydroxyl, C 1～6 Alkyl, three to six-membered cycloalkyl, C 1～6 Alkoxy, -N(R 4-1a R 4-1b ), phenyl, C 1～6 Halogenated alkyl, C 1～6 Haloalkoxy, -C(O)OR 4-12 、-C(O)R 4-12 、-C(O)N(R 4-1a R 4-1b )、-S(O)2R 4-12 、-S(O)R 4-12 、-OC(O)R 4-12 、-OC(O)OR 4-12 or R 4-12 、R 4-1a and R 4-1b are independently hydrogen, C 1～6 Alkyl, three to six-membered cycloalkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, C in which at least one hydrogen is replaced by halogen 1～6 Alkyl, C in which at least one hydrogen is replaced by halogen 2～6 alkenyl, a three- to six-membered cycloalkyl group in which at least one hydrogen is replaced by a halogen, or a C 2～6 Alkynyl, and R 4-1a and R 4-1b Can bond to each other to form a ring,

[0088] R 4-2 C 1～6 Alkyl or three to six-membered cycloalkyl, or when R 2 C 1～6 When alkyl, R 4-2 With R 2 Bonded to form a 4- to 8-membered ring,

[0089] R 4-3 C 1～6 Alkyl or C 1～6 alkoxy;

[0090] R 5 When the number is not 0, each is independently selected from halogen, nitro, nitrile, -N + (R 5-1)3. C 1～6 Halogenated alkyl,

[0091] -C(O)OR 5-1 、-C(O)R 5-1 、-C(O)N(R 5-1 R 5-1a )、-S(O)2R 5-1 、-S(O)R 5-1 、-S(O)2N(R 5-1 R 5-1a )、-S(O)N(R 5-1 R 5-1a ),-N=C(R 5-1 R 5-1a ), hydroxyl, C 1～6 Alkyl, phenyl, at least one hydrogen is replaced by R 5-1 Substituted phenyl, C 1～6 Alkoxy, -N(R 5-1 R 5-1a )、-N(R 5-1 )C(O)R 5-1a 、-N(R 5-1 )C(O)OR 5-1a 、-N(R 5-1 )C(O)N(R 5-1a R 5-1b ),-OC(O)R 5-1 、-OC(O)OR 5-1 、-OC(O)N(R 5-1 R 5-1a ) and -SR 5-1 , where R 5-1 、R 5-1a and R 5-1b are independently hydrogen, C 1～6 Alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, C in which at least one hydrogen is replaced by halogen 1～6 Alkyl, C in which at least one hydrogen is replaced by halogen 2～6 Alkenyl or C in which at least one hydrogen is replaced by halogen 2～6 Alkynyl.

[0092] In order to improve the medicinal effect of the compound, in some preferred embodiments, the compound has a structure shown in formula (II);

[0093]

[0094] Where R 2 For hydrogen, C 1～4 Alkyl, three- to six-membered cycloalkyl, or four- to six-membered epoxyalkyl;

[0095] R 3 for

[0096] Among them, R 3-1 For hydrogen, hydroxyl, C 1～4 Alkyl, C 1～4 Alkoxy, three to six-membered cycloalkyl, three to six-membered epoxyalkyl,

[0097] -N(R 3-2 R 3-2a )、-CH2C(O)R 3-2 、-CH2C(O)OR 3-2 or -CH2C(O)NR 3-2 R 3-2a ,

[0098] R 3-2 and R 3-2a are independently hydrogen, C 1～4 an alkyl group or a three- to six-membered cycloalkyl group,

[0099] Ar is phenyl, 5- or 6-membered monocyclic heteroaryl, at least one hydrogen atom of which is replaced by R 3-3 substituted 5- or 6-membered monocyclic heteroaryl, said R 3-3 For hydrogen, halogen, C 1～4 Alkyl, three to six-membered cycloalkyl, hydroxyl, C 1～4 Alkoxy, three to six-membered epoxyalkyl, C 1～4 Halogenated alkyl, C 2～4 Alkenyl, C 2～4 Alkynyl, -N(R 3-3a R 3-3b ) or phenyl,

[0100] R 3-3a and R 3-3b are independently hydrogen, C 1～4 Alkyl or three to six-membered cycloalkyl;

[0101] R 4 for

[0102] Among them, R 4-1 is a phenyl group, at least one hydrogen atom is replaced by R 4-11 Substituted phenyl, 5- or 6-membered monocyclic heteroaryl, at least one hydrogen atom replaced by R 4-11 substituted 5- or 6-membered monocyclic heteroaryl, 8- to 10-membered fused bicyclic heteroaryl, at least one hydrogen atom replaced by R 4-11 substituted 8- to 10-membered fused bicyclic heteroaryl, wherein R 4-11 For hydrogen, halogen, nitro, C 1～4 Alkyl, three to six-membered cycloalkyl, C 1～4Alkoxy, -N(R 4-1a R 4-1b ), phenyl, C 1～4 Halogenated alkyl, C 1～4 Haloalkoxy or R 4-1a and R 4-1b are independently hydrogen, C 1～4 alkyl or three to six-membered cycloalkyl, and R 4-1a and R 4-1b Can bond to each other to form a ring,

[0103] R 4-2 C 1～4 Alkyl, three to six-membered cycloalkyl, or when R 2 C 1～4 When alkyl, R 4-2 With R 2 Bonded to form a 4- to 8-membered ring,

[0104] R 4-3 C 1～4 Alkyl or C 1～4 alkoxy;

[0105] R 5 When the number is not 0, each is independently selected from halogen, nitro, nitrile, -N + (R 5-1 )3. C 1～4 Halogenated alkyl,

[0106] -C(O)OR 5-1 、-C(O)R 5-1 、-C(O)N(R 5-1 R 5-1a )、-S(O)2R 5-1 、-S(O)R 5-1 、-N=C(R 5-1 R 5-1a ), hydroxyl, C 1～4 Alkyl, phenyl, at least one hydrogen is replaced by R 5-1 Substituted phenyl, C 1～4 Alkoxy, -N(R 5-1 R 5-1a )、-N(R 5-1 )C(O)R 5-1a 、-OC(O)R 5-1 、-OC(O)N(R 5-1 R 5-1a ) or -SR 5-1 , where R 5-1 、R 5-1a and R 5-1b are independently hydrogen, C 1～4 Alkyl, C2～4 Alkenyl, C 2～4 Alkynyl, C in which at least one hydrogen is replaced by halogen 1～4 Alkyl, C in which at least one hydrogen is replaced by halogen 2～4 Alkenyl or C in which at least one hydrogen is replaced by halogen 2～4 Alkynyl.

[0107] In some more preferred embodiments, the compound has a structure shown in formula (II);

[0108]

[0109] Where R 2 For hydrogen, C 1～4 Alkyl, three- to six-membered cycloalkyl, or four- to six-membered epoxyalkyl;

[0110] R 3 for

[0111] Among them, R 3-1 For hydrogen, hydroxyl, C 1～4 Alkyl, C 1～4 Alkoxy, three to six-membered cycloalkyl, three to six-membered epoxyalkyl,

[0112] -N(R 3-2 R 3-2a )、-CH2C(O)R 3-2 、-CH2C(O)OR 3-2 、-CH2C(O)NR 3-2 R 3-2a ,

[0113] R 3-2 and R 3-2a are independently hydrogen, C 1～4 an alkyl group or a three- to six-membered cycloalkyl group,

[0114] Ar is phenyl, 5- or 6-membered monocyclic heteroaryl, at least one hydrogen atom of which is replaced by R 3-3 substituted 5- or 6-membered monocyclic heteroaryl, said R 3-3 For hydrogen, halogen, C 1～4 Alkyl, three to six-membered cycloalkyl, hydroxyl, C 1～4 Alkoxy, three to six-membered epoxyalkyl, C 1～4 Halogenated alkyl, C 2～4 Alkenyl, C 2～4 Alkynyl, -N(R 3-3a R 3-3b ) or phenyl,

[0115] R 3-3a and R 3-3b are independently hydrogen, C 1～4Alkyl or three to six-membered cycloalkyl;

[0116] R 4 for

[0117] Among them, R 4-1 is a phenyl group, at least one hydrogen atom is replaced by R 4-11 Substituted phenyl, 5- or 6-membered monocyclic heteroaryl, at least one hydrogen atom replaced by R 4-11 substituted 5- or 6-membered monocyclic heteroaryl, 8- to 10-membered fused bicyclic heteroaryl, at least one hydrogen atom replaced by R 4-11 substituted 8- to 10-membered fused bicyclic heteroaryl, wherein R 4-11 For hydrogen, halogen, nitro, C 1～4 Alkyl, three to six-membered cycloalkyl, C 1～4 Alkoxy, -N(R 4-1a R 4-1b ), phenyl, C 1～4 Halogenated alkyl, C 1～4 Haloalkoxy or R 4-1a and R 4-1b are independently hydrogen, C 1～4 alkyl or three to six-membered cycloalkyl, and R 4-1a and R 4-1b Can bond to each other to form a ring,

[0118] R 4-2 C 1～4 Alkyl, three to six-membered cycloalkyl, or when R 2 C 1～4 When alkyl, R 4-2 With R 2 Bonded to form a 4- to 8-membered ring,

[0119] R 4-3 C 1～4 Alkyl or C 1～4 alkoxy;

[0120] R 5 When the number is not 0, each is independently selected from halogen, nitro, nitrile, -N + (R 5-1 )3. C 1～4 Halogenated alkyl,

[0121] -C(O)OR 5-1 、-C(O)R 5-1 、-C(O)N(R 5-1 R 5-1a )、-S(O)2R 5-1 、-S(O)R 5-1 and -N=C(R 5-1 R5-1a ), where R 5-1 and R 5-1a are independently hydrogen, C 1～4 Alkyl, C 2～4 Alkenyl, C 2～4 Alkynyl, C in which at least one hydrogen is replaced by halogen 1～4 Alkyl, C in which at least one hydrogen is replaced by halogen 2～4 Alkenyl or C in which at least one hydrogen is replaced by halogen 2～4 Alkynyl.

[0122] Based on the advantages of enhancing the compound's ability to selectively induce autophagy, lower toxicity, and better metabolic stability, in some preferred embodiments, the compound has a structure shown in formula (III);

[0123]

[0124] Where R 2 For hydrogen, C 1～4 Alkyl, three- to six-membered cycloalkyl, or four- to six-membered epoxyalkyl;

[0125] R 3 for

[0126] Among them, R 3-1 For hydrogen, hydroxyl, C 1～4 Alkyl, C 1～4 Alkoxy, three to six-membered cycloalkyl, three to six-membered epoxyalkyl,

[0127] -N(R 3-2 R 3-2a )、-CH2C(O)R 3-2 、-CH2C(O)OR 3-2 or -CH2C(O)NR 3-2 R 3-2a ,

[0128] R 3-2 and R 3-2a are independently hydrogen, C 1～4 an alkyl group or a three- to six-membered cycloalkyl group,

[0129] Ar is phenyl, 5- or 6-membered monocyclic heteroaryl, at least one hydrogen atom of which is replaced by R 3-3 substituted 5- or 6-membered monocyclic heteroaryl, said R 3-3 For hydrogen, halogen, C 1～4 Alkyl, three to six-membered cycloalkyl, hydroxyl, C 1～4 Alkoxy, three to six-membered epoxyalkyl, C 1～4 Halogenated alkyl, C 2～4 Alkenyl, C 2～4 Alkynyl, -N(R3-3a R 3-3b ) or phenyl,

[0130] R 3-3a and R 3-3b are independently hydrogen, C 1～4 Alkyl or three to six-membered cycloalkyl;

[0131] R 4 for

[0132] Among them, R 4-1 is a phenyl group, at least one hydrogen atom is replaced by R 4-11 Substituted phenyl, 5- or 6-membered monocyclic heteroaryl, at least one hydrogen atom replaced by R 4-11 substituted 5- or 6-membered monocyclic heteroaryl, 8- to 10-membered fused bicyclic heteroaryl, or at least one hydrogen atom replaced by R 4-11 substituted 8- to 10-membered fused bicyclic heteroaryl, wherein R 4-11 For hydrogen, halogen, nitro, C 1～4 Alkyl, three to six-membered cycloalkyl, C 1～4 Alkoxy, -N(R 4-1a R 4-1b ), phenyl, C 1～4 Halogenated alkyl, C 1～4 Haloalkoxy or R 4-1a and R 4-1b are independently hydrogen, C 1～4 alkyl or three to six-membered cycloalkyl, and R 4-1a and R 4-1b Can bond to each other to form a ring,

[0133] R 4-2 C 1～4 Alkyl or three to six-membered cycloalkyl, or when R 2 C 1～4 When alkyl, R 4-2 With R 2 Bonded to form a 4- to 8-membered ring,

[0134] R 4-3 C 1～4 Alkyl or C 1～4 alkoxy;

[0135] R 5 When the number is not 0, each is independently selected from halogen, nitro, nitrile, -N + (R 5-1 )3. C 1～4 Halogenated alkyl,

[0136] -C(O)OR 5-1 、-C(O)R 5-1、-C(O)N(R 5-1 R 5-1a )、-S(O)2R 5-1 、-S(O)R 5-1 、-N=C(R 5-1 R 5-1a ), hydroxyl, C 1～4 Alkyl, phenyl, at least one hydrogen is replaced by R 5-1 Substituted phenyl, C 1～4 Alkoxy, -N(R 5-1 R 5-1a )、-N(R 5-1 )C(O)R 5-1a 、-OC(O)R 5-1 、-OC(O)N(R 5-1 R 5-1a ) and -SR 5-1 , where R 5-1 、R 5-1a and R 5-1b are independently hydrogen, C 1～4 Alkyl, C 2～4 Alkenyl, C 2～4 Alkynyl, C in which at least one hydrogen is replaced by halogen 1～4 Alkyl, C in which at least one hydrogen is replaced by halogen 2～4 Alkenyl or C in which at least one hydrogen is replaced by halogen 2～4 Alkynyl.

[0137] In some more preferred embodiments, the compound has a structure shown in formula (III);

[0138]

[0139] Where R 2 For hydrogen, C 1～4 Alkyl, three- to six-membered cycloalkyl, or four- to six-membered epoxyalkyl;

[0140] R 3 for

[0141] Among them, R 3-1 For hydrogen, hydroxyl, C 1～4 Alkyl, C 1～4 Alkoxy, three to six-membered cycloalkyl, three to six-membered epoxyalkyl,

[0142] -N(R 3-2 R 3-2a )、-CH2C(O)R 3-2 、-CH2C(O)OR 3-2 or -CH2C(O)NR 3-2 R 3-2a ,

[0143] R 3-2 and R 3-2a are independently hydrogen, C 1～4 an alkyl group or a three- to six-membered cycloalkyl group,

[0144] Ar is phenyl, 5- or 6-membered monocyclic heteroaryl, or at least one hydrogen atom replaced by R 3-3 substituted 5- or 6-membered monocyclic heteroaryl, wherein R 3-3 For hydrogen, halogen, C 1～4 Alkyl, three to six-membered cycloalkyl, hydroxyl, C 1～4 Alkoxy, three to six-membered epoxyalkyl, C 1～4 Halogenated alkyl, C 2～4 Alkenyl, C 2～4 Alkynyl, -N(R 3-3a R 3-3b ) or phenyl,

[0145] R 3-3a and R 3-3b are independently hydrogen, C 1～4 Alkyl or three to six-membered cycloalkyl;

[0146] R 4 for

[0147] Among them, R 4-1 is a phenyl group, at least one hydrogen atom is replaced by R 4-11 Substituted phenyl, 5- or 6-membered monocyclic heteroaryl, at least one hydrogen atom replaced by R 4-11 substituted 5- or 6-membered monocyclic heteroaryl, 8- to 10-membered fused bicyclic heteroaryl, or at least one hydrogen atom replaced by R 4-11 substituted 8- to 10-membered fused bicyclic heteroaryl, wherein R 4-11 For hydrogen, halogen, nitro, C 1～4 Alkyl, three to six-membered cycloalkyl, C 1～4 Alkoxy, -N(R 4-1a R 4-1b ), phenyl, C 1～4 Halogenated alkyl, C 1～4 Haloalkoxy or R 4-1a and R 4-1b are independently hydrogen, C 1～4 alkyl or three to six-membered cycloalkyl, and R 4-1a and R 4-1b Can bond to each other to form a ring,

[0148] R 4-2 C 1～4 Alkyl or three to six-membered cycloalkyl, or when R 2 C 1～4When alkyl, R 4-2 With R 2 Bonded to form a 4- to 8-membered ring,

[0149] R 4-3 C 1～4 Alkyl or C 1～4 alkoxy;

[0150] R 5 When the number is not 0, each independently selected from hydroxyl, C 1～4 Alkyl, phenyl, at least one hydrogen is replaced by R 5-1 Substituted phenyl, C 1～4 Alkoxy, -N(R 5-1 R 5-1a )、-N(R 5-1 )C(O)R 5-1a 、-OC(O)R 5-1 、-OC(O)N(R 5-1 R 5-1a ) and -SR 5-1 , where R 5-1 、R 5-1a and R 5-1b are independently hydrogen, C 1～4 Alkyl, C 2～4 Alkenyl, C 2～4 Alkynyl, C in which at least one hydrogen is replaced by halogen 1～4 Alkyl, C in which at least one hydrogen is replaced by halogen 2～4 Alkenyl or C in which at least one hydrogen is replaced by halogen 2～4 Alkynyl.

[0151] In the compounds of formula I to formula III, preferably, R 1 It is hydrogen or methyl, more preferably hydrogen.

[0152] In the compounds of formula I to formula III, preferably, R 2 For hydrogen, C 1～6 an alkyl group (preferably a methyl group), a three- to six-membered cycloalkyl group (preferably a cyclopropyl group), or a three- to six-membered epoxyalkyl group (preferably an oxetane group).

[0153] In the compounds of formula I to formula III, preferably, R 3 Selected from -CH2-COOH, -CH2-CONH2,

[0154] Wherein, Ar is a 5- or 6-membered monocyclic heteroaryl, more preferably a 5- or 6-membered monocyclic heteroaryl nitrogen-containing monocyclic heteroaryl, more preferably a triazole group (e.g. in particular ), tetrazolyl (e.g. ) or phenyl.

[0155] In the compounds of formula I to formula III, preferably, R 4 for:

[0156]

[0157] Among them, R 4-1 is selected from phenyl, 5 or 6 membered monocyclic heteroaryl (e.g., thienyl, pyrazolyl, isoxazolyl, pyridinyl) and 8 to 10 membered fused bicyclic heteroaryl (e.g., benzothienyl), each of which is optionally substituted by a group selected from the group consisting of halogen, nitro, phenyl, nitrile, hydroxyl, C 1～6 Alkyl, three to six-membered cycloalkyl, C 1～6 Alkoxy, C 1～6 Halogenated alkyl, C 1～6 Halogenated alkoxy, -N(R 4-1a R 4-1b )(R 4-1a and R 4-1b may bond to each other to form a ring, for example, to form a pyrrolidine ring);

[0158] R 4-2 For hydrogen, C 1～6 Alkyl, three to six-membered cycloalkyl, or when R 2 C 1～6 When alkyl, R 4-2 With R 2 bonded to form a 4- to 8-membered (e.g., 5- or 6-membered) ring;

[0159] R 4-3 For hydrogen, C 1～6 Alkyl or C 1～6 Alkoxy.

[0160] R 4-1a 、R 4-1b 、R 4-2 、R 4-3 、R 5 As defined herein.

[0161] In the compounds of formula I to formula III, preferably, R 5 The number is 0 to 2 (especially 0 to 1), and R 5 When the number is not 0, each independently selected from hydroxyl, C 1～4 Alkyl, C 1～4 Alkoxy, nitro, -COOH, -NHCO-C 1～4 Alkyl (e.g., -NHCO-CH3).

[0162] In some more preferred embodiments, the compound of the present invention is selected from any one of the following compounds, or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof:

[0163]

[0164]

[0165]

[0166]

[0167]

[0168]

[0169]

[0170]

[0171]

[0172]

[0173]

[0174]

[0175] In some preferred embodiments, the C 1～6 Alkyl is C 1～4 Alkyl, the C 1～4 The alkyl group is preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, for example methyl or ethyl.

[0176] In some preferred embodiments, the three to six-membered cycloalkyl group is preferably C 3～5 Cycloalkyl, the C 3～5 The cycloalkyl group is preferably For example:

[0177] In some preferred embodiments, the three to six-membered epoxyalkyl group is preferably For example:

[0178] In some preferred embodiments, the C 1～6 The alkyl-substituted phenyl group is preferably C 1～4The alkyl-substituted phenyl group is more preferably a phenyl group substituted by any one of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl groups.

[0179] In some preferred embodiments, the C 1～6 The alkoxy group is preferably C 1～4 The alkoxy group is more preferably methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy or isobutoxy.

[0180] In some preferred embodiments, the -N(R 3-2 R 3-2a )、-N(R 3-3a R 3-3b )、-N(R 4-1a R 4-1b )、-N(R 5-1 R 5-1a ) is preferably

[0181] In some preferred embodiments, the 5- or 6-membered monocyclic heteroaryl group is preferably wherein Y1, Y2, Y3, Y4, Y5, Y6, Y7, Y8, and Y9 are independently selected from C, N, O, or S, and Y1, Y2, Y3, and Y4 are not all C, and Y5, Y6, Y7, Y8, and Y9 are not all C; the 5- or 6-membered monocyclic heteroaryl is more preferably pyrrolyl, furyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridyl, pyranyl, thiopyranyl, pyridazinyl, pyrimidinyl, pyrazinyl, piperazinyl, triazolyl, or tetrazolyl; the 5- or 6-membered monocyclic heteroaryl is more preferably More preferably, the 5- or 6-membered monocyclic heteroaryl group is a 5- or 6-membered nitrogen-containing monocyclic heteroaryl group, for example:

[0182] Most preferably, the 5- or 6-membered monocyclic heteroaryl group is a 5-membered nitrogen-containing monocyclic heteroaryl group, for example:

[0183] In some preferred embodiments, the 8- to 10-membered fused bicyclic heteroaryl group is

[0184] Among them, Y 11 、Y 12 、Y 13 、Y 14 、Y 15 、Y 16 、Y17 、Y 18 and Y 19 are independently selected from C, N, O or S, and Y 11 、Y 12 、Y 13 、Y 14 、Y 15 、Y 16 、Y 17 、Y 18 and Y 19 Not all C; Y 21 、Y 22 、Y 23 、Y 24 、Y 25 and Y 26 are independently selected from C, N, O or S, and Y 21 、Y 22 、Y 23 、Y 24 、Y 25 and Y 26 Not all C; Y 31 、Y 32 、Y 33 、Y 34 、Y 35 、Y 36 and Y 37 are independently selected from C, N, O or S, and Y 31 、Y 32 、Y 33 、Y 34 、Y 35 、Y 36 and Y 37 Not all are C; the 8- to 10-membered fused bicyclic heteroaryl is more preferably indolyl, benzindolyl, benzothiophenyl, carbazolyl, quinolyl, pteridinyl, purinyl; the 8- to 10-membered fused bicyclic heteroaryl is most preferably

[0185] In some preferred embodiments, the halogen is preferably fluorine, chlorine, bromine or iodine.

[0186] In some preferred embodiments, the C 1～6 The haloalkyl group is preferably C 1～3 haloalkyl; more preferably fluoromethyl, fluoroethyl, fluoro-n-propyl, fluoro-isopropyl, chloromethyl, chloroethyl, chloro-n-propyl, chloro-isopropyl, bromomethyl, bromoethyl, bromo-n-propyl, bromo-isopropyl, iodomethyl, iodoethyl, iodo-n-propyl, iodo-isopropyl; most preferably trifluoromethyl.

[0187] In some preferred embodiments, the C1～6 The haloalkoxy group is preferably C 1～3 more preferably fluoromethoxy, fluoroethoxy, fluoro-n-propoxy, fluoroisopropoxy, chloromethoxy, chloroethoxy, chloro-n-propoxy, chloroisopropoxy, bromomethoxy, bromoethoxy, bromo-n-propoxy, bromoisopropoxy, iodinatedoxymethyl, iodinatedethoxy, iodinated-n-propoxy, iodinatedisopropoxy; most preferably trifluoromethoxy.

[0188] In some preferred embodiments, the C 2～6 Alkenyl is preferably C 2～4 Alkenyl is more preferably -CH=CH2, -CH=CH-CH3, -CH2-CH=CH2, -CH=CH-CH2-CH3, -CH=CH-CH=CH2.

[0189] In some preferred embodiments, the C 2～6 Alkynyl is preferably C 2～6 Alkynyl is more preferably -C≡CH, -CH2-C≡CH, -CH2-CH2-C≡CH, or -CH2-C≡C-CH3.

[0190] The second aspect of the present invention provides a pharmaceutical composition, which comprises the compound described in the first aspect of the present invention, and a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof.

[0191] The third aspect of the present invention provides the use of the compound described in the first aspect of the present invention, or its pharmaceutically acceptable salt, stereoisomer, solvate or prodrug, or the pharmaceutical composition described in the second aspect of the present invention in the preparation of a mitochondrial autophagy inducer (especially a selective mitochondrial autophagy inducer).

[0192] Compared with the prior art, the present invention has at least the following advantages:

[0193] (1) The compound provided in the first aspect of the present invention and its pharmaceutically acceptable salt, stereoisomer, solvate or prodrug, or the pharmaceutical composition provided in the second aspect of the present invention, can induce autophagy of damaged mitochondria, and selectively induce autophagy of damaged mitochondria without affecting or only slightly affecting normal mitochondria;

[0194] (2) The compound provided in the first aspect of the present invention, and its pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug, or the pharmaceutical composition provided in the second aspect of the present invention, has superior metabolic stability and pharmacokinetic properties compared to UMI-77;

[0195] (3) The compound provided in the first aspect of the present invention, and its pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug, or the pharmaceutical composition provided in the second aspect of the present invention, has lower toxicity and better drugability than UMI-77;

[0196] (4) The compound provided in the first aspect of the present invention and its pharmaceutically acceptable salt, stereoisomer, solvate or prodrug or the pharmaceutical composition provided in the second aspect of the present invention.

[0197] Therefore, the compounds of the present invention have the effects of inducing autophagy of damaged mitochondria or improving metabolic stability. Preferred compounds of the present invention have the effects of both inducing autophagy of damaged mitochondria and improving metabolic stability.

[0198] More preferably, the preferred compounds of the present invention have the effect of selectively inducing autophagy of damaged mitochondria or improving metabolic stability. Particularly preferred compounds of the present invention have the effect of both selectively inducing autophagy of damaged mitochondria and improving metabolic stability.

[0199] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features described in detail below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be listed here one by one. BRIEF DESCRIPTION OF THE DRAWINGS

[0200] One or more embodiments are exemplarily described by the figures in the corresponding drawings, and these exemplified descriptions do not constitute limitations on the embodiments.

[0201] FIG1 is a graph showing the test results of the ability of compound I-2 to induce autophagy in damaged mitochondria in Test Example 1 of the present invention;

[0202] FIG2 is a graph showing the test results of the ability of UMI-77, I-2, and I-1 to selectively induce autophagy in damaged mitochondria in Test Example 1 of the present invention;

[0203] FIG3 is a graph showing the in vitro liver microsome stability test results of compounds UMI-77, I-2, and I-1 in Test Example 2 of the present invention;

[0204] FIG4 is a graph showing the in vitro plasma stability test results of compounds UMI-77, I-2, and I-1 in Test Example 3 of the present invention;

[0205] FIG5 is a drug-time curve of the compound UMI-77 administered by IV in Test Example 4 of the present invention;

[0206] FIG6 is a drug-time curve of compound UMI-77 in Test Example 4 of the present invention administered via PO;

[0207] FIG7 is a drug-time curve of compound I-1 in Test Example 4 of the present invention administered to standard mice via IV;

[0208] FIG8 is a drug-time curve of compound I-1 in Test Example 4 of the present invention administered PO to standard mice;

[0209] FIG9 is a drug-time curve of compound I-1 in Test Example 4 of the present invention administered to standard mice via IP;

[0210] FIG10 is a drug-time curve of compound I-2 in Test Example 4 of the present invention administered to standard mice via IV;

[0211] FIG11 is a drug-time curve of compound I-2 in Test Example 4 of the present invention administered PO to standard mice;

[0212] FIG12 is a drug-time curve of compound I-1 in Test Example 4 of the present invention administered to SD rats by IV;

[0213] FIG13 is a drug-time curve of compound I-1 in Test Example 4 of the present invention administered to SD rats via IP;

[0214] FIG14 is a drug-time curve of compound I-1 in Test Example 4 of the present invention when administered PO to SD rats. DETAILED DESCRIPTION

[0215] The present inventors have found through detailed experimental studies that the compound described in the first aspect of the present invention has the effect of inducing autophagy of damaged mitochondria or improving metabolic stability.

[0216] Preferably, the preferred compounds of the present invention have the effects of both inducing autophagy of damaged mitochondria and improving metabolic stability.

[0217] More preferably, the preferred compounds of the present invention have the effect of selectively inducing autophagy of damaged mitochondria or improving metabolic stability. Particularly preferred compounds of the present invention have the effect of both selectively inducing autophagy of damaged mitochondria and improving metabolic stability.

[0218] the term

[0219] As used herein, the term "mitophagy" refers to the process by which mitochondria are selectively degraded by autophagy, which is an important mechanism for controlling mitochondrial quality and quantity.

[0220] As used herein, the term "mitochondrial autophagy inducer" refers to a compound that can induce mitophagy function.

[0221] As used herein, the term "alkyl" refers to a straight-chain or branched saturated aliphatic hydrocarbon group. 1-6“Alkyl” refers to a straight or branched chain alkyl group having 1 to 6 carbon atoms, and non-limiting examples include: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, and various branched chain isomers thereof. The term “C 1-4 "Alkyl" refers to a straight or branched chain alkyl group having 1 to 4 carbon atoms, C 1-4 If the alkyl group appears at the end of the molecule, it is, for example, but not limited to: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, or, when the two parts of the molecule are connected by the alkyl group, it is, for example, but not limited to: -CH2-, -CH2-CH2-, -CH(CH3)-, -CH2-CH2-CH2-, -CH(C2H5)-, -C(CH3)2-, C 1-4 Each hydrogen of an alkyl carbon may be replaced with a substituent as further enumerated herein.

[0222] As used herein, the term "alkenyl" refers to a straight or branched hydrocarbon chain containing at least one carbon-carbon double bond. Each hydrogen on the alkenyl carbon may be replaced by a substituent as further enumerated herein. 2～6 "Alkenyl" refers to a straight or branched hydrocarbon chain having 1 to 6 carbon atoms and containing at least one carbon-carbon double bond. If it appears at the end of a molecule, it is, for example, without limitation: -CH=CH2, -CH=CH-CH3, -CH2-CH=CH2, -CH=CH-CH2-CH3, -CH=CH-CH=CH2, or, when the two parts of the molecule are connected through the alkenyl, it is, for example, without limitation, -CH=CH-. C 2～6 Each hydrogen of an alkenyl carbon may be replaced with a substituent as further enumerated herein.

[0223] As used herein, the term "alkynyl" refers to a straight or branched hydrocarbon chain containing at least one carbon-carbon triple bond. Each hydrogen on an alkynyl carbon may be replaced by a substituent as further enumerated herein. 2～6 "Alkynyl" refers to a straight or branched hydrocarbon chain having 1 to 6 carbon atoms and containing at least one carbon-carbon triple bond. If it appears at the end of a molecule, it is, for example, but not limited to: -C≡CH, -CH2-C≡CH, -CH2-CH2-C≡CH, -CH2-C≡C-CH3, or, when two parts of the molecule are connected through the alkynyl, it is, for example, but not limited to, -C≡C-.2～6 Each hydrogen on an alkynyl carbon may be replaced with a substituent as further enumerated herein.

[0224] As used herein, the term "alkoxy" refers to a group having the structure "-O-alkyl," wherein alkyl is as defined above. 1-6 The term "alkoxy" refers to an alkoxy group having 1 to 6 carbon atoms, including, but not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, isobutoxy, n-pentoxy, and the like.

[0225] As used herein, the term "amino group" refers to a group formed by replacing at least one hydrogen atom in an amino group with an alkyl group, for example: In, R 3-11 and R 3-12 Any one of them is alkyl and the other is hydrogen; or R 3-11 and R 3-12 All are alkyl groups; when R 3-11 and R 3-12 When all are alkyl groups, R 3-11 and R 3-12 Can be bonded into a ring.

[0226] As used herein, the term "haloalkyl" refers to an alkyl group in which one or more (eg, 1, 2, 3, 4, or 5) hydrogen atoms are replaced by a halogen, wherein alkyl is as defined above.

[0227] As used herein, "(O)" refers to In one embodiment, -CH2C(O)R 3-2 refers to

[0228] As used herein, the term "halooxyalkyl" refers to an alkoxy group in which one or more hydrogen atoms are replaced by a halogen, wherein alkoxy is as defined above.

[0229] As used herein, the terms "aryl", "aryl ring" and "aromatic ring" are used interchangeably and refer to an all-carbon monocyclic, an all-carbon non-fused polycyclic (rings are connected by covalent bonds and are not fused) or an all-carbon fused polycyclic (i.e., rings that share adjacent pairs of carbon atoms) group, wherein at least one ring in the group is aromatic, i.e., has a conjugated π electron system forming a ring.

[0230] As used herein, the term "heteroaryl" refers to an aromatic group in which at least one of the ring carbon atoms constituting the aromatic group is replaced by a heteroatom, which is a non-carbon atom such as S, N or O.

[0231] As used herein, the term "monocyclic heteroaryl" refers to a heteroaryl group having only one aromatic ring, wherein heteroaryl is as defined above. The term "5- or 6-membered monocyclic heteroaryl" refers to a monocyclic heteroaryl group having 5 or 6 ring atoms, wherein 1, 2 or 3 of the ring atoms are heteroatoms selected from nitrogen, oxygen or S(=O)m' (wherein m' is an integer from 0 to 2), such as, but not limited to, thiophene, furan, thiazole, isothiazole, imidazole, oxazole, pyrrole, pyrazole, triazole (e.g., 1,2,3-triazole, 1,2,4-triazole, 1,2,5-triazole, 1,3,4-triazole, etc.), tetrazole, isoxazole, oxadiazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, thiadiazole, pyridine, pyridazine, pyrimidine, pyrazine, etc.

[0232] As used herein, the term "fused heteroaryl" refers to a fused heteroaryl group having at least two aromatic rings, wherein two ring atoms of the two aromatic rings are shared adjacent to each other, wherein heteroaryl is as defined above. The term "fused bicyclic heteroaryl" refers to a fused heteroaryl group having two aromatic rings, wherein fused heteroaryl is as defined above. The term "8- to 10-membered fused bicyclic heteroaryl" refers to a fused bicyclic heteroaryl group having 8 to 10 ring atoms, wherein 1, 2, 3, 4 or 5 ring atoms are heteroatoms selected from nitrogen, oxygen or S(=O)m' (wherein m' is an integer from 0 to 2), non-limiting examples of which include: benzo[d]isoxazole, 1H-indole, isoindole, 1H-benzo[d]imidazole, benzo[d]isothiazole, 1H-benzo[d][1,2,3]triazole, ... [d]oxazole, benzo[d]thiazole, indazole, benzofuran, benzo[b]thiophene, quinoline, isoquinoline, quinazoline, quinoxaline, cinnoline, pyrido[3,2-d]pyrimidine, pyrido[2,3-d]pyrimidine, pyrido[3,4-d]pyrimidine, pyrido[4,3-d]pyrimidine, 1,8-naphthyridine, 1,7-naphthyridine, 1,6-naphthyridine, 1,5-naphthyridine, pyrazolo[1,5-a]pyrimidine, imidazo[1,2-b]pyridazine, etc.

[0233] As used herein, the term "effective amount" or "therapeutically effective amount" refers to a sufficient amount of a chemical entity (e.g., a compound that exhibits activity as an NLRP1 / 3 modulator, or a pharmaceutically acceptable salt and / or hydrate and / or cocrystal thereof) that, when administered, will alleviate to some extent one or more of the symptoms of the disease or condition being treated. Results include alleviation and / or relief of signs, symptoms, or causes of the disease or any other desired change in a biological system. An appropriate "effective" amount in any individual case is determined using any suitable technique, such as a dose escalation study.

[0234] As used herein, the term "excipient" or "pharmaceutically acceptable excipient" means a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, carrier, solvent, or encapsulating material. In one embodiment, each component is "pharmaceutically acceptable" in the sense that it is compatible with the other ingredients of the pharmaceutical formulation and is suitable for use in contact with the tissues or organs of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications commensurate with a reasonable benefit / risk ratio.

[0235] As used herein, the term "pharmaceutically acceptable salt" may refer to a pharmaceutically acceptable addition salt prepared from a pharmaceutically acceptable non-toxic acid (including inorganic and organic acids). In some cases, a pharmaceutically acceptable salt is obtained by reacting a compound described herein with an acid. The term "pharmaceutically acceptable salt" may also refer to a pharmaceutically acceptable addition salt prepared by reacting a compound having an acidic group with a base to form a salt or by other methods previously determined. Pharmacologically acceptable salts are not particularly limited as long as they can be used in medicine. Examples of salts formed with bases of the compounds described herein include the following: salts thereof with inorganic bases such as sodium, potassium, magnesium, calcium and aluminum; salts thereof with organic bases such as methylamine, ethylamine and ethanolamine; or salts thereof with dicyclohexylamine, N-methyl-D-glucamine or tris(hydroxymethyl)methylamine; salts thereof with basic amino acids such as lysine and ornithine; and ammonium salts. The salt may be an acid addition salt, specifically exemplified by acid addition salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid; organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, and ethanesulfonic acid; and acidic amino acids such as aspartic acid and glutamic acid.

[0236] As used herein, the term "excipient" or "pharmaceutically acceptable excipient" means a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, carrier, solvent, or encapsulating material. In one embodiment, each component is "pharmaceutically acceptable" in the sense that it is compatible with the other ingredients of the pharmaceutical formulation and is suitable for use in contact with the tissues or organs of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications commensurate with a reasonable benefit / risk ratio.

[0237] As used herein, the term "pharmaceutical composition" refers to a mixture of a compound described herein and an "excipient," such as a carrier, stabilizer, diluent, dispersant, suspending agent, and / or thickener. Pharmaceutical compositions facilitate administration of the compound to an organism. Various techniques exist in the art for administering a compound, including, but not limited to, rectal, oral, intravenous, aerosol, parenteral, ophthalmic, pulmonary, and topical administration.

[0238] As used herein, the term "subject" refers to an animal, including but not limited to a primate (e.g., human), monkey, cow, pig, sheep, goat, horse, dog, cat, rabbit, rat, or mouse. The terms "subject" and "patient" are used interchangeably herein, e.g., with respect to a mammalian subject (e.g., human).

[0239] As used herein, the terms "treat," "treating," and "treatment," in the context of treating a disease or disorder, are meant to include alleviating or eliminating the disorder, disease, or condition, wherein the term "disorder," as used herein, should always be understood to mean "the disorder, disease, or condition," or one or more of the symptoms associated with the disorder; or slowing the progression, spread, or worsening of the disorder or condition, or one or more of its symptoms.

[0240] Unless otherwise indicated, "selectivity" as used herein refers to the property of significantly inducing autophagy of damaged mitochondria without affecting or only slightly affecting normal mitochondria. "Metabolic stability" as used herein includes but is not limited to liver microsomal stability and plasma stability.

[0241] Unless otherwise indicated, as used herein, Indicates that the naphthalene ring (including the two benzene rings on the left and right) is replaced by 0, 1, 2, 3, 4 or 5 R 5 substituted, and when the naphthalene ring is replaced by more than one R 5 When substituted, R 5 The same or different each time it appears.

[0242] In order to make the purpose, technical solutions and advantages of the embodiments of the present invention clearer, the present invention will be further described below in conjunction with specific examples. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention. The experimental methods in the following examples, for which specific conditions are not specified, are usually based on conventional conditions or the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are weight percentages and parts by weight. The experimental materials and reagents used in the following examples can be obtained from commercial sources unless otherwise specified.

[0243] Unless otherwise specified, the technical and scientific terms used herein have the same meaning as commonly understood by ordinary technicians in the technical field to which this application belongs. It should be noted that the terms used herein are only for describing specific embodiments and are not intended to limit the exemplary embodiments of this application.

[0244] Example 1. Synthesis and characterization of compound I-1

[0245]

[0246] UMI-77 (15 mg, 0.032 mmol) was suspended in DCM (0.5 mL) and stirred in a dry ice-ethanol bath. 85% mCPBA (6.5 mg, 0.032 mmol) was added, and the mixture was slowly returned to room temperature. LC-MS analysis confirmed the formation of product I-1. The organic solvent was evaporated under reduced pressure, and the resulting crude product was purified by preparative HPLC (MeCN / H2O / TFA) to afford product I-1 (6 mg).

[0247] The purified product I-1 was taken for structural characterization, LC-MS (ESI) m / z: 482,484 [MH] - . 1 H-NMR(400MHz,DMSO-d6)δ(ppm):13.1(s,1H),10.98(s,1H), 10.17(s,1H),8.25(d,J=7.4Hz,1H),8.00(d,J=8.6Hz,1H),7.71(d,J=8.3Hz,2H) ,7.64–7.50(m,4H),7.21(s,1H),4.00(d,J=14.2Hz,1H),3.45(d,J=14.2Hz,1H).

[0248] Example 2. Synthesis and Characterization of Compound I-2

[0249]

[0250] Under a nitrogen atmosphere, UMI-77 (45 mg, 0.096 mmol) was dissolved in DMF (0.5 mL) and stirred in an ice-water bath. KCO (39 mg, 0.28 mmol) and MeI (30 μL, 0.48 mmol) were added sequentially. The mixture was stirred in an ice-water bath for 10 minutes, then returned to room temperature and stirred overnight. LC-MS analysis revealed the formation of trimethylated product 1. The reaction mixture was diluted with DCM and purified by silica gel column chromatography (30% v / v ethyl acetate / petroleum ether) to afford intermediate 1 (42 mg).

[0251] Intermediate 1 (42 mg, 0.081 mmol) was dissolved in dry DCM (0.5 mL) and stirred in a dry ice-ethanol bath. A 1M BBr solution in DCM (0.24 mL, 0.24 mmol) was added dropwise, followed by slowly returning to room temperature and stirring for 2 hours. LC-MS analysis revealed the formation of a demethylated product. The demethylated product (15 mg, 0.031 mmol) was suspended in DCM (0.5 mL) and stirred in a dry ice-ethanol bath. 85% mCPBA (6.3 mg, 0.031 mmol) was added, followed by slowly returning to room temperature. LC-MS analysis revealed the formation of product I-2. The organic solvent was evaporated under reduced pressure, and the crude product was purified by preparative HPLC (MeCN / H2O / TFA) to give product I-2 (5 mg).

[0252] The purified product I-2 was taken for structural characterization, LC-MS (ESI) m / z: 496,498 [MH] - . 1 H-NMR(400MHz,DMSO-d6)δ(ppm):13.2(s,1H),11.23(s,1H),8.34 (d,J=8.5Hz,1H),8.20(d,J=8.4Hz,0.6H),8.13(d,J=8.4Hz,0.4H),7.91–7.81(m,2H),7.80–7.57(m,4H),7.09(s, 0.4H), 6.96 (s, 0.6H), 4.03 (dd, J=24.7, 14.2Hz, 1H), 3.60 (dd, J=25.4, 14.3Hz, 1H), 3.25 (s, 1.2H), 3.21 (s, 1.8H).

[0253] Example 3. Synthesis and characterization of compound I-3

[0254]

[0255] Intermediate 2 (0.8 mmol) and 2,2'-bipyridine (0.8 mmol) were dissolved in dry DCE (5 mL). Cyclopropylboronic acid (1.6 mmol), copper acetate (0.8 mmol), and sodium carbonate (1.6 mmol) were added sequentially. The mixture was heated at 80°C with stirring for 24 hours. LC-MS analysis revealed the formation of product 3. Purification by silica gel column chromatography afforded intermediate 3 (82 mg). Intermediate 3 (0.26 mmol) was dissolved in DCM (0.2 mL) and pyridine (0.2 mL) and stirred in an ice-water bath. p-Bromobenzenesulfonyl chloride (0.3 mmol) was added, and the mixture was then slowly returned to room temperature. LC-MS analysis revealed the formation of intermediate 4. Purification by silica gel column chromatography afforded intermediate 4 (120 mg).

[0256]

[0257] Using intermediate 4 (0.22 mmol) as raw material, compound I-3 (5 mg) was prepared according to the synthesis method of compound I-2.

[0258] The purified product I-3 was taken for structural characterization, LC-MS (ESI) m / z: 522,524 [MH] - .

[0259] Example 4. Synthesis and Characterization of Compound I-4

[0260]

[0261] Intermediate 2 and As raw materials, according to the synthesis method of compound I-3, Replace with Compound I-4 can be prepared.

[0262] The purified product I-4 was characterized by LC-MS (ESI) m / z: 538,540 [MH] - .

[0263] Example 5. Synthesis and characterization of compound I-5

[0264]

[0265] Intermediate 6 (50 mg, 0.1 mmol) was dissolved in 7 M methanolic ammonia solution (0.5 mL) and heated at 70°C with stirring for 24 hours. LC-MS analysis confirmed the formation of intermediate 7. The organic solvent was evaporated under reduced pressure, and the resulting crude product was used directly in the next reaction.

[0266]

[0267] Using intermediate 7 (0.1 mmol) as raw material, compound I-5 (3 mg) was prepared according to the synthesis method of compound I-2.

[0268] The purified product I-5 was characterized by LC-MS (ESI) m / z: 481,483 [MH] - .

[0269] Example 6. Synthesis and Characterization of Compound I-6

[0270]

[0271] Intermediate 7 (31 mg, 0.064 mmol) was dissolved in dry toluene (0.4 mL), Lawesson's reagent (0.04 mmol) was added, and the mixture was heated at 80°C with stirring for 24 hours. LC-MS analysis revealed the formation of Intermediate 9, which was purified by silica gel column chromatography to afford Intermediate 9 (22 mg).

[0272]

[0273] Using intermediate 9 (0.043 mmol) as raw material, compound I-6 (4 mg) was prepared according to the synthesis method of compound I-2.

[0274] The purified product I-6 was characterized by LC-MS (ESI) m / z: 497,499 [MH] - .

[0275] Example 7. Synthesis and Characterization of Compound I-7-1

[0276]

[0277] Compound I-7-1 (7 mg) was prepared using known compound 11 (J. Med. Chem. 2014, 57, 4111-4133) (0.04 mmol) as raw material according to the synthesis method of compound I-1.

[0278] The purified product I-7-1 was taken for structural characterization. 1 H-NMR(400MHz,Methanol-d4)δ 8.17(d,J=8.4Hz,1H),7.80(d,J=8.4Hz,1H),7.62-7.56(m,2H),7.56-7.4 5(m,4H),7.10(s,1H),4.70(d,J=2.8Hz,2H).LC-MS(ESI)m / z:506,508[MH] - .

[0279] Example 8. Synthesis and Characterization of Compound I-8

[0280]

[0281] Intermediate 7 (48 mg, 0.1 mmol) was dissolved in DMF-DMA (1.0 mL) and heated at 110°C with stirring for 15 hours. The DMF-DMA was evaporated under reduced pressure, and the residue was dissolved in acetic acid (1.0 mL). Hydrazine hydrate (0.2 mmol) was added and the mixture was heated at 90°C with stirring for 2 hours. LC-MS analysis confirmed the formation of Intermediate 12. Purification by silica gel column chromatography afforded Intermediate 12 (21 mg).

[0282]

[0283] Using intermediate 12 (0.04 mmol) as raw material, compound I-8 (4 mg) was prepared according to the synthesis method of compound I-2.

[0284] The purified product I-8 was characterized by LC-MS (ESI) m / z: 507, 509 [M+H] + .

[0285] Example 9. Synthesis and Characterization of Compounds I-9-1 and I-9-2

[0286]

[0287] Intermediate 15 was prepared using known compound 14 (5.0 mmol) as raw material. Sodium methyl mercaptan (1.2 eq), cesium carbonate (1.5 eq), lithium iodide (0.5 eq), and 14 (1.0 eq) were suspended in anhydrous THF under nitrogen. A 1.0 M zinc chloride THF solution (1.0 eq) was added via syringe and stirred at room temperature. Meanwhile, palladium acetate (0.1 eq) and XantPhos (0.1 eq) were mixed and dissolved in anhydrous THF, and this solution was transferred to the above suspension via syringe. The mixture was then heated in an oil bath at 70 degrees Celsius overnight. LC-MS showed that 14 was essentially consumed, with product generated. The reaction system was diluted with ethyl acetate and filtered through a layer of celite. The filtrate was spin-dried and the methylthio-substituted product (3.4 mmol) was obtained by silica gel column chromatography. This product was dissolved in anhydrous DCM and cooled in a dry ice-ethanol bath. mCPBA (1.1 eq) was added in one portion and the mixture was slowly returned to room temperature. LC-MS shows that the reaction is complete, and the solvent is removed by rotary evaporation. The residual solid is beaten with methyl tert-butyl ether to obtain sulfoxide product (3.3mmol). The sulfoxide product is dissolved in acetonitrile, pyridine (10eq) is added, and it is placed in -40 degree cold bath and stirred and bromine (2.0eq) is added dropwise, and room temperature is slowly restored subsequently. LC-MS shows that brominated product is generated. The reaction is quenched with saturated sodium bisulfite aqueous solution, and DCM extracts aqueous phase. After the organic phase is spin-dried, silica gel column chromatography prepares intermediate 15 (1.4mmol).

[0288]

[0289] Intermediate 15 (1.4 mmol) was used as the starting material, tetrazole (1.2 eq) as the nucleophile, and potassium carbonate (1.5 eq) as the base. The reaction was stirred at room temperature in DMF solvent until 15 was completely consumed. The two isomers obtained could not be separated by silica gel column chromatography. The mixture of the two isomers (1.1 eq) was used to prepare compounds I-9-1 (5 mg) and I-9-2 (1 mg) according to the synthetic route of UMI-77 (J. Med. Chem. 2014, 57, 4111-4133).

[0290] The purified product I-9-1 was characterized by LC-MS (ESI) m / z: 508, 510 [M+H] + .

[0291] The purified product I-9-2 was characterized by LC-MS (ESI) m / z: 508, 510 [M+H] + .

[0292] Example 10. Synthesis and Characterization of Compound I-10

[0293]

[0294] Known compound 14 (7.0 mmol), TMS-protected propargyl mercaptan (1.2 eq), cesium carbonate (2.5 eq), and lithium iodide (0.5 eq) were suspended in anhydrous THF under nitrogen. A 1.0 M solution of zinc chloride in THF (1.0 eq) was added via syringe and stirred at room temperature. Palladium acetate (0.1 eq) and XantPhos (0.1 eq) were mixed and dissolved in anhydrous THF, and this solution was transferred to the suspension via syringe. The mixture was then heated in an oil bath at 70°C overnight. LC-MS indicated that 14 was essentially consumed, with product formed. The reaction system was diluted with ethyl acetate and filtered through a layer of celite. The filtrate was spin-dried and purified by silica gel column chromatography to yield the thioproduct (4.1 mmol). This thioproduct was subjected to nitro reduction using reduced iron powder in acetic acid according to the UMI-77 synthetic route (J. Med. Chem. 2014, 57, 4111-4133), accompanied by removal of the TMS protecting group on the alkynyl group. After silica gel column chromatography, a naphthylamine intermediate (3.5 mmol) was obtained. Subsequently, the naphthylamine intermediate was sulfonylated according to the UMI-77 synthetic route (J. Med. Chem. 2014, 57, 4111-4133) to obtain a sulfonamide intermediate (3.2 mmol). This sulfonamide intermediate (3.2 mmol) was dissolved in a 2:1 mixture of methanol and DMF, and cuprous iodide (0.1 eq) was added. TMSN3 was added dropwise with stirring at room temperature and the reaction was allowed to proceed overnight. LC-MS indicated the formation of a triazole product, which was obtained by silica gel column chromatography (1.7 mmol). This triazole product was demethylated and oxidized according to the synthetic method of compound I-2 to prepare compound I-10.

[0295] The purified product I-10 was characterized by LC-MS (ESI) m / z: 507, 509 [M+H] + .

[0296] Example 11. Synthesis and Characterization of Compounds I-11-1 and I-11-2

[0297]

[0298] Referring to the synthetic routes of compounds I-9-1 and I-9-2, tetrazole Replaced with 1,2,3-triazole Compounds I-11-1 and I-11-2 can be prepared.

[0299] The purified product I-11-1 was characterized for structure, LC-MS (ESI) m / z: 507, 509 [M+H] + .

[0300] The purified product I-11-2 was characterized by LC-MS (ESI) m / z: 507, 509 [M+H] + .

[0301] Example 12. Synthesis and Characterization of Compound I-12

[0302]

[0303] Using known compound 14 as raw material, referring to the UMI-77 synthesis route (J.Med.Chem.2014,57,4111-4133), Replace with In the last step, according to the synthesis method of compound I-1, mCPBA is used to oxidize the sulfoxide to prepare compound I-12.

[0304] The purified product I-12 was taken for structural characterization. 1 H-NMR(400MHz,DMSO-d 6) δ10.92(br,1H),10.11(s,1H),8.24(d,J=9.6Hz,1H),7.99(d,J=9.6Hz,1H).7.58-7.56(m,2H),7.31-7.26(m,5H),7.14- 7.11(m,2H),7.09-7.06(m,2H),7.02(s,1H),4.27(d,J=12.4Hz,1H),3.91(d,J=12.4Hz,1H).LC-MS(ESI)m / z:516,518[M+H] + .

[0305] Example 13. Synthesis and Characterization of Compound I-13-1

[0306]

[0307] Using intermediate 2 as raw material, according to the synthesis method of UMI-77 and compound I-1, Replace Compound I-13-1 can be prepared.

[0308] The purified product I-13-1 was taken for structural characterization. 1 H-NMR (400MHz, DMSO-d6) δ13.19(br,1H),10.96(br,1H),10.23(s,1H),8.29-8.26(m,1H),8.03-8.00(m,1H),7.88(dd,J=2.0,5.2Hz,1H),7. 60-7.54(m,2H),7.39-7.37(m,1H),7.31(s,1H),7.09-7.06(m,1H),4.02(d,J=14.4Hz,1H),3.48(d,J=14.0Hz,1H).LC-MS(ESI)m / z:410[MH] - .

[0309] Example 14. Synthesis and Characterization of Compound I-14-1

[0310]

[0311] Using intermediate 2 as raw material, according to the synthesis method of UMI-77 and compound I-1, Replace Compound I-14-1 can be prepared.

[0312] The purified product I-14-1 was taken for structural characterization. 1 H-NMR (400MHz, DMSO-d6) δ10.28(s,1H),8.26-8.37(m,1H),7.97-7.94(m,1H),7.88(d,J=8.0Hz,2H),7.82(d,J=8. 0Hz,2H),7.58-7.51(m,2H),7.16(s,1H),3.95(d,J=14.0Hz,1H),3.42(d,J=14.0Hz,1H).LC-MS(ESI)m / z:472[MH] - .

[0313] Example 15. Synthesis and Characterization of Compound I-15-1

[0314]

[0315] Using intermediate 2 as raw material, according to the synthesis method of UMI-77 and compound I-1, Replace Compound I-15-1 can be prepared.

[0316] The purified product I-15-1 was characterized by LC-MS (ESI) m / z: 434 [MH] - .

[0317] Example 16. Synthesis and Characterization of Compound I-16-1

[0318]

[0319] Using intermediate 2 as raw material, according to the synthesis method of UMI-77 and compound I-1, Replace Compound I-16-1 can be prepared.

[0320] The purified product I-16-1 was taken for structural characterization. 1 H-NMR(400MHz,DMSO-d6)δ9.90(s,1H),8.25-8.22(m,1H),8.05-8.02(m,1H),7.59-7.56(m,4H),7.44-7.39(m,2H),7.22-7.18(m ,1H),7.12(s,1H),7.07-7.04(m,2H),7.02-7.00(m,2H),3.95(d,J=14.4Hz,1H),3.44(d,J=14.4Hz,1H).LC-MS(ESI)m / z:496[MH] - .

[0321] Example 17. Synthesis and Characterization of Compound I-17

[0322]

[0323] Using intermediate 2 as raw material, according to the synthesis method of UMI-77 and compound I-1, Replace Compound I-17-1 can be prepared.

[0324] The purified product I-17-1 was taken for structural characterization. 1H-NMR(400MHz,DMSO-d6)δ13.18(br,1H),11.04(br,1H),10.26(s,1H),8.30-8.27(m,1H),8.03-8.00(m,1H),7.81-7 .77(m,2H),7.62-7.55(m,3H),7.17(s,1H),4.02(d,J=14.0Hz,1H),3.45(d,J=14.0Hz,1H).LC-MS(ESI)m / z:472[MH] - .

[0325] Example 18. Synthesis and Characterization of Compound I-18

[0326]

[0327] Using intermediate 2 as raw material, according to the synthesis method of UMI-77 and compound I-1, Replace Compound I-18-1 can be prepared.

[0328] The purified product I-18-1 was characterized by LC-MS (ESI) m / z: 473 [MH] - .

[0329] Example 19. Synthesis and Characterization of Compound I-19

[0330]

[0331] Using intermediate 2 as raw material, according to the synthesis method of UMI-77 and compound I-1, Replace Compound I-19-1 can be prepared.

[0332] The purified product I-19-1 was characterized by LC-MS (ESI) m / z: 460 [MH] - .

[0333] Example 20. Synthesis and Characterization of Compound I-20-1

[0334]

[0335] Using intermediate 2 as raw material, according to the synthesis method of UMI-77 and compound I-1, Replace Compound I-20-1 can be prepared.

[0336] The purified product I-20-1 was taken for structural characterization.1 H-NMR(400MHz,DMSO-d6)δ9.90(s,1H),8.28-8.23(m,1H),8.06-8.02(m,1H),7.59-7.52(m,2H),7.50-7.44(m,2H),7.18-7.13(m,3H ),3.94(d,J=14.4Hz,1H),3.39(d,J=14.4Hz,1H),1.99-1.93(m,1H),1.01-0.95(m,2H),0.76-0.69(m,2H).LC-MS(ESI)m / z:444[MH] - .

[0337] Example 21. Synthesis and Characterization of Compound I-21-1

[0338]

[0339] Using intermediate 2 as raw material, according to the synthesis method of UMI-77 and compound I-1, Replace Compound I-21-1 can be prepared.

[0340] The purified product I-21-1 was taken for structural characterization. 1 H-NMR (400MHz, DMSO-d6) δ10.17(s,1H),8.24(d,J=8.0Hz,1H),7.93(d,J=8.0Hz,1H),7.74-7.70(m,2H),7.58-7.4 8(m,2H),7.48-7.45(m,2H),7.19(s,1H),3.98(d,J=14.4Hz,1H),3.44(d,J=14.4Hz,1H).LC-MS(ESI)m / z:488[MH] - .

[0341] Example 22. Synthesis and Characterization of Compound I-22-1

[0342]

[0343] Using intermediate 2 as raw material, according to the synthesis method of UMI-77 and compound I-1, Replace Compound I-22-1 can be prepared.

[0344] The purified product I-22-1 was taken for structural characterization. 1H-NMR(400MHz,DMSO-d6)δ10.41(s,1H),8.35-8.31(m,2H),8.27-8.24(m,1H),8.01-7.97(m,1H),7.90-7.86(m ,2H),7.59-7.54(m,2H),7.13(s,1H),3.96(d,J=14.4Hz,1H),3.40(d,J=14.4Hz,1H).LC-MS(ESI)m / z:449[MH] - .

[0345] Example 23. Synthesis and Characterization of Compound I-23-1

[0346]

[0347] Using intermediate 2 as raw material, according to the synthesis method of UMI-77 and compound I-1, Replace Compound I-23-1 can be prepared.

[0348] The purified product I-23-1 was taken for structural characterization. 1 H-NMR(400MHz,DMSO-d6)δ10.10(s,1H),8.26-8.23(m,1H),8.07-8.03(m,1H),7.89-7.86(m,1H),7.85-7.83(m,1H),7.62-7.51(m ,6H),7.50-7.45(m,2H),7.44-7.39(m,1H),7.28(s,1H),3.95(d,J=14.4Hz,1H),3.37(d,J=14.4Hz,1H).LC-MS(ESI)m / z:480[MH] - .

[0349] Example 24. Synthesis and Characterization of Compound I-24-1

[0350]

[0351] Using intermediate 2 as raw material, according to the synthesis method of UMI-77 and compound I-1, Replace Compound I-24-1 can be prepared.

[0352] The purified product I-24-1 was taken for structural characterization. 1H-NMR(400MHz,DMSO-d6)δ10.19(s,1H),8.27-8.25(m,1H),8.02-7.99(m,1H),7.59-7.54(m,3H),7.51-7.46(m ,2H),7.43-7.39(m,1H),7.20(s,1H),4.00(d,J=14.4Hz,1H),3.43(d,J=14.4Hz,1H).LC-MS(ESI)m / z:422[MH] - .

[0353] Example 25. Synthesis and Characterization of Compound I-25-1

[0354]

[0355] NaSO (3.8 g, 30 mmol) was dissolved in 30 mL of deionized water, and p-bromobenzenesulfonyl chloride (2.6 g, 10 mmol) was added portionwise with stirring. The mixture was heated in an oil bath at 75°C for 5 hours. After cooling, concentrated hydrochloric acid was added dropwise, and a white solid precipitated. The resulting solid was filtered and recrystallized in water to give Intermediate 16 (1.3 g). Intermediate 16 was suspended in 80 mL of DCM, and thionyl chloride (4 eq) was added dropwise. After the addition was complete, the mixture was heated to reflux in an oil bath. After 5 hours, the solvent was removed by rotary evaporation, and the residual thionyl chloride was removed with toluene to give Intermediate 17 (626 mg).

[0356]

[0357] Intermediate 17 (48 mg, 0.2 mmol) was suspended in 1 mL of DCM. Methylamine (1.5 eq) in alcohol was added under ice-water cooling, followed by triethylamine (2 eq). The mixture was allowed to return to room temperature and stirred for 2 hours. LC-MS indicated the formation of Intermediate 18. Purification by silica gel column chromatography (EA in hexane = 65% v / v) afforded Intermediate 18 as a pale yellow solid (30 mg).

[0358]

[0359] Intermediate 18 (30 mg, 0.13 mmol) was suspended in 0.5 mL of carbon tetrachloride and stirred in an ice-water bath. Tert-butyl chloride (1.5 eq) was added, and the solid immediately dissolved. Stirring was continued for 1 hour, and low-boiling substances were removed by rotary evaporation to obtain intermediate 19. 19 was then dissolved in 0.5 mL of DCM and stirred in an ice-water bath. Intermediate 2 (1 eq, prepared according to J. Med. Chem. 2014, 57, 4111-4133) was dissolved in 0.3 mL of pyridine, and this pyridine solution was added dropwise to the DCM solution of 19. The mixture was allowed to return to room temperature and stirred overnight. LC-MS indicated the formation of intermediate 20. Purification by silica gel column chromatography (EA in hexane = 40% v / v) gave intermediate 20 as an oil (51 mg).

[0360]

[0361] Intermediate 20 (51 mg, 0.1 mmol) was dissolved in 0.5 mL of DCM, and a DCM solution of BBr 3 (0.2 mL, 1 M in DCM) was added dropwise under cooling in a dry ice-ethanol bath. The mixture was slowly restored to room temperature and stirred for 3 hours. LC-MS showed that 20 was completely consumed and intermediate 21 was generated. Deionized water was added dropwise to quench the reaction, and the mixture was extracted three times with DCM. The organic phases were combined, the organic solvent was removed by rotary evaporation, and intermediate 21 (13 mg) was obtained by purification by preparative HPLC (MeCN / H 2 O / TFA). The purified 21 was subjected to structural characterization. LC-MS (ESI) m / z: 479, 481 [MH] - . 1 H-NMR(400MHz,DMSO-d6)δ(ppm):9.13(s,1H),8.36–8.28(m,1H),8.14–8.06(m,1H),7.93(d,J =8.4Hz,2H),7.83(d,J=8.4Hz,2H),7.55–7.39(m,3H),7.22(s,1H),3.61(s,2H),2.41(s,3H).

[0362]

[0363] Using intermediate 21 (13 mg) as raw material, compound I-25-1 (4 mg) was prepared according to the synthesis method of compound I-1.

[0364] The purified product I-25-1 was characterized by LC-MS (ESI) m / z: 495,497 [MH] - .

[0365] Example 26. Synthesis and Characterization of Compound I-26

[0366]

[0367] Intermediate 22 was prepared using intermediate 20 as the raw material according to the synthesis method of intermediate 1.

[0368]

[0369] Using intermediate 22 as raw material, compound I-26 was prepared according to the synthesis method of compound I-2.

[0370] The purified product I-26 was characterized by LC-MS (ESI) m / z: 509, 511 [MH] - .

[0371] Example 27. Synthesis and Characterization of Compound I-27

[0372]

[0373] According to the synthesis method of intermediate 20, the methylamine in the synthesis route is replaced by Intermediate 24 can be prepared. Intermediate 24 (1.9 mmol) was dissolved in THF, stirred at room temperature, and a 1 M TAF solution in THF was added dropwise. Stirring was continued for one hour until the TBS was completely removed. Silica gel column chromatography afforded Intermediate 25 (1.8 mmol). Intermediate 25 (1.8 mmol) and triphenylphosphine (1.2 eq) were dissolved in anhydrous THF, stirred at room temperature, and DIAD (1.2 eq) was added dropwise. Stirring was continued at room temperature overnight. LC-MS indicated the formation of the cyclized product 26. Silica gel column chromatography afforded Intermediate 26 (0.8 mmol).

[0374]

[0375] Compound I-27 can be prepared using intermediate 26 as a raw material according to the synthesis method of compound I-2.

[0376] The purified product I-27 was characterized by LC-MS (ESI) m / z: 507,509 [MH] - .

[0377] Example 28. Synthesis and Characterization of Compound I-28

[0378]

[0379] According to the synthesis method of compound I-27, Replace Compound I-28 can be prepared.

[0380] The purified product I-28 was characterized by LC-MS (ESI) m / z: 521, 523 [MH] - .

[0381] Example 29. Synthesis and Characterization of Compound I-29

[0382]

[0383] Using known compound 28 (CAS: 71127-64-5) (5.0 mmol) as starting material, intermediate 29 (0.8 mmol) was prepared according to the synthesis method described in the literature (J. Med. Chem. 2012, 55, 1978-1998). Intermediate 29 was then oxidized according to the synthesis method of compound I-1 to prepare compound I-29.

[0384] The purified product I-29 was characterized by LC-MS (ESI) m / z: 562 [MH] - .

[0385] Example 30. Synthesis and Characterization of Compound I-30

[0386]

[0387] Compound I-30 was prepared using the same synthetic route as compound I-29 using known compound 30 (CAS: 58200-82-1). The purified product I-30 was characterized for structure: LC-MS (ESI) m / z: 527, 529 [MH] - .

[0388] Example 31. Synthesis and Characterization of Compound I-31

[0389]

[0390] Compound I-31 can be prepared using the known compound 31 (CAS: 88437-16-5) as a raw material and the same synthetic route as compound I-29.

[0391] The purified product I-31 was characterized by LC-MS (ESI) m / z: 507, 509 [MH] - .

[0392] Example 32. Synthesis and Characterization of Compound I-32

[0393]

[0394] Compound I-32 can be prepared using the known compound 32 (CAS: 83441-11-6) as a raw material and the same synthetic route as compound I-29.

[0395] The purified product I-32 was characterized by LC-MS (ESI) m / z: 526,528 [MH] - .

[0396] Example 33. Synthesis and Characterization of Compound I-33

[0397]

[0398] Using intermediate 2 as raw material, referring to the synthesis methods of UMI-77 and compound I-1, the synthesis route Replace Compound I-33 can be prepared.

[0399] The purified product I-33 was characterized by LC-MS (ESI) m / z: 496,498 [MH] - .

[0400] Example 34: Synthesis and Characterization of Compound I-34

[0401]

[0402] Using intermediate 2 as raw material, according to the synthesis method of UMI-77 and compound I-34, Replace Compound I-34 can be prepared.

[0403] The purified product I-34 was taken for structural characterization. 1 H-NMR(400MHz,DMSO-d6)δ10.49(s,1H),8.35-8.32(m,1H),8.04-8.02(m,2H),7.97-7.93(m,1H),7.80-7.77(m,2 H),7.71(s,1H),7.68-7.61(m,2H),4.13(d,J=14.4Hz,1H),3.69(d,J=14.4Hz,1H).LC-MS(ESI)m / z:446,448[MH] - .

[0404] Example 35. Synthesis and Characterization of Compound I-35-1

[0405]

[0406] Using intermediate 2 as raw material, according to the synthesis method of UMI-77 and compound I-1, Replace Compound I-35-1 can be prepared.

[0407] The purified product I-35-1 was taken for structural characterization. 1 H-NMR(400MHz,DMSO-d6)δ 10.51(s,1H),8.34-8.31(m,1H),8.26(m,1H),8.07-8.05(m,1H),7.95-7.93(m,1H),7.83-7.81(m,1H),7.70(s,1H),7 .66-7.60(m,2H),7.53(t,J=8.0Hz,2H),4.11(d,J=14.4Hz,1H),3.69(d,J=14.4Hz,1H).LC-MS(ESI)m / z:446,448[MH] - .

[0408] Example 36. Synthesis and Characterization of Compound I-36

[0409]

[0410] Using intermediate 2 as raw material, according to the synthesis method of UMI-77 and compound I-1, Replace Compound I-36 can be prepared.

[0411] The purified product I-36 was taken for structural characterization. 1 H-NMR(400MHz,DMSO-d6)δ9.69(s,1H),8.25-8.23(m,1H),8.12-8.10(m,1H),8.00(s,1H),7.61-7.60(m,2H),7.5 9-7.52(m,1H),7.23(s,1H),3.86(d,J=14.4Hz,1H),3.80(s,3H),3.61(d,J=14.4Hz,1H).LC-MS(ESI)m / z:408[MH] - .

[0412] Example 37. Synthesis and Characterization of Compound I-37

[0413]

[0414] Using intermediate 2 as raw material, according to the synthesis method of UMI-77 and compound I-1, Replace Compound I-37 can be prepared.

[0415] The purified product I-37 was characterized by LC-MS (ESI) m / z: 423 [MH] - .

[0416] Example 38. Synthesis and Characterization of Compound I-38

[0417]

[0418] Using intermediate 2 as raw material, according to the synthesis method of UMI-77 and compound I-1, Replace Compound I-38 can be prepared.

[0419] The purified product I-38 was characterized by LC-MS (ESI) m / z: 483,485 [MH] - .

[0420] Example 39. Synthesis and Characterization of Compound I-39

[0421]

[0422] The known compound 30 (CAS: 58200-82-1) (10.0 mmol) was used as the raw material and the synthesis method of the literature (J. Med. Chem. 2012, 55, 1978-1998) was followed by an excess of In ethanol, nucleophilic substitution and reduction of 30 can be performed to obtain intermediate 33 (7.1 mmol). This 33 is dissolved in acetic acid and reduced iron powder (8.0 eq) is added. The mixture is heated and stirred at 50 degrees until the nitro group is completely reduced to intermediate 34. The filtrate is filtered and concentrated. The residue is dissolved in THF, triethylamine (5.0 eq) is added, and acetic anhydride (2.0 eq) is added dropwise with stirring at room temperature. Stirring is continued until LC-MS shows that intermediate 34 is completely acetylated to obtain intermediate 35. Silica gel column chromatography yields intermediate 35 (3.8 mmol). Compound I-39 can then be prepared using the same synthetic steps as compound I-29.

[0423] The purified product I-39 was characterized by LC-MS (ESI) m / z: 539,541 [MH] - .

[0424] Example 40. Synthesis and Characterization of Compound I-40-1

[0425]

[0426] Compound I-40-1 can be prepared using the known compound 36 (CAS: 4923-53-9) as the raw material and the same synthetic route as compound I-29.

[0427] The purified product I-40-1 was characterized by LC-MS (ESI) m / z: 498,500 [MH] - .

[0428] Example 41. Synthesis and Characterization of Compound I-41-1

[0429]

[0430] Compound I-41-1 can be prepared using the known compound 37 (CAS: 29263-68-1) as the raw material and the same synthetic route as compound I-29.

[0431] The purified product I-41-1 was characterized by LC-MS (ESI) m / z: 512, 514 [MH] - .

[0432] Example 42. Synthesis and Characterization of Compound I-42

[0433]

[0434] UMI-77 (15 mg, 0.032 mmol) was dissolved in DCM (0.5 mL) and stirred in a dry ice-ethanol bath. Two equivalents of 85% mCPBA (13 mg, 0.064 mmol) were added, and the mixture was slowly returned to room temperature. LC-MS analysis confirmed the formation of product I-42. The organic solvent was evaporated under reduced pressure, and the resulting crude product was purified by preparative HPLC (MeCN / H2O / TFA) to afford product I-42 (5 mg).

[0435] The purified product I-42 was taken for structural characterization. 1 H-NMR(400MHz,DMSO-d6)δ10.14(s,1H),8.37-8.34(m,1H),7.97-7.95(m,1H),7.72-7.69(m,2H ),7.64-7.61(m,2H),7.55-7.53(m,2H),7.27(s,1H),4.51(s,2H).LC-MS(ESI)m / z:498,500[MH] - .

[0436] Example 43. Synthesis and Characterization of Compound I-7-2

[0437]

[0438] Using known compound 11 (J.Med.Chem.2014, 57, 4111-4133) (0.04 mmol) as raw material, compound I-7-2 (4 mg) was prepared according to the synthesis method of compound I-42.

[0439] The purified product I-7-2 was characterized by LC-MS (ESI) m / z: 522,524 [MH] - .

[0440] Example 44. Synthesis and Characterization of Compound I-13-2

[0441]

[0442] According to the synthetic method of compounds I-13-1 and I-42, compound I-13-2 (5 mg) was prepared.

[0443] The purified product I-13-2 was characterized by LC-MS (ESI) m / z: 426 [MH] - .

[0444] Example 45. Synthesis and Characterization of Compound I-14-2

[0445]

[0446] According to the synthetic method of compounds I-14-1 and I-42, compound I-14-2 (7 mg) was prepared.

[0447] The purified product I-14-2 was characterized by LC-MS (ESI) m / z: 488 [MH] - .

[0448] Example 46. Synthesis and Characterization of Compound I-15-2

[0449]

[0450] According to the synthetic method of compounds I-15-1 and I-42, compound I-15-2 (12 mg) was prepared.

[0451] The purified product I-15-2 was characterized by LC-MS (ESI) m / z: 450 [MH] - .

[0452] Example 47. Synthesis and Characterization of Compound I-16-2

[0453]

[0454] According to the synthetic method of compounds I-16-1 and I-42, compound I-16-2 (15 mg) was prepared.

[0455] The purified product I-16-2 was characterized by LC-MS (ESI) m / z: 512 [MH] - .

[0456] Example 48. Synthesis and Characterization of Compound I-17-2

[0457]

[0458] According to the synthetic method of compounds I-17-1 and I-42, compound I-17-2 (17 mg) was prepared.

[0459] The purified product I-17-2 was taken for structural characterization, LC-MS (ESI) m / z: 488 [MH] - .

[0460] Example 49. Synthesis and Characterization of Compound I-18-2

[0461]

[0462] According to the synthetic method of compounds I-18-1 and I-42, compound I-18-2 (11 mg) was prepared.

[0463] The purified product I-18-2 was characterized by LC-MS (ESI) m / z: 489 [MH] - .

[0464] Example 50. Synthesis and Characterization of Compound I-19-2

[0465]

[0466] According to the synthetic method of compounds I-19-1 and I-42, compound I-19-2 (17 mg) was prepared.

[0467] The purified product I-19-2 was characterized by LC-MS (ESI) m / z: 476 [MH] - .

[0468] Example 51. Synthesis and Characterization of Compound I-20-2

[0469]

[0470] According to the synthetic method of compounds I-20-1 and I-42, compound I-20-2 (21 mg) was prepared.

[0471] The purified product I-20-2 was characterized by LC-MS (ESI) m / z: 460 [MH] - .

[0472] Example 52. Synthesis and Characterization of Compound I-21-2

[0473]

[0474] According to the synthetic method of compounds I-21-1 and I-42, compound I-21-2 (14 mg) was prepared.

[0475] The purified product I-21-2 was characterized by LC-MS (ESI) m / z: 504 [MH] - .

[0476] Example 53. Synthesis and Characterization of Compound I-22-2

[0477]

[0478] According to the synthetic method of compounds I-22-1 and I-42, compound I-22-2 (25 mg) was prepared.

[0479] The purified product I-22-2 was characterized by LC-MS (ESI) m / z: 465 [MH] - .

[0480] Example 54. Synthesis and Characterization of Compound I-23-2

[0481]

[0482] According to the synthetic method of compounds I-23-1 and I-42, compound I-23-2 (23 mg) was prepared.

[0483] The purified product I-23-2 was characterized by LC-MS (ESI) m / z: 496 [MH] - .

[0484] Example 55. Synthesis and Characterization of Compound I-24-2

[0485]

[0486] According to the synthetic method of compounds I-24-1 and I-42, compound I-24-2 (18 mg) was prepared.

[0487] The purified product I-24-2 was characterized by LC-MS (ESI) m / z: 438 [MH]- .

[0488] Example 56. Synthesis and Characterization of Compound I-25-2

[0489]

[0490] According to the synthetic method of compounds I-25-1 and I-42, compound I-25-2 (18 mg) was prepared.

[0491] The purified product I-25-2 was characterized by LC-MS (ESI) m / z: 511, 513 [MH] - .

[0492] Example 57. Synthesis and Characterization of Compound I-35-2

[0493]

[0494] According to the synthetic method of compounds I-35-1 and I-42, compound I-35-2 (14 mg) was prepared.

[0495] The purified product I-35-2 was taken for structural characterization. 1 H-NMR (400MHz, DMSO-d6) δ10.52(s,1H),8.44(d,J=8.0Hz,1H),8.27-8.26(m,1H),8.07(d,J=8.0Hz,1H),7.97(d,8.0Hz, 1H),7.85-7.83(m,1H),7.77(s,1H),7.76-7.67(m,1H),7.54(t,J=8.0Hz,1H),4.64(s,2H).LC-MS(ESI)m / z:462,464[MH] - .

[0496] Example 58. Synthesis and Characterization of Compound I-40-2

[0497]

[0498] According to the synthetic method of compounds I-40-1 and I-42, compound I-40-2 (3 mg) was prepared.

[0499] The purified product I-40-2 was taken for structural characterization, LC-MS (ESI) m / z: 514,516 [MH] - .

[0500] Example 59. Synthesis and Characterization of Compound I-41-2

[0501]

[0502] According to the synthetic method of compounds I-41-1 and I-42, compound I-41-2 (12 mg) was prepared.

[0503] The purified product I-41-2 was characterized by LC-MS (ESI) m / z: 528,530 [MH] - .

[0504] Example 60. Synthesis and Characterization of Compound I-43

[0505]

[0506] Using known compound 38 as raw material, compound I-43 can be prepared according to the synthetic route shown above.

[0507] The purified product I-43 was characterized by LC-MS (ESI) m / z: 462,464 [MH] - .

[0508] Example 61. Synthesis and Characterization of Compound I-44

[0509]

[0510] Intermediate 42 can be prepared from intermediate 41 by treating it with Lawesson's reagent.

[0511]

[0512] Intermediate 42 can be treated with boron tribromide to remove the methyl group to prepare compound I-44.

[0513] The purified product I-44 was characterized by LC-MS (ESI) m / z: 478,480 [MH] - .

[0514] Test Example 1: Functional test of mitochondrial autophagy inducer

[0515] Group 1: Human embryonic kidney transformed cells HEK293Tmtkeima cells were treated with 0μM, 1.25μM, 2.5μM, 5μM and 10μM CCCP, and the cells were treated with 1.5*10 5 Cells were seeded at 100 μL / well in a 96-well black microtiter plate. Compound I-2 was added 25 hours later, with triplicates set up. The cells were incubated at 37°C, 5% CO₂, and photographed every few hours using a biotekcytation 5 for a total of 20 hours. Nine images were taken per well using the bright field channel, and the images were processed using the instrument software. The resulting images are shown in Figure 1.

[0516] As shown in Figure 1, in cells treated with 0 μM CCCP, the color of the blocks treated with compound I-2 was lighter, indicating that compound I-2 could not induce mitochondrial autophagy in cells with intact mitochondria, that is, compound I-2 could not induce autophagy in non-damaged mitochondria.

[0517] As shown in Figure 1, compound I-2 was applied to cells without CCCP and cells with CCCP (10 μM), respectively. The color of the cells with CCCP was darker, indicating that in cells with damaged mitochondria, the level of mitochondrial autophagy was high after the application of compound I-2, that is, compound I-2 can selectively induce autophagy in damaged mitochondria.

[0518] Group 2: Human embryonic kidney transformed cells HEK293Tmtkeima cells were cultured at 1.5*10 5 Cells were seeded in a 96-well black microtiter plate at 100 μL per well. After 25 hours, compounds I-1 to I-44 and UMI-77 were added, with triplicates set up. The cells were cultured at 37°C and 5% CO2, and photographed every few hours using a biotekcytation 5 for a total of 20 hours. Another group of cells was cultured under the same conditions, and human embryonic kidney transformed cells, HEK293Tmtkeima cells, were cultured at 1.5*10 5 Cells were seeded in a 96-well black microtiter plate (100 μl per well) with 100 μM of each solution. After 24 hours, 5 μM or 10 μM CCCP (Carbonyl cyanide 3-chlorophenylhydrazone) was added to induce mitochondrial damage. One hour later, I-1 to I-44 and UMI-77 were added, with triplicates set up. Cultures were maintained at 37°C, 5% CO₂, and images were taken every few hours using a biotekcytation 5 for a total of 20 hours. For both groups, nine images were taken per well using the brightfield focus channel, and images were processed using the instrument software. Some of the resulting images are shown in Figure 2.

[0519] As shown in Figure 2, in the human embryonic kidney transformed cell system HEK293Tmtkeima, after treatment with 5uM or 10uM CCCP to induce mitochondrial damage, followed by the addition of compounds I-1 and I-2, the color of the blocks became darker compared to the treatment without CCCP, indicating that compounds I-1 and I-2 are more likely to induce autophagy in damaged mitochondria. In contrast, under the same conditions, UMI-77 produced darker blocks in both damaged and undamaged mitochondria, indicating that UMI-77 does not selectively induce autophagy in damaged mitochondria.

[0520] The results of the test on the ability of other compounds to induce mitochondrial autophagy are shown in Table 1:

[0521] Table 1

[0522]

[0523]

[0524] "+++" indicates that the compound has a strong ability to selectively induce autophagy of damaged mitochondria (the number of cells undergoing autophagy of damaged mitochondria / the total number of cells>0.30), "++" indicates that the compound has a moderate ability to selectively induce autophagy of damaged mitochondria (the number of cells undergoing autophagy of damaged mitochondria / the total number of cells is within the range of 0.2-0.3), "+" indicates that the compound has a weak ability to selectively induce autophagy of damaged mitochondria (the number of cells undergoing autophagy of damaged mitochondria / the total number of cells is within the range of 0.1-0.2), and "NA" indicates that no compound was detected with the ability to selectively induce autophagy of damaged mitochondria.

[0525] Note: The HEK293T mtkeima cells used in this experiment were generated by stably expressing the mtkeima protein in HEK293T cells using lentiviral packaging technology according to the method described in the literature [Cen, X. et al. Nat Commun 11, 5731 (2020)]. CCCP used in this experiment was purchased from Taoshu Biotechnology (Cat. No. T7081).

[0526] Test Example 2: In vitro liver microparticle stability test

[0527] Ketanserin was selected as the reference compound. The specific method is as follows:

[0528] Prepare 0.1M K3PO4 (pH 7.4) buffer and 3×NADPH stock solution (6mM, 5mg / mL) and preheat in a 37℃ water bath; prepare the spiking solution of the test compound and the control compound: add 5μL of the compound stock solution (10nM) to 95μL of acetonitrile; prepare 1.5μM spiking solution in microsomes (0.75mg / mL): add 1.5μL of spiking solution and 18.75μL of liver microsome solution (20mg / mL) to 479.75μL of K3PO4 buffer; take 30μL of spiking solution in microsomes and add it to the multiwell plate and incubate at 37℃ for 5min; add 15μL of The reaction was initiated with NADPH stock solution and timed. 150 μL of acetonitrile solution containing IS was added at 0, 5, 15, 30, and 45 minutes to terminate the reaction. After 10 minutes of shaking, the reaction was centrifuged at 6000 rpm for 15 minutes. 80 μL of the supernatant from each well was analyzed by LC / MS, and T1 / 2 was calculated. The test results are shown in Figure 3.

[0529] Figure 3 shows the elimination of compounds in vitro in mouse or human liver microsomes, measured by the elimination half-life (T1 / 2). In vitro liver microsomal stability studies of UMI-77 demonstrated that UMI-77 is unstable in liver microsomes and rapidly eliminated, while compounds I-1 and I-2 exhibited superior liver microsomal stability.

[0530] Note: Mouse and human liver microsomes used in the experiment were purchased from Xenotech.

[0531] Test Example 3: In vitro plasma stability test

[0532] Procaine was selected as the reference compound. The specific method is as follows:

[0533] Appropriate amounts of the test and control compounds' DMSO stock solutions were dissolved in 4 mL of plasma to a concentration of 200 μg / mL, with a DMSO content not exceeding 0.1%. The cells were incubated in a 37°C water bath for 0, 5, 15, and 30 minutes, and for 1, 2, 4, 6, 10, 24, and 48 hours. A 200 μL aliquot was added to 3 volumes of chromatography-grade acetonitrile for protein precipitation. The cells were vortexed for 5 minutes, centrifuged, and 200 μL of the supernatant was injected and analyzed by HPLC using the same HPLC conditions as before. The results are shown in Figure 4.

[0534] As shown in Figure 4, the half-life of UMI-77 is very short, indicating that UMI-77 is unstable in the plasma environment and will be eliminated quickly; while compounds I-1 and I-2 exhibit excellent plasma stability.

[0535] Test Example 4: Pharmacokinetic (PK) test in mice or rats

[0536] Experimental mice were administered an appropriate amount of the test compound according to the dosage and administration route shown in the figure. Three replicates were performed on three mice for each compound and each administration route. Numbers 101, 102, and 103 were grouped together; 201, 202, and 203 were grouped together; and 301, 302, and 303 were grouped together.

[0537] At the corresponding time points, 10 μL of mouse plasma sample was collected into a centrifuge tube, 100 μL of methanol:acetonitrile (1:1, v / v) was added, and voltammetry was performed for 1 min. After centrifugation at (14000 rpm) for 5 min, 50 μL of the supernatant was collected and mixed with an equal volume of water. After uniform mixing, the sample was analyzed by voltammetry.

[0538] The results of the mouse pharmacokinetic test are shown in Table 2.

[0539] Table 2

[0540]

[0541]

[0542] The results of the pharmacokinetic test in rats (administration I-1) are shown in Table 3.

[0543]

[0544] In Table 2 above, “NA” means that the item cannot be measured, and “ / ” means that the item was not measured.

[0545] The test results showed that UMI-77 was rapidly cleared in mouse PK experiments, and the blood drug concentration soon became unmeasurable; while compounds I-1 and I-2 exhibited good PK properties, and I-1 also exhibited good PK properties in rat PK experiments.

[0546] Note: The mice used in the PK experiments were ICR mice of SPF, purchased from Sino-British SIPPR Lab Animal Ltd, Shanghai, China. The rats used in the PK experiments were SD rats of SPF, purchased from Sino-British SIPPR Lab Animal Ltd, Shanghai, China.

[0547] Those skilled in the art will appreciate that the above-mentioned embodiments are specific examples for implementing the present invention, and that in actual applications, various changes may be made thereto in form and detail without departing from the spirit and scope of the present invention.

Claims

1. A compound having the structure shown in general formula (I) or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, wherein, where Z is R 1 is hydrogen or C 1～6 alkyl; R 2 is hydrogen, C 1～6 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkenyl, phenyl or C 1～6 alkyl-substituted phenyl; R 3 For wherein, R 3-1 is hydrogen, hydroxy, C 1～6 alkyl, C 1～6 alkoxy, C3-C6 cycloalkyl, C3-C6 epoxyalkyl, amino, C 1～6 amino, -CH 2 C(O)R 3-2 , -CH 2 C(O)OR 3-2 or -CH 2 C(O)N(R 3-2 R 3-2a ), R 3-2 and R 3-2a are each independently hydrogen, C 1～6 alkyl or C3-C6 cycloalkyl, Ar is phenyl, biphenyl, a 5- or 6-membered monocyclic heteroaryl, an 8- to 10-membered fused bicyclic heteroaryl, phenyl in which at least one hydrogen atom is replaced by R 3-3 substituted, biphenyl in which at least one hydrogen atom is replaced by R 3-3 substituted, a 5- or 6-membered monocyclic heteroaryl in which at least one hydrogen atom is replaced by R 3-3 substituted or an 8- to 10-membered fused bicyclic heteroaryl in which at least one hydrogen atom is replaced by R, wherein the R 3-3 is hydrogen, halogen, C 3-3 alkyl, a 3- to 6-membered cycloalkyl, hydroxy, C 1～6 alkoxy, a 3- to 6-membered epoxyalkyl, C 1～6 haloalkyl, C 1～6 alkenyl, C 2～6 alkynyl, -N(R 2～6 R 3-3a R 3-3b ) or phenyl, R 3-3a and R 3-3b are each independently hydrogen, C 1～6 alkyl or C3-C6 cycloalkyl; R 4 For Wherein, R 4-1 is phenyl, biphenyl, phenyl in which at least one hydrogen atom is substituted by R 4-11 , 5- or 6-membered monocyclic heteroaryl, 5- or 6-membered monocyclic heteroaryl in which at least one hydrogen atom is substituted by R 4-11 , 8- to 10-membered fused bicyclic heteroaryl or 8- to 10-membered fused bicyclic heteroaryl in which at least one hydrogen atom is substituted by R 4-11 , and the R 4-11 is hydrogen, halogen, nitro, nitrile, hydroxyl, C 1～6 alkyl, C3-C6 cycloalkyl, C 1～6 alkoxy, -N(R 4-1a R 4-1b ), phenyl, C 1～6 haloalkyl, C 1～6 haloalkoxy, -C(O)OR 4-12 , -C(O)R 4-12 , -C(O)N(R 4-1a R 4-1b ), -S(O) 2 R 4-12 , -S(O)R 4-12 , -OC(O)R 4-12 , -OC(O)OR 4-12 or R 4-12 , R 4-1a and R 4-1b are independently hydrogen, C 1～6 Alkyl, three to six membered cycloalkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, C 1～6 Alkyl, C in which at least one hydrogen is replaced by a halogen 2～6 alkenyl, a three- to six-membered cycloalkyl group in which at least one hydrogen atom is replaced by a halogen, or a C 2～6 Alkynyl, and R 4-1a and R 4-1b Can bond to each other to form a ring, R 4-2 is hydrogen, C 1～6 alkyl or C3-C6 cycloalkyl, or when R 2 is C 1～6 alkyl, R 4-2 and R 2 are bonded to form a 4- to 8-membered ring, R 4-3 is hydrogen, C 1～6 alkyl or C 1～6 alkoxy; R 5 is in the number of 0 to 5, and when R 5 is not in the number of 0, they are each independently selected from halogen, nitro, nitrile group, -N + (R 5-1 ), 3 C 1～6 haloalkyl, -C(O)OR 5-1 , -C(O)R 5-1 , -C(O)N(R 5-1 R 5-1a ), -S(O) 2 R 5-1 , -S(O)R 5-1 , -S(O) 2 N(R 5-1 R 5-1a ), -S(O)N(R 5-1 R 5-1a ), -N=C(R 5-1 R 5-1a ), hydroxyl group, C 1～6 alkyl, phenyl, phenyl with at least one hydrogen substituted by R 5-1 , C 1～6 alkoxy, -N(R 5-1 R 5-1a ), -N(R 5-1 )C(O)R 5-1a , -N(R 5-1 )C(O)OR 5-1a , -N(R 5-1 )C(O)N(R 5-1a R 5-1b ), -OC(O)R 5-1 , -OC(O)OR 5-1 , -OC(O)N(R 5-1 R 5-1a ) and -SR 5-1 , where R 5-1 , R 5-1a and R 5-1b are each independently hydrogen, C 1～6 alkyl, C 2～6 alkenyl, C 2～6 alkynyl, C 1～6 alkyl with at least one hydrogen substituted by halogen, C 2～6 alkenyl with at least one hydrogen substituted by halogen or C 2～6 alkynyl with at least one hydrogen substituted by halogen.

2. The compound according to claim 1 or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, wherein, The said Z is R 1 is hydrogen or C 1～4 alkyl; R 2 is hydrogen, C 1～4 alkyl, C3-C6 cycloalkyl or C4-C6 epoxyalkyl; R 3 For wherein, R 3-1 is hydrogen, hydroxyl, C 1～4 alkyl, C 1～4 alkoxy or -N(R 3-2 R 3-2a ), R 3-2 and R 3-2a are each independently hydrogen or C 1～4 alkyl Ar is phenyl, a 5- or 6-membered monocyclic heteroaryl or a 5- or 6-membered monocyclic heteroaryl in which at least one hydrogen atom is substituted by R 3-3 wherein the R 3-3 is hydrogen, halogen, C 1～4 alkyl, hydroxy, C 1～4 alkoxy, C 1～4 haloalkyl or -N(R 3-3a R 3-3b ), R 3-3a and R 3-3b are each independently hydrogen or C 1～4 alkyl; R 4 For Among them, R 4-1 is phenyl, phenyl in which at least one hydrogen atom is substituted by R 4-11 , 5- or 6-membered monocyclic heteroaryl, or 5- or 6-membered monocyclic heteroaryl in which at least one hydrogen atom is substituted by R 4-11 , where the R 4-11 is hydrogen, halogen, nitro, C 1～4 alkyl, C3-C6 cycloalkyl, C 1～4 alkoxy, -N(R 4-1a R 4-1b ), phenyl, C 1～4 haloalkyl, C 1～4 haloalkoxy or R 4-1a and R 4-1b are each independently hydrogen, C 1～4 alkyl or C3-C6 cycloalkyl, and R 4-1a and R 4-1b may be bonded to each other to form a ring, R 4-2 is C 1～4 alkyl, C3-C6 cycloalkyl, or when R 2 is C 1～4 alkyl, R 4-2 and R 2 are bonded to form a 4- to 8-membered ring, R 4-3 is C 1～4 alkyl or C 1～4 alkoxy; R 5 When the quantity is not 0, each independently selected from halogen, nitro, nitrile group, -N + (R 5-1 ) 3 、C 1～4 haloalkyl, -C(O)OR 5-1 、-C(O)R 5-1 、-C(O)N(R 5-1 R 5-1a )、-S(O) 2 R 5-1 、-S(O)R 5-1 、-N=C(R 5-1 R 5-1a )、hydroxyl group, C 1～4 alkyl, phenyl, phenyl with at least one hydrogen substituted by R 5-1 、C 1～4 alkoxy, -N(R 5-1 R 5-1a )、-N(R 5-1 )C(O)R 5-1a and -OC(O)R 5-1 , where R 5-1 、R 5-1a and R 5-1b are each independently hydrogen, C 1～4 alkyl, C 1～4 alkyl with at least one hydrogen substituted by halogen.

3. The compound according to claim 1 or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, wherein, wherein Z is and / or, R 1 is hydrogen; and / or, R 2 is hydrogen, methyl, ethyl, n-propyl, isopropyl, and / or, R 3 is wherein, R 3-1 is hydrogen, hydroxyl, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy or isobutoxy, Ar is phenyl, a 5- or 6-membered nitrogen-containing monocyclic heteroaryl; and / or, R 4 is wherein, R 4-1 is phenyl, phenyl in which at least one hydrogen atom is replaced by R 4-11 substituted phenyl, 5- or 6-membered monocyclic heteroaryl, 5- or 6-membered monocyclic heteroaryl in which at least one hydrogen atom is replaced by R 4-11 substituted 5- or 6-membered monocyclic heteroaryl, 8- to 10-membered fused bicyclic heteroaryl or 8- to 10-membered fused bicyclic heteroaryl in which at least one hydrogen atom is replaced by R 4-11 substituted 8- to 10-membered fused bicyclic heteroaryl, and the R 4-11 is hydrogen, halogen, nitro, methyl, ethyl, n-propyl, isopropyl, fluoromethyl, fluoroethyl, fluoropropyl, isofluoropropyl, chloromethyl, chloroethyl, chloropropyl, isochloropropyl, bromomethyl, bromoethyl, bromopropyl, isobromopropyl, iodomethyl, iodoethyl, iodopropyl, isopropyl, fluoromethoxy, fluoroethoxy, fluoropropoxy, isofluoropropoxy, chloromethoxy, chloroethoxy, chloropropoxy, isochloropropoxy, bromomethoxy, bromoethoxy, bromopropoxy, isobromopropoxy, iodooxymethyl, iodoethoxy, iodopropoxy, isopropyl or R 4-2 is methyl, ethyl, n-propyl or isopropyl, or when R 2 is methyl, ethyl or n-propyl, R 4-2 and R 2 bond to form a 4- to 8-membered ring, R 4-3 is methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy or isopropoxy; and / or, R 5 When the quantity is not 0, each independently selected from halogen, nitro, nitrile group, -N + (R 5-1 ) 3 , fluoromethyl, fluoroethyl, fluoropropyl, isofluoropropyl, chloromethyl, chloroethyl, chloropropyl, isochloropropyl, bromomethyl, bromoethyl, bromopropyl, isobromopropyl, -C(O)OR 5-1 , -C(O)R 5-1 , -C(O)N(R 5-1 R 5-1a ), -S(O) 2 R 5-1 、-S(O)R 5-1 、-N=C(R 5-1 R 5-1a )、hydroxy, methyl, ethyl, n-propyl, isopropyl, phenyl, phenyl in which at least one hydrogen is replaced by R 5-1 , methoxy, ethoxy, n-propoxy, isopropoxy, -N(R 5-1 R 5-1a ), -N(R 5-1 )C(O)R 5-1a and -OC(O)R 5-1 , wherein R 5-1 , R 5-1a and R 5-1b are each independently hydrogen, methyl, ethyl, n-propyl, isopropyl, fluoromethyl, fluoroethyl, fluoropropyl, fluoroisopropyl, chloromethyl, chloroethyl, chloropropyl, chloroisopropyl, bromomethyl, bromoethyl, bromopropyl or bromoisopropyl.

4. The compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, wherein, The Z is 5. The compound according to claim 1 or 2 or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, wherein, the compound has the structure shown in formula (II); In the formula, R 2 is hydrogen, C 1～4 alkyl, C3-C6 cycloalkyl or C4-C6 epoxyalkyl; R 3 For wherein, R 3-1 is hydrogen, hydroxyl, C 1～4 alkyl, C 1～4 alkoxy, C3-C6 cycloalkyl, C3-C6 epoxyalkyl, -N(R 3-2 R 3-2a )、-CH 2 C(O)R 3-2 、-CH 2 C(O)OR 3-2 或-CH 2 C(O)NR 3-2 R 3-2a , R 3-2 and R 3-2a are each independently hydrogen, C 1～4 alkyl or C3-C6 cycloalkyl, Ar is phenyl, a 5- or 6-membered monocyclic heteroaryl or a 5- or 6-membered monocyclic heteroaryl in which at least one hydrogen atom is substituted by R 3-3 wherein the R 3-3 is hydrogen, halogen, C 1～4 alkyl, a 3- to 6-membered cycloalkyl, hydroxy, C 1～4 alkoxy, a 3- to 6-membered epoxyalkyl, C 1～4 haloalkyl, C 2～4 alkenyl, C 2～4 alkynyl, -N(R 3-3a R 3-3b ), or phenyl, R 3-3a and R 3-3b are each independently hydrogen, C 1～4 alkyl or C3-C6 cycloalkyl; R 4 For Wherein, R 4-1 is phenyl, phenyl in which at least one hydrogen atom is substituted by R 4-11 , 5- or 6-membered monocyclic heteroaryl, 5- or 6-membered monocyclic heteroaryl in which at least one hydrogen atom is substituted by R 4-11 , 8- to 10-membered fused bicyclic heteroaryl or 8- to 10-membered fused bicyclic heteroaryl in which at least one hydrogen atom is substituted by R 4-11 , and the R 4-11 is hydrogen, halogen, nitro, C 1～4 alkyl, C3-C6 cycloalkyl, C 1～4 alkoxy, -N(R 4-1a R 4-1b ), phenyl, C 1～4 haloalkyl, C 1～4 haloalkoxy or R 4-1a and R 4-1b are each independently hydrogen, C 1～4 alkyl or C3-C6 cycloalkyl, and R 4-1a and R 4-1b may be bonded to each other to form a ring, R 4-2 is C 1～4 alkyl, C3-C6 cycloalkyl, or when R 2 is C 1～4 alkyl, R 4-2 and R 2 are bonded to form a 4- to 8-membered ring, R 4-3 is C 1～4 alkyl or C 1～4 alkoxy; R 5 When the quantity is not 0, each independently selected from halogen, nitro, nitrile group, -N + (R 5-1 ) 3 、C 1～4 haloalkyl, -C(O)OR 5-1 、 -C(O)R 5-1 、 -C(O)N(R 5-1 R 5-1a )、 -S(O) 2 R 5-1 、 -S(O)R 5-1 、 -N=C(R 5-1 R 5-1a )、 hydroxy, C 1～4 alkyl, phenyl, phenyl in which at least one hydrogen is replaced by R 5-1 , C 1～4 alkoxy, -N(R 5-1 R 5-1a ), -N(R 5-1 )C(O)R 5-1a 、 -OC(O)R 5-1 、 -OC(O)N(R 5-1 R 5-1a ) and -SR 5-1 , wherein R 5-1 , R 5-1a and R 5-1b are each independently hydrogen, C 1～4 alkyl, C 2～4 alkenyl, C 2～4 alkynyl, C 1～4 alkyl in which at least one hydrogen is replaced by halogen, C 2～4 alkenyl in which at least one hydrogen is replaced by halogen or C 2～4 alkynyl in which at least one hydrogen is replaced by halogen.

6. The compound according to claim 5 or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, wherein, R 5 When the quantity is not 0, each independently selected from halogen, nitro, cyano, -N + (R 5-1 ) 3 , C 1～4 haloalkyl, -C(O)OR 5-1 , -C(O)R 5-1 , -C(O)N(R 5-1 R 5-1a ), -S(O) 2 R 5-1 , -S(O)R 5-1 and -N=C(R 5-1 R 5-1a ); wherein, R 5-1 and R 5-1a are each independently hydrogen, C 1～4 alkyl, C 2～4 alkenyl, C 2～4 alkynyl, C 1～4 alkyl in which at least one hydrogen is substituted by a halogen, C 2～4 alkenyl in which at least one hydrogen is substituted by a halogen or C 2～4 alkynyl in which at least one hydrogen is substituted by a halogen.

7. The compound according to claim 1 or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, wherein, the compound has the structure shown in formula (III); In the formula, R 2 is hydrogen, C 1～4 alkyl, C3-C6 cycloalkyl or C4-C6 epoxyalkyl; R 3 For wherein, R 3-1 is hydrogen, hydroxy, C 1～4 alkyl, C 1～4 alkoxy, C3-C6 cycloalkyl, C3-C6 epoxyalkyl, -N(R 3-2 R 3-2a )、-CH 2 C(O)R 3-2 、-CH 2 C(O)OR 3-2 或-CH 2 C(O)NR 3-2 R 3-2a , R 3-2 and R 3-2a are each independently hydrogen, C 1～4 alkyl or C3-C6 cycloalkyl, Ar is phenyl, a 5- or 6-membered monocyclic heteroaryl, or a 5- or 6-membered monocyclic heteroaryl in which at least one hydrogen atom is replaced by R 3-3 wherein R 3-3 is hydrogen, halogen, C 1～4 alkyl, a 3- to 6-membered cycloalkyl, hydroxy, C 1～4 alkoxy, a 3- to 6-membered epoxyalkyl, C 1～4 haloalkyl, C 2～4 alkenyl, C 2～4 alkynyl, -N(R 3-3a R 3-3b ), or phenyl R 3-3a and R 3-3b are each independently hydrogen, C 1～4 alkyl or C3-C6 cycloalkyl; R 4 For Wherein, R 4-1 is phenyl, phenyl in which at least one hydrogen atom is replaced by R 4-11 substituted phenyl, 5- or 6-membered monocyclic heteroaryl, 5- or 6-membered monocyclic heteroaryl in which at least one hydrogen atom is replaced by R 4-11 substituted 5- or 6-membered monocyclic heteroaryl, 8- to 10-membered fused bicyclic heteroaryl or 8- to 10-membered fused bicyclic heteroaryl in which at least one hydrogen atom is replaced by R 4-11 substituted 8- to 10-membered fused bicyclic heteroaryl, and the R 4-11 is hydrogen, halogen, nitro, C 1～4 alkyl, C3-C6 cycloalkyl, C 1～4 alkoxy, -N(R 4-1a R 4-1b ), phenyl, C 1～4 haloalkyl, C 1～4 haloalkoxy or R 4-1a and R 4-1b are each independently hydrogen, C 1～4 alkyl or C3-C6 cycloalkyl, and R 4-1a and R 4-1b may be bonded to each other to form a ring, R 4-2 is C 1～4 alkyl or C3-C6 cycloalkyl, or when R 2 is C 1～4 alkyl, R 4-2 and R 2 are bonded to form a 4- to 8-membered ring R 4-3 is C 1～4 alkyl or C 1～4 alkoxy; R 5 When the quantity is not 0, each independently selected from halogen, nitro, nitrile group, -N + (R 5-1 ) 3 , C 1～4 haloalkyl, -C(O)OR 5-1 、 -C(O)R 5-1 、 -C(O)N(R 5-1 R 5-1a )、 -S(O) 2 R 5-1 、 -S(O)R 5-1 、 -N=C(R 5-1 R 5-1a )、 hydroxy, C 1～4 alkyl, phenyl, phenyl in which at least one hydrogen is replaced by R 5-1 , C 1～4 alkoxy, -N(R 5-1 R 5-1a ), -N(R 5-1 )C(O)R 5-1a 、 -OC(O)R 5-1 、 -OC(O)N(R 5-1 R 5-1a ) or -SR 5-1 , where R 5-1 , R 5-1a and R 5-1b are each independently hydrogen, C 1～4 alkyl, C 2～4 alkenyl, C 2～4 alkynyl, C 1～4 alkyl in which at least one hydrogen is replaced by halogen, C 2～4 alkenyl in which at least one hydrogen is replaced by halogen and C 2～4 alkynyl in which at least one hydrogen is replaced by halogen.

8. The compound according to claim 7 or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, wherein, R 5 When the quantity is not 0, they are each independently selected from hydroxy, C 1～4 alkyl, phenyl, phenyl in which at least one hydrogen is replaced by R 5-1 substituted phenyl, C 1～4 alkoxy, -N(R 5-1 R 5-1a ), -N(R 5-1 )C(O)R 5-1a , -OC(O)R 5-1 , -OC(O)N(R 5-1 R 5-1a ), or -SR 5-1 , where R 5-1 , R 5-1a and R 5-1b are each independently hydrogen, C 1～4 alkyl, C 2～4 alkenyl, C 2～4 alkynyl, C 1～4 alkyl in which at least one hydrogen is replaced by halogen, C 2～4 alkenyl in which at least one hydrogen is replaced by halogen and C 2～4 alkynyl in which at least one hydrogen is replaced by halogen.

9. The compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, wherein, the compound is selected from any one of the following compounds:

10. A pharmaceutical composition, wherein, the pharmaceutical composition comprises the compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof.

11. Use of the compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, or the pharmaceutical composition according to claim 10 in the preparation of a mitophagy inducer.

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