Low molecular weight compound having a naphthalene thiol ether structure and use thereof

Abstract

The present application discloses a small molecule compound having a naphthalene thiol ether structure and its use. The present application discloses a compound having a structure represented by general formula (I) and its pharma- ceutically acceptable salt, stereoisomer, solvate or prodrug, a pharmaceutical composition containing the same, and its use in the manufacture of a mitophagy inducer pharmaceutical. In the present application, the structure of the compound having a structure represented by general formula (I) is as follows. The compound provided by the present application and its pharma- ceutically acceptable salt, stereoisomer, solvate or prodrug, or the pharmaceutical composition provided by the present application, improves the ability to induce mitophagy. TIFF2024535879000098.tif60170

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This patent application claims priority to a Chinese patent application filed on September 22, 2021, with application number 2021111068648 and title "Low molecular weight compound having naphthalene thiol ether structure and use thereof," the entire text of which is incorporated herein by reference.

[0002] The present invention relates to the field of chemicals, and in particular to low molecular weight compounds having a naphthalene thiol ether structure and uses thereof. [Background technology]

[0003] Mitophagy is a type of cell-targeted autophagy whose primary purpose is to identify and remove dysfunctional mitochondria. Mitochondria play a central role in energy supply through oxidative phosphorylation and perform essential functions such as energy metabolism, amino acid synthesis, lipid synthesis, and ion homeostasis. Therefore, they are crucial for maintaining the function of cell types dependent on aerobic metabolism, such as neurons, muscle cells, and hepatocytes. Regulation of mitochondrial biogenesis and autophagy homeostasis is a crucial step for maintaining cellular function. Mitophagy dysfunction leads to the accumulation of damaged mitochondria, reduced ATP synthesis capacity, and the generation of large amounts of peroxides, which alters cellular intermediate metabolites and leads to a series of pathological consequences. By enhancing mitophagy and removing aged or dysfunctional mitochondria, mitophagy plays a protective role.

[0004] In the prior art, the Chinese patent application with application number 201910386493.X describes the compound UMI-77 as a mitophagy inducer. However, the inventors' research has revealed that the compound UMI-77 has problems as a mitophagy inducer, including unstable mitophagy induction, insufficient mitophagy induction ability, and low metabolic stability. Therefore, the development of an efficient and stable mitophagy inducer is crucial for the prevention or alleviation of various acute and chronic diseases caused by mitophagy dysfunction. Summary of the Invention

[0005] To solve the above problems, embodiments of the present invention provide a small molecule compound having a naphthalene thiol ether structure, which acts as a mitophagy inducer and has a strong ability to induce mitophagy.

[0006] A first aspect of the present invention provides compounds having a structure represented by general formula (I) and pharmaceutically acceptable salts, stereoisomers, solvates or prodrugs thereof. TIFF0007823934000001.tif60170wherein X is oxygen or nitrogen; R 3 is hydrogen, TIFF0007823934000002.tif17170, where R 31 and R 32 are each independently C 1~6 Alkyl or C 1~6 cycloalkyl, and n is 1 to 4; In each general formula and context of this specification, unless otherwise specified, R 4 may be absent (i.e., 0), or may be present in one or more instances simultaneously if the valence bond rules permit, so R 4 The number of R is, for example, 0 to 5, preferably 0 to 4, and more preferably 0 to 2 or 0 to 1. 4 If the number is not 0, each independently represents a halogen, nitro, nitrile, -N + (R4-1 )3, C 1~6 Haloalkyl, -C(O)OR 4-1 , -C(O)R 4-1 , -C(O)N(R 4-1 R 4-1a ), -S(O)R 4-1 , -S(O)R 4-1 , -N=C(R 4-1 R 4-1a ), where R 4-1 and R 4-1a are independently hydrogen, C 1~6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C with at least one hydrogen atom replaced by halogen 1~6 Alkyl, C with at least one hydrogen atom replaced by halogen 2-6 Alkenyl or C in which at least one hydrogen atom is replaced by halogen 2-6 alkynyl.

[0007] R 5 is phenyl, naphthyl, 5- or 6-membered monocyclic heteroaryl, 8- to 10-membered fused bicyclic heteroaryl, at least one hydrogen atom is R 5-1 phenyl substituted with at least one hydrogen atom 5-1 naphthyl substituted with at least one hydrogen atom of R 5-1 5- or 6-membered monocyclic heteroaryl substituted with at least one hydrogen atom of R 5-1 and 8-10 membered fused bicyclic heteroaryl substituted with R 5-1 is hydrogen, halogen, nitro, nitrile, hydroxyl, C 1~6 Alkyl, C 3~6 Cycloalkyl, C 1~6 Alkoxy, -N(R 5-1a R 5-1b ), phenyl, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, -C(O)OR 5-11 , -C(O)R 5-11 , -C(O)N(R 5-1a R 5-1b ), -S(O)R5-11 , -S(O)R 5-11 , -OC(O)R 5-11 , -OC(O)OR 5-11 or TIFF0007823934000003.tif15170, where R 5-11 , R 5-1a and R 5-1b are independently hydrogen, C 1~6 Alkyl, 3-6 membered cycloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C with at least one hydrogen atom replaced by halogen 1~6 Alkyl, C with at least one hydrogen atom replaced by halogen 2-6 Alkenyl, C with at least one hydrogen atom replaced by halogen 3~6 Cycloalkyl, C with at least one hydrogen atom replaced by halogen 2-6 alkynyl; R 6 -C(O)OR 6-1 , 5- or 6-membered monocyclic heteroaryl, where R 6-1 is hydrogen, C 1~6 Alkyl, 3-6 membered cycloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C with at least one hydrogen atom replaced by halogen 1~6 Alkyl, C with at least one hydrogen atom replaced by halogen 2-6 Alkenyl, C with at least one hydrogen atom replaced by halogen 3~6 Cycloalkyl, C with at least one hydrogen atom replaced by halogen 2-6 is alkynyl; m is 1 to 6; and If X is oxygen, the dotted line is absent and R 2 no longer exists, and R 1 is C 1~6 alkyl, 3- to 6-membered cycloalkyl, 3- to 6-membered epoxyalkyl, phenyl, at least one hydrogen atom of which is R 1-1 C replaced with 1~6 alkyl, at least one hydrogen atom is R 1-1phenyl substituted with, where R 1-1 is hydroxyl, halogen, amino or C 1~6 is alkoxy; If X is nitrogen, the dotted line becomes a single bond, R 1 is hydrogen, C 1~6 alkyl, 3- to 6-membered cycloalkyl, 3- to 6-membered epoxyalkyl, phenyl, at least one hydrogen atom of which is R 1-1 C replaced with 1~6 alkyl, at least one hydrogen atom is R 1-2 phenyl substituted with, where R 1-2 is hydroxyl, halogen, amino or C 1~6 is an alkoxy, R 2 is C 1~6 alkyl, 3- to 6-membered cycloalkyl, 3- to 6-membered epoxyalkyl, at least one hydrogen atom is R 2-1 C replaced with 1~6 alkyl, where R 2-1 is hydroxyl, halogen, amino or C 1~6 is alkoxy; X is nitrogen and R 1 and R 2 independently C 1~6 If it is alkyl, R 1 and R 2 can be linked to form a 4- to 8-membered ring.

[0008] In some preferred embodiments, the compound having the structure represented by general formula (I) is X is oxygen or nitrogen; R 3 is hydrogen, TIFF0007823934000004.tif17170, where R 31 and R 32 are each independently C 1~4 Alkyl or C 1~4 cycloalkyl, and n is 1 or 2; R 4When the number is not 0, each independently represents a halogen, nitro, nitrile, -N + (R 4-1 )3, C 1~4 Haloalkyl, -C(O)OR 4-1 , -C(O)R 4-1 , -C(O)N(R 4-1 R 4-1a ), -S(O)R 4-1 , -S(O)R 4-1 , -N=C(R 4-1 R 4-1a ), where R 4-1 and R 4-1a are independently hydrogen, C 1~4 Alkyl, C 2-4 Alkenyl, C 2-4 is alkynyl; R 5 is phenyl, naphthyl, 5- or 6-membered monocyclic heteroaryl, at least one hydrogen atom is R 5-1 phenyl substituted with at least one hydrogen atom 5-1 naphthyl substituted with at least one hydrogen atom of R 5-1 and R is a 5- or 6-membered monocyclic heteroaryl substituted with 5-1 is hydrogen, halogen, nitro, nitrile, hydroxyl, C 1~4 Alkyl, 3-6 membered cycloalkyl, C 1~4 Alkoxy, -N(R 5-1a R 5-1b ), phenyl, C 1~4 Haloalkyl, C 1~4 Haloalkoxy, -C(O)OR 5-11 , -C(O)R 5-11 , -C(O)N(R 5-1a R 5-1b ), -S(O)R 5-11 , -S(O)R 5-11 , -OC(O)R 5-11 , -OC(O)OR 5-11 or TIFF0007823934000005.tif15170, where R 5-11 , R 5-1a and R 5-1b are independently hydrogen, C1~4 Alkyl, 3-6 membered cycloalkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C with at least one hydrogen atom replaced by halogen 1~4 is alkyl; R 6 -C(O)OR 6-1 , 5- or 6-membered monocyclic heteroaryl, where R 6-1 is hydrogen, C 1~4 Alkyl, 3- to 6-membered cycloalkyl, C with at least one hydrogen atom replaced by halogen 1~4 is alkyl; m is 1 to 4; and If X is oxygen, the dotted line is absent and R 2 no longer exists, and R 1 is C 1~4 alkyl, 3- to 6-membered cycloalkyl, 3- to 6-membered epoxyalkyl, phenyl, at least one hydrogen atom of which is R 1-1 C replaced with 1~4 alkyl, at least one hydrogen atom is R 1-1 phenyl substituted with, where R 1-1 is hydroxyl, halogen, amino or C 1~4 is alkoxy; If X is nitrogen, the dotted line becomes a single bond, R 1 is hydrogen, C 1~4 alkyl, 3- to 6-membered cycloalkyl, 3- to 6-membered epoxyalkyl, phenyl, at least one hydrogen atom of which is R 1-1 C replaced with 1~4 alkyl, at least one hydrogen atom is R 1-2 phenyl substituted with, where R 1-2 is hydroxyl, halogen, amino or C 1~4 is an alkoxy, R 2 is C 1~4 alkyl, 3- to 6-membered cycloalkyl, 3- to 6-membered epoxyalkyl, at least one hydrogen atom is R 2-1 C replaced with 1~4 alkyl, where R 2-1is hydroxyl, halogen, amino or C 1~4 is alkoxy; X is nitrogen and R 1 and R 2 independently C 1~4 If it is alkyl, R 1 and R 2 can be linked to form a 4- to 8-membered ring.

[0009] In some preferred embodiments, the compound having the structure represented by general formula (I) is X is oxygen or nitrogen; R 3 is hydrogen, TIFF0007823934000006.tif17170, where R 31 and R 32 are each independently methyl, ethyl, n-propyl, or isopropyl, and n is 1; R 4 are each independently fluorine, chlorine, bromine, iodine, nitro, nitrile, fluoromethyl, fluoroethyl, fluoro-n-propyl, fluoroisopropyl, chloromethyl, chloroethyl, chloro-n-propyl, chloroisopropyl, bromomethyl, bromoethyl, bromo-n-propyl, bromoisopropyl, iodomethyl, iodoethyl, iodo-n-propyl, or iodoisopropyl, when the number is not 0; R 5 is phenyl, naphthyl, 5-membered monocyclic heteroaryl, at least one hydrogen atom is R 5-1 phenyl substituted with, where R 5-1is fluorine, chlorine, bromine, iodine, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butyloxy, sec-butoxy or isobutoxy, phenyl, 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-npropoxy, chloroisopropoxy, bromomethoxy, bromoethoxy, bromo-n-propoxy, bromoisopropoxy, iodooxymethyl, iodoethoxy, iodo-n-propoxy, iodoisopropoxy or TIFF0007823934000007.tif15170; R 6 -C(O)OR 6-1 , 5-membered nitrogen-containing monocyclic heteroaryl, preferably pyridyl, diazolyl, triazolyl or tetrazolyl, more preferably triazolyl or tetrazolyl, and even more preferably TIFF0007823934000008.tif17170 Here R 6-1 is hydrogen, methyl, ethyl, n-propyl, isopropyl, TIFF0007823934000009.tif14170m is 1; and If X is oxygen, the dotted line is absent and R 2 no longer exists, and R 1 is methyl, ethyl, n-propyl, isopropyl, TIFF0007823934000010.tif35170phenyl, methyl having at least one hydrogen atom substituted with hydroxyl, ethyl having at least one hydrogen atom substituted with hydroxyl, n-propyl having at least one hydrogen atom substituted with hydroxyl, isopropyl having at least one hydrogen atom substituted with hydroxyl; If X is nitrogen, the dotted line becomes a single bond, R 1 is hydrogen, methyl, ethyl, n-propyl, isopropyl, TIFF0007823934000011.tif35170 or phenyl, R 2 is methyl, ethyl, n-propyl, isopropyl, TIFF0007823934000012.tif35170Methyl having at least one hydrogen atom substituted with hydroxyl, ethyl having at least one hydrogen atom substituted with hydroxyl, n-propyl having at least one hydrogen atom substituted with hydroxyl, or isopropyl having at least one hydrogen atom substituted with hydroxyl; X is nitrogen and R 1 and R 2 is independently methyl, ethyl, n-propyl, or isopropyl, R 1 and R 2 can be linked to form a 4- to 8-membered ring.

[0010] In some preferred embodiments, the C 1~6 Alkyl is C 1~4 alkyl, 1~4 Alkyl is preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, for example: methyl or ethyl.

[0011] In some preferred embodiments, the C 3~6 Cycloalkyl is preferably C 3~5 cycloalkyl, wherein C 3~5 Cycloalkyl is preferably TIFF0007823934000013.tif14170

[0012] In some preferred embodiments, the 3- to 6-membered epoxyalkyl is preferably TIFF0007823934000014.tif35170

[0013] In some preferred embodiments, the C 1~6 The alkyl-substituted phenyl is preferably C 1~4 It is phenyl substituted with alkyl, and more preferably phenyl substituted with any one of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl.

[0014] In some preferred embodiments, the C 1~6 The alkoxy is preferably C 1~4 Alkoxy is more preferably methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butyloxy, sec-butoxy or isobutoxy.

[0015] 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 TIFF0007823934000015.tif46170

[0016] In some preferred embodiments, the 5- or 6-membered monocyclic heteroaryl is preferably TIFF0007823934000016.tif21170, wherein Y1, Y2, Y3, Y4, Y5, Y6, Y7, Y8, and Y9 are each 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, thiophenepyryl, pyridazinyl, pyrimidinyl, pyrazinyl, piperazinyl, triazolyl, or tetrazolyl; the 5- or 6-membered monocyclic heteroaryl is more preferably TIFF0007823934000017.tif161170; more preferably, the 5- or 6-membered monocyclic heteroaryl is a 5- or 6-membered nitrogen-containing monocyclic heteroaryl, such as: TIFF0007823934000018.tif55170; most preferably, the 5- or 6-membered monocyclic heteroaryl is a 5-membered nitrogen-containing monocyclic heteroaryl, such as: TIFF0007823934000019.tif18170

[0017] In some preferred embodiments, the 8-10 membered fused bicyclic heteroaryl is TIFF0007823934000020.tif91170; where Y 11 , Y 12 , Y 13 , Y 14 , Y 15 , Y 16 , Y 17 , Y 18 and Y 19 are each 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 All are Y instead of C. 21 , Y 22 , Y 23 , Y 24 , Y 25 and Y 26 are each independently selected from C, N, O, or S, and Y 21 , Y 22 , Y 23 , Y 24 , Y 25 and Y 26 All are Y instead of C. 31 , Y 32 , Y 33 , Y 34 , Y 35 , Y 36 and Y 37are each independently selected from C, N, O, or S, and Y 31 , Y 32 , Y 33 , Y 34 , Y 35 , Y 36 and Y 37 are not all C; said 8-10 membered fused bicyclic heteroaryl is more preferably indolyl, benzindolyl, carbazolyl, quinolyl, pteridinyl, purinyl; said 8-10 membered fused bicyclic heteroaryl is most preferably TIFF0007823934000021.tif22170

[0018] In some preferred embodiments, the halogen is preferably fluorine, chlorine, bromine, or iodine.

[0019] In some preferred embodiments, the C 1~6 Haloalkyl is preferably C 1~3 It is haloalkyl; more preferably fluoromethyl, fluoroethyl, fluoro-n-propyl, fluoroisopropyl, chloromethyl, chloroethyl, chloro-n-propyl, chloroisopropyl, bromomethyl, bromoethyl, bromo-n-propyl, bromoisopropyl, iodomethyl, iodoethyl, iodo-n-propyl, iodoisopropyl; and most preferably trifluoromethyl.

[0020] In some preferred embodiments, the C 1~6 Haloalkoxy is preferably C 1~3 It is haloalkoxy; more preferably fluoromethoxy, fluoroethoxy, fluoro-n-propoxy, fluoroisopropoxy, chloromethoxy, chloroethoxy, chloro-n-propoxy, chloroisopropoxy, bromomethoxy, bromoethoxy, bromo-n-propoxy, bromoisopropoxy, iodooxymethyl, iodoethoxy, iodo-n-propoxy, iodoisopropoxy; and most preferably trifluoromethoxy.

[0021] In some preferred embodiments, the C 2-6 Alkenyl is preferably C 2-4 Alkenyl, more preferably -CH=CH2, -CH=CH-CH3, -CH2-CH=CH2, -CH=CH-CH2-CH3, -CH=CH-CH=CH2.

[0022] In some preferred embodiments, the C 2-6 Alkynyl is preferably C 2-6 Alkynyl, more preferably -C≡CH, -CH2-C≡CH, -CH2-CH2-C≡CH, -CH2-C≡C-CH3.

[0023] In some more preferred embodiments, R 1 is hydrogen, C 1~6 alkyl (preferably methyl), 3- to 6-membered cycloalkyl (preferably cyclopropyl), 3- to 6-membered epoxyalkyl (preferably oxetane), phenyl, at least one hydrogen atom of which is R 1-1 (preferably hydroxyl as defined in the context of the present specification) 1~6 alkyl.

[0024] In some more preferred embodiments, R 4 When the number is not 0, each independently represents nitrile, amino, nitro, halogen, C 1~6 It is haloalkyl.

[0025] In some more preferred embodiments, R 5 is selected from phenyl, naphthyl, 5- or 6-membered monocyclic heteroaryl (e.g., thienyl, pyrazolyl, isoxazolyl, pyridyl), 8- to 10-membered fused bicyclic heteroaryl (e.g., benzothienyl), preferably phenyl or naphthyl; halogen, phenyl, nitrile, hydroxyl, C 1~6 Alkyl, C 1~6 haloalkyl, Optionally substituted with a group selected from TIFF0007823934000022.tif15170.

[0026] In some more preferred embodiments, m is 1.

[0027] In some more preferred embodiments, R 6 -C(O)OR 6-1 (R 6-1 is defined in the context of the present specification and is preferably hydrogen) and 5- or 6-membered monocyclic heteroaryl (preferably triazolyl and tetrazolyl).

[0028] In some more preferred embodiments, X is nitrogen and R 2 is C 1~6 alkyl (preferably methyl), 3- to 6-membered cycloalkyl (preferably cyclopropyl), 3- to 6-membered epoxyalkyl (preferably oxetane), phenyl, at least one hydrogen atom of which is R 1-1 (preferably hydroxyl as defined in the context of the present specification) 1~6 In particular, in some preferred embodiments, R 1 and R 2 are both C 1~6 alkyl, and R 1 and R 2 are bonded to form a 4- to 8-membered (preferably 5- or 6-membered) ring.

[0029] In some preferred embodiments, R 3 is hydrogen, TIFF0007823934000023.tif17170, where R 31 and R 32 are each independently methyl, n-propyl, or isopropyl, and n is 1.

[0030] In some preferred embodiments, R 4 The number of is 0 to 2 (especially 0 to 1), and R 4 When the number is not 0, each independently represents fluorine, chlorine, bromine, iodine, nitro, or nitrile.

[0031] In some preferred embodiments, R 5 is phenyl, naphthyl, thienyl, or at least one hydrogen atom is R 5-1 phenyl substituted with, where R 5-1 is fluorine, chlorine, bromine, iodine, phenyl, fluoromethyl or The file is TIFF0007823934000024.tif15170.

[0032] In some preferred embodiments, R 6 is —C(O)OH, triazolyl or tetrazolyl.

[0033] In some preferred embodiments, the compound having the structure represented by general formula (I) is selected from any one of the following compounds: TIFF0007823934000025.tif228170TIFF0007823934000026.tif246170TIFF0007823934000027.tif234170TIFF0007823934000028.tif246170TIFF0007823934000029.tif115170Furthermore, the inventors have also found that UMI-77 is unable to selectively induce autophagy in damaged mitochondria, and based on the fact that it would be beneficial to improve the ability of a compound to selectively induce autophagy in damaged mitochondria, in some preferred embodiments, the compound has a structure represented by formula (II): TIFF0007823934000030.tif66170 where, R 3 is hydrogen, TIFF0007823934000031.tif17170, where R 31 and R 32 are each independently C 1~6 Alkyl or C 1~6 cycloalkyl, and n is 1 to 4; R 4When the number is not 0, each independently represents a halogen, nitro, nitrile, -N + (R 4-1 )3, C 1~6 Haloalkyl, -C(O)OR 4-1 , -C(O)R 4-1 , -C(O)N(R 4-1 R 4-1a ), -S(O)R 4-1 , -S(O)R 4-1 , -N=C(R 4-1 R 4-1a ), where R 4-1 and R 4-1a are independently hydrogen, C 1~6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C with at least one hydrogen atom replaced by halogen 1~6 Alkyl, C with at least one hydrogen atom replaced by halogen 2-6 Alkenyl or C in which at least one hydrogen atom is replaced by halogen 2-6 is alkynyl; R 5 is phenyl, naphthyl, 5- or 6-membered monocyclic heteroaryl, 8- to 10-membered fused bicyclic heteroaryl, at least one hydrogen atom is R 5-1 phenyl substituted with at least one hydrogen atom 5-1 naphthyl substituted with at least one hydrogen atom of R 5-1 5- or 6-membered monocyclic heteroaryl substituted with at least one hydrogen atom of R 5-1 and 8-10 membered fused bicyclic heteroaryl substituted with R 5-1 is hydrogen, halogen, nitro, nitrile, hydroxyl, C 1~6 Alkyl, C 3~6 Cycloalkyl, C 1~6 Alkoxy, -N(R 5-1a R 5-1b ), phenyl, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, -C(O)OR 5-11 , -C(O)R 5-11 , -C(O)N(R 5-1a R5-1b ), -S(O)R 5-11 , -S(O)R 5-11 , -OC(O)R 5-11 , -OC(O)OR 5-11 or TIFF0007823934000032.tif15170, where R 5-11 , R 5-1a and R 5-1b are independently hydrogen, C 1~6 Alkyl, 3-6 membered cycloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C with at least one hydrogen atom replaced by halogen 1~6 Alkyl, C with at least one hydrogen atom replaced by halogen 2-6 Alkenyl, C with at least one hydrogen atom replaced by halogen 3~6 Cycloalkyl, C with at least one hydrogen atom replaced by halogen 2-6 is alkynyl; R 6 -C(O)OR 6-1 , 5- or 6-membered monocyclic heteroaryl, where R 6-1 is hydrogen, C 1~6 Alkyl, 3-6 membered cycloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C with at least one hydrogen atom replaced by halogen 1~6 Alkyl, C with at least one hydrogen atom replaced by halogen 2-6 Alkenyl, C with at least one hydrogen atom replaced by halogen 3~6 Cycloalkyl, C with at least one hydrogen atom replaced by halogen 2-6 is alkynyl; m is 1 to 6; R 1 is C 1~6 alkyl, 3- to 6-membered cycloalkyl, 3- to 6-membered epoxyalkyl, phenyl, at least one hydrogen atom of which is R 1-1 C replaced with 1~6 alkyl, at least one hydrogen atom is R 1-1 phenyl substituted with, where R1-1 is hydroxyl, halogen, amino or C 1~6 It is an alkoxy.

[0034] Based on the fact that it would be beneficial to improve the ability of a compound to selectively induce autophagy in damaged mitochondria, in some more preferred embodiments, the compound has a structure represented by formula (II): where R 3 is hydrogen, TIFF0007823934000033.tif17170, where R 31 and R 32 are each independently C 1~6 Alkyl or C 1~6 cycloalkyl, and n is 1 to 4; R 4 When the number is not 0, each independently represents a halogen, nitro, nitrile, -N + (R 4-1 )3, C 1~6 Haloalkyl, -C(O)OR 4-1 , -C(O)R 4-1 , -C(O)N(R 4-1 R 4-1a ), -S(O)R 4-1 , -S(O)R 4-1 , -N=C(R 4-1 R 4-1a ), where R 4-1 and R 4-1a are independently hydrogen, C 1~6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C with at least one hydrogen atom replaced by halogen 1~6 Alkyl, C with at least one hydrogen atom replaced by halogen 2-6 Alkenyl or C in which at least one hydrogen atom is replaced by halogen 2-6 is alkynyl; R 5 is phenyl, naphthyl, 5- or 6-membered monocyclic heteroaryl, 8- to 10-membered fused bicyclic heteroaryl, at least one hydrogen atom is R 5-1phenyl substituted with at least one hydrogen atom 5-1 naphthyl substituted with at least one hydrogen atom of R 5-1 5- or 6-membered monocyclic heteroaryl substituted with at least one hydrogen atom of R 5-1 and 8-10 membered fused bicyclic heteroaryl substituted with R 5-1 is hydrogen, halogen, nitro, nitrile, hydroxyl, C 1~6 Alkyl, C 3~6 Cycloalkyl, C 1~6 Alkoxy, -N(R 5-1a R 5-1b ), phenyl, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, -C(O)OR 5-11 , -C(O)R 5-11 , -C(O)N(R 5-1a R 5-1b ), -S(O)R 5-11 , -S(O)R 5-11 , -OC(O)R 5-11 , -OC(O)OR 5-11 or TIFF0007823934000034.tif15170, where R 5-11 , R 5-1a and R 5-1b are independently hydrogen, C 1~6 Alkyl, 3-6 membered cycloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C with at least one hydrogen atom replaced by halogen 1~6 Alkyl, C with at least one hydrogen atom replaced by halogen 2-6 Alkenyl, C with at least one hydrogen atom replaced by halogen 3~6 Cycloalkyl, C with at least one hydrogen atom replaced by halogen 2-6 is alkynyl; R 6 -C(O)OR 6-1 , 5- or 6-membered monocyclic heteroaryl, where R 6-1 is hydrogen, C 1~6 Alkyl, 3-6 membered cycloalkyl, C 2-6Alkenyl, C 2-6 Alkynyl, C with at least one hydrogen atom replaced by halogen 1~6 Alkyl, C with at least one hydrogen atom replaced by halogen 2-6 Alkenyl, C with at least one hydrogen atom replaced by halogen 3~6 Cycloalkyl, C with at least one hydrogen atom replaced by halogen 2-6 is alkynyl; m is 1 to 6.

[0035] Based on the fact that it would be beneficial to improve the ability of a compound to selectively induce autophagy in damaged mitochondria, in some more preferred embodiments, the compound is: TIFF0007823934000035.tif37170

[0036] Furthermore, based on the fact that it would be beneficial to further improve the ability of the compound to selectively induce autophagy in damaged mitochondria, in some preferred embodiments, the compound has a structure represented by formula (III): TIFF0007823934000036.tif73170 where, R 3 is hydrogen, TIFF0007823934000037.tif17170, where R 31 and R 32 are each independently C 1~6 Alkyl or C 1~6 cycloalkyl, and n is 1 to 4; R 4 When the number is not 0, each independently represents a halogen, nitro, nitrile, -N + (R 4-1 )3, C 1~6 Haloalkyl, -C(O)OR 4-1 , -C(O)R 4-1 , -C(O)N(R 4-1 R 4-1a ), -S(O)R 4-1 , -S(O)R 4-1 , -N=C(R 4-1 R4-1a ), where R 4-1 and R 4-1a are independently hydrogen, C 1~6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C with at least one hydrogen atom replaced by halogen 1~6 Alkyl, C with at least one hydrogen atom replaced by halogen 2-6 Alkenyl or C in which at least one hydrogen atom is replaced by halogen 2-6 is alkynyl; R 5 is phenyl, naphthyl, 5- or 6-membered monocyclic heteroaryl, 8- to 10-membered fused bicyclic heteroaryl, at least one hydrogen atom is R 5-1 phenyl substituted with at least one hydrogen atom 5-1 naphthyl substituted with at least one hydrogen atom of R 5-1 5- or 6-membered monocyclic heteroaryl substituted with at least one hydrogen atom of R 5-1 and 8-10 membered fused bicyclic heteroaryl substituted with R 5-1 is hydrogen, halogen, nitro, nitrile, hydroxyl, C 1~6 Alkyl, C 3~6 Cycloalkyl, C 1~6 Alkoxy, -N(R 5-1a R 5-1b ), phenyl, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, -C(O)OR 5-11 , -C(O)R 5-11 , -C(O)N(R 5-1a R 5-1b ), -S(O)R 5-11 , -S(O)R 5-11 , -OC(O)R 5-11 , -OC(O)OR 5-11 or TIFF0007823934000038.tif15170, where R 5-11 , R 5-1a and R 5-1b are independently hydrogen, C 1~6Alkyl, 3-6 membered cycloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C with at least one hydrogen atom replaced by halogen 1~6 Alkyl, C with at least one hydrogen atom replaced by halogen 2-6 Alkenyl, C with at least one hydrogen atom replaced by halogen 3~6 Cycloalkyl, C with at least one hydrogen atom replaced by halogen 2-6 is alkynyl; R 6 -C(O)OR 6-1 , 5- or 6-membered monocyclic heteroaryl, where R 6-1 is hydrogen, C 1~6 Alkyl, 3-6 membered cycloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C with at least one hydrogen atom replaced by halogen 1~6 Alkyl, C with at least one hydrogen atom replaced by halogen 2-6 Alkenyl, C with at least one hydrogen atom replaced by halogen 3~6 Cycloalkyl, C with at least one hydrogen atom replaced by halogen 2-6 is alkynyl; m is 1 to 6; R 1 is hydrogen, C 1~6 alkyl, 3- to 6-membered cycloalkyl, 3- to 6-membered epoxyalkyl, phenyl, at least one hydrogen atom of which is R 1-1 C replaced with 1~6 alkyl, at least one hydrogen atom is R 1-2 phenyl substituted with, where R 1-2 is hydroxyl, halogen, amino or C 1~6 is an alkoxy, R 2 is C 1~6 alkyl, 3- to 6-membered cycloalkyl, 3- to 6-membered epoxyalkyl, at least one hydrogen atom is R 2-1 C replaced with 1~6 alkyl, where R 2-1 is hydroxyl, halogen, amino or C1~6 is alkoxy; R 1 and R 2 independently C 1~6 If it is alkyl, R 1 and R 2 can be linked to form a 4- to 8-membered ring.

[0037] In some preferred embodiments, in formula (III), R 1 is hydrogen, methyl, ethyl, cyclopropyl or cyclobutanyl.

[0038] In some preferred embodiments, in formula (III), R 2 is hydrogen, methyl, ethyl, phenyl, cyclopropyl, cyclobutanyl, or 2-hydroxyethyl.

[0039] In some preferred embodiments, in formula (III), R 1 is methyl or ethyl, and R 1 is methyl or ethyl, R 1 and R 2 can be linked to form a 5- or 6-membered ring.

[0040] In some preferred embodiments, in formula (III), R 4 When the number is not 0, each independently represents bromine, nitro, or nitrile.

[0041] In some preferred embodiments, in formula (III), R 5 is phenyl or phenyl in which at least one hydrogen atom is replaced by bromine.

[0042] A second aspect of the present invention provides pharmaceutical compositions comprising a compound according to the first aspect of the present invention, and pharmaceutically acceptable salts, stereoisomers, solvates or prodrugs thereof.

[0043] A third aspect of the present invention provides use of a compound according to the first aspect of the present invention, or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, or a pharmaceutical composition according to the second aspect of the present invention, in the manufacture of a mitophagy inducer (particularly a selective mitophagy inducer).

[0044] Compared with the prior art, the present invention has at least the following advantages:

[0045] (1) The compounds provided in the first aspect of the present invention and pharmaceutically acceptable salts, stereoisomers, solvates or prodrugs thereof, or the pharmaceutical compositions provided in the second aspect of the present invention, have improved mitophagy induction ability compared to UMI-77.

[0046] (2) The compounds provided in the first aspect of the present invention and pharmaceutically acceptable salts, stereoisomers, solvates or prodrugs thereof, or the pharmaceutical compositions provided in the second aspect of the present invention have superior metabolic stability and pharmacokinetic properties compared to UMI-77.

[0047] (3) The compounds provided in the first aspect of the present invention and pharmaceutically acceptable salts, stereoisomers, solvates or prodrugs thereof, or the pharmaceutical compositions provided in the second aspect of the present invention, have lower toxicity and better druggability than UMI-77.

[0048] (4) A compound provided in the first aspect of the present invention and a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, or a pharmaceutical composition provided in the second aspect of the present invention.

[0049] Therefore, the compounds of the present invention have the effects of inducing autophagy of damaged mitochondria and improving metabolic stability.Preferred compounds of the present invention have the effects of inducing autophagy of damaged mitochondria and simultaneously improving metabolic stability.

[0050] More preferably, preferred compounds of the present invention have the effect of selectively inducing autophagy of damaged mitochondria and improving metabolic stability. Particularly preferred compounds of the present invention have the effect of inducing autophagy of damaged mitochondria and simultaneously improving metabolic stability.

[0051] 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 specifically described below (e.g., in the Examples) can be combined with each other to form new or preferred technical solutions, which will not be described one by one here due to space limitations. [Brief explanation of the drawings]

[0052] One or more embodiments are illustrated by way of example in the figures of the accompanying drawings, and these illustrative illustrations do not constitute limitations on the embodiments. [Figure 1] FIG. 1 is a graph showing the results of mitophagy induction in human embryonic kidney transformed cells HEK293Tmtkeima line directly treated with UMI-77 or compound I-4 in Test Example 1 of the present invention. [Figure 2] FIG. 2 is a graph showing the test results of UMI-77 or compound I-1, which selectively induces mitophagy, in Test Example 1 of the present invention. [Figure 3] FIG. 3 is a graph showing the results of an in vitro liver microsome stability test of compounds UMI-77 and I-4 in Test Example 2 of the present invention. DETAILED DESCRIPTION OF THE INVENTION

[0053] The present inventors have found through research that UMI-77 has a relatively weak ability to induce mitophagy, is metabolically unstable, and has poor drug potential. To solve this problem, the present inventors have conducted numerous experimental studies and discovered that by modifying a portion of the structure of UMI-77 to produce the compound described in the first aspect of the present invention, the ability to induce mitophagy is significantly improved and the drug potential is also enhanced.

[0054] Preferably, the inventors have based on UMI-77 a compound directly connected to the naphthalene ring. The hydrogens in TIFF0007823934000039.tif25170 are modified, for example, by alkylation as described in some of the embodiments of the present invention (where "H" is C 1~6 alkyl or 3-6 membered cycloalkyl), or "H" is R 1 They found that when substituted with a group (e.g., 3- to 6-membered epoxyalkyl, phenyl), the compounds could partially exhibit the ability to selectively induce autophagy of damaged mitochondria.

[0055] Preferably, we have based on UMI-77: Any one oxygen atom in TIFF0007823934000040.tif14170 may be modified to "NH", or "NR" as described in some embodiments of the present invention. 2 " further improved the compound's ability to induce mitophagy.

[0056] Preferably, the inventors have discovered that modifying the phenolic hydroxyl group on the naphthalene ring (e.g., esterification modification) as described in some of the embodiments of the present invention is beneficial in shielding the ionizable site and enhancing absorption through permeable membranes.

[0057] term As used herein, the term "mitophagy" refers to the process of selective degradation of mitochondria by autophagy, an important mechanism for controlling mitochondrial quality and quantity.

[0058] As used herein, the term "mitophagy inducer" refers to a compound capable of inducing mitophagy function.

[0059] As used herein, the term "alkyl" refers to a straight-chain or branched-chain saturated aliphatic hydrocarbon group. 1-6 "Alkyl" refers to a straight or branched chain alkyl group having from 1 to 6 carbon atoms, non-limiting examples of which 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 isomers thereof. 1-4 "Alkyl" refers to a straight or branched chain alkyl group having 1 to 4 carbon atoms, 1-4 When the alkyl is at the end of the molecule, non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl; or when two parts of the molecule are connected via an alkyl, non-limiting examples include -CH2-, -CH2-CH2-, -CH(CH3)-, -CH2-CH2-CH2-, -CH(C2H5)-, -C(CH3)2-; 1-4 Each hydrogen at an alkyl carbon may be optionally substituted with a substituent further listed herein.

[0060] The term "alkenyl" as used herein refers to a straight or branched hydrocarbon chain containing at least one carbon-carbon double bond. Each hydrogen at an alkenyl carbon may be replaced with a substituent as further listed herein. 2-6"Alkenyl" refers to a straight or branched hydrocarbon chain of 1 to 6 carbon atoms containing at least one carbon-carbon double bond. When it appears at the end of a molecule, non-limiting examples include -CH=CH2, -CH=CH-CH3, -CH2-CH=CH2, -CH=CH-CH2-CH3, -CH=CH-CH=CH2, or when two parts of a molecule are connected through the alkenyl, non-limiting examples include -CH=CH-. 2-6 Each hydrogen at an alkenyl carbon may be optionally replaced with a substituent as further mentioned herein.

[0061] The term "alkynyl" as used herein refers to a straight or branched hydrocarbon chain containing at least one carbon-carbon triple bond. Each hydrogen at an alkynyl carbon may be replaced with a substituent as further listed herein. 2-6 "Alkynyl" refers to a straight or branched hydrocarbon chain of 1 to 6 carbon atoms containing at least one carbon-carbon triple bond. When it appears at the end of a molecule, non-limiting examples include -C≡CH, -CH2-C≡CH, -CH2-CH2-C≡CH, -CH2-C≡C-CH3, or when two parts of a molecule are connected through the alkynyl, non-limiting examples include -C≡C-. 2-6 Each hydrogen at an alkynyl carbon may be optionally replaced with a substituent as further mentioned herein.

[0062] As used herein, the term "alkoxy" refers to a group having the structure "-O-alkyl," where alkyl is as defined above. 1-6 "Alkoxy" refers to an alkoxy having 1 to 6 carbon atoms, non-limiting examples of which include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, isobutoxy, n-pentyloxy, and the like.

[0063] As used herein, the term "amine group" refers to a group formed by replacing at least one hydrogen atom of an amino group with alkyl, e.g., In TIFF0007823934000041.tif19170, R 3-11 and R 3-12 is alkyl and the other is hydrogen; or 3-11 and R 3-12 are all alkyl groups; 3-11 and R 3-12 If all of R 3-11 and R 3-12 may be bonded to form a ring.

[0064] As used herein, the term "haloalkyl" refers to an alkyl in which one or more (eg, 1, 2, 3, 4, or 5) hydrogen atoms have been replaced with halogen, where alkyl is defined above.

[0065] As used herein, "(O)" means TIFF0007823934000042.tif15170. In one embodiment, -CHC(O)R 3-2 teeth, Points to TIFF0007823934000043.tif14170.

[0066] The term "haloalkoxy," as used herein, refers to an alkoxy in which one or more hydrogen atoms have been replaced with a halogen, where alkoxy is defined above.

[0067] As used herein, the terms "aryl," "aryl ring," and "aromatic ring" are used interchangeably and refer to an all-carbon monocyclic ring, an all-carbon non-fused polycyclic ring (the rings are connected by covalent bonds and are not fused), or an all-carbon fused polycyclic ring (i.e., rings that share adjacent pairs of carbon atoms) group in which at least one ring is aromatic, i.e., has a ring-forming conjugated π-electron system.

[0068] The term "heteroaryl," as used herein, refers to an aryl in which at least one of the ring carbon atoms that make up the aryl is replaced by a non-carbon heteroatom such as S, N, or O.

[0069] The term "monocyclic heteroaryl" as used herein refers to a heteroaryl having only one aromatic ring, where heteroaryl is defined above. The term "5- or 6-membered monocyclic heteroaryl" refers to a monocyclic heteroaryl having 5 or 6 ring atoms, of which 1, 2, or 3 ring atoms are heteroatoms selected from nitrogen, oxygen, or S(=O)m' (where m' is an integer from 0 to 2), non-limiting examples of which include 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.

[0070] As used herein, the term "fused-ring heteroaryl" refers to at least two aromatic rings in which two ring atoms are adjacent to one another, where heteroaryl is as defined above. The term "fused bicyclic heteroaryl" refers to a fused-ring heteroaryl having two aromatic rings, where fused-ring heteroaryl is as defined above. The term "8-10-membered fused bicyclic heteroaryl" refers to a fused bicyclic heteroaryl having 8 to 10 ring atoms, of which 1, 2, 3, 4, or 5 ring atoms are heteroatoms selected from nitrogen, oxygen, or S(=O)m', where m' is an integer from 0 to 2, including, but not limited to, benzo[d]isoxazole, 1H-indole, isoindole, 1H-benzo[d]imidazole, benzo[d]isothiazole, 1H-benzo[d][1,2,3]tri ... These include benzoxazole, 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, and imidazo[1,2-b]pyridazine.

[0071] As used herein, the term "effective amount" or "therapeutically effective amount" refers to the amount of a chemical entity (e.g., a compound exhibiting activity as a modulator of NLRP1 / 3, or a pharmaceutically acceptable salt and / or hydrate, and / or cocrystal thereof) that, when administered, is sufficient to relieve to some extent one or more of the symptoms of the disease or condition being treated. Results include reduction and / or alleviation of the signs, symptoms, or causes of the disease, or any other desired change in a biological system. An appropriate "effective" amount in any individual's situation may be determined using appropriate techniques, such as a dose escalation study.

[0072] As used herein, the term "excipient" or "pharmaceutically acceptable excipient" refers to 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 of being compatible with the other components of the pharmaceutical formulation, suitable for contact with the tissues or organs of humans and animals without undue toxicity, irritation, allergic response, immunogenicity, or other problem or complication, and commensurate with a reasonable benefit-risk ratio.

[0073] As used herein, the term "pharmaceutically acceptable salt" refers 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 specified. Pharmacologically acceptable salts are not particularly limited as long as they can be used in pharmaceuticals. Examples of salts of the compounds described herein with bases include salts with inorganic bases such as sodium, potassium, magnesium, calcium, and aluminum; salts with organic bases such as methylamine, ethylamine, and ethanolamine; or salts formed by reaction with dicyclohexylamine, N-methyl-D-glucosamine, or tris(hydroxymethyl)methylamine; salts with basic amino acids such as lysine and ornithine; and ammonium salts. The salt may be an acid addition salt, specific examples of which include addition salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid; addition salts with 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 addition salts with acidic amino acids such as aspartic acid and glutamic acid.

[0074] As used herein, the term "excipient" or "pharmaceutically acceptable excipient" refers to 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 of being compatible with the other components of the pharmaceutical formulation, suitable for contact with the tissues or organs of humans and animals without undue toxicity, irritation, allergic response, immunogenicity, or other problem or complication, and commensurate with a reasonable benefit-risk ratio.

[0075] The term "pharmaceutical composition" as used herein refers to a mixture of a compound described herein with an "excipient," such as a carrier, stabilizer, diluent, dispersant, suspending agent, and / or thickener. A pharmaceutical composition facilitates administration of a compound to an organism. Various techniques exist in the art for administering a compound, including, but not limited to, rectal, oral, intravenous, aerosol, parenteral, ocular, pulmonary, and topical administration.

[0076] As used herein, the term "subject" refers to an animal, including, but not limited to, a primate (e.g., a 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 reference to a mammalian subject (e.g., a human).

[0077] As used herein, the terms "treat," "treating," and "treatment" in the context of treating a disease or disorder are intended to include alleviating or eliminating the disorder, disease, or condition; or slowing the progression, spread, or worsening of the disorder or condition or one or more symptoms thereof, where the term "disorder" as used herein is always understood to mean "disorder, disease, or condition," or one or more symptoms associated with the disorder.

[0078] Unless otherwise specified, as used herein TIFF0007823934000044.tif26170 is a compound in which the naphthalene ring (including the two benzene rings on the left and right) has 0, 1, 2, 3, 4 or 5 R 4 and the naphthalene ring is substituted with more than one R 4 If replaced by R 4 indicates that each occurrence may be the same or different.

[0079] Unless otherwise specified, "selectivity" as used herein refers to the property of significantly inducing autophagy of damaged mitochondria while having no or only a weak effect on normal mitochondria. "Metabolic stability" as used herein includes, but is not limited to, liver microsomal stability and plasma stability.

[0080] In order to clarify the objectives, technical solutions, and advantages of the embodiments of the present invention, the present invention will be further described below based on specific examples. It should be understood that these examples are used only to illustrate the present invention and do not limit the scope of the present invention. In the following examples, experimental methods that do not specify specific experimental conditions generally follow conventional conditions or conditions recommended by manufacturers. Unless otherwise specified, percentages and parts are percentages and parts by weight. Experimental materials and reagents used in the following examples can be obtained from commercial sources unless otherwise specified.

[0081] Unless otherwise specified, technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. It should be noted that the terminology used herein is intended to describe specific embodiments only and is not intended to limit the exemplary embodiments of the present application.

[0082] Example 1: Synthesis and characterization of compound I-1 UMI-77 (45 mg, 0.096 mmol) was dissolved in DMF (0.5 mL) under nitrogen atmosphere 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 min, then returned to room temperature and stirred overnight. The formation of trimethylated product 1 was confirmed by LC-MS. The reaction mixture was diluted with DCM and subjected to silica gel column chromatography (30% v / v ethyl acetate / petroleum ether system) to obtain compound 1 (42 mg).

[0083] Compound 1 (42 mg, 0.081 mmol) was dissolved in dry DCM (0.5 mL) and stirred in a dry ice-ethanol bath. A 1 M solution of BBr3 in DCM (0.24 mL, 0.24 mmol) was added dropwise, and the mixture was then slowly returned to room temperature and stirred for 2 h. Product I was detected by LC-MS. The reaction was quenched by adding dilute hydrochloric acid, extracted with DCM, and the organic phase was separated and dried over anhydrous sodium sulfate. The organic phase was concentrated, and the resulting crude product was purified by preparative HPLC (MeCN / HO / TFA) to give product I-1 (23 mg).

[0084] The purified product I-1 was collected for structural characterization. LC-MS (ESI) m / z: 480, 482 [M−H] - . 1 H-NMR (400 MHz, DMSO-d6) δ (ppm): 12.90 (s, 1H), 10.08 (s, 1H), 8.22 (d, J = 8.2 Hz, 1H), 8.05 (d, J = 8.2 Hz, 1H), 7.88 (d, J = 8.1 Hz, 2H), 7.76 -7.53 (m, 4H), 6.85 (s, 1H), 3.54 (s, 2H), 3.19 (s, 3H). Example 2: Synthesis and characterization of compound I-2 Compound I-2 can be prepared according to the synthesis method of compound I-1 using the known intermediate 2 (J. Med. Chem. 2014, 57, 4111-4133) as a raw material.

[0085] The purified product I-2 was collected for structural characterization. LC-MS (ESI) m / z: 510, 512 [M−H] - . Example 3: Synthesis and characterization of compound I-3 Known compound 4 (J. Med. Chem. 2014, 57, 4111-4133) (1.0 mmol) and 2,2'-bipyridyl (0.8 mmol) were dissolved in dry DCE (8 mL). Phenylboronic acid (2.0 mmol), copper acetate (1.0 mmol), and sodium carbonate (2.0 mmol) were added in that order. The mixture was heated to 80 °C and stirred for 24 h. Product 5 was detected by LC-MS. Intermediate 5 (98 mg) was obtained by purification using silica gel column chromatography. Intermediate 5 (0.28 mmol) was dissolved in DCM (0.4 mL) and pyridine (0.3 mL), stirred in an ice-water bath, and p-bromobenzenesulfonyl chloride (0.3 mmol) was added. The mixture was then slowly cooled to room temperature. The formation of intermediate 6 was detected by LC-MS. Purification by silica gel column chromatography gave intermediate 6 (79 mg).

[0086] Compound I-3 (23 mg) was prepared using intermediate 6 (0.14 mmol) as the starting material according to the final step of the synthesis of compound I-2.

[0087] The purified product I-3 was collected for structural characterization. LC-MS (ESI) m / z: 542, 544 [M−H] - . Example 4: Synthesis and characterization of compound I-4 TIFF0007823934000048.tif20170Na2SO3 (3.8 g, 30 mmol) was dissolved in 30 mL of deionized water, and p-bromobenzenesulfonyl chloride (2.6 g, 10 mmol) was added in several portions while stirring. o The mixture was heated at RT for 5 hours, cooled, and concentrated hydrochloric acid was added dropwise to precipitate a white solid. After suction filtration, the resulting solid was recrystallized in water to obtain Intermediate 7 (1.3 g). Intermediate 7 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 using a rotary evaporator, and the remaining thionyl chloride was removed with toluene to obtain Intermediate 8 (626 mg). Intermediate 8 (48 mg, 0.2 mmol) was suspended in 1 mL of DCM and cooled in an ice-water bath. An alcoholic solution of methylamine (1.5 eq) was added, followed by triethylamine (2 eq). The mixture was allowed to warm to room temperature and stirred for 2 hours. LC-MS analysis indicated the formation of intermediate 9. Purification by silica gel column chromatography (EA in hexane = 65% v / v) afforded intermediate 9 as a pale yellow solid (30 mg). Intermediate 9 (30 mg, 0.13 mmol) was suspended in 0.5 mL of carbon tetrachloride and stirred in an ice-water bath. tert-Butyloxychloride (1.5 eq) was added, and the solid immediately dissolved. Stirring was continued for 1 h, and low-boiling substances were removed by rotary evaporation to obtain intermediate 10. Intermediate 10 was then dissolved in 0.5 mL of DCM and stirred in an ice-water bath. Intermediate 4 (1 eq, prepared with reference 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 intermediate 10. The mixture was allowed to warm to room temperature and stirred overnight. LC-MS indicated the formation of intermediate 11. Purification by silica gel column chromatography (EA in hexane=40% v / v) gave Intermediate 11 as an oil (51 mg). Intermediate 11 (51 mg, 0.1 mmol) was dissolved in 0.5 mL of DCM and cooled in a dry ice-ethanol bath. A solution of BBr3 in DCM (0.2 mL, 1 M in DCM) was added dropwise. The mixture was slowly warmed to room temperature and stirred for 3 h. LC-MS analysis indicated that intermediate 11 had been completely consumed, resulting in compound I-4. The reaction was quenched by the dropwise addition of deionized water and extracted three times with DCM. The organic phases were combined, the organic solvent was removed by rotary evaporation, and the mixture was purified by preparative HPLC (MeCN / H2O / TFA) to give product I-4 (13 mg).

[0088] The purified product I-4 was collected for structural characterization. LC-MS (ESI) m / z: 479, 481 [M−H] - . 1 H-NMR (400 MHz, DMSO-d6) δ (ppm): 9.13 (s, 1H), 8.36 - 8.28 (m, 1H), 8.14 - 8.06 (m, 1H), 7.93 (d, J = 8.4 Hz, 2H), 7.83 (d, J = 8.4 Hz, 2H), 7.55 - 7.39 (m, 3H), 7.22 (s, 1H), 3.61 (s, 2H), 2.41 (s, 3H). Example 5: Synthesis and characterization of compound I-5 Compound I-5 can be prepared by following the synthetic route of compound I-4, replacing methylamine with cyclopropylamine.

[0089] The purified product I-5 was collected for structural characterization. LC-MS (ESI) m / z: 505, 507 [M−H] - . 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 12.01 (s, 1H), 8.38 - 8.30 (m, 1H), 8.16 - 8.07 (m, 1H), 7.97 (d, J = 8.7 Hz, 2H), 7.84 (d, J = 8.6 Hz, 3H), 7.48 (qd, J = 6.8, 3.4 Hz, 2H), 7.23 (s, 1H), 3.52 (s, 2H), 2.17 - 2.09 (m, 1H), 0.47 - 0.38 (m, 1H), 0.38 - 0.23 (m, 2H), 0.21 - 0.11 (m, 1H). Example 6: Synthesis and characterization of compound I-6 TIFF0007823934000053.tif75170Following the synthesis route of compound I-4, methylamine was TIFF0007823934000054.tif9170, compound I-6 can be prepared.

[0090] The purified product I-6 was collected for structural characterization. LC-MS (ESI) m / z: 521, 523 [M−H] - . Example 7: Synthesis and characterization of compound I-7 TIFF0007823934000055.tif75170Following the synthesis route of compound I-4, methylamine was TIFF0007823934000056.tif7170 to prepare compound I-7.

[0091] The purified product I-7 was collected for structural characterization. LC-MS (ESI) m / z: 509, 511 [M−H] - . Example 8: Synthesis and characterization of compound I-8 Compound I-8 can be prepared by following the synthetic route of compound I-4, replacing methylamine with aniline.

[0092] The purified product I-8 was collected for structural characterization. LC-MS (ESI) m / z: 541, 543 [M−H] - . Example 9: Synthesis and characterization of compound I-9 According to the synthesis method of compound I-2, compound I-9 can be prepared using intermediate 11 as a raw material.

[0093] The purified product I-9 was collected for structural characterization. LC-MS (ESI) m / z: 493, 495 [M−H] - . Example 10: Synthesis and characterization of compound I-10 Intermediate 12 (1.9 mmol) was dissolved in THF and stirred at room temperature while adding a 1 M THF solution of TBAF. Stirring was continued for 1 hour until the TBS was completely removed. Silica gel column chromatography afforded the TBS-removed product (1.8 mmol). This TBS-removed product (1.8 mmol) and triphenylphosphine (1.2 eq) were dissolved in anhydrous THF and added dropwise with DIAD (1.2 eq) while stirring at room temperature. Stirring was continued overnight at room temperature. LC-MS indicated the formation of the cyclized product. Silica gel column chromatography afforded the cyclized product (0.8 mmol).

[0094] Compound I-10 was prepared by demethylating the cyclized product with boron tribromide, following the final step of the synthesis of compound I-2. The purified product I-10 was collected for structural characterization. LC-MS (ESI) m / z: 491, 493 [M−H] - . Example 11: Synthesis and characterization of compound I-11 TIFF0007823934000060.tif40170Compounds I-7 and I-10 were synthesized according to the method described above. TIFF0007823934000061.tif8170 to prepare compound I-11.

[0095] The purified product I-11 was collected for structural characterization. LC-MS (ESI) m / z: 505, 507 [M−H] - . Example 12: Synthesis and characterization of compound I-12 TIFF0007823934000062.tif87170 Using the intermediate 11 as a starting material, compound I-12 can be prepared according to the synthetic route shown in the diagram above.

[0096] The purified product I-12 was collected for structural characterization. LC-MS (ESI) m / z: 505, 507 [M+H] + . Example 13: Synthesis and characterization of compound I-13 TIFF0007823934000063.tif88170 Using the intermediate 13 as a starting material, compound I-13 can be prepared according to the synthetic route shown in the diagram above.

[0097] The purified product I-13 was collected for structural characterization. LC-MS (ESI) m / z: 504, 506 [M+H] + . Example 14: Synthesis and characterization of compound I-14 Compound I-14 can be prepared by using compound I-4 as a starting material and acylation of the phenolic hydroxyl group with acetyl chloride.

[0098] The purified product I-14 was collected for structural characterization. LC-MS (ESI) m / z: 523, 525 [M+H] + . Example 15: Synthesis and characterization of compound I-15 TIFF0007823934000065.tif47170 Compound I-4 was used as a raw material, and acetyl chloride was synthesized according to the synthesis method of compound I-14. TIFF0007823934000066.tif15170 to prepare compound I-15.

[0099] The purified product I-15 was collected for structural characterization. LC-MS (ESI) m / z: 551, 553 [M+H] + . Example 16: Synthesis and characterization of compound I-16 TIFF0007823934000067.tif48170 Compound I-16 can be prepared by a one-step alkylation reaction using compound I-4 as a starting material.

[0100] The purified product I-16 was collected for structural characterization. LC-MS (ESI) m / z: 597, 599 [M+H] + . Example 17: Synthesis and characterization of compound I-17 TIFF0007823934000068.tif87170 Using the intermediate 11 as a starting material, compound I-17 can be prepared according to the synthetic route shown in the diagram above.

[0101] The purified product I-17 was collected for structural characterization. LC-MS (ESI) m / z: 493 [M−H] - . Example 18: Synthesis and characterization of compound I-18 TIFF0007823934000069.tif83170 Using the intermediate 11 as a starting material, compound I-18 can be prepared according to the synthetic route shown in the diagram above.

[0102] The purified product I-18 was collected for structural characterization. LC-MS (ESI) m / z: 477 [M−H] - . Examples 19-22: Synthesis and characterization of compounds I-19 to I-22 TIFF0007823934000070.tif89170Following the synthetic route of compound I-4, TIFF0007823934000071.tif45170, respectively, to prepare compounds I-19 to I-22.

[0103] The purified product I-19 was collected for structural characterization. LC-MS (ESI) m / z: 469 [M−H] - . The purified product I-20 was collected for structural characterization. LC-MS (ESI) m / z: 451 [M−H] - . The purified product I-21 was collected for structural characterization. LC-MS (ESI) m / z: 407 [M−H] - . The purified product I-22 was collected for structural characterization. LC-MS (ESI) m / z: 477 [M−H] - . Example 23: Synthesis and characterization of compound I-23 Intermediate 4 (1.5 mmol) and 2,2'-bipyridyl (1.5 mmol) were dissolved in dry DCE (7 mL), and cyclopropylboronic acid (3.0 mmol), copper acetate (1.5 mmol), and sodium carbonate (3.3 mmol) were added in that order. The mixture was heated to 80 °C and stirred for 24 h. Product 16 was detected by LC-MS. Purification by silica gel column chromatography gave intermediate 16 (153 mg). Intermediate 16 (0.48 mmol) was dissolved in DCM (0.4 mL) and pyridine (0.2 mL) and stirred in an ice-water bath. Intermediate 10 (0.50 mmol) was added, and the mixture was then slowly cooled to room temperature. The formation of intermediate 17 was detected by LC-MS. Purification by silica gel column chromatography gave intermediate 17 (170 mg). Compound I-23 (37 mg) was prepared by using intermediate 17 (0.31 mmol) as a raw material and demethylating it with boron tribromide according to the synthesis method of compound I-2.

[0104] The purified product I-23 was collected for structural characterization. LC-MS (ESI) m / z: 519, 521 [M−H] - .

[0105] Example 24: Synthesis and characterization of compound I-24 TIFF0007823934000074.tif36170 According to the synthesis method of compound I-23, Compound I-24 was prepared by substituting TIFF0007823934000075.tif10170.

[0106] The purified product I-23 was collected for structural characterization. LC-MS (ESI) m / z: 535, 537 [M−H] - .

[0107] Example 25: Synthesis and characterization of compound I-25 Using the known compound 18 (CAS: 88437-16-5) (5.0 mmol) as a raw material, compound I-25 can be prepared according to the synthetic method described in the literature (J. Med. Chem. 2012, 55, 1978-1998).

[0108] The purified product I-25 was subjected to structural characterization. LC-MS (ESI) m / z: 504, 506 [M−H] - . Example 26: Synthesis and characterization of compound I-26 Using the known compound 19 (CAS: 58200-82-1) (5.0 mmol) as a raw material, compound I-26 can be prepared according to the synthetic method described in the literature (J. Med. Chem. 2012, 55, 1978-1998).

[0109] The purified product I-26 was subjected to structural characterization. LC-MS (ESI) m / z: 524, 526 [M−H] - . Test Example 1: Functional test of mitophagy inducers Human embryonic kidney transformed cells, HEK293Tmtkeima cells, were plated in a 96-well black enzyme plate at 1.5 x 10 5 Cells were seeded at 100 μL / well at 100 μL / ml. After 25 hours, UMI-77 and compounds I-1 to I-26 were added, with three replicates. The cells were incubated at 37°C with 5% CO and photographed every few hours using a BioTek Cytation 5 camera for a total of 20 hours. Brightfield was used as the focus channel, and nine images were taken per well. Images were processed using the instrument software and converted to mitophagy intensity. The results are shown in Figure 1, using UMI-77 and compound I-4 as examples.

[0110] Human embryonic kidney transformed cells, HEK293Tmtkeima cells, were plated in a 96-well black enzyme plate at 1.5 x 10 5 Cells were seeded at 100 μL / well in a volume of 100 μL / ml. After 24 hours, 5 μM or 10 μM of CCCP (carbonyl cyanide 3-chlorophenylhydrazone) was added. After 1 hour, UMI-77 and compounds I-1 to I-26 were added, respectively. Three replicates were set up and incubated at 37°C with 5% CO. Images were taken every few hours using a Biotek Cytation 5 camera for a total of 20 hours. Brightfield was used as the focus channel, and nine images were taken per well. Images were processed using the instrument software. The results are shown in Figures 2, 3, and 4, using UMI-77 and compounds I-1, I-4, and I-5 as examples (block color shading indicates the intensity of mitophagy).

[0111] As shown in Figure 1, in cells not treated with CCCP, compound I-4 has a stronger ability to induce mitophagy than UMI-77.

[0112] As shown in Figure 2, human embryonic kidney transformed cells (HEK293Tmtkeima) were treated with 5 μM or 10 μM CCCP to induce mitochondrial damage. The blocks containing compound I-1 were darker than those containing only the test compound without CCCP treatment, demonstrating that compound I-1 is more likely to induce autophagy of damaged mitochondria. Regarding UMI-77, under the same conditions, the color blocks of both damaged and undamaged mitochondria were darker, demonstrating that UMI-77 cannot selectively induce autophagy of damaged mitochondria.

[0113] The ability of other compounds to induce mitophagy was tested and the results are shown in Table 1 below.

[0114] Table 1 "+++" indicates that the compound has a strong ability to induce mitophagy (number of mitophagy-induced cells / total number of cells > 0.30), "++" indicates that the compound has a moderate ability to induce mitophagy (number of mitophagy-induced cells / total number of cells in the range of 0.2-0.3), "+" indicates that the compound has a weak ability to induce mitophagy (number of mitophagy-induced cells / total number of cells in the range of 0.1-0.2), and "NA" indicates that the compound was not detected to have the ability to induce mitophagy. NOTE: The HEK293Tmtkeima cells used in this experiment were obtained by stably expressing the mtkeima protein in HEK293T cells using lentiviral packaging technology according to the method described in [Cen, X. et al. Nat Commun 11, 5731 (2020)]. CCCP used in this experiment was purchased from Topscience Co. Ltd. (item number T7081).

[0115] Test Example 2: In vitro liver microsome stability test Ketanserin was used as a reference compound. The specific method is as follows.

[0116] 0.1 M K3PO4 (pH 7.4) buffer and 3x NADPH stock solution (6 mM, 5 mg / mL) were prepared and preheated in a 37°C water bath. Spiking solutions for test and control compounds were prepared: 5 μL of compound stock solution (10 nM) was added to 95 μL of acetonitrile. 1.5 μM spiking solution in microsomes (0.75 mg / mL) was prepared: 1.5 μL of spiking solution and 18.75 μL of liver microsome solution (20 mg / mL) were added to 479.75 μL of K3PO4 buffer. 30 μL of spiking solution in microsomes was added to a multiwell plate and incubated at 37°C for 5 minutes. The reaction was initiated by adding 15 μL of NADPH stock solution to each well and timed. At 0, 5, 15, 30, and 45 minutes, 150 μL of IS-containing acetonitrile solution was added to stop the reaction. After shaking for 10 minutes, the mixture was centrifuged at 6000 rpm for 15 minutes. 80 μL of the supernatant was collected from each well and subjected to LC / MS detection. 1 / 2 Some test effects are shown in Figure 5.

[0117] As shown in Figure 3, in vitro liver microsome stability experiments of UMI-77 showed that UMI-77 was unstable and rapidly eliminated in the mouse and human liver microsomal environment; compounds I-1 and I-4 showed relatively good stability.

[0118] NOTE: Mouse and human liver microsomes used in the experiments were purchased from Xenotech.

[0119] It will be understood by those skilled in the art that the above-described embodiments are specific examples for implementing the present invention, and that in actual applications, various changes in form and details may be made without departing from the spirit and scope of the present invention.

Claims

1. A compound having a structure represented by general formula (I), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, where X is oxygen or nitrogen; R ３ is hydrogen, where R ３１ and R ３２ are each independently C １～６ alkyl and n is 1; R ４ is 0 to 1, and when the number is not 0, each R 4 is independently selected from halogen, nitro, and nitrile; R ５ is phenyl, naphthyl, 5-membered monocyclic heteroaryl, at least one hydrogen atom is R ５－１ phenyl substituted with at least one hydrogen atom of R ５－１ naphthyl substituted with at least one hydrogen atom of R ５－１ is a 5-membered monocyclic heteroaryl substituted with ５－１ is hydrogen, halogen, phenyl, C １～６ haloalkyl or and R ６ is -C(O)OR ６－１ , 5-membered monocyclic heteroaryl, where R ６－１ is hydrogen; m is 1; and When X is oxygen, the dotted line is absent and R ２ no longer exists, and R １ is C １～６ alkyl, phenyl, at least one hydrogen atom is R １－１ C substituted with １～６ alkyl, where R 1-1 is hydroxyl, halogen, or amino; If X is nitrogen, the dotted line becomes a single bond, R １ is hydrogen, C １～６ Alkyl, and R ２ is C １～６ Alkyl, phenyl, At least one hydrogen atom is R ２－１ C substituted with １～６ alkyl, where R ２－１ is hydroxyl; X is nitrogen and R １ and R ２ became independent and became C １～６ When R is alkyl, １ and R ２ can be bonded to form a 5- or 6-membered ring, or a pharmaceutically acceptable salt, stereoisomer or solvate thereof.

2. X is oxygen or nitrogen; R ３ is hydrogen, where R ３１ and R ３２ are each independently C １～４ alkyl and n is 1; R ４ when the number is 1, are each independently selected from halogen, nitro, and nitrile; R ５ is phenyl, naphthyl, 5-membered monocyclic heteroaryl, at least one hydrogen atom is R ５－１ phenyl substituted with at least one hydrogen atom of R ５－１ naphthyl substituted with at least one hydrogen atom of R ５－１ is a 5-membered monocyclic heteroaryl substituted with ５－１ is hydrogen, halogen, phenyl, C １～４ haloalkyl or and R ６ is -C(O)OR ６－１ , 5-membered monocyclic heteroaryl, where R ６－１ is hydrogen; m is 1; and When X is oxygen, the dotted line is absent and R ２ no longer exists, and R １ is C １～４ alkyl, phenyl, at least one hydrogen atom is R １－１ C substituted with １～４ alkyl, where R １－１ is hydroxyl, halogen or amino; If X is nitrogen, the dotted line becomes a single bond, R １ is hydrogen, C １～４ Alkyl, and R ２ is C １～４ Alkyl, phenyl, At least one hydrogen atom is R ２－１ C substituted with １～４ alkyl, where R ２－１ is hydroxyl, halogen or amino; X is nitrogen and R １ and R ２ became independent and became C １～４ When R is alkyl, １ and R ２ can be bonded to form a 5- or 6-membered ring, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof.

3. X is oxygen or nitrogen; R ３ is hydrogen, where R ３１ and R ３２ are each independently methyl, ethyl, n-propyl, or isopropyl, and n is 1; R ４ when the number is 1, are each independently selected from fluorine, chlorine, bromine, iodine, nitro, and nitrile; R ５ is phenyl, naphthyl, 5-membered monocyclic heteroaryl, at least one hydrogen atom is R ５－１ phenyl substituted with, where R ５－１ is fluorine, chlorine, bromine, iodine, phenyl, fluoromethyl, fluoroethyl, fluoro-n-propyl, fluoroisopropyl, chloromethyl, chloroethyl, chloro-n-propyl, chloroisopropyl, bromomethyl, bromoethyl, bromo-n-propyl, bromoisopropyl, iodomethyl, iodoethyl, iodo-n-propyl, iodoisopropyl, or and R ６ is -C(O)OR ６－１ , 5-membered nitrogen-containing monocyclic heteroaryl, where R ６－１ is hydrogen, m is 1, and When X is oxygen, the dotted line is absent and R ２ no longer exists, and R １ is C １～４ alkyl, phenyl, at least one hydrogen atom is R １－１ C substituted with １～４ alkyl, at least one hydrogen atom is R １－１ phenyl substituted with, where R １－１ is hydroxyl; If X is nitrogen, the dotted line becomes a single bond, R １ is hydrogen, methyl, ethyl, n-propyl, isopropyl, and R ２ is methyl, ethyl, n-propyl, isopropyl, methyl in which at least one hydrogen atom is replaced by hydroxyl, ethyl in which at least one hydrogen atom is replaced by hydroxyl, n-propyl in which at least one hydrogen atom is replaced by hydroxyl, or isopropyl in which at least one hydrogen atom is replaced by hydroxyl; X is nitrogen and R １ and R ２ is independently methyl, ethyl, n-propyl, or isopropyl, R １ and R ２ can be bonded to form a 5- or 6-membered ring, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof.

4. R ３ is hydrogen, where R ３１ and R ３２ are each independently methyl, n-propyl, or isopropyl, and n is 1; and / or R ４ when the number is 1, are each independently selected from fluorine, chlorine, bromine, iodine, nitro, and nitrile; and / or R ５ is phenyl, naphthyl, thienyl, or at least one hydrogen atom is R ５－１ phenyl substituted with, where R ５－１ is fluorine, chlorine, bromine, iodine, phenyl, fluoromethyl or and and / or R ６ The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt, stereoisomer or solvate thereof, wherein is -C(O)OH, triazolyl or tetrazolyl.

5. 4. The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt, stereoisomer or solvate thereof, wherein X is nitrogen.

6. R １ is hydrogen, methyl, ethyl, cyclopropyl or cyclobutanyl; and / or R ２ is hydrogen, methyl, ethyl, phenyl, cyclopropyl, cyclobutanyl or 2-hydroxyethyl; and / or R １ is methyl or ethyl, and R １ is methyl or ethyl, R １ and R ２ can be bonded to form a 5- or 6-membered ring, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof.

7. R ４ when the number is 1, are each independently selected from bromine, nitro, and nitrile; and / or R ５ is phenyl or phenyl in which at least one hydrogen atom is substituted with bromine, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof.

8. The compound having a structure represented by general formula (I) is the compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, selected from the following compounds:

9. A pharmaceutical composition comprising the compound of claim 1 or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof.

10. Use of the compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, or the pharmaceutical composition of claim 9 in the manufacture of a mitophagy inducer.

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