SMALL-MOLECULE COMPOUND HAVING NAPHTHALENETHIOL ETHER STRUCTURE, AND USE THEREOF

Abstract

The present application discloses a small-molecule compound having a naphthalenethiol ether structure, and a use thereof. Disclosed in the present application are a compound having a structure represented by general formula (I), a pharmaceutically acceptable salt, a stereoisomer, a solvate or a prodrug thereof, a pharmaceutical composition containing the same, and a use thereof in the preparation of mitophagy inducer drugs. In the present application, the structure of the compound having the structure represented by general formula (I) is shown below. The compound and the pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, or the pharmaceutical composition provided in the present application can enhance the ability to induce mitophagy.

##STR00001##

Claims

1. A compound having a structure represented by general formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, ##STR00087## wherein X is oxygen or nitrogen; R.sup.3 is hydrogen, ##STR00088## wherein R.sup.31 and R.sup.32 are each independently C.sub.16 alkyl or C.sub.16 cycloalkyl, n is 14; the number of R.sup.4 is 05, and when the number of R.sup.4 is not 0, each is independently selected from halogen, nitro, nitrile, N.sup.+(R.sup.4-1).sub.3, C.sub.16 haloalkyl, C(O)OR.sup.4-1, C(O)R.sup.4-1, C(O)N(R.sup.4-1R.sup.4-1a), S(O).sub.2R.sup.4-1, S(O)R.sup.4-1, NC(R.sup.4-1R.sup.4-1a), wherein R.sup.4-1 and R.sup.4-1a are each independently hydrogen, C.sub.16 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 alkyl with at least one hydrogen substituted by halogen, C.sub.2-6 alkenyl with at least one hydrogen substituted by halogen, or C.sub.2-6 alkynyl with at least one hydrogen substituted by halogen; R.sup.5 is phenyl, naphthyl, 5- or 6-membered monocyclic heteroaryl, 8- to 10-membered fused bicyclic heteroaryl, phenyl with at least one hydrogen atom is substituted by R.sup.5-1, naphthyl with at least one hydrogen atom is substituted by R.sup.5-1, 5- or 6-membered monocyclic heteroaryl with at least one hydrogen atom substituted by R.sup.5-1, 8- to 10-membered fused bicyclic heteroaryl with at least one hydrogen atom substituted by R.sup.5-1, wherein R.sup.5-1 is hydrogen, halogen, nitro, nitrile, hydroxyl, C.sub.16 alkyl, C.sub.36 cycloalkyl, C.sub.16 alkoxy, N(R.sup.5-1aR.sup.5-1b), phenyl, C.sub.16 haloalkyl, C.sub.16 haloalkoxy, C(O)OR.sup.5-11, C(O)R.sup.5-11, C(O)N(R.sup.5-1aR.sup.5-1b), S(O).sub.2R.sup.5-11, S(O)R.sup.5-11, OC(O)R.sup.5-11, OC(O)OR.sup.5-11 or ##STR00089## wherein R.sup.5-11, R.sup.5-1a and R.sup.5-1b are each independently hydrogen, C.sup.16 alkyl, three- to six-membered cycloalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.16 alkyl with at least one hydrogen substituted by halogen, C.sub.2-6 alkenyl with at least one hydrogen substituted by halogen, C.sub.36 cycloalkyl with at least one hydrogen substituted by halogen, C.sub.2-6 alkynyl with at least one hydrogen substituted by halogen; R.sup.6 is C(O)OR.sup.6-1, 5 or 6-membered monocyclic heteroaryl, wherein R.sup.6-1 is hydrogen, C.sub.16 alkyl, three to six-membered cycloalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.16 alkyl with at least one hydrogen substituted by halogen, C.sub.2-6 alkenyl with at least one hydrogen substituted by halogen, C.sub.36 cycloalkyl with at least one hydrogen substituted by halogen, C.sub.2-6 alkynyl with at least one hydrogen substituted by halogen; m is 16; and when X is oxygen, a dotted line does not exist and R.sup.2 does not exist, R.sup.1 is C.sub.16 alkyl, three- to six-membered cycloalkyl, three- to six-membered epoxyalkyl, phenyl, C.sub.16 alkyl with at least one hydrogen substituted by R.sub.1-1, and phenyl with at least one hydrogen substituted by R.sub.1-1, wherein R.sub.1-1 is hydroxyl, halogen, amino or C.sub.16 alkoxy; when X is nitrogen, the dotted line is a single bond, R.sup.1 is hydrogen, C.sub.16 alkyl, three- to six-membered cycloalkyl, three- to six-membered epoxyalkyl, phenyl, C.sub.16 alkyl with at least one hydrogen substituted by R.sup.1-1, phenyl with at least one hydrogen substituted by R.sup.1-2, wherein R.sup.1-2 is hydroxyl, halogen, amino or C.sub.16 alkoxy, R.sup.2 is a C.sub.16 alkyl, a three- to six-membered cycloalkyl, a three- to six-membered epoxyalkyl, or a C.sub.16 alkyl with at least one hydrogen substituted by R.sup.2-1, wherein R.sup.2-1 is hydroxyl, halogen, amino or C.sub.16 alkoxy; when X is nitrogen and R.sup.1 and R.sup.2 are independently C.sub.1-6 alkyl, R.sup.1 and R.sup.2 can be bonded to form a 4- to 8-membered ring.

2. The compound or the pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof according to claim 1, wherein X is oxygen or nitrogen; R.sup.3 is hydrogen, ##STR00090## wherein R.sup.31 and R.sup.32 are each independently C.sub.14 alkyl or C.sub.14 cycloalkyl, n is 1 or 2; when the number of R.sup.4 is not 0, each is independently selected from halogen, nitro, nitrile, N.sup.+(R.sup.4-1).sub.3, C.sub.14 haloalkyl, C(O)OR.sup.4-1, C(O)R.sup.4-1, C(O)N(R.sup.4-1R.sup.4-1a), S(O).sub.2R.sup.4-1, S(O)R.sup.4-1, NC(R.sup.4-1R.sup.4-1a), wherein R.sup.4-1 and R.sup.4-1a are each independently hydrogen, C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl; R.sup.5 is phenyl, naphthyl, 5 -or 6-membered monocyclic heteroaryl, phenyl with at least one hydrogen atom substituted by R.sup.5-1, naphthyl with at least one hydrogen atom substituted with R.sup.5-1, 5- or 6-membered monocyclic heteroaryl with at least one hydrogen atom substituted by R.sup.5-1, wherein R.sup.5-1 is hydrogen, halogen, nitro, nitrile, hydroxyl, C.sub.14 alkyl, or three- to six-membered cycloalkyl, C.sub.14 alkoxy, N(R.sup.5-1a R.sup.5-1b), phenyl, C.sub.14 haloalkyl, C.sub.14 haloalkoxy, C(O)OR.sup.5-11, C(O)R.sup.3-11, C(O)N(R.sup.5-1aR.sup.5-1b), S(O).sub.2R.sup.5-11, S(O)R.sup.5-11, OC(O)R.sup.5-11, OC(O)OR.sup.5-11 or ##STR00091## wherein R.sup.5-11, R.sup.5-1a and R.sup.5-1b are each independently hydrogen, C.sub.14 alkyl, three- to six-membered cycloalkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, C.sub.14 alkyl with at least one hydrogen substituted by halogen; R.sup.6 is C(O)OR.sup.6-1, 5 or 6-membered monocyclic heteroaryl, wherein R.sup.6-1 is hydrogen, C.sub.14 alkyl, three to six-membered cycloalkyl, C.sub.14 alkyl with at least one hydrogen substituted by halogen; m is 14; and when X is oxygen, the dotted line does not exist, R.sup.2 does not exist, and R.sup.1 is C.sub.14 alkyl, three- to six-membered cycloalkyl, three- to six-membered epoxyalkyl, phenyl, C.sub.14 alkyl with at least one hydrogen substituted by R.sup.1-1, and phenyl with at least one hydrogen substituted by R.sup.1-1, wherein R.sup.1-1 is hydroxyl, halogen, amino, or C.sub.14 alkoxy; when X is nitrogen, the dotted line is a single bond, R.sup.1 is hydrogen, C.sub.14 alkyl, three- to six-membered cycloalkyl, three- to six-membered epoxyalkyl, phenyl, C.sub.14 alkyl with at least one hydrogen substituted by R.sup.1-1, phenyl with at least one hydrogen substituted by R.sup.1-2, wherein R.sup.1-2 is hydroxyl, halogen, amino or C.sub.14 alkoxy, R.sup.2 is C.sub.14 alkyl, three- to six-membered cycloalkyl, three- to six-membered epoxyalkyl, or C.sub.14 alkyl with at least one hydrogen substituted by R.sup.2-1, wherein R.sup.2-1 is hydroxyl, halogen, amino or C.sub.14 alkoxy; when X is nitrogen and R.sup.1 and R.sup.2 are independently C.sub.14 alkyl, R.sup.1 and R.sup.2 can be bonded to form a 48-membered ring.

3. The compound or the pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof according to claim 1, wherein X is oxygen or nitrogen; R.sup.3 is hydrogen, ##STR00092## wherein R.sup.31 and R.sup.32 are independently methyl, ethyl, n-propyl or isopropyl, n is 1; when the number of R.sup.4 is not 0, each is independently selected from fluorine, chlorine, bromine, iodine, nitro, nitrile, fluoromethyl, fluoroethyl, fluoro-n-propyl, fluoroisopropy, chloromethyl, chloroethyl, chloro-n-propyl, chloroisopropyl, bromomethyl, bromoethyl, bromo-n-propyl, bromoisopropyl, iodomethyl, iodoethyl, iodo-n-propyl or iodoisopropyl; R.sup.5 is phenyl, naphthyl, 5-membered monocyclic heteroaryl, and phenyl with at least one hydrogen atom is substituted by R.sup.5-1, wherein R.sup.5-1 is fluorine, chlorine, bromine, iodine, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, 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-n-propoxy, chloroisopropoxy, bromomethoxy, bromoethoxy, bromo-n-propoxy, bromoisopropoxy, iodooxymethyl, iodoethoxy, iodo-n-propoxy, iodoisopropoxy or ##STR00093## R.sup.6 is C(O)OR.sup.6-1, five-membered nitrogen-containing monocyclic heteroaryl, wherein R.sup.6-1 is hydrogen, methyl, ethyl, n-propyl, isopropyl, ##STR00094## m is 1; and when X is oxygen, the dotted line does not exist, R.sup.2 does not exist, and R.sup.1 is C.sub.14 alkyl, three- to six-membered cycloalkyl, three- to six-membered epoxyalkyl, phenyl, C.sup.14 alkyl with at least one hydrogen substituted by R.sup.1-1, phenyl with at least one hydrogen substituted by R.sup.1-1, wherein R.sup.1-1 is hydroxyl, halogen, amino or C.sub.14 alkoxy, when X is oxygen, the dotted line does not exist, R.sup.2 does not exist, and R.sup.1 is methyl, ethyl, n-propyl, or isopropyl, ##STR00095## phenyl, methyl with at least one hydrogen substituted by hydroxyl, ethyl with at least one hydrogen substituted by hydroxyl, n-propyl with at least one hydrogen substituted by hydroxyl, isopropyl with at least one hydrogen substituted by hydroxyl; when X is nitrogen, the dotted line is a single bond, R.sup.1 is hydrogen, methyl, ethyl, n-propyl, isopropyl, ##STR00096## or phenyl, R.sup.2 is methyl, ethyl, n-propyl, isopropyl, ##STR00097## methyl with at least one hydrogen substituted by hydroxyl, ethyl with at least one hydrogen substituted by hydroxyl, n-propyl with at least one hydrogen substituted by hydroxyl or isopropyl with at least one hydrogen substituted by hydroxyl; when X is nitrogen and R.sup.1 and R.sup.2 are independently any one of methyl, ethyl, n-propyl or isopropyl, R.sup.1 and R.sup.2 can be bonded to form a 4- to 8-membered ring.

4. The compound or the pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof according to claim 1, wherein R.sup.3 is hydrogen, ##STR00098## wherein R.sup.31 and R.sup.32 are each independently methyl, n-propyl or isopropyl, and n is 1; and/or, when the number of R.sup.4 is not 0, each is independently selected from fluorine, chlorine, bromine, iodine, nitro, and nitrile; and/or, R.sup.5 is phenyl, naphthyl, thienyl or phenyl with at least one hydrogen atom substituted by R.sup.5-1, wherein R.sup.5-1 is fluorine, chlorine, bromine, iodine, phenyl, fluoromethyl or ##STR00099## and/or, R.sup.6 is C(O)OH, triazolyl or tetrazolyl.

5. The compound or the pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof according to claim 1, wherein X is nitrogen.

6. The compound or the pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof according to claim 5, wherein R.sup.1 is hydrogen, methyl, ethyl, cyclopropanyl or cyclobutanyl; and/or, R.sup.2 is hydrogen, methyl, ethyl, phenyl, cyclopropyl, cyclobutanyl or 2-hydroxyethyl; and/or, when R.sup.1 is methyl or ethyl and R.sup.1 is methyl or ethyl, R.sup.1 and R.sup.2 can be bonded to form a 5- to 6-membered ring.

7. The compound or the pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof according to claim 6, wherein R.sup.4 is bromine, nitro or nitrile; and/or, R.sup.5 is phenyl or phenyl with at least one hydrogen atom substituted by bromine.

8. The compound or the pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof according to claim 1, wherein the compound having the structure represented by the general formula (I) is selected from any one of the following compounds: ##STR00100## ##STR00101## ##STR00102## ##STR00103## ##STR00104## ##STR00105##

9. A pharmaceutical composition, comprising the compound or the pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof according to claim 1.

10. (canceled)

11. A pharmaceutical composition, comprising the compound or the pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof according to claim 2.

12. A pharmaceutical composition, comprising the compound or the pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof according to claim 3.

13. A pharmaceutical composition, comprising the compound or the pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof according to claim 4.

14. A pharmaceutical composition, comprising the compound or the pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof according to claim 5.

15. A pharmaceutical composition, comprising the compound or the pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof according to claim 6.

16. A pharmaceutical composition, comprising the compound or the pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof according to claim 7.

17. A pharmaceutical composition, comprising the compound or the pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof according to claim 8.

18. Use of the compound, or the pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof according to claim 1.

19. Use of the compound, or the pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof according to claim 2.

20. Use of the compound, or the pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof according to claim 3.

21. Use of the pharmaceutical composition of claim 9 for the preparation of a mitophagy inducer.

Description

DESCRIPTION OF THE DRAWINGS

[0105] One or more embodiments are exemplified by the pictures in the corresponding drawings, and these exemplary illustrations do not constitute limitations to the embodiments.

[0106] FIG. 1 is a diagram showing the results of inducing mitophagy in human embryonic kidney transformed cells HEK293T-mtkeima system directly treated with UMI-77 or compound I-4 in Test Example 1 of the present invention;

[0107] FIG. 2 is a diagram showing the experimental results of selective induction of mitophagy by UMI-77 or compound I-1 in Test Example 1 of the present invention;

[0108] FIG. 3 is a diagram showing the results of the in vitro liver microsome stability experiment of UMI-77 and Compound I-4 in Test Example 2 of the present invention.

DETAILED DESCRIPTION

[0109] In the study, the inventors have found that UMI-77 has a relatively weak ability to induce mitophagy, and its metabolism is unstable and its druggability is poor. In order to solve this problem, the inventors of the present invention have conducted a large number of experimental studies and found that the compound as described in the first aspect of the present invention is prepared by modifying part of the structure of UMI-77, which can significantly enhance the ability to induce autophagy in mitochondria, and at the same time improve the druggability.

[0110] Preferably, the inventors have found that on the basis of UMI-77, modification of the hydrogen on the imine group

##STR00045##

directly attached to the naphthalene ring, such as alkylation (H is substituted by C.sub.1-6 alkyl or three- to six-membered cycloalkyl) described in some embodiments of the present invention, or when H is substituted by the R.sup.1 group described in some embodiments of the present invention, such as three to six-membered epoxyalkyl, phenyl substitution, allows the compounds to embody the ability to partially selectively induce autophagy in damaged mitochondria.

[0111] Preferably, the inventor has found that on the basis of UMI-77, the ability of the compound to induce mitophagy can be further enhanced by modifying any of the oxygens on the group

##STR00046##

to NH or to N-R.sup.2 as described in some embodiments of the present invention.

[0112] Preferably, the inventors have found that modifying the phenolic hydroxyl on the naphthalene ring as described in some embodiments of the present invention, such as esterification modification, is beneficial to shield ionizable sites and enhance transmembrane absorption.

Terms

[0113] As used herein, the term mitophagy refers to a process of selective degradation of mitochondria by autophagy, which is an important mechanism for the control of mitochondrial quality and quantity.

[0114] As used herein, the term mitophagy inducer refers to a compound that can induce mitophagy function.

[0115] As used herein, the term alkyl refers to a straight-chain or branched saturated aliphatic hydrocarbon group. The term C.sub.1-6 alkyl refers to a straight-chain or branched alkyl having 1 to 6 carbon atoms, non-limiting examples are: 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, etc. The term C.sub.1-4 alkyl refers to a straight-chain or branched alkyl having 1 to 4 carbon atoms. If the C.sub.1-4 alkyl appears at the end of the molecule, non-limiting examples are: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, or when two parts of the molecule are connected through the alkyl, non-limiting examples are: CH.sub.2,CH.sub.2CH.sub.2, CH(CH.sub.3), CH.sub.2CH.sub.2CH.sub.2, CH(C.sub.2H.sub.5), C(CH.sub.3).sub.2, each hydrogen of the C.sub.1-4 alkyl may be substituted by a substituent further enumerated herein.

[0116] As used herein, the term alkenyl refers to a straight or branched hydrocarbon chain containing at least one carbon-carbon double bond. Each hydrogen in the alkenyl carbon may be substituted by a substituent further enumerated herein. The term C.sub.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. If it appears at the end of the molecule, non-limiting examples are: CHCH.sub.2, CHCHCH.sub.3, CH.sub.2CHCH.sub.2, CHCHCH.sub.2CH.sub.3, CHCHCHCH.sub.2, or when two parts of the molecule are connected through the alkenyl, a non-limiting example is CHCH. Each hydrogen of the C.sub.26 alkenyl carbons may be substituted by a substituent further enumerated herein.

[0117] As used herein, the term alkynyl refers to a straight or branched hydrocarbon chain containing at least one carbon-carbon triple bond. Each hydrogen in the alkynyl carbon may be substituted by a substituent further enumerated herein. The term C.sub.26 alkynyl refers to a straight or branched hydrocarbon chain having 1 to 6 carbon atoms containing at least one carbon-carbon triple bond. If it appears at the end of the molecule, non-limiting examples are: CCH, CH.sub.2CCH, CH.sub.2CH.sub.2CCH, CH.sub.2CCCH.sub.3, or, when two parts of the molecule are connected through the alkynyl, a non-limiting example is CC. Each hydrogen in the C.sub.26 alkynyl carbon may be substituted by a substituent further enumerated herein.

[0118] As used herein, the term alkoxy refers to a group having the structure O-alkyl, wherein the alkyl is as defined above. The term C.sub.16 alkoxy refers to an alkoxy group having 1 to 6 carbon atoms, non-limiting examples are: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, isobutoxy, n-pentyloxy, etc.

[0119] As used herein, the term amido refers to a group formed by substituting at least one hydrogen atom in the amino with an alkyl. For example: in the amido

##STR00047##

either one of R.sup.3-11 and R.sup.3-12 is alkyl, the other is hydrogen; or R.sup.3-11 and R.sup.3-12 are all alkyl; when R.sup.3-11 and R.sup.3-12 are all alkyl, R.sup.3-11 and R.sup.3-12 can be bonded to form a ring.

[0120] As used herein, the term haloalkyl refers to an alkyl with one or more (e.g., 1, 2, 3, 4 or 5) hydrogen atoms substituted by halogen, wherein the alkyl is as defined above.

[0121] As used herein, (O) refers to

##STR00048##

In one embodiment, CH.sub.2C(O)R.sup.3-2 refers to

##STR00049##

[0122] As used herein, the term halooxyalkyl refers to an alkoxy with one or more hydrogen atoms substituted by halogen, wherein the alkoxy is as defined above.

[0123] As used herein, the terms aryl, aryl ring and aromatic ring are used interchangeably and refer to all-carbon monocyclic, all-carbon non-fused polycyclic (rings connected by covalent bonds, non-fused) or all-carbon fused polycyclic (that is, rings sharing pairs of adjacent carbon atoms) groups, at least one ring in the group is aromatic, that is, it has a ring-forming conjugated x electron system.

[0124] As used herein, the term heteroaryl refers to an aryl group in which at least one of the ring carbon atoms making up the aryl is replaced by a heteroatom that is a non-carbon atom, such as S, N, or O.

[0125] 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 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 (wherein m is an integer 0 to 2), non-limiting examples are: 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.

[0126] As used herein, the term fused ring heteroaryl refers to having at least two aromatic rings in which two ring atoms are adjacent to each other, wherein heteroaryl is as defined above. The term fused bicyclic heteroaryl refers to a fused ring heteroaryl having two aromatic rings, wherein the fused ring heteroaryl is as defined above. The term 8 to 10-membered fused bicyclic heteroaryl refers to those 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 (wherein m is an integer 0 to 2), non-limiting examples include: benzo [d] isoxazole, 1H-indole, isoindole, 1H-benzo [d]imidazole, benzo[d]isothiazole, 1H-benzo[d][1,2,3]triazole, benzo[d] oxazole, benzo[d]thiazole, indazole, benzofuran, benzo[b] thiophene, quinoline, isoquinoline, quinazoline, quinoxaline, 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.

[0127] As used herein, the term effective dose or therapeutically effective dose refers to a chemical entity (e.g., a compound that exhibits activity as a modulator of NLRP1/3, or a pharmaceutically acceptable salt and/or a hydrate and/or a cocrystal thereof;) in a sufficient amount that, when administered, the dose will alleviate to a certain extent one or more of the symptoms of the disease or condition being treated. Results include alleviation and/or remission of signs, symptoms or causes of disease or any other desired change in a biological system. The appropriate effective dose in any individual situation is determined using any appropriate technique, such as dose escalation studies.

[0128] 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 packaging materials. In one embodiment, each component is compatible with the other ingredients of the pharmaceutical formulation and is suitable for contacting with human and animal tissues or organs without undue toxicity, irritation, allergic response, immunogenicity or other problems or complications and is pharmaceutically acceptable in the sense of being proportionate to a reasonable benefit/risk ratio.

[0129] As used herein, the term pharmaceutically acceptable salts may refer to pharmaceutically acceptable addition salts prepared from pharmaceutically acceptable non-toxic acids, including inorganic acids and organic acids. In some cases, pharmaceutically acceptable salts are obtained by reacting a compound described herein with an acid. The term pharmaceutically acceptable salt may also refer to the formation of a salt by reacting a compound having an acidic group with a base or pharmaceutically acceptable addition salts prepared by other methods as previously determined. The pharmacologically acceptable salt is not particularly limited as long as it can be used in medicines. Examples of salts formed by the compounds described herein with bases include the following: salts with inorganic bases such as sodium, potassium, magnesium, calcium and aluminium; salts with organic bases such as methylamine, ethylamine, and ethanolamine; or 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, this is exemplified by the addition of salts to the following acids: 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; acidic amino acids such as aspartic acid and glutamic acid.

[0130] 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 compatible with the other ingredients of the pharmaceutical formulation and is suitable for contacting with human and animal tissues or organs without undue toxicity, irritation, allergic response, immunogenicity or other problems or complications, and is pharmaceutically acceptable in the sense of being proportionate to a reasonable benefit/risk ratio.

[0131] As used herein, the term pharmaceutical composition refers to a mixture of a compound described herein and excipients such as carriers, stabilizers, diluents, dispersing agents, suspending agents and/or thickening agents. Pharmaceutical compositions facilitate the administration of compounds to an organism. A variety of techniques for administering compounds exist in the art, including, but not limited to, rectal, oral, intravenous, aerosol, parenteral, ocular, pulmonary, and topical administration.

[0132] As used herein, the term subject refers to an animal, including, but not limited to, a primate (e.g., a human), a monkey, a cow, a pig, a sheep, a goat, a horse, a dog, a cat, a rabbit, a rat, or a mouse. The terms subject and patient are used interchangeably herein, for example with respect to mammalian subjects (e.g., humans).

[0133] As used herein, the terms treat, treating and treatment in the context of treating a disease or disorder are meant to include alleviation or elimination of the disorder, disease or condition, wherein the term disorder as used herein shall always be understood to mean a disorder, disease or condition or one or more of the symptoms associated with a disorder; or slowing a disorder or condition or slowing the progression, spread or worsening of one or more of its symptoms.

[0134] Unless otherwise specified, as used herein,

##STR00050##

means that the naphthalene ring (including the two benzene rings on the left and the right) is substituted by 0, 1, 2, 3, 4 or 5 R.sup.4, and when the naphthalene ring is substituted by more than 1 of R.sup.4, each R.sup.4 is the same or different.

[0135] Unless otherwise specified, selectively as used herein refers to the property of significantly inducing damaged mitophagy without affecting normal mitochondria or only weakly affecting normal mitochondria. Metabolic stability as used herein includes, but is not limited to, liver microsome stability and plasma stability.

[0136] 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 embodiments. It should be understood that these embodiments are only used to illustrate the invention and are not intended to limit the scope of the invention. Experimental methods without specifying specific conditions in the following examples usually follow conventional conditions or conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are by weight. The experimental materials and reagents used in the following examples can be obtained from commercial sources unless otherwise specified.

[0137] Unless otherwise specified, technical and scientific terms used herein have the same meanings as commonly understood by those of ordinary skill 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 the present invention.

Embodiment 1: Synthesis and Characterization of Compound I-1

##STR00051##

[0138] Dissolving UMI-77 (45 mg, 0.096 mmol) in DMF (0.5 mL) under nitrogen atmosphere and stirring in an ice-water bath, adding K.sub.2 CO.sub.3 (39 mg, 0.28 mmol) and MeI (30 L, 0.48 mmol) in sequence, keeping stirring in the ice-water bath for 10 min, then returning to room temperature and continuing stirring overnight. Detecting the forming of trimethylation product 1 by LC-MS. Diluting the reaction system with DCM and performing silica gel column chromatography (30% v/v ethyl acetate/petroleum ether system), thus obtaining compound 1 (42 mg).

[0139] Dissolving Compound 1 (4.2 mg, 0.081 mmol) in dry DCM (0.5 mL) and stirring in a dry ice-ethanol bath, adding a DCM solution of 1M BBr.sub.3 (0.24 mL, 0.24 mmol) dropwise, then slowly returning to room temperature and continuing stirring for 2 hours. Detecting the product I-1 by LC-MS. adding diluted hydrochloric acid to quench the reaction, extracting with DCM, and separating out an organic phase and drying over anhydrous sodium sulfate. Concentrating the organic phase, and purifying the obtained crude product by preparative HPLC (MeCN/H.sub.2O/TFA) to obtain product I-1 (23 mg).

[0140] Taking the purified product I-1 for a structural characterization, LC-MS (ESI) m/z: 480, 482 [M-H].sup.. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) (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).

Embodiment 2: Synthesis and Characterization of Compound I-2

##STR00052##

[0141] Using the known intermediate 2 (J. Med. Chem. 2014, 57, 4111-4133) as raw material, preparing the compound I-2 according to the synthesis route of the compound I-1.

[0142] Taking the purified product I-2 for a structural characterization, LC-MS (ESI) m/z: 510, 512 [M-H].sup..

Embodiment 3: Synthesis and Characterization of Compound I-3

##STR00053##

[0143] Dissolving a known compound 4 (J. Med. Chem. 2014, 57, 4111-4133) (1.0 mmol) and 2,2-dipyridyl (0.8 mmol) in dry DCE (8 mL), and adding phenylboronic acid (2.0 mmol), copper acetate (1.0 mmol) and sodium carbonate (2.0 mmol) sequentially and heating at 80 degrees Celsius and stirred for 24 hours. Detecting the product 5 by LC-MS. Purifying by silica gel column chromatography to obtain an intermediate 5(98 mg). Dissolving the intermediate 5 (0.28 mmol) in DCM (0.4 mL) and pyridine (0.3 mL) and stirring in an ice-water bath, adding p-bromobenzenesulfonyl chloride (0.3 mmol), and then slowly returning to room temperature. Detecting the production of intermediate 6 by LC-MS. Purifying by Silica gel column chromatography to obtain an intermediate 6 (79 mg).

[0144] Using the intermediate 6 (0.14 mmol) as raw material, preparing the compound I-3 (23 mg) according to the last step of the synthesis route of the compound I-2.

[0145] Taking the purified product I-3 for a structural characterization, LC-MS (ESI) m/z: 542, 544 [M-H].sup..

Embodiment 4: Synthesis and Characterization of Compound I-4

##STR00054##

[0146] Dissolving Na.sub.2SO.sub.3 (3.8 g, 30 mmol) in 30 mL deionized water, and adding p-bromobenzenesulfonyl chloride (2.6 g, 10 mmol) in batches while stirring. Heating in an oil bath at 75 C. for 5 hours, adding concentrated hydrochloric acid dropwise after cooling, precipitating a white solid out. After suction filtration, recrystallizing the obtained solid in water to obtain an intermediate 7 (1.3 g). Suspending the intermediate 7 in 80 mL DCM, adding thionyl chloride (4 eq) dropwise. After the complete of adding, heating in an oil bath to reflux, after 5 hours, removing the solvent by rotary evaporation, and taking the residual thionyl chloride out with toluene to obtain an intermediate 8 (626 mg).

##STR00055##

[0147] Suspending the intermediate 8 (4 8 mg, 0.2 mmol) in 1 mL DCM, adding the alcohol solution of methylamine (1.5 eq) while cooling in an ice-water bath, then adding triethylamine (2 eq), and returning to room temperature naturally, and stirring for 2 hours. LC-MS shows the formation of an intermediate 9. Purifying the intermediate 9 by silica gel column chromatography (EA in hexane=65% v/v) to obtain a light yellow solid (30 mg).

##STR00056##

[0148] Suspending the intermediate 9 (30 mg, 0.13 mmol) in 0.5 mL carbon tetrachloride, stirring in an ice-water bath, adding tert-butyloxychloride (1.5 eq), and the solid is dissolved immediately. Continuing stirring for 1 hour and removing low-boiling substances by rotary evaporation to obtain an intermediate 10. Then dissolving the intermediate 10 in 0.5 mL DCM, stirring in an ice water bath. Dissolving an intermediate 4 (1 eq, prepared with reference to J. Med. Chem. 2014, 57, 4111-4133) in 0.3 mL pyridine, and adding this pyridine solution dropwise to the DCM solution of the intermediate 10, returning to room temperature naturally and stirring overnight. LC-MS shows the formation of intermediate 11. Purifying by silica gel column chromatography (EA in hexane=40% v/v) to obtain an intermediate 11 as oil matter (51 mg).

##STR00057##

[0149] Dissolving the intermediate 11 (5 1 mg, 0.1 mmol) in 0.5 mL DCM, adding in a DCM solution of BBr.sub.3 (0.2 mL, 1 M in DCM) dropwise while cooling in a dry ice-ethanol bath. Slowly returning to room temperature and stirring for 3 hours, LC-MS shows that the intermediate 11 is completely consumed and compound I-4 is generated. adding deionized water dropwise to quenching the reaction, and extracting three times with DCM. Combining the organic phases, evaporating the organic solvent by rotary evaporation, and purifying by preparative HPLC (MeCN/H.sub.2O/TFA) to obtain a product I-4 (13 mg).

[0150] Taking the purified product I-4 for a structural characterization, LC-MS (ESI) m/z: 479, 481 [M-H].sup.. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) (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).

Embodiment 5: Synthesis and Characterization of Compound I-5

##STR00058##

[0151] According to the synthesis route of the compound I-4, preparing the compound I-5 by replacing methylamine therein with cyclopropylamine.

[0152] Taking the purified product I-5 for a structural characterization, LC-MS (ESI) m/z: 505, 507 [M-H].sup.. .sup.1 H-NMR (400 MHz, DMSO-d.sub.6) (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).

Embodiment 6: Synthesis and Characterization of Compound I-6

##STR00059##

[0153] According to the synthesis route of the compound I-4, preparing the compound I-6 by replacing the methylamine therein with

##STR00060##

[0154] Taking the purified product I-6 for a structural characterization, LC-MS (ESI) m/z: 521, 523 [M-H].sup..

Embodiment 7: Synthesis and Characterization of Compound I-7

##STR00061##

[0155] According to the synthesis route of the compound I-4, preparing the compound I-7 by replacing the methylamine therein with

##STR00062##

[0156] Taking the purified product I-7 for a structural characterization, LC-MS (ESI) m/z: 509, 511 [M-H].sup..

Embodiment 8: Synthesis and Characterization of Compound I-8

##STR00063##

[0157] According to the synthesis route of the compound I-4, preparing the compound I-8 by replacing methylamine therein with aniline.

[0158] Taking the purified product I-8 for a structural characterization, LC-MS (ESI) m/z: 541, 543 [M-H].sup..

Embodiment 9: Synthesis and Characterization of Compound I-9

##STR00064##

[0159] According to the synthesis route of the compound I-2, using the above-mentioned intermediate 11 as a raw material, preparing the compound I-9.

[0160] Taking the purified product I-9 for a structural characterization, LC-MS (ESI) m/z: 493, 495 [M-H].sup..

Embodiment 10: Synthesis and Characterization of Compound I-10

##STR00065##

[0161] Dissolving an intermediate 12 (1.9 mmol) in THF, stirring at room temperature and adding a THF solution of 1 M TBAF dropwise, and continuing stirring for one hour until the TBS is completely removed.

[0162] Obtaining an TBS-removed product (1.8 mmol) by silica gel column chromatography. Dissolving the TBS-removed product (1.8 mmol) and triphenylphosphine (1.2 eq) in anhydrous THF, stirring at room temperature and adding DIAD (1.2 eq) dropwise, continuing stirring at room temperature overnight, LC-MS shows that a cyclization product is produced, and performing silica gel column chromatography to obtain a cyclization product (0.8 mmol).

[0163] Using the cyclization product as raw material, according to the last step of the synthesis route of compound I-2, and performing demethylation with boron tribromide to prepare the compound I-10.

[0164] Taking the purified product I-10 for a structural characterization, LC-MS (ESI) m/z: 491, 493 [M-H].sup..

Embodiment 11: Synthesis and Characterization of Compound I-11

##STR00066##

[0165] According to the synthesis method of compounds I-7 and I-10, preparing the compound I-11 by replacing

##STR00067##

therein with

##STR00068##

[0166] Taking the purified product I-11 for a structural characterization, LC-MS (ESI) m/z: 505, 507 [M-H].sup..

Embodiment 12: Synthesis and Characterization of Compound I-12

##STR00069##

[0167] Using the above intermediate 11 as raw material, preparing the compound I-12 according to the synthetic route in the above figure.

[0168] Taking the purified product I-12 for a structural characterization, LC-MS (ESI) m/z: 505, 507 [M+H].sup.+.

Embodiment 13: Synthesis and Characterization of Compound I-13

##STR00070##

[0169] Using the above intermediate 13 as raw material, preparing the compound I-13 according to the synthetic route in the above figure.

[0170] Taking the purified product I-13 for a structural characterization, LC-MS (ESI) m/z: 504, 506 [M+H].sup.+.

Embodiment 14: Synthesis and Characterization of Compound I-14

##STR00071##

[0171] Preparing the compound I-14 by using compound I-4 as raw material and acylating the phenolic hydroxyl group with acetyl chloride.

[0172] Taking the purified product I-14 for a structural characterization, LC-MS (ESI) m/z: 523, 525 [M+H].sup.+.

Embodiment 15: Synthesis and Characterization of Compound I-15

##STR00072##

[0173] Using compound I-4 as raw material, according to the synthesis method of compound I-14, preparing the compound I-15 by replacing acetyl chloride therein with

##STR00073##

[0174] Taking the purified product I-15 for a structural characterization, LC-MS (ESI) m/z: 551, 553 [M+H].sup.+.

Embodiment 16: Synthesis and Characterization of Compound I-16

##STR00074##

[0175] Using compound I-4 as raw material, preparing the compound I-16through a one-step alkylation reaction.

[0176] Taking the purified product I-16 for a structural characterization, LC-MS (ESI) m/z: 597, 599 [M+H].sup.+.

Embodiment 17: Synthesis and Characterization of Compound I-17

##STR00075##

[0177] Using the above intermediate 11 as raw material, preparing the Compound I-17 according to the synthetic route in the above figure.

[0178] Taking the purified product I-17 for a structural characterization, LC-MS (ESI) m/z: 493 [M-H].sup..

Embodiment 18: Synthesis and Characterization of Compound I-18

##STR00076##

[0179] Using the above intermediate 11 as raw material, preparing the Compound I-18 according to the synthetic route in the above figure.

[0180] Taking the purified product 1-18 for a structural characterization, LC-MS (ESI) m/z: 477 [M-H].sup..

Embodiments 1922: Synthesis and Characterization of Compounds I-19I-22

##STR00077##

[0181] Preparing the compound I-19I-22 according to the synthesis route of the compound I-4 by replacing

##STR00078##

therein with

##STR00079##

respectively.

[0182] Taking the purified product I-19 for a structural characterization, LC-MS (ESI) m/z: 469 [M-H].sup..

[0183] Taking the purified product I-20 for a structural characterization, LC-MS (ESI) m/z: 451 [M-H].sup..

[0184] Taking the purified product I-21 for a structural characterization, LC-MS (ESI) m/z: 407 [M-H].sup..

[0185] Taking the purified product I-22 for a structural characterization, LC-MS (ESI) m/z: 477 [M-H].sup..

Embodiment 23: Synthesis and Characterization of Compound I-23

##STR00080##

[0186] Dissolving an intermediate 4 (1.5 mmol) and 2,2-dipyridyl (1.5 mmol) in dry DCE (7 mL), and adding cyclopropylboronic acid (3.0 mmol), copper acetate (1.5 mmol) and sodium carbonate (3.3 mmol) in sequence, heating to 80 degrees and stirring for 24 hours. Detecting the forming of a product 16 by LC-MS. Purifying the intermediate 16 (153 mg) by silica gel column chromatography. Dissolving the intermediate 16 (0.48 mmol) in DCM (0.4 mL) and pyridine (0.2 mL) and stirring in an ice-water bath, adding an intermediate 10 (0.50 mmol), then slowly returning to room temperature. Detecting the forming of an intermediate 17 by LC-MS. Purifying the tntermediate 17 (170 mg) by silica gel column chromatography.

##STR00081##

[0187] Using intermediate 17 (0.31 mmol) as raw material, preparing the compound I-23 (37 mg) by performing demethylation with boron tribromide according to the synthesis method of the compound I-2.

[0188] Taking the purified product I-23 for a structural characterization, LC-MS (ESI) m/z: 519, 521 [MH].sup..

Embodiment 24: Synthesis and Characterization of Compound I-24

##STR00082##

[0189] According to the synthesis method of compound I-23, preparing the compound I-24 by replacing

##STR00083##

therein with

##STR00084##

[0190] Taking the purified product I-23 for a structural characterization, LC-MS (ESI) m/z: 535, 537 [MH].sup..

Embodiment 25: Synthesis and Characterization of Compound I-25

##STR00085##

[0191] Using the known compound 18 (CAS: 88437-16-5) (5.0 mmol) as raw material, preparing the compound I-25 according to the synthesis method in the literature (J. Med. Chem. 2012, 55, 1978-1998).

[0192] Taking the purified product I-25 for a structural characterization: LC-MS (ESI) m/z: 504, 506 [MH].sup..

Embodiment 26: Synthesis and Characterization of Compound I-26

##STR00086##

[0193] Using the known compound 19 (CAS: 58200-82-1) (5.0 mmol) as raw material, preparing the compound I-26 according to the synthesis method in the literature (J. Med. Chem. 2012, 55, 1978-1998).

[0194] Taking the purified product I-26 for a structural characterization: LC-MS (ESI) m/z: 524, 526 [MH].sup..

Test Example 1. Functional Test of Mitophagy Inducer

[0195] Seeding human embryonic kidney transformed cells HEK293T-mtkeima cells in a 96-well black ELISA Plate at 1.5*10.sup.5 cells/ml, 100 l per well; after 25 hours, adding UMI-77 and compounds I-1I-26 respectively, and setting up 3 replicates; under 37 C., 5% CO.sub.2 incubation conditions, taking picture with biotekcytation5 every few hours for a total of 20 hours. Taking the bright field as the focusing channel, and taking 9pictures per well, and processing the pictures by using the instrument software and converting into the degree of mitophagy strength, exemplifying by UMI-77 and Compound I-4, the results are shown in FIG. 1.

[0196] Seeding human embryonic kidney transformed cells HEK293T-mtkeima cells in a 96-well black ELISA Plate at 1.5*10.sup.5 cells/ml, 100 l per well; after 24 hours, adding 5 uM or 10 uM CCCP (Carbonyl cyanide 3-chlorophenylhydrazone), after 1 hour, adding UMI-77 and compounds I-1I-26 respectively, and setting up 3 replicates; under 37 C., 5% CO.sub.2 incubation conditions, taking picture with biotekcytation5 every few hours for a total of 20 hours. Taking the bright field as the focusing channel, and taking 9 pictures per well, and processing the pictures by using the instrument software, exemplifying by UMI-77 and compounds I-1, I-4, and I-5, and the results are shown in FIGS. 2, 3, and 4 (the colour depth of the blocks represents the strength of mitophagy).

[0197] As shown in FIG. 1, on cells not treated with CCCP, compound I-4 induces mitophagy more strongly than UMI-77.

[0198] As shown in FIG. 2, the human embryonic kidney transformed cell HEK293T-mtkeima system is treated with 5 uM or 10 uM CCCP to induce mitochondrial damage, then adding compound I-1, compared with no CCCP treatment and only adding the test compound, the color of the block is darker, indicating that the compound I-1 is more likely to induce autophagy in damaged mitochondria. As for UMI-77, under the same conditions, the color blocks of damaged mitochondria and undamaged mitochondria are both darker, indicating that UMI-77 is unable to selectively induce autophagy in damaged mitochondria.

[0199] The ability of other compounds to induce mitophagy is shown in Table 1:

TABLE-US-00001 TABLE 1 Compound number Ability to induce mitophagy I-1 +++ I-2 ++ I-3 ++ I-4 +++ I-5 +++ I-6 +++ I-8 ++ I-9 ++ I-10 ++ I-11 ++ I-12 +++ I-13 ++ I-14 ++ I-17 +++ I-18 ++ I-19 +++ I-20 ++ I-21 +++ I-22 ++ UMI-77 + +++ indicates that the compound has a strong ability to induce mitophagy (number of cells in which mitophagy occurs/number of total cells >0.30), and ++ indicates that the compound has a moderate ability to induce mitophagy (number of cells in which mitophagy occurs/number of total cells is in the range of 0.2~0.3), + indicates that the compound has a weak ability to induce mitophagy (number of cells in which mitophagy occurs/number of total cells is in the range of 0.1~0.2), NA indicates that the compound is not detected with the ability to induce mitophagy.

[0200] Note: The HEK293T-mtkeima cells used in the experiments are HEK293T-mtkeima cells obtained according to the method mentioned in the literature [Cen, X. et al. Nat Commun 11, 5731 (2020).], by using lentiviral packaging technology, and stably expressing mtkeima protein in HEK293T cells. The CCCP used in the experiments is purchased from TargetMol (Item No. T7081).

Test Example 2, In Vitro Liver Microsome Stability Test

[0201] Selecting Ketanserin as the reference compound. The specific method is as follows:

[0202] Preparing 0.1M K.sub.3PO.sub.4 (pH 7.4) buffer and 3NADPH stock solution (6 mM, 5 mg/mL), and preheating in a 37 C. water bath; preparing of test compound and control compound spiking solution: adding 5 L compound stock solution (10 nM) into 95 L acetonitrile; preparing of 1.5 M spiking solution in microsomes (0.75 mg/mL): adding 1.5 L spiking solution and 18.75 L liver microsomes solution (20 mg/mL) into 479.75 L K.sub.3PO.sub.4 buffer; taking 30 L spiking solution in microsomes to the multi-well plate and incubating at 37 C. for 5 minutes; adding 15 L NADPH stock solution into each well to start the reaction, and timing; respectively at 0 min, 5 min, 15 min, 30 min and 45 min, adding 150 L of IS-containing acetonitrile solution to terminate the reaction; shaking for 10 mins and then centrifuging at 6000 rpm for 15 mins; taking 80 L of the supernatant from each well for LC/MS detection and calculating T.sub.1/2. Some test results are shown in FIG. 5.

[0203] As shown in FIG. 3, the in vitro liver microsome stability experiment of UMI-77 shows that UMI-77 is unstable in the environment of mice or human liver microsomes and will be eliminated rapidly; compounds I-1 and I-4 show relatively superior stability.

[0204] Note: The mice and human liver microsomes used in the experiments are purchased from Xenotech.

[0205] Those of ordinary skill in the art can understand that the above-mentioned embodiments are specific examples for implementing the present invention, and in practical applications, various changes can be made in form and details without departing from the spirit and scope of the present invention.