WO2023045909A1 - 一类具有萘胺结构的小分子化合物及其应用 - Google Patents

一类具有萘胺结构的小分子化合物及其应用 Download PDF

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WO2023045909A1
WO2023045909A1 PCT/CN2022/119825 CN2022119825W WO2023045909A1 WO 2023045909 A1 WO2023045909 A1 WO 2023045909A1 CN 2022119825 W CN2022119825 W CN 2022119825W WO 2023045909 A1 WO2023045909 A1 WO 2023045909A1
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hydrogen
alkyl
membered
phenyl
halogen
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PCT/CN2022/119825
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English (en)
French (fr)
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夏宏光
樊梦阳
岑旭峰
徐晓燕
吴荣海
刘栋
田珍
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杭州天玑济世生物科技有限公司
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Priority to CA3230925A priority Critical patent/CA3230925A1/en
Priority to IL311496A priority patent/IL311496A/en
Priority to AU2022350943A priority patent/AU2022350943A1/en
Priority to CN202280061842.0A priority patent/CN117957215A/zh
Publication of WO2023045909A1 publication Critical patent/WO2023045909A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D305/00—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms
    • C07D305/02—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D305/04—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D305/08—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring atoms

Definitions

  • the invention relates to the field of chemical medicines, in particular to a class of small molecule compounds with naphthylamine structures and applications thereof.
  • Mitophagy is a type of target-specific autophagy, and the main purpose of mitophagy is to identify and remove dysfunctional mitochondria. Since mitochondria play a central role in energy supply through oxidative phosphorylation, there are also some important functions including energy metabolism, amino acid production, lipid synthesis and ion homeostasis, which are important for the maintenance of cell types that depend on aerobic metabolism such as neuronal cells, muscle cells It is of great significance to the function of liver cells and so on. The homeostatic regulation of mitochondrial production and autophagy is an important link in maintaining cellular function.
  • Mitophagy dysfunction will lead to the accumulation of damaged mitochondria, the decline in the ability to synthesize ATP+, and the production of a large amount of peroxides, which will lead to changes in cellular intermediate metabolites and cause a series of pathological consequences. If aging or dysfunctional mitochondria are cleared by enhancing mitophagy, mitophagy will play a protective role in cells.
  • the object of the present invention is to provide a class of small molecular compounds with naphthylamine structure and applications thereof, which can selectively induce damaged mitochondrial autophagy without affecting normal mitochondria as a mitophagy inducer, and have stable metabolism Better performance and higher bioavailability.
  • the first aspect of the present invention provides a compound having a structure represented by general formula (I) and pharmaceutically acceptable salts, stereoisomers, solvates or prodrugs thereof,
  • R 1 is hydrogen or C 1-6 alkyl
  • R 2 is hydrogen, C 1-6 alkyl, three to six-membered cycloalkyl, three to six-membered epoxyalkyl, phenyl or phenyl substituted by C 1-6 alkyl;
  • R 3-1 is hydrogen, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, three to six-membered cycloalkyl, three to six-membered epoxyalkyl, amino, C 1-6 amine Group, -CH 2 C(O)R 3-2 , -CH 2 C(O)OR 3-2 or -CH 2 C(O)N(R 3-2 R 3-2a ),
  • R 3-2 and R 3-2a are independently hydrogen, C 1-6 alkyl or three to six-membered cycloalkyl,
  • Ar is phenyl, aphenylene, 5 or 6-membered monocyclic heteroaryl, 8 to 10-membered fused bicyclic heteroaryl, or 5 or 6-membered monocyclic heteroaryl with at least one hydrogen atom replaced by R 3-3 , an 8- to 10-membered fused bicyclic heteroaryl group in which at least one hydrogen atom is substituted by R 3-3 , said R 3-3 being hydrogen, halogen, C 1-6 alkyl, three- to six-membered cycloalkyl, hydroxyl , C 1 ⁇ 6 alkoxy, three to six membered epoxyalkyl, C 1 ⁇ 6 haloalkyl, C 2 ⁇ 6 alkenyl, C 2 ⁇ 6 alkynyl, -N(R 3-3a R 3-3b ) or phenyl,
  • R 3-3a and R 3-3b are independently hydrogen, C 1-6 alkyl or three to six-membered cycloalkyl;
  • R 4-1 is phenyl, aphenylene, phenyl with at least one hydrogen atom substituted by R 4-11 , 5 or 6-membered monocyclic heteroaryl, at least one hydrogen atom substituted by R 4-11 5 Or a 6-membered monocyclic heteroaryl group, an 8- to 10-membered fused bicyclic heteroaryl group, or an 8- to 10-membered fused bicyclic heteroaryl group in which at least one hydrogen atom is substituted by R 4-11 , said R 4-11 being hydrogen , halogen, nitro, nitrile, hydroxyl, C 1 ⁇ 6 alkyl, three to six membered cycloalkyl, C 1 ⁇ 6 alkoxy, -N(R 4-1a R 4-1b ), phenyl, C 1 ⁇ 6 haloalkyl, C 1 ⁇ 6 haloalkoxy, -C(O)OR 4-12 , -C(O)R 4-12 , -C(O)N(
  • R 4-2 is hydrogen, C 1-6 alkyl or three to six-membered cycloalkyl, or when R 2 is C 1-6 alkyl, R 4-2 and R 2 are bonded to form 4-8 membered ( For example, 5-6 member) ring,
  • R 4-3 is hydrogen, C 1-6 alkyl or C 1-6 alkoxy
  • R 5 may not exist (that is, 0), or one or more may exist at the same time when the valence bond rule allows, so the number of R 5
  • 0 to 5 pieces may be used, preferably 0 to 4 pieces, more preferably 0 to 2 pieces or 0 to 1 piece.
  • the Z is
  • R 1 is hydrogen or C 1-4 alkyl
  • R 2 is hydrogen, C 1-4 alkyl, three to six-membered cycloalkyl or four to six-membered epoxyalkyl;
  • R 3-1 is hydrogen, hydroxyl, C 1-4 alkyl, C 1-4 alkoxy, three to six-membered cycloalkyl, three to six-membered epoxyalkyl,
  • R 3-2 and R 3-2a are independently hydrogen, C 1-4 alkyl or three to six-membered cycloalkyl,
  • Ar is phenyl, 5 or 6 membered monocyclic heteroaryl, 5 or 6 membered monocyclic heteroaryl with at least one hydrogen atom replaced by R 3-3 , said R 3-3 being hydrogen, halogen, C 1 ⁇ 4 alkyl, three to six membered cycloalkyl, hydroxyl, C 1 to 4 alkoxy, three to six membered epoxyalkyl, C 1 to 4 haloalkyl, C 2 to 4 alkenyl, C 2 to 4 alkyne base, -N(R 3-3a R 3-3b ) or phenyl,
  • R 3-3a and R 3-3b are independently hydrogen, C 1-4 alkyl or three to six-membered cycloalkyl;
  • R 4-1 is phenyl, phenyl with at least one hydrogen atom substituted by R 4-11 , 5 or 6-membered monocyclic heteroaryl, at least one hydrogen atom substituted with R 4-11 5 or 6-membered monocyclic heteroaryl Ring heteroaryl, 8 to 10 membered fused bicyclic heteroaryl or 8 to 10 membered fused bicyclic heteroaryl with at least one hydrogen atom replaced by R 4-11 , said R 4-11 being hydrogen, halogen, nitric acid radical, C 1 ⁇ 4 alkyl, three to six membered cycloalkyl, C 1 ⁇ 4 alkoxy, -N(R 4-1a R 4-1b ), phenyl, C 1 ⁇ 4 haloalkyl, C 1 ⁇ 4 haloalkoxy or R 4-1a and R 4-1b are independently hydrogen, C 1-4 alkyl or three to six-membered cycloalkyl, and R 4-1a and R 4-1b can be bonded to each
  • R 4-2 is a C 1-4 alkyl group or a three- to six-membered cycloalkyl group, or when R 2 is a C 1-4 alkyl group, R 4-2 and R 2 are bonded to form a 4-8 membered ring,
  • R 4-3 is C 1-4 alkyl or C 1-4 alkoxy
  • the Z is
  • R 1 is hydrogen or C 1-4 alkyl
  • R 2 is hydrogen, C 1-4 alkyl, three to six-membered cycloalkyl or four to six-membered epoxyalkyl;
  • R 3-1 is hydrogen, hydroxyl, C 1 ⁇ 4 alkyl, C 1 ⁇ 4 alkoxy or -N(R 3-2 R 3-2a ),
  • R 3-2 and R 3-2a are independently hydrogen or C 1-4 alkyl
  • Ar is phenyl, 5 or 6 membered monocyclic heteroaryl, 5 or 6 membered monocyclic heteroaryl with at least one hydrogen atom replaced by R 3-3 , said R 3-3 being hydrogen, halogen, C 1 ⁇ 4 alkyl, hydroxyl, C 1 ⁇ 4 alkoxy, C 1 ⁇ 4 haloalkyl or -N(R 3-3a R 3-3b ),
  • R 3-3a and R 3-3b are independently hydrogen or C 1-4 alkyl
  • R 4-1 is phenyl, phenyl with at least one hydrogen atom substituted by R 4-11 , 5 or 6-membered monocyclic heteroaryl, at least one hydrogen atom substituted with R 4-11 5 or 6-membered monocyclic heteroaryl Ring heteroaryl
  • the R 4-11 is hydrogen, halogen, nitro, C 1-4 alkyl, three to six-membered cycloalkyl, C 1-4 alkoxy, -N(R 4-1a R 4-1b ), phenyl, C 1 ⁇ 4 haloalkyl, C 1 ⁇ 4 haloalkoxy or
  • R 4-1a and R 4-1b are independently hydrogen, C 1-4 alkyl or three to six-membered cycloalkyl, and R 4-1a and R 4-1b can be bonded to each other to form a ring,
  • R 4-2 is a C 1-4 alkyl group or a three- to six-membered cycloalkyl group, or when R 2 is a C 1-4 alkyl group, R 4-2 and R 2 are bonded to form a 4-8 membered ring,
  • R 4-3 is C 1-4 alkyl or C 1-4 alkoxy
  • R 5 When the number of R 5 is not 0, they are independently halogen, nitro, nitrile, -N + (R 5-1 ) 3 , C 1-4 haloalkyl,
  • R 5-1 , R 5-1a and R 5-1b are each independently hydrogen, C 1-4 alkyl, or C 1-4 alkyl in which at least one hydrogen is replaced by halogen.
  • the Z is
  • R 1 is hydrogen
  • R is hydrogen, methyl, ethyl, n-propyl, isopropyl
  • R3-1 is hydrogen, hydroxyl, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butyl Oxy, sec-butoxy or isobutoxy,
  • Ar is phenyl, 5- or 6-membered nitrogen-containing monocyclic heteroaryl
  • R 4-1 is phenyl, phenyl with at least one hydrogen atom substituted by R 4-11 , 5 or 6-membered monocyclic heteroaryl, at least one hydrogen atom substituted with R 4-11 5 or 6-membered monocyclic heteroaryl Ring heteroaryl, 8 to 10 membered fused bicyclic heteroaryl or 8 to 10 membered fused bicyclic heteroaryl with at least one hydrogen atom replaced by R 4-11 , said R 4-11 being hydrogen, halogen, nitric acid base, methyl, ethyl, n-propyl, isopropyl, Fluoromethyl, fluoroethyl, fluoro-n-propyl, fluoroisopropyl, chloromethyl, chloroethyl, chloro-n-propyl, chloroisopropyl, bromomethyl, bromine Ethyl bromide, n-propyl bromide, isopropyl bromide, methyl iod
  • R 4-2 is methyl, ethyl, n-propyl or isopropyl, or, when R 2 is methyl, ethyl or n-propyl, R 4-2 is bonded with R 2 to form a 4-8 member ring,
  • R 4-3 is methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy or isopropoxy;
  • each is independently selected from halogen, nitro, nitrile, -N + (R 5-1 ) 3 , fluoromethyl, fluoroethyl, fluoro-n-propyl, fluoroiso Propyl, chloromethyl, chloroethyl, chloro-n-propyl, chloroisopropyl, bromomethyl, bromoethyl, bromo-n-propyl, bromoisopropyl, -C( O)OR 5-1 , -C(O)R 5-1 , -C(O)N(R 5-1 R 5-1a ), -S(O) 2 R 5-1 ,
  • -S(O)R 5-1 , -N C(R 5-1 R 5-1a ), hydroxyl, methyl, ethyl, n-propyl, isopropyl, phenyl, at least one hydrogen replaced by R 5 -1- substituted phenyl, methoxy, ethoxy, n-propoxy, isopropoxy, -N(R 5-1 R 5-1a ), -N(R 5-1 )C(O) R 5-1a ,
  • R 5-1 , R 5-1a and R 5-1b are independently hydrogen, methyl, ethyl, n-propyl, isopropyl, fluoromethyl , fluoroethyl, fluoro-n-propyl, fluoroisopropyl, chloromethyl, chloroethyl, chloro-n-propyl, chloroisopropyl, bromomethyl, bromoethyl, bromo-n-propyl and bromo-isopropyl.
  • the compound represented by the general formula (I) is selected from any of the following compounds:
  • Z is selected from For example Z is
  • Z is
  • R 1 is hydrogen or C 1-6 alkyl
  • R 2 is hydrogen, C 1-6 alkyl, three to six-membered cycloalkyl, three to six-membered epoxyalkyl, phenyl or phenyl substituted by C 1-6 alkyl;
  • R 3-1 is hydrogen, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, three to six-membered cycloalkyl, three to six-membered epoxyalkyl, amino, C 1-6 amine Group, -CH 2 C(O)R 3-2 , -CH 2 C(O)OR 3-2 or -CH 2 C(O)N(R 3-2 R 3-2a ),
  • R 3-2 and R 3-2a are independently hydrogen, C 1-6 alkyl or three to six-membered cycloalkyl,
  • Ar is phenyl, aphenylene, 5- or 6-membered monocyclic heteroaryl, 8- to 10-membered condensed bicyclic heteroaryl, phenyl with at least one hydrogen atom replaced by R 3-3 , at least one hydrogen atom replaced by R 3-3 substituted acene, 5- or 6-membered monocyclic heteroaryl with at least one hydrogen atom substituted by R 3-3 , 8 to 10-membered fused bicyclic heteroaryl with at least one hydrogen atom substituted by R 3-3
  • the R 3-3 is hydrogen, halogen, C 1-6 alkyl, three to six-membered cycloalkyl, hydroxyl, C 1-6 alkoxy, three- to six-membered epoxyalkyl, C 1-6 6 haloalkyl, C 2 ⁇ 6 alkenyl, C 2 ⁇ 6 alkynyl, -N(R 3-3a R 3-3b ) or phenyl,
  • R 3-3a and R 3-3b are independently hydrogen, C 1-6 alkyl or three to six-membered cycloalkyl;
  • R 4-1 is phenyl, aphenylene, phenyl with at least one hydrogen atom substituted by R 4-11 , 5 or 6-membered monocyclic heteroaryl, at least one hydrogen atom substituted by R 4-11 5 Or a 6-membered monocyclic heteroaryl group, an 8- to 10-membered fused bicyclic heteroaryl group, or an 8- to 10-membered fused bicyclic heteroaryl group in which at least one hydrogen atom is substituted by R 4-11 , said R 4-11 being hydrogen , halogen, nitro, nitrile, hydroxyl, C 1 ⁇ 6 alkyl, three to six membered cycloalkyl, C 1 ⁇ 6 alkoxy, -N(R 4-1a R 4-1b ), phenyl, C 1 ⁇ 6 haloalkyl, C 1 ⁇ 6 haloalkoxy, -C(O)OR 4-12 , -C(O)R 4-12 , -C(O)N(
  • R 4-2 is a C 1-6 alkyl group or a three- to six-membered cycloalkyl group, or when R 2 is a C 1-6 alkyl group, R 4-2 and R 2 are bonded to form a 4-8-membered ring,
  • R 4-3 is C 1-6 alkyl or C 1-6 alkoxy
  • each is independently selected from halogen, nitro, nitrile, -N + (R 5-1 ) 3 , C 1-6 haloalkyl,
  • the compound has a structure represented by formula (II);
  • R is hydrogen, C 1-4 alkyl, three to six-membered cycloalkyl or four to six-membered epoxyalkyl;
  • R 3-1 is hydrogen, hydroxyl, C 1-4 alkyl, C 1-4 alkoxy, three to six-membered cycloalkyl, three to six-membered epoxyalkyl,
  • R 3-2 and R 3-2a are independently hydrogen, C 1-4 alkyl or three to six-membered cycloalkyl,
  • Ar is phenyl, 5 or 6 membered monocyclic heteroaryl, 5 or 6 membered monocyclic heteroaryl with at least one hydrogen atom replaced by R 3-3 , said R 3-3 is hydrogen, halogen, C 1 ⁇ 4 alkyl, three to six membered cycloalkyl, hydroxyl, C 1 to 4 alkoxy, three to six membered epoxyalkyl, C 1 to 4 haloalkyl, C 2 to 4 alkenyl, C 2 to 4 alkyne base, -N(R 3-3a R 3-3b ) or phenyl,
  • R 3-3a and R 3-3b are independently hydrogen, C 1-4 alkyl or three to six-membered cycloalkyl;
  • R 4-1 is phenyl, phenyl with at least one hydrogen atom substituted by R 4-11 , 5 or 6-membered monocyclic heteroaryl, at least one hydrogen atom substituted with R 4-11 5 or 6-membered monocyclic heteroaryl Ring heteroaryl, 8 to 10-membered fused bicyclic heteroaryl, 8 to 10-membered condensed bicyclic heteroaryl with at least one hydrogen atom replaced by R 4-11 , said R 4-11 being hydrogen, halogen, nitric acid radical, C 1 ⁇ 4 alkyl, three to six membered cycloalkyl, C 1 ⁇ 4 alkoxy, -N(R 4-1a R 4-1b ), phenyl, C 1 ⁇ 4 haloalkyl, C 1 ⁇ 4 haloalkoxy or R 4-1a and R 4-1b are independently hydrogen, C 1-4 alkyl or three to six-membered cycloalkyl, and R 4-1a and R 4-1b can be bonded to
  • R 4-2 is a C 1-4 alkyl group, a three- to six-membered cycloalkyl group, or when R 2 is a C 1-4 alkyl group, R 4-2 and R 2 are bonded to form a 4-8 membered ring,
  • R 4-3 is C 1-4 alkyl or C 1-4 alkoxy
  • each is independently selected from halogen, nitro, nitrile, -N + (R 5-1 ) 3 , C 1-4 haloalkyl,
  • R 5-1 , R 5-1a and R 5-1b are independently hydrogen, C 1-4 alkyl, C 2 ⁇ 4 alkenyl, C 2 ⁇ 4 alkynyl, C 1 ⁇ 4 alkyl in which at least one hydrogen is replaced by halogen, C
  • the compound has a structure shown in formula (II);
  • R is hydrogen, C 1-4 alkyl, three to six-membered cycloalkyl or four to six-membered epoxyalkyl;
  • R 3-1 is hydrogen, hydroxyl, C 1-4 alkyl, C 1-4 alkoxy, three to six-membered cycloalkyl, three to six-membered epoxyalkyl,
  • R 3-2 and R 3-2a are independently hydrogen, C 1-4 alkyl or three to six-membered cycloalkyl,
  • Ar is phenyl, 5 or 6 membered monocyclic heteroaryl, 5 or 6 membered monocyclic heteroaryl with at least one hydrogen atom replaced by R 3-3 , said R 3-3 is hydrogen, halogen, C 1 ⁇ 4 alkyl, three to six membered cycloalkyl, hydroxyl, C 1 to 4 alkoxy, three to six membered epoxyalkyl, C 1 to 4 haloalkyl, C 2 to 4 alkenyl, C 2 to 4 alkyne base, -N(R 3-3a R 3-3b ) or phenyl,
  • R 3-3a and R 3-3b are independently hydrogen, C 1-4 alkyl or three to six-membered cycloalkyl;
  • R 4-1 is phenyl, phenyl with at least one hydrogen atom substituted by R 4-11 , 5 or 6-membered monocyclic heteroaryl, at least one hydrogen atom substituted with R 4-11 5 or 6-membered monocyclic heteroaryl Ring heteroaryl, 8 to 10-membered fused bicyclic heteroaryl, 8 to 10-membered condensed bicyclic heteroaryl with at least one hydrogen atom replaced by R 4-11 , said R 4-11 being hydrogen, halogen, nitric acid radical, C 1 ⁇ 4 alkyl, three to six membered cycloalkyl, C 1 ⁇ 4 alkoxy, -N(R 4-1a R 4-1b ), phenyl, C 1 ⁇ 4 haloalkyl, C 1 ⁇ 4 haloalkoxy or R 4-1a and R 4-1b are independently hydrogen, C 1-4 alkyl or three to six-membered cycloalkyl, and R 4-1a and R 4-1b can be bonded to
  • R 4-2 is a C 1-4 alkyl group, a three- to six-membered cycloalkyl group, or when R 2 is a C 1-4 alkyl group, R 4-2 and R 2 are bonded to form a 4-8 membered ring,
  • R 4-3 is C 1-4 alkyl or C 1-4 alkoxy
  • each is independently selected from halogen, nitro, nitrile, -N + (R 5-1 ) 3 , C 1-4 haloalkyl,
  • R 5-1 and R 5-1a are independently hydrogen, C 1 ⁇ 4 alkyl, C 2 ⁇ 4- alkenyl, C 2-4 alkynyl, C 1-4 alkyl in which at least one hydrogen is replaced by halogen, C 2-4 alkenyl in which at least one hydrogen is substituted by halogen, or C 2-4 in which at least one hydrogen is substituted by halogen Alkynyl.
  • the compound has a structure shown in formula (III);
  • R is hydrogen, C 1-4 alkyl, three to six-membered cycloalkyl or four to six-membered epoxyalkyl;
  • R 3-1 is hydrogen, hydroxyl, C 1-4 alkyl, C 1-4 alkoxy, three to six-membered cycloalkyl, three to six-membered epoxyalkyl,
  • R 3-2 and R 3-2a are independently hydrogen, C 1-4 alkyl or three to six-membered cycloalkyl,
  • Ar is phenyl, 5 or 6 membered monocyclic heteroaryl, 5 or 6 membered monocyclic heteroaryl with at least one hydrogen atom replaced by R 3-3 , said R 3-3 is hydrogen, halogen, C 1 ⁇ 4 alkyl, three to six membered cycloalkyl, hydroxyl, C 1 to 4 alkoxy, three to six membered epoxyalkyl, C 1 to 4 haloalkyl, C 2 to 4 alkenyl, C 2 to 4 alkyne base, -N(R 3-3a R 3-3b ) or phenyl,
  • R 3-3a and R 3-3b are independently hydrogen, C 1-4 alkyl or three to six-membered cycloalkyl;
  • R 4-1 is phenyl, phenyl with at least one hydrogen atom substituted by R 4-11 , 5 or 6-membered monocyclic heteroaryl, at least one hydrogen atom substituted with R 4-11 5 or 6-membered monocyclic heteroaryl Ring heteroaryl, 8 to 10 membered fused bicyclic heteroaryl or 8 to 10 membered fused bicyclic heteroaryl with at least one hydrogen atom replaced by R 4-11 , said R 4-11 being hydrogen, halogen, nitric acid radical, C 1 ⁇ 4 alkyl, three to six membered cycloalkyl, C 1 ⁇ 4 alkoxy, -N(R 4-1a R 4-1b ), phenyl, C 1 ⁇ 4 haloalkyl, C 1 ⁇ 4 haloalkoxy or R 4-1a and R 4-1b are independently hydrogen, C 1-4 alkyl or three to six-membered cycloalkyl, and R 4-1a and R 4-1b can be bonded to each
  • R 4-2 is a C 1-4 alkyl group or a three- to six-membered cycloalkyl group, or when R 2 is a C 1-4 alkyl group, R 4-2 and R 2 are bonded to form a 4-8 membered ring,
  • R 4-3 is C 1-4 alkyl or C 1-4 alkoxy
  • each is independently selected from halogen, nitro, nitrile, -N + (R 5-1 ) 3 , C 1-4 haloalkyl,
  • R 5-1 , R 5-1a and R 5-1b are independently hydrogen, C 1 ⁇ 4 alkyl, C 2 ⁇ 4 alkenyl, C 2 ⁇ 4 alkynyl, C 1 ⁇ 4 alkyl in which at least one hydrogen is replaced by halogen,
  • the compound has a structure shown in formula (III);
  • R is hydrogen, C 1-4 alkyl, three to six-membered cycloalkyl or four to six-membered epoxyalkyl;
  • R 3-1 is hydrogen, hydroxyl, C 1-4 alkyl, C 1-4 alkoxy, three to six-membered cycloalkyl, three to six-membered epoxyalkyl,
  • R 3-2 and R 3-2a are independently hydrogen, C 1-4 alkyl or three to six-membered cycloalkyl,
  • Ar is phenyl, 5 or 6 membered monocyclic heteroaryl or 5 or 6 membered monocyclic heteroaryl with at least one hydrogen atom replaced by R 3-3 , said R 3-3 being hydrogen, halogen, C 1 ⁇ 4 alkyl, three to six membered cycloalkyl, hydroxyl, C 1 to 4 alkoxy, three to six membered epoxyalkyl, C 1 to 4 haloalkyl, C 2 to 4 alkenyl, C 2 to 4 alkyne base, -N(R 3-3a R 3-3b ) or phenyl,
  • R 3-3a and R 3-3b are independently hydrogen, C 1-4 alkyl or three to six-membered cycloalkyl;
  • R 4-1 is phenyl, phenyl with at least one hydrogen atom substituted by R 4-11 , 5 or 6-membered monocyclic heteroaryl, at least one hydrogen atom substituted with R 4-11 5 or 6-membered monocyclic heteroaryl Ring heteroaryl, 8 to 10 membered fused bicyclic heteroaryl or 8 to 10 membered fused bicyclic heteroaryl with at least one hydrogen atom replaced by R 4-11 , said R 4-11 being hydrogen, halogen, nitric acid radical, C 1 ⁇ 4 alkyl, three to six membered cycloalkyl, C 1 ⁇ 4 alkoxy, -N(R 4-1a R 4-1b ), phenyl, C 1 ⁇ 4 haloalkyl, C 1 ⁇ 4 haloalkoxy or R 4-1a and R 4-1b are independently hydrogen, C 1-4 alkyl or three to six-membered cycloalkyl, and R 4-1a and R 4-1b can be bonded to each
  • R 4-2 is a C 1-4 alkyl group or a three- to six-membered cycloalkyl group, or when R 2 is a C 1-4 alkyl group, R 4-2 and R 2 are bonded to form a 4-8 membered ring,
  • R 4-3 is C 1-4 alkyl or C 1-4 alkoxy
  • each is independently selected from hydroxyl, C 1-4 alkyl, phenyl, phenyl with at least one hydrogen replaced by R 5-1 , C 1-4 alkoxy, -N(R 5 -1 R 5-1a ), -N(R 5-1 )C(O)R 5-1a , -OC(O)R 5-1 , -OC(O)N(R 5-1 R 5-1a ) and -SR 5-1 , wherein, R 5-1 , R 5-1a and R 5-1b are independently hydrogen, C 1 ⁇ 4 alkyl, C 2 ⁇ 4 alkenyl, C 2 ⁇ 4 alkynyl , C 1-4 alkyl in which at least one hydrogen is substituted by halogen, C 2-4 alkenyl in which at least one hydrogen is substituted by halogen, or C 2-4 alkynyl in which at least one hydrogen is substituted by halogen.
  • R 1 is hydrogen or methyl, more preferably hydrogen.
  • R 2 is hydrogen, C 1-6 alkyl (preferably methyl), three to six-membered cycloalkyl (preferably cyclopropyl) or three to six-membered Oxiranyl (preferably oxetanyl).
  • R 3 is selected from -CH 2 -COOH, -CH 2 -CONH 2 ,
  • Ar is a 5 or 6-membered monocyclic heteroaryl, more preferably a 5 or 6-membered monocyclic heteroaryl nitrogen-containing monocyclic heteroaryl, more preferably a triazolyl (for example in particular ), tetrazolyl (for example ) or phenyl.
  • R 4 is:
  • R 4-1 is selected from phenyl, 5- or 6-membered monocyclic heteroaryl (such as thienyl, pyrazolyl, isoxazolyl, pyridyl) and 8 to 10-membered fused bicyclic heteroaryl (such as Benzothienyl), each of the above groups is optionally substituted by a group selected from the following groups: halogen, nitro, phenyl, nitrile, hydroxyl, C 1-6 alkyl, three to six-membered cycloalkyl, C 1 ⁇ 6 alkoxy, C 1 ⁇ 6 haloalkyl, C 1 ⁇ 6 haloalkoxy, -N(R 4-1a R 4-1b )(R 4-1a and R 4-1b may be bonded to each other to form a ring, for example, to form a pyrrolidine ring);
  • R 4-2 is hydrogen, C 1-6 alkyl, three to six -membered cycloalkyl, or when R 2 is C 1-6 alkyl, R 4-2 and R 2 are bonded to form 4-8 membered ( For example a 5- or 6-membered) ring;
  • R 4-3 is hydrogen, C 1-6 alkyl or C 1-6 alkoxy.
  • R 4-1a , R 4-1b , R 4-2 , R 4-3 , and R 5 are as defined in the context of this specification.
  • the number of R 5 is 0 to 2 (especially 0 to 1), and when the number of R 5 is not 0, each is independently selected from hydroxyl, C 1 to 4 alkyl, C 1-4 alkoxy, nitro, -COOH, -NHCO-C 1-4 alkyl (eg -NHCO-CH 3 ).
  • the compound of the present invention is selected from any one of the following compounds, or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof:
  • the C 1-6 alkyl group is a C 1-4 alkyl group, and the C 1-4 alkyl group is preferably methyl, ethyl, n-propyl, isopropyl, n-butyl , isobutyl or tert-butyl, eg methyl or ethyl.
  • the three- to six-membered cycloalkyl group is preferably a C 3-5 cycloalkyl group, and the C 3-5 cycloalkyl group is preferably For example:
  • the three- to six-membered epoxy group is preferably For example:
  • the C 1-6 alkyl substituted phenyl is preferably C 1-4 alkyl substituted phenyl, more preferably methyl, ethyl, n-propyl, isopropyl, n- A phenyl group substituted by any one of butyl, isobutyl and tert-butyl.
  • the C 1-6 alkoxy group is preferably a C 1-4 alkoxy group, more preferably methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy group, tert-butoxy, sec-butoxy or isobutoxy.
  • 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
  • the 5 or 6 membered monocyclic heteroaryl is preferably Wherein, Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Y 6 , Y 7 , Y 8 , Y 9 are independently selected from C, N, O or S, and Y 1 , Y 2 , Y 3 , Y 4 is not all C, Y 5 , Y 6 , Y 7 , Y 8 , Y 9 are not all C; the 5 or 6 membered monocyclic heteroaryl is more preferably pyrrolyl, furyl, thienyl, Pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridyl, pyryl, thiopyranyl, pyridazinyl, pyrimidinyl, pyrazinyl, piperazinyl, triazolyl, Tetrazolyl;
  • the 5- or 6-membered monocyclic heteroaryl is a 5-membered nitrogen-containing monocyclic heteroaryl, for example:
  • the 8- to 10-membered fused bicyclic heteroaryl is
  • the halogen is preferably fluorine, chlorine, bromine or iodine.
  • the C 1-6 haloalkyl group is preferably a C 1-3 haloalkyl group; more preferably fluoromethyl, fluoroethyl, fluoro-n-propyl, fluoroisopropyl, chlorine Chloromethyl, chloroethyl, chloro-n-propyl, chloroisopropyl, bromomethyl, bromoethyl, bromo-n-propyl, bromoisopropyl, iodomethyl, iodo Ethyl, iodo-n-propyl, iodo-isopropyl; most preferably trifluoromethyl.
  • the C 1-6 haloalkoxy group is preferably a C 1-3 haloalkoxy group; more preferably fluoromethoxy, fluoroethoxy, fluoro-n-propoxy, fluoro Isopropoxy, chloromethoxy, chloroethoxy, chloro-n-propoxy, chloroisopropoxy, bromomethoxy, bromoethoxy, bromo-n-propoxy, Bromoisopropoxy, iodooxymethyl, iodoethoxy, iodo-n-propoxy, iodoisopropoxy; most preferably trifluoromethoxy.
  • the C 2 ⁇ 6 alkynyl group is preferably a C 2 ⁇ 6 alkynyl group, more preferably -C ⁇ CH, -CH 2 -C ⁇ CH, -CH 2 -CH 2 -C ⁇ CH , -CH 2 -C ⁇ C-CH 3 .
  • the second aspect of the present invention provides a pharmaceutical composition, which comprises the compound described in the first aspect of the present invention, and a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof.
  • the third convenience of the present invention provides the compound described in the first aspect of the present invention, or its pharmaceutically acceptable salt, stereoisomer, solvate or prodrug, or the pharmaceutical composition described in the second aspect of the present invention in Use in the preparation of a mitophagy inducer (especially a selective mitophagy inducer).
  • the present invention has at least the following advantages:
  • the compound provided by the first aspect of the present invention and its pharmaceutically acceptable salt, stereoisomer, solvate or prodrug or the pharmaceutical composition provided by the second aspect of the present invention can induce damaged mitochondrial autophagy, and Selectively induce damaged mitophagy without affecting or only weakly affecting normal mitochondria;
  • the compound of the present invention has the effect of inducing damaged mitophagy or improving metabolic stability.
  • the preferred compounds of the present invention have the effects of inducing damaged mitophagy and improving metabolic stability at the same time.
  • the preferred compounds of the present invention have the effect of selectively inducing damaged mitophagy, or improving metabolic stability.
  • Particularly preferred compounds of the present invention simultaneously have the effect of selectively inducing damaged mitophagy and improving metabolic stability.
  • Fig. 1 is the test result figure of compound I-2 in the test example 1 of the present invention to induce damage mitophagy ability;
  • Fig. 2 is UMI-77 in test example 1 of the present invention, I-2, I-1 selectivity induces damage mitophagy ability test result figure;
  • Fig. 3 is the in vitro liver microsomal stability test result chart of compound UMI-77, I-2, I-1 in Test Example 2 of the present invention
  • Fig. 4 is the in vitro plasma stability test result figure of compound UMI-77, I-2, I-1 in Test Example 3 of the present invention
  • Fig. 5 is the drug-time curve diagram of compound UMI-77 administered by IV in Test Example 4 of the present invention.
  • Fig. 6 is the drug-time curve diagram of compound UMI-77 administered by PO in Test Example 4 of the present invention.
  • Fig. 7 is the drug-time curve diagram of compound I-1 in test example 4 of the present invention through IV administration to standard mice;
  • Fig. 8 is a drug-time curve diagram of compound I-1 administered PO to standard mice in Test Example 4 of the present invention.
  • Fig. 9 is a drug-time curve diagram of Compound I-1 administered IP to standard mice in Test Example 4 of the present invention.
  • Fig. 10 is a drug-time curve diagram of compound I-2 in Test Example 4 of the present invention through IV administration to standard mice;
  • Fig. 11 is a drug-time curve diagram of compound I-2 administered PO to standard mice in Test Example 4 of the present invention.
  • Fig. 12 is a drug-time curve diagram of compound I-1 administered to SD rats through IV in Test Example 4 of the present invention.
  • Fig. 13 is a drug-time curve diagram of Compound I-1 administered IP to SD rats in Test Example 4 of the present invention.
  • Fig. 14 is a drug-time curve of SD rats administered PO with compound I-1 in Test Example 4 of the present invention.
  • the compound according to the first aspect of the present invention has the effect of inducing damaged mitophagy or improving metabolic stability.
  • the preferred compounds of the present invention have both the effects of inducing damaged mitophagy and improving metabolic stability.
  • the preferred compounds of the present invention have the effect of selectively inducing damaged mitophagy, or improving metabolic stability.
  • Particularly preferred compounds of the present invention simultaneously have the effect of selectively inducing damaged mitophagy and improving metabolic stability.
  • mitochondria autophagy refers to the process of mitochondria being selectively degraded by autophagy, which is an important mechanism for the quality and quantity control of mitochondria.
  • mitochondrial autophagy inducer refers to a compound that can induce mitophagy function.
  • alkyl refers to a straight or branched chain saturated aliphatic hydrocarbyl group.
  • C 1-6 alkyl refers to a straight or branched chain alkyl group having 1 to 6 carbon atoms, such as, without limitation, methyl, ethyl, n-propyl, isopropyl, n-butyl Base, 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
  • C 1-4 alkyl refers to a straight chain or branched chain alkyl having 1 to 4 carbon atoms, if a C 1-4 alkyl occurs at the terminal of a 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 linked through the alkyl group, without limitation, for example:- CH 2 -, -CH 2 -CH 2 -, -CH(CH 3 )-, -CH 2 -CH 2 -CH 2 -, -CH(C 2 H 5 )-, -C(CH 3 ) 2 -, Each hydrogen of a C 1-4 alkyl carbon may be replaced by a substituent further recited herein.
  • alkenyl refers to a straight or branched hydrocarbon chain containing at least one carbon-carbon double bond. Each hydrogen on an alkenyl carbon may be replaced by a substituent further recited herein.
  • C2-6 alkenyl refers to a straight or branched hydrocarbon chain having 1 to 6 carbon atoms containing at least one carbon-carbon double bond.
  • Each hydrogen of a C 2-6 alkenyl carbon may be replaced by a substituent further recited herein.
  • alkynyl refers to a straight or branched hydrocarbon chain containing at least one carbon-carbon triple bond. Each hydrogen on an alkynyl carbon may be replaced by a substituent further recited herein.
  • C2-6 alkynyl refers to a straight or branched hydrocarbon chain having 1 to 6 carbon atoms containing at least one carbon-carbon triple bond.
  • non-limiting examples are: -C ⁇ CH, -CH2 -C ⁇ CH, -CH2 - CH2 -C ⁇ CH, -CH2- C ⁇ C- CH3 , or , when the two moieties of the molecule are linked through the alkynyl group, such as, without limitation, -C ⁇ C-.
  • Each hydrogen on a C 2-6 alkynyl carbon may be replaced by a substituent further recited herein.
  • alkoxy refers to a group having the structure "-O-alkyl", wherein alkyl is as defined above.
  • C 1-6 alkoxy refers to an alkoxy group having 1 to 6 carbon atoms, such as, without limitation, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, isobutoxy, n-pentoxy, etc.
  • amino group refers to a group formed after at least one hydrogen atom in an amino group is replaced by an alkyl group, for example: amino group In, any one of R 3-11 and R 3-12 is an alkyl group, and the other is hydrogen; or R 3-11 and R 3-12 are all alkyl groups; when R 3-11 and R 3-12 are all In the case of an alkyl group, R 3-11 and R 3-12 can be bonded to form a ring.
  • haloalkyl refers to an alkyl group in which one or more (eg, 1, 2, 3, 4 or 5) hydrogen atoms are replaced with a halogen, wherein alkyl is as defined above.
  • halooxyalkyl refers to an alkoxy group in which one or more hydrogen atoms are replaced by a halogen, wherein alkoxy group is as defined above.
  • aryl As used herein, the terms “aryl”, “aryl ring” and “aromatic ring” are used interchangeably to refer to all-carbon monocyclic, all-carbon non-fused polycyclic rings (rings are linked by covalent bonds, Non-fused) or all-carbon fused polycyclic (that is, rings that share adjacent pairs of carbon atoms) groups, at least one ring in the group is aromatic, that is, has a ring-forming conjugated ⁇ -electron system.
  • heteroaryl refers to an aryl group in which at least one ring carbon atom constituting the aryl group is replaced by a heteroatom, which is a non-carbon atom such as S, N, or O.
  • the term "monocyclic heteroaryl” refers to a heteroaryl group having only one aromatic ring, wherein heteroaryl is as defined above.
  • fused ring heteroaryl refers to at least two aromatic rings in which two ring atoms are shared adjacent, wherein heteroaryl is as defined above .
  • fused bicyclic heteroaryl refers to a fused ring heteroaryl having two aromatic rings, wherein fused ring heteroaryl is as defined above.
  • the term "effective amount” or “therapeutically effective amount” refers to a chemical entity (such as a compound exhibiting activity as a NLRP1/3 modulator, or a pharmaceutically acceptable salt and/or hydrate and/or co-crystal;) which when administered will alleviate to some extent one or more of the symptoms of the disease or disorder being treated. Outcomes include reduction and/or remission of signs, symptoms or causes of disease or any other desired change in a biological system. An appropriate "effective" amount in any individual case is determined using any suitable technique, such as a dose escalation study.
  • 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.
  • each component is compatible with the other ingredients of the pharmaceutical formulation and is suitable for use in contact with human and animal tissues or organs without undue toxicity, irritation, allergic response, immunogenicity, or other problems or complications.
  • pharmaceutically acceptable in the sense that it is commensurate with a reasonable benefit/risk ratio.
  • the term "pharmaceutically acceptable salt” may refer to pharmaceutically acceptable addition salts prepared from pharmaceutically acceptable non-toxic acids, including inorganic acids and organic acids. In certain instances, pharmaceutically acceptable salts are obtained by reacting a compound described herein with an acid.
  • 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 established. The pharmacologically acceptable salt is not particularly limited as long as it can be used in medicine.
  • salts of the compounds described herein with bases include the following: their salts with inorganic bases such as sodium, potassium, magnesium, calcium and aluminum; their salts with organic bases such as methylamine, ethylamine and ethanolamine; or their salts with di Formed by the reaction of cyclohexylamine, N-methyl-D-glucamine, or tris(hydroxymethyl)methylamine; their salts with basic amino acids such as lysine and ornithine; and ammonium salts.
  • inorganic bases such as sodium, potassium, magnesium, calcium and aluminum
  • organic bases such as methylamine, ethylamine and ethanolamine
  • their salts with basic amino acids such as lysine and ornithine
  • ammonium salts include the following: their salts with inorganic bases such as sodium, potassium, magnesium, calcium and aluminum; their salts with
  • the salt may be an acid addition salt, which is specifically exemplified by an acid addition salt with an inorganic acid such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid; an organic acid such as formic acid, acetic acid, Propionic, oxalic, malonic, succinic, fumaric, maleic, lactic, malic, tartaric, citric, methanesulfonic, and ethanesulfonic acids; acidic amino acids such as aspartic and glutamic acids .
  • an inorganic acid such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid
  • an organic acid such as formic acid, acetic acid, Propionic, oxalic, malonic, succinic, fumaric, maleic, lactic, malic, tartaric, citric, methanesulfonic, and e
  • 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.
  • each component is compatible with the other ingredients of the pharmaceutical formulation and is suitable for use in contact with human and animal tissues or organs without undue toxicity, irritation, allergic response, immunogenicity, or other problems or complications.
  • pharmaceutically acceptable in the sense that it is commensurate with a reasonable benefit/risk ratio.
  • compositions refers to a mixture of compounds described herein and "excipients” such as carriers, stabilizers, diluents, dispersants, suspending agents and/or thickening agents.
  • excipients such as carriers, stabilizers, diluents, dispersants, suspending agents and/or thickening agents.
  • Pharmaceutical compositions facilitate the administration of a compound to an organism.
  • Various techniques of administering compounds exist in the art including, but not limited to, rectal, oral, intravenous, aerosol, parenteral, ophthalmic, pulmonary, and topical administration.
  • the term "subject” refers to animals, including but not limited to primates (e.g., humans), monkeys, cows, pigs, sheep, goats, horses, dogs, cats, rabbits, rats, or small animals. mouse.
  • the terms "subject” and “patient” are used interchangeably herein, for example, with respect to a mammalian subject such as a human.
  • the terms “treat, treating and treatment” are meant to include the alleviation or elimination of a disorder, disease or condition, wherein the term “disorder” as used herein should always be understood to mean A "disorder, disease, or condition” or one or more of the symptoms associated with a disorder; or slowing the progression, spread, or worsening of a disorder or condition, or one or more symptoms thereof.
  • “selectivity” as used herein refers to the property of significantly inducing damaged mitophagy on the premise of no or only weak influence on normal mitochondria.
  • “Metabolic stability” as used herein includes, but is not limited to, hepatic microsomal stability and plasma stability.
  • naphthalene ring (including the two benzene rings on the left and the right) is substituted by 0, 1, 2, 3, 4 or 5 R 5 , and when the naphthalene ring is substituted by more than 1 R 5 , each occurrence of R 5 same or different.
  • compound I-7-1 (7 mg) was prepared according to the synthesis method of compound I-1.
  • the reaction system was diluted with ethyl acetate and filtered through a layer of diatomaceous earth, the filtrate was spin-dried, and silica gel column chromatography gave a methylthio-substituted product (3.4 mmol).
  • This product was dissolved in anhydrous DCM and cooled in a dry ice-ethanol bath, mCPBA (1.1 eq) was added in one portion and then slowly returned to room temperature.
  • LC-MS showed that the reaction was complete, and the solvent was removed by rotary evaporation, and the residual solid was slurried with methyl tert-butyl ether to obtain the sulfoxide product (3.3 mmol).
  • the reaction system was diluted with ethyl acetate and filtered through a layer of diatomaceous earth, the filtrate was spin-dried, and the thio product (4.1 mmol) was obtained by silica gel column chromatography.
  • the thio product was reduced to nitro group with reduced iron powder in acetic acid solvent, accompanied by the removal of the TMS protecting group on the alkynyl group,
  • the naphthylamine intermediate (3.5 mmol) was obtained after silica gel column chromatography.
  • the naphthylamine intermediate was then sulfonylated according to the UMI-77 synthesis route (J.Med.Chem.2014, 57, 4111-4133) to obtain a sulfonamide intermediate (3.2 mmol). Dissolve this sulfonamide intermediate (3.2mmol) in a 2:1 mixed solvent of methanol and DMF, add cuprous iodide (0.1eq), add TMSN 3 dropwise under stirring at room temperature, react overnight, LC-MS shows that there is trinitrogen The azole product was formed, and the triazole product (1.7 mmol) was obtained by silica gel column chromatography. Compound 1-10 was prepared by demethylating and oxidizing the triazole product according to the synthesis method of compound 1-2.
  • compound I-12 can be prepared by oxidizing sulfoxide with mCPBA according to the synthesis method of compound I-1.
  • Embodiment 19 the synthesis and characterization of compound I-19
  • intermediate 22 was prepared.
  • the methylamine in the synthetic route is replaced with Intermediate 24 can be prepared.
  • Intermediate 24 (1.9 mmol) was dissolved in THF, stirred at room temperature and 1 MTBAF solution in THF was added dropwise, stirring was continued for one hour until TBS was completely removed.
  • the intermediate 25 (1.8 mmol) was obtained by silica gel column chromatography.
  • Intermediate 25 (1.8mmol) and triphenylphosphine (1.2eq) were dissolved in anhydrous THF, stirred at room temperature and DIAD (1.2eq) was added dropwise, stirring was continued at room temperature overnight, LC-MS showed the cyclized product 26 Formation, silica gel column chromatography to obtain intermediate 26 (0.8mmol).
  • compound I-27 can be prepared according to the synthesis method of compound I-2.
  • intermediate 29 (0.8mmol) can be prepared according to the synthesis method of literature (J.Med.Chem.2012,55,1978-1998) ). Intermediate 29 was then oxidized according to the synthesis method of compound I-1 to prepare compound I-29.
  • compound I-30 can be prepared using the same synthetic route as compound I-29. Take the purified product I-30 for structural characterization: LC-MS (ESI) m/z: 527,529[MH] - .
  • compound I-31 can be prepared using the same synthetic route as compound I-29.
  • compound I-32 can be prepared using the same synthetic route as compound I-29.
  • compound I-40-1 can be prepared using the same synthetic route as compound I-29.
  • compound I-41-1 can be prepared using the same synthetic route as compound I-29.
  • compound I-7-2 (4 mg) was prepared according to the synthesis method of compound I-42.
  • compound I-41-2 (12 mg) was prepared.
  • compound I-43 can be prepared according to the above synthetic route.
  • Intermediate 42 can be prepared from intermediate 41 by treating with Lawson's reagent.
  • Group 1 Human embryonic kidney transformed cells HEK293Tmtkeima cells were treated with 0 ⁇ M, 1.25 ⁇ M, 2.5 ⁇ M, 5 ⁇ M and 10 ⁇ M CCCP respectively, and seeded in 96-well black microtiter plate at 1.5*10 5 cells/ml, 100 ⁇ L per well. Compound 1-2 was added after 25 hours, and 3 replicates were set up. Under the culture conditions of 37°C and 5% CO 2 , take pictures with biotekcytation 5 every few hours for a total of 20 hours, use the bright field as the focus channel, take 9 pictures for each well, and use the instrument software to process the images. The resulting photos are shown in Figure 1.
  • compound I-2 was applied to cells without CCCP and cells with CCCP (10 ⁇ M), and the color block of cells with CCCP was darker, indicating that in cells with mitochondrial damage, the application of Compound I-2 has a high level of mitophagy, that is, compound I-2 can selectively induce autophagy in damaged mitochondria.
  • Group 2 human embryonic kidney transformed cells HEK293Tmtkeima cells were planted in 96-well black microplates at 1.5*10 5 cells/ml, 100 ⁇ L per well; 25 hours later, compounds I-1 ⁇ I-44, UMI-77, Set up 3 repetitions; under the culture condition of 37°C and 5% CO 2 , take pictures with biotekcytation 5 every few hours for a total of 20 hours.
  • human embryonic kidney transformed cells HEK293Tmtkeima cells were seeded in 96-well black microtiter plate at 1.5*10 5 cells/ml, 100 ⁇ l per well; 5uM or 10uM CCCP (Carbonyl cyanide 3-chlorophenylhydrazone) to induce mitochondrial damage, add I-1 ⁇ I-44, UMI-77 after 1 hour, and set up 3 repetitions; at 37°C, 5% CO 2 culture conditions, take pictures with biotekcytation 5 every few hours , a total of 20 hours of shooting. Both groups used bright field as the focusing channel, took 9 pictures for each hole, and processed the images with instrument software. Some photos obtained are shown in Figure 2.
  • the HEK293Tmtkeima system of human embryonic kidney transformed cells was treated with 5uM or 10uM CCCP to induce mitochondrial damage, and compound I-1, I-2 was added, compared with no CCCP treatment, only the test compound was added, the color of the block Deeper, indicating that compounds I-1 and I-2 tend to induce autophagy in damaged mitochondria.
  • the damaged mitochondria and undamaged mitochondria were darker in color, indicating that UMI-77 could not selectively induce autophagy in damaged mitochondria.
  • the HEK293Tmtkeima cells used in the experiment are based on the method mentioned in the literature [Cen, X. et al. Nat Commun11, 5731 (2020).], using lentiviral packaging technology to stably express mtkeima protein in HEK293T cells, and the obtained HEK293Tmtkeima cell.
  • the CCCP used in the experiment was purchased from Taoshu Biology (Catalog No. T7081).
  • Ketanserin was selected as the reference compound.
  • the specific method is as follows:
  • FIG 3 shows the elimination of compounds in the context of in vitro mouse or human liver microsomes, as measured by the elimination half-life T1/2.
  • the in vitro liver microsomal stability test of UMI-77 showed that UMI-77 was unstable in the environment of liver microsomes and would be rapidly eliminated; Compounds I-1 and I-2 showed superior liver microsomal stability.
  • Procaine was selected as the reference compound.
  • the specific method is as follows:
  • Test example 4 mouse or rat pharmacokinetic (PK) test
  • mice were taken, and an appropriate amount of the test compound was administered to them according to the indicated dosage and route of administration.
  • three experimental mice were used for three parallel experiments. Numbers 101, 102 and 103 were the same group, 201, 202 and 203 were one group, and 301, 302 and 303 were one group.
  • mice The results of the pharmacokinetic test in mice are shown in Table 2.
  • mice used in the PK experiment were ICR mice of SPF, purchased from Sino-British SIPPR Lab Animal Ltd, Shanghai, China.
  • the rats used in the PK experiment were SD rat of SPF, purchased from Sino-British SIPPR Lab Animal Ltd, Shanghai, China.

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Abstract

本申请公开了一类具有萘胺结构的小分子化合物及其应用。本申请中，具有通式（I）所示结构的化合物结构如图所示。本申请提供的化合物及其药学上可接受的盐、立体异构体、溶剂化物或前药或者本申请提供的药物组合物可以在不影响或仅微弱影响正常线粒体的前提下，选择性诱导破损线粒体自噬；此外，还具有优越的代谢稳定性和药物代谢动力学特性，毒性更低，成药性更好。

Description

一类具有萘胺结构的小分子化合物及其应用
相关申请交叉引用
本专利申请要求于2021年09月22日提交的、申请号为2021111084176、发明名称为“一类具有萘胺结构的小分子化合物及其应用”的中国专利申请的优先权，上述申请的全文以引用的方式并入本文中。
技术领域
本发明涉及化学药物领域，特别涉及一类具有萘胺结构的小分子化合物及其应用。
背景技术
线粒体自噬作为细胞靶物特异性自噬的一种，线粒体自噬的主要目的是识别和清除功能障碍的线粒体。由于线粒体通过氧化磷酸化在能量供应中起中心作用，还有一些重要功能包括能量代谢、氨基酸生产、脂质合成和离子稳态，对于维持依赖有氧代谢的细胞类型如神经元细胞、肌肉细胞和肝脏细胞等的功能具有非常重要的意义。线粒体生成和自噬的稳态调节是维持细胞功能的重要环节。线粒体自噬功能障碍将导致损伤线粒体积累，合成ATP+能力下降，产生大量过氧化物，从而导致细胞中间代谢产物的改变，引发一系列病理后果。若通过增强线粒体自噬清除衰老或功能障碍的线粒体，则线粒体自噬将对细胞起到保护作用。
现有技术中，申请号为201910386493.X的中国专利申请记载了化合物UMI-77作为线粒体自噬诱导剂。然而发明人在研究中发现，UMI-77作为线粒体自噬诱导剂不能选择性诱导受损伤的线粒体发生自噬，因此在治疗过程中也同样会使正常的线粒体发生自噬，造成不良反应。另外，UMI-77代谢稳定性较差，在体外代谢稳定性实验和小鼠PK实验中快速消除，对成药性影响较大。因此，开发一种能够有效诱导损伤线粒体发生自噬、特别是可选择性诱导损伤线粒体发生自噬，并且代谢稳定性好的线粒体自噬诱导剂，对抑制或缓解由线粒体自噬功能障碍引起的各种急性慢性疾病至关重要。
发明内容
为解决上述问题，本发明的目的在于提供一类具有萘胺结构的小分子化合物及其应用，其作为线粒体自噬诱导剂能选择性地诱导破损线粒体自噬而不影响正常线粒体，而且代谢稳定性更好，生物利用度更高。
本发明第一方面提供了一种具有通式(I)所示结构的化合物及其药学上可接受的盐、立体异构体、溶剂化物或前药，
Figure PCTCN2022119825-appb-000001
其中，Z为
Figure PCTCN2022119825-appb-000002
R 1为氢或C 1～6烷基；
R 2为氢、C 1～6烷基、三至六元环烷基、三至六元环氧烷基、苯基或C 1～6烷基取代的苯基；
R 3为
Figure PCTCN2022119825-appb-000003
其中，R 3-1为氢、羟基、C 1～6烷基、C 1～6烷氧基、三至六元环烷基、三至六元环氧烷基、氨基、C 1～6胺基、-CH 2C(O)R 3-2、-CH 2C(O)OR 3-2或-CH 2C(O)N(R 3-2R 3-2a)，
R 3-2和R 3-2a分别独立地为氢、C 1～6烷基或三至六元环烷基，
Ar为苯基、并苯基、5或6元单环杂芳基、8至10元稠合双环杂芳基、至少一个氢原子被R 3-3取代的5或6元单环杂芳基、至少一个氢原子被R 3-3取代的8至10元稠合双环杂芳基，所述R 3-3为氢、卤素、C 1～6烷基、三至六 元环烷基、羟基、C 1～6烷氧基、三至六元环氧烷基、C 1～6卤代烷基、C 2～6烯基、C 2～6炔基、-N(R 3-3aR 3-3b)或苯基，
R 3-3a和R 3-3b分别独立地为氢、C 1～6烷基或三至六元环烷基；
R 4为
Figure PCTCN2022119825-appb-000004
其中，R 4-1为苯基、并苯基、至少一个氢原子被R 4-11取代的苯基、5或6元单环杂芳基、至少一个氢原子被R 4-11取代的5或6元单环杂芳基、8至10元稠合双环杂芳基或至少一个氢原子被R 4-11取代的8至10元稠合双环杂芳基，所述R 4-11为氢、卤素、硝基、腈基、羟基、C 1～6烷基、三至六元环烷基、C 1～6烷氧基、-N(R 4-1aR 4-1b)、苯基、C 1～6卤代烷基、C 1～6卤代烷氧基、-C(O)OR 4-12、-C(O)R 4-12、-C(O)N(R 4-1aR 4-1b)、-S(O) 2R 4-12、-S(O)R 4-12、-OC(O)R 4-12、-OC(O)OR 4-12或
Figure PCTCN2022119825-appb-000005
R 4-12、R 4-1a和R 4-1b分别独立地为氢、C 1～6烷基、三至六元环烷基、C 2～6烯基、C 2～6炔基、至少一个氢被卤素取代的C 1～6烷基、至少一个氢被卤素取代的C 2～6烯基、至少一个氢被卤素取代的三至六元环烷基或至少一个氢被卤素取代的C 2～6炔基，且R 4-1a和R 4-1b可相互键合形成环，
R 4-2为氢、C 1～6烷基或三至六元环烷基，或者当R 2为C 1～6烷基时，R 4-2与R 2键合形成4～8元(例如5～6元)环，
R 4-3为氢、C 1～6烷基或C 1～6烷氧基；
在本说明书的各通式及上下文中，除非明确指明，否则R 5可以不存在(即为0个)，或在价键规则允许的情况下可能同时存在一个或多个，因此R 5的数量可为例如0～5个，优选0～4个，更优选为0～2个或0～1个。R 5数量不为0时各自独立地选自卤素、硝基、腈基、-N +(R 5-1) 3、C 1～6卤代烷基、-C(O)OR 5-1、-C(O)R 5-1、-C(O)N(R 5-1R 5-1a)、-S(O) 2R 5-1、-S(O)R 5-1、-S(O) 2N(R 5-1R 5-1a)、-S(O)N(R 5-1R 5-1a)、-N＝C(R 5-1R 5-1a)、羟基、C 1～6烷基、苯基、至少一个氢被R 5-1取代的苯基、C 1～6烷氧基、-N(R 5-1R 5-1a)、-N(R 5-1)C(O)R 5-1a、-N(R 5-1)C(O)OR 5-1a、-N(R 5-1)C(O)N(R 5-1aR 5-1b)、-OC(O)R 5-1、-OC(O)OR 5-1、 -OC(O)N(R 5-1R 5-1a)或-SR 5-1，其中，R 5-1、R 5-1a和R 5-1b分别独立地为氢、C 1～6烷基、C 2～6烯基、C 2～6炔基、至少一个氢被卤素取代的C 1～6烷基、至少一个氢被卤素取代的C 2～6烯基和至少一个氢被卤素取代的C 2～6炔基。
在一些优选的方案中，所述Z为
Figure PCTCN2022119825-appb-000006
Figure PCTCN2022119825-appb-000007
R 1为氢或C 1～4烷基；
R 2为氢、C 1～4烷基、三至六元环烷基或四至六元环氧烷基；
R 3为
Figure PCTCN2022119825-appb-000008
其中，R 3-1为氢、羟基、C 1～4烷基、C 1～4烷氧基、三至六元环烷基、三至六元环氧烷基、
-N(R 3-2R 3-2a)、-CH 2C(O)R 3-2、-CH 2C(O)OR 3-2或-CH 2C(O)NR 3-2R 3-2a，
R 3-2和R 3-2a分别独立地为氢、C 1～4烷基或三至六元环烷基，
Ar为苯基、5或6元单环杂芳基、至少一个氢原子被R 3-3取代的5或6元单环杂芳基，所述R 3-3为氢、卤素、C 1～4烷基、三至六元环烷基、羟基、C 1～4烷氧基、三至六元环氧烷基、C 1～4卤代烷基、C 2～4烯基、C 2～4炔基、-N(R 3-3aR 3-3b)或苯基，
R 3-3a和R 3-3b分别独立地为氢、C 1～4烷基或三至六元环烷基；
R 4为
Figure PCTCN2022119825-appb-000009
其中，R 4-1为苯基、至少一个氢原子被R 4-11取代的苯基、5或6元单环杂芳基、至少一个氢原子被R 4-11取代的5或6元单环杂芳基、8至10元稠合双环杂芳基或至少一个氢原子被R 4-11取代的8至10元稠合双环杂芳基，所述R 4-11为氢、卤素、硝基、C 1～4烷基、三至六元环烷基、C 1～4烷氧基、 -N(R 4-1aR 4-1b)、苯基、C 1～4卤代烷基、C 1～4卤代烷氧基或
Figure PCTCN2022119825-appb-000010
R 4-1a和R 4-1b分别独立地为氢、C 1～4烷基或三至六元环烷基，且R 4-1a和R 4-1b可相互键合形成环，
R 4-2为C 1～4烷基或三至六元环烷基，或者当R 2为C 1～4烷基时，R 4-2与R 2键合形成4～8元环，
R 4-3为C 1～4烷基或C 1～4烷氧基；
R 5数量不为0时各自独立地为卤素、硝基、腈基、-N +(R 5-1) 3、C 1～4卤代烷基、-C(O)OR 5-1、-C(O)R 5-1、-C(O)N(R 5-1R 5-1a)、-S(O) 2R 5-1、-S(O)R 5-1、-N＝C(R 5-1R 5-1a)、羟基、C 1～4烷基、苯基、至少一个氢被R 5-1取代的苯基、C 1～4烷氧基、-N(R 5-1R 5-1a)、-N(R 5-1)C(O)R 5-1a、-OC(O)R 5-1、-OC(O)N(R 5-1R 5-1a)或-SR 5-1，其中，R 5-1、R 5-1a和R 5-1b分别独立地为氢、C 1～4烷基、C 2～4烯基、C 2～4炔基、至少一个氢被卤素取代的C 1～4烷基、至少一个氢被卤素取代的C 2～4烯基或至少一个氢被卤素取代的C 2～4炔基。
在一些优选的方案中，所述Z为
Figure PCTCN2022119825-appb-000011
Figure PCTCN2022119825-appb-000012
R 1为氢或C 1～4烷基；
R 2为氢、C 1～4烷基、三至六元环烷基或四至六元环氧烷基；
R 3为
Figure PCTCN2022119825-appb-000013
其中，R 3-1为氢、羟基、C 1～4烷基、C 1～4烷氧基或-N(R 3-2R 3-2a)，
R 3-2和R 3-2a分别独立地为氢或C 1～4烷基，
Ar为苯基、5或6元单环杂芳基、至少一个氢原子被R 3-3取代的5或6元单环杂芳基，所述R 3-3为氢、卤素、C 1～4烷基、羟基、C 1～4烷氧基、C 1～4 卤代烷基或-N(R 3-3aR 3-3b)，
R 3-3a和R 3-3b分别独立地为氢或C 1～4烷基；
R 4为
Figure PCTCN2022119825-appb-000014
其中，R 4-1为苯基、至少一个氢原子被R 4-11取代的苯基、5或6元单环杂芳基、至少一个氢原子被R 4-11取代的5或6元单环杂芳基，所述R 4-11为氢、卤素、硝基、C 1～4烷基、三至六元环烷基、C 1～4烷氧基、-N(R 4-1aR 4-1b)、苯基、C 1～4卤代烷基、C 1～4卤代烷氧基或
Figure PCTCN2022119825-appb-000015
R 4-1a和R 4-1b分别独立地为氢、C 1～4烷基或三至六元环烷基，且R 4-1a和R 4-1b可相互键合形成环，
R 4-2为C 1～4烷基或三至六元环烷基，或者当R 2为C 1～4烷基时，R 4-2与R 2键合形成4～8元环，
R 4-3为C 1～4烷基或C 1～4烷氧基；
R 5数量不为0时各自独立地为卤素、硝基、腈基、-N +(R 5-1) 3、C 1～4卤代烷基、
-C(O)OR 5-1、-C(O)R 5-1、-C(O)N(R 5-1R 5-1a)、-S(O) 2R 5-1、-S(O)R 5-1、-N＝C(R 5-1R 5-1a)、羟基、C 1～4烷基、苯基、至少一个氢被R 5-1取代的苯基、C 1～4烷氧基、-N(R 5-1R 5-1a)、-N(R 5-1)C(O)R 5-1a或-OC(O)R 5-1，其中，R 5-1、R 5-1a和R 5-1b分别独立地为氢、C 1～4烷基或至少一个氢被卤素取代的C 1～4烷基。
在一些优选的方案中，所述Z为
Figure PCTCN2022119825-appb-000016
Figure PCTCN2022119825-appb-000017
R 1为氢；
R 2为氢、甲基、乙基、正丙基、异丙基、
Figure PCTCN2022119825-appb-000018
Figure PCTCN2022119825-appb-000019
R 3为
Figure PCTCN2022119825-appb-000020
其中，R 3-1为氢、羟基、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、叔丁氧基、仲丁氧基或异丁氧基，
Ar为苯基、5或6元含氮单环杂芳基；
R 4为
Figure PCTCN2022119825-appb-000021
其中，R 4-1为苯基、至少一个氢原子被R 4-11取代的苯基、5或6元单环杂芳基、至少一个氢原子被R 4-11取代的5或6元单环杂芳基、8至10元稠合双环杂芳基或至少一个氢原子被R 4-11取代的8至10元稠合双环杂芳基，所述R 4-11为氢、卤素、硝基、甲基、乙基、正丙基、异丙基、
Figure PCTCN2022119825-appb-000022
Figure PCTCN2022119825-appb-000023
Figure PCTCN2022119825-appb-000024
氟代甲基、氟代乙基、氟代正丙基、氟代异丙基、氯代甲基、氯代乙基、氯代正丙基、氯代异丙基、溴代甲基、溴代乙基、溴代正丙基、溴代异丙基、碘代甲基、碘代乙基、碘代正丙基、碘代异丙基、氟代甲氧基、氟代乙氧基、氟代正丙氧基、氟代异丙氧基、氯代甲氧基、氯代乙氧基、氯代正丙氧基、氯代异丙氧基、溴代甲氧基、溴代乙氧基、溴代正丙氧基、溴代异丙氧基、碘代氧甲基、碘代乙氧基、碘代正 丙氧基、碘代异丙氧基或
Figure PCTCN2022119825-appb-000025
R 4-2为甲基、乙基、正丙基或异丙基，或者，当R 2为甲基、乙基或正丙基时，R 4-2与R 2键合形成4～8元环，
R 4-3为甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基或异丙氧基；
R 5数量不为0时各自独立地选自卤素、硝基、腈基、-N +(R 5-1) 3、氟代甲基、氟代乙基、氟代正丙基、氟代异丙基、氯代甲基、氯代乙基、氯代正丙基、氯代异丙基、溴代甲基、溴代乙基、溴代正丙基、溴代异丙基、-C(O)OR 5-1、-C(O)R 5-1、-C(O)N(R 5-1R 5-1a)、-S(O) 2R 5-1、
-S(O)R 5-1、-N＝C(R 5-1R 5-1a)、羟基、甲基、乙基、正丙基、异丙基、苯基、至少一个氢被R 5-1取代的苯基、甲氧基、乙氧基、正丙氧基、异丙氧基、-N(R 5-1R 5-1a)、-N(R 5-1)C(O)R 5-1a、
-OC(O)R 5-1，其中，R 5-1、R 5-1a和R 5-1b分别独立地为氢、甲基、乙基、正丙基、异丙基、氟代甲基、氟代乙基、氟代正丙基、氟代异丙基、氯代甲基、氯代乙基、氯代正丙基、氯代异丙基、溴代甲基、溴代乙基、溴代正丙基和溴代异丙基。
在一些更优选的方案中，所述通式(Ⅰ)所示结构的化合物选自下述化合物中的任一种：
Figure PCTCN2022119825-appb-000026
Figure PCTCN2022119825-appb-000027
Figure PCTCN2022119825-appb-000028
Figure PCTCN2022119825-appb-000029
Figure PCTCN2022119825-appb-000030
Figure PCTCN2022119825-appb-000031
Figure PCTCN2022119825-appb-000032
Figure PCTCN2022119825-appb-000033
Figure PCTCN2022119825-appb-000034
Figure PCTCN2022119825-appb-000035
Figure PCTCN2022119825-appb-000036
Figure PCTCN2022119825-appb-000037
本发明的发明人出人意料地发现，当Z为
Figure PCTCN2022119825-appb-000038
时，能够十分显著地提高诱导受损伤的线粒体发生自噬的选择性，同时显著地提高代谢稳定性。因此，在本发明一些更优选的方案中，Z选自
Figure PCTCN2022119825-appb-000039
Figure PCTCN2022119825-appb-000040
例如Z为
Figure PCTCN2022119825-appb-000041
在一些优选的方案中，Z为
Figure PCTCN2022119825-appb-000042
R 1为氢或C 1～6烷基；
R 2为氢、C 1～6烷基、三至六元环烷基、三至六元环氧烷基、苯基或C 1～6烷基取代的苯基；
R 3为
Figure PCTCN2022119825-appb-000043
其中，R 3-1为氢、羟基、C 1～6烷基、C 1～6烷氧基、三至六元环烷基、三至六元环氧烷基、氨基、C 1～6胺基、-CH 2C(O)R 3-2、-CH 2C(O)OR 3-2或-CH 2C(O)N(R 3-2R 3-2a)，
R 3-2和R 3-2a分别独立地为氢、C 1～6烷基或三至六元环烷基，
Ar为苯基、并苯基、5或6元单环杂芳基、8至10元稠合双环杂芳基、至少一个氢原子被R 3-3取代的苯基、至少一个氢原子被R 3-3取代的并苯基、至少一个氢原子被R 3-3取代的5或6元单环杂芳基、至少一个氢原子被R 3-3取代的8至10元稠合双环杂芳基，所述R 3-3为氢、卤素、C 1～6烷基、三至六元环烷基、羟基、C 1～6烷氧基、三至六元环氧烷基、C 1～6卤代烷基、C 2～6烯基、C 2～6炔基、-N(R 3-3aR 3-3b)或苯基，
R 3-3a和R 3-3b分别独立地为氢、C 1～6烷基或三至六元环烷基；
R 4为
Figure PCTCN2022119825-appb-000044
其中，R 4-1为苯基、并苯基、至少一个氢原子被R 4-11取代的苯基、5或6元单环杂芳基、至少一个氢原子被R 4-11取代的5或6元单环杂芳基、8至10元稠合双环杂芳基或至少一个氢原子被R 4-11取代的8至10元稠合双环杂芳基，所述R 4-11为氢、卤素、硝基、腈基、羟基、C 1～6烷基、三至六元环烷基、C 1～6烷氧基、-N(R 4-1aR 4-1b)、苯基、C 1～6卤代烷基、C 1～6卤代烷氧基、-C(O)OR 4-12、-C(O)R 4-12、-C(O)N(R 4-1aR 4-1b)、-S(O) 2R 4-12、-S(O)R 4-12、-OC(O)R 4-12、-OC(O)OR 4-12或
Figure PCTCN2022119825-appb-000045
R 4-12、R 4-1a和R 4-1b分别独立地为氢、C 1～6烷基、三至六元环烷基、C 2～6烯基、C 2～6炔基、至少一个氢被卤素取代的C 1～6烷基、至少一个氢被卤素取代的C 2～6烯基、至少一个氢被卤素 取代的三至六元环烷基或至少一个氢被卤素取代的C 2～6炔基，且R 4-1a和R 4-1b可相互键合形成环，
R 4-2为C 1～6烷基或三至六元环烷基，或者当R 2为C 1～6烷基时，R 4-2与R 2键合形成4～8元环，
R 4-3为C 1～6烷基或C 1～6烷氧基；
R 5数量不为0时各自独立地选自卤素、硝基、腈基、-N +(R 5-1) 3、C 1～6卤代烷基、
-C(O)OR 5-1、-C(O)R 5-1、-C(O)N(R 5-1R 5-1a)、-S(O) 2R 5-1、-S(O)R 5-1、-S(O) 2N(R 5-1R 5-1a)、-S(O)N(R 5-1R 5-1a)、-N＝C(R 5-1R 5-1a)、羟基、C 1～6烷基、苯基、至少一个氢被R 5-1取代的苯基、C 1～6烷氧基、-N(R 5-1R 5-1a)、-N(R 5-1)C(O)R 5-1a、-N(R 5-1)C(O)OR 5-1a、-N(R 5-1)C(O)N(R 5-1aR 5-1b)、-OC(O)R 5-1、-OC(O)OR 5-1、-OC(O)N(R 5-1R 5-1a)和-SR 5-1，其中，R 5-1、R 5-1a和R 5-1b分别独立地为氢、C 1～6烷基、C 2～6烯基、C 2～6炔基、至少一个氢被卤素取代的C 1～6烷基、至少一个氢被卤素取代的C 2～6烯基或至少一个氢被卤素取代的C 2～6炔基。
基于有利于化合物药用效果的提升，在一些优选的方案中，所述化合物具有式(II)所示的结构；
Figure PCTCN2022119825-appb-000046
式中，R 2为氢、C 1～4烷基、三至六元环烷基或四至六元环氧烷基；
R 3为
Figure PCTCN2022119825-appb-000047
其中，R 3-1为氢、羟基、C 1～4烷基、C 1～4烷氧基、三至六元环烷基、三至六元环氧烷基、
-N(R 3-2R 3-2a)、-CH 2C(O)R 3-2、-CH 2C(O)OR 3-2或-CH 2C(O)NR 3-2R 3-2a，
R 3-2和R 3-2a分别独立地为氢、C 1～4烷基或三至六元环烷基，
Ar为苯基、5或6元单环杂芳基、至少一个氢原子被R 3-3取代的5或6元单环杂芳基、所述R 3-3为氢、卤素、C 1～4烷基、三至六元环烷基、羟基、C 1～4烷氧基、三至六元环氧烷基、C 1～4卤代烷基、C 2～4烯基、C 2～4炔基、-N(R 3-3aR 3-3b)或苯基，
R 3-3a和R 3-3b分别独立地为氢、C 1～4烷基或三至六元环烷基；
R 4为
Figure PCTCN2022119825-appb-000048
其中，R 4-1为苯基、至少一个氢原子被R 4-11取代的苯基、5或6元单环杂芳基、至少一个氢原子被R 4-11取代的5或6元单环杂芳基、8至10元稠合双环杂芳基、至少一个氢原子被R 4-11取代的8至10元稠合双环杂芳基，所述R 4-11为氢、卤素、硝基、C 1～4烷基、三至六元环烷基、C 1～4烷氧基、-N(R 4-1aR 4-1b)、苯基、C 1～4卤代烷基、C 1～4卤代烷氧基或
Figure PCTCN2022119825-appb-000049
R 4-1a和R 4-1b分别独立地为氢、C 1～4烷基或三至六元环烷基，且R 4-1a和R 4-1b可相互键合形成环，
R 4-2为C 1～4烷基、三至六元环烷基，或者当R 2为C 1～4烷基时，R 4-2与R 2键合形成4～8元环，
R 4-3为C 1～4烷基或C 1～4烷氧基；
R 5数量不为0时各自独立地选自卤素、硝基、腈基、-N +(R 5-1) 3、C 1～4卤代烷基、
-C(O)OR 5-1、-C(O)R 5-1、-C(O)N(R 5-1R 5-1a)、-S(O) 2R 5-1、-S(O)R 5-1、-N＝C(R 5-1R 5-1a)、羟基、C 1～4烷基、苯基、至少一个氢被R 5-1取代的苯基、C 1～4烷氧基、-N(R 5-1R 5-1a)、-N(R 5-1)C(O)R 5-1a、-OC(O)R 5-1、-OC(O)N(R 5-1R 5-1a)或-SR 5-1，其中，R 5-1、R 5-1a和R 5-1b分别独立地为氢、C 1～4烷基、C 2～4烯基、C 2～4炔基、至少一个氢被卤素取代的C 1～4烷基、至少一个氢被卤素取代的C 2～4烯基或至少一个氢被卤素取代的C 2～4炔基。
在一些更优选的方案中，所述化合物具有式(II)所示的结构；
Figure PCTCN2022119825-appb-000050
式中，R 2为氢、C 1～4烷基、三至六元环烷基或四至六元环氧烷基；
R 3为
Figure PCTCN2022119825-appb-000051
其中，R 3-1为氢、羟基、C 1～4烷基、C 1～4烷氧基、三至六元环烷基、三至六元环氧烷基、
-N(R 3-2R 3-2a)、-CH 2C(O)R 3-2、-CH 2C(O)OR 3-2、-CH 2C(O)NR 3-2R 3-2a，
R 3-2和R 3-2a分别独立地为氢、C 1～4烷基或三至六元环烷基，
Ar为苯基、5或6元单环杂芳基、至少一个氢原子被R 3-3取代的5或6元单环杂芳基、所述R 3-3为氢、卤素、C 1～4烷基、三至六元环烷基、羟基、C 1～4烷氧基、三至六元环氧烷基、C 1～4卤代烷基、C 2～4烯基、C 2～4炔基、-N(R 3-3aR 3-3b)或苯基，
R 3-3a和R 3-3b分别独立地为氢、C 1～4烷基或三至六元环烷基；
R 4为
Figure PCTCN2022119825-appb-000052
其中，R 4-1为苯基、至少一个氢原子被R 4-11取代的苯基、5或6元单环杂芳基、至少一个氢原子被R 4-11取代的5或6元单环杂芳基、8至10元稠合双环杂芳基、至少一个氢原子被R 4-11取代的8至10元稠合双环杂芳基，所述R 4-11为氢、卤素、硝基、C 1～4烷基、三至六元环烷基、C 1～4烷氧基、 -N(R 4-1aR 4-1b)、苯基、C 1～4卤代烷基、C 1～4卤代烷氧基或
Figure PCTCN2022119825-appb-000053
R 4-1a和R 4-1b分别独立地为氢、C 1～4烷基或三至六元环烷基，且R 4-1a和R 4-1b可相互键合形成环，
R 4-2为C 1～4烷基、三至六元环烷基，或者当R 2为C 1～4烷基时，R 4-2与R 2键合形成4～8元环，
R 4-3为C 1～4烷基或C 1～4烷氧基；
R 5数量不为0时各自独立地选自卤素、硝基、腈基、-N +(R 5-1) 3、C 1～4卤代烷基、
-C(O)OR 5-1、-C(O)R 5-1、-C(O)N(R 5-1R 5-1a)、-S(O) 2R 5-1、-S(O)R 5-1和-N＝C(R 5-1R 5-1a)，其中，R 5-1和R 5-1a分别独立地为氢、C 1～4烷基、C 2～4烯基、C 2～4炔基、至少一个氢被卤素取代的C 1～4烷基、至少一个氢被卤素取代的C 2～4烯基或至少一个氢被卤素取代的C 2～4炔基。
基于有利于化合物选择性诱导自噬能力的提升、更低的毒性以及更好的代谢稳定性，在一些优选的方案中，所述化合物具有式(III)所示的结构；
Figure PCTCN2022119825-appb-000054
式中，R 2为氢、C 1～4烷基、三至六元环烷基或四至六元环氧烷基；
R 3为
Figure PCTCN2022119825-appb-000055
其中，R 3-1为氢、羟基、C 1～4烷基、C 1～4烷氧基、三至六元环烷基、三至六元环氧烷基、
-N(R 3-2R 3-2a)、-CH 2C(O)R 3-2、-CH 2C(O)OR 3-2或-CH 2C(O)NR 3-2R 3-2a，
R 3-2和R 3-2a分别独立地为氢、C 1～4烷基或三至六元环烷基，
Ar为苯基、5或6元单环杂芳基、至少一个氢原子被R 3-3取代的5或6元单环杂芳基、所述R 3-3为氢、卤素、C 1～4烷基、三至六元环烷基、羟基、C 1～4烷氧基、三至六元环氧烷基、C 1～4卤代烷基、C 2～4烯基、C 2～4炔基、-N(R 3-3aR 3-3b)或苯基，
R 3-3a和R 3-3b分别独立地为氢、C 1～4烷基或三至六元环烷基；
R 4为
Figure PCTCN2022119825-appb-000056
其中，R 4-1为苯基、至少一个氢原子被R 4-11取代的苯基、5或6元单环杂芳基、至少一个氢原子被R 4-11取代的5或6元单环杂芳基、8至10元稠合双环杂芳基或至少一个氢原子被R 4-11取代的8至10元稠合双环杂芳基，所述R 4-11为氢、卤素、硝基、C 1～4烷基、三至六元环烷基、C 1～4烷氧基、-N(R 4-1aR 4-1b)、苯基、C 1～4卤代烷基、C 1～4卤代烷氧基或
Figure PCTCN2022119825-appb-000057
R 4-1a和R 4-1b分别独立地为氢、C 1～4烷基或三至六元环烷基，且R 4-1a和R 4-1b可相互键合形成环，
R 4-2为C 1～4烷基或三至六元环烷基，或者当R 2为C 1～4烷基时，R 4-2与R 2键合形成4～8元环，
R 4-3为C 1～4烷基或C 1～4烷氧基；
R 5数量不为0时各自独立地选自卤素、硝基、腈基、-N +(R 5-1) 3、C 1～4卤代烷基、
-C(O)OR 5-1、-C(O)R 5-1、-C(O)N(R 5-1R 5-1a)、-S(O) 2R 5-1、-S(O)R 5-1、-N＝C(R 5-1R 5-1a)、羟基、C 1～4烷基、苯基、至少一个氢被R 5-1取代的苯基、C 1～4烷氧基、-N(R 5-1R 5-1a)、-N(R 5-1)C(O)R 5-1a、-OC(O)R 5-1、-OC(O)N(R 5-1R 5-1a)和-SR 5-1，其中，R 5-1、R 5-1a和R 5-1b分别独立地为氢、C 1～4烷基、C 2～4烯基、C 2～4炔基、至少一个氢被卤素取代的C 1～4烷基、至少一个氢被卤素取代的C 2～4烯基或至少一个氢被卤素取代的C 2～4炔基。
在一些更优选的方案中，所述化合物具有式(III)所示的结构；
Figure PCTCN2022119825-appb-000058
式中，R 2为氢、C 1～4烷基、三至六元环烷基或四至六元环氧烷基；
R 3为
Figure PCTCN2022119825-appb-000059
其中，R 3-1为氢、羟基、C 1～4烷基、C 1～4烷氧基、三至六元环烷基、三至六元环氧烷基、
-N(R 3-2R 3-2a)、-CH 2C(O)R 3-2、-CH 2C(O)OR 3-2或-CH 2C(O)NR 3-2R 3-2a，
R 3-2和R 3-2a分别独立地为氢、C 1～4烷基或三至六元环烷基，
Ar为苯基、5或6元单环杂芳基或至少一个氢原子被R 3-3取代的5或6元单环杂芳基，所述R 3-3为氢、卤素、C 1～4烷基、三至六元环烷基、羟基、C 1～4烷氧基、三至六元环氧烷基、C 1～4卤代烷基、C 2～4烯基、C 2～4炔基、-N(R 3-3aR 3-3b)或苯基，
R 3-3a和R 3-3b分别独立地为氢、C 1～4烷基或三至六元环烷基；
R 4为
Figure PCTCN2022119825-appb-000060
其中，R 4-1为苯基、至少一个氢原子被R 4-11取代的苯基、5或6元单环杂芳基、至少一个氢原子被R 4-11取代的5或6元单环杂芳基、8至10元稠合双环杂芳基或至少一个氢原子被R 4-11取代的8至10元稠合双环杂芳基，所述R 4-11为氢、卤素、硝基、C 1～4烷基、三至六元环烷基、C 1～4烷氧基、-N(R 4-1aR 4-1b)、苯基、C 1～4卤代烷基、C 1～4卤代烷氧基或
Figure PCTCN2022119825-appb-000061
R 4-1a 和R 4-1b分别独立地为氢、C 1～4烷基或三至六元环烷基，且R 4-1a和R 4-1b可相互键合形成环，
R 4-2为C 1～4烷基或三至六元环烷基，或者当R 2为C 1～4烷基时，R 4-2与R 2键合形成4～8元环，
R 4-3为C 1～4烷基或C 1～4烷氧基；
R 5数量不为0时各自独立地选自羟基、C 1～4烷基、苯基、至少一个氢被R 5-1取代的苯基、C 1～4烷氧基、-N(R 5-1R 5-1a)、-N(R 5-1)C(O)R 5-1a、-OC(O)R 5-1、-OC(O)N(R 5-1R 5-1a)和-SR 5-1，其中，R 5-1、R 5-1a和R 5-1b分别独立地为氢、C 1～4烷基、C 2～4烯基、C 2～4炔基、至少一个氢被卤素取代的C 1～4烷基、至少一个氢被卤素取代的C 2～4烯基或至少一个氢被卤素取代的C 2～4炔基。
在前述式I至式III的化合物中，较优选地，R 1为氢或甲基，更优选为氢。
在前述式I至式III的化合物中，较优选地，R 2为氢、C 1～6烷基(优选甲基)、三至六元环烷基(优选环丙烷基)或三至六元环氧烷基(优选氧杂环丁烷基)。
在前述式I至式III的化合物中，较优选地，R 3选自-CH 2-COOH、-CH 2-CONH 2、
Figure PCTCN2022119825-appb-000062
其中，Ar为5或6元单环杂芳基，更优选为5或6元单环杂芳基含氮单环杂芳基，更优选为三氮唑基(例如
Figure PCTCN2022119825-appb-000063
Figure PCTCN2022119825-appb-000064
特别是
Figure PCTCN2022119825-appb-000065
)、四氮唑基(例如
Figure PCTCN2022119825-appb-000066
)或苯基。
在前述式I至式III的化合物中，较优选地，R 4为：
Figure PCTCN2022119825-appb-000067
其中，R 4-1选自苯基、5或6元单环杂芳基(例如噻吩基、吡唑基、异噁唑基、吡啶基)和8至10元稠合双环杂芳基(例如苯并噻吩基)，上述各基团任选地被选自以下的基团取代：卤素、硝基、苯基、腈基、羟基、C 1～6烷基、三至六元环烷基、C 1～6烷氧基、C 1～6卤代烷基、C 1～6卤代烷氧基、
Figure PCTCN2022119825-appb-000068
-N(R 4-1aR 4-1b)(R 4-1a和R 4-1b可相互键合形成环，例如形成吡咯烷环)；
R 4-2为氢、C 1～6烷基、三至六元环烷基，或者当R 2为C 1～6烷基时，R 4-2与R 2键合形成4～8元(例如5元或6元)环；
R 4-3为氢、C 1～6烷基或C 1～6烷氧基。
R 4-1a、R 4-1b、R 4-2、R 4-3、R 5如本说明书上下文所定义。
在前述式I至式III的化合物中，较优选地，R 5数量为0～2个(特别是0～1个)，且R 5数量不为0时各自独立地选自羟基、C 1～4烷基、C 1～4烷氧基、硝基、-COOH、-NHCO-C 1～4烷基(例如-NHCO-CH 3)。
在一些更优选的实施方案中，本发明的化合物选自下述化合物中的任一种，或其药学上可接受的盐、立体异构体、溶剂化物或前药：
Figure PCTCN2022119825-appb-000069
Figure PCTCN2022119825-appb-000070
Figure PCTCN2022119825-appb-000071
Figure PCTCN2022119825-appb-000072
Figure PCTCN2022119825-appb-000073
Figure PCTCN2022119825-appb-000074
Figure PCTCN2022119825-appb-000075
Figure PCTCN2022119825-appb-000076
Figure PCTCN2022119825-appb-000077
Figure PCTCN2022119825-appb-000078
Figure PCTCN2022119825-appb-000079
Figure PCTCN2022119825-appb-000080
在一些优选的方案中，所述C 1～6烷基为C 1～4烷基，所述C 1～4烷基优选为甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基，例如：甲基或乙基。
在一些优选的方案中，所述三至六元环烷基优选为C 3～5环烷基，所述C 3～5环烷基优选为
Figure PCTCN2022119825-appb-000081
例如：
Figure PCTCN2022119825-appb-000082
在一些优选的方案中，所述三至六元环氧烷基优选为
Figure PCTCN2022119825-appb-000083
Figure PCTCN2022119825-appb-000084
例如：
Figure PCTCN2022119825-appb-000085
在一些优选的方案中，所述C 1～6烷基取代的苯基优选为C 1～4烷基取代的苯基，更优选为甲基、乙基、正丙基、异丙基、正丁基、异丁基和叔丁基中任一个取代的苯基。
在一些优选的方案中，所述C 1～6烷氧基优选为C 1～4烷氧基，更优选为甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、叔丁氧基、仲丁氧基或异丁氧基。
在一些优选的方案中，所述-N(R 3-2R 3-2a)、-N(R 3-3aR 3-3b)、-N(R 4-1aR 4-1b)、-N(R 5-1R 5-1a)优选为
Figure PCTCN2022119825-appb-000086
Figure PCTCN2022119825-appb-000087
在一些优选的方案中，所述5或6元单环杂芳基优选为
Figure PCTCN2022119825-appb-000088
Figure PCTCN2022119825-appb-000089
其中，Y 1、Y 2、Y 3、Y 4、Y 5、Y 6、Y 7、Y 8、Y 9分别独立地选自C、N、O或S，且Y 1、Y 2、Y 3、Y 4不全部为C，Y 5、Y 6、Y 7、Y 8、Y 9不全部为C；所述5或6元单环杂芳基更优选为吡咯基、呋喃基、噻吩基、吡唑基、咪唑基、噁唑基、异噁唑基、噻唑基、吡啶基、吡喃基、噻喃基、哒嗪基、嘧啶基、吡嗪基、哌嗪基、三氮唑基、四氮唑基；所述5或6元单环杂芳基更优选为
Figure PCTCN2022119825-appb-000090
Figure PCTCN2022119825-appb-000091
Figure PCTCN2022119825-appb-000092
更优选地，所述5或6元单环杂芳基为5或6元含氮单环杂芳基，例如：
Figure PCTCN2022119825-appb-000093
Figure PCTCN2022119825-appb-000094
最优选地，所述5或6元单环杂芳基为5元含氮单环杂芳基，例如：
Figure PCTCN2022119825-appb-000095
在一些优选的方案中，所述8至10元稠合双环杂芳基为
Figure PCTCN2022119825-appb-000096
Figure PCTCN2022119825-appb-000097
其中，Y 11、Y 12、Y 13、Y 14、Y 15、Y 16、Y 17、Y 18和Y 19分别独立地选自C、N、O或S，且Y 11、Y 12、Y 13、Y 14、Y 15、Y 16、Y 17、Y 18和Y 19不全部为C；Y 21、Y 22、Y 23、Y 24、Y 25和Y 26分别 独立地选自C、N、O或S，且Y 21、Y 22、Y 23、Y 24、Y 25和Y 26不全部为C；Y 31、Y 32、Y 33、Y 34、Y 35、Y 36和Y 37分别独立地选自C、N、O或S，且Y 31、Y 32、Y 33、Y 34、Y 35、Y 36和Y 37不全部为C；所述8至10元稠合双环杂芳基更优选为吲哚基、苯并吲哚基、苯并噻吩基、咔唑基、喹啉基、蝶啶基、嘌呤基；所述8至10元稠合双环杂芳基最优选为
Figure PCTCN2022119825-appb-000098
Figure PCTCN2022119825-appb-000099
在一些优选的方案中，所述卤素优选为氟、氯、溴或碘。
在一些优选的方案中，所述C 1～6卤代烷基优选为C 1～3卤代烷基；更优选为氟代甲基、氟代乙基、氟代正丙基、氟代异丙基、氯代甲基、氯代乙基、氯代正丙基、氯代异丙基、溴代甲基、溴代乙基、溴代正丙基、溴代异丙基、碘代甲基、碘代乙基、碘代正丙基、碘代异丙基；最优选为三氟甲基。
在一些优选的方案中，所述C 1～6卤代烷氧基优选为C 1～3卤代烷氧基；更优选为氟代甲氧基、氟代乙氧基、氟代正丙氧基、氟代异丙氧基、氯代甲氧基、氯代乙氧基、氯代正丙氧基、氯代异丙氧基、溴代甲氧基、溴代乙氧基、溴代正丙氧基、溴代异丙氧基、碘代氧甲基、碘代乙氧基、碘代正丙氧基、碘代异丙氧基；最优选为三氟甲氧基。
在一些优选的方案中，所述C 2～6烯基优选为C 2～4烯基，更优选为-CH＝CH 2、-CH＝CH-CH 3、-CH 2-CH＝CH 2、-CH＝CH-CH 2-CH 3、-CH＝CH-CH＝CH 2。
在一些优选的方案中，所述C 2～6炔基优选为C 2～6炔基，更优选为-C≡CH、-CH 2-C≡CH、-CH 2-CH 2-C≡CH、-CH 2-C≡C-CH 3。
本发明第二方面提供了一种药物组合物，所述药物组合物包括本发明第一方面所述的化合物，及其药学上可接受的盐、立体异构体、溶剂化物或前药。
本发明第三方便提供了本发明第一方面所述的化合物，或其药学上可接受的盐、立体异构体、溶剂化物或前药，或本发明第二方面所述的药物组合 物在线粒体自噬诱导剂(特别是选择性线粒体自噬诱导剂)的制备中的用途。
本发明相对于现有技术而言，至少具有下述优点：
(1)本发明第一方面提供的化合物及其药学上可接受的盐、立体异构体、溶剂化物或前药或者本发明第二方面提供的药物组合物，可以诱导破损线粒体自噬，并且在不影响或仅微弱影响正常线粒体的前提下，选择性诱导破损线粒体自噬；
(2)本发明第一方面提供的化合物及其药学上可接受的盐、立体异构体、溶剂化物或前药或者本发明第二方面提供的药物组合物，相比UMI-77具有优越的代谢稳定性和药物代谢动力学特性；
(3)本发明第一方面提供的化合物及其药学上可接受的盐、立体异构体、溶剂化物或前药或者本发明第二方面提供的药物组合物，相比UMI-77毒性更低，成药性更好；
(4)本发明第一方面提供的化合物及其药学上可接受的盐、立体异构体、溶剂化物或前药或者本发明第二方面提供的药物组合物。
因此，本发明的化合物具有诱导破损线粒体自噬、或提高代谢稳定性的效果。本发明的优选的化合物同时具有诱导破损线粒体自噬和提高代谢稳定性的效果。
更优选地，本发明的优选化合物具有选择性诱导破损线粒体自噬、或提高代谢稳定性的效果。本发明的特别优选的化合物同时具有选择性诱导破损线粒体自噬和提高代谢稳定性的效果。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。
附图说明
一个或多个实施例通过与之对应的附图中的图片进行示例性说明，这些示例性说明并不构成对实施例的限定。
图1是本发明测试例1中化合物I-2诱导损伤线粒体自噬能力测试结果图；
图2是本发明测试例1中UMI-77，I-2，I-1选择性诱导损伤线粒体自噬 能力测试结果图；
图3是本发明测试例2中化合物UMI-77，I-2，I-1的体外肝微粒体稳定性测试结果图；
图4是本发明测试例3中化合物UMI-77，I-2，I-1的体外血浆稳定性测试结果图；
图5是本发明测试例4中化合物UMI-77通过IV给药的药时曲线图；
图6是本发明测试例4中化合物UMI-77通过PO给药的药时曲线图；
图7是本发明测试例4中化合物I-1通过IV给药标准小鼠的药时曲线图；
图8是本发明测试例4中化合物I-1通过PO给药标准小鼠的药时曲线图；
图9是本发明测试例4中化合物I-1通过IP给药标准小鼠的药时曲线图；
图10是本发明测试例4中化合物I-2通过IV给药标准小鼠的药时曲线图；
图11是本发明测试例4中化合物I-2通过PO给药标准小鼠的药时曲线图；
图12是本发明测试例4中化合物I-1通过IV给药SD大鼠的药时曲线图；
图13是本发明测试例4中化合物I-1通过IP给药SD大鼠的药时曲线图；
图14是本发明测试例4中化合物I-1通过PO给药SD大鼠的药时曲线图。
具体实施方式
本发明人经过详细的实验研究发现，如本发明第一方面所述的化合物具有诱导破损线粒体自噬、或提高代谢稳定性的效果。
优选地，本发明的优选的化合物同时具有诱导破损线粒体自噬和提高代谢稳定性的效果。
更优选地，本发明的优选化合物具有选择性诱导破损线粒体自噬、或提高代谢稳定性的效果。本发明的特别优选的化合物同时具有选择性诱导破损线粒体自噬和提高代谢稳定性的效果。
术语
如本文所用，术语“线粒体自噬”是指线粒体被自噬选择性降解的过程，是线粒体质量和数量控制的重要机制。
如本文所用，术语“线粒体自噬诱导剂”指的是可诱导线粒体自噬功能的化合物。
如本文中所使用，术语“烷基”指的是直链或支链饱和脂肪族烃基基团。术语“C 1-6烷基”指的是具有1到6个碳原子的直链或支链烷基，非限制地例如是：甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基，及其各种支链异构体等。术语“C 1-4烷基”指的是具有1到4个碳原子的直链或支链烷基，C 1-4烷基如果在分子的端部出现，非限制地例如是∶甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基，或者，当分子的两个部分通过该烷基连接时，非限制地例如是：-CH 2-、-CH 2-CH 2-、-CH(CH 3)-、-CH 2-CH 2-CH 2-、-CH(C 2H 5)-、-C(CH 3) 2-，C 1-4烷基碳的每个氢可以被本文进一步列举的取代基替代。
如文本所用，术语“烯基”指的是含有至少一个碳-碳双键的直链或支链烃链。烯基碳上的每个氢可以被本文进一步列举的取代基替代。术语“C 2～6烯基”指的是具有1到6个碳原子的含有至少一个碳-碳双键的直链或支链烃链。如果在分子的端部出现，非限制地例如是∶-CH＝CH 2、-CH＝CH-CH 3、-CH 2-CH＝CH 2、-CH＝CH-CH 2-CH 3、-CH＝CH-CH＝CH 2，或者，当分子的两个部分通过该烯基连接时，非限制地例如是，-CH＝CH-。C 2～6烯基碳的每个氢可以被本文进一步列举的取代基替代。
如本文所用，术语“炔基”指的是指的是含有至少一个碳-碳三键的直链或支链烃链。炔基碳上的每个氢可以被本文进一步列举的取代基替代。术语“C 2～6炔基”指的是具有1到6个碳原子的含有至少一个碳-碳三键的直链或支链烃链。如果在分子的端部出现，非限制地例如是∶-C≡CH、-CH 2-C≡CH、 -CH 2-CH 2-C≡CH、-CH 2-C≡C-CH 3，或者，当分子的两个部分通过该炔基连接时，非限制地例如是，-C≡C-。C 2～6炔基碳上的每个氢可以被本文进一步列举的取代基替代。
如本文所用，术语“烷氧基”指的是具有“-O-烷基”结构的基团，其中烷基的定义如上所述。术语“C 1-6烷氧基”指的是具有有1到6个碳原子的烷氧基，非限制性地例如：甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、叔丁氧基、异丁氧基、正戊氧基等。
如本文所用，术语“胺基”指的是氨基中的至少一个氢原子被烷基取代后形成的基团，例如：胺基
Figure PCTCN2022119825-appb-000100
中，R 3-11和R 3-12中任一个为烷基，另一个为氢；或R 3-11和R 3-12全部为烷基；当R 3-11和R 3-12全部为烷基时，R 3-11和R 3-12可键合成环。
如本文所用，术语“卤代烷基”指的是一个或多个(如1、2、3、4或5个)氢原子被卤素取代的烷基，其中烷基的定义如上所述。
如本文所用，“(O)”指的是
Figure PCTCN2022119825-appb-000101
在一个实施例中，-CH 2C(O)R 3-2指的是
Figure PCTCN2022119825-appb-000102
如本文所用，术语“卤代氧烷基”指的是一个或多个氢原子被卤素取代的烷氧基，其中烷氧基的定义如上所述。
如本文所用，术语“芳基”，“芳基环”和“芳环”可互换使用，指的是全碳单环、全碳非稠合多环(环与环通过共价键连接，非稠合)或全碳稠合多环(也就是共享毗邻碳原子对的环)基团，基团中至少一个环为芳香性的，即具有成环的共轭π电子体系。
如本文所用，术语“杂芳基”指的是至少一个组成芳基的环碳原子被杂原子取代的芳基，所述杂原子为非碳原子，例如S、N或O。
如本文所用，术语“单环杂芳基”指的是仅有一个芳香性的环的杂芳基，其中杂芳基的定义如上所述。术语“5或6元单环杂芳基”指的是具有5或6个环原子，其中1、2或3个环原子为选自氮、氧或S(＝O)m’(其中m’是整 数0至2)的杂原子的单环杂芳基，非限制地例如：噻吩、呋喃、噻唑、异噻唑、咪唑、噁唑、吡咯、吡唑、三氮唑(例如1,2,3-三氮唑、1,2,4-三氮唑、1,2,5-三氮唑、1,3,4-三氮唑等)、四氮唑、异噁唑、噁二唑、1,2,3-噁二唑、1,2,4-噁二唑、1,2,5-噁二唑、1,3,4-噁二唑、噻二唑、吡啶、哒嗪、嘧啶、吡嗪等。
如本文所用，术语“稠环杂芳基”指的是至少有两个芳香性的环，且两个芳香性的环中两个环原子是共享毗邻的，其中杂芳基的定义如上所述。术语“稠合双环杂芳基”指的是有两个芳香性的环的稠环杂芳基，其中稠环杂芳基的定义如上所述。术语“8至10元稠合双环杂芳基”指的是指具有8到10个环原子，其中1、2、3、4或5个环原子为选自氮、氧或S(＝O)m’(其中m’是整数0至2)的杂原子的稠合双环杂芳基，非限制性实例包括：苯并[d]异噁唑、1H-吲哚、异吲哚、1H-苯并[d]咪唑、苯并[d]异噻唑、1H-苯并[d][1,2,3]三氮唑、苯并[d]噁唑、苯并[d]噻唑、吲唑、苯并呋喃、苯并[b]噻吩、喹啉、异喹啉、喹唑啉、喹喔啉、噌啉、吡啶并[3,2-d]嘧啶、吡啶并[2,3-d]嘧啶、吡啶并[3,4-d]嘧啶、吡啶并[4,3-d]嘧啶、1,8-萘啶、1,7-萘啶、1,6-萘啶、1,5-萘啶、吡唑并[1,5-a]嘧啶、咪唑并[1,2-b]哒嗪等。
如本文所用，术语“有效量”或“治疗有效量”是指化学实体(例如展现出作为NLRP1/3调节剂的活性的化合物，或其药学上可接受的盐和/或水合物和/或共晶体；)的足够量，所述量在施用时将在一定程度上减轻所治疗的疾病或病症的症状中的一个或多个。结果包括疾病的体征、症状或病因的减轻和/或缓解或者生物系统的任何其他所希望的变化。在任意个体情况中的适当“有效”量使用任何合适的技术如剂量递增研究来确定。
如本文所用，术语“赋形剂”或“药学上可接受的赋形剂”意指药学上可接受的材料、组合物或媒介物，如液体或固体填充剂、稀释剂、载体、溶剂、或包封材料。在一个实施例中，每种组分在于药物配制品的其他成分相容，且适用于与人和动物的组织或器官接触而无过度毒性、刺激、过敏应答、免疫原性或其他问题或并发症，与合理益处/风险比相称的意义上是“药学上可接受的”。
如本文所用，术语“药学上可接受的盐”可以是指由药学上可接受的无毒 酸(包括无机酸和有机酸)制备的药学上可接受的加成盐。在某些情况下，药学上可接受的盐是通过使本文所述的化合物与酸反应而获得的。术语“药学上可接受的盐”还可以指通过使具有酸性基团的化合物与碱反应形成盐或通过先前确定的其他方法制备的药学上可接受的加成盐。药理学上可接受的盐没有特别限制，只要它可以用于药物中。本文所述的化合物与碱形成的盐的实例包括以下：其与无机碱如钠、钾、镁、钙和铝的盐；其与有机碱如甲胺、乙胺和乙醇胺的盐；或与二环己胺、N-甲基-D-葡糖胺或三(羟甲基)甲基胺反应形成的；其与碱性氨基酸如赖氨酸和鸟氨酸的盐；以及铵盐。所述盐可以是酸加成盐，其具体示例为与以下的酸加成盐：无机酸，如盐酸、氢溴酸、氢碘酸、硫酸、硝酸和磷酸；有机酸，如甲酸、乙酸、丙酸、草酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、酒石酸、柠檬酸、甲磺酸和乙磺酸；酸性氨基酸，如天冬氨酸和谷氨酸。
如本文所用，术语“赋形剂”或“药学上可接受的赋形剂”意指药学上可接受的材料、组合物或媒介物，如液体或固体填充剂、稀释剂、载体、溶剂、或包封材料。在一个实施例中，每种组分在于药物配制品的其他成分相容，且适用于与人和动物的组织或器官接触而无过度毒性、刺激、过敏应答、免疫原性或其他问题或并发症，与合理益处/风险比相称的意义上是“药学上可接受的”。
如本文所用，术语“药物组合物”是指本文所述的化合物与“赋形剂”如载体、稳定剂、稀释剂、分散剂、悬浮剂和/或增稠剂的混合物。药物组合物有助于将化合物施用于生物体。本领域中存在施用化合物的多种技术，包括但不限于：直肠、口服、静脉内、气雾剂、肠胃外、眼、肺部和外用施用。
如本文所用，术语“受试者”是指动物，包括但不限于灵长类动物(例如，人)、猴、牛、猪、绵羊、山羊、马、狗、猫、兔、大鼠或小鼠。术语“受试者”和“患者”在本文中例如关于哺乳动物受试者(如人)可互换使用。
如本文所用，在治疗疾病或障碍的背景下，术语“治疗(treat、treating和treatment)”意指包括缓解或消除障碍、疾病或病症，其中本文所用的术语“障碍”应始终理解为意指“障碍、疾病或病症”或与障碍相关的症状中的一个或多个；或减慢障碍或病症或其一个或多个症状的进展、扩散或恶化。
除非另有指明，否则本文所述“选择性”是指在不影响或仅微弱影响正常线粒体的前提下，显著地诱导破损线粒体自噬的特性。本文所述的“代谢稳定性”包括但不限于肝微粒体稳定性和血浆稳定性。
除非另有指明，如本文所用，
Figure PCTCN2022119825-appb-000103
表示萘环(包括左边和右边的两个苯环)被0、1、2、3、4或5个R 5取代，且当萘环被大于1个R 5取代时，R 5每次出现时相同或不同。
为使本发明实施例的目的、技术方案和优点更加清楚，下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数是重量百分比和重量份数。以下实施例中所用的实验材料和试剂如无特别说明均可从市售渠道获得。
除非另有指明，本文所用的技术和科学术语具有与本申请所属技术领域的普通技术人员通常理解的相同含义，需要注意的是，本文所用的术语仅为了描述具体实施方式，而非意图限制本申请的示例性实施方式。
实施例1、化合物I-1的合成与表征
Figure PCTCN2022119825-appb-000104
将UMI-77(15mg，0.032mmol)悬浮于DCM(0.5mL)并置于干冰-乙醇浴中搅拌，加入85％mCPBA(6.5mg，0.032mmol)，随后缓慢恢复室温。LC-MS检测生成产物I-1。减压蒸除有机溶剂，所得粗产品用制备HPLC(MeCN/H 2O/TFA)纯化得产物I-1(6mg)。
取纯化的产物I-1进行结构表征，LC-MS(ESI)m/z:482,484[M-H] -. 1H-NMR(400MHz,DMSO-d 6)δ(ppm):13.1(s,1H),10.98(s,1H), 10.17(s,1H),8.25(d,J＝7.4Hz,1H),8.00(d,J＝8.6Hz,1H),7.71(d,J＝8.3Hz,2H),7.64–7.50(m,4H),7.21(s,1H),4.00(d,J＝14.2Hz,1H),3.45(d,J＝14.2Hz,1H).
实施例2、化合物I-2的合成与表征
Figure PCTCN2022119825-appb-000105
在氮气氛围保护下将UMI-77(45mg，0.096mmol)溶于DMF(0.5mL)并置于冰水浴中搅拌，依次加入K 2CO 3(39mg，0.28mmol)和MeI(30μL，0.48mmol)，保持冰水浴下搅拌10min，随后恢复室温继续搅拌过夜。LC-MS检测生成三甲基化产物1。用DCM稀释反应体系并硅胶柱层析(30％v/v乙酸乙酯/石油醚体系)，得到中间体1(42mg)。
将中间体1(42mg，0.081mmol)溶于干燥的DCM(0.5mL)并置于干冰-乙醇浴中搅拌，滴加1M BBr 3的DCM溶液(0.24mL，0.24mmol)，随后缓慢恢复室温并继续搅拌2小时。LC-MS检测生成脱甲基产物。将脱甲基产物(15mg，0.031mmol)悬浮于DCM(0.5mL)并置于干冰-乙醇浴中搅拌，加入85％mCPBA(6.3mg，0.031mmol)，随后缓慢恢复室温。LC-MS检测生成产物I-2。减压蒸除有机溶剂，所得粗产品用制备HPLC(MeCN/H 2O/TFA)纯化得产物I-2(5mg)。
取纯化的产物I-2进行结构表征，LC-MS(ESI)m/z:496,498[M-H] -. 1H-NMR(400MHz,DMSO-d 6)δ(ppm):13.2(s,1H),11.23(s,1H),8.34 (d,J＝8.5Hz,1H),8.20(d,J＝8.4Hz,0.6H),8.13(d,J＝8.4Hz,0.4H),7.91–7.81(m,2H),7.80–7.57(m,4H),7.09(s,0.4H),6.96(s,0.6H),4.03(dd,J＝24.7,14.2Hz,1H),3.60(dd,J＝25.4,14.3Hz,1H),3.25(s,1.2H),3.21(s,1.8H).
实施例3、化合物I-3的合成与表征
Figure PCTCN2022119825-appb-000106
将中间体2(0.8mmol)和2,2’-联吡啶(0.8mmol)溶于干燥的DCE(5mL)，依次加入环丙基硼酸(1.6mmol)，乙酸铜(0.8mmol)和碳酸钠(1.6mmol)，加热80度搅拌24小时。LC-MS检测生成产物3。硅胶柱层析纯化得中间体3(82mg)。将中间体3(0.26mmol)溶于DCM(0.2mL)和吡啶(0.2mL)并置于冰水浴中搅拌，加入对溴苯磺酰氯(0.3mmol)，随后缓慢恢复室温。LC-MS检测生成中间体4。硅胶柱层析纯化得中间体4(120mg)。
Figure PCTCN2022119825-appb-000107
以中间体4(0.22mmol)为原料，按照化合物I-2的合成方法，制备得化合物I-3(5mg)。
取纯化的产物I-3进行结构表征，LC-MS(ESI)m/z:522,524[M-H] -。
实施例4、化合物I-4的合成与表征
Figure PCTCN2022119825-appb-000108
以中间体2和
Figure PCTCN2022119825-appb-000109
为原料，按照化合物I-3的合成方法，将
Figure PCTCN2022119825-appb-000110
换为
Figure PCTCN2022119825-appb-000111
可制备得化合物I-4。
取纯化的产物I-4进行结构表征，LC-MS(ESI)m/z:538,540[M-H] -.
实施例5、化合物I-5的合成与表征
Figure PCTCN2022119825-appb-000112
将中间体6(50mg，0.1mmol)溶于7M氨甲醇溶液(0.5mL)并加热70℃搅拌24小时。LC-MS检测生成中间体7。减压蒸除有机溶剂，所得粗产品直接用于下一步反应。
Figure PCTCN2022119825-appb-000113
以中间体7(0.1mmol)为原料，按照化合物I-2的合成方法，制备得化合物I-5(3mg)。
取纯化的产物I-5进行结构表征，LC-MS(ESI)m/z:481,483[M-H] -.
实施例6、化合物I-6的合成与表征
Figure PCTCN2022119825-appb-000114
将中间体7(31mg，0.064mmol)溶于干燥的甲苯(0.4mL)，加入劳森试剂(0.04mmol)并加热80度搅拌24小时。LC-MS检测生成中间体9。硅胶柱层析纯化得中间体9(22mg)。
Figure PCTCN2022119825-appb-000115
以中间体9(0.043mmol)为原料，按照化合物I-2的合成方法，制备得化合物I-6(4mg)。
取纯化的产物I-6进行结构表征，LC-MS(ESI)m/z:497,499[M-H] -.
实施例7、化合物I-7-1的合成与表征
Figure PCTCN2022119825-appb-000116
以已知化合物11(J.Med.Chem.2014,57,4111-4133)(0.04mmol)为原料，按照化合物I-1的合成方法，制备得化合物I-7-1(7mg)。
取纯化的产物I-7-1进行结构表征， 1H-NMR(400MHz,Methanol-d4)δ 8.17(d,J＝8.4Hz,1H),7.80(d,J＝8.4Hz,1H),7.62-7.56(m,2H),7.56-7.45(m,4H),7.10(s,1H),4.70(d,J＝2.8Hz,2H).LC-MS(ESI)m/z:506,508[M-H] -.
实施例8、化合物I-8的合成与表征
Figure PCTCN2022119825-appb-000117
将中间体7(48mg，0.1mmol)溶于DMF-DMA(1.0mL)并110度加热搅拌15小时，减压蒸除DMF-DMA后，残余物溶于乙酸(1.0mL)，再加入水合肼(0.2mmol)并加热90度搅拌2小时。LC-MS检测生成中间体12。硅胶柱层析纯化得中间体12(21mg)。
Figure PCTCN2022119825-appb-000118
以中间体12(0.04mmol)为原料，按照化合物I-2的合成方法，制备得化合物I-8(4mg)。
取纯化的产物I-8进行结构表征，LC-MS(ESI)m/z:507,509[M+H] +.
实施例9、化合物I-9-1和I-9-2的合成与表征
Figure PCTCN2022119825-appb-000119
以已知化合物14(5.0mmol)为原料制备中间体15。将甲硫醇钠(1.2eq)，碳酸铯(1.5eq)，碘化锂(0.5eq)，14(1.0eq)在氮气保护下悬浮于无水THF中，注射器加入1.0M的氯化锌THF溶液(1.0eq)，室温下搅拌。同时将乙酸钯(0.1eq)和XantPhos(0.1eq)混合溶于无水THF中，并将此溶液用注射器转移至上述悬浮液中。随后油浴70摄氏度加热过夜。LC-MS显示14基本消耗完，有产物生成。反应体系用乙酸乙酯稀释后通过一层硅藻土过滤，滤液旋干，硅胶柱层析得甲硫基取代产物(3.4mmol)。将此产物溶于无水DCM并干冰-乙醇浴冷却，一次性加入mCPBA(1.1eq)后缓慢恢复至室温。LC-MS显示反应完全，旋蒸除去溶剂，残余固体用甲基叔丁基醚打浆，得亚砜产物(3.3mmol)。将亚砜产物溶于乙腈，加入吡啶(10eq)，置于-40度冷浴中搅拌并滴加液溴(2.0eq)，随后缓慢恢复室温，LC-MS显示有溴代产物生成。反应用饱和亚硫酸氢钠水溶液淬灭，DCM萃取水相，有机相旋干后硅胶柱层析制备得中间体15(1.4mmol)。
Figure PCTCN2022119825-appb-000120
以中间体15(1.4mmol)为原料，用四氮唑(1.2eq)作为亲核试剂，碳酸钾(1.5eq)作为碱，在DMF溶剂中室温下搅拌反应直至15完全消耗。所 得两个异构体产物无法通过硅胶柱层析分离，二者的混合物(1.1eq)按照UMI-77的合成路线(J.Med.Chem.2014,57,4111-4133)可制备得化合物I-9-1(5mg)和I-9-2(1mg)。
取纯化的产物I-9-1进行结构表征，LC-MS(ESI)m/z:508,510[M+H] +.
取纯化的产物I-9-2进行结构表征，LC-MS(ESI)m/z:508,510[M+H] +.
实施例10、化合物I-10的合成与表征
Figure PCTCN2022119825-appb-000121
将已知化合物14(7.0mmol)，TMS保护的炔丙硫醇(1.2eq)，碳酸铯(2.5eq)，碘化锂(0.5eq)在氮气保护下悬浮于无水THF中，注射器加入1.0M的氯化锌THF溶液(1.0eq)，室温下搅拌。同时将乙酸钯(0.1eq)和 XantPhos(0.1eq)混合溶于无水THF中，并将此溶液用注射器转移至上述悬浮液中。随后油浴70摄氏度加热过夜。LC-MS显示14基本消耗完，有产物生成。反应体系用乙酸乙酯稀释后通过一层硅藻土过滤，滤液旋干，硅胶柱层析得硫代产物(4.1mmol)。此硫代产物按照UMI-77合成路线(J.Med.Chem.2014,57,4111-4133)用还原铁粉在乙酸溶剂中进行硝基还原，同时伴随炔基上TMS保护基的脱除，硅胶柱层析后得到萘胺中间体(3.5mmol)。随后按照UMI-77合成路线(J.Med.Chem.2014,57,4111-4133)对此萘胺中间体进行磺酰化，得到磺酰胺中间体(3.2mmol)。将此磺酰胺中间体(3.2mmol)溶于甲醇和DMF的2:1混合溶剂中，加入碘化亚铜(0.1eq)，室温搅拌下滴加TMSN 3，反应过夜，LC-MS显示有三氮唑产物生成，硅胶柱层析得三氮唑产物(1.7mmol)。按照化合物I-2的合成方法对此三氮唑产物进行脱甲基和氧化制备得化合物I-10。
取纯化的产物I-10进行结构表征，LC-MS(ESI)m/z:507,509[M+H] +.
实施例11、化合物I-11-1和I-11-2的合成与表征
Figure PCTCN2022119825-appb-000122
参照化合物I-9-1和I-9-2的合成路线，将路线中的四氮唑
Figure PCTCN2022119825-appb-000123
换成1,2,3-三氮唑
Figure PCTCN2022119825-appb-000124
可制备得化合物I-11-1和I-11-2。
取纯化的产物I-11-1进行结构表征，LC-MS(ESI)m/z:507,509[M+H] +.
取纯化的产物I-11-2进行结构表征，LC-MS(ESI)m/z:507,509[M+H] +.
实施例12、化合物I-12的合成与表征
Figure PCTCN2022119825-appb-000125
以已知化合物14为原料，参照UMI-77合成路线(J.Med.Chem.2014,57,4111-4133)，将
Figure PCTCN2022119825-appb-000126
替换为
Figure PCTCN2022119825-appb-000127
并在最后一步按照化合物I-1的合成方法用mCPBA氧化出亚砜，可制备得化合物I-12。
取纯化的产物I-12进行结构表征， 1H-NMR(400MHz,DMSO-d 6)δ10.92(br,1H),10.11(s,1H),8.24(d,J＝9.6Hz,1H),7.99(d,J＝9.6Hz,1H).7.58-7.56(m,2H),7.31-7.26(m,5H),7.14-7.11(m,2H),7.09-7.06(m,2H),7.02(s,1H),4.27(d,J＝12.4Hz,1H),3.91(d,J＝12.4Hz,1H).LC-MS(ESI)m/z:516,518[M+H] +.
实施例13、化合物I-13-1的合成与表征
Figure PCTCN2022119825-appb-000128
以中间体2为原料，按照UMI-77和化合物I-1的合成方法，将合成路线中的
Figure PCTCN2022119825-appb-000129
换成
Figure PCTCN2022119825-appb-000130
可制备得化合物I-13-1。
取纯化的产物I-13-1进行结构表征， 1H-NMR(400MHz,DMSO-d6)δ13.19(br,1H),10.96(br,1H),10.23(s,1H),8.29-8.26(m,1H),8.03-8.00(m,1H),7.88(dd,J＝2.0,5.2Hz,1H),7.60-7.54(m,2H),7.39-7.37(m,1H),7.31(s,1H),7.09-7.06(m,1H),4.02(d,J＝14.4Hz,1H),3.48(d,J＝14.0Hz,1H).LC-MS(ESI)m/z:410[M-H] -.
实施例14、化合物I-14-1的合成与表征
Figure PCTCN2022119825-appb-000131
以中间体2为原料，按照UMI-77和化合物I-1的合成方法，将合成路线中的
Figure PCTCN2022119825-appb-000132
换成
Figure PCTCN2022119825-appb-000133
可制备得化合物I-14-1。
取纯化的产物I-14-1进行结构表征， 1H-NMR(400MHz,DMSO-d6)δ10.28(s,1H),8.26-8.37(m,1H),7.97-7.94(m,1H),7.88(d,J＝8.0Hz,2H),7.82(d,J＝8.0Hz,2H),7.58-7.51(m,2H),7.16(s,1H),3.95(d,J＝14.0Hz,1H),3.42(d,J＝14.0Hz,1H).LC-MS(ESI)m/z:472[M-H] -.
实施例15、化合物I-15-1的合成与表征
Figure PCTCN2022119825-appb-000134
以中间体2为原料，按照UMI-77和化合物I-1的合成方法，将合成路线中的
Figure PCTCN2022119825-appb-000135
换成
Figure PCTCN2022119825-appb-000136
可制备得化合物I-15-1。
取纯化的产物I-15-1进行结构表征，LC-MS(ESI)m/z:434[M-H] -.
实施例16、化合物I-16-1的合成与表征
Figure PCTCN2022119825-appb-000137
以中间体2为原料，按照UMI-77和化合物I-1的合成方法，将合成路线中的
Figure PCTCN2022119825-appb-000138
换成
Figure PCTCN2022119825-appb-000139
可制备得化合物I-16-1。
取纯化的产物I-16-1进行结构表征， 1H-NMR(400MHz,DMSO-d6)δ9.90(s,1H),8.25-8.22(m,1H),8.05-8.02(m,1H),7.59-7.56(m,4H),7.44-7.39(m,2H),7.22-7.18(m,1H),7.12(s,1H),7.07-7.04(m,2H),7.02-7.00(m,2H),3.95(d,J＝14.4Hz,1H),3.44(d,J＝14.4Hz,1H).LC-MS(ESI)m/z:496[M-H] -.
实施例17、化合物I-17的合成与表征
Figure PCTCN2022119825-appb-000140
以中间体2为原料，按照UMI-77和化合物I-1的合成方法，将合成路线中的
Figure PCTCN2022119825-appb-000141
换成
Figure PCTCN2022119825-appb-000142
可制备得化合物I-17-1。
取纯化的产物I-17-1进行结构表征， 1H-NMR(400MHz,DMSO-d6)δ13.18(br,1H),11.04(br,1H),10.26(s,1H),8.30-8.27(m,1H),8.03-8.00(m,1H),7.81-7.77(m,2H),7.62-7.55(m,3H),7.17(s,1H),4.02(d,J＝14.0Hz,1H),3.45(d,J＝14.0Hz,1H).LC-MS(ESI)m/z:472[M-H] -.
实施例18、化合物I-18的合成与表征
Figure PCTCN2022119825-appb-000143
以中间体2为原料，按照UMI-77和化合物I-1的合成方法，将合成路线中的
Figure PCTCN2022119825-appb-000144
换成
Figure PCTCN2022119825-appb-000145
可制备得化合物I-18-1。
取纯化的产物I-18-1进行结构表征，LC-MS(ESI)m/z:473[M-H] -.
实施例19、化合物I-19的合成与表征
Figure PCTCN2022119825-appb-000146
以中间体2为原料，按照UMI-77和化合物I-1的合成方法，将合成路线中的
Figure PCTCN2022119825-appb-000147
换成
Figure PCTCN2022119825-appb-000148
可制备得化合物I-19-1。
取纯化的产物I-19-1进行结构表征，LC-MS(ESI)m/z:460[M-H] -.
实施例20、化合物I-20-1的合成与表征
Figure PCTCN2022119825-appb-000149
以中间体2为原料，按照UMI-77和化合物I-1的合成方法，将合成路线中的
Figure PCTCN2022119825-appb-000150
换成
Figure PCTCN2022119825-appb-000151
可制备得化合物I-20-1。
取纯化的产物I-20-1进行结构表征， 1H-NMR(400MHz,DMSO-d6)δ9.90(s,1H),8.28-8.23(m,1H),8.06-8.02(m,1H),7.59-7.52(m,2H),7.50-7.44(m,2H),7.18-7.13(m,3H),3.94(d,J＝14.4Hz,1H),3.39(d,J＝14.4Hz,1H),1.99-1.93(m,1H),1.01-0.95(m,2H),0.76-0.69(m,2H).LC-MS(ESI)m/z:444[M-H] -.
实施例21、化合物I-21-1的合成与表征
Figure PCTCN2022119825-appb-000152
以中间体2为原料，按照UMI-77和化合物I-1的合成方法，将合成路线中的
Figure PCTCN2022119825-appb-000153
换成
Figure PCTCN2022119825-appb-000154
可制备得化合物I-21-1。
取纯化的产物I-21-1进行结构表征， 1H-NMR(400MHz,DMSO-d6)δ10.17(s,1H),8.24(d,J＝8.0Hz,1H),7.93(d,J＝8.0Hz,1H),7.74-7.70(m,2H),7.58-7.48(m,2H),7.48-7.45(m,2H),7.19(s,1H),3.98(d,J＝14.4Hz,1H),3.44(d,J＝14.4Hz,1H).LC-MS(ESI)m/z:488[M-H] -.
实施例22、化合物I-22-1的合成与表征
Figure PCTCN2022119825-appb-000155
以中间体2为原料，按照UMI-77和化合物I-1的合成方法，将合成路线中的
Figure PCTCN2022119825-appb-000156
换成
Figure PCTCN2022119825-appb-000157
可制备得化合物I-22-1。
取纯化的产物I-22-1进行结构表征， 1H-NMR(400MHz,DMSO-d6)δ10.41(s,1H),8.35-8.31(m,2H),8.27-8.24(m,1H),8.01-7.97(m,1H),7.90-7.86(m,2H),7.59-7.54(m,2H),7.13(s,1H),3.96(d,J＝14.4Hz,1H),3.40(d,J＝14.4Hz,1H).LC-MS(ESI)m/z:449[M-H] -.
实施例23、化合物I-23-1的合成与表征
Figure PCTCN2022119825-appb-000158
以中间体2为原料，按照UMI-77和化合物I-1的合成方法，将合成路线中的
Figure PCTCN2022119825-appb-000159
换成
Figure PCTCN2022119825-appb-000160
可制备得化合物I-23-1。
取纯化的产物I-23-1进行结构表征， 1H-NMR(400MHz,DMSO-d6)δ10.10(s,1H),8.26-8.23(m,1H),8.07-8.03(m,1H),7.89-7.86(m,1H),7.85-7.83(m,1H),7.62-7.51(m,6H),7.50-7.45(m,2H),7.44-7.39(m,1H),7.28(s,1H),3.95(d,J＝14.4Hz,1H),3.37(d,J＝14.4Hz,1H).LC-MS(ESI)m/z:480[M-H] -.
实施例24、化合物I-24-1的合成与表征
Figure PCTCN2022119825-appb-000161
以中间体2为原料，按照UMI-77和化合物I-1的合成方法，将合成路线中的
Figure PCTCN2022119825-appb-000162
换成
Figure PCTCN2022119825-appb-000163
可制备得化合物I-24-1。
取纯化的产物I-24-1进行结构表征， 1H-NMR(400MHz,DMSO-d6)δ10.19(s,1H),8.27-8.25(m,1H),8.02-7.99(m,1H),7.59-7.54(m,3H),7.51-7.46(m,2H),7.43-7.39(m,1H),7.20(s,1H),4.00(d,J＝14.4Hz,1H),3.43(d,J＝14.4Hz,1H).LC-MS(ESI)m/z:422[M-H] -.
实施例25、化合物I-25-1的合成与表征
Figure PCTCN2022119825-appb-000164
将Na 2SO 3(3.8g，30mmol)溶于30mL去离子水，搅拌下分批加入对溴苯磺酰氯(2.6g，10mmol)。油浴75℃加热5小时，冷却后滴加浓盐酸，有白色固体析出。抽滤，所得固体在水中重结晶得中间体16(1.3g)。将中间体16悬浮在80mL DCM中，滴加二氯亚砜(4eq)，滴加完后油浴加热至回流，5小时后旋转蒸发去除溶剂，用甲苯带出残留二氯亚砜，得到中间体17(626mg)。
Figure PCTCN2022119825-appb-000165
将中间体17(48mg，0.2mmol)悬浮在1mL DCM中，冰水浴冷却下加入甲胺(1.5eq)的醇溶液，再加入三乙胺(2eq)，自然恢复室温，搅拌2小时。LC-MS显示中间体18生成。采用硅胶柱层析纯化(EA in hexane＝65％v/v)得中间体18为淡黄色固体(30mg)。
Figure PCTCN2022119825-appb-000166
将中间体18(30mg，0.13mmol)悬浮于0.5mL四氯化碳，冰水浴下搅拌，加入叔丁基氧氯(1.5eq)，固体立即溶解。继续搅拌1小时，旋转蒸发除去低沸点物质，即可得中间体19。随后将19溶于0.5mL DCM，冰水浴下 搅拌。将中间体2(1eq，参考J.Med.Chem.2014,57,4111-4133制备)溶于0.3mL吡啶，并将此吡啶溶液滴加到19的DCM溶液中，自然恢复室温并搅拌过夜。LC-MS显示中间体20生成。硅胶柱层析纯化(EA in hexane＝40％v/v)得中间体20为油状物(51mg)。
Figure PCTCN2022119825-appb-000167
将中间体20(51mg，0.1mmol)溶解在0.5mL DCM中，干冰-乙醇浴冷却下滴加BBr3的DCM溶液(0.2mL，1M in DCM)。缓慢恢复室温，搅拌3小时，LC-MS显示20完全消耗并且生成中间体21。滴加去离子水淬灭反应，用DCM萃取三次。合并有机相，旋转蒸发蒸除有机溶剂，用制备HPLC纯化(MeCN/H 2O/TFA)得到中间体21(13mg)。取纯化的21进行结构表征，LC-MS(ESI)m/z:479,481[M-H] -. 1H-NMR(400MHz,DMSO-d 6)δ(ppm):9.13(s,1H),8.36–8.28(m,1H),8.14–8.06(m,1H),7.93(d,J＝8.4Hz,2H),7.83(d,J＝8.4Hz,2H),7.55–7.39(m,3H),7.22(s,1H),3.61(s,2H),2.41(s,3H).
Figure PCTCN2022119825-appb-000168
以中间体21(13mg)为原料，按照化合物I-1的合成方法，制备得化合物I-25-1(4mg)。
取纯化的产物I-25-1进行结构表征，LC-MS(ESI)m/z:495,497[M-H] -.
实施例26、化合物I-26的合成与表征
Figure PCTCN2022119825-appb-000169
以中间体20为原料，按照中间体1的合成方法，制备得中间体22。
Figure PCTCN2022119825-appb-000170
以中间体22为原料，按照化合物I-2的合成方法，制备得化合物I-26。
取纯化的产物I-26进行结构表征，LC-MS(ESI)m/z:509,511[M-H] -.
实施例27、化合物I-27的合成与表征
Figure PCTCN2022119825-appb-000171
按照中间体20的合成方法，将合成路线中的甲胺换成
Figure PCTCN2022119825-appb-000172
可制备得中间体24。将中间体24(1.9mmol)溶于THF，室温下搅拌并滴加1MTBAF的THF溶液，继续搅拌一小时至TBS完全脱除。硅胶柱层析得中间体25(1.8mmol)。将中间体25(1.8mmol)和三苯基膦(1.2eq)溶于无水THF中，室温下搅拌并滴加DIAD(1.2eq)，继续室温搅拌过夜，LC-MS显示有环化产物26生成，硅胶柱层析得中间体26(0.8mmol)。
Figure PCTCN2022119825-appb-000173
以中间体26为原料，按照化合物I-2的合成方法，可制备得化合物I-27。
取纯化的产物I-27进行结构表征，LC-MS(ESI)m/z:507,509[M-H] -.
实施例28、化合物I-28的合成与表征
Figure PCTCN2022119825-appb-000174
按照化合物I-27的合成方法，将合成路线中的
Figure PCTCN2022119825-appb-000175
换成
Figure PCTCN2022119825-appb-000176
可制备得化合物I-28。
取纯化的产物I-28进行结构表征，LC-MS(ESI)m/z:521,523[M-H] -.
实施例29、化合物I-29的合成与表征
Figure PCTCN2022119825-appb-000177
以已知化合物28(CAS:71127-64-5)(5.0mmol)为原料，按文献(J.Med.Chem.2012,55,1978-1998)的合成方法可制备得中间体29(0.8mmol)。再按照化合物I-1的合成方法对中间体29进行氧化，制备得化合物I-29。
取纯化的产物I-29进行结构表征：LC-MS(ESI)m/z:562[M-H] -.
实施例30、化合物I-30的合成与表征
Figure PCTCN2022119825-appb-000178
以已知化合物30(CAS:58200-82-1)为原料，采用和化合物I-29相同的合成路线，可制备得化合物I-30。取纯化的产物I-30进行结构表征：LC-MS(ESI)m/z:527,529[M-H] -.
实施例31、化合物I-31的合成与表征
Figure PCTCN2022119825-appb-000179
以已知化合物31(CAS:88437-16-5)为原料，采用和化合物I-29相同的合成路线，可制备得化合物I-31。
取纯化的产物I-31进行结构表征：LC-MS(ESI)m/z:507,509[M-H] -.
实施例32、化合物I-32的合成与表征
Figure PCTCN2022119825-appb-000180
以已知化合物32(CAS:83441-11-6)为原料，采用和化合物I-29相同的合成路线，可制备得化合物I-32。
取纯化的产物I-32进行结构表征：LC-MS(ESI)m/z:526,528[M-H] -.
实施例33、化合物I-33的合成与表征
Figure PCTCN2022119825-appb-000181
以中间体2为原料，参照UMI-77和化合物I-1的合成方法，将合成路线中的
Figure PCTCN2022119825-appb-000182
换成
Figure PCTCN2022119825-appb-000183
可制备得化合物I-33。
取纯化的产物I-33进行结构表征，LC-MS(ESI)m/z:496,498[M-H] -.
实施例34：化合物I-34的合成与表征
Figure PCTCN2022119825-appb-000184
以中间体2为原料，按照UMI-77和化合物I-34的合成方法，将合成路线中的
Figure PCTCN2022119825-appb-000185
换成
Figure PCTCN2022119825-appb-000186
可制备得化合物I-34。
取纯化的产物I-34进行结构表征， 1H-NMR(400MHz,DMSO-d6)δ10.49(s,1H),8.35-8.32(m,1H),8.04-8.02(m,2H),7.97-7.93(m,1H),7.80-7.77(m,2H),7.71(s,1H),7.68-7.61(m,2H),4.13(d,J＝14.4Hz,1H),3.69(d,J＝14.4Hz,1H).LC-MS(ESI)m/z:446,448[M-H] -.
实施例35、化合物I-35-1的合成与表征
Figure PCTCN2022119825-appb-000187
以中间体2为原料，按照UMI-77和化合物I-1的合成方法，将合成路线中的
Figure PCTCN2022119825-appb-000188
换成
Figure PCTCN2022119825-appb-000189
可制备得化合物I-35-1。
取纯化的产物I-35-1进行结构表征， 1H-NMR(400MHz,DMSO-d6)δ 10.51(s,1H),8.34-8.31(m,1H),8.26(m,1H),8.07-8.05(m,1H),7.95-7.93(m,1H),7.83-7.81(m,1H),7.70(s,1H),7.66-7.60(m,2H),7.53(t,J＝8.0Hz,2H),4.11(d,J＝14.4Hz,1H),3.69(d,J＝14.4Hz,1H).LC-MS(ESI)m/z:446,448[M-H] -.
实施例36、化合物I-36的合成与表征
Figure PCTCN2022119825-appb-000190
以中间体2为原料，按照UMI-77和化合物I-1的合成方法，将合成路线中的
Figure PCTCN2022119825-appb-000191
换成
Figure PCTCN2022119825-appb-000192
可制备得化合物I-36。
取纯化的产物I-36进行结构表征， 1H-NMR(400MHz,DMSO-d6)δ9.69(s,1H),8.25-8.23(m,1H),8.12-8.10(m,1H),8.00(s,1H),7.61-7.60(m,2H),7.59-7.52(m,1H),7.23(s,1H),3.86(d,J＝14.4Hz,1H),3.80(s,3H),3.61(d,J＝14.4Hz,1H).LC-MS(ESI)m/z:408[M-H] -.
实施例37、化合物I-37的合成与表征
Figure PCTCN2022119825-appb-000193
以中间体2为原料，按照UMI-77和化合物I-1的合成方法，将合成路线中的
Figure PCTCN2022119825-appb-000194
换成
Figure PCTCN2022119825-appb-000195
可制备得化合物I-37。
取纯化的产物I-37进行结构表征，LC-MS(ESI)m/z:423[M-H] -.
实施例38、化合物I-38的合成与表征
Figure PCTCN2022119825-appb-000196
以中间体2为原料，按照UMI-77和化合物I-1的合成方法，将合成路线中的
Figure PCTCN2022119825-appb-000197
换成
Figure PCTCN2022119825-appb-000198
可制备得化合物I-38。
取纯化的产物I-38进行结构表征，LC-MS(ESI)m/z:483,485[M-H] -.
实施例39、化合物I-39的合成与表征
Figure PCTCN2022119825-appb-000199
以已知化合物30(CAS:58200-82-1)(10.0mmol)为原料，按照文献 (J.Med.Chem.2012,55,1978-1998)的合成方法，过量
Figure PCTCN2022119825-appb-000200
在乙醇中可亲核取代并还原30得到中间体33(7.1mmol)。将此33溶于乙酸中并加入还原铁粉(8.0eq)，50度加热搅拌直至硝基完全还原至中间体34。过滤并将滤液浓缩，残余物溶于THF，加入三乙胺(5.0eq)，室温搅拌下滴加乙酸酐(2.0eq)，继续搅拌至LC-MS显示中间体34被完全乙酰化得中间体35，硅胶柱层析得中间体35(3.8mmol)。随后采用和化合物I-29相同的合成步骤，可制备得化合物I-39。
取纯化的产物I-39进行结构表征，LC-MS(ESI)m/z:539,541[M-H] -.
实施例40、化合物I-40-1的合成与表征
Figure PCTCN2022119825-appb-000201
以已知化合物36(CAS:4923-53-9)为原料，采用和化合物I-29相同的合成路线，可制备得化合物I-40-1。
取纯化的产物I-40-1进行结构表征：LC-MS(ESI)m/z:498,500[M-H] -.
实施例41、化合物I-41-1的合成与表征
Figure PCTCN2022119825-appb-000202
以已知化合物37(CAS:29263-68-1)为原料，采用和化合物I-29相同的合成路线，可制备得化合物I-41-1。
取纯化的产物I-41-1进行结构表征：LC-MS(ESI)m/z:512,514[M-H] -.
实施例42、化合物I-42的合成与表征
Figure PCTCN2022119825-appb-000203
将UMI-77(15mg，0.032mmol)溶于DCM(0.5mL)并置于干冰-乙醇浴中搅拌，加入2当量85％mCPBA(13mg，0.064mmol)，随后缓慢恢复室温。LC-MS检测生成产物I-42。减压蒸除有机溶剂，所得粗产品用制备HPLC(MeCN/H 2O/TFA)纯化得产物I-42(5mg)。
取纯化的产物I-42进行结构表征， 1H-NMR(400MHz,DMSO-d6)δ10.14(s,1H),8.37-8.34(m,1H),7.97-7.95(m,1H),7.72-7.69(m,2H),7.64-7.61(m,2H),7.55-7.53(m,2H),7.27(s,1H),4.51(s,2H).LC-MS(ESI)m/z:498,500[M-H] -.
实施例43、化合物I-7-2的合成与表征
Figure PCTCN2022119825-appb-000204
以已知化合物11(J.Med.Chem.2014,57,4111-4133)(0.04mmol)为原料，按照化合物I-42的合成方法，制备得化合物I-7-2(4mg)。
取纯化的产物I-7-2进行结构表征，LC-MS(ESI)m/z:522,524[M-H] -.
实施例44、化合物I-13-2的合成与表征
Figure PCTCN2022119825-appb-000205
按照化合物I-13-1和I-42的合成方法，制备得化合物I-13-2(5mg)。
取纯化的产物I-13-2进行结构表征，LC-MS(ESI)m/z:426[M-H] -.
实施例45、化合物I-14-2的合成与表征
Figure PCTCN2022119825-appb-000206
按照化合物I-14-1和I-42的合成方法，制备得化合物I-14-2(7mg)。
取纯化的产物I-14-2进行结构表征，LC-MS(ESI)m/z:488[M-H] -.
实施例46、化合物I-15-2的合成与表征
Figure PCTCN2022119825-appb-000207
按照化合物I-15-1和I-42的合成方法，制备得化合物I-15-2(12mg)。
取纯化的产物I-15-2进行结构表征，LC-MS(ESI)m/z:450[M-H] -.
实施例47、化合物I-16-2的合成与表征
Figure PCTCN2022119825-appb-000208
按照化合物I-16-1和I-42的合成方法，制备得化合物I-16-2(15mg)。
取纯化的产物I-16-2进行结构表征，LC-MS(ESI)m/z:512[M-H] -.
实施例48、化合物I-17-2的合成与表征
Figure PCTCN2022119825-appb-000209
按照化合物I-17-1和I-42的合成方法，制备得化合物I-17-2(17mg)。
取纯化的产物I-17-2进行结构表征，LC-MS(ESI)m/z:488[M-H] -.
实施例49、化合物I-18-2的合成与表征
Figure PCTCN2022119825-appb-000210
按照化合物I-18-1和I-42的合成方法，制备得化合物I-18-2(11mg)。
取纯化的产物I-18-2进行结构表征，LC-MS(ESI)m/z:489[M-H] -.
实施例50、化合物I-19-2的合成与表征
Figure PCTCN2022119825-appb-000211
按照化合物I-19-1和I-42的合成方法，制备得化合物I-19-2(17mg)。
取纯化的产物I-19-2进行结构表征，LC-MS(ESI)m/z:476[M-H] -.
实施例51、化合物I-20-2的合成与表征
Figure PCTCN2022119825-appb-000212
按照化合物I-20-1和I-42的合成方法，制备得化合物I-20-2(21mg)。
取纯化的产物I-20-2进行结构表征，LC-MS(ESI)m/z:460[M-H] -.
实施例52、化合物I-21-2的合成与表征
Figure PCTCN2022119825-appb-000213
按照化合物I-21-1和I-42的合成方法，制备得化合物I-21-2(14mg)。
取纯化的产物I-21-2进行结构表征，LC-MS(ESI)m/z:504[M-H] -.
实施例53、化合物I-22-2的合成与表征
Figure PCTCN2022119825-appb-000214
按照化合物I-22-1和I-42的合成方法，制备得化合物I-22-2(25mg)。
取纯化的产物I-22-2进行结构表征，LC-MS(ESI)m/z:465[M-H] -.
实施例54、化合物I-23-2的合成与表征
Figure PCTCN2022119825-appb-000215
按照化合物I-23-1和I-42的合成方法，制备得化合物I-23-2(23mg)。
取纯化的产物I-23-2进行结构表征，LC-MS(ESI)m/z:496[M-H] -.
实施例55、化合物I-24-2的合成与表征
Figure PCTCN2022119825-appb-000216
按照化合物I-24-1和I-42的合成方法，制备得化合物I-24-2(18mg)。
取纯化的产物I-24-2进行结构表征，LC-MS(ESI)m/z:438[M-H] -.
实施例56、化合物I-25-2的合成与表征
Figure PCTCN2022119825-appb-000217
按照化合物I-25-1和I-42的合成方法，制备得化合物I-25-2(18mg)。
取纯化的产物I-25-2进行结构表征，LC-MS(ESI)m/z:511,513[M-H] -.
实施例57、化合物I-35-2的合成与表征
Figure PCTCN2022119825-appb-000218
按照化合物I-35-1和I-42的合成方法，制备得化合物I-35-2(14mg)。
取纯化的产物I-35-2进行结构表征， 1H-NMR(400MHz,DMSO-d6)δ10.52(s,1H),8.44(d,J＝8.0Hz,1H),8.27-8.26(m,1H),8.07(d,J＝8.0Hz,1H),7.97(d,8.0Hz,1H),7.85-7.83(m,1H),7.77(s,1H),7.76-7.67(m,1H),7.54(t,J＝8.0Hz,1H),4.64(s,2H).LC-MS(ESI)m/z:462,464[M-H] -.
实施例58、化合物I-40-2的合成与表征
Figure PCTCN2022119825-appb-000219
按照化合物I-40-1和I-42的合成方法，制备得化合物I-40-2(3mg)。
取纯化的产物I-40-2进行结构表征，LC-MS(ESI)m/z:514,516[M-H] -.
实施例59、化合物I-41-2的合成与表征
Figure PCTCN2022119825-appb-000220
按照化合物I-41-1和I-42的合成方法，制备得化合物I-41-2(12mg)。
取纯化的产物I-41-2进行结构表征，LC-MS(ESI)m/z:528,530[M-H] -.
实施例60、化合物I-43的合成与表征
Figure PCTCN2022119825-appb-000221
以已知物38为原料，按照上图合成路线，可制备得化合物I-43。
取纯化的产物I-43进行结构表征，LC-MS(ESI)m/z:462,464[M-H] -.
实施例61、化合物I-44的合成与表征
Figure PCTCN2022119825-appb-000222
以中间体41为原料，通过劳森试剂处理，可制备得中间体42。
Figure PCTCN2022119825-appb-000223
中间体42通过三溴化硼处理脱去甲基，可制备得化合物I-44。
取纯化的产物I-44进行结构表征：LC-MS(ESI)m/z:478,480[M-H] -.
测试例1、线粒体自噬诱导剂的功能测试
组1：人胚肾转化细胞HEK293Tmtkeima细胞分别施加0μM、1.25μM、2.5μM、5μM和10μM的的CCCP，并以1.5*10 5个/ml种于96孔黑色酶标板中，每孔100μL。25小时后加入化合物I-2，设置3个重复。于37℃，5％CO 2培养条件下，每隔几小时用biotekcytation 5拍照，共拍摄20小时，以明场做对焦通道，每孔拍摄9张图片，利用仪器软件处理图像。所得照片见图1。
如图1所示，在施加0μM的CCCP的细胞中，施加化合物I-2的色块颜色均较浅，表明线粒体未损伤的细胞中施加化合物I-2，不能诱导线粒体自噬，即化合物I-2无法诱导非损伤线粒体发生自噬。
如图1所述，在未施加CCCP的细胞和施加了CCCP的细胞(10μM)中，再分别施加化合物I-2，施加CCCP的细胞色块颜色较深，表明在线粒体损伤的细胞中，施加化合物I-2，线粒体自噬水平高，即化合物I-2可选择性诱导损伤的线粒体发生自噬。
组2：人胚肾转化细胞HEK293Tmtkeima细胞以1.5*10 5个/ml种于96孔黑色酶标板中，每孔100μL；25小时后分别加入化合物I-1～I-44，UMI-77，设置3个重复；于37℃，5％CO 2培养条件下，每隔几小时用biotekcytation 5拍照，共拍摄20小时。另一组细胞在相同条件下，人胚肾转化细胞HEK293Tmtkeima细胞以1.5*10 5个/ml种于96孔黑色酶标板中，每孔100μl；24小时后先加入5uM或10uM CCCP(Carbonyl cyanide 3-chlorophenylhydrazone)诱导线粒体破损，1小时后再加入I-1～I-44，UMI-77，设置3个重复；于37℃，5％CO 2培养条件下，每隔几小时用biotekcytation 5拍照，共拍摄20小时。两组均以明场做对焦通道，每孔拍摄9张图片，利用仪器软件处理图像。部分所得照片见图2。
如图2所示，人胚肾转化细胞HEK293Tmtkeima系统在用5uM或10uM CCCP处理诱导线粒体损伤后再加化合物I-1，I-2，对比未使用CCCP处理，只加入受试化合物，图块颜色更深，表明化合物I-1，I-2更倾向诱导损伤的线粒体发生自噬。而UMI-77，同等条件下，损伤的线粒体和未损伤的线粒体色块颜色均较深，表明UMI-77无法选择性诱导损伤的线粒体发生自噬。
其他化合物诱导损伤线粒体自噬的能力测试结果如下表1：
表1
Figure PCTCN2022119825-appb-000224
Figure PCTCN2022119825-appb-000225
“+++”表示化合物具有较强的选择性诱导破损线粒体自噬的能力(破损线粒体自噬发生细胞数/全部细胞数>0.30)，“++”表示化合物具有中等的选择性诱导破损线粒体自噬的能力(破损线粒体自噬发生细胞数/全部细胞数在0.2～0.3范围内)，“+”表示化合物具有较弱的选择性诱导破损线粒体自噬的能力(破损线粒体自噬发生细胞数/全部细胞数在0.1～0.2范围内)，“NA”表示没有检出化合物具有选择性诱导破损线粒体自噬的能力。
注：实验所用HEK293Tmtkeima细胞是根据文献【Cen,X.et al.Nat Commun11,5731(2020).】中提到的方法，利用慢病毒包装技术，在HEK293T细胞中稳定表达mtkeima蛋白，得到的HEK293Tmtkeima细胞。实验中所用到的CCCP购买自陶术生物(货号T7081)。
测试例2、体外肝微粒稳定性测试
选用Ketanserin为参比化合物。具体方法如下：
配置0.1M K 3PO 4(pH为7.4)缓冲液及3×NADPH储存液(6mM，5mg/mL)，并在37℃水浴锅中预热；受试化合物及对照化合物spiking solution的配置：将5μL化合物储备液(10nM)加入到95μL乙腈中；1.5μM spiking solution in microsomes(0.75mg/mL)的配置：将1.5μL spiking solution和18.75μL肝微粒溶液(20mg/mL)加入到479.75μL K 3PO 4缓冲液中；取30μL spiking solution in microsomes加入到多孔板中，并在37℃条件下孵育5min；每孔加入15μL NADPH储存液开始反应，并计时；分别在0min、5min、15min、30min和45min加入150μL含IS的乙腈溶液，终止反应；振荡10min后6000rpm离心15min；每孔取80μL上清LC/MS检测，计算T1/2。测试结果如图3所示。
图3中显示了化合物在体外小鼠或人肝微粒体环境下的消除情况，用消除半衰期T1/2来衡量。UMI-77的体外肝微粒体稳定性实验表明UMI-77在肝微粒体环境下不稳定，会快速消除；化合物I-1和I-2则表现出优越的肝微粒体稳定性。
注：实验所用的小鼠和人肝微粒体购买自Xenotech。
测试例3、体外血浆稳定性测试
选用Procaine为参比化合物。具体方法如下：
取适量受试化合物及对照化合物的DMSO储备液溶于4mL血浆中，使其浓度为200μg/mL，DMSO含量不超过0.1％。水浴37℃孵育0、5、15和30分钟以及1、2、4、6、10、24和48小时，取200μL，加入3倍体积色谱级乙腈沉淀蛋白。漩涡震荡5min，离心后取上层清液200μL，HPLC进样分析，液相条件与之前相同。测试结果如图4所示。
图4中UMI-77半衰期很短，表明UMI-77在血浆环境下不稳定，会快速消除；而化合物I-1和I-2则表现出优越的血浆稳定性。
测试例4、小鼠或大鼠药物代谢动力学(PK)测试
取实验鼠，按照图示剂量和给药途径向其施加适量受试化合物。各化合物各给药方式均取三只实验鼠进行三次平行实验，编号101、102和103为同一组，201、202和203为一组，301、302和303为一组。
在相应的时间点取鼠血浆样品10μL至离心管，加入100μL的甲醇：乙腈(1：1，v/v)，进行1min伏安法，(14000rpm)5min离心，取上清液50μL，与水等体积混合，用伏安法均匀混合后进行分析。
小鼠药物代谢动力学测试结果见表2。
表2
Figure PCTCN2022119825-appb-000226
Figure PCTCN2022119825-appb-000227
大鼠药物代谢动力学测试结果(给药I-1)见表3。
Figure PCTCN2022119825-appb-000228
上表2中“NA”表示无法测算，“/”表示未测量该项。
测试结果表明UMI-77在小鼠PK实验中快速清除，很快便无法测得血药浓度；而化合物I-1，I-2则表现出良好的PK性质，I-1在大鼠PK实验中也表现出良好的PK性质。
注：PK实验所用的小鼠为ICR mice of SPF，采购自Sino-British SIPPR Lab Animal Ltd,Shanghai,China。PK实验所用的大鼠为SD rat of SPF，采购自Sino-British SIPPR Lab Animal Ltd,Shanghai,China。
本领域的普通技术人员可以理解，上述各实施方式是实现本发明的具体实施例，而在实际应用中，可以在形式上和细节上对其作各种改变，而不偏离本发明的精神和范围。

Claims (11)

  1. 一种具有通式(I)所示结构的化合物或其药学上可接受的盐、立体异构体、溶剂化物或前药，其特征在于，
    Figure PCTCN2022119825-appb-100001
    其中，Z为
    Figure PCTCN2022119825-appb-100002
    R 1为氢或C 1～6烷基；
    R 2为氢、C 1～6烷基、三至六元环烷基、三至六元环氧烷基、苯基或C 1～6烷基取代的苯基；
    R 3为
    Figure PCTCN2022119825-appb-100003
    其中，R 3-1为氢、羟基、C 1～6烷基、C 1～6烷氧基、三至六元环烷基、三至六元环氧烷基、氨基、C 1～6胺基、-CH 2C(O)R 3-2、-CH 2C(O)OR 3-2或-CH 2C(O)N(R 3-2R 3-2a)，
    R 3-2和R 3-2a分别独立地为氢、C 1～6烷基或三至六元环烷基，
    Ar为苯基、并苯基、5或6元单环杂芳基、8至10元稠合双环杂芳基、至少一个氢原子被R 3-3取代的苯基、至少一个氢原子被R 3-3取代的并苯基、至少一个氢原子被R 3-3取代的5或6元单环杂芳基或至少一个氢原子被R 3-3取代的8至10元稠合双环杂芳基，所述R 3-3为氢、卤素、C 1～6烷基、三至六元环烷基、羟基、C 1～6烷氧基、三至六元环氧烷基、C 1～6卤代烷基、C 2～6烯基、C 2～6炔基、-N(R 3-3aR 3-3b)或苯基，
    R 3-3a和R 3-3b分别独立地为氢、C 1～6烷基或三至六元环烷基；
    R 4为
    Figure PCTCN2022119825-appb-100004
    其中，R 4-1为苯基、并苯基、至少一个氢原子被R 4-11取代的苯基、5或6元单环杂芳基、至少一个氢原子被R 4-11取代的5或6元单环杂芳基、8至10元稠合双环杂芳基或至少一个氢原子被R 4-11取代的8至10元稠合双环杂芳基，所述R 4-11为氢、卤素、硝基、腈基、羟基、C 1～6烷基、三至六元环烷基、C 1～6烷氧基、-N(R 4-1aR 4-1b)、苯基、C 1～6卤代烷基、C 1～6卤代烷氧基、-C(O)OR 4-12、-C(O)R 4-12、-C(O)N(R 4-1aR 4-1b)、-S(O) 2R 4-12、-S(O)R 4-12、-OC(O)R 4-12、-OC(O)OR 4-12或
    Figure PCTCN2022119825-appb-100005
    R 4-12、R 4-1a和R 4-1b分别独立地为氢、C 1～6烷基、三至六元环烷基、C 2～6烯基、C 2～6炔基、至少一个氢被卤素取代的C 1～6烷基、至少一个氢被卤素取代的C 2～6烯基、至少一个氢被卤素取代的三至六元环烷基或至少一个氢被卤素取代的C 2～6炔基，且R 4-1a和R 4-1b可相互键合形成环，
    R 4-2为氢、C 1～6烷基或三至六元环烷基，或者当R 2为C 1～6烷基时，R 4-2与R 2键合形成4～8元环，
    R 4-3为氢、C 1～6烷基或C 1～6烷氧基；
    R 5的数量为0～5个，且R 5数量不为0时各自独立地选自卤素、硝基、腈基、-N +(R 5-1) 3、C 1～6卤代烷基、-C(O)OR 5-1、-C(O)R 5-1、-C(O)N(R 5-1R 5-1a)、-S(O) 2R 5-1、-S(O)R 5-1、-S(O) 2N(R 5-1R 5-1a)、-S(O)N(R 5-1R 5-1a)、-N＝C(R 5-1R 5-1a)、羟基、C 1～6烷基、苯基、至少一个氢被R 5-1取代的苯基、C 1～6烷氧基、-N(R 5-1R 5-1a)、-N(R 5-1)C(O)R 5-1a、-N(R 5-1)C(O)OR 5-1a、-N(R 5-1)C(O)N(R 5-1aR 5-1b)、-OC(O)R 5-1、-OC(O)OR 5-1、-OC(O)N(R 5-1R 5-1a)和-SR 5-1，其中，R 5-1、R 5-1a和R 5-1b分别独立地为氢、C 1～6烷基、C 2～6烯基、C 2～6炔基、至少一个氢被卤素取代的C 1～6烷基、至少一个氢被卤素取代的C 2～6烯基或至少一个氢被卤素取代的C 2～6炔基。
  2. 根据权利要求1所述的化合物或其药学上可接受的盐、立体异构体、 溶剂化物或前药，其特征在于，所述Z为
    Figure PCTCN2022119825-appb-100006
    Figure PCTCN2022119825-appb-100007
    R 1为氢或C 1～4烷基；
    R 2为氢、C 1～4烷基、三至六元环烷基或四至六元环氧烷基；
    R 3为
    Figure PCTCN2022119825-appb-100008
    其中，R 3-1为氢、羟基、C 1～4烷基、C 1～4烷氧基或-N(R 3-2R 3-2a)，
    R 3-2和R 3-2a分别独立地为氢或C 1～4烷基，
    Ar为苯基、5或6元单环杂芳基或至少一个氢原子被R 3-3取代的5或6元单环杂芳基，所述R 3-3为氢、卤素、C 1～4烷基、羟基、C 1～4烷氧基、C 1～4卤代烷基或-N(R 3-3aR 3-3b)，
    R 3-3a和R 3-3b分别独立地为氢或C 1～4烷基；
    R 4为
    Figure PCTCN2022119825-appb-100009
    其中，R 4-1为苯基、至少一个氢原子被R 4-11取代的苯基、5或6元单环杂芳基或至少一个氢原子被R 4-11取代的5或6元单环杂芳基，所述R 4-11为氢、卤素、硝基、C 1～4烷基、三至六元环烷基、C 1～4烷氧基、-N(R 4-1aR 4-1b)、苯基、C 1～4卤代烷基、C 1～4卤代烷氧基或
    Figure PCTCN2022119825-appb-100010
    R 4-1a和R 4-1b分别独立地为氢、C 1～4烷基或三至六元环烷基，且R 4-1a和R 4-1b可相互键合形成环，
    R 4-2为C 1～4烷基、三至六元环烷基，或者当R 2为C 1～4烷基时，R 4-2与R 2键合形成4～8元环，
    R 4-3为C 1～4烷基或C 1～4烷氧基；
    R 5数量不为0时各自独立地选自卤素、硝基、腈基、-N +(R 5-1) 3、C 1～4卤 代烷基、-C(O)OR 5-1、-C(O)R 5-1、-C(O)N(R 5-1R 5-1a)、-S(O) 2R 5-1、-S(O)R 5-1、-N＝C(R 5-1R 5-1a)、羟基、C 1～4烷基、苯基、至少一个氢被R 5-1取代的苯基、C 1～4烷氧基、-N(R 5-1R 5-1a)、-N(R 5-1)C(O)R 5-1a和-OC(O)R 5-1，其中，R 5-1、R 5-1a和R 5-1b分别独立地为氢、C 1～4烷基、至少一个氢被卤素取代的C 1～4烷基。
  3. 根据权利要求1所述的化合物或其药学上可接受的盐、立体异构体、溶剂化物或前药，其特征在于，所述Z为
    Figure PCTCN2022119825-appb-100011
    Figure PCTCN2022119825-appb-100012
    和/或，R 1为氢；
    和/或，R 2为氢、甲基、乙基、正丙基、异丙基、
    Figure PCTCN2022119825-appb-100013
    Figure PCTCN2022119825-appb-100014
    和/或，R 3为
    Figure PCTCN2022119825-appb-100015
    其中，R 3-1为氢、羟基、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、叔丁氧基、仲丁氧基或异丁氧基，
    Ar为苯基、5或6元含氮单环杂芳基；
    和/或，R 4为
    Figure PCTCN2022119825-appb-100016
    其中，R 4-1为苯基、至少一个氢原子被R 4-11取代的苯基、5或6元单环杂芳基、至少一个氢原子被R 4-11取代的5或6元单环杂芳基、8至10元稠合双环杂芳基或至少一个氢原子被R 4-11取代的8至10元稠合双环杂芳基， 所述R 4-11为氢、卤素、硝基、甲基、乙基、正丙基、异丙基、
    Figure PCTCN2022119825-appb-100017
    Figure PCTCN2022119825-appb-100018
    Figure PCTCN2022119825-appb-100019
    氟代甲基、氟代乙基、氟代正丙基、氟代异丙基、氯代甲基、氯代乙基、氯代正丙基、氯代异丙基、溴代甲基、溴代乙基、溴代正丙基、溴代异丙基、碘代甲基、碘代乙基、碘代正丙基、碘代异丙基、氟代甲氧基、氟代乙氧基、氟代正丙氧基、氟代异丙氧基、氯代甲氧基、氯代乙氧基、氯代正丙氧基、氯代异丙氧基、溴代甲氧基、溴代乙氧基、溴代正丙氧基、溴代异丙氧基、碘代氧甲基、碘代乙氧基、碘代正丙氧基、碘代异丙氧基或
    Figure PCTCN2022119825-appb-100020
    R 4-2为甲基、乙基、正丙基或异丙基，或者，当R 2为甲基、乙基或正丙基时，R 4-2与R 2键合形成4～8元环，
    R 4-3为甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基或异丙氧基；
    和/或，R 5数量不为0时各自独立地选自卤素、硝基、腈基、-N +(R 5-1) 3、氟代甲基、氟代乙基、氟代正丙基、氟代异丙基、氯代甲基、氯代乙基、氯代正丙基、氯代异丙基、溴代甲基、溴代乙基、溴代正丙基、溴代异丙基、-C(O)OR 5-1、-C(O)R 5-1、-C(O)N(R 5-1R 5-1a)、
    -S(O) 2R 5-1、-S(O)R 5-1、-N＝C(R 5-1R 5-1a)、羟基、甲基、乙基、正丙基、异丙基、苯基、至少一个氢被R 5-1取代的苯基、甲氧基、乙氧基、正丙氧基、异丙氧基、-N(R 5-1R 5-1a)、-N(R 5-1)C(O)R 5-1a和-OC(O)R 5-1，其中，R 5-1、R 5-1a和R 5-1b分别独立地为氢、甲基、乙基、正丙基、异丙基、氟代甲基、氟代乙 基、氟代正丙基、氟代异丙基、氯代甲基、氯代乙基、氯代正丙基、氯代异丙基、溴代甲基、溴代乙基、溴代正丙基或溴代异丙基。
  4. 根据权利要求1～3中任一项所述的化合物或其药学上可接受的盐、立体异构体、溶剂化物或前药，其特征在于，所述Z为
    Figure PCTCN2022119825-appb-100021
  5. 根据权利要求1或2所述的化合物或其药学上可接受的盐、立体异构体、溶剂化物或前药，其特征在于，所述化合物具有式(II)所示的结构；
    Figure PCTCN2022119825-appb-100022
    式中，R 2为氢、C 1～4烷基、三至六元环烷基或四至六元环氧烷基；
    R 3为
    Figure PCTCN2022119825-appb-100023
    其中，R 3-1为氢、羟基、C 1～4烷基、C 1～4烷氧基、三至六元环烷基、三至六元环氧烷基、
    -N(R 3-2R 3-2a)、-CH 2C(O)R 3-2、-CH 2C(O)OR 3-2或-CH 2C(O)NR 3-2R 3-2a，
    R 3-2和R 3-2a分别独立地为氢、C 1～4烷基或三至六元环烷基，
    Ar为苯基、5或6元单环杂芳基或至少一个氢原子被R 3-3取代的5或6元单环杂芳基，所述R 3-3为氢、卤素、C 1～4烷基、三至六元环烷基、羟基、C 1～4烷氧基、三至六元环氧烷基、C 1～4卤代烷基、C 2～4烯基、C 2～4炔基、-N(R 3-3aR 3-3b)或苯基，
    R 3-3a和R 3-3b分别独立地为氢、C 1～4烷基或三至六元环烷基；
    R 4为
    Figure PCTCN2022119825-appb-100024
    其中，R 4-1为苯基、至少一个氢原子被R 4-11取代的苯基、5或6元单环杂芳基、至少一个氢原子被R 4-11取代的5或6元单环杂芳基、8至10元稠合双环杂芳基或至少一个氢原子被R 4-11取代的8至10元稠合双环杂芳基，所述R 4-11为氢、卤素、硝基、C 1～4烷基、三至六元环烷基、C 1～4烷氧基、-N(R 4-1aR 4-1b)、苯基、C 1～4卤代烷基、C 1～4卤代烷氧基或
    Figure PCTCN2022119825-appb-100025
    R 4-1a和R 4-1b分别独立地为氢、C 1～4烷基或三至六元环烷基，且R 4-1a和R 4-1b可相互键合形成环，
    R 4-2为C 1～4烷基、三至六元环烷基，或者当R 2为C 1～4烷基时，R 4-2与R 2键合形成4～8元环，
    R 4-3为C 1～4烷基或C 1～4烷氧基；
    R 5数量不为0时各自独立地选自卤素、硝基、腈基、-N +(R 5-1) 3、C 1～4卤代烷基、
    -C(O)OR 5-1、-C(O)R 5-1、-C(O)N(R 5-1R 5-1a)、-S(O) 2R 5-1、-S(O)R 5-1、-N＝C(R 5-1R 5-1a)、羟基、C 1～4烷基、苯基、至少一个氢被R 5-1取代的苯基、C 1～4烷氧基、-N(R 5-1R 5-1a)、-N(R 5-1)C(O)R 5-1a、-OC(O)R 5-1、-OC(O)N(R 5-1R 5-1a)和-SR 5-1，其中，R 5-1、R 5-1a和R 5-1b分别独立地为氢、C 1～4烷基、C 2～4烯基、C 2～4炔基、至少一个氢被卤素取代的C 1～4烷基、至少一个氢被卤素取代的C 2～4烯基或至少一个氢被卤素取代的C 2～4炔基。
  6. 根据权利要求5所述的化合物或其药学上可接受的盐、立体异构体、溶剂化物或前药，其特征在于，R 5数量不为0时各自独立地选自卤素、硝基、腈基、-N +(R 5-1) 3、C 1～4卤代烷基、-C(O)OR 5-1、-C(O)R 5-1、-C(O)N(R 5-1R 5-1a)、-S(O) 2R 5-1、-S(O)R 5-1和-N＝C(R 5-1R 5-1a)；
    其中，R 5-1和R 5-1a分别独立地为氢、C 1～4烷基、C 2～4烯基、C 2～4炔基、至少一个氢被卤素取代的C 1～4烷基、至少一个氢被卤素取代的C 2～4烯基或至少一个氢被卤素取代的C 2～4炔基。
  7. 根据权利要求1所述的化合物或其药学上可接受的盐、立体异构体、溶剂化物或前药，其特征在于，所述化合物具有式(III)所示的结构；
    Figure PCTCN2022119825-appb-100026
    式中，R 2为氢、C 1～4烷基、三至六元环烷基或四至六元环氧烷基；
    R 3为
    Figure PCTCN2022119825-appb-100027
    其中，R 3-1为氢、羟基、C 1～4烷基、C 1～4烷氧基、三至六元环烷基、三至六元环氧烷基、
    -N(R 3-2R 3-2a)、-CH 2C(O)R 3-2、-CH 2C(O)OR 3-2或-CH 2C(O)NR 3-2R 3-2a，
    R 3-2和R 3-2a分别独立地为氢、C 1～4烷基或三至六元环烷基，
    Ar为苯基、5或6元单环杂芳基或至少一个氢原子被R 3-3取代的5或6元单环杂芳基，所述R 3-3为氢、卤素、C 1～4烷基、三至六元环烷基、羟基、C 1～4烷氧基、三至六元环氧烷基、C 1～4卤代烷基、C 2～4烯基、C 2～4炔基、-N(R 3-3aR 3-3b)或苯基，
    R 3-3a和R 3-3b分别独立地为氢、C 1～4烷基或三至六元环烷基；
    R 4为
    Figure PCTCN2022119825-appb-100028
    其中，R 4-1为苯基、至少一个氢原子被R 4-11取代的苯基、5或6元单环杂芳基、至少一个氢原子被R 4-11取代的5或6元单环杂芳基、8至10元稠合双环杂芳基或至少一个氢原子被R 4-11取代的8至10元稠合双环杂芳基，所述R 4-11为氢、卤素、硝基、C 1～4烷基、三至六元环烷基、C 1～4烷氧基、 -N(R 4-1aR 4-1b)、苯基、C 1～4卤代烷基、C 1～4卤代烷氧基或
    Figure PCTCN2022119825-appb-100029
    R 4-1a和R 4-1b分别独立地为氢、C 1～4烷基或三至六元环烷基，且R 4-1a和R 4-1b可相互键合形成环，
    R 4-2为C 1～4烷基或三至六元环烷基，或者当R 2为C 1～4烷基时，R 4-2与R 2键合形成4～8元环，
    R 4-3为C 1～4烷基或C 1～4烷氧基；
    R 5数量不为0时各自独立地选自卤素、硝基、腈基、-N +(R 5-1) 3、C 1～4卤代烷基、
    -C(O)OR 5-1、-C(O)R 5-1、-C(O)N(R 5-1R 5-1a)、-S(O) 2R 5-1、-S(O)R 5-1、-N＝C(R 5-1R 5-1a)、羟基、C 1～4烷基、苯基、至少一个氢被R 5-1取代的苯基、C 1～4烷氧基、-N(R 5-1R 5-1a)、-N(R 5-1)C(O)R 5-1a、-OC(O)R 5-1、-OC(O)N(R 5-1R 5-1a)或-SR 5-1，其中，R 5-1、R 5-1a和R 5-1b分别独立地为氢、C 1～4烷基、C 2～4烯基、C 2～4炔基、至少一个氢被卤素取代的C 1～4烷基、至少一个氢被卤素取代的C 2～4烯基和至少一个氢被卤素取代的C 2～4炔基。
  8. 根据权利要求7所述的化合物或其药学上可接受的盐、立体异构体、溶剂化物或前药，其特征在于，R 5数量不为0时各自独立地选自羟基、C 1～4烷基、苯基、至少一个氢被R 5-1取代的苯基、C 1～4烷氧基、-N(R 5-1R 5-1a)、-N(R 5-1)C(O)R 5-1a、-OC(O)R 5-1、-OC(O)N(R 5-1R 5-1a)或-SR 5-1，其中，R 5-1、R 5-1a和R 5-1b分别独立地为氢、C 1～4烷基、C 2～4烯基、C 2～4炔基、至少一个氢被卤素取代的C 1～4烷基、至少一个氢被卤素取代的C 2～4烯基和至少一个氢被卤素取代的C 2～4炔基。
  9. 根据权利要求1～3中任一项所述的化合物或其药学上可接受的盐、立体异构体、溶剂化物或前药，其特征在于，所述化合物选自下述化合物中的任一种：
    Figure PCTCN2022119825-appb-100030
    Figure PCTCN2022119825-appb-100031
    Figure PCTCN2022119825-appb-100032
    Figure PCTCN2022119825-appb-100033
    Figure PCTCN2022119825-appb-100034
    Figure PCTCN2022119825-appb-100035
    Figure PCTCN2022119825-appb-100036
    Figure PCTCN2022119825-appb-100037
    Figure PCTCN2022119825-appb-100038
    Figure PCTCN2022119825-appb-100039
    Figure PCTCN2022119825-appb-100040
    Figure PCTCN2022119825-appb-100041
  10. 一种药物组合物，其特征在于，所述药物组合物包括权利要求1～9中任一项所述的化合物，或者其药学上可接受的盐、立体异构体、溶剂化物或前药。
  11. 权利要求1～9中任一项所述的化合物，或其药学上可接受的盐、立体异构体、溶剂化物或前药，或权利要求10所述的药物组合物在制备线粒体自噬诱导剂中的用途。
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