Prodrug of small molecule compound with naphthylamine structure and application of prodrug

Abstract

The invention discloses a prodrug of a small molecule compound with a naphthylamine structure and application of the prodrug. In the application, the prodrug is as shown in the following formula I, and each R group is as shown in the upper and lower positions of the invention. The prodrug of the small molecule compound with the naphthylamine structure is good in stability and permeability and high in oral bioavailability, and compared with an original drug compound I-1, after the prodrug is administered, the plasma exposure amount is increased, or the retention time is long, the AUC is high, the safety is good, the adverse reaction is few, and the patent medicine prospect is good. # imgabs0 #

Description

[0001] Cross-reference declaration

[0002] This application claims the priority of a Chinese application with an application date of May 6, 2024 and an application number of 2024105516481, and incorporates its content herein by reference in its entirety.

[0003] This application claims the priority of a Chinese application with an application date of January 8, 2025 and an application number of 2025100325459, and incorporates its content herein by reference in its entirety. Technical Field

[0004] The present invention relates to the field of biomedicine, and particularly to prodrugs of small molecule compounds with a naphthylamine structure and their uses. Background Art

[0005] As a type of organelle-specific autophagy, mitophagy mainly aims to identify and eliminate dysfunctional mitochondria. Since mitochondria play a central role in energy supply through oxidative phosphorylation, and also have some important functions including energy metabolism, amino acid production, lipid synthesis, and ion homeostasis, it is of great significance for maintaining the functions of cell types dependent on aerobic metabolism such as neuronal cells, muscle cells, and liver cells. The homeostatic regulation of mitochondrial biogenesis and autophagy is an important link in maintaining cell function. Dysfunction of mitophagy will lead to the accumulation of damaged mitochondria, a decrease in ATP+ synthesis ability, and the production of a large amount of peroxides, thereby causing changes in cellular intermediate metabolites and triggering a series of pathological consequences. By enhancing mitophagy to clear senescent or dysfunctional mitochondria, mitophagy will play a protective role for cells.

[0006] With the continuous development of the drug research and development field, the oral bioavailability of drug molecules has become an important indicator for measuring drug efficacy and practicality. However, due to the limitations of their physicochemical properties, such as low solubility, poor stability, and easy degradation in the gastrointestinal environment, many prototype drugs have poor oral bioavailability, thus affecting their therapeutic effects. In order to improve the oral bioavailability of drugs, people have continuously explored new drug delivery strategies and molecular modification techniques.

[0007] The present inventors previously developed a class of small molecule compounds with a naphthylamine structure as mitophagy inducers, which were disclosed in a Chinese patent with the application number 202111108417.6. However, further research by the present inventors found that the pharmacokinetic data of these compounds showed that the oral bioavailability in mice and rats was only about 10%, the Caco2 cell permeability of the representative example compound I-1 was extremely low, and it was a potential substrate of the efflux transporters Pgp and BCRP, with limited drug-likeness. The prodrug strategy is an important means in the field of drug research and development to improve the physicochemical properties and pharmacokinetic characteristics of drugs. Therefore, there is an urgent need to specifically develop prodrugs of small molecule compounds with a naphthylamine structure to improve their stability, permeability, and oral bioavailability. Summary of the Invention

[0008] An object of the present invention is to provide a prodrug of a small molecule compound with a naphthylamine structure.

[0009] Another object of the present invention is to provide a pharmaceutical composition containing the prodrug of the small molecule compound with a naphthylamine structure.

[0010] Another object of the present invention is to provide the use of the prodrug of the small molecule compound with a naphthylamine structure.

[0011] To solve the above technical problems, in the first aspect of the present invention, there is provided a compound of general formula I and its deuterated compounds,

[0012]

[0013] wherein, R 1 is a hydroxyl group, R 11 , R 12 , R 13 , R 14 and R 15 are each independently selected from C 1-6 alkyl, C 3-10 cycloalkyl, C 1-6 alkyl substituted with an amino group, C 3-6 alkyl substituted with C 1-6 cycloalkyl, C 3-10 cycloalkyl substituted with an amino group, C 1-6 alkyl substituted with C 3-10 cycloalkyl;

[0014] R 2 is hydrogen, R 21 is C 1-6 alkyl, C 1-4 alkyl substituted with C 1-6 alkoxy, -N(Ra R b ); wherein, R a and R b are each independently methyl, ethyl, n-propyl, isopropyl, or R a and R b are bonded to form a ring; R 22 is a C 1-6 alkyl group;

[0015] R 3 is hydrogen, wherein, R 31 is selected from C 1-6 alkyl, C 3-6 cycloalkyl, phenyl, pyridyl, C 1-6 alkyl-substituted pyridyl; R 31 , R 32 , R 33 and R 34 are each independently selected from C 1-6 alkyl, C 3-10 cycloalkyl, C 1-6 alkyl-substituted C 3-10 cycloalkyl.

[0016] In some embodiments, R 1 is hydroxyl, R 11 , R 12 , R 13 , R 14 and R 15 are each independently selected from C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkyl substituted with an amino group, C 3-6 alkyl substituted with C 1-6 cycloalkyl;

[0017] R 2 is hydrogen, R 21 is C 1-6 alkyl, C 1-4 alkyl substituted with a C 1-6 alkoxy group, -N(R a R b ); wherein, R a and R b are each independently methyl, ethyl, n-propyl, isopropyl, or R a and R b are bonded to form a ring; R 22 is C 1-6 alkyl;

[0018] R3 is hydrogen, wherein R 31 is selected from C 1-6 alkyl, C 3-6 cycloalkyl, phenyl, pyridyl, C 1-6 alkyl-substituted pyridyl; R 31 , R 32 , R 33 and R 34 are each independently selected from C 1-6 alkyl, C 3-6 cycloalkyl.

[0019] Preferably, the compound of formula I is not the following compound I-1.

[0020]

[0021] In some preferred embodiments, R 11 is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-hexyl, n-pentyl, isopentyl, neopentyl, 2-methylpentyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3-methylpentyl, 2-ethylbutyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; more preferably methyl, ethyl, n-propyl, isopropyl, tert-butyl or cyclopropyl.

[0022] In some preferred embodiments, R 12 is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-hexyl, n-pentyl, isopentyl, neopentyl, 2-methylpentyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3-methylpentyl, 2-ethylbutyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; more preferably methyl, ethyl, n-propyl, isopropyl, tert-butyl or cyclopropyl.

[0023] In some preferred embodiments, R 13 is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-hexyl, n-pentyl, isopentyl, neopentyl, 2-methylpentyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3-methylpentyl 2-ethylbutyl; more preferably methyl, ethyl, n-propyl or isopropyl.

[0024] In some preferred embodiments, R 14 is tert-butyl, isopentyl, neopentyl or amino-substituted isopentyl.

[0025] In some preferred embodiments, R 15is methyl, isopropyl, tert-butyl, 2-ethylbutyl, cyclohexyl, bicyclo[2,2,1]heptyl (norbornanyl), 7,7-dimethylbicyclo[2.2.1]heptyl.

[0026] In some preferred embodiments, R 15 is 2-ethylbutyl.

[0027] In some preferred embodiments, is

[0028] In some preferred embodiments, is

[0029] In some preferred embodiments, is

[0030] In some preferred embodiments, is

[0031] In some preferred embodiments, is

[0032] In some preferred embodiments, is

[0033] In some preferred embodiments, R 15 is methyl, ethyl, n-butyl, isobutyl or tert-butyl.

[0034] In some preferred embodiments, R 1 is methoxy, ethoxy, isopropoxy, tert-butoxy,

[0035] In some preferred embodiments, R 1 is methoxy, ethoxy, isopropoxy, tert-butoxy,

[0036] In some most preferred embodiments, R 1 is hydroxy,

[0037] In some preferred embodiments, R 21 is C 1-4 alkyl, dimethylamino, diethylamino, N-methylethylamino or More preferably, it is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, dimethylamino, diethylamino or

[0038] In some preferred embodiments, R 22 is C 1-4 alkyl, more preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl.

[0039] In some preferred embodiments, is

[0040] In some preferred embodiments, is

[0041] In some preferred embodiments, R 2 is hydrogen,

[0042] In some preferred embodiments, R 31 is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, tert-pentyl, neopentyl, n-hexyl, pyridinyl in which the hydrogen atom on nitrogen is substituted by alkyl, cyclopropyl, cyclobutyl or phenyl.

[0043] In some preferred embodiments, R 32 is methyl, ethyl, n-propyl, isopropyl, n-pentyl, isopentyl, tert-pentyl, neopentyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, cyclopropyl substituted by one or more C 1-6 alkyl, cyclobutyl substituted by one or more C 1-6 alkyl, cyclopentyl substituted by one or more C 1-6 alkyl, cyclohexyl substituted by one or more C 1-6 alkyl.

[0044] In some preferred embodiments, R 32 is methyl, ethyl, n-propyl, isopropyl, n-pentyl, isopentyl, tert-pentyl, neopentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[2.2.1]heptyl (norbornanyl), 7,7-dimethylbicyclo[2.2.1]heptyl.

[0045] In some preferred embodiments, R 32 is methyl, ethyl, n-propyl, isopropyl, n-pentyl, isopentyl, tert-pentyl, neopentyl, cyclopropyl or cyclobutyl.

[0046] In some preferred embodiments, R 33is methyl, ethyl, n-propyl or isopropyl.

[0047] In some preferred embodiments, R 34 is methyl, ethyl, n-propyl or isopropyl.

[0048] In some preferred embodiments, is

[0049] In some preferred embodiments, is

[0050]

[0051] In some preferred embodiments, is In some preferred embodiments, is In some preferred embodiments, is In some preferred embodiments, R 3 is hydrogen,

[0052] In some preferred embodiments, R 3 is hydrogen,

[0053] In some preferred embodiments, at least one hydrogen of the compound of general formula I is replaced by deuterium to form a deuterated compound.

[0054] In some preferred embodiments, in the compound of general formula I, at least one hydrogen on at least one ring of the naphthylamine bicyclic ring is replaced by deuterium to form a deuterated compound.

[0055] In some preferred embodiments, in the compound of general formula I, at least one hydrogen on at least one aromatic ring is replaced by deuterium to form a deuterated compound.

[0056] In some preferred embodiments, the deuterated compound of general formula I is shown as the following general formula II (wherein, D is deuterium).

[0057]

[0058] In some preferred embodiments, the compound is selected from any one of the following:

[0059]

[0060]

[0061]

[0062]

[0063]

[0064]

[0065]

[0066]

[0067]

[0068] In a second aspect of the present invention, there is provided a pharmaceutical composition comprising the compound according to the first aspect of the present invention and a pharmaceutically acceptable carrier or excipient.

[0069] In a third aspect of the present invention, there is provided the use of the compound according to the first aspect of the present invention or the pharmaceutical composition according to the second aspect of the present invention for:

[0070] (i) non-therapeutically inducing mitophagy in vitro;

[0071] (ii) preventing and / or treating diseases related to mitophagy; and / or

[0072] (iii) preparing a medicament for preventing and / or treating diseases related to mitophagy.

[0073] Compared with the prior art, the present invention has at least the following advantages:

[0074] By reasonably selecting and introducing prodrug groups or isotope substitutions (especially deuteration), the physicochemical properties of the prototype drug are adjusted, thereby changing the pharmacokinetic characteristics, improving its oral bioavailability, and enhancing stability, safety and therapeutic effect. The prodrugs provided by the present invention have good stability and permeability, high oral bioavailability. Compared with the original drug compound I-1, the plasma exposure after prodrug administration is increased, or the residence time is long and the AUC is high, with good safety and few adverse reactions, and good prospects for drug development.

[0075] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described below (such as in the examples) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be elaborated one by one here. Detailed Embodiments

[0076] After extensive and in-depth research, the present inventor has developed a series of prodrugs with better stability, permeability or oral bioavailability than the small molecule compounds with a naphthylamine structure developed previously. These prodrugs can be used as mitophagy inducers to treat related diseases and have broad prospects for drug development. Based on this, the present invention has been completed.

[0077] Compound

[0078] Embodiments of the present invention relate to a compound of general formula I and its deuterated compounds,

[0079]

[0080] wherein, R 1 is hydroxyl, R 11 , R 12 , R 13 , R 14 and R 15 are each independently selected from C 1-6 alkyl, C 3-10 cycloalkyl, C 1-6 alkyl substituted with an amino group, C 3-6 cycloalkyl substituted C 1-6 alkyl, C 3-10 cycloalkyl substituted with an amino group, C 1-6 alkyl substituted C 3-10 cycloalkyl;

[0081] R 2 is hydrogen, R 21 is C 1-6 alkyl, C 1-4 alkoxy substituted C 1-6 alkyl, -N(R a R b ); wherein, R a and R b are each independently methyl, ethyl, n-propyl, isopropyl, or R a and R b bond to form a ring; R 22 is C 1-6 alkyl;

[0082] R 3 is hydrogen, wherein, R 31 is selected from C 1-6 alkyl, C 3-10 cycloalkyl, phenyl, pyridyl, C 1-6 alkyl substituted pyridyl; R 31 , R 32 , R 33, R 34 are each independently selected from C 1-6 alkyl, C 3-10 cycloalkyl, C 1-6 alkyl-substituted C 3-10 cycloalkyl;

[0083] Moreover, the compound of formula I is not of the following formula I-1.

[0084]

[0085] In some embodiments, R 1 is hydroxyl, R 11 , R 12 , R 13 , R 14 and R 15 are each independently selected from C 1-6 alkyl, C 3-6 cycloalkyl, amino-substituted C 1-6 alkyl, C 3-6 cycloalkyl-substituted C 1-6 alkyl.

[0086] In some embodiments, R 3 is hydrogen, wherein, R 31 is selected from C 1-6 alkyl, C 3-6 cycloalkyl, phenyl, pyridyl, C 1-6 alkyl-substituted pyridyl; R 31 , R 32 , R 33 , R 34 are each independently selected from C 1-6 alkyl, C 3-6 cycloalkyl.

[0087] In some preferred embodiments, the pyridyl is

[0088] In some preferred embodiments, the C 1-6 alkyl-substituted pyridyl is a pyridyl in which the hydrogen atom on the nitrogen is substituted by an alkyl group.

[0089] In some preferred embodiments, the C 1-6 alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-hexyl, n-pentyl, isopentyl, neopentyl, 2-methylpentyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3-methylpentyl or 2-ethylbutyl.

[0090] In some preferred embodiments, the C 3-10The cycloalkyl group is preferably C 3-6 cycloalkyl group, such as cyclopropyl group, cyclobutyl group, cyclopentyl group or cyclohexyl group.

[0091] In some preferred embodiments, C 3-6 the cycloalkyl group is cyclopropyl group, cyclobutyl group, cyclopentyl group or cyclohexyl group.

[0092] In some preferred embodiments, C 1-4 the alkoxy group is methoxy group, ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group, isobutoxy group or tert-butoxy group.

[0093] In some preferred embodiments, the C 1-6 alkyl group-substituted C 3-10 cycloalkyl group is methyl-substituted cyclohexane, methyl-substituted bicyclo[2,2,1]heptyl group (norbornanyl group), for example:

[0094] As R 1 In a more preferred embodiment of the present invention, R 1 is R 11 、R 12 and R 13 are respectively as shown in the context of the present invention.

[0095] Compared with the sodium salt of the original drug compound I-1, R 1 is helpful for simultaneously increasing the drug plasma exposure AUC and Cmax, wherein R 11 is preferably a straight-chain or branched-chain alkyl group of C 1-6 , such as methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, tert-butyl group, n-hexyl group, n-pentyl group, isopentyl group, neopentyl group, 2-methylpentyl group, 2,2-dimethylbutyl group, 2,3-dimethylbutyl group, 3-methylpentyl group, 2-ethylbutyl group; or R 11 is a cycloalkyl group of C 3-6 , such as cyclopropyl group, cyclobutyl group, cyclopentyl group or cyclohexyl group. R 11 is more preferably methyl group, ethyl group, n-propyl group, isopropyl group, tert-butyl group or cyclopropyl group. In a more preferred embodiment of the present invention, is

[0096] 1 is helpful for simultaneously increasing the drug plasma exposure Cmax and AUC, helpful for increasing the in vivo absorption rate and degree, wherein, R 12 is preferably a C 1-6The straight-chain or branched-chain alkyl group is, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-hexyl, n-pentyl, isopentyl, neopentyl, 2-methylpentyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3-methylpentyl, 2-ethylbutyl; or R 12 is C 3-6 cycloalkyl group, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. R 11 is more preferably methyl, ethyl, n-propyl, isopropyl, tert-butyl or cyclopropyl. In a more preferred embodiment of the present invention, is

[0097] Compared with the sodium salt of the original drug compound I-1, R 1 is which helps to increase the plasma exposure and AUC value of the drug, wherein R 13 is preferably a straight-chain or branched-chain alkyl group of C 1-6 , such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-hexyl, n-pentyl, isopentyl, neopentyl, 2-methylpentyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3-methylpentyl, 2-ethylbutyl. R 13 is more preferably methyl, ethyl, n-propyl or isopropyl. In a more preferred embodiment of the present invention, is R 1 is When the compound has a plasma exposure not inferior to that of the sodium salt of the original drug compound I-1, wherein R 14 is preferably tert-butyl, isopentyl, neopentyl or amino-substituted isopentyl. In a more preferred embodiment of the present invention, is In a preferred embodiment of the present invention, is In a preferred embodiment of the present invention, is

[0098] R 1 is and when R 15 is methyl, isobutyl, tert-butyl or 2-ethylbutyl, the compound has a plasma exposure not inferior to that of the sodium salt of the original drug compound I-1, but when R 15 is isopropyl, the plasma exposure of the compound becomes worse. In a more preferred embodiment of the present invention, R 15 is methyl, ethyl, n-butyl, isobutyl or tert-butyl.

[0099] In a more preferred embodiment of the present invention, R 1 is selected from any one of the following: methoxy, ethoxy, isopropoxy, tert-butoxy,

[0100] In the most preferred embodiment of the present invention, R 1 is hydroxyl, When R 1 is hydroxyl, at least one of R 2 and R 3 is different from the original drug compound I-1, that is, R 2 and R 3 are not both hydrogen.

[0101] As R 2 , in a more preferred embodiment of the present invention, R 2 is Compared with the sodium salt of the original drug compound I-1, R 2 is which helps to increase the plasma exposure AUC value. R 21 is C 1-4 alkyl, dimethylamino, diethylamino, N-methylethylamino or more preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, dimethylamino, diethylamino or R 22 is C 1-4 alkyl, more preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl. In a preferred embodiment of the present invention, is In a preferred embodiment of the present invention, is

[0102] In a preferred embodiment of the present invention, R 2 is hydrogen, When R 2 is hydrogen, at least one of R 1 and R 3 is different from the original drug compound I-1, that is, R 1 is not hydroxyl and / or R 3 is not hydrogen.

[0103] As R 3 , in a more preferred embodiment of the present invention, R 3 is

[0104] Compared with the sodium salt of the original drug compound I-1, R 3 is helpful for improving oral bioavailability, reducing the peak blood drug concentration and / or prolonging the residence time of the drug in the body, which is beneficial for the development of low-toxic sustained-release drugs. Among them, R 31 is preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, tert-pentyl, neopentyl, n-hexyl, pyridyl with the hydrogen atom on the nitrogen substituted by an alkyl group, cyclopropyl, cyclobutyl or phenyl. In a preferred embodiment of the present invention, is

[0105] Compared with the sodium salt of the original drug compound I-1, R 3 is helpful for improving oral bioavailability, reducing the peak blood drug concentration and / or prolonging the residence time of the drug in the body, which is beneficial for the development of low-toxic sustained-release drugs. Among them, R 32 is preferably methyl, ethyl, n-propyl, isopropyl, n-pentyl, isopentyl, tert-pentyl, neopentyl, cyclopropyl or cyclobutyl. In a preferred embodiment of the present invention, is

[0106] In a preferred embodiment of the present invention, R 3 is hydrogen,

[0107] Compared with the sodium salt of the original drug compound I-1, R 3 is also beneficial to the peak blood drug concentration C max and AUC of the compound. Among them, R 33 and R 34 are each independently preferably methyl, ethyl, n-propyl or isopropyl. In a preferred embodiment of the present invention, is In a preferred embodiment of the present invention, is

[0108] In the most preferred embodiment of the present invention, R 3 is hydrogen,

[0109] When R 3 is hydrogen, at least one of R 1 and R 2 is different from that of the original drug compound I-1, that is, R 1is not a hydroxyl group and / or R 2 is not hydrogen.

[0110] In a preferred embodiment of the present invention, R 1 is or R 3 is (For example, prodrugs 56, 57, 58) On the one hand, it increases the permeability of the parent drug, improves its oral bioavailability and plasma exposure, and at the same time, the borneol released in vivo from the prodrug plays a synergistic role in the pharmacological effect of the parent drug, significantly enhancing the drug efficacy.

[0111] In a preferred embodiment of the present invention, at least one hydrogen of the compound of formula I is replaced by deuterium to form a deuterated compound, and the deuterated compound has an increased plasma exposure compared to the original drug compound I-1. In a preferred embodiment of the present invention, in the compound of formula I, the hydrogen at the Rc and / or Rd positions is replaced by deuterium to form a deuterated compound, which can reduce or slow down the metabolism or elimination process of the original drug compound I-1, thereby achieving the effect of increasing the exposure.

[0112]

[0113] In a preferred embodiment of the present invention, the compound is selected from any one of the following:

[0114]

[0115]

[0116]

[0117]

[0118]

[0119]

[0120]

[0121]

[0122]

[0123] In a preferred embodiment of the present invention, there are provided the compound of formula I and its deuterated compound,

[0124]

[0125] wherein, R 1 is a hydroxyl group, R 11 and R 12 are each independently C1-6 alkyl or C 3-6 cycloalkyl;

[0126] R 2 is hydrogen, R 21 is C 1-6 alkyl or -N(R a R b ); wherein, R a and R b are each independently methyl or ethyl;

[0127] R 3 is hydrogen, wherein, R 31 is C 1-6 alkyl or C 3-6 cycloalkyl; R 32 and R 32 are each independently C 1-6 alkyl;

[0128] and the compound of general formula I is not compound I-1.

[0129] In a more preferred embodiment of the present invention, R 1 is hydroxyl, most preferably hydroxyl,

[0130] In a preferred embodiment of the present invention, R 2 is hydrogen, most preferably

[0131] In a preferred embodiment of the present invention, R 3 is hydrogen, most preferably

[0132] In a preferred embodiment of the present invention, the compound is selected from any one of the following:

[0133]

[0134]

[0135]

[0136] In a preferred embodiment of the present invention, the deuterated form of the compound of general formula I is shown as general formula II below (wherein, D is deuterium).

[0137]

[0138] Drug composition

[0139] Embodiments of the present invention also relate to a drug composition comprising a compound of general formula I or its deuterated form and a pharmaceutically acceptable excipient.

[0140] Use

[0141] Embodiments of the present invention also relate to the use of a compound of general formula I, its deuterated form or a drug composition containing the same for:

[0142] (i) non - therapeutically inducing mitophagy in vitro;

[0143] (ii) preventing and / or treating diseases related to mitophagy; and / or

[0144] (iii) preparing a drug for preventing and / or treating diseases related to mitophagy.

[0145] Treatment method

[0146] Embodiments of the present invention also relate to a method for preventing and / or treating diseases related to mitophagy, comprising the step of administering to a subject a therapeutically effective amount of a compound of general formula I or its deuterated form, or a drug composition containing the same.

[0147] In a preferred embodiment, the administration is by oral, intravenous or intramuscular injection.

[0148] As used herein, the term "alkyl" refers to a straight - chain or branched - chain saturated aliphatic hydrocarbon group. The term "C 1-6 alkyl" refers to a straight - chain or branched - chain alkyl having 1 to 6 carbon atoms, non - restrictively for example: methyl, ethyl, n - propyl, isopropyl, n - butyl, isobutyl, tert - butyl, sec - butyl, n - pentyl, 1,1 - dimethylpropyl, 1,2 - dimethylpropyl, 2,2 - dimethylpropyl, 1 - ethylpropyl, 2 - methylbutyl, 3 - methylbutyl, n - hexyl, 1 - ethyl - 2 - methylpropyl, 1,1,2 - trimethylpropyl, 1,1 - dimethylbutyl, 1,2 - dimethylbutyl, 2,2 - dimethylbutyl, 1,3 - dimethylbutyl, 2 - ethylbutyl, 2 - methylpentyl, 3 - methylpentyl, 4 - methylpentyl, 2,3 - dimethylbutyl, and its various branched isomers, etc. The term "C 1-4 alkyl" refers to a straight - chain or branched - chain alkyl having 1 to 4 carbon atoms, C 1-4If the alkyl group appears at the end of the molecule, non-limiting examples include: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, or, when two parts of the molecule are connected through the alkyl group, non-limiting examples include: -CH2-, -CH2-CH2-, -CH(CH3)-, -CH2-CH2-CH2-, -CH(C2H5)-, -C(CH3)2-, C 1-4 Each hydrogen of an alkyl carbon may be replaced with a substituent as further enumerated herein.

[0149] As used herein, the term "alkoxy" refers to a group having a "-O-alkyl" structure, wherein alkyl is as defined above. 1-6 The term "alkoxy" refers to an alkoxy group having 1 to 6 carbon atoms, such as, but not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, isobutoxy, n-pentoxy, and the like.

[0150] The term "cycloalkyl" refers to a monocyclic or bicyclic saturated carbocyclic ring, each having 3 to 10 carbon atoms. A "fused analog" of a cycloalkyl refers to a monocyclic ring fused to an aryl or heteroaryl group, wherein the point of attachment is on the non-aromatic portion. Examples of cycloalkyl and fused analogs thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydronaphthyl, decahydronaphthyl, dihydroindanyl, and the like. Further, the term "cycloalkyl" in the present disclosure includes bridged ring systems and spiro ring systems. The term "C 3-10 "Cycloalkyl" refers to a cycloalkyl group having 3 to 10 ring carbon atoms, and also includes spirocyclic or bridged cycloalkyl groups, exemplified by bicyclo[4.2.2]decane, bicyclo[2.2.1]heptyl, and adamantyl. These cycloalkyl groups may be optionally substituted by other substituents, such as pinanyl and bornanyl substituted by methyl.

[0151] As used herein, the term "amino group" refers to a group formed by replacing at least one hydrogen atom in an amino group with an alkyl group, such as "-N(R a R b )”, where R a and R b In the embodiment of the present invention, the amino group is dimethylamino, diethylamino or methylethylamino.

[0152] As used herein, the terms "aryl", "aryl ring" and "aromatic ring" are used interchangeably and refer to an all-carbon monocyclic, an all-carbon non-fused polycyclic (rings are connected by covalent bonds and are not fused) or an all-carbon fused polycyclic (i.e., rings that share adjacent pairs of carbon atoms) group, in which at least one ring is aromatic, i.e., has a conjugated π electron system forming a ring.

[0153] As used in the present invention, the term "deuterated" means that the hydrogen in a compound is replaced by deuterium. Deuterium is an isotope of hydrogen, with the chemical symbol D or 2H.

[0154] As used herein, the term "pharmaceutical composition" refers to a mixture of a compound described herein and an "excipient" such as a carrier, stabilizer, diluent, dispersant, suspending agent, and / or thickening agent. The pharmaceutical composition facilitates the administration of the compound to an organism. There are various techniques for administering compounds in the art, including but not limited to: rectal, oral, intravenous, aerosol, parenteral, ocular, pulmonary, and topical administration.

[0155] As used herein, the term "subject" refers to an animal, including but not limited to primates (e.g., humans), monkeys, cows, pigs, sheep, goats, horses, dogs, cats, rabbits, rats, or mice. The terms "subject" and "patient" are used interchangeably herein, for example, with respect to mammalian subjects such as humans.

[0156] As used herein, in the context of treating a disease or disorder, the terms "treat, treating, and treatment" mean including alleviating or eliminating the disorder, disease, or condition, where the term "disorder" as used herein should always be understood to mean "disorder, disease, or condition" or one or more of the symptoms associated with the disorder; or slowing the progression, spread, or worsening of the disorder or condition or one or more of its symptoms.

[0157] Citation statement

[0158] This patent application incorporates herein by reference in its entirety the Chinese patent application with the application number 2021111084176 and the invention title "A Class of Small Molecule Compounds with Naphthylamine Structure and Their Applications".

[0159] This patent application incorporates herein by reference in its entirety the Chinese patent application with the application number 202210575778X and the invention title "Uses of a Class of Small Molecule Compounds with Naphthylamine Structure".

[0160] This patent application incorporates herein by reference in its entirety the Chinese patent application with the application number 2023103137630 and the invention title "Solid Forms of Naphthylamine-Based Mitophagy Inducers, Their Preparation Methods, Pharmaceutical Compositions, and Uses".

[0161] This patent application incorporates herein by reference in its entirety the Chinese patent application with the application number 2023115506763 and the invention title "Uses of a Class of Small Molecule Compounds with Naphthylamine Structure".

[0162] This patent application incorporates by reference the entire text of the Chinese patent application with the application number 2023115501191 and the invention title "Naphthalene Ring-based Small Molecule Compounds".

[0163] This patent application incorporates by reference the entire text of the patent application with the application number PCT / CN2022 / 119825 and the invention title "Small Molecule Compounds with Naphthylamine Structure and Their Applications".

[0164] This patent application incorporates by reference the entire text of the patent application with the application number PCT / CN2023 / 095716 and the invention title "Uses of Small Molecule Compounds with Naphthylamine Structure".

[0165] This patent application incorporates by reference the entire text of the patent application with the application number PCT / CN2024 / 082357 and the invention title "Uses of Small Molecule Compounds with Naphthylamine Structure".

[0166] This patent application incorporates by reference the entire text of the patent application with the application number PCT / CN2024 / 082356 and the invention title "Naphthalene Ring-based Small Molecule Compounds".

[0167] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the present invention will be further described below in conjunction with specific embodiments. It should be understood that these embodiments are only used to illustrate the present invention and not to limit the scope of the present invention. The experimental methods without specific conditions noted in the following embodiments are generally in accordance with conventional conditions or the conditions recommended by the manufacturer. Unless otherwise specified, percentages and parts are by weight. The experimental materials and reagents used in the following embodiments can be obtained from commercial sources without special instructions.

[0168] Unless otherwise specified, the technical and scientific terms used herein have the same meanings as those commonly understood by those of ordinary skill in the technical field to which this application belongs. It should be noted that the terms used herein are only for describing specific embodiments and are not intended to limit the exemplary embodiments of this application.

[0169] Unless otherwise specified, the term "or" means the term "and / or" and can be used interchangeably with the term "and / or".

[0170] As used herein, including in the appended claims, unless the context clearly indicates otherwise, singular forms of words such as "a", "an", and "the" include their corresponding plural referents.

[0171] Example 1

[0172] In this example, compounds 1, 2, 3, 7, 9, 38, 41, and 56 were synthesized and characterized. Compounds 1, 2, 3, 7, 9, 38, 41, and 56 were synthesized according to the following reaction scheme:

[0173]

[0174] At room temperature, compound 8 (93 mg, 0.2 mmol, 1.0 eq) was dissolved in THF (20 mL), alcohol or methanesulfonamide (0.8 mmol, 4.0 eq) was added, and acetic acid (24 mg, 0.4 mmol, 2.0 eq) was added as a catalyst. The reaction was carried out overnight. After the overnight reaction, a small amount of aqueous sodium bicarbonate solution was added to adjust the pH to neutral, silica gel was added and mixed, and the corresponding compound was purified by silica gel column chromatography.

[0175] Compound 1 (84 mg, yield 85%). 1 H NMR (400 MHz, DMSO-d6) δ 11.01 (s, 1H), 10.19 (s, 1H), 8.31–8.13 (m, 1H), 8.08–7.97 (m, 1H), 7.77–7.68 (m, 2H), 7.63–7.51 (m, 4H), 7.19 (s, 1H), 4.09 (d, J = 13.8 Hz, 1H), 3.65 (s, 3H), 3.61 (d, J = 13.8 Hz, 1H). LCMS: m / z = 495.7 [M-H] - .

[0176] Compound 2 (75 mg, yield 71%). 1 H NMR (400 MHz, DMSO-d6) δ 10.97 (s, 1H), 10.17 (s, 1H), 8.31–8.22 (m, 1H), 8.05–7.96 (m, 1H), 7.76–7.68 (m, 2H), 7.62–7.52 (m, 4H), 7.19 (s, 1H), 4.87 (hept, J = 6.3 Hz, 1H), 4.01 (d, J = 13.7 Hz, 1H), 3.58 (d, J = 13.6 Hz, 1H), 1.13 (d, J = 6.2 Hz, 3H), 1.09 (d, J = 6.2 Hz, 3H). LCMS: m / z = 523.7 [M-H] - .

[0177] Compound 3 (24 mg, yield 22%). LCMS: m / z = 537.8 [M-H] - .

[0178] Compound 7 (77 mg, yield 65%). 1H-NMR (400 MHz, DMSO-d6) δ 10.19 (s, 1H), 8.26 (dd, J = 6.3, 3.2 Hz, 1H), 8.00 (dd, J = 6.3, 3.3 Hz, 1H), 7.71 (d, J = 8.6 Hz, 2H), 7.64–7.50 (m, 3H), 7.20 (s, 1H), 5.08–4.90 (m, 2H), 4.13 (d, J = 13.8 Hz, 1H), 3.67 (d, J = 13.8 Hz, 1H), 2.09 (s, 3H). LCMS: m / z = 594.0 [M-H] - .

[0179] Compound 9 (16 mg, yield 14%). LCMS: m / z = 558.7 [M-H] - .

[0180] Compound 38 (87 mg, yield 77%). LCMS: m / z = 565.8 [M-H] - .

[0181] Compound 41 (71 mg, yield 62%). LCMS: m / z = 571.7 [M-H] - .

[0182] Compound 56 (53 mg, yield 49%). 1 H NMR (400 MHz, DMSO-d6) δ 10.99 (s, 1H), 10.19 (s, 1H), 8.30–8.22 (m, 1H), 8.04–7.95 (m, 1H), 7.75–7.67 (m, 2H), 7.63–7.51 (m, 4H), 7.23 (s, 1H), 4.87–4.77 (m, 1H), 4.11 (dd, J = 13.7, 6.3 Hz, 1H), 3.64 (dd, J = 17.3, 13.7 Hz, 1H), 2.32–2.12 (m, 1H), 1.88–1.70 (m, 1H), 1.70–1.54 (m, 2H), 1.24–1.18 (m, 1H), 1.16–1.07 (m, 1H), 0.94 (dd, J = 13.8, 3.5 Hz, 1H), 0.87–0.78 (m, 6H), 0.77–0.67 (m, 3H). LCMS: m / z = 618.2 [M-H] - .

[0183] Example 2

[0184] In this example, compounds 4, 5, and 6 were synthesized and characterized. Compounds 4, 5, and 6 were synthesized according to the following reaction scheme:

[0185]

[0186] At room temperature, 2-((4-((4-bromophenyl)sulfamoyl)-1-hydroxynaphthalen-2-yl)sulfinyl)acetic acid (I-1) (484 mg, 1.0 mmol, 1.0 eq) was suspended in dichloromethane (5 mL), and silver oxide (462 mg, 2.0 mmol, 2.0 eq) and a chloromethyl substituent were added successively, and the reaction was carried out overnight. After the reaction was completed, the solid was filtered off, and the residue was concentrated and purified by silica gel column chromatography to obtain the corresponding product.

[0187] Compound 4 (101 mg, yield 17%). LCMS: m / z = 595.7 [M-H] - .

[0188] Compound 5 (171 mg, yield 28%). LCMS: m / z = 609.7 [M-H] - .

[0189] Compound 6 (75 mg, yield 12%). LCMS: m / z = 623.7 [M-H] - .

[0190] Example 3

[0191] In this example, compounds 10, 11, 12, 13, 14, 15, and 16 were synthesized and characterized. Compounds 10, 11, 12, 13, 14, 15, and 16 were synthesized according to the following reaction scheme:

[0192]

[0193] At room temperature, compound 8 (93 mg, 0.2 mmol, 1.0 eq) was dissolved in THF (20 mL), and an amine or a thiol (0.8 mmol, 4.0 eq) was added. After the reaction was completed, silica gel was added and stirred, and the mixture was purified by silica gel column chromatography to obtain the corresponding compound.

[0194] Compound 10 (79 mg, yield 77%). LCMS: m / z = 511.7 [M-H] - .

[0195] Compound 11 (56 mg, yield 52%). LCMS: m / z = 539.7 [M-H] - .

[0196] Compound 12 (95 mg, yield 81%). LCMS: m / z = 587.9 [M-H] - .

[0197] Compound 13 (69 mg, yield 70%). 1H-NMR (400 MHz, DMSO-d6) δ 10.91 (bs, 1H), 10.22 (bs, 1H), 8.24 (dd, J = 8.2, 1.0 Hz, 1H), 8.15 (m, 1H), 7.91 (dd, J = 8.3, 1.0 Hz, 1H), 7.76–7.63 (m, 2H), 7.60–7.42 (m, 4H), 7.30 (s, 1H), 3.85 (d, J = 13.4 Hz, 1H), 3.47 (d, J = 13.4 Hz, 1H), 2.63 (d, J = 4.6 Hz, 3H). LCMS: m / z = 494.6 [M-H] - .

[0198] Compound 14 (60 mg, yield 59%). 1 H-NMR (400 MHz, DMSO-d6) δ 10.92 (s, 1H), 10.16 (s, 1H), 8.32–8.18 (m, 1H), 8.08–7.97 (m, 1H), 7.73 (d, J = 8.6 Hz, 2H), 7.63–7.49 (m, 4H), 7.21 (s, 1H), 4.05 (d, J = 14.6 Hz, 1H), 3.79 (d, J = 14.6 Hz, 1H), 2.98 (s, 3H), 2.87 (s, 3H). LCMS: m / z = 508.5 [M-H] - .

[0199] Compound 15 (64 mg, yield 61%). 1 H-NMR (400 MHz, DMSO-d6) δ 10.90 (s, 1H), 10.22 (s, 1H), 8.30 (d, J = 4.1 Hz, 1H), 8.27–8.20 (m, 1H), 7.96–7.84 (m, 1H), 7.77–7.63 (m, 2H), 7.64–7.45 (m, 4H), 7.29 (s, 1H), 3.81 (d, J = 13.4 Hz, 1H), 3.43 (d, J = 13.4 Hz, 1H), 2.66 (m, 1H), 0.64 (m, 2H), 0.40 (dd, J = 3.8, 1.8 Hz, 2H). LCMS: m / z = 520.8 [M-H] - .

[0200] Compound 16 (43 mg, yield 38%). LCMS: m / z = 570.7 [M-H] - .

[0201] Example 4

[0202] In this example, compounds 17, 19, 20, 26, 40, and 58 were synthesized and characterized. Compounds 17, 19, 20, 26, 40, and 58 were synthesized according to the following reaction formula:

[0203]

[0204] Synthesis and characterization of compound 19:

[0205]

[0206] Step 1: Synthesis of intermediate Int-1:

[0207] At room temperature, methyl 2-((4-((4-bromophenyl)sulfamoyl)-1-hydroxynaphthalen-2-yl)thio)acetate (Cpd 32 in Journal of Medicinal Chemistry 2014, 57(10), 4111 - 4133) (2 g, 4.13 mmol, 1.0 eq), isobutyric acid (0.55 g, 6.23 mmol, 1.5 eq), methylimidazole (0.51 g, 6.23 mmol, 1.5 eq), and N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (1.74 g, 6.23 mmol, 1.5 eq) were dissolved in acetonitrile (20 ml), and stirred at room temperature overnight. The reaction mixture was washed with water (50 mL), extracted with ethyl acetate (20 mL × 2), the combined organic layers were washed with saturated brine (50 mL × 1), the organic phase was dried over anhydrous sodium sulfate and concentrated, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:8) to obtain a white solid intermediate Int-1 (480 mg, yield: 21%). LCMS: m / z = 549.6 [M - H] -

[0208] Step 2: Synthesis of intermediate Int-2:

[0209] At room temperature, intermediate Int-1 (1 g, 1.81 mmol, 1.0 eq) and potassium carbonate (1 g, 3.62 mmol, 2.0 eq) were dissolved in a mixed solution of tetrahydrofuran (10 mL) and water (1 mL), protected by nitrogen, and after addition, the temperature was raised to 70 °C and reacted overnight. After overnight reaction, the reaction solution was cooled to room temperature, poured into water (50 mL), and the pH of the solution was adjusted to ≈6 with 4M hydrochloric acid during stirring. A solid precipitated, and it was filtered by suction. The solid was washed with water (30 mL × 2) to obtain a reddish-brown intermediate Int-2 (0.98 g, yield 100%). LCMS: m / z = 534.6 [M - H] -

[0210] Step 3: Synthesis of compound 19:

[0211] The intermediate Int-2 (300 mg, 0.56 mmol, 1.0 eq) was dissolved in a mixed solution of tetrahydrofuran (1 mL) and water (1 mL). Under nitrogen protection, potassium peroxymonosulfate (96.5 mg, 0.28 mmol, 0.5 eq) was added while controlling the temperature below 0 °C. After the addition, the mixture was stirred for 10 min, and then potassium peroxymonosulfate (96.5 mg, 0.28 mmol, 0.5 eq) was added again. After the addition, the mixture was stirred at the same temperature for 10 min and then raised to room temperature for reaction for 3 h. 10% aqueous sodium thiosulfate solution (10 mL) was added, and the mixture was extracted with ethyl acetate (10 mL × 2). The combined organic layers were washed with saturated brine (10 mL × 1), dried over anhydrous sodium sulfate and concentrated. After concentration, the crude product was added with ethyl acetate, and crystallized at -40 °C. The crystals were filtered by suction, and the solid was rinsed with ethyl acetate (2 mL × 2) to obtain Compound 19 (80 mg, yield 26%). LCMS: m / z = 551.6 [M-H] - 。 1 1H-NMR (400 MHz, DMSO-d6) δ 13.38 (s, 1H), 10.64 (s, 1H), 8.16–8.13 (m, 1H), 7.88–7.86 (m, 1H), 7.76–7.72 (dt, 2H), 7.71–7.67 (m, 2H), 7.63–7.60 (dt, 2H), 7.46 (s, 1H), 3.86–3.82 (d, 1H), 3.64–3.60 (d, 1H), 3.19–3.05 (m, 1H), 1.37–1.33 (dd, 6H).

[0212] Synthesis and characterization of Compound 20:

[0213]

[0214] Step 1: Synthesis of intermediate Int-1:

[0215] At room temperature, methyl 2-((4-((4-bromophenyl)sulfonamido)-1-hydroxynaphthalen-2-yl)thio)acetate (Cpd 32 in Journal of Medicinal Chemistry 2014, 57(10), 4111 - 4133) (2 g, 4.13 mmol, 1.0 equiv) and pyridine (0.72 g, 9.09 mmol, 2.2 equiv) were added to a solution of tetrahydrofuran (20 mL). Under nitrogen protection, trimethylacetyl chloride (0.89 g, 8.26 mmol, 2.0 equiv) was added dropwise while controlling the temperature below 0 °C. After the addition, the temperature was raised to 70 °C and the reaction was carried out overnight. After overnight, the reaction mixture was cooled to room temperature. The reaction mixture was washed with water (50 mL), extracted with ethyl acetate (20 mL × 2), and the combined organic layers were washed with saturated brine (50 mL × 1). The organic phase was dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:10) to obtain a white solid intermediate Int-1 (600 mg, yield: 27%). LCMS: m / z = 563.7 [M - H] -

[0216] Step 2: Synthesis of intermediate Int-2:

[0217] At room temperature, intermediate Int-1 (1 g, 1.77 mmol, 1.0 eq), potassium carbonate (0.49 g, 3.53 mmol, 2.0 eq) were dissolved in a mixed solution of tetrahydrofuran (10 mL) and water (1 mL). Under nitrogen protection, after the addition, the temperature was raised to 70 °C and the reaction was carried out overnight. After overnight, the reaction solution was cooled to room temperature. The reaction solution was poured dropwise into water (100 mL), and the pH of the solution was adjusted to approximately 6 with 4 M hydrochloric acid during stirring. A solid precipitated out. The solid was filtered by suction and the solid was washed with water (30 mL × 2) to obtain a white intermediate Int-2 (0.98 g, yield 100%). LCMS: m / z = 549.7 [M - H] -

[0218] Step 3: Synthesis of compound 20:

[0219] Intermediate Int-2 (500 mg, 0.91 mmol, 1.0 eq) was dissolved in a mixed solution of tetrahydrofuran (2 mL) and water (2 mL). Under nitrogen protection, potassium peroxymonosulfate (156.7 mg, 0.45 mmol, 0.5 eq) was added while controlling the temperature below 0 °C. After the addition, the mixture was stirred for 10 min, then potassium peroxymonosulfate (156.7 mg, 0.45 mmol, 0.5 eq) was added again. After the addition, the mixture was stirred at the same temperature for 10 min and then raised to room temperature for reaction for 3 h. 10% aqueous sodium thiosulfate solution (10 mL) was added, and the mixture was extracted with ethyl acetate (10 mL × 2). The combined organic layers were washed with saturated brine (10 mL × 1). The organic phase was dried over anhydrous sodium sulfate and concentrated. After the concentrated crude product was dissolved in acetonitrile, crystallization was carried out at -40 °C. The solid was filtered by suction, and the solid was washed with acetonitrile (2 mL × 2) to obtain Compound 20 (160 mg, yield 31%). LCMS: m / z = 565.6 [M-H] - 。 1 1H-NMR (400 MHz, DMSO-d6) δ 13.35 (s, 1H), 10.60 (s, 1H), 8.14–8.10 (m, 1H), 7.92–7.88 (m, 1H), 7.63–7.60 (dt, 2H), 7.47 (s, 1H), 3.87–3.83 (d, 1H), 3.63–3.60 (d, 1H), 1.44 (s, 9H).

[0220] Synthesis and characterization of Compound 17: According to the synthesis procedure of Compound 20, trimethylacetyl chloride in Step 1 was replaced with dimethylcarbamoyl chloride to obtain Compound 17. LCMS: m / z = 552.6 [M-H] - 。 1 1H-NMR (400 MHz, DMSO-d6) δ 13.43 (s, 1H), 10.605 (s, 1H), 8.16–8.13 (dd, 1H), 7.77–7.68 (m, 5H), 7.76–7.73 (dt, 2H), 7.71–7.65 (m, 2H), 7.63–7.60 (dt, 2H), 7.44 (s, 1H), 3.90–3.86 (d, 1H), 3.60–3.56 (d, 1H), 2.97 (s, 1H).

[0221] Synthesis and characterization of Compound 26: According to the synthesis procedure of Compound 20, trimethylacetyl chloride in Step 1 was replaced with isopropyl chloroformate to obtain Compound 26. LCMS: m / z = 567.7 [M-H] - 。

[0222] Synthesis and Characterization of Compound 40: According to the synthesis procedure of Compound 20, replace pivaloyl chloride in Step 1 with benzoyl chloride to obtain Compound 40. LCMS: m / z = 585.7 [M-H] - 。

[0223] Synthesis and Characterization of Compound 58: According to the synthesis procedure of Compound 20, replace pivaloyl chloride in Step 1 with to obtain Compound 58. LCMS: m / z = 662.4 [M-H] - 。

[0224] Example 5

[0225] In this example, Compound 18 was synthesized and characterized.

[0226]

[0227] Step 1: Synthesis of Intermediate Int-1:

[0228] At room temperature, add methyl 2-((4-((4-bromophenyl)sulfonamido)-1-hydroxynaphthalen-2-yl)thio)acetate (Cpd 32 in Journal of Medicinal Chemistry 2014, 57(10), 4111 - 4133) (2 g, 4.13 mmol, 1.0 eq) and pyridine (0.72 g, 9.09 mmol, 2.2 eq) to a solution of tetrahydrofuran (20 mL). Under nitrogen protection, add dimethylcarbamoyl chloride (0.89 g, 8.26 mmol, 2.0 eq) dropwise while controlling the temperature below 0 °C. After the addition, raise the temperature to 70 °C and react overnight. After overnight reaction, cool the reaction mixture to room temperature. Wash the reaction mixture with water (50 mL), extract with ethyl acetate (20 mL × 2), combine the organic layers, wash with saturated brine (50 mL × 1), dry the organic phase with anhydrous sodium sulfate and concentrate. Purify the residue by silica gel column chromatography (petroleum ether:ethyl acetate = 1:10) to obtain off-white solid Intermediate Int-1 (571 mg, yield: 25%). LCMS: m / z = 550.7 [M-H] -

[0229] Step 2: Synthesis of Compound 18:

[0230] Intermediate Int-1 (200 mg, 0.22 mmol, 1.0 eq) was dissolved in a mixed solution of tetrahydrofuran (1 mL) and water (1 mL). Under nitrogen protection, potassium peroxymonosulfate (37.9 mg, 0.11 mmol, 0.5 eq) was added while controlling the temperature below 0 °C. After the addition, the mixture was stirred for 10 min, and then potassium peroxymonosulfate (37.9 mg, 0.11 mmol, 0.5 eq) was added again. After the addition, the mixture was stirred at the same temperature for 10 min and then allowed to react at room temperature for 3 h. 10% aqueous sodium thiosulfate solution (10 mL) was added, and the mixture was extracted with ethyl acetate (10 mL × 2). The combined organic layers were washed with saturated brine (10 mL × 1), dried over anhydrous sodium sulfate and concentrated. After the concentrate was dissolved in acetonitrile, crystallization was carried out at -40 °C. The solid was filtered by suction and washed with acetonitrile (2 mL × 2) to obtain Compound 18 (46 mg, yield 37%). LCMS: m / z = 564.8 [M-H] - 。 1 1H-NMR (400 MHz, DMSO-d6) δ 10.61 (s, 1H), 8.15–8.11 (m, 1H), 7.92–7.88 (m, 1H), 7.77–7.74 (dt, 2H), 7.70–7.67 (m, 2H), 7.64–7.60 (dt, 2H), 7.40 (s, 1H), 4.03–4.00 (d, 1H), 3.72–3.68 (d, 1H), 3.21 (s, 1H), 2.97 (s, 1H).

[0231] Example 6

[0232] In this example, Compound 21 was synthesized and characterized.

[0233]

[0234] Step 1: Synthesis of Intermediate Int-1:

[0235] At room temperature, methyl 2-((4-((4-bromophenyl)sulfonamido)-1-hydroxynaphthalen-2-yl)thio)acetate (Cpd 32 in Journal of Medicinal Chemistry 2014, 57(10), 4111 - 4133) (2 g, 4.13 mmol, 1.0 eq), 1,4-dihydrotrigonelline (0.87 g, 6.23 mmol, 1.5 eq), methylimidazole (0.51 g, 6.23 mmol, 1.5 eq), and N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (1.74 g, 6.23 mmol, 1.5 eq) were dissolved in acetonitrile (20 mL), and stirred at room temperature overnight. The reaction mixture was washed with water (50 mL), extracted with ethyl acetate (20 mL × 2), the combined organic layers were washed with saturated brine (50 mL × 1), the organic phase was dried over anhydrous sodium sulfate and concentrated, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:8) to obtain a white solid intermediate Int-1 (520 mg, yield: 21%). LCMS: m / z = 600.7 [M - H] -

[0236] Step 2: Synthesis of intermediate Int-2:

[0237] At room temperature, intermediate Int-1 (0.5 g, 0.83 mmol, 1.0 eq) and potassium carbonate (0.23 g, 1.66 mmol, 2.0 eq) were dissolved in a mixed solution of tetrahydrofuran (10 mL) and water (1 mL), protected by nitrogen, and after addition, the temperature was raised to 70 °C and reacted overnight. After overnight, the reaction solution was cooled to room temperature, the reaction solution was dropped into water (50 mL), and the pH of the solution was adjusted to ≈6 with 4 M hydrochloric acid during stirring. A solid precipitated out, filtered by suction, and the solid was washed with water (30 mL × 2) to obtain a brown-red intermediate Int-2 (0.48 g, yield 100%). LCMS: m / z = 586.6 [M - H] -

[0238] Step 3: Synthesis of compound 21:

[0239] The intermediate Int-2 (400 mg, 0.68 mmol, 1.0 eq) was dissolved in a mixed solution of tetrahydrofuran (1 ml) and water (1 ml). Under nitrogen protection, potassium peroxymonosulfate (117.8 mg, 0.34 mmol, 0.5 eq) was added while controlling the temperature below 0 °C. After the addition, the mixture was stirred for 10 min, and then potassium peroxymonosulfate (117.8 mg, 0.34 mmol, 0.5 eq) was added again. After the addition, the mixture was stirred at the same temperature for 10 min and then raised to room temperature for reaction for 3 h. 10% aqueous sodium thiosulfate solution (10 mL) was added, and the mixture was extracted with ethyl acetate (10 mL * 2). The combined organic layers were washed with saturated brine (10 mL * 1). The organic phase was dried over anhydrous sodium sulfate and concentrated. The crude product after concentration was added with ethyl acetate, and crystallization was carried out at -40 °C. Filtration was performed by suction, and the solid was rinsed with ethyl acetate (2 mL * 2) to obtain Compound 21 (67 mg, yield 16.3%). LCMS: m / z = 602.7 [M-H] -

[0240] Example 7

[0241] In this example, Compound 22 was synthesized and characterized.

[0242]

[0243] Step 1: Synthesis of intermediate Int-1

[0244] At room temperature, under nitrogen protection, the known compound methyl 2-((4-((4-bromophenyl)sulfonamido)-1-hydroxynaphthalen-2-yl)thio)acetate (Cpd 32 in Journal of Medicinal Chemistry 2014, 57(10), 4111 - 4133) (481 mg, 1.0 mmol, 1.0 eq) was dissolved in a mixed solution of tetrahydrofuran (10 mL) and N,N-dimethylformamide (1 mL). Tetrabutylammonium iodide (880 mg, 2.4 mmol, 2.4 eq) and sodium hydride (60%, 96 mg, 2.4 mmol, 2.4 eq) were added, and the reaction was carried out for 1 h. Chloromethyl isobutyrate (2.0 mmol, 2.0 eq) was added, and the temperature was raised to 45 °C for reaction overnight. After the reaction was completed, the reaction solution was poured into water (40 mL), and extracted with ethyl acetate (20 mL * 2). The combined organic phases were dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography to obtain the corresponding intermediate Int-1 (326 mg, yield: 48%).

[0245] Step 2: Synthesis of Compound 22

[0246] At room temperature, intermediate Int-1 (68 mg, 0.1 mmol, 1.0 eq) was dissolved in ethyl acetate (2 mL), and m-CPBA (85%, 21 mg, 1.2 mmol, 1.2 eq) was added. The reaction was carried out overnight. After overnight, a saturated solution of sodium thiosulfate (0.5 mL) was added to quench the reaction. The layers were separated, and the organic layer was dried over anhydrous sodium sulfate and concentrated. Purification by silica gel column chromatography gave compound 22 (40 mg, yield 63%). LCMS: m / z = 695.9 [M-H] - 。 1 1H-NMR (400 MHz, DMSO-d6) δ 8.23–8.11 (m, 2H), 7.88–7.71 (m, 5H), 7.66–7.61 (m, 1H), 7.41 - 7.25 (m, 1H), 6.00 (m, 2H), 5.84–5.73 (m, 1H), 5.52 (m, 1H), 4.07 (m, 1H), 3.67 (s, 2H), 3.57 (s, 1H), 2.66–2.54 (m, 1H), 2.41 (m, 1H), 1.13–1.02 (m, 6H), 0.95 (m, 6H).

[0247] Example 8

[0248] In this example, compounds 23 and 24 were synthesized and characterized. Compounds 23 and 24 were synthesized according to the following reaction scheme:

[0249]

[0250] Step 1: Synthesis of intermediate Int-1

[0251] At room temperature, the prototype drug I-1 (484 mg, 1.0 mmol, 1.0 eq) was suspended in dichloromethane (5 mL), imidazole (204 mg, 3.0 mmol, 3.0 eq) and 2-(trimethylsilyl)ethoxymethyl chloride (199 mg, 1.2 mmol, 1.2 eq) were added, and the reaction was carried out overnight. After the reaction was completed, it was concentrated and directly purified by silica gel column chromatography to obtain intermediate Int-1 (410 mg, yield: 67%).

[0252] Step 2: Synthesis of intermediate Int-2

[0253] At room temperature, intermediate Int-1 (0.4 mmol) was dissolved in acetonitrile (5 mL), potassium carbonate (65 mg, 0.48 mmol, 1.2 eq) and the corresponding chloromethyl ester (0.48 mmol, 1.2 eq) were added, and the reaction was carried out overnight. After the reaction was completed, it was concentrated and directly purified by silica gel column chromatography to obtain intermediate Int-2.

[0254] Step 3: Synthesis of Compounds 23 and 24

[0255] At room temperature, dissolve intermediate Int-2 (0.2 mmol, 1.0 eq) in tetrahydrofuran (5 mL), add acetic acid (14 mg, 0.24 mmol, 1.2 eq) and TBAF solution (1 M in THF, 0.2 mL, 2.0 eq), and react overnight. After the reaction is completed, quench with water (5 mL), wash the aqueous phase twice with ethyl acetate (5 mL * 2), combine the organic phases, wash with saturated brine (5 mL), dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify by silica gel column chromatography to obtain the target product.

[0256] Compound 23 (77 mg, yield 66%). LCMS: m / z = 581.7 [M - H] - .

[0257] Compound 24 (49 mg, yield 41%). LCMS: m / z = 597.6 [M - H] - .

[0258] Example 9

[0259] In this example, Compound 25 was synthesized and characterized.

[0260]

[0261] Dissolve Compound 19 (300 mg, 0.54 mmol, 1.0 eq), 4-(hydroxymethyl)-5-methyl-[1,3]dioxol-2-one (77.4 mg, 0.59 mmol, 1.1 eq), HATU (308.6 mg, 0.81 mmol, 1.5 eq), and N,N-diisopropylethylamine (104.9 mg, 0.81 mmol, 1.5 eq) in acetonitrile (3 mL), protect with nitrogen, and react at room temperature overnight. Add water (20 mL), extract with ethyl acetate (20 mL * 2), combine the organic layers, wash with saturated brine (10 mL * 1), dry the organic phase over anhydrous sodium sulfate and concentrate, and purify the residue by silica gel column chromatography (dichloromethane:methanol = 15:1) to obtain Compound 25 (180 mg, yield: 50%). LCMS: m / z = 663.7 [M - H] -

[0262] Example 10

[0263] In this example, Compounds 27, 28, 29, 30, 31, 32, 33, and 34 were synthesized and characterized. Compounds 27, 28, 29, 30, 31, 32, 33, and 34 were synthesized according to the following reaction scheme:

[0264]

[0265] Step 1: Synthesis of Intermediate Int-2

[0266] At room temperature, under nitrogen protection, dissolve the starting material (Intermediate Int-1 in the synthesis route of Compound 8) (450 mg, 1.0 mmol, 1.0 eq) in a mixed solution of tetrahydrofuran (10 mL) and N,N-dimethylformamide (1 mL). Add tetrabutylammonium iodide (440 mg, 1.2 mmol, 1.2 eq) and sodium hydride (60%, 48 mg, 1.2 mmol, 1.2 eq), and react for 1 hour. Add chloromethyl ester (2.0 mmol, 2.0 eq), and raise the temperature to 45 °C and react overnight. After the reaction is completed, pour the reaction solution into water (40 mL), extract with ethyl acetate (20 mL × 2), combine the organic phases, dry with anhydrous sodium sulfate, concentrate, and purify by silica gel column chromatography to obtain the corresponding Intermediate Int-2 (yield: 8% - 67%).

[0267] Step 2: Synthesis of Compounds 27, 28, 29, 30, 31, 32, 33, 34

[0268] At room temperature, dissolve Intermediate Int-2 (0.1 mmol, 1.0 eq) in acetonitrile (2.5 mL), add potassium monopersulfate (143 mg, 0.24 mmol, 2.4 eq), and react overnight. Filter the solid, add water (0.5 mL) to the obtained solution, and react at room temperature. After the reaction is completed, dry with anhydrous sodium sulfate, concentrate the reaction solution, and purify by silica gel column chromatography to obtain the corresponding product.

[0269] Compound 27 (20 mg, yield 34%). 1 1H-NMR (400 MHz, DMSO-d6) δ 8.34 (m, 2H), 8.04 (m, 2H), 7.83 (m, 4H), 7.77–7.59 (m, 7H), 7.26 - 7.18 (m, 1H), 5.97 (m, 2H), 5.44 (m, 2H), 3.95 (m, 2H), 3.60 (m, 1H), 3.44 (m, 1H), 0.99 (m, 16H). LCMS: m / z = 595.6 [M - H] -

[0270] Compound 28 (36 mg, yield 61%). LCMS: m / z = 597.6 [M - H] -

[0271] Compound 29 (27 mg, yield 47%). LCMS: m / z = 583.9 [M - H] -

[0272] Compound 30 (23 mg, yield 39%). 1 1H-NMR (400 MHz, DMSO-d6) δ 8.28 (m, 2H), 7.94 (m, 2H), 7.87–7.75 (m, 4H), 7.71–7.59 (m, 6H), 7.59–7.49 (m, 2H), 7.20 - 7.05 (m, 1H), 5.97 (m, 2H), 5.45 (m, 2H), 3.84–3.57 (m, 5H), 2.41 (m, 2H), 0.96 (m, 12H). LCMS: m / z = 581.5 [M-H] -

[0273] Compound 31 (32 mg, yield 52%). 1 1H-NMR (400 MHz, DMSO-d6) δ 8.27 (m, 1H), 7.88–7.74 (m, 3H), 7.63 (m, 3H), 7.54 (m, 1H), 7.24 - 7.04 (m, 1H), 5.97–5.84 (m, 1H), 5.47 (m, 1H), 3.68 (m, 2H), 2.09 (m, 2H), 0.89 (m, 9H). LCMS: m / z = 609.8 [M-H] -

[0274] Compound 32 (34 mg, yield 55%). LCMS: m / z = 611.7 [M-H] -

[0275] Compound 33 (26 mg, yield 42%). LCMS: m / z = 610.8 [M-H] -

[0276] Compound 34 (39 mg, yield 63%). 1 1H-NMR (400 MHz, DMSO-d6) δ 8.29 (m, 1H), 7.99 (m, 1H), 7.84 (m, 2H), 7.74–7.60 (m, 3H), 7.57 (m, 1H), 7.19 - 7.00 (m, 1H), 6.13–5.94 (m, 1H), 5.50–5.31 (m, 1H), 3.79 (m, 1H), 3.67–3.37 (m, 4H), 3.09 (m, 1H). LCMS: m / z = 624.8 [M-H] -

[0277] Example 11

[0278] In this example, Compound 35 was synthesized and characterized. Compound 35 was synthesized according to the following reaction scheme:

[0279]

[0280] Step 1: Synthesis of Intermediate Int-2

[0281] At room temperature, under nitrogen protection, the raw material (Intermediate Int-1 in the synthesis routes of Compounds 23 and 24) (615 mg, 1.0 mmol, 1.0 eq) was dissolved in a mixed solution of tetrahydrofuran (10 mL) and N,N-dimethylformamide (1 mL). Tetrabutylammonium iodide (880 mg, 2.4 mmol, 2.4 eq) and sodium hydride (60%, 96 mg, 2.4 mmol, 2.4 eq) were added, and the reaction was carried out for 1 hour. The chloromethyl substituent (2.0 mmol, 2.0 eq) was added, and the temperature was raised to 45 °C and the reaction was carried out overnight. After the reaction was completed, the reaction solution was poured into water (10 mL), extracted with ethyl acetate (20 mL × 2), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography to obtain the corresponding Intermediate Int-2 (210 mg, yield: 25%).

[0282] Step 2: Synthesis of Compound 35

[0283] At room temperature, Intermediate Int-2 (210 mg, 0.25 mmol, 1.0 eq) was dissolved in tetrahydrofuran (5 mL), acetic acid (18 mg, 0.3 mmol, 1.2 eq) and TBAF solution (1 M in THF, 0.25 mL, 2.0 eq) were added, and the reaction was carried out overnight. After the reaction was completed, water (5 mL) was added to quench the reaction. The aqueous phase was washed twice with ethyl acetate (5 mL × 2), the organic phases were combined, washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain the target product. LCMS: m / z = 713.9 [M-H] -

[0284] Example 12

[0285] In this example, Compounds 36 and 37 were synthesized and characterized. Compounds 36 and 37 were synthesized through the following reaction formula:

[0286]

[0287] Synthesis of Compound 36:

[0288] Compound 21 (300 mg, 0.50 mmol, 1.0 eq), 4-(hydroxymethyl)-5-methyl-[1,3]dioxol-2-one (71.1 mg, 0.55 mmol, 1.1 eq), HATU (283.3 mg, 0.75 mmol, 1.5 eq), and N,N-diisopropylethylamine (96.3 mg, 0.75 mmol, 1.5 eq) were dissolved in acetonitrile (3 mL). Under nitrogen protection, the reaction was carried out overnight at room temperature. Water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL × 2). The combined organic layers were washed with saturated brine (10 mL × 1), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (dichloromethane:methanol = 15:1) to obtain compound 36 (160 mg, yield: 50%). LCMS: m / z = 714.7 [M-H] -

[0289] Synthesis of compound 37:

[0290] Replacing 4-(hydroxymethyl)-5-methyl-[1,3]dioxol-2-one in the synthesis route of compound 36 with isopropanol gave compound 37 (165 mg, yield 51%). LCMS: m / z = 644.7 [M-H] -

[0291] Example 14

[0292] In this example, compound 39 was synthesized and characterized.

[0293]

[0294] Step 1: Synthesis of intermediate Int-1

[0295] At room temperature, I-1 (465 mg, 1.0 mmol, 1.0 eq) was dissolved in ethanol (5 mL). Cesium carbonate (387 mg, 1.2 mmol, 1.2 eq) and (N-tert-butoxycarbonyl)valine 1-chloroethyl ester (334 mg, 1.2 mmol, 1.2 eq) were added, and the reaction was carried out overnight. After the reaction was completed, water (5 mL) was added to quench the reaction. The aqueous phase was washed twice with ethyl acetate (5 mL × 2). The combined organic phases were washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain Int-1 (200 mg, yield: 27%).

[0296] Step 2: Synthesis of compound 39

[0297] At room temperature, the intermediate Int-1 (200 mg, 0.27 mmol, 1.0 eq) was dissolved in DCM (5 mL), and TFA (1 mL) was added. The reaction was carried out overnight. After the reaction was completed, saturated aqueous sodium bicarbonate solution (5 mL) was added to quench the reaction. The aqueous phase was washed twice with ethyl acetate (5 mL × 2). The organic phases were combined, washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain compound 39 (38 mg, yield: 22%). LCMS: m / z = 626.7 [M+H] +

[0298] Example 15

[0299] In this example, compound 42 was synthesized and characterized.

[0300]

[0301] Pentadeuterobromobenzene was dissolved in chloroform, cooled in an ice-water bath, and chlorosulfonic acid was added dropwise with stirring. After naturally returning to room temperature, stirring was continued for 3 - 4 hours. Then the reaction solution was concentrated under reduced pressure. The obtained residue (Int-1) was dissolved in DCM, cooled in an ice-water bath, and ammonia water was added dropwise with stirring. After naturally returning to room temperature, stirring was continued overnight. Then the reaction solution was poured onto crushed ice, and the precipitated solid was filtered by suction and dried to obtain Int-2. According to the synthetic route of Scheme 2 in the Journal of Medicinal Chemistry 2012, 55(5), 1978 - 1998 and the synthetic method of I-1 provided in the Chinese patent with the application number 202111108417.6, the above-mentioned tetradeuterated p-bromobenzenesulfonamide Int-2 was used to replace p-bromobenzenesulfonamide, and compound 42 was synthesized according to the following route. 1 1H NMR (400 MHz, DMSO-d6) δ 10.96 (s, 1H), 10.16 (s, 1H), 8.30–8.21 (m, 1H), 8.04–7.96 (m, 1H), 7.63–7.52 (m, 2H), 7.21 (s, 1H), 4.00 (d, J = 14.2 Hz, 1H), 3.45 (d, J = 14.2 Hz, 1H). LCMS: m / z = 485.7 [M-H] -

[0302]

[0303] Example 16

[0304] In this example, compound 43 was synthesized and characterized.

[0305]

[0306] Replace SM-2 in the first step of the I-1 synthesis route with methyl thioglycolate-d, replace the solvent water in the third step with heavy water, and replace the concentrated hydrochloric acid in the fourth step with deuterated hydrochloric acid. Compound 43 was synthesized according to the above route. LCMS: m / z = 483.7 [M-H] -

[0307] Example 17

[0308] In this example, compound 8 was synthesized and characterized.

[0309]

[0310] Step 1: Synthesis of intermediate Int-1:

[0311] At room temperature, 2-((4-((4-bromophenyl)sulfonamido)-1-hydroxynaphthalen-2-yl)thio)acetic acid (UMI-77) (4.68 g, 10 mmol, 1.0 equiv) and 1-methylimidazole (2.46 g, 30 mmol, 2.0 eq) were dissolved in acetonitrile (20 mL), TCFH (4.21 g, 15 mmol, 1.5 eq) was added, and the reaction was carried out overnight at room temperature. After overnight, ethyl acetate (100 mL) and saturated brine were added to quench the reaction. The layers were separated, the organic phase was extracted with ethyl acetate (20 mL * 2), the combined organic phases were washed with saturated brine (20 mL * 1), the organic phase was dried over anhydrous sodium sulfate and concentrated, and the resulting solid mixture was slurried with ethyl acetate (10 mL) at room temperature for 1 hour and then filtered. The obtained solid was dried to give intermediate Int-1 (3.14 g, yield 70%). LCMS: m / z = 447.6 [M-H] - .

[0312] Step 2: Synthesis of compound 8:

[0313] At room temperature, intermediate Int-1 (900 mg, 2.0 mmol, 1.0 equiv) was dissolved in ethyl acetate (20 mL), m-CPBA (85%, 413 mg, 2.4 mmol, 1.2 eq) was added, and the reaction was carried out overnight. After overnight, a white solid precipitated, the solution was filtered off, and the obtained solid was dried to give compound 8 (750 mg, yield 81%). 1 1H-NMR (400 MHz, DMSO-d6) δ 10.69 (s, 1H), 8.36–8.21 (m, 1H), 7.99 (d, J = 8.0 Hz, 1H), 7.78–7.67 (m, 4H), 7.64–7.59 (m, 2H), 7.58 (s, 1H), 4.67 (s, 2H). LCMS: m / z = 497.7 [M + MeOH + H] + .

[0314] Example 18

[0315] This example refers to Example 9, where 4-(hydroxymethyl)-5-methyl-[1,3]dioxol-2-one was replaced with D-(+)-Campholenic alcohol (CAS: 464-43-7) to synthesize Compound 57 and characterized it.

[0316]

[0317] Compound 19 (300 mg, 0.54 mmol, 1.0 eq), D-(+)-Campholenic alcohol (91 mg, 0.59 mmol, 1.1 eq), HATU (308.6 mg, 0.81 mmol, 1.5 eq), and N,N-diisopropylethylamine (104.9 mg, 0.81 mmol, 1.5 eq) were dissolved in acetonitrile (3 mL), protected by nitrogen, and reacted overnight at room temperature. Water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL × 2). The combined organic layers were washed with saturated brine (10 mL × 1), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (methylene chloride:methanol = 15:1) to obtain Compound 57 (122 mg, yield: 33%). LCMS: m / z = 688.3 [M-H] - 。

[0318] Test Example, Pharmacokinetics Test of Compounds

[0319] Experimental mice were taken, and an appropriate amount of the test compound was administered according to the specified dose and administration route. For the gavage route, the test compound was suspended in 0.5% sodium carboxymethylcellulose, and for the intravenous injection route, the test compound was dissolved in 5% DMSO + 30% PEG400 + 65% water for injection. For each compound and each administration method, three experimental mice were used for three parallel experiments. For example, G1M01, G1M02, and G1M03 were in the same group, and G2M01, G2M02, and G2M03 were in a group. Male CD1 mice were selected as the mouse strain.

[0320] At the corresponding time points after administration, 20.0 μL of whole blood samples were taken into centrifuge tubes, anticoagulated with EDTA-K2, and immediately placed on ice after collection. The whole blood samples were centrifuged at 4°C and 2000 g for 10 minutes within 30 minutes after collection. Another labeled 1.5 mL centrifuge tube was taken, 5.00 μL of 1.5% ascorbic acid was added, and then 10.0 μL of the above-obtained plasma was added, immediately placed on ice, and the plasma samples were frozen in a -60°C to -90°C refrigerator within 30 minutes.

[0321] The concentration of Compound I-1 in the above plasma samples was detected by liquid chromatography-tandem mass spectrometry (LC-MS / MS).

[0322] Table 2. Plasma drug concentration in mice after intragastric administration of 30 mg / kg compound I-1 sodium salt

[0323]

[0324] Table 3. Plasma drug concentration in mice after intravenous injection of 3 mg / kg compound I-1 sodium salt

[0325]

[0326]

[0327] Table 4. Plasma drug concentration in mice after intragastric administration of 36.93 mg / kg or intravenous injection of 3.693 mg / kg compound 7

[0328]

[0329] a: BQL = Below the lower limit of quantitation (LLOQ)

[0330] b: NC = not calculated

[0331] Note: The intragastric dose was calculated based on the equimolar amount with 30 mg / kg compound I-1 sodium salt

[0332] Table 5. Plasma drug concentration in mice after intragastric administration of 34.41 mg / kg or intravenous injection of 3.441 mg / kg compound 19

[0333]

[0334] Note: The intragastric dose was calculated based on the equimolar amount with 30 mg / kg compound I-1 sodium salt

[0335] Table 6. Plasma drug concentration in mice after intragastric administration of 35.28 mg / kg compound 20

[0336]

[0337]

[0338] Note: The intragastric dose was calculated based on the equimolar amount with 30 mg / kg compound I-1 sodium salt

[0339] Table 7. Plasma drug concentration in mice after intragastric administration of 32.67 mg / kg compound 2

[0340]

[0341] Note: The intragastric dose was calculated based on the equimolar amount with 30 mg / kg compound I-1 sodium salt

[0342] Table 8. Plasma drug concentration of mice after intragastric administration of 36.28 mg / kg of Compound 30

[0343]

[0344] Note: The intragastric dose was calculated according to the equimolar amount of 30 mg / kg of Compound I-1 sodium salt

[0345] Table 9. Comparison of pharmacokinetic parameters and effect analysis between the original drug I-1 and some prodrugs

[0346]

[0347] From the above comparison, it can be seen that the prodrug Compound 7 significantly increased the plasma exposure, from 8.56 h*μg / mL of I-1 sodium salt to 30.578 h*μg / mL. The prodrug Compounds 19 and 30 also increased the plasma exposure to 12.656 h*μg / mL and 9.799 h*μg / mL. The pharmacokinetic properties of the prodrug Compound 19 were significantly different from those of I-1 sodium salt. The Cmax of I-1 sodium salt reached its peak at 30 minutes and then decreased rapidly, while the prodrug Compound 19 reached its Cmax at 2-4 h, and then the elimination phase was relatively slow, with a long residence time, and the Cmax was less than half of that of I-1 sodium salt. Similarly, the prodrug Compounds 27 and 30 also showed pharmacokinetic characteristics similar to those of 19, that is, the plasma exposure (AUC) within 24 h was basically unchanged or slightly higher, but the Cmax was reduced and the residence time was prolonged, and 27 was particularly significant. This suggests that the prodrug Compounds 19, 27, and 30 slowly hydrolyze and release the original drug I-1 in the plasma, forming a short and fat drug-time curve. Such pharmacokinetic characteristics will greatly improve the efficacy and safety of the drug, because many drug adverse reactions are caused by too high a peak blood drug concentration, that is, Cmax. Reducing Cmax while maintaining AUC can reduce the incidence of adverse reactions while ensuring the efficacy..

[0348] Table 10. Comparison of pharmacokinetic parameters between prodrugs 7 and 9 and the control prodrugs 2, 8, 13, and 14 of the same type

[0349]

[0350]

[0351] Note: The intragastric dose was calculated according to the equimolar amount of 30 mg / kg of Compound I-1 sodium salt

[0352] As can be seen from the above comparison, introducing different prodrug groups at the carboxylic acid site of the original drug I-1 results in significantly different pharmacokinetic characteristics. The ester prodrug group of prodrug 7 significantly improves the oral bioavailability compared to other ester or lactone prodrugs, such as 2 or 8, leading to a significant increase in both plasma exposure Cmax and AUC. The acyl methanesulfonamide prodrug of prodrug 9 also achieves a similar effect. The effects of prodrugs 7 and 9 may come from their great promotion of the absorption process of gastrointestinal epithelial cells. After the prodrug molecules enter the blood circulation, they encounter hydrolases and quickly release the carboxylic acid original drug I-1. However, for amide prodrugs, such as 13 or 14, the plasma exposure Cmax and AUC of the original drug I-1 are very low, probably because the amide bond cannot be effectively hydrolyzed in the body. The above technical effects cannot be inferred from the prior art and are creative and novel.

[0353] Table 11. Comparison of pharmacokinetic parameters of prodrugs 19, 26 and control prodrugs 17, 18, 20 of the same type

[0354]

[0355] Note: The gavage dose was calculated according to the equimolar amount of 30 mg / kg of compound I-1 sodium salt.

[0356] a The original drug I-1 was not detected in the plasma at all time points, and only prodrug 17 was detected, indicating that 17 cannot be effectively hydrolyzed in the body.

[0357] b The concentration of the original drug I-1 in plasma at each time point is very low, but a higher concentration of 17 is detected, indicating that the carboxylic acid methyl ester of 18 can be rapidly hydrolyzed into 17 in vivo, but the prodrug group (dimethylaminoacyl) on the phenolic hydroxyl group of 17 cannot be effectively hydrolyzed. From the above comparison, it can be seen that the pharmacokinetic characteristics obtained by introducing different prodrug groups at the phenolic hydroxyl position of the original drug I-1 are significantly different. Compared with other phenolic hydroxyl prodrug groups, the isobutyl phenol ester prodrug group of prodrug 19 and the isopropyl carbonate phenol ester prodrug group of prodrug 26 can significantly improve oral bioavailability, reduce the peak blood drug concentration, and prolong the drug residence time in the body. Such an effect comes from the promotion of the absorption process by the prodrug on the one hand, and the characteristic of the prodrug to slowly hydrolyze and release the original drug in plasma on the other hand. Such a gentle pharmacokinetic curve feature is beneficial for maintaining a lasting drug effect and reducing the incidence of adverse reactions. In sharp contrast, the prodrugs 17 and 18 with dimethylaminoacyl groups on the phenolic hydroxyl group are difficult to hydrolyze in vivo, resulting in almost no exposure of the original drug I-1 after oral administration. Another comparative example is the pivalic acid phenol ester prodrug 20, the hydrolysis of which is more difficult than the isobutyric acid phenol ester in 19. Part of 20 that does not have time to hydrolyze and release the original drug is also metabolized and excreted, resulting in the overall plasma exposure AUC being affected and Cmax being further reduced. The above technical effects cannot be inferred from the prior art and are creative and novel.

[0358] Table 12. Comparison of pharmacokinetic parameters of prodrugs 27, 30, 33 and the same type of comparative prodrugs 28 and 29

[0359]

[0360] Note: The oral dose is calculated based on the equimolar amount of 30 mg / kg of compound I-1 sodium salt.

[0361] As can be seen from the above comparison, introducing different prodrug groups on the sulfonamide nitrogen atom of the original drug I-1 results in significantly different pharmacokinetic characteristics. The pivalic acid aminomethyl ester prodrug group of prodrug 27, the isobutyric acid aminomethyl ester prodrug group of prodrug 30, and the diethylcarbamic acid aminomethyl ester prodrug group of prodrug 33 can promote the absorption process in the digestive tract and increase the plasma exposure AUC compared with other prodrug groups on the sulfonamide nitrogen atom. At the same time, prodrug 33 also reduces the peak blood drug concentration and significantly prolongs the residence time and half-life of the drug in the body. Such a gentle pharmacokinetic curve characteristic is beneficial for maintaining a lasting drug effect and reducing the incidence of adverse reactions. In contrast, when the prodrug groups on the sulfonamide nitrogen atom are ethyl carbonate aminomethyl ester (29) or isopropyl carbonate aminomethyl ester (28), because of their very easy hydrolysis characteristics, most of the original drug I-1 is hydrolyzed and released before being absorbed in the digestive tract, so their pharmacokinetic characteristics are almost indistinguishable from directly gavage of the original drug I-1 and cannot achieve the effects brought by prodrugs 27, 30, and 33.

[0362] Table 13. Comparison of pharmacokinetic parameters of deuterated compounds 42, 43 and I-1

[0363]

[0364] Note: The gavage dose is calculated according to the equimolar amount of 30 mg / kg of compound I-1 sodium salt.

[0365] The pharmacokinetic characteristics of deuterated compound 42 are similar to those of I-1, that is, replacing the four hydrogen atoms of the p-bromobenzenesulfonamide fragment with deuterium atoms does not bring about a change in pharmacokinetic properties.

[0366] Compared with I-1, the pharmacokinetic properties of deuterated compound 43 show a significant increase in plasma exposure and an extended residence time of the compound, indicating that replacing the two hydrogen atoms on the methylene group with deuterium atoms can reduce or slow down the metabolism or elimination process of I-1, thus achieving the effect of increasing exposure.

[0367] Table 14. Comparison of pharmacokinetic parameters of (+)-borneol ester compound 56 and I-1

[0368]

[0369]

[0370] Note: The gavage dose is calculated according to the equimolar amount of 30 mg / kg of compound I-1 sodium salt.

[0371] Those of ordinary skill in the art can understand that the above embodiments are specific examples for implementing the present invention, and in actual applications, various changes can be made in form and details without departing from the spirit and scope of the present invention.

Claims

1. Compounds of general formula I and their deuterated forms, Among them, R 1 is a hydroxyl group, R 11 , R 12 , R 13 , R 14 and R 15 are each independently selected from C 1-6 alkyl, C 3-10 cycloalkyl, C 1-6 alkyl substituted with an amino group, C 3-6 alkyl substituted with C 1-6 cycloalkyl, C 3-10 cycloalkyl substituted with an amino group, C 1-6 alkyl substituted with C 3-10 cycloalkyl; R 2 is hydrogen, R 21 is C 1-6 alkyl, C 1-4 alkyl substituted by C 1-6 alkoxy; -N(R a R b )); wherein, R a and R b are each independently methyl, ethyl, n-propyl, isopropyl, or R a and R b are bonded to form a ring; R 22 is C 1-6 alkyl; R 3 is hydrogen, wherein R 31 is selected from C 1-6 alkyl, C 3-6 cycloalkyl, phenyl, pyridyl, C 1-6 alkyl-substituted pyridyl; R 32 , R 33 , R 34 are each independently selected from C 1-6 alkyl, C 3-10 cycloalkyl, C 1-6 alkyl-substituted C 3-10 cycloalkyl.

2. The compound according to claim 1, wherein The R 11 is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-hexyl, n-pentyl, isopentyl, neopentyl, 2-methylpentyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3-methylpentyl, 2-ethylbutyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; and / or, R 12 is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-hexyl, n-pentyl, isopentyl, neopentyl, 2-methylpentyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3-methylpentyl, 2-ethylbutyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; and / or, R 13 is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-hexyl, n-pentyl, isopentyl, neopentyl, 2-methylpentyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3-methylpentyl, 2-ethylbutyl; more preferably methyl, ethyl, n-propyl or isopropyl; and / or, R 14 is tert-butyl, isoamyl, neopentyl or amino-substituted isoamyl; and / or, R 15 is methyl, isopropyl, tert-butyl, 2-ethylbutyl, cyclohexyl, bicyclo[2,2,1]heptyl (norbornanyl), 7,7-dimethylbicyclo[2.2.1]heptyl.

3. The compound according to claim 2, wherein, R 1 is methoxy, ethoxy, isopropoxy, tert-butoxy, 4. The compound according to claim 1, wherein, R 21 is C 1-4 alkyl, dimethylamino, diethylamino, N-methylethylamino or and / or, R 22 is C 1-4 alkyl; more preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl.

5. The compound according to claim 4, characterized in that, R 2 For 6. The compound according to claim 1, wherein R 31 is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, tert-pentyl, neopentyl, n-hexyl, pyridyl in which the hydrogen atom on the nitrogen is substituted by an alkyl group, cyclopropyl, cyclobutyl or phenyl; and / or, R 32 is methyl, ethyl, n-propyl, isopropyl, n-pentyl, isopentyl, tert-pentyl, neopentyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, one or more C 1-6 alkyl-substituted cyclopropyl, one or more C 1-6 alkyl-substituted cyclobutyl, one or more C 1-6 alkyl-substituted cyclopentyl, one or more C 1-6 alkyl-substituted cyclohexyl; and / or, R 33 is methyl, ethyl, n-propyl or isopropyl.

7. The compound according to claim 6, characterized in that, R 3 is hydrogen, 8. The compound according to claim 1, wherein, The compounds are selected from any one of the following:

9. A pharmaceutical composition, characterized in that, The pharmaceutical composition comprises the compound or its deuterated form according to any one of claims 1-8, and a pharmaceutically acceptable carrier or excipient.

10. Use of the compound according to any one of claims 1-8 and its deuterated form, or the pharmaceutical composition according to claim 9, for: (i) non-therapeutically inducing mitophagy in vitro; (ii) preventing and / or treating diseases related to mitophagy; (iii) preparing a medicament for preventing and / or treating diseases related to mitophagy.

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