Prodrug of small molecule compound having naphthylamine structure and use thereof

Abstract

Provided are a prodrug of a small molecule compound having a naphthylamine structure and the use thereof, wherein the prodrug is as shown in the following formula I. The provided prodrug of the small molecule compound having the naphthylamine structure has good stability and permeability, and a high oral bioavailability. Compared with the parent drug compound I-1, the prodrug exhibits improved plasma exposure, or a prolonged residence time with a higher AUC after administration. Furthermore, the prodrug has high safety with fewer adverse reactions, and a strong drug development potential.

Description

Prodrugs of small molecule compounds with naphthylamine structure and their uses

[0001] Cross-reference declaration

[0002] This application claims priority to Chinese application No. 2024105516481, filed on May 6, 2024, the contents of which are incorporated herein by reference in their entirety.

[0003] This application claims priority to Chinese application No. 2025100325459, filed on January 8, 2025, the contents of which are incorporated herein by reference in their entirety. Technical Field

[0004] This invention relates to the field of biomedicine, and in particular to prodrugs of small molecule compounds with a naphthylamine structure and their uses. Background Technology

[0005] Mitophagy, a type of organelle-specific autophagy, primarily aims to identify and clear dysfunctional mitochondria. Mitochondria play a central role in energy supply through oxidative phosphorylation and also perform important functions including energy metabolism, amino acid production, lipid synthesis, and ion homeostasis. They are crucial for maintaining the function of aerobic-dependent cell types such as neurons, muscle cells, and liver cells. The homeostasis regulation of mitochondrial formation and autophagy is a vital step in maintaining cellular function. Dysphagy dysfunction leads to the accumulation of damaged mitochondria, decreased ATP+ synthesis, and the production of large amounts of peroxides, resulting in alterations in cellular intermediate metabolites and triggering a series of pathological consequences. By enhancing mitophagy to clear aging or dysfunctional mitochondria, mitophagy can protect cells.

[0006] With the continuous development of drug development, oral bioavailability of drug molecules has become an important indicator for measuring drug efficacy and practicality. However, many prototype drugs suffer from poor oral bioavailability due to limitations in their physicochemical properties, such as low solubility, poor stability, and susceptibility to degradation by the gastrointestinal environment, thus affecting their therapeutic effects. To improve the oral bioavailability of drugs, researchers are constantly exploring new drug delivery strategies and molecular modification technologies.

[0007] The inventors previously developed a class of small molecule compounds with a naphthylamine structure as mitophagy inducers, disclosed in Chinese patent application number 202111108417.6. However, further research by the inventors revealed that pharmacokinetic data showed that the oral bioavailability of these compounds in mice and rats was only about 10%. Compound I-1, a representative example, exhibited extremely low Caco2 cell permeability and was a potential substrate for the efflux transporters Pgp and BCRP, thus limiting its druggability. Prodrug strategies are an important means of improving the physicochemical properties and pharmacokinetic characteristics of drugs in the field of drug development. Therefore, there is an urgent need to develop prodrugs of small molecule compounds with a naphthylamine structure to improve their stability, permeability, and oral bioavailability. Summary of the Invention

[0008] The purpose of this 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 of a prodrug containing a small molecule compound with the above-described naphthylamine structure.

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

[0011] To address the aforementioned technical problems, a first aspect of the present invention provides a compound of general formula I and its deuterated derivatives.

[0012] Among them, R 1 It is a hydroxyl group. R 11 R 12 R 13 R 14 and R 15 Selected independently from C 1-6 Alkyl, C 3-10 Cycloalkyl groups, C substituted with amino groups 1-6 Alkyl, C 3-6 Cycloalkyl-substituted C 1-6 Alkyl groups, C substituted with amino groups 3-10 cycloalkyl, C 1-6 Alkyl-substituted C 3-10 cycloalkyl;

[0013] R 2 It is hydrogen. R 21 C 1-6 Alkyl, C 1-4 alkoxy-substituted C 1-6 alkyl, -N(R a R b); where R a and R b Each of the following can be independently methyl, ethyl, n-propyl, isopropyl, or R a and R b Bonding to form a ring; R 22 C 1-6 alkyl;

[0014] R 3 It is hydrogen. Among them, R 31 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 Selected independently from C 1-6 Alkyl, C 3-10 cycloalkyl, C 1-6 Alkyl-substituted C 3-10 Cycloalkyl.

[0015] In some implementations, R 1 It is a hydroxyl group. R 11 R 12 R 13 R 14 and R 15 Selected independently from C 1-6 Alkyl, C 3-6 Cycloalkyl groups, C substituted with amino groups 1-6 Alkyl, C 3-6 Cycloalkyl-substituted C 1-6 alkyl;

[0016] R 2 It is hydrogen. R 21 C 1-6 Alkyl, C 1-4 alkoxy-substituted C 1-6 alkyl, -N(R a R b ); where R a and R b Each of the following can be independently methyl, ethyl, n-propyl, isopropyl, or R a and R b Bonding to form a ring; R 22 C 1-6 alkyl;

[0017] R 3 It is hydrogen. Among them, R 31 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 Selected independently from C 1-6 Alkyl, C 3-6 Cycloalkyl.

[0018] Preferably, the compound of formula I is not the following compound I-1.

[0019] In some preferred solutions, R 11 The molecule 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.

[0020] In some preferred solutions, R 12 The molecule 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.

[0021] In some preferred solutions, R 13 The compounds are 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.

[0022] In some preferred solutions, R 14 It is an isopentyl group substituted with tert-butyl, isopentyl, neopentyl, or amino.

[0023] In some preferred solutions, R 15 The compounds are methyl, isopropyl, tert-butyl, 2-ethylbutane, cyclohexane, bicyclo[2,2,1]heptane (norborne), and 7,7-dimethylbicyclo[2.2.1]heptane.

[0024] In some preferred solutions, R 15 It is 2-ethylbutane.

[0025] In some preferred solutions, for

[0026] In some preferred solutions, for

[0027] In some preferred solutions, for

[0028] In some preferred solutions, for

[0029] In some preferred solutions, for

[0030] In some preferred solutions, for

[0031] In some preferred solutions, R 15 It can be methyl, ethyl, n-butyl, isobutyl or tert-butyl.

[0032] In some preferred solutions, R 1 It consists of methoxy, ethoxy, isopropoxy, and tert-butoxy compounds.

[0033] In some preferred solutions, R 1 It consists of methoxy, ethoxy, isopropoxy, and tert-butoxy compounds.

[0034] In some optimal solutions, R 1 It is a hydroxyl group.

[0035] In some preferred solutions, R 21 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

[0036] In some preferred solutions, R22 C 1-4 Alkyl, more preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl.

[0037] In some preferred solutions, for

[0038] In some preferred solutions, for

[0039] In some preferred solutions, R 2 It is hydrogen.

[0040] In some preferred solutions, R 31 It can be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, tert-pentyl, neopentyl, n-hexyl, pyridyl, cyclopropane, cyclobutane, or phenyl, where the hydrogen atom on the nitrogen atom is replaced by an alkyl group.

[0041] In some preferred solutions, R 32 It is methyl, ethyl, n-propyl, isopropyl, n-pentyl, isopentyl, tert-pentyl, neopentyl, cyclopropane, cyclobutane, cyclopentyl or cyclohexyl, one or more C 1-6 Alkyl-substituted cyclopropane, 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 groups.

[0042] In some preferred solutions, R 32 The derivatives are methyl, ethyl, n-propyl, isopropyl, n-pentyl, isopentyl, tert-pentyl, neopentyl, cyclopropane, cyclobutane, cyclopentane, cyclohexane, bicyclo[2,2,1]heptane (norbornel), and 7,7-dimethylbicyclo[2.2.1]heptane.

[0043] In some preferred solutions, R 32 It can be methyl, ethyl, n-propyl, isopropyl, n-pentyl, isopentyl, tert-pentyl, neopentyl, cyclopropane, or cyclobutane.

[0044] In some preferred solutions, R 33 It can be methyl, ethyl, n-propyl or isopropyl.

[0045] In some preferred solutions, R 34 It can be methyl, ethyl, n-propyl or isopropyl.

[0046] In some preferred solutions, for

[0047] In some preferred solutions, for

[0048] In some preferred solutions, for

[0049] In some preferred solutions, for

[0050] In some preferred solutions, for

[0051] In some preferred solutions, R 3 It is hydrogen.

[0052] In some preferred solutions, R 3 It is hydrogen.

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

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

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

[0056] In some preferred embodiments, the deuterated form of the compound of general formula I is shown in general formula II (where D is deuterium).

[0057] In some preferred embodiments, the compound is selected from any of the following:

[0058] A second aspect of the present invention provides a pharmaceutical composition comprising the compound described in the first aspect of the present invention and a pharmaceutically acceptable carrier or excipient.

[0059] A third aspect of the invention provides the use of the compound described in the first aspect or the pharmaceutical composition described in the second aspect of the invention for:

[0060] (i) In vitro non-therapeutic induction of mitophagy;

[0061] (ii) Prevention and / or treatment of diseases associated with mitophagy; and / or

[0062] (iii) Prepare drugs for the prevention and / or treatment of diseases related to mitophagy.

[0063] Compared with the prior art, the present invention has at least the following advantages:

[0064] This invention modifies the physicochemical properties of the original drug by rationally selecting and introducing prodrug groups or isotope substitutions (especially deuteration), thereby altering its pharmacokinetic characteristics, improving its oral bioavailability, and enhancing its stability, safety, and therapeutic efficacy. The prodrug provided by this invention exhibits good stability and permeability, high oral bioavailability, and compared to the original drug compound I-1, it shows increased plasma exposure after administration, longer residence time, and higher AUC, along with good safety and fewer adverse reactions, demonstrating promising prospects for drug development.

[0065] It should be understood that, within the scope of this invention, the above-described technical features of this invention and the technical features specifically described below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be described in detail here. Detailed Implementation

[0066] Through extensive and in-depth research, the inventors have developed a series of prodrugs with better stability, permeability, or oral bioavailability compared to previously developed naphthylamine structures. These prodrugs can be used as mitophagy inducers to treat related diseases and show great promise as pharmaceutical products. This invention is based on these findings.

[0067] compound

[0068] Embodiments of the present invention relate to a compound of general formula I and its deuterated derivatives.

[0069] Among them, R 1 It is a hydroxyl group. R 11 R 12 R 13 R 14and R 15 Selected independently from C 1-6 Alkyl, C 3-10 Cycloalkyl groups, C substituted with amino groups 1-6 Alkyl, C 3-6 Cycloalkyl-substituted C 1-6 Alkyl groups, C substituted with amino groups 3-10 cycloalkyl, C 1-6 Alkyl-substituted C 3-10 cycloalkyl;

[0070] R 2 It is hydrogen. R 21 C 1-6 Alkyl, C 1-4 alkoxy-substituted C 1-6 alkyl, -N(R a R b ); where R a and R b Each of the following can be independently methyl, ethyl, n-propyl, isopropyl, or R a and R b Bonding to form a ring; R 22 C 1-6 alkyl;

[0071] R 3 It is hydrogen. Among them, R 31 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 Selected independently from C 1-6 Alkyl, C 3-10 cycloalkyl, C 1-6 Alkyl-substituted C 3-10 cycloalkyl;

[0072] Furthermore, the compound of formula I is not of formula I-1.

[0073] In some schemes, R 1 It is a hydroxyl group. R 11 R 12 R 13 R 14 and R 15 Selected independently from C 1-6 Alkyl, C 3-6Cycloalkyl groups, C substituted with amino groups 1-6 Alkyl, C 3-6 Cycloalkyl-substituted C 1-6 alkyl.

[0074] In some schemes, R 3 It is hydrogen. Among them, R 31 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 Selected independently from C 1-6 Alkyl, C 3-6 Cycloalkyl.

[0075] In some preferred embodiments, the pyridinyl group is

[0076] In some preferred solutions, C 1-6 Alkyl-substituted pyridinyl groups are pyridinyl groups in which the hydrogen atom on the nitrogen atom is replaced by an alkyl group.

[0077] In some preferred solutions, C 1-6 The alkyl group 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.

[0078] In some preferred solutions, C 3-10 Cycloalkyl groups are preferably C 3-6 Cycloalkyl, such as cyclopropane, cyclobutane, cyclopentane, or cyclohexane.

[0079] In some preferred solutions, C 3-6 The cycloalkyl group is cyclopropane, cyclobutane, cyclopentane, or cyclohexane.

[0080] In some preferred solutions, C 1-4 The alkoxy group can be methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, or tert-butoxy.

[0081] In some preferred solutions, C 1-6 Alkyl-substituted C 3-10 Cycloalkyl groups are methyl-substituted cyclohexanes and methyl-substituted bicyclic [2,2,1]heptyl (norbornel), for example:

[0082] As R1 In a more preferred embodiment of the present invention, R 1 for R 11 R 12 and R 13 As shown in the context of this invention.

[0083] Compared to the sodium salt of the original drug compound I-1, R 1 for It helps to simultaneously increase the drug plasma exposure AUC and Cmax, where R 11 Preferably, it is C 1-6 Straight-chain or branched alkyl groups, 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; or R 11 C 3-6 Cycloalkyl groups, such as cyclopropane, cyclobutane, cyclopentane, or cyclohexane. R 11 More preferably, it is methyl, ethyl, n-propyl, isopropyl, tert-butyl, or cyclopropane. In a more preferred embodiment of the invention, for

[0084] Compared to the sodium salt of the original drug compound I-1, R 1 for It helps to simultaneously increase the drug's plasma exposure Cmax and AUC, and helps to improve the rate and extent of absorption in vivo, among which R 12 Preferably, it is C 1-6 Straight-chain or branched alkyl groups, 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; or R 12 C 3-6 Cycloalkyl groups, such as cyclopropane, cyclobutane, cyclopentane, or cyclohexane. R 11 More preferably, it is methyl, ethyl, n-propyl, isopropyl, tert-butyl, or cyclopropane. In a more preferred embodiment of the invention, for

[0085] Compared to the sodium salt of the original drug compound I-1, R 1 for It helps to increase drug plasma exposure and AUC value, among which R 13 Preferably, it is C1-6 Straight-chain or branched alkyl groups, 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 More preferably, it is methyl, ethyl, n-propyl, or isopropyl. In a more preferred embodiment of the invention, for R 1 for At that time, the compound had plasma exposure levels of sodium salt comparable to those of the original drug compound I-1, of which R 14 Preferably, it is tert-butyl, isopentyl, neopentyl, or amino-substituted isopentyl. In a more preferred embodiment of the invention, for In a preferred embodiment of the present invention for In a preferred embodiment of the present invention for

[0086] R 1 for And R 15 When the compound is methyl, isobutyl, tert-butyl, or 2-ethylbutane, it has plasma exposure levels comparable to the sodium salt of the original drug compound I-1, but R 15 When the compound is isopropyl, its plasma exposure actually decreases.

[0087] In a more preferred embodiment of the present invention, R 15 It can be methyl, ethyl, n-butyl, isobutyl or tert-butyl.

[0088] In a more preferred embodiment of the present invention, R 1 Selected from any of the following: methoxy, ethoxy, isopropoxy, tert-butoxy.

[0089] In the most preferred embodiment of the present invention, R 1 It is a hydroxyl group. When R 1 When it is a hydroxyl group, R 2 and R 3 At least one of them differs from the original drug compound I-1, namely R 2 and R 3 They are not both hydrogen.

[0090] As R 2In a more preferred embodiment of the present invention, R 2 for Compared to the sodium salt of the original drug compound I-1, R 2 for It helps increase the AUC value of plasma exposure. 21 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 R 22 C 1-4 Alkyl groups, more preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl. In a preferred embodiment of the invention... for In a preferred embodiment of the present invention for

[0091] In a preferred embodiment of the present invention, R 2 It is hydrogen. When R 2 When it is hydrogen, R 1 and R 3 At least one of them differs from the original drug compound I-1, namely R 1 Not hydroxyl and / or R 3 It is not hydrogen.

[0092] As R 3 In a more preferred embodiment of the present invention, R 3 for

[0093] Compared to the sodium salt of the original drug compound I-1, R 3 for It helps improve oral bioavailability, reduce peak plasma concentration, and / or prolong drug residence time in the body, which is beneficial for the development of low-toxicity sustained-release drugs. Among them, R 31 Preferably, the alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, tert-pentyl, neopentyl, n-hexyl, pyridyl, cyclopropane, cyclobutane, or phenyl, in which the hydrogen atom on the nitrogen atom is replaced by an alkyl group. In a preferred embodiment of the invention, for

[0094] Compared to the sodium salt of the original drug compound I-1, R 3 for It helps improve oral bioavailability, reduce peak plasma concentration, and / or prolong drug residence time in the body, which is beneficial for the development of low-toxicity sustained-release drugs. Among them, R 32 Preferably, it is methyl, ethyl, n-propyl, isopropyl, n-pentyl, isopentyl, tert-pentyl, neopentyl, cyclopropane, or cyclobutyl. In a preferred embodiment of the invention... for

[0095] In a preferred embodiment of the present invention, R 3 It is hydrogen.

[0096] Compared to the sodium salt of the original drug compound I-1, R 3 for Peak plasma concentration C of the compound max And AUC is also advantageous, among which R 33 and R 34 Each of the following is preferably methyl, ethyl, n-propyl, or isopropyl, individually and independently. In a preferred embodiment of the invention, for In a preferred embodiment of the present invention for

[0097] In the most preferred embodiment of the present invention, R 3 It is hydrogen. When R 3 When it is hydrogen, R 1 and R 2 At least one of them differs from the original drug compound I-1, namely R 1 Not hydroxyl and / or R 2 It is not hydrogen.

[0098] In a preferred embodiment of the present invention, R 1 for or R 3 for (For example, prodrugs 56, 57, and 58) On the one hand, they increase the permeability of the parent drug, thereby improving its oral bioavailability and plasma exposure. On the other hand, the dextromethorphan released by the prodrug in vivo has a synergistic effect on the pharmacological effects of the parent drug, significantly enhancing its efficacy.

[0099] In a preferred embodiment of the present invention, at least one hydrogen atom in the compound of general formula I is substituted with deuterium to form a deuterated product, which increases plasma exposure compared to the original drug compound I-1. In another preferred embodiment of the present invention, in the compound of general formula I, the substitution of hydrogen atoms at the Rc and / or Rd positions with deuterium to form a deuterated product can reduce or slow down the metabolism or elimination process of the original drug compound I-1, thereby achieving the effect of increasing exposure.

[0100] In a preferred embodiment of the present invention, the compound is selected from any of the following:

[0101] In a preferred embodiment of the present invention, compounds of general formula I and their deuterated derivatives are provided.

[0102] Among them, R 1 It is a hydroxyl group. R 11 and R 12 C, each independently 1-6 Alkyl or C 3-6 cycloalkyl;

[0103] R 2 It is hydrogen. R 21 C 1-6 Alkyl or -N(R) a R b ); where R a and R b Each can be independently methyl or ethyl;

[0104] R 3 It is hydrogen. Among them, R 31 C 1-6 Alkyl or C 3-6 cycloalkyl; R 32 and R 32 C, each independently 1-6 alkyl;

[0105] Furthermore, compounds of general formula I are not compounds I-1.

[0106] In a more preferred embodiment of the present invention, R 1 It is a hydroxyl group. The optimal choice is hydroxyl group.

[0107] In a preferred embodiment of the present invention, R 2 It is hydrogen. Optimal

[0108] In a preferred embodiment of the present invention, R 3 It is hydrogen. Optimal

[0109] In a preferred embodiment of the present invention, the compound is selected from any of the following:

[0110] In a preferred embodiment of the present invention, the deuterated form of the compound of formula I is shown in formula II (where D is deuterium).

[0111] Pharmaceutical Composition

[0112] Embodiments of the present invention also relate to pharmaceutical compositions comprising a compound of formula I or a deuterated thereof and pharmaceutically acceptable excipients.

[0113] use

[0114] Embodiments of the present invention also relate to the use of compounds of general formula I, their deuterated derivatives, or pharmaceutical compositions containing them, for:

[0115] (i) In vitro non-therapeutic induction of mitophagy;

[0116] (ii) Prevention and / or treatment of diseases associated with mitophagy; and / or

[0117] (iii) Prepare drugs for the prevention and / or treatment of diseases related to mitophagy.

[0118] Treatment

[0119] Embodiments of the present invention also relate to methods for preventing and / or treating diseases associated with mitophagy, comprising the steps of administering to a test subject a therapeutically effective amount of a compound of formula I or a deuterated form thereof, or a pharmaceutical composition containing the same.

[0120] In a preferred embodiment, the administration method is oral, intravenous, or intramuscular injection.

[0121] As used herein, the term "alkyl" refers to a straight-chain or branched saturated aliphatic hydrocarbon group. The term "C"...1-6 "Alkyl" refers to a straight-chain or branched alkyl group having 1 to 6 carbon atoms, and is not limited to, 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 their various branched isomers. The term "C"... 1-4 "Alkyl" refers to a straight-chain or branched alkyl group having 1 to 4 carbon atoms, C 1-4 If an alkyl group appears at the end of the molecule, it is not limited to, for example: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl; or, when two parts of the molecule are connected by the alkyl group, it is not limited to, for example: -CH2-, -CH2-CH2-, -CH(CH3)-, -CH2-CH2-CH2-, -CH(C2H5)-, -C(CH3)2-, C 1-4 Each hydrogen atom of an alkyl carbon can be replaced by a substituent further listed herein.

[0122] As used herein, the term "alkoxy" refers to a group having an "O-alkyl" structure, wherein the definition of alkyl is as described above. The term "C" 1-6 "Alkoxy" refers to alkoxy groups having 1 to 6 carbon atoms, and non-limiting examples include: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, isobutoxy, n-pentoxy, etc.

[0123] The term "cycloalkyl" refers to a monocyclic or bicyclic saturated carbon ring, each having 3 to 10 carbon atoms. "Fused analogues" of cycloalkyl refer to a monocyclic ring fused with an aryl or heteroaryl group, wherein the linking site is in the non-aromatic portion. Examples of cycloalkyl and their fused analogues include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydronaphthyl, decahydronaphthyl, dihydroindenyl, etc. Further, the term "cycloalkyl" in this disclosure includes bridged ring systems and spirocyclic systems. The term "C 3-10 "Cycloalkyl" refers to a cycloalkyl group having 3 to 10 carbon atoms, including spirocyclic or bridged cycloalkyl groups, exemplarily such as bicyclo[4.2.2]decane, bicyclo[2.2.1]heptyl, and adamantyl. These cycloalkyl groups may optionally be substituted with other substituents, such as pinyl, camphene, etc., substituted with methyl.

[0124] As used herein, the term "amino group" refers to a group formed when at least one hydrogen atom in an amino group is replaced by an alkyl group, such as "-N(R)".a R b As shown in the figure, R a and R b Each group is independently a straight-chain or branched alkyl group. In embodiments of the present invention, the amino group is dimethylamino, diethylamino, or methylethylamino, etc.

[0125] As used herein, the terms “aryl,” “aryl ring,” and “aromatic ring” are used interchangeably to refer to an all-carbon monocyclic, all-carbon non-fused polycyclic (rings connected by covalent bonds, not fused), or all-carbon fused polycyclic (i.e., rings sharing adjacent carbon atom pairs) group, wherein at least one ring in the group is aromatic, i.e., has a cyclic conjugated π-electron system.

[0126] As used in this invention, the term "deuterated" refers to the substitution of hydrogen in a compound by deuterium. Deuterium is an isotope of hydrogen, with the chemical symbol D or 2H.

[0127] As used herein, the term "pharmaceutical composition" refers to a mixture of the compound described herein with "excipients" such as carriers, stabilizers, diluents, dispersants, suspending agents, and / or thickeners. Pharmaceutical compositions facilitate the administration of compounds to a living organism. Various techniques for administering compounds exist in the art, including but not limited to: rectal, oral, intravenous, aerosol, parenteral, ocular, pulmonary, and topical administration.

[0128] As used herein, the term “subject” means an animal, including but not limited to primates (e.g., humans), monkeys, cattle, 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 (e.g., humans).

[0129] As used herein, in the context of treating a disease or disorder, the term “treat, treating, and treatment” means including the relief or elimination of a disorder, disease, or condition, wherein the term “disorder” as used herein should always be understood to mean “disorder, disease, or condition” or one or more symptoms associated with a disorder; or to slow the progression, spread, or worsening of a disorder or condition or one or more symptoms thereof.

[0130] Citation declaration

[0131] The full text of Chinese Patent Application No. 2021111084176, entitled "A Class of Small Molecule Compounds Having a Naphthylamine Structure and Their Applications", is incorporated herein by reference.

[0132] The full text of Chinese Patent Application No. 202210575778X, entitled "Use of a class of small molecule compounds having a naphthylamine structure," is incorporated herein by reference.

[0133] The full text of Chinese Patent Application No. 2023103137630, entitled "Solid Form of Naphthylamine Mitophagy Inducer, Preparation Method Thereof, Pharmaceutical Composition and Use", is incorporated herein by reference.

[0134] The full text of Chinese Patent Application No. 2023115506763, entitled "Use of a class of small molecule compounds having a naphthylamine structure," is incorporated herein by reference.

[0135] The full text of Chinese Patent Application No. 2023115501191, entitled "Naphthalene-ring Small Molecule Compounds", is incorporated herein by reference.

[0136] The full text of patent application No. PCT / CN2022 / 119825, entitled "A Class of Small Molecule Compounds Having a Naphthylamine Structure and Their Applications", is incorporated herein by reference.

[0137] The full text of patent application No. PCT / CN2023 / 095716, entitled "Use of a class of small molecule compounds having a naphthylamine structure," is incorporated herein by reference.

[0138] The full text of patent application No. PCT / CN2024 / 082357, entitled "Use of a class of small molecule compounds having a naphthylamine structure," is incorporated herein by reference.

[0139] The full text of patent application No. PCT / CN2024 / 082356, entitled "Naphthalene ring small molecule compounds", is incorporated herein by reference.

[0140] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the present invention is further described below in conjunction with specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments that do not specify specific conditions are generally performed under conventional conditions or as recommended by the manufacturer. Unless otherwise stated, percentages and parts are weight percentages and parts by weight. Unless otherwise specified, the experimental materials and reagents used in the following embodiments are commercially available.

[0141] Unless otherwise specified, the technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application pertains. It should be noted that the terms used herein are for the purpose of describing particular embodiments only and are not intended to limit the exemplary embodiments of this application.

[0142] Unless otherwise specified, the term “or” means the term “and / or” and is used interchangeably with the term “and / or”.

[0143] As used herein, including the appended claims, unless the context clearly indicates otherwise, the singular forms of words such as “an,” “a,” and “the” include their respective plural referents.

[0144] Example 1

[0145] In this embodiment, 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 via the following general reaction formula:

[0146] Compound 8 (93 mg, 0.2 mmol, 1.0 eq) was dissolved in 20 mL of THF at room temperature, and alcohol or methanesulfonamide (0.8 mmol, 4.0 eq) was added. Acetic acid (24 mg, 0.4 mmol, 2.0 eq) was added as a catalyst, and the reaction was allowed to proceed overnight. After the overnight reaction, a small amount of sodium bicarbonate aqueous solution was added to adjust the pH to neutral, silica gel was added and stirred, and the corresponding compound was purified by silica gel column chromatography.

[0147] Compound 1 (84 mg, yield 85%). 1 H NMR(400MHz,DMSO-d6)δ11.01(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=13.8Hz,1H),3.65(s,3H),3.61(d,J=13.8Hz,1H). LCMS: m / z=495.7[MH] - .

[0148] Compound 2 (75 mg, yield 71%). 1H NMR(400MHz,DMSO-d6)δ10.97(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 = 6.3Hz, 1H), 4.01 (d, J = 13.7Hz, 1H), 3.58 (d, J = 13.6Hz, 1H), 1.13 (d, J = 6.2Hz, 3H), 1.09 (d, J = 6.2Hz, 3H). LCMS: m / z=523.7[MH] - .

[0149] Compound 3 (24 mg, yield 22%). LCMS: m / z = 537.8 [MH] - .

[0150] Compound 7 (77 mg, yield 65%). 1 H-NMR (400MHz, DMSO-d6) δ10.19(s,1H),8.26(dd,J=6.3,3.2Hz,1H),8.00(dd,J=6.3,3.3Hz,1H),7.71(d,J=8.6Hz,2H),7.64– 7.50(m,3H),7.20(s,1H),5.08–4.90(m,2H),4.13(d,J=13.8Hz,1H),3.67(d,J=13.8Hz,1H),2.09(s,3H).LCMS: m / z=594.0[MH] - .

[0151] Compound 9 (16 mg, yield 14%). LCMS: m / z = 558.7 [MH] - .

[0152] Compound 38 (87 mg, yield 77%). LCMS: m / z = 565.8 [MH] - .

[0153] Compound 41 (71 mg, yield 62%). LCMS: m / z = 571.7 [MH] - .

[0154] Compound 56 (53 mg, yield 49%). 1H NMR(400MHz,DMSO-d6)δ10.99(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=13.7,6.3Hz,1H),3 .64(dd,J=17.3,13.7Hz,1H),2.32–2.12(m,1H),1.88–1.70(m,1H),1.70–1.54(m,2H),1.24–1.1 8(m,1H),1.16–1.07(m,1H),0.94(dd,J=13.8,3.5Hz,1H),0.87–0.78(m,6H),0.77–0.67(m,3H). LCMS: m / z=618.2[MH] - .

[0155] Example 2

[0156] In this embodiment, compounds 4, 5, and 6 were synthesized and characterized. Compounds 4, 5, and 6 were synthesized using the following general reaction formula:

[0157] At room temperature, 2-((4-((4-bromophenyl)sulfonamido)-1-hydroxynaphth-2-yl)sulfinyl)acetic acid (I-1) (484 mg, 1.0 mmol, 1.0 eq) was suspended in dichloromethane (5 mL), followed by the addition of silver oxide (462 mg, 2.0 mmol, 2.0 eq) and the chloromethyl derivative, and the reaction was allowed to proceed overnight. After the reaction was complete, the solid was removed by filtration, and the product was concentrated and purified by silica gel column chromatography to obtain the corresponding product.

[0158] Compound 4 (101 mg, yield 17%). LCMS: m / z = 595.7 [MH] - .

[0159] Compound 5 (171 mg, yield 28%). LCMS: m / z = 609.7 [MH] - .

[0160] Compound 6 (75 mg, yield 12%). LCMS: m / z = 623.7 [MH] - .

[0161] Example 3

[0162] In this embodiment, compounds 10, 11, 12, 13, 14, 15, and 16 were synthesized and characterized. Compounds 10, 11, 12, 13, 14, 15, and 16 were synthesized via the following general reaction formula:

[0163] Compound 8 (93 mg, 0.2 mmol, 1.0 eq) was dissolved in 20 mL of THF at room temperature, and an amine or thiol (0.8 mmol, 4.0 eq) was added. After the reaction was complete, silica gel was added and the mixture was purified by silica gel column chromatography to obtain the corresponding compound.

[0164] Compound 10 (79 mg, yield 77%). LCMS: m / z = 511.7 [MH] - .

[0165] Compound 11 (56 mg, yield 52%). LCMS: m / z = 539.7 [MH] - .

[0166] Compound 12 (95 mg, yield 81%). LCMS: m / z = 587.9 [MH] - .

[0167] Compound 13 (69 mg, yield 70%). 1 H-NMR (400MHz, DMSO-d6) δ10.91(bs,1H),10.22(bs,1H),8.24(dd,J=8.2,1.0Hz,1H),8.15(m,1H),7.91(dd,J=8.3,1.0Hz,1H),7.76–7 .63(m,2H),7.60–7.42(m,4H),7.30(s,1H),3.85(d,J=13.4Hz,1H),3.47(d,J=13.4Hz,1H),2.63(d,J=4.6Hz,3H).LCMS: m / z=494.6[MH] - .

[0168] Compound 14 (60 mg, yield 59%). 1 H-NMR (400MHz, DMSO-d6) δ10.92(s,1H),10.16(s,1H),8.32–8.18(m,1H),8.08–7.97(m,1H),7.73(d,J=8.6Hz,2H),7.63– 7.49(m,4H),7.21(s,1H),4.05(d,J=14.6Hz,1H),3.79(d,J=14.6Hz,1H),2.98(s,3H),2.87(s,3H).LCMS: m / z=508.5[MH]- .

[0169] Compound 15 (64 mg, yield 61%). 1 H-NMR (400MHz, DMSO-d6) δ10.90(s,1H),10.22(s,1H),8.30(d,J=4.1Hz,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=13.4Hz,1H),3.43(d,J=13.4Hz,1H),2.66(m,1H),0.64(m,2H),0.40(dd,J=3.8,1.8Hz,2H).LCMS: m / z=520.8[MH] - .

[0170] Compound 16 (43 mg, yield 38%). LCMS: m / z = 570.7 [MH] - .

[0171] Example 4

[0172] In this embodiment, compounds 17, 19, 20, 26, 40, and 58 were synthesized and characterized. Compounds 17, 19, 20, 26, 40, and 58 were synthesized via the following general reaction formula:

[0173] Synthesis and characterization of compound 19:

[0174] Step 1: Synthesis of intermediate Int-1:

[0175] At room temperature, methyl 2-((4-((4-bromophenyl)sulfonamido)-1-hydroxynaphth-2-yl)thio)acetate (Cpd 32 in the 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'-tetramethylchloroformamidine hexafluorophosphate (1.74 g, 6.23 mmol, 1.5 eq) were dissolved in acetonitrile (20 ml) and stirred overnight at room temperature. The reaction mixture was washed with water (50 mL), extracted with ethyl acetate (20 mL x 2), and the combined organic layers were washed with saturated brine (50 mL x 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 = 1:8) to give an off-white solid intermediate Int-1 (480 mg, yield: 21%). LCMS: m / z = 549.6 [MH] -

[0176] Step 2: Synthesis of intermediate Int-2:

[0177] 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 mixture of tetrahydrofuran (10 mL) and water (1 mL) under nitrogen protection. After the addition was complete, the mixture was heated to 70 °C and reacted overnight. After overnight reaction, the reaction solution was cooled to room temperature and poured into water (50 mL). While stirring, the pH of the solution was adjusted to approximately 6 with 4 M hydrochloric acid. A solid precipitated out. The solid was filtered, and washed with water (30 mL x 2) to obtain a brownish-red intermediate Int-2 (0.98 g, 100% yield). LCMS: m / z = 534.6 [MH] -

[0178] Step 3: Synthesis of Compound 19:

[0179] 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 peroxide monosulfonate (96.5 mg, 0.28 mmol, 0.5 eq) was added at a temperature below 0 °C. After the addition was complete, the mixture was stirred for 10 min, and then potassium peroxide monosulfonate (96.5 mg, 0.28 mmol, 0.5 eq) was added. After the addition was complete, the mixture was kept at a temperature below 0 °C and stirred for 10 min, then the mixture was allowed to rise to room temperature and reacted for 3 h. A 10% sodium thiosulfate aqueous 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 was then added to ethyl acetate and crystallized at -40 °C. The mixture was filtered, and the solid was washed with ethyl acetate (2 mL * 2) to give compound 19 (80 mg, yield 26%). LCMS: m / z = 551.6 [MH] - . 1 H-NMR (400MHz, DMSO-d6) δ13.38(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).

[0180] Synthesis and characterization of compound 20:

[0181] Step 1: Synthesis of intermediate Int-1:

[0182] At room temperature, methyl 2-((4-((4-bromophenyl)sulfonamido)-1-hydroxynaphth-2-yl)thio)acetate (Cpd 32 in the Journal of Medicinal Chemistry 2014, 57(10), 4111-4133) (2 g, 4.13 mmol, 1.0 equivalent) and pyridine (0.72 g, 9.09 mmol, 2.2 equivalent) were added to a 20 mL solution of tetrahydrofuran. Under nitrogen protection, trimethylacetyl chloride (0.89 g, 8.26 mmol, 2.0 equivalent) was added dropwise below 0 °C. After the addition was complete, the temperature was raised to 70 °C and the reaction was allowed to proceed overnight. After overnight cooling, the reaction mixture was washed with water (50 mL), extracted with ethyl acetate (20 mL x 2), and the combined organic layers were washed with saturated brine (50 mL x 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 give an off-white solid intermediate Int-1 (600 mg, yield: 27%). LCMS: m / z = 563.7 [MH] -

[0183] Step 2: Synthesis of intermediate Int-2:

[0184] At room temperature, intermediate Int-1 (1 g, 1.77 mmol, 1.0 eq) and potassium carbonate (0.49 g, 3.53 mmol, 2.0 eq) were dissolved in a mixture of tetrahydrofuran (10 mL) and water (1 mL) under nitrogen protection. After the addition was complete, the mixture was heated to 70 °C and reacted overnight. After overnight reaction, the reaction solution was cooled to room temperature and added dropwise to water (100 mL). While stirring, the pH of the solution was adjusted to approximately 6 with 4 M hydrochloric acid. A solid precipitated out. The solid was filtered, and washed with water (30 mL x 2) to obtain a white intermediate Int-2 (0.98 g, 100% yield). LCMS: m / z = 549.7 [MH] -

[0185] Step 3: Synthesis of Compound 20:

[0186] 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 peroxide monosulfonate (156.7 mg, 0.45 mmol, 0.5 eq) was added at a temperature below 0 °C. After the addition was complete, the mixture was stirred for 10 min, and then potassium peroxide monosulfonate (156.7 mg, 0.45 mmol, 0.5 eq) was added. After the addition was complete, the mixture was kept at a temperature below 0 °C and stirred for 10 min, then the mixture was allowed to rise to room temperature and reacted for 3 h. A 10% sodium thiosulfate aqueous 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 was dissolved in acetonitrile and crystallized at -40 °C. The crystals were filtered, and the solid was washed with acetonitrile (2 mL * 2) to give compound 20 (160 mg, yield 31%). LCMS: m / z = 565.6 [MH] - . 1 H-NMR(400MHz,DMSO-d6)δ13.35(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).

[0187] Synthesis and characterization of compound 17: Following the synthetic steps of compound 20, replacing trimethylacetyl chloride in step one with dimethylcarbamoyl chloride yields compound 17. LCMS: m / z = 552.6 [MH] - . 1 H-NMR(400MHz,DMSO-d6)δ13.43(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).

[0188] Synthesis and characterization of compound 26: Following the synthetic steps of compound 20, replacing trimethylacetyl chloride in step one with isopropyl chloroformate yields compound 26. LCMS: m / z = 567.7 [MH] - .

[0189] Synthesis and characterization of compound 40: Following the synthetic steps of compound 20, replacing trimethylacetyl chloride in step one with benzoyl chloride yields compound 40. LCMS: m / z = 585.7 [MH] - .

[0190] Synthesis and characterization of compound 58: Following the synthesis steps of compound 20, trimethylacetyl chloride in step one was replaced with... Compound 58 was obtained. LCMS: m / z = 662.4 [MH] - .

[0191] Example 5

[0192] In this embodiment, compound 18 was synthesized and characterized.

[0193] Step 1: Synthesis of intermediate Int-1:

[0194] At room temperature, methyl 2-((4-((4-bromophenyl)sulfonamido)-1-hydroxynaphth-2-yl)thio)acetate (Cpd 32 in the 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 equivalences) were added to a solution of tetrahydrofuran (20 mL). Under nitrogen protection, dimethylcarbamoyl chloride (0.89 g, 8.26 mmol, 2.0 equivalences) was added dropwise below 0 °C. After the addition was complete, the temperature was raised to 70 °C and the reaction was allowed to proceed overnight. After overnight cooling, the reaction mixture was washed with water (50 mL), extracted with ethyl acetate (20 mL x 2), and the combined organic layers were washed with saturated brine (50 mL x 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 give an off-white solid intermediate Int-1 (571 mg, yield: 25%). LCMS: m / z = 550.7 [MH] -

[0195] Step 2: Synthesis of Compound 18:

[0196] 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 peroxide monosulfonate (37.9 mg, 0.11 mmol, 0.5 eq) was added at a temperature below 0 °C. After the addition was complete, the mixture was stirred for 10 min, and then potassium peroxide monosulfonate (37.9 mg, 0.11 mmol, 0.5 eq) was added. After the addition was complete, the mixture was kept at a temperature below 0 °C and stirred for 10 min, then the mixture was allowed to rise to room temperature and reacted for 3 h. A 10% sodium thiosulfate aqueous 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 was dissolved in acetonitrile and crystallized at -40 °C. The crystals were filtered, and the solid was washed with acetonitrile (2 mL * 2) to give compound 18 (46 mg, yield 37%). LCMS: m / z = 564.8 [MH] - . 1 H-NMR(400MHz,DMSO-d6)δ10.61(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).

[0197] Example 6

[0198] In this embodiment, compound 21 was synthesized and characterized.

[0199] Step 1: Synthesis of intermediate Int-1:

[0200] At room temperature, methyl 2-((4-((4-bromophenyl)sulfonamido)-1-hydroxynaphth-2-yl)thio)acetate (Cpd 32 in the 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'-tetramethylchloroformamidine hexafluorophosphate (1.74 g, 6.23 mmol, 1.5 eq) were dissolved in acetonitrile (20 mL) and stirred overnight at room temperature. The reaction mixture was washed with water (50 mL), extracted with ethyl acetate (20 mL x 2), and the combined organic layers were washed with saturated brine (50 mL x 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 = 1:8) to give an off-white solid intermediate Int-1 (520 mg, yield: 21%). LCMS: m / z = 600.7 [MH] -

[0201] Step 2: Synthesis of intermediate Int-2:

[0202] 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 mixture of tetrahydrofuran (10 mL) and water (1 mL) under nitrogen protection. After the addition was complete, the mixture was heated to 70 °C and reacted overnight. After overnight reaction, the reaction solution was cooled to room temperature and added dropwise to water (50 mL). While stirring, the pH of the solution was adjusted to approximately 6 with 4 M hydrochloric acid. A solid precipitated out. The solid was filtered, and washed with water (30 mL x 2) to obtain a brownish-red intermediate Int-2 (0.48 g, 100% yield). LCMS: m / z = 586.6 [MH] -

[0203] Step 3: Synthesis of Compound 21:

[0204] 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 peroxide monosulfonate (117.8 mg, 0.34 mmol, 0.5 eq) was added at a temperature below 0 °C. After the addition was complete, the mixture was stirred for 10 min, and then potassium peroxide monosulfonate (117.8 mg, 0.34 mmol, 0.5 eq) was added. After the addition was complete, the mixture was kept at a temperature below 0 °C and stirred for 10 min, then the mixture was allowed to rise to room temperature and reacted for 3 h. A 10% sodium thiosulfate aqueous 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 was then added to ethyl acetate and crystallized at -40 °C. The mixture was filtered, and the solid was washed with ethyl acetate (2 mL * 2) to give compound 21 (67 mg, yield 16.3%). LCMS: m / z = 602.7 [MH] -

[0205] Example 7

[0206] In this embodiment, compound 22 was synthesized and characterized.

[0207] Step 1: Synthesis of intermediate Int-1

[0208] Methyl 2-((4-(((4-bromophenyl)sulfonamido)-1-hydroxynaphthyl-2-yl)thio)acetate (Cpd 32 in the 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) under nitrogen protection. Tetrabutylammonium iodide (880 mg, 2.4 mmol, 2.4 eq) and sodium hydrogen hydride (60%, 96 mg, 2.4 mmol, 2.4 eq) were added, and the reaction was allowed to proceed for 1 hour. Chloromethyl isobutyrate (2.0 mmol, 2.0 eq) was then added, and the reaction was allowed to proceed overnight at 45 °C. After the reaction was complete, the reaction solution was poured into water (40 mL), extracted with ethyl acetate (20 mL * 2), the organic phases were combined, dried with anhydrous sodium sulfate, concentrated and purified by silica gel column chromatography to obtain the corresponding intermediate Int-1 (326 mg, yield: 48%).

[0209] Step 2: Synthesis of Compound 22

[0210] Intermediate Int-1 (68 mg, 0.1 mmol, 1.0 eq) was dissolved in ethyl acetate (2 mL) at room temperature, and m-CPBA (85% , 21 mg, 1.2 mmol, 1.2 eq) was added. The reaction was allowed to proceed overnight. After overnight reaction, the reaction was quenched with saturated sodium thiosulfate solution (0.5 mL), separated, and the organic phase was dried over anhydrous sodium sulfate and concentrated. The concentrate was purified by silica gel column chromatography to give compound 22 (40 mg, yield 63%). LCMS: m / z = 695.9 [MH] - . 1 H-NMR(400MHz,DMSO-d6)δ8.23–8.11(m,2H),7.88–7.71(m,5H),7.66–7.61(m,1H),7.41-7.25(m,1H),6.00(m,2H),5.84–5.7 3(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).

[0211] Example 8

[0212] In this embodiment, compounds 23 and 24 were synthesized and characterized. Compounds 23 and 24 were synthesized using the following general reaction formula:

[0213] Step 1: Synthesis of intermediate Int-1

[0214] At room temperature, parent drug I-1 (484 mg, 1.0 mmol, 1.0 eq) was suspended in dichloromethane (5 mL), and 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 allowed to proceed overnight. After the reaction was complete, the concentrate was concentrated and purified directly by silica gel column chromatography to obtain intermediate Int-1 (410 mg, yield: 67%).

[0215] Step 2: Synthesis of intermediate Int-2

[0216] At room temperature, intermediate Int-1 (0.4 mmol) was dissolved in acetonitrile (5 mL), and potassium carbonate (65 mg, 0.48 mmol, 1.2 eq) and the corresponding chloromethyl ester (0.48 mmol, 1.2 eq) were added. The reaction was allowed to proceed overnight. After the reaction was complete, the solution was concentrated and purified directly by silica gel column chromatography to obtain intermediate Int-2.

[0217] Step 3: Synthesis of compounds 23 and 24

[0218] At room temperature, intermediate Int-2 (0.2 mmol, 1.0 eq) was dissolved in tetrahydrofuran (5 mL), followed by the addition of acetic acid (14 mg, 0.24 mmol, 1.2 eq) and TBAF solution (1 M in THF, 0.2 mL, 2.0 eq). The reaction was allowed to proceed overnight. After the reaction was complete, the mixture was quenched with water (5 mL). The aqueous phase was washed twice with ethyl acetate (5 mL x 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 the target product.

[0219] Compound 23 (77 mg, yield 66%). LCMS: m / z = 581.7 [MH] - .

[0220] Compound 24 (49 mg, yield 41%). LCMS: m / z = 597.6 [MH] - .

[0221] Example 9

[0222] In this embodiment, compound 25 was synthesized and characterized.

[0223] Compound 19 (300 mg, 0.54 mmol, 1.0 eq), 4-(hydroxymethyl)-5-methyl-[1,3]dioxane-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) were dissolved in acetonitrile (3 mL) and reacted overnight at room temperature under nitrogen protection. Water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL x 2). The combined organic layers were washed with saturated brine (10 mL x 1), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (dichloromethane:methanol = 15:1) to give compound 25 (180 mg, yield: 50%). LCMS: m / z = 663.7 [MH] -

[0224] Example 10

[0225] In this embodiment, 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 via the following general reaction formula:

[0226] Step 1: Synthesis of intermediate Int-2

[0227] At room temperature and under nitrogen protection, the starting material (intermediate Int-1 of the synthetic route of compound 8) (450 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 (440 mg, 1.2 mmol, 1.2 eq) and sodium hydroxide (60%, 48 mg, 1.2 mmol, 1.2 eq) were added, and the reaction was allowed to proceed for 1 hour. Chloromethyl ester (2.0 mmol, 2.0 eq) was added, and the reaction was heated to 45 °C and carried out overnight. After the reaction was complete, the reaction solution was poured into water (40 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 (yield: 8%-67%).

[0228] Step 2: Synthesis of compounds 27, 28, 29, 30, 31, 32, 33, and 34

[0229] At room temperature, intermediate Int-2 (0.1 mmol, 1.0 eq) was dissolved in acetonitrile (2.5 mL), and potassium persulfonate monooxide (143 mg, 0.24 mmol, 2.4 eq) was added. The reaction was allowed to proceed overnight. The solid was filtered off, and water (0.5 mL) was added to the resulting solution. The reaction was allowed to proceed at room temperature. After the reaction was complete, the solution was dried over anhydrous sodium sulfate. The reaction solution was concentrated and purified by silica gel column chromatography to obtain the corresponding product.

[0230] Compound 27 (20 mg, yield 34%). 1 H-NMR(400MHz,DMSO-d6)δ8.34(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[MH] -

[0231] Compound 28 (36 mg, yield 61%). LCMS: m / z = 597.6 [MH] -

[0232] Compound 29 (27 mg, yield 47%). LCMS: m / z = 583.9 [MH] -

[0233] Compound 30 (23 mg, yield 39%). 1H-NMR(400MHz,DMSO-d6)δ8.28(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[MH] -

[0234] Compound 31 (32 mg, yield 52%). 1 H-NMR(400MHz,DMSO-d6)δ8.27(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[MH] -

[0235] Compound 32 (34 mg, yield 55%). LCMS: m / z = 611.7 [MH] -

[0236] Compound 33 (26 mg, yield 42%). LCMS: m / z = 610.8 [MH] -

[0237] Compound 34 (39 mg, yield 63%). 1 H-NMR(400MHz,DMSO-d6)δ8.29(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[MH] -

[0238] Example 11

[0239] In this embodiment, compound 35 was synthesized and characterized. Compound 35 was synthesized via the following general reaction formula:

[0240] Step 1: Synthesis of intermediate Int-2

[0241] At room temperature and under nitrogen protection, the starting material (intermediate Int-1 in the synthetic 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 hydroxide (60%, 96 mg, 2.4 mmol, 2.4 eq) were added, and the reaction was carried out for 1 hour. A chloromethyl substituted product (2.0 mmol, 2.0 eq) was added, and the reaction was incubated at 45 °C overnight. After the reaction was complete, 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%).

[0242] Step 2: Synthesis of Compound 35

[0243] Intermediate Int-2 (210 mg, 0.25 mmol, 1.0 eq) was dissolved in tetrahydrofuran (5 mL) at room temperature, followed by the addition of acetic acid (18 mg, 0.3 mmol, 1.2 eq) and TBAF solution (1 M in THF, 0.25 mL, 2.0 eq). The reaction was allowed to proceed overnight. After the reaction was complete, the mixture was quenched with water (5 mL). The aqueous phase was washed twice with ethyl acetate (5 mL x 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 the target product. LCMS: m / z = 713.9 [MH] -

[0244] Example 12

[0245] In this embodiment, compounds 36 and 37 were synthesized and characterized. Compounds 36 and 37 were synthesized via the following general reaction formula:

[0246] Synthesis of compound 36:

[0247] Compound 21 (300 mg, 0.50 mmol, 1.0 eq), 4-(hydroxymethyl)-5-methyl-[1,3]dioxane-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) and reacted overnight at room temperature under nitrogen protection. Water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL x 2). The combined organic layers were washed with saturated brine (10 mL x 1), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (dichloromethane:methanol = 15:1) to give compound 36 (160 mg, yield: 50%). LCMS: m / z = 714.7 [MH] -

[0248] Synthesis of compound 37:

[0249] Replacing 4-(hydroxymethyl)-5-methyl-[1,3]dioxane-2-one with isopropanol in the synthetic route of compound 36 yields compound 37 (165 mg, 51% yield). LCMS: m / z = 644.7 [MH] -

[0250] Example 14

[0251] In this embodiment, compound 39 was synthesized and characterized.

[0252] Step 1: Synthesis of intermediate Int-1

[0253] At room temperature, I-1 (465 mg, 1.0 mmol, 1.0 eq) was dissolved in ethanol (5 mL), and 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. The reaction was allowed to proceed overnight. After the reaction was complete, the mixture was quenched with water (5 mL). The aqueous phase was washed twice with ethyl acetate (5 mL x 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%).

[0254] Step 2: Synthesis of Compound 39

[0255] Intermediate Int-1 (200 mg, 0.27 mmol, 1.0 eq) was dissolved in DCM (5 mL) at room temperature, and TFA (1 mL) was added. The reaction was allowed to proceed overnight. After the reaction was complete, saturated sodium bicarbonate aqueous solution (5 mL) was added to quench the reaction. The aqueous phase was washed twice with ethyl acetate (5 mL x 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 give compound 39 (38 mg, yield: 22%). LCMS: m / z = 626.7 [M + H] +

[0256] Example 15

[0257] In this embodiment, compound 42 was synthesized and characterized.

[0258] Pentadecanobromobenzene 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. The reaction solution was then concentrated under reduced pressure, and the resulting residue (Int-1) was dissolved in DCM, cooled in an ice-water bath, and ammonia was added dropwise with stirring. After naturally returning to room temperature, stirring was continued overnight. The reaction solution was then poured onto crushed ice, and the precipitated solid was filtered and dried to obtain Int-2. Following the synthetic route of Scheme 2 in Journal of Medicinal Chemistry 2012, 55(5), 1978-1998 and the synthetic method of I-1 provided in Chinese Patent Application No. 202111108417.6, p-bromobenzenesulfonamide was replaced with the above-mentioned tetradecanobromobenzenesulfonamide Int-2, and compound 42 was synthesized according to the following route. 1 H NMR(400MHz,DMSO-d6)δ10.96(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=14.2Hz,1H),3.45(d,J=14.2Hz,1H). LCMS: m / z=485.7[MH] -

[0259] Example 16

[0260] In this embodiment, compound 43 was synthesized and characterized.

[0261] By replacing SM-2 with deuterated mercaptoacetate in the first step of the I-1 synthetic route, replacing the solvent water with heavy water in the third step, and replacing the concentrated hydrochloric acid with deuterated hydrochloric acid in the fourth step, compound 43 was synthesized according to the above route. LCMS: m / z = 483.7 [MH] -

[0262] Example 17

[0263] In this embodiment, compound 8 was synthesized and characterized.

[0264] Step 1: Synthesis of intermediate Int-1:

[0265] At room temperature, 2-((4-((4-bromophenyl)sulfonamido)-1-hydroxynaphthyl-2-yl)thio)acetic acid (UMI-77) (4.68 g, 10 mmol, 1.0 eq) and 1-methylimidazole (2.46 g, 30 mmol, 2.0 eq) were dissolved in acetonitrile (20 mL), and TCFH (4.21 g, 15 mmol, 1.5 eq) was added. The reaction was allowed to proceed overnight at room temperature. After overnight reaction, ethyl acetate (100 mL) and saturated brine were added to quench the reaction mixture. The mixture was separated, and the organic phase was extracted with ethyl acetate (20 mL * 2). The combined organic phases were washed with saturated brine (20 mL * 1), dried over anhydrous sodium sulfate, and concentrated. The resulting solid mixture was slurried with ethyl acetate (10 mL) at room temperature for 1 hour and then filtered. The resulting solid was dried to obtain intermediate Int-1 (3.14 g, 70% yield). LCMS: m / z = 447.6 [MH] - .

[0266] Step 2: Synthesis of Compound 8:

[0267] At room temperature, intermediate Int-1 (900 mg, 2.0 mmol, 1.0 eq) was dissolved in ethyl acetate (20 mL), and m-CPBA (85%, 413 mg, 2.4 mmol, 1.2 eq) was added. The reaction was allowed to proceed overnight. After overnight reaction, a white solid precipitated. The solution was removed by filtration, and the resulting solid was dried to obtain compound 8 (750 mg, yield 81%). 1 H-NMR(400MHz,DMSO-d6)δ10.69(s,1H),8.36–8.21(m,1H),7.99(d,J=8.0Hz,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] + .

[0268] Example 18

[0269] In this embodiment, referring to Example 9, 4-(hydroxymethyl)-5-methyl-[1,3]dioxane-2-one was replaced with dextroborneol (CAS:464-43-7), and compound 57 was synthesized and characterized.

[0270] Compound 19 (300 mg, 0.54 mmol, 1.0 eq), dextroborneol (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) and reacted overnight at room temperature under nitrogen protection. Water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL x 2). The combined organic layers were washed with saturated brine (10 mL x 1), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (dichloromethane:methanol = 15:1) to give compound 57 (122 mg, yield: 33%). LCMS: m / z = 688.3 [MH] - .

[0271] Test examples, compound pharmacokinetic tests

[0272] Laboratory mice were used, and appropriate amounts of the test compound were administered according to the specified dosage and route of administration. For gavage, the test compound was suspended in 0.5% sodium carboxymethyl cellulose; for intravenous injection, the test compound was dissolved in 5% DMSO + 30% PEG400 + 65% water for injection. For each compound and each administration route, three mice were used for three parallel experiments. For example, mice numbered G1M01, G1M02, and G1M03 were in one group, and mice numbered G2M01, G2M02, and G2M03 were in another group. Male CD1 mice were used as the mouse strain.

[0273] Following drug administration, collect 20.0 μL of whole blood samples at the corresponding time points into centrifuge tubes, anticoagulated with EDTA-K2, and immediately place on ice. Within 30 minutes of collection, centrifuge the whole blood samples at 4°C and 2000g for 10 minutes. In a separate 1.5 mL centrifuge tube with a label, add 5.00 μL of 1.5% ascorbic acid, then add 10.0 μL of the obtained plasma sample. Immediately place on ice and freeze the plasma sample to -60°C to -90°C within 30 minutes.

[0274] The concentration of compound I-1 in the above plasma samples was detected by liquid chromatography-tandem mass spectrometry (LC-MS / MS).

[0275] Table 2. Plasma drug concentrations in mice after gavage administration of 30 mg / kg sodium salt of compound I-1

[0276] Table 3. Plasma drug concentrations in mice after intravenous injection of 3 mg / kg sodium salt of compound I-1

[0277] Table 4. Plasma drug concentrations in mice after gavage administration of 36.93 mg / kg or intravenous injection of compound 7. a: BQL = Below the lower limit of quantitation (LLOQ) b: NC = not calculated Note: The oral dose is calculated based on the equimolar amount of 30 mg / kg of compound I-1 sodium salt.

[0278] Table 5. Plasma drug concentrations in mice after gavage administration of 34.41 mg / kg or intravenous injection of compound 19 Note: The oral dose is calculated based on the equimolar amount of 30 mg / kg sodium salt of compound I-1.

[0279] Table 6. Plasma drug concentrations in mice after gavage administration of compound 35.28 mg / kg for 20 days. Note: The oral dose is calculated based on the equimolar amount of 30 mg / kg sodium salt of compound I-1.

[0280] Table 7. Plasma drug concentrations in mice after gavage administration of compound 2 at a dose of 32.67 mg / kg. Note: The oral dose is calculated based on the equimolar amount of 30 mg / kg sodium salt of compound I-1.

[0281] Table 8. Plasma drug concentrations in mice after gavage administration of 36.28 mg / kg compound for 30 minutes. Note: The oral dose is calculated based on the equimolar amount of 30 mg / kg sodium salt of compound I-1.

[0282] Table 9. Comparison of pharmacokinetic parameters and efficacy analysis of the original drug I-1 and some prodrugs

[0283] The above comparisons show that prodrug compound 7 significantly increased plasma exposure, from 8.56 h*ug / mL with sodium I-1 to 30.578 h*ug / mL. Prodrug compounds 19 and 30 also increased plasma exposure to 12.656 h*ug / mL and 9.799 h*ug / mL, respectively. The pharmacokinetic properties of prodrug compound 19 differed significantly from those of sodium I-1. Sodium I-1 reached its maximum Cmax within 30 minutes and then rapidly decreased, while prodrug compound 19 reached its maximum Cmax only after 2–4 hours, followed by relatively slow elimination, a longer residence time, and a Cmax less than half that of sodium I-1. Similarly, prodrug compounds 27 and 30 exhibited similar pharmacokinetic characteristics to 19, maintaining a relatively constant or slightly higher plasma exposure (AUC) over 24 hours, but decreasing Cmax and prolonging residence time, with 27 showing particularly significant effects. This suggests that prodrug compounds 19, 27, and 30 undergo slow hydrolysis in plasma to release the parent drug I-1, resulting in a short and stout pharmacokinetic profile. Such pharmacokinetic characteristics can significantly improve drug efficacy and safety, as many adverse drug reactions are caused by excessively high peak plasma concentrations (Cmax). Lowering Cmax while maintaining AUC can reduce the incidence of adverse reactions while ensuring efficacy.

[0284] Table 10. Comparison of pharmacokinetic parameters of prodrugs 7 and 9 with comparative prodrugs 2, 8, 13, and 14 of the same type. Note: The oral dose is calculated based on the equimolar amount of 30 mg / kg sodium salt of compound I-1.

[0285] The above comparison shows that introducing different prodrug groups into the carboxylic acid site of the original drug I-1 results in significantly different pharmacokinetic characteristics. The ester prodrug group in prodrug 7, compared to other ester or lactone prodrugs such as 2 or 8, significantly improves oral bioavailability, leading to a significant increase in plasma exposure Cmax and AUC. The acylmethanesulfonamide prodrug in prodrug 9 achieves a similar effect. The effects of prodrugs 7 and 9 may stem from their significant promotion of absorption by gastrointestinal epithelial cells; after entering the bloodstream, the prodrug molecule encounters hydrolytic enzymes, rapidly releasing the carboxylic acid original drug I-1. In contrast, amide prodrugs, such as 13 or 14, may result in low plasma exposure Cmax and AUC of the original drug I-1 because the amide bond cannot be effectively hydrolyzed after entering the body. These technical effects cannot be inferred from existing technologies and are inventive and novel.

[0286] Table 11. Comparison of pharmacokinetic parameters between prodrugs 19 and 26 and comparative prodrugs 17, 18, and 20 of the same type. Note: The oral dose is calculated based on the equimolar amount of 30 mg / kg sodium salt of compound I-1.

[0287] The parent drug I-1 was not detected in plasma at any time point; only prodrug 17 was detected, indicating that 17 cannot be effectively hydrolyzed in vivo.

[0288] b. At each time point, the plasma concentration of the original drug I-1 was very low, but a relatively high concentration of 17 was detected, indicating that the methyl carboxylate of 18 can be rapidly hydrolyzed in vivo to 17, but the prodrug group (dimethylaminoacyl group) on the phenolic hydroxyl group of 17 cannot be effectively hydrolyzed. The above comparison shows that introducing different prodrug groups at the phenolic hydroxyl site of the original drug I-1 results in significantly different pharmacokinetic characteristics. Compared with other phenolic hydroxyl prodrug groups, the isobutyrate phenolic ester prodrug group of prodrug 19 and the isopropyl carbonate phenolic ester prodrug group of prodrug 26 can significantly improve oral bioavailability, while reducing peak plasma concentration and prolonging drug residence time in vivo. This effect comes from both the prodrug's promotion of absorption and the slow hydrolysis and release of the original drug in plasma. Such a flat pharmacokinetic profile is beneficial for maintaining a sustained drug effect and reducing the incidence of adverse reactions. In stark contrast, prodrugs 17 and 18, with a dimethylaminoacyl group on the phenolic hydroxyl group, exhibit poor hydrolysis in vivo, resulting in minimal exposure of the parent drug I-1 after gavage. Another comparative example is tervaline phenol ester prodrug 20, whose hydrolysis is even more difficult than that of isobutyric acid phenol ester in 19. Part of 20 that could not be hydrolyzed and released the parent drug was also metabolized and excreted, affecting the overall plasma exposure AUC and further reducing Cmax. These technical effects cannot be inferred from existing technologies and are therefore inventive and novel.

[0289] Table 12. Comparison of pharmacokinetic parameters between prodrugs 27, 30, and 33 and comparative prodrugs 28 and 29 of the same type. Note: The oral dose is calculated based on the equimolar amount of 30 mg / kg sodium salt of compound I-1.

[0290] The above comparison shows that introducing different prodrug groups onto the sulfonamide nitrogen atom of the original drug I-1 results in significantly different pharmacokinetic characteristics. Compared to other prodrug groups on the sulfonamide nitrogen atom, the pentvalerate aminomethyl ester prodrug group in prodrug 27, the isobutyrate aminomethyl ester prodrug group in prodrug 30, and the diethylcarbamate aminomethyl ester prodrug group in prodrug 33 promote gastrointestinal absorption and increase plasma exposure AUC. Simultaneously, prodrug 33 also reduces peak plasma concentration and significantly prolongs drug residence time and half-life in vivo. Such a flat pharmacokinetic profile is beneficial for maintaining a sustained drug effect and reducing the incidence of adverse reactions. In contrast, when the nitrogen atom of sulfonamide is a prodrug group of ethyl carbonate aminomethyl ester (29) or isopropyl carbonate aminomethyl ester (28), due to their very easy hydrolysis, most of the original drug I-1 is released by hydrolysis before it is absorbed in the digestive tract. Therefore, their pharmacokinetic characteristics are almost the same as those of the original drug I-1 when directly administered by gavage, and they cannot achieve the effects brought by prodrugs 27, 30, and 33.

[0291] Table 13. Comparison of pharmacokinetic parameters of deuterated compounds 42, 43 and I-1 Note: The oral dose is calculated based on the equimolar amount of 30 mg / kg sodium salt of compound I-1.

[0292] The pharmacokinetic characteristics of deuterated compound 42 are similar to those of I-1, meaning that replacing four hydrogen atoms in the p-bromobenzenesulfonamide fragment with deuterium atoms did not alter the pharmacokinetic properties.

[0293] Compared to I-1, the pharmacokinetic properties of deuterated compound 43 showed a significant increase in plasma exposure and a prolonged residence time, 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, thereby increasing the exposure.

[0294] Table 14. Comparison of pharmacokinetic parameters of dexborneol ester compound 56 and I-1 Note: The oral dose is calculated based on the equimolar amount of 30 mg / kg sodium salt of compound I-1.

[0295] Those skilled in the art will understand that the above embodiments are specific examples of implementing the present invention, and in practical applications, various changes in form and detail may be made without departing from the spirit and scope of the present invention.

Claims

1. Compounds of general formula I and their deuterated derivatives, in, R 1 It is a hydroxyl group. R 11 R 12 R 13 R 14 and R 15 Selected independently from C 1-6 Alkyl, C 3-10 Cycloalkyl groups, C substituted with amino groups 1-6 Alkyl, C 3-6 Cycloalkyl-substituted C 1-6 Alkyl groups, C substituted with amino groups 3-10 cycloalkyl, C 1-6 Alkyl-substituted C 3-10 cycloalkyl; R 2 It is hydrogen. R 21 C 1-6 Alkyl, C 1-4 alkoxy-substituted C 1-6 alkyl, -N(R a R b ); where R a and R b Each of the following is independently methyl, ethyl, n-propyl, isopropyl, or R a and R b Bonding to form a ring; R 22 C 1-6 alkyl; R 3 It is hydrogen. Among them, R 31 Selected from C 1-6 Alkyl, C 3-6 Cycloalkyl, phenyl, pyridyl, C 1-6 Alkyl-substituted pyridyl; R 32 R 33 R 34 Selected independently 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, characterized in that, The R 11 The derivatives are 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 The derivatives are 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 The 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 It is an isopentyl group substituted with tert-butyl, isopentyl, neopentyl, or amino. And / or, R 15 The compounds are methyl, isopropyl, tert-butyl, 2-ethylbutane, cyclohexane, bicyclo[2,2,1]heptane (norborne), and 7,7-dimethylbicyclo[2.2.1]heptane.

3. The compound according to claim 2, characterized in that, R 1 It consists of methoxy, ethoxy, isopropoxy, and tert-butoxy compounds.

4. The compound according to claim 1, characterized in that, R 21 C 1-4 Alkyl, dimethylamino, diethylamino, N-methylethylamino or And / or, R 22 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, characterized in that, R 31 The following are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, tert-pentyl, neopentyl, n-hexyl, pyridyl, cyclopropane, cyclobutane, or phenyl groups in which the hydrogen atom on the nitrogen atom is replaced by an alkyl group. And / or, R 32 It is methyl, ethyl, n-propyl, isopropyl, n-pentyl, isopentyl, tert-pentyl, neopentyl, cyclopropane, cyclobutane, cyclopentyl or cyclohexyl, one or more C 1-6 Alkyl-substituted cyclopropane, 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 groups; And / or, R 33 It can be methyl, ethyl, n-propyl or isopropyl.

7. The compound according to claim 6, characterized in that, R 3 It is hydrogen.

8. The compound according to claim 1, characterized in that, The compound is selected from any one of the following:

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

10. The use of the compound according to any one of claims 1-8 and its deuterated derivatives, or the pharmaceutical composition according to claim 9, for: (i) In vitro non-therapeutic induction of mitophagy; (ii) Prevention and / or treatment of diseases associated with mitophagy; (iii) Prepare drugs for the prevention and / or treatment of diseases related to mitophagy.

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