Imidazolyl and dinitrophenyl combined derivative and application thereof

Abstract

The present invention relates to a compound (I), a stereoisomer thereof, a deuterated derivative thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer thereof or a pharmaceutically acceptable salt of the deuterated derivative thereof, a pharmaceutical composition comprising the same, and uses thereof.

Description

[0001] Cross-reference of related applications

[0002] This application claims priority to PCT / CN2023 / 097022 (filed on May 30, 2023) and PCT / CN2023 / 099755 (filed on June 12, 2023), the entire contents of which are incorporated herein by reference. Technical Field

[0003] This invention relates to compounds for regulating mitochondrial activity, reducing fat content, and treating diseases including diabetes and its related complications, compositions comprising these compounds, and methods of using these compounds. Background Technology

[0004] Obesity has become a global epidemic, affecting more than 600 million people worldwide. Obesity is often associated with many metabolic disorders and diseases, such as insulin resistance, type 2 diabetes, and cardiovascular disease. Mitochondria play a crucial role in energy metabolism, and impaired mitochondrial function is linked to obesity.

[0005] Mitochondrial decoupling agents are compounds that dissipate the proton gradient across the inner mitochondrial membrane, leading to reduced efficiency in the production of adenosine triphosphate (ATP). This decoupling may result in increased mitochondrial respiration, potentially reducing energy stored as fat and thus contributing to weight loss. The mechanism by which mitochondrial decoupling agents affect energy expenditure makes them an attractive target for developing therapies to treat obesity.

[0006] Several mitochondrial decoupling agents have been identified and investigated to evaluate their potential efficacy in treating obesity. One of the most well-known decoupling agents is 2,4-dinitrophenol (DNP), which was previously used for weight loss but has been banned due to its toxicity. However, novel mitochondrial decoupling agents have been developed, including carbonyl cyanide 4-(trifluoromethoxy)phenylhydrazone (FCCP) and 2,3,5-triiodo-L-thyroxine (T3), which have shown promising results in preclinical studies.

[0007] While research suggests the potential efficacy of mitochondrial uncoupling agents in treating obesity, concerns remain regarding their safety and potential side effects. Developing safe and effective mitochondrial uncoupling agents for obesity treatment remains an active area of ​​research. Summary of the Invention

[0008] The following disclosures are provided here:

[0009] [1]. Compounds of formula (I), their deuterated derivatives, stereoisomers, pharmaceutically acceptable salts of their stereoisomers, or pharmaceutically acceptable salts of their deuterated derivatives:

[0010]

[0011] Each occurrence of R1 is independently selected from hydrogen, deuterium, and -C. 1-6 Alkyl, Halogenated C 1-6 Alkyl or -C 1-6 Alkoxy; the -C 1-6 Alkyl, Halogenated C 1-6 Alkyl or -C 1-6 The alkoxy group may optionally be replaced by one or more R groups. 11 Replacement; when R1 is -CH3, the -CH3 is replaced by 1, 2 or 3 Rs. 11 replace;

[0012] The R 11 Selected from deuterium, halogens, -C 1-6 Alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, halogenated C 1-6 Alkyl, -C 1-6 Alkoxy, -CN, -COOH, -NH2, -NH(C 1-6 alkyl), -N(C) 1-6 Alkyl group 2, -OH, -O(C) 1-6 Alkyl), -SH, -S(C 1-6 Alkyl), -C(=O)(C 1-6 Alkyl), -S(=O)(C 1-6 Alkyl), -S(=O)2(C 1-6 Alkyl groups), -C(=O)NH2, -C(=O)NH(C 1-6 Alkyl), -C(=O)N(C 1-6 Alkyl)2、-NHC(=O)(C 1-6 alkyl), -N(C) 1-6 Alkyl)C(=O)(C 1-6 Alkyl), -C(=O)O(C 1-6 Alkyl), -OC (=O)(C 1-6 Alkyl groups), -S(=O)NH2, -S(=O)NH(C 1-6 Alkyl), -S(=O)N(C 1-6 Alkyl)2、-NHS(=O)(C 1-6 alkyl), -N(C) 1-6 Alkyl)S(=O)(C 1-6 Alkyl groups), -S(=O)2NH2, -S(=O)2NH(C 1-6 Alkyl), -S(=O)2N(C 1-6 alkyl) 2, 3-10 membered carbon rings, 3-10 membered heterocycles, 6-10 membered aryl or 5-10 membered heteroaryl; said R11 It may be optionally replaced by one or more deuteriums;

[0013] R2 and R3 are each independently selected from hydrogen, deuterium, halogen, and -C. 1-3 Alkyl, -C 2-3 alkenyl, -C 2-3 alkynyl, -halogenated C 1-3 Alkyl, -C 2-3 Alkoxy, -CN, -COOH, -NH2, -NH(C 1-3 alkyl), -N(C) 1-3 Alkyl group 2, -OH, -O(C) 1-3 Alkyl), -SH, -S(C 1-3 Alkyl), -C(=O)(C 1-6 Alkyl), -S(=O)(C 1-6 Alkyl), -S(=O)2(C 1-6 Alkyl groups), -C(=O)NH2, -C(=O)NH(C 1-3 Alkyl), -C(=O)N(C 1-3 Alkyl)2、-NHC(=O)(C 1-3 alkyl), -N(C) 1-3 Alkyl)C(=O)(C 1-3 Alkyl), -C(=O)O(C 1-3 Alkyl), -OC (=O)(C 1-3 Alkyl groups), -S(=O)NH2, -S(=O)NH(C 1-3 Alkyl), -S(=O)N(C 1-3 Alkyl)2、-NHS(=O)(C 1-3 alkyl), -N(C) 1-3 Alkyl)S(=O)(C 1-3 Alkyl groups), -S(=O)2NH2, -S(=O)2NH(C 1-3 Alkyl), -S(=O)2N(C 1-3 alkyl)2、-NHS(=O)2(C 1-3 alkyl), -N(C) 1-3 Alkyl)S(=O)2(C 1-3 Alkyl), 3-10 membered carbon rings, 3-10 membered heterocycles, 6-10 membered aryl or 5-10 membered heteroaryl; wherein the -C 1-3 Alkyl, -C 1-3 alkenyl, -C 1-3 alkynyl, -halogenated C 1-3 Alkyl, -C 2-3The alkoxy group, 3-10 membered carbocyclic ring, 3-10 membered heterocyclic ring, 6-10 membered aryl group, or 5-10 membered heteroaryl group may be independently and optionally substituted by one or more substituents selected from deuterium, halogens, and halogenated C. 1-3 Alkyl, -CN, -NH2, -C 1-3 Alkyl, -C 1-3 alkenyl, -C 1-3 alkynyl, -halogenated C 1-3 Alkyl, -C 2-3 Alkoxy, -CN, -COOH, -NH2, -NH(C 1-3 alkyl), -N(C) 1-3 Alkyl group 2, -OH, -O(C) 1-3 Alkyl), -SH, -S(C 1-3 Alkyl), -C(=O)(C 1-6 Alkyl), -S(=O)(C 1-6 Alkyl), -S(=O)2(C 1-6 Alkyl groups), -C(=O)NH2, -C(=O)NH(C 1-3 Alkyl), -C(=O)N(C 1-3 Alkyl)2、-NHC(=O)(C 1-3 alkyl), -N(C) 1-3 Alkyl)C(=O)(C 1-3 Alkyl), -C(=O)O(C 1-3 Alkyl), -OC (=O)(C 1-3 Alkyl groups), -S(=O)NH2, -S(=O)NH(C 1-3 Alkyl), -S(=O)N(C 1-3 Alkyl)2、-NHS(=O)(C 1-3 alkyl), -N(C) 1-3 Alkyl)S(=O)(C 1-3 Alkyl groups), -S(=O)2NH2, -S(=O)2NH(C 1-3 Alkyl), -S(=O)2N(C 1-3 alkyl)2、-NHS(=O)2(C 1-3 alkyl), -N(C) 1-3 Alkyl)S(=O)2(C 1-3 Alkyl group, 3-10 membered carbon ring, 3-10 membered heterocyclic ring, 6-10 membered aryl group or 5-10 membered heteroaryl group; wherein R3 or R2 may optionally be substituted with one or more deuterium groups;

[0014] Optionally, R2 and R3, together with the atoms they are attached to, form a 3-14 membered carbon ring, a 3-14 membered heterocycle, a 6-12 membered aromatic ring, or a 5-14 membered heteroaromatic ring; each ring may be independently and optionally bounded by n1 R atoms. S1replace;

[0015] R S1 Selected from halogens, -C 1-6 Alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl group, -C 1-6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, -CN, -NO2, -N3, oxo, -NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl group 2, -OH, -O(C) 1-6 Alkyl), -SH, -S(C 1-6 Alkyl), -S(=O)(C 1-6 Alkyl), -S(=O)2(C 1-6 Alkyl), -C(=O)(C 1-6 Alkyl), -C(=O)OH, -C(=O)(OC 1-6 Alkyl), -OC (=O)(C 1-6 Alkyl groups), -C(=O)NH2, -C(=O)NH(C 1-6 Alkyl), -C(=O)N(C 1-6 Alkyl)2、-NHC(=O)(C 1-6 alkyl), -N(C) 1-6 Alkyl)C(=O)(C 1-6 Alkyl), -OC(=O)O(C 1-6 Alkyl), -NHC(=O)(OC 1-6 alkyl), -N(C) 1-6 Alkyl)C(=O)(OC) 1-6 Alkyl), -OC(=O)NH(C 1-6 Alkyl), -OC(=O)N(C 1-6 Alkyl)2, -NHC(=O)NH2, -NHC(=O)NH(C 1-6 Alkyl), -NHC(=O)N(C 1-6 Alkyl)2, -N(C 1-6 Alkyl)C(=O)NH2、-N(C 1-6 alkyl)C(=O)NH(C 1-6 alkyl), -N(C) 1-6 Alkyl)C(=O)N(C 1-6 Alkyl)2、-S(=O)(OC 1-6 Alkyl), -OS (=O) (C 1-6 Alkyl groups), -S(=O)NH2, -S(=O)NH(C 1-6 Alkyl), -S(=O)N(C1-6 Alkyl)2、-NHS(=O)(C 1-6 alkyl), -N(C) 1-6 Alkyl)S(=O)(C 1-6 Alkyl), -S(=O)2(OC 1-6 Alkyl), -OS(=O)2(C 1-6 Alkyl groups), -S(=O)2NH2, -S(=O)2NH(C 1-6 Alkyl), -S(=O)2N(C 1-6 alkyl)2、-NHS(=O)2(C 1-6 alkyl), -N(C) 1-6 Alkyl)S(=O)2(C 1-6 Alkyl), -OS(=O)2O(C 1-6 Alkyl), -NHS(=O)2O(C 1-6 alkyl), -N(C) 1-6 Alkyl)S(=O)2O(C 1-6 Alkyl groups), -OS(=O)2NH2, -OS(=O)2NH(C 1-6 Alkyl), -OS(=O)2N(C 1-6 Alkyl)2, -NHS(=O)2NH2, -NHS(=O)2NH(C 1-6 Alkyl), -NHS(=O)2N(C 1-6 Alkyl)2, -N(C 1-6 Alkyl)S(=O)2NH2、-N(C 1-6 alkyl)S(=O)2NH(C 1-6 alkyl), -N(C) 1-6 Alkyl)S(=O)2N(C 1-6 alkyl)2, -PH(C 1-6 alkyl), -P(C 1-6 Alkyl)2、-P(=O)H(C 1-6 Alkyl), -P(=O)(C 1-6 Alkyl) 2, 3-7 membered carbon rings, 3-7 membered heterocycles, 6-10 membered aryl or 5-10 membered heteroaryl;

[0016] n1 is selected from 0, 1, 2, 3, 4, 5 or 6;

[0017] Each occurrence of R4 is independently selected from hydrogen, deuterium, halogens, and -C. 1-3 Alkyl, -C 2-3 alkenyl, -C 2-3 alkynyl, -halogenated C 1-3 Alkyl, -C 2-3 Alkoxy, -CN, -COOH, -NH2, -NH(C 1-3 alkyl), -N(C)1-3 Alkyl group 2, -OH, -O(C) 1-3 Alkyl), -SH, -S(C 1-3 Alkyl), -C(=O)(C 1-6 Alkyl), -S(=O)(C 1-6 Alkyl), -S(=O)2(C 1-6 Alkyl groups), -C(=O)NH2, -C(=O)NH(C 1-3 Alkyl), -C(=O)N(C 1-3 Alkyl)2、-NHC(=O)(C 1-3 alkyl), -N(C) 1-3 Alkyl)C(=O)(C 1-3 Alkyl), -C(=O)O(C 1-3 Alkyl), -OC (=O)(C 1-3 Alkyl groups), -S(=O)NH2, -S(=O)NH(C 1-3 Alkyl), -S(=O)N(C 1-3 Alkyl)2、-NHS(=O)(C 1-3 alkyl), -N(C) 1-3 Alkyl)S(=O)(C 1-3 Alkyl groups), -S(=O)2NH2, -S(=O)2NH(C 1-3 Alkyl), -S(=O)2N(C 1-3 alkyl)2、-NHS(=O)2(C 1-3 alkyl), -N(C) 1-3 Alkyl)S(=O)2(C 1-3 Alkyl), 3-10 membered carbon rings, 3-10 membered heterocycles, 6-10 membered aryl or 5-10 membered heteroaryl; wherein the -C 1-3 Alkyl, -C 1-3 alkenyl, -C 1-3 alkynyl, -halogenated C 1-3 Alkyl, -C 2-3 The alkoxy group, 3-10 membered carbocyclic ring, 3-10 membered heterocyclic ring, 6-10 membered aryl group, or 5-10 membered heteroaryl group may be independently and optionally substituted by one or more substituents selected from deuterium, halogens, and halogenated C. 1-3 Alkyl, -CN, -NH2, -C 1-3 Alkyl, -C 1-3 alkenyl, -C 1-3 alkynyl, -halogenated C 1-3 Alkyl, -C 2-3 Alkoxy, -CN, -COOH, -NH2, -NH(C 1-3 alkyl), -N(C) 1-3 Alkyl group 2, -OH, -O(C) 1-3Alkyl), -SH, -S(C 1-3 Alkyl), -C(=O)(C 1-6 Alkyl), -S(=O)(C 1-6 Alkyl), -S(=O)2(C 1-6 Alkyl groups), -C(=O)NH2, -C(=O)NH(C 1-3 Alkyl), -C(=O)N(C 1-3 Alkyl)2、-NHC(=O)(C 1-3 alkyl), -N(C) 1-3 Alkyl)C(=O)(C 1-3 Alkyl), -C(=O)O(C 1-3 Alkyl), -OC (=O)(C 1-3 Alkyl groups), -S(=O)NH2, -S(=O)NH(C 1-3 Alkyl), -S(=O)N(C 1-3 Alkyl)2、-NHS(=O)(C 1-3 alkyl), -N(C) 1-3 Alkyl)S(=O)(C 1-3 Alkyl groups), -S(=O)2NH2, -S(=O)2NH(C 1-3 Alkyl), -S(=O)2N(C 1-3 alkyl)2、-NHS(=O)2(C 1-3 alkyl), -N(C) 1-3 Alkyl)S(=O)2(C 1-3 The R4 may be substituted with one or more deuterium groups.

[0018] Each heterocyclic group independently contains 1, 2, 3, 4, 5 or 6 heteroatoms selected from N, O, S, S(=O) or S(=O)2;

[0019] Each heteroaryl group independently contains 1, 2, 3, 4, 5 or 6 heteroatoms selected from N, O or S.

[0020] [2]. Compounds of formula (I), their deuterated derivatives, stereoisomers, pharmaceutically acceptable salts of their stereoisomers, or pharmaceutically acceptable salts of their deuterated derivatives, wherein,

[0021] Each occurrence of R1 is independently selected from hydrogen, deuterium, and -C. 1-3 Alkyl or -C 2-3 Alkoxy;

[0022] R1 can be optionally divided by one or more R 11Replacement; when R1 is -CH3, the -CH3 is replaced by 1, 2 or 3 Rs. 11 replace;

[0023] The R 11 Selected from deuterium, -NH(C 1-3 alkyl), -N(C) 1-3 Alkyl)2、-O(C 1-3 alkyl), -S(C 1-3 Alkyl), -C 2-3 Alkoxy group, -C(=O)(C 1-3 Alkyl), -S(=O)(C 1-3 Alkyl), -S(=O)2(C 1-3 Alkyl groups, -C(=O)NH2, -C(=O)N(C 1-6 Alkyl), -C(=O)NH(C 1-6 Alkyl), -C(=O)N(C 1-3 Alkyl)2、-NHC(=O)(C 1-3 alkyl), -N(C) 1-3 Alkyl)C(=O)(C 1-3 Alkyl), -S(=O)NH(C 1-3 Alkyl), -S(=O)N(C 1-3 Alkyl)2、-NHS(=O)(C 1-3 alkyl), -N(C) 1-3 Alkyl)S(=O)(C 1-3 Alkyl group), -S(=O)2NH(C 1-3 Alkyl), -S(=O)2N(C 1-3 alkyl)2、-NHS(=O)2(C 1-3 alkyl) or -N(C) 1-3 Alkyl)S(=O)2(C 1-3 Alkyl); the R 11 It can be optionally replaced by one or more -D.

[0024] [3]. Compounds of formula (I), their deuterated derivatives, stereoisomers, pharmaceutically acceptable salts of their stereoisomers, or pharmaceutically acceptable salts of their deuterated derivatives, wherein,

[0025] Each occurrence of R1 is independently selected from -C 1-3 Alkyl or -C 2-3 Alkoxy;

[0026] The -C 1-3 Alkyl or -C 2-3 The alkoxy group may optionally be surrounded by 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 R groups. 11Replacement; when R1 is -CH3, the -CH3 is replaced by 1, 2 or 3 Rs. 11 replace;

[0027] The R 11 Selected from deuterium, -NH(C 1-3 alkyl), -N(C) 1-3 Alkyl)2、-O(C 1-3 alkyl), -S(C 1-3 Alkyl), -C 2-3 Alkoxy group, -C(=O)(C 1-6 Alkyl), -S(=O)(C 1-6 Alkyl) or -S(=O)2(C 1-6 Alkyl); the R 11 It can be optionally replaced by one or more -D.

[0028] [4]. Compounds of formula (I), their deuterated derivatives, stereoisomers, pharmaceutically acceptable salts thereof, pharmaceutically acceptable salts of stereoisomers, or pharmaceutically acceptable salts of deuterated derivatives, wherein,

[0029] Each occurrence of R1 is independently selected from -C 1-3 Alkyl or -C 2-3 Alkoxy;

[0030] R1 can be optionally divided by 1, 2 or 3 Rs. 11 Replacement; when R1 is -CH3, the -CH3 is replaced by 1, 2 or 3 Rs. 11 replace;

[0031] The R 11 Selected from deuterium, -C 2-3 alkoxy or -O(C) 1-3 Alkyl); the R 11 It can be optionally replaced by one or more -D.

[0032] [5]. Compounds of formula (I), their deuterated derivatives, stereoisomers, pharmaceutically acceptable salts thereof, pharmaceutically acceptable salts of stereoisomers, or pharmaceutically acceptable salts of deuterated derivatives, wherein,

[0033] Each occurrence of R1 is independently selected from -CH2D, -CHD2, -CD3, -CH2CH3, -CH2CH2CH3, -CH2CH2CD3, -CH2CD2CD3, -CD2CD2CD3, -CH(CH3)2, -CD(CH3)2, -CD(CD3)(CH3), -CH(CD3)2, -CD(CD3)2,

[0034]

[0035]

[0036]

[0037]

[0038]

[0039] [6]. Compounds of formula (I), their deuterated derivatives, stereoisomers, pharmaceutically acceptable salts thereof, pharmaceutically acceptable salts of stereoisomers, or pharmaceutically acceptable salts of deuterated derivatives, wherein,

[0040] Each occurrence of R1 is independently selected from -CD3, -CH2CH3, -CH2CH2CH3、

[0041] -CH2CH2CD3, -CH2CD2CD3, -CD2CD2CD3, -CH(CH3)2, -CD(CH3)2, -CD(CD3)2,

[0042]

[0043] [7]. Compounds of formula (I), their deuterated derivatives, stereoisomers, pharmaceutically acceptable salts thereof, pharmaceutically acceptable salts of stereoisomers, or pharmaceutically acceptable salts of deuterated derivatives, wherein,

[0044] Each occurrence of R1 is independently selected from -CD3.

[0045] [8]. Compounds of formula (I), their deuterated derivatives, stereoisomers, pharmaceutically acceptable salts thereof, pharmaceutically acceptable salts of stereoisomers, or pharmaceutically acceptable salts of deuterated derivatives, wherein,

[0046] Each occurrence of R1 is independently selected from -C 1-3 Alkyl group; R1 may optionally be substituted with 1, 2, 3, 4, 5, 6 or 7 deuteriums; when R1 is -CH3, the -CH3 is substituted with 1, 2 or 3 deuteriums.

[0047] [9]. Compounds of formula (I), their deuterated derivatives, stereoisomers, pharmaceutically acceptable salts thereof, pharmaceutically acceptable salts of stereoisomers, or pharmaceutically acceptable salts of deuterated derivatives, wherein,

[0048] Each occurrence of R1 is independently selected from -CH3, which is replaced by 1, 2 or 3 deuterium atoms.

[0049]

[10] . Compounds of formula (I), their deuterated derivatives, stereoisomers, pharmaceutically acceptable salts thereof, pharmaceutically acceptable salts of stereoisomers, or pharmaceutically acceptable salts of deuterated derivatives, wherein,

[0050] Each occurrence of R1 is independently selected from -CH2D, -CHD2, -CD3, -CH2CH3, -CH2CH2CH3, -CH2CH2CD3, -CH2CD2CD3, -CD2CD2CD3, -CH(CH3)2, -CD(CH3)2, -CD(CD3)(CH3), -CH(CD3)2, or -CD(CD3)2.

[0051]

[11] . Compounds of formula (I), their deuterated derivatives, stereoisomers, pharmaceutically acceptable salts thereof, pharmaceutically acceptable salts of stereoisomers, or pharmaceutically acceptable salts of deuterated derivatives, wherein,

[0052] Each occurrence of R1 is independently selected from -CD3, -CH2CH3, -CH2CH2CH3, -CH2CH2CD3, -CH2CD2CD3, -CD2CD2CD3, -CH(CH3)2, -CD(CH3)2, or -CD(CD3)2.

[0053]

[12] . Compounds of formula (I), their deuterated derivatives, stereoisomers, pharmaceutically acceptable salts thereof, pharmaceutically acceptable salts of stereoisomers, or pharmaceutically acceptable salts of deuterated derivatives, wherein,

[0054] Each occurrence of R1 is independently selected from -CD3.

[0055]

[13] . Compounds of formula (I-1), their deuterated derivatives, stereoisomers, pharmaceutically acceptable salts of their stereoisomers, or pharmaceutically acceptable salts of their deuterated derivatives:

[0056]

[0057] The definitions of R3, R2, or R4 are the same as in [1].

[0058]

[14] . Compounds of formula (I), their deuterated derivatives, stereoisomers, pharmaceutically acceptable salts thereof, pharmaceutically acceptable salts of stereoisomers, or pharmaceutically acceptable salts of deuterated derivatives, wherein,

[0059] Each occurrence of R1 is independently selected from -C 1-3 Alkyl group, wherein R1 is R 11 Replace; the R 11 Selected from -C 2-3 alkoxy, the R 11 It may be optionally replaced by one or more deuterium.

[0060]

[15] . Compounds of formula (I), their deuterated derivatives, stereoisomers, pharmaceutically acceptable salts thereof, pharmaceutically acceptable salts of stereoisomers, or pharmaceutically acceptable salts of deuterated derivatives, wherein,

[0061] Each occurrence of R1 is independently selected from -CH3, -CH2CH3, -CH2CH2CH3, or -CH(CH3)2, wherein R1 is controlled by R 11 Replace; the R 11 Selected from -CH2-O-CH3, -CH2-O-CH2-CH3, -CH2-CH2-O-CH3 or -CH(CH3)-O-CH3; the R 11 It can be optionally replaced by 1, 2, 3, 4, 5, 6 or 7 deuteriums.

[0062]

[16] . Compounds of formula (I), their deuterated derivatives, stereoisomers, pharmaceutically acceptable salts thereof, pharmaceutically acceptable salts of stereoisomers, or pharmaceutically acceptable salts of deuterated derivatives, wherein,

[0063] Each occurrence of R1 is independently selected from -CH3; said R1 is replaced by -CH2-O-CH3.

[0064]

[17] . Compounds of formula (I), their deuterated derivatives, stereoisomers, pharmaceutically acceptable salts thereof, pharmaceutically acceptable salts of stereoisomers, or pharmaceutically acceptable salts of deuterated derivatives, wherein,

[0065] Each occurrence of R1 is independently selected

[0066]

[18] . Compounds of formula (I), their deuterated derivatives, stereoisomers, pharmaceutically acceptable salts thereof, pharmaceutically acceptable salts of stereoisomers, or pharmaceutically acceptable salts of deuterated derivatives, wherein,

[0067] Each occurrence of R1 is independently selected

[0068]

[19] . Compounds of formula (I), their deuterated derivatives, stereoisomers, pharmaceutically acceptable salts thereof, pharmaceutically acceptable salts of stereoisomers, or pharmaceutically acceptable salts of deuterated derivatives, wherein,

[0069] Each occurrence of R1 is independently selected

[0070]

[20] . Compounds of formula (I-2), their deuterated derivatives, stereoisomers, pharmaceutically acceptable salts of their stereoisomers, or pharmaceutically acceptable salts of their deuterated derivatives:

[0071]

[0072] The definitions of R3, R2, or R4 are the same as in [1].

[0073]

[21] . Compounds of formula (I), their deuterated derivatives, stereoisomers, pharmaceutically acceptable salts thereof, pharmaceutically acceptable salts of stereoisomers, or pharmaceutically acceptable salts of deuterated derivatives, wherein,

[0074] Each occurrence of R1 is independently selected from -C 2-3 alkoxy, wherein R1 is R 11 Replace; the R 11 Selected from -C 2-3 alkoxy or -O(C) 1-3 Alkyl), the R 11 It may be optionally replaced by one or more deuterium.

[0075]

[22] . Compounds of formula (I), their deuterated derivatives, stereoisomers, pharmaceutically acceptable salts thereof, pharmaceutically acceptable salts of stereoisomers, or pharmaceutically acceptable salts of deuterated derivatives, wherein,

[0076] Each occurrence of R1 is independently selected from -CH2-O-CH3, -CH2-O-CH2-CH3, -CH2-CH2-O-CH3, or -CH(CH3)-O-CH3, wherein R1 is controlled by R 11 Replace; the R 11 Selected from -CH2-O-CH3, -CH2-O-CH2-CH3, -CH2-CH2-O-CH3, -CH(CH3)-O-CH3, -O-CH3, -O-CH2-CH3, -O-CH2-CH2-CH3 or -O-CH(CH3)2; the R 11 It can be optionally replaced by 1, 2, 3, 4, 5, 6 or 7 deuteriums.

[0077]

[23] . Compounds of formula (I), their deuterated derivatives, stereoisomers, pharmaceutically acceptable salts thereof, pharmaceutically acceptable salts of stereoisomers, or pharmaceutically acceptable salts of deuterated derivatives, wherein,

[0078] Each occurrence of R1 is independently selected from -CH2-CH2-O-CH3; said R1 is replaced by -CH2-O-CH3.

[0079]

[24] . Compounds of formula (I), their deuterated derivatives, stereoisomers, pharmaceutically acceptable salts thereof, pharmaceutically acceptable salts of stereoisomers, or pharmaceutically acceptable salts of deuterated derivatives, wherein,

[0080] Each occurrence of R1 is independently selected

[0081]

[0082]

[0083]

[25] . Compounds of formula (I), their deuterated derivatives, stereoisomers, pharmaceutically acceptable salts thereof, pharmaceutically acceptable salts of stereoisomers, or pharmaceutically acceptable salts of deuterated derivatives, wherein,

[0084] Each time it appears, R1 is selected independently.

[0085]

[26] . Compounds of formula (I), their deuterated derivatives, stereoisomers, pharmaceutically acceptable salts thereof, pharmaceutically acceptable salts of stereoisomers, or pharmaceutically acceptable salts of deuterated derivatives, wherein,

[0086] Each occurrence of R1 is independently selected

[0087]

[27] . Compounds of formula (I-3), their deuterated derivatives, stereoisomers, pharmaceutically acceptable salts of their stereoisomers, or pharmaceutically acceptable salts of their deuterated derivatives:

[0088]

[0089] The definitions of R3, R2, or R4 are the same as in [1].

[0090]

[28] . Deuterated derivatives, stereoisomers, pharmaceutically acceptable salts thereof, pharmaceutically acceptable salts of stereoisomers, or pharmaceutically acceptable salts of deuterated derivatives of compound (I), wherein,

[0091] R4 groups are independently selected from -H, -D, halogen, and -C. 1-3 Alkyl, Halogenated C 1-3 Alkyl, -C 2-3 Alkoxy, -C 2-3 alkenyl, -C 2-3 Alkyne group, -CN, -NH2, -NH(C) 1-3 alkyl), -N(C) 1-3 Alkyl group 2, -OH, -O(C) 1-3 Alkyl), -O (halogenated C) 1-3 Alkyl), -SH, -S(C 1-3 Alkyl), -C(=O)(C 1-3 Alkyl), -S(=O)(C 1-3 Alkyl), -S(=O)2(C 1-3 Alkyl groups, -C(=O)OH, -C(=O)NH2, -C(=O)NH(C 1-3 Alkyl), -C(=O)N(C 1-3 Alkyl)2、-NHC(=O)(C 1-3 Alkyl groups), -S(=O)NH2, -S(=O)NH(C 1-3 Alkyl), -S(=O)N(C 1-3 Alkyl)2、-NHS(=O)(C 1-3 Alkyl groups), -S(=O)2NH2, -S(=O)2NH(C 1-3 Alkyl), -S(=O)2N(C 1-3 alkyl)2 or -NHS(=O)2(C 1-3 Alkyl); the R4 may be substituted with one or more deuterium.

[0092]

[29] . Deuterated derivatives, stereoisomers, pharmaceutically acceptable salts thereof, pharmaceutically acceptable salts of stereoisomers, or pharmaceutically acceptable salts of deuterated derivatives of compound (I), wherein,

[0093] R4 groups are independently selected from -H, -D, halogen, and -C. 1-3 Alkyl, Halogenated C 1-3 Alkyl, -C 2-3 Alkoxy, -C 2-3 alkenyl, -C 2-3 Alkyne, -CN, -NH2, -C(=O)OH, -NH(C 1-3 alkyl), -N(C) 1-3 Alkyl group 2, -OH, -O(C) 1-3 Alkyl), -O (halogenated C) 1-3 Alkyl), -SH, -S(C 1-3 Alkyl), -C(=O)(C 1-3Alkyl), -S(=O)(C 1-3 Alkyl) or -S(=O)2(C 1-3 Alkyl); the R4 may be substituted with one or more deuterium.

[0094]

[30] . Deuterated derivatives, stereoisomers, pharmaceutically acceptable salts thereof, pharmaceutically acceptable salts of stereoisomers, or pharmaceutically acceptable salts of deuterated derivatives of compound (I), wherein,

[0095] R4 is each independently selected from -H, -D, -Cl, -F, -Br, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CHFCH3, -CF2CH3 , -CH2-O-CH3, -CH2-O-CH2-CH3, -CH2-CH2-O-CH3, -CH(CH3)-O-CH3, -CN, -C(=O)OH, -NH2, -NH(CH3), -N(CH3)2, -NH(CH2CH3), -OH, -O-CH3, -O- CH2-CH3, -O-CH2-CH2-CH3, -O-CH(CH3)2, -O-CF3, -SH, -S-CH3, -S-CH2CH3, -S-CH2CH2CH3, -S-CH(CH3)2, -C(=O)(CH3), -C(=O)(CH2CH3), -C(=O)(CH(CH3)2), -S(=O)(CH3), -S(=O)(CH2CH3), -S(=O)(CH(CH3)2), -S(=O)2(CH3), -S(=O)2(CH2CH3) or -S(=O)2(CH(CH3)2); the R4 may be substituted with one or more deuteriums.

[0096]

[31] . A deuterated derivative, stereoisomer, pharmaceutically acceptable salt thereof, pharmaceutically acceptable salt of a stereoisomer or a pharmaceutically acceptable salt of a deuterated derivative thereof, wherein R4 is independently selected from -H, -D, -CH3 or -CD3.

[0097]

[32] . A deuterated derivative, stereoisomer, pharmaceutically acceptable salt thereof, pharmaceutically acceptable salt of a stereoisomer, or pharmaceutically acceptable salt of a deuterated derivative thereof, wherein R4 is independently selected from -H.

[0098]

[33] . Deuterated derivatives, stereoisomers, pharmaceutically acceptable salts of the stereoisomers, or pharmaceutically acceptable salts of the deuterated derivatives of compound (II-1):

[0099]

[0100] The definitions of R3 or R2 are the same as in [1].

[0101]

[34] . Deuterated derivatives, stereoisomers, pharmaceutically acceptable salts of the stereoisomers, or pharmaceutically acceptable salts of the deuterated derivatives of compound (II-2):

[0102]

[0103] The definitions of R3 or R2 are the same as in [1].

[0104]

[35] . Deuterated derivatives, stereoisomers, pharmaceutically acceptable salts thereof, pharmaceutically acceptable salts of stereoisomers, or pharmaceutically acceptable salts of deuterated derivatives of compound (II-3):

[0105]

[0106] The definitions of R3 or R2 are the same as in [1].

[0107]

[36] . Deuterated derivatives, stereoisomers, pharmaceutically acceptable salts thereof, pharmaceutically acceptable salts of stereoisomers, or pharmaceutically acceptable salts of deuterated derivatives of compound (I), wherein,

[0108] R2 and R3 are each independently selected from -H, -D, halogen, and -C. 1-3 Alkyl, Halogenated C 1-3 Alkyl, -C 2-3 Alkoxy, -C 2-3 alkenyl, -C 2-3 Alkyne group, -CN, -NH2, -NH(C) 1-3 alkyl), -N(C) 1-3 Alkyl group 2, -OH, -O(C) 1-3 Alkyl), -O (halogenated C) 1-3 Alkyl), -SH, -S(C 1-3 Alkyl), -C(=O)(C 1-3 Alkyl), -S(=O)(C 1-3 Alkyl), -S(=O)2(C 1-3 Alkyl groups, -C(=O)OH, -C(=O)NH2, -C(=O)NH(C 1-3 Alkyl), -C(=O)N(C 1-3 Alkyl)2、-NHC(=O)(C 1-3 Alkyl groups), -S(=O)NH2, -S(=O)NH(C 1-3 Alkyl), -S(=O)N(C1-3 Alkyl)2、-NHS(=O)(C 1-3 Alkyl groups), -S(=O)2NH2, -S(=O)2NH(C 1-3 Alkyl), -S(=O)2N(C 1-3 alkyl)2 or -NHS(=O)2(C 1-3 Alkyl); R3 or R2 may be substituted with one or more deuterium.

[0109]

[37] . Deuterated derivatives, stereoisomers, pharmaceutically acceptable salts thereof, pharmaceutically acceptable salts of stereoisomers, or pharmaceutically acceptable salts of deuterated derivatives of compound (I), wherein,

[0110] R2 and R3 are each independently selected from -H, -D, halogen, and -C. 1-3 Alkyl, Halogenated C 1-3 Alkyl, -C 2-3 Alkoxy, -C 2-3 alkenyl, -C 2-3 Alkyne, -CN, -NH2, -C(=O)OH, -NH(C 1-3 alkyl), -N(C) 1-3 Alkyl group 2, -OH, -O(C) 1-3 Alkyl), -O (halogenated C) 1-3 Alkyl), -SH, -S(C 1-3 Alkyl), -C(=O)(C 1-3 Alkyl), -S(=O)(C 1-3 Alkyl) or -S(=O)2(C 1-3 Alkyl); R3 or R2 may be substituted with one or more deuterium.

[0111]

[38] . Deuterated derivatives, stereoisomers, pharmaceutically acceptable salts thereof, pharmaceutically acceptable salts of stereoisomers, or pharmaceutically acceptable salts of deuterated derivatives of compound (I), wherein,

[0112] R2 and R3 are each independently selected from -H, -D, -Cl, -F, -Br, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CHFCH3, -CF2CH3, -CH2-O-CH3, -CH2-O-CH2-CH3, -CH2-CH2-O-CH3, -CH(CH3)-O-CH3. -CN, -C(=O)OH, -NH2, -NH(CH3), -N(CH3)2, -NH(CH2CH3), -OH, -O-CH3, -O-CH2-CH3, -O-CH2-CH2-CH3, -O-CH(CH3)2, -O-CF3, -SH, -S-CH3, -S-CH2CH3, -S-CH2CH2CH3, -S-CH(CH3)2, -C(=O)(CH3), -C(=O)(CH2CH3), -C(=O)(CH(CH3)2), -S(=O)(CH3), -S(=O)(CH2CH3), -S(=O)(CH(CH3)2), -S(=O)2(CH3), -S(=O)2(CH2CH3) or -S(=O)2(CH(CH3)2); wherein R3 or R2 may be substituted with one or more deuterium.

[0113]

[39] . Deuterated derivatives, stereoisomers, pharmaceutically acceptable salts thereof, pharmaceutically acceptable salts of stereoisomers, or pharmaceutically acceptable salts of deuterated derivatives of compound (I), wherein,

[0114] R2 and R3 are each independently selected from -H, -D, -CD3, or -CH3.

[0115]

[40] . A deuterated derivative, stereoisomer, pharmaceutically acceptable salt thereof, pharmaceutically acceptable salt of a stereoisomer, or pharmaceutically acceptable salt of a deuterated derivative thereof, wherein R3 is selected from -H, -D, -CD3, or -CH3.

[0116]

[41] . A deuterated derivative, stereoisomer, pharmaceutically acceptable salt thereof, pharmaceutically acceptable salt of a stereoisomer, or pharmaceutically acceptable salt of a deuterated derivative thereof, wherein R3 is selected from -H.

[0117]

[42] . A deuterated derivative, stereoisomer, pharmaceutically acceptable salt thereof, pharmaceutically acceptable salt of a stereoisomer, or pharmaceutically acceptable salt of a deuterated derivative thereof, wherein R2 is selected from -H, -D, -CD3, or -CH3.

[0118]

[43] . A deuterated derivative, stereoisomer, pharmaceutically acceptable salt thereof, pharmaceutically acceptable salt of a stereoisomer, or pharmaceutically acceptable salt of a deuterated derivative thereof, wherein R2 is selected from -H.

[0119]

[44] . A deuterated derivative, stereoisomer, pharmaceutically acceptable salt thereof, pharmaceutically acceptable salt of a stereoisomer, or pharmaceutically acceptable salt of a deuterated derivative thereof, wherein R3 is selected from -H; and R2 is selected from -H.

[0120]

[45] . Deuterated derivatives, stereoisomers, pharmaceutically acceptable salts thereof, pharmaceutically acceptable salts of stereoisomers, or pharmaceutically acceptable salts of deuterated derivatives of compound (I):

[0121]

[0122] R1 is selected independently from -C each time it appears. 1-3 Alkyl or -C 2-3 Alkoxy;

[0123] R1 can be optionally divided by 1, 2 or 3 Rs. 11 Replacement; when R1 is -CH3, the -CH3 is replaced by 1, 2 or 3 Rs. 11 replace;

[0124] The R 11 Selected from deuterium, -C 2-3 alkoxy or -O(C) 1-3 Alkyl); the R 11 It can be replaced by one or more deuterium atoms;

[0125] R4 groups are independently selected from -H, -D, halogen, and -C. 1-3 Alkyl, Halogenated C 1-3 Alkyl, -C 2-3 Alkoxy, -C 2-3 alkenyl, -C 2-3 Alkyne, -CN, -NH2, -C(=O)OH, -NH(C 1-3 alkyl), -N(C) 1-3 Alkyl group 2, -OH, -O(C) 1-3 Alkyl), -O (halogenated C) 1-3 Alkyl), -SH, -S(C 1-3 Alkyl), -C(=O)(C 1-3 Alkyl), -S(=O)(C 1-3 Alkyl) or -S(=O)2(C 1-3 Alkyl); the R4 may be substituted with one or more deuterium atoms;

[0126] R2 and R3 are each independently selected from -H, -D, halogen, and -C. 1-3 Alkyl, Halogenated C 1-3 Alkyl, -C 2-3 Alkoxy, -C 2-3 alkenyl, -C 2-3 Alkyne, -CN, -NH2, -C(=O)OH, -NH(C 1-3 alkyl), -N(C) 1-3 Alkyl group 2, -OH, -O(C) 1-3 Alkyl), -O (halogenated C)1-3 Alkyl), -SH, -S(C 1-3 Alkyl), -C(=O)(C 1-3 Alkyl), -S(=O)(C 1-3 Alkyl) or -S(=O)2(C 1-3 Alkyl); R3 or R2 may be substituted with one or more deuterium.

[0127]

[46] . Deuterated derivatives, stereoisomers, pharmaceutically acceptable salts of the deuterated derivative of compound (I), pharmaceutically acceptable salts of the stereoisomers, or pharmaceutically acceptable salts of the deuterated derivative:

[0128]

[0129] R1 is selected independently from -C each time it appears. 1-3 Alkyl or -C 2-3 Alkoxy;

[0130] R1 can be optionally divided by 1, 2 or 3 Rs. 11 Replacement; when R1 is -CH3, the -CH3 is replaced by 1, 2 or 3 Rs. 11 replace;

[0131] The R 11 Selected from deuterium, -C 2-3 alkoxy or -O(C) 1-3 Alkyl); the R 11 It can be replaced by one or more deuterium atoms;

[0132] R4 is independently selected from -H, -D, and -C. 1-3 Alkyl group; R4 may optionally be substituted with 1, 2, 3, 4, 5 or 6 deuterium atoms;

[0133] R2 and R3 are each independently selected from -H, -D, and -C. 1-3 Alkyl group; R2 or R3 may optionally be substituted with 1, 2, 3, 4, 5 or 6 deuterium atoms.

[0134]

[47] . Deuterated derivatives, stereoisomers, pharmaceutically acceptable salts thereof, pharmaceutically acceptable salts of stereoisomers, or pharmaceutically acceptable salts of deuterated derivatives of compound (I):

[0135]

[0136] R1 is selected independently from -C each time it appears. 1-3 Alkyl group; R1 may optionally be substituted with 1, 2, 3, 4, 5, 6 or 7 deuteriums; when R1 is -CH3, the -CH3 is substituted with 1, 2 or 3 deuteriums;

[0137] R4 is independently selected from -H, -D, and -C. 1-3 Alkyl group; R4 may optionally be substituted with 1, 2, 3, 4, 5 or 6 deuterium atoms;

[0138] R2 and R3 are each independently selected from -H, -D, and -C. 1-3 Alkyl group; R2 or R3 may optionally be substituted with 1, 2, 3, 4, 5 or 6 deuterium atoms.

[0139]

[48] . Deuterated derivatives, stereoisomers, pharmaceutically acceptable salts of the deuterated derivative of compound (I), pharmaceutically acceptable salts of the stereoisomers, or pharmaceutically acceptable salts of the deuterated derivative:

[0140]

[0141] R1 is selected independently from -C each time it appears. 1-3 Alkyl group, wherein R1 is R 11 Replace; the R 11 Selected from -C 2-3 alkoxy, the R 11 It can be replaced by one or more deuterium atoms;

[0142] R4 is independently selected from -H, -D, and -C. 1-3 Alkyl group; R4 may optionally be substituted with 1, 2, 3, 4, 5 or 6 deuterium atoms;

[0143] R2 and R3 are each independently selected from -H, -D, and -C. 1-3 Alkyl group; R2 or R3 may optionally be substituted with 1, 2, 3, 4, 5 or 6 deuterium atoms.

[0144]

[48] . Deuterated derivatives, stereoisomers, pharmaceutically acceptable salts of the deuterated derivative of compound (I), pharmaceutically acceptable salts of the stereoisomers, or pharmaceutically acceptable salts of the deuterated derivative:

[0145]

[0146] R1 is selected independently from -C each time it appears. 2-3 alkoxy, wherein R1 is R 11 Replace; the R 11 Selected from -C 2-3 alkoxy or -O(C) 1-3 Alkyl), the R 11 It can be replaced by one or more deuterium atoms;

[0147] R4 is independently selected from -H, -D, and -C. 1-3 Alkyl group; R4 may optionally be substituted with 1, 2, 3, 4, 5 or 6 deuterium atoms;

[0148] R2 and R3 are each independently selected from -H, -D, and -C. 1-3 Alkyl group; R2 or R3 may optionally be substituted with 1, 2, 3, 4, 5 or 6 deuterium atoms.

[0149]

[49] . Deuterated derivatives, stereoisomers, pharmaceutically acceptable salts of the compound (I-1), pharmaceutically acceptable salts of the stereoisomers, or pharmaceutically acceptable salts of the deuterated derivatives:

[0150]

[0151] R4 is independently selected from -H, -D, and -C. 1-3 Alkyl group; R4 may optionally be substituted with 1, 2, 3, 4, 5 or 6 deuterium atoms;

[0152] R2 and R3 are each independently selected from -H, -D, and -C. 1-3 Alkyl group; R2 or R3 may optionally be substituted with 1, 2, 3, 4, 5 or 6 deuterium atoms.

[0153]

[50] . Deuterated derivatives, stereoisomers, pharmaceutically acceptable salts thereof, pharmaceutically acceptable salts of stereoisomers, or pharmaceutically acceptable salts of deuterated derivatives of compound (I-2):

[0154]

[0155] R4 is independently selected from -H, -D, and -C. 1-3 Alkyl group; R4 may optionally be substituted with 1, 2, 3, 4, 5 or 6 deuterium atoms;

[0156] R2 and R3 are each independently selected from -H, -D, and -C. 1-3 Alkyl group; R2 or R3 may optionally be substituted with 1, 2, 3, 4, 5 or 6 deuterium atoms.

[0157]

[51] . Deuterated derivatives, stereoisomers, pharmaceutically acceptable salts of the compound (I-3), pharmaceutically acceptable salts of the stereoisomers, or pharmaceutically acceptable salts of the deuterated derivatives:

[0158]

[0159] R4 is independently selected from -H, -D, and -C. 1-3 Alkyl group; R4 may optionally be substituted with 1, 2, 3, 4, 5 or 6 deuterium atoms;

[0160] R2 and R3 are each independently selected from -H, -D, and -C. 1-3 Alkyl group; R2 or R3 may optionally be substituted with 1, 2, 3, 4, 5 or 6 deuterium atoms.

[0161]

[52] . A deuterated derivative, stereoisomer, pharmaceutically acceptable salt thereof, pharmaceutically acceptable salt of a stereoisomer, or pharmaceutically acceptable salt of a deuterated derivative of compound (I), wherein the compound is represented by any of the following formulas:

[0162]

[0163]

[0164]

[0165]

[0166]

[0167]

[0168]

[0169]

[0170]

[0171]

[0172]

[0173]

[0174]

[0175]

[0176]

[0177]

[0178]

[0179]

[0180]

[0181]

[0182]

[0183]

[0184]

[0185]

[53] . A pharmaceutical composition comprising a compound, a deuterated derivative thereof, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer thereof or a pharmaceutically acceptable salt of the deuterated derivative thereof, and at least one pharmaceutically acceptable excipient, said compound being selected from any one of [1] to

[52] .

[0186]

[54] . A method for treating a subject with a mitochondrial-related disease or condition, the method comprising administering to the subject a therapeutically effective amount of a compound, a deuterated derivative thereof, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of a stereoisomer thereof, or a pharmaceutically acceptable salt of a deuterated derivative thereof, said compound being selected from any one of [1] to

[52] ; or administering a pharmaceutical composition described in

[53] .

[0187]

[55] . According to the method described in

[54] , the disease is obesity, excessive body fat, diabetes, insulin resistance or intolerance, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), hepatic steatosis, type 2 diabetes mellitus (T2DM), dyslipidemia, cardiovascular disease, heart disease or atherosclerosis.

[0188]

[56] . Use of a compound, its deuterated derivative, stereoisomer, pharmaceutically acceptable salt thereof, pharmaceutically acceptable salt of the stereoisomer or pharmaceutically acceptable salt of the deuterated derivative, or

[53] of the pharmaceutical composition thereof in the preparation of a medicament for treating mitochondrial-related diseases or conditions, wherein the compound is selected from any one of [1] to

[52] .

[0189]

[57] . According to the use described in

[56] , the disease is obesity, excessive body fat, diabetes, insulin resistance or intolerance, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), hepatic steatosis, type 2 diabetes mellitus (T2DM), dyslipidemia, cardiovascular disease, heart disease or atherosclerosis.

[0190]

[58] . A compound, its deuterated derivative, stereoisomer, pharmaceutically acceptable salt thereof, pharmaceutically acceptable salt of the stereoisomer or pharmaceutically acceptable salt of the deuterated derivative, or a pharmaceutical composition thereof

[53] , for the treatment of mitochondrial-related diseases or conditions, wherein the compound is selected from any one of [1] to

[52] .

[0191]

[59] . According to the use described in

[58] , wherein the disease is obesity, excessive body fat, diabetes, insulin resistance or intolerance, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), hepatic steatosis, type 2 diabetes mellitus (T2DM), dyslipidemia, cardiovascular disease, heart disease or atherosclerosis. Attached Figure Description

[0192] Figure 1 Compound 2-1 1 H-NMR spectrum.

[0193] Figure 2 Compound 2 1 H-NMR spectrum. Detailed Implementation

[0194] definition

[0195] The terms “halogen” or “halogenated” are used interchangeably herein unless otherwise specified, referring to fluorine, chlorine, bromine, or iodine. Preferred halogen groups include -F, -Cl, and -Br.

[0196] The term "alkyl," as used herein, unless otherwise specified, includes saturated monovalent hydrocarbon groups having a straight chain or branched chains. For example, alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 3-(2-methyl)butyl, 2-pentyl, 2-methylbutyl, neopentyl, n-hexyl, 2-hexyl, and 2-methylpentyl. 1-6 In -C 1-6 Alkyl groups are used to identify straight-chain or branched groups having 1, 2, 3, 4, 5 or 6 carbon atoms.

[0197] The term "haloalkyl" is used herein, unless otherwise stated, to refer to an alkyl group substituted with one or more (1, 2, 3, 4, 5, or 6) halogens (-F, -Cl, or -Br). In some embodiments, the haloalkyl group may be interchanged with -C. 1-6 Halogenated alkyl or halogenated C 1-6 Alkyl, wherein -C 1-6 Halogenated alkyl or halogenated C 1-6 C in alkyl 1-6 This indicates that the total number of carbon atoms in the alkyl group is 1 to 6. In some embodiments, -C 1-6 The alkyl halide is -C 1-3 Halogenated alkyl groups. In some embodiments, -C 1-3 The haloalkyl group (methyl, ethyl, propyl, or isopropyl) is substituted with 1, 2, 3, 4, 5, or 6 -F groups; preferably, -C 1-3 The alkyl halide is -CF3.

[0198] The term "alkylene" refers to a difunctional group obtained by removing an additional hydrogen atom from the aforementioned alkyl group. Examples include methylene (i.e., -CH2-), vinyl (i.e., -CH2-CH2- or -CH(CH3)-), and propenyl (i.e., -CH2-CH2-CH2-, -CH(-CH2-CH3)- or -CH2-CH(CH3)-).

[0199] The term "alkenyl" refers to a straight-chain or branched hydrocarbon group containing one or more double bonds, typically ranging in length from 2 to 20 carbon atoms. For example, "-C 2-6 "Alkenyl" contains 2 to 6 carbon atoms. Alkenyl groups include, but are not limited to, vinyl, propenyl, butenyl, 2-methyl-2-buten-1-yl, heptenyl, octenyl, etc.

[0200] The term "alkynyl" refers to a straight-chain or branched hydrocarbon group containing one or more triple bonds, typically with a length of 2 to 600 kJ / kJ. 20 One carbon atom. For example, "C 2-6 The alkynyl group contains 2 to 6 carbon atoms. Representative alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 1-butynyl, heptynyl, octyynyl, etc.

[0201] The term "alkoxy" refers to an oxygen ether formed from the aforementioned alkyl groups. Alkoxy refers to an alkyl group substituted with an -O-alkyl group, including but not limited to -CH2-O-CH3, -CH2CH2-O-CH3, -CH2-O-CH2CH3, -CH2(CH3)-O-CH3, and -CH2CH2-O-CH2CH2.

[0202] The term "haloalkoxy" is used herein, unless otherwise stated, to refer to an alkoxy group substituted with one or more (1, 2, 3, 4, 5, or 6) halogens (-F, -Cl, or -Br). In some embodiments, the haloalkoxy group may be interchanged with -C. 1-6 Halogenated alkoxy or halogenated C 1-6 alkoxy group, where -C 1-6 Halogenated alkoxy or halogenated C 1-6 C in alkoxy 1-6 This indicates that the total number of carbon atoms in the alkoxy group is 1 to 6. In some embodiments, -C 1-6 The haloalkoxy group is -C 1-3 Halogenated alkoxy groups. In some embodiments, -C 1-3 The haloalkoxy group (methoxy, ethoxy, propoxy, or isopropoxy) is substituted with 1, 2, 3, 4, 5, or 6 -F groups; preferably, -C 1-3 The haloalkoxy group is -OCF3.

[0203] The term "aryl," as used herein, unless otherwise specified, refers to an unsubstituted or substituted monocyclic or polycyclic aromatic ring system containing a carbon ring atom. Preferred aryl groups are monocyclic or bicyclic 6-10 membered aromatic ring systems. Phenyl and naphthyl are preferred aryl groups.

[0204] The interchangeable terms “heterocyclic” or “heterocyclic” are used herein, unless otherwise stated, to refer to unsubstituted and substituted monocyclic or polycyclic non-aromatic ring systems containing one or more heteroatoms, including monocyclic heterocycles, bicyclic heterocycles, bridged heterocycles, fused heterocycles, or spirocyclic heterocycles. Preferred heteroatoms include N, O, and S, including N-oxides, sulfur oxides, and dioxides. Preferably, the ring is tri- to deca-membered and may be fully saturated or have one or more degrees of unsaturation. This definition includes multiple degrees of substitution, preferably one, two, or three. Examples of such heterocyclic groups include, but are not limited to, azirrolyl, pyrrolylyl, piperidinyl, piperazine, oxoperazinyl, oxoperridinyl, oxoazirrolyl, azirrolyl, tetrahydrofuranyl, dioxohexacycloyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydrooxazolyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, and oxadiazolyl.

[0205] The term "heteroaryl," as used herein unless otherwise stated, refers to an aromatic ring system containing carbon and at least one heteroatom. Heteroaryl rings can be monocyclic or bicyclic, substituted or unsubstituted. Monocyclic heteroaryl rings can contain 1 to 4 heteroatoms, while bicyclic heteroaryl rings can contain 1 to 10 heteroatoms. Bicyclic heteroaryl rings can contain fused, spirocyclic, or bridged rings; for example, a bicyclic heteroaryl is a type of bicyclic heteroaryl. Bicyclic heteroaryl rings can contain 8 to 12 member atoms. Monocyclic heteroaryl rings can contain 5 to 8 member atoms (carbon and heteroatoms). Examples of heteroaryl groups include, but are not limited to, thienyl, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrroleyl, thiazolyl, thiadiazolyl, triazolyl, pyridyl, pyridinyl, indolyl, azaindolyl, indolyl, benzimidazolyl, benzofuranyl, benzothiophenyl, benziisoxazolyl, benzoxazolyl, benzopyrazolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, adenine, quinolinyl, or isoquinolinyl.

[0206] The term "carbocyclic ring" refers to a substituted or unsubstituted monocyclic, bicyclic, bridged, fused, or spirocyclic nonaromatic ring system containing only carbon atoms. Preferably, the ring is tri- to ten-membered and may be fully saturated or have one or more degrees of unsaturation. This definition includes multiple degrees of substitution, preferably one, two, or three. Carbocyclic rings include, but are not limited to, cycloalkyl, cycloalkenyl, and cycloynyl groups. Exemplary "cycloalkyl" groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.

[0207] The term "one or more" refers to one or more. In some embodiments, "one or more" refers to 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments, "one or more" refers to 1, 2, 3, 4, 5, or 6. In some embodiments, "one or more" refers to 1, 2, 3, or 4. In some embodiments, "one or more" refers to 1, 2, or 3. In some embodiments, "one or more" refers to 1 or 2. In some embodiments, "one or more" refers to 1. In some embodiments, "one or more" refers to 2. In some embodiments, "one or more" refers to 3. In some embodiments, "one or more" refers to 4. In some embodiments, "one or more" refers to 5. In some embodiments, "one or more" refers to 6.

[0208] When one or more substituents are substituted on the ring in this invention, it means that each substituent can independently substitute for each ring atom on the ring, including but not limited to ring carbon atoms or ring nitrogen atoms. Furthermore, when the ring is a bicyclic ring system, such as a fused ring, bridged ring, or spirocyclic ring, each substituent can independently substitute for each ring atom of the polycyclic ring.

[0209] The term "oxo" refers to the formation of a group by an oxygen atom and the carbon atom it is attached to.

[0210] The term "composition," as used herein, means a product containing a specified amount of a specified ingredient, and any product produced directly or indirectly from a combination of the specified amounts of the specified ingredients. Therefore, pharmaceutical compositions containing compounds of the present invention as active ingredients, and methods for preparing the compounds of the present invention, are also part of this invention. Furthermore, certain crystalline forms of the compounds of the present invention may exist in polymorphic forms and are therefore also included in this invention. Additionally, certain compounds of the present invention may form solvates with water (i.e., hydrates) or common organic solvents, and such solvates are also included within the scope of this invention.

[0211] The term "pharmaceutically acceptable salt" refers to a salt prepared from a pharmaceutically acceptable nontoxic base or acid. When the compounds of the present invention are acidic, their corresponding salts can be conveniently prepared from pharmaceutically acceptable nontoxic bases, including inorganic and organic bases. When the compounds of the present invention are basic, their corresponding salts can be conveniently prepared from pharmaceutically acceptable nontoxic acids, including inorganic and organic acids. Since the compounds of the present invention are intended for pharmaceutical use, they are preferably provided in substantially pure form, for example, at least 60% purity, more preferably at least 75% purity, and particularly preferably at least 98% purity (by weight).

[0212] This invention includes any prodrug of the compounds of this invention within its scope. Generally, such prodrugs will be functional derivatives of the compounds, which are readily converted into the desired compound in vivo. Therefore, in the treatment methods of this invention, the term "administration" should include treating the various diseases with a clearly disclosed compound or a compound that is not clearly disclosed but is converted into a specific compound in vivo after administration. Conventional procedures for selecting and preparing suitable prodrug derivatives are described, for example, in *Prodrug Design*, ed. H. Bundgaard, Elsevier, 1985.

[0213] It should be understood that the present invention is intended to include any possible substituents or variables when the definition of a substituent or variable at a particular position in the molecule is independent of its definition at other positions in the molecule. It should be understood that the substituents and substitution patterns of the compounds of the present invention can be selected by those skilled in the art to provide chemically stable compounds that can be readily synthesized by methods known in the art and described herein.

[0214] This invention includes compounds that may contain one or more chiral centers, thus potentially yielding diastereomers and optical isomers. This invention includes all possible diastereomers and their racemic mixtures, substantially pure resolved enantiomers, all possible geometric isomers, and their pharmaceutically acceptable salts.

[0215] This invention includes all stereoisomers of the said compound and their pharmaceutically acceptable salts. Furthermore, mixtures of stereoisomers and isolated specific stereoisomers are also included. In the synthesis used to prepare such compounds, or when using racemization or epimerization steps known to those skilled in the art, the products of such steps can be mixtures of stereoisomers.

[0216] The term "stereoisomer," as used in this invention, refers to isomers in which atoms or groups of atoms in a molecule are connected in the same order but arranged in different spatial arrangements, including conformational isomers and configurational isomers. Configurational isomers include geometric isomers and optical isomers, with optical isomers primarily including enantiomers and diastereomers. This invention encompasses all possible stereoisomers of compounds.

[0217] Some of the compounds described herein may exist as trans-isomers, which are conformational stereoisomers that arise from steric interactions of other parts of the molecule when rotation around a single bond is hindered or significantly slowed. The compounds described herein include all trans-isomers, including pure single trans-isomer formulations, enriched formulations of each, or nonspecific mixtures. When the rotational barrier of the single bond is sufficiently high and the interconversion between conformations is sufficiently slow, separation and isolation of the isomers may be permitted.

[0218] This invention is intended to include isotopes of all atoms appearing in the compounds of this invention. Isotopes include atoms having the same atomic number but different mass numbers. By general example, but not limited to, isotopes of hydrogen include deuterium and tritium. Isotopes of hydrogen can be represented as... 1 H (hydrogen) 2 H (deuterium) and 3 H (tritium). They are usually represented as D for deuterium and T for tritium. In this application, CD3 represents a methyl group in which all hydrogen atoms are deuterium. Carbon isotopes include 13 C and 14 C. The isotope-labeled compounds of the present invention can generally be prepared by conventional techniques known to those skilled in the art or by processes similar to those described herein, using appropriate isotope-labeling reagents instead of unlabeled reagents.

[0219] The term "deuterated derivative," as used herein unless otherwise stated, refers to a compound having the same chemical structure as the reference compound, but in which one or more hydrogen atoms are substituted with deuterium atoms ("D"). It should be recognized that the natural isotopic abundance in synthetic compounds can vary due to the different sources of the chemical materials used in the synthesis. The concentration of naturally occurring stable hydrogen isotopes, despite such variations, is small and insignificant compared to the degree of stable isotopic substitution in the deuterated derivatives described herein. Therefore, unless otherwise stated, when referring to the "deuterated derivative" of the compounds of the present invention, at least one hydrogen atom is substituted with deuterium, and its abundance is much higher than its natural isotopic abundance (natural abundance is typically about 0.015%). In some embodiments, the isotopic enrichment factor of each deuterium atom of the deuterated derivative of this disclosure is at least 3500 (52.5% deuterium doping per specified deuterium atom), at least 4500 (67.5% deuterium doping), at least 5000 (75% deuterium doping), at least 5500 (82.5% deuterium doping), at least 6000 (90% deuterium doping), at least 6333.3 (95% deuterium doping), at least 6466.7 (97% deuterium doping), or at least 6600 (99% deuterium doping).

[0220] When tautomers of the compounds of this invention are present, this invention includes any possible tautomers and their pharmaceutically acceptable salts and mixtures thereof, unless otherwise specified.

[0221] The pharmaceutical compositions of the present invention comprise the compound of the present invention (or a pharmaceutically acceptable salt thereof) as the active ingredient, a pharmaceutically acceptable carrier, and optionally other therapeutic ingredients or adjuvants. The compositions include those suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) administration, but the most suitable route in any given case will depend on the specific host and the nature and severity of the administration of the active ingredient. The pharmaceutical compositions can be conveniently presented in unit dose form and can be prepared by any method well known in the pharmaceutical field.

[0222] In practice, the compounds of the present invention, or their prodrugs, metabolites, or pharmaceutically acceptable salts, can be tightly mixed as active ingredients with pharmaceutical carriers according to conventional pharmaceutical formulation techniques. The carriers can take various forms depending on the desired formulation for administration, such as oral or parenteral (including intravenous) administration. Therefore, the pharmaceutical compositions of the present invention can be presented as discrete units suitable for oral administration, such as capsules, pouches, or tablets, each unit containing a predetermined amount of the active ingredient. Furthermore, the compositions can be presented as powders, granules, solutions, suspensions in aqueous liquids, non-aqueous liquids, water-in-oil emulsions, or oil-in-water emulsions. In addition to the common dosage forms described above, compounds represented by Formula I, or their pharmaceutically acceptable salts, can also be administered via controlled-release methods and / or delivery devices. The compositions can be prepared by any pharmaceutical method. Generally, such methods involve the step of combining the active ingredient with a carrier constituting one or more essential components. Generally, the compositions are prepared by uniformly and tightly mixing the active ingredient with a liquid carrier or a subdivided solid carrier, or both. The product can then be conveniently shaped into the desired presentation form.

[0223] Therefore, the pharmaceutical compositions of the present invention may comprise a pharmaceutically acceptable carrier and a compound of the present invention or a pharmaceutically acceptable salt. The compound of Formula I or a pharmaceutically acceptable salt may also be included in the pharmaceutical composition together with one or more other therapeutically active compounds.

[0224] The pharmaceutical carrier used can be, for example, solid, liquid, or gas. Examples of solid carriers include lactose, kaolin, sucrose, talc, gelatin, agar, pectin, gum arabic, magnesium stearate, and stearic acid. Examples of liquid carriers include syrup, peanut oil, olive oil, and water. Examples of gaseous carriers include carbon dioxide and nitrogen. In preparing compositions for oral dosage forms, any convenient pharmaceutical medium can be used. For example, water, ethylene glycol, oil, alcohol, flavoring agents, preservatives, coloring agents, etc., can be used to form oral liquid dosage forms, such as suspensions, elixirs, and solutions; while carriers such as starch, sugar, microcrystalline cellulose, diluents, granulators, lubricants, binders, disintegrants, etc., can be used to form oral solid dosage forms, such as powders, capsules, and tablets. Tablets and capsules are preferred oral dosage units due to their ease of administration, and therefore solid pharmaceutical carriers are used. Optionally, tablets can be coated using standard aqueous or non-aqueous techniques.

[0225] Tablets containing the compositions of the present invention can be prepared by compression or molding, optionally together with one or more excipients or adjuvants. Compressed tablets can be prepared by compressing a free-flowing active ingredient (such as powder or granules) in a suitable machine, optionally mixed with a binder, lubricant, inert diluent, surfactant, or dispersant. Molded tablets can be prepared by molding a mixture of powdered compounds wetted with an inert liquid diluent in a suitable machine. Each tablet preferably contains about 0.05 mg to about 5 g of active ingredient, and each capsule or pouch preferably contains about 0.05 mg to about 5 g of active ingredient. For example, formulations intended for oral administration to humans may contain about 0.5 mg to about 5 g of active ingredient, compounded with a suitable and convenient amount of carrier material, the amount of which can range from about 0.05 to about 95% of the total composition. Unit dosage forms typically contain from about 0.01 mg to about 2 g of active ingredient, usually in doses of 0.01 mg, 0.02 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg, 1000 mg, 1500 mg, or 2000 mg.

[0226] The pharmaceutical compositions of this invention suitable for parenteral administration can be prepared as solutions or suspensions of the active compound in water. Suitable surfactants, such as hydroxypropyl cellulose, may be included. The dispersions can also be prepared in a mixture of glycerol, liquid polyethylene glycol, and oils therein. Furthermore, preservatives may be included to prevent the growth of harmful microorganisms.

[0227] The pharmaceutical compositions suitable for injection according to this invention comprise sterile aqueous solutions or dispersions. Alternatively, the composition may be a sterile powder for provisional preparation of such sterile injectable solutions or dispersions. In all cases, the final injectable form must be sterile and flowable for easy injection. The pharmaceutical composition must be stable under the conditions of manufacture and storage; therefore, it is preferable to prevent contamination by microorganisms such as bacteria and fungi. The carrier may be a solvent or dispersion medium comprising, for example, water, ethanol, polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), vegetable oils, and suitable mixtures thereof.

[0228] The pharmaceutical compositions of the present invention can be in forms suitable for topical application, such as aerosols, creams, ointments, lotions, powders, etc. Furthermore, the compositions can be in forms suitable for use with transdermal devices. These formulations can be prepared using compounds of Formula I of the present invention or pharmaceutically acceptable salts thereof, by conventional processing methods. For example, creams or ointments are prepared by mixing a hydrophilic material and water, and about 0.05% by weight to about 10% by weight of the compound, to produce a cream or ointment with a desired consistency.

[0229] The pharmaceutical compositions of the present invention can be in a form suitable for rectal administration, wherein the carrier is solid. Preferably, the mixture is formed into a unit-dose suppository. Suitable carriers include cocoa butter and other materials commonly used in this field. Suppositories can be conveniently formed by first mixing the composition with a softened or melted carrier, then cooling and molding it in a mold.

[0230] In addition to the carrier components described above, the pharmaceutical formulations may also include one or more additional carrier components, such as diluents, buffers, flavoring agents, binders, surfactants, thickeners, lubricants, preservatives (including antioxidants), etc., as appropriate. Furthermore, other adjuvants may be included to make the formulation isotonic with the blood of the intended recipient. Compositions containing a compound of formula I or a pharmaceutically acceptable salt in powder or liquid concentrate form may also be prepared.

[0231] Generally, dosage levels of approximately 0.001 mg to approximately 150 mg per kilogram of body weight per day are useful for treating the above-mentioned indications, or approximately 0.05 mg to approximately 7 g per patient per day. For example, inflammation, cancer, psoriasis, allergies / asthma, diseases and conditions of the immune system, and diseases and conditions of the central nervous system can be effectively treated by administration at doses of approximately 0.001 mg / kg to 50 mg / kg of body weight, or approximately 0.05 mg to approximately 3.5 g per patient per day.

[0232] However, it should be understood that the specific dosage level for any particular patient will depend on a variety of factors, including age, weight, general health condition, sex, diet, timing of administration, route of administration, excretion rate, combination of drugs, and the severity of the specific disease being treated.

[0233] Unless the context clearly indicates otherwise, when a numerical value is expressed as “about” X or “approximately” X, the value of X shall be understood to be accurate to ±10%, preferably ±5%, ±2%.

[0234] These and other aspects will become apparent from the following written description of the invention.

[0235] Preparation method

[0236] The compounds of this invention can be synthesized from commercially available reagents using the synthetic methods and reaction schemes described herein. Examples of specific synthetic routes, as well as general schemes, are outlined below to provide guidance for synthetic chemists of ordinary skill who will find them easily understandable. Solvents, concentrations, reagents, protecting groups, the order of synthetic steps, time, temperature, etc., can be modified as needed, entirely within the skill range of ordinary skilled technicians.

[0237] Example

[0238] The following examples are provided to better illustrate the invention. Unless explicitly stated otherwise, all parts and percentages are by weight, and all temperatures are in degrees Celsius. The following abbreviations are used in the examples:

[0239] DMF: N,N-dimethylformamide EA, EtOAc: Ethyl acetate MeOH: Methanol DCM: Dichloromethane THF: Tetrahydrofuran RT / RT: Room temperature min(s): minutes h / hr(s): hours aq: aqueous solution Sat.: saturated Prep HPLC: Preparative High Performance Liquid Chromatography

[0240] Example 1

[0241]

[0242] Under stirring, an aqueous solution of HBF4 (6.4 mL, 50% by weight) and an aqueous solution of NaNO2 (12.9 mL, 77.34 mmol, 6 equivalents) were added dropwise to an aqueous solution of ethyl 2-amino-1H-imidazolium-5-carboxylate (2 g, 12.89 mmol) at 0 °C. After stirring at 0 °C for 1 hour, a mixture of CuSO4 (26.7 g, 0.16 mol) and bipyridine (261 mg, 1.67 mmol) in an aqueous solution (200 mL) was added dropwise at 0 °C, followed by the partial addition of NaNO2 (5.3 g, 77.34 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 3 hours under a nitrogen atmosphere, the pH was adjusted to 1–2 with aqueous HCl, and then extracted with ethyl acetate. The organic layer was washed successively with aqueous NaHSO3 solution and brine, dried over anhydrous sodium sulfate, and then concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (eluting with petroleum ether / ethyl acetate) to give compound 1-1 (2.08 g, 87% yield). LCMS: m / z = 186.1 [M+H] + .

[0243] To a solution of compound 1-1 (2.08 g, 11.24 mmol), CD3OD (445 mg, 12.36 mmol), and triphenylphosphine (4.4 g, 16.86 mmol) in dichloromethane (40 mL), DIAD (3.4 g, 16.86 mmol) was added dropwise at 0 °C. The reaction mixture was stirred under a nitrogen atmosphere for 3 hours, poured into water, and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated to give a crude product, which was purified by silica gel column chromatography (eluting with petroleum ether / ethyl acetate) to give compound 1-2 (1.1 g, 50% yield). LCMS: m / z = 203.1 [M+H] + .

[0244] To a solution of compound 1-2 (1.1 g, 5.44 mmol) in methanol (3 mL) and tetrahydrofuran (9 mL), NaBH4 (620 mg, 16.33 mmol) was added fractionally at 0 °C. The reaction mixture was stirred for 3 hours, quenched with ice water, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated to give the crude product, which was purified by silica gel column chromatography (eluting with petroleum ether / ethyl acetate) to give compound 1-3 (322 mg, 37% yield). LCMS: m / z = 161.1 [M+H] + .

[0245] To a solution of compounds 1-3 (322 mg, 2.01 mmol) and 1-fluoro-2,4-dinitrobenzene (412 mg, 2.21 mmol) in dioxane (4 mL), Cs₂CO₃ (1.96 g, 6.03 mmol) was added fractionally. The reaction mixture was stirred at 60 °C for 5 h under a nitrogen atmosphere, cooled to room temperature, quenched with ice water, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by preparative high-performance liquid chromatography (C18 column, acetonitrile / water elution) to give compound 1 (511 mg, 78% yield). LCMS: m / z = 327.1 [M+H] + .

[0246] Example 2

[0247]

[0248] To a DMF (5 mL) suspension of compound 1-1 (370 mg, 2 mmol), NaH (8 mg, 2.2 mmol, 60% by weight) was added at 0 °C. After stirring for 1.5 hours, 1-bromo-2-methoxyethane (303 mg, 2.2 mmol) and KI (166 mg, 1 mmol) were added at 0 °C. The reaction mixture was stirred at 110 °C for 5 hours under a nitrogen atmosphere, cooled to room temperature, quenched with ice water, and then extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated to give the crude product, which was purified by silica gel column chromatography (eluting with petroleum ether / ethyl acetate) to give compound 2-1 (200 mg, 41% yield). LCMS: m / z = 244.1 [M+H] + .

[0249] 1 H NMR (400MHz, DMSO-d6, ppm): δ7.70 (s, 1H), 5.13 (t, J=5.2Hz, 2H), 4.37 (q, J=6.8Hz, 2H), 3.61 (t, J=5.2Hz, 2H), 3.23 (s, 3H), 1.39 (t, J=7.2Hz, 3H).

[0250] To a solution of compound 2-1 (200 mg, 0.82 mmol) in methanol (2 mL) and tetrahydrofuran (2 mL), NaBH4 (62 mg, 1.64 mmol) was added fractionally at 0 °C. The resulting mixture was stirred for 3 hours, quenched with ice water, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated to give the crude product, which was purified by silica gel column chromatography (eluting with petroleum ether / ethyl acetate) to give compound 2-2 (50 mg, 30% yield). LCMS: m / z = 202.1 [M+H] + .

[0251] To a solution of compound 2-2 (50 mg, 0.25 mmol) and 1-fluoro-2,4-dinitrobenzene (93 mg, 0.3 mmol) in dioxane (1 mL), Cs₂CO₃ (244 mg, 0.75 mmol) was added fractionally. The reaction mixture was heated to 60 °C and stirred for 5 hours under a nitrogen atmosphere, cooled to room temperature, quenched with ice water, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated to give the crude product, which was purified by preparative high-performance liquid chromatography (C18 column, acetonitrile / water elution) to give compound 2 (27.4 mg, 30% yield). LCMS: m / z = 368.2 [M+H] + .

[0252] 1H-NMR (400MHz, DMSO-d6, ppm): δ8.79 (d, J=2.8Hz, 1H), 8.57 (dd, J=2.8, 9.2Hz, 1H), 7.81 (d, J=9 .2Hz, 1H), 7.41 (s, 1H), 5.64 (s, 2H), 4.62 (t, J=5.2Hz, 2H), 3.65 (t, J=5.2Hz, 2H), 3.18 (s, 3H).

[0253] Pharmacological experiments

[0254] 1. Determination of thermodynamic solubility

[0255] The materials, reagents, plates, and instruments used in the thermodynamic solubility determination experiment are shown in Table 1.

[0256] Table 1

[0257]

[0258] Detailed operation process

[0259] Preparation of FaSSIF solution, FaSSGF solution and stock solution

[0260] Dissolve 0.42 g NaOH, 3.44 g NaH₂PO₄, and 6.19 g NaCl in 900 mL of ultrapure water. Adjust the pH of the solution to 6.5 with either a 1 N NaOH aqueous solution or a 1 N HCl aqueous solution. Dilute the resulting mixture to 1000 mL with ultrapure water to obtain a buffer solution. Add 2.24 g of FaSSIF, FeSSIF, and FaSSGF powders to the buffer solution (500 mL), stir until completely dissolved, and then dilute to 1000 mL with the buffer solution. Allow the mixture to stand until slightly turbid to prepare a FaSSIF solution, which should be used within 48 hours at room temperature or within 24 hours at 37°C.

[0261] Dissolve 2.00 g of NaCl in 900 mL of ultrapure water. Adjust the pH of the solution to 1.6 with 1 N HCl aqueous solution, then dilute to 1000 mL with ultrapure water to obtain an HCl / NaCl solution. Add 0.06 g of FaSSIF, FeSSIF, and FaSSGF powders to 500 mL of the HCl / NaCl solution and stir until completely dissolved. Then dilute to 1000 mL with the HCl / NaCl solution. The resulting FaSSGF solution should be used within 48 hours at room temperature or within 24 hours at 37°C.

[0262] Preparation of standard solutions

[0263] Each test compound and positive control compound was diluted with DMSO to a concentration of 1 mg / mL, and then diluted with 50% acetonitrile containing an internal standard (IS, 100 ng / mL dexamethasone) to obtain a standard solution of each test compound and positive control compound (the dilution factor can be adjusted according to the LC-MS / MS response).

[0264] Preparation of test solutions and data analysis

[0265] Aliquots of each analyte (approximately 1 mg) into individual wells of a 96-well plate were prepared. Then, either FaSSIF or FaSSGF solution was added to each well to bring the concentration to 1 mg / mL. The 96-well plate was transferred to a thermostatic mixer and incubated at 37°C with shaking at 1200 rpm for 24 hours, followed by filtration. The filtrate (10 μL) was vortexed with a mixture of 50% acetonitrile (155°C, 100 ng / mL dexamethasone) (990 μL) for 5 minutes. The solution was then diluted with 50% acetonitrile containing the internal standard (155°C, 100 ng / mL dexamethasone) to obtain the test solution. The dilution factor could be adjusted based on the LC-MS / MS response. Wells containing the same percentage of diclofenac sodium served as positive controls. The solubility of the analyte was calculated using the following formula:

[0266] Sample solubility = Area Ratio sample *DF*[STD] / Area Ratio Std

[0267] Area Ratio sample This refers to the area ratio of the test solution (analyte peak area / internal standard peak area).

[0268] Area Ratio Std This refers to the area ratio of the standard solution (analyte peak area / internal standard peak area).

[0269] DF refers to the dilution factor.

[0270] [STD] refers to the concentration of the standard solution.

[0271] 2. Pharmacokinetic studies in mice

[0272] The aim of this study was to evaluate the pharmacokinetic properties of the compounds in ICR mice (♂) after administration. Nine mice were used for each compound, and these mice were randomly divided into three groups (n=3 per group): Group A, Group B, and Group C. Group A mice were administered a single oral dose of 5 mg / kg. Group B mice were administered a single oral dose of 10 mg / kg. Group C mice were administered a single oral dose of 20 mg / kg. For each mouse in Group A, blood samples were collected at 0.25, 0.5, 1, 2, 4, and 8 hours post-administration. Blood samples were kept on ice until centrifuged to obtain plasma samples. Plasma samples were stored at -80°C until analysis. The concentration of the compounds in the plasma samples was determined using LC-MS / MS.

[0273] It should be understood that if this article cites any prior art publications, such citation does not constitute an acknowledgment that such publications constitute part of the general knowledge of the field in any country.

[0274] All publications, patents, patent applications and published patent applications cited in this article are incorporated herein in their entirety.

[0275] Although the invention has been described in detail to a certain extent by way of embodiments and examples for the purpose of clarity, it will be apparent to those skilled in the art that minor changes and modifications can be made without departing from the scope of the invention. Therefore, the description and examples should not be construed as limiting the scope of the invention.

Claims

1. The compound shown in the following formula, its deuterated derivative, stereoisomer, pharmaceutically acceptable salt, pharmaceutically acceptable salt of the stereoisomer, or pharmaceutically acceptable salt of the deuterated derivative, 2. The following compounds, their deuterated derivatives, stereoisomers, pharmaceutically acceptable salts, pharmaceutically acceptable salts of stereoisomers, or pharmaceutically acceptable salts of deuterated derivatives, are listed below.

3. The compound shown in the following formula, its deuterated derivative, stereoisomer, pharmaceutically acceptable salt, pharmaceutically acceptable salt of the stereoisomer, or pharmaceutically acceptable salt of the deuterated derivative, 4. A pharmaceutical composition comprising the compound of any one of claims 1 to 3, a deuterated derivative thereof, a stereoisomer thereof, a pharmacologically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer thereof or a pharmaceutically acceptable salt of the deuterated derivative thereof, and at least one pharmacologically acceptable excipient.

5. A method for treating a subject suffering from a mitochondrial-related disease or condition, the method comprising administering to the subject a therapeutically effective amount of the compound of any one of claims 1 to 3, its deuterated derivative, stereoisomer, pharmaceutically acceptable salt, pharmaceutically acceptable salt of the stereoisomer, or a pharmaceutically acceptable salt of the deuterated derivative; or the pharmaceutical composition of claim 4; wherein, The diseases mentioned are obesity, excessive body fat, diabetes, insulin resistance or intolerance, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), hepatic steatosis, type 2 diabetes mellitus (T2DM), dyslipidemia, cardiovascular disease, heart disease, or atherosclerosis.

6. The use of the compound of any one of claims 1 to 3, its deuterated derivative, stereoisomer, pharmaceutically acceptable salt, pharmaceutically acceptable salt of the stereoisomer, or pharmaceutically acceptable salt of the deuterated derivative; or the use of the pharmaceutical composition of claim 4 in the preparation of a medicament for treating mitochondrial-related diseases or conditions; wherein, The diseases mentioned are obesity, excessive body fat, diabetes, insulin resistance or intolerance, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), hepatic steatosis, type 2 diabetes mellitus (T2DM), dyslipidemia, cardiovascular disease, heart disease, or atherosclerosis.

7. The compound of any one of claims 1 to 3, its deuterated derivative, stereoisomer, pharmaceutically acceptable salt, pharmaceutically acceptable salt of the stereoisomer, or pharmaceutically acceptable salt of the deuterated derivative; or the pharmaceutical composition of claim 4, for use in the treatment of mitochondrial-related diseases or conditions; wherein, The diseases mentioned are obesity, excessive body fat, diabetes, insulin resistance or intolerance, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), hepatic steatosis, type 2 diabetes mellitus (T2DM), dyslipidemia, cardiovascular disease, heart disease, or atherosclerosis.

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