Imidazolyl and dinitrophenyl derivative and application thereof

Abstract

The present invention relates to compounds of formula (I) or formula (II), stereoisomers thereof, deuterated derivatives thereof, pharmaceutically acceptable salts thereof, pharmaceutically acceptable salts of the stereoisomers, or pharmaceutically acceptable salts of the deuterated derivatives, pharmaceutical compositions thereof, and uses thereof. Formula (I) and formula (II).

Description

[0001] Cross-references to related applications

[0002] This application claims priority to international patent application PCT / CN2023 / 132521, filed on November 20, 2023, the entire contents of which are incorporated herein by reference. Technical Field

[0003] This invention relates to compounds that can be used to regulate mitochondrial activity, reduce obesity, and treat diseases including diabetes and diabetes-related complications, compositions comprising said compounds, and methods of using said compounds. Background Technology

[0004] Obesity has become a global epidemic, affecting more than 600 million people worldwide. Obesity is often associated with numerous 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 uncoupling agents are compounds that can dissipate the proton gradient of the inner mitochondrial membrane, leading to inefficient ATP production. This uncoupling can result in increased mitochondrial respiration, potentially reducing energy stored as fat and leading to weight loss. The mechanism of action of mitochondrial uncoupling agents in terms of energy expenditure makes them an attractive target for developing obesity therapies.

[0006] Several mitochondrial uncoupling agents have been identified and investigated for their potential therapeutic effects in treating obesity. One of the most well-known uncoupling agents is 2,4-dinitrophenol (DNP), which was previously used for weight loss but was later banned due to its toxicity. However, newer mitochondrial uncoupling 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 that mitochondrial uncoupling agents have potential therapeutic benefits for obesity, concerns remain regarding their safety and potential side effects. Developing safe and effective mitochondrial uncoupling agents for obesity treatment remains a hot research area. Summary of the Invention

[0008] This article provides the following publicly available information:

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

[0010]

[0011] Equation (I) Equation (II)

[0012] R1 is independently selected from hydrogen, deuterium, and -C each time it appears. 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 Alkoxy groups are optionally surrounded by one or more R groups. 11 Replace; 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), -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 group), -S(=O)2N(C 1-6 alkyl) 2, 3-10 membered carbocyclic, 3-10 membered heterocyclic, 6-10 membered aryl or 5-10 membered heteroaryl; said R 11 It can be arbitrarily 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), -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 group), -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 carbocyclic, 3-10-membered heterocyclic, 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, 3-10-membered carbocyclic, 3-10-membered heterocyclic, 6-10-membered aryl, or 5-10-membered heteroaryl groups are each independently and optionally substituted by one or more substituents selected from the following: deuterium, halogen, halogenated C. 1-3 Alkyl, -CN, -NH2, -C1-3 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), -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 group), -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 carbocyclic, 3-10-membered heterocyclic, 6-10-membered aryl or 5-10-membered heteroaryl; wherein R3 or R2 is optionally substituted with one or more deuterium groups;

[0014] Optionally, R2 and R3, together with the atoms they are attached to, form 3-14 membered carbon rings, 3-14 membered heterocycles, 6-12 membered aromatic rings, or 5-14 membered heteroaromatic rings; each ring is independently and optionally bounded by n1 R atoms. S1 replace;

[0015] R S1 Selected from halogens, -C 1-6 Alkyl, -C 2-6 alkenyl, -C 2-6alkynyl 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), -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(C 1-6 Alkyl)2、-NHS(=O)(C 1-6 alkyl), -N(C) 1-6 Alkyl)S(=O)(C 1-6 Alkyl), -S(=O)2(OC1-6 Alkyl), -OS(=O)2(C 1-6 Alkyl groups), -S(=O)2NH2, -S(=O)2NH(C 1-6 Alkyl group), -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 cycloyl, 3-7 membered heterocyclic, 6-10 membered aryl or 5-10 membered heteroaryl;

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

[0017] R4 is independently selected from hydrogen, deuterium, halogen, and -C each time it appears. 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 1-6Alkyl), -S(=O)(C 1-6 Alkyl), -S(=O)2(C 1-6 Alkyl), -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 group), -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 carbocyclic, 3-10-membered heterocyclic, 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, 3-10-membered carbocyclic, 3-10-membered heterocyclic, 6-10-membered aryl, or 5-10-membered heteroaryl groups are each independently and optionally substituted by one or more substituents selected from the following: deuterium, halogen, 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 1-6Alkyl), -S(=O)2(C 1-6 Alkyl), -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 group), -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 alkyl, 3-10-membered carbocyclic, 3-10-membered heterocyclic, 6-10-membered aryl, or 5-10-membered heteroaryl; wherein the R4 may optionally 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]. A compound of formula (I) as described in [1], its deuterated derivative, its stereoisomer, its pharmaceutically acceptable salt, a pharmaceutically acceptable salt of its stereoisomer, or a pharmaceutically acceptable salt of its deuterated derivative, wherein,

[0021] R1 is independently selected from hydrogen, deuterium, and -C each time it appears. 1-3 Alkyl or -C 2-3 alkoxy group; the R1 is optionally surrounded by one or more R groups. 11 Replace; the R 11 Selected from deuterium, -NH(C 1-3 alkyl), -N(C) 1-3 Alkyl)2、-O(C 1-3 alkyl), -S(C 1-3Alkyl), -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 group), -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 arbitrarily replaced by one or more -D.

[0022] [3]. A compound of formula (I) as described in any one of [1] to [2], its deuterated derivative, its stereoisomer, its pharmaceutically acceptable salt, a pharmaceutically acceptable salt of its stereoisomer, or a pharmaceutically acceptable salt of its deuterated derivative, wherein,

[0023] R1 is selected independently from -C each time it appears. 1-3 Alkyl or -C 2-3 Alkoxy; the -C 1-3 Alkyl or -C 2-3 The alkoxy group is optionally surrounded by 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 R groups. 11 Replace; 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(C1-6 Alkyl); the R 11 It can be arbitrarily replaced by one or more -D.

[0024] [4]. A compound of formula (I) as described in any one of [1] to [3], its deuterated derivative, its stereoisomer, its pharmaceutically acceptable salt, a pharmaceutically acceptable salt of its stereoisomer, or a pharmaceutically acceptable salt of its deuterated derivative, wherein,

[0025] R1 is selected independently from -C each time it appears. 1-3 Alkyl or -C 2-3 alkoxy group; wherein R1 is optionally surrounded by 1, 2 or 3 R groups. 11 Replace; the R 11 Selected from deuterium, -C 2-3 alkoxy or -O(C) 1-3 Alkyl); the R 11 It can be arbitrarily replaced by one or more -D.

[0026] [5]. A compound of formula (I) as described in any one of [1] to [4], its deuterated derivative, its stereoisomer, its pharmaceutically acceptable salt, a pharmaceutically acceptable salt of its stereoisomer, or a pharmaceutically acceptable salt of its deuterated derivative, wherein,

[0027] R1 is independently selected from -CH2D, -CHD2, -CD3, -CH2CH3 each time it appears. , , , -CH2CH2CH3, -CH2CH2CD3, -CH2CD2CD3, -CD2CD2CD3, -CH(CH3)2, -CD(CH3)2, -CD(CD3)(CH3), -CH(CD3)2, -CD(CD3)2, , , , , , , , , , , , , , or .

[0028] [6]. A compound of formula (I) as described in any one of [1] to [5], its deuterated derivative, its stereoisomer, its pharmaceutically acceptable salt, a pharmaceutically acceptable salt of its stereoisomer, or a pharmaceutically acceptable salt of its deuterated derivative, wherein,

[0029] R1 is independently selected from -CD3, -CH2CH3 each time it appears. , -CH2CH2CH3, -CH2CH2CD3, -CH2CD2CD3, -CD2CD2CD3, -CH(CH3)2, -CD(CH3)2, -CD(CD3)2, , , , or .

[0030] [7]. A compound of formula (I) as described in any one of [1] to [6], its deuterated derivative, its stereoisomer, its pharmaceutically acceptable salt, a pharmaceutically acceptable salt of its stereoisomer, or a pharmaceutically acceptable salt of its deuterated derivative, wherein R1 is independently selected from -CD3 in each occurrence. or .

[0031] [8]. A compound of formula (I) as described in any one of [1] to [7], its deuterated derivative, its stereoisomer, its pharmaceutically acceptable salt, a pharmaceutically acceptable salt of its stereoisomer, or a pharmaceutically acceptable salt of its deuterated derivative, wherein,

[0032] R1 is selected independently from -C each time it appears. 1-3 Alkyl; wherein R1 is optionally substituted with 1, 2, 3, 4, 5, 6 or 7 deuteriums; and when R1 is -CH3, the -CH3 is substituted with 1, 2 or 3 deuteriums.

[0033] [9]. A compound of formula (I) as described in [8], its deuterated derivative, its stereoisomer, its pharmaceutically acceptable salt, a pharmaceutically acceptable salt of its stereoisomer or a pharmaceutically acceptable salt of its deuterated derivative, wherein R1 is independently selected from -CH3 each time it appears, said -CH3 being substituted with 1, 2 or 3 deuteriums.

[0034]

[10] . A compound of formula (I) as described in any one of [8] to [9], its deuterated derivative, its stereoisomer, its pharmaceutically acceptable salt, a pharmaceutically acceptable salt of its stereoisomer, or a pharmaceutically acceptable salt of its deuterated derivative, wherein 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.

[0035]

[11] . A compound of formula (I) as described in any one of [8] to

[10] , its deuterated derivative, its stereoisomer, its pharmaceutically acceptable salt, a pharmaceutically acceptable salt of its stereoisomer, or a pharmaceutically acceptable salt of its deuterated derivative, wherein R1 is independently selected from -CD3, -CH2CH3, ... , -CH2CH2CH3, -CH2CH2CD3, -CH2CD2CD3, -CD2CD2CD3, -CH(CH3)2, -CD(CH3)2 or -CD(CD3)2.

[0036]

[12] . A compound of formula (I) as described in any one of [8] to

[11] , its deuterated derivative, its stereoisomer, its pharmaceutically acceptable salt, a pharmaceutically acceptable salt of its stereoisomer or a pharmaceutically acceptable salt of its deuterated derivative, wherein R1 is independently selected from -CD3 each time it appears.

[0037]

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

[0038]

[0039] Equation (I-1) Equation (II-1)

[0040] R3, R2, or R4 have the same definition as in [1].

[0041]

[14] . A compound of formula (I) as described in any one of [1] to [7], its deuterated derivative, its stereoisomer, its pharmaceutically acceptable salt, a pharmaceutically acceptable salt of its stereoisomer, or a pharmaceutically acceptable salt of its deuterated derivative, wherein R1 is independently selected from -C in each occurrence. 1-3Alkyl group, wherein R1 is R 11 Replace; the R 11 Selected from -C 2-3 Alkoxy, the R 11 It can be arbitrarily replaced by one or more deuterium.

[0042]

[15] . A compound of formula (I) as described in

[14] , its deuterated derivative, its stereoisomer, its pharmaceutically acceptable salt, a pharmaceutically acceptable salt of its stereoisomer, or a pharmaceutically acceptable salt of its deuterated derivative, wherein R1 is independently selected each time it appears from -CH3, -CH2CH3, -CH2CH2CH3, or -CH(CH3)2, wherein R1 is 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 The number of deuterium atoms can be 1, 2, 3, 4, 5, 6, or 7.

[0043]

[16] . A compound of formula (I) as described in any one of

[14] to

[15] , its deuterated derivative, its stereoisomer, its pharmaceutically acceptable salt, its pharmaceutically acceptable salt, or a pharmaceutically acceptable salt of its deuterated derivative, wherein R1 is independently selected from -CH3 each time it appears; said R1 is substituted with -CH2-O-CH3.

[0044]

[17] . A compound of formula (I) as described in any one of

[14] to

[16] , its deuterated derivative, its stereoisomer, its pharmaceutically acceptable salt, a pharmaceutically acceptable salt of its stereoisomer, or a pharmaceutically acceptable salt of its deuterated derivative, wherein R1 is independently selected each time it appears. or .

[0045]

[18] . A compound of formula (I) as described in any one of

[14] to

[17] , its deuterated derivative, its stereoisomer, its pharmaceutically acceptable salt, a pharmaceutically acceptable salt of its stereoisomer, or a pharmaceutically acceptable salt of its deuterated derivative, wherein R1 is independently selected each time it appears. , , , or .

[0046]

[19] . A compound of formula (I) as described in any one of

[14] to

[18] , its deuterated derivative, its stereoisomer, its pharmaceutically acceptable salt, a pharmaceutically acceptable salt of its stereoisomer, or a pharmaceutically acceptable salt of its deuterated derivative, wherein R1 is independently selected each time it appears. .

[0047]

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

[0048]

[0049] Equation (I-2) Equation (II-2)

[0050] R3, R2, or R4 have the same definition as in [1].

[0051]

[21] . A compound of formula (I) as described in any one of [1] to [7], its deuterated derivative, its stereoisomer, its pharmaceutically acceptable salt, a pharmaceutically acceptable salt of its stereoisomer, or a pharmaceutically acceptable salt of its deuterated derivative, wherein R1 is independently selected from -C in each occurrence. 2-3 alkoxy group, 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 arbitrarily replaced by one or more deuterium.

[0052]

[22] . A compound of formula (I) as described in

[21] , its deuterated derivative, its stereoisomer, its pharmaceutically acceptable salt, a pharmaceutically acceptable salt of its stereoisomer, or a pharmaceutically acceptable salt of its deuterated derivative, wherein R1 is independently selected each time it appears from -CH2-O-CH3, -CH2-O-CH2-CH3, -CH2-CH2-O-CH3, or -CH(CH3)-O-CH3, wherein R1 is 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 The number of deuterium atoms can be 1, 2, 3, 4, 5, 6, or 7.

[0053]

[23] . A compound of formula (I) as described in any one of

[21] to

[22] , 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, wherein R1 is independently selected from -CH2-CH2-O-CH3 each time it appears; said R1 is substituted by -CH2-O-CH3.

[0054]

[24] . A compound of formula (I) as described in any one of

[21] to

[23] , its deuterated derivative, its stereoisomer, its pharmaceutically acceptable salt, a pharmaceutically acceptable salt of its stereoisomer, or a pharmaceutically acceptable salt of its deuterated derivative, wherein,

[0055] R1 is selected independently each time it appears. , or .

[0056]

[25] . A compound of formula (I) as described in any one of

[21] to

[24] , its deuterated derivative, its stereoisomer, its pharmaceutically acceptable salt, a pharmaceutically acceptable salt of its stereoisomer, or a pharmaceutically acceptable salt of its deuterated derivative, wherein,

[0057] R1 is selected independently each time it appears. , , , , , or .

[0058]

[26] . A compound of formula (I) as described in any one of

[21] to

[25] , its deuterated derivative, its stereoisomer, its pharmaceutically acceptable salt, a pharmaceutically acceptable salt of its stereoisomer, or a pharmaceutically acceptable salt of its deuterated derivative, wherein R1 is independently selected each time it appears. .

[0059]

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

[0060]

[0061] Equation (I-3) Equation (II-3)

[0062] R3, R2, or R4 have the same definition as in [1].

[0063]

[28] . A compound of formula (I) as described in any one of [1] to

[27] , its deuterated derivative, its stereoisomer, its pharmaceutically acceptable salt, a pharmaceutically acceptable salt of its stereoisomer, or a pharmaceutically acceptable salt of its deuterated derivative, wherein R4 is independently selected from -H, -D, halogen, -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), -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 group), -S(=O)2N(C 1-3 alkyl)2 or -NHS(=O)2(C 1-3 Alkyl); the R4 may optionally be substituted with one or more deuterium.

[0064]

[29] . A compound of formula (I) as described in any one of [1] to

[28] , 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, wherein R4 is independently selected from: -H, -D, halogen, -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(C1-3 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 optionally be substituted with one or more deuterium atoms.

[0065]

[30] . A compound of formula (I) as described in any one of [1] to

[29] , 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, wherein,

[0066] R4 groups are 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 R4 is optionally substituted with one or more deuterium atoms.

[0067]

[31] . A compound of formula (I) as described in any one of [1] to

[30] , 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, wherein R4 is independently selected from: -H, -D, -CH3 or -CD3.

[0068]

[32] . A compound of formula (I) as described in any one of [1] to

[31] , its deuterated derivative, its stereoisomer, its pharmaceutically acceptable salt, a pharmaceutically acceptable salt of the stereoisomer or a pharmaceutically acceptable salt of the deuterated derivative, wherein R4 is independently selected from: -H.

[0069]

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

[0070]

[0071] Equation (I-1A) R3 or R2 has the same meaning as defined in [1].

[0072]

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

[0073]

[0074] Equation (I-2A) Equation (II-2A)

[0075] R3 or R2 has the same meaning as defined in [1].

[0076]

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

[0077]

[0078] Formula (I-3A) Formula (II-3A)

[0079] R3 or R2 has the same meaning as defined in [1].

[0080]

[36] . A compound of formula (I) as described in any one of [1] to

[35] , 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, wherein,

[0081] R2 and R3 are each independently selected from: -H, -D, halogen, -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), -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 group), -S(=O)2N(C 1-3 alkyl)2 or -NHS(=O)2(C 1-3 Alkyl); R3 or R2 may optionally be substituted with one or more deuterium atoms.

[0082]

[37] . A compound of formula (I) as described in any one of [1] to

[36] , its deuterated derivative, its stereoisomer, its pharmaceutically acceptable salt, a pharmaceutically acceptable salt of the stereoisomer, or a pharmaceutically acceptable salt of the deuterated derivative, wherein,

[0083] R2 and R3 are each independently selected from: -H, -D, halogen, -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(C1-3 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 optionally be substituted with one or more deuterium atoms.

[0084]

[38] . A compound of formula (I) as described in any one of [1] to

[37] , its deuterated derivative, its stereoisomer, its pharmaceutically acceptable salt, a pharmaceutically acceptable salt of the stereoisomer, or a pharmaceutically acceptable salt of the deuterated derivative, wherein,

[0085] 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 is optionally substituted with one or more deuterium atoms.

[0086]

[39] . A compound of formula (I) as described in any one of [1] to

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

[0087]

[40] . A compound of formula (I) as described in any one of [1] to

[39] , 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, wherein R3 is selected from: -H, -D, -CD3 or -CH3.

[0088]

[41] . A compound of formula (I) as described in any one of [1] to

[40] , 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, wherein R3 is selected from: -H.

[0089]

[42] . A compound of formula (I) as described in any one of [1] to

[41] , 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, wherein R2 is selected from: -H, -D, -CD3 or -CH3.

[0090]

[43] . The compound of formula (I) as described in any one of [1] to

[42] , its deuterated derivative, its stereoisomer, its pharmaceutically acceptable salt, the pharmaceutically acceptable salt of the stereoisomer or the pharmaceutically acceptable salt of the deuterated derivative, wherein R2 is selected from: -H.

[0091]

[44] . The compound of formula (I) as described in any one of [1] to

[43] , its deuterated derivative, its stereoisomer, its pharmaceutically acceptable salt, the pharmaceutically acceptable salt of the stereoisomer or the pharmaceutically acceptable salt of the deuterated derivative, wherein R3 is selected from: -H; and R2 is selected from: -H.

[0092]

[45] . Compounds of formula (I) or (II), their deuterated derivatives, their stereoisomers, their pharmaceutically acceptable salts, pharmaceutically acceptable salts of the stereoisomers, or pharmaceutically acceptable salts of the deuterated derivatives:

[0093]

[0094] Equation (I) Equation (II)

[0095] R1 is selected independently for each occurrence of -C 1-3 Alkyl or -C 2-3 Alkoxy;

[0096] R1 can be arbitrarily divided by 1, 2 or 3 Rs 11 replace;

[0097] The R 11 Selected from: deuterium, -C2-3 alkoxy or -O(C) 1-3 alkyl);

[0098] The R 11 It may be substituted by one or more deuterium atoms;

[0099] 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 optionally be substituted with one or more deuterium atoms;

[0100] R2 and R3 are each independently selected from: -H, -D, halogen, -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 optionally be substituted with one or more deuterium atoms.

[0101]

[46] . Compounds of formula (I) or (II), their deuterated derivatives, their stereoisomers, their pharmaceutically acceptable salts, pharmaceutically acceptable salts of the stereoisomers, or pharmaceutically acceptable salts of the deuterated derivatives:

[0102]

[0103] Equation (I) Equation (II)

[0104] R1 is selected independently for each occurrence of -C 1-3 Alkyl or -C 2-3 Alkoxy;

[0105] R1 can be arbitrarily divided by 1, 2 or 3 Rs 11 replace;

[0106] The R 11 Selected from: deuterium, -C 2-3 alkoxy or -O(C) 1-3 Alkyl); the R 11 It may be substituted by one or more deuterium atoms;

[0107] R4 is selected independently from: -H, -D, -C 1-3 Alkyl group; wherein R4 is optionally substituted with 1, 2, 3, 4, 5 or 6 deuterium atoms;

[0108] R2 and R3 are each independently selected from: -H, -D, -C 1-3 Alkyl group; R2 or R3 may optionally be substituted with 1, 2, 3, 4, 5 or 6 deuterium atoms.

[0109]

[47] . Compounds of formula (I) or (II), their deuterated derivatives, their stereoisomers, their pharmaceutically acceptable salts, pharmaceutically acceptable salts of the stereoisomers, or pharmaceutically acceptable salts of the deuterated derivatives:

[0110]

[0111] Equation (I) Equation (II)

[0112] R1 is selected independently for each occurrence of -C 1-3 Alkyl group; wherein R1 is optionally substituted with 1, 2, 3, 4, 5, 6 or 7 deuterium atoms; and R4 is independently selected from: -H, -D, -C. 1-3 Alkyl group; R4 is optionally substituted with 1, 2, 3, 4, 5 or 6 deuterium atoms; R2 and R3 are each independently selected from: -H, -D, -C 1-3 Alkyl group; R2 or R3 may optionally be substituted with 1, 2, 3, 4, 5 or 6 deuterium atoms.

[0113]

[48] . Compounds of formula (I) or (II), their deuterated derivatives, their stereoisomers, their pharmaceutically acceptable salts, pharmaceutically acceptable salts of the stereoisomers, or pharmaceutically acceptable salts of the deuterated derivatives:

[0114]

[0115] Equation (I) Equation (II)

[0116] R1 is selected independently for each occurrence of -C 1-3 Alkyl; the R1 is R 11 Replace; the R 11 Selected from: -C 2-3 alkoxy group; the R 11 It may be substituted by one or more deuterium atoms;

[0117] R4 is selected independently from: -H, -D, -C 1-3 Alkyl group; wherein R4 is optionally substituted with 1, 2, 3, 4, 5 or 6 deuterium atoms;

[0118] R2 and R3 are each independently selected from: -H, -D, -C 1-3 Alkyl group; R2 or R3 may optionally be substituted with 1, 2, 3, 4, 5 or 6 deuterium atoms.

[0119]

[48] . Compounds of formula (I) or (II), their deuterated derivatives, their stereoisomers, their pharmaceutically acceptable salts, pharmaceutically acceptable salts of the stereoisomers, or pharmaceutically acceptable salts of the deuterated derivatives:

[0120]

[0121] Equation (I) Equation (II)

[0122] R1 is selected independently for each occurrence of -C 2-3 alkoxy group; the R1 is R 11 Replace; the R 11 Selected from: -C 2-3 alkoxy or -O(C) 1-3 Alkyl); the R 11 R4 can be substituted by one or more deuterium atoms; each R4 atom is independently selected from: -H, -D, -C 1-3 Alkyl group; R4 is optionally substituted with 1, 2, 3, 4, 5 or 6 deuterium atoms; R2 and R3 are each independently selected from: -H, -D, -C 1-3 Alkyl group; R2 or R3 may optionally be substituted with 1, 2, 3, 4, 5 or 6 deuterium atoms.

[0123]

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

[0124]

[0125] Equation (I-1) Equation (II-1)

[0126] R4 is selected independently from: -H, -D, -C 1-3 Alkyl group; wherein R4 is optionally substituted with 1, 2, 3, 4, 5 or 6 deuterium atoms;

[0127] R2 and R3 are each independently selected from: -H, -D, -C 1-3 Alkyl group; R2 or R3 may optionally be substituted with 1, 2, 3, 4, 5 or 6 deuterium atoms.

[0128]

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

[0129]

[0130] Equation (I-2) Equation (II-2)

[0131] R4 is selected independently from: -H, -D, -C 1-3 Alkyl group; wherein R4 is optionally substituted with 1, 2, 3, 4, 5 or 6 deuterium atoms;

[0132] R2 and R3 are each independently selected from: -H, -D, -C 1-3 Alkyl group; R2 or R3 may optionally be substituted with 1, 2, 3, 4, 5 or 6 deuterium atoms.

[0133]

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

[0134]

[0135] Equation (I-3) Equation (II-3)

[0136] R4 is selected independently from: -H, -D, -C 1-3 Alkyl group; wherein R4 is optionally substituted with 1, 2, 3, 4, 5 or 6 deuterium atoms;

[0137] R2 and R3 are each independently selected from: -H, -D, -C 1-3 Alkyl group; R2 or R3 may optionally be substituted with 1, 2, 3, 4, 5 or 6 deuterium atoms.

[0138]

[52] . A compound of formula (I) as described in any one of [1] to

[51] , 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, wherein the compound is a compound represented by any of the following structural formulas: or .

[0139]

[53] . A pharmaceutical composition comprising a compound as described in any one of [1] to

[52] , a deuterated derivative thereof, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer or a pharmaceutically acceptable salt of the deuterated derivative thereof, and at least one pharmaceutically acceptable excipient.

[0140]

[54] . A method of treating a subject suffering from 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 the stereoisomer thereof, or a pharmaceutically acceptable salt of the deuterated derivative thereof, as described in any one of [1] to

[52] ; or a pharmaceutical composition as described in

[53] .

[0141]

[55] . The method as described in

[54] , 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.

[0142]

[56] . The use of any compound, deuterated derivative thereof, stereoisomer thereof, pharmaceutically acceptable salt thereof, pharmaceutically acceptable salt of the stereoisomer thereof or pharmaceutically acceptable salt of the deuterated derivative thereof, or pharmaceutical composition as described in

[53] , for the preparation of a medicament for treating mitochondrial-related diseases or conditions.

[0143]

[57] . Uses as described in

[56] , 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.

[0144]

[58] . A compound, a deuterated derivative thereof, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, as described in any one of [1] to

[52] ; or a pharmaceutical composition as described in

[53] , for the treatment of mitochondrial-related diseases or conditions.

[0145]

[59] . Uses as 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

[0146] Figure 1 Compound 1-1A 1 H-NMR spectrum.

[0147] Figure 2 Compound 1-1B 1 H-NMR spectrum. Detailed Implementation

[0148] definition

[0149] In this document, unless otherwise stated, "halogen" or "halogenated" is used interchangeably to refer to fluorine, chlorine, bromine, or iodine. Preferred halogen groups include -F, -Cl, and -Br.

[0150] In this document, unless otherwise stated, "alkyl" includes saturated monovalent hydrocarbon groups having a straight chain or branched chain. 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. -C 1-6 C in alkyl 1-6 This indicates that the group has 1, 2, 3, 4, 5 or 6 carbon atoms, arranged in a straight chain or branched chain.

[0151] In this document, unless otherwise stated, "haloalkyl" means that the alkyl group is 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 an alkyl group is 1 to 6. In some embodiments, -C 1-6 The alkyl halide is -C 1-3 Halogenated alkyl group. 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 halotype is -CF3.

[0152] "alkylene" refers to a bifunctional group obtained by removing one hydrogen atom from an alkyl group as defined above. Examples include methylene (i.e., -CH2-), ethylene (i.e., -CH2-CH2- or -CH(CH3)-), and propylene (i.e., -CH2-CH2-CH2-, -CH(-CH2-CH3)- or -CH2-CH(CH3)-).

[0153] "Alkenyl" refers to a straight-chain or branched hydrocarbon group containing one or more double bonds, typically ranging from 2 to 20 carbon atoms in length. 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.

[0154] "Alkyne" refers to a straight-chain or branched hydrocarbon group containing one or more triple bonds, typically ranging from 2 to 20 carbon atoms in length. 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, and octyynyl.

[0155] "Alkoxy" radicals are oxygen-containing ethers formed from the aforementioned alkyl groups. Alkoxy refers to alkyl groups substituted with -O-alkyl groups, including but not limited to -CH2-O-CH3, -CH2CH2-O-CH3, -CH2-O-CH2CH3, -CH(CH3)-O-CH3 and -CH2CH2-O-CH2CH2.

[0156] In this document, unless otherwise stated, "haloalkoxy" means that the alkoxy group is 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 groups, 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.

[0157] In this document, unless otherwise stated, "aryl" refers to an unsubstituted or substituted monocyclic or polycyclic aromatic ring system containing only a carbon ring atom. Preferred aryl groups are monocyclic or bicyclic 6-10 membered aromatic ring systems. Phenyl and naphthyl are preferred aryl groups.

[0158] The terms "heterocyclic group" or "heterocycle" are interchangeable and, unless otherwise stated herein, refer to an unsubstituted or substituted monocyclic or polycyclic non-aromatic ring system containing one or more heteroatoms, including monocyclic heterocyclic groups, bicyclic heterocyclic groups, bridged heterocyclic groups, fused heterocyclic groups, or spirocyclic groups. Preferred heteroatoms include N, O, and S, including N-oxides, sulfur oxides, and dioxides. Preferably, the ring is a three- to ten-membered ring and is fully saturated or has one or more unsaturations. The degree of multiple substitution (preferably one, two, or three) is included within this definition. Examples of such heterocyclic groups include, but are not limited to, azirrobutyl, pyrrolidinyl, piperidinyl, piperazinyl, oxoperazinyl, oxoperridinyl, oxoaziroxy, aziroxy, tetrahydrofuranyl, dioxopentyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydrooxazolyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, and oxadiazolyl.

[0159] In this document, unless otherwise stated, "heteroaryl" refers to an aromatic ring system containing a carbon atom and at least one heteroatom. Heteroaryl rings can be monocyclic or polycyclic, substituted or unsubstituted. Monocyclic heteroaryl rings may contain 1 to 4 heteroatoms, while polycyclic heteroaryl rings may contain 1 to 10 heteroatoms. Polycyclic heteroaryl rings may contain fused, spirocyclic, or bridged rings; for example, a bicyclic heteroaryl is a type of polycyclic heteroaryl. Bicyclic heteroaryl rings may contain 8 to 12 ring atoms. Monocyclic heteroaryl rings may contain 5 to 8 ring atoms (carbon and heteroatoms). Examples of heteroaryl groups include, but are not limited to, thienyl, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrroleyl, thiazolyl, thiadiazolyl, triazolyl, pyridinyl, pyridazinyl, indolyl, azaindolyl, indolyl, benzimidazolyl, benzofuranyl, benzothiophenyl, benzoisoxazolyl, benzoxazolyl, benzopyrazolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, adenine, quinolinyl, or isoquinolinyl.

[0160] "Carbocyclic ring" refers to a non-aromatic ring system containing only carbon atoms, whether substituted or unsubstituted, including monocyclic, bicyclic, bridged, fused, or spirocyclic rings. Preferably, the ring is a three- to ten-membered ring and is fully saturated or has one or more unsaturations. The degree of multiple substitution (preferably one, two, or three) is included within this definition. Carbocyclic rings include, but are not limited to, cycloalkyl, cycloalkenyl, and cycloynyl groups. Exemplary "cycloalkyl" groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl groups.

[0161] "One or more" means one or more. In some embodiments, "one or more" means 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments, "one or more" means 1, 2, 3, 4, 5, or 6. In some embodiments, "one or more" means 1, 2, 3, or 4. In some embodiments, "one or more" means 1, 2, or 3. In some embodiments, "one or more" means 1 or 2. In some embodiments, "one or more" means 1. In some embodiments, "one or more" means 2. In some embodiments, "one or more" means 3. In some embodiments, "one or more" means 4. In some embodiments, "one or more" means 5. In some embodiments, "one or more" means 6.

[0162] When one or more substituents in this invention are substituted on the ring, it means that each substituent can be substituted independently on each ring atom of the ring, including but not limited to ring carbon atoms or ring nitrogen atoms. Furthermore, when the ring is a polycyclic system (such as a fused ring, bridged ring, or spiro ring), each substituent can be substituted independently on each ring atom of the polycyclic system.

[0163] "Oxidation" refers to the formation of a group by an oxygen atom and the carbon atom it is attached to. .

[0164] In this document, the term "composition" is intended to encompass products comprising the specified ingredients and in the specified amounts, as well as any product resulting from the direct or indirect combination of the specified ingredients in the specified amounts. Therefore, pharmaceutical compositions comprising the 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, some crystal forms of the compounds of the present invention may exist in polymorphs, and these polymorphs are also intended to be included within the scope of this invention. Additionally, some compounds may form solvates with water (i.e., hydrates) or common organic solvents, and these solvates are also intended to be included within the scope of this invention.

[0165] "Pharmaceutically acceptable salt" refers to a salt prepared from a pharmaceutically acceptable non-toxic alkali or acid. When the compounds of the present invention are acidic, their corresponding salts can be readily prepared from pharmaceutically acceptable non-toxic alkalis (including inorganic and organic bases). When the compounds of the present invention are basic, their corresponding salts can be readily prepared from pharmaceutically acceptable non-toxic acids (including inorganic and organic acids). Since the compounds of the present invention are intended for pharmaceutical use, they are preferably provided in a substantially pure form, for example, with a purity of at least 60%, more preferably at least 75%, and especially at least 98% (by weight).

[0166] This invention encompasses prodrugs of the compounds of this invention. Typically, such prodrugs are functional derivatives of the compounds that are readily converted into the desired compound in vivo. Therefore, in the treatment methods of this invention, the term "administration" should cover treatment with the specifically disclosed compounds for the various conditions, or treatment with compounds not specifically disclosed but converted into the designated compounds in vivo after administration. Conventional procedures for selecting and preparing suitable prodrug derivatives are described, for example, in *Prodrug Design* (edited by H. Bundgaard, Elsevier, 1985).

[0167] It should be understood that the definition of any substituent or variable at a certain position in a molecule is independent of its definition at other positions in the molecule. It should be understood that the substituents and substitution modes 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 using techniques known in the art and the methods described herein.

[0168] This invention includes compounds that may contain one or more asymmetric centers, thereby potentially producing diastereomers and optical isomers. This invention includes all such possible diastereomers and their racemic mixtures, substantially pure resolved enantiomers, all possible geometric isomers and their pharmaceutically acceptable salts.

[0169] This invention includes all stereoisomers of the 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 procedures known to those skilled in the art, the products of such procedures may be mixtures of stereoisomers.

[0170] As used in this invention, the term "stereoisomer" refers to isomers in which atoms or groups of atoms 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 mainly including enantiomers and diastereomers. This invention includes all possible stereoisomers of the compound.

[0171] Some of the compounds described herein may exist as trans-isomers, which are conformational stereoisomers resulting from steric hindrance within the molecule that impedes or significantly slows down single-bond rotation. The compounds described herein include all trans-isomers, whether pure single-trans-isomer formulations, enriched formulations of various trans-isomers, or non-specific mixtures. When the rotational energy barrier of the single bond is sufficiently high and the interconversion between conformations is sufficiently slow, isomer species can be isolated and separated.

[0172] This invention aims to include all isotopes present in the compounds of this invention. An isotope refers to atoms having the same atomic number but different mass numbers. Common examples (but not limited to) include isotopes of hydrogen: deuterium and tritium. Isotopes of hydrogen can be represented as... 1 H (hydrogen) 2 H (deuterium) and 3 H (tritium). They are also often represented as D (deuterium) and T (tritium), respectively. In this application, CD3 represents methyl, where 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 methods similar to those described herein, using appropriate isotope-labeling reagents instead of unlabeled reagents.

[0173] As used herein, the term "deuterated derivative," unless otherwise stated, refers to a compound having the same chemical structure as the reference compound but with one or more hydrogen atoms substituted by deuterium atoms ("D"). It should be recognized that the abundance of natural isotopes in the synthesized compound may vary depending on the source of the chemical raw materials used in the synthesis. However, such variations in the concentration of natural stable hydrogen isotopes are small and negligible compared to the degree of stable isotope substitution in the deuterated derivatives described herein. Therefore, unless otherwise stated, when referring to the "deuterated derivatives" of the compounds disclosed herein, at least one hydrogen atom is substituted by deuterium, and its abundance is significantly higher than that of natural isotopes (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).

[0174] When tautomers of the compounds of this invention are present, this invention includes any possible tautomers and their pharmaceutically acceptable salts, as well as mixtures thereof, unless otherwise expressly stated.

[0175] 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, although the most suitable route of administration in any given situation will depend on the specific host and the nature and severity of the condition being treated. The pharmaceutical compositions of the present invention can be conveniently provided in unit dose form and can be prepared by any method well known in the pharmaceutical field.

[0176] In practice, the compounds of the present invention, or their prodrugs, metabolites, or pharmaceutically acceptable salts, can be used as active ingredients and closely mixed with a pharmaceutical carrier according to conventional pharmaceutical formulation techniques. The carrier can take various forms depending on the desired dosage form (e.g., oral or parenteral (including intravenous)). Therefore, the pharmaceutical compositions of the present invention can be presented as individual 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 of Formula I or their pharmaceutically acceptable salts can also be administered via controlled-release means and / or delivery devices. The compositions can be prepared by any pharmaceutical method. Typically, such methods involve the step of combining the active ingredient with a carrier constituting one or more essential components. Typically, the composition is prepared by uniformly and closely mixing the active ingredient with a liquid carrier or a finely dispersed solid carrier, or both. The product can then be conveniently shaped into the desired dosage form.

[0177] Therefore, the pharmaceutical compositions of the present invention may include a pharmaceutically acceptable carrier and a compound or a pharmaceutically acceptable salt thereof. Compounds of Formula I or pharmaceutically acceptable salts thereof may also be included in the pharmaceutical composition in combination with one or more other therapeutically active compounds.

[0178] The drug carrier used can be solid, liquid, or gaseous. 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. Any convenient drug medium can be used when preparing compositions for oral dosage forms. For example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, etc., can be used to form oral liquid dosage forms such as suspensions, elixirs, and solutions; while starch, sugars, 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 ease of administration, in which a solid drug carrier is used. Optionally, tablets can be coated using standard aqueous or non-aqueous techniques.

[0179] Tablets containing the compositions of the present invention can be prepared by compression or molding, optionally containing one or more excipients or adjuvants. Compressed tablets can be prepared by compressing the active ingredient in a free, flowing form (e.g., 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 the active ingredient, and each capsule or pouch preferably contains about 0.05 mg to about 5 g of the active ingredient. For example, formulations for oral administration to humans may contain about 0.5 mg to about 5 g of the active ingredient, compounded with a suitable and convenient carrier material, which may comprise about 0.05% to about 95% of the total composition. Unit doses typically contain about 0.01 mg to about 2 g of active ingredient, typically 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.

[0180] The pharmaceutical compositions of the present 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. Dispersions can also be prepared in glycerol, liquid polyethylene glycol, and mixtures thereof. Furthermore, preservatives may be included to prevent harmful microbial growth.

[0181] The pharmaceutical compositions of the present invention suitable for injection comprise sterile aqueous solutions or dispersions of the active compound. Alternatively, the compositions may be in sterile powder form for ad hoc preparation of such sterile injectable solutions or dispersions. In all cases, the final injectable dosage form must be sterile and must have sufficient flowability for injection. The pharmaceutical compositions must be stable under the conditions of manufacture and storage; therefore, contamination by microorganisms such as bacteria and fungi is preferably prevented. The carrier may be a solvent or dispersion medium, such as water, ethanol, polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), vegetable oils, and suitable mixtures thereof.

[0182] The pharmaceutical compositions of the present invention can be dosage forms suitable for topical application, such as aerosols, creams, ointments, lotions, powders, etc. Furthermore, the compositions can be dosage forms suitable for use with transdermal devices. These formulations can be prepared by conventional processing methods using compounds of Formula I of the present invention or pharmaceutically acceptable salts thereof. For example, a cream or ointment with a desired consistency can be prepared by mixing a hydrophilic material and water with about 0.05 wt% to about 10 wt% of the compound.

[0183] The pharmaceutical compositions of the present invention can be dosage forms suitable for rectal administration, wherein the carrier is solid. Preferably, the mixture forms a unit-dose suppository. Suitable carriers include cocoa butter and other materials commonly used in the art. The suppositories can be conveniently prepared by first mixing the composition with a softened or melted carrier, and then cooling and molding it in a mold.

[0184] In addition to the carrier components described above, the pharmaceutical formulations may, as needed, contain one or more additional carrier components, such as diluents, buffers, flavoring agents, binders, surfactants, thickeners, lubricants, preservatives (including antioxidants), etc. Furthermore, other adjuvants may be included to make the formulation isotonic with the blood of the intended receptor. Compositions containing a compound of formula I or a pharmaceutically acceptable salt thereof may also be prepared in powder or liquid concentrate form.

[0185] Typically, the dosage levels used to treat the above-mentioned conditions are approximately 0.001 mg / kg to approximately 150 mg / kg body weight / day, or alternatively approximately 0.05 mg to approximately 7 g / patient / day. For example, inflammation, cancer, psoriasis, allergies / asthma, immune system disorders and conditions, and central nervous system (CNS) disorders and conditions can be effectively treated by administering approximately 0.001 to 50 mg of the compound per kilogram of body weight per day, or alternatively approximately 0.05 mg to approximately 3.5 g of the compound per patient per day.

[0186] However, it should be understood that a particular dose level for any given 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.

[0187] Unless it is obvious from the context, when a numerical value is expressed as “about” or “approximately” X, the value of X should be understood to be accurate to ±10%, preferably ±5%, ±2%.

[0188] These and other aspects will become apparent from the following written description of the invention.

[0189] Preparation method

[0190] The compounds of this invention can be synthesized from commercially available reagents using the synthetic methods and reaction schemes described herein. The following examples outline specific synthetic routes; the general schemes are intended to guide synthetic chemists of ordinary skill, who will easily understand that solvents, concentrations, reagents, protecting groups, the order of synthetic steps, time, temperature, etc., can be modified as needed, entirely within the capabilities and judgment of those of ordinary skill.

[0191] Example

[0192] The following examples are intended to better illustrate the invention. Unless otherwise expressly stated, all parts and percentages are by weight, and all temperatures are in degrees Celsius. The following abbreviations have been used in the examples:

[0193] Example 1

[0194] To a solution of ethyl 2-nitro-1H-imidazolium-5-carboxylic acid ester (2.00 g, 10.81 mmol), 1-bromo-2-methoxyethane (2.23 g, 16.21 mmol), and KI (359.00 mg, 2.16 mmol) in DMF (20 mL), K₂CO₃ (4.47 g, 32.43 mmol) was added fractionally at 0 ºC. The resulting mixture was heated to 100 ºC under a nitrogen atmosphere and stirred overnight. The mixture was cooled to room temperature, quenched in ice water, and extracted with EtOAc. The organic solution was dried over anhydrous Na₂SO₄ and concentrated. The crude product was purified by silica gel column chromatography (PE / EtOAc elution) to give compound 1-1A (1.40 g, yield 53.8%) as a light yellow solid and compound 1-1B (168.00 mg, yield 6.5%) as a light yellow oil.

[0195] Compound 1-1A: LCMS: m / z = 244.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d6, ppm) δ7.77 (s, 1H), 4.61 (t, J = 4.8 Hz, 2H), 4.38 (q, J = 6.8 Hz, 1H), 3.71 (t, J= 4.8 Hz, 2H), 3.31 (s, 3H), 1.37 (t, J = 7.2 Hz, 3H).

[0196] Compound 1-1B: LCMS: m / z = 244.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6, ppm) δ7.70 (s, 1H), 5.13 (t, J = 5.2 Hz, 2H), 4.37 (q, J = 6.8 Hz, 2H), 3.61 (t, J= 5.2 Hz, 2H), 3.23 (s, 3H), 1.39 (t, J = 7.2 Hz, 3H).

[0197] To a solution of compound 1-1A (1.00 g, 5.76 mmol) in THF (20 mL), a solution of NaBH4 (0.65 g, 17.28 mmol) and MeONa (62.20 mg, 1.15 mmol) in MeOH (4 mL) was added dropwise at 0 ºC. The mixture was stirred for 3 hours. The reaction was quenched with ice water and extracted with EtOAc. The organic solution was dried over anhydrous Na2SO4 and concentrated. The crude product was purified by silica gel column chromatography (PE / EtOAc elution) to give compound 1-2 (100 mg, 12.1% yield). LCMS: m / z = 202.0 [M+H]⁺.

[0198] To a solution of compounds 1-2 (100.00 mg, 0.49 mmol) and 1-fluoro-3,5-dinitrobenzene (109.36 mg, 0.58 mmol) in dioxane (2 mL), Cs₂CO₃ (479.22 mg, 1.47 mmol) was added fractionally at 0 °C. The resulting mixture was heated to 75 °C and stirred overnight under a nitrogen atmosphere. The mixture was cooled to room temperature, quenched with water, and extracted with EtOAc. The organic solution was dried over anhydrous Na₂SO₄ and concentrated. The crude product was purified by preparative HPLC (C18 column, MeCN / H₂O elution) to give compound 1 (102.00 mg, yield 56.1%). LCMS: m / z = 368.2 [M+H]⁺.

[0199] The following compounds were synthesized using the steps described above with the corresponding isomers as starting materials.

[0200]

[0201] Example 2

[0202] To a solution of ethyl 2-nitro-1H-imidazolium-5-carboxylic acid ester (2.00 g, 10.81 mmol), 1-bromo-2-methoxyethane (2.23 g, 16.21 mmol), and KI (359.00 mg, 2.16 mmol) in DMF (20 mL), K₂CO₃ (4.47 g, 32.43 mmol) was added fractionally at 0 ºC. The resulting mixture was heated to 100 ºC under a nitrogen atmosphere and stirred overnight. The mixture was cooled to room temperature, quenched in ice water, and extracted with EtOAc. The organic solution was dried over anhydrous Na₂SO₄ and concentrated. The crude product was purified by silica gel column chromatography (PE / EtOAc elution) to give compound 1-1A (1.40 g, yield 53.8%) as a light yellow solid and compound 1-1B (168.00 mg, yield 6.5%) as a light yellow oil.

[0203] Compound 1-1A: LCMS: m / z = 244.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d6, ppm) δ7.77 (s, 1H), 4.61 (t, J = 4.8 Hz, 2H), 4.38 (q, J = 6.8 Hz, 1H), 3.71 (t, J= 4.8 Hz, 2H), 3.31 (s, 3H), 1.37 (t, J = 7.2 Hz, 3H).

[0204] Compound 1-1B: LCMS: m / z = 244.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6, ppm) δ7.70 (s, 1H), 5.13 (t, J = 5.2 Hz, 2H), 4.37 (q, J = 6.8 Hz, 2H), 3.61 (t, J= 5.2 Hz, 2H), 3.23 (s, 3H), 1.39 (t, J = 7.2 Hz, 3H).

[0205] To a solution of compound 1-1A (1.00 g, 5.76 mmol) in THF (20 mL), a solution of NaBH4 (0.65 g, 17.28 mmol) and MeONa (62.20 mg, 1.15 mmol) in MeOH (4 mL) was added dropwise at 0 ºC. The mixture was stirred for 3 hours. The reaction was quenched with ice water and extracted with EtOAc. The organic solution was dried over anhydrous Na2SO4 and concentrated. The crude product was purified by silica gel column chromatography (PE / EtOAc elution) to give compound 1-2 (100 mg, 12.1% yield). LCMS: m / z = 202.0 [M+H]⁺.

[0206] To a solution of compounds 1-2 (100.00 mg, 0.49 mmol) and 1-fluoro-2,6-dinitrobenzene (109.36 mg, 0.58 mmol) in dioxane (2 mL), Cs₂CO₃ (479.22 mg, 1.47 mmol) was added fractionally at 0 °C. The resulting mixture was heated to 75 °C and stirred overnight under a nitrogen atmosphere. The mixture was cooled to room temperature, quenched with water, and extracted with EtOAc. The organic solution was dried over anhydrous Na₂SO₄ and concentrated. The crude product was purified by preparative HPLC (C18 column, MeCN / H₂O elution) to give compound 3 (102.00 mg, yield 56.1%). LCMS: m / z = 368.2 [M+H]⁺.

[0207] The following compounds were synthesized using the above procedure with the corresponding isomers as starting materials.

[0208]

[0209] Pharmacological experiments

[0210] 1. Thermodynamic Solubility Determination: The materials, reagents, plates, and instruments for the thermodynamic solubility determination experiment are shown in Table 1 below.

[0211] Table 1

[0212] Detailed operating procedures Preparation of FaSSIF solution, FaSSGF solution and stock solutionDissolve 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 1 N NaOH or 1 N HCl aqueous solution. Dilute the resulting mixture to 1000 mL with ultrapure water to obtain a buffer solution. Add FaSSIF, FeSSIF, and FaSSGF powder (2.24 g) to 500 mL of the buffer solution and stir until completely dissolved. Dilute the solution to 1000 mL with the buffer solution. Allow the mixture to stand until slightly opalescent to prepare the FaSSIF solution, which should be used within 48 hours at room temperature or within 24 hours at 37°C.

[0213] Dissolve 2.00 g of NaCl in 900 mL of ultrapure water. Adjust the pH of the solution to 1.6 with 1N 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 powder 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.

[0214] Preparation of standard solutions

[0215] Each compound (test compound and positive control compound) was diluted with DMSO to a concentration of 1 mg / mL, and then diluted with 50% acetonitrile (IS, 100 ng / mL dexamethasone) to obtain standard solutions of each test compound and positive control compound (the dilution factor can be adjusted according to the LC-MS / MS response).

[0216] Preparation of test solutions and data analysis

[0217] Each analyte (~1 mg) was allocated to individual wells of a 96-well plate, followed by the addition of either FaSSIF or FaSSGF solution to each well to adjust the concentration to 1 mg / mL. The 96-well plate was transferred to a Thermomixer C and incubated at 37°C with shaking at 1200 rpm for 24 hours, followed by filtration. The filtrate (10 µL) was vortexed with 50% acetonitrile (IS, 100 ng / mL dexamethasone) (990 µL) for 5 minutes and diluted with 50% acetonitrile (IS, 100 ng / mL dexamethasone) to obtain the test solution. The dilution factor could be adjusted according to 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:

[0218] [Sample] = Sample peak area ratio × DF × [STD] / Standard peak area ratio

[0219] Sample peak area ratio refers to the peak area ratio of the test solution (analyte peak area / internal standard peak area). Standard peak area ratio refers to the peak area ratio of the standard solution (analyte peak area / internal standard peak area). DF refers to the dilution factor. [STD] refers to the concentration of the standard solution.

[0220] 2. Pharmacokinetic studies in mice

[0221] The aim of this study was to evaluate the pharmacokinetic properties of 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. Mice in Group A received a single oral dose of 5 mg / kg of the compound; mice in Group B received a single oral dose of 10 mg / kg of the compound; and mice in Group C received a single oral dose of 20 mg / kg of the compound. Blood samples were collected from each mouse in Group A at 0.25, 0.5, 1, 2, 4, and 8 hours after administration. Blood samples were kept on ice until centrifugation to obtain plasma samples. Plasma samples were stored at -80°C for analysis. The concentration of the compound in the plasma samples was determined using LC-MS / MS.

[0222] It should be understood that if any prior art publications are cited in this article, such citation does not constitute an admission that such publications constitute part of the general common knowledge in the field in any country.

[0223] All publications, patents, patent applications and published patent applications mentioned in this article through identifying citations are incorporated herein by reference in their entirety.

[0224] Although the foregoing invention has been described in considerable detail through examples and illustrations to facilitate clear understanding, those skilled in the art will obviously make some minor modifications and alterations. Therefore, the above description and embodiments should not be construed as limiting the scope of the invention.

Claims

1. The following compounds, their deuterated derivatives, their stereoisomers, their pharmaceutically acceptable salts, pharmaceutically acceptable salts of the stereoisomers, or pharmaceutically acceptable salts of the deuterated derivatives: , , or .

2. The following compounds, their deuterated derivatives, their stereoisomers, their pharmaceutically acceptable salts, pharmaceutically acceptable salts of the stereoisomers, or pharmaceutically acceptable salts of the deuterated derivatives: 。 3. The following compounds, their deuterated derivatives, their stereoisomers, their pharmaceutically acceptable salts, pharmaceutically acceptable salts of the stereoisomers, or pharmaceutically acceptable salts of the deuterated derivatives: 。 4. A pharmaceutical composition comprising the compound of any one of claims 1 to 3, a deuterated derivative thereof, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer, or a pharmaceutically acceptable salt of the deuterated derivative, and at least one pharmaceutically acceptable excipient.

5. A method of treating a subject suffering from a mitochondrial-related disease or condition, the method comprising administering to the subject a therapeutically effective amount of any one of claims 1 to 3, a deuterated derivative thereof, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a 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, its stereoisomer, its pharmaceutically acceptable salt, a pharmaceutically acceptable salt of the stereoisomer, or a pharmaceutically acceptable salt of the deuterated derivative; or the pharmaceutical composition of claim 4, for 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, its stereoisomer, its pharmaceutically acceptable salt, a pharmaceutically acceptable salt of the stereoisomer, or a pharmaceutically acceptable salt of the deuterated derivative; or the pharmaceutical composition of claim 4, 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.

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