Compound for treating obesity and related diseases and application

Abstract

The invention discloses application of a compound shown in a formula I or pharmaceutically acceptable salt or ester, a prodrug, an optical isomer, a stereoisomer or a solvate of the compound in prevention and treatment of obesity and related diseases thereof. The compound shows excellent effects of preventing and treating obesity and related diseases thereof, so that a brand new material basis is laid for developing medicines for preventing and treating obesity and related diseases thereof.

Description

Technical Field

[0001] This invention belongs to the field of medicinal chemistry. Specifically, this invention relates to compounds that have therapeutic effects on obesity and related diseases, and their use in the preparation of treatments for obesity and related diseases. Background Technology

[0002] Obesity can cause a variety of diseases, such as metabolic diseases, cardiovascular diseases, Alzheimer's disease, and other diseases, which can lead to a decline in quality of life, multiple illnesses, and even death.

[0003] Currently, the FDA-approved drugs for long-term weight management mainly include: Orlistat, a gastrointestinal lipase inhibitor. Orlistat is also the only over-the-counter weight-loss drug approved for marketing in China by the State Food and Drug Administration. After entering the body, Orlistat inhibits the activity of lipase, reducing the body's absorption of fat and thus exerting a weight-loss effect. Another type is appetite suppressants, such as the serotonin 2C receptor agonist Lorcaserin, the combination weight-loss drug Qsymia (a sustained-release formulation containing phenbutylidene and topiramate), the combination weight-loss drug Contrave (a sustained-release tablet containing naltrexone hydrochloride and bupropion hydrochloride), and the GLP-1 receptor agonist Liraglutide injection. These act on the central nervous system, suppressing appetite and thus controlling calorie intake to achieve weight loss. However, appetite suppressants act directly on the nervous system, easily causing adverse reactions.

[0005] The challenge of weight loss lies in achieving long-term, effective control. An ideal weight-loss drug should possess characteristics such as long-term weight loss, prevention of rebound, ease of administration, few adverse reactions, and low cost. Currently available weight-loss drugs cannot meet clinical needs; therefore, the development of new, effective weight-loss drugs with fewer side effects is urgently needed. Summary of the Invention

[0006] The purpose of this invention is to provide a compound that has a therapeutic effect on obesity and related diseases, and the compound should not only be effective against obesity and related diseases but also have the advantages of having few side effects.

[0007] In a first aspect, the present invention provides the use of compounds of Formula I, or pharmaceutically acceptable salts or esters thereof, prodrugs, optical isomers, stereoisomers or solvates thereof, in the preparation of medicaments for the prevention or treatment of obesity and related diseases.

[0008]

[0009] In the formula,

[0010] A is selected from C6-C10 aromatic rings or carbon rings, or 5-6 membered heterocycles or aromatic heterocycles containing 1, 2 or 3 heteroatoms selected from N, O or S;

[0011] R1 and R4 are each independently selected from H, D, OH, carbonyl, optionally substituted C1-C10 alkyl, optionally substituted C1-C10 alkoxy, optionally substituted phenoxy, optionally substituted benzyloxy, optionally substituted NH2, NHCH3, NHCOCH3, halogen, optionally substituted C1-C10 alkylformyloxy, optionally substituted benzoyloxy, optionally substituted aminoacetoxy ( B can be any group that forms amino acids, or an optionally substituted monosaccharide, disaccharide, or polysaccharide group;

[0012] R2 and R5 are each independently selected from H, D, OH, carbonyl, hydroxymethyl, optionally substituted C1-C10 alkyl, optionally substituted C1-C10 alkoxy, optionally substituted benzyloxy, optionally substituted phosphate ester, optionally substituted NH2, NHCH3, NHCOCH3, optionally substituted C1-C10 formyloxy, optionally substituted benzoyloxy, optionally substituted aminoacetoxy ( B can be any of the groups that form amino acids, such as COOH, COOCH3, CONH2, and sulfonic acid groups. (or sulfonates), halogens, optionally substituted monosaccharides, disaccharides or polysaccharides;

[0013] or,

[0014] R1 and R2 or R4 and R5 are linked to form an optionally substituted 3-6 member ring containing 0, 1 or 2 heteroatoms selected from oxygen, nitrogen or sulfur (preferably oxygen), such as a cyclic carbonate lactone, phosphate lactone or optionally substituted cyclic borate lactone.

[0015] R3 is selected from H, D, optionally substituted C1-C10 alkyl, D-substituted C1-C10 alkyl, optionally substituted C3-C10 cycloalkyl, optionally substituted 3-6-membered ring containing 1 or 2 heteroatoms selected from O, S or N, optionally substituted C2-C10 alkylalkenyl, hydroxyl, optionally substituted C1-C10 alkoxy, optionally substituted C1-C10 alkylthio, optionally substituted C1-C10 alkylformyloxy, optionally substituted C1-C10 acyl, hydroxyformyl, optionally substituted C1-C10 alkylformyloxy, nitro, optionally substituted amino, optionally substituted C1-C10 alkylamino, optionally substituted C1-C10 alkylformylamino, halogen, optionally substituted C2-6 alkynyl, optionally substituted monosaccharide, disaccharide or polysaccharide.

[0016] or,

[0017] Two adjacent R3 substituents form an optionally substituted C3-C6 carbon ring or an optionally substituted C3-C6 heterocycle containing one or two heteroatoms selected from oxygen, nitrogen or sulfur (preferably oxygen or nitrogen), an optionally substituted C5-C10 aromatic ring or an optionally substituted C5-C10 heteroaromatic ring containing one or two heteroatoms selected from oxygen, nitrogen or sulfur (preferably oxygen or nitrogen);

[0018] m is an integer from 1 to 5;

[0019] In the structure of Formula I, hydrogen may be optionally replaced by deuterium.

[0020] In a specific embodiment, the compound shown in Formula I is the same as the compound shown in Formula II.

[0021]

[0022] In the formula,

[0023] X1, X2, and X3 are each independently selected from CH, N, S, or O (preferably CH or N);

[0024] R1 and R4 are independently selected from H, D, OH, optionally substituted C1-C10 alkoxy, optionally substituted phenoxy, optionally substituted benzyloxy, optionally substituted NH2, NHCH3, NHCOCH3, optionally substituted C1-C10 alkylformyloxy, optionally substituted benzoyloxy, optionally substituted carbamoyloxy, optionally substituted monosaccharide, disaccharide or polysaccharide.

[0025] R2 and R5 are each independently selected from H, D, OH, hydroxymethyl, optionally substituted C1-C10 alkyl, optionally substituted C1-C10 alkoxy, optionally substituted benzyloxy, NH2, NHCH3, NHCOCH3, optionally substituted C1-C10 alkylformyloxy, optionally substituted benzoyloxy, optionally substituted carbamoyloxy, COOH, COOCH3, CONH2, optionally substituted monosaccharide, disaccharide or polysaccharide.

[0026] R1 and R2 can form 3-6 membered rings with optional substitutions containing 0, 1 or 2 heteroatoms selected from oxygen, nitrogen or sulfur (preferably oxygen);

[0027] R3 is selected from H, D, optionally substituted C1-C10 alkyl, D-substituted C1-C10 alkyl, optionally substituted C3-C10 cycloalkyl, optionally substituted 3-6-membered ring containing 1 or 2 heteroatoms selected from O, S or N, optionally substituted C1-C10 alkylalkenyl, hydroxyl, optionally substituted C1-C10 alkoxy, optionally substituted C1-C10 alkylthio, optionally substituted C1-C10 alkylformyloxy, formyl, hydroxyformyl, optionally substituted C1-C10 alkylformyloxy, nitro, optionally substituted amino, optionally substituted C1-C10 alkylamino, optionally substituted C1-C10 alkylformylamino, halogen, optionally substituted monosaccharide, disaccharide or polysaccharide.

[0028] Alternatively, it may be a C3-C6 carbon ring formed by two adjacent R3 substituents, or a C3-C6 heterocycle containing one or two heteroatoms selected from oxygen or nitrogen;

[0029] m is an integer from 1 to 5;

[0030] In the structure of Formula II, hydrogen may be optionally replaced by deuterium.

[0031] In a specific embodiment, the compound shown in Formula I is the same as the compound shown in Formula III.

[0032]

[0033] In the formula,

[0034] X is selected from CH or N;

[0035] R1 and R4 are independently selected from H, D, OH, optionally substituted C1-C10 alkoxy, optionally substituted phenoxy, optionally substituted benzyloxy, optionally substituted NH2, NHCH3, NHCOCH3, optionally substituted C1-C10 formyloxy, optionally substituted benzoyloxy, optionally substituted carbamoyloxy, optionally substituted aminoacetoxy. B can be any group that forms amino acids, or an optionally substituted monosaccharide, disaccharide, or polysaccharide group;

[0036] R2 and R5 are each independently selected from H, D, hydroxymethyl, optionally substituted C1-C10 alkyl, OH, optionally substituted C1-C10 alkoxy, optionally substituted benzyloxy, NH2, NHCH3, NHCOCH3, optionally substituted C1-C10 alkylformyloxy, optionally substituted benzoyloxy, optionally substituted carbamoyloxy, optionally substituted aminoacetoxy. B can be any group that forms amino acids, such as COOH, COOCH3, CONH2, or optionally substituted monosaccharides, disaccharides, or polysaccharides.

[0037] R1 and R2 can form 3-6 membered rings with optional substitutions containing 0, 1 or 2 heteroatoms selected from oxygen, nitrogen or sulfur (preferably oxygen);

[0038] R3 is selected from H, D, optionally substituted C1-C10 alkyl, D-substituted C1-C10 alkyl, optionally substituted C3-C10 cycloalkyl, optionally substituted 3-6-membered ring containing 1 or 2 heteroatoms selected from O, S or N, optionally substituted C2-C10 alkylalkenyl, hydroxyl, optionally substituted C1-C10 alkoxy, optionally substituted C1-C10 alkylthio, optionally substituted C1-C10 alkylformyloxy, formyl, hydroxyformyl, optionally substituted C1-C10 alkylformyloxy, nitro, amino, optionally substituted C1-C10 alkylamino, optionally substituted C1-C10 alkylformamide, fluorine, chlorine, bromine, optionally substituted monosaccharide, disaccharide or polysaccharide.

[0039] Alternatively, two adjacent R3 substituents may form an optionally substituted C3-C6 carbocyclic ring or an optionally substituted C3-C6 heterocyclic ring containing one or two oxygen atoms;

[0040] m is an integer from 1 to 5;

[0041] In the structure of Formula III, hydrogen may be optionally replaced by deuterium.

[0042] In a specific embodiment, the compound is shown as that of Formula IV.

[0043]

[0044] In the formula,

[0045] X is selected from CH or N;

[0046] R1 is selected from H, D, OH, NH2, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkylformyloxy, optionally substituted carbamoyloxy, optionally substituted aminoacetoxy. B can be any group that forms amino acids, or an optional substituted monosaccharide group;

[0047] R2 is selected from OH, NH2, COOH, COONH2, COONHCH3, optionally substituted C1-C3 alkoxyformyl, optionally substituted C1-C3 alkylformyloxy, optionally substituted carbamoyloxy, optionally substituted aminoacetoxy. B can be any group that forms amino acids, or an optional substituted monosaccharide group;

[0048] R3 is selected from H, D, optionally substituted C1-C5 alkyl, D-substituted C3-C5 cycloalkyl, optionally substituted 3-6-membered ring containing 1 or 2 O, optionally substituted C2-C10 alkylalkenyl, hydroxyl, optionally substituted C1-C5 alkoxy, optionally substituted C1-C3 alkylthio, optionally substituted C1-C3 alkylformyloxy, formyl, optionally substituted C1-C3 alkylformyl, hydroxyformyl, nitro, amino, optionally substituted C1-C3 alkylamino, optionally substituted C1-C3 alkylformylamino, fluorine, chlorine, and bromine;

[0049] Alternatively, two adjacent R3 substituents may form an optionally substituted C3-C6 carbocyclic ring or an optionally substituted C3-C6 heterocyclic ring containing one or two oxygen atoms;

[0050] m is an integer from 1 to 3;

[0051] In the structure of Formula IV, hydrogen may be optionally replaced by deuterium.

[0052] In a specific implementation method

[0053] A is selected from phenyl;

[0054] R1 and R4 are independently selected from H, D, OH, and optionally substituted C1-C6 alkoxy groups, respectively;

[0055] R2 and R5 are independently selected from H, D, OH, optionally substituted C1-C6 alkoxy, and optionally substituted C1-C6 formyloxy, respectively;

[0056] or,

[0057] R1 and R2 or R4 and R5 are linked to form a cyclic carbonate lactone containing 0, 1 or 2 heteroatoms selected from oxygen, nitrogen or sulfur (preferably oxygen) in a 3-6 member ring with optional substitution.

[0058] R3 is selected from H, D, optionally substituted C1-C6 alkyl, D-substituted C1-C6 alkyl, optionally substituted C2-C6 alkyl alkenyl, optionally substituted C1-C6 acyl;

[0059] or,

[0060] Two adjacent R3 substituents form an optionally substituted C3-C6 carbon ring or an optionally substituted C3-C6 heterocycle containing one or two heteroatoms selected from oxygen, nitrogen or sulfur (preferably oxygen or nitrogen);

[0061] m is an integer from 1 to 3;

[0062] In the structure of Formula I, hydrogen may be optionally replaced by deuterium.

[0063] In specific embodiments, "optionally substituted" means that the group modified by the term is substituted by C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, hydroxyl, halogen, amino, nitro, or acetyl.

[0064] In specific embodiments, the present invention provides the use of the following compounds, or their salts or esters, prodrugs, optical isomers or solvates, in the preparation of medicaments for the prevention and treatment of obesity and related diseases:

[0065]

[0066]

[0067]

[0068]

[0069]

[0070]

[0071]

[0072] Preferably, the compound is

[0073]

[0074] More preferably, the compound is selected from the group consisting of:

[0075]

[0076] In a specific implementation, obesity and related diseases include obesity-related diseases caused by various etiologies, including but not limited to various clinical conditions such as overweight and hyperlipidemia.

[0077] In a second aspect, the present invention provides a method for the prevention and treatment of obesity and related diseases, the method comprising the step of administering a preventive and therapeutically effective amount of the compound of the first aspect or a pharmaceutical composition comprising the compound to a subject in need.

[0078] In a specific implementation, the subject is a mammal, including but not limited to humans, pets, racing animals, livestock, etc.; preferably, the subject is a human.

[0079] It should be understood that, within the scope of this invention, the above-described technical features of this invention and the technical features specifically described below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be described in detail here. Attached Figure Description

[0080] Figure 1 The experimental design, grouping, and dosage of the compound for testing the preventive effect of the compound on high-fat diet-induced obesity in mice are shown (first batch of DIO mouse weight loss experiments); and

[0081] Figure 2 The experimental design, grouping, and dosage of the compound of the present invention for testing the preventive effect of the compound on high-fat diet-induced obesity in mice are shown (second batch of DIO mouse weight loss experiment). Detailed Implementation

[0082] Through extensive and in-depth research, the inventors unexpectedly discovered a series of compounds with therapeutic effects on obesity and related diseases, thus laying a completely new material foundation for the development of drugs for the treatment of obesity and related diseases. This invention was completed based on this discovery.

[0083] Terminology Definition

[0084] The terms used herein to refer to groups, substituents, or structures of compounds have the same meaning as understood by those skilled in the art. For clarity, the terms used in this specification are defined as follows.

[0085] In this article, “a”, “one”, “a type” or “a class” refers to the plural form including the object it modifies, that is, “a”, “one”, “a type” or “a class” means at least one / type or more than one / type.

[0086] In this article, the form "C" 1-n The expression "" refers to a group having 1-n carbon atoms, for example, "C 1-10 The expression “C6-C10” indicates that the group has 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms; similarly, “C6-C10” indicates that the group has 6, 7, 8, 9, or 10 carbon atoms. Furthermore, the description of the range of carbon atom counts in this document also includes sub-ranges. For example, when referring to 1-10 carbon atoms, this document also includes cases with 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, and 1-3 carbon atoms.

[0087] As used herein, the term "alkyl" has the same meaning as commonly understood by those skilled in the art, referring to various saturated or unsaturated straight-chain, side-chain, or cyclic hydrocarbon groups. For example, the alkyl group referred to herein refers to a lower alkyl group with 1-10 carbon atoms; preferably, it refers to a lower alkyl group with 1-8 carbon atoms; more preferably, it refers to a lower alkyl group with 1-6 carbon atoms. In specific embodiments, the alkyl group referred to herein includes, but is not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, etc.

[0088] As used herein, the terms "aryl" or "aromatic ring" have the same meaning as commonly understood by those skilled in the art, referring to a cyclic conjugated aromatic system; for example, the term "C6-C10 aryl" refers to an aromatic cyclic group with 6 to 10 carbon atoms that does not contain heteroatoms in the ring, such as phenyl or naphthyl. The term "heteroaryl," as used herein, refers to a cyclic conjugated aromatic system containing one or more heteroatoms such as N, O, or S in the ring; for example, pyridyl or pyrazinyl.

[0089] As used herein, the term "aminoacetyl" has the conventional meaning understood by those skilled in the art, namely, an amino-substituted acetyl group. In specific embodiments, the aminoacetyl group is as follows: As shown, R represents various amino acid substituents.

[0090] As used herein, the terms "heterocyclic group" or "heterocycle" have the same meaning, referring to a saturated or partially unsaturated non-aromatic cyclic group, including monocyclic, fused, spirocyclic, or bridged rings, wherein the heterocycle has at least one heteroatom selected from O, S, or N as a ring member. For example, "5- or 6-membered heterocyclic group" refers to a saturated or unsaturated 5- or 6-membered cycloalkyl group containing 1 to 3 heteroatoms selected from oxygen, sulfur, or nitrogen, such as dioxanepentyl.

[0091] The term "halogen" as used in this article refers to F, Cl, Br, or I.

[0092] Based on the teachings of this invention and common knowledge in the field, those skilled in the art will know that the compounds of this invention and the various substituents defined above can be further substituted, for example, by C1-6 alkyl, C1-6 alkoxy, halogen, nitro, amino, phenyl, hydroxyl, etc., as long as the intended combination of substituents is stable or a chemically feasible combination of substituents.

[0093] As used herein, the term "substitution" refers to the replacement of one or more hydrogen atoms on a specific group by a specific substituent. A specific substituent may be a substituent described above or a specific substituent appearing in the various embodiments. Therefore, in this invention, the substituents in general formula (I) or (II) may each independently be the corresponding group in the specific compound of the embodiments; that is, this invention includes combinations of the substituents in general formula (I) or (II) above, as well as combinations of some of the substituents shown in general formula (I) or (II) with other specific substituents appearing in the embodiments.

[0094] Unless otherwise specified, a substituted group may have a specific substituent at any substituted site on that group, and the substituents may be the same or different at each position. Cyclic substituents, such as heterocyclic groups, may be attached to another ring, such as a cycloalkyl group, thereby forming a spirobicyclic system, for example, where the two rings share a common carbon atom. The substituents are, for example (but not limited to): C 1-8 Alkyl, C 2-8 alkenyl, C 2-8 alkynyl group, C 3-8 Cycloalkyl, 3- to 12-membered heterocyclic groups, aryl, heteroaryl, halogen, hydroxyl, carboxyl (-COOH), C 1-8 Aldehyde group, C 2-10 Acyl group, C 2-10 Ester group, amino group, C 1-8 Alkoxy, nitro, cyano, mercapto, amino, etc. In specific embodiments, the hydrogen atoms on alkyl and aryl groups are replaced by amino, halogen, or other groups to become groups belonging to the above definitions.

[0095] For convenience and to conform to common understanding, the terms “arbitrarily substituted,” “optionally substituted,” or “substituted or unsubstituted” apply only to sites that can be substituted by substituents, and do not include chemically impractical substitutions.

[0096] As used herein, the term “independently selected” means that the multiple groups modified by the term can be selected relatively independently from the range described herein. For example, when this document states that “R1 and R4 are independently selected from H, OH, and carbonyl, respectively,” it is equivalent to disclosing that “R1 is selected from H, OH, or carbonyl” and “R4 is selected from H, OH, or carbonyl.”

[0097] The compounds of the present invention

[0098] This invention provides a series of novel compounds with preventive and therapeutic effects on obesity and related diseases, which have different mechanisms of action than existing preventive and therapeutic drugs.

[0099] In specific embodiments, the present invention provides compounds of formula I or II, or pharmaceutically acceptable salts or esters thereof, prodrugs, optical isomers, stereoisomers, or solvates thereof.

[0100]

[0101] The substituents in the general formula are as described above.

[0102] In a preferred embodiment, the compound shown in Formula I is the same as the compound shown in Formula II.

[0103]

[0104] The substituents in the formula are as described above.

[0105] In a preferred embodiment, the compound represented by Formula I is the same as the compound represented by Formula III.

[0106]

[0107] The substituents in the formula are as described above.

[0108] In a preferred embodiment, the compound shown in Formula I is the same as the compound shown in Formula IV.

[0109]

[0110] The substituents in the formula are as described above.

[0111] In specific embodiments, the preferred compounds of the present invention are the following compounds:

[0112]

[0113]

[0114] Based on the compounds of this invention, those skilled in the art can prepare pharmaceutically acceptable salts or esters, prodrugs, optical isomers, stereoisomers, or solvates. For example, the compounds of this invention can be reacted with inorganic or organic acids to form conventional pharmaceutically acceptable salts. The inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, aminosulfonic acid, and phosphoric acid, etc., and the organic acids include various amino acids, citric acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, naphthalenesulfonic acid, ethanesulfonic acid, naphthalenedisulfonic acid, maleic acid, malic acid, malonic acid, fumaric acid, succinic acid, propionic acid, oxalic acid, trifluoroacetic acid, stearic acid, pyric acid, hydroxymaleic acid, phenylacetic acid, benzoic acid, salicylic acid, glutamic acid, ascorbic acid, p-aminobenzenesulfonic acid, 2-acetoxybenzoic acid, and hydroxyethanesulfonic acid, etc.; or the compounds of the present invention are reacted with inorganic bases to form sodium salts, potassium salts, calcium salts, aluminum salts, or ammonium salts; or reacted with organic bases to form methylamine salts, ethylamine salts, or ethanolamine salts.

[0115] Since the compounds of the present invention contain chiral carbon atoms, the optical isomers or stereoisomers obtained by resolving the compounds of the present invention also fall within the protection scope of the present invention.

[0116] Based on the teachings herein, those skilled in the art should understand that the compounds provided by this invention, which have preventive and therapeutic effects on obesity and related diseases, should possess the various properties inherent in pharmaceuticals, such as therapeutic activity, drug-likeness, pharmacokinetic activity, etc., and the compounds of this invention should also possess acceptable toxicity. Therefore, this document implicitly discloses all pharmaceutically relevant activities of the compounds of this invention, and those skilled in the art can use methods known in the art to detect these properties.

[0117] Based on the compounds of the present invention or their pharmaceutically acceptable salts or esters, prodrugs, optical isomers, stereoisomers or solvates, the present invention also provides pharmaceutical compositions comprising the compounds of the present invention, said pharmaceutical compositions optionally comprising pharmaceutically acceptable excipients.

[0118] In specific embodiments, the pharmaceutical compositions of the present invention comprise, within a safe and effective range, the compound of the present invention or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier. Here, "safe and effective range" means that the amount of the compound is sufficient to significantly improve the condition without causing serious side effects.

[0119] "Pharmaceutically acceptable excipients or carriers" refers to one or more compatible solid or liquid fillers or gelling substances that are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here means that the components in the composition can be mixed with and with the compounds of the present invention without significantly reducing the efficacy of the compounds. Examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as... Wetting agents (such as sodium dodecyl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0120] There are no particular limitations on the administration of the compounds or pharmaceutical compositions of the present invention. Representative administration methods include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and local administration.

[0121] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following components: (a) fillers or compatibilizers, such as starch, lactose, sucrose, glucose, mannitol, and silica; (b) binders, such as hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; (c) humectants, such as glycerin; (d) disintegrants, such as agar, calcium carbonate, potato starch or cassava starch, alginate, certain complex silicates, and sodium carbonate; (e) slowing agents, such as paraffin; (f) absorption accelerators, such as quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glyceryl monostearate; (h) adsorbents, such as kaolin; and (i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium dodecyl sulfate, or mixtures thereof. Buffers may also be included in capsules, tablets, and pills.

[0122] Solid dosage forms such as tablets, sugar pills, capsules, pellets, and granules can be prepared using coatings and shells, such as casings and other materials known in the art. They may contain opacifying agents, and the release of the active compound or compound from such compositions can be delayed in a portion of the digestive tract. Examples of encapsulating components that can be used are polymeric substances and waxes. If necessary, the active compound may also be formed into microcapsules with one or more of the excipients described above.

[0123] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, or tinctures. In addition to the active compound, liquid dosage forms may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, e.g., ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil, or mixtures of these substances.

[0124] In addition to these inert diluents, the composition may also contain auxiliaries such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents and fragrances.

[0125] In addition to the active compound, the suspension may contain suspending agents such as ethoxylated isooctadecyl alcohol, polyoxyethylene sorbitol and dehydrated sorbitol esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances.

[0126] Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions, or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents, or excipients include water, ethanol, polyols, and suitable mixtures thereof.

[0127] Dosage forms of the compounds of the present invention for topical administration include ointments, powders, patches, sprays, and inhalers. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be necessary.

[0128] The compounds of this invention can be administered alone or in combination with other pharmaceutically acceptable compounds. When using the pharmaceutical composition, a safe and effective amount of the compound of this invention is applied to a mammal (such as a human) requiring prevention and treatment, wherein the dose administered is a pharmaceutically considered effective dose. The compounds and pharmaceutical compositions of this invention can be administered via the oral, nasal, skin, lung, or gastrointestinal routes. Oral administration is preferred, either as a single dose or in divided doses. Regardless of the method of administration, the optimal dose for an individual should be determined based on the specific prevention and treatment. Generally, a small dose is started, and the dose is gradually increased until the most suitable dose is found. Of course, the specific dose should also consider factors such as the route of administration and the patient's health condition, which are within the scope of a skilled physician's expertise. In specific embodiments, the compounds of this invention are preferably administered in a form suitable for nebulization.

[0129] Obesity and related diseases

[0130] In this article, the terms "obesity" and "obesity disorder" have the same meaning: both refer to a chronic metabolic disease caused by the interaction of multiple factors, including genetic and environmental factors, where the amount of fat stored in the body exceeds 20% of the ideal body weight. The mechanism of its occurrence is that energy intake exceeds energy expenditure, leading to excessive accumulation of body fat and excessive weight.

[0131] Long-term obesity can lead to a variety of diseases, including but not limited to: being overweight and having high blood lipids. In addition, obesity can increase the burden on joints, aggravate joint degeneration and lead to osteoarthritis; restrict chest wall movement and affect respiratory function; cause sleep apnea syndrome and lead to chronic hypoxia damage to the brain and body.

[0132] Advantages of this invention:

[0133] 1. This invention provides a series of novel compounds with therapeutic effects on obesity and related diseases; and

[0134] 2. The compounds of this invention lay a new material foundation for the development of novel therapeutic drugs for obesity and related diseases.

[0135] The technical solution of the present invention is further described below with reference to specific implementation examples. However, the following implementation examples do not constitute a limitation on the present invention. All application methods based on the principles and technical means of the present invention are within the scope of the present invention. Experimental methods in the following embodiments that do not specify specific conditions are generally performed under conventional conditions or as recommended by the manufacturer. Unless otherwise stated, percentages and parts are by weight.

[0136] Example

[0137] Example 1. Synthesis of a series of compounds

[0138] The compounds involved in the embodiments of this application may be commercially available, or may be prepared by those skilled in the art according to conventional routes or methods in the field of chemical synthesis, or may be obtained according to the methods or routes described herein.

[0139] The following are exemplary synthetic methods for some representative compounds.

[0140] Synthesis of 1,3-ethylphenylethylene glycol (Compound 1)

[0141]

[0142] Synthesis of Compound 1.3

[0143] Magnesium shavings (2.2 g, 90 mmol) were placed in a 250 mL three-necked reaction flask, and one grain of iodine was added. Compound 1.1 (15 g, 82 mmol) was dissolved in 120 mL of anhydrous tetrahydrofuran. 10 mL of the tetrahydrofuran solution of compound 1 was added dropwise to the reaction flask containing the magnesium shavings using a constant-pressure dropping funnel. The reaction was initiated by heating with a hairdryer. After the reaction started, the remaining 110 mL of the tetrahydrofuran solution of compound 1.1 was slowly added dropwise. After the addition was complete, the mixture was refluxed for 3.5 hours, finally yielding a tetrahydrofuran solution of compound 1.2.

[0144] Under ice bath conditions, a tetrahydrofuran solution of compounds 1.2 was added dropwise to an 80 mL solution of anhydrous tetrahydrofuran containing benzyloxyacetaldehyde (12 g, 80 mmol). After the addition was complete, the mixture was allowed to react at room temperature for 1 hour, followed by extraction with a saturated ammonium chloride aqueous solution to extinguish the reaction. Finally, the tetrahydrofuran was removed, and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and purified by column chromatography (PE:EA = 10:1) to give 12.4 g of the target compound, with a two-step yield of 59.6%.

[0145] 1 H NMR (400MHz, DMSO): δ7.36-7.15(m,8H),7.09(d,J=7.6Hz,1H),5.38(d,J=4.4Hz,1H),4.74-4.70( m,1H),4.51(s,2H),3.53-3.44(m,2H),2.61(q,J=7.6,2H),1.19(t,J=7.6,3H).LC-MS:255.30(MH) - .

[0146] Synthesis of Compound 1 (including the racemic mixture of Compound 1, the R-configuration 1-R of Compound 1, and the S-configuration 1-S of Compound 1)

[0147] Compound 1.3 (12.4 g, 48.4 mmol) was dissolved in 70 mL of ethanol, and 2.43 g of 10% palladium on carbon was added. The air was purged, H2 was added, and the mixture was stirred at 38 °C for 3 hours. After the reaction was complete, the solvent was removed, and the mixture was purified by column chromatography (PE:EA = 5:1) to give 6.42 g of the target compound, with a yield of 79%.

[0148] The R-configuration and S-configuration of compound 1 were obtained by chiral preparation.

[0149] 1H NMR (400MHz, CDCl3): δ7.28-7.12 (m, 4H), 4.78 (dd, J1=8.0Hz, J2=3.6Hz, 1H), 3. 74-3.62(m,2H),2.64(q,J=7.6Hz,2H),1.23(t,J=7.6Hz,3H).LC-MS:165.10(MH) - .

[0150] 13. Synthesis of 1-(3-cyclopropylphenyl)-1,2-ethylene glycol (Compound 13)

[0151]

[0152] Synthesis of 1-(3-cyclopropylphenyl)ethyl ketone

[0153] 3-Bromoacetophenone (5 g, 25.12 mmol), cyclopropionic acid (3.25 g, 37.68 mmol), anhydrous potassium phosphate (16 g, 75.36 mmol), and tricyclohexylphosphine (1.41 g, 5.02 mmol) were weighed and placed in a 100 mL round-bottom flask, dissolved in 20 mL toluene / water (v:v = 100:1), and palladium acetate (563 mg, 2.52 mmol) was added. The mixture was heated to 100 °C for 20 hours under nitrogen protection, and the reaction was monitored by TLC. After the reaction was completed, the system was cooled to room temperature, washed with water, and extracted three times with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, and the solvent was removed by vacuum distillation. Silica gel column chromatography (PE:EA = 100:1) yielded 3.6 g of a pale yellow oil, with a yield of 89%.

[0154] 1 H NMR (400MHz, DMSO) δ7.74-7.69(m,1H),7.64(t,J=1.6Hz,1H),7.39(t,J=7.6Hz,1H),7.34-7 .30(m,1H),2.56(s,3H),2.01(tt,J=8.4,5.1Hz,1H),1.03-0.95(m,2H),0.75-0.70(m,2H).

[0155] Synthesis of 3-cyclopropylbenzoic acid

[0156] A suspension of copper bromide (6.03 g, 26.98 mmol) was prepared in EA and heated to reflux with stirring. A solution of 1-(3-cyclopropylphenyl)ethyl ketone (3.6 g, 22.49 mmol) in EA was added dropwise using a constant-pressure dropping funnel, and the mixture was refluxed. The reaction was monitored by TLC. After the reaction was complete, the mixture was filtered through a diatomaceous earth filter, and the filter cake was washed with EA. The mother liquor was evaporated to dryness and extracted three times with EA / water. The combined organic phases were dried over anhydrous sodium sulfate and then evaporated to dryness. 6.2 g of the resulting oil was dissolved in 20 mL of methanol, and 5 g of sodium formate was added. The mixture was refluxed for 12 hours, and the reaction was monitored by TLC. After the reaction was complete, the solvent was removed under reduced pressure, and the mixture was extracted three times with EA / water. The combined organic layers were dried over anhydrous sodium sulfate. Purification by silica gel column chromatography (PE:EA = 50:1) yielded 1.2 g of a pale yellow oil, with a yield of 30%.

[0157] 1 H NMR (400MHz, DMSO) δ7.73-7.63(m,1H),7.61(dd,J=3.9,2.4Hz,1H),7.39(dd,J=14.6,6.9Hz,1H),7.34-7.28( m,1H),5.03(t,J=5.5Hz,1H),4.78(d,J=3.6Hz,1H),2.04-1.95(m,1H),1.02-0.94(m,2H),0.75-0.66(m,2H).

[0158] Synthesis of 1-(3-cyclopropylphenyl)-1,2-ethylene glycol

[0159] 3-Cyclopropylbenzoic acid (750 mg, 4.26 mmol) was dissolved in anhydrous tetrahydrofuran, and sodium borohydride (242 mg, 6.39 mmol) dissolved in THF was slowly added dropwise under ice bath conditions. The reaction progress was monitored by TLC. After the reaction was complete, saturated ammonium chloride solution was slowly added dropwise to quench the reaction. The mixture was extracted three times with DCM, and the organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was removed by vacuum evaporation. The solution was purified by silica gel column chromatography (PE:EA = 2:1) to give 180 mg of white solid, yield 24%.

[0160] 1H NMR (400MHz, DMSO) δ7.16(t,J=7.6Hz,1H),7.10-7.03(m,2H),6.91(d,J=7.6Hz,1H),5.15(d,J=3.9Hz,1H),4.67(t,J=5.1Hz,1H),4 .48(dd,J=9.5,5.7Hz,1H),3.40(t,J=5.5Hz,2H),1.93-1.85(m,1H),0.95-0.88(m,2H),0.67-0.59(m,2H).LC-MS:m / z:177.20(MH) - ,t R 7.537 min.

[0161] The following compounds were all synthesized using a route similar to the one described above:

[0162] 14. Synthesis of compound 1-(3-ethylphenyl)-2-hydroxyethane-1-one (Compound 14)

[0163]

[0164] The compound is a colorless oil with a yield of 36.7%.

[0165] 1 H NMR (400MHz, DMSO) δ7.80-7.71(m,2H),7.48(t,J=7.6Hz,1H),7.46-7.40(m,1H),5. 04(t,J=5.4Hz,1H),4.79(d,J=4.9Hz,2H),2.67(q,J=7.6Hz,2H),1.23-1.16(m,3H).

[0166] 15. Synthesis of compound 1-(3-methoxyphenyl)-1,2-ethylene glycol (Compound 15)

[0167]

[0168] The compound is a pale yellow solid with a yield of 50%.

[0169] 1 H NMR (400MHz, DMSO) δ7.24-7.17(m,1H),6.90(d,J=7.4Hz,2H),6.82-6.75(m,1H),4.5 0(t,J=5.9Hz,1H),3.73(s,3H),3.42(dd,J=8.9,4.6Hz,2H).LC-MS:m / z:167.15(MH) - .t R 6.105 min.

[0170] 16. Synthesis of compound 1-(2,3-dihydro-5-benzofuranyl)-1,2-ethylene glycol (compound 16)

[0171]

[0172] The compound is a pale yellow solid with a yield of 44%.

[0173] 1 H NMR (400MHz, DMSO) δ7.17(s,1H),7.01(dd,J=8.1,1.0Hz,1H),6.67(d,J=8.1Hz,1H),5.05(d,J=4.1Hz,1H),4.63(t,J= 5.8Hz,1H),4.48(t,J=8.7Hz,2H),4.46-4.41(m,1H),3.40-3.34(m,2H),3.13(t,J=8.7Hz,2H).LC-MS:m / z:179.15(MH) - ,t R 5.922 min.

[0174] 17. Synthesis of compound 1-(2,3-dihydro-1,4-benzodiazaox-6-yl)-1,2-ethylene glycol (compound 17)

[0175]

[0176] The compound is a yellow oil with a yield of 37.7%.

[0177] 1 H NMR (400MHz, DMSO) δ6.80 (s, 1H), 6.76 (s, 2H), 5.09 (d, J = 4.3Hz, 1H), 4.64 (t, J = 5.8Hz, 1H) ,4.40(dd,J=10.4,5.9Hz,1H),4.20(s,4H),3.37(d,J=5.9Hz,2H).LC-MS:m / z:195.15(MH) - ,t R 5.776 min.

[0178] 18. Synthesis of compound 1-(1,3-benzodiazol-5-yl)-1,2-ethylene glycol (Compound 18)

[0179]

[0180] The compound is a yellow solid with a yield of 40%.

[0181] 1H NMR (400MHz, DMSO) δ6.86(d,J=8.9Hz,1H),6.83(d,J=7.9Hz,1H),6.79(d,J=8.0Hz,1H),5.96(d,J=1.8Hz,2 H),5.16(d,J=3.5Hz,1H),4.66(s,1H),4.44(d,J=2.6Hz,1H),3.37(d,J=4.4Hz,2H).LC-MS:m / z:181.15(MH) - ,t R 5.803 min.

[0182] 19. Synthesis of compound 1-(4-hydroxyphenyl)-1,2-ethylene glycol (Compound 19)

[0183]

[0184] The compound is a white solid with a yield of 42%.

[0185] 1 H NMR (400MHz, DMSO) δ9.20 (s, 1H), 7.11 (d, J = 8.4Hz, 2H), 6.69 (d, J = 8.5Hz, 2H), 5.01 (d, J = 4.1Hz, 1 H),4.61(t,J=5.8Hz,1H),4.42(dd,J=10.4,5.7Hz,1H),3.39-3.35(m,2H).LC-MS:m / z:153.15(MH) - ,t R 2.187 min.

[0186] 20. Synthesis of compound 1-(3,4-dimethoxy)-1,2-ethylene glycol (compound 20)

[0187]

[0188] The compound is a powdery white solid with a yield of 45%.

[0189] 1 H NMR (400MHz, DMSO) δ6.92(d,J=1.5Hz,1H),6.87(d,J=8.2Hz,1H),6.83(dd,J=8.2,1.6Hz,1H),5.12(d,J=4.1Hz,1H),4. 64(t,J=5.8Hz,1H),4.46(dd,J=10.3,5.9Hz,1H),3.72(d,J=6.0Hz,6H),3.39(t,J=5.9Hz,2H).LC-MS:m / z:197.20(MH)- ,t R 5.529 min.

[0190] 21. Synthesis of compound 1-(4-methoxyphenyl)propane-1,2-diol (Compound 21)

[0191]

[0192] The compound is a white solid with a yield of 49.0%.

[0193] 1 H NMR (400MHz, DMSO-d6) δ7.03 (dd, J=148.6, 8.7Hz, 4H), 5.02 (d, J=4.3Hz, 1H), 4.38 (d, J=5. 4Hz, 1H), 4.28 (t, J = 4.8Hz, 1H), 3.72 (s, 3H), 3.60 (q, J = 5.5Hz, 1H), 0.97 (d, J = 6.3Hz, 3H).

[0194] 22. Synthesis of compound 1-(2-methoxyphenyl)ethane-1,2-diol (Compound 22)

[0195]

[0196] The compound is a white solid with a yield of 16.5%.

[0197] 1 H NMR (400MHz, DMSO-d6) δ7.41(dd,J=7.7,1.7Hz,1H),7.21(td,J=7.6,1.9Hz,1H),6.93(t,J=7.2Hz,2H),5.08(d,J=4.5Hz,1H),4.89(d t,J=7.9,3.6Hz,1H),4.69(dd,J=6.4,5.4Hz,1H),3.77(s,3H),3.47(ddd,J=11.1,6.5,3.1Hz,1H),3.22(ddd,J=11.0,7.9,5.4Hz,1H).

[0198] 23. Synthesis of compound 1-(4-methoxyphenyl)ethane-1,2-diol (Compound 23)

[0199]

[0200] The compound is a white solid with a yield of 6.5%.

[0201] 1H NMR (400MHz, DMSO-d6) δ7.24(d,J=8.7Hz,2H),6.86(d,J=8.7Hz,2H),5.13(d,J=4. 2Hz,1H),4.68(t,J=5.8Hz,1H),4.58-4.35(m,1H),3.72(s,3H),3.46-3.29(m,2H).

[0202] 24. Synthesis of compound 1-(4-bromophenyl)ethane-1,2-diol (Compound 24)

[0203]

[0204] The compound is a white solid with a yield of 6.3%.

[0205] 1 H NMR (400MHz, DMSO-d6) δ7.49(d,J=8.4Hz,2H),7.29(d,J=8.4Hz,2H),5.34(d,J=4.3Hz ,1H),4.75(t,J=5.8Hz,1H),4.51(dt,J=6.5,4.8Hz,1H),3.39(tt,J=11.4,5.7Hz,2H).

[0206] 25. Synthesis of compound 1-(4-hydroxy-2-methoxyphenyl)ethane-1,2-diol (Compound 25)

[0207]

[0208] The compound is a light brown oily liquid with a yield of 33%.

[0209] 1 H NMR (400MHz, DMSO-d6) δ9.28 (s, 1H), 7.13 (d, J=7.9Hz, 1H), 6.40-6.29 (m, 3H), 4.85 (d, J= 4.0Hz,1H),4.81-4.68(m,2H),4.59(t,J=5.6Hz,1H),3.70(s,3H).LCMS: calculated[MH] - C9H 11 O4 - =183.07, found:183.10.

[0210] 26. Synthesis of compound 1-(3-hydroxyphenyl)ethane-1,2-diol (Compound 26)

[0211]

[0212] The compound is a light brown oily liquid with a yield of 35%.

[0213] 1 H NMR (400MHz, DMSO-d6) δ9.27(s,1H),7.08(t,J=7.8Hz,1H),6.76(s,1H),6.73(d,J=7.6Hz,1H),6.61(dd,J=8.0,2.0Hz,1H ),5.17(d,J=4.0Hz,1H),4.71(t,J=5.8Hz,1H),4.44(dd,J=10.6,5.1Hz,1H),3.38(t,J=5.3Hz,2H).LCMS: calculated[MH] - C8H9O3 - =153.06, found:153.10.

[0214] 27. Synthesis of compound 1-phenylpropane-1,2-diol (Compound 27)

[0215]

[0216] The compound is a white solid with a yield of 67%.

[0217] 1 H NMR(400MHz,DMSO-d6)δ7.35-7.17(m,5H),5.20-5.11(m,1H),4.64-4.44(m,1H) ,4.37-4.26(m,1H),3.70-3.61(m,1H),1.05-0.79(m,3H).LCMS: calculated[MH] - C9H 11 O2 - =151.08, found:151.15.

[0218] 28. Synthesis of compound 1-(3-ethynylphenyl)ethane-1,2-diol (Compound 28)

[0219]

[0220] The compound is a brown solid with a yield of 25%.

[0221] 1H NMR (400MHz, DMSO-d6) δ7.43 (s, 1H), 7.38-7.31 (m, 3H), 5.32 (d, J = 4.3Hz, 1H), 4.74 (t, J = 5.6 Hz,1H),4.52(dd,J=10.6,5.4Hz,1H),4.14(s,1H),3.46-3.38(m,2H).LCMS: calculated[MH] - C 10 H9O2 - =161.06, found:161.15.

[0222] 29. Synthesis of compound 1-(3-(tert-butyl)phenyl)ethane-1,2-diol (Compound 29)

[0223]

[0224] The compound is a pale yellow solid with a yield of 27%.

[0225] 1 H NMR (400MHz, DMSO-d6) δ7.35(s,1H),7.27-7.19(m,2H),7.12(d,J=6.9Hz,1H),5.18(d,J=4.2Hz,1H),4.69 (t,J=5.8Hz,1H),4.51(dd,J=10.3,5.9Hz,1H),3.41(t,J=5.9Hz,2H),1.27(s,9H).LCMS: calculated[MH] - C 12 H 17 O2 - =193.12, found:193.20.

[0226] 30. The structure of 1-(3-hydroxy-4-methoxyphenyl)ethane-1,2-diol (Compound 30)

[0227]

[0228] The compound is a pale yellow solid with a yield of 30%.

[0229] 1H NMR (400MHz, DMSO-d6) δ8.82(s,1H),6.82(d,J=8.2Hz,1H),6.76(d,J=1.5Hz,1H),6.68(dd,J=8.1,1.5Hz,1H),5.04(d,J= 4.0Hz,1H),4.62(t,J=5.8Hz,1H),4.38(dd,J=10.0,5.7Hz,1H),3.72(s,3H),3.34(t,J=5.9Hz,2H).LCMS: calculated[MH] - C9H 11 O4 - =183.07, found:183.15.

[0230] 31. Synthesis of compound 1-(1,3-diethyl-2-hydroxy)-1,2-ethylene glycol (Compound 31)

[0231]

[0232] Synthesis of ethyl 2-(2,4-diethyl-3-hydroxyphenyl)-2-oxoethyl acetate

[0233] Weigh 1 g (6.67 mmol) of 2,6-diethylphenol into a 100 mL single-necked round-bottom flask, dissolve it in 20 mL of 1,2-dichloroethane, and slowly add anhydrous aluminum trichloride (2.7 g, 19.99 mmol) at 0 °C with stirring for 10 min. Then, slowly add 1 g (7.34 mmol) of monoethyl oxaloyl chloride dropwise and react at 0 °C for 10 min. Monitor the reaction progress by TLC. After the reaction is complete, slowly pour the reaction solution into ice water and extract three times with DCM / H2O. Combine the organic phases, dry them over anhydrous sodium sulfate, and then evaporate to dryness. The product is a white solid, requires no purification, and has a yield of 90%.

[0234] 1 H NMR (400 MHz, DMSO) δ9.69 (s, 1H), 7.54 (s, 2H), 4.40 (q, J = 7.1 Hz, 2H), 2.65 (q, J = 7.5 Hz, 4H), 1.32 (t, J = 7.1 Hz, 3H), 1.14 (t, J = 7.5 Hz, 6H).

[0235] Synthesis of 1-(2,4-diethyl-3-hydroxyphenyl)-1,2-ethylenediol

[0236] Ethyl 2-(2,4-diethyl-3-hydroxyphenyl)-2-oxoethyl acetate (627 mg, 2.52 mmol) was dissolved in 10 mL of methanol. Sodium borohydride (426.9 mg, 11.29 mmol) was slowly added in portions with stirring in an ice bath. The reaction was carried out at 0 °C for one hour. The reaction was monitored by TLC. After the reaction was complete, the reaction was quenched dropwise with saturated ammonium chloride solution. The mixture was extracted three times with EA / H₂O. The combined organic phases were dried over anhydrous sodium sulfate and the solvent was removed by vacuum evaporation. Recrystallization gave a white solid in 60% yield.

[0237] 1 H NMR (400 MHz, DMSO) δ7.91 (s, 1H), 6.86 (s, 2H), 4.94 (d, J = 4.0 Hz, 1H), 4.57 (t, J = 5.8 Hz, 1H), 4.38 (dd, J = 10.1, 5.9 Hz, 1H), 3.36 (t, J = 6.0 Hz, 2H), 2.55 (q, J=7.5 Hz, 4H), 1.11 (t, J=7.5 Hz, 6H). LC-MS: m / z: 209.20 (MH) - ,t R 6.736 min.

[0238] The following compounds were obtained via a synthetic route similar to that of 1-(2,4-diethyl-3-hydroxyphenyl)-1,2-ethylenediol (73):

[0239] 32. Synthesis of compound 1-(3,4-dihydro-1-benzopyran-6-yl)-1,2-ethylene glycol (compound 32)

[0240]

[0241] The compound is a white solid with a yield of 25%.

[0242] 1 H NMR (400 MHz, DMSO) δ7.02-6.95(m,2H),6.68-6.61(m,1H),5.04(d,J=3.7Hz,1H),4.64(t,J=5.2 Hz,1H),4.40(d,J=3.0 Hz,1H),4.17-3.97(m,2H),3.40-3.35(m,2H),2.71(t,J=6.4 Hz,2H),1.97-1.80(m,2H).LC-MS:m / z:193.20(MH) - ,t R 6.462 min.

[0243] 33. Synthesis of compound 1-(4-hydroxy-3-methoxy)-1,2-ethylene glycol (Compound 33)

[0244]

[0245] The compound is a pale yellow oil with a yield of 30%.

[0246] 1 H NMR (400 MHz, DMSO) δ8.75 (s, 1H), 6.87 (s, 1H), 6.69 (s, 2H), 5.04 (d, J = 4.0 Hz, 1H), 4.61 (t, J = 5.7 Hz, 1H), 4.41 (dd, J = 10.2, 5.9 Hz,1H),3.74(s,3H),3.37(t,J=6.0 Hz,2H).LC-MS:m / z:183.15(MH) - ,t R 2.213 min.

[0247] 34. Synthesis of compound 1-(5,6,7,8-tetrahydronaphth-2-yl)-1,2-ethylene glycol (compound 34)

[0248]

[0249] The compound is a white solid with a yield of 55%.

[0250] 1 H NMR (400MHz, DMSO) δ7.00(d,J=8.3Hz,2H),6.96(d,J=7.7Hz,1H),5.09(d,J=4.2Hz,1H),4.66(t,J=5.8Hz,1H),4 .43(dd,J=10.2,5.9Hz,1H),3.39-3.35(m,2H),2.68(d,J=5.2Hz,4H),1.76-1.66(m,4H).LC-MS:m / z:191.20(MH) - ,t R 8.760 min.

[0251] 35. Synthesis of compound 1-(3-ethyl-4-methylphenyl)-1,2-ethylene glycol (Compound 35)

[0252]

[0253] The compound is a pale yellow oil with a yield of 60%.

[0254] 1H NMR (400MHz, DMSO) δ7.26-6.80(m,3H),5.15-5.04(m,1H),4.74-4.64(m,1H),4.49-4.40(m,1H),3.40-3.35( m,2H),2.55(dt,J=12.5,7.3Hz,2H),2.28-2.19(m,3H),1.13(tt,J=7.5,4.9Hz,3H).LC-MS:m / z:179.20(MH) - ,t R 8.718 min.

[0255] 36. Synthesis of compound 1-(2,3-dihydro-1H-indenman-5-yl)-1,2-ethylene glycol (Compound 36)

[0256]

[0257] The compound is a white solid with a yield of 65%.

[0258] 1 H NMR (400MHz, DMSO) δ7.17(s,1H),7.13(d,J=7.7Hz,1H),7.05(d,J=7.6Hz,1H),5.10(d,J=4.1Hz,1H),4.65(t,J=5.8Hz,1H),4. 48(dd,J=10.3,5.7Hz,1H),3.38(t,J=5.9Hz,2H),2.81(dd,J=12.1,7.1Hz,4H),1.99(p,J=7.4Hz,2H).LC-MS:m / z:177.20(MH) - ,t R 8.265 min.

[0259] 37. Synthesis of compound 1-(3-ethyl-4-hydroxyphenyl)-1,2-ethylene glycol (Compound 37)

[0260]

[0261] The compound is a powdery white solid with a yield of 53%.

[0262] 1H NMR (400MHz, DMSO) δ9.06 (s, 1H), 7.00 (d, J = 1.7Hz, 1H), 6.92 (dd, J = 8.1, 2.0Hz, 1H), 6.69 (d, J = 8.1Hz, 1H), 4.97 (d, J = 4.0Hz, 1H), 4.59 (t, J=5.8Hz,1H),4.39(dd,J=10.1,5.9Hz,1H),3.37(dd,J=8.0,3.9Hz,2H),2.54-2.50(m,2H),1.11(t,J=7.5Hz,3H).LC-MS:m / z:181.20(MH) - ,t R 5.947 min.

[0263] 38. Synthesis of compound 3-(3-ethylphenyl)tetrahydrofuran-3-ol (Compound 38)

[0264]

[0265] 3-Bromoethylbenzene (200 mg, 1.08 mmol), a suitable amount of magnesium strip, 2 iodine granules, and 20 mL of anhydrous tetrahydrofuran were added to a dried 100 mL reaction flask. The reaction was carried out at room temperature under argon protection. After the Grignard reagent was prepared, 2-2H-furanone (112 mg, 1.30 mmol) was dissolved in anhydrous THF and added dropwise to the prepared Grignard reagent. The reaction was carried out at room temperature, and the reaction was detected by TLC to be complete. The reaction was quenched by saturated ammonium chloride, and the product was purified by silica gel column chromatography to obtain 80 mg of colorless oil, with a yield of 38.5%.

[0266] 1 H NMR (400MHz, CDCl3) δ7.31(s,1H),7.26(dd,J=6.8,4.8Hz,2H),7.15-7.07(m,1H),4.79-4.67(m,1H),4.21-4.13(m,1H),4.08(td,J=8.6, 3.4Hz,1H),3.98-3.85(m,2H),2.70(s,1H),2.65(q,J=7.6Hz,2H),2.39(dt,J=13.0,9.1Hz,1H),2.28-2.18(m,1H),1.23(t,J=7.6Hz,3H).

[0267] 39. Synthesis of compound 1-(5-ethylthiophen-3-yl)ethane-1,2-diol (Compound 39)

[0268]

[0269] Synthesis of 4-bromo-2-ethylthiophene

[0270] Thiophene ethyl ketone (2.05 g, 10 mmol) was dissolved in 80 mL of dry THF. Sodium borohydride (1.89 g, 50 mmol) was added in portions under ice bath conditions, followed by anhydrous aluminum trichloride (3.66 g, 27.5 mmol) in portions. The mixture was refluxed at 80 °C under nitrogen protection. The reaction was monitored by TLC (eluent: heptane). After 2 h, the reaction was complete. The reaction was carefully quenched with 30 mL of water. After removing the THF solvent by rotary evaporation, the mixture was extracted with dichloromethane. After routine post-treatment, the residue was purified by column chromatography (eluent: heptane) to give 0.98 g of the pure reduced product, with a yield of 51.3%.

[0271] Synthesis of (5-ethylthiophen-3-yl)magnesium bromide

[0272] Magnesium shavings (31 mg, 1.3 mmol) and a small particle of elemental iodine were added to a reaction flask. After purging with nitrogen, 0.5 mL of dry THF was added, followed by a 1.5 mL THF solution of the product (191 mg, 1 mmol). The temperature was raised to 35 °C to initiate the reaction. Under this temperature, the THF solution of the brominated product was added dropwise, keeping the reaction mixture at a gentle boil. After the addition was complete, the reaction was continued at 35 °C for 1 hour. The mixture was then cooled to room temperature for later use.

[0273] Synthesis of ethyl 2-(5-ethylthiophene-3-yl)-2-oxoethyl

[0274] Diethyl oxalate (0.41 mL, 3 mmol) and 2 mL THF were added to the reaction flask and cooled to -78 °C under nitrogen protection. The prepared Grignard reagent was slowly added dropwise. After the addition was complete, the mixture was kept at -78 °C for 2 h. The reaction was quenched with 1 mL of saturated ammonium chloride, extracted with EA, and after routine post-processing, the crude product was purified by column chromatography (PE / EA = 200:1 to 100:1) to obtain 180 mg of pure product, with a yield of 85.7%.

[0275] Synthesis of 1-(5-ethylthiophen-3-yl)ethane-1,2-diol

[0276] The above product (170 mg, 0.8 mmol) and 4 mL of methanol were added to a reaction flask and mixed thoroughly. Sodium borohydride (91 mg, 2.4 mmol) was then added in portions under ice bath conditions. After the addition was complete, the mixture was brought to room temperature. The reaction was monitored by TLC (dichloromethane / methanol = 25:1), yielding 30 mg of the pure product, with a yield of 22.2%.

[0277] 1H NMR (400MHz, CDCl3) δ6.98 (s, 1H), 6.72 (s, 1H), 4.77 (dd, J1 = 7.6Hz, J1 = 2.8Hz, 1H), 3.74(m,1H),3.66(m,1H),3.16(s,2H),2.79(q,J=7.6Hz,2H),1.28(t,J=7.6Hz,3H).

[0278] 40. Synthesis of the deuterated compound 3-ethylphenylethylene glycol (Compound 40)

[0279]

[0280] Weigh 5.00 g (33.7 mmol) of 3-ethylacetophenone into a 50 mL three-necked flask, add 25 mL of 1,4-dioxane and 25 mL of methanol for dilution, and add nitrogen protection. Stir for 10 min in an ice bath. Dissolve 5.39 g (33.7 mmol) of liquid bromine in 25 mL of methanol using a syringe, and slowly add it dropwise to the reaction mixture using a dropping funnel in an ice bath. After the addition is complete, continue stirring in an ice bath and monitor the reaction progress by TLC. The reaction is complete after 5 hours. Quench the reaction with an appropriate amount of anhydrous sodium sulfite solution. Remove the solvent by rotary evaporation. Extract the reaction mixture with ethyl acetate and water, wash the extract with ethyl acetate and saturated sodium chloride solution, and dry with anhydrous sodium sulfate. Rotary evaporation yields 6.15 g of crude product.

[0281] Compound A (1.08 g, 4.76 mmol), sodium formate (0.65 g, 9.56 mmol), and 10 mL of methanol were weighed into a 100 mL single-necked flask. The mixture was heated to 80 °C and refluxed. The reaction progress was monitored by thin-layer chromatography. The reaction was completed after 4.5 hours. The solvent was removed by rotary evaporation. The reaction mixture was extracted with ethyl acetate and water, and the extract was washed with ethyl acetate and saturated sodium chloride solution. The mixture was dried over anhydrous sodium sulfate. The product was obtained by rotary evaporation, yielding 0.75 g of crude product. The crude yield was 95.96% (including impurities).

[0282] Compound B (0.10 g, 0.61 mmol) was weighed into a 50 mL single-necked flask and diluted with 10 mL of methanol. The mixture was stirred in an ice bath for 10 min. Sodium borodeuteride (0.013 g, 0.31 mmol) was weighed and added to the reaction solution in portions in an ice bath. After the addition was complete, the ice bath was removed, and the reaction was allowed to proceed at room temperature. The reaction progress was monitored by TLC. The solvent was removed by rotary evaporation. The reaction solution was extracted with ethyl acetate and water, washed with ethyl acetate and saturated sodium chloride solution, dried with anhydrous sodium sulfate, and then rotary evaporated. A suitable amount of dichloromethane and silica gel were added, mixed, and then rotary evaporated to prepare the sample. The sample was dry-packed and loaded onto a column using petroleum ether:ethyl acetate = 4:1. The product obtained by rotary evaporation was 0.02 g. Yield: 19.63%.

[0283] 1H NMR (400MHz, DMSO-d6) δ7.21(t,J=7.5Hz,1H),7.17(s,1H),7.12(d,J=7.6Hz,1H),7.06(d,J=7.4Hz,1H),5.14(s, 1H),4.67(t,J=5.8Hz,1H),3.40(d,J=5.8Hz,2H),2.58(q,J=7.5Hz,2H),1.17(t,J=7.6Hz,3H).LCMS[MH]-:166.20

[0284] 41. Synthesis of the deuterated compound 3-ethylphenylethylene glycol (Compound 41)

[0285]

[0286] Weigh 0.50 g (3.4 mmol) of 3-ethylacetophenone into a 25 mL single-necked flask, add 4 mL of tetrahydrofuran, and stir at room temperature. Weigh 0.59 g (3.4 mmol) of N-bromosuccinimide and slowly add it to the reaction mixture, continuing to stir and monitoring the reaction progress via TLC. The reaction is stopped when the reactants no longer react and the reaction proceeds incompletely. Quench with an appropriate amount of water. Remove the solvent by rotary evaporation. Extract the reaction mixture with ethyl acetate and water, wash the extract with ethyl acetate and saturated sodium chloride solution, and dry with anhydrous sodium sulfate. The product obtained by rotary evaporation yields 0.52 g of crude product. (Since the product and reactants have similar polarities and are difficult to purify, they are directly added to the next step.)

[0287] Crude yield = 67.08% (including impurities)

[0288] Compound A (1.30 g, 5.72 mmol) was weighed into a 50 mL single-necked flask. 26 mL of toluene, 1.95 mL of deuterated water, and potassium carbonate (0.20 g, 1.45 mmol) were added, and the mixture was heated to 87 °C under reflux. After 4 hours, the aqueous layer was separated at 40–50 °C, and another 1.95 mL of deuterated water and potassium carbonate (0.20 g, 1.45 mmol) were added, and the reaction continued. This process was repeated once after 8 hours, and the reaction was completed after 12 hours. The aqueous layer was separated and washed with ethyl acetate. The solvent was removed by rotary evaporation. The reaction mixture was extracted with ethyl acetate and water, and the extract was washed with ethyl acetate and saturated sodium chloride solution. The mixture was dried over anhydrous sodium sulfate. The product was obtained by rotary evaporation, yielding 1.01 g of crude product. The crude yield was 77.11% (including impurities).

[0289] Compound A (1.00 g, 4.36 mmol), sodium formate (0.60 g, 8.82 mmol), and 5 mL of methanol were weighed into a 50 mL single-necked flask. The mixture was heated to 80 °C and refluxed. The reaction progress was monitored by thin-layer chromatography. The reaction was completed after 4.5 hours. The solvent was removed by rotary evaporation. The reaction mixture was extracted with ethyl acetate and water, and the extract was washed with ethyl acetate and saturated sodium chloride solution. The solution was dried over anhydrous sodium sulfate. The product was obtained by rotary evaporation, yielding 0.72 g of crude product. Crude yield = 99.35% (including impurities).

[0290] Compound C (1.00 g, 6.02 mmol) was weighed into a 50 mL single-necked flask and diluted with 5 mL of methanol. The mixture was stirred in an ice bath for 10 min. Sodium borohydride (0.23 g, 6.02 mmol) was weighed and added to the reaction mixture in portions in an ice bath. After the addition was complete, the ice bath was removed, and the reaction was allowed to proceed at room temperature. The reaction progress was monitored by TLC. The solvent was removed by rotary evaporation. The reaction mixture was extracted with ethyl acetate and water, washed with ethyl acetate and saturated sodium chloride solution, dried with anhydrous sodium sulfate, and then rotary evaporated. A suitable amount of dichloromethane and silica gel were added, mixed, and then rotary evaporated to prepare the sample. The sample was dry-packed and loaded onto a column using a petroleum ether:ethyl acetate ratio of 4:1. The product obtained by rotary evaporation was 0.21 g. Yield: 20.74%.

[0291] 1 H NMR(600MHz,Chloroform-d)δ7.35(d,J=7.6Hz,1H),7.33(s,1H),7.24-7.20(m,2H),4.85(s,1H),3.81 (dd,J=11.4,3.5Hz,1H),2.76(s,2H),2.72(q,J=7.6Hz,2H),1.31(t,J=7.6Hz,3H).LCMS[M+H]+:169.1

[0292] 42. The synthesis process of compounds 42-44

[0293] Synthesis of 1-(3-(1-hydroxy-1-deuterated-ethyl)phenyl)-1-deuterated-ethanol (2)

[0294]

[0295] Weigh 3.00 g (18.50 mmol) of 1,3-diacetylbenzene into a 100 mL single-necked flask, dissolve it in 20 mL of methanol, and stir at 0 °C. Separately, slowly add 0.39 g (9.29 mmol) of sodium borodeide to the reaction solution. After the addition is complete, stir at room temperature for 3 hours. Remove the solvent by rotary evaporation, extract the reaction mixture with ethyl acetate, wash the extract with saturated sodium chloride solution, and dry with anhydrous sodium sulfate. Purify the crude product by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1, v / v) to give 2.83 g of colorless crystalline solid, yield 91.1%.

[0296] 1 H NMR(400MHz, DMSO-d6)δ7.32(t,J=1.5Hz,1H),7.26-7.15(m,3H),5.09(s,2H),1.30(s,6H).MS

[0297] Synthesis of 1,3-bis(1-dideuterated ethyl)benzene (3a)

[0298]

[0299] Weigh 12.00 g (71.33 mmol) of 1-(3-(1-hydroxy-1-deuterated-ethyl)phenyl)-1-deuterated-ethanol into a 250 mL two-necked flask and dissolve it in 50 mL of deuterated ethanol. Add 2.00 g (25%) of 10% palladium on carbon to the reaction solution and purge with deuterium gas three times. Slowly add 1 mL of deuterated hydrochloric acid dropwise to the reaction solution using a syringe and stir overnight at room temperature. Filter the reaction solution with diatomaceous earth, extract the filtrate with dichloromethane, wash the extract with saturated sodium chloride solution, and dry with anhydrous sodium sulfate. Remove dichloromethane by rotary evaporation at 40 °C. Obtain 8.20 g of crude colorless transparent liquid, yield 83.3%.

[0300] 1 H NMR (400MHz, DMSO-d6) δ7.17(t,J=7.5Hz,1H),7.03(s,1H),7.00(d,J=7.5Hz,2H),1.15(s,6H).MS

[0301] Synthesis of 1,3-bis(1-deuterated-ethyl)benzene (3b)

[0302]

[0303] Weigh 1.00 g (5.94 mmol) of 1-(3-(1-hydroxy-1-deuterated-ethyl)phenyl)-1-deuterated-ethanol into a 100 mL two-necked flask, dissolve it in 5 mL of dichloromethane, and stir at 0 °C. Slowly add 4.90 g (42.14 mmol) of triethylsilane to the reaction solution under nitrogen protection. Separately, use a 10 mL syringe to slowly add 5.90 g (41.57 mmol) of boron trifluoride diethyl ether to the reaction solution at 0 °C. After the addition is complete, slowly raise the temperature to room temperature and stir overnight. Quench with saturated sodium bicarbonate solution until no more bubbles are generated. Extract the reaction solution with dichloromethane and water, wash the extract with dichloromethane and saturated sodium chloride solution, and dry with anhydrous sodium sulfate. Remove dichloromethane by rotary evaporation at 40 °C. Obtain 0.50 g of crude colorless transparent liquid, yield 61.7%.

[0304] 1H NMR(400MHz,Chloroform-d)δ7.12(t,J=7.6Hz,1H),6.97-6.90(m,3H),2.53(q,J=7.6Hz,2H),1.14(d,J=7.6Hz,6H).MS

[0305] Synthesis of 1-(3-(1-dideuterated ethyl)phenyl)ethyl ketone (4a)

[0306]

[0307] Weigh 8.20 g (59.31 mmol) of 1,3-bis(1-dideuterated ethyl)benzene and 3.20 g (19.62 mmol) of N-hydroxyphthalimide into a 100 mL three-necked flask, dissolve in 60 mL of acetonitrile, replace with oxygen three times, and heat to 40 °C. Using a 10 mL syringe, slowly add 6.10 g (59.15 mmol) of tert-butyl nitrite to the reaction solution, which gradually turns orange. After addition, heat to 55 °C and react for 2 hours. Remove the solvent by rotary evaporation. Add a small amount of dichloromethane; a white solid precipitates. Add diatomaceous earth and filter; evaporate the filtrate to dryness. Purify the crude product by silica gel column chromatography (petroleum ether / dichloromethane = 10:1, v / v) to give 2.80 g of a yellow liquid, with a yield of 31.4%.

[0308] 1 H NMR (400MHz, DMSO-d6) δ7.78(m,2H),7.49(d,J=7.7Hz,1H),7.43(t,J=7.4Hz,1H),2.57(s,3H),1.19(s,3H).

[0309] Synthesis of 1-(3-(1-deuterated ethyl)phenyl)ethyl ketone (4b)

[0310]

[0311] The synthesis steps were the same as in 4a, yielding a yellow liquid with a yield of 29.9%.

[0312] 1 H NMR (400MHz, DMSO-d6) δ7.76-7.80(m,2H),7.41-7.51(m,2H),2.66(q,J=7.6Hz,1H),2.57(s,3H),1.20(d,J=7.6Hz,3H).

[0313] Synthesis of 1-(3-(1-deuterated ethyl)phenyl)ethyl ketone (15c)

[0314]

[0315] The synthesis steps were the same as in 4a, yielding a yellow liquid with a yield of 35.3%.

[0316] 1 H NMR (600MHz, DMSO-d6) δ7.79-7.76(m,2H),7.48(d,J=7.6Hz,1H),7.43(t,J=7.5Hz,1H),2.68(q,J=7.6Hz,2H),2.57(s,3H),1.20(t,J=7.6Hz,3H).

[0317] Synthesis of 1-(3-(1-dideuterated ethyl)phenyl)-2-bromoethylone (5a)

[0318]

[0319] Weigh 2.80 g (18.64 mmol) of 1-(3-(1-dideuterated ethyl)phenyl)acetone and 1.66 g (9.64 mmol) of p-toluenesulfonic acid into a 100 mL single-necked flask, dissolve in 20 mL of acetonitrile, and stir at 0 °C. Weigh 3.64 g (20.45 mmol) of N-bromosuccinimide and slowly add to the reaction solution, react at 40 °C, and the reaction is complete after 3 hours. Quench the reaction with an appropriate amount of water. Remove the solvent by rotary evaporation. Extract the reaction solution with ethyl acetate and water, wash the extract with ethyl acetate and saturated sodium chloride solution, and dry with anhydrous sodium sulfate. Purify the crude product by silica gel column chromatography (petroleum ether / dichloromethane = 10:1, v / v) to give 2.12 g of yellow liquid, with a yield of 50.1%.

[0320] Synthesis of 1-(3-(1-deuterated ethyl)phenyl)-2-bromoethylone (5b)

[0321]

[0322] The synthesis steps are the same as in 5a, yielding a yellow liquid, which is directly added to the next step without purification.

[0323] Synthesis of 1-(3-(1-ethyl)phenyl)-2-bromoethylone (5c)

[0324]

[0325] The synthesis steps are the same as in 5a, yielding a yellow liquid, which is directly added to the next step without purification.

[0326] Synthesis of 1-(3-(1-di-deuterated ethyl)phenyl)-2-hydroxyethyl ketone (6a)

[0327]

[0328] Weigh 2.12 g (9.25 mmol) of 1-(3-(1-dideuterated ethyl)phenyl)-2-bromoethylone, 1.26 g (18.53 mmol) of sodium formate, and 20 mL of methanol into a 100 mL single-necked flask. Heat to 80 °C and reflux for 5 hours until the reaction is complete. Remove the solvent by rotary evaporation. Extract the reaction mixture with ethyl acetate and water, wash the extract with ethyl acetate and saturated sodium chloride solution, and dry with anhydrous sodium sulfate. Purify the crude product by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1, v / v) to give 0.93 g of a yellow liquid, yield 60.2%.

[0329] 1 H NMR (400MHz, Chloroform-d) δ7.77(s,1H),7.72(d,J=7.5Hz,1H),7.47(d,J=7.5Hz,1H),7.42(d,J=7.6Hz,1H),4.87(s,2H),1.20(s,3H).

[0330] Synthesis of 1-(3-(1-deuterated ethyl)phenyl)-2-hydroxyethyl ketone (6b)

[0331]

[0332] The synthesis steps were the same as in 6a, yielding a yellow liquid with a yield of 45.1%.

[0333] 1 H NMR (400MHz, DMSO-d6) δ7.72-7.77(m,2H),7.50(d,J=7.6Hz,1H),7.43(t,J=7.6Hz,1H),4.79(s,2H),2.66(q,J=7.6Hz,1H),1.19(d,J=7.6Hz,3H).

[0334] Synthesis of 1-(3-ethylphenyl)-2-hydroxyethyl ketone (17c)

[0335]

[0336] The synthesis steps were the same as in 6a, yielding a yellow liquid with a yield of 56.3%.

[0337] 1 H NMR(400MHz,Chloroform-d)δ7.76(s,1H),7.72(d,J=7.6Hz,1H),7.47(d,J=7.7Hz,1 H),7.41(t,J=7.6Hz,1H),4.87(s,2H),2.72(q,J=7.6Hz,2H),1.27(t,J=7.6Hz,3H).

[0338] Synthesis of 1-(3-(1-dideuterated ethyl)phenyl)-ethylene glycol (compound 42)

[0339]

[0340] Weigh 0.93 g (5.60 mmol) of 1-(3-(1-dideuterated ethyl)phenyl)-2-hydroxyethyl ketone into a 50 mL single-necked flask, dissolve it in 10 mL of methanol, and stir at 0 °C. Weigh 0.11 g (2.89 mmol) of sodium borohydride and slowly add it to the reaction mixture under ice bath conditions. After the addition is complete, allow the reaction to proceed at room temperature. Remove the solvent by rotary evaporation, extract the reaction mixture with ethyl acetate and water, wash the extract with ethyl acetate and saturated sodium chloride solution, and dry with anhydrous sodium sulfate. Purify the crude product by silica gel column chromatography (petroleum ether / ethyl acetate = 4:1, v / v) to give 0.77 g of a colorless solid, with a yield of 81.4%.

[0341] 1 H NMR (400MHz, DMSO-d6) δ7.21(t,J=7.5Hz,1H),7.17(s,1H),7.13(d,J=7.6Hz,1H),7.06(d,J=7.4Hz,1H) ,5.15(d,J=4.2Hz,1H),4.66(t,J=5.8Hz,1H),4.50(q,J=5.8Hz,1H),3.42(t,J=5.9Hz,2H),1.16(s,3H). 13 C NMR (151MHz, DMSO) δ143.90,143.59,128.25,126.68,126.19,124.16,74.41,68.02,28.26,28.13,28.00,27.87,27.75,16.00.HRMS(ESI):exact mass calcd for C 10 H 12 D2O2[M+Na] + ,191.1015; found191.1017.HPLC purity:95.5%, retention time=7.642min.

[0342] Synthesis of 1-(3-(1-deuterated ethyl)phenyl)-ethylene glycol (compound 43)

[0343]

[0344] The synthesis steps were the same as for TJH1, yielding a colorless solid in 80.1% yield.

[0345] 1H NMR (400MHz, DMSO-d6) δ7.20(t,J=7.5Hz,1H),7.16(s,1H),7.12(d,J=7.5Hz,1H),7.06(d,J=7.5Hz,1H),5.17(d,J=4.1H z,1H),4.68(t,J=5.8Hz,1H),4.49(q,J=5.6Hz,1H),3.40(t,J=5.9Hz,2H),2.56(q,J=7.6Hz,1H),1.16(d,J=7.6Hz,3H). 13 CNMR(151MHz,DMSO)δ143.90,143.61,128.25,126.68,126.18,124.16,74.41,68.02,28.48,28.36,28.23,16.08.HRMS(ESI):exact mass calcd for C 10 H 13 DO2[M+Na] + ,190.0952; found 190.0954.HPLC purity:97.2%, retention time=7.625min.

[0346] Synthesis of 1-(3-ethylphenyl)-1-deuterated ethylene glycol (compound 44)

[0347]

[0348] The synthesis steps were the same as for TJH1, yielding a colorless solid with a yield of 79.8%.

[0349] 1 H NMR (400MHz, DMSO-d6) δ7.21(t,J=7.5Hz,1H),7.17(s,1H),7.12(d,J=7.6Hz,1H),7.06(d,J=7.4Hz,1H),5.16(s,1H ),4.69(t,J=5.8Hz,1H),3.40(d,J=5.8Hz,2H),2.58(q,J=7.6Hz,2H),1.17(t,J=7.6Hz,3H).LC-MS: m / z: 166.20[MH] - .

[0350] 43. Synthesis process of compounds 45-49

[0351] Synthesis of 1-(3-(1-ethylphenyl)-ethylene glycol (7)

[0352]

[0353] Weigh 0.87 g (5.30 mmol) of 1-(3-ethylphenyl)-2-hydroxyethyl ketone into a 50 mL single-necked flask, dissolve it in 10 mL of methanol, and stir at 0 °C. Weigh 0.22 g (5.30 mmol) of sodium borohydride and slowly add it to the reaction mixture under ice bath conditions. After the addition is complete, allow the reaction to proceed at room temperature. Remove the solvent by rotary evaporation, extract the reaction mixture with ethyl acetate and water, wash the extract with ethyl acetate and saturated sodium chloride solution, and dry with anhydrous sodium sulfate. Purify the crude product by silica gel column chromatography (petroleum ether / ethyl acetate = 4:1, v / v) to give 0.75 g of a colorless solid, with a yield of 85.2%.

[0354] 1 H NMR (400MHz, DMSO-d6) δ7.21(t,J=7.5Hz,1H),7.17(s,1H),7.13(d,J=7.6Hz,1H),7.06(d,J=7.4Hz,1H),5.18(d,J=4.2H z,1H),4.69(t,J=5.8Hz,1H),4.50(q,J=5.9Hz,1H),3.41(t,J=5.9Hz,2H),2.59(q,J=7.6Hz,2H),1.17(t,J=7.6Hz,3H).

[0355] Synthesis of 1-(3-ethylphenyl)ethane-1,2-diacetic acid diester (compound 45)

[0356]

[0357] Weigh 0.50 g (3.01 mmol) of 1-(3-ethylphenyl)-ethylene glycol into a 50 mL single-necked flask, dissolve it in 5 mL of dichloromethane, and stir at room temperature. Weigh 0.04 g (0.33 mmol) of 4-dimethylaminopyridine and acetic anhydride (1.23 g (12.05 mmol) into the reaction solution and react at room temperature. Remove the solvent by rotary evaporation, extract the reaction solution with ethyl acetate and water, wash the extract with ethyl acetate and saturated sodium chloride solution, and dry with anhydrous sodium sulfate. Purify the crude product by silica gel column chromatography (petroleum ether / ethyl acetate = 25:1, v / v) to give 0.61 g of a colorless, clear liquid, with a yield of 81.0%.

[0358] 1 H NMR(400MHz,Chloroform-d)δ7.27(d,J=8.6Hz,1H),7.20-7.15(m,3H),6.00(dd,J=7.9,4.1Hz, 1H),4.35-4.27(m,2H),2.66(q,J=7.6Hz,2H),2.12(s,3H),2.06(s,3H),1.24(t,J=7.6Hz,3H).

[0359] Synthesis of 4-(3-ethylphenyl)-1,3-dioxolane-2-one (compound 46)

[0360]

[0361] Weigh 0.50 g (3.01 mmol) of 1-(3-ethylphenyl)-ethylene glycol into a 50 mL single-necked flask and dissolve it in 5 mL of toluene. Weigh 1.30 g (6.01 mmol) of di(2-pyridine) carbonate and add it to the reaction mixture. Heat the mixture to 60 °C and react. Remove the solvent by rotary evaporation. Extract the reaction mixture with ethyl acetate and water. Wash the extract with ethyl acetate and saturated sodium chloride solution and dry with anhydrous sodium sulfate. Purify the crude product by silica gel column chromatography (petroleum ether / ethyl acetate = 20:1, v / v) to give 0.38 g of a colorless, clear liquid, with a yield of 65.7%.

[0362] 1 H NMR(400MHz,Chloroform-d)δ7.35(t,J=7.6Hz,1H),7.26(d,J=7.6Hz,1H),7.19(s,1H),7.17(d,J=7.7Hz,1H),5 .65(t,J=8.0Hz,1H),4.79(t,J=8.4Hz,1H),4.35(t,J=8.3Hz,1H),2.68(q,J=7.6Hz,2H),1.25(t,J=7.6Hz,3H).

[0363] Synthesis of 4-(3-ethylphenyl)-2,2-dimethyl-1,3-dioxolane (compound 47)

[0364]

[0365] Weigh 0.50 g (3.01 mmol) of 1-(3-ethylphenyl)-ethylene glycol into a 50 mL single-necked flask and dissolve it in 3 mL of tetrahydrofuran. Weigh 0.17 g (1.50 mmol) of ferric chloride and 3 mL of acetone and add them to the reaction solution. React at room temperature; the reaction solution turns brown. Remove the solvent by rotary evaporation at room temperature. Extract the reaction solution with dichloromethane and water, wash the extract with dichloromethane and saturated sodium chloride solution, dry with anhydrous sodium sulfate, and remove dichloromethane by rotary evaporation at room temperature. Purify the crude product by silica gel column chromatography (petroleum ether / ethyl acetate = 50:1, v / v) to give 0.52 g of a pale yellow liquid, with a yield of 83.7%.

[0366] 1H NMR (400MHz, Chloroform-d) δ7.27(t,J=7.5Hz,1H),7.20(s,1H),7.18(d,J=7.7Hz,1H),7.14(d,J=7.4Hz,1H),5.05(dd,J=8.0,6.3 Hz,1H),4.29(dd,J=8.1,6.2Hz,1H),3.71(t,J=8.2Hz,1H),2.65(q,J=7.6Hz,2H),1.55(s,3H),1.49(s,3H),1.24(t,J=7.6Hz,3H).

[0367] Synthesis of 4-(3-ethylphenyl)-2-methyl-1,3-dioxolane (compound 48)

[0368]

[0369] Weigh 0.50 g (3.01 mmol) of 1-(3-ethylphenyl)-ethylene glycol into a 50 mL single-necked flask and dissolve it in 3 mL of tetrahydrofuran. Weigh 0.17 g (1.50 mmol) of ferric chloride and 0.54 g (12.27 mmol) of acetaldehyde and add them to the reaction solution. React at room temperature; the reaction solution turns brown. Remove the solvent by rotary evaporation at room temperature. Extract the reaction solution with dichloromethane and water, wash the extract with dichloromethane and saturated sodium chloride solution, dry with anhydrous sodium sulfate, and remove dichloromethane by rotary evaporation at room temperature. Purify the crude product by silica gel column chromatography (petroleum ether / ethyl acetate = 50:1, v / v) to give 0.36 g of a pale yellow liquid, with a yield of 62.1%.

[0370] 1 H NMR (400MHz, Chloroform-d) δ7.30-7.25(m,1H),7.20(s,1H),7.18(d,J=7.8Hz,1H),7.14(d,J=7.5Hz,1H),5.23(q,J=4.8Hz,1H),5.00( t,J=6.8Hz,1H),4.18(t,J=7.5Hz,1H),3.79(dd,J=7.8,6.4Hz,1H),2.66(q,J=7.6Hz,2H),1.53(d,J=4.8Hz,3H),1.24(t,J=7.6Hz,3H).

[0371] Synthesis of 2-(3-ethylphenyl)ethylene oxide (compound 49)

[0372]

[0373] Weigh 0.50 g (2.20 mmol) of 2-bromo-1-(3-ethylphenyl)ethane-1-one into a 50 mL single-necked flask, dissolve in 5 mL of anhydrous methanol, and stir at 0 °C. Weigh 0.08 g (2.11 mmol) of sodium borohydride and add to the reaction solution. After the addition is complete, remove the ice bath and react at room temperature, monitoring the reaction progress by TLC. After the reactants have reacted completely, weigh 0.60 g (4.40 mmol) of potassium carbonate into the reaction solution and stir overnight at room temperature. Remove the solvent by rotary evaporation, extract the reaction solution with dichloromethane and water, wash the extract with dichloromethane and saturated sodium chloride solution, and dry with anhydrous sodium sulfate. Purify the crude product by silica gel column chromatography (petroleum ether / ethyl acetate = 100:1, v / v) to give 0.11 g of a colorless liquid, with a yield of 33.7%.

[0374] 1 H NMR(400MHz,Chloroform-d)δ7.26(t,J=7.4Hz,1H),7.15-7.09(m,3H),3.84(dd,J=3.9,2.7Hz,1H),3 .13(dd,J=5.5,4.1Hz,1H),2.80(dd,J=5.5,2.6Hz,1H),2.65(q,J=7.6Hz,2H),1.23(t,J=7.6Hz,3H).

[0375] (R)-2-(3-Ethylphenyl)-2-hydroxyethyl-L-valine (Compound 50)

[0376]

[0377] Step 1 (R)-2-(3-ethylphenyl)-2-hydroxyethyl(tert-butoxycarbonyl)-L-valine (50-1)

[0378] In a 100 mL single-necked round-bottom flask, (R)-1-(3-ethylphenyl)ethane-1,2-diol (8.00 g, 48.0 mmol), (tert-butoxycarbonyl)-L-valine (2.10 g, 9.60 mmol), and 4-dimethylaminopyridine (0.23 g, 1.92 mmol) were added sequentially, followed by 40 mL of dichloromethane as a solvent. After cooling to 0 °C in an ice-salt bath, dicyclohexylcarbodiimide (3.90 g, 19.0 mmol) was added. The mixture was stirred in an ice bath for 2 h, then brought to room temperature and stirred for another 2 h. The reaction progress was monitored by thin-layer chromatography. After the reaction was complete, the reaction solution was filtered, concentrated, and extracted with ethyl acetate. The combined organic layers were washed sequentially with 1 M hydrochloric acid, water, saturated sodium bicarbonate, water, and saturated sodium chloride. The solution was then dried over anhydrous sodium sulfate and concentrated under reduced pressure to remove the solvent, yielding a pale yellow oily liquid. Rapid silica gel column chromatography (petroleum ether / ethyl acetate = 30:4) was used to separate and purify (R)-2-(3-ethylphenyl)-2-hydroxyethyl(tert-butoxycarbonyl)-L-valine 1.20 g, yield 34.0%.

[0379] LC-MS: m / z: 366.3 (M+H) + .

[0380] Step 2 (R)-2-(3-ethylphenyl)-2-hydroxyethyl-L-valine (50)

[0381] (R)-2-(3-ethylphenyl)-2-hydroxyethyl(tert-butoxycarbonyl)-L-valine (1.80 g, 4.90 mmol) and 20 mL of ethyl acetate hydrochloride were added to a 50 mL single-necked round-bottom flask as solvents. The mixture was stirred at room temperature for 3 h, and the reaction progress was monitored by thin-layer chromatography. After the reaction was completed, the reaction solution was concentrated and extracted with ethyl acetate. The combined organic layers were washed successively with saturated sodium bicarbonate, water, and saturated sodium chloride, and then dried over anhydrous sodium sulfate. The solvent was removed by concentration under reduced pressure to obtain a pale yellow oily liquid. The liquid was purified by rapid silica gel column chromatography (ethyl acetate / methanol = 10:1) to obtain 0.97 g of the corresponding white oily liquid (R)-2-(3-ethylphenyl)-2-hydroxyethyl-L-valine, with a yield of 75.0%.

[0382] 1H NMR (400MHz, DMSO-d6) δ7.29-7.08(m,4H),5.69-5.51(m,1H),4.74(d,J=6.0Hz,1H),4.17-3.99(m,1H),3.70-3.52(m,2H),3.22(d,J=5.0 Hz,1H),3.09(d,J=5.1Hz,1H),2.60(d,J=7.5Hz,2H),2.06-1.62(m,1H),1.17(q,J=7.1Hz,3H),0.94-0.54(m,6H).LC-MS:m / z:266.3(M+H) + .

[0383] (R)-2-((L-valine)oxy)-2-(3-ethylphenyl)valine ethyl ester (compound 51)

[0384]

[0385] Step 1 (R)-2-(((tert-butoxycarbonyl)-L-valine)oxy)-2-(3-ethylphenyl)ethyl(tert-butoxycarbonyl)valine (51-1)

[0386] In a 25 mL single-necked round-bottom flask, (R)-1-(3-ethylphenyl)ethane-1,2-diol (0.50 g, 3.00 mmol), (tert-butoxycarbonyl)-L-valine (4.60 g, 21.0 mmol), and 4-dimethylaminopyridine (0.60 g, 4.80 mmol) were added sequentially, followed by 5 mL of dichloromethane as a solvent. After cooling to 0 °C in an ice-salt bath, dicyclohexylcarbodiimide (8.70 g, 42.0 mmol) was added. The mixture was stirred in an ice bath for 2 h, then brought to room temperature and stirred for 2 h. The reaction progress was monitored by thin-layer chromatography. After the reaction was completed, the reaction solution was filtered, concentrated, and extracted with ethyl acetate. The combined organic layers were washed sequentially with 1 M hydrochloric acid, water, saturated sodium bicarbonate, water, and saturated sodium chloride. The solution was then dried over anhydrous sodium sulfate and concentrated under reduced pressure to remove the solvent, yielding a pale yellow oily liquid. Rapid silica gel column chromatography (petroleum ether / ethyl acetate = 30:4) was used to separate and purify (R)-2-(((tert-butoxycarbonyl)-L-valine)oxy)-2-(3-ethylphenyl)ethyl(tert-butoxycarbonyl)valine 1.01 g, yield 60.0%.

[0387] LC-MS: m / z: 565.4 (M+H) + .

[0388] Step 2 (R)-2-((L-valine)oxy)-2-(3-ethylphenyl)valine ethyl ester (51)

[0389] In a 50 mL single-necked round-bottom flask, (R)-2-(((tert-butoxycarbonyl)-L-valine)oxy)-2-(3-ethylphenyl)ethyl(tert-butoxycarbonyl)valine (1.00 g, 1.77 mmol) and 20 mL of ethyl acetate hydrochloride were added as solvent. The mixture was stirred at room temperature for 3 h, and the reaction progress was monitored by thin-layer chromatography. After the reaction was completed, the reaction solution was concentrated and extracted with ethyl acetate. The combined organic layers were washed successively with saturated sodium bicarbonate, water, and saturated sodium chloride, and then dried over anhydrous sodium sulfate. The solvent was removed by concentration under reduced pressure to obtain a pale yellow oily liquid. The liquid was purified by rapid silica gel column chromatography (ethyl acetate / methanol = 10:1) to obtain 0.45 g of the corresponding white oily liquid (R)-2-((L-valine)oxy)-2-(3-ethylphenyl)valine ethyl ester, with a yield of 70.0%.

[0390] 1 H NMR(400MHz, DMSO-d6)δ7.32-7.13(m,4H),5.91(dd,J=7.5,3.7Hz,1H),4.38(dd,J=11.8,3.7 Hz,1H),4.27(dd,J=11.8,7.5Hz,1H),3.17(d,J=5.2Hz,1H),3.09(d,J=5.1Hz,1H),2.90(d,J= 20.1Hz,4H),2.59(q,J=7.6Hz,2H),1.85(ddd,J=45.9,13.0,6.5Hz,2H),1.15(t,J=7.6Hz,3H ),0.83(t,J=6.5Hz,6H),0.77(d,J=6.8Hz,3H),0.70(d,J=6.8Hz,3H).LC-MS:m / z:365.3(M+H) + .

[0391] (R)-2-(3-ethylphenyl)-2-hydroxyethyl octanoate (52)

[0392]

[0393] Synthesis method:

[0394] In a 100 mL single-necked round-bottom flask, (R)-1-(3-ethylphenyl)ethane-1,2-diol (5.00 g, 30.0 mmol), n-octanoic acid (0.86 g, 6.00 mmol), and 4-dimethylaminopyridine (0.14 g, 1.20 mmol) were added sequentially, followed by 50 mL of dichloromethane as a solvent. After cooling to 0 °C in an ice-salt bath, dicyclohexylcarbodiimide (2.50 g, 12.0 mmol) was added. The mixture was stirred in an ice bath for 2 h, then brought to room temperature and stirred for 2 h. The reaction progress was monitored by thin-layer chromatography. After the reaction was completed, the reaction solution was filtered, concentrated, and extracted with ethyl acetate. The combined organic layers were washed sequentially with 1 M hydrochloric acid, water, saturated sodium bicarbonate, water, and saturated sodium chloride. The solution was then dried over anhydrous sodium sulfate and concentrated under reduced pressure to remove the solvent, yielding a pale yellow oily liquid. Rapid silica gel column chromatography (petroleum ether / ethyl acetate = 30:4) was used to separate and purify the corresponding yellow oily liquid (R)-2-(3-ethylphenyl)-2-hydroxyethyl octanoate, 0.45 g, yield 26.0%.

[0395] 1 H NMR (400MHz, DMSO-d6) δ7.33-7.03(m,4H),5.73-5.42(m,1H),4.84-4.64(m,1H),4.06(q,J=6.7Hz,2H) ,2.61(q,J=7.5Hz,2H),2.27(t,J=7.5Hz,2H),1.48(s,2H),1.34-1.07(m,11H),0.86(d,J=6.8Hz,3H).

[0396] Compounds 53-66 were synthesized using the following method:

[0397] Synthesis Route 1

[0398]

[0399] Reagents and conditions: (a) Pd(dppf)Cl2, K2CO3, 85℃, N2; (b) ADmixβ, t-BuOH, H2O, room temperature.

[0400] Synthetic Route 2

[0401]

[0402] Reagents and conditions: (c) Ag₂CO₃, AgOTf, DCM, room temperature; (d) K₂CO₃, MeOH / DCM, room temperature;

[0403] Synthesis of (R)-1-(3-cyclopropylphenyl)ethane-1,2-diol (Compound 53)

[0404] Step 1: Synthesis of 1-cyclopropyl-3-vinylbenzene (Compound 53)

[0405]

[0406] 1-Bromo-3-cyclopropylbenzene (1.01 mmol, 200 mg), potassium ethylenetrifluoroborate (1.21 mmol, 162 mg), Dppf palladium dichloride (0.10 mmol, 73 mg), and potassium carbonate (2.02 mmol, 279 mg) were added sequentially to a 10 mL Shrek tube. A mixture of dioxane and water (6:1) was used as the solvent. Under nitrogen protection to remove oxygen, the reaction was carried out at 85 °C for 2 hours, and the reaction progress was monitored by TLC. After the reaction was completed, the dioxane was removed by concentration, and the mixture was extracted three times with ethyl acetate and water. The combined organic phases were concentrated and subjected to column chromatography (pure PE) to give the intermediate 1-cyclopropyl-3-vinylbenzene (clear oil, 108 mg, yield 74.1%).

[0407] 1 H NMR (400MHz, Chloroform-d) δ7.23 (s, 1H), 7.22–7.19 (m, 2H), 7.12 (d, J = 2.1Hz, 1H), 6.99–6.91 (m, 1H), 5.73 (dd, J = 17. 6,1.0Hz,1H),5.22(dd,J=10.9,0.9Hz,1H),1.89(tt,J=8.4,5.1Hz,1H),1.00–0.92(m,2H),0.70(dt,J=6.6,4.6Hz,2H).

[0408] Step 2: Synthesis of (R)-1-(3-cyclopropylphenyl)ethane-1,2-diol (Compound 53)

[0409]

[0410] 1-Cyclopropyl-3-vinylbenzene (0.56 mmol, 80 mg) was added to a 50 mL single-necked flask, and AD-mix-β (0.34 mmol, 261 mg) was added under ice bath conditions. The mixture was reacted overnight at room temperature with tert-butanol and water in a 1:1 ratio. After the reaction was complete, the mixture was extracted three times with ethyl acetate and water. The combined organic phases were concentrated and subjected to column chromatography (PE:EA = 5:1) to give (R)-1-(2-ethylpyridin-4-yl)ethane-1,2-diol (white solid, 40 mg, yield 40.0%).

[0411] 1H NMR(600MHz,Chloroform-d)δ7.14(t,J=7.6Hz,1H),7.02(dt,J=7.6,1.4Hz,1H ),6.99(t,J=1.8Hz,1H),6.89(dt,J=7.8,1.4Hz,1H),4.68(dd,J=8.5,3.3Hz,1H ),3.77-3.61(m,1H),3.55(dd,J=11.4,8.4Hz,1H),3.25-2.71(m,2H),1.80(tt ,J=8.4,5.1Hz,1H),0.89-0.85(m,2H),0.60(dt,J=6.7,4.7Hz,2H).LC-MS: Calculated value C 11 H 14 NO2[M+NH4] + :196.10, experimental value 196.15. ee value: 97.1%.

[0412] The following compounds (54-66) were all synthesized according to the steps ab above:

[0413] Synthesis of (R)-1-(2-ethylpyridin-4-yl)ethane-1,2-diol (Compound 54)

[0414]

[0415] 1 H NMR(600MHz,Chloroform-d)δ8.30(d,J=5.1Hz,1H),7.12(d,J=1.6Hz,1H),7.03(dd,J=5.3,1.7Hz,1H),5.00(d,J=11.9Hz,1H),4.73(dd, J=7.8,3.5Hz,1H),3.74(dd,J=11.4,3.5Hz,1H),3.56(dd,J=11.3,7.7Hz,1H),2.72(q,J=7.6Hz,2H),1.21(t,J=7.6Hz,3H).LC-MS: Calculated value C9H 13 NO2[M+H] + :168.09, experimental value 168.1. ee value: 93.0%.

[0416] Synthesis of (R)-1-(3-(trifluoromethyl)phenyl)ethane-1,2-diol (Compound 56)

[0417]

[0418] 1¹H NMR (600MHz, Chloroform-d) δ 7.47 (s, 1H), 7.41 (d, J = 7.6 Hz, 1H), 7.34 (d, J = 7.7 Hz, 1H), 7.30 (t, J = 7.7 Hz, 1H), 4.69 (dd, J = 8.4, 3.1 Hz, 1H), 3.59 (dd, J = 11.8, 3.1 Hz, 1H), 3.45 (dd, J = 11.6, 8.5 Hz, 1H). LC-MS: Calculated value C9H9F3O2[M+COOH] - :251.06, experimental value 251.1. ee value: 94.3%.

[0419] (R)-1-(3-(1,1-difluoroethyl)phenyl)ethane-1,2-diol (Compound 58)

[0420]

[0421] 1 ¹H NMR (600MHz, DMSO-d⁶) δ 7.53 (s, 1H), 7.45 (q, J = 4.2Hz, 1H), 7.42 (d, J = 4.6Hz, 2H), 5.35 (d, J = 4.4Hz, 1H), 4.75 (td, J = 5.8, 1.7Hz, 1H), 4.62–4.55 (m, 1H), 3.45 (dtd, J = 11.2, 5.8, 3.1Hz, 2H), 1.95 (t, J = 18.8Hz, 3H). LC-MS: Calculated C 10 H 12 F2O2[M+COOH] - Measured value: 247.08, actual value: 247.10. ee value: 94.0%.

[0422] (R)-1-(3-fluorophenyl)ethane-1,2-diol (Compound 59)

[0423]

[0424] 1 ¹H NMR (500MHz, Chloroform-d) δ 7.32 (td, J = 8.1, 6.0 Hz, 1H), 7.16–7.05 (m, 2H), 7.04–6.95 (m, 1H), 4.81 (dd, J = 8.3, 3.2 Hz, 1H), 3.76 (dd, J = 11.6, 3.2 Hz, 1H), 3.62 (dd, J = 11.4, 8.1 Hz, 1H). LC-MS: Calculated value C₈H₉FO₂[M+COOH] - Measured value: 201.06, Actual value: 201.05. EE value: 92.3%.

[0425] (R)-1-(2-chloro-5-(trifluoromethyl)phenyl)ethane-1,2-diol (Compound 60)

[0426]

[0427] 1 ¹H NMR (600MHz, Chloroform-d) δ 7.95–7.89 (m, 1H), 7.54–7.45 (m, 2H), 5.27 (dd, J = 7.7, 3.1 Hz, 1H), 3.95 (dd, J = 11.4, 3.1 Hz, 1H), 3.56 (dd, J = 11.3, 7.8 Hz, 1H). LC-MS: Calculated value C9H8ClF3O2[M+COOH] - :285.02, experimental value 285.0. ee value: 82.9%.

[0428] (R)-1-(4-chloro-3-(trifluoromethyl)phenyl)ethane-1,2-diol (Compound 61)

[0429]

[0430] 1 ¹H NMR (600MHz, DMSO-d⁶) δ 7.80 (d, J = 1.9 Hz, 1H), 7.70–7.63 (m, 2H), 4.64 (q, J = 5.5 Hz, 1H), 3.51 (dt, J = 11.3, 5.7 Hz, 1H), 3.43 (dt, J = 10.9, 5.9 Hz, 1H). LC-MS: Calculated value C₁₈H₈ClF₃O₂[M + COOH] - :285.02, experimental value 285.0. ee value: 91.6%.

[0431] (R)-1-(3,5-bis(trifluoromethyl)phenyl)ethane-1,2-diol (compound 62)

[0432]

[0433] 1 ¹H NMR (600MHz, Chloroform-d) δ 7.86 (s, 2H), 7.82 (s, 1H), 4.97 (dd, J = 7.8, 3.4Hz, 1H), 3.87 (dd, J = 11.2, 3.3Hz, 1H), 3.66 (dd, J = 11.2, 7.8Hz, 1H). LC-MS: Calculated C 10 H8F6O2[M+COOH] -:319.04, experimental value 319.00.

[0434] (R)-1-(2-fluoro-5-(trifluoromethyl)phenyl)ethane-1,2-diol (compound 63)

[0435]

[0436] 1 ¹H NMR (600MHz, Chloroform-d) δ 7.82 (dd, J = 6.6, 2.4Hz, 1H), 7.53 (ddd, J = 7.8, 4.7, 2.4Hz, 1H), 7.11 (t, J = 9.1Hz, 1H), 5.14 (dd, J = 8.1, 3.0Hz, 1H), 3.83 (dd, J = 11.5, 3.0Hz, 1H), 3.60 (dd, J = 11.5, 8.0Hz, 1H). LC-MS: Calculated value C9H8F4O2[M+COOH] - :269.04, experimental value 269.00. ee value: 94.0%.

[0437] (R)-1-(3-fluoro-5-(trifluoromethyl)phenyl)ethane-1,2-diol (compound 64)

[0438]

[0439] 1 ¹H NMR (600MHz, Chloroform-d) δ 7.42 (s, 1H), 7.29 (dt, J = 9.1, 1.9Hz, 1H), 7.25 (dt, J = 8.4, 2.0Hz, 1H), 4.86 (dd, J = 8.0, 3.4Hz, 1H), 3.80 (dd, J = 11.4, 3.4Hz, 1H), 3.61 (dd, J = 11.4, 8.0Hz, 1H). LC-MS: Calculated value C9H8F4O2[M+COOH] - :269.05, experimental value 269.1. ee value: 90.9%.

[0440] (R)-1-(3-ethyl-4-fluorophenyl)ethane-1,2-diol (Compound 65)

[0441]

[0442] 1¹H NMR (600MHz, DMSO-d⁶) δ 7.24 (dd, J = 7.7, 2.2Hz, 1H), 7.17 (ddd, J = 7.9, 5.1, 2.2Hz, 1H), 7.04 (dd, J = 10.2, 8.4Hz, 1H), 5.22 (d, J = 4.2Hz, 1H), 4.69 (t, J = 5.8Hz, 1H), 4.52–4.46 (m, 1H), 3.44–3.36 (m, 2H), 2.60 (q, J = 7.6Hz, 2H), 1.16 (t, J = 7.6Hz, 3H). LC-MS: Calculated C 10 H 13 FO2[M+COOH] - Measured value: 229.09, actual value: 229.10. ee value: 80.6%.

[0443] (R)-1-(3-ethyl-2-methylphenyl)ethane-1,2-diol (Compound 66)

[0444]

[0445] 1 H NMR(600MHz,Chloroform-d)δ7.36(d,J=7.6Hz,1H),7.18(t,J=7.6Hz,1H),7.13-7.09(m,1H),5.13(dd,J=8.6,3.0Hz,1H),3.7 3(dd,J=11.5,3.0Hz,1H),3.60(dd,J=11.5,8.5Hz,1H),2.74(d,J=2.6Hz,3H),2.65(q,J=7.5Hz,2H),2.26(s,3H).LC-MS: Calculated value C 11 H 16 O2[M+H] + :181.12, measured value 181.15.

[0446] Synthetic routes of compounds 67-69

[0447] The specific synthesis method of the above steps for CD is as follows:

[0448] Step 1: Synthesis of (2S,3S,4R,5S)-2-(acetoxymethyl)-6-((R)-2-(3-ethylphenyl)-2-hydroxyethoxy)tetrahydro-2H-pyran-3,4,5-trimethyltriacetate (compound 67)

[0449]

[0450] In a 100 mL single-necked round-bottom flask, (R)-1-(3-ethylphenyl)ethane-1,2-diol (0.80 mmol, 133 mg), bromosulin (0.80 mmol, 397 mg), Ag₂CO₃ (0.48 mmol, 132 mg), and silver trifluoromethanesulfonate (0.48 mmol, 123 mg) were added sequentially. After stirring for 24 h, the reaction progress was monitored by TLC. After the reaction was completed, the mixture was filtered, and the solvent was removed by rotary evaporation. Column chromatography (PE:EA = 5:1) yielded the corresponding intermediate (2S,3S,4R,5S)-2-(acetoxymethyl)-6-((R)-2-(3-ethylphenyl)-2-hydroxyethoxy)tetrahydro-2H-pyran-3,4,5-trimethyltriacetate (119 mg, yield 30.0%).

[0451] Synthesis of (3S,4R,5R,6S)-2-((R)-2-(3-ethylphenyl)-2-hydroxyethoxy)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (Compound 67)

[0452]

[0453] In a 100 mL single-round-bottom flask, intermediate (2S,3S,4R,5S)-2-(acetoxymethyl)-6-((R)-2-(3-ethylphenyl)-2-hydroxyethoxy)tetrahydro-2H-pyran-3,4,5-trimethyltriacetate (0.24 mmol, 119 mg), potassium carbonate (0.24 mmol, 33 mg), and dichloro / methanol (1:1) were added sequentially. The reaction progress was monitored by TLC. After the reaction was completed, the mixture was concentrated by rotary evaporation and separated using a reverse-phase column (35 mg, yield 45.0%).

[0454] 1 ¹H NMR (500MHz, DMSO-d⁶) δ 7.37–6.94 (m, 4H), 5.38–4.39 (m, 6H), 4.12 (m, 1H), 3.81–3.42 (m, 4H), 3.23–2.84 (m, 4H), 2.59 (q, J = 7.6 Hz, 2H), 1.18 (td, J = 7.6, 2.3 Hz, 3H). LC-MS: Calculated C 16 H 24 O7[M+NH4] + Measured value: 346.18, actual value: 346.20. ee value: 82.2%.

[0455] The following compounds (68-69) were all synthesized according to the method described in step cd above:

[0456] (2R,3R,4R,5S)-6-((R)-2-(3-ethylphenyl)-2-hydroxyethoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid (Compound 68)

[0457]

[0458] 1 ¹H NMR (400MHz, DMSO-d⁶) δ 7.28–7.05 (m, 4H), 6.72 (s, 1H), 5.73 (d, J = 3.6 Hz, 1H), 5.20–4.92 (m, 2H), 4.84–4.61 (m, 1H), 4.32–4.05 (m, 1H), 3.75–3.56 (m, 2H), 3.27 (dd, J = 14.8, 8.9 Hz, 1H), 3.21–3.08 (m, 3H), 3.02 (td, J = 8.1, 3.7 Hz, 1H), 2.59 (q, J = 7.6 Hz, 2H), 1.17 (t, J = 7.6 Hz, 3H). LC-MS: Calculated C 16 H 22 O8[M+NH4] + 360.16, measured value 360.20.

[0459] (2S,3R,4S,5R,6R)-2-(((2S,4S,5S)-6-((R)-2-(3-ethylphenyl)-2-hydroxyethoxy)-4,5-dihydroxy-2-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)oxy)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (Compound 69)

[0460]

[0461] 1 ¹H NMR (500MHz, DMSO-d⁶) δ 7.29–7.05 (m, 4H), 5.24–5.16 (m, 2H), 5.07–4.94 (m, 2H), 4.81–4.55 (m, 4H), 4.38–4.21 (m, 2H), 3.85–3.51 (m, 5H), 3.47–3.38 (m, 1H), 3.34–3.12 (m, 6H), 3.12–2.94 (m, 3H), 2.59 (q, J = 7.6 Hz, 2H), 1.18 (td, J = 7.6, 1.6 Hz, 3H). LC-MS: Calculated C 22 H 34 O 12 [MH] - 489.20. Measured value [MH] - :489.30.

[0462] ee value testing method: The ee value analysis of all final compounds was performed on an Agilent 1260 Infinity series instrument using a CHIRALCEL OD-H, 4.6 mm × 250 mm, at a flow rate of 0.5 mL / min, with 90% n-hexane / 10% ethanol as the solvent.

[0463] Literature reference: Bolli MH, Abele S, Binkert C, et al. 2-imino-thiazolidin-4-onederivatives as potent, orally active S1P1 receptor agonists[J]. Journal of medical chemistry, 2010, 53(10): 4198-4211.

[0464] Experimental Example 2. Activity test of compound 1 against obesity-related diseases

[0465]

[0466] 2.1. The preventive effect of compound 1 on high-fat diet-induced obesity in mice (first batch of DIO mouse weight loss experiments)

[0467] NFD: Normal chow diet; HFD: High fat diet (D12492, Research Diet).

[0468] The experiment was divided into 4 groups: randomly assigned to each group of 8 Male C57BL / 6J mice (5-week-old mice were purchased, acclimatized for 1 week, and divided into cages of 2-3 mice before the experiment). The experimental design, grouping, and drug dosage were as follows. Figure 1 The drug was mixed into the food and fed to the patient. The original experimental period was 8 weeks.

[0469] Experimental procedure:

[0470] Feeding intensity (FIT) and body weight (BW) were recorded every 3 days. Based on the latest body weight, feed was prepared every 7 days (with the drug mixed in the food). In the first week, the calculated weight gain after drug administration was approximately 1g. For example, if the average body weight before the experiment was 23g, based on previous experience, the mice's weight might increase by 2g, so the calculated weight for the total drug administration was 24g. The mixed food was stored at -20°C, and the drug-infused food was added every 3-4 days. After 8 weeks, the mice were euthanized, and blood, liver, spleen, kidney, epididymal fat, perirenal fat, palm fat, and hypothalamus were collected (5 mice were used for Western blot analysis, and 3 for immunofluorescence).

[0471] Transaminase and blood lipid detection: Blood was collected from the eyeballs, allowed to stand at room temperature for 2 hours, and then centrifuged at 2000 rpm for 20 minutes. Serum was collected, and blood lipid components (low-density lipoprotein cholesterol LDL-C, high-density lipoprotein cholesterol HDL-C, total cholesterol TC, and triglycerides TG) and liver function indicators (alanine aminotransferase ALT and aspartate aminotransferase AST) were measured using a Hitachi fully automated biochemical analyzer (model: Hitachi 3100).

[0472] The experimental results are summarized in the table below:

[0473] Table 1. Inhibitory effect of compound 1 on body weight in high-fat diet-induced obese mice

[0474]

[0475] Compared with HFD, *P<0.05, **P<0.01, ***P<0.001.

[0476] Four weeks later, a significant difference in body weight was observed between the high-fat diet (HFD) group and the normal diet (NFD) group, and treatment with both doses of compound 1 inhibited HFD-induced weight gain. After eight weeks of feeding, the body weight of the HFD mice increased by 39.58% compared to the NFD group. The weight gain of mice on the high-fat diet supplemented with compound 1 was significantly lower than that of the HFD mice, and the effect increased with increasing compound 1 concentration. The body weight of mice treated with HFD + compound 1 at 10 mg / kg body weight and those treated with HFD + compound 1 at 150 mg / kg body weight was reduced by 23.63% and 26.95%, respectively, compared to the HFD mice. Therefore, the addition of compound 1 significantly inhibited HFD-induced obesity in mice.

[0477] Table 2. Effect of Compound 1 on food conversion rate (weight gain in mice / food intake)

[0478]

[0479] Compared with HFD, ***P < 0.001.

[0480] Table 2 shows the food conversion rate of mice in each group. The food conversion rate of the HFD group was 4.10 times that of the NFD group. The food conversion rates of mice with compound 1 at 10 mg / kg body weight and mice with HFD + compound 1 at 50 mg / kg body weight were 1.79 times and 1.36 times that of the NFD group, respectively. It can be seen that compound 1 can significantly inhibit the high food conversion rate induced by HFD.

[0481] Table 3. Effects of Compound 1 on fat distribution in different parts of high-fat diet-induced obese mice.

[0482]

[0483] Compared with HFD, ***P < 0.001.

[0484] Table 2 shows the fat weight at different locations in each group of mice. The weight of epididymal fat, subcutaneous fat, perirenal fat, and brown fat in HFD+compound 1 mice was significantly reduced compared with the HFD group.

[0485] Table 4. Effects of Compound 1 on the kidneys and spleen of mice induced by a high-fat diet.

[0486]

[0487] Compared with HFD, **P<0.01, ***P<0.001.

[0488] Table 4 records the weight of the kidneys and spleen of mice in each group. Compared with the NFD group, the weight of the kidneys and spleen of mice fed with HFD for 8 weeks did not increase significantly, while the weight of the kidneys and spleen of mice treated with compound 1 decreased, especially in the high-dose group.

[0489] Table 5. Effects of Compound 1 on blood lipids and transaminases in high-fat diet-induced obese mice.

[0490]

[0491] Compared with HFD, *P<0.05, **P<0.01, ***P<0.001.

[0492] The serum biochemical indicators of each group of mice are shown in Table 5. The serum CHO, LDL-C and ALT of HFD+ compound 1 mice were significantly lower than those of HFD mice, while there was no significant effect on serum TG and HDL-C.

[0493] Table 6. Effects of Compound 1 on triglycerides (TG) in the liver of high-fat diet-induced obese mice

[0494]

[0495] Compared with HFD, ***P < 0.001.

[0496] The results of TG detection in mouse liver showed that HFD significantly increased the TG content in the liver, while compound 1 significantly inhibited the accumulation of TG in the liver, and the effect increased with the increase of compound 1 concentration.

[0497] The results in Tables 5 and 6 indicate that compound 1 can reduce the elevation of CHO, LDL-C, ALT in mouse serum and TG in liver induced by HFD, and has a good preventive effect on obesity-related hyperlipidemia and liver lipid accumulation, and can play a protective role for the liver.

[0498] 2.2. The preventive effect of compound 1 on high-fat diet-induced obesity in mice (second batch of DIO mouse weight loss experiment)

[0499] NFD: Normal chow diet; HFD: High fat diet (D12492, Research Diet); LOR: Lorcaserin; ORL: Orlistat.

[0500] The experiment consisted of 8 groups: randomly assigned to 10 Male C57BL / 6J mice per group (5-week-old mice were purchased, acclimatized for 1 week, and divided into cages of 3-4 mice before the experiment). The experimental design, grouping, and drug dosage were as follows. Figure 2 The drug was mixed into food and fed to the patient for 8 weeks.

[0501] Experimental procedure:

[0502] Feeding and weight were recorded every 7 days, and feeding was adjusted every 7 days based on the latest weight. Body fat content was measured in the 8th week, after which the mice were euthanized, and blood, liver, heart, lungs, spleen, kidneys, epididymal fat, inguinal white fat, perirenal fat, subcutaneous fat, palm fat, and hypothalamus were collected (7 mice were used for Western blot analysis, and 3 for immunofluorescence).

[0503] 1) The body fat, lean meat and free water content of mice were detected using a low-field nuclear magnetic resonance small animal body composition analyzer (Suzhou Newmai, QMR06-060H).

[0504] 2) Transaminase and blood lipid detection: LDL-C, HDL-C, TC, TG, ALT and AST in serum were measured using a Hitachi fully automated biochemical analyzer (model: Hitachi 3100).

[0505] Experimental results:

[0506] Table 7. Inhibitory effect of compound 1 on body weight in high-fat diet-induced obese mice

[0507] Compared with HFD, *P<0.05, **P<0.01, ***P<0.001.

[0508] One week later, the body weight of mice in the high-fat diet (HFD) group was significantly different from that in the normal diet (NFD) group. Two weeks later, the low- and medium-dose groups of LOR, ORL, and compound 1 showed significant differences compared to the HFD group. After eight weeks of feeding, the body weight of the two positive control drugs (LOR and ORL) and the three doses of compound 1 treatment groups were significantly different from that of the HFD group. Furthermore, the weight loss effect of each dose of compound 1 was similar to that of the two positive control drugs, and its anti-obesity effect increased with increasing concentration of compound 1. Therefore, the addition of compound 1 can significantly inhibit HFD-induced obesity in mice.

[0509] Table 8. Effect of Compound 1 on food conversion rate (weight gain in mice / food intake)

[0510] Compared with HFD, ***P < 0.001.

[0511] Table 8 shows the food conversion rate of mice in each group. The food conversion rate of the HFD group was 6.14 times that of the NFD group. The food conversion rates of mice with compound 1 at 1 mg / kg body weight, 10 mg / kg body weight, and HFD + compound 1 at 50 mg / kg body weight were 4.26, 4.18, and 4.06 times that of the NFD group, respectively. It can be seen that compound 1 can significantly inhibit the high food conversion rate induced by HFD.

[0512] Table 9. Effects of Compound 1 on fat and muscle content in high-fat diet-induced obese mice

[0513]

[0514] Compared with HFD, *P<0.05, **P<0.01, ***P<0.001.

[0515] Table 2 shows the fat weight at different locations in each group of mice. The weight of epididymal fat, subcutaneous fat, perirenal fat, brown fat, and total fat content of HFD+compound 1 mice were significantly reduced compared with the HFD group, while the lean meat content was significantly higher than that of the HFD group.

[0516] Table 10. Effects of Compound 1 on the kidneys and spleen of mice induced by a high-fat diet. Compared with HFD, *P<0.05, **P<0.01.

[0517] Table 10 records the weight of the kidneys and spleen of mice in each group. Compared with the NFD group, the weight of the kidneys and spleen of mice fed with HFD for 8 weeks increased significantly. Except for the low-dose group of compound 1, where the kidneys were significantly lighter, the weight of the kidneys and spleen of mice treated with compound 1 in other groups did not change significantly.

[0518] Table 11. Effects of Compound 1 on blood lipids and transaminases in high-fat diet-induced obese mice. Compared with HFD, *P<0.05, **P<0.01, ***P<0.001.

[0519] The serum biochemical indicators of each group of mice are shown in Table 5. The two positive control drugs, LOR and ORL, can significantly reduce the levels of CHO and TG in the serum of mice induced by HFD. Compound 1 can also inhibit the rise of CHO and TG levels in the serum of mice. In particular, its inhibitory effect on the increase of CHO, TG, ALT and AST levels in the serum of mice induced by HFD is better than that of LOR and ORL at the same dose.

[0520] Table 12. Effects of Compound 1 on triglycerides (TG) in the liver of high-fat diet-induced obese mice. Compared with HFD, ***P < 0.001.

[0521] The results of TG detection in mouse liver showed that HFD significantly increased the TG content in the liver, while compound 1 significantly inhibited the accumulation of TG in the liver, and the effect increased with the increase of compound 1 concentration.

[0522] The results in Tables 11 and 12 indicate that compound 1 can reduce the elevation of CHO, ALT, TG in serum and TG in liver of mice induced by HFD, and has a good preventive effect on obesity-related hyperlipidemia and liver lipid accumulation, as well as a good liver protective effect.

[0523] Experimental Example 3

[0524] Following the experiment in Example 2, the inventors conducted activity tests against obesity-related diseases using optically pure compounds 1-R and 1-S obtained in Example 1.

[0525] The results showed that compound 1-S had a better weight loss effect than compound 1 and compound 1-R.

[0526] Experimental Example 4. Testing of other compounds for obesity-related diseases (weight)

[0527] Following the experiment in Example 2, the inventors repeated the above experimental method using other compounds, and the results are shown in the table below:

[0528] Table 13. Effects of a series of derivatives on body weight in high-fat diet-induced obese mice

[0529]

[0530]

[0531] The data in the table show that the high-fat fed mice gained a significant amount of weight within 8 weeks, from 20 grams to approximately 35 grams. After adding the compounds of this invention, some mice showed good weight control; for example, compound 1-S almost maintained a normal weight, demonstrating excellent weight loss. Generally, compared to high-fat fed mice, a weight control of less than 30 grams is considered to have a good weight loss effect.

[0532] All documents mentioned in this invention are incorporated herein by reference as if each document were individually incorporated by reference. Furthermore, it should be understood that after reading the foregoing teachings of this invention, those skilled in the art can make various alterations or modifications to this invention, and these equivalent forms also fall within the scope defined by the appended claims.

Claims

1. The use of the compound of Formula I, or a pharmaceutically acceptable salt or ester, prodrug, optical isomer, stereoisomer, or solvate thereof, in the preparation of a medicament for the prevention or treatment of obesity and related diseases. In the formula, A is selected from C6-C10 aromatic rings or carbon rings, or 5-6 membered heterocycles or aromatic heterocycles containing 1, 2 or 3 heteroatoms selected from N, O or S; R1 and R4 are each independently selected from H, D, OH, carbonyl, optionally substituted C1-C10 alkyl, optionally substituted C1-C10 alkoxy, optionally substituted phenoxy, optionally substituted benzyloxy, optionally substituted NH2, NHCH3, NHCOCH3, halogen, optionally substituted C1-C10 alkylformyloxy, optionally substituted benzoyloxy, optionally substituted aminoacetoxy ( B can be any group that forms amino acids, or an optionally substituted monosaccharide, disaccharide, or polysaccharide group; R2 and R5 are each independently selected from H, D, OH, carbonyl, hydroxymethyl, optionally substituted C1-C10 alkyl, optionally substituted C1-C10 alkoxy, optionally substituted benzyloxy, optionally substituted phosphate ester, optionally substituted NH2, NHCH3, NHCOCH3, optionally substituted C1-C10 formyloxy, optionally substituted benzoyloxy, optionally substituted aminoacetoxy ( B can be any of the groups that form amino acids, such as COOH, COOCH3, CONH2, and sulfonic acid groups. (or sulfonates), halogens, optionally substituted monosaccharides, disaccharides or polysaccharides; or, R1 and R2 or R4 and R5 are linked to form an optionally substituted 3-6 member ring containing 0, 1 or 2 heteroatoms selected from oxygen, nitrogen or sulfur (preferably oxygen), such as a cyclic carbonate lactone, phosphate lactone or optionally substituted cyclic borate lactone. R3 is selected from H, D, optionally substituted C1-C10 alkyl, D-substituted C1-C10 alkyl, optionally substituted C3-C10 cycloalkyl, optionally substituted 3-6-membered ring containing 1 or 2 heteroatoms selected from O, S or N, optionally substituted C2-C10 alkylalkenyl, hydroxyl, optionally substituted C1-C10 alkoxy, optionally substituted C1-C10 alkylthio, optionally substituted C1-C10 alkylformyloxy, optionally substituted C1-C10 acyl, hydroxyformyl, optionally substituted C1-C10 alkylformyloxy, nitro, optionally substituted amino, optionally substituted C1-C10 alkylamino, optionally substituted C1-C10 alkylformylamino, halogen, optionally substituted C2-6 alkynyl, optionally substituted monosaccharide, disaccharide or polysaccharide. or, Two adjacent R3 substituents form an optionally substituted C3-C6 carbon ring or an optionally substituted C3-C6 heterocycle containing one or two heteroatoms selected from oxygen, nitrogen or sulfur (preferably oxygen or nitrogen), an optionally substituted C5-C10 aromatic ring or an optionally substituted C5-C10 heteroaromatic ring containing one or two heteroatoms selected from oxygen, nitrogen or sulfur (preferably oxygen or nitrogen); m is an integer from 1 to 5; In the structure of Formula I, hydrogen may be optionally replaced by deuterium.

2. The use as described in claim 1, characterized in that, The compound shown in Formula I is the same as the compound shown in Formula II. In the formula, X1, X2, and X3 are each independently selected from CH, N, S, or O (preferably CH or N); R1 and R4 are independently selected from H, D, OH, optionally substituted C1-C10 alkoxy, optionally substituted phenoxy, optionally substituted benzyloxy, optionally substituted NH2, NHCH3, NHCOCH3, optionally substituted C1-C10 alkylformyloxy, optionally substituted benzoyloxy, optionally substituted carbamoyloxy, optionally substituted monosaccharide, disaccharide or polysaccharide. R2 and R5 are each independently selected from H, D, OH, hydroxymethyl, optionally substituted C1-C10 alkyl, optionally substituted C1-C10 alkoxy, optionally substituted benzyloxy, NH2, NHCH3, NHCOCH3, optionally substituted C1-C10 alkylformyloxy, optionally substituted benzoyloxy, optionally substituted carbamoyloxy, COOH, COOCH3, CONH2, optionally substituted monosaccharide, disaccharide or polysaccharide. R1 and R2 can form 3-6 membered rings with optional substitutions containing 0, 1 or 2 heteroatoms selected from oxygen, nitrogen or sulfur (preferably oxygen); R3 is selected from H, D, optionally substituted C1-C10 alkyl, D-substituted C1-C10 alkyl, optionally substituted C3-C10 cycloalkyl, optionally substituted 3-6-membered ring containing 1 or 2 heteroatoms selected from O, S or N, optionally substituted C1-C10 alkylalkenyl, hydroxyl, optionally substituted C1-C10 alkoxy, optionally substituted C1-C10 alkylthio, optionally substituted C1-C10 alkylformyloxy, formyl, hydroxyformyl, optionally substituted C1-C10 alkylformyloxy, nitro, optionally substituted amino, optionally substituted C1-C10 alkylamino, optionally substituted C1-C10 alkylformylamino, halogen, optionally substituted monosaccharide, disaccharide or polysaccharide. Alternatively, it may be a C3-C6 carbon ring formed by two adjacent R3 substituents or a C3-C6 heterocycle containing one or two heteroatoms selected from oxygen or nitrogen; m is an integer from 1 to 5; In the structure of Formula II, hydrogen may be optionally replaced by deuterium.

3. The use as described in claim 1, characterized in that, The compound shown in Formula I is the same as the compound shown in Formula III. In the formula, X is selected from CH or N; R1 and R4 are independently selected from H, D, OH, optionally substituted C1-C10 alkoxy, optionally substituted phenoxy, optionally substituted benzyloxy, optionally substituted NH2, NHCH3, NHCOCH3, optionally substituted C1-C10 formyloxy, optionally substituted benzoyloxy, optionally substituted carbamoyloxy, optionally substituted aminoacetoxy. B can be any group that forms amino acids, or an optionally substituted monosaccharide, disaccharide, or polysaccharide group; R2 and R5 are each independently selected from H, D, hydroxymethyl, optionally substituted C1-C10 alkyl, OH, optionally substituted C1-C10 alkoxy, optionally substituted benzyloxy, NH2, NHCH3, NHCOCH3, optionally substituted C1-C10 alkylformyloxy, optionally substituted benzoyloxy, optionally substituted carbamoyloxy, optionally substituted aminoacetoxy. B can be any group that forms amino acids, such as COOH, COOCH3, CONH2, or optionally substituted monosaccharides, disaccharides, or polysaccharides. R1 and R2 can form 3-6 membered rings with optional substitutions containing 0, 1 or 2 heteroatoms selected from oxygen, nitrogen or sulfur (preferably oxygen); R3 is selected from H, D, optionally substituted C1-C10 alkyl, D-substituted C1-C10 alkyl, optionally substituted C3-C10 cycloalkyl, optionally substituted 3-6-membered ring containing 1 or 2 heteroatoms selected from O, S or N, optionally substituted C2-C10 alkylalkenyl, hydroxyl, optionally substituted C1-C10 alkoxy, optionally substituted C1-C10 alkylthio, optionally substituted C1-C10 alkylformyloxy, formyl, hydroxyformyl, optionally substituted C1-C10 alkylformyloxy, nitro, amino, optionally substituted C1-C10 alkylamino, optionally substituted C1-C10 alkylformamide, fluorine, chlorine, bromine, optionally substituted monosaccharide, disaccharide or polysaccharide. Alternatively, two adjacent R3 substituents may form an optionally substituted C3-C6 carbocyclic ring or an optionally substituted C3-C6 heterocyclic ring containing one or two oxygen atoms; m is an integer from 1 to 5; In the structure of Formula III, hydrogen may be optionally replaced by deuterium.

4. The use as described in claim 1, characterized in that, The compound is shown in Formula IV. In the formula, X is selected from CH or N; R1 is selected from H, D, OH, NH2, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkylformyloxy, optionally substituted carbamoyloxy, optionally substituted aminoacetoxy. B can be any group that forms amino acids, or an optional substituted monosaccharide group; R2 is selected from OH, NH2, COOH, COONH2, COONHCH3, optionally substituted C1-C3 alkoxyformyl, optionally substituted C1-C3 alkylformyloxy, optionally substituted carbamoyloxy, optionally substituted aminoacetoxy. B can be any group that forms amino acids, or an optional substituted monosaccharide group; R3 is selected from H, D, optionally substituted C1-C5 alkyl, D-substituted C3-C5 cycloalkyl, optionally substituted 3-6-membered ring containing 1 or 2 O, optionally substituted C2-C10 alkylalkenyl, hydroxyl, optionally substituted C1-C5 alkoxy, optionally substituted C1-C3 alkylthio, optionally substituted C1-C3 alkylformyloxy, formyl, optionally substituted C1-C3 alkylformyl, hydroxyformyl, nitro, amino, optionally substituted C1-C3 alkylamino, optionally substituted C1-C3 alkylformylamino, fluorine, chlorine, and bromine; Alternatively, two adjacent R3 substituents may form an optionally substituted C3-C6 carbocyclic ring or an optionally substituted C3-C6 heterocyclic ring containing one or two oxygen atoms; m is an integer between 1 and 3; In the structure of Formula IV, hydrogen may be optionally replaced by deuterium.

5. The use as described in claim 1, characterized in that, In the formula, A is selected from phenyl; R1 and R4 are independently selected from H, D, OH, and optionally substituted C1-C6 alkoxy groups, respectively; R2 and R5 are independently selected from H, D, OH, optionally substituted C1-C6 alkoxy, and optionally substituted C1-C6 formyloxy, respectively; or R1 and R2 or R4 and R5 are linked to form a cyclic carbonate lactone containing 0, 1 or 2 heteroatoms selected from oxygen, nitrogen or sulfur (preferably oxygen) in a 3-6 member ring with optional substitution. R3 is selected from H, D, optionally substituted C1-C6 alkyl, D-substituted C1-C6 alkyl, optionally substituted C2-C6 alkyl alkenyl, optionally substituted C1-C6 acyl; or, Two adjacent R3 substituents form an optionally substituted C3-C6 carbon ring or an optionally substituted C3-C6 heterocycle containing one or two heteroatoms selected from oxygen, nitrogen or sulfur (preferably oxygen or nitrogen); m is an integer between 1 and 3; In the structure of Formula I, hydrogen may be optionally replaced by deuterium.

6. The use as described in any one of claims 1-5, characterized in that, "Optionally substituted" means that the group modified by the term is replaced by C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, hydroxyl, halogen, amino, nitro, or acetyl groups.

7. Use of the following compounds, or their salts or esters, prodrugs, optical isomers or solvates, in the preparation of medicaments for the prevention and treatment of obesity and related diseases: Preferably, the compound is More preferably, the compound is selected from the group consisting of:

8. The use as described in any one of claims 1-7, characterized in that, The obesity and related diseases mentioned include obesity-related diseases caused by various etiologies, including but not limited to various clinical conditions such as overweight and hyperlipidemia.

9. A method for the prevention and treatment of obesity and related diseases, the method comprising the step of administering a preventive and therapeutically effective amount of the compound of claims 1-8 or a pharmaceutical composition comprising the compound to a subject in need.

10. The method as described in claim 9, characterized in that, The subject is a mammal, including but not limited to humans, pets, racing animals, and livestock; preferably, the subject is a human.

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