Polyol derivative as TRPV4 antagonist and application thereof

Abstract

The invention discloses application of a compound as shown in a formula I, or pharmaceutically acceptable salt or ester, a prodrug, an optical isomer, a stereoisomer or a solvate of the compound as a TRPV4 inhibitor or antagonist and treatment of TRPV4 related diseases. The compound shows an excellent TRPV4 inhibitory activity effect, so that a brand-new material basis is laid for developing drugs for treating TRPV4 related diseases.

Description

Technical Field

[0001] The present invention belongs to the field of medicinal chemistry and specifically relates to novel polyol derivatives, their synthesis methods and their use as TRPV4 antagonists in the preparation of drugs for treating TRPV4-related diseases or antagonizing TRPV4. Background Art

[0002] TRPV4 (transient receptor potential vanilloid 4) is a 20-amino acid stretch at the C-terminus of the transient receptor potential ion channel that serves as a "folding recognition region," playing a crucial role in the dynamic regulation of channel protein maturation, membrane surface expression, and function. A key member of the transient receptor potential superfamily, TRPV4 has been shown over the past decade to be widely present in vascular smooth muscle, endothelial cells, alveolar epithelial cells, and bronchi, and plays a crucial role in the pathophysiology of lung diseases.

[0003] TRPV4 acts as a signal integrator, triggering the opening of voltage-gated ion channels via calcium ions, thereby initiating a multitude of intracellular events and ultimately leading to specific tissue responses. TRPV4 is a multimodal, non-selective cation channel with high Ca2+ permeability. It is expressed in the nervous system, respiratory system, kidney, and skin, and responds to high osmotic pressure, moderate heat, mechanical stress, and acidic pH levels. This channel is involved in the regulation of key physiological processes, including calcium signaling, temperature perception, cell volume maintenance, and energy homeostasis. Given the widespread distribution and physiological significance of TRPV4, its dysfunction has been implicated in the pathogenesis of a variety of diseases.

[0004] Lipopolysaccharide (LPS) is a common trigger of acute lung injury (ALI) and is often used to establish ALI models. Pulmonary edema and extensive inflammatory exudates are among its primary pathophysiological hallmarks. Studies have shown that blocking TRPV4 signaling can mitigate LPS-induced ALI inflammation and exert a protective effect in ALI mice, including improving lung pathology and reducing pulmonary edema and inflammation. Therefore, TRPV4 may become a new target for ALI treatment in the future.

[0005] Research aimed at developing TRPV4 antagonists for therapeutic use has flourished. The TRPV4 small molecule antagonists under development mainly include quinoline, spirocarbamate, and pyrrolidinesulfonamide antagonists developed by GlaxoSmithKline, but there are currently no drugs targeting TRPV4 on the market.

[0006] Therefore, research and development of drugs that antagonize TRPV4 have important clinical significance and application prospects. Summary of the Invention

[0007] The object of the present invention is to provide polyol derivatives as TRPV4 antagonists.

[0008] Another object of the present invention is to reveal the mechanism by which the above compounds antagonize TRPV4.

[0009] Another object of the present invention is to provide the use of the above-mentioned compound in the preparation of drugs for treating TRPV4-related diseases or antagonizing TRPV4.

[0010] In a first aspect, the present invention provides a compound of formula I, or a pharmaceutically acceptable salt or ester, prodrug, optical isomer, stereoisomer or solvate thereof, for use in the preparation of a TRPV4 inhibitor or antagonist.

[0011]

[0012] Where,

[0013] A is selected from a C6-C10 aromatic ring or carbocyclic ring, or a 5-6 membered heterocyclic ring or aromatic heterocyclic ring containing 1, 2 or 3 heteroatoms selected from N, O or S;

[0014] R1 and R4 are 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 may be various amino acid-forming groups), optionally substituted monosaccharide, disaccharide or polysaccharide groups;

[0015] R2 and R5 are independently selected from H, D, OH, carbonyl, hydroxymethyl, optionally substituted C1-C10 alkyl, optionally substituted C1-C10 alkoxy, optionally substituted benzyloxy, optionally substituted phosphate, optionally substituted NH2, NHCH3, NHCOCH3, optionally substituted C1-C10 formyloxy, optionally substituted benzoyloxy, optionally substituted aminoacetoxy ( B can be various amino acid forming groups), COOH, COOCH3, CONH2, sulfonic acid group, oxygen group or sulfonate), halogen, optionally substituted monosaccharide, disaccharide or polysaccharide groups;

[0016] or

[0017] R1 and R2 or R4 and R5 are linked to form an optionally substituted 3-6 membered ring containing 0, 1 or 2 heteroatoms (preferably oxygen) selected from oxygen, nitrogen or sulfur, a cyclic carbonate lactone, a phosphate lactone or an optionally substituted cyclic borate lactone;

[0018] 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, hydroxy, 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;

[0019] or,

[0020] Two adjacent R3 substituents form an optionally substituted C3-C6 carbocycle or an optionally substituted C3-C6 heterocycle containing 1 or 2 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 1 or 2 heteroatoms selected from oxygen, nitrogen or sulfur (preferably oxygen or nitrogen);

[0021] m is an integer from 1 to 5;

[0022] The hydrogens in the structures of Formula I are optionally deuterated.

[0023] In a specific embodiment, the compound of formula I is a compound of formula II,

[0024]

[0025] Where,

[0026] X1, X2, X3 are each independently selected from CH, N, S or O (preferably CH or N);

[0027] 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;

[0028] R2 and R5 are 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 group;

[0029] R1 and R2 may form an optionally substituted 3-6 membered ring containing 0, 1 or 2 heteroatoms (preferably oxygen) selected from oxygen, nitrogen or sulfur;

[0030] 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, hydroxy, 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;

[0031] or two adjacent R3 substituents form an optionally substituted C3-C6 carbocycle or an optionally substituted C3-C6 heterocycle containing 1 or 2 heteroatoms selected from oxygen or nitrogen;

[0032] m is an integer from 1 to 5;

[0033] The hydrogen atoms in the structure of formula II are optionally deuterated.

[0034] In a specific embodiment, the compound of formula I is a compound of formula III

[0035]

[0036] Where,

[0037] 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 may be various amino acid-forming groups), optionally substituted monosaccharide, disaccharide or polysaccharide groups;

[0038] R2 and R5 are 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 various amino acid forming groups), COOH, COOCH3, CONH2, optionally substituted monosaccharide, disaccharide or polysaccharide groups;

[0039] R1 and R2 may form an optionally substituted 3-6 membered ring containing 0, 1 or 2 heteroatoms (preferably oxygen) selected from oxygen, nitrogen or sulfur;

[0040] 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, hydroxy, 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 alkylformylamino, fluorine, chlorine, bromine, optionally substituted monosaccharide, disaccharide or polysaccharide;

[0041] Alternatively, two adjacent R3 substituents form an optionally substituted C3-C6 carbocycle or an optionally substituted C3-C6 heterocycle containing 1 or 2 oxygens;

[0042] m is an integer from 1 to 5;

[0043] The hydrogen atoms in the structure of formula III are optionally deuterated.

[0044] In a specific embodiment, the compound is as shown in Formula IV,

[0045]

[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 may be various groups forming amino acids), optionally substituted monosaccharide groups;

[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 may be various groups forming amino acids), optionally substituted monosaccharide groups;

[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, hydroxy, 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, bromine;

[0049] Alternatively, two adjacent R3 substituents form an optionally substituted C3-C6 carbocycle or an optionally substituted C3-C6 heterocycle containing 1 or 2 oxygens;

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

[0051] The hydrogen atoms in the structure of formula IV are optionally deuterated.

[0052] In a preferred embodiment, "optionally substituted" means that the group modified by the term is substituted by C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, hydroxy, halogen, amino, nitro, or acetyl.

[0053] In a specific embodiment, wherein,

[0054] A is selected from phenyl;

[0055] R1 and R4 are independently selected from H, D, OH, and optionally substituted C1-C6 alkoxy;

[0056] R2 and R5 are independently selected from H, D, OH, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 formyloxy;

[0057] or

[0058] R1 and R2 or R4 and R5 are linked to form an optionally substituted 3-6 membered ring containing 0, 1 or 2 heteroatoms (preferably oxygen) selected from oxygen, nitrogen or sulfur, a cyclic carbonate lactone;

[0059] R3 is selected from H, D, optionally substituted C1-C6 alkyl, D-substituted C1-C6 alkyl, optionally substituted C2-C6 alkylalkenyl, optionally substituted C1-C6 acyl;

[0060] or,

[0061] Two adjacent R3 substituents form an optionally substituted C3-C6 carbocycle or an optionally substituted C3-C6 heterocycle containing 1 or 2 heteroatoms selected from oxygen, nitrogen or sulfur (preferably oxygen or nitrogen);

[0062] m is an integer from 1 to 3;

[0063] The hydrogens in the structures of Formula I are optionally deuterated.

[0064] In a specific embodiment, the compound is the following compound, or a salt or ester, prodrug, optical isomer or solvate thereof:

[0065]

[0066]

[0067]

[0068]

[0069]

[0070]

[0071] Preferably, the compound is

[0072]

[0073]

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

[0075]

[0076]

[0077] In a preferred embodiment, the TRPV4 inhibitor or antagonist is a drug for preventing or treating TRPV4-related diseases.

[0078] In a preferred embodiment, the TRPV4-related disease is a lung disease (acute lung injury, asthma, pulmonary fibrosis, cough and chronic obstructive pulmonary disease), a gastrointestinal disease (Crohn's disease and colitis), a bladder disease (including overactive bladder and interstitial cystitis), an eye disease (glaucoma and diabetic retinopathy), a cerebral edema, or a disease such as itching; preferably a lung disease; more preferably acute lung injury.

[0079] In a second aspect, the present invention provides a compound of formula I, or a pharmaceutically acceptable salt or ester, prodrug, optical isomer, stereoisomer or solvate thereof,

[0080]

[0081] Where,

[0082] A is selected from an optionally substituted C6-C10 aromatic ring or a 5-6 membered aromatic heterocycle containing 1, 2 or 3 heteroatoms selected from N, O or S;

[0083] R1 and R4 are independently selected from H, D, OH, NH2, carbonyl (one of R1 or R4), optionally substituted C1-C10 alkyl (preferably C1-C6 alkyl), optionally substituted C1-C10 alkoxy (preferably C1-C6 alkoxy), optionally substituted aminoacetoxy ( B can be any group that forms an amino acid);

[0084] R2 and R5 are independently selected from H, D, OH, COOH, sulfonic acid, oxygen ( Can the group in be called sulfonic acid groupoxy), optionally substituted aminoacetoxy ( B may be various amino acid-forming groups), optionally substituted NH2, optionally substituted C1-C10 alkyl (preferably C1-C6 alkyl), optionally substituted C1-C10 alkoxy (preferably C1-C6 alkoxy), phosphate group;

[0085] or,

[0086] R1 and R2 or R4 and R5 are linked to form an optionally substituted 3-6 membered ring containing 0, 1 or 2 heteroatoms (preferably oxygen) selected from oxygen, nitrogen or sulfur, a cyclic carbonate lactone, a phosphate lactone or an optionally substituted cyclic borate lactone;

[0087] R3 is selected from H, D, optionally substituted C1-C10 alkyl (preferably C1-C6 alkyl) or alkenyl, optionally substituted C1-C10 alkyl (preferably C1-C6 alkyl) formyl, optionally substituted C1-C10 alkyl (preferably C1-C6 alkyl), D-substituted C1-C10 alkyl, halogen, optionally substituted C3-C10 cycloalkyl, optionally substituted C2-6 alkynyl;

[0088] or,

[0089] Two adjacent R3 substituents form an optionally substituted C3-C6 carbocycle or an optionally substituted C3-C6 heterocycle containing 1 or 2 heteroatoms selected from oxygen, nitrogen or sulfur (preferably oxygen), an optionally substituted C5-C10 aromatic ring or an optionally substituted C5-C10 heteroaromatic ring containing 1 or 2 heteroatoms selected from oxygen, nitrogen or sulfur (preferably oxygen);

[0090] m is an integer from 1 to 5;

[0091] The hydrogens in the structures of Formula I are optionally deuterated.

[0092] In a specific embodiment, wherein,

[0093] A is selected from a C6-C10 aromatic ring or a 5-6 membered aromatic heterocycle containing 1, 2 or 3 heteroatoms selected from N, O or S;

[0094] R1 and R4 are independently selected from H, D, OH, NH2, halogen, carbonyl;

[0095] R2 and R5 are independently selected from H, D, OH, COOH, optionally substituted sulfonic acid group, optionally substituted NH2, halogen, optionally substituted phosphate group;

[0096] or

[0097] R1 and R2 or R4 and R5 are linked to form an optionally substituted 3-6 membered ring containing 0, 1 or 2 heteroatoms (preferably oxygen) selected from oxygen, nitrogen or sulfur, a cyclic carbonate lactone, a phosphate lactone or an optionally substituted cyclic borate lactone;

[0098] R3 is selected from H, D, optionally substituted C1-C10 alkyl (preferably C1-C6 alkyl) alkenyl, formyl, optionally substituted C1-C10 alkyl (preferably C1-C6 alkyl) formyl, optionally substituted C1-C10 alkyl (preferably C1-C6 alkyl), D-substituted C1-C10 alkyl, halogen, optionally substituted C3-C10 cycloalkyl, optionally substituted C2-6 alkynyl;

[0099] or,

[0100] Two adjacent R3 substituents form an optionally substituted C3-C6 carbocycle or an optionally substituted C3-C6 heterocycle containing 1 or 2 oxygen atoms, an optionally substituted C5-C10 aromatic ring, or an optionally substituted C5-C10 heteroaromatic ring containing 1 or 2 oxygen atoms;

[0101] m is an integer from 1 to 5;

[0102] The hydrogens in the structures of Formula I are optionally deuterated.

[0103] In a specific embodiment, the compound is the following compound, or a salt or ester, prodrug, optical isomer or solvate thereof:

[0104]

[0105]

[0106] In a third aspect, the present invention provides a pharmaceutical composition comprising the compound of the second aspect, or a pharmaceutically acceptable salt or ester, prodrug, optical isomer, stereoisomer or solvate thereof, and a pharmaceutically acceptable carrier or excipient.

[0107] In a fourth aspect, the present invention provides a method for treating a TRPV4-related disease, comprising administering a therapeutically effective amount of the compound of the second aspect or the pharmaceutical composition of the third aspect to a subject in need thereof.

[0108] In a preferred embodiment, the subject is a mammal, including but not limited to humans, pets, racing animals, livestock, etc.

[0109] In a preferred embodiment, the subject is a human.

[0110] In a preferred embodiment, the TRPV4 inhibitor or antagonist is a drug for preventing or treating TRPV4-related diseases.

[0111] In a preferred embodiment, the TRPV4-related disease is a lung disease (acute lung injury, asthma, pulmonary fibrosis, cough and chronic obstructive pulmonary disease), a gastrointestinal disease (Crohn's disease and colitis), a bladder disease (including overactive bladder and interstitial cystitis), an eye disease (glaucoma and diabetic retinopathy), a cerebral edema, or a disease such as itching; preferably a lung disease; more preferably acute lung injury.

[0112] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features described in detail 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 listed here one by one. BRIEF DESCRIPTION OF THE DRAWINGS

[0113] Figure 1 Shows the results of respiratory function test experiments. DETAILED DESCRIPTION

[0114] After extensive and in-depth research, the inventors unexpectedly discovered a series of compounds with excellent inhibitory activity against TRPV4 and therapeutic effects on related diseases. They also clarified the antagonistic mechanism of these compounds in the intracellular region of the TRPV4 channel. This has important theoretical significance and practical application value for understanding its physiological and pathological functions and for the development of new drugs targeting the TRPV4 channel. This is the basis for the completion of the present invention.

[0115] Definition of terms

[0116] The terms used herein with respect to the groups, substituents or structures of the compounds have the same meanings as understood by those skilled in the art. For the sake of clarity, the terms used in this specification are defined as follows.

[0117] In this document, "a", "an", "a kind" or "a category" refers to the plural form including the objects it modifies, that is, "a", "an", "a kind" or "a category" refers to at least one / kind / category or one / kind / category or more than one / kind / category.

[0118] In this article, the form "C 1-n " means that the group has 1-n carbon atoms, for example, "C 1-10 " means that the group has 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms; similarly, "C6-C10" means that the group has 6, 7, 8, 9 or 10 carbon atoms. At the same time, the description of the range of carbon atoms herein also includes sub-ranges therein. For example, when 1-10 carbon atoms are mentioned herein, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, and 1-3 carbon atoms are also included.

[0119] The term "alkyl" as used herein has the same meaning as commonly understood by those skilled in the art, and refers to various saturated or unsaturated, linear, side-chain, or cyclic hydrocarbon groups. For example, the alkyl group described herein refers to a lower alkyl group having 1-10 carbon atoms; preferably, a lower alkyl group having 1-8 carbon atoms; and more preferably, a lower alkyl group having 1-6 carbon atoms. In specific embodiments, the alkyl group described herein includes, but is not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, and the like.

[0120] As used herein, the terms "aryl" and "aromatic ring" have the same meaning as commonly understood by those skilled in the art, and refer to a cyclic conjugated aromatic system. For example, the term "C6-C10 aryl" refers to an aromatic ring group having 6 to 10 carbon atoms, such as phenyl and naphthyl, that does not contain heteroatoms in the ring. The term "heteroaryl" as used herein refers to a cyclic conjugated aromatic system that contains one or more heteroatoms, such as N, O, or S, in the ring; for example, pyridyl and pyrazinyl.

[0121] The term "aminoacetyl" as used herein has its conventional meaning as understood by those of ordinary skill in the art, i.e., an acetyl group substituted with an amino group. In a specific embodiment, the aminoacetyl group is As shown, wherein R is various amino acid substituents.

[0122] As used herein, the terms "heterocyclyl" and "heterocycle" have the same meaning and refer to a saturated or partially unsaturated non-aromatic cyclic group, including a monocyclic, fused, spirocyclic or bridged ring, wherein the heterocycle has at least one heteroatom selected from O, S or N as a ring member. For example, a "5- or 6-membered heterocyclyl" refers to a saturated or unsaturated 5- or 6-membered cycloalkyl group containing 1 to 3 heteroatoms selected from oxygen, sulfur or nitrogen in the ring, such as dioxolanyl.

[0123] The term "halogen" as used herein refers to F, Cl, Br or I.

[0124] Based on the teachings of the present invention and common knowledge in the art, those skilled in the art will know that the compounds of the present 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 desired combination of substituents is a stable or chemically feasible combination of substituents.

[0125] As used herein, the term "substituted" refers to the replacement of one or more hydrogen atoms on a specific group with a specific substituent. The specific substituent may be the substituent described above or the specific substituents described in the examples. Therefore, in the present invention, the substituents in general formula (I) or (II) may each independently be the corresponding group in the specific compounds described in the examples; that is, the present invention includes combinations of the substituents in the above-mentioned general formula (I) or (II), as well as combinations of some of the substituents shown in general formula (I) or (II) with other specific substituents described in the examples.

[0126] Unless otherwise specified, a substituted group may have a specific substituent at any substitutable position of the group, and the substituents may be the same or different at each position. A cyclic substituent, such as a heterocyclic group, may be attached to another ring, such as a cycloalkyl group, to form a spirobicyclic ring system, for example, where the two rings share a common carbon atom. Examples of such substituents include (but are not limited to): C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 3-8 Cycloalkyl, 3- to 12-membered heterocyclic group, aryl, heteroaryl, halogen, hydroxyl, carboxyl (-COOH), C 1-8 Aldehyde, C 2-10 Acyl, C 2-10 Ester group, amino group, C 1-8 Alkoxy, nitro, cyano, mercapto, amino, etc. In a specific embodiment, the hydrogen atoms on the alkyl and aryl groups are replaced by amino, halogen or other groups to become groups within the above definitions.

[0127] For convenience and in accordance with common understanding, the terms "optionally substituted", "optionally substituted" or "substituted or unsubstituted" only apply to sites that can be substituted by substituents, and do not include those substitutions that are chemically unfeasible.

[0128] As used herein, the term "independently selected" means that the multiple groups modified by the term can be selected relatively independently within the specified range. For example, when "R1 and R4 are independently selected from H, OH, and carbonyl" is stated herein, this is equivalent to disclosing "R1 is selected from H, OH, or carbonyl" and "R4 is selected from H, OH, or carbonyl."

[0129] Compounds of the present invention

[0130] The present invention provides a series of novel compounds that have excellent inhibitory activity against TRPV4TRPV4 and therapeutic effects on related diseases. These compounds have different mechanisms from existing therapeutic drugs.

[0131] In a specific embodiment, the present invention provides a compound represented by the following formula I or II, or a pharmaceutically acceptable salt or ester, prodrug, optical isomer, stereoisomer or solvate thereof:

[0132]

[0133] Each substituent in the general formula is as described above.

[0134] In a preferred embodiment, the compound represented by formula I is a compound represented by formula II,

[0135]

[0136] Each substituent in the formula is as described above.

[0137] In a preferred embodiment, the compound represented by formula I is a compound represented by formula III,

[0138]

[0139] Each substituent in the formula is as described above.

[0140] In a preferred embodiment, the compound represented by formula I is a compound represented by formula IV,

[0141]

[0142] Each substituent in the formula is as described above.

[0143] In a specific embodiment, the preferred compounds of the present invention are the following compounds:

[0144]

[0145]

[0146] Based on the compounds of the present invention, those skilled in the art can prepare pharmaceutically acceptable salts or esters, prodrugs, optical isomers, stereoisomers or solvates thereof. For example, the compounds of the present invention can be reacted with inorganic acids 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, 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, pamoic acid, hydroxymaleic acid, phenylacetic acid, benzoic acid, salicylic acid, glutamic acid, ascorbic acid, p-aminobenzenesulfonic acid, 2-acetoxybenzoic acid and isethionic acid, etc.; or the compound of the present invention is reacted with an inorganic base to form a sodium salt, potassium salt, calcium salt, aluminum salt or ammonium salt; or it is reacted with an organic base to form a methylamine salt, ethylamine salt or ethanolamine salt.

[0147] Since there are chiral carbon atoms in the compounds of the present invention, the optical isomers or stereoisomers obtained by resolving the compounds of the present invention also fall within the protection scope of the present invention.

[0148] Based on the teachings herein, those skilled in the art will understand that the compounds provided herein for treating heart failure and related diseases should possess various inherent pharmaceutical properties, such as therapeutic activity, druggability, and pharmacokinetic activity. Furthermore, the compounds of the present invention should also possess acceptable toxicity. Therefore, all pharmaceutically relevant activities of the compounds of the present invention are implicitly disclosed herein, and those skilled in the art can determine these properties using methods known in the art.

[0149] Based on the compound of the present invention or its pharmaceutically acceptable salt or ester, prodrug, optical isomer, stereoisomer or solvate, the present invention also provides a pharmaceutical composition comprising the compound of the present invention, which optionally contains a pharmaceutically acceptable excipient.

[0150] In specific embodiments, the pharmaceutical composition of the present invention comprises a safe and effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier. "Safe and effective amount" means an amount of the compound sufficient to significantly improve the condition without causing serious side effects.

[0151] "Pharmaceutically acceptable excipients or carriers" refer to: one or more compatible solid or liquid fillers or gel substances, which 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 the compounds of the present invention and with each other without significantly reducing the efficacy of the compounds. Some 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, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as ), wetting agents (such as sodium lauryl sulfate), colorants, flavorings, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0152] There is no particular limitation on the administration of the compound or pharmaceutical composition of the present invention. Representative administration routes include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.

[0153] 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 ingredients: (a) fillers or extenders, for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose, and acacia; (c) humectants, for example, glycerol; (d) disintegrants, for example, agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solubilizers, for example, paraffin; (f) absorption accelerators, for example, quaternary ammonium compounds; (g) wetting agents, for example, cetyl alcohol and glyceryl monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.

[0154] Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared using coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifying agents, and the release of the active compound or compounds in such compositions can be delayed in a certain portion of the digestive tract. Examples of useful encapsulating components are polymeric substances and waxes. If desired, the active compound can also be microencapsulated with one or more of the above-mentioned excipients.

[0155] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, the liquid dosage form may contain an inert diluent conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil, or mixtures thereof.

[0156] Besides such inert diluents, the composition may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and flavoring agents.

[0157] Suspensions, in addition to the active compounds, may contain suspending agents such as, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances.

[0158] 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.

[0159] Dosage forms for topical administration of the compounds of this invention include ointments, powders, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required.

[0160] The compounds of the present invention can be administered alone or in combination with other pharmaceutically acceptable compounds. When using a pharmaceutical composition, a safe and effective amount of the compound of the present invention is applied to a mammal (such as a human) in need of treatment, wherein the dosage during administration is a pharmaceutically effective dosage. The compounds and pharmaceutical compositions of the present invention can be administered via the mouth, nose, skin, lungs or gastrointestinal tract. Oral administration is most 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 treatment. Generally, the dose is started with a small dose and gradually increased until the most suitable dose is found. Of course, the specific dose should also take into account factors such as the route of administration and the patient's health status, which are all within the skill of a skilled physician. In a specific embodiment, the compound of the present invention is preferably administered in a form suitable for aerosolization.

[0161] TRPV4-related diseases

[0162] As used herein, the term "TRPV4-related disease" refers to various diseases in which TRPV4 is associated with the pathogenesis, such as various diseases in which TRPV4 is associated with the pathogenesis. In a specific embodiment, the TRPV4-related disease is a lung disease (acute lung injury, asthma, pulmonary fibrosis, cough, and chronic obstructive pulmonary disease), a gastrointestinal disease (Crohn's disease and colitis), a bladder disease (including overactive bladder and interstitial cystitis), an eye disease (glaucoma and diabetic retinopathy), cerebral edema, or pruritus; preferably a lung disease; more preferably acute lung injury.

[0163] Advantages of the present invention:

[0164] 1. The present invention provides a series of novel compounds with excellent inhibitory activity against TRPV4 and therapeutic effects on TRPV4-related diseases; and

[0165] 2. The compounds of the present invention lay a new material foundation for the development of new TRPV4 inhibitors or antagonists and therapeutic drugs for related diseases.

[0166] The technical solutions of the present invention are further described below with reference to specific examples. However, the following examples do not constitute a limitation of the present invention. All various application methods adopted in accordance with the principles and technical means of the present invention are within the scope of the present invention. Experimental methods in the following examples, where specific conditions are not specified, are generally carried out under conventional conditions or the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are calculated by weight.

[0167] Example

[0168] Some known compounds are available for purchase.

[0169] The compounds of the present invention can be prepared according to conventional routes or methods, or can be obtained according to the methods or routes described herein.

[0170] Example 1. Synthesis of a series of compounds

[0171] 1. Synthesis of 3-ethylphenyl glycol (Compound 1)

[0172]

[0173] Synthesis of compound 1.3

[0174] Magnesium turnings (2.2 g, 90 mmol) were placed in a 250 mL three-necked reaction flask. One iodine pellet 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 turnings using a constant pressure dropping funnel. Heat with a hair dryer to initiate the reaction. Once the reaction began, the remaining 110 mL of the tetrahydrofuran solution of compound 1.1 was slowly added dropwise. After the addition was complete, the reaction was refluxed for 3.5 hours to yield a tetrahydrofuran solution of compound 1.2.

[0175] Under an ice bath, a tetrahydrofuran solution of compound 1.2 was added dropwise to an 80 mL solution of benzyloxyacetaldehyde (12 g, 80 mmol) in anhydrous tetrahydrofuran. After the addition was complete, the mixture was allowed to warm to room temperature and react for 1 hour. Saturated aqueous ammonium chloride was then added to quench 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 afford 12.4 g of the title compound, with a two-step yield of 59.6%.

[0176] 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) - .

[0177] Synthesis of Compound 1 (including Compound 1 racemate, Compound 1 R-configuration 1-R, Compound 1 S-configuration 1-S)

[0178] 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 replaced with hydrogen, and the mixture was stirred at 38°C for 3 hours. After the reaction, the solvent was removed and the product was purified by column chromatography (PE:EA = 5:1) to obtain 6.42 g of the title compound in a 79% yield.

[0179] The R-configuration and the S-configuration of compound 1 were obtained by chiral preparation.

[0180] 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) - .

[0181] 2. Synthesis of Compound 2

[0182]

[0183] Synthesis of compound 2.6

[0184] Magnesium turnings (0.17 g, 7 mmol) were placed in a 50 mL three-necked reaction flask, and one iodine pellet was added. Compound 2.4 (1 g, 6.4 mmol) was dissolved in 12 mL of anhydrous tetrahydrofuran. 2 mL of the tetrahydrofuran solution of compound 4 was added dropwise to the reaction flask via a constant pressure dropping funnel. Heat with a hair dryer to initiate the reaction. Once the reaction began, the remaining 10 mL of the tetrahydrofuran solution of compound 2.4 was slowly added dropwise. After the addition was complete, the reaction was refluxed for 3.5 hours to yield a tetrahydrofuran solution of compound 2.5.

[0185] Under an ice bath, a tetrahydrofuran solution of compound 2.5 was added dropwise to an 8 mL solution of benzyloxyacetaldehyde (0.97 g, 6.4 mmol) in anhydrous tetrahydrofuran. After the addition was complete, the mixture was allowed to warm to room temperature and react for 1 hour. Saturated aqueous ammonium chloride was then added to quench 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 afford 0.98 g of the title compound, with a two-step yield of 67.6%.

[0186] 1 H NMR (400MHz, DMSO): δ7.37-7.22 (m, 10H), 5.41 (d, J = 4.0Hz, 1H), 4.78-4.74 (m, 1H), 4.51 (s, 2H), 3.51-3.48 (m, 2H). LC-MS: 227.30 (MH) - .

[0187] Synthesis of compound 2

[0188] Compound 2.6 (0.9 g, 4 mmol) was dissolved in 10 mL of ethanol, and 0.2 g of 10% palladium on carbon was added. The air was replaced with hydrogen, and the mixture was stirred at 38°C for 3 hours. After the reaction, the solvent was removed and the product was purified by column chromatography (PE:EA = 5:1) to obtain 0.24 g of the title compound in a 45% yield.

[0189] 1 H NMR (400MHz, DMSO): δ7.34-7.28(m,4H),7.24-7.20(m,1H),5.24(d,J=4.4Hz,1H) ,4.74(t,J=6Hz,1H),4.55(q,J=6Hz,1H),3.43(t,J=6Hz,2H).LC-MS:137.10(MH) - .

[0190] 3. Synthesis of Compound 3

[0191]

[0192] Synthesis of compound 3.9

[0193] Magnesium turnings (0.33 g, 13.8 mmol) were placed in a 100 mL three-necked reaction flask and 1 iodine pellet was added. Compound 3.7 (2 g, 11.7 mmol) was dissolved in 20 mL of anhydrous tetrahydrofuran. 3 mL of the tetrahydrofuran solution of compound 3.7 was added dropwise to the reaction flask using a constant pressure dropping funnel. Heat with a hair dryer was used to initiate the reaction. After the reaction began, the remaining 17 mL of the tetrahydrofuran solution of compound 7 was slowly added dropwise. After the addition was complete, the reaction was refluxed for 3.5 hours to obtain a tetrahydrofuran solution of compound 3.8.

[0194] Under an ice bath, a tetrahydrofuran solution of compound 3.8 was added dropwise to a 14 mL solution of benzyloxyacetaldehyde (1.74 g, 11.6 mmol) in anhydrous tetrahydrofuran. After the addition was complete, the mixture was allowed to warm to room temperature and react for 1 hour. Saturated aqueous ammonium chloride was then added to quench the reaction. Finally, the tetrahydrofuran was removed, and the product was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and purified by column chromatography (PE:EA = 10:1) to afford 0.95 g of the title compound, with a two-step yield of 34%.

[0195] 1 H NMR (400MHz, DMSO): δ7.34-7.04(m,9H),5.34(d,J=4.0Hz,1H),4.73-4.69(m,1H),4.51(s,2H),3.52-3.43(m,2H),2.28(s,3H).LC-MS:241.30(MH) - .

[0196] Synthesis of compound 3

[0197] Compound 3.9 (0.9 g, 3.8 mmol) was dissolved in 10 mL of ethanol, and 0.2 g of 10% palladium on carbon was added. The air was replaced with hydrogen, and the mixture was stirred at 38°C for 3 hours. After the reaction, the solvent was removed and the product was purified by column chromatography (PE:EA = 5:1) to obtain 0.28 g of the title compound in a 50% yield.

[0198] 1 H NMR (400MHz, CDCl3): δ7.26-7.09 (m, 4H), 4.76 (dd, J1=8.0Hz, J2=3.6Hz, 1H), 3.72-3.59 (m, 2H), 3.09 (s, 2H), 2.34 (s, 3H). LC-MS: 151.10 (MH) - .

[0199] 4. Synthesis of Compound 4

[0200]

[0201] Synthesis of compound 4.12

[0202] Magnesium turnings (0.31 g, 12.9 mmol) were placed in a 100 mL three-necked reaction flask, and one iodine pellet was added. Compound 4.10 (2 g, 10.9 mmol) was dissolved in 20 mL of anhydrous tetrahydrofuran. 3 mL of the tetrahydrofuran solution of compound 10 was added dropwise to the reaction flask via a constant pressure dropping funnel. The reaction was initiated by heating with a hair dryer. After the reaction began, the remaining 17 mL of the tetrahydrofuran solution of compound 4.10 was slowly added dropwise. After the addition was complete, the reaction was refluxed for 3.5 hours to obtain a tetrahydrofuran solution of compound 11.

[0203] Under an ice bath, a tetrahydrofuran solution of compound 4.11 was added dropwise to a solution of benzyloxyacetaldehyde (1.62 g, 10.8 mmol) in 14 mL of anhydrous tetrahydrofuran. After the addition was complete, the mixture was allowed to warm to room temperature and react for 1 hour. Saturated aqueous ammonium chloride was then added to quench the reaction. Finally, the tetrahydrofuran was removed, and the product was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and purified by column chromatography (PE:EA = 10:1) to afford 1 g of the title compound in a two-step yield of 36%.

[0204] 1 H NMR (400MHz, DMSO): δ7.35-7.14(m,9H),5.33(d,J=4.0Hz,1H),4.74-4.70(m,1H),4.51(s ,2H),3.52-3.43(m,2H),2.57(q,J=7.6Hz,2H),1.16(t,J=7.6Hz,3H).LC-MS:255.30(MH) - .

[0205] Synthesis of compound 4

[0206] Compound 4.12 (0.9 g, 3.5 mmol) was dissolved in 10 mL of ethanol, and 0.2 g of 10% palladium on carbon was added. The air was replaced with hydrogen, and the mixture was stirred at 38°C for 3 hours. After the reaction, the solvent was removed and the product was purified by column chromatography (PE:EA = 5:1) to obtain 0.24 g of the title compound in a 37% yield.

[0207] 1 H NMR (400MHz, CDCl3): δ7.20-7.10 (m, 4H), 4.72 (dd, J1=8.0Hz, J2=3.6Hz, 1H), 3.66-3.5 5(m,2H),2.59(q,J=7.6Hz,2H),2.46(s,2H),1.15(t,J=7.6Hz,3H).LC-MS:165.10(MH) - .

[0208] 6. Synthesis of Compound 6

[0209]

[0210] Synthesis of compound 6.18

[0211] Magnesium turnings (0.31 g, 12.9 mmol) were placed in a 100 mL three-necked reaction flask and 1 iodine pellet was added. Compound 6.16 (2 g, 8.5 mmol) was dissolved in 20 mL of anhydrous tetrahydrofuran. 3 mL of the tetrahydrofuran solution of compound 16 was added dropwise to the reaction flask via a constant pressure dropping funnel. Heat with a hair dryer was used to initiate the reaction. After the reaction began, the remaining 17 mL of the tetrahydrofuran solution of compound 6.16 was slowly added dropwise. After the addition was complete, the reaction was refluxed for 3.5 hours to obtain a tetrahydrofuran solution of compound 6.17.

[0212] Under an ice bath, a tetrahydrofuran solution of compound 6.17 was added dropwise to a 14 mL solution of benzyloxyacetaldehyde (1.28 g, 8.5 mmol) in anhydrous tetrahydrofuran. After the addition was complete, the mixture was allowed to warm to room temperature and react for 1 hour. Saturated aqueous ammonium chloride was then added to quench the reaction. Finally, the tetrahydrofuran was removed, and the product was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and purified by column chromatography (PE:EA = 10:1) to afford 0.9 g of the title compound, with a two-step yield of 32%.

[0213] 1H NMR (400MHz, DMSO): δ7.38-7.02 (m, 9H), 5.33 (d, J = 4.4Hz, 1H), 4.75-4.70 (m, 1H), 4.47 (s, 2H), 3.56-3.49 (m, 2H). LC-MS: 307.30 (MH) - .

[0214] Synthesis of compound 6

[0215] Compound 6.18 (0.85 g, 2.8 mmol) was dissolved in 10 mL of ethanol, and 0.23 g of 10% palladium on carbon was added. The air was replaced with hydrogen, and the mixture was stirred at 38°C for 3 hours. After the reaction, the solvent was removed and the product was purified by column chromatography (PE:EA = 5:1) to obtain 0.2 g of the title compound in a 33% yield.

[0216] 1 H NMR (400MHz, DMSO): δ7.35-7.29(m,1H),7.19-7.13(m,2H),7.02-6.98(m,1H),5.34(d,J =4Hz,1H),4.70(t,J=6Hz,1H),4.51(q,J=5.6Hz),3.40(t,J=6Hz,2H).LC-MS:217.10(MH) - .

[0217] 7. Synthesis of Compound 7

[0218]

[0219] Synthesis of compound 7.21

[0220] Magnesium turnings (0.31 g, 12.9 mmol) were placed in a 100 mL three-necked reaction flask and 1 iodine pellet was added. Compound 7.19 (2 g, 11.7 mmol) was dissolved in 20 mL of anhydrous tetrahydrofuran. 3 mL of the tetrahydrofuran solution of compound 19 was added dropwise to the reaction flask via a constant pressure dropping funnel. The reaction was initiated by heating with a hair dryer. After the reaction began, the remaining 7.17 mL of the tetrahydrofuran solution of compound 7.19 was slowly added dropwise. After the addition was complete, the reaction was refluxed for 3.5 hours to obtain a tetrahydrofuran solution of compound 7.20.

[0221] Under an ice bath, a tetrahydrofuran solution of compound 7.20 was added dropwise to a 14 mL solution of benzyloxyacetaldehyde (1.76 g, 11.7 mmol) in anhydrous tetrahydrofuran. After the addition was complete, the mixture was allowed to warm to room temperature and react for 1 hour. Saturated aqueous ammonium chloride was then added to quench the reaction. Finally, the tetrahydrofuran was removed, and the product was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and purified by column chromatography (PE:EA = 10:1) to afford 1.32 g of the title compound, with a two-step yield of 47.2%.

[0222] 1 H NMR (400MHz, DMSO): δ7.44-7.14(m,9H),5.36(d,J=4.4Hz,1H),4.71-4.67(m,1H),4.50(s,2H),3.50-3.41(m,2H).LC-MS:245.30(MH) -

[0223] Synthesis of compound 7

[0224] Compound 7.21 (1.3 g, 5.4 mmol) was dissolved in 10 mL of ethanol, and 0.23 g of 10% palladium on carbon was added. The air was replaced with hydrogen, and the mixture was stirred at 38°C for 3 hours. After the reaction, the solvent was removed and the product was purified by column chromatography (PE:EA = 5:1) to obtain 0.2 g of the title compound in a 33% yield.

[0225] 1 H NMR (400MHz, DMSO): δ7.37-7.31(m,1H),7.18-7.12(m,2H),7.06-7.01(m,1H),5.39(d,J=4 .4Hz,1H),4.77(t,J=5.6Hz,1H),4.56(q,J=5.6Hz),3.43(t,J=6Hz,2H).LC-MS:155.10(MH) - .

[0226] 8. Synthesis of Compound 8

[0227]

[0228] Synthesis of compound 8.24

[0229] Magnesium turnings (0.57 g, 22.2 mmol) were placed in a 100 mL three-necked reaction flask and 1 iodine pellet was added. Compound 8.22 (4 g, 21.5 mmol) was dissolved in 40 mL of anhydrous tetrahydrofuran. 5 mL of the tetrahydrofuran solution of compound 8.22 was added dropwise to the reaction flask using a constant pressure dropping funnel. Heat with a hair dryer was used to initiate the reaction. Once the reaction began, the remaining 35 mL of the tetrahydrofuran solution of compound 8.22 was slowly added dropwise. After the addition was complete, the reaction was refluxed for 3.5 hours to obtain a tetrahydrofuran solution of compound 8.23.

[0230] Under an ice bath, a tetrahydrofuran solution of compound 8.23 ​​was added dropwise to a 30 mL solution of benzyloxyacetaldehyde (3.21 g, 21.5 mmol) in anhydrous tetrahydrofuran. After the addition was complete, the mixture was allowed to warm to room temperature and react for 1 hour. Saturated aqueous ammonium chloride was then added to quench the reaction. Finally, the tetrahydrofuran was removed, and the product was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and purified by column chromatography (PE:EA = 10:1) to afford 4 g of the title compound, with a two-step yield of 63.6%.

[0231] 1 H NMR (400MHz, DMSO): δ7.35-7.14(m,9H),5.33(d,J=4.0Hz,1H),4.74-4.70(m,1H),4.51(s,2H),3.73(s,3H),3.52-3.43(m,2H).LC-MS:257.30(MH) - .

[0232] Synthesis of compound 8

[0233] Compound 8.24 (3.5 g, 13.6 mmol) was dissolved in 30 mL of ethanol, and 0.69 g of 10% palladium on carbon was added. The air was replaced with hydrogen, and the mixture was stirred at 38°C for 3 hours. After the reaction, the solvent was removed and the product was purified by column chromatography (PE:EA = 5:1) to obtain 1.42 g of the title compound in a 62.3% yield.

[0234] 1 H NMR (400MHz, DMSO): δ7.23 (t, J = 8Hz, 1H), 6.91 (d, J = 7.6Hz, 2H), 6.80-6.77 (m, 1H), 5.24 (d, J = 4.4Hz, 1H),4.73(t,J=5.6Hz,1H),4.53(q,J=4.8Hz,1H),3.73(s,3H),3.43-3.36(m,2H).LC-MS:167.10(MH) - .

[0235] 9. Synthesis of Compound 9

[0236]

[0237] Synthesis of compound 9.26

[0238] Dissolve p-isopropylaniline (4 g, 29.6 mmol) in dichloromethane (40 ml). Add NBS (5.8 g, 32.6 mmol) in portions under an ice bath. The reaction temperature is then raised to room temperature and the reaction is allowed to proceed for 1 hour. Purification affords 4.6 g of the product, with a yield of 74%.

[0239] 1 H NMR (400MHz, CDCl3): δ7.28 (d, J=1.6Hz, 1H), 6.98 (dd, J1=1.6Hz, J2=1.6Hz, 1H), 6.7 1(d,J=8Hz,1H),3.76(s,2H),2.79(m,1H),1.20(d,J=6.8Hz,6H).LC-MS:214.10(M+H) + .

[0240] Synthesis of compound 9.27

[0241] Compound 9.26 (2 g, 9.3 mmol) was dissolved in a mixed solution of acetic acid (10 mL), water (4 mL), and concentrated HCl (1 mL). A solution of NaNO₂ (0.78 g, 11.2 mmol) in water (2 mL) was then added dropwise to the solution under an ice bath. After the reaction proceeded for half an hour, the resulting reaction mixture was added dropwise to a 50% H₃PO₂ solution in water (12 mL) under an ice bath. The reaction was continued for 8 hours, and the reaction temperature was then raised to 25 degrees Celsius for 3 days. After completion of the reaction, the product was purified by column chromatography. 1.4 g of the product was obtained with a yield of 75.3%.

[0242] 1 H NMR (400MHz, DMSO): δ7.42 (s, 1H), 7.37-7.34 (m, 1H), 7.25 (d, J = 4.8Hz, 2H), 1.20 (d, J = 6.8Hz, 6H). LC-MS: 199.20 (M+H) + .

[0243] Synthesis of compound 9.29

[0244] Magnesium turnings (0.17 g, 7.1 mmol) were placed in a 100 mL three-necked reaction flask, and one iodine pellet was added. Compound 9.27 (1.3 g, 7.5 mmol) was dissolved in 12 mL of anhydrous tetrahydrofuran. 2 mL of the tetrahydrofuran solution of compound 9.27 was added dropwise to the reaction flask using a constant pressure dropping funnel. The reaction was initiated by heating with a hair dryer. After the reaction began, the remaining 10 mL of the tetrahydrofuran solution of compound 9.27 was slowly added dropwise. After the addition was complete, the reaction was refluxed for 3.5 hours to obtain a tetrahydrofuran solution of compound 9.28.

[0245] Under an ice bath, a tetrahydrofuran solution of compound 9.28 was added dropwise to a 10 mL solution of benzyloxyacetaldehyde (0.98 g, 7.1 mmol) in anhydrous tetrahydrofuran. After the addition was complete, the mixture was allowed to warm to room temperature and react for 1 hour. Saturated aqueous ammonium chloride was then added to quench the reaction. Finally, the tetrahydrofuran was removed, and the product was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and purified by column chromatography (PE:EA = 10:1) to afford 1 g of the title compound in a two-step yield of 56%.

[0246] 1 H NMR (400MHz, DMSO): δ7.36-7.15(m,8H),7.09(d,J=8Hz,1H),5.38(d,J=4Hz,1H),4.74-4.70(m,1 H),4.51(s,2H),3.53-3.44(m,2H),2.83-2.76(m,1H),1.20(d,J=7.6Hz,6H).LC-MS:271.30(M+H) + .

[0247] Synthesis of compound 9

[0248] Compound 9.28 (1 g, 3.6 mmol) was dissolved in 10 mL of ethanol, and 0.19 g of 10% palladium on carbon was added. The air was replaced with hydrogen, and the mixture was stirred at 38°C for 3 hours. After the reaction, the solvent was removed and the product was purified by column chromatography (PE:EA = 5:1) to obtain 0.51 g of the title compound in 80% yield.

[0249] 1 H NMR (400MHz, CDCl3): δ7.19-7.04(m,4H),4.69(d,J=4.0Hz,1H),3.64-3.52(m, 2H),3.22(s,2H),2.83-2.76(m,1H),1.15(d,J=7.6Hz,6H).LC-MS:179.10(MH) - .

[0250] 10. Synthesis of Compound 10

[0251]

[0252] Synthesis of compound 10.30 (protection of carbonyl group)

[0253] 4-Bromoacetophenone (5g, 25.4mmol) was placed in a 100mL three-necked flask, and 60mL of toluene was added as solvent. Ethylene glycol (10g, 161.3mmol) and p-toluenesulfonic acid (1g, 5mmol) were then added. The temperature was raised to 130°C and refluxed for 16 hours. After the reaction, brine was added with stirring, and the layers were allowed to stand. The organic phase was collected, dried over anhydrous sodium sulfate, and purified by column chromatography to obtain 3g of the compound in a 48% yield.

[0254] 1 H NMR (400MHz, CDCl3): δ7.49-7.44(m,2H), δ7.37-7.34(m,2H),4.05(m,2H),3.77-3.73(m,2H),1.62(s,3H).LC-MS:242.10(MH) - .

[0255] Synthesis of compound 10.32

[0256] Magnesium turnings (0.31 g, 12.9 mmol) were placed in a 100 mL three-necked reaction flask, and one iodine pellet was added. p-Bromobenzene acetal (2.5 g, 10.4 mmol) was dissolved in 20 mL of anhydrous tetrahydrofuran. 3 mL of the tetrahydrofuran solution of acetal was added dropwise to the reaction flask using a constant pressure dropping funnel. The reaction was initiated by heating with a hair dryer. After the reaction began, the remaining 17 mL of the tetrahydrofuran solution was slowly added dropwise. After the addition was complete, the reaction was refluxed for 3.5 hours to obtain a tetrahydrofuran solution of the Grignard reagent.

[0257] Under an ice bath, a solution of ethyl acetal in tetrahydrofuran was added dropwise to a solution of benzyloxyacetaldehyde (1.5 g, 10 mmol) in 14 mL of anhydrous tetrahydrofuran. After the addition was complete, the mixture was allowed to warm to room temperature and react for 1 hour. Saturated aqueous ammonium chloride was then added to quench the reaction. Finally, the tetrahydrofuran was removed, and the product was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and purified by column chromatography (PE:EA = 10:1) to afford 0.8 g of the title compound, with a two-step yield of 25%.

[0258] 1H NMR(400MHz, CDCl3): δ7.44-7.29(m,10H),4.9 0(dd,J=8.8Hz,3.2Hz,1H),4.57(q,J=12Hz,2H),3.98(t,J=6Hz,2H),3.71(t,J=6Hz ,2H),3.60(dd,J=8Hz,3.2Hz),3.39(t,J=8Hz,1H),1.62(s,3H).LC-MS:313.20(MH) - .

[0259] Synthesis of compound 10.33 (debenzylation reaction)

[0260] The compound (0.75 g, 2.4 mmol) was dissolved in 10 mL of ethanol, and 0.23 g of 10% palladium on carbon was added. The air was replaced with hydrogen, and the mixture was stirred at 38°C for 3 hours. After the reaction, the solvent was removed and the product was purified by column chromatography (PE:EA = 2:1) to obtain 0.2 g of the title compound in a 29% yield.

[0261] 1 H NMR (400MHz, DMSO): δ7.35-7.29(m,4H),5.23(d,J=4Hz,1H),4.74(t,J=6Hz,1H),4.54- 4.49(m,1H),3.98-3.94(m,2H),3.43(t,J=6.8Hz,2H),1.53(s,3H).LC-MS:223.10(MH) - .

[0262] Synthesis of compound 10

[0263] Compound 10.33 (0.18 g, 0.8 mmol) was added to 10 mL of ethanol and 5 drops of hydrochloric acid, and the mixture was reacted at 50°C for 15 h. Water was added, and the mixture was extracted with DCM. The organic phase was dried over anhydrous sodium sulfate and purified by column chromatography to obtain 0.06 g of the product with a yield of 40%.

[0264] 1 H NMR (400MHz, DMSO): δ7.91(d,J=8.4Hz,2H),7.49(d,J=8.4Hz,2H),5.42(d,J=4Hz,1H),4.80 (t,J=6Hz,1H),4.63(q,J=5.6Hz,1H),3.46(t,J=6Hz,2H),2.56(s,3H).LC-MS:181.10(M+H) + .

[0265] 11. Synthesis of Compound 11(D)

[0266]

[0267] 1. Synthesis of 3-vinylphenyl oxirane (B)

[0268] Under nitrogen, potassium tert-butoxide (2.214 g, 0.02 mol), THF (2 ml), and DMSO (12 ml) were added dropwise to a three-necked flask containing trivinylbenzaldehyde (A, 1.215 g, 0.009 mol), trimethylsulfide iodide (2.118 g, 0.011 mol), THF (8 ml), and DMSO (15 ml). The reaction was allowed to proceed in an ice bath for 12 h. The reaction progress was monitored by TLC. Upon completion of the reaction, the product was extracted with dichloromethane, and the organic layer was dried over anhydrous sodium sulfate and separated by column chromatography (PE:EA = 150:1) to yield 0.755 g (56%) of 3-vinylphenyloxirane (B).

[0269] 1 H NMR (DMSO, 400MHz): δ7.43-7.21 (m, 4H), 6.77 (dd, J = 10.8 17.7Hz,1H,),5.83(d,J=17.7Hz,1H),5.29(d,J=10.8Hz,1H),3.93(dd,J=2.7,4.0Hz,1H),3.13(dd,J=4.0,5.5Hz,1H,),2.88(q,J=2.7Hz,1H).

[0270] 2. Synthesis of 3-(1-hydroxy-2-benzoyloxyethyl)styrene (C)

[0271] Benzoic acid (1.22 g, 10.0 mmol), tetrabutylammonium iodide (0.369 g, 1.0 mmol), and 3-vinylphenyloxirane (B, 1.46 g, 10.0 mmol) were dissolved in 5 mL of DMF under nitrogen and reacted at 100°C for 12 h. The reaction progress was monitored by TLC. Upon completion, the product was extracted with dichloromethane, and the organic layer was dried over anhydrous sodium sulfate and separated by column chromatography (PE:EA = 10:1) to yield 0.818 g (30.47%) of 3-(1-hydroxy-2-benzoyloxyethyl)styrene (C).

[0272] 1 H NMR (DMSO, 400MHz): δ7.33-7.95 (m, 9H), 6.78 (dd, J=10.9, 17.6Hz, 1H), 5.85 (d, J=17.6Hz, 1H), 5.78 (d, J = 4.6Hz, 1H), 5.27 (d, J = 10.9, 1H), 4.96 (q, J = 4.6, 1H), 4.34 (d, J = 5.7Hz, 2H).

[0273] Synthesis of compound 11(D)

[0274] 3-(1-Hydroxy-2-benzoyloxyethyl)styrene (C, 0.20 g, 0.745 mmol) and sodium hydroxide (0.043 g, 1.08 mmol) were dissolved in 4 ml of methanol and refluxed for 2 hours before adding 1 ml of H₂O. The reaction progress was monitored by TLC. Upon completion, the product was extracted with dichloromethane, and the organic layer was dried over anhydrous sodium sulfate and separated by column chromatography (PE:EA = 1:1) to yield 0.07 g (57.2%) of 3-(1,2-dihydroxyethyl)styrene (D).

[0275] 1 H NMR (CDCl3, 400MHz): δ7.12-7.29 (m, 4H), 6.65 (dd, J=11.1, 17.7Hz, 1H), 5.69 (d, J=17.7Hz, 1H) ,5.19(d,J=11.1Hz,1H),4.71(dd,J=3.3,8.3Hz,1H),3.65(m,2H),3.07(s,2H).MS(EI):164.1.

[0276] 12. Synthesis of Compound 12

[0277]

[0278] Compound 1 (1.66 g, 0.01 mol) was dissolved in 7 mL of DCM and 1 drop of concentrated sulfuric acid was added. After gentle heating, an exothermic reaction began. After completion of the reaction, 20 mL of solvent was added, and the mixture was washed with sodium bicarbonate solution. The residue was dried, concentrated, and purified by column chromatography (PE:EA = 10:1) to afford 2.00 g of the title compound in 80% yield.

[0279] 1 H NMR (400MHz, CDCl3): δ7.21-7.00 (m, 4H), 4.75 (dd, J1=8.0Hz, J2=3.6Hz, 1H), 3.72-3.60 (m, 2H ),2.66(q,J=7.6Hz,2H),2.21(s,3H),2.10(s,3H),1.25(t,J=7.6Hz,3H).LC-MS:251.17(M+H) + .

[0280] 13. Synthesis of 1-(3-cyclopropylphenyl)-1,2-ethanediol (Compound 13)

[0281]

[0282] Synthesis of 1-(3-cyclopropylphenyl)ethanone

[0283] 3-Bromoacetophenone (5 g, 25.12 mmol), cyclopropaneboronic acid (3.25 g, 37.68 mmol), anhydrous potassium phosphate (16 g, 75.36 mmol), and tricyclohexylphosphine (1.41 g, 5.02 mmol) were placed in a 100 ml round-bottom flask and dissolved in 20 mL of toluene / water (v:v = 100:1). Palladium acetate (563 mg, 2.52 mmol) was added and heated to 100°C under nitrogen for 20 hours. The reaction progress 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 evaporated under reduced pressure. Purification on a silica gel column (PE:EA = 100:1) afforded 3.6 g of a light yellow oil with a yield of 89%.

[0284] 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).

[0285] Synthesis of 3-cyclopropylbenzoic acid

[0286] Copper bromide (6.03 g, 26.98 mmol) was suspended in EA and heated with stirring to reflux. A solution of 1-(3-cyclopropylphenyl)ethanone (3.6 g, 22.49 mmol) in EA was added dropwise using a constant pressure dropping funnel and refluxed. The reaction was monitored by TLC. After completion of the reaction, the mixture was filtered through a pad of celite, and the filter cake was washed with EA. The mother liquor was then dried by spin-drying and extracted three times with EA / water. The combined organic phases were dried over anhydrous sodium sulfate and then spin-dried. The resulting 6.2 g oil was dissolved in 20 mL of methanol, and 5 g of sodium formate was added. The mixture was refluxed for 12 hours, with TLC monitoring. After completion of the reaction, the solvent was evaporated under reduced pressure, and the mixture was extracted three times with EA / water. The combined organic phases were dried over anhydrous sodium sulfate. Purification on a silica gel column (PE:EA = 50:1) afforded 1.2 g of a slightly yellow oil in a 30% yield.

[0287] 1H 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).

[0288] Synthesis of 1-(3-cyclopropylphenyl)-1,2-ethanediol

[0289] 3-Cyclopropylbenzoic acid (750 mg, 4.26 mmol) was dissolved in anhydrous tetrahydrofuran. Sodium borohydride (242 mg, 6.39 mmol) dissolved in THF was slowly added dropwise under an ice bath. The reaction progress was monitored by TLC. After completion, saturated ammonium chloride solution was slowly added dropwise to quench the reaction. The mixture was extracted three times with dichloromethane (DCM). The combined organic phases were dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. Purification on a silica gel column (PE:EA = 2:1) afforded 180 mg of a white solid in a 24% yield.

[0290] 1 H 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 :7.537min.

[0291] The following compounds were synthesized by similar routes as above:

[0292] 14. Synthesis of Compound 1-(3-ethylphenyl)-2-hydroxyethane-1-one (Compound 14)

[0293]

[0294] The compound was a colorless oil with a yield of 36.7%.

[0295] 1H 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).

[0296] 15. Synthesis of 1-(3-methoxyphenyl)-1,2-ethanediol (Compound 15)

[0297]

[0298] The compound was a light yellow solid with a yield of 50%.

[0299] 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 :6.105min.

[0300] 16. Synthesis of 1-(2,3-dihydro-5-benzofuranyl)-1,2-ethanediol (Compound 16)

[0301]

[0302] The compound was a light yellow solid with a yield of 44%.

[0303] 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 :5.922min.

[0304] 17. Synthesis of 1-(2,3-dihydro-1,4-benzodiazepine-6-yl)-1,2-ethanediol (Compound 17)

[0305]

[0306] The compound was a yellow oil with a yield of 37.7%.

[0307] 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 :5.776min.

[0308] 18. Synthesis of 1-(1,3-benzodiazol-5-yl)-1,2-ethanediol (Compound 18)

[0309]

[0310] The compound was a yellow solid with a yield of 40%.

[0311] 1 H 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 :5.803min.

[0312] 19. Synthesis of 1-(4-hydroxyphenyl)-1,2-ethanediol (Compound 19)

[0313]

[0314] The compound was a white solid with a yield of 42%.

[0315] 1H 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 :2.187min.

[0316] 20. Synthesis of 1-(3,4-dimethoxy)-1,2-ethanediol (Compound 20)

[0317]

[0318] The compound is a white solid with a yield of 45%.

[0319] 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 :5.529min.

[0320] 21. Synthesis of 1-(4-methoxyphenyl)propane-1,2-diol (Compound 21)

[0321]

[0322] The compound was a white solid with a yield of 49.0%.

[0323] 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).

[0324] 22. Synthesis of 1-(2-methoxyphenyl)ethane-1,2-diol (Compound 22)

[0325]

[0326] The compound was a white solid with a yield of 16.5%.

[0327] 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).

[0328] 23. Synthesis of 1-(4-methoxyphenyl)ethane-1,2-diol (Compound 23)

[0329]

[0330] The compound was a white solid with a yield of 6.5%.

[0331] 1 H 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).

[0332] 24. Synthesis of 1-(4-bromophenyl)ethane-1,2-diol (Compound 24)

[0333]

[0334] The compound was a white solid with a yield of 6.3%.

[0335] 1H 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).

[0336] 25. Synthesis of 1-(4-hydroxy-2-methoxyphenyl)ethane-1,2-diol (Compound 25)

[0337]

[0338] The compound was a light brown oily liquid with a yield of 33%.

[0339] 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.

[0340] 26. Synthesis of 1-(3-hydroxyphenyl)ethane-1,2-diol (Compound 26)

[0341]

[0342] The compound was a light brown oily liquid with a yield of 35%.

[0343] 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.

[0344] 27. Synthesis of Compound 1-Phenylpropane-1,2-diol (Compound 27)

[0345]

[0346] The compound was a white solid with a yield of 67%.

[0347] 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.

[0348] 28. Synthesis of 1-(3-ethynylphenyl)ethane-1,2-diol (Compound 28)

[0349]

[0350] The compound was a brown solid with a yield of 25%.

[0351] 1 H 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.

[0352] 29. Synthesis of 1-(3-(tert-butyl)phenyl)ethane-1,2-diol (Compound 29)

[0353]

[0354] The compound was a light yellow solid with a yield of 27%.

[0355] 1H 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.

[0356] 30. Structure of 1-(3-hydroxy-4-methoxyphenyl)ethane-1,2-diol (Compound 30)

[0357]

[0358] The compound was a light yellow solid with a yield of 30%.

[0359] 1 H 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.

[0360] 31. Synthesis of Compound 1-(1,3-diethyl-2-hydroxy)-1,2-ethanediol (Compound 31)

[0361]

[0362] Synthesis of ethyl 2-(2,4-diethyl-3-hydroxyphenyl)-2-oxoacetate

[0363] Weigh 2,6-diethylphenol (1 g, 6.67 mmol) into a 100 mL single-necked round-bottom flask and dissolve in 20 mL of 1,2-dichloroethane. Slowly add anhydrous aluminum chloride (2.7 g, 19.99 mmol) at 0°C and stir for 10 minutes. Then slowly add ethyl oxalyl chloride (1 g, 7.34 mmol) dropwise. Allow to react at 0°C for 10 minutes. TLC monitoring of the reaction progress was performed. After completion of the reaction, slowly pour the reaction solution into ice water and extract with DCM / H2O three times. The combined organic phases were dried over anhydrous sodium sulfate and then spin-dried to dryness. The product was a white solid and did not require purification. The yield was 90%.

[0364] 1 H NMR (400MHz, DMSO) δ9.69 (s, 1H), 7.54 (s, 2H), 4.40 (q, J = 7.1Hz, 2H), 2.65 (q, J = 7.5Hz, 4H), 1.32 (t, J = 7.1Hz, 3H), 1.14 (t, J = 7.5Hz, 6H).

[0365] Synthesis of 1-(2,4-diethyl-3-hydroxyphenyl)-1,2-ethanediol

[0366] Ethyl 2-(2,4-diethyl-3-hydroxyphenyl)-2-oxoacetate (627 mg, 2.52 mmol) was dissolved in 10 mL of methanol. Sodium borohydride (426.9 mg, 11.29 mmol) was slowly added portionwise with stirring in an ice bath. The reaction was allowed to react at 0°C for one hour. TLC was used to monitor the reaction progress. After completion, saturated ammonium chloride was added dropwise to quench the reaction. The reaction was then extracted three times with EA / H₂O. The combined organic phases were dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The product was recrystallized to obtain a white solid in a 60% yield.

[0367] 1 H NMR (400MHz, DMSO) δ7.91 (s, 1H), 6.86 (s, 2H), 4.94 (d, J = 4.0Hz, 1H), 4.57 (t, J = 5.8Hz, 1H), 4.38 (dd, J = 10 .1,5.9Hz,1H),3.36(t,J=6.0Hz,2H),2.55(q,J=7.5Hz,4H),1.11(t,J=7.5Hz,6H).LC-MS:m / z:209.20(MH) - ,t R :6.736min.

[0368] The following compounds were prepared by a synthetic route similar to that of 1-(2,4-diethyl-3-hydroxyphenyl)-1,2-ethanediol (73):

[0369] 32. Synthesis of 1-(3,4-dihydro-1-benzopyran-6-yl)-1,2-ethanediol (Compound 32)

[0370]

[0371] The compound was obtained as a white solid with a yield of 25%.

[0372] 1 H NMR (400MHz, DMSO) δ7.02–6.95(m,2H),6.68–6.61(m,1H),5.04(d,J=3.7Hz,1H),4.64(t,J=5.2Hz,1H),4.40(d,J= 3.0Hz,1H),4.17–3.97(m,2H),3.40–3.35(m,2H),2.71(t,J=6.4Hz,2H),1.97–1.80(m,2H).LC-MS:m / z:193.20(MH) - ,t R :6.462min.

[0373] 33. Synthesis of 1-(4-hydroxy-3-methoxy)-1,2-ethanediol (Compound 33)

[0374]

[0375] The compound was a light yellow oil with a yield of 30%.

[0376] 1 H NMR (400MHz, DMSO) δ8.75(s,1H),6.87(s,1H),6.69(s,2H),5.04(d,J=4.0Hz,1H),4.61(t,J=5.7 Hz, 1H), 4.41 (dd, J=10.2, 5.9Hz, 1H), 3.74 (s, 3H), 3.37 (t, J=6.0Hz, 2H). LC-MS: m / z: 183.15 (MH) - ,t R :2.213min.

[0377] 34. Synthesis of Compound 1-(5,6,7,8-Tetrahydronaphthalen-2-yl)-1,2-ethanediol (Compound 34)

[0378]

[0379] The compound was a white solid with a yield of 55%.

[0380] 1H 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 :8.760min.

[0381] 35. Synthesis of 1-(3-ethyl-4-methylphenyl)-1,2-ethanediol (Compound 35)

[0382]

[0383] The compound was a light yellow oil with a yield of 60%.

[0384] 1 H 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 :8.718min.

[0385] 36. Synthesis of 1-(2,3-dihydro-1H-indan-5-yl)-1,2-ethanediol (Compound 36)

[0386]

[0387] The compound was a white solid with a yield of 65%.

[0388] 1H 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 :8.265min.

[0389] 37. Synthesis of 1-(3-ethyl-4-hydroxyphenyl)-1,2-ethanediol (Compound 37)

[0390]

[0391] The compound is a white solid with a yield of 53%.

[0392] 1 H 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 :5.947min.

[0393] 38. Synthesis of 3-(3-ethylphenyl)tetrahydrofuran-3-ol (Compound 38)

[0394]

[0395] 3-Bromoethylbenzene (200 mg, 1.08 mmol), an appropriate amount of magnesium stick, 2 iodine particles, and 20 mL of anhydrous tetrahydrofuran were added to a dried 100 mL reaction bottle. The reaction was allowed to proceed 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 allowed to proceed at room temperature. The reaction was complete as determined by TLC. The reaction was quenched with saturated ammonium chloride and purified by silica gel column separation to obtain 80 mg of a colorless oil with a yield of 38.5%.

[0396] 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).

[0397] 39. Synthesis of 1-(5-ethylthiophen-3-yl)ethane-1,2-diol (Compound 39)

[0398]

[0399] Synthesis of 4-bromo-2-ethylthiophene

[0400] Thiophene acetonide (2.05 g, 10 mmol) was dissolved in 80 mL of dry THF. Sodium borohydride (1.89 g, 50 mmol) was added portionwise under an ice bath, followed by anhydrous aluminum chloride (3.66 g, 27.5 mmol). The mixture was refluxed at 80°C under nitrogen. The reaction progress was monitored by TLC (developing solvent: heptane). After 2 h, the reaction was complete. The reaction was quenched by the careful addition of 30 mL of water. The THF solvent was removed by vortexing, and the mixture was extracted with dichloromethane. After conventional post-processing, the residue was purified by column chromatography (eluent: heptane) to obtain 0.98 g of the pure reduced product in a 51.3% yield.

[0401] Synthesis of (5-ethylthiophen-3-yl)magnesium bromide

[0402] Add magnesium turnings (31 mg, 1.3 mmol) and a small particle of iodine to the reaction flask. After nitrogen flow, add 0.5 mL of dry THF. Then, add a solution of the above product (191 mg, 1 mmol) in THF (1.5 mL). Raise the temperature to 35°C to initiate the reaction. While maintaining the temperature, continue adding the THF solution of the bromide dropwise, keeping the reaction mixture at a slight boil. Continue the reaction at 35°C for 1 hour. After the reaction is complete, cool to room temperature and set aside.

[0403] Synthesis of ethyl 2-(5-ethylthiophen-3-yl)-2-oxoacetate

[0404] Diethyl oxalate (0.41 mL, 3 mmol) and 2 mL of THF were added to the reaction flask, cooled to -78°C under nitrogen protection, and the Grignard reagent prepared in the first step was slowly added dropwise. After completion of the dropwise addition, 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 subjected to conventional post-treatment. The crude product was purified by column chromatography (PE / EA = 200:1 to 100:1) to obtain 180 mg of the pure product with a yield of 85.7%.

[0405] Synthesis of 1-(5-ethylthiophen-3-yl)ethane-1,2-diol

[0406] 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 added portionwise in an ice bath. After addition, the mixture was allowed to cool to room temperature. TLC (dichloromethane / methanol = 25:1) was used to monitor the reaction progress. 30 mg of the pure product was obtained, with a yield of 22.2%.

[0407] 1 H 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).

[0408] 40. Synthesis of deuterated 3-ethylphenyl glycol (Compound 40)

[0409]

[0410] Weigh 3-ethylacetophenone (5.00 g, 33.7 mmol) into a 50 mL three-necked flask, add 25 mL of 1,4-dioxane, dilute with 25 mL of methanol, and stir under nitrogen in an ice bath for 10 minutes. Use a syringe to draw up liquid bromine (5.39 g, 33.7 mmol) and dissolve it in 25 mL of methanol. Slowly add this dropwise to the reaction solution using a dropping funnel in an ice bath. Continue stirring in an ice bath and monitor the reaction progress with a plate. After 5 hours, the reaction is complete. Add an appropriate amount of anhydrous sodium sulfite solution to quench the reaction. 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 over anhydrous sodium sulfate. Rotary evaporation yields 6.15 g of crude product.

[0411] Compound A (1.08 g, 4.76 mmol), sodium formate (0.65 g, 9.56 mmol), and 10 mL of methanol were placed in a 100 mL single-necked flask and heated to 80°C under reflux. The reaction progress was monitored by TLC. The reaction was complete after 4.5 hours. 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, and dried over anhydrous sodium sulfate. The product was rotary evaporated to yield 0.75 g of crude product. Crude yield = 95.96% (including impurities).

[0412] Weigh compound B (0.10 g, 0.61 mmol) into a 50 mL single-necked flask, dilute with 10 mL of methanol, and stir in an ice bath for 10 min. Weigh sodium borodeuteride (0.013 g, 0.31 mmol) and add it portionwise to the reaction mixture in an ice bath. Remove the ice bath after addition and allow the reaction to proceed at room temperature. Monitor the reaction progress by a platen. 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, dry over anhydrous sodium sulfate, and rotary evaporation. Add appropriate amounts of dichloromethane and silica gel, mix thoroughly, and rotary evaporation to prepare a sample. Dry-pack the column and dry-load the sample using a 4:1 ratio of petroleum ether to ethyl acetate. Rotary evaporation yields 0.02 g of product. Yield = 19.63%.

[0413] 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),5.14(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

[0414] 41. Synthesis of deuterated 3-ethylphenyl glycol (Compound 41)

[0415]

[0416] Weigh 3-ethylacetophenone (0.50 g, 3.4 mmol) in a 25 mL single-necked bottle, add 4 mL of tetrahydrofuran, and stir at room temperature. Weigh N-bromosuccinimide (0.59 g, 3.4 mmol) and slowly add it to the reaction solution. Continue stirring and monitor the progress of the reaction by tapping the plate. The reactants cannot react completely. When the raw materials no longer react, stop the reaction. Add an appropriate amount of water to quench. Rotary evaporate to remove the solvent. Extract the reaction solution with ethyl acetate and water, wash the extract with ethyl acetate and saturated sodium chloride solution, and dry it over anhydrous sodium sulfate. Rotary evaporate the resulting product to obtain 0.52 g of crude product. (The product and the raw material have little difference in polarity, making it difficult to purify, so it is directly used in the next step)

[0417] Crude yield = 67.08% (including impurities)

[0418] Weigh compound A (1.30 g, 5.72 mmol) in a 50 mL single-necked bottle, add 26 mL of toluene, 1.95 mL of deuterated water and potassium carbonate (0.20 g, 1.45 mmol), and heat to 87 ° C and reflux. After 4 hours, separate the aqueous layer at 40-50 ° C, add 1.95 mL of deuterated water and potassium carbonate (0.20 g, 1.45 mmol), and continue the reaction. Repeat the operation once after 8 hours, and the reaction is complete after 12 hours. Separate the aqueous layer and wash it with ethyl acetate. Rotary evaporate to remove the solvent. Extract the reaction solution with ethyl acetate and water, wash the extract with ethyl acetate and saturated sodium chloride solution, and dry it over anhydrous sodium sulfate. Rotary evaporate the resulting product to obtain 1.01 g of crude product. Crude yield = 77.11% (containing impurities)

[0419] 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 and heated to 80°C under reflux. The reaction progress was monitored by TLC. The reaction was complete after 4.5 hours. 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, and dried over anhydrous sodium sulfate. The product was rotary evaporated to obtain 0.72 g of crude product. Crude yield = 99.35% (including impurities).

[0420] Weigh compound C (1.00 g, 6.02 mmol) in a 50 mL single-necked bottle, add 5 mL of methanol to dilute, and stir in an ice bath for 10 min. Weigh sodium borohydride (0.23 g, 6.02 mmol) and add it to the reaction solution in batches in an ice bath. After the addition, remove the ice bath and react at room temperature. Monitor the progress of the reaction by dot plate. 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, dry it with anhydrous sodium sulfate, and rotary evaporation. Add appropriate amount of dichloromethane and silica gel, mix well, and rotary evaporation to prepare the sample. Dry column loading, dry sample loading, petroleum ether: ethyl acetate = 4:1. The product obtained by rotary evaporation is 0.21 g. Yield = 20.74%

[0421] 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

[0422] 42. Synthesis process of compounds 42-44

[0423] Synthesis of 1-(3-(1-hydroxy-1-deutero-ethyl)phenyl)-1-deutero-ethanol (2)

[0424]

[0425] Weigh 1,3-diacetylbenzene (3.00 g, 18.50 mmol) into a 100 mL single-necked flask, add 20 mL of methanol to dissolve, and stir at 0°C. Separately, slowly add sodium borodeuteride (0.39 g, 9.29 mmol) to the reaction mixture. Stir at room temperature for 3 hours. Remove the solvent by rotary evaporation, extract the reactant with ethyl acetate, wash the extract with saturated sodium chloride solution, and dry over anhydrous sodium sulfate. The crude product is purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1, v / v) to obtain 2.83 g of a colorless crystalline solid in a 91.1% yield.

[0426] 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

[0427] Synthesis of 1,3-bis(1-dideuteroethyl)benzene(3a)

[0428]

[0429] Weigh 1-(3-(1-hydroxy-1-deutero-ethyl)phenyl)-1-deutero-ethanol (12.00 g, 71.33 mmol) into a 250 mL two-necked flask and dissolve in 50 mL of deuteroethanol. Add 2.00 g of 10% palladium on carbon (25%) to the reaction solution and replace the deuterium three times. Use a syringe to slowly add 1 mL of deuterohydrochloric acid to the reaction solution, stirring overnight at room temperature. Filter the reaction solution through celite, extract the filtrate with dichloromethane, wash the extract with saturated sodium chloride solution, and dry it over anhydrous sodium sulfate. Remove the dichloromethane by rotary evaporation at 40°C. 8.20 g of the crude product is obtained as a colorless, transparent liquid with a yield of 83.3%.

[0430] 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

[0431] Synthesis of 1,3-di(1-deuterated-ethyl)benzene (3b)

[0432]

[0433] Weigh 1-(3-(1-hydroxy-1-deutero-ethyl)phenyl)-1-deutero-ethanol (1.00 g, 5.94 mmol) into a 100 mL two-necked flask. Dissolve in 5 mL of dichloromethane and stir at 0°C. Slowly add triethylsilane (4.90 g, 42.14 mmol) to the reaction mixture under nitrogen. Add boron trifluoride etherate (5.90 g, 41.57 mmol) dropwise to the reaction mixture at 0°C using a 10 mL syringe. Slowly warm the mixture to room temperature and stir overnight. Quench the mixture by adding saturated sodium bicarbonate solution until bubbles cease. Extract the reaction mixture with dichloromethane and water, wash the extract with dichloromethane and saturated sodium chloride solution, and dry over anhydrous sodium sulfate. Remove the dichloromethane by rotary evaporation at 40°C. The crude product is obtained as a colorless, transparent liquid (0.50 g, 61.7% yield).

[0434] 1 H 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

[0435] Synthesis of 1-(3-(1-bis(deuterated ethyl)phenyl)ethanone (4a)

[0436]

[0437] Weigh 1,3-bis(1-dideuteroethyl)benzene (8.20 g, 59.31 mmol) and N-hydroxyphthalimide (3.20 g, 19.62 mmol) into a 100 mL three-necked flask. Dissolve the mixture in 60 mL of acetonitrile. Replace the oxygen three times and heat to 40°C. Add tert-butyl nitrite (6.10 g, 59.15 mmol) via a 10 mL syringe and slowly add it dropwise to the reaction mixture, which gradually turns orange. After addition, heat the mixture to 55°C and react for 2 hours. Remove the solvent by rotary evaporation. Add a small amount of dichloromethane to precipitate a white solid. Filter the solid over diatomaceous earth and spin dry the filtrate. Purify the crude product by silica gel column chromatography (petroleum ether / dichloromethane = 10:1, v / v) to obtain 2.80 g of a yellow liquid with a yield of 31.4%.

[0438] 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).

[0439] Synthesis of 1-(3-(1-deuteroethyl)phenyl)ethanone (4b)

[0440]

[0441] The synthesis steps were the same as those in 4a, and a yellow liquid was obtained with a yield of 29.9%.

[0442] 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).

[0443] Synthesis of 1-(3-(1-deuteroethyl)phenyl)ethanone (15c)

[0444]

[0445] The synthesis steps were the same as those in 4a, and a yellow liquid was obtained with a yield of 35.3%.

[0446] 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).

[0447] Synthesis of 1-(3-(1-bis(deuterated ethyl)phenyl)-2-bromoethanone (5a)

[0448]

[0449] 1-(3-(1-bisdeuterated ethyl)phenyl)ethanone (2.80 g, 18.64 mmol) and p-toluenesulfonic acid (1.66 g, 9.64 mmol) were weighed into a 100 mL single-necked flask and dissolved in 20 mL of acetonitrile. Stir at 0°C. N-bromosuccinimide (3.64 g, 20.45 mmol) was slowly added to the reaction mixture and allowed to react at 40°C for 3 hours. The reaction was complete after 3 hours. An appropriate amount of water was added to quench the reaction. 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, and dried over anhydrous sodium sulfate. The crude product was purified by silica gel column chromatography (petroleum ether / dichloromethane = 10:1, v / v) to obtain 2.12 g of a yellow liquid with a yield of 50.1%.

[0450] Synthesis of 1-(3-(1-deuteroethyl)phenyl)-2-bromoethanone (5b)

[0451]

[0452] The synthetic steps were the same as those in step 5a to obtain a yellow liquid, which was directly used in the next step without purification.

[0453] Synthesis of 1-(3-(1-ethyl)phenyl)-2-bromoethanone (5c)

[0454]

[0455] The synthetic steps were the same as those in step 5a to obtain a yellow liquid, which was directly used in the next step without purification.

[0456] Synthesis of 1-(3-(1-bis(deuterated ethyl)phenyl)-2-hydroxyethanone (6a)

[0457]

[0458] 1-(3-(1-bisdeuterated ethyl)phenyl)-2-bromoethanone (2.12 g, 9.25 mmol), sodium formate (1.26 g, 18.53 mmol), and 20 mL of methanol were placed in a 100 mL single-necked flask and heated to 80°C under reflux. The reaction was complete after 5 hours. 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, and dried over anhydrous sodium sulfate. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1, v / v) to obtain 0.93 g of a yellow liquid with a yield of 60.2%.

[0459] 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).

[0460] Synthesis of 1-(3-(1-deuteroethyl)phenyl)-2-hydroxyethanone (6b)

[0461]

[0462] The synthesis steps were the same as those in 6a, and a yellow liquid was obtained with a yield of 45.1%.

[0463] 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).

[0464] Synthesis of 1-(3-ethylphenyl)-2-hydroxyethanone (17c)

[0465]

[0466] The synthesis steps were the same as those in 6a, and a yellow liquid was obtained with a yield of 56.3%.

[0467] 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).

[0468] Synthesis of 1-(3-(1-bis(deuterated ethyl)phenyl)-ethylene glycol) (Compound 42)

[0469]

[0470] 1-(3-(1-bisdeuterated ethyl)phenyl)-2-hydroxyethanone (0.93 g, 5.60 mmol) was weighed into a 50 mL single-necked flask and dissolved in 10 mL of methanol. Stirring was carried out at 0°C. Sodium borohydride (0.11 g, 2.89 mmol) was slowly added to the reaction mixture in an ice bath. After addition, the reaction was allowed to react at room temperature. The solvent was removed by rotary evaporation, and the reaction mixture was extracted with ethyl acetate and water. The extract was washed with ethyl acetate and saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4:1, v / v) to obtain 0.77 g of a colorless solid with a yield of 81.4%.

[0471] 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.

[0472] Synthesis of 1-(3-(1-deuteroethyl)phenyl)-ethylene glycol (Compound 43)

[0473]

[0474] The synthesis steps were the same as those of TJH1, and a colorless solid was obtained with a yield of 80.1%.

[0475] 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.

[0476] Synthesis of 1-(3-ethylphenyl)-1-deutero-ethylene glycol (Compound 44)

[0477]

[0478] The synthesis steps were the same as those of TJH1, and a colorless solid was obtained with a yield of 79.8%.

[0479] 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] - .

[0480] 43. Synthesis process of compounds 45-49

[0481] Synthesis of 1-(3-(1-ethylphenyl)-ethylene glycol (7)

[0482]

[0483] Weigh 1-(3-ethylphenyl)-2-hydroxyethanone (0.87 g, 5.30 mmol) into a 50 mL single-necked flask, add 10 mL of methanol and dissolve, stirring at 0°C. Slowly add sodium borohydride (0.22 g, 5.30 mmol) to the reaction mixture in an ice bath. After addition, 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 over anhydrous sodium sulfate. Purify the crude product by silica gel column chromatography (petroleum ether / ethyl acetate = 4:1, v / v) to obtain 0.75 g of a colorless solid with a yield of 85.2%.

[0484] 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).

[0485] Synthesis of 1-(3-ethylphenyl)ethane-1,2-diacetic acid diester (Compound 45)

[0486]

[0487] Weigh 1-(3-ethylphenyl)-ethylene glycol (0.50 g, 3.01 mmol) into a 50 mL single-necked flask, add 5 mL of dichloromethane to dissolve, and stir at room temperature. Add 4-dimethylaminopyridine (0.04 g, 0.33 mmol) and acetic anhydride (1.23 g, 12.05 mmol) to the reaction mixture and allow to react 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 over anhydrous sodium sulfate. Purify the crude product by silica gel column chromatography (petroleum ether / ethyl acetate = 25:1, v / v) to obtain 0.61 g of a colorless, clear liquid with a yield of 81.0%.

[0488] 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).

[0489] Synthesis of 4-(3-ethylphenyl)-1,3-dioxolane-2-one (Compound 46)

[0490]

[0491] Weigh 1-(3-ethylphenyl)-ethylene glycol (0.50 g, 3.01 mmol) into a 50 mL single-necked flask and dissolve in 5 mL of toluene. Add 2-pyridyl carbonate (1.30 g, 6.01 mmol) to the reaction mixture, and heat to 60°C for reaction. 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 over anhydrous sodium sulfate. Purify the crude product by silica gel column chromatography (petroleum ether / ethyl acetate = 20:1, v / v) to obtain 0.38 g of a colorless, clear liquid with a yield of 65.7%.

[0492] 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).

[0493] Synthesis of 4-(3-ethylphenyl)-2,2-dimethyl-1,3-dioxolane (Compound 47)

[0494]

[0495] Weigh 1-(3-ethylphenyl)-ethylene glycol (0.50 g, 3.01 mmol) into a 50 mL single-necked flask and dissolve in 3 mL of tetrahydrofuran. Add ferric chloride (0.17 g, 1.50 mmol) and 3 mL of acetone to the reaction mixture and allow to react at room temperature, resulting in a brownish color. Remove the solvent by rotary evaporation at room temperature. Extract the reaction mixture with dichloromethane and water. Wash the extract with dichloromethane and saturated sodium chloride solution, dry over anhydrous sodium sulfate, and remove the 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 obtain 0.52 g of a light yellow liquid with a yield of 83.7%.

[0496] 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).

[0497] Synthesis of 4-(3-ethylphenyl)-2-methyl-1,3-dioxolane (Compound 48)

[0498]

[0499] 1-(3-Ethylphenyl)-ethylene glycol (0.50 g, 3.01 mmol) was weighed into a 50 mL single-necked flask and dissolved in 3 mL of tetrahydrofuran. Ferric chloride (0.17 g, 1.50 mmol) and acetaldehyde (0.54 g, 12.27 mmol) were added to the reaction solution and allowed to react at room temperature, resulting in a brownish color. The solvent was removed by rotary evaporation at room temperature, and the reaction solution was extracted with dichloromethane and water. The extract was washed with dichloromethane and saturated sodium chloride solution, dried over anhydrous sodium sulfate, and then rotary evaporated at room temperature to remove dichloromethane. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 50:1, v / v) to obtain 0.36 g of a light yellow liquid with a yield of 62.1%.

[0500] 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).

[0501] Synthesis of 2-(3-ethylphenyl)oxirane (Compound 49)

[0502]

[0503] Weigh 2-bromo-1-(3-ethylphenyl)ethan-1-one (0.50 g, 2.20 mmol) into a 50 mL single-necked flask and dissolve in 5 mL of anhydrous methanol. Stir at 0°C. Weigh sodium borohydride (0.08 g, 2.11 mmol) and add it to the reaction mixture. After addition, remove the ice bath and allow the reaction to proceed at room temperature. Monitor the reaction progress with a plate count. Once the starting materials have reacted, weigh potassium carbonate (0.60 g, 4.40 mmol) and add it to the reaction mixture. Stir overnight at room temperature. Remove the solvent by rotary evaporation, extract the reaction mixture with dichloromethane and water, wash the extract with dichloromethane and saturated sodium chloride solution, and dry over anhydrous sodium sulfate. Purify the crude product by silica gel column chromatography (petroleum ether / ethyl acetate = 100:1, v / v) to obtain 0.11 g of a colorless liquid with a yield of 33.7%.

[0504] 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).

[0505] (R)-2-(3-Ethylphenyl)-2-hydroxyethyl-L-valine (Compound 50)

[0506]

[0507] Step 1 (R)-2-(3-ethylphenyl)-2-hydroxyethyl(tert-butoxycarbonyl)-L-valine (50-1)

[0508] To a 100 mL single-necked round-bottom flask were added (R)-1-(3-ethylphenyl)ethane-1,2-diol (8.00 g, 48.0 mmol), (tert-butyloxycarbonyl)-L-valine (2.10 g, 9.60 mmol), and 4-dimethylaminopyridine (0.23 g, 1.92 mmol), followed by 40 mL of dichloromethane as the 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 warmed to room temperature and stirred for 2 h. The reaction progress was monitored by thin-layer chromatography. After completion of the reaction, 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, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent, yielding a pale yellow oily liquid. The corresponding (R)-2-(3-ethylphenyl)-2-hydroxyethyl(tert-butoxycarbonyl)-L-valine was separated and purified by rapid silica gel column chromatography (petroleum ether / ethyl acetate = 30:4) to obtain 1.20 g of the corresponding yellow oily liquid (R)-2-(3-ethylphenyl)-2-hydroxyethyl(tert-butoxycarbonyl)-L-valine in a yield of 34.0%.

[0509] LC-MS: m / z: 366.3 (M+H) + .

[0510] Step 2 (R)-2-(3-ethylphenyl)-2-hydroxyethyl-L-valine (50)

[0511] To a 50 mL single-necked round-bottom flask, (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 as the solvent. The mixture was stirred at room temperature for 3 h, and the reaction progress was monitored by thin-layer chromatography. After completion of the reaction, the reaction solution was concentrated and extracted with ethyl acetate. The combined organic layers were washed sequentially with saturated sodium bicarbonate, water, and saturated sodium chloride, then dried over anhydrous sodium sulfate and concentrated under reduced pressure to remove the solvent, yielding a pale yellow oily liquid. Purification by flash silica gel column chromatography (ethyl acetate / methanol = 10:1) afforded 0.97 g of the corresponding (R)-2-(3-ethylphenyl)-2-hydroxyethyl-L-valine as a white oily liquid, yielding 75.0%.

[0512] 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) + .

[0513] (R)-2-((L-valyl)oxy)-2-(3-ethylphenyl)valine ethyl ester (Compound 51)

[0514]

[0515] Step 1: (R)-2-(((tert-Butoxycarbonyl)-L-valyl)oxy)-2-(3-ethylphenyl)ethyl(tert-Butoxycarbonyl)valine (51-1)

[0516] To a 25 mL single-necked round-bottom flask were added (R)-1-(3-ethylphenyl)ethane-1,2-diol (0.50 g, 3.00 mmol), (tert-butyloxycarbonyl)-L-valine (4.60 g, 21.0 mmol), and 4-dimethylaminopyridine (0.60 g, 4.80 mmol), followed by 5 mL of dichloromethane as the 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 warmed to room temperature and stirred for 2 h. The reaction progress was monitored by thin-layer chromatography. After completion of the reaction, 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, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent, yielding a pale yellow oil. The product was separated and purified by flash silica gel column chromatography (petroleum ether / ethyl acetate = 30:4) to obtain 1.01 g of the corresponding yellow oily liquid (R)-2-(((tert-butoxycarbonyl)-L-valyl)oxy)-2-(3-ethylphenyl)ethyl(tert-butoxycarbonyl)valine in a yield of 60.0%.

[0517] LC-MS: m / z: 565.4 (M+H) + .

[0518] Step 2 (R)-2-((L-valyl)oxy)-2-(3-ethylphenyl)valine ethyl ester (51)

[0519] To a 50 mL single-necked round-bottom flask was added (R)-2-(((tert-butoxycarbonyl)-L-valyl)oxy)-2-(3-ethylphenyl)ethyl(tert-butoxycarbonyl)valine (1.00 g, 1.77 mmol) and 20 mL of ethyl acetate hydrochloride as solvent. The mixture was stirred at room temperature for 3 h, and the reaction progress was monitored by thin-layer chromatography. After completion of the reaction, the reaction solution was concentrated and extracted with ethyl acetate. The combined organic layers were washed sequentially with saturated sodium bicarbonate, water, and saturated sodium chloride, then dried over anhydrous sodium sulfate and concentrated under reduced pressure to remove the solvent, yielding a pale yellow oily liquid. Purification by flash silica gel column chromatography (ethyl acetate / methanol = 10:1) afforded 0.45 g of the corresponding (R)-2-((L-valyl)oxy)-2-(3-ethylphenyl)valine ethyl ester as a white oily liquid, yielding 70.0%.

[0520] 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) + .

[0521] (R)-2-(3-Ethylphenyl)-2-hydroxyethyl octanoate (52)

[0522]

[0523] Synthesis method:

[0524] To a 100 mL single-necked round-bottom flask were added (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), followed by 50 mL of dichloromethane as the 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 warmed to room temperature and stirred for 2 h. The reaction progress was monitored by thin-layer chromatography. After completion of the reaction, 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, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent, yielding a pale yellow oil. The corresponding yellow oily liquid (R)-2-(3-ethylphenyl)-2-hydroxyethyl octanoate (0.45 g) was separated and purified by rapid silica gel column chromatography (petroleum ether / ethyl acetate = 30:4) with a yield of 26.0%.

[0525] 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).

[0526] Compounds 53-66 were synthesized using the following method:

[0527] Synthesis Route 1

[0528]

[0529] Reagents and conditions: (a) Pd(dppf)Cl2, K2CO3, 85℃, N2; (b) ADmixβ, t-BuOH, H2O at room temperature.

[0530] Synthesis Route 2

[0531]

[0532] Reagents and conditions: (c) Ag2CO3, AgOTf, DCM, room temperature; (d) K2CO3, MeOH / DCM, room temperature;

[0533] Synthesis of (R)-1-(3-cyclopropylphenyl)ethane-1,2-diol (Compound 53)

[0534] Step 1: Synthesis of 1-cyclopropyl-3-vinylbenzene (Compound 53)

[0535]

[0536] To a 10 mL Shrek tube, 1-bromo-3-cyclopropylbenzene (1.01 mmol, 200 mg), potassium ethylene trifluoroborate (1.21 mmol, 162 mg), Dppf palladium dichloride (0.10 mmol, 73 mg), and potassium carbonate (2.02 mmol, 279 mg) were added sequentially. A 4 mL mixture of dioxane and water (6:1) was used as the solvent. Oxygen was removed under nitrogen protection. The reaction was allowed to proceed at 85°C for 2 hours, and the reaction progress was monitored by TLC. After completion of the reaction, the dioxane was removed by concentration, and the product was extracted three times with ethyl acetate and water. The combined organic phases were concentrated and purified by column chromatography (pure PE) to afford the intermediate 1-cyclopropyl-3-vinylbenzene (a transparent oil, 108 mg, 74.1% yield).

[0537] 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).

[0538] Step 2: Synthesis of (R)-1-(3-cyclopropylphenyl)ethane-1,2-diol (Compound 53)

[0539]

[0540] To a 50 mL single-necked flask, 1-cyclopropyl-3-vinylbenzene (0.56 mmol, 80 mg) was added, followed by AD-mix-β (0.34 mmol, 261 mg) in an ice bath. The reaction was allowed to proceed overnight at room temperature using a 1:1 ratio of tert-butanol and water as the solvent. After completion of the reaction, the mixture was extracted three times with ethyl acetate and water. The combined organic phases were concentrated and purified by column chromatography (PE:EA = 5:1) to afford (R)-1-(2-ethylpyridin-4-yl)ethane-1,2-diol as a white solid, 40 mg, 40.0% yield.

[0541] 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%.

[0542] The following compounds (54-66) were synthesized according to the above steps ab:

[0543] Synthesis of (R)-1-(2-ethylpyridin-4-yl)ethane-1,2-diol (Compound 54)

[0544]

[0545] 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%.

[0546] Synthesis of (R)-1-(3-isopropylphenyl)ethane-1,2-diol (Compound 55)

[0547]

[0548] 1H NMR (600 MHz, Chloroform-d) δ 7.28 (t, J = 7.5 Hz, 1H), 7.21 (d, J = 1.8 Hz, 1H), 7.20–7.14 (m, 2H), 4.93–4.68 (m, 1H), 3.93–3.51 (m, 2H), 2.90 (hept, J = 6.9 Hz, 1H), 2.52 (s, 2H), 1.25 (s, 3H), 1.24 (s, 3H). LC-MS: calculated value C 11 H 14 NO2[MH] - :179.12, experimental value 179.1. ee value: 92.5%.

[0549] Synthesis of (R)-1-(3-(trifluoromethyl)phenyl)ethane-1,2-diol (Compound 56)

[0550]

[0551] 1 H NMR (600 MHz, 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 for C9H9F3O2 [M+COOH] - :251.06, experimental value 251.1. ee value: 94.3%.

[0552] (R)-1-(3-Methoxyphenyl)ethane-1,2-diol (Compound 57)

[0553]

[0554] 1 H NMR(400MHz,DMSO-d6)δ7.21(t,J=8.0Hz,1H),6.93–6.88(m,2H),6.81–

[0555] 6.76 (m, 1H), 5.22 (d, J = 4.3 Hz, 1H), 4.70 (t, J = 5.8 Hz, 1H), 4.52 (dt, J = 6.7, 4.8 Hz, 1H), 3.74 (s, 3H), 3.46–3.39 (m, 2H). LC-MS: calculated for C9H 12 O3[M+COOH] -:213.08, measured value 213.10. ee value: 97.2%.

[0556] (R)-1-(3-(1,1-difluoroethyl)phenyl)ethane-1,2-diol (Compound 58)

[0557]

[0558] 1 H NMR (600 MHz, DMSO-d6) δ 7.53 (s, 1H), 7.45 (q, J = 4.2 Hz, 1H), 7.42 (d, J = 4.6 Hz, 2H), 5.35 (d, J = 4.4 Hz, 1H), 4.75 (td, J = 5.8, 1.7 Hz, 1H), 4.62–4.55 (m, 1H), 3.45 (dtd, J = 11.2, 5.8, 3.1 Hz, 2H), 1.95 (t, J = 18.8 Hz, 3H). LC-MS: calculated value C 10 H 12 F2O2[M+COOH] - :247.08, measured value 247.10. ee value: 94.0%.

[0559] (R)-1-(3-Fluorophenyl)ethane-1,2-diol (Compound 59)

[0560]

[0561] 1 H NMR (500 MHz, 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 for C8H9FO2 [M+COOH] - :201.06, measured value 201.05. ee value: 92.3%.

[0562] (R)-1-(2-Chloro-5-(trifluoromethyl)phenyl)ethane-1,2-diol (Compound 60)

[0563]

[0564] 1H NMR (600 MHz, 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 for C9H8ClF3O2 [M + COOH] - :285.02, experimental value 285.0. ee value: 82.9%.

[0565] (R)-1-(4-Chloro-3-(trifluoromethyl)phenyl)ethane-1,2-diol (Compound 61)

[0566]

[0567] 1 H NMR (600 MHz, 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 for C9H8ClF3O2 [M+COOH] - :285.02, experimental value 285.0. ee value: 91.6%.

[0568] (R)-1-(3,5-bis(trifluoromethyl)phenyl)ethane-1,2-diol (Compound 62)

[0569]

[0570] 1 H NMR (600 MHz, Chloroform-d) δ 7.86 (s, 2H), 7.82 (s, 1H), 4.97 (dd, J = 7.8, 3.4 Hz, 1H), 3.87 (dd, J = 11.2, 3.3 Hz, 1H), 3.66 (dd, J = 11.2, 7.8 Hz, 1H). LC-MS: calculated value C 10 H8F6O2[M+COOH] - :319.04, experimental value 319.00.

[0571] (R)-1-(2-Fluoro-5-(trifluoromethyl)phenyl)ethane-1,2-diol (Compound 63)

[0572]

[0573] 1 H NMR (600 MHz, Chloroform-d) δ 7.82 (ddd, J = 6.6, 2.4 Hz, 1H), 7.53 (ddd, J = 7.8, 4.7, 2.4 Hz, 1H), 7.11 (t, J = 9.1 Hz, 1H), 5.14 (dd, J = 8.1, 3.0 Hz, 1H), 3.83 (dd, J = 11.5, 3.0 Hz, 1H), 3.60 (dd, J = 11.5, 8.0 Hz, 1H). LC-MS: calculated for C9H8F4O2 [M+COOH] - :269.04, experimental value 269.00. ee value: 94.0%.

[0574] (R)-1-(3-Fluoro-5-(trifluoromethyl)phenyl)ethane-1,2-diol (Compound 64)

[0575]

[0576] 1 H NMR (600 MHz, Chloroform-d) δ 7.42 (s, 1H), 7.29 (dt, J = 9.1, 1.9 Hz, 1H), 7.25 (dt, J = 8.4, 2.0 Hz, 1H), 4.86 (dd, J = 8.0, 3.4 Hz, 1H), 3.80 (dd, J = 11.4, 3.4 Hz, 1H), 3.61 (dd, J = 11.4, 8.0 Hz, 1H). LC-MS: calculated for C9H8F4O2 [M+COOH] - :269.05, experimental value 269.1. ee value: 90.9%.

[0577] (R)-1-(3-Ethyl-4-fluorophenyl)ethane-1,2-diol (Compound 65)

[0578]

[0579] 1 H NMR (600 MHz, DMSO-d6) δ 7.24 (dd, J = 7.7, 2.2 Hz, 1H), 7.17 (ddd, J = 7.9, 5.1, 2.2 Hz, 1H), 7.04 (dd, J = 10.2, 8.4 Hz, 1H), 5.22 (d, J = 4.2 Hz, 1H), 4.69 (t, J = 5.8 Hz, 1H), 4.52–4.46 (m, 1H), 3.44–3.36 (m, 2H), 2.60 (q, J = 7.6 Hz, 2H), 1.16 (t, J = 7.6 Hz, 3H). LC-MS: calculated value C 10 H 13FO2[M+COOH] - :229.09, measured value 229.10. ee value: 80.6%.

[0580] (R)-1-(3-Ethyl-2-methylphenyl)ethane-1,2-diol (Compound 66)

[0581]

[0582] 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.

[0583] Synthesis route of compounds 67-69

[0584] The specific synthesis method of the above steps cd is as follows:

[0585] Step 1 Synthesis of (2S, 3S, 4R, 5S)-2-(acetoxymethyl)-6-((R)-2-(3-ethylphenyl)-2-hydroxyethoxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate (Compound 67)

[0586]

[0587] To a 100 mL single-necked round-bottom flask were added (R)-1-(3-ethylphenyl)ethane-1,2-diol (0.80 mmol, 133 mg), bromosugar (0.80 mmol, 397 mg), AgCO (0.48 mmol, 132 mg), and silver trifluoromethanesulfonate (0.48 mmol, 123 mg). After stirring for 24 h, the reaction was monitored by TLC. After completion, the reaction was filtered and the solvent was removed by rotary evaporation. Column chromatography (PE:EA = 5:1) afforded the corresponding intermediate, (2S,3S,4R,5S)-2-(acetoxymethyl)-6-((R)-2-(3-ethylphenyl)-2-hydroxyethoxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate (119 mg, 30.0% yield).

[0588] Synthesis of (3S,4R,5R,6S)-2-((R)-2-(3-ethylphenyl)-2-hydroxyethoxy)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (Compound 67)

[0589]

[0590] To a 100 mL round-bottom flask, the intermediate (2S,3S,4R,5S)-2-(acetoxymethyl)-6-((R)-2-(3-ethylphenyl)-2-hydroxyethoxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate (0.24 mmol, 119 mg), potassium carbonate (0.24 mmol, 33 mg), and dichloromethane / methanol (1:1) were added sequentially. The reaction progress was monitored by TLC. After completion of the reaction, the product was concentrated by rotary evaporation and separated using a reverse-phase column (35 mg, 45.0% yield).

[0591] 1 H NMR (500 MHz, 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 value C 16 H 24 O7[M+NH4] + :346.18, measured value 346.20. ee value: 82.2%.

[0592] The following compounds (68-69) were synthesized according to the method of steps cd above:

[0593] (2R,3R,4R,5S)-6-((R)-2-(3-ethylphenyl)-2-hydroxyethoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid (Compound 68)

[0594]

[0595] 1H NMR (400 MHz, 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 value C 16 H 22 O8[M+NH4] + :360.16, measured value 360.20.

[0596] (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)

[0597]

[0598] 1 H NMR (500 MHz, 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 value C 22 H 34 O 12 [MH] - :489.20. Measured value [MH] - :489.30.

[0599] EE value test method: The ee value analysis of all final compounds was performed on an Agilent 1260 infinity series using a CHIRALCEL OD-H, 4.6 mm × 250 mm, a flow rate of 0.5 mL / min, and a solvent of 90% n-hexane / 10% ethanol.

[0600] Experimental Example 2. Cryo-EM electron microscopy to obtain the structure of the TRPV4-Compound 1-R complex

[0601] In this study, we obtained a high-resolution cryo-electron microscopy structure of human TRPV4 and a novel selective inhibitor, compound 1-R (PDB ID: 8W82, resolution The structure captures TRPV4 in a "closed" conformation. We discovered that compound 1-R resides in a novel binding pocket in TRPV4. Through structural comparison, long-range molecular dynamics simulations, and single- and multi-site mutagenesis experiments, we elucidated the unique allosteric gating mechanism of compound 1-R.

[0602] Materials and methods

[0603] 1.1 Expression and purification of MBP-TRPV4 protein

[0604] Human TRPV4 protein (amino acids 148 to 787) was cloned into the pEGBacMam vector. The resulting protein contained a maltose-binding protein tag at its N-terminus. P4 baculovirus was produced in Sf9 cells using the Bac-to-Bac Baculovirus Expression System (Invitrogen). HEK293F cells were cultured at 2.0–3.0 × 10 6 Cells were infected with 10% (v / v) P4 baculovirus at a density of 10 cells / ml to express proteins at 37° C. After 12 to 18 hours, 10 mM sodium butyrate was added and the temperature was lowered to 30° C. Cells were harvested within 72 hours after transfection and frozen at −80° C.

[0605] Prior to lysis, cells were suspended in a buffer containing 50 mM Hepes, 150 mM NaCl, pH 7.5, and an EDTA-free protease inhibitor cocktail, and cell membranes were disrupted by the Donaldson homogenization method. Lysed cell membranes were collected by ultracentrifugation at 40,000 rpm for 60 minutes, and the pellet was resuspended and homogenized by the Donaldson method in a buffer containing 1.0% (wt / vol) N-dodecyl-β-D-maltopyranoside (DDM; Anatrace), 0.1% (wt / vol) cholesterol hemisuccinate (CHS; Anatrace), 50 mM Hepes, pH 7.5, and 150 mM NaCl, pH 7.5, plus an EDTA-free protease inhibitor cocktail. Protein solubilization was performed at 4°C for 3 hours, followed by ultracentrifugation at 40,000 rpm for 60 minutes. After centrifugation, the soluble supernatant was incubated with maltose resin (Bio Labs) for 4 hours at 4°C. The resin was eluted with 50 mM Hepes, 150 mM NaCl, 0.05% (wt / vol) GDN (Anatrace). The protein was eluted with six column volumes of 50 mM Hepes, 150 mM NaCl, 0.05% (wt / vol) GDN and 40 mM maltose. To remove the MBP tag on TRPV4, recombinant human rhinovirus (HRV 3C) protease was added and the reaction was allowed to react at 4°C overnight. Finally, the protein was concentrated to 1.0 mL using a 100 kDa molecular weight cutoff concentrator (Millipore) and further purified by Superose 6 gel exclusion column (Cytiva) in 50 mM Hepes, 150 mM NaCl, pH 7.5, 0.05% (wt / vol) GDN. Peak fractions were collected and concentrated to 5 mg / mL for cryo-EM sample preparation.

[0606] 1.2 Cryo-electron microscopy analysis of the TRPV4-compound 1-R complex

[0607] 18.3 μL of purified hTRPV4 protein at a concentration of 5.5 mg / mL was incubated with 2.0 μL of compound 1-R at a concentration of 0.25 mg / mL at a molar ratio of 1:20 on ice for 40 minutes before centrifugation (16200 g, 4°C, 5 minutes). The TRPV4-compound 1-R complex sample was then used to prepare cryo-EM grids.

[0608] A 4 μL protein sample of the TRPV4-Compound 1-R complex was applied to a glow-discharged 300 mesh grid (Quantifoil Au R1.2 / 1.3) and patted dry with filter paper for 3.0 seconds and 3 times. Subsequently, the grids were flash-frozen in liquid ethane using a Thermo Fisher Vitrobot Mark IV at 8°C and 100% humidity. Cryo-EM grids were stored in liquid nitrogen prior to data acquisition. Cryo-EM micrographs were collected using a 300 kV Thermo Fisher Titan Krios G3i electron microscope equipped with a K3 direct detection camera and a BioContinuum energy filter (GIF, slit width of 20 eV). These micrographs were collected at a calibrated magnification of 64,000 times with a pixel size of 1 in super-resolution mode. A total of 15,646 micrographs were collected, with a cumulative electron dose of The image was divided into 32-frame stacks with a defocus range of -1.0μm to -2.0μm. The exposure time and dose rate were 2.6 seconds and approximately 22e-pixel-1s-1, respectively.

[0609] Frame stacks were corrected for beam-induced motion using MotionCorr2. Contrast transfer function (CTF) parameters were determined using CTFFIND4. A total of 15,646 good micrographs were selected for further data processing using CryoSPARC. These micrographs were screened to remove suboptimal data, resulting in a final set of 13,043 micrographs retained. Automated particle picking was performed in CryoSPARC using the blob picker and template picker routines, followed by three rounds of reference-free 2D classification. Next, 1,751,252 particles were selected from the good 2D classes and subjected to three rounds of multi-reference 3D classification using a model generated by conventional 3D classification. From each round of multi-reference 3D classification, a 3D class with converged TRPV4 features was selected, and duplicate particles were removed. For the final heterogeneity refinement, 1,040,133 particles were selected from the 3D class showing the highest resolution features and subjected to a round of 3D refinement with C4 symmetry, ultimately achieving a global resolution of 0.143 under the gold standard Fourier shell correlation criterion. The local resolution is then calculated on the final density map.

[0610] The model of the TRPV4-Compound 1-R complex was constructed by fitting the AlphaFold2-predicted complex structure to the density map in UCSF Chimera, and the complex was subsequently manually modeled in COOT and structure refined in PHENIX.

[0611] Results and discussion

[0612] In this study, we obtained a high-resolution cryo-electron microscopy structure of human TRPV4 and a novel selective inhibitor, compound 1-R (PDB ID: 8W82, resolution The high-quality cryo-electron microscopy data collected revealed clearly visible secondary structural elements, as determined by 2D class averaging. A four-fold rotationally symmetric (C4) 3D reconstruction of the TRPV4-Compound 1-R structure was generated. For each subunit in the TRPV4-Compound 1-R homotetramer, a precise model was constructed for residues 148–787, excluding the S5-P region (residues 639–654), a loop that was not clearly resolved in the cryo-EM density.

[0613] Based on this density map, we constructed a three-dimensional structural model of TRPV4-Compound 1-R, revealing that TRPV4 adopts a typical tetrameric assembly of TRP channels, consisting of a central transmembrane domain (TMD) flanked by extracellular and intracellular domains. Within the TMD, there are six transmembrane helices (S1-S6), with the TRP helices oriented parallel to the membrane, and several adjacent helices in the elbow and pore regions. S1-S4 form an α-helical VSLD bundle, while S5-S6 extend outward from the S1-S4 bundle and interact with adjacent monomers to form the pore domain through domain exchange. The adjacent intracellular skirt domain is composed of ankyrin repeat domains (ARDs), an N-terminal helical region, and a C-terminal β-sheet coiled domain. ARDs oligomerize with the β-pleated regions of adjacent monomers, including one at the C-terminus and two in the linker domain between the ARD and S1. The overall structure of TRPV4-compound 1-R is similar to the previously reported TRPV4-4α-PDD structure.

[0614] Compound 1-R binding induces a significant conformational rearrangement within the pore, leading to a conformational closure of the ion channel. Compared to the “open” structure of TRPV4 (PDB:7AA5), in our TRPV4-compound 1-R structure, the lower gate region of the ion permeation pathway has significant changes in both pore shape and electrostatic potential. The S6 helix rotates clockwise, and the gating M718 shifts toward the central pore, resulting in a decrease in pore diameter. Notably, M718 rotates nearly 100° and extends into the channel lumen, forming a hydrophobic seal whose diameter changes from the open state to the Significantly reduced to closed state Therefore, in the closed state, the pore radius at M718 decreases and is shorter than the narrowest region (I715) in the open state ( Compare ), effectively preventing the passage of cations. Therefore, Cyro-EM captured the TRPV4-compound 1-R structure in a "Closed" state.

[0615] Within the transmembrane helical region, there are four well-defined "C"-shaped densities, comparable in size to the compound 1-R molecule. Compound 1-R is wedged in the cleft between these helices, and the ligand matches well with the shape of this independent density. This is because we refer to the ligands with hydroxyl and phenylethyl cores as "tails" and "heads," respectively, with the hydrophobic "head" pointing toward the pore domain. From the high-resolution density map, it can be seen that the binding of compound 1-R is stabilized by extensive hydrogen bonding and salt bridge contacts, as well as hydrophobic interactions. Within the binding pocket, polar residues play an important role in attracting the hydrophilic "tail" of compound 1-R by forming hydrogen bonds and salt bridge interactions. Hydrophobic residues help stabilize the phenylethyl group ("head").

[0616] Example 3: Point mutation experiment to verify binding site (mutation of key amino acid residues to verify binding)

[0617] Electrophysiological testing and analysis:

[0618] hTRPV4 electrophysiological assays were performed using stably transfected cell lines based on the HEK293 standard cell line provided by ICE Bioscience (Beijing, China).

[0619] Electrophysiological analysis of hTRPV4 mutations was performed using transiently transfected HEK-293T cells. The full-length hTRPV4 cDNA (NM_021625.5) was amplified using HEK293 cDNA as a template. The hTRPV4 cDNA was subcloned into the pcDNA3.1 vector (Invitrogen). All hTRPV4 mutants were generated by site-directed mutagenesis. All mutant plasmids used in this study were verified by DNA sequencing.

[0620] Whole-cell patch-clamp recordings were performed at room temperature using a HEKA EPC10 amplifier and PatchMaster software (HEKA Harvard, Holliston, Church Hill, TN, USA). Currents were filtered at 2 kHz and sampled at 10 kHz. For ramp recordings, the pipette solution contained 50 mM CsCl, 10 mM NaCl, 10 mM HEPES, 60 mM CsF, and 20 mM EGTA (buffered to pH 7.2 with CsOH), and the bath solution contained 140 mM NaCl, 3.5 mM KCl, 1 mM MgCl2·6H2O, 2 mM CaCl2·2H2O, 10 mM D-Glucose, 10 mM HEPES, and 1.25 mM NaH2PO4·2H2O (buffered to pH 7.4 with NaOH solution). Cells were held at 0 mV, and then a ramp stimulus from -100 mV to +100 mV was applied every 5 seconds.

[0621] The dose-response curve was calculated using the Hill equation Y = 1 / (1 + 10^((LogIC 50 -X)*HillSlope)) for fitting, IC 50 Calculations and curve fitting were performed using GraphPad Prism software.

[0622] All recordings were performed at room temperature, with all compounds pumped into the bath at the same rate. All agonists were purchased from Sigma-Aldrich.

[0623] The results of the point mutation test on TRPV4 are shown in Table 1. IC of compound 1-R inhibiting TRPV4 50 The value was 2.27 μM.

[0624] Table 1: Electrophysiological results of TRPV4 point mutation experiments

[0625]

[0626] discuss:

[0627] In this study, by mutating the amino acids around the binding site of compound 1-R, it can be seen that the binding of compound 1-R to TRPV4 changes significantly, thus verifying the binding site of compound 1-R to TRPV4.

[0628] Example 4: Study on the antagonistic activity of compound-R derivatives against TRPV4

[0629] The in vitro antagonistic effect of the compounds provided by the present invention on TRPV4 was tested as follows. The electrophysiological detection method was the same as in Example 2. The antagonistic activity of all compounds was determined at a concentration of 5 μM.

[0630] The test results are shown in Table 2.

[0631] Table 2: Antagonistic activity of aryl vicinal diol compounds against TRPV4 (5 μM inhibition rate)

[0632]

[0633]

[0634]

[0635] Example 4: Selectivity experiment of compound 1-R for TRP family

[0636] Electrophysiological testing and analysis:

[0637] Electrophysiological assays of hTRPV4, hTRPV1, hTRPA1, and hTRPM8 were performed using stably transfected cell lines based on the HEK293 standard cell line, which was provided by ICE Bioscience (Beijing, China).

[0638] The remaining experimental steps are the same as those in Example 2.

[0639] IC of compound 1-R for inhibition of TRPV4 50 The IC value is 2.27 μM for other proteins in the TRP family (TRPV1, TRPA1, TRPV3 and hTRPM8). 50 The values ​​were all much larger than 100 μM, showing good family selectivity.

[0640] discuss:

[0641] This study conducted electrophysiological in vitro experiments on other TRP family proteins (TRPV1, TRPA1, TRPV3 and hTRPM8) and found that compound 1-R is a TRPV4 selective antagonist.

[0642] Example 5: Therapeutic effect of compound 1-R on lipopolysaccharide (LPS)-induced lung inflammation

[0643] 1) Grouping:

[0644] 1. Lipopolysaccharide (LPS)-induced lung inflammation model

[0645] 1) control group (NT);

[0646] 2) LPS in the surgical group;

[0647] 3) Surgery group + positive drug group (nintedanib)

[0648] 4) Surgery group + positive drug group (pirfenidone)

[0649] 5) Surgery group + drug to be tested 1

[0650] 6) Surgery group + drugs to be tested 10

[0651] 7) Surgery group + drugs to be tested 50

[0652] 2) Purchase of mice

[0653] Requirements: SPF-grade C57 male mice, 6-8 weeks old;

[0654] Quantity: 60;

[0655] Purchasing company: Shanghai Slake Laboratory Animal Co., Ltd.;

[0656] 3) Purchase of reagents

[0657] 1. Lipopolysaccharide (LPS)

[0658] 1) Total dosage: 10 mg / kg per mouse. 50 mice weighing approximately 25 g, so a total of 12.5 mg is required.

[0659] 4) Model Construction

[0660] 1. Model construction method:

[0661] 1) Lipopolysaccharide (LPS)-induced lung inflammation model

[0662] Lipopolysaccharide (LPS) was induced by intraperitoneal injection of LPS solution at 5 mg / kg body weight for three times.

[0663] 2. Dosage method:

[0664] Two weeks after model establishment, the drug was administered by feeding water and then continued for two weeks.

[0665] A lung inflammation model was induced in C57 male mice by intraperitoneal injection of lipopolysaccharide (LPS) at a dose of 5 mg / kg three times. Two weeks after modeling, the mice were administered the drug via water for two consecutive weeks. The mice were divided into a control group, a surgical group, a surgical group plus nintedanib (positive drug), a surgical group plus Compound 1R (1 mg / kg), a surgical group plus Compound 1R (10 mg / kg), and a surgical group plus Compound 1R (50 mg / kg). The results showed that the enhanced expiratory interval (Penh) index was significantly different from that of the surgical group in all three treatment groups, including the positive drug and Compound 1R, indicating comparable therapeutic efficacy. The minute ventilation (MV) index was also significantly different in all three Compound 1R treatment groups compared to the surgical group.

[0666] All documents mentioned in this application are incorporated herein by reference, just as if each document were incorporated herein by reference individually. It should also be understood that after reading the above teachings of the present invention, those skilled in the art may make various changes or modifications to the present invention, and that such equivalents also fall within the scope of the claims appended hereto.

Claims

1. Use of a compound of formula I, or a pharmaceutically acceptable salt or ester, prodrug, optical isomer, stereoisomer or solvate thereof, in the preparation of a TRPV4 inhibitor or antagonist. Where, A is selected from a C6-C10 aromatic ring or carbocyclic ring, or a 5-6 membered heterocyclic ring or aromatic heterocyclic ring containing 1, 2 or 3 heteroatoms selected from N, O or S; R1 and R4 are 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 may be various amino acid-forming groups), optionally substituted monosaccharide, disaccharide or polysaccharide groups; R2 and R5 are independently selected from H, D, OH, carbonyl, hydroxymethyl, optionally substituted C1-C10 alkyl, optionally substituted C1-C10 alkoxy, optionally substituted benzyloxy, optionally substituted phosphate, optionally substituted NH2, NHCH3, NHCOCH3, optionally substituted C1-C10 formyloxy, optionally substituted benzoyloxy, optionally substituted aminoacetoxy ( B can be various amino acid forming groups), COOH, COOCH3, CONH2, sulfonic acid group ( or sulfonate), halogen, optionally substituted monosaccharide, disaccharide or polysaccharide groups; or R1 and R2 or R4 and R5 are linked to form an optionally substituted 3-6 membered ring containing 0, 1 or 2 heteroatoms (preferably oxygen) selected from oxygen, nitrogen or sulfur, a cyclic carbonate lactone, a phosphate lactone or an 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, hydroxy, 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 carbocycle or an optionally substituted C3-C6 heterocycle containing 1 or 2 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 1 or 2 heteroatoms selected from oxygen, nitrogen or sulfur (preferably oxygen or nitrogen); m is an integer from 1 to 5; The hydrogens in the structures of Formula I are optionally deuterated.

2. The use according to claim 1, characterized in that The compound represented by formula I is the compound represented by formula II, Where, X1, X2, 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 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 group; R1 and R2 may form an optionally substituted 3-6 membered ring containing 0, 1 or 2 heteroatoms (preferably oxygen) selected from oxygen, nitrogen or sulfur; 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, hydroxy, 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; or two adjacent R3 substituents form an optionally substituted C3-C6 carbocycle or an optionally substituted C3-C6 heterocycle containing 1 or 2 heteroatoms selected from oxygen or nitrogen; m is an integer from 1 to 5; The hydrogen atoms in the structure of formula II are optionally deuterated.

3. The use according to claim 1, characterized in that The compound shown in formula I is the compound shown in formula III Where, 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 may be various amino acid-forming groups), optionally substituted monosaccharide, disaccharide or polysaccharide groups; R2 and R5 are 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 various amino acid forming groups), COOH, COOCH3, CONH2, optionally substituted monosaccharide, disaccharide or polysaccharide groups; R1 and R2 may form an optionally substituted 3-6 membered ring containing 0, 1 or 2 heteroatoms (preferably oxygen) selected from oxygen, nitrogen or sulfur; 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, hydroxy, 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 alkylformylamino, fluorine, chlorine, bromine, optionally substituted monosaccharide, disaccharide or polysaccharide; Alternatively, two adjacent R3 substituents form an optionally substituted C3-C6 carbocycle or an optionally substituted C3-C6 heterocycle containing 1 or 2 oxygens; m is an integer from 1 to 5; The hydrogen atoms in the structure of formula III are optionally deuterated.

4. The use according to claim 1, characterized in that The compound is shown in formula IV, 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 may be various groups forming amino acids), optionally substituted monosaccharide groups; 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 may be various groups forming amino acids), optionally substituted monosaccharide groups; 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, hydroxy, 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, bromine; Alternatively, two adjacent R3 substituents form an optionally substituted C3-C6 carbocycle or an optionally substituted C3-C6 heterocycle containing 1 or 2 oxygens; m is an integer from 1 to 3; The hydrogen atoms in the structure of formula IV are optionally deuterated.

5. The use according to claim 1, characterized in that Where, A is selected from phenyl; R1 and R4 are independently selected from H, D, OH, and optionally substituted C1-C6 alkoxy; R2 and R5 are independently selected from H, D, OH, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 formyloxy; or R1 and R2 or R4 and R5 are linked to form an optionally substituted 3-6 membered ring containing 0, 1 or 2 heteroatoms (preferably oxygen) selected from oxygen, nitrogen or sulfur, a cyclic carbonate lactone; R3 is selected from H, D, optionally substituted C1-C6 alkyl, D-substituted C1-C6 alkyl, optionally substituted C2-C6 alkylalkenyl, optionally substituted C1-C6 acyl; or, Two adjacent R3 substituents form an optionally substituted C3-C6 carbocycle or an optionally substituted C3-C6 heterocycle containing 1 or 2 heteroatoms selected from oxygen, nitrogen or sulfur (preferably oxygen or nitrogen); m is an integer from 1 to 3; The hydrogens in the structures of Formula I are optionally deuterated.

6. Use of the following compounds, or their salts, esters, prodrugs, optical isomers, or solvates, in the preparation of medicaments for preventing or treating heart failure and related diseases: Preferably, the compound is Most preferably, the compound is a compound selected from the group consisting of:

7. A compound of formula I, or a pharmaceutically acceptable salt or ester, prodrug, optical isomer, stereoisomer or solvate thereof, Where, A is selected from an optionally substituted C6-C10 aromatic ring or a 5-6 membered aromatic heterocycle containing 1, 2 or 3 heteroatoms selected from N, O or S; R1 and R4 are independently selected from H, D, OH, NH2, carbonyl (one of R1 or R4), optionally substituted C1-C10 alkyl (preferably C1-C6 alkyl), optionally substituted C1-C10 alkoxy (preferably C1-C6 alkoxy), optionally substituted aminoacetoxy ( B can be any group that forms an amino acid); R2 and R5 are independently selected from H, D, OH, COOH, sulfonic acid, oxygen ( Can the group in be called sulfonic acid groupoxy), optionally substituted aminoacetoxy ( B may be various amino acid-forming groups), optionally substituted NH2, optionally substituted C1-C10 alkyl (preferably C1-C6 alkyl), optionally substituted C1-C10 alkoxy (preferably C1-C6 alkoxy), phosphate group; or, R1 and R2 or R4 and R5 are linked to form an optionally substituted 3-6 membered ring containing 0, 1 or 2 heteroatoms (preferably oxygen) selected from oxygen, nitrogen or sulfur, a cyclic carbonate lactone, a phosphate lactone or an optionally substituted cyclic borate lactone; R3 is selected from H, D, optionally substituted C1-C10 alkyl (preferably C1-C6 alkyl) or alkenyl, optionally substituted C1-C10 alkyl (preferably C1-C6 alkyl) formyl, optionally substituted C1-C10 alkyl (preferably C1-C6 alkyl), D-substituted C1-C10 alkyl, halogen, optionally substituted C3-C10 cycloalkyl, optionally substituted C2-6 alkynyl; or, Two adjacent R3 substituents form an optionally substituted C3-C6 carbocycle or an optionally substituted C3-C6 heterocycle containing 1 or 2 heteroatoms selected from oxygen, nitrogen or sulfur (preferably oxygen), an optionally substituted C5-C10 aromatic ring or an optionally substituted C5-C10 heteroaromatic ring containing 1 or 2 heteroatoms selected from oxygen, nitrogen or sulfur (preferably oxygen); m is an integer from 1 to 5; The hydrogens in the structures of Formula I are optionally deuterated.

8. The compound according to claim 7, or a pharmaceutically acceptable salt or ester, prodrug, optical isomer, stereoisomer or solvate thereof, Where, A is selected from a C6-C10 aromatic ring or a 5-6 membered aromatic heterocycle containing 1, 2 or 3 heteroatoms selected from N, O or S; R1 and R4 are independently selected from H, D, OH, NH2, halogen, carbonyl; R2 and R5 are independently selected from H, D, OH, COOH, optionally substituted sulfonic acid group, optionally substituted NH2, halogen, optionally substituted phosphate group; or R1 and R2 or R4 and R5 are linked to form an optionally substituted 3-6 membered ring containing 0, 1 or 2 heteroatoms (preferably oxygen) selected from oxygen, nitrogen or sulfur, a cyclic carbonate lactone, a phosphate lactone or an optionally substituted cyclic borate lactone; R3 is selected from H, D, optionally substituted C1-C10 alkyl (preferably C1-C6 alkyl) alkenyl, formyl, optionally substituted C1-C10 alkyl (preferably C1-C6 alkyl) formyl, optionally substituted C1-C10 alkyl (preferably C1-C6 alkyl), D-substituted C1-C10 alkyl, halogen, optionally substituted C3-C10 cycloalkyl, optionally substituted C2-6 alkynyl; or, Two adjacent R3 substituents form an optionally substituted C3-C6 carbocycle or an optionally substituted C3-C6 heterocycle containing 1 or 2 oxygen atoms, an optionally substituted C5-C10 aromatic ring, or an optionally substituted C5-C10 heteroaromatic ring containing 1 or 2 oxygen atoms; m is an integer from 1 to 5; The hydrogens in the structures of Formula I are optionally deuterated.

9. The following compounds, or their salts, esters, prodrugs, optical isomers or solvates:

10. A pharmaceutical composition comprising the compound according to any one of claims 7 to 9, or a pharmaceutically acceptable salt or ester, prodrug, optical isomer, stereoisomer or solvate thereof, and a pharmaceutically acceptable carrier or excipient.

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