Compounds for treatment of pain-related diseases

Abstract

The invention provides a compound as shown in a formula I, or pharmaceutically acceptable salt or ester, prodrug, optical isomer, stereoisomer or solvate thereof. The compound disclosed by the invention can be used for preparing medicines for preventing or treating pain and related diseases thereof, so that a brand new material basis is laid for developing the pain and the related diseases thereof. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to the field of medicinal chemistry. Specifically, the present invention relates to a class of compounds having therapeutic effects on pain-related diseases. The present invention also relates to pharmaceutical compositions containing these compounds and the use of these compounds and pharmaceutical compositions in the preparation of drugs for pain-related diseases. Background Art

[0002] The International Association for the Study of Pain (IASP) published a new definition of pain in 2021: an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or an experience similar to this. Because pain greatly affects people's quality of life and causes huge socioeconomic costs, it has become a medical problem of widespread concern in countries around the world.

[0003] The pathophysiological pain classification method covers most of the common acute and chronic pain in clinical practice, mainly including: inflammatory pain, neuropathic pain, cancer pain, spasmodic pain, psychogenic pain and other pain. Pain can be divided into acute pain and chronic pain according to its duration. Usually, acute pain lasts from a few days to 12 weeks, is caused by injury or disease, and disappears after the primary cause is treated, so it is also considered to have a protective biological effect. Chronic pain is persistent or recurrent pain that lasts for more than 3 months. Since chronic pain is the result of a series of combined factors, it can be divided into three types according to its pathophysiological differences, namely nociceptive, neuropathic and plastic pain.

[0004] Acute pain is common in postoperative pain, cancer pain, and traumatic pain in certain disciplines (such as burns, intensive care units, and emergency departments). Among the current drug management strategies for acute pain, acetaminophen and non-steroidal anti-inflammatory drugs (NSAIDs) are the first-line treatment options for most patients with acute mild to moderate pain, while for severe or refractory acute pain, a combination of acetaminophen or NSAIDs and opioids is often recommended. However, when using these drugs, it is necessary to consider whether the patient has contraindications. For example, acetaminophen should be used with caution in patients with advanced liver disease, malnutrition, or severe alcohol use disorder, and NSAIDs should be used with caution in patients with a history of gastrointestinal bleeding, cardiovascular disease, or chronic kidney disease.

[0005] Nociceptive pain usually originates from tissue damage caused by trauma, non-healing injury or inflammatory process. It is a type of pain caused by activation of nociceptors by persistent inflammation and tissue damage. Treatment strategies for nociceptive pain include the use of opioids to directly inhibit activation of cortical areas that can produce subjective sensations of pain; the use of NSAIDs and cyclooxygenase 2 inhibitors can reduce the production of prostaglandin E2, thereby inhibiting the generation and development of immune responses. Although the long-term use of opioids is undisputed in the treatment of severe acute pain, current studies have reported that opioids are not recommended for the treatment of chronic non-cancer pain.

[0006] Neuropathic pain is defined as pain caused by damage or disease of the somatosensory nervous system. Common neuropathic pain includes herpes zoster neuralgia, trigeminal neuralgia, diabetes-related neuralgia, chemotherapy-induced neuralgia, and stroke. The treatment strategy for neuropathic pain mainly targets clinical symptoms, and currently available treatments include pharmacological and non-pharmacological methods. First-line treatment drugs mainly include tricyclic antidepressants (TCA), serotonin norepinephrine reuptake inhibitors (SNRI), and gabapentinoids (i.e., gabapentin and pregabalin); second-line drugs mainly include weak opioid analgesics (e.g., tramadol and tapentadol); and in the third-line drug regimen, strong opioids (e.g., morphine and oxycodone) are recommended for central and peripheral neuralgia, while botulinum toxin type A hemagglutinin complex is only recommended for peripheral use. Although there are many treatments for neuropathic pain, most drug therapies do not show satisfactory analgesic effects, and these drugs all have side effects to varying degrees, such as dry mouth, urinary retention, constipation, and postural hypotension caused by TCA drugs, dizziness and sedation caused by gabapentin drugs, and erythema and itching caused by topical drugs such as lidocaine ointment and capsaicin patches.

[0007] The causes of inflammatory pain include infection and injury. Infection is caused by bacteria, viruses, tuberculosis or other microorganisms, and injury is caused by degeneration, trauma, surgery, etc. Inflammation can be divided into tissue-induced, immunogenic and neurogenic inflammation. Most of the pain in the head, neck, shoulder, waist and legs, and myofascial pain belong to the category of inflammatory pain, which has the largest patient population.

[0008] Plastic pain has been described as a third type of chronic pain. This type of pain is mechanistically different from nociceptive pain, which is caused by ongoing inflammation and tissue damage, and neuropathic pain, which is caused by nerve damage. The mechanisms that cause this type of pain are not fully understood, but abnormalities in pain sensory processing in the central nervous system and altered pain modulation are thought to play an important role.

[0009] In short, for pain management, we are still actively seeking treatments with definite efficacy, fewer side effects and higher safety. This unmet medical need has also greatly promoted the study of the physiology and pathology of pain mechanisms and promoted the development of analgesic drugs to provide potential treatment strategies. Summary of the invention

[0010] The object of the present invention is to provide a compound having a therapeutic effect on pain and related diseases, wherein the compound is not only effective for pain and related diseases but also has the advantages of few side effects.

[0011] In the first aspect, the present invention provides the 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 drug for preventing or treating pain and related diseases.

[0012]

[0013] In the formula,

[0014] 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;

[0015] 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;

[0016] 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 oxygen group ( or sulfonate), halogen, optionally substituted monosaccharide, disaccharide or polysaccharide;

[0017] or

[0018] 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 boric acid lactone;

[0019] 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;

[0020] or,

[0021] Two adjacent R3 substituents form an optionally substituted C3-C6 carbocyclic ring or an optionally substituted C3-C6 heterocyclic ring 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);

[0022] m is an integer from 1 to 5;

[0023] The hydrogens in the structures of Formula I are optionally substituted with deuterium.

[0024] In a specific embodiment, the compound represented by formula I is a compound represented by formula II,

[0025]

[0026] In the formula,

[0027] X1, X2, X3 are each independently selected from CH, N, S or O (preferably CH or N);

[0028] 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 aminoformyloxy, optionally substituted monosaccharide, disaccharide or polysaccharide;

[0029] 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;

[0030] 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;

[0031] 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;

[0032] or an optionally substituted C3-C6 carbocyclic ring or an optionally substituted C3-C6 heterocyclic ring containing 1 or 2 heteroatoms selected from oxygen or nitrogen is formed by two adjacent R3 substituents;

[0033] m is an integer from 1 to 5;

[0034] The hydrogen in the structure of formula II is optionally substituted with deuterium.

[0035] In a specific embodiment, the compound of formula I is a compound of formula III

[0036]

[0037] In the formula,

[0038] 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;

[0039] 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;

[0040] 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;

[0041] 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;

[0042] Alternatively, two adjacent R3 substituents form an optionally substituted C3-C6 carbocyclic ring or an optionally substituted C3-C6 heterocyclic ring containing 1 or 2 oxygens;

[0043] m is an integer from 1 to 5;

[0044] The hydrogen in the structure of formula III is optionally substituted with deuterium.

[0045] In a specific embodiment, the compound is as shown in Formula IV,

[0046]

[0047] R1 is selected from H, D, OH, NH2, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkylformyloxy, optionally substituted carbamoyloxy, optionally substituted aminoacetoxy B can be various amino acid-forming groups), optionally substituted monosaccharide groups;

[0048] R2 is selected from OH, NH2, COOH, COONH2, COONHCH3, optionally substituted C1-C3 alkoxyformyl, optionally substituted C1-C3 alkylformyloxy, optionally substituted carbamoyloxy, optionally substituted aminoacetoxy B can be various amino acid-forming groups), optionally substituted monosaccharide groups;

[0049] 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;

[0050] Alternatively, two adjacent R3 substituents form an optionally substituted C3-C6 carbocyclic ring or an optionally substituted C3-C6 heterocyclic ring containing 1 or 2 oxygens;

[0051] m is an integer from 1 to 3;

[0052] The hydrogen in the structure of formula IV is optionally substituted with deuterium.

[0053] 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.

[0054] In a specific embodiment, wherein,

[0055] A is selected from phenyl;

[0056] R1 and R4 are independently selected from H, D, OH, and optionally substituted C1-C6 alkoxy;

[0057] R2 and R5 are independently selected from H, D, OH, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 formyloxy;

[0058] or

[0059] 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;

[0060] 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;

[0061] or,

[0062] Two adjacent R3 substituents form an optionally substituted C3-C6 carbocyclic ring or an optionally substituted C3-C6 heterocyclic ring containing 1 or 2 heteroatoms selected from oxygen, nitrogen or sulfur (preferably oxygen or nitrogen);

[0063] m is an integer from 1 to 3;

[0064] The hydrogens in the structures of Formula I are optionally substituted with deuterium.

[0065] In a specific embodiment, the present invention provides the use of the following compounds, or their salts or esters, prodrugs, optical isomers or solvates in the preparation of drugs for preventing or treating pain-related diseases:

[0066]

[0067]

[0068]

[0069]

[0070]

[0071]

[0072] Preferably, the compound is

[0073]

[0074]

[0075] More preferably, the compound is a compound selected from the group consisting of:

[0076]

[0077]

[0078] In a preferred embodiment, the compounds of the present invention are used to prevent or treat pain and its related diseases.

[0079] In a preferred embodiment, the pain and related diseases include but are not limited to acute pain or chronic pain.

[0080] In a preferred embodiment, the pain and its related diseases include, but are not limited to, inflammatory pain, neuropathic pain, cancer pain, spastic pain, psychogenic pain and other pain.

[0081] In a specific embodiment, the pain and its related diseases are mechanical and thermal hyperalgesia, acute inflammatory pain, chronic inflammatory pain, visceral pain, neuropathic pain or traumatic pain.

[0082] In a preferred embodiment, the pain and its related diseases include but are not limited to: neuropathic pain, peripheral neuropathy, herpes zoster neuralgia, trigeminal neuralgia, diabetes-related neuropathy, chemotherapy-induced neuropathy and stroke; acute nociceptive pain, postoperative pain, cancer pain, traumatic pain (such as burn pain); various types of inflammatory pain, including pain in the head, neck, shoulder, waist and leg joints, myofascial pain, etc.

[0083] 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,

[0084]

[0085] In the formula,

[0086] 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;

[0087] 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);

[0088] R2 and R5 are independently selected from H, D, OH, COOH, sulfonic acid, oxygen ( Can the group in be called sulfonic acid group?), optionally substituted aminoacetoxy group ( 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;

[0089] or,

[0090] 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 boric acid lactone;

[0091] 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;

[0092] or,

[0093] Two adjacent R3 substituents form an optionally substituted C3-C6 carbocyclic ring or an optionally substituted C3-C6 heterocyclic ring 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);

[0094] m is an integer from 1 to 5;

[0095] The hydrogens in the structures of Formula I are optionally substituted with deuterium.

[0096] In a specific embodiment, wherein,

[0097] A is selected from a C6-C10 aromatic ring or a 5-6 membered aromatic heterocyclic ring containing 1, 2 or 3 heteroatoms selected from N, O or S;

[0098] R1 and R4 are independently selected from H, D, OH, NH2, halogen, carbonyl;

[0099] R2 and R5 are independently selected from H, D, OH, COOH, optionally substituted sulfonic acid group, optionally substituted NH2, halogen, optionally substituted phosphate group;

[0100] or

[0101] 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 boric acid lactone;

[0102] 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;

[0103] or,

[0104] Two adjacent R3 substituents form an optionally substituted C3-C6 carbocyclic ring or an optionally substituted C3-C6 heterocyclic ring 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;

[0105] m is an integer from 1 to 5;

[0106] The hydrogens in the structures of Formula I are optionally substituted with deuterium.

[0107] In a specific embodiment, the present invention provides the following compounds, or salts or esters, prodrugs, optical isomers or solvates thereof:

[0108]

[0109]

[0110]

[0111]

[0112]

[0113] In a third aspect, the present invention provides a pharmaceutical composition comprising the compound described in any one 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.

[0114] In a preferred embodiment, the pharmaceutical composition is used to prevent or treat pain and pain-related diseases.

[0115] In a preferred embodiment, the pain and related diseases include, but are not limited to, clinically common acute pain or chronic pain.

[0116] In a preferred embodiment, the pain and its related diseases include, but are not limited to, inflammatory pain, neuropathic pain, cancer pain, spastic pain, psychogenic pain and other pain.

[0117] In a preferred embodiment, the pain and its related diseases include but are not limited to: neuropathic pain, peripheral neuropathy, herpes zoster neuralgia, trigeminal neuralgia, diabetes-related neuropathy, chemotherapy-induced neuropathy and stroke; acute nociceptive pain, postoperative pain, cancer pain, traumatic pain (such as burn pain); various types of inflammatory pain, including pain in the head, neck, shoulder, waist and leg joints, myofascial pain, etc.

[0118] In a preferred embodiment, the subject is a mammal, including but not limited to humans, pets, racing animals, livestock, etc.

[0119] In a preferred embodiment, the subject is a human.

[0120] 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 specifically described below (such as embodiments) can be combined with each other to form a new or preferred technical solution. Due to space limitations, they will not be described one by one here. BRIEF DESCRIPTION OF THE DRAWINGS

[0121] Figure 1 It shows that compound 1-R can effectively inhibit CFA-induced mechanical and thermal hyperalgesia. Among them, Figure (A) (B) shows that compound 1-R can effectively inhibit CFA-induced mechanical allodynia; Figure (C) (D) shows that compound 1-R can effectively inhibit CFA-induced thermal allodynia; compared with the model group, *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001; compared with the indomethacin group, #p<0.05, ####p<0.0001. n=8.

[0122] Figure 2 The results show the effect of compound 1-R on formalin-induced acute inflammatory pain; compared with the model group, *p<0.05, ***p<0.001. n=8.

[0123] Figure 3 It showed that compound 1-R could effectively relieve visceral pain induced by glacial acetic acid; compared with the model group, *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001. n=9.

[0124] Figure 4 The effects of compound 1-R on CCI-induced mechanical and thermal hyperalgesia are shown. Figures A and B show the effects of compound 1-R on CCI-induced mechanical allodynia; Figures C and D show the effects of compound 1-R on CCI-induced thermal allodynia; compared with the model group, *p<0.05, **p<0.01, ****p<0.0001; compared with the indomethacin group, #p<0.05, ##p<0.01, ###p<0.001. n=8.

[0125] Figure 5 The effect of compound 1-R on mechanical and thermal hyperalgesia induced by PTX is shown. Figures A and B show the effect of compound 1-R on mechanical allodynia induced by PTX; Figures C and D show the effect of compound 1-R on thermal allodynia induced by PTX. Compared with the model group, ****p<0.0001; compared with the indomethacin group, ####p<0.0001. n=6. DETAILED DESCRIPTION

[0126] After extensive and in-depth research, the inventor unexpectedly discovered a series of compounds that have good inhibitory effects on pain and related diseases and have the advantages of rapid onset, etc. On this basis, the present invention was completed.

[0127] Definition of terms

[0128] The terms used herein for 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.

[0129] In this document, "a", "an", "a kind" or "a category" are meant to include the plural forms of the objects they modify, that is, "a", "an", "a kind" or "a category" means at least one / kind / category or one / kind / category or more than one / kind / category.

[0130] 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 in this article also includes the sub-ranges therein. For example, when 1-10 carbon atoms are mentioned in this article, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, and 1-3 carbon atoms are also included.

[0131] The term "alkyl" as used herein has the same meaning as that generally understood by those of ordinary skill in the art, and refers to various saturated or unsaturated straight-chain, side-chain or cyclic hydrocarbon groups. For example, the alkyl described herein refers to a lower alkyl group of 1-10 carbon atoms; preferably, a lower alkyl group of 1-8 carbon atoms; more preferably, a lower alkyl group of 1-6 carbon atoms. In a specific embodiment, the alkyl described herein includes, but is not limited to: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, and the like.

[0132] The term "aryl" or "aromatic ring" as used herein has the same meaning as that generally understood by those of ordinary skill in the art, and refers 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 without heteroatoms in the ring, such as phenyl, naphthyl, etc. The term "heteroaryl" as used herein refers to a cyclic conjugated aromatic system containing one or more heteroatoms such as N, O or S in the ring; for example, pyridyl, pyrazinyl.

[0133] The term "aminoacetyl" as used herein has the conventional meaning as understood by those of ordinary skill in the art, i.e., an acetyl group substituted with an amino group. As shown, wherein R is various amino acid substituents.

[0134] The terms "heterocyclyl" or "heterocycle" used herein have the same meaning, and both refer to saturated or partially unsaturated non-aromatic cyclic groups, including monocyclic, fused, spirocyclic or bridged rings, wherein the heterocyclic ring has at least one heteroatom selected from O, S or N as a ring member. For example, "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, etc.

[0135] The term "halogen" as used herein refers to F, Cl, Br or I.

[0136] Based on the teachings of the present invention and common knowledge in the art, those skilled in the art will appreciate that the compounds of the present invention and the various substituents defined above may 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.

[0137] The term "substituted" as used herein means that one or more hydrogen atoms on a specific group are replaced by a specific substituent. The specific substituent may be the substituent described above, or the specific substituent appearing in the examples. Therefore, in the present invention, the substituents in the general formula (I) or (II) may each independently be the corresponding group in the specific compound in the examples; that is, the present invention includes the combination of the substituents in the above-mentioned general formula (I) or (II), and also includes the combination of some of the substituents shown in the general formula (I) or (II) and other specific substituents appearing in the examples.

[0138] Unless otherwise specified, a substituted group may have a specific substituent at any substitutable position of the group, and the substituent 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, the two rings have a common carbon atom. The substituents are, for example (but not limited to): C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, 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, C1-8 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 the groups defined above.

[0139] 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.

[0140] The term "independently selected from" as used herein means that the multiple groups modified by the term can be selected relatively independently within the scope. For example, when it is mentioned herein that "R1 and R4 are independently selected from H, OH, and carbonyl", it is equivalent to disclosing "R1 is selected from H, OH or carbonyl" and "R4 is selected from H, OH or carbonyl".

[0141] Compounds of the present invention

[0142] The present invention provides a series of novel compounds having therapeutic effects on pain and related diseases, which have different mechanisms from existing therapeutic drugs. The pain and related diseases include but are not limited to mechanical and thermal hyperalgesia, acute inflammatory pain, chronic inflammatory pain, visceral pain, neuropathic pain or traumatic pain.

[0143] 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:

[0144]

[0145] Each substituent in the general formula is as described above.

[0146] In a preferred embodiment, the compound represented by formula I is a compound represented by formula II,

[0147]

[0148] Each substituent in the formula is as described above.

[0149] In a preferred embodiment, the compound represented by formula I is a compound represented by formula III,

[0150]

[0151] Each substituent in the formula is as described above.

[0152] In a preferred embodiment, the compound represented by formula I is a compound represented by formula IV,

[0153]

[0154] Each substituent in the formula is as described above.

[0155] In a specific embodiment, the preferred compounds of the present invention are the following compounds:

[0156]

[0157]

[0158] 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 acid includes hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, aminosulfonic acid and phosphoric acid, and the organic acid includes various amino acids, citric acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, naphthalenesulfonic acid, ethanesulfonic acid, naphthalene disulfonic 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.

[0159] 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.

[0160] Based on the teachings of this article, those skilled in the art should understand that the compounds provided by the present invention that have therapeutic effects on pain and related diseases should have various properties inherent to drugs, such as therapeutic activity, drugability, pharmacokinetic activity, etc., and the compounds of the present invention should also have 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 detect these properties using methods known in the art.

[0161] 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, wherein the pharmaceutical composition optionally comprises a pharmaceutically acceptable excipient.

[0162] In a specific embodiment, the pharmaceutical composition of the present invention comprises a safe and effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient or carrier. Wherein "safe and effective amount" means: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects.

[0163] "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, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0164] There is no particular limitation on the administration of the compound or pharmaceutical composition of the present invention. Representative administrations include, but are not limited to, oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.

[0165] 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 starch 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.

[0166] Solid dosage forms such as tablets, pills, 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 opacifiers, and the release of the active compound or compounds in such compositions can be delayed in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxes. If necessary, the active compound can also be formed into microencapsulated form with one or more of the above-mentioned excipients.

[0167] 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, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide and oils, in particular cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances.

[0168] Besides these inert diluents, the composition may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweeteners, flavoring agents, and perfumes.

[0169] Suspensions, in addition to the active compounds, may contain suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methanol and agar, or mixtures of these substances, and the like.

[0170] Compositions for parenteral injection may include 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.

[0171] Dosage forms for topical administration of the compounds of the 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.

[0172] 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 compounds 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 by oral, nasal, skin, lung or gastrointestinal tract administration. Oral administration, one-time or divided administration, is most preferred. Regardless of the method of administration, the optimal dose for an individual should be determined based on the specific treatment. Usually, it is started with a small dose and the dose is 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 range of skilled physicians. In a specific embodiment, the compounds of the present invention are preferably in a form suitable for aerosol administration.

[0173] Advantages of the present invention:

[0174] 1. The present invention provides a series of novel compounds having therapeutic effects on pain and related diseases;

[0175] 2. The compounds of the present invention are fast-acting in treating pain and related diseases; and

[0176] 3. The compounds of the present invention lay a brand new material foundation for developing brand new therapeutic drugs for pain and related diseases.

[0177] The technical scheme of the present invention is further described below in conjunction with specific implementation cases, but the following implementation cases do not constitute a limitation of the present invention, and all various application methods adopted according to the principles and technical means of the present invention belong to the scope of the present invention. The experimental methods in the following examples where specific conditions are not specified are usually carried out under conventional conditions or under conditions recommended by the manufacturer. Unless otherwise specified, percentages and parts are calculated by weight.

[0178] Example

[0179] 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.

[0180] Synthesis part:

[0181] Example 1. Synthesis of a series of compounds

[0182] 1. Synthesis of 3-ethylphenyl glycol (Compound 1)

[0183]

[0184] Synthesis of compound 1.3

[0185] Magnesium chips (2.2 g, 90 mmol) were placed in a 250 mL three-necked reaction bottle, and one grain of iodine was added. Compound 1.1 (15 g, 82 mmol) was dissolved in 120 mL of anhydrous tetrahydrofuran, and 10 mL of the tetrahydrofuran solution of compound 1 was dripped into the reaction bottle containing magnesium chips through a constant pressure dropping funnel. The reaction was initiated by heating with a hair dryer, and the remaining 110 mL of the tetrahydrofuran solution of compound 1.1 was slowly dripped in after the reaction started. After the dripping was completed, the reaction was refluxed for 3.5 hours to finally obtain a tetrahydrofuran solution of compound 1.2.

[0186] Under ice bath, the tetrahydrofuran solution of compound 1.2 was added dropwise to a solution of benzyloxyacetaldehyde (12 g, 80 mmol) in anhydrous tetrahydrofuran (80 mL). After the addition was completed, the mixture was heated to room temperature for 1 hour, and then a saturated aqueous ammonium chloride solution was 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 obtain 12.4 g of the target compound, with a two-step yield of 59.6%.

[0187] 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) - .

[0188] Synthesis of Compound 1 (including Compound 1 racemate, R-configuration 1-R of Compound 1, and S-configuration 1-S of Compound 1)

[0189] 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, H2 was added, and the mixture was stirred at 38°C for 3 hours. After the reaction, the solvent was removed and purified by column chromatography (PE:EA=5:1) to obtain 6.42 g of the target compound with a yield of 79%.

[0190] The R-configuration of compound 1 and the S-configuration of compound 1 were obtained by chiral preparation, and the R-configuration of compound 1 was confirmed by single crystal diffraction.

[0191] 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) - .

[0192] 2. Synthesis of Compound 2

[0193]

[0194] Synthesis of compound 2.6

[0195] Magnesium chips (0.17 g, 7 mmol) were placed in a 50 mL three-necked reaction bottle, 1 grain of iodine 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 dripped into the reaction bottle through a constant pressure dropping funnel, and the reaction was initiated by heating with a hair dryer. After the reaction started, the remaining 10 mL of the tetrahydrofuran solution of compound 2.4 was slowly dripped in. After the dripping was completed, the reaction was refluxed for 3.5 hours to finally obtain a tetrahydrofuran solution of compound 2.5.

[0196] Under ice bath, the tetrahydrofuran solution of compound 2.5 was added dropwise to a solution of benzyloxyacetaldehyde (0.97 g, 6.4 mmol) in anhydrous tetrahydrofuran (8 mL). After the addition was completed, the mixture was heated to room temperature for 1 hour, and then a saturated aqueous ammonium chloride solution was 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 obtain 0.98 g of the target compound, with a two-step yield of 67.6%.

[0197] 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) - .

[0198] Synthesis of compound 2

[0199] 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, H2 was added, and the mixture was stirred at 38°C for 3 hours. After the reaction, the solvent was removed and the mixture was purified by column chromatography (PE:EA=5:1) to obtain 0.24 g of the target compound with a yield of 45%.

[0200] 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) - .

[0201] 3. Synthesis of Compound 3

[0202]

[0203] Synthesis of compound 3.9

[0204] Magnesium chips (0.33 g, 13.8 mmol) were placed in a 100 mL three-necked reaction bottle, 1 grain of iodine 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 dripped into the reaction bottle through a constant pressure dropping funnel, and the reaction was initiated by heating with a hair dryer. After the reaction started, the remaining 17 mL of the tetrahydrofuran solution of compound 7 was slowly dripped in. After the dripping was completed, the reaction was refluxed for 3.5 hours to finally obtain a tetrahydrofuran solution of compound 3.8.

[0205] Under ice bath, the 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 completed, the mixture was heated to room temperature for 1 hour, and then a saturated aqueous solution of ammonium chloride was 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 obtain 0.95 g of the target compound, with a two-step yield of 34%.

[0206] 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) - .

[0207] Synthesis of compound 3

[0208] 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, H2 was added, and the mixture was stirred at 38°C for 3 hours. After the reaction, the solvent was removed and the mixture was purified by column chromatography (PE:EA=5:1) to obtain 0.28 g of the target compound with a yield of 50%.

[0209] 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) - .

[0210] 4. Synthesis of Compound 4

[0211]

[0212] Synthesis of compound 4.12

[0213] Magnesium chips (0.31 g, 12.9 mmol) were placed in a 100 mL three-necked reaction bottle, 1 grain of iodine 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 dripped into the reaction bottle through a constant pressure dropping funnel, and the reaction was initiated by heating with a hair dryer. After the reaction started, the remaining 17 mL of the tetrahydrofuran solution of compound 4.10 was slowly dripped in. After the addition was completed, the reaction was refluxed for 3.5 hours to finally obtain a tetrahydrofuran solution of compound 11.

[0214] Under ice bath, the tetrahydrofuran solution of compound 4.11 was added dropwise to a 14 mL solution of benzyloxyacetaldehyde (1.62 g, 10.8 mmol) in anhydrous tetrahydrofuran. After the addition was completed, the mixture was heated to room temperature for 1 hour, and then a saturated aqueous ammonium chloride solution was 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 obtain 1 g of the target compound, with a two-step yield of 36%.

[0215] 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) - .

[0216] Synthesis of compound 4

[0217] 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, H2 was added, and the mixture was stirred at 38°C for 3 hours. After the reaction, the solvent was removed and the mixture was purified by column chromatography (PE:EA=5:1) to obtain 0.24 g of the target compound with a yield of 37%.

[0218] 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) - .

[0219] 5. Synthesis of Compound 5

[0220]

[0221] Synthesis of compound 5.15

[0222] Magnesium chips (0.31 g, 12.9 mmol) were placed in a 100 mL three-necked reaction bottle, 1 grain of iodine was added, compound 5.13 (2 g, 10.9 mmol) was dissolved in 20 mL of anhydrous tetrahydrofuran, 3 mL of the tetrahydrofuran solution of compound 5.13 was dripped into the reaction bottle through a constant pressure dropping funnel, and the reaction was initiated by heating with a hair dryer. After the reaction started, the remaining 17 mL of the tetrahydrofuran solution of compound 5.13 was slowly dripped in. After the addition was completed, the reaction was refluxed for 3.5 hours to finally obtain a tetrahydrofuran solution of compound 5.14.

[0223] Under ice bath, the tetrahydrofuran solution of compound 5.14 was added dropwise to a 14 mL solution of benzyloxyacetaldehyde (1.62 g, 10.8 mmol) in anhydrous tetrahydrofuran. After the addition was completed, the mixture was heated to room temperature for 1 hour, and then a saturated aqueous ammonium chloride solution was 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 obtain 1.4 g of the target compound, with a two-step yield of 50%.

[0224] 1H NMR (400MHz, DMSO): δ7.44-7.42(m,1H),7.35-7.25(m,5H),7.19-7.12(m,3H),5.33(d,J=4.4Hz,1H),5.0 1-4.97(m,1H),4.55-4.47(m,2H),3.51-3.40(m,2H),2.66(m,2H),1.15(t,J=7.6,3H).LC-MS:255.30(MH) - .

[0225] Synthesis of compound 5

[0226] Compound 5.15 (1.2 g, 4.7 mmol) was dissolved in 15 mL of ethanol, and 0.3 g of 10% palladium on carbon was added, the air was replaced, H2 was added, and the mixture was stirred at 38°C for 3 hours. After the reaction, the solvent was removed and the mixture was purified by column chromatography (PE:EA=5:1) to obtain 0.43 g of the target compound with a yield of 47%.

[0227] 1 H NMR (400MHz, DMSO): δ7.41-7.14(m,4H),5.14(d,J=4.0Hz,1H),4.81-4.76(m,2H),3.37(q,J=7.6Hz,2H),1.16(t,J=7.6Hz,3H).LC-MS:165.10(MH) - .

[0228] 6. Synthesis of Compound 6

[0229]

[0230] Synthesis of Compound 6.18

[0231] Magnesium chips (0.31 g, 12.9 mmol) were placed in a 100 mL three-necked reaction bottle, 1 grain of iodine 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 dripped into the reaction bottle through a constant pressure dropping funnel, and the reaction was initiated by heating with a hair dryer. After the reaction started, the remaining 17 mL of the tetrahydrofuran solution of compound 6.16 was slowly dripped in. After the addition was completed, the reaction was refluxed for 3.5 hours to finally obtain a tetrahydrofuran solution of compound 6.17.

[0232] Under ice bath, the 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 completed, the mixture was heated to room temperature for 1 hour, and then a saturated aqueous solution of ammonium chloride was 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 obtain 0.9 g of the target compound, with a two-step yield of 32%.

[0233] 1 H 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) - .

[0234] Synthesis of compound 6

[0235] Compound 6.18 (0.85 g, 2.8 mmol) was dissolved in 10 mL of ethanol, and 0.23 g of 10% palladium carbon was added, the air was replaced, H2 was added, and the mixture was stirred at 38°C for 3 hours. After the reaction, the solvent was removed and the mixture was purified by column chromatography (PE:EA=5:1) to obtain 0.2 g of the target compound with a yield of 33%.

[0236] 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) - .

[0237] 7. Synthesis of Compound 7

[0238]

[0239] Synthesis of Compound 7.21

[0240] Magnesium chips (0.31 g, 12.9 mmol) were placed in a 100 mL three-necked reaction bottle, 1 grain of iodine 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 dripped into the reaction bottle through a constant pressure dropping funnel, and the reaction was initiated by heating with a hair dryer. After the reaction started, the remaining 7.17 mL of the tetrahydrofuran solution of compound 7.19 was slowly dripped in. After the addition was completed, the reaction was refluxed for 3.5 hours to finally obtain a tetrahydrofuran solution of compound 7.20.

[0241] Under ice bath, the 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 completed, the mixture was heated to room temperature for 1 hour, and then a saturated aqueous solution of ammonium chloride was 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 obtain 1.32 g of the target compound, with a two-step yield of 47.2%.

[0242] 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) -

[0243] Synthesis of compound 7

[0244] Compound 7.21 (1.3 g, 5.4 mmol) was dissolved in 10 mL of ethanol, and 0.23 g of 10% palladium carbon was added, the air was replaced, H2 was added, and the mixture was stirred at 38°C for 3 hours. After the reaction, the solvent was removed and the mixture was purified by column chromatography (PE:EA=5:1) to obtain 0.2 g of the target compound with a yield of 33%.

[0245] 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) - .

[0246] 8. Synthesis of Compound 8

[0247]

[0248] Synthesis of compound 8.24

[0249] Magnesium chips (0.57 g, 22.2 mmol) were placed in a 100 mL three-necked reaction bottle, 1 iodine 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 dripped into the reaction bottle through a constant pressure dropping funnel, and the reaction was initiated by heating with a hair dryer. After the reaction started, the remaining 35 mL of the tetrahydrofuran solution of compound 8.22 was slowly dripped in. After the addition was completed, the reaction was refluxed for 3.5 hours to finally obtain a tetrahydrofuran solution of compound 8.23.

[0250] Under ice bath, the 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 completed, the mixture was heated to room temperature for 1 hour, and then a saturated aqueous ammonium chloride solution was added to quench the reaction. Finally, the tetrahydrofuran was removed, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and purified by column chromatography (PE:EA=10:1) to obtain 4 g of the target compound, with a two-step yield of 63.6%.

[0251] 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) - .

[0252] Synthesis of compound 8

[0253] Compound 8.24 (3.5 g, 13.6 mmol) was dissolved in 30 mL of ethanol, and 0.69 g of 10% palladium carbon was added, the air was replaced, H2 was added, and the mixture was stirred at 38°C for 3 hours. After the reaction, the solvent was removed and the mixture was purified by column chromatography (PE:EA=5:1) to obtain 1.42 g of the target compound with a yield of 62.3%.

[0254] 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) - .

[0255] 9. Synthesis of Compound 9

[0256]

[0257] Synthesis of compound 9.26

[0258] Dissolve p-isopropylaniline (4 g, 29.6 mmol) in dichloromethane (40 ml), and add NBS (5.8 g, 32.6 mmol) to the dichloromethane solution in batches under an ice bath, then raise the reaction temperature to room temperature and react for 1 hour to complete. After purification, 4.6 g of the product is obtained with a yield of 74%.

[0259] 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) + .

[0260] Synthesis of Compound 9.27

[0261] 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), and then an aqueous solution (2 mL) of NaNO2 (0.78 g, 11.2 mmol) was added dropwise to the mixed solution under an ice bath. After the reaction was carried out for half an hour, the obtained reaction mixture was added dropwise to a 50% aqueous solution (12 mL) of H3PO2 under an ice bath. After the addition was completed, the reaction was continued for 8 hours, and then the reaction temperature was raised to 25 degrees Celsius for 3 days. After the reaction was completed, it was purified by column. 1.4 g of product was obtained with a yield of 75.3%.

[0262] 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) + .

[0263] Synthesis of Compound 9.29

[0264] Magnesium chips (0.17 g, 7.1 mmol) were placed in a 100 mL three-necked reaction bottle, 1 grain of iodine 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 dripped into the reaction bottle through a constant pressure dropping funnel, and the reaction was initiated by heating with a hair dryer. After the reaction started, the remaining 10 mL of the tetrahydrofuran solution of compound 9.27 was slowly dripped in. After the dripping was completed, the reaction was refluxed for 3.5 hours to finally obtain a tetrahydrofuran solution of compound 9.28.

[0265] Under ice bath, the 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 completed, the mixture was heated to room temperature for 1 hour, and then a saturated aqueous ammonium chloride solution was 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 obtain 1 g of the target compound, with a two-step yield of 56%.

[0266] 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) + .

[0267] Synthesis of compound 9

[0268] 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, H2 was added, and the mixture was stirred at 38°C for 3 hours. After the reaction, the solvent was removed and the mixture was purified by column chromatography (PE:EA=5:1) to obtain 0.51 g of the target compound with a yield of 80%.

[0269] 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) - .

[0270] 10. Synthesis of Compound 10

[0271]

[0272] Synthesis of compound 10.30 (protection of carbonyl group)

[0273] Take p-bromoacetophenone (5g, 25.4mmol) in a 100mL three-necked flask, add 60mL of toluene as solvent, add ethylene glycol (10g, 161.3mmol), p-toluenesulfonic acid (1g, 5mmol), heat to 130℃, reflux and separate water for 16h. After the reaction is completed, add brine and stir, let it stand and separate, take the organic phase, dry it with anhydrous sodium sulfate, and pass it through column chromatography to obtain 3g of compound with a yield of 48%.

[0274] 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) - .

[0275] Synthesis of compound 10.32

[0276] Magnesium chips (0.31 g, 12.9 mmol) were placed in a 100 mL three-necked reaction bottle, 1 grain of iodine was added, p-bromobenzene acetal (2.5 g, 10.4 mmol) was dissolved in 20 mL of anhydrous tetrahydrofuran, 3 mL of tetrahydrofuran solution of acetal was dripped into the reaction bottle through a constant pressure dropping funnel, and the reaction was initiated by heating with a hair dryer. After the reaction started, the remaining 17 mL of tetrahydrofuran solution was slowly dripped in. After the dripping was completed, the reaction was refluxed for 3.5 hours to finally obtain a tetrahydrofuran solution of Grignard reagent.

[0277] Under ice bath, the tetrahydrofuran solution of acetal was added dropwise to a 14 mL solution of benzyloxyacetaldehyde (1.5 g, 10 mmol) in anhydrous tetrahydrofuran. After the addition was completed, the mixture was heated to room temperature for 1 hour, and then a saturated aqueous solution of ammonium chloride was 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 obtain 0.8 g of the target compound, with a two-step yield of 25%.

[0278] 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) - .

[0279] Synthesis of compound 10.33 (debenzylation reaction)

[0280] The compound (0.75 g, 2.4 mmol) was dissolved in 10 mL of ethanol, and 0.23 g of 10% palladium carbon was added, the air was replaced, H2 was added, and the mixture was stirred at 38°C for 3 hours. After the reaction, the solvent was removed and the mixture was purified by column chromatography (PE:EA=2:1) ​​to obtain 0.2 g of the target compound with a yield of 29%.

[0281] 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) - .

[0282] Synthesis of compound 10

[0283] Compound 10.33 (0.18 g, 0.8 mmol) was added with 10 mL of ethanol and 5 drops of hydrochloric acid, and reacted at 50°C for 15 h. Water was added, and DCM was extracted. The organic phase was dried over anhydrous sodium sulfate and subjected to column chromatography to obtain 0.06 g, with a yield of 40%.

[0284] 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) + .

[0285] 11. Synthesis of Compound 11(D)

[0286]

[0287] 1. Synthesis of 3-vinylphenyl oxirane (B)

[0288] Under nitrogen protection, potassium tert-butoxide (2.214g, 0.02mol), THF (2ml), DMSO (12ml) were added dropwise into a three-necked flask containing trivinylbenzaldehyde (A, 1.215g, 0.009mol), trimethylsulfur iodide (2.118g, 0.011mol), THF (8ml), and DMSO (15ml), and the mixture was reacted under ice bath for 12h. The progress of the reaction was monitored by TLC during the reaction. After the reaction, the mixture was extracted with dichloromethane, and the organic layer was dried over anhydrous sodium sulfate, and finally separated by column chromatography (PE:EA=150:1) to obtain 0.755g (56%) of 3-vinylphenyl oxirane (B).

[0289] 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).

[0290] 2. Synthesis of 3-(1-hydroxy-2-benzoyloxyethyl)styrene (C)

[0291] Benzoic acid (1.22 g, 10.0 mmol), tetrabutylammonium iodide (0.369 g, 1.0 mmol), and 3-vinylphenyl oxirane (B, 1.46 g, 10.0 mmol) were dissolved in 5 mL DMF under nitrogen protection and reacted at 100°C for 12 h. The reaction progress was monitored by TLC during the reaction. After the reaction was completed, the product was extracted with dichloromethane, and the organic layer was dried over anhydrous sodium sulfate. Finally, it was separated by column chromatography (PE:EA=10:1) to obtain 0.818 g (30.47%) of 3-(1-hydroxy-2-benzoyloxyethyl)styrene (C).

[0292] 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).

[0293] Synthesis of compound 11(D)

[0294] 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 1 ml of H2O was added after reflux reaction for 2 h. The reaction progress was monitored by TLC. After the reaction was completed, dichloromethane was used for extraction, and the organic layer was dried over anhydrous sodium sulfate, and finally separated by column chromatography (PE:EA=1:1) to obtain 0.07 g (57.2%) of 3-(1,2-dihydroxyethyl)styrene (D).

[0295] 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.

[0296] 12. Synthesis of Compound 12

[0297]

[0298] 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 slight heating, an exothermic reaction began. After the reaction was completed, 20 mL of solvent was added, and the mixture was washed with sodium bicarbonate solution, dried, concentrated, and purified by column (PE:EA=10:1) to obtain 2.00 g of the target compound with a yield of 80%.

[0299] 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) + .

[0300] 13. Synthesis of 1-(3-cyclopropylphenyl)-1,2-ethanediol (Compound 13)

[0301]

[0302] Synthesis of 1-(3-cyclopropylphenyl)ethanone

[0303] 3-Bromoacetophenone (5g, 25.12mmol), cyclopropaneboronic acid (3.25g, 37.68mmol), anhydrous potassium phosphate (16g, 75.36mmol) and tricyclohexylphosphine (1.41g, 5.02mmol) were weighed and placed in a 100ml round-bottom flask, dissolved with 20mL toluene / water (v:v=100:1), palladium acetate (563mg, 2.52mmol) was added, and heated to 100℃ under nitrogen protection for 20 hours. The reaction progress was tracked by TLC. After the reaction was completed, the system was cooled to room temperature, washed with water, extracted with ethyl acetate 3 times, the organic layers were combined, dried with anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. Purification on a silica gel column (PE:EA=100:1) gave 3.6g of a light yellow oil with a yield of 89%.

[0304] 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).

[0305] Synthesis of 3-cyclopropylbenzoic acid

[0306] Copper bromide (6.03 g, 26.98 mmol) was placed in EA to make a suspension, heated and stirred to reflux, and 1-(3-cyclopropylphenyl)ethanone (3.6 g, 22.49 mmol) in EA was added dropwise with a constant pressure dropping funnel, and refluxed for reaction. TLC spot plate was used to monitor the reaction progress. After the reaction was completed, it was filtered with a diatomaceous earth pad and the filter cake was washed with EA. After the mother liquor was dried, it was extracted with EA / water for 3 times, and the organic phases were combined and dried over anhydrous sodium sulfate and then dried. The obtained 6.2 g oily substance was dissolved in 20 mL of methanol, 5 g of sodium formate was added, and the reaction was refluxed for 12 hours. The reaction progress was monitored by TLC spot plate. After the reaction was complete, the solvent was evaporated under reduced pressure, extracted with EA / water three times, and the organic layers were combined and dried over anhydrous sodium sulfate. Silica gel column purification (PE:EA=50:1) gave 1.2 g of a slightly yellow oily substance with a yield of 30%.

[0307] 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).

[0308] Synthesis of 1-(3-cyclopropylphenyl)-1,2-ethanediol

[0309] 3-Cyclopropylbenzoic acid (750 mg, 4.26 mmol) was dissolved in anhydrous tetrahydrofuran, and sodium borohydride (242 mg, 6.39 mmol) dissolved in THF was slowly added dropwise under ice bath conditions, and the reaction progress was monitored by TLC spot plate. After the reaction was complete, saturated ammonium chloride solution was slowly added dropwise to quench the reaction, and DCM was extracted three times. The organic phases were combined and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. Purification on a silica gel column (PE: EA = 2: 1) gave 180 mg of a white solid with a yield of 24%.

[0310] 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.

[0311] The following compounds were synthesized by similar routes as above:

[0312] 14. Synthesis of Compound 1-(3-ethylphenyl)-2-hydroxyethane-1-one (Compound 14)

[0313]

[0314] The compound was a colorless oil with a yield of 36.7%.

[0315] 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).

[0316] 15. Synthesis of Compound 1-(3-methoxyphenyl)-1,2-ethylenediol (Compound 15)

[0317]

[0318] The compound was a light yellow solid with a yield of 50%.

[0319] 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.

[0320] 16. Synthesis of Compound 1-(2,3-dihydro-5-benzofuranyl)-1,2-ethanediol (Compound 16)

[0321]

[0322] The compound was a light yellow solid with a yield of 44%.

[0323] 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.

[0324] 17. Synthesis of Compound 1-(2,3-dihydro-1,4-benzodiazepine-6-yl)-1,2-ethanediol (Compound 17)

[0325]

[0326] The compound was a yellow oil with a yield of 37.7%.

[0327] 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.

[0328] 18. Synthesis of Compound 1-(1,3-benzodiazole-5-yl)-1,2-ethanediol (Compound 18)

[0329]

[0330] The compound was a yellow solid with a yield of 40%.

[0331] 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.

[0332] 19. Synthesis of Compound 1-(4-Hydroxyphenyl)-1,2-ethylenediol (Compound 19)

[0333]

[0334] The compound was a white solid with a yield of 42%.

[0335] 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.

[0336] 20. Synthesis of Compound 1-(3,4-dimethoxy)-1,2-ethanediol (Compound 20)

[0337]

[0338] The compound was a white solid with a yield of 45%.

[0339] 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.

[0340] 21. Synthesis of Compound 1-(4-methoxyphenyl)propane-1,2-diol (Compound 21)

[0341]

[0342] The compound was a white solid with a yield of 49.0%.

[0343] 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).

[0344] 22. Synthesis of Compound 1-(2-methoxyphenyl)ethane-1,2-diol (Compound 22)

[0345]

[0346] The compound was a white solid with a yield of 16.5%.

[0347] 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).

[0348] 23. Synthesis of Compound 1-(4-methoxyphenyl)ethane-1,2-diol (Compound 23)

[0349]

[0350] The compound was a white solid with a yield of 6.5%.

[0351] 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).

[0352] 24. Synthesis of Compound 1-(4-bromophenyl)ethane-1,2-diol (Compound 24)

[0353]

[0354] The compound was a white solid with a yield of 6.3%.

[0355] 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).

[0356] 25. Synthesis of Compound 1-(4-hydroxy-2-methoxyphenyl)ethane-1,2-diol (Compound 25)

[0357]

[0358] The compound was a light brown oily liquid with a yield of 33%.

[0359] 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.

[0360] 26. Synthesis of Compound 1-(3-Hydroxyphenyl)ethane-1,2-diol (Compound 26)

[0361]

[0362] The compound was a light brown oily liquid with a yield of 35%.

[0363] 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.

[0364] 27. Synthesis of Compound 1-Phenylpropane-1,2-diol (Compound 27)

[0365]

[0366] The compound was a white solid with a yield of 67%.

[0367] 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.

[0368] 28. Synthesis of Compound 1-(3-ethynylphenyl)ethane-1,2-diol (Compound 28)

[0369]

[0370] The compound was a brown solid with a yield of 25%.

[0371] 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.

[0372] 29. Synthesis of Compound 1-(3-(tert-butyl)phenyl)ethane-1,2-diol (Compound 29)

[0373]

[0374] The compound was a light yellow solid with a yield of 27%.

[0375] 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.

[0376] 30. Structure of 1-(3-hydroxy-4-methoxyphenyl)ethane-1,2-diol (Compound 30)

[0377]

[0378] The compound was a light yellow solid with a yield of 30%.

[0379] 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.

[0380] 31. Synthesis of Compound 1-(1,3-diethyl-2-hydroxy)-1,2-ethanediol (Compound 31)

[0381]

[0382] Synthesis of ethyl 2-(2,4-diethyl-3-hydroxyphenyl)-2-oxoacetate

[0383] Weigh 2,6-diethylphenol (1g, 6.67mmol) and place it in a 100mL single-mouth round-bottom flask, add 20mL 1,2-dichloroethane to dissolve, slowly add anhydrous aluminum chloride (2.7g, 19.99mmol) at 0℃ and stir for 10min, slowly add ethyl oxalyl chloride (1g, 7.34mmol) dropwise, and react at 0℃ for 10min. TLC spot plate tracks the reaction progress. After the reaction is completed, slowly pour the reaction solution into ice water, extract it with DCM / H2O 3 times, combine the organic phases, dry it over anhydrous sodium sulfate, and spin dry. The product is a white solid, no purification is required, and the yield is 90%.

[0384] 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).

[0385] Synthesis of 1-(2,4-diethyl-3-hydroxyphenyl)-1,2-ethanediol

[0386] Dissolve ethyl 2-(2,4-diethyl-3-hydroxyphenyl)-2-oxoacetate (627 mg, 2.52 mmol) in 10 mL of methanol, slowly add sodium borohydride (426.9 mg, 11.29 mmol) in batches under ice bath stirring, and react at 0°C for one hour. TLC spot plate tracking reaction progress. After the reaction is complete, saturated ammonium chloride aqueous solution is added dropwise to quench, EA / H2O is extracted 3 times, the organic phases are combined, dried over anhydrous sodium sulfate, and the solvent is evaporated under reduced pressure. The product is recrystallized to obtain a white solid with a yield of 60%.

[0387] 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.

[0388] The following compounds were prepared by a synthetic route similar to 1-(2,4-diethyl-3-hydroxyphenyl)-1,2-ethanediol (73):

[0389] 32. Synthesis of Compound 1-(3,4-dihydro-1-benzopyran-6-yl)-1,2-ethanediol (Compound 32)

[0390]

[0391] The compound was a white solid with a yield of 25%.

[0392] 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.

[0393] 33. Synthesis of Compound 1-(4-hydroxy-3-methoxy)-1,2-ethylenediol (Compound 33)

[0394]

[0395] The compound was a light yellow oil with a yield of 30%.

[0396] 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.

[0397] 34. Synthesis of Compound 1-(5,6,7,8-Tetrahydronaphthalene-2-yl)-1,2-ethanediol (Compound 34)

[0398]

[0399] The compound was a white solid with a yield of 55%.

[0400] 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.

[0401] 35. Synthesis of Compound 1-(3-ethyl-4-methylphenyl)-1,2-ethanediol (Compound 35)

[0402]

[0403] The compound was a light yellow oil with a yield of 60%.

[0404] 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.

[0405] 36. Synthesis of Compound 1-(2,3-dihydro-1H-indan-5-yl)-1,2-ethanediol (Compound 36)

[0406]

[0407] The compound was a white solid with a yield of 65%.

[0408] 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.

[0409] 37. Synthesis of Compound 1-(3-ethyl-4-hydroxyphenyl)-1,2-ethanediol (Compound 37)

[0410]

[0411] The compound was a white solid with a yield of 53%.

[0412] 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.

[0413] 38. Synthesis of Compound 3-(3-ethylphenyl)tetrahydrofuran-3-ol (Compound 38)

[0414]

[0415] 3-Bromoethylbenzene (200 mg, 1.08 mmol), an appropriate amount of magnesium stick, 2 iodine grains, and 20 mL of anhydrous tetrahydrofuran were added to a dried 100 mL reaction bottle. The reaction was carried out at room temperature under argon protection. After the Grignard reagent was prepared, 2-2H-furanone (112 mg, 1.30 mmol) was dissolved in anhydrous THF and then added dropwise to the prepared Grignard reagent. The reaction was carried out at room temperature. The reaction was complete when detected by TLC. The reaction was quenched with saturated ammonium chloride and separated and purified by silica gel column to obtain 80 mg of a colorless oil with a yield of 38.5%.

[0416] 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).

[0417] 39. Synthesis of Compound 1-(5-ethylthiophen-3-yl)ethane-1,2-diol (Compound 39)

[0418]

[0419] Synthesis of 4-bromo-2-ethylthiophene

[0420] Thiophene acetone (2.05 g, 10 mmol) was dissolved in 80 mL of dry THF, sodium borohydride (1.89 g, 50 mmol) was added in batches under an ice bath, and finally anhydrous aluminum chloride (3.66 g, 27.5 mmol) was added in batches, and refluxed at 80°C under nitrogen protection. The reaction progress was monitored by TLC (developing solvent: heptane), and the reaction was complete after 2 hours. 30 mL of water was carefully added to quench the reaction, and the solvent THF was removed by rotation and extracted with dichloromethane. After conventional post-treatment, the residue was purified by column chromatography (eluent: heptane) to obtain 0.98 g of pure reduced product with a yield of 51.3%.

[0421] Synthesis of (5-ethylthiophen-3-yl)magnesium bromide

[0422] Add magnesium chips (31 mg, 1.3 mmol) and a small particle of iodine to the reaction flask, add 0.5 mL of dry THF after nitrogen is passed, and then add the THF (1.5 mL) solution of the above product (191 mg, 1 mmol). Heat to 35°C to initiate the reaction, and continue to drop the THF solution of the bromide under heat preservation to keep the reaction liquid slightly boiling. After the dropwise addition, continue the reaction at 35°C for 1 hour, and cool to room temperature for use after the reaction.

[0423] Synthesis of ethyl 2-(5-ethylthiophen-3-yl)-2-oxyacetate

[0424] 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 prepared Grignard reagent was slowly added dropwise. After the addition was completed, 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 a pure product with a yield of 85.7%.

[0425] Synthesis of 1-(5-ethylthiophen-3-yl)ethane-1,2-diol

[0426] The above product (170 mg, 0.8 mmol) and 4 mL of methanol were added to the reaction flask, mixed evenly, and sodium borohydride (91 mg, 2.4 mmol) was added in batches under an ice bath. After the addition was complete, the mixture was brought to room temperature. The reaction progress was monitored by TLC (dichloromethane / methanol = 25:1), and 30 mg of pure product was obtained, with a yield of 22.2%.

[0427] 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).

[0428] 40. Synthesis of deuterated compound 3-ethylphenyl glycol (Compound 40)

[0429]

[0430] Weigh 3-ethylacetophenone (5.00g, 33.7mmol) in a 50mL three-necked flask, add 25mL 1,4-dioxane, dilute with 25mL methanol, and add nitrogen protection, stirring in an ice bath for 10min. Use a syringe to draw liquid bromine (5.39g, 33.7mmol) and dissolve it in 25mL methanol. Slowly add it to the reaction solution with a dropping funnel in an ice bath. After the drop is completed, continue stirring in an ice bath and monitor the progress of the reaction by tapping the plate. After 5 hours, the reaction is complete. Add an appropriate amount of anhydrous sodium sulfite solution to quench the reaction. 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 with anhydrous sodium sulfate. Rotary evaporate the obtained product to obtain 6.15g of crude product.

[0431] Weigh compound A (1.08 g, 4.76 mmol), sodium formate (0.65 g, 9.56 mmol), and 10 mL of methanol in a 100 mL single-mouth bottle, heat to 80 ° C and reflux, monitor the progress of the reaction by TLC spot plate, and the reaction is complete after 4.5 hours. 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 add anhydrous sodium sulfate to dry. Rotary evaporate the obtained product to obtain 0.75 g of crude product. Crude yield = 95.96% (including impurities).

[0432] Weigh compound B (0.10g, 0.61mmol) in a 50mL single-mouth bottle, add 10mL methanol to dilute, and stir for 10min in an ice bath. Weigh sodium borodeuteride (0.013g, 0.31mmol) and add it to the reaction solution in batches in an ice bath. Remove the ice bath after adding and react at room temperature. Monitor the progress of the reaction by spot 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, add anhydrous sodium sulfate to dry, and rotary evaporation. Add appropriate amount of dichloromethane and silica gel, mix well, and rotary evaporation to prepare samples. Dry column loading, dry sample loading, petroleum ether: ethyl acetate = 4:1. The product obtained by rotary evaporation is 0.02g. Yield = 19.63%.

[0433] 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

[0434] 41. Synthesis of deuterated compound 3-ethylphenyl glycol (Compound 41)

[0435]

[0436] Weigh 3-ethylacetophenone (0.50g, 3.4mmol) in a 25mL single-mouth bottle, add 4mL of tetrahydrofuran, and stir at room temperature. Weigh N-bromosuccinimide (0.59g, 3.4mmol) 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, and the reaction is stopped when the raw materials no longer react. 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 obtained product to obtain 0.52g of crude product. (The product and the raw material have little difference in polarity, which is difficult to purify, so it is directly used in the next step)

[0437] Crude yield = 67.08% (including impurities)

[0438] Weigh compound A (1.30 g, 5.72 mmol) in a 50 mL single-mouth bottle, add 26 mL toluene, 1.95 mL deuterated water and potassium carbonate (0.20 g, 1.45 mmol), and heat to 87 ° C reflux. After 4 hours, separate the water layer at 40-50 ° C, add 1.95 mL 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 water 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 add anhydrous sodium sulfate to dry. Rotary evaporate the obtained product to obtain 1.01 g of crude product. Crude yield = 77.11% (containing impurities)

[0439] Weigh compound A (1.00 g, 4.36 mmol), sodium formate (0.60 g, 8.82 mmol), and 5 mL of methanol in a 50 mL single-mouth bottle, heat to 80 ° C and reflux, monitor the progress of the reaction with a thin layer chromatography plate, and the reaction is complete after 4.5 hours. 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 add anhydrous sodium sulfate to dry. Rotary evaporate the obtained product to obtain 0.72 g of crude product. Crude yield = 99.35% (including impurities)

[0440] Weigh compound C (1.00g, 6.02mmol) in a 50mL single-mouth bottle, add 5mL of methanol to dilute, and stir for 10min in an ice bath. Weigh sodium borohydride (0.23g, 6.02mmol) and add it to the reaction solution in batches in an ice bath. Remove the ice bath after adding and react at room temperature. Monitor the progress of the reaction by spot 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 with anhydrous sodium sulfate, and rotary evaporate. Add appropriate amount of dichloromethane and silica gel, mix well, and rotary evaporate to prepare samples. Dry column loading, dry sample loading, petroleum ether: ethyl acetate = 4:1. The product obtained by rotary evaporation is 0.21g. Yield = 20.74%

[0441] 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

[0442] 42. Synthesis process of compounds 42-44

[0443] Synthesis of 1-(3-(1-hydroxy-1-deutero-ethyl)phenyl)-1-deutero-ethanol (2)

[0444]

[0445] Weigh 1,3-diacetylbenzene (3.00 g, 18.50 mmol) into a 100 mL single-mouth bottle, add 20 mL of methanol to dissolve, and stir at 0 ° C. Take sodium borodeuteride (0.39 g, 9.29 mmol) and slowly add it to the reaction solution. After the addition is complete, 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 it with 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 colorless crystalline solid with a yield of 91.1%.

[0446] 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

[0447] Synthesis of 1,3-bis(1-dideuteroethyl)benzene(3a)

[0448]

[0449] Weigh 1-(3-(1-hydroxy-1-deuterated-ethyl)phenyl)-1-deuterated-ethanol (12.00g, 71.33mmol) and place it in a 250mL two-necked bottle, add 50mL deuterated ethanol to dissolve. Take 10% palladium carbon (2.00g, 25%) and add it to the reaction solution, and replace the deuterium gas 3 times. Use a syringe to take 1mL of deuterated hydrochloric acid, slowly drip it into the reaction solution, and stir it at room temperature overnight. The reaction solution was filtered with diatomaceous earth, the filtrate was extracted with dichloromethane, and the extract was washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. Remove dichloromethane by rotary evaporation at 40°C. 8.20g of crude colorless transparent liquid was obtained with a yield of 83.3%.

[0450] 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

[0451] Synthesis of 1,3-di(1-deuterated-ethyl)benzene (3b)

[0452]

[0453] Weigh 1-(3-(1-hydroxy-1-deuterated-ethyl)phenyl)-1-deuterated-ethanol (1.00g, 5.94mmol) and place it in a 100mL two-necked bottle, add 5mL of dichloromethane to dissolve, and stir at 0℃. Take triethylsilane (4.90g, 42.14mmol) and slowly add it to the reaction solution under nitrogen protection. Take boron trifluoride ether (5.90g, 41.57mmol) with a 10mL syringe and slowly drip it into the reaction solution at 0℃. After the dripping is completed, slowly warm it to room temperature and stir overnight. Add saturated sodium bicarbonate solution to quench until no bubbles are generated. Extract the reaction solution with dichloromethane and water, wash the extract with dichloromethane and saturated sodium chloride solution, and dry it with anhydrous sodium sulfate. Remove dichloromethane by rotary evaporation at 40℃. Obtain 0.50g of crude colorless transparent liquid with a yield of 61.7%.

[0454] 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

[0455] Synthesis of 1-(3-(1-dideuteroethyl)phenyl)ethanone (4a)

[0456]

[0457] Weigh 1,3-di(1-dideuterated ethyl)benzene (8.20g, 59.31mmol) and N-hydroxyphthalimide (3.20g, 19.62mmol) in a 100mL three-necked flask, add 60mL acetonitrile to dissolve, replace oxygen three times, and heat to 40°C. Use a 10mL syringe to draw tert-butyl nitrite (6.10g, 59.15mmol) and slowly drip into the reaction solution, which gradually turns orange. After the dripping, heat to 55°C and react for 2 hours. Remove the solvent by rotary evaporation. Add a small amount of dichloromethane, and a white solid precipitates. Add diatomaceous earth to filter, and take the filtrate and spin dry. The crude product is purified by silica gel column chromatography (petroleum ether / dichloromethane = 10:1, v / v) to obtain 2.80g of yellow liquid with a yield of 31.4%.

[0458] 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).

[0459] Synthesis of 1-(3-(1-deuterated ethyl)phenyl)ethanone (4b)

[0460]

[0461] The synthesis steps were the same as those of 4a, and a yellow liquid was obtained with a yield of 29.9%.

[0462] 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).

[0463] Synthesis of 1-(3-(1-deuterated ethyl)phenyl)ethanone (15c)

[0464]

[0465] The synthesis steps were the same as those of 4a, and a yellow liquid was obtained with a yield of 35.3%.

[0466] 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).

[0467] Synthesis of 1-(3-(1-dideuterated ethyl)phenyl)-2-bromoethanone (5a)

[0468]

[0469] Weigh 1-(3-(1-di-deuterated ethyl)phenyl)ethanone (2.80 g, 18.64 mmol) and p-toluenesulfonic acid (1.66 g, 9.64 mmol) in a 100 mL single-mouth bottle, add 20 mL of acetonitrile to dissolve, and stir at 0°C. Weigh N-bromosuccinimide (3.64 g, 20.45 mmol) and slowly add it to the reaction solution, react at 40°C, and the reaction is completed after 3 hours. Add an appropriate amount of water 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 it with anhydrous sodium sulfate. The crude product is purified by silica gel column chromatography (petroleum ether / dichloromethane = 10:1, v / v) to obtain 2.12 g of yellow liquid with a yield of 50.1%.

[0470] Synthesis of 1-(3-(1-deuterated ethyl)phenyl)-2-bromoethanone (5b)

[0471]

[0472] The synthetic steps were the same as those of 5a to obtain a yellow liquid, which was directly used in the next step without purification.

[0473] Synthesis of 1-(3-(1-ethyl)phenyl)-2-bromoethanone (5c)

[0474]

[0475] The synthetic steps were the same as those of 5a to obtain a yellow liquid, which was directly used in the next step without purification.

[0476] Synthesis of 1-(3-(1-dideuteroethyl)phenyl)-2-hydroxyethanone (6a)

[0477]

[0478] Weigh 1-(3-(1-di-deuterated ethyl)phenyl)-2-bromoethanone (2.12g, 9.25mmol), sodium formate (1.26g, 18.53mmol), and 20mL of methanol in a 100mL single-mouth bottle, heat to 80°C and reflux. After 5 hours, the reaction is complete. Rotate and 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 with anhydrous sodium sulfate. The crude product is purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1, v / v) to obtain 0.93g of yellow liquid with a yield of 60.2%.

[0479] 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).

[0480] Synthesis of 1-(3-(1-deuterated ethyl)phenyl)-2-hydroxyethanone (6b)

[0481]

[0482] The synthesis steps were the same as those of 6a to obtain a yellow liquid with a yield of 45.1%.

[0483] 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).

[0484] Synthesis of 1-(3-ethylphenyl)-2-hydroxyethanone (17c)

[0485]

[0486] The synthesis steps were the same as those of 6a to obtain a yellow liquid with a yield of 56.3%.

[0487] 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).

[0488] Synthesis of 1-(3-(1-dideuteroethyl)phenyl)-ethylene glycol (Compound 42)

[0489]

[0490] Weigh 1-(3-(1-di-deuterated ethyl)phenyl)-2-hydroxyethanone (0.93g, 5.60mmol) in a 50mL single-mouth bottle, add 10mL methanol to dissolve, and stir at 0℃. Weigh sodium borohydride (0.11g, 2.89mmol) and slowly add it to the reaction solution in an ice bath. After the addition is complete, react at room temperature. Remove the solvent by rotary evaporation, extract the reaction solution with ethyl acetate and water, wash the extract with ethyl acetate and saturated sodium chloride solution, and dry it with anhydrous sodium sulfate. The crude product is purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4:1, v / v) to obtain 0.77g of colorless solid with a yield of 81.4%.

[0491] 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.

[0492] Synthesis of 1-(3-(1-deuterated ethyl)phenyl)-ethylene glycol (Compound 43)

[0493]

[0494] The synthesis steps were the same as TJH1 to obtain a colorless solid with a yield of 80.1%.

[0495] 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.

[0496] Synthesis of 1-(3-ethylphenyl)-1-deuterated-ethylene glycol (Compound 44)

[0497]

[0498] The synthesis steps were the same as TJH1 to obtain a colorless solid with a yield of 79.8%.

[0499] 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] - .

[0500] 43. Synthesis process of compounds 45-49

[0501] Synthesis of 1-(3-(1-ethylphenyl)-ethylene glycol (7)

[0502]

[0503] Weigh 1-(3-ethylphenyl)-2-hydroxyethanone (0.87g, 5.30mmol) in a 50mL single-mouth bottle, add 10mL methanol to dissolve, and stir at 0℃. Weigh sodium borohydride (0.22g, 5.30mmol) and slowly add it to the reaction solution in an ice bath. After the addition is complete, react at room temperature. Remove the solvent by rotary evaporation, extract the reaction solution with ethyl acetate and water, wash the extract with ethyl acetate and saturated sodium chloride solution, and dry it with anhydrous sodium sulfate. The crude product is purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4:1, v / v) to obtain 0.75g of colorless solid with a yield of 85.2%.

[0504] 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).

[0505] Synthesis of 1-(3-ethylphenyl)ethane-1,2-diacetic acid diester (Compound 45)

[0506]

[0507] Weigh 1-(3-ethylphenyl)-ethylene glycol (0.50, 3.01mmol) in a 50mL single-mouth bottle, add 5mL of dichloromethane to dissolve, and stir at room temperature. Weigh 4-dimethylaminopyridine (0.04g, 0.33mmol) and acetic anhydride (1.23g, 12.05mmol) and add them to the reaction solution, and react at room temperature. Remove the solvent by rotary evaporation, extract the reaction solution with ethyl acetate and water, wash the extract with ethyl acetate and saturated sodium chloride solution, and dry it with anhydrous sodium sulfate. The crude product is purified by silica gel column chromatography (petroleum ether / ethyl acetate = 25:1, v / v) to obtain 0.61g of colorless clear liquid with a yield of 81.0%.

[0508] 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).

[0509] Synthesis of 4-(3-ethylphenyl)-1,3-dioxolane-2-one (Compound 46)

[0510]

[0511] Weigh 1-(3-ethylphenyl)-ethylene glycol (0.50, 3.01mmol) in a 50mL single-mouth bottle, add 5mL toluene to dissolve. Weigh di(2-pyridyl) carbonate (1.30g, 6.01mmol) and add to the reaction solution, heat to 60℃ for 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 with anhydrous sodium sulfate. The crude product is purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20:1, v / v) to obtain 0.38g of colorless clear liquid with a yield of 65.7%.

[0512] 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).

[0513] Synthesis of 4-(3-ethylphenyl)-2,2-dimethyl-1,3-dioxolane (Compound 47)

[0514]

[0515] Weigh 1-(3-ethylphenyl)-ethylene glycol (0.50, 3.01mmol) in a 50mL single-mouth bottle, add 3mL tetrahydrofuran to dissolve. Weigh ferric chloride (0.17g, 1.50mmol) and 3mL acetone to the reaction solution, react at room temperature, and the reaction solution is brown. Rotate and evaporate to remove the solvent at room temperature, extract the reaction solution with dichloromethane and water, wash the extract with dichloromethane and saturated sodium chloride solution, add anhydrous sodium sulfate to dry, and remove dichloromethane by rotary evaporation at room temperature. The crude product is purified by silica gel column chromatography (petroleum ether / ethyl acetate = 50:1, v / v) to obtain 0.52g of light yellow liquid with a yield of 83.7%.

[0516] 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).

[0517] Synthesis of 4-(3-ethylphenyl)-2-methyl-1,3-dioxolane (Compound 48)

[0518]

[0519] Weigh 1-(3-ethylphenyl)-ethylene glycol (0.50, 3.01mmol) in a 50mL single-mouth bottle, add 3mL tetrahydrofuran to dissolve. Weigh ferric chloride (0.17g, 1.50mmol) and acetaldehyde (0.54g, 12.27mmol) and add to the reaction solution, react at room temperature, and the reaction solution is brown. Remove the solvent by rotary evaporation at room temperature, extract the reaction solution with dichloromethane and water, wash the extract with dichloromethane and saturated sodium chloride solution, add anhydrous sodium sulfate to dry, and remove dichloromethane by rotary evaporation at room temperature. The crude product is purified by silica gel column chromatography (petroleum ether / ethyl acetate = 50:1, v / v) to obtain 0.36g of light yellow liquid with a yield of 62.1%.

[0520] 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).

[0521] Synthesis of 2-(3-ethylphenyl)oxirane (Compound 49)

[0522]

[0523] Weigh 2-bromo-1-(3-ethylphenyl)ethane-1-one (0.50, 2.20mmol) in a 50mL single-mouth bottle, add 5mL of anhydrous methanol to dissolve, and stir at 0°C. Weigh sodium borohydride (0.08g, 2.11mmol) and add it to the reaction solution. After the addition is complete, remove the ice bath, react at room temperature, and monitor the reaction progress with a plate. After the reaction of the raw materials is completed, weigh potassium carbonate (0.60g, 4.40mmol) in the reaction solution and stir at room temperature overnight. Remove the solvent by rotary evaporation, extract the reaction solution with dichloromethane and water, wash the extract with dichloromethane and saturated sodium chloride solution, and dry it with anhydrous sodium sulfate. The crude product is purified by silica gel column chromatography (petroleum ether / ethyl acetate = 100:1, v / v) to obtain 0.11g of colorless liquid with a yield of 33.7%.

[0524] 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).

[0525] (R)-2-(3-Ethylphenyl)-2-hydroxyethyl-L-valine (Compound 50)

[0526]

[0527] Step 1 (R)-2-(3-ethylphenyl)-2-hydroxyethyl (tert-butoxycarbonyl)-L-valine (50-1)

[0528] In a 100mL single-necked round-bottom flask, (R)-1-(3-ethylphenyl)ethane-1,2-diol (8.00g, 48.0mmol), (tert-butyloxycarbonyl)-L-valine (2.10g, 9.60mmol) and 4-dimethylaminopyridine (0.23g, 1.92mmol) were added in sequence, and then 40mL of dichloromethane was added as solvent. After cooling to 0°C in an ice-salt bath, dicyclohexylcarbodiimide (3.90g, 19.0mmol) was added, and after stirring for 2h in an ice bath, the mixture was warmed to room temperature and stirred for 2h. The reaction progress was monitored by thin-layer chromatography. After the reaction was completed, the reaction solution was filtered, concentrated, and extracted with ethyl acetate in sequence. The organic layers were combined and washed with 1M hydrochloric acid, water, saturated sodium bicarbonate, water, and saturated sodium chloride in sequence, and then dried over anhydrous sodium sulfate. The solvent was removed by concentration under reduced pressure to obtain a light yellow oily liquid. The corresponding yellow oily liquid (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 give 1.20 g of the product with a yield of 34.0%.

[0529] LC-MS: m / z: 366.3 (M+H) + .

[0530] Step 2 (R)-2-(3-Ethylphenyl)-2-hydroxyethyl-L-valine (50)

[0531] In a 50mL single-mouth round-bottom flask, add (R)-2-(3-ethylphenyl)-2-hydroxyethyl (tert-butoxycarbonyl)-L-valine (1.80g, 4.90mmol) and 20ml of ethyl acetate hydrochloride as solvent. Stir at room temperature for 3h, and monitor the reaction progress by thin layer chromatography. After the reaction is completed, the reaction solution is concentrated and extracted with ethyl acetate. The organic layers are combined and washed with saturated sodium bicarbonate, water, and saturated sodium chloride in sequence, and then dried with anhydrous sodium sulfate. The solvent is removed by concentration under reduced pressure to obtain a light yellow oily liquid. Rapid silica gel column chromatography separation and purification (ethyl acetate / methanol = 10:1) separates and obtains the corresponding white oily liquid (R)-2-(3-ethylphenyl)-2-hydroxyethyl-L-valine 0.97g, with a yield of 75.0%.

[0532] 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) + .

[0533] (R)-2-((L-valyl)oxy)-2-(3-ethylphenyl)valine ethyl ester (Compound 51)

[0534]

[0535] Step 1 (R)-2-(((tert-butoxycarbonyl)-L-valyl)oxy)-2-(3-ethylphenyl)ethyl(tert-butoxycarbonyl)valine (51-1)

[0536] In a 25mL single-mouth round-bottom flask, (R)-1-(3-ethylphenyl)ethane-1,2-diol (0.50g, 3.00mmol), (tert-butyloxycarbonyl)-L-valine (4.60g, 21.0mmol) and 4-dimethylaminopyridine (0.60g, 4.80mmol) were added in sequence, and then 5mL of dichloromethane was added as solvent. After cooling to 0°C in an ice-salt bath, dicyclohexylcarbodiimide (8.70g, 42.0mmol) was added, and after stirring for 2h in an ice bath, the mixture was warmed to room temperature and stirred for 2h. The reaction progress was monitored by thin-layer chromatography. After the reaction was completed, the reaction solution was filtered, concentrated, and extracted with ethyl acetate in sequence. The organic layers were combined and washed with 1M hydrochloric acid, water, saturated sodium bicarbonate, water, and saturated sodium chloride in sequence, and then dried over anhydrous sodium sulfate. The solvent was removed by concentration under reduced pressure to obtain a light yellow oily liquid. The corresponding yellow oily liquid (R)-2-(((tert-butoxycarbonyl)-L-valyl)oxy)-2-(3-ethylphenyl)ethyl(tert-butoxycarbonyl)valine was separated and purified by rapid 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%.

[0537] LC-MS: m / z: 565.4 (M+H) + .

[0538] Step 2 (R)-2-((L-valyl)oxy)-2-(3-ethylphenyl)valine ethyl ester (51)

[0539] In a 50mL single-mouth round-bottom flask, add (R)-2-(((tert-butoxycarbonyl)-L-valyl)oxy)-2-(3-ethylphenyl)ethyl(tert-butoxycarbonyl)valine (1.00g, 1.77mmol) and 20ml of ethyl acetate hydrochloride as solvent. Stir at room temperature for 3h, and monitor the reaction progress by thin layer chromatography. After the reaction is completed, the reaction solution is concentrated and extracted with ethyl acetate. The organic layers are combined and washed with saturated sodium bicarbonate, water, and saturated sodium chloride in sequence, and then dried over anhydrous sodium sulfate. The solvent is removed by concentration under reduced pressure to obtain a light yellow oily liquid. Rapid silica gel column chromatography separation and purification (ethyl acetate / methanol = 10:1) separates and obtains the corresponding white oily liquid (R)-2-((L-valyl)oxy)-2-(3-ethylphenyl) valine ethyl ester 0.45g, with a yield of 70.0%.

[0540] 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) + .

[0541] (R)-2-(3-Ethylphenyl)-2-hydroxyethyl octanoate (52)

[0542]

[0543] Synthesis method:

[0544] In a 100mL single-mouth round-bottom flask, (R)-1-(3-ethylphenyl)ethane-1,2-diol (5.00g, 30.0mmol), n-octanoic acid (0.86g, 6.00mmol) and 4-dimethylaminopyridine (0.14g, 1.20mmol) were added in sequence, and then 50mL of dichloromethane was added as solvent. After cooling to 0°C in an ice-salt bath, dicyclohexylcarbodiimide (2.50g, 12.0mmol) was added, and after stirring for 2h in an ice bath, the mixture was warmed to room temperature and stirred for 2h. The reaction progress was monitored by thin-layer chromatography. After the reaction was completed, the reaction solution was filtered, concentrated, and extracted with ethyl acetate in sequence. The organic layers were combined and washed with 1M hydrochloric acid, water, saturated sodium bicarbonate, water, and saturated sodium chloride in sequence, and then dried over anhydrous sodium sulfate. The solvent was removed by concentration under reduced pressure to obtain a light yellow oily liquid. 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%.

[0545] 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).

[0546] Experimental Example 2. Evaluation of the analgesic efficacy of compound 1-R

[0547] 1. Evaluation of the analgesic activity of compound 1-R in a CFA-induced chronic inflammatory pain mouse model

[0548] 1.1 Experimental plan

[0549] The analgesic effect of compound 1-R was investigated by using a chronic inflammatory pain mouse model induced by CFA (complete Freund's adjuvant). In this experiment, ICR male mice were randomly divided into a model group, a drug administration group, and a positive control group, with 8 mice in each group. The drug administration group was given 150 mg / kg of compound 1-R, the positive control group was given 10 mg / kg (indo), and the model group was given an equal volume of pure water. All drugs were prepared with pure water, the administration volume was 0.2 mL per mouse, and the administration method was intragastric administration (ig).

[0550] Pain behavior tests were performed using mechanical withdrawal threshold (MWT) and thermal withdrawal threshold (TWL). The test time points were -1, 0, 1, 3, 5, and 7 days: the basal threshold (denoted as BL) was determined 1 day before modeling, and then 25 μL of CFA solution was subcutaneously injected into the toe of the right hind paw of the mouse. On the first day after modeling, the changes in pain thresholds were measured before administration (denoted as 0 min) and 15 min, 60 min, 120 min, and 180 min after administration. The time point with the best analgesic effect was determined, and the threshold changes at this time point were tested after administration on the 3rd, 5th, and 7th days. Compound 1-R was tested at 15 min after administration in MWT and 60 min after administration in TWL; the positive control group was tested at 60 min after administration.

[0551] For MWT, an electronic Von Frey tester was used for measurement. The mice were adapted in a transparent resin box for three days, two hours a day. If the mice showed a reaction of retraction / licking the paw when using the electronic Von Frey test, it was recorded as positive, and the value (g) was recorded, and the average of 3 times was recorded. For TWL, a classic infrared radiometer was used for measurement, and the temperature of the infrared radiometer was set to 35°C. The mice were adapted as before. During the test, the radiation light source was aimed at the right hind paw of the mouse. The latency of the mouse to retraction / licking the paw was taken as TWL. The test was repeated 3 times at intervals of 5 minutes, and the average was recorded. To avoid tissue damage, the cutoff time was set to 20s.

[0552] 1.2 Experimental Results

[0553] Figure 1 It was shown that compound 1-R can effectively inhibit CFA-induced mechanical and thermal hyperalgesia.

[0554] 1.3 Results Analysis

[0555] The experimental results showed that compound 1-R had a good inhibitory effect on CFA-induced mechanical and thermal hyperalgesia. For the mechanical hyperalgesia, compared with the model group, compound 1-R produced a good analgesic effect 15 minutes after administration (p < 0.01), and lost its effect at 120 minutes; while the positive control group, although superior to compound 1-R in terms of duration, did not show a good analgesic effect until 60 minutes after administration (p = 0.0001), indicating that compound 1-R has the advantage of rapid onset, and the optimal analgesic time points for compound 1-R and indo are 15 minutes and 60 minutes after administration, respectively. Subsequently, we tested the analgesic effects of compound 1-R 15 minutes after administration and indo 60 minutes after administration on days 1, 3, 5 and 7 after modeling. Figure 1B shows that the analgesic effect of compound 1-R on the 1st and 5th days was comparable to that of indo, and was slightly inferior to that of indo on the 3rd and 7th days (p<0.05). However, compared with the model group, compound 1-R still showed a good analgesic effect (p<0.0001).

[0556] However, in the thermal allodynia test using a 35°C thermal radiation instrument, it was found that compared with the model group, compound 1-R showed a significant increase in pain sensitivity 15 minutes after administration ( Figure 1 CFA, p<0.0001) showed analgesic effect, but the best analgesic effect was not shown until 60 minutes after administration, and then a downward trend appeared and it was ineffective at 180 minutes; the result trend of indo was consistent with its mechanical pain sensation. Therefore, we believe that in the CFA-induced thermal allodynia experiment, the best analgesic time point for compound 1-R and indo was 60 minutes after administration. Then we tested the analgesic effect of compound 1-R and indo 60 minutes after administration on the 1st, 3rd, 5th and 7th days after modeling. Figure 1 D shows that compared with the model group, compound 1-R showed a good analgesic effect (p<0.0001), and there was no statistical difference between it and indo.

[0557] 2. Evaluation of the analgesic activity of compound 1-R in a formalin-induced acute inflammatory pain mouse model

[0558] 2.1 Experimental plan

[0559] This experiment adopted the previously reported formalin-induced acute inflammatory pain mouse model (Antinociceptive and anti-inflammatory activities of Cuscuta chinensis seeds in mice [J]. Am J Chin Med, 2014, 42 (1): 223-42; Antinociceptive effects of haloperidol and its metabolites in the formalin test in mice [J]. Psychopharmacology (Berl), 2005, 182 (4): 485-93.), and ICR male mice were randomly divided into a model (pure water) group, three different doses of compound 1-R (i.e., 50 mg / kg group, 100 mg / kg group, and 150 mg / kg group) and an indo (10 mg / kg) group, with 8 mice in each group. The drug was prepared with pure water, the administration volume was 0.2 mL per mouse, and the administration method was oral gavage (ig). 10% tissue fixative was diluted into 5% formalin solution using physiological saline.

[0560] The mice were placed in a transparent resin box to adapt to the environment for 3 days, and a mirror with an angle of 45° was placed at the bottom of the transparent resin box to observe the changes in the behavior of the mouse's hind paws. On the day of the experiment, 0.2 mL of the corresponding drug or solvent was first given to each mouse by gavage, and 20 μL of 5% formalin solution was subcutaneously injected into the toe of the right hind paw of the mouse 45 minutes later. After the injection of formalin solution, the mouse was quickly placed back in the resin box, and the pain behavior of the mouse was observed by video recording 0-30 minutes after the formalin injection. The acute pain response phase of Phase I usually occurs 0-5 minutes after the administration of formalin solution, and the pain phase of Phase II appears 15-30 minutes after the formalin solution. In the later data analysis, a stopwatch was used to record the time when the mouse licked, shook, and bit the right hind paw in Phase I and Phase II.

[0561] 2.2 Experimental Results

[0562] Figure 2 The effect of compound 1-R on formalin-induced acute inflammatory pain is shown.

[0563] 2.3 Results Analysis

[0564] Based on previous experimental results, we set 60 minutes after administration of compound 1-R as the optimal analgesic time point. Figure 2 It was found that in Phase I, compared with the model group, indo and different doses of compound 1-R showed no analgesic effect, while in Phase II, only high-dose (150 mg / kg) compound 1-R and indo produced good analgesic effects, and there was no statistical difference between the two. Therefore, we believe that high-dose compound 1-R can alleviate formalin-induced acute inflammatory pain.

[0565] 3. Evaluation of the analgesic activity of compound 1-R in a mouse model of visceral pain induced by glacial acetic acid

[0566] 3.1 Experimental plan

[0567] This experiment adopted the previously reported glacial acetic acid-induced visceral pain mouse model (Social disruption-induced stress pre-exposure aggravates, while the presence of conspecifics diminishes, acetic acid-induced pain [J]. Psychopharmacology (Berl), 2021, 238 (10): 2851-65.). In this experiment, ICR male mice were randomly divided into a model (pure water) group, three different doses of compound 1-R (i.e., 50 mg / kg group, 100 mg / kg group, and 150 mg / kg group) and an indo (10 mg / kg) group, with 9 mice in each group. The drug was prepared with pure water, the administration volume was 0.2 mL per mouse, and the administration method was ig. First, prepare a 10% glacial acetic acid concentrated stock solution, put it in a 4°C refrigerator for 15 minutes, take an appropriate amount of dilution to 1% glacial acetic acid, put it in a 4°C refrigerator for 12 minutes, and then put it in a 37°C water bath for 3 minutes.

[0568] The mice were placed in the test environment for three days in advance to adapt. On the test day, each mouse was given 0.2 mL of the corresponding drug or solvent by gavage. 45 minutes later, 1% glacial acetic acid was injected intraperitoneally at a dosage volume of 0.01 mL / g. Five minutes later, the number of twists within 15 minutes was recorded. The twisting criteria were back arching, hind limb extension, and abdominal muscle tissue contraction.

[0569] 3.2 Experimental Results

[0570] Figure 3 It showed that compound 1-R could effectively relieve glacial acetic acid-induced visceral pain.

[0571] 3.3 Results Analysis

[0572] As mentioned above, we set 60 min after administration of compound 1-R as the optimal analgesic time point, injected 1% glacial acetic acid intraperitoneally 45 min after oral administration, and evaluated the pain behavior of mice within 15 min 5 min later. Figure 3 It was found that three different doses of compound 1-R and Indo all produced good analgesic effects, and the pain behavior of each group of compound 1-R showed a dose-dependent decrease, indicating that compound 1-R has excellent analgesic activity. Therefore, we believe that compound 1-R helps to relieve visceral pain induced by glacial acetic acid.

[0573] 4. Evaluation of the analgesic activity of compound 1-R in a rat model of neuropathic pain induced by CCI (Chronic compression injury)

[0574] 4.1 Experimental plan

[0575] The neuropathic pain model induced by chronic compression injury of the left sciatic nerve in rats reported in the literature was adopted (AMPK activation by peri-sciatic nerve administration of ozone attenuatesCCI-induced neuropathic pain in rats[J].J Mol Cell Biol,2017,9(2):132-43.). In this experiment, SD male rats were randomly divided into model group, compound 1-R group and PB group, with 8 rats in each group. The compound 1-R group was given compound 1-R 150mg / kg, the PB group was given pregabalin 30mg / kg, and the model group was given an equal volume of pure water. The drug was prepared with pure water, the administration volume was 2mL per rat, and the administration method was ig.

[0576] During modeling, 5% isoflurane was used to induce anesthesia in rats, and then adjusted to 3% for anesthesia maintenance. The rats were placed in the left lateral decubitus position, the surface landmarks of the sciatic nerve were confirmed, the skin was prepared with a shaver and disinfected with an iodine cotton swab. A No. 11 scalpel blade was used to incise the skin along the direction of the nerve at the positioning point, the sciatic nerve was peeled off with a glass needle, and the sciatic nerve was ligated with a surgical knot using a catgut. The tightness of the ligature was appropriate when the rat's left leg shook slightly when the surgical knot was slowly tightened. Four surgical knots were tied in sequence, each with an interval of 1 mm. After the ligation was completed, the nerve was returned with a glass needle, and the muscle and skin were sutured with a 5-0 suture and a suture needle. Finally, the rats were returned to the cage and waited for anesthesia to wake up.

[0577] Pain behavior tests were performed using MWT and TWL. The basal threshold (denoted as BL) was measured one day before modeling, and the pain threshold was measured before administration (denoted as 0) and 15min, 60min, 120min and 180min after administration on the 7th day after modeling. The threshold was measured 8-14 days after administration at the time point with the best analgesic effect. Compound 1-R was 60min after administration, and PB was 120min. The specific operation method for MWT was the same as before. When testing TWL, the temperature of the infrared radiator was set to 55°C, and the rest of the operations were the same as before.

[0578] 4.2 Experimental Results

[0579] Figure 4 Shown are the effects of compound 1-R on CCI-induced mechanical and thermal hyperalgesia.

[0580] 4.3 Results Analysis

[0581] Depend on Figure 4A found that in the CCI-induced mechanical allodynia experiment, both compounds 1-R and PB showed the advantage of rapid onset, but compound 1-R could achieve the best analgesic effect faster (60 minutes after administration, p < 0.0001), while PB was 120 minutes after administration. Therefore, in the CCI-induced mechanical allodynia experiment, we determined the best analgesic time points of compounds 1-R and PB as 60 minutes and 120 minutes after administration, respectively, and tested the analgesic effects of the two at the best time points on days 8-14. It was found that compound 1-R can effectively alleviate CCI-induced mechanical allodynia ( Figure 4 B, p<0.0001).

[0582] In the CCI-induced thermal allodynia experiment ( Figure 4 C), we found that the analgesic trend of compound 1-R was consistent with its performance in mechanical allodynia. Although PB showed an analgesic effect 120 min after administration, the intensity was not as strong as that of compound 1-R ( Figure 4 D, *p<0.05), and the analgesic time of PB only lasted for 180 min. Then, we tested the analgesic effects of compound 1-R and PB at 60 min and 120 min after administration on days 8-14 after modeling. Figure 4 D shows that compounds 1-R and PB can effectively alleviate CCI-induced thermal allodynia (p<0.0001), and there is no statistical difference in the analgesic intensity between the two at the optimal time point.

[0583] 5. Evaluation of the analgesic activity of compound 1-R in a PTX (Paclitaxel)-induced neuropathic pain mouse model

[0584] 5.1 Experimental plan

[0585] The PTX-induced neuropathic pain model reported in the literature was adopted (Resolvin D5 Inhibits Neuropathic and Inflammatory Pain in Male But Not Female Mice: Distinct Actions of D-Series Resolvins in Chemotherapy-Induced Peripheral Neuropathy [J]. Front Pharmacol, 2019, 10: 745.). In this experiment, ICR male mice were randomly divided into sham group, model group, compound 1-R group and PB group, with 6 mice in each group. The compound 1-R group was given 150 mg / kg of compound 1-R, the PB group was given 30 mg / kg of pregabalin, and the sham group and model group were given an equal volume of pure water. Compound 1-R and pregabalin were prepared with pure water, the administration volume was 0.2 mL per mouse, and the administration method was ig. Paclitaxel was prepared to 2 mg / kg, 0.2 mL per mouse, and the solvent was ethanol: hydrogenated castor oil: saline = 4:4:17.

[0586] Pain behavior tests included MWT and cold withdrawal latency (CWL). The basal threshold (denoted as BL) was determined one day before modeling. The model group, compound 1-R group, and pregabalin group were given 2 mg / kg paclitaxel by intraperitoneal injection every day on days 0, 2, 4, and 6, with a cumulative total of 8 mg / kg, while the sham group was given an equal volume of the corresponding solvent. The pain threshold was measured before administration (denoted as 0) and 15 min, 60 min, 120 min, and 180 min after administration on day 8. The best analgesic time point was taken for threshold determination 10, 12, and 14 days after administration. Compound 1-R was tested 60 min after administration, PB was tested 120 min after administration in MWT, and CWL was 60 min.

[0587] The specific operation method for MWT is the same as above. For CWL, dry ice is used for measurement. The animals are placed on a glass plate for three days to adapt. During the test, the dry ice is aimed at the left hind paw of the mouse, and the time when the mouse shrinks / licks / flicks the paw is recorded. The test is repeated 3 times at 5-min intervals, and the average value is recorded. To avoid tissue damage, the cutoff time is set to 35s.

[0588] 5.2 Experimental Results

[0589] Figure 5 Shown are the effects of compound 1-R on PTX-induced mechanical and thermal hyperalgesia.

[0590] 5.3 Experimental Analysis

[0591] For PTX-induced mechanical allodynia, Figure 5 A shows that compared with the model group, compound 1-R can produce good analgesic effect 15 minutes after administration, and can last for 120 minutes, and lose efficacy at 180 minutes; although it is not as good as PB in terms of duration, there is no statistical difference in the analgesic intensity within 120 minutes. Then we tested the analgesic effect of compound 1-R 60 minutes after administration and PB 120 minutes after administration on the 10th, 12th and 14th days after modeling, respectively. Figure 5 The results of B showed that compound 1-R could effectively alleviate PTX-induced mechanical allodynia (p<0.0001), and the analgesic intensity was not statistically different from that of PB.

[0592] In the PTX-induced cold allodynia, the analgesic trend of compound 1-R was consistent with its performance in mechanical allodynia, while the optimal analgesic time of PB was only 120 minutes, and there was a significant decline at 180 minutes. Therefore, in the PTX-induced cold allodynia experiment, we believe that 60 minutes after administration is the optimal analgesic time point for compound 1-R and PB, and test the analgesic effects of the two at 60 minutes after administration on days 8-14. Figure 5 D shows that compounds 1-R and PB can effectively alleviate PTX-induced thermal allodynia (p<0.0001), and there is no statistical difference in analgesic intensity between the two.

[0593] 6. Comparison of in vivo analgesic activity of compound 1-R

[0594] 6.1 Experimental protocol (CFA-induced chronic inflammatory pain mouse model, same protocol as above)

[0595] This experiment adopted the previously reported CFA-induced chronic inflammatory pain mouse model. In this experiment, ICR male mice were randomly divided into model group, compound 1-R group and indo group, with 8 mice in each group. The dose of compound 1-R group was 150 mg / kg, the indo group was given indomethacin 10 mg / kg, and the model group was given an equal volume of pure water. The drug was prepared with pure water, the administration volume was 0.2 mL per mouse, and the administration method was intragastric administration (ig).

[0596] The pain behavior test adopts the thermal withdrawal reflex threshold measurement (TWL). The test time points are selected as -1, 0, and 1 days for behavioral experiments: that is, the basic threshold (recorded as BL) is measured 1 day before modeling, and then 25 μL of CFA solution is subcutaneously injected into the toe of the right hind paw of the mouse, and then the pain threshold is measured before administration (recorded as 0min) and 15min, 60min, 120min, and 180min after administration on the first day after modeling.

[0597] For TWL, a classic infrared radiometer was used for measurement, and the temperature of the infrared radiometer was set to 35°C. The mice were adapted as before. During the test, the radiation light source was aimed at the right hind paw of the mouse. The latency of the mouse to shrink / lick the paw was taken as TWL. The test was repeated 3 times at intervals of 5 minutes, and the average value was recorded. To avoid tissue damage, the cutoff time was set to 20 seconds.

[0598] 6.2 Results Analysis

[0599] In the CFA-induced thermal hypersensitivity experiment in vivo, compound 1-R can produce a good analgesic effect.

[0600] The statistical method used in this example is as follows: The data were analyzed using GraphPad software version 8.0 and expressed as The CFA test, formalin test, CCI test, PTX test, incisional pain test and hot plate test were analyzed using one-way ANOVA, followed by Tukey's test for multiple comparisons. The writhing test was analyzed using one-way ANOVA, followed by Tukey's test for multiple comparisons. p<0.05 was considered statistically significant.

[0601] Example 3

[0602] According to Example 2, the present inventors verified the anti-pain effects of the following derivatives of Compound 1 and found that these compounds also exhibited good anti-pain effects:

[0603]

[0604] All documents mentioned in the present invention are cited as references in this application, just as each document is cited as reference individually. In addition, it should be understood that after reading the above teachings of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the claims attached to this application.

Claims

1. Use of the compound of formula I, or its pharmaceutically acceptable salt or ester, prodrug, optical isomer, stereoisomer or solvate in the preparation of a drug for preventing or treating pain and related diseases, In the formula, 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 oxygen group ( or sulfonate), halogen, optionally substituted monosaccharide, disaccharide or polysaccharide; 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 boric acid 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 carbocyclic ring or an optionally substituted C3-C6 heterocyclic ring 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 substituted with deuterium.

2. The use according to claim 1, characterized in that The compound represented by formula I is the compound represented by formula II, In the formula, 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 aminoformyloxy, 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; 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 an optionally substituted C3-C6 carbocyclic ring or an optionally substituted C3-C6 heterocyclic ring containing 1 or 2 heteroatoms selected from oxygen or nitrogen is formed by two adjacent R3 substituents; m is an integer from 1 to 5; The hydrogen in the structure of formula II is optionally substituted with deuterium.

3. The use thereof as claimed in claim 1, characterized in that The compound shown in formula I is the compound shown in formula III In the formula, 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 carbocyclic ring or an optionally substituted C3-C6 heterocyclic ring containing 1 or 2 oxygens; m is an integer from 1 to 5; The hydrogen in the structure of formula III is optionally substituted with deuterium.

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 can be various amino acid-forming groups), 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 can be various amino acid-forming groups), 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 carbocyclic ring or an optionally substituted C3-C6 heterocyclic ring containing 1 or 2 oxygens; m is an integer from 1 to 3; The hydrogen in the structure of formula IV is optionally substituted with deuterium.

5. The use according to claim 1, characterized in that In the formula, A is selected from phenyl; R1 and R4 are independently selected from H, D, OH, and optionally substituted C1-C6 alkoxy; 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 carbocyclic ring or an optionally substituted C3-C6 heterocyclic ring 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 substituted with deuterium.

6. Use of the following compounds, or their salts or esters, prodrugs, optical isomers or solvates in the preparation of drugs for preventing or treating pain-related diseases: Preferably, the compound is More preferably, the compound is a compound selected from the group consisting of:

7. The use according to any one of claims 1 to 6, characterized in that The pain and its related diseases are mechanical and thermal hyperalgesia, acute inflammatory pain, chronic inflammatory pain, visceral pain, neuropathic pain or traumatic pain.

8. A compound of formula I, or a pharmaceutically acceptable salt or ester, prodrug, optical isomer, stereoisomer or solvate thereof, In the formula, 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 group?), optionally substituted aminoacetoxy group ( 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; 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 boric acid 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 carbocyclic ring or an optionally substituted C3-C6 heterocyclic ring 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 substituted with deuterium.

9. The compound of claim 8, or a pharmaceutically acceptable salt or ester, prodrug, optical isomer, stereoisomer or solvate thereof, In the formula, A is selected from a C6-C10 aromatic ring or a 5-6 membered 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, 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 boric acid 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 carbocyclic ring or an optionally substituted C3-C6 heterocyclic ring 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 substituted with deuterium.

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

11. A pharmaceutical composition comprising the compound according to any one of claims 8 to 10, 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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