Cannabidiol derivatives, processes for their preparation and their use in medicine

Abstract

The present application relates to cannabidiol derivatives and their use in medicine, in particular to pyrimidine derivatives as shown in general formula (I), or stereoisomers, solvates, metabolites, prodrugs, pharmaceutically acceptable salts or co-crystals thereof, wherein the definitions of the substituents in general formula (I) are the same as those in the specification.

Description

Technical Field

[0001] This invention relates to cannabidiol derivatives, or their stereoisomers, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals, pharmaceutical compositions thereof, and their use in the preparation of pharmaceuticals. Background Technology

[0002] Cannabis (Cannabis sativa L.) is an annual herbaceous plant belonging to the genus Cannabis in the family Moraceae. Originating in Central and East Asia, it is widely distributed in the United States, India, Brazil, and other regions. Cannabis has a long history of medicinal use, but its addictive and hallucinogenic effects severely limit its clinical application. Cannabis contains hundreds of different chemical substances, approximately 70 of which are called cannabinoids, primarily including cannabidiol (CBD), cannabinol (CBN), tetrahydrocannabinol (THC), and their homologues, with CBD being the most abundant. CBD not only antagonizes the psychoactive effects induced by THC but also possesses a wide range of therapeutic properties, showing significant improvement in neurological disorders including anxiety, schizophrenia, addiction, neurodegenerative diseases, neonatal hypoxic-ischemic encephalopathy, and epilepsy. Furthermore, it shows promising applications in anti-tumor, anti-inflammatory, hepatoprotective, pain-relieving, anti-anxiety, anti-insomnia, anticonvulsant, antiemetic, antispasmodic, antioxidant, and neuroprotective treatments. Summary of the Invention

[0003] The purpose of this application is to provide cannabidiol derivatives, or their stereoisomers, solvates, metabolites, pharmaceutically acceptable salts, cocrystals or prodrugs, pharmaceutical compositions thereof, and their use in the preparation of pharmaceuticals.

[0004] One or more embodiments of this application provide cannabidiol derivatives that, while possessing good pharmacological activity, have higher bioavailability (e.g., oral bioavailability) and a longer half-life, can significantly reduce the production of inactive or toxic metabolites after administration, while prolonging the duration of drug action, exhibiting better pharmacokinetic characteristics, and reducing toxic side effects.

[0005] One or more embodiments of this application provide compounds of general formula (I), or their stereoisomers, solvates, prodrugs, metabolites, pharmaceutically acceptable salts, or cocrystals:

[0006]

[0007] in,

[0008] R0 is selected from methyl, -CH2OH, -C(=O)OC 1-6Alkyl, -C(=O)NR b1 R b2 Alternatively, it may be a carboxyl group, and at least one hydrogen atom of R0 is replaced by a deuterium atom, and when R0 is selected from -CD2H or -CD3, R is not -(CH2)4CH3;

[0009] X is selected from hydrogen, deuterium, hydroxyl group, and C. 1-6 Alkyl or halogen;

[0010] R1 is selected from C 1-6 Alkyl, C 3-8 carbon cyclo group or C 2-6 alkenyl, the C 1-6 Alkyl, C 2-6 alkenyl, C 3-8 The carbocyclic group may be further selected by one to three halogens, hydroxyl groups, C... 3-8 carbon cyclo group or C 1-6 The alkyl group is substituted, and R1 is optionally substituted by one or more deuterium atoms;

[0011] R2 and R3 are each independently selected from hydrogen, hydroxyl, or C. 1-6 The alkoxy group, R2 and R3, are each independently and optionally substituted by one or more deuterium atoms, and at least one of R2 and R3 is not H;

[0012] r can be selected from 0, 1, 2, or 3;

[0013] n is selected from 0, 1, or 2;

[0014] Y is selected from hydrogen, carboxyl group, C 1-6 Alkyl or halogen, Y may be substituted by one or more deuterium atoms;

[0015] R is selected from C 1-12 Alkyl, C 1-12 Heteroalkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 3-12 carbon cyclo group, C 3-12 Heterocyclic group, -C 1-6 Alkylene-C 3-12 carbonyl group, -C 1-6 Alkylene-C 3-12 Heterocyclic group, -NR b1 R b2 -C 1-6 Alkylene-C(=O)OC 1-6 Alkyl or -C 1-6 Alkylene-C(=O)NR b1 R b2 And the C mentioned 1-12 Alkyl, C 1-12 Heteroalkyl, C2-12 alkenyl, C 2-12 alkynyl group, C 1-6 Alkylene, C 3-12 carbon cyclo group, C 3-12 The heterocyclic group is optionally surrounded by one or more groups selected from hydroxyl, carboxyl, halogen, cyano, =O, C 1-6 Alkyl, -NR b1 R b2 C 3-12 carbon cyclo group, C 3-12 Heterocyclic group, C 2-6 alkenyl, C 2-6 alkynyl group, -C(=O)OC 1-6 Alkyl group, -C(=O)C 1-6 Alkyl, -C(=O)NR b1 R b2 -S(=O)C 1-6 Alkyl or -S(=O)2C 1-6 The alkyl group is substituted, and the C group that is the substituent is... 1-6 Alkyl, C 3-12 carbon cyclo group, C 3-12 The heterocyclic group may be further selected by one or more groups chosen from =O, hydroxyl, carboxyl, halogen, cyano, -C(=O)OC 1-6 Alkyl or -C(=O)C 1-6 The alkyl group is substituted, and R is optionally substituted by one or more deuterium atoms;

[0016] R b1 R b2 Each is independently selected from H and C. 1-6 Alkyl, C 3-12 carbon cyclo group, C 3-12 Heterocyclic groups, -C(=O)R b3 -C(=O)NR b4 R b5 The C mentioned therein 1-6 Alkyl, C 3-12 carbon cyclo group, C 3-12 The heterocyclic group may be further selected by one or more elements chosen from hydroxyl, deuterium, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 6-12 Aryl, C 5-12 heteroaryl, C 3-12 cycloalkyl or C 3-12 Substituents of heterocyclic alkyl groups; or R b4 With R b5 The N atom forms a 3- to 12-membered heterocycle, wherein the heterocycle contains one or more heteroatoms selected from N, O, or S, R b1 R b2It can be substituted by one or more deuterium atoms;

[0017] R b3 Selected from C 1-6 Alkyl, C 1-6 Alkoxy or C 6-12 Aryl, R b3 It can be substituted by one or more deuterium atoms;

[0018] R b4 R b5 Selected from H or C 1-6 Alkyl, R b4 R b5 It can be substituted by one or more deuterium atoms;

[0019] It can be a single bond or a double bond.

[0020] One or more embodiments of this application provide compounds, or their stereoisomers, solvates, prodrugs, metabolites, pharmaceutically acceptable salts, or cocrystals, wherein said compounds have one of the following structures:

[0021] or

[0022] One or more embodiments of this application provide intermediates for preparing compounds of general formula (I), or their stereoisomers, solvates, prodrugs, metabolites, pharmaceutically acceptable salts, or cocrystals, wherein the intermediate is selected from:

[0023] or

[0024] This invention also provides a method for preparing compound A or its stereoisomers, deuterated derivatives, solvates, prodrugs, metabolites, pharmaceutically acceptable salts, or cocrystals, characterized by comprising the following steps:

[0025]

[0026] Step 1: Compound AI, 3,5-dihydroxypentane, and a protic acid react in an organic solvent to give compound A-II;

[0027] Step 2: Compound A is prepared by dehydration reaction of compound A-II in an organic solvent.

[0028] The organic solvent can be determined in the art based on common knowledge in the field.

[0029] One or more embodiments of this application provide a pharmaceutical composition comprising:

[0030] (1) The compound or its stereoisomer, solvate, metabolite, pharmaceutically acceptable salt, cocrystal or prodrug described in this application;

[0031] (2) One or more other active ingredients selected by choice; and

[0032] (3) Pharmaceutically acceptable carriers and / or excipients.

[0033] In one or more embodiments of this application, the other active ingredients are selected from one or more of ginkgolide, antitumor agents, anticoagulants, antiepileptic agents, antidepressants, anxiolytics, hypnotics, analgesics, or anesthetics, or stereoisomers, hydrates, metabolites, solvates, pharmaceutically acceptable salts, or cocrystals of the other active ingredients.

[0034] In one or more embodiments of this application, the ginkgolide is one or any two or more of ginkgolide A, ginkgolide B, ginkgolide C, ginkgolide D, ginkgolide J, ginkgolide M, ginkgolide K, ginkgolide L, ginkgolide N, ginkgolide P, ginkgolide Q, and ginkgolide in any proportion.

[0035] One or more embodiments of this application provide the compound of this application or its stereoisomers, solvates, metabolites, pharmaceutically acceptable salts or cocrystals, or pharmaceutical compositions for the preparation of treatments for post-traumatic stress disorder, facial paralysis, stroke, migraine, stable angina pectoris, cerebral infarction, thromboembolism, myocardial infarction, myocardial ischemia, coronary artery disease, hypertension, cerebral ischemia, improvement of sexual function, spasms, acute and chronic pain, fibromyalgia, postoperative pain, cluster headache, tension headache, back pain, limb pain, low back pain, neck pain, neuropathic pain, cancer pain, trigeminal neuralgia, arthritis pain, inflammatory pain, Dravet syndrome, Lennox-Gastaut syndrome, etc. Use in medications for: UT syndrome, Prader-Willi syndrome, Sturge-Weber syndrome, Fragile X syndrome, anxiety, bipolar disorder, autism, generalized anxiety disorder, social anxiety disorder, epilepsy, Parkinson's disease, Alzheimer's disease, Huntington's disease, opioid abuse, alcoholism, nicotine addiction, anorexia, cachexia, chemotherapy-related nausea and vomiting, postoperative nausea and vomiting, amyotrophic lateral sclerosis (ALS), Friedreich's ataxia, schizophrenia, obsessive-compulsive disorder, multiple sclerosis, depression, sleep disorders, spasticity caused by multiple sclerosis, dystonia, sleep apnea, paralytic dementia, memory loss, or glioblastoma.

[0036] One or more embodiments of this application provide the above-described compounds of this application for use as pharmaceuticals.

[0037] One or more embodiments of this application provide the above-described compounds of this application or their stereoisomers, solvates, metabolites, pharmaceutically acceptable salts, or cocrystals for use in methods of treating the following conditions: post-traumatic stress disorder, facial paralysis, stroke, migraine, stable angina pectoris, cerebral infarction, thromboembolism, myocardial infarction, myocardial ischemia, coronary artery disease, hypertension, cerebral ischemia, improvement of sexual function, spasm, acute and chronic pain, fibromyalgia, postoperative pain, cluster headache, tension headache, back pain, limb pain, low back pain, neck pain, neuropathic pain, cancer pain, trigeminal neuralgia, arthritis pain, inflammatory pain, Dravet syndrome, Lennox-Gastau syndrome. T syndrome, Prader-Willi syndrome, Sturge-Weber syndrome, Fragile X syndrome, anxiety, bipolar disorder, autism, generalized anxiety disorder, social anxiety disorder, epilepsy, Parkinson's disease, Alzheimer's disease, Huntington's disease, opioid abuse, alcoholism, nicotine addiction, anorexia, cachexia, chemotherapy-related nausea and vomiting, postoperative nausea and vomiting, amyotrophic lateral sclerosis (ALS), Friedreich ataxia, schizophrenia, obsessive-compulsive disorder, multiple sclerosis, depression, sleep disorders, spasticity caused by multiple sclerosis, dystonia, sleep apnea, paralytic dementia, memory loss, or glioblastoma.

[0038] One or more embodiments of this application provide methods for treating the following diseases, comprising administering to a subject in need the aforementioned compound or its stereoisomers, solvates, metabolites, pharmaceutically acceptable salts, or cocrystals of this application: post-traumatic stress disorder, facial paralysis, stroke, migraine, stable angina pectoris, cerebral infarction, thromboembolism, myocardial infarction, myocardial ischemia, coronary artery disease, hypertension, cerebral ischemia, improvement of sexual function, spasm, acute and chronic pain, fibromyalgia, postoperative pain, cluster headache, tension headache, back pain, limb pain, lower back pain, neck pain, and so on. Menstrual pain, cancer pain, trigeminal neuralgia, arthritis pain, inflammatory pain, Dravet syndrome, Lennox-Gastaut syndrome, Prader-Willi syndrome, Sturge-Weber syndrome, Fragile X syndrome, anxiety, bipolar disorder, autism, generalized anxiety disorder, social anxiety disorder, epilepsy, Parkinson's disease, Alzheimer's disease, Huntington's disease, opioid abuse, alcoholism, nicotine addiction, anorexia, cachexia, chemotherapy-related nausea and vomiting, postoperative nausea and vomiting, amyotrophic lateral sclerosis (ALS), Friedreich's ataxia, schizophrenia, obsessive-compulsive disorder, multiple sclerosis, depression, sleep disorders, spasticity caused by multiple sclerosis, dystonia, sleep apnea, paralytic dementia, memory loss, or glioblastoma.

[0039] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0040] The carbon, hydrogen, oxygen, sulfur, nitrogen, or F, Cl, Br, I involved in the groups and compounds described in this invention include their isotopes, and the carbon, hydrogen, oxygen, sulfur, or nitrogen involved in the groups and compounds described in this invention may optionally be further replaced by one or more of their corresponding isotopes, wherein the isotopes of carbon include 12 C 13 C and 14 C, the isotopes of hydrogen include protium (H), deuterium (D, also called heavy hydrogen), and tritium (T, also called superheavy hydrogen), and the isotopes of oxygen include 16 O、 17 O and 18 O, isotopes of sulfur include 32 S, 33 S, 34 S and 36 S, nitrogen isotopes include 14 N and 15 N, isotopes of fluorine include 17 F and 19 F, isotopes of chlorine include 35 Cl and 37 Cl, isotopes of bromine include 79 Br and81 Br.

[0041] "Hydrocarbon group" refers to a group containing only carbon and hydrogen atoms.

[0042] "alkyl" refers to a straight-chain or branched saturated aliphatic hydrocarbon group with 1 to 20 carbon atoms, preferably an alkyl group with 1 to 8 carbon atoms (e.g., 1, 2, 3, 4, 5, 6, 7, 8), more preferably an alkyl group with 1 to 6 carbon atoms, and even more preferably an alkyl group with 1 to 4 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, and various branched isomers thereof; when the alkyl group is substituented, it may optionally be further substituted by one or more substituents.

[0043] "Heteroalkyl" refers to a group in which at least one carbon atom of an alkyl group is replaced by an O, S, N, or P atom. Non-limiting examples include thiomethyl, thioethyl, thio-n-propyl, thioisopropyl, thio-n-butyl, thio-sec-butyl, and thio-tert-butyl. The definition of alkyl is the same as that of "alkyl" as described above.

[0044] "Alkoxy" refers to a group formed by replacing at least one carbon atom in an alkyl group with an oxygen atom. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexoxy, cyclopropoxy, and cyclobutoxy. The definition of alkyl is the same as that of "alkyl" as described above.

[0045] "Alkenyl" refers to a straight-chain or branched unsaturated aliphatic hydrocarbon group containing 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10) carbon-carbon double bonds, composed of 2 to 20 carbon atoms, preferably an alkenyl group with 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12) carbon atoms, more preferably an alkenyl group with 2 to 8 carbon atoms, and even more preferably an alkenyl group with 2 to 6 carbon atoms. Non-limiting examples include vinyl, propen-2-yl, buten-2-yl, buten-2-yl, penten-2-yl, penten-4-yl, hexen-2-yl, hexen-3-yl, hepten-2-yl, hepten-3-yl, hepten-4-yl, octen-3-yl, nonen-3-yl, decen-4-yl, and undecen-3-yl. The alkenyl group may optionally be further replaced by one or more substituents.

[0046] "Alynyl" refers to a straight-chain or branched unsaturated aliphatic hydrocarbon group consisting of 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) carbon-carbon triple bonds and composed of 2 to 20 carbon atoms, preferably an alkynyl group with 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12) carbon atoms, more preferably an alkynyl group with 2 to 8 carbon atoms, and even more preferably an alkynyl group with 2 to 6 carbon atoms. Non-limiting embodiments include ethynyl, propyn-1-yl, propyn-2-yl, butyn-1-yl, butyn-2-yl, butyn-3-yl, 3,3-dimethylbutyn-2-yl, pentyne-1-yl, pentyne-2-yl, hexyn-1-yl, 1-heptyne-1-yl, heptyne-3-yl, heptyne-4-yl, octyne-3-yl, nonyne-3-yl, decanyne-4-yl, undecanyne-3-yl, and dodecanyne-4-yl. The ethynyl group may optionally be further substituted with one or more substituents.

[0047] "Aryl" refers to a substituted or unsubstituted aromatic ring, which can be a 5- to 8-membered (e.g., 5, 6, 7, 8-membered) monocyclic ring, a 5- to 12-membered (e.g., 5, 6, 7, 8, 9, 10, 11, 12-membered) bicyclic ring, or a 10- to 15-membered (e.g., 10, 11, 12, 13, 14, 15-membered) tricyclic system. It can be a bridged ring or a spirocyclic ring. Non-limiting examples include phenyl and naphthyl groups. The aryl group may optionally be further substituted by one or more substituents.

[0048] "Heteroaryl" refers to a substituted or unsubstituted aromatic ring, which can be a 3- to 8-membered (e.g., 3, 4, 5, 6, 7, 8-membered) monocyclic ring, a 5- to 12-membered (e.g., 5, 6, 7, 8, 9, 10, 11, 12-membered) bicyclic ring, or a 10- to 15-membered (e.g., 10, 11, 12, 13, 14, 15-membered) tricyclic system, and contains 1 to 6 (e.g., 1, 2, 3, 4, 5, 6) heteroatoms selected from N, O, or S, preferably 5- to 8-membered heteroaryl. The 1 to 4 (e.g., 1, 2, 3, 4) N and S atoms selectively substituted in the ring of the heteroaryl can be oxidized to various oxidation states. The heterocyclic group can be attached to a heteroatom or a carbon atom. The heteroaryl group can be a bridged ring or a spiro ring. Non-limiting examples include cyclopyridyl, furanyl, thiophenyl, pyranyl, pyrrolidinyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinylbenzimidazolyl, benzopyridyl, and pyrrolopyridyl. The heteroaryl group may optionally be further substituted with one or more substituents.

[0049] "Carbocyclic group" or "carbocyclic" refers to a saturated or unsaturated aromatic ring or non-aromatic ring. When it is an aromatic ring, its definition is the same as that of "aryl" above; when it is a non-aromatic ring, it can be a monocyclic ring of 3 to 10 members (e.g., 3, 4, 5, 6, 7, 8, 9, 10 members), a bicyclic ring of 4 to 12 members (e.g., 4, 5, 6, 7, 8, 9, 10, 11, 12 members), or a tricyclic system of 10 to 15 members (e.g., 10, 11, 12, 13, 14, 15 members). It can be a bridged ring or a spirocyclic ring. Non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2-enyl, 1-cyclopentyl-3-enyl, cyclohexyl, 1-cyclohexyl-2-enyl, 1-cyclohexyl-3-enyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, etc. The “carbocyclic group” or “carbocyclic” may optionally be further replaced by one or more substituents.

[0050] "Heterocyclic group" or "heterocycle" refers to a saturated or unsaturated aromatic heterocycle or a non-aromatic heterocycle. When it is an aromatic heterocycle, its definition is the same as the definition of "heteroaryl" above. When it is a non-aromatic heterocycle, it can be a 3- to 10-membered (e.g., 3, 4, 5, 6, 7, 8, 9, 10-membered) monocyclic, a 4- to 12-membered (e.g., 4, 5, 6, 7, 8, 9, 10, 11, 12-membered) bicyclic, or a 10- to 15-membered (e.g., 10, 11, 12, 13, 14, 15-membered) tricyclic system, and contains 1 to 4 heteroatoms selected from N, O, or S, preferably a 3- to 8-membered heterocyclic group. The selectively substituted 1 to 4 (e.g., 1, 2, 3, 4) N and S atoms in the ring of the "heterocyclic group" or "heterocycle" can be oxidized to various oxidation states; the "heterocyclic group" or "heterocycle" can be attached to a heteroatom or a carbon atom; the "heterocyclic group" or "heterocycle" can be a bridged ring or a spirocycle. Non-limiting examples of "heterocyclic group" or "heterocycle" include epoxide ethyl, epoxide propyl, aziroxide butyl, aziroxide butyl, thioheroxide, 1,3-dioxopentyl, 1,4-dioxopentyl, 1,3-dioxahexacyclol, aziroxide heptyl, aziroxide heptyl, thioheptyl, oxazonyl, diazonyl, thioazonyl, pyridyl, piperidinyl, homopiperidinyl, furanyl, thiopheneyl, pyranyl, N-alkylpyrroleyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperazinyl, homopiperidinyl, imidazolyl, piperidinyl, morpholinyl, thiomorpholinyl, thiooxalyl, 1,3-dithiaalkyl, dihydrofuranyl, dithiapentyl, tetrahydrofuranyl, tetrahydrothiophene, tetrahydropyranyl, tetrahydrothia ... Hydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, benzimidazolyl, benzopyridyl, pyrrolopyridyl, benzodihydrofuranyl, 2-pyrrololinyl, 3-pyrrololinyl, dihydroindolyl, 2H-pyranyl, 4H-pyranyl, dioxacyclohexyl, 1,3-dioxopentyl, pyrazolinyl, dithiamethyleneyl, dithiaphenyl, pyrazolyl, imidazolinyl, imidazolinyl, 1,2,3,4-tetrahydroisoquinolinyl, 3-azabicyclo[3.1.0]hexyl, 3-azabicyclo[4.1.0]heptyl, azabicyclo[2.2.2]hexyl, 3H-indolylquinazinyl, N-pyridylurea, 1,1-dioxothiomorpholinyl, azabicyclo[3.2.1]octyl, Azabicyclo[5.2.0]nonyl, oxatricyclo[5.3.1.1]dodecyl, azaadamantyl, and oxaspiro[3.3]heptyl. The “heterocyclic group” or “heterocycle” may optionally be further substituted with 0 or more substituents.

[0051] "Cycloalkyl" refers to a saturated cyclic hydrocarbon group, the ring of which can be a 3- to 10-membered (e.g., 3, 4, 5, 6, 7, 8, 9, 10-membered) monocyclic ring, a 4- to 12-membered (e.g., 4, 5, 6, 7, 8, 9, 10, 11, 12-membered) bicyclic ring, or a 10- to 20-membered (e.g., 4, 5, 6, 7, 8, 9, 10, 11, 12-membered) polycyclic system, preferably with 3 to 10 carbon atoms, more preferably with 3 to 8 carbon atoms. Non-limiting examples of "cycloalkyl" include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, 1,5-cyclooctadienyl, 1,4-cyclohexadienyl, and cyclohepttrienyl, etc. When the cycloalkyl group is substituted, it may optionally be further substituted by one or more substituents.

[0052] "Heterocyclic alkyl" refers to a substituted or unsubstituted saturated non-aromatic cyclic group, which can be a 3- to 8-membered (e.g., 3, 4, 5, 6, 7, 8-membered) monocyclic, a 4- to 12-membered (e.g., 4, 5, 6, 7, 8, 9, 10, 11, 12-membered) bicyclic, or a 10- to 15-membered (e.g., 10, 11, 12, 13, 14, 15-membered) tricyclic system, and contains 1, 2, or 3 heteroatoms selected from N, O, or S, preferably a 3- to 8-membered heterocyclic group. The selectively substituted N or S in the ring of the "heterocyclic alkyl" can be oxidized to various oxidation states; the "heterocyclic alkyl" can be attached to a heteroatom or a carbon atom; the "heterocyclic alkyl" can be a bridged ring or a spirocyclic ring. Non-limiting examples of “heterocyclic alkyl” include epoxyethyl, aziridine, oxacyclobutyl, aziridine, 1,3-dioxolanecycloyl, 1,4-dioxolanecycloyl, 1,3-dioxahexacycloyl, aziridine, piperidinyl, piperinyl, morpholinyl, thiomorpholinyl, 1,3-dithiaalkyl, tetrahydrofuranyl, tetrahydropyrroleyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, aziridine[3.2.1]octyl, aziridine[5.2.0]nonyl, oxacyclo[5.3.1.1]dodecyl, aziridine, and oxaspiro[3.3]heptyl.

[0053] When the terms "alkyl", "alkoxy", "alkenyl", "alkynyl", "aryl", "heteroaryl", "carbocyclic", "carbocyclic", "heterocyclic", "cycloalkyl", "heterocyclic", or "heterocyclic" mentioned above are substituted, they may optionally be further replaced by 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 selected from F, Cl, Br, I, hydroxyl, mercapto, nitro, cyano, amino, C 1-6 Alkylamino, =O, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, -NR q4 R q5 =NRq6 -C(=O)OC 1-6 Alkyl group, -OC (=O)C 1-6 Alkyl, -C(=O)NR q4 R q5 C 3-8 cycloalkyl, C 3-8 Heterocyclic alkyl, C 6-10 Aryl, C 5-10 heteroaryl, -C(=O)OC 6-10 Aryl, -OC(=O)C 6-10 Aryl, -OC(=O)C 5-10 heteroaryl, -C(=O)OC 5-10 heteroaryl, -OC(=O)C 3-8 Heterocyclic alkyl, -C(=O)OC 3-8 Heterocyclic alkyl groups, -OC (=O)C 3-8 Cycloalkyl, -C(=O)OC 3-8 cycloalkyl, -NHC(=O)C 3-8 Heterocyclic alkyl groups, -NHC(=O)C 6-10 Aryl, -NHC(=O)C 5-10 heteroaryl, -NHC(=O)C 3-8 cycloalkyl, -NHC(=O)C 3-8 Heterocyclic alkyl groups, -NHC(=O)C 2-6 alkenyl or -NHC(=O)C 2-6 The alkynyl group is replaced by a substituent, and the substituent C is described in the figure. 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 cycloalkyl, C 3-8 Heterocyclic alkyl, C 6-10 Aryl, C 5-10 heteroaryl, -NHC(=O)C 6-10 Aryl, -NHC(=O)C 5-10 heteroaryl, -NHC(=O)C 3-8 Heterocyclic alkyl groups or -NHC(=O)C 3-8 The cycloalkyl group may optionally be further surrounded by one to three elements selected from OH, F, Cl, Br, I, C. 1-6 Alkyl, C 1-6 Alkoxy, -NR q4 R q5 Or replaced by the =O substituent; R q1 Selected from C 1-6 Alkyl, C 1-6 Alkoxy or C 6-10 Aryl; R q2 Rq3 Selected from H or C1-6 alkyl; wherein, R q4 R q5 Selected from H, C 1-6 Alkyl group, -NH (C=NR) q1 )NR q2 R q3 -S(=O)2NR q2 R q3 -C(=O)R q1 Or -C(=O)NR q2 R q3 The C mentioned therein 1-6 The alkyl group may optionally be further influenced by one or more elements selected from OH, F, Cl, Br, I, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 6-10 Aryl, C 5-10 heteroaryl, C 3-8 cycloalkyl or C 3-8 Substituents of heterocyclic alkyl groups; or R q4 With R q5 The N atom forms a 3- to 8-membered heterocycle, which may contain one or more heteroatoms selected from N, O or S.

[0054] "Amino acid side chain" refers to the group in an amino acid molecule other than the amino and carboxyl groups.

[0055] "Pharmaceutically acceptable salt" or "its pharmaceutically acceptable salt" means that the compound of the present invention retains the bioavailability and properties of a free acid or a free base, wherein the free acid is obtained by reacting with a non-toxic inorganic or organic base, and the free base is obtained by reacting with a non-toxic inorganic or organic acid.

[0056] "Pharmaceutical composition" refers to a mixture of one or more compounds described in this invention, their pharmaceutically acceptable salts or prodrugs, and other chemical components, wherein "other chemical components" refers to pharmaceutically acceptable carriers, excipients, and / or one or more other therapeutic agents.

[0057] "Carrier" refers to a material that does not cause significant stimulation to an organism and does not eliminate the biological activity and properties of the compound given.

[0058] "Excipients" are inert substances added to a pharmaceutical composition to facilitate administration of the compound. Non-limiting examples include calcium carbonate, calcium phosphate, sugar, starch, cellulose derivatives (including microcrystalline cellulose), gelatin, vegetable oils, polyethylene glycols, diluents, granulating agents, lubricants, binders, and disintegrants.

[0059] "Prodrug" refers to a compound of the present invention that can be metabolized in vivo and converted into a biologically active compound. The prodrug of the present invention is prepared by modifying the amino or carboxyl groups in the compound of the present invention. This modification can be performed through conventional procedures or removed in vivo to obtain the parent compound. When the prodrug of the present invention is administered to a mammalian individual, the prodrug is cleaved to form free amino or carboxyl groups.

[0060] "Co-crystal" refers to a crystal formed by the bonding of an active pharmaceutical ingredient (API) and a co-crystal form (CCF) through hydrogen bonds or other non-covalent bonds. Both API and CCF are solids at room temperature in their pure states, and a fixed stoichiometric ratio exists between the components. Co-crystal is a multi-component crystal, encompassing both binary co-crystals formed between two neutral solids and multi-component co-crystals formed between a neutral solid and a salt or solvate.

[0061] "Stereoisomers" are isomers that are produced by different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers, and conformational isomers.

[0062] "Optional," "optionally," "selectively," or "selectively" means that the event or condition described below may or may not occur, and the description includes both cases in which the event or condition occurs and cases in which it does not occur. For example, "selectively alkyl-substituted heterocyclic group" means that the alkyl group may or may not be present, and the description includes both cases in which the heterocyclic group is substituted with an alkyl group and cases in which the heterocyclic group is not substituted with an alkyl group. Detailed Implementation

[0063] The following embodiments illustrate the technical solution of the present invention in detail, but the scope of protection of the present invention includes, but is not limited to, these embodiments.

[0064] The structure of the compound was determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (δ) were expressed in 10⁻¹⁰ increments. -6 The unit (ppm) is given. NMR measurements were performed using a Bruker Avance III 400 and Bruker Avance 300 NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD). The internal standard was tetramethylsilane (TMS).

[0065] MS determination was performed using (Agilent 6120B (ESI) and Agilent 6120B (APCI));

[0066] HPLC determinations were performed using an Agilent 1260DAD high-performance liquid chromatograph (Zorbax SB-C18 100×4.6mm, 3.5μM).

[0067] Thin-layer chromatography silica gel plates are Yantai Huanghai HSGF254 or Qingdao GF254. The silica gel plates used in thin-layer chromatography (TLC) are 0.15mm-0.20mm in diameter, and the silica gel plates used for thin-layer chromatography separation and purification are 0.4mm-0.5mm in diameter.

[0068] Column chromatography typically uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier;

[0069] The known starting materials of this invention can be synthesized using or according to methods known in the art, or can be purchased from companies such as Titan Technology, Anaiji Chemical, Shanghai Demo, Chengdu Kelong Chemical, Shaoyuan Chemical Technology, and Bailingwei Technology.

[0070] Nitrogen atmosphere refers to a reaction flask connected to a nitrogen balloon with a volume of approximately 1L.

[0071] A hydrogen atmosphere refers to a reaction vessel connected to a hydrogen balloon with a volume of approximately 1L.

[0072] The hydrogenation reaction is usually carried out under vacuum, filled with hydrogen gas, and repeated 3 times.

[0073] Unless otherwise specified in the examples, the reaction was carried out under a nitrogen atmosphere;

[0074] Unless otherwise specified in the examples, "solution" refers to an aqueous solution.

[0075] Unless otherwise specified in the examples, the reaction temperature is room temperature, and the optimal reaction temperature is 20℃-30℃.

[0076] DCM: Dichloromethane;

[0077] EA: Ethyl acetate;

[0078] HCl: hydrochloric acid;

[0079] THF: Tetrahydrofuran;

[0080] DMF: N,N-dimethylformamide;

[0081] PE: Petroleum ether;

[0082] TLC: Thin-layer chromatography;

[0083] SFC: Supercritical Fluid Chromatography;

[0084] NCS: N-chlorosuccinimide;

[0085] Pd(dppf)Cl2: [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride;

[0086] DMSO: Dimethyl sulfoxide;

[0087] DTT: Dithiothreitol;

[0088] ATP: adenosine triphosphate;

[0089] DNA: Deoxyribonucleotides.

[0090] Example

[0091] The following embodiments illustrate the technical solution of the present invention in detail, but the scope of protection of the present invention includes, but is not limited to, these embodiments.

[0092] Example 1

[0093] 4-Methyl-5'-(methyl-d3)-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol (Compound 1)

[0094] 4-methyl-5'-(methyl-d3)-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol

[0095]

[0096]

[0097] first step:

[0098] 3-Ethoxy-6-(2-hydroxypropyl-2-yl)cyclohex-2-en-1-one 1b

[0099] 3-ethoxy-6-(2-hydroxypropan-2-yl)cyclohex-2-en-1-one

[0100] Under nitrogen protection at -70°C, 10.0 g (71.0 mmol) of 3-ethoxycyclohexyl-2-en-1-one 1a was added dropwise to a tetrahydrofuran (100 mL) solution of lithium diisopropylamino (54 mL, 107.0 mmol, 2.0 N). The mixture was stirred for 0.5 h after the addition was complete. Acetone (9.2 g, 142.0 mmol) was added dropwise, and the mixture was stirred for another 3 h after the addition was complete. The reaction was monitored by TLC until the reaction was complete. The reaction was quenched by adding saturated ammonium chloride solution (180 mL). The mixture was separated into two phases. The aqueous phase was extracted with ethyl acetate (150 mL × 2). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound 1b (yellow oil, 18.0 g, yield: 99.0%).

[0101] 1H NMR (400MHz, DMSO) δ5.29(s,1H),4.93(s,1H),3.98–3.87(m,2H),2.46(dd,J=11.2,5.0Hz,1H),2.37(dt,J=17.4,4.5Hz,1H),2.21 (dd,J=12.1,4.7Hz,1H),2.12–2.03(m,1H),1.67(ddd,J=24.2,12.3,5.1Hz,1H),1.27(t,J=7.0Hz,3H),0.99(s,3H),0.73(s,3H).

[0102] LC-MS m / z(ESI)=199.2[M+1].

[0103] Step Two:

[0104] 4-(2-hydroxypropan-2-yl)cyclohex-2-en-1-one 1c

[0105] 4-(2-hydroxypropan-2-yl)cyclohex-2-en-1-one

[0106] Under nitrogen protection at 0°C, red aluminum (67 mL, 234.1 mmol, 3.5 N) was added dropwise to a tetrahydrofuran (200 mL) solution of compound 1b (17.0 g, 78.0 mmol). After the addition was complete, the mixture was slowly raised to room temperature and stirred for 2 h. The reaction was monitored by TLC until completion. The temperature was lowered to 0°C, and the reaction was quenched by adding saturated ammonium chloride solution (13 mL). The mixture was filtered, and the aqueous phase was extracted with ethyl acetate (200 mL × 2). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. Furan (40 mL) was dissolved, and hydrochloric acid aqueous solution (40 mL, 2 N) was added dropwise. After the addition was complete, the mixture was stirred at room temperature for 1.5 h. The reaction was monitored by TLC until it was complete. The reaction was quenched by adding saturated sodium bicarbonate solution, and the mixture was concentrated under reduced pressure. The aqueous phase was extracted with ethyl acetate (100 mL × 4). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether (v / v) = 1 / 3) to give the title compound 1c (colorless oil, 5.8 g, yield: 48.0%).

[0107] 1H NMR(400MHz, DMSO)δ7.19(dt,J=10.4,1.9Hz,1H),5.93(dd,J=10.4,2.8Hz,1H),4.58(s,1H),2.44–2.38(m ,1H),2.38–2.29(m,2H),2.08–1.96(m,1H),1.62(tdd,J=12.9,9.4,5.0Hz,1H),0.99(s,3H),0.73(s,3H).

[0108] LC-MS m / z(ESI)=155.4[M+1].

[0109] Step 3:

[0110] 4-(2-hydroxypropan-2-yl)-1-(methyl-d3)cyclohex-2-en-1-ol 1d

[0111] 4-(2-hydroxypropan-2-yl)-1-(methyl-d3)cyclohex-2-en-1-ol

[0112] Under nitrogen protection at 0 °C, deuterated methyl magnesium iodide (34 mL, 33.7 mmol, 1.0 N) was added dropwise to a tetrahydrofuran (20 mL) solution of anhydrous lithium chloride (1.4 g, 33.7 mmol), and the reaction was stirred for 0.5 h after the addition was complete. A tetrahydrofuran solution (5 mL) of compound 1c (1.8 g, 11.2 mmol) was added dropwise, and the reaction was stirred for 0.5 h after the addition was complete. The reaction was monitored by TLC until the end of the reaction. The reaction was quenched by adding saturated ammonium chloride solution (20 mL), and the aqueous phase was extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether (v / v) = 2 / 1) to give the title compound 1d (white solid, 1.2 g, yield: 60.0%).

[0113] 1H NMR (400MHz, DMSO) δ5.61(d,J=10.4Hz,1H),5.52(d,J=10.6Hz,1H),4.38(s,1H),4.17(s,1H),2.00(ddd,J=10.8 ,5.1,2.4Hz,1H),1.73–1.65(m,2H),1.57–1.48(m,1H),1.21(dd,J=10.1,6.8Hz,1H),0.99(s,3H),0.73(s,3H).

[0114] LC-MS m / z(ESI)=174.6[M+1].

[0115] Step 4:

[0116] 2'-(2-hydroxypropane-2-yl)-4-methyl-5'-(methyl-d3)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol 1e

[0117] 2'-(2-hydroxypropan-2-yl)-4-methyl-5'-(methyl-d3)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol

[0118] 4-(2-hydroxypropan-2-yl)-1-(methyl-d3)cyclohexyl-2-en-1-ol 1d (500 mg, 2.9 mmol), 5-methylphenyl-1,3-diol (1080 mg, 8.7 mmol), and 4A molecular sieve (1.5 g) were dissolved in 10 mL of dichloromethane, purged with nitrogen, and stirred at room temperature for 10 minutes. Finally, L-camphor sulfonic acid (67.34 mg, 0.29 mmol) was added. The mixture was stirred at room temperature for 1 hour. The reaction was quenched by adding 20 mL of saturated sodium bicarbonate aqueous solution, and extracted with ethyl acetate (10 mL × 4). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 700 mg of crude product. Column chromatography yielded 2'-(2-hydroxypropane-2-yl)-4-methyl-5'-(methyl-d3)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol 1e (white solid, 375 mg, yield 46%).

[0119] 1H NMR(400MHz,DMSO-d6)δ9.03(s,1H),8.79(s,1H),6.09(d,1H),5.95(d,1H),4.92(s,1H), 3.90(d,1H),2.14(d,5H),1.37–1.21(m,2H),0.99(s,3H),0.91–0.79(m,2H),0.73(s,3H).

[0120] Step 5:

[0121] 4-Methyl-5'-(methyl-d3)-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol (Compound 1)

[0122] 4-methyl-5'-(methyl-d3)-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol

[0123] 2'-(2-hydroxypropan-2-yl)-4-methyl-5'-(methyl-d3)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol 1e (350 mg, 1.25 mmol) was dissolved in 6 mL of tetrahydrofuran, purged with nitrogen, and cooled to 0 °C. Burgess reagent (595 mg, 2.5 mmol) was then added to the system, and the temperature was rapidly raised to room temperature. The reaction was allowed to proceed for 20 minutes. The reaction was quenched by adding 20 mL of saturated sodium bicarbonate aqueous solution, and extracted with ethyl acetate (10 mL × 4). The organic phases were combined, dried with anhydrous sodium sulfate, filtered, and concentrated to obtain 500 mg of crude product, which was used to prepare 4-methyl-5'-(methyl-d3)-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol (compound 1) (purple-red solid, 30 mg, yield 9.2%).

[0124] 1H NMR(400MHz,Chloroform-d)δ6.28–6.15(m,2H),5.54(d,1H),4.65(p,1H),4.53–4.37(m,1H),3.61–3 .46(m,1H),2.45(ddd,1H),2.22(ddt,1H),2.14(s,3H),2.10(q,1H),1.86–1.69(m,2H),1.56(t,3H).

[0125] Example 2

[0126] 4-Ethyl-5'-(methyl-d3)-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol (Compound 2)

[0127] 4-ethyl-5'-(methyl-d3)-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol

[0128]

[0129] first step:

[0130] ((((5-vinyl-1,3-phenylene)bis(oxy))bis(methylene))diphenyl 2b

[0131] (((5-vinyl-1,3-phenylene)bis(oxy))bis(methylene))dibenzene

[0132] t-BuOK (1.5 g, 13.0 mmol) was added to a solution of methyltriphenylphosphine bromide (5.0 g, 13.0 mmol) dissolved in THF at 0 °C. The mixture was stirred at 0 °C for 0.5 h, and then 2a (3.0 g, 10.8 mmol) was added. The mixture was then transferred to room temperature and stirred until the reaction was complete. After the reaction was complete, the mixture was extracted with EA, dried over anhydrous Na₂SO₄, and concentrated under vacuum to obtain a crude product. The crude product was purified by column chromatography to obtain 2b (white solid, 3.0 g, 88.8%).

[0133] 1H NMR (400MHz, DMSO): δ (ppm) 7.58–7.30 (m, 10H), 6.68 (d, 2H), 6.67–6.60 (m, 1H), 6.56 (t, 1H), 5.72 (d, 1H), 5.26 (d, 1H), 5.05 (s, 4H).

[0134] LC-MS m / z(ESI)=317.20[M+1].

[0135] Step Two:

[0136] 5-Ethylphenyl-1,3-diol 2c

[0137] 5-ethylbenzene-1,3-diol

[0138] 2b (3.0 g, 9.5 mmol) was dissolved in a mixed solution of EA and methanol (v1 / v2 = 5 / 1), followed by the addition of 10% Pd / C (600.0 mg). The mixture was stirred overnight under H2 conditions. After the reaction was complete, the reaction solution was filtered, the filtrate was extracted with EA, the organic phase was dried over anhydrous Na2SO4, concentrated under vacuum, and purified by column chromatography to obtain 2c (white solid, 1.2 g, 91.7%).

[0139] 1H NMR (400MHz, DMSO): δ (ppm) 6.27 (d, 2H), 6.20 (t, 1H), 4.14 (q, 1H), 2.51 (q, 2H), 1.16 (t, 3H).

[0140] LC-MS m / z(ESI)=139.10[M+1].

[0141] Step 3:

[0142] 4-Ethyl-2'-(2-hydroxypropane-2-yl)-5'-(methyl-d3)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol 2d

[0143] 4-ethyl-2'-(2-hydroxypropan-2-yl)-5'-(methyl-d3)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol

[0144] 2c (1.2 g, 8.7 mmol) and L-camphor sulfonic acid (69.7 mg, 0.3 mmol) were dissolved in dry DCM solution and stirred for 10 min. Then, 1d (502.1 mg, 2.9 mmol) was added to the solution. After three aeration cycles, the mixture was stirred at room temperature for approximately 1 h. After the reaction was complete, the pH of the reaction solution was adjusted to 7-8 with saturated NaHCO3, extracted with dichloromethane, dried over anhydrous Na2SO4, and concentrated under vacuum to obtain the crude product. The crude product was purified by column chromatography to obtain 2d (white solid, 200.0 mg, 23.5%).

[0145] 1H NMR (400MHz, DMSO): δ (ppm) 6.50 (s, 1H), 6.39–6.25 (m, 2H), 5.70–5.62 (m, 1H), 3.90–3. 79(m,1H),2.50(q,2H),2.18–1.86(m,4H),1.75–1.64(m,1H),1.23(s,6H),1.18(t,3H).

[0146] LC-MS m / z(ESI)=316.20[M+23].

[0147] Step 4:

[0148] 4-Ethyl-5'-(methyl-d3)-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol (Compound 2)

[0149] 4-ethyl-5'-(methyl-d3)-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol

[0150] Weigh 2d (200.0 mg, 0.7 mmol) into a reaction flask, purge three times, add 5 mL of TH F at room temperature and stir until completely dissolved. Slowly add Burgess reagent (333.6 mg, 1.4 mmol) under ice bath conditions. After addition, return to room temperature and stir for approximately 20 min. Detect by TLC until 2d is completely consumed. Adjust pH to 7-8 with saturated NaHCO3, extract with ethyl acetate, wash the organic phase with saturated NaCl, dry with anhydrous Na2SO4, concentrate, and purify by column chromatography to obtain the crude product. Purify the crude product using a preparative chromatography column to obtain the target product compound 2 (purple solid, 16.0 mg, 35.5%).

[0151] 1H NMR (400MHz, DMSO): δ (ppm) 8.67 (s, 2H), 6.04 (s, 2H), 5.08 (s, 1H), 4.50 (d, 1H), 4.41 (dd, 1H), 3.91–3.77 (m, 1H), 3 .09–2.98(m,1H),2.34(q,2H),2.21–2.02(m,1H),1.98–1.86(m,1H),1.73–1.60(m,2H),1.59(s,3H),1.08(t,3H).

[0152] LC-MS m / z(ESI)=270.20[M+1].

[0153] Example 3

[0154] 4-Ethyl-5'-(methyl-d3)-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol (Compound 3)

[0155] 4-ethyl-5'-(methyl-d3)-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol

[0156]

[0157] first step:

[0158] (E)-((((5-(prop-1-en-1-yl)-1,3-phenylene)bis(oxy))bis(methylene))diphenyl3a

[0159] (E)-(((5-(prop-1-en-1-yl)-1,3-phenylene)bis(oxy))bis(methylene))dibenzene

[0160] t-BuOK (1.4 g, 12.5 mmol) was added to a solution of methyltriphenylphosphine bromide (4.5 g, 12.1 mmol) dissolved in THF at 0 °C. The mixture was stirred at 0 °C for 0.5 h, and then 2a (3.2 g, 10.1 mmol) was added. The mixture was then cooled to room temperature and stirred until the reaction was complete. After the reaction was complete, the mixture was extracted with EA, dried over anhydrous Na₂SO₄, and concentrated under vacuum to obtain a crude product. The crude product was purified by column chromatography to obtain 3a (white solid, 3.0 g, 90.3%).

[0161] 1H NMR (400MHz, DMSO): δ (ppm) 7.50–7.30 (m, 10H), 6.61 (d, 1H), 6.56 (d, 2H), 6.54 (t, 1H), 6.37 (dd, 1H), 5.78 (dd, 1H), 5.05 (s, 4H), 1.85 (dd, 3H).

[0162] LC-MS m / z(ESI)=331.20[M+1].

[0163] Step Two:

[0164] 5-Propylphenyl-1,3-diol 3b

[0165] 5-propylbenzene-1,3-diol

[0166] 3a (3.0 g, 9.1 mmol) was dissolved in a mixed solution of EA and methanol (v1 / v2 = 5 / 1), followed by the addition of 10% Pd / C (300.0 mg), and stirred overnight under H2 conditions. After the reaction was complete, the reaction solution was filtered, and the filtrate was extracted with EA. The resulting organic phase was concentrated under vacuum and purified by column chromatography to obtain the corresponding target compound 3b (white solid, 1.3 g, 96.3%).

[0167] 1H NMR (400MHz, DMSO): δ (ppm) (d, 2H), 6.18 (t, 1H), 2.47 (dd, 2H), 1.59 (dt, 2H), 0.93 (t, 3H).

[0168] LC-MS m / z(ESI)=153.10[M+1].

[0169] Step 3:

[0170] 2'-(2-hydroxypropane-2-yl)-5'-(methyl-d3)-4-propyl-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol 3c

[0171] 2'-(2-hydroxypropan-2-yl)-5'-(methyl-d3)-4-propyl-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol

[0172] 3b (1.3 g, 8.7 mmol) and L-camphor sulfonic acid (67.1 mg, 0.3 mmol) were dissolved in dry DCM solution and stirred for 10 min. Then, 1d (502.1 mg, 2.9 mmol) was added to the above solution. After purging three times, the mixture was stirred at room temperature for about 1 h. After the reaction was complete, the pH of the reaction solution was adjusted to 7-8 with saturated NaHCO3, extracted with DCM, dried over anhydrous Na2S O4, and concentrated under vacuum to obtain the crude product. The crude product was purified by column chromatography to obtain the target compound 3c (white solid, 300.0 mg, 11.3%).

[0173] 1H NMR (400MHz, DMSO): δ (ppm) 6.50 (s, 1H), 6.29 (d, 2H), 5.72–5.65 (m, 1H), 3.89–3.81 (m, 1H), 2. 44(t,2H),2.18–1.87(m,4H),1.77–1.67(m,1H),1.66–1.53(m,2H),1.24(s,6H),0.92(t,3H).

[0174] LC-MS m / z(ESI)=330.20[M+23].

[0175] Step 4:

[0176] 5'-(methyl-d3)-2'-(prop-1-en-2-yl)-4-propyl-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol (compound 3)

[0177] 5'-(methyl-d3)-2'-(prop-1-en-2-yl)-4-propyl-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol

[0178] Weigh 3c (350.0 mg, 1.2 mmol) into a reaction flask, purge three times with N2, add 5 mL of THF at room temperature and stir until completely dissolved. Slowly add Burgess reagent (571.9 mg, 2.4 mmol) under ice bath conditions. After addition, return to room temperature and stir for approximately 20 min. Detect by TLC until 3c is completely consumed. Adjust pH to 7-8 with saturated NaHCO3, extract with ethyl acetate, wash the organic phase with saturated NaCl solution, dry with anhydrous Na2SO4, concentrate, and purify by column chromatography to obtain the crude product. Purify the crude product using a preparative chromatography column to obtain the target product compound 3 (purple solid, 20.0 mg, 6.1%).

[0179] 1H NMR (400MHz, DMSO): δ (ppm) 8.66 (s, 2H), 6.01 (s, 2H), 5.08 (s, 1H), 4.49 (d, 1H), 4.40 (dd, 1H), 3.87–3.75 (m, 1H), 3.09–2 .96(m,1H),2.28(t,2H),2.14(s,1H),1.96–1.87(m,1H),1.73–1.60(m,2H),1.58(s,3H),1.55–1.41(m,2H),0.86(t,3H).

[0180] LC-MS m / z(ESI)=290.20[M+23].

[0181] Example 4

[0182] 4-Butyl-5'-(methyl-d3)-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol (compound 4)

[0183] 4-butyl-5'-(methyl-d3)-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol

[0184]

[0185] first step:

[0186] (E)-((((5-(1--1-en-1-yl)-1,3-phenylene)bis(oxy))bis(methylene))diphenyl4a

[0187] (E)-(((5-(but-1-en-1-yl)-1,3-phenylene)bis(oxy))bis(methylene))dibenzene

[0188] t-BuOK (1.5 g, 13.0 mmol) was added to a solution of methyltriphenylphosphine bromide (5.0 g, 13.0 mmol) dissolved in THF at 0 °C. The mixture was stirred at 0 °C for 0.5 h, and then 2a (3.4 g, 10.8 mmol) was added. The mixture was then transferred to room temperature and stirred until the reaction was complete. After the reaction was complete, the mixture was extracted with EA, dried over anhydrous Na₂SO₄, and concentrated under vacuum to obtain a crude product. The crude product was purified by column chromatography to obtain 4a (white solid, 3.6 g, 96.7%).

[0189] 1H NMR (400MHz, DMSO): δ (ppm) 7.47–7.29 (m, 10H), 6.52 (s, 2H), 6.34–6.23 (m, 1H), 5.67–5.58 (m, 1H), 5.04 (s, 4H), 2.34–2.18 (m, 2H), 1.02 (t, 3H).

[0190] LC-MS m / z(ESI)=345.20[M+1].

[0191] Step Two:

[0192] 5-Butylbenzene-1,3-diol 4b

[0193] 5-butylbenzene-1,3-diol

[0194] 4a (3.6 g, 10.4 mmol) was dissolved in a mixed solution of EA and methanol (v1 / v2 = 5 / 1), followed by the addition of 10% Pd / C (360.0 mg), and stirred overnight under H2 conditions. After the reaction was complete, the reaction solution was filtered, and the filtrate was extracted with EA. The resulting organic phase was concentrated under vacuum and purified by column chromatography to obtain the corresponding target compound 4b (white solid, 1.4 g, 80.6%).

[0195] 1H NMR (400MHz, DMSO): δ (ppm) (d, 2H), 6.18 (t, 1H), 2.47 (dd, 2H), 1.59 (dt, 2H), 0.93 (t, 3H).

[0196] LC-MS m / z(ESI)=167.1[M+1].

[0197] Step 3:

[0198] 4-Butyl-2'-(2-hydroxypropane-2-yl)-5'-(methyl-d3)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol 4c

[0199] 4-butyl-2'-(2-hydroxypropan-2-yl)-5'-(methyl-d3)-1',2',3',4'-tetrahydro-[1,1'-bi-phenyl]-2,6-diol

[0200] 4b (1.4 g, 4.3 mmol) and L-camphor sulfonic acid (67.1 mg, 0.3 mmol) were dissolved in dry DCM solution and stirred for 10 min. Then, 1d (502.1 mg, 2.9 mmol) was added to the above solution. After venting three times, the mixture was stirred at room temperature for about 1 h. After the reaction was complete, the pH of the reaction solution was adjusted to 7-8 with saturated NaHCO3, extracted with DCM, dried over anhydrous Na2S O4, and concentrated under vacuum to obtain the crude product. The crude product was purified by column chromatography to obtain the target compound 4c (white solid, 250 mg, 9.2%).

[0201] 1H NMR (400MHz, Chloroform-d): δ (ppm) 6.48 (s, 1H), 6.36–6.24 (m, 2H), 5.73–5.64 (m, 1H), 3.88–3.80 (m, 1H), 2.51–2 .41(m,2H),2.20–1.86(m,4H),1.76–1.65(m,1H),1.61–1.49(m,2H),1.37–1.30(m,2H),1.23(s,6H),0.90(t,3H).

[0202] LC-MS m / z(ESI)=343.20[M+23].

[0203] Step 4:

[0204] 4-Butyl-5'-(methyl-d3)-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol (compound 4)

[0205] 4-butyl-5'-(methyl-d3)-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol

[0206] Weigh 4c (250.0 mg, 0.8 mmol) into a reaction flask, purge three times, add 5 mL of THF at room temperature and stir until completely dissolved. Slowly add Burgess reagent (381.3 mg, 1.6 mmol) under ice bath conditions. After addition, return to room temperature and stir for approximately 20 min. TLC analysis showed complete consumption of 4c. Adjust pH to 7-8 with saturated NaHCO3, extract with EA, wash the organic phase with saturated NaCl, dry with anhydrous Na2SO4, concentrate, and purify by column chromatography to obtain the crude product. Purify the crude product using a preparative chromatography column to obtain the target product compound 4 (purple solid, 25 mg, 10.6%).

[0207] 1H NMR (400MHz, DMSO): δ (ppm) 8.66 (s, 2H), 6.01 (s, 2H), 5.07 (s, 1H), 4.49 (d, 1H), 4.40 (dd, 1H), 3.90–3.75 (m, 1H), 3.07–2.96 (m, 1H), 2 .30(t,2H),2.19–2.02(m,1H),1.99–1.84(m,1H),1.73–1.60(m,2H),1.58(s,3H),1.51–1.39(m,2H),1.36–1.20(m,2H),0.87(t,3H).

[0208] LC-MS m / z(ESI)=304.20[M+23].

[0209] Example 5

[0210] Methyl-2,6-dihydroxy-5'-(methyl-d3)-4-pentyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-3-carboxylate (compound 5)

[0211] Methyl-2,6-dihydroxy-5'-(methyl-d3)-4-pentyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-3-carboxylate

[0212]

[0213] first step:

[0214] methyl-2,6-dihydroxy-2'-(2-hydroxypropane-2-yl)-5'-(methyl-d3)-4-pentyl-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-3-carboxylate 5b

[0215] methyl-2,6-dihydroxy-2'-(2-hydroxypropan-2-yl)-5'-(methyl-d3)-4-pentyl-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-3-carboxylate

[0216] 1d (150 mg, 0.86 mmol), 5a (619 mg, 2.6 mmol), and 4A molecular sieve (450 mg) were added to a flask. Under nitrogen protection, L-camphor sulfonic acid (19 mg, 0.086 mmol) was added. The mixture was stirred at room temperature and the reaction was completed in 1.5 h. The product was separated by column chromatography (PE:EA = 15:1) to obtain the target product 5b (yellow oily product, 207 mg, yield 61.4%).

[0217] 1H NMR(400MHz,DMSO-d6)δ11.51(s,1H),9.87(s,1H),6.21(s,1H),4.87(d,1H),3.83(s,3H),3.75(d,1H),2.71-2.63(m,2H),2 .38(td,1H),2.16–1.98(m,2H),1.92–1.81(m,1H),1.45(q,2H),1.28(ddd,10.5,6H),0.97(s,3H),0.86(t,3H),0.79(s,3H).

[0218] Step Two:

[0219] Methyl-2,6-dihydroxy-5'-(methyl-d3)-4-pentyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-3-carboxylate (compound 5)

[0220] methyl-2,6-dihydroxy-5'-(methyl-d3)-4-pentyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-3-carboxylate

[0221] 5b (207 mg, 0.52 mmol) and tetrahydrofuran (3 mL) were added to a flask, and nitrogen gas was introduced for protection. Burgess reagent (250 mg, 1.01 mmol) was added at 0 °C. After 20 min, the reaction was completed. 5 mL of sodium bicarbonate aqueous solution was added to quench the reaction. Column chromatography was used to separate the target product compound 5 (white solid product, 66 mg, yield 33.5%).

[0222] 1H NMR(400MHz,DMSO-d6)δ11.54(s,1H),9.90(s,1H),6.20(s,1H),5.09(d,1H),4.52-4.36(m,2H),3.96–3.86(m,1H),3.83(s,4H),3.02(td,11.0, 1H),2.73-2.62(m,2H),2.18-2.07(m,1H),2.00-1.91(m,1H),1.75-1.60 (m,2H),1.58(s,3H),1.44(t,2H),1.32-1.26(m,4H),0.90-0.84(m,3H).

[0223] Example 6

[0224] Ethyl-2,6-dihydroxy-5'-(methyl-d3)-4-pentyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-3-carboxylate (compound 6)

[0225] ethyl-2,6-dihydroxy-5'-(methyl-d3)-4-pentyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-3-carboxylate

[0226]

[0227] first step:

[0228] Ethyl-2,6-dihydroxy-2'-(2-hydroxypropane-2-yl)-5'-(methyl-d3)-4-pentyl-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-3-carboxylate 6b

[0229] ethyl-2,6-dihydroxy-2'-(2-hydroxypropan-2-yl)-5'-(methyl-d3)-4-pentyl-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-3-carboxylate

[0230] 1d (150 mg, 0.86 mmol), 6a (655 mg, 2.6 mmol), and 4A molecular sieve (450 mg) were added to a flask. Under nitrogen protection, L-camphor sulfonic acid (19 mg, 0.086 mmol) was added. The mixture was stirred at room temperature and the reaction was completed in 1.5 h. The product was separated by column chromatography (PE:EA = 15:1) to obtain the target product 6b (yellow oily product, 200 mg, yield 57.1%).

[0231] 1H NMR(400MHz,DMSO-d6)δ11.77(d,1H),9.89(s,1H),6.21(s,1H),4.86(d,1H),4.32(q,2H),3.80(s,2H),2.71(s,2H),2.39(td, 1H),2.16–1.99(m,2H),1.92–1.80(m,1H),1.49–1.42(m,2H),1.36–1.29(m,7H),0.97(s,4H),0.88–0.84(m,3H),0.79(s,3H).

[0232] Step Two:

[0233] Ethyl-2,6-dihydroxy-5'-(methyl-d3)-4-pentyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-3-carboxylate (compound 6)

[0234] ethyl-2,6-dihydroxy-5'-(methyl-d3)-4-pentyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-3-carboxylate

[0235] 6b (200 mg, 0.51 mmol) and tetrahydrofuran (3 mL) were added to a flask, and nitrogen gas was introduced for protection. Burgess reagent (254 mg, 1.02 mmol) was added at 0 °C. After 20 min, the reaction was completed. 5 mL of sodium bicarbonate aqueous solution was added to quench the reaction. Column chromatography was used to separate the target product compound 6 (white solid product, 66 mg, yield 33.5%).

[0236] 1H NMR(400MHz,DMSO-d6)δ11.78(s,1H),9.91(s,1H),6.19(s,1H),5.08(d, 1H),4.47-4.42(m,2H),4.33(t,2H),3.90(d,1H),3.02(td,10.9,1H),2. 69(d,2H),2.15-2.09(m,1H),1.98-1.91(m,1H),1.71-1.61(m,2H),1.58 (s,3H),1.48-1.43(m,2H),1.31(d,3H),1.29-1.24(m,4H),0.87(q,3H).

[0237] Example 7

[0238] (1'R,2'R)-5'-(methyl-d3)-4-pentyl-2'-(prop-1-en-2-yl-d5)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol (compound 7)

[0239] (1'R,2'R)-5'-(methyl-d3)-4-pentyl-2'-(prop-1-en-2-yl-d5)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol

[0240]

[0241]

[0242] first step:

[0243] 3-Ethoxy-6-(2-hydroxypropyl-2-yl-1,1,1,3,3,3-d6)cyclohexyl-2-en-1-one 7b

[0244] 3-ethoxy-6-(2-hydroxypropan-2-yl-1,1,1,3,3,3-d6)cyclohex-2-en-1-one

[0245] 3-ethoxycyclohexyl-2-en-1-one 7a (10.0 g, 71.0 mmol) was added dropwise to a tetrahydrofuran (100 mL) solution of lithium diisopropylamino (54 mL, 107.0 mmol, 2.0 N) at -70 °C under nitrogen protection. The reaction was stirred for 0.5 h after the addition was complete. Deuterated acetone (9.2 g, 142.0 mmol) was added dropwise, and the reaction was stirred for another 3 h after the addition was complete. The reaction was monitored by TLC until the end of the reaction. The reaction was quenched by adding saturated ammonium chloride solution (180 mL). The mixture was separated into two phases. The aqueous phase was extracted with ethyl acetate (150 mL × 2). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound 7b (yellow oil, 18.0 g, yield: 99.0%).

[0246] 1H NMR (400MHz, DMSO). δ5.29(s,1H),4.93(s,1H),3.98–3.87(m,2H),2.46(dd,J=11.2,5.0Hz,1H),2.37(dt,J=17.4,4.5Hz,1H),2 .21(dd,J=12.1,4.7Hz,1H),2.12–2.03(m,1H),1.67(ddd,J=24.2,12.3,5.1Hz,1H),1.27(t,J=7.0Hz,3H).

[0247] LC-MS m / z(ESI)=205.1[M+1].

[0248] Step Two:

[0249] (R)-4-(2-hydroxypropan-2-yl-1,1,1,3,3,3-d6)cyclohexyl-2-en-1-one 7c

[0250] (R)-4-(2-hydroxypropan-2-yl-1,1,1,3,3,3-d6)cyclohex-2-en-1-one

[0251] At 0 °C under nitrogen protection, red aluminum (67 mL, 234.1 mmol, 3.5 N) was added dropwise to a tetrahydrofuran (200 mL) solution of compound 7b (17.0 g, 78.0 mmol). After the addition was complete, the mixture was slowly raised to room temperature and stirred for 2 h. The reaction was monitored by TLC until completion. The temperature was lowered to 0 °C, and the reaction was quenched by adding saturated ammonium chloride solution (13 mL). The mixture was filtered, and the aqueous phase was extracted with ethyl acetate (200 mL × 2). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product, which was dissolved in tetrahydrofuran (40 mL). Hydrochloric acid aqueous solution (40 mL, 2N) was added dropwise, and the mixture was stirred at room temperature for 1.5 h after the addition was complete. TLC was used to monitor the reaction until completion. The reaction was quenched by adding saturated sodium bicarbonate solution, and the mixture was concentrated under reduced pressure. The aqueous phase was extracted with ethyl acetate (100 mL × 4). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether (v / v) = 1 / 3). The obtained racemic mixture was purified by preparative liquid chromatography (AD column, n-hexane:isopropanol = 95:5, 214 nm, 25 °C, retention time: 8.611 min) to give the title compound 7c (colorless oil, 5.8 g, yield: 48.0%).

[0252] 1H NMR (400MHz, DMSO) δ7.19 (dt, J=10.4, 1.9Hz, 1H), 5.93 (dd, J=10.4, 2.8Hz, 1H), 4.58 (s, 1H), 2.44–2.38(m,1H),2.38–2.29(m,2H),2.08–1.96(m,1H),1.62(tdd,J=12.9,9.4,5.0Hz,1H).

[0253] LC-MS m / z(ESI)=161.1[M+1].

[0254] Step 3:

[0255] (1R,4R)-4-(2-hydroxypropan-2-yl-1,1,1,3,3,3-d6)-1-(methyl-d3)cyclohexyl-2-en-1-ol 7d

[0256] (1R,4R)-4-(2-hydroxypropan-2-yl-1,1,1,3,3,3-d6)-1-(methyl-d3)cyclohex-2-en-1-ol

[0257] Under nitrogen protection at 0 °C, deuterated methyl magnesium iodide (34 mL, 33.7 mmol, 1.0 N) was added dropwise to a tetrahydrofuran (20 mL) solution of anhydrous lithium chloride (1.4 g, 33.7 mmol), and the reaction was stirred for 0.5 h after the addition was complete. A tetrahydrofuran solution (5 mL) of compound 7c (1.8 g, 11.2 mmol) was added dropwise, and the reaction was stirred for 0.5 h after the addition was complete. The reaction was monitored by TLC until the end of the reaction. The reaction was quenched by adding saturated ammonium chloride solution (20 mL), and the aqueous phase was extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether (v / v) = 2 / 1) to give the title compound 7d (white solid, 1.2 g, yield: 60.0%).

[0258] 1H NMR (400MHz, DMSO) δ5.61(d,J=10.4Hz,1H),5.52(d,J=10.6Hz,1H),4.38(s,1H),4.17(s,1H),2.00 (ddd,J=10.8,5.1,2.4Hz,1H),1.73–1.65(m,2H),1.57–1.48(m,1H),1.21(dd,J=10.1,6.8Hz,1H).

[0259] Step 4:

[0260] (1'R,2'R)-2'-(2-hydroxypropane-2-yl-1,1,1,3,3-d6)-5'-(methyl-d3)-4-pentyl-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol 7e

[0261] (1'R,2'R)-2'-(2-hydroxypropan-2-yl-1,1,1,3,3,3-d6)-5'-(methyl-d3)-4-pentyl-1',2',3',4'-tet-rahydro-[1,1'-biphenyl]-2,6-diol

[0262] Under nitrogen protection, L-(-)camphorsulfonic acid (65 mg, 0.28 mmol) was added dropwise to a solution of compound 7d (500 mg, 2.79 mmol), 3,5-dihydroxypentane (750 mg, 4.18 mmol), and 4A molecular sieve (1.5 g) in dichloromethane (10 mL). After the addition was complete, the mixture was stirred at room temperature for 1.5 h. The reaction was monitored by TLC until completion. The reaction was quenched by adding saturated sodium bicarbonate solution (10 mL). The aqueous phase was extracted with dichloromethane (30 mL × 3). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether (v / v) = 1 / 10) to give the title compound 7e (white solid, 380 mg, yield: 39.0%).

[0263] 1H NMR (400MHz, DMSO) δ8.73(d,J=110.7Hz,2H),6.03(s,2H),4.88(s,1H),3.65(s,2H),2.38–2.28(m,3H),2.09(d,J=1 2.2Hz,1H),2.03–1.95(m,1H),1.83(d,J=16.8Hz,1H),1.51–1.43(m,2H),1.30–1.21(m,5H),0.85(t,J=7.0Hz,3H).

[0264] LC-MS m / z(ESI)=342.3[M+1].

[0265] Step 5:

[0266] (1'R,2'R)-5'-(methyl-d3)-4-pentyl-2'-(1-en-2-yl-d5)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol (compound 7)

[0267] (1'R,2'R)-5'-(methyl-d3)-4-pentyl-2'-(prop-1-en-2-yl-d5)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol

[0268] At 0 °C under nitrogen protection, Burgess reagent (390 mg, 1.66 mmol) was added to a tetrahydrofuran (6 mL) solution of compound 7e (380 mg, 1.10 mmol), and the mixture was stirred at room temperature for 20 min. The reaction was monitored by TLC until completion. The reaction was quenched by adding saturated sodium bicarbonate solution (10 mL), and the aqueous phase was extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether (v / v) = 1 / 30) to give the title compound 7 (white solid, 44 mg, HPLC: 98%, yield: 12.0%).

[0269] 1H NMR (400MHz, DMSO) δ8.64(s,2H),6.01(s,2H),5.08(s,1H),3.82(dd,J=8.8,1.8Hz,1H),3.07–2.97(m,1H),2.32–2.27(m,2H),2.1 4–2.04(m,1H),1.91(d,J=16.8Hz,1H),1.72–1.57(m,2H),1.47(dt,J=14.8,7.4Hz,2H),1.30–1.22(m,4H),0.86(t,J=7.0Hz,3H).

[0270] LC-MS m / z(ESI)=323.3[M+1].

[0271] Example 8

[0272] (1'S,2'S)-5'-(methyl-d3)-4-pentyl-2'-(prop-1-en-2-yl-d5)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol (compound 8)

[0273] (1'S,2'S)-5'-(methyl-d3)-4-pentyl-2'-(prop-1-en-2-yl-d5)-1',2',3',4'-tetrahydro-[1,1'-biphe-nyl]-2,6-diol

[0274]

[0275] first step:

[0276] (S)-4-(2-hydroxypropan-2-yl-1,1,1,3,3,3-d6)cyclohexyl-2-en-1-one 8a

[0277] (S)-4-(2-hydroxypropan-2-yl-1,1,1,3,3,3-d6)cyclohex-2-en-1-one

[0278] At 0 °C under nitrogen protection, red aluminum (67 mL, 234.1 mmol, 3.5 N) was added dropwise to a tetrahydrofuran (200 mL) solution of compound 7b (17.0 g, 78.0 mmol). After the addition was complete, the mixture was slowly raised to room temperature and stirred for 2 h. The reaction was monitored by TLC until completion. The temperature was lowered to 0 °C, and the reaction was quenched by adding saturated ammonium chloride solution (13 mL). The mixture was filtered, and the aqueous phase was extracted with ethyl acetate (200 mL × 2). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product, which was dissolved in tetrahydrofuran (40 mL). Hydrochloric acid aqueous solution (40 mL, 2N) was added dropwise, and the mixture was stirred at room temperature for 1.5 h after the addition was complete. TLC was used to monitor the reaction until completion. The reaction was quenched by adding saturated sodium bicarbonate solution, and the mixture was concentrated under reduced pressure. The aqueous phase was extracted with ethyl acetate (100 mL × 4). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether (v / v) = 1 / 3). The obtained racemic mixture was purified by preparative liquid chromatography (AD column, n-hexane:isopropanol = 95:5, 214 nm, 25 °C, retention time: 9.877 min) to give the title compound 8a (colorless oil, 5.8 g, yield: 48.0%).

[0279] 1H NMR (400MHz, DMSO) δ7.19 (dt, J=10.4, 1.9Hz, 1H), 5.93 (dd, J=10.4, 2.8Hz, 1H), 4.58 (s, 1H), 2.44–2.38(m,1H),2.38–2.29(m,2H),2.08–1.96(m,1H),1.62(tdd,J=12.9,9.4,5.0Hz,1H).

[0280] LC-MS m / z(ESI)=161.1[M+1].

[0281] Step Two:

[0282] (1S,4S)-4-(2-hydroxypropan-2-yl-1,1,1,3,3,3-d6)-1-(methyl-d3)cyclohexyl-2-en-1-ol 8b

[0283] (1S,4S)-4-(2-hydroxypropan-2-yl-1,1,1,3,3,3-d6)-1-(methyl-d3)cyclohex-2-en-1-ol

[0284] Under nitrogen protection at 0 °C, deuterated methyl magnesium iodide (34 mL, 33.7 mmol, 1.0 N) was added dropwise to a tetrahydrofuran (20 mL) solution of anhydrous lithium chloride (1.4 g, 33.7 mmol), and the reaction was stirred for 0.5 h after the addition was complete. A tetrahydrofuran solution (5 mL) of compound 8a (1.8 g, 11.2 mmol) was added dropwise, and the reaction was stirred for 0.5 h after the addition was complete. The reaction was monitored by TLC until the end. The reaction was quenched by adding saturated ammonium chloride solution (20 mL), and the aqueous phase was extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether (v / v) = 2 / 1) to give the title compound 8b (white solid, 1.2 g, yield: 60.0%).

[0285] 1H NMR (400MHz, DMSO) δ5.61(d,J=10.4Hz,1H),5.52(d,J=10.6Hz,1H),4.38(s,1H),4.17(s,1H),2.00 (ddd,J=10.8,5.1,2.4Hz,1H),1.73–1.65(m,2H),1.57–1.48(m,1H),1.21(dd,J=10.1,6.8Hz,1H).

[0286] Step 3:

[0287] (1'S,2'S)-2'-(2-hydroxypropane-2-yl-1,1,1,3,3-d6)-5'-(methyl-d3)-4-pentyl-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol 8c

[0288] (1'S,2'S)-2'-(2-hydroxypropan-2-yl-1,1,1,3,3,3-d6)-5'-(methyl-d3)-4-pentyl-1',2',3',4'-tetr-ahydro-[1,1'-biphenyl]-2,6-diol

[0289] Under nitrogen protection, L-(-)camphorsulfonic acid (65 mg, 0.28 mmol) was added dropwise to a solution of compound 8b (500 mg, 2.79 mmol), 3,5-dihydroxypentane (0.75 g, 4.18 mmol), and 4A molecular sieve (1.5 g) in dichloromethane (10 mL). After the addition was complete, the mixture was stirred at room temperature for 1.5 h. The reaction was monitored by TLC until completion. The reaction was quenched by adding saturated sodium bicarbonate solution (10 mL). The aqueous phase was extracted with dichloromethane (30 mL × 3). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether (v / v) = 1 / 10) to give the title compound 8c (white solid, 390 mg, yield: 40.0%).

[0290] 1H NMR (400MHz, DMSO) δ8.73(d,J=110.9Hz,2H),6.02(d,J=11.4Hz,2H),4.88(s,1H),3.66(d,J=5.5Hz,2H),2.33(dt,J=15.2,8.7Hz,3H),2.13 –2.06(m,1H),2.02(s,1H),1.83(d,J=16.6Hz,1H),1.46(dd,J=14.6,7.2Hz,2H),1.25(ddd,J=11.6,11.1,5.5Hz,5H),0.85(t,J=7.0Hz,3H).

[0291] LC-MS m / z(ESI)=342.3[M+1].

[0292] Step 4:

[0293] (1'S,2'S)-5'-(methyl-d3)-4-pentyl-2'-(prop-1-en-2-yl-d5)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol (compound 8)

[0294] (1'S,2'S)-5'-(methyl-d3)-4-pentyl-2'-(prop-1-en-2-yl-d5)-1',2',3',4'-tetrahydro-[1,1'-biphe-nyl]-2,6-diol

[0295] At 0 °C under nitrogen protection, Burgess reagent (400 mg, 1.70 mmol) was added to a tetrahydrofuran (8 mL) solution of compound 8c (390 mg, 1.13 mmol), and the mixture was stirred at room temperature for 20 min. The reaction was monitored by TLC until completion. The reaction was quenched by adding saturated sodium bicarbonate solution (10 mL), and the aqueous phase was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether (v / v) = 1 / 30) to give the title compound 8 (white solid, 81 mg, HPLC: 95%, yield: 23.0%).

[0296] 1H NMR (400MHz, DMSO) δ8.64(s,2H),6.01(s,2H),5.08(s,1H),3.82(d,J=10.5Hz,1H),3.12–2.95(m,1H),2.32–2.25(m,2H),2.15– 2.04(m,1H),1.91(d,J=16.8Hz,1H),1.71–1.55(m,2H),1.47(dt,J=14.8,7.4Hz,2H),1.31–1.22(m,4H),0.86(t,J=7.0Hz,3H).

[0297] LC-MS m / z(ESI)=323.3[M+1].

[0298] Example 9

[0299] (1'R,2'R)-4-heptyl-5'-(methyl-d3)-2'-(1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol (compound 9)

[0300] (1'R,2'R)-4-heptyl-5'-(methyl-d3)-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol

[0301]

[0302] first step:

[0303] (E)-((5-(hepta-1-en-1-yl)-1,3-phenylene)bis(oxy)bis(methylene)diphenyl 9a

[0304] (E)-(((5-(hept-1-en-1-yl)-1,3-phenylene)bis(oxy))bis(methylene))dibenzene

[0305] Under nitrogen protection at 0°C, sodium bis(trimethylsilyl)amino (113 mL, 226.1 mmol, 2.0 N) was added dropwise to a tetrahydrofuran (500 mL) solution of n-bromohexyltriphenylphosphine (100.0 g, 235.0 mmol). After the addition was complete, the temperature was raised to 10°C and the reaction was stirred for 0.5 h. Then, a tetrahydrofuran (100 mL) solution of 3,5-dibenzyloxybenzaldehyde 2a (30.0 g, 94.0 mmol) was added dropwise, and stirring was continued for 1 hour after the addition was complete. 0.5h; TLC monitoring until the reaction was complete; saturated ammonium chloride solution (300mL) was added dropwise to quench the reaction, the phases were separated, the aqueous phase was extracted with petroleum ether (300mL×2), the combined organic phases were washed with saturated brine (200mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether (v / v) = 1 / 10) to give title compound 9a (colorless oil, 47.0g, yield: 99.0%).

[0306] 1H NMR (400MHz, DMSO) δ7.44–7.30(m,11H),6.60(t,J=2.1Hz,1H),6.53(t,J=7.6Hz,2H),6.32(d,J=12.0Hz,1H),5.60(dt,J= 11.7,7.2Hz,1H),5.08(s,4H),2.24–2.14(m,2H),1.35(dd,J=14.2,7.2Hz,2H),1.27–1.18(m,4H),0.84(t,J=6.9Hz,3H).

[0307] LC-MS m / z(ESI)=387.3[M+1].

[0308] Step Two:

[0309] 5-Heptylphenyl-1,3-diol 9b

[0310] 5-heptylbenzene-1,3-diol

[0311] Palladium on carbon (3.2 g, 10%) was added to a solution of compound 9a (32.0 g, 83.0 mmol) in anhydrous methanol (150 mL) and ethyl acetate (150 mL), and the reaction was hydrogenated for 15 h. The reaction was monitored by TLC until completion. The mixture was filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether (v / v) = 1 / 3) to give the title compound 9b (white solid, 17.4 g, yield: 99.0%).

[0312] 1H NMR (400MHz, DMSO) δ8.98 (s, 2H), 6.02 (s, 3H), 2.42–2.30 (m, 2H), 1.47 (dd, J = 13.9, 6.9Hz, 2H), 1.26 (d, J = 5.8Hz, 8H), 0.86 (t, J = 6.9Hz, 3H).

[0313] LC-MS m / z(ESI)=209.1[M+1].

[0314] Step 3:

[0315] (R)-4-(2-hydroxypropan-2-yl)cyclohex-2-en-1-one 9c

[0316] (R)-4-(2-hydroxypropan-2-yl)cyclohex-2-en-1-one

[0317] Racemate 1c was separated and purified by preparative liquid chromatography (AD column, n-hexane:isopropanol = 95:5, 214 nm, 25 °C, retention time: 8.638 min) to give the title chiral compound 9c.

[0318] Step 4:

[0319] (1R,4R)-4-(2-hydroxypropan-2-yl)-1-(methyl-d3)cyclohex-2-en-1-ol 9d

[0320] (1R,4R)-4-(2-hydroxypropan-2-yl)-1-(methyl-d3)cyclohex-2-en-1-ol

[0321] Under nitrogen protection at 0 °C, deuterated methyl magnesium iodide (34 mL, 33.7 mmol, 1.0 N) was added dropwise to a tetrahydrofuran (20 mL) solution of anhydrous lithium chloride (1.4 g, 33.7 mmol), and the reaction was stirred for 0.5 h after the addition was complete. A tetrahydrofuran solution (5 mL) of compound 9c (1.8 g, 11.2 mmol) was added dropwise, and the reaction was stirred for 0.5 h after the addition was complete. The reaction was monitored by TLC until the end of the reaction. The reaction was quenched by adding saturated ammonium chloride solution (20 mL), and the aqueous phase was extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether (v / v) = 2 / 1) to give the title compound 9d (white solid, 1.2 g, yield: 60.0%).

[0322] 1H NMR (400MHz, DMSO) δ5.61(d,J=10.4Hz,1H),5.52(d,J=10.6Hz,1H),4.38(s,1H),4.17(s,1H),2.00(ddd,J=10.8 ,5.1,2.4Hz,1H),1.73–1.65(m,2H),1.57–1.48(m,1H),1.21(dd,J=10.1,6.8Hz,1H),0.99(s,3H),0.73(s,3H).

[0323] LC-MS m / z(ESI)=174.6[M+1].

[0324] Step 5:

[0325] (1'R,2'R)-4-heptyl-2'-(2-hydroxypropane-2-yl)-5'-(methyl-d3)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol 9e

[0326] (1'R,2'R)-4-heptyl-2'-(2-hydroxypropan-2-yl)-5'-(methyl-d3)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol

[0327] Under nitrogen protection, L-(-)camphorsulfonic acid (67 mg, 0.29 mmol) was added to a solution of compound 9b (1.6 g, 8.67 mmol), compound 9d (500 mg, 2.89 mmol), and 4A molecular sieve (1.5 g) in dichloromethane (10 mL). After the addition was complete, the mixture was stirred at room temperature for 1.5 h. The reaction was monitored by TLC until the reaction was complete. The reaction was quenched by adding saturated sodium bicarbonate solution (10 mL). The aqueous phase was extracted with dichloromethane (30 mL × 2). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether (v / v) = 1 / 6) to give the title compound 9e (colorless oil, 410 mg, yield: 41.0%).

[0328] 1H NMR (400MHz, DMSO) δ8.67(dd,J=96.6,46.4Hz,2H),6.03(s,2H),4.89(s,1H),3.66(d,J=10.8Hz,2H),2.40–2.28(m,3H),2.05(ddd,J=14.8,5 .7,1.9Hz,2H),1.83(d,J=16.5Hz,1H),1.47(dd,J=14.1,7.2Hz,2H),1.28(d,J=24.3Hz,9H),0.97(s,3H),0.85(t,J=6.8Hz,3H),0.80(s,3H).

[0329] LC-MS m / z(ESI)=364.3[M+1].

[0330] Step 6:

[0331] (1'R,2'R)-4-heptyl-5'-(methyl-d3)-2'-(1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol (compound 9)

[0332] (1'R,2'R)-4-heptyl-5'-(methyl-d3)-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol

[0333] At 0 °C under nitrogen protection, Burgess reagent (540 mg, 2.26 mmol) was added to a tetrahydrofuran (5 mL) solution of compound 9e (410 mg, 1.13 mmol), and the mixture was stirred at room temperature for 30 min. The reaction was monitored by TLC until completion. The reaction was quenched by adding saturated sodium bicarbonate solution (10 mL), and the aqueous phase was extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether (v / v) = 1 / 30) to give the title compound 9 (white solid, 245 mg, HPLC: 99.5%, yield: 63%).

[0334] 1H NMR (400MHz, DMSO) δ8.63 (s, 2H), 6.01 (s, 2H), 5.08 (s, 1H), 4.49 (d, J = 2.5Hz, 1 H),4.40(d,J=1.0Hz,1H),3.82(d,J=10.5Hz,1H),3.08–2.95(m,1H),2.30(dd,J =14.0,6.5Hz,2H),2.15–2.04(m,1H),1.91(d,J=16.6Hz,1H),1.72–1.63(m,1H ),1.58(s,3H),1.50–1.42(m,2H),1.26(d,J=5.7Hz,9H),0.85(t,J=6.8Hz,3H).

[0335] LC-MS m / z(ESI)=346.3[M+1].

[0336] Example 10

[0337] (1'S,2'S)-4-heptyl-5'-(methyl-d3)-2'-(1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol (compound 10)

[0338] (1'S,2'S)-4-heptyl-5'-(methyl-d3)-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol

[0339]

[0340] first step:

[0341] (S)-4-(2-hydroxypropan-2-yl)cyclohex-2-en-1-one 10a

[0342] (S)-4-(2-hydroxypropan-2-yl)cyclohex-2-en-1-one

[0343] Racemate 1c was separated and purified by preparative liquid chromatography (AD column, n-hexane:isopropanol = 95:5, 214 nm, 25 °C, retention time: 9.894 min) to give the title chiral compound 10a.

[0344] Step Two:

[0345] (1S,4S)-4-(2-hydroxypropan-2-yl)-1-(methyl-d3)cyclohex-2-en-1-ol 10b

[0346] (1S,4S)-4-(2-hydroxypropan-2-yl)-1-(methyl-d3)cyclohex-2-en-1-ol

[0347] Under nitrogen protection at 0 °C, deuterated methyl magnesium iodide (34 mL, 33.7 mmol, 1.0 N) was added dropwise to a tetrahydrofuran (20 mL) solution of anhydrous lithium chloride (1.4 g, 33.7 mmol), and the reaction was stirred for 0.5 h after the addition was complete. A tetrahydrofuran solution (5 mL) of compound 10a (1.8 g, 11.2 mmol) was added dropwise, and the reaction was stirred for 0.5 h after the addition was complete. The reaction was monitored by TLC until the end. The reaction was quenched by adding saturated ammonium chloride solution (20 mL), and the aqueous phase was extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether (v / v) = 2 / 1) to give the title compound 10b (white solid, 1.2 g, yield: 60.0%).

[0348] 1H NMR (400MHz, DMSO) δ5.61(d,J=10.4Hz,1H),5.52(d,J=10.6Hz,1H),4.38(s,1H),4.17(s,1H),2.00(ddd,J=10.8 ,5.1,2.4Hz,1H),1.73–1.65(m,2H),1.57–1.48(m,1H),1.21(dd,J=10.1,6.8Hz,1H),0.99(s,3H),0.73(s,3H).

[0349] LC-MS m / z(ESI)=174.6[M+1].

[0350] Step 3:

[0351] (1'S,2'S)-4-heptyl-2'-(2-hydroxypropane-2-yl)-5'-(methyl-d3)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol 10c

[0352] (1'S,2'S)-4-heptyl-2'-(2-hydroxypropan-2-yl)-5'-(methyl-d3)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol

[0353] Under nitrogen protection, L-(-)camphorsulfonic acid (67 mg, 0.29 mmol) was added to a solution of compound 10b (500 mg, 2.89 mmol), 5-heptyl-1,3-diol 9b (1.6 g, 8.67 mmol), and 4A molecular sieve (1.5 g) in dichloromethane (10 mL). After the addition was complete, the mixture was stirred at room temperature for 1.5 h. The reaction was monitored by TLC until the reaction was complete. The reaction was quenched by adding saturated sodium bicarbonate solution (10 mL). The aqueous phase was extracted with dichloromethane (30 mL × 2). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether (v / v) = 1 / 6) to give the title compound 10c (colorless oil, 400 mg, yield: 40.0%).

[0354] 1H NMR (400MHz, DMSO) δ8.67(dd,J=101.3,50.3Hz,2H),6.03(s,2H),4.89(s,1H),3.66(d,J=11.0Hz,2H),2.39–2.27(m,3H),2.14–1.9 7(m,2H),1.83(d,J=16.5Hz,1H),1.47(dd,J=14.2,7.2Hz,2H),1.30–1.18(m,9H),0.97(s,3H),0.85(t,J=6.9Hz,3H),0.80(s,3H).

[0355] LC-MS m / z(ESI)=364.3[M+1].

[0356] Step 4:

[0357] (1'S,2'S)-4-heptyl-5'-(methyl-d3)-2'-(1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol (compound 10)

[0358] (1'S,2'S)-4-heptyl-5'-(methyl-d3)-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol

[0359] Under nitrogen protection at 0 °C, 1.5 g of molecular sieve 4A, 230 mg of triethylamine (2.20 mmol), and 524 mg of Burgess reagent (2.26 mmol) were added to a tetrahydrofuran (5 mL) solution of compound 10c (400 mg, 1.10 mmol). The mixture was heated to room temperature and stirred for 30 min. The reaction was monitored by TLC until completion. The reaction was quenched by adding 10 mL of saturated sodium bicarbonate solution. The aqueous phase was extracted with 30 mL of ethyl acetate. The combined organic phases were washed with 30 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether (v / v) = 1 / 30) to give compound 10 (white solid, 220 mg, HPLC: 99.5%, yield: 57%).

[0360] 1H NMR (400MHz, DMSO) δ8.63 (s, 2H), 6.01 (s, 2H), 5.08 (s, 1H), 4.49 (d, J = 2.5H z,1H),4.40(d,J=1.0Hz,1H),3.82(d,J=10.5Hz,1H),3.09–2.96(m,1H),2. 34–2.21(m,2H),2.16–2.04(m,1H),1.99–1.85(m,1H),1.71–1.64(m,1H),1 .58(s,3H),1.51–1.42(m,2H),1.26(d,J=5.6Hz,9H),0.85(t,J=6.8Hz,3H).

[0361] LC-MS m / z(ESI)=346.3[M+1].

[0362] Example 11

[0363] 4-(heptyl-1,1-d2)-5'-(methyl-d3)-2'-(1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol (compound 11)

[0364] 4-(heptyl-1,1-d2)-5'-(methyl-d3)-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol

[0365]

[0366] first step:

[0367] 4-(heptyl-1,1-d2)-2'-(2-hydroxypropane-2-yl)-5'-(methyl-d3)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol 11a

[0368] 4-(heptyl-1,1-d2)-2'-(2-hydroxypropan-2-yl)-5'-(methyl-d3)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol

[0369] Under nitrogen protection, L-(-)camphorsulfonic acid (67 mg, 0.29 mmol) was added to a solution of compound 1d (500 mg, 2.89 mmol), 5-(heptyl-1,1-d2)phenyl-1,3-diol (1.6 g, 8.67 mmol), and 4A molecular sieve (1.5 g) in dichloromethane (10 mL). After the addition was complete, the mixture was stirred at room temperature for 1.5 h. The reaction was monitored by TLC until the end of the reaction. The reaction was quenched by adding saturated sodium bicarbonate solution (10 mL). The aqueous phase was extracted with dichloromethane (30 mL × 2). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether (v / v) = 1 / 6) to give the title compound 11a (colorless oil, 400 mg, yield: 40.0%).

[0370] 1H NMR(400MHz,DMSO)δ8.67(dd,2H),6.03(s,2H),4.89(s,1H),3.66(d,2H),2.39–2.27(m,1H),2.14– 1.97(m,2H),1.83(d,1H),1.47(dd,2H),1.30–1.18(m,9H),0.97(s,3H),0.85(t,3H),0.80(s,3H).

[0371] LC-MS m / z(ESI)=366.3[M+1].

[0372] Step Two:

[0373] 4-(heptyl-1,1-d2)-5'-(methyl-d3)-2'-(1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol (compound 11)

[0374] 4-(heptyl-1,1-d2)-5'-(methyl-d3)-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol

[0375] Under nitrogen protection at 0 °C, 1.5 g of molecular sieve 4A, 230 mg of triethylamine (2.20 mmol), and 524 mg of Burgess reagent (2.26 mmol) were added to a tetrahydrofuran (5 mL) solution of compound 11a (400 mg, 1.10 mmol). The mixture was heated to room temperature and stirred for 30 min. The reaction was monitored by TLC until completion. The reaction was quenched by adding 10 mL of saturated sodium bicarbonate solution. The aqueous phase was extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with 30 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether (v / v) = 1 / 30) to give compound 11 (white solid, 141 mg, yield: 37%).

[0376] 1H NMR(400MHz,DMSO)δ8.63(s,2H),6.01(s,2H),5.08(s,1H),4.49(d,1H),4.40(d,1H),3.82(d,1H),3.09–2.96(m,1H) ,2.16–2.04(m,1H),1.99–1.85(m,1H),1.71–1.64(m,1H),1.58(s,3H),1.51–1.42(m,2H),1.26(d,9H),0.85(t,3H).

[0377] LC-MS m / z(ESI)=348.3[M+1].

[0378] Example 12

[0379] (1'R,2'R)-5'-(methyl-d3)-4-pentyl-2'-(propyl-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-4'-d-2,6-diol (compound 12)

[0380] (1'R,2'R)-5'-(methyl-d3)-4-pentyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-4'-d-2,6-diol

[0381]

[0382] first step:

[0383] (4R)-4-(2-hydroxypropan-2-yl)cyclohex-2-en-1-one-6-d 12a

[0384] (4R)-4-(2-hydroxypropan-2-yl)cyclohex-2-en-1-one-6-d

[0385] Under nitrogen protection, heavy water (7 mL, 350.0 mmol) and potassium carbonate (54 mg, 0.4 mmol) were added to a solution of (R)-4-(2-hydroxypropane-2-yl)cyclohex-2-en-1-one 9c (3.0 g, 19.5 mmol) in tetrahydrofuran (14 mL) and deuterated methanol (14 mL). The mixture was stirred at room temperature for 48 h. The reaction was confirmed to be complete by LC-MS. The mixture was concentrated under reduced pressure, and the aqueous phase was extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether (v / v) = 1 / 1) to give the title compound 12a (colorless oil, 2.4 g, yield: 79.0%).

[0386] 1H NMR (400MHz, DMSO) δ7.19 (dt, J=10.3, 1.9Hz, 1H), 5.99–5.88 (m, 1H), 4.60 (s, 1H), 2.44–2.38 ( m,1H),2.32(d,J=10.7Hz,1H),2.06–1.99(m,1H),1.67–1.56(m,1H),1.15(s,3H),1.05(s,3H).

[0387] LC-MS m / z (ESI) = 178.1 [M+Na].

[0388] Step Two:

[0389] (1R,4R)-4-(2-hydroxypropan-2-yl)-1-(methyl-d3)cyclohexyl-2-en-6-d-1-ol 12b

[0390] (1R,4R)-4-(2-hydroxypropan-2-yl)-1-(methyl-d3)cyclohex-2-en-6-d-1-ol

[0391] Under nitrogen protection at 0 °C, deuterated methyl magnesium iodide (14 mL, 13.5 mol, 1.0 N) was added dropwise to a tetrahydrofuran (10 mL) solution of anhydrous lithium chloride (570 mg, 13.5 mol), and the reaction was stirred for 0.5 h after the addition was complete. A tetrahydrofuran solution (5 mL) of compound 12a (700 mg, 4.0 mmol) was added dropwise, and the reaction was stirred for 0.5 h after the addition was complete. The reaction was monitored by TLC until the end. The reaction was quenched by adding saturated ammonium chloride solution (20 mL), and the aqueous phase was extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether (v / v) = 2 / 1) to give the title compound 12b (white solid, 430 mg, yield: 55.0%).

[0392] 1H NMR (400MHz, DMSO) δ5.66–5.58(m,1H),5.55–5.46(m,1H),4.40(d,J=1.8Hz,1H),4.21(s,1H),1.99(dd d,J=10.4,5.4,2.4Hz,1H),1.68(dd,J=12.9,5.5Hz,2H),1.24–1.20(m,1H),1.03(s,3H),0.97(s,3H).

[0393] Step 3:

[0394] (1'R,2'R)-2'-(2-hydroxypropane-2-yl)-5'-(methyl-d3)-4-pentyl-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-4'-d-2,6-diol 12c

[0395] (1'R,2'R)-2'-(2-hydroxypropan-2-yl)-5'-(methyl-d3)-4-pentyl-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-4'-d-2,6-diol

[0396] Under nitrogen protection, L-(-)camphorsulfonic acid (53 mg, 0.23 mmol) was added to a solution of compound 12b (400 mg, 2.29 mmol), 3,5-dihydroxypentane (621 mg, 3.44 mmol), and 4A molecular sieve (1.2 g) in dichloromethane (10 mL). After the addition was complete, the mixture was stirred at room temperature for 1.5 h. The reaction was monitored by TLC until the reaction was complete. The reaction was quenched by adding saturated sodium bicarbonate solution (10 mL). The aqueous phase was extracted with dichloromethane (30 mL × 3). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether (v / v) = 1 / 6) to give the title compound 12c (white solid, 270 mg, yield: 35.0%).

[0397] 1H NMR (400MHz, DMSO) δ9.02–8.43(m,2H),6.03(s,2H),4.88(d,J=2.3Hz,1H),3.66(d,J=11.0Hz,2H),2.39–2.28(m,3H),2.09(d, J=12.6Hz,1H),1.81(s,1H),1.46(dt,J=14.6,7.4Hz,2H),1.32–1.22(m,6H),0.97(s,3H),0.85(t,J=7.0Hz,3H),0.79(s,3H).

[0398] LC-MS m / z(ESI)=337.3[M+1].

[0399] Step 4:

[0400] (1'R,2'R)-5'-(methyl-d3)-4-pentyl-2'-(propyl-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-4'-d-2,6-diol (compound 12)

[0401] (1'R,2'R)-5'-(methyl-d3)-4-pentyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-4'-d-2,6-diol

[0402] At 0 °C under nitrogen protection, Burgess reagent (284 mg, 1.12 mmol) was added to a tetrahydrofuran (6 mL) solution of compound 12c (270 mg, 0.79 mmol), and the mixture was stirred at room temperature for 30 min. The reaction was monitored by TLC until completion. The reaction was quenched by adding saturated sodium bicarbonate solution (10 mL), and the aqueous phase was extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether (v / v) = 1 / 30) to give the title compound 12 (white solid, 73 mg, HPLC: 99%, yield: 28.0%).

[0403] 1H NMR (400MHz, DMSO) δ8.64(s,2H),6.01(s,2H),5.08(s,1H),4.49(d,J=2.4Hz,1H),4.40(s,1H),3.82(d,J=10.4Hz,1H),3.08–2.95(m,1H) ,2.34–2.25(m,2H),1.89(s,1H),1.71–1.61(m,1H),1.58(s,3H),1.47(dt,J=14.7,7.4Hz,2H),1.36–1.20(m,5H),0.86(t,J=7.0Hz,3H).

[0404] LC-MS m / z(ESI)=319.2[M+1].

[0405] Example 13

[0406] (1'R,2'R)-5'-(methyl-d3)-4-pentyl-2'-(propyl-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-4',4'-d2,6-diol (compound 13)

[0407] (1'R,2'R)-5'-(methyl-d3)-4-pentyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-4',4'-d2-2,6-diol

[0408]

[0409] first step:

[0410] (R)-4-(2-hydroxypropyl-2-yl)cyclohex-2-en-1-one-6,6-d2 13a

[0411] (R)-4-(2-hydroxypropan-2-yl)cyclohex-2-en-1-one-6,6-d2

[0412] Under nitrogen protection at -70°C, 14 mL (27.0 mmol) of diisopropylaminolithium was added dropwise to a tetrahydrofuran (20 mL) solution of (4R)-4-(2-hydroxypropane-2-yl)cyclohex-2-en-1-one-6-d 12a (2.0 g, 12.9 mmol). The mixture was stirred for 0.5 h after the addition was complete. Then, 5 mL (250.0 mmol) of heavy water was added dropwise, and the mixture was brought to room temperature and stirred for 20 min. The aqueous phase was extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether (v / v) = 1 / 1) to give the title compound 13a (colorless oil, 1.4 g, yield: 70.0%).

[0413] 1H NMR (400MHz, DMSO) δ7.19 (dt, J=10.3, 1.9Hz, 1H), 5.99–5.88 (m, 1H), 4.60 (s, 1H), 2. 32(d,J=10.7Hz,1H),2.06–1.99(m,1H),1.67–1.56(m,1H),1.15(s,3H),1.05(s,3H).

[0414] LC-MS m / z (ESI) = 179.1 [M+Na].

[0415] Step Two:

[0416] (1R,4R)-4-(2-hydroxypropan-2-yl)-1-(methyl-d3)cyclohexyl-2-en-6,6-d2-1-ol 13b

[0417] (1R,4R)-4-(2-hydroxypropan-2-yl)-1-(methyl-d3)cyclohex-2-en-6,6-d2-1-ol

[0418] Under nitrogen protection at 0 °C, deuterated methyl magnesium iodide (12 mL, 11.5 mmol, 1.0 N) was added dropwise to a tetrahydrofuran (10 mL) solution of anhydrous lithium chloride (488 mg, 11.5 mmol), and the reaction was stirred for 0.5 h after the addition was complete. A tetrahydrofuran solution (5 mL) of compound 13a (600 mg, 3.8 mmol) was added dropwise, and the reaction was stirred for 0.5 h after the addition was complete. The reaction was monitored by TLC until the end of the reaction. The reaction was quenched by adding saturated ammonium chloride solution (20 mL), and the aqueous phase was extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether (v / v) = 2 / 1) to give the title compound 13b (white solid, 410 mg, yield: 60.0%).

[0419] 1H NMR (400MHz, DMSO) δ5.66–5.58(m,1H),5.55–5.46(m,1H),4.40(d,J=1.8Hz,1H),4.21(s,1H),1.99(dd d,J=10.4,5.4,2.4Hz,1H),1.68(dd,J=12.9,5.5Hz,1H),1.24–1.20(m,1H),1.03(s,3H),0.97(s,3H).

[0420] Step 3:

[0421] (1'R,2'R)-2'-(2-hydroxypropane-2-yl)-5'-(methyl-d3)-4-pentyl-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-4',4'-d2-2,6-diol 13c

[0422] (1'R,2'R)-2'-(2-hydroxypropan-2-yl)-5'-(methyl-d3)-4-pentyl-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-4',4'-d2-2,6-diol

[0423] Under nitrogen protection, L-(-)camphorsulfonic acid (53 mg, 0.23 mmol) was added to a solution of compound 13b (400 mg, 2.29 mmol), 3,5-dihydroxypentane (621 mg, 3.44 mmol), and 4A molecular sieve (1.2 g) in dichloromethane (10 mL). After the addition was complete, the mixture was stirred at room temperature for 1.5 h. The reaction was monitored by TLC until completion. The reaction was quenched by adding saturated sodium bicarbonate solution (10 mL). The aqueous phase was extracted with dichloromethane (30 mL × 3). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether (v / v) = 1 / 6) to give the title compound 13c (white solid, 250 mg, yield: 32.5%).

[0424] 1H NMR (400MHz, DMSO) δ9.02–8.43(m,2H),6.03(s,2H),4.88(d,J=2.3Hz,1H),3.66(d,J=11.0Hz,2H),2.39–2.28(m,3 H),1.81(s,1H),1.46(dt,J=14.6,7.4Hz,2H),1.32–1.22(m,6H),0.97(s,3H),0.85(t,J=7.0Hz,3H),0.79(s,3H).

[0425] LC-MS m / z(ESI)=338.3[M+1].

[0426] Step 4:

[0427] (1'R,2'R)-5'-(methyl-d3)-4-pentyl-2'-(propyl-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-4',4'-d2,6-diol (compound 13)

[0428] (1'R,2'R)-5'-(methyl-d3)-4-pentyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-4',4'-d2-2,6-diol

[0429] At 0 °C under nitrogen protection, Burgess reagent (264 mg, 1.11 mmol) was added to a tetrahydrofuran (6 mL) solution of compound 13c (250 mg, 0.74 mmol), and the mixture was stirred at room temperature for 30 min. The reaction was monitored by TLC until completion. The reaction was quenched by adding saturated sodium bicarbonate solution (10 mL), and the aqueous phase was extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether (v / v) = 1 / 30) to give the title compound 13 (white solid, 55 mg, yield: 23.3%).

[0430] 1H NMR (400MHz, DMSO) δ8.64(s,2H),6.01(s,2H),5.08(s,1H),4.49(d,J=2.4Hz,1H),4.40(s,1H),3.82(d,J=10.4Hz,1H),3.08–2. 95(m,1H),2.34–2.25(m,2H),1.89(s,1H),1.58(s,3H),1.47(dt,J=14.7,7.4Hz,2H),1.36–1.20(m,5H),0.86(t,J=7.0Hz,3H).

[0431] LC-MS m / z(ESI)=320.2[M+1].

[0432] Example 14

[0433] 4-(methyl-d3)-5'-(methyl-d3)-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol (compound 14)

[0434] 4-(methyl-d3)-methyl-5'-(methyl-d3)-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol

[0435]

[0436] first step:

[0437] 2'-(2-hydroxypropane-2-yl)-4-(methyl-d3)-5'-(methyl-d3)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol 14b

[0438] 2'-(2-hydroxypropan-2-yl)-4-(methyl-d3)-5'-(methyl-d3)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol

[0439] 4-(2-hydroxypropan-2-yl)-1-(methyl-d3)cyclohexyl-2-en-1-ol 1d (500 mg, 2.9 mmol), 5-(methyl-d3)-benzene-1,3-diol 14a (1080 mg, 8.7 mmol), and 4A molecular sieve (1.5 g) were dissolved in 10 mL of dichloromethane, purged with nitrogen, and stirred at room temperature for 10 minutes. Finally, L-camphor sulfonic acid (67.34 mg, 0.29 mmol) was added. The mixture was stirred at room temperature for 1 hour. The reaction was quenched by adding 20 mL of saturated sodium bicarbonate aqueous solution, and extracted with ethyl acetate (10 mL × 4). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 700 mg of crude product. Column chromatography yielded 2'-(2-hydroxypropane-2-yl)-4-(methyl-d3)-5'-(methyl-d3)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol 14b (white solid, 375 mg, yield 46%).

[0440] 1H NMR(400MHz,DMSO-d6)δ9.03(s,1H),8.79(s,1H),6.09(d,1H),5.95(d,1H),4.92(s,1H), 3.90(d,1H),2.14(d,2H),1.37–1.21(m,2H),0.99(s,3H),0.91–0.79(m,2H),0.73(s,3H).

[0441] Step Two:

[0442] 4-(methyl-d3)-5'-(methyl-d3)-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol (compound 14)

[0443] 4-(methyl-d3)-5'-(methyl-d3)-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol

[0444] 2'-(2-hydroxypropane-2-yl)-4-(methyl-d3)-5'-(methyl-d3)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol 14b (350 mg, 1.25 mmol) was dissolved in 6 mL of tetrahydrofuran, purged with nitrogen, and cooled to 0 °C. Burgess reagent (595 mg, 2.5 mmol) was then added to the system, and the mixture was rapidly heated to room temperature. The reaction was allowed to proceed for 20 minutes. The reaction was quenched by adding 20 mL of saturated sodium bicarbonate solution, and extracted with ethyl acetate (10 mL × 4). The organic phases were combined, dried with anhydrous sodium sulfate, filtered, and concentrated to obtain 500 mg of crude product, which was used to prepare 4-(methyl-d3)-5'-(methyl-d3)-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol (compound 14) (purple-red solid, 30 mg, yield 9.2%).

[0445] 1H NMR(400MHz,Chloroform-d)δ6.28–6.15(m,2H),5.54(d,1H),4.65(p,1H),4.53–4.37(m,1H), 3.61–3.46(m,1H),2.45(ddd,1H),2.22(ddt,1H),2.10(q,1H),1.86–1.69(m,2H),1.56(t,3H).

[0446] Example 15

[0447] 5'-(hydroxymethyl-d2)-4-pentyl-2'-(1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol (compound 15)

[0448] 5'-(hydroxymethyl-d2)-4-pentyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol

[0449]

[0450] first step:

[0451] 2'-(2-hydroxypropyl-2-yl)-5'-(methyl-d3)-4-pentyl-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol 15a

[0452] 2'-(2-hydroxypropan-2-yl)-5'-(methyl-d3)-4-pentyl-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol

[0453] 4-(2-hydroxypropan-2-yl)-1-(methyl-d3)cyclohexyl-2-en-1-ol 1d (2.37 g, 13.7 mmol), 3,5-dihydroxypentane (3.7 g, 20.6 mmol), and 4A molecular sieve (6 g) were dissolved in 30 mL of dichloromethane, purged with nitrogen, and stirred at room temperature for 20 minutes. Finally, L-camphor sulfonic acid (317.8 mg, 1.37 mmol) was added. The mixture was stirred at room temperature for 1 hour. The reaction was quenched by adding 60 mL of saturated sodium bicarbonate aqueous solution, and extracted with ethyl acetate (30 mL × 4). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. Purification by silica gel column chromatography (eluent: ethyl acetate / petroleum ether (v / v) = 1 / 6) gave the title compound 15a (colorless oil, 1.3 g, yield: 28.5%).

[0454] 1H NMR (400MHz, DMSO) δ9.04–8.43(m,2H),6.03(s,2H),4.89(s,1H),3.66(m,2H),2.32(m,3H),2.14–2.06(m,1 H),2.02(m,1H),1.88–1.79(m,1H),1.47(m,2H),1.32–1.19(m,5H),0.97(s,3H),0.85(t,3H),0.80(s,3H).

[0455] LC-MS m / z (ESI) = 336.20 [M+1]

[0456] Step Two:

[0457] 5'-(methyl-d3)-4-pentyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol 15b

[0458] 5'-(methyl-d3)-4-pentyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol

[0459] Compound 15a (1.3 g, 3.9 mmol), Burgess reagent (1.1 g, 4.7 mmol), and tetrahydrofuran (10 mL) were added sequentially to a reaction flask at 0 °C. The mixture was stirred for 3 h under nitrogen protection. The reaction was monitored by TLC until completion. Ethyl acetate (50 mL) was added, and the organic phase was washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether (v / v) = 1 / 15) to give the title compound 15b (colorless oil, 794 mg, yield: 64.0%).

[0460] 1H NMR (400MHz, DMSO) δ8.65(s,2H),6.01(s,2H),5.08(s,1H),4.49(d,1H),4.43–4.37(d,1H),3.85–3.78(m,1H),3.08–2.98(m,1H),2. 32–2.26(m,2H),2.13–2.04(m,1H),1.95–1.87(m,1H),1.71–1.63(m,1H),1.58(s,3H),1.47(m,2H),1.35–1.22(m,5H),0.86(t,3H).

[0461] LC-MS m / z(ESI)=318.20[M+1].

[0462] Step 3

[0463] 5'-(hydroxymethyl-d2)-4-pentyl-2'-(1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol (compound 15)

[0464] 5'-(hydroxymethyl-d2)-4-pentyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol

[0465] N-hydroxyphthalimide (0.5 mmol) and anhydrous t-BuOOH (1.5 mmol) were added to a mixture of 15b (2.5 mmol) and N-Bu4NI (0.05 mmol). The reaction mixture was stirred at 75 °C for 1 hour under a sealed air atmosphere. The reaction was quenched by adding saturated Na2S2O8 (10 mL), and the mixture was extracted with ethyl acetate (3 × 30 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, and the solvent was removed under vacuum. At room temperature, HCl (1.5 mL) was slowly added to a flask containing the above mixture (140 mg, 0.5 mmol) and zinc powder (325 mg, 10 mmol) in methanol (3 mL). The reaction mixture was stirred at room temperature for 20 minutes. The reaction mixture was filtered through diatomaceous earth, the solvent was removed under vacuum, the residue was diluted with water, and extracted with EA (3 × 15 mL). The combined organic phases were dried over sodium sulfate. The solution was concentrated under vacuum and then purified by PE / EA silica gel column chromatography to give compound 15 (white solid, 51 mg, 31%).

[0466] LC-MS m / z(ESI)=333.2[M+1].

[0467] Example 22

[0468] 2'-Isopropyl-5'-(methyl-d3)-4-pentyl-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol (Compound 22)

[0469] 2'-isopropyl-5'-(methyl-d3)-4-pentyl-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol

[0470]

[0471] 15b (0.544 g, 1.73 mmol) was dissolved in ethyl acetate (10 mL) at 10 psi, and platinum (0.021 g) was hydrogenated at 10 psi for 30 min. The mixture was purified by silica gel chromatography using petroleum ether and diethyl ether as eluents to give compound 22 (white solid, 534 mg, 98%).

[0472] LC-MS m / z(ESI)=320.3[M+1].

[0473] Example 24

[0474] 2',6'-Dimethoxy-5-(methyl-d3)-4'-pentyl-2-(propyl-1-en-2-yl)-1,2,3,4-tetrahydro-1,1'-biphenyl (Compound 24)

[0475] 2',6'-dimethoxy-5-(methyl-d3)-4'-pentyl-2-(prop-1-en-2-yl)-1,2,3,4-tetrahydro-1,1'-biphenyl

[0476]

[0477]

[0478] 15b (1 mmol) was dissolved in DMF (55 mL), and K₂CO₃ (5 mmol) and CH₃I (3.6 mmol) were added to the reaction mixture. The mixture was stirred at room temperature for 4 hours. The reaction was monitored by thin-layer chromatography (10% diethyl ether / light petroleum ether) until the starting material disappeared. 200 mL of water was added to the reaction mixture, and the solution was extracted with diethyl ether. The organic phase was washed with brine to neutral pH, dried over sodium sulfate, and separated by column chromatography under reduced pressure to remove the solvent. Compound 24 was given (white solid, 342 mg, 99%).

[0479] LC-MS m / z(ESI)=346.3[M+1].

[0480] The following intermediates are synthesized according to the methods indicated in the table.

[0481]

[0482]

[0483]

[0484] The following compounds were synthesized according to the methods indicated in the table.

[0485]

[0486]

[0487] Rat Pharmacokinetics

[0488] Three healthy adult SD rats were used. After fasting overnight (with free access to water), each rat was administered the drug via gavage (po), 50 mg / kg. Blood samples of 0.1 mL were collected from the jugular venous plexus at 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, and 24 h post-administration. All blood samples were anticoagulated with K-EDTA. Plasma was then separated by centrifugation at 3500 rpm for 10 min at 5 °C and stored at -20 °C for analysis. An LC / MS / MS method was established to determine the concentration of the parent drug in plasma. The pharmacokinetic parameters of the compound in rats after oral administration (po) are as follows:

[0489]

[0490] Experimental results show that, after oral administration to rats, the compound of the present invention exhibits superior pharmacokinetic characteristics and better oral bioavailability compared to CBD.

[0491] This invention specification provides a detailed description of specific embodiments. Those skilled in the art should recognize that the above embodiments are exemplary and should not be construed as limiting the invention. For those skilled in the art, various improvements and modifications can be made to the invention without departing from its principles, and the resulting technical solutions also fall within the scope of protection of the claims of this invention.

Claims

1. A compound, or a pharmaceutically acceptable salt thereof, wherein said compound is selected from one of the following structures: , , ,or , .

2. An intermediate for preparing the compound of claim 1, wherein the intermediate is selected from: , ,or .

3. A pharmaceutical composition comprising: (1) The compound of claim 1 or a pharmaceutically acceptable salt thereof; (2) One or more other active ingredients selected by choice; and (3) Pharmaceutically acceptable carriers and / or excipients.

4. The pharmaceutical composition according to claim 3, characterized in that, The other active ingredients are selected from one or more of ginkgolide, antitumor agents, anticoagulants, antiepileptic agents, antidepressants, anxiolytics, hypnotics, analgesics, or anesthetics, or pharmaceutically acceptable salts of the other active ingredients.

5. The pharmaceutical composition according to claim 4, wherein the ginkgolide is one or any two or more of ginkgolide A, ginkgolide B, ginkgolide C, ginkgolide D, ginkgolide J, ginkgolide M, ginkgolide K, ginkgolide L, ginkgolide N, ginkgolide P, ginkgolide Q, and ginkgolide in any proportion.

6. Use of the compound of claim 1 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of any one of claims 3-5, in the preparation of a medicament for the treatment of post-traumatic stress disorder, facial paralysis, stroke, stable angina pectoris, thromboembolism, myocardial ischemia, coronary artery disease, hypertension, cerebral ischemia, improvement of sexual function, spasm, acute and chronic pain, Dravet syndrome, Lennox-Gastaut syndrome, Prader-Willi syndrome, Sturge-Weber syndrome, Fragile X syndrome, anxiety, bipolar disorder, autism, epilepsy, Parkinson's disease, Alzheimer's disease, Huntington's disease, opioid abuse, alcoholism, nicotine addiction, anorexia, cachexia, chemotherapy-related nausea and vomiting, postoperative nausea and vomiting, amyotrophic lateral sclerosis (ALS), Friedreich ataxia, schizophrenia, obsessive-compulsive disorder, multiple sclerosis, depression, sleep disorders, dystonia, paralytic dementia, memory loss, or glioblastoma.

7. The use according to claim 6, wherein the thromboembolism is cerebral infarction or myocardial infarction.

8. The use according to claim 6, wherein the spasm is a spasm caused by multiple sclerosis.

9. The use according to claim 6, wherein the acute and chronic pain is migraine, fibromyalgia, postoperative pain, cluster headache, tension headache, back pain, limb pain, low back pain, neck pain, neuropathic pain, cancer pain, or inflammatory pain.

10. The use according to claim 9, wherein the inflammatory pain is arthritis pain.

11. The use according to claim 9, wherein the neuropathic pain is trigeminal neuralgia.

12. The use according to claim 6, wherein the anxiety is generalized anxiety disorder or social anxiety disorder.

13. The use according to claim 6, wherein the sleep disorder is sleep apnea.

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