HK1206329B - Phenol derivative, method of preparing same, and pharmaceutical application of same - Google Patents

Abstract

The present invention relates to a phenol derivative and its preparation method, as well as its application in medicine. Specifically, the present invention relates to compounds represented by general formula (I) or their stereoisomers, solvates, metabolites, pharmaceutically acceptable salts, eutectics or prodrugs, their preparation methods, pharmaceutical compositions comprising them, and the use of the compounds or compositions of the present invention in the field of central nervous system. The definitions of each substituent in general formula (I) are the same as those in the specification

Description

Phenol derivative, preparation method and medical application thereof

Technical Field

The invention relates to a phenol derivative shown in a general formula (I), a stereoisomer, a pharmaceutically usable salt, a eutectic crystal or a prodrug thereof, a preparation method thereof, a pharmaceutical composition containing the same, and application of the compound and the composition in the field of central nerves.

Background

GABA_AReceptors are the major inhibitory neurotransmitter receptors in the central nervous system. GABA_AThe receptor is composed of a pentamer of transmembrane polypeptide subunits, with 19 different subunits constituting a variety of different GABA' s_AThe receptor subtype. GABA_AThe receptor is involved in the pathogenesis and diagnosis and treatment of various diseases such as anesthesia, depression, anxiety, epilepsy, dysmnesia, drug dependence and the like. Thus, GABA_AReceptors are pharmacologically and clinically important targets for drug action. Propofol and its derivatives are important GABA_AA compound that is a target.

Propofol activates multiple GABA_AThe receptor subtype, a clinically mature intravenous anesthetic, is widely used for induction and maintenance of general anesthesia. Clinical dose-related propofol can directly activate GABA in mammalian neurons_AThe receptor-chloride channel complex increases chloride conductance, decreases excitability of the neural network, and in turn causes general anesthesia (ManamiHara et al (1993) Anesthesiology, 79, 781-. The propofol has the remarkable pharmacokinetic and pharmacodynamic properties of quick response, short maintenance time and quickness and reversibility, after intravenous administration, the propofol quickly enters high perfusion areas such as heart, lung and liver from blood, and high lipid solubility enables the propofol to easily cross blood brain barrier and enter brain to play a general anesthetic effect.

However, propofol also has obvious limitations and disadvantages. It has been reported that about 70% of patients experience some degree of pain or discomfort upon injection of propofol (Pascale Picard (2000), Anesthesia & Analgesia, 90, 963 and 969). Although it has been reported that pre-treatment with other drugs or combinations of drugs can reduce the incidence and severity of propofol injection pain (c.h. tan et al (1998). analestheia, 53, 302305), this pain is still difficult to avoid. Propofol has been shown to lower systolic, diastolic and mean arterial blood pressure, thus clinically causing hypotension. At the same time, respiratory depression, apnea, hypoxemia, etc. are also considerable risks when propofol is used. These adverse effects largely hamper the use of propofol in some clinical cases, such as cardiovascular disease, brain damage and chronic hypotension.

Fospropofol is a water-soluble prodrug of propofol, which is rapidly hydrolyzed by alkaline phosphatase, releasing propofol, phosphate and formaldehyde. Although fospropofol alleviates pain at the site of intravenous injection of propofol, there is still a risk of respiratory depression and adverse hemodynamic effects since it is still acting as a prodrug of propofol (Cohen LB (2008). At the same time, fospropofol can also cause paresthesia and itching.

In view of the limitations and disadvantages of propofol and fospropofol, there is a need to develop new GABA with better pharmacokinetic and pharmacodynamic properties and fewer side effects_AA receptor agonist.

US 393939769463 describes fluoroaliphatic phenolic compounds for use in protective compositions for the skin, having the general formula:

wherein X is-CHClCH₂-、-CH＝CH-、-CH₂-CH₂-，R_fIs perfluoroalkyl of 3 to 20 carbon atoms, R¹、R₂、R₃、R₄Is selected from methyl, ethyl, methoxy, phenyl, phenoxy, hydroxy, hydrogen, halogen or two adjacent R groups form a carbocyclyl or heterocyclyl group, R₁、R₃May be-CH₂XR_fThe structure of the compound is greatly different from that of the compound of the invention.

CN1228414 describes benzo-four-membered ring derivatives and their addition salts with a pharmaceutically acceptable acid for the treatment of depression, anxiety, phobias, which compounds have the general formula:

wherein Z₁、Z₂、Z₃And Z₄Each independently selected from H, F, Cl, Br, I, C_1-6Alkyl radical, C_2-6Alkenyl or C_2-6Alkynyl and X represents O. The structure of the invention is greatly different from that of the invention.

US5552508 describes benzo-tetracyclic derivatives of the general formula:

wherein Z is selected from H or cyclobutane; x and Y may be independently selected from-COOH, -NH₂the-OH, -COCl, -NCO or bisacetoyl halide groups, which are of considerable structural difference from the present invention, are not considered to be part of the present invention as specifically described in this patent.

CN1323794 describes benzo-four-membered ring derivatives and their addition salts with pharmaceutically acceptable acids or bases, which have the following general formula:

wherein:represents a single or double bond; n is an integer of 1 to 6; r₁And R₂Each independently selected from H, C₁-₆Alkyl, cycloalkyl, aryl; x is selected from-CH ═ CH-, O, S (═ O)_mM is an integer of 0 to 2 or NR₃Wherein R is₃Selected from H, C₁-₆Alkyl, aryl. Y represents-CH or-CH₂(ii) a T represents a monocyclic or polycyclic ring C₃-₁₂Cycloalkyl radicals, in whichOne of the carbon atoms of the cycloalkyl group may be optionally substituted by a group selected from O, Se or S (═ O)_pWherein p is an integer of 0 to 2, NR₃This invention differs greatly from the structure of the present invention and is not considered to be part of the present invention as specifically described in this patent.

WO9615099 describes compounds for use in the treatment of central nervous system disorders, of the general formula:

wherein N is an integer of 0 to 2, X is selected from O, S, -N (R)⁵) Or methylene, R¹Selected from H, -NH₂、-NHR⁵Or a hydroxyl group; r²、R³Each independently selected from H, -COOH, -COOR⁵、-CONH₂、-CONHR⁵、-CON(R⁵)₂、CONHSO₂R⁵Or tetrazole, R⁴Selected from H, hydroxy, amino, -NHR⁵、CF³、C_1-8Alkyl radical, C₂-₈Alkenyl radical, C₂-₈Alkynyl, C_3-6Cycloalkyl, phenyl or C_1-4Alkoxy radical, R⁵Can be H, C_1-8Alkyl radical, C₂-₈Alkenyl radical, C₂-₈Alkynyl, C_3-6Cycloalkyl, ring a may be a partially or fully saturated aromatic ring or a pharmaceutically acceptable salt, which is a structure that is quite different from the present invention.

Disclosure of Invention

The invention aims to provide GABA with novel structure, better drug effect and higher safety_AReceptor agonists, or all stereoisomers, solvates, metabolites, pharmaceutically acceptable salts, co-crystals or prodrugs thereof, process for their preparation, pharmaceutical compositions and their use in the central nervous field for inducing or maintaining a systemic body in an animal or a humanAnaesthesia, sedation, hypnosis promotion, and the treatment and/or prevention of anxiety, nausea, vomiting, migraine, convulsions, epilepsy, neurodegenerative diseases and central nervous system related disorders provide more and more optimal drug selection routes.

In a preferred embodiment of the present invention, there is provided a compound represented by the general formula (I), and all stereoisomers, solvates, metabolites, pharmaceutically acceptable salts, co-crystals or prodrugs thereof:

wherein:

r is selected from-CR¹＝CR²R³or-C.ident.CR¹；

R¹、R²And R³Each independently selected from H, F, Cl, Br, I, hydroxyl and C_2-6Alkenyl radical, C_2-6Alkynyl, cyano, C_1-6Alkyl radical, C_1-6Alkoxy, 3-to 8-membered carbocyclyl, 3-to 8-membered heterocyclyl, 3-to 8-membered carbocyclyloxy or 3-to 8-membered heterocyclyloxy, said alkenyl, alkynyl, alkyl, alkoxy, carbocyclyl, heterocyclyl, carbocyclyloxy or heterocyclyloxy optionally further substituted with 0 to 5 substituents selected from F, Cl, Br, I, hydroxy, amino, cyano, mercapto, C_1-6Alkyl radical, C_1-6Alkoxy, 3-to 8-membered carbocyclyl, or 3-to 8-membered heterocyclyl, said heterocyclyl containing 1 to 2 heteroatoms selected from N, O or S;

alternatively, R¹And R²、R²And R³Or R¹And R³Any one of the groups of carbon atoms to which they may be attached may form a 3 to 8 membered ring, the 3 to 8 membered ring may contain 0 to 2 heteroatoms selected from N, O or S, and the formed 3 to 8 membered ring may optionally be further substituted0 to 4R⁸Substitution;

r 'and R' are each independently selected from H, F, Cl, Br, I, hydroxy, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Alkyl radical, C_1-6Alkoxy, 3-to 8-membered carbocyclyl, 3-to 8-membered heterocyclyl, 3-to 8-membered carbocyclyloxy or 3-to 8-membered heterocyclyloxy, said alkenyl, alkynyl, alkyl, alkoxy, carbocyclyl, heterocyclyl, carbocyclyloxy or heterocyclyloxy optionally further substituted with 0 to 5 substituents selected from F, Cl, Br, I, hydroxy, amino, cyano, mercapto, C_1-6Alkyl radical, C_1-6Alkoxy, 3-to 8-membered carbocyclyl, or 3-to 8-membered heterocyclyl, said heterocyclyl containing 1 to 2 heteroatoms selected from N, O or S;

R⁴、R⁵、R⁶and R⁷Each independently selected from H, F, Cl, Br, I, hydroxyl and C_2-6Alkenyl radical, C_2-6Alkynyl, cyano, azido, C_1-6Alkyl radical, C_1-6Alkoxy, 3-to 8-membered carbocyclyl, 3-to 8-membered heterocyclyl, 3-to 8-membered carbocyclyloxy or 3-to 8-membered heterocyclyloxy, said alkenyl, alkynyl, alkyl, alkoxy, carbocyclyl, heterocyclyl, carbocyclyloxy or heterocyclyloxy optionally further substituted with 0 to 5 substituents selected from F, Cl, Br, I, cyano, mercapto, C_1-6Alkyl radical, C_1-6Alkoxy, 3-to 8-membered carbocyclyl, or 3-to 8-membered heterocyclyl, said heterocyclyl containing 1 to 2 heteroatoms selected from N, O or S;

alternatively, R⁴And R⁵、R⁶And R⁷Any one of the groups of carbon atoms to which it may be attached forms a 3-to 8-membered ring, which may contain 0 to 2 heteroatoms selected from N, O or S, and the formed 3-to 8-membered ring may optionally be further substituted with 0 to 4R⁸Substitution;

alternatively, R⁴And R⁵May form (═ O);

alternatively, R⁶And R⁷Can be formed (═ i-O)；

R⁸Selected from F, Cl, Br, I, (═ O), hydroxyl, amino, cyano, mercapto, carboxyl, carboxylic ester, amido and C_1-6Alkyl radical, C_1-6Alkoxy, 3-to 8-membered carbocyclyl, or 3-to 8-membered heterocyclyl, said heterocyclyl containing 1 to 2 heteroatoms selected from N, O or S;

in a preferred embodiment of the present invention, the compound is selected from compounds represented by the general formula (I-a):

wherein:

r is selected from

R¹、R²And R³Each independently selected from H, F, Cl, Br, I, hydroxy, cyano, C_1-6Alkyl radical, C_1-6Alkoxy, 3-to 8-membered carbocyclyl, 3-to 8-membered heterocyclyl, 3-to 8-membered carbocyclyloxy or 3-to 8-membered heterocyclyloxy, preferably H, F, Cl, Br, I, hydroxy, C_1-4Alkyl radical, C_1-4Alkoxy, 3-to 6-membered carbocyclyloxy, 3-to 6-membered heterocyclyloxy, 3-to 6-membered carbocyclyl or 3-to 6-membered heterocyclyl, more preferably H, F, Cl, Br, I, hydroxy, C_1-4Alkyl radical, C_1-4Alkoxy or 3-to 6-membered carbocyclic group, further preferably H, C_1-4Alkyl or 3 to 6 membered carbocyclyl, said alkyl, alkoxy, carbocyclyl, heterocyclyl, carbocyclyloxy or heterocyclyloxy optionally further substituted with 0 to 5 substituents selected from F, Cl, Br, I, hydroxy, C_1-6Alkyl radical, C_1-6Alkoxy, 3-to 8-membered carbocyclyl, or 3-to 8-membered heterocyclyl, said heterocyclyl containing 1 to 2 heteroatoms selected from N, O or S;

alternatively, R¹And R²、R²And R³Or R¹And R³Any one of the groups of carbon atoms to which they may be attached may form a 3 to 6 membered ring, the 3 to 6 membered ring may contain 0 to 2 heteroatoms selected from N, O or S, and the formed 3 to 6 membered ring may optionally be further substituted with 0 to 4R⁸Substitution;

R⁴and R⁵Each independently selected from H, F, Cl, Br, I, hydroxyl and C_2-4Alkenyl radical, C_2-4Alkynyl, cyano, azido, C_1-6Alkyl radical, C_1-6Alkoxy, 3-to 8-membered carbocyclyloxy, 3-to 8-membered heterocyclyloxy, 3-to 8-membered carbocyclyl or 3-to 8-membered heterocyclyl, preferably H, F, Cl, Br, I, hydroxy, C_2-4Alkenyl radical, C_2-4Alkynyl, cyano, azido, C_1-4Alkyl radical, C_1-4Alkoxy, 3-to 6-membered carbocyclyl, 3-to 6-membered heterocyclyl, 3-to 6-membered carbocyclyloxy or 3-to 6-membered heterocyclyloxy, more preferably H, F, Cl, Br, I, hydroxy, C_2-4Alkenyl radical, C_2-4Alkynyl, cyano, azido, C_1-4Alkyl radical, C_1-4Alkoxy or 3-to 6-membered carbocyclic group, more preferably H, cyano, azido, C_1-4Alkyl radical, C_1-4Alkoxy or 3 to 6 membered carbocyclyl, said alkenyl, alkynyl, alkyl, alkoxy, carbocyclyl, heterocyclyl, carbocyclyloxy or heterocyclyloxy optionally further substituted with 0 to 5 substituents selected from F, Cl, Br, I, C_1-6Alkyl radical, C_1-6Alkoxy, 3-to 8-membered carbocyclyl, or 3-to 8-membered heterocyclyl, and said heterocyclyl may contain 1 to 2 heteroatoms selected from N, O or S;

alternatively, R⁴And R⁵May form a 3 to 6-membered ring with the carbon atom to which it is attached, the 3 to 6-membered ring may contain 0 to 2 heteroatoms selected from N, O or S, and the formed 3 to 6-membered ring may be optionally further substituted with 0 to 4R⁸Substitution;

alternatively, R⁴And R⁵May form (═ O);

R⁶and R⁷Each independently selected from H,F. Cl, Br, I or hydroxy;

R⁸selected from F, Cl, Br, I, hydroxyl, carboxyl, amino, carboxylic ester, amido and C_1-6Alkyl radical, C_1-6Alkoxy, 3-to 8-membered carbocyclyl, or 3-to 8-membered heterocyclyl, said heterocyclyl containing 1 to 2 heteroatoms selected from N, O or S.

In a preferred embodiment of the present invention, the compound is selected from compounds represented by the general formula (I-b):

wherein:

r is selected from

R¹、R²And R³Each independently selected from H, F, Cl, Br, I, hydroxy, cyano, C_1-4Alkyl radical, C_1-4Alkoxy, 3-to 6-membered carbocyclyl, 3-to 6-membered heterocyclyl, 3-to 6-membered carbocyclyloxy or 3-to 6-membered heterocyclyloxy, preferably H, F, Cl, Br, I, hydroxy, C_1-4Alkyl radical, C_1-4Alkoxy or 3-to 6-membered carbocyclic group, more preferably H, C_1-4Alkyl or 3-to 6-membered carbocyclic group, further preferably H, C_1-3Alkyl or 3 to 6 membered carbocyclyl, said alkyl, alkoxy, carbocyclyl, heterocyclyl, carbocyclyloxy or heterocyclyloxy optionally further substituted with 0 to 5 substituents selected from F, Cl, Br, I, hydroxy, C_1-4Alkyl radical, C_1-4Alkoxy radical, C_3-5Cycloalkyl or 3 to 5 membered heterocyclyl;

alternatively, R¹And R²、R²And R³Or R¹And R³Any one of which may be attached to carbon atoms to form a 3 to 6 membered ring, which 3 to 6 membered ring may contain 0 to 2 heteroatoms selected from N, O or S,and the 3 to 6 membered ring formed may optionally be further substituted with 0 to 4R⁸Substitution;

R⁴and R⁵Each independently selected from H, F, Cl, Br, I, hydroxyl and C_2-4Alkenyl radical, C_2-4Alkynyl, cyano, azido, C_1-4Alkyl radical, C_1-4Alkoxy, 3-to 6-membered carbocyclyl, 3-to 6-membered heterocyclyl, 3-to 6-membered carbocyclyloxy or 3-to 6-membered heterocyclyloxy, preferably H, F, Cl, Br, I, hydroxy, C_2-4Alkenyl radical, C_2-4Alkynyl, cyano, azido, C_1-4Alkyl radical, C_1-4Alkoxy, 3-to 6-membered carbocyclyloxy or 3-to 6-membered carbocyclyloxy, more preferably H, hydroxy, cyano, azido, C_1-4Alkyl radical, C_1-4Alkoxy or 3-to 6-membered carbocyclic group, more preferably H, cyano, azido, C_1-3Alkyl radical, C_1-3Alkoxy or 3-membered carbocyclyl, said alkenyl, alkynyl, alkyl, alkoxy, carbocyclyl, heterocyclyl, carbocyclyloxy or heterocyclyloxy optionally further substituted with 0 to 5 substituents selected from F, Cl, Br, I, C_1-4Alkyl radical, C_1-4Alkoxy, 3-to 6-membered carbocyclyl, or 3-to 6-membered heterocyclyl, said heterocyclyl containing 1 to 2 heteroatoms selected from N, O or S;

alternatively, R⁴And R⁵May form a 3 to 6-membered ring with the carbon atom to which it is attached, the 3 to 6-membered ring may contain 0 to 2 heteroatoms selected from N, O or S, and the formed 3 to 6-membered ring may be optionally further substituted with 0 to 4R⁸Substitution;

alternatively, R⁴And R⁵May form (═ O);

R⁸selected from F, Cl, Br, I, hydroxy, C_1-4Alkyl radical, C_1-4Alkoxy, 3-to 6-membered carbocyclyl, or 3-to 6-membered heterocyclyl.

In a preferred embodiment of the present invention, the compound is selected from compounds represented by the general formula (II):

wherein:

R¹、R²and R³Each independently selected from H, F, Cl, Br, I, hydroxyl and C_1-4Alkyl radical, C_1-4Alkoxy or 3-to 6-membered carbocyclic radical, preferably H, C_1-4Alkyl or 3-to 6-membered carbocyclic group, more preferably H, C_1-3Alkyl or 3 to 6 membered carbocyclyl, said alkyl, alkoxy or carbocyclyl optionally further substituted with 0 to 3 substituents selected from F, Cl, Br, I, hydroxy, C_1-4Alkyl radical, C_1-4Alkoxy or a 3-to 6-membered carbocyclic group;

alternatively, R¹And R²、R²And R³Or R¹And R³Any one of the groups of carbon atoms to which they may be attached may form a 3 to 6 membered ring, the 3 to 6 membered ring may contain 0 to 2 heteroatoms selected from N, O or S, and the formed 3 to 6 membered ring may optionally be further substituted with 0 to 3R⁸Substitution;

R⁴and R⁵Each independently selected from H, F, Cl, Br, I, hydroxyl and C_2-4Alkenyl radical, C_2-4Alkynyl, cyano, azido, C_1-4Alkyl radical, C_1-4Alkoxy, 3-to 6-membered carbocyclyloxy or 3-to 6-membered carbocyclyloxy, preferably H, hydroxy, cyano, azido, C_1-4Alkyl radical, C_1-4Alkoxy or 3-membered carbocyclic group, more preferably H, hydroxy, cyano, azido, C_1-3Alkyl radical, C_1-3Alkoxy or 3-membered carbocyclic group, more preferably H, cyano, azido, C_1-2Alkyl or C_1-2Alkoxy, said alkenyl, alkynyl, alkyl, alkoxy, carbocyclyl or carbocyclyloxy optionally further substituted with 0 to 3 substituents selected from F, Cl, Br, I, hydroxy, C_1-4Alkyl radical, C_1-4Alkoxy or a 3-to 6-membered carbocyclic group;

R⁸selected from F, Cl, Br, I, hydroxyBase, C_1-4Alkyl or C_1-4An alkoxy group.

In a preferred embodiment of the present invention, there is provided a compound represented by the general formula (II), or all stereoisomers, solvates, metabolites, pharmaceutically acceptable salts, co-crystals or prodrugs thereof, wherein:

R¹、R²and R³Each independently selected from H, F, Cl, Br, cyano, C_1-4Alkyl or 3-to 6-membered carbocyclic group, preferably H, C_1-4Alkyl or 3-to 6-membered carbocyclic group, more preferably H, C_1-3Alkyl or 3-to 6-membered carbocyclic group, further preferably H, C_1-2Alkyl or 3 to 4 membered carbocyclyl; said alkyl or carbocyclyl is optionally further substituted by 0 to 3 substituents selected from F, Cl, Br, hydroxy, C_1-4Alkyl radical, C_1-4Alkoxy or a 3-to 6-membered carbocyclic group; wherein R is¹、R²And R³At least one group is H;

alternatively, R¹And R²、R²And R³Or R¹And R³Any group of carbon atoms to which it may be attached forms a 3 to 6 membered ring, preferably a 5 to 6 membered carbocyclic group, said 3 to 6 membered carbocyclic group may optionally be further substituted with 0 to 3R⁸Substitution;

R⁴and R⁵Each independently selected from H, hydroxy, C_2-4Alkenyl radical, C_2-4Alkynyl, cyano, azido, C_1-4Alkyl radical, C_1-4Alkoxy, 3-to 6-membered carbocyclyl or 3-to 6-membered carbocycloxy, preferably H, hydroxy, cyano, azido, C_1-4Alkyl radical, C_1-4Alkoxy or 3-membered carbocyclic group, more preferably H, hydroxy, C_1-3Alkyl radical, C_1-3Alkoxy or 3-membered carbocyclic group, more preferably H, cyano, azido, C_1-2Alkyl or C_1-2Alkoxy, said alkenyl, alkynyl, alkyl, alkoxy, carbocyclyl or carbocyclyloxy optionally further substituted with 0 to 3 substituents selected from F, Cl, Br, hydroxy, C_1-4Alkyl radical, C_1-4Alkoxy orSubstituted with a substituent of a 3-to 6-membered carbocyclic group;

R⁸selected from F, Cl, Br, hydroxyl, C_1-4Alkyl or C_1-4An alkoxy group.

In a preferred embodiment of the present invention, there is provided a compound represented by the general formula (II), or all stereoisomers, solvates, metabolites, pharmaceutically acceptable salts, co-crystals or prodrugs thereof, wherein:

R¹、R²and R³Each independently selected from H, F, Cl, Br, cyano, C_1-4Alkyl or 3 to 6 membered carbocyclyl optionally further substituted with 0 to 3F, preferably H, C_1-4Alkyl or 3-to 6-membered carbocyclic group, more preferably H, C_1-3Alkyl or 3-to 6-membered carbocyclic group, further preferably H, C_1-2Alkyl or 3 to 4 membered carbocyclyl; wherein R is¹、R²And R³At least one group is H;

alternatively, R¹And R²、R²And R³Or R¹And R³Any group of carbon atoms to which it may be attached form a 3 to 6 membered ring, preferably a 5 to 6 membered carbocyclic group;

R⁴and R⁵Each independently selected from H, hydroxy, C_2-4Alkenyl radical, C_2-4Alkynyl, cyano, azido, C_1-4Alkyl radical, C_1-4Alkoxy, 3-to 6-membered carbocyclyloxy or 3-to 6-membered carbocyclyloxy, preferably H, hydroxy, cyano, azido, C_1-4Alkyl radical, C_1-4Alkoxy or 3-membered carbocyclic group, more preferably H, hydroxy, cyano, azido, C_1-3Alkyl radical, C_1-3Alkoxy or 3-membered carbocyclic group, more preferably H, cyano, azido, C_1-2Alkyl or C_1-2An alkoxy group.

In a preferred embodiment of the present invention, there is provided a compound represented by the general formula (II), or all stereoisomers, solvates, metabolites, pharmaceutically acceptable salts, co-crystals or prodrugs thereof, wherein:

R¹、R²and R³Each independently selected from H, cyano, C_1-4Alkyl or 3-to 6-membered carbocyclic group, preferably H, C_1-3Alkyl or 3-to 6-membered carbocyclic group, more preferably H, C_1-2Alkyl or 3 to 4 membered carbocyclyl; wherein R is¹、R²And R³At least one group is H;

alternatively, R¹And R²、R²And R³Or R¹And R³Any group may form a 3 to 6 membered ring, preferably a 5 to 6 membered carbocyclic group, with the carbon atoms to which it is attached;

R⁴and R⁵Each independently selected from H, hydroxy, C_2-4Alkenyl radical, C_2-4Alkynyl, cyano, azido, C_1-4Alkyl radical, C_1-4Alkoxy, 3-to 6-membered carbocyclyloxy or 3-to 6-membered carbocyclyloxy, preferably H, hydroxy, cyano, azido, C_1-4Alkyl radical, C_1-4Alkoxy or 3-membered carbocyclic group, more preferably H, hydroxy, cyano, azido, C_1-3Alkyl radical, C_1-3Alkoxy or 3-membered carbocyclic group, more preferably H, cyano, azido, C_1-2Alkyl or C_1-2An alkoxy group;

in a preferred embodiment of the present invention, there is provided a compound represented by the general formula (II), or all stereoisomers, solvates, metabolites, pharmaceutically acceptable salts, co-crystals or prodrugs thereof, wherein:

R¹、R²and R³Each independently selected from H, F, Cl, Br, CF₃、CHF₂、CH₂F. Cyano, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, preferably H, methyl, ethyl, n-propyl, isopropyl or cyclopropyl, more preferably H, methyl, ethyl or cyclopropyl, further preferably H, methyl or ethyl; wherein R is¹、R²And R³At least one group is H;

alternatively, R¹And R²、R²And R³Or R¹And R³Any group of carbon atoms to which it may be attached forms a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group, preferably a cyclopentyl or cyclohexyl group;

R⁴and R⁵Each independently selected from H, hydroxy, vinyl, ethynyl, cyano, azido, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, cyclopropyl, cyclobutyl or cyclopentyl, preferably H, hydroxy, cyano, azido, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy or cyclopropyl, more preferably H, cyano, azido, methyl, ethyl, methoxy, ethoxy or cyclopropyl, further preferably H, methyl, cyano, azido or methoxy.

In a preferred embodiment of the present invention, there is provided a compound represented by the general formula (II), or all stereoisomers, solvates, metabolites, pharmaceutically acceptable salts, co-crystals or prodrugs thereof, wherein:

R¹、R²and R³Each independently selected from H, cyano, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, preferably H, methyl, ethyl, n-propyl, isopropyl or cyclopropyl, more preferably H, methyl, ethyl or cyclopropyl, even more preferably H, methyl or ethyl; wherein R is¹、R²And R³At least one group is H;

alternatively, R¹And R²、R²And R³Or R¹And R³Any group of carbon atoms to which it may be attached forms a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group, preferably a cyclopentyl or cyclohexyl group;

R⁴and R⁵Each independently of the otherSelected from the group consisting of H, hydroxy, vinyl, ethynyl, cyano, azido, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy or cyclopropyl, preferably H, hydroxy, cyano, azido, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy or cyclopropyl, more preferably H, cyano, azido, methyl, ethyl, methoxy, ethoxy or cyclopropyl, and even more preferably H, methyl, cyano, azido or methoxy.

In a preferred embodiment of the present invention, there is provided a compound represented by the general formula (II), or all stereoisomers, solvates, metabolites, pharmaceutically acceptable salts, co-crystals or prodrugs thereof, wherein:

R¹、R²and R³Each independently selected from H or C_1-4Alkyl, preferably H or C_1-3Alkyl, more preferably H or C_1-2An alkyl group; wherein R is¹、R²And R³At least one group is H;

alternatively, R¹And R²、R²And R³Or R¹And R³Any one group may form a 3-to 6-membered carbocyclic group, preferably a 5-to 6-membered carbocyclic group, with the carbon atoms to which it is attached;

R⁴and R⁵Each independently selected from H, hydroxy, C_2-4Alkenyl radical, C_2-4Alkynyl, cyano, azido, C_1-4Alkyl radical, C_1-4Alkoxy, 3-to 6-membered carbocyclyloxy or 3-to 6-membered carbocyclyloxy, preferably H, hydroxy, cyano, azido, C_1-4Alkyl radical, C_1-4Alkoxy or 3-membered carbocyclic group, more preferably H, hydroxy, cyano, azido, C_1-3Alkyl radical, C_1-3Alkoxy or 3-membered carbocyclic group, more preferably H, cyano, azido, C_1-2Alkyl or C_1-2An alkoxy group.

In a preferred embodiment of the present invention, there is provided a compound represented by the general formula (II), or all stereoisomers, solvates, metabolites, pharmaceutically acceptable salts, co-crystals or prodrugs thereof, wherein:

R¹、R²and R³Each independently selected from H or C_1-4Alkyl, preferably H or C_1-3Alkyl, more preferably H or C_1-2An alkyl group; wherein R is¹、R²And R³At least one group is H;

R⁴and R⁵Each independently selected from H, hydroxy, cyano, azido, C_1-4Alkyl radical, C_1-4Alkoxy, 3-to 5-membered carbocyclyloxy or 3-to 5-membered carbocyclyloxy, preferably H, hydroxy, cyano, azido, C_1-4Alkyl radical, C_1-4Alkoxy or 3-membered carbocyclic group, more preferably H, hydroxy, cyano, azido, C_1-3Alkyl radical, C_1-3Alkoxy or 3-membered carbocyclic group, more preferably H, cyano, azido, C_1-2Alkyl or C_1-2An alkoxy group.

In a preferred embodiment of the present invention, there is provided a compound represented by the general formula (II), or all stereoisomers, solvates, metabolites, pharmaceutically acceptable salts, co-crystals or prodrugs thereof, wherein:

R¹、R²and R³Each independently selected from H or C_1-4Alkyl, preferably H or C_1-3Alkyl, more preferably H or C_1-2An alkyl group; wherein R is¹、R²And R³At least one group is H;

R⁴and R⁵Each independently selected from H, hydroxy, cyano, azido, C_1-4Alkyl radical, C_1-4Alkoxy, 3-to 5-membered carbocyclyloxy or 3-to 5-membered carbocyclyloxy, preferably H, hydroxy, cyano, azido, C_1-4Alkyl radical, C_1-4Alkoxy, 3-or 3-to 5-membered carbocyclyloxy, more preferably H, hydroxy, cyano, azido, C_1-3Alkyl radical, C_1-3Alkoxy or 3-membered carbocyclic group, more preferably H, cyano, azido, C_1-2Alkyl or C_1-2An alkoxy group.

In a preferred embodiment of the present invention, there is provided a compound represented by the general formula (II), or all stereoisomers, solvates, metabolites, pharmaceutically acceptable salts, co-crystals or prodrugs thereof, wherein:

R¹、R²and R³Each independently selected from H or C_1-2Alkyl radical, wherein R¹、R²And R³At least one group is H;

R⁴and R⁵Each independently selected from H, hydroxy, cyano, azido, C_1-4Alkyl radical, C_1-4Alkoxy, 3-to 4-membered carbocyclyloxy or 3-to 4-membered carbocyclyloxy, preferably H, hydroxy, cyano, azido, C_1-4Alkyl radical, C_1-4Alkoxy, 3-or 3-to 4-membered carbocyclyloxy, more preferably H, hydroxy, cyano, azido, C_1-3Alkyl radical, C_1-3Alkoxy or 3-membered carbocyclic group, more preferably H, cyano, azido, C_1-2Alkyl or C_1-2An alkoxy group.

In a preferred embodiment of the present invention, there is provided a compound represented by the general formula (II), or all stereoisomers, solvates, metabolites, pharmaceutically acceptable salts, co-crystals or prodrugs thereof, wherein:

R¹、R²and R³Each independently selected from H, methyl or ethyl, preferably H or methyl;

R⁴and R⁵Each independently selected from H, hydroxy, cyano, azido, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, cyclopropyl or cyclopropyloxy, preferably H, hydroxy, cyano, azido, methyl, methoxy, ethoxy or cyclopropyl, more preferably H, cyano, azido, methyl or methoxy.

In a preferred embodiment of the present invention, there is provided a compound represented by the general formula (I) or a stereoisomer, solvate, metabolite, pharmaceutically acceptable salt, co-crystal or prodrug thereof:

wherein:

r is selected from

R¹、R²And R³Each independently selected from H, F, Cl, Br, I, hydroxyl and C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, cyano, C_1-6Alkoxy, 3-to 8-membered carbocyclyl, 3-to 8-membered heterocyclyl, 3-to 8-membered carbocyclyloxy or 3-to 8-membered heterocyclyloxy, said alkyl, alkenyl, alkynyl, alkoxy, carbocyclyl, heterocyclyl, carbocyclyloxy or heterocyclyloxy being optionally further substituted by 0 to 5 substituents selected from F, Cl, Br, I, hydroxy, amino, cyano, mercapto, C_1-6Alkyl radical, C_1-6Alkoxy, 3-to 8-membered carbocyclyl, or 3-to 8-membered heterocyclyl, said heterocyclyl containing 1 to 2 heteroatoms selected from N, O or S;

alternatively, R¹And R²、R²And R³Or R¹And R³Any one of the groups connected theretoThe carbon atom in (b) may form a 3-to 8-membered ring, the 3-to 8-membered ring may contain 0 to 2 heteroatoms selected from N, O or S, and the formed 3-to 8-membered ring may optionally be further substituted with 0 to 4R⁸Substitution;

r 'and R' are each independently selected from H, F, Cl, Br, I, hydroxy, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Alkyl radical, C_1-6Alkoxy, 3-to 8-membered carbocyclyl, 3-to 8-membered heterocyclyl, 3-to 8-membered carbocyclyloxyOr 3 to 8 membered heterocyclyloxy, said alkenyl, alkynyl, alkyl, alkoxy, carbocyclyl, heterocyclyl, carbocyclyloxy or heterocyclyloxy optionally further substituted with 0 to 5 substituents selected from F, Cl, Br, I, hydroxy, amino, cyano, mercapto, C_1-6Alkyl radical, C_1-6Alkoxy, 3-to 8-membered carbocyclyl, or 3-to 8-membered heterocyclyl, said heterocyclyl containing 1 to 2 heteroatoms selected from N, O or S;

R⁴、R⁵、R⁶and R⁷Each independently selected from H, F, Cl, Br, I, hydroxyl and C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, cyano, azido, C_1-6Alkoxy, 3-to 8-membered carbocyclyl, 3-to 8-membered heterocyclyl, 3-to 8-membered carbocyclyloxy or 3-to 8-membered heterocyclyloxy, said alkyl, alkenyl, alkynyl, alkoxy, carbocyclyl, heterocyclyl, carbocyclyloxy or heterocyclyloxy being optionally further substituted by 0 to 5 substituents selected from F, Cl, Br, I, hydroxy, amino, cyano, mercapto, C_1-6Alkyl radical, C_1-6Alkoxy, 3-to 8-membered carbocyclyl, or 3-to 8-membered heterocyclyl, said heterocyclyl containing 1 to 2 heteroatoms selected from N, O or S;

alternatively, R⁴And R⁵、R⁶And R⁷Any one of the groups of carbon atoms to which it may be attached forms a 3-to 8-membered ring, which may contain 0 to 2 heteroatoms selected from N, O or S, and the formed 3-to 8-membered ring may optionally be further substituted with 0 to 4R⁸Substitution;

alternatively, R⁴And R⁵May form (═ O);

alternatively, R⁶And R⁷May form (═ O);

R⁸selected from F, Cl, Br, I, hydroxyl, carboxyl, amino, carboxylic ester, amido and C_1-6Alkyl radical, C_1-6Alkoxy, 3-to 8-membered carbocyclyl or 3-to 8-membered heterocyclyl, said heterocyclyl containing 1 to 2 substituents selected from N, O orOr a heteroatom of S.

In a preferred embodiment of the present invention, the compound represented by the general formula (I) or a stereoisomer, solvate, metabolite, pharmaceutically acceptable salt, co-crystal or prodrug thereof, wherein:

r is selected from

R¹、R²And R³Each independently selected from H or C_1-6Alkyl, preferably H or C_1-4An alkyl group, more preferably H, methyl, ethyl, n-propyl or isopropyl, further preferably H, methyl or ethyl;

r' is selected from H;

r' is selected from H, F, Cl, Br or I, preferably H, F, Cl or Br, more preferably H;

R⁴、R⁵、R⁶and R⁷Each independently selected from H, hydroxy, C_1-6Alkyl, cyano, azido, C_1-6Alkoxy or 3 to 8 membered carbocyclyl, said alkyl, alkoxy or carbocyclyl optionally being further substituted by 0 to 3 substituents selected from C_1-6Alkyl or C_1-6Substituted by a substituent of alkoxy; preferably R⁴、R⁵、R⁶And R⁷Each independently selected from H, hydroxy, methyl, ethyl, n-propyl, isopropyl, cyano, azido, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy,Cyclopropyl or cyclobutyl, more preferably H, hydroxy, methyl, ethyl, cyano, azido, methoxy, ethoxy, isopropoxy, n-butoxy, tert-butoxy,Or cyclopropyl, more preferably H, methyl, ethyl, cyano, azido, methoxy or cycloPropyl, more preferably H, methyl, cyano, azido or methoxy;

alternatively, R⁴And R⁵May be formed (═ O).

In a preferred embodiment of the present invention, the compound represented by the general formula (I) or a stereoisomer, a solvate, a metabolite, a pharmaceutically acceptable salt, a co-crystal or a prodrug thereof, wherein the compound is selected from compounds represented by the general formula (II):

wherein:

R¹、R²and R³Each independently selected from H or C_1-4Alkyl, preferably H, methyl, ethyl, n-propyl or isopropyl, more preferably H, methyl or ethyl; wherein R is¹、R²And R³At least one group is H;

R⁴and R⁵Each independently selected from H, hydroxy, C_1-4Alkyl, cyano, azido, C_1-4Alkoxy or 3 to 5 membered carbocyclyl, said alkyl, alkoxy or carbocyclyl optionally being further substituted by 0 to 3 substituents selected from C_1-4Alkyl or C_1-4Substituted by a substituent of alkoxy; preferably R⁴And R⁵Each independently selected from H, hydroxy, methyl, ethyl, n-propyl, isopropyl, cyano, azido, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy,Cyclopropyl or cyclobutyl, more preferably H, hydroxy, methyl, ethyl, cyano, azido, methoxy, ethoxy, isopropoxy, n-butoxy, tert-butoxy,Or cyclopropyl, more preferably H, methylAn ethyl group, a cyano group, an azido group, a methoxy group or a cyclopropyl group, and more preferably a H group, a methyl group, a cyano group, an azido group or a methoxy group.

In a preferred embodiment of the present invention, the compound represented by the general formula (II) or a stereoisomer, solvate, metabolite, pharmaceutically acceptable salt, co-crystal or prodrug thereof, wherein:

R¹、R²and R³Each independently selected from H, methyl, ethyl, n-propyl or isopropyl, preferably H, methyl or ethyl; wherein R is¹、R²And R³At least one group is H;

R⁴and R⁵Each independently selected from H, hydroxy, methyl, ethyl, n-propyl, isopropyl, cyano, azido, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy,Cyclopropyl or cyclobutyl, preferably H, hydroxy, methyl, ethyl, cyano, azido, methoxy, ethoxy, isopropoxy, n-butoxy, tert-butoxy,Or a cyclopropyl group, more preferably H, methyl, ethyl, cyano, azido, methoxy or cyclopropyl, and still more preferably H, methyl, cyano, azido or methoxy.

In a preferred embodiment of the present invention, the compound represented by the general formula (II) or a stereoisomer, solvate, metabolite, pharmaceutically acceptable salt, co-crystal or prodrug thereof, wherein:

R¹、R²and R³Each independently selected from H, methyl or ethyl, wherein R¹、R²And R³At least one group is H;

R⁴and R⁵Each independently selected from H, hydroxy, methyl, ethyl, cyano, azido, methoxy,Ethoxy, isopropoxy, n-butoxy,Or a cyclopropyl group, preferably H, methyl, ethyl, cyano, azido, methoxy or cyclopropyl, more preferably H, methyl, cyano, azido or methoxy.

In a preferred embodiment of the invention, the compound of the invention is selected from, but not limited to:

the present invention also provides a process for preparing a compound of the present invention represented by the general formula (I), which comprises:

carrying out Grignard reaction on the compound of the general formula (I-b) to obtain a compound of the general formula (I-c);

removing hydroxyl from the compound of the general formula (I-c) under reducing conditions to obtain a compound of the general formula (I-d); or reacting the compound of the general formula (I-c) with cyanide, azide or an alcohol solution under acidic conditions to obtain a compound of the general formula (I-d);

removing R from the compound of the general formula (I-d)¹⁰To obtain a compound of the general formula (I), wherein R¹⁰Selected from methyl, methoxymethyl, ethyl, benzyl, p-methoxybenzyl, trityl, trimethylsilyl or tert-butyldimethylsilyl, R, R 'and R', R⁴、R⁵、R⁶And R⁷The definitions of (a) and (b) are in accordance with those stated for the compounds of the general formula (I).

Further, the present invention provides a process for preparing a compound of the general formula (I-b), which comprises:

under alkaline conditions, the compound of the general formula (I-a) and dialkoxyl olefin compounds undergo a [2+2] cycloaddition reaction, and the obtained product is further hydrolyzed under acidic conditions to obtain the compound of the general formula (I-b). Wherein the definitions of the substituents are the same as those described above.

According to a specific embodiment of the present invention, there is provided a process for preparing a compound represented by the general formula (I) of the present invention, comprising:

under alkaline conditions, the compound of the general formula (I-a) and dialkoxyl olefin compounds undergo [2+2] cycloaddition reaction, and the obtained product is further hydrolyzed under acidic conditions to obtain a compound of the general formula (I-b);

carrying out Grignard reaction on the compound of the general formula (I-b) to obtain a compound of the general formula (I-c);

removing hydroxyl from the compound of the general formula (I-c) under reducing conditions to obtain a compound of the general formula (I-d); or reacting the compound of the general formula (I-c) with cyanide, azide or an alcohol solution under acidic conditions to obtain a compound of the general formula (I-d);

removing R from the compound of the general formula (I-d)¹⁰To obtain a compound of the general formula (I), wherein R¹⁰Selected from methyl, methoxymethyl, ethyl, benzyl, p-methoxybenzyl, trityl, trimethylsilyl or tert-butyldimethylsilyl, R, R 'and R', R⁴、R⁵、R⁶And R⁷The definitions of (a) and (b) are in accordance with those stated for the compounds of the general formula (I).

According to a preferred embodiment of the present invention, there is provided a method of synthesizing the compound as follows:

under the alkaline condition, tetrahydrofuran is taken as a solvent, and the compound with the general formula (I-a) and 1, 1-diethoxyethylene generate [2+2]]Performing addition reaction, and further performing hydrolysis under an acidic condition to obtain a compound shown as a general formula (I-b), wherein the base is selected from sodium amide, potassium tert-butoxide, butyl lithium and lithium diisopropylamide, and the acid is selected from hydrochloric acid, sulfuric acid or phosphoric acid; tetrahydrofuran, toluene, diethyl ether or methyl tert-butyl ether is used as a solvent, and a compound of a general formula (I-b) is subjected to a Grignard reaction under the protection of nitrogen to obtain a compound of a general formula (I-c), wherein the Grignard reagent is selected from methyl magnesium bromide or ethyl magnesium bromide; removing hydroxyl from the compound of the general formula (I-c) under the protection of nitrogen and with dichloromethane as a solvent under the action of a reducing agent to obtain the compound of the general formula (I-d), wherein the reducing agent is selected from triethylsilane, palladium/carbon, TMSCl/NaI or CS₂The term "TMSCl" means trimethylchlorosilane or the reaction of a compound of the general formula (I-c) with a cyanide, azide or alcohol solution under acidic conditions to give a compound of the general formula (I-d), the acid being selected from the group consisting of methanesulfonic acid, trifluoromethanesulfonic acidAcid, trifluoroacetic acid, p-toluenesulfonic acid, hydrochloric acid, glacial acetic acid or boron trifluoride diethyl etherate, wherein the alcohol is selected from methanol, ethanol, isopropanol, tert-butanol, cyclopropyl alcohol, cyclopropyl methanol, n-butanol or methoxyethanol, the cyanide is selected from trimethylsilyl cyanide, p-toluenesulfonic acid isocyanide or tetrabutyl ammonium cyanide, and the azide is selected from sodium azide or potassium azide; removing phenolic hydroxyl protecting group (R) from the compound of the general formula (I-d)¹⁰) Obtaining the compound shown in the general formula (I), wherein a deprotection reagent is selected from palladium/carbon, palladium hydroxide, raney nickel, trifluoroacetic acid, hydrochloric acid, tetrabutylammonium fluoride, aluminum trifluoride, aluminum trichloride or boron trifluoride; wherein R, R 'and R', R⁴、R⁵、R⁶And R⁷In accordance with the definition of compounds of the general formula (I), R¹⁰As defined above.

The present invention also provides a pharmaceutical composition comprising: the compound of the present invention or a stereoisomer, solvate, metabolite, pharmaceutically acceptable salt, co-crystal or prodrug thereof, and one or more pharmaceutically acceptable carriers and/or excipients.

The invention also provides a pharmaceutical composition comprising: the compounds of the present invention, and one or more therapeutic agents selected from opioid analgesics, sedative hypnotics and/or cardiovascular agents. The pharmaceutical composition provided by the invention is any pharmaceutically acceptable dosage form, preferably lipid emulsion, injection, tablet, aerosol, powder spray, membrane, granule, dispersible tablet, freeze-dried powder injection, capsule, ointment, suppository, cream, implant, syrup, oral solution, oral suspension, oral emulsion, powder or gel, more preferably freeze-dried powder injection, injection or lipid emulsion.

The compound or the stereoisomer, the solvate, the metabolite, the pharmaceutically acceptable salt, the eutectic crystal or the prodrug thereof or the pharmaceutical composition can be used as GABA_AReceptor agonists for the preparation ofCentral nervous system related drugs to provide a more superior route of drug selection for inducing or maintaining general anesthesia, promoting sedation hypnosis, treating and/or preventing anxiety, nausea, vomiting, migraine, convulsions, epilepsy, neurodegenerative diseases and central nervous system related diseases in animals or humans. Novel GABA of the present invention_AReceptor agonists, which are safer and have a shorter duration of action, and more particularly, which are present in solid form and have better water solubility than propofol, can be administered in a non-fat emulsion, thereby reducing the likelihood of injection pain, while avoiding emulsifier-induced allergic reactions and reducing the chance of bacterial infection of the formulation. The compound or the stereoisomer, the solvate, the metabolite, the pharmaceutically acceptable salt, the eutectic crystal or the prodrug thereof is used for preparing related medicaments or treating related diseases, and has better medicinal effect and higher safety.

Therefore, the invention also provides the application of the compound shown in the general formula (I) or all stereoisomers, solvates, metabolites, pharmaceutically acceptable salts, co-crystals, prodrugs or a pharmaceutical composition comprising the compound in the preparation of medicines in the central nervous field.

In a preferred embodiment of the present invention, there is provided a use of a compound represented by general formula (I), or all stereoisomers, solvates, metabolites, pharmaceutically acceptable salts, co-crystals, prodrugs thereof, or a pharmaceutical composition comprising the same, in the preparation of a medicament in the central nervous field, wherein the medicament in the central nervous field comprises: a drug for inducing and maintaining anesthesia in animals including mammals such as companion animals, zoo animals and livestock, preferably horses or dogs, a drug for promoting sedation and hypnosis in animals or humans, or a drug for treating and/or preventing anxiety, depression, insomnia, nausea, vomiting, migraine, schizophrenia, convulsions or epilepsy.

In a preferred embodiment of the present invention, there is provided a use of a compound represented by general formula (I), or all stereoisomers, solvates, metabolites, pharmaceutically acceptable salts, co-crystals, prodrugs thereof, or a pharmaceutical composition comprising the same, for preparing a medicament in the central nervous field, including a medicament for inducing and maintaining anesthesia in an animal or human.

The present invention also provides a method for inducing and maintaining anesthesia in an animal or human, which comprises administering to the animal or human an effective amount of a compound represented by the general formula (I) or all stereoisomers, solvates, metabolites, pharmaceutically acceptable salts, co-crystals, prodrugs thereof or a pharmaceutical composition comprising the same.

The present invention also provides a method for promoting sedative-hypnotic activity in animals or humans, which comprises administering an effective amount of a compound represented by the general formula (I) or all stereoisomers, solvates, metabolites, pharmaceutically acceptable salts, co-crystals, prodrugs thereof or pharmaceutical compositions comprising the same to animals or humans.

The present invention also provides a method for treating and/or preventing anxiety, depression, insomnia, nausea, vomiting, migraine, schizophrenia, convulsion or epilepsy in an animal or human, which comprises administering to the animal or human an effective amount of a compound represented by the general formula (I) or all stereoisomers, solvates, metabolites, pharmaceutically acceptable salts, co-crystals, prodrugs thereof or a pharmaceutical composition comprising the same.

Unless stated to the contrary, the terms used in the specification and claims have the following meanings.

Carbon, hydrogen, oxygen, sulfur, nitrogen or halogen referred to in the groups and compounds of the invention all include their isotopes, and carbon, hydrogen, oxygen, sulfur or nitrogen referred to in the groups and compounds of the invention are optionally further replaced by one or more of their corresponding isotopes, wherein isotopes of carbon include¹²C、¹³C and¹⁴c, isotopes of hydrogen including protium (H), deuterium (D, also called deuterium), tritium (T, also called deuterium), oxygenThe site element comprises¹⁶O、¹⁷O and¹⁸isotopes of O, sulfur including³²S、³³S、³⁴S and³⁶isotopes of S, nitrogen include¹⁴N and¹⁵isotopes of N, F include¹⁷F and¹⁹isotopes of F, chlorine including³⁵Cl and³⁷cl, isotopes of bromine including⁷⁹Br and⁸¹Br。

"alkyl" means a straight or branched chain saturated aliphatic hydrocarbon group of 1 to 20 carbon atoms, preferably an alkyl group of 1 to 8 carbon atoms, more preferably an alkyl group of 1 to 6 carbon atoms, and further preferably an alkyl group of 1 to 4 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, and various branched isomers thereof; said alkyl group may optionally be further substituted by 0 to 5 substituents selected from F, Cl, Br, I, ═ O, hydroxy, mercapto, -SR¹⁸Nitro, cyano, amino, alkylamino, amido, alkenyl, alkynyl, C_1-6Alkyl radical, C_1-6Hydroxyalkyl radical, C_1-6Alkoxy, 3-to 8-membered carbocyclyl, 3-to 8-membered heterocyclyl, 3-to 8-membered carbocyclyloxy, 3-to 8-membered heterocyclyloxy, carboxy, or carboxylate, wherein R is substituted¹⁸Is selected from C_1-6Alkyl, 3-to 8-membered carbocyclyl, or 3-to 8-membered heterocyclyl, alkyl as found herein, and as defined above.

"alkoxy" means-O-alkyl. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexoxy, cyclopropoxy, and cyclobutoxy. Said alkyl group may optionally be further substituted by 0 to 5 substituents selected from F, Cl, Br, I, ═ O, hydroxy, mercapto, -SR¹⁸Nitro, cyano, amino, alkylamino, amido, alkenyl, alkynyl, alkyl, hydroxyalkyl, alkoxy, carbocyclyl, heterocyclyl, carbocyclyloxy, heterocyclyloxy, carboxyl or a carboxylate group, wherein R is substituted with a substituent¹⁸As defined above.

"PEG" or "polyethylene glycol" means containingWherein n is an integer in the range of 2 to about 1000, preferably 2 to about 500, more preferably 2 to about 250, more preferably 2 to about 125, and still more preferably 2 to about 25.

"amino" means-NH₂。

"alkylamino" refers to an amino group having one or two alkyl substituents.

By "cyano" is meant

"nitro" means-NO₂。

"hydroxy" means-OH.

"mercapto" means-SH.

"carboxyl" means-COOH.

"carbonyl" means- (C ═ O) -.

"carboxylate group" means-COOR¹⁹Wherein R is¹⁹Is C_1-6An alkyl group.

"amido" means-CONR²⁰R²¹Wherein R is²⁰And R²¹Each independently selected from H, alkyl or carbocyclyl, R²⁰And R²¹May optionally be further substituted by 0 to 3 substituents selected from F, Cl, Br, I, hydroxy, mercapto, -SR¹⁸Nitro, cyano, amino, alkylamino, amido, alkenyl, alkynyl, alkyl, hydroxyalkyl, alkoxy, carbocyclyl, heterocyclyl, carbocyclyloxy, heterocyclyloxy, carboxyl or a carboxylic ester substituent, wherein R is substituted¹⁸As defined above.

"═ O" is a commonly used practice in the art and refers to doubly bonded oxygen atoms, such as the doubly bonded oxygen atom of a carbonyl group that is bonded to a carbon atom.

"hydroxyalkyl" is an alkyl group substituted with 1, 2 or 3 hydroxyl groups, preferably C_1-4An alkyl group. Non-limiting examples include hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1, 2-dihydroxypropyl, 1, 3-dihydroxypropyl and 2, 3-dihydroxypropyl.

"alkenyl" means a straight or branched chain unsaturated aliphatic hydrocarbon group consisting of 2 to 20 carbon atoms, preferably 2 to 12 carbon atoms, more preferably 2 to 8 carbon atoms, containing 1 to 3 carbon-carbon double bonds. Non-limiting examples include vinyl, propen-2-yl, buten-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 be optionally further substituted with 0 to 5 substituents selected from F, Cl, Br, I, hydroxy, alkyl, alkoxy, linear alkenyl, linear alkynyl, amino, nitro, cyano, mercapto, amido, carbocyclyl, or heterocyclyl, and the heterocyclyl contains 1 to 2 heteroatoms selected from N, O or S.

"alkynyl" means a straight or branched chain unsaturated aliphatic hydrocarbon group containing from 1 to 3 carbon-carbon triple bonds and consisting of 2 to 20 carbon atoms, preferably alkynyl of 2 to 12 carbon atoms, more preferably alkynyl of 2 to 8 carbon atoms. Non-limiting examples include ethynyl, propyn-1-yl, propyn-2-yl, butyn-1-yl, butyn-2-yl, butyn-3-yl, 3-dimethylbutyn-2-yl, pentyn-1-yl, pentyn-2-yl, hexyn-1-yl, 1-heptyn-1-yl, heptyn-3-yl, heptyn-4-yl, octyn-3-yl, nonyn-3-yl, decyn-4-yl, undec-3-yl, dodecyn-4-yl. The alkynyl group may be optionally further substituted with 0 to 5 substituents selected from F, Cl, Br, I, hydroxy, alkyl, alkoxy, linear alkenyl, linear alkynyl, amino, nitro, cyano, mercapto, amido, carbocyclyl, or heterocyclyl, and the heterocyclyl contains 1 to 2 heteroatoms selected from N, O or S.

"carbocyclyl" means a saturated or unsaturated aromatic or non-aromatic ring which may be a 3-to 8-membered monocyclic, 4-to 12-membered bicyclic, or 10-to 15-membered tricyclic ring system to which the carbocyclyl may be attached an bridged or spiro ring, non-limiting examples of which include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl and cyclododecyl, cyclohexene, cyclohexenyl, and cyclohexenyl,Said carbocyclyl may optionally be further substituted with 0 to 8 substituents selected from F, Cl, Br, I, ═ O, hydroxy, mercapto, -SR¹⁸Nitro, cyano, amino, alkylamino, amido, alkenyl, alkynyl, alkyl, hydroxyalkyl, alkoxy, carbocyclyl, heterocyclyl, carbocyclyloxy, heterocyclyloxy, carboxyl or carboxylate, wherein R is substituted¹⁸As defined above.

"heterocyclyl" means a substituted or unsubstituted saturated or unsaturated aromatic or non-aromatic ring which may be a 3 to 8 membered monocyclic, 4 to 12 membered bicyclic or 10 to 15 membered tricyclic ring system and contain 1 to 3 heteroatoms selected from N, O or S, preferably a 3 to 8 membered heterocyclyl, the optionally substituted N, S in the ring of the heterocyclyl may be oxidized to various oxidation states. The heterocyclic group may be attached at a heteroatom or carbon atom, the heterocyclic group may be attached to a bridged ring or a spiro ring, non-limiting examples include oxiranyl, aziridinyl, oxetanyl, azetidinyl, 1, 3-dioxolanyl, 1, 4-dioxolanyl, 1, 3-dioxanyl, azepinyl, pyridyl, furyl, thienyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinyl, perinyl, morpholinyl, thiomorpholinyl, 1, 3-dithianyl, dihydrofuranyl, dihydropyranyl, dithiainyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydroimidazolyl, thiazolidinyl, tetrahydropyranyl, benzimidazolyl, benzopyranyl, pyrrolopyridyl, chromanyl, benzodihydrofuranyl, azabicyclo [.3.2.1]Octyl, azabicyclo [5.2.0 ] groups]Nonoalkyl oxatricyclo [5.3.1.1 ]]Dodecyl, azaadamantyl and oxaspiro [3.3 ]]A heptalkyl group. Said heterocyclyl may optionally be further substituted by 0 to 5 substituents selected from F, Cl, Br, I, ═ O, hydroxy, mercapto, -SR¹⁸Nitro, cyano, amino, alkylamino, amido, alkenyl, alkynyl, alkyl, hydroxyalkyl, alkoxy, carbocyclyl, heterocyclyl, carbocyclyloxy, heterocyclyloxy, carboxyl or a carboxylate group, wherein R is substituted with a substituent¹⁸As defined above.

"pharmaceutical composition" refers to a mixture of one or more compounds of the present invention, pharmaceutically acceptable salts or prodrugs thereof, and other chemical components, wherein "other chemical components" refers to pharmaceutically acceptable carriers, excipients, and/or one or more other therapeutic agents; "other therapeutic agents" refers to sedative-hypnotic agents, anesthetic agents, analgesic agents, paralytic agents, antiemetics, cardiovascular agents, or mood-modifying agents.

By "carrier" is meant a material that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered compound.

"excipient" refers to an inert substance added to a pharmaceutical composition to facilitate administration of a compound. Non-limiting examples include calcium carbonate, calcium phosphate, sugars, starches, cellulose derivatives (including microcrystalline cellulose), gelatin, vegetable oils, polyethylene glycols, diluents, granulating agents, lubricants, binders, and disintegrating agents.

By "prodrug" is meant a compound of the invention that is metabolically convertible in vivo to a biologically active compound. Prodrugs of the invention are prepared by modifying the phenolic groups in compounds of the invention, which modifications may be removed by routine manipulation or in vivo, to yield the parent compound. When a prodrug of the present invention is administered to a mammal or human subject, the prodrug is cleaved to form a free hydroxyl group.

"cocrystal" refers to a crystal in which the active pharmaceutical ingredient and the cocrystal former are bound by hydrogen bonding or other non-covalent bonds, wherein the API (active pharmaceutical ingredient) and the CCF (cocrystal former) are both solid in pure form at room temperature and a fixed stoichiometric ratio exists between the components. A co-crystal is a multi-component crystal that contains both a binary co-crystal formed between two neutral solids and a multicomponent co-crystal formed between a neutral solid and a salt or solvate. Non-limiting examples of co-crystal formers include alanine, valine, leucine, isoleucine, proline, phenylalanine, tryptophan, methionine, glycine, serine, threonine, cysteine, tyrosine, asparagine, glutamine, lysine, arginine, histidine, aspartic acid, glutamic acid, pyroglutamic acid, sulfuric acid, phosphoric acid, nitric acid, hydrobromic acid, hydrochloric acid, formic acid, acetic acid, propionic acid, benzenesulfonic acid, benzoic acid, phenylacetic acid, salicylic acid, alginic acid, anthranilic acid, camphoric acid, citric acid, vinylsulfonic acid, formic acid, fumaric acid, furoic acid, gluconic acid, glucuronic acid, glutamic acid, glycolic acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, mucic acid, pamoic acid, pantothenic acid, stearic acid, succinic acid, sulfanilic acid, tartaric acid, p-toluenesulfonic acid, malonic acid, tartaric acid, glutamic acid, tartaric acid, citric acid, tartaric acid, and, 2-hydroxypropionic acid, oxalic acid, glycolic acid, glucuronic acid, galacturonic acid, citric acid, cinnamic acid, p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid or trifluoromethanesulfonic acid, ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, caffeine, procaine, choline, betaine, phentermine, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine, purine, piperazine, piperidine, and N-ethylpiperidine.

"animal" is meant to include mammals, such as companion animals, zoo animals, and livestock animals, preferably horses or dogs.

"stereoisomers" refers to isomers resulting from the different arrangement of atoms in a molecule, including cis, trans isomers, enantiomers and conformational isomers.

"optional" or "optionally" or "selective" or "selectively" means that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "a heterocyclic group optionally substituted with an alkyl group" means that the alkyl group may, but need not, be present, and the description includes the case where the heterocyclic group is substituted with an alkyl group, and the case where the heterocyclic group is not substituted with an alkyl group.

ED₅₀(effective half amount): the dose required to cause 50% of mice to lose orthotropic reflex was tested.

ED₉₅(95% effective amount): the dose required to cause loss of the orthotropic reflex in 95% of mice was tested.

LD₅₀(median lethal dose): the dose required to cause death in 50% of mice was tested.

LD₅(5% lethal dose): the dose required to cause 5% of mice to die was tested.

Anesthesia induction time and anesthesia maintenance time: timing was started after administration and animals were closely observed for general symptoms and changes in local, respiratory, administration. If the normal animal pushes it down or lies on its back, it can turn over immediately, and this reflection is known as a turning-over reflection. And otherwise, regarding the animal as the righting reflection disappears, recording the disappearance time of the reflection, and recording the recovery time of the reflection when the animal reappears the righting reflection. The time from the end of the administration to the righting reflex was recorded as the onset time of anesthesia, and the time from the disappearance of the righting reflex to the recovery of the reflex was recorded as the maintenance time of anesthesia.

TI (therapeutic index, i.e. LD)₅₀/ED₅₀) SI (safety index, LD)₅/ED₉₅)。

MTD (maximum tolerated dose): the maximum dose at which the righting reflex disappears but there is no death can be 100% total.

Detailed Description

The following detailed description is provided for the purpose of illustrating the embodiments and the advantageous effects thereof, and is not intended to limit the scope of the present disclosure.

In the present invention, the structure of the compound is determined by Nuclear Magnetic Resonance (NMR) or (and) Mass Spectrometry (MS). NMR shift () at 10^-6The units in (ppm) are given. NMR was measured using (Bruker Avance III 400 and Bruker Avance300) nuclear magnetic instrument in deuterated dimethyl sulfoxide (DMSO-d)₆) Deuterated chloroform (CDCl)₃) Deuterated methanol (CD)₃OD), internal standard Tetramethylsilane (TMS);

MS measurements were performed using Agilent 6120B (ESI) and Agilent 6120B (APCI);

HPLC was carried out using an Agilent 1260DAD high pressure liquid chromatograph (Agilent Zorbax SB-C18100X 4.6mm, 3.5 μm);

the thin-layer chromatography silica gel plate adopts a tobacco yellow sea HSGF254 or Qingdao GF254 silica gel plate, the specification of the silica gel plate used by thin-layer chromatography (TLC) is 0.15-0.20 mm, and the specification of the thin-layer chromatography separation and purification product is 0.4-0.5 mm;

the column chromatography generally uses 200-300 mesh silica gel of the Tibet Huanghai silica gel as a carrier;

the known starting materials of the present invention can be synthesized by methods known in the art or can be purchased from companies such as Tatan technology, Annaiji chemistry, Shanghai Demer, Chengdong chemical industry, Shaoshanghi chemical technology, and Bailingwei technology;

the nitrogen atmosphere refers to a reaction bottle connected with a nitrogen balloon with the volume of about 1L;

the hydrogen atmosphere refers to that a reaction bottle is connected with a hydrogen balloon with the volume of about 1L;

the hydrogenation reaction is usually vacuumized, filled with hydrogen and repeatedly operated for 3 times;

in the examples, the reaction was carried out under a nitrogen atmosphere unless otherwise specified;

in the examples, unless otherwise specified, the solution means an aqueous solution;

in the examples, the reaction temperature is room temperature, and the optimum reaction temperature is 20 ℃ to 30 ℃;

me, methyl;

et, ethyl;

bn, benzyl;

bz, benzoyl;

DMSO, dimethyl sulfoxide;

saline, normal Saline;

soluto HS15, polyethylene glycol stearic acid 15;

RT, peak retention time.

Intermediate 1: 5-benzyloxy-4-isopropyl-bicyclo [4, 2, 0]]Octane-1, 3, 5-trien-7-one (1f)

5-(benzyloxy)-4-isopropylbicyclo[4.2.0]octa-1，3，5-trien-7-one

The first step is as follows: 2-bromo-6-isopropylphenol (1b)

2-bromo-6-isopropylphenol

2-isopropylphenol 1a (10.00g, 73.4mmol), dichloromethane (200mL) and diisopropylamine (0.74g, 7.3mmol) were added to a reaction flask in this order, and after cooling to 0 ℃ in an ice bath, N-bromosuccinimide (13.07g, 73.4mmol) was added, and the reaction was continued for 2 hours with stirring, 0.2M sulfuric acid (100mL) was added, followed by uniform stirring, liquid separation by standing, washing of the organic layer with water (50 mL. times.2), washing with saturated brine (50 mL. times.2), combining the organic layers and drying with anhydrous sodium sulfate, filtration, and concentration of the filtrate under reduced pressure to give 2-bromo-6-isopropylphenol 1b as a pale yellow oil (15.00g, 95.0% yield).

¹H NMR(300MHz，CDCl₃)：7.31(d，1H)，7.16(d，1H)，6.79(t，1H)，5.57(s，1H)，3.34(dt，1H)，1.25(d，6H).

The second step is that: 2-benzyloxy-1-bromo-3-isopropylbenzene (1c)

2-(benzyloxy)-1-bromo-3-isopropylbenzene

2-bromo-6-isopropylphenol 1b (5g, 23.2mmol), potassium carbonate (6.44g, 46.6mmol), bromobenzyl (3.97g, 23.2mmol) and acetonitrile (100mL) were added to a reaction flask in this order, and the mixture was heated under reflux with stirring for 2 hours, cooled to room temperature, concentrated under reduced pressure, added with ether (100mL), filtered, and the filtrate was concentrated under reduced pressure to give 2-benzyloxy-1-bromo-3-isopropylbenzene 1c (6.46g, 91.1% yield) as a colorless oil.

¹H NMR(300MHz，CDCl₃)：7.65-7.27(m，6H)，7.22(d，1H)，6.99(t，1H)，4.96(s，2H)，3.48-3.28(m，1H)，1.27-1.13(m，6H).

The third step: 1, 1-diethoxyethylene (1e)

1，1-diethoxyethene

Bromoacetaldehyde diethyl acetal 1d (58.8g, 29.8mmol), octadecanohexa-ether (1.59g, 6.0mmol) and tetrahydrofuran (200mL) are sequentially added into a reaction flask, potassium tert-butoxide (34.2g, 30.5mmol) is added after cooling to 0 ℃ in an ice bath, the reaction is stirred at 0 ℃ for 2 hours, and filtration is carried out, wherein the filtrate is distilled under normal pressure, tetrahydrofuran and tert-butanol fractions are collected at 65 ℃ to 80 ℃, and then reduced pressure distillation is carried out by a water pump to obtain 1, 1-diethoxyethylene 1e (15.00g, yield 43.3%) as colorless oil.

¹H NMR(400MHz，CDCl₃)：3.83-3.73(m，4H)，3.04(d，2H)，1.33-1.24(m，6H).

The fourth step: 5-benzyloxy-4-isopropyl-bicyclo [4, 2, 0] octane-1, 3, 5-trien-7-one (1f)

5-benzyloxy-4-isopropyl-bicyclo[4.2.0]octa-1，3，5-trien-7-one

To a reaction flask were added 2-benzyloxy-1-bromo-3-isopropylbenzene 1c (19.76g, 64.7mmol), 1-diethoxyethylene 1e (15.00g, 129.1mmol), tetrahydrofuran (250mL), and sodium amide (5.04g, 129.1mmol) in this order, under nitrogen protection, heated under reflux for 15 hours, cooled to room temperature, added ice water (200mL), concentrated hydrochloric acid (30mL), stirred at room temperature for 2 hours, extracted with ethyl acetate (200mL × 2), the combined organic phases were dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) 50: 1) to give 5-benzyloxy-4-isopropyl-bicyclo [4, 2, 0] octane-1, 3, 5-trien-7-one 1f (8.5 g), yield 49.0%).

¹H NMR(300MHz，CDCl₃)：7.51-7.29(m，6H)，7.02(d，1H)，5.50(s，2H)，3.88(s，2H)，3.37(dt，1H)，1.21(d，6H).

Example 1

4-isopropyl-7-methyl-bicyclo [4, 2, 0]]Octane-1, 3, 5-trien-5-ol (Compound 1)

4-isopropyl-7-methyl-bicyclo[4.2.0]octa-1，3，5-trien-5-ol

The first step is as follows: 5-benzyloxy-4-isopropyl-7-methyl-bicyclo [4.2.0] octane-1, 3, 5-trien-7-ol (1B)

5-benzyloxy-4-isopropyl-7-methyl-bicyclo[4.2.0]octa-1，3，5-trien-7-ol

To a reaction flask were added 5-benzyloxy-4-isopropyl-bicyclo [4, 2, 0] octane-1, 3, 5-trien-7-one 1f (3.00g, 11.3mmol, intermediate 1) and tetrahydrofuran (30mL), a methyl magnesium bromide solution (13.5mL, 13.5mmol) was slowly added dropwise at 78 ℃ to react at room temperature for 2 hours, a saturated ammonium chloride solution (30mL) was added thereto, the mixture was stirred at room temperature for 1 hour, extracted with ethyl acetate (50mL × 2), the organic phases were combined, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 20: 1) to give 5-benzyloxy-4-isopropyl-7-methyl-bicyclo [4, 2, 0] octane-1, 3, 5-trien-7-ol 1B (0.91g, yield 28.6%).

¹H NMR(300MHz，CDCl₃)：8.36-7.17(m，6H)，6.77(d，1H)，5.37(s，2H)，3.64(s，2H)，3.59(dt，1H)，1.78(s，3H)，1.25(d，6H).

The second step is that: 5-benzyloxy-4-isopropyl-7-methyl-bicyclo [4.2.0] octane-1, 3, 5-triene (1C)

5-benzyloxy-4-isopropyl-7-methyl-bicyclo[4.2.0]octa-1，3，5-triene

To a reaction flask were added 5-benzyloxy-4-isopropyl-7-methyl-bicyclo [4, 2, 0] octane-1, 3, 5-trien-7-ol 1B (3.50g, 12.4mmol), dichloromethane (40mL) and triethylsilane (1.72g, 14.8mmol) in this order, boron trifluoride ether (2.11g, 14.9mmol) was slowly added dropwise at 78 ℃, stirred at room temperature for 1 hour, a saturated sodium bicarbonate solution (30mL) was added, stirred at room temperature for 2 hours, extracted with dichloromethane (50mL × 2), the organic phases were combined, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) 50: 1) to give 5-benzyloxy-4-isopropyl-7-methyl-bicyclo [4 ] as a pale yellow oil, 2, 0] octane-1, 3, 5-triene 1C (1.97g, 59.7% yield).

¹H NMR(300MHz，CDCl₃)：7.54-7.21(m，6H)，7.11(d，1H)，5.23(d，1H)，5.12(d，1H)，3.71(s，2H)，3.35(dd，1H)，2.65(d，1H)，1.53(d，3H)，1.21(d，6H).

The third step: 4-isopropyl-7-methyl-bicyclo [4, 2, 0] octane-1, 3, 5-trien-5-ol (Compound 1)

4-isopropyl-7-methyl-bicyclo[4.2.0]octa-1，3，5-trien-5-ol

5-benzyloxy-4-isopropyl-7-methyl-bicyclo [4, 2, 0] octane-1, 3, 5-triene 1C (1.80g, 6.8mmol), palladium on charcoal (0.14g, palladium content w/w ═ 10%) and methanol (100mL) were added in this order to a reaction flask, and the mixture was reacted at room temperature for 4 hours under a hydrogen atmosphere, followed by filtration, concentration of the filtrate under reduced pressure, and separation and purification of the residue by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 20: 1) to obtain 4-isopropyl-7-methyl-bicyclo [4, 2, 0] octane-1, 3, 5-trien-5-ol compound 1(1.04g, yield 87.3%, HPLC: 97.40%) as a colorless oil.

MS m/z(ESI)：177.1[M+1].

¹H NMR(300MHz，CDCl₃)：7.00(d，1H)，6.60(d，1H)，4.51(s，1H)，3.59-3.43(m，1H)，3.16(ddd，2H)，2.42(d，1H)，1.38(d，3H)，1.17(d，6H).

Chiral resolution was performed on 4-isopropyl-7-methyl-bicyclo [4, 2, 0] octane-1, 3, 5-trien-5-ol compound 1(20g, 113.6mmol), and chiral isomers were separated by HPLC using a preparative apparatus and a chiral column (separation conditions: chiral column CHIRALPAK AD-H, 20 × 250mm, 5 μm, mobile phase: n-hexane: isopropanol ═ 99: 1(v/v) isocratic elution for 41 minutes, flow rate: 14.0 mL/min, UV ═ 220/275nm, column temperature: 35 ℃), and the corresponding fractions were collected and concentrated under reduced pressure to give compound 1-1(3.2g, ee > 98%, RT ═ 24.4min) and compound 1-2(4.8g, ee > 98%, RT ═ 32.3 min).

MS m/z(ESI)：175.1[M-1].

¹H NMR(400MHz，CDCl3)7.06(d，1H)，6.66(d，1H)，4.56(s，1H)，3.62-3.50(m，1H)，3.28(dd，1H)，3.19(dt，1H)，2.60(dd，1H)，1.44(d，3H)，1.24(dd，6H).

(theoretically, the mass spectrum and nuclear magnetic hydrogen spectrum data of the compound 1 and the isomer compounds 1-1 and 1-2 are consistent, and the actually obtained result is the same, and the isomer obtained by racemate resolution is the same and is not repeated again.)

Example 2

5-hydroxy-4-isopropyl-bicyclo [4, 2, 0]]Octane-1, 3, 5-trien-7-one (Compound 2)

5-hydroxy-4-isopropyl-bicyclo[4.2.0]octa-1，3，5-trien-7-one

To a 250mL reaction flask, 5-benzyloxy-4-isopropyl-bicyclo [4, 2, 0] octane-1, 3, 5-trien-7-one 1f (3.50g, 13.1mmol, intermediate 1), palladium on charcoal (2.10g, palladium content w/w ═ 10%) and methanol (70mL) were added in this order, reacted at room temperature for 80 minutes under a hydrogen atmosphere, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 15: 1) to obtain 5-hydroxy-4-isopropyl-bicyclo [4, 2, 0] octane-1, 3, 5-trien-7-one compound 2 as a white solid (1.23g, yield 53.1%, HPLC: 99.50%).

MS m/z(ESI)：175.0[M+1].

¹H NMR(300MHz，CDCl₃)：7.77(s，1H)，7.42(d，1H)，7.00(d，1H)，3.87(s，2H)，3.31(dt，6.9Hz，1H)，1.23(d，6H).

Example 3

7-ethyl-4-isopropyl-bicyclo [4, 2, 0]]Octane-1, 3, 5-trien-5-ol (Compound 3)

7-ethyl-4-isopropyl-bicyclo[4.2.0]octa-1，3，5-trien-5-ol

The first step is as follows: 5-benzyloxy-7-ethyl-4-isopropyl-bicyclo [4, 2, 0] octane-1, 3, 5-trien-7-ol (3B)

5-benzyloxy-7-ethyl-4-isopropyl-bicyclo[4.2.0]octa-1，3，5-trien-7-ol

To a reaction flask were added 5-benzyloxy-4-isopropyl-bicyclo [4, 2, 0] octane-1, 3, 5-trien-7-one 1f (10.00g, 37.6mmol, intermediate 1) and tetrahydrofuran (100mL), an ethylmagnesium bromide solution (45mL, 45mmol) was added dropwise at 78 ℃, stirred at room temperature for 1 hour, a saturated ammonium chloride solution (100mL) was added, extracted with ethyl acetate (50mL × 2), the organic phases were combined and dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 20: 1) to give 5-benzyloxy-7-ethyl-4-isopropyl-bicyclo [4, 2, 0] octane-1 as a pale yellow oil, 3, 5-Trien-7-ol 3B (6.77g, 60.8% yield).

The second step is that: 5-benzyloxy-7-ethyl-4-isopropyl-bicyclo [4, 2, 0] octane-1, 3, 5-triene (3C)

5-benzyloxy-7-ethyl-4-isopropyl-bicyclo[4.2.0]octa-1，3，5-triene

To a reaction flask were added 5-benzyloxy-7-ethyl-4-isopropyl-bicyclo [4, 2, 0] octane-1, 3, 5-trien-7-ol 3B (4.50g, 15.2mmol), triethylsilane (2.12g, 18.2mmol) and dichloromethane (100mL) in this order, boron trifluoride ether (2.59g, 18.3mmol) was added at 78 ℃, stirred at room temperature for 30 minutes to complete the reaction, a saturated sodium bicarbonate solution (50mL) was added, stirred at room temperature for 1 hour, allowed to stand for liquid separation, extracted with dichloromethane (100mL × 2), the combined organic phases were dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 50: 1) to give 5-benzyloxy-7-ethyl-4-isopropyl-bicyclo [4 ] as a colorless oil, 2, 0] octane-1, 3, 5-triene 3C (3.30g, 64.6% yield).

¹H NMR(300MHz，CDCl₃)：7.31(dt，5H)，7.04(d，1H)，6.64(d，1H)，5.16(d，1H)，5.00(d，1H)，3.47(m，1H)，3.40-3.10(m，2H)，2.63(d，1H)，2.13-1.92(m，1H)，1.62(ddd，1H)，1.12(t，6H)，0.94(t，3H).

The third step: 7-Ethyl-4-isopropyl-bicyclo [4, 2, 0] octane-1, 3, 5-trien-5-ol (Compound 3)

7-ethyl-4-isopropyl-bicyclo[4.2.0]octa-1，3，5-trien-5-ol

5-benzyloxy-7-ethyl-4-isopropyl-bicyclo [4, 2, 0] octane-1, 3, 5-triene 3C (3.30g, 11.8mmol), palladium on charcoal (0.25g, palladium content w/w ═ 10%) and methanol (100mL) were added in this order to a reaction flask, and the mixture was reacted at room temperature for 3 hours under a hydrogen atmosphere, followed by filtration, concentration of the filtrate under reduced pressure, and separation and purification of the residue by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 30: 1) to obtain 7-ethyl-4-isopropyl-bicyclo [4, 2, 0] octane-1, 3, 5-trien-5-ol compound 3 as a pale yellow oil (1.50g, yield 67%, HPLC: 96.33%).

MS m/z(ESI)：189.1[M-1].

1H NMR(300MHz，CDCl₃)：7.07(d，1H)，6.68(d，1H)，4.58(s，1H)，3.52-3.35(m，1H)，3.33-3.12(m，2H)，2.60-2.47(m，1H)，1.49(m，2H)，1.25(d，6H)，1.09(t，3H).

Example 4

4-isopropyl-7-methyl-bicyclo [4, 2, 0]]Octane-1, 3, 5-triene-5, 7-diol (Compound 4)

4-isopropyl-7-methyl-bicyclo[4.2.0]octa-1，3，5-triene-5，7-diol

Adding 5-hydroxy-4-isopropyl-bicyclo [4, 2, 0] octane-1, 3, 5-trien-7-one compound 2(270mg, 1.4mmol) and tetrahydrofuran (10mL) to a reaction flask, slowly adding a methylmagnesium bromide solution (4.66mL, 14.0mmol) dropwise at 78 ℃, stirring at room temperature for 10 hours, adding a saturated ammonium chloride solution (10mL), extracting with ethyl acetate (10mL × 2), combining the organic phases and drying with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, separating and purifying the residue with silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 15: 1) to obtain 4-isopropyl-7-methyl-bicyclo [4, 2, 0] octane-1, 3, 5-trien-5 as a pale yellow oil, 7-diol compound 4(130mg, yield 48%, HPLC: 97.55%).

MS m/z(ESI)：190.9[M-1].

1H NMR(400MHz，DMSO)8.95(s，1H)，6.99(d，1H)，6.56(d，1H)，5.39(s，1H)，3.23-3.16(m，1H)，3.01-2.91(m，2H)，1.57(s，3H)，1.14-1.11(m，6H).

Example 5

3-Ethyl-8-methoxy-8-methylcyclo [4.2.0]Octane-1, 3, 5-trien-2-ol (Compound 5)

3-ethyl-8-methoxy-8-methylbicyclo[4.2.0]octa-1，3，5-trien-2-ol

The first step is as follows: 2-bromo-6-ethylphenol (5B)

2-bromo-6-ethyl-phenol

2-ethylphenol 5A (26.80g, 0.2mol), dichloromethane (130mL) and diisopropylamine (2.23g, 22.0mmol) were sequentially added to a reaction flask, N-bromosuccinimide (40.00g, 0.2mol) was added at-40 ℃, after completion of the dropwise addition, the mixture was naturally warmed to room temperature and stirred overnight, water (100mL) was added to the reaction system, pH was adjusted to about 3 with 2M dilute hydrochloric acid solution, extraction was performed with dichloromethane (150 mL. times.3), washing was performed with saturated brine (300 mL. times.1), the organic phases were combined and dried over anhydrous sodium sulfate, filtration was performed, and the filtrate was concentrated under reduced pressure to obtain 2-bromo-6-ethylphenol 5B as a pale yellow oil (32.50g, yield 73.0%).

The second step is that: 2-benzyloxy-1-bromo-3-ethylbenzene (5C)

2-benzyloxy-1-bromo-3-ethyl-benzene

2-bromo-6-ethylphenol 5B (32.50g, 0.2mol), potassium carbonate (30.60g, 0.2mol), bromobenzyl (44.16g, 0.3mol) and acetonitrile (200mL) were added sequentially to the reaction flask, heated to 80 deg.C, stirred overnight, cooled to room temperature, filtered, washed with acetonitrile (50 mL. times.2), and the filtrate was concentrated under reduced pressure to give 2-benzyloxy-1-bromo-3-ethylbenzene 5C (42.00g, 90.52% yield) as a yellow oil.

The third step: 5-benzyloxy-4-ethyl-bicyclo [4, 2, 0] octane-1, 3, 5-trien-7-one (5D)

5-benzyloxy-4-ethyl-bicyclo[4.2.0]octa-1，3，5-trien-7-one

2-benzyloxy-1-bromo-3-ethylbenzene 5C (10.00g, 34.5mmol), 1-diethoxyethylene 1e (12.10g, 103.4mmol), tetrahydrofuran (50mL) and sodium amide (6.10g, 155.1mmol) were added to a reaction flask in this order, the mixture was heated to 60 ℃ under nitrogen protection and stirred overnight, the reaction mixture was cooled to room temperature, slowly added to an ice concentrated hydrochloric acid solution, stirred for 10 minutes, extracted with ethyl acetate (50 mL. times.3), washed with saturated brine (100 mL. times.1), the organic phases were combined and dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v): 100: 1) to give 5-benzyloxy-4-ethyl-bicyclo [4, 2, 0] octane-1 as a brown oil, 3, 5-Trien-7-one 5D (3.4g, 39.10% yield).

The fourth step: 5-benzyloxy-7-methyl-4-ethyl-bicyclo [4, 2, 0] octane-1, 3, 5-trien-7-ol (5E)

5-(benzyloxy)-4-ethyl-7-methylbicyclo[4.2.0]octa-1，3，5-trien-7-ol

To a reaction flask were added 5-benzyloxy-4-ethyl-bicyclo [4, 2, 0] bicyclo-1, 3, 5-trien-7-one 5D (2.32g, 9.2mmol) and tetrahydrofuran (50mL), -a methylmagnesium bromide solution (4.3mL, 12.9mmol) was added at 78 ℃, stirred at room temperature for 2 hours, a saturated ammonium chloride solution (30mL) was added, stirred at room temperature for 1 hour, extracted with ethyl acetate (50mL × 2), the organic phases were combined and dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 20: 1) to give 5-benzyloxy-7-methyl-4-ethyl-bicyclo [4, 2, 0] octane-1 as a yellow oil, 3, 5-Trien-7-ol 5E (1.78g, 72.3% yield).

The fifth step: 2-benzyloxy-3-ethyl-8-methoxy-cyclo [4, 2, 0] octane-1, 3, 5-triene (5F)

2-(benzyloxy)-3-ethyl-8-methoxy-8-methylbicyclo[4.2.0]octa-1，3，5-triene

To a reaction flask were added 5-benzyloxy-7-methyl-4-ethyl-bicyclo [4, 2, 0] octane-1, 3, 5-trien-7-ol 5E (1.78g, 6.6mmol), p-toluenesulfonic acid (1.77g, 10.0mmol) and methanol (60mL), stirred at 70 ℃ for 3 hours, saturated sodium bicarbonate solution (10mL) was added to adjust PH > 7, extracted with ethyl acetate (50mL × 2), the organic phases were combined and dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 20: 1) to give 2-benzyloxy-3-ethyl-8-methoxybicyclo [4, 2, 0] octane-1, 3, 5-trien-5F (1.86g, yield 99.5%)

And a sixth step: 3-Ethyl-8-methoxy-8-methylcyclo [4.2.0] octane-1, 3, 5-trien-2-ol (Compound 5)

3-ethyl-8-methoxy-8-methylbicyclo[4.2.0]octa-1，3，5-trien-2-ol

To a reaction flask were added 2-benzyloxy-3-ethyl-8-methoxybicyclo [4, 2, 0] octane-1, 3, 5-triene 5F (1.86g, 6.6mmol), palladium on charcoal (0.19g, palladium content w/w ═ 10%), potassium carbonate (126mg, 0.9mmol), and methanol (20mL) in this order, and the mixture was stirred at room temperature for 4 hours under a hydrogen atmosphere, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 20: 1) to obtain 3-ethyl-8-methoxy-8-methylcyclo [4.2.0] octane-1, 3, 5-trien-2-ol compound 5(0.97g, yield 77.0%, HPLC: 98.67%) as a white solid.

MS m/z(ESI)：191.0[M-H].

¹H NMR(400MHz，CDCl₃)：87.09(d，1H)，6.69(d，1H)，3.38(d，1H)，3.34(s，3H)，2.95(d，1H)，2.62(q，2H)，1.70(s，3H)，1.22(t，3H).

Example 6

4-isopropyl-7-methoxy-7-methyl-bicyclo [4, 2, 0%]Octane-1, 3, 5-trien-5-ol (Compound 6)

4-isopropyl-7-methoxy-7-methyl-bicyclo[4.2.0]octa-1，3，5-trien-5-ol

The first step is as follows: 2- (benzyloxy) -3-isopropyl-8-methoxy-8-methylcyclo [4.2.0] octa-1, 3, 5-triene 6B

2-(benzyloxy)-3-isopropyl-8-methoxy-8-methylbicyclo[4.2.0]octa-1，3，5-triene

To a reaction flask were added 5-benzyloxy-4-isopropyl-7-methyl-bicyclo [4, 2, 0] octane-1, 3, 5-trien-7-ol 1B (0.56g, 2.0mmol), methanol (30mL) and p-toluenesulfonic acid (0.53g, 3.0mmol) in this order, stirred at 70 ℃ for 6 hours, adjusted to pH > 7 by addition of a saturated sodium bicarbonate solution, extracted with ethyl acetate (60mL × 2), the organic phases were combined and dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 50: 1) to give 2- (benzyloxy) -3-isopropyl-8-methoxy-8-methylcyclo [4.2.0] oct-1, 3 as a colorless oil, 5-triene 6B (0.37g, 62% yield).

The second step is that: 4-isopropyl-7-methoxy-7-methyl-bicyclo [4, 2, 0] octane-1, 3, 5-trien-5-ol (Compound 6)

4-isopropyl-7-methoxy-7-methyl-bicyclo[4.2.0]octa-1，3，5-trien-5-ol

To a reaction flask were added 2- (benzyloxy) -3-isopropyl-8-methoxy-8-methylcyclo [4.2.0] octa-1, 3, 5-triene 6B (2.00g, 7.0mmol), palladium on charcoal (0.37g, palladium content w/w ═ 10%) and methanol (100mL) in this order, reacted at room temperature for 4 hours under a hydrogen atmosphere, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 30: 1) to give 4-isopropyl-7-methoxy-7-methyl-pentacyclo [4, 2, 0] octane-1, 3, 5-trien-5-ol compound 6(0.60g, yield 41.1%, HPLC: 99.24%) as a white solid.

4-isopropyl-7-methoxy-7-methyl-bicyclo [4, 2, 0] octane-1, 3, 5-trien-5-ol compound 6(0.20g, 1mmol) was subjected to chiral resolution, and the chiral isomers were separated by a preparative instrument and a chiral column by an HPLC method (separation conditions: chiral column CHIRALPAK IC 250 × 4.6mm, mobile phase: n-hexane/dichloromethane/acetic acid (v/v/v) ═ 80/20/0.1, flow rate: 1.0 mL/min, UV ═ 254nm, column temperature: 35 ℃), the corresponding fractions were collected, and concentrated under reduced pressure to give compound 6-1(35.0mg, ee > 98%, RT ═ 5.79min) and compound 6-2(34.9mg, ee > 98%, RT ═ 6.51 min).

MS m/z(ESI)：205.1[M-1].

¹H NMR(400MHz，CDCl₃)：7.14(d，1H)，6.71(d，1H)，5.14(s，1H)，3.36(d，1H)，3.33(s，3H)，3.27-3.14(m，1H)，2.95(d，1H)，1.70(s，3H)，1.24(dd，6H).

Example 7

5-isopropyl-1, 2-dihydrocyclobutylphenyl-1, 6-diol (Compound 7)

5-isopropyl-1，2-dihydrocyclobutabenzene-1，6-diol

To a reaction flask were added 5-hydroxy-4-isopropyl-bicyclo [4, 2, 0] octane-1, 3, 5-trien-7-one compound 2(0.58g, 3.3mmol), methanol (15mL), and sodium borohydride (0.25g, 6.4mmol) in this order, stirred at room temperature for 25 minutes, a saturated ammonium chloride solution (4mL) was added, the organic phases were combined and dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 15: 1) to obtain 5-isopropyl-1, 2-dihydrocyclobutylphenyl-1, 6-diol compound 7(0.35g, yield 59.7%, HPLC: 98.82%) as a white solid.

MS m/z(ESI)：177.0[M-1].

¹H NMR(400MHz，DMSO)：7.02(d，1H)，6.55(d，1H)，5.31(d，1H)，5.20-4.98(m，1H)，3.28(dd，1H)，3.17(dq，1H)，2.72(d，1H)，2.50(s，1H)，1.12(d，6H).

Example 8

3-sec-butyl-8-methoxy-8-methylbicyclo [4.2.0]Octane-1, 3, 5-trien-2-ol (Compound 8)

3-(sec-butyl)-8-methoxy-8-methylbicyclo[4.2.0]octa-1，3，5-trien-2-ol

The first step is as follows: 2-bromo-6-sec-butylphenol (8B)

2-bromo-6-sec-butylphenol

2-Sec-butylphenol 8A (30g, 199.7mmol), dichloromethane (300mL) and diisopropylamine (2.02g, 19.9mmol) were added to a reaction flask in this order, N-bromosuccinimide (35.4g, 198.9mmol) was added at 0 ℃, stirred for 2 hours in an ice-water bath, 0.2M sulfuric acid (100mL) was added, washed with water (50 mL. times.2), washed with saturated brine (50 mL. times.2), the organic phases were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 2-bromo-6-sec-butylphenol 8B as a pale yellow oil (41g, 89.6% yield).

¹H NMR(400MHz，CDCl₃)：7.29(dd，1H)，7.09(dd，1H)，6.83-6.72(m，1H)，5.55(s，1H)，3.17-3.03(m，1H)，1.77-1.45(m，3H)，1.22(p，2H)，0.86(q，3H).

The second step is that: 2-benzyloxy-1-bromo-3-sec-butylbenzene (8C)

2-(benzyloxy)-1-bromo-3-sec-butylbenzene

2-bromo-6-sec-butylphenol 8B (40g, 175mmol), potassium carbonate (48g, 347mmol), bromobenzyl (30g, 175mmol) and acetonitrile (250mL) were added sequentially to a reaction flask, and the mixture was heated under reflux with stirring for 2 hours, cooled to room temperature, concentrated under reduced pressure, added with diethyl ether (100mL), filtered, and the filtrate was concentrated under reduced pressure to give 2-benzyloxy-1-bromo-3-sec-butylbenzene 8C as a colorless oil (52g, 93.3% yield).

¹H NMR(400MHz，CDCl₃)：7.57-7.53(m，2H)，7.40(ddd，4H)，7.17(dd，1H)，7.00(t，1H)，5.01-4.95(t，2H)，3.13(dd，1H)，1.63-1.51(m，3H)，1.21-1.15(m，2H)，0.86-0.77(m，3H).

The third step: 5-benzyloxy-4-sec-butyl-bicyclo [4, 2, 0] bicyclo-1, 3, 5-trien-7-one (8D)

5-benzyloxy-4-sec-butyl-bicyclo[4.2.0]octa-1，3，5-trien-7-one

To a reaction flask were added 2-benzyloxy-1-bromo-3-sec-butylbenzene 8C (25g, 78.3mmol), 1-diethoxyethylene 1e (18.18g, 156.5mmol), tetrahydrofuran (200mL), and sodium amide (6.04g, 154.8mmol) in this order, under nitrogen, heated under reflux for 15 hours, cooled to room temperature, added ice water (200mL), concentrated hydrochloric acid (30mL), stirred at room temperature for 2 hours, extracted with ethyl acetate (200mL × 2), the combined organic phases were dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) 50: 1) to give 5-benzyloxy-4-sec-butyl-bicyclo [4, 2, 0] bicyclo-1, 3, 5-trien-7-one 8D (6.21 g), yield 28.3%).

¹H NMR(400MHz，CDCl₃)：7.46(d，2H)，7.41-7.35(m，3H)，7.32(t，1H)7.02(d，1H)，5.51(s，2H)，3.88(s，2H)，3.15(dt，1H)，1.64-1.54(m，2H)，1.18(d，3H)，0.87-0.77(m，3H).

The fourth step: 5-benzyloxy-7-methyl-4-sec-butyl-bicyclo [4, 2, 0] octane-1, 3, 5-trien-7-ol (8E)

5-benzyloxy-7-methyl-4-sec-butyl-bicyclo[4.2.0]octa-1，3，5-trien-7-ol

To a reaction flask, 5-benzyloxy-4-sec-butyl-bicyclo [4, 2, 0] bicyclo-1, 3, 5-trien-7-one 8D (2.00g, 7.1mmol) and tetrahydrofuran (50mL) were added, a methylmagnesium bromide solution (8.6mL, 8.6mmol) was added at 78 ℃, the mixture was stirred at room temperature for 2 hours, a saturated ammonium chloride solution (30mL) was added, the mixture was stirred at room temperature for 1 hour, extracted with ethyl acetate (50mL × 2), the organic phases were combined and dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 20: 1) to give 5-benzyloxy-7-methyl-4-sec-butyl-bicyclo [4, 2, 0] octane-1 as a yellow oil, 3, 5-Trien-7-ol 8E (1.60g, 75.7% yield).

The fifth step: 2-benzyloxy-3-sec-butyl-8-methoxy-8-methylcyclo [4, 2, 0] octane-1, 3, 5-triene (8F)

2-(benzyloxy)-3-(sec-butyl)-8-methoxy-8-methylbicyclo[4.2.0]octa-1，3，5-triene

To a reaction flask, 5-benzyloxy-7-methyl-4-sec-butyl-bicyclo [4, 2, 0] octane-1, 3, 5-trien-7-ol 8E (1.17g, 4.0mmol), p-toluenesulfonic acid (1.06g, 6.0mmol) and methanol (36mL) were added, stirred at 70 ℃ for 3 hours, a saturated sodium bicarbonate solution (10mL) was added to adjust PH > 7, extracted with ethyl acetate (50mL × 2), the organic phases were combined and dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 20: 1) to give 2-benzyloxy-3-sec-butyl-8-methoxy-8-methylcyclo [4, 2, 0] octane-1 as a yellow oil, 3, 5-triene 8F (1.00g, yield 80.6%)

And a sixth step: 3-sec-butyl-8-methoxy-8-methylbicyclo [4.2.0] octane-1, 3, 5-trien-2-ol (Compound 8)

3-(sec-butyl)-8-methoxy-8-methylbicyclo[4.2.0]octa-1，3，5-trien-2-ol

2-benzyloxy-3-sec-butyl-8-methoxy-8-methylcyclo [4, 2, 0] octane-1, 3, 5-triene 8F (1.00g, 3.2mmol), palladium on charcoal (0.1g, palladium content w/w ═ 10%), potassium carbonate (0.45g, 3.2mmol), and methanol (100mL) were added in this order to a reaction flask, and stirred at room temperature for 4 hours under a hydrogen atmosphere, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 20: 1) to give 3-sec-butyl-8-methoxy-8-methylbicyclo [4.2.0] octane-1, 3, 5-trien-2-ol compound 8(0.28g, yield 39.4%, HPLC: 99.28%) as a white solid.

MS m/z(ESI)：218.9[M-H].

¹H NMR(400MHz，CDCl₃)：7.10(q，1H)，6.71(q，1H)，3.34(d，1H)，3.32(s，3H)，2.95(d，1H)，2.62(q，2H)，1.70(s，3H)，1.64-1.55(m，2H)，1.22(d，3H)，0.89-0.84(m，3H).

Example 9

5-hydroxy-4-isopropyl-7-methyl-bicyclo [4.2.0]Octane-1, 3, 5-triene-7-cyano (Compound 9)

5-hydroxy-4-isopropyl-7-methyl-bicyclo[4.2.0]octa-1，3，5-triene-7-carbonitrile

The first step is as follows: 5-benzyloxy-4-isopropyl-7-methyl-bicyclo [4.2.0] -1, 3, 5-triene-7-cyano (9B)

5-benzyloxy-4-isopropyl-7-methyl-bicyclo[4.2.0]octa-1，3，5-triene-7-carbonitrile

5-benzyloxy-4-isopropyl-7-methyl-bicyclo [4, 2, 0] octane-1, 3, 5-trien-7-ol 1B (1.12g, 3.2mmol) was charged into a reaction flask, dichloromethane (30mL) was added at 0 ℃ under nitrogen protection, trimethylsilyl cyanide (412mg, 4.2mmol) was added after stirring uniformly, boron trifluoride ether (4.68g, 33mmol) was slowly added dropwise, reaction was carried out at 0 ℃ for 3 hours, a saturated sodium bicarbonate solution was slowly added dropwise to terminate the reaction, extraction was carried out with dichloromethane (60 mL. times.2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was chromatographed on a silica gel column (petroleum ether/ethyl acetate (v/v): 200: 1) to give 5-benzyloxy-4-isopropyl-7-methyl-bicyclo [4.2.0] -1 as a yellow oil, 3, 5-triene-7-cyano 9B (943mg, 81% yield).

¹H NMR(400MHz，CDCl₃)7.49(dd，2H)，7.44-7.39(m，2H)，7.36(ddd，1H)，7.23(d，1H)，6.77(d，1H)，5.34-5.27(m，2H)，3.77(d，1H)，3.36(dq，1H)，3.19(d，1H)，1.90(s，3H)，1.18(t，6H).

The second step is that: 5-hydroxy-4-isopropyl-7-methyl-bicyclo [4.2.0] octane-1, 3, 5-triene-7-cyano (compound 9)

5-hydroxy-4-isopropyl-7-methyl-bicyclo[4.2.0]octa-1，3，5-triene-7-carbonitrile

Adding 5-benzyloxy-4-isopropyl-7-methyl-bicyclo [4.2.0] -1, 3, 5-triene-7-cyano 9B (940mg, 3.2mmol) and ethyl acetate (10mL) to a reaction flask, stirring uniformly, then adding potassium carbonate (446mg, 3.2mmol) and palladium on charcoal (100mg, palladium content w/w ═ 10%) in this order, stirring at room temperature under a hydrogen atmosphere for 1 hour, suction-filtering, adjusting PH of the filtrate with 2M hydrochloric acid to be less than 3, extracting with ethyl acetate (5mL × 2), combining the organic phases, drying over anhydrous sodium sulfate, filtering, concentrating under reduced pressure, beating the residue with petroleum ether, suction-filtering to obtain 5-hydroxy-4-isopropyl-7-methyl-bicyclo [4.2.0] octane-1, 3 as a white solid, 5-triene-7-cyano compound 9(363mg, yield 56%, HPLC: 99.30%).

Chiral resolution was performed on 5-hydroxy-4-isopropyl-7-methyl-bicyclo [4.2.0] octane-1, 3, 5-triene-7-cyano compound 9(2.0g, 10mmol), and chiral isomers were separated using preparative equipment and a chiral column by the HPLC method (separation conditions: chiral column CHIRALPAK AD-H, 20 × 250mm, 5 μm, mobile phase: n-hexane: isopropanol ═ 99: 1(v/v) isocratic elution for 45 minutes, flow rate: 12.0 mL/min, UV ═ 220/275nm, column temperature: 25 ℃), and the corresponding fractions were collected and concentrated under reduced pressure to give compound 9-1(860mg, ee > 99%, RT ═ 28.97min) and compound 9-2(875mg, ee > 99%, RT ═ 37.24 min).

MS m/z(ESI)：202.1[M+1].

¹H NMR(400MHz，CDCl₃)7.17(d，1H)，6.69(d，1H)，6.14(s，1H)，3.69(d，1H)，3.22(dt，1H)，3.15(d，1H)，，1.85(s，3H)，1.22(dd，6H).

Example 10

8-ethoxy-3-isopropyl-8-methylcyclo [4.2.0]Octane-1, 3, 5-trien-2-ol (Compound 10)

8-ethoxy-3-isopropyl-8-methylbicyclo[4.2.0]octa-1，3，5-trien-2-ol

The first step is as follows: 2- (benzyloxy) -8-ethoxy-3-isopropyl-8-methylcyclo [4.2.0] octane-1, 3, 5-triene (10B)

2-(benzyloxy)-8-ethoxy-3-isopropyl-8-methylbicyclo[4.2.0]octa-1，3，5-triene

To a reaction flask were added 5-benzyloxy-4-isopropyl-7-methyl-bicyclo [4, 2, 0] octane-1, 3, 5-trien-7-ol 1B (1.13g, 4.0mmol), ethanol (30mL), and p-toluenesulfonic acid (1.06g, 6.0mmol) in this order, stirred at 70 ℃ for 4 hours, adjusted to pH > 7 by addition of a saturated sodium bicarbonate solution, extracted with dichloromethane (80mL × 2), the organic phases were combined and dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 50: 1) to give 2- (benzyloxy) -8-ethoxy-3-isopropyl-8-methylcyclo [4.2.0] octane-1 as a yellow oil, crude 3, 5-triene compound 10B (1.45g, 93.5% yield) was used directly in the next reaction.

The second step is that: 8-ethoxy-3-isopropyl-8-methylcyclo [4.2.0] octane-1, 3, 5-trien-2-ol (Compound 10)

8-ethoxy-3-isopropyl-8-methylbicyclo[4.2.0]octa-1，3，5-trien-2-ol

To a reaction flask were added 2- (benzyloxy) -8-ethoxy-3-isopropyl-8-methylcyclo [4.2.0] octane-1, 3, 5-triene 10B (1.14g, 3.7mmol), palladium on charcoal (0.11g, palladium content w/w ═ 10%), potassium carbonate (0.51g, 3.7mmol) and methanol (60mL) in this order, stirred at room temperature for 1.5 hours under a hydrogen atmosphere, filtered, the filtrate was acidified with 3M hydrochloric acid, extracted with dichloromethane (80mL × 2), the organic phases were combined and dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 15: 1) to give 8-ethoxy-3-isopropyl-8-methylcyclo [4.2.0] octane-1 as a yellow oil, 3, 5-triene-2-ol Compound 10(0.44g, yield 54%, HPLC: 95.10%).

MS m/z(ESI)：219.2[M-1].

¹H NMR(400MHz，CDCl₃)7.15(d，1H)，6.71(d，1H)，5.70(s，1H)，3.63-3.52(m，1H)，3.51-3.41(m，1H)，3.34(t，1H)，3.23(dt，1H)，3.00-2.91(m，1H)，1.71(d，3H)，1.27-1.20(m，9H).

Example 11

8-Isopropoxy-3-isopropyl-8-methylcyclo [4.2.0]Octane-1, 3, 5-trien-2-ol (Compound 11)

8-isopropoxy-3-isopropyl-8-methylbicyclo[4.2.0]octa-1，3，5-trien-2-ol

The first step is as follows: 2- (benzyloxy) -8-isopropoxy-3-isopropyl-8-methylcyclo [4.2.0] octane-1, 3, 5-triene (11B)

2-(benzyloxy)-8-isopropoxy-3-isopropyl-8-methylbicyclo[4.2.0]octa-1，3，5-triene

To a reaction flask were added 5-benzyloxy-4-isopropyl-7-methyl-bicyclo [4, 2, 0] octane-1, 3, 5-trien-7-ol 1B (0.55g, 2.0mmol), isopropanol (30mL), and p-toluenesulfonic acid (0.53g, 3.0mmol) in this order, stirred at 70 ℃ overnight, adjusted to pH > 7 by addition of saturated sodium bicarbonate solution, extracted with dichloromethane (60mL × 2), the organic phases were combined and dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 40: 1) to give 2- (benzyloxy) -8-isopropoxy-3-isopropyl-8-methylcyclo [4.2.0] octane-1 as a colorless oil, 3, 5-triene 11B (0.47g, 74% yield).

¹H NMR(400MHz，CDCl3)7.46(d，2H)，7.39(dd，2H)，7.31(dd，1H)，7.18(d，1H)，6.73(d，1H)，5.30(dd，2H)，3.76(dt，1H)，3.44-3.35(m，1H)，3.32(d，1H)，3.06(d，1H)，1.74(s，3H)，1.241.16(m，9H)，1.12(d，J＝6.1Hz，3H).

The second step is that: 8-Isopropoxy-3-isopropyl-8-methylcyclo [4.2.0] octane-1, 3, 5-trien-2-ol (Compound 11)

8-isopropoxy-3-isopropyl-8-methylbicyclo[4.2.0]octa-1，3，5-trien-2-ol

2- (benzyloxy) -8-isopropoxy-3-isopropyl-8-methylcyclo [4.2.0] octane-1, 3, 5-triene 11B (0.39g, 1.2mmol), palladium on charcoal (0.04g, palladium content w/w ═ 10%), potassium carbonate (0.17g, 1.2mmol), and ethyl acetate (30mL) were added in this order to a reaction flask, and stirred at room temperature for 2 hours under a hydrogen atmosphere, followed by filtration, the filtrate was adjusted to pH 3 with 3M hydrochloric acid, extracted with ethyl acetate (60 mL. times.2), the organic phases were combined and dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v): 30: 1) to give 8-isopropoxy-3-isopropyl-8-methylcyclo [4.2.0] octane-1 as a yellow oil, 3, 5-triene-2-ol Compound 11(0.21g, yield 75%, HPLC: 95.58%).

MS m/z(ESI)：233.3[M-1].

¹H NMR(400MHz，CDCl₃)7.14(d，1H)，6.70(d，1H)，5.28(s，1H)，3.77(dt，1H)，3.28(d，1H)，3.21(dd，1H)，3.01(d，1H)，1.68(s，3H)，1.23(dd，6H)，1.19(d，3H)，1.13(d，3H).

Example 12

8-butoxy-3-isopropyl-8-methylcyclo [4.2.0]Octane-1, 3, 5-trien-2-ol (Compound 12)

8-butoxy-3-isopropyl-8-methylbicyclo[4.2.0]octa-1，3，5-trien-2-ol

The first step is as follows: 2- (benzyloxy) -8-butoxy-3-isopropyl-8-methylcyclo [4.2.0] octane-1, 3, 5-triene (12B)

2-(benzyloxy)-8-butoxy-3-isopropyl-8-methylbicyclo[4.2.0]octa-1，3，5-triene

To a reaction flask were added 5-benzyloxy-4-isopropyl-7-methyl-bicyclo [4, 2, 0] octane-1, 3, 5-trien-7-ol 1B (0.56g, 2.0mmol), n-butanol (30mL) and p-toluenesulfonic acid (0.53g, 3.0mmol) in this order, stirred at 70 ℃ for 6 hours, adjusted to pH > 7 by addition of a saturated sodium bicarbonate solution, extracted with ethyl acetate (60mL × 2), the organic phases were combined and dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v): 50: 1) to give 2- (benzyloxy) -8-butoxy-3-isopropyl-8-methylcyclo [4.2.0] octane-1 as a colorless oil, 3, 5-triene 12B (0.55g, 81% yield).

¹H NMR(400MHz，CDCl₃)7.45(d，2H)，7.39(t，2H)，7.32(t，1H)，7.19(d，1H)，6.74(d，1H)，5.23(dd，2H)，3.53-3.46(m，1H)，3.44(d，1H)，3.41-3.33(m，2H)，2.96(d，1H)，1.75(s，3H)，1.56(td，2H)，1.41-1.29(m，2H)，1.21(t，6H)，0.87(t，3H).

The second step is that: 8-butoxy-3-isopropyl-8-methylcyclo [4.2.0] octane-1, 3, 5-trien-2-ol (Compound 12)

8-butoxy-3-isopropyl-8-methylbicyclo[4.2.0]octa-1，3，5-trien-2-ol

To a reaction flask were added 2- (benzyloxy) -8-butoxy-3-isopropyl-8-methylcyclo [4.2.0] octa-1, 3, 5-triene 12B (0.55g, 1.6mmol), palladium on charcoal (55mg, palladium content w/w ═ 10%), potassium carbonate (0.22g, 1.6mmol), and ethyl acetate (20mL) in this order, stirred at room temperature for 2 hours under a hydrogen atmosphere, filtered, the filtrate was adjusted to pH 3 with 3M hydrochloric acid, extracted with ethyl acetate (60mL × 2), the organic phases were combined and dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 50: 1) to give 8-butoxy-3-isopropyl-8-methylcyclo [4.2.0] octane-1 as a yellow oil, 3, 5-triene-2-ol Compound 12(0.34g, yield 83.58%, HPLC: 98%).

MS m/z(ESI)：233.3[M-1].

¹H NMR(400MHz，CDCl₃)7.14(d，1H)，6.71(d，1H)，5.03(t，1H)，3.49(dt，1H)，3.43-3.36(m，1H)，3.33(d，1H)，3.21(dt，1H)，2.96(d，1H)，1.69(s，3H)，1.55(dd，2H)，1.42-1.32(m，2H)，1.24(d，6H)，0.93-0.86(m，3H).

Example 13

8-azido-3-isopropyl-8-methylcyclo [4.2.0]Octane-1, 3, 5-trien-2-ol (Compound 13)

8-azido-3-isopropyl-8-methylbicyclo[4.2.0]octa-1，3，5-trien-2-ol

The first step is as follows: 8-azido-3-isopropyl-8-methylcyclo [4.2.0] octane-1, 3, 5-trien-2-ol (Compound 13)

8-azido-3-isopropyl-8-methylbicyclo[4.2.0]octa-1，3，5-trien-2-ol

To a reaction flask were added 4-isopropyl-7-methoxy-7-methyl-bicyclo [4, 2, 0] octane-1, 3, 5-triene-5-ol compound 6(1.5g, 7.3mmol), sodium azide (1.6g, 23.3mmol), nitrogen protected, dichloromethane (180mL), trifluoroacetic acid (3.6mL, 46mmol) slowly added dropwise at 0 ℃, naturally warmed to room temperature overnight, sodium bicarbonate particles were slowly added to terminate the reaction, the reaction was filtered, the filtrate was concentrated under reduced pressure, and the residue was chromatographically purified (petroleum ether/ethyl acetate (v/v) 100: 1) to give 8-azido-3-isopropyl-8-methyl-bicyclo [4.2.0] octane-1, 3, 5-triene-2-ol compound 13(1.33g, yield 84%).

MS m/z(ESI)：175.1[M-N₃].

¹H NMR(400MHz，CDCl₃)7.17(d，1H)，6.73(d，1H)，5.15(s，1H)，3.36(d，1H)，3.22-3.11(m，2H)，1.73(s，3H)，1.25(dd，6H).

Example 14

3-isopropyl-8- (2-methoxyethoxy) -8-methylcyclo [4.2.0]Octane-1, 3, 5-trien-2-ol (esterified) Compound 14)

3-isopropyl-8-(2-methoxyethoxy)-8-methylbicyclo[4.2.0]octa-1，3，5-trien-2-ol

The first step is as follows: 2- (benzyloxy) -3-isopropyl-8- (2-methoxyethoxy) -8-methylocyclo [4.2.0] octane-1, 3, 5-triene (14B)

2-(benzyloxy)-3-isopropyl-8-(2-methoxyethoxy)-8-methylbicyclo[4.2.0]octa-1，3，5-triene

5-benzyloxy-4-isopropyl-7-methyl-bicyclo [4, 2, 0] octane-1, 3, 5-trien-7-ol 1B (0.56g, 2.0mmol), ethylene glycol monomethyl ether (30mL) and p-toluenesulfonic acid (0.53g, 3.0mmol) were added to a reaction flask in this order, stirred at 70 ℃ for 3 hours, adjusted to pH > 7 by addition of a saturated sodium bicarbonate solution, extracted with ethyl acetate (60 mL. times.2), the organic phases were combined and dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v): 40: 1) to give 2- (benzyloxy) -3-isopropyl-8- (2-methoxyethoxy) -8-methyl-bicyclo [4.2.0] octane-1 as a brown oil, 3, 5-triene 14B (0.53g, 78% yield).

¹H NMR(400MHz，CDCl₃)7.49-7.45(m，2H)，7.42-7.36(m，2H)，7.35-7.29(m，1H)，7.19(d，1H)，6.73(d，1H)，5.25(dd，2H)，3.66(dt，1H)，3.59-3.54(m，1H)，3.54-3.50(m，2H)，3.47(d，1H)，3.43-3.33(m，1H)，3.32(s，3H)，2.99(d，1H)，1.79(s，3H)，1.20(t，6H).

The second step is that: 3-isopropyl-8- (2-methoxyethoxy) -8-methylcyclo [4.2.0] octane-1, 3, 5-trien-2-ol (Compound 14)

3-isopropyl-8-(2-methoxyethoxy)-8-methylbicyclo[4.2.0]octa-1，3，5-trien-2-ol

To a reaction flask were added 2- (benzyloxy) -3-isopropyl-8- (2-methoxyethoxy) -8-methylcyclo [4.2.0] octane-1, 3, 5-triene 14B (0.53g, 1.6mmol), palladium on charcoal (0.57g, palladium content w/w ═ 10%), potassium carbonate (0.6g, 4.3mmol), and ethyl acetate (30mL) in this order, stirred at room temperature for 4 hours under a hydrogen atmosphere, filtered, the filtrate was adjusted to pH 3 with 3M hydrochloric acid, extracted with ethyl acetate (60mL × 2), the combined organic phases were dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 100: 1) to give 3-isopropyl-8- (2-methoxyethoxy) -8-methylcyclo [4.2.0] octane-1 as a yellow oil, 3, 5-triene-2-ol Compound 14(0.25g, yield 65%, HPLC: 97.80%).

MS m/z(ESI)：249.3[M-1].

¹H NMR(400MHz，CDCl₃)7.28(s，1H)，7.15(d，1H)，6.69(d，1H)，3.74-3.62(m，3H)，3.53-3.47(m，1H)，3.45(s，3H)，3.35-3.19(m，2H)，2.99(d，1H)，1.68(s，3H)，1.23(dd，6H).

Example 15

8-Ethyl-3-isopropyl-8-methoxycyclo [4.2.0]]Octane-1, 3, 5-trien-2-ol (Compound 15)

8-ethyl-3-isopropyl-8-methoxybicyclo[4.2.0]octa-1，3，5-trien-2-ol

The first step is as follows: 2- (benzyloxy) -8-ethyl-3-isopropyl-8-methoxycyclo [4.2.0] octane-1, 3, 5-triene (15B)

2-(benzyloxy)-8-ethyl-3-isopropyl-8-methoxybicyclo[4.2.0]octa-1，3，5-triene

To a reaction flask were added 5-benzyloxy-7-ethyl-4-isopropyl-bicyclo [4, 2, 0] octane-1, 3, 5-trien-7-ol 3B (1.48g, 5.0mmol), methanol (45mL), and p-toluenesulfonic acid (1.33g, 7.5mmol) in this order, stirred at 70 ℃ for 3 hours, a saturated sodium bicarbonate solution was added to adjust pH > 7, the mixture was concentrated under reduced pressure, extracted with ethyl acetate (60mL × 2), the organic phases were combined and dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 100: 1) to give 2- (benzyloxy) -8-ethyl-3-isopropyl-8-methoxybicyclo [4.2.0] octane-1 as a yellow solid, crude 3, 5-triene 15B (1.55g) was directly subjected to the next reaction.

The second step is that: 8-Ethyl-3-isopropyl-8-methoxycyclo [4.2.0] octane-1, 3, 5-trien-2-ol (Compound 15)

8-ethyl-3-isopropyl-8-methoxybicyclo[4.2.0]octa-1，3，5-trien-2-ol

To a reaction flask were added 2- (benzyloxy) -8-ethyl-3-isopropyl-8-methoxybicyclo [4.2.0] octane-1, 3, 5-triene 15B (1.45g, 4.7mmol), palladium on charcoal (0.15g, palladium content w/w ═ 10%), potassium carbonate (0.65g, 4.7mmol) and ethyl acetate (50mL) in this order, stirred at room temperature for 3 hours under a hydrogen atmosphere, filtered, the filtrate was adjusted to pH 3 with 3M hydrochloric acid, extracted with ethyl acetate (60mL × 2), the organic phases were combined and dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 60: 1) to give 8-ethyl-3-isopropyl-8-methoxybicyclo [4.2.0] octane-1 as a yellow oil, 3, 5-triene-2-ol Compound 15(0.42g, yield 41%, HPLC: 97.19%).

MS m/z(ESI)：219.0[M-1].

1H NMR(400MHz，CDCl₃)7.14(d，1H)，6.71(d，1H)，5.34(s，1H)，3.32(s，3H)，3.27(d，1H)，3.21(dd，1H)，2.95(d，1H)，2.40(t，1H)，1.99(q，2H)，1.24(dd，6H)，1.06-1.01(m，3H)。

Example 16

8-cyclopropyl-3-isopropyl-bicyclo [4.2.0]Octane-1, 3, 5-trien-2-ol (Compound 16)

8-cyclopropyl-3-isopropylbicyclo[4.2.0]octa-1，3，5-trien-2-ol

The first step is as follows: 5- (benzyloxy) -7-cyclopropyl-4-isopropylbicyclo [4.2.0] octane-1, 3, 5-trien-7-ol (16B)

5-(benzyloxy)-7-cyclopropyl-4-isopropylbicyclo[4.2.0]octa-1，3，5-trien-7-ol

Adding 5-benzyloxy-4-isopropyl-bicyclo [4, 2, 0] octane-1, 3, 5-trien-7-one 1f (6.0g, 22.6mmol) and tetrahydrofuran (150mL) into a reaction flask, slowly adding a cyclopropyl magnesium bromide solution (35mL, 35mmol) dropwise at-78 ℃ under the protection of nitrogen, naturally raising the temperature to room temperature after the addition of the cyclopropyl magnesium bromide solution for reaction for 3 hours, adding a saturated ammonium chloride solution (200mL), stirring at room temperature for 20 minutes, extracting with ethyl acetate (100 mL. times.2), combining the organic phases, concentrating under reduced pressure, separating and purifying the residue by silica gel column chromatography (petroleum ether/ethyl acetate (v/v): 50: 1) to obtain 5- (benzyloxy) -7-cyclopropyl-4-isopropyl-bicyclo [4.2.0] octane-1 as a yellow oil, 3, 5-Trien-7-ol 16B (2.7g, 39% yield).

The second step is that: 2- (benzyloxy) -8-cyclopropyl-3-isopropylcyclo [4.2.0] octane-1, 3, 5-triene (16C)

2-(benzyloxy)-8-cyclopropyl-3-isopropylbicyclo[4.2.0]octa-1，3，5-triene

To a reaction flask were added 5- (benzyloxy) -7-cyclopropyl-4-isopropylbicyclo [4.2.0] octane-1, 3, 5-trien-7-ol 16B (700mg, 2.3mmol), dichloromethane (30mL) and triethylsilane (20mL, 105.6mmol) in this order, trifluoroacetic acid (2.5mL, 32mmol) was slowly added dropwise at 0 ℃, followed by stirring at 0 ℃ for 2 hours, a saturated sodium bicarbonate solution (60mL) was added, stirring at room temperature for 1 hour, extraction with dichloromethane (60mL × 2) was carried out, the organic phases were combined, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 30: 1) to give 2- (benzyloxy) -8-cyclopropyl-3-isopropylbicyclo [4.2.0] octane-1 as a colorless oil, 3, 5-Triene 16C (450mg, 74% yield).

The third step: 8-cyclopropyl-3-isopropylbicyclo [4.2.0] octane-1, 3, 5-trien-2-ol (Compound 16)

8-cyclopropyl-3-isopropylbicyclo[4.2.0]octa-1，3，5-trien-2-ol

To a reaction flask were added 2- (benzyloxy) -8-cyclopropyl-3-isopropylbicyclo [4.2.0] octane-1, 3, 5-triene 16C (450mg, 1.5mmol), palladium on charcoal (45mg, palladium content w/w ═ 10%), potassium carbonate (0.21g, 1.5mmol), and ethyl acetate (45.0mL) in this order, and the mixture was stirred at room temperature for 3 hours under a hydrogen atmosphere, followed by filtration, adjusting the pH of the filtrate to 3 with 3M hydrochloric acid, extraction with ethyl acetate (30mL × 2), combining the organic phases, drying over anhydrous sodium sulfate, filtration, concentration of the filtrate under reduced pressure, and separation and purification of the residue by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 60: 1) to give 8-cyclopropyl-3-isopropylbicyclo [4.2.0] octane-1, 3, 5-triene-2-ol compound 16(265mg, yield 85%, HPLC: 97.24%).

MS m/z(ESI)：201.0[M-1].

¹H NMR(400MHz，CDCl₃)7.08(d，1H)，6.67(d，1H)，4.52(s，1H)，3.23(ddd，2H)，2.97-2.90(m，1H)，2.84(dd，1H)，1.24(dd，6H)，1.12-1.01(m，1H)，0.60(t，1H)，0.59-0.57(m，1H)，0.400.34(m，1H)，0.28-0.21(m，1H).

Example 17

5-bromo-3-isopropyl-8-methoxy-8-methylcyclo [4.2.0]Octane-1, 3, 5-trien-2-ol (compound) 17)

5-bromo-3-isopropyl-8-methoxy-8-methylbicyclo[4.2.0]octa-1，3，5-trien-2-ol

The first step is as follows: 5- (benzyloxy) -2-bromo-4-isopropylocyclo [4.2.0] octane-1, 3, 5-trien-7-one (17B)

5-(benzyloxy)-2-bromo-4-isopropylbicyclo[4.2.0]octa-1，3，5-trien-7-one

To a reaction flask were added 5-benzyloxy-4-isopropyl-bicyclo [4, 2, 0] octane-1, 3, 5-trien-7-one 1f (1.00g, 3.8mmol, intermediate 1) and glacial acetic acid (50mL), and benzyltrimethylammonium tribromide (6.59g, 16.9mmol) and zinc chloride (1.28g, 9.4mmol) were added, followed by stirring at room temperature for 5 hours. After completion of the reaction, water (40mL), sodium thiosulfate (2.5g, 10mmol) were added, extraction was performed with dichloromethane (40mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate (v/v) ═ 10: 1) to give 5- (benzyloxy) -2-bromo-4-isopropylcyclo [4.2.0] octane-1, 3, 5-trien-7-one 17B as a pale yellow solid (1.02g, 78% yield).

¹H NMR(400MHz，DMSO)7.57(s，1H)，7.41(m，5H)，5.44(s，2H)，3.93(s，2H)，3.22(dt，1H)，1.15(d，6H).

The second step is that: 5- (benzyloxy) -2-bromo-4-isopropyl-7-methylcyclo [4.2.0] octane-1, 3, 5-trien-7-ol (17C)

5-(benzyloxy)-2-bromo-4-isopropyl-7-methylbicyclo[4.2.0]octa-1，3，5-trien-7-ol

5- (benzyloxy) -2-bromo-4-isopropylcyclo [4.2.0] octane-1, 3, 5-trien-7-one 17B (1.01g, 2, 9mmol) and toluene (15mL) were added to a reaction flask under a nitrogen atmosphere, 3M methylmagnesium bromide (1.46mL, 4.4mmol) was slowly added dropwise at 78 ℃, and after completion of the addition, the temperature was slowly raised to room temperature for reaction for 3 hours. After the reaction was complete, the reaction was quenched by addition of saturated aqueous ammonium chloride (10 mL). The aqueous layer was extracted with dichloromethane (10mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: dichloromethane (v/v) ═ 10: 1) to give 5- (benzyloxy) -2-bromo-4-isopropyl-7-methylcyclo [4.2.0] octane-1, 3, 5-trien-7-ol 17C as a pale yellow solid (0.95g, 90% yield).

¹H NMR(400MHz，CDCl₃)7.40(d，5H)，7.23(s，1H)，5.30(m，3H)，3.24(m，3H)，1.77(s，3H)，1.18(dd，6H).

The third step: 2- (benzyloxy) -5-bromo-3-isopropyl-8-methoxy-8-methylcyclo [4.2.0] octane-1, 3, 5-triene (17D)

2-(benzyloxy)-5-bromo-3-isopropyl-8-methoxy-8-methylbicyclo[4.2.0]octa-1，3，5-triene

5- (benzyloxy) -2-bromo-4-isopropyl-7-methylcyclo [4.2.0] octane-1, 3, 5-trien-7-ol 17C (0.94g, 2.6mmol) was charged into a reaction flask, p-toluenesulfonic acid (0.69g, 3.9mmol) and methanol (30ml) were sequentially added, and the mixture was heated to reflux for 48 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, a saturated aqueous sodium bicarbonate solution (10mL) was added, water 10(mL) was added, the aqueous layer was extracted with dichloromethane (20mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate (v/v) ═ 5: 1) to give 2- (benzyloxy) -5-bromo-3-isopropyl-8-methoxy-8-methylcyclo-cyclo [4.2.0] octane-1, 3, 5-triene 17D (0.85g, yield 87%) as a colorless transparent oily liquid.

¹H NMR(400MHz，DMSO)7.39(d，5H)，7.25(s，1H)，5.16(s，2H)，3.38(d，1H)，3.21(d，4H)，2.86(d，1H)，1.67(s，3H)，1.14(m，6H).

The fourth step: 5-bromo-3-isopropyl-8-methoxy-8-methylcyclo [4.2.0] octane-1, 3, 5-trien-2-ol (Compound 17)

5-bromo-3-isopropyl-8-methoxy-8-methylbicyclo[4.2.0]octa-1，3，5-trien-2-ol

Under the protection of nitrogen atmosphere, 2- (benzyloxy) -5-bromo-3-isopropyl-8-methoxy-8-methyl-cyclo [4.2.0] octane-1, 3, 5-triene 17D (0.55g, 1.4mmol) and dichloromethane (15mL) are added into a reaction bottle, a solution of boron tribromide (0.3mL, 2.9mmol) in dichloromethane (5mL) is added dropwise into the reaction system at-15 ℃, and after the dropwise addition is finished, the temperature is raised to 0 ℃ for reaction for 0.5 hour. After completion of the reaction, methanol (3mL) was added to quench the reaction, water (15mL) was added, extraction was performed with methylene chloride (15mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate (v/v) ═ 20: 1) to give 5-bromo-3-isopropyl-8-methoxy-8-methylcyclo [4.2.0] octane-1, 3, 5-trien-2-ol compound 17(0.22g, yield 53.6%, HPLC: 96.38%) as a pale yellow solid.

MS m/z(ESI)：283.9，284.8[M-1].

¹H NMR(400MHz，DMSO)9.47(s，1H)，7.11(s，1H)，3.17(m，5H)，2.78(d，1H)，1.61(s，3H)，1.13(d，6H).

Biological test example

Mouse righting reflex experiment

Purpose of the experiment: the anesthetic effect of the test compounds was studied using a mature mouse model of anesthesia (RatnakumariLingamani et al (2001). Anestheology, 94, 1050-7). ED (electronic device)₅₀(half effective amount), LD₅₀(median lethal dose), TI (therapeutic index, TI ═ LD)₅₀/ED₅₀) SI (safety index, SI ═ LD)₅/ED₉₅) The anesthesia effect and safety are evaluated by indexes such as anesthesia induction time, anesthesia maintenance time, MTD (maximum tolerated dose) and the like.

The instrument equipment comprises: electronic balances (sartorius, BSA224S-Cw), Vortex oscillators (Linbel, Vortex-5), etc.

Experimental animals: SPF grade ICR mice (SCXY-2008-24-WUDUDOU Biotechnology Co., Ltd.), 18-22g, half male and half female.

The experimental method comprises the following steps: the test compound was formulated to the desired concentration in a solvent of 10% DMSO, 15% solutol HS15, 75% saline, and ready for use. Experimental animals were fasted for 12 hours after acclimation in the laboratory environment. The following day was dosed at a volume of 10ml/kg, and after intravenous injection, the disappearance and recovery times of the righting reflex were recorded. The time from disappearance of righting reflex to recovery of righting reflex after administration is anesthesia induction time, the time from disappearance of righting reflex to recovery of righting reflex is anesthesia duration time, and the anesthesia induction time and the anesthesia duration time are used for representing the strength of anesthesia.

The experimental results are as follows: see tables 1 and 2.

TABLE 1 evaluation of pharmacodynamic Activity in mice

TABLE 2 evaluation of safe dose

And (4) conclusion: the compound has good activity, quick response and high therapeutic index and safety index.

Claims (14)

1. A compound represented by the general formula (I) or a chiral isomer, a pharmaceutically acceptable salt thereof:

wherein:

r is selected from

R¹、R²And R³Each independently selected from H or C_1-6An alkyl group;

r' is selected from H;

r' is selected from H;

R⁴、R⁵each independently selected from H, hydroxy, C_1-6Alkyl, cyano, azido, C_1-6Alkoxy or 3 to 8 membered carbocyclyl, said alkyl, alkoxy or carbocyclyl optionally being further substituted by 0 to 3 substituents selected from C_1-6Alkyl or C_1-6Substituted by a substituent of alkoxy;

R⁶and R⁷Each is independently selected from H;

alternatively, R⁴And R⁵May form (═ O);

with the proviso that the following compounds are excluded:

2. the compound according to claim 1, wherein the compound is selected from compounds represented by the general formula (II):

wherein:

R¹、R²and R³Each independently selected from H or C_1-4Alkyl radical, wherein R¹、R²And R³At least one group is H;

R⁴and R⁵Each independently selected from H, hydroxy, C_1-4Alkyl, cyano, azido, C_1-4Alkoxy or 3 to 5 membered carbocyclyl, said alkyl, alkoxy or carbocyclyl optionally being further substituted by 0 to 3 substituents selected from C_1-4Alkyl or C_1-4Substituted by a substituent of alkoxy.

3. A compound according to claim 2, or a chiral isomer, pharmaceutically acceptable salt thereof, wherein:

R¹、R²and R³Each independently selected from H, methyl, ethyl, n-propyl or isopropyl, wherein R¹、R²And R³At least one group is H;

R⁴and R⁵Each independently selected from H, hydroxy, methyl, ethyl, n-propyl, isopropyl, cyano, azido, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, cyclopropyl or cyclobutyl.

4. A compound according to claim 3, or a chiral isomer, pharmaceutically acceptable salt thereof, wherein:

R¹、R²and R³Each independently selected from H, methyl or ethyl, wherein R¹、R²And R³At least one group is H;

R⁴and R⁵Each independently selected from H, hydroxy, methyl, ethyl, cyano, azido, methoxy, ethoxy, isopropoxy, n-butoxy or cyclopropyl.

5. The compound according to claim 1, or a chiral isomer, a pharmaceutically acceptable salt thereof, wherein said compound is selected from the group consisting of:

6. a process for preparing a compound according to any one of claims 1-5, comprising:

carrying out Grignard reaction on the compound of the general formula (I-b) to obtain a compound of the general formula (I-c);

removing hydroxyl from the compound of the general formula (I-c) under reducing conditions to obtain a compound of the general formula (I-d); or reacting the compound of the general formula (I-c) with cyanide, azide or an alcohol solution under acidic conditions to obtain a compound of the general formula (I-d);

removing R from the compound of the general formula (I-d)¹⁰To obtain a compound of the general formula (I), wherein R¹⁰Selected from methyl, methoxymethyl, ethyl, benzyl, p-methoxybenzyl, trityl, trimethylsilyl or tert-butyldimethylsilyl, R, R ' and R ', R '⁴、R⁵、R⁶And R⁷The definitions of (a) and (b) are in accordance with those stated for the compounds of the general formula (I).

7. A pharmaceutical composition comprising: a compound according to any one of claims 1 to 5, or a chiral isomer, a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers and/or excipients.

8. A pharmaceutical composition comprising: a compound as claimed in any one of claims 1 to 5, and one or more therapeutic agents selected from opioid analgesics, sedative hypnotics or cardiovascular agents.

9. The pharmaceutical composition according to claim 7 or 8, which is in any pharmaceutically acceptable dosage form.

10. The pharmaceutical composition according to claim 9, wherein the dosage form is selected from the group consisting of lipid emulsion, injection, tablet, aerosol, powder spray, film, granule, capsule, ointment, suppository, cream, implant, syrup, oral solution, oral suspension, oral emulsion, dispersion tablet, lyophilized powder for injection, powder, or gel.

11. The pharmaceutical composition according to claim 10, wherein the dosage form is selected from a lyophilized powder injection, an injection or a lipid emulsion.

12. Use of a compound of any one of claims 1-5, or a chiral isomer, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of any one of claims 7-11, for the manufacture of a medicament in the central nervous field.

13. The use according to claim 12, wherein the central nervous field drug comprises: drugs for inducing and maintaining anesthesia in animals or humans, drugs for promoting sedation and hypnosis in animals or humans, or drugs for treating and/or preventing anxiety, depression, insomnia, nausea, vomiting, migraine, schizophrenia, convulsions, epilepsy.

14. The use according to claim 13, wherein the central nervous field drug comprises a drug for inducing and maintaining anesthesia in animals or humans.