WO2014180327A1

WO2014180327A1 - Phenol derivative, method of preparing same, and pharmaceutical application of same

Info

Publication number: WO2014180327A1
Application number: PCT/CN2014/077051
Authority: WO
Inventors: 张晨; 李芳琼; 黄安邦; 雷鸣; 王健民; 何平; 魏用刚; 邓炳初
Original assignee: 四川海思科制药有限公司
Priority date: 2013-05-10
Filing date: 2014-05-08
Publication date: 2014-11-13
Also published as: CN104507898B; HK1206329A1; CN104507898A

Abstract

The present invention relates to a phenol derivative, a method of preparing same, and a pharmaceutical application of same, and more particularly, the present invention relates to a compound shown by the general formula (I) or a stereoisomer, a solvate, a metabolite, a pharmaceutically acceptable salt, an eutectic or a prodrug of same, methods of preparing same, a pharmaceutical composition containing same, and use of the compound or composition of the present invention in the field of central nervous, where the definition of each substituent in the general formula (I) is the same as the that defined in the specification.

Description

苯酚衍生物及其制备方法和在医药上的应用技术领域 Phenol derivative, preparation method thereof and application in medicine

本发明涉及一种通式所示的苯酚衍生物，其立体异构体、药学上可用的盐、共晶或前药，其制备方法，包含其的药物组合物，以及本发明的化合物和组合物在中枢神经领域的用途。背景技术 The present invention relates to a phenol derivative represented by the formula, a stereoisomer thereof, a pharmaceutically usable salt, a eutectic or a prodrug, a process for the preparation thereof, a pharmaceutical composition comprising the same, and a compound and a combination of the present invention The use of objects in the field of central nervous system. Background technique

GABA_A受体是中枢神经***中主要的抑制性神经递质受体。 GABA_A受体由跨膜多肽亚基的五聚体构成， 19种不同的亚基组成了多种不同的 GABA_A受体亚型。 GABA_A受体涉及麻醉、抑郁、焦虑、癫痫、记忆障碍、药物依赖等多种疾病的发病机制和诊断治疗。因此， GABA_A 受体是药理学和临床上重要的药物作用靶点。丙泊酚及其衍生物即是一类重要的以 GABA_A为靶点的化合物。 The GABA _A receptor is the major inhibitory neurotransmitter receptor in the central nervous system. The GABA _A receptor consists of a pentamer of transmembrane polypeptide subunits, and 19 different subunits make up a variety of different GABA _A receptor subtypes. GABA _A receptors are involved in the pathogenesis and diagnosis of various diseases such as anesthesia, depression, anxiety, epilepsy, memory disorders, and drug dependence. Therefore, the GABA _A receptor is a pharmacological and clinically important drug target. Propofol and its derivatives are an important class of compounds targeting GABA _A.

丙泊酚可激活多种 GABA_A受体亚型，是一个临床上成熟的静脉***，广泛用于全身麻醉的诱导和维持。临床剂量相关的丙泊酚可直接激活哺乳动物神经元中的 GABA_A受体-氯离子通道复合体，增加氯离子传导，降低神经网络的兴奋性，进而引起全身麻醉（Manami Ham等 (1993).Anesthesiology, 79, 781-788)。丙泊酚的显著药代动力学和药效学性质是起效快，维持时间短和快速可逆，静脉给药后，丙泊酚迅速从血液进入心、肺和肝等高灌注区，高脂溶性使丙泊酚容易跨越血脑屏障进入大脑发挥全身麻醉作用。 Propofol activates a variety of GABA _A receptor subtypes and is a clinically mature intravenous anesthetic widely used for the induction and maintenance of general anesthesia. Clinical dose-related propofol directly activates the GABA _A receptor-chloride channel complex in mammalian neurons, increases chloride conduction, reduces neural network excitability, and causes general anesthesia (Manami Ham et al. (1993) .Anesthesiology, 79, 781-788). The significant pharmacokinetic and pharmacodynamic properties of propofol are rapid onset, short duration of maintenance and rapid reversibility. After intravenous administration, propofol rapidly enters the high perfusion area of the heart, lungs and liver from the blood, high fat. Solubility allows propofol to cross the blood-brain barrier and enter the brain for general anesthesia.

然而，丙泊酚也有显而易见的局限性和缺点。据报道，约 70%的病人在注射丙泊酚时有一定程度的疼痛或不适（Pascale Picard (2000). Anesthesia& Analgesia, 90, 963-969)。虽然有报道称用其他药物预处理或联合用药的方法可降低丙泊酚注射疼痛的发生率和严重程度（C. H. Tan 等 (1998). Anaesthesia, 53, 302-305), 但这种疼痛仍难以避免。丙泊酚已被证明可降低收缩压，舒张压和平均动脉血压，因此在临床上会引起低血压。同时，呼吸抑制、呼吸暂停、低氧血症等也是使用丙泊酚时不可忽视的风险。这些不良反应很大程度上阻碍了丙泊酚在一些临床病例中的应用，如心血管疾病，脑损伤和慢性低血压。 However, propofol also has obvious limitations and disadvantages. It is reported that about 70% of patients have a certain degree of pain or discomfort when taking propofol (Pascale Picard (2000). Anesthesia & Analgesia, 90, 963-969). Although it has been reported that pretreatment with other drugs or combination therapy can reduce the incidence and severity of propofol injection pain (CH Tan et al. (1998). Anaesthesia, 53, 302-305), this pain is still difficult avoid. Propofol has been shown to reduce systolic blood pressure, diastolic blood pressure and mean arterial blood pressure, thus causing hypotension in the clinic. At the same time, respiratory depression, apnea, hypoxemia, etc. are also risks that cannot be ignored when using propofol. These adverse effects have largely hampered the use of propofol in a number of clinical cases, such as cardiovascular disease, brain damage and chronic hypotension.

磷丙泊酚是丙泊酚的水溶性前药，它可迅速被碱性磷酸酶水解，释放丙泊酚、磷酸盐和甲醛。虽然磷丙泊酚缓解了丙泊酚的静脉注射部位疼痛，但由于其仍是以丙泊酚原药形式起效，因此仍存在呼吸抑制和不良的血液动力学效应的风险（Cohen LB (2008). Aliment Pharmacol Ther, 27, 597)。同时磷丙泊酚还可引起感觉异常和瘙痒。 Phospodopropanol is a water-soluble prodrug of propofol that is rapidly hydrolyzed by alkaline phosphatase to release propofol, phosphate and formaldehyde. Although fospropofol relieves the pain of intravenous injection of propofol, it still has a risk of respiratory depression and poor hemodynamic effects because it still works as a propofol (Cohen LB (2008) ). Aliment Pharmacol Ther, 27, 597). At the same time, fospropofol can also cause paresthesia and itching.

鉴于丙泊酚和磷丙泊酚的局限性和缺点，需要开发新的具有更好药代动力学和药效学特性，且有较少副作用的 GABA_A受体激动剂。 In view of the limitations and shortcomings of propofol and fospropofol, it is desirable to develop new GABA _A receptor agonists with better pharmacokinetic and pharmacodynamic properties with fewer side effects.

US3979463 描述了用于皮肤的保护性组合物的氟脂族酚类化合物，其通式化合物结构如

No. 3,979,463 describes fluoroaliphatic phenolic compounds for use in protective compositions for the skin, the structure of which is

其中 X是 -CHClCH₂-、 -CH=CH -、 -CH₂-CH₂-， R_f是 3-20个碳原子的全氟垸基， I ¹、 R₂、Wherein X is -CHClCH ₂ -, -CH=CH -, -CH ₂ -CH ₂ -, R _f is a perfluorodecyl group of 3 to 20 carbon atoms, I ¹ , R ₂ ,

R₃、 R4的任意一个选自甲基、乙基、甲氧基、苯基、苯氧基、羟基、氢、卤素或者两个相邻的 R基团形成碳环基或杂环基， Ri, R₃可以是 -CH₂XR_f，该发明与本发明的化合物结构差异较大。 Any one of R ₃ and R 4 is selected from a methyl group, an ethyl group, a methoxy group, a phenyl group, a phenoxy group, a hydroxyl group, a hydrogen group, a halogen or two adjacent R groups to form a carbocyclic group or a heterocyclic group, Ri R ₃ may be -CH ₂ XR _f , and the structure of the invention differs greatly from the structure of the compound of the present invention.

CN1228414描述了用于治疗抑郁、焦虑、恐怖症的苯并四元环衍生物及其与一种药学上可接受的酸的加成盐，其通式化合物结构：

CN1228414 describes benzotetragonal ring derivatives for the treatment of depression, anxiety, phobia and their addition salts with a pharmaceutically acceptable acid, the structure of which:

其中 Zi、 Z₂、 Z₃和 Z₄各自独立选自 H、 F、 Cl、 Br、 I、 d_₆垸基、 C₂_₆链烯基或者 C₂_₆炔基， X代表 0。该发明与本发明的结构相差较大。 Wherein Zi, Z ₂ , Z ₃ and Z ₄ are each independently selected from H, F, Cl, Br, I, d- ₆ fluorenyl, C ₂ _-6 alkenyl or C ₂ _-6 alkynyl, and X represents 0. This invention differs greatly from the structure of the present invention.

US5552508描述了苯并四元环衍生物，物结构如下： U.S. Patent No. 5,552,508 describes a benzo four-membered ring derivative having the following structure:

其中 Z选自 H或者环丁垸； X和 Y可以独立选自 -COOH、 -NH₂、 -OH、 -COCK -NCO或双乙酰卤基团，该发明与本发明的结构相差较大，不认为此专利中具体描述是本发明的一部分。 Wherein Z is selected from H or cyclobutyl fluorene; X and Y may be independently selected from -COOH, -NH ₂ , -OH, -COCK -NCO or a diacetyl halide group, and the invention differs greatly from the structure of the present invention, The detailed description in this patent is considered to be part of the present invention.

CN1323794描述了苯并四元环衍生物及其与可药用酸或碱形成的加成盐，其通式化合物结构如下:

CN1323794 describes benzotetra-membered derivatives and their addition salts with pharmaceutically acceptable acids or bases, the structures of which are as follows:

其中：代表单键或双键； n为 1-6的整数；和 R₂各自独立选自 H、 C_r6垸基、环垸基、芳基； X选自 -CH=CH -、 0、 S(=0)_m， m为 0至 2的整数或者 NR₃，其中 R₃选自 H、 C_r6 垸基、芳基。 Y表示 -CH或 -CH_{2 ;} T表示单环或多环 ^-₁₂环垸基，其中，环垸基的碳原子之一可选择性地被一种基团取代，所述基团选自 0、 Se或者 S(=0)_p，其中 p为 0至 2的整数、 NR₃，该发明与本发明的结构相差较大，不认为此专利中具体描述是本发明的一部分。 Wherein: represents a single bond or a double bond; n is an integer from 1 to 6; and R ₂ are each independently selected from H, C _r6 fluorenyl, cyclodecyl, aryl; X is selected from -CH=CH -, 0, S (=0) _m , m is an integer from 0 to 2 or NR ₃ , wherein R _{3 is} selected from H, C _r6 fluorenyl, aryl. Y represents -CH or -CH _{2 ;} T represents a monocyclic or polycyclic ring of ₁₂ -fluorenyl, wherein one of the carbon atoms of the cycloalkyl group may be optionally substituted by a group selected from the group consisting of 0, Se or S(=0) _p , where p is an integer from 0 to 2, NR ₃ , and the invention differs greatly from the structure of the present invention, and the detailed description in this patent is not considered to be part of the present invention.

W09615099描述了用于治疗中枢神经***疾病的化合物，其通式化合物结构如下：其中 n为 0至 2的整数， X选自 0、 S、 -N(R⁵)-或者亚甲基， R¹选自 H、 -NH₂、 -NHR⁵或者羟基； R²、 R³各 R自 2独立选自 H、 -COOH、 -COOR⁵、 -CONH₂、 -CONHR⁵、 -CON(R⁵)₂、 CONHS0₂R⁵ 或四氮唑， R⁴选自 H、羟基、氨基、 -NHR⁵、 CF³、 d— ₈垸基、 C₂-₈烯基、 C₂-₈炔基、 C₃— ₆环垸基、苯基或 d_₄垸氧基， R⁵可以为 H、 d_₈垸基、 C₂-₈烯基、 C₂-₈炔基、 C₃_₆环垸基，环 A可以为部分或完全饱和芳环或药学上可用盐，该发明与本发明的结构相差较大。发明内容 W09615099 describes compounds for the treatment of diseases of the central nervous system, the structure of which is as follows: Wherein n is an integer from 0 to 2, X is selected from 0, S, -N(R ⁵ )- or methylene, R ^{1 is} selected from H, -NH ₂ , -NHR ⁵ or hydroxy; R ² and R ^{3 are} each R is independently selected from H, -COOH, -COOR ⁵ , -CONH ₂ , -CONHR ⁵ , -CON(R ⁵ ) ₂ , CONHS0 ₂ R ⁵ or tetrazolium, and R ^{4 is} selected from H, hydroxy, amino, -NHR ^5, CF ^3, d- ₈ embankment group, C ₂ - ₈ alkenyl, C ₂ - ₈ alkynyl group, C ₃ - ₆ cycloalkyl embankment group, a phenyl group, or embankment d_ _4, R ⁵ may be H, d_ ₈ embankment group, C ₂ - ₈ alkenyl, C ₂ - ₈ alkynyl, C ₃ _ ₆ cycloalkyl embankment group, ring a may be used a salt structure, the invention of the present invention is a partially or fully saturated aromatic ring or a pharmaceutically The difference is large. Summary of the invention

本发明的目的是提供一种结构新颖、药效更好、更安全的 GABA_A受体激动剂，或者其所有的立体异构体、溶剂化物、代谢产物、药学上可接受的盐、共晶或者前药，制备方法、药物组合物以及其在中枢神经领域上的用途，以便为动物或者人类诱导或维持全身麻醉，促进镇静催眠，治疗和 /或预防焦虑、恶心、呕吐、偏头痛、惊厥、癫痫、神经变性疾病以及中枢神经 ***相关的疾病提供更多更优的药物选择途径。 The object of the present invention is to provide a novel, more potent and safer GABA _A receptor agonist, or all stereoisomers, solvates, metabolites, pharmaceutically acceptable salts thereof, eutectic Or a prodrug, a preparation method, a pharmaceutical composition, and its use in the field of central nervous system to induce or maintain general anesthesia for an animal or human, promote sedative hypnosis, treat and/or prevent anxiety, nausea, vomiting, migraine, convulsions Epilepsy, neurodegenerative diseases, and diseases related to the central nervous system provide more and better drug selection pathways.

本发明优选方案，提供一种通式 ω所示的化合物，以及其所有的立体异构体、溶剂化物、代谢产物，药学上可接受的盐、共晶或前药： In a preferred embodiment of the invention, there is provided a compound of the formula ω, and all stereoisomers, solvates, metabolites, pharmaceutically acceptable salts, eutectic or prodrugs thereof:

其中- among them-

R选自⁵ R³ 、 -CR^CI^R³或者 -CECR¹ ; R is selected from ⁵ R ³ , -CR^CI^R ³ or -CECR ¹ ;

R¹, R²和 R³各自独立选自 H、 F、 Cl、 Br、 I、羟基、 C₂_₆烯基、 C₂_₆炔基、氰基、 d_₆垸基、 d— ₆垸氧基、 3至 8元碳环基、 3至 8元杂环基、 3至 8元碳环基氧基或者 3至 8元杂环基氧基，所述的烯基、炔基、垸基、垸氧基、碳环基、杂环基、碳环基氧基或者杂环基氧基任选进一步被 0至 5个选自 F、 Cl、 Br、 I、羟基、氨基、氰基、巯基、 d— ₆垸基、 d— ₆垸氧基、 3 至 8元碳环基或者 3至 8元杂环基的取代基所取代，且所述的杂环基含有 1至 2个选自 N、 0 或者 S的杂原子； R ¹ , R ² and R ³ are each independently selected from the group consisting of H, F, Cl, Br, I, hydroxy, C ₂ _-6 alkenyl, C ₂ _-6 alkynyl, cyano, d- ₆ fluorenyl, d- ₆垸An oxy group, a 3 to 8 membered carbocyclic group, a 3 to 8 membered heterocyclic group, a 3 to 8 membered carbocyclic oxy group or a 3 to 8 membered heterocyclic oxy group, said alkenyl group, alkynyl group, fluorenyl group Further, the methoxy group, the carbocyclic group, the heterocyclic group, the carbocyclic oxy group or the heterocyclic oxy group is further further selected from 0 to 5 selected from the group consisting of F, Cl, Br, I, hydroxy, amino, cyano, fluorenyl Substituted with a substituent of d- ₆ fluorenyl, d- ₆ methoxy, 3 to 8 membered carbocyclyl or 3 to 8 membered heterocyclic group, and said heterocyclic group contains 1 to 2 selected from N a hetero atom of 0 or S;

作为选择， R¹与 R²、 R²与 R³或者 R¹与 R³任意一组可以与其相连接的碳原子形成一个 3 至 8元环，所述 3至 8元环可以含有 0至 2个选自 N、 0或者 S的杂原子，且形成的 3至 8元环可以任选进一步被 0至 4个 R⁸取代； R'和 R"各自独立选自 H、 F、 Cl、 Br、 I、羟基、 C₂_₆烯基、 C₂_₆炔基、 d_₆垸基、 d_₆垸氧基、 3至 8元碳环基、 3至 8元杂环基、 3至 8元碳环基氧基或者 3至 8元杂环基氧基，所述的烯基、炔基、垸基、垸氧基、碳环基、杂环基、碳环基氧基或者杂环基氧基任选进一步被 0 至 5个选自 F、 Cl、 Br、 I、羟基、氨基、氰基、巯基、 d— ₆垸基、 d— ₆垸氧基、 3至 8元碳环基或者 3至 8元杂环基的取代基所取代，且所述的杂环基含有 1至 2个选自 N、 0或者 S的杂原子； Alternatively, R ¹ and R ² , R ² and R ³ or any group of R ¹ and R ³ may form a 3 to 8 membered ring with the carbon atom to which they are attached, and the 3 to 8 membered ring may contain 0 to 2 a hetero atom selected from N, 0 or S, and the formed 3 to 8 membered ring may be optionally further substituted with 0 to 4 R ⁸ ; R' and R" are each independently selected from the group consisting of H, F, Cl, Br, I, hydroxy, C ₂ _-6 alkenyl, C ₂ _-6 alkynyl, d ₆ fluorenyl, d ₆ methoxy, 3 to 8 a carbocyclic group, a 3 to 8 membered heterocyclic group, a 3 to 8 membered carbocyclic oxy group or a 3 to 8 membered heterocyclic oxy group, said alkenyl group, alkynyl group, fluorenyl group, decyloxy group, carbocyclic group Or a heterocyclic group, a carbocyclic oxy group or a heterocyclic oxy group, optionally further selected from 0 to 5 selected from the group consisting of F, Cl, Br, I, hydroxy, amino, cyano, decyl, d- ₆ fluorenyl, Substituted with a d- _6- methoxy group, a 3- to 8-membered carbocyclic group or a 3- to 8-membered heterocyclic group, and the heterocyclic group contains 1 to 2 hetero atoms selected from N, 0 or S ;

R⁴、 R⁵、 R⁶和 R⁷各自独立选自 H、 F、 Cl、 Br、 I、羟基、 C₂_₆烯基、 C₂_₆炔基、氰基、叠氮基、 d— ₆垸基、 d— ₆垸氧基、 3至 8元碳环基、 3至 8元杂环基、 3至 8元碳环基氧基或者 3 至 8元杂环基氧基，所述的烯基、炔基、垸基、垸氧基、碳环基、杂环基、碳环基氧基或者杂环基氧基任选进一步被 0至 5个选自 F、 Cl、 Br、 I、氰基、巯基、 d— ₆垸基、 d— ₆垸氧基、 3 至 8元碳环基或者 3至 8元杂环基的取代基所取代，且所述的杂环基含有 1至 2个选自 N、 0 或者 S的杂原子； R ⁴ , R ⁵ , R ⁶ and R ⁷ are each independently selected from the group consisting of H, F, Cl, Br, I, hydroxy, C ₂ _-6 alkenyl, C ₂ _-6 alkynyl, cyano, azide, d- ₆ mercapto, d- ₆ methoxy, 3 to 8 membered carbocyclic, 3 to 8 membered heterocyclic, 3 to 8 membered carbocyclyloxy or 3 to 8 membered heterocyclyloxy, said Alkenyl, alkynyl, decyl, decyloxy, carbocyclyl, heterocyclyl, carbocyclyloxy or heterocyclyloxy optionally further selected from 0 to 5 selected from F, Cl, Br, I, Substituted with a substituent of a cyano group, a fluorenyl group, a d- ₆ fluorenyl group, a d- ₆ methoxy group, a 3 to 8 membered carbocyclic group or a 3 to 8 membered heterocyclic group, and the heterocyclic group has 1 to 2 a hetero atom selected from N, 0 or S;

作为选择， R⁴与 R⁵、 R⁶与 R⁷任意一组可以与其相连接的碳原子形成一个 3至 8元环，所述 3至 8元环可以含有 0至 2个选自 N、 0或者 S的杂原子，且形成的 3至 8元环可以任选进一步被 0至 4个 R⁸取代； Alternatively, any one of R ⁴ and R ⁵ , R ⁶ and R ⁷ may form a 3 to 8 membered ring with a carbon atom to which it is attached, and the 3 to 8 membered ring may have 0 to 2 selected from N, 0. Or a hetero atom of S, and the formed 3 to 8 membered ring may be optionally further substituted with 0 to 4 R ⁸ ;

作为选择， R⁴和 R⁵可以形成（=0); Alternatively, R ⁴ and R ⁵ may form (=0);

作为选择， R⁶和 R⁷可以形成（=0); Alternatively, R ⁶ and R ⁷ may form (=0);

R⁸选自 F、 Cl、 Br、 I、（=0)、羟基、氨基、氰基、巯基、羧基、羧酸酯、酰胺基、 d_₆垸基、 d— ₆垸氧基、 3至 8元碳环基或者 3至 8元杂环基，所述的杂环基含有 1至 2个选自 N、 0 或者 S的杂原子； R ^{8 is} selected from the group consisting of F, Cl, Br, I, (=0), hydroxy, amino, cyano, decyl, carboxy, carboxylic acid ester, amide group, d- ₆ fluorenyl group, d- ₆ methoxy group, 3 to 8 a carbocyclic group or a 3 to 8 membered heterocyclic group, the heterocyclic group having 1 to 2 hetero atoms selected from N, 0 or S;

本发明优选方案，所述的化合物选自通式 I-a)所示的化合物： In a preferred embodiment of the invention, the compound is selected from the group consisting of the compounds of formula I-a):

R\ R²和 R³各自独立选自 H、 F、 CI Br、 I、羟基、氰基、 d— ₆垸基、 d— ₆垸氧基、 3至R\R ² and R ³ are each independently selected from the group consisting of H, F, CI Br, I, hydroxy, cyano, d- ₆ fluorenyl, d- ₆ methoxy, 3 to

8元碳环基、 3至 8元杂环基、 3至 8元碳环基氧基或者 3至 8元杂环基氧基，优选 H、 F、 Cl、 Br、 I、羟基、 d— 4垸基、 d— 4垸氧基、 3至 6元碳环基氧基、 3至 6元杂环基氧基、 3至 6元碳环基或者 3至 6元杂环基，更优选 H、 F、 Cl、 Br、 I、羟基、 d_₄垸基、 d_₄垸氧基或者 3至 6 元碳环基，进一步优选 H、 d—₄垸基或者 3至 6元碳环基，所述的垸基、垸氧基、碳环基、杂环基、碳环基氧基或者杂环基氧基任选进一步被 0至 5个选自 F、 Cl、 Br、 I、羟基、 d— ₆垸基、 d— ₆垸氧基、 3至 8元碳环基或者 3至 8元杂环基的取代基所取代，且所述的杂环基含有 1至 2个选自 N、 0或者 S的杂原子； 8-membered carbocyclic group, 3- to 8-membered heterocyclic group, 3- to 8-membered carbocyclic oxy group or 3- to 8-membered heterocyclic oxy group, preferably H, F, Cl, Br, I, hydroxy, d-4 Anthracenyl, d-4 methoxy, 3 to 6 membered carbocyclyloxy, 3 to 6 membered heterocyclyloxy, 3 to 6 membered carbocyclic or 3 to 6 membered heterocyclic group, more preferably H, F, Cl, Br, I, hydroxy, d_ ₄ fluorenyl, d ₄ methoxy or 3 to 6 membered carbocyclic group, further preferably H, d - ₄ fluorenyl or 3 to 6 membered carbocyclic group, said Sulfhydryl, decyloxy, carbocyclic, hetero The cyclo, carbocyclyloxy or heterocyclyloxy group is further further selected from 0 to 5 selected from the group consisting of F, Cl, Br, I, hydroxy, d- ₆ fluorenyl, d- ₆ methoxy, 3 to 8 Substituted by a substituent of a carbocyclic group or a 3- to 8-membered heterocyclic group, and the heterocyclic group contains 1 to 2 hetero atoms selected from N, 0 or S;

作为选择， R¹与 R²、 R²与 R³或者 R¹与 R³任意一组可以与其相连接的碳原子形成一个 3 至 6元环，所述 3至 6元环可以含有 0至 2个选自 N、 0或者 S的杂原子，且形成的 3至 6元环可以任选进一步被 0至 4个 R⁸取代； Alternatively, R ¹ and R ² , R ² and R ³ or any group of R ¹ and R ³ may form a 3 to 6 membered ring with a carbon atom to which they are attached, and the 3 to 6 membered ring may contain 0 to 2 a hetero atom selected from N, 0 or S, and the formed 3 to 6 membered ring may be optionally further substituted with 0 to 4 R ⁸ ;

R⁴和 R⁵各自独立选自 H、 F、 Cl、 Br、 I、羟基、 C₂— ₄烯基、 C₂— ₄炔基、氰基、叠氮基、 d— ₆ 垸基、 ₆垸氧基、 3至 8元碳环基氧基、 3至 8元杂环基氧基、 3至 8元碳环基或者 3至 8元杂环基，优选 H、 F、 Cl、 Br、 I、羟基、 C₂— ₄烯基、 C₂— ₄炔基、氰基、叠氮基、 d— ₄垸基、 d— ₄ 垸氧基、 3至 6元碳环基、 3至 6元杂环基、 3至 6元碳环基氧基或者 3至 6元杂环基氧基，更优选 H、 F、 Cl、 Br、 I、羟基、 C₂— ₄烯基、 C₂— ₄炔基、氰基、叠氮基、 d— ₄垸基、 d— ₄垸氧基或者 3至 6元碳环基，进一步优选 H、氰基、叠氮基、 d— ₄垸基、 d— ₄垸氧基或者 3至 6元碳环基，所述的烯基、炔基、垸基、垸氧基、碳环基、杂环基、碳环基氧基或者杂环基氧基任选进一步被 0至 5个选自 F、 Cl、 Br、 I、 d_₆垸基、 d_₆垸氧基、 3至 8元碳环基或者 3至 8元杂环基的取代基所取代，且所述的杂环基可以含有 1至 2个选自 N、 0或者 S的杂原子；作为选择， R⁴与 R⁵可以与其相连接的碳原子形成一个 3至 6元环，所述的 3至 6元环可以含有 0至 2个选自 N、 0或者 S的杂原子，且形成的 3至 6元环可以任选进一步被 0至 4个 R⁸取代； R ⁴ and R ⁵ are each independently selected from the group consisting of H, F, Cl, Br, I, hydroxy, C ₂ - ₄ alkenyl, C ₂ - ₄ alkynyl, cyano, azide, d- ₆ fluorenyl, ₆垸Oxy, 3 to 8 membered carbocyclyloxy, 3 to 8 membered heterocyclyloxy, 3 to 8 membered carbocyclic or 3 to 8 membered heterocyclic, preferably H, F, Cl, Br, I, Hydroxy, C ₂ _-4 alkenyl, C ₂ _-4 alkynyl, cyano, azido, d- ₄ fluorenyl, d- ₄ decyloxy, 3 to 6-membered carbocyclic, 3 to 6-membered heterocyclic ring a 3- to 6-membered carbocyclic oxy group or a 3 to 6-membered heterocyclic oxy group, more preferably H, F, Cl, Br, I, hydroxy, C ₂ - ₄ alkenyl, C ₂ - ₄ alkynyl, a cyano group, an azide group, a d- ₄ fluorenyl group, a d- ₄ methoxy group or a 3 to 6 membered carbocyclic group, further preferably H, a cyano group, an azide group, a d- ₄ fluorenyl group, a d- ₄ oxo group Or a 3- to 6-membered carbocyclic group, said alkenyl, alkynyl, decyl, decyloxy, carbocyclyl, heterocyclyl, carbocyclyloxy or heterocyclooxy optionally further to 5 substituents selected from F, Cl, Br, I, d_ 6 alkyl with, d_ ₆ embankment group, 3-8 yuan carbocyclic group of 3 to 8-membered heterocyclic group Substituted with a substituent, and the heterocyclic group may contain 1 to 2 heteroatoms selected from N, 0 or S heteroatom; and alternatively, R ⁴ and the carbon atoms R ⁵ may be connected thereto form a 3-6 yuan a ring, the 3 to 6 membered ring may contain 0 to 2 heteroatoms selected from N, 0 or S, and the formed 3 to 6 membered ring may be optionally further substituted with 0 to 4 R ⁸ ;

R⁶和 R⁷各自独立选自 H、 F、 Cl、 Br、 I或者羟基； R ⁶ and R ⁷ are each independently selected from H, F, Cl, Br, I or a hydroxyl group;

R⁸选自 F、 Cl、 Br、 I、羟基、羧基、氨基、羧酸酯、酰胺基、 d— ₆垸基、 d— ₆垸氧基、 3 至 8元碳环基或者 3至 8元杂环基，所述的杂环基含有 1至 2个选自 N、 0或者 S的杂原子。 R ^{8 is} selected from the group consisting of F, Cl, Br, I, hydroxy, carboxy, amino, carboxylic acid ester, amide group, d- ₆ fluorenyl group, d- ₆ methoxy group, 3 to 8 membered carbocyclic group or 3 to 8 membered A heterocyclic group having 1 to 2 hetero atoms selected from N, 0 or S.

本发明优选方案，所述的化合物选自通式 I-b)所示的化合物：

In a preferred embodiment of the invention, the compound is selected from the group consisting of the compounds of the formula Ib):

其中- among them-

R选自 ³ ； R is selected from ³ ;

R¹, R²和 R³各自独立选自 H、 F、 Cl、 Br、 I、羟基、氰基、 d— ₄垸基、 d— ₄垸氧基、 3至 6元碳环基、 3至 6元杂环基、 3至 6元碳环基氧基或者 3至 6元杂环基氧基、，优选 H、 F、 Cl、 Br、 I、羟基、 d— 4垸基、 d— 4垸氧基或者 3至 6元碳环基，更优选 H、 d— ₄垸基或者 3至 6 元碳环基，进一步优选 H、 d— ₃垸基或者 3至 6元碳环基，所述的垸基、垸氧基、碳环基、杂环基、碳环基氧基或者杂环基氧基任选进一步被 0至 5个选自 F、 Cl、 Br、 I、羟基、 d— ₄垸基、 d— ₄垸氧基、 C₃— ₅环垸基或者 3至 5元杂环基的取代基所取代； R ¹ , R ² and R ³ are each independently selected from the group consisting of H, F, Cl, Br, I, hydroxy, cyano, d- ₄ fluorenyl, d- _4- decyloxy, 3 to 6-membered carbocyclic, 3 to a 6-membered heterocyclic group, a 3 to 6-membered carbocyclic oxy group or a 3 to 6-membered heterocyclic oxy group, preferably H, F, Cl, Br, I, hydroxy, d-4 fluorenyl, d-4 垸An oxy group or a 3 to 6 membered carbocyclic group, more preferably H, d- ₄ fluorenyl or a 3 to 6 membered carbocyclic group, further preferably H, d- ₃ fluorenyl or 3 to 6 membered carbocyclic group, said Sulfhydryl, decyloxy, carbocyclic, hetero The cyclo, carbocyclyloxy or heterocyclyloxy group is further further selected from 0 to 5 selected from the group consisting of F, Cl, Br, I, hydroxy, d- ₄ fluorenyl, d- _4- decyloxy, C ₃ — Substituted by a _5- cycloalkyl group or a 3- to 5-membered heterocyclic group;

R⁴和 R⁵各自独立选自 H、 F、 Cl、 Br、 I、羟基、 C₂— ₄烯基、 C₂— ₄炔基、氰基、叠氮基、 d— ₄ 垸基、 CM垸氧基、 3至 6元碳环基、 3至 6元杂环基、 3至 6元碳环基氧基或者 3至 6元杂环基氧基，优选 H、 F、 Cl、 Br、 I、羟基、 C₂— ₄烯基、 C₂— ₄炔基、氰基、叠氮基、 d— ₄垸基、 d— ₄ 垸氧基、 3至 6元碳环基或者 3至 6元碳环基氧基，更优选 H、羟基、氰基、叠氮基、 d— ₄垸基、 CM垸氧基或者 3至 6元碳环基，进一步优选 H、氰基、叠氮基、 d— ₃垸基、 d— ₃垸氧基或者 3元碳环基，所述的烯基、炔基、垸基、垸氧基、碳环基、杂环基、碳环基氧基或者杂环基氧基任选进一步被 0至 5个选自 F、 Cl、 Br、 I、 d— ₄垸基、 d— ₄垸氧基、 3至 6元碳环基或者 3 至 6元杂环基的取代基所取代，且所述的杂环基含有 1至 2个选自 N、 0或者 S的杂原子；作为选择， R⁴与 R⁵可以与其相连接的碳原子形成一个 3至 6元环，所述的 3至 6元环可以含有 0至 2个选自 N、 0或者 S的杂原子，且形成的 3至 6元环可以任选进一步被 0至 4个 R⁸取代； R ⁴ and R ⁵ are each independently selected from the group consisting of H, F, Cl, Br, I, hydroxy, C ₂ - ₄ alkenyl, C ₂ - ₄ alkynyl, cyano, azide, d- ₄ fluorenyl, CM 垸An oxy group, a 3 to 6 membered carbocyclic group, a 3 to 6 membered heterocyclic group, a 3 to 6 membered carbocyclic oxy group or a 3 to 6 membered heterocyclic oxy group, preferably H, F, Cl, Br, I, Hydroxy, C ₂ _-4 alkenyl, C ₂ _-4 alkynyl, cyano, azido, d- ₄ fluorenyl, d- _4- decyloxy, 3 to 6-membered carbocyclic or 3 to 6-membered carbocyclic More preferably H, hydroxy, cyano, azide, d- ₄ fluorenyl, CM methoxy or 3 to 6 membered carbocyclic group, further preferably H, cyano, azide, d- ₃ Indenyl, d- ₃ methoxy or 3-membered carbocyclyl, said alkenyl, alkynyl, decyl, decyloxy, carbocyclyl, heterocyclyl, carbocyclyloxy or heterocyclooxy Further optionally, the substituent is further selected from 0 to 5 substituents selected from the group consisting of F, Cl, Br, I, d- ₄ fluorenyl, d- _4- decyloxy, 3 to 6-membered carbocyclic or 3- to 6-membered heterocyclic. substituted, and said heterocyclic group containing 1 to 2 heteroatoms selected from N, 0 or S heteroatom; and alternatively, R ⁴ R ⁵ may form with the carbon atom attached a 3-6 yuan rings, 3 to 6-membered ring may contain 0 to 2 heteroatoms selected from N, 0 or S heteroatom, and the form 3 to 6-membered ring Optionally optionally substituted by 0 to 4 R ⁸ ;

R⁸选自 F、 Cl、 Br、 I、羟基、 d_₄垸基、 d_₄垸氧基、 3至 6元碳环基或者 3至 6元杂环基。 R ^{8 is} selected from the group consisting of F, Cl, Br, I, hydroxy, d ₄ fluorenyl, d ₄ methoxy, 3 to 6-membered carbocyclyl or 3 to 6-membered heterocyclic.

本发明优选方案，所述的化合物选自通式 II)所示的化合物：

In a preferred embodiment of the invention, the compound is selected from the group consisting of the compounds of formula II):

其中- among them-

R¹, R²和 R³各自独立选自 H、 F、 Cl、 Br、 I、羟基、 d_₄垸基、 d_₄垸氧基或者 3至 6元碳环基，优选 H、 d— ₄垸基或者 3至 6元碳环基，更优选 H、 d— ₃垸基或者 3至 6元碳环基，所述的垸基、垸氧基或者碳环基任选进一步被 0至 3个选自 F、 Cl、 Br、 I、羟基、 d— ₄垸基、 d— ₄垸氧基或者 3至 6元碳环基的取代基所取代； R ¹ , R ² and R ³ are each independently selected from H, F, Cl, Br, I, hydroxy, d_ ₄ fluorenyl, d ₄ methoxy or 3 to 6 membered carbocyclic, preferably H, d - ₄垸a 3- or 6-membered carbocyclic group, more preferably an H, d- ₃ fluorenyl or a 3 to 6-membered carbocyclic group, the fluorenyl, decyloxy or carbocyclic group optionally further selected from 0 to 3 Substituted from a substituent of F, Cl, Br, I, hydroxy, d- ₄ fluorenyl, d- ₄ methoxy or a 3- to 6-membered carbocyclic group;

作为选择， R¹与 R²、 R²与 R³或者 R¹与 R³任意一组可以与其相连接的碳原子形成一个 3 至 6元环，所述 3至 6元环可以含有 0至 2个选自 N、 0或者 S的杂原子，并且形成的 3至 6 元环可以任选进一步被 0至 3个 R⁸取代； Alternatively, R ¹ and R ² , R ² and R ³ or any group of R ¹ and R ³ may form a 3 to 6 membered ring with a carbon atom to which they are attached, and the 3 to 6 membered ring may contain 0 to 2 a hetero atom selected from N, 0 or S, and the formed 3 to 6 membered ring may be optionally further substituted with 0 to 3 R ⁸ ;

R⁴和 R⁵各自独立选自 H、 F、 Cl、 Br、 I、羟基、 C₂— ₄烯基、 C₂— ₄炔基、氰基、叠氮基、 d— ₄ 垸基、 ₄垸氧基、 3至 6元碳环基或者 3至 6元碳环基氧基，优选 H、羟基、氰基、叠氮基、 d— ₄垸基、 d— ₄垸氧基或者 3元碳环基，更优选 H、羟基、氰基、叠氮基、 d— ₃垸基、 d— ₃垸氧基或者 3元碳环基，进一步优选 H、氰基、叠氮基、 d— ₂垸基或者 — ₂垸氧基，所述的烯基、炔基、垸基、垸氧基、碳环基或者碳环基氧基任选进一步被 0至 3个选自 F、 Cl、 Br、 I、羟基、 d— 4垸基、 d— 4垸氧基或者 3至 6元碳环基的取代基所取代； R ⁴ and R ⁵ are each independently selected from the group consisting of H, F, Cl, Br, I, hydroxy, C ₂ - ₄ alkenyl, C ₂ - ₄ alkynyl, cyano, azide, d- ₄ Indenyl, _4- decyloxy, 3- to 6-membered carbocyclic or 3- to 6-membered carbocyclic oxy, preferably H, hydroxy, cyano, azide, d- ₄ fluorenyl, d- ₄ fluorenyloxy Or a 3-membered carbocyclic group, more preferably H, a hydroxyl group, a cyano group, an azido group, a d- ₃ fluorenyl group, a d- ₃ decyloxy group or a 3-membered carbocyclic group, further preferably H, a cyano group, an azide group, alkyl with or d- ₂ - ₂ embankment group, the alkenyl group, alkynyl group, alkyl with, embankment group, a carbocyclyl group or a carbocyclic group optionally further substituted with 0 to 3 substituents selected from F, Cl Substituted with a substituent of Br, I, hydroxy, d-4 fluorenyl, d-4 decyloxy or a 3 to 6 membered carbocyclic group;

R⁸选自 F、 Cl、 Br、 I、羟基、 d— ₄垸基或者 d— ₄垸氧基。 R ^{8 is} selected from the group consisting of F, Cl, Br, I, hydroxy, d- ₄ fluorenyl or d- ₄ methoxy.

本发明优选方案，提供一种通式（II)所示的化合物，或者其所有的立体异构体、溶剂化物、代谢产物，药学上可接受的盐、共晶或前药，其中： According to a preferred embodiment of the present invention, there is provided a compound of the formula (II), or all stereoisomers, solvates, metabolites, pharmaceutically acceptable salts, eutectic or prodrugs thereof, wherein:

R¹, R²和 R³各自独立选自 H、 F、 Cl、 Br、氰基、 d—₄垸基或者 3至 6元碳环基，优选 H、 d— ₄垸基或者 3至 6元碳环基，更优选 H、 d— ₃垸基或者 3至 6元碳环基，进一步优选 H、 d_₂ 垸基或者 3至 4元碳环基；所述的垸基或者碳环基任选进一步被 0至 3个选自 F、 Cl、 Br、羟基、 d— ₄垸基、 d— ₄垸氧基或者 3至 6元碳环基的取代基所取代；其中 R R²和 R³至少有一个基团为 H; R ¹ , R ² and R ³ are each independently selected from H, F, Cl, Br, cyano, d- ₄ fluorenyl or a 3 to 6 membered carbocyclic group, preferably H, d- ₄ fluorenyl or 3 to 6 a carbocyclic group, more preferably H, d- ₃ fluorenyl or a 3 to 6 membered carbocyclic group, further preferably H, d ₂ fluorenyl or a 3 to 4 membered carbocyclic group; said fluorenyl or carbocyclic group is optional Further substituted by 0 to 3 substituents selected from the group consisting of F, Cl, Br, hydroxy, d- ₄ fluorenyl, d- ₄ decyloxy or a 3 to 6 membered carbocyclic group; wherein RR ² and R ^{3 are} at least One group is H;

作为选择， R¹与 R²、 R²与 R³或者 R¹与 R³任意一组可以与其相连接的碳原子形成一个 3 至 6元环，优选 5至 6元碳环基，所述的 3至 6元碳环基可以任选进一步被 0至 3个 R⁸取代； R⁴和 R⁵各自独立选自 H、羟基、 C₂— ₄烯基、 C₂— ₄炔基、氰基、叠氮基、 d— ₄垸基、 d— ₄垸氧基、 3至 6元碳环基或者 3至 6元碳环氧基，优选 H、羟基、氰基、叠氮基、 d— ₄垸基、 d— ₄ 垸氧基或者 3元碳环基，更优选 H、羟基、 d— ₃垸基、 d— ₃垸氧基或者 3元碳环基，进一步优选11、氰基、叠氮基、 d— ₂垸基或者 — ₂垸氧基，所述的烯基、炔基、垸基、垸氧基、碳环基或者碳环基氧基任选进一步被 0至 3个选自 F、 Cl、 Br、羟基、 d— ₄垸基、 d— ₄垸氧基或者 3 至 6元碳环基的取代基所取代； Alternatively, R ¹ and R ² , R ² and R ³ or any group of R ¹ and R ³ may form a 3- to 6-membered ring, preferably a 5- to 6-membered carbocyclic group, with a carbon atom to which they are attached. The 3- to 6-membered carbocyclic group may be optionally further substituted with 0 to 3 R ⁸ ; R ⁴ and R ⁵ are each independently selected from H, hydroxy, C ₂ - ₄ alkenyl, C ₂ - ₄ alkynyl, cyano, Azido, d- ₄ fluorenyl, d- ₄ decyloxy, 3 to 6 membered carbocyclic or 3 to 6 membered carbocyclic, preferably H, hydroxy, cyano, azide, d- ₄ a group, a d- _4- methoxy group or a 3-membered carbocyclic group, more preferably H, a hydroxyl group, a d- ₃ fluorenyl group, a d- ₃ methoxy group or a 3-membered carbocyclic group, further preferably 11, a cyano group, an azide group Or d- ₂ fluorenyl or - ₂ decyloxy, said alkenyl, alkynyl, decyl, decyloxy, carbocyclyl or carbocyclyloxy optionally further selected from 0 to 3 selected from F, Substituted by a substituent of Cl, Br, hydroxy, d- ₄ fluorenyl, d- ₄ decyloxy or a 3- to 6-membered carbocyclic group;

R⁸选自 F、 Cl、 Br、羟基、 d— 4垸基或者 — 4垸氧基。 R ^{8 is} selected from the group consisting of F, Cl, Br, hydroxy, d-4 fluorenyl or -4-decyloxy.

R R²和 R³各自独立选自 H、 F、 Cl、 Br、氰基、 d—₄垸基或者 3至 6元碳环基，所述的垸基或者碳环基任选进一步被 0至 3个 F取代，优选 H、 d—₄垸基或者 3至 6元碳环基，更优选11、 d— ₃垸基或者 3至 6元碳环基，进一步优选 H、 d— ₂垸基或者 3至 4元碳环基；其中 I ¹、 R²和 R³至少有一个基团为 H; RR ² and R ³ are each independently selected from H, F, Cl, Br, cyano, d- ₄ fluorenyl or a 3 to 6 membered carbocyclic group, and the fluorenyl or carbocyclic group is optionally further 0 to 3 Substituting F, preferably H, d- ₄ fluorenyl or 3 to 6 membered carbocyclic group, more preferably 11, d- ₃ fluorenyl or 3 to 6 membered carbocyclic group, further preferably H, d- ₂ fluorenyl or a 4-membered carbocyclic group; wherein at least one of I ¹ , R ² and R ³ is H;

作为选择， R¹与 R²、 R²与 R³或者 R¹与 R³任意一组可以与其相连接的碳原子形成一个 3 至 6元环，优选 5至 6元碳环基； Alternatively, R ¹ and R ² , R ² and R ³ or any of R ¹ and R ³ may form a 3- to 6-membered ring, preferably a 5- to 6-membered carbocyclic group, with the carbon atom to which they are attached;

R⁴和 R⁵各自独立选自 H、羟基、 C₂— ₄烯基、 C₂— ₄炔基、氰基、叠氮基、 d— ₄垸基、 d— ₄垸氧基、 3至 6元碳环基或者 3至 6元碳环基氧基，优选 H、羟基、氰基、叠氮基、 d— ₄垸基、 CM垸氧基或者 3元碳环基，更优选 H、羟基、氰基、叠氮基、 d— ₃垸基、 d— ₃垸氧基或者 3 元碳环基，进一步优选 H、氰基、叠氮基、 d— ₂垸基或者 — ₂垸氧基。 R ⁴ and R ⁵ are each independently selected from the group consisting of H, hydroxy, C ₂ - ₄ alkenyl, C ₂ - ₄ alkynyl, cyano, azide, d- ₄ fluorenyl, d- _4- decyloxy, 3 to 6 a carbocyclic group or a 3 to 6 membered carbocyclic oxy group, preferably H, hydroxy, cyano, azide, d- ₄ fluorenyl, CM methoxy or 3-membered carbocyclic group, more preferably H, hydroxy, cyano, azido, d- ₃ fluorenyl, d- ₃ decyloxy or a 3-membered carbocyclic group, further preferably H, cyano, Azido, d- ₂ fluorenyl or - ₂ fluorenyloxy.

R¹, R²和 R³各自独立选自 H、氰基、 d_₄垸基或者 3至 6元碳环基，优选 H、 d_₃垸基或者 3至 6元碳环基，更优选 H、 d— ₂垸基或者 3至 4元碳环基；其中 R R²和 R³至少有一个基团为 H; R ¹ , R ² and R ³ are each independently selected from H, cyano, d ₄ fluorenyl or 3 to 6 membered carbocyclic group, preferably H, d ₃ fluorenyl or 3 to 6 membered carbocyclic group, more preferably H, a d- ₂ fluorenyl or a 3- to 4-membered carbocyclic group; wherein at least one of RR ² and R ³ is H;

作为选择， R¹与 R²、 R²与 R³或者 R¹与 R³任意一组可以与其所连接的碳原子形成一个 3 至 6元环，优选 5至 6元碳环基； Alternatively, R ¹ and R ² , R ² and R ³ or any group of R ¹ and R ³ may form a 3- to 6-membered ring, preferably a 5- to 6-membered carbocyclic group, with the carbon atom to which they are attached;

R⁴和 R⁵各自独立选自 H、羟基、 C₂— ₄烯基、 C₂— ₄炔基、氰基、叠氮基、 d— ₄垸基、 d— ₄垸氧基、 3至 6元碳环基或者 3至 6元碳环基氧基，优选 H、羟基、氰基、叠氮基、 d— ₄垸基、 CM垸氧基或者 3元碳环基，更优选 H、羟基、氰基、叠氮基、 d— ₃垸基、 d— ₃垸氧基或者 3 元碳环基，进一步优选 H、氰基、叠氮基、 d— ₂垸基或者 — ₂垸氧基； R ⁴ and R ⁵ are each independently selected from the group consisting of H, hydroxy, C ₂ - ₄ alkenyl, C ₂ - ₄ alkynyl, cyano, azide, d- ₄ fluorenyl, d- _4- decyloxy, 3 to 6 a carbocyclic group or a 3 to 6 membered carbocyclic oxy group, preferably H, hydroxy, cyano, azide, d- ₄ fluorenyl, CM methoxy or a 3-membered carbocyclic group, more preferably H, hydroxy, cyano, azido, d- ₃ alkyl with, d- ₃ embankment group or 3-membered carbocyclic ring group, more preferably H, cyano, azido, d- _2-yl or embankment - ₂ embankment group;

R¹, R²和 R³各自独立选自 H、 F、 Cl、 Br、 CF₃、 CHF₂、 CH₂F、氰基、甲基、乙基、正丙基、异丙基、正丁基、仲丁基、叔丁基、环丙基、环丁基、环戊基或者环己基，优选 H、甲基、乙基、正丙基、异丙基、或者环丙基，更优选 H、甲基、乙基或者环丙基，进一步优选 H、甲基或者乙基；其中 R R²和 R³至少有一个基团为 H; R ¹ , R ² and R ³ are each independently selected from the group consisting of H, F, Cl, Br, CF ₃ , CHF ₂ , CH ₂ F, 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 at least one of RR ² and R ³ is H;

作为选择， R¹与 R²、 R²与 R³或者 R¹与 R³任意一组可以与其相连接的碳原子形成环丙基、环丁基、环戊基或者环己基，优选环戊基或者环己基； Alternatively, R ¹ and R ² , R ² and R ³ or any of R ¹ and R ³ may form a cyclopropyl group, a cyclobutyl group, a cyclopentyl group or a cyclohexyl group, preferably a cyclopentyl group, with a carbon atom to which it is attached. Or cyclohexyl;

R⁴和 R⁵各自独立选自 H、羟基、乙烯基、乙炔基、氰基、叠氮基、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、环丙基、环丁基或者环戊基，优选 H、羟基、氰基、叠氮基、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基，正丙氧基、异丙氧基或者环丙基，更优选 H、氰基、叠氮基、甲基、乙基、甲氧基、乙氧基或者环丙基，进一步优选 H、甲基、氰基、叠氮基或者甲氧基。 R ⁴ and R ⁵ are each independently selected from the group consisting of H, hydroxy, vinyl, ethynyl, cyano, azido, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, cyclopropane , cyclobutyl or cyclopentyl, preferably H, hydroxy, cyano, azido, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, iso Propyloxy or cyclopropyl, more preferably H, cyano, azido, methyl, ethyl, methoxy, ethoxy or cyclopropyl, further preferably H, methyl, cyano, azide Or methoxy.

R¹, R²和 R³各自独立选自 H、氰基、甲基、乙基、正丙基、异丙基、正丁基、仲丁基、叔丁基、环丙基、环丁基、环戊基或者环己基，优选 H、甲基、乙基、正丙基、异丙基、或者环丙基，更优选 H、甲基、乙基或者环丙基，进一步优选 H、甲基或者乙基；其中 R R²和 R³至少有一个基团为 H; 作为选择， R¹与 R²、 R²与 R³或者 R¹与 R³任意一组可以与其相连接的碳原子形成环丙基、环丁基、环戊基或者环己基，优选环戊基或者环己基； R ¹ , R ² and R ³ are each independently selected from the group consisting of 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, further preferably H, methyl Or ethyl; wherein at least one of RR ² and R ³ is H; Alternatively, R ¹ and R ² , R ² and R ³ or any of R ¹ and R ³ may form a cyclopropyl group, a cyclobutyl group, a cyclopentyl group or a cyclohexyl group, preferably a cyclopentyl group, with a carbon atom to which it is attached. Or cyclohexyl;

R⁴和 R⁵各自独立选自 H、羟基、乙烯基、乙炔基、氰基、叠氮基、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基或者环丙基，优选 H、羟基、氰基、叠氮基、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基、异丙氧基或者环丙基，更优选 H、氰基、叠氮基、甲基、乙基、甲氧基、乙氧基或者环丙基，进一步优选 H、甲基、氰基、叠氮基或者甲氧基。 R ⁴ and R ⁵ are each independently selected from H, hydroxy, vinyl, ethynyl, cyano, azido, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy or cyclopropane a group, preferably H, hydroxy, cyano, azido, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy or cyclopropyl, More preferably, H, cyano, azide, methyl, ethyl, methoxy, ethoxy or cyclopropyl, further preferably H, methyl, cyano, azide or methoxy.

R¹ , R²和 R³各自独立选自 H或者 d— ₄垸基，优选 H或者 d— ₃垸基，更优选 H或者 d— ₂ 垸基；其中 R R²和 R³至少有一个基团为 H; R ¹ , R ² and R ³ are each independently selected from H or d- ₄ fluorenyl, preferably H or d- ₃ fluorenyl, more preferably H or d- ₂ fluorenyl; wherein RR ² and R ^{3 have} at least one group Is H;

作为选择， R¹与 R²、 R²与 R³或者 R¹与 R³任意一组可以与其相连接的碳原子形成 3至 6 元碳环基，优选 5至 6元碳环基； Alternatively, R ¹ and R ² , R ² and R ³ or any of R ¹ and R ³ may form a 3 to 6 membered carbocyclic group, preferably a 5 to 6 membered carbocyclic group, with a carbon atom to which they are attached;

R⁴和 R⁵各自独立选自 H、羟基、 C₂— ₄烯基、 C₂— ₄炔基、氰基、叠氮基、 d— ₄垸基、 d— ₄垸氧基、 3至 6元碳环基或者 3至 6元碳环基氧基，优选 H、羟基、氰基、叠氮基、 d— ₄垸基、 CM垸氧基或者 3元碳环基，更优选 H、羟基、氰基、叠氮基、 d— ₃垸基、 d— ₃垸氧基或者 3 元碳环基，进一步优选 H、氰基、叠氮基、 d— ₂垸基或者 — ₂垸氧基。 R ⁴ and R ⁵ are each independently selected from the group consisting of H, hydroxy, C ₂ - ₄ alkenyl, C ₂ - ₄ alkynyl, cyano, azide, d- ₄ fluorenyl, d- _4- decyloxy, 3 to 6 a carbocyclic group or a 3 to 6 membered carbocyclic oxy group, preferably H, hydroxy, cyano, azide, d- ₄ fluorenyl, CM methoxy or a 3-membered carbocyclic group, more preferably H, hydroxy, cyano, azido, d- ₃ alkyl with, d- ₃ embankment group or 3-membered carbocyclic ring group, more preferably H, cyano, azido, d- _2-yl or embankment - ₂ embankment group.

本发明优选方案，提供一种通式（II)所示的化合物，或者其所有的立体异构体、溶剂化物、代谢产物、药学上可接受的盐、共晶或前药，其中： According to a preferred embodiment of the present invention, there is provided a compound of the formula (II), or all stereoisomers, solvates, metabolites, pharmaceutically acceptable salts, eutectic or prodrugs thereof, wherein:

R⁴和 R⁵各自独立选自 H、羟基、氰基、叠氮基、 d— ₄垸基、 d— ₄垸氧基、 3至 5元碳环基或者 3至 5元碳环基氧基，优选 H、羟基、氰基、叠氮基、 d— ₄垸基、 d— ₄垸氧基或者 3元碳环基，更优选 H、羟基、氰基、叠氮基、 d— ₃垸基、 d— ₃垸氧基或者 3元碳环基，进一步优选 H、氰基、叠氮基、 d— ₂垸基或者^— ₂垸氧基。 R ⁴ and R ⁵ are each independently selected from H, hydroxy, cyano, azide, d- ₄ fluorenyl, d- ₄ methoxy, 3 to 5 membered carbocyclyl or 3 to 5 membered carbocyclic oxy. Preferred is H, hydroxy, cyano, azido, d- ₄ fluorenyl, d- _4- decyloxy or a 3-membered carbocyclic group, more preferably H, hydroxy, cyano, azide, d- ₃ fluorenyl , d- ₃ embankment group or 3-membered carbocyclic ring group, more preferably H, cyano, azido, d- _2-yl or embankment ^ - ₂ embankment group.

R⁴和 R⁵各自独立选自 H、羟基、氰基、叠氮基、 d— ₄垸基、 d— ₄垸氧基、 3至 5元碳环基或者 3至 5元碳环基氧基，优选 H、羟基、氰基、叠氮基、 d— ₄垸基、 d— ₄垸氧基、 3元碳环基或者 3至 5元碳环基氧基，更优选 H、羟基、氰基、叠氮基、 d— ₃垸基、 d— ₃垸氧基或者 3元碳环基，进一步优选 H、氰基、叠氮基、 d— ₂垸基或者 — ₂垸氧基。本发明优选方案，提供一种通式（II)所示的化合物，或者其所有的立体异构体、溶剂化物、代谢产物、药学上可接受的盐、共晶或前药，其中： R ⁴ and R ⁵ are each independently selected from H, hydroxy, cyano, azide, d- ₄ fluorenyl, d- ₄ methoxy, 3 to 5 membered carbocyclyl or 3 to 5 membered carbocyclic oxy. Preferred is H, hydroxy, cyano, azide, d- ₄ fluorenyl, d- ₄ methoxy, 3 membered carbocyclyl or 3 to 5 membered carbocyclyloxy, more preferably H, hydroxy, cyano Further, an azide group, a d- ₃ fluorenyl group, a d- ₃ methoxy group or a 3-membered carbocyclic group, further preferably H, a cyano group, an azide group, a d- ₂ fluorenyl group or a - ₂ fluorenyloxy group. According to a preferred embodiment of the present invention, there is provided a compound of the formula (II), or all stereoisomers, solvates, metabolites, pharmaceutically acceptable salts, eutectic or prodrugs thereof, wherein:

R¹, R²和 R³各自独立选自 H或者 d_₂垸基，其中 R R²和 R³至少有一个基团为 H; R⁴和 R⁵各自独立选自 H、羟基、氰基、叠氮基、 d— ₄垸基、 d— ₄垸氧基、 3至 4元碳环基或者 3至 4元碳环基氧基，优选 H、羟基、氰基、叠氮基、 d— ₄垸基、 d— ₄垸氧基、 3元碳环基或者 3至 4元碳环基氧基，更优选 H、羟基、氰基、叠氮基、 d— ₃垸基、 d— ₃垸氧基或者 3元碳环基，进一步优选 H、氰基、叠氮基、 d— ₂垸基或者^— ₂垸氧基。 R ¹ , R ² and R ³ are each independently selected from H or d ₂ fluorenyl, wherein at least one of RR ² and R ³ is H; R ⁴ and R ⁵ are each independently selected from H, hydroxy, cyano, and Nitrogen, d- ₄ fluorenyl, d- ₄ decyloxy, 3 to 4 membered carbocyclic or 3 to 4 membered carbocyclyloxy, preferably H, hydroxy, cyano, azide, d- ₄ a group, d- ₄ methoxy, 3 membered carbocyclyl or 3 to 4 membered carbocyclyloxy, more preferably H, hydroxy, cyano, azide, d- ₃ fluorenyl, d- ₃ methoxy or 3-membered carbon ring group, more preferably H, cyano, azido, d- _2-yl or embankment ^ - ₂ embankment group.

R R²和 R³各自独立选自 H、甲基或者乙基，优选 H或者甲基； RR ² and R ³ are each independently selected from H, methyl or ethyl, preferably H or methyl;

R⁴和 R⁵各自独立选自 H、羟基、氰基、叠氮基、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基，正丙氧基、异丙氧基、环丙基或者环丙基氧基，优选 H、羟基、氰基、叠氮基、甲基、甲氧基、乙氧基或者环丙基，更优选 H、氰基、叠氮基、甲基或者甲氧基。 R ⁴ and R ⁵ are each independently selected from the group consisting of H, hydroxy, cyano, azido, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy Or a cyclopropyl or cyclopropyloxy group, preferably H, hydroxy, cyano, azide, methyl, methoxy, ethoxy or cyclopropyl, more preferably H, cyano, azide, Methyl or methoxy.

本发明优选方案，提供一种通式（I)所示的化合物或者其立体异构体、溶剂化物、代谢产物、药学上可接受的盐、共晶或前药：

According to a preferred embodiment of the present invention, there is provided a compound of the formula (I) or a stereoisomer, solvate, metabolite, pharmaceutically acceptable salt, eutectic or prodrug thereof:

(I) (I)

其中： among them:

R选自

； R is selected from

;

R¹, R²和 R³各自独立选自 H、 F、 Cl、 Br、 I、羟基、 d_₆垸基、 C₂_₆烯基、 C₂_₆炔基、氰基、 d— ₆垸氧基、 3至 8元碳环基、 3至 8元杂环基、 3至 8元碳环基氧基或者 3至 8元杂环基氧基，所述的垸基、烯基、炔基、垸氧基、碳环基、杂环基、碳环基氧基或者杂环基氧基任选进一步被 0至 5个选自 F、 Cl、 Br、 I、羟基、氨基、氰基、巯基、 d— ₆垸基、 d— ₆垸氧基、 3 至 8元碳环基或者 3至 8元杂环基的取代基所取代，且所述的杂环基含有 1至 2个选自 N、 0 或者 S的杂原子； R ¹ , R ² and R ³ are each independently selected from the group consisting of H, F, Cl, Br, I, hydroxy, d- ₆ fluorenyl, C ₂ _-6 alkenyl, C ₂ _-6 alkynyl, cyano, d- ₆垸An oxy group, a 3 to 8 membered carbocyclic group, a 3 to 8 membered heterocyclic group, a 3 to 8 membered carbocyclic oxy group or a 3 to 8 membered heterocyclic oxy group, said fluorenyl, alkenyl or alkynyl group Further, the methoxy group, the carbocyclic group, the heterocyclic group, the carbocyclic oxy group or the heterocyclic oxy group is further further selected from 0 to 5 selected from the group consisting of F, Cl, Br, I, hydroxy, amino, cyano, fluorenyl Substituted with a substituent of d- ₆ fluorenyl, d- ₆ methoxy, 3 to 8 membered carbocyclyl or 3 to 8 membered heterocyclic group, and said heterocyclic group contains 1 to 2 selected from N a hetero atom of 0 or S;

作为选择， R¹与 R²、 R²与 R³或者 R¹与

中的碳原子可以形成一个 3至 8元环，所述 3至 8元环可以含有 0至 2个选自 N、 0或者 S的杂原子，且形成的 3至 8元环可以任选进一步被 0至 4个 R⁸取代； Alternatively, R ¹ and R ² , R ² and R ³ or R ¹ and

The carbon atom in the ring may form a 3 to 8 membered ring, and the 3 to 8 membered ring may have 0 to 2 hetero atoms selected from N, 0 or S, and the formed 3 to 8 membered ring may optionally be further 0 to 4 R ⁸ substitutions;

R'和 R"各自独立选自 H、 F、 Cl、 Br、 I、羟基、 C₂_₆烯基、 C₂_₆炔基、 d_₆垸基、 d_₆垸氧基、 3至 8元碳环基、 3至 8元杂环基、 3至 8元碳环基氧基或者 3至 8元杂环基氧基，所述的烯基、炔基、垸基、垸氧基、碳环基、杂环基、碳环基氧基或者杂环基氧基任选进一步被 0 至 5个选自 F、 Cl、 Br、 I、羟基、氨基、氰基、巯基、 d_₆垸基、 d_₆垸氧基、 3至 8元碳环基或者 3至 8元杂环基的取代基所取代，且所述的杂环基含有 1至 2个选自 N、 0或者 S的杂原子； R' and R" are each independently selected from the group consisting of H, F, Cl, Br, I, hydroxy, C ₂ _-6 alkenyl, C ₂ _-6 alkynyl, d ₆ fluorenyl, d ₆ oxo a 3- to 8-membered carbocyclic group, a 3- to 8-membered heterocyclic group, a 3- to 8-membered carbocyclic oxy group or a 3- to 8-membered heterocyclic oxy group, said alkenyl group, alkynyl group, fluorenyl group, a methoxy group, a carbocyclic group, a heterocyclic group, a carbocyclic oxy group or a heterocyclic oxy group, optionally further from 0 to 5 selected from the group consisting of F, Cl, Br, I, hydroxy, amino, cyano, fluorenyl, Substituted with a d- ₆ fluorenyl group, a d ₆ methoxy group, a 3 to 8 membered carbocyclic group or a 3 to 8 membered heterocyclic group, and the heterocyclic group contains 1 to 2 selected from N, 0 or a hetero atom of S;

R⁴、 R⁵、 R⁶和 R⁷各自独立选自 H、 F、 Cl、 Br、 I、羟基、 d_₆垸基、 C₂_₆烯基、 C₂_₆炔基、氰基、叠氮基、 d— ₆垸氧基、 3至 8元碳环基、 3至 8元杂环基、 3至 8元碳环基氧基或者 3至 8元杂环基氧基，所述的垸基、烯基、炔基、垸氧基、碳环基、杂环基、碳环基氧基或者杂环基氧基任选进一步被 0至 5个选自 F、 Cl、 Br、 I、羟基、氨基、氰基、巯基、 d— ₆垸基、 d— ₆ 垸氧基、 3至 8元碳环基或者 3至 8元杂环基的取代基所取代，且所述的杂环基含有 1至 2个选自 N、 0或者 S的杂原子； R ⁴ , R ⁵ , R ⁶ and R ⁷ are each independently selected from the group consisting of H, F, Cl, Br, I, hydroxy, d- ₆ fluorenyl, C ₂ _-6 alkenyl, C ₂ _-6 alkynyl, cyano, a stack a nitrogen group, a d- ₆ methoxy group, a 3 to 8 membered carbocyclic group, a 3 to 8 membered heterocyclic group, a 3 to 8 membered carbocyclic oxy group or a 3 to 8 membered heterocyclic oxy group, said hydrazine Or alkoxy, alkenyl, alkynyl, decyloxy, carbocyclyl, heterocyclyl, carbocyclyloxy or heterocyclyloxy optionally further selected from 0 to 5 selected from the group consisting of F, Cl, Br, I, hydroxy Substituted with a substituent of an amino group, a cyano group, a decyl group, a d- ₆ fluorenyl group, a d- ₆ methoxy group, a 3 to 8 membered carbocyclic group or a 3 to 8 membered heterocyclic group, and the heterocyclic group is contained 1 to 2 hetero atoms selected from N, 0 or S;

本发明优选方案，通式（I)所示的化合物或者其立体异构体、溶剂化物、代谢产物、药学上可、共晶或前药，其中：

A preferred embodiment of the invention, a compound of the formula (I) or a stereoisomer, solvate, metabolite, pharmaceutically acceptable, co-crystal or prodrug thereof, wherein:

R¹, R²和 R³各自独立选自 Η或者 d— ₆垸基，优选 H或者 d— ₄垸基，更优选 H、甲基、乙基、正丙基或者异丙基，进一步优选 H、甲基或者乙基； R ¹ , R ² and R ³ are each independently selected from fluorene or d- ₆ fluorenyl, preferably H or d- ₄ fluorenyl, more preferably H, methyl, ethyl, n-propyl or isopropyl, further preferably H , methyl or ethyl;

R'选自 H; R' is selected from H;

R"选自 H、 F、 Cl、 Br或者 I，优选 H、 F、 CI或者 Br，更优选 H; R" is selected from H, F, Cl, Br or I, preferably H, F, CI or Br, more preferably H;

R⁴、 R⁵、 R⁶和 R⁷各自独立选自 H、羟基、 d_₆垸基、氰基、叠氮基、 d_₆垸氧基或者 3至 8元碳环基，所述的垸基、垸氧基或者碳环基可以任选进一步被 0至 3个选自 d— ₆垸基或者 d— ₆ 垸氧基的取代基所取代；优选 R⁴、 R⁵、 R⁶和 R⁷各自独立选自 H、羟基、甲基、乙基、正丙基、异丙基、氰基、叠氮基、甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、 ⁰^^。z、环丙基或者环丁基，更优选 H、羟基、甲基、乙基、氰基、叠氮基、甲氧基、乙氧基、异丙氧基、正丁氧基、 -"^^^QZ或者环丙基，进一步优选 H、甲基、乙基、氰基、叠氮基、甲氧基或者环丙基，更进一步优选、甲基、氰基、叠氮基或者甲氧基； R ⁴ , R ⁵ , R ⁶ and R ⁷ are each independently selected from H, hydroxy, d- ₆ fluorenyl, cyano, azide, d- ₆ methoxy or 3 to 8 valent carbocyclyl. The methoxy or carbocyclic group may be optionally further substituted with from 0 to 3 substituents selected from the group consisting of d- ₆ fluorenyl or d- ₆ fluorenyloxy; preferably each of R ⁴ , R ⁵ , R ⁶ and R ⁷ Independently selected from H, hydroxy, methyl, ethyl, n-propyl, isopropyl, cyano, azide, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy , ⁰ ^^. z, cyclopropyl or cyclobutyl, more preferably H, hydroxy, methyl, ethyl, cyano, azide, methoxy, ethoxy, isopropoxy, n-butoxy, -"^ ^^QZ or cyclopropyl, further preferably H, methyl, ethyl, cyano, azide, methoxy Or a cyclopropyl group, still more preferably a methyl group, a cyano group, an azide group or a methoxy group;

作为选择，和可以形成（ )。 As an option, and can be formed ( ).

本发明优选方案，通式（所示的化合物或者其立体异构体、溶剂化物、代谢产物、药学上可接受的盐、共晶或前药，其中所述化合物选自通式（所示的化合物：

其中： A preferred embodiment of the invention, a compound of the formula (or a stereoisomer, solvate, metabolite, pharmaceutically acceptable salt, eutectic or prodrug thereof, wherein the compound is selected from the group consisting of Compound:

among them:

和各自独立选自或者 d— ₄垸基，优选、甲基、乙基、正丙基或者异丙基，更优选、甲基或者乙基；其中和至少有一个基团为 And d- ₄ are each independently selected from alkyl with or, preferably, methyl, ethyl, n-propyl or isopropyl, more preferably methyl or ethyl; and wherein there is at least one group

和各自独立选自、羟基、 d— ₄垸基、氰基、叠氮基、 d— ₄垸氧基或者至元碳环基，所述的垸基、垸氧基或者碳环基可以任选进一步被至个选自 d—₄垸基或者 d—₄垸氧基的取代基所取代；优选和各自独立选自、羟基、甲基、乙基、正丙基、异丙基、氰基、叠氮基、甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、。^^、环丙基或者环丁基，更优选、羟基、甲基、乙基、氰基、叠氮基、甲氧基、乙氧基、异丙氧基、正丁氧基、 ¾^^^₀ 或者环丙基，进一步优选、甲基、乙基、氰基、叠氮基、甲氧基或者环丙基，更进一步优选、甲基、氰基、叠氮基或者甲氧基。 And each independently selected from a hydroxyl group, a d- ₄ fluorenyl group, a cyano group, an azide group, a d- ₄ methoxy group or a to a carbocyclic group, and the fluorenyl group, the decyloxy group or the carbocyclic group may be optionally selected. Further substituted with a substituent selected from a d- ₄ fluorenyl group or a d- ₄ methoxy group; preferably and independently selected from the group consisting of a hydroxyl group, a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a cyano group, Azido, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy,. ^^, cyclopropyl or cyclobutyl, more preferably, hydroxy, methyl, ethyl, cyano, azide, methoxy, ethoxy, isopropoxy, n-butoxy, 3⁄4^^ ^ ₀ or cyclopropyl, further preferred, methyl, ethyl, cyano, azide, methoxy or cyclopropyl, still more preferably, methyl, cyano, azide or methoxy.

本发明优选方案，通式（所示的化合物或者其立体异构体、溶剂化物、代谢产物，药学上可接受的盐、共晶或前药，其中： A preferred embodiment of the invention, a compound of the formula (or a stereoisomer, solvate, metabolite, pharmaceutically acceptable salt, eutectic or prodrug thereof, wherein:

和各自独立选自、甲基、乙基、正丙基或者异丙基，优选、甲基或者乙基; 其中和至少有一个基团为 And each independently selected from the group consisting of methyl, ethyl, n-propyl or isopropyl, preferably methyl or ethyl; wherein at least one group is

和各自独立选自、羟基、甲基、乙基、正丙基、异丙基、氰基、叠氮基、甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、 ⁰^^、环丙基或者环丁基，优选、羟基、甲基、乙基、氰基、叠氮基、甲氧基、乙氧基、异丙氧基、正丁氧基、 '^ 或者环丙基，更优选、甲基、乙基、氰基、叠氮基、甲氧基或者环丙基，进一步优选、甲基、氰基、叠氮基或者甲氧基。 And each independently selected from, hydroxy, methyl, ethyl, n-propyl, isopropyl, cyano, azide, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy Base, ⁰ ^^, cyclopropyl or cyclobutyl, preferably, hydroxy, methyl, ethyl, cyano, azide, methoxy, ethoxy, isopropoxy, n-butoxy, ' Or a cyclopropyl group, more preferably a methyl group, an ethyl group, a cyano group, an azide group, a methoxy group or a cyclopropyl group, further preferably a methyl group, a cyano group, an azide group or a methoxy group.

本发明优选方案，通式（所示化合物或者其立体异构体、溶剂化物、代谢产物，药学上可接受的盐、共晶或前药，其中： A preferred embodiment of the invention, a compound of the formula (or a stereoisomer, solvate, metabolite, pharmaceutically acceptable salt, eutectic or prodrug thereof, wherein:

和各自独立选自、甲基或者乙基，其中和至少有一个基团为和各自独立选自、羟基、甲基、乙基、氰基、叠氮基、甲氧基、乙氧基、异丙氧基、正丁氧基、 -"^^^ 或者环丙基，优选、甲基、乙基、氰基、叠氮基、甲氧基或者环丙基，更优选 H、甲基、氰基、叠氮基或者甲氧基。 And each independently selected from methyl or ethyl, wherein at least one of the groups is and independently selected from the group consisting of: hydroxy, methyl, ethyl, cyano, azide, methoxy, ethoxy, iso Propyloxy, n-butoxy, -"^^^ or cyclopropyl, preferably, methyl, ethyl, cyano, azide, methoxy or The cyclopropyl group is more preferably H, methyl, cyano, azide or methoxy.

案，本选自， Case, this is selected,

或者

or

本发明还提供了一种（I)所示化合物的方法，该方法包括:

The invention also provides a method of the compound of (I), the method comprising:

通式（I-b)化合物经过格氏反应得到通式（I-c)化合物;

通式（I-c)化合物在还原性条件下脱去羟基得到通式（I-d)化合物；或者在酸性条件下，通式（I-c)化合物与氰化物、叠氮化物或者醇溶液反应得到通式 I-d)化合物； The compound of the formula (Ib) is subjected to a Grignard reaction to obtain a compound of the formula (Ic);

The compound of the formula (Ic) is dehydroxylated under reducing conditions to give a compound of the formula (Id); or under acidic conditions, the compound of the formula (Ic) is reacted with a cyanide, azide or alcohol solution to give the formula Id) Compound

通式（I-d)化合物脱去 R^1Q得到通式（I)化合物，其中， R^1Q选自甲基、甲氧基甲基、乙基、苄基、对甲氧基苄基、三苯甲基、三甲基硅基或者叔丁基二甲基硅基， R、 R'和 R"、 R⁴、 R⁵、 R⁶和 R⁷的定义与通式（I)化合物所述定义一致。 The compound of the formula (Id) is subjected to the removal of R ^{1Q to} give a compound of the formula (I), wherein R ^{1Q is} selected from the group consisting of methyl, methoxymethyl, ethyl, benzyl, p-methoxybenzyl, trityl. , trimethylsilyl or tert-butyldimethylsilyl, the definitions of R, R' and R", R ⁴ , R ⁵ , R ⁶ and R ^{7 are} in accordance with the definitions of the compounds of the formula (I).

此外，本发明还提供一种制备通式（I-b)化法包括： Further, the present invention provides a process for preparing the general formula (I-b) comprising:

在碱性条件下，通式（I-a)化合物与二垸氧基烯烃类化合物发生 [2+2]环加成反应，得到的产物在酸性条件下进一步水解得到通式（I-b)化合物。其中，各取代基定义与前述一致。 Under the alkaline conditions, the compound of the formula (I-a) undergoes a [2+2] cycloaddition reaction with a dimethoxy olefin compound, and the obtained product is further hydrolyzed under acidic conditions to give a compound of the formula (I-b). Wherein, the definition of each substituent is identical to the above.

根据本发明的一具体实施方案，本发明提供的一种制备本发明通式 ω所示化合物的方法包括： According to a particular embodiment of the invention, a method of preparing a compound of the formula ω of the invention provided by the invention comprises:

在碱性条件下，通式（I-a)化合物与二垸氧基烯烃类化合物发生 [2+2]环加成反应，得到的产物在酸性条件下进一 I-b)化合物； Under basic conditions, a compound of the formula (I-a) undergoes a [2+2] cycloaddition reaction with a dimethoxy olefin compound, and the obtained product is subjected to an I-b) compound under acidic conditions;

通式（I-b)化合物经过格氏反应得到通式（I-c)化

The compound of the formula (Ib) is subjected to a Grignard reaction to obtain a formula (Ic)

(l-c) d-d) (l-c) d-d)

通式（I-c)化合物在还原性条件下脱去羟基得到通式（I-d)化合物；或者在酸性条件下，通式（I-c)化合物与氰化物、叠氮化物或者醇溶液反应得到通式 I-d)化合物； The compound of the formula (Ic) is dehydroxylated under reducing conditions to give a compound of the formula (Id); or under acidic conditions, the compound of the formula (Ic) is reacted with a cyanide, azide or alcohol solution to give the formula Id) Compound

根据本发明的一优选具体实施方案，本发明提供的一种合成所述化合物的方法如下： According to a preferred embodiment of the present invention, a method of synthesizing the compound provided by the present invention is as follows:

在碱性条件下，以四氢呋喃为溶剂，氮气保护下，通式（I-a)化合物与 1,1-二乙氧基乙烯发生 [2+2]加成反应，再进一步在酸性条件下水解得到通式（I-b)化合物，其中所述的碱选自氨基钠、叔丁醇钾、丁基锂和二异丙基胺基锂，所述的酸选自盐酸、硫酸或者磷酸；以四氢呋喃、甲苯、 ***或者甲基叔丁基醚为溶剂，氮气保护下，通式（I-b)化合物通过格氏反应得到通式 (I-c)化合物，其中格氏试剂选自甲基溴化镁或者乙基溴化镁；通式（I-c)化合物在以二氯甲垸为溶剂、氮气保护条件下，在还原剂作用下脱去羟基得到通式（I-d)化合物，所述的还原剂选自三乙基硅垸、钯 /炭、 TMSCl/Nal或者 CS₂/NaH， TMSC1是指三甲基氯硅垸，或者在酸性条件下，通式（I-c)化合物与氰化物、叠氮化物或者醇溶液反应得到通式（I-d)化合物，所述的酸选自甲基磺酸、三氟甲磺酸、三氟乙酸、对甲苯磺酸、盐酸、冰乙酸或者三氟化硼***，所述醇选自甲醇、乙醇、异丙醇、叔丁醇、环丙基醇、环丙基甲醇、正丁醇或者甲氧基乙醇，所述的氰化物选自三甲基氰硅垸、对甲苯磺酸异氰酯或者氰化四丁基胺，所述的叠氮化物选自叠氮化钠或者叠氮化钾；通式（I-d)化合物脱去酚羟基保护基团（R 得到通式①化合物，脱保护基试剂选自钯 /炭、氢氧化钯、兰尼镍、三氟乙酸、盐酸、四丁基氟化铵、三氟化铝、三氯化铝或者三氟化硼；其中， R、 R'和 R"、 R⁴、 R⁵、 R⁶和 R⁷的定义与通式（I)化合物所述定义一致， R^1Q如上文定义。 Under the alkaline condition, the compound of the formula (Ia) is subjected to a [2+2] addition reaction with 1,1-diethoxyethylene under the protection of nitrogen under the protection of nitrogen, and further hydrolyzed under acidic conditions. a compound of the formula (Ib), wherein the base is selected from the group consisting of sodium amide, potassium t-butoxide, lithium butylate and lithium diisopropylamide, the acid being selected from the group consisting of hydrochloric acid, sulfuric acid or phosphoric acid; tetrahydrofuran, toluene, The compound of the formula (Ib) is obtained by a Grignard reaction to obtain a compound of the formula (Ic) by using diethyl ether or methyl tert-butyl ether as a solvent, wherein the Grignard reagent is selected from methyl magnesium bromide or ethyl magnesium bromide. The compound of the formula (Ic) is obtained by removing the hydroxyl group under the action of a reducing agent under the protection of nitrogen with methylene chloride as a solvent to obtain a compound of the formula (Id), the reducing agent being selected from the group consisting of triethylsilyl, Palladium/carbon, TMSCl/Nal or CS ₂ /NaH, TMSC1 means trimethylchlorosilane, or under acidic conditions, a compound of the formula (Ic) is reacted with a cyanide, azide or alcohol solution to give a formula ( Id) a compound selected from the group consisting of methanesulfonic acid and trifluoromethanesulfonic acid Trifluoroacetic acid, p-toluenesulfonic acid, hydrochloric acid, glacial acetic acid or boron trifluoride diethyl ether, the alcohol being selected from the group consisting of methanol, ethanol, isopropanol, tert-butanol, cyclopropyl alcohol, cyclopropylmethanol, n-butanol Or methoxyethanol, the cyanide is selected from the group consisting of trimethylcyanosilicate, isocyanuric acid isocyanate or tetrabutylamine cyanide, and the azide is selected from sodium azide or azide. Potassium; a compound of the formula (Id) is deprotected from a phenolic hydroxyl group (R to give a compound of the formula 1, the deprotecting agent is selected from the group consisting of palladium/carbon, palladium hydroxide, Raney nickel, trifluoroacetic acid, hydrochloric acid, tetrabutyl a group of ammonium fluoride, aluminum trifluoride, aluminum trichloride or boron trifluoride; wherein R, R' and R", R ⁴ , R ⁵ , R ⁶ and R ⁷ are defined as a compound of the formula (I) Said Consistently, R ^{1Q is} as defined above.

本发明还提供了一种药物组合物，该药物组合物包含：本发明所述的化合物或者其立体异构体、溶剂化物、代谢产物、药学上可接受的盐、共晶或者前药，和一种或者多种药学上可接受的载体和 /或赋形剂。 The present invention also provides a pharmaceutical composition comprising: a compound of the present invention or a stereoisomer, solvate, metabolite, pharmaceutically acceptable salt, eutectic or prodrug thereof, and One or more pharmaceutically acceptable carriers and/or excipients.

本发明还提供了一种药物组合物，该药物组合物包括：本发明所述的化合物，和一种或多种选自阿片类镇痛剂、镇静催眠剂和 /或心血管药剂的治疗剂。本发明涉及的药物组合物为药学上可以接受的任一剂型，优选为脂质乳剂、注射剂、片剂、气雾剂、粉雾剂、喷雾剂、膜剂、颗粒剂、分散片、冻干粉针剂、胶囊剂、软膏剂、栓剂、乳膏剂、植入剂、糖浆剂、口服溶液剂、口服混悬剂、口服乳剂、散剂或者凝胶剂，更优选冻干粉针剂、注射剂或者脂质乳剂。 The present invention also provides a pharmaceutical composition comprising: a compound of the present invention, and one or more therapeutic agents selected from the group consisting of an opioid analgesic, a sedative hypnotic, and/or a cardiovascular agent . The pharmaceutical composition of the present invention is pharmaceutically acceptable in any dosage form, preferably a lipid emulsion, an injection, a tablet, an aerosol, a powder, a spray, a film, a granule, a dispersible tablet, and a lyophilized tablet. Powder injection, capsule, ointment, suppository, cream, implant, syrup, oral solution, oral suspension, oral emulsion, powder or gel, more preferably lyophilized powder injection, injection or lipid Emulsion.

本发明的化合物或者其立体异构体、溶剂化物、代谢产物、药学上可接受的盐、共晶或者前药，或者所述的药物组合物，可以作为一种 GABA_A受体激动剂，用于制备中枢神经领域相关药物，以便为动物或者人类诱导或维持全身麻醉，促进镇静催眠，治疗和 /或预防焦虑、恶心、呕吐、偏头痛、惊厥、癫痫、神经变性疾病以及中枢神经***相关的疾病提供更多更优的药物选择途径。本发明的新型 GABA_A受体激动剂，它们安全范围更大，起效时间更短，更为突出的是它们以固体的形式存在，相对于丙泊酚有更好的水溶性，因此可以以非脂肪乳剂的形式给药，从而降低产生注射疼痛的可能性，同时避免了乳化剂导致的过敏反应以并降低了制剂被细菌感染的几率。本发明的化合物或者其立体异构体、溶剂化物、代谢产物、药学上可接受的盐、共晶或者前药用于制备相关药物或治疗相关疾病，其药效更好，更安全。 The compound of the present invention, or a stereoisomer, solvate, metabolite, pharmaceutically acceptable salt, eutectic or prodrug thereof, or the pharmaceutical composition, can be used as a GABA _A receptor agonist. For the preparation of drugs related to the central nervous system, in order to induce or maintain general anesthesia for animals or humans, promote sedative hypnosis, treat and / or prevent anxiety, nausea, vomiting, migraine, convulsions, epilepsy, neurodegenerative diseases and central nervous system related The disease provides more and better ways to choose drugs. The novel GABA _A receptor agonists of the present invention have a larger safety range and a shorter onset time, and more prominently, they exist in a solid form and have better water solubility than propofol, so It is administered in the form of a non-fat emulsion, thereby reducing the likelihood of developing injection pain while avoiding allergic reactions caused by the emulsifier and reducing the chance of the formulation being infected by the bacteria. The compounds of the present invention, or stereoisomers, solvates, metabolites, pharmaceutically acceptable salts, eutectic or prodrugs thereof, are useful for the preparation of related drugs or treatment-related diseases, which are more potent and safer.

从而，本发明还提供了通式（I)所示的化合物或者其所有的立体异构体、溶剂化物、代谢产物、药学上可接受的盐、共晶、前药或者包括其的药物组合物在制备中枢神经领域的药物中的用途。 Accordingly, the present invention also provides a compound represented by the formula (I) or all stereoisomers, solvates, metabolites, pharmaceutically acceptable salts, co-crystals, prodrugs or pharmaceutical compositions thereof. Use in the preparation of drugs in the field of central nervous system.

本发明优选方案，提供了一种通式（I)所示的化合物，或者其所有的立体异构体、溶剂化物、代谢产物、药学上可接受的盐、共晶、前药或者包括其的药物组合物在制备中枢神经领域的药物中的用途，所述中枢神经领域的药物包括：用于诱导和维持动物或者人类的麻醉的药物，促进动物或者人类的镇静催眠的药物，或者治疗和 /或预防焦虑、抑郁、失眠、恶心、呕吐、偏头痛、精神***、惊厥或者癫痫的药物，所述的动物包括哺乳动物，例如陪伴动物、动物园动物和家畜，优选马或者犬。 According to a preferred embodiment of the present invention, there is provided a compound of the formula (I), or all stereoisomers, solvates, metabolites, pharmaceutically acceptable salts, eutectic, prodrugs thereof or the like thereof The use of a pharmaceutical composition for the preparation of a medicament in the field of central nervous system, comprising: an agent for inducing and maintaining anesthesia in an animal or a human, a drug for promoting sedation and hypnosis in an animal or a human, or a treatment and/or Or a medicament for preventing anxiety, depression, insomnia, nausea, vomiting, migraine, schizophrenia, convulsions or epilepsy, said animal comprising a mammal, such as a companion animal, a zoo animal and a domestic animal, preferably a horse or a dog.

本发明优选方案，提供了一种通式（I)所示的化合物，或者其所有的立体异构体、溶剂化物、代谢产物、药学上可接受的盐、共晶、前药或者包括其的药物组合物在制备中枢神经领域的药物中的用途，所述中枢神经领域的药物包括用于诱导和维持动物或者人类的麻醉的药物。 According to a preferred embodiment of the present invention, there is provided a compound of the formula (I), or all stereoisomers, solvates, metabolites, pharmaceutically acceptable salts, eutectic, prodrugs thereof or the like thereof The use of a pharmaceutical composition for the preparation of a medicament in the field of central nervous system, the medicament for the central nervous system includes a medicament for inducing and maintaining anesthesia of an animal or a human.

本发明还提供了一种诱导和维持动物或者人类的麻醉的方法，该方法包括给予动物或者人类有效量的通式 (I)所示的化合物或者其所有的立体异构体、溶剂化物、代谢产物、药学上可接受的盐、共晶、前药或者包括其的药物组合物。 The present invention also provides a method of inducing and maintaining anesthesia in an animal or a human, which comprises administering to an animal or a human an effective amount of a compound of the formula (I) or all stereoisomers, solvates, metabolism thereof. Product, pharmaceutically acceptable A salt, eutectic, prodrug or pharmaceutical composition comprising the same.

本发明还提供了一种促进动物或者人类的镇静催眠的方法，该方法包括给予动物或者人类有效量的通式 (I)所示的化合物或者其所有的立体异构体、溶剂化物、代谢产物、药学上可接受的盐、共晶、前药或者包括其的药物组合物。 The present invention also provides a method for promoting sedative and hypnotic in an animal or a human, which comprises administering to an animal or a human an effective amount of a compound of the formula (I) or all stereoisomers, solvates, metabolites thereof. A pharmaceutically acceptable salt, eutectic, prodrug or pharmaceutical composition comprising the same.

本发明还提供了一种治疗和 /或预防动物或者人类焦虑、抑郁、失眠、恶心、呕吐、偏头痛、精神***、惊厥或者癫痫的方法，该方法包括给予动物或者人类有效量的通式 ω所示的化合物或者其所有的立体异构体、溶剂化物、代谢产物、药学上可接受的盐、共晶、前药或者包括其的药物组合物。 The invention also provides a method of treating and/or preventing anxiety, depression, insomnia, nausea, vomiting, migraine, schizophrenia, convulsions or epilepsy in an animal or human, the method comprising administering to the animal or human an effective amount of the formula ω The compound shown, or all stereoisomers, solvates, metabolites, pharmaceutically acceptable salts, eutectic, prodrugs thereof or pharmaceutical compositions comprising the same.

除非有相反的陈述，在说明书和权利要求书中使用的术语具有下述含义。 Terms used in the specification and claims have the following meanings unless stated to the contrary.

本发明所述基团和化合物中所涉及的碳、氢、氧、硫、氮或卤素均包括它们的同位素情况，及本发明所述基团和化合物中所涉及的碳、氢、氧、硫或氮任选进一步被一个或多个它们对应的同位素所替代，其中碳的同位素包括 ¹²C、 ¹³C和 ¹⁴C，氢的同位素包括氕（H)、氘（D，又叫重氢 )、氚（T，又叫超重氢； I，氧的同位素包括¹⁶0、 ¹⁷0和¹⁸0，硫的同位素包括 ³²S、 ³³S、 ³⁴S 和 ³⁶S，氮的同位素包括 ¹⁴N和 ¹⁵N，氟的同位素包括 ¹⁷F和 ¹⁹F，氯的同位素包括 ³⁵C1和 ³⁷C1，溴的同位素包括 ⁷¾r和 ⁸¹Br。 The carbon, hydrogen, oxygen, sulfur, nitrogen or halogen involved in the groups and compounds of the present invention include their isotopic conditions, and the carbon, hydrogen, oxygen, sulfur involved in the groups and compounds of the present invention. Or the nitrogen is optionally further replaced by one or more of their corresponding isotopes, wherein the carbon isotopes include ¹² C, ¹³ C, and ¹⁴ C, and the hydrogen isotopes include helium (H), helium (D, also known as heavy hydrogen),氚 (T, also known as super heavy hydrogen; I, oxygen isotopes include ¹⁶ 0, ¹⁷ 0 and ¹⁸ 0, sulfur isotopes include ³² S, ³³ S, ³⁴ S and ³⁶ S, nitrogen isotopes include ¹⁴ N and ¹⁵ N, The fluorine isotopes include ¹⁷ F and ¹⁹ F, the chlorine isotopes include ³⁵ C1 and ³⁷ C1, and the bromine isotopes include ⁷ 3⁄4r and ⁸¹ Br.

"垸基 "是指 1至 20个碳原子的直链或支链饱和脂肪族烃基，优选为 1至 8个碳原子的垸基，更优选为 1至 6个碳原子的垸基，进一步优选为 1至 4个碳原子的垸基。非限制性实施例包括甲基、乙基、正丙基、异丙基、正丁基、仲丁基、叔丁基、正戊基、异戊基、新戊基、正己基及其各种支链异构体；所述的垸基可以任选进一步被 0至 5个选自 F、 Cl、 Br、 I、 =0、羟基、巯基、 -SR¹⁸、硝基、氰基、氨基、垸基氨基、酰胺基、烯基、炔基、 d— ₆垸基、 d— ₆羟基垸基、 ₆垸氧基、 3至 8元碳环基、 3至 8元杂环基、 3至 8元碳环基氧基、 3至 8元杂环基氧基、羧基或者羧酸酯基的取代基所取代，其中 R¹⁸选自 d— ₆垸基、 3至 8元碳环基或者 3 至 8元杂环基，本文中出现的垸基，其定义如上所述。 The "mercapto group" means a linear or branched saturated aliphatic hydrocarbon group of 1 to 20 carbon atoms, preferably a fluorenyl group of 1 to 8 carbon atoms, more preferably a fluorenyl group of 1 to 6 carbon atoms, further preferably A fluorenyl 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 thereof A branched chain isomer; the thiol group may be further optionally 0 to 5 selected from the group consisting of F, Cl, Br, I, =0, hydroxy, decyl, -SR ¹⁸ , nitro, cyano, amino, hydrazine Base amino, amide, alkenyl, alkynyl, d- ₆ fluorenyl, d- ₆ hydroxy fluorenyl, ₆ methoxy, 3 to 8 membered carbocyclic, 3 to 8 membered heterocyclic, 3 to 8 Substituted by a carbocyclic oxy group, a 3- to 8-membered heterocyclic oxy group, a carboxy group or a carboxylate group, wherein R ^{18 is} selected from the group consisting of d- ₆ fluorenyl, 3 to 8 membered carbocyclyl or 3 to 8 The heterocyclic group, the fluorenyl group appearing herein, is as defined above.

"垸氧基"是指 -0-垸基。非限制性实施例包括甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、仲丁氧基、叔丁氧基、正戊氧基、正己氧基、环丙氧基和环丁氧基。所述的垸基可以任选进一步被 0至 5个选自 F、 Cl、 Br、 I、 =0、羟基、巯基、 -SR¹⁸、硝基、氰基、氨基、垸基氨基、酰胺基、烯基、炔基、垸基、羟基垸基、垸氧基、碳环基、杂环基、碳环基氧基、杂环基氧基、羧基或者羧酸酯基的取代基所取代，其中 R¹⁸如上文定义。 "Alkoxy" means -0-fluorenyl. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentyloxy, n-hexyloxy, cyclopropane Oxyl and cyclobutoxy. The thiol group may be further optionally further selected from 0 to 5 selected from the group consisting of F, Cl, Br, I, =0, hydroxy, decyl, -SR ¹⁸ , nitro, cyano, amino, decylamino, amide, Substituted by a substituent of an alkenyl group, an alkynyl group, a decyl group, a hydroxy fluorenyl group, a decyloxy group, a carbocyclic group, a heterocyclic group, a carbocyclic oxy group, a heterocyclic oxy group, a carboxy group or a carboxylate group, wherein R ^{18 is} as defined above.

"PEG"或 "聚乙二醇"是指含有 ^^^^H的聚合物，其中 n是 2〜大约 1000范围内的整数，优选 2〜大约 500，更优选 2〜大约 250，更优选 2〜大约 125，进一步优选 2〜大约 25范围内的整数。 "PEG" or "polyethylene glycol" means a polymer containing ^^^^H, wherein n is an integer in the range of from 2 to about 1000, preferably from 2 to about 500, more preferably from 2 to about 250, more preferably 2 ~ about 125, further preferably an integer in the range of 2 to about 25.

"氨基 "是指 -NH₂。 "垸基氨基"是指具有一个或者两个垸基取代基的氨基基团。 "Amino" means -NH ₂ . "Mercaptoamino" means an amino group having one or two mercapto substituents.

"氰基 "是指 Λ "Cyano" means Λ

。 .

"硝基 "是指 ί-Ν0_{2 ο} "Nitro" means ί-Ν0 _{2 ο}

"羟基 "是指 "hydroxy" means

"巯基 "是指- οSH。 "巯基" means - οSH.

"羧基 "是指 ί-COOHo "carboxy" means ί-COOHo

"羰基 "是指-(c=o)-。 "Carbonyl" means -(c=o)-.

"羧酸酯基"是指 -COOR¹⁹，其中 1 ¹⁹为 d— ₆垸基。 "Carboxylic acid ester group" means -COOR ¹⁹ wherein 1 ¹⁹ is d- ₆ fluorenyl.

"酰胺基"是指 -CONR^2QR²¹，其中 R^2Q和 R²¹各自独立选自 H、垸基或者碳环基， R^2Q和 R²¹ 可以任选进一步被 0至 3个选自 F、 Cl、 Br、 I、羟基、巯基、 -SR¹⁸、硝基、氰基、氨基、垸基氨基、酰胺基、烯基、炔基、垸基、羟基垸基、垸氧基、碳环基、杂环基、碳环基氧基、杂环基氧基、羧基或者羧酸酯的取代基所取代，其中 R¹⁸如上文定义。 "Amido" means -CONR ^2Q R ²¹ , wherein R ^2Q and R ²¹ are each independently selected from H, fluorenyl or carbocyclyl, and R ^2Q and R ²¹ may optionally be further selected from 0 to 3 selected from F, Cl. , Br, I, hydroxy, fluorenyl, -SR ¹⁸ , nitro, cyano, amino, decylamino, amide, alkenyl, alkynyl, fluorenyl, hydroxy fluorenyl, decyloxy, carbocyclyl, hetero cycloalkyl group, a carbocyclic group, a heterocyclic oxy group, a carboxyl group or a carboxylate group substituted with a substituent, wherein R ¹⁸ is as defined above.

"=0"为本领域通常习惯用法，是指以双键相连的氧原子，譬如羰基中与碳原子相连的双键氧原子。 "=0" is a commonly used practice in the art and refers to an oxygen atom connected by a double bond, such as a double bond oxygen atom to a carbon atom in a carbonyl group.

"羟基垸基"是被 1、 2或者 3个羟基取代的垸基，所述的垸基优选为 d—₄垸基。非限制性实施例包括羟基甲基、 1-羟基乙基、 2-羟基乙基、 1 ,2-二羟基丙基、 1 ,3-二羟基丙基和 2,3-二羟基丙基。 "Hydroxymethane" is a fluorenyl group substituted by 1, 2 or 3 hydroxy groups, and the fluorenyl group is preferably a d- ₄ fluorenyl group. Non-limiting examples include hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1 ,2-dihydroxypropyl, 1 ,3-dihydroxypropyl, and 2,3-dihydroxypropyl.

"烯基 "是指含有 1至 3个碳-碳双键、由 2-20个碳原子组成的直链或者支链不饱和脂肪族烃基，优选 2- 12个碳原子的烯基，更优选 2-8个碳原子的烯基。非限制性实施例包括乙烯基、丙烯 -2-基、丁烯 -2-基、丁烯 -2-基、戊烯 -2-基、戊烯 -4-基、己烯 -2-基、己烯 -3基、庚烯 -2-基、庚烯 -3-基、庚烯 -4-基、辛烯 -3-基、壬烯 -3-基、癸烯 -4-基和十一烯 -3-基。所述的烯基可以任选进一步被 0至 5个选自 F、 Cl、 Br、 I、羟基、垸基、垸氧基、直链烯基、直链炔基、氨基、硝基、氰基、巯基、酰胺基、碳环基或者杂环基的取代基所取代，且所述的杂环基含有 1至 2个选自 N、 0或者 S的杂原子。 "Alkenyl" means an alkyl group having from 1 to 3 carbon-carbon double bonds, a linear or branched unsaturated aliphatic hydrocarbon group consisting of 2 to 20 carbon atoms, preferably 2 to 12 carbon atoms, more preferably Alkenyl of 2-8 carbon atoms. Non-limiting examples include vinyl, propen-2-yl, buten-2-yl, buten-2-yl, penten-2-yl, penten-4-yl, hexene-2-yl, Hexene-3,hepten-2-yl,hepten-3-yl,hepten-4-yl,octen-3-yl,nonen-3-yl,nonen-4-yl and eleven Alk-3-yl. The alkenyl group may be further optionally further selected from 0 to 5 selected from the group consisting of F, Cl, Br, I, hydroxy, decyl, decyloxy, linear alkenyl, linear alkynyl, amino, nitro, cyano Substituted with a substituent of a mercapto group, an amide group, a carbocyclic group or a heterocyclic group, and the heterocyclic group contains 1 to 2 hetero atoms selected from N, 0 or S.

"炔基 "是指含有 1至 3个碳-碳叁键、由 2-20个碳原子组成的直链或者支链不饱和脂肪族烃基，优选 2- 12个碳原子的炔基，更优选 2-8个碳原子的炔基。非限制性实施例包括乙炔基、丙炔 - 1 -基、丙炔 -2-基、丁炔 - 1 -基、丁炔 -2-基、丁炔 -3-基、 3,3-二甲基丁炔 -2-基、戊炔 - 1 -基、戊炔 -2-基、己炔 - 1 -基、 1 -庚炔 - 1 -基、庚炔 -3-基、庚炔 -4-基、辛炔 -3-基、壬炔 -3-基、癸炔 -4- 基、十一炔 -3-基、十二炔 -4-基。所述的炔基可以任选进一步被 0至 5个选自 F、 Cl、 Br、 I、羟基、垸基、垸氧基、直链烯基、直链炔基、氨基、硝基、氰基、巯基、酰胺基、碳环基或者杂环基的取代基所取代，且所述的杂环基含有 1至 2个选自 N、 0或者 S的杂原子。 "Alkynyl" means an alkynyl group having 1 to 3 carbon-carbon triple bonds, a linear or branched unsaturated aliphatic hydrocarbon group consisting of 2 to 20 carbon atoms, preferably 2 to 12 carbon atoms, more preferably Alkynyl group of 2-8 carbon atoms. Non-limiting examples include ethynyl, propynyl-1-yl, propyn-2-yl, butyn-1-yl, butyn-2-yl, butyn-3-yl, 3,3-dimethyl Butyrynyl-2-yl, pentyne-1-yl, pentyn-2-yl, hexyne-1-yl, 1-hexyne-1-enyl, heptyn-3-yl, heptyne-4- Base, octyn-3-yl, decyn-3-yl, decyn-4-yl, undecy-3-yl, dodecyn-4-yl. The alkynyl group may be further optionally further selected from 0 to 5 selected from the group consisting of F, Cl, Br, I, hydroxy, decyl, decyloxy, linear alkenyl, linear alkynyl, amino, nitro, cyano Substituted with a substituent of a mercapto group, an amide group, a carbocyclic group or a heterocyclic group, and the heterocyclic group contains 1 to 2 hetero atoms selected from N, 0 or S.

"碳环基"是指饱和或者不饱和的芳香环或者非芳香环，芳香环或者非芳香环可以是 3至 8 元料的单环、 4至 12元双环或者 10至 15元三环体系，碳环基可以连接有桥环或者螺环，非限制性实施例包括环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环癸基和环十二垸基、环己烯、 ^、、 ' vv。所述的碳环基可以任选进一步被 0至 8个选自 _F、 _α、 _Br、 I、 =0、羟基、巯基、 -SR¹⁸、硝基、氰基、氨基、垸基氨基、酰胺基、烯基、炔基、垸基、羟基垸基、垸氧基、碳环基、杂环基、碳环基氧基、杂环基氧基、羧基或者羧酸酯基所取代，其中 R¹⁸如上文定义。 "Carbocyclyl" means a saturated or unsaturated aromatic or non-aromatic ring, and an aromatic or non-aromatic ring may be 3 to 8 a monocyclic, 4 to 12 membered bicyclic or 10 to 15 membered tricyclic system of the material, a carbocyclic group may be attached to a bridged ring or a spiro ring, and non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, Cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl and cyclododecanyl, cyclohexene, ^, , 'vv. The carbocyclic group may be further optionally further selected from 0 to 8 selected from the group consisting of _F , _α , _Br , I, =0, hydroxy, decyl, -SR ¹⁸ , nitro, cyano, amino, decylamino, amide Substituted by alkenyl, alkynyl, decyl, hydroxyindenyl, decyloxy, carbocyclyl, heterocyclyl, carbocyclyloxy, heterocyclyloxy, carboxy or carboxylate, wherein R ¹⁸ As defined above.

"杂环基"是指取代的或未取代的饱和或不饱和的芳香环或者非芳香环，芳香环或者非芳香环可以是 3至 8元的单环、 4至 12元双环或者 10至 15元三环体系，且包含 1至 3个选自 N、 0或 S的杂原子，优选 3至 8元杂环基，杂环基的环中选择性取代的 N、 S可被氧化成各种氧化态。杂环基可以连接在杂原子或者碳原子上，杂环基可以连接有桥环或者螺环，非限制性实施例包括环氧乙基、氮杂环丙基、氧杂环丁基、氮杂环丁基、 1,3-二氧戊环基、 1,4-二氧戊环基、 1,3-二氧六环基、氮杂环庚基、吡啶基、呋喃基、噻吩基、吡喃基、 N-垸基吡咯基、嘧啶基、吡嗪基、哒嗪基、咪唑基、哌啶基、哌叮基、吗啉基、硫代吗啉基、 1,3-二噻基、二氢呋喃基、二氢吡喃基、二噻戊环基、四氢呋喃基、四氢吡咯基、四氢咪唑基、四氢噻唑基、四氢吡喃基、苯并咪唑基、苯并吡啶基、吡咯并吡啶基、苯并二氢呋喃基、氮杂二环 [3.2.1]辛垸基、氮杂二环 [5.2.0]壬垸基、氧杂三环 [5.3.1.1]十二垸基、氮杂金刚垸基和氧杂螺 [3.3]庚垸基。所述的杂环基可以任选进一步被 0至 5个选自 F、 Cl、 Br、 I、 =0、羟基、巯基、 -SR¹⁸、硝基、氰基、氨基、垸基氨基、酰胺基、烯基、炔基、垸基、羟基垸基、垸氧基、碳环基、杂环基、碳环基氧基、杂环基氧基、羧基或者羧酸酯基的取代基所取代，其中 R¹⁸如上文定义。 "Heterocyclyl" means a substituted or unsubstituted saturated or unsaturated aromatic or non-aromatic ring, and the aromatic or non-aromatic ring may be a 3 to 8 membered monocyclic ring, a 4 to 12 membered bicyclic ring or 10 to 15 a tricyclic ring system, and comprising 1 to 3 hetero atoms selected from N, 0 or S, preferably a 3 to 8 membered heterocyclic group, and optionally substituted N, S in the ring of the heterocyclic group may be oxidized into various Oxidation state. The heterocyclic group may be attached to a hetero atom or a carbon atom, and the heterocyclic group may be bonded to a bridged or spiro ring, and non-limiting examples include epoxyethyl, azacyclopropyl, oxetanyl, aza. Cyclobutyl, 1,3-dioxolanyl, 1,4-dioxolanyl, 1,3-dioxolyl, azepanyl, pyridyl, furyl, thienyl, pyridyl Cyclol, N-fluorenylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinyl, piperidinyl, morpholinyl, thiomorpholinyl, 1,3-dithia, Dihydrofuranyl, dihydropyranyl, dithiapentanyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, benzimidazolyl, benzopyridinyl , pyrrolopyridyl, benzodihydrofuranyl, azabicyclo[3.2.1]octyl, azabicyclo[5.2.0]decyl, oxatricyclo[5.3.1.1]dodedecyl , aza-adamantyl and oxaspiro[3.3]heptanyl. The heterocyclic group may be further optionally 0 to 5 selected from the group consisting of F, Cl, Br, I, =0, hydroxy, decyl, -SR ¹⁸ , nitro, cyano, amino, decylamino, amide Substituted by a substituent of an alkenyl group, an alkynyl group, a decyl group, a hydroxy fluorenyl group, a decyloxy group, a carbocyclic group, a heterocyclic group, a carbocyclic oxy group, a heterocyclic oxy group, a carboxy group or a carboxylate group, Wherein R ^{18 is} as defined above.

"药物组合物 "是指一种或多种本发明所述化合物、其药学上可接受的盐或前药和其它化学组分形成的混合物，其中， "其它化学组分"是指药学上可接受的载体、赋形剂和 /或一种或多种其它治疗剂； "其它治疗剂 "是指镇静催眠剂、麻醉剂、镇痛剂、麻痹剂、止吐药、心血管药剂或者情绪调节剂。 "Pharmaceutical composition" means a mixture of one or more compounds of the present invention, pharmaceutically acceptable salts or prodrugs thereof and other chemical components, wherein "other chemical component" means pharmaceutically acceptable Accepted carrier, excipient and/or one or more other therapeutic agents; "other therapeutic agents" means sedative hypnotics, anesthetics, analgesics, numbing agents, antiemetics, cardiovascular agents or mood modulators .

"载体 "是指不会对生物体产生明显刺激且不会消除所给予化合物的生物活性和特性的材 "Carrier" means a material that does not cause significant irritation to the organism and does not eliminate the biological activity and properties of the administered compound.

"赋形剂"是指加入到药物组合物中以促进化合物给药的惰性物质。非限制性实施例包括碳酸钙、磷酸钙、糖、淀粉、纤维素衍生物（包括微晶纤维素)、明胶、植物油、聚乙二醇类、稀释剂、成粒剂、润滑剂、粘合剂和崩解剂。 "Excipient" means an inert substance that is added to a pharmaceutical composition to facilitate administration of the compound. Non-limiting examples include calcium carbonate, calcium phosphate, sugar, starch, cellulose derivatives (including microcrystalline cellulose), gelatin, vegetable oils, polyethylene glycols, diluents, granulating agents, lubricants, bonding Agent and disintegrant.

"前药 "是指可经体内代谢转化为具有生物活性的本发明化合物。本发明的前药通过修饰本发明化合物中的酚基团来制备，该修饰可以通过常规的操作或者在体内被除去，而得到母体化合物。当本发明的前药被施予哺乳动物或人类个体时，前药被割裂形成游离的羟基。 "共晶"是指活性药物成分和共晶形成物在氢键或其他非共价键的作用下结合而成的晶体，其中 API (活性用药成分）和 CCF (共晶形成物）的纯态在室温下均为固体，并且各组分间存在固定的化学计量比。共晶是一种多组分晶体，既包含两种中性固体之间形成的二元共晶，也包含中性固体与盐或溶剂化物形成的多元共晶。共晶形成物的非限定性实例包括丙氨酸、缬氨酸、亮氨酸、异亮氨酸、脯氨酸、苯丙氨酸、色氨酸、蛋氨酸、甘氨酸、丝氨酸、苏氨酸、半胱氨酸、酪氨酸、天冬酰胺、谷氨酰胺、赖氨酸、精氨酸、组氨酸、天冬氨酸、门冬氨酸、谷氨酸、焦谷氨酸、硫酸、磷酸、硝酸、氢溴酸、盐酸、甲酸、乙酸、丙酸、苯磺酸、苯甲酸、苯乙酸、水杨酸、褐藻酸、氨茴酸、樟脑酸、柠檬酸、乙烯磺酸、蚁酸、富马酸、糠酸、葡萄糖酸、葡萄糖醛酸、谷氨酸、乙醇酸、羟乙磺酸、乳酸、马来酸、苹果酸、扁桃酸、粘液酸、双羟萘酸、泛酸、硬脂酸、琥珀酸、磺胺酸、酒石酸、对甲苯磺酸、丙二酸、 2-羟基丙酸、草酸、羟乙酸、葡萄糖醛酸、半乳糖醛酸、枸橼酸、肉桂酸、对甲苯磺酸、甲磺酸、乙磺酸或三氟甲磺酸、氨、异丙基胺、三甲基胺、二乙胺、三乙胺、三丙基胺、二乙醇胺、乙醇胺、二甲基乙醇胺、 2-二甲基氨基乙醇、 2-二乙基氨基乙醇、二环己基胺、咖啡碱、普鲁卡因、胆碱、甜菜碱、苯明青霉素、乙二胺、葡萄糖胺、甲基葡糖胺、可可碱、三乙醇胺、氨丁三醇、嘌吟、哌嗪、哌啶和 N-乙基哌啶。 "Prodrug" means a compound of the invention that can be converted to biological activity by metabolism in vivo. Prodrugs of the invention are prepared by modifying a phenolic group in a compound of the invention which can be removed by conventional procedures or in vivo to provide the parent compound. When a prodrug of the invention is administered to a mammal or a human subject, the prodrug is cleaved to form a free hydroxyl group. "eutectic" refers to a crystal in which an active pharmaceutical ingredient and a eutectic formation are combined by hydrogen bonding or other non-covalent bond, wherein the API (active pharmaceutical ingredient) and CCF (eutectic formation) are in a pure state. They are all solid at room temperature and there is a fixed stoichiometric ratio between the components. Eutectic is a multi-component crystal that contains both a binary eutectic formed between two neutral solids and a multi-eutectoid formed from a neutral solid with a salt or solvate. Non-limiting examples of eutectic formations include alanine, valine, leucine, isoleucine, valine, phenylalanine, tryptophan, methionine, glycine, serine, threonine, Cysteine, tyrosine, asparagine, glutamine, lysine, arginine, histidine, aspartic acid, 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, vinyl sulfonic acid, formic acid , fumaric acid, citric acid, gluconic acid, glucuronic acid, glutamic acid, glycolic acid, isethionate, lactic acid, maleic acid, malic acid, mandelic acid, mucic acid, pamoic acid, pantothenic acid, hard Fatty acid, succinic acid, sulfamic acid, tartaric acid, p-toluenesulfonic acid, malonic acid, 2-hydroxypropionic acid, oxalic acid, glycolic acid, glucuronic acid, galacturonic acid, citric acid, cinnamic acid, p-toluene Acid, methanesulfonic acid, ethanesulfonic acid or trifluoromethanesulfonic acid , ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylamino Ethanol, dicyclohexylamine, caffeine, procaine, choline, betaine, phenamine, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine, hydrazine , piperazine, piperidine and N-ethylpiperidine.

"动物"是指包括哺乳动物，例如陪伴动物、动物园动物和家畜，优选马或者犬。 "Animal" is meant to include mammals, such as companion animals, zoo animals, and domestic animals, preferably horses or dogs.

"立体异构体 "是指由分子中原子在空间上排列方式不同所产生的异构体，包括顺反异构体、对映异构体和构象异构体。 "Stereoisomer" refers to isomers resulting from the arrangement of atoms in a molecule in a spatial arrangement, including cis-trans isomers, enantiomers, and conformational isomers.

"任选 "或"任选地 "或"选择性的"或"选择性地"是指随后所述的事件或状况可以但未必发生，该描述包括其中发生该事件或状况的情况及其中未发生的情况。例如， "选择性地被垸基取代的杂环基 "是指该垸基可以但未必存在，该描述包括其中杂环基被垸基取代的情况，及其中杂环基未被垸基取代的情况。 "Optional" or "optionally" or "optional" or "optionally" means that the subsequently described event or condition may, but does not necessarily, occur, including where the event or condition occurred and What happened. For example, "heterocyclic group optionally substituted by a thiol group" means that the fluorenyl group may, but does not necessarily exist, the description including the case where the heterocyclic group is substituted by a thiol group, and wherein the heterocyclic group is not substituted by a thiol group Happening.

ED₅₀ (半数有效量 )：通过测试导致 50%小鼠翻正反射丧失需要的剂量。 ED ₅₀ (half effective amount): The dose required to cause 50% of the mice to have a righting reflex loss by testing.

ED₉₅(95%有效量 )：通过测试导致 95%小鼠翻正反射丧失需要的剂量。 ED ₉₅ (95% effective amount): The dose required to cause 95% of mice to lose righting reflexes by testing.

LD_5Q(半数致死量; )：通过测试导致 50%小鼠死亡需要的剂量。 LD _5Q (half lethal dose; ): The dose required to kill 50% of mice by testing.

LD₅(5%致死量 )：通过测试导致 5%小鼠死亡需要的剂量。 LD ₅ (5% lethal dose): The dose required to kill 5% of mice by testing.

麻醉诱导时间和麻醉维持时间：给药后开始计时，密切观察动物一般症状和给药局部、呼吸的变化。如正常动物将其推倒或呈背位仰卧时，能立即翻正过来，这种反射判为翻正反射。反之，则视为翻正反射消失，记录反射消失时间，待动物重新出现翻正反射时，记录反射恢复时间。将给药结束至翻正反射的时间记为麻醉起效时间，自翻正反射消失至反射恢复时间记为麻醉维持时间。 Anesthesia induction time and anesthesia maintenance time: Start timing after administration, and closely observe the general symptoms of the animal and the changes in local administration and respiration. If a normal animal pushes it down or is lying on its back, it can be turned over immediately. This reflection is judged as a righting reflection. On the contrary, it is regarded as the disappearance of the righting reflection, and the reflection disappearance time is recorded. When the animal reappears the righting reflection, the reflection recovery time is recorded. The time from the end of 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 anesthesia maintenance time.

TI (治疗指数，即 LD₅₀/ ED₅₀ )、 SI (安全指数，即 LD₅/ ED₉₅ )。具体实施方式 TI (therapeutic index, ie LD ₅₀ / ED ₅₀ ), SI (safety index, ie LD ₅ / ED ₉₅ ). Detailed ways

以下通过具体实施例详细说明本发明的实施过程和产生的有益效果，旨在帮助阅读者更好地理解本发明的实质和特点，不作为对本案可实施范围的限定。本发明中，化合物的结构是通过核磁共振（NMR) 或（和）质谱（MS)来确定的。 NMR位移（δ) 以 10- ⁶ (ppm) 的单位给出。 NMR的测定是用（Bruker Avance III 400和 Bruker Avance 300) 核磁仪，测定溶剂为氘代二甲基亚砜（DMSO-d₆)，氘代氯仿（CDC1₃)，氘代甲醇 (CD₃OD), 内标为四甲基硅垸 (TMS); The embodiments of the present invention and the beneficial effects thereof are described in detail below by way of specific examples, which are intended to provide a better understanding of the nature and characteristics of the present invention. In the present invention, the structure of the compound is determined by nuclear magnetic resonance (NMR) or (and) mass spectrometry (MS). The NMR shift (δ) is given in units of 10 - ⁶ (ppm). The NMR was measured using a (Bruker Avance III 400 and Bruker Avance 300) nuclear magnetic apparatus, and the solvent was deuterated dimethyl sulfoxide (DMSO-d ₆ ), deuterated chloroform (CDC1 ₃ ), deuterated methanol (CD ₃ OD). ), the internal standard is tetramethylsilane (TMS);

MS的测定用 (Agilent 6120B(ESI)和 Agilent 6120B(APCI); For the determination of MS (Agilent 6120B (ESI) and Agilent 6120B (APCI);

HPLC的测定使用 Agilent 1260DAD高压液相色谱仪（Agilent Zorbax SB-C18 100 4.6 mm, 3.5 μηι); HPLC was determined using an Agilent 1260 DAD high pressure liquid chromatograph (Agilent Zorbax SB-C18 100 4.6 mm, 3.5 μηι);

薄层层析硅胶板使用烟台黄海 HSGF254 或青岛 GF254硅胶板，薄层色谱法（TLC)使用的硅胶板采用的规格是 0.15 mm~0.20 mm, 薄层层析分离纯化产品采用的规格是 0.4 mm ~ 0.5 mm; The thin layer chromatography silica gel plate uses Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plate. The silica gel plate used for thin layer chromatography (TLC) has a specification of 0.15 mm~0.20 mm, and the thin layer chromatography separation and purification product adopts the specification of 0.4 mm. ~ 0.5 mm;

柱层析一般使用烟台黄海硅胶 200~300目硅胶为载体； Column chromatography generally uses Yantai Huanghai silica gel 200~300 mesh silica gel as carrier;

本发明的己知起始原料可以采用或按照本领域已知的方法来合成，或可购买于泰坦科技、安耐吉化学、上海德默、成都科龙化工、韶远化学科技、百灵威科技等公司； The starting materials of the present invention may be synthesized by or according to methods known in the art, or may be purchased from Titan Technology, Anike Chemical, Shanghai Demo, Chengdu Kelon Chemical, Suiyuan Chemical Technology, Belling Technology, etc. the company;

氮气氛围是指反应瓶连接一个约 1L容积的氮气气球； Nitrogen atmosphere means that the reaction flask is connected to a nitrogen balloon of about 1L volume;

氢气氛围是指反应瓶连接一个约 1L容积的氢气气球； The hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon of about 1L volume;

氢化反应通常抽真空，充入氢气，反复操作 3次； The hydrogenation reaction is usually evacuated, filled with hydrogen, and operated three times;

实施例中无特殊说明，反应在氮气氛围下进行； There is no special description in the examples, and the reaction is carried out under a nitrogen atmosphere;

实施例中无特殊说明，溶液是指水溶液； There is no special description in the examples, and the solution means an aqueous solution;

实施例中无特殊说明，反应的温度为室温，室温最适宜的反应温度，为 20°C ~ 30°C; Me, 甲基； There is no special description in the examples, the reaction temperature is room temperature, and the optimum reaction temperature at room temperature is 20 ° C ~ 30 ° C; Me, methyl;

Et，乙基； Et, ethyl;

Bn，苄基； Bn, benzyl;

Bz，苯甲酰基； Bz, benzoyl;

DMSO, 二甲基亚砜； DMSO, dimethyl sulfoxide;

Saline, 生理盐水； Saline, saline;

Soluto HS15 , 聚乙二醇硬脂酸 15; Soluto HS15, polyethylene glycol stearic acid 15;

RT，峰保留时间。中间体 1: 5-苄氧基 -4-异丙基 -并环『4,2,01辛垸 -1，3，5-三烯 -7-酮 (If) RT, peak retention time. Intermediate 1: 5-Benzyloxy-4-isopropyl-cyclo[4,2,01 octone-1,3,5-trien-7-one (If)

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

第一步： 2-溴 -6-异丙基苯酚（lb)

First step: 2-bromo-6-isopropylphenol (lb)

2-bromo-6-isopropylphenol

向反应瓶中依次加入 2-异丙基苯酚 la (10.00 g, 73.4 mmol), 二氯甲垸（200 mL)和二异丙胺 (0.74 g, 7.3 mmol), 冰浴冷却至 0 °C后加入 N-溴代丁二酰亚胺 (13.07 g, 73.4 mmol), 继续搅拌反应 2小时，加入 0.2 M硫酸（lOO mL), 搅拌均匀后静置分液，有机层用水洗涤（50 mL X 2), 饱和食盐水洗涤（50 mL x 2)，合并有机相并用无水硫酸钠干燥，过滤，将滤液减压浓缩，得到到淡黄色油状的 2-溴 -6-异丙基苯酚 lb (15.00 g，产率 95.0%)。 To the reaction flask were added 2-isopropylphenol la (10.00 g, 73.4 mmol), dichloromethane (200 mL) and diisopropylamine (0.74 g, 7.3 mmol), and then cooled to 0 ° C. N-bromosuccinimide (13.07 g, 73.4 mmol), stirring reaction for 2 hours, adding 0.2 M sulfuric acid (100 mL), stirring well, standing still, and washing the organic layer with water (50 mL X 2) The mixture was washed with brine (50 mL EtOAc) , yield 95.0%).

¾ NMR (300 MHz, CDC1₃): δ 7.31 (d, 1Η), 7.16 (d, 1H), 6.79 (t, 1H), 5.57 (s, 1H), 3.34 (dt, 1H), 1.25 (d, 6H). 3⁄4 NMR (300 MHz, CDC1 ₃ ): δ 7.31 (d, 1Η), 7.16 (d, 1H), 6.79 (t, 1H), 5.57 (s, 1H), 3.34 (dt, 1H), 1.25 (d, 6H).

第二步： 2-苄氧基 -1-溴 -3-异丙基苯（lc) Second step: 2-benzyloxy-1-bromo-3-isopropylbenzene (lc)

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

向反应瓶中依次加入 2-溴 -6-异丙基苯酚 lb (5 g, 23.2 mmol),碳酸钾（6.44 g, 46.6 mmol), 溴苄（3.97 g， 23.2 mmol)和乙腈（lOO mL), 加热回流搅拌反应 2小时，冷却至室温，减压浓缩，加入***（lOO mL), 过滤，将滤液减压浓缩得到无色油状的 2-苄氧基 -1-溴 -3-异丙基苯 lc (6.46 g, 产率 91.1%)。 To the reaction flask were added 2-bromo-6-isopropylphenol lb (5 g, 23.2 mmol), potassium carbonate (6.44 g, 46.6 mmol), benzyl bromide (3.97 g, 23.2 mmol) and acetonitrile (100 mL) The reaction was stirred with mp EtOAc (EtOAc) (HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH Benzene lc (6.46 g, yield 91.1%).

¾ NMR (300 MHz, CDC1₃): δ 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). 3⁄4 NMR (300 MHz, CDC1 ₃ ): δ 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).

第三步： 1,1-二乙氧基乙烯（le) The third step: 1,1-diethoxyethylene (le)

1 , 1 -diethoxyethene 1 , 1 -diethoxyethene

CH₂ CH ₂

人。 people.

向反应瓶中依次加入溴乙醛缩二乙醇 Id (58.8 g, 29.8 mmol), 十八冠六醚（1.59 g, 6.0 mmol), 四氢呋喃（200 mL)，冰浴冷却至 0°C后加入叔丁醇钾（34.2 g， 30.5 mmol), 0°C下搅拌反应 2小时，过滤，首先将滤液进行常压蒸馏， 65°C至 80°C收集四氢呋喃和叔丁醇馏分，然后用水泵减压蒸馏得到无色油状的 1,1-二乙氧基乙烯 le (15.00 g，产率 43.3%)。 To the reaction flask were added bromoacetaldehyde diethyl diol Id (58.8 g, 29.8 mmol), octadecyl hexaether (1.59 g, 6.0 mmol), tetrahydrofuran (200 mL), and cooled to 0 ° C in an ice bath. Potassium butoxide (34.2 g, 30.5 mmol), stirred at 0 ° C for 2 hours, filtered, first the filtrate was subjected to atmospheric distillation, and the tetrahydrofuran and tert-butanol fractions were collected at 65 ° C to 80 ° C, and then decompressed with a water pump. Distillation gave 1,1-diethoxyethylene le (15.00 g, yield 43.3%) as a colorless oil.

¾ NMR (400 MHz, CDC1₃): δ 3.83― 3.73 (m, 4H), 3.04 (d, 2H), 1.33― 1.24 (m, 6H). 3⁄4 NMR (400 MHz, CDC1 ₃ ): δ 3.83 - 3.73 (m, 4H), 3.04 (d, 2H), 1.33 - 1.24 (m, 6H).

第四步： 5-苄氧基 -4-异丙基 -并环 [4，2，0】辛垸 -1,3,5-三烯 -7-酮 (If) Step 4: 5-Benzyloxy-4-isopropyl-cyclo[4,2,0]octyl-1,3,5-triene-7-one (If)

5-benzyloxy-4-isopropyl-bicyclo[4.2.0]octa-l -trien-7-one 5-benzyloxy-4-isopropyl-bicyclo[4.2.0]octa-l -trien-7-one

向反应瓶中依次加入 2-苄氧基 -1-溴 -3-异丙基苯 lc (19.76 g， 64.7 mmol), 1,1-二乙氧基乙烯 le (15.00 g， 129.1 mmol), 四氢呋喃（250 mL)和氨基钠（5.04 g， 129.1 mmol), 氮气保护，加热回流反应 15小时，冷却至室温，加入冰水（200 mL)，浓盐酸（30 mL)，室温搅拌 2小时，乙酸乙酯萃取（200 mL x 2)，合并有机相并用无水硫酸钠干燥，过滤，将滤液减压浓缩，残留物用硅胶柱色谱分离提纯 (石油醚 /乙酸乙酯 i N、 = 50: 1)得到黄色油状的 5-苄氧基 -4-异丙基- 并环 [4,2,0]辛垸 -1,3,5-三烯 -7-酮 If (8.5 g, 产率 49.0 %)。 2-Benzyloxy-1-bromo-3-isopropylbenzene lc (19.76 g, 64.7 mmol), 1,1-diethoxyethylene le (15.00 g, 129.1 mmol), tetrahydrofuran were added to the reaction flask. (250 mL) and sodium amide (5.04 g, 129.1 mmol), with nitrogen, EtOAc (EtOAc), EtOAc (HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH The ester was extracted (200 mL x 2), EtOAc (EtOAc m. 5-benzyloxy-4-isopropyl-cyclo[4,2,0]octyl-1,3,5-trien-7-one If (8.5 g, yield 49.0%) was obtained as a yellow oil. .

¾ NMR (300 MHz, CDC1₃): δ 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). 实施例 1 3⁄4 NMR (300 MHz, CDC1 ₃ ): δ 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-异丙基 -7-甲基 -并环【4,2,01辛烷 -1,3,5-三烯 -5-醇（化合物 1) 4-isopropyl-7-methyl-cyclo[4,2,01 octane-1,3,5-triene-5-ol (Compound 1)

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

第一步： 5-苄氧基 -4-异丙基 -7-甲基 -并环 [4.2.0】辛烷 -1,3,5-三烯 -7-醇 (1B)

First step: 5-benzyloxy-4-isopropyl-7-methyl-cyclo[4.2.0]octane-1,3,5-triene-7-ol (1B)

5-benzyloxy-4-isopropyl-7-methyl-bicyclo[4.2 rien-7-ol 5-benzyloxy-4-isopropyl-7-methyl-bicyclo[4.2 rien-7-ol

向反应瓶中加入 5-苄氧基 -4-异丙基 -并环 [4,2,0]辛垸 -1,3,5-三烯 -7-酮 If (3.00 g, 11.3 mmol, 中间体 1)和四氢呋喃（30 mL)， -78°C下缓慢滴加甲基溴化镁溶液（13.5 mL， 13.5 mmol), 室温反应 2小时，加入饱和氯化铵溶液（30 mL)，室温搅拌 1小时，用乙酸乙酯萃取（50 mL x 2)，合并有机相，减压浓缩，残留物用硅胶柱色谱分离提纯（石油醚 /乙酸乙酯（v/_V;» = 20_: l ) 得到黄色油状的 5-苄氧基 -4-异丙基 -7-甲基 -并环 [4,2,0]辛垸 -1,3,5-三烯 -7-醇 1B (0.91 g，产率 28.6%)。 To the reaction flask was added 5-benzyloxy-4-isopropyl-cyclo[4,2,0]octyl-1,3,5-trien-7-one If (3.00 g, 11.3 mmol, middle 1) and tetrahydrofuran (30 mL), slowly add methyl magnesium bromide solution (13.5 mL, 13.5 mmol) at -78 °C, react at room temperature for 2 hours, add saturated ammonium chloride solution (30 mL), stir at room temperature to give _l): »= 20; 1 h, extracted with ethyl acetate (50 mL x 2), and the combined organic phase was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / _V 5-benzyloxy-4-isopropyl-7-methyl-cyclo[4,2,0]octyl-1,3,5-trien-7-ol 1B (0.91 g, yellow oil) The rate is 28.6%).

¾ NMR (300 MHz, CDC1₃): δ 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). 3⁄4 NMR (300 MHz, CDC1 ₃ ): δ 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).

第二步： 5-苄氧基 -4-异丙基 -7-甲基 -并环 [4.2.0】辛院 -1,3,5-三烯（1C) The second step: 5-benzyloxy-4-isopropyl-7-methyl-cyclo[4.2.0] Xinyuan -1,3,5-triene (1C)

5-benzyloxy-4-isopropyl-7-methyl-bicyclo[4.2. triene 5-benzyloxy-4-isopropyl-7-methyl-bicyclo[4.2. triene

向反应瓶中依次加入 5-苄氧基 -4-异丙基 -7-甲基 -并环 [4,2,0]辛垸 -1,3,5-三烯 -7-醇 1B (3.50 g, 12.4 mmol), 二氯甲垸 (40 mL)和三乙基硅垸 (1.72 g, 14.8 mmol), -78。C下缓慢滴加三氟化硼***（2.11 g， 14.9 mmol), 室温搅拌 1小时，加入饱和碳酸氢钠溶液（30 mL)，室温搅拌 2小时，用二氯甲垸萃取（50 mL x 2)，合并有机相，减压浓缩，残留物用硅胶柱色谱分离提纯 (石油醚 /乙酸乙酯（v/v) = 50: 1)得到淡黄色油状的 5-苄氧基 -4-异丙基 -7-甲基 -并环 [4,2,0]辛垸 -1,3,5-三烯 1C (1.97 g，产率 59.7%)。 Add 5-benzyloxy-4-isopropyl-7-methyl-cyclo[4,2,0]octyl-1,3,5-trien-7-ol 1B (3.50) to the reaction flask. g, 12.4 mmol), dichloromethane (40 mL) and triethylsilyl (1.72 g, 14.8 mmol), -78. C. Boron trifluoride etherate (2.11 g, 14.9 mmol) was added dropwise, and the mixture was stirred at room temperature for 1 hour, and then a saturated sodium hydrogen carbonate solution (30 mL) was added, and the mixture was stirred at room temperature for 2 hours, and extracted with dichloromethane (50 mL x 2) The organic phase was combined and concentrated under reduced pressure. EtOAcjjjjjjjjjj Base-7-methyl-cyclo[4,2,0]octyl-1,3,5-triene 1C (1.97 g, yield 59.7%).

¾ NMR (300 MHz, CDC1₃): δ 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). 3⁄4 NMR (300 MHz, CDC1 ₃ ): δ 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).

第三步： 4-异丙基 -7-甲基 -并环 [4,2,0】辛垸 -1,3,5-三烯 -5-醇（化合物 1) Step 3: 4-isopropyl-7-methyl-cyclo[4,2,0]octyl-1,3,5-triene-5-ol (Compound 1)

4-isopropyl-7-methyl-bicyclo[4.2.0]octa-l,3,5-trien-5-ol 向反应瓶中依次加入 5-苄氧基 -4-异丙基 -7-甲基 -并环 [4,2,0]辛垸 -1,3,5-三烯 1C (1.80 g, 6.8 mmol)、钯 /炭（0.14 g，钯含量 w/w = 10%)和甲醇（100 mL)，在氢气氛围下，室温反应 4小时，过滤，将滤液减压浓缩，残留物用硅胶柱色谱分离提纯（石油醚 /乙酸乙酯（v/_V;» = 20_: l)得到无色油状的 4-异丙基 -7-甲基 -并环 [4,2,0]辛垸 -1,3,5-三烯 -5-醇化合物 1 (1.04 g，产率 87.3%， HPLC: 97.40%) 4-isopropyl-7-methyl-bicyclo[4.2.0]octa-l,3,5-trien-5-ol Add 5-benzyloxy-4-isopropyl-7-methyl-cyclo[4,2,0]octyl-1,3,5-triene 1C (1.80 g, 6.8 mmol) to the reaction flask. Palladium/carbon (0.14 g, palladium content w/w = 10%) and methanol (100 mL) were reacted under a hydrogen atmosphere at room temperature for 4 hours, filtered, and the filtrate was concentrated under reduced pressure. Purification (petroleum ether/ethyl acetate (v/ _v ; » = 20 _: 1) afforded 4-isopropyl-7-methyl-cyclo[4,2,0] sin-1,3 as colorless oil. , 5-trien-5-ol compound 1 (1.04 g, yield 87.3%, HPLC: 97.40%)

MS m/z (ESI): 177.1 [M+1]. MS m/z (ESI): 177.1 [M+1].

¾ NMR (300 MHz, CDC1₃): δ 7.00 (d, 1Η), 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). 将 4-异丙基 -7-甲基 -并环 [4,2,0]辛垸 -1,3,5-三烯 -5-醇化合物 1 (20 g, 113.6 mmol)进行手性拆分，采用 HPLC 法，用制备设备和手性柱对手性异构体进行分离（分离条件：手性柱 CHIRALPAK AD-H, 20x250 mm, 5μηι, 流动相：正己垸:异丙醇 = 99: 1 (ν/ν) 等度洗脱 41分钟，流速： 14.0mL/分钟， UV = 220/275 nm，柱温： 35°C)，收集其相应组分，减压浓缩，得到化合物 1-1 (3.2 g, ee > 98%， RT = 24.4 min)和化合物 1-2 (4.8 g， ee > 98%， RT =32.3 min)。 3⁄4 NMR (300 MHz, CDC1 ₃ ): δ 7.00 (d, 1Η), 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). 4-isopropyl-7-methyl-cyclo[4,2,0]octane-1,3,5-three The ene-5-ol compound 1 (20 g, 113.6 mmol) was subjected to chiral resolution, separation by preparative equipment and chiral column chiral isomers by HPLC (separation conditions: chiral column CHIRALPAK AD-H, 20x250 mm, 5μηι, mobile phase: n-hexyl: isopropanol = 99: 1 (ν/ν) isocratic elution for 41 minutes, flow rate: 14.0 mL/min, UV = 220/275 nm, column temperature: 35 °C The corresponding fractions were collected and concentrated under reduced pressure to give compound 1-1 (3.2 g, ee > 98%, RT = 24.4 min) and compound 1-2 (4.8 g, ee > 98%, RT = 32.3 min) .

MS m/z (ESI): 175.1 [M-l]. MS m/z (ESI): 175.1 [M-l].

¾ NMR (400 MHz, CDC13) δ 7.06 (d, 1H), 6.66 (d,lH), 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). 3⁄4 NMR (400 MHz, CDC13) δ 7.06 (d, 1H), 6.66 (d, lH), 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).

(理论上，化合物 1以及其异构体化合物 1-1和 1-2的质谱和核磁氢谱数据一致，实际上得到的结果也是如此，以下涉及消旋体拆分得到异构体的情况相同，不再赘述。）实施例 2 (In theory, the mass spectrum and the NMR data of Compound 1 and its isomers 1-1 and 1-2 are identical, and the results are actually obtained. The following is the same as the case where the racemate is resolved to obtain the isomer. , will not repeat them.) Example 2

5-羟基 -4-异丙基 -并环『4,2,01辛垸 -1,3,5-三烯 -7-酮（化合物 2) 5-hydroxy-4-isopropyl-cyclo[4,2,01 octane-1,3,5-triene-7-one (compound 2)

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

向 250 mL反应瓶中依次加入 5-苄氧基 -4-异丙基 -并环 [4,2,0]辛垸 -1,3,5-三烯 -7-酮 If (3.50 g, 13.1 mmol, 中间体 1)、钯 /炭（2.10 g，钯含量 w/w = 10%)和甲醇（70 mL)，在氢气氛围下，室温反应 80分钟，过滤，将滤液减压浓缩，残留物用硅胶柱色谱分离提纯（石油醚 /乙酸乙酯 (v/v) =15: 1) 得到到白色固体状的 5-羟基 -4-异丙基 -并环 [4,2,0]辛垸 -1,3,5-三烯 -7-酮化合物 2Add 5-benzyloxy-4-isopropyl-cyclo[4,2,0]octyl-1,3,5-trien-7-one If (3.50 g, 13.1) to a 250 mL reaction vial. Ment, intermediate 1), palladium/carbon (2.10 g, palladium content w/w = 10%) and methanol (70 mL), reacted under a hydrogen atmosphere at room temperature for 80 minutes, filtered, and concentrated under reduced pressure. Purification by silica gel column chromatography (petroleum ether / ethyl acetate (v/v) = 15: 1) 5-hydroxy-4-isopropyl-cyclo[4,2,0]octyl-1,3,5-trien-7-one as a white solid Compound 2

(1.23 g, 产率 53.1 %， HPLC: 99.50%)。 (1.23 g, yield 53.1%, HPLC: 99.50%).

MS m/z (ESI): 175.0 [M+l]. MS m/z (ESI): 175.0 [M+l].

¾ NMR (300 MHz, CDC1₃)： δ 7.77 (s, 1H), 7.42 (d, 1H), 7.00 (d, 1H), 3.87 (s, 2H), 3.31 (dt, 6.9 Hz, 1H), 1.23 (d, 6H). 实施例 3 3⁄4 NMR (300 MHz, CDC1 ₃ ): δ 7.77 (s, 1H), 7.42 (d, 1H), 7.00 (d, 1H), 3.87 (s, 2H), 3.31 (dt, 6.9 Hz, 1H), 1.23 (d, 6H). Example 3

7-乙基 -4-异丙基 -并环『4,2,01辛垸 -1，3，5-三烯 -5-醇（化合物 3) 7-Ethyl-4-isopropyl-cyclo[4,2,01 octane-1,3,5-triene-5-ol (Compound 3)

7-eth -4-isopropyl-bicyclo[4.2.0]octa-l,3,5-trien-5-ol 7-eth -4-isopropyl-bicyclo[4.2.0]octa-l,3,5-trien-5-ol

第一步： ₅_节氧基 _₇_乙基 _₄_异丙基 -并环 [₄，2，₀】辛院 ^ 三烯 _₇_醇 (3Β) First step: ₅ _ alkoxy _ ₇ _ ethyl _ ₄ _ isopropyl-cyclo [ ₄ , 2, ₀ 】 Xinyuan ^ triene _ ₇ - alcohol (3 Β)

5-benzyloxy-7-ethyl-4-isopropyl-bicyclo[4.2. en-7-ol 5-benzyloxy-7-ethyl-4-isopropyl-bicyclo[4.2. en-7-ol

向反应瓶中加入 5-苄氧基 -4-异丙基 -并环 [4,2,0]辛垸 -1,3,5-三烯 -7-酮 If (10.00 g, 37.6 mmol, 中间体 1)和四氢呋喃 (lOO mL), -78。C下滴加乙基溴化镁溶液 (45 mL， 45 mmol), 室温搅拌 1小时，加入饱和氯化铵溶液（100 mL)，用乙酸乙酯萃取（50 mL x 2)，合并有机相并用无水硫酸钠干燥，过滤，将滤液减压浓缩，残留物用硅胶柱色谱分离提纯（石油醚 /乙酸乙酯（v/v) = 20: 1)得到淡黄色油状的 5-苄氧基 -7-乙基 -4-异丙基 -并环 [4,2,0]辛垸 -1,3,5-三烯 -7-醇 3B (6.77 g, 产率 60.8%)。 Add 5-benzyloxy-4-isopropyl-cyclo[4,2,0]octyl-1,3,5-trien-7-one If (10.00 g, 37.6 mmol, middle) to the reaction flask 1) and tetrahydrofuran (100 mL), -78. Ethyl magnesium bromide solution (45 mL, 45 mmol) was added dropwise with EtOAc. EtOAc (EtOAc m. Drying over anhydrous sodium sulfate, EtOAc (EtOAc m.) 7-Ethyl-4-isopropyl-cyclo[4,2,0]octyl-1,3,5-trien-7-ol 3B (6.77 g, yield 60.8%).

第二步： 5-苄氧基 -7-乙基 -4-异丙基 -并环 [4，2，0】辛烷 -1,3,5-三烯（3C) Step 2: 5-Benzyloxy-7-ethyl-4-isopropyl-cyclo[4,2,0]octane-1,3,5-triene (3C)

5-benzyloxy-7-ethyl-4-isopropyl-bicyclo[4.2. ene 5-benzyloxy-7-ethyl-4-isopropyl-bicyclo[4.2. ene

向反应瓶中依次加入 5-苄氧基 -7-乙基 -4-异丙基 -并环 [4,2,0]辛垸- 1 ,3 -三烯 -7-醇 3B (4.50 g, 15.2 mmol), 三乙基硅垸（2.12 g， 18.2 mmol)和二氯甲垸（lOO mL), -78。C下加入三氟化硼***（2.59 g， 18.3 mmol), 室温搅拌 30分钟，反应完全，加入饱和碳酸氢钠溶液（50 mL)，室温搅拌 1小时，静置分液，用二氯甲垸萃取（100 mL x 2)，合并有机相并用无水硫酸钠干燥，过滤，将滤液减压浓缩，残留物用硅胶柱色谱分离提纯（石油醚 /乙酸乙酯（v/v) = 50: 1)得到无色油状的 5-苄氧基 -7-乙基 -4-异丙基 -并环 [4,2,0]辛垸 -1,3,5-三烯 3C (3.30 g, 产率 64.6 %)。 To the reaction flask was added 5-benzyloxy-7-ethyl-4-isopropyl-cyclo[4,2,0]octyl-1,3-triene-7-ol 3B (4.50). g, 15.2 mmol), triethylsilyl (2.12 g, 18.2 mmol) and methylene chloride (100 mL), -78. Add boron trifluoride diethyl ether (2.59 g, 18.3 mmol) under C, stir at room temperature for 30 minutes, complete the reaction, add saturated sodium bicarbonate solution (50 mL), stir at room temperature for 1 hour, and stand for liquid separation with methylene chloride. The mixture was extracted with EtOAc (EtOAc) (EtOAc) Obtained 5-benzyloxy-7-ethyl-4-isopropyl-cyclo[4,2,0]octyl-1,3,5-triene 3C (3.30 g, yield) 64.6 %).

¾ NMR (300 MHz, CDC1₃): δ 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). 3⁄4 NMR (300 MHz, CDC1 ₃ ): δ 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).

第三步： 7-乙基 -4-异丙基 -并环 [4,2,0】辛垸 -1,3,5-三烯 -5-醇（化合物 3) The third step: 7-ethyl-4-isopropyl-cyclo[4,2,0]octyl-1,3,5-triene-5-ol (compound 3)

7-ethyl-4-isopropyl-bicyclo[4.2.0]octa-l,3,5

7-ethyl-4-isopropyl-bicyclo[4.2.0]octa-l,3,5

向反应瓶中依次加入 5-苄氧基 -7-乙基 -4-异丙基 -并环 [4,2,0]辛垸 -1,3,5-三烯 3C (3.30 g， 11.8 mmol),钯 /炭 (0.25 g，钯含量 w/w = 10%)和甲醇（lOO mL), 在氢气氛围下，室温反应 3小时，过滤，将滤液减压浓缩，残留物用硅胶柱色谱分离提纯（石油醚 /乙酸乙酯（v/v) = 30: 1)得到淡黄色油状的 7-乙基 -4-异丙基 -并环 [4,2,0]辛垸 -1,3,5-三烯 -5-醇化合物 3 (1.50 g，产率 67%， HPLC: 96.33%) To the reaction flask was added 5-benzyloxy-7-ethyl-4-isopropyl-cyclo[4,2,0]octyl-1,3,5-triene 3C (3.30 g, 11.8 mmol). Palladium/carbon (0.25 g, palladium content w/w = 10%) and methanol (100 mL) were reacted under a hydrogen atmosphere at room temperature for 3 hours, filtered, and the filtrate was concentrated under reduced pressure. Purification (petroleum ether/ethyl acetate (v/v) = 30: 1) to give 7-ethyl-4-isopropyl-cyclo[4,2,0] octane-1,3 as a pale yellow oil. 5-trien-5-ol compound 3 (1.50 g, yield 67%, HPLC: 96.33%)

MS m/z (ESI): 189.1 [M-l]. MS m/z (ESI): 189.1 [M-l].

1H NMR (300 MHz, CDC1₃): δ 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). 实施例 4 1H NMR (300 MHz, CDC1 ₃ ): δ 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-异丙基 -7-甲基 -并环【4，2，01辛烷 -1，3，5-三烯 -5，7-二醇（化合物 4) 4-isopropyl-7-methyl-cyclo[4,2,01 octane-1,3,5-triene-5,7-diol (compound 4)

4-isopropyl-7-methyl-bicyc -l,3,5-triene-5,7-diol 4-isopropyl-7-methyl-bicyc -l,3,5-triene-5,7-diol

化合物 2 化合物 4 Compound 2 compound 4

向反应瓶中加入 5-羟基 -4-异丙基 -并环 [4,2,0]辛垸 -1,3,5-三烯 -7-酮化合物 2 (270 mg， 1.4 mmol)和四氢呋喃（10 mL)， -78°C下缓慢滴加甲基溴化镁溶液（4.66 mL， 14.0 mmol), 室温搅拌 10小时，加入饱和氯化铵溶液（10 mL)，用乙酸乙酯萃取（10 mL x 2)，合并有机相并用无水硫酸钠干燥，过滤，将滤液减压浓缩，残留物用硅胶柱色谱分离提纯（石油醚 /乙酸乙酯 (v/v) = 15: 1)得到淡黄色油状的 4-异丙基 -7-甲基 -并环 [4,2,0]辛垸 -1,3,5-三烯 -5,7-二醇化合物 4 (130 mg, 产率 48%， HPLC: 97.55%)。 To the reaction flask was added 5-hydroxy-4-isopropyl-cyclo[4,2,0]octyl-1,3,5-trien-7-one compound 2 (270 mg, 1.4 mmol) and tetrahydrofuran. (10 mL), a solution of methylmagnesium bromide (4.66 mL, 14.0 mmol) was slowly added dropwise at -78 °C, stirred at room temperature for 10 hr, then aq. </ RTI></RTI><RTIgt;</RTI><RTIgt;</RTI><RTIgt;</RTI><RTIgt; 4-isopropyl-7-methyl-cyclo[4,2,0]octyl-1,3,5-triene-5,7-diol compound 4 as yellow oil (130 mg, yield 48%, HPLC: 97.55%).

MS m/z (ESI): 190.9 [M-l]. MS m/z (ESI): 190.9 [M-l].

IH NMR (400 MHz, DMSO) δ 8.95 (s, IH), 6.99 (d, IH), 6.56 (d, IH), 5.39 (s, IH), 3.23-3.16 (m, IH), 3.01-2.91 (m, 2H), 1.57 (s, 3H), 1.14-1.11 (m, 6H). 实施例 5 IH NMR (400 MHz, DMSO) δ 8.95 (s, IH), 6.99 (d, IH), 6.56 (d, IH), 5.39 (s, IH), 3.23-3.16 (m, IH), 3.01-2.91 ( m, 2H), 1.57 (s, 3H), 1.14-1.11 (m, 6H). Example 5

3-乙基 -8-甲氧基 -8-甲基并环【4.2.01辛烷 -1,3,5-三烯 -2-醇（化合物 5) 3-ethyl-8-methoxy-8-methyl-cyclo[4.2.01 octane-1,3,5-trien-2-ol (compound 5)

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

向反应瓶中依次加入 2-乙基苯酚 5A (26.80 g， 0.2 mol)、二氯甲垸（130 mL)和二异丙胺 (2.23 g, 22.0 mmol), -40。C下加入 N-溴代丁二酰亚胺（40.00 g， 0.2 mol), 滴加完毕后自然升至室温搅拌过夜，向反应体系中加入水（100 mL), 用 2M的稀盐酸溶液调节 pH为 3左右，用二氯甲垸萃取（150 mL x 3)，饱和食盐水洗涤（300 mL x 1)，合并有机相并用无水硫酸钠干燥，过滤，将滤液减压浓缩，得到淡黄色油状的 2-溴 -6-乙基苯酚 5B (32.50 g，产率 73.0%)。 To the reaction flask were added 2-ethylphenol 5A (26.80 g, 0.2 mol), dichloromethane (130 mL) and diisopropylamine (2.23 g, 22.0 mmol), -40. Add N-bromosuccinimide (40.00 g, 0.2 mol) under C. After the dropwise addition, naturally warm to room temperature and stir overnight. Add water (100 mL) to the reaction system, and adjust pH with 2M diluted hydrochloric acid solution. It is about 3, and it is extracted with dichloromethane (150 mL x 3), and brine (300 mL x 1), and the organic phase is combined and dried over anhydrous sodium sulfate. 2-Bromo-6-ethylphenol 5B (32.50 g, yield 73.0%).

第二步： 2-苄氧基 -1-溴 -3-乙基苯（5C) Second step: 2-benzyloxy-1-bromo-3-ethylbenzene (5C)

2-benzyloxy-l-bromo-3 -ethyl-benzene

2-benzyloxy-l-bromo-3 -ethyl-benzene

向反应瓶中依次加入 2-溴 -6-乙基苯酚 5B (32.50 g， 0.2 mol)、碳酸钾（30.60 g， 0.2 mol)、溴苄（44.16 g， 0.3 mol)和乙腈（200 mL)，加热至 80°C搅拌过夜，冷却至室温，过滤，用乙腈洗涤（50 mL x 2)，将滤液减压浓缩得到黄色油状的 2-苄氧基 -1-溴 -3-乙基苯 5C (42.00 g，产率 90.52%)。 2-bromo-6-ethylphenol 5B (32.50 g, 0.2 mol), potassium carbonate (30.60 g, 0.2 mol), benzyl bromide (44.16 g, 0.3 mol) and acetonitrile (200 mL) were sequentially added to the reaction flask. After heating to 80 ° C, the mixture was stirred overnight, cooled to EtOAc EtOAc (EtOAc) 42.00 g, yield 90.52%).

第三步： 5-苄氧基 -4-乙基 -并环 [4，2，0】辛垸 -1,3,5-三烯 -7-酮 (5D) Step 3: 5-Benzyloxy-4-ethyl-cyclo[4,2,0]octyl-1,3,5-triene-7-one (5D)

5-benzyloxy-4-ethyl-bicyclo[4.2.0]octa-l,3,5 5-benzyloxy-4-ethyl-bicyclo[4.2.0]octa-l,3,5

向反应瓶中依次加入 2-苄氧基 -1-溴 -3-乙基苯 5C (10.00 g， 34.5 mmol), 1,1-二乙氧基乙烯 le (12.10 g, 103.4 mmol), 四氢呋喃（50 mL)和氨基钠（6.10 g， 155.1 mmol)，氮气保护，加热至 60°C搅拌过夜，冷却至室温，将反应液缓慢加入冰的浓盐酸溶液中，搅拌 10分钟后，用乙酸乙酯萃取（50 mL x 3)，饱和食盐水洗涤（100 mL x l)，合并有机相并用无水硫酸钠干燥，过滤，将滤液减压浓缩，残留物用硅胶柱色谱分离提纯（石油醚 /乙酸乙酯（v/_V;» = 100: 1)得到棕色油状的 5-苄氧基 -4-乙基 -并环 [4,2,0]辛垸 -1,3,5-三烯 -7-酮 5D (3.4 g, 产率 39.10 %)。 2-Benzyloxy-1-bromo-3-ethylbenzene 5C (10.00 g, 34.5 mmol), 1,1-diethoxyethylene le (12.10 g, 103.4 mmol), tetrahydrofuran was added to the reaction flask. 50 mL) and sodium amide (6.10 g, 155.1 mmol), nitrogen-protected, heated to 60 ° C, stirred overnight, cooled to room temperature, slowly added to the iced concentrated hydrochloric acid solution, stirred for 10 min, then ethyl acetate The extract (50 mL x 3), washed with saturated brine (100 mL EtOAc), EtOAcjjjjjjjjjj Ester (v/ _V ; » = 100: 1) gives 5-benzyloxy-4-ethyl-cyclo[4,2,0]octyl-1,3,5-triene-7- as a brown oil. Ketone 5D (3.4 g, yield 39.10%).

第四步： 5-苄氧基 -7-甲基 -4-乙基 -并环 [4,2,0】辛烧 -1,3,5-三烯 -7-醇 (5E) Step 4: 5-Benzyloxy-7-methyl-4-ethyl-cyclo[4,2,0]octane-1,3,5-triene-7-ol (5E)

-(benzyloxy)-4-ethyl-7-methylbicyclo[4.2.0 -7-ol -(benzyloxy)-4-ethyl-7-methylbicyclo[4.2.0 -7-ol

向反应瓶中加入 5-苄氧基 -4-乙基 -并环 [4,2,0]并环 -1,3,5-三烯 -7-酮 5D (2.32 g, 9.2 mmol)和四氢呋喃（50 mL)， -78°C下加入甲基溴化镁溶液（4.3 mL， 12.9 mmol), 室温搅拌 2小时，加入饱和氯化铵溶液（30 mL), 室温搅拌 1小时，用乙酸乙酯萃取（50 mL x 2), 合并有机相并用无水硫酸钠干燥，过滤，将滤液减压浓缩，残留物用硅胶柱色谱分离提纯（石油醚 /乙酸乙酯 (v/v) = 20: 1)得到黄色油状的 5-苄氧基 -7-甲基 -4-乙基 -并环 [4,2,0]辛垸 -1,3,5-三烯 -7-醇 5E (1.78 g, 产率 72.3%)。 To the reaction flask was added 5-benzyloxy-4-ethyl-cyclo[4,2,0]cyclo-1,3,5-trien-7-one 5D (2.32 g, 9.2 mmol) and tetrahydrofuran. (50 mL), a solution of methylmagnesium bromide (4.3 mL, 12.9 mmol) was added at -78 °C, stirred at room temperature for 2 h, then aq. The mixture was extracted with EtOAc (EtOAc) (EtOAc) Obtaining 5-benzyloxy-7-methyl-4-ethyl-cyclo[4,2,0]octyl-1,3,5-trien-7-ol 5E (1.78 g, The yield was 72.3%).

第五步： 2-苄氧基 -3-乙基 -8-甲氧基并环 [4，2，0】辛垸 -1,3,5-三烯（5F) 2-(benzyloxy)-3-ethyl-8-methoxy-8-methylbicyclo[4.2.0]octa-l ,3,5-triene Step 5: 2-Benzyloxy-3-ethyl-8-methoxycyclo[4,2,0]octyl-1,3,5-triene (5F) 2-(benzyloxy)-3-ethyl-8-methoxy-8-methylbicyclo[4.2.0]octa-l ,3,5-triene

向反应瓶中加入 5-苄氧基 -7-甲基 -4-乙基 -并环 [4,2,0]辛垸 -1 ,3,5-三烯 -7-醇 5E (1.78 g， 6.6 mmol)、对甲苯磺酸（1.77 g， 10.0 mmol)和甲醇（60 mL)， 70°C下搅拌 3小时，加入饱和碳酸氢钠溶液（10 mL)调节 PH>7，用乙酸乙酯萃取（50 mL x 2)，合并有机相并用无水硫酸钠干燥，过滤，将滤液减压浓缩，残留物用硅胶柱色谱分离提纯（石油醚 /乙酸乙酯（v/_V;» = 20_: l) 得到黄色油状的 2-苄氧基 -3-乙基 -8-甲氧基并环 [4,2,0]辛垸 -1 ,3,5-三烯 5F (1.86 g，产率 99.5%) 第六步： 3-乙基 -8-甲氧基 -8-甲基并环 [4.2.0】辛烷 -1,3,5-三烯 -2-醇（化合物 5) To the reaction flask was added 5-benzyloxy-7-methyl-4-ethyl-cyclo[4,2,0]octyl-1,3,5-trien-7-ol 5E (1.78 g, 6.6 mmol), p-toluenesulfonic acid (1.77 g, 10.0 mmol) and methanol (60 mL), stirred at 70 ° C for 3 h, then added saturated sodium bicarbonate (10 mL) (50 mL x 2), organic phases were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate _{(v / V; »= 20} : l Obtained 2-benzyloxy-3-ethyl-8-methoxycyclo[4,2,0]octyl-1,3,5-triene 5F (1.86 g, yield 99.5%) ) Step 6: 3-Ethyl-8-methoxy-8-methyl-cyclo[4.2.0]octane-1,3,5-trien-2-ol (Compound 5)

3-ethyl-8-methoxy-8-methylbicyclo[4.2.0 l

3-ethyl-8-methoxy-8-methylbicyclo [4.2.0 l

向反应瓶中依次加入 2-苄氧基 -3-乙基 -8-甲氧基并环 [4,2,0]辛垸 -1 ,3,5-三烯 5F (1.86 g， 6.6 mmol),钯 /炭 (0.19 g, 钯含量 w/w = 10%)、碳酸钾（126mg, 0.9 mmol)和甲醇 (20 mL), 氢气氛围下，室温搅拌 4小时，过滤，将滤液减压浓缩，残留物用硅胶柱色谱分离提纯（石油醚 /乙酸乙酯 i N、 = 20: 1)得到白色固体状的 3-乙基 -8-甲氧基 -8-甲基并环 [4.2.0]辛垸 -1 ,3,5-三烯 -2-醇化合物 5 (0.97 g，产率 77.0%， HPLC: 98.67%)。 2-Benzyloxy-3-ethyl-8-methoxycyclo[4,2,0]octyl-1,3,5-triene 5F (1.86 g, 6.6 mmol) was added to the reaction flask. Palladium/carbon (0.19 g, palladium content w/w = 10%), potassium carbonate (126 mg, 0.9 mmol) and methanol (20 mL), stirred under a hydrogen atmosphere at room temperature for 4 hours, filtered, and concentrated. The residue was purified by silica gel column chromatography (EtOAc /EtOAcEtOAc Inosine-1,3,5-trien-2-ol compound 5 (0.97 g, yield 77.0%, HPLC: 98.67%).

MS m/z (ESI) : 191.0 [M-H]. MS m/z (ESI): 191.0 [M-H].

¾ NMR (400 MHz, CDC1₃): δ 7.09 (d, 1Η), 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). 实施例 6 3⁄4 NMR (400 MHz, CDC1 ₃ ): δ 7.09 (d, 1Η), 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-异丙基 -7-甲氧基 -7-甲基 -并环【4,2,01辛烷 -1,3,5-三烯 -5-醇（化合物 6) 4-isopropyl-7-methoxy-7-methyl-cyclo[4,2,01 octane-1,3,5-triene-5-ol (compound 6)

4-isopropyl-7-methoxy-7-methyl-bicyclo[4. -l ,3,5-trien-5-ol 4-isopropyl-7-methoxy-7-methyl-bicyclo[4. -l ,3,5-trien-5-ol

第一步： 2- (苄氧基) -3-异丙基 -8-甲氧基 -8-甲基并环 [4.2.0】辛 -1,3,5 -三烯 6B

First step: 2-(Benzyloxy)-3-isopropyl-8-methoxy-8-methyl-cyclo[4.2.0]oct-1,3,5-triene 6B

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

向反应瓶中依次加入 5-苄氧基 -4-异丙基 -7-甲基 -并环 [4,2,0]辛垸 -1,3,5-三烯 -7-醇 1B (0.56 g, 2.0 mmol)、甲醇 (30 mL)和对甲苯磺酸 (0.53 g, 3.0 mmol), 70°C搅拌 6小时，加入饱和碳酸氢钠溶液调节 pH > 7，用乙酸乙酯萃取（60 mL x 2), 合并有机相并用无水硫酸钠干燥，过滤，将滤液减压浓缩，残留物用硅胶柱色谱分离提纯（石油醚 /乙酸乙酯（v/v) = 50: 1)得到无色油状的 2- (苄氧基) -3-异丙基 -8-甲氧基 -8-甲基并环 [4.2.0]辛 -1,3,5-三烯 6B (0.37 g，产率 62%) Add 5-benzyloxy-4-isopropyl-7-methyl-cyclo[4,2,0]octyl-1,3,5-trien-7-ol 1B (0.56) to the reaction flask. g, 2.0 mmol), methanol (30 mL) and p-toluenesulfonic acid (0.53 g, 3.0 mmol), stirring at 70 ° C for 6 hours, adding saturated sodium bicarbonate solution to adjust pH > 7, extraction with ethyl acetate (60 mL) The organic phase was combined and dried over anhydrous sodium sulfate. EtOAc was evaporated. Oily 2-(benzyloxy)-3-isopropyl-8-methoxy-8-methylcyclo[4.2.0]oct-1,3,5-triene 6B (0.37 g, yield 62%)

第二步： 4-异丙基 -7-甲氧基 -7-甲基 -并环 [4,2,0】辛烷 -1,3,5-三烯 -5-醇（化合物 6) Second step: 4-isopropyl-7-methoxy-7-methyl-cyclo[4,2,0]octane-1,3,5-triene-5-ol (compound 6)

4-isopropyl-7-methoxy-7-methyl-bicyclo[4.2 -5-ol

4-isopropyl-7-methoxy-7-methyl-bicyclo[4.2 -5-ol

向反应瓶中依次加入 2- (苄氧基; )-3-异丙基 -8-甲氧基 -8-甲基并环 [4.2.0]辛 -1,3,5-三烯 6B (2.00 g, 7.0 mmol), 钯 /炭（0.37 g，钯含量 w/w = 10%)和甲醇（lOO mL), 在氢气氛围下，室温反应 4小时，过滤，将滤液减压浓缩，残留物用硅胶柱色谱分离提纯（石油醚 /乙酸乙酯（v/v) = 30: 1)得到白色固体状的 4-异丙基 -7-甲氧基 -7-甲基 -并环 [4,2,0]辛垸 -1,3,5-三烯 -5-醇化合物 6 (0.60 g, 产率 41.1%， HPLC: 99.24%)。 2-(Benzyloxy;)-3-isopropyl-8-methoxy-8-methylcyclo[4.2.0]oct-1,3,5-triene 6B was added to the reaction flask in sequence ( 2.00 g, 7.0 mmol), palladium/carbon (0.37 g, palladium content w/w = 10%) and methanol (100 mL), reacted under a hydrogen atmosphere at room temperature for 4 hours, filtered, and the filtrate was concentrated under reduced pressure. Purification by silica gel column chromatography (EtOAc/EtOAc (EtOAc/EtOAc) 2,0]octyl-1,3,5-trien-5-ol compound 6 (0.60 g, yield 41.1%, HPLC: 99.24%).

将 4-异丙基 -7-甲氧基 -7-甲基 -并环 [4,2,0]辛垸 -1,3,5-三烯 -5-醇化合物 6 (0.20 g， 1 mmol)进行手性拆分，采用 HPLC法，用制备设备和手性柱对手性异构体进行分离（分离条件：手性柱 CHIRALPAK IC 250 4.6mm，流动相：正己垸 /二氯甲垸 /乙酸（v/v/v) = 80/20/0.1，流速： l.OmL/ 分钟, UV = 254 nm，柱温： 35°C)，收集其相应组分，减压浓缩，得到化合物 6-1 (35.0 mg, ee > 98%, RT = 5.79 min)和化合物 6-2 (34.9 mg， ee > 98%， RT =6.51 min)。 4-Isopropyl-7-methoxy-7-methyl-cyclo[4,2,0]octyl-1,3,5-trien-5-ol compound 6 (0.20 g, 1 mmol Chiral resolution, separation by HPLC and preparative equipment and chiral column chiral isomers (separation conditions: chiral column CHIRALPAK IC 250 4.6 mm, mobile phase: n-hexane/dichloromethane/acetic acid) (v/v/v) = 80/20/0.1, flow rate: l.OmL/min, UV = 254 nm, column temperature: 35 ° C), collect the corresponding components, concentrate under reduced pressure to give compound 6-1 (35.0 mg, ee > 98%, RT = 5.79 min) and compound 6-2 (34.9 mg, ee > 98%, RT = 6.51 min).

MS m/z (ESI): 205.1 [M-l]. MS m/z (ESI): 205.1 [M-l].

¾ NMR (400 MHz, CDC1₃): δ 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). 实施例 7 3⁄4 NMR (400 MHz, CDC1 ₃ ): δ 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-异丙基 -1，2-二氢环丁基苯基 -1，6-二醇（化合物 7) 5-isopropyl-1,2-dihydrocyclobutylphenyl-1,6-diol (compound 7)

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

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

化合物 2 化合物' Compound 2 compound'

向反应瓶中依次加入 5-羟基 -4-异丙基 -并环 [4,2,0]辛垸 -1,3,5-三烯 -7-酮化合物 2 (0.58 g, 3.3 mmol)、甲醇（15 mL)和硼氢化钠（0.25 g， 6.4 mmol)，室温搅拌 25分钟，加入饱和氯化铵溶液（4 mL), 合并有机相并用无水硫酸钠干燥，过滤，将滤液减压浓缩，残留物用硅胶柱色谱分离提纯（石油醚 /乙酸乙酯（v/v) =15: 1) 得到白色固体状的 5-异丙基 -1,2-二氢环丁基苯基 -1,6-二醇化合物 7 (0.35 g，产率 59.7 %， HPLC: 98.82%)。 To the reaction flask was added 5-hydroxy-4-isopropyl-cyclo[4,2,0]octyl-1,3,5-trien-7-one compound 2 (0.58 g, 3.3 mmol), Methanol (15 mL) and sodium borohydride (0.25 g, 6.4 mmol), EtOAc. The residue was purified by silica gel column chromatography (EtOAc/EtOAc (EtOAc) , 6-diol compound 7 (0.35 g, yield 59.7 %, HPLC: 98.82%).

MS m/z (ESI): 177.0 [M-1]. MS m/z (ESI): 177.0 [M-1].

¾ NMR (400 MHz, DMSO): δ 7.02 (d, 1Η), 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). 实施例 8 3⁄4 NMR (400 MHz, DMSO): δ 7.02 (d, 1Η), 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-仲丁基 -8-甲氧基 -8-甲基双环【4.2.0谇垸 -1，3，5-三烯 -2-醇（化合物 8) 3-sec-butyl-8-methoxy-8-methylbicyclo[4.2.0谇垸-1,3,5-trien-2-ol (compound 8)

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

化合物 8 第一步： 2-溴 -6-仲丁基苯酚（8B) Compound 8 First step: 2-bromo-6-sec-butylphenol (8B)

2-bromo-6-sec-butylphenol

向反应瓶中依次加入 2-仲丁基苯酚 8A (30 g， 199.7 mmol)、二氯甲垸（300 mL)和二异丙胺 (2.02 g， 19.9 mmol), 0°C下加入 N-溴代丁二酰亚胺 (35.4 g, 198.9 mmol), 冰水浴下搅拌 2 小时，加入 0.2 M硫酸（100 mL)，用水洗涤（50 mL x 2), 饱和食盐水洗涤（50 mL x 2), 合并有机相并用无水硫酸钠干燥，过滤，将滤液减压浓缩得到淡黄色油状的 2-溴 -6-仲丁基苯酚 8B (41 g, 产率 89.6%)。 2-bromo-6-sec-butylphenol

Add 2-sec-butylphenol 8A (30 g, 199.7 mmol), dichloromethane (300 mL) and diisopropylamine (2.02 g, 19.9 mmol) to the reaction flask, and add N-bromo at 0 °C. Succinimide (35.4 g, 198.9 mmol), stirred for 2 hours in an ice water bath, added with 0.2 M sulfuric acid (100 mL), washed with water (50 mL x 2), washed with brine (50 mL x 2), combined The organic layer was dried over anhydrous sodium sulfate (MgSO4).

¾ NMR (400 MHz, CDC1₃): δ 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). 第二步： 2-苄氧基 -1-溴 -3-仲丁基苯（8C) 3⁄4 NMR (400 MHz, CDC1 ₃ ): δ 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). Step 2: 2-Benzyloxy-1-bromo-3-sec-butylbenzene (8C)

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

向反应瓶中依次加入 2-溴 -6-仲丁基苯酚 8B (40 g， 175 mmol), 碳酸钾（48 g， 347 mmol)、溴苄（30 g， 175 mmol)和乙腈（250 mL)，加热回流搅拌反应 2小时，冷却至室温，减压浓缩，加入***（lOO mL), 过滤，将滤液减压浓缩得到无色油状的 2-苄氧基 -1-溴 -3-仲丁基苯 8C (52 g, 产率 93.3%)。 To the reaction flask were added 2-bromo-6-sec-butylphenol 8B (40 g, 175 mmol), potassium carbonate (48 g, 347 mmol), benzyl bromide (30 g, 175 mmol) and acetonitrile (250 mL). The reaction was stirred with mp EtOAc (EtOAc) (HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH Benzene 8C (52 g, yield 93.3%).

¾ NMR (400 MHz, CDC1₃): δ 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). 第三步： 5-苄氧基 -4-仲丁基 -并环 [4，2，0】并环 -1，3，5-三烯 -7-酮 (8D) 3⁄4 NMR (400 MHz, CDC1 ₃ ): δ 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). Step 3: 5-Benzyloxy-4-sec-butyl- Cyclo[4,2,0]-cyclo-1,3,5-trien-7-one (8D)

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

向反应瓶中依次加入 2-苄氧基 -1-溴 -3-仲丁基苯 8C (25 g， 78.3 mmol), 1,1-二乙氧基乙烯 le (18.18 g， 156.5 mmol), 四氢呋喃 (200 mL)和氨基钠 (6.04 g, 154.8 mmol), 氮气保护，加热回流 15小时，冷却至室温，加入冰水（200 mL)，浓盐酸（30 mL)，室温搅拌 2小时，用乙酸乙酯萃取（200 mL x 2)，合并有机相并用无水硫酸钠干燥，过滤，将滤液减压浓缩，残留物用硅胶柱色谱分离提纯（石油醚 /乙酸乙酯 ( N、 = 50: 1)得到黄色油状的 5-苄氧基 -4-仲丁基- 并环 [4,2,0]并环 -1,3,5-三烯 -7-酮 8D (6.21 g, 产率 28.3%)。 To the reaction flask was added 2-benzyloxy-1-bromo-3-sec-butylbenzene 8C (25 g, 78.3 mmol), 1,1-diethoxyethylene le (18.18 g, 156.5 mmol), tetrahydrofuran. (200 mL) and sodium amide (6.04 g, 154.8 mmol), EtOAc (m.), EtOAc (HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH Ester extraction (200 mL x 2), EtOAc (EtOAc m. Purification by silica gel column chromatography (petrole ether / ethyl acetate (N, = 50: 1) to give 5-benzyloxy-4-sec-butyl-cyclo-[4,2,0]-cyclo-1 as a yellow oil. 3,5-Trien-7-one 8D (6.21 g, yield 28.3%).

¾ NMR (400 MHz, CDC1₃): δ 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). 第四步： 5-苄氧基 -7-甲基 -4-仲丁基 -并环 [4，2，0】辛垸 -1，3，5-三烯 -7-醇 (8E) 3⁄4 NMR (400 MHz, CDC1 ₃ ): δ 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). Step 4: 5-Benzyloxy-7-methyl 4-sec-butyl-cyclo[4,2,0]octyl-1,3,5-triene-7-ol (8E)

5-benzyloxy-7-methyl-4-sec-butyl-bicyclo[4 -l ,3,5-trien-7-ol 5-benzyloxy-7-methyl-4-sec-butyl-bicyclo[4 -l ,3,5-trien-7-ol

向反应瓶中加入 5-苄氧基 -4-仲丁基 -并环 [4,2,0]并环 -1 ,3,5-三烯 -7-酮 8D (2.00 g, 7.1 mmol) 和四氢呋喃 (50 mL)， -78°C下加入甲基溴化镁溶液 (8.6 mL， 8.6 mmol), 室温搅拌 2小时，加入饱和氯化铵溶液（30 mL), 室温搅拌 1小时，用乙酸乙酯萃取（50 mL x 2), 合并有机相并用无水硫酸钠干燥，过滤，将滤液减压浓缩，残留物用硅胶柱色谱分离提纯（石油醚 /乙酸乙酯（v/v) = 20: 1)得到黄色油状的 5-苄氧基 -7-甲基 -4-仲丁基 -并环 [4,2,0]辛垸 -1 ,3,5-三烯 -7-醇 8E (1.60 g, 产率 75.7%)。第五步： 2-苄氧基 -3-仲丁基 -8-甲氧基 -8-甲基并环 [4,2,0】辛烷 -1,3,5-三烯（8F) To the reaction flask was added 5-benzyloxy-4-sec-butyl-cyclo[4,2,0]-cyclo-1,3,5-trien-7-one 8D (2.00 g, 7.1 mmol) and Tetrahydrofuran (50 mL), add methylmagnesium bromide solution (8.6 mL, 8.6 mmol) at -78 ° C, stir at room temperature for 2 hours, add saturated ammonium chloride solution (30 mL), stir at room temperature for 1 hour, with acetic acid The ester was extracted (50 mL×2), EtOAc (EtOAc m. 1) 5-benzyloxy-7-methyl-4-sec-butyl-cyclo[4,2,0]octyl-1,3,5-trien-7-ol 8E (1.60) as a yellow oil. g, yield 75.7%). Step 5: 2-Benzyloxy-3-sec-butyl-8-methoxy-8-methyl-cyclo[4,2,0]octane-1,3,5-triene (8F)

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

向反应瓶中加入 5-苄氧基 -7-甲基 -4-仲丁基 -并环 [4,2,0]辛垸 -1 ,3,5-三烯 -7-醇 8E (1.17 g, 4.0 mmol),对甲苯磺酸（1.06g， 6.0 mmol)和甲醇（36 mL)， 70°C下搅拌 3小时，加入饱和碳酸氢钠溶液（10 mL)调节 PH>7，用乙酸乙酯萃取（50 mL x 2)，合并有机相并用无水硫酸钠干燥，过滤，将滤液减压浓缩，残留物用硅胶柱色谱分离提纯（石油醚 /乙酸乙酯（v/v) = 20: 1)得到黄色油状的 2-苄氧基 -3-仲丁基 -8-甲氧基 -8-甲基并环 [4,2,0]辛垸 -1 ,3,5-三烯 8F (1.00 g，产率 80.6%) 第六步： 3-仲丁基 -8-甲氧基 -8-甲基双环 [4.2.0】辛烷 -1,3,5-三烯 -2-醇（化合物 8) To the reaction flask was added 5-benzyloxy-7-methyl-4-sec-butyl-cyclo[4,2,0]octyl-1,3,5-trien-7-ol 8E (1.17 g) , 4.0 mmol), p-toluenesulfonic acid (1.06 g, 6.0 mmol) and methanol (36 mL), stirred at 70 ° C for 3 h, then added saturated sodium bicarbonate (10 mL) to adjust pH > The mixture was extracted with EtOAc (EtOAc) (EtOAc) Obtained 2-benzyloxy-3-sec-butyl-8-methoxy-8-methylcyclo[4,2,0]octyl-1,3,5-triene 8F (1.00) g, yield 80.6%) Step 6: 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-l ,3,5-trien-2-ol

向反应瓶中依次加入 2-苄氧基 -3-仲丁基 -8-甲氧基 -8-甲基并环 [4,2,0]辛垸 -1,3,5-三烯 8F (1.00 g, 3.2 mmol)、钯 /炭 (0.1 g, 钯含量 w/w = 10%)、碳酸钾 (0.45g, 3.2 mmol)和甲醇 (100 mL), 氢气氛围下，室温搅拌 4小时，过滤，将滤液减压浓缩，残留物用硅胶柱色谱分离提纯 (石油醚 /乙酸乙酯（v/v) = 20: 1)得到白色固体状的 3-仲丁基 -8-甲氧基 -8-甲基双环 [4.2.0]辛垸 -1,3,5-三烯 -2-醇化合物 8 (0.28 g，产率 39.4%， HPLC: 99.28%)。 3-(sec-butyl)-8-methoxy-8-methylbicyclo[4.2.0]octa-l ,3,5-trien-2-ol

2-benzyloxy-3-sec-butyl-8-methoxy-8-methyl-cyclo[4,2,0]octyl-1,3,5-triene 8F was added to the reaction flask in sequence ( 1.00 g, 3.2 mmol), palladium/carbon (0.1 g, palladium content w/w = 10%), potassium carbonate (0.45 g, 3.2 mmol) and methanol (100 mL), stirred under a hydrogen atmosphere at room temperature for 4 hours, filtered The filtrate was concentrated under reduced pressure. EtOAc mjjjjjjjjjjjjj -Methylbicyclo[4.2.0]octyl-1,3,5-trien-2-ol Compound 8 (0.28 g, yield 39.4%, HPLC: 99.28%).

MS m/z (ESI): 218.9 [M-H]. MS m/z (ESI): 218.9 [M-H].

¾ NMR (400 MHz, CDC1₃): δ 7.10 (q, 1Η), 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). 3⁄4 NMR (400 MHz, CDC1 ₃ ): δ 7.10 (q, 1Η), 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).

实施例 9 Example 9

5-羟基 -4-异丙基 -7-甲基 -并环『4.2.01辛烷 -1，3，5-三烯 -7-氰基（化合物 9) 5-hydroxy-4-isopropyl-7-methyl-cyclo[4.2.01 octane-1,3,5-triene-7-cyano (compound 9)

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

第一步： 5-苄氧基 -4-异丙基 -7-甲基 -并环 [4.2.0】-l，3，5-三烯 -7-氰基（9B) First step: 5-benzyloxy-4-isopropyl-7-methyl-cyclo[4.2.0]-l,3,5-triene-7-cyano (9B)

5-benzyloxy-4-isopropyl-7-methyl-bicyclo[4 2.0]octa-1 ,5 riene-7-carbonitrile 5-benzyloxy-4-isopropyl-7-methyl-bicyclo[4 2.0]octa-1 ,5 riene-7-carbonitrile

向反应瓶中加入 5-苄氧基 -4-异丙基 -7-甲基 -并环 [4,2,0]辛垸 -1,3,5-三烯 -7-醇 1B (1.12 g, 3.2 mmol),氮气保护， 0。C下加入二氯甲垸（30 mL)，搅拌均匀后加入三甲基氰硅垸（412 mg， 4.2 mmol), 缓慢滴加三氟化硼***（4.68 g， 33 mmol), 0。C下反应 3小时，缓慢滴加饱和碳酸氢钠溶液终止反应，用二氯甲垸（60 mL x 2)萃取，合并有机相，用无水硫酸钠干燥，过滤，减压浓缩，残留物硅胶柱色谱分离提纯（石油醚 /乙酸乙酯（v/_V;» = 200: 1)得到黄色油状的 5-苄氧基 -4-异丙基 -7-甲基 -并环 [4.2.0]-1,3,5-三烯 -7-氰基 9B (943 mg, 产率 81%)。 To the reaction flask was added 5-benzyloxy-4-isopropyl-7-methyl-cyclo[4,2,0]octyl-1,3,5-trien-7-ol 1B (1.12 g) , 3.2 mmol), nitrogen protection, 0. Add m-chloroformamide (30 mL) under C, stir well, then add trimethylcyanocyanosilane (412 mg, 4.2 mmol), and slowly add boron trifluoride etherate (4.68 g, 33 mmol), 0. The reaction was carried out for 3 hours, and the reaction was quenched with EtOAc EtOAc (EtOAc) Purification by column chromatography (petroleum ether / ethyl acetate (v/ _v ; s = 200: 1) afforded 5-benzyloxy-4-isopropyl-7-methyl--[[. -1,3,5-Triene-7-cyano 9B (943 mg, yield 81%).

¾ NMR (400 MHz, CDC1₃) δ 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). 第二步： 5-羟基 -4-异丙基 -7-甲基 -并环 [4.2.0】辛垸 -1，3，5-三烯 -7-氰基（化合物 9) 3⁄4 NMR (400 MHz, CDC1 ₃ ) δ 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) Step 2: 5-Hydroxy-4-isopropyl-7-methyl-cyclo[4.2.0]octyl-1,3,5-triene-7-cyano (Compound 9)

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

向反应瓶中加入 5-苄氧基 -4-异丙基 -7-甲基 -并环 [4.2.0]-1,3,5-三烯 -7-氰基 9B (940 mg， 3.2 mmol)和乙酸乙酯 (10 mL ),搅拌均匀后，依次加入碳酸钾 (446 mg, 3.2 mmol)和钯 /炭 (100 mg, 钯含量 w/w = 10%)，氢气氛围下，室温搅拌反应 1小时，抽滤，滤液用 2M的盐酸调节 PH<3，用乙酸乙酯（5 mL x 2)萃取，合并有机相，用无水硫酸钠干燥，过滤，减压浓缩，残留物用石油醚打浆，抽滤，得到白色固体状的 5-羟基 -4-异丙基 -7-甲基 -并环 [4.2.0]辛垸 -1,3,5- 三烯 -7-氰基化合物 9 (363 mg，产率 56%， HPLC: 99.30%)。 To the reaction flask was added 5-benzyloxy-4-isopropyl-7-methyl-cyclo[4.2.0]-1,3,5-triene-7-cyano 9B (940 mg, 3.2 mmol And ethyl acetate (10 mL), after stirring, add potassium carbonate (446 mg, 3.2 mmol) and palladium on carbon (100 mg, palladium content w/w = 10%), and stir under a hydrogen atmosphere at room temperature. After 1 hour, the mixture was filtered with EtOAc (EtOAc) (EtOAc) Beating, suction filtration to give 5-hydroxy-4-isopropyl-7-methyl-cyclo[4.2.0]octyl-1,3,5-triene-7-cyano compound 9 as a white solid. (363 mg, yield 56%, HPLC: 99.30%).

将 5-羟基 -4-异丙基 -7-甲基 -并环 [4.2.0]辛垸 -1,3,5-三烯 -7-氰基化合物 9 (2.0 g， 10 mmol)进行手性拆分，采用 HPLC法，用制备设备和手性柱对手性异构体进行分离（分离条件：手性柱 CHIRALPAK AD-H, 20x250 mm, 5μηι, 流动相：正己垸:异丙醇 = 99: 1 (ν/ν) 等度洗脱 45分钟，流速： 12.0mL/分钟， UV = 220/275 nm，柱温： 25°C)，收集其相应组分，减压浓缩，得到化合物 9-1 (860 mg, ee > 99%, RT = 28.97 min)和化合物 9-2 (875 mg, ee > 99%, RT =37.24 min)。 Handling 5-hydroxy-4-isopropyl-7-methyl-cyclo[4.2.0]octane-1,3,5-triene-7-cyano compound 9 (2.0 g, 10 mmol) Separation by HPLC, separation by preparative equipment and chiral column chiral isomers (separation conditions: chiral column CHIRALPAK AD-H, 20x250 mm, 5μηι, mobile phase: n-hexyl: isopropanol = 99 : 1 (ν/ν) isocratic elution for 45 minutes, flow rate: 12.0 mL/min, UV = 220/275 nm, column temperature: 25 ° C), the corresponding fractions were collected and concentrated under reduced pressure to give compound 9- 1 (860 mg, ee > 99%, RT = 28.97 min) and compound 9-2 (875 mg, ee > 99%, RT = 37.24 min).

MS m/z (ESI): 202.1 [M+l]. MS m/z (ESI): 202.1 [M+l].

¾ NMR (400 MHz, CDC1₃) δ 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). 实施例 10 3⁄4 NMR (400 MHz, CDC1 ₃ ) δ 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-乙氧基 -3-异丙基 -8-甲基并环【4.2.01辛垸 -1,3,5-三烯 -2-醇（化合物 10) 8-Ethoxy-3-isopropyl-8-methyl-cyclo[4.2.01 垸--1,3,5-trien-2-ol (compound 10)

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

第一步： 2- (苄氧基) -8-乙氧基 -3-异丙基 -8-甲基并环 [4.2.0】辛垸 -1,3,5-三烯（10B)

First step: 2-(Benzyloxy)-8-ethoxy-3-isopropyl-8-methyl-cyclo[4.2.0]octane-1,3,5-triene (10B)

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

向反应瓶中依次加入 5-苄氧基 -4-异丙基 -7-甲基 -并环 [4,2,0]辛垸 -1,3,5-三烯 -7-醇 1B (1.13 g, 4.0 mmol)、乙醇（30 mL)和对甲苯磺酸（1.06 g， 6.0 mmol), 70°C搅拌 4小时，加入饱和碳酸氢钠溶液调节 pH > 7，用二氯甲垸萃取（80 mL x 2), 合并有机相并用无水硫酸钠干燥，过滤，将滤液减压浓缩，残留物用硅胶柱色谱分离提纯（石油醚 /乙酸乙酯（v/_V;» = 50: 1)得到黄色油状的 2- (苄氧基) -8-乙氧基 -3-异丙基 -8-甲基并环 [4.2.0]辛垸 -1,3,5-三烯化合物 10B 粗品 (1.45 g, 产率 93.5 %)，直接用于下步反应。 To the reaction flask was added 5-benzyloxy-4-isopropyl-7-methyl-cyclo[4,2,0]octyl-1,3,5-trien-7-ol 1B (1.13). g, 4.0 mmol), ethanol (30 mL) and p-toluenesulfonic acid (1.06 g, 6.0 mmol), stirred at 70 ° C for 4 hours, added saturated sodium bicarbonate solution to adjust pH > 7, extracted with methylene chloride (80) mL x 2), organic phases were combined and dried over anhydrous sodium sulfate, filtered, and 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-methyl-cyclo[4.2.0]octane-1,3,5-triene compound 10B crude oil (1.45) g, yield 93.5 %), used directly in the next step.

第二步： 8-乙氧基 -3-异丙基 -8-甲基并环 [4.2.0】辛烷 -1,3,5-三烯 -2-醇（化合物 10) Step 2: 8-Ethoxy-3-isopropyl-8-methyl-cyclo[4.2.0]octane-1,3,5-trien-2-ol (compound 10)

8-ethoxy-3-isopropyl-8-methylbicyclo[4.2 l

向反应瓶中依次加入 2- (苄氧基； )-8-乙氧基 -3-异丙基 -8-甲基并环 [4.2.0]辛垸 -1,3,5-三烯 10B (1.14 g， 3.7 mmol)、钯 /炭 (0.11 g,钯含量 w/w = 10%)、碳酸钾 (0.51 g, 3.7 mmol)和甲醇 (60 mL), 氢气氛围下，室温搅拌 1.5小时，过滤，滤液用 3M盐酸酸化，用二氯甲垸萃取（80 mL x 2)，合并有机相并用无水硫酸钠干燥，过滤，将滤液减压浓缩，残留物用硅胶柱色谱分离提纯（石油醚 /乙酸乙酯（v/v) = 15: 1)得到黄色油状的 8-乙氧基 -3-异丙基 -8-甲基并环 [4.2.0]辛垸 -1,3,5-三烯 -2-醇化合物 10 (0.44 g，产率 54%， HPLC: 95.10%)。 8-ethoxy-3-isopropyl-8-methylbicyclo[4.2 l

2-(Benzyloxy;)-8-ethoxy-3-isopropyl-8-methylcyclo[4.2.0]octyl-1,3,5-triene 10B was added to the reaction flask in order. (1.14 g, 3.7 mmol), palladium/carbon (0.11 g, palladium content w/w = 10%), potassium carbonate (0.51 g, 3.7 mmol) and methanol (60 mL), stirred under a hydrogen atmosphere at room temperature for 1.5 hours. Filtration, and the filtrate was acidified with EtOAc (EtOAc) (EtOAc) /ethyl acetate (v/v) = 15: 1) to give 8-ethoxy-3-isopropyl-8-methyl-cyclo[4.2.0] octyl-1,3,5- as a yellow oil. Trien-2-ol compound 10 (0.44 g, yield 54%, HPLC: 95.10%).

MS m/z (ESI): 219.2 [M-l]. MS m/z (ESI): 219.2 [M-l].

^ NMR (400 MHz, CDC1₃) δ 7.15 (d, 1H), 6.71 (d, 1H), 5.70 (s, 1H), 3.63― 3.52 (m, 1H), 3.51^ NMR (400 MHz, CDC1 ₃ ) δ 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). 实施例 11 — 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-异丙氧基 -3-异丙基 -8-甲基并环【4.2.01辛烷 -1,3,5-三烯 -2-醇（化合物 11) 8-isopropoxy-3-isopropyl-8-methyl-cyclo[4.2.01 octane-1,3,5-trien-2-ol (compound 11)

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

11B 化合物 11 11B Compound 11

第一步： 2- (苄氧基) -8-异丙氧基 -3-异丙基 -8-甲基并环 [4.2.0】辛烷 -1,3,5-三烯（11B) First step: 2-(Benzyloxy)-8-isopropoxy-3-isopropyl-8-methyl-cyclo[4.2.0]octane-1,3,5-triene (11B)

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

向反应瓶中依次加入 5-苄氧基 -4-异丙基 -7-甲基 -并环 [4,2,0]辛垸 -1,3,5-三烯 -7-醇 1B (0.55 g, 2.0 mmol)、异丙醇 (30 mL)和对甲苯磺酸 (0.53 g, 3.0 mmol), 70°C搅拌过夜，加入饱和碳酸氢钠溶液调节 pH > 7，用二氯甲垸萃取（60 mL x 2), 合并有机相并用无水硫酸钠干燥，过滤，将滤液减压浓缩，残留物用硅胶柱色谱分离提纯（石油醚 /乙酸乙酯（v/_V;» = 40: 1)得到无色油状的 2- (苄氧基) -8-异丙氧基 -3-异丙基 -8-甲基并环 [4.2.0]辛垸 -1,3,5-三烯 11B (0.47 g，产率 74 %)。 Add 5-benzyloxy-4-isopropyl-7-methyl-cyclo[4,2,0]octyl-1,3,5-trien-7-ol 1B (0.55) to the reaction flask. g, 2.0 mmol), isopropanol (30 mL) and p-toluenesulfonic acid (0.53 g, 3.0 mmol), stir at 70 ° C overnight, add saturated sodium bicarbonate solution to adjust pH > 7, extract with methylene chloride ( 60 mL x 2), organic phases were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate _{(v / V; »= 40} : 1) 2-(Benzyloxy)-8-isopropoxy-3-isopropyl-8-methylcyclo[4.2.0]octyl-1,3,5-triene 11B (yield as colorless oil) 0.47 g, yield 74%).

^ NMR (400 MHz, CDC13) δ 7.46 (d, 2H), 7.39 (dd, 2H), 7.31 (dd, IH), 7.18 (d, IH), 6.73 (d, IH), 5.30 (dd, 2H), 3.76 (dt, IH), 3.44 - 3.35 (m, IH), 3.32 (d, IH), 3.06 (d, IH), 1.74 (s, 3H), 1.24 - 1.16 (m, 9H), 1.12 (d, J = 6.1 Hz, 3H). ^ NMR (400 MHz, CDC13) δ 7.46 (d, 2H), 7.39 (dd, 2H), 7.31 (dd, IH), 7.18 (d, IH), 6.73 (d, IH), 5.30 (dd, 2H) , 3.76 (dt, IH), 3.44 - 3.35 (m, IH), 3.32 (d, IH), 3.06 (d, IH), 1.74 (s, 3H), 1.24 - 1.16 (m, 9H), 1.12 (d , J = 6.1 Hz, 3H).

第二步： 8-异丙氧基 -3-异丙基 -8-甲基并环 [4.2.0】辛垸 -1，3，5-三烯 -2-醇（化合物 11) Step 2: 8-Isopropoxy-3-isopropyl-8-methyl-cyclo[4.2.0]octyl-1,3,5-trien-2-ol (Compound 11)

向反应瓶中依次加入 2- (苄氧基; )-8-异丙氧基 -3-异丙基 -8-甲基并环 [4.2.0]辛垸 -1,3,5-三烯 11B (0.39 g, 1.2 mmol), 钯 /炭 (0.04 g, 钯含量 w/w = 10%)、碳酸钾 (0.17 g, 1.2 mmol)和乙酸乙酯（30 mL)，氢气氛围下，室温搅拌 2小时，过滤，滤液用 3M盐酸调节 pH为 3，用乙酸乙酯萃取（60 mL X 2), 合并有机相并用无水硫酸钠干燥，过滤，将滤液减压浓缩，残留物用硅胶柱色谱分离提纯（石油醚 /乙酸乙酯（v/_V;» = 30_: l)得到黄色油状的 8-异丙氧基 -3-异丙基 -8- 甲基并环 [4.2.0]辛垸 -1,3,5-三烯 -2-醇化合物 11 (0.21 g，产率 75%， HPLC: 95.58%)。 MS m/z (ESI): 233.3[M-1]. 2-[Benzyloxy;]-8-isopropoxy-3-isopropyl-8-methylcyclo[4.2.0]octane-1,3,5-triene was added to the reaction flask in order. 11B (0.39 g, 1.2 mmol), palladium on charcoal (0.04 g, palladium content w/w = 10%), potassium carbonate (0.17 g, 1.2 mmol) and ethyl acetate (30 mL). After 2 hours, the mixture was filtered, and the filtrate was evaporated to m. Separation and purification (petroleum ether/ethyl acetate (v/ _v ; » = 30 _: 1) afforded 8-isopropoxy-3-isopropyl-8-methyl-cyclo-[4. -1,3,5-Trien-2-ol compound 11 (0.21 g, yield 75%, HPLC: 95.58%). MS m/z (ESI): 233.3 [M-1].

¾ NMR (400 MHz, CDC1₃) δ 7.14 (d, IH), 6.70 (d, IH), 5.28 (s, IH), 3.77 (dt, IH), 3.28 ( IH), 3.21 (dd, IH), 3.01 (d, IH), 1.68 (s, 3H), 1.23 (dd, 6H), 1.19 (d, 3H), 1.13 (d, 3H). 实施例 12 3⁄4 NMR (400 MHz, CDC1 ₃ ) δ 7.14 (d, IH), 6.70 (d, IH), 5.28 (s, IH), 3.77 (dt, IH), 3.28 (IH), 3.21 (dd, IH), 3.01 (d, IH), 1.68 (s, 3H), 1.23 (dd, 6H), 1.19 (d, 3H), 1.13 (d, 3H). Example 12

8-丁氧基 -3-异丙基 -8-甲基并环【4.2.0谇垸 -1，3，5-三烯 -2-醇（化合物 12) 8-butoxy-3-isopropyl-8-methyl-cyclo[4.2.0谇垸-1,3,5-trien-2-ol (compound 12)

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

1 B 12B 化合物 12 1 B 12B compound 12

第一步： 2- (苄氧基) -8-丁氧基 -3-异丙基 -8-甲基并环 [4.2.0】辛垸 -1,3,5-三烯（12B) First step: 2-(Benzyloxy)-8-butoxy-3-isopropyl-8-methyl-cyclo[4.2.0]octane-1,3,5-triene (12B)

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

向反应瓶中依次加入 5-苄氧基 -4-异丙基 -7-甲基 -并环 [4,2,0]辛垸 -1,3,5-三烯 -7-醇 1B (0.56 g, 2.0 mmol), 正丁醇 (30 mL)和对甲苯磺酸 (0.53 g, 3.0 mmol), 70°C搅拌 6小时，加入饱和碳酸氢钠溶液调节 pH > 7，用乙酸乙酯萃取（60 mL x 2), 合并有机相并用无水硫酸钠干燥，过滤，将滤液减压浓缩，残留物用硅胶柱色谱分离提纯（石油醚 /乙酸乙酯（v/v) = 50: 1)得到无色油状的 2- (苄氧基) -8-丁氧基 -3-异丙基 -8-甲基并环 [4.2.0]辛垸 -1,3,5-三烯 12B (0.55 g，产率 81%)。 Add 5-benzyloxy-4-isopropyl-7-methyl-cyclo[4,2,0]octyl-1,3,5-trien-7-ol 1B (0.56) to the reaction flask. g, 2.0 mmol), n-butanol (30 mL) and p-toluenesulfonic acid (0.53 g, 3.0 mmol), stirred at 70 ° C for 6 hours, added saturated sodium bicarbonate solution to adjust pH > The organic phase was combined and dried over anhydrous sodium sulfate (MgSO4). 2-(Benzyloxy)-8-butoxy-3-isopropyl-8-methyl-cyclo[4.2.0]octane-1,3,5-triene 12B (0.55 g) as a colorless oil , yield 81%).

¾ NMR (400 MHz, CDC1₃) δ 7.45 (d, 2H), 7.39 (t, 2H), 7.32 (t, IH), 7.19 (d, IH), 6.74 (d, IH), 5.23 (dd, 2H), 3.53― 3.46 (m, IH), 3.44 (d, IH), 3.41― 3.33 (m, 2H), 2.96 (d, IH), 1.75 (s, 3H), 1.56 (td, 2H), 1.41 - 1.29 (m, 2H), 1.21 (t, 6H), 0.87 (t, 3H). 3⁄4 NMR (400 MHz, CDC1 ₃ ) δ 7.45 (d, 2H), 7.39 (t, 2H), 7.32 (t, IH), 7.19 (d, IH), 6.74 (d, IH), 5.23 (dd, 2H ), 3.53 - 3.46 (m, IH), 3.44 (d, IH), 3.41 - 3.33 (m, 2H), 2.96 (d, IH), 1.75 (s, 3H), 1.56 (td, 2H), 1.41 - 1.29 (m, 2H), 1.21 (t, 6H), 0.87 (t, 3H).

第二步： 8-丁氧基 -3-异丙基 -8-甲基并环 [4.2.0】辛院 -1,3,5-三烯 -2-醇（化合物 12) The second step: 8-butoxy-3-isopropyl-8-methyl-cyclo[4.2.0] Xinyuan -1,3,5-trien-2-ol (compound 12)

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

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

向反应瓶中依次加入 2- ( 氧基) -8-丁氧基 -3-异丙基 -8-甲基并环 [4.2.0]辛 -1,3,5-三烯 12B (0.55 g, 1.6 mmol)、钯 /炭 (55 mg, 钯含量 w/w = 10%) 、碳酸钾 (0.22 g, 1.6 mmol)和乙酸乙酯（20 mL)，氢气氛围下，室温搅拌 2小时，过滤，滤液用 3M盐酸调节 pH为 3，用乙酸乙酯萃取（60 mL x 2)，合并有机相并用无水硫酸钠干燥，过滤，将滤液减压浓缩，残留物用硅胶柱色谱分离提纯（石油醚 /乙酸乙酯（v/_V;» = 50_: l)得到黄色油状的 8-丁氧基 -3-异丙基 -8-甲基并环 [4.2.0]辛垸 -1,3,5-三烯 -2-醇化合物 12 (0.34 g，产率 83.58%， HPLC: 98%)。 To the reaction flask was added 2-(oxy)-8-butoxy-3-isopropyl-8-methylcyclo[4.2.0]oct-1,3,5-triene 12B (0.55 g). , 1.6 mmol), palladium on charcoal (55 mg, palladium content w/w = 10%), potassium carbonate (0.22 g, 1.6 mmol) and ethyl acetate (20 mL), stirred at room temperature for 2 hours under hydrogen atmosphere, filtered The filtrate was adjusted to pH 3 with 3M EtOAc (EtOAc) (EtOAc (EtOAc) Ether/ethyl acetate (v/ _v ; » = 50 _: 1) afforded 8-butoxy-3-isopropyl-8-methyl-cyclo[4. 5-Trien-2-ol compound 12 (0.34 g, yield 83.58%, HPLC: 98%).

MS m/z (ESI): 233.3[M-1]. MS m/z (ESI): 233.3 [M-1].

^ NMR (400 MHz, CDC1₃) δ 7.14 (d,lH), 6.71 (d,lH), 5.03 (t, 1H), 3.49 (dt, 1H), 3.43― 3.36 (m, 1H), 3.33 (d,lH), 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). 实施例 13 ^ NMR (400 MHz, CDC1 ₃ ) δ 7.14 (d, lH), 6.71 (d, lH), 5.03 (t, 1H), 3.49 (dt, 1H), 3.43 - 3.36 (m, 1H), 3.33 (d ,lH), 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-叠氮基 -3-异丙基 -8-甲基并环【4.2.01辛烷 -1,3,5-三烯 -2-醇（化合物 13) 8-azido-3-isopropyl-8-methyl-cyclo[4.2.01 octane-1,3,5-trien-2-ol (compound 13)

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

化合物 6 化合物 13 Compound 6 compound 13

第一步： 8-叠氮基 -3-异丙基 -8-甲基并环 [4.2.0】辛浣 -1,3,5-三烯 -2-醇（化合物 13) First step: 8-azido-3-isopropyl-8-methyl-cyclo[4.2.0]octane-1,3,5-trien-2-ol (compound 13)

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

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

向反应瓶中加入 4-异丙基 -7-甲氧基 -7-甲基 -并环 [4,2,0]辛垸 -1,3,5-三烯 -5-醇化合物 6 (1.5 g， 7.3 mmol), 叠氮化钠（1.6 g， 23.3 mmol), 氮气保护，加入二氯甲垸（180 mL)， 0°C下缓慢滴加三氟乙酸（3.6 mL， 46 mmol), 自然升温至室温反应过夜，缓慢加入碳酸氢钠颗粒终止反应，抽滤，滤液减压浓缩，残留物硅胶柱色谱分离提纯（石油醚 /乙酸乙酯（v/_V;» = 100: 1)得到黄色油状的 8-叠氮基 -3-异丙基 -8-甲基并环 [4.2.0]辛垸 -1,3,5-三烯 -2-醇化合物 13 (1.33 g，产率 84%)。 To the reaction flask was added 4-isopropyl-7-methoxy-7-methyl-cyclo[4,2,0]octyl-1,3,5-trien-5-ol compound 6 (1.5 g, 7.3 mmol), sodium azide (1.6 g, 23.3 mmol), nitrogen-protected, added dichloromethane (180 mL), slowly added trifluoroacetic acid (3.6 mL, 46 mmol) at 0 ° C, The mixture was warmed to room temperature overnight, and the reaction was quenched with sodium bicarbonate, and the mixture was filtered with suction. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography ( petroleum ether / ethyl acetate (v/ _v ; Oily 8-azido-3-isopropyl-8-methylcyclo[4.2.0]octyl-1,3,5-trien-2-ol compound 13 (1.33 g, produced Rate 84%).

MS m/z (ESI): 175.1 [M-N₃]. MS m/z (ESI): 175.1 [MN ₃ ].

¾ NMR (400 MHz, CDC1₃) δ 7.17 (d,lH), 6.73 (d,lH), 5.15 (s, 1H), 3.36 (d,lH), 3.22 - 3. (m, 2H), 1.73 (s, 3H), 1.25 (dd, 6H). 3⁄4 NMR (400 MHz, CDC1 ₃ ) δ 7.17 (d,lH), 6.73 (d,lH), 5.15 (s, 1H), 3.36 (d,lH), 3.22 - 3. (m, 2H), 1.73 ( s, 3H), 1.25 (dd, 6H).

实施例 14 Example 14

3-异丙基 -8-(2-甲氧基乙氧基 )-8-甲基并环【4.2.01辛焼 -1,3,5-三烯 -2-醇（化合物 14) 3-isopropyl-8-(2-methoxyethoxy)-8-methyl-cyclo[4.2.01-indole-1,3,5-trien-2-ol (compound 14)

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

第一步： 2- (苄氧基) -3-异丙基 -8-(2-甲氧基乙氧基 )-8-甲基并环 [4.2.0】辛垸 -1，3，5-三烯 (14B) 2-(benzyloxy)-3-isopropyl-8-(2-methoxyethoxy)-8-methylbicyclo[4.2.0]octa-l,3,5-triene First step: 2-(Benzyloxy)-3-isopropyl-8-(2-methoxyethoxy)-8-methyl-cyclo[4.2.0]octane-1,3,5 -Triene (14B) 2-(benzyloxy)-3-isopropyl-8-(2-methoxyethoxy)-8-methylbicyclo[4.2.0]octa-l,3,5-triene

向反应瓶中依次加入 5-苄氧基 -4-异丙基 -7-甲基 -并环 [4,2,0]辛垸 -1,3,5-三烯 -7-醇 1B (0.56 g, 2.0 mmol)、乙二醇单甲醚 (30 mL)和对甲苯磺酸 (0.53 g, 3.0 mmol), 70°C搅拌 3小时，加入饱和碳酸氢钠溶液调节 pH > 7，用乙酸乙酯萃取（60 mL x 2)，合并有机相并用无水硫酸钠干燥，过滤，将滤液减压浓缩，残留物用硅胶柱色谱分离提纯（石油醚 /乙酸乙酯（v/_V;» = 40_: l) 得到棕色油状的 2- (苄氧基； )-3-异丙基 -8-(2-甲氧基乙氧基 )-8-甲基并环 [4.2.0]辛垸 -1,3,5-三烯 14B (0.53 g, 产率 78 %)。 Add 5-benzyloxy-4-isopropyl-7-methyl-cyclo[4,2,0]octyl-1,3,5-trien-7-ol 1B (0.56) to the reaction flask. g, 2.0 mmol), ethylene glycol monomethyl ether (30 mL) and p-toluenesulfonic acid (0.53 g, 3.0 mmol), stirred at 70 ° C for 3 hours, added saturated sodium bicarbonate solution to adjust pH > 7, with acetic acid ester extraction (60 mL x 2), organic phases were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / _V; »= 40 _: l) 2-(Benzyloxy;)-3-isopropyl-8-(2-methoxyethoxy)-8-methyl-cyclo[4.2.0]octane-1 as a brown oil , 3,5-triene 14B (0.53 g, yield 78%).

¾ NMR (400 MHz, CDC1₃) δ 7.49― 7.45 (m, 2H), 7.42― 7.36 (m, 2H), 7.35― 7.29 (m, 1H), 7.19 (d,lH), 6.73 (d,lH), 5.25 (dd,2H), 3.66 (dt, 1H), 3.59― 3.54 (m, 1H), 3.54― 3.50 (m, 2H), 3.47 (d,lH), 3.43 - 3.33 (m, 1H), 3.32 (s, 3H), 2.99 (d,lH), 1.79 (s, 3H), 1.20 (t,6H). 3⁄4 NMR (400 MHz, CDC1 ₃ ) δ 7.49 - 7.45 (m, 2H), 7.42 - 7.36 (m, 2H), 7.35 - 7.29 (m, 1H), 7.19 (d, lH), 6.73 (d, lH) , 5.25 (dd, 2H), 3.66 (dt, 1H), 3.59 - 3.54 (m, 1H), 3.54 - 3.50 (m, 2H), 3.47 (d, lH), 3.43 - 3.33 (m, 1H), 3.32 (s, 3H), 2.99 (d, lH), 1.79 (s, 3H), 1.20 (t, 6H).

第二步： 3-异丙基 -8-(2-甲氧基乙氧基 )-8-甲基并环 [4.2.0】辛垸 -1，3，5-三烯 -2-醇（化合物 14) 3-isopropyl-8-(2-methoxyethoxy)-8-methylbicyclo[4.2.0]octa-l,3,5-trien-2-ol

Second step: 3-isopropyl-8-(2-methoxyethoxy)-8-methyl-cyclo[4.2.0]octyl-1,3,5-trien-2-ol ( Compound 14) 3-isopropyl-8-(2-methoxyethoxy)-8-methylbicyclo[4.2.0]octa-l,3,5-trien-2-ol

向反应瓶中依次加入 2- (苄氧基;) -3-异丙基 -8-(2-甲氧基乙氧基 )-8-甲基并环 [4.2.0]辛垸 -1,3,5-三烯 14B (0.53 g, 1.6 mmol),钯 /炭 (0.57 g,钯含量 w/w = 10%)、碳酸钾（0.6 g, 4.3 mmol) 和乙酸乙酯（30 mL)，氢气氛围下，室温搅拌 4小时，过滤，滤液用 3M盐酸调节 pH为 3，用乙酸乙酯萃取（60 mL x 2)，合并有机相并用无水硫酸钠干燥，过滤，将滤液减压浓缩，残留物用硅胶柱色谱分离提纯（石油醚 /乙酸乙酯（v/v) = 100: 1)得到黄色油状的 3-异丙基 -8-(2-甲氧基乙氧基) -8-甲基并环 [4.2.0]辛垸 -1,3,5-三烯 -2-醇化合物 14 (0.25 g, 产率 65%， HPLC: 97.80%) 2-(Benzyloxy;)-3-isopropyl-8-(2-methoxyethoxy)-8-methylcyclo[4.2.0]octane-1 was added to the reaction flask in that order. 3,5-triene 14B (0.53 g, 1.6 mmol), palladium on charcoal (0.57 g, palladium content w/w = 10%), potassium carbonate (0.6 g, 4.3 mmol) and ethyl acetate (30 mL). The mixture was stirred at room temperature for 4 hr. EtOAc (EtOAc m. The residue was purified by EtOAc EtOAc EtOAc (EtOAc(EtOAc) Methylcyclo[4.2.0]octyl-1,3,5-trien-2-ol compound 14 (0.25 g, yield 65%, HPLC: 97.80%)

MS m/z (ESI): 249.3 [M-l]. MS m/z (ESI): 249.3 [M-l].

¾ NMR (400 MHz, CDC1₃) δ 7.28 (s, 1H), 7.15 (d,lH), 6.69 (d,lH), 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,lH), 1.68 (s, 3H), 1.23 (dd, 6H). 实施例 15 3⁄4 NMR (400 MHz, CDC1 ₃ ) δ 7.28 (s, 1H), 7.15 (d,lH), 6.69 (d,lH), 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, lH), 1.68 (s, 3H), 1.23 (dd, 6H). Example 15

8-乙基 -3-异丙基 -8-甲氧基并环【4.2.01辛烷 -1，3，5-三烯 -2-醇（化合物 15) 8-ethyl-3-isopropyl-8-methoxycyclo[4.2.01 octane-1,3,5-trien-2-ol (compound 15)

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

3B 15B 化合物 15 3B 15B Compound 15

第一步： 2- (苄氧基) -8-乙基 -3-异丙基 -8-甲氧基并环 [4.2.0】辛垸 -1,3,5-三烯（15B) First step: 2-(Benzyloxy)-8-ethyl-3-isopropyl-8-methoxy-cyclo[4.2.0]octane-1,3,5-triene (15B)

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

向反应瓶中依次加入 5-苄氧基 -7-乙基 -4-异丙基 -并环 [4,2,0]辛垸 -1,3,5-三烯 -7-醇 3B (1.48 g， 5.0 mmol), 甲醇（45 mL)和对甲苯磺酸（1.33 g， 7.5 mmol), 70°C搅拌 3小时，加入饱和碳酸氢钠溶液调节 pH > 7，减压浓缩，用乙酸乙酯萃取（60 mL x 2)，合并有机相并用无水硫酸钠干燥，过滤，将滤液减压浓缩，残留物用硅胶柱色谱分离提纯（石油醚 /乙酸乙酯 i N、 = 100: 1)得到黄色固体状的 2- (苄氧基；) -8-乙基 -3-异丙基 -8-甲氧基并环 [4.2.0]辛垸 -1 ,3,5-三烯 15B 粗品（1.55 g)，直接进行下一步反应。 To the reaction flask was added 5-benzyloxy-7-ethyl-4-isopropyl-cyclo[4,2,0]octyl-1,3,5-trien-7-ol 3B (1.48). g, 5.0 mmol), methanol (45 mL) and p-toluenesulfonic acid (1.33 g, 7.5 mmol), stirred at 70 ° C for 3 h, sat. The mixture was concentrated under reduced pressure. Purification (petroleum ether / ethyl acetate i N, = 100: 1) afforded 2-(benzyloxy;) -8-ethyl-3-isopropyl-8-methoxy-cyclohexane as a yellow solid. .0] Xinyi-1,3,5-triene 15B crude (1.55 g), directly subjected to the next reaction.

第二步： 8-乙基 -3-异丙基 -8-甲氧基并环 [4.2.0】辛院 -1,3,5-三烯 -2-醇（化合物 15) The second step: 8-ethyl-3-isopropyl-8-methoxy-cyclo[4.2.0] Xinyuan -1,3,5-trien-2-ol (compound 15)

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

向反应瓶中依次加入 2- (苄氧基； )-8-乙基 -3-异丙基 -8-甲氧基并环 [4.2.0]辛垸 -1 ,3,5-三烯 15B (1.45 g, 4.7 mmol)、钯 /炭 (0.15 g, 钯含量 w/w = 10%)、碳酸钾 (0.65 g, 4.7 mmol)和乙酸乙酯（50 mL), 氢气氛围下，室温搅拌 3小时，过滤，滤液用 3M盐酸调节 pH为 3，用乙酸乙酯萃取（60 mL X 2), 合并有机相并用无水硫酸钠干燥，过滤，将滤液减压浓缩，残留物用硅胶柱色谱分离提纯（石油醚 /乙酸乙酯（v/_V;» = 60_: l)得到黄色油状的 8-乙基 -3-异丙基 -8-甲氧基并环 [4.2.0]辛垸 -1 ,3,5-三烯 -2-醇化合物 15 (0.42 g，产率 41%， HPLC: 97.19%)。 2-(Benzyloxy;)-8-ethyl-3-isopropyl-8-methoxycyclo[4.2.0]octyl-1,3,5-triene 15B was sequentially added to the reaction flask. (1.45 g, 4.7 mmol), palladium/carbon (0.15 g, palladium content w/w = 10%), potassium carbonate (0.65 g, 4.7 mmol) and ethyl acetate (50 mL), stirred under a hydrogen atmosphere at room temperature 3 Purification (petroleum ether/ethyl acetate (v/ _v ; » = 60 _: 1) afforded 8-ethyl-3-isopropyl-8-methoxy-cyclo[4. , 3,5-Trien-2-ol compound 15 (0.42 g, yield 41%, HPLC: 97.19%).

MS m/z (ESI): 219.0 [M-l]. MS m/z (ESI): 219.0 [M-l].

IH NMR (400 MHz, CDC1₃) δ 7.14 (d,lH), 6.71 (d,lH), 5.34 (s, 1H), 3.32 (s, 3H), 3.27 (d,lH),IH NMR (400 MHz, CDC1 ₃ ) δ 7.14 (d,lH), 6.71 (d,lH), 5.34 (s, 1H), 3.32 (s, 3H), 3.27 (d,lH),

3.21 (dd, 1H), 2.95 (d,lH), 2.40 (t,lH), 1.99 (q,2H), 1.24 (dd,6H), 1.06— 1.01 (m, 3H)。实施例 16 3.21 (dd, 1H), 2.95 (d,lH), 2.40 (t,lH), 1.99 (q,2H), 1.24 (dd,6H), 1.06—1.01 (m, 3H). Example 16

8-环丙基 -3-异丙基 -并环『4.2.01辛垸 -1，3，5-三烯 -2-醇（化合物 16) 8-cyclopropyl-3-isopropyl-cyclohexane "4.2.01 octone -1,3,5-trien-2-ol (compound 16)

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

第一步： 5- (苄氧基) -7-环丙基 -4-异丙基并环 [4.2.0】辛垸 -1,3,5-三烯 -7-醇（16B)

First step: 5-(Benzyloxy)-7-cyclopropyl-4-isopropylcyclo[4.2.0]octyl-1,3,5-triene-7-ol (16B)

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

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

向反应瓶中加入 5-苄氧基 -4-异丙基 -并环 [4,2,0]辛垸 -1,3,5-三烯 -7-酮 If (6.0 g, 22.6 mmol) 和四氢呋喃（150 mL)，氮气保护， -78°C下缓慢滴加环丙基溴化镁溶液（35 mL， 35 mmol), 滴加完毕后自然升至室温反应 3小时，加入饱和氯化铵溶液（200 mL)，室温搅拌 20分钟，用乙酸乙酯萃取（100mL x 2)，合并有机相，减压浓缩，残留物用硅胶柱色谱分离提纯（石油醚 /乙酸乙酯（v/v) = 50:1) 得到黄色油状的 5- (苄氧基) -7-环丙基 -4-异丙基并环 [4.2.0]辛垸 -1,3,5- 三烯 -7-醇 16B (2.7 g, 产率 39%)。 To the reaction flask was added 5-benzyloxy-4-isopropyl-cyclo[4,2,0]octyl-1,3,5-trien-7-one If (6.0 g, 22.6 mmol) and Tetrahydrofuran (150 mL), nitrogen protection, slowly add cyclopropylmagnesium bromide solution (35 mL, 35 mmol) at -78 °C. After the addition is completed, naturally raise to room temperature for 3 hours, add saturated ammonium chloride solution. (200 mL), EtOAc (EtOAc) (EtOAc/EtOAc) 50:1) 5-(Benzyloxy)-7-cyclopropyl-4-isopropylcyclo[4.2.0]octyl-1,3,5-trien-7-ol 16B as a yellow oil (2.7 g, yield 39%).

第二步： 2- (苄氧基) -8-环丙基 -3-异丙基并环 [4.2.0】辛烷 -1,3,5-三烯（16C) Step 2: 2-(Benzyloxy)-8-cyclopropyl-3-isopropyl-cyclo[4.2.0]octane-1,3,5-triene (16C)

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

向反应瓶中依次加入 5- (苄氧基; 1-7-环丙基 -4-异丙基并环 [4.2.0]辛垸 -1,3,5-三烯 -7-醇 16B (700mg, 2.3 mmol), 二氯甲垸（30 mL)和三乙基硅垸（20 mL， 105.6 mmol), 0。C下缓慢滴加三氟乙酸（2.5 mL， 32 mmol), 加完 0。C搅拌 2小时，加入饱和碳酸氢钠溶液（60 mL)，室温搅拌 1小时，用二氯甲垸萃取（60 mL x 2)，合并有机相，减压浓缩，残留物用硅胶柱色谱分离提纯（石油醚 /乙酸乙酯（v/v) = 30:l)得到无色油状 2- (苄氧基) -8-环丙基 -3-异丙基并环 [4.2.0] 辛垸 -1,3,5-三烯 16C (450 mg, 产率 74%)。第三步： 8-环丙基 -3-异丙基并环 [4.2.0】辛垸 -1,3,5-三烯 -2-醇（化合物 16) To the reaction flask was added 5-(benzyloxy; 1-7-cyclopropyl-4-isopropylcyclo[4.2.0]octyl-1,3,5-trien-7-ol 16B ( 700 mg, 2.3 mmol), dichloromethane (30 mL) and triethylsilyl (20 mL, 105.6 mmol), slowly added dropwise trifluoroacetic acid (2.5 mL, 32 mmol) at 0 ° C. After stirring for 2 hours, a saturated sodium hydrogen carbonate solution (60 mL) was added, and the mixture was stirred at room temperature for 1 hour, and extracted with dichloromethane (60 mL x 2). (petroleum ether/ethyl acetate (v/v) = 30:1) to give 2-(benzyloxy)-8-cyclopropyl-3-isopropylcyclo[4.2.0] 1,3,5-Triene 16C (450 mg, yield 74%). Step 3: 8-cyclopropyl-3-isopropyl-cyclo[4.2.0]octane-1,3,5- Trien-2-ol (compound 16)

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

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

向反应瓶中依次加入 2- ( 氧基) -8-环丙基 -3-异丙基并环 [4.2.0]辛垸 -1,3,5-三烯 16C (450 mg, 1.5 mmol), 钯 /炭 (45 mg, 钯含量 w/w= 10%)、碳酸钾 (0.21 g, 1.5 mmol)和乙酸乙酯 (45.0 mL), 氢气氛围下，室温搅拌 3小时，过滤，滤液用 3M盐酸调节 pH=3，用乙酸乙酯萃取（30 mL X 2), 合并有机相并用无水硫酸钠干燥，过滤，将滤液减压浓缩，残留物用硅胶柱色谱分离提纯（石油醚 /乙酸乙酯（v/v) = 60: 1) 得到黄色油状的 8-环丙基 -3-异丙基并环 [4.2.0]辛垸2-(Aoxy)-8-cyclopropyl-3-isopropylcyclo[4.2.0]octane-1,3,5-triene 16C (450 mg, 1.5 mmol) was added to the reaction flask. , palladium/carbon (45 mg, palladium content w/w = 10%), potassium carbonate (0.21 g, 1.5 mmol) and ethyl acetate (45.0 mL), stirred under a hydrogen atmosphere at room temperature for 3 hours, filtered, and filtrated with 3M Hydrochloric acid was adjusted to pH = 3, and extracted with ethyl acetate (30 mL EtOAc). Deprotection (petroleum ether/ethyl acetate (v/v) = 60: 1) afforded 8-cyclopropyl-3-isopropylcyclo[4.

-1,3,5-三烯 -2-醇化合物 16 (265 mg，产率 85%， HPLC: 97.24%)。 -1,3,5-Trien-2-ol compound 16 (265 mg, yield 85%, HPLC: 97.24%).

MS m/z (ESI): 201.0 [M-l]. MS m/z (ESI): 201.0 [M-l].

¾ NMR (400 MHz, CDC1₃) δ 7.08 (d,lH), 6.67 (d, IH), 4.52 (s, IH), 3.23 (ddd, 2H), 2.97― 2.90 (m, IH), 2.84 (dd, IH), 1.24 (dd,6H), 1.12 - 1.01 (m, IH), 0.60 (t,lH), 0.59 - 0.57 (m, IH), 0.40 - 0.34 (m, IH), 0.28― 0.21 (m, IH). 实施例 17 3⁄4 NMR (400 MHz, CDC1 ₃ ) δ 7.08 (d,lH), 6.67 (d, IH), 4.52 (s, IH), 3.23 (ddd, 2H), 2.97- 2.90 (m, IH), 2.84 (dd , IH), 1.24 (dd,6H), 1.12 - 1.01 (m, IH), 0.60 (t,lH), 0.59 - 0.57 (m, IH), 0.40 - 0.34 (m, IH), 0.28 - 0.21 (m , IH). Example 17

5-溴 -3-异丙基 -8-甲氧基 -8-甲基并环【4.2.01辛烷 -1,3,5-三烯 -2-醇（化合物 17) 5-bromo-3-isopropyl-8-methoxy-8-methyl-cyclo[4.2.01 octane-1,3,5-trien-2-ol (compound 17)

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

第一步： 5- (苄氧基) -2-溴 -4-异丙基并环 [4.2.0】辛垸 -1,3,5-三烯 -7-酮 (17B) First step: 5-(Benzyloxy)-2-bromo-4-isopropylcyclo[4.2.0]octane-1,3,5-triene-7-one (17B)

5-(benzyloxy)-2-bromo-4-isopropylbicyclo[ ,5-trien-7-one 5-(benzyloxy)-2-bromo-4-isopropylbicyclo[ ,5-trien-7-one

向反应瓶中加入 5-苄氧基 -4-异丙基 -并环 [4,2,0]辛垸 -1,3,5-三烯 -7-酮 If (1.00 g, 3.8 mmol, 中间体 1)和冰醋酸 (50 mL)，加入苄基三甲基三溴化铵 (6.59 g, 16.9 mmol)、氯化锌 (1.28 g, 9.4 mmol), 室温下搅拌 5小时。反应结束后加入水（40 mL)，硫代硫酸钠（2.5g， 10 mmol), 用二氯甲垸萃取（40 mL x 3 ) ，合并有机相，无水硫酸钠干燥，过滤，将滤液减压浓缩，残留物用硅胶柱层析分离提纯（石油醚:乙酸乙酯（v/v) =10: 1)得到淡黄色固体状的 5- ( 氧基) -2- 溴 -4-异丙基并环 [4.2.0]辛垸 -1,3,5-三烯 -7-酮 17B (1.02 g, 产率 78%)。 To the reaction flask was added 5-benzyloxy-4-isopropyl-cyclo[4,2,0]octyl-1,3,5-trien-7-one If (1.00 g, 3.8 mmol, middle 1) and glacial acetic acid (50 mL), benzyltrimethylammonium tribromide (6.59 g, 16.9 mmol), zinc chloride (1.28 g, 9.4 mmol) were added and stirred at room temperature for 5 hours. After the end of the reaction, water (40 mL), sodium thiosulfate (2.5 g, 10 mmol), and extracted with dichloromethane (40 mL x 3), combined organics, dried over anhydrous sodium sulfate, filtered The mixture was concentrated with EtOAc (EtOAc) (EtOAc (EtOAc) Benzocyclo[4.2.0]octane-1,3,5-trien-7-one 17B (1.02 g, yield 78%).

¾ NMR (400 MHz, DMSO) δ 7.57 (s, IH), 7.41 (m, 5H), 5.44 (s, 2H), 3.93 (s, 2H), 3.22 (dt, IH), 1.15 (d, 6H). 3⁄4 NMR (400 MHz, DMSO) δ 7.57 (s, IH), 7.41 (m, 5H), 5.44 (s, 2H), 3.93 (s, 2H), 3.22 (dt, IH), 1.15 (d, 6H) .

第二步： 5- (节氧基) -2-溴 -4-异丙基 -7-甲基并环 [4.2.0】辛院 -1,3,5 -三烯 -7-醇（17C) Step 2: 5-(Hydroxy)-2-bromo-4-isopropyl-7-methyl-cyclo[4.2.0] Xinyuan-1,3,5-triene-7-ol (17C )

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

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

氮气氛围下，向反应瓶中加入 5- (苄氧基) -2-溴 -4-异丙基并环 [4.2.0]辛垸 -1,3,5-三烯 -7-酮 17B (1.01 g, 2,9 mmol)和甲苯 (15 mL)，-78。C下缓慢滴加 3M甲基溴化镁 (1.46 ml, 4.4 mmol), 加完后缓慢升温至室温反应 3小时。反应结束后加入饱和氯化铵水溶液（10 mL) 淬灭反应。用二氯甲垸萃取水层（10 mL x 3)，合并有机相，无水硫酸钠干燥，过滤，将滤液减压浓缩，残留物用硅胶柱层析分离提纯（石油醚：二氯甲垸 iy =10: 1)得到淡黄色固体状的 5- (苄氧基) -2-溴 -4-异丙基 -7-甲基并环 [4.2.0]辛垸 -1,3,5 -三烯 -7-醇 17C (0.95 g, 产率 90%)。 To the reaction flask was added 5-(benzyloxy)-2-bromo-4-isopropylcyclo[4.2.0]octyl-1,3,5-trien-7-one 17B under nitrogen atmosphere ( 1.01 g, 2,9 mmol) and toluene (15 mL), -78. 3M methylmagnesium bromide (1.46 ml, 4.4 mmol) was slowly added dropwise under C. After the addition, the mixture was slowly warmed to room temperature for 3 hours. After completion of the reaction, a saturated aqueous ammonium chloride solution (10 mL) was added to quench the reaction. The aqueous layer was extracted with chloroform (10 mL, EtOAc), EtOAc (EtOAc m. Iy = 10: 1) 5-(Benzyloxy)-2-bromo-4-isopropyl-7-methyl-cyclo[4.2.0]octane-1,3,5- Trien-7-ol 17C (0.95 g, yield 90%).

¾ NMR (400 MHz, CDC1₃) δ 7.40 (d, 5H), 7.23 (s, 1H), 5.30 (m, 3H), 3.24 (m, 3H), 1.77 (s, 3H), 1.18 (dd, 6H). 3⁄4 NMR (400 MHz, CDC1 ₃ ) δ 7.40 (d, 5H), 7.23 (s, 1H), 5.30 (m, 3H), 3.24 (m, 3H), 1.77 (s, 3H), 1.18 (dd, 6H) ).

第三步： 2- (苄氧基) -5-溴 -3-异丙基 -8-甲氧基 -8-甲基并环 [4.2.0】辛烷 -1，3，5-三烯（17D) Step 3: 2-(Benzyloxy)-5-bromo-3-isopropyl-8-methoxy-8-methyl-cyclo[4.2.0]octane-1,3,5-triene (17D)

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

将 5- (苄氧基) -2-溴 -4-异丙基 -7-甲基并环 [4.2.0]辛垸 -1,3,5 -三烯 -7-醇 17C (0.94 g, 2.6 mmo) 加入到反应瓶中，依次加入对甲基苯磺酸（0.69 g， 3.9 mmol)和甲醇（30 ml)，升温至回流反应 48小时。反应结束，冷却至室温，加入饱和碳酸氢钠水溶液（10 mL)，加入水 10 (mL)，用二氯甲垸萃取水层（20 mLx 3)，合并有机相，无水硫酸钠干燥，过滤，将滤液减压浓缩，残留物用硅胶柱层析分离提纯（石油醚:乙酸乙酯（v/v) =5: 1) 得到无色透明油状液体状的 2- (苄氧基) -5-溴 -3-异丙基 -8-甲氧基 -8-甲基并环 [4.2.0]辛垸 -1,3,5-三烯 17D (0.85 g, 产率 87%) 。 5-(Benzyloxy)-2-bromo-4-isopropyl-7-methylcyclo[4.2.0]octyl-1,3,5-trien-7-ol 17C (0.94 g, 2.6 mmo) was added to the reaction flask, p-toluenesulfonic acid (0.69 g, 3.9 mmol) and methanol (30 ml) were sequentially added, and the mixture was warmed to reflux for 48 hours. After the reaction was completed, the mixture was cooled to room temperature. EtOAc EtOAc (EtOAc m. The filtrate was concentrated under reduced pressure, and the residue was purified (jjjjjjjjj -Bromo-3-isopropyl-8-methoxy-8-methylcyclo[4.2.0]octyl-1,3,5-triene 17D (0.85 g, yield 87%).

¾ NMR (400 MHz, DMSO) δ 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). 3⁄4 NMR (400 MHz, DMSO) δ 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).

第四步： 5-溴 -3-异丙基 -8-甲氧基 -8-甲基并环 [4.2.0】辛浣 -1,3,5-三烯 -2-醇（化合物 17) Fourth step: 5-bromo-3-isopropyl-8-methoxy-8-methyl-cyclo[4.2.0]octane-1,3,5-trien-2-ol (compound 17)

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

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

氮气氛围保护，将 2- ( 氧基) -5-溴 -3-异丙基 -8-甲氧基 -8-甲基并环 [4.2.0]辛垸 -1,3,5-三烯 17D (0.55 g, 1.4 mmol)和二氯甲垸（15mL)加入到反应瓶中， -15。C下将三溴化硼（0.3 ml, 2.9 mmol) 的二氯甲垸（5mL)溶液滴加到反应体系中，滴加完后升温至 0°C反应 0.5小时。反应结束后加入甲醇（3 mL) 淬灭反应，加入水（15 mL)，用二氯甲垸萃取（15 mL x 3)，合并有机相，无水硫酸钠干燥，过滤，将滤液减压浓缩，残留物用硅胶柱层析分离提纯（石油醚:乙酸乙酯（v/v) =20: 1)得到淡黄色固体 5-溴 -3-异丙基 -8-甲氧基 -8-甲基并环 [4.2.0]辛垸 -1,3,5-三烯 -2- 醇化合物 17 (0.22 g，产率 53.6%， HPLC: 96.38%)。 Protected by nitrogen atmosphere, 2-(oxy)-5-bromo-3-isopropyl-8-methoxy-8-methyl-cyclo[4.2.0]octane-1,3,5-triene 17D (0.55 g, 1.4 mmol) and dichloromethane (15 mL) were added to the reaction flask, -15. Boron tribromide (0.3 ml, 2.9) A solution of mmol of dichloromethane (5 mL) was added dropwise to the reaction system, and after the completion of the dropwise addition, the mixture was heated to 0 ° C for 0.5 hour. After the reaction was completed, methanol (3 mL) was added and the mixture was evaporated, evaporated, evaporated, evaporated, evaporated, evaporated The residue was purified by silica gel column chromatography (ethyl ether (ethyl acetate (v/v) = 20:1) to give pale yellow solid 5-bromo-3-isopropyl-8-methoxy-8- Benzocyclo[4.2.0]octane-1,3,5-trien-2-ol compound 17 (0.22 g, yield 53.6%, HPLC: 96.38%).

MS m/z (ESI): 283.9, 284.8 [M-l]. MS m/z (ESI): 283.9, 284.8 [M-l].

¾ NMR (400 MHz, DMSO) δ 9.47 (s, 1H), 7.11 (s, 1H), 3.17 (m, 5H), 2.78 (d, 1H), 1.61 (s, 3H), 1.13 (d, 6H). 生物测试例 3⁄4 NMR (400 MHz, DMSO) δ 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 case

小鼠翻正反射实验 Mouse righting reflex experiment

实验目的：利用成熟的小鼠麻醉模型研究受试化合物的麻醉效果 (Ratnakumari Lingamaneni 等（2001). Anesthesiology, 94, 1050-7 )。 ED₅₍₎ (半数有效量)、 LD₅₍₎(半数致死量)、 TI (治疗指数， ΤΙ = LDso/EDso), SI (安全指数， SI = LD₅/ED₉₅)、麻醉诱导时间，麻醉维持时间， MTD (最大耐受剂量）等指标评价麻醉效果和安全性。 Experimental purposes: The anesthetic effect of test compounds was studied using a mature mouse anesthesia model (Ratnakumari Lingamaneni et al. (2001). Anesthesiology, 94, 1050-7). ED ₅₍₎ (half effective amount), LD ₅₍₎ (half lethal dose), TI (therapeutic index, ΤΙ = LDso/EDso), SI (safety index, SI = LD ₅ /ED ₉₅ ), anesthesia induction time, Anesthesia maintenance time, MTD (maximum tolerated dose) and other indicators to evaluate the anesthetic effect and safety.

仪器设备：电子天平（sartorius, BSA224 S-Cw), 涡旋振荡器（其林贝尔, Vortex-5)等。实验动物： SPF级 ICR小鼠（ SCXY (川） -2008-24-成都达硕生物科技有限公司）， 18-22 g, 雌雄各半。 Equipment: Electronic balance (sartorius, BSA224 S-Cw), vortex oscillator (Limbel, Vortex-5), etc. Experimental animals: SPF grade ICR mice (SCXY (chuan) -2008-24-Chengdu Dashuo Biotechnology Co., Ltd.), 18-22 g, male and female.

实验方法：用 10% DMSO、 15% solutol HS15、 75% saline的溶剂将待测化合物配制为所需浓度备用。将实验动物在实验室环境中适应后禁食 12小时。次日以 10 ml/kg体积给药，静脉注射后，记录翻正反射消失时间和恢复时间。给药后到翻正反射消失的时间为麻醉诱导时间，翻正反射消失到翻正反射恢复的时间为麻醉持续时间，以麻醉诱导时间和麻醉持续时间表示麻醉作用的强弱。 Experimental method: The test compound was formulated to the desired concentration for use in a solvent of 10% DMSO, 15% solutol HS15, 75% saline. The experimental animals were fasted for 12 hours after acclimation in a laboratory environment. The next day, the drug was administered in a volume of 10 ml/kg, and after the intravenous injection, the disappearance time and recovery time of the righting reflex were recorded. The time from the administration to the disappearance of the righting reflex is the induction time of anesthesia, the time when the righting reflex disappears until the recovery of the righting reflex is the duration of the anesthesia, and the anesthesia induction time and the duration of the anesthesia indicate the strength of the anesthesia.

实验结果：见表 1和表 2。 Experimental results: See Table 1 and Table 2.

表 1 小鼠药效活性评价 Table 1 Evaluation of pharmacodynamic activity of mice

化合物 6 5.8 <15.0 324.8 10.0 化合物 6-1 5.6 <15.0 1 161.8 30.0 化合物 6-2 5.6 <15.0 385.2 5.0 化合物 7 24.5 <15.0 417.0 50.0 化合物 8 5.0 <15.0 1579.2 40.0 化合物 9 4.9 < 15.0 1 108.1 50.0 化合物 9-1 17.8 < 15.0 707.1 40.0 化合物 9-2 7.7 < 15.0 1290.7 80.0 化合物 13 9.4 <15.0 720.0 40.0 化合物 15 10.0 <15.0 874.8 40.0 化合物 16 18.5 19.5 364.4 60.0 表 2 安全剂量评价

Compound 6 5.8 <15.0 324.8 10.0 Compound 6-1 5.6 <15.0 1 161.8 30.0 Compound 6-2 5.6 <15.0 385.2 5.0 Compound 7 24.5 <15.0 417.0 50.0 Compound 8 5.0 <15.0 1579.2 40.0 Compound 9 4.9 < 15.0 1 108.1 50.0 Compound 9 -1 17.8 < 15.0 707.1 40.0 Compound 9-2 7.7 < 15.0 1290.7 80.0 Compound 13 9.4 <15.0 720.0 40.0 Compound 15 10.0 <15.0 874.8 40.0 Compound 16 18.5 19.5 364.4 60.0 Table 2 Safety dose evaluation

结论：本发明化合物具有良好的活性，起效快，治疗指数和安全指数高。 Conclusion: The compound of the present invention has good activity, fast onset, high therapeutic index and high safety index.

Claims

权利要求书 Claim

1.一种通式（I)所示的化合物或者其立体异构体、溶剂化物、代谢产物、药学上可接受的盐、共晶或前药： A compound represented by the formula (I) or a stereoisomer, solvate, metabolite, pharmaceutically acceptable salt, eutectic or prodrug thereof:

:

Κλ R²和 R³各自独立选自 H、 F、 Cl、 Br、 I、羟基、 C_1-6烷基、 C_2-6烯基、 C_2-6炔基、氰基、 d_₆烷氧基、 3至 8元碳环基、 3至 8元杂环基、 3至 8元碳环基氧基或者 3至 8元杂环基氧基，所述的烷基、烯基、炔基、烷氧基、碳环基、杂环基、碳环基氧基或者杂环基氧基任选进一步被 0至 5个选自 F、 Cl、 Br、 I、羟基、氨基、氰基、巯基、 d_₆烷基、 C^烷氧基、 3至 8元碳环基或者 3至 8元杂环基的取代基所取代，且所述的杂环基含有 1 至 2个选自 N、 0或者 S的杂原子； Κλ R ² and R ³ are each independently selected from the group consisting of H, F, Cl, Br, I, hydroxy, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, cyano, d- ₆ alkoxy a 3-, 8-membered carbocyclic group, a 3- to 8-membered heterocyclic group, a 3- to 8-membered carbocyclic oxy group or a 3- to 8-membered heterocyclic oxy group, said alkyl, alkenyl, alkynyl, Alkoxy, carbocyclyl, heterocyclyl, carbocyclyloxy or heterocyclyloxy optionally further from 0 to 5 selected from the group consisting of F, Cl, Br, I, hydroxy, amino, cyano, fluorenyl, Substituted with a d ₆ alkyl group, a C alkoxy group, a 3 to 8 membered carbocyclic group or a 3 to 8 membered heterocyclic group, and the heterocyclic group contains 1 to 2 selected from N, 0 or a hetero atom of S;

作为选择， R¹与 R²、 R²与 R³或者 R¹与 R³任意一组可以与其相连接的碳原子形成一个 3至 8元环，所述 3至 8元环可以含有 0至 2个选自 N、 0或者 S的杂原子，且形成的 3至 8元环可以任选进一步被 0至 4个 R⁸取代； Alternatively, R ¹ and R ² , R ² and R ³ or any group of R ¹ and R ³ may form a 3 to 8 membered ring with a carbon atom to which they are attached, and the 3 to 8 membered ring may contain 0 to 2 a hetero atom selected from N, 0 or S, and the formed 3 to 8 membered ring may be optionally further substituted with 0 to 4 R ⁸ ;

R'和 R"各自独立选自 H、 F、 Cl、 Br、 I、羟基、 C_2-6烯基、 C_2-6炔基、 C_1-6烷基、 C_1-6 烷氧基、 3至 8元碳环基、 3至 8元杂环基、 3至 8元碳环基氧基或者 3至 8元杂环基氧基，所述的烯基、炔基、烷基、烷氧基、碳环基、杂环基、碳环基氧基或者杂环基氧基任选进一步被 0至 5个选自 F、 Cl、 Br、 I、羟基、氨基、氰基、巯基、 d_₆烷基、 d_₆烷氧基、 3 至 8元碳环基或者 3至 8元杂环基的取代基所取代，且所述的杂环基含有 1至 2个选自 N、 0或者 S的杂原子； R' and R" are each independently selected from the group consisting of H, F, Cl, Br, I, hydroxy, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkyl, C _1-6 alkoxy, a 3- to 8-membered carbocyclic group, a 3- to 8-membered heterocyclic group, a 3- to 8-membered carbocyclic oxy group or a 3- to 8-membered heterocyclic oxy group, said alkenyl group, alkynyl group, alkyl group, alkoxy group Further, the carbocyclic group, the heterocyclic group, the carbocyclic oxy group or the heterocyclic oxy group is further further selected from 0 to 5 selected from the group consisting of F, Cl, Br, I, hydroxy, amino, cyano, decyl, d- ₆ Substituted with an alkyl group, a d- ₆ alkoxy group, a 3- to 8-membered carbocyclic group or a 3- to 8-membered heterocyclic group, and the heterocyclic group contains 1 to 2 selected from N, 0 or S. Hetero atom

R⁴、 R⁵、 R⁶和 R⁷各自独立选自 H、 F、 Cl、 Br、 I、羟基、 C_1-6烷基、 C_2-6烯基、 C_2-6 炔基、氰基、叠氮基、烷氧基、 3至 8元碳环基、 3至 8元杂环基、 3至 8元碳环基氧基或者 3至 8元杂环基氧基，所述的烷基、烯基、炔基、烷氧基、碳环基、杂环基、碳环基氧基或者杂环基氧基任选进一步被 0至 5个选自 F、 Cl、 Br、 I、羟基、氨基、氰基、巯基、烷基、 d_₆烷氧基、 3至 8元碳环基或者 3至 8元杂环基的取代基所取代，且所述的杂环基含有 1至 2个选自 N、 0或者 S的杂原子；作为选择， R⁴与 R⁵、 R⁶与 R⁷任意一组可以与其相连接的碳原子形成一个 3至 8元环，所述 3至 8元环可以含有 0至 2个选自 N、 0或者 S的杂原子，且形成的 3至 8元环可以任选进一步被 0至 4个 R⁸取代； R ⁴ , R ⁵ , R ⁶ and R ⁷ are each independently selected from the group consisting of H, F, Cl, Br, I, hydroxy, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, cyano , azido, alkoxy, 3 to 8 membered carbocyclyl, 3 to 8 membered heterocyclic, 3 to 8 membered carbocyclyloxy or 3 to 8 membered heterocyclyloxy, said alkyl Or alkenyl, alkynyl, alkoxy, carbocyclyl, heterocyclyl, carbocyclyloxy or heterocyclyloxy optionally further selected from 0 to 5 selected from the group consisting of F, Cl, Br, I, hydroxy, Substituted with an amino group, a cyano group, a decyl group, an alkyl group, a d- ₆ alkoxy group, a 3- to 8-membered carbocyclic group or a 3- to 8-membered heterocyclic group, and the heterocyclic group contains 1 to 2 a hetero atom from N, 0 or S; Alternatively, any one of R ⁴ and R ⁵ , R ⁶ and R ⁷ may form a 3 to 8 membered ring with a carbon atom to which it is attached, and the 3 to 8 membered ring may have 0 to 2 selected from N, 0. Or a hetero atom of S, and the formed 3 to 8 membered ring may be optionally further substituted with 0 to 4 R ⁸ ;

R⁸选自 F、 Cl、 Br、 I、羟基、羧基、氨基、羧酸酯、酰胺基、 d_₆烷基、 d_₆烷氧基、 3至 8元碳环基或者 3至 8元杂环基，所述的杂环基含有 1至 2个选自 N、 0或者 S的杂原子。 R ^{8 is} selected from the group consisting of F, Cl, Br, I, hydroxy, carboxy, amino, carboxylic acid ester, amide group, d- ₆ alkyl group, d- ₆ alkoxy group, 3 to 8 membered carbocyclic group or 3 to 8 membered heterocyclic ring The heterocyclic group contains 1 to 2 hetero atoms selected from N, 0 or S.

2.根据权利要求 1所述的化合物或者其立体异构体、溶剂化物、代谢产物、药学上可接受的盐、共晶或前药，其中： 2. A compound according to claim 1 or a stereoisomer, solvate, metabolite, pharmaceutically acceptable salt, eutectic or prodrug thereof, wherein:

R选自

R is selected from

Κλ R²和 R³各自独立选自 Η或者 C^烷基； Κλ R ² and R ³ are each independently selected from hydrazine or C^alkyl;

R'选自 H; R' is selected from H;

R"选自 H、 F、 Cl、 Br或者 I; R" is selected from H, F, Cl, Br or I;

R⁴、 R⁵、 R⁶和 R⁷各自独立选自 H、羟基、 d_₆烷基、氰基、叠氮基、 d_₆烷氧基或者R ⁴ , R ⁵ , R ⁶ and R ⁷ are each independently selected from H, hydroxy, d- ₆ alkyl, cyano, azide, d- ₆ alkoxy or

3至 8元碳环基，所述的烷基、烷氧基或者碳环基可以任选进一步被 0至 3个选自 d_₆烷基或者 d_₆烷氧基的取代基所取代； a 3- to 8-membered carbocyclic group, which may be optionally further substituted with 0 to 3 substituents selected from d- ₆ alkyl or d- ₆ alkoxy;

作为选择， R⁴和 R⁵可以形成（=0)。 Alternatively, R ⁴ and R ⁵ may form (=0).

3.根据权利要求 2所述的化合物或者其立体异构体、溶剂化物、代谢产物、药学上可接受的盐、共晶或前药，其中所述化合物选自通式（Π)所示的化合物：

其中： The compound according to claim 2 or a stereoisomer, solvate, metabolite, pharmaceutically acceptable salt, eutectic or prodrug thereof, wherein the compound is selected from the group consisting of the formula (Π) Compound:

among them:

Κλ R²和 R³各自独立选自 Η或者 d_₄烷基，其中 R²和 R³至少有一个基团为 Η;Κλ R ² and R ³ are each independently selected from fluorene or d ₄ alkyl, wherein at least one of R ² and R ³ is hydrazine;

R⁴和 R⁵各自独立选自 Η、羟基、 d_₄烷基、氰基、叠氮基、 d_₄烷氧基或者 3至 5元碳环基，所述的烷基、烷氧基或者碳环基可以任选进一步被 0至 3个选自 d_₄烷基或者 d_₄ 烷氧基的取代基所取代。 R ⁴ and R ⁵ are each independently selected from the group consisting of hydrazine, hydroxy, d- ₄ alkyl, cyano, azide, d- ₄ alkoxy or a 3 to 5 membered carbocyclic group, said alkyl group, alkoxy group or carbon The cyclic group may be optionally further substituted with 0 to 3 substituents selected from d- ₄ alkyl or d- ₄ alkoxy.

4.根据权利要求 3所述化合物或者其立体异构体、溶剂化物、代谢产物，药学上可接受的盐、共晶或前药，其中： Κλ R²和 R³各自独立选自 H、甲基、乙基、正丙基或者异丙基，其中 R²和 R³ 至少有一个基团为 Η; 4. A compound according to claim 3 or a stereoisomer, solvate, metabolite, pharmaceutically acceptable salt, eutectic or prodrug thereof, wherein: Κλ R ² and R ³ are each independently selected from H, methyl, ethyl, n-propyl or isopropyl, wherein at least one of R ² and R ³ is deuterium;

R⁴和 R⁵各自独立选自 Η、羟基、甲基、乙基、正丙基、异丙基、氰基、叠氮基、甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、 ⁰^^。z、环丙基或者环丁基。 R ⁴ and R ⁵ are each independently selected from the group consisting of hydrazine, hydroxy, methyl, ethyl, n-propyl, isopropyl, cyano, azide, methoxy, ethoxy, n-propoxy, isopropoxy Base, n-butoxy, ⁰ ^^. z, cyclopropyl or cyclobutyl.

5.根据权利要求 4所述化合物或者其立体异构体、溶剂化物、代谢产物，药学上可接受的盐、共晶或前药，其中： 5. A compound according to claim 4 or a stereoisomer, solvate, metabolite thereof, pharmaceutically acceptable salt, eutectic or prodrug thereof, wherein:

Κλ R²和 R³各自独立选自 H、甲基或者乙基，其中 R²和 R³至少有一个基团为 H; R⁴和 R⁵各自独立选自 Η、羟基、甲基、乙基、氰基、叠氮基、甲氧基、乙氧基、异丙氧基、正丁氧基、 '"^"^Q/或者环丙基。 Κλ R ² and R ³ are each independently selected from H, methyl or ethyl, wherein at least one of R ² and R ³ is H; R ⁴ and R ⁵ are each independently selected from the group consisting of hydrazine, hydroxy, methyl, ethyl. , cyano, azido, methoxy, ethoxy, isopropoxy, n-butoxy, '"^"^Q/ or cyclopropyl.

6.根据权利要求 1所述的化合物或者其立体异构体、溶剂化物、代谢产物、药学上可接受的盐、共晶或前药，其中所述的化合物选自： The compound according to claim 1 or a stereoisomer, solvate, metabolite, pharmaceutically acceptable salt, eutectic or prodrug thereof, wherein the compound is selected from the group consisting of:

7.一种制备根据权利要求 1-6中所述通式（I) 所示的化合物的方法，该方法包括:

通式（I-b) 化合物经过格氏反应得到通式（I-c) 7. A process for the preparation of a compound of the formula (I) according to claims 1-6, the process comprising:

通式（I-c) 化合物在还原性条件下脱去羟基得到通式（I-d) 化合物；或者在酸性条件下，通式（I-c)化合物与氰化物、叠氮化物或者醇溶液反应得到通式（I-d) 化合物； The compound of the formula (Ic) is dehydroxylated under reducing conditions to give a compound of the formula (Id); or, under acidic conditions, a compound of the formula (Ic) is reacted with a cyanide, azide or alcohol solution to give a formula (Id) Compound;

通式（I-d) 化合物脱去 R^1Q得到通式（I)化合物，其中， R^1Q选自甲基、甲氧基甲基、乙基、苄基、对甲氧基苄基、三苯甲基、三甲基硅基或者叔丁基二甲基硅基， R、 R'和 R"、 R⁴、 R⁵、 R⁶和 R⁷的定义与通式（I) 化合物所述定义一致。 The compound of the formula (Id) is subjected to the removal of R ^{1Q to} give a compound of the formula (I), wherein R ^{1Q is} selected from the group consisting of methyl, methoxymethyl, ethyl, benzyl, p-methoxybenzyl, trityl. , trimethylsilyl or tert-butyldimethylsilyl, the definitions of R, R' and R", R ⁴ , R ⁵ , R ⁶ and R ^{7 are} in accordance with the definitions of the compounds of the formula (I).

8.一种药物组合物，所述药物组合物包含：权利要求 1-6任一项所述的化合物或者其立体异构体、溶剂化物、代谢产物、药学上可接受的盐、共晶或者前药，和一种或者多种药学上可接受的载体和 /或赋形剂。 A pharmaceutical composition comprising: a compound according to any one of claims 1 to 6 or a stereoisomer, solvate, metabolite, pharmaceutically acceptable salt, eutectic or Prodrugs, and one or more pharmaceutically acceptable carriers and/or excipients.

9.一种药物组合物，所述药物组合物包含：权利要求 1-6中任一项所述的化合物，和一种或多种选自阿片类镇痛剂、镇静催眠剂或者心血管药剂的治疗剂。 A pharmaceutical composition comprising: the compound according to any one of claims 1 to 6, and one or more selected from the group consisting of an opioid analgesic, a sedative hypnotic or a cardiovascular agent Therapeutic agent.

10.根据权利要求 8或者 9所述的药物组合物，该药物组合物为药学上可以接受的任一剂型。 The pharmaceutical composition according to claim 8 or 9, which is pharmaceutically acceptable in any dosage form.

11.根据权利要求 10所述的药物组合物，其中所述剂型选自脂质乳剂、注射剂、片剂、气雾剂、粉雾剂、喷雾剂、膜剂、颗粒剂、胶囊剂、软膏剂、栓剂、乳膏剂、植入剂、糖浆剂、口服溶液剂、口服混悬剂、口服乳剂、分散片剂、冻干粉针剂、散剂或者凝胶剂。 The pharmaceutical composition according to claim 10, wherein the dosage form is selected from the group consisting of a lipid emulsion, an injection, a tablet, an aerosol, a powder, a spray, a film, a granule, a capsule, and an ointment. , suppositories, creams, implants, syrups, oral solutions, oral suspensions, oral emulsions, dispersible tablets, lyophilized powders, powders or gels.

12.根据权利要求 11所述的药物组合物，其中所述剂型选自冻干粉针剂、注射剂或者脂质乳剂。 The pharmaceutical composition according to claim 11, wherein the dosage form is selected from the group consisting of a lyophilized powder injection, an injection, or a lipid emulsion.

13.权利要求 1-6中任一项所述的化合物或者其立体异构体、溶剂化物、代谢产物、药学上可接受的盐、共晶或前药，或者权利要求 8-12中任一项所述的药物组合物在制备中枢神经领域的药物中的用途。 The compound according to any one of claims 1 to 6, or a stereoisomer, solvate, metabolite, or drug thereof Use of a pharmaceutically acceptable salt, eutectic or prodrug, or a pharmaceutical composition according to any one of claims 8 to 12 for the preparation of a medicament in the field of central nervous system.

14.根据权利要求 13所述的用途，其中所述中枢神经领域的药物包括：用于诱导和维持动物或者人类的麻醉的药物，促进动物或者人类的镇静催眠的药物，或者治疗和 /或预防焦虑、抑郁、失眠、恶心、呕吐、偏头痛、精神***、惊厥、癫痫的药物。 The use according to claim 13, wherein the drug in the field of the central nervous system comprises: a drug for inducing and maintaining anesthesia of an animal or a human, a drug for promoting sedation and hypnosis of an animal or a human, or a treatment and/or prevention Drugs for anxiety, depression, insomnia, nausea, vomiting, migraine, schizophrenia, convulsions, and epilepsy.

15.根据权利要求 14所述的用途，其中所述中枢神经领域的药物包括用于诱导和维持动物或者人类的麻醉的药物。 The use according to claim 14, wherein the drug in the field of the central nervous system comprises a drug for inducing and maintaining anesthesia of an animal or a human.

16.一种诱导和维持动物或者人类的麻醉的方法，该方法包括给予动物或者人类有效量的权利要求 1-6中任一项所述的化合物或者其立体异构体、溶剂化物、代谢产物、药学上可接受的盐、共晶或前药、或者权利要求 8-12中任一项所述的药物组合物。 16. A method of inducing and maintaining anesthesia in an animal or a human, the method comprising administering to the animal or a human an effective amount of a compound of any one of claims 1 to 6 or a stereoisomer, solvate, metabolite thereof A pharmaceutically acceptable salt, eutectic or prodrug, or a pharmaceutical composition according to any one of claims 8-12.

17.一种促进动物或者人类的镇静催眠的方法，该方法包括给予动物或者人类有效量的权利要求 1-6中任一项所述的化合物或者其立体异构体、溶剂化物、代谢产物、药学上可接受的盐、共晶或前药、或者权利要求 8-12中任一项所述的药物组合物。 17. A method of promoting sedation and hypnosis in an animal or a human, the method comprising administering to an animal or a human, an effective amount of a compound of any one of claims 1 to 6, or a stereoisomer, solvate, metabolite thereof, A pharmaceutically acceptable salt, eutectic or prodrug, or a pharmaceutical composition according to any one of claims 8-12.

18.—种治疗和 /或预防动物或者人类焦虑、抑郁、失眠、恶心、呕吐、偏头痛、精神 ***、惊厥或者癫痫的方法，该方法包括给予动物或者人类有效量的权利要求 1-6中任一项所述的化合物或者其立体异构体、溶剂化物、代谢产物、药学上可接受的盐、共晶或前药、或者权利要求 8-12中任一项所述的药物组合物。 18. A method of treating and/or preventing anxiety or depression, insomnia, nausea, vomiting, migraine, schizophrenia, convulsions, or epilepsy in an animal or human, the method comprising administering to the animal or human an effective amount of claims 1-6 A compound according to any one of the preceding claims, or a stereoisomer, solvate, metabolite, pharmaceutically acceptable salt, eutectic or prodrug thereof, or a pharmaceutical composition according to any one of claims 8-12.