WO2016082792A1

WO2016082792A1 - Abiraterone derivative, and preparation method therefor and medical applications thereof

Info

Publication number: WO2016082792A1
Application number: PCT/CN2015/095776
Authority: WO
Inventors: 张晨; 魏用刚; 黄安邦; 黄龙彬; 何平; 雷鸣; 徐立宁; 宫爱申; 刘建余
Original assignee: 四川海思科制药有限公司
Priority date: 2014-11-28
Filing date: 2015-11-27
Publication date: 2016-06-02
Also published as: CN106061990A; CN105646637B; TW201629083A; CN105646637A; CN106061990B; TWI641616B

Abstract

The present invention relates to a compound represented by general formula (I) and a stereoisomer or a pharmaceutically acceptable salt, and applications in the preparation of drugs used to prevent and treat cancers. The structure of the compound represented by general formula (I) is shown below, and the definition of A is consistent with that in a specification.

Description

一种阿比特龙衍生物及其制备方法和医药用途Abitra derivative, preparation method thereof and medical use thereof

技术领域Technical field

本发明涉及一种阿比特龙衍生物及其立体异构体或药学上可接受的盐，以及在制备用于预防和治疗癌症相关药物中的用途。The present invention relates to an abiraterone derivative and a stereoisomer or pharmaceutically acceptable salt thereof, and to the use in the preparation of a medicament for the prevention and treatment of cancer.

背景技术Background technique

***癌是常见的恶性致死性癌症，近年我国的该病的发病率呈上升趋势，其市场需求将持续快速增长。Prostate cancer is a common malignant lethal cancer. In recent years, the incidence of this disease in China is on the rise, and its market demand will continue to grow rapidly.

雄激素是***癌发生的关键因素。雄激素生物合成首先通过17α-羟化酶活化将孕烯醇酮和孕酮转化为17α-羟基衍生物，再通过C17，20-裂解酶活形成脱氢表雄酮和雄烯二酮，两者均为睾酮的前体。在这个过程中，细胞色素P450是物合成途径中的关键酶。CYP17是一种细胞色素P450酶，它能催化两种独立调节类固醇17α-羟化酶和C17，20-裂解酶的酶活性，从而调节睾丸和身体其他部位的性类固醇前体的体内合成。Androgen is a key factor in the development of prostate cancer. Androgen biosynthesis first converts pregnenolone and progesterone to 17α-hydroxy derivatives by 17α-hydroxylase activation, and then dehydroepiandrosterone and androstenedione by C17,20-lyase Both are precursors of testosterone. In this process, cytochrome P450 is a key enzyme in the pathway of protein synthesis. CYP17 is a cytochrome P450 enzyme that catalyzes the in vivo synthesis of two independent steroid precursors in the testis and other parts of the body, catalyzing the two enzyme activities that independently regulate steroid 17α-hydroxylase and C17,20-lyase.

醋酸阿比特龙为阿比特龙前体药物，是一种CYP17酶抑制剂，于2011年在美国批准上市，适用于***癌(CRPC)患者的治疗，推荐剂量为口服给予1000mg每天1次与***5mg口服给药每天2次联用。Abiraterone acetate is an abiraterone prodrug, a CYP17 enzyme inhibitor approved for marketing in the United States in 2011. It is recommended for the treatment of patients with prostate cancer (CRPC). The recommended dose is 1000 mg once daily. Nisson 5mg was administered orally twice a day.

目前有文献报道了阿比特龙的前体药物。There are reports in the literature on the prodrugs of abiraterone.

CN102477061公开了吡啶雄甾衍生物及其在制备预防和/或治疗***癌药物中的用途，其中Rx选自多种酯类、碳酸酯类或胺类等前体药物基团，该文献涉及的通式结构如下：CN102477061 discloses pyridine andrazine derivatives and their use in the preparation of a medicament for preventing and/or treating prostate cancer, wherein Rx is selected from a plurality of prodrug groups such as esters, carbonates or amines, the literature The general structure is as follows:

CN102686600公开了甾体CYP17抑制剂/抗雄激素物质的新型药物前体，其中Y选自Z-L-C(＝O)O-，Z是在正常生理条件下带有电荷的带电基团，其中带电基团是具有化学式(R₃N⁺)^-的季铵基团，该文献涉及的通式结构如下： CN102686600 discloses novel prodrugs of steroidal CYP17 inhibitor/antiandrogen, wherein Y is selected from ZLC(=O)O-, Z is a charged group charged under normal physiological conditions, wherein a charged group It is a quaternary ammonium group having the formula (R ₃ N ⁺ ) ^- and the general structure involved in this document is as follows:

CN104017045公开了甾体CYP17抑制剂的新型药物前体，所述的前体药物可用于治疗泌尿生殖***、雄激素相关的癌症，该文献涉及的结构如下：CN104017045 discloses novel prodrugs of steroidal CYP17 inhibitors which are useful in the treatment of genitourinary systems, androgen-related cancers, the structure of which is as follows:

WO2014111815公开了阿比特龙类似物及其在预防和/或治疗***癌药物中的用途，其中R选自低链烷基、环烷基、胺基等，该文献涉及的结构如下：WO2014111815 discloses abiraterone analogs and their use in the prevention and/or treatment of prostate cancer drugs, wherein R is selected from the group consisting of low chain alkyl groups, cycloalkyl groups, amine groups and the like, and the structure involved in this document is as follows:

本发明的目的在于提供一种新颖的具有高稳定性、良好溶解度、高生物利用度、低剂量、低毒副作用或具备长效潜力的阿比特龙前体药物，为癌症患者提供新的选择，所述癌症可选自泌尿生殖***、雄激素相关的疾病，如***癌。It is an object of the present invention to provide a novel abiraterone prodrug with high stability, good solubility, high bioavailability, low dose, low toxic side effects or long-term potential, providing a new choice for cancer patients, The cancer may be selected from the group consisting of the genitourinary system, androgen-related diseases such as prostate cancer.

发明内容Summary of the invention

本发明涉及一种通式(I)所示化合物及其立体异构体或药学上可接受的盐，The present invention relates to a compound of the formula (I), and a stereoisomer or pharmaceutically acceptable salt thereof,

其中：A选自-R^A-R¹；R^A为C(＝O)；Wherein: A is selected from -R ^A -R ¹ ; R ^A is C(=O);

R¹选自3元杂环、4元杂环、5元杂环、6元杂环、7元杂环、8元杂环、9元杂环或10元杂环，优选5元杂环、6元杂环、7元杂环或8元杂环，进一步优选5元杂环或 6元杂环，更优选

且当杂环为饱和环时，与R^A相连接的原子为杂环上的碳原子；所述的杂环、

任选进一步被0至4个选自F、Cl、Br、I、OH、NH₂、-NHC(＝O)C_1-4烷氧基、C(＝O)C_1-4烷氧基、C(＝O)R^1h、S(＝O)₂R^1h、R^1h或4至6元杂环的取代基所取代，优选杂环任选进一步被0至4个选自H、NH₂、-(CH₂)₂N(C_1-4烷基)₂、-NHC(＝O)OC(CH₃)₃、-C(＝O)OC(CH₃)₃、C(＝O)R^1h、S(＝O)₂R^1h、R^1h、吡啶或氮杂五元环的取代基所取代，所述的杂环含有1至4个选自N、O或S的杂原子；R ^{1 is} selected from a 3-membered heterocyclic ring, a 4-membered heterocyclic ring, a 5-membered heterocyclic ring, a 6-membered heterocyclic ring, a 7-membered heterocyclic ring, an 8-membered heterocyclic ring, a 9-membered heterocyclic ring or a 10-membered heterocyclic ring, preferably a 5-membered heterocyclic ring a 6-membered heterocyclic ring, a 7-membered heterocyclic ring or an 8-membered heterocyclic ring, further preferably a 5-membered heterocyclic ring or a 6-membered heterocyclic ring, more preferably

And when the heterocyclic ring is a saturated ring, the atom bonded to R ^A is a carbon atom on the hetero ring; the heterocyclic ring,

Optionally further from 0 to 4 selected from the group consisting of F, Cl, Br, I, OH, NH ₂ , -NHC(=O)C _1-4 alkoxy, C(=O)C _1-4 alkoxy, Substituting for a substituent of a C(=O)R ^1h , S(=O) ₂ R ^1h , R ^1h or 4 to 6-membered heterocyclic ring, preferably the heterocyclic ring is optionally further further selected from 0 to 4 selected from H, NH ₂ , -(CH ₂ ) ₂ N(C _1-4 alkyl) ₂ , -NHC(=O)OC(CH ₃ ) ₃ , -C(=O)OC(CH ₃ ) ₃ , C(=O)R ^1h Substituting a substituent of S(=O) ₂ R ^1h , R ^1h , pyridine or aza five-membered ring containing from 1 to 4 heteroatoms selected from N, O or S;

R^1h各自独立的选自C_1-4烷基、C_1-4烷基-NH₂、C_1-4烷氧基或C_3-6碳环，所述的NH₂、烷基、烷氧基和碳环任选进一步被0至4个选自F、Cl、Br、I、OH、C_1-4烷基、C_1-4烷氧基或C_3-6碳环的取代基所取代，优选进一步被0至4个选自F、Cl、Br、OH、甲基、乙基、异丙基、甲氧基、乙氧基、异丙氧基、环丙基、环丁基或环戊基的取代基所取代；R ^{1h is} independently selected from C _1-4 alkyl, C _1-4 alkyl-NH ₂ , C _1-4 alkoxy or C _3-6 carbocyclic ring, said NH ₂ , alkyl, alkoxy The base and carbocyclic ring are optionally further substituted with from 0 to 4 substituents selected from the group consisting of F, Cl, Br, I, OH, C _1-4 alkyl, C _1-4 alkoxy or C _3-6 carbocyclic , preferably further from 0 to 4 selected from the group consisting of F, Cl, Br, OH, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl or cyclic Substituted by a substituent of a pentyl group;

R^1h各自独立的优选取代或未取代的甲基、乙基、2-氨基乙基、丙基、异丙基、甲氧基、乙氧基、异丙氧基或环丙基，当被取代时，任选进一步被1至4个选自F、Cl、Br、OH、甲基、乙基、异丙基、甲氧基、乙氧基、异丙氧基或环丙基的取代基所取代。R ^1h each independently substituted or unsubstituted methyl, ethyl, 2-aminoethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy or cyclopropyl, when substituted When optionally further substituted with from 1 to 4 substituents selected from the group consisting of F, Cl, Br, OH, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy or cyclopropyl Replace.

本发明优选方案，一种通式(I)所示化合物及其立体异构体或药学上可接受的盐，A preferred embodiment of the invention, a compound of the formula (I), and a stereoisomer or pharmaceutically acceptable salt thereof,

A选自C(＝O)R¹；A is selected from C(=O)R ¹ ;

R¹选自取代或为取代的如下结构之一：R ^{1 is} selected from one of the following structures substituted or substituted:

当被取代时，任选进一步被1至4个选自NH₂、-(CH₂)₂N(CH₃)₂、-NHC(＝O)OC(CH₃)₃、-C(＝O)OC(CH₃)₃、C(＝O)R^1h、S(＝O)₂R^1h、R^1h或吡啶的取代基所取代；

When substituted, optionally further 1 to 4 are selected from the group consisting of NH ₂ , -(CH ₂ ) ₂ N(CH ₃ ) ₂ , -NHC(=O)OC(CH ₃ ) ₃ , -C(=O) Substituting OC(CH ₃ ) ₃ , C(=O)R ^1h , S(=O) ₂ R ^1h , R ^1h or a substituent of pyridine;

R^1h各自独立的选自取代或未取代的甲基、乙基、2-氨基乙基、丙基、异丙基、甲氧基、乙氧基、异丙氧基或环丙基，当被取代时，任选进一步被1至4个选自F、Cl、Br、OH、甲基、乙基或环丙基的取代基所取代。R ^{1h is} independently selected from substituted or unsubstituted methyl, ethyl, 2-aminoethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy or cyclopropyl, when When substituted, it is optionally further substituted with from 1 to 4 substituents selected from the group consisting of F, Cl, Br, OH, methyl, ethyl or cyclopropyl.

本发明优选方案，一种通式(I)所示化合物及其立体异构体或药学上可接受的盐，其中该化合物选自如下结构之一： A preferred embodiment of the invention, a compound of the formula (I), and a stereoisomer or pharmaceutically acceptable salt thereof, wherein the compound is selected from one of the following structures:

本发明还提供一种药物组合物，所述药物组合物含有治疗有效剂量的本发明化合物及其立体异构体或药学上可接受的盐，以及药学上可接受的载体和赋形剂。The invention also provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of the invention, and a stereoisomer or pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier and excipient.

进一步，本发明还提供本发明所述的化合物及其立体异构体或药学上可接受的盐，以及本发明化合物的组合物在制备治疗与癌症相关疾病药物中的用途。Further, the present invention provides the use of the compound of the present invention and a stereoisomer or pharmaceutically acceptable salt thereof, and a composition of the compound of the present invention for the preparation of a medicament for treating a disease associated with cancer.

本发明优选方案，其中所述的癌症为***癌。A preferred embodiment of the invention wherein the cancer is prostate cancer.

本发明还提供一种治疗与癌症相关疾病的方法，所述方法包括给药本发明所述的化合物或其立体异构体或药学上可接受的盐，或本发明所述的组合物。 The invention also provides a method of treating a cancer-related disease, the method comprising administering a compound of the invention, or a stereoisomer or pharmaceutically acceptable salt thereof, or a composition according to the invention.

根据本发明所述的方法，其中所述的癌症为***癌。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。The method according to the invention, wherein the cancer is prostate cancer. 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，及本发明所述基团和化合物中所涉及的碳、氢、氧、硫、氮或卤素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，又称为重氢)、氚(T，又称为超重氢)，氧的同位素包括¹⁶O、¹⁷O和¹⁸O，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¹⁹F，氯的同位素包括³⁵Cl和³⁷Cl，溴的同位素包括⁷⁹Br和⁸¹Br。The carbon, hydrogen, oxygen, sulfur, nitrogen or halogen involved in the groups and compounds of the present invention include their isotopes, and the carbon, hydrogen, oxygen, sulfur, and the groups and compounds involved in the present invention. The nitrogen or halogen 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), oxygen isotopes include ¹⁶ O, ¹⁷ O and ¹⁸ O, sulfur isotopes include ³² S, ³³ S, ³⁴ S and ³⁶ S, nitrogen isotopes including ¹⁴ N and ¹⁵ N, the fluorine isotope ¹⁹ F, the chlorine isotope includes ³⁵ Cl and ³⁷ Cl, and the bromine isotopes include ⁷⁹ Br and ⁸¹ Br.

“烷基”是指直链和支链的饱和脂肪族烃基团，主链包括1至20个碳原子，优选为1至12个碳原子，进一步优选为1至8个碳原子，更优选为1至6个碳原子，再进一步优选1至4个碳原子的直链与支链基团，最优选1至2个碳原子；烷基的实例包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、2-戊基、3-戊基、2-甲基-2-丁基、3-甲基-2-丁基、3-甲基-1-丁基、2-甲基-1-丁基、正己基、2-己基、3-己基、2-甲基-2-戊基、3-甲基-2-戊基、4-甲基-2-戊基、3-甲基-3-戊基、2-甲基-3-戊基、2,3-二甲基-2-丁基、3,3-二甲基-2-丁基、正庚基、2-甲基己基、3-甲基己基、4-甲基己基、5-甲基己基、2,2-二甲基戊基、2,3-二甲基戊基、2,4-二甲基戊基、3,3-二甲基戊基、2-乙基戊基、3-乙基戊基、正辛基、2,2-二甲基己基、2,3-二甲基己基、2,4-二甲基己基、2,5-二甲基己基、3,3-二甲基己基、4,4-二甲基己基、2-乙基己基、3-乙基己基、4-乙基己基、2-甲基-2-乙基戊基、2-甲基-3-乙基戊基、正壬基、2-甲基-2-乙基己基和正癸基；烷基可以是取代的或未取代的，当被取代时，取代基可以在任何可使用的连接点上被取代，取代基优选为1至5个选自F、Cl、Br、I、烷基、环烷基、烷氧基、卤代烷基、硫醇、羟基、硝基、巯基、氨基、氰基、异氰基、芳基、杂芳基、杂环基、桥环基、螺环基、并环基、羟基烷基＝O、羰基、醛、羧酸、羧酸酯芳基硫基、硫代羰基或硅烷基等。"Alkyl" means a straight-chain or branched saturated aliphatic hydrocarbon group, and the main chain includes 1 to 20 carbon atoms, preferably 1 to 12 carbon atoms, further preferably 1 to 8 carbon atoms, more preferably a linear and branched group of 1 to 6 carbon atoms, still more preferably 1 to 4 carbon atoms, most preferably 1 to 2 carbon atoms; examples of the alkyl group include, but are not limited to, methyl, ethyl, n-propyl Base, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl -2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, n-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl Benzyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, 3,3-Dimethyl-2-butyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,2-dimethylpentyl , 2,3-dimethylpentyl, 2,4-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2 ,2-dimethylhexyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethyl Hexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-decyl, 2-methyl-2-ethylhexyl and n-decyl; alkyl may be substituted or unsubstituted, when substituted, the substituent may be Any substituent which may be used is substituted, and the substituent is preferably from 1 to 5 selected from the group consisting of F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxy, nitro, Mercapto, amino, cyano, isocyano, aryl, heteroaryl, heterocyclyl, bridged, spiro, cyclo, hydroxyalkyl = O, carbonyl, aldehyde, carboxylic acid, carboxylate An arylthio group, a thiocarbonyl group, a silyl group or the like.

“烷氧基”是指-O-烷基，其中烷基如本文上述定义。烷氧基可以是取代的或未取代的，烷氧基实施例包括但不限于甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基、仲丁氧基、正戊氧基和正己氧基；当被取代时，取代基优选为1至5个选自F、Cl、Br、I、烷基、环烷基、烷氧基、卤代烷基、硫醇、羟基、硝基、巯基、氨基、氰基、异氰基、芳基、杂芳基、杂环基、桥环基、螺环基、并环基、羟基烷基、＝O、羰基、醛、羧酸、羧酸酯芳基硫基、硫代羰基或硅烷基等。"Alkoxy" means an -O-alkyl group wherein alkyl is as defined above. Alkoxy groups may be substituted or unsubstituted, and alkoxy embodiments include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, untertiary Butoxy, sec-butoxy, n-pentyloxy and n-hexyloxy; when substituted, the substituent is preferably from 1 to 5 selected from the group consisting of F, Cl, Br, I, alkyl, cycloalkyl, alkoxy , haloalkyl, thiol, hydroxy, nitro, decyl, amino, cyano, isocyano, aryl, heteroaryl, heterocyclyl, bridged, spiro, cyclo, hydroxyalkyl , =0, a carbonyl group, an aldehyde, a carboxylic acid, a carboxylate arylthio group, a thiocarbonyl group or a silyl group.

“氨基”是指-NH₂，可以是取代的或未取代的，当被取代时，取代基优选为1至3个以下基团，独立地选自烷基、环烷基、卤代烷基、硫醇、羟基、巯基、氨基、氰基、异氰基、芳基、杂芳基、杂环基、桥环基、螺环基、并环基、羟基烷基、＝O、羰基、醛、羧酸、羧酸酯芳基硫基、硫代羰基或硅烷基等。"Amino" means -NH ₂ and may be substituted or unsubstituted, and when substituted, the substituent is preferably 1 to 3 or less, independently selected from alkyl, cycloalkyl, haloalkyl, sulphur Alcohol, hydroxy, decyl, amino, cyano, isocyano, aryl, heteroaryl, heterocyclyl, bridged, spiro, cyclo, hydroxyalkyl, =0, carbonyl, aldehyde, carboxy An acid, a carboxylic acid arylthio group, a thiocarbonyl group or a silyl group.

“杂环”或“杂环基”是指取代的或未取代的饱和或不饱和的至少含有1至5个选自N、O、S、S(＝O)或S(＝O)₂原子或基团的非芳香环***，非芳香环***包含3至20个环原子，优选3至10个环原子，更优选3至8个环原子；杂环基环中选择性取代的N、S可被氧化成各种氧化态；非限制性实施例包括氧杂环丙烷基、氧杂环丁基、氧杂环戊基、氧杂环己基、氧杂环己基、氧杂环辛基、氮杂环丙烷基、氮杂环丁基、氮杂环戊基、氮杂环己基、氮杂环丙烯基、1,3二氧环戊基、1,4-二氧环戊基、1,3-二氧环戊基、1,3-二氧环己基、1,3-二硫环己基、氮杂环庚烯基、吗啉基、哌嗪基、吡啶基、呋喃基、噻吩基、吡咯基、吡喃基、N-烷基吡咯基、嘧啶基、吡嗪基、哒嗪基、咪唑基、哌啶基、硫代吗啉基、二氢吡喃、噻二唑基、噁唑基、噁二唑基、吡唑基、1,4-二氧杂环己二烯基、2H-1,2-噁嗪基或2,5-二氢噻吩基等；当被取代时，取代基为1至5个选自F、Cl、Br、I、烷基、环烷基、烷氧基、卤代烷基、硫醇、羟基、硝基、巯基、氨基、氰基、异氰基、芳基、杂芳基、杂环基、桥环基、螺环基、并环基、羟基烷基、＝O、羰基、醛、羧酸、羧酸酯芳基硫基、硫代羰基或硅烷基等。"Heterocycle" or "heterocyclyl" means substituted or unsubstituted, saturated or unsaturated, having at least 1 to 5 atoms selected from N, O, S, S(=O) or S(=O) ₂ atoms Or a non-aromatic ring system of a group, the non-aromatic ring system comprising 3 to 20 ring atoms, preferably 3 to 10 ring atoms, more preferably 3 to 8 ring atoms; optionally substituted N, S in the heterocyclic ring It can be oxidized to various oxidation states; non-limiting examples include oxiranyl, oxetanyl, oxetanyl, oxetanyl, oxetanyl, oxetanyl, nitrogen Heterocyclopropane, azetidinyl, azacyclopentyl, azacyclohexyl, azacyclopropenyl, 1,3 dioxocyclopentyl, 1,4-dioxocyclopentyl, 1,3 - Dioxocyclopentyl, 1,3-dioxocyclohexyl, 1,3-dithiocyclohexyl, azepanyl, morpholinyl, piperazinyl, pyridyl, furyl, thienyl, pyrrole , pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinyl, thiomorpholinyl, dihydropyran, thiadiazolyl, oxazolyl , oxadiazolyl, pyrazolyl, 1,4-dioxadienyl, 2H-1, 2-oxazinyl or 2,5-dihydrothienyl, etc.; when substituted, the substituent is from 1 to 5 selected from the group consisting of F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkane Base, thiol, hydroxy, nitro, decyl, amino, cyano, isocyano, aryl, heteroaryl, heterocyclic, bridged, spiro, cyclyl, hydroxyalkyl, =0 A carbonyl group, an aldehyde, a carboxylic acid, a carboxylate arylthio group, a thiocarbonyl group or a silyl group.

“碳环”是指饱和或者不饱和的芳香环或者非芳香环，芳香环或者非芳香可以是3至8元的单环，4至12元双环或者10至15元三环***，碳环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、环己烯基、环庚基、环戊烯、环己二烯、环庚三烯、苯基、萘基、苯并环戊基、二环[3.2.1]辛烷基、二环[5.2.0]壬烷基、三环[5.3.1.1]十二烷基、金刚烷基或螺[3.3]庚烷基等。碳环可以被取代，当被取代时，取代基优选为1至5个，独立地选自F、Cl、Br、I、＝O、烷基、烯基、炔基、烷氧基、烷巯基、烷基氨基、巯基、羟基、硝基、氰基、氨基、烷基酰基氨基、环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷基巯基、羟基烷基、羧酸、羧酸酯或杂环烷基巯基。"Carbocycle" means a saturated or unsaturated aromatic ring or a non-aromatic ring. The aromatic ring or non-aromatic may be a single ring of 3 to 8 members, a 4 to 12 membered double ring or a 10 to 15 membered three ring system. Linked to a bridged or spiro ring, non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclopentene, cyclohexadiene, cyclohepta Alkene, phenyl, naphthyl, benzocyclopentyl, bicyclo[3.2.1]octyl, bicyclo[5.2.0]decyl, tricyclo[5.3.1.1]dodecyl, adamantane Base or spiro [3.3] heptyl and the like. The carbocyclic ring may be substituted, and when substituted, the substituent is preferably from 1 to 5, independently selected from the group consisting of F, Cl, Br, I, =O, alkyl, alkenyl, alkynyl, alkoxy, alkanoyl. , alkylamino, fluorenyl, hydroxy, nitro, cyano, amino, alkyl acylamino, cycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylindolyl, hydroxy An alkyl group, a carboxylic acid, a carboxylic acid ester or a heterocycloalkyl fluorenyl group.

“任选”或“任选地”是指随后所描述的事件或环境可以但不必须发生，该说明包括该事件或环境发生或不发生的场合，如：“任选被F取代的烷基”指烷基可以但不必须被F取代，说明包括烷基被F取代的情形和烷基不被F取代的情形。"Optional" or "optionally" means that the subsequently described event or environment may, but need not, occur, including where the event or environment occurs or does not occur, such as: "Alkyl optionally substituted by F" "Alkyl can be, but is not necessarily, substituted by F, and is meant to include the case where the alkyl group is substituted by F and the case where the alkyl group is not substituted by F.

“取代”是指基团中一个或多个氢原子被其它基团取代的情形，如果所述的基团被氢原子取代，形成的基团与被氢原子取代的基团相同。基团被取代的情形，例如氨基、C_1-4烷基、C_1-4烷氧基、C_3-6碳环、3至6元杂环任选进一步被0至4个选自H、F、Cl、Br、 I、羟基、氰基、氨基、C_1-4烷基或C_1-4烷氧基的取代基所取代，形成的基团包括但不限于甲基、氯甲基、三氯甲基、羟基甲基、-CH₂OCH₃、-CH₂SH、-CH₂CH₂CN、-CH₂NH₂、-NHOH、-NHCH₃、-OCH₂Cl、-OCH₂OCH₂CH₃、-OCH₂CH₂NH₂、-OCH₂CH₂SH、-OCH₂CH₂OH、1-羟基环丙基、2-羟基环丙基、2-氨基环丙基、4-甲基呋喃基、2-羟基苯基、4-氨基苯基、苯基。"Substitution" refers to the case where one or more hydrogen atoms in a group are substituted by another group, and if the group is substituted by a hydrogen atom, the group formed is the same as the group substituted by a hydrogen atom. Where the group is substituted, for example, amino, C _1-4 alkyl, C _1-4 alkoxy, C _3-6 carbocyclic, 3 to 6 membered heterocyclic ring, optionally further from 0 to 4 selected from H, Substituted by a substituent of F, Cl, Br, I, hydroxy, cyano, amino, C _1-4 alkyl or C _1-4 alkoxy, the groups formed include, but are not limited to, methyl, chloromethyl, Trichloromethyl, hydroxymethyl, -CH ₂ OCH ₃ , -CH ₂ SH, -CH ₂ CH ₂ CN, -CH ₂ NH ₂ , -NHOH, -NHCH ₃ , -OCH ₂ Cl, -OCH ₂ OCH ₂ CH ₃ , -OCH ₂ CH ₂ NH ₂ , -OCH ₂ CH ₂ SH, -OCH ₂ CH ₂ OH, 1-hydroxycyclopropyl, 2-hydroxycyclopropyl, 2-aminocyclopropyl, 4-methyl Furanyl, 2-hydroxyphenyl, 4-aminophenyl, phenyl.

“取代或未取代的”是指基团可以被取代或不被取代的情形，若在本发明中没有指出基团可以被取代，则表示该基团为未取代的情形。"Substituted or unsubstituted" refers to a situation in which a group may be substituted or unsubstituted, and if it is not indicated in the present invention that a group may be substituted, it means that the group is unsubstituted.

“作为选择”是指“作为选择”之后的方案与“作为选择”之前的方案为并列关系，而不是在前方案中的进一步选择情形。“As a choice” means that the scheme after “as a choice” is a side-by-side relationship with the scheme before “as a choice” rather than a further selection in the previous scheme.

“药学上可接受的盐”或“其药学上可接受的盐”指的是保持游离酸或游离碱的生物有效性和特性，且所述的游离酸通过与无毒的无机碱或有机碱，或所述的游离酸通过与无毒的无机酸或有机酸反应获得的那些盐。"Pharmaceutically acceptable salt" or "pharmaceutically acceptable salt thereof" refers to maintaining the biological effectiveness and properties of the free acid or free base, and the free acid is passed through a non-toxic inorganic or organic base. Or those salts obtained by reacting the free acid with a non-toxic inorganic or organic acid.

具体实施方式detailed description

以下结合附图及实施例详细说明本发明的技术方案，但本发明的保护范围包括但是不限于此。The technical solutions of the present invention are described in detail below with reference to the accompanying drawings and embodiments, but the scope of protection of the present invention includes but is not limited thereto.

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 Avance300)核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d₆)，氘代氯仿(CDCl₃)，氘代甲醇(CD₃OD)，氘代乙腈(CD₃CN)，内标为四甲基硅烷(TMS)。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). NMR was measured using a (Bruker Avance III 400 and Bruker Avance 300) NMR instrument and the solvent was deuterated dimethyl sulfoxide (DMSO-d ₆ ), deuterated chloroform (CDCl ₃ ), deuterated methanol (CD ₃ OD). , deuterated acetonitrile (CD ₃ CN), internal standard is tetramethylsilane (TMS).

MS的测定用(Agilent 6120B(ESI)和Agilent 6120B(APCI))。The measurement of MS was carried out (Agilent 6120B (ESI) and Agilent 6120B (APCI)).

HPLC的测定使用安捷伦1260DAD高压液相色谱仪(Zorbax SB-C18100×4.6mm)。The HPLC was measured using an Agilent 1260 DAD high pressure liquid chromatograph (Zorbax SB-C18100 x 4.6 mm).

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0.15mm～0.20mm，薄层层析分离纯化产品采用的规格是0.4mm～0.5mm。Thin layer chromatography silica gel plate uses Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plate. The specification of silica gel plate used for thin layer chromatography (TLC) is 0.15mm~0.20mm. The specification for thin layer chromatography separation and purification is 0.4mm. ~0.5mm.

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 a carrier.

本发明的己知的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 known 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, Anheji Chemical, Shanghai Demer, Chengdu Kelon Chemical, Suiyuan Chemical Technology, and Belling Technology. And other companies.

BOC：叔丁氧基羰基；BOC: tert-butoxycarbonyl;

DMAP：4-二甲氨基吡啶； DMAP: 4-dimethylaminopyridine;

DCC：二环己基碳二亚胺；DCC: dicyclohexylcarbodiimide;

EDCI：N,N-羰基二咪唑。EDCI: N,N-carbonyldiimidazole.

实施例1Example 1

[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]咪唑-1-甲酸酯(化合物1)[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14, 15-decahydro-1H-cyclopenta[a]phenanthr-3-yl]imidazole-1-carboxylate (Compound 1)

[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]imidazole-1-carboxylate[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro -1H-cyclopenta[a]phenanthren-3-yl]imidazole-1-carboxylate

将(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-醇(1a)(20.0g,57.2mmol)溶于二氯甲烷(200mL)中，加入N'N-羰基二咪唑(18.5g,114.4mmol),50℃下反应2小时。向上述反应液中加入水(200mL×3)洗涤，无水硫酸钠干燥，减压浓缩得到白色固体状的[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]咪唑-1-甲酸酯(化合物1)(22.4g,产率88％)。(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14, 15-Decahydro-1H-cyclopenta[a]phenanthrene-3-ol (1a) (20.0 g, 57.2 mmol) was dissolved in dichloromethane (200 mL) and N.N-carbonyldiimidazole (18.5) was added. g, 114.4 mmol), reacted at 50 ° C for 2 hours. Water (200 mL × 3) was added to the mixture, and dried over anhydrous sodium sulfate. -17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthr-3-yl]imidazole 1-carboxylic acid ester (Compound 1) (22.4 g, yield 88%).

MS m/z(ESI):444.2[M+1]。MS m/z (ESI): 44422.

¹H NMR(400MHz,CDCl₃)δ8.63(d,1H),8.47(dd,1H),8.14(s,1H),7.65(d,1H),7.42(s,1H),7.23(dd,1H),7.07(s,1H),6.08–5.94(m,1H),5.49(d,1H),4.96–4.77(m,1H),2.53(m,2H),2.28(m,1H),2.08(m,4H),1.97(m,1H),1.83–1.49(m,7H),1.24(m,2H),1.13(s,3H),1.06(s,3H)。 ^{_{1 H NMR (400MHz, CDCl 3}} ) δ8.63 (d, 1H), 8.47 (dd, 1H), 8.14 (s, 1H), 7.65 (d, 1H), 7.42 (s, 1H), 7.23 (dd, 1H), 7.07 (s, 1H), 6.08–5.94 (m, 1H), 5.49 (d, 1H), 4.96–4.77 (m, 1H), 2.53 (m, 2H), 2.28 (m, 1H), 2.08 (m, 4H), 1.97 (m, 1H), 1.83 - 1.49 (m, 7H), 1.24 (m, 2H), 1.13 (s, 3H), 1.06 (s, 3H).

实施例2Example 2

[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基](2S)-吡咯烷-2-甲酸酯(化合物2) [(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14, 15-decahydro-1H-cyclopenta[a]phenanthren-3-yl](2S)-pyrrolidine-2-carboxylate (Compound 2)

[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl](2S)-pyrrolidine-2-carboxylate[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro -1H-cyclopenta[a]phenanthren-3-yl](2S)-pyrrolidine-2-carboxylate

第一步：(2S)-1-叔丁氧基羰基吡咯烷-2-羧酸(2b)First step: (2S)-1-tert-butoxycarbonylpyrrolidine-2-carboxylic acid (2b)

(2S)-1-tert-butoxycarbonylpyrrolidine-2-carboxylicacid(2S)-1-tert-butoxycarbonylpyrrolidine-2-carboxylic acid

将二碳酸二叔丁酯(30.8mL，144mmol)溶于四氢呋喃(150mL)中，冰浴下缓慢滴加至的L-脯氨酸(2a)(15.07g，131mmol)和饱和碳酸氢钠(200mL)体系中，室温搅拌16小时，用2N的盐酸调节pH＜3，用乙酸乙酯(150mL×2)萃取，合并有机相，用无水硫酸钠干燥，过滤，减压浓缩，得到白色固状的(2S)-1-叔丁氧基羰基吡咯烷-2-羧酸(2b)(25.18g，产率89％)。Di-tert-butyl dicarbonate (30.8 mL, 144 mmol) was dissolved in tetrahydrofuran (150 mL), and slowly added dropwise to L-valine (2a) (15.07 g, 131 mmol) and saturated sodium bicarbonate (200 mL). The mixture was stirred at room temperature for 16 hours, and the mixture was adjusted to pH 3 with 2N hydrochloric acid, and ethyl acetate (150 mL×2) was evaporated. (2S)-1-tert-Butoxycarbonylpyrrolidine-2-carboxylic acid (2b) (25.18 g, yield 89%).

¹H NMR(400MHz,CDCl3)δ4.30(d,1H),3.45(t,2H),2.32(d,1H),2.15–1.74(m,3H),1.46(d,9H)。 ¹ H NMR (400 MHz, CDCl 3 ) δ 4.30 (d, 1H), 3.45 (t, 2H), 2.32 (d, 1H), 2.15 - 1.74 (m, 3H), 1.46 (d, 9H).

第二步：O₁-叔丁基O₂-[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基](2S)-吡咯烷-1,2-二羧酸酯(2c)Second step: O ₁ -tert-butyl O ₂ -[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4 ,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl](2S)-pyrrolidine-1,2-dicarboxylate ( 2c)

O₁-tert-butylO₂-[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl](2S)-pyrro-lidine-1,2-dicarboxylateO ₁ -tert-butylO ₂ -[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11 ,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl](2S)-pyrro-lidine-1,2-dicarboxylate

向反应瓶中依次加入(2S)-1-叔丁氧基羰基吡咯烷-2-羧酸(2b)(2.59g，12mmol)、阿比特龙(1.68g，4.81mmol)、4-二甲氨基吡啶(DMAP)(0.18g,1.44mmol)、N,N-羰基二咪唑(EDCI)(2.3g,12mmol)和二氯甲烷(120mL)，室温反应24小时，体系加入100mL水，用二氯甲烷(100mL×3)萃取，有机相用无水硫酸镁干燥，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)＝4:1)得到得到白色固状的O₁-叔丁基O₂-[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基](2S)-吡咯烷-1,2-二羧酸酯(2c)(1.6g，产率61％)。(2S)-1-tert-Butoxycarbonylpyrrolidine-2-carboxylic acid (2b) (2.59 g, 12 mmol), abiraterone (1.68 g, 4.81 mmol), 4-dimethylamino group were sequentially added to the reaction flask. Pyridine (DMAP) (0.18 g, 1.44 mmol), N,N-carbonyldiimidazole (EDCI) (2.3 g, 12 mmol) and methylene chloride (120 mL) were reacted at room temperature for 24 hours. (100 mL × 3), the organic phase was dried (MgSO4) Obtained as a white solid O ₁ -tert-butyl O ₂ -[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3, 4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl](2S)-pyrrolidine-1,2-dicarboxylate (2c) (1.6 g, yield 61%).

MS m/z(ESI):547.3[M+1]。MS m/z (ESI): 547.3 [M+].

¹H NMR(400MHz,CDCl3)δ8.63(s,1H),8.47(d,1H),7.69(d,1H),7.29–7.23(m,1H),6.02(s,1H),5.42(s,1H),4.65(d,1H),4.33–4.16(m,1H),3.47(m,2H),2.42–2.12(m,4H),2.07(m,3H),2.00–1.80(m,5H),1.80–1.55(m,6H),1.49(m,1H),1.45(d,9H),1.24(d,2H),1.08(d,3H),1.05(s,3H)。 ^{1 H NMR (400MHz, CDCl3)} δ8.63 (s, 1H), 8.47 (d, 1H), 7.69 (d, 1H), 7.29-7.23 (m, 1H), 6.02 (s, 1H), 5.42 (s , 1H), 4.65 (d, 1H), 4.33–4.16 (m, 1H), 3.47 (m, 2H), 2.42–2.12 (m, 4H), 2.07 (m, 3H), 2.00–1.80 (m, 5H) ), 1.80 - 1.55 (m, 6H), 1.49 (m, 1H), 1.45 (d, 9H), 1.24 (d, 2H), 1.08 (d, 3H), 1.05 (s, 3H).

第三步：[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]-(2S)-吡咯烷-2-甲酸酯(化合物2)The third step: [(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11, 12,14,15-Decahydro-1H-cyclopenta[a]phenanthren-3-yl]-(2S)-pyrrolidine-2-carboxylate (Compound 2)

[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl](2S)-pyrrolidine-2-carboxyl--ate[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro -1H-cyclopenta[a]phenanthren-3-yl](2S)-pyrrolidine-2-carboxyl--ate

将O₁-叔丁基O₂-[(3S，8R，9S，10R，13S，14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11，12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]-(2S)-吡咯烷-1,2-二羧酸酯(2c)(1.1g，2.0mmol)溶于二氯甲烷(20mL)，冰浴，缓慢滴加三氟乙酸(4mL)，加完恢复室温反应2小时。冰浴下，体系加入氨水调节pH>7，用二氯甲烷(100mL×2)萃取，有机相用无水硫酸镁干燥，过滤，将滤液减压浓缩，残留物用硅胶柱色谱分离提纯(二氯甲烷/甲醇(v/v)＝20:1)得到得到白色固状的[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基](2S)-吡咯烷-2-甲酸酯(化合物2)(0.86g，产率88％)。O ₁ -tert-butyl O ₂ -[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7, 8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]-(2S)-pyrrolidine-1,2-dicarboxylate (2c) (1.1 g, 2.0 mmol) was dissolved in dichloromethane (20 mL). Under ice-cooling, the system was added with aqueous ammonia to adjust the pH>7, and extracted with dichloromethane (100 mL×2). The organic phase was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Methyl chloride/methanol (v/v) = 20:1) gave [(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl) as a white solid. )-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl](2S)-pyrrolidine-2- Formate (Compound 2) (0.86 g, yield 88%).

MS m/z(ESI):447.2[M+1]。MS m/z (ESI): 447.2 [M + 1].

¹H NMR(400MHz,CDCl3)δ8.62(d,1H),8.46(dd,1H),7.64(m,1H),7.21(m,1H), 5.99(m,1H),5.42(d,1H),4.77–4.57(m,1H),3.80(m 1H),3.13(m,1H),2.97(m,1H),2.36(d,2H),2.27(m,1H),2.23–2.12(m,1H),2.11–2.00(m,3H),1.93–1.54(m,11H),1.51(m,1H),1.18(m 2H),1.08(s,3H),1.05(s,3H)。 ^{1 H NMR (400MHz, CDCl3)} δ8.62 (d, 1H), 8.46 (dd, 1H), 7.64 (m, 1H), 7.21 (m, 1H), 5.99 (m, 1H), 5.42 (d, 1H ), 4.77–4.57 (m, 1H), 3.80 (m 1H), 3.13 (m, 1H), 2.97 (m, 1H), 2.36 (d, 2H), 2.27 (m, 1H), 2.23–2.12 (m) , 1H), 2.11 - 2.00 (m, 3H), 1.93 - 1.54 (m, 11H), 1.51 (m, 1H), 1.18 (m 2H), 1.08 (s, 3H), 1.05 (s, 3H).

实施例3Example 3

[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基](3S)-吡咯-3-甲酸酯(化合物3)[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14, 15-decahydro-1H-cyclopenta[a]phenanthren-3-yl](3S)-pyrrole-3-carboxylate (compound 3)

[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl](3S)-pyrrolidine-3-carboxylate[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro -1H-cyclopenta[a]phenanthren-3-yl](3S)-pyrrolidine-3-carboxylate

第一步：O₁-叔丁基O₃-[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基](3S)-吡咯-1,3-二甲酸酯(3b)First step: O ₁ -tert-butyl O ₃ -[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4 ,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthr-3-yl](3S)-pyrrole-1,3-dicarboxylate (3b )

O₁-tert-butyl O₃-[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl](3S)-pyrrolidine-1,3-dicarboxylateO ₁ -tert-butyl O ₃ -[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9, 11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl](3S)-pyrrolidine-1,3-dicarboxylate

向反应瓶中依次加入(3S)-1-叔丁氧基羰基吡咯烷-3-羧酸(3a)(1.06g，3.57mmol)、(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-醇(1a)(1.68g，4.81mmol)、4-二甲氨基吡啶(DMAP)(0.18g,1.44mmol)、N’N-羰基二咪唑(EDCI)(2.3g,12mmol)和二氯甲烷(120mL)，室温反应8小时，体系加入水(100mL)，用二氯甲烷(100mL×3)萃取，合并有机相，有机相用无水硫酸镁干燥，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)＝4:1)得到得到白色固状的O₁-叔丁基O₃-[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基](3S)-吡咯-1,3-二甲酸酯(3b)(1.49g，产率78％)。(3S)-1-tert-Butoxycarbonylpyrrolidine-3-carboxylic acid (3a) (1.06 g, 3.57 mmol), (3S, 8R, 9S, 10R, 13S, 14S)-10 was added to the reaction flask in order. ,13-Dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthrene 3-ol (1a) (1.68 g, 4.81 mmol), 4-dimethylaminopyridine (DMAP) (0.18 g, 1.44 mmol), N'N-carbonyldiimidazole (EDCI) (2.3 g, 12 mmol) and The chloromethane (120 mL) was stirred at room temperature for 8 hr. EtOAc (EtOAc)EtOAc. the residue was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 4: 1) to give to give a white solid of O ₁ - tert-butyl _{O 3 - [(3S, 8R} , 9S, 10R, 13S,14S)-10,13-Dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopentane Iso[a]phenanthren-3-yl](3S)-pyrrole-1,3-dicarboxylate (3b) (1.49 g, yield 78%).

MS m/z(ESI):547.4[M+1]。MS m/z (ESI): 547.4 [M+].

¹H NMR(400MHz,CDCl3)δ8.62(s,1H),8.47(d,1H),7.69(dd,1H),7.25(m,1H),6.02(d,1H),5.42(d,1H),4.64(m,1H),3.50(m,4H),3.00(d,1H),2.34(m,2H),2.28(m,1H),2.07(m,5H),1.87(m,2H),1.67(m,6H),1.15(m,1H),1.47(d,9H),1.19(m,2H),1.09(s,3H),1.05(d,3H)。 ^{1 H NMR (400MHz, CDCl3)} δ8.62 (s, 1H), 8.47 (d, 1H), 7.69 (dd, 1H), 7.25 (m, 1H), 6.02 (d, 1H), 5.42 (d, 1H ), 4.64 (m, 1H), 3.50 (m, 4H), 3.00 (d, 1H), 2.34 (m, 2H), 2.28 (m, 1H), 2.07 (m, 5H), 1.87 (m, 2H) , 1.67 (m, 6H), 1.15 (m, 1H), 1.47 (d, 9H), 1.19 (m, 2H), 1.09 (s, 3H), 1.05 (d, 3H).

第二步：[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基](3S)-吡咯-3-甲酸酯(化合物3)Second step: [(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11, 12,14,15-Decahydro-1H-cyclopenta[a]phenanthren-3-yl](3S)-pyrrole-3-carboxylate (Compound 3)

将O1-叔丁基O3-[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基](3S)-吡咯-1,3-二甲酸酯(3b)(1.28g，2.34mmol)溶于二氯甲烷(40mL)，冰浴，缓慢滴加三氟乙酸(4mL)，加完恢复室温反应2小时。冰浴下，体系加入氨水调节pH>7，用二氯甲烷(100mL×2)萃取，合并有机相，有机相用无水硫酸镁干燥，过滤，将滤液减压浓缩，残留物用硅胶柱色谱分离提纯(二氯甲烷/甲醇(v/v)＝20:1)得到得到白色固状的[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基](3S)-吡咯-3-甲酸酯(化合物3)(0.91g，产率87％)。O1-tert-butyl O3-[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8, 9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl](3S)-pyrrole-1,3-dicarboxylate (3b) (1.28 g, 2.34 mmol) was dissolved in dichloromethane (40 mL), ice-cooled, and trifluoroacetic acid (4 mL) was slowly added dropwise. Under ice-cooling, the system was added with aqueous ammonia to adjust the pH>7, and extracted with dichloromethane (100 mL×2). The organic phase was combined, the organic phase was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Separation and purification (dichloromethane/methanol (v/v) = 20:1) gave [(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17- (white solid). 3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthr-3-yl](3S)-pyrrole 3-formate (Compound 3) (0.91 g, yield 87%).

MS m/z(ESI):447.2[M+1]。MS m/z (ESI): 447.2 [M + 1].

¹H NMR(400MHz,CDCl3)δ8.62(d,1H),8.46(dd,1H),7.64(m,1H),7.21(m,1H),5.99(m,1H),5.42(d,1H),4.63(m,1H),3.13(m,3H),2.91(m,2H),2.43(m,1H),2.34(d,2H),2.27(m 1H),2.04(m,5H),1.88(m,2H),1.63(m,7H),1.17(m,2H),1.09(s,3H),1.05(s,3H)。 ^{1 H NMR (400MHz, CDCl3)} δ8.62 (d, 1H), 8.46 (dd, 1H), 7.64 (m, 1H), 7.21 (m, 1H), 5.99 (m, 1H), 5.42 (d, 1H ), 4.63 (m, 1H), 3.13 (m, 3H), 2.91 (m, 2H), 2.43 (m, 1H), 2.34 (d, 2H), 2.27 (m 1H), 2.04 (m, 5H), 1.88 (m, 2H), 1.63 (m, 7H), 1.17 (m, 2H), 1.09 (s, 3H), 1.05 (s, 3H).

实施例4 Example 4

[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]1-甲基哌啶-4-甲酸酯(化合物4)[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14, 15-Decahydro-1H-cyclopenta[a]phenanthr-3-yl]1-methylpiperidine-4-carboxylate (Compound 4)

[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]1-methylpiperidine-4-carboxylate[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro -1H-cyclopenta[a]phenanthren-3-yl]1-methylpiperidine-4-carboxylate

将(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-醇(1a)(10.49g，30mmol)、1-甲基哌啶-4-甲酸(8.6g，60mmol)、4-二甲氨基吡啶(1.1g，9.0mmol)和二氯甲烷(300mL)加入反应瓶中，搅拌下分批加入N’N-羰基二咪唑(EDCI)(17.26g，90mmol)，室温搅拌反应10小时。向反应液中加入水(300mL)，搅拌5分钟，静置分层，有机层用无水硫酸钠干燥，过滤，减压浓缩干，残留物用硅胶柱层析分离(二氯甲烷：甲醇(v/v)＝50:1)得白色固体状[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊二烯并[a]菲-3-基]1-甲基哌啶-4-甲酸酯(化合物4)，(7.8g，产率：55％)。(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14, 15-decahydro-1H-cyclopenta[a]phenanthrene-3-ol (1a) (10.49 g, 30 mmol), 1-methylpiperidine-4-carboxylic acid (8.6 g, 60 mmol), 4-di Methylaminopyridine (1.1 g, 9.0 mmol) and dichloromethane (300 mL) were added to a reaction flask, and N'N-carbonyldiimidazole (EDCI) (17.26 g, 90 mmol) was added portionwise with stirring, and the reaction was stirred at room temperature for 10 hours. Water (300 mL) was added to the reaction mixture, and the mixture was stirred for 5 minutes, and the mixture was evaporated to dryness. v/v)=50:1) as a white solid [(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4 ,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthr-3-yl]1-methylpiperidine-4-carboxylate (Compound 4) , (7.8 g, yield: 55%).

MS m/z(ESI):475.2[M+1]。MS m/z (ESI): 475.2 [M + 1].

¹H NMR(400MHz,CDCl₃)δ8.62(d,1H),8.46(dd,1H),7.66(dt,1H),7.24(dd,1H),6.00(dd,1H),5.43(d,1H),4.66-4.59(m,1H),2.84-2.81(m,2H),2.34-2.22(m,7H),2.10-2.02(m,5H),1.93-1.45(m,13H),1.20-1.05(m,8H)。 ^{_{1 H NMR (400MHz, CDCl 3}} ) δ8.62 (d, 1H), 8.46 (dd, 1H), 7.66 (dt, 1H), 7.24 (dd, 1H), 6.00 (dd, 1H), 5.43 (d, 1H), 4.66-4.59 (m, 1H), 2.84-2.81 (m, 2H), 2.34-2.22 (m, 7H), 2.10-2.02 (m, 5H), 1.93-1.45 (m, 13H), 1.20- 1.05 (m, 8H).

实施例5Example 5

[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H-环戊二烯并[a]菲-3-基]哌啶-4-羧酸酯(化合物5)[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14, 15 decahydro-1H-cyclopenta[a]phenanthr-3-yl]piperidine-4-carboxylate (compound 5)

[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]piperidine-4-carboxylate [(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro -1H-cyclopenta[a]phenanthren-3-yl]piperidine-4-carboxylate

第一步：O₁-叔丁基O₄-[(3S 8R,9S,10R,13,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H-环戊二烯并[a]菲-3-基]氧基羰基氧基甲基哌啶-1,4-二羧酸酯(5b)First step: O ₁ -tert-butyl O ₄ -[(3S 8R,9S,10R,13,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4, 7,8,9,11,12,14,15 decahydro-1H-cyclopenta[a]phenanthr-3-yl]oxycarbonyloxymethylpiperidine-1,4-dicarboxylate (5b)

O1-tert-butyl O4-[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]piperidine-1,4-dicarboxylateO1-tert-butyl O4-[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11, 12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]piperidine-1,4-dicarboxylate

向反应瓶中依次加入1-叔丁氧基羰基哌啶-4-羧酸(5a)(1.87g，8.2mmol)、阿比特龙(2.8g，8.0mmol)、4-二甲氨基吡啶(DMAP)(0.29g,2.4mmol)、N,N-羰基二咪唑(EDCI)(3.83g,20mmol)和二氯甲烷(150mL)，室温反应7小时，体系加入100mL水，用二氯甲烷(100mL×3)萃取，有机相用无水硫酸镁干燥，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)＝5:1)得到得到白色固状的O₁-叔丁基O₄-[(3S 8R,9S,10R,13,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H-环戊二烯并[a]菲-3-基]氧基羰基氧基甲基哌啶-1,4-二羧酸酯(5b)(3.13g，产率70％)。1-tert-Butoxycarbonylpiperidine-4-carboxylic acid (5a) (1.87 g, 8.2 mmol), abiraterone (2.8 g, 8.0 mmol), 4-dimethylaminopyridine (DMAP) were sequentially added to the reaction flask. (0.29g, 2.4mmol), N,N-carbonyldiimidazole (EDCI) (3.83g, 20mmol) and dichloromethane (150mL), reacted at room temperature for 7 hours, the system was added 100mL water, with dichloromethane (100mL × 3) Extraction, the organic phase is dried over anhydrous magnesium sulfate, filtered, and the filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography ( petroleum ether / ethyl acetate (v/v) = 5:1) to give white solid. O ₁ -tert-butyl O ₄ -[(3S 8R,9S,10R,13,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7, 8,9,11,12,14,15 decahydro-1H-cyclopenta[a]phenanthren-3-yl]oxycarbonyloxymethylpiperidine-1,4-dicarboxylate (5b (3.13 g, yield 70%).

MS m/z(ESI):561.4[M+1]。MS m/z (ESI): 561.4 [M + 1].

¹H NMR(400MHz,CDCl3)δ8.63(s,1H),8.46(d,1H),7.66(d,1H),7.23(dd,1H),6.00(dd,1H),5.42(d,1H),4.63(m,1H),3.99(m,2H),2.85(t,2H),2.34(m,4H),2.07(m,3H),1.87(m,4H),1.62(m,9H),1.46(s,9H),1.17(m,2H),1.08(s,3H),1.05(s,3H)。 ^{1 H NMR (400MHz, CDCl3)} δ8.63 (s, 1H), 8.46 (d, 1H), 7.66 (d, 1H), 7.23 (dd, 1H), 6.00 (dd, 1H), 5.42 (d, 1H ), 4.63 (m, 1H), 3.99 (m, 2H), 2.85 (t, 2H), 2.34 (m, 4H), 2.07 (m, 3H), 1.87 (m, 4H), 1.62 (m, 9H) , 1.46 (s, 9H), 1.17 (m, 2H), 1.08 (s, 3H), 1.05 (s, 3H).

第二步：[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15 十氢-1H-环戊二烯并[a]菲-3-基]哌啶-4-羧酸酯(化合物5)Second step: [(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11, 12,14,15 Decahydro-1H-cyclopenta[a]phenanthr-3-yl]piperidine-4-carboxylate (Compound 5)

[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]piperidine-4-carboxylate[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro -1H-cyclopenta[a]phenanthren-3-yl]piperidine-4-carboxylate

冰浴，反应瓶中依次加入O₁-叔丁基O₄-[(3S 8R,9S,10R,13,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H-环戊二烯并[a]菲-3-基]氧基羰基氧基甲基哌啶-1,4-二羧酸酯(5b)(2.0g，3.57mmol)，缓慢滴加3N浓度的盐酸乙酸乙酯溶液(15mL，45mmol)，加完恢复室温反应1.5小时。体系抽滤，得到的白色盐酸盐用乙酸乙酯(10mL×2)洗，得到的白色固体用水溶解，体系加入氨水调节pH>7，用二氯甲烷(100mL×2)萃取，有机相用无水硫酸镁干燥，过滤，将滤液减压浓缩得到白色固状的[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H-环戊二烯并[a]菲-3-基]哌啶-4-羧酸酯(化合物5)(1.45g，产率88％)。In an ice bath, O ₁ -tert-butyl O ₄ -[(3S 8R,9S,10R,13,14S)-10,13-dimethyl-17-(3-pyridyl)-2 was added to the reaction flask. 3,4,7,8,9,11,12,14,15 decahydro-1H-cyclopenta[a]phenanthren-3-yl]oxycarbonyloxymethylpiperidine-1,4- The dicarboxylic acid ester (5b) (2.0 g, 3.57 mmol) was slowly added dropwise with a 3N aqueous solution of ethyl acetate (15 mL, 45 mmol). The system was suction filtered, and the obtained white hydrochloride was washed with ethyl acetate (10 mL×2), and the obtained white solid was dissolved in water, and the system was adjusted to pH >7 with aqueous ammonia, and extracted with dichloromethane (100 mL×2). The organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was evaporated to vacuo to give [[3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)- 2,3,4,7,8,9,11,12,14,15 decahydro-1H-cyclopenta[a]phenanthr-3-yl]piperidine-4-carboxylate (compound 5) (1.45 g, yield 88%).

MS m/z(ESI):461.2[M+1]。MS m/z (ESI): 4621.

¹H NMR(400MHz,CDCl3)δ8.62(d,1H),8.46(dd,1H),7.64(d,1H),7.21(dd,1H),5.99(dd,1H),5.42(d,1H),4.62(m,1H),3.11(d,2H),2.67(t,2H),2.34(m,5H),2.06(m,3H),1.87(m,4H),1.61(m,9H),1.15(m,2H),1.08(s,3H),1.05(s,3H)。 ^{1 H NMR (400MHz, CDCl3)} δ8.62 (d, 1H), 8.46 (dd, 1H), 7.64 (d, 1H), 7.21 (dd, 1H), 5.99 (dd, 1H), 5.42 (d, 1H ), 4.62 (m, 1H), 3.11 (d, 2H), 2.67 (t, 2H), 2.34 (m, 5H), 2.06 (m, 3H), 1.87 (m, 4H), 1.61 (m, 9H) , 1.15 (m, 2H), 1.08 (s, 3H), 1.05 (s, 3H).

实施例6Example 6

[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H-环戊[一]菲-3-基]1-甲基吡咯烷-3-羧酸酯(化合物6)[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14, 15 decahydro-1H-cyclopenta[1]phenanthr-3-yl]1-methylpyrrolidin-3-carboxylate (compound 6)

[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]1-methylpyrrolidine-3-carboxylate[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro -1H-cyclopenta[a]phenanthren-3-yl]1-methylpyrrolidine-3-carboxylate

向反应瓶中依次加入1-甲基吡咯烷-3-甲酸盐酸盐(42a，2.25g,13.5mmol)、阿比特龙(3.15g,9mmol)、DMAP(0.6g,4.9mmol)、DCC(7.5g，36mmol)和二氯甲烷(300mL)，室温反应8小时。向反应液中加入二氯甲烷(200mL)，用水(100mL×3)洗涤，无水硫酸钠干燥，减压浓缩，残留物用硅胶柱色谱分离(二氯甲烷/甲醇(v/v)＝50:1)得白色固体[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H-环戊[一]菲-3-基]1-甲基吡咯烷-3-羧酸酯(化合物6)(3.02g，产率76％)。1-methylpyrrolidine-3-formate (42a, 2.25 g, 13.5 mmol), abiraterone (3.15 g, 9 mmol), DMAP (0.6 g, 4.9 mmol), DCC were added to the reaction flask. (7.5 g, 36 mmol) and dichloromethane (300 mL) were reacted at room temperature for 8 hours. Dichloromethane (200 mL) was added to the reaction mixture, and the mixture was evaporated. :1) A white solid [(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9, 11,12,14,15 decahydro-1H-cyclopenta[1]phenanthr-3-yl]1-methylpyrrolidin-3-carboxylate (Compound 6) (3.02 g, yield 76%).

¹H NMR(400MHz,CDCl₃)δ8.62(d,1H),8.46(dd,1H),7.63(m,1H),7.21(m,1H),5.99(dd,1H),5.41(d,1H),4.63(m,1H),,3.10–2.97(m,1H),2.90(m,1H),2.72–2.61(m,2H),2.59–2.47(m,1H),2.39(s,3H),2.34(m,2H),2.27(m,1H),2.15–1.99(m,3H),1.98–1.83(m,3H),1.82–1.44(m,7H),1.42–1.28(m,1H),1.16(m,2H),1.09(s,3H),1.05(s,3H)。 ^{_{1 H NMR (400MHz, CDCl 3}} ) δ8.62 (d, 1H), 8.46 (dd, 1H), 7.63 (m, 1H), 7.21 (m, 1H), 5.99 (dd, 1H), 5.41 (d, 1H), 4.63 (m, 1H),, 3.10 - 2.97 (m, 1H), 2.90 (m, 1H), 2.72 - 2.61 (m, 2H), 2.59 - 2.47 (m, 1H), 2.39 (s, 3H) ), 2.34 (m, 2H), 2.27 (m, 1H), 2.15 - 1.99 (m, 3H), 1.98 - 1.83 (m, 3H), 1.82 - 1.44 (m, 7H), 1.42 - 1.28 (m, 1H) ), 1.16 (m, 2H), 1.09 (s, 3H), 1.05 (s, 3H).

MS m/z(ESI):461.2[M+H]。MS m/z (ESI): 4621. [M+H].

实施例7Example 7

[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H-环戊[一]菲-3-基]四氢吡喃-4-羧酸酯(化合物7)[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14, 15 decahydro-1H-cyclopenta[1]phenanthr-3-yl]tetrahydropyran-4-carboxylate (compound 7)

[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]tetrahydropyran-4-carboxylate[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro -1H-cyclopenta[a]phenanthren-3-yl]tetrahydropyran-4-carboxylate

向反应瓶中依次加入四氢吡喃-4-甲酸(7a)(0.78g，6.0mmol)、阿比特龙(1.4g，4.0mmol)、4-二甲氨基吡啶(DMAP)(0.25g,2.0mmol)、N,N-羰基二咪唑(EDCI)(3.07g,16mmol)和二氯甲烷(100mL)，室温反应6小时，体系加入100mL水，用二氯甲烷(100mL×3)萃取，有机相用无水硫酸镁干燥，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)＝3:1)得到得到白色固状[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H-环戊[一]菲-3-基]四氢吡喃-4-羧酸酯(化合物7)(0.89g，产率60％)。Tetrahydropyran-4-carboxylic acid (7a) (0.78 g, 6.0 mmol), abiraterone (1.4 g, 4.0 mmol), 4-dimethylaminopyridine (DMAP) (0.25 g, 2.0) were sequentially added to the reaction flask. Methyl), N,N-carbonyldiimidazole (EDCI) (3.07 g, 16 mmol) and dichloromethane (100 mL) were reacted at room temperature for 6 hours. The system was added with 100 mL of water and extracted with dichloromethane (100 mL×3). The organic layer was dried (MgSO4 / ethyl acetate (v/v) = 3:1). ,9S,10R,13S,14S)-10,13-Dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15 decahydro-1H -cyclopenta[1]phenanthr-3-yl]tetrahydropyran-4-carboxylate (Compound 7) (0.89 g, yield 60%).

¹H NMR(400MHz,CDCl₃)δ8.63(d,1H),8.53–8.40(m,1H),7.69(m,1H),7.26(m,1H),6.02(dd,1H),5.42(d,1H),4.73–4.54(m,1H),3.96(dt,2H),3.43(td,2H),2.56–2.44(m,1H),2.39–2.21(m,3H),2.13–2.00(m,3H),1.92–1.40(m,13H),1.20–1.10(m,2H),1.08(m,3H),1.05(s,3H)。 ^{_{1 H NMR (400MHz, CDCl 3}} ) δ8.63 (d, 1H), 8.53-8.40 (m, 1H), 7.69 (m, 1H), 7.26 (m, 1H), 6.02 (dd, 1H), 5.42 ( d, 1H), 4.73–4.54 (m, 1H), 3.96 (dt, 2H), 3.43 (td, 2H), 2.56–2.44 (m, 1H), 2.39–2.21 (m, 3H), 2.13–2.00 ( m, 3H), 1.92 - 1.40 (m, 13H), 1.20 - 1.10 (m, 2H), 1.08 (m, 3H), 1.05 (s, 3H).

MS m/z(ESI):462.1[M+H]。MS m/z (ESI): 4621. [M+H].

实施例8Example 8

[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H-环戊[一]菲-3-基](2S)-1-甲基吡咯烷-2-羧酸酯(化合物8)[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14, 15 decahydro-1H-cyclopenta[1]phenanthr-3-yl](2S)-1-methylpyrrolidine-2-carboxylate (compound 8)

[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl](2S)-1-methylpyrrolidine-2-carboxylate[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro -1H-cyclopenta[a]phenanthren-3-yl](2S)-1-methylpyrrolidine-2-carboxylate

第一步：N-甲基-L-脯氨酸(8b)First step: N-methyl-L-proline (8b)

N-Methyl-l-ProlineN-Methyl-l-Proline

向反应瓶中依次加入L-脯氨酸(8a)(2.0g，17.4mmol)、甲醛(1.4mL，19.1 mmol)、钯碳(0.5g)和甲醇(20mL)，氢气氛下室温反应20小时，过滤，将滤液减压浓缩，残留物用硅胶柱色谱分离提纯(二氯甲烷/甲醇(v/v)＝1:1)得到得到白色固状的N-甲基-L-脯氨酸(8b)(0.8g，产率36％)。L-valine (8a) (2.0 g, 17.4 mmol) and formaldehyde (1.4 mL, 19.1) were sequentially added to the reaction flask. Palladium-carbon (0.5g) and methanol (20mL) were reacted in a hydrogen atmosphere at room temperature for 20 hours, filtered, and the filtrate was concentrated under reduced pressure. = 1:1) N-methyl-L-valine (8b) (0.8 g, yield 36%) was obtained as white solid.

¹H NMR(400MHz,MeOD)δ3.81(dd,1H),3.73(ddd,1H),3.22–3.06(m,1H),2.94(s,3H),2.61–2.40(m,1H),2.22–2.07(m,2H),2.02–1.90(m,1H)。 ^{1 H NMR (400MHz, MeOD)} δ3.81 (dd, 1H), 3.73 (ddd, 1H), 3.22-3.06 (m, 1H), 2.94 (s, 3H), 2.61-2.40 (m, 1H), 2.22 –2.07 (m, 2H), 2.02–1.90 (m, 1H).

第二步：[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H-环戊[一]菲-3-基](2S)-1-甲基吡咯烷-2-羧酸酯(化合物8)Second step: [(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11, 12,14,15 decahydro-1H-cyclopenta[1]phenanthr-3-yl](2S)-1-methylpyrrolidine-2-carboxylate (compound 8)

向反应瓶中依次加入N-甲基-L-脯氨酸(8b)(0.68g，5.26mmol)、阿比特龙(1.22g，3.51mmol)、4-二甲氨基吡啶(DMAP)(0.13g,1.05mmol)、DCC(1.81g,8.78mmol)和二氯甲烷(100mL)，室温反应72小时，体系加入100mL水，用二氯甲烷(100mL×3)萃取，有机相用无水硫酸镁干燥，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)＝3:1)得到白色固状[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H-环戊[一]菲-3-基](2S)-1-甲基吡咯烷-2-羧酸酯(化合物8)(0.54g，产率34％)。N-methyl-L-valine (8b) (0.68 g, 5.26 mmol), abiraterone (1.22 g, 3.51 mmol), 4-dimethylaminopyridine (DMAP) (0.13 g) were sequentially added to the reaction flask. , 1.05 mmol), DCC (1.81 g, 8.78 mmol), methylene chloride (100 mL), EtOAc (EtOAc) (EtOAc) Filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography ( petroleum ether / ethyl acetate (v/v) = 3:1) to give white solids [(3S,8R,9S,10R,13S, 14S)-10,13-Dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15 decahydro-1H-cyclopenta[1]phenanthrene 3-yl](2S)-1-methylpyrrolidine-2-carboxylate (Compound 8) (0.54 g, yield 34%).

¹H NMR(400MHz,CDCl₃)δ8.74(s,1H),8.56(d,1H),7.95(d,1H),7.49(m,1H),6.15(dd,1H),5.44(d,1H),4.73(m,1H),2.95(s,3H),2.58–2.00(m,11H),1.91-1.40(m,,10H),1.26–1.12(m,2H),1.09(s,3H),1.07(s,3H),0.92-0.88(m,1H)。 ^{_{1 H NMR (400MHz, CDCl 3}} ) δ8.74 (s, 1H), 8.56 (d, 1H), 7.95 (d, 1H), 7.49 (m, 1H), 6.15 (dd, 1H), 5.44 (d, 1H), 4.73 (m, 1H), 2.95 (s, 3H), 2.58 - 2.00 (m, 11H), 1.91-1.40 (m,, 10H), 1.26 - 1.12 (m, 2H), 1.09 (s, 3H) ), 1.07 (s, 3H), 0.92-0.88 (m, 1H).

MS m/z(ESI):461.2[M+H]。MS m/z (ESI): 4621. [M+H].

实施例9Example 9

[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H环戊二烯并[a]菲-3-基]1-(2,2,2-三氟乙酰基)哌啶-4-羧酸酯(化合物9)[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14, 15 decahydro-1H cyclopenta[a]phenanthr-3-yl]1-(2,2,2-trifluoroacetyl)piperidine-4-carboxylate (compound 9)

[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahyd ro-1H-cyclopenta[a]phenanthren-3-yl]1-(2,2,2-trifluoroacetyl)piperidine-4-carboxylate[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahyd ro-1H-cyclopenta[a]phenanthren-3-yl]1-(2,2,2-trifluoroacetyl)piperidine-4-carboxylate

向反应瓶中依次加入[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H-环戊二烯并[a]菲-3-基]哌啶-4-羧酸酯(化合物5)(1.61g，3.5mmol)、三氟乙酸酐(2.2g，10.5mmol)和二氯甲烷(30mL)，40℃反应5小时，减压浓缩，残留物用硅胶柱色谱分离提纯(二氯甲烷/甲醇(v/v)＝100:1)得到得到无色油状[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H环戊二烯并[a]菲-3-基]1-(2,2,2-三氟乙酰基)哌啶-4-羧酸酯(化合物9)(1.6g，产率82％)。[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9 was sequentially added to the reaction flask. 11,12,14,15 decahydro-1H-cyclopenta[a]phenanthr-3-yl]piperidine-4-carboxylate (compound 5) (1.61 g, 3.5 mmol), trifluoroacetic anhydride (2.2 g, 10.5 mmol) and methylene chloride (30 mL) were reacted at 40 ° C for 5 hours, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 100:1) Obtained as a colorless oil [(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11, 12,14,15 decahydro-1H cyclopenta[a]phenanthr-3-yl]1-(2,2,2-trifluoroacetyl)piperidine-4-carboxylate (compound 9) 1.6 g, yield 82%).

¹H NMR(400MHz,CDCl₃)δ8.92(s,1H),8.76(d,1H),8.37(d,1H),7.85(dd,1H),6.50–6.30(m,1H),5.43(d,1H),4.79–4.50(m,1H),4.39–4.16(m,1H),3.94(d,1H),3.39–3.24(m,1H),3.10(dd,1H),2.61(m,1H),2.44–2.27(m,3H),2.23–1.96(m,5H),1.94–1.43(m,11H),1.29-1.33(m,2H),1.11(d,3H),1.10(s,3H)。 ^{_{1 H NMR (400MHz, CDCl 3}} ) δ8.92 (s, 1H), 8.76 (d, 1H), 8.37 (d, 1H), 7.85 (dd, 1H), 6.50-6.30 (m, 1H), 5.43 ( d, 1H), 4.79–4.50 (m, 1H), 4.39–4.16 (m, 1H), 3.94 (d, 1H), 3.39–3.24 (m, 1H), 3.10 (dd, 1H), 2.61 (m, 1H), 2.44–2.27 (m, 3H), 2.23–1.96 (m, 5H), 1.94–1.43 (m, 11H), 1.29-1.33 (m, 2H), 1.11 (d, 3H), 1.10 (s, 3H).

MS m/z(ESI):557.2[M+H]。MS m/z (ESI): 557.2 [M+H].

实施例10Example 10

[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H环戊二烯并[a]菲-3-基]1-乙酰哌啶-4-羧酸酯(化合物10)[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14, 15 decahydro-1H cyclopenta[a]phenanthr-3-yl]1-acetylpiperidine-4-carboxylate (Compound 10)

[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]1-acetylpiperidine-4-carboxylate[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro -1H-cyclopenta[a]phenanthren-3-yl]1-acetylpiperidine-4-carboxylate

向反应瓶中依次加入[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H-环戊二烯并[a]菲-3-基]哌啶-4-羧酸酯(化合物5)(1.38g，3mmol)、吡啶(1.42g，18mmol)和二氯甲烷(50mL)，室温下滴加乙酰氯(0.94g，12mmol)，室温反应0.5小时，体系加入水(100mL)，用二氯甲烷(100mL×3)萃取，有机相用无水硫酸镁干燥，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)＝1:1)得到得到白色固状[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H环戊二烯并[a]菲-3-基]1-乙酰哌啶-4-羧酸酯(化合物10)(1.2g，产率80％)。[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9 was sequentially added to the reaction flask. 11,12,14,15 decahydro-1H-cyclopenta[a]phenanthr-3-yl]piperidine-4-carboxylate (Compound 5) (1.38 g, 3 mmol), pyridine (1.42 g, 18 mmol) and dichloromethane (50 mL), acetyl chloride (0.94 g, 12 mmol) was added dropwise at room temperature, and reacted for 0.5 hour at room temperature. Water (100 mL) was added and extracted with dichloromethane (100 mL×3). The mixture was dried over MgSO.sub.4, filtered, evaporated, evaporated, evaporated. ,10R,13S,14S)-10,13-Dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15 decahydro-1H cyclopentane Dienyl[a]phenanthr-3-yl]1-acetylpiperidine-4-carboxylate (Compound 10) (1.2 g, yield 80%).

¹H NMR(400MHz,CDCl₃)δ8.62(s,1H),8.46(d,1H),7.66(d,1H),7.32–7.10(m,1H),6.00(dd,1H),5.42(d,1H),4.64(m,1H),4.39(d,1H),3.85–3.68(m,1H),3.14(m,1H),2.90–2.72(m,1H),2.51(m,1H),2.39–2.22(m,3H),2.13–2.08(m,4H),2.08-1.99(m,2H),1.97–1.81(m,4H),1.81–1.44(m,9H),1.29-1.33(m,2H),1.09(s,3H),1.05(s,3H)。 ^{_{1 H NMR (400MHz, CDCl 3}} ) δ8.62 (s, 1H), 8.46 (d, 1H), 7.66 (d, 1H), 7.32-7.10 (m, 1H), 6.00 (dd, 1H), 5.42 ( d, 1H), 4.64 (m, 1H), 4.39 (d, 1H), 3.85 - 3.68 (m, 1H), 3.14 (m, 1H), 2.90 - 2.72 (m, 1H), 2.51 (m, 1H) , 2.39–2.22 (m, 3H), 2.13–2.08 (m, 4H), 2.08-1.99 (m, 2H), 1.97–1.81 (m, 4H), 1.81–1.44 (m, 9H), 1.29-1.33 ( m, 2H), 1.09 (s, 3H), 1.05 (s, 3H).

MS m/z(ESI):503.4[M+H]。MS m/z (ESI): 503.4 [M+H].

实施例11Example 11

O4-[(3S，8R，9S，10R，13S，14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊[a]菲-3-基]O1异丙哌啶-1,4-二羧酸酯(化合物11)O4-[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12, 14,15-Decahydro-1H-cyclopenta[a]phenanthren-3-yl]O1 isopropionyl-1,4-dicarboxylate (Compound 11)

O4-[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]O1-isopropyl piperidine-1,4-dicarboxylateO4-[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15 -decahydro-1H-cyclopenta[a]phenanthren-3-yl]O1-isopropyl piperidine-1,4-dicarboxylate

向反应瓶中依次加入[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H-环戊二烯并[a]菲-3-基]哌啶-4-羧酸酯(化合物5)(0.45g，0.98mmol)、吡啶(0.233g，2.94mmol)和二氯甲烷(30mL)，室温下滴加氯甲酸异丙酯(0.24g，1.95mmol)，室温反应0.5小时，体系加入100mL水，用二氯甲烷(100mL×3)萃取，有机相用无水硫酸镁干燥，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)＝1:1)得到得到白色固状O4-[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊[a]菲-3-基]O1异丙哌啶-1,4-二羧酸酯(化合物11)(0.45g,产率88％)。[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9 was sequentially added to the reaction flask. 11,12,14,15 decahydro-1H-cyclopenta[a]phenanthr-3-yl]piperidine-4-carboxylate (Compound 5) (0.45 g, 0.98 mmol), pyridine (0.233 g) , 2.94 mmol) and dichloromethane (30 mL), isopropyl chloroformate (0.24 g, 1.95 mmol) was added dropwise at room temperature, and reacted at room temperature for 0.5 hour. The system was added with 100 mL of water and extracted with dichloromethane (100 mL×3). The organic phase was dried over anhydrous magnesium sulfate, filtered, evaporated, evaporated, evaporated, (3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15 - decahydro-1H-cyclopenta[a]phenanthren-3-yl]O1isopropylpiperidine-1,4-dicarboxylate (Compound 11) (0.45 g, yield 88%).

¹H NMR(400MHz,CDCl₃)δ8.62(d,1H),8.51–8.42(m,1H),7.68–7.58(m,1H),7.22(dd,1H),5.99(dd,1H),5.42(d,1H),4.91(m,1H),4.71–4.54(m,1H),4.04(d,2H),2.95–2.80(m,2H),2.43(m,1H),2.38–2.16(m,3H),2.14–1.99(m,3H),1.86(m,4H),1.81–1.42(m,10H),1.25(m,7H),1.08(s,3H),1.05(s,3H)。 ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.62 (d, 1H), 8.51 - 8.42 (m, 1H), 7.68 - 7.58 (m, 1H), 7.22 (dd, 1H), 5.99 (dd, 1H), 5.42 (d, 1H), 4.91 (m, 1H), 4.71 - 4.54 (m, 1H), 4.04 (d, 2H), 2.95 - 2.80 (m, 2H), 2.43 (m, 1H), 2.38 - 2.16 ( m, 3H), 2.14–1.99 (m, 3H), 1.86 (m, 4H), 1.81–1.42 (m, 10H), 1.25 (m, 7H), 1.08 (s, 3H), 1.05 (s, 3H) .

实施例12Example 12

O4-[(3S，8R，9S，10R，13S，14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊[a]菲-3-基]O1乙基哌啶-1,4-二羧酸酯(化合物12)O4-[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12, 14,15-Decahydro-1H-cyclopenta[a]phenanthren-3-yl]O1 ethylpiperidine-1,4-dicarboxylate (Compound 12)

O4-[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]O1-ethyl piperidine-1,4-dicarboxylateO4-[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15 -decahydro-1H-cyclopenta[a]phenanthren-3-yl]O1-ethyl piperidine-1,4-dicarboxylate

向反应瓶中依次加入[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H-环戊二烯并[a]菲-3-基]哌啶-4-羧酸酯(化合物5)(2.21g，4.8mmol)、吡啶(1.4g，14.4mmol)和二氯甲烷(50mL)，室温下滴加氯甲酸乙酯(1.04g，9.6mmol)，室温反应5小时，体系加入100mL水，用二氯甲烷(100mL×3)萃取，有机相用无水硫酸镁干燥，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)＝1:1)得到白色固状O4-[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15-十氢-1H-环戊[a]菲-3-基]O1乙基哌啶-1,4-二羧酸酯(化合物12)(2.1g，产率82％)。[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9 was sequentially added to the reaction flask. 11,12,14,15 decahydro-1H-cyclopenta[a]phenanthr-3-yl]piperidine-4-carboxylate (compound 5) (2.21 g, 4.8 mmol), pyridine (1.4 g , 14.4 mmol) and dichloromethane (50 mL), ethyl chloroformate (1.04 g, 9.6 mmol) was added dropwise at room temperature, and reacted at room temperature for 5 hours. The system was added with 100 mL of water and extracted with dichloromethane (100 mL×3). The organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was evaporated, evaporated, mjjjjjjjjjjjjj ,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-ten Hydrogen-1H-cyclopenta[a]phenanthren-3-yl]O1 ethylpiperidine-1,4-dicarboxylate (Compound 12) (2.1 g, yield 82%).

¹H NMR(400MHz,CDCl₃)δ8.62(s,1H),8.46(d,1H),7.65(d,1H),7.22(dd,1H),6.00(dd,1H),5.42(d,1H),4.63(m,1H),4.16-4.10(m,2H),4.07–3.96(m,2H),2.91(t,2H),2.43(m,1H),2.37–2.22(m,3H),2.12–2.00(m,3H),1.93–1.81(m,4H),1.80–1.38(m,9H),1.26(t,3H),1.22-1.10(m,2H),1.08(s,3H),1.05(s,3H)。 ^{_{1 H NMR (400MHz, CDCl 3}} ) δ8.62 (s, 1H), 8.46 (d, 1H), 7.65 (d, 1H), 7.22 (dd, 1H), 6.00 (dd, 1H), 5.42 (d, 1H), 4.63 (m, 1H), 4.16-4.10 (m, 2H), 4.07–3.96 (m, 2H), 2.91 (t, 2H), 2.43 (m, 1H), 2.37–2.22 (m, 3H) , 2.12–2.00 (m, 3H), 1.93–1.81 (m, 4H), 1.80–1.38 (m, 9H), 1.26 (t, 3H), 1.22-1.10 (m, 2H), 1.08 (s, 3H) , 1.05 (s, 3H).

MS m/z(ESI):533.3[M+H]。MS m/z (ESI): 533.3 [M+H].

实施例13Example 13

[(3S，8R，9S，10R，13S，14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H环戊二烯并[a]菲-3-基]1-(2-羟丙基)哌啶-4-羧酸酯(化合物13)[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14, 15 decahydro-1H cyclopenta[a]phenanthr-3-yl]1-(2-hydroxypropyl)piperidine-4-carboxylate (compound 13)

[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]1-(2-hydroxypropyl)piperidine-4-carboxylate[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro -1H-cyclopenta[a]phenanthren-3-yl]1-(2-hydroxypropyl)piperidine-4-carboxylate

向密封瓶中依次加入[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H-环戊二烯并[a]菲-3-基]哌啶-4-羧酸酯(化合物5)(0.16g，0.35mmol)、环氧丙烷(0.02g，0.35mmol)和乙醇(4mL)，90℃反应5小时，减压浓缩，残留物用硅胶柱色谱分离提纯(石油醚/二氯甲烷/甲醇(v/v/v)＝20:20:1)得到黄色固状[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H环戊二烯并[a]菲-3-基]1-(2-羟丙基)哌啶-4-羧酸酯(化合物13)(0.11g，产率60％)。[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9 was sequentially added to the sealed bottle. 11,12,14,15 decahydro-1H-cyclopenta[a]phenanthr-3-yl]piperidine-4-carboxylate (compound 5) (0.16 g, 0.35 mmol), propylene oxide ( 0.02 g, 0.35 mmol) and ethanol (4 mL) were reacted at 90 ° C for 5 hours, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography ( petroleum ether / methylene chloride / methanol (v / v / v) = 20:20 :1) A yellow solid is obtained [(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9 , 11, 12, 14, 15 decahydro-1H cyclopenta[a]phenanthr-3-yl]1-(2-hydroxypropyl)piperidine-4-carboxylate (Compound 13) (0.11 g , yield 60%).

¹H NMR(400MHz,CDCl₃)δ8.62(d,1H),8.46(dd,1H),7.64(m,1H),7.21(dd,1H),5.99(dd,1H),5.42(d,1H),4.72–4.56(m,1H),3.82(dd,1H),2.99(d,1H),2.77(d,1H),2.41–2.16(m,7H),2.13–1.96(m,4H),1.69(m,14H),1.23–1.15(m,1H),1.16–1.01(m,10H)。 ^{_{1 H NMR (400MHz, CDCl 3}} ) δ8.62 (d, 1H), 8.46 (dd, 1H), 7.64 (m, 1H), 7.21 (dd, 1H), 5.99 (dd, 1H), 5.42 (d, 1H), 4.72–4.56 (m, 1H), 3.82 (dd, 1H), 2.99 (d, 1H), 2.77 (d, 1H), 2.41–2.16 (m, 7H), 2.13–1.96 (m, 4H) , 1.69 (m, 14H), 1.23 - 1.15 (m, 1H), 1.16 - 1.01 (m, 10H).

MS m/z(ESI):260.1[M+2H/2]。MS m/z (ESI): 260.1 [M+2H/2].

实施例14Example 14

[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H-环戊[一]菲-3-基]1-乙基哌啶-4-羧酸酯(化合物14)[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14, 15 decahydro-1H-cyclopenta[1]phenanthr-3-yl]1-ethylpiperidine-4-carboxylate (compound 14)

[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]1-ethylpiperidine-4-carboxylate[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro -1H-cyclopenta[a]phenanthren-3-yl]1-ethylpiperidine-4-carboxylate

第一步：N-乙基-4-哌啶甲酸乙酯(14b)First step: ethyl N-ethyl-4-piperidinecarboxylate (14b)

1-ethyl-piperidine-4-carboxylic acid ethyl ester 1-ethyl-piperidine-4-carboxylic acid ethyl ester

向反应瓶中依次加入4-哌啶甲酸乙酯(14a)(4.72g，30mmol)、碘乙烷(5.15g，33mmol)和乙醇(100mL)，80℃反应16小时，过滤，将滤液减压浓缩，体系加入100mL水，用二氯甲烷(100mL×3)萃取，有机相用无水硫酸镁干燥，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/甲醇(v/v/v)＝5:5:1)得到黄色油状N-乙基-4-哌啶甲酸乙酯(14b)(3.8g，产率68％)。4-Piperidinecarboxylic acid ethyl ester (14a) (4.72g, 30mmol), ethyl iodide (5.15g, 33mmol) and ethanol (100mL) were added to the reaction flask, and reacted at 80 ° C for 16 hours, filtered, and the filtrate was decompressed. The mixture was concentrated, and the mixture was combined with EtOAc (EtOAc) (EtOAc) /Methanol (v/v/v) = 5:5:1) EtOAc (yield: 68%)

第二步：N-乙基-4-哌啶甲酸(14c)Second step: N-ethyl-4-piperidinecarboxylic acid (14c)

1-ethyl-piperidine-4-carboxylic acid1-ethyl-piperidine-4-carboxylic acid

向反应瓶中依次加入N-乙基-4-哌啶甲酸乙酯(14b)(3.8g，20mmol)、浓盐酸(39mL，468mmol)和水(20mL)，100℃反应8小时，减压浓缩，残留物用硅胶柱色谱分离提纯(石油醚/甲醇(v/v)＝5:1)得到黄色固体N-乙基-4-哌啶甲酸(14c)(2.5g，产率70％)。N-ethyl-4-piperidinecarboxylic acid ethyl ester (14b) (3.8 g, 20 mmol), concentrated hydrochloric acid (39 mL, 468 mmol) and water (20 mL) were added to the reaction mixture, and the mixture was reacted at 100 ° C for 8 hours. The residue was purified by silica gel column chromatography (EtOAc (EtOAc) (EtOAc)

第三步：[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H-环戊[一]菲-3-基]1-乙基哌啶-4-羧酸酯(化合物14)The third step: [(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11, 12,14,15 decahydro-1H-cyclopenta[1]phenanthr-3-yl]1-ethylpiperidine-4-carboxylate (compound 14)

向反应瓶中依次加入N-乙基-4-哌啶甲酸(14c)(0.71g，4.5mmol)、阿比特龙(1.05g，3mmol)、4-二甲氨基吡啶(DMAP)(0.11g,0.9mmol)、N,N-羰基二咪唑(EDCI)(1.73g,9.0mmol)和二氯甲烷(60mL)，室温反应5小时，体系加入100mL水，用二氯甲烷(100mL×3)萃取，有机相用无水硫酸镁干燥，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)＝5:1)得到得到白色固状的[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H-环戊[一]菲-3-基]1-乙基哌啶-4-羧酸酯(化合物14)(0.9g，产率61％)。 N-ethyl-4-piperidinecarboxylic acid (14c) (0.71 g, 4.5 mmol), abiraterone (1.05 g, 3 mmol), 4-dimethylaminopyridine (DMAP) (0.11 g, </ RTI> <RTIgt; The organic phase was dried over anhydrous magnesium sulfate (MgSO4), EtOAcjjjjjjjjj 3S,8R,9S,10R,13S,14S)-10,13-Dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15 Hydrogen-1H-cyclopenta[1]phenanthr-3-yl]1-ethylpiperidine-4-carboxylate (Compound 14) (0.9 g, yield 61%).

¹H NMR(400MHz,CDCl₃)δ8.62(d,1H),8.46(dd,1H),7.70–7.58(m,1H),7.21(ddd,1H),5.99(dd,1H),5.42(d,1H),4.76–4.50(m,1H),2.91(d,2H),2.50–2.37(m,2H),2.37–2.20(m,4H),2.171.43(m,18H),1.33-1.06(m,11H)。 ^{_{1 H NMR (400MHz, CDCl 3}} ) δ8.62 (d, 1H), 8.46 (dd, 1H), 7.70-7.58 (m, 1H), 7.21 (ddd, 1H), 5.99 (dd, 1H), 5.42 ( d,1H), 4.76–4.50 (m, 1H), 2.91 (d, 2H), 2.50–2.37 (m, 2H), 2.37–2.20 (m, 4H), 2.171.43 (m, 18H), 1.33 1.06 (m, 11H).

MS m/z(ESI):489.3[M+1]。MS m/z (ESI): 489.3 [M+].

实施例15Example 15

[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H-环戊[一]菲-3-基]1-(3-吡啶基)哌啶-4-羧酸酯(化合物15)[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14, 15 decahydro-1H-cyclopenta[1]phenanthr-3-yl]1-(3-pyridyl)piperidine-4-carboxylate (compound 15)

[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]1-(3-pyridyl)piperidine-4-carboxylate[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro -1H-cyclopenta[a]phenanthren-3-yl]1-(3-pyridyl)piperidine-4-carboxylate

第一步：1-吡啶基-3-哌啶-4-甲酸乙酯(15b)First step: 1-pyridyl-3-piperidine-4-carboxylic acid ethyl ester (15b)

1-pyridin-3-ylpiperidine-4-carboxylic acid ethyl ester1-pyridin-3-ylpiperidine-4-carboxylic acid ethyl ester

向反应瓶中依次加入4-哌啶甲酸乙酯(15a)(20g，127mmol)、溴苯(21.1g，133.5mmol)、叔丁醇钠(18.4g,191mmol)、1,1'-联萘-2,2'-双二苯膦(BINAP)(0.83g,13.3mmol)、三(二亚苄基茚丙酮)二钯(0.62g，0.68mmol)和二氧六环(300mL)，86℃反应6小时，减压浓缩，体系加入800mL二氯甲烷，饱和食盐水(600mL×1)洗涤，有机相用无水硫酸镁干燥，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)＝4:1)得到得到黄色油状的1-吡啶基-3-哌啶-4-甲酸乙酯(15b)(8.0g，产率26％)。 To the reaction flask were added 4-piperidinic acid ethyl ester (15a) (20 g, 127 mmol), bromobenzene (21.1 g, 133.5 mmol), sodium tert-butoxide (18.4 g, 191 mmol), 1,1'-binaphthyl. -2,2'-bisdiphenylphosphine (BINAP) (0.83 g, 13.3 mmol), tris(dibenzylidenefluoreneacetone) dipalladium (0.62 g, 0.68 mmol) and dioxane (300 mL), 86 ° C The reaction was carried out for 6 hours, and the mixture was evaporated to dryness. (Petroleum Ether/Ethyl acetate (v/v) = 4:1) gave 1-pyridyl-3-piperidine-4-carboxylic acid ethyl ester (15b) (8.0 g, yield 26%).

¹H NMR(400MHz,CDCl₃)δ8.31(d,1H),8.08(dd,1H),7.23–7.10(m,2H),4.16(q,2H),3.65(dt,2H),2.85(td,2H),2.46(ddd,1H),2.11–1.96(m,2H),1.94–1.78(m,2H),1.27(t,3H)。 ^{_{1 H NMR (400MHz, CDCl 3}} ) δ8.31 (d, 1H), 8.08 (dd, 1H), 7.23-7.10 (m, 2H), 4.16 (q, 2H), 3.65 (dt, 2H), 2.85 ( Td, 2H), 2.46 (ddd, 1H), 2.11 - 1.96 (m, 2H), 1.94 - 1.78 (m, 2H), 1.27 (t, 3H).

第二步：1-吡啶基-3-哌啶-4-甲酸(15c)Second step: 1-pyridyl-3-piperidine-4-carboxylic acid (15c)

1-pyridin-3-ylpiperidine-4-carboxylic acid1-pyridin-3-ylpiperidine-4-carboxylic acid

向反应瓶中依次加入1-吡啶基-3-哌啶-4-甲酸乙酯(15b)(4.36g，18.6mmol)、八水氢氧化钡(10.57g，33.5mmol)、乙醇(50ml)和水(40mL)，60℃反应2.5小时，减压浓缩，加水30mL，分批加入碳酸铵(7.3g，74.4mmol)，室温反应2小时。抽滤，将滤液减压浓缩得到黄色固体1-吡啶基-3-哌啶-4-甲酸(15c)(2.5g，产率66％)。To the reaction flask were added 1-pyridyl-3-piperidine-4-carboxylic acid ethyl ester (15b) (4.36 g, 18.6 mmol), cesium hydroxide octahydrate (10.57 g, 33.5 mmol), ethanol (50 ml) and Water (40 mL) was reacted at 60 ° C for 2.5 hours, concentrated under reduced pressure, and water (30 mL). After suction filtration, the filtrate was concentrated under reduced pressure to yield crystals crystals crystals crystals

¹H NMR(400MHz,DMSO)δ8.29(d,1H),7.96(dd,1H),7.31(ddd,1H),7.19(dd,1H),3.67(dt,2H),2.80(td,2H),2.37(tt,1H),2.03–1.80(m,2H),1.71–1.55(m,2H)。 ^{1 H NMR (400MHz, DMSO)} δ8.29 (d, 1H), 7.96 (dd, 1H), 7.31 (ddd, 1H), 7.19 (dd, 1H), 3.67 (dt, 2H), 2.80 (td, 2H ), 2.37 (tt, 1H), 2.03–1.80 (m, 2H), 1.71–1.55 (m, 2H).

第三步：[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H-环戊[一]菲-3-基]1-(3-吡啶基)哌啶-4-羧酸酯(化合物15)The third step: [(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11, 12,14,15 decahydro-1H-cyclopenta[1]phenanthr-3-yl]1-(3-pyridyl)piperidine-4-carboxylate (compound 15)

向反应瓶中依次加入1-吡啶基-3-哌啶-4-甲酸(15c)(2.06g，10mmol)、阿比特龙(3.5g，10mmol)、4-二甲氨基吡啶(DMAP)(0.37g,3.0mmol)、N,N-羰基二咪唑(EDCI)(5.75g,30mmol)和二氯甲烷(100mL)，室温反应8小时，体系加入100mL水，用二氯甲烷(100mL×3)萃取，有机相用无水硫酸镁干燥，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/二氯甲烷/甲醇(v/v/v)＝30:30:1)得到白色固状的[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H-环戊[一]菲-3-基]1-(3-吡啶基)哌啶-4-羧酸酯(化合物15)(3.7g，产率69％)。1-pyridyl-3-piperidine-4-carboxylic acid (15c) (2.06 g, 10 mmol), abiraterone (3.5 g, 10 mmol), 4-dimethylaminopyridine (DMAP) (0.37) were sequentially added to the reaction flask. g, 3.0 mmol), N,N-carbonyldiimidazole (EDCI) (5.75 g, 30 mmol) and dichloromethane (100 mL) were reacted at room temperature for 8 hours. The system was added with 100 mL of water and extracted with dichloromethane (100 mL×3) The organic phase was dried over anhydrous magnesium sulfate, filtered, and the filtrate was evaporated to dryness, and the residue was purified by silica gel column chromatography ( petroleum ether / methylene chloride / methanol (v / v / v) = 30:30:1) [(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11, white solid 12,14,15 decahydro-1H-cyclopenta[1]phenanthr-3-yl]1-(3-pyridyl)piperidine-4-carboxylate (Compound 15) (3.7 g, yield 69%) .

¹H NMR(400MHz,CDCl3)δ8.62(d,1H),8.46(dd,1H),8.31(d,1H),8.08(dd,1H), 7.64(dt,1H),7.24–7.07(m,3H),5.99(dd,1H),5.43(d,1H),4.66(tdd,1H),3.65(dt,2H),2.87(td,2H),2.45(ddd,1H),2.40–2.32(m,2H),2.27(ddd,1H),2.06(ddd,5H),1.94–1.81(m,4H),1.81–1.39(m,7H),1.22-1.10(m，2H),1.09(s,3H),1.05(s,3H)。 ^{1 H NMR (400MHz, CDCl3)} δ8.62 (d, 1H), 8.46 (dd, 1H), 8.31 (d, 1H), 8.08 (dd, 1H), 7.64 (dt, 1H), 7.24-7.07 (m , 3H), 5.99 (dd, 1H), 5.43 (d, 1H), 4.66 (tdd, 1H), 3.65 (dt, 2H), 2.87 (td, 2H), 2.45 (ddd, 1H), 2.40–2.32 ( m, 2H), 2.27 (ddd, 1H), 2.06 (ddd, 5H), 1.94 - 1.81 (m, 4H), 1.81 - 1.39 (m, 7H), 1.22-1.10 (m, 2H), 1.09 (s, 3H), 1.05 (s, 3H).

MS m/z(ESI):538.3[M+H]+。MS m/z (ESI): 538.3 [M+H]+.

实施例16Example 16

[(3S,8R,9S,10R,13S,14S)-10,13二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H-环戊[a]菲-3-基]1-(2-二甲氨基乙基)哌啶-4-羧酸酯(化合物16)[(3S,8R,9S,10R,13S,14S)-10,13 dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15 Decahydro-1H-cyclopenta[a]phenanthr-3-yl]1-(2-dimethylaminoethyl)piperidine-4-carboxylate (Compound 16)

[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]1-(2-dimethylaminoethyl)piperidine-4-carboxylate[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro -1H-cyclopenta[a]phenanthren-3-yl]1-(2-dimethylaminoethyl)piperidine-4-carboxylate

第一步：1-(2-二甲基氨基-乙基)-哌啶-4-羧酸乙酯(16b)First step: ethyl 1-(2-dimethylamino-ethyl)-piperidine-4-carboxylate (16b)

1-(2-dimethylamino-ethyl)-piperidine-4-carboxylic acid ethyl ester1-(2-dimethylamino-ethyl)-piperidine-4-carboxylic acid ethyl ester

向反应瓶中依次加入二甲氨基氯乙烷盐酸(14a)(2.88g，20mmol)、4-哌啶甲酸乙酯(1.57g，10mmol)、碳酸钠(2.12g,20mmol)和甲苯(30mL)，120℃反应16小时，过滤，将滤液减压浓缩，残留物用硅胶柱色谱分离提纯(二氯甲烷/甲醇(v/v)＝25:1)得到黄色油状的1-(2-二甲基氨基-乙基)-哌啶-4-羧酸乙酯(16b)(0.83g，产率36％)。Dimethylaminochloroethane hydrochloride (14a) (2.88 g, 20 mmol), 4-piperidinic acid ethyl ester (1.57 g, 10 mmol), sodium carbonate (2.12 g, 20 mmol) and toluene (30 mL) were sequentially added to the reaction flask. The reaction was carried out at 120 ° C for 16 hours, filtered, and the filtrate was concentrated under reduced pressure. mjjjjjjjjjjjjjjjj Ethylamino-ethyl)-piperidine-4-carboxylic acid ethyl ester (16b) (0.83 g, yield 36%).

¹H NMR(400MHz,CDCl₃)δ4.13(q,2H),2.89(dt,2H),2.51–2.36(m,4H),2.33–2.18(m,7H),2.04(td,2H),1.94–1.83(m,2H),1.83–1.70(m,2H),1.24(t,3H)。 ^{_{1 H NMR (400MHz, CDCl 3}} ) δ4.13 (q, 2H), 2.89 (dt, 2H), 2.51-2.36 (m, 4H), 2.33-2.18 (m, 7H), 2.04 (td, 2H), 1.94–1.83 (m, 2H), 1.83–1.70 (m, 2H), 1.24 (t, 3H).

第二步：1-(2-二甲基氨基-乙基)-哌啶-4-羧酸(16c)Second step: 1-(2-dimethylamino-ethyl)-piperidine-4-carboxylic acid (16c)

1-(2-dimethylamino-ethyl)-piperidine-4-carboxylicacid 1-(2-dimethylamino-ethyl)-piperidine-4-carboxylic acid

向反应瓶中依次加入1-(2-二甲基氨基-乙基)-哌啶-4-羧酸乙酯(16b)(3.3g，14.4mmol)、八水氢氧化钡(8.19g，26mmol)、乙醇(50ml)和水(40mL)，60℃反应2.5小时，减压浓缩，加水30mL，分批加入碳酸铵(7.3g，74.4mmol)，室温反应2小时。抽滤，将滤液减压浓缩得到黄色固体1-(2-二甲基氨基-乙基)-哌啶-4-羧酸(16c)(2.5g，产率87％)。Ethyl 1-(2-dimethylamino-ethyl)-piperidine-4-carboxylate (16b) (3.3 g, 14.4 mmol) and cesium hydroxide octahydrate (8.19 g, 26 mmol) were added to the reaction flask. Ethanol (50 ml) and water (40 mL) were reacted at 60 ° C for 2.5 hours, concentrated under reduced pressure, and water (30 mL) was added, and ammonium carbonate (7.3 g, 74.4 mmol) was added portionwise, and reacted at room temperature for 2 hours. After suction filtration, the filtrate was concentrated under reduced pressure toieldield, m,jjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj

第三步：[(3S，10R，13S)-10,13二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H-环戊[a]菲-3-基]1-(2-二甲氨基乙基)哌啶-4-羧酸酯(化合物16)The third step: [(3S,10R,13S)-10,13 dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15 decahydrogen -1H-cyclopenta[a]phenanthr-3-yl]1-(2-dimethylaminoethyl)piperidine-4-carboxylate (Compound 16)

向反应瓶中依次加入1-(2-二甲基氨基-乙基)-哌啶-4-羧酸(16c)(2.0g，10mmol)、阿比特龙(3.5g，10mmol)、4-二甲氨基吡啶(DMAP)(0.37g,3.0mmol)、N,N-羰基二咪唑(EDCI)(5.75g,30mmol)和二氯甲烷(100mL)，室温反应8小时，体系加入100mL水，用二氯甲烷(100mL×3)萃取，有机相用无水硫酸镁干燥，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/二氯甲烷/甲醇(v/v/v)＝30:30:1)得到白色固状的[(3S,8R,9S,10R,13S,14S)-10,13二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H-环戊[a]菲-3-基]1-(2-二甲氨基乙基)哌啶-4-羧酸酯(化合物16)(2.2g，产率41％)。To the reaction flask were added 1-(2-dimethylamino-ethyl)-piperidine-4-carboxylic acid (16c) (2.0 g, 10 mmol), abiraterone (3.5 g, 10 mmol), 4-di. Methylaminopyridine (DMAP) (0.37 g, 3.0 mmol), N,N-carbonyldiimidazole (EDCI) (5.75 g, 30 mmol) and dichloromethane (100 mL) were reacted at room temperature for 8 hours, and the system was added with 100 mL of water. The mixture was extracted with chloroform (100 mL×3). =30:30:1)[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7 was obtained as a white solid. ,8,9,11,12,14,15 decahydro-1H-cyclopenta[a]phenanthr-3-yl]1-(2-dimethylaminoethyl)piperidine-4-carboxylate (Compound 16 (2.2 g, yield 41%).

¹H NMR(400MHz,CDCl3)δ8.62(d,1H),8.45(dd,1H),7.64(dt,1H),7.21(dd,1H),6.04–5.94(m,1H),5.41(d,1H),4.73–4.51(m,1H),2.55–2.40(m,4H),2.35–2.19(m,10H),2.11–1.99(m,7H),1.94–1.54(m,13H),1.28–1.09(m,2H),1.08(s,3H),1.04(s,3H)。 ^{1 H NMR (400MHz, CDCl3)} δ8.62 (d, 1H), 8.45 (dd, 1H), 7.64 (dt, 1H), 7.21 (dd, 1H), 6.04-5.94 (m, 1H), 5.41 (d , 1H), 4.73–4.51 (m, 1H), 2.55–2.40 (m, 4H), 2.35–2.19 (m, 10H), 2.11–1.99 (m, 7H), 1.94–1.54 (m, 13H), 1.28 –1.09 (m, 2H), 1.08 (s, 3H), 1.04 (s, 3H).

MS m/z(ESI):532.5[M+1]。MS m/z (ESI): 532.5 [M + 1].

实施例17Example 17

[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H环戊二烯并[a]菲-3-基]1-(2-氟乙基)哌啶-4-羧酸乙酯盐酸盐(化合物17) [(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14, 15 decahydro-1H cyclopenta[a]phenanthr-3-yl]1-(2-fluoroethyl)piperidine-4-carboxylic acid ethyl ester hydrochloride (Compound 17)

[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]1-(2-fluoroethyl)piperidine-4-carboxylate hydrochloride[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro -1H-cyclopenta[a]phenanthren-3-yl]1-(2-fluoroethyl)piperidine-4-carboxylate hydrochloride

第一步：[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H环戊二烯并[a]菲-3-基]1-(2-氟乙基)哌啶-4-羧酸乙酯(化合物17b)First step: [(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11, 12,14,15 decahydro-1H cyclopenta[a]phenanthr-3-yl]1-(2-fluoroethyl)piperidine-4-carboxylic acid ethyl ester (compound 17b)

[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]1-(2-fluoroethyl)piperidine-4-carboxylate[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro -1H-cyclopenta[a]phenanthren-3-yl]1-(2-fluoroethyl)piperidine-4-carboxylate

向反应瓶中依次加入[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H-环戊二烯并[a]菲-3-基]哌啶-4-羧酸酯(化合物5)(1.61g，3.5mmol)、1-溴-2-氟乙烷(2.22g，17.5mmol)碳酸钾(2.9g，21mmol)和丙酮(30mL)，回流反应6小时，体系加入100mL水，用二氯甲烷(100mL×3)萃取，有机相用无水硫酸镁干燥，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)＝1:1)得到得到褐色固状[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H环戊二烯并[a]菲-3-基]1-(2-氟乙基)哌啶-4-羧酸乙酯(化合物17b)(0.38g，产率20％)。[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9 was sequentially added to the reaction flask. 11,12,14,15 decahydro-1H-cyclopenta[a]phenanthr-3-yl]piperidine-4-carboxylate (Compound 5) (1.61 g, 3.5 mmol), 1-bromo- 2-Fluoroethane (2.22 g, 17.5 mmol) potassium carbonate (2.9 g, 21 mmol) and acetone (30 mL), refluxed for 6 hrs, then 100 mL water was added and extracted with dichloromethane (100 mL×3). The residue was dried over anhydrous magnesium sulfate (MgSO4) 9S,10R,13S,14S)-10,13-Dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15 decahydro-1H ring Ethylpenta[a]phenanthr-3-yl]1-(2-fluoroethyl)piperidine-4-carboxylate (Compound 17b) (0.38 g, yield 20%).

¹H NMR(400MHz,MeOD)δ8.87(s,1H),8.72(d,1H),8.65(d,1H),8.05(dd,1H),6.50(dd,1H),5.48(d,1H),4.94(d,1H),4.62(d,1H),3.72(d,2H),3.63–3.47(m,2H),3.16(t,2H),2.70(s,1H),2.42(ddd,3H),2.34–2.20(m,3H),2.20–2.06(m,3H),2.03–1.82(m,5H),1.82–1.51(m,6H),1.23(dt,2H),1.17(s,3H),1.16(s,3H)。 ^{1 H NMR (400MHz, MeOD)} δ8.87 (s, 1H), 8.72 (d, 1H), 8.65 (d, 1H), 8.05 (dd, 1H), 6.50 (dd, 1H), 5.48 (d, 1H ), 4.94 (d, 1H), 4.62 (d, 1H), 3.72 (d, 2H), 3.63 - 3.47 (m, 2H), 3.16 (t, 2H), 2.70 (s, 1H), 2.42 (ddd, 3H), 2.34–2.20 (m, 3H), 2.20–2.06 (m, 3H), 2.03–1.82 (m, 5H), 1.82–1.51 (m, 6H), 1.23 (dt, 2H), 1.17 (s, 3H), 1.16 (s, 3H).

MS m/z(ESI):507.2[M+H]。 MS m/z (ESI): 507.2 [M+H].

第二步：[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H环戊二烯并[a]菲-3-基]1-(2-氟乙基)哌啶-4-羧酸乙酯盐酸盐(化合物17)Second step: [(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11, 12,14,15 decahydro-1H cyclopenta[a]phenanthr-3-yl]1-(2-fluoroethyl)piperidine-4-carboxylic acid ethyl ester hydrochloride (Compound 17)

[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]1-(2-fluoroethyl)piperidine-4-carboxylatehydrochloride[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro -1H-cyclopenta[a]phenanthren-3-yl]1-(2-fluoroethyl)piperidine-4-carboxylatehydrochloride

向反应瓶中依次加入[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H环戊二烯并[a]菲-3-基]1-(2-氟乙基)哌啶-4-羧酸乙酯(17b)(0.38g，0.75mmol)盐酸乙酸乙酯溶液(4N，10mL，40mmol)，室温反应1小时，过滤，滤饼用乙酸乙酯(5mL×2)洗，得到白色固状[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H环戊二烯并[a]菲-3-基]1-(2-氟乙基)哌啶-4-羧酸乙酯盐酸盐(化合物17)(0.35g，产率86％)。[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9 was sequentially added to the reaction flask. 11,12,14,15 decahydro-1H cyclopenta[a]phenanthr-3-yl]1-(2-fluoroethyl)piperidine-4-carboxylic acid ethyl ester (17b) (0.38 g, 0.75 mmol) ethyl acetate solution (4N, 10 mL, 40 mmol),jjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjs 13S,14S)-10,13-Dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15 decahydro-1H cyclopentadiene [a]Phenanthren-3-yl]1-(2-fluoroethyl)piperidine-4-carboxylic acid ethyl ester hydrochloride (Compound 17) (0.35 g, yield 86%).

MS m/z(ESI):507.2[M+H]。MS m/z (ESI): 507.2 [M+H].

实施例18Example 18

[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H环戊二烯并[a]菲-3-基]1-甲基磺酰哌啶-4-羧酸酯(化合物18)[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14, 15 decahydro-1H cyclopenta[a]phenanthren-3-yl]1-methylsulfonylpiperidine-4-carboxylate (compound 18)

[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]1-methylsulfonylpiperidine-4-carboxylate[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro -1H-cyclopenta[a]phenanthren-3-yl]1-methylsulfonylpiperidine-4-carboxylate

向反应瓶中依次加入[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H-环戊二烯并[a]菲-3-基]哌啶-4-羧酸酯(化合物5)(1.38g，3mmol)、甲基磺酰氯(0.29g，3.6mmol)、吡啶(0.36g，4.5mmol)和二氯甲烷(50mL)，室温反应6小时，体系加入100mL水，用二氯甲烷(100mL×3)萃取，有机相用无水硫酸镁干燥，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)＝1:1)得到白色固状[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H环戊二烯并[a]菲-3-基]1-甲基磺酰哌啶-4-羧酸酯(化合物18)(1.4g，产率87％)。[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9 was sequentially added to the reaction flask. 11,12,14,15 decahydro-1H-cyclopenta[a]phenanthr-3-yl]piperidine-4-carboxylate (compound 5) (1.38 g, 3 mmol), methanesulfonyl chloride ( 0.29g, 3.6mmol), pyridine (0.36g, 4.5mmol) and dichloromethane (50mL), reacted at room temperature for 6 hours, the system was added to 100mL of water, extracted with dichloromethane (100mL × 3), the organic phase with anhydrous sulfuric acid The magnesium was dried, filtered, and the filtrate was concentrated under reduced pressure. mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj 13S,14S)-10,13-Dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15 decahydro-1H cyclopentadiene [a]phenanthren-3-yl]1-methylsulfonylpiperidine-4-carboxylate (Compound 18) (1.4 g, yield 87%).

¹H NMR(400MHz,DMSO)δ8.63(d,1H),8.48(d,1H),7.85(d,1H),7.41(dd,1H),6.17(s,1H),5.41(d,1H),4.52(dd,1H),3.48(dd,3H),3.43–3.10(m,3H),2.86(s,2H),2.84–2.76(m,2H),2.49–2.42(m,1H),2.36–2.18(m,3H),2.14–1.98(m,3H),1.98–1.35(m,12H),1.06(s,3H),1.04(s,3H)。 ^{1 H NMR (400MHz, DMSO)} δ8.63 (d, 1H), 8.48 (d, 1H), 7.85 (d, 1H), 7.41 (dd, 1H), 6.17 (s, 1H), 5.41 (d, 1H ), 4.52 (dd, 1H), 3.48 (dd, 3H), 3.43–3.10 (m, 3H), 2.86 (s, 2H), 2.84–2.76 (m, 2H), 2.49–2.42 (m, 1H), 2.36–2.18 (m, 3H), 2.14–1.98 (m, 3H), 1.98–1.35 (m, 12H), 1.06 (s, 3H), 1.04 (s, 3H).

MS m/z(ESI):539.2[M+H]。MS m/z (ESI): 539.2 [M+H].

实施例19Example 19

[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H环戊二烯并[a]菲-3-基]1-环丙基磺酰基哌啶-4-羧酸酯(化合物19)[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14, 15 decahydro-1H cyclopenta[a]phenanthr-3-yl]1-cyclopropylsulfonylpiperidine-4-carboxylate (Compound 19)

[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]1-cyclopropylsulfonylpiperidine-4-carboxylate[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro -1H-cyclopenta[a]phenanthren-3-yl]1-cyclopropylsulfonylpiperidine-4-carboxylate

向反应瓶中依次加入[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H-环戊二烯并[a]菲-3-基]哌啶-4-羧酸酯(化合物5)(2.21g，4.8mmol)、环丙基磺酰氯(2.7g，19.2mmol)、吡啶(2.28g，28.8mmol)和二氯甲烷(60mL)，室温反应10小时，体系加入100mL水，用二氯甲烷(100mL×3)萃取，有机相用无水硫酸镁干燥，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)＝1:1)得到得到白色固状[(3S，8R，9S，10R，13S，14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H环戊二烯并[a]菲-3-基]1-环丙基磺酰基哌啶-4-羧酸酯(化合物19)(1.2g，产率44％)。[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9 was sequentially added to the reaction flask. 11,12,14,15 decahydro-1H-cyclopenta[a]phenanthr-3-yl]piperidine-4-carboxylate (compound 5) (2.21 g, 4.8 mmol), cyclopropylsulfonate The acid chloride (2.7 g, 19.2 mmol), pyridine (2.28 g, 28.8 mmol) and dichloromethane (60 mL) were reacted at room temperature for 10 hours. The system was added with 100 mL of water and extracted with dichloromethane (100 mL×3). The mixture was dried over MgSO.sub.4, filtered, evaporated, evaporated, evaporated. ,10R,13S,14S)-10,13-Dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15 decahydro-1H cyclopentane Dienyl[a]phenanthren-3-yl]1-cyclopropylsulfonylpiperidine-4-carboxylate (Compound 19) (1.2 g, yield 44%).

¹H NMR(400MHz,CDCl₃)δ8.62(s,1H),8.47(d,1H),7.68(d,1H),7.26–7.22(m,1H),6.01(dd,1H),5.43(d,1H),4.64(ddd,1H),3.71(dt,2H),3.05–2.90(m,2H),2.48–2.38(m,1H),2.38–2.20(m,4H),2.15–1.93(m,6H),1.93–1.41(m,12H),1.17(dd,2H),1.09(s,3H),1.05(s,3H),1.01–0.93(m,2H)。 ^{_{1 H NMR (400MHz, CDCl 3}} ) δ8.62 (s, 1H), 8.47 (d, 1H), 7.68 (d, 1H), 7.26-7.22 (m, 1H), 6.01 (dd, 1H), 5.43 ( d, 1H), 4.64 (ddd, 1H), 3.71 (dt, 2H), 3.05–2.90 (m, 2H), 2.48–2.38 (m, 1H), 2.38–2.20 (m, 4H), 2.15–1.93 ( m, 6H), 1.93 - 1.41 (m, 12H), 1.17 (dd, 2H), 1.09 (s, 3H), 1.05 (s, 3H), 1.01 - 0.93 (m, 2H).

MS m/z(ESI):565.3[M+H]。MS m/z (ESI): 565.3 [M+H].

实施例20Example 20

[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H-环戊[一]菲-3-基]1-(环丙基甲基)哌啶-4-羧酸酯(化合物20)[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14, 15 decahydro-1H-cyclopenta[1]phenanthr-3-yl]1-(cyclopropylmethyl)piperidine-4-carboxylate (compound 20)

[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]1-(cyclopropylmethyl)piperidine-4-carboxylate[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro -1H-cyclopenta[a]phenanthren-3-yl]1-(cyclopropylmethyl)piperidine-4-carboxylate

第一步：1-(环丙基甲基)哌啶-4-羧酸(20b)First step: 1-(cyclopropylmethyl)piperidine-4-carboxylic acid (20b)

1-(cyclopropylmethyl)piperidine-4-carboxylate1-(cyclopropylmethyl)piperidine-4-carboxylate

向反应瓶中依次加入4-哌啶甲酸(20a)(1.29g，10mmol)、环丙甲醛(4.2g，60mmol)、Pd/C(0.26g)和甲醇(30mL)，氢气氛下室温反应42小时，过滤，将滤液减压浓缩，残留物用硅胶柱色谱分离提纯(二氯甲烷/甲醇(v/v)＝1:1)得到得到淡黄色油状1-(环丙基甲基)哌啶-4-羧酸(20b)(1.6g，产率87％)。4-piperidinecarboxylic acid (20a) (1.29 g, 10 mmol), cyclopropionaldehyde (4.2 g, 60 mmol), Pd/C (0.26 g) and methanol (30 mL) were sequentially added to the reaction flask, and reacted at room temperature under a hydrogen atmosphere. The filtrate was concentrated under reduced pressure. The residue was purified (jjjjjjlili 4-carboxylic acid (20b) (1.6 g, yield 87%).

¹H NMR(400MHz,MeOD)δ3.37–3.20(m,2H),2.90–2.78(m,2H),2.76(d,2H),2.20(dd,1H),1.90(dd,2H),1.75(d,2H),0.97–0.82(m,1H),0.61–0.47(m,2H),0.24–0.15(m,2H)。 ^{1 H NMR (400MHz, MeOD)} δ3.37-3.20 (m, 2H), 2.90-2.78 (m, 2H), 2.76 (d, 2H), 2.20 (dd, 1H), 1.90 (dd, 2H), 1.75 (d, 2H), 0.97 - 0.82 (m, 1H), 0.61 - 0.47 (m, 2H), 0.24 - 0.15 (m, 2H).

第二步：[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H-环戊[a]菲-3-基]1-(环丙基甲基)哌啶-4-羧酸酯(化合物20)Second step: [(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11, 12,14,15 decahydro-1H-cyclopenta[a]phenanthr-3-yl]1-(cyclopropylmethyl)piperidine-4-carboxylate (compound 20)

向反应瓶中依次加入1-(环丙基甲基)哌啶-4-羧酸(20b)(1.47g，8mmol)、阿比特龙(1.4g，4mmol)、4-二甲氨基吡啶(DMAP)(0.25g,2.0mmol)、N,N-羰基二咪唑(EDCI)(3.3g,16mmol)和二氯甲烷(100mL)，室温反应5小时，体系加入100mL水，用二氯甲烷(100mL×3)萃取，有机相用无水硫酸镁干燥，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/甲醇(v/v/v)＝50:50:1)得到得到白色固状的[(3S,8R,9S,10R,13S,14S)-10,13-二甲基-17-(3-吡啶基)-2,3,4,7,8,9,11,12,14,15十氢-1H-环戊[a]菲-3-基]1-(环丙基甲基)哌啶-4-羧酸酯(化合物20)(0.56g，产率28％)。 1-(cyclopropylmethyl)piperidine-4-carboxylic acid (20b) (1.47 g, 8 mmol), abiraterone (1.4 g, 4 mmol), 4-dimethylaminopyridine (DMAP) were sequentially added to the reaction flask. (0.25g, 2.0mmol), N,N-carbonyldiimidazole (EDCI) (3.3g, 16mmol) and dichloromethane (100mL), reacted at room temperature for 5 hours, the system was added 100mL water, with dichloromethane (100mL × 3) Extraction, the organic phase was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography ( petroleum ether / ethyl acetate / methanol (v / v / v) = 50:50: 1) Obtaining [(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8, which is obtained as a white solid. 9,11,12,14,15 decahydro-1H-cyclopenta[a]phenanthren-3-yl]1-(cyclopropylmethyl)piperidine-4-carboxylate (Compound 20) (0.56 g, Yield 28%).

¹H NMR(400MHz,CDCl₃)δ8.62(d,1H),8.46(dd,1H),7.69–7.58(m,1H),7.21(dd,1H),5.99(dd,1H),5.42(d,1H),4.70–4.56(m,1H),3.02(d,2H),2.43–2.17(m,6H),2.10-2.03(m,5H),1.99–1.42(m,13H),1.23–1.10(m,2H),1.08(s,3H),1.05(s,3H),0.92-0.86(m,1H),0.53-0.51(m,2H),0.11-0.10(m,2H)。 ^{_{1 H NMR (400MHz, CDCl 3}} ) δ8.62 (d, 1H), 8.46 (dd, 1H), 7.69-7.58 (m, 1H), 7.21 (dd, 1H), 5.99 (dd, 1H), 5.42 ( d, 1H), 4.70–4.56 (m, 1H), 3.02 (d, 2H), 2.43–2.17 (m, 6H), 2.10-2.03 (m, 5H), 1.99–1.42 (m, 13H), 1.23– 1.10 (m, 2H), 1.08 (s, 3H), 1.05 (s, 3H), 0.92 - 0.86 (m, 1H), 0.53 - 0.51 (m, 2H), 0.11 - 0.10 (m, 2H).

MS m/z(ESI):515.3[M+1]。MS m/z (ESI): 515.3 [M+1].

生物测试例Biological test case

1、大鼠药代动力学实验1. Rat pharmacokinetic experiments

雄性SD大鼠(购自北京维通利华实验动物中心，动物生产许可证号SCXK(京)2012-0001)180-220g，禁食给水过夜，3只大鼠口服灌胃100mg/kg(以阿比特龙原形药物计)。于给药前及给药后30分钟,1.0,2.0,4.0,6.0,8.0,12.0,24.0h由眼眶采血0.1ml，肝素抗凝，4℃3000rpm离心10分钟后分离血浆，于-80℃保存。取各时间点大鼠血浆30μL，加入内标含维拉帕米7.5ng/的乙腈溶液800μL混合后，涡旋混合1.5分钟，13000转/分钟离心10分钟，取上清液10μL进行LC-MS/MS(AB SCIEX公司，API4000+)分析。主要药代动力学参数用WinNonlin 6.3软件非房室模型分析。测试结果见表1。Male SD rats (purchased from Beijing Weitong Lihua Experimental Animal Center, animal production license number SCXK (Beijing) 2012-0001) 180-220g, fasting water supply overnight, 3 rats orally administered 100mg/kg (to Abitrone prototype drug meter). Before administration and 30 minutes after administration, 1.0, 2.0, 4.0, 6.0, 8.0, 12.0, 24.0 h, 0.1 ml of blood was collected from the eyelids, and heparin was anticoagulated. After centrifugation at 3000 ° C for 10 minutes at 4 ° C, the plasma was separated and stored at -80 ° C. . Take 30 μL of rat plasma at each time point, add 800 μL of acetonitrile solution containing 7.5 ng of verapamil, and mix with vortex for 1.5 minutes, centrifuge at 13000 rpm for 10 minutes, and take 10 μL of supernatant for LC-MS. /MS (AB SCIEX, API4000+) analysis. The main pharmacokinetic parameters were analyzed using the WinNonlin 6.3 software non-compartmental model. The test results are shown in Table 1.

表1大鼠药代动力学实验结果Table 1 results of rat pharmacokinetic experiments

结论：本发明化合物具有良好的药代动力学特征。Conclusion: The compounds of the invention have good pharmacokinetic characteristics.

2、猴药代动力学实验2, monkey pharmacokinetics experiment

健康雄性恒河猴，3～5kg，适应观察5天后禁食给水过夜，胶囊口服给药醋酸阿比特龙50mg/kg或实施例化合物50mg/kg、20mg/kg、10mg/kg(以阿比特龙原形药物计)，给药后5小时给食。于给药前及给药后15分钟，30分钟,1.0,2.0,4.0,6.0,8.0,12.0,24.0小时以肝素抗凝真空采血管静脉采血0.5ml，4℃ 3000rpm离心10分钟后分离血浆，于-80℃保存。各时刻血浆样品经乙腈沉淀蛋白处理后，进行LC-MS/MS(AB SCIEX公司，API4000+)分析，WinNonlin 6.3(Pharsight公司)软件非房室模型计算主要药动学参数。测试结果见表2。Healthy male rhesus monkey, 3 ~ 5kg, fasted to feed water overnight after 5 days of observation, oral administration of abiraterone acetate 50mg/kg or example compound 50mg/kg, 20mg/kg, 10mg/kg (with abiraterone) The original drug count) was fed 5 hours after administration. Before the administration and 15 minutes after the administration, 30 minutes, 1.0, 2.0, 4.0, 6.0, 8.0, 12.0, 24.0 hours, 0.5 ml of blood was collected by heparin anticoagulation vacuum blood collection tube, and the plasma was separated by centrifugation at 3000 ° C for 10 minutes at 4 ° C. Store at -80 °C. Plasma samples were treated with acetonitrile precipitation protein at each time, and analyzed by LC-MS/MS (AB SCIEX, API4000+), and the main pharmacokinetic parameters were calculated by WinNonlin 6.3 (Pharsight) software non-compartment model. The test results are shown in Table 2.

表2猴药代动力学实验结果Table 2 monkey pharmacokinetics experimental results

结论：在50mg/kg的剂量下，化合物4和化合物20的暴露量大约分别是醋酸阿比特龙的9倍和4倍，特别是化合物4，在给药剂量仅为醋酸阿比特龙的1/5、2/5的剂量下，暴露量仍高于醋酸阿比特龙，约分别为醋酸阿比特龙的1.6倍和3倍，表明本发明化合物与醋酸阿比特龙相比具有更好的生物利用度。 Conclusion: At the dose of 50 mg/kg, the exposure of compound 4 and compound 20 is about 9 times and 4 times that of abiraterone acetate, especially compound 4, and the dose is only 1/bit of abiraterone acetate. At the doses of 5 and 2/5, the exposure was still higher than that of abiraterone acetate, which was about 1.6 times and 3 times that of abiraterone acetate, respectively, indicating that the compound of the present invention has better bioavailability than abiraterone acetate. degree.

Claims

一种通式(I)所示化合物及其立体异构体或药学上可接受的盐，a compound of the formula (I): and a stereoisomer or pharmaceutically acceptable salt thereof,

其中：A选自-R^A-R¹；R^A为C(＝O)；Wherein: A is selected from -R ^A -R ¹ ; R ^A is C(=O);

R¹选自3至10元杂环，且当杂环为饱和环时，与R^A相连接的原子为杂环上的碳原子，所述的杂环任选进一步被0至4个选自F、Cl、Br、I、OH、NH₂、-(CH₂)₂N(C_1-4烷基)₂、-NHC(＝O)C_1-4烷氧基、C(＝O)C_1-4烷氧基、C(＝O)R^1h、S(＝O)₂R^1h、R^1h或4至6元杂环的取代基所取代，所述的杂环含有1至4个选自N、O或S的杂原子；R ^{1 is} selected from a 3- to 10-membered heterocyclic ring, and when the heterocyclic ring is a saturated ring, the atom bonded to R ^A is a carbon atom on the hetero ring, and the heterocyclic ring is optionally further selected from 0 to 4 F, Cl, Br, I, OH, NH ₂ , -(CH ₂ ) ₂ N(C _1-4 alkyl) ₂ , -NHC(=O)C _1-4 alkoxy, C(=O)C Substituted by a substituent of a _1-4 alkoxy group, C(=O)R ^1h , S(=O) ₂ R ^1h , R ^1h or a 4 to 6 membered heterocyclic ring containing 1 to 4 selected a hetero atom from N, O or S;

R^1h各自独立的选自C_1-4烷基、C_1-4烷基-NH₂、C_1-4烷氧基或C_3-6碳环，所述的NH₂、烷基、烷氧基和碳环任选进一步被0至4个选自F、Cl、Br、I、OH、C_1-4烷基、C_1-4烷氧基或C_3-6碳环的取代基所取代。R ^{1h is} independently selected from C _1-4 alkyl, C _1-4 alkyl-NH ₂ , C _1-4 alkoxy or C _3-6 carbocyclic ring, said NH ₂ , alkyl, alkoxy The base and carbocyclic ring are optionally further substituted with from 0 to 4 substituents selected from the group consisting of F, Cl, Br, I, OH, C _1-4 alkyl, C _1-4 alkoxy or C _3-6 carbocyclic .
根据权利要求1所述的化合物及其立体异构体或药学上可接受的盐，The compound according to claim 1 and a stereoisomer or pharmaceutically acceptable salt thereof,

R¹选自5至8元杂环，且当杂环为饱和环时，与R^A相连接的原子为杂环上的碳原子，所述的杂环任选进一步被0至4个选自F、Cl、Br、I、OH、NH₂、-(CH₂)₂N(C_1-4烷基)₂、NHC(＝O)C_1-4烷氧基、C(＝O)C_1-4烷氧基、C(＝O)R^1h、S(＝O)₂R^1h、R^1h或4至6元杂环的取代基所取代，所述的杂环含有1至4个选自N、O或S的杂原子；R ^{1 is} selected from a 5- to 8-membered heterocyclic ring, and when the heterocyclic ring is a saturated ring, the atom bonded to R ^A is a carbon atom on the hetero ring, and the heterocyclic ring is optionally further selected from 0 to 4 F, Cl, Br, I, OH, NH ₂ , -(CH ₂ ) ₂ N(C _1-4 alkyl) ₂ , NHC(=O)C _1-4 alkoxy, C(=O)C ₁ Substituted by a substituent of _-4 alkoxy, C(=O)R ^1h , S(=O) ₂ R ^1h , R ^1h or a 4 to 6 membered heterocyclic ring containing from 1 to 4 selected from 1 to 4 a hetero atom of N, O or S;

R^1h各自独立的选自C_1-4烷基、C_1-4烷氧基、C_1-4烷基-NH₂或C_3-6碳环，所述的烷基、NH₂、烷氧基和碳环任选进一步被0至4个选自F、Cl、Br、OH、甲基、乙基、异丙基、甲氧基、乙氧基、异丙氧基、环丙基、环丁基或环戊基的取代基所取代。R ^{1h is} independently selected from C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkyl-NH ₂ or C _3-6 carbocyclic ring, said alkyl group, NH ₂ , alkoxy group The base and carbocyclic ring are optionally further selected from 0 to 4 selected from the group consisting of F, Cl, Br, OH, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, and ring. Substituted by a butyl or cyclopentyl substituent.
根据权利要求2所述的化合物及其立体异构体或药学上可接受的盐，其中：A compound according to claim 2 and a stereoisomer or pharmaceutically acceptable salt thereof, wherein:

R¹选自5至6元杂环，且当杂环为饱和环时，与R^A相连接的原子为杂环上的碳原子，所述的杂环任选进一步被0至4个选自NH₂、-(CH₂)₂N(CH₃)₂、-NHC(＝O)OC(CH₃)₃、-C(＝O)OC(CH₃)₃、C(＝O)R^1h、S(＝O)₂R^1h、R^1h、吡啶或氮杂五元环的取代基所取代；R ^{1 is} selected from a 5- to 6-membered heterocyclic ring, and when the heterocyclic ring is a saturated ring, the atom bonded to R ^A is a carbon atom on the hetero ring, and the heterocyclic ring is optionally further selected from 0 to 4 NH ₂ , -(CH ₂ ) ₂ N(CH ₃ ) ₂ , -NHC(=O)OC(CH ₃ ) ₃ , -C(=O)OC(CH ₃ ) ₃ , C(=O)R ^1h , Substituted by a substituent of S(=O) ₂ R ^1h , R ^1h , pyridine or aza 5-membered ring;

R^1h各自独立的选自取代或未取代的甲基、乙基、2-氨基乙基、丙基、异丙基、甲氧基、乙氧基、异丙氧基或环丙基，当被取代时，任选进一步被1至4个选自F、Cl、Br、OH、甲基、乙基、异丙基、甲氧基、乙氧基、异丙氧基或环丙基的取代基所取代。 R ^{1h is} independently selected from substituted or unsubstituted methyl, ethyl, 2-aminoethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy or cyclopropyl, when When substituted, optionally further substituted with from 1 to 4 substituents selected from the group consisting of F, Cl, Br, OH, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy or cyclopropyl Replaced.
根据权利要求3所述的化合物及其立体异构体或药学上可接受的盐，其中：A compound according to claim 3 and a stereoisomer or pharmaceutically acceptable salt thereof, wherein:

A选自C(＝O)R¹；A is selected from C(=O)R ¹ ;

R¹选自取代或为取代的如下结构之一：R ^{1 is} selected from one of the following structures substituted or substituted:

当被取代时，任选进一步被1至4个选自NH₂、-(CH₂)₂N(CH₃)₂、-NHC(＝O)OC(CH₃)₃、-C(＝O)OC(CH₃)₃、C(＝O)R^1h、S(＝O)₂R^1h、R^1h或吡啶的取代基所取代；
When substituted, optionally further 1 to 4 are selected from the group consisting of NH ₂ , -(CH ₂ ) ₂ N(CH ₃ ) ₂ , -NHC(=O)OC(CH ₃ ) ₃ , -C(=O) Substituting OC(CH ₃ ) ₃ , C(=O)R ^1h , S(=O) ₂ R ^1h , R ^1h or a substituent of pyridine;

R^1h各自独立的选自取代或未取代的甲基、乙基、2-氨基乙基、丙基、异丙基、甲氧基、乙氧基、异丙氧基或环丙基，当被取代时，任选进一步被1至4个选自F、Cl、Br、OH、甲基、乙基或环丙基的取代基所取代。R ^{1h is} independently selected from substituted or unsubstituted methyl, ethyl, 2-aminoethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy or cyclopropyl, when When substituted, it is optionally further substituted with from 1 to 4 substituents selected from the group consisting of F, Cl, Br, OH, methyl, ethyl or cyclopropyl.
根据权利要求1所示的化合物及其立体异构体或药学上可接受的盐，其中该化合物选自如下结构之一：A compound according to claim 1 and a stereoisomer or pharmaceutically acceptable salt thereof, wherein the compound is selected from one of the following structures:
一种药物组合物，所述药物组合物含有治疗有效剂量的权利要求1～5中任意一项所述的化合物或其立体异构体或药学上可接受的盐，以及药学上可接受的载体和赋形剂。A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 5, or a stereoisomer or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier And excipients.
权利要求1～5中任意一项所述的化合物或其立体异构体或药学上可接受的盐，以及权利要求6所述的组合物在制备治疗与癌症相关疾病药物中的用途。The use of a compound according to any one of claims 1 to 5, or a stereoisomer or pharmaceutically acceptable salt thereof, and a composition according to claim 6 for the preparation of a medicament for the treatment of a disease associated with cancer.
根据权利要求7所述的用途，其中所述的癌症为***癌。The use according to claim 7, wherein the cancer is prostate cancer.
一种治疗与癌症相关疾病的方法，所述方法包括给药权利要求1～5中任意一项所述的化合物或其立体异构体或药学上可接受的盐，或权利要求6所述的组合物。A method for treating a cancer-related disease, the method comprising administering the compound according to any one of claims 1 to 5, or a stereoisomer or pharmaceutically acceptable salt thereof, or the method according to claim 6. combination.
根据权利要求9所述的方法，其中所述的癌症为***癌。 The method of claim 9 wherein said cancer is prostate cancer.