WO2018082503A1

WO2018082503A1 - Heterocyclic compound and preparation method and application thereof

Info

Publication number: WO2018082503A1
Application number: PCT/CN2017/108016
Authority: WO
Inventors: 蔡家强; 宋帅; 邓汉文; 曾宏; 宋宏梅; 唐祖建; 刘瑶; 田强; 黄海涛; 王利春; 王晶翼
Original assignee: 四川科伦博泰生物医药股份有限公司
Priority date: 2016-11-02
Filing date: 2017-10-27
Publication date: 2018-05-11
Also published as: CN108602842A; CN108602842B

Abstract

The present invention relates to a heterocyclic compound having anti-viral activity, a drug composition comprising same, a preparation method thereof, and an application thereof for the prevention or treatment of viral diseases including but not limited to viral hepatitis A, viral hepatitis B, viral hepatitis C, influenza, herpes, and acquired immunodeficiency syndrome (AIDS).

Description

杂环化合物及其制备方法和用途Heterocyclic compound, preparation method and use thereof

发明领域Field of invention

本发明涉及具有抗病毒活性的杂环化合物、包含其的药物组合物、其制备方法及其在预防或治疗包括但不限于甲型病毒性肝炎、乙型病毒性肝炎、丙型病毒性肝炎、流行性感冒、疱疹和获得性免疫缺陷综合征(AIDS)的病毒性疾病中的用途。The present invention relates to a heterocyclic compound having antiviral activity, a pharmaceutical composition comprising the same, a process for the preparation thereof, and its prevention or treatment including but not limited to hepatitis A virus, hepatitis B virus, hepatitis C virus, Use in influenza, herpes, and viral diseases of acquired immunodeficiency syndrome (AIDS).

发明背景Background of the invention

病毒由一种核酸分子(DNA或RNA)与蛋白质构成或仅由蛋白质构成(如朊病毒)。病毒可引起多种传染性疾病，常见的由病毒引起的疾病包括但不限于甲型病毒性肝炎、乙型病毒性肝炎、丙型病毒性肝炎、流行性感冒、疱疹和获得性免疫缺陷综合征(AIDS)。A virus consists of a nucleic acid molecule (DNA or RNA) or a protein (such as a prion). The virus can cause a variety of infectious diseases. Common diseases caused by viruses include, but are not limited to, viral hepatitis A, hepatitis B, hepatitis C, influenza, herpes and acquired immunodeficiency syndrome. (AIDS).

目前临床使用的抗病毒药物通过抑制病毒的附着、脱壳、病毒基因复制、成熟或释放，或者通过影响宿主的免疫***来发挥作用，其主要包括逆转录酶抑制剂和衣壳蛋白装配抑制剂等。Currently used antiviral drugs play a role by inhibiting virus attachment, uncoating, viral gene duplication, maturation or release, or by affecting the host's immune system, including reverse transcriptase inhibitors and capsid protein assembly inhibitors. Wait.

乙型肝炎病毒(HBV)是一种常见的嗜肝性DNA病毒性病原体。这类病毒可以引起急性肝炎、慢性肝炎、肝纤维化、肝硬化和肝癌等疾病。Hepatitis B virus (HBV) is a common hepadnavirus-like viral pathogen. Such viruses can cause diseases such as acute hepatitis, chronic hepatitis, liver fibrosis, cirrhosis and liver cancer.

乙型病毒性肝炎可以使用以下核苷类似物进行治疗：Hepatitis B can be treated with the following nucleoside analogues:

其中，替诺福韦(Tenofovir)为核苷类似物逆转录酶抑制剂，其对人类免疫缺陷病毒(HIV)和乙型肝炎病毒(HBV)感染疗效显著(Antivir Ther,2004,9,57-65；J Viral Hepat,2000,7,161-165)。其作用原理是通过与天然底物脱氧腺苷-5′-三磷酸竞争性整合到HBV的DNA后终止DNA链的合成，从而抑制逆转录酶活性。但是替诺福韦几乎不被胃肠道吸收。而其酯化前药替诺福韦二吡呋酯富马酸盐(TDF)和酰胺化前药替诺福韦艾拉酚胺富马酸盐(TAF)水溶性良好(Nucleosides Nucleotides Nucleic Acids.2001,20,1085-1090；Antimicrob Agents Chemother.2005,49,1898-1906；Antimicrob Agents Chemother.2015,59,3563-3569；Journal of Hepatology.2015,62,533-540)。Among them, Tenofovir is a nucleoside analog reverse transcriptase inhibitor, which is effective against human immunodeficiency virus (HIV) and hepatitis B virus (HBV) infection (Antivir Ther, 2004, 9, 57- 65; J Viral Hepat, 2000, 7, 161-165). Its principle of action is to inhibit reverse transcriptase activity by competing with the natural substrate deoxyadenosine-5'-triphosphate to integrate DNA into HBV and then terminate DNA strand synthesis. But tenofovir is hardly absorbed by the gastrointestinal tract. The esterified prodrug tenofovir disoproxil fumarate (TDF) and the amidated prodrug tenofovir alafenamide fumarate (TAF) are well-soluble (Nucleosides Nucleotides Nucleic Acids. 2001, 20, 1085-1090; Antimicrob Agents Chemother. 2005, 49, 1898-1906; Antimicrob Agents Chemother. 2015, 59, 3563-3569; Journal of Hepatology. 2015, 62, 533-540).

此外，乙型病毒性肝炎还可以使用非核苷类似物进行治疗。Deres等人研究发现杂芳基二氢嘧啶类化合物(Bay41-4109)可以通过抑制病毒衣壳蛋白装配进而阻止HBV病毒复制(Science,2003,299,893-896)。其具体作用机制是二氢嘧啶类化合物诱导核心蛋白错误装配，从而形成不稳定的衣壳蛋白，加速核心蛋白的降解(Biochem.Pharmacol.,2003,66,2273-2279)。Zlotnick等人发现的杂芳基二氢嘧啶类化合物HAP1(Proc.Natl.Acad.Sci.,2005,102,8138-8143)以及广东东阳光药业有限公司报道的杂芳基二氢嘧啶类化合物(GLS4)(Antimicrob.Agents Chemother.,2013,57,5344-5354；WO2015078391,US2016206616)也具有抗HBV活性。In addition, hepatitis B can also be treated with non-nucleoside analogs. Deres et al. found that heteroaryldihydropyrimidines (Bay 41-4109) can block HBV virus replication by inhibiting viral capsid protein assembly (Science, 2003, 299, 893-896). Its specific mechanism of action is that dihydropyrimidines induce misassembly of core proteins, resulting in unstable capsid proteins that accelerate the degradation of core proteins (Biochem. Pharmacol., 2003, 66, 2273-2279). The heteroaryl dihydropyrimidine compound HAP1 (Proc. Natl. Acad. Sci., 2005, 102, 8138-8143) discovered by Zlotnick et al. and the heteroaryl dihydropyrimidine compound reported by Guangdong Dongyang Pharmaceutical Co., Ltd. (GLS4) (Antimicrob. Agents Chemother., 2013, 57, 5344-5354; WO2015078391, US2016206616) also has anti-HBV activity.

虽然上述两类化合物均不同程度地表现出了抗病毒活性，但它们的活性还不能达到令人满意的程度。因此，寻找更有效的且毒副作用更小的药物有着迫切的需求和重要的意义。Although both of the above compounds exhibit antiviral activity to varying degrees, their activity has not been satisfactory. Therefore, the search for more effective drugs with less toxic side effects has urgent needs and important significance.

发明概述Summary of invention

本发明提供一种抗病毒杂环化合物，其可通过对逆转录酶和/或衣壳蛋白装配的抑制作用来发挥抗病毒作用。特别地，本发明的优选化合物可同时表现出对逆转录酶和衣壳蛋白装配的抑制作用，从而在更小的剂量下取得更优异的抗病毒效果。此外，本发明的化合物还具有更好的物理化学性质(例如溶解度、物理和/或化学稳定性)、改善的药物代谢动力学性质(例如改善的生物利用度、合适的半衰期和作用持续时间)、改善的安全性(较低的毒性和/或较少的副作用)、较不易产生耐药性等更优异的性质。The present invention provides an antiviral heterocyclic compound which exerts an antiviral action by inhibiting the assembly of reverse transcriptase and/or capsid protein. In particular, preferred compounds of the invention can simultaneously exhibit inhibition of reverse transcriptase and capsid protein assembly, thereby achieving superior antiviral effects at lower doses. In addition, the compounds of the invention also have better physicochemical properties (e.g., solubility, physical and/or chemical stability), improved pharmacokinetic properties (e.g., improved bioavailability, suitable half-life, and duration of action). , improved safety (lower toxicity and / or fewer side effects), less susceptible to drug resistance and other superior properties.

本发明的一个方面提供化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物或前药，其中所述化合物具有式(I)的结构：One aspect of the invention provides a compound or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph thereof Or a solvate, metabolite or prodrug, wherein the compound has the structure of formula (I):

其中：among them:

B选自：B is selected from:

A选自任选地被一个或多个R^b取代的C_1-6亚烷基、C_2-6亚烯基、C_2-6亚炔基，所述亚烷基、亚烯基或亚炔基任选地被一个或多个-O-、-NR-或-S-间断；A is selected from C _1-6 alkylene, C _2-6 alkenylene, C _2-6 alkynylene, optionally substituted by one or more R ^b , said alkylene, alkenylene or sub An alkynyl group is optionally interrupted by one or more -O-, -NR- or -S-;

或者A选自下列基团：Or A is selected from the following groups:

其中

表示单键或双键，并且1位置处与B连接，2位置处与磷原子(P)连接；among them

Represents a single bond or a double bond, and is connected to B at the 1 position and to the phosphorus atom (P) at the 2 position;

X、Y和Z在每次出现时各自独立地选自CH₂、O、S和NR；X, Y and Z are each independently selected from CH ₂ , O, S and NR at each occurrence;

R^a和R^b在每次出现时各自独立地选自卤素、-OH、-CN、-NO₂、-N(R)₂、-N₃、C_1-6烷基和C_3-6环烷基；R ^a and R ^b are each independently selected from the group consisting of halogen, -OH, -CN, -NO ₂ , -N(R) ₂ , -N ₃ , C _1-6 alkyl and C _3-6 ring at each occurrence. alkyl;

R²选自H、C_1-12烷基、C_3-6环烷基、C_6-14芳基、5-14元杂芳基、C_6-20芳烷基、-C_1-6亚烷基-COOH、-C_1-6亚烷基-C(＝O)O-C_1-6烷基、-C_1-6亚烷基-OC(＝O)-C_1-6烷基、-C_1-6亚烷基-OC(＝O)O-C_1-6烷基和-((CH₂)_iO)_m-(CH₂)_q-O-C_1-6烷基，上述基团各自任选地被一个或多个选自卤素、-OH、-CN、-NO₂、-N(R)₂、C_1-6烷基、卤代C_1-6烷基、C_1-6烷基硫基和C_3-6环烷基的取代基取代；R ^{2 is} selected from the group consisting of H, C _1-12 alkyl, C _3-6 cycloalkyl, C _6-14 aryl, 5-14 membered heteroaryl, C _6-20 aralkyl, -C _1-6 Alkyl-COOH, -C _1-6 alkylene-C(=O)OC _1-6 alkyl, -C _1-6 alkylene-OC(=O)-C _1-6 alkyl, -C _1-6 alkylene-OC(=O)OC _1-6 alkyl and -((CH ₂ ) _i O) _m -(CH ₂ ) _q -OC _1-6 alkyl, each of the above groups optionally One or more selected from the group consisting of halogen, -OH, -CN, -NO ₂ , -N(R) ₂ , C _1-6 alkyl, halogenated C _1-6 alkyl, C _1-6 alkylthio Substituted with a substituent of a C _3-6 cycloalkyl group;

i和q在每次出现时各自独立地为1、2、3、4、5或6；i and q are each independently 1, 2, 3, 4, 5 or 6 at each occurrence;

m为选自0-50，优选0-20，特别优选0-6中的任意整数；m is any integer selected from 0-50, preferably 0-20, particularly preferably 0-6;

R¹选自：R ^{1 is} selected from:

表示3至14元氮杂环系，其任选地另外含有独立地选自N、O、C＝O、S、S＝O和S(＝O)₂的1、2或3个环成员；

Representing a 3 to 14 membered nitrogen heterocycle, optionally additionally containing 1, 2 or 3 ring members independently selected from N, O, C=O, S, S=O and S(=O) ₂ ;

Ar¹和Ar²各自独立地选自C_6-14芳基和5-14元杂芳基，其任选地被一个或多个选自卤素、-OH、-CN、-NO₂、-N(R)₂、C_1-6烷基、卤代C_1-6烷基、C_1-6烷基硫基和C_3-6环烷基的取代基取代；Ar ¹ and Ar ² are each independently selected from a C _6-14 aryl group and a 5-14 membered heteroaryl group, which are optionally selected from one or more selected from the group consisting of halogen, -OH, -CN, -NO ₂ , -N Substituent substitution of (R) ₂ , C _1-6 alkyl, halo C _1-6 alkyl, C _1-6 alkylthio and C _3-6 cycloalkyl;

L不存在或者选自-O-、-S-和-NR-；L is absent or selected from -O-, -S-, and -NR-;

R³和R⁴各自独立地选自H、C_1-4烷基和C_3-6环烷基；R ³ and R ⁴ are each independently selected from the group consisting of H, C _1-4 alkyl and C _3-6 cycloalkyl;

R⁵在每次出现时以单键或双键与分子的其余部分连接；R ⁵ is attached to the remainder of the molecule with a single or double bond at each occurrence;

R⁵和R⁶在每次出现时各自独立地选自卤素、-OH、-COOH、-CN、-NO₂、-N(R)₂、C_1-6烷基、卤代C_1-6烷基、-W-C_1-6烷基、-C_1-6亚烷基-W-R、-W-C_1-6亚烷基-W’-R、-W-C_2-6烯基、-C_2-6亚烯基-W-R、-W-C_2-6亚烯基-W’-R和C_3-6环烷基，其中所述亚烷基和亚烯基任选地进一步被一个或多个W间隔；R ⁵ and R ⁶ are each independently selected from the group consisting of halogen, -OH, -COOH, -CN, -NO ₂ , -N(R) ₂ , C _1-6 alkyl, halogenated C _1-6 Alkyl, -WC _1-6 alkyl, -C _1-6 alkylene-WR, -WC _1-6 alkylene-W'-R, -WC _2-6 alkenyl, -C _2-6 Alkenyl-WR, -WC _2-6 alkenylene-W'-R and C _3-6 cycloalkyl, wherein the alkylene and alkenylene are optionally further separated by one or more W;

W和W’在每次出现时各自独立地选自O、C(＝O)、C(＝O)O、NR、S、S＝O和S(＝O)₂；W and W' are each independently selected from the group consisting of O, C(=O), C(=O)O, NR, S, S=O, and S(=O) ₂ ;

R在每次出现时各自独立地选自H、C_1-6烷基和C_3-6环烷基；R is each independently selected from the group consisting of H, C _1-6 alkyl and C _3-6 cycloalkyl;

n在每次出现时各自独立地为0、1、2、3、4或5，条件是n不大于对应基团上可被取代的位置的数目；并且n each independently is 0, 1, 2, 3, 4 or 5, with the proviso that n is not greater than the number of positions on the corresponding group that can be substituted;

当n大于1时，每个R^a可以相同或不同，每个R^b可以相同或不同，每个R⁵可以相同或不同，每个R⁶可以相同或不同。When n is greater than 1, each R ^a may be the same or different, and each R ^b may be the same or different, and each R ⁵ may be the same or different, and each R ⁶ may be the same or different.

本发明的另一方面提供药物组合物，其包含预防或治疗有效量的本发明的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物或前药以及一种或多种药学上可接受的载体。Another aspect of the invention provides a pharmaceutical composition comprising a prophylactically or therapeutically effective amount of a compound of the invention or a pharmaceutically acceptable compound thereof Accepted salts, esters, stereoisomers, tautomers, polymorphs, solvates, metabolites or prodrugs and one or more pharmaceutically acceptable carriers.

本发明的另一方面提供制备药物组合物的方法，所述方法包括将本发明的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物或前药与一种或多种药学上可接受的载体组合。Another aspect of the invention provides a method of preparing a pharmaceutical composition comprising administering a compound of the invention, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph thereof, The solvate, metabolite or prodrug is combined with one or more pharmaceutically acceptable carriers.

本发明的另一方面提供本发明的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物或前药或者本发明的药物组合物在制备用于预防或治疗病毒性疾病的药物中的用途。Another aspect of the invention provides a compound of the invention, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite or prodrug thereof, or the invention Use of a pharmaceutical composition for the preparation of a medicament for the prevention or treatment of a viral disease.

本发明的另一方面提供本发明的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物或前药或者本发明的药物组合物，其用于预防或治疗病毒性疾病。Another aspect of the invention provides a compound of the invention, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite or prodrug thereof, or the invention A pharmaceutical composition for preventing or treating a viral disease.

本发明的另一方面提供预防或治疗病毒性疾病的方法，所述方法包括向需要其的个体给药有效量的本发明的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物或前药或者本发明的药物组合物。Another aspect of the invention provides a method of preventing or treating a viral disease, the method comprising administering to an individual in need thereof an effective amount of a compound of the invention, or a pharmaceutically acceptable salt, ester, stereoisomer thereof, Tautomers, polymorphs, solvates, metabolites or prodrugs or pharmaceutical compositions of the invention.

上述病毒性疾病包括但不限于甲型病毒性肝炎、乙型病毒性肝炎、丙型病毒性肝炎、流行性感冒、疱疹和获得性免疫缺陷综合征(AIDS)。The above viral diseases include, but are not limited to, viral hepatitis A, hepatitis B virus, hepatitis C virus, influenza, herpes, and acquired immunodeficiency syndrome (AIDS).

本发明的另一方面提供制备本发明的化合物的方法，所述方法包括以下步骤：Another aspect of the invention provides a method of preparing a compound of the invention, the method comprising the steps of:

或者or

其中：among them:

R¹²、R¹³和R¹⁴各自独立地选自F、Cl、Br、I、-NHR、羟基、三氟甲磺酸酯基、对甲基苯磺酸酯基和硼酸酯基；R ¹² , R ¹³ and R ¹⁴ are each independently selected from the group consisting of F, Cl, Br, I, -NHR, hydroxy, triflate, p-toluenesulfonate and borate;

PG选自叔丁氧羰基、苄氧羰基、9-芴甲氧羰基、烯丙氧羰基、三甲基硅乙氧羰基、甲氧羰基、乙氧羰基、对甲苯磺酰基、邻硝基苯磺酰基、对硝基苯磺酰基、甲酰基、乙酰基、三氟乙酰基、丙酰基、特戊酰基、苯基、苯甲酰基、三苯甲基、苄基、2,4-二甲氧基苄基和对甲氧基苄基；PG is selected from the group consisting of tert-butoxycarbonyl, benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl, allyloxycarbonyl, trimethylsilyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl, p-toluenesulfonyl, o-nitrobenzenesulfonate Acyl, p-nitrophenylsulfonyl, formyl, acetyl, trifluoroacetyl, propionyl, pivaloyl, phenyl, benzoyl, trityl, benzyl, 2,4-dimethoxy Benzyl and p-methoxybenzyl;

其余各基团如上述所定义；The remaining groups are as defined above;

第一步在有机碱或无机碱和/或缩合试剂(特别优选DCC、DIC、EDC、BOP、PyAOP或PyBOP)的存在下，在非质子性溶剂中或无溶剂条件下进行；The first step is carried out in the presence of an organic base or an inorganic base and/or a condensation reagent (particularly preferably DCC, DIC, EDC, BOP, PyAOP or PyBOP) in an aprotic solvent or without solvent;

第二步在适于脱除PG基团的条件下进行；The second step is carried out under conditions suitable for removal of the PG group;

第三步在非质子性溶剂中，在有机碱或无机碱的存在下进行；并且The third step is carried out in an aprotic solvent in the presence of an organic or inorganic base;

第四步在非质子性溶剂中，优选在有机碱或无机碱和/或缩合试剂(特别优选DCC、DIC、EDC、BOP、PyAOP或PyBOP)的存在下进行。 The fourth step is carried out in an aprotic solvent, preferably in the presence of an organic base or an inorganic base and/or a condensation reagent, particularly preferably DCC, DIC, EDC, BOP, PyAOP or PyBOP.

其中：among them:

R¹²选自F、Cl、Br、I、-NHR、羟基、三氟甲磺酸酯基、对甲基苯磺酸酯基和硼酸酯基；R ^{12 is} selected from the group consisting of F, Cl, Br, I, -NHR, hydroxy, triflate, p-toluenesulfonate, and borate;

LG为离去基团，其优选为五氟苯基和对硝基苯基；LG is a leaving group, which is preferably a pentafluorophenyl group and a p-nitrophenyl group;

其余各基团如上述所定义；The remaining groups are as defined above;

第一步在有机碱或无机碱的存在下，在非质子性溶剂中进行；The first step is carried out in an aprotic solvent in the presence of an organic or inorganic base;

第二步在有机碱或无机碱的存在下，在非质子性溶剂中进行；并且The second step is carried out in an aprotic solvent in the presence of an organic or inorganic base;

第三步在有机碱或无机碱的存在下，在非质子性溶剂中进行。The third step is carried out in an aprotic solvent in the presence of an organic or inorganic base.

定义definition

除非在下文中另有定义，本文中所用的所有技术术语和科学术语的含义意图与本领域技术人员通常所理解的相同。提及本文中使用的技术意图指在本领域中通常所理解的技术，包括那些对本领域技术人员显而易见的技术的变化或等效技术的替换。虽然相信以下术语对于本领域技术人员很好理解，但仍然阐述以下定义以更好地解释本发明。Unless otherwise defined below, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. References to techniques used herein are intended to refer to techniques that are generally understood in the art, including those that are obvious to those skilled in the art. While the following terms are believed to be well understood by those skilled in the art, the following definitions are set forth to better explain the invention.

术语“包括”、“包含”、“具有”、“含有”或“涉及”及其在本文中的其它变体形式为包含性的(inclusive)或开放式的，且不排除其它未列举的元素或方法步骤。The terms "comprising," "comprising," "having," "containing," Or method steps.

如本文中所使用，术语“亚烷基”表示饱和二价烃基，优选表示具有1、2、3、4、5或6个碳原子的饱和二价烃基，例如亚甲基、亚乙基、亚丙基或亚丁基。The term "alkylene" as used herein denotes a saturated divalent hydrocarbon group, preferably a saturated divalent hydrocarbon group having 1, 2, 3, 4, 5 or 6 carbon atoms, such as methylene, ethylene, Propylene or butylene.

如本文中所使用，术语“亚烯基”表示包含一个或多个双键的二价烃基，其优选具有2、3、4、5或6个碳原子，例如亚乙烯基、亚丙烯基或亚烯丙基。当本发明的化合物含有亚烯基时，所述化合物可以纯E(异侧(entgegen))形式、纯Z(同侧(zusammen))形式或其任意混合物形式存在。The term "alkenylene" as used herein denotes a divalent hydrocarbon radical containing one or more double bonds, preferably having 2, 3, 4, 5 or 6 carbon atoms, such as ethenylene, propenylene or Allylene. When the compounds of the invention contain alkenylene groups, the compounds may exist in pure E (entgegen) form, pure Z (zusammen) form, or any mixture thereof.

如本文中所使用，术语“亚炔基”表示包含一个或多个三键的二价烃基，其优选具有2、3、4、5或6个碳原子，例如亚乙炔基或亚丙炔基。The term "alkynylene" as used herein denotes a divalent hydrocarbon radical containing one or more triple bonds, preferably having 2, 3, 4, 5 or 6 carbon atoms, for example ethynylene or propynylene. .

如本文中所使用，术语“烷基”定义为直链或支链饱和脂肪族烃基。在一些实施方案中，烷基具有1至12个碳原子，例如1至6个碳原子。例如，如本文中所使用，术语“C_1-6烷基”指具有1至6个碳原子的直链或支链饱和脂肪族烃基(例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基或正己基)，其任选地被1或多个(诸如1至3个)适合的取代基如卤素取代(此时该基团被称作“卤代烷基”)(例如CF₃、C₂F₅、CHF₂、CH₂F、CH₂CF₃、CH₂Cl或-CH₂CH₂CF₃等)。术语“C_1-4烷基”指具有1至4个碳原子的直链或支链饱和脂肪族烃基(即甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基)。As used herein, the term "alkyl" is defined as a straight or branched saturated aliphatic hydrocarbon group. In some embodiments, an alkyl group has from 1 to 12 carbon atoms, such as from 1 to 6 carbon atoms. For example, as used herein, the term " _C1-6 alkyl" refers to a straight or branched saturated aliphatic hydrocarbon group having from 1 to 6 carbon atoms (eg, methyl, ethyl, n-propyl, isopropyl) , n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl or n-hexyl), which are optionally substituted by one or more (such as 1 to 3) suitable substituents such as halogen (this This group is referred to as "haloalkyl" (for example, CF ₃ , C ₂ F ₅ , CHF ₂ , CH ₂ F, CH ₂ CF ₃ , CH ₂ Cl or -CH ₂ CH ₂ CF _{3 ,} etc.). The term "C _1-4 alkyl" refers to a straight or branched saturated aliphatic hydrocarbon group having 1 to 4 carbon atoms (ie, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl) , sec-butyl or tert-butyl).

如本文中所使用，术语“环烷基”指饱和或不饱和的非芳族单环或多环(诸如双环)烃环(例如单环，诸如环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环壬基，或双环，包括螺环、稠合或桥连***(诸如双环[1.1.1]戊基、双环[2.2.1]庚基、双环[3.2.1]辛基或双环[5.2.0]壬基、十氢化萘基等))，其任选地被1或多个(诸如1至3个)适合的取代基取代。所述环烷基具有3至15个碳原子。例如，术语“C_3-6环烷基”指具有3至6个成环碳原子的饱和或不饱和的非芳族单环或多环(诸如双环)烃环(例如环丙基、环丁基、环戊基或环己基)，其任选地被1或多个(诸如1至3个)适合的取代基取代，例如甲基取代的环丙基。As used herein, the term "cycloalkyl" refers to a saturated or unsaturated, non-aromatic monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (eg, a monocyclic ring such as cyclopropyl, cyclobutyl, cyclopentyl, Cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, or bicyclic, including spiro, fused or bridged systems (such as bicyclo [1.1.1] pentyl, bicyclo [2.2.1] heptyl, bicyclo [ 3.2.1] Octyl or bicyclo [5.2.0] anthracenyl, decalinyl, etc.)), which is optionally substituted by one or more (such as 1 to 3) suitable substituents. The cycloalkyl group has 3 to 15 carbon atoms. For example, the term "C _3-6 cycloalkyl" refers to a saturated or unsaturated, non-aromatic monocyclic or polycyclic (such as bicyclic) hydrocarbon ring having from 3 to 6 ring-forming carbon atoms (eg, cyclopropyl, cyclobutyl) A group, a cyclopentyl group or a cyclohexyl group, which is optionally substituted by one or more (such as 1 to 3) suitable substituents, such as a methyl-substituted cyclopropyl group.

如本文中所使用，术语“芳基”指具有共轭π电子***的全碳单环或稠合环多环芳族基团。例如，如本文中所使用，术语“C_6-14芳基”意指含有6至14个碳原子的芳族基团，诸如苯基或萘基。芳基任选地被1或多个(诸如1至3个)适合的取代基(例如卤素、-OH、-CN、-NO₂、C_1-6烷基等)取代。As used herein, the term "aryl" refers to an all-carbon monocyclic or fused-ring polycyclic aromatic group having a conjugated pi-electron system. For example, as used herein, the term " _C6-14 aryl" means an aromatic group containing from 6 to 14 carbon atoms, such as phenyl or naphthyl. The aryl group is optionally substituted by one or more (such as 1 to 3) suitable substituents (e.g., halogen, -OH, -CN, -NO ₂ , C _1-6 alkyl, etc.).

如本文中所使用，术语“芳烷基”表示被芳基取代的烷基，其中所述芳基和所述烷基如本文中所定义。通常，所述芳基可具有6-14个碳原子，并且所述烷基可具有1-6个碳原子。示例性芳烷基包括但不限于苄基、苯基乙基、苯基丙基、苯基丁基。The term "aralkyl" as used herein denotes an alkyl group substituted with an aryl group, wherein the aryl group and the alkyl group are as defined herein. Typically, the aryl group can have from 6 to 14 carbon atoms and the alkyl group can have from 1 to 6 carbon atoms. Exemplary aralkyl groups include, but are not limited to, benzyl, phenylethyl, phenylpropyl, phenylbutyl.

如本文中所使用，术语“杂芳基”指单环、双环或三环芳族环系，其具有5、6、8、9、10、11、12、13或14个环原子，特别是1或2或3或4或5或6或9或10个碳原子，且其包含至少一个可以相同或不同的杂原子(所述杂原子是例如氧、氮或硫)，并且，另外在每一种情况下可为苯并稠合的。特别地，杂芳基选自噻吩基、呋喃基、吡咯基、噁唑基、噻唑基、咪唑基、吡唑基、异噁唑基、异噻唑基、噁二唑基、***基、噻二唑基等，以及它们的苯并衍生物；或吡啶基、哒嗪基、嘧啶基、吡嗪基、三嗪基等，以及它们的苯并衍生物。The term "heteroaryl" as used herein refers to a monocyclic, bicyclic or tricyclic aromatic ring system having 5, 6, 8, 9, 10, 11, 12, 13 or 14 ring atoms, in particular 1 or 2 or 3 or 4 or 5 or 6 or 9 or 10 carbon atoms, and which contain at least one hetero atom which may be the same or different (the hetero atom is, for example, oxygen, nitrogen or sulfur), and additionally In one case, it may be benzo-fused. In particular, the heteroaryl is selected from the group consisting of thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thia A oxazolyl group or the like, and a benzo derivative thereof; or a pyridyl group, a pyridazinyl group, a pyrimidinyl group, a pyrazinyl group, a triazinyl group or the like, and a benzo derivative thereof.

如本文中所使用，术语“卤代”或“卤素”基团定义为包括F、Cl、Br或I。The term "halo" or "halogen" group, as used herein, is defined to include F, Cl, Br or I.

如本文中所使用，术语“烷基硫基”指通过硫原子连接至母体分子部分的如上文所定义的烷基。C_1-6烷基硫基的代表性实例包括但不限于甲硫基、乙硫基、叔丁硫基及己硫基。As used herein, the term "alkylthio" refers to an alkyl group, as defined above, appended to the parent molecular moiety through a sulfur atom. Representative examples of _C1-6 alkylthio include, but are not limited to, methylthio, ethylthio, tert-butylthio, and hexylthio.

如本文中所使用，术语“氮杂环系”指饱和或不饱和的单环或双环基团，其在环中具有2、3、4、5、6、7、8、9、10、11、12或13个碳原子和至少一个氮原子，其还可任选地包含一个或多个(例如一个、两个、三个或四个)选自N、O、C＝O、S、S＝O和S(＝O)₂的环成员；所述氮杂环系通过氮原子与分子的其余部分连接。特别地，3至14元氮杂环系为在环中具有3-14个碳原子及杂原子(其中至少一个为氮原子)的环状基团，其包括但不限于氮丙啶基、氮杂环丁烷基、吡咯基、吡咯烷基、吡咯啉基、吡咯烷酮基、咪唑基、咪唑烷基、咪唑啉基、吡唑基、吡唑啉基、哌啶基、吗啉基、硫吗啉基、哌嗪基、吲哚基、吲哚啉基等。As used herein, the term "nitrogen heterocycle" refers to a saturated or unsaturated monocyclic or bicyclic group having 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 in the ring. , 12 or 13 carbon atoms and at least one nitrogen atom, which may also optionally comprise one or more (eg one, two, three or four) selected from the group consisting of N, O, C=O, S, S a ring member of =O and S(=O) ₂ ; the nitrogen heterocycle is attached to the remainder of the molecule through a nitrogen atom. In particular, the 3 to 14 membered nitrogen heterocycle is a cyclic group having 3 to 14 carbon atoms and a hetero atom (at least one of which is a nitrogen atom) in the ring, including but not limited to aziridine, nitrogen Heterocyclic butane, pyrrolyl, pyrrolidinyl, pyrrolinyl, pyrrolidinyl, imidazolyl, imidazolidinyl, imidazolinyl, pyrazolyl, pyrazolinyl, piperidinyl, morpholinyl, sulfur? A phenyl group, a piperazinyl group, a fluorenyl group, a porphyrin group or the like.

术语“取代”指所指定的原子上的一个或多个(例如一个、两个、三个或四个)氢被从所指出的基团的选择代替，条件是未超过所指定的原子在当前情况下的正常原子价并且所述取代形成稳定的化合物。取代基和/或变量的组合仅仅当这种组合形成稳定的化合物时才是允许的。The term "substituted" means that one or more (eg, one, two, three or four) hydrogens on the designated atom are replaced by the selection of the indicated group, provided that the specified atom is not present at present. The normal valence in the case and the substitution form a stable compound. Combinations of substituents and/or variables are permissible only if such combinations form stable compounds.

如果取代基被描述为“任选地被取代”，则取代基可(1)未被取代或(2)被取代。如果取代基的碳被描述为任选地被取代基列表中的一个或多个取代，则碳上的一个或多个氢(至存在的任何氢的程度)可单独和/或一起被独立地选择的任选的取代基替代。如果取代基的氮被描述为任选地被取代基列表中的一个或多个取代，则氮上的一个或多个氢(至存在的任何氢的程度)可各自被独立地选择的任选的取代基替代。If a substituent is described as "optionally substituted," the substituent may be unsubstituted or (2) substituted. If the carbon of the substituent is described as being optionally substituted by one or more of the list of substituents, then one or more hydrogens on the carbon (to the extent of any hydrogen present) may be independently and/or together independently The optional substituents selected are substituted. If the nitrogen of the substituent is described as being optionally substituted by one or more of the list of substituents, then one or more hydrogens on the nitrogen (to the extent of any hydrogen present) may each be independently selected. Substitute substitution.

如果取代基被描述为“独立地选自”一组，则各取代基独立于另一者被选择。因此，各取代基可与另一(其他)取代基相同或不同。If a substituent is described as being "independently selected from" a group, each substituent is selected independently of the other. Thus, each substituent may be the same or different from another (other) substituent.

如本文中所使用，术语“一个或多个”意指在合理条件下的1个或超过1个，例如2个、3个、4个、5个或10个。As used herein, the term "one or more" means 1 or more than 1, such as 2, 3, 4, 5 or 10 under reasonable conditions.

除非指明，否则如本文中所使用，取代基的连接点可来自取代基的任意适宜位置。Unless otherwise indicated, a point of attachment of a substituent, as used herein, may come from any suitable position of the substituent.

当取代基的键显示为穿过环中连接两个原子的键时，则这样的取代基可键连至该可取代的环中的任一成环原子。When a bond of a substituent is shown to pass through a bond connecting two atoms in the ring, such a substituent may be bonded to any of the ring-forming atoms in the substitutable ring.

本发明还包括所有药学上可接受的同位素标记的化合物，其与本发明的化合物相同，除了一个或多个原子被具有相同原子序数但原子质量或质量数不同于在自然界中占优势的原子质量或质量数的原子替代。适合包含入本发明的化合物中的同位素的实例包括(但不限于)氢的同位素(例如²H、³H)；碳的同位素(例如¹¹C、¹³C及¹⁴C)；氯的同位素(例如³⁶Cl)；氟的同位素(例如¹⁸F)；碘的同位素(例如¹²³I及¹²⁵I)；氮的同位素(例如¹³N及¹⁵N)；氧的同位素(例如¹⁵O、¹⁷O及¹⁸O)；磷的同位素(例如³²P)；及硫的同位素(例如³⁵S)。某些同位素标记的本发明的化合物(例如掺入放射性同位素的那些)可用于药物和/或底物组织分布研究(例如分析)中。放射性同位素氚(即³H)及碳-14(即¹⁴C)因易于掺入且容易检测而特别可用于该目的。用正电子发射同位素(例如¹¹C、¹⁸F、¹⁵O及¹³N)进行取代可在正电子发射断层显像术(PET)研究中用于检验底物受体占据情况。被同位素标记的本发明的化合物可通过与描述于随附路线和/或实施例及制备中的那些类似的方法通过使用适当的被同位素标记的试剂代替之前采用的非标记的试剂来制备。本发明的药学上可接受的溶剂合物包括其中结晶溶剂可被同位素取代的那些，例如，D₂O、丙酮-d₆或DMSO-d₆。 The invention also includes all pharmaceutically acceptable isotopically-labeled compounds which are identical to the compounds of the invention, except that one or more atoms are of the same atomic number but the atomic mass or mass number differs from the atomic mass prevailing in nature. Or atomic substitution of mass. Examples of isotopes suitable for inclusion in the compounds of the invention include, but are not limited to, isotopes of hydrogen (e.g., ² H, ³ H); isotopes of carbon (e.g., ¹¹ C, ¹³ C, and ¹⁴ C); isotopes of chlorine (e.g. ³⁶ Cl); isotope of fluorine (eg ¹⁸ F); isotopes of iodine (eg ¹²³ I and ¹²⁵ I); isotopes of nitrogen (eg ¹³ N and ¹⁵ N); isotopes of oxygen (eg ¹⁵ O, ¹⁷ O and ¹⁸ O) ); an isotope of phosphorus (eg, ³² P); and an isotope of sulfur (eg, ³⁵ S). Certain isotopically-labeled compounds of the invention (e.g., those incorporating radioisotopes) are useful in drug and/or substrate tissue distribution studies (e.g., assays). The radioisotope ruthenium (i.e., ³ H) and carbon-14 (i.e., ¹⁴ C) are particularly useful for this purpose because of their ease of incorporation and ease of detection. Substitution with positron emitting isotopes (eg, ¹¹ C, ¹⁸ F, ¹⁵ O, and ¹³ N) can be used to examine substrate receptor occupancy in positron emission tomography (PET) studies. Isotopically labeled compounds of the invention can be prepared by replacing the previously employed non-labeled reagents with suitable isotopically labeled reagents by methods analogous to those described in the accompanying routes and/or examples and preparations. The pharmaceutically acceptable solvates of the present invention include those in which the crystallization solvent can be substituted with an isotope, for example, D ₂ O, acetone-d ₆ or DMSO-d ₆ .

术语“立体异构体”表示由于至少一个不对称中心形成的异构体。在具有一个或多个(例如一个、两个、三个或四个)不对称中心的化合物中，其可产生外消旋混合物、单一对映异构体、非对映异构体混合物和单独的非对映异构体。特定个别分子也可以几何异构体(顺式/反式)存在。类似地，本发明的化合物可以两种或更多种处于快速平衡的结构不同的形式的混合物(通常称作互变异构体)存在。互变异构体的代表性实例包括酮-烯醇互变异构体、苯酚-酮互变异构体、亚硝基-肟互变异构体、亚胺-烯胺互变异构体等。例如，二氢嘧啶基团在溶液中可以下列互变异构形式平衡存在：

要理解，本申请的范围涵盖所有这样的以任意比例(例如60％、65％、70％、75％、80％、85％、90％、95％、96％、97％、98％、99％)的异构体或其混合物。The term "stereoisomer" denotes an isomer formed by at least one asymmetric center. In a compound having one or more (eg, one, two, three or four) asymmetric centers, it can produce a racemic mixture, a single enantiomer, a mixture of diastereomers, and Diastereomers. Specific individual molecules can also exist as geometric isomers (cis/trans). Similarly, the compounds of the invention may exist as mixtures (often referred to as tautomers) of two or more different forms in a rapidly balanced structure. Representative examples of tautomers include keto-enol tautomers, phenol-keto tautomers, nitroso-oxime tautomers, imine-enamine tautomers Wait. For example, a dihydropyrimidinyl group can exist in equilibrium in the following tautomeric forms:

It is to be understood that the scope of the present application covers all such ratios in any ratio (eg, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99). %) isomer or a mixture thereof.

本文中可使用实线

、实楔形

或虚楔形

描绘本发明的化合物的碳-碳键。使用实线以描绘键连至不对称碳原子的键欲表明，包括该碳原子处的所有可能的立体异构体(例如，特定的对映异构体、外消旋混合物等)。使用实或虚楔形以描绘键连至不对称碳原子的键欲表明，存在所示的立体异构体。当存在于外消旋混合物中时，使用实及虚楔形以定义相对立体化学，而非绝对立体化学。除非另外指明，否则本发明的化合物意欲可以立体异构体(其包括顺式及反式异构体、光学异构体(例如R及S对映异构体)、非对映异构体、几何异构体、旋转异构体、构象异构体、阻转异构体及其混合物)的形式存在。本发明的化合物可表现一种以上类型的异构现象，且由其混合物(例如外消旋混合物及非对映异构体对)组成。Solid lines can be used in this article

Solid wedge

Virtual wedge

The carbon-carbon bonds of the compounds of the invention are depicted. The use of solid lines to delineate linkages bonded to an asymmetric carbon atom is intended to include all possible stereoisomers at the carbon atom (eg, specific enantiomers, racemic mixtures, etc.). The use of a solid or virtual wedge to characterize a bond to an asymmetric carbon atom is intended to indicate the presence of the stereoisomers shown. When present in a racemic mixture, solid and virtual wedges are used to define relative stereochemistry rather than absolute stereochemistry. Unless otherwise indicated, the compounds of the invention are intended to be stereoisomers (including cis and trans isomers, optical isomers (eg, R and S enantiomers), diastereomers, Geometric isomers, rotamers, conformers, atropisomers, and mixtures thereof exist. The compounds of the invention may exhibit more than one type of isomerism and consist of a mixture thereof (e.g., a racemic mixture and a diastereomeric pair).

本发明涵盖本发明的化合物的所有可能的结晶形式或多晶型物，其可为单一多晶型物或多于一种多晶型物的任意比例的混合物。The invention encompasses all possible crystalline forms or polymorphs of the compounds of the invention, which may be a single polymorph or a mixture of more than one polymorph in any ratio.

还应当理解，本发明的某些化合物可以游离形式存在用于治疗，或适当时，以其药学上可接受的衍生物形式存在。在本发明中，药学上可接受的衍生物包括但不限于，药学上可接受的盐、酯、溶剂合物、代谢物或前药，在将它们向需要其的患者给药后，能够直接或间接提供本发明的化合物或其代谢物或残余物。因此，当在本文中提及“本发明的化合物”时，也意在涵盖化合物的上述各种衍生物形式。It will also be understood that certain compounds of the invention may exist in free form for treatment or, where appropriate, in the form of their pharmaceutically acceptable derivatives. In the present invention, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, esters, solvates, metabolites or prodrugs, which are capable of being administered directly to a patient in need thereof The compound of the invention or a metabolite or residue thereof is provided indirectly or indirectly. Thus, when reference is made herein to a "compound of the invention," it is also intended to encompass the various derivative forms described above for the compound.

本发明的化合物的药学上可接受的盐包括其酸加成盐及碱加成盐。The pharmaceutically acceptable salts of the compounds of the present invention include the acid addition salts and base addition salts thereof.

适合的酸加成盐由形成药学可接受盐的酸来形成。实例包括天冬氨酸盐、碳酸氢盐/碳酸盐、延胡索酸盐、葡庚糖酸盐、葡糖酸盐、葡糖醛酸盐、六氟磷酸盐、氢溴酸盐/溴化物、氢碘酸盐/碘化物、萘甲酸盐(naphthylate)、烟酸盐、硝酸盐、乳清酸盐、棕榈酸盐及其它类似的盐。Suitable acid addition salts are formed from acids which form pharmaceutically acceptable salts. Examples include aspartate, bicarbonate/carbonate, fumarate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate, hydrobromide/bromide, hydrogen Iodate/iodide, naphthylate, nicotinate, nitrate, orotate, palmitate and other similar salts.

适合的碱加成盐由形成药学可接受盐的碱来形成。实例包括铝盐、精氨酸盐、胆碱盐、赖氨酸盐、镁盐、葡甲胺盐、氨丁三醇盐及其它类似的盐。Suitable base addition salts are formed from bases which form pharmaceutically acceptable salts. Examples include aluminum salts, arginine salts, choline salts, lysine salts, magnesium salts, meglumine salts, tromethamine salts, and other similar salts.

适合的盐的综述参见Stahl及Wermuth的“Handbook of Pharmaceutical Salts:Properties,Selection,and Use”(Wiley-VCH,2002)。用于制备本发明的化合物的药学上可接受的盐的方法为本领域技术人员已知的。For a review of suitable salts, see "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" by Stahl and Wermuth (Wiley-VCH, 2002). Methods for preparing pharmaceutically acceptable salts of the compounds of the invention are known to those skilled in the art.

如本文中所使用，术语“酯”意指衍生自本申请中各个通式化合物的酯，其包括生理上可水解的酯(可在生理条件下水解以释放游离酸或醇形式的本发明的化合物)。本发明的化合物本身也可以是酯。As used herein, the term "ester" means an ester derived from a compound of the formulae herein, which includes a physiologically hydrolyzable ester (which can be hydrolyzed under physiological conditions to release the free acid or alcohol form of the invention). Compound). The compounds of the invention may also be esters per se.

本发明的化合物可以溶剂合物(优选水合物)的形式存在，其中本发明的化合物包含作为所述化合物晶格的结构要素的极性溶剂，特别是例如水、甲醇或乙醇。极性溶剂特别是水的量可以化学计量比或非化学计量比存在。The compound of the present invention may exist in the form of a solvate (preferably a hydrate) wherein the compound of the present invention contains a polar solvent as a structural element of the crystal lattice of the compound, particularly such as water, methanol or ethanol. The amount of polar solvent, particularly water, may be present in stoichiometric or non-stoichiometric ratios.

在本发明的范围内还包括本发明的化合物的代谢物，即在给药本发明的化合物时体内形成的物质。这样的产物可由例如被给药的化合物的氧化、还原、水解、酰胺化、脱酰胺化、酯化、脱脂化、酶解等产生。因此，本发明包括本发明的化合物的代谢物，包括通过使本发明的化合物与哺乳动物接触足以产生其代谢产物的时间的方法制得的化合物。Also included within the scope of the invention are metabolites of the compounds of the invention, i.e., substances formed in vivo upon administration of a compound of the invention. Such products may be produced, for example, by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, delipidization, enzymatic hydrolysis, and the like of the administered compound. Accordingly, the invention includes metabolites of the compounds of the invention, including compounds prepared by contacting a compound of the invention with a mammal for a time sufficient to produce a metabolic product thereof.

本发明在其范围内进一步包括本发明的化合物的前药，其为自身可具有较小药理学活性或无药理学活性的本发明的化合物的某些衍生物当被给药至身体中或其上时可通过例如水解裂解转化成具有期望活性的本发明的化合物。通常这样的前药会是所述化合物的官能团衍生物，其易于在体内转化成期望的治疗活性化合物。关于前药的使用的其他信息可参见“Pro-drugs as Novel Delivery Systems”，第14卷，ACS Symposium Series(T.Higuchi及V.Stella)及“Bioreversible Carriers in Drug Design,”Pergamon Press,1987(E.B.Roche编辑，American Pharmaceutical Association)。本发明的前药可例如通过用本领域技术人员已知作为“前-部分(pro-moiety)(例如“Design of Prodrugs”，H.Bundgaard(Elsevier,1985)中所述)”的某些部分替代本发明的化合物中存在的适当官能团来制备。The invention further includes within its scope prodrugs of the compounds of the invention which are certain derivatives of the compounds of the invention which may themselves have less or no pharmacological activity, when administered to or into the body It can be converted to a compound of the invention having the desired activity by, for example, hydrolytic cleavage. Typically such prodrugs will be functional group derivatives of the compounds which are readily converted in vivo to the desired therapeutically active compound. Additional information on the use of prodrugs can be found in "Pro-drugs as Novel Delivery" Systems, Vol. 14, ACS Symposium Series (T. Higuchi and V. Stella) and "Bioreversible Carriers in Drug Design," Pergamon Press, 1987 (EB Roche, ed., American Pharmaceutical Association). Prodrugs of the invention can be passed, for example, Substituting certain parts of the compounds of the invention as known to the "pro-moiety" (for example "Design of Prodrugs", H. Bundgaard (Elsevier, 1985)" by those skilled in the art Prepare with appropriate functional groups.

本发明还涵盖含有保护基的本发明的化合物。在制备本发明的化合物的任何过程中，保护在任何有关分子上的敏感基团或反应基团可能是必需的和/或期望的，由此形成本发明的化合物的化学保护的形式。这可以通过常规的保护基实现，例如，在Protective Groups in Organic Chemistry,ed.J.F.W.McOmie,Plenum Press,1973；和T.W.Greene&P.G.M.Wuts,Protective Groups in Organic Synthesis,John Wiley&Sons,1991中所述的那些保护基，这些参考文献通过援引加入本文。使用本领域已知的方法，在适当的后续阶段可以移除保护基。The invention also encompasses compounds of the invention containing a protecting group. In any process for preparing a compound of the invention, it may be necessary and/or desirable to protect a sensitive group or reactive group on any of the molecules of interest, thereby forming a chemically protected form of the compound of the invention. This can be achieved by conventional protecting groups such as those described in Protective Groups in Organic Chemistry, ed. JFW McOmie, Plenum Press, 1973; and TW Greene & P. GM Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991. Protecting groups, which are incorporated herein by reference. The protecting group can be removed at a suitable subsequent stage using methods known in the art.

术语“约”是指在所述数值的±10％范围内，优选±5％范围内，更优选±2％范围内。The term "about" means within ±10% of the stated value, preferably within ±5%, more preferably within ±2%.

发明详细描述Detailed description of the invention

化合物及其制备方法Compound and preparation method thereof

在一个实施方案中，本发明提供化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物或前药，其中所述化合物具有式(I)的结构：In one embodiment, the invention provides a compound, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite or prodrug thereof, wherein The compound has the structure of formula (I):

其中：among them:

B选自：B is selected from:

或者A选自下列基团：Or A is selected from the following groups:

其中

R¹选自：R ^{1 is} selected from:

表示3至14元氮杂环系，其任选地另外含有独立地选自N、O、C＝O、S、S＝O和S(＝O)₂ 的1、2或3个环成员；

n在每次出现时各自独立地为0、1、2、3、4或5，条件是n不大于对应基团上可被取代的位置的数目，并且n each independently is 0, 1, 2, 3, 4 or 5, with the proviso that n is not greater than the number of positions on the corresponding group that can be substituted, and

在优选的实施方案中，X、Y和Z在每次出现时各自独立地选自CH₂、O和NH。In a preferred embodiment, X, Y, and Z at each occurrence is independently selected from CH _2, O, and NH.

在特别优选的实施方案中，X、Y和Z在每次出现时各自独立地选自O和NH。In a particularly preferred embodiment, X, Y and Z are each independently selected from O and NH at each occurrence.

在优选的实施方案中，R^a和R^b在每次出现时各自独立地选自卤素、-OH、-N(R)₂、-N₃和C_1-6烷基。In a preferred embodiment, R ^a and R ^b are each independently selected from the group consisting of halogen, -OH, -N(R) ₂ , -N ₃ and C _1-6 alkyl.

在特别优选的实施方案中，R^a和R^b在每次出现时各自独立地选自F、-OH、氨基、环丙基氨基和甲基。In a particularly preferred embodiment, R ^a and R ^b are each independently selected from the group consisting of F, -OH, amino, cyclopropylamino and methyl at each occurrence.

在优选的实施方案中，B选自：In a preferred embodiment, B is selected from the group consisting of:

在特别优选的实施方案中，B为

In a particularly preferred embodiment, B is

在优选的实施方案中，A选自：In a preferred embodiment, A is selected from the group consisting of:

其中1位置处与B连接，2位置处与磷原子(P)连接。One of the positions is connected to B, and the second position is connected to the phosphorus atom (P).

在更优选的实施方案中，A为

其中1位置处与B连接，2位置处与磷原子(P)连接。In a more preferred embodiment, A is

One of the positions is connected to B, and the second position is connected to the phosphorus atom (P).

在特别优选的实施方案中，A为

其中1位置处与B连接，2位置处与磷原子(P)连接。 In a particularly preferred embodiment, A is

在优选的实施方案中，

表示3元、4元、5元或6元氮杂环系。In a preferred embodiment,

Represents a 3-, 4-, 5-, or 6-membered nitrogen heterocycle.

在特别优选的实施方案中，

选自氮杂环丁烷基、吡咯烷基、哌啶基、吗啉基和哌嗪基。In a particularly preferred embodiment,

It is selected from the group consisting of azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl and piperazinyl.

在优选的实施方案中，R¹选自：In a preferred embodiment, R ^{1 is} selected from the group consisting of

在优选的实施方案中，Ar¹和Ar²各自独立地选自咪唑基、噁唑基、噻唑基、吡啶基、嘧啶基、哌嗪基和苯基，其各自任选地被一个或多个相同或不同的卤素、C_1-6烷基、卤代C_1-6烷基和C_3-6环烷基取代。In a preferred embodiment, Ar ¹ and Ar ² are each independently selected from the group consisting of imidazolyl, oxazolyl, thiazolyl, pyridyl, pyrimidinyl, piperazinyl and phenyl, each of which is optionally one or more The same or different halogen, C _1-6 alkyl, halo C _1-6 alkyl and C _3-6 cycloalkyl are substituted.

在更优选的实施方案中，Ar¹和Ar²各自独立地选自咪唑基、噁唑基、噻唑基、吡啶基、嘧啶基、哌嗪基和苯基，其各自任选地被一个或多个相同或不同的卤素、C_1-6烷基和C_3-6环烷基取代。In a more preferred embodiment, Ar ¹ and Ar ² are each independently selected from the group consisting of imidazolyl, oxazolyl, thiazolyl, pyridyl, pyrimidinyl, piperazinyl and phenyl, each of which is optionally one or more The same or different halogen, C _1-6 alkyl and C _3-6 cycloalkyl substituted.

在优选的实施方案中，Ar¹选自：In a preferred embodiment, Ar ^{1 is} selected from the group consisting of

其中R^c在每次出现时各自独立地选自F、Cl、Br、I、C_1-6烷基、卤代C_1-6烷基和C_3-6环烷基；Wherein R ^c is each independently selected from the group consisting of F, Cl, Br, I, C _1-6 alkyl, halo C _1-6 alkyl, and C _3-6 cycloalkyl;

优选地R^c在每次出现时各自独立地选自F、Cl、Br、I、C_1-6烷基和C_3-6环烷基；Preferably, each occurrence of R ^c is independently selected from the group consisting of F, Cl, Br, I, C _1-6 alkyl and C _3-6 cycloalkyl;

Ar¹优选自：Ar ¹ is preferably selected from:

Ar¹更优选自：Ar ^{1 is} more preferably from:

在优选的实施方案中，Ar²选自：In a preferred embodiment, Ar ^{2 is} selected from the group consisting of

以上基团任选地被一个或多个选自卤素、C_1-6烷基、卤代C_1-6烷基和C_3-6环烷基的基团取代。The above groups are optionally substituted by one or more groups selected from the group consisting of halogen, _C1-6 alkyl, halogenated _C1-6 alkyl and _C3-6 cycloalkyl.

在更优选的实施方案中，Ar²选自：In a more preferred embodiment, Ar ^{2 is} selected from the group consisting of

以上基团任选地被一个或多个选自卤素、C_1-6烷基和C_3-6环烷基的基团取代。The above groups are optionally substituted by one or more groups selected from the group consisting of halogen, C _1-6 alkyl and C _3-6 cycloalkyl.

在优选的实施方案中，L为-O-。In a preferred embodiment, L is -O-.

在优选的实施方案中，R³和R⁴各自独立地选自甲基、乙基、正丙基和异丙基。In a preferred embodiment, R ³ and R ⁴ are each independently selected from the group consisting of methyl, ethyl, n-propyl and isopropyl.

在特别优选的实施方案中，R⁴为H。In a particularly preferred embodiment, R ⁴ is H.

在优选的实施方案中，R⁵和R⁶在每次出现时各自独立地选自F、Cl、Br、I、-OH、-COOH、甲基、乙基、-CH₂OH、-OCH₃、-CH₂COOH、-CH₂CH₂COOH、-CH₂CH₂CH₂COOH、-CH＝CHCOOH、-OCH₂COOH、-SCH₂COOH、-N(CH₃)CH₂COOH、-CH₂OCH₂COOH、-CH₂SCH₂COOH和 -CH₂N(CH₃)CH₂COOH。In a preferred embodiment, each occurrence of R ⁵ and R ⁶ is independently selected from the group consisting of F, Cl, Br, I, -OH, -COOH, methyl, ethyl, -CH ₂ OH, -OCH ₃ , -CH ₂ COOH, -CH ₂ CH ₂ COOH, -CH ₂ CH ₂ CH ₂ COOH, -CH=CHCOOH, -OCH ₂ COOH, -SCH ₂ COOH, -N(CH ₃ )CH ₂ COOH, -CH ₂ OCH ₂ COOH, -CH ₂ SCH ₂ COOH and -CH ₂ N(CH ₃ )CH ₂ COOH.

在优选的实施方案中，R²选自H、C_1-12烷基、C_3-6环烷基、C_6-14芳基、5-14元杂芳基、C_6-20芳烷基、-C_1-6亚烷基-C(＝O)O-C_1-6烷基、-C_1-6亚烷基-OC(＝O)-C_1-6烷基、-C_1-6亚烷基-OC(＝O)O-C_1-6烷基和-((CH₂)_iO)_m-(CH₂)_q-O-C_1-6烷基，上述基团各自任选地被一个或多个选自卤素、-OH、-CN、-NO₂、-N(R)₂、C_1-6烷基、卤代C_1-6烷基、C_1-6烷基硫基和C_3-6环烷基的取代基取代；In a preferred embodiment, R ^{2 is} selected from the group consisting of H, C _1-12 alkyl, C _3-6 cycloalkyl, C _6-14 aryl, 5-14 membered heteroaryl, C _6-20 aralkyl , -C _1-6 alkylene-C(=O)OC _1-6 alkyl, -C _1-6 alkylene-OC(=O)-C _1-6 alkyl, -C _1-6 Alkyl-OC(=O)OC _1-6 alkyl and -((CH ₂ ) _i O) _m -(CH ₂ ) _q -OC _1-6 alkyl, each of which is optionally one or more One selected from the group consisting of halogen, -OH, -CN, -NO ₂ , -N(R) ₂ , C _1-6 alkyl, halogenated C _1-6 alkyl, C _1-6 alkylthio and C _3- a substituent of a ₆ cycloalkyl group;

在更优选的实施方案中，R²选自：C_1-6烷基、-((CH₂)_iO)_m-(CH₂)_q-O-C_1-6烷基、In a more preferred embodiment, R ^{2 is} selected from the group consisting of: C _1-6 alkyl, -((CH ₂ ) _i O) _m -(CH ₂ ) _q -OC _1-6 alkyl,

其中：among them:

R⁷、R⁸和R⁹各自独立地选自H、C_1-10烷基、C_3-6环烷基、C_6-20芳基和C_7-20芳烷基，所述烷基、环烷基、芳基和芳烷基各自任选地被一个或多个选自卤素、-OH、-CN和-NO₂的取代基取代；R ⁷ , R ⁸ and R ⁹ are each independently selected from the group consisting of H, C _1-10 alkyl, C _3-6 cycloalkyl, C _6-20 aryl and C _7-20 aralkyl, said alkyl group, The cycloalkyl, aryl and aralkyl groups are each optionally substituted by one or more substituents selected from the group consisting of halogen, -OH, -CN and -NO ₂ ;

或者R⁷和R⁸连同其所连接的碳原子共同形成C_3-6环烷基；Or R ⁷ and R ⁸ together with the carbon atom to which they are attached form a C _3-6 cycloalkyl group;

R¹⁰和R¹¹各自独立地选自H、卤素、-OH、-CN、-NO₂、C_1-10烷基和C_3-6环烷基。R ¹⁰ and R ¹¹ are each independently selected from the group consisting of H, halogen, -OH, -CN, -NO ₂ , C _1-10 alkyl, and C _3-6 cycloalkyl.

在更优选的实施方案中，R²选自：C_1-6烷基、-((CH₂)_iO)_m-(CH₂)_q-O-C_1-4烷基、

In a more preferred embodiment, R ^{2 is} selected from the group consisting of: C _1-6 alkyl, -((CH ₂ ) _i O) _m -(CH ₂ ) _q -OC _1-4 alkyl,

其中：among them:

i和q在每次出现时各自独立地为1、2、3或4；i and q are each independently 1, 2, 3 or 4 at each occurrence;

m为1、2、3、4、5或6；m is 1, 2, 3, 4, 5 or 6;

R⁷和R⁹各自独立地选自H或C_1-4烷基，所述烷基任选地被一个或多个选自卤素、-OH、-CN和-NO₂的取代基取代；R ⁷ and R ⁹ are each independently selected from H or C _1-4 alkyl, and the alkyl group is optionally substituted with one or more substituents selected from the group consisting of halogen, -OH, -CN, and -NO ₂ ;

R¹⁰和R¹¹各自独立地选自H、卤素、-OH、-CN、-NO₂或C_1-4烷基。R ¹⁰ and R ¹¹ are each independently selected from H, halogen, -OH, -CN, -NO ₂ or C _1-4 alkyl.

在特别优选的实施方案中，R²选自H、甲基、乙基、丙基、丁基、戊基、-((CH₂)₂O)₆-(CH₂)₂-O-CH₃、

In a particularly preferred embodiment, R ^{2 is} selected from the group consisting of H, methyl, ethyl, propyl, butyl, pentyl, -((CH ₂ ) ₂ O) ₆ -(CH ₂ ) ₂ -O-CH ₃ ,

在特别优选的实施方案中，R²选自甲基、乙基、丙基、丁基、-((CH₂)₂O)₆-(CH₂)₂-O-CH₃、

In a particularly preferred embodiment, R ^{2 is} selected from the group consisting of methyl, ethyl, propyl, butyl, -((CH ₂ ) ₂ O) ₆ -(CH ₂ ) ₂ -O-CH ₃ ,

在优选的实施方案中，n为0、1、2或3。In a preferred embodiment, n is 0, 1, 2 or 3.

在优选的实施方案中，本发明提供化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物或前药，其中所述化合物具有式(II)或式(II)-1的结构：In a preferred embodiment, the invention provides a compound, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite or prodrug thereof, wherein The compound has the structure of formula (II) or formula (II)-1:

在优选的实施方案中，本发明提供化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物或前药，其中所述化合物具有任意下式的结构：In a preferred embodiment, the invention provides a compound, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite or prodrug thereof, wherein The compound has any structure of the following formula:

本发明涵盖对各个实施方案进行任意组合所得的化合物。The present invention encompasses compounds obtained by any combination of the various embodiments.

在优选的实施方案中，本发明提供化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物或前药，其中所述化合物选自：In a preferred embodiment, the invention provides a compound, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite or prodrug thereof, wherein Said compound is selected from:

本发明的一个实施方案提供制备本发明的化合物的方法，所述方法包括以下步骤：One embodiment of the invention provides a method of preparing a compound of the invention, the method comprising the steps of:

或者

or

其中：among them:

其余各基团如上述所定义；The remaining groups are as defined above;

第一步在有机碱或无机碱和/或缩合试剂的存在下，在非质子性溶剂中或无溶剂条件下进行；The first step is carried out in the presence of an organic base or an inorganic base and/or a condensation reagent in an aprotic solvent or without a solvent;

第四步在非质子性溶剂中，优选在有机碱或无机碱和/或缩合试剂的存在下进行。The fourth step is carried out in an aprotic solvent, preferably in the presence of an organic base or an inorganic base and/or a condensation reagent.

其中：among them:

其余各基团如上述所定义；The remaining groups are as defined above;

在优选的实施方案中，R¹²、R¹³和R¹⁴各自独立地选自F、Cl、Br、I、NH₂或羟基。In a preferred embodiment, R ¹² , R ¹³ and R ¹⁴ are each independently selected from the group consisting of F, Cl, Br, I, NH ₂ or a hydroxyl group.

在优选的实施方案中，PG可为叔丁氧羰基，适于脱除叔丁氧羰基的条件可为例如在酸(例如三氟乙酸)催化下于溶剂(例如二氯甲烷)中，在0℃至室温下进行。In a preferred embodiment, PG may be a tert-butoxycarbonyl group, and the conditions suitable for the removal of the tert-butoxycarbonyl group may be, for example, catalyzed by an acid such as trifluoroacetic acid in a solvent such as dichloromethane at 0. °C to room temperature.

在优选的实施方案中，LG-OH可为五氟苯酚、对硝基苯酚。In a preferred embodiment, LG-OH can be pentafluorophenol, p-nitrophenol.

在优选的实施方案中，可在本发明的化合物制备方法中使用的非质子性溶剂包括但不限于四氢呋喃、二氯甲烷、1,2-二氯乙烷、乙腈、N,N-二甲基甲酰胺(DMF)、N-甲基吡咯烷酮、1,3-二甲基-2-咪唑啉酮(DMI)、二甲基亚砜(DMSO)和六甲基磷酰三胺(HMPA)。In a preferred embodiment, the aprotic solvent which can be used in the method of preparing the compound of the present invention includes, but is not limited to, tetrahydrofuran, dichloromethane, 1,2-dichloroethane, acetonitrile, N,N-dimethyl Formamide (DMF), N-methylpyrrolidone, 1,3-dimethyl-2-imidazolidinone (DMI), dimethyl sulfoxide (DMSO), and hexamethylphosphoric triamide (HMPA).

在优选的实施方案中，可在本发明的化合物制备方法中使用的有机碱包括但不限于叔丁醇钠、叔丁基氯化镁、三乙胺、N,N-二异丙基乙胺(DIPEA)、吡啶或4-二甲氨基吡啶(DMAP)；可在本发明的化合物制备方法中使用的无机碱包括但不限于NaH、NaOH、Na₂CO₃或K₂CO₃。In a preferred embodiment, the organic bases which can be used in the preparation of the compounds of the invention include, but are not limited to, sodium t-butoxide, t-butylmagnesium chloride, triethylamine, N,N-diisopropylethylamine (DIPEA) , pyridine or 4-dimethylaminopyridine (DMAP); inorganic bases which can be used in the preparation of the compounds of the invention include, but are not limited to, NaH, NaOH, Na ₂ CO ₃ or K ₂ CO ₃ .

在优选的实施方案中，可在本发明的化合物制备方法中使用的缩合试剂包括但不限于二环己基碳二亚胺(DCC)、N,N-二异丙基碳二亚胺(DIC)、1-(3-二甲氨基丙基)-3-乙基碳二亚胺(EDC)、苯并三氮唑-1-基氧基三(二甲基氨基)磷鎓六氟磷酸盐(BOP)、(3H-1,2,3-***并[4,5-b]吡啶-3-氧基)三-1-吡咯烷基磷鎓六氟磷酸盐(PyAOP)和1H-苯并***-1-基氧三吡咯烷基磷鎓六氟磷酸盐(PyBOP)。In a preferred embodiment, the condensation reagents which can be used in the method of preparing the compounds of the invention include, but are not limited to, dicyclohexylcarbodiimide (DCC), N,N-diisopropylcarbodiimide (DIC). , 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate ( BOP), (3H-1,2,3-triazolo[4,5-b]pyridin-3-yloxy)tri-1-pyrrolidinylphosphonium hexafluorophosphate (PyAOP) and 1H-benzo Triazol-1-yloxytripyrrolidinylphosphonium hexafluorophosphate (PyBOP).

药物组合物和治疗方法Pharmaceutical compositions and methods of treatment

在另种实施方案中，本发明提供药物组合物，其包含预防或治疗有效量的本发明的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物或前药以及一种或多种药学上可接受的载体。在另种实施方案中，所述药物组合物还可包含一种或多种其它治疗剂，例如用于预防或治疗病毒性疾病的其它治疗剂。 In another embodiment, the invention provides a pharmaceutical composition comprising a prophylactically or therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph thereof, or a pharmaceutically acceptable salt thereof A form, solvate, metabolite or prodrug and one or more pharmaceutically acceptable carriers. In another embodiment, the pharmaceutical composition may further comprise one or more additional therapeutic agents, such as other therapeutic agents for preventing or treating viral diseases.

在另种实施方案中，本发明提供制备药物组合物的方法，所述方法包括将本发明的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物或前药与一种或多种药学上可接受的载体组合。In another embodiment, the invention provides a method of preparing a pharmaceutical composition comprising the compound of the invention, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph thereof, or a pharmaceutically acceptable salt thereof The form, solvate, metabolite or prodrug is combined with one or more pharmaceutically acceptable carriers.

在另种实施方案中，本发明提供本发明的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物或前药或者本发明的药物组合物在制备用于预防或治疗病毒性疾病的药物中的用途。In another embodiment, the invention provides a compound of the invention, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite or prodrug thereof, Or the use of the pharmaceutical composition of the present invention in the preparation of a medicament for preventing or treating a viral disease.

在另种实施方案中，本发明提供本发明的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物或前药或者本发明的药物组合物，其用于预防或治疗病毒性疾病。In another embodiment, the invention provides a compound of the invention, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite or prodrug thereof, Or a pharmaceutical composition of the invention for use in the prevention or treatment of a viral disease.

在另种实施方案中，本发明提供预防或治疗病毒性疾病的方法，所述方法包括向需要其的个体给药有效量的本发明的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物或前药或者本发明的药物组合物。In another embodiment, the invention provides a method of preventing or treating a viral disease, the method comprising administering to an individual in need thereof an effective amount of a compound of the invention, or a pharmaceutically acceptable salt, ester, or stereoisod thereof A construct, tautomer, polymorph, solvate, metabolite or prodrug or a pharmaceutical composition of the invention.

本发明的优选化合物通过对逆转录酶和/或衣壳蛋白装配的抑制作用来发挥抗病毒作用。因此，本发明的化合物可用于治疗在影响宿主的过程中涉及到逆转录酶和/或衣壳蛋白装配的任意病毒，其包括但不限于甲型肝炎病毒(HAV)、乙型肝炎病毒(HBV)、丙型肝炎病毒(HCV)、流行性感冒病毒、疱疹病毒(HSV)和人类免疫缺陷病毒(HIV)。Preferred compounds of the invention exert an antiviral effect by inhibiting the assembly of reverse transcriptase and/or capsid protein. Thus, the compounds of the invention are useful in the treatment of any virus involved in the assembly of reverse transcriptase and/or capsid proteins in the process of affecting a host, including but not limited to hepatitis A virus (HAV), hepatitis B virus (HBV) ), hepatitis C virus (HCV), influenza virus, herpes virus (HSV) and human immunodeficiency virus (HIV).

因此，可使用本发明的化合物进行预防和治疗的病毒性疾病包括但不限于甲型病毒性肝炎、乙型病毒性肝炎、丙型病毒性肝炎、流行性感冒、疱疹和获得性免疫缺陷综合征(AIDS)，以及由上述疾病引发的相关症状或疾病(例如炎症、肝纤维化、肝硬化和肝癌等)。Thus, viral diseases which can be prevented and treated using the compounds of the present invention include, but are not limited to, viral hepatitis A, hepatitis B virus, hepatitis C virus, influenza, herpes, and acquired immunodeficiency syndrome. (AIDS), and related symptoms or diseases caused by the above diseases (for example, inflammation, liver fibrosis, cirrhosis, liver cancer, etc.).

本发明中“药学上可接受的载体”是指与治疗剂一同给药的稀释剂、辅剂、赋形剂或媒介物，并且其在合理的医学判断的范围内适于接触人类和/或其它动物的组织而没有过度的毒性、刺激、过敏反应或与合理的益处/风险比相应的其它问题或并发症。"Pharmaceutically acceptable carrier" in the context of the present invention means a diluent, adjuvant, excipient or vehicle with which the therapeutic agent is administered, and which is suitable for contacting humans and/or within the scope of sound medical judgment. Tissues of other animals without excessive toxicity, irritation, allergic reactions, or other problems or complications corresponding to a reasonable benefit/risk ratio.

在本发明的药物组合物中可使用的药学上可接受的载体包括但不限于无菌液体，例如水和油，包括那些石油、动物、植物或合成来源的油，例如花生油、大豆油、矿物油、芝麻油等。当所述药物组合物通过静脉内给药时，水是示例性载体。还可以使用生理盐水和葡萄糖及甘油水溶液作为液体载体，特别是用于注射液。适合的药物赋形剂包括淀粉、葡萄糖、乳糖、蔗糖、明胶、麦芽糖、白垩、硅胶、硬脂酸钠、单硬脂酸甘油酯、滑石、氯化钠、脱脂奶粉、甘油、丙二醇、水、乙醇等。所述组合物还可以视需要包含少量的湿润剂、乳化剂或pH缓冲剂。口服制剂可以包含标准载体，如药物级的甘露醇、乳糖、淀粉、硬脂酸镁、糖精钠、纤维素、碳酸镁等。适合的药学上可接受的载体的实例如在Remington’s Pharmaceutical Sciences(1990)中所述。Pharmaceutically acceptable carriers that can be used in the pharmaceutical compositions of the present invention include, but are not limited to, sterile liquids such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, minerals. Oil, sesame oil, etc. Water is an exemplary carrier when the pharmaceutical composition is administered intravenously. It is also possible to use physiological saline and an aqueous solution of glucose and glycerin as a liquid carrier, particularly for injection. Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, maltose, chalk, silica gel, sodium stearate, glyceryl monostearate, talc, sodium chloride, skimmed milk powder, glycerin, propylene glycol, water, Ethanol and the like. The composition may also contain minor amounts of wetting agents, emulsifying agents or pH buffering agents as needed. Oral formulations may contain standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, and the like. Examples of suitable pharmaceutically acceptable carriers are as described in Remington's Pharmaceutical Sciences (1990).

本发明的药物组合物可以***地作用和/或局部地作用。为此目的，它们可以适合的途径给药，例如通过注射(如静脉内、动脉内、皮下、腹膜内、肌内注射，包括滴注)或经皮给药；或通过口服、含服、经鼻、透粘膜、局部、以眼用制剂的形式或通过吸入给药。The pharmaceutical compositions of the invention may act systemically and/or locally. For this purpose, they may be administered in a suitable route, for example by injection (for example intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular, including instillation) or transdermal administration; or by oral, buccal, or oral administration. Nasal, transmucosal, topical, in the form of ophthalmic preparations or by inhalation.

对于这些给药途径，可以适合的剂型给药本发明的药物组合物。For these routes of administration, the pharmaceutical compositions of the invention may be administered in a suitable dosage form.

所述剂型包括但不限于片剂、胶囊剂、锭剂、硬糖剂、散剂、喷雾剂、乳膏剂、软膏剂、栓剂、凝胶剂、糊剂、洗剂、软膏剂、水性混悬剂、可注射溶液剂、酏剂、糖浆剂。The dosage forms include, but are not limited to, tablets, capsules, troches, hard candy, powders, sprays, creams, ointments, suppositories, gels, pastes, lotions, ointments, aqueous suspensions. Injectable solutions, elixirs, syrups.

如本文中所使用的术语“有效量”指被给药后会在一定程度上缓解所治疗病症的一或多种症状的化合物的量。The term "effective amount" as used herein refers to an amount of a compound that, to a certain extent, relieves one or more symptoms of the condition being treated after administration.

可调整给药方案以提供最佳所需响应。例如，可给药单次推注，可随时间给药数个分剂量，或可如治疗情况的急需所表明而按比例减少或增加剂量。要注意，剂量值可随要减轻的病况的类型及严重性而变化，且可包括单次或多次剂量。要进一步理解，对于任何特定个体，具体的给药方案应根据个体需要及给药组合物或监督组合物的给药的人员的专业判断来随时间调整。The dosing regimen can be adjusted to provide the optimal desired response. For example, a single bolus may be administered, several divided doses may be administered over time, or the dose may be proportionally reduced or increased as indicated by the urgent need for treatment. It is noted that the dose value can vary with the type and severity of the condition to be alleviated and can include single or multiple doses. It is to be further understood that for any particular individual, the particular dosage regimen will be adjusted over time according to the individual needs and the professional judgment of the person administering the composition or the composition of the supervised composition.

所给药的本发明的化合物的量会取决于所治疗的个体、病症或病况的严重性、给药的速率、化合物的处置及处方医师的判断。一般而言，有效剂量在每日每kg体重约0.0001至约50mg，例如约0.01至约10mg/kg/日(单次或分次给药)。对70kg的人而言，这会合计为约0.007mg/日至约3500mg/日，例如约0.7mg/日至约700mg/日。在一些情况下，不高于前述范围的下限的剂量水平可以是足够的，而在其它情况下，仍可在不引起任何有害副作用的情况下采用较大剂量，条件是首先将所述较大剂量分成数个较小剂量以在一整天中给药。The amount of the compound of the invention administered will depend on the severity of the individual, condition or condition being treated, the rate of administration, the handling of the compound, and the judgment of the prescribing physician. Generally, an effective dose will be from about 0.0001 to about 50 mg per kg body weight per day, for example from about 0.01 to about 10 mg/kg/day (single or divided doses). For a 70 kg person, this would add up to about 0.007 mg/day to about 3500 mg/day, such as from about 0.7 mg/day to about 700 mg/day. In some cases, a dose level that is not higher than the lower limit of the aforementioned range may be sufficient, while in other cases, a larger dose may still be employed without causing any harmful side effects, provided that the larger The dose is divided into several smaller doses to be administered throughout the day.

本发明的化合物在药物组合物中的含量或用量可以是约0.01mg至约1000mg，适合地是0.1-500mg，优选0.5-300mg，更优选1-150mg，特别优选1-50mg，例如1.5mg、2mg、4mg、10mg、25mg等。 The amount or amount of the compound of the present invention in the pharmaceutical composition may be from about 0.01 mg to about 1000 mg, suitably from 0.1 to 500 mg, preferably from 0.5 to 300 mg, more preferably from 1 to 150 mg, particularly preferably from 1 to 50 mg, for example, 1.5 mg, 2 mg, 4 mg, 10 mg, 25 mg, and the like.

除非另外说明，否则如本文中所使用，术语“治疗(treating)”意指逆转、减轻、抑制这样的术语所应用的病症或病况或者这样的病症或病况的一或多种症状的进展，或预防这样的病症或病况或者这样的病症或病况的一或多种症状。The term "treating" as used herein, unless otherwise indicated, means reversing, alleviating, inhibiting the progression of a condition or condition to which such a term applies or one or more symptoms of such a condition or condition, or Prevention of such a condition or condition or one or more symptoms of such condition or condition.

如本文所使用的“个体”包括人或非人动物。示例性人个体包括患有疾病(例如本文所述的疾病)的人个体(称为患者)或正常个体。本发明中“非人动物”包括所有脊椎动物，例如非哺乳动物(例如鸟类、两栖动物、爬行动物)和哺乳动物，例如非人灵长类、家畜和/或驯化动物(例如绵羊、犬、猫、奶牛、猪等)。"Individual" as used herein includes human or non-human animals. Exemplary human individuals include a human individual (referred to as a patient) or a normal individual having a disease, such as the disease described herein. "Non-human animals" in the present invention include all vertebrates, such as non-mammals (eg, birds, amphibians, reptiles) and mammals, such as non-human primates, domestic animals, and/or domesticated animals (eg, sheep, dogs). , cats, cows, pigs, etc.).

在另种实施方案中，本发明的药物组合物还可以包含一种或多种另外的治疗剂或预防剂，其包括但不限于拉米夫定、替比夫定、恩替卡韦、阿德福韦酯、替诺福韦、替诺福韦二吡呋酯富马酸盐以及替诺福韦艾拉酚胺富马酸盐。In another embodiment, the pharmaceutical compositions of the present invention may further comprise one or more additional therapeutic or prophylactic agents including, but not limited to, lamivudine, telbivudine, entecavir, adefovir Ester, tenofovir, tenofovir disoproxil fumarate, and tenofovir alafenamide fumarate.

实施例Example

以下结合实施例进一步描述本发明，但提供这些实施例并非意在限制本发明的范围。The invention is further described in the following examples, but these examples are not intended to limit the scope of the invention.

除非另外说明，均使用市售的无水溶剂和HPLC级溶剂而不经进一步的纯化。Commercially available anhydrous solvents and HPLC grade solvents were used without further purification unless otherwise stated.

用Bruker仪器(400MHz)在环境温度下记录¹H NMR光谱，使用TMS为内标。化学位移(δ)以ppm为单位给出，耦合常数(J)以赫兹(Hz)为单位给出。¹H NMR波谱峰的裂分重数缩写如下：s(单峰)、d(双峰)、t(三重峰)、q(四重峰)、m(多重峰)、br(宽峰)。 ¹ H NMR spectra were recorded at ambient temperature using a Bruker instrument (400 MHz) using TMS as an internal standard. The chemical shift (δ) is given in ppm and the coupling constant (J) is given in hertz (Hz). ^The fractional weights of the ¹ H NMR spectrum peaks are abbreviated as follows: s (single peak), d (doublet), t (triplet), q (quadruple), m (multiplet), br (broad).

LC-MS采用Aglient 1200液相色谱仪联用Aglient 6120Quadrupole型质谱仪，在214nm及254nm下检测。制备液相色谱法使用SHIMADZU CBM-20A及Aglient 1260型制备液相仪，C18OBD 19×150mm 5μM制备柱，检测波长214nm，流动相A为水，流动相B为乙腈(添加0.5‰甲酸)，按下表进行线性梯度洗脱：LC-MS was detected on an Aglient 1200 liquid chromatograph using an Aglient 6120 Quadrupole mass spectrometer at 214 nm and 254 nm. Prepare liquid chromatography using SHIMADZU CBM-20A and Aglient 1260 to prepare liquid phase meter, C18OBD 19×150mm 5μM preparative column, detection wavelength 214nm, mobile phase A is water, mobile phase B is acetonitrile (add 0.5 ‰ formic acid), press The following table performs a linear gradient elution:

时间(min)Time (min)	A％A%	B％B%
00	9090	1010
1515	4040	6060
3030	1010	9090

实施例一(4R)-6-((4-(4-((((((R)-1-(6-氨基-9H-嘌呤-9-基)丙-2-基)氧基)甲基)((2-甲基苄基)氧基)膦酰基)氧基)苯基)哌啶-1-基)甲基)-4-(2-氯-4-氟苯基)-2-(噻唑-2-基)-1,4-二氢嘧啶-5-羧酸乙酯(化合物1)Example 1 (4R)-6-((4-(4-(((((()))))))))) ((2-methylbenzyl)oxy)phosphonyloxy)phenyl)piperidin-1-yl)methyl)-4-(2-chloro-4-fluorophenyl)-2- Ethyl (thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (Compound 1)

步骤一：4-(4-羟基苯基)哌啶-1-羧酸叔丁酯(化合物1-2)的合成Step 1: Synthesis of 4-(4-hydroxyphenyl)piperidine-1-carboxylic acid tert-butyl ester (Compound 1-2)

室温下，将4-(4-(苄氧基)苯基)-3,6-二氢吡啶-1(2H)-羧酸叔丁酯(化合物1-1)(3.0g，8.2mmol)加入到四氢呋喃(10mL)和甲醇(20mL)中，化合物溶解完全后，于氮气保护下加入10％Pd/C(300mg)，加毕，氢气置换，在室温下反应18h，过滤，将滤液后处理得标题化合物(2.0g)。ESI-MS(m/z):222.1[M-55+H]⁺。4-(4-(Benzyloxy)phenyl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (Compound 1-1) (3.0 g, 8.2 mmol) was added at room temperature After the compound was completely dissolved in tetrahydrofuran (10 mL) and methanol (20 mL), 10% Pd/C (300 mg) was added under nitrogen atmosphere, and the mixture was replaced with hydrogen. The mixture was reacted at room temperature for 18 hours, filtered, and the filtrate was post-treated. The title compound (2.0 g). ESI-MS (m/z): 2221. [M-55+H] ⁺ .

步骤二：4-(4-((((((R)-1-(6-氨基-9H-嘌呤-9-基)丙-2-基)氧基)甲基)(羟基)膦酰基)氧基)苯基)哌啶-1-羧酸叔丁酯(化合物1-3)的合成Step 2: 4-(4-((((()))))))))))))))))) Synthesis of tert-butyl ester of oxy)phenyl)piperidine-1-carboxylate (Compound 1-3)

室温下，将(R)-9-(2-磷酸甲氧基丙基)-腺嘌呤(3.1g，10.8mmol)、化合物1-2(2.0g，7.2mmol)溶于N-甲基吡咯烷酮(20mL)中，升温至85℃，滴加三乙胺(879mg，8.9mmol)，加毕后继续升温至 100℃，滴加二环己基碳二亚胺(4.8g，23.1mmol)的N-甲基吡咯烷酮(10mL)溶液，滴毕，在100℃下反应过夜，后处理得标题化合物(1.0g)。ESI-MS(m/z):547.2[M+H]⁺。(R)-9-(2-methoxymethoxypropyl)-adenine (3.1 g, 10.8 mmol) and compound 1-2 (2.0 g, 7.2 mmol) were dissolved in N-methylpyrrolidone at room temperature ( In 20 mL), the temperature was raised to 85 ° C, and triethylamine (879 mg, 8.9 mmol) was added dropwise. After the addition, the temperature was further increased to 100 ° C, and dicyclohexylcarbodiimide (4.8 g, 23.1 mmol) of N-A was added dropwise. A solution of the pyrrolidone (10 mL) was added dropwise, and the reaction was carried out at 100 ° C overnight to give the title compound (1.0 g). ESI-MS (m/z): 547.2 [M+H] ⁺ .

步骤三：((((R)-1-(6-氨基-9H-嘌呤-9-基)丙-2-基)氧基)甲基)-4-(哌啶-4-基)-苯基-单磷酸酯(化合物1-4)的合成Step 3: ((((R)-1-(6-amino-9H-indol-9-yl)propan-2-yl)oxy)methyl)-4-(piperidin-4-yl)-benzene Synthesis of base-monophosphate (compounds 1-4)

室温下，将化合物1-3(200mg，0.4mmol)加入到二氯甲烷(5.0mL)中，化合物溶解完全后加入三氟乙酸(0.2mL)，加毕，使其在室温下反应2.5h，后处理得标题化合物的三氟乙酸盐(200mg)。ESI-MS(m/z):447.2[M+H]⁺。Compound 1-3 (200 mg, 0.4 mmol) was added to dichloromethane (5.0 mL) at room temperature. After the compound was dissolved, trifluoroacetic acid (0.2 mL) was added, and the mixture was allowed to react at room temperature for 2.5 h. The title compound was trifluoroacetate (200 mg). ESI-MS (m/z): 447.2 [M+H] ⁺ .

步骤四：(4R)-6-((4-(4-((((((R)-1-(6-氨基-9H-嘌呤-9-基)丙-2-基)氧基)甲基)(羟基)膦酰基)氧基)苯基)哌啶-1-基)甲基)-4-(2-氯-4-氟苯基)-2-(噻唑-2-基)-1,4-二氢嘧啶-5-羧酸乙酯(化合物1-5)的合成Step 4: (4R)-6-((4-(4-(((((())))))))) (hydroxy)phosphonyloxy)phenyl)piperidin-1-yl)methyl)-4-(2-chloro-4-fluorophenyl)-2-(thiazol-2-yl)-1 Synthesis of 4-Dihydropyrimidine-5-carboxylic acid ethyl ester (Compound 1-5)

室温下，将化合物1-4的三氟乙酸盐(163mg,0.4mmol)溶于1,2-二氯乙烷(4mL)中，依次加入(R)-6-(溴甲基)-4-(2-氯-4-氟苯基)-2-(噻唑-2-基)-1,4-二氢嘧啶-5-羧酸乙酯(204mg，0.4mmol)和N,N-二异丙基乙胺(0.1mL)，加毕，在室温下反应过夜，后处理得标题化合物(130mg)。ESI-MS(m/z):824.2[M+H]⁺。Trifluoroacetate salt of compound 1-4 (163 mg, 0.4 mmol) was dissolved in 1,2-dichloroethane (4 mL) at room temperature, followed by (R)-6-(bromomethyl)-4 -(2-Chloro-4-fluorophenyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylic acid ethyl ester (204 mg, 0.4 mmol) and N,N-diiso The propyl ethylamine (0.1 mL) was added and the mixture was evaporated. ESI-MS (m/z): 824.2 [M+H] ⁺ .

步骤五：(4R)-6-((4-(4-((((((R)-1-(6-氨基-9H-嘌呤-9-基)丙-2-基)氧基)甲基)((2-甲基苄基)氧基)膦酰基)氧基)苯基)哌啶-1-基)甲基)-4-(2-氯-4-氟苯基)-2-(噻唑-2-基)-1,4-二氢嘧啶-5-羧酸乙酯(化合物1)的合成Step 5: (4R)-6-((4-(4-(((((()))))))))) ((2-methylbenzyl)oxy)phosphonyloxy)phenyl)piperidin-1-yl)methyl)-4-(2-chloro-4-fluorophenyl)-2- Synthesis of Ethyl (thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (Compound 1)

室温下，将化合物1-5(30mg，0.04mmol)、邻甲基苯甲醇(9.0mg，0.07mmol)、1H-苯并***-1-基氧三吡咯烷基磷鎓六氟磷酸盐(PyBOP)(38mg，0.07mmol)溶于N,N-二甲基甲酰胺(3mL)中，溶解完全后，滴加N,N-二异丙基乙胺(19mg，0.14mmol)，加毕，在室温下反应4h，纯化后得标题化合物(9mg)。Compound 1-5 (30 mg, 0.04 mmol), o-methylbenzyl alcohol (9.0 mg, 0.07 mmol), 1H-benzotriazol-1-yloxytripyrrolidinylphosphonium hexafluorophosphate (at room temperature) PyBOP) (38 mg, 0.07 mmol) was dissolved in N,N-dimethylformamide (3 mL). After dissolved, N,N-diisopropylethylamine (19 mg, 0.14 mmol) was added dropwise. After reacting for 4 h at rt, the title compound (9 mg).

其结构表征如下：Its structural representation is as follows:

¹H NMR(400MHz,DMSO-d₆)δ9.78(s,1H),8.13(s,1H),8.05-8.03(m,2H),7.95(d,J＝3.13Hz,1H),7.44-7.40(m,2H),7.30-7.14(m,9H),7.03(d,J＝8.20Hz,1H),6.96(d,J＝8.12Hz,1H),6.06(s,1H),5.15-5.08(m,2H),4.28-4.16(m,2H),4.11-3.87(m,7H),3.06(d,J＝10.39Hz,1H),2.88(d,J＝10.29Hz,1H),2.60-2.57(m,1H),2.44-2.39(m,1H),2.32-2.24(m,4H),1.88-1.67(m,4H),1.09-1.04(m,6H).ESI-MS(m/z):928.2[M+H]⁺。 ^{1 H NMR (400MHz, DMSO-} d 6) δ9.78 (s, 1H), 8.13 (s, 1H), 8.05-8.03 (m, 2H), 7.95 (d, J = 3.13Hz, 1H), 7.44- 7.40 (m, 2H), 7.30-7.14 (m, 9H), 7.03 (d, J = 8.20 Hz, 1H), 6.96 (d, J = 8.12 Hz, 1H), 6.06 (s, 1H), 5.15-5.08 (m, 2H), 4.28-4.16 (m, 2H), 4.11-3.87 (m, 7H), 3.06 (d, J = 10.39 Hz, 1H), 2.88 (d, J = 10.29 Hz, 1H), 2.60- 2.57(m,1H),2.44-2.39(m,1H),2.32-2.24(m,4H),1.88-1.67(m,4H),1.09-1.04(m,6H).ESI-MS(m/z ): 928.2 [M+H] ⁺ .

实施例二(4R)-6-((4-(4-((((((R)-1-(6-氨基-9H-嘌呤-9-基)丙-2-基)氧基)甲基)(((S)-1-乙氧基-1-氧代丙-2-基)氧基)膦酰基)氧基)苯基)哌啶-1-基)甲基)-4-(2-氯-4-氟苯基)-2-(噻唑-2-基)-1,4-二氢嘧啶-5-羧酸乙酯(化合物2)Example 2(4R)-6-((4-(4-(((((()))))))))) ((S)-1-ethoxy-1-oxopropan-2-yl)oxy)phosphonyl)oxy)phenyl)piperidin-1-yl)methyl)-4-( Ethyl 2-chloro-4-fluorophenyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (Compound 2)

室温下，将化合物1-5(30mg,0.04mmol)、L-乳酸乙酯(8.0mg,0.07mmol)和PyBOP(38mg,0.07mmol)溶于N,N-二甲基甲酰胺(3mL)中，溶解完全后，滴加N,N-二异丙基乙胺(19mg,0.14mmol)，加毕，在室温下反应约4h，纯化后得标题化合物(5.0mg)。Compound 1-5 (30 mg, 0.04 mmol), L-ethyl lactate (8.0 mg, 0.07 mmol) and PyBOP (38 mg, 0.07 mmol) were dissolved in N,N-dimethylformamide (3 mL). After the dissolution was completed, N,N-diisopropylethylamine (19 mg, 0.14 mmol) was added dropwise.

其结构表征如下：Its structural representation is as follows:

¹H NMR(400MHz,DMSO-d₆)δ9.77(s,1H),8.13(s,1H),8.05(s,1H),8.03(d,J＝23.26Hz,1H),7.95(d,J＝3.13Hz,1H),7.44-7.40(m,2H),7.27-7.16(m,5H),7.05-7.03(m,2H),6.06(s,1H),5.00-4.92(m,1H),4.31-3.87(m,11H),3.06(d,J＝9.75Hz,1H),2.88(d,J＝11.02Hz,1H),2.60-2.57(m,1H),2.43-2.40(m,1H),2.33-2.26(m,1H),1.88-1.68(m,4H),1.35(dd,J＝21.76Hz,6.84Hz,3H),1.10(d,J＝6.22Hz,3H),1.05(t,J＝7.11Hz,3H),1.17(dt,J＝7.11Hz,3.05Hz,3H).ESI-MS(m/z):924.2[M+H]⁺。 ^{1 H NMR (400MHz, DMSO-} d 6) δ9.77 (s, 1H), 8.13 (s, 1H), 8.05 (s, 1H), 8.03 (d, J = 23.26Hz, 1H), 7.95 (d, J=3.13Hz,1H),7.44-7.40(m,2H), 7.27-7.16(m,5H),7.05-7.03(m,2H),6.06(s,1H),5.00-4.92(m,1H) , 4.31-3.87 (m, 11H), 3.06 (d, J = 9.75 Hz, 1H), 2.88 (d, J = 11.02 Hz, 1H), 2.60-2.57 (m, 1H), 2.43-2.40 (m, 1H) ), 2.33 - 2.26 (m, 1H), 1.88-1.68 (m, 4H), 1.35 (dd, J = 21.76 Hz, 6.84 Hz, 3H), 1.10 (d, J = 6.22 Hz, 3H), 1.05 (t , J = 7.11 Hz, 3H), 1.17 (dt, J = 7.11 Hz, 3.05 Hz, 3H). ESI-MS (m/z): 924.2 [M+H] ⁺ .

实施例三(4R)-6-((4-(4-((((((R)-1-(6-氨基-9H-嘌呤-9-基)丙-2-基)氧基)甲基)(((R)-1-乙氧基-1-氧代丙-2-基)氧基)膦酰基)氧基)苯基)哌啶-1-基)甲基)-4-(2-氯-4-氟苯基)-2-(噻唑-2-基)-1,4-二氢嘧啶-5-羧酸乙酯(化合物3) Example 3(4R)-6-((4-(4-(((((()))))))))) (((R)-1-ethoxy-1-oxopropan-2-yl)oxy)phosphonyl)oxy)phenyl)piperidin-1-yl)methyl)-4-( Ethyl 2-chloro-4-fluorophenyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (Compound 3)

室温下，将化合物1-5(30mg，0.04mmol)、D-乳酸乙酯(8.0mg，0.07mmol)和PyBOP(38mg，0.07mmol)溶于N,N-二甲基甲酰胺(3mL)中，溶解完全后，滴加N,N-二异丙基乙胺(19mg，0.14mmol)，加毕，在室温下反应4h，纯化后得标题化合物(6.0mg)。Compound 1-5 (30 mg, 0.04 mmol), D-ethyl lactate (8.0 mg, 0.07 mmol) and PyBOP (38 mg, 0.07 mmol) were dissolved in N,N-dimethylformamide (3 mL). After the dissolution was completed, N,N-diisopropylethylamine (19 mg, 0.14 mmol) was added dropwise.

其结构表征如下：Its structural representation is as follows:

¹H NMR(400MHz,CDCl₃)δ9.80(brs,1H),8.34(s,1H),7.99-7.89(m,2H),7.44(s,1H),7.33(s,1H),7.19(d,J＝8.15Hz,2H),7.14-7.11(m,1H),7.01-6.92(m,3H),6.22(s,1H),5.64(brs,2H),5.05-4.98(m,1H),4.39-4.34(m,1H),4.23-3.79(m,10H),3.02(d,J＝46.30Hz,2H),2.54-2.38(m,3H),1.90-1.86(m,4H),1.51(dd,J＝25.54Hz,6.92Hz,3H),1.29-1.21(m,6H),1.14(t,J＝7.10Hz,3H).ESI-MS(m/z):924.2[M+H]⁺。 ^{_{1 H NMR (400MHz, CDCl 3}} ) δ9.80 (brs, 1H), 8.34 (s, 1H), 7.99-7.89 (m, 2H), 7.44 (s, 1H), 7.33 (s, 1H), 7.19 ( d, J=8.15 Hz, 2H), 7.14-7.11 (m, 1H), 7.01-6.92 (m, 3H), 6.22 (s, 1H), 5.64 (brs, 2H), 5.05-4.98 (m, 1H) , 4.39-4.34 (m, 1H), 4.23 - 3.79 (m, 10H), 3.02 (d, J = 46.30 Hz, 2H), 2.54-2.38 (m, 3H), 1.90 - 1.86 (m, 4H), 1.51 (dd, J=25.54 Hz, 6.92 Hz, 3H), 1.29-1.21 (m, 6H), 1.14 (t, J = 7.10 Hz, 3H). ESI-MS (m/z): 924.2 [M+H] ⁺ .

实施例四(4R)-6-((4-(4-(((2,5,8,11,14,17,20-七氧杂二十二烷-22-基氧基)((((R)-1-(6-氨基-9H-嘌呤-9-基)丙-2-基)氧基)甲基)膦酰基)氧基)苯基)哌啶-1-基)甲基)-4-(2-氯-4-氟苯基)-2-(噻唑-2-基)-1,4-二氢嘧啶-5-羧酸乙酯(化合物4)Example 4(4R)-6-((4-(4-((2,5,8,11,14,17,20-heptaoxadocosin-22-yloxy)) ((( (R)-1-(6-Amino-9H-indol-9-yl)propan-2-yl)oxy)methyl)phosphonyloxy)phenyl)piperidin-1-yl)methyl) Ethyl 4-(2-chloro-4-fluorophenyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (Compound 4)

室温下，将化合物1-5(30mg，0.04mmol)、七甘醇单甲醚(24.0mg，0.07mmol)和PyBOP(38mg，0.07mmol)溶于N,N-二甲基甲酰胺(3mL)中，溶解完全后，滴加N,N-二异丙基乙胺(19mg，0.14mmol)，加毕，在室温下反应4h，纯化后得标题化合物(5.0mg)。Compound 1-5 (30 mg, 0.04 mmol), heptaethylene glycol monomethyl ether (24.0 mg, 0.07 mmol) and PyBOP (38 mg, 0.07 mmol) were dissolved in N,N-dimethylformamide (3 mL) After the dissolution was completed, N,N-diisopropylethylamine (19 mg, 0.14 mmol) was added dropwise.

其结构表征如下：Its structural representation is as follows:

¹H NMR(400MHz,CDCl₃)δ9.78(brs,1H),8.33(d,J＝2.16Hz,1H),7.97(d,J＝13.35Hz,1H),7.90(dd,J＝5.33Hz,3.17Hz,1H),7.44(d,J＝2.98Hz,1H),7.32(dd,J＝8.45Hz,6.24Hz,1H),7.22-7.16(m,2H),7.14-7.09(m,2H),7.01(d,J＝7.95Hz,1H),6.91(td,J＝8.36Hz,2.27Hz,1H),6.22(s,1H),5.79(brs,2H),4.36(ddd,J＝14.48Hz,6.43Hz,2.82Hz,1H),4.30-4.21(m,1H),4.17-4.12(m,1H),4.06-3.98(m,4H),3.88(d,J＝17.09Hz,1H),3.81-3.73(m,1H),3.64-3.53(m,28H),3.37(s,3H),3.05(d,J＝10.76Hz,1H),2.92(d,J＝10.87Hz,1H),2.53-2.47(m,2H),2.35(t,J＝8.41Hz,1H),1.89-1.77(m,4H),1.24(dd,J＝6.02Hz,4.16Hz,3H),1.13(t,J＝7.10Hz,3H).ESI-MS(m/z):573.8[M/2+H]⁺。 ^{_{1 H NMR (400MHz, CDCl 3}} ) δ9.78 (brs, 1H), 8.33 (d, J = 2.16Hz, 1H), 7.97 (d, J = 13.35Hz, 1H), 7.90 (dd, J = 5.33Hz , 3.17 Hz, 1H), 7.44 (d, J = 2.98 Hz, 1H), 7.32 (dd, J = 8.45 Hz, 6.24 Hz, 1H), 7.22 - 7.16 (m, 2H), 7.14 - 7.09 (m, 2H) ), 7.01 (d, J = 7.95 Hz, 1H), 6.91 (td, J = 8.36 Hz, 2.27 Hz, 1H), 6.22 (s, 1H), 5.79 (brs, 2H), 4.36 (ddd, J = 14.48) Hz, 6.43 Hz, 2.82 Hz, 1H), 4.30-4.21 (m, 1H), 4.17-4.12 (m, 1H), 4.06-3.98 (m, 4H), 3.88 (d, J = 17.09 Hz, 1H), 3.81-3.73 (m, 1H), 3.64-3.53 (m, 28H), 3.37 (s, 3H), 3.05 (d, J = 10.76 Hz, 1H), 2.92 (d, J = 10.87 Hz, 1H), 2.53 -2.47 (m, 2H), 2.35 (t, J = 8.41 Hz, 1H), 1.89-1.77 (m, 4H), 1.24 (dd, J = 6.02 Hz, 4.16 Hz, 3H), 1.13 (t, J = 7.10 Hz, 3H). ESI-MS (m/z): 573.8 [M / 2+H] ⁺ .

实施例五(4R)-6-((4-(4-((((((R)-1-(6-氨基-9H-嘌呤-9-基)丙-2-基)氧基)甲基)(戊氧基)膦酰基)氧基)苯基)哌啶-1-基)甲基)-4-(2-氯-4-氟苯基)-2-(噻唑-2-基)-1,4-二氢嘧啶-5-羧酸乙酯(化合物5)Example 5(4R)-6-((4-(4-(((((())))))))))) (pentyloxy)phosphonyloxy)phenyl)piperidin-1-yl)methyl)-4-(2-chloro-4-fluorophenyl)-2-(thiazol-2-yl) -1,4-dihydropyrimidine-5-carboxylic acid ethyl ester (Compound 5)

室温下，将化合物1-5(30mg，0.04mmol)、正戊醇(6.0mg，0.07mmol)和PyBOP(38mg，0.07mmol)溶于N,N-二甲基甲酰胺(3mL)中，溶解完全后，滴加N,N-二异丙基乙胺(19mg，0.14mmol)，加毕，在室温下反应3.5h，纯化后理得标题化合物(4.0mg)。Compound 1-5 (30 mg, 0.04 mmol), n-pentanol (6.0 mg, 0.07 mmol) and PyBOP (38 mg, 0.07 mmol) were dissolved in N,N-dimethylformamide (3 mL) at room temperature to dissolve After completion, N,N-diisopropylethylamine (19 mg, 0.14 mmol) was added dropwise.

其结构表征如下：Its structural representation is as follows:

¹H NMR(400MHz,DMSO-d₆)δ9.77(s,1H),8.13(s,1H),8.04-8.03(m,2H),7.95(d,J＝3.08Hz,1H),7.44-7.40(m,2H),7.27-7.16(m,5H),7.07(d,J＝7.99Hz,1H),7.00(d,J＝8.27Hz,1H),6.06(s,1H),4.30-4.16(m,2H),4.03-3.91(m,9H),3.06(d,J＝10.38Hz,1H),2.88(d,J＝11.44Hz,1H),2.60-2.58(m,1H),2.44-2.39(m,1H),2.33-2.26(m,1H),1.87-1.67(m,4H),1.53-1.43(m,2H),1.23-1.18(m,4H),1.11(t,J＝6.57Hz,3H),1.05(t,J＝7.11Hz,3H).ESI-MS(m/z):894.3[M+H]⁺。 ^{1 H NMR (400MHz, DMSO-} d 6) δ9.77 (s, 1H), 8.13 (s, 1H), 8.04-8.03 (m, 2H), 7.95 (d, J = 3.08Hz, 1H), 7.44- 7.40 (m, 2H), 7.27-7.16 (m, 5H), 7.07 (d, J = 7.99 Hz, 1H), 7.00 (d, J = 8.27 Hz, 1H), 6.06 (s, 1H), 4.30-4.16 (m, 2H), 4.03-3.91 (m, 9H), 3.06 (d, J = 10.38 Hz, 1H), 2.88 (d, J = 11.44 Hz, 1H), 2.60-2.58 (m, 1H), 2.44- 2.39(m,1H),2.33-2.26(m,1H),1.87-1.67(m,4H),1.53-1.43(m,2H),1.23-1.18(m,4H),1.11(t,J=6.57 Hz, 3H), 1.05 (t, J = 7.11 Hz, 3H). ESI-MS (m/z): 894.3 [M+H] ⁺ .

实施例六(4R)-6-((4-(4-((((((R)-1-(6-氨基-9H-嘌呤-9-基)丙-2-基)氧基)甲基)((特戊酰氧基)甲氧基)膦酰基)氧基)苯基)哌啶-1-基)甲基)-4-(2-氯-4-氟苯基)-2-(噻唑-2-基)-1,4-二氢嘧啶-5-羧酸乙酯(化合物6)Example 6(4R)-6-((4-(4-(((((())))))))))) ((p-Pentyloxy)methoxy)phosphonyl)oxy)phenyl)piperidin-1-yl)methyl)-4-(2-chloro-4-fluorophenyl)-2- Ethyl (thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (Compound 6)

室温下，将化合物1-5(30mg，0.04mmol)溶于N-甲基吡咯烷酮(2mL)中，溶解完全后，依次加入N,N-二异丙基乙胺(9mg，0.07mmol)和特戊酸碘甲酯(13mg，0.06mmol)，加毕，在室温下反应1.5h，纯化后得标题化合物(5.0mg)。Compound 1-5 (30 mg, 0.04 mmol) was dissolved in N-methylpyrrolidone (2 mL) at room temperature, and after complete dissolution, N,N-diisopropylethylamine (9 mg, 0.07 mmol) and Iomethyl valerate (13 mg, 0.06 mmol) was added.

其结构表征如下：Its structural representation is as follows:

¹H NMR(400MHz,CDCl₃)δ9.19(s,2H),8.38-8.34(m,1H),7.95-7.89(m,2H),7.44(m,1H),7.35-7.30(m,1H),7.23-7.19(m,2H),7.17-7.08(m,2H),7.03-6.90(m,3H),6.22(s,1H),5.75-5.59(m,2H),4.40-4.34(m,2H),4.11-3.98(m,5H),3.82-2.75(m,1H),3.48-3.35(m,2H),3.11-3.01(m,1H),2.94-2.84(m,1H),2.59-2.42(m,2H),1.98-1.84(m,4H),1.34-1.12(m,15H).ESI-MS(m/z):938.2[M+H]⁺。 ^{_{1 H NMR (400MHz, CDCl 3}} ) δ9.19 (s, 2H), 8.38-8.34 (m, 1H), 7.95-7.89 (m, 2H), 7.44 (m, 1H), 7.35-7.30 (m, 1H ), 7.23-7.19 (m, 2H), 7.17-7.08 (m, 2H), 7.03-6.90 (m, 3H), 6.22 (s, 1H), 5.75-5.59 (m, 2H), 4.40-4.34 (m , 2H), 4.11-3.98 (m, 5H), 3.82-2.75 (m, 1H), 3.48-3.35 (m, 2H), 3.11-3.01 (m, 1H), 2.94-2.84 (m, 1H), 2.59 - 2.42 (m, 2H), 1.98-1.84 (m, 4H), 1.34-1.12 (m, 15H). ESI-MS (m/z): 938.2 [M+H] ⁺ .

实施例七(4R)-6-((4-((((((R)-1-(6-氨基-9H-嘌呤-9-基)丙-2-基)氧基)甲基)(((S)-1-乙氧基-1-氧代丙-2-基)氧基)膦酰基)氧基)-3,3-二氟哌啶-1-基)甲基)-4-(2-氯-4-氟苯基)-2-(噻唑-2-基)-1,4-二氢嘧啶-5-羧酸乙酯(化合物27)Example 7(4R)-6-((4-(((((((()))))))))))))) ((S)-1-ethoxy-1-oxopropan-2-yl)oxy)phosphonyl)oxy)-3,3-difluoropiperidin-1-yl)methyl)-4- (2-Chloro-4-fluorophenyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylic acid ethyl ester (Compound 27)

步骤一：4-((((((R)-1-(6-氨基-9H-嘌呤-9-基)丙-2-基)氧基)甲基)(羟基)膦酰基)氧基)-3,3-二氟哌啶-1-羧酸叔丁酯(化合物7-2)的合成Step 1: 4-(((((()))))))))))))))))) Synthesis of tert-butyl-3,3-difluoropiperidine-1-carboxylate (compound 7-2)

室温下，将(R)-9-(2-磷酸甲氧基丙基)-腺嘌呤(55mg,0.19mmol)和3,3-二氟-4-羟基哌啶-1-羧酸叔丁酯(化合物7-1)(30mg,0.13mmol)在吡啶(2mL)中溶解，于氮气保护下加入二环己基碳二亚胺(80mg,0.39mmol)，升温至80℃反应过夜。纯化后得标题化合物(10mg)。ESI-MS(m/z):507.1[M+H]⁺。(R)-9-(2-methoxymethoxypropyl)-adenine (55 mg, 0.19 mmol) and tert-butyl 3,3-difluoro-4-hydroxypiperidine-1-carboxylate at room temperature (Compound 7-1) (30 mg, 0.13 mmol) was dissolved in pyridine (2 mL), and dicyclohexylcarbodiimide (80 mg, 0.39 mmol) was added under a nitrogen atmosphere, and the mixture was warmed to 80 ° C overnight. The title compound (10 mg) was obtained after purification. ESI-MS (m/z): 507.1 [M+H] ⁺ .

步骤二：((((R)-1-(6-氨基-9H-嘌呤-9-基)丙-2-基)氧基)甲基)-(3,3-二氟哌啶-4-基)-单磷酸酯三氟乙酸盐(化合物7-3)的合成Step 2: ((((R)-1-(6-Amino-9H-indol-9-yl)propan-2-yl)oxy)methyl)-(3,3-difluoropiperidin-4- Synthesis of mono)triphosphate trifluoroacetate (compound 7-3)

在室温下，将化合物7-2(10mg，0.02mmol)加入到二氯甲烷(1.0mL)中，溶解完全加入三氟乙酸(0.2mL)，加入完毕后，在室温下反应。将反应液减压蒸干溶剂得到标题化合物(10mg)，将其在未纯化下直接用于下一步反应。ESI-MS(m/z):407.1[M+H]⁺。Compound 7-2 (10 mg, 0.02 mmol) was added to dichloromethane (1.0 mL) at room temperature, and trifluoroacetic acid (0.2 mL) was added and dissolved. The reaction mixture was evaporated to drynessjjjjjjjjjj ESI-MS (m/z): 407.1 [M+H] ⁺ .

步骤三：(4R)-6-((4-((((((R)-1-(6-氨基-9H-嘌呤-9-基)丙-2-基)氧基)甲基)(羟基)膦酰基)氧基)-3,3-二氟哌啶-1-基)甲基)-4-(2-氯-4-氟苯基)-2-(噻唑-2-基)-1,4-二氢嘧啶-5-羧酸乙酯(化合物7-4)的合成Step 3: (4R)-6-((4-(((((((())))))))))) Hydroxy)phosphono)oxy)-3,3-difluoropiperidin-1-yl)methyl)-4-(2-chloro-4-fluorophenyl)-2-(thiazol-2-yl)- Synthesis of Ethyl 1,4-dihydropyrimidine-5-carboxylate (Compound 7-4)

室温下，将化合物7-3(10mg,0.025mmol)溶于1,2-二氯乙烷(2mL)中，依次加入(R)-6-(溴甲基)-4-(2-氯-4-氟苯基)-2-(噻唑-2-基)-1,4-二氢嘧啶-5-羧酸乙酯(14mg，0.030mmol)和N,N-二异丙基乙胺(0.1mL)，加入完毕后，在室温下反应过夜。纯化后得标题化合物(10mg)。ESI-MS(m/z):784.1[M+H]⁺。Compound 7-3 (10 mg, 0.025 mmol) was dissolved in 1,2-dichloroethane (2 mL) at room temperature, followed by (R)-6-(bromomethyl)-4-(2-chloro- Ethyl 4-fluorophenyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (14 mg, 0.030 mmol) and N,N-diisopropylethylamine (0.1 (mL), after the addition was completed, the reaction was allowed to proceed overnight at room temperature. The title compound (10 mg) was obtained after purification. ESI-MS (m/z): 784.1 [M+H] ⁺ .

步骤四：(4R)-6-((4-((((((R)-1-(6-氨基-9H-嘌呤-9-基)丙-2-基)氧基)甲基)(((S)-1-乙氧基-1-氧代丙-2-基)氧基)膦酰基)氧基)-3,3-二氟哌啶-1-基)甲基)-4-(2-氯-4-氟苯基)-2-(噻唑-2-基)-1,4-二氢嘧啶-5-羧酸乙酯(化合物27)的合成Step 4: (4R)-6-((4-((((((((())))))))))) ((S)-1-ethoxy-1-oxopropan-2-yl)oxy)phosphonyl)oxy)-3,3-difluoropiperidin-1-yl)methyl)-4- Synthesis of (2-Chloro-4-fluorophenyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylic acid ethyl ester (Compound 27)

室温下，将化合物7-4(40mg,0.05mmol)、L-乳酸乙酯(10mg,0.1mmol)和PyBOP(52mg,0.1mmol)溶于N,N-二甲基甲酰胺(3mL)中，溶解完全后，滴加N,N-二异丙基乙胺(26mg,0.2mmol)，加入完毕后，在室温下反应过夜。纯化后得标题化合物(10mg)。Compound 7-4 (40 mg, 0.05 mmol), L-ethyl lactate (10 mg, 0.1 mmol) and PyBOP (52 mg, 0.1 mmol) were dissolved in N,N-dimethylformamide (3 mL). After the dissolution was completed, N,N-diisopropylethylamine (26 mg, 0.2 mmol) was added dropwise, and the mixture was stirred at room temperature overnight. The title compound (10 mg) was obtained after purification.

其结构表征如下：Its structural representation is as follows:

1H NMR(400MHz,CDCl₃)δ9.46(d,J＝11.90Hz,1H),8.35(t,J＝2.16Hz,1H),8.07-7.98(m,1H),7.85(d,J＝3.24,1H),7.43(d,J＝2.87Hz,1H),7.31(ddd,J＝9.02,6.15,3.19Hz,1H),7.13(dd,J＝8.60,2.57Hz,1H),6.93(td,J＝8.32,2.42Hz,1H),6.21(t,J＝2.29Hz,1H),5.91(s,2H),5.02-4.90(m,1H),4.78-4.67(m,1H),4.45-4.34(m,1H),4.27-3.90(m,9H),3.74-3.66(m,1H),3.02-2.63(m,3H),2.25-1.99(m,3H),1.55-1.44(m,3H),1.31-1.23(m,6H),1.13(t,J＝7.16,1.39Hz,3H).ESI-MS(m/z):884.1[M+H]⁺。1H NMR (400MHz, CDCl ₃ ) δ 9.46 (d, J = 11.90 Hz, 1H), 8.35 (t, J = 2.16 Hz, 1H), 8.07-7.98 (m, 1H), 7.85 (d, J = 3.24) , 1H), 7.43 (d, J = 2.87 Hz, 1H), 7.31 (ddd, J = 9.02, 6.15, 3.19 Hz, 1H), 7.13 (dd, J = 8.60, 2.57 Hz, 1H), 6.93 (td, J=8.32, 2.42 Hz, 1H), 6.21 (t, J=2.29 Hz, 1H), 5.91 (s, 2H), 5.02-4.90 (m, 1H), 4.78-4.67 (m, 1H), 4.45-4.34 (m, 1H), 4.27-3.90 (m, 9H), 3.74-3.66 (m, 1H), 3.02-2.63 (m, 3H), 2.25-1.99 (m, 3H), 1.55-1.44 (m, 3H) , 1.31-1.23 (m, 6H), 1.13 (t,J = 7.16, 1.39 Hz, 3H). ESI-MS (m/z): 884.1 [M+H] ⁺ .

实施例八(4R)-6-((4-((((((R)-1-(6-氨基-9H-嘌呤-9-基)丙-2-基)氧基)甲基)(羟基)膦酰基)氧基)-3,3-二氟吡咯烷-1-基)甲基)-4-(2-氯-4-氟苯基)-2-(噻唑-2-基)-1,4-二氢嘧啶-5-羧酸乙酯(化合物28)Example VIII (4R)-6-((4-(((((((()))))))))))) Hydroxy)phosphono)oxy)-3,3-difluoropyrrolidin-1-yl)methyl)-4-(2-chloro-4-fluorophenyl)-2-(thiazol-2-yl)- Ethyl 1,4-dihydropyrimidine-5-carboxylate (Compound 28)

步骤一：4-((((((R)-1-(6-氨基-9H-嘌呤-9-基)丙-2-基)氧基)甲基)(羟基)膦酰基)氧基)-3,3-二氟吡咯烷-1-羧酸叔丁酯(化合物8-2)的合成Step 1: 4-(((((()))))))))))))))))) Synthesis of -3,3-difluoropyrrolidine-1-carboxylic acid tert-butyl ester (Compound 8-2)

室温下，将替诺福韦(化合物8-1)(966mg,3.36mmol)和3,3-二氟-4-羟基吡咯烷-1-羧酸叔丁酯(500mg,2.24mmol)溶于吡啶(6mL)中，氮气保护下，加入二环己基碳二亚胺(1.39g,6.72mmol)，升温至80℃反应过夜。纯化后得标题化合物(240mg)。ESI-MS(m/z):493.1[M+H]⁺。Tenofovir (Compound 8-1) (966 mg, 3.36 mmol) and 3,3-difluoro-4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester (500 mg, 2.24 mmol) were dissolved in pyridine at room temperature. (6 mL), dicyclohexylcarbodiimide (1.39 g, 6.72 mmol) was added under a nitrogen atmosphere, and the mixture was heated to 80 ° C overnight. The title compound (240 mg) was obtained after purification. ESI-MS (m/z): 493.1 [M+H] ⁺ .

步骤二：((((R)-1-(6-氨基-9H-嘌呤-9-基)丙-2-基)氧基)甲基)-4,4-二氟吡咯烷-3-基-单磷酸酯三氟乙酸盐(化合物8-3)的合成Step 2: ((((R)-1-(6-Amino-9H-indol-9-yl)propan-2-yl)oxy)methyl)-4,4-difluoropyrrolidin-3-yl Synthesis of monophosphate trifluoroacetate (compound 8-3)

室温下，将化合物8-2(100mg，0.2mmol)加入到二氯甲烷(1.5mL)中，溶解完全后加入三氟乙酸(0.5mL)，加毕，在室温下反应。减压蒸干溶剂得标题化合物(120mg)，将其未纯化直接用于下一步反应。ESI-MS(m/z):393.1[M+H]⁺。Compound 8-2 (100 mg, 0.2 mmol) was added to dichloromethane (1.5 mL) at room temperature. After the mixture was dissolved, trifluoroacetic acid (0.5 mL) was added, and the mixture was stirred at room temperature. The solvent was evaporated to dryness crystall ESI-MS (m/z): 393.1 [M+H] ⁺ .

步骤三：(4R)-6-((4-((((((R)-1-(6-氨基-9H-嘌呤-9-基)丙-2-基)氧基)甲基)(羟基)膦酰基)氧基)-3,3-二氟吡咯烷-1-基)甲基)-4-(2-氯-4-氟苯基)-2-(噻唑-2-基)-1,4-二氢嘧啶-5-羧酸乙酯(化合物28)的合成Step 3: (4R)-6-((4-(((((((())))))))))) Hydroxy)phosphono)oxy)-3,3-difluoropyrrolidin-1-yl)methyl)-4-(2-chloro-4-fluorophenyl)-2-(thiazol-2-yl)- Synthesis of Ethyl 1,4-dihydropyrimidine-5-carboxylate (Compound 28)

室温下，将化合物8-3(80mg,0.2mmol)溶于二氯甲烷(4mL)中，依次加入(R)-6-(溴甲基)-4-(2-氯-4-氟苯基)-2-(噻唑-2-基)-1,4-二氢嘧啶-5-羧酸乙酯(100mg，0.22mmol)和N,N-二异丙基乙胺(0.5mL)，加毕，室温反应过夜。纯化后得标题化合物(80mg)。Compound 8-3 (80 mg, 0.2 mmol) was dissolved in dichloromethane (4 mL) at room temperature, then (R)-6-(bromomethyl)-4-(2-chloro-4-fluorophenyl) Ethyl 2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (100 mg, 0.22 mmol) and N,N-diisopropylethylamine (0.5 mL) Reactive overnight at room temperature. The title compound (80 mg) was obtained after purification.

其结构表征如下： Its structural representation is as follows:

¹H NMR(400MHz,甲醇-d₄)δ8.31(d,J＝1.6Hz,1H),8.18(d,J＝2.7Hz,1H),7.87(dd,J＝5.3,3.2Hz,1H),7.67(dd,J＝5.8,3.1Hz,1H),7.46-7.39(m,1H),7.21(dd,J＝8.8,2.6Hz,1H),7.08-7.02(m,2H),6.14(d,J＝2.0Hz,1H),4.87-4.75(m,1H),4.38-4.32(m,1H),4.24-4.00(m,5H),3.88-3.84(m,1H),3.77-3.68(m,1H),3.40-3.36(m,1H),3.29-2.95(m,2H),2.78-2.76(m,1H),1.13-1.07(m,6H).ESI-MS(m/z):770.1[M+H]⁺。 ¹ H NMR (400 MHz, methanol-d ₄ ) δ 8.31 (d, J = 1.6 Hz, 1H), 8.18 (d, J = 2.7 Hz, 1H), 7.78 (dd, J = 5.3, 3.2 Hz, 1H) , 7.67 (dd, J = 5.8, 3.1 Hz, 1H), 7.46-7.39 (m, 1H), 7.21 (dd, J = 8.8, 2.6 Hz, 1H), 7.08-7.02 (m, 2H), 6.14 (d) , J=2.0 Hz, 1H), 4.87-4.75 (m, 1H), 4.38-4.32 (m, 1H), 4.24-4.00 (m, 5H), 3.88-3.84 (m, 1H), 3.77-3.68 (m , 1H), 3.40-3.36 (m, 1H), 3.29-2.95 (m, 2H), 2.78-2.76 (m, 1H), 1.13-1.07 (m, 6H). ESI-MS (m/z): 770.1 [M+H] ⁺ .

实施例九(4R)-6-((4-((((((R)-1-(6-氨基-9H-嘌呤-9-基)丙-2-基)氧基)甲基)(((S)-1-乙氧基-1-氧代丙-2-基)氧基)膦酰基)氧基)-3,3-二氟吡咯烷-1-基)甲基)-4-(2-氯-4-氟苯基)-2-(噻唑-2-基)-1,4-二氢嘧啶-5-羧酸乙酯(化合物29)Example 9 (4R)-6-((4-(((((((()))))))))))) ((S)-1-ethoxy-1-oxopropan-2-yl)oxy)phosphonyl)oxy)-3,3-difluoropyrrolidin-1-yl)methyl)-4- (2-Chloro-4-fluorophenyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylic acid ethyl ester (Compound 29)

采用与实施例七步骤四中所描述的类似操作，以化合物28代替化合物7-4，得标题化合物(20mg)。ESI-MS(m/z):870.1[M+H]⁺。The title compound (20 mg) was obtained from the compound (m. ESI-MS (m/z): 870.1 [M+H] ⁺ .

实施例十(4R)-6-((4-((((((R)-1-(6-氨基-9H-嘌呤-9-基)丙-2-基)氧基)甲基)(((R)-1-乙氧基-1-氧代丙-2-基)氧基)膦酰基)氧基)-3,3-二氟吡咯烷-1-基)甲基)-4-(2-氯-4-氟苯基)-2-(噻唑-2-基)-1,4-二氢嘧啶-5-羧酸乙酯(化合物30)Example X(4R)-6-((4-((((((()))))))))))) ((R)-1-ethoxy-1-oxopropan-2-yl)oxy)phosphonyl)oxy)-3,3-difluoropyrrolidin-1-yl)methyl)-4- (2-Chloro-4-fluorophenyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylic acid ethyl ester (Compound 30)

采用与实施例九中所描述的类似操作，以D-乳酸乙酯代替L-乳酸乙酯，得标题化合物(10mg)。ESI-MS(m/z):870.1[M+H]⁺。The title compound (10 mg) was obtained from the title compound (d. ESI-MS (m/z): 870.1 [M+H] ⁺ .

实施例十一2-((((((R)-1-(6-氨基-9H-嘌呤-9-基)丙-2-基)氧基)甲基)((1-(((R)-6-(2-氯-4-氟苯基)-5-(乙氧羰基)-2-(噻唑-2-基)-3,6-二氢嘧啶-4-基)甲基)-4,4-二氟吡咯烷-3-基)氧基)膦酰基)氧基)乙酸(化合物31)Example 11 2-(((((())))))))) - 6-(2-chloro-4-fluorophenyl)-5-(ethoxycarbonyl)-2-(thiazol-2-yl)-3,6-dihydropyrimidin-4-yl)methyl)- 4,4-difluoropyrrolidin-3-yl)oxy)phosphono)oxy)acetic acid (Compound 31)

室温下，将化合物28(30mg,0.04mmol)溶于N-甲基吡咯烷酮(2mL)中，依次加入溴乙酸(27mg，0.20mmol)和碳酸钾(16mg，0.12mmol)，加毕，升温至60℃反应2h。反应液过滤，将滤液纯化后得标题化合物(5.0mg)。ESI-MS(m/z):828.0[M+H]⁺。Compound 28 (30 mg, 0.04 mmol) was dissolved in N-methylpyrrolidone (2 mL), bromoacetic acid (27 mg, 0.20 mmol) and potassium carbonate (16 mg, 0.12 mmol). °C reaction for 2h. The reaction mixture was filtered. ESI-MS (m/z): 828.0 [M+H] ⁺ .

实施例十二(4R)-4-(2-氯-4-氟苯基)-6-((3,3-二氟-4-(((((2S,3R,5S)-3-羟基-5-(5-甲基-2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)四氢呋喃-2-基)甲氧基)(((S)-1-异丙氧-1-氧代丙-2-基)氨基)膦酰基)氧基)吡咯烷-1-基)甲基)-2-(噻唑-2-基)-1,4-二氢嘧啶-5-羧酸乙酯(化合物32) EXAMPLE Twelve (4R)-4-(2-chloro-4-fluorophenyl)-6-((3,3-difluoro-4-((((())))) -5-(5-Methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)tetrahydrofuran-2-yl)methoxy)(((S)-1- Isopropoxy-1-oxopropan-2-yl)amino)phosphono)oxy)pyrrolidin-1-yl)methyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine -5-carboxylate (Compound 32)

步骤一：(4R)-4-(2-氯-4-氟苯基)-6-((4-((二氯膦酰基)氧基)-3,3-二氟吡咯烷-1-基)甲基)-2-(噻唑-2-基)-1,4-二氢嘧啶-5-羧酸乙酯(化合物12-2)的合成Step 1: (4R)-4-(2-Chloro-4-fluorophenyl)-6-((4-((dichlorophosphonyl)oxy)-3,3-difluoropyrrolidin-1-yl) Synthesis of ethyl (ethyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (Compound 12-2)

室温下，将(4R)-4-(2-氯-4-氟苯基)-6-((3,3-二氟-4-羟基吡咯烷-1-基)甲基)-2-(噻唑-2-基)-1,4-二氢嘧啶-5-羧酸乙酯(化合物12-1)(50mg,0.1mmol)溶于二氯甲烷(2mL)中，氮气保护下降温至-20℃，滴加三氯氧磷(0.2mL)，加毕，滴加三乙胺(0.2mL)，在-20℃下反应30min。将反应液直接旋干，所得粗品未纯化直接用于下一步反应。(4R)-4-(2-chloro-4-fluorophenyl)-6-((3,3-difluoro-4-hydroxypyrrolidin-1-yl)methyl)-2-() at room temperature Ethyl thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (Compound 12-1) (50 mg, 0.1 mmol) was dissolved in dichloromethane (2 mL). At ° C, phosphorus oxychloride (0.2 mL) was added dropwise, and triethylamine (0.2 mL) was added dropwise, and the mixture was reacted at -20 ° C for 30 min. The reaction solution was directly dried to dryness, and the obtained crude material was applied to the next reaction without purification.

步骤二：(4R)-4-(2-氯-4-氟苯基)-6-((3,3-二氟-4-(((((S)-1-异丙氧-1-氧代丙-2-基)氨基)(五氟苯氧基)膦酰基)氧基)吡咯烷-1-基)甲基)-2-(噻唑-2-基)-1,4-二氢嘧啶-5-羧酸乙酯(化合物12-3)的合成Step 2: (4R)-4-(2-chloro-4-fluorophenyl)-6-((3,3-difluoro-4-(((()))) Oxopropan-2-yl)amino)(pentafluorophenoxy)phosphonyloxy)pyrrolidin-1-yl)methyl)-2-(thiazol-2-yl)-1,4-dihydro Synthesis of pyrimidine-5-carboxylate ethyl ester (compound 12-3)

室温下，将化合物12-2(60mg,0.1mmol)溶于二氯甲烷(2mL)中，氮气保护下降温至-20℃，滴加L-丙氨酸异丙酯盐酸盐(50mg,0.3mmol)的二氯甲烷(1.0mL)溶液，加毕，滴加三乙胺(0.2mL)的二氯甲烷(0.5mL)溶液，加毕移至室温反应1h。氮气保护下再降温至-20℃，滴加五氟苯酚(50mg,0.3mmol)和三乙胺(0.1mL)的二氯甲烷(2.0mL)溶液，加毕，-20℃下反应1h，将反应液直接旋干，用四氢呋喃(4.0mL)溶解，滤去不溶物，将滤液直接用于下一步反应。Compound 12-2 (60 mg, 0.1 mmol) was dissolved in dichloromethane (2 mL) at room temperature, and the temperature was lowered to -20 ° C under nitrogen, and L-alanine isopropyl ester hydrochloride (50 mg, 0.3) was added dropwise. A solution of methylene chloride (1.0 mL) was added, and a solution of triethylamine (0.2 mL) in dichloromethane (0.5 mL) was evaporated. Under nitrogen protection, the temperature was further lowered to -20 ° C, and a solution of pentafluorophenol (50 mg, 0.3 mmol) and triethylamine (0.1 mL) in dichloromethane (2.0 mL) was added dropwise, and the reaction was carried out at -20 ° C for 1 h. The reaction solution was directly sparged, dissolved in tetrahydrofuran (4.0 mL), and the insoluble material was filtered, and the filtrate was directly used for the next reaction.

步骤三：(4R)-4-(2-氯-4-氟苯基)-6-((3,3-二氟-4-(((((2S,3R,5S)-3-羟基-5-(5-甲基-2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)四氢呋喃-2-基)甲氧基)(((S)-1-异丙氧-1-氧代丙-2-基)氨基)膦酰基)氧基)吡咯烷-1-基)甲基)-2-(噻唑-2-基)-1,4-二氢嘧啶-5-羧酸乙酯(化合物32)的合成Step 3: (4R)-4-(2-chloro-4-fluorophenyl)-6-((3,3-difluoro-4-((((())))) 5-(5-Methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)tetrahydrofuran-2-yl)methoxy)(((S)-1-iso) Propoxy-1-oxopropan-2-yl)amino)phosphono)oxy)pyrrolidin-1-yl)methyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine- Synthesis of ethyl 5-carboxylate (Compound 32)

室温下，将替比夫定(50mg,0.2mmol)溶于四氢呋喃(2mL)中，氮气保护下降温至-20℃，滴加叔丁基氯化镁(0.4mL,1M)，加毕移至室温反应1h，氮气保护下再降温至-20℃，滴加步骤二所得的四氢呋喃溶液，加毕，氮气保护下室温反应过夜。纯化后得标题化合物(2.0mg)。ESI-MS(m/z):918.0[M+H]⁺。At room temperature, telbivudine (50 mg, 0.2 mmol) was dissolved in tetrahydrofuran (2 mL), the temperature was lowered to -20 ° C under nitrogen, and t-butyl magnesium chloride (0.4 mL, 1 M) was added dropwise. After 1 h, the temperature was further lowered to -20 ° C under nitrogen atmosphere, and the tetrahydrofuran solution obtained in the second step was added dropwise, and the reaction was carried out overnight under nitrogen atmosphere at room temperature. The title compound (2.0 mg) was obtained after purification. ESI-MS (m/z): 918.0 [M+H] ⁺ .

实施例十三(4R)-6-((4-((((((R)-1-(6-氨基-9H-嘌呤-9-基)丙-2-基)氧基)甲基)(((R)-1-乙氧基-1-氧代丙-2-基)氧基)膦酰基)氧基)-3,3-二氟哌啶-1-基)甲基)-4-(2-氯-4-氟苯基)-2-(噻唑-2-基)-1,4-二氢嘧啶-5-羧酸乙酯(化合物33)Example XIII(4R)-6-((4-(((((())))))))))))))) (((R)-1-ethoxy-1-oxopropan-2-yl)oxy)phosphonyl)oxy)-3,3-difluoropiperidin-1-yl)methyl)-4 -(2-Chloro-4-fluorophenyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylic acid ethyl ester (Compound 33)

采用与实施例七步骤四中所描述的类似操作，以D-乳酸乙酯代替L-乳酸乙酯，得标题化合物(15mg)。ESI-MS(m/z):884.1[M+H]⁺。The title compound (15 mg) was obtained from m. ESI-MS (m/z): 884.1 [M+H] ⁺ .

本申请中的其他化合物均可参考上述实施例中类似的方法合成。Other compounds in the present application can be synthesized by referring to methods similar to those in the above examples.

生物活性检测Biological activity test

测试本发明的化合物对乙型肝炎病毒(HBV)的抑制作用。在病毒-细胞水平测试本发明的化合物的细胞毒性以及对病毒(HBV)核酸(DNA)复制水平的影响。 The inhibitory effect of the compounds of the invention on hepatitis B virus (HBV) was tested. The cytotoxicity of the compounds of the invention and the effect on viral (HBV) nucleic acid (DNA) replication levels were tested at the virus-cell level.

试验方法experiment method

将对数生长期的HepG2 2.2.15细胞接种于96孔板中，细胞浓度为40个/μL。于37℃，5％CO₂培养箱中培养3天；加入化合物前用新培养基(200μL/孔)更换。各待测化合物的母液浓度为200μM。以200μM为最高浓度，用DMSO稀释为多个不同浓度，取1μL待测化合物置于相应培养基孔，化合物的最终测试浓度为0.06、0.24、0.98、3.9、15.6、62.5、250、1000nM(用于计算半数有效浓度(EC₅₀))。HepG2 2.2.15 cells in logarithmic growth phase were seeded in 96-well plates at a cell concentration of 40/μL. Incubate for 3 days at 37 ° C in a 5% CO ₂ incubator; replace with fresh medium (200 μL/well) before adding the compound. The mother liquor concentration of each test compound was 200 μM. The highest concentration was 200 μM, diluted to a number of different concentrations in DMSO, and 1 μL of the test compound was placed in the corresponding medium well. The final test concentrations of the compounds were 0.06, 0.24, 0.98, 3.9, 15.6, 62.5, 250, 1000 nM (using Calculate the half effective concentration (EC ₅₀ )).

将各待测化合物的母液用DMSO稀释为600μM和60μM，各取1μL加入相应培养基孔中，化合物的最终测试浓度为3μM和0.3μM(用于计算百分比抑制率)。The mother liquor of each test compound was diluted to 600 μM and 60 μM with DMSO, and 1 μL of each was added to the corresponding medium well, and the final test concentrations of the compounds were 3 μM and 0.3 μM (for calculating the percent inhibition).

空白对照：取1μL DMSO加入相应培养基孔中作为对照。Blank control: 1 μL of DMSO was added to the corresponding medium wells as a control.

加入待测化合物后于37℃，5％CO₂培养箱中共培养10天，每隔两天更换培养基，并重新添加化合物。After the test compound was added, it was co-cultured for 10 days at 37 ° C in a 5% CO ₂ incubator, the medium was changed every two days, and the compound was re-added.

于第11天每孔收集150μL细胞上清液用于qPCR检测。150 μL of cell supernatant was collected per well on day 11 for qPCR detection.

所测试化合物的EC₅₀，以及在3μM和0.3μM浓度下抑制率的结果如表1、表2所示。The results of the EC _{50 of} the tested compounds and the inhibition rates at the concentrations of 3 μM and 0.3 μM are shown in Tables 1 and 2.

表1Table 1

化合物Compound	EC₅₀(nM)EC ₅₀ (nM)
22	59.4359.43
33	54.6554.65
2727	52.152.1
2929	5.185.18
3030	8.218.21
3232	26.9526.95
3333	53.153.1

由表1数据可知，所测试化合物在抑制乙型肝炎病毒(HBV)的脱氧核糖核酸(DNA)复制的活性测试中显示出较强的抑制活性，一些化合物的EC₅₀<60nM，优选化合物(例如化合物29和30)的EC₅₀<10nM，表明本发明的化合物具有非常优异的抑制活性。As can be seen from the data in Table 1, the tested compounds showed strong inhibitory activity in the activity test for inhibiting the replication of deoxyribonucleic acid (DNA) of hepatitis B virus (HBV), and some compounds had an EC _{50 of} <60 nM, preferably a compound (for example). The EC _{50 of the} compounds 29 and 30) was <10 nM, indicating that the compound of the present invention has very excellent inhibitory activity.

表2Table 2

化合物(3μM)Compound (3 μM)	抑制率％Inhibition rate%
11	96.5496.54
22	100.20100.20
33	101.67101.67

由以上结果可见，所测试化合物在3μM的浓度下，在抑制乙型肝炎病毒(HBV)的脱氧核糖核酸(DNA)复制的活性测试中表现出优异的抑制效果。所测试的化合物在0.3μM的浓度下同样表现出优异的抑制效果，表明本发明的化合物具有非常优异的抑制效果。From the above results, it was found that the tested compound exhibited an excellent inhibitory effect in the activity test for inhibiting the deoxyribonucleic acid (DNA) replication of hepatitis B virus (HBV) at a concentration of 3 μM. The compound tested also exhibited an excellent inhibitory effect at a concentration of 0.3 μM, indicating that the compound of the present invention has a very excellent inhibitory effect.

细胞毒性检测Cytotoxicity test

将待测化合物用DMSO稀释为30mM，以30mM为最高浓度，三倍稀释为多个不同的浓度，取0.2μL各浓度的化合物于384孔板中，每孔加入2000个/50μL的HepG2 2.2.15细胞，待测化合物最高终浓度为150μM；将1μL DMSO加入相应孔中作为对照。The test compound was diluted to 30 mM with DMSO, diluted to a maximum concentration of 30 mM, and diluted to a plurality of different concentrations. 0.2 μL of each compound was added to a 384-well plate, and 2000/50 μL of HepG2 was added to each well. For 15 cells, the highest concentration of the test compound was 150 μM; 1 μL of DMSO was added to the corresponding wells as a control.

于37℃，5％CO₂培养箱中共培养4天。The cells were co-cultured for 4 days at 37 ° C in a 5% CO ₂ incubator.

4天后每孔加入50μL CellTiter-Glo，进行读板检测，计算得到致半数细胞毒性浓度(CC₅₀)值。After 4 days, 50 μL of CellTiter-Glo was added to each well to perform a plate reading test, and a half-cytotoxic concentration (CC ₅₀ ) value was calculated.

优选化合物(例如实施例5的化合物)的CC₅₀值大于150μM，这说明其细胞毒性较低，安全性较高。Preferred compounds (e.g. compound of Example 5) CC ₅₀ value of greater than 150 M, indicating its low cytotoxicity and high safety.

除本文中描述的那些外，根据前述描述，本发明的多种修改对本领域技术人员而言会是显而易见的。这样的修改也意图落入所附权利要求书的范围内。本申请中所引用的各参考文献(包括所有专利、专利申请、期刊文章、书籍及任何其它公开)均以其整体援引加入本文。 Various modifications of the invention in addition to those described herein will be apparent to those skilled in the art. Such modifications are also intended to fall within the scope of the appended claims. Each of the references (including all patents, patent applications, journal articles, books, and any other publications) cited in this application are hereby incorporated by reference in their entirety.

Claims

化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物或前药，其中所述化合物具有式(I)的结构：a compound, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite or prodrug thereof, wherein the compound has the structure of formula (I):

其中：among them:

B选自：B is selected from:

A选自任选地被一个或多个R^b取代的C_1-6亚烷基、C_2-6亚烯基、C_2-6亚炔基，所述亚烷基、亚烯基或亚炔基任选地被一个或多个-O-、-NR-或-S-间断；A is selected from C _1-6 alkylene, C _2-6 alkenylene, C _2-6 alkynylene, optionally substituted by one or more R ^b , said alkylene, alkenylene or sub An alkynyl group is optionally interrupted by one or more -O-, -NR- or -S-;

或者A选自下列基团：Or A is selected from the following groups:

其中
表示单键或双键，并且1位置处与B连接，2位置处与磷原子(P)连接；among them
Represents a single bond or a double bond, and is connected to B at the 1 position and to the phosphorus atom (P) at the 2 position;

X、Y和Z在每次出现时各自独立地选自CH₂、O、S和NR；X, Y and Z are each independently selected from CH ₂ , O, S and NR at each occurrence;

R^a和R^b在每次出现时各自独立地选自卤素、-OH、-CN、-NO₂、-N(R)₂、-N₃、C_1-6烷基和C_3-6环烷基；R ^a and R ^b are each independently selected from the group consisting of halogen, -OH, -CN, -NO ₂ , -N(R) ₂ , -N ₃ , C _1-6 alkyl and C _3-6 ring at each occurrence. alkyl;

R²选自H、C_1-12烷基、C_3-6环烷基、C_6-14芳基、5-14元杂芳基、C_6-20芳烷基、-C_1-6亚烷基-COOH、-C_1-6亚烷基-C(＝O)O-C_1-6烷基、-C_1-6亚烷基-OC(＝O)-C_1-6烷基、-C_1-6亚烷基-OC(＝O)O-C_1-6烷基和-((CH₂)_iO)_m-(CH₂)_q-O-C_1-6烷基，上述基团各自任选地被一个或多个选自卤素、-OH、-CN、-NO₂、-N(R)₂、C_1-6烷基、卤代C_1-6烷基、C_1-6烷基硫基和C_3-6环烷基的取代基取代；R ^{2 is} selected from the group consisting of H, C _1-12 alkyl, C _3-6 cycloalkyl, C _6-14 aryl, 5-14 membered heteroaryl, C _6-20 aralkyl, -C _1-6 Alkyl-COOH, -C _1-6 alkylene-C(=O)OC _1-6 alkyl, -C _1-6 alkylene-OC(=O)-C _1-6 alkyl, -C _1-6 alkylene-OC(=O)OC _1-6 alkyl and -((CH ₂ ) _i O) _m -(CH ₂ ) _q -OC _1-6 alkyl, each of the above groups optionally One or more selected from the group consisting of halogen, -OH, -CN, -NO ₂ , -N(R) ₂ , C _1-6 alkyl, halogenated C _1-6 alkyl, C _1-6 alkylthio Substituted with a substituent of a C _3-6 cycloalkyl group;

i和q在每次出现时各自独立地为1、2、3、4、5或6；i and q are each independently 1, 2, 3, 4, 5 or 6 at each occurrence;

m为选自0-50，优选0-20，特别优选0-6中的任意整数；m is any integer selected from 0-50, preferably 0-20, particularly preferably 0-6;

R¹选自：R ^{1 is} selected from:

表示3至14元氮杂环系，其任选地另外含有独立地选自N、O、C＝O、S、S＝O和S(＝O)₂的1、2或3个环成员；
Representing a 3 to 14 membered nitrogen heterocycle, optionally additionally containing 1, 2 or 3 ring members independently selected from N, O, C=O, S, S=O and S(=O) ₂ ;

Ar¹和Ar²各自独立地选自C_6-14芳基和5-14元杂芳基，其任选地被一个或多个选自卤素、-OH、-CN、-NO₂、-N(R)₂、C_1-6烷基、卤代C_1-6烷基、C_1-6烷基硫基和C_3-6环烷基的取代基取代；Ar ¹ and Ar ² are each independently selected from a C _6-14 aryl group and a 5-14 membered heteroaryl group, which are optionally selected from one or more selected from the group consisting of halogen, -OH, -CN, -NO ₂ , -N Substituent substitution of (R) ₂ , C _1-6 alkyl, halo C _1-6 alkyl, C _1-6 alkylthio and C _3-6 cycloalkyl;

L不存在或者选自-O-、-S-和-NR-；L is absent or selected from -O-, -S-, and -NR-;

R³和R⁴各自独立地选自H、C_1-4烷基和C_3-6环烷基；R ³ and R ⁴ are each independently selected from the group consisting of H, C _1-4 alkyl and C _3-6 cycloalkyl;

R⁵在每次出现时以单键或双键与分子的其余部分连接；R ⁵ is attached to the remainder of the molecule with a single or double bond at each occurrence;

R⁵和R⁶在每次出现时各自独立地选自卤素、-OH、-COOH、-CN、-NO₂、-N(R)₂、C_1-6烷基、卤代C_1-6烷基、-W-C_1-6烷基、-C_1-6亚烷基-W-R、-W-C_1-6亚烷基-W’-R、-W-C_2-6烯基、-C_2-6亚烯基-W-R、-W-C_2-6亚烯基-W’-R和C_3-6环烷基，其中所述亚烷基和亚烯基任选地进一步被一个或多个W间隔；R ⁵ and R ⁶ are each independently selected from the group consisting of halogen, -OH, -COOH, -CN, -NO ₂ , -N(R) ₂ , C _1-6 alkyl, halogenated C _1-6 Alkyl, -WC _1-6 alkyl, -C _1-6 alkylene-WR, -WC _1-6 alkylene-W'-R, -WC _2-6 alkenyl, -C _2-6 Alkenyl-WR, -WC _2-6 alkenylene-W'-R and C _3-6 cycloalkyl, wherein the alkylene and alkenylene are optionally further separated by one or more W;

W和W’在每次出现时各自独立地选自O、C(＝O)、C(＝O)O、NR、S、S＝O和S(＝O)₂；W and W' are each independently selected from the group consisting of O, C(=O), C(=O)O, NR, S, S=O, and S(=O) ₂ ;

R在每次出现时各自独立地选自H、C_1-6烷基和C_3-6环烷基； R is each independently selected from the group consisting of H, C _1-6 alkyl and C _3-6 cycloalkyl;

n在每次出现时各自独立地为0、1、2、3、4或5，条件是n不大于对应基团上可被取代的位置的数目；并且n each independently is 0, 1, 2, 3, 4 or 5, with the proviso that n is not greater than the number of positions on the corresponding group that can be substituted;

当n大于1时，每个R^a可以相同或不同，每个R^b可以相同或不同，每个R⁵可以相同或不同，每个R⁶可以相同或不同。When n is greater than 1, each R ^a may be the same or different, and each R ^b may be the same or different, and each R ⁵ may be the same or different, and each R ⁶ may be the same or different.
权利要求1的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物或前药，其中R²选自H、C_1-12烷基、C_3-6环烷基、C_6-14芳基、5-14元杂芳基、C_6-20芳烷基、-C_1-6亚烷基-C(＝O)O-C_1-6烷基、-C_1-6亚烷基-OC(＝O)-C_1-6烷基、-C_1-6亚烷基-OC(＝O)O-C_1-6烷基和-((CH₂)_iO)_m-(CH₂)_q-O-C_1-6烷基，上述基团各自任选地被一个或多个选自卤素、-OH、-CN、-NO₂、-N(R)₂、C_1-6烷基、卤代C_1-6烷基、C_1-6烷基硫基和C_3-6环烷基的取代基取代。A compound according to claim 1 or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite or prodrug thereof, wherein R ^{2 is} selected from the group consisting of H and C _1-12 alkyl, C _3-6 cycloalkyl, C _6-14 aryl, 5-14 membered heteroaryl, C _6-20 aralkyl, -C _1-6 alkylene-C (=O OC _1-6 alkyl, -C _1-6 alkylene-OC(=O)-C _1-6 alkyl, -C _1-6 alkylene-OC(=O)OC _1-6 alkyl And -((CH ₂ ) _i O) _m -(CH ₂ ) _q -OC _1-6 alkyl, each of the above groups optionally being selected from one or more selected from the group consisting of halogen, -OH, -CN, -NO ₂ Substituted with a substituent of -N(R) ₂ , C _1-6 alkyl, halo C _1-6 alkyl, C _1-6 alkylthio and C _3-6 cycloalkyl.
权利要求1或2的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物或前药，其中B选自：A compound according to claim 1 or 2, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite or prodrug thereof, wherein B is selected from the group consisting of:
权利要求1-3中任一项的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物或前药，其中A选自：A compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite or prodrug thereof, wherein A From:

其中1位置处与B连接，2位置处与磷原子(P)连接。One of the positions is connected to B, and the second position is connected to the phosphorus atom (P).
权利要求1-4中任一项的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物或前药，其中R¹选自：A compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite or prodrug thereof, wherein R ^{1 is} selected from:
权利要求1-5中任一项的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物或前药，其中Ar¹选自： A compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite or prodrug thereof, wherein Ar ^{1 is} selected from:

其中R^c在每次出现时各自独立地选自F、Cl、Br、I、C_1-6烷基、卤代C_1-6烷基和C_3-6环烷基；Wherein R ^c is each independently selected from the group consisting of F, Cl, Br, I, C _1-6 alkyl, halo C _1-6 alkyl, and C _3-6 cycloalkyl;

优选地，R^c在每次出现时各自独立地选自F、Cl、Br、I、C_1-6烷基和C_3-6环烷基；Preferably, R ^c is each independently selected from the group consisting of F, Cl, Br, I, C _1-6 alkyl and C _3-6 cycloalkyl;

Ar¹优选自：Ar ¹ is preferably selected from:

Ar¹特别优选自：Ar ^{1 is} particularly preferred from:
权利要求1-6中任一项的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物或前药，其中Ar²选自：A compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite or prodrug thereof, wherein Ar ^{2 is} selected from:

以上基团任选地被一个或多个选自卤素、C_1-6烷基、卤代C_1-6烷基和C_3-6环烷基的基团取代；The above groups are optionally substituted by one or more groups selected from the group consisting of halogen, C _1-6 alkyl, halo C _1-6 alkyl and C _3-6 cycloalkyl;

优选地，Ar²选自：Preferably, Ar ^{2 is} selected from the group consisting of

以上基团任选地被一个或多个选自卤素、C_1-6烷基和C_3-6环烷基的基团取代。The above groups are optionally substituted by one or more groups selected from the group consisting of halogen, C _1-6 alkyl and C _3-6 cycloalkyl.
权利要求1-7中任一项的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物或前药，其中R²选自：C_1-6烷基、-((CH₂)_iO)_m-(CH₂)_q-O-C_1-6烷基、A compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite or prodrug thereof, wherein R ^{2 is} selected from the group consisting of: C _1-6 alkyl, -((CH ₂ ) _i O) _m -(CH ₂ ) _q -OC _1-6 alkyl,

其中：among them:

i和q在每次出现时各自独立地为1、2、3、4、5或6；i and q are each independently 1, 2, 3, 4, 5 or 6 at each occurrence;

m为选自0-50，优选0-20，特别优选0-6中的任意整数；m is any integer selected from 0-50, preferably 0-20, particularly preferably 0-6;

R⁷、R⁸和R⁹各自独立地选自H、C_1-10烷基、C_3-6环烷基、C_6-20芳基和C_7-20芳烷基，所述烷基、环烷基、芳基和芳烷基各自任选地被一个或多个选自卤素、-OH、-CN和-NO₂的取代基取代；R ⁷ , R ⁸ and R ⁹ are each independently selected from the group consisting of H, C _1-10 alkyl, C _3-6 cycloalkyl, C _6-20 aryl and C _7-20 aralkyl, said alkyl group, The cycloalkyl, aryl and aralkyl groups are each optionally substituted by one or more substituents selected from the group consisting of halogen, -OH, -CN and -NO ₂ ;

或者R⁷和R⁸连同其所连接的碳原子共同形成C_3-6环烷基；Or R ⁷ and R ⁸ together with the carbon atom to which they are attached form a C _3-6 cycloalkyl group;

R¹⁰和R¹¹各自独立地选自H、卤素、-OH、-CN、-NO₂、C_1-10烷基和C_3-6环烷基。R ¹⁰ and R ¹¹ are each independently selected from the group consisting of H, halogen, -OH, -CN, -NO ₂ , C _1-10 alkyl, and C _3-6 cycloalkyl.
权利要求1-8中任一项的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物或前药，其中所述化合物具有式(II)或式(II)-1的结构：A compound according to any one of claims 1-8, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite or prodrug thereof, wherein The compound has the structure of formula (II) or formula (II)-1:
权利要求1-9中任一项的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物或前药，其中所述化合物具有任意下式的结构： A compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite or prodrug thereof, wherein The compound has any structure of the following formula:
权利要求1-10中任一项的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物或前药，其中所述化合物选自：A compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite or prodrug thereof, wherein Said compound is selected from:
药物组合物，其包含预防或治疗有效量的权利要求1-11中任一项的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物或前药以及一种或多种药学上可接受的载体，所述药物组合物优选是固体制剂、液体制剂或透皮制剂。A pharmaceutical composition comprising a prophylactically or therapeutically effective amount of a compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph thereof, A solvate, metabolite or prodrug and one or more pharmaceutically acceptable carriers, preferably a solid formulation, a liquid formulation or a transdermal formulation.
制备药物组合物的方法，所述方法包括将权利要求1-11中任一项的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物或前药与一种或多种药学上可接受的载体组合。A method of preparing a pharmaceutical composition, which comprises a compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph thereof, The solvate, metabolite or prodrug is combined with one or more pharmaceutically acceptable carriers.
权利要求1-11中任一项的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物或前药或者权利要求12的药物组合物在制备用于预防或治疗病毒性疾病的药物中的用途。 A compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite or prodrug thereof, or claim Use of a pharmaceutical composition of 12 for the manufacture of a medicament for the prevention or treatment of a viral disease.
权利要求14的用途，其中所述药物为通过口服、静脉内、动脉内、皮下、腹膜内、肌内或经皮途径给药的药物。The use according to claim 14, wherein the drug is a drug administered by oral, intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular or transdermal routes.
权利要求14的用途，其中所述病毒性疾病选自甲型病毒性肝炎、乙型病毒性肝炎、丙型病毒性肝炎、流行性感冒、疱疹和获得性免疫缺陷综合征(AIDS)。The use according to claim 14, wherein the viral disease is selected from the group consisting of hepatitis A virus, hepatitis B virus, hepatitis C virus, influenza, herpes and acquired immunodeficiency syndrome (AIDS).
制备权利要求1-11中任一项的化合物的方法，所述方法包括以下步骤：A method of preparing a compound according to any one of claims 1-11, the method comprising the steps of:

或者or

其中：among them:

R¹²、R¹³和R¹⁴各自独立地选自F、Cl、Br、I、-NHR、羟基、三氟甲磺酸酯基、对甲基苯磺酸酯基和硼酸酯基；R ¹² , R ¹³ and R ¹⁴ are each independently selected from the group consisting of F, Cl, Br, I, -NHR, hydroxy, triflate, p-toluenesulfonate and borate;

PG选自叔丁氧羰基、苄氧羰基、9-芴甲氧羰基、烯丙氧羰基、三甲基硅乙氧羰基、甲氧羰基、乙氧羰基、对甲苯磺酰基、邻硝基苯磺酰基、对硝基苯磺酰基、甲酰基、乙酰基、三氟乙酰基、丙酰基、特戊酰基、苯基、苯甲酰基、三苯甲基、苄基、2,4-二甲氧基苄基和对甲氧基苄基；PG is selected from the group consisting of tert-butoxycarbonyl, benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl, allyloxycarbonyl, trimethylsilyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl, p-toluenesulfonyl, o-nitrobenzenesulfonate Acyl, p-nitrophenylsulfonyl, formyl, acetyl, trifluoroacetyl, propionyl, pivaloyl, phenyl, benzoyl, trityl, benzyl, 2,4-dimethoxy Benzyl and p-methoxybenzyl;

其余各基团如权利要求1-11中任一项所定义；The remaining groups are as defined in any one of claims 1-11;

第一步在有机碱或无机碱和/或缩合试剂(特别优选DCC、DIC、EDC、BOP、PyAOP或PyBOP)的存在下，在非质子性溶剂中或无溶剂条件下进行；The first step is carried out in the presence of an organic base or an inorganic base and/or a condensation reagent (particularly preferably DCC, DIC, EDC, BOP, PyAOP or PyBOP) in an aprotic solvent or without solvent;

第二步在适于脱除PG基团的条件下进行；The second step is carried out under conditions suitable for removal of the PG group;

第三步在非质子性溶剂中，在有机碱或无机碱的存在下进行；并且The third step is carried out in an aprotic solvent in the presence of an organic or inorganic base;

第四步在非质子性溶剂中，优选在有机碱或无机碱和/或缩合试剂(特别优选DCC、DIC、EDC、BOP、PyAOP或PyBOP)的存在下进行；The fourth step is carried out in an aprotic solvent, preferably in the presence of an organic base or an inorganic base and/or a condensation reagent, particularly preferably DCC, DIC, EDC, BOP, PyAOP or PyBOP;

或者所述方法包括以下步骤： Or the method comprises the steps of:

其中：among them:

R¹²选自F、Cl、Br、I、-NHR、羟基、三氟甲磺酸酯基、对甲基苯磺酸酯基和硼酸酯基；R ^{12 is} selected from the group consisting of F, Cl, Br, I, -NHR, hydroxy, triflate, p-toluenesulfonate, and borate;

LG为离去基团，其优选为五氟苯基和对硝基苯基；LG is a leaving group, which is preferably a pentafluorophenyl group and a p-nitrophenyl group;

其余各基团如权利要求1-11中任一项所定义；The remaining groups are as defined in any one of claims 1-11;

第一步在有机碱或无机碱的存在下，在非质子性溶剂中进行；The first step is carried out in an aprotic solvent in the presence of an organic or inorganic base;

第二步在有机碱或无机碱的存在下，在非质子性溶剂中进行；并且The second step is carried out in an aprotic solvent in the presence of an organic or inorganic base;

第三步在有机碱或无机碱的存在下，在非质子性溶剂中进行。 The third step is carried out in an aprotic solvent in the presence of an organic or inorganic base.