技术领域Technical Field
本发明属于药物领域，其涉及一种稠合三环类化合物及其作为药物的用途，尤其是作为用于治疗和/或预防乙型肝炎的药物的用途。本发明还涉及这些稠合三环类化合物同其他抗病毒剂组成的组合物，及其在用于治疗和/或预防乙型肝炎病毒(HBV)感染中的应用。The present invention belongs to the field of medicine, and relates to a fused tricyclic compound and its use as a medicine, especially as a medicine for treating and/or preventing hepatitis B. The present invention also relates to a composition composed of these fused tricyclic compounds and other antiviral agents, and its use in treating and/or preventing hepatitis B virus (HBV) infection.
背景技术Background Art
乙型肝炎病毒属于肝病毒科。它可引起急性的和/或持续渐进的慢性病。乙型肝炎病毒还可引起病理形态中的许多其他的临床表征——尤其是肝脏的慢性炎症、肝硬化和肝细胞的癌变。据世界卫生组织估计，全球有20亿人感染过HBV，约有3.5亿的慢性感染者，每年大约有100万人死于HBV感染所致的肝衰竭、肝硬化和原发性肝细胞癌(hepatocellularcarcinoma，HCC)。Hepatitis B virus belongs to the family of Hepatoviridae. It can cause acute and/or progressive chronic diseases. Hepatitis B virus can also cause many other clinical manifestations in pathological morphology - especially chronic inflammation of the liver, cirrhosis and carcinogenesis of liver cells. According to the World Health Organization, 2 billion people have been infected with HBV, about 350 million are chronically infected, and about 1 million people die each year from liver failure, cirrhosis and primary hepatocellular carcinoma (HCC) caused by HBV infection.
目前对于慢性乙型肝炎(Chronic hepatitis B，CHB)的治疗主要为抗病毒治疗。干扰素α(IFN-α)和聚乙二醇化IFN-α及5种核苷(酸)类似物(拉米夫定、阿德福韦酯、恩替卡韦、替比夫定和替诺福韦)被美国食品药品监督管理局(FDA)批准用于临床治疗。干扰素是最早通过FDA批准的抗HBV药物，其主要通过直接抗病毒作用及诱导机体的免疫反应以达到清除病毒的效果，但因其应答率低，具有多种副作用，价格昂贵且治疗对象局限等原因，其应用受到很多限制。核苷(酸)类药物抗HBV共同点是特异性作用于病毒DNA聚合酶，具有强大的抑制病毒复制的效果，患者对药物的耐受性比干扰素好。但是核苷(酸)类药物的广泛长期使用，可诱导DNA聚合酶突变形成耐药性，导致耐药株的不断出现，使治疗远不能达到理想疗效。Currently, the main treatment for chronic hepatitis B (CHB) is antiviral therapy. Interferon α (IFN-α) and pegylated IFN-α and five nucleoside (acid) analogs (lamivudine, adefovir dipivoxil, entecavir, telbivudine and tenofovir) have been approved by the US Food and Drug Administration (FDA) for clinical treatment. Interferon is the first anti-HBV drug approved by the FDA. It mainly eliminates the virus through direct antiviral effects and inducing the body's immune response. However, its application is subject to many restrictions due to its low response rate, multiple side effects, high price and limited treatment targets. The common point of nucleoside (acid) drugs against HBV is that they specifically act on viral DNA polymerase and have a strong effect of inhibiting viral replication. Patients have better tolerance to drugs than interferon. However, the widespread and long-term use of nucleoside (acid) drugs can induce DNA polymerase mutations to form drug resistance, leading to the continuous emergence of drug-resistant strains, making the treatment far from achieving the ideal therapeutic effect.
因此，目前临床上仍然需要有新的能够有效地用作抗病毒药物的化合物，尤其是用作治疗和/或预防乙型肝炎的药物的化合物。Therefore, there is still a clinical need for new compounds that can be effectively used as antiviral drugs, especially compounds that can be used as drugs for treating and/or preventing hepatitis B.
发明内容Summary of the invention
本发明涉及一类新型的稠合三环类化合物和其在制备治疗与预防HBV感染的药物中的用途。发明人发现，本发明涉及的新型的稠合三环类化合物具有药代动力学性质较好、溶解性好、毒性小、肝微粒体稳定性好以及对HBsAg的生成或分泌和HBV DNA的复制都有很好的抑制作用等优点，其在抗HBV方面有很好的应用前景。特别地，本发明所涉及的化合物，及其药学上可接受的组合物，也都可以有效抑制HBV感染。The present invention relates to a novel fused tricyclic compound and its use in preparing a drug for treating and preventing HBV infection. The inventors have found that the novel fused tricyclic compound of the present invention has the advantages of good pharmacokinetic properties, good solubility, low toxicity, good liver microsome stability, and good inhibitory effects on the generation or secretion of HBsAg and the replication of HBV DNA, and has a good application prospect in anti-HBV. In particular, the compounds involved in the present invention and their pharmaceutically acceptable compositions can also effectively inhibit HBV infection.
一方面，本发明涉及一种如式(I)所示的化合物或式(I)所示的化合物的立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或它们的前药，In one aspect, the present invention relates to a compound as represented by formula (I) or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof of the compound as represented by formula (I),
X1为CR8或N；X1 is CR8 or N;
X2为CR7或N；X2 is CR7 or N;
R1为R-(C＝O)-、3-6个环原子组成的杂环基、5-6个环原子组成的杂芳基或R-S(＝O)2-NH-(C＝O)-，其中所述的3-6个环原子组成的杂环基和5-6个环原子组成的杂芳基各自独立地未被取代或被1、2、3或4个Rg所取代；R1 is R-(C=O)-, a heterocyclic group consisting of 3-6 ring atoms, a heteroaryl group consisting of 5-6 ring atoms, or RS(=O)2 -NH-(C=O)-, wherein the heterocyclic group consisting of 3-6 ring atoms and the heteroaryl group consisting of 5-6 ring atoms are each independently unsubstituted or substituted by 1, 2, 3 or 4 Rg ;
R为HO-、C1-6烷氧基、C1-6烷基、C6-10芳基、C3-7环烷基、3-6个环原子组成的杂环基或5-6个环原子组成的杂芳基，其中所述的C1-6烷氧基、C1-6烷基、C6-10芳基、C3-7环烷基、3-6个环原子组成的杂环基和5-6个环原子组成的杂芳基各自独立地未被取代或被1、2、3或4个Rw所取代；R is HO-, C1-6 alkoxy, C1-6 alkyl, C6-10 aryl, C3-7 cycloalkyl, heterocyclic group consisting of 3-6 ring atoms or heteroaryl consisting of 5-6 ring atoms, wherein the C1-6 alkoxy, C1-6 alkyl, C6-10 aryl, C3-7 cycloalkyl, heterocyclic group consisting of 3-6 ring atoms and heteroaryl consisting of 5-6 ring atoms are each independently unsubstituted or substituted by 1, 2, 3 or 4 Rw ;
X为CH或N，当X为CH时，R不为HO-；X is CH or N. When X is CH, R is not HO-;
R2为苯基、呋喃基、吡咯基、吡啶基、吡唑基、咪唑基、三唑基、四唑基、噁唑基、异噁唑基、噁二唑基、1,3,5-三嗪基、噻唑基、噻吩基、吡嗪基、哒嗪基或嘧啶基，其中，所述的苯基、呋喃基、吡咯基、吡啶基、吡唑基、咪唑基、三唑基、四唑基、噁唑基、异噁唑基、噁二唑基、1,3,5-三嗪基、噻唑基、噻吩基、吡嗪基、哒嗪基和嘧啶基各自独立地未被取代或被1、2或3个Rw所取代；R2 is phenyl, furanyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl or pyrimidinyl, wherein the phenyl, furanyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl and pyrimidinyl are each independently unsubstituted or substituted with 1, 2 or 3Rw ;
R3为C1-6烷基、C2-6烯基、C2-6炔基、C3-7环烷基、3-10个环原子组成的杂环基、C6-10芳基、5-10个环原子组成的杂芳基或R11-C1-4亚烷基-，其中所述的C1-6烷基、C2-6烯基、C2-6炔基、C3-7环烷基、3-10个环原子组成的杂环基、C6-10芳基、5-10个环原子组成的杂芳基和所述R11-C1-4亚烷基-中的C1-4亚烷基各自独立地未被取代或被1、2、3或4个Rx所取代；R3 is C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, heterocyclyl consisting of 3-10 ring atoms, C6-10 aryl, heteroaryl consisting of 5-10 ring atoms, or R11 -C1-4 alkylene-, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, heterocyclyl consisting of 3-10 ring atoms, C6-10 aryl, heteroaryl consisting of 5-10 ring atoms, and the C1-4 alkylene in the R11 -C1-4 alkylene- are each independently unsubstituted or substituted by 1, 2, 3 or 4 Rx ;
R11为氘、环丙基、环丁基、环戊基、环己基、C1-6烷氧基、3-6个环原子组成的杂环基或5-10个环原子组成的杂芳基，其中所述的环丙基、环丁基、环戊基、环己基、C1-6烷氧基、3-6个环原子组成的杂环基和5-10个环原子组成的杂芳基各自独立地未被取代或被1、2、3或4个Rj所取代；R11 is deuterium, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, C1-6 alkoxy, a heterocyclic group consisting of 3-6 ring atoms, or a heteroaryl group consisting of 5-10 ring atoms, wherein the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, C1-6 alkoxy, a heterocyclic group consisting of 3-6 ring atoms, and a heteroaryl group consisting of 5-10 ring atoms are each independently unsubstituted or substituted by 1, 2, 3 or 4 Rj ;
各Rx和Rj独立地为氘、F、Cl、Br、CN、O＝、HO-、HOOC-、氨基、C1-6烷基、C1-6烷氧基、C1-6烷硫基、C1-6烷氨基、C2-6烯基、C2-6炔基、C3-7环烷基、3-8个环原子组成的杂环基、C6-10芳基或5-10个环原子组成的杂芳基，其中所述的氨基、C1-6烷基、C1-6烷氧基、C1-6烷硫基、C1-6烷氨基、C2-6烯基、C2-6炔基、C3-7环烷基、3-8个环原子组成的杂环基、C6-10芳基和5-10个环原子组成的杂芳基各自独立地未被取代或被1、2、3或4个Rf所取代；each Rx and Rj is independently deuterium, F, Cl, Br, CN, O=, HO-, HOOC-, amino, C1-6 alkyl, C1-6 alkoxy, C 1-6 alkylthio, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, a heterocyclyl consisting of 3-8 ring atoms, C6-10 aryl, or a heteroaryl consisting of 5-10 ring atoms, wherein the amino, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, a heterocyclyl consisting of 3-8 ring atoms, C6-10 aryl, and a heteroaryl consisting of 5-10 ring atoms are each independently unsubstituted or substituted with 1, 2, 3 or 4 Rf ;
各R4、R5、R7、R8和R9独立地为氢、氘、F、Cl、Br、C1-6烷基、C1-6烷氨基、C1-6烷氧基、C2-6炔基、C2-6烯基、C3-7环烷基或3-10个环原子组成的杂环基，其中所述的C1-6烷基、C1-6烷氨基、C1-6烷氧基、C2-6炔基、C2-6烯基、C3-7环烷基和3-10个环原子组成的杂环基各自独立地未被取代或被1、2、3或4个Rw所取代；Each of R4 , R5 , R7 , R8 and R9 is independently hydrogen, deuterium, F, Cl, Br, C1-6 alkyl, C1-6 alkylamino, C1-6 alkoxy, C 2-6 alkynyl, C2-6 alkenyl, C3-7 cycloalkyl or a heterocyclic group consisting of 3-10 ring atoms, wherein the C1-6 alkyl, C1-6 alkylamino, C1-6 alkoxy, C2-6 alkynyl, C2-6 alkenyl, C3-7 cycloalkyl and the heterocyclic group consisting of3-10 ring atoms are each independently unsubstituted or substituted by 1, 2, 3 or 4 Rw ;
R6为氢、氘、C1-6烷基、C2-6烯基、C3-7环烷基、3-8个环原子组成的杂环基、C6-10芳基或5-10个环原子组成的杂芳基，其中所述的C1-6烷基、C2-6烯基、C3-7环烷基、3-8个环原子组成的杂环基、C6-10芳基和5-10个环原子组成的杂芳基各自独立地未被取代或被1、2、3或4个Rz所取代；R6 is hydrogen, deuterium, C1-6 alkyl, C2-6 alkenyl, C3-7 cycloalkyl, a heterocyclic group consisting of 3-8 ring atoms, a C6-10 aryl, or a heteroaryl group consisting of 5-10 ring atoms, wherein the C1-6 alkyl, C2-6 alkenyl, C3-7 cycloalkyl, a heterocyclic group consisting of 3-8 ring atoms, a C6-10 aryl, and a heteroaryl group consisting of 5-10 ring atoms are each independently unsubstituted or substituted by 1, 2, 3 or 4 Rz ;
或R6、R4，和与其各自所连接的原子一起形成5-6个环原子组成的杂环基或5-6个环原子组成的环烷基，其中所述的5-6个环原子组成的杂环基和5-6个环原子组成的环烷基各自独立地未被取代或被1、2、3或4个Rw所取代；or R6 , R4 , together with the atoms to which they are attached, form a heterocyclic group consisting of 5-6 ring atoms or a cycloalkyl group consisting of 5-6 ring atoms, wherein the heterocyclic group consisting of 5-6 ring atoms and the cycloalkyl group consisting of 5-6 ring atoms are each independently unsubstituted or substituted by 1, 2, 3 or 4 Rw ;
各Rw、Rf、Rg和Rz独立地为氘、F、Cl、Br、HO-、HOOC-、O＝、C1-6烷基-S(＝O)2-、C3-6环烷基-S(＝O)2-、氨基、C1-6烷基、C1-6烷氧基、C1-6烷硫基、C1-6烷氨基、C2-6烯基、C2-6炔基或C3-7环烷基，其中所述C1-6烷基-S(＝O)2-、C3-6环烷基-S(＝O)2-、氨基、C1-6烷基、C1-6烷氧基、C1-6烷硫基、C1-6烷氨基、C2-6烯基、C2-6炔基和C3-7环烷基各自独立地未被取代或被1、2、3或4个选自F、Cl、Br、CN、HO-、O＝、氨基、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6烷硫基、C1-6卤代烷氧基或C1-6烷氨基的取代基所取代。Each of Rw , Rf , Rg and Rz is independently deuterium, F, Cl, Br, HO—, HOOC—, O═, C1-6 alkyl-S(═O)2 —, C3-6 cycloalkyl-S(═O)2 —, amino, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 alkylamino, C 2-6alkenyl , C2-6 alkynyl or C3-7 cycloalkyl, wherein the C1-6 alkyl-S(═O)2 —, C3-6 cycloalkyl-S(═O)2 —, amino, C1-6 alkyl, C 1-6 alkoxy, C1-6 alkylthio, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl and C3-7 cycloalkyl are The3-7 cycloalkyl groups are each independently unsubstituted or substituted by 1, 2, 3 or 4 substituents selected from F, Cl, Br, CN, HO-, O=, amino,C1-6 alkyl,C1-6 haloalkyl,C1-6 alkoxy,C1-6 alkylthio,C1-6 haloalkoxy orC1-6 alkylamino.
在一些实施例中，本发明所述R1为R-(C＝O)-、5-6个环原子组成的杂环基、5-6个环原子组成的杂芳基或R-S(＝O)2-NH-(C＝O)-，其中所述的5-6个环原子组成的杂环基和5-6个环原子组成的杂芳基各自独立地未被取代或被1、2、3或4个Rg所取代；In some embodiments, R1 of the present invention is R-(C=O)-, a heterocyclic group consisting of 5-6 ring atoms, a heteroaryl group consisting of 5-6 ring atoms, or RS(=O)2 -NH-(C=O)-, wherein the heterocyclic group consisting of 5-6 ring atoms and the heteroaryl group consisting of 5-6 ring atoms are each independently unsubstituted or substituted by 1, 2, 3 or 4 Rg ;
R为HO-、C1-4烷氧基、C1-4烷基、苯基、C3-6环烷基、3-6个环原子组成的杂环基或5-6个环原子组成的杂芳基，其中所述的C1-4烷氧基、C1-4烷基、苯基、C3-6环烷基、3-6个环原子组成的杂环基和5-6个环原子组成的杂芳基各自独立地未被取代或被1、2、3或4个Rw所取代；R is HO-, C1-4 alkoxy, C1-4 alkyl, phenyl, C3-6 cycloalkyl, heterocyclic group consisting of 3-6 ring atoms or heteroaryl consisting of 5-6 ring atoms, wherein the C1-4 alkoxy, C1-4 alkyl, phenyl, C3-6 cycloalkyl, heterocyclic group consisting of 3-6 ring atoms and heteroaryl consisting of 5-6 ring atoms are each independently unsubstituted or substituted by 1, 2, 3 or 4 Rw ;
其中，各Rg和Rw具有本发明所述的含义。wherein each of Rg and Rw has the meanings as defined in the present invention.
在一些实施例中，本发明所述R1为R-(C＝O)-、吡咯烷基、吡唑烷基、咪唑烷基、四氢呋喃基、四氢噻吩基、四氢吡喃基、四氢噻喃基、四氢噻唑基哌啶基、吗啉基、硫代吗啉基、哌嗪基、呋喃基、吡咯基、吡啶基、吡唑基、咪唑基、三唑基、四唑基、噁唑基、异噁唑基、噁二唑基、1,3,5-三嗪基、噻唑基、噻二唑基噻吩基、吡嗪基、哒嗪基、嘧啶基或R-S(＝O)2-NH-(C＝O)-，其中所述的吡咯烷基、吡唑烷基、咪唑烷基、四氢呋喃基、四氢噻吩基、四氢吡喃基、四氢噻喃基、四氢噻唑基、哌啶基、吗啉基、硫代吗啉基、哌嗪基、呋喃基、吡咯基、吡啶基、吡唑基、咪唑基、三唑基、四唑基、噁唑基、异噁唑基、噁二唑基、1,3,5-三嗪基、噻唑基、噻二唑基、噻吩基、吡嗪基、哒嗪基和嘧啶基各自独立地未被取代或被1、2、3或4个Rg所取代；In some embodiments, R1 of the present invention is R-(C=O)-, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrothiazolyl piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, furanyl, pyrrolyl, pyridinyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thiadiazolyl thienyl, pyrazinyl, pyridazinyl, pyrimidinyl or RS(=O)2 -NH-(C=O)-, wherein the pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrothiazolyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, furanyl, pyrrolyl, pyridinyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thiadiazolyl, thienyl, pyrazinyl, pyridazinyl and pyrimidinyl are each independently unsubstituted or substituted with 1, 2, 3 or 4Rg ;
R为HO-、甲氧基、乙氧基、1-丙氧基、2-丙氧基、1-丁氧基、2-甲基-l-丙氧基、2-丁氧基、甲基、乙基、正丙基、异丙基、正丁基、异丁基、苯基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、氧杂环丁基、硫杂环丁基、氧杂环丙基、吡咯烷基、吡唑烷基、咪唑烷基、四氢呋喃基、四氢噻吩基、四氢吡喃基、四氢噻喃基、哌啶基、吗啉基、硫代吗啉基、哌嗪基、呋喃基、吡咯基、吡啶基、吡唑基、咪唑基、三唑基、四唑基、噁唑基、异噁唑基、噁二唑基、1,3,5-三嗪基、噻唑基、噻吩基、吡嗪基、哒嗪基或嘧啶基，其中所述的甲氧基、乙氧基、1-丙氧基、2-丙氧基、1-丁氧基、2-甲基-l-丙氧基、2-丁氧基、甲基、乙基、正丙基、异丙基、正丁基、异丁基、苯基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、氧杂环丁基、硫杂环丁基、氧杂环丙基、吡咯烷基、吡唑烷基、咪唑烷基、四氢呋喃基、四氢噻吩基、四氢吡喃基、四氢噻喃基、哌啶基、吗啉基、硫代吗啉基、哌嗪基、呋喃基、吡咯基、吡啶基、吡唑基、咪唑基、三唑基、四唑基、噁唑基、异噁唑基、噁二唑基、1,3,5-三嗪基、噻唑基、噻吩基、吡嗪基、哒嗪基和嘧啶基各自独立地未被取代或被1、2、3或4个Rw所取代；R is HO-, methoxy, ethoxy, 1-propoxy, 2-propoxy, 1-butoxy, 2-methyl-1-propoxy, 2-butoxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, thietanyl, oxirane, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, furanyl, pyrrolyl, pyridinyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl or pyrimidinyl, wherein the methoxy, R w is each independently unsubstituted or substituted with 1, 2, 3 or 4 Rw ;
其中，各Rg和Rw具有本发明所述的含义。wherein each of Rg and Rw has the meanings as defined in the present invention.
在一些实施例中，本发明所述R3为C1-4烷基、C2-4烯基、C2-4炔基、C3-6环烷基、3-6个环原子组成的杂环基、苯基、5个环原子组成的杂芳基、6个环原子组成的杂芳基或R11-C1-4亚烷基-，其中所述的C1-4烷基C2-4烯基、C2-4炔基、C3-6环烷基、3-6个环原子组成的杂环基、苯基、5个环原子组成的杂芳基、6个环原子组成的杂芳基和所述R11-C1-4亚烷基-中的C1-4亚烷基各自独立地未被取代或被1、2、3或4个Rx所取代；In some embodiments, R3 of the present invention is C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C3-6 cycloalkyl, a heterocyclyl consisting of 3-6 ring atoms, phenyl, a heteroaryl consisting of 5 ring atoms, a heteroaryl consisting of 6 ring atoms, or R11 -C1-4 alkylene-, wherein the C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C3-6 cycloalkyl, a heterocyclyl consisting of 3-6 ring atoms, phenyl, a heteroaryl consisting of 5 ring atoms, a heteroaryl consisting of 6 ring atoms, and the C1-4 alkylene in the R11 -C1-4 alkylene- are each independently unsubstituted or substituted by 1, 2, 3 or 4 Rx ;
R11为氘、环丙基、环丁基、环戊基、环己基、C1-4烷氧基、3-6个环原子组成的杂环基、5个环原子组成的杂芳基或6个环原子组成的杂芳基，其中所述的环丙基、环丁基、环戊基、环己基、C1-4烷氧基、3-6个环原子组成的杂环基、5个环原子组成的杂芳基和6个环原子组成的杂芳基各自独立地未被取代或被1、2、3或4个Rj所取代；R11 is deuterium, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, C1-4 alkoxy, a heterocyclic group consisting of 3-6 ring atoms, a heteroaryl consisting of 5 ring atoms, or a heteroaryl consisting of 6 ring atoms, wherein the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, C1-4 alkoxy, a heterocyclic group consisting of 3-6 ring atoms, a heteroaryl consisting of 5 ring atoms, and a heteroaryl consisting of 6 ring atoms are each independently unsubstituted or substituted by 1, 2, 3 or 4 Rj ;
其中，各Rx和Rj具有本发明所述的含义。wherein each Rx and Rj has the meanings as defined in the present invention.
在一些实施例中，本发明所述R3为甲基、乙基、正丙基、异丙基正丁基、乙烯基、丙烯基、乙炔基、丙炔基、炔丙基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、氧杂环丁基、硫杂环丁基、氧杂环丙基、吡咯烷基、吡唑烷基、咪唑烷基、四氢呋喃基、四氢噻吩基、四氢吡喃基、四氢噻喃基、哌啶基、吗啉基、硫代吗啉基、哌嗪基、苯基、呋喃基、吡咯基、吡啶基、吡唑基、咪唑基、三唑基、四唑基、噁唑基、异噁唑基、噁二唑基、1,3,5-三嗪基、噻唑基、噻吩基、吡嗪基、哒嗪基、嘧啶基或R11-C1-4亚烷基-，其中所述的甲基、乙基、正丙基、异丙基、正丁基、乙烯基、丙烯基、乙炔基、丙炔基、炔丙基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、氧杂环丁基、硫杂环丁基、氧杂环丙基、吡咯烷基、吡唑烷基、咪唑烷基、四氢呋喃基、四氢噻吩基、四氢吡喃基、四氢噻喃基、哌啶基、吗啉基、硫代吗啉基、哌嗪基、苯基、呋喃基、吡咯基、吡啶基、吡唑基、咪唑基、三唑基、四唑基、噁唑基、异噁唑基、噁二唑基、1,3,5-三嗪基、噻唑基、噻吩基、吡嗪基、哒嗪基、嘧啶基和R11-C1-4亚烷基-中的C1-4亚烷基各自独立地未被取代或被1、2、3或4个Rx所取代；In some embodiments, R3 of the present invention is methyl, ethyl, n-propyl, isopropyl-n-butyl, vinyl, propenyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, thietanyl, oxetanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, phenyl, furanyl, pyrrolyl, pyridinyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl, pyrimidinyl or R11 -C R 11 -C1-4 alkylene-, wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, vinyl, propenyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, thietanyl, oxirane, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, phenyl, furanyl, pyrrolyl, pyridinyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl, pyrimidinyl and the C in R11 -C1-4 alkylene-1-4 alkylene groups are each independently unsubstituted or substituted with 1, 2, 3 or 4 Rx ;
R11为氘、环丙基、环丁基、环戊基、环己基、甲氧基、乙氧基、1-丙氧基、2-丙氧基、1-丁氧基、2-甲基-l-丙氧基、2-丁氧基、氮杂环丁基、氧杂环丁基、硫杂环丁基、氧杂环丙基、吡咯烷基、吡唑烷基、咪唑烷基、四氢呋喃基、四氢噻吩基、四氢吡喃基、四氢噻喃基、哌啶基、吗啉基、硫代吗啉基、哌嗪基、呋喃基、吡咯基、吡啶基、吡唑基、咪唑基、三唑基、四唑基、噁唑基、异噁唑基、噁二唑基、1,3,5-三嗪基、噻唑基、噻吩基、吡嗪基、哒嗪基或嘧啶基，其中所述的环丙基、环丁基、环戊基、环己基、甲氧基、乙氧基、1-丙氧基、2-丙氧基、1-丁氧基、2-甲基-l-丙氧基、2-丁氧基、氮杂环丁基、氧杂环丁基、硫杂环丁基、氧杂环丙基、吡咯烷基、吡唑烷基、咪唑烷基、四氢呋喃基、四氢噻吩基、四氢吡喃基、四氢噻喃基、哌啶基、吗啉基、硫代吗啉基、哌嗪基、呋喃基、吡咯基、吡啶基、吡唑基、咪唑基、三唑基、四唑基、噁唑基、异噁唑基、噁二唑基、1,3,5-三嗪基、噻唑基、噻吩基、吡嗪基、哒嗪基和嘧啶基基各自独立地未被取代或被1、2、3或4个Rj所取代；R11 is deuterium, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, 1-propoxy, 2-propoxy, 1-butoxy, 2-methyl-1-propoxy, 2-butoxy, azetidinyl, oxetanyl, thietanyl, oxirane, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, furanyl, pyrrolyl, pyridinyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl or pyrimidinyl, wherein the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, 1-propoxy, 2-propoxy, 1-butoxy, 2-methyl-1-propoxy, 2-butoxy, azetidinyl, oxetanyl, thietanyl, oxirane, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, furanyl, pyrrolyl, pyridinyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl butyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, 1-propoxy, 2-propoxy, 1-butoxy, 2-methyl-1-propoxy, 2-butoxy, azetidinyl, oxetanyl, thietanyl, oxirane, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, furanyl, pyrrolyl, pyridinyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl and pyrimidinyl are each independently unsubstituted or substituted with 1, 2, 3 or 4 Rj ;
其中，各Rx和Rj具有本发明所述的含义。wherein each Rx and Rj has the meanings as defined in the present invention.
在一些实施例中，本发明所述各Rx和Rj独立地为氘、F、Cl、Br、CN、O＝、HO-、HOOC-、氨基、C1-4烷基、C1-4烷氧基、C1-4烷硫基、C1-4烷氨基、C2-4烯基、C2-4炔基、C3-6环烷基、3-6个环原子组成的杂环基、苯基、5个环原子组成的杂芳基或6个环原子组成的杂芳基，其中所述的氨基、C1-4烷基、C1-4烷氧基、C1-4烷硫基、C1-4烷氨基、C2-4烯基、C2-4炔基、C3-6环烷基、3-6个环原子组成的杂环基、苯基、5个环原子组成的杂芳基和6个环原子组成的杂芳基各自独立地未被取代或被1、2、3或4个Rf所取代；In some embodiments, each Rx and Rj of the present invention is independently deuterium, F, Cl, Br, CN, O＝, HO-, HOOC-, amino, C1-4 alkyl, C1-4 alkoxy, C1-4 alkylthio, C1-4 alkylamino, C2-4 alkenyl, C2-4 alkynyl, C3-6 cycloalkyl, a heterocyclyl consisting of 3-6 ring atoms, phenyl, a heteroaryl consisting of 5 ring atoms, or a heteroaryl consisting of 6 ring atoms, wherein the amino, C1-4 alkyl, C 1-4 alkoxy, C1-4 alkylthio, C1-4 alkylamino, C2-4 alkenyl, C2-4 alkynyl, C3-6 cycloalkyl, a heterocyclyl consisting of3-6 ring atoms, phenyl, a heteroaryl consisting of 5 ring atoms, and a heteroaryl consisting of 6 ring atoms are each independently unsubstituted or substituted with 1, 2, 3 or 4 Rf ;
其中，各Rf具有本发明所述的含义。wherein eachRf has the meaning as defined in the present invention.
在一些实施例中，本发明所述各Rx和Rj独立地为氘、F、Cl、Br、CN、O＝、HO-、HOOC-、氨基、甲基、乙基、正丙基、异丙基、正丁基、异丁基、甲氧基、乙氧基、1-丙氧基、2-丙氧基、1-丁氧基、2-甲基-l-丙氧基、2-丁氧基、C1-3烷硫基、N-甲氨基、N-乙氨基、N,N-二甲氨基、N,N-二乙氨基、N-丙氨基、乙烯基、丙烯基、乙炔基、丙炔基、炔丙基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、氧杂环丁基、硫杂环丁基、氧杂环丙基、吡咯烷基、吡唑烷基、咪唑烷基、四氢呋喃基、四氢噻吩基、四氢吡喃基、四氢噻喃基、哌啶基、吗啉基、硫代吗啉基、哌嗪基、苯基、呋喃基、吡咯基、吡啶基、吡唑基、咪唑基、三唑基、四唑基、噁唑基、异噁唑基、噁二唑基、1,3,5-三嗪基、噻唑基、噻吩基、吡嗪基、哒嗪基或嘧啶基，其中所述的氨基、甲基、乙基、正丙基、异丙基、正丁基、异丁基、甲氧基、乙氧基、1-丙氧基、2-丙氧基、1-丁氧基、2-甲基-l-丙氧基、2-丁氧基、C1-3烷硫基、N-甲氨基、N-乙氨基、N,N-二甲氨基、N,N-二乙氨基、N-丙氨基、乙烯基、丙烯基、乙炔基、丙炔基、炔丙基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、氧杂环丁基、硫杂环丁基、氧杂环丙基、吡咯烷基、吡唑烷基、咪唑烷基、四氢呋喃基、四氢噻吩基、四氢吡喃基、四氢噻喃基、哌啶基、吗啉基、硫代吗啉基、哌嗪基、苯基、呋喃基、吡咯基、吡啶基、吡唑基、咪唑基、三唑基、四唑基、噁唑基、异噁唑基、噁二唑基、1,3,5-三嗪基、噻唑基、噻吩基、吡嗪基、哒嗪基和嘧啶基各自独立地未被取代或被1、2、3或4个Rf所取代；In some embodiments, eachRx andRj described in the present invention is independently deuterium, F, Cl, Br, CN, O=, HO-, HOOC-, amino, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, methoxy, ethoxy, 1-propoxy, 2-propoxy, 1-butoxy, 2-methyl-l-propoxy, 2-butoxy,C1-3 alkylthio, N-methylamino, N-ethylamino, N,N-dimethylamino, N,N-diethylamino, N-propylamino, vinyl, propenyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, thiazole, oxetanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, 1-propyl, 2-propyl, 3-butyl, 3-isobutyl, 3-methoxy, 4-butyl, 5-dinitro-1-propoxy, 5-butyl, 6-dinitro-1-propoxy, 6 ... Rf is each independently unsubstituted or substituted with1 , 2, 3 or 4Rf ;
其中，各Rf具有本发明所述的含义。wherein eachRf has the meaning as defined in the present invention.
在一些实施例中，本发明所述各R4、R5、R7、R8和R9独立地为氢、氘、F、Cl、Br、甲基、乙基、正丙基、异丙基、正丁基、异丁基、C1-4烷氨基、C1-4烷氧基、C2-4炔基、C2-4烯基、C3-6环烷基或3-6个环原子组成的杂环基，其中所述的甲基、乙基、正丙基、异丙基、正丁基、异丁基、C1-4烷氨基、C1-4烷氧基、C2-4炔基、C2-4烯基、C3-6环烷基和3-6个环原子组成的杂环基各自独立地未被取代或被1、2、3或4个Rw所取代；In some embodiments, each of R4 , R5 , R7 , R8 and R9 described in the present invention is independently hydrogen, deuterium, F, Cl, Br, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, C1-4 alkylamino, C1-4 alkoxy, C2-4 alkynyl, C2-4 alkenyl, C3-6 cycloalkyl or a heterocyclic group consisting of 3-6 ring atoms, wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, C1-4 alkylamino, C1-4 alkoxy, C2-4 alkynyl, C2-4 alkenyl, C3-6 cycloalkyl and a heterocyclic group consisting of 3-6 ring atoms are each independently unsubstituted or substituted by 1, 2, 3 or 4 Rw ;
R6为氢、氘、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、C2-4烯基、C3-6环烷基、3-6个环原子组成的杂环基、苯基、5个环原子组成的杂芳基或6个环原子组成的杂芳基，其中所述的甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、C2-4烯基、C3-6环烷基、3-6个环原子组成的杂环基、苯基、5个环原子组成的杂芳基和6个环原子组成的杂芳基各自独立地未被取代或被1、2、3或4个Rz所取代；R6 is hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, C2-4 alkenyl, C3-6 cycloalkyl, a heterocyclic group consisting of 3-6 ring atoms, phenyl, a heteroaryl consisting of 5 ring atoms, or a heteroaryl consisting of 6 ring atoms, wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, C2-4 alkenyl, C3-6 cycloalkyl, a heterocyclic group consisting of 3-6 ring atoms, phenyl, a heteroaryl consisting of 5 ring atoms, and a heteroaryl consisting of 6 ring atoms are each independently unsubstituted or substituted by 1, 2, 3 or 4 Rz ;
或R6、R4，和与其各自所连接的原子一起形成环戊基、环己基、吡咯烷基或哌啶基，其中所述的环戊基、环己基、吡咯烷基和哌啶基各自独立地未被取代或被1、2、3或4个Rw所取代；or R6 , R4 , together with the atoms to which they are attached, form cyclopentyl, cyclohexyl, pyrrolidinyl or piperidinyl, wherein the cyclopentyl, cyclohexyl, pyrrolidinyl and piperidinyl are each independently unsubstituted or substituted with 1, 2, 3 or 4 Rw ;
其中，各Rw和Rz具有本发明所述的含义。wherein each of Rw and Rz has the meanings as defined in the present invention.
在一些实施例中，本发明所述各Rw、Rf、Rg和Rz独立地为氘、F、Cl、Br、HO-、HOOC-、O＝、C1-4烷基-S(＝O)2-、C3-6环烷基-S(＝O)2-、氨基、C1-4烷基、C1-4烷氧基、C1-4烷硫基、C1-4烷氨基、C2-4烯基、C2-4炔基或C3-6环烷基，其中所述C1-4烷基-S(＝O)2-、C3-6环烷基-S(＝O)2-、氨基、C1-4烷基、C1-4烷氧基、C1-4烷硫基、C1-4烷氨基、C2-4烯基、C2-4炔基和C3-6环烷基各自独立地未被取代或被1、2、3或4个选自F、Cl、Br、CN、HO-、O＝、氨基、C1-4烷基、C1-4卤代烷基、C1-4烷氧基、C1-4烷硫基、C1-4卤代烷氧基或C1-4烷氨基的取代基所取代。In some embodiments, each of Rw , Rf , Rg and Rz described in the present invention is independently deuterium, F, Cl, Br, HO-, HOOC-, O=, C1-4 alkyl-S(=O)2 -, C3-6 cycloalkyl-S(=O)2 -, amino, C1-4 alkyl, C1-4 alkoxy, C1-4 alkylthio, C1-4 alkylamino, C2-4 alkenyl, C2-4 alkynyl or C3-6 cycloalkyl, wherein the C1-4 alkyl-S(=O)2 -, C3-6 cycloalkyl-S(=O)2 -, amino, C1-4 alkyl, C1-4 alkoxy, C1-4 alkylthio, C1-4 alkylamino, C2-4 alkenyl, C2-4 alkynyl and C 3-6 cycloalkyl The3-6 cycloalkyl groups are each independently unsubstituted or substituted by 1, 2, 3 or 4 substituents selected from F, Cl, Br, CN, HO-, O=, amino,C1-4 alkyl,C1-4 haloalkyl,C1-4 alkoxy,C1-4 alkylthio,C1-4 haloalkoxy orC1-4 alkylamino.
在一些实施例中，本发明所述各Rw、Rf、Rg和Rz独立地为氘、F、Cl、Br、HO-、HOOC-、O＝、甲基-S(＝O)2-、乙基-S(＝O)2-、丙基-S(＝O)2-、异丙基-S(＝O)2-、环丙基-S(＝O)2-、环丁基-S(＝O)2-、环戊基-S(＝O)2-、环己基-S(＝O)2-、氨基、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、甲氧基、乙氧基、1-丙氧基、2-丙氧基、1-丁氧基、2-甲基-l-丙氧基、2-丁氧基、C1-4烷硫基、C1-4烷氨基、C2-4烯基、C2-4炔基、环丙基、环丁基、环戊基或环己基，其中所述甲基-S(＝O)2-、乙基-S(＝O)2-、丙基-S(＝O)2-、异丙基-S(＝O)2-、环丙基-S(＝O)2-、环丁基-S(＝O)2-、环戊基-S(＝O)2-、环己基-S(＝O)2-、氨基、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、甲氧基、乙氧基、1-丙氧基、2-丙氧基、1-丁氧基、2-甲基-l-丙氧基、2-丁氧基、C1-4烷硫基、C1-4烷氨基、C2-4烯基、C2-4炔基、环丙基、环丁基、环戊基和环己基各自独立地未被取代或被1、2、3或4个选自F、Cl、Br、CN、HO-、O＝、氨基、C1-3烷基、C1-3卤代烷基、C1-3烷氧基、C1-3烷硫基、C1-3卤代烷氧基或C1-4烷氨基的取代基所取代。In some embodiments, each of Rw , Rf , Rg and Rz described in the present invention is independently deuterium, F, Cl, Br, HO-, HOOC-, O=, methyl-S(=O)2 -, ethyl-S(=O)2 -, propyl-S(=O)2 -, isopropyl-S(=O)2 -, cyclopropyl-S(=O)2 -, cyclobutyl-S(=O)2 -, cyclopentyl-S(=O)2 -, cyclohexyl-S(=O)2 -, amino, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methoxy, ethoxy, 1-propoxy, 2-propoxy, 1-butoxy, 2-methyl-1-propoxy, 2-butoxy, C1-4 alkylthio, C 1-4 alkylamino, C2-4 alkenyl, C2-4 The methyl-S(＝O)2- , ethyl-S(＝O)2- , propyl-S(＝O)2- , isopropyl-S(＝O)2- , cyclopropyl-S(＝O)2- , cyclobutyl-S(＝O)2- , cyclopentyl-S(＝O)2-, cyclohexyl-S(＝O)2- , amino, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methoxy, ethoxy, 1-propoxy, 2-propoxy, 1-butoxy, 2-methyl-1-propoxy,2 -butoxy, C1-4 alkylthio, C1-4 alkylamino,C2-4 alkenyl,C1-4 The2-4 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl are each independently unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from F, Cl, Br, CN, HO-, O=, amino,C1-3 alkyl,C1-3 haloalkyl,C1-3 alkoxy,C1-3 alkylthio,C1-3 haloalkoxy orC1-4 alkylamino.
另一方面，本发明还提供了一种包含本发明所述的化合物的药物组合物，任选地，所述药物组合物进一步包含药学上可接受的辅料或所述辅料的组合。On the other hand, the present invention also provides a pharmaceutical composition comprising the compound of the present invention, optionally, the pharmaceutical composition further comprises a pharmaceutically acceptable excipient or a combination of the excipients.
在一些实施例中，本发明所述的药物组合物，其进一步地包含其它抗HBV药物。In some embodiments, the pharmaceutical composition of the present invention further comprises other anti-HBV drugs.
在一些实施例中，本发明所述的药物组合物，其中所述其它抗HBV药物为HBV聚合酶抑制剂、免疫调节剂或干扰素。In some embodiments, in the pharmaceutical composition described herein, the other anti-HBV drug is a HBV polymerase inhibitor, an immunomodulator or an interferon.
在一些实施例中，本发明所述的药物组合物，其中所述其它抗HBV药物为拉米夫定、替比夫定、替诺福韦酯、恩替卡韦、阿德福韦酯、Alfaferone、Alloferon、西莫白介素、克拉夫定、恩曲他滨、法昔洛韦、干扰素、宝甘灵CP、因特芬、干扰素α-1b、干扰素α、干扰素α-2a、干扰素β-1a、干扰素α-2、白细胞介素-2、米伏替酯、硝唑尼特、聚乙二醇干扰素α-2a、病毒唑、罗扰素-A、西佐喃、Euforavac、安普利近、Phosphazid、Heplisav、干扰素α-2b、左旋咪唑或丙帕锗。In some embodiments, the pharmaceutical composition described in the present invention, wherein the other anti-HBV drug is lamivudine, telbivudine, tenofovir disoproxil, entecavir, adefovir dipivoxil, Alfaferone, Alloferon, simu-leukin, clavudine, emtricitabine, famciclovir, interferon, Baoganling CP, Intefen, interferon α-1b, interferon α, interferon α-2a, interferon β-1a, interferon α-2, interleukin-2, mivotilide, nitazoxanide, polyethylene glycol interferon α-2a, ribavirin, roentgen-A, sizoran, Euforavac, Ampligen, Phosphazid, Heplisav, interferon α-2b, levamisole or propagermanium.
另一方面，本发明还提供了所述化合物或所述药物组合物在制备用于预防、治疗或减轻患者病毒性疾病的药物中的用途。On the other hand, the present invention also provides use of the compound or the pharmaceutical composition in preparing a drug for preventing, treating or alleviating viral diseases in patients.
在一些实施例中，本发明所述的用途，其中所述病毒性疾病是指乙型肝炎病毒感染或乙型肝炎病毒感染引起的疾病。In some embodiments, the use described in the present invention, wherein the viral disease refers to hepatitis B virus infection or a disease caused by hepatitis B virus infection.
在另外一些实施例中，本发明所述的用途，其中所述乙型肝炎病毒感染引起的疾病是指肝硬化或肝细胞癌变。In other embodiments, the use described in the present invention, wherein the disease caused by hepatitis B virus infection refers to cirrhosis or hepatocellular carcinoma.
另一方面，本发明还提供了所述的化合物或所述的药物组合物在制备药物中的用途，所述药物用于抑制HBsAg的生成或分泌，和/或用于抑制HBV DNA的生成。On the other hand, the present invention also provides the use of the compound or the pharmaceutical composition in the preparation of a drug for inhibiting the production or secretion of HBsAg and/or for inhibiting the production of HBV DNA.
另一方面，本发明涉及所述的化合物或药物组合物在制备用于预防、治疗或减轻患者乙型肝炎疾病的药物中的用途。On the other hand, the present invention relates to the use of the compound or pharmaceutical composition in the preparation of a drug for preventing, treating or alleviating hepatitis B disease in a patient.
本发明另一方面涉及预防、治疗或减轻患者HBV病症的方法，所述方法包含使用药学上可接受的有效剂量的本发明化合物对患者进行给药。Another aspect of the present invention relates to a method for preventing, treating or ameliorating HBV symptoms in a patient, the method comprising administering to the patient a pharmaceutically acceptable effective dose of a compound of the present invention.
本发明另一方面涉及预防、治疗或减轻患者HBV病症的方法，所述方法包含使用药学上可接受的有效剂量的含有本发明化合物的药物组合物对患者进行给药。Another aspect of the present invention relates to a method for preventing, treating or alleviating HBV symptoms in a patient, the method comprising administering to the patient a pharmaceutical composition containing a compound of the present invention in a pharmaceutically acceptable effective dose.
本发明另一方面涉及使用一种本发明化合物在制备用于预防、处理或治疗患者HBV病症，并减轻其严重程度的药品的用途。Another aspect of the present invention relates to the use of a compound of the present invention in the preparation of a medicament for preventing, treating or curing HBV symptoms in patients and reducing their severity.
本发明另一方面涉及使用一种包含本发明化合物的药物组合物在制备用于预防或治疗患者HBV病症，并减轻其严重程度的药物的用途。Another aspect of the present invention relates to the use of a pharmaceutical composition comprising the compound of the present invention in the preparation of a medicament for preventing or treating HBV disease in a patient and reducing its severity.
本发明另一方面涉及一种抑制HBV感染的方法，该方法包含细胞与有效抑制HBV剂量的本发明化合物或组合物接触。另外一些实施例是，所述方法更进一步地包含细胞与抗HBV剂的接触。Another aspect of the present invention relates to a method for inhibiting HBV infection, which comprises contacting cells with a compound or composition of the present invention at an effective dose to inhibit HBV. In some other embodiments, the method further comprises contacting cells with an anti-HBV agent.
本发明另一方面涉及治疗患者HBV疾病的方法，该方法包含给予患者有效治疗量的本发明化合物或其组合物。另外一些实施例是，所述方法更进一步地包含其它HBV治疗的给药。Another aspect of the present invention relates to a method for treating HBV disease in a patient, the method comprising administering to the patient an effective therapeutic amount of a compound of the present invention or a composition thereof. In some other embodiments, the method further comprises administering other HBV treatments.
本发明另一方面涉及一种抑制患者HBV感染的方法，该方法包含给予患者有效治疗量的本发明化合物或其组合物。另外一些实施例是，所述方法更进一步地包含其它HBV治疗的给药。Another aspect of the present invention relates to a method for inhibiting HBV infection in a patient, the method comprising administering to the patient an effective therapeutic amount of a compound of the present invention or a composition thereof. In some other embodiments, the method further comprises administering other HBV treatments.
本发明另一方面涉及式(I)或式(Ia)所包含的化合物的制备、分离和纯化的方法。Another aspect of the present invention relates to methods for preparing, isolating and purifying the compounds encompassed by formula (I) or formula (Ia).
前面所述内容只概述了本发明的某些方面，但并不限于这些方面。这些方面及其他的方面的内容将在下面作更加具体完整的描述。The foregoing description only summarizes certain aspects of the present invention, but is not limited to these aspects. These aspects and other aspects will be described in more detail and fully below.
本发明的详细说明书Detailed description of the present invention
定义和一般术语Definitions and general terms
本发明将会把确定的具体化的内容所对应的文献详细列出，实施例都伴随有结构式和化学式的图解。本发明有预期地涵盖所有的选择余地、变体和同等物，这些可能像权利要求所定义的那样包含在现有发明领域。所属领域的技术人员将识别许多类似或等同于在此所描述的方法和物质，这些可以应用于本发明的实践中去。本发明绝非限于方法和物质的描述。有很多文献和相似的物质与本发明申请相区别或抵触，其中包括但绝不限于术语的定义，术语的用法，描述的技术，或像本发明申请所控制的范围。The present invention will list the literature corresponding to the determined specific content in detail, and the embodiments are accompanied by diagrams of structural formulas and chemical formulas. The present invention is expected to cover all options, variants and equivalents, which may be included in the existing invention field as defined in the claims. Those skilled in the art will recognize many methods and materials similar or equivalent to those described herein, which can be applied to the practice of the present invention. The present invention is by no means limited to the description of methods and materials. There are many documents and similar materials that are different from or conflict with the present application, including but not limited to the definition of terms, the usage of terms, the technology described, or the scope controlled by the present application.
本发明将应用以下定义除非其他方面表明。根据本发明的目的，化学元素根据元素周期表，CAS版本和化学药品手册，75，thEd，1994来定义。另外，有机化学一般原理见"Organic Chemistry,"Thomas Sorrell,University Science Books,Sausalito:1999,and"March's Advanced Organic Chemistry,"by Michael B.Smith and Jerry March,John Wiley&Sons,New York:2007，因此所有的内容都融合了参考文献。The following definitions shall apply to the present invention unless otherwise indicated. For purposes of the present invention, chemical elements are defined according to the Periodic Table of the Elements, CAS version and Handbook of Chemicals, 75,th Ed, 1994. In addition, general principles of organic chemistry are found in "Organic Chemistry," Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry," by Michael B. Smith and Jerry March, John Wiley & Sons, New York: 2007, all of which are incorporated by reference.
像本发明所描述的，本发明的化合物被一个或多个取代基所取代，如上面的通式化合物，或者像实施例里面特殊的例子，子类，和本发明所包含的一类化合物。一般而言，术语“取代”，表示所给结构中的一个或多个氢原子被具体取代基所取代。除非其他方面表明，一个取代的基团可以有一个取代基在基团各个可取代的位置进行取代。当所给出的结构式中不止一个位置能被选自具体基团的一个或多个取代基所取代，那么取代基可以相同或不同地在各个位置取代。在本说明书的各部分，本发明公开化合物的取代基按照基团种类或范围公开。特别指出，本发明包括这些基团种类和范围的各个成员的每一个独立的次级组合。例如，术语“C1-6烷基”特别指独立公开的甲基、乙基、C3烷基、C4烷基、C5烷基和C6烷基。As described herein, the compounds of the present invention are substituted with one or more substituents, such as the general formula compounds above, or as the specific examples, subclasses, and classes of compounds included in the embodiments. In general, the term "substituted" means that one or more hydrogen atoms in a given structure are replaced by a specific substituent. Unless otherwise indicated, a substituted group may have a substituent substituted at each substitutable position of the group. When more than one position in a given structural formula can be substituted by one or more substituents selected from a specific group, the substituents may be substituted at each position in the same or different manner. In various parts of this specification, the substituents of the compounds disclosed in the present invention are disclosed according to group types or ranges. It is specifically pointed out that the present invention includes each independent subcombination of each member of these group types and ranges. For example, the term "C1-6 alkyl" specifically refers to methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl and C6 alkyl disclosed independently.
另外，需要说明的是，除非以其他方式明确指出，在本发明中所采用的描述方式“各…独立地为”与“…各自独立地为”和“…独立地为”可以互换，均应做广义理解，其既可以是指在不同基团中，相同符号之间所表达的具体选项之间互相不影响，也可以表示在相同的基团中，相同符号之间所表达的具体选项之间互相不影响。In addition, it should be noted that, unless explicitly stated otherwise, the description methods used in the present invention, "each... is independently" and "... are each independently" and "... are independently" can be interchanged and should be understood in a broad sense, which can mean that in different groups, the specific options expressed by the same symbols do not affect each other, or that in the same group, the specific options expressed by the same symbols do not affect each other.
本发明使用的术语“烷基”包括1-20个碳原子饱和直链或支链的单价烃基，其中烷基可以独立任选地被一个或多个本发明所描述的取代基所取代。其中一些实施例是，烷基基团含有1-12个碳原子，另外一些实施例是，烷基基团含有1-8个碳原子，另外一些实施例是，烷基基团含有1-6个碳原子，另外一些实施例是，烷基基团含有1-4个碳原子，另外一些实施例是，烷基基团含有1-3个碳原子。烷基基团更进一步的实例包括，但并不限于，甲基(Me，-CH3)，乙基(Et，-CH2CH3)，正丙基(n-Pr，-CH2CH2CH3)，异丙基(i-Pr，-CH(CH3)2)，正丁基(n-Bu，-CH2CH2CH2CH3)，2-甲基丙基或异丁基(i-Bu，-CH2CH(CH3)2)，1-甲基丙基或仲丁基(s-Bu，-CH(CH3)CH2CH3)，叔丁基(t-Bu，-C(CH3)3)，正戊基(-CH2CH2CH2CH2CH3)，2-戊基(-CH(CH3)CH2CH2CH3)，3-戊基(-CH(CH2CH3)2)，2-甲基-2-丁基(-C(CH3)2CH2CH3)，3-甲基-2-丁基(-CH(CH3)CH(CH3)2)，3-甲基-1-丁基(-CH2CH2CH(CH3)2)，2-甲基-1-丁基(-CH2CH(CH3)CH2CH3)，正己基(-CH2CH2CH2CH2CH2CH3)，2-己基(-CH(CH3)CH2CH2CH2CH3)，3-己基(-CH(CH2CH3)(CH2CH2CH3))，2-甲基-2-戊基(-C(CH3)2CH2CH2CH3)，3-甲基-2-戊基(-CH(CH3)CH(CH3)CH2CH3)，4-甲基-2-戊基(-CH(CH3)CH2CH(CH3)2)，3-甲基-3-戊基(-C(CH3)(CH2CH3)2)，2-甲基-3-戊基(-CH(CH2CH3)CH(CH3)2)，2,3-二甲基-2-丁基(-C(CH3)2CH(CH3)2)，3,3-二甲基-2-丁基(-CH(CH3)C(CH3)3)、3,3-二甲基-丁基(-CH2CH2C(CH3)3)，正庚基，正辛基，等等。术语“烷基”和其前缀“烷”在此处使用，都包含直链和支链的饱和碳链。本发明使用的术语“卤代脂肪族”表示脂肪族基团被一个或多个相同或不同的卤原子所取代，其中脂肪族基团或者烷基具有如本发明所述的含义，卤原子即氟，氯，溴或碘，这样的实例包括，但并不限于三氟甲基，三氟乙基等。The term "alkyl" used in the present invention includes saturated straight or branched monovalent hydrocarbon groups of 1 to 20 carbon atoms, wherein the alkyl group may be independently and optionally substituted by one or more substituents described in the present invention. In some embodiments, the alkyl group contains 1 to 12 carbon atoms, in other embodiments, the alkyl group contains 1 to 8 carbon atoms, in other embodiments, the alkyl group contains 1 to 6 carbon atoms, in other embodiments, the alkyl group contains 1 to 4 carbon atoms, and in other embodiments, the alkyl group contains 1 to 3 carbon atoms. Further examples of alkyl groups include, but are not limited to, methyl (Me, -CH3 ), ethyl (Et, -CH2 CH3 ), n-propyl (n-Pr, -CH2 CH2 CH3 ), isopropyl (i-Pr, -CH(CH3 )2 ), n-butyl (n-Bu, -CH2 CH2 CH2 CH3 ), 2-methylpropyl or isobutyl (i-Bu, -CH2 CH(CH3 )2 ), 1-methylpropyl or sec-butyl (s-Bu, -CH(CH3 )CH2 CH3 ), tert-butyl (t-Bu, -C(CH3 )3 ), n-pentyl (-CH2 CH2 CH2 CH2 CH 3 ), 2-pentyl (-CH(CH3 )CH 2 CH 2 CH3 ), 3-pentyl (-CH(CH 3 )CH2 CH2 CH3 ),2 CH3 )2 ), 2-methyl-2-butyl (-C(CH3 )2 CH2 CH3 ), 3-methyl-2-butyl (-CH(CH3 )CH(CH3 )2 ), 3-methyl-1-butyl (-CH2 CH2 CH(CH3 )2 ), 2-methyl-1-butyl (-CH2 CH(CH3 )CH2 CH3 ), n-hexyl (-CH2 CH2 CH2 CH2 CH2 CH3 ), 2-hexyl (-CH(CH3 )CH2 CH2 CH2 CH3 ), 3-hexyl (-CH(CH2 CH3 )(CH2 CH2 CH3 )), 2-methyl-2-pentyl (-C(CH3 )2 CH2 CH2 CH3 ), 3-methyl-2-pentyl (-CH(CH3 )CH(CH3 )CH2 CH3 ), 4-methyl-2-pentyl (-CH(CH3 )CH2 CH(CH3 )2 ), 3-methyl-3-pentyl (-C(CH3 )(CH2 CH3 )2 ), 2-methyl-3-pentyl (-CH(CH2 CH3 ) CH(CH3 )2 ), 2,3-dimethyl-2-butyl (-C(CH3 )2 CH(CH3 )2 ), 3,3-dimethyl-2-butyl (-CH(CH3 )C(CH3 )3 ), 3,3-dimethyl-butyl (-CH2 CH2 C(CH3 )3 ), n-heptyl, n-octyl, and the like. The term "alkyl" and its prefix "alkane" as used herein include both straight and branched saturated carbon chains. The term "halogenated aliphatic" as used herein means that an aliphatic group is substituted with one or more halogen atoms, which may be the same or different, wherein the aliphatic group or alkyl group has the meaning as described herein, and the halogen atom is fluorine, chlorine, bromine or iodine, such examples include, but are not limited to, trifluoromethyl, trifluoroethyl, etc.
术语“卤代烷基”表示烷基基团被一个或多个卤素原子所取代，其中烷基具有本发明所述的含义。其中一些实施例是，卤代烷基基团含有1-12个碳原子；另外一些实施例是，卤代烷基基团含有1-10个碳原子；另外一些实施例是，卤代烷基基团含有1-8个碳原子；另外一些实施例是，卤代烷基基团含有1-6个碳原子；另外一些实施例是，卤代烷基基团含有1-4个碳原子，另外一些实施例是，卤代烷基基团含有1-3个碳原子。这样的实例包含，但并不限于，三氟甲基，三氟乙基等。The term "haloalkyl" means an alkyl group substituted with one or more halogen atoms, wherein alkyl has the meaning as described herein. In some embodiments, the haloalkyl group contains 1-12 carbon atoms; in other embodiments, the haloalkyl group contains 1-10 carbon atoms; in other embodiments, the haloalkyl group contains 1-8 carbon atoms; in other embodiments, the haloalkyl group contains 1-6 carbon atoms; in other embodiments, the haloalkyl group contains 1-4 carbon atoms; in other embodiments, the haloalkyl group contains 1-3 carbon atoms. Such examples include, but are not limited to, trifluoromethyl, trifluoroethyl, etc.
术语“羧基”，无论是单独使用还是和其他术语连用(如“羧烷基”)，表示-CO2H或-COOH。The term "carboxy", whether used alone or in combination with other terms (such as "carboxyalkyl"), means-CO2H or -COOH.
术语“羰基”，无论是单独使用还是和其他术语连用(如“氨基羰基”或“酰氧基”)，表示-(C＝O)-。The term "carbonyl", whether used alone or in combination with other terms (such as "aminocarbonyl" or "acyloxy"), refers to -(C=O)-.
术语“烷基氨基”和“烷氨基”可以交换使用，包括“N-烷基氨基”和“N,N-二烷基氨基”，其中氨基基团分别独立地被一个或两个C1-12烷基基团所取代。其中一些实施例中，烷基氨基是一个或两个C1-12烷基连接到氮原子上的较低级的烷基氨基基团，一些实施例中，烷基氨基是C1-6的较低级的烷基氨基基团，一些实施例中，烷基氨基是C1-4的较低级的烷基氨基基团。合适的烷基氨基基团可以是单烷基氨基或二烷基氨基，这样的实例包括，但并不限于，N-甲氨基，N-乙氨基，N,N-二甲氨基，N,N-二乙氨基，N-丙氨基，N,N-二丙氨基，等等，其中所述烷基氨基基团可以独立地未被取代或被一个或多个本发明所描述的取代基所取代。The terms "alkylamino" and "alkylamino" are used interchangeably, including "N-alkylamino" and "N,N-dialkylamino", wherein the amino groups are independently substituted with one or two C1-12 alkyl groups. In some embodiments, the alkylamino group is a lower alkylamino group with one or two C1-12 alkyl groups attached to the nitrogen atom, in some embodiments, the alkylamino group is a C1-6 lower alkylamino group, and in some embodiments, the alkylamino group is a C1-4 lower alkylamino group. Suitable alkylamino groups can be monoalkylamino or dialkylamino, such examples include, but are not limited to, N-methylamino, N-ethylamino, N,N-dimethylamino, N,N-diethylamino, N-propylamino, N,N-dipropylamino, and the like, wherein the alkylamino groups can be independently unsubstituted or substituted with one or more substituents described herein.
术语“亚烷基”表示从直链或支链的饱和烃基中去掉两个氢原子所得到的饱和的二价烃基基团。除非另外详细说明，亚烷基基团含有1-12个碳原子，另外一些实施例是，亚烷基基团含有1-6个碳原子，另外一些实施例是，亚烷基基团含有1-4个碳原子，另外一些实施例是，亚烷基基团含有1-3个碳原子。另外一些实施例是，亚烷基基团含有1-2个碳原子。这样的实例包括亚甲基(-CH2-)、亚乙基(-CH2CH2-)，亚丙基(-CH2CH2CH2-)、亚异丙基(-CH(CH3)CH2-)、亚丁基(-CH2CH2CH2CH2-)、亚戊基(-CH2CH2CH2CH2CH2-)、亚己基(-CH2CH2CH2CH2CH2CH2-)、亚庚基(-CH2CH2CH2CH2CH2CH2CH2-)、亚辛基(-CH2CH2CH2CH2CH2CH2CH2CH2-)等等，其中所述亚烷基基团可以独立地未被取代或被一个或多个本发明所描述的取代基所取代。The term "alkylene" refers to a saturated divalent hydrocarbon group obtained by removing two hydrogen atoms from a straight or branched saturated hydrocarbon group. Unless otherwise specified, the alkylene group contains 1-12 carbon atoms, in some other embodiments, the alkylene group contains 1-6 carbon atoms, in some other embodiments, the alkylene group contains 1-4 carbon atoms, in some other embodiments, the alkylene group contains 1-3 carbon atoms. In some other embodiments, the alkylene group contains 1-2 carbon atoms. Such examples includemethylene (-CH2- ), ethylene (-CH2CH2-) , propylene(-CH2CH2CH2- ),isopropylene (-CH(CH3 )CH2-) ,butylene (-CH2CH2CH2CH2-) ,pentylene( -CH2CH2CH2CH2CH2-),hexylene (-CH2CH2CH2CH2CH2CH2-) ,heptylene(-CH2CH2CH2CH2CH2CH2CH2-),octylene (-CH2CH2CH2CH2CH2CH2CH2CH2CH2-), andthelike ,where thealkylene groupsindependentlymay be unsubstituted orsubstitutedwith one ormore substituentsdescribedherein .
术语“烯基”表示含有2-12个碳原子，或2-8个碳原子，或2-6个碳原子，或2-4个碳原子的直链或支链的一价烃基，其中至少有一个位置的C-C为sp2双键，其中烯基的基团可以独立地未被取代或被一个或多个本发明所描述的取代基所取代，包括有“顺”、“反”或"Z"、"E"异构体，其中具体的实例包括，但并不限于，乙烯基(-CH＝CH2)，丙烯基(-CH＝CHCH3)、烯丙基(-CH2CH＝CH2)等等，其中所述烯基基团可以独立地未被取代或被一个或多个本发明所描述的取代基所取代。The term "alkenyl" refers to a straight or branched monovalent hydrocarbon group containing 2-12 carbon atoms, or 2-8 carbon atoms, or 2-6 carbon atoms, or 2-4 carbon atoms, wherein at least one position of CC is ansp2 double bond, wherein the alkenyl group may be independently unsubstituted or substituted with one or more substituents described in the present invention, including "cis", "trans" or "Z", "E" isomers, wherein specific examples include, but are not limited to, vinyl (-CH=CH2 ), propenyl (-CH=CHCH3 ), allyl (-CH2CH =CH2 ), etc., wherein the alkenyl group may be independently unsubstituted or substituted with one or more substituents described in the present invention.
术语“炔基”表示含有2-12个碳原子，或2-8个碳原子，或2-6个碳原子，或2-4个碳原子的直链或支链的一价烃基，其中至少有一个位置的C-C为sp三键，其中炔基基团可以独立地未被取代或被一个或多个本发明所描述的取代基所取代，具体的实例包括，但并不限于，乙炔基(-C≡CH)、炔丙基(-CH2C≡CH)、丙炔基(-C≡C-CH3)、1-炔丁基(-CH2CH2C≡CH)、2-炔丁基(-CH2C≡CCH3)、3-炔丁基(-C≡CCH2CH3)等等，其中所述炔基基团可以独立地未被取代或被一个或多个本发明所描述的取代基所取代。The term "alkynyl" refers to a straight or branched monovalent hydrocarbon group containing 2-12 carbon atoms, or 2-8 carbon atoms, or 2-6 carbon atoms, or 2-4 carbon atoms, wherein at least one position of CC is an sp triple bond, wherein the alkynyl group may be independently unsubstituted or substituted with one or more substituents described in the present invention, specific examples include, but are not limited to, ethynyl (-C≡CH), propargyl (-CH2 C≡CH), propynyl (-C≡C-CH3 ), 1-ynylbutyl (-CH2 CH2 C≡CH), 2-ynylbutyl (-CH2 C≡CCH3 ), 3-ynylbutyl (-C≡CCH2 CH3 ) and the like, wherein the alkynyl group may be independently unsubstituted or substituted with one or more substituents described in the present invention.
术语“烷氧基”表示烷基基团通过氧原子与分子其余部分相连，其中烷基基团具有如本发明所述的含义。除非另外详细说明，所述烷氧基基团含有1-20个碳原子，其中一些实施例是，烷氧基基团含有1-12个碳原子，另外一些实施例是，烷氧基基团含有1-8个碳原子，另外一些实施例是，烷氧基基团含有1-6个碳原子，另外一些实施例是，烷氧基基团含有1-4个碳原子，另外一些实施例是，烷氧基基团含有1-3个碳原子。The term "alkoxy" means an alkyl group attached to the rest of the molecule via an oxygen atom, wherein the alkyl group has the meaning as described herein. Unless otherwise specified, the alkoxy group contains 1-20 carbon atoms, in some embodiments, the alkoxy group contains 1-12 carbon atoms, in other embodiments, the alkoxy group contains 1-8 carbon atoms, in other embodiments, the alkoxy group contains 1-6 carbon atoms, in other embodiments, the alkoxy group contains 1-4 carbon atoms, and in other embodiments, the alkoxy group contains 1-3 carbon atoms.
烷氧基基团的实例包含，但并不限于，甲氧基(MeO,-OCH3)、乙氧基(EtO,-OCH2CH3)、1-丙氧基(n-PrO,n-丙氧基,-OCH2CH2CH3)、2-丙氧基(i-PrO,i-丙氧基,-OCH(CH3)2)、1-丁氧基(n-BuO,n-丁氧基,-OCH2CH2CH2CH3)、2-甲基-l-丙氧基(i-BuO,i-丁氧基,-OCH2CH(CH3)2)、2-丁氧基(s-BuO,s-丁氧基,-OCH(CH3)CH2CH3)、2-甲基-2-丙氧基(t-BuO,t-丁氧基,-OC(CH3)3)、1-戊氧基(n-戊氧基,-OCH2CH2CH2CH2CH3)、2-戊氧基(-OCH(CH3)CH2CH2CH3)、3-戊氧基(-OCH(CH2CH3)2)、2-甲基-2-丁氧基(-OC(CH3)2CH2CH3)、3-甲基-2-丁氧基(-OCH(CH3)CH(CH3)2)、3-甲基-l-丁氧基(-OCH2CH2CH(CH3)2)、2-甲基-l-丁氧基(-OCH2CH(CH3)CH2CH3)，等等，其中所述烷氧基基团可以独立地未被取代或被一个或多个本发明所描述的取代基所取代。Examples of alkoxy groups include, but are not limited to, methoxy (MeO, -OCH3 ), ethoxy (EtO, -OCH2 CH3 ), 1-propoxy (n-PrO, n-propoxy, -OCH2 CH2 CH3 ), 2-propoxy (i-PrO, i-propoxy, -OCH(CH3 )2 ), 1-butoxy (n-BuO, n-butoxy, -OCH2 CH2 CH2 CH3 ), 2-methyl-1-propoxy (i-BuO, i-butoxy, -OCH2 CH(CH3 )2 ), 2-butoxy (s-BuO, s-butoxy, -OCH(CH3 )CH2 CH3 ), 2-methyl-2-propoxy (t-BuO, t-butoxy, -OC(CH3 )3 ), 1-pentoxy (n-pentoxy, -OCH2 CH2 CH2 CH2 CH3 ), 2-pentyloxy (-OCH(CH3 )CH2 CH2 CH3 ), 3-pentyloxy (-OCH(CH2 CH3 )2 ), 2-methyl-2-butoxy (-OC(CH3 )2 CH2 CH3 ), 3-methyl-2-butoxy (-OCH(CH3 )CH(CH3 )2 ), 3-methyl-1-butoxy (-OCH2 CH2 CH(CH3 )2 ), 2-methyl-1-butoxy (-OCH2 CH(CH3 )CH2 CH3 ), and the like, wherein the alkoxy groups independently may be unsubstituted or substituted with one or more substituents described herein.
术语“卤代烷氧基”表示烷氧基基团被一个或多个卤素原子所取代，其中烷氧基具有本发明所述的含义。其中一些实施例是，卤代烷氧基基团含有1-12个碳原子；另外一些实施例是，卤代烷氧基基团含有1-10个碳原子；另外一些实施例是，卤代烷氧基基团含有1-8个碳原子；另外一些实施例是，卤代烷氧基基团含有1-6个碳原子；另外一些实施例是，卤代烷氧基基团含有1-4个碳原子，另外一些实施例是，卤代烷氧基基团含有1-3个碳原子。这样的实例包含，但并不限于，三氟甲氧基等。The term "haloalkoxy" means an alkoxy group substituted with one or more halogen atoms, wherein alkoxy has the meaning as described herein. In some embodiments, the haloalkoxy group contains 1-12 carbon atoms; in other embodiments, the haloalkoxy group contains 1-10 carbon atoms; in other embodiments, the haloalkoxy group contains 1-8 carbon atoms; in other embodiments, the haloalkoxy group contains 1-6 carbon atoms; in other embodiments, the haloalkoxy group contains 1-4 carbon atoms; in other embodiments, the haloalkoxy group contains 1-3 carbon atoms. Such examples include, but are not limited to, trifluoromethoxy and the like.
术语“环烷基”是指有一个或多个连接点连接到分子的其余部分，饱和的，含有3-12个环碳原子的单环，双环或三环体系。其中一些实施例，环烷基是含3-10个环碳原子的环体系；另外一些实施例，环烷基是含3-8个环碳原子的环体系；另外一些实施例，环烷基是含3-7个环碳原子的环体系；另外一些实施例，环烷基是含5-8个环碳原子的环体系；另外一些实施例，环烷基是含3-6个环碳原子的环体系；另外一些实施例，环烷基是含5-6个环碳原子的环体系；环烷基基团的实例包含，但并不限于，环丙基，环丁基，环戊基，环己基等等，且所述环烷基基团可以独立地未被取代或被一个或多个本发明所描述的取代基所取代。The term "cycloalkyl" refers to a saturated, monocyclic, bicyclic or tricyclic ring system having 3-12 ring carbon atoms and having one or more points of attachment to the rest of the molecule. In some embodiments, the cycloalkyl group has 3-10 ring carbon atoms; in other embodiments, the cycloalkyl group has 3-8 ring carbon atoms; in other embodiments, the cycloalkyl group has 3-7 ring carbon atoms; in other embodiments, the cycloalkyl group has 5-8 ring carbon atoms; in other embodiments, the cycloalkyl group has 3-6 ring carbon atoms; in other embodiments, the cycloalkyl group has 5-6 ring carbon atoms; Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc., and the cycloalkyl groups may be independently unsubstituted or substituted with one or more substituents described herein.
术语“杂环基”和“杂环”在此处可交换使用，都是指包含3-12个环原子的饱和或部分不饱和的，非芳香性的单环、双环或三环体系，其中至少有一个环原子选自氮，硫和氧原子，且此环体系有一个或多个连接点与分子的其余部分相连。术语“杂环基”包括单环、双环或多环稠合、螺式或桥连杂环环系，还包括其中杂环可与一个或多个非芳香族碳环或杂环或一个或多个芳环或其组合稠合的多环环系，其中连接的原子团或点在杂环上。双环杂环基包括桥连双环杂环基、稠合双环杂环基和螺双环杂环基。除非另外说明，杂环基上的-CH2-基团可以任选地被-C(＝O)-替代。环的硫原子可以任选地被氧化成S-氧化物。环的氮原子可以任选地被氧化成N-氧化合物。在一些实施方案中，杂环基为3-12个环原子组成的环体系；在其它一些实施方案中，杂环基为3-8个环原子组成的环体系；在其它一些实施方案中，杂环基为3-6个环原子组成的环体系；在其他一些实施方案中，杂环基为5-7个环原子组成的环体系；在其他一些实施方案中，杂环基为5-8个环原子组成的环体系；在其他一些实施方案中，杂环基为6-8个环原子组成的环体系；在其他一些实施方案中，杂环基为5-6个环原子组成的环体系；在其它一些实施方案中，杂环基为3个环原子组成的环体系；在其他一些实施方案中，杂环基为4个环原子组成的环体系；在其他一些实施方案中，杂环基为5个环原子组成的环体系；在其他一些实施方案中，杂环基为6个环原子组成的环体系；在其他一些实施方案中，杂环基为7个环原子组成的环体系；在其他一些实施方案中，杂环基为8个环原子组成的环体系。The terms "heterocyclyl" and "heterocycle" are used interchangeably herein and refer to a saturated or partially unsaturated, non-aromatic monocyclic, bicyclic or tricyclic ring system containing 3-12 ring atoms, wherein at least one ring atom is selected from nitrogen, sulfur and oxygen atoms, and the ring system has one or more points of attachment to the rest of the molecule. The term "heterocyclyl" includes monocyclic, bicyclic or polycyclic fused, spiro or bridged heterocyclic ring systems, and also includes polycyclic ring systems in which the heterocyclic ring may be fused to one or more non-aromatic carbocyclic or heterocyclic rings or one or more aromatic rings or combinations thereof, wherein the radical or point of attachment is on the heterocyclic ring. Bicyclic heterocyclyl includes bridged bicyclic heterocyclyl, fused bicyclic heterocyclyl and spiro bicyclic heterocyclyl. Unless otherwise specified, the-CH2- group on the heterocyclyl may be optionally replaced by -C(=O)-. The sulfur atom of the ring may be optionally oxidized to S-oxide. The nitrogen atom of the ring may be optionally oxidized to N-oxide. In some embodiments, heterocyclyl is a ring system consisting of 3-12 ring atoms; in other embodiments, heterocyclyl is a ring system consisting of 3-8 ring atoms; in other embodiments, heterocyclyl is a ring system consisting of 3-6 ring atoms; in other embodiments, heterocyclyl is a ring system consisting of 5-7 ring atoms; in other embodiments, heterocyclyl is a ring system consisting of 5-8 ring atoms; in other embodiments, heterocyclyl is a ring system consisting of 6-8 ring atoms; in other embodiments, heterocyclyl is a ring system consisting of 5-6 ring atoms; in other embodiments, heterocyclyl is a ring system consisting of 3 ring atoms; in other embodiments, heterocyclyl is a ring system consisting of 4 ring atoms; in other embodiments, heterocyclyl is a ring system consisting of 5 ring atoms; in other embodiments, heterocyclyl is a ring system consisting of 6 ring atoms; in other embodiments, heterocyclyl is a ring system consisting of 7 ring atoms; in other embodiments, heterocyclyl is a ring system consisting of 8 ring atoms.
杂环的实例包括，但并不限于，吡咯烷基，四氢呋喃基，二氢呋喃基，四氢噻吩基，四氢吡喃基，四氢噻唑基二氢吡喃基，四氢噻喃基，哌啶基，吗啉基，硫代吗啉基，噻噁烷基，哌嗪基，高哌嗪基，氮杂环丁基，氧杂环丁基，硫杂环丁基，高哌啶基，氧杂环丙基，氮杂环庚基，氧杂环庚基，硫杂环庚基，氧氮杂卓基，二氮杂卓基，硫氮杂卓基，2-吡咯啉基，3-吡咯啉基，二氢吲哚基，2H-吡喃基，4H-吡喃基，二氧杂环己基，1,3-二氧戊基，吡唑啉基，二噻烷基，二噻茂烷基，二氢噻吩基，吡唑烷基，咪唑啉基，咪唑烷基，1,2,3,4-四氢异喹啉基，3-氮杂双环[3.1.0]己基，3-氮杂双环[4.1.0]庚基，氮杂双环[2.2.2]己基，3H-吲哚基喹嗪基和N-吡啶基尿素。杂环基团的实例还包括，1,1-二氧硫代吗啉基；其中，环上碳原子被氧代(＝O)基团所取代的实例包括，但不限于嘧啶二酮基、1,2,4-噻二唑-5(4H)-酮基，1,2,4-噁二唑-5(4H)-酮基，1H-1,2,4-三唑-5(4H)-酮基等；其中环上碳原子被＝S基团所取代的实例包括，但不限于1,2,4-噁二唑-5(4H)-硫酮基，1,3,4-噁二唑-2(3H)-硫酮基等。所述的杂环基基团可以任选地被一个或多个本发明所描述的取代基所取代。Examples of heterocyclic rings include, but are not limited to, pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiazolyl dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, thioxanyl, piperazinyl, homopiperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxirane, azepanyl, oxepinyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H- pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydrothiophenyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 1,2,3,4-tetrahydroisoquinolinyl, 3-azabicyclo[3.1.0]hexyl, 3-azabicyclo[4.1.0]heptyl, azabicyclo[2.2.2]hexyl, 3H-indolylquinolizinyl and N-pyridylurea. Examples of heterocyclic groups also include 1,1-dioxothiomorpholinyl; examples of ring carbon atoms substituted by oxo (=O) groups include, but are not limited to, pyrimidinedione, 1,2,4-thiadiazole-5(4H)-one, 1,2,4-oxadiazole-5(4H)-one, 1H-1,2,4-triazole-5(4H)-one, etc.; examples of ring carbon atoms substituted by =S groups include, but are not limited to, 1,2,4-oxadiazole-5(4H)-thione, 1,3,4-oxadiazole-2(3H)-thione, etc. The heterocyclic group may be optionally substituted by one or more substituents described in the present invention.
术语“M-M1个环原子组成的”表示所述环状基团由M-M1个环原子所组成，所述的环原子包括碳原子和/或O、N、S、P等杂原子。例如，“6-10个环原子组成的杂芳基”代表其包括6、7、8、9或10个环原子组成的杂芳基。The term "consisting of MM1 ring atoms" means that the cyclic group consists of MM1 ring atoms, and the ring atoms include carbon atoms and/or heteroatoms such as O, N, S, and P. For example, "heteroaryl consisting of 6-10 ring atoms" means a heteroaryl consisting of 6, 7, 8, 9 or 10 ring atoms.
术语“杂原子”表示一个或多个O，S，N，P和Si，包括N，S和P任何氧化态的形式；伯，仲，叔胺和季铵盐的形式；或者杂环中氮原子上的氢被取代的形式，例如，N(像3,4-二氢-2H-吡咯基中的N)，NH(像吡咯烷基中的NH)或NR(像N-取代的吡咯烷基中的NR，R表示本发明所描述的取代基)。The term "heteroatom" means one or more O, S, N, P and Si, including N, S and P in any oxidation state; in the form of primary, secondary, tertiary amines and quaternary ammonium salts; or in the form of a nitrogen atom in a heterocyclic ring in which the hydrogen is substituted, for example, N (such as N in 3,4-dihydro-2H-pyrrolyl), NH (such as NH in pyrrolidinyl) or NR (such as NR in N-substituted pyrrolidinyl, R represents a substituent described in the present invention).
术语“卤素”或“卤原子”是指F，Cl，Br或I。The term "halogen" or "halogen atom" refers to F, Cl, Br or I.
本发明所使用的术语“不饱和的”表示部分含有一个或多个不饱和度。As used herein, the term "unsaturated" means that the moiety contains one or more degrees of unsaturation.
术语“芳基”可以单独使用或作为“芳烷基”，“芳烷氧基”或“芳氧基烷基”的一大部分，表示含有6-14个碳原子，或6-12个碳原子，或6-10个碳原子的单环，双环，和三环的碳环体系，其中，至少有一个环体系是芳香族的，其中每一个环体系包含3-7个碳原子组成的环，且有一个或多个附着点与分子的其余部分相连。术语“芳基”可以和术语“芳环”或“芳香环”交换使用，如芳基可以包括苯基，萘基和蒽基。所述芳基基团可以独立地未被取代或被一个或多个本发明所描述的取代基所取代。The term "aryl" may be used alone or as a part of "aralkyl", "aralkyloxy" or "aryloxyalkyl" to refer to monocyclic, bicyclic, and tricyclic carbon ring systems containing 6-14 carbon atoms, or 6-12 carbon atoms, or 6-10 carbon atoms, wherein at least one of the ring systems is aromatic, wherein each ring system contains 3-7 carbon atoms and has one or more points of attachment to the rest of the molecule. The term "aryl" may be used interchangeably with the term "aromatic ring" or "aromatic ring", such as aryl may include phenyl, naphthyl and anthracenyl. The aryl groups may be independently unsubstituted or substituted with one or more substituents described herein.
术语“杂芳基”可以单独使用或作为“杂芳基烷基”或“杂芳基烷氧基”的一大部分，表示含有5-16个环原子的单环，双环或三环体系，其中至少有一个环体系是芳香族的，且至少有一个环体系包含一个或多个杂原子，其中每一个环体系包含5-7个环原子组成的环，且有一个或多个附着点与分子其余部分相连。术语“杂芳基”可以与术语“杂芳环”或“杂芳族化合物”交换使用。在一些实施方案中，杂芳基为包含1，2，3或4个独立选自O，S和N的杂原子的5-14个环原子组成的杂芳基。在另一些实施方案中，杂芳基为包含1，2，3或4个独立选自O，S和N的杂原子的5-12个环原子组成的杂芳基。在另一些实施方案中，杂芳基为包含1，2，3或4个独立选自O，S和N的杂原子的5-10个环原子组成的杂芳基。在另一些实施方案中，杂芳基为包含1，2，3或4个独立选自O，S和N的杂原子的5-8个环原子组成的杂芳基。在另一些实施方案中，杂芳基为包含1，2，3或4个独立选自O，S和N的杂原子的5-7个环原子组成的杂芳基。在另一些实施方案中，杂芳基为包含1，2，3或4个独立选自O，S和N的杂原子的5-6个环原子组成的杂芳基。在另一些实施方案中，杂芳基为包含1，2，3或4个独立选自O，S和N的杂原子的5个环原子组成的杂芳基。在另一些实施方案中，杂芳基为包含1，2，3或4个独立选自O，S和N的杂原子的6个环原子组成的杂芳基。The term "heteroaryl" may be used alone or as a large part of "heteroarylalkyl" or "heteroarylalkoxy" to refer to a monocyclic, bicyclic or tricyclic ring system containing 5-16 ring atoms, wherein at least one of the ring systems is aromatic and at least one of the ring systems contains one or more heteroatoms, wherein each ring system contains 5-7 ring atoms and has one or more points of attachment to the rest of the molecule. The term "heteroaryl" may be used interchangeably with the terms "heteroaromatic ring" or "heteroaromatic compound". In some embodiments, heteroaryl is a heteroaryl consisting of 5-14 ring atoms containing 1, 2, 3 or 4 heteroatoms independently selected from O, S and N. In other embodiments, heteroaryl is a heteroaryl consisting of 5-12 ring atoms containing 1, 2, 3 or 4 heteroatoms independently selected from O, S and N. In other embodiments, heteroaryl is a heteroaryl consisting of 5-10 ring atoms containing 1, 2, 3 or 4 heteroatoms independently selected from O, S and N. In other embodiments, heteroaryl is a heteroaryl consisting of 5-8 ring atoms containing 1, 2, 3 or 4 heteroatoms independently selected from O, S and N. In other embodiments, heteroaryl is a heteroaryl consisting of 5-7 ring atoms containing 1, 2, 3 or 4 heteroatoms independently selected from O, S and N. In other embodiments, heteroaryl is a heteroaryl consisting of 5-6 ring atoms containing 1, 2, 3 or 4 heteroatoms independently selected from O, S and N. In other embodiments, heteroaryl is a heteroaryl consisting of 5 ring atoms containing 1, 2, 3 or 4 heteroatoms independently selected from O, S and N. In other embodiments, heteroaryl is a heteroaryl consisting of 6 ring atoms containing 1, 2, 3 or 4 heteroatoms independently selected from O, S and N.
另外一些实施例是，杂芳基包括以下的单环基团，但并不限于这些单环基团：呋喃基(如2-呋喃基，3-呋喃基)，咪唑基(如N-咪唑基，2-咪唑基，4-咪唑基，5-咪唑基)，异噻唑基(如3-异噁唑基，4-异噁唑基，5-异噁唑基)，噁唑基(如2-噁唑基，4-噁唑基，5-噁唑基)，吡咯基(如N-吡咯基，2-吡咯基，3-吡咯基)，吡啶基(如2-吡啶基，3-吡啶基，4-吡啶基)，嘧啶基(如2-嘧啶基，4-嘧啶基，5-嘧啶基)，哒嗪基(如3-哒嗪基)，噻唑基(如2-噻唑基，4-噻唑基，5-噻唑基)，噻二唑基四唑基(如5H-四唑基，2H-四唑基)，三唑基(如2-三唑基，5-三唑基，4H-1,2,4-三唑基，1H-1,2,4-三唑基，1,2,3-三唑基)，噻吩基(如2-噻吩基，3-噻吩基)，吡唑基(如，2-吡唑基和3-吡唑基)，噁唑基(如1,2,3-噁二唑基，1,2,5-噁二唑基，1,2,4-噁二唑基，1,3,4-噁二唑基)，硫代二唑基(如1,2,3-硫代二唑基，1,3,4-硫代二唑基，1,2,5-硫代二唑基)，吡嗪基，1,3,5-三嗪基；也包括以下的双或者三环基团，但绝不限于这些基团：苯并咪唑基，苯并呋喃基，苯并噻吩基，吲哚基(如2-吲哚基)，嘌呤基，喹啉基(如2-喹啉基，3-喹啉基，4-喹啉基)，异喹啉基(如1-异喹啉基，3-异喹啉基或4-异喹啉基)，吩噁噻基，二苯并咪唑基，二苯并呋喃基或二苯并噻吩基等。所述杂芳基基团任选地被一个或多个本发明所描述的取代基所取代。In other embodiments, the heteroaryl group includes the following monocyclic groups, but is not limited to these monocyclic groups: furanyl (such as 2-furanyl, 3-furanyl), imidazolyl (such as N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), isothiazolyl (such as 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl), oxazolyl (such as 2-oxazolyl, 4-oxazolyl, 5-oxazolyl), pyrrolyl (such as N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), pyridyl (such as 2-pyridyl, 3-pyridyl, 4-pyridyl), pyrimidinyl (such as 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl), pyridazinyl (such as 3-pyridazinyl), thiazolyl (such as 2-thiazolyl, 4-thiazolyl, 5-thiazolyl), thiadiazolyl tetrazolyl (e.g., 5H-tetrazolyl, 2H-tetrazolyl), triazolyl (e.g., 2-triazolyl, 5-triazolyl, 4H-1,2,4-triazolyl, 1H-1,2,4-triazolyl, 1,2,3-triazolyl), thienyl (e.g., 2-thienyl, 3-thienyl), pyrazolyl (e.g., 2-pyrazolyl and 3-pyrazolyl), oxazolyl (e.g., 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl), thiodiazolyl (e.g., 1,2,3-thiodiazolyl), The invention also includes the following bicyclic or tricyclic groups, but is by no means limited to these groups: benzimidazolyl, benzofuranyl, benzothiophenyl, indolyl (such as 2-indolyl), purinyl, quinolyl (such as 2-quinolyl, 3-quinolyl, 4-quinolyl), isoquinolyl (such as 1-isoquinolyl, 3-isoquinolyl or 4-isoquinolyl), phenoxathiol, dibenzimidazolyl, dibenzofuranyl or dibenzothiophenyl, etc. The heteroaryl group is optionally substituted with one or more substituents described in the present invention.
术语“杂芳基烷基”和“杂芳基亚烷基”在此处交换使用，表示烷基基团被一个或多个相同或不同的杂芳基基团所取代，其中亚烷基，烷基基团和杂芳基基团具有如本发明所述的含义，这样的实例包括，但并不限于吡啶-2-乙基，噻唑-2-甲基，咪唑-2-乙基，嘧啶-2-丙基等。The terms "heteroarylalkyl" and "heteroarylalkylene" are used interchangeably herein to refer to an alkyl group substituted with one or more identical or different heteroaryl groups, wherein alkylene, alkyl and heteroaryl groups have the meanings as described herein, such examples include, but are not limited to, pyridine-2-ethyl, thiazole-2-methyl, imidazole-2-ethyl, pyrimidin-2-propyl and the like.
术语“磺酰基”，无论是单独使用还是和其他的术语像“烷基磺酰基”连用，分别表示二价的基团-SO2-。术语“烷基磺酰基”是指烷基取代的磺酰基基团，形成烷基磺酰基(例如：-SO2CH3)。The term "sulfonyl", whether used alone or in combination with other terms like "alkylsulfonyl", refers to the divalent group -SO2 -. The term "alkylsulfonyl" refers to a sulfonyl group substituted with an alkyl group, forming an alkylsulfonyl group (eg: -SO2 CH3 ).
术语“烷硫基”包括C1-12直链或支链的烷基连接到二价的硫原子上，其中烷基基团具有如本发明所述的含义。其中一些实施例是，烷硫基是较低级的C1-6烷硫基，另外一些实施例是，烷硫基是较低级的C1-4烷硫基，另外一些实施例是，烷硫基是较低级的C1-3烷硫基，这样的实例包括，但并不限于甲硫基(CH3S-)，乙硫基等。The term "alkylthio" includes a C1-12 straight or branched alkyl group connected to a divalent sulfur atom, wherein the alkyl group has the meaning as described in the present invention. In some embodiments, the alkylthio group is a lower C1-6 alkylthio group, in other embodiments, the alkylthio group is a lower C1-4 alkylthio group, and in other embodiments, the alkylthio group is a lower C1-3 alkylthio group, such examples include, but are not limited to, methylthio (CH3 S-), ethylthio, etc.
除非其他方面表明，本发明所描述的结构式包括所有的同分异构形式(如对映异构，非对映异构，和几何异构(或构象异构)：例如含有不对称中心的R、S构型，双键的(Z)、(E)异构体，和(Z)、(E)的构象异构体。因此，本发明的化合物的单个立体化学异构体或其对映异构体，非对映异构体，或几何异构体(或构象异构体)的混合物都属于本发明的范围。Unless otherwise indicated, the structural formulas described in the present invention include all isomeric forms (such as enantiomers, diastereomers, and geometric isomers (or conformational isomers): for example, R, S configurations containing asymmetric centers, (Z), (E) isomers of double bonds, and (Z), (E) conformational isomers. Therefore, single stereochemical isomers of the compounds of the present invention or mixtures of their enantiomers, diastereomers, or geometric isomers (or conformational isomers) are all within the scope of the present invention.
本发明所使用的“氮氧化物”是指当化合物含几个胺官能团时，可将1个或大于1个的氮原子氧化形成N-氧化物。N-氧化物的特殊实例是叔胺的N-氧化物或含氮杂环氮原子的N-氧化物。可用氧化剂(例如过氧化氢)或过酸(例如过氧羧酸)处理相应的胺形成N-氧化物(参见Advanced Organic Chemistry,Wiley Interscience,第4版,Jerry March,pages)。尤其是，N-氧化物可用L.W.Deady的方法制备(Syn.Comm.1977,7,509-514)，其中例如在惰性溶剂(例如二氯甲烷)中，使胺化合物与间-氯过氧苯甲酸(MCPBA)反应。As used herein, "nitrogen oxide" means that when a compound contains several amine functional groups, one or more nitrogen atoms can be oxidized to form an N-oxide. Specific examples of N-oxides are N-oxides of tertiary amines or N-oxides of nitrogen atoms of nitrogen-containing heterocyclic rings. The corresponding amines can be treated with oxidants (e.g., hydrogen peroxide) or peracids (e.g., peroxycarboxylic acids) to form N-oxides (see Advanced Organic Chemistry, Wiley Interscience, 4th edition, Jerry March, pages). In particular, N-oxides can be prepared by the method of L. W. Deady (Syn. Comm. 1977, 7, 509-514), wherein, for example, the amine compound is reacted with meta-chloroperoxybenzoic acid (MCPBA) in an inert solvent (e.g., dichloromethane).
本发明所使用的术语“前药”，代表一个化合物在体内转化为式(I)或式(Ia)所示的化合物。这样的转化受前体药物在血液中水解或在血液或组织中经酶转化为母体结构的影响。本发明前体药物类化合物可以是酯，在现有的发明中酯可以作为前体药物的有苯酯类，脂肪族(C1-24)酯类，酰氧基甲基酯类，碳酸酯，氨基甲酸酯类和氨基酸酯类。例如本发明里的一个化合物包含羟基，即可以将其酰化得到前体药物形式的化合物。其他的前体药物形式包括磷酸酯，如这些磷酸酯类化合物是经母体上的羟基磷酸化得到的。关于前体药物完整的讨论可以参考以下文献：T.Higuchi and V.Stella,Pro-drugs as Novel DeliverySystems,Vol.14of the A.C.S.Symposium Series,Edward B.Roche,ed.,BioreversibleCarriers in Drug Design,American Pharmaceutical Association and PergamonPress,1987,J.Rautio et al,Prodrugs:Design and Clinical Applications,NatureReview Drug Discovery,2008,7,255-270,and S.J.Hecker et al,Prodrugs ofPhosphates and Phosphonates,Journal of Medicinal Chemistry,2008,51，2328-2345。The term "prodrug" used in the present invention refers to a compound that is converted into a compound represented by formula (I) or formula (Ia) in vivo. Such conversion is affected by the hydrolysis of the prodrug in the blood or the conversion of the prodrug into the parent structure by enzymes in the blood or tissues. The prodrug compound of the present invention can be an ester. In the existing invention, the esters that can be used as prodrugs include phenyl esters, aliphatic (C1-24 ) esters, acyloxymethyl esters, carbonates, carbamates and amino acid esters. For example, a compound in the present invention contains a hydroxyl group, which can be acylated to obtain a compound in the form of a prodrug. Other prodrug forms include phosphate esters, such as these phosphate ester compounds that are obtained by phosphorylation of the hydroxyl group on the parent. For a complete discussion of prodrugs, please refer to the following literature: T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the ACSSymposium Series, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, J. Rautio et al, Prodrugs: Design and Clinical Applications, Nature Review Drug Discovery, 2008, 7, 255-270, and SJ Hecker et al, Prodrugs of Phosphates and Phosphonates, Journal of Medicinal Chemistry, 2008, 51, 2328-2345.
除非其他方面表明，本发明的化合物的所有互变异构形式都包含在本发明的范围之内。另外，除非其他方面表明，本发明所描述的化合物的结构式包括一个或多个不同的原子的富集同位素。Unless otherwise indicated, all tautomeric forms of the compounds of the present invention are included within the scope of the present invention. In addition, unless otherwise indicated, the structural formulas of the compounds described in the present invention include enriched isotopes of one or more different atoms.
“代谢产物”是指具体的化合物或其盐在体内通过代谢作用所得到的产物。一个化合物的代谢产物可以通过所属领域公知的技术来进行鉴定，其活性可以通过如本发明所描述的那样采用试验的方法进行表征。这样的产物可以是通过给药化合物经过氧化，还原，水解，酰氨化，脱酰氨作用，酯化，脱脂作用，酶裂解等等方法得到。相应地，本发明包括化合物的代谢产物，包括将本发明的化合物与哺乳动物充分接触一段时间所产生的代谢产物。"Metabolite" refers to a product obtained by the metabolism of a specific compound or salt thereof in vivo. The metabolites of a compound can be identified by techniques known in the art, and their activity can be characterized by experimental methods as described herein. Such products can be obtained by administering the compound through oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic cleavage, etc. Accordingly, the present invention includes metabolites of compounds, including metabolites produced by contacting a compound of the present invention with a mammal for a period of time.
本发明中立体化学的定义和惯例的使用通常参考以下文献：S.P.Parker,Ed.,McGraw-Hill Dictionary of Chemical Terms(1984)McGraw-Hill Book Company,NewYork；and Eliel,E.and Wilen,S.,"Stereochemistry of Organic Compounds",JohnWiley&Sons,Inc.,New York,1994.本发明的化合物可以包含不对称中心或手性中心，因此存在不同的立体异构体。本发明的化合物所有的立体异构形式，包括但绝不限于，非对映体，对映异构体，阻转异构体，和它们的混合物，如外消旋混合物，组成了本发明的一部分。很多有机化合物都以光学活性形式存在，即它们有能力旋转平面偏振光的平面。在描述光学活性化合物时，前缀D、L或R、S用来表示分子手性中心的绝对构型。前缀d、l或(+)、(-)用来命名化合物平面偏振光旋转的符号，(-)或l是指化合物是左旋的，前缀(+)或d是指化合物是右旋的。这些立体异构体的化学结构是相同的，但是它们的立体结构不一样。特定的立体异构体可以是对映体，异构体的混合物通常称为对映异构体混合物。50：50的对映体混合物被称为外消旋混合物或外消旋体，这可能导致化学反应过程中没有立体选择性或立体定向性。术语“外消旋混合物”和“外消旋体”是指等摩尔的两个对映异构体的混合物，缺乏光学活性。术语“互变异构体”或“互变异构的形式”是指不同能量的结构的同分异构体可以通过低能垒互相转化。例如质子互变异构体(即质子转移的互变异构体)包括通过质子迁移的互变，如酮式-烯醇式和亚胺-烯胺的同分异构化作用。原子价(化合价)互变异构体包括重组成键电子的互变。The definitions and conventions of stereochemistry used in this invention are generally based on the following references: S.P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994. The compounds of the present invention may contain asymmetric centers or chiral centers and therefore exist in different stereoisomers. All stereoisomeric forms of the compounds of the present invention, including but not limited to diastereomers, enantiomers, atropisomers, and mixtures thereof, such as racemic mixtures, constitute a part of this invention. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane polarized light. When describing optically active compounds, the prefixes D, L or R, S are used to indicate the absolute configuration of the chiral center of the molecule. The prefixes d, l or (+), (-) are used to name the sign of rotation of plane polarized light in a compound, (-) or l means that the compound is levorotatory, and the prefix (+) or d means that the compound is dextrorotatory. These stereoisomers have the same chemical structure, but their stereostructures are different. Specific stereoisomers can be enantiomers, and a mixture of isomers is usually called an enantiomeric mixture. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which may result in no stereoselectivity or stereospecificity during chemical reactions. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomers that lacks optical activity. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that can be interconverted through a low energy barrier. For example, proton tautomers (i.e., proton-transfer tautomers) include interconversions through proton migration, such as keto-enol and imine-enamine isomerization. Valence (chemical valence) tautomers include interconversions that reorganize bonding electrons.
本发明所使用的“药学上可接受的盐”是指本发明的化合物的有机盐和无机盐。药学上可接受的盐在所属领域是为我们所熟知的，如文献：S.M.Berge et al.,describepharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences,66:1-19,1977.所记载的。药学上可接受的无毒的酸形成的盐包括，但并不限于，与氨基基团反应形成的无机酸盐有盐酸盐，氢溴酸盐，磷酸盐，硫酸盐，高氯酸盐，和有机酸盐如乙酸盐，草酸盐，马来酸盐，酒石酸盐，柠檬酸盐，琥珀酸盐，丙二酸盐，或通过书籍文献上所记载的其他方法如离子交换法来得到这些盐。其他药学上可接受的盐包括己二酸盐，苹果酸盐，2-羟基丙酸盐，藻酸盐，抗坏血酸盐，天冬氨酸盐，苯磺酸盐，苯甲酸盐，重硫酸盐，硼酸盐，丁酸盐，樟脑酸盐，樟脑磺酸盐，环戊基丙酸盐，二葡萄糖酸盐，十二烷基硫酸盐，乙磺酸盐，甲酸盐，反丁烯二酸盐，葡庚糖酸盐，甘油磷酸盐，葡萄糖酸盐，半硫酸盐，庚酸盐，己酸盐，氢碘酸盐，2-羟基-乙磺酸盐，乳糖醛酸盐，乳酸盐，月桂酸盐，月桂基硫酸盐，苹果酸盐，丙二酸盐，甲磺酸盐，2-萘磺酸盐，烟酸盐，硝酸盐，油酸盐，棕榈酸盐，扑酸盐，果胶酸盐，过硫酸盐，3-苯基丙酸盐，苦味酸盐，特戊酸盐，丙酸盐，硬脂酸盐，硫氰酸盐，对甲苯磺酸盐，十一酸盐，戊酸盐，等等。如果本发明的化合物是酸性的，则想得到的盐可以通过合适的方法制备得到，如，使用无机碱或有机碱，如氨(伯氨、仲氨、叔氨)，碱金属氢氧化物，铵，N+(R14)4的盐和碱土金属氢氧化物，等等。合适的盐包括，但并不限于，从氨基酸得到的有机盐，如甘氨酸和精氨酸，氨，如伯氨、仲氨和叔氨，N+(R14)4的盐，如R14是H、C1-4烷基、C6-10芳基、C6-10芳基C1-4烷基等，和环状氨，如哌啶、吗啉和哌嗪等，和从钠、钙、钾、镁、锰、铁、铜、锌、铝和锂得到无机盐。也包括适当的、无毒的铵，季铵盐和抗平衡离子形成的胺阳离子，如卤化物、氢氧化物、羧化物、硫酸化物、磷酸化物、硝酸化物、C1-8磺酸化物和芳香磺酸化物。The "pharmaceutically acceptable salt" used in the present invention refers to organic salts and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well known in the art, as described in the literature: SM Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19, 1977. Pharmaceutically acceptable salts formed by non-toxic acids include, but are not limited to, inorganic acid salts formed by reaction with amino groups, such as hydrochlorides, hydrobromides, phosphates, sulfates, perchlorates, and organic acid salts such as acetates, oxalates, maleates, tartrates, citrates, succinates, malonates, or other methods described in books and literature, such as ion exchange methods, to obtain these salts. Other pharmaceutically acceptable salts include adipate, malate, 2-hydroxypropionate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, cyclopentylpropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, stearate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. If the compound of the present invention is acidic, the desired salt can be prepared by a suitable method, for example, using an inorganic base or an organic base, such as ammonia (primary, secondary, tertiary), an alkali metal hydroxide, ammonium, a salt of N+ (R14 )4 and an alkaline earth metal hydroxide, etc. Suitable salts include, but are not limited to, organic salts derived from amino acids, such as glycine and arginine, ammonia, such as primary, secondary and tertiary, a salt of N+ (R14 )4 , such as R14 is H, C1-4 alkyl, C6-10 aryl, C6-10 arylC1-4 alkyl, etc., and cyclic amines, such as piperidine, morpholine and piperazine, etc., and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium. Also included are appropriate, non-toxic ammonium, quaternary ammonium salts and amine cations which counter-form counterions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C1-8 sulfonates and aromatic sulfonates.
本发明的“溶剂化物”是指一个或多个溶剂分子与本发明的化合物所形成的缔合物。形成溶剂化物的溶剂包括，但并不限于，水，异丙醇，乙醇，甲醇，二甲亚砜，乙酸乙酯，乙酸，氨基乙醇。术语“水合物”是指溶剂分子是水所形成的缔合物。The "solvate" of the present invention refers to an association formed by one or more solvent molecules and the compound of the present invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, aminoethanol. The term "hydrate" refers to an association formed by the solvent molecule being water.
术语“保护基团”或“Pg”是指一个取代基与别的官能团起反应的时候，通常用来阻断或保护特殊的功能性。例如，“氨基的保护基团”是指一个取代基与氨基基团相连来阻断或保护化合物中氨基的功能性，合适的氨基保护基团包括乙酰基，三氟乙酰基，叔丁氧羰基(BOC)，苄氧羰基(CBZ)和9-芴亚甲氧羰基(Fmoc)。相似地，“羟基保护基团”是指羟基的取代基用来阻断或保护羟基的功能性，合适的保护基团包括乙酰基和甲硅烷基。“羧基保护基团”是指羧基的取代基用来阻断或保护羧基的功能性，一般的羧基保护基包括-CH2CH2SO2Ph，氰基乙基，2-(三甲基硅烷基)乙基，2-(三甲基硅烷基)乙氧基甲基，2-(对甲苯磺酰基)乙基，2-(对硝基苯磺酰基)乙基，2-(二苯基膦基)乙基，硝基乙基，等等。对于保护基团一般的描述可参考文献：T W.Greene,Protective Groups in Organic Synthesis,John Wiley&Sons,New York,1991；and P.J.Kocienski,Protecting Groups,Thieme,Stuttgart,2005。The term "protecting group" or "Pg" refers to a substituent that is used to block or protect a specific functionality when reacting with another functional group. For example, an "amino protecting group" refers to a substituent attached to an amino group to block or protect the functionality of the amino group in the compound. Suitable amino protecting groups include acetyl, trifluoroacetyl, tert-butyloxycarbonyl (BOC), benzyloxycarbonyl (CBZ) and 9-fluorenylmethyleneoxycarbonyl (Fmoc). Similarly, a "hydroxy protecting group" refers to a substituent of a hydroxy group used to block or protect the functionality of the hydroxy group. Suitable protecting groups include acetyl and silyl. A "carboxyl protecting group" refers to a substituent of a carboxyl group used to block or protect the functionality of the carboxyl group. Typical carboxyl protecting groups include -CH2 CH2 SO2 Ph, cyanoethyl, 2-(trimethylsilyl)ethyl, 2-(trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl, 2-(p-nitrobenzenesulfonyl)ethyl, 2-(diphenylphosphino)ethyl, nitroethyl, and the like. For a general description of protecting groups, reference may be made to: T W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991; and P J Kocienski, Protecting Groups, Thieme, Stuttgart, 2005.
本发明化合物的描述Description of the compounds of the present invention
本发明所涉及的化合物，及其药学上可接受的组合物，都可以有效抑制HBV感染。The compounds involved in the present invention and their pharmaceutically acceptable compositions can effectively inhibit HBV infection.
一方面，本发明涉及一种如式(I)所示的化合物或式(I)所示的化合物的立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或它们的前药，In one aspect, the present invention relates to a compound as represented by formula (I) or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof of the compound as represented by formula (I),
X1为CR8或N；X1 is CR8 or N;
X2为CR7或N；X2 is CR7 or N;
R1为R-(C＝O)-、3-6个环原子组成的杂环基、5-6个环原子组成的杂芳基或R-S(＝O)2-NH-(C＝O)-，其中所述的3-6个环原子组成的杂环基和5-6个环原子组成的杂芳基各自独立地未被取代或被1、2、3或4个Rg所取代；R1 is R-(C=O)-, a heterocyclic group consisting of 3-6 ring atoms, a heteroaryl group consisting of 5-6 ring atoms, or RS(=O)2 -NH-(C=O)-, wherein the heterocyclic group consisting of 3-6 ring atoms and the heteroaryl group consisting of 5-6 ring atoms are each independently unsubstituted or substituted by 1, 2, 3 or 4 Rg ;
R为HO-、C1-6烷氧基、C1-6烷基、C6-10芳基、C3-7环烷基、3-6个环原子组成的杂环基或5-6个环原子组成的杂芳基，其中所述的C1-6烷氧基、C1-6烷基、C6-10芳基、C3-7环烷基、3-6个环原子组成的杂环基和5-6个环原子组成的杂芳基各自独立地未被取代或被1、2、3或4个Rw所取代；R is HO-, C1-6 alkoxy, C1-6 alkyl, C6-10 aryl, C3-7 cycloalkyl, heterocyclic group consisting of 3-6 ring atoms or heteroaryl consisting of 5-6 ring atoms, wherein the C1-6 alkoxy, C1-6 alkyl, C6-10 aryl, C3-7 cycloalkyl, heterocyclic group consisting of 3-6 ring atoms and heteroaryl consisting of 5-6 ring atoms are each independently unsubstituted or substituted by 1, 2, 3 or 4 Rw ;
X为CH或N，当X为CH时，R不为HO-；X is CH or N. When X is CH, R is not HO-;
R2为苯基、呋喃基、吡咯基、吡啶基、吡唑基、咪唑基、三唑基、四唑基、噁唑基、异噁唑基、噁二唑基、1,3,5-三嗪基、噻唑基、噻吩基、吡嗪基、哒嗪基或嘧啶基，其中，所述的苯基、呋喃基、吡咯基、吡啶基、吡唑基、咪唑基、三唑基、四唑基、噁唑基、异噁唑基、噁二唑基、1,3,5-三嗪基、噻唑基、噻吩基、吡嗪基、哒嗪基和嘧啶基各自独立地未被取代或被1、2或3个Rw所取代；R2 is phenyl, furanyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl or pyrimidinyl, wherein the phenyl, furanyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl and pyrimidinyl are each independently unsubstituted or substituted with 1, 2 or 3Rw ;
R3为C1-6烷基、C2-6烯基、C2-6炔基、C3-7环烷基、3-10个环原子组成的杂环基、C6-10芳基、5-10个环原子组成的杂芳基或R11-C1-4亚烷基-，其中所述的C1-6烷基、C2-6烯基、C2-6炔基、C3-7环烷基、3-10个环原子组成的杂环基、C6-10芳基、5-10个环原子组成的杂芳基和所述R11-C1-4亚烷基-中的C1-4亚烷基各自独立地未被取代或被1、2、3或4个Rx所取代；R3 is C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, heterocyclyl consisting of 3-10 ring atoms, C6-10 aryl, heteroaryl consisting of 5-10 ring atoms, or R11 -C1-4 alkylene-, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, heterocyclyl consisting of 3-10 ring atoms, C6-10 aryl, heteroaryl consisting of 5-10 ring atoms, and the C1-4 alkylene in the R11 -C1-4 alkylene- are each independently unsubstituted or substituted by 1, 2, 3 or 4 Rx ;
R11为氘、环丙基、环丁基、环戊基、环己基、C1-6烷氧基、3-6个环原子组成的杂环基或5-10个环原子组成的杂芳基，其中所述的环丙基、环丁基、环戊基、环己基、C1-6烷氧基、3-6个环原子组成的杂环基和5-10个环原子组成的杂芳基各自独立地未被取代或被1、2、3或4个Rj所取代；R11 is deuterium, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, C1-6 alkoxy, a heterocyclic group consisting of 3-6 ring atoms, or a heteroaryl group consisting of 5-10 ring atoms, wherein the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, C1-6 alkoxy, a heterocyclic group consisting of 3-6 ring atoms, and a heteroaryl group consisting of 5-10 ring atoms are each independently unsubstituted or substituted by 1, 2, 3 or 4 Rj ;
各Rx和Rj独立地为氘、F、Cl、Br、CN、O＝、HO-、HOOC-、氨基、C1-6烷基、C1-6烷氧基、C1-6烷硫基、C1-6烷氨基、C2-6烯基、C2-6炔基、C3-7环烷基、3-8个环原子组成的杂环基、C6-10芳基或5-10个环原子组成的杂芳基，其中所述的氨基、C1-6烷基、C1-6烷氧基、C1-6烷硫基、C1-6烷氨基、C2-6烯基、C2-6炔基、C3-7环烷基、3-8个环原子组成的杂环基、C6-10芳基和5-10个环原子组成的杂芳基各自独立地未被取代或被1、2、3或4个Rf所取代；each Rx and Rj is independently deuterium, F, Cl, Br, CN, O=, HO-, HOOC-, amino, C1-6 alkyl, C1-6 alkoxy, C 1-6 alkylthio, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, a heterocyclyl consisting of 3-8 ring atoms, C6-10 aryl, or a heteroaryl consisting of 5-10 ring atoms, wherein the amino, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, a heterocyclyl consisting of 3-8 ring atoms, C6-10 aryl, and a heteroaryl consisting of 5-10 ring atoms are each independently unsubstituted or substituted with 1, 2, 3 or 4 Rf ;
各R4、R5、R7、R8和R9独立地为氢、氘、F、Cl、Br、C1-6烷基、C1-6烷氨基、C1-6烷氧基、C2-6炔基、C2-6烯基、C3-7环烷基或3-10个环原子组成的杂环基，其中所述的C1-6烷基、C1-6烷氨基、C1-6烷氧基、C2-6炔基、C2-6烯基、C3-7环烷基和3-10个环原子组成的杂环基各自独立地未被取代或被1、2、3或4个Rw所取代；Each of R4 , R5 , R7 , R8 and R9 is independently hydrogen, deuterium, F, Cl, Br, C1-6 alkyl, C1-6 alkylamino, C1-6 alkoxy, C 2-6 alkynyl, C2-6 alkenyl, C3-7 cycloalkyl or a heterocyclic group consisting of 3-10 ring atoms, wherein the C1-6 alkyl, C1-6 alkylamino, C1-6 alkoxy, C2-6 alkynyl, C2-6 alkenyl, C3-7 cycloalkyl and the heterocyclic group consisting of3-10 ring atoms are each independently unsubstituted or substituted by 1, 2, 3 or 4 Rw ;
R6为氢、氘、C1-6烷基、C2-6烯基、C3-7环烷基、3-8个环原子组成的杂环基、C6-10芳基或5-10个环原子组成的杂芳基，其中所述的C1-6烷基、C2-6烯基、C3-7环烷基、3-8个环原子组成的杂环基、C6-10芳基和5-10个环原子组成的杂芳基各自独立地未被取代或被1、2、3或4个Rz所取代；R6 is hydrogen, deuterium, C1-6 alkyl, C2-6 alkenyl, C3-7 cycloalkyl, a heterocyclic group consisting of 3-8 ring atoms, a C6-10 aryl, or a heteroaryl group consisting of 5-10 ring atoms, wherein the C1-6 alkyl, C2-6 alkenyl, C3-7 cycloalkyl, a heterocyclic group consisting of 3-8 ring atoms, a C6-10 aryl, and a heteroaryl group consisting of 5-10 ring atoms are each independently unsubstituted or substituted by 1, 2, 3 or 4 Rz ;
或R6、R4，和与其各自所连接的原子一起形成5-6个环原子组成的杂环基或5-6个环原子组成的环烷基，其中所述的5-6个环原子组成的杂环基和5-6个环原子组成的环烷基各自独立地未被取代或被1、2、3或4个Rw所取代；or R6 , R4 , together with the atoms to which they are attached, form a heterocyclic group consisting of 5-6 ring atoms or a cycloalkyl group consisting of 5-6 ring atoms, wherein the heterocyclic group consisting of 5-6 ring atoms and the cycloalkyl group consisting of 5-6 ring atoms are each independently unsubstituted or substituted by 1, 2, 3 or 4 Rw ;
各Rw、Rf、Rg和Rz独立地为氘、F、Cl、Br、HO-、HOOC-、O＝、C1-6烷基-S(＝O)2-、C3-6环烷基-S(＝O)2-、氨基、C1-6烷基、C1-6烷氧基、C1-6烷硫基、C1-6烷氨基、C2-6烯基、C2-6炔基或C3-7环烷基，其中所述C1-6烷基-S(＝O)2-、C3-6环烷基-S(＝O)2-、氨基、C1-6烷基、C1-6烷氧基、C1-6烷硫基、C1-6烷氨基、C2-6烯基、C2-6炔基和C3-7环烷基各自独立地未被取代或被1、2、3或4个选自F、Cl、Br、CN、HO-、O＝、氨基、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6烷硫基、C1-6卤代烷氧基或C1-6烷氨基的取代基所取代。Each of Rw , Rf , Rg and Rz is independently deuterium, F, Cl, Br, HO—, HOOC—, O═, C1-6 alkyl-S(═O)2 —, C3-6 cycloalkyl-S(═O)2 —, amino, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 alkylamino, C 2-6alkenyl , C2-6 alkynyl or C3-7 cycloalkyl, wherein the C1-6 alkyl-S(═O)2 —, C3-6 cycloalkyl-S(═O)2 —, amino, C1-6 alkyl, C 1-6 alkoxy, C1-6 alkylthio, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl and C3-7 cycloalkyl are The3-7 cycloalkyl groups are each independently unsubstituted or substituted by 1, 2, 3 or 4 substituents selected from F, Cl, Br, CN, HO-, O=, amino,C1-6 alkyl,C1-6 haloalkyl,C1-6 alkoxy,C1-6 alkylthio,C1-6 haloalkoxy orC1-6 alkylamino.
在一些实施例中，本发明所述R1为R-(C＝O)-、5-6个环原子组成的杂环基、5-6个环原子组成的杂芳基或R-S(＝O)2-NH-(C＝O)-，其中所述的5-6个环原子组成的杂环基和5-6个环原子组成的杂芳基各自独立地未被取代或被1、2、3或4个Rg所取代；In some embodiments, R1 of the present invention is R-(C=O)-, a heterocyclic group consisting of 5-6 ring atoms, a heteroaryl group consisting of 5-6 ring atoms, or RS(=O)2 -NH-(C=O)-, wherein the heterocyclic group consisting of 5-6 ring atoms and the heteroaryl group consisting of 5-6 ring atoms are each independently unsubstituted or substituted by 1, 2, 3 or 4 Rg ;
R为HO-、C1-4烷氧基、C1-4烷基、苯基、C3-6环烷基、3-6个环原子组成的杂环基或5-6个环原子组成的杂芳基，其中所述的C1-4烷氧基、C1-4烷基、苯基、C3-6环烷基、3-6个环原子组成的杂环基和5-6个环原子组成的杂芳基各自独立地未被取代或被1、2、3或4个Rw所取代；R is HO-, C1-4 alkoxy, C1-4 alkyl, phenyl, C3-6 cycloalkyl, heterocyclic group consisting of 3-6 ring atoms or heteroaryl consisting of 5-6 ring atoms, wherein the C1-4 alkoxy, C1-4 alkyl, phenyl, C3-6 cycloalkyl, heterocyclic group consisting of 3-6 ring atoms and heteroaryl consisting of 5-6 ring atoms are each independently unsubstituted or substituted by 1, 2, 3 or 4 Rw ;
其中，各Rg和Rw具有本发明所述的含义。wherein each of Rg and Rw has the meanings as defined in the present invention.
在一些实施例中，本发明所述R1为R-(C＝O)-、吡咯烷基、吡唑烷基、咪唑烷基、四氢呋喃基、四氢噻吩基、四氢吡喃基、四氢噻喃基、四氢噻唑基、哌啶基、吗啉基、硫代吗啉基、哌嗪基、呋喃基、吡咯基、吡啶基、吡唑基、咪唑基、三唑基、四唑基、噁唑基、异噁唑基、噁二唑基、1,3,5-三嗪基、噻唑基、噻二唑基、噻吩基、吡嗪基、哒嗪基、嘧啶基或R-S(＝O)2-NH-(C＝O)-，其中所述的吡咯烷基、吡唑烷基、咪唑烷基、四氢呋喃基、四氢噻吩基、四氢吡喃基、四氢噻喃基、四氢噻唑基、哌啶基、吗啉基、硫代吗啉基、哌嗪基、呋喃基、吡咯基、吡啶基、吡唑基、咪唑基、三唑基、四唑基、噁唑基、异噁唑基、噁二唑基、1,3,5-三嗪基、噻唑基、噻二唑基、噻吩基、吡嗪基、哒嗪基和嘧啶基各自独立地未被取代或被1、2、3或4个Rg所取代；In some embodiments, R1 of the present invention is R-(C=O)-, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrothiazolyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, furanyl, pyrrolyl, pyridinyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thiadiazolyl, thienyl, pyrazinyl, pyridazinyl, pyrimidinyl or RS(=O)2 -NH-(C=O)-, wherein the pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrothiazolyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, furanyl, pyrrolyl, pyridinyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thiadiazolyl, thienyl, pyrazinyl, pyridazinyl and pyrimidinyl are each independently unsubstituted or substituted with 1, 2, 3 or 4 Rg ;
R为HO-、甲氧基、乙氧基、1-丙氧基、2-丙氧基、1-丁氧基、2-甲基-l-丙氧基、2-丁氧基、甲基、乙基、正丙基、异丙基、正丁基、异丁基、苯基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、氧杂环丁基、硫杂环丁基、氧杂环丙基、吡咯烷基、吡唑烷基、咪唑烷基、四氢呋喃基、四氢噻吩基、四氢吡喃基、四氢噻喃基、哌啶基、吗啉基、硫代吗啉基、哌嗪基、呋喃基、吡咯基、吡啶基、吡唑基、咪唑基、三唑基、四唑基、噁唑基、异噁唑基、噁二唑基、1,3,5-三嗪基、噻唑基、噻吩基、吡嗪基、哒嗪基或嘧啶基，其中所述的甲氧基、乙氧基、1-丙氧基、2-丙氧基、1-丁氧基、2-甲基-l-丙氧基、2-丁氧基、甲基、乙基、正丙基、异丙基、正丁基、异丁基、苯基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、氧杂环丁基、硫杂环丁基、氧杂环丙基、吡咯烷基、吡唑烷基、咪唑烷基、四氢呋喃基、四氢噻吩基、四氢吡喃基、四氢噻喃基、哌啶基、吗啉基、硫代吗啉基、哌嗪基、呋喃基、吡咯基、吡啶基、吡唑基、咪唑基、三唑基、四唑基、噁唑基、异噁唑基、噁二唑基、1,3,5-三嗪基、噻唑基、噻吩基、吡嗪基、哒嗪基和嘧啶基各自独立地未被取代或被1、2、3或4个Rw所取代；R is HO-, methoxy, ethoxy, 1-propoxy, 2-propoxy, 1-butoxy, 2-methyl-1-propoxy, 2-butoxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, thietanyl, oxirane, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, furanyl, pyrrolyl, pyridinyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl or pyrimidinyl, wherein the methoxy, R w is each independently unsubstituted or substituted with 1, 2, 3 or 4 Rw ;
其中，各Rg和Rw具有本发明所述的含义。wherein each of Rg and Rw has the meanings as defined in the present invention.
在一些实施例中，本发明所述R3为C1-4烷基、C2-4烯基、C2-4炔基、C3-6环烷基、3-6个环原子组成的杂环基、苯基、5个环原子组成的杂芳基、6个环原子组成的杂芳基或R11-C1-4亚烷基-，其中所述的C1-4烷基C2-4烯基、C2-4炔基、C3-6环烷基、3-6个环原子组成的杂环基、苯基、5个环原子组成的杂芳基、6个环原子组成的杂芳基和所述R11-C1-4亚烷基-中的C1-4亚烷基各自独立地未被取代或被1、2、3或4个Rx所取代；In some embodiments, R3 of the present invention is C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C3-6 cycloalkyl, a heterocyclyl consisting of 3-6 ring atoms, phenyl, a heteroaryl consisting of 5 ring atoms, a heteroaryl consisting of 6 ring atoms, or R11 -C1-4 alkylene-, wherein the C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C3-6 cycloalkyl, a heterocyclyl consisting of 3-6 ring atoms, phenyl, a heteroaryl consisting of 5 ring atoms, a heteroaryl consisting of 6 ring atoms, and the C1-4 alkylene in the R11 -C1-4 alkylene- are each independently unsubstituted or substituted by 1, 2, 3 or 4 Rx ;
R11为氘、环丙基、环丁基、环戊基、环己基、C1-4烷氧基、3-6个环原子组成的杂环基、5个环原子组成的杂芳基或6个环原子组成的杂芳基，其中所述的环丙基、环丁基、环戊基、环己基、C1-4烷氧基、3-6个环原子组成的杂环基、5个环原子组成的杂芳基和6个环原子组成的杂芳基各自独立地未被取代或被1、2、3或4个Rj所取代；R11 is deuterium, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, C1-4 alkoxy, a heterocyclic group consisting of 3-6 ring atoms, a heteroaryl consisting of 5 ring atoms, or a heteroaryl consisting of 6 ring atoms, wherein the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, C1-4 alkoxy, a heterocyclic group consisting of 3-6 ring atoms, a heteroaryl consisting of 5 ring atoms, and a heteroaryl consisting of 6 ring atoms are each independently unsubstituted or substituted by 1, 2, 3 or 4 Rj ;
其中，各Rx和Rj具有本发明所述的含义。wherein each Rx and Rj has the meanings as defined in the present invention.
在一些实施例中，本发明所述R3为甲基、乙基、正丙基、异丙基正丁基、乙烯基、丙烯基、乙炔基、丙炔基、炔丙基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、氧杂环丁基、硫杂环丁基、氧杂环丙基、吡咯烷基、吡唑烷基、咪唑烷基、四氢呋喃基、四氢噻吩基、四氢吡喃基、四氢噻喃基、哌啶基、吗啉基、硫代吗啉基、哌嗪基、苯基、呋喃基、吡咯基、吡啶基、吡唑基、咪唑基、三唑基、四唑基、噁唑基、异噁唑基、噁二唑基、1,3,5-三嗪基、噻唑基、噻吩基、吡嗪基、哒嗪基、嘧啶基或R11-C1-4亚烷基-，其中所述的甲基、乙基、正丙基、异丙基、正丁基、乙烯基、丙烯基、乙炔基、丙炔基、炔丙基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、氧杂环丁基、硫杂环丁基、氧杂环丙基、吡咯烷基、吡唑烷基、咪唑烷基、四氢呋喃基、四氢噻吩基、四氢吡喃基、四氢噻喃基、哌啶基、吗啉基、硫代吗啉基、哌嗪基、苯基、呋喃基、吡咯基、吡啶基、吡唑基、咪唑基、三唑基、四唑基、噁唑基、异噁唑基、噁二唑基、1,3,5-三嗪基、噻唑基、噻吩基、吡嗪基、哒嗪基、嘧啶基和R11-C1-4亚烷基-中的C1-4亚烷基各自独立地未被取代或被1、2、3或4个Rx所取代；In some embodiments, R3 of the present invention is methyl, ethyl, n-propyl, isopropyl, n-butyl, vinyl, propenyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, thietanyl, oxetanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, phenyl, furanyl, pyrrolyl, pyridinyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl, pyrimidinyl or R11 -C R 11 -C1-4 alkylene-, wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, vinyl, propenyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, thietanyl, oxirane, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, phenyl, furanyl, pyrrolyl, pyridinyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl, pyrimidinyl and the C in R11 -C1-4 alkylene-1-4 alkylene groups are each independently unsubstituted or substituted with 1, 2, 3 or 4 Rx ;
R11为氘、环丙基、环丁基、环戊基、环己基、甲氧基、乙氧基、1-丙氧基、2-丙氧基、1-丁氧基、2-甲基-l-丙氧基、2-丁氧基、氮杂环丁基、氧杂环丁基、硫杂环丁基、氧杂环丙基、吡咯烷基、吡唑烷基、咪唑烷基、四氢呋喃基、四氢噻吩基、四氢吡喃基、四氢噻喃基、哌啶基、吗啉基、硫代吗啉基、哌嗪基、呋喃基、吡咯基、吡啶基、吡唑基、咪唑基、三唑基、四唑基、噁唑基、异噁唑基、噁二唑基、1,3,5-三嗪基、噻唑基、噻吩基、吡嗪基、哒嗪基或嘧啶基，其中所述的环丙基、环丁基、环戊基、环己基、甲氧基、乙氧基、1-丙氧基、2-丙氧基、1-丁氧基、2-甲基-l-丙氧基、2-丁氧基、氮杂环丁基、氧杂环丁基、硫杂环丁基、氧杂环丙基、吡咯烷基、吡唑烷基、咪唑烷基、四氢呋喃基、四氢噻吩基、四氢吡喃基、四氢噻喃基、哌啶基、吗啉基、硫代吗啉基、哌嗪基、呋喃基、吡咯基、吡啶基、吡唑基、咪唑基、三唑基、四唑基、噁唑基、异噁唑基、噁二唑基、1,3,5-三嗪基、噻唑基、噻吩基、吡嗪基、哒嗪基和嘧啶基基各自独立地未被取代或被1、2、3或4个Rj所取代；R11 is deuterium, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, 1-propoxy, 2-propoxy, 1-butoxy, 2-methyl-1-propoxy, 2-butoxy, azetidinyl, oxetanyl, thietanyl, oxirane, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, furanyl, pyrrolyl, pyridinyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl or pyrimidinyl, wherein the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, 1-propoxy, 2-propoxy, 1-butoxy, 2-methyl-1-propoxy, 2-butoxy, azetidinyl, oxetanyl, thietanyl, oxirane, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, furanyl, pyrrolyl, pyridinyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl butyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, 1-propoxy, 2-propoxy, 1-butoxy, 2-methyl-1-propoxy, 2-butoxy, azetidinyl, oxetanyl, thietanyl, oxirane, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, furanyl, pyrrolyl, pyridinyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl and pyrimidinyl are each independently unsubstituted or substituted with 1, 2, 3 or 4 Rj ;
其中，各Rx和Rj具有本发明所述的含义。wherein each Rx and Rj has the meanings as defined in the present invention.
在一些实施例中，本发明所述各Rx和Rj独立地为氘、F、Cl、Br、CN、O＝、HO-、HOOC-、氨基、C1-4烷基、C1-4烷氧基、C1-4烷硫基、C1-4烷氨基、C2-4烯基、C2-4炔基、C3-6环烷基、3-6个环原子组成的杂环基、苯基、5个环原子组成的杂芳基或6个环原子组成的杂芳基，其中所述的氨基、C1-4烷基、C1-4烷氧基、C1-4烷硫基、C1-4烷氨基、C2-4烯基、C2-4炔基、C3-6环烷基、3-6个环原子组成的杂环基、苯基、5个环原子组成的杂芳基和6个环原子组成的杂芳基各自独立地未被取代或被1、2、3或4个Rf所取代；In some embodiments, eachRx andRj of the present invention is independently deuterium, F, Cl, Br, CN, O=, HO-, HOOC-, amino,C1-4 alkyl,C1-4 alkoxy,C1-4 alkylthio,C1-4 alkylamino,C2-4 alkenyl,C2-4 alkynyl,C3-6 cycloalkyl, a heterocyclyl consisting of 3-6 ring atoms, phenyl, a heteroaryl consisting of 5 ring atoms, or a heteroaryl consisting of 6 ring atoms, wherein the amino,C1-4 alkyl, C1-4 alkoxy,C1-4 alkylthio,C1-4 alkylamino,C2-4 alkenyl,C2-4 alkynyl,C3-6 cycloalkyl, a heterocyclyl consisting of3-6 ring atoms, phenyl, a heteroaryl consisting of 5 ring atoms, and a heteroaryl consisting of 6 ring atoms are each independently unsubstituted or substituted with 1, 2, 3 or 4Rf ;
其中，各Rf具有本发明所述的含义。wherein eachRf has the meaning as defined in the present invention.
在一些实施例中，本发明所述各Rx和Rj独立地为氘、F、Cl、Br、CN、O＝、HO-、HOOC-、氨基、甲基、乙基、正丙基、异丙基、正丁基、异丁基、甲氧基、乙氧基、1-丙氧基、2-丙氧基、1-丁氧基、2-甲基-l-丙氧基、2-丁氧基、C1-3烷硫基、N-甲氨基、N-乙氨基、N,N-二甲氨基、N,N-二乙氨基、N-丙氨基、乙烯基、丙烯基、乙炔基、丙炔基、炔丙基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、氧杂环丁基、硫杂环丁基、氧杂环丙基、吡咯烷基、吡唑烷基、咪唑烷基、四氢呋喃基、四氢噻吩基、四氢吡喃基、四氢噻喃基、哌啶基、吗啉基、硫代吗啉基、哌嗪基、苯基、呋喃基、吡咯基、吡啶基、吡唑基、咪唑基、三唑基、四唑基、噁唑基、异噁唑基、噁二唑基、1,3,5-三嗪基、噻唑基、噻吩基、吡嗪基、哒嗪基或嘧啶基，其中所述的氨基、甲基、乙基、正丙基、异丙基、正丁基、异丁基、甲氧基、乙氧基、1-丙氧基、2-丙氧基、1-丁氧基、2-甲基-l-丙氧基、2-丁氧基、C1-3烷硫基、N-甲氨基、N-乙氨基、N,N-二甲氨基、N,N-二乙氨基、N-丙氨基、乙烯基、丙烯基、乙炔基、丙炔基、炔丙基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、氧杂环丁基、硫杂环丁基、氧杂环丙基、吡咯烷基、吡唑烷基、咪唑烷基、四氢呋喃基、四氢噻吩基、四氢吡喃基、四氢噻喃基、哌啶基、吗啉基、硫代吗啉基、哌嗪基、苯基、呋喃基、吡咯基、吡啶基、吡唑基、咪唑基、三唑基、四唑基、噁唑基、异噁唑基、噁二唑基、1,3,5-三嗪基、噻唑基、噻吩基、吡嗪基、哒嗪基和嘧啶基各自独立地未被取代或被1、2、3或4个Rf所取代；In some embodiments, eachRx andRj described in the present invention is independently deuterium, F, Cl, Br, CN, O=, HO-, HOOC-, amino, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, methoxy, ethoxy, 1-propoxy, 2-propoxy, 1-butoxy, 2-methyl-l-propoxy, 2-butoxy,C1-3 alkylthio, N-methylamino, N-ethylamino, N,N-dimethylamino, N,N-diethylamino, N-propylamino, vinyl, propenyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, thiazole, oxetanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, 1-propyl, 2-propyl, 3-butyl, 3-isobutyl, 3-methoxy, 4-butyl, 5-dinibutyl, 6-dinibutyl, 7-dinibutyl, 8-dinibutyl, 9-dinibutyl, 10-dinibutyl, 11-dinibutyl, 12-dinibutyl, 13-dinibutyl, 14-dinibutyl, 15-dinibutyl, 16-dinibutyl, 17-dinibutyl, 18-dinibutyl, 19-dinibutyl, 22-dinibutyl, 23-dinibutyl, 24-dinibutyl, 25-dinibutyl, 26-dinibutyl, 27-dinibutyl, 28-dinibutyl, 29-dinibutyl, 30-dinibutyl, 31-32-33-34-35-36-37-38-38-39-40-41-42-43-44-46-47-39-50-51-6 Rf is each independently unsubstituted or substituted with1 , 2, 3 or 4Rf ;
其中，各Rf具有本发明所述的含义。wherein eachRf has the meaning as defined in the present invention.
在一些实施例中，本发明所述各R4、R5、R7、R8和R9独立地为氢、氘、F、Cl、Br、甲基、乙基、正丙基、异丙基、正丁基、异丁基、C1-4烷氨基、C1-4烷氧基、C2-4炔基、C2-4烯基、C3-6环烷基或3-6个环原子组成的杂环基，其中所述的甲基、乙基、正丙基、异丙基、正丁基、异丁基、C1-4烷氨基、C1-4烷氧基、C2-4炔基、C2-4烯基、C3-6环烷基和3-6个环原子组成的杂环基各自独立地未被取代或被1、2、3或4个Rw所取代；In some embodiments, each of R4 , R5 , R7 , R8 and R9 described in the present invention is independently hydrogen, deuterium, F, Cl, Br, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, C1-4 alkylamino, C1-4 alkoxy, C2-4 alkynyl, C2-4 alkenyl, C3-6 cycloalkyl or a heterocyclic group consisting of 3-6 ring atoms, wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, C1-4 alkylamino, C1-4 alkoxy, C2-4 alkynyl, C2-4 alkenyl, C3-6 cycloalkyl and a heterocyclic group consisting of 3-6 ring atoms are each independently unsubstituted or substituted by 1, 2, 3 or 4 Rw ;
R6为氢、氘、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、C2-4烯基、C3-6环烷基、3-6个环原子组成的杂环基、苯基、5个环原子组成的杂芳基或6个环原子组成的杂芳基，其中所述的甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、C2-4烯基、C3-6环烷基、3-6个环原子组成的杂环基、苯基、5个环原子组成的杂芳基和6个环原子组成的杂芳基各自独立地未被取代或被1、2、3或4个Rz所取代；R6 is hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, C2-4 alkenyl, C3-6 cycloalkyl, a heterocyclic group consisting of 3-6 ring atoms, phenyl, a heteroaryl consisting of 5 ring atoms, or a heteroaryl consisting of 6 ring atoms, wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, C2-4 alkenyl, C3-6 cycloalkyl, a heterocyclic group consisting of 3-6 ring atoms, phenyl, a heteroaryl consisting of 5 ring atoms, and a heteroaryl consisting of 6 ring atoms are each independently unsubstituted or substituted by 1, 2, 3 or 4 Rz ;
或R6、R4，和与其各自所连接的原子一起形成环戊基、环己基、吡咯烷基或哌啶基，其中所述的环戊基、环己基、吡咯烷基和哌啶基各自独立地未被取代或被1、2、3或4个Rw所取代；or R6 , R4 , together with the atoms to which they are attached, form cyclopentyl, cyclohexyl, pyrrolidinyl or piperidinyl, wherein the cyclopentyl, cyclohexyl, pyrrolidinyl and piperidinyl are each independently unsubstituted or substituted with 1, 2, 3 or 4 Rw ;
其中，各Rw和Rz具有本发明所述的含义。wherein each of Rw and Rz has the meanings as defined in the present invention.
在一些实施例中，本发明所述各Rw、Rf、Rg和Rz独立地为氘、F、Cl、Br、HO-、HOOC-、O＝、C1-4烷基-S(＝O)2-、C3-6环烷基-S(＝O)2-、氨基、C1-4烷基、C1-4烷氧基、C1-4烷硫基、C1-4烷氨基、C2-4烯基、C2-4炔基或C3-6环烷基，其中所述C1-4烷基-S(＝O)2-、C3-6环烷基-S(＝O)2-、氨基、C1-4烷基、C1-4烷氧基、C1-4烷硫基、C1-4烷氨基、C2-4烯基、C2-4炔基和C3-6环烷基各自独立地未被取代或被1、2、3或4个选自F、Cl、Br、CN、HO-、O＝、氨基、C1-4烷基、C1-4卤代烷基、C1-4烷氧基、C1-4烷硫基、C1-4卤代烷氧基或C1-4烷氨基的取代基所取代。In some embodiments, each of Rw , Rf , Rg and Rz described in the present invention is independently deuterium, F, Cl, Br, HO-, HOOC-, O=, C1-4 alkyl-S(=O)2 -, C3-6 cycloalkyl-S(=O)2 -, amino, C1-4 alkyl, C1-4 alkoxy, C1-4 alkylthio, C1-4 alkylamino, C2-4 alkenyl, C2-4 alkynyl or C3-6 cycloalkyl, wherein the C1-4 alkyl-S(=O)2 -, C3-6 cycloalkyl-S(=O)2 -, amino, C1-4 alkyl, C1-4 alkoxy, C1-4 alkylthio, C1-4 alkylamino, C2-4 alkenyl, C2-4 alkynyl and C 3-6 cycloalkyl The3-6 cycloalkyl groups are each independently unsubstituted or substituted by 1, 2, 3 or 4 substituents selected from F, Cl, Br, CN, HO-, O=, amino,C1-4 alkyl,C1-4 haloalkyl,C1-4 alkoxy,C1-4 alkylthio,C1-4 haloalkoxy orC1-4 alkylamino.
在一些实施例中，本发明所述各Rw、Rf、Rg和Rz独立地为氘、F、Cl、Br、HO-、HOOC-、O＝、甲基-S(＝O)2-、乙基-S(＝O)2-、丙基-S(＝O)2-、异丙基-S(＝O)2-、环丙基-S(＝O)2-、环丁基-S(＝O)2-、环戊基-S(＝O)2-、环己基-S(＝O)2-、氨基、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、甲氧基、乙氧基、1-丙氧基、2-丙氧基、1-丁氧基、2-甲基-l-丙氧基、2-丁氧基、C1-4烷硫基、C1-4烷氨基、C2-4烯基、C2-4炔基、环丙基、环丁基、环戊基或环己基，其中所述甲基-S(＝O)2-、乙基-S(＝O)2-、丙基-S(＝O)2-、异丙基-S(＝O)2-、环丙基-S(＝O)2-、环丁基-S(＝O)2-、环戊基-S(＝O)2-、环己基-S(＝O)2-、氨基、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、甲氧基、乙氧基、1-丙氧基、2-丙氧基、1-丁氧基、2-甲基-l-丙氧基、2-丁氧基、C1-4烷硫基、C1-4烷氨基、C2-4烯基、C2-4炔基、环丙基、环丁基、环戊基和环己基各自独立地未被取代或被1、2、3或4个选自F、Cl、Br、CN、HO-、O＝、氨基、C1-3烷基、C1-3卤代烷基、C1-3烷氧基、C1-3烷硫基、C1-3卤代烷氧基或C1-4烷氨基的取代基所取代。In some embodiments, each of Rw , Rf , Rg and Rz described in the present invention is independently deuterium, F, Cl, Br, HO-, HOOC-, O=, methyl-S(=O)2 -, ethyl-S(=O)2 -, propyl-S(=O)2 -, isopropyl-S(=O)2 -, cyclopropyl-S(=O)2 -, cyclobutyl-S(=O)2 -, cyclopentyl-S(=O)2 -, cyclohexyl-S(=O)2 -, amino, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methoxy, ethoxy, 1-propoxy, 2-propoxy, 1-butoxy, 2-methyl-1-propoxy, 2-butoxy, C1-4 alkylthio, C 1-4 alkylamino, C2-4 alkenyl, C2-4 The methyl-S(＝O)2- , ethyl-S(＝O)2- , propyl-S(＝O)2- , isopropyl-S(＝O)2- , cyclopropyl-S(＝O)2- , cyclobutyl-S(＝O)2- , cyclopentyl-S(＝O)2-, cyclohexyl-S(＝O)2- , amino, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methoxy, ethoxy, 1-propoxy, 2-propoxy, 1-butoxy, 2-methyl-1-propoxy,2 -butoxy, C1-4 alkylthio, C1-4 alkylamino,C2-4 alkenyl,C1-4 The2-4 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl are each independently unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from F, Cl, Br, CN, HO-, O=, amino,C1-3 alkyl,C1-3 haloalkyl,C1-3 alkoxy,C1-3 alkylthio,C1-3 haloalkoxy orC1-4 alkylamino.
还在一些实施例方案中，本发明涉及到以下其中之一的化合物或它们的立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或它们的前药，但绝不限于这些化合物：In some embodiments, the present invention relates to one of the following compounds or their stereoisomers, tautomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts or prodrugs thereof, but is in no way limited to these compounds:
除非另作说明，式(I)所示化合物的立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或它的前药都包含在本发明范围内。Unless otherwise indicated, stereoisomers, tautomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts or prodrugs thereof of the compound represented by formula (I) are all included in the scope of the present invention.
另一方面，本发明还提供了一种包含本发明所述的化合物的药物组合物，任选地，所述药物组合物进一步包含在药学上可接受的辅料或所述辅料的组合。On the other hand, the present invention also provides a pharmaceutical composition comprising the compound of the present invention, optionally, the pharmaceutical composition further comprises a pharmaceutically acceptable excipient or a combination of the excipients.
在一些实施例中，本发明所述的药物组合物，其进一步地包含其它抗HBV药物。In some embodiments, the pharmaceutical composition of the present invention further comprises other anti-HBV drugs.
在另一些实施例中，本发明所述的药物组合物，其中所述抗HBV药物为HBV聚合酶抑制剂、免疫调节剂或干扰素。In other embodiments, the pharmaceutical composition of the present invention, wherein the anti-HBV drug is a HBV polymerase inhibitor, an immunomodulator or an interferon.
还在一些实施例中，本发明所述的药物组合物，其中所述抗HBV药物为拉米夫定、替比夫定、替诺福韦酯、恩替卡韦、阿德福韦酯、Alfaferone、Alloferon、西莫白介素、克拉夫定、恩曲他滨、法昔洛韦、干扰素、宝甘灵CP、因特芬、干扰素α-1b、干扰素α、干扰素α-2a、干扰素β-1a、干扰素α-2、白细胞介素-2、米伏替酯、硝唑尼特、聚乙二醇干扰素α-2a、病毒唑、罗扰素-A、西佐喃、Euforavac、安普利近、Phosphazid、Heplisav、干扰素α-2b、左旋咪唑或丙帕锗。Also in some embodiments, the pharmaceutical composition of the present invention, wherein the anti-HBV drug is lamivudine, telbivudine, tenofovir disoproxil, entecavir, adefovir dipivoxil, Alfaferone, Alloferon, simu-leukin, clavudine, emtricitabine, famciclovir, interferon, Baoganling CP, Intefen, interferon α-1b, interferon α, interferon α-2a, interferon β-1a, interferon α-2, interleukin-2, mivotilide, nitazoxanide, pegylated interferon α-2a, ribavirin, rointerferon-A, sizoran, Euforavac, Ampligen, Phosphazid, Heplisav, interferon α-2b, levamisole or propagermanium.
另一方面，本发明还提供了所述化合物或所述药物组合物在制备用于预防、治疗或减轻患者病毒性疾病的药物中的用途。On the other hand, the present invention also provides use of the compound or the pharmaceutical composition in preparing a drug for preventing, treating or alleviating viral diseases in patients.
在一些实施例中，本发明所述的用途，其中所述病毒性疾病是指乙型肝炎病毒感染或乙型肝炎病毒感染引起的疾病。In some embodiments, the use described in the present invention, wherein the viral disease refers to hepatitis B virus infection or a disease caused by hepatitis B virus infection.
在另外一些实施例中，本发明所述的用途，其中所述乙型肝炎感染引起的疾病是指肝硬化或肝细胞癌变。In other embodiments, the use described in the present invention, wherein the disease caused by hepatitis B infection refers to cirrhosis or hepatocellular carcinoma.
另一方面，本发明还提供了所述的化合物或所述的药物组合物在制备药物中的用途，所述药物用于抑制HBsAg生成或分泌，和/或用于抑制HBV DNA生成或复制的用途。On the other hand, the present invention also provides the use of the compound or the pharmaceutical composition in the preparation of a drug for inhibiting the production or secretion of HBsAg and/or for inhibiting the production or replication of HBV DNA.
另一方面，本发明涉及所述的化合物或药物组合物在制备用于预防、治疗或减轻患者乙型肝炎疾病的药物中的用途。On the other hand, the present invention relates to the use of the compound or pharmaceutical composition in the preparation of a drug for preventing, treating or alleviating hepatitis B disease in a patient.
本发明另一方面涉及预防、治疗或减轻患者HBV病症的方法，所述方法包含使用本发明的化合物药学上可接受的有效剂量对患者进行给药。Another aspect of the present invention relates to a method for preventing, treating or ameliorating HBV symptoms in a patient, the method comprising administering to the patient a pharmaceutically acceptable effective dose of a compound of the present invention.
本发明另一方面涉及预防、治疗或减轻患者HBV病症的方法，所述方法包含使用含有本发明的化合物的药物组合物的药学上可接受的有效剂量对患者进行给药。Another aspect of the present invention relates to a method for preventing, treating or ameliorating HBV symptoms in a patient, the method comprising administering to the patient a pharmaceutically acceptable effective dose of a pharmaceutical composition containing a compound of the present invention.
本发明另一方面涉及使用一种本发明的化合物在制备用于预防、处理或治疗患者HBV病症，并减轻其严重程度的药物的用途。Another aspect of the present invention relates to the use of a compound of the present invention in the preparation of a medicament for preventing, managing or treating HBV disease in a patient and reducing its severity.
本发明另一方面涉及使用一种包含本发明的化合物的药物组合物在制备用于预防或治疗患者HBV病症，并减轻其严重程度的药物的用途。Another aspect of the present invention relates to the use of a pharmaceutical composition comprising the compound of the present invention in the preparation of a medicament for preventing or treating HBV disease in a patient and reducing its severity.
本发明另一方面涉及一种抑制HBV感染的方法，该方法包含细胞与本发明的化合物或组合物能有效抑制HBV的剂量接触。另外一些实施例是，所述方法更进一步地包含细胞与抗HBV剂的接触。Another aspect of the present invention relates to a method for inhibiting HBV infection, which comprises contacting cells with a dose of the compound or composition of the present invention that is effective in inhibiting HBV. In some other embodiments, the method further comprises contacting cells with an anti-HBV agent.
本发明另一方面涉及治疗患者HBV疾病的方法，该方法包含给予患者有效治疗量的本发明的化合物或其组合物。另外一些实施例是，所述方法更进一步地包含其它HBV治疗的给药。Another aspect of the present invention relates to a method for treating HBV disease in a patient, the method comprising administering to the patient an effective therapeutic amount of a compound of the present invention or a composition thereof. In some other embodiments, the method further comprises administering other HBV treatments.
本发明另一方面涉及一种抑制患者HBV感染的方法，该方法包含给予患者有效治疗量的本发明的化合物或其组合物。另外一些实施例是，所述方法更进一步地包含其它HBV治疗的给药。Another aspect of the present invention relates to a method for inhibiting HBV infection in a patient, the method comprising administering to the patient an effective therapeutic amount of a compound of the present invention or a composition thereof. In some other embodiments, the method further comprises administering other HBV treatments.
本发明另一方面涉及式(I)或式(Ia)所包含的化合物的制备、分离和纯化的方法。Another aspect of the present invention relates to methods for preparing, isolating and purifying the compounds encompassed by formula (I) or formula (Ia).
本发明还包含本发明的化合物及其药学上可接受的盐的应用，用于生产医药产品有效抑制HBV感染，包括那些本发明所描述的：本发明的化合物在生产有效抑制HBV感染药物中的应用。本发明的化合物同样用于生产一种医药品用来减轻，阻止，控制或治疗患者乙型肝炎的病症。本发明包含药物组合物，该药物组合物包括式(I)或式(Ia)所代表的化合物与至少一个药学上可接受的辅料的结合所需的有效治疗用量。The present invention also includes the use of the compounds of the present invention and their pharmaceutically acceptable salts for producing pharmaceutical products that effectively inhibit HBV infection, including those described in the present invention: the use of the compounds of the present invention in producing drugs that effectively inhibit HBV infection. The compounds of the present invention are also used to produce a pharmaceutical product for alleviating, preventing, controlling or treating symptoms of hepatitis B in patients. The present invention includes a pharmaceutical composition comprising a compound represented by formula (I) or formula (Ia) in combination with at least one pharmaceutically acceptable excipient in an effective therapeutic amount.
本发明同样包含有效抑制HBV感染的疾病，或对此病症敏感的方法，该方法包含使用式(I)或式(Ia)所代表化合物的治疗有效量对患者进行治疗。The present invention also includes a method for effectively inhibiting HBV-infected diseases, or diseases susceptible to such diseases, which comprises treating a patient with a therapeutically effective amount of a compound represented by formula (I) or formula (Ia).
除非其他方面表明，本发明的化合物所有的立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或它的前药都属于本发明的范围。Unless otherwise indicated, all stereoisomers, tautomers, N-oxides, solvates, metabolites, pharmaceutically acceptable salts or prodrugs thereof of the compounds of the present invention are within the scope of the present invention.
具体地说，盐是药学上可接受的盐。术语“药学上可接受的”包括物质或组合物必须是适合化学或毒理学地，与组成制剂的其他组分和用于治疗的哺乳动物有关。In particular, the salts are pharmaceutically acceptable salts. The term "pharmaceutically acceptable" includes that the substance or composition must be suitable chemically and toxicologically with the other ingredients that make up the formulation and with the mammal to be treated.
术语“药学上可接受的”是指从毒理学观点来看可接受用于制药应用且不会不利地与活性成分相互作用的物质。The term "pharmaceutically acceptable" refers to materials that are acceptable for pharmaceutical use from a toxicological point of view and do not adversely interact with the active ingredients.
本发明的化合物的盐还包括用于制备或纯化式(I)或式(Ia)所示化合物的中间体或式(I)或式(Ia)所示化合物分离的对映异构体的盐，但不一定是药学上可接受的盐。The salts of the compounds of the present invention also include intermediates used in the preparation or purification of the compounds of formula (I) or (Ia) or salts of separated enantiomers of the compounds of formula (I) or (Ia), but are not necessarily pharmaceutically acceptable salts.
如果本发明的化合物是碱性的，则想得到的盐可以通过文献上提供的任何合适的方法制备得到，例如，使用无机酸，如盐酸、氢溴酸、硫酸、硝酸和磷酸等等；或者使用有机酸，如乙酸、马来酸、琥珀酸、扁桃酸、富马酸、丙二酸、丙酮酸、苹果酸、2-羟基丙酸、枸橼酸、草酸、羟乙酸和水杨酸；吡喃糖酸，如葡萄糖醛酸和半乳糖醛酸；α-羟酸，如柠檬酸和酒石酸；氨基酸，如天门冬氨酸和谷氨酸；芳香族酸，如苯甲酸和肉桂酸；磺酸，如对甲苯磺酸、苯磺酸、甲磺酸、乙磺酸、三氟甲磺酸等等或它们的组合。If the compound of the present invention is basic, the desired salt can be prepared by any suitable method provided in the literature, for example, using inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid, etc.; or using organic acids such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, malic acid, 2-hydroxypropionic acid, citric acid, oxalic acid, glycolic acid and salicylic acid; pyranose acids such as glucuronic acid and galacturonic acid; α-hydroxy acids such as citric acid and tartaric acid; amino acids such as aspartic acid and glutamic acid; aromatic acids such as benzoic acid and cinnamic acid; sulfonic acids such as p-toluenesulfonic acid, benzenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, trifluoromethanesulfonic acid, etc. or combinations thereof.
如果本发明的化合物是酸性的，则想得到的盐可以通过合适的方法制备得到，无机碱，如式(I)所示化合物的锂盐、钠盐、钾盐、钙盐、镁盐、铝盐、铁盐、亚铁盐、锰盐、亚锰盐、铜盐、锌盐和铵盐等；无机碱，如式(I)所示化合物与甲胺、二甲胺、三甲胺、乙胺、二乙胺、三乙胺、氨基丁三醇、二乙氨基乙醇、异丙胺、2-乙氨基乙醇、吡啶、甲基吡啶、乙醇胺、二乙醇胺、铵、二甲基乙醇胺、四甲基铵、四乙基铵、三乙醇胺、哌啶、哌嗪、吗啉、咪唑盐、赖氨酸、精氨酸、L-精氨酸、组氨酸、N-甲基葡糖胺、二甲基葡糖胺、乙基葡糖胺、二环己基胺、1,6-己二胺、乙二胺、葡糖胺、肌氨酸、丝氨醇、氨基丙二醇、1-氨基-2,3,4-丁三醇、L-赖氨酸和鸟氨酸等形成的盐。If the compound of the present invention is acidic, the desired salt can be prepared by a suitable method, an inorganic base, such as a lithium salt, sodium salt, potassium salt, calcium salt, magnesium salt, aluminum salt, iron salt, ferrous salt, manganese salt, manganous salt, copper salt, zinc salt and ammonium salt of the compound of formula (I); an inorganic base, such as a compound of formula (I) and methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, tromethamine, diethylaminoethanol, isopropylamine, 2-ethylaminoethanol, pyridine, Salts formed by methylpyridine, ethanolamine, diethanolamine, ammonium, dimethylethanolamine, tetramethylammonium, tetraethylammonium, triethanolamine, piperidine, piperazine, morpholine, imidazole salts, lysine, arginine, L-arginine, histidine, N-methylglucamine, dimethylglucamine, ethylglucamine, dicyclohexylamine, 1,6-hexanediamine, ethylenediamine, glucosamine, sarcosine, serinol, aminopropylene glycol, 1-amino-2,3,4-butanetriol, L-lysine and ornithine.
本发明的化合物的药物组合物，制剂，给药和化合物及药物组合物的用途Pharmaceutical compositions, formulations, administration and uses of the compounds and pharmaceutical compositions of the present invention
本发明的药物组合物包括式(I)或式(Ia)所示结构化合物或实施例中所示结构的化合物，或其立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物以及药学上可接受的盐或前药，以及药学上可以接受的辅料。HBV引发的慢性病毒病可能导致病态变严重，慢性乙型肝炎病毒感染在许多情况下可导致肝硬化和/或肝细胞癌变，本发明的组合物中化合物能有效的抑制乙型肝炎病毒，适用于病毒引起的疾病尤其是急性和慢性持续的HBV病毒感染的治疗。The pharmaceutical composition of the present invention comprises a compound of the structure shown in formula (I) or formula (Ia) or a compound of the structure shown in the embodiment, or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, and pharmaceutically acceptable salt or prodrug thereof, and a pharmaceutically acceptable excipient. Chronic viral diseases caused by HBV may cause the morbidity to become serious. Chronic hepatitis B virus infection may lead to cirrhosis and/or hepatocellular carcinoma in many cases. The compound in the composition of the present invention can effectively inhibit hepatitis B virus and is suitable for the treatment of viral diseases, especially acute and chronic persistent HBV virus infection.
本发明的化合物尤其适合治疗慢性乙肝感染和急性和慢性乙肝病毒感染。The compounds of the invention are particularly suitable for the treatment of chronic hepatitis B infections and acute and chronic hepatitis B virus infections.
本发明包括药物制剂，除了无毒，惰性的制药学上合适的辅料外，还含有一种或多种本发明的化合物(I)或组合物。The present invention includes pharmaceutical preparations containing one or more compounds (I) or compositions of the present invention in addition to non-toxic, inert pharmaceutically suitable excipients.
上述药物制剂也可以包含化合物(I)或式(Ia)以外的其他活性药物成分。The above-mentioned pharmaceutical preparations may also contain other active pharmaceutical ingredients besides Compound (I) or Formula (Ia).
本发明的化合物存在自由形态，或合适的、作为药学上可接受的衍生物。根据本发明，药学上可接受的衍生物包括，但并不限于，药学上可接受的前药，盐，酯，酯类的盐，或能直接或间接地根据患者的需要给药的其他任何加合物或衍生物，本发明其他方面所描述的化合物，其代谢产物或它的残留物。The compounds of the present invention exist in free form, or are suitable as pharmaceutically acceptable derivatives. According to the present invention, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable prodrugs, salts, esters, salts of esters, or any other adducts or derivatives that can be directly or indirectly administered according to the needs of patients, compounds described in other aspects of the present invention, their metabolites or their residues.
像本发明所描述的，本发明药物组合物包含任何一种本发明的式(I)或式(Ia)所示化合物，进一步包含药学上可接受的辅料，这些辅料，例如像本发明所应用的，包括任何溶剂，固体赋形剂，稀释剂，粘合剂，崩解剂，或其他液体赋形剂，分散剂，矫味剂或悬浮剂，表面活性剂，等渗剂，增稠剂，乳化剂，防腐剂，固体粘合剂或润滑剂，等等，适合于特有的目标剂型。如以下文献所描述的：In Remington:The Science and Practice of Pharmacy,21st edition,2005,ed.D.B.Troy,Lippincott Williams&Wilkins,Philadelphia,andEncyclopedia of Pharmaceutical Technology,eds.J.Swarbrick and J.C.Boylan,1988-1999,Marcel Dekker,New York,综合此处文献的内容，表明不同的辅料可应用于药学上可接受的组合物的制剂和它们公知的制备方法。除了任何常规的辅料与本发明的化合物不相容的范围，例如所产生的任何不良的生物效应或与药学上可接受的组合物的任何其他组分以有害的方式产生的相互作用，它们的用途也是本发明所考虑的范围。As described in the present invention, the pharmaceutical composition of the present invention comprises any one of the compounds of formula (I) or formula (Ia) of the present invention, and further comprises a pharmaceutically acceptable excipient, such as any solvent, solid excipient, diluent, binder, disintegrant, or other liquid excipient, dispersant, flavoring agent or suspending agent, surfactant, isotonic agent, thickener, emulsifier, preservative, solid binder or lubricant, etc., suitable for a specific target dosage form. As described in the following documents: In Remington: The Science and Practice of Pharmacy, 21st edition, 2005, ed. D. B. Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J. C. Boylan, 1988-1999, Marcel Dekker, New York, the contents of the documents herein are summarized, indicating that different excipients can be applied to the preparation of pharmaceutically acceptable compositions and their known preparation methods. Except insofar as any conventional excipients are incompatible with the compounds of the present invention, for example by producing any undesirable biological effect or interacting in a deleterious manner with any other component of the pharmaceutically acceptable composition, their use is contemplated by the present invention.
可作为药学上可接受辅料的物质包括，但并不限于，离子交换剂；铝；硬脂酸铝；卵磷脂；血清蛋白，如人血清蛋白；缓冲物质如磷酸盐；甘氨酸；山梨酸；山梨酸钾；饱和植物脂肪酸的部分甘油酯混合物；水；盐或电解质，如硫酸鱼精蛋白，磷酸氢二钠，磷酸氢钾，氯化钠，锌盐；胶体硅；三硅酸镁；聚乙烯吡咯烷酮；聚丙烯酸脂；蜡；聚乙烯-聚氧丙烯-阻断聚合体；羊毛脂；糖，如乳糖，葡萄糖和蔗糖；淀粉如玉米淀粉和土豆淀粉；纤维素和它的衍生物如羧甲基纤维素钠，乙基纤维素和乙酸纤维素；树胶粉；麦芽；明胶；滑石粉；辅料如可可豆脂和栓剂蜡状物；油如花生油，棉子油，红花油，麻油，橄榄油，玉米油和豆油；二醇类化合物，如丙二醇和聚乙二醇；酯类如乙基油酸酯和乙基月桂酸酯；琼脂；缓冲剂如氢氧化镁和氢氧化铝；海藻酸；无热原的水；等渗盐；林格(氏)溶液；乙醇；磷酸缓冲溶液；和其他无毒的合适的润滑剂如月桂硫酸钠和硬脂酸镁；着色剂；释放剂；包衣衣料；甜味剂；调味剂；香料；防腐剂和抗氧化剂。Substances that can be used as pharmaceutically acceptable excipients include, but are not limited to, ion exchangers; aluminum; aluminum stearate; lecithin; serum proteins, such as human serum albumin; buffer substances such as phosphates; glycine; sorbic acid; potassium sorbate; partial glyceride mixtures of saturated vegetable fatty acids; water; salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts; colloidal silicon; magnesium trisilicate; polyvinyl pyrrolidone; polyacrylates; waxes; polyethylene-polyoxypropylene-blocking polymers; lanolin; sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as carboxymethyl cellulose sodium cellulose, ethylcellulose and cellulose acetate; gum powder; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycol compounds such as propylene glycol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethanol; phosphate buffer solution; and other non-toxic suitable lubricants such as sodium lauryl sulfate and magnesium stearate; colorants; release agents; coatings; sweeteners; flavorings; fragrances; preservatives and antioxidants.
本发明化合物的的药物组合物，可以以下方面的任意方式施予：口服给药，喷雾吸入法，局部给药，经直肠给药，经鼻给药，阴道给药，非肠道给药如皮下，静脉，肌内，腹腔内，肺内，鞘内，心室内，胸骨内，或颅内注射或输液，或借助一种外植的储器用药。优选的方式为口服给药，肌注，向腹膜内给药或静脉注射。The pharmaceutical composition of the compound of the present invention can be administered in any of the following ways: oral administration, spray inhalation, topical administration, rectal administration, nasal administration, vaginal administration, parenteral administration such as subcutaneous, intravenous, intramuscular, intraperitoneal, intrapulmonary, intrathecal, intraventricular, intrasternal, or intracranial injection or infusion, or medication via an explanted reservoir. The preferred mode is oral administration, intramuscular injection, intraperitoneal administration or intravenous injection.
本发明化合物或含有药学上可接受的组合物可以是以单位剂量形式给药。给药剂型可以是液体剂型、固体剂型。液体剂型可以是真溶液类、胶体类、微粒剂型、混悬剂型。其他剂型例如片剂、胶囊、滴丸、气雾剂、丸剂、粉剂、溶液剂、混悬剂、乳剂、颗粒剂、栓剂、冻干粉针剂、包合物、埋植剂、贴剂、擦剂等。The compounds of the present invention or pharmaceutically acceptable compositions thereof may be administered in a unit dosage form. The dosage form may be a liquid dosage form or a solid dosage form. The liquid dosage form may be a true solution, a colloid, a microparticle dosage form, or a suspension dosage form. Other dosage forms include tablets, capsules, dripping pills, aerosols, pills, powders, solutions, suspensions, emulsions, granules, suppositories, freeze-dried powder injections, inclusion compounds, implants, patches, liniments, etc.
口服片剂和胶囊可以含有赋形剂如粘合剂，例如糖浆，阿拉伯胶，山梨醇，黄芪胶，或聚乙烯吡咯烷酮；填充剂，例如乳糖，蔗糖，玉米淀粉，磷酸钙，山梨醇，氨基乙酸；润滑剂，例如硬脂酸镁，滑石，聚乙二醇，硅土；崩解剂，例如马铃薯淀粉；或可接受的增润剂例如月桂醇钠硫酸盐。片剂可以用制药学上公知的方法包衣。Tablets and capsules for oral administration may contain excipients such as binders, for example, syrup, gum arabic, sorbitol, tragacanth, or polyvinylpyrrolidone; fillers, for example, lactose, sucrose, corn starch, calcium phosphate, sorbitol, aminoacetic acid; lubricants, for example, magnesium stearate, talc, polyethylene glycol, silica; disintegrants, for example, potato starch; or acceptable wetting agents, for example, sodium lauryl sulfate. Tablets may be coated by methods known in the pharmaceutical industry.
口服液可以制成水和油的悬浮液，溶液，乳浊液，糖浆或酏剂，也可以制成干品，用前补充水或其它合适的媒质。这种液体制剂可以包含常规的添加剂，如悬浮剂，山梨醇，纤维素甲醚，葡萄糖糖浆，凝胶，羟乙基纤维素，羧甲基纤维素，硬脂酸铝凝胶，氢化的食用油脂；乳化剂，如卵磷脂，山梨聚醣单油酸盐，阿拉伯胶；或非水辅料(可能包含可食用油)，如杏仁油；油脂如甘油，乙二醇或乙醇；防腐剂，如对羟基苯甲酸甲酯或丙酯，山梨酸。如需要可添加调味剂或着色剂。Oral liquid can be made into water and oil suspension, solution, emulsion, syrup or elixir, or it can be made into dry product, and water or other suitable medium is added before use. Such liquid preparations can contain conventional additives, such as suspending agents, sorbitol, cellulose methyl ether, glucose syrup, gel, hydroxyethyl cellulose, carboxymethyl cellulose, aluminum stearate gel, hydrogenated edible oils and fats; emulsifiers, such as lecithin, sorbitan monooleate, gum arabic; or non-aqueous excipients (which may contain edible oils), such as almond oil; oils such as glycerol, ethylene glycol or ethanol; preservatives, such as methyl or propyl parahydroxybenzoate, sorbic acid. Flavoring agents or coloring agents can be added as needed.
栓剂可包含常规的栓剂基质，如可可黄油或其他甘油酯。Suppositories may contain conventional suppository bases such as cocoa butter or other glycerides.
对胃外投药，液态剂型通常由化合物和一种消毒的辅料制成。辅料首选水。依照所选辅料和药物浓度的不同，化合物既可溶于辅料中也可制成悬浮溶液，在制成注射用溶液时先将化合物溶于水中，过滤消毒后装入封口瓶或安瓿中。For extragastric administration, liquid dosage forms are usually made of the compound and a sterile excipient. The excipient is preferably water. Depending on the selected excipient and the drug concentration, the compound can be dissolved in the excipient or made into a suspension solution. When making an injection solution, the compound is first dissolved in water, filtered and sterilized, and then filled into a sealed bottle or ampoule.
当皮肤局部施用时，本发明化合物可以制成适当的软膏，洗剂或霜剂的形式，其中活性成分悬浮或溶解于一种或多种的辅料中。其中，软膏制剂可以使用的辅料包括但不局限于：矿物油，液体凡士林，白凡士林，丙二醇，聚氧化乙烯，聚氧化丙烯，乳化蜡和水；洗剂和霜剂可使用的辅料包括但不限于：矿物油，脱水山梨糖醇单硬脂酸酯，吐温60，十六烷酯蜡，十六碳烯芳醇，2-辛基十二烷醇，苄醇和水。When applied topically to the skin, the compounds of the present invention can be prepared into the form of suitable ointments, lotions or creams, wherein the active ingredient is suspended or dissolved in one or more excipients. Among them, the excipients that can be used in ointment preparations include but are not limited to: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyethylene oxide, polypropylene oxide, emulsifying wax and water; the excipients that can be used in lotions and creams include but are not limited to: mineral oil, sorbitan monostearate, Tween 60, hexadecyl ester wax, hexadecene aromatic alcohol, 2-octyldodecanol, benzyl alcohol and water.
一般而言，已经证明有利的是无论在人体医药还是在兽医药中，本发明活性化合物的给药总量每24小时为约0.01-500mg/kg体重，优选0.01-100mg/kg体重，如果合适的话，分多次单剂量给药，以达到所要求的效果。单剂量中含活性化合物的量优选为约1-80mg/kg体重，更优选为1-50mg/kg体重，但也可以不按照上述的剂量，即取决于治疗对象的种类和体重、疾病的性质和严重程度、制剂的类型和药物的给药方式，以及给药周期或时间间隔。In general, it has proven to be advantageous that the total amount of the active compound of the invention administered per 24 hours is about 0.01-500 mg/kg body weight, preferably 0.01-100 mg/kg body weight, if appropriate, in a plurality of single doses to achieve the desired effect, both in human and veterinary medicine. The amount of active compound contained in a single dose is preferably about 1-80 mg/kg body weight, more preferably 1-50 mg/kg body weight, but it may not be in accordance with the above dosage, i.e., it depends on the type and body weight of the treated subject, the nature and severity of the disease, the type of preparation and the mode of administration of the drug, as well as the administration cycle or time interval.
本发明提供的药物组合物中还包含抗HBV药物。其中抗HBV药物为HBV聚合酶抑制剂、免疫调节剂、干扰素或其它新型抗HBV剂如HBV RNA复制抑制剂、HBsAg分泌抑制剂、HBV衣壳抑制剂、反义寡聚体、siRNA、HBV治疗疫苗、HBV预防疫苗、HBV抗体疗法(单克隆或多克隆)以及用于治疗或预防HBV的激动剂。The pharmaceutical composition provided by the present invention also contains anti-HBV drugs, wherein the anti-HBV drugs are HBV polymerase inhibitors, immunomodulators, interferons or other novel anti-HBV agents such as HBV RNA replication inhibitors, HBsAg secretion inhibitors, HBV capsid inhibitors, antisense oligomers, siRNA, HBV therapeutic vaccines, HBV preventive vaccines, HBV antibody therapy (monoclonal or polyclonal) and agonists for treating or preventing HBV.
抗HBV药物有拉米夫定，替比夫定，替诺福韦酯，恩替卡韦，阿德福韦酯，Alfaferone，Alloferon，西莫白介素，克拉夫定，恩曲他滨，法普洛韦，干扰素，宝甘灵CP，因特芬，干扰素α-1b，干扰素α，干扰素α-2a，干扰素β-1a，干扰素α-2，白细胞介素-2，米伏替酯，硝唑尼特，聚乙二醇干扰素α-2a，病毒唑，罗扰素-A，西佐喃，Euforavac，安普利近，Phosphazid，Heplisav，干扰素α-2b，左旋咪唑或丙帕锗等。Anti-HBV drugs include lamivudine, telbivudine, tenofovir disoproxil, entecavir, adefovir dipivoxil, Alfaferone, Alloferon, simu-leukin, clavudine, emtricitabine, facloprid, interferon, baoganling CP, intefen, interferon alpha-1b, interferon alpha, interferon alpha-2a, interferon beta-1a, interferon alpha-2, interleukin-2, mivotilide, nitazoxanide, peginterferon alpha-2a, ribavirin, roentgen-A, sirox, Euforavac, Ampligen, Phosphazid, Heplisav, interferon alpha-2b, levamisole or propagermanium, etc.
一方面，本发明所述的化合物或药物组合物在制备用于预防、处理、治疗或减轻患者乙型肝炎疾病的药品的用途。乙型肝炎疾病是指由乙肝病毒感染或乙型肝炎感染导致引起的肝脏疾病，包括急性肝炎，慢性肝炎，肝硬化和肝癌。急性乙型肝炎病毒感染可以是无症状或表现为急性肝炎症状。慢性病毒感染患者患有活动性疾病，可发展为肝硬化和肝癌。In one aspect, the compounds or pharmaceutical compositions of the present invention are used in the preparation of a drug for preventing, treating, curing or alleviating hepatitis B disease in a patient. Hepatitis B disease refers to a liver disease caused by hepatitis B virus infection or hepatitis B infection, including acute hepatitis, chronic hepatitis, cirrhosis and liver cancer. Acute hepatitis B virus infection can be asymptomatic or manifest as symptoms of acute hepatitis. Chronic viral infection patients suffer from active disease and can develop cirrhosis and liver cancer.
本发明所述化合物或药物组合物可以用于抑制HBsAg生成或分泌的用途，包括给予患者药学上可接受的有效剂量对患者进行给药。The compound or pharmaceutical composition of the present invention can be used to inhibit the generation or secretion of HBsAg, including administering a pharmaceutically acceptable effective dose to a patient.
本发明所述化合物或药物组合物可以用于抑制HBV DNA生成的用途，包括给予患者药学上可接受的有效剂量对患者进行给药。The compound or pharmaceutical composition of the present invention can be used for inhibiting the generation of HBV DNA, comprising administering a pharmaceutically acceptable effective dose to a patient.
一方面，本发明所述化合物或药物组合物可以用于抑制HBV基因表达的用途，包括给予患者药学上可接受的有效剂量对患者进行给药。On the one hand, the compound or pharmaceutical composition of the present invention can be used to inhibit HBV gene expression, comprising administering a pharmaceutically acceptable effective dose to a patient.
其它抗HBV药物可以与包含本发明的化合物的组合物分开给药，作为多给药方案的一部分。或者，那些药物可以是单剂型的一部分，与本发明的化合物混合在一起形成单个组合物。如果给药作为多给药方案的一部分，两个活性剂可以同时连续地或在一段时间内互相传递，从而得到目标试剂活性。Other anti-HBV drugs can be administered separately from the composition comprising the compounds of the present invention as part of a multiple administration regimen. Alternatively, those drugs can be part of a single dosage form, mixed with the compounds of the present invention to form a single composition. If the administration is part of a multiple administration regimen, the two active agents can be delivered to each other simultaneously, continuously or over a period of time, so as to obtain the target agent activity.
可以结合辅料物质产生单剂型的化合物和组合物的用量(那些包含一个组合物像本发明所描述的)的改变取决于主治和特殊给药模式。正常地，本发明的组合物的量将不超过组合物包含作为唯一的活性剂的正常给药的量。The amount of the compound and composition that can be combined with the auxiliary materials to produce a single dosage form (those containing a composition as described herein) will vary depending on the indication and the particular mode of administration. Normally, the amount of the composition of the present invention will not exceed the amount normally administered when the composition contains the active agent as the only active agent.
本发明的化合物显示出较强的抗病毒作用。这类化合物对HBV具有出乎预料的抗病毒活性，因此适于用来治疗病毒引起的各种疾病，尤其是急性和慢性持久性HBV感染引起的疾病。由HBV引起的慢性病毒性疾病可以导致各种不同严重程度的综合症状，众所周知，慢性乙肝病毒感染可导致肝硬化和/或肝癌。The compounds of the present invention show strong antiviral effects. Such compounds have unexpected antiviral activity against HBV and are therefore suitable for treating various diseases caused by the virus, especially diseases caused by acute and chronic persistent HBV infection. Chronic viral diseases caused by HBV can lead to various complex symptoms of varying severity. It is well known that chronic hepatitis B virus infection can lead to cirrhosis and/or liver cancer.
可用本发明化合物治疗的适应症的实例有：治疗可导致感染性肝炎的急性和慢性病毒感染，例如乙型肝炎病毒感染，特别优选的是慢性乙型肝炎病毒感染的治疗和急性乙型肝炎病毒感染的治疗。Examples of indications that can be treated with the compounds of the present invention are: treatment of acute and chronic viral infections that can lead to infectious hepatitis, such as hepatitis B virus infection, with the treatment of chronic hepatitis B virus infection and the treatment of acute hepatitis B virus infection being particularly preferred.
本发明还涉及，本发明的化合物和组合物用于制备治疗和预防病毒性疾病特别是乙型肝炎的药物的用途。The present invention also relates to the use of the compounds and compositions of the present invention for preparing drugs for treating and preventing viral diseases, especially hepatitis B.
一般合成方法General Synthesis Methods
为描述本发明，以下列出了实施例。但需要理解，本发明不限于这些实施例，只是提供实践本发明的方法。To describe the present invention, the following examples are listed. However, it should be understood that the present invention is not limited to these examples, which are only provided to provide methods for practicing the present invention.
一般地，本发明的化合物可以通过本发明所描述的方法制备得到，除非有进一步的说明，其中取代基的定义如式(I)所示。下面的合成方案和实施例用于进一步举例说明本发明的内容。Generally, the compounds of the present invention can be prepared by the methods described herein, unless otherwise specified, wherein the substituents are defined as shown in formula (I). The following synthetic schemes and examples are provided to further illustrate the present invention.
所属领域的技术人员将认识到：本发明所描述的化学反应可以用来合适地制备许多本发明的其他化合物，且用于制备本发明的化合物的其它方法都被认为是在本发明的范围之内。例如，根据本发明那些非例证的化合物的合成可以成功地被所属领域的技术人员通过修饰方法完成，如适当的保护干扰基团，通过利用其他已知的试剂除了本发明所描述的，或将反应条件做一些常规的修改。另外，本发明所公开的反应或已知的反应条件也公认地适用于本发明其他化合物的制备。Those skilled in the art will recognize that the chemical reactions described herein can be used to appropriately prepare many other compounds of the invention, and other methods for preparing the compounds of the invention are considered to be within the scope of the invention. For example, the synthesis of non-exemplified compounds according to the invention can be successfully accomplished by those skilled in the art through modification methods, such as appropriate protection of interfering groups, by utilizing other known reagents in addition to those described herein, or by making some conventional modifications to the reaction conditions. In addition, the reactions disclosed herein or known reaction conditions are also recognized to be applicable to the preparation of other compounds of the invention.
下面所描述的实施例，除非其他方面表明所有的温度定为摄氏度(℃)。试剂购买于商品供应商如Aldrich Chemical Company,Arco Chemical Company and AlfaChemical Company，使用时都没有经过进一步纯化，除非其他方面表明。一般的试剂从汕头西陇化工厂，广东光华化学试剂厂，广州化学试剂厂，天津好寓宇化学品有限公司，青岛腾龙化学试剂有限公司，和青岛海洋化工厂购买得到。In the examples described below, all temperatures are in degrees Celsius (°C) unless otherwise indicated. Reagents were purchased from commercial suppliers such as Aldrich Chemical Company, Arco Chemical Company and Alfa Chemical Company and were used without further purification unless otherwise indicated. Common reagents were purchased from Shantou Xilong Chemical Factory, Guangdong Guanghua Chemical Reagent Factory, Guangzhou Chemical Reagent Factory, Tianjin Haoyuyu Chemical Co., Ltd., Qingdao Tenglong Chemical Reagent Co., Ltd., and Qingdao Ocean Chemical Factory.
核磁共振光谱数据通过Bruker Avance 400核磁共振谱仪或Bruker Avance IIIHD 600核磁共振谱仪来测定，以CDCl3、DMSO-d6、CD3OD或d6-丙酮为溶剂(报导以ppm为单位)，用TMS(0ppm)或氯仿(7.26ppm)作为参照标准。当出现多重峰的时候，将使用下面的缩写：s(singlet，单峰)，s,s(singlet，singlet，单峰，单峰)，d(doublet，双峰)，t(triplet，三重峰)，m(multiplet，多重峰)，br(broadened，宽峰)，dd(doublet of doublets，双二重峰)，ddd(doublet of doublet of doublets，双双二重峰)，dt(doublet of triplets，双三重峰)，ddt(doublet of doublet of triplets，双双三重峰)，td(triplet ofdoublets，三双重峰)，br.s(broadened singlet，宽单峰)。偶合常数J，单位用赫兹(Hz)表示。NMR spectroscopic data were measured on a Bruker Avance 400 NMR spectrometer or a Bruker Avance IIIHD 600 NMR spectrometer using CDCl3 , DMSO-d6 , CD3 OD or d6 -acetone as solvents (reported in ppm) and TMS (0 ppm) or chloroform (7.26 ppm) as reference standards. When multiple peaks appear, the following abbreviations are used: s (singlet), s,s (singlet, singlet, singlet), d (doublet), t (triplet), m (multiplet), br (broadened), dd (doublet of doublets), ddd (doublet of doublet of doublets), dt (doublet of triplets), ddt (doublet of doublet of triplets), td (triplet of doublets), br.s (broadened singlet). The coupling constant J is expressed in Hertz (Hz).
低分辨率质谱(MS)数据通过配备G1312A二元泵和a G1316A TCC(柱温保持在30℃)的Agilent 6320系列LC-MS的光谱仪来测定，G1329A自动采样器和G1315B DAD检测器应用于分析，ESI源应用于LC-MS光谱仪。Low-resolution mass spectrometry (MS) data were determined by an Agilent 6320 series LC-MS spectrometer equipped with a G1312A binary pump and a G1316A TCC (column temperature was maintained at 30 °C). A G1329A autosampler and a G1315B DAD detector were used for analysis, and an ESI source was applied to the LC-MS spectrometer.
低分辨率质谱(MS)数据通过配备G1311A四元泵和G1316A TCC(柱温保持在30℃)的Agilent 6120系列LC-MS的光谱仪来测定，G1329A自动采样器和G1315D DAD检测器应用于分析，ESI源应用于LC-MS光谱仪。Low-resolution mass spectrometry (MS) data were determined by an Agilent 6120 series LC-MS spectrometer equipped with a G1311A quaternary pump and a G1316A TCC (column temperature was maintained at 30 °C), a G1329A autosampler and a G1315D DAD detector were used for analysis, and an ESI source was applied to the LC-MS spectrometer.
以上两种光谱仪都配备了Agilent Zorbax SB-C18柱，规格为2.1×30mm，5μm。注射体积是通过样品浓度来确定；流速为0.6mL/min；HPLC的峰值是通过在210nm和254nm处的UV-Vis波长来记录读取的。流动相为0.1％的甲酸乙腈溶液(相A)和0.1％的甲酸超纯水溶液(相B)。梯度洗脱条件如表1所示：表1：梯度洗脱条件Both spectrometers were equipped with an Agilent Zorbax SB-C18 column with a size of 2.1×30 mm, 5 μm. The injection volume was determined by the sample concentration; the flow rate was 0.6 mL/min; the HPLC peak was recorded and read at UV-Vis wavelengths at 210 nm and 254 nm. The mobile phase was 0.1% formic acid in acetonitrile (phase A) and 0.1% formic acid in ultrapure water (phase B). The gradient elution conditions are shown in Table 1: Table 1: Gradient elution conditions
化合物纯化是通过Agilent 1100系列高效液相色谱(HPLC)来评价的，其中UV检测在210nm和254nm处，Zorbax SB-C18柱，规格为2.1×30mm，4μm，10分钟，流速为0.6mL/min，5-95％的(0.1％甲酸乙腈溶液)的(0.1％甲酸水溶液)，柱温保持在40℃。Compound purification was evaluated by Agilent 1100 series high performance liquid chromatography (HPLC) with UV detection at 210 nm and 254 nm, a Zorbax SB-C18 column, 2.1×30 mm, 4 μm, 10 min, a flow rate of 0.6 mL/min, 5-95% (0.1% formic acid in acetonitrile) in (0.1% formic acid in water), and the column temperature was maintained at 40°C.
下面简写词的使用贯穿本发明：The following abbreviations are used throughout this invention:
合成方法Synthesis method
以下合成方案列出了制备本发明中公开化合物的实验步骤。其中，各R2、R3、R4、R5、R6、X1、X2和R9具有如本发明所述的含义，各X3独立地为为Cl、Br或I，R1a为C1-6烷基或C3-7环烷基。The following synthetic scheme lists the experimental steps for preparing the compounds disclosed in the present invention. Wherein, each of R2 , R3 , R4 , R5 , R6 , X1 , X2 and R9 has the meaning as described in the present invention, each X3 is independently Cl, Br or I, and R1a is C1-6 alkyl or C3-7 cycloalkyl.
合成方案1Synthesis Scheme 1
式(a-19)所示化合物可以通过合成方案1中所描述的方法制备得到。首先，化合物(a-1)与化合物(a-2)在钯催化剂(如Pd(dba)2、Pd2(dba)3等)、配体(如Xantphos等)、合适的碱(如叔丁醇钠等)作用下以及在合适的溶剂中(如THF，甲苯等)发生偶联反应生成化合物(a-3)。化合物(a-3)与NH4OAc在还原剂(如NaBH3CN等)作用下以及在合适的溶剂(如甲醇等)中，发生还原胺化反应生成化合物(a-4)。化合物(a-4)与甲酸或甲酸乙酯在合适的溶剂中(如1,4二氧六环，四氢呋喃等)反应生成化合物(a-5)。然后，化合物(a-5)与三氯氧磷在合适的溶剂(如DCM等)中反应生成化合物(a-6)。接下来，化合物(a-6)与化合物(a-7)或化合物(a-8)在合适的溶剂(如异丙醇、乙醇、DMSO等)中发生成环反应，生成化合物(a-9)。化合物(a-9)与化合物(a-10)或化合物(a-11)在钯催化剂(如双三苯基磷二氯化钯等)作用下以及在合适的溶剂中(如二氧六环等)发生偶联反应生成化合物(a-12)。化合物(a-12)与四氯苯醌，在合适的溶剂(如DME等)中发生脱氢反应，生成化合物(a-13)。化合物(a-13)在Pa/C催化剂和氢气还原剂的作用下，以及合适的溶剂中(如极性溶剂)，脱掉苄基，得到化合物(a-14)。化合物(a-14)与R3X3在碱性(如碳酸钾等)条件下，得到化合物(a-15)。化合物(a-15)在碱(如氢氧化锂、氢氧化钠等)作用下和在合适的溶剂中(如THF/H2O、EtOH/H2O、MeOH/H2O、MeOH/THF、H2O等)发生酯水解反应，或者在酸(如TFA等)作用下和在合适溶剂中(如DCM等)发生酯水解反应，得到化合物(a-16)。化合物(a-16)胺化得到化合物(a-17)。化合物(a-17)与1,1-二甲氧基-N,N-二甲基甲胺反应，得到化合物(a-18)。最后，化合物(a-18)与水合肼，以及酸性条件下(如乙酸等)反应，得到化合物(a-19)。The compound represented by formula (a-19) can be prepared by the method described in Synthesis Scheme 1. First, compound (a-1) and compound (a-2) undergo coupling reaction in the presence of a palladium catalyst (such as Pd(dba)2 , Pd2 (dba)3 , etc.), a ligand (such as Xantphos, etc.), a suitable base (such as sodium tert-butoxide, etc.) and in a suitable solvent (such as THF, toluene, etc.) to produce compound (a-3). Compound (a-3) undergoes reductive amination reaction with NH4 OAc in the presence of a reducing agent (such as NaBH3 CN, etc.) and in a suitable solvent (such as methanol, etc.) to produce compound (a-4). Compound (a-4) reacts with formic acid or ethyl formate in a suitable solvent (such as 1,4-dioxane, tetrahydrofuran, etc.) to produce compound (a-5). Then, compound (a-5) reacts with phosphorus oxychloride in a suitable solvent (such as DCM, etc.) to produce compound (a-6). Next, compound (a-6) and compound (a-7) or compound (a-8) undergo cyclization reaction in a suitable solvent (such as isopropanol, ethanol, DMSO, etc.) to generate compound (a-9). Compound (a-9) and compound (a-10) or compound (a-11) undergo coupling reaction under the action of palladium catalyst (such as bistriphenylphosphine palladium dichloride, etc.) and in a suitable solvent (such as dioxane, etc.) to generate compound (a-12). Compound (a-12) and tetrachlorobenzoquinone undergo dehydrogenation reaction in a suitable solvent (such as DME, etc.) to generate compound (a-13). Compound (a-13) undergoes benzyl removal under the action of Pa/C catalyst and hydrogen reducing agent and in a suitable solvent (such as polar solvent) to obtain compound (a-14). Compound (a-14) and R3 X3 under alkaline conditions (such as potassium carbonate, etc.) to obtain compound (a-15). Compound (a-15) undergoes ester hydrolysis reaction under the action of a base (such as lithium hydroxide, sodium hydroxide, etc.) and in a suitable solvent (such as THF/H2 O, EtOH/H2 O, MeOH/H2 O, MeOH/THF, H2 O, etc.), or undergoes ester hydrolysis reaction under the action of an acid (such as TFA, etc.) and in a suitable solvent (such as DCM, etc.) to obtain compound (a-16). Compound (a-16) is aminized to obtain compound (a-17). Compound (a-17) reacts with 1,1-dimethoxy-N,N-dimethylmethylamine to obtain compound (a-18). Finally, compound (a-18) reacts with hydrazine hydrate and under acidic conditions (such as acetic acid, etc.) to obtain compound (a-19).
合成方案2Synthesis Scheme 2
式(b-9)所示化合物可以通过合成方案2中所描述的方法制备得到。化合物(b-1)与化合物(b-2)在碱性(如碳酸钾，碳酸钠等)条件下及合适的溶剂中(如乙腈，DMF等)反应，得到化合物(b-3)；化合物(b-3)在酸性条件(如三氟乙酸等)及合适的溶剂(如DCM等)中反应得到化合物(b-4)；化合物(b-4)与化合物(b-5)在浓硫酸的作用下，生成化合物(b-6)；化合物(b-6)与化合物(b-7)在碱性(如碳酸钾，碳酸钠等)条件下及合适的溶剂中(如乙腈等)反应，得到化合物(b-8)；化合物(b-8)在Pd催化剂(如溴化钯等)，碱(如乙酸钾等)及合适的溶剂(如DMA等)中，发生分子间的偶联反应，得到化合物(b-9)。The compound represented by formula (b-9) can be prepared by the method described in Synthesis Scheme 2. Compound (b-1) reacts with compound (b-2) under alkaline conditions (such as potassium carbonate, sodium carbonate, etc.) and in a suitable solvent (such as acetonitrile, DMF, etc.) to obtain compound (b-3); compound (b-3) reacts under acidic conditions (such as trifluoroacetic acid, etc.) and in a suitable solvent (such as DCM, etc.) to obtain compound (b-4); compound (b-4) and compound (b-5) react under concentrated sulfuric acid to generate compound (b-6); compound (b-6) and compound (b-7) react under alkaline conditions (such as potassium carbonate, sodium carbonate, etc.) and in a suitable solvent (such as acetonitrile, etc.) to obtain compound (b-8); compound (b-8) reacts with a Pd catalyst (such as palladium bromide, etc.), a base (such as potassium acetate, etc.) and a suitable solvent (such as DMA, etc.) to undergo an intermolecular coupling reaction to obtain compound (b-9).
合成方案3Synthesis Scheme 3
式(b-14)所示化合物可以通过合成方案3中所描述的方法制备得到。首先，化合物(b-9)脱去苄基保护基得到化合物(b-10)，然后化合物(b-10)与N-苯基双(三氟甲烷磺酰)亚胺在碱性条件下(如三乙胺等)及合适的溶剂(如二氯甲烷等)中反应生成化合物(b-11)，最后，化合物(b-11)与化合物(b-12)在钯催化剂(如双三苯基磷二氯化钯等)作用下以及合适的溶剂中(如1,4二氧六环等)发生偶联反应生成化合物(b-14)，或者化合物(b-11)与化合物(b-13)在钯催化剂(如四三苯基磷钯等)、合适的溶剂(如1,4二氧六环等)以及合适的碱(如碳酸钠、磷酸钾、碳酸钾等)中发生偶联反应生成化合物(b-14)。The compound represented by formula (b-14) can be prepared by the method described in Synthesis Scheme 3. First, the benzyl protecting group of compound (b-9) is removed to obtain compound (b-10), and then compound (b-10) reacts with N-phenylbis(trifluoromethanesulfonyl)imide under alkaline conditions (such as triethylamine, etc.) and in a suitable solvent (such as dichloromethane, etc.) to produce compound (b-11). Finally, compound (b-11) and compound (b-12) undergo a coupling reaction under the action of a palladium catalyst (such as bistriphenylphosphine palladium dichloride, etc.) and in a suitable solvent (such as 1,4-dioxane, etc.) to produce compound (b-14), or compound (b-11) and compound (b-13) undergo a coupling reaction under a palladium catalyst (such as tetrakistriphenylphosphine palladium, etc.), a suitable solvent (such as 1,4-dioxane, etc.) and a suitable base (such as sodium carbonate, potassium phosphate, potassium carbonate, etc.) to produce compound (b-14).
合成方案4Synthesis Scheme 4
式(c-6)所示化合物可以通过合成方案4中所描述的方法制备得到。首先，化合物(c-1)(其合成方法可以按照合成方案1中步骤1-2中所述的方法得到)经Boc保护，得到化合物(c-2)。化合物(c-2)经卤素取代，得到化合物(c-3)。化合物(c-3)经甲酰化反应，得到化合物(c-4)。化合物(c-4)酸性条件下(如三氟乙酸等)及合适的溶剂中(如DCM等)，发生成环反应，得到化合物(c-5)。接下来，化合物(c-5)与化合物(a-7)或化合物(a-8)在合适的溶剂(如异丙醇、乙醇、DMSO等)中发生成环反应，生成化合物(c-6)。The compound represented by formula (c-6) can be prepared by the method described in Synthesis Scheme 4. First, compound (c-1) (whose synthesis method can be obtained according to the method described in step 1-2 in Synthesis Scheme 1) is protected by Boc to obtain compound (c-2). Compound (c-2) is substituted by halogen to obtain compound (c-3). Compound (c-3) is subjected to formylation reaction to obtain compound (c-4). Compound (c-4) undergoes cyclization reaction under acidic conditions (such as trifluoroacetic acid, etc.) and in a suitable solvent (such as DCM, etc.) to obtain compound (c-5). Next, compound (c-5) undergoes cyclization reaction with compound (a-7) or compound (a-8) in a suitable solvent (such as isopropanol, ethanol, DMSO, etc.) to generate compound (c-6).
合成方案1中的化合物(a-16)还可以以化合物(c-6)为原料，按照合成方案3中的合成方法得到。Compound (a-16) in Synthesis Scheme 1 can also be obtained using compound (c-6) as a raw material according to the synthesis method in Synthesis Scheme 3.
具体实施方式DETAILED DESCRIPTION
以下实施例用于说明本发明，但不用来限制本发明的范围。The following examples are used to illustrate the present invention but are not intended to limit the scope of the present invention.
制备实施例Preparation Example
在以下制备实施例中，发明人以本发明的部分化合物为例，详细描述了本发明化合物的制备过程。In the following preparation examples, the inventors describe in detail the preparation process of the compounds of the present invention by taking some of the compounds of the present invention as examples.
实施例1：9-(2-环丙基乙氧基)-6-异丙基-10-(噻唑-2-基)-3-(1H-1,2,4-三唑-Example 1: 9-(2-cyclopropylethoxy)-6-isopropyl-10-(thiazol-2-yl)-3-(1H-1,2,4-triazole-5-基)-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-2-酮5-yl)-6,7-dihydro-2H-pyrido[2,1-a]isoquinolin-2-one
步骤1：2-(苄氧基)-1-溴-4-碘苯Step 1: 2-(Benzyloxy)-1-bromo-4-iodobenzene
于单口瓶中加入2-溴-5-碘苯酚(20g,66.9mmol)、碳酸钾(18.5g,134mmol)、乙腈(100mL)和苄溴(8.74mL,73.6mmol)，加热至80℃搅拌2h，然后过滤除去固体，减压蒸馏浓缩滤液，得标题化合物为白色固体(26.0g,99.9％)。Add 2-bromo-5-iodophenol (20 g, 66.9 mmol), potassium carbonate (18.5 g, 134 mmol), acetonitrile (100 mL) and benzyl bromide (8.74 mL, 73.6 mmol) into a single-necked bottle, heat to 80 °C and stir for 2 h, then filter to remove the solid, and concentrate the filtrate by distillation under reduced pressure to obtain the title compound as a white solid (26.0 g, 99.9%).
MS(ESI,neg.ion)m/z:386.9,388.9[M-H]-。MS(ESI,neg.ion)m/z:386.9,388.9[MH]- .
步骤2：1-(3-(苄氧基)-4-溴苯基)-3-甲基-2-丁酮Step 2: 1-(3-(Benzyloxy)-4-bromophenyl)-3-methyl-2-butanone
于单口瓶中加入2-(苄氧基)-1-溴-4-碘苯(10.0g,25.7mmol)、3-甲基-2-丁酮(4.14mL,38.6mmol)、叔丁醇钠(4.94g,51.4mmol)、四氢呋喃(100mL)、双(二亚芐基丙酮)钯(1.06g,1.81mmol)和4,5-双二苯基膦-9,9-二甲基氧杂蒽(1.07g,1.79mmol)。混合物氮气置换3次，然后加热至60℃搅拌10h。反应完后，将反应混合物减压浓缩，所得残留物经硅胶柱层析(PE/EA(V/V)＝10/1)纯化，得标题化合物为浅黄色固体物(7.10g,79.5％)。2-(Benzyloxy)-1-bromo-4-iodobenzene (10.0 g, 25.7 mmol), 3-methyl-2-butanone (4.14 mL, 38.6 mmol), sodium tert-butoxide (4.94 g, 51.4 mmol), tetrahydrofuran (100 mL), bis(dibenzylideneacetone)palladium (1.06 g, 1.81 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (1.07 g, 1.79 mmol) were added to a single-mouth bottle. The mixture was replaced with nitrogen three times, and then heated to 60°C and stirred for 10 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE/EA (V/V) = 10/1) to obtain the title compound as a light yellow solid (7.10 g, 79.5%).
1H NMR(400MHz,CDCl3)δ7.54–7.48(m,3H),7.41(t,J＝7.4Hz,2H),7.37–7.32(m,1H),6.82(d,J＝1.6Hz,1H),6.71(dd,J＝8.0,1.7Hz,1H),5.17(s,2H),3.69(s,2H),2.76–2.62(m,1H),1.10(s,3H),1.09(s,3H)。1 H NMR (400MHz, CDCl3 ) δ7.54–7.48 (m, 3H), 7.41 (t, J = 7.4Hz, 2H), 7.37–7.32 (m, 1H), 6.82 (d, J = 1.6Hz, 1H),6.71(dd,J＝8.0,1.7Hz,1H),5.17(s,2H),3.69(s,2H),2.76–2.62(m,1H),1.10(s,3H),1.09(s ,3H).
步骤3：1-(3-(苄氧基)-4-溴苯基)-3-甲基丁基-2-胺Step 3: 1-(3-(Benzyloxy)-4-bromophenyl)-3-methylbutyl-2-amine
于单口瓶中加入1-(3-(苄氧基)-4-溴苯基)-3-甲基-2-丁酮(5.20g,15.0mmol)、甲醇(50mL)和醋酸铵(5.77g,74.9mmol)，反应于室温搅拌1h，再加入氰基硼氢化钠(1.41g,22.4mmol)，然后移至室温搅拌12h。反应完后，反应混合物减压蒸馏浓缩，残留物加入水(50mL)和氢氧化钠溶液(10mL,10％)稀释，然后用二氯甲烷(50mL×2)萃取，合并有机相，有机相用饱和食盐水(50mL×1)洗涤，无水硫酸钠干燥，减压浓缩，得标题化合物无色油状物(5.0g,96％)。1-(3-(Benzyloxy)-4-bromophenyl)-3-methyl-2-butanone (5.20 g, 15.0 mmol), methanol (50 mL) and ammonium acetate (5.77 g, 74.9 mmol) were added to a single-mouth bottle, and the reaction was stirred at room temperature for 1 h. Sodium cyanoborohydride (1.41 g, 22.4 mmol) was then added, and then the mixture was moved to room temperature and stirred for 12 h. After the reaction was completed, the reaction mixture was concentrated by distillation under reduced pressure, and the residue was diluted with water (50 mL) and sodium hydroxide solution (10 mL, 10%), and then extracted with dichloromethane (50 mL × 2), and the organic phases were combined, washed with saturated brine (50 mL × 1), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound as a colorless oil (5.0 g, 96%).
MS(ESI,pos.ion)m/z:348.0[M+H]+。MS(ESI,pos.ion)m/z:348.0[M+H]+ .
步骤4：N-(1-(3-苄氧基)-4-溴苯基)-3-甲基-2-丁基)甲酰胺Step 4: N-(1-(3-benzyloxy)-4-bromophenyl)-3-methyl-2-butyl)formamide
于单口瓶中加入1-(3-(苄氧基)-4-溴苯基)-3-甲基丁基-2-胺(13.0g,37.3mmol)和甲酸乙酯(100mL)。反应混合物加热回流搅拌12h，然后冷却至室温，再减压浓缩，得标题化合物为浅黄色固体(14g,99.7％)。1-(3-(Benzyloxy)-4-bromophenyl)-3-methylbutyl-2-amine (13.0 g, 37.3 mmol) and ethyl formate (100 mL) were added to a single-necked bottle. The reaction mixture was heated under reflux and stirred for 12 h, then cooled to room temperature and concentrated under reduced pressure to obtain the title compound as a light yellow solid (14 g, 99.7%).
MS(ESI,pos.ion)m/z:376.5[M+H]+。MS(ESI,pos.ion)m/z:376.5[M+H]+ .
步骤5：6-(苄氧基)-7-溴-3-异丙基-3,4-二氢异喹啉Step 5: 6-(Benzyloxy)-7-bromo-3-isopropyl-3,4-dihydroisoquinoline
于单口瓶中加入N-(1-(3-苄氧基)-4-溴苯基)-3-甲基-2-丁基)甲酰胺(14g,37.2mmol)和二氯甲烷(100mL)，混合物于0℃冷浴下，再加入三氯氧磷(17mL,182.4mmol)。加完后，反应混合物移至室温并搅拌12h。反应完后，用饱和碳酸氢钠溶液调节至中性，再用二氯甲烷(40mL×2)萃取，合并有机相，合并的有机相用饱和氯化钠溶液(100mL)洗涤，无水硫酸钠干燥，减压浓缩，得标题化合物为棕黄色粘稠物(11.0g,82.5％)。N-(1-(3-benzyloxy)-4-bromophenyl)-3-methyl-2-butyl)formamide (14g, 37.2mmol) and dichloromethane (100mL) were added to a single-mouth bottle. The mixture was placed in a cold bath at 0℃, and phosphorus oxychloride (17mL, 182.4mmol) was added. After the addition, the reaction mixture was moved to room temperature and stirred for 12h. After the reaction was completed, it was adjusted to neutral with saturated sodium bicarbonate solution, and then extracted with dichloromethane (40mL×2), and the organic phases were combined. The combined organic phases were washed with saturated sodium chloride solution (100mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound as a brown-yellow viscous substance (11.0g, 82.5%).
MS(ESI,pos.ion)m/z:358.5[M+H]+。MS(ESI,pos.ion)m/z:358.5[M+H]+ .
步骤6：9-(苄氧基)-10-溴-6-异丙基-2-氧代-2,6,7,11b-四氢-1H-吡啶并[2,1-Step 6: 9-(Benzyloxy)-10-bromo-6-isopropyl-2-oxo-2,6,7,11b-tetrahydro-1H-pyrido[2,1-a]异喹啉-3-甲酸乙酯a]Ethyl isoquinoline-3-carboxylate
于单口瓶中加入6-(苄氧基)-7-溴-3-异丙基-3,4-二氢异喹啉(10.0g,28mmol)、2-(乙氧基亚甲基)-3-氧代-丁酸乙酯(10.4g,56mmol)和叔丁醇(50mL)，反应混合物加热至100℃并搅拌12h。反应完后，反应混合物减压浓缩，所得残留物经柱层析(PE/EA(V/V)＝1/1)纯化，得标题化合物为棕色固体(6.0g,43％)。6-(Benzyloxy)-7-bromo-3-isopropyl-3,4-dihydroisoquinoline (10.0 g, 28 mmol), 2-(ethoxymethylene)-3-oxo-butyric acid ethyl ester (10.4 g, 56 mmol) and tert-butyl alcohol (50 mL) were added to a single-mouth bottle, and the reaction mixture was heated to 100°C and stirred for 12 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (PE/EA (V/V) = 1/1) to obtain the title compound as a brown solid (6.0 g, 43%).
MS:(ESI,pos.ion)m/z:498.1/500.1[M+H]+。MS:(ESI,pos.ion)m/z:498.1/500.1[M+H]+ .
步骤7：9-苄氧基)-6-异丙基-2-氧代-10-(噻唑-2-基)-2,6,7,11b-四氢-1H-吡啶Step 7: 9-benzyloxy)-6-isopropyl-2-oxo-10-(thiazol-2-yl)-2,6,7,11b-tetrahydro-1H-pyridine并[2,1-a]异喹啉-3-甲酸乙酯2-[2,1-a]isoquinoline-3-carboxylic acid ethyl ester
于单口瓶中加入9-(苄氧基)-10-溴-6-异丙基-2-氧代-2,6,7,11b-四氢-1H-吡啶并[2,1-a]异喹啉-3-甲酸乙酯(4.0g,8.0mmol)、双三苯基膦二氯化钯(1.1g,1.6mmol)、2-三丁基甲锡烷基噻唑(4.5g,12mmol)和二氧六环(20mL)。反应混合物用氮气置换3次，然后加热至100℃搅拌12h。反应完后，减压浓缩溶剂，残留物经硅胶柱层析(DCM/MeOH(V/V)＝10/1)纯化，得标题化合物为棕色固体(3.80g,94％)。Add 9-(benzyloxy)-10-bromo-6-isopropyl-2-oxo-2,6,7,11b-tetrahydro-1H-pyrido[2,1-a]isoquinoline-3-carboxylic acid ethyl ester (4.0 g, 8.0 mmol), bistriphenylphosphine palladium dichloride (1.1 g, 1.6 mmol), 2-tributylstannylthiazole (4.5 g, 12 mmol) and dioxane (20 mL) into a single-mouth bottle. The reaction mixture was replaced with nitrogen three times, and then heated to 100°C and stirred for 12 hours. After the reaction was completed, the solvent was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM/MeOH (V/V) = 10/1) to obtain the title compound as a brown solid (3.80 g, 94%).
MS(ESI,pos.ion)m/z:503.2[M+H]+。MS(ESI,pos.ion)m/z:503.2[M+H]+ .
步骤8：9-(苄氧基)-6-异丙基-2-氧代-10-(噻唑-2-基)-6,7-二氢-2H-吡啶并[2,Step 8: 9-(Benzyloxy)-6-isopropyl-2-oxo-10-(thiazol-2-yl)-6,7-dihydro-2H-pyrido[2,1-a]异喹啉-3-甲酸乙酯1-a] Ethyl isoquinoline-3-carboxylate
于单口瓶中加入9-(苄氧基)-6-异丙基-2-氧代-10-(噻唑-2-基)-2,6,7,11b-四氢-1H-吡啶并[2,1-a]异喹啉-3-甲酸乙酯(3.80g,7.56mmol)、四氯苯醌(2.04g,8.30mmol)和DME(40mL)。反应混合物加热至80℃搅拌2h，然后冷却至室温，再减压浓缩溶剂，所得残留物经硅胶柱层析(DCM/MeOH(V/V)＝10/1)纯化，得标题化合物为灰色固体(3.0g,79％)。In a single-necked bottle, add 9-(benzyloxy)-6-isopropyl-2-oxo-10-(thiazol-2-yl)-2,6,7,11b-tetrahydro-1H-pyrido[2,1-a]isoquinoline-3-carboxylic acid ethyl ester (3.80 g, 7.56 mmol), tetrachlorobenzoquinone (2.04 g, 8.30 mmol) and DME (40 mL). The reaction mixture is heated to 80°C and stirred for 2 h, then cooled to room temperature, and the solvent is concentrated under reduced pressure. The residue is purified by silica gel column chromatography (DCM/MeOH (V/V) = 10/1) to obtain the title compound as a gray solid (3.0 g, 79%).
MS(ESI,pos.ion)m/z:501.1[M+H]+。MS(ESI,pos.ion)m/z:501.1[M+H]+ .
步骤9：9-羟基-6-异丙基-2-氧代-10-(噻唑-2-基)-6,7-二氢-2H-吡啶并[2,1-a]Step 9: 9-Hydroxy-6-isopropyl-2-oxo-10-(thiazol-2-yl)-6,7-dihydro-2H-pyrido[2,1-a]异喹啉-3-甲酸乙酯Ethyl isoquinoline-3-carboxylate
单口烧瓶中加入9-(苄氧基)-6-异丙基-2-氧代-10-(噻唑-2-基)-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸乙酯(1.50g,3.00mmol)、甲醇(15mL)、钯/碳(0.50g,0.47mmol)，氢气交换3次，氢气球下室温搅拌12h。通过硅藻土过滤除去钯/碳，真空减压浓缩溶剂，所得残留物晶硅胶柱层析(DCM/MeOH(V/V)＝10/1)纯化，得标题化合物为棕黑色固体(1.10g,89.4％)Add 9-(benzyloxy)-6-isopropyl-2-oxo-10-(thiazol-2-yl)-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylic acid ethyl ester (1.50 g, 3.00 mmol), methanol (15 mL), palladium/carbon (0.50 g, 0.47 mmol) to a single-necked flask, exchange hydrogen three times, and stir at room temperature for 12 hours under a hydrogen balloon. Remove palladium/carbon by filtration through diatomaceous earth, concentrate the solvent under vacuum, and purify the residue by silica gel column chromatography (DCM/MeOH (V/V) = 10/1) to obtain the title compound as a brown-black solid (1.10 g, 89.4%)
MS(ESI,pos.ion)m/z：411.2[M+H]+。MS(ESI,pos.ion)m/z: 411.2[M+H]+ .
步骤10：9-(2-环丙基乙氧基)-6-异丙基-2-氧代-10-(噻唑-2-基)-6,7-二氢-2H-Step 10: 9-(2-cyclopropylethoxy)-6-isopropyl-2-oxo-10-(thiazol-2-yl)-6,7-dihydro-2H-吡啶并[2,1-a]异喹啉-3-甲酸乙酯Ethyl pyrido[2,1-a]isoquinoline-3-carboxylate
于单口瓶中加入9-羟基-6-异丙基-2-氧代-10-(噻唑-2-基)-6,7-二氢吡啶并[2,1-a]异喹啉-3-甲酸乙酯(250mg,0.61mmol)、碳酸钾(336mg,2.4mmol)、乙腈(3mL)和2-环丙基乙基溴(270mg,1.5mmol)。反应混合物加热至80℃并搅拌8h，减压浓缩，所得残留物经硅胶柱层析(DCM/CH3OH(V/V)＝10/1)纯化，得标题化合物为黄色固体(180mg,73％)。In a single-necked bottle, ethyl 9-hydroxy-6-isopropyl-2-oxo-10-(thiazol-2-yl)-6,7-dihydropyrido[2,1-a]isoquinoline-3-carboxylate (250 mg, 0.61 mmol), potassium carbonate (336 mg, 2.4 mmol), acetonitrile (3 mL) and 2-cyclopropylethyl bromide (270 mg, 1.5 mmol) were added. The reaction mixture was heated to 80°C and stirred for 8 h, then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM/CH3 OH (V/V) = 10/1) to give the title compound as a yellow solid (180 mg, 73%).
MS(ESI,pos.ion)m/z:479.1[M+H]+。MS(ESI,pos.ion)m/z:479.1[M+H]+ .
步骤11：9-(2-环丙基乙氧基)-6-异丙基-2-氧代-10-(噻唑-2-基)-6,7-二氢-2H-Step 11: 9-(2-cyclopropylethoxy)-6-isopropyl-2-oxo-10-(thiazol-2-yl)-6,7-dihydro-2H-吡啶并[2,1-a]异喹啉-3-甲酸Pyrido[2,1-a]isoquinoline-3-carboxylic acid
于单口瓶中加入9-(2-环丙基乙氧基)-6-异丙基-2-氧代-10-(噻唑-2-基)-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸乙酯(270mg,0.32mmol)、一水合氢氧化锂(95mg,2.3mmol)和甲醇(5mL)。反应混合物于室温搅拌8h，然后加入1M盐酸调节至pH＝5，抽滤得到黄色固体，滤饼用甲醇(3mL)重结晶，得标题化合物为浅黄色固体(120mg,47％)。In a single-mouth bottle, add 9-(2-cyclopropylethoxy)-6-isopropyl-2-oxo-10-(thiazol-2-yl)-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylic acid ethyl ester (270 mg, 0.32 mmol), lithium hydroxide monohydrate (95 mg, 2.3 mmol) and methanol (5 mL). The reaction mixture was stirred at room temperature for 8 h, then 1 M hydrochloric acid was added to adjust the pH to 5, and a yellow solid was obtained by suction filtration. The filter cake was recrystallized with methanol (3 mL) to obtain the title compound as a light yellow solid (120 mg, 47%).
MS(ESI,pos.ion)m/z:451.17[M+H]+。MS(ESI,pos.ion)m/z:451.17[M+H]+ .
步骤12：9-(2-环丙基乙氧基)-6-异丙基-2-氧代-10-(噻唑-2-基)-6,7-二氢-2H-Step 12: 9-(2-cyclopropylethoxy)-6-isopropyl-2-oxo-10-(thiazol-2-yl)-6,7-dihydro-2H-吡啶并[2,1-a]异喹啉-3-甲酰胺Pyrido[2,1-a]isoquinoline-3-carboxamide
将9-(2-环丙基乙氧基)-6-异丙基-2-氧代-10-(噻唑-2-基)-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸(100mg,0.22mmol)和DCM(4mL)加入两口瓶中，冷却至0℃，加入五氯化磷(83.0mg,0.40mmol)，加毕，继续搅拌30min，缓慢加入氨水(0.22mL)，加毕，混合物移至室温下反应12h。反应完后，加入水(25mL)稀释，DCM(10mL×3)萃取分液，收集有机相，无水硫酸钠干燥后，过滤，滤液减压蒸馏除去溶剂。残留物经制备薄层色谱(DCM/MeOH(V/V)＝10/1)纯化，得到标题化合物为白色固体(40.0mg,40.1％)。9-(2-cyclopropylethoxy)-6-isopropyl-2-oxo-10-(thiazol-2-yl)-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylic acid (100 mg, 0.22 mmol) and DCM (4 mL) were added to a two-necked bottle, cooled to 0°C, phosphorus pentachloride (83.0 mg, 0.40 mmol) was added, stirring was continued for 30 min, ammonia water (0.22 mL) was slowly added, and the mixture was moved to room temperature for reaction for 12 h. After the reaction was completed, water (25 mL) was added to dilute, and DCM (10 mL×3) was used to extract the liquid, collect the organic phase, dry it over anhydrous sodium sulfate, filter it, and distill the filtrate under reduced pressure to remove the solvent. The residue was purified by preparative thin layer chromatography (DCM/MeOH (V/V) = 10/1) to obtain the title compound as a white solid (40.0 mg, 40.1%).
MS(ESI,pos.ion)m/z:450.2[M+H]+。MS(ESI,pos.ion)m/z:450.2[M+H]+ .
步骤13：(9-(2-环丙基乙氧基)-N-((二甲基氨基)亚甲基)-6-异丙基-2-氧代-10-Step 13: (9-(2-cyclopropylethoxy)-N-((dimethylamino)methylene)-6-isopropyl-2-oxo-10-(噻唑-2-基)-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酰胺(Thiazol-2-yl)-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxamide
依次将9-(2-环丙基乙氧基)-6-异丙基-2-氧代-10-(噻唑-2-基)-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酰胺(40.0mg,0.09mmol)和1,1-二甲氧基-N,N-二甲基甲胺(1.50mL)加入两口瓶中，反应混合物于90℃下搅拌1h。旋干溶剂，得到标题化合物为白色固体(44.9mg,100％)，直接用于下一步反应。9-(2-cyclopropylethoxy)-6-isopropyl-2-oxo-10-(thiazol-2-yl)-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxamide (40.0 mg, 0.09 mmol) and 1,1-dimethoxy-N,N-dimethylmethanamine (1.50 mL) were added to a two-necked bottle, and the reaction mixture was stirred at 90°C for 1 h. The solvent was dried to give the title compound as a white solid (44.9 mg, 100%), which was directly used in the next step.
步骤14：9-(2-环丙基乙氧基)-6-异丙基-10-(噻唑-2-基)-3-(1H-1,2,4-三唑-5-Step 14: 9-(2-cyclopropylethoxy)-6-isopropyl-10-(thiazol-2-yl)-3-(1H-1,2,4-triazole-5-yl)-基)-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-2-酮2H-pyrido[2,1-a]isoquinolin-2-one
依次将(9-(2-环丙基乙氧基)-N-((二甲基氨基)亚甲基)-6-异丙基-2-氧代-10-(噻唑-2-基)-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酰胺(44.9mg,0.09mmol)、乙酸(3.00mL)和水合肼(45.0μL)加入两口瓶中，于95℃下反应2h。自然降温至室温，然后减压蒸馏除去溶剂，所得残留物经薄层色谱分离(DCM/MeOH(V/V)＝8/1)纯化，得到标题化合物为白色固体(20.0mg,47.5％)。(9-(2-cyclopropylethoxy)-N-((dimethylamino)methylene)-6-isopropyl-2-oxo-10-(thiazol-2-yl)-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxamide (44.9 mg, 0.09 mmol), acetic acid (3.00 mL) and hydrazine hydrate (45.0 μL) were added to a two-necked bottle in sequence and reacted at 95°C for 2 h. The temperature was naturally lowered to room temperature, and then the solvent was distilled off under reduced pressure. The residue was purified by thin layer chromatography (DCM/MeOH (V/V) = 8/1) to give the title compound as a white solid (20.0 mg, 47.5%).
MS(ESI,pos.ion)m/z:474.2[M+H]+；MS(ESI,pos.ion)m/z:474.2[M+H]+ ;
1H NMR(400MHz,DMSO-d6)δ8.69(d,J＝10.1Hz,2H),7.97(s,2H),7.81(s,1H),7.40(s,1H),6.88(s,1H),4.46–4.25(m,3H),1.88–1.76(m,2H),1.66–1.52(m,1H),1.33–1.23(m,1H),1.04–0.94(m,1H),0.87(d,J＝6.5Hz,3H),0.83-0.78(m,1H),0.73(d,J＝6.5Hz,3H),0.44(d,J＝7.4Hz,2H),0.16(d,J＝4.1Hz,2H)。1 H NMR (400MHz, DMSO-d6 ) δ8.69 (d, J = 10.1Hz, 2H), 7.97 (s, 2H), 7.81 (s, 1H), 7.40 (s, 1H), 6.88 (s, 1H),4.46–4.25(m,3H),1.88–1.76(m,2H),1.66–1.52(m,1H),1.33–1.23(m,1H),1.04–0.94(m,1H),0.87( d,J＝6.5Hz,3H),0.83-0.78(m,1H),0.73(d,J＝6.5Hz,3H),0.44(d,J＝7.4Hz,2H),0.16(d,J＝4.1 Hz,2H).
实施例2：9-(2-环丙基乙氧基)-6-异丙基-2-氧代-10-(噻唑-2-基)-6,7-二氢-Example 2: 9-(2-cyclopropylethoxy)-6-isopropyl-2-oxo-10-(thiazol-2-yl)-6,7-dihydro-2H-吡啶并[2,1-a]酞嗪-3-甲酸2H-Pyrido[2,1-a]phthalazine-3-carboxylic acid
步骤1：2-环丙基乙基甲磺酰酯Step 1: 2-Cyclopropylethyl methanesulfonyl ester
在250mL的双口瓶中，加入2-环丙基乙醇(6.5g,75.5mmol)、三乙胺(15mL,106mmol)和二氯甲烷(100mL)，然后冷却至0℃，缓慢滴加甲磺酰氯(7.01mL,90.6mmol)，加毕，0℃下继续搅拌2h。后处理：加入水(50mL)洗涤，DCM萃取三次(50mL×3)，合并有机相，有机相用饱和的食盐水洗涤(30mL×3)，旋干浓缩得到标题化合物为无色油状液体(12.4g,100％)。In a 250mL two-necked bottle, add 2-cyclopropylethanol (6.5g, 75.5mmol), triethylamine (15mL, 106mmol) and dichloromethane (100mL), then cool to 0℃, slowly add methanesulfonyl chloride (7.01mL, 90.6mmol), and continue stirring at 0℃ for 2h. Post-treatment: add water (50mL) for washing, extract with DCM three times (50mL×3), combine the organic phases, wash the organic phases with saturated brine (30mL×3), spin dry and concentrate to obtain the title compound as a colorless oily liquid (12.4g, 100%).
步骤2：4-(苄氧基)-3-(2-环丙基乙氧基)苯甲醛Step 2: 4-(Benzyloxy)-3-(2-cyclopropylethoxy)benzaldehyde
于单口瓶中加入2-环丙基乙基甲磺酰酯(12.3g,74.9mmol)、4-苄氧基-3-羟基苯甲醛(11.4g,50.0mmol)、K2CO3(34.5g,250mmol)和DMF(200mL)，升温到80℃下搅拌过夜，降温到室温，加入水(100mL)，乙酸乙酯(80mL×3)萃取，合并有机相，有机相用饱和食盐水洗涤(50mL×3)，无水硫酸钠干燥，过滤，减压浓缩，所得残留物经硅胶柱层析(PE/EA(V/V)＝10/1)分离，得到标题化合物为淡黄色油状物(14.8g,49.9mmol,100％)。2-Cyclopropylethyl methanesulfonyl ester (12.3 g, 74.9 mmol), 4-benzyloxy-3-hydroxybenzaldehyde (11.4 g, 50.0 mmol), K2 CO3 (34.5 g, 250 mmol) and DMF (200 mL) were added to a single-necked bottle, the temperature was raised to 80°C and stirred overnight, the temperature was lowered to room temperature, water (100 mL) was added, and the mixture was extracted with ethyl acetate (80 mL×3). The organic phases were combined, washed with saturated brine (50 mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated by silica gel column chromatography (PE/EA (V/V)＝10/1) to give the title compound as a light yellow oil (14.8 g, 49.9 mmol, 100%).
MS(ESI,pos.ion)m/z：297.2[M+H]+。MS(ESI,pos.ion)m/z: 297.2[M+H]+ .
步骤3：4-(苄氧基)-3-(2-环丙基乙氧基)苯甲醇Step 3: 4-(Benzyloxy)-3-(2-cyclopropylethoxy)benzyl alcohol
将4-(苄氧基)-3-(2-环丙基乙氧基)苯甲醛(14.8g,49.9mmol)和MeOH(150mL)加入到500mL的单口瓶中，室温搅拌下分批加入硼氢化钠(5.67g,150mmol)，加完后室温下搅拌6h，浓缩溶剂，加入水(500mL)和乙酸乙酯(100mL)稀释，萃取分层，水层再用乙酸乙酯萃取(100mL×3)。合并有机相，再浓缩，所得残留物经硅胶柱层析(PE/EA(V/V)＝5/1)纯化，得标题化合物为白色固体(14.9g,100％)。4-(Benzyloxy)-3-(2-cyclopropylethoxy)benzaldehyde (14.8g, 49.9mmol) and MeOH (150mL) were added to a 500mL single-mouth bottle, and sodium borohydride (5.67g, 150mmol) was added in batches under stirring at room temperature. After the addition, the mixture was stirred at room temperature for 6h, and the solvent was concentrated. Water (500mL) and ethyl acetate (100mL) were added to dilute the mixture, and the layers were separated by extraction. The aqueous layer was extracted with ethyl acetate (100mL×3). The organic phases were combined and concentrated again. The residue was purified by silica gel column chromatography (PE/EA (V/V)＝5/1) to obtain the title compound as a white solid (14.9g, 100%).
MS(ESI,pos.ion)m/z：321.1[M+Na]+。MS(ESI,pos.ion)m/z: 321.1[M+Na]+ .
步骤4：4-(苄氧基)-5-(2-环丙基乙氧基)-2-碘苯)甲醇Step 4: 4-(Benzyloxy)-5-(2-cyclopropylethoxy)-2-iodophenyl)methanol
将4-(苄氧基)-3-(2-环丙基乙氧基)苯甲醇(2.0g,6.7mmol)和AcOH(15mL)加入到100mL的单口瓶中，分批加入N-碘代丁二酰亚胺(1.583g,7.036mmol)，加毕，室温下搅拌过夜，加入饱和亚硫酸钠溶液(10mL)淬灭反应，加入水(30mL)稀释，再用DCM萃取(30mL×3)，合并有机，有机相减压浓缩，所得残留物经硅胶柱层析(PE/EA(V/V)＝5/1)纯化，得到标题化合物为淡黄色油状物(2.844g,6.70mmol,100％)。4-(Benzyloxy)-3-(2-cyclopropylethoxy)benzyl alcohol (2.0 g, 6.7 mmol) and AcOH (15 mL) were added to a 100 mL single-mouth bottle, and N-iodosuccinimide (1.583 g, 7.036 mmol) was added in batches. After the addition was completed, the mixture was stirred at room temperature overnight, and a saturated sodium sulfite solution (10 mL) was added to quench the reaction. Water (30 mL) was added to dilute the mixture, and the mixture was extracted with DCM (30 mL×3). The organic phases were combined and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE/EA (V/V)=5/1) to give the title compound as a light yellow oil (2.844 g, 6.70 mmol, 100%).
MS(ESI,pos.ion)m/z：447.1[M+Na]+。MS(ESI,pos.ion)m/z: 447.1[M+Na]+ .
步骤5：1-(苄氧基)-4-(氯甲基)-2-(2-环丙基乙氧基)-5-碘苯Step 5: 1-(Benzyloxy)-4-(chloromethyl)-2-(2-cyclopropylethoxy)-5-iodobenzene
将2,4,6-三氯[1,3,5]三嗪(45mg,0.24mmol)和DMF(2mL)加入到25mL的单口瓶中，并加入4-(苄氧基)-5-(2-环丙基乙氧基)-2-碘苯)甲醇(100mg,0.23mmol)的DMF(1mL)溶液，反应混合物于室温搅拌12h。后处理：加入水(10mL)，DCM萃取(20mL×3)，合并有机相，有机相用饱和的食盐水洗涤(20mL×3)，有机相减压浓缩，得到标题化合物为无色油状物(104mg,0.24mmol,99％)，直接投入下一步反应中。2,4,6-Trichloro[1,3,5]triazine (45 mg, 0.24 mmol) and DMF (2 mL) were added to a 25 mL single-mouth bottle, and a DMF (1 mL) solution of 4-(benzyloxy)-5-(2-cyclopropylethoxy)-2-iodobenzyl)methanol (100 mg, 0.23 mmol) was added, and the reaction mixture was stirred at room temperature for 12 h. Post-treatment: water (10 mL) was added, DCM was extracted (20 mL × 3), the organic phases were combined, the organic phases were washed with saturated brine (20 mL × 3), and the organic phases were concentrated under reduced pressure to obtain the title compound as a colorless oil (104 mg, 0.24 mmol, 99%), which was directly put into the next step reaction.
步骤6：2-((二甲基氨基)亚甲基)-3-氧代丁酸叔丁酯Step 6: tert-Butyl 2-((dimethylamino)methylene)-3-oxobutanoate
反应瓶中加入化合物乙酰乙酸叔丁酯(30g,189.63mmol)、N,N-二甲基甲酰胺二甲基缩醛(45g,0.38mol)和1,4-二氧六环(200mL)，室温搅拌反应12h。反应液减压除去溶剂，残余物中加入乙酸乙酯(200mL)稀释，然后用水洗涤(200mL×3)，有机层用无水硫酸钠干燥，过滤，旋干滤液得标题化合物为棕色油状物(40g,187.56mmol,98.90％)。Add tert-butyl acetoacetate (30 g, 189.63 mmol), N,N-dimethylformamide dimethyl acetal (45 g, 0.38 mol) and 1,4-dioxane (200 mL) to the reaction flask and stir at room temperature for 12 h. Remove the solvent from the reaction solution under reduced pressure, add ethyl acetate (200 mL) to the residue and dilute, then wash with water (200 mL × 3), dry the organic layer with anhydrous sodium sulfate, filter, and spin dry the filtrate to obtain the title compound as a brown oil (40 g, 187.56 mmol, 98.90%).
MS(ESI,pos.ion)m/z：214.3[M+H]+。MS(ESI,pos.ion)m/z: 214.3[M+H]+ .
步骤7：4-氧代-4H-吡喃-3-甲酸叔丁酯Step 7: tert-Butyl 4-oxo-4H-pyran-3-carboxylate
反应瓶中加入2-((二甲基氨基)亚甲基)-3-氧代丁酸叔丁酯(20g,93.778mmol)、四氢呋喃(200mL)和甲酸乙酯(14g,189.0mmol)，冰浴下，加入叔丁醇钠(24g,242.2mmol)，加完后升至室温搅拌12h，向反应液加入HCl(500mL,1M)淬灭，再用乙酸乙酯萃取(200mL×3)，合并有机相，依次用饱和碳酸氢钠水溶液(300mL×2)和饱和氯化钠水溶液洗涤(300mL×1)，旋干有机相，残留物经硅胶柱层析分离(PE/EA(V/V)＝1/1)纯化，得标题化合物为黄色固体产物(10g,50.97mmol,54.35％)。tert-Butyl 2-((dimethylamino)methylene)-3-oxobutanoate (20 g, 93.778 mmol), tetrahydrofuran (200 mL) and ethyl formate (14 g, 189.0 mmol) were added to the reaction flask. Sodium tert-butoxide (24 g, 242.2 mmol) was added under ice bath. After the addition, the temperature was raised to room temperature and stirred for 12 h. HCl (500 mL, 1 M) was added to the reaction solution to quench it. The mixture was extracted with ethyl acetate (200 mL × 3). The organic phases were combined and washed with saturated aqueous sodium bicarbonate solution (300 mL × 2) and saturated aqueous sodium chloride solution (300 mL × 1) in sequence. The organic phase was spin-dried and the residue was purified by silica gel column chromatography (PE/EA (V/V) = 1/1) to give the title compound as a yellow solid product (10 g, 50.97 mmol, 54.35%).
MS(ESI,pos.ion)m/z：141.2[M-56+1]+。MS(ESI,pos.ion)m/z: 141.2[M-56+1]+ .
步骤8：1-((叔丁氧羰基)氨基)-4-氧代-1,4二氢吡啶-3-甲酸叔丁酯Step 8: tert-Butyl 1-((tert-Butyloxycarbonyl)amino)-4-oxo-1,4-dihydropyridine-3-carboxylate
向反应瓶中加入4-氧代-4H-吡喃-3-甲酸叔丁酯(18g,91.743mmol)，肼基甲酸叔丁酯(24.3g,184mmol)，乙醇180mL，升温回流反应12h。TLC检测反应完全后，反应液浓缩，残留物经硅胶柱层析分离(PE/EA(V/V)＝1/2)纯化，得标题化合物为橘黄色固体(28g,90.24mmol,98.36％)。Add tert-butyl 4-oxo-4H-pyran-3-carboxylate (18 g, 91.743 mmol), tert-butyl carbazate (24.3 g, 184 mmol), and 180 mL of ethanol to the reaction bottle, and heat and reflux for 12 hours. After the reaction is complete, the reaction solution is concentrated and the residue is purified by silica gel column chromatography (PE/EA (V/V) = 1/2) to obtain the title compound as an orange solid (28 g, 90.24 mmol, 98.36%).
MS(ESI,pos.ion)m/z：311.1[M+H]+。MS(ESI,pos.ion)m/z: 311.1[M+H]+ .
步骤9：1-((叔丁氧羰基)(异丙基)氨基)-4-氧代-1,4-二氢吡啶-3-甲酸叔丁酯Step 9: tert-Butyl 1-((tert-Butyloxycarbonyl)(isopropyl)amino)-4-oxo-1,4-dihydropyridine-3-carboxylate
向反应瓶中加1-((叔丁氧羰基)氨基)-4-氧代-1,4-二氢吡啶-3-甲酸叔丁酯(28g,90.24mmol)、乙腈(300mL)、碳酸钾(25g,180.89mmol)和2-溴丙烷(22g,178.87mmol)，加完后升温至80℃反应12h。反应液过滤，滤液旋干，残留物未经纯化直接进行下步反应。Add tert-butyl 1-((tert-butyloxycarbonyl)amino)-4-oxo-1,4-dihydropyridine-3-carboxylate (28 g, 90.24 mmol), acetonitrile (300 mL), potassium carbonate (25 g, 180.89 mmol) and 2-bromopropane (22 g, 178.87 mmol) to the reaction bottle, and heat to 80 ° C for 12 h. Filter the reaction solution, spin dry the filtrate, and directly carry out the next step without purification.
MS(ESI,pos.ion)m/z：353.3[M+H]+。MS(ESI,pos.ion)m/z: 353.3[M+H]+ .
步骤10：1-(异丙基氨基)-4-氧代-1,4-二氢吡啶-3-甲酸Step 10: 1-(Isopropylamino)-4-oxo-1,4-dihydropyridine-3-carboxylic acid
将第9步得到的1-((叔丁氧羰基)(异丙基)氨基)-4-氧代-1,4-二氢吡啶-3-甲酸叔丁酯溶于二氯甲烷(200mL)，冰浴下缓慢加入三氟乙酸(100mL,1323mmol)，加完后升至室温搅拌12h。旋干反应液溶剂，残留物未经纯化直接进行下步反应。Dissolve the tert-butyl 1-((tert-butyloxycarbonyl)(isopropyl)amino)-4-oxo-1,4-dihydropyridine-3-carboxylate obtained in step 9 in dichloromethane (200 mL), slowly add trifluoroacetic acid (100 mL, 1323 mmol) under ice bath, and heat to room temperature and stir for 12 h. The solvent of the reaction solution was dried by spin drying, and the residue was directly used for the next step without purification.
MS(ESI,pos.ion)m/z：197.2[M+H]+。MS(ESI,pos.ion)m/z: 197.2[M+H]+ .
步骤11：1-(异丙基氨基)-4-氧代-1,4-二氢吡啶-3-甲酸甲酯Step 11: 1-(Isopropylamino)-4-oxo-1,4-dihydropyridine-3-carboxylic acid methyl ester
向反应瓶中加入第5步得到的1-(异丙基氨基)-4-氧代-1,4-二氢吡啶-3-甲酸、MeOH(200mL)和浓硫酸(5mL,90.90mmol,18.18mol/L)，加完后升温回流反应24h。反应液冰浴下缓慢加入固体碳酸氢钠至无气泡生成，然后将反应液过滤，滤液减压浓缩，所得残留物经硅胶柱层析(EA)纯化，得标题化合物为深红色固体(10g,47.57mmol,三步产率为：53％)。Add 1-(isopropylamino)-4-oxo-1,4-dihydropyridine-3-carboxylic acid obtained in step 5, MeOH (200 mL) and concentrated sulfuric acid (5 mL, 90.90 mmol, 18.18 mol/L) to the reaction flask, and heat and reflux for 24 h after the addition. Slowly add solid sodium bicarbonate to the reaction solution under ice bath until no bubbles are generated, then filter the reaction solution, concentrate the filtrate under reduced pressure, and purify the residue by silica gel column chromatography (EA) to obtain the title compound as a dark red solid (10 g, 47.57 mmol, three-step yield: 53%).
MS(ESI,pos.ion)m/z：211.1[M+H]+。MS(ESI,pos.ion)m/z: 211.1[M+H]+ .
步骤12：1-((4-(苄氧基)-5-(2-环丙基乙氧基)-2-碘苄基)(异丙基)氨基)-4-氧Step 12: 1-((4-(Benzyloxy)-5-(2-cyclopropylethoxy)-2-iodobenzyl)(isopropyl)amino)-4-oxo代-1,4-二氢吡啶-3-甲酸甲酯Methyl 1,4-dihydropyridine-3-carboxylate
将1-(苄氧基)-4-(氯甲基)-2-(2-环丙基乙氧基)-5-碘苯(6.13g,13.8mmol)、DMF(50mL)、1-(异丙基氨基)-4-氧代-1,4-二氢吡啶-3-甲酸甲酯(1.94g,9.23mmol)和K2CO3(3.82g,27.7mmol)加入到50m L的单口瓶中，50℃下搅拌12h。反应完后，加入乙酸乙酯(200mL)和饱和食盐水(100mL)稀释，萃取分层，水相再用EA萃取(30mL×3)，合并有机相，有机相在用饱和的食盐水洗涤(100Ml×3)，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，所得残留物经硅胶柱层析(DCM/CH3OH(V/V)＝20/1)纯化，得到标题化合物为黄色油状物(3.6g,5.8mmol,63％)。Add 1-(Benzyloxy)-4-(chloromethyl)-2-(2-cyclopropylethoxy)-5-iodobenzene (6.13 g, 13.8 mmol), DMF (50 mL), 1-(isopropylamino)-4-oxo-1,4-dihydropyridine-3-carboxylic acid methyl ester (1.94 g, 9.23 mmol) and K2 CO3 (3.82 g, 27.7 mmol) into a 50 mL single-necked bottle and stir at 50° C. for 12 h. After the reaction, ethyl acetate (200 mL) and saturated brine (100 mL) were added to dilute, the layers were separated, the aqueous phase was extracted with EA (30 mL×3), the organic phases were combined, the organic phases were washed with saturated brine (100 mL×3), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM/CH3 OH (V/V)＝20/1) to give the title compound as a yellow oil (3.6 g, 5.8 mmol, 63%).
MS(ESI,pos.ion)m/z：617.2[M+H]+。MS(ESI,pos.ion)m/z: 617.2[M+H]+ .
步骤13：10-(苄氧基)-9-(2-环丙基乙氧基)-6-异丙基-2-氧代-6,7-二氢-2H-吡Step 13: 10-(Benzyloxy)-9-(2-cyclopropylethoxy)-6-isopropyl-2-oxo-6,7-dihydro-2H-pyrrolidone啶并[2,1-a]酞嗪-3-甲酸甲酯Methyl phthalazine-3-carboxylate
将1-((4-(苄氧基)-5-(2-环丙基乙氧基)-2-碘苄基)(异丙基)氨基)-4-氧代-1,4-二氢吡啶-3-甲酸甲酯(1.3mg,2.1mmol)、PdBr2(110mg,0.42mmol)、DMF(10mL)和乙酸钾(410mg,4.2mmol)加入到50mL的双口瓶中，氮气保护升温到100℃下搅拌4h，加入乙酸乙酯(50mL)和水(20mL)稀释乙酸乙酯萃取(30mL×3)，合并有机相，有机相用饱和的食盐水洗涤(20mL×3)，然后减压浓缩，所得残留物经薄层色谱分离(DCM/MeOH(V/V)＝10/1)纯化，得标题化合物为黑色油状物(140mg,0.28mmol,14％)。Methyl 1-((4-(benzyloxy)-5-(2-cyclopropylethoxy)-2-iodobenzyl)(isopropyl)amino)-4-oxo-1,4-dihydropyridine-3-carboxylate (1.3 mg, 2.1 mmol), PdBr2 (110 mg, 0.42 mmol), DMF (10 mL) and potassium acetate (410 mg, 4.2 mmol) were added to a 50 mL two-necked flask, the temperature was raised to 100°C and stirred for 4 h under nitrogen protection, ethyl acetate (50 mL) and water (20 mL) were added to dilute the ethyl acetate for extraction (30 mL×3), the organic phases were combined, the organic phases were washed with saturated brine (20 mL×3), and then concentrated under reduced pressure, the residue was purified by thin layer chromatography (DCM/MeOH (V/V)＝10/1) to obtain the title compound as a black oil (140 mg, 0.28 mmol, 14%).
MS(ESI,pos.ion)m/z：489.30[M+H]+。MS(ESI,pos.ion)m/z: 489.30[M+H]+ .
步骤14：9-(2-环丙基乙氧基)-10-羟基-6-异丙基-2-氧代-6,7-二氢-2H-吡啶并Step 14: 9-(2-cyclopropylethoxy)-10-hydroxy-6-isopropyl-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]酞嗪-3-甲酸甲酯[2,1-a]Phthaloazine-3-carboxylic acid methyl ester
将10-(苄氧基)-9-(2-环丙基乙氧基)-6-异丙基-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]酞嗪-3-甲酸甲酯(160mg,0.327mmol)、THF(6mL)、MeOH(3mL)和钯/碳(50mg,质量比为10％)加入到反应瓶中，氢气氛围下室温下搅拌24h，过滤，滤饼用二氯甲烷和甲醇的混合溶剂(22mL,DCM/MeOH(V/V)＝10/1)冲洗，滤液浓缩，所得残留物经硅胶柱层析(DCM/MeOH(V/V)＝10/1)纯化，得标题化合物为褐色油状物(130mg,0.32mmol,99.65％)。10-(Benzyloxy)-9-(2-cyclopropylethoxy)-6-isopropyl-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]phthalazine-3-carboxylic acid methyl ester (160 mg, 0.327 mmol), THF (6 mL), MeOH (3 mL) and palladium/carbon (50 mg, mass ratio of 10%) were added to a reaction bottle, stirred at room temperature for 24 h under a hydrogen atmosphere, filtered, and the filter cake was rinsed with a mixed solvent of dichloromethane and methanol (22 mL, DCM/MeOH (V/V) = 10/1). The filtrate was concentrated and the residue was purified by silica gel column chromatography (DCM/MeOH (V/V) = 10/1) to give the title compound as a brown oil (130 mg, 0.32 mmol, 99.65%).
MS(ESI,pos.ion)m/z：399.3[M+H]+。MS(ESI,pos.ion)m/z: 399.3[M+H]+ .
步骤15：9-(2-环丙基乙氧基)-6-异丙基-2-氧代-10-(((三氟甲基)磺酰基)氧Step 15: 9-(2-cyclopropylethoxy)-6-isopropyl-2-oxo-10-(((trifluoromethyl)sulfonyl)oxy基)-6,7-二氢-2H-吡啶并[2,1-a]酞嗪-3-甲酸甲酯6,7-dihydro-2H-pyrido[2,1-a]phthalazine-3-carboxylic acid methyl ester
将9-(2-环丙基乙氧基)-10-羟基-6-异丙基-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]酞嗪-3-甲酸甲酯(130mg,0.32mmol)溶解在DCM(6mL)中，降温到0℃，再加入三乙胺(77mg,0.98mmol)，分批加入PhN(OTf)2(233mg,0.65mmol)，然后升温到室温下搅拌12h。加入饱和食盐水(20mL)，然后用DMC(30mL×2)萃取，合并有机相，有机相用饱和的食盐水洗涤(20mL×3)，浓缩，残留物经硅胶柱层析(DCM/MeOH(V/V)＝10/1)纯化，得到标题化合物为褐色固体(125mg,0.24mmol,72.21％)。Dissolve 9-(2-cyclopropylethoxy)-10-hydroxy-6-isopropyl-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]phthalazine-3-carboxylic acid methyl ester (130 mg, 0.32 mmol) in DCM (6 mL), cool to 0°C, add triethylamine (77 mg, 0.98 mmol), add PhN(OTf)2 (233 mg, 0.65 mmol) in batches, then warm to room temperature and stir for 12 h. Add saturated brine (20 mL), then extract with DMC (30 mL×2), combine the organic phases, wash with saturated brine (20 mL×3), concentrate, and purify the residue by silica gel column chromatography (DCM/MeOH (V/V)＝10/1) to obtain the title compound as a brown solid (125 mg, 0.24 mmol, 72.21%).
MS(ESI,pos.ion)m/z：531.2[M+H]+。MS(ESI,pos.ion)m/z: 531.2[M+H]+ .
步骤16：9-(2-环丙基乙氧基)-6-异丙基-2-氧代-10-(噻唑-2-基)-6,7-二氢-2H-Step 16: 9-(2-cyclopropylethoxy)-6-isopropyl-2-oxo-10-(thiazol-2-yl)-6,7-dihydro-2H-吡啶并[2,1-a]酞嗪-3-甲酸Pyrido[2,1-a]phthalazine-3-carboxylic acid
将9-(2-环丙基乙氧基)-6-异丙基-2-氧代-10-(((三氟甲基)磺酰基)氧基)-6,7-二氢-2H-吡啶并[2,1-a]酞嗪-3-甲酸甲酯(125mg,0.24mmol)、三丁基(噻唑-2-基)锡(176mg,0.47mmol)、无水DMF(10mL)和[1,1'-双(二苯基膦基)二茂铁]二氯化钯(34mg,0.046mmol)加入到50mL的单口瓶中，然后氮气保护，升温到100℃下搅拌12h。降温到室温，然后加入水(15mL)，DCM(20mL×4)萃取，合并有机相，有机相用饱和的食盐水(20mL×3)洗涤，有机相减压浓缩，残留物经薄层色谱分离(DCM/MeOH(V/V)＝5/1)纯化，得到标题化合物为白色固体(16mg,0.035mmol,15％)。9-(2-Cyclopropylethoxy)-6-isopropyl-2-oxo-10-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-2H-pyrido[2,1-a]phthalazine-3-carboxylic acid methyl ester (125 mg, 0.24 mmol), tributyl(thiazol-2-yl)tin (176 mg, 0.47 mmol), anhydrous DMF (10 mL) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (34 mg, 0.046 mmol) were added to a 50 mL single-necked bottle, then protected with nitrogen, heated to 100 °C and stirred for 12 h. The mixture was cooled to room temperature, and water (15 mL) was added, extracted with DCM (20 mL×4), the organic phases were combined, washed with saturated brine (20 mL×3), and concentrated under reduced pressure. The residue was purified by thin layer chromatography (DCM/MeOH (V/V)=5/1) to give the title compound as a white solid (16 mg, 0.035 mmol, 15%).
MS(ESI,pos.ion)m/z：452.2[M+H]+；MS(ESI,pos.ion)m/z: 452.2[M+H]+ ;
1H NMR(400MHz,CDCl3)δ15.91(s,1H),8.95(s,1H),8.61(s,1H),7.99(d,J＝2.9Hz,1H),7.50(d,J＝2.9Hz,1H),7.27(s,1H),6.98(s,1H),4.48(s,2H),4.38(t,J＝6.3Hz,2H),3.05(dt,J＝12.3,6.1Hz,1H),1.96(dd,J＝13.2,6.5Hz,2H),1.111–0.97(m,6H),0.94(d,J＝6.9Hz,1H),0.58(d,J＝7.6Hz,2H),0.22(d,J＝4.4Hz,2H)。1 H NMR (400MHz, CDCl3 ) δ15.91(s,1H),8.95(s,1H),8.61(s,1H),7.99(d,J＝2.9Hz,1H),7.50(d,J＝ 2.9Hz,1H),7.27(s,1H),6.98(s,1H),4.48(s,2H),4.38(t,J＝6.3Hz,2H),3.05(dt,J＝12.3,6.1Hz, 1H),1.96(dd,J＝13.2,6.5Hz,2H),1.111–0.97(m,6H),0.94(d,J＝6.9Hz,1H),0.58(d,J＝7.6Hz,2H), 0.22(d,J=4.4Hz,2H).
实施例3：9-(2-环丙基乙氧基)-6-异丙基-3-(1H-四唑-5-基)-10-(噻唑-2-基)-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-2-酮Example 3: 9-(2-cyclopropylethoxy)-6-isopropyl-3-(1H-tetrazol-5-yl)-10-(thiazol-2-yl)-6,7-dihydro-2H-pyrido[2,1-a]isoquinolin-2-one
步骤1：2-(乙氧基亚甲基)-3-氧代丁腈Step 1: 2-(Ethoxymethylene)-3-oxobutyronitrile
将氰基丙酮(1.60g,19.3mmol)加入两口瓶中后，氮气置换三次，于氮气保护下，依次加入乙酸酐(4.81mL,50.7mmol)和原甲酸三乙酯(9.60mL,57.7mmol)，升温至130℃下，反应1.5h。自然冷却至室温后，减压蒸馏除去溶剂，残留物经正己烷(10mL)，于0℃下重结晶得标题化合物为红棕色固体(1.34g,19.3mmol,50.0％)。After adding cyanoacetone (1.60 g, 19.3 mmol) into a two-necked bottle, the nitrogen was replaced three times, and under nitrogen protection, acetic anhydride (4.81 mL, 50.7 mmol) and triethyl orthoformate (9.60 mL, 57.7 mmol) were added in sequence, and the temperature was raised to 130°C for 1.5 hours. After cooling naturally to room temperature, the solvent was removed by distillation under reduced pressure, and the residue was recrystallized with n-hexane (10 mL) at 0°C to obtain the title compound as a reddish brown solid (1.34 g, 19.3 mmol, 50.0%).
MS(ESI,pos.ion)m/z:139.2[M+H]+。MS(ESI,pos.ion)m/z:139.2[M+H]+ .
步骤2：7-溴-6-(2-环丙基乙氧基)-3-异丙基-3,4-二氢异喹啉Step 2: 7-Bromo-6-(2-cyclopropylethoxy)-3-isopropyl-3,4-dihydroisoquinoline
以2-溴-5-碘苯酚和(2-溴甲基)环丙烷为原料，参考实施例1步骤1至步骤5的合成方法得标题化合物为褐色状物。Using 2-bromo-5-iodophenol and (2-bromomethyl)cyclopropane as raw materials, the title compound was obtained as a brown substance by referring to the synthesis method of steps 1 to 5 of Example 1.
MS(ESI,pos.ion)m/z:336.1/338.1[M+H]+。MS(ESI,pos.ion)m/z:336.1/338.1[M+H]+ .
步骤3：9-(2-环丙基乙氧基)-6-异丙基-2-氧代-10-(噻唑-2-基)-6,7-二氢-2H-Step 3: 9-(2-cyclopropylethoxy)-6-isopropyl-2-oxo-10-(thiazol-2-yl)-6,7-dihydro-2H-吡啶并[2,1-a]异喹啉-3-腈Pyrido[2,1-a]isoquinoline-3-carbonitrile
以2-(乙氧基亚甲基)-3-氧代丁腈和7-溴-6-(2-环丙基乙氧基)-3-异丙基-3,4-二氢异喹啉为原料，参考实施例1步骤6至步骤8的合成方法，得标题化合物为白色固体。Using 2-(ethoxymethylene)-3-oxobutyronitrile and 7-bromo-6-(2-cyclopropylethoxy)-3-isopropyl-3,4-dihydroisoquinoline as raw materials and referring to the synthesis method of steps 6 to 8 of Example 1, the title compound was obtained as a white solid.
MS(ESI,pos.ion)m/z:432.2[M+H]+。MS(ESI,pos.ion)m/z:432.2[M+H]+ .
步骤4：9-(2-环丙基乙氧基)-6-异丙基-3-(1H-四唑-5-基)-10-(噻唑-2-基)-6,Step 4: 9-(2-cyclopropylethoxy)-6-isopropyl-3-(1H-tetrazol-5-yl)-10-(thiazol-2-yl)-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-2-酮7-Dihydro-2H-pyrido[2,1-a]isoquinolin-2-one
向反应瓶中依次加入DMF(5.00mL)、9-(2-环丙基乙氧基)-6-异丙基-2-氧代-10-(噻唑-2-基)-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-腈(50.0mg,0.12mmol)、NaN3(114mg,1.74mmol)和氯化铵(46.0mg,0.86mmol)，于氮气保护下，升温至150℃下反应9h后，补加NaN3(75.0mg,1.14mmol)，继续反应12h。冷却室温，3M稀盐酸调节pH至1，然后加入EA(30mL)和饱和食盐水(30mL)，收集有机相，无水硫酸钠干燥，减压蒸馏除去溶剂，残留物经高效制备色谱分离纯化得到标题化合物白色固体(16mg,0.03mmol,29.10％)。DMF (5.00 mL), 9-(2-cyclopropylethoxy)-6-isopropyl-2-oxo-10-(thiazol-2-yl)-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carbonitrile (50.0 mg, 0.12 mmol), NaN3 (114 mg, 1.74 mmol) and ammonium chloride (46.0 mg, 0.86 mmol) were added to the reaction flask in sequence. Under nitrogen protection, the temperature was raised to 150° C. and the reaction was carried out for 9 h. NaN3 (75.0 mg, 1.14 mmol) was then added and the reaction was continued for 12 h. The mixture was cooled to room temperature, and the pH was adjusted to 1 with 3 M dilute hydrochloric acid. EA (30 mL) and saturated brine (30 mL) were then added. The organic phase was collected and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure. The residue was separated and purified by high performance preparative chromatography to give the title compound as a white solid (16 mg, 0.03 mmol, 29.10%).
MS(ESI,pos.ion)m/z:475.2[M+H]+；MS(ESI,pos.ion)m/z:475.2[M+H]+ ;
1H NMR(400MHz,CDCl3)δ8.97(s,1H),8.63(s,1H),7.79(d,J＝3.0Hz,1H),7.51(d,J＝2.9Hz,1H),7.28(s,1H),6.99(s,1H),4.38(dd,J＝10.1,6.5Hz,2H),4.02–3.85(m,1H),3.44(dd,J＝16.4,4.5Hz,1H),3.21(d,J＝16.2Hz,1H),2.05–1.96(m,2H),1.86(dt,J＝13.5,6.7Hz,1H),1.12-1.05(m,1H),0.99(d,J＝6.6Hz,3H),0.86(d,J＝6.7Hz,3H),0.59(d,J＝7.6Hz,2H),0.24(d,J＝4.9Hz,2H)。1 H NMR (400MHz, CDCl3 ) δ8.97 (s, 1H), 8.63 (s, 1H), 7.79 (d, J = 3.0Hz, 1H), 7.51 (d, J = 2.9Hz, 1H), 7.28 (s,1H),6.99(s,1H),4.38(dd,J＝10.1,6.5Hz,2H),4.02–3.85(m,1H),3.44(dd,J＝16.4,4.5Hz,1H), 3 .21(d,J＝16.2Hz,1H),2.05–1.96(m,2H),1.86(dt,J＝13.5,6.7Hz,1H),1.12-1.05(m,1H),0.99(d,J =6.6Hz, 3H), 0.86 (d, J = 6.7Hz, 3H), 0.59 (d, J = 7.6Hz, 2H), 0.24 (d, J = 4.9Hz, 2H).
实施例4：6-异丙基-9-(3-甲氧基丙氧基)-3-(1H-四唑-5-基)-10-(噻唑-2-基)-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-2-酮Example 4: 6-isopropyl-9-(3-methoxypropoxy)-3-(1H-tetrazolyl-5-yl)-10-(thiazol-2-yl)-6,7-dihydro-2H-pyrido[2,1-a]isoquinolin-2-one
2-溴-5-碘苯酚和1-溴-3-甲氧基丙烷为原料，参考实施例3步骤2至步骤4的合成方法，得标题化合物为白色固体。2-Bromo-5-iodophenol and 1-bromo-3-methoxypropane were used as raw materials, and the synthetic method from step 2 to step 4 of reference example 3 was used to obtain the title compound as a white solid.
MS(ESI,pos.ion)m/z:479.3[M+H]+；MS(ESI,pos.ion)m/z:479.3[M+H]+ ;
1H NMR(400MHz,CDCl3)δ8.98(s,1H),8.64(s,1H),7.89(d,J＝3.1Hz,1H),7.53(d,J＝2.7Hz,1H),7.38(s,1H),701(s,1H),4.47–4.36(m,2H),3.99–3.89(m,1H),3.76–3.60(m,2H),3.53–3.36(m,4H),3.26–3.17(m,1H),2.36–2.25(m,2H),2.09–1.98(m,1H),0.98(d,J＝6.4Hz,3H),0.85(d,J＝6.1Hz,3H)。1 H NMR (400MHz, CDCl3 ) δ8.98 (s, 1H), 8.64 (s, 1H), 7.89 (d, J = 3.1Hz, 1H), 7.53 (d, J = 2.7Hz, 1H), 7.38 (s,1H),701(s,1H),4.47–4.36(m,2H),3.99–3.89(m,1H),3.76–3.60(m,2H),3.53–3.36(m,4H),3.26 –3.17(m,1H),2.36–2.25(m,2H),2.09–1.98(m,1H),0.98(d,J＝6.4Hz,3H),0.85(d,J＝6.1Hz,3H).
实施例5：9-(2-环丙乙氧基)-N-(环丙磺酰基)-6-异丙基-2-氧代-10-(噻唑-2-基)-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酰胺Example 5: 9-(2-cyclopropylethoxy)-N-(cyclopropylsulfonyl)-6-isopropyl-2-oxo-10-(thiazol-2-yl)-6,7-dihydro-2H -pyrido[2,1-a]isoquinoline-3-carboxamide
步骤1:9-(苄氧基)-10-溴-6-异丙基-2-氧代-6,7,-二氢-2H-吡啶并[2,1-a]异喹Step 1: 9-(Benzyloxy)-10-bromo-6-isopropyl-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline啉-3-甲酸乙酯Ethyl 3-Phenylinecarboxylate
于单口烧瓶中依次加入9-(苄氧基)-10-溴-6-异丙基-2-氧代-2,6,7,11b-四氢-1H-吡啶[2,1-a]异喹啉-3-甲酸乙酯(0.7g,1mmol)，四氯苯醌(0.3g,1mmol)和乙二醇二甲醚(10mL)中加热至80℃搅拌3h。减压浓缩溶剂，残留物经硅胶柱层析(DCM/MeOH(V/V)＝10/1)得标题化合物为白色固体(0.577g,80％)。In a single-necked flask, 9-(benzyloxy)-10-bromo-6-isopropyl-2-oxo-2,6,7,11b-tetrahydro-1H-pyrido[2,1-a]isoquinoline-3-carboxylic acid ethyl ester (0.7 g, 1 mmol), tetrachlorobenzoquinone (0.3 g, 1 mmol) and ethylene glycol dimethyl ether (10 mL) were added in sequence and heated to 80°C and stirred for 3 h. The solvent was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM/MeOH (V/V) = 10/1) to obtain the title compound as a white solid (0.577 g, 80%).
MS(ESI,pos.ion)m/z：496.1[M+H]+。MS(ESI,pos.ion)m/z: 496.1[M+H]+ .
步骤2：9-羟基-10-溴-6-异丙基-2-氧代-6,7,-二氢-2H-吡啶并[2,1-a]异喹啉-Step 2: 9-Hydroxy-10-bromo-6-isopropyl-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-甲酸乙酯3-Ethyl formate
于单口烧瓶中依次加入9-(苄氧基)-10-溴-6-异丙基-2-氧代-6,7,-二氢-2H-吡啶并[2,1-a]异喹-3-甲酸乙酯(150mg,0.30mmol)和三氟乙酸(5mL)，加热75℃回流反应2h。浓缩溶剂，得标题化合物为黑褐色固体(0.11g,90％)。In a single-necked flask, add 9-(benzyloxy)-10-bromo-6-isopropyl-2-oxo-6,7,-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylic acid ethyl ester (150 mg, 0.30 mmol) and trifluoroacetic acid (5 mL) in sequence, heat to 75°C and reflux for 2 h. Concentrate the solvent to obtain the title compound as a dark brown solid (0.11 g, 90%).
MS(ESI,pos.ion)m/z：406.2[M+H]+。MS(ESI,pos.ion)m/z: 406.2[M+H]+ .
步骤3：9-(2-环丙乙氧基)-10-溴-6-异丙基-2-氧代-6,7,-二氢-2H-吡啶并[2,1-Step 3: 9-(2-cyclopropylethoxy)-10-bromo-6-isopropyl-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]异喹-3-甲酸乙酯a]Ethyl isoquinoline-3-carboxylate
向烧瓶中依次加入9-羟基-10-溴-6-异丙基-2-氧代-6,7,-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸乙酯(0.10g,0.25mmol)、DMF(5mL)和碳酸钾(0.172g,1.23mmol)，加热至80℃搅拌12h。冷却至室温，饱和食盐水(20mL)洗涤，水相用二氯甲烷(20×3mL)萃取，浓缩，得标题化合物为黑褐色油状物。Add 9-hydroxy-10-bromo-6-isopropyl-2-oxo-6,7,-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylic acid ethyl ester (0.10 g, 0.25 mmol), DMF (5 mL) and potassium carbonate (0.172 g, 1.23 mmol) to the flask in sequence, heat to 80°C and stir for 12 h. Cool to room temperature, wash with saturated brine (20 mL), extract the aqueous phase with dichloromethane (20×3 mL), and concentrate to obtain the title compound as a dark brown oil.
MS(ESI,pos.ion)m/z：474.1/476.1[M+H]+。MS(ESI,pos.ion)m/z: 474.1/476.1[M+H]+ .
步骤4：9-(2-环丙乙氧基)-10-溴-6-异丙基-2-氧代-6,7,-二氢-2H-吡啶并[2,1-Step 4: 9-(2-cyclopropylethoxy)-10-bromo-6-isopropyl-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]异喹啉-3-甲酸a]Isoquinoline-3-carboxylic acid
于单口烧瓶中依次加入9-(2-环丙乙氧基)-10-溴-6-异丙基-2-氧代-6,7,-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸乙酯(0.12g,0.247mmol)，甲醇(5mL)，一水合氢氧化锂(0.06g，2mmol)室温搅拌4h。加入1M稀盐酸(5mL)，调节pH至3-4，有大量固体析出，过滤，甲醇洗涤滤饼，得标题化合物为白色固体。In a single-necked flask, add 9-(2-cyclopropylethoxy)-10-bromo-6-isopropyl-2-oxo-6,7,-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylic acid ethyl ester (0.12 g, 0.247 mmol), methanol (5 mL), and lithium hydroxide monohydrate (0.06 g, 2 mmol) in sequence and stir at room temperature for 4 hours. Add 1M dilute hydrochloric acid (5 mL) and adjust the pH to 3-4. A large amount of solid precipitates. Filter and wash the filter cake with methanol to obtain the title compound as a white solid.
MS(ESI,pos.ion)m/z：448.2[M+H]+。MS(ESI,pos.ion)m/z: 448.2[M+H]+ .
步骤5：10-溴-9-(2-环丙乙氧基)-N-(环丙磺酰基)-6-异丙基-2-氧代-6,7-二氢-Step 5: 10-bromo-9-(2-cyclopropylethoxy)-N-(cyclopropylsulfonyl)-6-isopropyl-2-oxo-6,7-dihydro-2H-吡啶并[2,1-a]异喹啉-3-甲酰胺2H-Pyrido[2,1-a]isoquinoline-3-carboxamide
于单口烧瓶中依次加入9-(2-环丙乙氧基)-10-溴-6-异丙基-2-氧代-6,7,-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸(0.4g,0.9mmol)，无水二氯甲烷(8mL)和SOCl2(8mL)，在40℃下搅拌反应2h。减压浓缩反应液，所得残留物溶解于无水二氯甲烷(4mL)中。将环丙基磺酰胺(0.17g,1.42mmol)和三乙胺(0.20mL,1.43mmol)溶在无水二氯甲烷(4mL)中，冷却至0℃，将上述浓缩的酰氯化合物的二氯甲烷溶液慢慢加入到体系中，继续搅拌反应2h，加热至40℃继续反应12h。减压浓缩溶剂，残留物经硅胶柱层析分离纯化(DCM/MeOH(V/V)＝20/1)得标题化合物为淡黄色固体(340mg,70％)。9-(2-cyclopropylethoxy)-10-bromo-6-isopropyl-2-oxo-6,7,-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylic acid (0.4 g, 0.9 mmol), anhydrous dichloromethane (8 mL) and SOCl2 (8 mL) were added to a single-necked flask in sequence, and the mixture was stirred at 40°C for 2 h. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in anhydrous dichloromethane (4 mL). Cyclopropylsulfonamide (0.17 g, 1.42 mmol) and triethylamine (0.20 mL, 1.43 mmol) were dissolved in anhydrous dichloromethane (4 mL), cooled to 0°C, and the concentrated dichloromethane solution of the acyl chloride compound was slowly added to the system, and the reaction was continued with stirring for 2 h, and heated to 40°C for 12 h. The solvent was concentrated under reduced pressure and the residue was separated and purified by silica gel column chromatography (DCM/MeOH (V/V) = 20/1) to give the title compound as a light yellow solid (340 mg, 70%).
MS(ESI,pos.ion)m/z：549.1/551.1[M+H]+。MS(ESI,pos.ion)m/z: 549.1/551.1[M+H]+ .
步骤6：9-(2-环丙乙氧基)-N-(环丙磺酰基)-6-异丙基-2-氧代-10-(2-噻唑-2-Step 6: 9-(2-cyclopropylethoxy)-N-(cyclopropylsulfonyl)-6-isopropyl-2-oxo-10-(2-thiazole-2-yl)-基)-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酰胺2H-pyrido[2,1-a]isoquinoline-3-carboxamide
将10-溴-9-(2-环丙乙氧基)-N-(环丙磺酰基)-6-异丙基-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酰胺(0.350g,0.637mmol)和PdCl2(pddf)CH2Cl2(0.090g,0.13mmol)溶于1,4-二氧六环(20mL)中，加入三丁基噻唑锡(0.358g,0.957mmol)，氮气置换3次，加热至100℃搅拌反应12h。减压浓缩溶剂，残留物经硅胶柱层析分离纯化(DCM/MeOH(V/V)＝30/1)得到标题化合物为白色固体(0.050g,14％)。10-Bromo-9-(2-cyclopropylethoxy)-N-(cyclopropylsulfonyl)-6-isopropyl-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxamide (0.350 g, 0.637 mmol) and PdCl2 (pddf)CH2 Cl2 (0.090 g, 0.13 mmol) were dissolved in 1,4-dioxane (20 mL), tributylthiazolyltin (0.358 g, 0.957 mmol) was added, nitrogen was replaced three times, and the mixture was heated to 100° C. and stirred for 12 h. The solvent was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (DCM/MeOH (V/V)=30/1) to obtain the title compound as a white solid (0.050 g, 14%).
MS(ESI,pos.ion)m/z：554.0[M+H]+；MS(ESI,pos.ion)m/z: 554.0[M+H]+ ;
1H NMR(400MHz,CDCl3)δ13.68(s,1H),8.89(s,1H),8.44(s,1H),7.95(d,J＝3.1Hz,1H),7.45(d,J＝3.2Hz,2H),6.94(s,1H),4.34(dd,J＝13.0,6.5Hz,2H),3.94–3.86(m,1H),3.41(dd,J＝16.0,4.8Hz,1H),3.18(d,J＝15.9Hz,1H),3.03(td,J＝8.2,4.1Hz,1H),1.93(dd,J＝13.4,6.7Hz,3H),1.85–1.80(m,1H),1.09(d,J＝8.0Hz,3H),0.96(d,J＝6.5Hz,3H),0.56(q,J＝5.1Hz,2H),0.20(dd,J＝9.6,4.8Hz,2H),0.90–0.70(m,4H)。1 H NMR (400MHz, CDCl3 ) δ 13.68 (s, 1H), 8.89 (s, 1H), 8.44 (s, 1H), 7.95 (d, J＝3.1Hz, 1H), 7.45 (d, J＝ 3.2Hz,2H),6.94(s,1H),4.34(dd,J＝13.0,6.5Hz,2H),3.94–3.86(m,1H),3.41(dd,J＝16.0,4.8Hz,1H), 3.18(d,J＝15.9Hz ,1H),3.03(td,J＝8.2,4.1Hz,1H),1.93(dd,J＝13.4,6.7Hz,3H),1.85–1.80(m,1H),1.09(d,J＝8.0Hz, 3H), 0.96 (d, J＝6.5Hz, 3H), 0.56 (q, J＝5.1Hz, 2H), 0.20 (dd, J＝9.6, 4.8Hz, 2H), 0.90–0.70 (m, 4H).
实施例6：N-(环丙磺酰基)-6-异丙基-9-(3-甲氧基丙氧基)-2-氧代-10-(噻唑-2-基)-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酰胺Example 6: N-(Cyclopropanesulfonyl)-6-isopropyl-9-(3-methoxypropoxy)-2-oxo-10-(thiazol-2-yl)-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxamide
以9-羟基-10-溴-6-异丙基-2-氧代-6,7,-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸乙酯和1-溴-3-甲氧基丙烷为原料，参考实施例5步骤3至步骤6的合成方法，得到标题化合物为白色固体。Using 9-hydroxy-10-bromo-6-isopropyl-2-oxo-6,7,-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylic acid ethyl ester and 1-bromo-3-methoxypropane as raw materials, refer to the synthetic method of steps 3 to 6 of Example 5 to obtain the title compound as a white solid.
MS(ESI,pos.ion)m/z：558.2[M+H]+；MS(ESI,pos.ion)m/z: 558.2[M+H]+ ;
1H NMR(400MHz,CDCl3)δ13.60(s,1H),8.85(s,1H),8.43(s,1H),7.96(d,J＝3.1Hz,1H),7.46(d,J＝3.2Hz,2H),6.91(s,1H),4.47–4.34(m,2H),3.98–3.84(m,1H),3.76–3.67(m,2H),3.52–3.35(m,4H),3.26-3.16(m,1H),2.36–2.24(m,2H),2.07–1.91(m,1H),1.85–1.80(m,1H),0.978(d,J＝6.4Hz,3H),0.847(d,J＝6.0Hz,3H),0.90–0.70(m,4H)。1 H NMR (400MHz, CDCl3 ) δ 13.60 (s, 1H), 8.85 (s, 1H), 8.43 (s, 1H), 7.96 (d, J＝3.1Hz, 1H), 7.46 (d, J＝ 3.2Hz,2H),6.91(s,1H),4.47–4.34(m,2H),3.98–3.84(m,1H),3.76–3.67(m,2H),3 .52–3.35(m,4H),3.26-3.16(m,1H),2.36–2.24(m,2H),2.07–1.91(m,1H),1.85–1.80(m,1H),0.978(d, J=6.4Hz, 3H), 0.847 (d, J=6.0Hz, 3H), 0.90–0.70 (m, 4H).
实施例7:12-(2-环丙基乙氧基)-3,3-二甲基-8-氧代-11-(噻唑-2-基)-2,3,8,13b-四氢-1H-吡啶[2,1-a]吡咯[1,2-c]邻苯二嗪-7-甲酸Example 7: 12-(2-cyclopropylethoxy)-3,3-dimethyl-8-oxo-11-(thiazol-2-yl)-2,3,8,13b-tetrahydro-1H-pyrido[2,1-a]pyrrole[1,2-c]ophthalazine-7-carboxylic acid
步骤1：2-苄氧基-4-溴苯酚Step 1: 2-Benzyloxy-4-bromophenol
反应瓶中加入2-(苄氧基)苯酚(5.0g,25mmol)，二氯甲烷(40mL)，乙酸(20mL)，冷却至0℃。将溴素(1.3mL,25mmol)溶于乙酸(15ml)，缓慢滴加到上述溶液中，滴完后继续搅拌20min。TLC检测反应完全后，反应液分别用饱和亚硫酸钠溶液(50mL)和饱和氯化钠(50mL)洗涤，减压浓缩溶剂，残留物经硅胶柱层析(PE/EA(V/V)＝10/1)纯化，得标题化合物为无色油状产物(3.6g,13mmol,52％)。Add 2-(benzyloxy)phenol (5.0g, 25mmol), dichloromethane (40mL), acetic acid (20mL) to the reaction flask and cool to 0℃. Dissolve bromine (1.3mL, 25mmol) in acetic acid (15ml) and slowly drop it into the above solution. Continue stirring for 20min after the drop is complete. After TLC detection, the reaction solution is washed with saturated sodium sulfite solution (50mL) and saturated sodium chloride (50mL) respectively, and the solvent is concentrated under reduced pressure. The residue is purified by silica gel column chromatography (PE/EA (V/V) = 10/1) to obtain the title compound as a colorless oily product (3.6g, 13mmol, 52%).
1H NMR(400MHz,CDCl3)δ7.50–7.40(m,5H),7.10(d,J＝2.0Hz,1H),7.05(dd,J＝8.5,2.1Hz,1H),6.86(d,J＝8.5Hz,1H),5.70(s,1H),5.09(s,2H)。1 H NMR (400MHz, CDCl3 ) δ7.50–7.40 (m, 5H), 7.10 (d, J = 2.0Hz, 1H), 7.05 (dd, J = 8.5, 2.1Hz, 1H), 6.86 (d, J＝8.5Hz,1H),5.70(s,1H),5.09(s,2H).
步骤2：2-(苄氧基)-4-溴-1-(2-环丙基乙氧基)苯Step 2: 2-(Benzyloxy)-4-bromo-1-(2-cyclopropylethoxy)benzene
反应瓶中加入2-苄氧基-4-溴苯酚(5.0g,18mmol)，环丙基乙基甲基磺酸酯(4.4g,27mmol)，乙腈(50mL)和碳酸钾(5.0g,36mmol)，升温回流反应6h。TLC检测反应完全，反应液加水(100mL)，乙酸乙酯萃取(100mL×2)，合并有机相，饱和氯化钠溶液(200mL)洗涤，无水硫酸钠干燥，减压蒸馏除去溶剂，所得残留物直接进行下步反应。2-Benzyloxy-4-bromophenol (5.0 g, 18 mmol), cyclopropylethyl methanesulfonate (4.4 g, 27 mmol), acetonitrile (50 mL) and potassium carbonate (5.0 g, 36 mmol) were added to the reaction flask, and the temperature was raised to reflux for 6 h. TLC detected that the reaction was complete, and the reaction solution was added with water (100 mL), extracted with ethyl acetate (100 mL × 2), and the organic phases were combined, washed with saturated sodium chloride solution (200 mL), dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was directly used for the next step reaction.
步骤3：1-(苄氧基)-5-溴-2-(2-环丙基乙氧基)-4-碘苯Step 3: 1-(Benzyloxy)-5-bromo-2-(2-cyclopropylethoxy)-4-iodobenzene
将2-(苄氧基)-4-溴-1-(2-环丙基乙氧基)苯(3.7g,11mmol)溶于甲醇(55mL)中，加入硫酸银(3.7g,12mmol)和碘单质(3.0g,12mmol)，室温搅拌6h。TLC检测反应完全，滤液浓缩，残留物经硅胶柱层析(PE/EA(V/V)＝15/1)纯化，得标题化合物为浅黄色油状产物(4.0g,8.5mmol,79％)。Dissolve 2-(Benzyloxy)-4-bromo-1-(2-cyclopropylethoxy)benzene (3.7 g, 11 mmol) in methanol (55 mL), add silver sulfate (3.7 g, 12 mmol) and iodine (3.0 g, 12 mmol), and stir at room temperature for 6 hours. The reaction is complete after TLC detection, the filtrate is concentrated, and the residue is purified by silica gel column chromatography (PE/EA (V/V) = 15/1) to obtain the title compound as a light yellow oily product (4.0 g, 8.5 mmol, 79%).
1H NMR(600MHz,CDCl3)δ7.48–7.30(m,6H),7.17(s,1H),5.10(s,2H),4.07(t,J＝6.7Hz,2H),1.74(q,J＝6.8Hz,2H),0.90–0.77(m,1H),0.62–0.42(m,2H),0.15(d,J＝5.2Hz,2H)。1 H NMR (600MHz, CDCl3 ) δ7.48–7.30 (m, 6H), 7.17 (s, 1H), 5.10 (s, 2H), 4.07 (t, J = 6.7Hz, 2H), 1.74 (q, J＝6.8Hz,2H),0.90–0.77(m,1H),0.62–0.42(m,2H),0.15(d,J＝5.2Hz,2H).
步骤4：5-(4-(4-苯氧基)-2-溴-5-(2-环丙乙氧基)苯基-2.2-二甲基吡咯烷-1-醇Step 4: 5-(4-(4-phenoxy)-2-bromo-5-(2-cyclopropylethoxy)phenyl-2,2-dimethylpyrrolidin-1-ol
将2-(苄氧基)-4-溴-1-(2-环丙基乙氧基)苯(4.4g,9.3mmol)溶解于四氢呋喃(45mL)中，氮气保护下，冷却至-20℃。缓慢滴加异丙基氯化镁的THF溶液(6mL,12mmol,2.0mol/L)，滴完后继续搅拌15min。加入5,5-二甲基-1-吡咯啉-N-氧化物(1.3g,11mmol)，加完继续搅拌15min。LC-MS检测反应完全。向反应液中加入饱和氯化铵溶液(100mL)淬灭，乙酸乙酯萃取(100mL×2)，合并有机相，用饱和氯化钠洗涤(100mL)，减压浓缩，残留物经硅胶柱层析(PE/EA(V/V)＝10/1)纯化，得标题化合物为白色固体产物(3.0g,6.5mmol,70％)。Dissolve 2-(Benzyloxy)-4-bromo-1-(2-cyclopropylethoxy)benzene (4.4 g, 9.3 mmol) in tetrahydrofuran (45 mL) and cool to -20°C under nitrogen protection. Slowly add isopropylmagnesium chloride in THF solution (6 mL, 12 mmol, 2.0 mol/L) dropwise, and continue stirring for 15 min after the addition. Add 5,5-dimethyl-1-pyrroline-N-oxide (1.3 g, 11 mmol) and continue stirring for 15 min after the addition. LC-MS detection shows that the reaction is complete. Add saturated ammonium chloride solution (100 mL) to the reaction solution for quenching, extract with ethyl acetate (100 mL×2), combine the organic phases, wash with saturated sodium chloride (100 mL), and concentrate under reduced pressure. The residue is purified by silica gel column chromatography (PE/EA (V/V)＝10/1) to obtain the title compound as a white solid product (3.0 g, 6.5 mmol, 70%).
MS(ESI,pos.ion)m/z：460.2[M+H]+。MS(ESI,pos.ion)m/z: 460.2[M+H]+ .
步骤5：5-(4-(苄氧基)-2-溴-5-(2-环丙基乙氧基)苯基)-2,2-二甲基吡咯烷Step 5: 5-(4-(Benzyloxy)-2-bromo-5-(2-cyclopropylethoxy)phenyl)-2,2-dimethylpyrrolidine
反应瓶中加入5-(4-(4-苯氧基)-2-溴-5-(2-环丙乙氧基)苯基-2-二甲基吡咯烷-1-醇(3.5g,7.6mmol)，甲醇(20mL)和冰乙酸(20mL)，冰浴下加入加锌粉(10g,153mmol)，加完后升温至60℃反应3h。反应液过滤，滤液浓缩，残余物中加入100mL水，用碳酸钾调pH＝8-9，乙酸乙酯萃取(50mL×2)，合并有机相，用饱和氯化钠洗涤(50mL)，无水硫酸钠干燥，旋干溶剂直接进行下步反应。5-(4-(4-phenoxy)-2-bromo-5-(2-cyclopropylethoxy)phenyl-2-dimethylpyrrolidin-1-ol (3.5 g, 7.6 mmol), methanol (20 mL) and glacial acetic acid (20 mL) were added to the reaction flask, and zinc powder (10 g, 153 mmol) was added under ice bath. After the addition, the temperature was raised to 60 ° C and reacted for 3 h. The reaction solution was filtered, the filtrate was concentrated, 100 mL of water was added to the residue, the pH was adjusted to 8-9 with potassium carbonate, and extracted with ethyl acetate (50 mL × 2), the organic phases were combined, washed with saturated sodium chloride (50 mL), dried over anhydrous sodium sulfate, and the solvent was directly dried to proceed to the next step.
MS:(ESI,pos.ion)m/z:444.1/446.1[M+H]+。MS:(ESI,pos.ion)m/z:444.1/446.1[M+H]+ .
步骤6：5-(4-(苄氧基)-2-溴-3-(2-环丙基乙氧基)苯基)-2,2-二甲基-1-亚硝基Step 6: 5-(4-(Benzyloxy)-2-bromo-3-(2-cyclopropylethoxy)phenyl)-2,2-dimethyl-1-nitroso吡咯烷Pyrrolidine
反应瓶中加入5-(4-(苄氧基)-3-(2-环丙基乙氧基)苯基)-2,2-二甲基吡咯烷(2.5g,5.6mmol)和四氢呋喃(20mL)，将亚硝酸钠(0.97g,14mmol)溶于水(1mL)中，加入到上述溶液中，再加入冰乙酸(0.85g,14mmol)，加完后升温至50℃反应1h。LC-MS检测反应完全，反应液加压蒸去溶剂，残余物加入乙酸乙酯(100mL)溶解，用饱和氯化钠洗涤(100mL)，无水硫酸钠干燥，旋干溶剂，所得残留物直接进行下步反应。5-(4-(Benzyloxy)-3-(2-cyclopropylethoxy)phenyl)-2,2-dimethylpyrrolidine (2.5 g, 5.6 mmol) and tetrahydrofuran (20 mL) were added to the reaction flask, sodium nitrite (0.97 g, 14 mmol) was dissolved in water (1 mL), added to the above solution, and then glacial acetic acid (0.85 g, 14 mmol) was added. After the addition, the temperature was raised to 50°C and reacted for 1 h. LC-MS detected that the reaction was complete, the reaction solution was pressurized to evaporate the solvent, and the residue was dissolved in ethyl acetate (100 mL), washed with saturated sodium chloride (100 mL), dried over anhydrous sodium sulfate, and the solvent was spin-dried. The residue was directly used for the next step reaction.
MS:(ESI,pos.ion)m/z:473.1[M+H]+。MS:(ESI,pos.ion)m/z:473.1[M+H]+ .
步骤8：1-(5-(4-(苄氧基)-2-溴-5-(2-环丙基乙氧基)苯基)-2,2-二甲基吡咯烷-Step 8: 1-(5-(4-(Benzyloxy)-2-bromo-5-(2-cyclopropylethoxy)phenyl)-2,2-dimethylpyrrolidine-1-基)-4-氧代-1,4-二氢吡啶-3-甲酸乙酯1-yl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid ethyl ester
反应瓶中加入5-(4-(苄氧基)-2-溴-3-(2-环丙基乙氧基)苯基)-2,2-二甲基-1-亚硝基吡咯(2.7g,5.9mmol)，三氟乙酸(20mL,261mmol)和乙醇(10mL)，冰浴下加入锌粉(1.9g,30mmol)，升温至50℃反应1h。LC-MS检测反应完全，反应液过滤，滤液减压蒸馏除去溶剂，向残余物中加入乙醇(25mL)和4-氧代-4H-吡喃-3-甲酸乙酯(1g,5.9mmol)，升温回流反应4h。反应液减压蒸去溶剂，残余物加入乙酸乙酯(50mL)溶解，依次用1M HCl(50mL)，饱和碳酸氢钠(50mL)和饱和氯化钠(50mL)洗涤，减压浓缩有机相，残留物经硅胶柱层析(DCM/MeOH(V/V)＝10/1)纯化，得标题化合物为棕色固体产物(3.4g,5.6mmol,95％)。5-(4-(Benzyloxy)-2-bromo-3-(2-cyclopropylethoxy)phenyl)-2,2-dimethyl-1-nitrosopyrrole (2.7 g, 5.9 mmol), trifluoroacetic acid (20 mL, 261 mmol) and ethanol (10 mL) were added to the reaction flask, and zinc powder (1.9 g, 30 mmol) was added under ice bath, and the temperature was raised to 50°C for reaction for 1 h. LC-MS detected that the reaction was complete, the reaction solution was filtered, and the filtrate was distilled under reduced pressure to remove the solvent, and ethanol (25 mL) and ethyl 4-oxo-4H-pyran-3-carboxylate (1 g, 5.9 mmol) were added to the residue, and the temperature was raised to reflux for reaction for 4 h. The reaction solution was evaporated under reduced pressure to remove the solvent, and the residue was dissolved in ethyl acetate (50 mL), washed with 1M HCl (50 mL), saturated sodium bicarbonate (50 mL) and saturated sodium chloride (50 mL) in sequence. The organic phase was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (DCM/MeOH (V/V) = 10/1) to give the title compound as a brown solid product (3.4 g, 5.6 mmol, 95%).
MS:(ESI,pos.ion)m/z：609.1/611.1[M+H]+。MS: (ESI,pos.ion)m/z: 609.1/611.1[M+H]+ .
步骤9：12-(2-环丙基乙氧基)-3,3-二甲基-8-氧代-11-(噻唑-2-基)-2,3,8,13b-Step 9: 12-(2-cyclopropylethoxy)-3,3-dimethyl-8-oxo-11-(thiazol-2-yl)-2,3,8,13b-四氢-1H-吡啶[2,1-a]吡咯[1,2-c]邻苯二嗪-7-甲酸Tetrahydro-1H-pyrido[2,1-a]pyrrolo[1,2-c]phthalazine-7-carboxylic acid
以1-(5-(4-(苄氧基)-2-溴-5-(2-环丙基乙氧基)苯基)-2,2-二甲基吡咯烷-1-基)-4-氧代-1,4-二氢吡啶-3-甲酸乙酯为原料，参考实施2步骤12至步骤16的合成方法，得标题化合物白色固体。Using 1-(5-(4-(benzyloxy)-2-bromo-5-(2-cyclopropylethoxy)phenyl)-2,2-dimethylpyrrolidin-1-yl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid ethyl ester as raw material, refer to the synthetic method of step 12 to step 16 of implementation 2 to obtain the title compound as a white solid.
MS:(ESI,pos.ion)m/z：478.3[M+H]+；MS: (ESI,pos.ion)m/z: 478.3[M+H]+ ;
1H NMR(400MHz,CDCl3)δ16.10(s,1H),8.92(s,1H),8.52(s,1H),7.95(d,J＝3.2Hz,1H),7.48(d,J＝3.2Hz,1H),7.29(s,1H),6.98(s,1H),4.89(d,J＝6.0Hz,1H),4.42–4.29(m,2H),2.62–2.42(m,2H),1.99–1.88(m,3H),1.71–1.64(m,1H),1.39(s,3H),1.10–0.98(m,1H),0.69(s,3H),0.61–0.53(m,2H),0.21(d,J＝4.7Hz,2H)。1 H NMR (400 MHz, CDCl3 )δ16.10(s,1H),8.92(s,1H),8.52(s,1H),7.95(d,J＝3.2Hz,1H),7.48(d,J＝3.2Hz,1H),7.29(s,1H),6.98(s,1H),4.89(d,J＝6.0Hz,1H),4.42–4.29( m,2H),2.62–2.42(m,2H),1.99–1.88(m,3H),1.71–1.64(m,1H),1.39(s,3H),1.10–0.98(m,1H),0.69(s,3H),0.61–0.53(m,2H),0.21(d,J＝4.7Hz ,2H).
实施例8:6-异丙基-9-(3-甲氧基丙氧基)-2-氧代-10-(噻唑-2-基)-6,7-二氢-2H-吡啶并[2,1-a]酞嗪-3-甲酸Example 8: 6-isopropyl-9-(3-methoxypropoxy)-2-oxo-10-(thiazol-2-yl)-6,7-dihydro-2H-pyrido[2,1-a]phthalazine-3-carboxylic acid
以4-苄氧基-3-羟基苯甲醛和1-溴-3-甲氧基丙烷为原料，参考实施例2的合成步骤2至步骤16的合成方法，得到标题化合物为白色固体。Using 4-benzyloxy-3-hydroxybenzaldehyde and 1-bromo-3-methoxypropane as raw materials, and referring to the synthesis method of steps 2 to 16 of Example 2, the title compound was obtained as a white solid.
MS:(ESI,pos.ion)m/z：456.3[M+H]+；MS: (ESI,pos.ion)m/z: 456.3[M+H]+ ;
1H NMR(400MHz,CDCl3)δ15.92(s,1H),8.96(s,1H),8.62(s,1H),7.95(d,J＝2.9Hz,1H),7.51(d,J＝2.9Hz,1H),7.28(s,1H),6.99(s,1H),4.23(t,J＝6.4Hz,2H),3.58(t,J＝5.9Hz,3H),3.45(s,1H),3.34(s,3H),3.02–2.94(m,1H),2.18–2.12(m,2H),1.02(s,6H)。1 H NMR (400MHz, CDCl3 ) δ15.92(s,1H),8.96(s,1H),8.62(s,1H),7.95(d,J＝2.9Hz,1H),7.51(d,J＝ 2.9Hz,1H),7.28(s,1H),6.99(s,1H),4.23(t,J＝6.4Hz,2H),3.58(t,J＝5.9Hz,3H),3.45(s,1H) ,3.34(s,3H),3.02–2.94(m,1H),2.18–2.12(m,2H),1.02(s,6H).
实施例9:9-(2-环丙基乙氧基)-6-异丁基-2-氧代-10-(噻唑-2-基)-6,7-二氢-2H-吡啶并[2,1-a]酞嗪-3-甲酸Example 9: 9-(2-cyclopropylethoxy)-6-isobutyl-2-oxo-10-(thiazol-2-yl)-6,7-dihydro-2H-pyrido[2,1-a]phthalazine-3-carboxylic acid
以1-((叔丁氧羰基)氨基)-4-氧代-1,4-二氢吡啶-3-甲酸叔丁酯和1-溴-2-甲基丙烷为原料，参考实施例2步骤9至步骤16的合成方法，得标题化合物为白色固体。Using tert-butyl 1-((tert-butyloxycarbonyl)amino)-4-oxo-1,4-dihydropyridine-3-carboxylate and 1-bromo-2-methylpropane as raw materials, and referring to the synthetic method of steps 9 to 16 of Example 2, the title compound was obtained as a white solid.
MS:(ESI,pos.ion)m/z：466.1[M+H]+；MS: (ESI,pos.ion)m/z: 466.1[M+H]+ ;
1H NMR(400MHz,CDCl3/CD3OD)δ8.904(s,1H),8.616(s,1H),7.954(d,J＝1.6Hz,1H),7.568(d,J＝1.2Hz,1H),7.332(s,1H),7.100(s,1H),4.124–3.969(m,1H),3.333(m,4H),2.652–2.546(m,2H),1.953–1.899(m,1H),0.985(d,J＝4.4Hz,6H),0.897–0.831(m,2H),0.581–0.495(m,2H),0.218–0.149(m,2H)。1 H NMR (400MHz, CDCl3 /CD3 OD) δ8.904 (s, 1H), 8.616 (s, 1H), 7.954 (d, J = 1.6Hz, 1H), 7.568 (d, J = 1.2Hz, 1H),7.332(s,1H),7.100(s,1H),4.124–3.969(m,1H),3.333(m,4H),2.652–2.546(m,2H),1.953–1.899(m,1H) ,0.985(d,J＝4.4Hz,6H),0.897–0.831(m,2H),0.581–0.495(m,2H),0.218–0.149(m,2H).
实施例10:3-(2-环丙基乙氧基)-6-异丙基-10-氧代-2-(噻唑-2-基)-6,10-二氢-5H-吡啶并[2,1-f][1,6]萘啶-9-甲酸Example 10: 3-(2-cyclopropylethoxy)-6-isopropyl-10-oxo-2-(thiazol-2-yl)-6,10-dihydro-5H-pyrido[2,1-f][1,6]naphthyridine-9-carboxylic acid
步骤1：2-溴-6-碘吡啶-3-醇Step 1: 2-Bromo-6-iodopyridin-3-ol
向单口烧瓶依次加入2-溴吡啶-3-醇(20g,114.94mmol)、碳酸钾(32g,231.8841mmol)和水(200mL)，然后加入碘(32g,126.08mmol)，室温搅拌8h，减压蒸馏反应溶液，加入1M盐酸调节pH＝6.5，乙酸乙酯萃取(50mL×3)，合并有机相，饱和硫代硫酸钠溶液(50mL)洗涤,无水硫酸钠干燥，过滤，减压浓缩滤液，得标题化合物为白色固体(35.86g,119.6mmol,104.0％)。To a single-necked flask, 2-bromopyridin-3-ol (20 g, 114.94 mmol), potassium carbonate (32 g, 231.8841 mmol) and water (200 mL) were added in sequence, and then iodine (32 g, 126.08 mmol) was added. The mixture was stirred at room temperature for 8 h, and the reaction solution was distilled under reduced pressure. 1 M hydrochloric acid was added to adjust the pH to 6.5, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated sodium thiosulfate solution (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound as a white solid (35.86 g, 119.6 mmol, 104.0%).
1H NMR(600MHz,CDCl3)δ8.01(s,1H),7.58(d,J＝8.2Hz,1H),7.01(d,J＝8.2Hz,1H)。1 H NMR (600MHz, CDCl3 ) δ 8.01 (s, 1H), 7.58 (d, J = 8.2 Hz, 1H), 7.01 (d, J = 8.2 Hz, 1H).
步骤2：3-(苄氧基)-2-溴-6-碘吡啶Step 2: 3-(Benzyloxy)-2-bromo-6-iodopyridine
取单口烧瓶依次加入2-溴-6-碘吡啶-3-醇(35g,116.71mmol)、乙腈(300mL)、碳酸钾(32g,231.88mmol)和苄溴(14.6mL,123mmol)，加热至50℃搅拌4h,后处理：过滤除去固体，减压浓缩滤液，残留物经硅胶柱层析分离(PE/EA(V/V)＝100/1)，得标题化合物为白色固体(32g,82.05mmol,70.3％)Take a single-necked flask and add 2-bromo-6-iodopyridin-3-ol (35 g, 116.71 mmol), acetonitrile (300 mL), potassium carbonate (32 g, 231.88 mmol) and benzyl bromide (14.6 mL, 123 mmol) in sequence, heat to 50 ° C and stir for 4 hours. Post-treatment: filter to remove the solid, concentrate the filtrate under reduced pressure, and separate the residue by silica gel column chromatography (PE/EA (V/V) = 100/1) to obtain the title compound as a white solid (32 g, 82.05 mmol, 70.3%)
1H NMR(600MHz,CDCl3)δ7.55(d,J＝8.3Hz,1H),7.46–7.35(m,5H),6.87(d,J＝8.3Hz,2H)。1 H NMR (600MHz, CDCl3 ) δ7.55 (d, J = 8.3 Hz, 1H), 7.46–7.35 (m, 5H), 6.87 (d, J = 8.3 Hz, 2H).
步骤3：3-(苄氧基)-2-(2-环丙基乙氧基)-6-碘吡啶Step 3: 3-(Benzyloxy)-2-(2-cyclopropylethoxy)-6-iodopyridine
向单口烧瓶依次加入2-环丙基乙醇(2.4g,28mmol)和DMF(30mL)。冷却至0℃，加入钠氢(1.3g,33mmol)，室温搅拌20min，加入3-(苄氧基)-2-溴-6-碘吡啶(10g,25.640mmol)，加热至100℃搅拌12h。后处理：加入水(50mL)淬灭反应，乙酸乙酯萃取(20mL×3)，合并有机相，饱和食盐水洗涤(50mL×3)无水硫酸钠干燥，过滤，减压浓缩滤液，残留物经硅胶柱层析分离(PE/EA(V/V)＝2/1)，得标题化合物为无色油状物(6.8g,17mmol,67％)。Add 2-cyclopropylethanol (2.4 g, 28 mmol) and DMF (30 mL) to a single-necked flask. Cool to 0°C, add sodium hydrogen (1.3 g, 33 mmol), stir at room temperature for 20 min, add 3-(benzyloxy)-2-bromo-6-iodopyridine (10 g, 25.640 mmol), heat to 100°C and stir for 12 h. Post-treatment: add water (50 mL) to quench the reaction, extract with ethyl acetate (20 mL × 3), combine the organic phases, wash with saturated brine (50 mL × 3), dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and separate the residue by silica gel column chromatography (PE/EA (V/V) = 2/1) to obtain the title compound as a colorless oil (6.8 g, 17 mmol, 67%).
1H NMR(400MHz,CDCl3)δ7.44–7.31(m,5H),7.14(d,J＝7.9Hz,1H),6.74(d,J＝7.9Hz,1H),5.13(s,2H),4.46(t,J＝6.8Hz,2H),1.74(q,J＝6.9Hz,2H),0.93–0.78(m,1H),0.50(q,J＝5.0Hz,2H),0.16(q,J＝4.9Hz,2H)。1 H NMR (400MHz, CDCl3 ) δ7.44–7.31(m,5H),7.14(d,J＝7.9Hz,1H),6.74(d,J＝7.9Hz,1H),5.13(s,2H) ,4.46(t,J＝6.8Hz,2H),1.74(q,J＝6.9Hz,2H),0.93–0.78(m,1H),0.50(q,J＝5.0Hz,2H),0.16(q, J=4.9Hz,2H).
步骤4：1-(5-(苄氧基)-6-(2-环丙基乙氧基)吡啶-2-基)-3-甲基丁烷-2-酮Step 4: 1-(5-(Benzyloxy)-6-(2-cyclopropylethoxy)pyridin-2-yl)-3-methylbutan-2-one
向单口烧瓶依次加入叔丁醇钠(3.3g,34mmol)、Xantphos(1.0g,1.7mmol)和Pd2(dba)3(1.6g,1.7mmol)，氮气置换三次，加入3-(苄氧基)-2-(2-环丙基乙氧基)-6-碘吡啶(6.8g,17mmol)的THF(67mL)溶液和3-甲基丁烷-2-酮(3.7mL,34mmol)加热至50℃搅拌2h。后处理：减压浓缩，残留物经硅胶柱层析分离(PE/EA(V/V)＝2/1)，得标题化合物为无色油状物(4.9g,14mmol,81％)。Sodium tert-butoxide (3.3 g, 34 mmol), Xantphos (1.0 g, 1.7 mmol) and Pd2 (dba)3 (1.6 g, 1.7 mmol) were added to a single-necked flask in sequence, the atmosphere was replaced with nitrogen three times, a THF (67 mL) solution of 3-(benzyloxy)-2-(2-cyclopropylethoxy)-6-iodopyridine (6.8 g, 17 mmol) and 3-methylbutane-2-one (3.7 mL, 34 mmol) were added, and the mixture was heated to 50°C and stirred for 2 h. Post-treatment: the mixture was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (PE/EA (V/V) = 2/1) to obtain the title compound as a colorless oil (4.9 g, 14 mmol, 81%).
MS:(ESI,pos.ion)m/z：354.2[M+H]+。MS: (ESI,pos.ion)m/z: 354.2[M+H]+ .
步骤5：1-(5-(苄氧基)-6-(2-环丙基乙氧基)吡啶-2-基)-3-甲基丁烷-2-胺Step 5: 1-(5-(Benzyloxy)-6-(2-cyclopropylethoxy)pyridin-2-yl)-3-methylbutan-2-amine
向单口烧瓶依次加入1-(5-(苄氧基)-6-(2-环丙基乙氧基)吡啶-2-基)-3-甲基丁烷-2-酮(4.9g,14mmol)，甲醇(50mL)和乙酸铵(7.54g,97.8mmol)，室温搅拌30min，冷却至0℃，搅拌30min。加入氰基硼氢化钠(1.7g,27mmol)，升温至室温搅拌12h。后处理：加入饱和碳酸钠溶液50mL淬灭反应，DCM萃取(3×50mL)，合并有机相，无水硫酸钠干燥，过滤，减压浓缩滤液，得标题化合物为无色油状物(4.9g,14mmol,100％)，直接用于下一步反应。Add 1-(5-(benzyloxy)-6-(2-cyclopropylethoxy)pyridin-2-yl)-3-methylbutan-2-one (4.9 g, 14 mmol), methanol (50 mL) and ammonium acetate (7.54 g, 97.8 mmol) to a single-necked flask, stir at room temperature for 30 min, cool to 0 ° C, and stir for 30 min. Add sodium cyanoborohydride (1.7 g, 27 mmol), warm to room temperature and stir for 12 h. Post-treatment: add 50 mL of saturated sodium carbonate solution to quench the reaction, extract with DCM (3×50 mL), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the title compound as a colorless oil (4.9 g, 14 mmol, 100%), which is directly used in the next step.
MS(ESI,pos.ion)m/z:355.3[M+H]+。MS(ESI,pos.ion)m/z:355.3[M+H]+ .
步骤6：(1-(5-(苄氧基)-6-(2-环丙基乙氧基)-吡啶-2-基)-3-甲基丁烷-2-基)甲Step 6: (1-(5-(Benzyloxy)-6-(2-cyclopropylethoxy)-pyridin-2-yl)-3-methylbutan-2-yl)methyl酸叔丁酯Tert-butyl ester
向单口烧瓶依次加入1-(5-(苄氧基)-6-(2-环丙基乙氧基)吡啶-2-基)-3-甲基丁烷-2-胺(4.9g,14mmol)，DCM(50mL)，TEA(3.8mL,27mmol)和Boc2O(3.6g,17mmol)，室温搅拌2h.后处理：加入1M盐酸(50mL)淬灭反应，DCM萃取(50mL×3)，合并有机相，无水硫酸钠干燥，过滤，减压浓缩滤液，残留物经硅胶柱层析分离(PE/EA(V/V)＝5/1)纯化，得标题化合物为白色固体产物(4.6g,10mmol,73％)。To a single-necked flask were added 1-(5-(benzyloxy)-6-(2-cyclopropylethoxy)pyridin-2-yl)-3-methylbutan-2-amine (4.9 g, 14 mmol), DCM (50 mL), TEA (3.8 mL, 27 mmol) and Boc2 O (3.6 g, 17 mmol) in sequence and stirred at room temperature for 2 h. Post-treatment: 1 M hydrochloric acid (50 mL) was added to quench the reaction, and DCM was used for extraction (50 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE/EA (V/V)=5/1) to give the title compound as a white solid product (4.6 g, 10 mmol, 73%).
步骤7：(1-(5-(苄氧基)-3-溴-6-(2-环丙基乙氧基)吡啶-2-基)-3-甲基丁烷-2-Step 7: (1-(5-(Benzyloxy)-3-bromo-6-(2-cyclopropylethoxy)pyridin-2-yl)-3-methylbutane-2-yl基)甲酸叔丁酯tert-Butyl formate
向单口烧瓶依次加入(1-(5-(苄氧基)-6-(2-环丙基乙氧基)吡啶-2-基)-3-甲基丁烷-2-基)甲酸叔丁酯(500mg,1.100mmol)，乙腈(10mL)和NBS(215mg,1.21mmol)，室温搅拌3h，加入水(20mL)淬灭反应，乙酸乙酯萃取(20mL×3)，合并有机相，无水硫酸钠干燥，过滤，减压浓缩滤液，残留物经硅胶柱层析分离(PE/EA(V/V)＝5/1)，得标题化合物为白色固体产物(492mg,0.92mmol,83.9％)。To a single-necked flask was added tert-butyl (1-(5-(benzyloxy)-6-(2-cyclopropylethoxy)pyridin-2-yl)-3-methylbutan-2-yl)carboxylate (500 mg, 1.100 mmol), acetonitrile (10 mL) and NBS (215 mg, 1.21 mmol) in sequence, and the mixture was stirred at room temperature for 3 h. Water (20 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (20 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by silica gel column chromatography (PE/EA (V/V)=5/1) to give the title compound as a white solid product (492 mg, 0.92 mmol, 83.9%).
MS:(ESI,pos.ion)m/z：533.1/535.1[M+H]+。MS: (ESI,pos.ion)m/z: 533.1/535.1[M+H]+ .
步骤8：(1-(5-(苄氧基)-6-(2-环丙基乙氧基)-3-甲酰基吡啶-2-基)-3-甲基丁Step 8: (1-(5-(Benzyloxy)-6-(2-cyclopropylethoxy)-3-formylpyridin-2-yl)-3-methylbutane烷-2-基)甲酸叔丁酯tert-Butyl 2-( ...
将(1-(5-(苄氧基)-3-溴-6-(2-环丙基乙氧基)吡啶-2-基)-3-甲基丁烷-2-基)甲酸叔丁酯(490mg,0.92mmol)溶解于THF(10mL)中，冷却至-78℃，加入甲基锂(0.7mL,1mmol)，搅拌15min，加入正丁基锂(0.5mL,1mmol)，搅拌45min，加入DMF(0.3mL,4mmol)，搅拌30min，加入甲醇(3mL)，升温至室温，后处理：加入饱和氯化铵溶液淬灭反应，乙酸乙酯萃取(20mL×3)，合并有机相，无水硫酸钠干燥，过滤，减压浓缩滤液，残留物经硅胶柱层析分离(PE/EA(V/V)＝10/1)纯化，得标题化合物为白色固体产物(164mg,0.34mmol,37.0％)。Dissolve tert-butyl (1-(5-(benzyloxy)-3-bromo-6-(2-cyclopropylethoxy)pyridin-2-yl)-3-methylbutan-2-yl)formate (490 mg, 0.92 mmol) in THF (10 mL), cool to -78°C, add methyl lithium (0.7 mL, 1 mmol), stir for 15 min, add n-butyl lithium (0.5 mL, 1 mmol), stir for 45 min, add DMF (0.3 mL, 4 mmol), stir for 30 min, add methanol (3 mL), warm to room temperature, post-treatment: add saturated ammonium chloride solution to quench the reaction, extract with ethyl acetate (20 mL×3), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The residue is purified by silica gel column chromatography (PE/EA (V/V)=10/1) to obtain the title compound as a white solid product (164 mg, 0.34 mmol, 37.0%).
MS:(ESI,pos.ion)m/z:483.4[M+H]+。MS:(ESI,pos.ion)m/z:483.4[M+H]+ .
步骤9：3-(苄氧基)-2-(2-环丙基乙氧基)-7-异丙基-7,8-二氢-1,6-萘啶Step 9: 3-(Benzyloxy)-2-(2-cyclopropylethoxy)-7-isopropyl-7,8-dihydro-1,6-naphthyridine
取单口烧瓶依次加入(1-(5-(苄氧基)-6-(2-环丙基乙氧基)-3-甲酰基吡啶-2-基)-3-甲基丁烷-2-基)甲酸叔丁酯(100mg,0.21mmol)、TFA(1mL)和DCM(1mL)，室温搅拌3h。后处理：加入饱和碳酸氢钠溶液调节pH＝7，乙酸乙酯萃取(20mL×3)，合并有机相，无水硫酸钠干燥，过滤，减压浓缩滤液，得标题化合物为白色固体产物(93mg,0.25mmol,123.1％)Take a single-necked flask and add tert-butyl (1-(5-(benzyloxy)-6-(2-cyclopropylethoxy)-3-formylpyridin-2-yl)-3-methylbutan-2-yl)formate (100 mg, 0.21 mmol), TFA (1 mL) and DCM (1 mL) in sequence, and stir at room temperature for 3 hours. Post-treatment: add saturated sodium bicarbonate solution to adjust pH = 7, extract with ethyl acetate (20 mL × 3), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the title compound as a white solid product (93 mg, 0.25 mmol, 123.1%)
MS(ESI,pos.ion)m/z：365.3[M+H]+。MS(ESI,pos.ion)m/z: 365.3[M+H]+ .
步骤10：2-(苄氧基)-3-(2-环丙基乙氧基)-6-异丙基-10-氧代-6,10-二氢-5H-吡Step 10: 2-(Benzyloxy)-3-(2-cyclopropylethoxy)-6-isopropyl-10-oxo-6,10-dihydro-5H-pyrrolidone啶并[2,1-f][1,6]萘啶-9-甲酸乙酯Ethyl pyrido[2,1-f][1,6]naphthyridine-9-carboxylate
取单口烧瓶依次加入3-(苄氧基)-2-(2-环丙基乙氧基)-7-异丙基-7,8-二氢-1,6-萘啶(1g,2.74mmol)、2-甲基四氢呋喃(1mL)、水(6mL)、2-(乙氧基亚甲基)-3-氧代丁酸乙酯(1.5g,8.1mmol)和氯化钠(1g)，加热至70℃,后处理：加入水(20mL)，乙酸乙酯萃取(20mL×3)，合并有机相，无水硫酸钠干燥，过滤，减压浓缩滤液。向残留物中加入DME(10mL)和四氯苯醌(1.4g,5.7mmol)，加热至80℃搅拌1h。后处理：减压浓缩，残留物经硅胶柱层析分离(PE/EA(V/V)＝2/1)，得标题化合物为黑色油状产物(1.2g,2.4mmol,86％)。Take a single-necked flask and add 3-(benzyloxy)-2-(2-cyclopropylethoxy)-7-isopropyl-7,8-dihydro-1,6-naphthyridine (1g, 2.74mmol), 2-methyltetrahydrofuran (1mL), water (6mL), ethyl 2-(ethoxymethylene)-3-oxobutanoate (1.5g, 8.1mmol) and sodium chloride (1g) in sequence, and heat to 70℃. Post-treatment: add water (20mL), extract with ethyl acetate (20mL×3), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. Add DME (10mL) and tetrachlorobenzoquinone (1.4g, 5.7mmol) to the residue, heat to 80℃ and stir for 1h. Post-treatment: concentrate under reduced pressure, and separate the residue by silica gel column chromatography (PE/EA (V/V)＝2/1) to obtain the title compound as a black oily product (1.2g, 2.4mmol, 86%).
MS:(ESI,pos.ion)m/z：505.2[M+H]+。MS: (ESI,pos.ion)m/z: 505.2[M+H]+ .
步骤11：3-(2-环丙基乙氧基)-2-羟基-6-异丙基-10-氧代-6,10-二氢-5H-吡啶并Step 11: 3-(2-cyclopropylethoxy)-2-hydroxy-6-isopropyl-10-oxo-6,10-dihydro-5H-pyrido[2,1-f][1,6]萘啶-9-甲酸乙酯[2,1-f][1,6]naphthyridine-9-carboxylic acid ethyl ester
取单口烧瓶依次加入2-(苄氧基)-3-(2-环丙基乙氧基)-6-异丙基-10-氧代-6,10-二氢-5H-吡啶并[2,1-f][1,6]萘啶-9-甲酸乙酯(1.2g,2.4mmol)、甲醇(10mL)和钯碳(0.25g,0.24mmol)，氢气置换三次后，室温搅拌12h。后处理：通过硅藻土过滤，减压浓缩滤液，得标题化合物为褐色油状产物(1g,2.424mmol,100％)，直接用于下一步反应。Take a single-necked flask and add 2-(benzyloxy)-3-(2-cyclopropylethoxy)-6-isopropyl-10-oxo-6,10-dihydro-5H-pyrido[2,1-f][1,6]naphthyridine-9-carboxylic acid ethyl ester (1.2 g, 2.4 mmol), methanol (10 mL) and palladium carbon (0.25 g, 0.24 mmol) in sequence. After hydrogen replacement three times, stir at room temperature for 12 hours. Post-treatment: filter through diatomaceous earth, concentrate the filtrate under reduced pressure, and obtain the title compound as a brown oily product (1 g, 2.424 mmol, 100%), which is directly used in the next step reaction.
步骤12：3-(2-环丙基乙氧基)-6-异丙基-10-氧代-2-(((三氟甲基)磺酰基)氧Step 12: 3-(2-cyclopropylethoxy)-6-isopropyl-10-oxo-2-(((trifluoromethyl)sulfonyl)oxy代)-6,10-二氢-5H-吡啶并[2,1-f][1,6]萘啶-9-甲酸乙酯(substituted)-6,10-dihydro-5H-pyrido[2,1-f][1,6]naphthyridine-9-carboxylic acid ethyl ester
向单口烧瓶依次加入3-(2-环丙基乙氧基)-2-羟基-6-异丙基-10-氧代-6,10-二氢-5H-吡啶并[2,1-f][1,6]萘啶-9-甲酸乙酯(1g,2.424mmol)，三乙胺(0.7mL,5mmol)和DCM(20mL)，冷却至0℃，分批加入N-苯基双(三氟甲烷磺酰)亚胺(1g,2.7992mmol)，移至室温搅拌24h。后处理：用氯化钠溶液(20mL)洗涤分液，无水硫酸钠干燥，旋干溶剂。所得残留物经硅胶柱层析(MeOH/DCM(V/V)＝1/15)纯化，得标题化合物为棕黄色固体(850mg,1.56mmol,64.4％)。To a single-necked flask, add 3-(2-cyclopropylethoxy)-2-hydroxy-6-isopropyl-10-oxo-6,10-dihydro-5H-pyrido[2,1-f][1,6]naphthyridine-9-carboxylic acid ethyl ester (1 g, 2.424 mmol), triethylamine (0.7 mL, 5 mmol) and DCM (20 mL) in sequence, cool to 0°C, add N-phenylbis(trifluoromethanesulfonyl)imide (1 g, 2.7992 mmol) in batches, move to room temperature and stir for 24 h. Post-treatment: wash the separated liquid with sodium chloride solution (20 mL), dry over anhydrous sodium sulfate, and spin dry the solvent. The obtained residue is purified by silica gel column chromatography (MeOH/DCM (V/V) = 1/15) to obtain the title compound as a brown-yellow solid (850 mg, 1.56 mmol, 64.4%).
MS:(ESI,pos.ion)m/z：545.2[M+H]+。MS: (ESI,pos.ion)m/z: 545.2[M+H]+ .
步骤13：3-(2-环丙基乙氧基)-6-异丙基-10-氧代-2-(((三氟甲基)磺酰基)氧Step 13: 3-(2-cyclopropylethoxy)-6-isopropyl-10-oxo-2-(((trifluoromethyl)sulfonyl)oxy代)-6,10-二氢-5H-吡啶并[2,1-f][1,6]萘啶-9-甲酸乙酯(substituted)-6,10-dihydro-5H-pyrido[2,1-f][1,6]naphthyridine-9-carboxylic acid ethyl ester
向单口烧瓶依次加入3-(2-环丙基乙氧基)-6-异丙基-10-氧代-2-(((三氟甲基)磺酰基)氧代)-6,10-二氢-5H-吡啶并[2,1-f][1,6]萘啶-9-甲酸乙酯(300mg,0.5510mmol)、DMF(6mL)、Pd(dppf)Cl2(80mg,0.1093mmol)、4A分子筛(600mg)和三丁基(噻唑-2-基)锡烷(412mg,1.101mmol)，氮气置换三次，加热至100℃搅拌12h。后处理：减压浓缩，残留物经硅胶柱层析分离(DCM/CH3OH(V/V)＝10/1)，得标题化合物为白色固体产物(57mg,0.126mmol,22.9％)。To a single-necked flask, 3-(2-cyclopropylethoxy)-6-isopropyl-10-oxo-2-(((trifluoromethyl)sulfonyl)oxy)-6,10-dihydro-5H-pyrido[2,1-f][1,6]naphthyridine-9-carboxylic acid ethyl ester (300 mg, 0.5510 mmol), DMF (6 mL), Pd(dppf)Cl2 (80 mg, 0.1093 mmol), 4A molecular sieves (600 mg) and tributyl(thiazol-2-yl)stannane (412 mg, 1.101 mmol) were added in sequence, the atmosphere was replaced with nitrogen three times, and the mixture was heated to 100°C and stirred for 12 h. Post-treatment: the mixture was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (DCM/CH3 OH (V/V) = 10/1) to obtain the title compound as a white solid product (57 mg, 0.126 mmol, 22.9%).
MS:(ESI,pos.ion)m/z：452.2[M+H]+；MS: (ESI,pos.ion)m/z: 452.2[M+H]+ ;
1H NMR(400MHz,CDCl3)δ15.87(s,1H),9.07(s,1H),8.52(s,1H),8.00(s,1H),7.53(s,1H),7.27(s,1H),4.73(t,J＝6.2Hz,2H),4.06(s,1H),3.59–3.45(m,1H),3.36(d,J＝16.3Hz,1H),1.88(dd,J＝13.1,6.4Hz,2H),1.07–0.78(m,8H),0.55(d,J＝7.4Hz,2H),0.20(d,J＝4.3Hz,2H)。1H NMR (400MHz, CDCl3 ) δ15.87(s,1H),9.07(s,1H),8.52(s,1H),8.00(s,1H),7.53(s,1H),7.27(s,1H ),4.73(t,J＝6.2Hz,2H),4.06(s,1H),3.59–3.45(m,1H),3.36(d,J＝16.3Hz,1H),1.88(dd,J＝13.1, 6.4Hz, 2H), 1.07–0.78 (m, 8H), 0.55 (d, J = 7.4Hz, 2H), 0.20 (d, J = 4.3Hz, 2H).
生物活性测试Biological activity test
HBV细胞系HBV cell lines
HepG2.2.15细胞(SELLS,PNAS,1987和SELLS,JV,1988)的染色体整合有完整的HBV基因组，并稳定表达病毒RNA和病毒蛋白质。HepG2.2.15细胞能够向培养基中分泌成熟的乙肝病毒颗粒和HBsAg。HepG 2.2.15细胞分泌的病毒粒子DNA和HBsAg可以通过qPCR和ELISA的方法来定量，并由此检测化合物对病毒复制和HBsAg分泌的影响。HepG2.2.15 cells (SELLS, PNAS, 1987 and SELLS, JV, 1988) have a complete HBV genome integrated into their chromosomes and stably express viral RNA and viral proteins. HepG2.2.15 cells can secrete mature hepatitis B virus particles and HBsAg into the culture medium. The viral particle DNA and HBsAg secreted by HepG 2.2.15 cells can be quantified by qPCR and ELISA methods, and the effects of compounds on viral replication and HBsAg secretion can be detected.
测试1：本发明化合物对HBVDNA复制的抑制实验Test 1: Inhibition experiment of the compounds of the present invention on HBV DNA replication
实验方法：Experimental methods:
HepG 2.2.15细胞接种到96孔细胞培养板，8,000个每孔，一式两份，培养3天至细胞长至满孔。用4倍系列稀释的化合物处理细胞10天，隔天换液给药一次，所有孔中DMSO的终浓度为0.5％并将DMSO用作无药物对照。第11天收取上清液用作HBV DNA定量检测。HepG 2.2.15 cells were seeded into 96-well cell culture plates, 8,000 cells per well, in duplicate, and cultured for 3 days until the cells grew to full wells. The cells were treated with 4-fold serial dilutions of the compound for 10 days, and the medium was changed every other day. The final concentration of DMSO in all wells was 0.5% and DMSO was used as a drug-free control. The supernatant was collected on the 11th day for HBV DNA quantitative detection.
qPCR方法检测病毒基因组DNA，HBV引物如下：The qPCR method was used to detect viral genomic DNA. The HBV primers were as follows:
HBV-For-202，CAGGCGGGGTTTTTCTTGTTGA(SEQ ID NO:1)；HBV-For-202, CAGGCGGGGTTTCTTGTTGA (SEQ ID NO: 1);
HBV-Rev-315，GTGATTGGAGGTTGGGGACTGC(SEQ ID NO:2)。HBV-Rev-315, GTGATTGGAGGTTGGGGACTGC (SEQ ID NO: 2).
使用SYBR Premix Ex Taq II–Takara DRR081S试剂盒，以1μL细胞培养上清液作为模板，用包含HBV基因组的质粒做标准曲线，并以标准曲线来计算病毒拷贝数。用Graphpad Prism 5软件处理浓度-病毒拷贝数，通过四参数非线性回归模型计算化合物对病毒复制抑制的IC50。The SYBR Premix Ex Taq II–Takara DRR081S kit was used, with 1 μL of cell culture supernatant as the template, and a plasmid containing the HBV genome was used as the standard curve to calculate the viral copy number. The concentration-viral copy number was processed using Graphpad Prism 5 software, and the IC50 of the compound's inhibition of viral replication was calculated using a four-parameter nonlinear regression model.
结论：本发明化合物对HBV病毒复制的抑制实验表明，本发明化合物对HBV DNA的复制具有很好的抑制作用，其中，本发明化合物对HBV DNA的复制抑制活性的IC50小于0.1μM，大部分化合物对HBV DNA的复制抑制活性的IC50小于0.05μM。Conclusion: The inhibition experiment of the compounds of the present invention on HBV virus replication shows that the compounds of the present invention have a good inhibitory effect on the replication of HBV DNA, wherein theIC50 of the compounds of the present invention on the replication inhibition of HBV DNA is less than 0.1μM, and theIC50 of most compounds on the replication inhibition of HBV DNA is less than 0.05μM.
本发明部分化合物对HBV DNA的复制抑制活性如表2所示。The inhibitory activities of some compounds of the present invention on HBV DNA replication are shown in Table 2.
表2：本发明部分化合物对HBV DNA的复制抑制活性Table 2: Inhibitory activity of some compounds of the present invention on HBV DNA replication
测试2：本发明化合物对HBsAg分泌的抑制实验Test 2: Inhibition experiment of the compounds of the present invention on HBsAg secretion
实验方法：Experimental methods:
HepG 2.2.15细胞接种到96孔细胞培养板，8,000个每孔，一式两份，培养3天至细胞长至满孔。用4倍系列稀释的化合物处理细胞10天，隔天换液给药一次，所有孔中DMSO的终浓度为0.5％并将DMSO用作无药物对照。第11天收取上清用作HBsAg定量检测。HepG 2.2.15 cells were seeded into 96-well cell culture plates, 8,000 cells per well, in duplicate, and cultured for 3 days until the cells grew to full wells. The cells were treated with 4-fold serial dilutions of the compound for 10 days, and the medium was changed every other day. The final concentration of DMSO in all wells was 0.5% and DMSO was used as a drug-free control. The supernatant was collected on the 11th day for HBsAg quantitative detection.
使用ELISA方法检测化合物处理后细胞分泌的HBsAg水平，该方法使用乙型肝炎表面抗原诊断试剂盒(上海科华生物工程股份有限公司S10910113)。在ELISA板中每孔加入25μL待检上清液(PBS稀释至75μL)，并设置试剂盒阳性对照和阴性对照。用封片纸封闭ELISA板后，37℃孵育60分钟。取出ELISA板，撕去封片，每孔中加入50μL酶结合物。振荡器上震荡10秒，用封片纸封闭ELISA板，37℃孵育30分钟。取出ELISA板，撕去封片纸，重复洗涤5次：每次弃去孔内液体，加洗涤液注满各孔，静置60秒，甩干，在吸水纸上拍干液体残留。洗涤结束后立即在所有孔内加入新鲜配制的显色剂A和显色剂B的混合液：100μL每孔。振荡器上震荡10秒钟，用封片纸封闭ELISA板后，37℃孵育30分钟。在所有孔内加入50μL终止液。在Envision读板仪上以波长450nm读数。用Graphpad Prism 5软件处理浓度---HBsAg OD450值数据，通过四参数非线性回归模型计算化合物对HBsAg分泌抑制的IC50。The ELISA method was used to detect the level of HBsAg secreted by cells after compound treatment. The method used the Hepatitis B Surface Antigen Diagnostic Kit (Shanghai Kehua Bioengineering Co., Ltd. S10910113). 25 μL of the supernatant to be tested (PBS diluted to 75 μL) was added to each well of the ELISA plate, and the positive and negative controls of the kit were set. After sealing the ELISA plate with sealing paper, incubate at 37°C for 60 minutes. Take out the ELISA plate, tear off the sealing paper, and add 50 μL of enzyme conjugate to each well. Oscillate on the oscillator for 10 seconds, seal the ELISA plate with sealing paper, and incubate at 37°C for 30 minutes. Take out the ELISA plate, tear off the sealing paper, and repeat the washing 5 times: discard the liquid in the well each time, add washing solution to fill each well, let it stand for 60 seconds, spin dry, and pat the liquid residue on absorbent paper. After washing, add a freshly prepared mixture of color developer A and color developer B to all wells immediately: 100 μL per well. Oscillate on an oscillator for 10 seconds, seal the ELISA plate with a sealing paper, and incubate at 37°C for 30 minutes. Add 50 μL of stop solution to all wells. Read the plate at a wavelength of 450 nm on an Envision plate reader. Use Graphpad Prism 5 software to process the concentration-HBsAg OD450 value data, and calculate the IC50 of the compound's inhibition of HBsAg secretion using a four-parameter nonlinear regression model.
结论：本发明化合物对HBsAg分泌的抑制实验表明。本发明化合物对HBsAg分泌具有很好的抑制作用，其中，本发明化合物对HBsAg分泌的抑制活性的IC50小于0.1μM，大部分化合物对HBsAg分泌的抑制活性的IC50小于0.05μM。Conclusion: The inhibition experiment of the compounds of the present invention on HBsAg secretion shows that the compounds of the present invention have a good inhibitory effect on HBsAg secretion, wherein the IC50 of the inhibitory activity of the compounds of the present invention on HBsAg secretion is less than 0.1 μM, and the IC50 of the inhibitory activity of most compounds on HBsAg secretion is less than 0.05 μM.
本发明部分化合物对HBsAg分泌的抑制活性如表3所示。The inhibitory activities of some compounds of the present invention on HBsAg secretion are shown in Table 3.
表3：本发明部分化合物对HBsAg分泌的抑制活性Table 3: Inhibitory activity of some compounds of the present invention on HBsAg secretion
测试3：本发明化合物在比格犬、小鼠、大鼠中的药代动力学实验Test 3: Pharmacokinetics of the compounds of the present invention in beagle dogs, mice and rats
(1)比格犬PK测试实验(1) Beagle dog PK test experiment
本发明化合物在比格犬(体重10-12kg，雄性，年龄10-12个月，口服每组3只，静脉注射每组3只)体内的PK测定实验如下所示：The PK assay of the compound of the present invention in beagle dogs (weight 10-12 kg, male, age 10-12 months, 3 dogs per group for oral administration, 3 dogs per group for intravenous injection) is as follows:
实验方法：Experimental methods:
比格犬经口灌胃给予2.5mg/kg或5mg/kg或经静脉注射1mg/kg或2mg/kg的测试化合物。Beagle dogs were given 2.5 mg/kg or 5 mg/kg of the test compound by oral gavage or 1 mg/kg or 2 mg/kg by intravenous injection.
给药后按时间点(0.083、0.25、0.5、1、2、4、6、8和24小时)静脉采血，收集于加EDTA-K2的抗凝管内。血浆样品经液液萃取后，在三重四极杆串联质谱仪上，以多重反应离子监测(MRM)方式进行定量分析。采用WinNonlin 6.3软件用非房室模型法计算药代动学参数。After administration, venous blood was collected at time points (0.083, 0.25, 0.5, 1, 2, 4, 6, 8 and 24 hours) and collected in anticoagulant tubes with EDTA-K2. After liquid-liquid extraction, plasma samples were quantitatively analyzed on a triple quadrupole tandem mass spectrometer using multiple reaction ion monitoring (MRM). Pharmacokinetic parameters were calculated using WinNonlin 6.3 software using the non-compartmental model method.
本发明部分化合物在比格犬体内的药代动力学性质如表4所示。The pharmacokinetic properties of some compounds of the present invention in beagle dogs are shown in Table 4.
表4：本发明部分化合物在比格犬体内的药代动力学性质Table 4: Pharmacokinetic properties of some compounds of the present invention in beagle dogs
结论：药代实验数据表明，本发明化合物在比格犬体内具有较好的药代动力学性质，在抗HBV方面有很好的应用前景。Conclusion: The pharmacokinetic experimental data show that the compound of the present invention has good pharmacokinetic properties in beagle dogs and has a good application prospect in anti-HBV.
(2)小鼠PK测试实验(2) Mouse PK test experiment
本发明化合物在小鼠(体重20-25g，雄性，年龄45-60天，口服每组3只，静脉注射每组3只)体内的PK测定实验如下所示：The PK assay of the compound of the present invention in mice (weight 20-25 g, male, age 45-60 days, 3 mice per group for oral administration, 3 mice per group for intravenous injection) is as follows:
实验方法：Experimental methods:
ICR小鼠经口灌胃给予10mg/kg或经尾静脉注射2mg/kg或10mg/kg的测试化合物。给药后按时间点(0.083，0.25，0.5，1，2，4，6，8和24小时)眼眶静脉采血，收集于加EDTA-K2的抗凝管内。血浆样品经液液萃取后，在三重四极杆串联质谱仪上，以多重反应离子监测(MRM)方式进行定量分析。采用WinNonlin 6.3软件用非房室模型法计算药代动学参数。ICR mice were given 10 mg/kg of the test compound by oral gavage or 2 mg/kg or 10 mg/kg by tail vein injection. Blood was collected from the orbital vein at time points (0.083, 0.25, 0.5, 1, 2, 4, 6, 8 and 24 hours) after administration and collected in anticoagulant tubes with EDTA-K2. After liquid-liquid extraction, plasma samples were quantitatively analyzed by multiple reaction ion monitoring (MRM) on a triple quadrupole tandem mass spectrometer. Pharmacokinetic parameters were calculated using the non-compartmental model method using WinNonlin 6.3 software.
结论：药代实验数据表明，本发明化合物在小鼠体内具有较好的药代动力学性质，在抗HBV病毒方面有很好的应用前景。Conclusion: The pharmacokinetic experimental data show that the compound of the present invention has good pharmacokinetic properties in mice and has good application prospects in anti-HBV virus.
(3)SD大鼠PK测试实验(3) PK test experiment in SD rats
本发明化合物在SD大鼠(体重200-250g，雄性，年龄2-3个月，口服每组3只，静脉注射每组3只)体内的PK测定实验如下所示：The PK assay of the compound of the present invention in SD rats (weight 200-250 g, male, age 2-3 months, 3 rats per group for oral administration, 3 rats per group for intravenous injection) is as follows:
实验方法：Experimental methods:
SD大鼠经口灌胃给予2.5mg/kg或5mg/kg或经静脉注射1mg/kg的测试化合物。给药后按时间点(0.083、0.25、0.5、1、2、5、7和24小时)静脉采血，收集于加EDTA-K2的抗凝管内。血浆样品经液液萃取后，在三重四极杆串联质谱仪上，以多重反应离子监测(MRM)方式进行定量分析。采用WinNonlin 6.3软件用非房室模型法计算药代动学参数。SD rats were given 2.5 mg/kg or 5 mg/kg of the test compound by oral gavage or 1 mg/kg by intravenous injection. After administration, venous blood was collected at time points (0.083, 0.25, 0.5, 1, 2, 5, 7 and 24 hours) and collected in anticoagulant tubes with EDTA-K2. After liquid-liquid extraction, plasma samples were quantitatively analyzed by multiple reaction ion monitoring (MRM) on a triple quadrupole tandem mass spectrometer. Pharmacokinetic parameters were calculated using the non-compartmental model method using WinNonlin 6.3 software.
本发明部分化合物在SD大鼠的药代动力学性质如表5所示。The pharmacokinetic properties of some compounds of the present invention in SD rats are shown in Table 5.
表5：本发明部分化合物在SD大鼠的药代动力学性质Table 5: Pharmacokinetic properties of some compounds of the present invention in SD rats
结论：药代实验数据表明，本发明化合物在SD大鼠体内具有较好的药代动力学性质，在抗HBV方面有很好的应用前景。Conclusion: The pharmacokinetic experimental data show that the compound of the present invention has good pharmacokinetic properties in SD rats and has good application prospects in anti-HBV.
测试4：本发明化合物在不同种属的肝微粒体中的稳定性测试Test 4: Stability test of the compounds of the present invention in liver microsomes of different species
实验方法：Experimental methods:
向96孔板中加入空白溶液与肝微粒体的混合溶液30μL，在各孔中加入15μL含待测化合物的缓冲液，平行做两份样品。37℃预孵育10min后按0min、15min、20min和60min时间点加入15μL NADPH溶液(8mM)，待测化合物的终浓度为1μM，肝微粒体的浓度为0.1mg/mL，NADPH的终浓度为2mM。分别孵育0、15、30、60min，孵育结束后将150μL乙腈(含内标)加入混合体系中。乙腈稀释后的样品在4000rpm下离心5min，取150μL上清液至LC-MS/MS进行分析。Add 30 μL of the blank solution and liver microsomes mixed solution to a 96-well plate, add 15 μL of buffer containing the test compound to each well, and make two samples in parallel. After pre-incubation at 37°C for 10 minutes, add 15 μL of NADPH solution (8 mM) at 0 min, 15 min, 20 min and 60 min. The final concentration of the test compound is 1 μM, the concentration of liver microsomes is 0.1 mg/mL, and the final concentration of NADPH is 2 mM. Incubate for 0, 15, 30, and 60 min respectively. After the incubation, add 150 μL of acetonitrile (containing internal standard) to the mixed system. The sample diluted with acetonitrile is centrifuged at 4000 rpm for 5 minutes, and 150 μL of supernatant is taken for LC-MS/MS analysis.
结论：肝微粒体稳定性实验数据表明，本发明化合物在不同种属的肝微粒体中稳定性较好。Conclusion: The experimental data of liver microsome stability show that the compounds of the present invention have good stability in liver microsomes of different species.
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