CN112912368A - 乙型肝炎病毒的抑制剂 - Google Patents
乙型肝炎病毒的抑制剂 Download PDFInfo
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- CN112912368A CN112912368A CN201980061329.XA CN201980061329A CN112912368A CN 112912368 A CN112912368 A CN 112912368A CN 201980061329 A CN201980061329 A CN 201980061329A CN 112912368 A CN112912368 A CN 112912368A
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/56—Nitrogen atoms
- C07D211/58—Nitrogen atoms attached in position 4
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D305/00—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms
- C07D305/02—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms not condensed with other rings
- C07D305/04—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D305/08—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/18—Sulfonamides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
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Abstract
本发明涉及作为乙型肝炎病毒(HBV)抑制剂的化合物。本发明的化合物可单独使用或与其它试剂组合用于治疗、改善、预防或治愈HBV感染和相关病症。本发明还涉及含有所述化合物的药物组合物。
Description
技术领域
本发明涉及作为乙型肝炎病毒(HBV)抑制剂的化合物。
本发明的化合物可单独使用或与其它试剂组合用于治疗、改善、预防或治愈HBV感染和相关病症。本发明还涉及含有所述化合物的药物组合物。
背景技术
乙型肝炎病毒(HBV)是肝炎病毒科的一种有包膜的部分双链DNA(dsDNA)病毒,它通过与感染的血液和体液接触而传播,并引起各种严重程度的急性和慢性坏死性炎性肝病(Guidotti LG,Chisari FV.Annu Rev Pathol.2006;1:23-61)。HBV脂质包膜包含3种框架内病毒包膜蛋白(大、中、小),每种都具有乙型肝炎病毒表面抗原(HBsAg)决定簇(SeegerC,Mason WS.Virology.2015年5月;479-480:672-86)。该包膜包含一个蛋白质壳或衣壳,其包含240个核心蛋白单体,每个单体都具有乙型肝炎病毒核心抗原(HBcAg或Cp)决定簇。衣壳进而又包围病毒基因组的一部分双链、松弛的环状DNA(rcDNA)形式以及病毒聚合酶的分子。在通过大包膜蛋白与肝细胞膜上特定受体的相互作用进入易感细胞(即肝细胞)后,衣壳被释放到细胞质中并在核膜处运输。然后rcDNA被释放到细胞核中,并通过细胞聚合酶修复为游离的“微型染色体”,称为共价闭合环状DNA(cccDNA),其代表病毒转录模板。病毒DNA的负链编码3.5、2.4、2.1和0.7kb的mRNA物质,其可被翻译成病毒的结构(包膜和核心)蛋白和非结构(聚合酶,前核和X)蛋白。运输到细胞质中之后,3.5kb RNA中的一种(称为前基因组RNA)通过与已从其各自的mRNA翻译而来的核心和聚合酶蛋白相互作用而被选择性地包装到新生衣壳中。在这些衣壳中,病毒聚合酶将前基因组RNA反转录为单个负(-)链DNA分子,其用作病毒聚合酶介导的DNA正(+)链合成的模板,且线性DNA中间体的内聚结构将它们转化成松弛环状双链分子。这些含有HBV DNA的“成熟”衣壳的一部分被运输回核,在那里完成第二链合成,且两条链的末端被连接,导致cccDNA库的扩增。衣壳的另一部分与已被独立翻译并易位至具有内质网(ER)样结构的膜的病毒包膜蛋白结合。结合后,有包膜的衣壳进入ER腔,并以感染性病毒粒子的形式离开细胞,从而开始新的感染周期。
因此,HBV核心蛋白和相关衣壳是HBV生命周期的重要组成部分和调节物。全长核心蛋白Cp183,或其N末端结构域Cp149,主要组装成T=4二十面体衣壳。由于其在衣壳装配、前基因组RNA包装和cccDNA维持中的关键作用,HBV核心蛋白和相关衣壳被广泛认为是有吸引力的抗病毒靶标是意料之中的(Durantel D,Zoulim F;J Hepatol.2016年4月;64(1增刊):S117-S131)。
根据世界卫生组织(WHO)的统计,HBV感染是当今时代的主要医疗祸患之一。作为一种也可以通过静脉内吸毒和出生时母婴传播的性传播疾病,世界上超过三分之一的人口在其生命中的某个时刻被HBV感染(Burns GS,Thompson AJ;Cold Spring Harb PerspectMed.2014年10月30日;4(12))。尽管这些人中的大多数人已经成功清除了病毒,但仍有超过2.5亿人持续处于该病毒感染状态,每年约有90万人死于慢性感染的并发症(如肝硬化和/或肝细胞癌)。在撒哈拉以南的非洲,太平洋地区,特别是亚洲,HBV感染是高度流行的。慢性HBV感染率高的地区还包括中东、印度次大陆、南美和中美洲地区以及东欧和中欧的南部地区。近年来,在西方世界,慢性病毒携带者的数量也在稳步增加,这主要归因于来自疾病流行地区的移民涌入。此外,乙肝病毒是丁型肝炎病毒(HDV)的辅助病毒,应该指出的是,超过1500万同时感染HBV和HDV的人快速发展为肝硬化和肝代偿失调的风险升高(Hughes,S.A.等.Lancet 2011,378,73-85)。
耐受良好的疫苗可引发针对HBsAg的中和抗体,可有效预防HBV从头感染,但对已经受到持续感染的数百万人群没有治疗潜力(Zoulim,Durantel D;Cold Spring HarbPerspect Med.2015年4月1日;5(4))。这些个体的治疗主要依靠抑制病毒产生但不能从肝脏根除HBV的直接作用型抗病毒(DAA)药物(例如替诺福韦、拉米夫定、阿德福韦、恩替卡韦或替比夫定),需要终生治疗。研究组中的患者仍接受基于聚乙二醇化干扰素-α(PEG-IFN-α)的治疗,其优点是有限的治疗持续时间,较高的HBsAg血清转化率,但不利的是具有较大副作用。这样,接受PEG-IFN-α的患者数量逐渐减少。
靶向HBV衣壳化过程的不同化学类别的抑制剂(也称为衣壳组装调节剂或CAM)正在开发中,它们包括杂芳基二氢嘧啶(HAP)和氨磺酰基苯甲酰胺(SBA)。例如,诺维拉治疗公司(Novira Therapeutics)最近利用了人源化的HBV感染小鼠模型,显示CAM和PEG-IFN-α的组合具有的抗病毒活性高于以前用DAA观察到的情况。NVR3-778是此类CAM的第一个成员,在概念验证阶段1b期临床研究中显示HBV DNA和血清HBV RNA均显著降低。该化合物最近已停产。詹森药业(Janssen)开发的化合物JNJ-56136379(或JNJ-379)最近显示出了有力的抗病毒活性,目前正在进入2期临床试验。
2013年1月10日公布的WO2013/006394涉及一种具有通式A的氨磺酰基-芳基酰胺的亚类,其可用于治疗乙型肝炎病毒(HBV)感染:
2013年6月26日公布的WO2013/096744涉及具有抗HBV活性的式B的氨磺酰基-芳基酰胺:
2014年7月3日公布的WO2014/106019涉及式C的化合物,其可用作用于治疗病毒的核壳体组装抑制剂,尤其但不限于,包括用于治疗乙型肝炎病毒(HBV)感染和相关病症的HBV的前基因组RNA衣壳化抑制剂:
2014年10月9日公布的WO2014/165128、2015年7月23日公布的WO2015/109130、2015年10月1日公布的US2015274652,均涉及对HBV具有活性的氨磺酰基-芳基酰胺化合物。
2015年8月13日公布的WO2015/120178涉及用于与聚乙二醇干扰素α-2a或另一种干扰素类似物联合用于治疗HBV感染的氨磺酰基-芳基酰胺化合物。
2016年6月9日公布的WO2016/089990涉及用于HBV治疗的硫化烷基和吡啶基反向磺酰胺化合物。
2016年6月30日公布的US2016185748涉及用于HBV治疗的吡啶基反向磺酰胺。
2016年6月2日公布的US2016151375涉及用于HBV治疗的硫化烷基化合物。
2017年1月5日公布的WO2017/001655A1涉及环化的氨磺酰芳基胺衍生物。
JP49040221(也公布为GB 1,313,217)描述了化合物2-氨基-N-(4-氯-2-甲基苯基)-5-氨磺酰基苯甲酰胺(CAS号55455-09-9)。
WO2010/123139描述了化合物N-(2-甲氧基苯基)-2-(甲基氨基)-5-(哌啶-1-基磺酰基)苯甲酰胺(CAS号1253220-93-7)。
HBV直接抗病毒药可能会遇到的问题是毒性、诱变性、缺乏选择性、疗效差、生物利用度差、溶解度低和/或脱靶活性,而迄今为止,尚未批准上述任何结构类别的化合物作为治疗HBV患者的药物。
需要其它HBV抑制剂,它们可以克服这些缺点中的至少一个或具有其它优点,例如增加的功效、增加的生物利用度或增加的安全期。
本发明提供了通过对已知的氨磺酰基芳基酰胺衍生物进行化学修饰而获得的小分子药物。从结构角度来看,表征本发明的氨磺酰基酰胺的区别特征是氨磺酰基的邻位或对位存在氨基。该取代模式可产生具有改善的药代动力学特性、良好的动力学溶解性、在小鼠和人类肝细胞中具有稳定性、体内清除率低和正肝对血浆浓度(liver-to-plasmaconcentration)的有力HBV抑制剂。鉴于肝脏在代谢调节中的关键作用以及它是受乙肝疾病影响的主要组织这一事实,设计具有肝选择性分布特征的HBV抑制剂是开发安全候选药物的重要策略(Tu M.等,Current Topics in Medicinal Chemistry,2013,13,857-866)。
发明内容
本发明的化合物是乙型肝炎病毒(HBV)的抑制剂。
因此,本发明的目的之一是通式(I)的化合物:
其中:
A是6元芳族或杂芳族环;
B是任选地含有一个或多个N原子的6元芳基;
X是H或NR3R4;
Y选自下组:氢,卤素,C1-6烷基,NH2,NH(C1-6烷基),N(CH3)2,NHC(O)CH3,OH,饱和或部分不饱和的C3-7环烷基,5-或6-元杂芳基和CN,或不存在;
限制条件是,当X是H时,Y选自下组:NH2,NH(C1-6烷基),N(CH3)2,NHC(O)CH3;
R1及R2各自独立地选自H,直链或支化1-6烷基,饱和或部分不饱和的C3-7环烷基,C3-7杂环烷基和杂芳基,所述直链或支化的C1-6烷基,饱和或部分不饱和的C3-7环烷基,C3-7杂环烷基或杂芳基各自任选地被选自以下的一个或多个取代基取代:OH,卤素,NH2,NH(C=O)OC1-6烷基,NH(C1-6烷基),C1-6烷基,C3-7环烷基,C3-7杂环烷基,C1-6羟烷基,5-或6-元杂芳基,C(=O)C1-6烷基,C(=O)OC1-6烷基,OC1-6烷基,O(CH2)nC3-10环烷基和O(CH2)nC3-10杂环烷基;
或R1和R2与它们所连接的N原子一起形成饱和或部分不饱和的3-10元杂环,其任选地包含选自N、O和S的另一个杂原子,所述饱和或部分不饱和的3-10元杂环任选地被选自OH,卤素,C1-6烷基,C1-6卤代烷基和(CH2)nR5的一个或多个取代基取代;
n在每次出现时独立地是0、1、2、3或4;
R3和R4各自独立地是H,或直链或支化C1-3烷基,其任选地被选自卤素,NH2,NHC1-6烷基,N(C1-6烷基)2,NH(C=O)C1-6烷基,NH(C=O)OC1-6烷基,OC1-6烷基,O(CH2)nC3-10环烷基和O(CH2)nC3-10杂环烷基的一个或多个基团取代,限制条件是NR3R4不形成饱和、部分饱和或不饱和的杂环;
R5选自下组:OH,NH2,NH(CH3),N(CH3)2,NHC(O)CH3,CN,卤代C1-3烷基,C1-3烷氧基,卤代C1-3烷氧基,杂环,芳基和杂芳基;
Ra选自下组:氢,卤素,C1-3烷基,卤代C1-3烷基,C1-3烷氧基,卤代C1-3烷氧基,NH2,NH(CH3),N(CH3)2,NHC(O)CH3,OH和CN;或不存在;
Rb选自下组:氢,卤素,C1-3烷基,卤代C1-3烷基,C1-3烷氧基,卤代C1-3烷氧基,NH2,NH(CH3),N(CH3)2,NHC(O)CH3,OH和CN;或不存在;
Rc选自下组:氢,卤素,C1-3烷基,卤代C1-3烷基,C1-3烷氧基,卤代C1-3烷氧基,NH2,NH(CH3),N(CH3)2,NHC(O)CH3,OH和CN;或不存在;
Rd选自下组:氢,卤素,C1-3烷基,卤代C1-3烷基,C1-3烷氧基,卤代C1-3烷氧基,NH2,NH(CH3),N(CH3)2,NHC(O)CH3,OH和CN;或不存在;
Re选自下组:氢,卤素,C1-3烷基;或不存在;
Rf是氢,卤素,C1-3烷基;或不存在;
限制条件是:该化合物不是2-氨基-N-(4-氯-2-甲基苯基)-5-氨磺酰基苯甲酰胺或N-(2-甲氧基苯基)-2-(甲基氨基)-5-(哌啶-1-基磺酰基)苯甲酰胺;
及其药学上可接受的盐、互变异构体、异构体、立体异构体。
优选地,A是苯基。优选地,B是苯基。优选地,A和B均为苯基。
优选地,X是NR3R4,其中更优选地,R3和R4均为H。
优选地,Y选自下组:氢,卤素(特别是Cl或Br),C1-6烷基(特别是甲基)和NH2。在另一个优选的实施方式中,X是氢且Y是NH2。优选地,R1和R2各自独立地选自:氢,任选被卤素取代的直链或支化C1-6烷基,任选被OH或被NH(C=O)OC1-6取代的饱和C3-6环烷基,和任选被NH(C=O)OC1-6烷基取代的C3-6杂环烷基。在一个优选的实施方式中,R1和R2与它们所连接的N原子一起形成饱和的4-6元杂环,其任选地被OH或被CH2OH取代。更优选地,R1是氢,甲基或选自下组: 同样优选地,R2是H或甲基。
优选地,R3和R4都是H。优选地,R5是OH。优选地,Ra是H。优选地,Rb和Rd各自独立地选自下组:氢,F,CF3,CN,CHF2,Cl和甲基。优选地,Rc是F。优选地,Re是氢或C1-3烷基,特别是甲基。优选地,Rf是氢。
在一个优选的实施方式中,本发明的化合物具有通式(Ia):
其中:
A是6元芳族或杂芳族环;
B是任选地含有一个或多个N原子的6元芳基;
Y选自下组:氢,卤素,C1-3烷基,NH2,NH(C1-6烷基),N(CH3)2,NHC(O)CH3,OH,饱和或部分不饱和的C3-7环烷基,5-或6-元杂芳基和CN,或不存在;
R1及R2各自独立地选自H,直链或支化1-6烷基,饱和或部分不饱和的C3-7环烷基,C3-7杂环烷基和杂芳基,所述直链或支化的C1-6烷基,饱和或部分不饱和的C3-7环烷基,C3-7杂环烷基或杂芳基各自任选地被选自以下的一个或多个取代基取代:OH,卤素,NH2,NH(C=O)OC1-6烷基,NH(C1-6烷基),C1-6烷基,C3-7环烷基,C3-7杂环烷基,C1-6羟烷基,5-或6-元杂芳基,C(=O)C1-6烷基,C(=O)OC1-6烷基,OC1-6烷基,O(CH2)nC3-10环烷基和O(CH2)nC3-10杂环烷基;
或R1和R2与它们所连接的N原子一起形成饱和或部分不饱和的3-10元杂环,其任选地包含选自N、O和S的另一个杂原子,所述饱和或部分不饱和的3-10元杂环任选地被选自OH,卤素,C1-6烷基,C1-6卤代烷基、(CH2)nR5的一个或多个取代基取代;
n在每次出现时独立地是0、1、2、3或4;
R3和R4各自独立地是H,或直链或支化C1-3烷基,其任选地被选自卤素,NH2,NHC1-6烷基,N(C1-6烷基)2,NH(C=O)C1-6烷基,NH(C=O)OC1-6烷基,OC1-6烷基,O(CH2)nC3-10环烷基和O(CH2)nC3-10杂环烷基的一个或多个基团取代,限制条件是:NR3R4不形成饱和、部分饱和或不饱和的杂环;
R5选自下组:OH,NH2,NH(CH3),N(CH3)2,NHC(O)CH3,CN,卤代C1-3烷基,C1-3烷氧基,卤代C1-3烷氧基,杂环,芳基和杂芳基;
Ra选自下组:氢,卤素,C1-3烷基,卤代C1-3烷基,C1-3烷氧基,卤代C1-3烷氧基,NH2,NH(CH3),N(CH3)2,NHC(O)CH3,OH和CN;或不存在;
Rb选自下组:氢,卤素,C1-3烷基,卤代C1-3烷基,C1-3烷氧基,卤代C1-3烷氧基,NH2,NH(CH3),N(CH3)2,NHC(O)CH3,OH和CN;或不存在;
Rc选自下组:氢,卤素,C1-3烷基,卤代C1-3烷基,C1-3烷氧基,卤代C1-3烷氧基,NH2,NH(CH3),N(CH3)2,NHC(O)CH3,OH和CN;或不存在;
Rd选自下组:氢,卤素,C1-3烷基,卤代C1-3烷基,C1-3烷氧基,卤代C1-3烷氧基,NH2,NH(CH3),N(CH3)2,NHC(O)CH3,OH和CN;或不存在;
Re选自下组:氢,卤素和C1-3烷基;或不存在;
Rf是氢,卤素和C1-3烷基;或不存在;
及其药学上可接受的盐、互变异构体、异构体、立体异构体。
在另一个优选的实施方式中,本发明涉及式(Ia)的化合物,其中:
A是6元芳族或杂芳族环;
B是任选地含有一个或多个N原子的6元芳基;
Y选自下组:氢,卤素,C1-3烷基,NH2,NH(C1-6烷基),N(CH3)2,NHC(O)CH3,OH和CN,或不存在;
R1是H,直链或支化C1-6烷基,环丙基,环丁基,环戊基,环己基,哌啶基,吡咯烷基,氧杂环丁烷基(oxetanyl),四氢呋喃基,吡啶基,所述C1-6烷基,环丙基,环丁基,环戊基,环己基,哌啶基,吡咯烷基,氧杂环丁烷基,四氢呋喃基或吡啶基任选地被选自以下的一个或多个取代基取代:OH,卤素,NH2,NH(C=O)OC1-6烷基,NH(C1-6烷基),C1-6羟烷基,5或6-元杂芳基,C(=O)C1-6烷基,C(=O)OC1-6烷基,OC1-6烷基;
R2是H或甲基;
或R1和R2与它们所连接的N原子一起形成选自哌啶,吡咯烷,吗啉,硫代吗啉和哌嗪的杂环,所述环任选地被选自卤素,C1-3烷基,OH和CH2R5的一个或多个取代基取代;
R3和R4各自独立地是H或C1-3烷基;特别是氢或甲基;
R5选自下组:OH,NH2,NH(CH3),N(CH3)2,NHC(O)CH3,CN,卤代C1-3烷基,C1-3烷氧基,卤代C1-3烷氧基,杂环,芳基和杂芳基;
Ra选自下组:氢,卤素,C1-3烷基,卤代C1-3烷基和CN;或不存在;
Rb选自下组:氢,卤素,C1-3烷基,卤代C1-3烷基和CN;或不存在;
Rc选自下组:氢,卤素,C1-3烷基,卤代C1-3烷基和CN;或不存在;
Rd选自下组:氢,卤素,C1-3烷基,卤代C1-3烷基和CN;或不存在;
Re选自下组:氢,卤素,C1-3烷基;或不存在;
Rf是氢或不存在;
及其药学上可接受的盐、互变异构体、异构体、立体异构体。
在一个优选的实施方式中,本发明的化合物具有式(Ia),其中:
A是6元芳族或杂芳族环;
B是任选地含有一个或多个N原子的6元芳基;
Y选自下组:氢,卤素,C1-3烷基;或不存在;
R2是H或甲基;
R3和R4各自独立地是H或C1-3烷基;特别是氢或甲基;
Ra选自下组:氢,卤素,C1-3烷基,卤代C1-3烷基和CN;或不存在;
Rb选自下组:氢,卤素,C1-3烷基,卤代C1-3烷基和CN;或不存在;
Rc选自下组:氢,卤素,C1-3烷基,卤代C1-3烷基和CN;或不存在;
Rd选自下组:氢,卤素,C1-3烷基,卤代C1-3烷基和CN;或不存在;
Re选自下组:氢,卤素,C1-3烷基;或不存在;
Rf是氢或不存在;
及其药学上可接受的盐、互变异构体、异构体、立体异构体。
优选地,A是苯基或吡啶基。优选地,B是苯基或吡啶基。优选地,A是苯基,并且B是苯基。
优选地,Ra,Rb,Rc和Rd中的至少一个是F,其它为氢。
取代基的所有定义,例如“烷基”,“烷氧基”,“芳基”,“杂芳基”等,均在下文报告,并适用于式(I)和式(Ia)。
在另一个实施方式中,本发明涉及式(Ia)的化合物,其中R1,R2,R3,R4,R5,Re,Rf和Y如上定义,并且A为苯基或吡啶基,B为苯基或吡啶基;和
Ra选自下组:氢,卤素,C1-3烷基,卤代C1-3烷基和CN;
Rb选自下组:氢,卤素,C1-3烷基,卤代C1-3烷基和CN;
Rc选自下组:氢,卤素,C1-3烷基,卤代C1-3烷基和CN;
Rd选自下组:氢,卤素,C1-3烷基,卤代C1-3烷基和CN;
及其药学上可接受的盐、互变异构体、异构体、立体异构体。
在另一个实施方式中,本发明涉及式(Ia)的化合物,其中R1,R2,R3,R4,R5,Re,Rf和Y如上定义,并且A为苯基,B为苯基;和
Ra选自下组:氢,卤素,C1-3烷基,卤代C1-3烷基和CN;
Rb选自下组:氢,卤素,C1-3烷基,卤代C1-3烷基和CN;
Rc选自下组:氢,卤素,C1-3烷基,卤代C1-3烷基和CN;
Rd选自下组:氢,卤素,C1-3烷基,卤代C1-3烷基和CN;
及其药学上可接受的盐、互变异构体、异构体、立体异构体。
在另一个实施方式中,本发明涉及式(Ia)的化合物,其中R1,R2,R3,R4,R5,Re,Rf和Y如上所定义,且A是苯基;B是苯基;Ra,Rb,Rc和Rd中至少一个是F,其它为氢;及其药学上可接受的盐、互变异构体、异构体、立体异构体。
在另一个实施方式中,本发明涉及式(Ia)的化合物,其中R1,R2,R3,R4,R5,Re,Rf和Y如上所定义,且A是苯基;B是苯基;Ra,Rb,Rc和Rd中至少两个是F,其它为氢;及其药学上可接受的盐、互变异构体、异构体、立体异构体。
在另一个实施方式中,本发明涉及式(Ia)的化合物,其中R1,R2,R3,R4,R5,Re,Rf和Y如上所定义,且A是苯基;B是苯基;Ra,Rb,Rc和Rd中至少三个是F,其它为氢;及其药学上可接受的盐、互变异构体、异构体、立体异构体。
在另一个实施方式中,本发明涉及式(Ia)的化合物,其中R1,R2,R3,R4,R5,Re,Rf和Y如上定义,且A是苯基,B是苯基;Ra,Rc和Rd各自独立地是氢或F;Rb选自下组:甲基,Cl,CF3,CHF2和CN;及其药学上可接受的盐、互变异构体、异构体、立体异构体。
在另一个实施方式中,本发明涉及一种化合物,其中R1,R2,R4,R5,Re,Rf和Y如上所定义,且A为苯基,B为苯基;R3各自为氢;和
Ra选自下组:氢,卤素,C1-3烷基,卤代C1-3烷基和CN;
Rb选自下组:氢,卤素,C1-3烷基,卤代C1-3烷基和CN;
Rc选自下组:氢,卤素,C1-3烷基,卤代C1-3烷基和CN;
Rd选自下组:氢,卤素,C1-3烷基,卤代C1-3烷基和CN;
及其药学上可接受的盐、互变异构体、异构体、立体异构体。
具体地,优选的化合物选自以下列表:
-4-氨基-3-(N-甲基氨磺酰基)-N-(3,4,5-三氟苯基)苯甲酰胺;
-4-氨基-3-氨磺酰基-N-(3,4,5-三氟苯基)苯甲酰胺;
-4-氨基-N-(3,4-二氟苯基)-3-氨磺酰基苯甲酰胺;
-4-氨基-2-氯-5-氨磺酰基-N-(3,4,5-三氟苯基)苯甲酰胺;
-4-氨基-2-溴-5-氨磺酰基-N-(3,4,5-三氟苯基)苯甲酰胺;
-4-氨基-N-(4-氟-3-(三氟甲基)苯基)-3-氨磺酰基苯甲酰胺;
-4-氨基-N-(3-氰基-4-氟苯基)-3-氨磺酰基苯甲酰胺;
-4-氨基-N-(3-(二氟甲基)-4-氟苯基)-3-氨磺酰基苯甲酰胺;
-4-氨基-N-(3-氯-4-氟苯基)-3-氨磺酰基苯甲酰胺;
-4-氨基-N-(4-氟-3-甲基苯基)-3-氨磺酰基苯甲酰胺;
-4-氨基-2-甲基-5-氨磺酰基-N-(3,4,5-三氟苯基)苯甲酰胺;
-(R)-4-氨基-N-(3,4,5-三氟苯基)-3-(N-(1,1,1-三氟丙烷-2-基)氨磺酰基)苯甲酰胺;
-(S)-4-氨基-N-(3,4,5-三氟苯基)-3-(N-(1,1,1-三氟丙烷-2-基)氨磺酰基)苯甲酰胺;
-4-氨基-3-(N-环丙基氨磺酰基)-N-(3,4,5-三氟苯基)苯甲酰胺;
-反式-4-氨基-3-(N-(4-羟基环己基)氨磺酰基)-N-(3,4,5-三氟苯基)苯甲酰胺;
-顺式-4-氨基-3-(N-(4-羟基环己基)氨磺酰基)-N-(3,4,5-三氟苯基)苯甲酰胺;
-反式-4-氨基-5-(N-(4-羟基环己基)氨磺酰基)-2-甲基-N-(3,4,5-三氟苯基)苯甲酰胺;
-顺式-4-氨基-3-(N-3-羟基环丁基)氨磺酰基)-N-(3,4,5-三氟苯基)苯甲酰胺;
-反式-4-氨基-3-(N-3-羟基环丁基)氨磺酰基)-N-(3,4,5-三氟苯基)苯甲酰胺;
-4-氨基-3-(N-((1R,3R)-3-羟基环戊基)氨磺酰基)-N-(3,4,5-三氟苯基)苯甲酰胺;
-4-氨基-3-((4-羟基哌啶-1-基)磺酰基)-N-(3,4,5-三氟苯基)苯甲酰胺;
-4-氨基-3-(N-(氧杂环丁-3-基)氨磺酰基)-N-(3,4,5-三氟苯基)苯甲酰胺;
-(S)-3-((2-氨基-5-(((3,4,5-三氟苯基)氨基甲酰基)苯基)磺酰胺基)吡咯烷-1-羧酸叔丁酯;
-4-氨基-3-甲基-5-氨磺酰基-N-(3,4,5-三氟苯基)苯甲酰胺;
-4-氨基-3-(N-(3-(羟甲基)氧杂环丁-3-基)氨磺酰基)-N-(3,4,5-三氟苯基)苯甲酰胺;
-4-氨基-3-(N-((1-羟基环己基)甲基)氨磺酰基)-N-(3,4,5-三氟苯基)苯甲酰胺;
-4-氨基-N-(4-氟-3-甲基苯基)-2-甲基-5-氨磺酰基苯甲酰胺;
-4-氨基-5-(N-((1R,4R)-4-羟基环己基)氨磺酰基)-2-甲基-N-(3,4,5-三氟苯基)苯甲酰胺;
-反式-4-氨基-N-(3-氯-4-氟苯基)-3-(N-(4-羟基环己基)氨磺酰基)苯甲酰胺;
-4-氨基-N-(3-(二氟甲基)-4-氟苯基)-3-(N-((1r1R,4r4R)-4-羟基环己基)氨磺酰基)苯甲酰胺;
-反式-4-氨基-N-(3-(二氟甲基)-4-氟苯基)-3-(N-(4-羟基环己基)氨磺酰基)苯甲酰胺;
-4-氨基-3-(N-((1S,3R)-3-羟基环戊基)氨磺酰基)-N-(3,4,5-三氟苯基)苯甲酰胺;
-4-氨基-3-(N-((1R,3S)-3-羟基环戊基)氨磺酰基)-N-(3,4,5-三氟苯基)苯甲酰胺;
-4-氨基-3-((4-羟基-4-(羟甲基)哌啶-1-基)磺酰基)-N-(3,4,5-三氟苯基)苯甲酰胺;
-((1R,2S)-2-((2-氨基-5-((3,4,5-三氟苯基)氨基甲酰基)苯基)磺酰胺基)环戊基)氨基甲酸叔丁酯;
-((1S,2R)-2-((2-氨基-5-((3,4,5-三氟苯基)氨基甲酰基)苯基)磺酰胺基)环戊基)氨基甲酸叔丁酯;
-4-氨基-3-((3-羟基吡咯烷-1-基)磺酰基)-N-(3,4,5-三氟苯基)苯甲酰胺;
-4-氨基-N-(3-氯-4-氟苯基)-3-((4-羟基哌啶-1-基)磺酰基)苯甲酰胺;
-4-氨基-N-(3-氯-4-氟苯基)-3-((3-羟基氮杂环丁烷-1-基)磺酰基)苯甲酰胺;
-4-氨基-3-(N-(2,3-二羟基丙基)氨磺酰基)-N-(3,4,5-三氟苯基)苯甲酰胺;
-反式-4-氨基-3-(N-(3-羟基环戊基)氨磺酰基)-N-(3,4,5-三氟苯基)苯甲酰胺;
-反式-2-氨基-5-(N-(4-羟基环己基)氨磺酰基)-N-(3,4,5-三氟苯基)苯甲酰胺;
-2-氨基-5-((4-羟基哌啶-1-基)磺酰基)-N-(3,4,5-三氟苯基)苯甲酰胺;
-(R)-4-氨基-2-甲基-N-(3,4,5-三氟苯基)-5-(N-(1,1,1-三氟丙烷-2-基)氨磺酰基)苯甲酰胺;
-(S)-4-氨基-2-甲基-N-(3,4,5-三氟苯基)-5-(N-(1,1,1-三氟丙烷-2-基)氨磺酰基)苯甲酰胺;
-4-氨基-N-(3-氯-4,5-二氟苯基)-2-甲基-5-氨磺酰基苯甲酰胺;
-4-氨基-N-(4-氟-3-(三氟甲基)苯基)-2-甲基-5-氨磺酰基苯甲酰胺;
-4-氨基-N-(3-(二氟甲基)-4-氟苯基)-2-甲基-5-氨磺酰基苯甲酰胺;
-4-氨基-N-(3-氰基-4-氟苯基)-2-甲基-5-氨磺酰基苯甲酰胺;
-4-氨基-N-(3-氯-4-氟苯基)-2-甲基-5-氨磺酰基苯甲酰胺;
及其药学上可接受的盐、互变异构体、异构体、立体异构体。
特别地,化合物4-氨基-3-氨磺酰基-N-(3,4,5-三氟苯基)苯甲酰胺和4-氨基-2-甲基-5-氨磺酰基-N-(3,4,5-三氟苯基)苯甲酰胺是优选的。
优选的化合物在测试浓度下具有如下定义的HBV抑制百分比活性,大于50%(优选大于60%,更优选大于75%),和/或如下定义的EC50,小于1μM。HBV抑制表示对HBV表达和/或复制的抑制。本发明化合物的抑制活性可以如下所述测定。
本发明的一个目的是用于医学用途的如上所定义的化合物。优选地,如上所定义的化合物用于治疗和/或预防HBV感染和/或与HBV感染有关的病症。
在一个优选的实施方式中,用于治疗和/或预防HBV感染和/或与HBV感染有关的病症的化合物具有通式(I):
其中:
A是6元芳族或杂芳族环;
B是任选地含有一个或多个N原子的6元芳基;
X是H或NR3R4;
Y选自下组:氢,卤素,C1-6烷基,NH2,NH(C1-6烷基),N(CH3)2,NHC(O)CH3,OH,饱和或部分不饱和的C3-7环烷基,5-或6-元杂芳基和CN,或不存在;
限制条件是,当X是H时,Y选自下组:NH2,NH(C1-6烷基),N(CH3)2,NHC(O)CH3;
R1及R2各自独立地选自H,直链或支化1-6烷基,饱和或部分不饱和的C3-7环烷基,C3-7杂环烷基和杂芳基,所述直链或支化的C1-6烷基,饱和或部分不饱和的C3-7环烷基,C3-7杂环烷基或杂芳基各自任选地被选自以下的一个或多个取代基取代:OH,卤素,NH2,NH(C=O)OC1-6烷基,NH(C1-6烷基),C1-6烷基,C3-7环烷基,C3-7杂环烷基,C1-6羟烷基,5-或6-元杂芳基,C(=O)C1-6烷基,C(=O)OC1-6烷基,OC1-6烷基,O(CH2)nC3-10环烷基和O(CH2)nC3-10杂环烷基;
或R1和R2与它们所连接的N原子一起形成饱和或部分不饱和的3-10元杂环,其任选地包含选自N、O和S的另一个杂原子,所述饱和或部分不饱和的3-10元杂环任选地被选自OH,卤素,C1-6烷基,C1-6卤代烷基和(CH2)nR5的一个或多个取代基取代;
n在每次出现时独立地是0、1、2、3或4;
R3和R4各自独立地是H,或直链或支化C1-3烷基,其任选地被选自卤素,NH2,NHC1-6烷基,N(C1-6烷基)2,NH(C=O)C1-6烷基,NH(C=O)OC1-6烷基,OC1-6烷基,O(CH2)nC3-10环烷基和O(CH2)nC3-10杂环烷基的一个或多个基团取代,限制条件是NR3R4不形成饱和、部分饱和或不饱和的杂环;
R5选自下组:OH,NH2,NH(CH3),N(CH3)2,NHC(O)CH3,CN,卤代C1-3烷基,C1-3烷氧基,卤代C1-3烷氧基,杂环,芳基和杂芳基;
Ra选自下组:氢,卤素,C1-3烷基,卤代C1-3烷基,C1-3烷氧基,卤代C1-3烷氧基,NH2,NH(CH3),N(CH3)2,NHC(O)CH3,OH和CN;或不存在;
Rb选自下组:氢,卤素,C1-3烷基,卤代C1-3烷基,C1-3烷氧基,卤代C1-3烷氧基,NH2,NH(CH3),N(CH3)2,NHC(O)CH3,OH和CN;或不存在;
Rc选自下组:氢,卤素,C1-3烷基,卤代C1-3烷基,C1-3烷氧基,卤代C1-3烷氧基,NH2,NH(CH3),N(CH3)2,NHC(O)CH3,OH和CN;或不存在;
Rd选自下组:氢,卤素,C1-3烷基,卤代C1-3烷基,C1-3烷氧基,卤代C1-3烷氧基,NH2,NH(CH3),N(CH3)2,NHC(O)CH3,OH和CN;或不存在;
Re选自下组:氢,卤素,C1-3烷基;或不存在;
Rf是氢,卤素,C1-3烷基;或不存在;
及其药学上可接受的盐、互变异构体、异构体、立体异构体。
本发明的另一个目的是用于在有此需要的个体中治疗、根除、减少、减慢或抑制HBV感染,和/或用于在有此需要的个体中用于减少与HBV感染相关联的病毒载量,和/或用于在有此需要的个体中减少HBV感染的复发,和/或用于在有此需要的个体中诱导由HBV感染引起的肝损伤的缓解,和/或用于在具有潜在HBV感染的个体中预防性治疗HBV感染的如上所定义的化合物。
优选地,如上所定义的化合物与至少一种其它治疗剂组合使用。优选地,所述组合使用包括至少一种治疗剂的给予。
本发明的目的是药物组合物,其包含单独或与至少一种其它治疗剂组合的如上所定义的化合物,以及至少一种药学上可接受的赋形剂。
优选地,至少一种其它治疗剂选自下组:治疗性疫苗;RNA干扰治疗剂/反义寡核苷酸;免疫调节剂;STING激动剂;RIG-I调节剂;NKT调节剂;IL激动剂;白介素或其它免疫作用蛋白;治疗性和预防性疫苗;免疫检查点调节剂/抑制剂;HBV进入抑制剂;cccDNA调节剂;HBV蛋白表达抑制剂;靶向HBV RNA的物质;衣壳组装抑制剂/调节剂;核心或X蛋白靶向剂;核苷酸类似物;核苷类似物;干扰素或修饰的干扰素;机理不同或未知的HBV抗病毒剂;亲环蛋白抑制剂;sAg释放抑制剂;HBV聚合酶抑制剂;二核苷酸;SMAC抑制剂;HDV靶向剂;病毒成熟抑制剂;逆转录酶抑制剂和HBV RNA去稳定剂或HBV蛋白表达的其它小分子抑制剂;或其组合。
优选地,治疗性疫苗选自:HBsAG-HBIG,HB-Vac,ABX203,NASVAC,GS-4774,GX-110(HB-110E),CVI-HBV-002,RG7944(INO-1800),TG-1050,FP-02(Hepsyn-B),AIC649,VGX-6200,KW-2,TomegaVax-HBV,ISA-204,NU-500,INX-102-00557,HBVMVA和PepTcell。
优选地,RNA干扰治疗剂是siRNA,ddRNA或shRNA。优选地,RNA干扰治疗剂选自:TKM-HBV(ARB-1467),ARB-1740,ARC-520,ARC-521,BB-HB-331,REP-2139,ALN-HBV,ALN-PDL,LUNAR-HBV,GS3228836和GS3389404。
优选地,免疫调节剂是TLR激动剂。优选地,TLR激动剂是TLR7,TLR8或TLR9激动剂。优选地,TLR7,TLR8或TLR9激动剂选自:RG7795(RO-6864018),GS-9620,SM360320(9-苄基-8-羟基-2-(2-甲氧基-乙氧基)腺嘌呤),AZD 8848([3-({[3-(6-氨基-2-丁氧基-8-氧代-7,8-二氢-9H-嘌呤-9-基)丙基][3-(4-吗啉基)丙基]氨基}甲基)苯基]乙酸甲酯)和ARB-1598。
优选地,RIG-1调节剂是SB-9200。优选地,IL激动剂或其它免疫作用蛋白是INO-9112或重组IL12。优选地,免疫检查点调节剂/抑制剂是BMS-936558(欧狄沃(Opdivo)(纳武单抗))或派姆单抗。优选地,HBV进入抑制剂是MyRcludex B,IVIG-TonRol或GC-1102。
优选地,cccDNA调节剂选自:直接cccDNA抑制剂,cccDNA形成或维持的抑制剂,cccDNA表观遗传修饰剂和cccDNA转录抑制剂。
优选地,衣壳组装抑制剂/调节剂,核心或X蛋白靶向剂,直接cccDNA抑制剂,cccDNA形成或维持的抑制剂或cccDNA表观遗传修饰剂选自:BAY41-4109,NVR3-778,GLS-4,NZ-4(W28F),Y101,ARB-423,ARB-199,ARB-596,AB-506,JNJ-56136379,ASMB-101(AB-V102),ASMB-103,CHR-101,CC-31326,AT-130和RO7049389。
优选地,干扰素或修饰的干扰素选自:干扰素α(IFN-α),聚乙二醇化干扰素α(PEG-IFN-α),干扰素α-2a,重组干扰素α-2a,聚乙二醇化干扰素α-2a(派罗欣(Pegasys)),干扰素α-2b(内含子A),重组干扰素α-2b,干扰素α-2b XL,聚乙二醇化干扰素α-2b,糖基化干扰素α-2b,干扰素α-2c,重组干扰素α-2c,干扰素β,干扰素β-1a,聚乙二醇化干扰素β-1a,干扰素δ,干扰素λ(IFN-λ),聚乙二醇化干扰素λ-1,干扰素ω,干扰素τ,干扰素γ(IFN-γ),干扰素Alfacon-1,干扰素α-nl,干扰素α-n3,alb-干扰素α-2b,BLX-883,DA-3021,PI 101(也称为AOP2014),PEG-干复津,Belerofon,INTEFEN-IFN,白蛋白/干扰素α2a融合蛋白,rHSA-IFNα2a,rHSA-IFNα2b,PEG-IFN-SA和干扰素α生物改良剂。特别优选的是:聚乙二醇化干扰素α-2a,聚乙二醇化干扰素α-2b,糖基化干扰素α-2b,聚乙二醇化干扰素β-1a和聚乙二醇化干扰素λ-1。更特别优选的是聚乙二醇化干扰素α-2a。
优选地,机理不同或未知的HBV抗病毒剂选自:AT-61((E)-N-(1-氯-3-氧代-1-苯基-3-(哌啶-1-基)丙-1-烯-2-基)苯甲酰胺),AT130((E)-N-(1-溴-1-(2-甲氧基苯基)-3-氧代-3-(哌啶-1-基)丙-1-烯-2-基)-4-硝基苯甲酰胺),其类似物,REP-9AC(REP-2055),REP-9AC’(REP-2139),REP-2165和HBV-0259。
优选地,亲环蛋白抑制剂选自:OCB-030(NVP-018),SCY-635,SCY-575和CPI-431-32。
优选地,所述HBV聚合酶抑制剂选自:恩替卡韦(博路定(Baraclude),恩他韦(Entavir)),拉米夫定(3TC,干安能(Zeffix),贺普丁(Heptovir),益平维(Epivir)和益平维-HBV),替比夫定(替泽卡(Tyzeka),素比伏(Sebivo)),克列夫定,贝西福韦,阿德福韦(贺维力(Hepsera)),替诺福韦。优选地,替诺福韦为盐形式。优选地,替诺福韦为盐形式,选自:替诺福韦富马酸替索罗韦(Viread),替诺福韦富马酸阿芬太尼(TAF),替诺福韦替泊罗乳清酸酯(DA-2802),替诺福韦二异丙氧基天冬氨酸酯(CKD-390),AGX-1009和CMX157。
优选地,二核苷酸是SB9200。优选地,SMAC抑制剂是比瑞那帕(Birinapant)。优选地,HDV靶向剂是洛那法尼(Lonafamib)。
优选地,HBV RNA去稳定剂或HBV蛋白表达的其它小分子抑制剂是RG7834或AB-452。
优选地,至少一种其它治疗剂是可用于治疗和预防乙型肝炎的药剂。优选地,至少一种其它治疗剂是抗HDV剂,抗HCV剂和/或抗HIV剂。
优选地,至少一种其它治疗剂选自:HBV聚合酶抑制剂,干扰素,病毒进入抑制剂,BAY41-4109,逆转录酶抑制剂,TLR激动剂,AT-61((E)-N-(1-氯-3-氧代-1-苯基-3-(哌啶-1-基)丙-1-烯-2-基)苯甲酰胺),AT-130((E)-N-(1-溴-1-(2-甲氧基苯基)-3-氧代-3-(哌啶-1-基)丙-1-烯-2-基)-4-硝基苯甲酰胺,及其组合,其中HBV聚合酶抑制剂优选为拉米夫定,恩替卡韦,替诺福韦,阿德福韦,替比夫定,克列夫定中的至少一种;并且其中TLR激动剂优选选自下组:SM360320(9-苄基-8-羟基-2-(2-甲氧基-乙氧基)腺嘌呤),AZD8848([3-({[3-(6-氨基-2-丁氧基-8-氧代-7,8-二氢-9H-嘌呤-9-基)丙基][3-(4-吗啉基)丙基]氨基}甲基)苯基]乙酸甲酯),及其组合。
优选地,本发明的化合物与一种、两种或更多种如上定义的其它治疗剂组合使用。
优选地,本发明的药物组合物包含一种、两种或更多种如上定义的其它治疗剂。
如上所定义的药物组合物优选旨在用于治疗和/或预防HBV感染和/或与HBV感染有关的病症。优选地,本发明的药物组合物用于在有此需要的个体中治疗、根除、减少、减慢或抑制HBV感染,和/或用于在有此需要的个体中用于减少与HBV感染相关联的病毒载量,和/或用于在有此需要的个体中减少HBV感染的复发,和/或用于在有此需要的个体中诱导由HBV感染引起的肝损伤的缓解,和/或用于在具有潜在HBV感染的个体中预防性治疗HBV感染。
在一个实施方式中,本发明提供了一种试剂盒或药盒,其包含至少一个药学上可接受的小瓶或容器,其中含有一个或多个剂量的本发明的化合物或本发明的药物组合物,和任选地a)其用于哺乳动物的使用说明和/或b)包含药学上可接受的稀释剂的输液袋或容器。
本发明的另一个目的是用于合成通式(I)或(Ia)的化合物的方法。
具体地,本发明的另一个目的是合成式I化合物或其药学上可接受的盐,互变异构体,溶剂化物,异构体或立体异构体(如上定义)的方法,所述方法包括以下步骤中的至少一个:
-使式(2)的化合物与式NHR3R4的胺反应,以获得式(3)的化合物,其中A,B,Ra,Rb,Rc,Rd,Re,Rf,Y,R1,R2,R3和R4如上定义,且Lg是离去基团,如Cl或F;
-使式(2)的化合物与铵盐如NH4OH反应,以获得式(4)的化合物,其中A,B,Ra,Rb,Rc,Rd,Re,Rf,Y,R1和R2如上定义,且Lg是离去基团,如Cl或F;
-使式(5)化合物与式(CH3)2NH或(C1-6)烷基NH2的胺,或与NH4OH反应,得到式(6)化合物,其中A,B,Ra,Rb,Rc,Rd,Re,Rf,R1和R2如上定义,并且Lg是离去基团,如Cl或F。
本发明的另一个目的是药物组合物,其包含有效量的一种或多种如上定义的化合物或其药学上可接受的前药,其单独或与其它活性化合物组合,和至少一种药学上可接受的赋形剂。
本发明在其范围内包括上述式(I)或(Ia)的化合物的前药。通常,此类前药将是本发明化合物的功能性衍生物,其易于体内转化为所需的式(I)或(Ia)的化合物。选择和制备适当前药衍生物的常规操作描述于例如“Design of Prodrugs(《前药设计》)”,H.Bundgaard编,埃尔斯威尔出版社(Elsevier),1985。
前药可以是生物活性物质的药理学惰性衍生物(“母体药物”或“母体分子”),其需要在体内转化以释放活性药物,并且与母体药物分子相比具有改善的递送性质。体内转化可以是例如某些代谢过程的结果,例如羧酸、磷酸或硫酸酯的化学或酶促水解,或易感官能团的还原或氧化。
本发明还包括本公开化合物的所有合适的同位素变体。可以掺入本公开的化合物中的同位素的示例包括分别例如2H,3H,13C,14C,15N,17O,18O,31P,32P,35S,18F和36Cl的同位素。本公开的某些同位素变体,如其中掺有放射性同位素如3H或14C的那些,可用于药物和/或底物的组织分布研究。并且,用同位素如氘2H取代可以提供更大代谢稳定性带来的某些治疗优势。本公开化合物的同位素变体可以通过常规技术一般地制备,例如采用合适的反应试剂的同位素变体通过示例性方法或者实施例中描述的制备过程制备。
本发明在其范围内包括式(I)或(Ia)的化合物或相关盐的溶剂化物,例如水合物,醇化物等。
本发明的化合物可以具有不对称中心、手性轴和手性平面(如描述于:E.L.Eliel和S.H.Wilen,《碳化合物的立体化学》(Stereochemistry of Carbon Compounds),约翰父子出版公司(John Wiley&Sons),纽约,1994,第1119-1190页),且以外消旋体、外消旋混合物和个别非对映体形式存在,所有可能的异构体及其混合物,包括旋光异构体,所有这些立体异构体都包括在本发明中。
本发明化合物和中间体的纯立体异构形式可以通过应用本领域已知的方法获得,并且意在被本发明的范围所涵盖。特别地,“纯立体异构形式”或“立体异构纯”是指具有至少80%,优选至少85%的过量立体异构体的化合物。例如,对映异构体可以通过其非对映异构体盐的选择性结晶或通过使用手性固定相的色谱技术彼此分离。纯的立体化学异构形式也可以衍生自合适起始原料的相应的纯的立体化学异构形式,前体条件是该反应是立体定向地发生的。术语“对映体纯”应以类似方式解释,考虑到对映体比例。
另外,本文公开的化合物可以互变异构体的形式存在,并且所有互变异构形式都意图被本发明的范围所涵盖,即使仅描绘了一种互变异构结构也是如此。
化合物可以不同的异构体形式存在,所有这些均被本发明涵盖。例如,本发明的特定化合物可以顺式和反式几何异构体形式存在,并且全部被本发明涵盖。
当任何变量(例如R3和R4等)在任何组成部分中多次出现时,其在每次出现时的定义在其它每次出现时均独立。而且,仅当取代基和变量的组合产生稳定的化合物时,这些组合才是被允许的。从取代基引入环系统的线表示所指示的键可以连接至任何可被取代的环原子。如果环系统是多环的,则意味着该键仅与近端环上的任何合适的碳原子连接。
可以理解,本发明化合物的取代基和取代方式可以由本领域普通技术人员选择,以提供化学上稳定并且可以容易地通过本领域已知技术以及下述那些方法由可以容易获得的起始物质合成的化合物。如果取代基本身被多于一个基团取代,则可以理解,这些多个基团可以在相同的碳上或在不同的碳上,只要能够形成稳定的结构即可。短语“任选地被取代(的)”应被认为等同于短语“未被取代或被一个或多个取代基取代(的)”,在这种情况下,优选的实施方式将具有零至三个取代基。更特别地,存在0-2个取代基。
技术人员将容易理解述及给定的取代基时术语“不存在”的含义。特别地,将理解的是,该术语适用于当取代基将结合的原子已经达到其最大化合价并且因此不能容纳任何其它取代基时的情况。例如,当与取代基结合的原子涉及多键时,取代基可能不存在。
还应理解,(述及给定的取代基时)表述“不存在”是指将与取代基结合的原子是杂原子,优选为氮,其包含在杂芳基环中,例如吡啶或嘧啶环。
表述“一个或多个取代基”特别地是指1、2、3、4或更多个取代基,特别地是指1、2、3或4个取代基,更特别地是指1、2或3个取代基。
如本文所用,“烷基”旨在包括具有指定碳原子数的支化和直链饱和脂族烃基。例如,“C1-6烷基”被定义为包括具有直链或支化排列的1,2,3,4,5或6个碳的基团。例如,“C1-6烷基”具体包括甲基,乙基,正丙基,异丙基,正丁基,叔丁基,异丁基,戊基,己基等。“C1-4烷基”被定义为包括具有直链或支化排列的1,2,3或4个碳原子的基团。“C1-3烷基”被定义为包括具有直链或支化排列的1、2或3个碳的基团。优选的烷基是甲基,乙基,异丙基或叔丁基。
如本文所用,“烷氧基”表示通过氧桥连接的所示碳原子数的烷基。因此,“烷氧基”涵盖以上烷基的定义。C1-6烷氧基优选为直链或支化的C1-4烷氧基,更优选C1-3烷氧基,还更优选C1-2烷氧基。合适的烷氧基的实例包括但不限于:甲氧基,乙氧基,正丙氧基,异丙氧基,正丁氧基,仲丁氧基或叔丁氧基。优选的烷氧基是甲氧基。
如本文所用,术语“卤代C1-6烷基”和“卤代C1-6烷氧基”是指其中一个或多个(特别是1-3个)氢原子已被卤素原子(尤其是氟或氯原子)取代的C1-6烷基或C1-6烷氧基。卤代C1-6烷氧基优选为直链或支化的卤代C1-4烷氧基,更优选卤代C1-3烷氧基,还更优选卤代C1-2烷氧基,例如OCF3,OCHF2,OCH2F,OCH2CH2F,OCH2CHF2或OCH2CF3,最特别地是OCF3或OCHF2。卤代C1-6烷基优选是直链或支化的卤代C1-3烷基,更优选地是卤代C1-2烷基,例如CF3,CHF2,CH2F,CH2CH2F,CH2CHF2,CH2CF3或CH(CH3)CF3,且更特别地是CF3,CHF2或CH(CH3)CF3。
如本文所用,术语“C1-6羟烷基”是指其中一个或多个(特别是1-3个)氢原子被羟基取代的C1-6烷基。类似地,术语“羟基C1-4烷基”是指其中一个或多个(特别是1-2个)氢原子被羟基取代的C1-4烷基。说明性实例包括但不限于CH2OH,CH2CH2OH,CH(CH3)OH和CHOHCH2OH。
如本文所用,术语“芳基”是指包含碳原子和氢原子的单环或多环芳族环。如果指示,则此类芳族环可包含一个或多个杂原子,则也称为“杂芳基”或“杂芳族环”,优选地是独立地选自氮,氧和硫的1-3个,优选地是氮的杂原子。如本领域技术人员所公知的,杂芳基环比其全碳对位部分具有更少的芳族特性。因此,出于本发明的目的,杂芳基仅需要具有一定程度的芳族特性。芳基的说明性实例是任选取代的苯基。根据本发明的杂芳基的说明性实例包括任选取代的噻吩,噁唑,噻唑,噻二唑,咪唑,吡唑,嘧啶,吡嗪和吡啶。因此,任选地包含一个或多个杂原子,例如一个或两个杂原子的单环芳基的示例是5元或6元芳基或杂芳基,例如但不限于苯基,吡啶基,嘧啶基,吡嗪基,哒嗪基,吡咯基,噻吩基,噻唑基,噻二唑基,吡唑基,咪唑基,三唑基,四唑基,呋喃基,异噁唑基,噁二唑基和噁唑基。任选地包含一个或多个杂原子,例如一个或两个杂原子的多环芳族环的示例有:8-10元芳基或杂芳基,例如但不限于,苯并咪唑基,苯并呋喃二酰基,苯并呋喃基,苯并呋吖基,苯并吡唑基,苯并三唑基,苯并噻吩基,苯并噁唑基,苯并噁唑啉基(benzoxazolonyl),苯并噻唑基,苯并噻二唑基,苯并二噁唑基,苯并噁二唑基,苯并异噁唑基,苯并异噻唑基,吲哚基,吲哚嗪基,异吲哚啉基,吲唑基,异苯并呋喃基,异吲哚基,异喹啉基,喹唑啉基,喹啉基,喹喔啉基,喹嗪基,萘基,萘啶基和酞嗪基。根据本发明的优选的芳环是苯基。根据本发明的优选的杂芳族环是吡啶基。
杂环,杂环化合物或环结构是具有至少两种不同元素的原子作为其环成员的环状化合物。
如本文所用,术语“杂环”是3至10元的饱和或部分饱和的非芳族单环或双环系统,其包含选自N,O或S的一个或多个杂原子。示例包括但不限于:氮杂环丁烷基,哌嗪基,哌啶基,吗啉基,硫代吗啉基,噻唑烷基,吡咯烷基,氮杂环庚烷基,二氮杂环庚烷基,氧氮杂环庚烷基(oxazepanyl),硫氮杂环庚烷基(thiazepanyl),氮杂环辛烷基,氧氮杂环辛烷基(oxazocanyl),六氢呋喃并[2,3-b]呋喃基或八氢环戊二烯并[b]吡咯。
饱和,部分饱和或不饱和杂环上的取代基可以连接在任何可取代的位置上。
如本文所用,术语“C3-7环烷基”,“C3-10环烷基分别”是指具有3、4、5、6或7或具有3、4、5、6、7、8、9或10个碳原子的饱和环烃(环烷基),且分别类属为环丙基,环丁基,环戊基,环己基,环庚基,和环丙基,环丁基,环戊基,环己基,环庚基,环辛基,环壬基或环癸基。所述饱和环任选地包含一个或多个杂原子(也称为杂环基,C3-10杂环烷基,杂环或杂环烷基),从而至少一个碳原子被选自N、O和S特别是N和O的杂原子替代。根据环的尺寸,它可以是环状或双环状的环结构。示例包括但不限于氧杂环丁烷基,氮杂环丁烷基,四氢-2H-吡喃基,哌嗪基,哌啶基,四氢呋喃基,吗啉基,硫代吗啉基,噻唑烷基,噻吩1,1-二氧化物,吡咯烷基,氮杂环庚烷基,二氮杂环庚烷基,氧氮杂环庚烷基,硫氮杂环庚烷基,氮杂环辛烷基,或氧氮杂环辛烷基。优选具有3、4或5个碳原子和1个氧或1个氮原子的饱和环状烃。示例包括氧杂环丁烷基,四氢呋喃基,四氢-2H-吡喃基,哌啶基或吡咯烷基。
应该注意的是,在整个说明书中所使用的定义中,可以存在各种杂环的不同异构体。例如,吡咯基可以是1H-吡咯基或2H-吡咯基。
还应该注意的是,在定义中使用的任何分子部分上的基团位置可以在该部分上的任何位置,只要它是化学稳定的即可。例如,吡啶基包括2-吡啶基,3-吡啶基,4-吡啶基。
如本文所用,术语“卤素”包括氟,氯,溴和碘,其中优选氟,氯和溴。
术语“杂原子”是指在本文定义的环结构或饱和主链中除碳或氢以外的原子。典型的杂原子包括N(H),O,S。
本发明包括式(I)或(Ia)化合物的游离碱,及其药学上可接受的盐和立体异构体。本文举例的某些具体化合物是胺化合物的质子化盐。含有一个或多个N原子的式(I)或(Ia)的化合物可以在任何一个,一些或全部N个原子上质子化。术语“游离碱”是指非盐形式的胺化合物。所涵盖的药学上可接受的盐不仅包括对于本文所述的具体化合物所例举的盐,而且还包括式(I)或(Ia)的化合物的游离形式的所有典型的药学上可接受的盐。可以使用本领域已知的技术分离所述特定盐化合物的游离形式。例如,可以通过用合适的稀释水性碱溶液例如稀释水性NaOH,碳酸钾,氨水和碳酸氢钠处理盐来再生游离形式。所述游离形式可能在某些物理性质(例如在极性溶剂中的溶解度)上与它们各自的盐形式有所不同,但是出于本发明的目的,酸式盐和碱式盐在药学上等同于它们各自的游离形式。
本发明化合物的药学上可接受的盐可以通过常规化学方法由含有碱性或酸性部分的本发明化合物合成。通常,碱性化合物的盐通过离子交换色谱或通过使游离碱与化学计量的量或与过量的所需成盐的无机或有机酸在合适的溶剂或溶剂的各种组合中反应来制备。类似地,酸性化合物的盐通过与合适的无机或有机碱反应来形成。在一个优选的实施方式中,本发明的化合物具有至少一个酸性质子,并且相应的钠盐或钾盐可以例如通过与合适的碱反应而形成。
因此,本发明化合物的药学上可接受的盐包括通过使碱性速溶(instant)化合物与无机或有机酸或酸性化合物与无机或有机碱反应而形成的本发明化合物的常规无毒盐。例如,这种常规的无毒盐包括衍生自无机酸的盐,所述无机酸例如盐酸,氢溴酸,硫酸,氨基磺酸,磷酸,硝酸等;有机酸制备的盐,所述有机酸例如乙酸,丙酸,琥珀酸,乙醇酸,硬脂酸,乳酸,苹果酸,酒石酸,柠檬酸,抗坏血酸,双羟萘酸,马来酸,羟基马来酸,苯乙酸,谷氨酸,苯甲酸,水杨酸,磺胺酸,2-乙酰氧基苯甲酸,富马酸,甲苯磺酸,甲磺酸,乙烷二磺酸,草酸,羟乙磺酸,三氟醋酸等。常规的无毒盐还包括衍生自无机碱的那些,例如氢氧化钾,氢氧化钠,氢氧化镁或氢氧化钙,以及从有机碱例如乙二胺,赖氨酸,三甲胺,葡甲胺等制备的盐。优选地,本发明的药学上可接受的盐包含一当量的式(I)或(Ia)的化合物和1、2或3当量的无机或有机酸或碱。更特别地,本发明的药学上可接受的盐是酒石酸盐,三氟乙酸盐或氯化物盐。
当本发明的化合物为酸性时,合适的“药学上可接受的盐”是指由药学上可接受的无毒碱,包括无机碱和有机碱制备的盐。衍生自无机碱的盐包括铝,铵,钙,铜,铁,亚铁,锂,镁,锰盐,锰,钾,钠,锌等。特别优选的是铵盐,钙盐,镁盐,钾盐和钠盐。衍生自药学上可接受的有机无毒碱的盐包括以下的盐:伯、仲和叔胺,取代胺,包括天然存在的取代胺,环胺和碱性离子交换树脂,例如精氨酸,甜菜碱咖啡因,胆碱,N,N1-二苄基乙二胺,二乙胺,2-二乙氨基乙醇,2-二甲氨基乙醇,乙醇胺,乙二胺,N-乙基吗啉,N-乙基哌啶,葡糖胺,氨基葡萄糖,组氨酸,肼苯二胺,异丙胺,赖氨酸,甲基葡糖胺,吗啉,哌嗪,哌啶,聚胺树脂,普鲁卡因,嘌呤,可可碱,三乙胺,三甲胺,三丙胺,氨丁三醇等。
上述药学上可接受的盐和其它典型的药学上可接受的盐的制备更详细地描述于Berg等,“Pharmaceutical Salts(药用盐),”J.Pharm.Sci.,1977:66:1-19。
还应注意,本发明的化合物潜在地是内盐或两性离子,因为在生理条件下,化合物中的去质子化的酸性部分,例如羧基,可以是阴离子的,并且该电荷可以被质子化或烷基化碱性部分(如季氮原子)的阳离子电荷内部平衡掉。
本发明的化合物可用于人类和动物健康的多种应用中。本发明的化合物是乙型肝炎病毒(HBV)的抑制剂。
在本发明的上下文中,HBV可以是HBV的任何已知的分离物,基因型,毒株等。
尤其是,乙型肝炎病毒已被分类为八种主要基因型(称为A-H),并初步提出了另外两种基因型(I和J)。HBV基因型已被进一步分为几个亚基因型,它们在整个核苷酸序列中相差4.0%至7.5%。HBV基因型在许多病毒学和可能的某些临床参数上有很大的不同;然而,HBV基因型在感染演化中的准确作用仍存在争议。由于地理分布,在世界上大多数地区只有两种或三种HBV基因型共同流通,从而限制了基因型比较。
本发明的化合物是可用于治疗和/或预防HBV感染的乙型肝炎病毒(HBV)抑制剂。特别地,本发明的化合物是可用于治疗和/或预防HBV感染的乙型肝炎病毒(HBV)核心(HBc)蛋白的抑制剂。
特别认为本文提供的化合物,组合物和方法可用于治疗、改善或预防HBV感染和相关疾病,包括慢性乙型肝炎,HBV/HDV共同感染,HBV/HCV共同感染,HBV/HIV共同感染,乙肝病毒感染引起的炎症,坏死,肝硬化,肝细胞癌,肝代偿失调和肝损伤。
在本发明中,表述“HBV感染”包括源自HBV感染的任何和所有病症,包括但不限于乙型肝炎,优选慢性乙型肝炎,HBV/HDV共同感染,HBV/HCV共同感染,HBV/HIV共同感染。
HBV感染导致广泛的肝并发症,所有这些都是与HBV感染有关的疾病。如本文所用,“与HBV感染有关的病症”优选选自下组:慢性乙型肝炎,HBV/HDV共同感染,HBV/HCV共同感染,HBV/HIV共同感染,乙肝病毒感染引起的炎症,坏死,肝硬化,肝细胞癌,肝代偿失调和肝损伤。
例如“治疗,根除,减少,减慢或抑制HBV感染”之类的表述用于指示向患者施用或给予治疗剂(即本发明的化合物),其单独或与另一种药剂组合施用或给予,或者向来自患者的分离的组织或细胞系施用或给予治疗剂(例如,用于诊断或离体应用),所述患者具有HBV感染,HBV感染症状或可能发展为HBV感染,旨在治愈,疗愈,减轻,缓解,改变,补救,改善,改进或影响HBV感染,HBV感染的症状或发展为HBV感染的可能性。基于从药物基因组学领域获得的知识,可以具体地定制或修改这样的治疗。
可以使用病毒载量的定量或其它感染证据来确定治疗效果,例如通过测量HBeAg,HBsAg,HBV DNA水平,ALT活性水平,血清HBV水平等,从而可以调整治疗剂量,治疗频率和治疗长度。
HBeAg代表乙型肝炎e抗原。这种抗原是一种来自乙型肝炎病毒的蛋白质,当该病毒处于活性复制状态时,它会在受感染的血液中循环。
ALT代表丙氨酸转氨酶,其是一种将氨基从氨基酸丙氨酸转移至α-酮戊二酸以产生谷氨酸(盐或酯)和丙酮酸(盐或酯)的酶。ALT主要位于肝脏和肾脏,心脏和骨骼肌中的含量较少。ALT通常在临床上作为肝功能测试的一部分进行测量。
本发明的化合物可以降低患有HBV感染的个体的病毒载量。在一个非限制性实施方式中,本发明的化合物在有此需要的个体中导致治疗期间病毒载量的减少,从最小的一个或两个对数减少到最大的约八个对数的减少。
如本文所用,表述“减轻HBV感染所致肝损伤”是指慢性坏死性炎性肝病由于病毒抗原已从器官中消失(并且免疫系统不再攻击肝细胞)这一事实而停止。
如本文所用,术语“预防性治疗”是指没有疾病或疾病的发展(如果没有发生),或没有进一步的疾病或疾病的发展(如果已经有疾病或疾病的发展)。还考虑了预防与疾病或病症有关的某些或全部症状的能力。预防性治疗的一个示例可能还表明有必要降低感染肝移植物的风险(在慢性感染患者中进行肝移植的情况)或感染新生儿的风险(慢性感染母亲在分娩时通过病毒传播的情况)。
如本文所用,“减少HBV感染的再次发生”表示在静止数年后患者可能会具有HBV复制的再次活化和与HBV感染有关的病症例如肝炎的恶化。这些患者可能仍处于发展与HBV感染相关的疾病(例如肝细胞癌的发展)的风险中。对于HBsAg阳性的患者以及HBsAg阴性且乙型肝炎核心抗体阳性的患者(其需要用免疫抑制疗法治疗,其具有中等至高HBV再次活化风险)也建议使用抗病毒治疗作为预防措施。
根据标准药学实践,本发明的化合物可以在药物组合物中单独地或与药学上可接受的运载体、赋形剂或稀释剂组合给予哺乳动物,优选人。在一个实施方式中,本发明的化合物可以给予动物。化合物可以口服或胃肠外给药,包括静脉内,肌内,腹膜内,皮下,直肠和局部给药途径。
本发明还提供了包含一种或多种本发明化合物和药学上可接受的运载体的药物组合物。包含活性成分的药物组合物可以是适合口服使用的形式,例如片剂、含片、锭剂、水性或油性混悬剂、可分散粉末剂或粒剂、乳剂、硬或软胶囊、糖浆剂或酏剂。可根据药物组合物制造领域已知的任意方法来制备用于口服使用的组合物,所述组合物可以包含一种或多种试剂,所述试剂选自:甜味剂、调味剂、着色剂和防腐剂,以提供药学上精良的和可口的制剂。片剂含有活性成分和药学上可接受的无毒赋形剂的混合物,所述药学上可接受的无毒赋形剂适合用于制备片剂。这些赋形剂可以是:例如,惰性稀释剂,如碳酸钙、碳酸钠、乳糖、磷酸钙或磷酸钠;成粒剂和崩解剂,如微晶纤维素,交联羧甲纤维素钠,玉米淀粉或藻酸;粘合剂,如淀粉、明胶、聚乙烯吡咯烷酮或阿拉伯胶;和润滑剂,例如硬脂酸镁、硬脂酸或滑石粉。片剂可以是未包衣的,也可以通过已知技术进行包衣,以掩盖药物的不良味道或延迟胃肠道中的崩解和吸收,从而在更长的时间内提供持续的作用。例如,可以使用水溶性掩味材料,例如羟丙基-甲基纤维素或羟丙基纤维素,或延时材料,例如乙基纤维素,乙酸丁酸纤维素。
口服使用的制剂也可制备成其中混有活性成分与惰性固体稀释剂(如碳酸钙、磷酸钙或高岭土)的硬明胶胶囊,或其中混有活性成分与水溶性运载体(例如聚乙二醇)或油性介质(如花生油、液体石蜡或橄榄油)的软明胶胶囊。
含水悬浮液含有活性物质与适用于制造含水悬浮液的赋形剂的混合物。此赋形剂是悬浮剂,如羧甲基纤维素钠、甲基纤维素、羟丙基甲基纤维素、藻酸钠、聚乙烯基吡咯烷酮、黄芪树胶和阿拉伯胶;分散剂或湿润剂可以是天然产生的磷脂(如卵磷脂),或环氧烷与脂肪酸的缩合产物(如聚氧乙烯硬脂酸酯),或环氧乙烷与长链脂肪醇的缩合产物(如十七烷基乙烯氧基十六烷醇(heptadecaethyleneoxycetanol)),或者环氧乙烷与衍生自脂肪酸和己糖醇的偏酯的缩合产物(如聚氧乙烯山梨糖醇单油酸酯),或者环氧乙烷与衍生自脂肪酸和己糖醇酐的偏酯的缩合产物(如聚乙烯山梨聚糖单油酸酯)。含水悬浮液也可含有一种或多种防腐剂(如对羟基苯甲酸乙酯或者对羟基苯甲酸正丙酯)、一种或多种着色剂、一种或多种调味剂、以及一种或多种甜味剂(如蔗糖,糖精或阿斯巴甜)。
油性悬浮液可通过将活性成分悬浮于植物油(例如,花生油、橄榄油、芝麻油或椰子油)或例如液体石蜡的矿物油中来制备。含油悬浮液可含有增稠剂,如蜂蜡、硬石蜡或鲸蜡醇。可加入甜味剂(例如,如上所述的那些)和调味剂,以提供可口的口服制剂。这些组合物可以通过添加抗氧化剂例如丁基化羟基苯甲醚或α-生育酚来保存。
适用于通过加水制备水性悬浮液的可分散粉末和颗粒提供活性成分,其与分散剂或湿润剂、悬浮剂和一种或多种防腐剂混合。合适的分散剂或湿润剂和悬浮剂的例子通过上文所提及的那些进行列举。也可存在其它赋形剂,例如甜味剂、调味剂和着色剂。这些组合物可以通过添加抗氧化剂例如抗坏血酸来保存。
本发明的药物组合物也可以是水包油乳剂的形式。油相可以是植物油(如橄榄油或落花生油),或者是矿物油(如液体石蜡),或者是它们的混合物。合适的乳化剂可以是天然产生的磷脂,例如大豆卵磷脂,和衍生自脂肪酸和己糖醇酐的酯或偏酯,例如脱水山梨醇单油酸酯,以及所述偏酯与环氧乙烷的缩合产物,例如聚氧乙烯脱水山梨糖醇单油酸酯。乳液还可以包含甜味剂,调味剂,防腐剂和抗氧化剂。
糖浆剂和酏剂可与甜味剂(例如甘油、丙二醇、山梨糖醇或蔗糖)一起配制。这样的制剂还可以包含缓和剂,防腐剂,调味剂和着色剂以及抗氧化剂。
药物组合物可以是无菌可注射水溶液的形式。可用的可接受载剂和溶剂是水、林格氏溶液和等渗氯化钠溶液。
无菌注射制剂也可以是无菌注射水包油微乳剂,其中活性成分溶解在油相中。例如,可以首先将活性成分溶解在大豆油和卵磷脂的混合物中。然后将油溶液引入水和甘油的混合物中,并进行加工以形成微乳液。
可通过局部推注将可注射溶液或微乳剂引入患者的血流中。或者,以保持本发明化合物的恒定循环浓度的方式给予溶液或微乳剂可能是有利的。为了维持这样的恒定浓度,可以使用连续的静脉内输送装置。这种装置的一个例子是Deltec CADD-PLUSTM5400型静脉泵。
药物组合物可以是用于肌内和皮下给药的无菌可注射水性或油性悬浮液的形式。该悬浮液可以根据已知技术使用上文已经提到的那些合适的分散剂或湿润剂和悬浮剂来配制。无菌注射制剂也可以是配制在无毒的肠胃外可接受稀释剂或溶剂中的无菌可注射溶液或悬浮液,例如配制在1,3-丁二醇中的溶液剂。此外,常将无菌的非挥发油用作溶剂或悬浮介质。为此,可采用各种低刺激非挥发油,包括合成的甘油单酯或甘油二酯。此外,注射剂的制备中还用到脂肪酸如油酸。
式(I)或(Ia)的化合物也可以栓剂的形式给药,用于直肠给药。这些组合物可通过将药物与合适的无刺激性赋形剂混合进行制备,这些合适的无刺激性赋形剂在常温下是固体,但在直肠温度下是液体,并因此在直肠中融化并释放药物。这些材料包括可可豆脂、甘油明胶、氢化植物油、各种分子量的聚乙二醇的混合物和聚乙二醇的脂肪酸酯。
对于局部使用,使用含有式(I)或(Ia)的化合物的乳膏,软膏,胶冻,溶液或悬浮液等。(出于本申请的目的,局部应用应包括漱口水和含漱剂。)
本发明的化合物可通过局部使用合适的鼻内载剂和递送装置以鼻内形式给予,或使用本领域普通技术人员熟知的那些形式的经皮皮肤贴剂通过经皮途径给予。为了以透皮递送系统的形式给药,在整个给药方案中,剂量给药当然将会是连续的而不是间断的。本发明的化合物也可以使用基质(例如可可脂,甘油明胶,氢化植物油,各种分子量的聚乙二醇的混合物和聚乙二醇的脂肪酸酯)以栓剂形式递送。
本发明的化合物可以脂质体或其它微颗粒或其它纳米颗粒的形式存在,所述脂质体或其它微颗粒或其它纳米颗粒设计为靶向所述化合物。可接受的脂质体可以是中性,带负电或带正电的,其电荷是脂质体组分的电荷和脂质体溶液的pH的函数。脂质体通常可以使用磷脂和胆固醇的混合物制备。合适的磷脂包括磷脂酰胆碱,磷脂酰乙醇胺,磷脂酸,磷脂酰甘油,磷脂酰肌醇。可以添加聚乙二醇以改善脂质体的血液循环时间。可接受的纳米颗粒包括白蛋白纳米颗粒和金纳米颗粒。
当将本发明的化合物给予人类对象时,每日剂量通常将由处方医师确定,该剂量通常根据个体患者的年龄,体重,性别和反应以及患者症状的严重程度而变化。
在一个示例性的应用中,向经历抗HBV治疗的哺乳动物给予合适量的化合物。给予的量通常为每天约0.01mg/kg体重至约100mg/kg体重,优选每天约0.01mg/kg体重至约60mg/kg体重,优选每天约0.1mg/kg体重至约50mg/kg体重,优选每天约0.5mg/kg体重至约40mg/kg体重。
本发明化合物也可与已知治疗剂组合用于同时、分开或顺序给药。
在一个实施方式中,本发明的化合物可以与至少一种或多种其它治疗剂,特别是抗HBV剂组合使用。
本发明化合物用于治疗和/或预防HBV感染的迹象表明该化合物对于治疗,根除,减少,减慢或抑制HBV感染是有效的。
治疗剂是通常用于治疗和/或预防和/或改善HBV感染或与HBV感染有关的病症的任何试剂。治疗剂是本领域已知的。
术语“抗HBV剂”或更简单地“(一种或多种)HBV抗病毒剂”还包括处于其天然形式或化学修饰和/或稳定化的治疗性核酸、抗体或蛋白质的化合物。术语治疗性核酸包括但不限于核苷酸和核苷,寡核苷酸,多核苷酸,其非限制性示例是反义寡核苷酸,miRNA,siRNA,shRNA,治疗性载体和DNA/RNA编辑组分。
术语抗HBV剂还包括能够通过免疫调节来治疗HBV感染的化合物,即免疫调节剂或免疫调节化合物。免疫调节剂的示例有干扰素-α(IFN-α),聚乙二醇化干扰素-α或先天免疫系统的刺激物,例如Toll样受体7和/或8激动剂以及治疗性或预防性疫苗。本发明的一个实施方式涉及如本文所指定的式(I)或(Ia)的化合物或其任何亚组,与免疫调节化合物,更具体地是Toll样受体7和/或8激动剂的组合。
其它HBV抗病毒剂可以选自,例如,治疗性疫苗;RNA干扰治疗剂/反义寡核苷酸(例如siRNA,ddRNA,shRNA);免疫调节剂(例如TLR激动剂(例如TLR7,TLR8或TLR9激动剂);STING激动剂;RIG-I调节剂;NKT调节剂;IL激动剂;白介素或其它免疫活性蛋白,治疗和预防性疫苗,和免疫检查点调节剂;HBV进入抑制剂;cccDNA调节剂(例如直接cccDNA抑制剂,cccDNA形成或维持的抑制剂,cccDNA表观遗传修饰剂,cccDNA转录抑制剂);HBV蛋白表达抑制剂;靶向HBV RNA的试剂;衣壳组装抑制剂/调节剂;核心或X蛋白靶向剂;核苷酸类似物;核苷类似物;干扰素或修饰的干扰素;机理不同或未知的HBV抗病毒剂;亲环蛋白抑制剂;sAg释放抑制剂;HBV聚合酶抑制剂;二核苷酸;SMAC抑制剂;HDV靶向剂;病毒成熟抑制剂;逆转录酶抑制剂和HBV RNA稳定剂,以及HBV蛋白表达的其它小分子抑制剂。
具体地,先前已知的抗HBV剂,例如干扰素-α(IFN-α),聚乙二醇化干扰素-α,3TC,替诺福韦,拉米夫定,恩替卡韦,替比夫定和阿德福韦或其组合,以及式(I)或(Ia)或其任何亚组的组合可以作为药物用于联合疗法中。可以与本发明的化合物组合的其它治疗剂的其它示例包括:齐多夫定,地达诺辛,扎西他滨,司他夫定,阿巴卡韦,ddA,恩曲他滨,阿普西他滨,阿维哌汀,利巴韦林,阿昔洛韦,伐昔洛韦,泛昔洛韦,更昔洛韦,缬更昔洛韦,西多福韦,依法韦伦,奈韦拉平,地拉韦定和依曲韦林。
此类HBV抗病毒剂的特定示例包括但不限于:
-RNA干扰(RNAi)治疗剂:TKM-HBV(也称为ARB-1467),ARB-1740,ARC-520,ARC-521,BB-HB-331,REP-2139,ALN-HBV,ALN-PDL,LUNAR-HBV,GS3228836和GS3389404;
-HBV进入抑制剂:MyRcludex B,IVIG-TonRol,GC-1102;
-HBV衣壳抑制剂/调节剂,核心或X蛋白靶向剂,直接cccDNA抑制剂,cccDNA形成或维持的抑制剂或cccDNA表观遗传修饰剂:BAY41-4109,NVR3-778,GLS-4,NZ-4(也称为W28F),Y101,ARB-423,ARB-199,ARB-596,AB-506,JNJ-56136379,ASMB-101(也称为AB-V102),ASMB-103,CHR-101,CC-31326,AT-130,RO7049389。
-HBV聚合酶抑制剂:恩替卡韦(博路定,恩他韦),拉米夫定(3TC,干安能,贺普丁,益平维和益平维-HBV),替比夫定(替泽卡,素比伏),克列夫定,贝西福韦,阿德福韦(贺维力),替诺福韦(特诺洛韦(特别是富马酸替诺福韦酯(韦瑞德),替诺福韦阿拉芬酰胺富马酸酯(TAF)),替诺福韦二异丙酚乳清酸酯(也称为DA-2802),替诺福韦二异丙酚天冬氨酸(也称为CKD-390),AGX-1009和CMX157);
-HBV RNA去稳定剂和HBV蛋白表达的其它小分子抑制剂:RG7834,AB-452;
-亲环蛋白抑制剂:OCB-030(也称为NVP-018),SCY-635,SCY-575和CPI-431-32;
-二核苷酸:SB9200;
机理不同或未知的化合物,例如但不限于:AT-61((E)-N-(1-氯-3-氧代-1-苯基-3-(哌啶-1-基)丙-1-烯-2-基)苯甲酰胺),AT130((E)-N-(1-溴-1-(2-甲氧基苯基)-3-氧代-3-(哌啶-1-基)丙-1-烯-2-基)-4-硝基苯甲酰胺),以及相似的类似物;REP-9AC(也称为REP-2055),REP-9AC’(也称为REP-2139),REP-2165和HBV-0259;
-TLR激动剂(TLR7、8和/或9):RG7795(也称为RO-6864018),GS-9620,SM360320(9-苄基-8-羟基-2-(2-甲氧基-乙氧基)腺嘌呤),和AZD 8848([3-({[3-(6-氨基-2-丁氧基-8-氧代-7,8-二氢-9H-嘌呤-9-基)丙基][3-(4-吗啉基)丙基]氨基}甲基)苯基]乙酸甲酯)和ARB-1598;
-RIG-I调节剂:SB-9200;
-SMAC抑制剂:比瑞那帕;
-治疗性疫苗:HBsAG-HBIG,HB-Vac,ABX203,NASVAC,GS-4774,GX-110(也称为HB-110E),CVI-HBV-002,RG7944(也称为INO-1800),TG-1050,FP-02(Hepsyn-B),AIC649,VGX-6200,KW-2,TomegaVax-HBV,ISA-204,NU-500,INX-102-00557HBV MVA,PepTcell;
-IL激动剂和免疫作用蛋白:INO-9112;重组IL12;
-干扰素:干扰素α(IFN-α),干扰素α-2a,重组干扰素α-2a,聚乙二醇化干扰素α-2a(派罗欣),干扰素α-2b(内含子A),重组干扰素α-2b,干扰素α-2b XL,聚乙二醇化干扰素α-2b,糖基化干扰素α-2b,干扰素α-2c,重组干扰素α-2c,干扰素β,干扰素β-la,聚乙二醇化干扰素β-1a,干扰素δ,干扰素λ(IFN-λ),聚乙二醇化干扰素λ-1,干扰素ω,干扰素τ,干扰素γ(IFN-γ),干扰素Alfacon-1,干扰素α-n1,干扰素α-n3,alb干扰素α-2b,BLX-883,DA-3021,PI 101(也称为AOP2014),PEG-干扰素,Belerofon,INTEFEN-IFN,白蛋白/干扰素α2a融合蛋白,rHSA-IFNα2a,rHSA-IFNα2b,PEG-IFN-SA,干扰素α生物改良剂;具体是,聚乙二醇化干扰素α-2a,聚乙二醇化干扰素α-2b,糖基化干扰素α-2b,聚乙二醇化干扰素β-1a和聚乙二醇化干扰素λ-1;更具体地,聚乙二醇化干扰素α-2a;
-HDV靶向剂:洛那法尼。
述及本发明的化合物,术语“给药”及其变化形式(例如,“给予”化合物)是指将化合物或化合物的前药引入需要治疗的动物的系统中。当将本发明的化合物或其前药与一种或多种其它活性剂(例如,细胞毒性剂等)组合提供时,“给药”及其变化形式应理解为包括同时或相继引入化合物或其前药和其它药剂。
在一些实施方式中,脉冲给药比连续治疗更有效,因为总脉冲剂量通常低于连续给药相同组合物所预期的剂量。可以减少每个脉冲剂量,并在治疗过程中使给予的药物总量最小化。可以在几个小时(例如大约2、4、6、8、10、12、14或16小时)的时间段或几天(例如2、3、4、5、6或7天)内连续将单个脉冲递送给患者。
如本文所用,术语“组合物”旨在包括含有特定量特定成分的产品,以及直接或间接由特定量的特定成分组合获得的产品。
如本文所用,术语“治疗有效量”是指引起研究人员,兽医,医生或其它临床医师所寻求的在组织,系统,动物或人中的生物学或医学反应的活性化合物或药剂的量。
将通过以下非限制性实施例描述本发明,并提供生物学数据。
材料和方法
化学
概述
除非另有说明,否则无需进一步纯化即可使用市售试剂和溶剂(HPLC级)。
具体来说,在实验方法的描述中可能使用了以下缩写:
NMR:核磁共振;NMR;1H:质子;MHz:兆赫;Hz:赫兹;HPLC:高效液相色谱;LC-MS:液相色谱质谱法;s:秒;min:分钟;h:小时;mg:毫克;g:克;Ml:微升;mL:毫升;mmol:毫摩尔;nm:纳米;μM:微摩尔;M:克分子浓度或摩尔浓度;Rt:保留时间,以分钟为单位;MW:微波;Boc:叔丁氧羰基保护基;DMF:二甲基甲酰胺;DMSO:二甲亚砜;MeOH:甲醇;EtOH:乙醇;EtOAc:乙酸乙酯;DCM:二氯甲烷;MeCN:乙腈;PE:石油醚;TFA:三氟乙酸;(g):气体;eq.:当量;RT:室温;DIPEA:N,N-二异丙基乙胺;DIAD:偶氮二羧酸二异丙酯;sat.aq.:饱和水性溶液;TEA:三乙胺;THF:四氢呋喃;IPA:异丙胺;pTSA:对甲苯磺酸;TBDMS:叔丁基二甲基甲硅烷基;LiHMDS:双(三甲基甲硅烷基)酰胺锂;TBTU:2-(1H-苯并三唑-1-基)-1,1,3,3-四甲基四氟硼酸铵。
除另有说明外,所有温度均以℃(摄氏度)或K(开尔文)表示。
1H-NMR谱用Avance II 300MHz Bruker谱仪获得。化学位移以百万分之一(ppm,δ单位)表示。耦合常数以赫兹(Hz)表示,裂解模式描述为s(单峰),bs(宽信号),d(双峰),t(三重峰),q(四重奏),quint(五重峰),m(多峰)。
LC-MS分析通过UPLC Acquity Waters系统(配备有SQD光谱仪,单四极杆质量检测器和TUV检测器)进行,采用柱1:ACQUITY UPLC BEH SHIELD,RP18(2.1x50mm,id=1.7μm);柱2:ACQUITY UPLC HSS T3,RP18(2.1x50mm,id=1.8μm)和柱3:ACQUITY UPLC BEH SHIELD,RP18(2.1x100mm,id=1.7μm)。柱温40℃。样品温度25℃。A相包含水(HiPerSolv ChromanormWater VWR,用于HPLC-MS)+0,05%三氟乙酸;B相包含CH3CN(HiPerSolv ChromanormAcetonitrile SuperGradient VWR;适用于UPLC/UHPLC仪器)+0,05%三氟乙酸;流速:0,5mL/分钟;紫外检测(DIODE阵列)200nm;ESI+和ESI-检测于100-1000m/z范围。
方法1:柱1,运行时间:3分钟,运行梯度:2.80分钟内5%B至100%B+100%B持续0.2分钟,平衡时间:0,8分钟,电离模式:ESI+。
方法2:柱2,运行时间:4分钟,运行梯度:3.5分钟内0%B至45%B+0.05分钟内45%B至100%B+100%B持续0.45分钟,平衡时间:0,8分钟,电离模式:ESI+。
方法3:柱3,运行时间:6分钟,运行梯度:5分钟内5%B至100%B+100%B持续1分钟,平衡时间:2分钟。
方法4:柱3,运行时间:6分钟,运行梯度:5分钟内5%B至50%B+0.2分钟内50%B至100%B,100%B持续0.8分钟,平衡时间:2分钟,电离模式:ESI+。
方法5:柱1,运行时间:3分钟,运行梯度:2.80分钟内,5%B至100%B+100%B持续0.2分钟,平衡时间:0,8分钟,电离模式:ESI+。
方法6:柱2,运行时间:4分钟,运行梯度:3.5分钟内0%B至45%B+0.05分钟内45%B至100%B+100%B持续0.45分钟,平衡时间:0,8分钟,电离模式:ESI+。
方法7:柱3,运行时间:6分钟,运行梯度:5分钟内,5%B至100%B+100%B持续1分钟,平衡时间:2分钟,电离模式:ESI+。
方法8:柱3,运行时间:6分钟,运行梯度:5分钟内5%B至50%B+0.2分钟内50%B至100%B,100%B持续0.8分钟,平衡时间:2分钟,电离模式:ESI+。
方法9:柱1,运行时间:4分钟,柱1,运行时间:4分钟,运行梯度:3.00分钟内5%B至100%B+100%B持续1分钟,平衡时间:0,8分钟,电离模式:ESI+。
方法10:柱1,运行时间:4分钟,运行梯度:3.00分钟内5%B至100%B+100%B持续1分钟,平衡时间:0,8分钟,电离模式:ESI-。
方法11:柱1,运行时间:3分钟,运行梯度:2.80分钟内40%B至100%B+100%B持续0.2分钟,平衡时间:0,8分钟,电离模式:ESI+。
方法12:柱3,运行时间:6分钟,运行梯度:5分钟内25%B至70%B+100%B持续1分钟,平衡时间:2分钟,流:0,5mL/分钟,电离模式:ESI+。
合成
根据本发明的另一方面,提供了一种用于制备式(I)、(Ia)的化合物或其盐的方法。以下方案是可用于合成本发明化合物的合成方案的示例。在以下方案中,可以根据公认的技术用保护基团保护反应性基团和脱保护。
在以下方案中,除非另有说明,A,B,Y,R1,R2,R3,R4,R5,Ra,Rb,Rc,Rd,Re,Rf如上在式(I)或(Ia)中那样定义。
本领域技术人员应理解,可以根据标准化学方法将本发明的某些化合物转化为本发明的其它化合物。
除非另有说明,否则可以根据方案1按照通用程序制备本发明的化合物:
方案1
步骤A)SOCl2,回流;步骤B)ARNH2,甲苯,回流或ARNH2,碱,甲苯,回流;步骤C)NH4OH,1,4-二噁烷,90-100℃;步骤D)NH4OH,1,4-二噁烷,0℃;步骤E)NH2CH3,碱,DMSO,MeCN;步骤F)NHR1R2,MeCN,碱,0℃至室温;步骤G)NHR3-R4,37%水性H2CO;10%HCl,90℃;步骤H)NH4OH,90-100℃。
可以根据方案2制备实施例E36:
方案2
步骤A)NH4OH,1,4-二噁烷,0℃;步骤B)ARNH2,(1M)LiHMDS,于THF中,室温;步骤C)NH4OH,90℃-120℃,1,4-二噁烷
可以根据以下方案3制备实施例E37和E58:
方案3
步骤A)NH4OH,1,4-二噁烷,室温,或步骤A’)NH2R1,MeCN,碱,0℃至室温;步骤B)ARNH2(1M)LiHMDS,于THF中,室温;步骤C)NH4OH,95℃,1,4-二噁烷
实施例E59,E61和E62可以根据方案4制备:
方案4
步骤A)SOCl2,回流;步骤B)ArNH2,甲苯,回流,步骤C)NHR1R2,MeCN,碱,0℃至室温;步骤D)NH4OH,1,4-二噁烷,0℃。
下列实施例说明某些式(I)、(Ia)化合物或其盐的制备。说明1至40说明了用于制备本发明化合物或其盐的中间体的制备。实施例1至71说明了本发明。
在随后的程序中,通常在说明或实施例中提供程序的起始原料参考。这仅为向熟练的化学研究者提供帮助。起始原料不一定必须由所描述的说明书或实施例制备。
实施例
说明1:3-(氯磺酰基)-4-氟苯甲酰氯(D1)
3-氯磺酰基-4-氟苯甲酸(Fluorochem,目录号037319)(14.2g,59.51mmol)一次加入亚硫酰氯(80.39mL,1106.9mmol)中。将所得的淡黄色溶液加热至回流4小时,得到浆液。通过与甲苯共蒸发来真空除去溶剂,得到标题化合物D1(15.4g,59.91mmol),为棕色油。
说明2:2-氯-5-(氯磺酰基)-4-氟苯甲酰氯(D2)
由2-氯-5-氯磺酰基-4-氟-苯甲酸(Enamine,目录号EN300-01843)起始,根据所述用于制备化合物D1时描述的方法类似地进行制备。
说明3:2-溴-5-(氯磺酰基)-4-氟苯甲酰氯(D3)
由2-溴-5-(氯磺酰基)-4-氟苯甲酸(Enamine,目录号EN300-52736)起始,根据用于制备D1时描述的方法类似地进行制备。
说明4:5-(氯磺酰基)-2,4-二氟苯甲酰氯(D4)
由5-(氯磺酰基)-2,4-二氟苯甲酸(Enamine,目录号EN300-59276)起始,根据用于制备D1时描述的方法类似地进行制备。
说明5:3-(氯磺酰基)-4,5-二氟苯甲酰氯(D5)
由3-(氯磺酰基)-4,5-二氟苯甲酸(Enamine,目录号EN300-107773)起始,根据用于制备D1时描述的方法类似地进行制备。
说明6:5-(氯磺酰基)-4-氟-2-甲基苯甲酰氯(D6)
由5-(氯磺酰基)-4-氟-2-甲基苯甲酸(Enamine,目录号EN300-114063)起始,根据用于制备D1时描述的方法类似地进行制备。
说明7:2-氟-5-((3,4,5-三氟苯基)氨基甲酰基)苯磺酰氯(D7)
将D1(15.4g,59.91mmol)溶解在甲苯(140mL)中,加热至回流,然后在10分钟内滴加甲苯(50mL)中的3,4,5-三氟苯胺(8.81g,59.91mmol)溶液。形成悬浮液并回流1小时。将反应冷却至室温,过滤,并将所得滤饼用少量甲苯洗涤,得到标题化合物D7(14.5g,39.43mmol),为灰白色固体。1H NMR(300MHz,DMSO-d6)δppm 7.32(t,J 9.03Hz,1H)7.68-7.81(m,2H)7.90-8.03(m,1H)8.30(dd,J=6.83,2.43Hz,1H)10.71(s,1H).方法1:Rt=2.43min,m/z=368.32(M+H)+.
说明8:5-((3,4-二氟苯基)氨基甲酰基)-2-氟苯磺酰氯(D8)
在90℃下,向D1(1.8g,7.0mmol)在无水甲苯(13.5mL)中的溶液逐滴添加三乙胺(1mL,7.175mmol)和3,4-二氟苯胺(0.904g,7.0mmol)在无水甲苯(3.5mL)中的溶液。反应混合物在回流下搅拌30分钟,然后在室温下冷却,并用二氯甲烷稀释。有机层用盐水洗涤,经Na2SO4干燥,过滤并减压蒸发,以得到米色固体(2.39g)为粗产物,将其悬浮在DCM(5mL)中并超声处理。所得固体经过滤,用DCM洗涤,并在真空泵下干燥,得到标题化合物D8,为白色粉末(1.73g)。1H NMR(300MHz,DMSO-d6)δppm 7.26-7.48(m,3H)7.52-7.61(m,1H)7.91-7.99(m,2H)8.30(dd,J=6.88,2.38Hz,1H)10,59(s,1H).方法1:Rt=2.43min,m/z=350.02(M+H)+.
说明9:5-[(3-氯-4-氟苯基)氨基甲酰基]-2-氟苯-1-磺酰氯(D9)
与就制备D8所述方法类似的方式进行制备,由3-(氯磺酰基)-4-氟苯甲酰氯D1起始,并使用3-氯-4-氟苯胺代替3,4-二氟苯胺,得到标题化合物D9。方法1:Rt=2.43min,m/z=366.01(M+H)+.
说明10:2-氟-5-((4-氟-3-(三氟甲基)苯基)氨基甲酰基)苯磺酰氯(D10)
根据与制备D7所述方法类似地进行制备,使用D1(500mg,1.94mmol)和4-氟-3-(三氟甲基)苯胺(0.25mL,1.94mmol)代替3,4,5-三氟苯胺作为起始原料。将反应混合物真空浓缩,得到标题化合物D10(805mg),为米色固体,将其直接用于下一合成步骤。
说明11:5-((3-氰基-4-氟苯基)氨基甲酰基)-2-氟苯磺酰氯(D11)
根据与制备D7所述方法类似地进行制备,使用D1和5-氨基-2-氟苄腈代替3,4,5-三氟苯胺作为起始原料。
说明12:5-((3-(二氟甲基)-4-氟苯基)氨基甲酰基)-2-氟苯磺酰氯(D12)
根据与制备D7所述方法类似地进行制备,使用D1和3-(二氟甲基)-4-氟苯胺代替3,4,5-三氟苯胺作为起始原料。
说明13:5-((6-氯吡啶-3-基)氨基甲酰基)-2-氟苯磺酰氯(D13)
将D1(307mg,1.19mmol)溶解在甲苯(2.7mL)中,并加热至90℃。缓慢加入6-氯吡啶-3-胺(153.5mg,1.19mmol)在甲苯(1.2mL)中的悬浮液,并使反应混合物在110℃下回流20分钟。然后添加DIPEA(0.31mL,1.79mmol),并使该反应在110℃下另回流1小时50分钟。将混合物真空浓缩,得到粗制标题化合物D13(702mg),为棕色油,将其直接用于下一合成步骤。方法1;Rt=2.17min,m/z=349.00(M+H)+.
说明14:2-氟-4-甲基-5-((3,4,5-三氟苯基)氨基甲酰基)苯磺酰氯(D14)
与根据制备D7所述的方法类似地进行制备,由5-(氯磺酰基)-4-氟-2-甲基苯甲酰氯D6代替D1起始。方法1;Rt=2.49min,m/z=382.11(M+H)+.
说明15:2-氟-5-((4-氟-3-甲基苯基)氨基甲酰基)苯磺酰氯(D15)
根据与制备D7所述方法类似地进行制备,使用D1和4-氟-3-甲基苯胺代替3,4,5-三氟苯胺作为起始原料。方法1;Rt=2.38min,m/z=346.17(M+H)+.
说明16:5-((3,5-二氟-4-甲基苯基)氨基甲酰基)-2-氟苯磺酰氯(D16)
根据与制备D7所述方法类似地进行制备,使用D1和3,5-二氟-4-甲基苯胺代替3,4,5-三氟苯胺作为起始原料。方法1;Rt=2.54min,m/z=364.20(M+H)+.
说明17:2-氟-5-((2,3,4-三氟苯基)氨基甲酰基)苯磺酰氯(D17)
根据与制备D7所述方法类似地进行制备,使用D1和2,3,4-三氟苯胺代替3,4,5-三氟苯胺作为起始原料。方法1;Rt=2.29min,m/z=368.19(M+H)+.
说明18:2-氟-5-((2,4,5-三氟苯基)氨基甲酰基)苯磺酰氯(D18)
根据与制备D7所述方法类似地进行制备,使用D1和2,4,5-三氟苯胺代替3,4,5-三氟苯胺作为起始原料。方法1;Rt=2.32min,m/z=368.39(M+H)+.
说明19:2-氟-5-((2,4,5-三氟苯基)氨基甲酰基)苯磺酰氯(D19)
根据与制备D7所述方法类似地进行制备,使用原料D1和2-氯-4-氟苯胺代替3,4,5-三氟苯胺作为起始原料。方法1;Rt=2.32min,m/z=366.03(M+H)+.
说明20:4-氟-3-氨磺酰基-N-(3,4,5-三氟苯基)苯甲酰胺(D20)
使D7(3g,8.16mmol)溶解在1,4-二噁烷(20mL,0.23mol)中,并在0℃下单次添加至氨(10.42mL,163.18mmol)。反应搅拌15分钟,然后用水稀释,并用2Me-THF萃取。有机层用6NHCl洗涤并蒸发,得到棕色固体(2.5g),使其与DCM一起研磨,得到标题化合物D20(2g,5.74mmol),为灰白色固体。方法1;Rt:1.85min.m/z:349.21(M+H)+.
说明21:2-氯-4-氟-5-氨磺酰基-N-(3,4,5-三氟苯基)苯甲酰胺(D21)
在20mL小瓶中装入3,4,5-三氟苯胺(245.4mg,1.67mmol),然后单次添加D2(221.04mg,0.76mmol)在甲苯(5mL)中的溶液。将小瓶密封并使反应混合物在室温搅拌10分钟,得到白色浆液。反应用甲苯(3mL)稀释,并由微波辐射在70℃加热20分钟。将反应浆液冷却至室温,然后倒入含acqu.NH4OH(约30mL)的烧瓶中,并在室温下剧烈搅拌过夜。将所得白色浆液用DCM稀释,用冰处理,并用6N HCl酸化直至pH=1。有机层用EtOAc稀释,用6N HCl洗涤两次,用盐水洗涤,用MgSO4(干)干燥,过滤,最后蒸发,得到标题化合物D21(250mg,0.65mmol),为白色固体。1H NMR(300MHz,DMSO-d6)δppm 7.13-7.30(m,1H)7.53-7.66(m,2H)7.89-8.02(m,3H)11.05(s,1H).方法9;Rt:2.02min.m/z:383.05(M+H)+.
说明22:2-溴-4-氟-5-氨磺酰基-N-(3,4,5-三氟苯基)苯甲酰胺(D22)
在20mL小瓶中装入D3(500mg,1.49mmol),3,4,5-三氟苯胺(437.85mg,2.98mmol)和甲苯(4mL)。小瓶被密封并在室温下搅拌10分钟后得到白色悬浮液。反应用甲苯(3mL)稀释,且反应混合物在100℃通过微波辐射加热15分钟,用甲苯(5mL)稀释并倒入37%NH4OH(20mL)中。添加MeCN(2mL),并将所得混合物在室温搅拌4小时。
反应混合物用EtOAc稀释并用EtOAc萃取;有机层经MgSO4(干)干燥,过滤并蒸发,得到标题化合物D22(700mg,纯度75%)。该中间体无需任何纯化即可用于下一步。方法1;Rt:1.93min.m/z:427.16(M+H)+.
说明23:N-(3-氯-4-氟苯基)-4-氟-3-氨磺酰基苯甲酰胺(D23)
将D9(200mg,0.55mmol)悬浮于MeCN(2mL)中,用冰浴冷却至0℃,然后用单份氨水(2.18mL,10.92mmol)处理。反应在0℃搅拌5分钟,得到淡黄色溶液。真空除去溶剂,并将残余物用水稀释并用EtOAc萃取。真空除去溶剂,得到标题化合物D23(200mg,0.55mmol)。方法1;Rt:1.88min.m/z:346.98(M+H)+.
说明24:4-氟-3-(甲基氨磺酰基)-N-(3,4,5-三氟苯基)苯甲酰胺(D24)
向冷却至0℃的D7(150mg,0.41mmol)在MeCN(3.55mL)中的溶液,添加DIPEA(217.17uL,1.22mmol)和甲胺(27.54mg,0.41mmol),并使反应混合物在室温搅拌1.5小时。加入水(5mL),并使反应混合物搅拌15分钟。加入DCM(5mL),并继续搅拌另外15分钟。溶液在相分离器上过滤,有机层在真空下浓缩,得到粗制标题化合物D24(151mg),其无需纯化即可使用。方法1;Rt=2.01min,m/z=362.79(M+H)+.
说明25:(R)-4-氟-N-(3,4,5-三氟苯基)-3-(N-(1,1,1-三氟丙烷-2-基)氨磺酰基)苯甲酰胺(D25)
使D7(100mg,0.27mmol)悬浮在MeCN(2mL)中,添加DIPEA(0.24mL,1.36mmol)和(2R)-1,1,1,1-三氟-2-丙胺盐酸盐(81.34mg,0.54mmol),将得到的溶液在室温搅拌3小时。反应用EtOAc稀释,并用3N HCl溶液洗涤两次。有机层经Na2SO4干燥,过滤并真空浓缩,得到粗制标题化合物D25(88mg),其无需进一步纯化即可用于下一步骤。方法1;Rt=2.32min,m/z=445.06(M+H)+.
说明26:(S)-4-氟-N-(3,4,5-三氟苯基)-3-(N-(1,1,1-三氟丙烷-2-基)氨磺酰基)苯甲酰胺(D26)
根据制备化合物D25所述的方法类似地进行制备,使用(2S)-1,1,1-三氟-2-丙胺盐酸盐代替(2R)-1,1,1-三氟-2-丙胺盐酸盐。方法1;Rt=2.32min,m/z=445.13(M+H)+.
说明27:3-(N-环丙基氨磺酰基)-4-氟-N-(3,4,5-三氟苯基)苯甲酰胺(D27)
在0℃,用DIPEA然后用D7(150mg,0.41mmol)处理环丙烷胺盐酸盐(113.06uL,1.63mmol)在MeCN(1mL)中的悬浮液。得到的黄色溶液在室温下搅拌。真空除去溶剂,将残余物溶于1/1EtOAC/2-甲基-THF,倒入分液漏斗中。有机层用6N HCl,NaHCO3饱和水性溶液和盐水洗涤,用Na2SO4干燥,过滤,最后蒸发,得到标题化合物D27(125mg),为白色固体。方法1;Rt:2.16min.m/z:389.13(M+H)+.
说明28:反式-4-氟-3-(N-(4-羟基环己基)氨磺酰基)-N-(3,4,5-三氟苯基)苯甲酰胺(D28)
于0℃用三乙胺(197.92uL,1.43mmol)随后D7(150mg,0.41mmol)处理反式-4-氨基环己-1-醇盐酸盐(80mg,0.53mmol)在MeCN(1mL)中的悬浮液。所得溶液变为白色悬浮液,将其在室温搅拌。真空除去溶剂,将残余物溶于1/1EtOAC/2-甲基-THF,倒入分液漏斗中。有机层用6N HCl,NaHCO3饱和水性溶液和盐水洗涤,经Na2SO4干燥,过滤并最终蒸发,得到标题化合物D28(100mg),为白色固体。方法1;Rt:1.90min.m/z:447.16(M+H)+.
说明29:顺式-4-氟-3-(N-(4-羟基环己基)氨磺酰基)-N-(3,4,5-三氟苯基)苯甲酰胺(D29)
根据制备D25所述的方法类似地进行制备,使用顺式-4-氨基-环己醇盐酸盐代替(2R)-1,1,1-三氟-2-丙胺盐酸盐。方法1;Rt=2.00min,m/z=447.22(M+H)+.
说明30:反式-4-氟-5-(N-((4-羟基环己基)氨磺酰基)-2-甲基-N-(3,4,5-三氟苯基)苯甲酰胺(D30)
将D14(100mg,0.26mmol)溶解于MeCN(1.3mL)中,并冷却至0℃。添加三乙胺(0.13mL,0.92mmol)和反式-4-氨基环己醇盐酸盐(43.7mg,0.29mmol),并使反应混合物在室温搅拌1小时。添加EtOAc和几滴MeOH,混合物用5%柠檬酸溶液和饱和NaHCO3溶液洗涤。有机层经Na2SO4干燥,过滤并在真空下浓缩,得到粗D30(122mg),为白色固体。方法1;Rt:2.03min.m/z:461.34(M+H)+.
说明31:4-((2-氟-5-((3,4,5-三氟苯基)氨基甲酰基)苯基)磺酰胺基)哌啶-1-甲酸叔丁酯(D31)
使4-氨基哌啶-1-羧酸叔丁酯(245.11mg,1.22mmol)悬浮于MeCN(2mL)中,冷却至0℃,并用单份的D7(150mg,0.41mmol)处理。将得到的白色悬浮液在室温搅拌1小时。真空除去溶剂,将残余物溶于1/1EtOAC/2-甲基-THF,倒入分液漏斗中。有机层用6N HCl,NaHCO3饱和溶液和盐水洗涤,用Na2SO4干燥,过滤,最后蒸发,得到标题化合物D31(140mg),为白色固体。方法1;Rt:2.37min.m/z:432.23(M-Boc)+.
说明32:4-氟-3-(N-(吡啶-4-基)氨磺酰基)-N-(3,4,5-三氟苯基)苯甲酰胺(D32)
使D7(50mg,0.14mmol)悬浮于MeCN(1mL)中,用三乙胺(56.55uL,0.41mmol)和吡啶-4-胺(40mg,0.43mmol)处理,得到淡黄色溶液。反应用2-甲基-THF和EtOAc稀释,并用1NHCl酸化至pH=1(通过纸),倒入分液漏斗中,并分离水层。将水层用NaHCO3碱化,并用EtOAc萃取;蒸发合并的有机萃取物,得到含有粗产物的残余物(60mg)。将粗产物悬浮于DCM中并过滤,得到标题化合物D32,为淡黄色固体。方法1;Rt:1.57min.m/z:426.15(M+H)+.
说明D33:4-氟-3-(N-(氧杂环丁-3-基)氨磺酰基)-N-(3,4,5-三氟苯基)苯甲酰胺(D33)
在室温下,将D7(300mg,0.82mmol)在MeCN(2mL)中的溶液单次添加到3-氧杂环丁胺(0.06mL,0.82mmol)中。所得白色悬浮液在相同温度下搅拌1小时。真空除去溶剂,将残余物溶于DCM,用5%柠檬酸水性溶液洗涤,经Na2SO4干燥,过滤,最后蒸发,得到标题化合物D33(300mg,0.74mmol),为白色固体。方法1;Rt:1.99min.m/z:405.14(M+H)+.
说明34:(S)-3-((2-氟-5-((3,4,5-三氟苯基)氨基甲酰基)苯基)磺酰胺基)吡咯烷-1-羧酸叔丁酯(D34)
在室温下,将D7(200mg,0.54mmol)在MeCN(2mL)中的溶液一次加至(S)-3-氨基吡咯烷-1-羧酸叔丁酯(202.61mg,1.09mmol)中。所得白色悬浮液在室温下搅拌1小时真空除去溶剂,将残余物溶于DCM,用5%柠檬酸水性溶液洗涤,经Na2SO4干燥,过滤,最后蒸发,得到标题化合物D34(280mg,0.54mmol),为油状物。方法1;Rt:2.35min.m/z:518.22(M+H)+.
说明35:4-氟-3-(N-(3-羟基环丁基)氨磺酰基)-N-(3,4,5-三氟苯基)苯甲酰胺(D35)
用单份的DIPEA(229.33uL,1.63mmol)随后用D7(200mg,0,54mmol)处理3-氨基环丁醇盐酸盐(134.44mg,1.09mmol)在MeCN(2mL)中的溶液。将所得溶液在室温搅拌1小时。真空除去溶剂,将残余物溶于DCM,用5%柠檬酸水性溶液洗涤,经Na2SO4干燥,过滤,最后蒸发,得到标题化合物D35(220mg,0.526mmol),为油状物。方法1;Rt:1.89min.m/z:419.19(M+H)+.
说明36:4-氟-3-(N-((1R,3R)-3-羟基环戊基)氨磺酰基)-N-(3,4,5-三氟苯基)苯甲酰胺(D36)
用N-乙基-N-异丙基丙-2-胺(198.95uL,1.14mmol)处理(1S,3S)-3-氨基环戊-1-醇盐酸盐56.14mg,0.410mmol(Cod.I-9981,Advanced ChemBlocks)在MeCN(1.5mL)中的悬浮液,并在室温搅拌15分钟。将反应溶液用冰浴冷却,并用单份的D7(100.mg,0.270mmol)处理,并在0℃下搅拌5分钟,在室温下搅拌10分钟,得到黄色溶液。真空除去溶剂,将残余物分配在DCM和柠檬酸(5%水性溶液)中。有机层经Na2SO4(无水)干燥,过滤并蒸发,得到D36(105mg)。
说明37:4-氟-3-甲基-5-氨磺酰基苯甲酸甲酯(D37)
根据制备D20所述的方法类似地进行制备,采用3-(氯磺酰基)-4-氟-5-甲基苯甲酸甲酯作为起始原料(Enamine,目录号EN300-266824)。方法1;Rt=1.39min,m/z=248.14(M+H)+.
说明38:化合物的合成:4-氟-3-甲基-5-氨磺酰基-N-(3,4,5-三氟苯基)苯甲酰胺(D38)
将双(三甲基甲硅烷基)氨基锂1M在THF(3.52mL,3.52mmol)中的溶液逐滴添加至4-氟-3-甲基-5-氨磺酰基苯甲酸甲酯D37(150mg,0.610mmol)和3,4,5-三氟苯胺(116mg0.79mmol)在无水THF(3mL)中的溶液。将反应混合物在室温搅拌3小时,然后添加更多的3,4,5-三氟苯胺(50mg,0.340mmol)和双(三甲基甲硅烷基)氨基锂1M在THF(1mL,1mmol)中的溶液,并使反应混合物在室温搅拌过夜。反应用饱和NH4Cl溶液淬灭,添加EtOAc。有机层用盐水洗涤,然后经Na2SO4干燥,过滤并在真空下浓缩。将残余物与PE一起研磨,得到标题化合物D38(218mg)为浅棕色固体,其无需进一步纯化即可使用。方法1;Rt=1.97min,m/z=363.12(M+H)+.1H NMR(300MHz,DMSO-d6)δppm 2.40(d,J=2.11Hz,3H)7.63-8.01(m,4H)8.12-8.19(m,1H)8.19-8.25(m,1H)10.79(br s,1H).
说明39:6-氯-5-氨磺酰基烟酸甲酯(D39)
将6-氯-5-(氯磺酰基)烟酸甲酯(Enamine,EN300-41733;525mg,1.94mmol)溶于1,4-二噁烷(2mL),加入33%氨水(2.29mL,19.44mmol),将反应混合物在室温搅拌20分钟。反应用EtOAc和水稀释,分离各相,有机层经Na2SO4干燥,过滤并真空浓缩,得到粗制标题化合物D39(285mg),其无需进一步纯化即可使用。方法1;Rt=1.20min,m/z=250.91(M+H)+.
说明D40:6-氯-5-氨磺酰基-N-(3,4,5-三氟苯基)烟酰胺(D40)
向粗化合物D39(144mg,0,570mmol)和3,4,5-三氟苯胺(109.9mg,0.750mmol)在无水THF(2.5mL)中的溶液逐滴添加THF(3.33mL,3.33mmol)中的双(三甲基甲硅烷基)氨基锂1M。反应混合物在室温搅拌1小时。反应用饱和NH4Cl溶液淬灭,添加EtOAc。有机层经Na2SO4干燥,过滤并真空浓缩。所得粗产物通过制备型HPLC(H2O/CH3CN+1%TFA)纯化,冻干后获得标题化合物D40(40mg),为浅黄色固体。方法3;Rt:3.17min,m/z:366.10(M+H)+.1H NMR(300MHz,DMSO-d6)δppm 7.61-7.82(m,2H)8.01(s,2H)8.81(d,J=2.29Hz,1H)9.13(d,J=2.29Hz,1H)11.00(s,1H).
实施例1:4-(甲氨基)-3-氨磺酰基-N-(3,4,5-三氟苯基)苯甲酰胺(E1)
将D20(58.mg,0.170mmol)溶解在DMSO(1mL,0.014mol)中,并用甲胺(77.59mg,2.5mmol)和三乙胺(346.27uL,2.5mmol)处理。反应溶液在室温搅拌过夜。添加第二部分甲胺(77.59mg,2.5mmol),然后添加三乙胺(346.27uL,2.5mmol)。室温5小时后,添加MeCN(200uL),并使反应在室温下搅拌过夜。反应用水和DCM稀释,倒入分液漏斗中,有机层用水和盐水洗涤两次,用MgSO4(干)干燥,过滤,最后蒸发,得到淡黄色固体(72mg)。添加DCM(1mL),并将得到的白色悬浮液过滤,得到标题化合物E1(33mg),为白色固体。方法3;Rt:3.27min.MS(ES+)m/z:360.15(M+H)+.1H NMR(300MHz,DMSO-d6)δppm 2.93(d,J=4.86Hz,3H)6.30-6.47(m,1H)6.86(d,J=8.89Hz,1H)7.43(br s,2H)7.64-7.86(m,2H)8.06(dd,J=8.76,2.06Hz,1H)8.33(d,J=2.20Hz,1H)10.41(br s,1H).
实施例2:4-氨基-3-(N-甲基氨磺酰基)-N-(3,4,5-三氟苯基)苯甲酰胺(E2)
向粗制D24(151mg)在1,4-二噁烷(1.04mL)中的溶液添加氨水(517uL,13.27mmol),并使反应混合物在密封的小瓶中于90℃搅拌2小时,室温过夜。减压蒸发溶剂。通过制备型HPLC(H2O/CH3CN+1%TFA)纯化粗产物(40.06mg),冷冻干燥后得到标题化合物E2(17.25mg),为白色粉末。剩余的粗制标题化合物无需纯化即可使用。方法3;Rt:3.23min.m/z:360.15(M+H)+.1H NMR(300MHz,DMSO-d6)δppm 2.44(d,J=5.10Hz,3H)6.57(br s,2H)6.95(d,J=8.70Hz,1H)7.50-7.59(m,1H)7.68-7.81(m,2H)0.00(dd,J=9.80,2.10Hz,1H)0.00(d,J=2.10Hz,1H)10.36(br s,1H).
实施例3:4-氨基-3-氨磺酰基-N-(3,4,5-三氟苯基)苯甲酰胺(E3)
在压力容器中装入D7(1.2g,3.26mmol),1,4-二噁烷(6mL)和33%氨水(4mL,34mmol)。将压力容器密封,将反应混合物室温搅拌5分钟,然后在95℃加热8小时。反应混合物用EtOAc和水稀释,有机层经Na2SO4干燥,过滤并真空浓缩。所得粗产物通过制备型HPLC(H2O/CH3CN+1%TFA)纯化,冷冻干燥后,获得标题化合物E3(840mg),为白色固体。方法3;Rt=3.01min,m/z=346.10(M+H)+.1H NMR(300MHz,DMSO-d6)δppm 6.49(br s,2H)6.88(d,J=8.71Hz,1H)7.37(s,2H)7.62-7.81(m,2H)7.88(dd,J=8.80,2.20Hz,1H)8.26(d,J=2.11Hz,1H)10.33(s,1H).
实施例4:4-氨基-N-(3,4-二氟苯基)-3-氨磺酰基苯甲酰胺(E4)
由D8起始,根据制备E3所述的方法类似地进行制备。方法3;Rt=2.79min,m/z=328.20(M+H)+.1H NMR(300MHz,DMSO-d6)δppm 6.49(br s,2H)6.88(d,J=8.71Hz,1H)7.37(s,2H)7.62-7.81(m,2H)7.88(dd,J=8.80,2.20Hz,1H)8.26(d,J=2.11Hz,1H)10.33(s,1H).
实施例5:4-氨基-2-氯-5-氨磺酰基-N-(3,4,5-三氟苯基)苯甲酰胺(E5)
将D21(250mg,0.650mmol)溶解在1,4-二噁烷(0.5mL)中,用氨(2.mL,117.44mmol)处理,并在封闭的小瓶中于90℃加热12小时。倒出淡黄色的反应溶液,用EtOAc(约20mL)和水稀释。有机层用盐水和0.2N HCl(2mL)洗涤,然后蒸发,得到残余物(220mg)。通过制备型HPLC(H2O/CH3CN+1%TFA)纯化一定量(20mg),得到标题化合物E5(11mg),为白色粉末。方法3;Rt:3.21min.m/z:380.15(M+H)+.1H NMR(300MHz,DMSO-d6)δppm 6.46(br s,2H)6.96(s,1H)7.46(br s,2H)7.53-7.70(m,2H)7.76(br s,1H)10.69(br s,1H)
实施例6:4-氨基-2-溴-5-氨磺酰基-N-(3,4,5-三氟苯基)苯甲酰胺(E6)
根据制备E5所述的方法类似地进行制备,由D22 2-溴-4-氟-5-氨磺酰基-N-(3,4,5-三氟苯基)苯甲酰胺起始,并通过制备型HPLC(H2O,CH3CN,0.1%HCOOH)纯化。方法3;Rt:3.24min.m/z:424.12(M+H)+.1H NMR(300MHz,DMSO-d6)δppm 6.42(s,2H)7.14(s,1H)7.47(br s,2H)7.60(dd,J=10.22,6.56Hz,2H)7.71(s,1H)10.73(br s,1H).
实施例7:4-氨基-N-(4-氟-3-(三氟甲基)苯基)-3-氨磺酰基苯甲酰胺(E7)
由D10起始,根据制备化合物E3所述的方法类似地进行制备。方法3;Rt=3.16min,m/z=378.12(M+H)+.1H NMR(300MHz,DMSO-d6)δppm 6.47(s,2H)6.88(d,J=8.62Hz,1H)7.36(s,2H)7.50(t,J=9.90Hz,1H)7.91(dd,J=8.67,2.15Hz,1H)8.05-8.13(m,1H)8.22(dd,J=6.69,2.48Hz,1H)8.29(d,J=2.11Hz,1H)10.34(s,1H).
实施例8:4-氨基-N-(3-氰基-4-氟苯基)-3-氨磺酰基苯甲酰胺(E8)
由D11起始,根据制备E3所述的方法类似地进行制备。方法3;Rt=2.65min,m/z=334.95,(M+H)+.1H NMR(300MHz,DMSO-d6)δppm 6.44(br s,2H)6.88(d,J=8.71Hz,1H)7.37(s,2H)7.53(t,J=9.17Hz,1H)7.90(dd,J=8.62,2.11Hz,1H)7.99-8.13(m,1H)8.25(dd,J=5.78,2.66Hz,1H)8.28(d,J=2.11Hz,1H)10.36(s,1H).
实施例9:4-氨基-N-(3-(二氟甲基)-4-氟苯基)-3-氨磺酰基苯甲酰胺(E9)
由D12 LF_042_097起始,根据制备E3所述的方法类似地进行制备。方法3;Rt=2.85,m/z=360.08(M+H)+.1H NMR(300MHz,DMSO-d6)δppm 6.45(br s,2H)6.87(d,J=8.62Hz,1H)7.01-7.45(m,4H)7.86-7.98(m,2H)8.03-8.12(m,1H)8.28(d,J=2.11Hz,1H)10.25(s,1H).
实施例10:4-氨基-N-(3-氯-4-氟苯基)-3-氨磺酰基苯甲酰胺(E10)
将D23(200.mg,0,580mmol),1,4-二噁烷(2mL)和氨水(2.3mL,10.38mmol)的混合物在密闭的小瓶中在100℃加热10小时。除去溶剂,将残余物悬浮在DCM中并过滤,得到灰白色固体(110mg)。将该粗产物的一半通过制备型HPLC(H2O/CH3CN+1%TFA)纯化,得到标题化合物E10(8.4mg),为灰白色固体。方法3;Rt:2.98min.m/z:344.07(M+H)+.1H NMR(300MHz,DMSO-d6)δppm 6.45(br s,2H)6.87(d,J=8.71Hz,1H)7.31-7.43(m,3H)7.64-7.77(m,1H)7.89(dd,J=8.67,2.16Hz,1H)8.05(dd,J=6.92,2.52Hz,1H)8.26(d,J=2.11Hz,1H)10.20(s,1H).
实施例11:4-氨基-N-(6-氯吡啶-3-基)-3-氨磺酰基苯甲酰胺(E11)
由D13起始,根据制备E3所述的方法类似地进行制备。方法3;Rt=2.33min,m/z=327.05(M+H)+.1H NMR(300MHz,DMSO-d6)δppm 6.49(br s,2H)6.88(d,J=8.71Hz,1H)7.37(s,2H)7.50(d,J=8.71Hz,1H)7.91(dd,J=8.62,2.02Hz,1H)8.23(dd,J=8.71,2.75Hz,1H)8.29(d,J=2.02Hz,1H)8.77(d,J=2.57Hz,1H)10.35(s,1H).
实施例12:4-氨基-N-(4-氟-3-甲基苯基)-3-氨磺酰基苯甲酰胺(E12)
由D15起始,根据制备E3所述的方法类似地进行制备。方法3;Rt=2.83,m/z=324.14(M+H)+.1H NMR(300MHz,DMSO-d6)δppm 2.23(br d,J=1.60Hz,3H)6.40(s,2H)6.86(d,J=8.62Hz,1H)7.10(t,J=9.26Hz,1H)7.34(s,2H)7.50-7.60(m,1H)7.60-7.71(m,1H)7.89(dd,J=8.62,2.11Hz,1H)8.25(d,J=2.11Hz,1H)9.99(s,1H).
实施例13:4-氨基-N-(3,5-二氟-4-甲基苯基)-3-氨磺酰基苯甲酰胺(E13)
由D16 LF_042_134起始,根据制备E3所述的方法类似地进行制备。方法3;Rt=3.17,m/z=342.25(M+H)+.1H NMR(300MHz,DMSO-d6)δppm 2.11(s,3H)6.47(s,2H)6.87(d,J=8.71Hz,1H)7.36(s,2H)7.44-7.57(m,2H)7.88(dd,J=8.67,2.16Hz,1H)8.25(d,J=2.11Hz,1H)10.25(s,1H).
实施例14:4-氨基-3-氨磺酰基-N-(2,3,4-三氟苯基)苯甲酰胺(E14)
由D17起始,根据制备E3所述的方法类似地进行制备。方法3;Rt=2.65,m/z=346.17(M+H)+.1H NMR(300MHz,DMSO-d6)δppm 6.47(s,2H)6.87(d,J=8.71Hz,1H)7.22-7.47(m,4H)7.88(dd,J=8.71,2.20Hz,1H)8.27(d,J=2.11Hz,1H)10.11(br s,1H).
实施例15:4-氨基-3-氨磺酰基-N-(2,4,5-三氟苯基)苯甲酰胺(E15)
由D18起始,根据制备E3所述的方法类似地进行制备。方法3;Rt=2.68,m/z=346.17(M+H)+.1H NMR(300MHz,DMSO-d6)δppm 6.47(s,2H)6.87(d,J=8.71Hz,1H)7.22-7.47(m,4H)7.88(dd,J=8.71,2.20Hz,1H)8.27(d,J=2.11Hz,1H)10.11(br s,1H)
实施例16:4-氨基-N-(2-氯-4-氟苯基)-3-氨磺酰基苯甲酰胺(E16)
由D19起始,根据制备E3所述的方法类似地进行制备。1H NMR(300MHz,DMSO-d6)δppm 6.44(br s,2H)6.87(d,J=8.62Hz,1H)7.22-7.31(m,1H)7.35(s,2H)7.47-7.62(m,2H)7.89(dd,J=8.80,2.20Hz,1H)8.27(d,J=2.20Hz,1H)9.85(s,1H)
实施例17:4-氨基-2-甲基-5-氨磺酰基-N-(3,4,5-三氟苯基)苯甲酰胺(E17)
将D14(150mg,0.390mmol)悬浮在1,4-二噁烷(1mL)中。加入氨水(0.96mL,24.6mmol),并将反应混合物在100℃搅拌8小时,并在室温下搅拌过夜。添加更多的氨水(0.3mL,7.69mmol),并将反应混合物在100℃下再搅拌8小时。反应混合物用EtOAc和水稀释,有机层经Na2SO4干燥,过滤并真空浓缩。通过制备型HPLC(H2O/CH3CN+1%TFA)纯化所得粗产物,冻干后获得标题化合物E17(110mg),为白色固体。方法3;Rt=3.16min,m/z=360.22(M+H)+.1H NMR(300MHz,DMSO-d6)δppm 2.32(s,3H)6.22(br s,2H)6.68(s,1H)7.26(s,2H)7.56-7.70(m,2H)7.74(s,1H)10.49(s,1H).
实施例18:(R)-4-氨基-N-(3,4,5-三氟苯基)-3-(N-(1,1,1-三氟丙烷-2-基)氨磺酰基)苯甲酰胺(E18)
由D25起始,根据制备E3所述的方法类似地进行制备。方法3;Rt:3.75min,m/z:442.16(M+H)+.1H NMR(300MHz,DMSO-d6)δppm 1.06(d,J=6.88Hz,3H)3.95-4.03(m,1H)6.56(br s,2H)6.92(d,J=8.71Hz,1H)7.58-7.80(m,2H)7.91(dd,J=8.71,2.20Hz,1H)8.25(d,J=2.11Hz,1H)8.55(d,J=9.17Hz,1H)10.35(s,1H).
实施例19:(S)-4-氨基-N-(3,4,5-三氟苯基)-3-(N-(1,1,1-三氟丙烷-2-基)氨磺酰基)苯甲酰胺(E19)
由D26起始,根据制备E3所述的方法类似地进行制备。方法3;Rt:3.75min,m/z:442.16(M+H)+.1H NMR(300MHz,DMSO-d6)δppm 1.06(d,J=6.88Hz,3H)3.95-4.00(m,1H)6.57(br s,2H)6.92(d,J=8.80Hz,1H)7.63-7.78(m,2H)7.91(dd,J=8.80,2.20Hz,1H)8.25(d,J=2.20Hz,1H)8.55(d,J=9.17Hz,1H)10.35(s,1H).
实施例20:4-氨基-3-(N-环丙基氨磺酰基)-N-(3,4,5-三氟苯基)苯甲酰胺(E20)
将D27(125mg,0.32mmol)在氨水(0.38mL,3.22mmol)和1,4-二噁烷(1.1mL,0.013mol)中的溶液在密闭的小瓶中于100℃加热8小时。真空除去溶剂,残余物用甲苯处理,并通过高真空泵进一步蒸发,得到残余物(107mg,灰白色固体)。通过制备型HPLC(H2O/CH3CN+1%TFA)纯化该粗物质的样品(24.5mg),冷冻干燥后,得到标题化合物E20(13.2mg),为白色固体。方法3;Rt:3.55min.m/z:386.23(M+H)+.1H NMR(300MHz,DMSO-d6)δppm 0.35-0,50(m,4H)2.11(td,J=6.51,3.12Hz,1H)6.54(br s,2H)6.91(d,J=8.71Hz,1H)7.64-7.80(m,2H)7.88(dd,J=8.70,2.00Hz,1H)7.95(dd,J=2.50Hz,1H)8.25(d,J=2.11Hz,1H)10.35(br s,1H).
实施例21:反式-4-氨基-3-(N-(4-羟基环己基)氨磺酰基)-N-(3,4,5-三氟苯基)苯甲酰胺(E21)
将D28(100mg,0.22mmol)在氨水(801.08uL,2.24mmol)和1,4-二噁烷(1mL)中的溶液在100℃下在封闭的小瓶中加热8小时。真空除去溶剂,残余物用甲苯处理并进一步蒸发。通过高真空泵除去痕量溶剂,得到残余物,为灰白色固体(108mg)。通过制备型HPLC(H2O/CH3CN+1%TFA)纯化该粗物质的样品(20mg),得到标题化合物E21(9mg),为白色固体。方法3;Rt:3.11.m/z:444.25(M+H)+.1H NMR(300MHz,DMSO-d6)δppm 0.87-1.35(m,4H)1.50-1.86(m,4H)2.78-2.97(m,1H)3.20-3.34(m,2H)6.51(br s,2H)6.88(d,J=8.71Hz,1H)7.54-7.82(m,3H)7.89(dd,J=8.71,2.11Hz,1H)8.23(d,J=2.11Hz,1H)10.34(s,1H).1H NMR(300MHz,DMSO-d6+TFA)δppm 0.87-1.37(m,4H)1.45-1.86(m,4H)2.79-3.01(m,1H)3.14-3.43(m,1H)6.88(d,J=8.71Hz,1H)7.55-7.82(m,3H)0.00(dd,J=8.50,2.20Hz,1H)8.23(d,J=2.11Hz,1H)10.33(s,1H).
实施例22:顺式-4-氨基-3-(N-(4-羟基环己基)氨磺酰基)-N-(3,4,5-三氟苯基)苯甲酰胺(E22)
由D29起始,根据制备化合物E3所述的方法类似地进行制备。方法3;Rt=3.24min,m/z=444.25(M+H)+.1H NMR(300MHz,DMSO-d6)δppm 1.35(m,J=3.30Hz,4H)1.43-1.62(m,4H)2.82-3.08(m,1H)3.49-3.58(m,2H)6.52(br s,2H)6.87(d,J=8.62Hz,1H)7.53-7.79(m,3H)7.88(dd,J=8.71,2.29Hz,1H)8.23(d,J=2.20Hz,1H)10.33(s,1H).
实施例23:反式-4-氨基-5-(N-(4-羟基环己基)氨磺酰基)-2-甲基-N-(3,4,5-三氟苯基)苯甲酰胺(E23)
由D30 LF_042_146起始,根据制备化合物E3所述的方法类似地进行制备。方法3;Rt=2.03min,m/z=461.34(M+H)+.1H NMR(300MHz,DMSO-d6)δppm 0.94-1.30(m,4H)1.54-1.83(m,4H)2.34(s,3H)2.77-2.96(m,1H)3.20-3.41(m,1H)6.24(br s,2H)6.68(s,1H)7.54(d,J=7.52Hz,1H)7.58-7.70(m,2H)7.73(s,1H)10.46(s,1H).
实施例24:顺式-4-氨基-3-(N-3-羟基环丁基)氨磺酰基)-N-(3,4,5-三氟苯基)苯甲酰胺(E24)
根据关于合成D35所述的方法,使用顺式-3-氨基环丁醇替代3-氨基环丁醇,制备顺式4-氟-3-(N-(3-羟基环丁基)氨磺酰基)-N-(3,4,5-三氟苯基)苯甲酰胺。根据制备E10所述的方法,使中间体化合物进一步与1,4-二噁烷中的氨水反应。方法3;Rt:3.12.m/z:416.29(M+H)+.1H NMR(300MHz,DMSO-d6)δppm 1.43-1.74(m,2H)2.11-2.26(m,2H)2.94-3.17(m,1H)3.59-3.71(m,1H)6.55(br s,2H)6.88(d,J=8.71Hz,1H)7.72(dd,J=10.64,6.60Hz,2H)7.86-7.95(m,2H)8.16-8.24(m,1H)10.33(s,1H).
实施例25:反式-4-氨基-3-(N-3-羟基环丁基)氨磺酰基)-N-(3,4,5-三氟苯基)苯甲酰胺(E25)
根据关于合成D35所述的方法,使用反式-3-氨基环丁醇替代3-氨基环丁醇,制备反式-4-氟-3-(N-(3-羟基环丁基)氨磺酰基)-N-(3,4,5-三氟苯基)苯甲酰胺。根据制备E10所述的方法,使中间体化合物进一步与1,4-二噁烷中的氨水反应。方法3;Rt:3.04.m/z:416.35(M+H)+.1H NMR(300MHz,DMSO-d6)δppm 1.88(br dd,J=7.93,4.08Hz,2H)1.92-2.04(m,2H)3.70(br d,J=7.70Hz,2H)4.13(br t,J=3.58Hz,1H)6.54(br s,2H)6.88(d,J=8.71Hz,1H)7.61-7.81(m,2H)7.90(dd,J=8.71,2.20Hz,1H)7.97(d,J=8.16Hz,1H)8.19(d,J=2.20Hz,1H)10.34(s,1H).
实施例26:4-氨基-3-(N-((1R,3R)-3-羟基环戊基)氨磺酰基)-N-(3,4,5-三氟苯基)苯甲酰胺(E26)
将D36(105mg,0.24mmol)在氨水(0.5mL,4.6mmol)和1,4-二噁烷(0.5mL)中的溶液在密闭的小瓶中在100℃下加热8小时。反应溶液用DCM/EtOAc(约7/3)和水稀释,然后蒸发有机层,得到残余物(80mg),其通过制备型HPLC(H2O/CH3CN+0.1%TFA)纯化。方法3;Rt:3.11.m/z:430.27(M+H)+.1H NMR(300MHz,DMSO-d6)δppm 1.12-1.36(m,2H)1.36-1.50(m,1H)1.50-1.64(m,1H)1.64-1.90(m,3H)3.49-3.66(m,3H)3.95-4.15(m,1H)6.53(br s,2H)6.89(d,J=8.71Hz,1H)7.66-7.77(m,3H)7.90(dd,J=8.71,2.20Hz,1H)8.23(d,J=2.20Hz,1H)10.35(s,1H)
实施例27:4-((2-氨基-5-((3,4,5-三氟苯基)氨基甲酰基)苯基)磺酰氨基)哌啶-1-羧酸叔丁酯(E27)
将D31(147mg,0.28mmol)在氨水(0.99mL,2.77mmol)和1,4-二噁烷(1.1mL)中的溶液在密闭的小瓶中在100℃加热8小时。真空除去溶剂,残余物用甲苯处理并进一步蒸发。通过高真空泵除去痕量溶剂,得到残余物,为灰白色固体(107mg)。通过制备型HPLC(H2O/CH3CN+1%TFA)纯化该粗物质的样品(20mg),得到标题化合物E27(19.86mg),为白色固体。方法3;Rt:3.93min.m/z:529.09(M+H)+.1H NMR(300MHz,DMSO-d6)δppm 1.13-1.32(m,2H)1.36(s,9H)1.47-1.65(m,2H)2.75-2.95(m,2H)3.05-3.23(m,1H)3.67(br d,J=13.57Hz,2H)6.53(br s,2H)6.89(d,J=8.71Hz,1H)7.64-7.78(m,2H)7.82(d,J=7.89Hz,1H)7.90(dd,J=8.67,2.15Hz,1H)8.24(d,J=2.11Hz,1H)10.34(br s,1H)
实施例28:4-氨基-3-(N-(哌啶-4-基)氨磺酰基)-N-(3,4,5-三氟苯基)苯甲酰胺(E28)
E27在DCM(1mL)中的溶液在室温用TFA(1mL)处理。黄色反应溶液在室温磁力搅拌1小时。真空除去溶剂,并将残余物通过制备型HPLC(H2O/CH3CN+1‰TFA)纯化,得到标题化合物E28(8.6mg),为TFA盐。1H NMR(300MHz,DMSO-d6)δppm 1.40-1.64(m,2H)1.64-1.87(m,2H)2.78-3.03(m,2H)3.08-3.28(m,3H)6.54(br s,2H)6.91(d,J=8.71Hz,1H)7.72(dd,J=10,59,6.56Hz,2H)7.91(dd,J=8.71,2.11Hz,1H)8.03(d,J=7.61Hz,1H)8.17(br s,1H)8.25(d,J=2.11Hz,1H)8.41(br s,1H)10.36(br s,1H).1H NMR(300MHz,DMSO-d6+TFA)δppm1.43-1.64(m,2H)1.75(br dd,J=13.75,3.30Hz,2H)2.79-3.00(m,2H)3.08-3.22(m,2H)3.22-3.38(m,1H)6.91(d,J=8.71Hz,1H)7.61-7.81(m,2H)7.91(dd,J=8.71,2.20Hz,1H)8.03(d,J=7.52Hz,1H)8.13-8.34(m,2H)8.35-8.60(m,1H)10.35(s,1H).方法3;Rt:2.48min.m/z:429.26(M+H)+.
实施例29:4-氨基-3-((4-羟基哌啶-1-基)磺酰基)-N-(3,4,5-三氟苯基)苯甲酰胺(E29)
4-氟-3-((4-羟基哌啶-1-基)磺酰基)-N-(3,4,5-三氟苯基)苯甲酰胺(根据WO2013/096744制备)(50mg,0.11mmol)、1,4-二噁烷(150uL)和氨水(0.3mL,2.29mmol)的混合物在密封管中于100℃加热8小时。反应用EtOAc和水稀释,有机层经Na2SO4干燥,过滤并最终蒸发。将残余物悬浮在DCM中并过滤,得到标题化合物E29(15.5mg),为白色固体。方法3;Rt:3.26min.m/z:430.2(M+H)+.1H NMR(300MHz,DMSO-d6)δppm 1.30-1.52(m,2H)1.60-1.83(m,2H)2.77-2.92(m,2H)3.25(br s,2H)3.45-3.65(m,1H)4.67(d,J=3.76Hz,1H)6.53-6.75(m,2H)6.93(d,J=8.71Hz,1H)7.69(dd,J=10,50,6.46Hz,2H)7.81-7.98(m,1H)8.08(d,J=2.02Hz,1H)10.31(s,1H)
实施例30:3-((4-羟基哌啶-1-基)磺酰基)-4-(甲氨基)-N-(3,4,5-三氟苯基)苯甲酰胺(E30)
3-((4-羟基哌啶-1-基)磺酰基)-N-(3,4,5-三氟苯基)苯甲酰胺(根据WO2013/096744制备)(50mg,0.12mmol)、甲胺(1.04mL,2.08mmol)在DMSO(700uL,0.010mol)和MeCN(140uL,0.003mol)混合物中的混合物用三乙胺(480.87uL,3.47mmol)处理并在室温搅拌过夜。反应溶液通过制备型HPLC(H2O/CH3CN+1%TFA)纯化,得到标题化合物E30(23mg)。1H NMR(300MHz,DMSO-d6)δppm 1.28-1.51(m,2H)1.58-1.81(m,2H)2.75-2.97(m,5H)3.19-3.28(m,2H)3.46-3.65(m,1H)4.66(d,J=3.90Hz,1H)6.72-6.81(m,1H)6.89(d,J=8.90Hz,1H)7.63-7.77(m,2H)8.03-8.11(m,1H)8.15(d,J=2.11Hz,1H)10.35(s,1H).
实施例31:4-氨基-3-(N-(吡啶-4-基)氨磺酰基)-N-(3,4,5-三氟苯基)苯甲酰胺(E31)
在5mL小瓶中装入D32(100mg,0.24mmol)二噁烷(1mL)和氨水(2mL)。将小瓶密封并在100℃加热8小时。通过蒸发除去溶剂,并使残余物在水和EtOAc之间分配。有机萃取液经合并、蒸发,将残余物溶于1/2二噁烷/氨水(2mL)中,并在封闭的小瓶中于100℃加热8小时。真空除去溶剂,使残余物在水和EtOAc之间分配。蒸发有机萃取物,并使残余物通过快速色谱在直接相(EtOAC/MeOH)上纯化。将含有产物的级分合并、蒸发,得到残余物(20mg),使其通过制备型HPLC(H2O/CH3CN+1‰TFA))纯化,得到标题化合物E31,为TFA盐(1.24mg)。方法3;Rt:2.63min.m/z:423.1(M+H)+.1H NMR(300MHz,DMSO-d6)δppm 6.52(br s,1H)6.82(d,J=8.62Hz,1H)7.03(br d,J=6.88Hz,2H)7.66-7.79(m,2H)7.83(dd,J=8.67,2.16Hz,1H)8.03(d,J=6.00Hz,2H)8.35(d,J=2.11Hz,1H)10.35(s,1H).
实施例32:4-氨基-3-(N-(3-羟基环丁基)氨磺酰基)-N-(3,4,5-三氟苯基)苯甲酰胺(E32)
由D35起始,根据制备E10所述的方法类似地进行制备。方法1;Rt:1.81min.m/z:416.40(M+H)+.
实施例33:4-氨基-3-(N-(氧杂环丁-3-基)氨磺酰基)-N-(3,4,5-三氟苯基)苯甲酰胺(E33)
由D33起始,根据制备E10所述的方法类似地进行制备。方法3;Rt:3.20.m/z:402.30(M+H)+.1H NMR(300MHz,DMSO-d6)δppm 4.23-4.43(m,3H)4.44-4.54(m,2H)6.58(brs,2H)6.90(d,J=8.71Hz,1H)7.60-7.80(m,2H)7.90(dd,J=8.71,2.20Hz,1H)8.18(d,J=2.20Hz,1H)8.66(br s,1H)10.36(br s,1H).
实施例34:(S)-3-((2-氨基-5-((3,4,5-三氟苯基)氨基甲酰基)苯基)磺酰氨基)吡咯烷-1-羧酸叔丁酯(E34)
如关于制备E10所述的方法类似地进行制备,使用D34作为起始原料,并通过制备型HPLC(H2O/CH3CN+0.1%HCOOH)纯化。方法3;Rt:3.81min.m/z:515.24(M+H)+.1H NMR(300MHz,DMSO-d6)δppm 1.35(br d,J=5.69Hz,9H)1.55-1.77(m,1H)1.78-2.00(m,1H)2.88-3.05(m,1H)3.07-3.31(m,4H)3.64(br s,1H)6.56(br s,2H)6.91(d,J=8.71Hz,1H)7.64-7.79(m,2H)7.92(dd,J=8.71,2.11Hz,1H)8.07(br s,1H)8.24(d,J=2.02Hz,1H)10.37(s,1H).
实施例E35:(S)-4-氨基-3-(N-(吡咯烷-3-基)氨磺酰基)-N-(3,4,5-三氟苯基)苯甲酰胺(E35)
E34(30mg,0.06mmol)在DCM(0,5mL)中的溶液在室温用三氟乙酸(0,5mL,6.53mmol)处理。真空除去溶剂,得到残余物,使其通过制备型HPLC(H2O/CH3CN 0.1%TFA)纯化,得到标题化合物E35(10mg),为白色固体。方法3;Rt:2.47min.m/z:415.27(M+H)+.1H NMR(300MHz,DMSO-d6)δppm1.61-1.85(m,1H)1.85-2.10(m,1H)2.94(br s,1H)3.17(br s,3H)3.57-3.88(m,1H)6.60(br s,2H)6.95(d,J=8.71Hz,1H)7.63-7.80(m,2H)7.95(dd,J=8.76,2.16Hz,1H)8.16(d,J=6.42Hz,1H)8.24(d,J=2.11Hz,1H)8.47-8.68(m,1H)8.70-9.02(m,1H)10.38(s,1H).
实施例36:4-氨基-3-甲基-5-氨磺酰基-N-(3,4,5-三氟苯基)苯甲酰胺(E36)
在压力容器中装入D38(217mg,0.600mmol),1,4-二噁烷(1.5mL)和33%氨水(0.75mL,6.36mmol)。密封压力容器,并使反应混合物在95℃加热7.5小时,然后在室温搅拌过夜。加入更多的33%氨水(0.5mL,4.24mmol),并使反应混合物在100℃再搅拌8.5小时。反应混合物用EtOAc和水稀释,有机层经Na2SO4干燥,过滤并真空浓缩。残余物用DCM研磨,然后通过制备型HPLC(H2O/CH3CN+1%TFA)纯化,冻干后获得标题化合物E36(86mg),为灰白色固体。方法3;Rt=3.19min,m/z=360.15(M+H)+.1H NMR(300MHz,DMSO-d6)δppm2.22(s,3H)6.21(s,2H)7.41(s,2H)7.65-7.79(m,2H)7.80-7.89(m,1H)8.19(d,J=2.02Hz,1H)10.33(s,1H).
实施例37:6-氨基-5-氨磺酰基-N-(3,4,5-三氟苯基)烟酰胺(E37)
由D40起始,根据制备化合物E3所述的方法类似地进行制备。方法3:Rt=2.82min,m/z=347.04(M+H)+.1H NMR(300MHz,DMSO-d6)δppm 7.07(br s,2H)7.60(s,2H)7.65-7.81(m,2H)8.46(d,J=2.20Hz,1H)8.80(d,J=2.20Hz,1H)10.48(s,1H).
表1所示的实施例是根据上述合成方法制备的。通过参考合适的方案,在表1中指出了通用合成策略,合适的中间体材料和相关的反应步骤(合适时)。
表1
生物学
试验
细胞和培养条件
HepAD38细胞系(Ladner等,Antimicrob Agents Chemother,1997,41,1715-20)用于HBV抑制试验。HepAD38是源自肝母细胞瘤细胞系HepG2(编号:HB-8065TM)的亚克隆,它在TET-OFF系统中在四环素响应性启动子的转录控制下表达HBV基因组:添加四环素(TET)或强力霉素可抑制HBV复制,而它的去除转而将会允许HBV病毒颗粒在细胞上清液中释放。HepAD38细胞系维持在DMEM/F12中,其补充有10%的胎牛血清,1%的谷氨酰胺,1%的青霉素/链霉素,0.4mg/ml的G418和0.3ug/ml的四环素。对于HBV抑制试验,使用无强力霉素的培养基以允许病毒体产生。
采用用对应于不同分离株的HBV质粒转染的HepG2肝癌细胞来进行针对不同HBV基因型的抗病毒试验。通过将含有1.1聚体HBV基因组的片段克隆到pcDNA3.1zeo(-)质粒(V86520,赛墨飞世尔科学公司(Thermofisher Scientific))的SacI/SalI位点中来获得HBV质粒。HepG2细胞系维持在DMEM中,其补充有10%的FBS,1%的谷氨酰胺和1%的青霉素/链霉素。
使用HepG2-NTCP肝癌细胞系进行感染实验。HepG2-NTCP通过使用表达人NTCP的慢病毒载体在具有人牛磺胆酸钠共转运多肽受体(hNTCP)的HepG2细胞中异位表达来获得(Seeger等,Molecular Therapy-Nucleic Acids,2014)。hNTCP最近被鉴定为HBV受体(YanH.等,Elife.2012年11月13日;3)。HBV的完整病毒生命周期可以在HepG2-NTCP细胞系中获得。HepG2-NTCP细胞维持在DMEM中,其补充有10%的FBS,1%的谷氨酰胺和1%的青霉素/链霉素。
体外抗HBV活性
在96孔板中进行体外HBV抑制活性。在初次(首次)筛选期间,化合物首先以0.1μM,0.5μM和1μM的浓度测试(设三重复)。对于选定的化合物,使用1:2系列稀释(从2.5μM,1.25μM或0.4μM开始,取决于初次筛选时观察到的抑制程度)获得8点剂量反应曲线。根据剂量反应曲线,可以计算出半最大有效浓度(EC50)(另请参见下文)。
更详细地,将通常溶解于DMSO储备溶液中的化合物在100μl的上述培养基(无强力霉素)中稀释至最终所需浓度的2倍,并设三重复接种在96孔板中。
同时,将HepAD38细胞-在无四环素的培养基中充分预洗涤以诱导HBV产生-以2×104个细胞悬浮于100μl无四环素的培养基中,并添加到平板的每个孔中,以产生200μl的最终试验体积。
用于储备溶液和化合物稀释液的DMSO始终以0.5%的最终浓度存在于试验中。
然后使平板在37℃下孵育96小时,然后进行细胞活力试验和细胞外HBV定量分析,以评估化合物的细胞毒性潜力和抗病毒活性。
细胞毒性通过商业荧光测定法评估,该测定法测量与细胞活力直接相关的细胞的代谢活性(Cell Titer Blue,普罗梅加公司(Promega))。对于各化合物,以与评估其抗HBV活性相同的浓度评估细胞毒性。
抗HBV活性通过直接qPCR定量细胞外HBV DNA来评估。具体地,上清液经收集和离心以澄清细胞碎片,通过添加裂解缓冲液(1mM 1,4-二硫苏糖醇、0.2%十二烷基磺酸钠)并在95℃孵育10分钟来从病毒体提取病毒DNA。然后,样品1:40稀释并进行实时PCR扩增,采用SYBR绿测定法(Power SYBRTM Green PCR主混物-赛墨飞世尔科学公司(Thermo FisherScientific))和特定HBV引物(HBV-DF:5’-ATTTGTTCAGTGGTTCGTAGGG-3’(SEQ ID No.1),HBV-DR:5’-CGGTAAAAAGGGACTCAAGATG-3’(SEQ ID No.2))。
HBV抑制活性在不同的HBV基因型上测定。为此,将表达HBV基因型A,B,C,D,E的质粒pcDNA3.1Zeo(-)-HBV1.1转染到HepG2细胞系中,并如上所述通过直接qPCR进行细胞外HBV定量。具体地,将细胞以20,000个细胞/孔的密度接种在聚赖氨酸包被的96孔板中,并在24小时后用脂质体转染HBV质粒,采用制造商的方法(Lipofectamine 3000试剂,赛墨飞世尔科学公司)。转染后五小时,细胞用PBS充分洗涤,然后按照上述方法在0.5%DMSO中以8点剂量反应曲线添加化合物。在37℃孵育4天后,对细胞进行了细胞活力试验和细胞外HBV定量,以评估化合物的细胞毒性潜力和抗病毒活性,如上所述。为了避免在实时PCR检测过程中过载质粒,在直接qPCR之前,将上清液在37℃下用1单位DNA酶I(DNA酶I扩增级,西格玛公司(Sigma))处理1小时。采用amp特异性引物(AMP-F:5’-TGCTTAATCAGTGAGGCACCTA-3’(SEQID No.3),AMP-R:5’-AGCCCTCCCGTATCGTAGTTAT-3’(SEQ ID No.4)),通过实时PCR扩增验证了无质粒污染。
在乙肝病毒感染的体外模型中研究了化合物抑制感染细胞中HBV cccDNA建立的能力。为此,使用经工程改造以稳定表达HBV受体人牛磺胆酸钠共转运多肽(hNTCP)的HepG2-NTCP细胞系,并按照标准公布的程序(乙型肝炎方法和规程(Hepatitis B methodsand protocols),Guo H.,Cuconati,A.;2017;胡马纳出版社(Humana press))在HepAD38中生产HBV颗粒。具体地,将HepG2-NTCP以20.000个细胞/孔接种在胶原蛋白包被的96多孔板中。24小时后,将上述产生的HBV颗粒以500mge(对于每个细胞,基因组数量,或基因组当量的倍数)的浓度添加到每个孔中,于80μl含有4%PEG和2.5%DMSO的完全培养基中。16小时后,HBV颗粒用PBS大量洗涤,并使细胞在200ul完全培养基中于37℃孵育6天。化合物处理以12点剂量反应曲线进行,以1:2稀释,始于2μM,于0.5%最终DMSO中,如上所述。从添加病毒颗粒之前的3小时开始,化合物存在于试验的所有6天中。通过用ELISA(Elisa试剂盒HBE.CE.制造商:DIA.PRO)定量细胞外HBeAg来评价化合物抑制HBV cccDNA建立的能力。
所有HBV抑制或抗病毒活性数据通常以相对于未处理参考样品的百分比(%)报告。Excel和Graphpad Prism程序通常用于数据细化和EC50计算。
药代动力学
肝细胞稳定性研究
肝脏代谢通常是导致体内药物清除的主要因素。将合并的冻存人肝细胞(例如,可从Bioreclamation IVT公司,利物浦20供体人肝细胞产品,编号X008000商购)融化并重悬于完全肝细胞培养基(HCM)中(可商购,例如,购自隆萨公司(Lonza),HBM肝细胞基础培养基,目录号CC-3199+HCM SingleQuots,目录号CC-4182)。化合物从DMSO中的3mM储备溶液稀释到细胞悬浮液(2.5μl/2.5mL,1百万细胞/mL)中,得到3μM浓度(0.1%DMSO)。取150μl(x2)的该混合物,转移到装有等体积淬灭溶液(100%乙腈加0.1%甲酸)的96深孔板中,进行时间0孵育。然后将1mL/孔的细胞悬浮液-化合物混合物(x2)分配到24孔板中。在37℃于DUBNOFF水浴中于低振摇下进行孵育。设双重复,在6个时间点测试化合物:0、30、60、120、180和240分钟。在各时间点,取150μl的等分试样,转移到96深孔板,然后反应通过添加一体积的100%乙腈加0.1%甲酸停止。
在0、120和240分钟时,通过台盼蓝排除测试进行活力测定。
样品在+4℃以1100xg离心30分钟,然后将250μl的上清液转移到新的96深孔板用于生物分析。
分析操作:
将用于分析操作的样品在4℃下于4500g离心5分钟,然后分入两个96深孔板。
将研究样品进一步n倍稀释或在25℃的氮气下干燥,然后根据开发的分析方法进行重构。将最终板混合10分钟,超声处理5分钟,然后将样品注入LC-MS/MS或LC-HRMS系统中。样品分析采用以下进行:API 4000QTrap质谱仪,该质谱仪通过Turbo Ion Spray(ESI)联接至LC系统(由Acquity UPLC样品管理器自动进样器和Acquity UPLC二元溶剂管理器泵组成),或Thermo Scientific Orbitrap QExactive,其联接至LC系统(由DionexUltimated 3000UHPLC组成)。
结果:
使用面积比(分析物峰面积对比内标峰面积),根据化合物消失与孵育时间的函数关系来确定稳定性。通过在半对数标度上绘制平均消失值并拟合最佳拟合线性回归来计算消除常数k。以小时计的半衰期(t1/2)采用等式1导出:等式1:t1/2=ln2/(-k)。当半衰期无法计算时,数据报告为:<0.5或>4小时。内在清除率以μl/分钟/百万细胞表示,且采用以下等式计算:Clint=KV/N。其中K=0.693/t1/2,V=孵育体积(ml),而N=肝细胞/样品数量。
小鼠PK研究
C57BL/6小鼠用于评价静脉内和经口给予(2-200mpk,根据测试的化合物和给予途径)之后的血浆和肝脏暴露和药代动力学参数。12只(+3只备用)健康C57BL/6N雄性小鼠获自查尔斯河公司(Charles River S.p.A.)意大利卡里科(科莫)。订购的动物重21-27克,大约7周龄。在测试之前和测试期间,将动物圈养在带有锯末作为垫料的独立通风笼(IVCTecniplast)中(三只动物/笼)。笼用彩色代码标签标识,其上记录了样品编号,动物编号和处理细节(途径、剂量和性别)。动物通过在尾巴上永久标记唯一编号来识别。动物室控制设置为保持温度在20至24℃的范围内,相对湿度在40至70%的范围内,并且平均每日气流为每小时至少要换10次新鲜空气。记录实际情况。房间被荧光管照亮,其经控制以提供人工周期:每日12小时明12小时暗。所有动物在测试前即刻称重。在喂养状态下向动物IV给予,在禁食状态下向动物PO给予。
化合物(0.4至20mg/mL,根据测试的化合物和给药途径)溶于DMSO/PEG400/H2O(20/60/20)中,以进行IV给药,和加入0.5%Methocel E50或20%羟丙基-β-环糊精(HP-β-CD)(柠檬酸缓冲液pH=5中),用于PO给药。根据体重计算出适合每只动物的测试项目剂量体积(给药体积:5mL/kg用于IV或5mL/kg或10mL/kg用于PO),通过使用2.5mL注射器(BDPlasipak)注射进入侧尾静脉来进行IV给药;通过管饲法使用5mL注射器(BD Plastipak)来进行PO给药。使用异氟烷作为麻醉剂,通过眼眶后窦收集全血样品(约0.200mL)。在适当标记的指示动物数量和时间点的Li-Heparin SartstedR凝胶管中收集血液。将试管放入湿冰中,然后在采血后15分钟内离心。使用Heraeus MultifugeR 3S/3S-R装置以2200xg离心10分钟,内部温度保持在4℃。离心后,获得约100μL血浆样品,然后立即转移至1.5mLEppendorf管中,并在-20℃冷冻(24/24小时警示)。全血样品在给药后不同时间点(0-0.25-0.5–1–2–4–6–8-24小时)收集,并保持冷冻(-20℃),直到通过LC/MS/MS测定。在不同的时间点(0–8–24小时)外植肝脏,用盐水溶液洗涤,转移到Eppendorf管中,并于-80℃冷冻,直至通过LC/MS/MS测定。
分析操作:血浆样品使用Liquid Handling Robot Hamilton StarPlus通过乙腈进行蛋白质沉淀来提取。然后将样品离心(4℃,3000rpm x 15分钟),转移上清液并在氮气下干燥。样品在水/乙腈90/10或50/50中重构,然后直接注入UPLC色谱柱中。样品分析使用API 4000或/和API 5000或/和API 4000QTrap质谱仪进行,该质谱仪通过Turbo离子喷雾(ESI)联接至LC系统(由AcquityUPLC样品管理器自动进样器和Acquity UPLC二元溶剂管理器泵组成)。结果使用分析软件(Analyst Software)线性回归,以1/x*x权重计算。试验精度通过Watson Lims数据库计算,用于质量控制。
C最大是口服给药的最大化合物浓度;T最大是达到C最大的时间;AUC(0-24)是从0到24小时的浓度-时间曲线下的面积;AUC外推是根据最后观察到的浓度从给药时间开始,外推到无穷大的曲线下面积(AUC)。
药代动力学分析:化合物的血浆清除率(CLp)(使用Watson PK程序)计算为剂量除以从时间零到无穷大的血浆浓度-时间曲线下的面积(AUC0-∞)。根据对数血浆浓度-时间数据的末相的斜率估计表观半衰期。分配量(Vdss)使用以下非分区方法确定:
Vdss=(剂量IV x AUMC)/(AUC0-∞)2
其中AUMC是从时间零到无穷大的药物浓度时间曲线的第一时刻下的总面积。生物利用度估计为口服和静脉内给药后的AUC0-∞比率,针对剂量差异进行标准化。
结果
本文所述的示例性化合物在上述试验中进行了测试。在测试的化合物浓度下,所有化合物均未显示出可测量的细胞毒性。
HBV抑制的结果记录在下表2中。
图例:A表示在表中所示浓度下,HBV抑制大于50%或EC50小于1μM;B表示在表中指示的浓度下,HBV抑制小于50%或EC50大于1μM。
表2.HBV抑制结果
表2中的结果清楚地表明本发明的化合物显示出抗HBV活性。
在体外感染模型中,评估了化合物E17对不同HBV基因型的抗病毒活性。结果分别在表3和表4中表示为HBV抑制EC50和HBeAg抑制EC50。数据表示为至少三个独立实验的平均值和标准偏差。
表3.E17对不同HBV基因型的抗病毒活性
在上表3中,报告了化合物E17对每种HBV基因型的HBV抑制的EC50。数据表示为至少三个独立实验的平均值和标准偏差。
表4.E17的HBeAg抑制EC50
在上表4中,报告了化合物E17的HBeAg抑制的EC50。数据表示为至少三个独立实验的平均值和标准偏差。有趣的是,上述化合物在具有相同功效(potency)的不同基因型之间显示出保守的活性。有趣的是,采用HBeAg的释放来替代cccDNA的建立,如Zhou T.等在Antiviral Res.2006中所报道的,该化合物显示对cccDNA生物发生具有抑制活性,EC50为0.147μM,因此对于彻底根除HBV病毒具有重要作用。
体内性质
在体外和体内药代动力学研究中评估了本发明的化合物。化合物4-氨基-3-氨磺酰基-N-(3,4,5-三氟苯基)苯甲酰胺(E3)在小鼠和人肝细胞中是稳定的(数据未显示)。当对小鼠体内给药时,该化合物显示出低体内清除率(10mL/分钟/Kg)。
对于化合物E3,评价了以0.5%甲基纤维素溶液(methocell)中100mpk在小鼠中PO给药后的血浆PK参数以及血浆和肝脏浓度,总结于下表5、表6和表7中。
表5.化合物E3的血浆PK参数
表6.以0.5%甲基纤维素溶液(methocell)中100mpk PO给药后化合物E3的血浆浓度(uM)
表7.以0.5%甲基纤维素溶液(methocell)中100mpk PO给药后化合物E3的肝脏浓度(uM)
如表6和表7所报告的,PO给药后,E3肝脏水平(8小时)比血浆高13倍。数据表示相同时间点(8小时)肝脏和血浆浓度之间的比率。
还评估了在小鼠中以不同剂量PO给药后,化合物E17的血浆PK参数和肝脏浓度。结果报告于下表8。
表8.以0.5%甲基纤维素溶液(methocell)中指定剂量PO给药后,化合物E17的肝脏浓度和肝脏/血浆浓度
鉴于肝脏是受乙型肝炎疾病影响的主要组织,因此E3和E17的高肝对血浆浓度是一个重要的考虑因素。具有肝选择性分布特征的HBV抑制剂代表了开发安全候选药物的重要策略(Tu M.等,Current Topics in Medicinal Chemistry,2013,13,857-866)。
序列表
<110> 圣拉斐尔医院有限公司(PROMIDIS S.R.L.)
IRBM股份公司(IRBM S.P.A.)
普罗米迪斯有限责任公司(OSPEDALE SAN RAFFAELE S.R.L.)
分子遗传国家研究所(INGM)(ISTITUTO NAZIONALE DI GENETICA MOLECOLARE -INGM)
<120> 乙型肝炎病毒的抑制剂
<130> PCT 140713
<160> 4
<170> PatentIn version 3.5
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<212> DNA
<213> 人工序列
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<223> 合成引物
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<213> 人工序列
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Claims (23)
1.一种通式(I)的化合物:
其中:
A是6元芳族或杂芳族环;
B是任选地含有一个或多个N原子的6元芳基;
X是H或NR3R4;
Y选自下组:氢,卤素,C1-6烷基,NH2,NH(C1-6烷基),N(CH3)2,NHC(O)CH3,OH,饱和或部分不饱和的C3-7环烷基,5-或6-元杂芳基和CN,或不存在;
限制条件是,当X是H时,Y选自下组:NH2,NH(C1-6烷基),N(CH3)2,NHC(O)CH3;
R1及R2各自独立地选自H,直链或支化1-6烷基,饱和或部分不饱和的C3-7环烷基,C3-7杂环烷基和杂芳基,所述直链或支化的C1-6烷基,饱和或部分不饱和的C3-7环烷基,C3-7杂环烷基或杂芳基各自任选地被选自以下的一个或多个取代基取代:OH,卤素,NH2,NH(C=O)OC1-6烷基,NH(C1-6烷基),C1-6烷基,C3-7环烷基,C3-7杂环烷基,C1-6羟烷基,5-或6-元杂芳基,C(=O)C1-6烷基,C(=O)OC1-6烷基,OC1-6烷基,O(CH2)nC3-10环烷基和O(CH2)nC3-10杂环烷基;
或R1和R2与它们所连接的N原子一起形成饱和或部分不饱和的3-10元杂环,其任选地包含选自N、O和S的另一个杂原子,所述饱和或部分不饱和的3-10元杂环任选地被选自OH,卤素,C1-6烷基,C1-6卤代烷基和(CH2)nR5的一个或多个取代基取代;
n在每次出现时独立地是0、1、2、3或4;
R3和R4各自独立地是H,或直链或支化C1-3烷基,其任选地被选自卤素,NH2,NHC1-6烷基,N(C1-6烷基)2,NH(C=O)C1-6烷基,NH(C=O)OC1-6烷基,OC1-6烷基,O(CH2)nC3-10环烷基和O(CH2)nC3-10杂环烷基的一个或多个基团取代,限制条件是NR3R4不形成饱和、部分饱和或不饱和的杂环;
R5选自下组:OH,NH2,NH(CH3),N(CH3)2,NHC(O)CH3,CN,卤代C1-3烷基,C1-3烷氧基,卤代C1-3烷氧基,杂环,芳基和杂芳基;
Ra选自下组:氢,卤素,C1-3烷基,卤代C1-3烷基,C1-3烷氧基,卤代C1-3烷氧基,NH2,NH(CH3),N(CH3)2,NHC(O)CH3,OH和CN;或不存在;
Rb选自下组:氢,卤素,C1-3烷基,卤代C1-3烷基,C1-3烷氧基,卤代C1-3烷氧基,NH2,NH(CH3),N(CH3)2,NHC(O)CH3,OH和CN;或不存在;
Rc选自下组:氢,卤素,C1-3烷基,卤代C1-3烷基,C1-3烷氧基,卤代C1-3烷氧基,NH2,NH(CH3),N(CH3)2,NHC(O)CH3,OH和CN;或不存在;
Rd选自下组:氢,卤素,C1-3烷基,卤代C1-3烷基,C1-3烷氧基,卤代C1-3烷氧基,NH2,NH(CH3),N(CH3)2,NHC(O)CH3,OH和CN;或不存在;
Re选自下组:氢,卤素,C1-3烷基;或不存在;
Rf是氢,卤素,C1-3烷基;或不存在;
限制条件是:该化合物不是2-氨基-N-(4-氯-2-甲基苯基)-5-氨磺酰基苯甲酰胺或N-(2-甲氧基苯基)-2-(甲基氨基)-5-(哌啶-1-基磺酰基)苯甲酰胺;
及其药学上可接受的盐、互变异构体、异构体、立体异构体。
2.如权利要求1所述的化合物,其具有式(Ia):
其中:
A是6元芳族或杂芳族环;
B是任选地含有一个或多个N原子的6元芳基;
Y选自下组:氢,卤素,C1-3烷基,NH2,NH(C1-6烷基),N(CH3)2,NHC(O)CH3,OH,饱和或部分不饱和的C3-7环烷基,5-或6-元杂芳基和CN,或不存在;
R1及R2各自独立地选自H,直链或支化1-6烷基,饱和或部分不饱和的C3-7环烷基,C3-7杂环烷基和杂芳基,所述直链或支化的C1-6烷基,饱和或部分不饱和的C3-7环烷基,C3-7杂环烷基或杂芳基各自任选地被选自以下的一个或多个取代基取代:OH,卤素,NH2,NH(C=O)OC1-6烷基,NH(C1-6烷基),C1-6烷基,C3-7环烷基,C3-7杂环烷基,C1-6羟烷基,5-或6-元杂芳基,C(=O)C1-6烷基,C(=O)OC1-6烷基,OC1-6烷基,O(CH2)nC3-10环烷基和O(CH2)nC3-10杂环烷基;
或R1和R2与它们所连接的N原子一起形成饱和或部分不饱和的3-10元杂环,其任选地包含选自N、O和S的另一个杂原子,所述饱和或部分不饱和的3-10元杂环任选地被选自OH,卤素,C1-6烷基,C1-6卤代烷基、(CH2)nR5的一个或多个取代基取代;
n在每次出现时独立地是0、1、2、3或4;
R3和R4各自独立地是H,或直链或支化C1-3烷基,其任选地被选自卤素,NH2,NHC1-6烷基,N(C1-6烷基)2,NH(C=O)C1-6烷基,NH(C=O)OC1-6烷基,OC1-6烷基,O(CH2)nC3-10环烷基和O(CH2)nC3-10杂环烷基的一个或多个基团取代,限制条件是:NR3R4不形成饱和、部分饱和或不饱和的杂环;
R5选自下组:OH,NH2,NH(CH3),N(CH3)2,NHC(O)CH3,CN,卤代C1-3烷基,C1-3烷氧基,卤代C1-3烷氧基,杂环,芳基和杂芳基;
Ra选自下组:氢,卤素,C1-3烷基,卤代C1-3烷基,C1-3烷氧基,卤代C1-3烷氧基,NH2,NH(CH3),N(CH3)2,NHC(O)CH3,OH和CN;或不存在;
Rb选自下组:氢,卤素,C1-3烷基,卤代C1-3烷基,C1-3烷氧基,卤代C1-3烷氧基,NH2,NH(CH3),N(CH3)2,NHC(O)CH3,OH和CN;或不存在;
Rc选自下组:氢,卤素,C1-3烷基,卤代C1-3烷基,C1-3烷氧基,卤代C1-3烷氧基,NH2,NH(CH3),N(CH3)2,NHC(O)CH3,OH和CN;或不存在;
Rd选自下组:氢,卤素,C1-3烷基,卤代C1-3烷基,C1-3烷氧基,卤代C1-3烷氧基,NH2,NH(CH3),N(CH3)2,NHC(O)CH3,OH和CN;或不存在;
Re选自下组:氢,卤素,C1-3烷基;或不存在;
Rf是氢,卤素和C1-3烷基;或不存在;
及其药学上可接受的盐、互变异构体、异构体、立体异构体。
3.如权利要求1或2所述的化合物,其中:
A是6元芳族或杂芳族环;
B是任选地含有一个或多个N原子的6元芳基;
Y选自下组:氢,卤素,C1-3烷基,NH2,NH(C1-6烷基),N(CH3)2,NHC(O)CH3,OH和CN,或不存在;
R1是H,直链或支化C1-6烷基,环丙基,环丁基,环戊基,环己基,哌啶基,吡咯烷基,氧杂环丁烷基,四氢呋喃基,吡啶基,所述C1-6烷基,环丙基,环丁基,环戊基,环己基,哌啶基,吡咯烷基,氧杂环丁烷基,四氢呋喃基或吡啶基任选地被选自以下的一个或多个取代基取代:OH,卤素,NH2,NH(C=O)OC1-6烷基,NH(C1-6烷基),C1-6羟烷基,5或6-元杂芳基,C(=O)C1-6烷基,C(=O)OC1-6烷基,OC1-6烷基;
R2是H或甲基;
或R1和R2与它们所连接的N原子一起形成选自哌啶,吡咯烷,吗啉,硫代吗啉和哌嗪的杂环,所述环任选地被选自卤素,C1-3烷基,OH和CH2R5的一个或多个取代基取代;
R3和R4各自独立地是H或C1-3烷基;特别是氢或甲基;
R5选自下组:OH,NH2,NH(CH3),N(CH3)2,NHC(O)CH3,CN,卤代C1-3烷基,C1-3烷氧基,卤代C1-3烷氧基,杂环,芳基和杂芳基;
Ra选自下组:氢,卤素,C1-3烷基,卤代C1-3烷基和CN;或不存在;
Rb选自下组:氢,卤素,C1-3烷基,卤代C1-3烷基和CN;或不存在;
Rc选自下组:氢,卤素,C1-3烷基,卤代C1-3烷基和CN;或不存在;
Rd选自下组:氢,卤素,C1-3烷基,卤代C1-3烷基和CN;或不存在;
Re选自下组:氢,卤素,C1-3烷基;或不存在;
Rf是氢或不存在;
及其药学上可接受的盐、互变异构体、异构体、立体异构体。
4.根据前述权利要求中任一项所述的化合物,其中:
A是6元芳族或杂芳族环;
B是任选地含有一个或多个N原子的6元芳基;
Y选自下组:氢,卤素,C1-3烷基;或不存在;
R2是H或甲基;
R3和R4各自独立地是H或C1-3烷基;特别是氢或甲基;
Ra选自下组:氢,卤素,C1-3烷基,卤代C1-3烷基和CN;或不存在;
Rb选自下组:氢,卤素,C1-3烷基,卤代C1-3烷基和CN;或不存在;
Rc选自下组:氢,卤素,C1-3烷基,卤代C1-3烷基和CN;或不存在;
Rd选自下组:氢,卤素,C1-3烷基,卤代C1-3烷基和CN;或不存在;
Re选自下组:氢,卤素,C1-3烷基;或不存在;
Rf是氢或不存在;
及其药学上可接受的盐、互变异构体、异构体、立体异构体。
5.如前述权利要求中任一项所述的化合物,其中:
A是苯基或吡啶基;
B是苯基或吡啶基;
及其药学上可接受的盐、互变异构体、异构体、立体异构体。
6.如前述权利要求中任一项所述的化合物,其中A是苯基且B是苯基,及其药学上可接受的盐、互变异构体、异构体、立体异构体。
7.如前述权利要求中任一项所述的化合物,其中,Ra、Rb、Rc和Rd中至少一个是F,且其余是氢,及其药学上可接受的盐、互变异构体、异构体、立体异构体。
8.如权利要求1所述的化合物,其选自以下列表:
-4-氨基-3-(N-甲基氨磺酰基)-N-(3,4,5-三氟苯基)苯甲酰胺;
-4-氨基-3-氨磺酰基-N-(3,4,5-三氟苯基)苯甲酰胺;
-4-氨基-N-(3,4-二氟苯基)-3-氨磺酰基苯甲酰胺;
-4-氨基-2-氯-5-氨磺酰基-N-(3,4,5-三氟苯基)苯甲酰胺;
-4-氨基-2-溴-5-氨磺酰基-N-(3,4,5-三氟苯基)苯甲酰胺;
-4-氨基-N-(4-氟-3-(三氟甲基)苯基)-3-氨磺酰基苯甲酰胺;
-4-氨基-N-(3-氰基-4-氟苯基)-3-氨磺酰基苯甲酰胺;
-4-氨基-N-(3-(二氟甲基)-4-氟苯基)-3-氨磺酰基苯甲酰胺;
-4-氨基-N-(3-氯-4-氟苯基)-3-氨磺酰基苯甲酰胺;
-4-氨基-N-(4-氟-3-甲基苯基)-3-氨磺酰基苯甲酰胺;
-4-氨基-2-甲基-5-氨磺酰基-N-(3,4,5-三氟苯基)苯甲酰胺;
-(R)-4-氨基-N-(3,4,5-三氟苯基)-3-(N-(1,1,1-三氟丙烷-2-基)氨磺酰基)苯甲酰胺;
-(S)-4-氨基-N-(3,4,5-三氟苯基)-3-(N-(1,1,1-三氟丙烷-2-基)氨磺酰基)苯甲酰胺;
-4-氨基-3-(N-环丙基氨磺酰基)-N-(3,4,5-三氟苯基)苯甲酰胺;
-反式-4-氨基-3-(N-(4-羟基环己基)氨磺酰基)-N-(3,4,5-三氟苯基)苯甲酰胺;
-顺式-4-氨基-3-(N-(4-羟基环己基)氨磺酰基)-N-(3,4,5-三氟苯基)苯甲酰胺;
-反式-4-氨基-5-(N-(4-羟基环己基)氨磺酰基)-2-甲基-N-(3,4,5-三氟苯基)苯甲酰胺;
-顺式-4-氨基-3-(N-3-羟基环丁基)氨磺酰基)-N-(3,4,5-三氟苯基)苯甲酰胺;
-反式-4-氨基-3-(N-3-羟基环丁基)氨磺酰基)-N-(3,4,5-三氟苯基)苯甲酰胺;
-4-氨基-3-(N-((1R,3R)-3-羟基环戊基)氨磺酰基)-N-(3,4,5-三氟苯基)苯甲酰胺;
-4-氨基-3-((4-羟基哌啶-1-基)磺酰基)-N-(3,4,5-三氟苯基)苯甲酰胺;
-4-氨基-3-(N-(氧杂环丁-3-基)氨磺酰基)-N-(3,4,5-三氟苯基)苯甲酰胺;
-(S)-3-((2-氨基-5-((3,4,5-三氟苯基)氨基甲酰基)苯基)磺酰胺基)吡咯烷-1-羧酸叔丁酯;
-4-氨基-3-甲基-5-氨磺酰基-N-(3,4,5-三氟苯基)苯甲酰胺;
-4-氨基-3-(N-(3-(羟甲基)氧杂环丁-3-基)氨磺酰基)-N-(3,4,5-三氟苯基)苯甲酰胺;
-4-氨基-3-(N-((1-羟基环己基)甲基)氨磺酰基)-N-(3,4,5-三氟苯基)苯甲酰胺;
-4-氨基-N-(4-氟-3-甲基苯基)-2-甲基-5-氨磺酰基苯甲酰胺;
-4-氨基-5-(N-((1R,4R)-4-羟基环己基)氨磺酰基)-2-甲基-N-(3,4,5-三氟苯基)苯甲酰胺;
-反式-4-氨基-N-(3-氯-4-氟苯基)-3-(N-(4-羟基环己基)氨磺酰基)苯甲酰胺;
-4-氨基-N-(3-(二氟甲基)-4-氟苯基)-3-(N-((1r1R,4r4R)-4-羟基环己基)氨磺酰基)苯甲酰胺;
-反式-4-氨基-N-(3-(二氟甲基)-4-氟苯基)-3-(N-(4-羟基环己基)氨磺酰基)苯甲酰胺;
-4-氨基-3-(N-((1S,3R)-3-羟基环戊基)氨磺酰基)-N-(3,4,5-三氟苯基)苯甲酰胺;
-4-氨基-3-(N-((1R,3S)-3-羟基环戊基)氨磺酰基)-N-(3,4,5-三氟苯基)苯甲酰胺;
-4-氨基-3-((4-羟基-4-(羟甲基)哌啶-1-基)磺酰基)-N-(3,4,5-三氟苯基)苯甲酰胺;
-((1R,2S)-2-((2-氨基-5-((3,4,5-三氟苯基)氨基甲酰基)苯基)磺酰胺基)环戊基)氨基甲酸叔丁酯;
-((1S,2R)-2-((2-氨基-5-((3,4,5-三氟苯基)氨基甲酰基)苯基)磺酰胺基)环戊基)氨基甲酸叔丁酯;
-4-氨基-3-((3-羟基吡咯烷-1-基)磺酰基)-N-(3,4,5-三氟苯基)苯甲酰胺;
-4-氨基-N-(3-氯-4-氟苯基)-3-((4-羟基哌啶-1-基)磺酰基)苯甲酰胺;
-4-氨基-N-(3-氯-4-氟苯基)-3-((3-羟基氮杂环丁烷-1-基)磺酰基)苯甲酰胺;
-4-氨基-3-(N-(2,3-二羟基丙基)氨磺酰基)-N-(3,4,5-三氟苯基)苯甲酰胺;
-反式-4-氨基-3-(N-(3-羟基环戊基)氨磺酰基)-N-(3,4,5-三氟苯基)苯甲酰胺;
-反式-2-氨基-5-(N-(4-羟基环己基)氨磺酰基)-N-(3,4,5-三氟苯基)苯甲酰胺;
-2-氨基-5-((4-羟基哌啶-1-基)磺酰基)-N-(3,4,5-三氟苯基)苯甲酰胺;
-(R)-4-氨基-2-甲基-N-(3,4,5-三氟苯基)-5-(N-(1,1,1-三氟丙烷-2-基)氨磺酰基)苯甲酰胺;
-(S)-4-氨基-2-甲基-N-(3,4,5-三氟苯基)-5-(N-(1,1,1-三氟丙烷-2-基)氨磺酰基)苯甲酰胺;
-4-氨基-N-(3-氯-4,5-二氟苯基)-2-甲基-5-氨磺酰基苯甲酰胺;
-4-氨基-N-(4-氟-3-(三氟甲基)苯基)-2-甲基-5-氨磺酰基苯甲酰胺;
-4-氨基-N-(3-(二氟甲基)-4-氟苯基)-2-甲基-5-氨磺酰基苯甲酰胺;
-4-氨基-N-(3-氰基-4-氟苯基)-2-甲基-5-氨磺酰基苯甲酰胺;
-4-氨基-N-(3-氯-4-氟苯基)-2-甲基-5-氨磺酰基苯甲酰胺;
及其药学上可接受的盐、互变异构体、异构体、立体异构体。
9.如前述权利要求中任一项所定义的化合物,或其药学上可接受的盐,互变异构体,异构体或立体异构体,其用于医疗用途。
10.如权利要求9所定义的化合物或其药学上可接受的盐,互变异构体,异构体或立体异构体,其用于治疗和/或预防HBV感染和/或与HBV感染有关的病症。
11.一种通式(I)的化合物:
其中:
A是6元芳族或杂芳族环;
B是任选地含有一个或多个N原子的6元芳基;
X是H或NR3R4;
Y选自下组:氢,卤素,C1-6烷基,NH2,NH(C1-6烷基),N(CH3)2,NHC(O)CH3,OH,饱和或部分不饱和的C3-7环烷基,5-或6-元杂芳基和CN,或不存在;
限制条件是,当X是H时,Y选自下组:NH2,NH(C1-6烷基),N(CH3)2,NHC(O)CH3;
R1及R2各自独立地选自H,直链或支化1-6烷基,饱和或部分不饱和的C3-7环烷基,C3-7杂环烷基和杂芳基,所述直链或支化的C1-6烷基,饱和或部分不饱和的C3-7环烷基,C3-7杂环烷基或杂芳基各自任选地被选自以下的一个或多个取代基取代:OH,卤素,NH2,NH(C=O)OC1-6烷基,NH(C1-6烷基),C1-6烷基,C3-7环烷基,C3-7杂环烷基,C1-6羟烷基,5-或6-元杂芳基,C(=O)C1-6烷基,C(=O)OC1-6烷基,OC1-6烷基,O(CH2)nC3-10环烷基和O(CH2)nC3-10杂环烷基;
或R1和R2与它们所连接的N原子一起形成饱和或部分不饱和的3-10元杂环,其任选地包含选自N、O和S的另一个杂原子,所述饱和或部分不饱和的3-10元杂环任选地被选自OH,卤素,C1-6烷基,C1-6卤代烷基和(CH2)nR5的一个或多个取代基取代;
n在每次出现时独立地是0、1、2、3或4;
R3和R4各自独立地是H,或直链或支化C1-3烷基,其任选地被选自卤素,NH2,NHC1-6烷基,N(C1-6烷基)2,NH(C=O)C1-6烷基,NH(C=O)OC1-6烷基,OC1-6烷基,O(CH2)nC3-10环烷基和O(CH2)nC3-10杂环烷基的一个或多个基团取代,限制条件是NR3R4不形成饱和、部分饱和或不饱和的杂环;
R5选自下组:OH,NH2,NH(CH3),N(CH3)2,NHC(O)CH3,CN,卤代C1-3烷基,C1-3烷氧基,卤代C1-3烷氧基,杂环,芳基和杂芳基;
Ra选自下组:氢,卤素,C1-3烷基,卤代C1-3烷基,C1-3烷氧基,卤代C1-3烷氧基,NH2,NH(CH3),N(CH3)2,NHC(O)CH3,OH和CN;或不存在;
Rb选自下组:氢,卤素,C1-3烷基,卤代C1-3烷基,C1-3烷氧基,卤代C1-3烷氧基,NH2,NH(CH3),N(CH3)2,NHC(O)CH3,OH和CN;或不存在;
Rc选自下组:氢,卤素,C1-3烷基,卤代C1-3烷基,C1-3烷氧基,卤代C1-3烷氧基,NH2,NH(CH3),N(CH3)2,NHC(O)CH3,OH和CN;或不存在;
Rd选自下组:氢,卤素,C1-3烷基,卤代C1-3烷基,C1-3烷氧基,卤代C1-3烷氧基,NH2,NH(CH3),N(CH3)2,NHC(O)CH3,OH和CN;或不存在;
Re选自下组:氢,卤素,C1-3烷基;或不存在;
Rf是氢,卤素,C1-3烷基;或不存在;
以及其药学上可接受的盐、互变异构体、异构体、立体异构体,其用于治疗和/或预防HBV感染和/或与HBV感染有关的病症。
12.如权利要求9-11中任一项所述的所述用途的化合物或其药学上可接受的盐、互变异构体、异构体、立体异构体,其中所述与HBV感染有关的病症选自下组:慢性乙型肝炎,HBV/HDV共同感染,HBV/HCV共同感染,HBV/HIV共同感染,HBV感染引起的炎症,坏死,肝硬化,肝细胞癌,肝代偿失调和肝损伤。
13.如权利要求9-12中任一项所述的所述用途的化合物或其药学上可接受的盐、互变异构体、异构体、立体异构体,其中,所述用途是在有此需要的个体中治疗、根除、减少、减慢或抑制HBV感染,和/或用于在有此需要的个体中减少与HBV感染相关联的病毒载量,和/或用于在有此需要的个体中减少HBV感染的复发,和/或用于在有此需要的个体中诱导由HBV感染引起的肝损伤的缓解,和/或用于在具有潜在HBV感染的个体中预防性治疗HBV感染。
14.如权利要求9-13中任一项所述的所述用途的化合物或其药学上可接受的盐、互变异构体、异构体、立体异构体,其中所述用途与至少一种其它治疗剂组合。
15.如权利要求14所述的所述用途的化合物或其药学上可接受的盐、互变异构体、异构体、立体异构体,其中,所述至少一种其它治疗剂选自下组:治疗性疫苗;RNA干扰治疗剂/反义寡核苷酸;免疫调节剂;STING激动剂;RIG-I调节剂;NKT调节剂;IL激动剂;白介素或其它免疫作用蛋白;治疗性和预防性疫苗;免疫检查点调节剂/抑制剂;HBV进入抑制剂;cccDNA调节剂;HBV蛋白表达抑制剂;靶向HBV RNA的物质;衣壳组装抑制剂/调节剂;核心或X蛋白靶向剂;核苷酸类似物;核苷类似物;干扰素或修饰的干扰素;机制不同或未知的HBV抗病毒剂;亲环蛋白抑制剂;sAg释放抑制剂;HBV聚合酶抑制剂;二核苷酸;SMAC抑制剂;HDV靶向剂;病毒成熟抑制剂;逆转录酶抑制剂和HBV RNA去稳定剂或HBV蛋白表达的其它小分子抑制剂;或其组合。
16.如权利要求15所述的所述用途的化合物或其药学上可接受的盐、互变异构体、异构体、立体异构体,其中,所述治疗性疫苗选自:HBsAG-HBIG、HB-Vac、ABX203、NASVAC、GS-4774、GX-110(HB-110E)、CVI-HBV-002、RG7944(INO-1800)、TG-1050、FP-02(Hepsyn-B)、AIC649、VGX-6200、KW-2、TomegaVax-HBV、ISA-204、NU-500、INX-102-00557、HBV MVA和PepTcell;其中,所述RNA干扰治疗剂选自:TKM-HBV(ARB-1467)、ARB-1740、ARC-520、ARC-521、BB-HB-331、REP-2139、ALN-HBV、ALN-PDL、LUNAR-HBV、GS3228836和GS3389404;其中所述免疫调节剂是TLR激动剂;其中所述RIG-I调节剂是SB-9200;其中所述IL激动剂或其它免疫作用蛋白是INO-9112或重组IL12;其中所述免疫检查点调节剂/抑制剂是BMS-936558(欧狄沃(纳武单抗))或派姆单抗;其中所述HBV进入抑制剂是Myrcludex B、IVIG-Tonrol或GC-1102;其中所述cccDNA调节剂选自:直接cccDNA抑制剂、cccDNA形成或维持的抑制剂、cccDNA表观调节剂和cccDNA转录的抑制剂;其中所述衣壳组装抑制剂/调节剂、核心或X蛋白靶向剂、直接cccDNA抑制剂、cccDNA形成或维持的抑制剂或cccDNA表观调节剂选自:BAY41-4109、NVR 3-778、GLS-4、NZ-4(W28F)、Y101、ARB-423、ARB-199、ARB-596、AB-506、JNJ-56136379、ASMB-101(AB-V102)、ASMB-103、CHR-101、CC-31326、AT-130和RO7049389;其中所述干扰素或修饰的干扰素选自:干扰素α(IFN-α)、聚乙二醇化干扰素α(PEG-IFN-α)、干扰素α-2a、重组干扰素α-2a、聚乙二醇化干扰素α-2a(派罗欣)、干扰素α-2b(内含子A)、重组干扰素α-2b、干扰素α-2b XL、聚乙二醇化干扰素α-2b、糖基化干扰素α-2b、干扰素α-2c、重组干扰素α-2c、干扰素β、干扰素β-la、聚乙二醇化干扰素β-la、干扰素δ、干扰素λ(IFN-λ)、聚乙二醇化干扰素λ-1、干扰素ω、干扰素τ、干扰素γ(IFN-γ)、干扰素Alfacon-1、干扰素α-nl、干扰素α-n3、alb干扰素α-2b、BLX-883、DA-3021、PI 101(也称为AOP2014)、PEG-干复津、Belerofon、INTEFEN-IFN、白蛋白/干扰素α2a融合蛋白、rHSA-IFNα2a、rHSA-IFNα2b、PEG-IFN-SA和干扰素α生物改良剂;其中所述机理不同或未知的HBV抗病毒剂选自:AT-61((E)-N-(1-氯-3-氧代-1-苯基-3-(哌啶-1-基)丙-1-烯-2-基)苯甲酰胺)、AT130((E)-N-(1-溴-1-(2-甲氧基苯基)-3-氧代-3-(哌啶-1-基)丙-1-烯-2-基)-4-硝基苯甲酰胺)、其类似物、REP-9AC(REP-2055)、REP-9AC’(REP-2139)、REP-2165和HBV-0259;其中所述亲环蛋白抑制剂选自:OCB-030(NVP-018)、SCY-635、SCY-575和CPI-431-32;其中所述HBV聚合酶抑制剂选自:恩替卡韦(博路定、恩他韦)、拉米夫定(3TC、干安能、贺普丁、益平维和益平维-HBV),替比夫定(替泽卡、素比伏)、克列夫定、贝西福韦、阿德福韦(贺维力)、替诺福韦、替诺福韦富马酸替索罗韦(Viread)、替诺福韦富马酸阿芬太尼(TAF)、替诺福韦替泊罗乳清酸酯(DA-2802)、替诺福韦二异丙氧基天冬氨酸酯(CKD-390)、AGX-1009和CMX157;其中所述二核苷酸是SB9200;其中所述SMAC抑制剂是比瑞那帕;其中所述HDV靶向剂是洛那法尼;其中所述HBVRNA去稳定剂或HBV蛋白表达的其它小分子抑制剂是RG7834或AB-452。
17.一种药物组合物,其包含如权利要求1-8或11中任一项所定义的化合物或其药学上可接受的盐、互变异构体、异构体、立体异构体,其单独存在或与至少一种其它治疗剂组合,以及至少一种药学上可接受的赋形剂。
18.如权利要求17所述的药物组合物,其中,所述至少一种其它治疗剂选自下组:治疗性疫苗;RNA干扰治疗/反义寡核苷酸;免疫调节剂;STING激动剂;RIG-I调节剂;NKT调节剂;IL激动剂;白介素或其它免疫作用蛋白;治疗性和预防性疫苗;免疫检查点调节剂/抑制剂;HBV进入抑制剂;cccDNA调节剂;HBV蛋白表达抑制剂;靶向HBV RNA的物质;衣壳组装抑制剂/调节剂;核心或X蛋白靶向剂;核苷酸类似物;核苷类似物;干扰素或修饰的干扰素;机制不同或未知的HBV抗病毒剂;亲环蛋白抑制剂;sAg释放抑制剂;HBV聚合酶抑制剂;二核苷酸;SMAC抑制剂;HDV靶向剂;病毒成熟抑制剂;逆转录酶抑制剂和HBV RNA去稳定剂或HBV蛋白表达的其它小分子抑制剂;或其组合。
19.如权利要求18所述的药物组合物,其中,所述治疗性疫苗选自:HBsAG-HBIG,HB-Vac,ABX203,NASVAC,GS-4774,GX-110(HB-110E),CVI-HBV-002,RG7944(INO-1800),TG-1050,FP-02(Hepsyn-B),AIC649,VGX-6200,KW-2,TomegaVax-HBV,ISA-204,NU-500,INX-102-00557,HBV MVA和PepTcell;所述RNA干扰治疗剂选自:TKM-HBV(ARB-1467)、ARB-1740、ARC-520、ARC-521、BB-HB-331、REP-2139、ALN-HBV、ALN-PDL、LUNAR-HBV、GS3228836和GS3389404;其中所述免疫调节剂是TLR激动剂;其中所述RIG-I调节剂是SB-9200;其中所述IL激动剂或其它免疫作用蛋白是INO-9112或重组IL12;其中所述免疫检查点调节剂/抑制剂是BMS-936558(欧狄沃(纳武单抗))或派姆单抗;其中所述HBV进入抑制剂是MyrcludexB、IVIG-Tonrol或GC-1102;其中所述cccDNA调节剂选自:直接cccDNA抑制剂、cccDNA形成或维持的抑制剂、cccDNA表观调节剂和cccDNA转录的抑制剂;其中所述衣壳组装抑制剂/调节剂、核心或X蛋白靶向剂、直接cccDNA抑制剂、cccDNA形成或维持的抑制剂或cccDNA表观调节剂选自:BAY 41-4109、NVR 3-778、GLS-4、NZ-4(W28F)、Y101、ARB-423、ARB-199、ARB-596、AB-506、JNJ-56136379、ASMB-101(AB-V102)、ASMB-103、CHR-101、CC-31326、AT-130和RO7049389;其中所述干扰素或修饰的干扰素选自:干扰素α(IFN-α)、聚乙二醇化干扰素α(PEG-IFN-α)、干扰素α-2a、重组干扰素α-2a、聚乙二醇化干扰素α-2a(派罗欣)、干扰素α-2b(内含子A)、重组干扰素α-2b、干扰素α-2b XL、聚乙二醇化干扰素α-2b、糖基化干扰素α-2b、干扰素α-2c、重组干扰素α-2c、干扰素β、干扰素β-la、聚乙二醇化干扰素β-la、干扰素δ、干扰素λ(IFN-λ)、聚乙二醇化干扰素λ-1、干扰素ω、干扰素τ、干扰素γ(IFN-γ)、干扰素Alfacon-1、干扰素α-nl、干扰素α-n3、alb干扰素α-2b、BLX-883、DA-3021、PI 101(也称为AOP2014)、PEG-干复津、Belerofon、INTEFEN-IFN、白蛋白/干扰素α2a融合蛋白、rHSA-IFNα2a、rHSA-IFNα2b、PEG-IFN-SA和干扰素α生物改良剂;其中所述机理不同或未知的HBV抗病毒剂选自:AT-61((E)-N-(1-氯-3-氧代-1-苯基-3-(哌啶-1-基)丙-1-烯-2-基)苯甲酰胺)、AT130((E)-N-(1-溴-1-(2-甲氧基苯基)-3-氧代-3-(哌啶-1-基)丙-1-烯-2-基)-4-硝基苯甲酰胺)、其类似物、REP-9AC(REP-2055)、REP-9AC’(REP-2139)、REP-2165和HBV-0259;其中所述亲环蛋白抑制剂选自:OCB-030(NVP-018)、SCY-635、SCY-575和CPI-431-32;其中所述HBV聚合酶抑制剂选自:恩替卡韦(博路定、恩他韦)、拉米夫定(3TC、干安能、贺普丁、益平维和益平维-HBV),替比夫定(替泽卡、素比伏)、克列夫定、贝西福韦、阿德福韦(贺维力)、替诺福韦、替诺福韦富马酸替索罗韦(Viread)、替诺福韦富马酸阿芬太尼(TAF)、替诺福韦替泊罗乳清酸酯(DA-2802)、替诺福韦二异丙氧基天冬氨酸酯(CKD-390)、AGX-1009和CMX157;其中所述二核苷酸是SB9200;其中所述SMAC抑制剂是比瑞那帕;其中所述HDV靶向剂是洛那法尼;其中所述HBV RNA去稳定剂或HBV蛋白表达的其它小分子抑制剂是RG7834或AB-452。
20.如权利要求17-19中任一项所述的药物组合物,其用于治疗和/或预防HBV感染和/或与HBV感染有关的病症。
21.如权利要求20所述的所述用途的药物组合物,其中,所述与HBV感染有关的病症选自下组:慢性乙型肝炎,HBV/HDV共同感染,HBV/HCV共同感染,HBV/HIV共同感染,乙肝病毒感染引起的炎症,坏死,肝硬化,肝细胞癌,肝代偿失调和肝损伤。
22.如权利要求20或21所述的所述用途的药物组合物,其中,所述用途是在有此需要的个体中治疗、根除、减少、减慢或抑制HBV感染,和/或用于在有此需要的个体中减少与HBV感染相关联的病毒载量,和/或用于在有此需要的个体中减少HBV感染的复发,和/或用于在有此需要的个体中诱导由HBV感染引起的肝损伤的缓解,和/或用于在具有潜在HBV感染的个体中预防性治疗HBV感染。
23.用于合成如权利要求1-8或11中任一项所定义的式(I)化合物或其药学上可接受的盐、互变异构体、溶剂化物、异构体或立体异构体的方法,所述方法包括以下步骤中的至少一个:
-使式(2)的化合物与式NHR3R4的胺反应,以获得式(3)的化合物,其中A,B,Ra,Rb,Rc,Rd,Re,Rf,Y,R1,R2,R3和R4如权利要求1-8或11中任一项定义,且Lg是离去基团,如Cl或F;或
-使式(2)的化合物与铵盐如NH4OH反应,以获得式(4)的化合物,其中A,B,Ra,Rb,Rc,Rd,Re,Rf,Y,R1和R2如权利要求1-8或11中任一项定义,且
Lg是离去基团,如Cl或F;或
-使式(5)化合物与式(CH3)2NH或(C1-6)烷基NH2的胺,或与NH4OH反应,得到式(6)化合物,其中A,B,Ra,Rb,Rc,Rd,Re,Rf,R1和R2如权利要求1-8或11中任一项定义,并且Lg是离去基团,如Cl或F。
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CN115677545B (zh) * | 2022-10-28 | 2024-03-15 | 潍坊医学院 | 一种抗hbv磺胺苯甲酰胺类衍生物及其制备方法和应用 |
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BR112021000938A2 (pt) | 2021-04-27 |
EP3597637A1 (en) | 2020-01-22 |
JP2021531344A (ja) | 2021-11-18 |
WO2020016427A1 (en) | 2020-01-23 |
EP3823957A1 (en) | 2021-05-26 |
CA3106839A1 (en) | 2020-01-23 |
US20210276967A1 (en) | 2021-09-09 |
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