CN113301958A - 神经视网膜疾病的治疗和/或预防中作为治疗性活性物质使用的化合物 - Google Patents
神经视网膜疾病的治疗和/或预防中作为治疗性活性物质使用的化合物 Download PDFInfo
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- CN113301958A CN113301958A CN201980085675.1A CN201980085675A CN113301958A CN 113301958 A CN113301958 A CN 113301958A CN 201980085675 A CN201980085675 A CN 201980085675A CN 113301958 A CN113301958 A CN 113301958A
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- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D263/32—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/42—Oxazoles
- A61K31/421—1,3-Oxazoles, e.g. pemoline, trimethadione
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- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/06—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom
- C07D213/16—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom containing only one pyridine ring
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- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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Abstract
本发明涉及式(I)的化合物
或其药学上可接受的盐，其中：A是5‑噁唑基残基或吡啶‑4‑基残基，R1选自由氟和氯组成的组；苯环B的R2、R3、R4、R5和R6相互独立地选自由以下组成的组：氢、具有1至4个碳原子的直链或支链烷基、三氟甲基、2,2,2‑三氟乙基、甲硫基、乙硫基、甲磺酰基、乙磺酰基、二氟甲氧基、三氟甲氧基、氟、溴、氯、甲氧基、乙氧基、丙氧基、丁氧基、羟基和氨基；并且R2、R3、R4、R5和R6中的至少2个是氢，条件是如果R1是氯，R5不是甲氧基。所述化合物可作为治疗性活性物质用于治疗和/或预防神经视网膜疾病，并且特别用于治疗和/或预防导致外层视网膜光感受器丧失或变性的神经视网膜疾病。
Description
本发明涉及作为治疗性活性物质用于治疗和/或预防神经视网膜疾病的化合物，特别是用于治疗和/或预防导致外层视网膜光感受器丧失或变性的神经视网膜疾病。
神经退行性疾病的主要特征是神经细胞的日益丧失，导致各种神经系统症状。这些疾病可以在生命的不同时期出现，其进行是弥漫性的或普遍性的，并产生特定的损害模式。
特别重要的是眼睛的神经退行性疾病。视网膜变性是指视网膜的衰变，最终可能导致视网膜细胞的死亡。视网膜变性的最重要形式之一是所谓的色素性视网膜炎(RP)，也被称为色素性视网膜病变。视网膜的主要功能是通过视杆和视锥将光线转变成神经冲动。色素性视网膜炎是一种慢性视网膜变性，其恶化伴随着视网膜的视杆中的色素的异常沉积。这种疾病导致周边视力逐渐下降，从而导致侧视功能失常。最终，患有色素性视网膜炎的人只能看到正前方，因此患者会经历一种被称为“隧道视觉”的状况。
治疗由视网膜细胞损伤引起的视力丧失的治疗策略各不相同，但它们都致力于控制引起损伤的疾病，而不是通过恢复或再生视网膜细胞来逆转疾病引起的损伤。
WO 2016/073931公开了一种治疗人视网膜色素变性的方法，该方法包括向人施用治疗有效量的N-乙酰半胱氨酸酰胺(NACA)，该方法可减少眼睛中视锥细胞的死亡。
EP 2734202公开了一种含有4-溴-N-(咪唑啉-2-烯基)-1H-苯并咪唑-5-胺作为调节α2肾上腺素受体的活性成分的药物组合物。研究表明，所述化合物减少并保护视网膜免受蓝光的损害。
US 2015/290215披露了一种包含氯氮平、正去甲氯氮平、奥氮平或其衍生物的组合物，用于治疗由氧化应激引起的视网膜疾病。
US 2016/0213671涉及一种用于治疗或预防神经退行性疾病的药物组合物，该疾病不是基于蛋白质折叠障碍，所述组合物包括作为活性剂的含缬酪肽的蛋白的抑制剂(VCP抑制剂)。
WO 2014/079850披露了两种取代的杂环化合物，据信它们可以刺激成体神经元干细胞，并且所述化合物可用于多种不同的疾病。然而，尽管神经元干细胞具有分化为若干细胞类型的能力，但无法预测所述的新细胞类型是否能被相同的化合物所刺激。然而，大量刺激神经元干细胞的化合物对其他细胞类型(如视网膜前体细胞)没有活性或只有微弱的活性。
US 6117675披露了从哺乳动物视网膜中分离出来的干细胞和从这些干细胞中分化出来的视网膜细胞，以及从哺乳动物的视网膜色素上皮层中获得细胞的方法。
目前，还没有办法扭转视网膜的永久性损伤并恢复视力。药物治疗的重点是治疗疾病及其症状，以防止对视网膜的进一步损害。有必要通过内源性生成新的视网膜细胞或移植视网膜细胞来逆转对视网膜的损害并恢复视力。
术语“前体细胞”在这里包括任何形式的增殖性和非增殖性细胞，如干细胞本身和能产生进一步分化的眼睛功能组织的祖细胞。这种前体细胞尤其包括视网膜前体细胞。
因此，本发明的问题是提供能刺激视网膜前体细胞的增殖的新的化合物。
该问题由式(I)和(Ia)的化合物解决。进一步的优选实施方式是从属权利要求的主题。
已经显示出式(I)和(Ia)化合物刺激哺乳动物视网膜前体细胞的产生。内源性前体细胞的选择性激活使得可以对视网膜进行受控的修复和再生。因此，可以以本发明的化合物通过内源性地产生新的前体细胞来恢复视力。因此，该化合物可作为治疗神经视网膜疾病的治疗性活性物质使用，即作为药物使用。
因此，本发明涉及式(I)的化合物
或其药学上可接受的盐，
其中：
A是5-噁唑基残基或吡啶-4-基残基，
R1选自由氟和氯组成的组；
苯环B的R2、R3、R4、R5和R6相互独立地选自由以下组成的组：氢、具有1至4个碳原子的直链或支链烷基、三氟甲基、2,2,2-三氟乙基、甲硫基、乙硫基、甲磺酰基、乙磺酰基、二氟甲氧基、三氟甲氧基、氟、溴、氯、甲氧基、乙氧基、丙氧基、丁氧基、羟基和氨基；并且
R2、R3、R4、R5和R6中的至少2个是氢，条件是如果R1是氯，R5不是甲氧基。
术语“药学上可接受的盐”代表治疗活性的无毒酸的盐形式，根据本发明的化合物能够形成这种盐。
术语“烷基”作为基团是指含有1至4个碳原子的直链或支链烃。这里所用的“烷基”的实例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基和叔丁基。
残基A可以是式(II)的5-噁唑基
其中“*”表示与分子其余部分连接的点。
作为另选，残基A可以是式(III)的吡啶基
其中“*”表示与分子其余部分连接的点。
优选的是，本发明化合物中的苯环B是单取代的或二取代的，但也可以R2、R3、R4、R5和R6全部是氢。术语“单取代”是指R2、R3、R4、R5和R6中的一个不是氢。术语“二取代”是指R2、R3、R4、R5和R6中的两个不是氢。
优选的是，在本发明的化合物中，R1是氯。所述化合物显示出优异的生物活性。
在本发明的一个实施方式中，R1是如上定义的残基，且苯基环B未被取代，即R2、R3、R4、R5和R6全部为氢。
在本发明的另一个实施方式中，R1是如上定义的残基，且苯基环B是单取代的，即R2、R3、R4、R5和R6中的一个不是氢。
如果苯环B是单取代的，R2优选选自由以下组成的组：甲基、三氟甲基、甲硫基、甲磺酰基、二氟甲氧基、氟、溴、氯、甲氧基和乙氧基，最优选二氟甲氧基和氯，并且R2、R3、R4、R5和R6是氢。这种带有大体积残基R2的单取代的苯环B导致对视网膜前体细胞的特别好的刺激。
作为另选，如果苯环B是单取代的，R2是氢并且R3、R4、R5和R6中的一个优选选自由以下组成的组：三氟甲基、二氟甲氧基、甲氧基，优选三氟甲基和二氟甲氧基。
在本发明的另一个实施方式中，苯环B是双取代的，即，R2、R3、R4、R5和R6中的两个不是氢。双取代可以是邻位、间位或对位取代。
优选的是，R2选自由氟、溴和氯组成的组，并且R3、R4或R5中的一个选自由氟、溴和氯组成的组。与氢不同的两个残基可以相同，或相互不同。优选的是，R2是氯并且R5是氟，导致对位取代，或者R2和R4都是氟，导致间位取代。
优选的是，式(I)的化合物选自由以下组成的组：其中A、R1、R2、R3、R4、R5和R6如下的式(I)的化合物：
通过本发明的下列化合物可以获得特别好的结果：
C*＝对照实验(没有根据本发明的化合物)
特别是，式(1)、(10)、(4)、(9)、(3)和(2)的化合物在刺激前体细胞、特别是视网膜前体细胞方面显示出优异的效果。在一周内，式(1)化合物显示细胞增殖增加103％，式(10)化合物增加58％，式(4)化合物增加57％，式(9)化合物增加49％，式(3)化合物增加43％，而式(2)化合物增加42％。
在另一个实施方式中，本发明涉及一种药物组合物，其包括药学上可接受的载体和/或佐剂；以及式(Ia)的化合物作为治疗活性物：
或其药学上可接受的盐，其中：
A是5-噁唑基残基或吡啶-4-基残基；
R1’选自由以下组成的组：甲氧基、氢、氟和氯；
苯环B的R2、R3、R4、R5和R6相互独立地选自由以下组成的组：氢、具有1至4个碳原子的直链或支链烷基、三氟甲基、2,2,2-三氟乙基、甲硫基、乙硫基、甲磺酰基、乙磺酰基、二氟甲氧基、三氟甲氧基、氟、溴、氯、甲氧基、乙氧基、丙氧基、丁氧基、羟基和氨基；并且
R2、R3、R4、R5和R6中的至少2个是氢，
条件是如果R1’是氢或甲氧基，则A是吡啶-4-基残基。
式(Ia)化合物的定义与式(I)化合物的定义不同之处在于：R1’选自由以下组成的组：甲氧基、氢、氟和氯，而R1仅选自氟和氯组成的组。
术语“预防”是指预防或减少与神经视网膜疾病相关的症状和体征，特别是在有发病风险的受试者中导致光感受器丧失或视网膜光感受器层变性的原发性神经视网膜疾病相关的症状和体征。在这些受试者中，可能保留了易感因素，但疾病的症状和/或体征没有发生或需要明显更长时间来发展。此外，它还包括防止一旦疾病已经发生后症状的进一步恶化。
这里所用的术语“药物组合物”是指适合于施用于人类患者以治疗疾病的组合物。所述药物组合物有效地刺激患者体内的内源性视网膜前体细胞的增殖和/或迁移。
在本发明的一个优选实施方式中，所述药物组合物包括药学上可接受的载体和/或佐剂；以及如上定义的式(I)化合物，特别是表1和/或表2中公开的式(I)化合物。
在本发明的另一个实施方式中，药物组合物包括其中R1、R2、R3、R4、R5和R6如下的式(Ia)化合物：
通过本发明的下列化合物可获得特别好的结果：
特别是，式(23)、(21)、(22)、(24)和(27)的化合物在刺激前体细胞、特别是视网膜前体细胞方面显示出优异的效果。在一周内，式(23)化合物显示细胞增殖增加48％，式(21)化合物增加44％，式(22)化合物增加35％，式(24)化合物增加34％，而式(27)化合物增加40％。
如前所述，可以显示出根据本发明的化合物和根据本发明的组合物可以刺激视网膜前体细胞的增殖。因此，它们适用于治疗和/或预防神经视网膜疾病，特别是导致光感受器丧失或视网膜光感受器层变性的原发性神经视网膜疾病。
根据本发明的化合物和组合物适合用于治疗和/或预防选自由以下组成的组的疾病：遗传性视网膜营养不良症，包括：色素性视网膜炎(RP)，包括综合征和非综合征形式、X染色体连锁、隐性、显性和散发性形式，视杆-视锥营养不良症、乌谢尔综合征(Usher’ssyndrome)、Stargardt病、视锥-视杆营养不良症、视锥营养不良症、全色盲、蓝锥体单色症(blue cone monochromacy)、增强型S-视锥综合征、视杆营养不良症、无脉络膜症(choroideremia)、莱伯氏先天性黑矇(Leber’s congenital amaurosis)、青少年X染色体连锁性视网膜劈裂症(JXLR)、白点状眼底(fundus albipunctatus)、白点状视网膜炎、Kandori斑点视网膜、Bietti结晶性视网膜营养不良症、有孔光泽黄斑营养不良症(fenestrated sheen macular dystrophy)、成人型卵黄样黄斑营养不良症(adult-onsetfoveomacular vitelliform dystrophy)、Batten病、先天性静止夜盲症、家族性渗出性玻璃体视网膜病变(FEVR)、眼白化病、眼皮肤白化病、中央凹发育不良、无β脂蛋白血症(abetalipoproteinemia)、Stickler综合征和视网膜营养不良症(Bothnia型)。最优选的是，本发明的化合物用于治疗色素性视网膜炎(RP)，包括综合征和非综合征形式、X染色体连锁、隐性、显性和散发性形式。
根据本发明的化合物和组合物适合用于治疗和/或预防选自由以下组成的组的获得性变性：结晶性黄斑病(与药物有关、高草酸尿症、胱氨酸病、Sjogren-Larsson综合征)、西非结晶性黄斑病、日光性视网膜病、滑石视网膜病、糖尿病性视网膜病、镰状细胞性视网膜病、黄斑毛细血管扩张症、伊尔斯氏病(eales disease)、视网膜脱离、锯齿缘断离(retinal dialysis)、周围性视网膜劈裂症。
根据本发明的化合物和组合物适合用于治疗和/或预防选自由以下组成的组的血管相关的视网膜变性：中央/分支视网膜动脉闭塞(CRAO/BRAO)、中央/分支视网膜静脉闭塞(CRVO/BRVO)、出血性闭塞性视网膜血管炎(HORV)。
根据本发明的化合物和组合物适合用于治疗和/或预防选自由以下组成的组的疾病：选自氯喹、羟氯喹、吩噻嗪、硫酸奎宁、硫利达嗪、氯法齐明、氯丙嗪、去铁胺、氯喹衍生物、顺铂、卡莫司汀、氯苯吩嗪和氨己烯酸的药物引起的黄斑病；以及，包括他莫昔芬、滑石、角黄素(canthaxanthine)、甲氧氟烷、呋喃妥因在内的晶体引起的黄斑病；包括肾上腺素、拉坦前列腺素和烟酸在内的囊样黄斑水肿(CME)。
根据本发明的化合物和组合物适合用于治疗和/或预防选自由以下组成的组的感染性和/或炎症性眼病：进行性外层视网膜坏死(PORN)、急性视网膜坏死(ARN)、CMV-视网膜炎、肉状瘤病(Sarcoidosis)、急性梅毒性后部鳞状脉络膜视网膜炎、结核性脉络膜视网膜炎、弓形虫视网膜脉络膜炎、后葡萄膜炎和视网膜血管炎、中间葡萄膜炎、扁平部睫状体炎(pars planitis)+/-CME、内眼炎(前部和/或后部)、后部巩膜炎和伪装综合征。
根据本发明的化合物和组合物适合用于治疗和/或预防选自由以下组成的组的白点综合征：多灶性脉络膜炎和全葡萄膜炎(MCP)、点状内层脉络膜病(PIC)、鸟枪弹丸样视网膜脉络膜病(birdshot retinochoroidopathy)、急性黄斑神经性视网膜病(AMN)和急性区域性隐匿性外层视网膜病(AZOOR)。
根据本发明的化合物或组合物可以单独或与一种或多种额外的治疗剂一起施用于患者。本文所用的“患者”包括哺乳动物，如人、非人灵长类动物、大鼠、小鼠、兔、野兔、狗、猫、马、牛和猪，优选是人。
根据本发明的药物组合物可以包括一种或多种额外的治疗剂。
优选的是，这种药物组合物提供控释性质。这里的术语“控释药物组合物”是指任何组合物或剂型，它包括本发明的化合物，并被配制成在施用该剂型后提供比通常在服用包含相同量的相同药物的相应速释组合物后更长的药理响应持续时间。根据所使用的基质，控释可以延长达至多几个月。优选的是，根据本发明的化合物的释放在长达12个月的时间、最优选在长达6个月的时间发生。这样的控释配方可以提高病人的舒适度，并大大降低成本。
用于根据本发明的药物组合物的基质材料可包括疏水性释放控制剂。它优选选自但不限于聚乙酸乙烯酯分散体、乙基纤维素、乙酸纤维素、丙酸纤维素(低、中或高分子量)、乙酸丙酸纤维素、乙酸丁酸纤维素、乙酸邻苯二甲酸纤维素、三乙酸纤维素、聚(甲基丙烯酸甲酯)、聚(甲基丙烯酸乙酯)、聚(甲基丙烯酸丁酯)、聚(甲基丙烯酸异丁酯)、和聚(甲基丙烯酸己酯)、聚(甲基丙烯酸异癸酯)、聚(甲基丙烯酸月桂酯)、聚(甲基丙烯酸苯酯)、聚(丙烯酸甲酯)、聚(丙烯酸异丙酯)、聚(丙烯酸异丁酯)、聚(丙烯酸十八烷基酯)，蜡(例如，蜂蜡、棕榈蜡、石蜡、微晶蜡和地蜡)；脂肪醇，如鲸蜡醇、硬脂醇、十六烷醇和肉豆蔻醇；以及脂肪酸酯，如单硬脂酸甘油酯、单油酸甘油酯、乙酰化单甘油酯、三硬脂精、三棕榈精、十六烷酯蜡、棕榈酸硬脂酸甘油酯、山嵛酸甘油酯或氢化植物油。
本发明的化合物可以通过各种途径递送到眼睛，包括但不限于在眼睛上局部应用或通过眼内注射到例如玻璃体或视网膜下(光感受器间)的空间；通过插入或注射到眼睛周围的组织局部递送；通过口服途径或通过皮下、静脉或肌肉内注射系统性递送；或通过导管或植入物递送。最优选的是，本发明的化合物是通过眼内注射施用。本发明的化合物可以在病况发生之前施用以预防其发生，例如在眼部手术期间；在病理性病况发生后立即施用；或在急性或长期病况发生期间施用。
根据预期的施用方式，根据本发明的化合物可以纳入任何药学上可接受的剂型中，例如，液体(包括溶液、悬浮液和乳液)、片剂、栓剂、丸剂、胶囊、粉末或类似物，优选是适合精确剂量的单次施用的剂型，或适合持续控制施用的持续释放剂型。最优选的是液体。
液体药物可施用剂型可以是例如溶液、悬浮液或乳液，优选是在载体中包含本发明的化合物和可选的药物助剂的溶液，所述载体例如是水、盐水、葡萄糖水、甘油、乙醇、DMSO等，从而形成溶液或悬浮液。如果需要，待施用的药物组合物还可包含少量的无毒辅助物质，如润湿剂或乳化剂、pH缓冲剂等。这种辅助剂的典型实例是乙酸钠、脱水山梨糖醇单月桂酸酯、三乙醇胺、乙酸钠和油酸三乙醇胺。
本发明还涉及一种治疗导致光感受器丧失或外视网膜变性的神经视网膜疾病的方法，包括将式(Ia)化合物或其药学上可接受的盐施用于具有该视网膜疾病的患者，以便向该患者的眼睛中递送有效治疗该视网膜疾病的量。式(Ia)化合物的定义详见上文。
本发明化合物的制备
式(I)化合物可通过下述方法以及有机化学领域已知的合成方法或本领域普通技术人员熟悉的修改来制备。此处使用的起始材料可商购获得，或可通过本领域已知的常规方法制备，如标准参考书"Compendium of organic Synthetic Methods,Vol.I-XlN"(Wiley-Interscience出版，ISSN：1934-4783)中描述的那些方法。优选的方法包括但不限于以下所述的方法。
这些方案是在合成本发明的化合物和支持性实例中有用的代表性方法。它们并不是要对本发明的范围进行任何限制。
制备型HPLC
用于纯化以下实施例中的反应物和制剂的制备型高压液相色谱法(HPLC)是按照以下方法进行的，除非在具体实施例中进行修改。带有YMC Triart C18(250x21.2mm,5μ)柱的Waters自动纯化仪器在室温运行，流速为16mL/min。样品用20mM碳酸氢铵水溶液(流动相A)和乙腈(流动相B)洗脱，梯度曲线为初始70％A和30％B，然后在3分钟内45％A和55％B，在20分钟内调整为20％A和80％B，然后在21分钟内调整为5％A和95％B，保持2分钟不变。纯的级分被浓缩，得到最终产品。
分析型HPLC
以下实施例和制备中使用的分析型超高效液相色谱法(UPLC)是按照以下方法进行的，除非在具体实施例中进行修改。Chromegabond WR C18(3cm x 3.2mm,3μ)柱以流速为1.5mL/min运行。用0.02％的TFA水溶液(流动相C)和0.02％的TFA CH3CN溶液(流动相D)作为流动相以以下梯度使用：从90％的C和10％的D开始，在3.0分钟内变为10％的C和90％的D，然后在4.0分钟内变为90％的C和10％的D，一直到5.1分钟保持不变。
通用方法——合成
方法1：
方案1：
其中R1、R2、R3、R4、R5、R6如式I所述。
通式I的化合物(方案1)可通过使用本领域熟练的化学家已知的程序使通式IV的化合物与通式V的羧酸反应来制备。
方法2：
方案2：
其中R1如式I所述，R是羟基，或R与硼原子一起形成4,4,5,5-四甲基-l,3,2-二氧硼烷基团。
通式IVa的化合物(方案2)可在钯催化剂如四(三苯基膦)钯(0)和碱如碳酸钾的存在下，或在有机合成领域中熟练的化学家已知的其他Suzuki-Miyaura偶联反应条件下由通式VI和VII的化合物制备。
方法3：
方案3：
其中R1如式I所述。
通式IVb的化合物(方案3)可使用本领域熟练的化学家已知的程序通过还原通式X的化合物中的硝基来制备。通式X的化合物可由通式VIII的醛类通过在试剂如异氰基甲烷)磺酰基-4-甲基苯(IX)存在下且在碱如碳酸钾存在下的反应制备。
包含5-噁唑基残基的化合物的合成
中间体1：
向经搅拌的2-氯-4-硝基苯甲醛(3.00g,16.2mmol)在甲醇(20mL)中的溶液中，加入1-(异氰基甲烷)磺酰基-4-甲基苯(3.80g,19.5mmol)，然后加入K2CO3(8.00g,58.0mmol)，并将反应混合物加热至80℃并在2小时内冷却至室温。反应完成后，将反应物倒入饱和NaHCO3溶液(20mL)中，并萃取到乙酸乙酯(3x200mL)中。有机层用水、盐水洗涤，在无水硫酸钠上干燥，并在真空下浓缩，得到粗品，用硅胶(100-200)通过柱色谱纯化(在30％乙酸乙酯的己烷溶液中洗脱)，得到5-(2-氯-4-硝基苯基)-1,3-噁唑(中间体1)(2.9g,80％)，为黄色固体。LCMS：225.2(M+H)。
中间体2：
向经搅拌的5-(2-氯-4-硝基苯基)-1,3-噁唑(中间体1)(3g,13.39mmol)在EtOH(40mL)的溶液中，在0℃下滴加SnCl2二水合物(12.08g,53.57mmol)和浓HCl(5mL)，将反应混合物在80℃搅拌30分钟。反应完成后，用2N NaOH溶液中和反应物，用乙酸乙酯萃取(2x50mL)。有机层用水彻底清洗，在无水硫酸钠上干燥，真空浓缩，得到3-氯-4-(1,3-噁唑-5-基)苯胺(中间体2)(1.5g,57％)，为黄色固体。LCMS：195(M+H)。
中间体3：
向经搅拌的2-氟-4-硝基苯甲醛(5g,29.56mmol)和1-(异氰基甲烷)磺酰基-4-甲基苯(7.5g,38.43mmol)在MeOH(35mL)的溶液中，加入K2CO3(16.3g,118.27mmol)，并将反应混合物加热至80℃2h。反应完成后，将反应物倒入饱和NaHCO3溶液(50mL)，用乙酸乙酯萃取(2x50mL)。有机层用水、盐水洗涤，在无水硫酸钠上干燥，并在真空下浓缩，得到粗品，用硅胶(100-200)通过柱色谱纯化(用30％乙酸乙酯在己烷中的溶液洗脱)，得到5-(2-氟-4-硝基苯基)-1,3-噁唑(中间体3)(2.5g,40％)，为黄色固体。LCMS：209.2(M+H)。
中间体4：
向经搅拌的5-(2-氟-4-硝基苯基)-1,3-噁唑(中间体3)(700mg,3.36mmol)在EtOH(35mL)的溶液中，在0℃下滴加氯化锡(II)SnCl2二水合物(3.03g,13.46mmol)和浓HCl(2mL)，并将反应混合物在80℃搅拌30分钟。反应完成后，反应物用2N NaOH溶液中和，并用乙酸乙酯萃取(2x50mL)。有机层用水彻底清洗，在无水硫酸钠上干燥，真空浓缩，得到3-氟-4-(1,3-噁唑-5-基)苯胺(中间体4)(350mg,53％)，为黄色固体。LCMS：179(M+H)。
合成化合物(1)：
向经搅拌的3-氯-4-(噁唑-5-基)苯胺(中间体2)(100mg,0.51mmol)和2-(3-甲氧基苯基)乙酸(111mg,0.67mmol)在DMF(1mL)的溶液中，室温下加入DIPEA(0.26mL)和HATU(391.9mg,1.03mmol)，并将该反应在室温下搅拌16h。反应完成后，将反应物质通过制备型HPLC纯化，得到N-(3-氯-4-(噁唑-5-基)苯基)-2-(3-甲氧基苯基)乙酰胺(化合物(1))(46mg,26％)。UPLC Rt：1.50min；MS：343.1(M+H)。
合成化合物(2)：
向经搅拌的3-氯-4-(噁唑-5-基)苯胺(中间体2)(100mg,0.51mmol)和2-(2-(三氟甲基)苯基)乙酸(137mg,0.67mmol)在DMF(1mL)的溶液中，室温下加入DIPEA(0.26mL)和HATU(391.9mg,1.03mmol)，并将该反应在室温下搅拌16h。反应完成后，将反应物质通过制备型HPLC纯化，得到N-(3-氯-4-(噁唑-5-基)苯基)-2-(2-(三氟甲基)苯基)乙酰胺(化合物(2))(68mg,35％)。UPLC Rt：1.74min；MS：381.1(M+H)。
合成化合物(3)：
向经搅拌的3-氯-4-(噁唑-5-基)苯胺(中间体2)(100mg,0.51mmol)和(2-氯-5-氟-苯基)-乙酸(144mg,0.67mmol)在DMF(1mL)的溶液中，室温下加入DIPEA(0.26mL)和HATU(391.9mg,1.03mmol)，并将该反应在室温下搅拌16h。反应完成后，将反应物质通过制备型HPLC纯化，得到2-(3-溴苯基)-N-(3-氯-4-(噁唑-5-基)苯基)乙酰胺(化合物(3))(62mg,31％)。UPLC Rt：1.77min；MS：393.1(M+H)。
合成化合物(4)：
向经搅拌的3-氯-4-(噁唑-5-基)苯胺(中间体2)(100mg,0.51mmol)和(2-氯-5-氟-苯基)-乙酸(115mg,0.67mmol)在DMF(1mL)的溶液中，室温下加入DIPEA(0.26mL)和HATU(391.9mg,1.03mmol)，并将该反应在室温下搅拌16h。反应完成后，将反应物质通过制备型HPLC纯化，得到N-(3-氯-4-(噁唑-5-基)苯基)-2-(2,4-二氟苯基)乙酰胺(化合物(4))(57mg,32％)。UPLC Rt：1.59min；MS：349.1(M+H)。
合成化合物(5)：
向经搅拌的3-氯-4-(噁唑-5-基)苯胺(中间体2)(100mg,0.51mmol)和(2-氯-5-氟-苯基)-乙酸(126mg,0.67mmol)在DMF(1mL)的溶液中，室温下加入DIPEA(0.26mL)和HATU(391.9mg,1.03mmol)，并将该反应在室温下搅拌16h。反应完成后，将反应物质通过制备型HPLC纯化，得到N-(3-氯-4-(噁唑-5-基)苯基)-2-(2-氯-5-氟苯基)乙酰胺(化合物(5))(34mg,18％)。UPLC Rt：1.64min；MS：365(M+H)。
合成化合物(6)：
向经搅拌的3-氯-4-(噁唑-5-基)苯胺(中间体2)(100mg,0.51mmol)和(3-三氟甲基-苯基)-乙酸(136mg,0.67mmol)在DMF(1mL)的溶液中，室温下加入DIPEA(0.26mL)和HATU(392mg,1.03mmol)，并将该反应在室温下搅拌16h。反应完成后，将反应物质通过制备型HPLC纯化，得到N-(3-氯-4-(噁唑-5-基)苯基)-2-(3-(三氟甲基)苯基)乙酰胺(化合物(6))(26mg,13％)。UPLC Rt：1.76min；MS：381(M+H)。
合成化合物(7)：
向经搅拌的3-氯-4-(噁唑-5-基)苯胺(中间体2)(100mg,0.51mmol)和(4-氯-苯基)-乙酸(114mg,0.67mmol)在DMF(1mL)的溶液中，室温下加入DIPEA(0.26mL)和HATU(391.9mg,1.03mmol)，并将该反应在室温下搅拌16h。反应完成后，将反应物质通过制备型HPLC纯化，得到N-(3-氯-4-(噁唑-5-基)苯基)-2-(4-氯苯基)乙酰胺(化合物(7))(21mg,11％)。UPLC Rt：1.68min；MS：347.2(M+H)。
合成化合物(8)：
向经搅拌的3-氯-4-(噁唑-5-基)苯胺(中间体2)(150mg,0.77mmol)和2-(二氟甲氧基)苯基乙酸(203mg,1mmol)在DMF(1.5mL)的溶液中，室温下加入DIPEA(0.39mL)和HATU(588mg,1.55mmol)，并将该反应在室温下搅拌16h。反应完成后，将反应物质通过制备型HPLC纯化，得到N-(3-氯-4-(噁唑-5-基)苯基)-2-(2-(二氟甲氧基)苯基)乙酰胺(化合物(8))(56mg,19％)。UPLC Rt：1.59min；MS：379.2(M+H)。
合成化合物(9)：
向经搅拌的3-氯-4-(噁唑-5-基)苯胺(中间体2)(150mg,0.77mmol)和苯基乙酸(136.85mg,1.00mmol)在DMF(1.5mL)的溶液中，室温下加入DIPEA(0.39mL)和HATU(588mg,1.55mmol)，并将该反应在室温下搅拌16h。反应完成后，将反应物质通过制备型HPLC纯化，得到N-(3-氯-4-(噁唑-5-基)苯基)-2-苯基乙酰胺(化合物(9))(69mg,28％)。UPLC Rt：1.46min；MS：313.2(M+H)。
合成化合物(10)：
向经搅拌的3-氯-4-(噁唑-5-基)苯胺(中间体2)(150mg,0.77mmol)和2-氯苯基乙酸(171mg,1.00mmol)在DMF(1.5mL)的溶液中，室温下加入DIPEA(0.39mL)和HATU(588mg,1.55mmol)，并将该反应在室温下搅拌16h。反应完成后，将反应物质通过制备型HPLC纯化，得到N-(3-氯-4-(噁唑-5-基)苯基)-2-(2-氯苯基)乙酰胺(化合物(10))(73mg,27％)。UPLCRt：1.59min；MS：347.1(M+H)。
合成化合物(11)：
向经搅拌的3-氯-4-(噁唑-5-基)苯胺(中间体2)(150mg,0.77mmol)和2-甲氧基-苯基乙酸(167mg,1.00mmol)在DMF(1.5mL)的溶液中，室温下加入DIPEA(0.39mL)和HATU(588mg,1.55mmol)，并将该反应在室温下搅拌16h。反应完成后，将反应物质通过制备型HPLC纯化，得到N-(3-氯-4-(噁唑-5-基)苯基)-2-(2-甲氧基苯基)乙酰胺(化合物(11))(84mg,30％)。UPLC Rt：1.48min；MS：343.2(M+H)。
合成化合物(12)：
向经搅拌的3-氯-4-(噁唑-5-基)苯胺(中间体2)(200mg,1.03mmol)和3-(二氟甲氧基)苯基乙酸(270.93mg,1.34mmol)在DMF(2mL)的溶液中，室温下加入DIPEA(0.52mL)和HATU(784mg,2.06mmol)，并将该反应在室温下搅拌16h。反应完成后，将反应物质通过制备型HPLC纯化，得到N-(3-氯-4-(噁唑-5-基)苯基)-2-(3-(二氟甲氧基)苯基)乙酰胺(化合物(12))(34mg,18％)。UPLC Rt：1.66min；MS：379.2(M+H)。
合成化合物(13)：
向经搅拌的3-氟-4-(噁唑-5-基)苯胺(中间体4)(200mg,1.12mmol)和2-(3-(二氟甲氧基)苯基)乙酸(295.3mg,1.46mmol)在DMF(2mL)的溶液中，室温加入DIPEA(0.58mL)和HATU(854.4mg,2.24mmol)，并将该反应在室温下搅拌16h。反应完成后，将反应物质通过制备型HPLC纯化，得到2-(3-(二氟甲氧基)苯基)-N-(3-氟-4-(噁唑-5-基)苯基)乙酰胺(化合物(13))(104mg,25％)。UPLC Rt：1.55min；MS：363.2(M+H)。
合成化合物(14)：
向经搅拌的3-氟-4-(噁唑-5-基)苯胺(中间体4)(200mg,1.12mmol)和2-(二氟甲氧基)苯基乙酸(295.3mg,1.46mmol)在DMF(2mL)的溶液中，室温下加入DIPEA(0.58mL)和HATU(854.4mg,2.24mmol)，并将该反应在室温下搅拌16h。反应完成后，将反应物质通过制备型HPLC纯化，得到2-(2-(二氟甲氧基)苯基)-N-(3-氟-4-(噁唑-5-基)苯基)乙酰胺(化合物(14))(147mg,36％)。UPLC Rt：1.50min；MS：363.2(M+H)。
合成化合物(15)：
向经搅拌的3-氟-4-(噁唑-5-基)苯胺(中间体4)(200mg,1.12mmol)和(2-氯-5-氟-苯基)-乙酸(275.5mg,1.46mmol)在DMF(2mL)的溶液中，室温下加入DIPEA(0.58mL)和HATU(854.4mg,2.24mmol)，并将该反应在室温下搅拌16h。反应完成后，将反应物质通过制备型HPLC纯化，得到2-(2-氯-5-氟苯基)-N-(3-氟-4-(噁唑-5-基)苯基)乙酰胺(化合物(15))(137mg,34％)。UPLC Rt：1.57min；MS：349.2(M+H)。
合成化合物(16)：
向经搅拌的3-氟-4-(噁唑-5-基)苯胺(中间体4)(100mg,0.56mmol)和2-苯基乙酸(99.4mg,0.73mmol)在DMF(1mL)的溶液中，室温下加入DIPEA(0.29mL)和HATU(427mg,1.12mmol)，并将该反应在室温下搅拌16h。反应完成后，将反应物质通过制备型HPLC纯化，得到N-(3-氟-4-(噁唑-5-基)苯基)-2-苯基乙酰胺(化合物(16))(43mg,25％)。UPLC Rt：1.36min；MS：297.2(M+H)。
合成化合物(17)：
向经搅拌的3-氟-4-(噁唑-5-基)苯胺(中间体4)(150mg,0.84mmol)和2-(2-氯苯基)乙酸(186.9mg,1.09mmol)在DMF(1.5mL)的溶液中，室温下加入DIPEA(0.44mL)和HATU(641mg,1.68mmol)，并将该反应在室温下搅拌16h。反应完成后，将反应物质通过制备型HPLC纯化，得到2-(2-氯苯基)-N-(3-氟-4-(噁唑-5-基)苯基)乙酰胺(化合物(17))(123mg,44％)。UPLC Rt：1.50min；MS：331.2(M+H)。
合成化合物(18)：
向经搅拌的3-氟-4-(噁唑-5-基)苯胺(中间体4)(150mg,0.84mmol)和3-甲氧基-苯基乙酸(182.1mg,1.09mmol)在DMF(1.5mL)的溶液中，室温下加入DIPEA(0.44mL)和HATU(641mg,1.68mmol)，并将该反应在室温下搅拌16h。反应完成后，将反应物质通过制备型HPLC纯化，得到N-(3-氟-4-(噁唑-5-基)苯基)-2-(3-甲氧基苯基)乙酰胺(化合物(18))(87mg,31％)。UPLC Rt：1.37min；MS：327.2(M+H)。
合成化合物(19)：
向经搅拌的3-氟-4-(噁唑-5-基)苯胺(中间体4)(150mg,0.84mmol)和2,4-二氟苯基乙酸(188.56mg,1.09mmol)在DMF(1.5mL)的溶液中，室温下加入DIPEA(0.44mL)和HATU(641mg,1.68mmol)，并将该反应在室温下搅拌16h。反应完成后，将反应物质通过制备型HPLC纯化，得到2-(2,4-二氟苯基)-N-(3-氟-4-(噁唑-5-基)苯基)乙酰胺(化合物(19))(125mg,44％)。UPLC Rt：1.52min；MS：333.2(M+H)。
合成化合物(20)：
向经搅拌的3-氟-4-(噁唑-5-基)苯胺(中间体4)(150mg,0.84mmol)和2-(三氟甲基)苯基乙酸(223.6mg,1.09mmol)在DMF(1.5mL)的溶液中，室温下加入DIPEA(0.44mL)和HATU(641mg,1.68mmol)，并将该反应在室温下搅拌16h。反应完成后，将反应物质通过制备型HPLC纯化，得到N-(3-氟-4-(噁唑-5-基)苯基)-2-(2-(三氟甲基)苯基)乙酰胺(化合物(20))(125mg,40％)。UPLC Rt：1.69min；MS：365(M+H)。
合成包含吡啶-4-基残基的化合物
中间体5：
向经搅拌的1-溴-2-甲氧基-4-硝基苯(5g,21.55mmol)在1,4-二氧杂环己烷(50ml)和水(10ml)的溶液中，加入(吡啶-4-基)硼酸(3.97g,32.32mmol)和K2CO3(8.92g,64.65mmol)。用氮气脱气10分钟后，加入Pd(Ph3P)4(0.498g,0.431mmol)，并将烧瓶再次用氮气脱气，然后让反应混合物在85-90℃下搅拌12小时。反应完成后，反应混合物用乙酸乙酯(100毫升)稀释，然后用水(2×50毫升)和盐水(2×50毫升)先后洗涤乙酸乙酯层。有机层用Na2SO4干燥并浓缩至干，粗品通过快速柱色谱提纯，用15％E.A-己烷洗脱，得到4-(2-甲氧基-4-硝基苯基)吡啶(中间体5)(2.5g,50.4％)，为白色固体。LCMS：230(M+H)。
中间体6：
将装有4-(2-甲氧基-4-硝基苯基)吡啶(中间体5)(2.5g,10.8mmol)的烧瓶用N2冲洗，加入10％Pd/C(2.3g,21.7mmol)。向混合物中加入乙酸乙酯(50mL)，用H2代替N2，在H2下将黑色悬浮液搅拌5小时，之后反应完成。悬浮液经硅藻土过滤，用乙酸乙酯洗涤，真空浓缩，得到3-甲氧基-4-(吡啶-4-基)苯胺(中间体6)(1.42g,65.2％)，为黄色固体。LCMS：200(M+H)。
合成化合物(21)：
向经搅拌的4-(吡啶-4-基)苯胺(75mg,0.441mmol)和2-(2-氯苯基)乙酸(112.5mg,0.66mmol)在DMF(3mL)的溶液中，室温下加入DIPEA(0.169mL)和HATU(252.7mg,0.66mmol)，并将该反应在室温下搅拌12h。反应完成后，反应混合物经制备型HPLC纯化后，得到2-(2-氯苯基)-N-(4-(吡啶-4-基)苯基)乙酰胺(化合物(21))(51.3mg,36％)。UPLCRt：0.92min；MS：323.2(M+H)。
合成化合物(22)：
向经搅拌的4-(吡啶-4-基)苯胺(75mg,0.441mmol)和2-(3-甲氧基苯基)乙酸(110mg,0.66mmol)在DMF(3mL)的溶液中，室温下加入DIPEA(0.169mL)和HATU(252.7mg,0.66mmol)，并将该反应在室温下搅拌12h。反应完成后，反应混合物经制备型HPLC纯化后，得到2-(3-甲氧基苯基)-N-(4-(吡啶-4-基)苯基)乙酰胺(化合物(22))(56mg,40％)。UPLCRt：0.86min；MS：319.2(M+H)。
合成化合物(23)：
向经搅拌的3-甲氧基-4-(吡啶-4-基)苯胺(中间体6)(75mg,0.375mmol)和2-(2-氯苯基)乙酸(96mg,0.563mmol)在DMF(2mL)的溶液中，室温下加入DIPEA(0.144mL)和HATU(214.8mg,0.563mmol)，并将该反应在室温下搅拌12h。反应完成后，反应混合物经制备型HPLC纯化后，得到2-(2-氯苯基)-N-(3-甲氧基-4-(吡啶-4-基)苯基)乙酰胺(化合物(23))(20mg,15％)。UPLC Rt：0.96min；MS：353.25(M+H)。
合成化合物(24)：
向经搅拌的3-甲氧基-4-(吡啶-4-基)苯胺(中间体6)(75mg,0.375mmol)和2-(2-氯-5-氟苯基)乙酸(105.7mg,0.563mmol)在DMF(2mL)的溶液中，室温下加入DIPEA(0.144mL)和HATU(214.8mg,0.563mmol)，并将该反应在室温下搅拌12h。反应完成后，反应混合物经制备型HPLC纯化后，得到2-(2-氯-5-氟苯基)-N-(3-甲氧基-4-(吡啶-4-基)苯基)乙酰胺(化合物(24))(69mg,50％)。UPLC Rt：1.05min；MS：371.2(M+H)。
合成化合物(25)：
向经搅拌的3-甲氧基-4-(吡啶-4-基)苯胺(中间体6)(75mg,0.375mmol)和2-苯基乙酸(73.1mg,0.563mmol)在DMF(2mL)的溶液中，室温下加入DIPEA(0.144mL)和HATU(214.8mg,0.563mmol)，并将该反应在室温下搅拌12h。反应完成后，反应混合物经制备型HPLC纯化后，得到N-(3-甲氧基-4-(吡啶-4-基)苯基)-2-苯基乙酰胺(化合物(25))(46mg,39％)。UPLC Rt：0.88min；MS：319.2(M+H)。
合成化合物(26)：
向经搅拌的3-甲氧基-4-(吡啶-4-基)苯胺(中间体6)(75mg,0.375mmol)和2-(2-(三氟甲基)苯基)乙酸(114.9mg,0.563mmol)在DMF(2mL)中的溶液中，室温加入DIPEA(0.144mL)和HATU(214.8mg,0.563mmol)，并将该反应在室温下搅拌12h。反应完成后，反应混合物经制备型HPLC纯化得到N-(3-甲氧基-4-(吡啶-4-基)苯基)-2-(2-(三氟甲基)苯基)乙酰胺(化合物(26))(118mg,81％)。UPLC Rt：1.13min；MS：387.3(M+H)。
合成化合物(27)：
向经搅拌的3-甲氧基-4-(吡啶-4-基)苯胺(中间体6)(75mg,0.375mmol)和2-(3-甲氧基苯基)乙酸(93.3mg,0.563mmol)在DMF(2mL)的溶液中，室温下加入DIPEA(0.144mL)和HATU(214.8mg,0.563mmol)，并将该反应在室温下搅拌12h。反应完成后，反应混合物经制备型HPLC纯化后，得到N-(3-甲氧基-4-(吡啶-4-基)苯基)-2-(3-甲氧基苯基)乙酰胺(化合物(27))(68mg,52％)。UPLC Rt：0.91min；MS：349.3(M+H)。
合成化合物(28)：
向经搅拌的3-甲氧基-4-(吡啶-4-基)苯胺(中间体6)(75mg,0.375mmol)和2-(2-(二氟甲氧基)苯基)乙酸(113.6mg,0.563mmol)在DMF(2mL)的溶液中，室温下加入DIPEA(0.144mL)和HATU(214.8mg,0.563mmol)，并将该反应在室温下搅拌12h。反应完成后，反应混合物经制备型HPLC纯化后，得到2-(2-(二氟甲氧基)苯基)-N-(3-甲氧基-4-(吡啶-4-基)苯基)乙酰胺(化合物(28))(75.3mg,52％)。UPLC Rt：1.03min；MS：385.3(M+H)。
解离液和酶溶液的制备
称出犬尿酸(0.2mg/mL)、胰蛋白酶(1.33mg/mL)和透明质酸酶(0.67mg/mL)，并在37℃下溶解于高镁/低钙人工脑脊液(aCSF)中。将成纤维细胞生长因子2(FGF2；10ng/mL)和肝素(2μg/mL)加入100mL无血清培养基(SFM)中。将卵母细胞胰蛋白酶抑制剂(1mg/mL)溶解在温热的SFM中，并进行无菌过滤(22μm)。
从眼睛的睫状上皮分离视网膜前体细胞和初级球体测定
在无菌生物安全柜(BSC)内设置了解剖显微镜、冷光源和无菌手术器械。哺乳动物的眼睛被切除，放在含有冷的、无菌的aCSF的培养皿中。在解剖显微镜下，用两套镊子将毛发、结缔组织、后斜肌和前斜肌从巩膜/角膜边界清除。接下来，用弧形或有角度的微型解剖剪刀劈开任何剩余的眼外肌组织、视神经，并将眼球切成对称的两半；切割起止于视神经留下的孔。用两套镊子抓住角膜，将两半眼球剥离开。将晶状体、视神经和玻璃体从眼壳中分离出来，并将眼壳转移到一个新的培养皿中(也含有冷的、无菌的aCSF)。为了分离睫状上皮(CE)，眼壳的方向是角膜在右边，视网膜色素上皮(RPE)在左边。用一对直钳夹住RPE一侧的眼壳，同时将手术刀插入CE和虹膜之间，用压力将虹膜/角膜一侧与眼壳的其他部分切开。接下来，手术刀沿着CE和RPE之间的边界运行，以获得作为一个薄的组织条分离的CE。然后将CE条转移到含有2mL分散酶溶液(Sigma；T1005)的35mm皿中，在37℃下温育10分钟。接下来，将条从分散酶转移到含有2mL无菌过滤的犬尿酸、胰蛋白酶和透明质酸酶溶液的35mm皿中，并在37℃温育10分钟。温育后，将皿放回解剖镜，用无锯齿的直钳夹住CE条，同时用无锯齿的弯钳将CE从巩膜下层刮除。然后丢弃裸露的巩膜条，这样，只有CE细胞留在酶溶液中。使用火抛光的棉塞玻璃吸管，将细胞和酶溶液转移到15mL管中，并搅拌约45次以分解组织。将15mL管/细胞悬液以1500rpm离心5分钟。用火抛光的棉塞玻璃吸管从产生的沉淀中轻轻吸出上清液，并在沉淀中加入2mL的胰蛋白酶抑制剂溶液。使用小孔、火抛光、塞棉的玻璃吸管，将样品搅拌约45次，直到它成为单细胞悬浮液。将15mL管/细胞悬液以1500rpm离心5分钟。从得到的沉淀中轻轻吸出上清液，加入1-2mL含有FGF2和肝素的SFM(铺板培养基)。将细胞和培养基混合以确保均匀的细胞悬浮液，取10uL样品并测定细胞密度。然后将细胞接种并以10c/μL在培养处理过的平板或烧瓶中培养。一周后，大约500个细胞中有1个细胞增殖，形成自由漂浮的、直径大于80μm的克隆球体。
球体传代和高通量药物筛选
使用犬尿酸、胰蛋白酶、透明质酸酶溶液并加入胶原酶I(0.5mg/mL)、胶原酶II(0.5mg/mL)和弹性蛋白酶(0.1mg/mL)进行人源球体传代。使用溶于Accustase溶液(Sigma；SCR005)的透明质酸酶(0.67mg/mL)、胶原酶I(0.5mg/mL)和胶原酶II(0.5mg/mL)对小鼠来源的球体进行传代。从培养板或烧瓶中大量收集球体，转移到一个或多个50mL管中，在1500rpm下离心5分钟。从沉淀中轻轻吸出上清液，将2-5mL的酶液加入沉淀中并充分混合。将2-5mL的酶和球体悬浮液转移到15mL的管中，在37℃下水平放置在自动摇床中45分钟。温育后，将带有球体的酶溶液研磨约45次，使球体机械地解离。细胞悬浮液以1500rpm离心5分钟。轻轻吸出上清液，将1-2mL的胰蛋白酶抑制剂溶液加入到沉淀中，并反复研磨约45次。将细胞悬液以1500rpm离心5分钟。从得到的沉淀中轻轻吸出上清液，加入1-2mL含有FGF2和肝素的SFM(铺板培养基)。将细胞和培养基混合，以确保细胞悬浮液均匀，取10uL样品，从该样品中确定细胞密度。然后在带有0.1％DMSO或在0.1％DMSO中选定浓度的药物的准备好的96孔或24孔板中，以10c/μL接种和培养其余细胞。细胞生长一周，然后活体染色检测细胞核(Hoechst 33258；10μg/mL)。对于小鼠组织，使用肌动蛋白-绿色荧光蛋白(GFP)转基因小鼠品系(FVB.Cg-Tg(CAG-EGFP)B5Nagy/J)，根据细胞核和基于GFP的定量进行细胞数比较。对于人体组织，使用绿色荧光细胞活力染料钙黄素AM(ThermoFisher C3100MP；2μM)，根据细胞核和基于钙黄素荧光的定量进行细胞数量比较。
药物筛选结果的统计学评价
统计学意义是在板与板之间的基础上进行评估的，采用没有药物处理的对照孔和培养基中同等浓度的DMSO。96孔板的最小对照孔数为8，24孔板为6。确定平均数和标准差，细胞数在对照值附近三个标准差范围之外的化合物孔被归类为命中。每块板上的单个化合物处理条件总是至少存在两份，以内部验证结果的有效性。然后对每个化合物的数值进行平均。
结果：
C*＝对照实验(没有本发明的化合物)
Claims (16)
1.一种式(I)的化合物
或其药学上可接受的盐，
其中：
A是5-噁唑基残基或吡啶-4-基残基，
R1选自由氟和氯组成的组；
苯环B的R2、R3、R4、R5和R6相互独立地选自由以下组成的组：氢、具有1至4个碳原子的直链或支链烷基、三氟甲基、2,2,2-三氟乙基、甲硫基、乙硫基、甲磺酰基、乙磺酰基、二氟甲氧基、三氟甲氧基、氟、溴、氯、甲氧基、乙氧基、丙氧基、丁氧基、羟基和氨基；并且
R2、R3、R4、R5和R6中的至少2个是氢，条件是如果R1是氯，则R5不是甲氧基。
2.如权利要求1所述的化合物，其中，R1是氯。
3.如权利要求1所述的化合物，其中，A是5-噁唑基残基。
4.如权利要求1所述的化合物，其中，苯环B是单取代或双取代的。
5.如权利要求1所述的化合物，其中，苯环B是单取代的。
6.如权利要求5所述的化合物，其中，R2选自由以下组成的组：甲基、三氟甲基、甲硫基、甲磺酰基、二氟甲氧基、氟、溴、氯、甲氧基和乙氧基，优选二氟甲氧基或氯。
7.如权利要求5所述的化合物，其中，R3或R4选自由以下组成的组：三氟甲基、二氟甲氧基、甲氧基，优选三氟甲基和二氟甲氧基。
8.如权利要求1所述的化合物，其中，苯环B是双取代的。
9.如权利要求8所述的化合物，其中，R2选自由氟、溴和氯组成的组，并且R3、R4或R5中的一个选自由氟、溴和氯组成的组。
10.如权利要求10所述的化合物，其中，R2是氯并且R5是氟，或者R2和R4都是氟。
11.如前述权利要求中任一项所述的式(I)的化合物，其中，所述化合物选自由以下组成的组：
12.一种药物组合物，其包含式(Ia)的化合物作为治疗活性物，应用于治疗和/或预防导致光感受器丧失或视网膜光感受器层变性的原发性神经视网膜疾病，
A是5-噁唑基残基或吡啶-4-基残基；
R1’选自由以下组成的组：甲氧基、氢、氟和氯；
苯环B的R2、R3、R4、R5和R6相互独立地选自由以下组成的组：氢、具有1至4个碳原子的直链或支链烷基、三氟甲基、2,2,2-三氟乙基、甲硫基、乙硫基、甲磺酰基、乙磺酰基、二氟甲氧基、三氟甲氧基、氟、溴、氯、甲氧基、乙氧基、丙氧基、丁氧基、羟基和氨基；并且
R2、R3、R4、R5和R6中的至少2个是氢，
条件是如果R1’是氢或甲氧基，则A是吡啶-4-基残基。
13.如权利要求12所述应用的组合物，其中，所述应用选自由以下组成的组：遗传性视网膜营养不良症、获得性或药物诱导的光感受器变性、感染性眼病和炎症性眼病，其中所述药物组合物在施用时通过诱导视网膜前体细胞的增殖来治疗视网膜疾病，优选应用于治疗选自由以下组成的组的视网膜疾病：色素性视网膜炎(RP)，包括综合征形式和非综合征形式、X染色体连锁形式、隐性形式、显性形式和散发性形式，视杆-视锥营养不良症、乌谢尔综合征、Stargardt病、视锥-视杆营养不良症、视锥营养不良症、全色盲、蓝锥体单色症、增强型S-视锥综合征、视杆营养不良症、无脉络膜症、莱伯氏先天性黑矇、青少年X染色体连锁性视网膜劈裂症(JXLR)、白点状眼底、白点状视网膜炎、Kandori斑点视网膜、Bietti结晶性视网膜营养不良症、有孔光泽黄斑营养不良症、成人型卵黄样黄斑营养不良症、Batten病、先天性静止性夜盲症、家族性渗出性玻璃体视网膜病变(FEVR)、眼白化病、眼皮肤白化病、中央凹发育不良、无β脂蛋白血症、Stickler综合征、视网膜营养不良症(Bothnia型)、结晶性黄斑病(与药物有关、高草酸尿症、胱氨酸病、Sjogren-Larsson综合征)、西非结晶性黄斑病、日光性视网膜病、滑石视网膜病、糖尿病性视网膜病、镰状细胞性视网膜病、黄斑毛细血管扩张症、伊尔斯氏病、视网膜脱离、锯齿缘断离、周围性视网膜劈裂症、中央/分支视网膜动脉闭塞(CRAO/BRAO)、中央/分支视网膜静脉闭塞(CRVO/BRVO)、出血性闭塞性视网膜血管炎(HORV)；包括氯喹、羟氯喹、吩噻嗪、硫酸奎宁、硫利达嗪、氯法齐明、氯丙嗪、去铁胺、氯喹衍生物、顺铂、卡莫司汀、氯苯吩嗪和氨己烯酸在内的药物引起的黄斑病；包括他莫昔芬、滑石、角黄素、甲氧氟烷和呋喃妥因在内的晶体引起的黄斑病；包括肾上腺素、拉坦前列腺素、烟酸在内的囊样黄斑水肿(CME)；进行性外层视网膜坏死(PORN)、急性视网膜坏死(ARN)、CMV-视网膜炎、肉状瘤病、急性梅毒性后部鳞状脉络膜视网膜炎、结核性脉络膜视网膜炎、弓形虫视网膜脉络膜炎、后葡萄膜炎和视网膜血管炎、中间葡萄膜炎、扁平部睫状体炎+/-CME、内眼炎(前部和/或后部)、后部巩膜炎、伪装综合征、多灶性脉络膜炎和全葡萄膜炎(MCP)、点状内层脉络膜病(PIC)、鸟枪弹丸样视网膜脉络膜病、急性黄斑神经性视网膜病(AMN)和急性区域性隐匿性外层视网膜病(AZOOR)。
14.如权利要求12或13所述应用的组合物，其应用于治疗和/或预防遗传性视网膜营养不良症，优选应用于治疗色素性视网膜炎(RP)。
15.如权利要求11-14中任一项所述应用的组合物，选自由以下组成的组：
16.如权利要求10-15中任一项所述应用的组合物，其中，所述组合物适合于眼内注射。
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| US16/235,543 US10752593B2 (en) | 2018-12-28 | 2018-12-28 | Compounds for use as therapeutically active substances in the treatment of retinal diseases |
| PCT/US2019/068759 WO2020140043A1 (en) | 2018-12-28 | 2019-12-27 | Compounds for use as therapeutically active substances in the treatment and/or prevention of neuroretinal diseases |
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| WO2013029338A1 (en) * | 2011-09-01 | 2013-03-07 | Glaxo Group Limited | Novel compounds |
| WO2014079850A1 (en) * | 2012-11-23 | 2014-05-30 | F. Hoffmann-La Roche Ag | Substituted heterocyclic derivatives |
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| AU4582797A (en) | 1996-09-13 | 1998-04-02 | Regents Of The University Of California, The | Methods for treatment of retinal diseases |
| CA2216439A1 (en) | 1996-09-25 | 1998-03-25 | Derek Van Der Kooy | Pharmaceuticals containing retinal stem cells |
| WO2001039792A2 (en) | 1999-12-03 | 2001-06-07 | Alcon Universal Ltd. | The use of caspase 9 inhibitors to treat ocular neural pathology |
| CA2707492A1 (en) | 2007-12-13 | 2009-06-18 | Amgen Inc. | Gamma secretase modulators |
| US9018202B2 (en) | 2010-12-03 | 2015-04-28 | Allergan, Inc. | Methods for treating diseases of the retina |
| US20130046003A1 (en) | 2011-07-22 | 2013-02-21 | Mohammed I. Dibas | Pharmaceutical compositions comprising 4-bromo-n-(imidazolidin-2-ylidene)-1h-benzimidazol-5-amine for treating retinal diseases |
| DE102013110714A1 (de) | 2013-09-27 | 2015-04-02 | Eberhard Karls Universität Tübingen Medizinische Fakultät | Prophylaxe und Behandlung einer nicht auf einer Proteinfaltungsstörung beruhenden neurodegenerativen Erkrankung |
| AU2015342831B2 (en) | 2014-11-07 | 2019-09-12 | Nacuity Pharmaceuticals, Inc. | Treatment of retinitis pigmentosa with N-acetylcysteine amide |
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- 2019-12-27 MX MX2021007813A patent/MX2021007813A/es unknown
- 2019-12-27 KR KR1020217023914A patent/KR20210110849A/ko active Search and Examination
- 2019-12-27 JP JP2021537220A patent/JP2022516086A/ja not_active Withdrawn
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2021
- 2021-05-11 PH PH12021551092A patent/PH12021551092A1/en unknown
- 2021-06-22 IL IL284298A patent/IL284298A/en unknown
- 2021-06-25 CL CL2021001725A patent/CL2021001725A1/es unknown
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2013029338A1 (en) * | 2011-09-01 | 2013-03-07 | Glaxo Group Limited | Novel compounds |
| WO2014079850A1 (en) * | 2012-11-23 | 2014-05-30 | F. Hoffmann-La Roche Ag | Substituted heterocyclic derivatives |
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| CL2021001725A1 (es) | 2021-12-17 |
| US20200207719A1 (en) | 2020-07-02 |
| PH12021551092A1 (en) | 2021-12-06 |
| EA202191057A1 (ru) | 2021-10-07 |
| BR112021011599A2 (pt) | 2021-08-31 |
| KR20210110849A (ko) | 2021-09-09 |
| MX2021007813A (es) | 2021-10-01 |
| IL284298A (en) | 2021-08-31 |
| JP2022516086A (ja) | 2022-02-24 |
| AU2019414950A1 (en) | 2021-06-03 |
| SG11202104958UA (en) | 2021-07-29 |
| WO2020140043A1 (en) | 2020-07-02 |
| EP3902606A1 (en) | 2021-11-03 |
| CA3125278A1 (en) | 2020-07-02 |
| US10752593B2 (en) | 2020-08-25 |
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