CN115006392A - PI5P4K-β抑制剂的组合物及其应用 - Google Patents

PI5P4K-β抑制剂的组合物及其应用 Download PDF

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Publication number
CN115006392A
CN115006392A CN202210189153.XA CN202210189153A CN115006392A CN 115006392 A CN115006392 A CN 115006392A CN 202210189153 A CN202210189153 A CN 202210189153A CN 115006392 A CN115006392 A CN 115006392A
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China
Prior art keywords
disease
pi5p4k
carcinoma
kinase
phosphatidylinositol
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CN202210189153.XA
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Inventor
魏林
王果
方磊
温晓明
王小晨
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Shenzhen Jingtai Technology Co Ltd
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Shenzhen Jingtai Technology Co Ltd
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Priority to CN202210189153.XA priority Critical patent/CN115006392A/zh
Publication of CN115006392A publication Critical patent/CN115006392A/zh
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    • A61K31/4164—1,3-Diazoles
    • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
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Abstract

本发明涉及磷脂酰肌醇‑5‑磷酸‑4‑激酶(PI5P4K)的抑制剂的组合物及其应用；特别是PI5P4K‑β抑制剂，其可用于治疗与PI5P4K的调节相关的疾病或病症；所述疾病或病症具体为癌症或细胞增殖性病症、代谢病症、神经变性疾病和炎性疾病。

Description

PI5P4K-β抑制剂的组合物及其应用
技术领域
本发明涉及磷脂酰肌醇-5-磷酸-4-激酶(PI5P4K)的抑制剂的组合物及其应用；特别是PI5P4K-β抑制剂，其可用于治疗与PI5P4K的调节相关的疾病或病症；所述疾病或病症具体为癌症或细胞增殖性病症、代谢病症、神经变性疾病和炎性疾病。
背景技术
癌症是人类死亡的主要原因之一。所有这些癌症中约有50％与p53基因的突变有关。近年来，已被确定磷脂酰肌醇-5-磷酸-4-激酶β(PI5P4Kβ)是一种肌醇磷脂激酶，为p53突变型癌症肿瘤形成的重要因素。因此，需要开发抑制PI5P4Kβ功能并可用作抗肿瘤剂的化合物。已有的PI5P4Kβ抑制剂并不能满足人类健康所需，寻找更多新颖结构骨架的化合物来开发PI5P4Kβ抑制剂成为了现有目的之一。
发明内容
本发明通过虚拟筛选磷脂酰肌醇-5-磷酸-4-激酶β等方法获得了全新结构骨架的PI5P4Kβ抑制剂，解决了目前急需解决的问题之一，为更多方位的探索该领域提供了方向和可能。
具体的，
一方面，本发明提供了一种药物组合物，包括至少之一的下列化合物或其药学上接受的盐和药学上可接受的载体、稀释剂或赋形剂：
Figure BDA0003524734830000011
Figure BDA0003524734830000021
Figure BDA0003524734830000031
在一些实施例中，所述组合物还包括附加治疗剂，其中所述附加治疗剂包括其他抗癌剂、其他治疗肺动脉高压药或他们的组合。
在一些实施例中，所述组合物用于制备治疗与磷脂酰肌醇-5-磷酸-4-激酶(PI5P4K)调节相关的疾病或病症药物。
在一些实施例中，所述组合物用于制备抑制磷脂酰肌醇-5-磷酸-4-激酶(PI5P4K)的活性药物。
另一方面，本发明提供了下列化合物或本发明所述的组合物在制备治疗与磷脂酰肌醇-5-磷酸-4-激酶(PI5P4K)调节相关的疾病或病症药物中的用途：
Figure BDA0003524734830000032
Figure BDA0003524734830000041
在一些实施例中，磷脂酰肌醇-5-磷酸-4-激酶(PI5P4K)为PI5P4Kα、PI5P4Kβ和/或PI5P4Kγ。
在一些实施例中，磷脂酰肌醇-5-磷酸-4-激酶(PI5P4K)为PI5P4Kβ。
在一些实施例中，如本发明所述的用途，其中所述与PI5P4K的调节相关的疾病或病症是癌症或细胞增殖性病症、代谢病症、神经变性疾病和炎性疾病。
在一些实施例中，如本发明所述的用途，所述癌症或细胞增殖性病症是白血病(例如急性白血病、急性淋巴细胞性白血病、急性髓细胞性白血病、急性成髓细胞性白血病、急性早幼粒细胞性白血病、急性粒单核细胞性白血病、急性单核细胞性白血病、急性红白血病、慢性白血病、慢性髓细胞性白血病、慢性淋巴细胞性白血病)、真性红细胞增多症、淋巴瘤(霍奇金氏病、非霍奇金氏病)、瓦尔登斯特伦氏巨球蛋白血症、重链病以及实体瘤诸如肉瘤和癌(例如，纤维肉瘤、粘液肉瘤、脂肪肉瘤、软骨肉瘤、骨原性肉瘤、脊索瘤、血管肉瘤、内皮肉瘤、淋巴管肉瘤、淋巴管内皮肉瘤、滑膜瘤、间皮瘤、尤文氏瘤、平滑肌肉瘤、横纹肌肉瘤、结肠癌、胰腺癌、乳腺癌、卵巢癌、前列腺癌、鳞状细胞癌、基底细胞癌、腺癌、汗腺癌、皮脂腺癌、乳头状癌、乳头状腺癌、囊腺癌、髓样癌、支气管原癌、肾细胞癌、肝细胞瘤、胆管癌、绒毛膜癌、精原细胞瘤、胚胎性癌、威尔姆氏肿瘤、子宫颈癌、子宫癌、睾丸癌、肺癌、小细胞肺癌、膀胱癌、上皮癌、神经胶质瘤、星形细胞瘤、成神经管细胞瘤、颅咽管瘤、室管膜瘤、松果体瘤、成血管细胞瘤、听神经瘤、少突神经胶质瘤、神经鞘瘤、脑膜瘤、黑素瘤、成神经细胞瘤以及成视网膜细胞瘤)。
在一些实施例中，如本发明所述的用途，所述代谢疾病是II型糖尿病、胰岛素抗性心血管疾病、心律不齐、动脉粥样硬化、冠状动脉疾病、高甘油三酯血症、血脂异常、视网膜病变、肾病变、神经病变或黄斑水肿。
在一些实施例中，如本发明所述的用途，所述神经变性疾病是脑创伤、脊髓创伤、周围神经系统创伤、阿尔茨海默氏病、匹克氏病、弥漫性路易体病、进行性核上性麻痹(史提尔-里查德森综合征)、多系统变性(夏伊-德雷格综合征)、运动神经元疾病包括肌萎缩性侧索硬化、变性共济失调、皮质基底变性、关岛ALS-帕金森氏病-痴呆复合征、亚急性硬化性全脑炎、亨廷顿氏病、帕金森氏病、突触核蛋白病、原发进行性失语症、纹状体黑质变性、马查多-约瑟夫病/脊髓小脑性共济失调3型和橄榄体脑桥小脑变性、基列得拉图雷特氏病、延髓性麻痹和假延髓性麻痹、脊髓性和脊髓延髓性肌萎缩症(肯尼迪氏病)、原发性侧索硬化、家族性痉挛性截瘫、韦德尼希-霍夫曼病、库格伯格-韦兰德病、泰-萨二氏病、桑德霍夫病、家族性痉挛病、沃尔夫特-库格伯格-韦兰德病、痉挛性轻截瘫、进行性多灶性白质脑病和朊病毒病(包括克罗伊茨费尔特-雅格布病、格斯特曼-施特劳斯-沙因克尔病、库鲁病和致死性家族性失眠症、年龄相关性痴呆、血管性痴呆、弥漫性白质病(宾斯万格病)、内分泌或代谢起源的痴呆、头创伤和弥漫性脑损伤引起的痴呆、拳击员痴呆或额叶痴呆、由以下引起的神经变性病症：脑缺血或梗塞，包括栓塞性闭塞和血栓性闭塞以及任何类型的颅内出血、颅内和椎骨内损伤、遗传性脑血管病、normeuropathic遗传性淀粉样变性、唐氏综合征、巨球蛋白血症、继发性家族性地中海热、穆-韦二氏综合征、多发性骨髓瘤、胰腺和心脏有关的淀粉样变性、慢性血液透析关节病或芬兰型和爱荷华型淀粉样变性。
在一些实施例中，如本发明所述的用途，所述炎性疾病是回肠炎、溃疡性结肠炎、巴雷特综合征或克罗恩氏病。
另一方面，本发明还提供了下列化合物或本发明所述的组合物在制备抑制磷脂酰肌醇-5-磷酸-4-激酶(PI5P4K)的活性药物的用途；
Figure BDA0003524734830000061
Figure BDA0003524734830000071
在一些实施例中，磷脂酰肌醇-5-磷酸-4-激酶(PI5P4K)为PI5P4Kα、PI5P4Kβ和/或PI5P4Kγ；
在一些实施例中，磷脂酰肌醇-5-磷酸-4-激酶(PI5P4K)为PI5P4Kβ。
另一方面，本发明还提供了一种抑制磷脂酰肌醇-5-磷酸-4-激酶(PI5P4K)的方法，所述方法包括施用至少一种下列化合物或本发明所述的组合物：
Figure BDA0003524734830000072
Figure BDA0003524734830000081
Figure BDA0003524734830000091
在一些实施例中，磷脂酰肌醇-5-磷酸-4-激酶(PI5P4K)为PI5P4Kα、PI5P4Kβ和/或PI5P4Kγ；
在一些实施例中，磷脂酰肌醇-5-磷酸-4-激酶(PI5P4K)为PI5P4Kβ。
另一方面，本发明还提供了一种诱导细胞周期停滞、肿瘤细胞的细胞凋亡和/或增强的肿瘤特异性T细胞免疫的方法，所述方法包括使所述细胞与有效量的下列化合物接触：
Figure BDA0003524734830000092
Figure BDA0003524734830000101
为方便起见，在此聚集说明书、实施例和附加说明中使用的某些术语。
如本文所用，术语“包含”或“包括”应解释为详细说明如所提到的所述特征、整数、步骤或组分的存在，但不排除一个或多个特征、整数、步骤或组分或其组的存在或添加。然而，在本公开的上下文中，术语“包含”或“包括”包括更具限制性的术语“基本上由......组成”和“由......组成”。“包含(comprising)”一词的变体(如“comprise”和“comprises”)以及“包括(including)”(如“include”和“includes”)具有相应变化的含义。
如本文所用，术语“磷脂酰肌醇5-磷酸4-激酶家族”和/或术语“(PI5P4K)”意指包含三种同种型PI5P4Kα、PI5P4Kβ和PI5P4Kγ的PI5P4K酶家族。PI5P4K也被称作PIP4K2。
术语“受试者”在本文中定义为脊椎动物，特别是哺乳动物，更特别的是人。出于研究目的，受试者可以特别是至少一种动物模型，例如小鼠，大鼠等。然而，对于过度增殖障碍的治疗，受试者可以是携带癌细胞的人。
在本发明的上下文中使用的术语“治疗”是指预防、改善、医治性或治愈性治疗。
如本公开中所用，术语“施用”是指直接向受试者施用所公开的化合物或所公开的化合物的药学上可接受的盐或组合物，或向所述受试者施用所述化合物或所述化合物的药学上可接受的盐或组合物的前药衍生物或类似物，所述前药衍生物或类似物可在受试者体内形成等效量的活性化合物。
除非另外指示，否则术语“病症”在本公开中用于意指术语疾病、疾患或患病，并且与所述术语可互换地使用。
术语“过度增殖细胞”在本文中意指通常包括天然存在的癌细胞系。转化的细胞不一定与过度增殖细胞相同。
另外，本领域技术人员可以使用常规技术和/或根据标准和/或接受的药学实践常规地实现合适的配制品的制备。
根据本发明使用的任何药物配制品中化合物的量将取决于各种因素，如待治疗病症的严重性、待治疗的特定患者以及采用的一种或多种化合物。在任何情况下，配制品中化合物的量可以由技术人员常规确定。
例如，固体口服组合物如片剂或胶囊可含有1％至99％(w/w)活性成分；0至99％(w/w)稀释剂或填料；0至20％(w/w)崩解剂；0至5％(w/w)润滑剂；0-5％(w/w)流动助剂；0至50％(w/w)造粒剂或粘合剂；0到5％(w/w)抗氧化剂；和0至5％(w/w)颜料。控释片剂可另外含有0至90％(w/w)的控释聚合物。
肠胃外配制品(如用于注射的溶液或悬浮液或用于输注的溶液)可含有1％至50％(w/w)活性成分；50％(w/w)至99％(w/w)的液体或半固体载剂或运载体(例如溶剂，如水)；和0-20％(w/w)的一种或多种其他赋形剂，如缓冲剂、抗氧化剂、悬浮稳定剂、张力调节剂和防腐剂。
取决于待治疗的障碍和患者以及施用的途径，化合物可以以不同的治疗有效剂量施用给有需要的患者。
然而，在本发明的上下文中施用给哺乳动物(特别是人)的剂量应足以在合理的时间范围内在哺乳动物中实现治疗反应。本领域技术人员将认识到精确剂量和组合物以及最合适的递送方案的选择还将受到尤其以下的影响：配制品的药理学特性，所治疗病症的性质和严重性，以及身体状况的影响和接受者的精神敏锐度，以及特定化合物的效力，待治疗患者的年龄、状况、体重、性别和反应，以及疾病的阶段/严重程度。
像本发明所描述的，可接受的赋形剂，包括任何溶剂，稀释剂，或其他液体赋形剂，分散剂或悬浮剂，表面活性剂，等渗剂，增稠剂，乳化剂，防腐剂，固体粘合剂或润滑剂，等等，适合于特有的目标剂型。如以下文献所描述的：In Remington:The Science andPractice of Pharmacy,21st edition,2005,ed.D.B.Troy,Lippincott Williams&Wilkins,Philadelphia,and Encyclopedia of Pharmaceutical Technology,eds.J.Swarbrick and J.C.Boylan,1988-1999,Marcel Dekker,New York，综合此处文献的内容，表明不同的赋形剂可应用于药学上可接受的组合物的制剂和它们公知的制备方法。除了任何常规的赋形剂与本发明的化合物不相容的范围，例如所产生的任何不良的生物效应或与药学上可接受的组合物的任何其他组分以有害的方式产生的相互作用，它们的用途也是本发明所考虑的范围。
本文所使用的术语“治疗有效量”是指足以显示出有意义的患者益处(例如病毒负荷减少)的各活性组分的总量。当可用于治疗时，治疗有效量的本发明化合物，尤其是本发明提供的化合物及其药学上可接受的盐可作为未加工的化学药品给予，还可作为药物组合物的活性成分提供。因此，本发明内容还提供药物组合物，该药物组合物包括治疗有效量的本发明化合物，或其药学上可接受的盐和一种或多种药学上可接受的载体、稀释剂或赋形剂。
当使用单独的活性成分单独给药时，该术语仅指该成分。当组合应用时，该术语则是指不论组合，依次或同时给药时，都引起治疗效果的活性成分的组合量。本发明化合物，及其药学上可接受的盐如上所述。从与制剂其他成分相容以及对其接受者无害的意义上来讲，载体、稀释剂或赋形剂必须是可接受的。根据本发明内容的另一方面，还提供用于制备药物制剂的方法，该方法包括将本发明化合物或其药学上可接受的盐与一种或多种药学上可接受的载体、稀释剂或赋形剂混匀。
与一种或多种赋形剂结合以制备单剂型的活性成分的量将必需根据治疗的宿主和具体的给药路径而变化。例如，预期用于口服给药至人的制剂通常会包含，例如0.5mg-2g与合适和方便量的赋形剂复合的活性成分(合适的0.5mg-1g活性成分，例如0.5mg-0.5g活性剂，更合适地0.5-100mg，例如1-30mg)，所述赋形剂可为总组合物的约5％-约98％重量。本发明化合物与载体材料混合以制备单一剂型的活性成分的量将根据待治疗的疾病、疾病的严重程度、给药时间、给药途径、所用化合物的排泄速率、治疗时间和患者年龄、性别、体重和情况而改变。优选的单位剂型是含有本文上述活性成分的日剂量或分剂量或其适宜分数的单位剂型。可用显然低于化合物最佳剂量的小剂量开始治疗。此后，以较小的增量来加大剂量直到在这种情况下达到最佳效果。一般而言，最理想地给予化合物的浓度水平是通常可在抗肿瘤方面提供有效结果而又不至于引起任何有害或有毒的副作用。
在采用本发明化合物进行治疗或预防过程中，假如需要分开的剂量，通常会给药以使得获得的日剂量为例如0.1mg/kg-75mg/kg体重。总之，当采用肠胃外路径时将给予较低剂量。因此，例如，就静脉或腹腔给药而言，通常使用的剂量为例如0.1mg/kg-30mg/kg体重。同样，就吸入给药而言，将采用的剂量为例如0.05mg/kg–25mg/kg体重。口服给药也是合适的，特别是以片剂形式。通常，单位剂型将包含约0.5mg-0.5g本发明化合物且单位剂型可每日给药一次、二次、三次或四次或如果需要的话，以更高频率给药。
本发明的化合物及其组合物的医药剂型可以以速释、控释、缓释或靶药物释放系统形式提供。例如，常用剂型包括溶液和悬浮液、(微)乳液、软膏、凝胶和贴片、脂质体、片剂、糖衣药丸、软壳或硬壳胶囊、栓剂、胚珠、植入物、非晶形或结晶粉末、气溶胶和冻干制剂。视所用的给药途径而定，可能需要特殊装置来施用或给予药物，例如注射器和针、吸入器、泵、注射笔、涂药器或专用瓶(Special flask)。药物剂型常常由药物、赋形剂和容器/密封系统组成。可将一种或多种赋形剂(又称为非活性成分)添加到本发明的化合物中来改善或促进药物的制造、稳定性、给药和安全性，并且可提供获得所需药物释放曲线的方法。因此，添加到药物中的赋形剂类型可视各种因素而定，例如药物的物理和化学特性、给药途径和制备步骤。在该领域中存在药用赋形剂并且包括各种药典中所列的那些。(参见美国药典(U.S.Pharmacopeia,USP)、日本药典(Japanese Pharmacopoeia,JP)、欧洲药典(EuropeanPharmacopoeia,EP)和英国药典(British pharmacopoeia,BP)；美国食品与药品管理局(the U.S.Food and Drug Administration,www.fda.gov)药物评价与研究中心(Centerfor Drug Evaluation and Research,CEDR)出版物，例如《非活性组分指南》(InactiveIngredient Guide,1996)；Ash和Ash编写的《药物添加剂手册》(Handbook ofPharmaceutical Additives,2002,联合信息资源公司(Synapse Information Resources,Inc.,Endicott NY；etc.))。
药物组合物适于通过任何合适的途径给药，例如通过口服(包括口腔或舌下)、直肠、鼻、局部(包括口腔、舌下或经皮)、阴道或胃肠外(包括皮下、皮内、肌内、关节内、滑膜内、胸骨内、鞘内、病灶内、静脉内或者真皮下注射或输注)途径。可按药剂学领域的任何已知方法制备这类制剂，例如通过将活性成分与载体或赋形剂混合。优选口服给药或注射给药。
适于口服给药的药物制剂按独立的单位提供，例如胶囊剂或片剂；散剂或颗粒剂；水性或非水性液体中的溶液剂或混悬剂；可食用泡沫制剂或起泡制剂(whip)；或水包油乳液剂或油包水乳液剂。
举例来说，对于以片剂或胶囊剂形式的口服给药，活性药物组分可与药学上可接受的口服无毒惰性载体(例如乙醇、甘油、水等)相混合。通过将化合物粉碎成合适的微细尺寸，并与被同样粉碎的药用载体(例如淀粉或甘露醇等可食用的糖类)混匀来制备散剂。还可存在矫味剂、防腐剂、分散剂和着色剂。
通过制备如上所述的粉状混合物，并装填到成形的明胶壳内，来制备胶囊剂。在装填操作之前，可将助流剂和润滑剂(例如胶态二氧化硅、滑石粉、硬脂酸镁、硬脂酸钙或固态聚乙二醇)加到粉状混合物中。还可加入当服下胶囊剂时将改进药物可利用性的崩解剂或增溶剂(例如琼脂、碳酸钙或碳酸钠)。
此外需要或必需时，也可将合适的粘合剂、润滑剂、崩解剂和着色剂掺到混合物中。合适的粘合剂包括淀粉、明胶、天然糖(例如葡萄糖或β-乳糖)、玉米甜味剂、天然和合成树胶(例如阿拉伯树胶、西黄蓍胶或藻酸钠)、羧甲基纤维素、聚乙二醇等。用于这些剂型的润滑剂包括油酸钠、氯化钠等。崩解剂包括但并不限于淀粉、甲基纤维素、琼脂、皂土、黄原胶等。例如，通过制成粉状混合物，制粒或预压片，加入润滑剂和崩解剂，压制成片，从而制成片剂。将适当粉碎的化合物与如上述所述的稀释剂或基料、任选与粘合剂(例如羧甲基纤维素、藻酸盐、明胶或聚乙烯吡咯烷酮)、溶解阻止剂(例如石蜡)、吸收加速剂(季盐)和/或吸收剂(例如皂土、高岭土或磷酸二钙)混合，来制备粉状混合物。可用粘合剂(例如糖浆、淀粉浆、阿拉伯胶浆(acadiamucilage)或纤维素材料或聚合材料溶液)润湿后加压过筛，将粉状混合物制粒。制粒的一个替代方法是，可将粉状混合物通过压片机，结果是将形成不佳的团块再击碎制成颗粒。可通过加入硬脂酸、硬脂酸盐，滑石粉或矿物油使颗粒润滑以防止粘到压片机的冲模上。然后将经润滑的混合物压制成片。本发明内容的化合物还可与自由流动的惰性载体混合，无需通过制粒或预压片步骤便可压制成片。可提供透明或不透明的由虫胶密封衣、糖衣或聚合材料衣和蜡质抛光衣(polish coating of wax)组成的保护性包衣材料。可将染料加到这些包衣材料中以区分不同的单位剂量。
口服液体制剂例如溶液剂、糖浆剂和酏剂可以剂量单位形式制备，从而给定量含有预定量的化合物。糖浆剂可通过将化合物溶于适当调味的水溶液中来制备，而酏剂可通过使用无毒溶媒来制备。还可加入增溶剂和乳化剂(例如乙氧基化异硬脂醇和聚氧乙烯山梨醇醚)、防腐剂、矫味添加剂(例如薄荷油或天然甜味剂或糖精或其他人造甜味剂)等。
如果适当的话，可将用于口服给药的剂量单位制剂微胶囊化。也可将制剂制成延时或持续释放，例如通过包衣或包埋在聚合物、蜡等微粒材料中。
本发明化合物及其药学上可接受的盐还可以脂质体递药系统给予，例如小单层脂质体、大单层脂质体和多层脂质体。脂质体可由多种磷脂(例如胆固醇、十八烷基胺或磷脂酰胆碱)构成。
本发明化合物及其药学上可接受的盐也可通过使用单克隆抗体作为单独的载体(化合物分子与之偶联)递药。化合物也可与作为可靶向药物载体的可溶性聚合物偶联。这类聚合物可包括聚乙烯吡咯烷酮、吡喃共聚物、聚羟丙基甲基丙烯酰胺苯酚、聚羟乙基天冬酰胺苯酚或被棕榈酰残基取代的聚氧化乙烯聚赖氨酸。此外，化合物可与一类生物可降解的聚合物偶联，用于达到药物的控释，这类聚合物例如聚乳酸、聚ε-己内酯、聚羟基丁酸、聚原酸酯、聚缩醛、聚二氢吡喃、聚氰基丙烯酸酯和水凝胶的交联共聚物或两亲性嵌段共聚物。
适于经皮给药的药物制剂可作为离散的贴剂(discrete patch)以在长时间内保持与接受者表皮密切接触。例如，活性成分可由通过离子导入贴剂递药，通常可参见Pharmaceutical Research 1986,3(6),318。
适于局部给药的药物制剂可制成软膏剂、乳膏剂、混悬剂、洗剂、散剂、溶液剂、糊剂、凝胶剂、喷雾剂、气雾剂、油制剂或透皮贴剂。
适于直肠给药的药物制剂可作为栓剂或作为灌肠剂提供。
适于阴道给药的药物制剂可以阴道栓、阴道塞、乳膏剂、霜剂、凝胶剂、糊剂、泡沫剂或喷雾剂提供。
适于胃肠外给药的药物制剂包括水性和非水性无菌注射溶液剂及水性和非水性无菌混悬剂，水性和非水性无菌注射溶液剂可含有抗氧化剂、缓冲剂、抑菌剂和使所述制剂与待接受者血液等渗的溶质，水性和非水性无菌混悬剂可包括悬浮剂和增稠剂。制剂可以单位剂量或多剂量容器提供，例如密封的安凯和小瓶，并可保存在冷冻干燥(冻干)条件下，只需在临用前加入无菌液体载体，例如注射用水。临用时配置的注射溶液剂和混悬剂可由无菌粉针剂、颗粒剂和片剂制备。
适于经鼻给药的药物制剂(其中载体为固体)包括粒径为例如20-500微米范围的粗粉剂，通过以鼻吸方式给药，即通过鼻通道从接近鼻子的粗粉剂容器中快速吸入。其中载体为液体、适于作为鼻腔喷雾剂或滴鼻剂给药的合适制剂包括活性成分的水性溶液剂或油性溶液剂。
适于通过吸入给药的药物制剂包括干粉、气溶胶、悬浮剂或溶液组合物。
通过吸入递送至肺的干粉剂组合物，典型地包含与作为细微粉碎的粉末的一种或多种药学上可接受的赋形剂一起的、作为细微粉碎的粉末的本发明式(I)化合物或药学上可接受的盐。特别适合用于干粉剂的药学上可接受的赋形剂为本领域技术人员已知，并且包括乳糖、淀粉、甘露醇和单-、二-和多糖类。可通过例如，微粉化(micronisation)和碾磨，制备细微粉碎的粉末。一般来说，尺寸减小的(如微粉化的)化合物可通过约1至约10微米的D50值(例如，如采用激光衍射法检测的)定义。
可经由储库干粉吸入器(RDPI)给予患者干粉剂，所述吸入器有适宜储存干粉剂形式的多次给药(未经计量的剂量)的药物的储库。RDPI典型地包括用于计量每个从储库至递送位置的药物剂量的装置。例如，计量装置可包括计量杯，其可从第一位置移动至第二位置，在第一位置杯可装载来自储库的药物，在第二位置制备可用于患者吸入的计量的药物剂量。
或者，干粉剂可呈现为用于多-剂量干粉剂吸入器(MDPI)的胶囊(如明胶或塑料)、药筒或泡罩包装。MDPI是吸入器，其中药物包含在多-剂量包装中，含有(或用其它方式携带)多重限定的剂量(或其部分)的药物。当干粉剂呈现为泡罩包装时，其包括多个用于容纳干粉剂形式的药物的泡罩。泡罩典型地以规则的方式排列以易于使药物从其中释放。例如，通常可在圆盘型泡罩包装上以圆形方式排列泡罩，或可将泡罩拉长呈，例如，包括条或带形式。
可通过将本发明的式(I)化合物或药学上可接受的盐悬浮或溶解于液化抛射剂中形成气雾剂。适宜的抛射剂包括卤代烃、烃类和其它液化气。代表性的抛射剂包括：三氯氟甲烷(抛射剂11)、二氯氟甲烷(抛射剂12)、二氯四氟乙烷(抛射剂114)、四氟乙烷(HFA-134a)、1，1-二氟乙烷(HFA-152a)、二氟甲烷(HFA-32)、五氟乙烷(HFA-12)、七氟丙烷(HFA-227a)、全氟丙烷、全氟丁烷、全氟戊烷、丁烷、异丁烷和戊烷。典型地经由计量剂量吸入器(MDI)将包含本发明多晶形物或盐的气雾剂给予患者。这样的装置为本领域技术人员所知晓。
气雾剂可含额外的药学上可接受的赋形剂，所述赋形剂通常随同MDI使用，例如表面活性剂、滑润剂、共溶剂和其它赋形剂以改善制剂的物理稳定性、改善阀门特性、改善溶解性或改善口味。
应当了解的是，除了以上特别提到的成分以外，制剂还包括与所述制剂类型有关的本领域常用的其它成分，例如适于口服给药的这类制剂可包括矫味剂。
具体实施方式
为了方便，本说明书中提及的参考文献以参考文献列表的形式列出并在添加实施例的末尾。这些参考文献的全部内容在此引入作为参考。虽然现在已大体上描述了本发明，但通过参考以下实施例将更容易地理解本发明，所述实施例是以说明方式提供，并且不作为本发明的限制。
结构来源如表1：
表1
Figure BDA0003524734830000161
Figure BDA0003524734830000171
Figure BDA0003524734830000181
Figure BDA0003524734830000191
Figure BDA0003524734830000201
实施例1
活性测试方法：
1.制备试剂。
待测化合物溶解在二甲基亚砜(DMSO)中。1％DMSO作为载体对照。准备了以下溶液：
1)1×Assay缓冲液：50mM 4-(2-羟基乙基)-1-哌嗪乙基磺酸(HEPES)PH7.5；3mMMnCl2；0.5mM乙二醇四乙酸(EGTA)；0.1％3-[(3-胆酰胺丙基)二甲基铵]-1-丙磺酸盐(CHAPS)；2mM二硫苏糖醇(DTT)(使用时添加)。
2)2×脂质缓冲液：50mM HEPES PH7.5；1mM EGTA。
3)2×PIP4K工作液：PI5P4Kβ原液浓度为0.2mg/ml，终浓度为0.8μg/ml。所以2X是1.6μg/ml。使用1X Assay缓冲液将0.2mg/ml PIP4K2B稀释至1.6μg/ml；2×底物工作溶液：磷酸肌醇-5-磷酸(PI5P):磷脂酰丝氨酸(PS)，原液浓度为1μg/ml，最终浓度为0.2μg/ml。所以2X为0.4μg/ml ATP，原液浓度为10mM，最终浓度为30μM。因此2X为60μM。使用2X脂质缓冲液将PI5P:PS和ATP稀释至0.4μg/ml PI5P:PS和60μM ATP。
2.化合物筛选。
将步骤1中制备的化合物、载体对照和阳性对照转移到测定板(6008280，PerkinElmer)的每个孔中。密封测定板，以1000g离心复合板1分钟。然后向384孔板添加2μl/孔的2×PI5P4Kβ工作溶液，使用摇床将化合物和PIP4K2B工作溶液混合30秒，并在25℃下孵育15分钟。然后向384孔板中加入2μl/孔的2×Substrate工作溶液以启动反应。然后密封检测板并在25℃下孵育60分钟。然后向384孔板中加入4μl/孔的10mM MgCl2的ADP-Glo试剂缓冲液(MgCl2的原液浓度为1mol/L，使用ADP-Glo试剂稀释100倍)。然后密封检测板并在25℃下孵育40分钟。然后向384孔板中加入8μl/孔的激酶检测试剂。密封检测板并在25℃下孵育40分钟。最后，阅读Envision 2105，了解RLU(相对发光单位)的值。检测每个孔的发光信号(RLU)。抑制百分比计算如下：
Figure BDA0003524734830000211
抑制率结果如表2：
表2抑制率(20μM)
Figure BDA0003524734830000212
其中
Figure BDA0003524734830000221
是整个平板上阳性对照的平均RLU，并且
Figure BDA0003524734830000222
是整个平板上阴性对照的平均RLU。通过使用Graphpad Prism 8将抑制值％和化合物浓度的对数拟合到非线性回归(剂量响应-可变斜率)来计算IC50。
Figure BDA0003524734830000223
其中X：抑制剂浓度的对数；Y：抑制百分比。
IC50结果如表3：
表3
Figure BDA0003524734830000224
A：0μM<IC50≤5μM，B：5μM<IC50≤10μM，C：10μM<IC50≤20μM，D：>20μM
本领域技术人员仅使用常规实验将会认识到或将能够确定本文中确切描述的具体实施方案的许多等效方案。此类等效方案意图涵盖在以下权利要求书的范围中。

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1.一种药物组合物，包括至少之一的下列化合物或其药学上接受的盐和药学上可接受的载体、稀释剂或赋形剂：
Figure FDA0003524734820000011
Figure FDA0003524734820000021
任选的，所述组合物还包括附加治疗剂，其中所述附加治疗剂包括其他抗癌剂、其他治疗肺动脉高压药或他们的组合。
2.下列化合物或权利要求1所述的组合物在制备治疗与磷脂酰肌醇-5-磷酸-4-激酶(PI5P4K)调节相关的疾病或病症药物中的用途：
Figure FDA0003524734820000022
Figure FDA0003524734820000031
Figure FDA0003524734820000041
任选的，磷脂酰肌醇-5-磷酸-4-激酶(PI5P4K)为PI5P4Kα、PI5P4Kβ和/或PI5P4Kγ；
任选的，磷脂酰肌醇-5-磷酸-4-激酶(PI5P4K)为PI5P4Kβ。
3.如权利要求2所述的用途，其中所述与PI5P4K的调节相关的疾病或病症是癌症或细胞增殖性病症、代谢病症、神经变性疾病和炎性疾病。
4.如权利要求3所述的用途，
所述癌症或细胞增殖性病症是白血病(例如急性白血病、急性淋巴细胞性白血病、急性髓细胞性白血病、急性成髓细胞性白血病、急性早幼粒细胞性白血病、急性粒单核细胞性白血病、急性单核细胞性白血病、急性红白血病、慢性白血病、慢性髓细胞性白血病、慢性淋巴细胞性白血病)、真性红细胞增多症、淋巴瘤(霍奇金氏病、非霍奇金氏病)、瓦尔登斯特伦氏巨球蛋白血症、重链病以及实体瘤诸如肉瘤和癌(例如，纤维肉瘤、粘液肉瘤、脂肪肉瘤、软骨肉瘤、骨原性肉瘤、脊索瘤、血管肉瘤、内皮肉瘤、淋巴管肉瘤、淋巴管内皮肉瘤、滑膜瘤、间皮瘤、尤文氏瘤、平滑肌肉瘤、横纹肌肉瘤、结肠癌、胰腺癌、乳腺癌、卵巢癌、前列腺癌、鳞状细胞癌、基底细胞癌、腺癌、汗腺癌、皮脂腺癌、乳头状癌、乳头状腺癌、囊腺癌、髓样癌、支气管原癌、肾细胞癌、肝细胞瘤、胆管癌、绒毛膜癌、精原细胞瘤、胚胎性癌、威尔姆氏肿瘤、子宫颈癌、子宫癌、睾丸癌、肺癌、小细胞肺癌、膀胱癌、上皮癌、神经胶质瘤、星形细胞瘤、成神经管细胞瘤、颅咽管瘤、室管膜瘤、松果体瘤、成血管细胞瘤、听神经瘤、少突神经胶质瘤、神经鞘瘤、脑膜瘤、黑素瘤、成神经细胞瘤以及成视网膜细胞瘤)。
5.如权利要求3所述的用途，
所述代谢疾病是II型糖尿病、胰岛素抗性心血管疾病、心律不齐、动脉粥样硬化、冠状动脉疾病、高甘油三酯血症、血脂异常、视网膜病变、肾病变、神经病变或黄斑水肿。
6.如权利要求3所述的用途，
所述神经变性疾病是脑创伤、脊髓创伤、周围神经系统创伤、阿尔茨海默氏病、匹克氏病、弥漫性路易体病、进行性核上性麻痹(史提尔-里查德森综合征)、多系统变性(夏伊-德雷格综合征)、运动神经元疾病包括肌萎缩性侧索硬化、变性共济失调、皮质基底变性、关岛ALS-帕金森氏病-痴呆复合征、亚急性硬化性全脑炎、亨廷顿氏病、帕金森氏病、突触核蛋白病、原发进行性失语症、纹状体黑质变性、马查多-约瑟夫病/脊髓小脑性共济失调3型和橄榄体脑桥小脑变性、基列得拉图雷特氏病、延髓性麻痹和假延髓性麻痹、脊髓性和脊髓延髓性肌萎缩症(肯尼迪氏病)、原发性侧索硬化、家族性痉挛性截瘫、韦德尼希-霍夫曼病、库格伯格-韦兰德病、泰-萨二氏病、桑德霍夫病、家族性痉挛病、沃尔夫特-库格伯格-韦兰德病、痉挛性轻截瘫、进行性多灶性白质脑病和朊病毒病(包括克罗伊茨费尔特-雅格布病、格斯特曼-施特劳斯-沙因克尔病、库鲁病和致死性家族性失眠症、年龄相关性痴呆、血管性痴呆、弥漫性白质病(宾斯万格病)、内分泌或代谢起源的痴呆、头创伤和弥漫性脑损伤引起的痴呆、拳击员痴呆或额叶痴呆、由以下引起的神经变性病症：脑缺血或梗塞，包括栓塞性闭塞和血栓性闭塞以及任何类型的颅内出血、颅内和椎骨内损伤、遗传性脑血管病、normeuropathic遗传性淀粉样变性、唐氏综合征、巨球蛋白血症、继发性家族性地中海热、穆-韦二氏综合征、多发性骨髓瘤、胰腺和心脏有关的淀粉样变性、慢性血液透析关节病或芬兰型和爱荷华型淀粉样变性。
7.如权利要求3所述的用途，
所述炎性疾病是回肠炎、溃疡性结肠炎、巴雷特综合征或克罗恩氏病。
8.下列化合物或权利要求1所述的组合物在制备抑制磷脂酰肌醇-5-磷酸-4-激酶(PI5P4K)的活性药物的用途；
Figure FDA0003524734820000051
Figure FDA0003524734820000061
Figure FDA0003524734820000071
任选的，磷脂酰肌醇-5-磷酸-4-激酶(PI5P4K)为PI5P4Kα、PI5P4Kβ和/或PI5P4Kγ；
任选的，磷脂酰肌醇-5-磷酸-4-激酶(PI5P4K)为PI5P4Kβ。
9.一种抑制磷脂酰肌醇-5-磷酸-4-激酶(PI5P4K)的方法，所述方法包括施用至少一种下列化合物或权利要求1所述的组合物：
Figure FDA0003524734820000072
Figure FDA0003524734820000081
Figure FDA0003524734820000091
任选的，磷脂酰肌醇-5-磷酸-4-激酶(PI5P4K)为PI5P4Kα、PI5P4Kβ和/或PI5P4Kγ；
任选的，磷脂酰肌醇-5-磷酸-4-激酶(PI5P4K)为PI5P4Kβ。
10.一种诱导细胞周期停滞、肿瘤细胞的细胞凋亡和/或增强的肿瘤特异性T细胞免疫的方法，所述方法包括使所述细胞与有效量的下列化合物接触：
Figure FDA0003524734820000092
Figure FDA0003524734820000101
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