CN112839938A - 作为ctps1抑制剂的氨基嘧啶/吡嗪衍生物 - Google Patents
作为ctps1抑制剂的氨基嘧啶/吡嗪衍生物 Download PDFInfo
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- CN112839938A CN112839938A CN201980063914.3A CN201980063914A CN112839938A CN 112839938 A CN112839938 A CN 112839938A CN 201980063914 A CN201980063914 A CN 201980063914A CN 112839938 A CN112839938 A CN 112839938A
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- Prior art keywords
- ethoxypyrazin
- pyridin
- cyclopropanesulfonamido
- salt
- compound according
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Abstract
式(I)的化合物和相关方面。
Description
发明领域
本发明涉及新颖的化合物、制备此类化合物的方法、相关的中间体,包含此类化合物的组合物以及此类化合物作为胞苷三磷酸合酶1抑制剂的用途,特别是在治疗或预防与细胞增殖相关的疾病中的用途。
发明背景
核苷酸是细胞代谢过程(例如脱氧核糖核酸(DNA)和核糖核酸(RNA)合成)的关键结构单元。有两类核苷酸,分别含有嘌呤或嘧啶碱基,两者对代谢过程都很重要。基于此,已经开发了针对核苷酸合成的不同方面的许多疗法,其中一些抑制嘌呤核苷酸和一些嘧啶核苷酸的产生或同时抑制它们两者产生。
嘧啶核苷酸胞苷5′三磷酸(CTP)不仅为DNA和RNA合成代谢、而且还为磷脂和蛋白质的唾液酸化所需的前体。CTP来自两个来源:挽救途径和重新合成途径,这取决于两种酶,即CTP合酶(或合成酶)1和2(CTPS1和CTPS2)(Evans和Guy 2004;Higgins,等人2007;Ostrander,等人1998)。
CTPS1和CTPS2催化尿苷三磷酸(UTP)和谷氨酰胺转化成尿苷三磷酸(CTP)和L-谷氨酸盐:
两种酶都具有两个结构域,即N-末端合成酶结构域和C-末端谷氨酰胺酶结构域(Kursula,等人2006)。合成酶结构域将磷酸酯从三磷酸腺苷(ATP)转移至UTP的4-位,以生成活化的中间体4-磷酸-UTP。谷氨酰胺酶结构域通过具有保守的活性位点半胱氨酸的共价硫酯中间体从谷氨酰胺生成氨,从而产生谷氨酸盐。该铵经由隧道从谷氨酰胺酶结构域转移至合成酶结构域,或者可以衍生自外部铵。然后该氨被合成酶结构域用来从4-磷酸-UTP生成CTP(Lieberman,1956)。
尽管CTPS作为人类和其他真核生物中的两种同功酶CTPS1和CTPS2存在,但尚未充分阐明这两种同功酶之间的功能差异(van Kuilenburg,等人2000)。
免疫系统提供了免受感染的保护,因此已进化为对个体可能暴露其中的多种病原体做出快速反应。这种反应可以采取多种形式,但是免疫种群的扩展和分化是关键因素,且由此与细胞快速增殖密切相关。在这种情况下,CTP合酶活性显然在DNA合成和活化后淋巴细胞的快速扩增中起重要作用(Fairbanks,等人1995;van den Berg,等人1995)。
强有力的临床验证表明,CTPS1是人类淋巴细胞增殖中的关键酶,伴随着该酶功能缺失的纯合突变(rs145092287)的鉴定,该突变引起明显且危及生命的免疫缺陷,其特征在于活化T-和B细胞响应于受体介导的活化的增殖的能力受损。活化的CTPS1缺陷细胞显示CTP水平降低。通过表达野生型CTPS1或添加胞苷,可以在缺乏CTPS1的细胞中恢复正常的T细胞增殖。发现在静止的淋巴细胞中CTPS1表达低,但是在活化这些细胞后迅速上调。CTPS1在其他组织中的表达通常较低。CTPS2显然在各种细胞和组织中普遍表达,但水平很低,而仍在患者体内完整的CTPS2不能补偿突变的CTPS1,支持CTPS1是患者中受影响的免疫人群的关键酶(Martin,等人2014)。
总体而言,这些发现启示,CTPS1为满足几种重要的免疫细胞群要求的CTP的供应必不可少的关键酶。
正常情况下,免疫反应受到严格调节,以确保免受感染,同时控制针对宿主组织的任何反应。在某些情况下,对该过程的控制可能无效,从而导致免疫介导的病理学情况。认为广泛的人类疾病归因于免疫系统的不同元素介导的这种不适当的反应。
考虑到细胞群(例如T和B淋巴细胞)在多种自身免疫和其他疾病中的作用,CTPS1代表了新型免疫抑制剂的目标。因此,抑制CTPS1提供了一种抑制活化的淋巴细胞和所选的某些其他免疫细胞群的新方法,例如,通过人突变患者的表型突出显示了天然杀伤细胞、粘膜相关不变T(MAIT)和不变天然杀伤T细胞(Martin,等人2014)。
癌症可以影响多种细胞类型和组织,但根本原因在于细胞分裂控制失灵。该过程非常复杂,需要谨慎地协调多个途径,其中许多仍待充分表征。细胞分裂需要细胞DNA和其他成分的有效复制。多年来,通过靶向核酸合成来干扰细胞的复制能力一直是癌症疗法中的核心方法。以这种方式起作用的疗法的例子是6-硫鸟嘌呤、6-巯嘌呤、5-氟尿嘧啶、阿糖胞苷、吉西他滨和培美曲塞。
如上所述,提供核酸复制的关键结构单元所牵涉的途径为嘌呤和嘧啶合成途径,并且已观察到嘧啶的生物合成在肿瘤和赘生性细胞中被上调。
尽管在患者中观察到异质性,但CTPS活性在血液和非血液来源的多种肿瘤类型中均上调。在高酶水平和对化疗剂的抗性之间也建立了联系。
目前,尚不完全清楚CTPS1和CTPS2在癌症中可能发挥的确切作用。已经开发了几种非选择性CTPS抑制剂用于I/II期临床试验的肿瘤学适应症,但由于毒性和功效问题而被终止。
大多数已开发的抑制剂为核苷-类似物前药(3-脱氮尿苷,CPEC,carbodine),它们通过参与嘧啶生物合成的激酶转化为活性三磷酸化代谢物:尿苷/胞苷激酶、核苷单磷酸激酶(NMP-激酶)和核苷二磷酸激酶(NDP-激酶)。其余的抑制剂(阿西维辛acivicin,DON)为是谷氨酰胺的反应性类似物,其不可逆地抑制CTPS的谷氨酰胺酶结构/或。还报道吉西他滨对CTPS具有一定的抑制活性(McClusky等人,2016)。
因此,CTPS显然是癌症领域的重要靶标。所有上述化合物的性质使得对其他途径的作用可能有助于它们显示出抑制肿瘤的功效。
因此,选择性CTPS抑制剂提供了一种有吸引力的治疗肿瘤的替代方法。根据它们对这些酶的相对依赖性的不同,具有针对CTPS1和CTPS2的不同效力的化合物可能会提供靶向不同肿瘤的重要机会。
还启示CTPS1在血管损伤或手术后在血管平滑肌细胞增殖中起作用(Tang,等人2013)。
迄今为止,尚未开发出选择性的CTPS1抑制剂。最近,已经鉴定出CTPS1选择性抑制肽CTpep-3。但是,CTpep-3的抑制作用在无细胞试验中可见,但在细胞环境中却没有。不过,这并不出乎意料,因为该肽不太可能进入细胞,因此不容易被开发为治疗剂(Sakamoto,等人2017)。
总之,现有的信息和数据有力地启示,CTPS1抑制剂将减少许多免疫和癌细胞群的增殖,并可能影响其他选定的细胞类型,例如还有血管平滑肌细胞。因此,可以预期CTPS1的抑制剂在广泛的适应症中具有治疗或预防的用途,其病理学情况由这些人群驱动。
CTPS1抑制剂代表了抑制各种组织中免疫系统所选成分以及相关病理学情况或病理学病症的新方法,这些病理学情况或病理学病症通常是指例如移植细胞和组织的排斥、移植物相关疾病或障碍、过敏症和自身免疫性疾病。此外,CTPS1抑制剂还可以在一定范围的癌症适应症以及增强从血管损伤或手术中的恢复以及降低与新内膜和再狭窄相关的发病率和死亡率方面提供治疗潜能。
国际专利申请WO2019/106156、WO2019/106146、WO2019/179652和WO2019/180244公开了CTPS1抑制剂。
需要进一步的CTPS1抑制剂,这些抑制剂可以显示出有益的特性,例如:
-高效;
-超过CTPS2的对CTPS1的选择性抑制;
-良好的细胞渗透性;
-高的游离分数;
-理想的药效学和药动学参数;
-不同的代谢物;
-低至中度的亲脂性。
发明概述
本发明提供了式(I)化合物:
其中:
(a)当R4、R5、X、Y和R1为如下时:
则W是N、CH或CF;
(b)当R4、R5、X、W和R1为如下时:
则Y是CH或N;
(c)当W、X、Y和R1为如下时:
则R4和R5一起以形成下列的结构:
(d)当W、R4、R5、X和Y为如下时:
则R1是甲基或环丙基;且
(e)所述的化合物选自:
可以提供式(I)化合物,其为盐和/或溶剂化物和/或其衍生物形式。适合地,可以提供式(I)的化合物,其为药学上可接受的盐和/或溶剂化物和/或其衍生物形式。特别地,可以提供式(I)的化合物,其为药学上可接受的盐和/或溶剂化物形式,例如药学上可接受的盐。
还提供了式(I)的化合物或其药学上可接受的盐和/或溶剂化物和/或其衍生物,其用作药物,特别是用于抑制受试者的CTPS1,或预防或治疗相关疾病或障碍,例如其中T细胞和/或B细胞增殖减少可能为有益的那些。
还提供了用于抑制受试者的CTPS1或预防或治疗相关疾病或障碍、例如其中T细胞和/或B细胞增殖减少可能为有益的那些的方法,通过向有此需要的受试者施用式(I)的化合物或其药学上可接受的盐和/或溶剂化物和/或衍生物来进行。
还提供了式(I)的化合物或其药学上可接受的盐和/或溶剂化物和/或其衍生物在制备用于抑制受试者的CTPS1或预防或治疗相关疾病或障碍、例如其中T细胞和/或B细胞增殖减少可能为有益的那些的药物中的用途。
适合地,所述疾病或障碍选自:炎症性皮肤病,例如银屑病或扁平苔藓;急性和/或慢性GVHD,例如类固醇抵抗急性GVHD;急性淋巴细胞增生综合征(ALPS);系统性红斑狼疮、狼疮肾炎或皮肤狼疮;和移植。此外,所述疾病或障碍可以选自重症肌无力、多发性硬化和硬皮病/系统性硬化病。
还提供了式(I)的化合物或其药学上可接受的盐和/或溶剂化物和/或其衍生物,用于治疗癌症。
还提供了用于治疗受试者的癌症的方法,通过向有此需要的受试者施用式(I)的化合物或其药学上可接受的盐和/或溶剂化物和/或衍生物来进行。
还提供了式(I)的化合物或其药学上可接受的盐和/或溶剂化物和/或其衍生物在制备用于治疗受试者的癌症的药物中的用途。
还提供了式(I)的化合物或其药学上可接受的盐和/或溶剂化物和/或其衍生物,用于增强受试者从血管损伤或手术中恢复的能力和降低其与新内膜和再狭窄相关的发病率和死亡率。
还提供了用于增强受试者从血管损伤或手术中恢复的能力和降低其与新内膜和再狭窄相关的发病率和死亡率的方法,通过向有此需要的受试者施用式(I)的化合物或其药学上可接受的盐和/或溶剂化物和/或衍生物来进行。
还提供了式(I)的化合物或其药学上可接受的盐和/或溶剂化物和/或其衍生物在制备用于增强受试者从血管损伤或手术中恢复的能力和降低其与新内膜和再狭窄相关的发病率和死亡率的药物中的用途。
还提供了药物组合物,其包含式(I)的化合物或其药学上可接受的盐和/或溶剂化物和/或其衍生物和药学上可接受的载体或赋形剂。
还提供了用于制备式(I)的化合物和用于制备式(I)的化合物中使用的新的中间体的方法。
发明详述
本发明提供了式(I)化合物:
其中:
(a)当R4、R5、X、Y和R1为如下时:
则W是N、CH或CF;
(b)当R4、R5、X、W和R1为如下时:
则Y是CH或N;
(c)当W、X、Y和R1为如下时:
则R4和R5一起以形成下列的结构:
(d)当W、R4、R5、X和Y为如下时:
则R1是甲基或环丙基;且
(e)所述的化合物选自:
或盐和/或其溶剂合物和/或其衍生物。
适宜地R4和R5为以下的构型:
或者,R4和R5为以下的构型:
本发明提供下列的化合物:
(R)-2-(2-(环丙烷磺酰氨基)嘧啶-4-基)-N-(5-(6-乙氧基吡嗪-2-基)吡啶-2-基)-2-氟丁酰胺;
(S)-2-(2-(环丙烷磺酰氨基)嘧啶-4-基)-N-(5-(6-乙氧基吡嗪-2-基)吡啶-2-基)-2-氟丁酰胺;
4-(2-(环丙烷磺酰氨基)嘧啶-4-基)-N-(5-(6-乙氧基吡嗪-2-基)吡啶-2-基)四氢-2H-吡喃-4-甲酰胺;
1-(2-(环丙烷磺酰氨基)嘧啶-4-基)-N-(5-(6-乙氧基吡嗪-2-基)吡啶-2-基)环戊烷-1-甲酰胺;
4-(2-(环丙烷磺酰氨基)嘧啶-4-基)-N-(4-(6-乙氧基吡嗪-2-基)苯基)四氢-2H-吡喃-4-甲酰胺;
4-(2-(环丙烷磺酰氨基)嘧啶-4-基)-4-((5-(6-乙氧基吡嗪-2-基)吡啶-2-基)氨基甲酰基)哌啶-1-甲酸叔丁酯;
4-(2-(环丙烷磺酰氨基)嘧啶-4-基)-N-(4-(6-乙氧基吡嗪-2-基)-2-氟苯基)四氢-2H-吡喃-4-甲酰胺;
2-(2-(环丙烷磺酰氨基)嘧啶-4-基)-N-(5-(6-乙氧基吡嗪-2-基)吡啶-2-基)-4-甲氧基丁酰胺;
(R)-N-(5-(6-乙氧基吡嗪-2-基)吡啶-2-基)-2-氟-2-(2-(甲基磺酰氨基)嘧啶-4-基)丁酰胺;
(S)-N-(5-(6-乙氧基吡嗪-2-基)吡啶-2-基)-2-氟-2-(2-(甲基磺酰氨基)嘧啶-4-基)丁酰胺;
4-(6-(环丙烷磺酰氨基)吡啶-2-基)-N-(5-(6-乙氧基吡嗪-2-基)吡啶-2-基)四氢-2H-吡喃-4-甲酰胺;
4-(6-(环丙烷磺酰氨基)吡嗪-2-基)-N-(5-(6-乙氧基吡嗪-2-基)吡啶-2-基)四氢-2H-吡喃-4-甲酰胺;
(R)-2-(6-(环丙烷磺酰氨基)吡嗪-2-基)-N-(5-(6-乙氧基吡嗪-2-基)吡啶-2-基)-2-氟丁酰胺;和
(S)-2-(6-(环丙烷磺酰氨基)吡嗪-2-基)-N-(5-(6-乙氧基吡嗪-2-基)吡啶-2-基)-2-氟丁酰胺。
本发明的化合物可以以药学上可接受的盐和/或溶剂化物和/或其衍生物的形式提供。特别地,式(I)的化合物可以以药学上可接受的盐和/或溶剂化物、例如药学上可接受的盐的形式提供。
本发明特别关注的化合物为使用实施例的方法(或相差无几的方法)显示出相对于CTPS1酶IC50为1uM或以下的那些,尤其是100nM或以下的那些。
本发明特别关注的化合物为使用实施例的方法(或相差无几的方法)显示出对CTPS1的选择性超过对CTPS22-30倍、适合地>30-60倍或更适合地>60倍。理想地,对人CTPS1的选择性超过对人CTPS2的选择性。
应当理解,对于式(I)化合物的盐,在医学上应是药学上可接受的。式(I)的化合物的非药学上可接受的盐可以具有用作其他环境中的用途,例如在制备式(I)的化合物期间。适合的药学上可接受的盐对于本领域技术人员将是显而易见的。药学上可接受的盐包括Berge等人(1977)描述的那些。这样的药学上可接受的盐包括酸和碱加成盐。药学上可接受的酸加成的盐可以与无机酸形成,例如盐酸、氢溴酸、硫酸、硝酸或磷酸;和与有机酸形成,例如琥珀酸、马来酸、乙酸、富马酸、柠檬酸、酒石酸、苯甲酸、对甲苯磺酸、甲磺酸或萘磺酸。其他盐例如草酸盐或甲酸盐可以用于例如式(I)化合物分离中并且包括在本发明的范围内。
式(I)的化合物的某些可以与一个或多个当量的酸或碱形成酸或碱加成的盐。本发明在其范围内包括所有可能的化学计算和非化学计算形式。
可以制备结晶或非结晶形式的式(I)的化合物,如果结晶,则可以任选地被溶剂化,例如水合物。本发明在其范围内包括化学计算量的溶剂化物(例如水合物)和包含可变量的溶剂(例如水)的化合物。
应当理解,本发明包括式(I)的化合物的药学上可接受的衍生物,且它们包括在本发明范围内。
如本文所用,″药学上可接受的衍生物″包括任意药学上可接受的前药,例如式(I)的化合物的酯或盐,在施用于接受者时,其酯或这类酯的盐能够提供(直接或间接)式(I)的化合物或其活性代谢物或残留物。
应当理解,本发明包括式(I)的所有异构体及其药学上可接受的衍生物,包括所有的几何、互变异构和光学形式,以及它们的混合物(例如外消旋混合物)。如果其他的手性中心存在于式(I)的化合物中,则本发明在其范围内包括所有可能的非对映异构体,包括其混合物。不同的异构体形式可以通过常规方法彼此分离或拆分,或者可以通过常规合成方法或通过立体选择性或不对称合成得到任何指定的异构体。
本公开包括本文提供的本发明化合物的所有同位素形式,无论其是否为如下形式:(i),其中给定原子序数的所有原子均具有实际上占优势(在本文中称为“天然变体同位素形式”)的质量数(或质量数的混合物);或(ii),其中一个或多个原子被具有相同原子数、但质量数不同于自然界占主导地位的原子质量数的原子替代(在本文中称为“非天然变体同位素形式”)。应当理解,原子天然可以作为质量数的混合物天然存在。术语“非天然变体同位素形式”还包括这样的实施方案,其中原子具有在自然界中较不普遍发现的质量数(在本文中称作“非常见同位素”)的给定原子数的比例相对于天然存在的增加至该原子数的原子数量>20%、>50%、>75%、>90%、>95%或>99%的水平(后一实施方案称作“同位素富集的变体形式”)。术语“非天然变体同位素形式”也包括这样的实施方案,其中相对于天然存在的比例,罕见同位素的比例降低。同位素形式可以包括放射性形式(即它们结合了放射性同位素)和非放射性形式。放射性形式典型地为同位素富集的变体形式。
因此,化合物的非天然同位素形式可以包含一种或多种人工或不常见的同位素,例如在一个或多个原子上的氘(2H或D)、碳-11(11C)、碳-13(13C)、碳-14(14C)、氮-13(13N)、氮-15(15N)、氧-15(15O)、氧-17(17O)、氧-18(18O)、磷-32(32P)、硫-35(35S)、氯-36(36Cl)、氯-37(37Cl)、氟-18(18F)、碘-123(123I)、碘-125(125I),或包含与一个或多个原子在自然界中占主导地位的比例相比增加的所述同位素比例。
例如,包含放射性同位素的非天然变体同位素形式可用于药物和/或底物组织分布研究。考虑到放射性同位素的掺入和易于检测的方式,放射性同位素氚(即3H)和碳-14(即14C)对此特别有用。掺入氚(即2H或D)的非天然同位素形式可能具有某些治疗优势,因为它们具有更高的代谢稳定性,例如,体内半衰期增加或剂量需求降低,因此在某些情况下可以优先使用。此外,可以制备非天然变体同位素形式,其掺入正电子发射同位素,例如11C、18F、15O和13N,并且可以用于正电子发射形貌(PET)研究中以检查底物受体的占有率。
在一个实施方案中,本发明的化合物以天然同位素形式提供。
在一个实施方案中,本发明的化合物以非天然的同位素形式提供。在一个具体的实施方案中,非天然变体同位素形式为其中氘(即2H或D)被掺入的形式,其中氢在本发明化合物的一个或多个原子的化学结构中被指定。在一个实施方案中,本发明化合物的原子呈同位素形式,其为非放射性的。在一个实施方案中,本发明化合物的一个或多个原子为放射性形式的同位素形式。适合地,放射性同位素是稳定的同位素。适合地,非天然变体同位素形式为药学上可接受的形式。
在一个实施方案中,提供本发明的化合物,其中该化合物的单一原子以非天然变体同位素形式存在。在另一个实施方案中,提供本发明的化合物,其中两个或多个原子以非天然变体同位素形式存在。
非天然同位素变体形式通常可以通过本领域技术人员已知的常规技术或通过本文所述的方法制备,例如与制备天然同位素形式的所附实施例中描述的那些方法类似的方法。因此,可以通过使用适当的同位素变体(或标记的)试剂代替实施例中使用的常规试剂来制备非天然同位素变体形式。由于式(I)的化合物旨在用于药物组合物中,因此将容易理解,它们各自优选以基本上纯的形式提供,例如至少60%纯,更适合地,至少75%纯,优选为至少85%,尤其是至少98%纯(%基于重量)。化合物的不纯制品可以用于制备药物组合物中使用的更纯的形式。
通常,式(I)的化合物可以根据本领域技术人员公知的有机合成技术以及在实施例中举出的有代表性的方法及其变型制备。
本发明的中间体
本发明还涉及合成式(I)化合物中的新中间体,例如式(II)、(XXIV)、(XXXI)、(LVIII)和(IIa)的化合物,其中可变基团和相关优选如先前对式(I)化合物所定义:
-式(II)的化合物:
其中R是H、C1-6烷基(例如甲基和乙基)或苄基;
-式(XXIV)的化合物:
其中P是氮保护基诸如对-甲氧基苄基;
-式(XXXI)的化合物:
-式(LVIII)的化合物:
-式(IIa)的化合物:
其中P是氮保护基诸如对-甲氧基苄基,且M是金属离子诸如Li+。
作为本发明的一个方面包括实施例中描述的所有新的中间体,包括编号为INTC1至INTC179的那些中间体。
作为本发明的一个方面包括盐,诸如本文公开的任何一种中间体诸如式(II)、(XXIV)、(XXXI)、(LVIII)和(IIa)的药学上可接受的盐。
式(LVIII)化合物可以在Suzuki条件下与通式(XII)的硼酸酯偶联,如方案1所示。硼酸酯通常是二羟基硼酰基或二烷氧基硼酰基,通常是4,4,5,5-四甲基-1,3,3,2-二.氧杂硼杂环戊烷-2-基。根据Suzuki方法的偶联例如通过在催化剂如[1,1′-双(二苯基膦基)二茂铁]二氯钯(II)和无机碱如碳酸钾存在下在二噁烷和水的溶剂混合物中通过加热进行。本领域技术人员将理解,许多催化剂和条件可用于这种偶联。
方案1
治疗方法
本发明的式(I)的化合物具有CTPS1抑制剂的用途。
因此,本发明还提供式(I)的化合物或其药学上可接受的盐和/或溶剂化物(例如盐)和/或衍生物,用作药物,特别是用于治疗或预防疾病或障碍,其中CTPS1抑制剂为有益的,例如下文举出的那些疾病和障碍。
本发明提供用于治疗或预防疾病或障碍的方法,其中CTPS1抑制剂为有益的,例如下文举出的那些疾病或障碍,该方法包含对有此需要的受试者施用有效量的式(I)的化合物或其药学上可接受的盐和/或溶剂化物(例如盐)和/或衍生物。
本发明还提供式(I)的化合物或其药学上可接受的盐和/或溶剂化物(例如盐)和/或衍生物在制备用于治疗或预防疾病或障碍的药物中的用途,其中CTPS1抑制剂为有益的,例如下文举出的那些疾病和障碍。
更适合地,所述疾病或障碍,其中CTPS1抑制剂为有益的,为这样的疾病或障碍,其中T细胞和/或B细胞增殖的减少可能为有益的。
本发明还提供式(I)的化合物或其药学上可接受的盐和/或溶剂化物(例如盐)和/或衍生物,用于抑制受试者的CTPS1。
本发明提供用于抑制受试者的CTPS1的方法,该方法包含对该受试者施用有效量的式(I)的化合物或其药学上可接受的盐和/或溶剂化物(例如盐)和/或衍生物。
本发明还提供式(I)的化合物或其药学上可接受的盐和/或溶剂化物(例如盐)和/或衍生物在制备用于抑制受试者的CTPS1的药物中的用途。
本发明还提供式(I)的化合物或其药学上可接受的盐和/或溶剂化物(例如盐)和/或衍生物,用于减少受试者的T细胞和/或B细胞增殖。
本发明提供用于减少受试者的T细胞和/或B细胞增殖的方法,该方法包含对该受试者施用有效量的式(I)的化合物或其药学上可接受的盐和/或溶剂化物(例如盐)和/或衍生物。
本发明还提供式(I)的化合物或其药学上可接受的盐和/或溶剂化物(例如盐)和/或衍生物在制备用于减少受试者的T细胞和/或B细胞增殖的药物中的用途。
更适合地,所述疾病或障碍(其中CTPS1抑制剂为有益的)为这样的疾病或障碍,其中T细胞和/或B细胞增殖减少可能为有益的。
如本文所用,术语‘治疗’包括控制、缓解、减轻或调节疾病状态或其症状。
如本文所用,术语‘预防’或‘防止’是指预防受试者的疾病或障碍的症状或预防患病受试者的疾病或障碍的症状复发,并且不限于完全预防患病。
适合地,所述疾病或障碍选自移植细胞和组织的排斥反应、移植相关疾病或障碍、变态反应和自身免疫性疾病。
在一个实施方案中,所述疾病或障碍为移植细胞和组织的排斥反应。受试者可能已经移植了选自以下的移植物:心脏、肾脏、肺、肝、胰腺、胰岛、脑组织、胃、大肠、小肠、角膜、皮肤、气管、骨骼、骨髓(或任何其他来源的造血前体细胞和干细胞,包括从骨髓动员到外周血或脐带血细胞中的造血细胞)、肌肉或膀胱。本发明的化合物可以具有预防或抑制与受试者体内供体组织、细胞、移植物或器官移植排斥相关的免疫反应的用途。
在另一个实施方案中,所述疾病或障碍为与移植相关的疾病或病症。移植相关疾病或失调包括移植物抗宿主病(GVHD),例如与骨髓移植相关的GVHD,以及因器官、组织或细胞移植(例如,组织或细胞同种异体移植物或异种移植物)排斥而导致或与之相关的免疫病变,包括例如皮肤、肌肉、神经元、胰岛、器官、肝实质细胞等的移植物,以及宿主-移植物病(HVGD)。本发明的化合物可以具有预防或抑制受体的这种移植的急性排斥反应和/或用于长期维持疗法以防止受体的这种移植的排斥(例如,抑制来自患有糖尿病的受试者接受者的供体的产生胰岛素的胰岛细胞移植的排斥)。因此,本发明的化合物具有预防宿主抗移植物疾病(HVGD)和移植物抗宿主疾病(GVHD)的用途。
CTPS1抑制剂可以在移植后和/或移植期间施用于受试者。在一些实施方案中,CTPS1抑制剂可以在移植之前和/或之后定期施用于受试者。
在另一个实施方案中,所述疾病或障碍为过敏症。
在另外的实施方案中,所述免疫相关疾病或障碍为自身免疫疾病。如本文所用,″自身免疫疾病″为定向于受试者自身组织的疾病或障碍。自身免疫疾病的实例包括、但不限于阿狄森病、成人期发病斯蒂尔病、斑秃、阿尔茨海默病、抗中性白细胞胞质抗体(ANCA)-相关血管炎、强直性脊柱炎、抗磷脂综合征(Hughes综合征)、再生障碍性贫血、关节炎、哮喘、动脉粥样硬化、粥样硬化斑块、特应性皮炎、自身免疫性溶血性贫血、自身免疫性肝炎、自身免疫性垂体炎(淋巴细胞性垂体炎)、自身免疫性内耳病、自身免疫性淋巴组织增生综合征、自身免疫性心肌炎、自身免疫性中性粒细胞减少症、自身免疫性卵巢炎、自身免疫性睾丸炎、需要免疫抑制治疗的自身炎症性疾病、无精子症、贝切特病、Berger病、大疱性类天疱疮、心肌疾病、心血管病、乳糜泻包括难治性乳糜泻病(I型和II型)、慢性疲劳免疫功能障碍综合征(CFIDS)、慢性特发性黄瘤病、慢性炎症性脱髓鞘性多发性神经病(CIPD)、慢性复发性多发性神经病(格-巴二氏综合征)、丘斯综合征(CSS)、瘢痕性类天疱疮冷凝集素疾病(CAD)、慢性阻塞性肺疾病(COPD)、CREST综合征、冷球蛋白综合征、皮肤狼疮、疱疹样皮炎、皮肌炎、湿疹、获得性大疱性表皮松解、特发性混合性冷球蛋白血症、埃文斯综合征、突眼、纤维肌痛、古德帕斯彻氏综合征、格雷夫斯病、嗜血细胞性淋巴组织细胞增多症(HLH)(包括1型嗜血细胞性淋巴组织细胞增多症)、组织细胞增多症/细胞组织降碍、桥本甲状腺炎、特发性肺纤维化、特发性血小板减少性紫癜(ITP)、IgA肾病变、免疫增生性病或障碍、炎性肠病(IBD)、间质性肺病、少年关节炎、青少年特发性关节炎(JIA)、川畸病、朗-爱二氏肌无力综合征、扁平苔癣、局部性硬皮病、狼疮肾炎、梅尼埃病、微血管病性溶血性贫血、显微多脉管炎、Miller Fischer综合征/急性弥散性脑脊髓脊神经根病、混合性结缔组织病、多发性硬化(MS)、肌风湿病、肌痛脑脊髓炎(ME)、重症肌无力、眼部炎症、落叶型天疱疮、寻常型天疱疮、恶性贫血、结节性多发性动脉炎、多软骨炎、多腺体综合征(Whitaker综合征)、风湿性多肌痛、多发性肌炎、原发性无丙种球蛋白血症、原发性胆汁性肝硬变/自身免疫性胆管病、原发性肾小球肾炎、原发性硬化性胆管炎、银屑病、牛皮癣关节炎、单纯红细胞性贫血、雷诺现象、赖特综合征/反应性关节炎、复发性多软骨炎、再狭窄、风湿热、风湿性疾病、类风湿性关节炎、结节病、施密特氏综合征、硬皮病/系统性硬化症、斯耶格仑综合征、僵人综合征、斯威特综合征(热性嗜中性皮肤疾病)、系统性红斑狼疮(SLE)、系统性硬皮病、高安动脉炎、颞动脉炎/巨细胞动脉炎、甲状腺炎、1型糖尿病、2型糖尿病、葡萄膜炎、血管炎、白癜风、韦格纳肉芽肿病和X-连锁淋巴组织增生病。
特别关注这样的疾病和障碍,其主要由T细胞活化和增殖驱动,包括:
-与同种异体反应性无关的疾病和障碍,包括:
■斑秃、特应性皮炎、湿疹、银屑病、扁平苔癣、牛皮癣关节炎、白斑;
■葡萄膜炎;
■强直性脊柱炎、赖特综合征/反应性关节炎;
■再生障碍性贫血、自身免疫性淋巴组织增生综合征/障碍、嗜血细胞性淋巴组织细胞增多症;
■1型糖尿病;和
■难治性乳糜泻病;
-移植组织和移植器官的急性排斥反应;骨髓细胞或任意其他来源的同种细胞包括造血前体细胞和/或干细胞移植后急性移植物抗宿主病(GVHD)。
另外关注的为T和B细胞活化和增殖驱动的疾病和障碍,其中重要的是牵涉B细胞,包括:
-牵涉病原性自身抗体得到充分表征的疾病和障碍,包括:
●过敏症;
●瘢痕性类天疱疮、大疱性类天疱疮、获得性大疱性表皮松解、落叶型天疱疮、寻常型天疱疮、疱疹样皮炎;
●ANCA-伴随血管炎和显微小血管炎、脉管炎、韦格纳肉芽肿病;丘斯综合征(CSS)、结节性多发性动脉炎、冷球蛋白综合征和特发性混合性冷球蛋白血症;
●系统性红斑狼疮(SLE)、抗磷脂综合征(Hughes综合征)、皮肤狼疮、狼疮肾炎、混合性结缔组织病;
●甲状腺炎、桥本甲状腺炎、格雷夫斯病、眼球突出;
●自身免疫性溶血性贫血、自身免疫性中性粒细胞减少症、ITP、恶性贫血、单纯红细胞性贫血、微血管病性溶血性贫血;
●原发性肾小球肾炎、Berger病、古德帕斯彻氏综合征、IgA肾病;和
●慢性特发性多神经炎、慢性炎症性脱髓鞘性多发性神经病(CIPD)、慢性复发性多神经病(格-巴二氏综合征)、Miller Fischer综合征、僵人综合征、朗-爱二氏肌无力综合征、重症肌无力。
-牵涉B细胞尚未得到清楚地表征(不过,有时通过抗-CD20单克隆抗体或仅免疫球蛋白输注的功效示例)并且可能对病原性抗体的产生无应答或限于其产生的疾病和障碍(尽管如此,但是有时描述了非致病性抗体,乃至存在,并且用作诊断生物标志物),包括:
●阿狄森病,自身免疫性卵巢炎和无精子症,多腺体综合征(Whitaker综合征),施密特氏综合征;
●自身免疫性心肌炎、心肌病、川崎病;
●类风湿性关节炎、斯耶格仑综合征、混合性结缔组织病、多肌炎和皮肌炎;多软骨炎;
●原发性肾小球肾炎;
●多发性硬化;
●自身免疫性肝炎、原发性胆汁性肝硬变/自身免疫性胆管病;
■移植器官的超急性排斥反应;
■移植物或植入物慢性排斥反应;
■慢性移植物对宿主反应/骨髓细胞或造血前体细胞移植后疾病。
另外关注的为这样的疾病和病症,其机制在T细胞的活化/增殖与先天免疫细胞和其他炎性细胞亚群(包括骨髓细胞诸如巨噬细胞或粒细胞)和常驻细胞(例如成纤维细胞和内皮细胞)的活化/增殖之间共有,包括:
■COPD,特发性肺纤维化、间质性肺病、结节病;
■成人期发病斯蒂尔病、青少年特发性关节炎、系统性硬化症、CREST综合征,其中B细胞和病原体抗体也起作用;斯威特综合征;高动脉炎、颞动脉炎/巨细胞动脉炎;
■溃疡性胆道炎、包括克罗恩病和溃疡性结肠炎的炎性肠病(IBD)、原发性硬化性胆管炎。
另外关注的为这样的疾病和障碍,其机制仍然难以表征,但牵涉T细胞活化和增殖,包括:
■阿尔茨海默病、心血管综合征、2型糖尿病、再狭窄、慢性疲劳免疫功能障碍综合征(CFIDS)。
-自身免疫性淋巴组织增殖性疾病,包括:
■自身免疫性淋巴组织增生综合征和X-连锁淋巴组织增生病。
适合地,所述疾病或障碍选自:炎症性皮肤病,例如银屑病或扁平苔藓;急性和/或慢性GVHD,例如类固醇抵抗急性GVHD;急性淋巴细胞增生综合征;系统性红斑狼疮,狼疮肾炎或皮肤狼疮;或移植。另外,该疾病或障碍可以选自重症肌无力、多发性硬化症和硬皮病/系统性硬化症。
式(I)的化合物可以用于治疗癌症。
因此,在一个实施方案中,提供了式(I)的化合物或其药学上可接受的盐和/或溶剂化物和/或其衍生物,用于治疗癌症。
还提供了方法用于治疗受试者的癌症的方法,通过对有此需要的受试者施用式(I)的化合物或其药学上可接受的盐和/或溶剂化物和/或其衍生物来进行。
还提供了式(I)的化合物或其药学上可接受的盐和/或溶剂化物和/或其衍生物在制备用于治疗受试者的癌症的药物中的用途。
适合地,所述癌症为血癌,例如急性髓细胞性白血病、血管免疫母细胞性T细胞淋巴瘤、B细胞性急性淋巴细胞性白血病、斯威特综合征、T细胞非霍奇金淋巴瘤(包括物杀伤/T细胞淋巴瘤、成人T细胞白血病/淋巴瘤、肠病型T细胞淋巴瘤、肝脾性T细胞淋巴瘤和皮肤T细胞淋巴瘤)、T细胞急性淋巴细胞白血病、B细胞非霍奇金淋巴瘤(包括伯基特淋巴瘤、弥漫性大B细胞淋巴瘤、滤泡性淋巴瘤、外套细胞淋巴瘤、边缘带淋巴瘤)、多毛细胞白血病、霍奇金淋巴瘤、淋巴母细胞淋巴瘤、淋巴浆细胞性淋巴瘤、粘膜相关淋巴样组织淋巴瘤、多发性骨髓瘤、骨髓增生异常综合征、浆细胞骨髓瘤、原发性纵隔大B细胞淋巴瘤、慢性骨髓增生性疾病(例如慢性髓样白血病、原发性骨髓纤维化、原发性血小板减少症、真性红细胞增多症)或慢性淋巴细胞性白血病。
或者,所述癌症为非血癌,例如选自膀胱癌、乳腺癌、黑素瘤、神经母细胞瘤、恶性胸膜间皮瘤和肉瘤。
另外,式(I)的化合物可以用于增强受试者的血管损伤或手术的恢复,并降低与其新内膜和再狭窄相关的发病率和死亡率。例如,式(I)的化合物可以预防、减少或抑制新内膜的形成。可以在插入或植入之前用有效量的包含式(I)化合物的组合物对医疗装置进行治疗,以防止、减少或抑制在将装置或移植物植入或植入受试者后形成新的内膜。该装置可以是暂时插入受试者的装置,也可以是永久植入的装置。在一些实施方案中,该装置为手术装置。医疗装置的实例包括、但不限于针、套管、导管,分流器、球囊和植入物,例如支架和瓣膜。
适合地,受试者为哺乳动物,特别地受试者为人。
药物组合物
对于疗法中的应用,本发明的化合物通常作为药物组合物施用。本发明还提供药物组合物,其包含式(I)的化合物或其药学上可接受的盐和/或溶剂化物(例如盐)和/或其衍生物和药学上可接受的载体或赋形剂。
在一个实施方案中,提供了药物组合物,其包含式(I)的化合物或其药学上可接受的盐和/或溶剂化物(例如盐)和/或其衍生物,该药物组合物用于治疗或预防如本文所述的疾病或障碍。
在另一个实施方案中,提供了用于预防或治疗如本文所述的疾病或障碍的方法,包含对有此需要的受试者施用有效量的包含式(I)的化合物或其药学上可接受的盐和/或溶剂化物(例如盐)和/或其衍生物的药物组合物。
本发明还提供包含式(I)的化合物或其药学上可接受的盐和/或溶剂化物(例如盐)和/或其衍生物的药物组合物在制备用于治疗或预防如本文所述的疾病或障碍的药物中的用途。
式(I)的化合物或其药学上可接受的盐和/或溶剂化物和/或其衍生物可以通过任意便利的方法施用,例如通过口服、胃肠外、口含、舌下、鼻部、直肠或透皮施用,且由此药物组合物适用。
式(I)的化合物或其药学上可接受的盐和/或溶剂化物和/或其衍生物可以通过局部例如施用于眼、肠或皮肤。因此,在一个实施方案中,提供了药物组合物,其包含本发明的化合物和任选地一种或多种局部可接受的稀释剂或载体。
本发明的药物组合物可以通过局部递送至皮肤。适合于透皮施用的组合物包括软膏剂、凝胶和贴剂。这类药物组合物还可以适合地为霜剂、洗剂、泡沫体、粉末、糊剂或酊剂的形式。
该药物组合物可以适合地包括维生素D3类似物(例如钙三醇和马沙骨化醇)、类固醇(例如丙酸氟替卡松、戊酸倍他米松和丙酸氯倍他索)、维A酸(例如他扎罗汀)、煤焦油和地蒽酚。局部药物通常相互结合使用(例如维生素D3和类固醇)或与其他活性剂(例如水杨酸)结合使用。
本发明的药物组合物可以局部递送至眼部。这类药物组合物可以适合地为滴眼液或软膏剂形式。
本发明的药物组合物可以局部递送至肠。这类药物组合物适合地通过口服递送,例如为片剂或胶囊形式,或通过直肠递送,例如为栓剂形式。
适合地,延迟释放制剂为胶囊形式。
当口服给予时,可以将为活性的式(I)的化合物或其药学上可接受的盐和/或溶剂化物和/或其衍生物配制成液体或固体,例如为糖浆剂、混悬液、乳剂、片剂、胶囊或锭剂。
液体制剂通常由活性成分(例如式(I)的化合物或其药学上可接受的盐和/或溶剂化物(例如盐)和/或其衍生物)在适合的液体载体例如水性溶剂,例如水、乙醇或甘油,或非水性溶剂,例如聚乙二醇或油中的的混悬液或溶液组成。该制剂还可以包含助悬剂、防腐剂、矫味剂和/或着色剂。
可以制备片剂形式的组合物,使用通常用于制备固体制剂的任意适合的药物载体,例如硬脂酸镁、淀粉、乳糖、蔗糖和纤维素。
可以通过常规的包囊方法制备胶囊形式的组合物,例如,可以使用标准载体制备包含活性成分(例如式(I)的化合物或其药学上可接受的盐和/或溶剂化物(例如盐)和/或其衍生物)的丸粒,然后装入硬明胶胶囊中;或者可以制备分散体或混悬剂,使用任意适合的药用载体,例如水性树胶、纤维素、硅酸盐或油,然后将分散液或混悬液填充到软明胶胶囊中。
典型的肠胃外组合物由活性成分(例如式(I)的化合物或其药学上可接受的盐和/或溶剂化物(例如盐)和/或其衍生物)在无菌水性载体或胃肠外可接受的油例如聚乙二醇、聚乙烯吡咯烷酮、卵磷脂、花生油或芝麻油中的溶液或混悬液组成。或者,可以将溶液冻干,然后在施用前用适合的溶剂重构。
可以将经鼻施用的组合物便利地配制成气雾剂、滴剂、凝胶和散剂。气雾剂制剂典型地包含活性成分在药学上可接受的水性或非水性溶剂中的溶液或精细混悬液,并且通常以无菌形式以单剂量或多剂量形式存在于密封容器中,该密封容器可以采用药筒的形式或再填充以雾化装置使用。或者,密封容器可以是一次性分配装置,例如单剂量鼻吸入器或配有计量阀的气雾剂分配器,其中剂型包含气雾剂分配器,它将包含抛射剂,该抛射剂可以是压缩气体,例如空气,或有机抛射剂,例如氟-氯-烃或氢氟碳化合物。气雾剂剂型也可以采取泵雾化器的形式。
适合于口含或舌下施用的组合物包括片剂、锭剂和软锭剂,其中用载体例如糖和阿拉伯胶、黄蓍胶或明胶和甘油配制活性成分。
用于直肠施用的组合物便利地为包含常规栓剂基质例如可可脂的栓剂形式。
适合地,所述组合物为单位剂量形式,例如片剂、胶囊或安瓿。
根据施用方法的不同,该组合物可以包含0.1%-100%重量例如10-60%重量的活性物质。根据施用方法的不同,该组合物可以包含0%-99%重量例如40%-90%重量的载体。根据施用方法的不同,该组合物可以包含0.05mg-2000mg例如1.0mg-500mg的活性物质。根据施用方法的不同,该组合物可以包含50mg-1000mg例如100mg-400mg的载体。用于治疗或预防上述疾病的化合物的剂量将以通常的方式随疾病的严重性;患者的体重和其他类似因素而变化。然而,作为一般指导,适合的单位剂量可以为0.05mg-1000mg,更适合地为1.0mg-500mg,并且此类单位剂量可以每天施用一次以上,例如一天两次或三次。这种疗法可能会持续数周或数月。
在另一个方面,本发明提供了包含式(I)的化合物或其药学上可接受的盐、溶剂化物和/或衍生物与另一种或多种药学上可接受的活性成分的组合(例如,包含式(I)的化合物或其药学上可接受的衍生物的组合)。
本发明提供式(I)的化合物,用于与另外的药学上可接受的活性成分组合。
当这些化合物与其他治疗剂联合使用时,这些化合物可以通过任何便利的途径分别、依次或同时施用。
最佳组合可以取决于疾病或障碍。可能的组合包括与选自以下的一种或多种活性剂的那些组合:5-氨基水杨酸或其前药(例如柳氮磺胺硫酸盐、奥沙拉秦或bisalazide);皮质类固醇(例如泼尼松龙、甲泼尼龙或布地奈德);免疫抑制剂(例如环孢菌素、他克莫司、西罗莫司、甲氨蝶呤、硫唑嘌呤、麦考酚酸吗乙酯、来氟米特、环磷酰胺、6-巯嘌呤或抗淋巴细胞(或胸腺细胞)球蛋白);抗-TNF-α抗体(例如英夫利昔单抗、阿达木单抗、培化舍珠单抗或戈利木单抗);抗-IL12/IL23抗体(例如乌司奴单抗);抗-IL6或抗-IL6R抗体、抗-IL17抗体或小分子IL12/IL23抑制剂(例如阿吡莫德);抗α-4-β-7抗体(例如维多珠单抗);MAdCAM-1阻断剂(例如PF-00547659);抗细胞粘附分子α-4-整联蛋白的抗体(例如那他珠单抗);抗IL2抗体受体α亚单位的抗体(例如,达克珠单抗或巴利昔西单抗);JAK抑制剂,包括JAK1和JAK3抑制剂(例如,tofacitinib、baricitinib、R348);Syk抑制剂及其前药(例如福他替尼和R-406);磷酸二酯酶-4抑制剂(例如替托司特);HMPL-004;益生菌;德沙拉秦;塞马莫德/CPSI-2364;以及蛋白激酶C抑制剂(例如AEB-071)。
对于癌症,其他药学上可接受的活性成分可以选自抗有丝分裂剂,例如长春碱、紫杉醇和多西他赛;烷化剂,例如顺铂、卡铂、达卡巴嗪和环磷酰胺;抗代谢药,例如5-氟尿嘧啶、胞嘧啶阿拉伯糖苷和羟基脲;嵌入剂,例如阿霉素和博来霉素;拓扑异构酶抑制剂,例如依托泊苷、托泊替康和伊立替康;胸苷酸合酶抑制剂,例如雷替曲塞;PI3激酶抑制剂,例如idelalisib;mTor抑制剂,例如依维莫司和坦罗莫司;蛋白酶体抑制剂,例如硼替佐米;组蛋白脱乙酰酶抑制剂,例如帕比司他或伏林司他;和hedgehog途径阻滞剂,例如维莫德吉(vismodegib)。
其他药学上可接受的活性成分可以选自酪氨酸激酶抑制剂,例如,阿西替尼、达沙替尼、厄洛替尼、伊马替尼、尼洛替尼、帕唑帕尼和舒尼替尼。
抗癌抗体可以包括在联合疗法中,并且可以选自奥拉单抗(olaratumab)、达雷木单抗、奈昔木单抗、地努图希单抗(dinutuximab)、曲妥珠单抗-美坦新(traztuzumabemtansine)、培妥珠单抗、阿托珠单抗、本妥昔单抗(brentuximab)、奥法木单抗、帕木单抗、卡妥索单抗、贝伐单抗、西妥昔单抗、托西莫单抗、曲妥珠单抗(traztuzumab)、gentuzumabozogamycin和利妥昔单抗。
本发明的化合物或药物组合物还可以与放疗组合。
上面提及的一些组合可以便利地以药物制剂的形式呈现,因此包含如上定义的组合以及药学上可接受的载体或赋形剂的药物制剂构成了本发明的另一个方面。此类组合的各个成分可以以单独或组合的药物制剂依次或同时施用。组合的各个成分也可以通过相同或不同的途径分别施用。
当与另一种对同一疾病状态具有活性的治疗剂联合使用时,每种化合物的剂量可能与单独使用该化合物时的剂量不同。适合的剂量将被本领域技术人员容易地理解。
医疗装置
在一个实施方案中,可以将本发明的化合物或包含所述化合物的药物组合物配制成允许掺入医疗装置中,从而提供将化合物或组合物直接施用于该部位以预防或治疗本文公开的病症。
在一个实施方案中,本发明的化合物或其药物组合物通过将其包含在医疗装置上的涂层中制成。可以使用各种涂层,例如,可以在规定时间内释放化合物的聚合物涂层。该化合物或其药物组合物可以直接包埋在医疗装置内。在一些实施方案中,该化合物被涂覆在递送介质中的装置上或内部,例如有助于其释放和输送的微粒或脂质体。在一些实施方案中,该化合物或药物组合物可与涂层材料混溶。
在一些实施方案中,医疗装置为血管植入物,例如支架。支架在医学中用于预防或消除血管限制。可以将植入物插入受限血管中,从而使受限血管变宽。血管植入后相邻细胞的过度生长导致血管的限制,特别是在植入物的末端,这导致植入物的有效性降低。如果将血管植入物插入人的动脉以消除动脉硬化狭窄,则在一年之内,血管植入物的末端会发生内膜增生,并导致新的狭窄(“再狭窄”)。
因此,在一些实施方案中,所述支架被涂覆或装载有组合物,其包括本发明的化合物或其药物组合物以及任选地靶向信号、递送媒介物或其组合。许多支架是可商购的,否则就是本领域已知的。
在一些实施方案中,支架为药物洗脱支架。在向壁组织提供人造径向支撑的同时向治疗部位同时递送治疗物质的各种药物洗脱支架是本领域已知的。包括支架在内的腔内装置有时在其外表面上涂覆有物质,例如药物释放剂、生长因子等。还开发出具有中空管状结构的支架,该支架具有穿过侧壁切开的孔或端口以允许药物从中央腔中洗脱。尽管支架的中空性质允许中心管腔内载有通过支架侧壁上的端口或孔输送的药液,但中空的管状结构可能不具有适合的机械强度以在容器内提供足够的支撑。
在一些实施方案中,所述装置也用本发明的化合物或其药物组合物和一种或多种其他治疗剂包被或浸渍,包括但不限于抗血小板药、抗凝药、抗炎药、抗微生物药、抗代谢药、其他抗新内膜药物、其他抗增殖剂、免疫调节剂、抗增殖剂、影响迁移和胞外基质产生的活性剂、影响血小板沉积或血栓形成的活性剂以及促进血管愈合和再内皮化的活性剂,例如Sousa等人(2003)和Salu等人(2004)所述的那些和其他活性剂。
抗凝血酶剂的实例包括、但不限于肝素(包括低分子量肝素)、R-水蛭素、水蛭肽、阿加曲班、依非加群、Tick抗凝肽和Ppack。
抗增殖剂的实例包括,但不限于紫杉醇(Taxol)、QP-2长春新碱、甲氨蝶呤、血管肽素、丝裂霉素、BCP 678、反义c-myc、ABT 578、放线菌素-D、RestenASE、1-氯-脱氧腺苷、PCNARibozym和塞来昔布。
抗再狭窄剂的实例包括、但不预定免疫调节剂、例如西罗莫司(雷帕霉素)、他克莫司、Biorest、Mizoribin、环孢菌素、干扰素-γlb、来氟米特、曲尼司特、皮质类固醇、麦考酚酸和双膦酸盐。
抗迁移剂和胞外基质调节剂的实例包括、但不限于:卤夫酮、丙基羟化酶抑制剂、C-蛋白酶抑制剂、MMP抑制剂、巴马司他、普罗布考。
抗血小板药的实例包括、但不限于肝素。
伤口愈合剂和内皮化促进剂的实例包括血管上皮生长因子(″VEGF″)、17-雌二醇、Tkase-抑制剂、BCP 671、他汀类、一氧化氮(″NO″)-供体和内皮祖细胞(″EPC″)-抗体。
除冠状动脉应用外,还可以将药物和活性剂掺入支架或支架涂层中以作其他适应症,例如,在泌尿外科应用中,可以将抗生素剂掺入支架或支架涂层中以预防感染。在胃肠病学和泌尿外科应用中,可以将活性剂掺入支架或支架涂层中以局部治疗癌症。在支架上掺入造影剂、不透射线的标记物或其他添加剂以使支架在体内成像以用于跟踪、定位和其他目的也是有利的。可以将这样的添加剂添加到用于制造支架或支架涂层的可吸收组合物中,或者吸收、熔化或喷涂到部分或全部支架的表面上。为此目的优选的添加剂包括银、碘和碘标记的化合物、硫酸钡、氧化钆、铋衍生物、二氧化锆、镉、钨、金钽、铋、铂、铱和铑。这些添加剂可以为、但不限于微米或纳米尺寸的颗粒或纳米粒。射线不透性可以通过X线透视检查或x-射线分析确定。
可以通过在加工之前将化合物和一种或多种其他活性剂或其药物组合物装载到可吸收材料中和/或用活性剂涂覆支架表面,将本发明的化合物和一种或多种其他活性剂或其药物组合物掺入支架中。活性剂的释放速率可以通过多种方法来控制,包括改变以下各项:可吸收材料与化合物以及一种或多种其他活性剂或药物组合物的比例、可吸收材料的分子量、化合物和一种或多种其他活性剂的组合物、可吸收聚合物的组成、涂层厚度、涂层层数及其相对厚度、和/或化合物和一种或多种其他活性剂或药物组合物浓度。也可以将聚合物和其他材料(包括可吸收的聚合物)的顶涂层涂布在活性剂涂层上以控制释放速率。例如,P4HB可以作为涂有P4HB(包括活性剂)的金属支架上的顶涂层涂布,以阻止活性剂的释放。
本发明通过下列非限制性实施例来示例。
实施例
本文所用的缩写如下所定义。未定义的任何缩写预期传达其通常可接受的含义。
缩写
通用方法
所有原料和溶剂均可从商业渠道获得或根据文献制备。除非另有说明,否则搅拌所有反应体系。通常将有机溶液用无水硫酸镁干燥。在所述条件下,在Thales H-cube流式反应器上进行氢化。
柱色谱法在预装的硅胶(230-400目,40-63um)柱上进行,使用所指示的量。SCX购自Supelco,并且在使用前用1M盐酸处理。除非另有描述,否则将纯化的反应混合物首先用MeOH稀释,并用几滴AcOH形成酸性。将该溶液直接上SCX,并用MeOH洗涤。然后通过用0.7MNH3的MeOH溶液洗涤来洗脱期望的物质。
制备型反相高效液相色谱法
制备型HPLC
酸性制备型
Waters X-Select CSH柱C18,5um(19x50mm),流速28mL min-1,用包含0.1%v/v甲酸的H2O-MeCN梯度洗脱,历时6.5min,在254nm使用UV检测。
碱性制备型
Waters X-Bridge Prep柱C18,5um(19x50mm),流速28mL min-1,用10mM NH4HCO3-MeCN梯度洗脱,历时6.5min,在254nm使用UV检测。
分析方法
用于LCMS分析方法的反相HPLC条件
HPLC酸性:酸性LCMS 4分钟(5-95%)
使用Waters X-Select CSH C18,2.5um,4.6x30mm柱进行分析型LCMS,以在0.1%甲酸水溶液中的0.1%甲酸的MeCN溶液梯度洗脱。5-95%0.1%甲酸的MeCN溶液的梯度发生在0.00-3.00分钟之间,2.5mL/min,冲洗时间为3.01-3.5分钟,4.5mL/min。柱再平衡至5%MeCN,以2.5mL/min的速率3.60-4.00分钟。使用Agilent 1260Infinity VWD在254nm下测定洗脱峰的UV光谱。使用正/负切换运行的Agilent 6120MSD测定质谱。
HPLC碱性:碱性LCMS 4分钟(5-95%)
使用Waters X-Select BEH C18,2.5um,4.6x30 mm柱,用MeCN在10mM碳酸氢铵水溶液中的梯度洗脱进行分析型LCMS。5-95%MeCN的梯度发生在0.00-3.00分钟之间,2.5mL/min,冲洗时间为3.01-3.5分钟,4.5mL/min。柱再平衡至5%MeCN,以2.5mL/min的速率3.60-4.00分钟。使用Agilent 1260Infinity VWD在254nm下测定洗脱峰的UV光谱。使用正/负切换运行的Agilent 6120MSD测定质谱。
条件用于UPLC分析方法的反相HPLC
UPLC酸性:酸性UPLC 3分钟
使用Waters Acquity CSH C18,1.7um,2.1x30mm柱进行分析型UPLC/MS,用在0.1%甲酸水溶液中的0.1%甲酸的MeCN溶液梯度洗脱。梯度以保持在0.0-0.11分钟为起始点的5%MeCN进行结构化。5-95%的梯度发生在0.11-2.15分钟之间,在2.15-2.56分钟进行冲洗。再平衡至5%MeCN的柱为2.56-2.83分钟。使用Acquity PDA测定洗脱峰的UV光谱,并且使用带有ESI正/负切换的Acquity QDa检测器记录质谱。
酸性UPLC2:酸性UPLC1分钟
使用Waters Acquity CSH C18,1.7um,2.1x30mm柱进行分析型UPLC/MS,用在0.1%甲酸水溶液中的0.1%甲酸的MeCN溶液梯度洗脱。梯度以保持在0.0-0.08分钟为起始点的5%MeCN 进行结构化。5-95%的梯度发生在0.08-0.70分钟之间,在0.7-0.8分钟进行冲洗。再平衡至5%MeCN的柱为0.8-0.9分钟。使用Acquity PDA测定洗脱峰的UV光谱,并且使用带有ESI正/负切换的Acquity QDa检测器记录质谱。
UPLC碱性:碱性UPLC 3分钟
使用Waters Acquity BEH C18,1.7um,2.1x30mm柱进行分析型UPLC/MS,用10mM碳酸氢铵水溶液中的MeCN梯度洗脱。梯度以保持0.0-0.11分钟为起始点的5%MeCN进行结构化。5-95%的梯度发生在0.11-2.15分钟之间,2.15-2.56分钟为冲洗时间。再平衡至5%MeCN的柱为2.56-2.83分钟。使用Acquity PDA测定洗脱峰的UV光谱,并且使用带有ESI正/负切换的Acquity QDa检测器记录质谱。
碱性UPLC 2:碱性UPLC 1分钟
使用Waters Acquity BEH C18,1.7um,2.1x30mm柱进行分析型UPLC/MS,用10mM碳酸氢铵水溶液中的MeCN梯度洗脱。梯度以保持0.0-0.08分钟为起始点的5%MeCN进行结构化。5-95%的梯度发生在0.08-0.70分钟之间,0.7-0.8分钟为冲洗时间。再平衡至5%MeCN的柱为0.8-0.9分钟。使用Acquity PDA测定洗脱峰的UV光谱,并且使用带有ESI正/负切换的Acquity QDa检测器记录质谱。
在所有运行中柱温为40℃。注射体积为3uL且流速为0.77mL/min。在所有运行时PDA扫描210-400nm。
用于手性分析方法的正相HPLC条件
手性IC3方法:手性HPLC(Diacel Chiralpak IC,5um,4.6x250mm,1.0mL/min,在异己烷(0.2%TFA)中25-70%EtOH(0.2%TFA)。
手性IC5方法:手性HPLC(Diacel Chiralpak IC,5um,4.6x250mm,1.0mL/min,在异己烷(0.2%TFA)中20%EtOH(0.2%TFA)。
用于手性分析方法的反相HPLC条件
手性IC6方法:手性HPLC(Diacel Chiralpak IC,5um,4.6x250mm,1.0mL/min,在水(0.1%甲酸)中50%MeCN(0.1%甲酸)。
1H NMR光谱法
使用Bruker Avance III光谱仪在400MHz或Bruker Avance III HD光谱仪在500MHz获取1H NMR光谱,使用残留未氘代溶剂作为参比,且除非另有具体指定,否则使用DMSO-d6运行。
中间体的制备
已知的合成中间体得自商品来源或使用公布的文献方法得到。另外的中间体通过本文所述的有代表性的合成方法制备。
双-酯中间体的制备
1-(叔丁基)3-甲基2-(2-氯嘧啶-4-基)丙二酸酯INTC1
将NaH(60wt%的矿物油溶液,5.10g,128mmol)逐步加入到冰冷的搅拌的叔丁基甲基丙二酸酯(20.5mL,121mmol)在THF(160mL)中的溶液中.将该反应体系在0℃搅拌20min,然后在RT搅拌60min,直至氢气停止放出。然后加入2,4-二氯嘧啶(10g,67.1mmol),将得到的混合物在70℃搅拌3hr。冷却该反应体系,使其分配在NH4Cl(饱和水溶液,500mL)与EtOAc(500mL)之间,分离两相,使有机层通过分相器。通过硅胶色谱法纯化粗产物(220g柱,0-30%EtOAc/异己烷),得到1-叔丁基3-甲基2-(2-氯嘧啶-4-基)丙二酸酯(13.1g,44.3mmol,66%收率),为澄清淡黄色油状物;Rt 2.09min(HPLC酸性);m/z 230(M+H-tBu)+(ES+)和287(M+H)+(ES+);1H NMR(400MHz,DMSO-d6)δ8.83(d,J=5.1Hz,1H),7.65(d,J=5.1Hz,1H),5.21(s,1H),3.73(s,3H),1.42(s,9H)。
氯-嘧啶的脱羧
2-(2-氯嘧啶-4-基)乙酸甲酯INTC4
将TFA(55.3mL,717mmol)滴加到冰冷的搅拌的1-叔丁基3-甲基2-(2-氯嘧啶-4-基)丙二酸酯INTC1(12.1g,42.2mmol)在DCM(50mL)中的溶液中。将该反应体系在25℃搅拌1hr,然后真空浓缩。将残余物溶于EtOAc(200mL),用NaHCO3(200mL)碱化,分离有机层,使其通过分相器,真空除去溶剂。通过硅胶色谱法纯化粗产物(220g柱,0-50%EtOAc/异己烷),得到2-(2-氯嘧啶-4-基)乙酸甲酯(7.12g,37.8mmol,90%收率),为淡黄色油状物。Rt1.16min(HPLC酸性);m/z 187(M+H)+(ES+);1H NMR(500MHz,DMSO-d6)δ8.76(d,J=5.0Hz,1H),7.60(d,J=5.0Hz,1H),3.96(s,2H),3.66(s,3H)。
方法A:氯-杂环例如氯-嘧啶的脱羧
将TFA(10eq)滴加到冰冷的搅拌的丙二酸酯衍生物(1eq)在DCM(15个体积)中的溶液中。将反应容器在RT搅拌18hr,然后浓缩。通过正相色谱法纯化粗产物。
表1:根据方法A制备下列中间体。
方法B:烷基化
将碱(2.5-5eq)加入到冰冷的搅拌的2-(2-氯嘧啶-4-基)乙酸甲酯(1eq)在适合的极性非质子溶剂例如DMF或丙酮(10个体积)中的溶液中。20min后,加入烷基卤(1-5eq)或hal-CH2-CH2-hal(1-1.5eq)。将反应容器在0℃搅拌30min,然后在RT搅拌2hr。用NH4Cl(水溶液)或1M HCl(水溶液)使反应淬灭,搅拌20min,然后用EtOAc萃取。干燥有机相(分相器),浓缩。通过正相色谱法纯化粗产物。
表2:根据方法B制备下列中间体。
通过烷基化的杂环形成
4-(2-氯嘧啶-4-基)四氢-2H-吡喃-4-甲酸甲酯INTC52
在0℃向2-(2-氯嘧啶-4-基)乙酸甲酯INTC4(2.0g,10.7mmol)在DMF(10mL,10.7mmol)中的溶液中加入NaOH(0.986g,24.6mmol)。将该反应混合物在0℃搅拌20min,然后加入1-溴-2-(2-溴乙氧基)乙烷(1.8mL,12.9mmol)。将该反应体系在RT搅拌23hr。使用1MHCl(水溶液,53.6mL,53.6mmol)酸化该反应混合物,然后用DCM(70mL)萃取。使用分相器柱分离各相,再用DCM(2x50mL)萃取水相。真空浓缩合并的有机相。通过硅胶色谱法纯化粗产物(80g柱,0-50%EtOAc/异己烷),得到4-(2-氯嘧啶-4-基)四氢-2H-吡喃-4-甲酸甲酯(1.83g,5.57mmol,52%收率),为黄色油状物。Rt 1.56min(HPLC,酸性);m/z 257(35Cl M+H)+(ES+);1H NMR(500MHz,DMSO-d6)δ8.80(d,J=5.3Hz,1H),7.69(d,J=5.3Hz,1H),3.72-3.67(m,2H),3.66(s,3H),3.55-3.50(m,2H),2.33-2.22(m,2H),2.16-2.06(m,2H)。
通过烯醇化物SNAR的杂环形成
1-叔丁基4-甲基4-(2-氯嘧啶-4-基)哌啶-1,4-二甲酸酯INTC66
将LiHMDS(1.61mL,1.61mmol)一次性加入到冰冷的搅拌的1-叔丁基4-甲基哌啶-1,4-二甲酸酯(340mg,1.40mmol)和2,4-二氯嘧啶(200mg,1.34mmol)在THF(10mL)中的溶液中。将该反应混合物温热至RT,搅拌2hr。通过添加NaH2PO4(水溶液,1M,3mL)使反应淬灭。用DCM(2x10mL)萃取产物。通过疏水分相器干燥合并的有机萃取物,真空浓缩。通过硅胶色谱法纯化粗产物(24g柱,0-50%EtOAc/异己烷),得到1-叔丁基4-甲基4-(2-氯嘧啶-4-基)哌啶-1,4-二甲酸酯(315mg,0.66mmol,49%收率),为无色油状物。Rt 2.29min(HPLC,酸性);m/z 255(35Cl M-Boc+H)+(ES+);1H NMR(500MHz,DMSO-d6)δ8.79(d,J=5.3Hz,1H),7.68(d,J=5.3Hz,1H),3.69-3.59(m,5H),3.13(s,2H),2.26-2.22(m,2H),2.06-2.00(m,2H),1.40(s,9H)。
氯-嘧啶的水解
2-(2-氯嘧啶-4-基)-4-甲氧基丁酸锂INTC68
向2-(2-氯嘧啶-4-基)-4-甲氧基丁酸甲酯INTC60(479mg,1.96mmol)在THF(5mL)和MeOH(2.5mL)中的溶液中加入LiOH(56mg,2.35mmol)在水(3mL)中的溶液。将该反应混合物在RT搅拌72hr。真空浓缩该反应混合物,得到2-(2-氯嘧啶-4-基)-4-甲氧基丁酸锂(441mg,1.49mmol,76%收率),为无色固体。Rt 1.34min(HPLC酸性);m/z 231(为游离酸35ClM+H)+(ES+);1H NMR(500MHz,DMSO-d6)δ8.64(d,J=5.1Hz,1H),7.48(d,J=5.1Hz,1H),3.39-3.33(m,1H),3.22(s,3H),2.82-2.75(m,2H),1.96-1.85(m,2H)。
方法C:由芳族卤化物形成磺酰胺
将2-氯嘧啶中间体(1eq)、磺酰胺(1.2eq)和碱(2eq)溶于二噁烷(40个体积)。给该混合物脱气(N2,5min),然后加入催化剂(5mol%)。将得到的混合物在氮气气氛中在90℃加热2hr。过滤该混合物,用EtOAc或DCM洗涤,浓缩得到的滤液。通过正相色谱法或研磨、使用适合的溶剂纯化粗产物。
表3:根据方法C制备下列中间体。
方法D:带有磺酰胺的嘧啶的脱羧
将TFA(10当量)滴加到冰冷、搅拌的丙二酸衍生物(1当量)的DCM(15体积)溶液中。将反应容器在室温下搅拌18小时,然后浓缩。粗产物通过正相色谱纯化。
表4:根据方法D制备下列中间体。
PMB保护
2-(2-(N-(4-甲氧基苄基)环丙烷磺酰氨基)嘧啶-4-基)丁酸甲酯INTC48
将1-(溴甲基)-4-甲氧基苯(0.470mL,3.34mmol)加入搅拌的2-(2-(环丙烷磺酰氨基)嘧啶-4-基)丁酸甲酯(1g,3.34mmol)INTC35和K2CO3(0.46g,3.34mmol)在DMF(20mL)中的不均匀混合物中。将得到的反应混合物在RT搅拌18hr,然后倾入水(200mL),用EtOAc(3x50mL)萃取.用水(100mL)和盐水(100mL)洗涤有机萃取物,用MgSO4干燥,过滤,真空除去溶剂。通过硅胶色谱法纯化粗产物(40g柱,0-50%EtOAc/异己烷),得到2-(2-(N-(4-甲氧基苄基)环丙烷磺酰氨基)嘧啶-4-基)丁酸甲酯(844mg,1.95mmol,58%收率),为无色油状物。Rt 2.43min(HPLC,酸性);m/z 420(M+H)+(ES+);1H NMR(500MHz,DMSO-d6)δ8.64(d,J=5.1Hz,1H),7.25(d,J=8.3Hz,2H),7.19(d,J=5.1Hz,1H),6.86(d,J=8.3Hz,2H),5.17-5.02(m,2H),3.71(s,3H),3.64-3.55(m,4H),2.05-1.93(m,2H),1.89-1.76(m,1H),1.10-0.96(m,4H),0.82(t,J=7.3Hz,3H)。
氟化
2-氟-2-(2-(N-(4-甲氧基苄基)环丙烷磺酰氨基)嘧啶-4-基)丁酸甲酯INTC49
在-78℃向2-(2-(N-(4-甲氧基苄基)环丙烷磺酰氨基)嘧啶-4-基)丁酸甲酯INTC48(400mg,0.95mmol)在THF(10mL)中的溶液中滴加LHMDS(1.19mL,1.19mmol,1 M的THF溶液),历时5min。将得到的混合物温热至RT,搅拌1hr。再将该溶液冷却至-78℃,滴加N-氟-N-(苯基磺酰基)苯磺酰胺(376mg,1.19mmol)在THF(3mL)中的溶液,历时5min。将得到的混合物温热至RT,搅拌1hr。用饱和NaHCO3(水溶液,100mL)和EtOAc(100mL)稀释该溶液,分离各相。用EtOAc(2x50mL)萃取水相。用Na2SO4干燥合并的有机层,过滤,真空除去溶剂。通过硅胶色谱法纯化粗产物(24g柱,0-50%EtOAc/异己烷),得到2-氟-2-(2-(N-(4-甲氧基苄基)环丙烷磺酰氨基)嘧啶-4-基)丁酸甲酯(390mg,0.865mmol,91%收率),为澄清油状物。Rt2.48min(HPLC,酸性);m/z 438(M+H)+(ES+);1H NMR(500MHz,DMSO-d6)δ8.81(d,J=5.1Hz,1H),7.37(dd,J=5.1,1.5Hz,1H),7.29-7.19(m,2H),6.90-6.83(m,2H),5.17-5.03(m,2H),3.72(s,3H),3.69(s,3H)3.65-3.57(m,1H),2.40-2.14(m,2H),1.11-0.97(m,4H),0.84(t,J=7.4Hz,3H)。
使用如下方法制备INTC49,其富含对映体:
在-40℃向2-(2-(N-(4-甲氧基苄基)环丙烷磺酰氨基)嘧啶-4-基)丁酸甲酯INTC48(0.066g,0.157mmol)在THF(2.5mL)中的溶液中滴加LHMDS(0.189mL,0.189mmol),历时5min。将得到的混合物温热至RT,搅拌1hr。制备(-)-辛可尼定(0.069g,0.236mmol)和Selectfluor(0.072g,0.205mmol)在MeCN(2.5mL)中的第二种溶液,将其在RT搅拌30min。然后将氟化剂溶液冷却至-40℃,滴加脱质子化的酯的溶液,历时5min。将该反应混合物在-40℃搅拌1h,在冷却期结束时温热至RT,历时2h。将该反应混合物在RT搅拌20h。用饱和NaHCO3(水溶液,10mL)和EtOAc(20mL)稀释该反应混合物。分离各相,再用饱和NaHCO3(水溶液,10mL)、然后用1M HCl(水溶液,10mL)洗涤有机层。干燥合并的有机层(MgSO4),过滤,真空浓缩。通过硅胶色谱法纯化粗产物(4g柱,0-50%EtOAc/异己烷),得到2-氟-2-(2-(N-(4-甲氧基苄基)环丙烷磺酰氨基)嘧啶-4-基)丁酸甲酯(0.024g,0.052mmol,33%收率),为无色油状物。Rt 0.70min(UPLC 2,酸性);m/z 438(M+H)+(ES+);1H NMR(500MHz,DMSO-d6)δ8.81(d,J=5.1Hz,1H),7.37(dd,J=5.1,1.5Hz,1H),7.29-7.19(m,2H),6.90-6.83(m,2H),5.17-5.03(m,2H),3.72(s,3H),3.69(s,3H)3.65-3.57(m,1H),2.40-2.14(m,2H),1.11-0.97(m,4H),0.84(t,J=7.4Hz,3H)。
锂盐形成
2-氟-2-(2-(N-(4-甲氧基苄基)环丙烷磺酰氨基)嘧啶-4-基)丁酸锂INTC50
向2-氟-2-(2-(N-(4-甲氧基苄基)环丙烷磺酰氨基)嘧啶-4-基)丁酸甲酯INTC49(1.45g,3.31mmol)在THF(15mL)和MeOH(7.5mL)中的溶液中加入LiOH(0.091g,3.81mmol)在水(5mL)中的溶液。将该反应混合物在RT搅拌3hr。真空浓缩该反应混合物,将得到的黄色油状物溶于MeCN(10mL),真空浓缩,得到2-氟-2-(2-(N-(4-甲氧基苄基)环丙烷磺酰氨基)嘧啶-4-基)丁酸锂(1.46g,3.30mmol,定量收率),为淡黄色泡沫体,不经进一步纯化使用。Rt0.95min(UPLC,碱性);m/z 424(作为COOH电离,M+H)+(ES+);1H NMR(500MHz,DMSO-d6)δ8.57-8.52(m,1H),7.34-7.28(m,2H),7.20-7.14(m,1H),6.90-6.83(m,2H),5.19-5.04(m,2H),4.14-4.10(m,1H),3.71(s,3H),2.33-2.20(m,1H),2.17-2.08(m,1H),1.15-1.04(m,1H),1.06-0.97(m,1H),0.93-0.80(m,2H),0.80-0.73(m,3H)。
通过硫醚的四氢吡喃衍生物
4-(2-(甲硫基)嘧啶-4-基)四氢-2H-吡喃-4-甲酸甲酯INTC178
在30℃下向4-氯-2-(甲硫基)嘧啶(0.55g,3.42mmol)和四氢-2H-吡喃-4-甲酸甲酯(494mg,3.42mmol)的THF(5mL)溶液中滴加LHMDS(1M的THF溶液)(4.11mL,4.11mmol)。将反应混合物在30℃下搅拌5分钟,然后倒入水(100mL)中并用EtOAc(2×200mL)萃取。将有机萃取物用盐水(1×100mL)洗涤,干燥(MgSO4),过滤并真空除去溶剂,得到4-(2-(甲硫基)嘧啶-4-基)四氢-2H-吡喃-4-甲酸甲酯(915mg,3.24mmol,95%收率),为浅黄色油状物。Rt1.74min(HPLC酸性);m/z 269(M+H)+(ES+);1H NMR(500MHz,DMSO-d6)δ8.62(d,J=5.3Hz,1H),7.27(d,J=5.3Hz,1H),3.76-3.70(m,2H),3.67(s,3H),3.54-3.46(m,2H),2.49(s,3H),2.27-2.20(m,2H),2.14-2.04(m,2H)。
4-(2-(甲基磺酰基)嘧啶-4-基)四氢-2H-吡喃-4-甲酸甲酯INTC179
将mCPBA(1.60g,7.13mmol)分批加入到搅拌的4-(2-(甲硫基)嘧啶-4-基)四氢-2H-吡喃-4-甲酸甲酯INTC178(915mg,3.24mmol)的DCM(50mL)溶液中。并将所得反应混合物在室温下搅拌3小时。将反应混合物倒入饱和NaHCO3(aq,200mL)中并用DCM(3×100mL)萃取。依次用饱和NaHCO3(aq,100mL)和盐水(100mL)洗涤有机萃取物,干燥(MgSO4),过滤并真空除去溶剂,得到4-(2-(甲基磺酰基)嘧啶-4-甲基)四氢-2H-吡喃-4-甲酸甲酯(1.10g,3.30mmol,定量收率),为浓稠胶状物。Rt 1.20min(HPLC酸性);m/z 301(M+H)+(ES+);1H NMR(500MHz,DMSO-d6)δ9.09(d,J=5.3Hz,1H),7.95(d,J=5.3Hz,1H),3.77-3.70(m,2H),3.68(s,3H),3.60-3.49(m,2H),3.42(s,3H),2.34-2.24(m,2H),2.23-2.13(m,2H)。
4-(2-(环丙烷磺酰氨基)嘧啶-4-基)四氢-2H-吡喃-4-甲酸甲酯INTC53
向4-(2-(甲基磺酰基)嘧啶-4-基)四氢-2H-吡喃-4-甲酸甲酯INTC179(1.0g,3.33mmol)和环丙烷磺酰胺(0.52g,4.33mmol)的NMP(100mL)溶液中加入碳酸铯(3.25g,9.99mmol)并加热至90℃1小时。将反应混合物冷却至室温并用水(100mL)稀释,并将混合物用MTBE(2×100mL)洗涤,并使用稀HCl(20mL)将水缓慢酸化至pH 3.过滤得到的沉淀物,得到无色固体状的4-(2-(环丙烷磺酰氨基)嘧啶-4-基)四氢-2H-吡喃-4-甲酸甲酯(755mg,2.21mmol,66%收率)。Rt.0.88(UPLC,酸性),m/z 342(M+H)+(ES+);1H NMR(500MHz,DMSO-d6)δ11.30(s,1H),8.60(d,J=5.3Hz,1H),7.20(d,J=5.3Hz,1H),3.79-3.72(m,2H),3.67(s,3H),3.52-3.44(m,2H),3.25-3.14(m,1H),2.30-2.17(m,2H),2.12-2.04(m,2H),1.14-1.01(m,4H)。
选择的结构单元的酰胺形成
表5:根据如下用于合成式(I)的化合物所述的方法4制备下列中间体。
通过烷基化的杂环形成
4-(6-溴吡啶-2-基)四氢-2H-吡喃-4-甲酸乙酯INTC105
如对INTC52所述,使用商品2-(6-溴吡啶-2-基)乙酸乙酯(2.51g,10.28mmol)和1-溴-2-(2-溴乙氧基)乙烷制备,得到4-(6-溴吡啶-2-基)四氢-2H-吡喃-4-甲酸乙酯(52%收率),为澄清油状物。Rt 1.42min(UPLC碱性);m/z 314(79Br M+H)+(ES+);1H NMR(400MHz,DMSO-d6)δ7.80-7.76(m,1H),7.57(d,J=7.9Hz,1H),7.49(d,J=7.7Hz,1H),4.12(q,J=7.1Hz,2H),3.77-3.70(m,2H),3.52-3.45(m,2H),2.30-2.23(m,2H),2.07-2.01(m,2H),1.12(t,J=7.1Hz,3H)。
方法I:Buchwald偶联-磺酰化
将2-溴吡啶中间体(1eq)、磺酰胺(1.2eq)和碱(2eq)溶于二噁烷(40个体积)。给该混合物脱气(N2,5min),然后加入催化剂(5mol%)。将得到的混合物在氮气气氛中在90℃加热2hr。过滤该混合物,用EtOAc或DCM洗涤,浓缩得到的滤液。通过正相色谱法纯化粗产物。
表6:根据方法I制备下列中间体。
酯形成
2-(6-氯吡嗪-2-基)乙酸甲酯INTC112
在0℃将亚硫酰氯(1.15mL,15.65mmol)滴加入搅拌的2-(6-氯吡嗪-2-基)乙酸(2.70g,15.65mmol)在MeOH(50mL)中的溶液中。在添加后,将该反应混合物在RT搅拌1hr。真空浓缩该反应混合物,用DCM(100mL)稀释粗残余物,依次用饱和NaHCO3(水溶液,2x100mL)和盐水(100mL)洗涤。干燥有机萃取物(MgSO4),过滤,真空除去溶剂,得到2-(6-氯吡嗪-2-基)乙酸甲酯(2.63g,13.67mmol,87%收率),为棕色油状物。Rt 1.25min(HPLC,酸性);m/z187(35Cl M+H)+(ES+);1H NMR(500MHz,DMSO-d6)δ8.74(s,1H),8.68(s,1H),4.00(s,2H),3.66(s,3H)。
2-(6-(环丙烷磺酰氨基)吡嗪-2-基)-2-氟丁酸INTC133
向2-(6-(环丙烷磺酰氨基)吡嗪-2-基)-2.氟丁酸甲酯(14.2g,44.7mmol)INTC130的THF(100L)溶液中加入MeOH(30mL)和LiOH(3.21g,134mmol)的水(30mL)溶液。将反应在室温下搅拌18小时。将反应混合物真空浓缩,并将所得残余物用1M HCl(200mL)酸化。使用EtOAc(5×100mL)萃取产物,干燥合并的有机物(Na2SO4),过滤并真空浓缩,得到2-(6-(环丙烷磺酰氨基)吡嗪-2-基)-2-氟丁酸(13.87g,42.1mmol,95%收率),为浓稠红色糊状物。Rt0.89min(UPLC,酸性);m/z 304(M+H)+(ES+);1H NMR(500MHz,DMSO-d6)δ13.74(s,1H),11.23(s,1H),8.45(s,1H),8.33(s,1H),3.153.09(m,1H),2.45-2.21(m,2H),1.21-1.15(m,1H),1.15-0.97(m,3H),0.92(t,J=7.4Hz,3H)。
通过烷基化的杂环形成
4-(6-氯吡嗪-2-基)四氢-2H-吡喃-4-甲酸甲酯INTC123
如对INTC52所述,使用2-(6-氯吡嗪-2-基)乙酸甲酯INTC112制备,得到4-(6-氯吡嗪-2-基)四氢-2H-吡喃-4-甲酸甲酯(12%收率),为黄色油状物。Rt 1.05min(UPLC,酸性);m/z 257(35Cl M+H)+(ES+);1H NMR(500MHz,DMSO-d6)δ8.81(s,1H),8.76(s,1H),3.77-3.62(m,5H),3.58-3.49(m,2H),2.38-2.26(m,2H),2.21-2.10(m,2H)。
吡嗪中间体的氟化
方法H:杂芳族酯的苄基氟化
将杂芳族酯(1eq)在THF(10体积)中的溶液冷却至-78℃,向其中加入LiHMDS(1.25eq1M的THF溶液)。然后将反应混合物温热至室温1小时。将溶液冷却至-78℃,滴加NSFI(1.25eq)或固体NSFI(1.25eq)的溶液(在THF中),然后温热至室温2小时。该溶液用饱和NaHCO3(aq)稀释,产物萃取到EtOAe中。粗产物通过正相色谱纯化。
表7:根据方法H制备下列中间体。
胺中间体制备
方法F:杂芳族卤化物与苯胺硼酸酯的Suzuki偶联
将Pd催化剂(5mol%)加入到脱气的(N2,5min)杂芳基-X(1eq)、乙氧基吡嗪-Z(1eq)和碱(3eq,6.85mmol)在溶剂(3个体积)中的溶液中。然后再给该溶液脱气(N2,5min),然后加热至90℃2hr,然后冷却至RT。通常,通过柱色谱法纯化期望的化合物。
苯胺
表8:根据方法F制备下列中间体,
实施例的制备
通用方法
方法2:AlMe3为介体的从酯的酰胺偶联
向冰冷却的苯胺(2eq)在甲苯(40个体积)中的溶液中加入AIMe3(2.0M的庚烷溶液,2eq)。将该混合物在此温度下搅拌5min,然后在RT搅拌10min。向该溶液中一次性加入酯(1eq),加热得到的混合物,在80℃搅拌2hr。用冰浴冷却该反应混合物,谨慎地用MeOH(10个体积)淬灭。搅拌20min后,用DCM/MeOH(10个体积)混合物稀释该混合物,通过硅藻土过滤,浓缩滤液。通过反相或正相色谱法纯化粗产物。
方法4:使用T3P从锂盐的酰胺偶联
在0℃下,向锂盐磺酰胺(1eq)的DMF(4体积)溶液中加入苯胺(1.2eq),然后加入吡啶(6eq)和T3P(50重量%的DMF溶液)(2eq)。将反应混合物在0℃下搅拌2小时,然后温热至室温20小时。将反应混合物冷却至0℃,并进一步加入T3P(50wt%的DMF溶液)(0.6eq)。将反应混合物在0℃下搅拌1小时,然后RT 3小时。将反应混合物用饱和NH4Cl(aq,38体积)稀释,过滤分离所得沉淀物,用水(2×17体积)洗涤。将得到的黄色沉淀物溶于DCM(25体积)和MeOH(25体积)中并在二氧化硅上浓缩。粗产物通过硅胶色谱纯化。
方法7:芳族氯化物的磺酰化
将2-氯-杂芳族中间体(1eq)、磺酰胺(1.2eq)和碱(2eq)溶于二噁烷(40体积)中。将混合物脱气(抽真空并用N2×3回填),然后加入催化剂(10mol%)。将所得混合物在氮气下在90℃下加热2小时。将混合物冷却至室温,用饱和NH4Cl(aq,80体积)和DCM(80体积)稀释。分离各相,并用另外的DCM(2×80体积)萃取水溶液。将合并的有机物干燥(MgSO4),过滤并真空浓缩。粗产物通过正相色谱法纯化或使用合适的溶剂研磨。
方法10:具有游离酸的T3P
将吡啶(10eq)、然后将T3P(50wt%的DMF溶液,2eq)加入到搅拌的胺(1.1eq)和羧酸(1eq)在DMF(16个体积)中的混悬液中。将得到的反应体系在RT搅拌24 hr。真空浓缩粗反应混合物,然后用NH4Cl(饱和水溶液)稀释,用DCM萃取。干燥合并的有机萃取物(分相器),除去溶剂。通过反相或正相色谱法纯化粗产物。
酰胺形成
N-(5-(6-乙氧基吡嗪-2-基)吡啶-2-基)-2-氟-2-(2-(N-(4-甲氧基苄基)环丙烷磺酰氨基)嘧啶-4-基)丁酰胺INTC51
在0℃向2-氟-2-(2-(N-(4-甲氧基苄基)环丙烷-磺酰氨基)嘧啶-4-基)丁酸锂INTC50(0.50g,1.17mmol)在DMF(5mL)中的溶液中加入5-(6-乙氧基吡嗪-2-基)吡啶-2-胺INTD33(0.30g,1.40mmol),然后加入吡啶(0.57mL,7.01mmol)和T3P(50wt%的DMF溶液)(1.69mL,2.34mmol)。将该反应混合物在0℃搅拌2hr,然后温热至RT 20hr。将该反应混合物冷却至0℃,再加入T3P(50wt%的DMF溶液)(0.5mL,0.69mmol)。将该反应混合物在0℃搅拌1hr,然后在RT搅拌3hr。用饱和NH4Cl(水溶液,45mL)稀释该反应混合物,通过过滤分离得到的沉淀,用水(2x20mL)洗涤。将得到的黄色沉淀溶于DCM(30mL)和MeOH(30mL),用硅胶浓缩。通过硅胶色谱法纯化粗产物(24g柱,0-60%EtOAc/异己烷),得到N-(5-(6-乙氧基吡嗪-2-基)吡啶-2-基)-2-氟-2-(2-(N-(4-甲氧基苄基)环丙烷磺酰氨基)嘧啶-4-基)丁酰胺(0.274g,0.433mmol,37%收率),为无色油状物。Rt 1.84min(UPLC,酸性);m/z 622(M+H)+(ES+);1H NMR(500MHz,DMSO-d6)δ10.69(s,1H),9.10(d,J=2.5Hz,1H),8.88-8.81(m,2H),8.52(dd,J=8.7,2.5Hz,1H),8.27(s,1H),8.10(d,J=8.7Hz,1H),7.52(dd,J=5.2,1.3Hz,1H),7.30-7.23(m,2H),6.81-6.74(m,2H),5.20-5.08(m,2H),4.48(q,J=7.0Hz,2H),3.76-3.70(m,1H),3.65(s,3H),2.50-2.39(m,1H),2.38-2.24(m,1H),1.40(t,J=7.0Hz,3H),1.14-1.06(m,1H),1.10-0.97(m,2H),0.96-0.92(m,1H),0.89(t,J=7.3Hz,3H)。
2-(2-(环丙烷磺酰氨基)嘧啶-4-基)-N-(5-(6-乙氧基吡嗪-2-基)吡啶-2-基)-2-氟丁酰胺P112
将TFA(0.28mL,3.70mmol)加入到搅拌的N-(5-(6-乙氧基吡嗪-2-基)吡啶-2-基)-2-氟-2-(2-(N-(4-甲氧基苄基)环丙烷磺酰氨基)嘧啶-4-基)丁酰胺INTC51(115mg,0.185mmol)在DCM(10mL)中的溶液中,将得到的反应混合物在RT搅拌4hr。真空浓缩该反应混合物,通过硅胶色谱法纯化粗产物(12g柱,0-100%EtOAc/异己烷),得到2-(2-(环丙烷磺酰氨基)嘧啶-4-基)-N-(5-(6-乙氧基吡嗪-2-基)吡啶-2-基)-2-氟丁酰胺(77mg,0.15mmol,81%收率),为白色固体。Rt 2.28min(HPLC,酸性);m/z 502(M+H)+(ES+);1H NMR(500MHz,DMSO-d6)δ11.50(s,1H),10.60(d,J=2.3Hz,1H),9.10(d,J=2.5Hz,1H),8.87(s,1H),8.76(d,J=5.1Hz,1H),8.53(dd,J=8.8,2.5Hz,1H),8.27(s,1H),8.10(d,J=8.8Hz,1H),7.48(d,J=5.1Hz,1H),4.49(q,J=7.0Hz,2H),3.38-3.27(m,1H),2.44-2.29(m,2H),1.40(t,J=7.0Hz,3H),1.20-0.92(m,7H)。
通过手性制备型HPLC,使用Diacel Chiralpak IC柱(在[4∶1庚烷∶氯仿(0.2%TFA):]中20%EtOH)分离外消旋体P112,得到P113和P114。
表9:实施例的制备方法和表征数据
生物学实施例
生物学实施例1-人CTPS1酶抑制
使用ADP-GloTM Max测定法(Promega,UK)测定本发明化合物对目标靶标的酶抑制活性。在包含50mM Tris、10mM MgCl2、0.01%Tween-20,pH至8.0的1x测定缓冲液中进行人CTPS1测定。最终,在使用前即刻将L-半胱氨酸加入1x测定缓冲液中至终浓度为2mM。除非另有说明,否则所有试剂均来自Sigma-Aldrich。人全长活性C-末端FLAG-His8-标记CTPS1(UniProtKB-P17812,CTPS[1-591]-GGDYKDDDDKGGHHHHHHHH)得自Proteros biostructuresGmbH。
测定方法
在1x测定缓冲液中制备3x人CTPS1蛋白至反应所需的最终工作蛋白浓度。将每孔2uL体积的3x人CTPS1蛋白与每孔2uL的3x测试化合物(在1x测定缓冲液中制备的化合物至相当于测试中为化合物设计的浓度响应曲线的最终3x浓度)在25℃下混合10分钟。然后通过每孔体积添加2uL的预混合底物混合物(来自ADP-GloTM Max试剂盒的UltraPure ATP(0.31mM)、GTP(0.034mM)、UTP(0.48mM)和L-谷氨酰胺(0.186mM))来启动酶反应,并将该混合物在确定的反应线性阶段中在25℃在密封板条件下以500转/分钟(rpm)的恒定搅拌温育适当的时间。加入ADP-GloTM Max试剂60分(6μL/孔),随后加入ADP-GloTM Max展开试剂60分钟(12uL/孔),然后在微量平板读出器(EnMultilabel Reader,Perkin Elmer)中进行信号检测。在测定过程中加入每种试剂后,将测定板以500rpm脉冲离心30秒。
在所有情况下,酶都会将ATP转化成ADP,随后ADP-GloTM Max试剂会耗尽反应系统中任何残留的内源性ATP。ADP-GloTM Max检测试剂将通过酶促产生的ADP转换回ATP,并使用ATP作为底物与荧光素酶的荧光素一起产生发光,从而产生可检测的发光。测定的发光信号与酶反应产生的ADP的量成正比,且化合物处理时该信号的减少表明酶抑制。使用以下方程计算每种浓度的化合物产生的抑制百分比:
然后将抑制百分比对化合物浓度作图,并根据所得的浓度-响应曲线确定50%抑制浓度(IC50)。全部测试的式(I)的化合物的数据如下所示。
表10:人CTPS1酶抑制数据按效价范围分组(++表示IC50在>0.1-1微摩尔之间,+++表示IC50≤0.1微摩尔)
P | CTPS1 | P | CTPS1 |
P113 | +++ | P145 | +++ |
P114 | +++ | P165 | +++ |
P115 | +++ | P166 | +++ |
P136 | +++ | P186 | +++ |
P137 | +++ | P197 | +++ |
P139 | ++ | P206 | +++ |
P143 | +++ | P207 | +++ |
发现已经测试的本发明的全部化合物在本测定法中显示出CTPS1酶抑制作用。因此,可以预期这些化合物具有抑制CTPS1的用途。还预期本发明的化合物具有作为研究工具的用途,例如,用于CTPS测定。
生物学实施例2-基于RapidFire/MS的酶选择性测定
通过RapidFire/MS分析的人CTPS1与CTPS2的选择性评价
可以使用优化的RapidFire高通量质谱(RF/MS)测定方式测定本发明的化合物对每个关注的靶标同种型的酶抑制活性。因此,可以在由50mM HEPES(Merck)、20mM MgCl2、5mM KCl、1mM DTT、0.01%Tween-20、pH至8.0组成的测定缓冲液中进行人CTPS1和CTPS2的RF/MS测定。人全长活性C-末端FLAG-His-标记CTPS1(UniProtKB-P17812,CTPS[1-591]-GGDYKDDDDKGGHHHHHHHH)可以得自Proteros biostructures GmbH.人全长活性C-末端FLAG-His-Avi标记的CTPS2(UniProtKB-Q9NRF8,CTPS2[1-586]-DYKDDDDKHHHHHHGLNDIFEAQKIEWHE)可以得自Harker Bio。
测定方法
可以在1x测定缓冲液中将人CTPS(1或2)蛋白制备为反应所需的最终工作蛋白浓度。可以使用声学(ECHO)递送将每孔2x CTPS(1或2)蛋白的2uL体积与40nL的化合物混合,并在25℃下温育10分钟。随后可以通过在测定缓冲液中每孔加入2uL 2x底物混合物来启动每个同工酶反应。对于hCTPS1:UTP(0.2mM)、GTP(0.07mM)和L-谷氨酰胺(0.1mM)。对于hCTPS2:ATP(0.1mM)、UTP(0.04mM)、GTP(0.03mM)和L-谷氨酰胺(0.1mM)。每种混合物可以在25℃的确定线性反应期中温育每种同工型适当的时间。可以加入60uL的终止溶液(在H20中含0.5uM的0.5uM 13C9-15N3-CTP的1%甲酸),立即将板加热密封,并以4,000rpm下离心10分钟。离心后,可以将板装载到与API4000三重四极杆质谱仪(RF/MS)偶联的AgilentRapidFire微流体固相萃取系统上进行分析。
在所有情况下,酶都会将UTP转化成CTP。可以针对检测酶促反应产物CTP和稳定同位素标记的产物标准品13C9-15N3-CTP的高特异性和敏感性多反应监测(MRM)MS方法进行优化。数据分析的读出值可以计算为产品CTP峰面积与内标13C9-15N3-CTP之比。对于数据报告,可以使用以下方程
(R=比率/读出值,P=产品信号面积,IS=内标信号面积)
对于每个筛选板,均使用阴性(DMSO)和阳性对照值的平均值来计算相应测定窗(S/B)和Z’值。相应对照值的中位值用于根据如下方程计算抑制百分比:
(I=抑制率,R阴性=阴性对照读出值的中位值,R阳性=阳性对照读出值的中位值,R样品=样品读出值)
然后将抑制百分比对化合物浓度作图,并根据所得的浓度-响应曲线确定50%抑制浓度(IC50)。
随后根据如下方程计算CTPS1与CTPS2之间的倍数选择性:
在上述测定法中测试了式(I)的某些化合物。全部测试化合物的数据如下所示。
表11:选择性数据分为2-30倍(+)或>60倍(+++)的分组
发现在生物学实施例2中描述的测定法中测试的所有化合物对CTPS1的选择性是对CTPS2的至少2倍,其中许多化合物对CTPS1的选择性超过60倍。特别地可以预期,这些化合物具有治疗疾病的用途,由此选择性CTPS1化合物是有益的。
在整个说明书和随后的权利要求中,除非上下文另有要求,否则词语“包含”和变化形式,例如“包括”和“含有”将理解为暗示包括所述整数、步骤、整数或步骤组,但不排除任何其他整数、步骤、整数组或步骤组。
本说明书和权利要求书构成其组成部分的本申请可以用作任何后续申请的优先权基础。这种后续申请的权利要求可以针对本文所述的任何特征或特征的组合。它们可以采取产品、组合物、方法或用途权利要求的形式,通过实施例非限制地可以包括所附权利要求。
本说明书中引用的所有出版物,包括、但不限于专利和专利申请,均通过引用并入本文,如同每个单独的出版物均被明确地和单独地指示为通过引用并入本文,如同已充分阐述一样。
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Claims (31)
16.根据权利要求1-15的任意一项的化合物,其中所述的化合物为药学上可接受的盐形式。
17.根据权利要求1-15的任意一项的化合物,其中所述的化合物不是盐的形式。
18.根据权利要求1的化合物,其选自:
(R)-2-(2-(环丙烷磺酰氨基)嘧啶-4-基)-N-(5-(6-乙氧基吡嗪-2-基)吡啶-2-基)-2-氟丁酰胺;
(S)-2-(2-(环丙烷磺酰氨基)嘧啶-4-基)-N-(5-(6-乙氧基吡嗪-2-基)吡啶-2-基)-2-氟丁酰胺;
4-(2-(环丙烷磺酰氨基)嘧啶-4-基)-N-(5-(6-乙氧基吡嗪-2-基)吡啶-2-基)四氢-2H-吡喃-4-甲酰胺;
1-(2-(环丙烷磺酰氨基)嘧啶-4-基)-N-(5-(6-乙氧基吡嗪-2-基)吡啶-2-基)环戊烷-1-甲酰胺;
4-(2-(环丙烷磺酰氨基)嘧啶-4-基)-N-(4-(6-乙氧基吡嗪-2-基)苯基)四氢-2H-吡喃-4-甲酰胺;
4-(2-(环丙烷磺酰氨基)嘧啶-4-基)-4-((5-(6-乙氧基吡嗪-2-基)吡啶-2-基)氨基甲酰基)哌啶-1-甲酸叔丁酯;
4-(2-(环丙烷磺酰氨基)嘧啶-4-基)-N-(4-(6-乙氧基吡嗪-2-基)-2-氟苯基)四氢-2H-吡喃-4-甲酰胺:
2-(2-(环丙烷磺酰氨基)嘧啶-4-基)-N-(5-(6-乙氧基吡嗪-2-基)吡啶-2-基)-4-甲氧基丁酰胺;
(R)-N-(5-(6-乙氧基吡嗪-2-基)吡啶-2-基)-2-氟-2-(2-(甲基磺酰氨基)嘧啶-4-基)丁酰胺;
(S)-N-(5-(6-乙氧基吡嗪-2-基)吡啶-2-基)-2-氟-2-(2-(甲基磺酰氨基)嘧啶-4-基)丁酰胺;
4-(6-(环丙烷磺酰氨基)吡啶-2-基)-N-(5-(6-乙氧基吡嗪-2-基)吡啶-2-基)四氢-2H-吡喃-4-甲酰胺;
4-(6-(环丙烷磺酰氨基)吡嗪-2-基)-N-(5-(6-乙氧基吡嗪-2-基)吡啶-2-基)四氢-2H-吡喃-4-甲酰胺;
(R)-2-(6-(环丙烷磺酰氨基)吡嗪-2-基)-N-(5-(6-乙氧基吡嗪-2-基)吡啶-2-基)-2-氟丁酰胺;和
(S)-2-(6-(环丙烷磺酰氨基)吡嗪-2-基)-N-(5-(6-乙氧基吡嗪-2-基)吡啶-2-基)-2-氟丁酰胺。
19.根据权利要求1-18任一项的化合物,用作药物。
20.根据权利要求19的化合物,用于减少受试者的T细胞和/或B细胞增殖。
21.根据权利要求19的化合物,用于治疗或预防:炎性皮肤病,例如银屑病或扁平苔藓;急性和/或慢性GVHD,例如类固醇抗性急性GVHD;急性淋巴细胞增生综合征(ALPS);系统性红斑狼疮、狼疮肾炎或皮肤狼疮;或移植。
22.根据权利要求19的化合物,用于治疗或预防重症肌无力、多发性硬化或硬皮病/系统性硬化病。
23.根据权利要求19的化合物,用于治疗癌症。
24.根据权利要求23的化合物,其中所述癌症为血癌。
25.根据权利要求24的化合物,其中所述血癌选自急性髓样白血病、血管免疫母细胞性T细胞淋巴瘤、B细胞急性淋巴母细胞性白血病、斯威特综合征、T细胞非霍奇金淋巴瘤(包括天然杀伤细胞/T细胞淋巴瘤、成人T细胞白血病/淋巴瘤、肠病型T细胞淋巴瘤、肝脾T细胞淋巴瘤和皮肤T细胞淋巴瘤)、T细胞急性淋巴母细胞性白血病、B细胞非霍奇金淋巴瘤(包括伯基特淋巴瘤、弥漫性大B细胞性淋巴瘤、滤泡淋巴瘤、外套细胞淋巴瘤、边缘带淋巴瘤)、多毛细胞白血病、何杰金氏淋巴瘤、淋巴母细胞淋巴瘤、淋巴浆细胞性淋巴瘤、粘膜相关淋巴样组织淋巴瘤、多发性骨髓瘤、骨髓增生异常综合征、浆细胞性骨髓瘤、原发性纵膈大B细胞淋巴瘤、慢性脊髓增生性障碍(例如慢性髓样白血病、原发性骨髓纤维化、原发性血小板增多症、真性红细胞增多症)和慢性淋巴细胞白血病。
26.根据权利要求19的化合物,用于增强从血管损伤或手术中恢复并且降低与受试者的新内膜和再狭窄相关的发病率和死亡率。
27.药物组合物,包含根据权利要求1-18任一项的化合物。
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