CN111065635B - 作为mth1抑制剂的新型嘧啶衍生物 - Google Patents
作为mth1抑制剂的新型嘧啶衍生物 Download PDFInfo
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- CN111065635B CN111065635B CN201880031003.8A CN201880031003A CN111065635B CN 111065635 B CN111065635 B CN 111065635B CN 201880031003 A CN201880031003 A CN 201880031003A CN 111065635 B CN111065635 B CN 111065635B
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- cancer
- amino
- phenyl
- methylpyrimidin
- diamine
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- 101000744394 Homo sapiens Oxidized purine nucleoside triphosphate hydrolase Proteins 0.000 title claims abstract description 53
- 102100039792 Oxidized purine nucleoside triphosphate hydrolase Human genes 0.000 title claims abstract description 53
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- 150000003230 pyrimidines Chemical class 0.000 title description 12
- 229940083082 pyrimidine derivative acting on arteriolar smooth muscle Drugs 0.000 title description 3
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- 150000003839 salts Chemical class 0.000 claims abstract description 21
- -1 4- (2-amino-5-methylpyrimidin-4-yl) phenyl Chemical group 0.000 claims description 14
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- GDSMYAXXHCWXCF-UHFFFAOYSA-N 4-(4-aminophenyl)-5-ethylpyrimidin-2-amine Chemical compound NC1=CC=C(C=C1)C1=NC(=NC=C1CC)N GDSMYAXXHCWXCF-UHFFFAOYSA-N 0.000 claims description 3
- HCROZSFKVOKROF-UHFFFAOYSA-N 5-ethyl-4-(4-nitrophenyl)pyrimidin-2-amine Chemical compound C(C)C=1C(=NC(=NC=1)N)C1=CC=C(C=C1)[N+](=O)[O-] HCROZSFKVOKROF-UHFFFAOYSA-N 0.000 claims description 3
- CMWACSAKKKYDMU-UHFFFAOYSA-N 5-methyl-4-[4-[(2-morpholin-4-ylpyrimidin-4-yl)amino]phenyl]pyrimidin-2-amine Chemical compound CC=1C(=NC(=NC=1)N)C1=CC=C(C=C1)NC1=NC(=NC=C1)N1CCOCC1 CMWACSAKKKYDMU-UHFFFAOYSA-N 0.000 claims description 3
- YQUIPTVERTXROH-UHFFFAOYSA-N 5-methyl-4-[4-[(5-methyl-2-morpholin-4-ylpyrimidin-4-yl)amino]phenyl]pyrimidin-2-amine Chemical compound Cc1cnc(nc1Nc1ccc(cc1)-c1nc(N)ncc1C)N1CCOCC1 YQUIPTVERTXROH-UHFFFAOYSA-N 0.000 claims description 3
- QRQVMWBVMWOCLZ-UHFFFAOYSA-N 5-methyl-4-[4-[[2-(4-methylpiperazin-1-yl)pyrimidin-4-yl]amino]phenyl]pyrimidin-2-amine Chemical compound CC=1C(=NC(=NC=1)N)C1=CC=C(C=C1)NC1=NC(=NC=C1)N1CCN(CC1)C QRQVMWBVMWOCLZ-UHFFFAOYSA-N 0.000 claims description 3
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- KUYXNOZIJALPRB-UHFFFAOYSA-N ClC1=NC=CC(=N1)NC1=CC=C(C=C1)C1=NC(=NC=C1C)N Chemical compound ClC1=NC=CC(=N1)NC1=CC=C(C=C1)C1=NC(=NC=C1C)N KUYXNOZIJALPRB-UHFFFAOYSA-N 0.000 claims description 3
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- VGSVXVKQPUZWEL-UHFFFAOYSA-N NC1=NC=C(C(=N1)C1=CC=C(C=C1)NC1=NC(=NC=C1)NCC=1C=C(C#N)C=CC=1)C Chemical compound NC1=NC=C(C(=N1)C1=CC=C(C=C1)NC1=NC(=NC=C1)NCC=1C=C(C#N)C=CC=1)C VGSVXVKQPUZWEL-UHFFFAOYSA-N 0.000 claims description 3
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
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Abstract
本文公开了通式I的化合物及其在药学上可接受的盐。所述的化合物是MTH1的抑制剂。优选的化合物用于治疗可获益于MTH1的抑制的疾病如癌症。
Description
技术领域
本发明涉及新型化合物和含这些化合物的药物组份,以及合成和使用这些化合物和药物组分的方法。所述化合物是MTH1抑制剂,因此可用于治疗通过抑制 MTH1的活性来发挥治疗效果的疾病,如癌症。
背景技术
目前主流的治疗癌症的方法,如化疗、放疗等,其靶向癌细胞和正常细胞无选择性,并且在复发的恶性肿瘤的治疗中往往无效。最近的治疗策略,如靶向特定的基因改变或信号通路,在治疗癌症的过程中受到癌细胞基因型多样性和肿瘤内异质性的限制,并且癌细胞对该类治疗策略的耐药性快速发展。因此,仍需要能够更广泛、更有效地杀死各种类型癌细胞同时不影响正常细胞的新型治疗药物。在这方面,靶向对癌细胞的生存至关重要但对正常细胞来说可有可无的特异性生化途径被认为是最有希望的癌症治疗策略之一(zecchini and Frezza,Biochim Biophys Acta,2017,1858:723-731)。
癌细胞的活性氧(reactive oxygen species,ROS)水平通常高于正常细胞,这在驱动肿瘤进展的同时对肿瘤细胞存活也是一个巨大威胁(Moloney and Cotter,SeminCell Dev Biol,2017 June 3,Epub ahead of print)。ROS会与大分子如DNA、蛋白质、脂质和游离核苷酸(NTPs和 dNTPs)发生反应。ROS水平增加会导致细胞组分发生致命损伤,进而对细胞存活产生威胁。例如,ROS氧化的脱氧核苷酸(dNTPs)可以掺入DNA中,从而导致修复相关的DNA断裂的积累和随后的程序性细胞死亡的诱导(Nakabeppu et al.,Mutat Res,2010,703:5158);此外,癌细胞中与ROS相关的氧化压力的升高也使它们容易产生氧化损伤(Rai et a1.,PNAS,2009, 106:169-174)。为了生存,癌细胞重绕生化代谢通路以拮抗升高的ROS的毒性并增强修复系统的功能,包括核苷酸池清洁酶等,以抵抗由此产生的氧化损伤(Rudd et a1.,DNA Repair, 2016:193-204)。
MTH1(MutT同源物1,又称NUDT1)是主要的核苷酸池清洁酶,其降解含量最丰富的氧化修饰的脱氧核苷酸8-oxodGTP(8-氧代-7,8-二氢-脱氧鸟苷三磷酸)和2-OH-4ATP(2-羟基- 脱氧腺苷三磷酸)(Nakabeppu,Int J Mol Sci,2014,15:12543-12557)。MTH1通过去除8-oxodGTP和2-OH-dATP从而使DNA损伤相关的细胞死亡最小化并允许ROS水平较高的癌细胞存活。研究发现在多种癌症中MTH1的表达水平出现上调,并且显示MTH1过表达有助于细胞应对氧化压力和Ras蛋白诱导的细胞衰老和程序性细胞死亡(Yoshimura et al.,J BiolChem,2003,278:3796537973;Rai et al.,Oncogene,2011,30:14891496)。相反,MTH1 的遗传缺失阻止了OGG1缺陷的小鼠的癌症的发展(Sakumi et al.,Cancer Res,2003, 63:902905);同样,RNAi介导的MTH1基因敲除促进了Ras介导的细胞衰老的发生(Rai et al.,PNAS,2009,106:169-174)并导致8-oxodGTP掺入基因组DNA的增加,以及各种癌细胞系中广泛的DNA断裂和生长抑制(Gad et al.,Nature,2014,508:215-221;Huber et al.,Nature,2014,508:222-227),表明MTH1通常是癌细胞存活所必需的。相反,MTH1对于正常细胞并不是必需的(Tsuzuki et al.,Mutat Res,2001,477:71-78)。综上所述,抑制MTH1活性将降低癌细胞清除氧化dNTP的能力和存活的能力,因此无论是作为单一治疗还是与其他抗癌药物联合治疗,都是一种很有前景的新策略。
ROS的产生还与许多其他病理相关,其中包括但不限于炎性和自身免疫性疾病(zhang et al.,Antioxid Redox Signal,2011,15:2867-908),而MTH1的抑制可提供改善的、额外的或替代的治疗效果。
因此,非常需要能够高效和特异性抑制MTH1活性的化合物。迄今为止,已有几类可作为MTH1抑制剂的化合物见于报导。然而,它们中的大多数仅表现出较弱的抗癌活性或没有抗癌活性(Kettle et al,J Med Chem,2016,59:2346-2361;Petrocchi et a1,BioorgMed Chem Lett,2016,26:1503-1507;Kawamura et al,Sci Rep,2016,6:26521;Ellermannet al,ACS Chem Biol,2017,12:1986-1992)或未公开生物活性数据(Streib et al,AngewChem Int Ed Engl,2014, 53:305-309;WO 2015/172747;WO 2016/128140A1;WO 2016/145383A1;WO 2016/135137; WO 2016/135138;WO 2016/135139;WO 2016/135140)。WO2014/033136根据一些生物学数据将氨基异芳基化合物作为MTH1抑制剂,这些化合物与本发明中的化合物没有结构相关性。嘧啶衍生物作为MTH1抑制剂的生物学数据在WO 2014/084778和WO 2015/187088中有涉及,但其中所有化合物均具有2,4-二氨基嘧啶结构,嘧啶环在第6位被(杂)芳基、乙炔基或非芳香环取代。
摘要
为了寻找最有效和最合适的化合物用于开发临床有效和有用的药物,仍然非常需要筛选更多或改进的MTH1抑制剂。
因此,本发明提供了新的嘧啶衍生物作为新型MTH1抑制剂,可用于癌症等疾病的治疗和预防。如下文所述,本发明的化合物不仅具有优越的MTH1抑制活性(其中一些IC50值在低纳摩尔范围内),而且对癌细胞具有显著的细胞毒性(部分IC50值在亚微摩尔范围内)。
本发明公开了通式I的化合物:
及其药学上可接受的盐或溶剂化合物,
其中:
R1代表烷基、环烷基或杂环烷基;
R2和R3各自独立地为氢、氧代、烷基、丙酮、芳香基、可被烷氧基和羟基选择性取代的杂萘,或可被一个或多个R4选择性取代的嘧啶;
R4选自烷基、卤素或NR5R6;
R5和R6各自代表氢、烷氧基、亚烃基、三烷胺、环烷基、可被一个或多个卤素选择性取代的芳香基、以及可被R7选择性取代的环烷基,或
R5、R6连同它们所连接的原子一起形成可被烷基或氨基选择性取代的杂环烷基;
R7代表呋喃、环烷基、杂环烷基,或芳香基,其中所述芳香基可被一个或多个卤素、甲基卤素、烷基、烷氧基、亚硝基和氰基选择性取代。
在某些实施例中,R1是甲基。
在某些实施例中,R2和R3均可以是氢或氧代。
根据某些实施例,R2是氢,R3是烷基、烷氧基、芳香基或被烷氧基和羟基取代的杂萘。
根据某些实施例,R2为氢,R3为可被1个或多个R4选择性取代的嘧啶。
根据某些实施例,R2为氢,R3为被两个R4取代的嘧啶,其中一个R4为氢或甲基,另一个R4为卤素。
根据某些实施例,R2为氢,R3为被两个R4取代的嘧啶,其中一个R4为氢或甲基,另一个R4为NR5R6。
根据某些实施例,R5为氢,R6为氢、烷氧基、环烷基、亚烃基、三烷胺、烷基或卤代芳香基。
根据某些实施例,R5为氢,R6为被R7取代的烷基。
根据某些实施例,R7是呋喃或被卤素、甲基卤素、烷基、烷氧基、亚硝基或氰基选择性取代的芳烃基。
根据某些实施例,R5和R6连同它们所附着的原子形成可被烷基或氨基选择性取代的杂环烷基环。
根据某些实施例,所述化合物选自:
4-(4-氨基苯基)-5-甲基嘧啶-2-胺;
4-(4-氨基苯基)嘧啶-2-胺;
4-(4-氨基苯基)-5-乙基嘧啶-2-胺;
5-乙基-4-(4-硝基苯基)嘧啶-2-胺;
5-甲基-4-(4-(甲氨基)苯基)嘧啶-2-胺;
N-(4-(2-氨基-5-甲基嘧啶-4-基)苯基)乙酰胺;
N-(4-( 2-氨基-5-甲基嘧啶-4-基)苯基)-6,7-二甲氧基喹唑啉-4-胺;
4-((4-(2-氨基-5-甲基嘧啶-4-基)苯基)氨基)-7-甲氧基喹唑啉-6-醇;
5-甲基-4-(4-(苯胺基)苯基)嘧啶-2-胺;
4-((4-(2-氯-5-甲基嘧啶-4-基)氨基)苯基)-5-甲基嘧啶-2-胺;
4-(4-((2-氯嘧啶-4-基)氨基)苯基)-5-甲基嘧啶-2-胺;
N4-(4-(2-氨基-5-甲基嘧啶-4-基)苯基)嘧啶-2,4-二胺;
N4-(4-(2-氨基-5-甲基嘧啶-4-基)苯基)-N2-(2-甲氧乙基)嘧啶-2,4-二胺;
N2-烯丙基-N4-(4-(2-氨基-5-甲基嘧啶-4-基)苯基)嘧啶-2,4-二胺;
N4-(4-(2-氨基-5-甲基嘧啶-4-基)苯基)-N2-(2-(二乙胺基)乙基)嘧啶-2,4-二胺;
N4-(4-(2-氨基-5-甲基嘧啶-4-基)苯基)-N2-(3-氯苯基)-5-甲基嘧啶-2,4-二胺;
N4-(4-(2-氨基-5-甲基嘧啶-4-基)苯基)-N2-(3-氯苯基)嘧啶-2,4-二胺;
N4-(4-(2-氨基-5-甲基嘧啶-4-基)苯基)-N2-甲基嘧啶-2,4-二胺;
N4-(4-(2-氨基-5-甲基嘧啶-4-基)苯基)-N2-异丙基-5-甲基嘧啶-2,4-二胺;
N4-(4-(2-氨基-5-甲基嘧啶-4-基)苯基)-N2-异丙基嘧啶-2,4-二胺;
N4-(4-(2-氨基-5-甲基嘧啶-4-基)苯基)-N2-异丁基-5-甲基嘧啶-2,4-二胺;
N4-(4-(2-氨基-5-甲基嘧啶-4-基)苯基)-N2-异丁基嘧啶-2,4-二胺;
N4-(4-(2-氨基-5-甲基嘧啶-4-基)苯基)-N2-环丙基-2,4-二胺;
N4-(4-(2-氨基-5-甲基嘧啶-4-基)苯基)-N2-环丙戊基嘧啶-2,4-二胺;
N4-(4-(2-氨基-5-甲基嘧啶-4-基)苯基)-N2-(呋喃-3-乙甲基)嘧啶-2,4-二胺;
N4-(4-(2-氨基-5-甲基嘧啶-4-基)苯基)-N2-苄基嘧啶-2,4-二胺;
N4-(4-(2-氨基-5-甲基嘧啶-4-基)苯基)-N2-(3-氟苄基)-5-甲基嘧啶-2,4-二胺;
N4-(4-(2-氨基-5-甲基嘧啶-4-基)苯基)-N2-(3-氟苄基)嘧啶-2,4-二胺;
N4-(4-(2-氨基-5-甲基嘧啶-4-基)苯基)-N2-(4-氟苄基)嘧啶-2,4-二胺;
N4-(4-(2-氨基-5-甲基嘧啶-4-基)苯基)-N2-(2-氟苄基)嘧啶-2,4-二胺;
N4-(4-(2-氨基-5-甲基嘧啶-4-基)苯基)-N2-(3-溴苄基)嘧啶-2,4-二胺;
N4-(4-(2-氨基-5-甲基嘧啶-4-基)苯基)-N2-(3-氯苄基)嘧啶-2,4-二胺;
N4-(4-(2-氨基-5-甲基嘧啶-4-基)苯基)-N2-(4-氯苄基)嘧啶-2,4-二胺;
N4-(4-(2-氨基-5-甲基嘧啶-4-基)苯基)-N2-(2-氯苄基)嘧啶-2,4-二胺;
N4-(4-(2-氨基-5-甲基嘧啶-4-基)苯基)-N2-(3-(三氟甲基)苄基)嘧啶-2,4-二胺;
N4-(4-(2-氨基-5-甲基嘧啶-4.基)苯基)-N2-(3.甲苄基)嘧啶-2,4-二胺;
N4-(4-(2-氨基-5-甲基嘧啶-4-基)苯基)-N2-(3-甲氧苄基)嘧啶-2,4-二胺;
N4-(4-(2-氨基-5-甲基嘧啶-4-基)苯基)-N2-(3-硝基苄基)嘧啶-2,4-二胺;
3-(((4-((4-(2-氨基-5-甲基嘧啶-4-基)苯基)氨基)嘧啶-2-基)氨基)甲基)苯腈;
5-甲基-4-(4-((5-甲基-2-(4-甲基哌嗪基-1-基)嘧啶-4-基)氨基)苯基)嘧啶-2-胺;
5-甲基-4-(4-((2-(4-甲基哌嗪基-1-基)嘧啶-4-基)氨基)苯基)嘧啶-2-胺;
5-甲基-4-(4-((5-甲基-2-吗啉基嘧啶-4-基)氨基)苯基)嘧啶-2-胺;
5-甲基-4-(4-((2-吗啉基嘧啶-4-基)氨基)苯基)嘧啶-2-胺;
4-(4-((2-(4-氨基哌啶-1-基)嘧啶-4-基)氨基)苯基)-5-甲基嘧啶-2-胺。
本发明提供了一种药物组合物,该药物组合物包括通式I的化合物和药学上可接受的载体、佐剂或媒介物。
本发明提供了具有通式I的化合物或其药学上可接受的盐或溶剂化合物用于制备药物。
本发明提供了一个通式I的化合物或其药学上可接受的盐或溶剂化合物用于癌症等疾病的治疗和预防。
本发明还提供了一种治疗MTH1介导的病症的方法,包括给受试者施用治疗有效量的通式I的化合物或其药学上可接受的盐或溶剂化合物。
在一些实施例中,受试者是人。
在一些实施例中,MTH1介导的病症是癌症。
在一些实施例中,癌症包括以下种类:肺癌、乳腺癌、前列腺癌、卵巢癌、膀胱癌、结肠癌、直肠癌、肾癌、胰腺癌、甲状腺癌、子宫内膜癌、白血病、黑色素瘤、脑瘤、宫颈癌、食道癌、尤因肉瘤、颅外生殖细胞肿瘤、肝外胆管癌、眼癌、输卵管癌、胆囊癌、胃癌、生殖细胞肿瘤、头部和颈部癌症、心脏肿瘤、肝细胞癌、肝癌、淋巴瘤、霍奇金淋巴瘤、非霍奇金淋巴瘤、胰岛细胞癌症、卡波西肉瘤、喉癌、嘴唇和口腔癌症、梅克尔细胞癌、间皮瘤、骨髓瘤、鼻腔和鼻窦癌、鼻咽癌、神经母细胞瘤、甲状旁腺癌、咽癌、垂体瘤、唾液腺癌、皮肤癌、睾丸癌、咽喉癌、胸腺瘤和胸腺上皮腺癌、子宫癌、阴道癌和外阴癌。更适用于治疗肺癌、乳腺癌、前列腺癌、卵巢癌、膀胱癌、结直肠癌、胰腺癌、白血病、黑色素瘤和神经母细胞瘤。
附图说明
图1显示用体外MTH1酶学测定法检测的MTH1酶活性被抑制的情况。所显示结果为用本发明的实施例38、41和43,以及两个阳性对照:TH588(Gad et al.,Nature,2014, 508:215-221)和(S)-crizotinib(Huber et al.,Nature,2014,508:222-227)测得的数据。实施例 38、41、43以及两种阳性对照TH588和(S)-crizotinib的IC50分别为4.238nM、2.410nM、1.952nM、33.54nM和258.4nM。本发明的所有实施例的IC50数值列于本发明的表1。
图2显示用MTT测定法检测的癌细胞存活被抑制的情况。(A)本发明的实施例17、28和39以及两种阳性对照TH588和(S)-crizotinib对人SW480结肠癌细胞的生长抑制情况。实施例17、28、39以及对照TH588和(S)-crizotinib的IC50分别为0.8058μM、2.335μM、2.110μM、8.769μM和5.183μM。本发明所有实施例的IC50数值列于发明的表1。(B)本发明的实施例28对各种人癌细胞系和正常细胞系的生长抑制情况。实施例28降低了人MG63 骨肉瘤、HepG2肝癌、SW480结肠癌、SW116结肠癌、MCF7乳腺癌、Hela宫颈癌和A549 肺癌细胞的存活率,而对正常人皮肤成纤维细胞HSF细胞的存活率影响较小。
图3显示用细胞温度敏感性迁移法(Cellular Thermal Shift Assay)检测得到的本发明实施例在细胞内与MTH1蛋白结合的结果。显示的数据为本发明实施例1、16、20、21、22 和28在细胞内与MTH1蛋白的结合。在未加入能与MTH1结合的化学物的对照组中,当温度升至57.1℃时,MTH1蛋白条带的强度显著降低,当温度升至61.5℃时,MTH1蛋白条带的信号完全消失;然而,当加入10μM本发明的实施例1、16、20、21、22或28时,当温度高达67.7℃时,MTH1蛋白条带仍可检测到。
发明内容详述
在描述本发明的实施例之前,应理解,提供这样的实施例是为了帮助本领域技术人员使用本发明。本文描述的公开内容不限于本文公开的具体实施例的范围,因为这些实施例仅作为实例提供,旨在说明本公开的若干方面。根据本发明的介绍,本领域技术人员可以衍生出各种修改,这些修改也属于本发明的范围。
通式I的化合物:
及其在药理学上可接受的盐或溶剂化合物。
其中:
R1代表烷基、环烷基或杂环烷基;
R2和R3均可以是氢、氧代、烷基、丙酮、芳香基、可被烷氧基和羟基选择性取代的杂萘,以及可被一个或多个R4选择性取代的嘧啶;
R4可以是烷基、卤素或NR5R6;
R5和R6代表氢、烷氧基、亚烃基、三烷胺、环烷基、可被一个或多个卤素取代的芳香基、以及可被R7选择性取代的环烷基,或
R5、R6连同它们所连接的原子一起形成可被烷基或氨基选择性取代的杂环烷基;
R7代表呋喃、环烷基、杂环烷基,或可被一个或多个卤素、甲基卤素、烷基、烷氧基、亚硝基和氰基选择性取代的芳香基。
在优选的实施例中,R1是甲基。
在某些实施例中,R2和R3均可以是氢或氧代。
根据某些实施例,R2是氢,R3是烷基、烷氧基、芳香基或被烷氧基和羟基取代的杂萘。
根据某些实施例,R2为氢,R3为可被1个或多个R4选择性取代的嘧啶。
根据某些实施例,R2为氢,R3为被两个R4取代的嘧啶,其中一个R4为氢或甲基,另一个R4为卤素。
根据某些实施例,R2为氢,R3为被两个R4取代的嘧啶,其中一个R4为氢或甲基,另一个R4为NR5R6。
根据某些实施例,R5为氢,R6为氢、烷氧基、环烷基、亚烃基、三烷胺、烷基或卤代芳香基。
根据某些实施例,R5为氢,R6为被R7取代的烷基。
根据某些实施例,R7是呋喃或被卤素、甲基卤素、烷基、烷氧基、亚硝基或氰基选择性取代的芳香基。
根据某些实施例,R5和R6连同它们所附着的原子形成可被烷基或氨基选择性取代的杂环烷基环。
同时提供的实施例还包括,上述任何实施例可以单独使用或与上述任何其他一个或多个实施例组合,只要该组合不是相互排斥的。
在特定实施例中,本发明的化合物选自本文公开的实施例1-44的化合物。
在一个实施例中,本发明提供一种药物组合物,该组合物包括一个通式I的化合物和一个在药学上可接受的载体、佐剂或媒介物。
在一个实施例中,本发明提供一个本发明的化合物或其药学上可接受的盐或溶剂化合物,用于疾病的治疗和预防,更优选用于癌症的治疗和预防。
在一个实施例中,本发明提供一个通式I的化合物或其在医学上可接受的盐或溶剂化合物,用于制备一种药物。
术语和定义
“药学上可接受的盐(Pharmaceutically acceptable salts)”,包括本发明化合物的酸加成盐和碱加成盐。此外,盐的溶剂化合物也包括在本发明的范围内。药学上可接受的盐包括那些通过本领域已知的方法将化合物与有机和无机酸或碱形成的盐。用无机碱制备的盐包括但不限于铝、铵、钙、铜、铁、亚铁、锂、镁、锰盐、锰、钾、钠、锌等。有机碱衍生的盐包括但不限于伯胺、仲胺、叔胺、乙二胺、2-二乙胺乙醇、2-二甲胺乙醇、N-乙基吗啉、N-乙基哌啶、还原葡糖胺、葡萄糖胺、组氨酸、羟基胺、异丙胺、甲基葡聚糖胺、吗啡、哌嗪、哌啶、多胺树脂、普鲁卡因、嘌呤、可可碱、三乙胺、三甲胺、三丙胺、氨丁三醇等形成的盐。合适的酸加成盐包括但不限于盐酸盐、氢溴酸盐、氢碘酸盐、硝酸盐、硫酸盐、硫酸氢盐、磷酸盐、乙酸盐、乳酸盐、水杨酸盐、柠檬酸盐、酒石酸盐、酒石酸氢盐、泛酸盐、抗坏血酸盐、琥珀酸盐、马来酸盐、富马酸盐、葡糖酸盐、葡糖酸(glucaronate)、糖酸钠、甲酸盐、苯甲酸盐和谷氨酸盐。
某些化合物或药物组合物本身可能不具有或仅具有最低的药理活性,但可在体内代谢形成具有药理活性的本发明的化合物。这些化合物或组合物可被描述为本发明化合物的“前药 (prodrugs)”。本发明化合物的所有前药均包含在本发明的范围内。
本发明的化合物可以以不同的立体异构体、几何异构体或互变异构体的形式存在。化合物通式I及其混合物的所有立体异构体、几何异构体和互变异构体都包含在本发明的化合物中。
本发明的化合物还包括其中一个或多个原子被同位素取代的化合物,因此,本发明的化合物的同位素标记包括在本发明的范围内。本发明中的同位素标记化合物包括氘化化合物,即其中一个或多个氢原子被氢的同位素氘取代。
本文所说的“选择性取代(optionally substituted)”,是指给定结构中的氢自由基可以被指定的取代基取代,也可以不被指定的取代基取代。除非另有说明,否则选择性被取代基团可以在基团的每个可取代位置上被取代,并且取代基可以是相同的,也可以是不同的。
“烷基(alkyl)”是指含有1至15个碳原子,最好是1至10个碳原子的直链或支链的烃基链。
“亚烷基(alkylene)”本身或作为另一取代基的一部分,是指由烷基衍生的二价基团。除非另有说明,“烷基”一词可包括“亚烷基”。
“环烷基(cycloalkyl)”是指单环或多环饱和碳环,最好是环戊基或环己基。
“杂环烷基(heterocycloalkyl)”是指含有至少一个杂原子作为环成员的饱和或不饱和的单环或多环杂基团,其中每个杂原子可以是O、S或N。
“烷氧基(alkoxy)”是指烷基-氧基团。烷氧基的首选例子是甲氧基或乙氧基。
“芳香基(aryl)”指仅含有碳原子的单环或多环环,其中至少有一个环是芳香族的。
“杂芳基(heteroaryl)”是指至少有一个环是芳香族的单环或多环环,并且其中至少一个芳香环包含O、S或N中的至少一个杂原子。
″氧代(oxo)″指氧。
“腈基(-CN)”是指通过碳原子连接的腈基。
“卤素(halo,halogen)”是指氟、氯、溴或碘。
″羟基(Hydroxy)″是指羟基(-OH)。
IC50是指将MTH1活性降低至最高水平的一半时抑制剂的浓度。在某些实施例中,化合物对于MTH1的IC50不超过100nM;在另一些实施例中,化合物对MTH1的IC50不超过 10nM;在其他的实施例中,化合物对MTH1的IC50不超过5nM。
药物组合
在某些实施例中,提供了一种药物组合物,该组合物包括一个本发明中的化合物以及其在药学上可接受的载体、佐剂或媒介物。载体必须是“可接受的”,其应与制剂的其他成分相容并且对接受者无害。
因此,本文提供了适合于所选给药途径的药物制剂。药物制剂被制备成方便的独立单位剂型,包括口服给药的片剂或胶囊、直肠给药的栓剂、肠外或肌内给药的无菌溶液或悬浮液等。或者,该制剂也被制备成可施用于皮肤的乳膏、凝胶或泡沫的形式,或可通过鼻腔施用的吸入剂。这些制剂可以按照制药领域中已知的标准和公认的工艺制备。
例如,对于口服给药的片剂或胶囊,活性成分可以与无毒的、药学上可接受的惰性赋形剂(如乙醇、甘油、水等)组合。将化合物粉碎至适当大小粉末并将其与药物赋形剂(如以类似方式粉碎的可食用碳水化合物)混合。也可能存在一定量的香料、防腐剂、分散剂和染料。适用于肠胃外给药的药物制剂含有包含抗氧化剂、缓冲剂、抑菌剂和溶质的水性及非水性无菌注射溶液,借助该溶液使制剂与受体的血液等渗。这些制剂可置于单剂量或多剂量容器中,例如密封的安瓿和小瓶,或以干燥(冻干)状态储存。
治疗方法
本发明还提供了在有此需要的受试者中治疗MTH1介导的病症的方法,包括给受试者施用治疗有效量的本发明的化合物或其药学上可接受的盐。
根据某些实施例,受试者是人。
根据某些实施例,MTH1介导的病症是癌症。
一方面,本发明涉及通过向患者施用治疗有效量的本发明化合物来治疗患者体内癌症的方法。治疗的癌症包括但不限于肺癌、乳腺癌、前列腺癌、卵巢癌、膀胱癌、结肠癌、直肠癌,肾癌、胰腺癌、甲状腺癌、子宫内膜癌、白血病、黑素瘤、脑瘤、宫颈癌、食道癌、尤文肉瘤、颅外生殖细胞瘤、肝外胆管癌、眼癌、输卵管癌、胆囊癌、胃癌、生殖细胞瘤、头颈癌、心癌症、肝细胞癌、肝癌、淋巴瘤、霍奇金淋巴瘤、非霍奇金淋巴瘤、胰岛细胞癌、卡波西肉瘤、喉癌,嘴唇和口腔癌症、梅克尔细胞癌、间皮瘤、骨髓瘤、鼻腔和鼻窦癌、鼻咽癌、神经母细胞瘤、甲状旁腺癌症、咽癌、垂体瘤、唾液腺癌、皮肤癌、睾丸癌、喉癌、胸腺瘤和胸腺上皮癌、子宫癌、阴道癌和外阴癌。优选地治疗癌症是肺癌、乳腺癌、前列腺癌、卵巢癌、膀胱癌、结直肠癌、胰腺癌、白血病、黑色素瘤和神经母细胞瘤。
另一方面,本发明涉及向患者施用包含一种或多种本发明化合物和一种或多种含有其他药物活性的化合物的组合来治疗患者体内癌症的方法。本发明的化合物和含有其他药物活性的化合物可以同时给药(以相同剂型或以不同剂型)或依次给药。一种或多种含有其他药物活性的化合物可选自以下几种:(1)烷化剂,包括但不限于顺铂(PLATIN)、卡铂(PARAPLATIN)、奥沙利铂(ELOXATIN)、链脲菌素(ZANOSAR)、白消安(MYLERAN)和环磷酰胺(ENDOXAN);(2)抗代谢物,包括但不限于巯基嘌呤(PURINETHOL)、硫鸟嘌呤、喷司他丁(NIPENT)、阿糖胞苷(ARA-C)、吉西他滨(GEMZAR)、氟尿嘧啶(CARAC)、甲酰四氢叶酸(FUSILEV)和甲氨蝶呤(RHEUMATREX);(3)植物生物碱和萜类化合物,包括但不限于长春新碱(ONCOVIN)、长春花碱和紫杉醇(TAXOL);(4)拓扑异构酶抑制剂,包括但不限于伊立替康(CAMPTOSAR)、拓扑替康(HYCAMTIN)和依托泊苷(EPOSIN);(5)细胞毒性抗生素,包括但不限于放线菌素D(COSMEGEN)、阿霉素(ADRIAMYCIN),博来霉素 (BLENOXANE)和丝裂霉素(MITOSOL);(6)血管生成抑制剂,包括但不限于舒尼替尼(SUTENT)和贝伐单抗(AVASTEST);(7)酪氨酸激酶抑制剂,包括但不限于伊马替尼 (GLEEVEC)、厄洛替尼(TARCEVA)、拉帕替尼(TYKERB)和阿西替尼(INLYTA);(8)吲哚胺 -2,3-双加氧酶抑制剂;(9)抗PD-1抗体、抗PD-L1抗体、抗CTLA4抗体;(10)抗增殖剂和细胞周期抑制剂;(11)组蛋白去乙酰化酶(HDAC)抑制剂;(12)Bcl-2抑制剂和Mcl-1抑制剂。
此外,本发明的化合物还有望作为目前手术、化疗、放疗、免疫治疗等抗癌治疗的增敏剂,其中免疫治疗包括使用单克隆抗体、过继细胞转移、细胞因子和疫苗的抗癌治疗。因此,在其中一个实施例中,本发明叙述了一种或多种本发明化合物与另一种抗癌治疗组合,用于同时、单独或依次给药。
实施例
本发明的各种化合物对MTH1活性的抑制、对各种癌细胞的细胞毒性和在细胞内与MTH1蛋白结合的能力通过以下实施例进行详细描述。
化合物的制备
为了进一步阐明本发明,下面给出一系列实施例,这些实施例完全是例证性的,它们仅用来对本发明进行描述,不应当理解为对本发明的限制。用于制备本发明化合物的起始原料既可以在市场上获得,也可以使用该领域已知的常规方法制备。
缩写词表:
aq 水的
CDCl3 氘代氯仿
DCM 二氯甲烷
DIPEA N,N-二异丙基乙胺(Hunigs base)
DMF 二甲基甲酰胺
DMSO 二甲基亚砜
DTT 二硫苏糖醇
EtAc 乙酸乙酯
EtOH 乙醇
ESI-MS 电喷雾电离质谱
h 小时
min 分钟
KOH 氢氧化钾
LC 液相色谱法
LCMS 液相色谱-电喷雾质谱法
TLC 薄层色谱法
MeOH 甲醇
MgSO4 硫酸镁
N2 氮气
Na2CO3 碳酸盐
NaHCO3 碳酸氢钠
Na2SO4 硫酸钠
NH3 氨
NH4Cl 氯化铵
NH4OH 氢氧化铵
NMR 核磁共振
Pd(PPh3)4 四(三苯基膦)钯(0)
TsOH 对甲基苯磺酸
中间化合物1
2-氯-5-甲基-4-(4-硝基苯)嘧啶
在N2存在的条件下,将四(三苯基膦)钯(0)(2.29g,1.98mmol)、乙酸钾(11.64g,118.8 mmol)和1-溴-4-硝基苯(8g,39.6mmol)分别加入到bis(pinacolato)diboron(12.065g,47.5mmol) 和1,4-二恶烷(70ml)的混合物中。将反应混合物在110℃下搅拌直至TLC(PE∶EA=10∶1)显示起始的1-溴-4-硝基苯被完全消耗。在室温条件下依次加入2,4-二氯-5-甲基嘧啶(9.623g, 59.4mmol)、Pd(PPh3)4(0.9g,0.78mmol,0.02eq)和饱和Na2CO3水溶液(40ml)。将混合物在110℃搅拌直至TLC(PE∶EA=5∶1)显示原料已完全耗尽。加入水(100ml)。用乙酸乙酯 (100ml×6)萃取混合物。将有机相用盐水(20mL)洗涤并用MgSO4干燥。将得到的粗产物用乙酸乙酯重结晶两次得到最终产物(7.3g,81%)。1H NMR(300MHz,CDCl3)δ8.60(d,J=0.7Hz, 1H),8.44-8.34(m,2H),7.89-7.79(m,2H),2.41(d,J=0.6Hz,3H).
中间化合物2
5-甲基-4-(4-硝基苯)嘧啶-2-胺
将中间化合物1(3.4g,13.6mmol,1.0eq)在饱和氨的甲醇溶液(40mL)中于110℃下搅拌12h,此时TLC(PE∶EA=1∶1)显示原料已完全耗尽。沉淀的物质经过滤后得到的产物(1.2g, 38.2%),无需纯化,可直接用于下一步。LCMS[M+H]+231.5.
中间化合物3
4-(4-氨基苯)-5-甲基嘧啶-2-胺
在MeOH/H2O(v∶v=2∶1)中,将NH4Cl(0.85g,15.6mmol,3eq)和Zn(2.7g,41.7mmol,8eq)分别加入到中间化合物2(1.2g,5.21mmol,1.0eq)的混合物中。反应混合物经过过滤、减压浓缩、层析纯化得到黄色固体产物(0.7g,67.3%)。LCMS[M+H]+201.5;1H NMR(300 MHz,CDCl3)δ8.38(s,1H),7.56(d,J=8.5Hz,2H),6.74(d,J=8.5Hz,2H),3.99(s,2H),2.41 (s,4H).
中间化合物4
4-(4-((2-氯嘧啶-4-基)氨基苯)-5-甲基嘧啶-2-胺
在EtOH(20mL)中,将DIPEA(1.35g,10.5mmol,3eq)和2,4-二氯嘧啶(52mg,3.5mmol, 1eq)分别加入到中间化合物3(0.7g,3.5mmol,1eq)溶液中。将混合物在80℃下搅拌17h。减压浓缩反应混合物,残余物用EtAc(20mL)萃取3次。用盐水(10mL)冲洗有机相并用Na2SO4干燥。浓缩最终物质并通过色谱法纯化,得到黄色固体产物(0.3g,27.4%)。LCMS[M+H] +313.4;1H NMR(300MHz,DMSO-d6)δ10.28(s,1H),8.29(d,J=5.9Hz,1H),8.22(d,J=0.7Hz,1H),7.79(d,J=8.7Hz,2H),7.71(d,J=8.7Hz,2H),6.90(d,J=5.9Hz,1H),6.46(s,2H), 2.24(d,J=0.6Hz,3H).
通用程序
以下通用程序可用于合成本发明中的多数化合物:
中间化合物4的混合物(3g,9.6mmol,1.0eq)以及在二恶烷中适量的胺(R-NH2)(1.9g, 14.4mmol,1.5eq)和TsOH(2.7g,14.4mmol,1.5eq)的混合物(20mL)于110℃下在密封管中搅拌直至TLC(DCM∶MeOH=10∶1)显示原料已完全耗尽。将反应混合物在10ml DCM中稀释,在2M aq NaOH和盐水中依次洗涤,用Na2SO4干燥。采用层析法对有机层进行浓缩纯化,得到产物。
实施例1
4-(4-氨基苯)-5-甲基嘧啶-2-胺
如中间化合物3所示。将NH4Cl(0.85g,15.6mmol,3eq)和Zn(2.7g,41.7mmol,8eq)分别加入到中间化合物2(1.2g,5.21mmol,1.0eq)和MeOH/H2O(30mL)的混合物(v∶v=2∶1)中。然后将混合物在80℃下搅拌3h,直至TLC(DCM∶MeOH=10∶1)显示原料已完全耗尽。过滤反应混合物,减压浓缩滤液,通过色谱法纯化残余物,得到黄色固体产物(0.7g,67.3%)。LCMS[M+H]+201.5;1H NMR(300MHz,CDCl3)δ8.38(s,1H),7.56(d,J=8.5Hz,2H),6.74 (d,J=8.5Hz,2H),3.99(s,2H),2.41(s,4H)。
实施例2
4-(4-氨基苯)嘧啶-2-胺
按照与本发明实施例1相同的步骤合成,只是在合成中间化合物1时用2,4-二氯嘧啶代替 2,4-二氯-5-甲基嘧啶。1H NMR(300MHz,DMSO)δ8.12(d,J=5.4Hz,1H),7.79(tt,J=2.7, 1.8Hz,2H),6.92(d,J=5.4Hz,1H),6.59(tt,J=2.7,1.8Hz,2H),6.47-6.28(brs,2H),5.63(brs, 2H).
实施例3
4-(4-氨基苯)-5-乙基嘧啶-2-胺
除合成中间化合物1时使用2,4-二氯-5-乙基嘧啶代替2,4-二氯-5-甲基嘧啶外,其余均与合成中间化合物1的合成步骤相同。1H NMR(300MHz,cdcl3)δ8.63(s,5H)、8.63(s,5H)、8.42- 8.35(m,11H),8.42-8.31(m,12H),7.80-7.70(m,11H),7.82-7.68(m,12H),7.27(s,1H), 2.79-2.70(m,12H),2.73(q,J=7.6Hz,14H),1.37(s,10H),1.40-1.29(m,15H),1.29-1.16 (m,21H),1.22(t,J=7.6Hz,19H),0.00(s,1H).
实施例4
5-乙基-4-(4-硝基苯基)嘧啶-2-胺
除合成中间化合物1时使用2,4-二氯-5-乙基嘧啶代替2,4-二氯-5-甲基嘧啶外,其余均与合成中间化合物2的合成步骤相同。1H NMR(300MHZ,cdcl3)δ8.39-8.24(m,1H),7.75-7.59(m, 1H),5.09(s,1H),2.53(q,J=7.5Hz,1H),1.10(t,J=7.5Hz,1H).
实施例5
5-甲基-4-(4-(甲氨基)苯基)嘧啶-2-胺
当TLC显示原料已完全耗尽时,在甲苯(3.5mL)中将中间化合物3(200mg,0.913mmol)、甲基碘(259.3mg,1.826mmol)和N,N-二异丙基乙胺(318μl,1.846mmol)的混合物于90℃在密封管中搅拌22h。将反应混合物冷却至室温,然后在15ml水中稀释,用二氯甲烷萃取(30 ml×14),色谱纯化,得到产物(132mg,62%)。1H NMR(300MHZ,cdcl3)δ8.11(s,0H),7.50 (d,J=8.6Hz,1H),6.65(d,J=8.6Hz,1H),5.00(s,1H),3.96(s,0H),2.89(s,1H),2.25(s, 1H).
实施例6
N-(4-(2-氨基-5-甲基嘧啶-4-基)苯基)乙酰胺
在15mL二氯甲烷中将中间化合物3(219mg,1mmol)和三乙胺(121mg,1.2mmol)混合。将混合物回流加热至40℃,并逐滴向反应混合物中加入乙酸酐直至TLC显示反应完成。以乙酸乙酯为萃取剂,Na2SO4为干燥剂,并通过色谱法纯化得到产物(132mg,61%)。1H NMR(300MHz,cdcl3)δ8.18(s,1H),7.59(dd,J=19.8,8.7Hz,3H),7.37(s,1H),5.04(s,1H),2.21 (s,4H),1.93(s,1H).
实施例7
N-(4-(2-氨基-5-甲基嘧啶-4-基)苯基)-6,7-二甲氧基喹唑啉-4-胺
在二恶烷(20mL)中将4-氯-6,7-二甲氧基喹唑啉(392mg,3.96mmol)、中间化合物3(1.064g,4.752mmol)和TsOH(2.7g,14.4mmol)的混合物搅拌4h。使用NaHCO3将pH调节至10,从有机层析出的固体物质为产物(1.37mg,79%)。1H NMR(300MHz,DMSO)δ9.63(s,1H),8.53(s,1H),8.16(s,1H),7.97(d,J=8.7Hz,2H),7.90(s,1H),7.67(d,J=8.7Hz,2H),7.23(s, 1H),3.99(s,3H),3.96(s,3H),2.20(s,3H).
实施例8
4-((4-(2-氨基-5-甲基嘧啶-4-基)苯基)氨基)-7-甲氧基喹唑啉-6-醇
在二恶烷(20mL)中将4-氯-6-甲氧基喹唑啉-7-醇(392mg,3.96mmol)、中间化合物3(1.064g, 4.752mmol)和TsOH(2.7g,14.4mmol)的混合物搅拌4h。使用NaHCO3将pH值调节至10,从有机层析出的固体物质为产物(43mg,13%)。1H NMR(300MHz,DMSO)δ9.71(s,1H),9.58(s,1H),8.51(s,1H),8.15(s,1H),8.01(d,J=8.7Hz,2H),7.87(s,1H),7.63(d,J=8.7Hz, 2H),7.23(s,1H),6.39(s,2H),3.99(s,3H),2.18(s,3H).
实施例9
5-甲基-4-(4-(苯胺基)苯基)嘧啶-2-胺
在N2中将中间化合物3(330mg,1.5mmol)与溴苯(2.25mmol)混合,当TLC显示反应完成后,将混合物置于油浴中24h,然后冷却至室温。用二氯甲烷(30ml×6)萃取产物并用Na2SO4干燥。最后用色谱法对产物进行纯化,得到终产物(210mg,47%)。1H NMR(300MHZ,DMSO) δ8.44(s,1H),8.09(s,1H),7.54(d,J=8.6Hz,2H),7.34-7.23(m,2H),7.13(t,J=8.9Hz,4H),6.89(t,J=7.3Hz,1H),6.30(s,2H),2.17(s,3H).
实施例10
4-(4-((2-氯-5-甲基嘧啶-4-基)氨基)苯基)-5-甲基嘧啶-2-胺
将2,4-二氯-5-甲基嘧啶(112mg,0.75mmoI)和三乙胺(0.104ml,0.75mmol)加入到含有中间化合物3(100mg,0.5mmol)的乙醇溶液中。将混合物在80℃下搅拌14h,然后蒸发干燥。加入50m1水,液相用DCM∶MeOH=10∶1(20ml×3)进行萃取。用盐水洗涤得到有机相,用Na2SO4干燥,通过色谱法纯化,得到所需产物。1H NMR(300MHz,DMSO)δ10.21(s,1H), 8.21(d,J=5.9Hz,1H),8.14(d,J=0.6Hz,1H),7.75-7.67(m,2H),7.67-7.60(m,2H),6.83 (d,J=5.9Hz,1H),6.39(s,2H),2.16(s,3H).
实施例11
4-(4-((2-氯嘧啶-4-基)氨基)苯基)-5-甲基嘧啶-2-胺
参见中间化合物4。将DIPEA(1.35g,10.5mmol,3eq)和2,4-二氯嘧啶(52mg,3.5mmol, 1eq)分别加入到含有中间化合物3(0.7g,3.5mmol,1eq)的乙醇溶液(20mL)中。将混合物在80℃下搅拌17h。减压浓缩反应混合物,残余物用EtAc(20mL)萃取三次。将有机相用盐水(10mL)洗涤并用Na2SO4干燥。浓缩最终物质并通过色谱法纯化,得到黄色固体终产物(0.3g,27.4%)。LCMS[M+H]+313.4;1H NMR(300MHz,DMSO-d6)δ10.28(s,1H),8.29(d, J=5.9Hz,1H),8.22(d,J=0.7Hz,1H),7.79(d,J=8.7Hz,2H),7.71(d,J=8.7Hz,2H),6.90(d,J=5.9Hz,1H),6.46(s,2H),2.24(d,J=0.6Hz,3H).
实施例12
N4-(4-(2-氨基-5-甲基嘧啶-4-基)苯基)嘧啶-2,4-二胺
在二恶烷(20mL)中将中间化合物4(3g,9.6mmol,1.0eq)、氨(1.9g,14.4mmol,1.5eq) 和TsOH(2.7g,14.4mmol,1.5eq)的混合物密封管中于110℃下搅拌直到TLC(DCM∶MeOH =10∶1)显示原料已完全耗尽。将反应混合物在10ml DCM中稀释,依次用2M NaOH水溶液和盐水洗涤,并用Na2SO4干燥。采用层析法对有机层进行浓缩纯化,得到产物。ESI-MS:394.2[M+H]+;m.p.269.1-271.1℃;1H NMR(300MHZ,DMSO-d6)δ9.31(s,1H),8.12(s,1H),7.84(dd,J=7.2,1.4Hz,3H),7.55(d,J=8.7Hz,2H),6.37(s,2H),6.29(s,2H),6.05(d,J=5.7 Hz,1H),2.16(s,3H).
实施例13
N4-(4-(2-氨基-5-甲基嘧啶-4-基)苯基)-N2-(2-甲氧乙基)嘧啶-2,4-二胺
在二恶烷中将2.甲氧基乙(Methoxyethan)-1-胺(1.9g,14.4mmol,1.5eq)加入到中间化合物4 (3g,9.6mmol,1.0eq)和TsOH(2.7g,14.4mmol,1.5eq)的混合物中(20mL)。将反应混合物于110℃下在密封管中搅拌直至TLC(DCM∶MeOH=10∶1)显示原料已完全耗尽。将反应混合物在10ml DCM中稀释,依次用2M NaOH水溶液和盐水洗涤,并用Na2SO4干燥。采用层析法对有机层进行浓缩纯化,得到产物。ESI-MS:352.1[M+H]+;m.p.134.6-139℃;1H NMR(300MHZ,DMSO-d6)δ9.37(s,1H),8.12(s,1H),7.88(d,J=5.7HZ,1H),7.85(d,J=8.4 Hz,2H),7.56(d,J=8.7Hz,2H),6.79(d,J=5.2Hz,1H),6.37(s,2H),6.05(d,J=5.7Hz,1H),3.533.40(m,J=8.2,4.7Hz,5H),3.27(s,3H),2.16(s,3H).
实施例14
N2-烯丙基-N4-(4-(2-氨基-5-甲基嘧啶-4-基)苯基)嘧啶-2,4-二胺
在二恶烷中将中间化合物4(3g,9.6mmol,1.0eq)、丙-2-烯-1-胺(1.9g,14.4mmol,1.5eq) 和TsOH(2.7g,14.4mmol,1.5eq)的混合物(将20mL)于110℃下在密封管中搅拌直至TLC (DCM∶MeOH=10∶1)显示原料已完全耗尽。将反应混合物在10ml DCM中稀释,依次用2MNaOH水溶液和盐水洗涤,并用Na2SO4干燥。采用层析法对有机层进行浓缩纯化,得到产物。ESI-MS:334.2[M+H]+;m.p.91.6-94.7℃;1H NMR(300MHz,DMSO-d6)δ9.31(s,1H),8.12(s,1H),7.84(dd,J=7.2,1.4Hz,3H),7.55(d,J=8.7Hz,2H),6.37(s,2H),6.29(s,2H), 6.05(d,J=5.7Hz,1H),2.16(s,3H).
实施例15
N4-(4-(2-氨基-5-甲基嘧啶-4-基)苯基)-N2-(2-(二乙胺基)乙基)嘧啶-2,4-二胺
在二恶烷(20mL)中将N1,N1-二乙基乙烷-1,2-二胺(1.9g,14.4mmol,1.5eq)加入到中间化合物4(3g,9.6mmol,1.0eq)和TsOH(2.7g,14.4mmol,1.5eq)的混合物中。将反应混合物于110℃的密封管中搅拌,直至TLC(DCM∶MeOH=10∶1)显示原料已完全耗尽。将反应混合物在10ml DCM中稀释,依次用2M NaOH水溶液和盐水洗涤,并用Na2SO4干燥。采用层析法对有机层进行浓缩纯化,得到产物。ESI-MS:393.1[M+H]+;m.p.80.0-82.1℃;1H NMR(300MHz,DMSO-d6)δ9.34(s,1H),8.11(s,1H),7.90-7.80(m,3H),7.54(d,J=8.7 Hz,2H),6.57(s,1H),6.34(s,2H),6.03(d,J=5.7Hz,1H),3.34(d,J=7.6Hz,3H),2.57-2.49 (m,7H)、0.98-0.92(m,J=9.9,4.3Hz,7H).
实施例16
N4-(4-(2-氨基-5-甲基嘧啶-4-基)苯基)-N2-(3-氯苯基)-5-甲基嘧啶-2,4-二胺
在二恶烷(5mL)中将3-氯苯胺(317mg,2.5mmol)加入到本发明实施例10(165mg,0.5mmol) 和TsOH(190mg,1mmol)的混合物中。将反应混合物于110℃的密封管中搅拌,直至TLC (DCM∶MeOH=10∶1)显示原料已完全耗尽。将反应混合物在10ml DCM中稀释,依次用2MNaOH水溶液和盐水洗涤,并用Na2SO4干燥。采用层析法对有机层进行浓缩纯化,得到产物。1HNMR(300MHz,DMSO)δ9.26(s,1H),8.48(s,1H),8.14(s,1H),7.98(d,J=0.7Hz,1H), 7.93(t,J=2.0Hz,1H),7.86(d,J=8.7Hz,2H),7.59(dd,J=10.7,4.9Hz,3H),7.19(t,J=8.1Hz,1H),6.89(d,J=1.3Hz,1H),6.35(s,2H),5.31(s,0H),2.19(s,3H),2.16(s,3H);ESI-MS: m/z 418.4[M+H]+.
实施例17
N4-(4-(2-氨基-5-甲基嘧啶-4-基)苯基)-N2-(3-氯苯基)嘧啶-2,4-二胺
在二恶烷(2mL)中将3-氯苯胺(45.5mg,0.35mmol,2eq)和TsOH(45mg,0.264mmol,1.5 eq)依次加入到中间化合物4(55mg,0.176mmol,1.0eq)的溶液中。将混合物于110℃下在密封管中搅拌12h。TLC(DCM∶MeOH=10∶1)显示原料耗尽并形成一个新的物质。减压浓缩反应混合物,然后通过色谱法纯化残余物,得到浅黄色固体最终产物(30mg,42.3%)。 LCMS[M+H]+404.4;1H NMR(300MHz,DMSO-d6)δ9.94(s,1H),9.67(s,1H),8.18(d,J= 0.8Hz,2H),8.09(d,J=6.0Hz,1H),8.05(s,2H),7.83(d,J=8.7Hz,3H),7.30(s,1H),6.94 (ddd,J=7.9,2.2,0.9Hz,1H),6.38(d,J=6.0Hz,3H),2.18(d,J=0.7Hz,3H).
实施例18
N4-(4-(2-氨基-5-甲基嘧啶-4-基)苯基)-N2-甲基嘧啶-2,4-二胺
在二恶烷(20mL)中将中间化合物4(3g,9.6mmol,1.0eq),甲胺(1.9g,14.4mmol,1.5eq) 和TsOH(2.7g,14.4mmol,1.5eq)的混合物于110℃下在密封管中搅拌直到TLC(DCM∶MeOH=10∶1)显示原料已完全耗尽。将反应混合物在10ml DCM中稀释,依次用2M NaOH 水溶液和盐水洗涤,并用Na2SO4干燥。采用层析法对有机层进行浓缩纯化,得到产物。 ESI-MS:308.1[M+H]+;m.p.240.1-242.1℃;1H NMR(300MHz,DMSO-d6)δ9.41(s,1H), 8.12(s,1H),7.93-7.81(m,3H),7.57(d,J=8.6Hz,2H),6.80(d,J=4.6Hz,1H),6.34(s,2H), 6.06(t,J=4.7Hz,1H),2.82(d,J=4.6Hz,3H),2.17(s,3H).
实施例19
N4-(4-(2-氨基-5-甲基嘧啶-4-基)苯基)-N2-异丙基-5-甲基嘧啶-2,4-二胺
在二恶烷(5mL)中将丙-2-胺(147mg,2.5mmol)加入到本发明实施例10(165mg,0.5mmol) 和TsOH(190mg,1mmol)的混合物中。将反应混合物于110℃下在密封管中搅拌直至TLC(DCM∶MeOH=10∶1)显示原料已完全耗尽。将反应混合物在10m1 DCM中稀释,依次用2MNaOH水溶液和盐水洗涤,并用Na2SO4干燥。采用层析法对有机层进行浓缩纯化,得到产物。1HNMR(300MHz,DMSO)δ8.16(s,1H),8.12(s,1H),7.94(d,J=8.7Hz,2H),7.75 (s,1H),7.56(d,J=8.7Hz,2H),6.35(s,2H),6.31(d,J=8.0Hz,1H),4.05-3.89(m,1H),2.17 (s,3H),2.06(s,3H),1.14(d,J=6.5Hz,7H);ESI-MS:m/z 364.3[M+H]+.
实施例20
N4-(4-(2-氨基-5-甲基嘧啶-4-基)苯基)-N2-异丙基嘧啶-2,4-二胺
将丙-2-胺(13mg,0.21mmol,1.5当量)和TsOH(37.2mg,0.21mmol,1.5当量)依次加入到中间体4(45mg,0.14mmol,1.0当量)的二恶烷(2mL)溶液中。将混合物在110℃下在密封管中搅拌12h。减压浓缩混合物,然后通过色谱法纯化残余物,得到产物(30mg,21.6%),为黄色固体。LCMS[M+H]+336.3;1H NMR(300MHz,DMSO-d6)δ9.69(s,1H),8.12(s, 1H),7.87(d,J=5.9Hz,2H),7.58(d,J=8.7Hz,2H),7.47(d,J=8.0Hz,1H),7.11(d,J= 7.8Hz,1H),6.35(s,2H),6.10(d,J=6.0Hz,1H),4.02(tt,J=12.9,6.2Hz,1H),2.16(s,3H), 1.17(s,6H).
实施例21
N4-(4-(2-氨基-5-甲基嘧啶-4-基)苯基)-N2-异丁基-5-甲基嘧啶-2,4-二胺
将2-甲基丙-1-胺(185mg,2.5mmol)加入到本发明实施例10(165mg,0.5mmol)和TsOH (190mg,1mmol)的二恶烷(5mL)混合物中。将反应混合物在110℃下在密封管中搅拌直至TLC(DCM∶MeOH=10∶1)显示原料完全耗尽。用10ml DCM稀释反应混合物,依次用2M NaOH水溶液和盐水洗涤,并用Na2SO4干燥。浓缩有机层并通过色谱法纯化,得到产物。1H NMR(300MHz,DMSO)δ8.17(s,1H),8.12(s,1H),7.96(d,J=8.7Hz,2H), 7.74(s,1H),7.55(d,J=8.7Hz,2H),6.65(s,1H),6.36(s,2H),3.04(t,J=6.5Hz,2H),2.17 (s,3H),2.06(s,3H),1.86(dp,J=13.4,6.8Hz,1H),0.88(d,J=6.7Hz,7H).ESI-MS:m/z 364.3[M+H]+.
实施例22
N4-(4-(2-氨基-5甲基嘧啶-4-基)苯基)-N2-异丁基嘧啶-2,4-二胺
将2-甲基丙-1-胺(14.3mg,0.192mmol,1.5当量)和TsOH(33mg,0.192mmol,1.5当量)依次加入到溶于二恶烷(2mL)的中间体4(40mg,0.13mmol,1.0当量)的溶液中。将混合物在110℃下在密封管中搅拌12h。减压浓缩混合物,然后通过色谱法纯化残余物,得到产物(30mg,21.6%),为黄色固体。LCMS[M+H]+350.4;1H NMR(300MHz,DMSO-d6) δ9.50(s,1H),8.11(s,1H),7.92-7.77(m,2H),7.55(d,J=8.3Hz,2H),7.10(s,2H),6.35(s, 2H),6.04(s,1H),3.09(t,J=6.5Hz,2H),2.16(s,3H),1.90(s,1H),0.91(d,J=6.6Hz,6H).
实施例23
N4-(4-(2-氨基-5-甲基嘧啶-4-基)苯基)-N2-环丙基嘧啶-2,4-二胺
将中间体4(3g,9.6mmol,1.0当量),环丙胺(1.9g,14.4mmol,1.5当量)和TsOH(2.7g, 14.4mmol,1.5当量)的混合物溶于二恶烷(20mL)中并在110℃下搅拌。在密封管中直到TLC (DCM∶MeOH=10∶1)显示起始材料完全消耗。用10ml DCM稀释反应混合物,依次用2M NaOH水溶液和盐水洗涤,并用Na2SO4干燥。浓缩有机层并通过色谱法纯化,得到产物。ESI-MS:334.2[M+H]+;m.p.171.2-173.1℃;1H NMR(300MHz,DMSO-d6)δ9.37(s,1H), 8.11(d,J=0.6Hz,1H),7.95(d,J=8.5Hz,2H),7.90(d,J=5.7Hz,1H),7.56(d,J=8.8Hz, 2H),7.03(s,1H),6.33(s,2H),6.08(d,J=5.7Hz,1H),2.75-2.62(m,1H),2.16(s,3H), 0.73-0.65(m,2H),0.55-0.44(m,2H).
实施例24
N4-(4-(2-氨基-5-甲基嘧啶-4-基)苯基)-N2-环丙基嘧啶-2,4-二胺
将中间体4(3g,9.6mmol,1.0当量),环戊胺(1.9g,14.4mmol,1.5当量)和TsOH(2.7g, 14.4mmol,1.5当量)的混合物溶于二恶烷(20mL)中并在110℃下搅拌。在密封管中直到TLC (DCM∶MeOH=10∶1)显示起始材料完全消耗。用10ml DCM稀释反应混合物,依次用2M NaOH水溶液和盐水洗涤,并用Na2SO4干燥。浓缩有机层并通过色谱法纯化,得到产物。ESI-MS:362.2[M+H]+;m.p.104-108℃;1H NMR(300MHz,DMSO-d6)δ9.39-9.26(m,1H),8.11(d,J=0.6Hz,1H),7.93-7.81(m,3H),7.55(d,J=8.7Hz,2H),6.85-6.73(m, 1H),6.35(s,2H),6.02(d,J=5.7Hz,1H),4.25-4.09(m,1H),2.16(s,3H),1.90(s,2H), 1.79-1.65(m,2H),1.58-1.47(m,4H).
实施例25
N4-(4-(2-氨基-5-甲基嘧啶-4-基)苯基)-N2-(呋喃-3-基甲基)嘧啶-2,4-二胺
将呋喃-3-基甲胺(1.9g,14.4mmol,1.5当量)加入溶于二恶烷(20mL)中的中间体4(3g, 9.6mmol,1.0当量)和TsOH(2.7g,14.4mmol,1.5当量)混合物。将反应混合物在110℃下在密封管中搅拌直至TLC(DCM∶MeOH=10∶1)显示原料完全耗尽。用10ml DCM稀释反应混合物,依次用2M NaOH水溶液和盐水洗涤,并用Na2SO4干燥。浓缩有机层并通过色谱法纯化,得到产物。ESI-MS:374.1[M+H]+;m.p.104.2-106.5℃;1H NMR(300 MHz,DMSO-d6)δ9.38(s,1H),8.11(s,1H),7.90(d,J=5.7Hz,1H),7.82(d,J=7.8Hz, 2H),7.56(dd,J=7.5,5.2Hz,4H),7.17(s,1H),6.48(d,J=1.0Hz,1H),6.37(s,2H),6.06(d, J=5.7Hz,1H),4.32(d,J=6.0Hz,2H),2.17(d,J=8.1Hz,3H).
实施例26
N4-(4-(2-氨基-5-甲基嘧啶-4-基)苯基)-N2-苄基嘧啶-2,4-二胺
将中间体4(3g,9.6mmol,1.0当量),苯基甲胺(1.9g,14.4mmol,1.5当量)和TsOH(2.7 g,14.4mmol,1.5当量)的混合物溶于二恶烷(20mL)中,在110℃下搅拌。在密封管中直到TLC(DCM∶MeOH=10∶1)显示起始材料完全消耗。用10ml DCM稀释反应混合物,依次用2MNaOH水溶液和盐水洗涤,并用Na2SO4干燥。浓缩有机层并通过色谱法纯化,得到产物。浓缩有机层并通过色谱法纯化,得到产物。ESI-MS:384.2[M+H]+; m.p.110.9-112.0℃;1H NMR(300MHz,DMSO-d6)δ9.36(s,1H),8.12(s,1H),7.89(s,1H), 7.85-7.59(m,2H),7.59-7.42(m,1H),7.42-7.07(m,5H),6.38(s,2H),6.05(s,1H),4.50 (s,2H),2.15(s,3H).
实施例27
N4-(4-(2-氨基-5-甲基嘧啶-4-基)苯基)-N2-(3-氟苄基)-5-甲基嘧啶-2,4-二胺
将(3-氟苯基)甲胺(312mg,2.5mmol)加入到本发明实施例10(165mg,0.5mmol)和TsOH (190mg,1mmol)的二恶烷(5mL)混合物中。将反应混合物在110℃下在密封管中搅拌直至TLC(DCM∶MeOH=10∶1)显示原料完全耗尽。用10ml DCM稀释反应混合物,依次用2M NaOH水溶液和盐水洗涤,并用Na2SO4干燥。浓缩有机层并通过色谱法纯化,得到产物。1H NMR(300MHz,DMSO)δ8.20(s,1H),8.12(d,J=0.5Hz,1H),7.77(d,J= 0.6Hz,3H),7.47(d,J=8.5Hz,2H),7.33(td,J=7.9,6.2Hz,1H),7.22(s,1H),7.14(d,J= 7.7Hz,1H),7.08(d,J=10.4Hz,1H),7.05-6.96(m,1H),6.35(s,2H),4.45(d,J=6.2Hz, 2H),2.16(s,3H),2.06(s,3H).ESI-MS:m/z416.3[M+H]+.
实施例28
N4-(4-(2-氨基-5-甲基嘧啶-4-基)苯基)-N2-(3-氟苄基)嘧啶-2,4-二胺
将(3-氟苯基)甲胺(20mg,0.16mmol,1当量)和TsOH(41mg,0.23mmol,1.5当量)分别加入到中间体4(50mg,0.16mmol,1.0当量)的二恶烷溶液中(2mL)。将混合物在 110二下在密封管中搅拌12h。TLC(DCM∶MeOH=10∶1)显示起始材料完全消耗并形成一个新斑点。减压浓缩反应混合物,然后通过色谱法纯化残余物,得到最终产物(38 mg,59%),为黄色固体。LCMS[M+H]+402.3;1H NMR(300MHz,DMSO-d6)δ9.36(s, 1H),8.11(d,J=0.7Hz,1H),7.89(d,J=5.6Hz,1H),7.68(s,2H),7.56-7.41(m,3H),7.34 (dd,J=7.9,6.1Hz,1H),7.22-7.08(m,2H),7.02(d,J=1.5Hz,1H),6.34(s,2H),6.06(d,J =5.7Hz,1H),4.50(d,J=6.2Hz,2H),2.15(d,J=0.7Hz,3H).
实施例29
N4-(4-(2-氨基-5-甲基嘧啶-4-基)苯基)-N2-(4-氟苄基)嘧啶-2,4-二胺
将(4-氟苯基)甲胺(20mg,0.16mmol,1当量)和TsOH(41mg,0.23mmol,1.5当量)分别加入到中间体4(50mg,0.16mmol,1.0当量)的二恶烷溶液中(2mL)。将混合物在110℃下在密封管中搅拌12h。TLC(DCM:MeOH=10:1)显示起始材料完全消耗并形成一个新斑点。减压浓缩反应混合物,然后通过色谱法纯化残余物,得到最终产物(38mg, 59%),为黄色固体。ESI-MS:402.1[M+H]+;m.p.109.0-110.0℃;1H NMR(300MHz, DMSO-d6)δ8.17(s,1H),7.97(d,J=5.8Hz,1H),7.54-7.49(m,2H),7.41(d,J=8.5Hz, 2H),7.32(dd,J=8.4,5.4Hz,2H),7.06-6.96(m,3H),6.09(d,J=5.8Hz,1H),5.58(s,1H), 5.12(s,2H),4.59(d,J=6.0Hz,2H),2.21(s,4H).
实施例30
N4-(4-(2-氨基-5-甲基嘧啶-4-基)苯基)-N2-(2-氟苄基)嘧啶-2,4-二胺
将(2-氟苯基)甲胺(20mg,0.16mmol,1当量)和TsOH(41mg,0.23mmol,1.5当量)分别加入到中间体4(50mg,0.16mmol,1.0当量)的二恶烷溶液中(2mL)。将混合物在110℃下在密封管中搅拌12h。TLC(DCM∶MeOH=10∶1)显示起始材料完全消耗并形成一个新斑点。减压浓缩反应混合物,然后通过色谱法纯化残余物,得到最终产物(38mg, 59%),为黄色固体。ESI-MS:402.1[M+H]+;m.p.105.0-107.0℃;1H NMR(300MHz, DMSO-d6)δ9.37(s,1H),8.11(s,1H),7.90(d,J=5.7Hz,1H),7.86-7.82(m,0H),7.67(s, 2H),7.53-7.32(m,4H),7.32-7.04(m,3H),6.35(s,2H),6.07(d,J=5.7Hz,1H),4.55(d, J=6.0Hz,2H),2.15(s,3H).
实施例31
N4-(4-(2-氨基-5-甲基嘧啶-4-基)苯基)-N2-(3-溴苄基)嘧啶-2,4-二胺
将(3-溴苯基)甲胺(20mg,0.16mmol,1当量)和TsOH(41mg,0.23mmol,1.5当量)分别加入到中间体4(50mg,0.16mmol,1.0当量)的二恶烷溶液中(2mL)。将混合物在110℃下在密封管中搅拌12h。TLC(DCM∶MeOH=10∶1)显示起始材料完全消耗并形成一个新斑点。减压浓缩反应混合物,然后通过色谱法纯化残余物,得到最终产物(38mg, 59%),为黄色固体。ESI-MS:462.1[M+H]+;m.p.134.0-136.0℃;1H NMR(300MHz, DMSO-d6)δ9.37(s,1H),8.11(s,1H),7.89(d,J=5.7Hz,1H),7.66(s,2H),7.58-7.42(m, 5H),7.42-7.32(m,2H),7.27(t,J=7.7Hz,1H),6.34(s,2H),6.06(d,J=5.7Hz,1H), 4.48(d,J=6.2Hz,2H),2.16(s,3H)
实施例32
N4-(4-(2-氨基-5-甲基嘧啶-4-基)苯基)-N2-(3-氯苄基)嘧啶-2,4-二胺
将(3-氯苯基)甲胺(20mg,0.16mmol,1当量)和TsOH(41mg,0.23mmol,1.5当量)分别加入到中间体4(50mg,0.16mmol,1.0当量)的二恶烷溶液中(2mL)。将混合物在110℃下在密封管中搅拌12h。TLC(DCM∶MeOH=10∶1)显示起始材料完全消耗并形成一个新斑点。减压浓缩反应混合物,然后通过色谱法纯化残余物,得到最终产物(38mg, 59%),为黄色固体。ESI-MS:418.2[M+H]+;m.p.120.9-123.6℃;1H NMR(300MHz, DMSO-d6)δ9.37(s,1H),8.11(s,1H),7.89(d,J=5.6Hz,1H),7.65(s,2H),7.50(s,3H), 7.41-7.22(m,4H),6.34(s,2H),6.06(d,J=5.5Hz,1H),4.49(d,J=6.2Hz,2H),2.16(s, 3H).
实施例33
N4-(4-(2-氨基-5-甲基嘧啶-4-基)苯基)-N2-(4-氯苄基)嘧啶-2,4-二胺
将(4-氯苯基)甲胺(20mg,0.16mmol,1当量)和TsOH(41mg,0.23mmol,1.5当量)分别加入到中间体4(50mg,0.16mmol,1.0当量)的二恶烷溶液中(2mL)。将混合物在110℃下在密封管中搅拌12h。TLC(DCM∶MeOH=10∶1)显示起始材料完全消耗并形成一个新斑点。减压浓缩反应混合物,然后通过色谱法纯化残余物,得到最终产物(38mg, 59%),为黄色固体。ESI-MS:418.2[M+H]+;m.p.120.9-123.6℃;1H NMR(300MHz, DMSO-d6)δ9.36(s,1H),8.11(s,1H),7.98-7.85(m,1H),7.84-7.58(m,2H),7.58-7.43 (m,3H),7.36(s,4H),6.34(s,2H),6.05(s,1H),4.48(s,2H),2.15(s,3H).
实施例34
N4-(4-(2-氨基-5-甲基嘧啶-4-基)苯基)-N2-(2-氯苄基)嘧啶-2,4-二胺
将(2-氯苯基)甲胺(20mg,0.16mmol,1当量)和TsOH(41mg,0.23mmol,1.5当量)分别加入到中间体4(50mg,0.16mmol,1.0当量)的二恶烷溶液中(2mL)。将混合物在110℃下在密封管中搅拌12h。TLC(DCM:MeOH=10:1)显示起始材料完全消耗并形成一个新斑点。减压浓缩反应混合物,然后通过色谱法纯化残余物,得到最终产物(38mg, 59%),为黄色固体。ESI-MS:418.2[M+H]+;m.p.110.9-113.3℃;1H NMR(300MHz, DMSO-d6)δ9.38(s,1H),8.10(d,J=6.3Hz,1H),7.90(d,J=5.6Hz,1H),7.46(d,J=7.5 Hz,4H),7.38-7.30(m,2H),7.30-7.20(m,2H),6.35(s,2H),6.07(d,J=5.7Hz,1H),4.55 (d,J=6.1Hz,2H),2.14(s,3H).
实施例35
N4-(4-(2-氨基-5-甲基嘧啶-4-基)苯基)-N2-(3-(三氟甲基)苄基)嘧啶-2,4-二胺
将(3-(三氟甲基)苯基)甲胺(20mg,0.16mmol,1当量)和TsOH(41mg,0.23mmol,1.5当量)分别加入到中间体4(50mg,0.16mmol,1.0当量)的二恶烷(2mL)溶液中。将混合物在110℃下在密封管中搅拌12h。TLC(DCM∶MeOH=10∶1)显示起始材料完全消耗并形成一个新斑点。减压浓缩反应混合物,然后通过色谱法纯化残余物,得到最终产物(38mg,59%),为黄色固体。ESI-MS:452.1[M+H]+;m.p.148.5-150.7℃;1H NMR(300 MHz,DMSO-d6)δ9.40(s,1H),8.12(s,1H),7.90(d,J=5.6Hz,1H),7.79-7.64(m,J= 13.3Hz,3H),7.62-7.44(m,J=23.2Hz,5H),6.36(s,2H),6.07(d,J=5.3Hz,1H),4.57(d, J=6.0Hz,2H),2.14(s,3H).
实施例36
N4-(4-(2-氨基-5-甲基嘧啶-4-基)苯基)-N2-(3-甲基苄基)嘧啶-2,4-二胺
将间-甲苯基胺(20mg,0.16mmol,1当量)和TsOH(41mg,0.23mmol,1.5当量)分别加入到中间体4(50mg,0.16mmol,1.0当量)的二恶烷(2mL)溶液中。将混合物在110℃下在密封管中搅拌12h。TLC(DCM∶MeOH=10∶1)显示起始材料完全消耗并形成一个新斑点。减压浓缩反应混合物,然后通过色谱法纯化残余物,得到最终产物(38mg, 59%),为黄色固体。ESI-MS:398.3[M+H]+;m.p.115.0-118.0℃;1H NMR(300MHz, DMSO-d6)δ9.43-9.27(m,1H),8.11(s,1H),7.88(d,J=5.6Hz,1H),7.73(s,2H),7.58- 7.34(m,3H),7.26-7.07(m,3H),7.01(d,J=7.1Hz,1H),6.35(s,2H),6.04(d,J=5.5Hz, 1H),4.46(d,J=6.1Hz,2H),2.26(s,3H),2.16(s,3H).
实施例37
N4-(4-(2-氨基-5-甲基嘧啶-4-基)苯基)-N2-(3-甲氧基苄基)嘧啶-2,4-二胺
将(3-甲氧基苯基)甲胺(20mg,0.16mmol,1当量)和TsOH(41mg,0.23mmol,1.5当量)分别加入到中间体4(50mg,0.16mmol,1.0当量)的二恶烷(2mL)溶液中。将混合物在110℃下在密封管中搅拌12h。TLC(DCM∶MeOH=10∶1)显示起始材料完全消耗并形成一个新斑点。减压浓缩反应混合物,然后通过色谱法纯化残余物,得到最终产物 (38mg,59%),为黄色固体。ESI-MS:414.2[M+H]+;m.p.113.6-136.0℃;1H NMR(300 MHz,DMSO-d6)δ9.36(s,1H),8.12(s,1H),7.89(d,J=5.5Hz,1H),7.84-7.60(m,2H), 7.59-7.37(m,3H),7.22(t,J=7.7Hz,1H),7.02-6.86(m,2H),6.77(d,J=7.7Hz,1H), 6.36(s,2H),6.05(d,J=5.2Hz,1H),4.46(d,J=5.6Hz,2H),3.35(s,4H),2.16(s,3H).
实施例38
N4-(4-(2-氨基-5-甲基嘧啶-4-基)苯基)-N2-(3-硝基苄基)嘧啶-2,4-二胺
将(3-硝基苯基)甲胺(20mg,0.16mmol,1当量)和TsOH(41mg,0.23mmol,1.5当量)分别加入到中间体4(50mg,0.16mmol,1.0当量)的二恶烷溶液中(2mL)。将混合物在 110℃下在密封管中搅拌12h。TLC(DCM∶MeOH=10∶1)显示起始材料完全消耗并形成一个新斑点。减压浓缩反应混合物,然后通过色谱法纯化残余物,得到最终产物(38 mg,59%),为黄色固体。ESI-MS:429.1[M+H]+;m.p.129.3-133.7℃;1H NMR(300MHz, DMSO-d6)δ9.38(s,1H),8.21(s,1H),8.12(s,1H),8.11-8.04(m,1H),7.90(d,J=5.7Hz, 1H),7.81(d,J=7.7Hz,1H),7.62(t,J=7.9Hz,4H),7.48(s,2H),6.34(s,2H),6.08(d,J= 5.7Hz,1H),4.61(d,J=6.2Hz,2H),2.14(s,3H)。
实施例39
3-(((4-((4-(2-氨基-5-甲基嘧啶-4-基)苯基)氨基)嘧啶-2-基)氨基)甲基)苯甲腈
将3-(氨基甲基)苄腈(1.9g,14.4mmol,1.5当量)加入到溶于二恶烷(20mL)中的中间体 4(3g,9.6mmol,1.0当量)和TsOH(2.7g,14.4mmol,1.5当量)的混合物中。将混合物在110℃下在密封管中搅拌12h。减压浓缩反应混合物,然后用饱和NaHCO3溶液将残余物调节至pH 8.0。将混合物用DCM(30mL)萃取三次。将有机相用盐水(15mL) 洗涤,用Na2SO4干燥,浓缩并通过色谱法纯化,得到最终产物(0.5g,12.5%),为黄色固体。LCMS[M+H]+409.49;1HNMR(300MHz,DMSO-d6)δ10.27(s,1H),8.15-8.12(m, 1H),7.92(d,J=6.4Hz,1H),7.79(d,J=1.7Hz,1H),7.76-7.61(m,4H),7.60-7.41(m, 4H),6.38(s,2H),6.25(d,J=6.4Hz,1H),4.59(d,J=6.1Hz,2H),2.15(s,3H).
实施例40
5-甲基-4-(4-((5-甲基-2-(4-甲基哌嗪-1-基)嘧啶-4-基)氨基)苯基)嘧啶-2-胺
将1-甲基哌嗪(250mg,2.5mmol)加入到本发明实施例10(165mg,0.5mmol)和TsOH(190mg,1mmol)的二恶烷(5mL)混合物中。将反应混合物在110℃下在密封管中搅拌直至TLC(DCM∶MeOH=10∶1)显示原料完全耗尽。将反应混合物在10ml DCM中稀释,依次用2M NaOH水溶液和盐水洗涤,并用Na2SO4干燥。浓缩有机层并通过色谱法纯化,得到产物。1H NMR(300MHz,DMSO)δ8.33(s,1H),8.12(d,J=0.6Hz,1H),7.85 (d,J=0.8Hz,1H),7.82(s,1H),7.80(d,J=1.9Hz,1H),7.60(s,1H),7.57(d,J=1.8Hz, 1H),6.35(s,2H),3.63(s,4H),2.36(d,J=4.7Hz,4H),2.20(s,3H),2.17(s,3H),2.09(s, 3H).ESI-MS:m/z 391.1[M+H]+.
实施例41
5-甲基-4-(4-((2-(4-甲基哌嗪-1-基)嘧啶-4-基)氨基)苯基)嘧啶-2-胺
将1-甲基哌嗪(250mg,2.5mmol)加入到中间体4(165mg,0.5mmol)和TsOH(190mg,1mmol)的二恶烷(5mL)混合物中。将反应混合物在110℃下在密封管中搅拌直至TLC (DCM∶MeOH=10∶1)显示原料完全耗尽。将反应混合物在10ml DCM中稀释,依次用2M NaOH水溶液和盐水洗涤,并用Na2SO4干燥。浓缩有机层并通过色谱法纯化,得到产物。1H NMR(300MHz,DMSO)δ10.99(s,1H),9.71(s,1H),8.13(s,1H),8.02(d,J =5.7Hz,1H),7.74(d,J=8.7Hz,2H),7.61(d,J=8.7Hz,2H),6.36(s,2H),6.24(d,J=5.7 Hz,1H),3.34(dt,J=45.4,22.6Hz,8H),2.76(s,3H),2.17(s,3H).ESI-MS:m/z 377.1 [M+H]+.
实施例42
5-甲基-4-(4-((5-甲基-2-吗啉嘧啶-4-基)氨基)苯基)嘧啶-2-胺
将吗啉(217mg,2.5mmol)加入到本发明实施例10(163mg,0.5mmol)和TsOH(190mg,1mmol)的二恶烷(5mL)混合物中。将反应混合物在110℃下在密封管中搅拌直至TLC (DCM∶MeOH=10∶1)显示原料完全耗尽。将反应混合物在10ml DCM中稀释,依次用2M NaOH水溶液和盐水洗涤,并用Na2SO4干燥。浓缩有机层并通过色谱法纯化,得到产物。1H NMR(300MHz,DMSO)δ8.36(s,1H),8.12(d,J=0.6Hz,1H),7.87(d,J= 0.8Hz,1H),7.84-7.78(m,2H),7.63-7.56(m,2H),6.35(s,2H),5.76(s,0H),3.72-3.52 (m,9H),2.17(d,J=0.4Hz,3H),2.10(d,J=0.6Hz,3H)..ESI-MS:m/z 378.3[M+H]+.
实施例43
5-甲基-4-(4-((2-吗啉嘧啶-4-基)氨基)苯基)嘧啶-2-胺
将吗啉(83.7mg,0.96mmol)加入到中间体4(165mg,0.5mmol)和TsOH(190mg,1mmol) 的二恶烷(5mL)混合物中。将反应混合物在110℃下在密封管中搅拌直至TLC(DCM∶MeOH=10∶1)显示原料完全耗尽。将反应混合物在10ml DCM中稀释,依次用2M NaOH水溶液和盐水洗涤,并用Na2SO4干燥。浓缩有机层并通过色谱法纯化,得到产物。1H NMR(300MHz,DMSO)δ9.49(s,1H),8.12(s,1H),7.99(d,J=5.7Hz,1H),7.75(s, 1H),7.72(s,1H),7.61(s,1H),7.58(s,1H),6.36(s,2H),6.13(d,J=5.7Hz,1H),3.67(s, 8H),2.17(s,3H).ESI-MS:m/z 364.2[M+H]+.
实施例44
4-(4-((-2-(4-氨基哌啶-1-基)嘧啶-4-基)氨基)苯基)-5-甲基嘧啶-2-胺
中间体4(3g,9.6mmol,1.0当量),哌啶-4-胺(1.9g,14.4mmol,1.5当量)和TsOH(2.7 g,14.4mmol,1.5当量)溶于二恶烷(20mL)中,将所得物在110℃下在密封管中搅拌直至TLC(DCM:MeOH=10:1)显示原料完全耗尽。ESI-MS:377.1[M+H]+;m.p. 108.2-110.5℃;1HNMR(300MHz,DMSO-d6)δ9.40(s,1H),8.12(s,1H),7.95(d,J=5.6 Hz,1H),7.73(d,J=8.8Hz,2H),7.59(d,J=8.7Hz,2H),6.35(s,2H),6.05(d,J=5.6Hz, 1H),4.47(d,J=13.1Hz,2H),2.97(t,J=11.0Hz,2H),2.80(s,1H),2.17(s,3H),1.74(d,J =10.0Hz,2H),1.64(s,2H),1.16(d,J=10.6Hz,2H).
生物学实例
生物学实例1
MTH1酶学实验和IC50值测定
MTH1可以水解脱氧鸟嘌呤三磷酸以产生脱氧鸟苷一磷酸和焦磷酸。在过量无机焦磷酸酶的存在下,所有焦磷酸盐都转化为无机磷酸盐,其可以使用基于孔雀石绿的吸光度测定法定量,从而可以测定MTH1活性。
在由100mM Tris-乙酸盐(pH 8.0),40mM氯化钠,10mM乙酸镁,0.005%吐温20 和1mM DTT组成的测定缓冲液中制备待测化合物的系列稀释液。接下来,向系统缓冲液中加入0.5nM重组人MTH1(ab99390,Abcam,Cambridge,UK),100μM dGTP(R0106, Thermo FisherScientific,Waltham,MA,USA)和0.2U/mL无机焦磷酸酶(EF0221,Thermo FisherScientific),并将板在板振荡器上在室温下孵育1h。在96孔板中最终反应体积为 100μL。在反应结束时,加入孔雀石绿,并将孔板在室温条件下再温育15分钟。通过酶标仪测量630nm处的吸光度。使用GraphPad Prism软件通过非线性回归分析确定半数最大抑制浓度(IC50)值。
本发明实施例的IC50值示于本发明的图1和表1中。图1显示了本发明实施例38,41和43的数据,以及两个阳性对照:TH588(来源于Gad et al.,Nature,2014,508:215-221 的一个代表性MTH1抑制剂)和(S)-crizotinib(来源于Huber et al.,Nature,2014,508:222-227的一个代表性MTH1抑制剂)。TH588和(S)-crizotinib都被认为是具有显着抗癌活性的MTH1抑制剂。本发明测到的TH588和(S)-crizotinib对MTH1的IC50分别为33.54 nM和258.4nM,而本发明的许多化合物具有低于5nm的IC50。该测定的结果表明,本发明化合物具有更优越的MTH1抑制活性。
生物学实例2
细胞活力测定(MTT测定法)和IC50值测定
本发明的化合物的抗癌活性,即对各种类型癌细胞的细胞毒性,通过若干方法进行了研究和测定,如下面的MTT法所示。
在治疗前一天,将待测的癌细胞以每孔1×104个细胞的密度接种在96孔板中,然后用不同浓度的所示化合物处理24h或48h。除去培养基,用PBS洗涤细胞,然后用 20μL 3-(4,5-二甲基噻唑-2-基)-2,5-二苯基溴化四唑(MTT)溶液(5mg/mL在PBS中, pH 7.2)(M6494,Thermo Fisher Scientific)加入每个孔中。将孔板在37℃下再孵育4h。最后,除去MTT溶液并向每个孔中加入150μL DMSO。将平板在平板振荡器上孵育10 min,并通过酶标仪测量570nm处的吸光度。每个实验三组平行进行两次。使用GraphPad Prism软件分析数据。使用非线性回归分析确定IC50值。
图2显示了在用本发明化合物和两个阳性对照(TH588和(S)-crizotini)处理后各种癌细胞(MG63骨肉瘤,HepG2肝细胞癌,SW480结肠癌,SW116结肠癌,MCF7乳腺癌,Hela宫颈癌,A549肺癌细胞系)的生长抑制的代表性结果。本发明化合物降低了人类癌细胞的存活率,而正常细胞如HSF人皮肤成纤维细胞的存活受到的影响较小。实施例17,28,39和两种对照TH588和(S)-crizotinib的IC50分别为0.8058μM,2.335μM, 2.110μM,8.769μM和5.183μM。本发明的所有实施例的IC50清单列于本发明的表1中,一些IC50在低或亚微摩尔范围内(实施例17,20,22,24,25,28,30,31,32,33,34,35,36, 37,38和39)。该测定的结果表明,本发明的化合物在人癌细胞中具有突出的和选择性的细胞毒性。
生物学实例3
细胞温度敏感性迁移法(Cellular thermal shift assay)
将MCF-7乳腺癌细胞接种到T225培养瓶中。24h后,将细胞用含1%DMSO的细胞培养基或10μM本发明化合物处理3-5h。使用胰蛋白酶收获细胞,离心并随后重悬于TBS中。将细胞悬浮液均等分配到12个PCR管中并在42,44.5,47.9,52.1,57.1, 61.5,64.8,67.7或69.2℃加热3min。通过在干冰上的乙醇反复冻融三次,循环冻融裂解细胞。以17,000xg转速离心20min将沉淀的蛋白质与可溶性组份分离。将上清液保持在-80℃直至Western印迹分析。将试样等分后的五分之一加到4-25%SDS-PAGE凝胶上,印迹在硝酸纤维素膜上,并使用来自Novus Biologicals的MTH1抗体以1∶500的浓度分析MTH1含量。
图3显示了本发明的一些实施例的代表性结果。在没有加入能与MTH1结合的化合物的对照中,当温度升至57.1℃时,MTH1蛋白的强度显着下降,当温度升至61.5℃时, MTH1蛋白的强度完全消失;当加入本发明实施例的10μM化合物时,MTH1蛋白仍可检测到高达67.7℃。该实验的结果表明,本发明的化合物可以增加MTH1的细胞热稳定性,证明了这些化合物在细胞内与MTH1蛋白的结合。
表1.本发明实施例的名称,化学结构和代表性IC50值
如上述代表性生物学实施例所示,本发明的化合物能够进入癌细胞,在细胞内与MTH1蛋白结合,并且抑制细胞内MTH1酶活性,抑制活性的IC50低于100nM,或甚至低于5nM,更重要的是,本发明的化合物降低了各种癌细胞系的细胞存活率(实施例17,20,22,24,25,28,30,31,32,33,34,35,36,37,38和39抑制癌细胞的IC50均低于10 μM),而对正常细胞的影响较小。因此,很明显,本发明的化合物具有优异的MTH1抑制活性以及对癌细胞选择性细胞毒性。
Claims (7)
1.化合物选自:
4-(4-氨基苯基)-5-乙基嘧啶-2-胺;
5-乙基-4-(4-硝基苯基)嘧啶-2-胺;
5-甲基-4-(4-(甲氨基)苯基)嘧啶-2-胺;
N-(4-(2-氨基-5-甲基嘧啶-4-基)苯基)乙酰胺;
N-(4-( 2-氨基-5-甲基嘧啶-4-基)苯基)-6,7-二甲氧基喹唑啉-4-胺;
4-((4-(2-氨基-5-甲基嘧啶-4-基)苯基)氨基)-7-甲氧基喹唑啉-6-醇;
5-甲基-4-(4-(苯胺基)苯基)嘧啶-2-胺;
4-((4-(2-氯-5-甲基嘧啶-4-基)氨基)苯基)-5-甲基嘧啶-2-胺;
4-(4-((2-氯嘧啶-4-基)氨基)苯基)-5-甲基嘧啶-2-胺;
N4-(4-(2-氨基-5-甲基嘧啶-4-基)苯基)嘧啶-2,4-二胺;
N4-(4-(2-氨基-5-甲基嘧啶-4-基)苯基)-N2-(2-甲氧乙基)嘧啶-2,4-二胺;
N2-烯丙基- N4-(4-(2-氨基-5-甲基嘧啶-4-基)苯基)嘧啶-2,4-二胺;
N4-(4-(2-氨基-5-甲基嘧啶-4-基)苯基)-N2-(2-(二乙胺基)乙基)嘧啶-2,4-二胺;
N4-(4-(2-氨基-5-甲基嘧啶-4-基)苯基)-N2-(3-氯苯基)-5-甲基嘧啶-2,4-二胺;
N4-(4-(2-氨基-5-甲基嘧啶-4-基)苯基)-N2-(3-氯苯基)嘧啶-2,4-二胺;
N4-(4-(2-氨基-5-甲基嘧啶-4-基)苯基)-N2-甲基嘧啶-2,4-二胺;
N4-(4-(2-氨基-5-甲基嘧啶-4-基)苯基)-N2-异丙基-5-甲基嘧啶-2,4-二胺;
N4-(4-(2-氨基-5-甲基嘧啶-4-基)苯基)-N2-异丙基嘧啶-2,4-二胺;
N4-(4-(2-氨基-5-甲基嘧啶-4-基)苯基)-N2-异丁基-5-甲基嘧啶-2,4-二胺;
N4-(4-(2-氨基-5-甲基嘧啶-4-基)苯基)-N2-异丁基嘧啶-2,4-二胺;
N4-(4-(2-氨基-5-甲基嘧啶-4-基)苯基)-N2-环丙基-2,4-二胺;
N4-(4-(2-氨基-5-甲基嘧啶-4-基)苯基)-N2-环丙戊基嘧啶-2,4-二胺;
N4-(4-(2-氨基-5-甲基嘧啶-4-基)苯基)-N2-(呋喃-3-乙甲基) 嘧啶-2,4-二胺;
N4-(4-(2-氨基-5-甲基嘧啶-4-基)苯基)-N2-苄基嘧啶-2,4-二胺;
N4-(4-(2-氨基-5-甲基嘧啶-4-基)苯基)-N2-(3-氟苄基)-5-甲基嘧啶-2,4-二胺;
N4-(4-(2-氨基-5-甲基嘧啶-4-基)苯基)-N2-(3-氟苄基)嘧啶-2,4-二胺;
N4-(4-(2-氨基-5-甲基嘧啶-4-基)苯基)-N2-(4-氟苄基)嘧啶-2,4-二胺;
N4-(4-(2-氨基-5-甲基嘧啶-4-基)苯基)-N2-(2-氟苄基)嘧啶-2,4-二胺;
N4-(4-(2-氨基-5-甲基嘧啶-4-基)苯基)-N2-(3-溴苄基)嘧啶-2,4-二胺;
N4-(4-(2-氨基-5-甲基嘧啶-4-基)苯基)-N2-(3-氯苄基)嘧啶-2,4-二胺;
N4-(4-(2-氨基-5-甲基嘧啶-4-基)苯基)-N2-(4-氯苄基)嘧啶-2,4-二胺;
N4-(4-(2-氨基-5-甲基嘧啶-4-基)苯基)-N2-(2-氯苄基)嘧啶-2,4-二胺;
N4-(4-(2-氨基-5-甲基嘧啶-4-基)苯基)-N2-(3-(三氟甲基)苄基)嘧啶-2,4-二胺;
N4-(4-(2-氨基-5-甲基嘧啶-4-基)苯基)-N2-(3-甲苄基)嘧啶-2,4-二胺;
N4-(4-(2-氨基-5-甲基嘧啶-4-基)苯基)-N2-(3-甲氧苄基)嘧啶-2,4-二胺;
N4-(4-(2-氨基-5-甲基嘧啶-4-基)苯基)-N2-(3-硝基苄基)嘧啶-2,4-二胺;
3-(((4-((4-(2-氨基-5-甲基嘧啶-4-基)苯基)氨基)嘧啶-2-基)氨基)甲基)苯腈;
5-甲基-4-(4-((5-甲基-2-(4-甲基哌嗪基-1-基)嘧啶-4-基)氨基)苯基)嘧啶-2-胺;
5-甲基-4-(4-((2-(4-甲基哌嗪基-1-基)嘧啶-4-基)氨基)苯基)嘧啶-2-胺;
5-甲基-4-(4-((5-甲基-2-吗啉基嘧啶-4-基)氨基)苯基)嘧啶-2-胺;
5-甲基-4-(4-((2-吗啉基嘧啶-4-基)氨基)苯基)嘧啶-2-胺;
4-(4-((2-(4-氨基哌啶-1-基)嘧啶-4-基)氨基)苯基)-5-甲基嘧啶-2-胺。
2.一种药物组合物,其中包含权利要求1所述的化合物和药学上可接受的载体、佐剂或媒介物。
3.权利要求1所述的化合物或其药学上可接受的盐在制备用于给有需要的受试者治疗MTH1介导的病症的药物上的用途。
4.根据权利要求3所述的用途,其中所述受试者是人。
5.根据权利要求3所述的用途,其中所述MTH1介导的病症是癌症。
6.根据权利要求5所述的用途,其中所述癌症选自:肺癌,乳腺癌,前列腺癌,卵巢癌,膀胱癌,结肠癌,直肠癌,肾癌,胰腺癌,甲状腺癌,子宫内膜癌,白血病,黑色素瘤,脑瘤,宫颈癌,食道癌,尤文肉瘤,颅外生殖细胞肿瘤,肝外胆管癌,眼癌,输卵管癌,胆囊癌,胃癌,生殖细胞肿瘤,头颈癌,心脏癌,肝细胞癌,肝癌,淋巴瘤,霍奇金淋巴瘤,非霍奇金淋巴瘤,胰岛细胞癌,卡波西肉瘤,喉癌,唇癌和口腔癌,Merkel细胞癌,间皮瘤,骨髓瘤,鼻腔和鼻窦癌,鼻咽癌,神经母细胞瘤,甲状旁腺癌,咽癌,垂体瘤,唾液腺癌,皮肤癌,睾丸癌,咽喉癌,胸腺瘤和胸腺癌,子宫癌,阴道癌和外阴癌。
7.权利要求1所述的化合物或其药学上可接受的盐在制备用于抗癌疗法中的增敏剂的用途。
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