CN112939966A - 嘧啶衍生物、其制备及应用 - Google Patents
嘧啶衍生物、其制备及应用 Download PDFInfo
- Publication number
- CN112939966A CN112939966A CN201911262106.8A CN201911262106A CN112939966A CN 112939966 A CN112939966 A CN 112939966A CN 201911262106 A CN201911262106 A CN 201911262106A CN 112939966 A CN112939966 A CN 112939966A
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- China
- Prior art keywords
- cyclopropyl
- pyrimidin
- methylmorpholino
- methyl
- imino
- 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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- 229940083082 pyrimidine derivative acting on arteriolar smooth muscle Drugs 0.000 title description 2
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- 125000003118 aryl group Chemical group 0.000 claims description 21
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- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 17
- 201000011510 cancer Diseases 0.000 claims description 15
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 15
- 125000002373 5 membered heterocyclic group Chemical group 0.000 claims description 14
- 125000004070 6 membered heterocyclic group Chemical group 0.000 claims description 14
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- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 1
- WLJNZVDCPSBLRP-UHFFFAOYSA-N pamoic acid Chemical compound C1=CC=C2C(CC=3C4=CC=CC=C4C=C(C=3O)C(=O)O)=C(O)C(C(O)=O)=CC2=C1 WLJNZVDCPSBLRP-UHFFFAOYSA-N 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 229920003175 pectinic acid Polymers 0.000 description 1
- 150000004968 peroxymonosulfuric acids Chemical class 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- OXNIZHLAWKMVMX-UHFFFAOYSA-N picric acid Chemical compound OC1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-N 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 1
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 1
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
- 235000019394 potassium persulphate Nutrition 0.000 description 1
- WSHYKIAQCMIPTB-UHFFFAOYSA-M potassium;2-oxo-3-(3-oxo-1-phenylbutyl)chromen-4-olate Chemical compound [K+].[O-]C=1C2=CC=CC=C2OC(=O)C=1C(CC(=O)C)C1=CC=CC=C1 WSHYKIAQCMIPTB-UHFFFAOYSA-M 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 230000002062 proliferating effect Effects 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 238000004537 pulping Methods 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 229940107700 pyruvic acid Drugs 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- BOLDJAUMGUJJKM-LSDHHAIUSA-N renifolin D Natural products CC(=C)[C@@H]1Cc2c(O)c(O)ccc2[C@H]1CC(=O)c3ccc(O)cc3O BOLDJAUMGUJJKM-LSDHHAIUSA-N 0.000 description 1
- 230000008439 repair process Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- SYBXSZMNKDOUCA-UHFFFAOYSA-J rhodium(2+);tetraacetate Chemical compound [Rh+2].[Rh+2].CC([O-])=O.CC([O-])=O.CC([O-])=O.CC([O-])=O SYBXSZMNKDOUCA-UHFFFAOYSA-J 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000013207 serial dilution Methods 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- 229910001961 silver nitrate Inorganic materials 0.000 description 1
- AWUCVROLDVIAJX-GSVOUGTGSA-N sn-glycerol 3-phosphate Chemical compound OC[C@@H](O)COP(O)(O)=O AWUCVROLDVIAJX-GSVOUGTGSA-N 0.000 description 1
- RMBAVIFYHOYIFM-UHFFFAOYSA-M sodium methanethiolate Chemical compound [Na+].[S-]C RMBAVIFYHOYIFM-UHFFFAOYSA-M 0.000 description 1
- VGTPCRGMBIAPIM-UHFFFAOYSA-M sodium thiocyanate Chemical compound [Na+].[S-]C#N VGTPCRGMBIAPIM-UHFFFAOYSA-M 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 239000012089 stop solution Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
- 125000005555 sulfoximide group Chemical group 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000004853 tetrahydropyridinyl group Chemical group N1(CCCC=C1)* 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
- 230000005748 tumor development Effects 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 230000001875 tumorinhibitory effect Effects 0.000 description 1
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- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
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Abstract
本发明公开了可用作ATR蛋白激酶抑制剂的通式(I)化合物、其异构体、或药学上可接受的盐。本发明的化合物、其异构体、或药学上可接受的盐能够用于制备治疗和/或预防过度增殖性疾病的药物。
Description
技术领域
本发明涉及一种新型化合物,具体而言,涉及新型ATR抑制剂嘧啶衍生物、其制备及应用。
背景技术
DNA修复是癌症生物学研究的核心内容,对癌症的诊断和治疗具有重要意义。癌细胞通常缺乏正常的DNA修复功能,而这种功能的缺失使得肿瘤的发展具有基因组不稳定性(Lengauer C,Kinzler KW,Vogelstein B.Genetic instabilities in humancancers.Nature.1998;396:643-649)。
事实上,DNA修复只是被称为DNA损伤应答(DDR)的一系列细胞反应中的一类。DDR包括细胞周期检查点的激活、细胞凋亡的激活和DNA损伤耐受的激活。最后一种机制允许细胞“接受”DNA损伤并继续DNA复制,即使在高突变频率的情况下也是如此。因此,DDR是一系列高度协调的信号事件。这些应答需要一个DNA损伤传感器(如传感器激酶、毛细血管扩展性共济失调突变蛋白ATM或共济失调毛细血管扩张突变基因Rad3相关激酶ATR)和效应激酶,以及用于DNA修复、凋亡或检查点活动的下游蛋白机器(Kastan MB,Bartek J.Cell-cycle checkpoints and cancer.Nature.2004;432:316-323)。
在面对潜在的致命形式的DNA损伤时,ATM和ATR作为DDR中的“顶端传感器”一起工作,以维持基因组的稳定性和细胞的存活。然而受损的ATM信号是肿瘤细胞的一个共同特征,这使得肿瘤细胞更依赖ATR来介导DDR,并且ATM功能健康的组织可以耐受ATR抑制。因此ATR是维持肿瘤基因组的稳定性和细胞存活的关键信号通路,并且肿瘤细胞的存活与正常健康细胞的存活相比,更依赖它们切断的DNA修复机制(Anika MW,Anderson JR.ATM andATR as therapeutic targets in cancer.Pharmacology&Therapeutics.2015,149:124-138)。
一旦激活,ATR通过其下游目标促进DNA修复,稳定和重新启动停滞的复制叉和短暂的细胞周期停止(Chen,J.Ataxia telangiectasia-related protein is involved inthe phosphorylation of BRCA1 following deoxyr ibonucleic acid damage.CancerRes 2000,60:5037-5039)。许多这些功能是通过ATR下游的CHK1调节的。并且在正常细胞周期S期和DNA损伤应答过程中,ATR在S期检验位点执行起着重要作用。它通过介导CHK1对Cdc25A的降解来抑制复制起始点的激活,从而延缓DNA复制的进程,为解决应激源提供时间(et.al.Chk1 regulates the S phase checkpoint by coupling thephysiological turnover and ionizing radiation-induced accelerated proteolysisof Cdc25A.Cancer Cell.2003,3:247-258.)。ATR也是G2/M细胞周期检查点的主要介质,以防止细胞在DNA复制完成或存在DNA损伤前过早进入有丝分裂。这种依赖ATR的G2/Mcell周期阻滞主要通过两种机制介导:①Cdc25A的降解(Zhao et.al.Disruption of thecheckpoint kinase 1/cell division cycle 25A pathway abrogates ionizingradiation-induced S and G2 checkpoints.Proc Natl Acad Sci U S A 2002,99:14795-14800);②Cdc25C磷酸酶通过CHK1在丝氨酸216位点的自磷酸化,为14-3-3蛋白建立一个结合位点(Peng et.Al.Mitotic and G2 checkpoint control:Regulation of 14-3-3protein binding by phosphorylation of Cdc25C on serine-216.Science 1997.277:1501–1505)。
几项研究表明,功能ATR的缺失增加了癌细胞对致癌基因诱导的复制应激的敏感性,从而阻碍了肿瘤的生长和诱导细胞的广泛死亡(Gilad et.al.Combining ATRsuppression with oncogenic Ras synergistically increases genomic instability,causing synthetic lethality or tumorigenesis in a dosage dependentmanner.Cancer Res 70,9693–9702;Murga et.al.Exploiting oncogene-inducedreplicative stress for the selective killing of Myc-driven tumors.Nat StructMol Biol 2011,18:1331-1335;Schoppy et.al.Oncogenic stress sensitizesmurinecancers to hypomorphic suppression of ATR.J Clin Invest.2012.122:241-252)。另外的研究利用激酶死亡表达的原理证明研究ATR蛋白已经证明ATR功能的丧失会导致DNA损伤引起的G2/M细胞周期阻滞和细胞对IR和多种DNA损伤化疗药物的敏感(Clibyet.al.Overexpression of a kinase-inactive ATR protein causes sensitivity toDNA-damaging agents and defects in cell cycle checkpoints.EMBO J.1998.17:159-169;Caporali et.al.DNA damage induced by temozolomide signals to both ATM andATR:Role of the mismatch repair system.Mol Pharmacol.2004.66:478-491)。
综上所述,ATR对于肿瘤的DNA损失修复是必不可少的,并且抑制ATR可增加肿瘤细胞对毒性药物或放疗更加敏感。因此,作为单一药物制剂或作为联合放疗或化疗,尤其是DNA损伤化疗联用制剂用于治疗肿瘤,ATR抑制剂是一种更强效和选择性的治疗方法。
已知的ATR抑制剂有WO2011154737公开的如下通式所示的吗啉代嘧啶化合物。
其中,结构式为
发明内容
本发明要解决的问题是提供一种新的ATR抑制剂化合物,发明人惊奇地发现,本发明的通式(I)所示化合物、其异构体或其药学上可接受的盐具有抑制ATR的活性,而且在ATR抑制活性上比WO2011154737公开的化合物AZD6738出乎意料地优异,预期将会成为新的肿瘤抑制化合物。
本发明提供式(I)所示的化合物、其异构体、前药或其药学上可接受的盐,
其中,
其中T1,T2分别独立选自C(Ra)和N;
Ra,Rb,Rc,Rd分别独立选自H,卤素,-OH,-NH2,-COOH,-CF3,-OCH3,C1-C4链烷基,C1-C4烷氧基,C3-C6环烷烃,芳香基,杂环芳香基,其中每个C1-C4链烷基,C1-C4烷氧基,C3-C6环烷烃,芳香基,杂环芳香基可以选择性彼此独立地被任选的下列基团取代一次或者多次:卤素,-OH,-NH2,-CONH2,-COOH,-CN,-OCH3;
其中Re,Rf分别独立选自-CONH2,-CN,-CF3,-S(O)2Rw,C2-C6链烷基,C1-C6烷氧基,C3-C6环烷基,C1-C6杂环烷基,芳香基,杂芳香基,其中每个C2-C6链烷基,C1-C6烷氧基,C3-C6环烷基,C1-C6杂环烷基,芳香基,杂芳香基可以选择性彼此独立地被任选的下列基团取代一次或者多次:卤素、-OH、-CN,-NH2,-CF3,-CH3,-OCH3;
或者,Re,Rf分别一起代表4-、5-、6-或7-元杂环基团,其中4-、5-、6-、或7-元杂环基团可以选择性彼此独立地被任选的下列基团取代一次或者多次:卤素、-OH、-CN,-NH2,-CF3,-OCH3;
Rg,Rh分别独立选自-CONH2,-CN,-CF3,C1-C6链烷基,C1-C6烷氧基,C3-C6环烷基,C1-C6杂环烷基,芳香基,杂芳香基,其中每个C1-C6链烷基,C1-C6烷氧基,C3-C6环烷基,C1-C6杂环烷基,芳香基,杂芳香基可以选择性彼此独立地被任选的下列基团取代一次或者多次:卤素、-OH、-CN,-NH2,-CF3,-CH3,-OCH3;
或者,Rg,Rh分别一起代表4-、5-、6-或7-元杂环基团,其中4-、5-、6-、或7-元杂环基团可以选择性彼此独立地被任选的下列基团取代一次或者多次:卤素、-OH、-CN,-NH2,-CF3,-OCH3;
R3,R4分别独立选自H,卤素,-CN,C1-C4链烷基,C1-C4烷氧基,C3-C6环烷烃,芳香基,C3-C6杂环烷烃;其中每个C1-C4链烷基,C1-C4烷氧基,C3-C6环烷烃,芳香基,C3-C6杂环烷烃可以选择性彼此独立地被任选的下列基团取代一次或者多次:卤素、-OH、-CN,-NH2,-CF3,-CH3,-OCH3;
或者R3,R4分别一起代表4-、5-、6-或7-元环基团,其中4-、5-、6-、或7-元环基团可以选择性彼此独立地被任选的下列基团取代一次或者多次:卤素、-OH、-CN,-NH2,-CF3,-OCH3;
其中Rw选自-CH3,-Et,环丙基;
其中*表示所述基团与分子剩余部分的连接点。
优选地,上述通式(1)的化合物中,R1选自其中Rb,Rc,Rd分别独立选自-H,-卤素,-CN,-OCH3,-OCH2CH3,-NH2,-CH3,-CH2F,-CHF2,-CF3,-Et,-CH2OH,
优选地,上述通式(1)的化合物中,R2选自其中Rh,Rg分别独立地选自卤素,-CN,C1-C6链烷基,C3-C6环烷基,C1-C6烷氧基,C1-C6杂环烷基,芳香基,杂环芳香基,其中每个C1-C6链烷基,C3-C6环烷基,C1-C6烷氧基,C1-C6杂环烷基,芳香基,杂环芳香基可以选择性彼此独立地被任选的下列基团取代一次或者多次:卤素,-OH,-NH2,-CONH2,-COOH,-CN,C1-C4链烷基,C1-C4卤代烷基,C1-C4烷氧基,C3-C6环烷基。
优选地,上述通式(1)的化合物中,R2选自其中Rh和Rg与硫原子一起代表4-、5-、6-或7-元杂环基团,所述4-、5-、6-或7-元杂环基团可以选择性彼此独立地被任选的下列基团取代一次或者多次:卤素,-CN,-OH,-NH2,-CONH2,-OMe,C1-C4链烷基,C1-C4卤代烷基,C3-C6环烷基。
优选地,上述通式(1)的化合物为:
N-((R)-甲基(1-(6-((R)-3-甲基吗啉代)-2-(1H-吡咯并[2,3-b]吡啶-4-基)嘧啶-4-基)环丙基)(氧代)-6-亚磺酰基)氰胺、
N-((R)-甲基(1-(6-((R)-3-甲基吗啉代)-2-(1H-吡咯并[2,3-b]吡啶-4-基)嘧啶-4-基)环丙基)(氧代)-6-亚磺酰基)甲磺酰胺、
N-((R)-甲基(1-(6-((R)-3-甲基吗啉代)-2-(1H-吡咯并[2,3-b]吡啶-4-基)嘧啶-4-基)环丙基)(氧代)-6-亚磺酰基)环丙烷磺酰胺、
1-((R)-甲基(1-(6-((R)-3-甲基吗啉代)-2-(1H-吡咯并[2,3-b]吡啶-4-基)嘧啶-4-基)环丙基)(氧代)-6-亚磺酰基)脲、
N-((R)-甲基(1-(6-((R)-3-甲基吗啉代)-2-(1H-吡咯并[2,3-b]吡啶-4-基)嘧啶-4-基)环丙基)(氧代)-6-亚磺酰基氧杂环丁烷-3-磺酰胺、
1-(1-(6-((R)-3-甲基吗啉代)-2-(1H-吡咯并[2,3-b]吡啶-4-基)嘧啶-4-基)环丙基)-4,5-二氢-3H-异噻唑1-氧化物、
(R)-(1-(2-(2-氨基吡啶-4-基)-6-((R)-3-甲基吗啉代)嘧啶-4-基)环丙基)(亚氨基)(甲基)-6-砜、
2-((((R)-甲基(1-(6-((R)-3-甲基吗啉代))-2-(1H-吡咯并[2,3-b]吡啶-4-基)嘧啶-4-基))环丙基)(氧代)-6-亚磺酰基)氨基)乙腈、
(R)二甲基((1-(6-(3-甲基吗啉代)-2-(1H-吡咯并[2,3-b]吡啶-4-基)嘧啶-4-基)环丙基)亚氨基)-6-砜、
亚氨基(1-(6-((R)-3-甲基吗啉代)-2-(1H-吡咯并[2,3-b]吡啶-4-基)嘧啶-4-基)环丙基)(三氟甲基)-6-砜、
(R)-((1-(2-(2-(2-氨基吡啶-4-基)-6-(3-甲基吗啉代)嘧啶-4-基)环丙基)亚氨基)二甲基-6-砜、
(R)-((1-(2-(2-氨基-6-甲氧基吡啶-4-基)-6-(3-甲基吗啉代)嘧啶-4-基)环丙基)亚氨基)二甲基-6-砜、
(R)-((1-(2-(2-氨基-3-氟吡啶-4-基)-6-(3-甲基吗啉代)嘧啶-4-基)环丙基)亚氨基)二甲基-6-砜、
(R)-((1-(2-(2-氨基-3-甲基吡啶-4-基)-6-(3-甲基吗啉代)嘧啶-4-基)环丙基)亚氨基)二甲基-6-砜、
((1-(2-(2-氨基吡啶-4-基)-6-((R)-3-甲基吗啉代)嘧啶-4-基)环丙基)亚氨基)(甲基)(三氟甲基)-6-砜、
((1-(2-(2-氨基吡啶-4-基)-6-((R)-3-甲基吗啉代)嘧啶-4-基)环丙基)亚氨基)(环丙基)(甲基)-6-砜、
((1-(2-(2-氨基吡啶-4-基)-6-((R)-3-甲基吗啉代)嘧啶-4-基)环丙基)亚氨基)(异丙基)(甲基)-6-砜、
(R)-1-((1-(2-(2-(2-氨基吡啶-4-基)-6-(3-甲基吗啉代)嘧啶-4-基)环丙基)亚氨基)四氢-1H-6-噻吩1-氧化物、
(R)-甲基(1-(6-((R)-3-甲基吗啉代)-2-(1H-吡咯并[2,3-b]吡啶-4-基)嘧啶-4-基)环丙基)((三氟甲基)亚氨基)-6-砜、
(R)-(1-(2-(6-(二氟甲基)-1H-吡咯并[2,3-b]吡啶-4-基])-6-(((R)-3-甲基吗啉代)嘧啶-4-基)环丙基)(亚氨基)(甲基)-砜、
(R)-(1-(6-((1R,6S)-3-氧杂双环[4.1.0]庚烷-6-基)-2-(1H-吡咯并[2,3-b]吡啶-4-基)嘧啶-4-基)环丙基)(亚氨基)(甲基)-砜、
(R)-(1-(6-((1S,6R)-3-氧杂双环[4.1.0]庚烷-6-基)-2-(1H-吡咯并[2,3-b]吡啶-4-基)嘧啶-4-基)环丙基)(亚氨基)(甲基)-砜。
本发明还提供上述任一项化合物或其药学上可接受的盐在制备治疗和/或预防过度增殖性疾病的药物中的用途。
所述过度增殖性疾病例如是肿瘤,以及非恶性疾病,例如炎性疾病、阻塞性气道疾病、免疫疾病或心血管疾病。
本发明还提供上述任一项化合物或其药学上可接受的盐在制备用于预防和/或治疗对抑制ATR激酶敏感的肿瘤的药物中的用途。
本发明还提供一种药物组合物,其包含上述任一项所述的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。
本发明还提供一种药物组合物,药物组合物,包含:
一种两种或多种或两种以上的活性成分,
一种选自上述任一项所述的通式(I)的化合物或其药学上可接受的盐,
另一种或多种选自上述任一项所述的化合物或其药学上可接受的盐之外的用于治疗癌症的抗过度增殖、抑制细胞生长或细胞毒性物质。
本文中提及的术语具有下列含义:
术语“卤素”、“卤代-(halo)”应被理解为是指氟、氯、溴或碘原子。
术语“C1-C4链烷基”应被理解为是指具有1、2、3、4个碳原子的直链或支链的饱和单价烃基团,术语“C1-C6链烷基”应被理解为是指具有1、2、3、4、5、6个碳原子的直链或支链的饱和单价烃基团。上述C1-C4链烷基和C1-C6链烷基具体可以例举,甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、1-甲基-正丁基、2-甲基-正丁基、3-甲基-正丁基、1,1-二甲基-正丙基、1,2-二甲基-正丙基、2,2-二甲基-正丙基、1-乙基-正丙基、正己基、1-甲基-正戊基、2-甲基-正戊基、3-甲基-正戊基、4-甲基-正戊基、1,1-二甲基-正丁基、1,2-二甲基-正丁基、1,3-二甲基-正丁基、2,2-二甲基-正丁基、2,3-二甲基-正丁基、3,3-二甲基-正丁基、1-乙基-正丁基、2-乙基-正丁基、1,1,2-三甲基-正丙基、1,2,2-三甲基-正丙基、1-乙基-1-甲基-正丙基、1-乙基-2-甲基-正丙基等。
术语“C3-C6环烷基”应被理解为是具有3、4、5、6个碳原子的环状饱和单价烃基团,具体可以是,环丙基、环丁基、1-甲基-环丙基、2-甲基-环丙基、环戊基、1-甲基-环丁基、2-甲基-环丁基、3-甲基-环丁基、1,2-二甲基-环丙基、2,3-二甲基-环丙基、1-乙基-环丙基、2-乙基-环丙基、环己基、1-甲基-环戊基、2-甲基-环戊基、3-甲基-环戊基、1-乙基-环丁基、2-乙基-环丁基、3-乙基-环丁基、1,2-二甲基-环丁基、1,3-二甲基-环丁基、2,2-二甲基-环丁基、2,3-二甲基-环丁基、2,4-二甲基-环丁基、3,3-二甲基-环丁基、1-正丙基-环丙基、2-正丙基-环丙基、1-异丙基-环丙基、2-异丙基-环丙基、1,2,2-三甲基-环丙基、1,2,3-三甲基-环丙基、2,2,3-三甲基-环丙基、1-乙基-2-甲基-环丙基、2-乙基-1-甲基-环丙基、2-乙基-2-甲基-环丙基、2-乙基-3-甲基-环丙基等。
术语“C1-C6烷氧基”应理解为是指式-O-烷基的直链或支链的饱和单价烃基团,其中,术语“烷基”如上文C1-C6链烷基所定义,例如,甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基、仲丁氧基、正戊氧基、1-甲基-正丁氧基、2-甲基-正丁氧基、3-甲基-正丁氧基、1,1-二甲基-正丙氧基、1,2-二甲基-正丙氧基、2,2-二甲基-正丙氧基、1-乙基-正丙氧基、正己氧基、1-甲基-正戊氧基、2-甲基-正戊氧基、3-甲基-正戊氧基、4-甲基-正戊氧基、1,1-二甲基-正丁氧基、1,2-二甲基-正丁氧基、1,3-二甲基-正丁氧基、2,2-二甲基-正丁氧基、2,3-二甲基-正丁氧基、3,3-二甲基-正丁氧基、1-乙基-正丁氧基、2-乙基-正丁氧基、1,1,2-三甲基-正丙氧基、1,2,2-三甲基-正丙氧基、1-乙基-1-甲基-正丙氧基、1-乙基-2-甲基-正丙氧基等,或其异构体。
术语“C1-C6卤代烷基”应理解为是指直链或支链的饱和单价烃基团,其中,术语“C1-C6卤代烷基”中的烷基如上文C1-C6链烷基所定义,其中一个或多个氢原子被相同或不同的卤素原子替换,即一个卤素原子独立于另一个卤素原子。优选所述卤素原子是F。例如,-CF3,-CHF2、-CH2F、-CF2CF3或-CH2CF3。
术语“C1-C6杂烷基”应理解为是指由一定数目碳原子和至少一个杂原子或杂原子组成的,稳定的直链或支链的烷基原子团或其组合物。在一些实施方案中,杂原子选自B、O、N、和S,其中氮和硫原子任选地被氧化,氮杂原子任选地被季铵化。在一些实施方案中,杂原子团选自-C(=O)O-、-C(=O)-、-C(=S)-、-S(=O)-、-S(=O)2-、-C(=O)N(H)-、-N(H)-、-S(=O)2N(H)-、-S(=O)2N(H)-。
术语“3-至7-元杂环烷基”应理解为是指饱和的单价的单-或双环烃环,其含有2、3、4、5、6、7个碳原子,以及一个或多个选自C(=O)、O、S、S(=O)、S(O)2、NRx的含有杂原子的基团,其中,Rx代表氢原子或C1-C6-烷基或者C1-C6-卤代烷基;所述杂环烷基可以通过任何一个碳原子,或,如果存在的话,氮原子,与分子的其余部分相连接。
尤其是,所述3-至7-元杂环烷基可以含有2、3、4或5个碳原子,以及一个或多个上述含有杂原子的基团。例如可以是,氧杂环丙烷基、氧杂环丁烷基、吡咯烷基、哌啶基、氮杂环丁烷基、吗啉基、二氢-2H-吡喃基、四氢吡啶基、四氢呋喃基等。
术语“杂芳基”应被理解为是指单价的单环或双环的芳香环系统,其具有5、6、7、8、9、10、11或12个环原子,尤其是5或6个环原子,并且含有至少一个可以相同或不同的杂原子,所述杂原子是,例如,氧、氮或硫,另外,在每种情况下,可以是苯并稠合的。具体地,可以是2-噻吩基、3-噻吩基、2-呋喃基、3-呋喃基、2-噁唑基、4-噁唑基、5-噁唑基、3-异噁唑基、4-异噁唑基、5-异噁唑基、2-噻唑基、4-噻唑基、5-噻唑基、3-异噻唑基、4-异噻唑基、5-异噻唑基、2-咪唑基、4-咪唑基、2-吡啶基、3-吡啶基、4-吡啶基等。术语“任选”或“任选地”应被理解为是随后描述的事件或状况可能但不是必须出现的,并且该描述包括其中所描述事件或状况发生的情况以及所述事件或状况不发生的情况。
术语“取代的”是指在指定原子上的一个或多个氢被选自指出的基团替换,条件是:不超过所指定原子的现有情况下的正常价,并且该取代产生稳定化合物。取代基和/或变量可以组合,只要这种组合可以产生稳定化合物即可。
术语“任选取代的”是指被具体基团、原子团或部分任选取代。环系取代是指与芳香族或非芳香族环体系链接的取代基,例如替换环体系上的可得氢。
本文使用的术语“一个或多个”,例如,在本发明的通式的化合物的取代基的定义中,是指“一个、两个、三个、四个或五个,尤其是一个、两个、三个或四个,更尤其是一个、两个或三个,更加尤其是一个或两个”。
术语“药学上可接受的载体”是指与配制品的其他成分相容的载体,例如稀释剂或赋形剂。赋形剂表示不具有治疗活性且无毒的任何成分,例如配制药品的崩解剂、粘合剂、填充剂、稳定剂、抗氧化剂、表面活性剂、润滑剂等。
术语“增殖性疾病”包括恶性疾病,例如癌症,以及非恶性疾病,例如炎性疾病、阻塞性气道疾病、免疫疾病或心血管疾病。
根据所关注的各种取代基的位置和性质,本发明的化合物可以包含一个或多个非对称中心。不对称碳原子可以存在(R)或(S)构型,在单一非对称中心的情况下,形成外消旋混合物,在多个非对称中心的情况下,形成非对映异构体的混合物。
本发明的化合物可以包含非对称的硫原子,例如,下列结构的非对称的亚砜或亚砜亚胺基团,
其中,*表示可以与分子的其余部分键合的原子。
优选的化合物是得到更合乎需要的生物活性的那些化合物。本发明化合物的分离、纯化或部分纯化的异构体和立体异构体或外消旋的或非对映体的混合物,也包括在发明范围内。这种材料的纯化和分离可以通过本领域已知的标准技术实现。
为了限制彼此类型不同的异构体,参考IUPAC Rules Section E(Pure Appl Chem45,11-30,1976)
本发明包括本发明化合物的所有可能的立体异构体,可以是单一立体异构体,或任何比例的所述立体异构体,例如R或S异构体,或E或Z异构体的任何混合物。利用任何合适的本领域说明的方法,例如,色谱,尤其是手性色谱,可以实现本发明化合物的单一立体异构体的分离,例如,单一对映异构体或单一非对应异构体的分离。
本发明的化合物可以以N-氧化物形式存在,其定义为:本发明化合物的至少一个氮被氧化。本发明包括所有这种可能的N-氧化物。
本发明还涉及本文公开的化合物的可用形式,例如,代谢物、水合物、溶剂化物、前药、盐,尤其是药学上可接受的盐,以及共沉淀。
本发明的化合物可以以水合物或溶剂化物形式存在,其中,本发明的化合物含有极性溶剂,尤其是水、甲醇或乙醇,例如,作为化合物的晶格的结构要素。极性溶剂尤其是水的量,可以以化学计量或非化学计量的比例存在。化学计量的溶剂化合物例如水合物的情况下,可以分别是半(部分)、一、一又二分之一、二、三、四、五溶剂化合物或水合物,等等。本发明包括所有这种水合物或溶剂化物。
进一步的,本发明的化合物可以游离形式存在,例如,作为游离碱或游离酸或两性离子,或可以以盐形式存在。所述盐可以是药学通常使用的任何盐,有机或无机加成盐,尤其是任何药学上可接受的有机或无机加成盐。
本发明化合物的药学上可接受的盐可以是,例如,链或环中携带氮原子的本发明化合物的酸加成盐,例如,充分碱性的本发明化合物的酸加成盐,例如,与无机酸形成的酸加成盐,例如,盐酸、氢溴酸、氢碘酸、硫酸、重硫酸、磷酸或硝酸,或与有机酸形成的酸加成盐,例如,甲酸、乙酸、乙酰乙酸、丙酮酸、三氟乙酸、丙酸、丁酸、己酸、庚酸、十一烷酸、月桂酸、苯甲酸、水杨酸、2-(4-羟基苯甲酰基)-苯甲酸、樟脑酸、肉桂酸、环戊酸、二葡糖酸、3-羟基-2-萘酸、烟酸、双羟萘酸、果胶酯酸、过硫酸、3-苯基丙酸、苦味酸、新戊酸、2-羟基乙磺酸、衣康酸、氨基磺酸、三氟甲磺酸、十二烷基硫酸、乙磺酸、苯磺酸、对甲苯磺酸、甲磺酸、2-萘磺酸、萘二磺酸、樟脑磺酸、柠檬酸、酒石酸、硬脂酸、乳酸、草酸、丙二酸、琥珀酸、苹果酸、己二酸、马来酸、富马酸、D-葡糖酸、扁桃酸、抗坏血酸、葡庚糖酸、甘油磷酸、天冬氨酸、磺基水杨酸、半硫酸或硫氰酸。
本发明采用下述缩略词:CDI代表N,N'-羰基二咪唑,m-CPBA代表3-氯过氧苯甲酸,DCM代表二氯甲烷;PE代表石油醚;DMF代表N,N-二甲基甲酰胺;DMSO代表二甲亚砜;EA代表乙酸乙酯;EtOH代表乙醇;MeOH代表甲醇;CBz代表苄氧羰基,BOC代表叔丁氧羰基是一种胺保护基团;THF代表四氢呋喃;Boc2O代表二-叔丁基二碳酸酯;TFA代表三氟乙酸;DIPEA代表二异丙基乙基胺;SOCl2代表氯化亚砜;TsOH代表对甲苯磺酸;TsCl代表4-甲苯磺酰氯;NaH代表钠氢;HOAc代表乙酸;B2Pin2代表双联频哪醇基二硼;Pd(dppf)Cl2代表1,1-双(二苯基膦)二茂铁二氯化钯;TEA或者Et3N代表三乙胺;DMAP代表4-二甲氨基吡啶;TLC代表薄层色谱法;eq代表当量,等量;mp代表熔点;aq代表水溶液;h代表小时。
在本发明的背景下,术语“治疗”包括抑制、延迟、检查、缓解、减弱、限制、减少、压制、抵制或治愈疾病(术语“疾病”包括但不限于病状、病症、损失或健康问题),或者这种状态和/或这种状态的症状的发展、进程或进展、术语“疗法”在本文理解为与术语“治疗”同义。
术语“防止”、“预防”或“阻止”在本发明的背景下是同义使用的,并且是指避免或减少感染、经历、患有或具有疾病的风险或者这种和/或这种状态的症状的发展或进展。
治疗或预防疾病可以是部分或完全的。
本发明的化合物可以通过本领域技术人员所熟知的多种合成方法来制备,包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术人员所熟知的等同替换方式,优选的实施方式包括但不限于本发明的实施例。
本发明的化合物可以有多种用途或适应症,包括但不限于本申请所列举的具体用途或适应症。
有益效果
本发明的化合物的酶活性和细胞活性比现有技术(阳性对照)优异,且具有显著性差异。因此本发明的化合物在药学上可用于治疗癌症。
具体实施方式
下面通过实施例对本发明进行详细描述,但并不意味着对本发明任何不利限制。本文已经详细地描述了本发明,其中也公开了其具体实施例方式,对本领域的技术人员而言,在不脱离本发明精神和范围的情况下针对本发明具体实施方式进行各种变化和改进将是显而易见的。
中间体合成
中间体A1的合成:
合成路线:
步骤一:A1-2的合成
向反应瓶中加入A1-1(10g,50.7mmol),加入DMF(200mL)降温至0℃,加入NaH(2.4g,100mmol)搅拌30min,加入TsCl(12g,62.8mmol),室温反应16h。显示原料反应完全,加水200mL,EA(2×100mL)萃取,分层,无水硫酸钠干燥,真空浓缩有机相,得到黄色固体中间体A1-2(17.0g,收率96%)。
LCMS(MS-ESI,m/z):(M+1)=351.2,353.1
步骤二:A1的合成
向反应瓶中加入A1-2(7g,20.0mmol),B2Pin2(10g,39.3mmol),KOAc(6g,61mmol),Pd(dppf)Cl2(0.9g,1.2mmol)溶于DMF(70mL)后,氮气置换三次,搅拌;反应液加热至110℃反应3h;TLC显示原料反应完全,降温至室温,过滤,加水200mL,EA(100mL)萃取,水洗3次,分层,无水硫酸钠干燥,真空浓缩有机相,拌样,用PE:EA(5:1-1:1)过柱纯化得到中间体A1(6.1g,收率77%)。
LCMS(MS-ESI,m/z):(M+1)=399.2,401.0
1H NMR(400MHz,CDCl3,ppm)δ1.27(d,J=2.76Hz,3H),1.32-1.39(m,1H),1.33-1.38(m,1H),1.36(s,10H),6.95-7.05(m,1H),7.02(d,J=4.02Hz,1H),7.20-7.26(m,1H),7.24(d,J=8.03Hz,1H),7.52(d,J=4.77Hz,1H),7.72-7.78(m,1H),7.75(d,J=3.76Hz,1H),8.02-8.04(m,2H),8.43(d,J=4.77Hz,1H).
中间体A2的合成:
步骤一:A2-2的合成
向反应瓶中加入A2-1(5g,24.1mmol)和R-3-甲基吗啡啉(2.4g,23.8mmol),加入DCM(20mL)和TEA(2.6g,24mmol),室温反应16小时,TLC显示原料约5%未反应完全,加入100mL水,分层,用1N盐酸洗涤,饱和碳酸氢钠、氯化钠洗涤,无水硫酸钠干燥,浓缩有机相得固体A2-2(5.2g,收率80%)。
LCMS(MS-ESI,m/z):(M+1)=272.1
步骤二:A2-3的合成
向反应瓶中加入A2-2(20g,73.5mmol)溶于MeOH(500mL)中,搅拌;将反应液降温至0℃,分批加入NaBH4,然后缓慢升至室温,反应1h,TLC显示原料反应完全,加水50mL,DCM(2×100mL)萃取,水洗2次,饱和氯化钠洗涤,干燥,真空浓缩有机相,得油状物中间体A2-3(17g,收率98%)。
LCMS(MS-ESI,m/z):(M+1)=244.2
步骤三:A2的合成
向反应瓶中加入A2-3(17g,70.0mmol)溶于DCM(50mL)中,缓慢加入三乙胺(40g,0.40mol),在搅拌情况下,将反应液降温至0℃,10分钟内滴加MsCl(12g,0.1mol),完毕,升至室温反应1h,TLC显示原料反应完全,加水100mL,DCM(2×150mL)萃取,水洗2次,饱和氯化钠洗涤,硫酸钠干燥,浓缩有机相,得中间体油状物A2(21g,产率98%)。
LCMS(MS-ESI,m/z):(M+1)=322.1
中间体A3的合成
步骤一:A3-1的合成
向反应瓶中加入A2(1.86g,6.2mmol)和NaI(100mg,0.5mmol)溶于MeCN(50mL)中,搅拌,反应液降温至0℃后,加入甲硫醇钠(1g,7.4mmol,40%)的水溶液,反应10min后用TLC监控显示原料反应完全,加入水(100mL)猝灭反应,用EA(2×50mL)萃取,分层,有机相用饱和氯化钠洗涤,无水硫酸钠干燥,真空浓缩有机相得黄色固体粗品A3-1(1.3g,收率90%)。
LCMS(MS-ESI,m/z):(M+1)=274.1
步骤二:A3-2的合成
向反应瓶中加入A3-1(9g,32.8mmol)溶于DCM(20mL)中搅拌,反应液降温至0℃,加入m-CPBA(7g,32.5mmol,80%),室温下反应30min;TLC监控显示原料反应完全,加入水50mL,DCM(2×20mL)萃取,分层,有机相用饱和氯化钠洗涤,无水硫酸钠干燥,真空浓缩有机相,用柱层析硅胶过柱,PE:EA(5:1-1:1)得到油状物A3-2(8g,收率80%)。
LCMS(MS-ESI,m/z):(M+1)=290.2
1H NMR(400MHz,DMSO-d6,ppm)δ1.22(d,3H),2.64(d,3H),3.14-3.26(m,1H),3.45(m,1H),3.59(m,1H),3.73(d,1H),3.88-3.96(m,2H),4.00(d,1H),4.07(m,1H),4.33(s,1H),6.81(s,1H)。
步骤三:A3-3的合成
向反应瓶中加入A3-2(20g,69.2mmol),碘苯二乙酸(24g,76.1mmol),三氟乙酰胺(16g,138.4mmol),氧化镁(12g,276.8mmol),二聚醋酸铑(0.8g,1.8mmol)溶于DCM(500mL)中,氮气置换3次,室温下搅拌16h;TLC监控显示原料反应完全,过滤,滤液真空浓缩,用硅胶柱纯化(PE:EA=1:1-0:1)得到黄色固体A3-3(27g,产率98%)。
LCMS(MS-ESI,m/z):(M+1)=401.1
步骤四:A3的合成
向反应瓶中加入A3-3(5.6g,14mmol)和四正锌基溴化铵(680mg,1.4mmol)溶于甲基四氢呋喃(200mL)中,加入二溴乙烷(300mg,14mmol),反应液降温至0℃,滴加NaOH(1.2g,30mmol)水溶液(50%),室温反应过夜;TLC显示原料反应完全,加入水100mL,用EA(3×100mL)萃取,分层,有机相用饱和氯化钠洗涤,硫酸钠干燥,真空浓缩,用硅胶柱纯化(PE:EA=1:1-0:1)得到油状物A3(5g,收率90%)。
LCMS(MS-ESI,m/z):(M+1)=399.2
1H NMR(400MHz,CDCl3,ppm)δ1.31(t,3),1.43(m,2H),1.67-1.75(m,2H),2.33(s,1H),3.09(s,3H),3.29(m,1H),3.53(m,1H),3.67(dd,1H),3.78(d,1H),4.00(m,2H),4.33(s,1H),6.78(s,1H)
中间体A4的合成
步骤一:A4-2的合成
向反应瓶中加入A2(800mg,2.49mmol)和MeCN(10mL),加入NaSCN(242.2mg,2.99mmol),升温110℃反应1h,加入CS2CO3(812mg,2.49mmol),加入TMSCF3(425mg,2.98mmol),0℃反应2h。TLC显示原料反应完全,加水20mL,EA(2×10mL)萃取,分层,干燥,浓缩有机相,得到淡黄色固体A4-2(204mg,收率25%)。
LCMS(MS-ESI,m/z):(M+1)=328
步骤二:A4-3的合成
向反应瓶中加入A4-2(204mg,0.62mmol)和DCM(5mL),0℃加入m-CPBA(106.9mg,0.62mmol),25℃反应4h。TLC显示原料反应完全,加水10mL,EA(2×5mL)萃取,分层,干燥,浓缩有机相,得到黄色固体A4-3(117.3mg,收率55%)。
LCMS(MS-ESI,m/z):(M+1)=344
步骤三:A4-4的合成
向反应瓶中加入A4-3(100mg,0.29mmol)和DCM(5mL),加入PhI(OAc)2(93.8mg,0.29mmol),CF3CONH2(65.5mg,0.58mmol),MgO(46.4mg,1.16mmol),(CH3COO)2Rh(3.2mg,0.007mmol),氮气保护,25℃反应16h。TLC显示原料反应完全,加水20mL,EA(2×10mL)萃取,分层,干燥,浓缩有机相,得到淡黄色固体A4-4(60.9mg,收率46%)。
LCMS(MS-ESI,m/z):(M+1)=455
步骤二:A4的合成
向反应瓶中加入A4-4(60mg,0.16mmol)和2-MeTHF(5mL),1,2-二溴乙烷(30mg,0.16mmol),正四锌基溴化铵(8.7mg,0.016mmol),0℃加入NaOH(768mg,50%),25℃反应12h。TLC显示原料反应完全,加水10mL,EA(2×5mL)萃取,分层,干燥,浓缩有机相,得到黄色固体A4(20.3mg,收率40%)。
LCMS(MS-ESI,m/z):(M+1)=385
中间体A5的合成
步骤一:A5-2的合成
向100mL的三口烧瓶中加入A5-1(1g,5mmol),硝酸银(170mg,1mmol),K2S2O8(3.38g,12.5mmol)和10mL乙腈,搅拌下加入二氟乙酸(960mg,10mmol)和5mL水,反应在50度下反应24小时后,TLC监控,剩余部分原料没有完全反应,停止反应,冷却到室温;加入20ml水猝灭反应,乙酸乙酯萃取,饱和碳酸氢钠洗涤后,饱和氯化钠干燥,有机相真空浓缩后,用硅胶柱纯化(PE:EA=1:1-0:1)得到油状物A5-1(300mg,收率25%)
LCMS(MS-ESI,m/z):(M+1)=248.1
1H NMR(400MHz,DMSO-d6,ppm)δ11.9(sbroad,1H),7.9(t,1H),7.3(s,1H),7.1(t,1H),6.59(m,1H).
步骤二:A5-3的合成
向反应瓶中加入A5-2(100mg,0.4mmol),加入DMF(50mL)降温至0℃,加入NaH(20mg,0.5mmol)搅拌30min,加入TsCl(100mg,0.5mmol),室温反应16h。显示原料反应完全,加水10mL,EA(2×10mL)萃取,分层,无水硫酸钠干燥,真空浓缩有机相,得到黄色固体中间体A5-3(120mg,收率75%)。
LCMS(MS-ESI,m/z):(M+1)=402.1
步骤三:A5的合成
向反应瓶中加入A5-3(200mg,0.5mmol),B2Pin2(250mg,1.0mmol),KOAc(100mg,1.0mmol),Pd(dppf)Cl 2(140mg,0.2mmol)溶于DMF(5mL)后,氮气置换三次,搅拌;反应液加热至110℃反应3h;TLC显示原料反应完全,降温至室温,过滤,加水10mL,EA(20mL)萃取,水洗3次,分层,无水硫酸钠干燥,真空浓缩有机相,拌样,用PE:EA(5:1-1:1)过柱纯化得到中间体A5(150mg,收率67%)。
LCMS(MS-ESI,m/z):(M+1)=449
1H NMR(400MHz,DMSO-d6,ppm)δ1.27(d,J=2.76Hz,3H),1.32-1.39(m,1H),1.33-1.38(m,1H),1.36(s,10H),6.59(m,1H),6.95-7.05(m,1H),7.02(d,J=4.02Hz,1H),7.20-7.26(m,1H),7.24(d,J=8.03Hz,1H),7.52(d,J=4.77Hz,1H),7.72-7.78(m,1H),7.75(d,J=3.76Hz,1H),8.02-8.04(s,1H),8.43(d,J=4.77Hz,1H).
具体实施例
化合物的合成
实施例1:化合物1
合成路线:
步骤一:向反应瓶中加入1-1(800mg,1.4mmol),BrCN(300mg,2.8mmol)和DMAP(341,2.8mmol)溶于DCM(20mL)中,搅拌,室温反应16,用TLC监控显示原料反应完全,加入水(20mL),用DCM(2×50mL)萃取,分层,有机相用饱和氯化钠洗涤,无水硫酸钠干燥,真空浓缩有机相得黄色固体粗品,用柱层析硅胶过柱,PE:EA(1:1-0:1)得到油状物1-2(400mg,收率48%)。
LCMS(MS-ESI,m/z):(M+1)=592
步骤二:向反应瓶中加入1-2(400mg,0.67mmol)溶于MeOH(10mL)中,降温至0℃后,加入NaOH(134mg,3.35mmol,50%水溶液)搅拌,室温反应3h,用TLC监控显示原料反应完全,加入水100ml,有大量固体析出过滤得粗品,用MeOH/DMSO打浆得黄色固体1(65mg,收率22%)
LCMS(MS-ESI,m/z):(M+1)=438
1H NMR(400MHz,DMSO-d6,ppm)δ11.82(s,1H),8.33(d,J=5.0Hz,1H),7.94(d,J=5.0Hz,1H),7.60–7.56(m,1H),7.20(m,1H),6.99(s,1H),4.56(s,1H),4.28(s,1H),4.01(m,1H),3.79(d,J=11.5Hz,1H),3.70(s,3H),3.64(m,1H),3.50(m,1H),3.29–3.25(m,1H),2.04(m,1H),1.96(m,1H),1.85(m,1H),1.65(m,1H),1.28(d,J=6.7Hz,3H).
实施例2:化合物2
合成路线:
步骤一:向反应瓶中加入2-1(2.2g,3.8mmol)溶于MeOH(100mL)中,搅拌,反应液降温至0℃后,加入NaOH(0.8g,19mmol,50%)的水溶液,反应3h后用TLC监控显示原料反应完全,加入水(100mL)猝灭反应,用DCM(2×200mL)萃取,分层,有机相用饱和氯化钠洗涤,无水硫酸钠干燥,真空浓缩有机相得黄色固体粗品,用柱层析硅胶过柱,PE:EA-MeOH:DCM(1:1-1:10)得到黄色固体2-2(1.5g,收率90%)
LCMS(MS-ESI,m/z):(M+1)=413.2
步骤二:向反应瓶中加入2-2(500mg,1.2mmol),DMAP(14mg,0.12mmol)溶于DCM(20mL)中搅拌,反应液降温至0℃,加入TEA(363mg,3.6mmol)和MsCl(276mg,2.4mmol)室温下反应16h;TLC监控显示原料反应完全,加入水50mL,DCM(2×50mL)萃取,分层,有机相用饱和氯化钠洗涤,无水硫酸钠干燥,真空浓缩有机相,用柱层析硅胶过柱PE:EA-DCM:MeOH(1:1-15:1)得到白色固体2(400mg,收率60%)。
LCMS(MS-ESI,m/z):(M+1)=491.2
1H NMR(400MHz,DMSO-d6,ppm)δ11.81(s,1H),8.33(d,J=5.0Hz,1H),7.93(d,J=5.0Hz,1H),7.65–7.54(m,1H),7.20(m,1H),7.00(s,1H),4.52(s,1H),4.24(s,1H),4.00(m,1H),3.76(m,1H),3.67–3.62(m,3H),3.49(m,1H),3.28–3.11(m,1H),2.94(s,3H),1.88(m,3H),1.58(m,1H),1.27(d,J=6.7Hz,3H)
实施例3:化合物3
合成路线:
步骤一:向反应瓶中加入3-1(2.2g,3.8mmol)溶于MeOH(20mL)中,搅拌,反应液降温至0℃后,加入NaOH(0.8g,19mmol,50%)的水溶液,反应3h后用TLC监控显示原料反应完全,加入水(100mL)猝灭反应,用DCM(2×200mL)萃取,分层,有机相用饱和氯化钠洗涤,无水硫酸钠干燥,真空浓缩有机相得黄色固体粗品,用柱层析硅胶过柱,PE:EA-MeOH:DCM(1:1-1:10)得到黄色固体3-2(1.5g,收率90%)
LCMS(MS-ESI,m/z):(M+1)=413.2
步骤二:向反应瓶中加入3-2(100mg,0.24mmol),DMAP(2.8mg,0.024mmol)溶于DCM(10mL)中搅拌,反应液降温至0℃,加入TEA(75mg,0.72mmol)和环丙磺酰氯(56mg,0.48mmol)室温下反应16h;TLC监控显示原料反应30%,加入水50mL,DCM(2×50mL)萃取,分层,有机相用饱和氯化钠洗涤,无水硫酸钠干燥,真空浓缩有机相,用柱层析硅胶过柱PE:EA-DCM:MeOH(1:1-15:1)得到白色固体(18mg,收率8%)。
LCMS(MS-ESI,m/z):(M+1)=517.3
1H NMR(400MHz,DMSO-d6,ppm)δ11.82(s,1H),8.32(d,J=5.0Hz,1H),7.92(d,J=5.0Hz,1H),7.62–7.52(m,1H),7.19(m,1H),7.01(s,1H),4.54(s,1H),4.22(s,1H),4.00(m,1H),3.84–3.74(m,1H),3.67–3.59(m,3H),3.48(m,1H),3.26(m,1H),2.58–2.50(m,1H),1.96–1.76(m,3H),1.64–1.51(m,1H),1.30–1.23(m,3H),1.22–1.18(m,1H),0.88–0.80(m,3H).
实施例4:化合物4
步骤一:向反应瓶中加入4-1(300mg,0.68mmol)溶于3MHCl(10mL)中加热至90℃反应1h,TLC监控显示原料反应完全,将至室温,用NaOH水溶液调至pH=9.0,用EA(2×50mL)萃取,分层,有机相用饱和氯化钠洗涤,无水硫酸钠干燥,真空浓缩有机相得黄色固体,粗品用柱层析硅胶过柱,PE:EA(1:1-0:1)得到白色固体4(50mg,收率20%)。
LCMS(MS-ESI,m/z):(M+1)=456
1H NMR(400MHz,DMSO-d6,ppm)δ11.82(s,1H),8.33(d,J=5.0Hz,1H),7.94(d,J=5.0Hz,1H),7.62–7.55(m,1H),7.20(m,1H),6.99(s,1H),4.42(d,J=113.1Hz,3H),4.21–3.80(m,2H),3.80(s,1H),3.79(d,J=11.5Hz,1H),3.73–3.58(m,4H),3.50(m,1H),3.42–3.04(m,7H),2.48(m,2H),2.13–1.91(m,2H),1.85(m,1H),1.65(m,1H),1.28(d,J=6.7Hz,3H).
实施例5:化合物5
步骤一:向100mL三口烧瓶中加入5-1(100mg,0.3mmol),A5-1(160mg,0.36mmol),Pd(dppf)Cl2(45mg,0.06mmol),Cs2CO3(120mg,0.36mmol)在10mLDMF(10%含水量)中,氮气置换三次,反应液在110℃下反应16小时,LCMS监控反应。反应完成后,加水猝灭,乙酸乙酯萃取,有机相用氯化钠水洗,无水硫酸钠干燥,粗品用柱层析硅胶过柱,PE:EA(1:1-0:1)得到淡黄色固体5-2(40mg,产率22%)。
LCMS(MS-ESI,m/z):(M+1)=617.2
步骤二:向100mL三口烧瓶中加入5-2(40mg,0.06mmol),5NNaOH(4mL)和甲醇(5mL),在25℃下搅拌3小时后,TLC监控反应,反应完全后用稀盐酸(1N)猝灭反应至pH=7-8之间,乙酸乙酯萃取反应,粗品用HPLC进行制备,流动相为乙腈和水,得到白色固体5(10mg,产率36%)
LCMS(MS-ESI,m/z):(M+1)=463
1H NMR(400MHz,DMSO-d6,ppm)δ11.82(s,1H),8.33(d,J=5.0Hz,1H),7.94(d,J=5.0Hz,1H),7.60–7.56(m,1H),7.20(m,1H),6.99(s,1H),6.59(m,1H),4.56(s,1H),4.28(s,1H),4.01(m,1H),3.79(d,J=11.5Hz,1H),3.70(s,3H),3.64(m,1H),3.50(m,1H),3.29–3.25(m,1H),2.04(m,1H),1.96(m,1H),1.85(m,1H),1.65(m,1H),1.28(d,J=6.7Hz,3H).
分析方法和制备方法
分析方法:
仪器:Agilent LCMS(G6125C)
色谱柱:Phenomenex KinetexEVOC 18 30×2.1mm 5um
进样量:2uL,柱温:35℃,流速:1.5mL/min
检测波长:254\220\365nm
流动相A:0.02%甲酸水溶液
流动相B:0.02%甲酸乙腈溶液
洗脱梯度:
T/min | A% | B% |
0 | 95 | 5 |
1.5 | 5 | 95 |
2.5 | 5 | 95 |
化合物具有手性问题,因此建立了手性制备方法如下:
仪器 | Agilent 1260 |
色谱柱 | CHIRALPAKIH-3(150mm*4.6mm*3μm) |
流动相(单泵) | 正己烷-甲醇-乙醇-二乙胺(500:250:250:0.4) |
流速 | 0.5ml/min |
进样量 | 2μL |
柱温 | 35℃ |
检测波长 | 228nm |
活性试验
一、ATR激酶体外抑制活性检测
试验方法及内容
ATR/ATRIP(h)在含有50nM GST-cMyc-p53和Mg/ATP(所需浓度)的缓冲液中孵育,其中根据试验设计加入不同浓度(0.0001,0.0003,0.001,0.003,0.01,0.03,0.1,0.3,1μM)的受试样品或不加;加入Mg/ATP混合物时反应开始。在室温下孵育30分钟后,加入含有EDTA的停止液停止反应。最后加入检测缓冲液,其中含有d2标记的抗GST单克隆抗体和Europiu标记的抗磷酸化p53 Ser15抗体。然后在时间分辨荧光模式下读取平板(PerkinElmer 1450Trilux),根据公式HTRF=10000x(Em665nm/Em620nm)确定均匀时间分辨荧光(HTRF)信号。
试验结果(对于IC50测定,数据使用XLFit version 5.3(ID业务解决方案)进行分析,Siamoidal dose response(variable slope)曲线根据使用非线性回归分析的每个测试浓度的平均结果进行拟合。)
表1:本发明化合物体外筛选对ATR酶学的实验结果
化合物 | 激酶(Kinase) | IC<sub>50</sub>(nM) |
阳性对照(AZD6738) | ATR/ATRIP(h) | 171 |
1 | ATR/ATRIP(h) | 48 |
2 | ATR/ATRIP(h) | 462 |
3 | ATR/ATRIP(h) | 137 |
由表1可知,化合物1、3的酶活性比阳性对照要好,因此在药学上可用于治疗癌症。
二、mTOR激酶体外抑制活性检测
试验方法及内容
mTOR(h)与50mm HEPES pH 7.5、1mm EGTA、0.01%Tween 20、2mg/mL底物、3mmMnCl2和y-3Pl-ATP(根据需要的比活性和浓度)孵育,根据试验设计加入不同浓度(0.001,0.003,0.01,0.03,0.1,0.3,1,3,10μM)的受试样品或不加。加入Mn/ATP混合物时反应开始。室温孵育40分钟后,加入浓度为0.5%的磷酸停止反应。10μL的反应液在P30的过滤垫上,在干燥和闪烁计数(PerkinElmer 1450Trilux)之前用0.425%的磷酸洗涤4次,甲醇洗涤1次,每次持续4分钟。
试验结果(对于IC50测定,数据使用XLFit version 5.3(ID业务解决方案)进行分析,Siamoidal dose response(variable slope)曲线根据使用非线性回归分析的每个测试浓度的平均结果进行拟合。)
表2:本发明化合物体外筛选对mTOR酶学的实验结果
由表2可知,化合物1、2、3对mTOR酶活性远远小于ATR酶。
三、体外LoVo细胞杀伤试验
试验方法及内容:
LoVo细胞于Ham's F12-K+10%FBS+1%P/S,95%空气+5%CO2,37℃,饱和湿度条件下培养;受试物溶于DMSO至50mM,再用DMSO配制成需要的浓度的200倍,然后用F12-K完全培养基稀释至需要的浓度的20倍。然后将受试物以25μM最高浓度开始的5倍连续稀释液作为整套浓度同时添加至细胞培养基,最终细胞体积为200μL,然后细胞在37℃、5%CO2中孵育72h后,每孔加入10μL MTT溶液,37℃孵育4h。仔细吸去上清,每孔加入150μL DMSO,轻轻振荡以使甲臜溶解。1h内在检测波长570nm处用酶标仪测定OD值。
实验结果采用Graphpad Prism 7.0软件进行分析计算。
表3:本发明化合物体外LoVo细胞抑制增殖实验结果
根据表3的结果,化合物1、2、3的细胞活性都比阳性对照要好,因此本发明的化合物在药学上可用于治疗癌症的药物。
尽管已用具体实施例来说明和描述了本发明,然而应意识到,在不背离本发明的精神和范围的情况下可以作出许多其它的更改和修改。因此,这意味着在所附权利要求中包括属于本发明范围内的所有这些变化和修改。
Claims (18)
1.式(I)所示化合物,
其中,
其中T1,T2分别独立选自C(Ra)和N;
Ra,Rb,Rc,Rd分别独立选自H,卤素,-OH,-NH2,-COOH,-CF3,-OCH3,C1-C4链烷基,C1-C4烷氧基,C3-C6环烷烃,芳香基,杂环芳香基,其中每个C1-C4链烷基,C1-C4烷氧基,C3-C6环烷烃,芳香基,杂环芳香基可以选择性彼此独立地被任选的下列基团取代一次或者多次:卤素,-OH,-NH2,-CONH2,-COOH,-CN,-OCH3;
其中Re,Rf分别独立选自H,-CONH2,-CN,-CF3,-S(O)2Rw,C2-C6链烷基,C1-C6烷氧基,C3-C6环烷基,C1-C6杂环烷基,芳香基,杂芳香基,其中每个C2-C6链烷基,C1-C6烷氧基,C3-C6环烷基,C1-C6杂环烷基,芳香基,杂芳香基可以选择性彼此独立地被任选的下列基团取代一次或者多次:卤素、-OH、-CN,-NH2,-CF3,-CH3,-OCH3;
或者,Re,Rf分别一起代表4-、5-、6-或7-元杂环基团,其中4-、5-、6-、或7-元杂环基团可以选择性彼此独立地被任选的下列基团取代一次或者多次:卤素、-OH、-CN,-NH2,-CF3,-OCH3;
Rg,Rh分别独立选自-CONH2,-CN,-CF3,C1-C6链烷基,C1-C6烷氧基,C3-C6环烷基,C1-C6杂环烷基,芳香基,杂芳香基,其中每个C1-C6链烷基,C1-C6烷氧基,C3-C6环烷基,C1-C6杂环烷基,芳香基,杂芳香基可以选择性彼此独立地被任选的下列基团取代一次或者多次:卤素、-OH、-CN,-NH2,-CF3,-CH3,-OCH3;
或者,Rg,Rh分别一起代表4-、5-、6-或7-元杂环基团,其中4-、5-、6-、或7-元杂环基团可以选择性彼此独立地被任选的下列基团取代一次或者多次:卤素、-OH、-CN,-NH2,-CF3,-OCH3;
其中Rw选自-CH3,-Et,环丙基;
R3,R4分别独立选自H,卤素,-CN,C1-C4链烷基,C1-C4烷氧基,C3-C6环烷烃,芳香基,C3-C6杂环烷烃;其中每个C1-C4链烷基,C1-C4烷氧基,C3-C6环烷烃,芳香基,C3-C6杂环烷烃可以选择性彼此独立地被任选的下列基团取代一次或者多次:卤素、-OH、-CN,-NH2,-CF3,-CH3,-OCH3;
或者R3,R4分别一起代表4-、5-、6-或7-元环基团,其中4-、5-、6-、或7-元环基团可以选择性彼此独立地被任选的下列基团取代一次或者多次:卤素、-OH、-CN,-NH2,-CF3,-OCH3;
其中*表示所述基团与分子剩余部分的连接点。
11.根据权利要求1-10任一项所述的化合物,选自:
N-((R)-甲基(1-(6-((R)-3-甲基吗啉代)-2-(1H-吡咯并[2,3-b]吡啶-4-基)嘧啶-4-基)环丙基)(氧代)-6-亚磺酰基)氰胺、
N-((R)-甲基(1-(6-((R)-3-甲基吗啉代)-2-(1H-吡咯并[2,3-b]吡啶-4-基)嘧啶-4-基)环丙基)(氧代)-6-亚磺酰基)甲磺酰胺、
N-((R)-甲基(1-(6-((R)-3-甲基吗啉代)-2-(1H-吡咯并[2,3-b]吡啶-4-基)嘧啶-4-基)环丙基)(氧代)-6-亚磺酰基)环丙烷磺酰胺、
1-((R)-甲基(1-(6-((R)-3-甲基吗啉代)-2-(1H-吡咯并[2,3-b]吡啶-4-基)嘧啶-4-基)环丙基)(氧代)-6-亚磺酰基)脲、
N-((R)-甲基(1-(6-((R)-3-甲基吗啉代)-2-(1H-吡咯并[2,3-b]吡啶-4-基)嘧啶-4-基)环丙基)(氧代)-6-亚磺酰基氧杂环丁烷-3-磺酰胺、
1-(1-(6-((R)-3-甲基吗啉代)-2-(1H-吡咯并[2,3-b]吡啶-4-基)嘧啶-4-基)环丙基)-4,5-二氢-3H-异噻唑1-氧化物、
(R)-(1-(2-(2-氨基吡啶-4-基)-6-((R)-3-甲基吗啉代)嘧啶-4-基)环丙基)(亚氨基)(甲基)-6-砜、
2-((((R)-甲基(1-(6-((R)-3-甲基吗啉代))-2-(1H-吡咯并[2,3-b]吡啶-4-基)嘧啶-4-基))环丙基)(氧代)-6-亚磺酰基)氨基)乙腈、
(R)二甲基((1-(6-(3-甲基吗啉代)-2-(1H-吡咯并[2,3-b]吡啶-4-基)嘧啶-4-基)环丙基)亚氨基)-6-砜、
亚氨基(1-(6-((R)-3-甲基吗啉代)-2-(1H-吡咯并[2,3-b]吡啶-4-基)嘧啶-4-基)环丙基)(三氟甲基)-6-砜、
(R)-((1-(2-(2-(2-氨基吡啶-4-基)-6-(3-甲基吗啉代)嘧啶-4-基)环丙基)亚氨基)二甲基-6-砜、
(R)-((1-(2-(2-氨基-6-甲氧基吡啶-4-基)-6-(3-甲基吗啉代)嘧啶-4-基)环丙基)亚氨基)二甲基-6-砜、
(R)-((1-(2-(2-氨基-3-氟吡啶-4-基)-6-(3-甲基吗啉代)嘧啶-4-基)环丙基)亚氨基)二甲基-6-砜、
(R)-((1-(2-(2-氨基-3-甲基吡啶-4-基)-6-(3-甲基吗啉代)嘧啶-4-基)环丙基)亚氨基)二甲基-6-砜、
((1-(2-(2-氨基吡啶-4-基)-6-((R)-3-甲基吗啉代)嘧啶-4-基)环丙基)亚氨基)(甲基)(三氟甲基)-6-砜、
((1-(2-(2-氨基吡啶-4-基)-6-((R)-3-甲基吗啉代)嘧啶-4-基)环丙基)亚氨基)(环丙基)(甲基)-6-砜、
((1-(2-(2-氨基吡啶-4-基)-6-((R)-3-甲基吗啉代)嘧啶-4-基)环丙基)亚氨基)(异丙基)(甲基)-6-砜、
(R)-1-((1-(2-(2-(2-氨基吡啶-4-基)-6-(3-甲基吗啉代)嘧啶-4-基)环丙基)亚氨基)四氢-1H-6-噻吩1-氧化物、
(R)-甲基(1-(6-((R)-3-甲基吗啉代)-2-(1H-吡咯并[2,3-b]吡啶-4-基)嘧啶-4-基)环丙基)((三氟甲基)亚氨基)-6-砜、
(R)-(1-(2-(6-(二氟甲基)-1H-吡咯并[2,3-b]吡啶-4-基])-6-(((R)-3-甲基吗啉代)嘧啶-4-基)环丙基)(亚氨基)(甲基)-砜、
(R)-(1-(6-((1R,6S)-3-氧杂双环[4.1.0]庚烷-6-基)-2-(1H-吡咯并[2,3-b]吡啶-4-基)嘧啶-4-基)环丙基)(亚氨基)(甲基)-砜、
(R)-(1-(6-((1S,6R)-3-氧杂双环[4.1.0]庚烷-6-基)-2-(1H-吡咯并[2,3-b]吡啶-4-基)嘧啶-4-基)环丙基)(亚氨基)(甲基)-砜。
12.权利要求1-11中任一项所述的化合物的N-氧化物、异构体、代谢物、水合物、溶剂化物、共沉淀、或其药学上可接受的盐。
13.权利要求1-11中任一项所述的化合物或其药学上可接受的盐在制备治疗和/或预防过度增殖性疾病的药物中的用途。
14.权利要求1-11中任一项所述的化合物或其药学上可接受的盐在制备治疗和/或预防肿瘤的药物中的用途。
15.权利要求14所述的用途,所述肿瘤是对抑制ATR激酶敏感的肿瘤。
16.权利要求1-11中任一项所述的化合物或其药学上可接受的盐在制备LoVo细胞增殖抑制剂中的用途。
17.药物组合物,其包含权利要求1-11中任一项所述的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。
18.药物组合物,包含:
两种或两种以上的活性成分,
一种选自权利要求1-11中任一项所述的化合物或其药学上可接受的盐,
另一种或多种选自权利要求1-11所述的化合物或其药学上可接受的盐之外的用于治疗癌症的抗过度增殖、抑制细胞生长或细胞毒性物质。
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