CN110950868B - 吡唑并嘧啶化合物及制备方法与制备抗癌症药物的应用 - Google Patents
吡唑并嘧啶化合物及制备方法与制备抗癌症药物的应用 Download PDFInfo
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Abstract
本发明提供了式(I)所示的一类吡唑并嘧啶化合物或其药学可接受的盐及其制备方法和在制备治疗或预防癌症的药物中的应用。该类化合物是PI3K抑制剂，具有优异的抑制活性，有望用于多种恶性肿瘤的治疗。
Description
技术领域
本发明属于医药化学领域，尤其涉及一类新型的吡唑并嘧啶化合物及其制备方法，该吡唑并嘧啶化合物具有磷酸肌醇-3-激酶(PI3K)抑制活性，可用于制备预防和治疗肿瘤的药物。
背景技术
PI3K是一种胞内磷脂酰肌醇激酶。威尔康乃尔医学院癌症生物医学教授LewisC.Cantley发现了磷酸肌醇-3-激酶(PI3K)信号通路，同时阐明了其在肿瘤发展过程中所扮演的关键角色。PI3K信号通路通常会被细胞表面的受体所激活，如受体酪氨酸激酶、GPCR以及一些癌基因，如RAS等。活化后的p110亚基催化PIP2向PIP3转化，并激活Akt活性。Akt则会进一步将信号传递至下游分子，如mTORC1、GSK3以及BCL-2等来调节不同的细胞生理学过程。mTORC2则通过473位Ser的磷酸化来活化Akt分子。与此相反，PTEN则能够将PIP3去磷酸化成为PIP2。PI3K分子下游信号通路传递较为复杂，包含了一些反馈循环。I类PI3K的四种催化异构体中的每一种都优先调节特定的信号转导及肿瘤细胞的存活，这取决于恶性肿瘤的类型及其所发生的基因或表观遗传学改变。例如，p110α对于PIK3CA突变或癌基因RAS及受体酪氨酸激酶所驱动的肿瘤细胞的生长至关重要；p110β则会介导PTEN缺失型的肿瘤发生；而p110δ则在白细胞中高表达，从而使其成为治疗血液系统恶性肿瘤的理想靶点。
在二十世纪八十年代后期，发现PI3激酶(PI3K)是将磷脂酰肌醇的肌醇环的3-位磷酸化的酶(D.Whitman等人(1988)Nature，332664)。最初认为PI3K是一种单一酶，但现已澄清，PI3K中存在多个亚型，PI3Kα是其中的一种。PI3Kα在乳腺癌中发生高频激活突变，与乳腺癌发生发展以及耐药密切相关，已成为治疗乳腺癌的重要靶标。
2017年9月14日，美国FDA加速批准拜耳(Bayer Healthcare Pharmaceuticals)的
(Copanlisib)上市，
为商品名。用于治疗罹患复发性滤泡性淋巴瘤。
Copanlisib是磷脂酰肌醇-3-激酶(PI3K)抑制剂，主要针对恶性B细胞中表达的PI3K-α和PI3K-δ两种亚型有很好的抑制活性。
现有PI3Kα抑制剂的种类有限且在临床试验中疗效个体差异大，亟需发现新的PI3Kα抑制剂以及疗效预测生物标志物。
2019年上半年，美国FDA宣布，批准诺华公司(NVS.US)开发的Piqray(alpelisib)上市，与内分泌疗法氟维司群(fulvestrant)联用，治疗携带PIK3CA基因突变的HR+/HER2-晚期或转移性乳腺癌患者。这些患者在接受内分泌疗法之后疾病继续恶化。这是FDA批准的第一款用于治疗乳腺癌的PI3K抑制剂。转移性乳腺癌患者的肿瘤已经扩散到身体的其它部分，最常见的转移器官包括骨骼、肺部、肝脏和大脑。在HR+/HER2-晚期乳腺癌中，PI3K通路的改变是肿瘤恶化，疾病进展和产生治疗耐药性的最常见原因。大约40％的HR+/HER2-晚期乳腺癌患者携带PIK3CA基因突变。Piqray是诺华公司开发的一款口服小分子α特异性PI3K抑制剂，即PI3Kα抑制剂。在携带PIK3CA基因突变的乳腺癌细胞系中，它已显示出抑制PI3K通路的潜力，并具有抑制细胞增殖的作用。本发明也将PI3Kα作为靶点研究新药的起点，尤其是国内还未见有中国发明的PI3Kα抑制剂用于治疗恶性肿瘤。本发明的创新性研究结构将填补国内这一空白。如最终上市将具有重大的社会效益和经济效益。
发明内容
本发明所要解决的技术问题是提供一类具有PI3K抑制活性的吡唑并嘧啶化合物。
本发明同时还提供了一种制备上述吡唑并嘧啶化合物的中间体。
本发明同时还提供了一种制备上述吡唑并嘧啶化合物的方法。
为解决以上技术问题，本发明采取如下一种技术方案：
一种具有式(I)所示的吡唑并嘧啶化合物或其异构体、可药用盐、溶剂化物或结晶(在本文中有时统称为“本发明化合物”)：
式中，A为-OH、-NH2、-SH、
B为-CnH2n，n为1、2、3或4；其中，当A为
时，其一端连接所述B，另一端与所述B所连接的苯环上的碳原子连接；
Z为氢、羟基、C1-3烷基、氟、氯或溴，或为被选自氟、氯和溴中的一个或多个所取代的C1-3烷基；
M为H、-CH3或-CH2CH3。
进一步地，Z优选为氢、羟基、氟、氯、溴、甲基、乙基、异丙基、三氟甲基或五氟乙基等。
根据本发明的一些优选且具体的方面，所述吡唑并嘧啶化合物的结构如下式(I-a)所示：
其中，A、B和M的定义分别同前，Z1的定义同Z。进一步地，Z1为氢、羟基、氟、氯、溴、甲基、乙基、异丙基、三氟甲基或五氟乙基等。
根据本发明的进一步实施方案，所述B可以是直链或支链，没有特别限制。
根据本发明的一些优选方面，所述B为-CH2-、-CH2CH2-、-CH2CH2CH2-、-CH(CH3)-、-CH(CH3)CH2-、-C(CH3)2-或-CH2C(CH3)2。尤其优选地，所述B为-CH2-或者为-C(CH3)2-。
根据本发明的一些优选方面，当A为
时，其中C连接所述B，N与所述B所连接的苯环上的碳原子连接，且A、B与它们所连接的碳原子一起构成5至7元环。在一些具体实施方式中，组成A的N原子所连接的碳原子、B所连接的碳原子处于苯环的相邻位置。进一步优选地，其中B为-C(CH3)2-。
根据本发明的一些优选方面，B为-CH2-，A为-OH、
根据本发明的另一些优选方面，B为-C(CH3)2-，A为-OH或
根据本发明的一些优选且具体的方面，所述吡唑并嘧啶化合物选自如下结构所示化合物：
本发明还进一步提供包含一种或多种上述提供的吡唑并嘧啶化合物、其异构体、其药物可接受的盐或其溶剂化物的药物组合物。在一些实施实例中，该组合物还包括药物可接受的载体。
本发明提供了上述所述的吡唑并嘧啶化合物或其异构体、可药用盐、水合物、溶剂化物、结晶或含有所述吡唑并嘧啶化合物的药物组合物在制备治疗和/或预防由磷脂酰肌醇-3-激酶介导的疾病的药物中的应用。
由磷脂酰肌醇-3-激酶介导的疾病通常包括癌症。癌症包括但不限于肾癌、肝癌、结肠癌、胃肠道间质瘤、非小细胞肺癌、乳腺癌、胰腺癌、神经胶质瘤、淋巴癌，纤维肉瘤、卵巢癌、白血病和前列腺癌等。
本发明同时还提供所述药物组合物在制备用于治疗和/或预防癌症药物中的应用以及采用所述药物组合物治疗或预防癌症的方法。
根据本发明的药物组合物，其中本发明化合物优选以治疗有效量存在。
上述药物组合物中药学上可接受的载体，可以是例如药学上可接受的稀释剂、赋型剂、填充剂、粘合剂、崩解剂、吸收促进剂、表面活性剂、润滑剂、香味剂、甜味剂等。
以本发明化合物为活性成分制备的药物可以是片剂、粉剂、胶囊、粒剂、口服液以及注射制剂等多种形式。药物组合物的剂型优选为片剂、胶囊或针剂。
上述各种剂型的药物均可以按药学领域的常规方法制备。
本发明同时还提供制备本发明上述通式(I)所示的吡唑并嘧啶化合物，其立体异构体、可药用盐、溶剂化物或结晶的中间体，该中间体具有如式(II)所示结构：
式(II)中，A1为叔丁基二甲基硅氧基(TBSO)或者A1与A相同；
B、Z则对应与通式(I)中的B、Z相同。
根据本发明的一些具体方面，所述制备本发明上述所述的吡唑并嘧啶化合物，其立体异构体、可药用盐、溶剂化物或结晶的中间体包括如下一些化合物：
本发明还进一步提供本发明上述通式(I)所示的吡唑并嘧啶化合物，其立体异构体、可药用盐、溶剂化物或结晶的制备方法，其包括使上述式(II)所示中间体与水合肼进行反应的步骤。
在本发明的一些实施方式中，所述式(II)所示中间体与水合肼的反应在20-100℃下进行，优选在30-95℃下进行，更优选在40-90℃下进行，进一步优选在55-80℃下进行，再进一步优选在60-75℃下进行。
根据本发明的一些优选且具体的方面，所述式(II)所示中间体与水合肼的反应在65-70℃下进行。
进一步地，式(II)所示的中间体可通过使如下化合物
与式(III)所示化合物
反应得到；式(III)中，A1、B和Z的定义同式(II)。
根据本发明的一些优选方面，制备所述的式(II)所示中间体的过程中，所述反应在碱性条件下、温度30-120℃下进行，还选择性地在惰性气氛下进行。更优选地，制备所述的式(II)所示中间体的过程中，所述反应在温度40-110℃下进行，进一步优选在温度50-105℃下进行，更进一步优选在温度60-100℃下进行，再进一步优选在温度70-95℃下进行。根据本发明的一些具体方面，制备所述的式(II)所示中间体的过程中，所述反应在温度85-90℃下进行。
根据本发明的一些实施方案，所述惰性气氛为氮气气氛。
根据本发明的一些实施方案，所述碱性条件通过添加碱性物质形成，所述碱性物质为选自乙酸钾、碳酸钾、苯酚钾、磷酸钾、叔丁醇钾、碳酸钠、碳酸氢钠、叔丁醇钠、甲醇钠、乙醇钠、三乙基胺、三正丁基胺和二异丙基乙基胺中的一种或多种的组合。根据本发明的一个优选且具体的方面，所述碱性物质为碳酸氢钠。
由于以上技术方案的实施，本发明与现有技术相比存在如下优势：
本发明提供了新型的吡唑并嘧啶化合物，该类吡唑并嘧啶化合物具有优异的PI3K抑制活性，可以应用于治疗由磷脂肌醇-3-激酶(PI3K)介导的疾病，为癌症治疗提供更多更优的药物选择。此外，相比已有PI3K抑制剂，本发明的吡唑并嘧啶化合物结构简单，制备成本相对较低。
附图说明
图1显示了化合物I-1至化合物I-6以及阳性对照化合物GDC-0941对PI3Kα的抑制率的关系曲线。
具体实施方式
术语定义
除非另外定义，本文使用的所有技术和科学术语具有与本发明所属领域的普通技术人员通常理解的相同的含义。
术语“异构体”是指由分子中原子在空间上排列方式不同所产生的异构体。包括顺反异构体、对映异构体和构象异构体。所有立体异构体均属于本发明的范围。本发明的化合物可以为单独立体异构体或其它异构体的混合例如外消旋体，或者所有其它立体异构体的混合。
术语“盐”是指本发明所述的化合物与酸形成的药学上可接受的盐，所述的酸可以是有机酸或无机酸，具体可选自：磷酸、硫酸、盐酸、氢溴酸、柠檬酸、马来酸、丙二酸、扁桃酸、琥珀酸、富马酸、醋酸、乳酸、硝酸、磺酸、对甲苯磺酸、苹果酸、甲烷磺酸或其类似物。
术语“溶剂化物”是指通过与溶剂分子配位形成固态或液态的配合物的本发明化合物的形式。水合物是溶剂化物的特殊形式，其中与水发生配位。在本发明范围内，溶剂化物优选是水合物。
术语“结晶”是指本发明所述的化合物形成的各种固体形态，包括晶型、无定形。
以下实施例可以使本专业技术人员更全面地理解本发明，但不以任何方式限制本发明。所有化合物的结构均经1H NMR或MS所确定。
实施例中用到的化合物名称缩写如下：
DBU：1,8-二氮杂二环十一碳-7-烯；DMF：N,N-二甲基甲酰胺；THF:四氢呋喃；Pd(dppf)Cl2：[1,1'-双(二苯基膦基)二茂铁]二氯化钯；DTT：二硫苏糖醇；ATP：三磷酸腺苷；TK：酪氨酸激酶；HEPES：4-羟乙基哌嗪乙磺酸。
实施例1化合物I-1的制备
采取以下路线合成化合物I-1：
1.1.化合物2的合成化合物2：中文名称为5-氟-2,6-二氧-1,2,3,6-四氢嘧啶-4-羧酸甲酯；英文名称为methyl5-fluoro-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-carboxylate；
将5-氟乳清酸(化合物1)(40g,0.23mol)溶于N,N-二甲基甲酰胺(500mL)中，缓慢滴加DBU(35.0g,0.23mol),室温下搅拌1h,再缓慢滴加碘甲烷(32.0g,0.23mol)，在60度下搅拌4h。反应结束后，搅拌下加入100mL的冰水，析出固体，过滤，滤饼用水洗涤(100mL x3)，真空干燥，得到化合物2(30g,产率＝70％)。测得：1H NMR(CDCl3,400MHz):δ11.85(s,1H),10.84(s,1H),3.88(s,3H).
1.2.化合物3的合成化合物3：中文名称为2,6-二氯-5-氟嘧啶-4-羧酸甲酯；英文名称为methyl2,6-dichloro-5-fluoropyrimidine-4-carboxylate；
在三氯氧磷(700mL)中依次加入化合物2(46.0g，0.24mol)，N,N-二甲基甲酰胺(0.5mL)，1,4-二氧六环(20mL)，在110度下搅拌7天。LCMS检测反应结束后，减压浓缩，将所得残余物缓慢滴加到碳酸氢钠水溶液中，并用乙酸乙酯萃取(500mL x 3)，有机相用硫酸钠干燥浓缩后得到化合物3(53.7g,产率>90％)。测得：ESI-MS m/z＝225[M+1]+.1H NMR(CDCl3,400MHz):3.94(s,3H).
1.3.化合物4的合成化合物4：中文名称为2-氯-5-氟-6-吗啉嘧啶-4-羧酸甲酯；英文名称为methyl2-chloro-5-fluoro-6-morpholinopyrimidine-4-carboxylate；
将化合物3(53.7g,12.9mmol)溶在乙酸乙酯(1.5L)中，反应液冷却到零度，然后分次加入吗啉(44.6g，0.5mol)。在此温度下反应1h,LCMS检测反应结束后，加入100mL的水，有机相用硫酸钠干燥后浓缩，得到化合物4(60.0g,产率＝90％)。测得：ESI-MS m/z＝276[M+1]+.1H NMR(CDCl3,400MHz):δ3.97(s,3H),3.90-3.86(m,4H),3.82-3.79(m,4H).
1.4.化合物5的合成化合物5：中文名称为2-氯-5-氟-6-吗啉嘧啶-4-甲酰胺；英文名称为2-chloro-5-fluoro-6-morpholinopyrimidine-4-carboxamide；
将化合物4(55.0g,0.2mol)溶于甲醇(250mL)、四氢呋喃(750mL)和水(250mL)中，分次加入氢氧化锂(12.6g,1.5mol)。反应液在0度下反应1h，LCMS检测反应结束后，加入盐酸水溶液(1M)调至pH＝5,减压浓缩得到粗品(50.0g,产率>90％).将该粗品(50g,0.19mol)溶于氯化亚砜(200mL)中，在室温搅拌4h。LCMS检测反应结束后，减压浓缩干后，加入1,4-二氧六环(1L)配成溶液，然后不断通入氨气，反应液在0度下搅拌4h。LCMS检测反应结束后，将反应液浓缩后，加入乙酸乙酯(500mL),滤掉固体，滤液旋干，用柱层析纯化(石油醚/乙酸乙酯＝1：1)，得到化合物5(36.5g,产率＝71％)。测得：ESI-MS m/z＝261[M+1]+.1H NMR(DMSO-d6,400MHz):δ8.01(s,1H)δ7.85(s,1H),3.76-3.71(m,4H),3.70-3.68(m,4H).
1.5.化合物6的合成化合物6：中文名称为2-氯-5-氟-6-吗啉嘧啶-4-碳腈；英文名称为2-chloro-5-fluoro-6-morpholinopyrimidine-4-carbonitrile；
将化合物5(36.5g,0.138mol)溶在二氯甲烷(1.5L)中，反应液冷却到零度，分别加入三乙胺(140g,1.38mol)，三氟乙酸酐(82g，0.69mol)。室温下反应过夜,LCMS检测反应结束后，将反应液浓缩后，加入乙酸乙酯,有机相用碳酸氢钠水洗，饱和盐水洗，用硫酸钠干燥后浓缩，用柱层析纯化(石油醚/乙酸乙酯＝10：1)，得到化合物6(25.0g,产率＝73％)。测得：ESI-MS m/z＝243[M+1]+.1H NMR(CDCl3,400MHz):δ3.90-3.88(m,4H),3.84-3.80(m,4H).
1.6.化合物8的合成化合物8：中文名称为2-(4-异氰酸酯苯基)-4,4,5,5-四甲基-1,3,2-二氧杂环戊烷；英文名称为2-(4-isocyanatophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane；
在300mL的二氯甲烷中分别加入4-氨基苯硼酸频哪醇酯化合物7(10g,45.6mmol)，三乙胺(13.8g，136.8mmol)，冷却到零度，在零度分批缓慢加入三光气(8.1g,27.4mmol)，之后在零度下搅拌50分钟得到化合物8的溶液，直接用于下一步。
1.7.化合物9的合成化合物9：中文名称为1-(4-(羟甲基)苯基)-3-(4-(4,4,5,5-四甲基-1,3,2-二恶英-2-基)苯基)脲；英文名称为：
1-(4-(hydroxymethyl)phenyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea；
在零度向上述化合物8的溶液加入对氨基苯甲醇(8.4g，68mmol)，之后在零度下搅拌15分钟，升温至室温，在室温下再搅拌3h。LC-MS检测反应结束后，将反应液浓缩旋干，用二氯甲烷萃取，有机相用碳酸氢钠饱和溶液和氯化钠饱和溶液洗涤，无水硫酸钠干燥，过滤，滤液旋干，经柱层析纯化(二氯甲烷/甲醇＝40:1)，得到黄色固体化合物9(11g,产率＝60％)。测得：ESI-MS m/z＝369[M+1]+.1H NMR(DMSO-d6,400MHz):δ9.02(s,1H),8.89(s,1H),7.60-7.58(d,J＝8Hz,2H),7.49-7.47(d,J＝8.4Hz,2H),7.42-7.40(d,J＝8Hz,2H),7.24-7.21(d,J＝8.4Hz,2H),5.06(m,1H),4.44-4.42(d,J＝5.6Hz,2H),1.28(s,12H).
1.8.化合物10的合成化合物10：中文名称为1-(4-(4-氰基-5-氟-6-吗啉嘧啶-2-基)苯基)-3-(4-(羟甲基)苯基)尿素；英文名称为：
1-(4-(4-cyano-5-fluoro-6-morpholinopyrimidin-2-yl)phenyl)-3-(4-(hydroxymethyl)phenyl)urea；
将化合物(9)(3.5g,9.5mmol)溶于二氧六环(100mL)和水(5mL)中，再加入化合物(6)(2.9g,12mmol),碳酸氢钠(2.4g,28.5mmol)，XPhos(400mg)和Pd2(dba)3(180mg)，氮气置换3次。在氮气保护下在85度搅拌2天。反应液减压浓缩，加入乙酸乙酯(20mL)和水(30mL),室温下搅拌0.5小时，过滤，滤饼用水洗，乙酸乙酯洗涤。滤饼加入乙酸乙酯(15mL)再搅拌0.5小时，过滤，真空干燥得到化合物(10)(1.9g,产率＝44.7％)。测得：ESI-MS m/z＝449[M+1]+.1H NMR(DMSO-d6,400MHz):δ8.98(s,1H),8.72(s,1H),8.17-8.15(d,J＝8.4Hz,2H),7.58-7.56(d,J＝9.2Hz,2H),7.43-7.41(d,J＝8Hz,2H),7.24-7.22(d,J＝8Hz,2H),5.08-5.05(t,J＝6Hz,1H),4.44-4.42(d,J＝5.6Hz,2H),3.87-3.86(m,4H),3.77-3.75(m,4H).
1.9.化合物I-1的合成
化合物I-1：中文名称为1-(4-(3-氨基-7-吗啉-1H-吡唑啉[4,3-d]嘧啶-5-基)苯基)-3-(4-羟甲基)苯基)脲；英文名称为：
1-(4-(3-amino-7-morpholino-1H-pyrazolo[4,3-d]pyrimidin-5-yl)phenyl)-3-(4-(hydroxymethyl)ph enyl)urea；
将化合物10(0.9g,2.5mmol)混悬于1,4-二氧六环(80mL)中，加入水合肼(20mL,85％)，在65度下搅拌20h，LCMS检测反应结束后，加入20mL的水，浓缩，析出固体，过滤，滤饼用水洗(10mL×2)，经柱层析纯化(二氯甲烷/甲醇＝20：1～5:1)，得到化合物I-1(0.55g,产率＝59.7％)。测得：1H NMR(DMSO-d6+D2O,400MHz):δ8.29(m,2H),7.54-7.52(m,2H),7.44-7.41(m,2H),7.26-7.214(m,2H),4.44(s,2H),4.28-3.79(m,8H).LCMS[mobile phase:from85％water(0.02％NH4Ac)and 15％CH3CN to 40％water(0.02％NH4Ac)and 60％CH3CN in15min,finally under these conditions for 0.5min.]purity is>96％,Rt＝9.205min；MS Calcd.:460；MS Found:461[M+H]+.
实施例2化合物I-2的制备
采取以下路线合成化合物I-2：
2.1.化合物11的合成化合物11：中文名称为1-(4-(2-羟丙基)苯基)-3-(4-(4,4,5,5-四甲基-1,3,2-二氧杂醇-2-基)苯基)尿素；英文名称为：
1-(4-(2-hydroxypropan-2-yl)phenyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ur ea；
在零度向化合物8的溶液(100mL，来自4.34g的化合物7,19.8mmol)加入胺(
2.0g，13.2mmol)。反应液在零度下搅拌15分钟，自然升至室温，在室温下再搅拌4h。LC-MS检测反应结束后，氯化钠饱和溶液洗涤，有机相用无水硫酸钠干燥，过滤，滤液旋干，残余物加入乙醚(10mL)，过滤，真空干燥得到白色固体化合物11(5.0g,产率＝96％)。测得：ESI-MS m/z＝397[M+1]+
2.2.化合物12的合成化合物12：中文名称为1-(4-(4-氰基-5-氟-6-吗啉嘧啶-2-基)苯基)-3-(4-(2-羟丙基-2-基)苯基)尿素；英文名称为：
1-(4-(4-cyano-5-fluoro-6-morpholinopyrimidin-2-yl)phenyl)-3-(4-(2-hydroxypropan-2-yl)phenyl)urea；
将化合物11(2.0g,5mmol)溶于二氧六环(40mL)和水(4mL)中，再加入化合物6(1.5g,6
mmol),碳酸氢钠(1.3g,15mmol)，XPhos(400mg)和Pd2(dba)3(180mg)，氮气置换3次。在氮气保护下在90度搅拌16小时。反应液减压浓缩，加入乙酸乙酯(20mL)和水(30mL),室温下搅拌0.5小时，过滤，滤饼用水洗，乙酸乙酯洗涤。滤饼加入乙酸乙酯(10mL)再搅拌0.5小时，过滤，真空干燥得到化合物12(1.2g,产率＝50％)。测得：ESI-MS m/z＝477[M+1]+。
2.3.化合物I-2的合成化合物I-2：中文名称为1-(4-(3-氨基-7-吗啉-1H-吡唑啉[4,3-d]嘧啶-5-基)苯基)-3-(4-(2-羟丙基-2-基)苯基)尿素；英文名称为：
1-(4-(3-amino-7-morpholino-1H-pyrazolo[4,3-d]pyrimidin-5-yl)phenyl)-3-(4-(2-hydroxypropan-2-yl)phenyl)urea；
将化合物12(2.0g,4.2mmol)混悬于二氧六环(50mL)中，加入水合肼(10mL,85％)，在70度下搅拌16h，LCMS检测反应结束后，加入20mL的水，浓缩，析出固体，过滤，得到滤饼，并以水洗(10mL×2)，经柱层析纯化(二氯甲烷/甲醇＝20：1～5:1)，得到化合物I-2(1.0g,产率＝48.8％)。测得：1H NMR(DMSO-d6,400MHz):δ11.86(1H),8.79(s,1H),8.62(s,1H),8.31-8.29(d,J＝8.4Hz,2H),7.57-7.53(d,J＝8.8Hz,2H),7.37(s,4H),5.43-5.40(m,1.5H),4.90(s,H),3.97(s,3H),3.78(m,8H),1.41(s,6H).LCMS[mobile phase:from 80％water(0.02％NH4Ac)and 20％CH3CN to 50％water(0.02％NH4Ac)and 50％CH3CN in6.5min,finally under these conditions for 0.5min.]purity is>95％,Rt＝3.198min；MS Calcd.:488；MS Found:489[M+H]+.
实施例3化合物I-3的制备
采取以下路线合成化合物I-3：
3.1.化合物14的合成
化合物14：中文名称为N-(甲磺酰基)-2-(4-硝基苯基)乙酰胺；英文名称为：
N-(methylsulfonyl)-2-(4-nitrophenyl)acetamide；
将化合物13(6.0g,0.033mol)溶解于二氯甲烷(100mL)中，加入CDI(10.7g,0.066mol，N,N'-羰基二咪唑)，在室温下搅拌1h，加入甲基磺酰胺(3.45g,0.036mol)。反应液在室温下搅拌过夜，加入DBU(10.0g,0.066mol),然后室温搅拌过夜。反应液用盐酸(4N)调pH＝1,有机相用水洗涤，无水硫酸钠干燥，过滤。滤液减压浓缩，过滤，用二氯甲烷洗滤饼。滤饼真空干燥得到黄色固体化合物14(4.4g,产率＝59.7％)。测得：ESI-MS m/z＝257[M-1]+.1H NMR(DMSO-d6,400MHz):δ12.07(s,1H),8.22-8.20(d,J＝8.8Hz,2H),7.57-7.55(d,J＝8.4Hz,2H),3.83(s,2H),3.25(s,3H).
3.2.化合物15的合成
化合物15：中文名称为2-(4-氨基苯基)-N-(甲磺酰)乙酰胺；英文名称为：
2-(4-aminophenyl)-N-(methylsulfonyl)acetamide；
将化合物14)(4.4g,0.017mol)溶于乙醇(100mL)中，加入浓盐酸(1.6mL)，钯碳(10％，0.4g)，氢气置换3次。反应液在氢气球下室温搅拌过夜。LCMS监控反应完全后，减压浓缩。残余物加入水(50mL),滤掉钯碳。滤液经减压旋蒸至干，得到白色固体化合物15(4.1g,产率＝91.7％)。测得：ESI-MS m/z＝229[M+1]+.1H NMR(DMSO-d6,300MHz):δ7.38-7.33(m,4H),3.70(s,2H),3.26(s,3H).
3.3.化合物16的合成
化合物16：中文名称为N-(甲磺酰基)-2-(4-(3-(4,4,5,5-四甲基-1,3,2-二氧杂醇-2-基)苯基)脲基)苯基)乙酰胺；英文名称为：
N-(methylsulfonyl)-2-(4-(3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ureido)phenyl)acetamide；
将化合物15(6.3g,0.026mol)溶解于二氯甲烷(60mL)中，加入三乙胺(5.9mL,0.044mol),在冰水浴冷却下加入化合物8的溶液(100mL，来自4.7g的化合物7,17mmol),缓慢升至室温，搅拌过夜，用水(30mL*3)萃取，水相用盐酸(2N)酸化使pH＝6,过滤，真空干燥得到白色固体粗品化合物16(6.1g,产率>76.2％).测得：ESI-MS m/z＝474[M+1]+
3.4.化合物17的合成
化合物17：中文名称为2-(4-(4-(4-氰基-5-氟-6-吗啉嘧啶-2-基)苯基)脲基)苯基)-N-(甲磺酰基)乙酰胺；英文名称为：
2-(4-(3-(4-(4-cyano-5-fluoro-6-morpholinopyrimidin-2-yl)phenyl)ureido)phenyl)-N-(methylsulfo nyl)acetamide；
将化合物16(5.0g,10.6mmol)溶于1,4-二氧六环(100mL)和水(5mL)中，再加入化合物6(2.6g,10.6mmol),碳酸氢钠(2.7g,31.8mmol)，XPhos(400mg)和Pd2(dba)3(180mg)，氮气置换3次。在氮气保护下85度搅拌2天。反应液减压浓缩，加入乙酸乙酯(50mL)和水(200mL),室温下搅拌0.5小时，过滤，滤饼用水洗，乙酸乙酯洗涤。水相用盐酸(2N)酸化使pH＝6,过滤，滤饼在乙酸乙酯(15mL)中搅拌0.5h,过滤真空干燥得到灰色固体化合物17(2.8g,产率>47.8％).测得：ESI-MS m/z＝554[M+1]+
3.5.化合物I-3的合成
化合物I-3：中文名称为2-(4-(3-(3-氨基-7-吗啉-1H-吡唑啉[4,3-D]嘧啶-5-基)苯基)脲基)苯基)-N-(甲磺酰基)乙酰胺；英文名称为：
2-(4-(3-(4-(3-amino-7-morpholino-1H-pyrazolo[4,3-d]pyrimidin-5-yl)phenyl)ureido)phenyl)-N-(methylsulfonyl)acetamide；
将化合物8(2.0g,3.6mmol)混悬于二氧六环(50mL)中，加入水合肼(20mL,85％)，在65度下搅拌15min，在冰水冷却下用盐酸(2N)酸化使pH＝7,过滤，滤饼经硅胶柱纯化(DCM:MeOH＝30:1～5:1),得到黄色固体，再进一步用HPLC制备，得到化合物I-3(125mg,产率＝6.25％)。测得：1H NMR(DMSO-d6,400MHz):δ11.90(bs,1H),8.82(s,1H),8.69(s,1H),8.31-8.28(d,J＝8.4Hz,2H),7.53-7.51(d,J＝8.4Hz,2H),7.42-7.40(d,J＝8.4Hz,2H),7.19-7.17(d,J＝8.8Hz,2H),5.42(bs,2H),3.97(m,4H),3.79(m,4H),3.49(s,2H),3.14(s,3H).LCMS[mobile phase:from 90％water(0.02％NH4Ac)and 10％CH3CN to 50％water(0.02％NH4Ac)and 50％CH3CN in 6.5min,finally under these conditions for0.5min.]purity is>95％,Rt＝2.992min；MS Calcd.:565；MS Found:566[M+H]+.
实施例4化合物I-4的制备
采取以下路线合成化合物I-4：
4.1.化合物19的合成
化合物19：中文名称为2-(2-氰基丙烷-2-基)苯甲腈；英文名称为：
2-(2-cyanopropan-2-yl)benzonitrile；
将氢化钠(60％，12.0g,0.3mol)加入到四氢呋喃(150mL),冰水浴冷却至0度，滴加化合物18(14.2g,0.1mol)的四氢呋喃(50mL)溶液，加完后在室温搅拌1小时。将反应液再冷却到0度，滴加CH3I(57.0g,0.4mol),室温搅拌过夜，倒入冰水(200mL)淬灭，乙酸乙酯萃取(50mL x 2)，有机相用硫酸钠干燥浓缩，加入甲基叔丁基醚(20mL)和石油醚(50mL),搅拌过滤，真空干燥得到黄色固体化合物19(13.8g,产率18.1％)。测得：1H NMR(CDCl3,400MHz):δ7.79-7.76(m,2H),7.67-7.62(m,1H),7.48-7.44(m,1H),1.97(s,6H).
4.2.化合物20的合成
化合物20：中文名称为4,4-二甲基异喹啉-1,3(2H，4H)-二酮；英文名称为：
4,4-dimethylisoquinoline-1,3(2H,4H)-dione；
在冰水浴冷却下将化合物19(13.8g,0.081mol)加入到H2SO4(90％,44mL)中，室温下搅拌2天，再60度搅拌过夜。反应液冷却到室温再倒入搅拌的冰水中，过滤，水洗，真空干燥得到类白色固体化合物20(14.9g,产率97.3％)。测得：ESI-MS m/z＝188[M-1]-.1H NMR(CDCl3,400MHz):8.41(bs,1H)，8.24-8.22(m,1H),7.70-7.66(m,1H),7.51-7.44(m,2H),1.66(s,6H).
4.3.化合物21的合成
化合物21：中文名称为4,4-二甲基-7-硝基异喹啉-1,3(2H，4H)-二酮；英文名称为：
4,4-dimethyl-7-nitroisoquinoline-1,3(2H,4H)-dione；
将发烟硝酸(60mL)冷却到0度，缓慢加入浓硫酸(60mL)，再分次加入化合物20(14.0g,0.074mol),得到黄色的溶液，0～5度搅拌2小时后倒入搅拌的冰水(400mL)中，过滤，水洗，真空干燥得到类白色固体化合物21(17g,产率98.2％)。测得：ESI-MS m/z＝233[M-1]-.1H NMR(acetone-d6,400MHz):δ10.44(bs,1H),8.89-8.86(d,J＝2.8Hz,1H),8.58-8.55(m,1H),8.10-8.08(d,J＝8.4Hz,1H),1.76(s,6H).
4.4.化合物22的合成
化合物22：中文名称为3,3-二甲基-6-硝基吲哚啉-2-酮3,3-dimethyl-6-nitroindolin-2-one
将NaOH(19.6g,0.49mol)溶于水(300mL)中，在冰水浴冷却至5度以下，分次加入Br2(20.7g,0.13mol),搅拌10分钟后加入化合物21(19.0g,0.081mol),室温搅拌过夜。在反应液中加入NaOH(10.0g,0.25mol)和水(40mL)。将反应液在80度搅拌0.5小时，再冷却至室温，在冰水浴冷却下，用浓盐酸调pH＝1,过滤，水洗，真空干燥得到黄色固体化合物22(10.0g,产率59.9％)。测得：ESI-MS m/z＝205[M-1]-.1H NMR(CDCl3,400MHz):δ9.00(s,1H),8.00-7.97(m,1H),7.79-7.78(d,J＝2.4Hz,1H),7.35-7.33(d,J＝7.6Hz,1H),1.45(s,6H).
4.5.化合物23的合成
化合物23：中文名称为6-氨基-3,3-二甲基吲哚啉-2-酮；英文名称为：
6-amino-3,3-dimethylindolin-2-one；
将化合物22(10.0g,0.19mol)溶于乙醇(700mL)和二氯甲烷(150mL)中，加入浓盐酸(10mL)，钯碳(10％，400mg),氢气球置换3次，室温搅拌过夜。过滤掉钯碳，滤液减压浓缩，剩余物加入甲基叔丁基醚，过滤，真空干燥得到黄色固体化合物23(9.0g,产率87.3％)。测得：ESI-MS m/z＝177[M+1]+.1H NMR(CDCl3,400MHz):δ10.48(s,1H),7.31-7.29(d,J＝7.6Hz,1H),6.83-6.79(m,2H),1.22(s,6H).
4.6.化合物24的合成
化合物24：中文名称为1-(3,3-二甲基-2-氧吲哚-6-基)-3-(4,4,5,5-四甲基-1,3,2-二氧杂醇-2-基)苯基)尿素；英文名称为：
1-(3,3-dimethyl-2-oxoindolin-6-yl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea；
在0～5度向化合物8的溶液(100mL，来自5.3g的化合物7,23.7mmol)滴加化合物23(4.0g,18.8mmol)和三乙胺(2.6mL,18.8mmol)的二氯甲烷溶液。反应液在室温搅拌过夜，用碳酸氢钠水溶液洗涤，水洗，有机相减压浓缩，过滤，少量二氯甲烷洗滤饼，真空干燥得到类白色固体化合物24(5.2g,产率65.7％)。测得：ESI-MS m/z＝295[M+1]+
4.7.化合物25的合成
化合物25：中文名称为1-(4-(4-氰基-5-氟-6-吗啉嘧啶-2-基)苯基)-3-(4-(羟甲基)苯基)尿素；英文名称为：
1-(4-(4-cyano-5-fluoro-6-morpholinopyrimidin-2-yl)phenyl)-3-(4-(hydroxymethyl)phenyl)urea；
将化合物24(2.0g,4.7mmol)溶于1,4-二氧六环(25mL)和水(1.25mL)中，再加入化合物6(1.1g,4.7mmol),碳酸氢钠(1.2g,14.2mmol)，XPhos(600mg)和Pd2(dba)3(300mg)。反应液在90度下搅拌过夜，LCMS检测反应结束后，加入10mL的水，并用乙酸乙酯萃取，有机相用无水硫酸钠干燥后过滤，滤液减压浓缩，经柱层析纯化(二氯甲烷/甲醇＝20：1)，得到化合物25(500mg,产率＝20％)。测得：ESI-MS m/z＝502[M+1]+.1H NMR(DMSO-d6,400MHz):δ10.28(s,1H),8.92(s,1H),8.74(s,1H),8.17-8.15(d,J＝7.2Hz,1H),7.58-7.56(d,J＝8Hz,2H),7.27(s,1H),7.17-7.15(d,J＝8Hz,1H),6.88-6.84(m,1H).
4.8.化合物I-4的合成
化合物I-4：中文名称为1-(4-(3-氨基-7-吗啉-1H-吡唑[4,3-d]嘧啶-5-基)苯基)-3-(3,3-二甲基-2-氧吲哚啉-6-基)尿素；英文名称为：
1-(4-(3-amino-7-morpholino-1H-pyrazolo[4,3-d]pyrimidin-5-yl)phenyl)-3-(3,3-dimethyl-2-oxoin dolin-6-yl)urea；
将化合物25(1.26g,2.5mmol)溶于1,4-二氧六环(80mL)中，再加入水合肼(25mL,85％)，在70度下搅拌20h，LCMS检测反应结束后，加入10mL的水，浓缩，析出固体，过滤，滤饼用水洗(10mL x 2)，经柱层析纯化(二氯甲烷/甲醇＝20：1)，得到化合物I-4(0.86g,产率＝47％)。测得：1H NMR(DMSO-d6,400MHz):δ12.84(s,0.3H),11.85(s,0.6H),10.28(s,1H),8.88-8.70(m,2H),8.301(s,2H),7.53-7.51(d,J＝8Hz,2H),7.30(s,1H),7.16-7.14(d,J＝8Hz,1H),6.86-6.83(d,J＝8Hz,1H),5.70(s,0.6H),5.28(s,1H),4.34-4.16(m,1H),4.10-3.78(m,7H),3.18-3.17(d,J＝4Hz,1H),1.23(s,6H).LCMS[mobile phase:from 80％water(0.02％NH4Ac)and 20％CH3CN to 30％water(0.02％NH4Ac)and 70％CH3CN in 6.5min,finally under these conditions for 0.5min.]purity is>96％,Rt＝2.888min；MSCalcd.:513；MS Found:514[M+H]+.
实施例5化合物I-5的制备
采取以下路线合成化合物I-5：
5.1.化合物27的合成
化合物27：中文名称为(4-硝基-2-(三氟甲基)苯基)甲醇；英文名称为：
(4-nitro-2-(trifluoromethyl)phenyl)methanol；
将化合物26(25.0g,106.4mmol)溶于四氢呋喃(100mL)中，冰浴下缓慢加入硼氢化钠(11.5g,319.1mmol),再缓慢滴加三氟化硼乙醚(20mL)，之后室温搅拌过夜。TLC显示反应结束后，加入100mL的盐水，使用乙酸乙酯(300mL x 3)萃取，有机相用硫酸钠干燥浓缩后，得到化合物27(14.5g,产率＝61％).测得：ESI-MS m/z＝222[M+1]+
5.2.化合物28的合成
化合物28：中文名称为叔丁基二甲基(4-硝基-2-(三氟甲基)苄基)氧基)硅烷；英文名称为tert-butyldimethyl((4-nitro-2-(trifluoromethyl)benzyl)oxy)silane；
冰浴下在二氯甲烷(120mL)中分别加入化合物27(14.0g，63.64mmol)，叔丁基二甲基氯硅烷(19.2g,127.27mmol)，三乙胺(16.1g,159.1mmol)，对二甲胺基吡啶(0.78g,6.36mmol)，然后反应液在室温搅拌2h。TLC检测反应结束后，加入100mL的盐水,并用二氯甲烷(200mL x 3)萃取，有机相用硫酸钠干燥浓缩后，用柱层析纯化(石油醚/乙酸乙酯＝100:1-50:1)，得到化合物28(15.0g,产率＝70％),直接用于下一步反应。
5.3.化合物29的合成
化合物29：中文名称为4-((叔丁基二甲基硅)氧基)甲基)-3-(三氟甲基)苯胺；英文名称为4-(((tert-butyldimethylsilyl)oxy)methyl)-3-(trifluoromethyl)aniline；
将化合物28(15.0g,44.78mmol)溶在乙醇/水(200mL/80mL)中，加入氯化铵(15.0g,268.68mmol)，温度升到80度，再次加入铁粉(11.0g,201.49mmol),反应在此温度下反应1h,LCMS检测反应结束后，加入盐水(100mL)过滤，滤液使用乙酸乙酯(200mL x 3)萃取,有机相用硫酸钠干燥后浓缩，得到化合物29(11.0g,产率＝80％)。测得：ESI-MS m/z＝306[M+1]+.1H NMR(CDCl3,400MHz):δ7.49(d,J＝8.0Hz,1H),6.90(s,1H),6.83(d,J＝8.0Hz,1H),4.78(s,2H),0.94(s,9H),0.09(s,6H).
5.4.化合物30的合成
化合物30：中文名称为1-(4-((叔丁基二甲基硅基)氧基)甲基)-3-(三氟甲基)苯基)-3-(4-(4,4,5,5-四甲基-1,3,2-二氧杂醇-2-基)苯基)尿素；英文名称为：
1-(4-(((tert-butyldimethylsilyl)oxy)methyl)-3-(trifluoromethyl)phenyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea；
将化合物29(6.0g,19.68mol)溶于四氢呋喃(90mL)中，加入化合物8(12.0g,49.19mmol)。室温反应过夜，LCMS检测反应结束后，减压浓缩，用柱层析纯化(石油醚/乙酸乙酯＝10:1-5:1)，得到化合物30(5.5g,产率50％)。测得：ESI-MS m/z＝551.6[M+1]+
5.5.化合物31的合成
化合物31：中文名称为1-(4-((叔丁基二甲基硅氧基)甲基)-3-(三氟甲基)苯基)-3-(4-(4-氰基-5-氟-6-吗啉嘧啶-2-基)苯基)尿素；英文名称为：
1-(4-(((tert-butyldimethylsilyl)oxy)methyl)-3-(trifluoromethyl)phenyl)-3-(4-(4-cyano-5-fluoro-6-morpholinopyrimidin-2-yl)phenyl)urea；
将化合物30(6.5g,11.82mmol)溶于二氧六环(50mL)\水(5mL)中，再加入化合物6(3.2g,13.00mmol),碳酸氢钠(3.0g,35.46mmol)，XPhos(563mg,1.19mmol)和Pd2(dba)3(220mg,0.24mmol)。反应在85度下反应过夜，LCMS检测反应结束后，加入35mL的盐水，并用乙酸乙酯萃取，有机相用硫酸钠干燥后浓缩，用柱层析纯化(石油醚/乙酸乙酯＝3:1-1:2)，得到化合物31(3.0g,产率＝40％)。测得：ESI-MS m/z＝629.7[M-1]-.
5.6.化合物32的合成
化合物32：中文名称为1-(4-(3-氨基-7-吗啉-1H-吡唑[4,3-D]嘧啶-5-基)苯基)-3-(4-((叔丁基二甲基硅基)氧基)甲基)-3-(三氟甲基)苯基)尿素；英文名称为：
1-(4-(3-amino-7-morpholino-1H-pyrazolo[4,3-d]pyrimidin-5-yl)phenyl)-3-(4-(((tert-butyldimethy lsilyl)oxy)methyl)-3-(trifluoromethyl)phenyl)urea；
将化合物31(2.8g,4.45mmol)溶于1,4-二氧六环(50mL)中，再加入水合肼(12mL,85％)。反应在70度下反应2天，LCMS检测反应结束后，加入35mL的盐水，并用乙酸乙酯萃取，有机相用硫酸钠干燥后浓缩，用硅胶柱层析纯化(二氯甲烷/甲醇＝100:1-10:1),再使用反相柱纯化得到化合物32(1.30g,产率＝45％)。测得：ESI-MS m/z＝643.7[M+1]+.1H NMR(DMSO-d6,400MHz):δ9.02(s,1H),8.89(s,1H),8.21(d,J＝8.0Hz,2H),7.92(s,1H),7.52(brs,2H),7.44(d,J＝8.0Hz,2H),4.69(s,2H),3.78–3.50(m,8H),0.81(s,9H),0.00(s,6H).
5.7.化合物I-5的合成
化合物I-5：中文名称为1-(4-(3-氨基-7-吗啉-1H-吡唑[4,3-D]嘧啶-5-基)苯基)-3-(4-(羟甲基)-3-(三氟甲基)苯基)脲；英文名称为：
1-(4-(3-amino-7-morpholino-1H-pyrazolo[4,3-d]pyrimidin-5-yl)phenyl)-3-(4-(hydroxymethyl)-3-(trifluoromethyl)phenyl)urea；
将化合物32(1.3g,2.02mmol)溶解在0.5M的1,4-二氧六环(20mL)溶液里,再加入水(3mL).室温下搅拌2h,LCMS检测反应结束后，过滤。得到的不溶物分别使用乙腈，乙酸乙酯和甲基叔丁醚打浆，干燥得到化合物I-5(0.85g,产率80％)。测得：1H NMR(DMSO-d6,400MHz):δ9.67(s,1H),9.57(s,1H),8.37(d,J＝8.4Hz,2H),7.95(s,1H),7.69-7.62(m,4H),4.61(s,2H),4.45-4.15(m,4H),3.84-3.78(m,4H).1H NMR(DMSO-d6+D2O,400MHz):δ9.60(s,0.3H),9.48(s,0.3H),8.33(d,J＝8.4Hz,2H),7.97(s,1H),7.72-7.64(m,4H),4.64(s,2H),4.46-4.24(m,4H),3.87(brs,4H).LCMS[mobile phase:from 80％water(0.02％NH4Ac)and 20％CH3CN to30％water(0.02％NH4Ac)and 70％CH3CN in 6.5min,finallyunder these conditions for 0.5min.]purity is>95％,Rt＝2.974min；MS Calcd.:528；MS Found:529[M+H]+.
实施例6化合物I-6的制备
采取以下路线合成化合物I-6：
6.1.化合物34的合成
化合物34：中文名称为4-(2-(苄氧基)乙基)吗啉；英文名称为：
4-(2-(benzyloxy)ethyl)morpholine；
将化合物33(32.8g,0.25mol)溶于DMF(200mL)中，在冰水浴冷却下分次加入NaH(10g，0.25mol)，在室温搅拌1.5小时，滴加溴化苄(39.3g,0.23mol)。反应液在室温搅拌16小时，减压浓缩，加入乙酸乙酯(100mL)，用水洗涤，饱和食盐水洗涤。有机相减压浓缩，经硅胶柱纯化(DCM:MeOH＝10:1)，得到无色的油化合物34(40g,产率78％)。测得：ESI-MSm/z＝222[M+1]+
6.2.化合物35的合成
化合物35：中文名称为4-(2-((4-硝基苄基)氧基)乙基)吗啉；英文名称为：
4-(2-((4-nitrobenzyl)oxy)ethyl)morpholine；
将化合物34(40.0g,0.18mol)溶于乙酸酐(200mL)中，在冰水浴冷却至5度，滴加发烟硝酸(60mL)，在5度搅拌4小时。反应液缓慢倒入碳酸钠水溶液中,使得pH>8，用乙酸乙酯萃取。有机相用水洗涤，饱和食盐水洗涤，减压浓缩，经硅胶柱纯化(DCM:MeOH＝10:1)，得到无色的油化合物35(30.1g,产率62％)。测得：ESI-MS m/z＝267[M+1]+
6.3.化合物36的合成
化合物36：中文名称为4-((2-吗啉氧基)甲基)苯胺；英文名称为：
4-((2-morpholinoethoxy)methyl)aniline；
将化合物35(5.0g,0.018mol)溶于乙酸乙酯(200mL)中，加入10％的钯碳(1.0g)，氢气置换3次，在氢气球下室温搅拌16小时。反应液过滤，滤液减压浓缩至干，得到红色粗品化合物36(4.5g)，直接用于下一步。测得：ESI-MS m/z＝237[M+1]+
6.4.化合物37的合成
化合物37：中文名称为1-(4-((2-吗啉氧基)甲基)苯基)-3-(4-(4,4,5,5-四甲基-1,3,2-二氧杂醇-2-基)苯基)尿素；英文名称为：
1-(4-((2-morpholinoethoxy)methyl)phenyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phe nyl)urea；
冰浴下向化合物8的二氯甲烷溶液(100mL，来自6.6g的化合物7,30mmol)，滴加化合物36(5.9g,25mmol)的二氯甲烷(30mL)溶液。反应液在室温搅拌过夜，用碳酸氢钠水溶液洗涤，水洗，有机相减压浓缩，经硅胶柱纯化(DCM:MeOH＝10:1)，得到黄色固体化合物37(8.7g,产率72.3％)。测得：ESI-MS m/z＝482[M+1]+
6.5.化合物38的合成
化合物38：中文名称为1-(4-(4-氰基-5-氟-6-吗啉嘧啶-2-基)苯基)-3-(4-((2-吗啉氧基)甲基)苯基)尿素；英文名称为：
1-(4-(4-cyano-5-fluoro-6-morpholinopyrimidin-2-yl)phenyl)-3-(4-((2-morpholinoethoxy)methyl)phenyl)urea；
将化合物37(4.0g,8.3mmol)溶于1,4-二氧六环(100mL)和水(10mL)中，再加入化合物6(3.0g,12mmol),碳酸氢钠(2.5g,29.7mmol)，XPhos(600mg)和Pd2(dba)3(300mg)。反应液在85度下搅拌过夜，LCMS检测反应结束后，加入20mL的水，并用乙酸乙酯萃取，有机相用无水硫酸钠干燥后过滤，滤液减压浓缩，得到红色固体化合物38(6.0g,粗品),直接用于下一步。测得：ESI-MS m/z＝562[M+1]+
6.6.化合物I-6的合成
化合物I-6：中文名称为1-(4-(3-氨基-7-吗啉-1H-吡唑啉[4,3-D]嘧啶-5-基)苯基)-3-(4-((2-吗啉氧基)甲基)苯基)尿；
英文名称为：1-(4-(3-amino-7-morpholino-1H-pyrazolo[4,3-d]pyrimidin-5-yl)phenyl)-3-(4-((2-morpholinoethoxy)methyl)phenyl)urea；
将化合物38(5.5g,粗品)溶于1,4-二氧六环(100mL)中，再加入水合肼(15mL,85％)，在70度下搅拌16h，LCMS检测反应结束后，加入10mL的水，浓缩，析出固体，过滤，滤饼用水洗(10mL x 2)，经柱层析纯化(二氯甲烷/甲醇＝20：1)，得到化合物I-6(900mg,19％)。测得：1H NMR(DMSO-d6,400MHz):δ11.76(s,1H),8.81(s,1H),8.71(s,1H),8.31-8.29(m,2H),7.54-7.52(m,2H),7.46-7.44(m,2H),7.25-7.23(m,2H),5.36(bs,2H),4.40(s,2H),3.96(bs,3H),3.76(s,4H),3.55-3.52(m,6H),2.40(s,4H).LCMS[mobile phase:from 80％water(0.02％NH4Ac)and 20％CH3CN to 30％water(0.02％NH4Ac)and 70％CH3CN in6.5min,finally under these conditions for 0.5min.]purity is>95％,Rt＝2.823min；MS Calcd.:573；MS Found:574[M+H]+.
实施例7实施例化合物的生物活性实验
应用PI3-Kinase(human)HTRFTM Assay kit检测(PI3-Kinase(human)HTRFTMAssay kit检测的方法为国际通用方法)实施例的六个化合物I-1，I-2，I-3，I-4，I-5，I-6(以下实验中分别给予代号RMP-D09，RMP-D01，RMP-D02，RMP-D03，RMP-D04，RMP-D05)对PI3Kalpha酶的半数抑制浓度(IC50测定)，采用化合物GDC-0941作为阳性对照。阳性对照品：GDC0941(Pictilisib)
7.1材料和仪器
2104
Multilabel Reader(Cat:2104-0010,PerkinElmer)；
384well opaque balck plate(Cat.6007270,PerkinElmer)；
PI3-Kinase(human)HTRFTM Assay kit(Cat.33-016,Millipore)；
4×Reaction Buffer(Cat.33-002,Millipore)；PIP2 1mM(Cat.33-004,Millipore)；Stop A(Cat.
33-006,Millipore)；Stop B(Cat.33-008,Millipore)；DM A(Cat.33-010,Millipore)；DM B
(Cat.33-012,Millipore)；DM C(Cat.33-014,Millipore)；PI3k alpha(Cat.14-602,
Millipore)；ATP 10mM(cat PV3227,Invitrogen)；DTT 1M(cat D5545,Sigma)；
待测化化合物I-1，I-2，I-3，I-4，I-5，I-6(以下实验中分别给予代号RMP-D09，RMP-D01，
RMP-D02，RMP-D03，RMP-D04，RMP-D05)，以及GDC-0941。
7.2试剂配制
1×Reaction
Buffer
4×Reaction Buffer用ddH2O稀释至1×，并加入1M DTT使其终浓度为5mM。每次使用前新鲜配制。例如配制10mL 1×Reaction Buffer，加入2.5mL 4×Reaction Buffer,50μL 1M DTT，ddH2O 7.45mL。整个实验中，用新鲜配制的1×Reaction Buffer配制ATP工作液，底物和酶混合工作液等。
4×化合物工作液
待测化合物用DMSO溶解至1mM作为储存液，然后用DMSO4倍倍比稀释，共10个浓度点。各取1μL加入24μL 1×Reaction Buffer中。每个稀释溶液各取5μL加入384孔板中，并含有1％DMSO。
2×PIP2工作液
用1×reaction buffer配制2×PIP2工作液，使其终浓度为20μM，PIP2的反应终浓度为10μM，例如配制1ml 1x reaction buffer/PIP2工作液，取20μL PIP2加入到980μL1×reaction buffer中。这个工作液要多配0.1-0.2ml,以满足对照使用和死体积。
2×PIP2/激酶工作液
用2×PIP2工作液稀释激酶，激酶工作液的浓度为10ng/well。
无激酶对照(可视为100％抑制)
即2×PIP2工作液。
4×ATP工作液
10mM的ATP用1×reaction buffer稀释至40μM。在20μL激酶反应体系中，ATP的浓度为10μM。例如配制2ml ATP工作液，取8μL10 mM ATP加入到1992μL 1×reactionbuffer中。
终止液
Stop A和Stop B按3：1的比例混合，室温放置至少2小时后才可用，终止液可在室温下稳定12个小时。
检测液
DM C，DM A和DM B按照18：1：1的比例混合，室温放置至少2小时后才可用，检测液可在室温下稳定12个小时。
7.3实验流程
数据分析
计算各孔的Emission Ratio(ER)
Emission Ratio(ER)＝665nM Emission signal/620nm Emission signal
100％抑制对照的平均发射强度比(Emission Ratio)记为：ER100％
0％抑制对照的平均Emission Ratio记为：ER0％
计算抑制率
抑制率用以下公式计算：
抑制率＝(ERsample-ER0％)/(ER100％-ER0％)×100％【(ER阳性―ER样品)/(ER阳性―ER阴性)*100％】
7.4实验结果
应用PI3-Kinase(human)HTRFTM Assay kit检测6个化合物不同浓度下对PI3K-alpha酶的抑制率，控制DMSO浓度为1％，每个浓度为复孔，并选取GDC-0941作为阳性参照物进行测定，结果如图1所示。根据检测结果，各化合物对PI3K-alpha酶的半数抑制浓度(IC50)总结如下表1所示。
表1、待测化合物对PI3K-alpha的半数抑制浓度(IC50)
以上实验证明了本发明的新型吡唑并嘧啶化合物对磷脂肌醇-3-激酶(PI3Kα)的抑制作用，表明本发明的新型吡唑并嘧啶化合物(包括其可药用盐等)是一种新型PI3Kα抑制剂。因此，可以应用于治疗由磷脂肌醇-3-激酶介导的疾病，可治疗的恶性肿瘤包括但不限于肾癌、肝癌、结肠癌、胃肠道间质瘤、非小细胞肺癌、乳腺癌、胰腺癌、神经胶质瘤、淋巴癌，纤维肉瘤、卵巢癌，白血病和前列腺癌等。
本发明的其他化合物与化合物I-1至化合物I-6具有基本相同的结构，可以预期他们具有与化合物I-1至化合物I-6相当的优异活性。该类化合物是世界上首创的新型化合物，已经显示了明显的强活性,将用于进一步的新药研究，发明出国产的创新药物，用于市场急需的作用强，副作用小而且便宜的抗癌药。
以上实施例的说明只是用于帮助理解本发明的方法及其核心思想。应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明原理的前提下，还可以对本发明进行若干改进和修饰，这些改进和修饰也落入本发明权利要求的保护范围内。
Claims (11)
1.通式(I)所示的吡唑并嘧啶化合物或其可药用盐，
式中，A为-OH、-NH2、-SH、
B为-CnH2n-，n为1、2、3或4；其中，当A为
时，其中的C连接所述B，N与所述B所连接的苯环上的碳原子连接，且A、B与它们所连接的碳原子一起构成5元环；
Z为氢、羟基、C1-3烷基、氟、氯或溴，或为被选自氟、氯和溴中的一个或多个所取代的C1-3烷基；
M为H、-CH3或-CH2CH3。
2.根据权利要求1所述的通式(I)所示的吡唑并嘧啶化合物或其可药用盐，其特征在于：所述吡唑并嘧啶化合物的结构如下式(I-a)所示：
其中，A、B和M的定义分别同前述权利要求，Z1为氢、羟基、氟、氯、溴、甲基、乙基、异丙基、三氟甲基或五氟乙基。
3.根据权利要求1或2所述的通式(I)所示的吡唑并嘧啶化合物或其可药用盐，其特征在于：所述B为-CH2-、-CH2CH2-、-CH2CH2CH2-、-CH(CH3)-、-CH(CH3)CH2-、-C(CH3)2-或-CH2C(CH3)2-。
4.根据权利要求1或2所述的通式(I)所示的吡唑并嘧啶化合物或其可药用盐，其特征在于：
B为-CH2-，A为-OH、
或者，B为-C(CH3)2-，A为-OH或
5.根据权利要求1或2所述的通式(I)所示的吡唑并嘧啶化合物或其可药用盐，其特征在于：所述吡唑并嘧啶化合物为选自如下结构所示化合物：
6.如权利要求1至5中任一项权利要求所述的通式(I)所示的吡唑并嘧啶化合物或其可药用盐在制备预防和/或治疗由磷脂酰肌醇-3-激酶(PI3K)介导的疾病的药物中的应用。
7.根据权利要求6所述的应用，其特征在于：所述由磷脂酰肌醇-3-激酶(PI3K)介导的疾病为癌症，所述癌症为肾癌、肝癌、结肠癌、胃肠道间质瘤、非小细胞肺癌、乳腺癌、胰腺癌、神经胶质瘤、淋巴癌，纤维肉瘤、卵巢癌、白血病或前列腺癌。
8.一种药物组合物，其特征在于：包括一种或多种如权利要求1至5中任一项权利要求所述的通式(I)所示的吡唑并嘧啶化合物或其可药用盐，以及药学可接受的载体。
9.一种制备如权利要求1至5中任意一项权利要求所述的通式(I)所示的吡唑并嘧啶化合物或其可药用盐的中间体，其特征在于：所述中间体具有通式(II)所示结构：
式(II)中，A1为叔丁基二甲基硅氧基，或者A1与所述通式(I)中的A相同；B、Z分别与所述通式(I)中的B、Z相同。
10.根据权利要求9所述的中间体，其特征在于：所述中间体选自如下结构所示化合物：
11.一种如权利要求1至5中任意一项权利要求所述的通式(I)所示的吡唑并嘧啶化合物或其可药用盐的制备方法，其特征在于：所述制备方法包括使权利要求9或10所述的式(II)所示中间体与水合肼进行反应的步骤。
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Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1629145A (zh) * | 2000-04-27 | 2005-06-22 | 山之内制药株式会社 | 稠合杂芳基衍生物 |
| CN101238127A (zh) * | 2005-05-20 | 2008-08-06 | 艾伦托斯制药控股公司 | 嘧啶或三嗪稠合的二环金属蛋白酶抑制剂 |
| WO2009097446A1 (en) * | 2008-01-30 | 2009-08-06 | Genentech, Inc. | Pyrazolopyrimidine pi3k inhibitor compounds and methods of use |
| WO2010118367A2 (en) * | 2009-04-10 | 2010-10-14 | Progenics Pharmaceuticals, Inc. | Antiviral pyrimidines |
| CN102014914A (zh) * | 2008-01-15 | 2011-04-13 | 惠氏有限责任公司 | 3h-[1,2,3]三唑并[4,5-d]嘧啶化合物、其作为mtor激酶和pi3激酶抑制剂的用途、以及它们的合成 |
| CN102712642A (zh) * | 2009-11-12 | 2012-10-03 | 霍夫曼-拉罗奇有限公司 | N-7 取代的嘌呤和吡唑并嘧啶化合物、组合物和使用方法 |
| CN105143209A (zh) * | 2013-03-14 | 2015-12-09 | 诺华股份有限公司 | 作为激酶抑制剂的联芳基酰胺化合物 |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20070155738A1 (en) * | 2005-05-20 | 2007-07-05 | Alantos Pharmaceuticals, Inc. | Heterobicyclic metalloprotease inhibitors |
| US20080234262A1 (en) * | 2007-03-21 | 2008-09-25 | Wyeth | Pyrazolopyrimidine analogs and their use as mtor kinase and pi3 kinase inhibitors |
| US20090192176A1 (en) * | 2008-01-30 | 2009-07-30 | Wyeth | 1H-PYRAZOLO[3,4-D]PYRIMIDINE, PURINE, 7H-PURIN-8(9H)-ONE, 3H-[1,2,3]TRIAZOLO[4,5-D]PYRIMIDINE, AND THIENO[3,2-D]PYRIMIDINE COMPOUNDS, THEIR USE AS mTOR KINASE AND PI3 KINASE INHIBITORS, AND THEIR SYNTHESES |
| CN112707907B (zh) * | 2019-10-24 | 2023-05-23 | 张飞 | 嘌呤衍生物及其中间体与制备抗癌症药物的应用 |
-
2019
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- 2019-09-25 US US17/280,245 patent/US12054488B2/en active Active
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1629145A (zh) * | 2000-04-27 | 2005-06-22 | 山之内制药株式会社 | 稠合杂芳基衍生物 |
| CN101238127A (zh) * | 2005-05-20 | 2008-08-06 | 艾伦托斯制药控股公司 | 嘧啶或三嗪稠合的二环金属蛋白酶抑制剂 |
| CN102014914A (zh) * | 2008-01-15 | 2011-04-13 | 惠氏有限责任公司 | 3h-[1,2,3]三唑并[4,5-d]嘧啶化合物、其作为mtor激酶和pi3激酶抑制剂的用途、以及它们的合成 |
| WO2009097446A1 (en) * | 2008-01-30 | 2009-08-06 | Genentech, Inc. | Pyrazolopyrimidine pi3k inhibitor compounds and methods of use |
| WO2010118367A2 (en) * | 2009-04-10 | 2010-10-14 | Progenics Pharmaceuticals, Inc. | Antiviral pyrimidines |
| CN102712642A (zh) * | 2009-11-12 | 2012-10-03 | 霍夫曼-拉罗奇有限公司 | N-7 取代的嘌呤和吡唑并嘧啶化合物、组合物和使用方法 |
| CN105143209A (zh) * | 2013-03-14 | 2015-12-09 | 诺华股份有限公司 | 作为激酶抑制剂的联芳基酰胺化合物 |
Non-Patent Citations (1)
| Title |
|---|
| Synthesis and SAR of Novel 4-Morpholinopyrrolopyrimidine Derivatives as Potent Phosphatidylinositol 3-Kinase Inhibitors;Zecheng Chen et al.,;《J. Med. Chem.》;20100324;第53卷;第3169-3182页 * |
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