CN113354630B - 一种5,6-二氢苯并[h]喹唑啉类化合物及其应用 - Google Patents
一种5,6-二氢苯并[h]喹唑啉类化合物及其应用 Download PDFInfo
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- CN113354630B CN113354630B CN202110733903.0A CN202110733903A CN113354630B CN 113354630 B CN113354630 B CN 113354630B CN 202110733903 A CN202110733903 A CN 202110733903A CN 113354630 B CN113354630 B CN 113354630B
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- dihydrobenzo
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- -1 5,6-dihydrobenzo [ h ] quinazoline compound Chemical class 0.000 title claims abstract description 54
- 101000932478 Homo sapiens Receptor-type tyrosine-protein kinase FLT3 Proteins 0.000 claims abstract description 28
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- 206010028980 Neoplasm Diseases 0.000 claims abstract description 15
- LVGPUDKBSXRFFI-UHFFFAOYSA-N 5,6-dihydrobenzo[h]quinazoline Chemical class C1=CC=C2CCC3=CN=CN=C3C2=C1 LVGPUDKBSXRFFI-UHFFFAOYSA-N 0.000 claims abstract description 13
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- 125000000217 alkyl group Chemical group 0.000 claims description 18
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- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 2
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Abstract
本发明公开了一种5,6‑二氢苯并[h]喹唑啉类化合物及其应用，属于医药领域。本发明通式I所示的5,6‑二氢苯并[h]喹唑啉类化合物具有优异的抑制FLT3的生物活性对FLT3的抑制活性达到80％以上，可以被用作FLT3的抑制剂，为寻找新的治疗癌症、代谢与免疫疾病、心血管病以及神经性疾病等开辟新途径。
Description
技术领域
本发明涉及一种5,6-二氢苯并[h]喹唑啉类化合物及其应用，属于医药领域。
背景技术
白血病是一种血液癌症，其特征是骨髓中的髓样或淋巴样祖细胞异常增殖，导致正常的造血功能受损。根据国际癌症研究机构发布的数据显示，2020年全球估计有1930万例癌症新发病例和1000万癌症死亡病例。其中，新增白血病约47.5万例，占癌症总新发病例的2.5％。新增白血病死亡病例31.2万例，占癌症总死亡病例的3.1％。急性髓细胞性白血病(acute myeloid leukemia,AML)是最常见的血液癌症，与其他急性白血病相比，AML的发生率最高，约占成年人所有急性白血病的90％，且在血液系统疾病中死亡率也最高，五年存活率仅为20％～30％。根据涉及细胞类型的不同，可将AML分为M0-M7八个亚型，AML的发病机制涉及克隆的髓样干细胞群体的异常增殖和分化。当前针对AML患者的一线治疗通常是“7+3化疗”[阿糖胞苷7天和柔红霉素3天]和同种异体造血干细胞移植(hematopoietic stemcell transplantation,HSCT)。但是，使用这些细胞毒剂通常会导致不良的毒性。虽然HSCT对AML患者是可以预防复发的重要治疗策略，但会导致更高的与治疗相关的发病率和死亡率，尤其是在老年患者中，而AML主要是中位年龄为68岁的老年人。在65岁或65岁以上的人群中，高达70％的患者仍无法存活超过1年。因此，迫切需要开发新药来提高AML患者的生存率。
FLT3是位于13q12染色体上的原癌基因的表达产物，在骨髓造血干细胞上表达，随细胞分化而丧失表达，在调节造血祖细胞的存活、增殖和分化中起着重要作用。在大约70％的AML患者中，FLT3均是过表达的。许多临床研究表明，FLT3过表达与预后不良有关。大约30％的AML患者均检测到FLT3突变，其中包括JMD中的内部串联重复(internal tandemduplication,ITD,占25％)和TKD中的点突变(占7～10％)。通常，大多数肿瘤驱动因子突变是错义突变，而缺失和插入则不常见，而FLT3有所不同。尽管识别出少数驱动致癌性的错义突变，但大多数致癌突变是插入，最长可达几十个氨基酸(amino acid,AA)。这些突变的主要类型是在突变位置之前插入序列，有时带有修饰。这种插入称为ITD。FLT3-ITD突变破坏了FLT3的自抑制调节，诱导了配体独立和FLT3的自磷酸化。患有FLT3-ITD突变的AML患者预后不良且易产生耐药性，5年复发率高达79％，5年OS(Overall Survival,OS)为15％。FLT3-TKD突变最常见于TKD的D835或I836残基。与FLT3-ITD突变相似，FLT3-TKD突变导致二聚化和自磷酸化激活FLT3，从而导致不受控制的增殖。因此，FLT3被认为是治疗AML最有潜力的靶点。
目前已上市的FLT3抑制剂有Quizartinib、Gilteritinib、Sorafenib、Sunitinib和Midostaurin等8个药物。Quizartinib和Gilteritinib属于第二代FLT3抑制剂，具有更高的选择性和单药活性。所有FLT3抑制剂与细胞内TKD的ATP结合位点相互作用，竞争性地抑制ATP结合，从而阻止受体的自磷酸化和下游信号的激活。然而，当受体激活时，I型抑制剂与ATP结合位点结合，而II型抑制剂则与紧挨着ATP结合位点的疏水区域相互作用，只有当受体处于非活性构象时才能进入疏水区域，它们阻止了受体的激活。
考虑到信号转导的复杂性和各种途径之间的冗余和串扰，特异性激酶抑制剂的识别允许在对其他途径有限抑制的情况下进行准确的靶向，从而降低这些抑制化合物的毒性。我们仍然需要能够有效抑制激酶活性且靶向性更强的化合物。
发明内容
本发明的目的在于提供一种5,6-二氢苯并[h]喹唑啉类似物，其结构如式I所示的化合物或其药学上可接受的盐，具有抑制FLT3的生物学功能，从而为寻找新的治疗癌症、代谢与免疫疾病、心血管病以及神经性疾病等开辟新途径。
本发明的第一个目的是提供一种5,6-二氢苯并[h]喹唑啉类化合物，结构式如式I所示；
其中：R1选自H、卤素(F、Cl、Br、I)、未取代或卤素取代的C1-C8直链或支链烷基、未取代或卤素取代的C3-C6环烷基、未取代或卤素取代的1～4个杂原子取代的脂肪杂环基、-OR2、-NR2R3、-SR2、-(CH2)mC(O)OR2、-OC(O)R2、-(CH2)mC(O)NR2R3、-NR2C(O)R3、-(CH2)mC(S)OR2、-OC(S)R2、-NO2、-CN、-(CH2)mCN；
A1选自空、-NR4A3-、-OA3-、-SA3-、-(CH2)nC(O)O(CH2)pA3-、-(CH2)nC(O)N(CH2)pA3-、-(CH2)nC(S)(CH2)pA3-和-(CH2)nC(N-OH)(CH2)pA3-；
A2选自未取代或卤素或C1-C6直链或C1-C6支链烷基取代的苯环、C1-C6直链或C1-C6支链烷基取代的杂环；
X1、X2独立地选自N、O、S、CRx；Rx选自H、卤素、CH3、CF3；
L1选自直键、-O-、-NH(CH2)m-、-NHCO(CH2)m-和-CONH(CH2)m-；
L2选自
其中，R2和R3独立地选自H、未取代或卤素取代的C1-C6直链或支链烷基、未取代或卤素取代的C3-C5环烷基、1～4个杂原子取代的脂肪杂环、-(CH2)qR4；
A3选自未取代或1～4个基团取代的4～10个原子的芳基或杂环芳基，其中每一个取代基团独立地选自H、-X、未取代或卤素取代的C1-C8直链或支链烷基或者未取代或卤素取代的C3-C6环烷基或杂环烷基、-OR5、-NR5R6、-SR5、-(CH2)wC(O)OR5、-OC(O)R5、-(CH2)wC(O)NR5R6、-NR5C(O)R6、-(CH2)wC(S)OR5、-OC(S)R5、-(CH2)wC(N-OH)OR5、-OC(N-OH)R5、-NO2、-CN、-(CH2)wCN；
X3、X4独立地选自-(CH2)z、-(CH2)zNR7-、-(CH2)zO(CH2)z-和-(CH2)zS(CH2)z-。
其中，R4选自未取代或卤素取代的C3-C5环烷基、或1～4个杂原子取代的脂肪杂环；R5、R6和R7独立地选自H、未取代或卤素取代的C1-C6直链或支链烷基、未取代或卤素取代的C3-C5环烷基、未取代或卤素取代的1～4个杂原子取代的脂肪杂环；
m、n、p、q、w和z各自独立地选自0、1、2、3和4；Y代表O和S。
在本发明的一种实施方式中，上述杂环基或者脂肪杂环中杂原子包括N、O、S中一种或多种。
在本发明的一种实施方式中，R1具体可选-OR2。
在本发明的一种实施方式中，R2具体可选-Me、-(CH2)qR4。
在本发明的一种实施方式中，q具体可为2。
在本发明的一种实施方式中，R4具体可选吗啉。
在本发明的一种实施方式中，A1具体可选空键、-NH(C6H4)-、-NH2CO(C6H4)-和-NH2COCH2(C6H4)-。
在本发明的一种实施方式中，A2为芳杂环或者脂肪杂环。
在本发明的一种实施方式中，A2的结构具体可为：
在本发明的一种实施方式中，A2具体可选3-甲基异噁唑、3-叔丁基异噁唑、5-甲基异噁唑和5-叔丁基异噁唑。
在本发明的一种实施方式中，X1具体可选N、CH、CCH3、CF。
在本发明的一种实施方式中，X2具体可选CH、N。
在本发明的一种实施方式中，L1具体可选-NH-、-NHCH2-和-NHCO-。
在本发明的一种实施方式中，L2为直键的含义是指：L2两端的结构直接相连，即L2为0。
在本发明的一种实施方式中，L2具体可选
在本发明的一种实施方式中，通式I的化合物可以选自以下具体化合物：
本发明的第二个目的是提供一种组合物，含有上述5,6-二氢苯并[h]喹唑啉类化合物。
在本发明的一种实施方式中，所述组合物包含通式I的5,6-二氢苯并[h]喹唑啉类化合物或其药学可接受的盐以及至少一种药学可接受的赋形剂、载体和稀释剂。
其中所述的药学上可接受的盐为无机盐或有机盐，无机盐包括盐酸盐、氢溴酸盐、氢碘酸盐、高氯酸盐、硫酸盐、硫酸氢盐、硝酸盐、磷酸盐、酸式磷酸盐；所述有机盐包括甲酸盐、乙酸盐、三氟乙酸盐、丙酸盐、丙酮酸盐、羟乙酸盐、乙二酸盐、丙二酸盐、丁二酸盐、戊二酸盐、富马酸盐、马来酸盐、乳酸盐、苹果酸盐、柠檬酸盐、酒石酸盐、甲磺酸盐、乙磺酸盐、苯磺酸盐、水杨酸盐、对甲苯磺酸盐、抗坏血酸盐。
本发明化合物或其药学上可接受的盐可以配制为用于口服给药的固体制剂，包括，但不限于胶囊剂、片剂、丸剂、散剂、颗粒剂等。在这些固体剂型中，本发明通式通式Ⅰ化合物作为活性成分与至少一种常规惰性赋形剂(或载体)混合，例如与柠檬酸钠或磷酸二钙。或与下属成分混合：(1)填料或增溶剂，例如，淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸等；(2)粘合剂，例如，羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖、阿拉伯胶等；(3)保湿剂，例如，甘油等；(4)崩解剂，例如琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些符合硅酸盐和碳酸钠等；(5)缓溶剂，例如石蜡等；(6)吸收加速剂，例如季铵化合物等；(7)润湿剂，例如鲸蜡醇和单硬脂酸甘油酯等；(8)吸附剂，例如，高岭土等；(9)润滑剂，例如，滑石、硬脂酸钙、固体聚乙二醇、十二烷基硫酸钠等，或其混合物。胶囊剂、片剂、丸剂中也可包含缓冲剂。
所述固体剂型例如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材料如肠溶衣和其他本领域公知的材料晶型包衣或微囊化。他们可包含不透明剂，并且，这种组合物中活性成分的释放可以延迟的方式在消化道的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时，活性成分也可与上述赋形剂中的一种或者多种形成微胶囊形式。
本发明5,6-二氢苯并[h]喹唑啉类化合物或其药学上可接受的盐可以配制为用于口服给药的液体剂型，包括，但不限于药学上可接受的乳液、溶液、悬浮液、糖浆、酊剂等。除了作为活性成分的通式Ⅰ所示的5,6-二氢苯并[h]喹唑啉类化合物或其药学上可接受的盐外，液体剂型可包含本领域中常规采用的惰性稀释剂，例如水和其他溶剂，增溶剂和乳化剂、例如，乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油类，特别是棉籽油、花生油、玉米油、橄榄油、蓖麻油、芝麻油等或这些物质的混合物等。除了这些惰性稀释剂外，本发明液体剂型也可包括常规助剂，如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料等。
所述悬浮剂包括，例如，乙氧基化十八烷醇、聚氧乙烯山梨醇、和脱水山梨醇、微晶纤维素、琼脂等或这些物质的混合物。
本发明5,6-二氢苯并[h]喹唑啉类化合物和其药学上可接受的盐可以配置为用于胃肠外注射的剂型，包括，但不限于生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液，以及用于重新溶解成无菌的可注射溶液和分散液的无菌粉末。适宜的载体、稀释剂、溶剂、赋形剂包括水、乙醇、多元醇及其适宜的混合物。
本发明5,6-二氢苯并[h]喹唑啉类化合物或其药学上可接受的盐可以配置为用于局部给药的剂型，包括如软膏剂、散剂、栓剂、滴剂、喷射剂和吸入剂等。作为活性成分的本发明通式Ⅰ和通式Ⅱ化合物或其药学上可接受的盐在无菌条件下和生理上可接受的载体及任选的防腐剂、缓冲剂，和必要时可能需要的推进剂一起混合。
本发明通式Ⅰ所示的5,6-二氢苯并[h]喹唑啉类化合物或其药学上可接受的盐将以0.01-2000mg/kg、特别是2.5-1000mg/kg、特别是5-500mg/kg范围内的单位剂量向哺乳动物给予，并且这应该提供一个有效剂量。然而，每日剂量将必然取决于被治疗宿主、具体的给药途径、以及正在被治疗的疾病的严重性而变化。因此，可以由治疗任何具体患者的从业者决定最适剂量。
本发明的第三个目的是提供所述通式Ⅰ所示的5,6-二氢苯并[h]喹唑啉类化合物或其药学可接受的盐在制备FLT3激酶抑制剂中的应用。
本发明的第四个目的是提供所述通式Ⅰ所示的5,6-二氢苯并[h]喹唑啉类化合物或其药学可接受的盐在制备用于治疗哺乳动物关于酪氨酸激酶(如FLT3激酶)的酶活性并干扰由所述激酶转导的信号来调节、调节或抑制与异常细胞增殖的疾病的药物中的应用。
所述疾病包括白血病和多种实体瘤。
所述实体瘤包括但不限于：癌、肉瘤、成红细胞瘤、成胶质细胞瘤、脑膜瘤、星形细胞瘤、黑色素瘤和成肌细胞瘤。适应症可包括但不限于：卵巢癌、宫颈癌、结直肠癌、乳腺癌、胰腺癌、神经胶质瘤、恶性胶质瘤、黑色素瘤、前列腺癌、白血病、淋巴瘤、非霍奇金淋巴瘤、肺癌、肝细胞癌、胃癌、胃肠道间质瘤、甲状腺癌、胆管癌、子宫内膜癌、肾癌、间变性大细胞淋巴瘤、多发性骨髓瘤、黑色素瘤以及间皮瘤。优选地，其中所述的癌症包括急性骨髓性白血病(AML)、B前体细胞急性淋巴细胞性白血病、骨髓增生异常白血病、T细胞急性淋巴细胞性白血病和慢性粒细胞性白血病(CML)。
本发明所述FLT3激酶，特别是激活型突变体形式的FLT3、耐药型突变体形式的FLT3活性治疗可作为单独的疗法应用或除本发明化合物之外，可以涉及常规的同种异基因造血干细胞移植、化学疗法或放射疗法，可与其他药学上可接受的治疗剂联合给药，与其他抗肿瘤药物组合，此联合治疗可通过同时、顺序或分开使用治疗的各组分来实现。所述治疗剂肿瘤剂包括但不限于：作用于DNA化学结构的抗肿瘤药物，如阿糖胞苷、阿扎胞苷、地西他宾、依托泊苷和等，蛋白酶体抑制剂伏立诺他、硼替佐米和panobinostat等，影响核酸转录的抗肿瘤药物如伊达比星、柔红霉素、阿霉素、表阿霉素、阿克拉霉素等，细胞信号通路抑制剂如FMS样受体酪氨酸激酶抑制剂舒尼替尼、索拉非尼、吉利替尼、奎扎替尼、来他替尼、米哚妥林、Crenolanib等，血管内皮生长因子(VEGF)抑制剂西地尼布和塞马西尼等，抗肿瘤单抗，例如抗Gentuzumab Ozogamicine抗体、免疫抑制剂PD-1、PD-L1、OX40激动剂抗体等，待组合的各成分可同时或顺序的给予，以单一制剂形式或者以不同制剂的形式给予。所述组合不仅包括本发明化合物的一种或其他活性剂的组合，而且也包括本发明化合物的两种或更多的其他活性剂的组合。
有益效果：
本发明的化合物对FLT3的抑制活性达到80％以上，因此，本发明的化合物呈现很好的FLT3的抑制活性，可以被用作FLT3的抑制剂。
具体实施方式
本发明所用的“烷基”是指直链或支链饱和烃基基团。在一些实施方案中，烷基基团可具有1至10个碳原子(例如1至8个碳原子)。烷基基团的实例包括甲基(Me)、乙基(Et)、丙基(例如，正丙基和异丙基)、丁基(例如，正丁基、异丁基、仲丁基、叔丁基)、戊基基团(例如，正戊基、异戊基、新戊基)、己基(例如，正己基及其异构体)等。低级烷基基团一般最多有4个碳原子。低级烷基基团的实例包括甲基、乙基、丙基(例如正丙基和异丙基)和丁基基团(例如正丁基、异丁基、仲丁基、叔丁基)。在一个实施方案中一个烷基基团或两个或多个烷基基团可形成桥连的烷基基团。即其中烷基基团经另一个基团连接(特别显示于环状基团)，通过烷基链桥连形成环，即，形成桥连的稠合环。
如本发明所用，“环烷基”是指非芳香碳环基团，包括环状烷基、链烯基和炔基基团。环烷基基团可以是单环(例如环己基)或多环(例如，包含稠合、桥连和/或螺环体系)，其中碳原子位于环体系内部或外部。环烷基基团作为整体可具有3至14个环原子(例如，3至8个碳原子用于单环环烷基基团和7至14个碳原子用于多环环烷基基团)。环烷基基团的任何适宜环上位置可与所定义的化学结构共价连接。环烷基基团的实例包括环丙基、环丁基、环戊基、环己基、环庚基、环戊烯基、环己烯基、环己二烯基、环庚三烯基、冰片基、norpinyl、norcaryl、金刚烷基和螺[4.5]癸基，及其同系物、异构体等。
本发明包括通式I化合物的全部药学上可接受的同位素标记化合物，其中一个或多个原子被有相同原子数的原子替换，但原子质量或质量数与通常见于自然中的原子质量或质量数不同。
适于包含在本发明化合物中的同位素实例包括氢的同位素，例如2H和3H，碳，例如11C、13C和14C氮例如13N和15N，氧例如15O、17O和18O。
用较重的同位素例如氘即2H取代可提供某些治疗优势，其有更好的代谢稳定性，例如，体内半衰期增加或降低了剂量需求，并因此在某些情况下优选。
以下将通过实施例详细描述本发明的以上化合物1-37的合成方法。
下述实施例中涉及的中间体化合物通过如此过程制备得到：
(Z)-2-((二甲基氨基)亚甲基)-6-甲氧基-3,4-二氢萘-1(2H)-酮(M-2)
将6-甲氧基-1-萘满酮(M-1,17.62g,0.1mol)加入DMF(150mL)中，搅拌溶解后加入DMF-DMA(35.75g,0.3mol)，110℃反应12h。TLC监测反应至完成，待反应体系冷却至室温，向反应液中加入MeOH(100mL)，室温搅拌30min后减压除去部分溶剂，剩余物继续下一步反应。
8-甲氧基-5,6-二氢苯并[h]喹唑啉-2-胺(M-3)
向上一步的残余物中加入盐酸胍(14.32g,0.15mol)和Na2CO3(15.90g,0.15mol)，于120℃反应8h。待反应体系冷却至室温，冰水浴下向反应液中缓慢加入H2O(1.5L)，过滤，滤饼用PE打浆得黄色固体M-3(16.50g,72.6％)。MS-ESI(m/z):228.11[M+H]+；1H NMR(400MHz,DMSO-d6)δ:8.12-7.98(m,2H),6.91(dd,J＝8.6,2.6Hz,1H),6.87(d,J＝2.5Hz,1H),6.32(s,2H),3.81(s,3H),2.83(t,J＝7.2Hz,2H),2.67(t,J＝7.3Hz,2H)。
8-甲氧基-N-(4-硝基苯基)-5,6-二氢苯并[h]喹唑啉-2-胺(M-4a)
将化合物M-3(4.55g,20.0mmol)、对溴硝基苯(4.85g,24.0mmol)和Pd2(dba)3(0.46g,0.5mmol)加入PhMe(80mL)中，再加入x-phos(0.48g,1.0mmol)和t-BuOK(3.37g,30.0mmol)后，在N2条件下回流反应3h。将反应液于冰水浴中搅拌20min，过滤，滤饼用PhMe洗涤3次后收集滤饼，DCM打浆，过滤得黄色固体M-4a(6.24g,89.7％)。MS-ESI(m/z):349.12[M+H]+；1H NMR(400MHz,DMSO-d6)δ:10.34(s,1H),8.43(s,1H),8.26-8.15(m,3H),8.08(d,J＝9.1Hz,2H),7.01(dd,J＝8.6,2.6Hz,1H),6.94(d,J＝2.5Hz,1H),3.84(s,3H),2.92(t,J＝7.3Hz,2H),2.82(t,J＝7.2Hz,2H)。
N-(8-甲氧基-5,6-二氢苯并[h]喹唑啉-2-基)-4-硝基苯甲酰胺(M-4b)
将化合物M-3(4.55g,20.0mmol)和TEA(7.08g,70.0mmol)加入反应瓶中，再加入对硝基苯甲酰氯(11.13g,60.0mmol)和1,4-二氧六环(80mL)，N2条件下回流反应1h。待反应液冷却至室温后，过滤，滤饼用硅胶柱层析[洗脱剂：DCM：MeOH＝100：1(v/v)]纯化得白色固体M-4b(3.34g,44.4％)。MS-ESI(m/z):377.12[M+H]+；1H NMR(400MHz,DMSO-d6)δ:11.18(s,1H),8.50(s,1H),8.31(d,J＝8.8Hz,2H),8.13(d,J＝8.8Hz,2H),8.00(d,J＝9.3Hz,1H),6.97-6.85(m,2H),3.80(s,3H),2.96-2.87(m,2H),2.88-2.82(m,2H)。
8-甲氧基-N-(4-硝基苄基)-5,6-二氢苯并[h]喹唑啉-2-胺(M-4c)
将化合物M-3(0.91g,4.0mmol)、对硝基苄溴(3.46g,16.0mmol)和DIPEA(3.10g,24.0mmol)加入封管中，再加入1,4-二氧六环(15mL)，130℃反应8h。待反应液冷却至室温后，过滤，滤饼干燥得黄色固体M-4c(1.20g,82.8％)。MS-ESI(m/z):363.14[M+H]+；1H NMR(400MHz,DMSO-d6)δ:8.76(s,1H),8.49(s,1H),8.27(d,J＝8.8Hz,2H),8.17(d,J＝8.7Hz,1H),7.62(d,J＝8.8Hz,2H),7.08(dd,J＝8.8,2.5Hz,1H),7.04(d,J＝2.3Hz,1H),5.55(s,2H),3.89(s,3H),2.99(t,J＝7.1Hz,2H),2.84(t,J＝7.0Hz,2H)。
N1-(8-甲氧基-5,6-二氢苯并[h]喹唑啉-2-基)苯-1,4-二胺(M-5a)
将化合物M-4a(6.00g,17.2mmol)溶于MeOH(60mL)中，加入Pd/C(0.60g)，H2作用下室温反应6h。TLC监测反应完后，硅藻土助滤，滤液浓缩得黄色固体M-5a(3.48g,63.8％)。MS-ESI(m/z):319.16[M+H]+；1H NMR(400MHz,DMSO-d6)δ:8.84(s,1H),8.16(s,1H),8.06(d,J＝8.6Hz,1H),7.37(d,J＝8.7Hz,2H),6.94(dd,J＝8.5,2.5Hz,1H),6.87(d,J＝2.3Hz,1H),6.51(d,J＝8.7Hz,2H),4.67(s,2H),3.79(s,3H),2.84(t,J＝7.1Hz,2H),2.69(t,J＝7.2Hz,2H)。
4-氨基-N-(8-甲氧基-5,6-二氢苯并[h]喹唑啉-2-基)苯甲酰胺(M-5b)
以化合物M-4b为原料合成化合物M-5b，合成方法参照化合物M-5a。黄色固体2.24g，收率75.2％。MS-ESI(m/z):347.15[M+H]+；1H NMR(400MHz,DMSO-d6)δ:10.26(s,1H),8.47(s,1H),8.15(d,J＝8.5Hz,1H),7.74(d,J＝8.6Hz,2H),6.96(dd,J＝8.6,2.6Hz,1H),6.93(d,J＝2.5Hz,1H),6.58(d,J＝8.7Hz,2H),5.80(s,2H),3.83(s,3H),2.94-2.90(m,2H),2.88-2.84(m,2H)。
N-(4-氨基苄基)-8-甲氧基-5,6-二氢苯并[h]喹唑啉-2-胺(M-5c)
以化合物M-4c为原料合成化合物M-5c，合成方法参照化合物M-5a。黄色固体0.56g，收率56.4％。MS-ESI(m/z):371.13[M+K]+；1H NMR(400MHz,DMSO-d6)δ:8.12-8.05(m,2H),7.17(t,J＝6.2Hz,1H),7.03(d,J＝8.2Hz,2H),6.92(dd,J＝8.6,2.5Hz,1H),6.86(d,J＝2.3Hz,1H),6.49(d,J＝8.3Hz,2H),4.86(s,2H),4.37(d,J＝6.2Hz,2H),3.80(s,3H),2.82(t,J＝7.2Hz,2H),2.66(t,J＝7.2Hz,2H)。
苯基(5-(叔丁基)异噁唑-3-基)氨基甲酸酯(M-7a)
将3-氨基-5-叔丁基异噁唑(M-6a,2.80g,200.0mmol)溶于无水THF(20mL)中，加入K2CO3(3.59g,26.0mmol)，N2保护，室温搅拌下用恒压滴液漏斗逐滴加入氯甲酸苯酯(3.29g,21.0mmol)，滴毕，将反应体系于室温搅拌12h。过滤，滤液浓缩，残余物中加入EtOH和H2O打浆，室温搅拌2h，过滤，滤饼干燥得白色固体M-7a(2.93g,56.5％)。MS-ESI(m/z):261.12[M+H]+；1H NMR(400MHz,DMSO-d6)δ:11.12(s,1H),7.46-7.40(m,2H),7.27(t,J＝7.3Hz,1H),7.21(d,J＝7.6Hz,2H),6.43(s,1H),1.29(s,9H)。
苯基(5-甲基异噁唑-3-基)氨基甲酸酯(M-7b)
以化合物M-6b为原料合成化合物M-7b，合成方法参照化合物M-7a。白色固体2.90g，收率66.6％。MS-ESI(m/z):219.07[M+H]+；1H NMR(400MHz,DMSO-d6)δ:11.08(s,1H),7.47-7.39(m,2H),7.28(d,J＝6.3Hz,1H),7.21(d,J＝8.4Hz,2H),6.46(s,1H),2.37(s,3H)。
苯基(3-(叔丁基)异噁唑-5-基)氨基甲酸酯(M-7c)
以化合物M-6c为原料合成化合物M-7c，合成方法参照化合物M-7a。黄色固体3.75g，收率72.1％。MS-ESI(m/z):261.12[M+H]+；1H NMR(400MHz,DMSO-d6)δ:11.83(s,1H),7.45(t,J＝7.9Hz,2H),7.29(t,J＝7.4Hz,1H),7.25(d,J＝8.0Hz,2H),6.05(s,1H),1.25(s,9H)。
苯基(3-甲基异噁唑-5-基)氨基甲酸酯(M-7d)
以化合物M-6d为原料合成化合物M-7d，合成方法参照化合物M-7a。白色固体2.00g，收率45.8％。MS-ESI(m/z):219.07[M+H]+；1H NMR(400MHz,DMSO-d6)δ:11.84(s,1H),7.45(t,J＝7.8Hz,2H),7.29(t,J＝7.3Hz,1H),7.25(d,J＝7.5Hz,2H),5.95(s,1H),2.18(s,3H)。
N-(4-((8-甲氧基-5,6-二氢苯并[h]喹唑啉-2-基)氨基)苯基)-2-(4-硝基苯基)乙酰胺(M-8a)
将化合物M-5a(0.80g,2.5mmol)和对硝基苯乙酸(0.45g,2.5mmol)溶于DMF(8mL)中，加入HATU(1.09g,2.875mmol)后，将反应体系于0℃搅拌10min，向反应液中缓慢滴加DIPEA(0.69g,5.4mmol)，滴毕，将反应体系移至室温下反应1h。TLC监测，茚三酮显色原料反应完。向反应液中缓慢加入H2O(40mL)，过滤，滤饼加入DCM打浆，过滤得黄色固体M-8a(1.12g,93.3％)。MS-ESI(m/z):482.18[M+H]+；1H NMR(400MHz,DMSO-d6)δ:10.13(s,1H),9.36(s,1H),8.28(s,1H),8.21(d,J＝8.8Hz,2H),8.13(d,J＝8.6Hz,1H),7.74(d,J＝9.0Hz,2H),7.62(d,J＝8.8Hz,2H),7.50(d,J＝9.0Hz,2H),6.99(dd,J＝8.6,2.6Hz,1H),6.91(d,J＝2.5Hz,1H),3.82(d,J＝4.0Hz,5H),2.88(t,J＝7.1Hz,2H),2.75(t,J＝7.2Hz,2H)。
N-(4-((8-甲氧基-5,6-二氢苯并[h]喹唑啉-2-基)氨基)苯基)-4-硝基苯甲酰胺(M-8b)
以M-5a为原料合成化合物M-8b，合成方法参照化合物M-4b。黄色固体1.10g，收率94.0％。MS-ESI(m/z):468.16[M+H]+；1H NMR(400MHz,DMSO-d6)δ:10.50(s,1H),9.45(s,1H),8.36(d,J＝8.8Hz,2H),8.31(s,1H),8.21(d,J＝8.8Hz,2H),8.16(d,J＝8.6Hz,1H),7.83(d,J＝9.0Hz,2H),7.71(d,J＝8.9Hz,2H),7.01(dd,J＝8.7,2.5Hz,1H),6.92(d,J＝2.4Hz,1H),3.83(s,3H),2.92-2.87(m,2H),2.80-2.75(m,2H)。
N1-(8-甲氧基-5,6-二氢苯并[h]喹唑啉-2-基)-N4-(4-硝基苯基)苯-1,4-二胺(M-8c)
以M-5a为原料合成化合物M-8c，合成方法参照化合物M-4a。黄色固体1.03g，收率93.7％。MS-ESI(m/z):440.16[M+H]+；1H NMR(400MHz,DMSO-d6)δ:9.50(s,1H),8.30(s,1H),8.16(d,J＝8.6Hz,1H),8.05(d,J＝9.3Hz,2H),7.86(d,J＝8.8Hz,2H),7.19(d,J＝8.8Hz,2H),7.05-6.86(m,5H),3.82(s,3H),2.91-2.86(m,2H),2.79-2.74(m,2H)。
2-(4-氨基苯基)-N-(4-((8-甲氧基-5,6-二氢苯并[h]喹唑啉-2-基)氨基)苯基)乙酰胺(M-9a)
将M-8a(0.96g,2.0mmol)、铁粉(0.56g,10.0mmmol)和NH4Cl(0.75g,14.0mmol)依次加入反应瓶中，再加入EtOH：H2O＝3：1混合溶剂(24mL)，于90℃下回流反应8h。待反应液冷却至室温后，向反应液中加入饱和NaHCO3水溶液调PH至8左右，加入DCM(100mL)和MeOH(100mL)，室温搅拌30min后，硅藻土助滤，滤液浓缩后有明显固体析出，过滤，滤饼经硅胶柱层析分离纯化得黄色固体M-9a(0.58g,64.2％)。MS-ESI(m/z):452.22[M+H]+；1H NMR(400MHz,DMSO-d6)δ:9.87(s,1H),9.35(s,1H),8.28(s,1H),8.13(d,J＝8.6Hz,1H),7.72(d,J＝8.9Hz,2H),7.50(d,J＝8.9Hz,2H),7.1-6.93(m,3H),6.92(d,J＝2.5Hz,1H),6.51(d,J＝8.2Hz,2H),4.93(s,2H),3.83(s,3H),3.39(s,2H),2.89(t,J＝7.1Hz,2H),2.76(t,J＝7.0Hz,2H)。
4-氨基-N-(4-((8-甲氧基-5,6-二氢苯并[h]喹唑啉-2-基)氨基]苯基)苯甲酰胺(M-9b)
以M-8b为原料合成化合物M-9b，合成方法参照化合物MM-9a。黄色固体0.38g，收率43.5％。MS-ESI(m/z):438.22[M+H]+；1H NMR(400MHz,DMSO-d6)δ:9.66(s,1H),9.37(s,1H),8.30(s,1H),8.15(d,J＝8.6Hz,1H),7.75(d,J＝9.1Hz,2H),7.72(d,J＝8.7Hz,2H),7.65(d,J＝9.1Hz,2H),7.01(dd,J＝8.6,2.6Hz,1H),6.93(d,J＝2.5Hz,1H),6.60(d,J＝8.7Hz,2H),5.71(s,2H),3.83(s,3H),2.90(t,J＝7.2Hz,2H),2.77(t,J＝7.3Hz,2H)。
N1-(4-氨基苯基)-N4-(8-甲氧基-5,6-二氢苯并[h]喹唑啉-2-基)苯-1,4-二胺(M-9c)
以M-8c为原料合成化合物M-9c，合成方法参照化合物M-9a。淡黄色固体0.32g，收率39.1％。MS-ESI(m/z):410.20[M+H]+；1H NMR(400MHz,DMSO-d6)δ:9.06(s,1H),8.22(s,1H),8.11(d,J＝8.6Hz,1H),7.54(d,J＝8.9Hz,2H),7.24(s,1H),6.98(dd,J＝8.6,2.6Hz,1H),6.90(d,J＝2.5Hz,1H),6.80(dd,J＝8.7,5.2Hz,4H),6.53(d,J＝8.6Hz,2H),4.67(s,2H),3.82(s,3H),2.87(t,J＝7.2Hz,2H),2.74(t,J＝7.3Hz,2H)。
6-(2-吗啉代乙氧基)-3,4-二氢萘-1(2H)-酮(M-11)
将6-羟基-1-四氢萘酮(M-10,2.92g,18.0mmol)溶于DMF(40mL)中，再依次加入N-(2-氯乙基)吗啉盐酸盐(3.52g,18.9mmol)和Cs2CO3(7.63g,23.4mmol)，于100℃反应2.5h。向反应液中加入H2O(50mL)，用DCM(100mL×3)萃取，合并有机相，饱和NaCl洗涤，无水Na2SO4干燥，浓缩得黄色固体M-11(4.45g,89.8％)。MS-ESI(m/z):276.15[M+H]+；1H NMR(400MHz,DMSO-d6)δ:7.81(d,J＝9.4Hz,1H),6.91-6.86(m,2H),4.17(t,J＝5.7Hz,2H),3.60-3.54(m,4H),2.90(t,J＝6.0Hz,2H),2.70(t,J＝5.7Hz,2H),2.53(t,J＝6.6Hz,2H),2.49-2.43(m,4H)。
8-(2-吗啉代乙氧基)-5,6-二氢苯并[h]喹唑啉-2-胺(M-13)
以化合物M-11与DMF-DMA合成化合物M-12，合成方法参照化合物M-2。以化合物M-12合成M-13，合成方法参照化合物M-3。黄色固体3.83g，收率78.3％。MS-ESI(m/z):327.18[M+H]+；1H NMR(400MHz,DMSO-d6)δ:8.06(s,1H),8.03(d,J＝8.5Hz,1H),6.91(dd,J＝8.5,2.4Hz,1H),6.88(d,J＝2.0Hz,1H),6.30(s,2H),4.14(t,J＝5.7Hz,2H),3.60-3.55(m,4H),2.82(t,J＝7.2Hz,2H),2.71-2.64(m,4H)。
8-(2-吗啉代乙氧基)-N-(4-硝基苯基)-5,6-二氢苯并[h]喹唑啉-2-胺(M-14a)
以化合物M-13和对溴硝基苯合成M-14a，合成方法参照化合物M-4a。黄色固体1.25g，收率93.5％。MS-ESI(m/z):448.22[M+H]+；1H NMR(400MHz,DMSO-d6)δ:10.34(s,1H),8.42(s,1H),8.26-8.14(m,3H),8.05(d,J＝9.3Hz,2H),7.01(dd,J＝8.8,2.1Hz,1H),6.96(d,J＝1.9Hz,1H),4.18(t,J＝5.7Hz,2H),3.63-3.53(m,4H),2.93-2.87(m,2H),2.85-2.78(m,2H),2.72(t,J＝5.7Hz,2H)。
8-(2-吗啉代乙氧基)-N-(5-硝基吡啶-2-基)-5,6-二氢苯并[h]喹唑啉-2-胺(M-14b)
以化合物M-13和2-溴-5-硝基吡啶合成M-14b，合成方法参照化合物M-4a。黄色固体1.22g，收率90.8％。MS-ESI(m/z):449.23[M+H]+；1H NMR(400MHz,DMSO-d6)δ:9.03(s,1H),8.78(d,J＝3.2Hz,1H),8.43(s,1H),8.16(d,J＝7.7Hz,1H),7.68(dd,J＝9.5,3.3Hz,1H),6.97(dd,J＝8.6,0.8Hz,1H),6.95(d,J＝2.1Hz,1H),5.71(d,J＝9.4Hz,1H),4.17(t,J＝5.6Hz,2H),3.64-3.50(m,4H),2.94-2.87(m,2H),2.86-2.78(m,2H),2.71(t,J＝5.6Hz,2H)。
8-(2-吗啉代乙氧基)-N-(6-硝基吡啶-3-基)-5,6-二氢苯并[h]喹唑啉-2-胺(M-14c)
以化合物M-13和5-溴-2-硝基吡啶合成M-14c，合成方法参照化合物M-4a。黄色固体0.85g，收率87.2％。MS-ESI(m/z):487.14[M+K]+；1H NMR(400MHz,DMSO-d6)δ:10.53(s,1H),9.01(d,J＝2.0Hz,1H),8.59(dd,J＝8.8,2.2Hz,1H),8.43(s,1H),8.34(d,J＝9.0Hz,1H),8.15(d,J＝8.5Hz,1H),7.01(dd,J＝8.6,1.6Hz,1H),6.95(d,J＝2.2Hz,1H),4.16(t,J＝5.5Hz,2H),3.60-3.54(m,4H),2.92-2.86(m,2H),2.84-2.78(m,2H),2.70(t,J＝5.4Hz,2H)。
N-(2-氟-4-硝基苯基)-8-(2-吗啉代乙氧基)-5,6-二氢苯并[h]喹唑啉-2-胺(M-14d)
以化合物M-13和1-溴-2-氟-4-硝基苯合成M-14d，合成方法参照化合物M-4a。黄色固体0.87g，收率93.3％。MS-ESI(m/z):466.26[M+H]+；1H NMR(400MHz,DMSO-d6)δ:8.26(s,1H),8.10(d,J＝8.5Hz,1H),7.83(t,J＝9.2Hz,1H),7.75(dd,J＝9.4,2.5Hz,1H),7.68(d,J＝12.9Hz,1H),7.17(d,J＝7.8Hz,1H),6.94(dd,J＝8.6,2.5Hz,1H),6.90(d,J＝2.5Hz,1H),4.16(t,J＝5.7Hz,2H),3.61-3.56(m,4H),2.89-2.84(m,2H),2.77-2.69(m,4H)。
N-(2-甲基-4-硝基苯基)-8-(2-吗啉代乙氧基)-5,6-二氢苯并[h]喹唑啉-2-胺(M-14e)
以化合物M-13和2-溴-5-硝基甲苯合成M-14e，合成方法参照化合物M-4a。黄色固体0.39g，收率84.5％。MS-ESI(m/z):462.25[M+H]+；1H NMR(400MHz,DMSO-d6)δ:8.85(s,1H),8.38(s,1H),8.30(d,J＝9.0Hz,1H),8.10(q,J＝4.0Hz,3H),6.97(dd,J＝8.6,2.6Hz,1H),6.94(d,J＝2.5Hz,1H),4.16(t,J＝5.7Hz,2H),3.60-3.56(m,4H),2.90(t,J＝7.3Hz,2H),2.81(t,J＝7.2Hz,2H),2.71(t,J＝5.7Hz,2H),2.42(s,3H)。
N1-(8-(2-吗啉代乙氧基)-5,6-二氢苯并[h]喹唑啉-2-基)苯-1,4-二胺(M-15a)
以化合物M-14a为原料合成化合物M-15a，合成方法参照化合物M-5a。黄色固体0.70g，收率59.8％。MS-ESI(m/z):456.17[M+K]+；1H NMR(400MHz,DMSO-d6)δ:8.87(s,1H),8.19(s,1H),8.07(d,J＝8.5Hz,1H),7.39(d,J＝8.7Hz,2H),6.96(dd,J＝8.6,2.4Hz,1H),6.91(d,J＝2.1Hz,1H),6.53(d,J＝8.7Hz,2H),4.70(s,2H),4.15(t,J＝5.7Hz,2H),3.60-3.55(m,4H),2.85(t,J＝7.0Hz,2H),2.74-2.68(m,4H)。
N2-(8-(2-吗啉代乙氧基)-5,6-二氢苯并[h]喹唑啉-2-基)吡啶-2,5-二胺(M-15b)
以化合物M-14b为原料合成化合物M-15b，合成方法参照化合物M-5a。黄色固体0.56g，收率49.3％。MS-ESI(m/z):419.21[M+H]+；1H NMR(400MHz,DMSO-d6)δ:8.98(s,1H),8.27(s,1H),8.10(d,J＝8.6Hz,1H),7.95(d,J＝8.8Hz,1H),7.70(d,J＝2.8Hz,1H),7.06(dd,J＝8.8,2.9Hz,1H),6.98(dd,J＝8.5,2.5Hz,1H),6.93(d,J＝2.2Hz,1H),5.18(s,2H),4.18(t,J＝5.6Hz,2H),3.63-3.57(m,4H),2.90-2.84(m,2H),2.80-2.72(m,4H)。
N5-(8-(2-吗啉代乙氧基)-5,6-二氢苯并[h]喹唑啉-2-基)吡啶-2,5-二胺(M-15c)
以化合物M-14c为原料合成化合物M-15c，合成方法参照化合物M-5a。黄色固体0.45g，收率62.2％。MS-ESI(m/z):419.19[M+H]+；1H NMR(400MHz,DMSO-d6)δ:9.02(s,1H),8.29(d,J＝2.1Hz,1H),8.21(s,1H),8.04(d,J＝8.6Hz,1H),7.72(dd,J＝8.8,2.6Hz,1H),6.96(dd,J＝8.6,2.5Hz,1H),6.92(d,J＝2.3Hz,1H),6.48(d,J＝8.8Hz,1H),5.71(s,2H),4.16(t,J＝5.6Hz,2H),3.60-3.56(m,4H),2.88-2.83(m,2H),2.76-2.70(m,4H)。
2-氟-N1-(8-(2-吗啉代乙氧基)-5,6-二氢苯并[h]喹唑啉-2-基)苯-1,4-二胺(M-15d)
以化合物M-14d为原料合成化合物M-15d，合成方法参照化合物M-5a。黄色固体0.40g，收率48.9％。MS-ESI(m/z):474.17[M+K]+；1H NMR(400MHz,DMSO-d6)δ:8.26(s,1H),8.13(s,1H),7.96(d,J＝8.5Hz,1H),7.16(t,J＝8.7Hz,1H),6.94-6.87(m,2H),6.42-6.34(m,2H),5.17(s,2H),4.14(t,J＝5.7Hz,2H),3.58(t,J＝4.7Hz,4H),2.84(t,J＝7.3Hz,2H),2.74-2.66(m,4H)。
2-甲基-N1-(8-(2-吗啉代乙氧基)-5,6-二氢苯并[h]喹唑啉-2-基)苯-1,4-二胺(M-15e)
以化合物M-14e为原料合成化合物M-15e，合成方法参照化合物M-5a。黄色固体0.26g，收率72.1％。MS-ESI(m/z):432.27[M+H]+；1H NMR(400MHz,DMSO-d6)δ:8.13(s,1H),8.09(s,1H),7.93(d,J＝8.4Hz,1H),6.99(d,J＝8.3Hz,1H),6.92-6.87(m,2H),6.44(d,J＝2.6Hz,1H),6.38(dd,J＝8.4,2.6Hz,1H),4.80(s,2H),4.13(t,J＝5.7Hz,2H),3.59-3.55(m,4H),2.85-2.80(m,2H),2.72-2.66(m,4H),2.06(s,3H)。
实施例1 1-(5-(叔丁基)异噁唑-3-基)-3-(4-((8-甲氧基-5,6-二氢苯并[h]喹唑啉-2-基)氨基)苯基)脲(化合物1)
将化合物M-5a(63.6mg,0.2mmol)、M-7a(62.5mg,0.24mmol)和DMAP(2.4mg,0.02mmol)加入反应瓶中，再加入CHCl3(2mL)和1滴TEA于60℃搅拌反应16h。硅胶柱层析分离纯化[洗脱剂：DCM：MeOH＝200：1～50：1(v/v)]得黄色固体1(70.0mg,72.2％)。MS-ESI(m/z):485.23[M+H]+；1H NMR(400MHz,DMSO-d6)δ:9.39(s,1H),9.32(s,1H),8.62(s,1H),8.27(d,J＝9.8Hz,1H),8.12(d,J＝8.6Hz,1H),7.73(d,J＝9.0Hz,2H),7.34(d,J＝8.9Hz,2H),6.97(dd,J＝8.6,2.6Hz,1H),6.89(d,J＝2.4Hz,1H),6.46(s,1H),3.80(s,3H),2.85(t,J＝7.2Hz,2H),2.74(t,J＝7.2Hz,2H),1.27(s,9H)；13C NMR(101MHz,DMSO-d6)δ:180.52,161.83,159.77,159.10,158.97,156.77,151.86,142.27,136.75,132.66,127.06,125.65,119.66,119.42,118.03,113.74,113.39,92.87,55.77,32.93,28.83,28.21,23.60。
实施例2 1-(4-((8-甲氧基-5,6-二氢苯并[h]喹唑啉-2-基)氨基)苯基)-3-(5-甲基异噁唑-3-基)脲(化合物2)
以化合物M-5a与化合物M-7b合成化合物2，合成方法参照化合物1。淡黄色固体82.0mg，收率92.7％。MS-ESI(m/z):443.19[M+H]+；1H NMR(400MHz,DMSO-d6)δ:9.37(s,1H),9.35(s,1H),8.65(s,1H),8.29(d,J＝11.1Hz,1H),8.14(d,J＝8.6Hz,1H),7.75(d,J＝9.0Hz,2H),7.36(d,J＝9.0Hz,2H),7.00(dd,J＝8.6,2.5Hz,1H),6.91(d,J＝2.4Hz,1H),6.52(s,1H),3.82(s,3H),2.88(t,J＝7.2Hz,2H),2.76(t,J＝7.2Hz,2H),2.36(s,3H)；13CNMR(101MHz,DMSO-d6)δ:169.56,161.83,159.77,159.25,159.10,156.77,151.82,142.27,136.75,132.66,127.07,125.65,119.72,119.43,118.03,113.74,113.40,95.97,55.78,28.21,23.60,12.59。
实施例3 1-(3-(叔丁基)异噁唑-5-基)-3-(4-((8-甲氧基-5,6-二氢苯并[h]喹唑啉-2-基)氨基)苯基)脲(化合物3)
以化合物M-5a与化合物M-7c合成化合物3，合成方法参照化合物1。淡黄色固体49.9mg，收率51.6％。MS-ESI(m/z):485.31[M+H]+；1H NMR(400MHz,DMSO-d6)δ:10.00(s,1H),9.37(s,1H),8.63(s,1H),8.28(s,1H),8.14(d,J＝8.6Hz,1H),7.76(d,J＝9.0Hz,2H),7.38(d,J＝9.0Hz,2H),6.99(dd,J＝8.7,2.5Hz,1H),6.92(d,J＝2.3Hz,1H),6.04(s,1H),3.83(s,3H),2.89(t,J＝7.0Hz,2H),2.76(t,J＝7.2Hz,2H),1.25(s,9H)；13C NMR(101MHz,DMSO-d6)δ:172.96,162.34,161.83,159.76,159.11,156.76,150.23,142.28,136.90,132.44,127.05,125.64,119.78,119.40,118.07,113.74,113.39,83.74,55.78,32.40,29.54,28.20,23.60。
实施例4 1-(4-((8-甲氧基-5,6-二氢苯并[h]喹唑啉-2-基)氨基)苯基)-3-(3-甲基异噁唑-5-基)脲(化合物4)
以化合物M-5a与化合物M-7d合成化合物4，合成方法参照化合物1。淡黄色固体55.0mg，收率62.2％。MS-ESI(m/z):443.20[M+H]+；1H NMR(400MHz,DMSO-d6)δ:10.08(s,1H),9.36(s,1H),8.80(s,1H),8.29(s,1H),8.15(d,J＝8.6Hz,1H),7.76(d,J＝8.9Hz,2H),7.38(d,J＝9.0Hz,2H),7.01(dd,J＝8.6,2.5Hz,1H),6.92(d,J＝2.4Hz,1H),5.94(s,1H),3.83(s,3H),2.89(t,J＝7.2Hz,2H),2.77(t,J＝7.2Hz,2H),2.17(s,3H)；13C NMR(101MHz,DMSO-d6)δ:162.52,161.83,161.10,159.77,159.12,156.76,150.22,142.25,136.88,132.50,127.08,125.65,119.70,119.44,118.04,113.73,113.37,86.44,55.75,28.20,23.59,11.86。
实施例5 4-(3-(5-(叔丁基)异噁唑-3-基)脲基)-N-(8-甲氧基-5,6-二氢苯并[h]喹唑啉-2-基)苯甲酰胺(化合物5)
以化合物M-5b与化合物M-7a合成化合物5，合成方法参照化合物1。白色固体38.4mg，收率37.5％。MS-ESI(m/z):513.34[M+H]+；1H NMR(400MHz,DMSO-d6)δ:10.69(s,1H),9.66(s,1H),9.22(s,1H),8.51(s,1H),8.14(d,J＝8.6Hz,1H),7.97(d,J＝8.7Hz,2H),7.58(d,J＝8.7Hz,2H),6.97(dd,J＝8.5Hz,2.6Hz,1H),6.94(d,J＝2.3Hz,1H),6.54(s,1H),3.83(s,3H),2.96-2.91(m,2H),2.90-2.85(m,2H),1.31(s,9H)；13C NMR(101MHz,DMSO-d6)δ:180.75,165.37,162.17,159.75,158.67,157.65,156.73,151.73,142.90,142.21,129.83,128.39,127.53,125.06,123.24,117.85,113.74,113.43,92.98,55.83,32.97,28.82,27.70,23.70。
实施例6N-(8-甲氧基-5,6-二氢苯并[h]喹唑啉-2-基)-4-(3-(5-甲基异噁唑-3-基)脲基)苯甲酰胺(化合物6)
以化合物M-5b与化合物M-7b合成化合物6，合成方法参照化合物1。白色固体43.0mg，收率45.7％。MS-ESI(m/z):471.18[M+H]+；1H NMR(400MHz,DMSO-d6)δ:10.69(s,1H),9.60(s,1H),9.21(s,1H),8.51(s,1H),8.14(d,J＝8.5Hz,1H),7.97(d,J＝8.7Hz,2H),7.57(d,J＝8.7Hz,2H),6.97(dd,J＝8.7,2.4Hz,1H),6.94(d,J＝2.3Hz,1H),6.57(s,1H),3.83(s,3H),2.98-2.91(m,2H),2.90-2.83(m,2H),2.38(s,3H)；13C NMR(101MHz,DMSO-d6)δ:169.82,165.38,162.17,159.75,158.94,157.65,156.73,151.67,142.90,142.22,129.84,128.38,127.53,125.06,123.25,117.85,113.73,113.43,96.06,55.83,27.70,23.70,12.62。
实施例7 4-(3-(3-(叔丁基)异噁唑-5-基)脲基)-N-(8-甲氧基-5,6-二氢苯并[h]喹唑啉-2-基)苯甲酰胺(化合物7)
以化合物M-5b与化合物M-7c合成化合物7，合成方法参照化合物1。白色固体21.0mg，收率20.5％。MS-ESI(m/z):513.22[M+H]+；1H NMR(400MHz,DMSO-d6)δ:10.70(s,1H),10.21(s,1H),9.14(s,1H),8.51(s,1H),8.14(d,J＝8.5Hz,1H),7.98(d,J＝8.8Hz,2H),7.60(d,J＝8.8Hz,2H),6.97(dd,J＝8.6,2.5Hz,1H),6.94(d,J＝2.3Hz,1H),6.10(s,1H),3.84(s,3H),2.98-2.91(m,2H),2.91-2.84(m,2H),1.27(s,9H)；13C NMR(101MHz,DMSO-d6)δ:173.03,165.34,162.18,161.96,159.74,157.65,156.74,150.08,142.64,142.21,129.81,128.65,127.52,125.07,123.25,118.03,113.75,113.44,84.40,55.83,32.43,29.52,27.71,23.71。
实施例8N-(8-甲氧基-5,6-二氢苯并[h]喹唑啉-2-基)-4-(3-(3-甲基异噁唑-5-基)脲基)苯甲酰胺(化合物8)
以化合物M-5b与化合物M-7d合成化合物8，合成方法参照化合物1。白色固体24.6mg，收率26.2％。MS-ESI(m/z):471.18[M+H]+；1H NMR(400MHz,DMSO-d6)δ:10.69(s,1H),10.62(s,1H),9.90(s,1H),8.51(s,1H),8.14(d,J＝8.6Hz,1H),7.97(d,J＝8.6Hz,2H),7.58(d,J＝8.5Hz,2H),7.01-6.94(m,1H),6.94(d,J＝2.3Hz,1H),5.98(s,1H),3.83(s,3H),3.03-2.90(m,2H),2.90-2.80(m,2H),2.18(s,3H)；13C NMR(101MHz,DMSO-d6)δ:165.39,162.17,162.05,161.12,159.75,157.65,156.74,150.19,142.82,142.21,129.87,128.46,127.54,125.07,123.23,117.66,113.75,113.43,86.86,55.84,27.71,23.71,11.87。
实施例9 1-(5-(叔丁基)异噁唑-3-基)-3-(4-(((8-甲氧基-5,6-二氢苯并[h]喹唑啉-2-基)氨基)甲基)苯基)脲(化合物9)
以化合物M-5c与化合物M-7a合成化合物9，合成方法参照化合物1。白色固体29.0mg，收率29.1％。MS-ESI(m/z):499.25[M+H]+；1H NMR(400MHz,DMSO-d6)δ:9.42(s,1H),8.73(s,1H),8.10(s,1H),8.07(d,J＝8.6Hz,1H),7.40(t,J＝6.5Hz,1H),7.36(d,J＝8.6Hz,2H),7.29(d,J＝8.4Hz,2H),6.92(dd,J＝8.6,2.6Hz,1H),6.86(d,J＝2.4Hz,1H),6.47(s,1H),4.48(d,J＝6.3Hz,2H),3.80(s,3H),2.82(t,J＝7.2Hz,2H),2.67(t,J＝7.2Hz,2H),1.28(s,9H)；13CNMR(101MHz,DMSO-d6)δ:180.58,162.17,161.58,158.85,156.79,151.77,142.10,137.71,135.61,128.23,126.86,125.88,118.84,116.06,115.67,113.59,113.15,92.87,55.71,44.23,32.92,28.81,28.39,23.53。
实施例10 1-(4-(((8-甲氧基-5,6-二氢苯并[h]喹唑啉-2-基)氨基)甲基)苯基)-3-(5-甲基异噁唑-3-基)脲(化合物10)
以化合物M-5c与化合物M-7b合成化合物10，合成方法参照化合物1。白色固体34.9mg，收率38.3％。MS-ESI(m/z):457.19[M+H]+；1H NMR(400MHz,DMSO-d6)δ:9.37(s,1H),8.72(s,1H),8.10(s,1H),8.06(d,J＝8.6Hz,1H),7.40(t,J＝6.3Hz,1H),7.35(d,J＝8.6Hz,2H),7.28(d,J＝8.2Hz,2H),6.92(dd,J＝8.7,2.4Hz,1H),6.87(d,J＝2.4Hz,1H),6.51(s,1H),4.48(d,J＝6.2Hz,2H),3.80(s,3H),2.82(t,J＝7.0Hz,2H),2.67(t,J＝7.3Hz,2H),2.34(s,3H)；13CNMR(101MHz,DMSO-d6)δ:169.61,162.18,161.58,159.13,158.92,156.79,151.74,142.11,137.70,135.61,128.22,126.86,125.88,118.88,116.06,113.58,113.15,95.98,55.71,44.23,28.39,23.53,12.58。
实施例11 1-(3-(叔丁基)异噁唑-5-基)-3-(4-(((8-甲氧基-5,6-二氢苯并[h]喹唑啉-2-基)氨基)甲基)苯基)脲(化合物11)
以化合物M-5c与化合物M-7c合成化合物11，合成方法参照化合物1。黄色固体29.7mg，收率29.8％。MS-ESI(m/z):499.23[M+H]+；1H NMR(400MHz,DMSO-d6)δ:9.27(s,1H),9.10(s,1H),8.39(s,1H),7.77(d,J＝8.6Hz,1H),7.56(d,J＝8.6Hz,2H),7.38(d,J＝8.4Hz,2H),7.08(dd,J＝8.6,2.6Hz,1H),6.93(d,J＝2.4Hz,1H),6.79(t,J＝6.5Hz,1H),6.60(s,1H),4.23(d,J＝6.3Hz,2H),3.70(s,3H),2.95(t,J＝7.2Hz,2H),2.89(t,J＝7.2Hz,2H),1.31(s,9H)。
实施例12 1-(4-(((8-甲氧基-5,6-二氢苯并[h]喹唑啉-2-基)氨基)甲基)苯基)-3-(3-甲基异噁唑-5-基)脲(化合物12)
以化合物M-5c与化合物M-7d合成化合物12，合成方法参照化合物1。黄色固体18.5mg，收率20.3％。MS-ESI(m/z):457.19[M+H]+；1H NMR(400MHz,DMSO-d6)δ:9.27(s,1H),9.10(s,1H),8.39(s,1H),7.77(d,J＝8.6Hz,1H),6.79(t,J＝6.3Hz,1H),7.56(d,J＝8.6Hz,2H),7.38(d,J＝8.2Hz,2H),7.08(dd,J＝8.7,2.4Hz,1H),6.93(d,J＝2.4Hz,1H),6.60(s,1H),4.23(d,J＝6.2Hz,2H),3.70(s,3H),2.95(t,J＝7.0Hz,2H),2.89(t,J＝7.3Hz,2H),2.42(s,3H)。
实施例13 2-(4-(3-(5-(叔丁基)异噁唑-3-基)脲基)苯基)-N-(4-((8-甲氧基-5,6-二氢苯并[h]喹唑啉-2-基)氨基)苯基)乙酰胺(化合物13)
以化合物M-9a与化合物M-7a合成化合物13，合成方法参照化合物1。淡黄色固体47.5mg，收率51.3％。MS-ESI(m/z):618.30[M+H]+；1H NMR(400MHz,DMSO-d6)δ:10.00(s,1H),9.46(s,1H),9.37(s,1H),8.78(s,1H),8.28(s,1H),8.14(d,J＝8.5Hz,1H),7.74(d,J＝8.7Hz,2H),7.51(d,J＝8.7Hz,2H),7.41(d,J＝8.3Hz,2H),7.27(d,J＝8.1Hz,2H),7.00(dd,J＝8.5Hz,2.4Hz,1H),6.92(d,J＝2.2Hz,1H),6.50(s,1H),3.83(s,3H),3.56(s,2H),2.89(t,J＝6.8Hz,2H),2.77(t,J＝7.1Hz,2H),1.29(s,9H)；13C NMR(101MHz,DMSO-d6)δ:180.61,169.18,161.82,159.74,159.10,158.85,156.75,151.78,142.26,137.83,137.10,133.19,130.79,129.96,127.05,125.63,120.05,119.16,118.94,118.08,113.73,113.41,92.90,55.77,43.08,32.94,28.81,28.19,23.59。
实施例13 N-(4-((8-甲氧基-5,6-二氢苯并[h]喹唑啉-2-基)氨基)苯基)-2-(4-(3-(5-甲基异噁唑-3-基)脲基)苯基乙酰胺(化合物14)
以化合物M-9a与化合物M-7b合成化合物14，合成方法参照化合物1。淡黄色固体68.2mg，收率79.0％。MS-ESI(m/z):576.28[M+H]+；1H NMR(400MHz,DMSO-d6)δ:9.98(s,1H),9.39(s,1H),9.35(s,1H),8.77(s,1H),8.28(s,1H),8.13(d,J＝8.5Hz,1H),7.73(d,J＝8.9Hz,2H),7.51(d,J＝9.0Hz,2H),7.39(d,J＝8.4Hz,2H),7.27(d,J＝8.5Hz,2H),7.00(dd,J＝8.6,2.5Hz,1H),6.92(d,J＝2.2Hz,1H),6.53(s,1H),3.83(s,3H),3.56(s,2H),2.91-2.86(m,2H),2.79-2.73(m,2H),2.36(s,3H)；13C NMR(101MHz,DMSO-d6)δ:169.65,169.18,161.82,159.73,159.12,158.85,156.76,151.74,142.27,137.82,137.09,133.18,130.79,129.95,127.05,125.63,120.05,119.16,119.00,118.08,113.74,113.42,96.00,55.78,43.08,28.19,23.59,12.59。
实施例15 2-(4-(3-(3-(3-(叔丁基)异噁唑-5-基)脲基)苯基)-N-(4-((8-甲氧基-5,6-二氢苯并[h]喹唑啉-2-基)氨基)苯基)乙酰胺(化合物15)
以化合物M-9a与化合物M-7c合成化合物15，合成方法参照化合物1。淡黄色固体47.7mg，收率51.5％。MS-ESI(m/z):618.33[M+H]+；1H NMR(400MHz,DMSO-d6)δ:10.02(s,1H),9.99(s,1H),9.35(s,1H),8.78(s,1H),8.28(s,1H),8.13(d,J＝8.6Hz,1H),7.73(d,J＝8.9Hz,2H),7.51(d,J＝8.9Hz,2H),7.42(d,J＝8.4Hz,2H),7.28(d,J＝8.4Hz,2H),7.00(dd,J＝8.6,2.5Hz,1H),6.91(d,J＝2.1Hz,1H),6.05(s,1H),3.82(s,3H),3.56(s,2H),2.89(t,J＝7.3Hz,2H),2.76(t,J＝7.3Hz,2H),1.25(s,9H)；13C NMR(101MHz,DMSO-d6)δ:172.98,169.16,162.18,161.82,159.73,159.10,156.75,150.16,142.26,137.65,137.10,133.18,130.97,129.97,127.05,125.63,120.05,119.16,119.03,118.08,113.73,113.41,83.96,55.77,43.08,32.41,29.52,28.19,23.59。
实施例16 N-(4-((8-甲氧基-5,6-二氢苯并[h]喹唑啉-2-基)氨基)苯基)-2-(4-(3-(3-甲基异噁唑-5-基)脲基)苯基乙酰胺(化合物16)
以化合物M-9a与化合物M-7d合成化合物16，合成方法参照化合物1。淡黄色固体37.4mg，收率43.4％。MS-ESI(m/z):614.33[M+K]+；1H NMR(400MHz,DMSO-d6)δ:10.14(s,1H),10.01(s,1H),9.34(s,1H),9.00(s,1H),8.28(s,1H),8.13(d,J＝8.6Hz,1H),7.73(d,J＝8.8Hz,2H),7.51(d,J＝8.9Hz,2H),7.41(d,J＝8.5Hz,2H),7.27(d,J＝8.3Hz,2H),6.99(dd,J＝8.5,2.4Hz,1H),6.91(d,J＝2.1Hz,1H),5.94(s,1H),3.82(s,3H),3.56(s,2H),2.95-2.83(m,2H),2.76(t,J＝7.0Hz,2H),2.16(s,3H)；13C NMR(101MHz,DMSO-d6)δ:169.18,162.33,161.82,161.09,159.73,159.09,156.76,150.16,142.26,137.68,137.08,133.20,130.93,129.97,127.05,125.62,120.05,119.15,118.95,118.07,113.73,113.41,86.61,55.77,43.08,28.18,23.58,11.86。
实施例17 4-(3-(5-(叔丁基)异噁唑-3-基)脲基)-N-(4-((8-甲氧基-5,6-二氢苯并[h]喹唑啉-2-基]氨基)苯基苯甲酰胺(化合物17)
以化合物M-9b与化合物M-7a合成化合物17，合成方法参照化合物1。淡黄色固体28.7mg，收率31.7％。MS-ESI(m/z):604.26[M+H]+；1H NMR(400MHz,DMSO-d6)δ:10.03(s,1H),9.63(s,1H),9.43(s,1H),9.12(s,1H),8.31(s,1H),8.17(d,J＝8.6Hz,1H),7.96(d,J＝8.7Hz,2H),7.80(d,J＝9.0Hz,2H),7.69(d,J＝9.0Hz,2H),7.60(d,J＝8.8Hz,2H),7.02(dd,J＝8.6,2.5Hz,1H),6.93(d,J＝2.4Hz,1H),6.54(s,1H),3.84(s,3H),2.90(t,J＝7.1Hz,2H),2.78(t,J＝7.2Hz,2H),1.31(s,9H)；13C NMR(101MHz,DMSO-d6)δ:180.78,164.85,161.86,159.76,159.14,158.70,156.74,151.69,142.33,142.29,137.38,133.15,129.13,129.09,127.06,125.66,121.36,119.02,118.13,117.98,113.75,113.43,92.97,55.79,32.97,28.83,28.21,23.61。
实施例18 N-(4-((8-甲氧基-5,6-二氢苯并[h]喹唑啉-2-基)氨基)苯基)-4-(3-(5-甲基异噁唑-3-基)脲基)苯甲酰胺(化合物18)
以化合物M-9b与化合物M-7b合成化合物18，合成方法参照化合物1。淡黄色固体32.7mg，收率38.9％。MS-ESI(m/z):562.21[M+H]+；1H NMR(400MHz,DMSO-d6)δ:10.01(s,1H),9.59(s,1H),9.39(s,1H),9.22(s,1H),8.31(s,1H),8.16(d,J＝8.6Hz,1H),7.95(d,J＝8.7Hz,2H),7.79(d,J＝9.0Hz,2H),7.68(d,J＝9.1Hz,2H),7.59(d,J＝8.8Hz,2H),7.01(dd,J＝8.7,2.5Hz,1H),6.93(d,J＝2.5Hz,1H),6.57(s,1H),3.84(s,3H),2.93-2.88(m,2H),2.78(t,J＝7.1Hz,2H),2.38(s,3H)；13C NMR(101MHz,DMSO-d6)δ:169.79,164.88,161.84,159.76,159.13,158.96,156.80,151.68,142.38,142.29,137.39,133.13,129.14,129.09,127.06,125.65,121.36,118.98,118.12,117.93,113.75,113.43,96.07,55.79,28.20,23.60,12.62。
实施例19 4-(3-(3-(叔丁基)异噁唑-5-基)脲基)-N-(4-((8-甲氧基-5,6-二氢苯并[h]喹唑啉-2-基)氨基)苯基苯甲酰胺(化合物19)
以化合物M-9b与化合物M-7c合成化合物19，合成方法参照化合物1。黄色固体20.3mg，收率22.4％。MS-ESI(m/z):604.26[M+H]+；1H NMR(400MHz,DMSO-d6)δ:10.27(s,1H),10.02(s,1H),9.40(s,1H),9.20(s,1H),8.31(s,1H),8.16(d,J＝8.6Hz,1H),7.95(d,J＝8.7Hz,2H),7.79(d,J＝9.0Hz,2H),7.68(d,J＝9.0Hz,2H),7.61(d,J＝8.7Hz,2H),7.01(dd,J＝8.6,2.5Hz,1H),6.93(d,J＝2.4Hz,1H),6.10(s,1H),3.84(s,3H),2.95-2.85(m,2H),2.78(t,J＝7.2Hz,2H),1.27(s,9H)；13C NMR(101MHz,DMSO-d6)δ:173.01,164.84,162.10,161.84,159.75,159.13,156.79,150.19,142.30,142.22,137.39,133.11,129.24,129.12,127.06,125.64,121.34,118.97,118.13,118.03,113.75,113.44,84.32,55.79,32.44,29.52,28.20,23.60。
实施例20 N-(4-((8-甲氧基-5,6-二氢苯并[h]喹唑啉-2-基)氨基)苯基)-4-(3-(3-甲基异噁唑-5-基)脲基)苯甲酰胺(化合物20)
以化合物M-9b与化合物M-7d合成化合物20，合成方法参照化合物1。淡黄色固体22.5mg，收率26.7％。MS-ESI(m/z):562.31[M+H]+；1H NMR(400MHz,DMSO-d6)δ:10.22(s,1H),10.01(s,1H),9.39(s,1H),9.22(s,1H),8.30(s,1H),8.16(d,J＝8.6Hz,1H),7.95(d,J＝8.7Hz,2H),7.79(d,J＝8.9Hz,2H),7.68(d,J＝8.9Hz,2H),7.60(d,J＝8.6Hz,2H),7.01(dd,J＝8.7,2.5Hz,1H),6.93(d,J＝2.2Hz,1H),6.00(s,1H),3.84(s,3H),2.93-2.87(m,2H),2.82-2.75(m,2H),2.18(s,3H)；13C NMR(101MHz,DMSO-d6)δ:164.86,162.12,161.84,161.18,159.75,159.12,156.77,150.03,142.29,142.13,137.40,133.11,129.32,129.14,127.06,125.64,121.36,118.98,118.13,118.07,113.74,113.43,87.08,55.79,28.20,23.60,11.87。
实施例21 1-(5-(叔丁基)异噁唑-3-基)-3-(4-((4-((8-甲氧基-5,6-二氢苯并[h]喹唑啉-2-基]氨基)苯基)氨基)苯基)脲(化合物21)
以化合物M-9c与化合物M-7a合成化合物21，合成方法参照化合物1。黄色固体47.5mg，收率55.0％。MS-ESI(m/z):576.37[M+H]+；1H NMR(400MHz,DMSO-d6)δ:9.39(s,1H),9.21(s,1H),8.59(s,1H),8.25(s,1H),8.13(d,J＝8.6Hz,1H),7.78(s,1H),7.67(d,J＝8.9Hz,2H),7.27(d,J＝8.8Hz,2H),7.04-6.92(m,5H),6.91(d,J＝2.4Hz,1H),6.47(s,1H),3.82(s,3H),2.88(t,J＝7.1Hz,2H),2.75(t,J＝7.2Hz,2H),1.29(s,9H)；13C NMR(101MHz,DMSO-d6)δ:180.46,161.76,159.93,159.06,159.01,156.73,151.90,142.23,140.42,138.00,134.28,130.93,127.05,125.71,120.83,120.37,118.02,117.60,116.83,113.74,113.33,92.86,55.76,32.92,28.82,28.25,23.60。
实施例22 1-(4-((4-((8-甲氧基-5,6-二氢苯并[h]喹唑啉-2-基]氨基)苯基)氨基)苯基)-3-(5-甲基异噁唑-3-基)脲(化合物22)
以化合物M-9c与化合物M-7b合成化合物22，合成方法参照化合物1。黄色固体61.1mg，收率76.5％。MS-ESI(m/z):534.23[M+H]+；1H NMR(400MHz,DMSO-d6)δ:9.31(s,1H),9.20(s,1H),8.55(s,1H),8.26(s,1H),8.14(d,J＝8.6Hz,1H),7.78(s,1H),7.68(d,J＝8.8Hz,2H),7.27(d,J＝8.8Hz,2H),7.03-6.94(m,5H),6.91(d,J＝2.5Hz,1H),6.51(s,1H),3.83(s,3H),2.89(t,J＝7.1Hz,2H),2.79-2.73(m,2H),2.36(s,3H)；13C NMR(101MHz,DMSO-d6)δ:169.50,161.76,159.94,159.29,159.07,156.72,151.86,142.23,140.45,138.03,134.29,130.91,127.05,125.73,120.91,120.38,118.01,117.60,116.89,113.74,113.34,95.97,55.76,28.26,23.61,12.59。
实施例23 1-(3-(叔丁基)异噁唑-5-基)-3-(4-((4-((8-甲氧基-5,6-二氢苯并[h]喹唑啉-2-基]氨基)苯基)氨基)苯基)脲(化合物23)
以化合物M-9c与化合物M-7c合成化合物23，合成方法参照化合物1。浅绿色固体28.7mg，收率33.3％。MS-ESI(m/z):576.39[M+H]+；1H NMR(400MHz,DMSO-d6)δ:10.02(s,1H),9.21(s,1H),8.60(s,1H),8.26(s,1H),8.14(d,J＝8.6Hz,1H),7.79(s,1H),7.68(d,J＝8.9Hz,2H),7.29(d,J＝8.8Hz,2H),7.10-6.93(m,5H),6.91(d,J＝2.4Hz,1H),6.02(s,1H),3.83(s,3H),2.89(t,J＝7.1Hz,2H),2.76(t,J＝7.2Hz,2H),1.25(s,9H)；13C NMR(101MHz,DMSO-d6)δ:172.93,162.44,161.77,159.94,159.07,156.73,150.30,142.23,140.60,137.95,134.35,130.71,127.05,125.72,120.93,120.37,118.12,117.62,116.76,113.74,113.34,83.62,55.77,32.39,29.55,28.26,23.60。
实施例24 1-(4-((4-((8-甲氧基-5,6-二氢苯并[h]喹唑啉-2-基)氨基)苯基)氨基)苯基)-3-(3-甲基异噁唑-5-基)脲(化合物24)
以化合物M-9c与化合物M-7d合成化合物24，合成方法参照化合物1。浅绿色固体28.7mg，收率45.3％。MS-ESI(m/z):534.32[M+H]+；1H NMR(400MHz,DMSO-d6)δ:9.97(s,1H),9.20(s,1H),8.61(s,1H),8.26(s,1H),8.14(d,J＝8.6Hz,1H),7.80(s,1H),7.68(d,J＝8.8Hz,2H),7.28(d,J＝8.8Hz,2H),7.10-6.93(m,5H),6.91(d,J＝2.3Hz,1H),5.92(s,1H),3.83(s,3H),2.89(t,J＝7.0Hz,2H),2.79-2.71(m,2H),2.16(s,3H)；13C NMR(101MHz,DMSO-d6)δ:162.57,161.77,161.06,159.94,159.07,156.73,150.22,142.23,140.60,137.96,134.33,130.66,127.05,125.72,120.97,120.37,118.07,117.61,116.81,113.74,113.34,86.38,55.77,28.26,23.60,11.86。
实施例25 1-(5-(叔丁基)异噁唑-3-基)-3-(4-((8-(2-吗啉代乙氧基)-5,6-二氢苯并[h]喹唑啉-2-基)氨基)苯基)尿素(化合物25)
以化合物M-15a与化合物M-7a合成化合物25，合成方法参照化合物1。黄色固体35.0mg，收率40.0％。MS-ESI(m/z):584.21[M+H]+；1H NMR(400MHz,DMSO-d6)δ:9.42(s,1H),9.34(s,1H),8.65(s,1H),8.28(s,1H),8.13(d,J＝8.6Hz,1H),7.75(d,J＝8.9Hz,2H),7.37(d,J＝8.9Hz,2H),7.00(dd,J＝8.6,2.1Hz,1H),6.93(d,J＝2.5Hz,1H),6.49(s,1H),4.17(t,J＝5.8Hz,2H),3.61-3.53(m,4H),2.91-2.84(m,2H),2.79-2.69(m,4H),1.29(s,9H)；13CNMR(101MHz,DMSO-d6)δ:180.58,161.03,159.76,159.09,158.96,156.77,151.89,142.28,136.74,132.66,127.05,125.64,119.71,119.45,118.07,114.33,113.81,92.87,66.62,65.90,57.38,54.05,32.92,28.82,28.16,23.58。
实施例26 1-(5-甲基异噁唑-3-基)-3-(4-((8-(2-吗啉代乙氧基)-5,6-二氢苯并[h]喹唑啉-2-基)氨基)苯基)脲(化合物26)
以化合物M-15a与化合物M-7b合成化合物26，合成方法参照化合物1。黄色固体49.2mg，收率56.6％。MS-ESI(m/z):580.16[M+K]+；1H NMR(400MHz,DMSO-d6)δ:9.57-9.11(m,3H),8.28(s,1H),8.13(d,J＝8.6Hz,1H),7.73(d,J＝8.9Hz,2H),7.39(d,J＝8.9Hz,2H),7.00(dd,J＝8.4Hz,2.4Hz,1H),6.93(d,J＝2.5Hz,1H),6.53(s,1H),4.16(t,J＝5.5Hz,2H),3.62-3.53(m,4H),2.91-2.85(m,2H),2.79-2.69(m,4H),2.35(s,3H)；13C NMR(101MHz,DMSO-d6)δ:169.30,161.02,159.78,159.43,159.06,156.79,152.11,142.25,136.48,133.12,127.04,125.66,119.53,119.42,117.97,114.32,113.83,96.10,66.65,65.91,57.41,54.07,28.17,23.59,12.60。
实施例27 1-(3-(叔丁基)异噁唑-5-基)-3-(4-((8-(2-吗啉代乙氧基)-5,6-二氢苯并[h]喹唑啉-2-基)氨基)苯基)尿素(化合物27)
以化合物M-15a与化合物M-7c合成化合物27，合成方法参照化合物1。黄色固体31.0mg，收率35.4％。MS-ESI(m/z):584.15[M+H]+；1H NMR(400MHz,DMSO-d6)δ:10.02(s,1H),9.35(s,1H),8.67(s,1H),8.28(s,1H),8.13(d,J＝8.6Hz,1H),7.75(d,J＝9.0Hz,2H),7.38(d,J＝9.0Hz,2H),7.00(dd,J＝8.7,2.5Hz,1H),6.93(d,J＝2.4Hz,1H),6.03(s,1H),4.17(t,J＝5.4Hz,2H),3.63-3.53(m,4H),2.90-2.85(m,2H),2.81-2.69(m,4H),1.26(s,9H)；13C NMR(101MHz,DMSO-d6)δ:172.96,162.34,161.01,159.76,159.09,156.78,150.24,142.28,136.87,132.46,127.04,125.66,119.74,119.40,118.07,114.34,113.83,83.73,66.59,65.93,57.35,54.03,32.40,29.54,28.16,23.59。
实施例28 1-(3-甲基异噁唑-5-基)-3-(4-((8-(2-吗啉代乙氧基)-5,6-二氢苯并[h]喹唑啉-2-基)氨基)苯基)脲(化合物28)
以化合物M-15a与化合物M-7d合成化合物28，合成方法参照化合物1。黄色固体44.9mg，收率51.7％。MS-ESI(m/z):580.07[M+K]+；1H NMR(400MHz,DMSO-d6)δ:9.99(s,1H),9.35(s,1H),8.67(s,1H),8.28(s,1H),8.13(d,J＝8.6Hz,1H),7.76(d,J＝8.9Hz,2H),7.37(d,J＝8.9Hz,2H),7.00(dd,J＝8.5,2.4Hz,1H),6.93(d,J＝2.3Hz,1H),5.94(s,1H),4.17(t,J＝5.6Hz,2H),3.67-3.51(m,4H),2.92-2.84(m,2H),2.81-2.67(m,4H),2.16(s,3H)；13CNMR(101MHz,DMSO-d6)δ:162.49,161.10,161.03,159.75,159.10,156.77,150.16,142.28,136.91,132.41,127.05,125.64,119.81,119.39,118.08,114.32,113.84,86.50,66.62,65.89,57.40,54.06,28.16,23.59,11.86。
实施例29 1-(5-(叔丁基)异噁唑-3-基)-3-(6-((8-(2-吗啉代乙氧基)-5,6-二氢苯并[h]喹唑啉-2-基)氨基)吡啶-3-基)脲(化合物29)
以化合物M-15b与化合物M-7a合成化合物29，合成方法参照化合物1。黄色固体64.9mg，收率74.1％。MS-ESI(m/z):585.34[M+H]+；1H NMR(400MHz,DMSO-d6)δ:9.62(s,1H),9.47(s,1H),8.84(s,1H),8.36(d,J＝2.8Hz,1H),8.35(s,1H),8.32(d,J＝9.0Hz,1H),8.15(d,J＝8.6Hz,1H),7.89(dd,J＝9.0,2.7Hz,1H),7.00(dd,J＝8.8,2.5Hz,1H),6.94(d,J＝2.3Hz,1H),6.50(s,1H),4.18(t,J＝5.7Hz,2H),3.62-3.56(m,4H),2.92-2.87(m,2H),2.82-2.77(m,2H),2.74(t,J＝5.3Hz,2H),1.30(s,9H)；13C NMR(101MHz,DMSO-d6)δ:180.60,159.20,158.86,158.77,156.83,152.14,149.24,142.36,139.16,130.10,129.35,127.26,125.53,119.21,115.67,114.35,113.93,112.73,92.95,66.32,66.27,53.83,46.04,32.94,28.83,28.04,23.58。
实施例30 1-(5-甲基异噁唑-3-基)-3-(6-((8-(2-吗啉代乙氧基)-5,6-二氢苯并[h]喹唑啉-2-基)氨基)吡啶-3-基)脲(化合物30)
以化合物M-15b与化合物M-7b合成化合物30，合成方法参照化合物1。黄色固体52.5mg，收率64.5％。MS-ESI(m/z):543.30[M+H]+；1H NMR(400MHz,DMSO-d6)δ:9.53(s,1H),9.45(s,1H),8.77(s,1H),8.36-8.29(m,3H),8.15(d,J＝8.8Hz,1H),7.88(dd,J＝9.2Hz,2.5Hz,1H),6.99(dd,J＝8.5Hz,2.4Hz,1H),6.94(d,J＝2.3Hz,1H),6.52(s,1H),4.17(t,J＝5.4Hz,2H),3.64-3.53(m,4H),2.92-2.85(m,2H),2.79(t,J＝7.6Hz,2H),2.72(d,J＝5.3Hz,2H),2.36(s,3H)；13C NMR(101MHz,DMSO-d6)δ:169.65,159.21,159.13,158.77,156.83,152.10,149.24,142.35,139.23,130.09,129.83,129.39,127.28,119.21,115.67,114.34,113.94,112.71,96.05,66.58,66.47,53.91,46.03,28.03,23.58,12.61,9.04。
实施例31 1-(3-(叔丁基)异噁唑-5-基)-3-(6-((8-(2-吗啉代乙氧基)-5,6-二氢苯并[h]喹唑啉-2-基)氨基)吡啶-3-基)脲(化合物31)
以化合物M-15b与化合物M-7c合成化合物31，合成方法参照化合物1。黄色固体25.0mg，收率28.5％。MS-ESI(m/z):585.35[M+H]+；1H NMR(400MHz,DMSO-d6)δ:10.23(s,1H),9.49(s,1H),8.84(s,1H),8.41-8.28(m,3H),8.15(d,J＝8.6Hz,1H),7.88(dd,J＝9.0,2.5Hz,1H),7.00(dd,J＝8.5,2.4Hz,1H),6.95(d,J＝2.3Hz,1H),6.06(s,1H),4.17(t,J＝5.8Hz,2H),3.64-3.54(m,4H),2.92-2.86(m,2H),2.82-2.76(m,2H),2.76-2.68(m,2H),1.25(s,9H)；13CNMR(101MHz,DMSO-d6)δ:172.97,162.24,161.18,159.25,158.75,156.80,150.58,149.37,142.34,139.30,129.92,129.43,127.27,125.41,119.23,114.33,113.89,112.70,84.03,66.63,65.91,57.39,54.06,32.40,29.54,28.03,23.59。
实施例32 1-(3-甲基异噁唑-5-基)-3-(6-((8-(2-吗啉代乙氧基)-5,6-二氢苯并[h]喹唑啉-2-基)氨基)吡啶-3-基)脲(化合物32)
以化合物M-15b与化合物M-7d合成化合物32，合成方法参照化合物1。黄色固体22.5mg，收率27.6％。MS-ESI(m/z):543.30[M+H]+；1H NMR(400MHz,DMSO-d6)δ:10.19(s,1H),9.49(s,1H),8.82(s,1H),8.37-8.30(m,3H),8.15(d,J＝8.5Hz,1H),7.88(m,1H),6.99(dd,J＝8.3Hz,1.8Hz,1H),6.94(d,J＝2.3Hz,1H),5.95(s,1H),4.19-4.14(m,2H),3.61-3.55(m,4H),2.91-2.86(m,2H),2.81-2.76(m,2H),2.74-2.69(m,2H),2.16(s,3H)。
实施例33 1-(5-(叔丁基)异噁唑-3-基)-3-(5-((8-(2-吗啉代乙氧基)-5,6-二氢苯并[h]喹唑啉-2-基)氨基)吡啶-2-基)脲(化合物33)
以化合物M-15c与化合物M-7a合成化合物33，合成方法参照化合物1。黄色固体41.2mg，收率47.0％。MS-ESI(m/z):585.29[M+H]+；1H NMR(400MHz,DMSO-d6)δ:10.71(s,1H),9.52(s,1H),9.44(s,1H),8.69(d,J＝2.6Hz,1H),8.32(s,1H),8.23(dd,J＝9.0,2.5Hz,1H),8.12(d,J＝8.6Hz,1H),7.58(d,J＝9.0Hz,1H),7.01(dd,J＝8.5,2.5Hz,1H),6.95(d,J＝2.5Hz,1H),6.56(s,1H),4.19(t,J＝5.6Hz,2H),3.64-3.57(m,4H),2.92-2.86(m,2H),2.82-2.73(m,4H),1.31(s,9H)；13C NMR(101MHz,DMSO-d6)δ:180.80,161.09,159.57,159.26,158.56,156.87,151.65,146.36,142.34,137.67,133.60,129.41,127.03,125.48,118.62,114.36,113.87,112.29,93.16,66.52,57.32,53.99,46.08,32.98,28.82,28.10,23.58。
实施例34 1-(3-(叔丁基)异噁唑-5-基)-3-(5-((8-(2-吗啉代乙氧基)-5,6-二氢苯并[h]喹唑啉-2-基)氨基)吡啶-2-基)脲(化合物34)
以化合物M-15c与化合物M-7c合成化合物34，合成方法参照化合物1。黄色固体40.0mg，收率45.6％。MS-ESI(m/z):585.29[M+H]+；1H NMR(400MHz,DMSO-d6)δ:11.29(s,1H),9.54(s,1H),9.48(s,1H),8.70(d,J＝2.5Hz,1H),8.32(s,1H),8.24(dd,J＝9.0,2.7Hz,1H),8.11(d,J＝8.5Hz,1H),7.56(d,J＝8.9Hz,1H),7.01(dd,J＝8.6,2.4Hz,1H),6.94(d,J＝2.5Hz,1H),6.11(s,1H),4.17(t,J＝5.8Hz,2H),3.65-3.53(m,4H),2.92-2.86(m,2H),2.78(t,J＝7.4Hz,2H),2.72(t,J＝5.7Hz,2H),1.27(s,9H)；13C NMR(101MHz,DMSO-d6)δ:173.07,161.65,161.14,159.56,159.29,156.82,149.97,146.09,142.34,137.60,133.74,129.51,127.05,125.43,118.67,114.34,113.84,112.31,84.56,66.65,65.94,57.41,54.07,32.44,29.52,28.10,23.59。
实施例35 1-(5-(叔丁基)异噁唑-3-基)-3-(3-氟-4-((8-(2-吗啉代乙氧基)-5,6-二氢苯并[h]喹唑啉-2-基)氨基)苯基)脲(化合物35)
以化合物M-15d与化合物M-7a合成化合物35，合成方法参照化合物1。黄色固体70.0mg，收率77.6％。MS-ESI(m/z):602.30[M+H]+；1H NMR(400MHz,DMSO-d6)δ:9.53(s,1H),8.90(s,1H),8.68(s,1H),8.22(s,1H),8.01(d,J＝8.6Hz,1H),7.70(t,J＝8.9Hz,1H),7.52(dd,J＝13.1,2.4Hz,1H),7.13-7.10(m,1H),6.94(dd,J＝8.6,2.6Hz,1H),6.91(d,J＝2.5Hz,1H),6.50(s,1H),4.15(t,J＝5.7Hz,2H),3.60-3.55(m,4H),2.86(t,J＝7.2Hz,2H),2.77-2.69(m,4H),1.30(s,9H)；13C NMR(101MHz,DMSO-d6)δ:180.68,161.02,160.26,159.18,158.77,156.77,151.79,142.22,135.98,135.88,126.99,125.92,125.52,123.00,122.89,118.26,114.45,114.24,113.74,92.94,66.64,65.88,57.41,54.07,32.95,28.82,28.15,23.55。
实施例36 1-(3-(叔丁基)异噁唑-5-基)-3-(3-氟-4-((8-(2-吗啉代乙氧基)-5,6-二氢苯并[h]喹唑啉-2-基)氨基)苯基)脲(化合物36)
以化合物M-15d与化合物M-7c合成化合物36，合成方法参照化合物1。黄色固体16.2mg，收率18.0％。MS-ESI(m/z):602.30[M+H]+；1H NMR(400MHz,DMSO-d6)δ:10.12(s,1H),8.92(s,1H),8.68(s,1H),8.22(s,1H),8.01(d,J＝8.5Hz,1H),7.70(t,J＝8.9Hz,1H),7.51(dd,J＝12.9,2.3Hz,1H),7.14(d,J＝8.8Hz,1H),6.96-6.92(m,1H),6.91(d,J＝2.5Hz,1H),6.06(s,1H),4.15(t,J＝5.8Hz,2H),3.57(t,J＝4.6Hz,4H),2.86(t,J＝7.3Hz,2H),2.76-2.68(m,4H),1.26(s,9H)；13C NMR(101MHz,DMSO-d6)δ:172.98,162.13,161.02,160.23,159.19,156.75,150.23,142.20,135.79,135.68,126.99,125.80,125.52,123.15,123.04,118.27,114.54,114.23,113.71,84.13,66.64,65.88,57.41,54.07,32.41,29.52,28.16,23.56。
实施例37 1-(5-(叔丁基)异噁唑-3-基)-3-(3-甲基-4-((8-(2-吗啉代乙氧基)-5,6-二氢苯并[h]喹唑啉-2-基)氨基)苯基)脲(化合物37)
以化合物M-15e与化合物M-7a合成化合物37，合成方法参照化合物1。黄色固体33.8mg，收率37.7％。MS-ESI(m/z):598.36[M+H]+；1H NMR(400MHz,DMSO-d6)δ:8.13(s,1H),8.09(s,1H),7.93(d,J＝8.4Hz,1H),6.99(d,J＝8.3Hz,1H),6.92-6.87(m,2H),6.44(d,J＝2.6Hz,1H),6.38(dd,J＝8.4,2.6Hz,1H),4.80(s,2H),4.13(t,J＝5.7Hz,2H),3.59-3.55(m,4H),2.85-2.80(m,2H),2.72-2.66(m,4H),2.06(s,3H)；13C NMR(101MHz,DMSO-d6)δ:180.58,160.93,159.78,159.07,158.93,156.79,151.82,142.16,135.29,133.87,133.16,126.90,125.77,125.68,120.78,117.47,116.75,114.22,113.69,92.88,66.64,65.89,57.42,54.07,32.94,28.83,28.24,23.56,18.86。
实施例38化合物活性的测定
1.激酶反应
1)配制1×Kinase buffer。
2)化合物的配制：受试化合物测试浓度为500nM,复孔检测。在384孔板中稀释成100倍终浓度的100％DMSO溶液。使用分液器Echo 550向目的板OptiPlate-384F转移250nL100倍终浓度的化合物。阴性对照孔和阳性对照孔中分别加250nl的100％DMSO。
3)用1×Kinase buffer配制2.5倍终浓度的激酶溶液。
4)在化合物孔和阳性对照孔分别加10μL的2.5倍终浓度的激酶溶液；在阴性对照孔中加10μL的1×Kinase buffer。
5)1000rpm离心30秒，振荡混匀后室温孵育10分钟。
6)用1×Kinase buffer配制25/15倍终浓度的ATP和Kinase substrate 2的混合溶液。
7)加入15μL的25/15倍终浓度的ATP和底物的混合溶液，起始反应。
8)将384孔板1000rpm离心30秒，振荡混匀后室温孵育40min。
9)加入30μL终止检测液停止激酶反应，1000rpm离心30秒，振荡混匀。
10)用Caliper EZ Reader读取转化率。计算公式：
Inhibition％＝(Conversion％max-Conversion％sample)/(Conversion％max-Conversion％min)×100，其中Conversion％max表示阳性对照孔转化率读数，Conversion％sample表示样品转化率读数，Conversion％min表示阴性对照孔转化率读数。
2.MV4-11细胞增殖抑制活性评价
1)完全培养基的配制：向89mL的IMDM基础培养基中加入10mL胎牛血清，再加入1mL青霉素/链霉素溶液，配成MV4-11细胞的培养液，储存于4℃冰箱备用。
2)待测化合物的配制：用分析天平准确称取待测化合物的质量，加入DMSO溶液配成2mg·mL-1的母液，于4℃冰箱储存备用。
3)传代培养：将MV4-11细胞于培养箱(二氧化碳5％，温度：37℃)中静置4h后，采用半换液法传代，维持细胞培养密度为1×105～1×106cells·mL-1。将传代后的细胞于37℃含5％CO2的培养箱中继续培养。
4)铺板加药：将细胞离心、去上清、加新的培养基、计数板计数后按照1.5×105cells·mL-1的接种密度接种于96孔板中。将待测化合物用培养基稀释成不同浓度，9个浓度，3个平行，同时有空白对照组(加培养基)和阳性对照组(加细胞和培养基，不加药)。将不同浓度的待测化合物加入对应的孔中，于培养箱中孵育72h。
5)OD值的测定：向空白孔、阳性对照孔和药物作用孔中加入10μL的CCK-8溶液，继续在CO2培养箱中培养4h。振板(4min)后，酶标仪测定每孔在450nm下的OD值。
6)IC50值的计算：采用GraphPad Prism 5软件计算不同浓度下的抑制率，根据抑制率曲线拟合成对应的函数，计算IC50值。
表1化合物激酶和细胞活性数据
其中，“--”是指未检测到活性。
目前FLT3抑制剂主要用于白血病等血液疾病，尤其是急性髓细胞性白血病等恶性肿瘤的治疗，本发明化合物已显示出较强的体外活性。从以上表1可以看出，本发明的少数化合物(包括化合物25、27、29、31和35)在500nM下对FLT3-ITD激酶的抑制率较高，特别是化合物29的抑制率高达89％。上述5个化合物对MV4-11细胞的IC50值均小于0.08μM，特别是化合物29对MV4-11细胞的IC50值仅为0.03μM。因此，本发明的化合物呈现很好的FLT3的抑制活性，可以被用作FLT3的抑制剂。
虽然本发明已以较佳实施例公开如上，但其并非用以限定本发明，任何熟悉此技术的人，在不脱离本发明的精神和范围内，都可做各种的改动与修饰，因此本发明的保护范围应该以权利要求书所界定的为准。
Claims (10)
1.一种结构如通式I所示的5,6-二氢苯并[h]喹唑啉类化合物及其在药学上可接受的盐，
其中：
R1选自-OR2；R2选自未取代或卤素取代的C1-C6直链或支链烷基、-(CH2)qR4；R4为吗啉；
A1为空键、-NH(C6H4)-、-NH2CO(C6H4)-和-NH2COCH2(C6H4)-；
A2的结构为：
R’选自C1-C6直链或C1-C6支链烷基；
X1、X2独立地选自N、CRx；Rx选自H、卤素、CH3；
L1选自-NH-、-NHCH2-和-NHCO-；
L2为
q选自0、1、2、3、4。
2.根据权利要求1所述的5,6-二氢苯并[h]喹唑啉类化合物及其在药学上可接受的盐，其特征在于，A2选自3-甲基异噁唑、3-叔丁基异噁唑、5-甲基异噁唑、5-叔丁基异噁唑。
3.根据权利要求1所述的5,6-二氢苯并[h]喹唑啉类化合物及其在药学上可接受的盐，其特征在于，所述的药学上可接受的盐为无机盐或有机盐；无机盐选自盐酸盐、氢溴酸盐、氢碘酸盐、高氯酸盐、硫酸盐、硫酸氢盐、硝酸盐、磷酸盐、酸式磷酸盐；有机盐选自甲酸盐、乙酸盐、三氟乙酸盐、丙酸盐、丙酮酸盐、羟乙酸盐、乙二酸盐、丙二酸盐、丁二酸盐、戊二酸盐、富马酸盐、马来酸盐、乳酸盐、苹果酸盐、柠檬酸盐、酒石酸盐、甲磺酸盐、乙磺酸盐、苯磺酸盐、水杨酸盐、对甲苯磺酸盐、抗坏血酸盐。
4.一种药物组合物，其特征在于，含有权利要求1～3任一所述的5,6-二氢苯并[h]喹唑啉类化合物及其在药学上可接受的盐。
5.根据权利要求4所述的药物组合物，其特征在于，还含有药学上可接受的载体、赋形剂或稀释剂。
6.根据权利要求4所述的药物组合物，其特征在于，药物组合物的剂型为用于口服给药的固体制剂，或者用于口服给药的液体剂型，或者用于胃肠外注射的剂型，或者用于局部给药的剂型。
7.根据权利要求4所述的药物组合物，其特征在于，包含其他药学上可接受的治疗剂进行联合给药。
8.权利要求1～3任一所述的5,6-二氢苯并[h]喹唑啉类化合物及其在药学上可接受的盐在制备FLT3激酶抑制剂中的应用。
9.权利要求1～3任一所述的5,6-二氢苯并[h]喹唑啉类化合物及其在药学上可接受的盐在制备用于治疗白血病和多种实体瘤药物中的应用。
10.权利要求1～3任一所述的5,6-二氢苯并[h]喹唑啉类化合物及其在药学上可接受的盐、或权利要求4～6任一所述的组合物在制备用于预防或治疗癌症的药物中的应用。
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