CN116217551A - 取代的吲唑或氮杂吲唑类化合物及其应用 - Google Patents
取代的吲唑或氮杂吲唑类化合物及其应用 Download PDFInfo
- Publication number
- CN116217551A CN116217551A CN202310142117.2A CN202310142117A CN116217551A CN 116217551 A CN116217551 A CN 116217551A CN 202310142117 A CN202310142117 A CN 202310142117A CN 116217551 A CN116217551 A CN 116217551A
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- CN
- China
- Prior art keywords
- indazol
- benzimidazol
- substituted
- unsubstituted
- benzoimidazol
- 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.)
- Pending
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- 125000003453 indazolyl group Chemical class N1N=C(C2=C1C=CC=C2)* 0.000 title abstract 2
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- -1 azaindazole compound Chemical class 0.000 claims abstract description 163
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- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 7
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- 125000000217 alkyl group Chemical group 0.000 claims description 25
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- 150000002367 halogens Chemical class 0.000 claims description 15
- 229910052757 nitrogen Inorganic materials 0.000 claims description 15
- JOXWSDNHLSQKCC-UHFFFAOYSA-N ethenesulfonamide Chemical compound NS(=O)(=O)C=C JOXWSDNHLSQKCC-UHFFFAOYSA-N 0.000 claims description 14
- 229910052739 hydrogen Inorganic materials 0.000 claims description 14
- 239000001257 hydrogen Substances 0.000 claims description 14
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 13
- 125000004432 carbon atom Chemical group C* 0.000 claims description 11
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Abstract
本发明涉及取代的吲唑或氮杂吲唑类化合物及其应用,具有优良的FLT3抑制活性,并表现出较强的抗肿瘤活性,该化合物包括其药学可接受的盐、溶剂化物、异构体、酯、酸、代谢物或前药,药理测试结果表明,本发明化合物对FLT3具有较强的抑制活性,对其他激酶表现出一定的选择性,可用于预防或治疗与FLT3有关的临床疾病,有显著的经济和社会效益。
Description
技术领域
本发明涉及医药领域,特别是新型FLT3激酶抑制剂化合物、包括该化合物的药物组合物、以及使用这些化合物和组合物来降低或抑制细胞或受试者的FLT3激酶和/或突变型FLT3激酶活性以及在受试者中预防或治疗细胞增殖性病症和/或FLT3相关病症的取代的吲唑或氮杂吲唑类化合物及其应用。
背景技术
蛋白激酶(protein kinases,PK)是细胞功能的关键调节因子,人体中已发现的PK约500多种,分子内都存在一个同源的由250~300个氨基酸残基构成的催化结构区。PK广泛存在于细胞信号传导、细胞周期调控等***中。这类酶催化从ATP转移出磷酸并共价结合到特定蛋白质分子中的某些丝氨酸、苏氨酸或酪氨酸残基的羟基上,从而改变蛋白质、酶的构象和活性。病理学及药理学研究表明,PK的功能失调与很多疾病密切相关,包括中枢神经***疾病、肿瘤、心血管疾病及自身免疫,等等。
研究发现,FLT3已成为急性淋巴细胞白血病(ALL)、急性髓性白血病(AML)、淋巴瘤、霍奇金病等不同血液***恶性肿瘤的重要标志物。银屑病是一种慢性易复发的炎性皮肤疾病,研究表明FLT3抑制剂也可用于免疫***疾病如银屑病的治疗。
AML是成人最常见的白血病之一,据统计,全世界每年有超过25万成年人被诊断为AML,AML患者的5年总生存期小于50%。在FLT3的临床应用中,FLT3抑制剂被广泛用于AML的治疗。大约70%的AML患者中,FLT3是过表达的。临床研究表明,FLT3的过表达与预后不良有关。根据化合物对FLT3选择性的强弱,可逆FLT3抑制剂分为第一代非选择性FLT3抑制剂和第二代选择性FLT3抑制剂。第一代的非选择性抑制剂有Cabozantinib、Sunitinib、Midostourin等。根据研究发现,第一代FLT3抑制剂为多靶点激酶抑制剂,对FLT3缺乏特异性,除了抑制FLT3,这些药物也抑制PDGFR、KIT和VEGFR,常因脱靶而引起毒性和不良反应,限制临床治疗效果。随后,人们进一步开发了新一代高效、高选择性的FLT3抑制剂,主要有Quizartinib、Crenolanib、Gilteritinib等。目前,Quizartinib、Crenolanib、Gilteritinib均已上市用于AML的治疗,但是,在临床应用中仍然会面临耐药,导致疾病复发。
发明内容
本发明的目的在于:为解决上述问题,本发明了提供一类化合物,具有优良的FLT3抑制活性,并表现出较强的抗肿瘤活性。其包括式(I)的化合物或其药学可接受的盐、溶剂化物、异构体、酯、酸、代谢物或前药:
本发明的技术方案如下:
1.具有以下结构式(I)的化合物或其药学上可接受的盐:
其中:
R1为-L-Ra,L表示键、O、NH、S、C(O)NH、C(O)、NHC(O)、NHC(O)NH、取代或未取代的C1-3亚烷基;Ra是选自氢、卤原子、-NH2、-OH、羟基、硝基、羧基、腈基、取代或未取代的C1-6烷基、取代或未取代的C3-8的环烷基、取代或未取代的C4-8的环烯基、取代或未取代C1-6烷硫基、取代或未取代的C1-6烷氧基、取代或未取代的C2-6烯基、取代或未取代的C1-6烷胺基、取代或未取代的C3-8杂环烷基;
A为N或CR2,B为N或CR3,D和E各自独立的为N、CR4或CR5,D和E中有且只有一个为CR5,R2、R3、R4是各自独立的选自氢、卤素、羟基、氰基、甲氧基、取代或未取代C1-6烷基,R5选自-NRb-SO2-Rc或-NRb-CO-Rc,Rc为-CRd=CHRe、 Rb、Rd、Re各自独立的选自H、-CN、取代或未取代的C1-6烷基;
所述取代基选自卤素、C1-6卤代烷基、羟基、C1-6烷基、C1-6烷氧基、C1-6烷胺基或C1-6烷硫基、C3-8杂环烷基中的一种或多种;
卤素为选自氟、氯、溴或碘;
C1-6卤代烷基为被卤素取代的且具有1-6个碳原子的直链或支链饱和烃基;
C2-6烯基为具有2-6个碳原子的直链或支链烯烃基;
C1-6烷基为具有1-6个碳原子的直链或支链饱和烃基;
C3-8环烷基为由3-8个碳原子形成的环状烷烃基;
C4-8环烯基为由4-8个碳原子形成的部分不饱和的环状烯烃;
C3-8杂环烷基为具有3-8个碳原子的饱和或部分不饱和的含一个或多个(例如2或3个)选自O、N和S的杂原子的杂环烷基。
本发明的优选方案在于:
R1为-L-Ra,L各自独立地表示键、O、NH、C(O)NH、C(O)、NHC(O)、NHC(O)NH、取代或未取代的C1-3亚烷基;Ra是选自氢、卤原子、-NH2、-OH、取代或未取代的C1-6烷基、取代或未取代C1-6烷硫基、取代或未取代的C1-6烷氧基、取代或未取代的C1-6烷胺基、取代或未取代的C3-8的环烷基、取代或未取代的C4-8的环烯基、取代或未取代的C3-8杂环烷基;
所述取代基选自卤素、C1-6卤代烷基、羟基、C1-6烷基中的一种或多种;
A为N或CR2,B为N或CR3,D和E各自独立的为N、CR4或CR5,D和E中有且只有一个为CR5,R2、R3、R4是各自独立的选自氢、卤素、羟基、氰基、甲氧基、取代或未取代C1-6烷基,R5选自-NH-SO2-Rc或-NH-CO-Rc,Rc为-CH=CHRe、 Re选自H、-CN、C1-6烷基。/>
本发明的另一优选方案在于:
R1为-L1-Ra,L1各自独立地表示键、S、O、NH、C(O)NH、C(O)、NHC(O)、NHC(O)NH、取代或未取代的C1-3亚烷基;Ra是选自氢、卤原子、-NH2、-OH、取代或未取代的C1-6烷基、取代或未取代C1-6烷硫基、取代或未取代的C1-6烷氧基、取代或未取代的C1-6烷胺基、取代或未取代的C3-8杂环烷基、取代或未取代的C3-8的环烷基、取代或未取代的C4-8的环烯基;
所述取代基选自卤素、C1-6卤代烷基、羟基、C1-6烷基中的一种或多种;
A为N或CR2,B为CR3,D和E各自独立的为CR4或CR5,D和E中有且只有一个为CR5,R2、R3、R4是各自独立的选自氢、卤素、羟基、氰基、甲氧基、取代或未取代C1-6烷基,R5选自-NH-SO2-Rc或-NH-CO-Rc,Rc为-CH=CHRe、 Re各选自H、取代或未取代的C1-4烷基。
本发明的另一优选方案在于:
R1为-L1-Ra,L1选自键、O、NH、C(O)NH、C(O)、NHC(O)、NHC(O)NH、亚甲基、亚乙基;Ra是选自取代或未取代的C3-8的环烷基、取代或未取代的C4-8的环烯基、取代或未取代C1-6烷基、取代或未取代的C3-8杂环烷基;
A为N或CR2,B为CR3,D和E各自独立的为CR4或CR5,D和E中有且只有一个为CR5,R2、R3、R4是各自独立的选自氢、卤素、羟基、氰基、甲氧基、取代或未取代C1-6烷基,R5选自-NH-SO2-Rc或-NH-CO-Rc,Rc为-CH=CHRe、 Re各选自H、取代或未取代的C1-4烷基。
本发明的另一优选方案在于:
R1为-L1-Ra,L1选自键、O、NH、C(O)NH、C(O)、NHC(O)、NHC(O)NH或亚甲基;Ra是选自四氢吡咯基、哌啶基、N-甲基哌啶-4-基、吗啉基、N-甲基哌嗪基、3-甲基哌啶-1-基、哌嗪基,或选自下列的取代氨基、取代氧基:N,N-二丙基氨基、N,N-二乙基氨基、N,N-二甲基氨基、正丁基氨基、2-(环己烯-1-基)乙基氨基、2-甲氧基乙氧基、2-羟基乙基氨基、N,N-二(2-甲氧基乙基)氨基;
A为N或CR2,B为CR3,D和E各自独立的为CR4或CR5,D和E中有且只有一个为CR5,R2、R3、R4是各自独立的选自氢、卤素、羟基、氰基、甲氧基、甲基、乙基、异丙基或三氟甲基,R5选自-NH-SO2-Rc或-NH-CO-Rc,Rc为-CH=CHRe、 Re选自H、-CN、甲基、乙基、异丙基或丙基。
本申请的进一步优选技术方案,是如下化合物:
N-(3-(6-吗啉基-1H-苯并咪唑-2-基)-1H-吲唑-5-基)丙烯酰胺(I-1)
N-(3-(6-(4-甲基哌嗪-1-基)-1H-苯并咪唑-2-基)-1H-吲唑-5-基)丙烯酰胺(I-2)
N-(3-(6-氟-1H-苯并咪唑-2-基)-1H-吲唑-5-基丙烯酰胺(I-3)
N-(3-(6-吗啉基-1H-苯并咪唑-2-基)-1H-吲唑-5-基)乙烯磺酰胺(I-4)
N-(3-(6-(4-甲基哌嗪-1-基)-1H-苯并咪唑-2-基)-1H-吲唑-5-基)乙烯磺酰胺(I-5)
N-(3-(6-氟-1H-苯并咪唑-2-基)-1H-吲唑-5-基乙烯磺酰胺(I-6)
3-氯-N-(3-(6-吗啉基-1H-苯并咪唑-2-基)-1H-吲唑-5-基丙酰胺(I-7)
3-氯-N-(3-(6-(4-甲基哌嗪-1-基)-1H-苯并咪唑-2-基)-1H-吲唑-5-基丙酰胺(I-8)
3-氯-N-(3-(6-氟-1H-苯并咪唑-2-基)-1H-吲唑-5-基)丙酰胺(I-9)
3-氯-N-(3-(6-吗啉甲基)-1H-苯并咪唑-2-基)-1H-吲唑-4-基丙酰胺(I-10)
3-氯-N-(3-(6-(4-甲基哌嗪-1-基)甲基)-1H-苯并咪唑-2-基)-1H-吲唑-4-基丙酰胺(I-11)
3-氯-N-(3-(6-(4-甲基哌嗪-1-羰基)-1H-苯并咪唑-2-基)-1H-吲唑-4-基丙酰胺(I-12)
N-(3-(6-吗啉甲基)-1H-苯并咪唑-2-基)-1H-吲唑-4-基丙烯酰胺(I-13)
N-(3-(6-(4-甲基哌嗪-1-基)甲基)-1H-苯并咪唑-2-基-1H-吲唑-4-基丙烯酰胺(I-14)
N-(3-(6-(4-甲基哌嗪-1-羰基)-1H-苯并咪唑-2-基)-1H-吲唑-4-基丙烯酰胺(I-15)
N-(3-(6-吗啉甲基)-1H-苯并咪唑-2-基-1H-吲唑-4-基)乙烯磺酰胺(I-16)
N-(3-(6-(4-甲基哌嗪-1-基)甲基)-1H-苯并咪唑-2-基-1H-吲唑-4-基乙烯磺酰胺(I-17)
N-(3-(6-(4-甲基哌嗪-1-基)甲基)-1H-苯并咪唑-2-基-1H-吲唑-4-基乙烯磺酰胺(I-18)
3-氯-N-(3-(6-(4-甲基哌嗪-1-基)-1H-苯并咪唑-2-基)-1H-吲唑-4-基丙酰胺(I-19)
3-氯-N-(3-(6-氟-1H-苯并咪唑-2-基)-1H-吲唑-4-基)丙酰胺(I-20)
3-氯-N-(3-(6-吗啉基-1H-苯并咪唑-2-基)-1H-吲唑-4-基)丙酰胺(I-21)
N-(3-(6-(4-甲基哌嗪-1-基)-1H-苯并咪唑-2-基)-1H-吲唑-4-基)乙烯磺酰胺(I-22)
N-(3-(6-氟-1H-苯并咪唑-2-基)-1H-吲唑-4-基)乙烯磺酰胺(I-23)
N-(3-(6-吗啉基-1H-苯并咪唑-2-基)-1H-吲唑-4-基)乙烯磺酰胺(I-24)
N-(3-(6-(4-甲基哌嗪-1-基)-1H-苯并咪唑-2-基)-1H-吲唑-4-基)丙烯酰胺(I-25)
N-(3-(6-氟-1H-苯并咪唑-2-基)-1H-吲唑-4-基丙烯酰胺(I-26)
N-(3-(6-吗啉基-1H-苯并咪唑-2-基)-1H-吲唑-4-基丙烯酰胺(I-27)
3-氯-N-(3-(6-(4-甲基哌嗪-1-基)-1H-苯并咪唑-2-基)-1H-吡唑并[3,4-b]吡啶-5-基)丙酰胺(I-28)3-氯-N-(3-(6-氟-1H-苯并咪唑-2-基)-1H-吡唑并[3,4-b]吡啶-5-基)丙酰胺(I-29)
3-氯-N-(3-(6-(4-甲基哌嗪-1-羰基)-1H-苯并咪唑-2-基)-1H-吡唑并[3,4-b]吡啶-5-基)丙酰胺(I-30)3-氯-N-(3-(6-吗啉-4-羰基)-1H-苯并咪唑-2-基)-1H-吡唑并[3,4-b]吡啶-5-基)丙酰胺(I-31)
N-(3-(6-(4-甲基哌嗪-1-基)-1H-苯并咪唑-2-基)-1H-吡唑并[3,4-b]吡啶-5-基)乙烯磺酰胺(I-32)N-(3-(6-吗啉基-1H-苯并咪唑-2-基)-1H-吡唑并[3,4-b]吡啶-5-基)乙烯磺酰胺(I-33)
N-(3-(6-氟-1H-苯并咪唑-2-基)-1H-吡唑并[3,4-b]吡啶-5-基)乙烯磺酰胺(I-34)
N-(3-(6-(4-甲基哌嗪-1-羰基)-1H-苯并咪唑-2-基)-1H-吡唑并[3,4-b]吡啶-5-基)乙烯磺酰胺(I-35)N-(3-(6-(4-甲基哌嗪-1-基)-1H-苯并咪唑-2-基)-1H-吡唑并[3,4-b]吡啶-5-基)丙烯酰胺(I-36)N-(3-(6-氟-1H-苯并咪唑-2-基)-1H-吡唑并[3,4-b]吡啶-5-基)丙烯酰胺(I-37)
N-(3-(6-吗啉基-1H-苯并咪唑-2-基)-1H-吡唑并[3,4-b]吡啶-5-基)丙烯酰胺(I-38)
N-(3-(6-(4-甲基哌嗪-1-羰基)-1H-苯并咪唑-2-基)-1H-吡唑并[3,4-b]吡啶-5-基)丙烯酰胺(I-39)N-(3-(6-(二乙氨基)-1H-苯并咪唑-2-基)-1H-吲唑-5-基)丙烯酰胺(I-40)
N-(3-(6-(二乙氨基)-1H-苯并咪唑-2-基)-1H-吲唑-4-基)丙烯酰胺(I-41)
分子结构式分别如下:
本发明的部分化合物制备方法如下:方法一:
方法二:
方法三:
本发明化合物都可以用上述或类似上述的制备方法制备得到,根据取代基的不同和取代基位置的不同选用相应的原料即可。
药理测试结果表明,本发明化合物对FLT3具有较强的抑制活性,对其他激酶表现出一定的选择性,可用于预防或治疗与FLT3有关的临床疾病,这些疾病可以是:白血病、淋巴(非霍奇金淋巴瘤)、霍奇金病(也称为霍奇金淋巴瘤)和骨髓瘤例如,急性淋巴细胞白血病(ALL)、急性粒细胞白血病或急性髓性白血病(AML)、急性早幼粒细胞白血病(APL)、慢性淋巴细胞白血病(CLL)、慢性粒细胞白病(CML)、慢性嗜中性细胞白血病(CNL)、急性未分化细胞白血病(AUL)、运行发育性大细胞性淋巴瘤(ALCL)、成人T细胞ALL、伴有兰语系(trilineage)脊髓发育不良的AML(AML/TMDS)、混合型语系白血病(MLL)、脊髓发育不良综合征(MDSs)、骨髓增生异常(MPD)、多发性骨髓瘤(MM)和脊髓肉瘤、肺癌、黑色素瘤、肝癌、肾癌、白血病、非小细胞肺癌、***癌、甲状腺癌、皮肤癌、胰腺癌、卵巢癌、睾丸癌、乳腺癌、膀胱癌、胆囊癌、骨髓增生异常综合症、淋巴瘤、食管癌、甲状腺滤泡癌、胃肠道癌、中枢或外周神经***的肿瘤(例如星形细胞瘤、神经母细胞瘤、神经胶质瘤或神经鞘瘤)、间皮瘤、II型或非胰岛素依赖型糖尿病、自身免疫性疾病、银屑病等。
附图说明
图1为本发明化合物的分子结构通式图。
具体实施方式
以下结合实施例和具体情况对本发明的具体实施方式作详细说明。
本发明在具体实施中可由以下实施例给出。
实施例1:5-吗啉基-2-硝基苯胺(1a)
在150mL单颈瓶中加入5-氟-2-硝基苯胺(6.0g,0.0384mol),用80mL N-甲基吡咯烷酮溶解,随后加入DIPEA(16.76mL,0.0960mol)和吗啉(13.4397mL,0.1536mol),加毕在100℃加热回流8h,TLC检测原料消失(甲醇:二氯甲烷=1:60)。将反应液加入400mL饱和碳酸氢钠溶液中,析出黄色固体,抽滤,减压干燥得黄色固体1a(7.5g),收率92.6%,MS[M+H]+:224.19。产品无需进一步纯化,直接进行下一步反应。
实施例2:4-吗啉基苯-1,2-二胺(1b)
在250mL单颈瓶中加入1a粗品(7.5g,0.0336mol),用150mL甲醇溶解,随后加入10%钯碳(375mg),加毕通入氢气抽排空气三次,室温下反应2h,TLC检测原料消失(乙酸乙酯:石油醚=1:1)。将反应液抽滤,滤液真空浓缩得黑紫色固体1b(6.49g),收率100%,MS[M+H]+:194.31。产品无需进一步纯化,直接进行下一步反应。
实施例3:5-(4-甲基哌嗪-1-基)-2-硝基苯胺(1c)
以5-氟-2-硝基苯胺(6.0g,0.0384mol)和甲基哌嗪(17.052mL,0.1536mol)为原料,制备方法同1a,得黄色固体1c(8.6g),收率95.6%,MS[M+H]+:237.25。产品无需进一步纯化,直接进行下一步反应。
实施例4:4-(4-甲基哌嗪-1-基)苯-1,2-二胺(1d)
以1c(8.6g,0.0364mol)为原料,制备方法同1b,得黑紫色固体1d(7.5g),收率100%,MS[M+H]+:207.17。产品无需进一步纯化,直接进行下一步反应。
实施例5:4-氟苯-1,2-二胺(1e)
以5-氟-2-硝基苯胺(6.0g,0.0384mol)为原料,制备方法同1b,得黑紫色固体1e(4.845g),收率100%,MS[M+H]+:127.22。产品无需进一步纯化,直接进行下一步反应。
实施例6:(3,4-二硝基苯基)-吗啉-4-基-甲酮(1f)
在100mL单颈瓶中加入3,4-二硝基苯甲酸(10.0g,0.0471mol)和30mL氯化亚砜,加毕在85℃下加热回流2h。待反应液冷却至室温后,加入少许甲苯,真空浓缩除去过量的氯化亚砜。随后用100mL四氢呋喃溶解残渣,在0℃下,向混合物中加入吗啉(4.1mL,0.0472moL)和三乙胺(7.2mL,0.0977mol),加毕在室温下搅拌3h,TLC检测原料消失(甲醇∶氯仿=1∶10)。向反应液中加入100mL水,然后用乙酸乙酯萃取,有机层用饱和氯化钠溶液洗涤三次,随后用无水硫酸钠干燥。将干燥液抽滤,滤液真空浓缩,用甲醇对残渣重结晶得黄色固体1f(8.23g),收率62.1%,MS[M+H]+:282.13。
实施例7:4-(3,4-二硝基苄基)吗啉(1g)
在150mL单颈瓶中加入1f(2.84g,0.0101mol),然后加入50mL无水四氢呋喃使其溶解,随后向混合物中加入NaBH4(954mg),并滴加三氟化硼***3.2mL,加毕在室温下搅拌3h,TLC检测原料消失(甲醇∶二氯甲烷=1∶30)。加入少许甲醇淬灭,真空浓缩,随后向残渣中加入100mL水,用乙酸乙酯萃取,有机层用饱和氯化钠溶液洗涤三次,并用无水硫酸钠干燥。干燥液抽滤,滤液真空浓缩,制砂,通过柱层析色谱纯化得1g(1.08g),收率40.1%,MS[M+H]+:268.11。
实施例8:4-(吗啉甲基)苯-1,2-二胺(1h)
以1g(1.08g,0.0040mol)为原料,制备方法同1b,得黑紫色固体1h(0.8376g),收率100%,MS[M+H]+:208.14。产品无需进一步纯化,直接进行下一步反应。
实施例9:(3,4-二氨基苯基)(吗啉基)甲酮(1i)
以1f(1.08g,0.0040mol)为原料,制备方法同1b,得黑紫色固体1i(0.9648g),收率100%,MS[M+H]+:252.12。产品无需进一步纯化,直接进行下一步反应。
实施例10:(3,4-二硝基苯基)(4-甲基哌嗪-1-基)甲酮(1j)
以3,4-二硝基苯甲酸(10.0g,0.0472mol)和甲基哌嗪(8.2140mL,0.0742mol)为原料,制备方法同1f,得黄色固体1j(9.04g),收率65.2%,MS[M+H]+:295.15。
实施例11:1-(3,4-二硝基苄基)-4-甲基哌嗪(1k)
以1i(2.84g,0.0097mol)为原料,制备方法同1g,得1k(1.14g),收率42.1%,MS[M+H]+:281.21。
实施例12:4-((4-甲基哌嗪-1-基)甲基)苯-1,2-二胺(1l)
以1j(1.14g,0.0041mol)为原料,制备方法同1b,得黑紫色固体1l(0.896g),收率100%,MS[M+H]+:221.23。产品无需进一步纯化,直接进行下一步反应。
实施例13:(3,4-二氨基苯基)(4-甲基哌嗪-1-基)甲酮(1m)
以1i(3.0g,0.0102mol)为原料,制备方法同1b,得黑紫色固体1m(2.388g),收率100%,MS[M+H]+:235.10。产品无需进一步纯化,直接进行下一步反应。
实施例14:N1,N1-二乙基-4-硝基苯-1,3-二胺(1n)
以5-氟-2-硝基苯胺(6.0g,0.0384mol)和二乙胺(15.89ml,0.1536mol)为原料,制备方法同1a,得黄色固体1n(7.346g),收率91.4%,MS[M+H]+:210.17。
实施例15:N4,N4-二乙基苯-1,2,4-三胺(1o)
以1m(3.0g,0.0143mol)为原料,制备方法同1b,得黑紫色固体1o(2.57g),收率100%,MS[M+H]+:180.20。产品无需进一步纯化,直接进行下一步反应。
实施例16:4-(2-(5-硝基-1H-吲唑-3-基)-1H-苯并咪唑-6-基吗啉(2a)
在50ml圆底烧瓶中加入5-硝基吲唑甲醛(2.0g,0.0105mol),加入15ml无水DMF使之溶解。随后加入4A分子筛(3.0g),1b(3.07g,0.0159mol),加毕在80℃下加热反应3.5h。TLC检测原料消失(甲醇:二氯甲烷=1:15)。反应液抽滤,在滤液中加入过量饱和NaCl溶液,然后用DCM进行萃取,收集有机层,无水NaSO4干燥,真空浓缩,制砂,通过柱层析色谱纯化得固体2a(1.11g),收率29.1%,MS[M+H]+:365.19。
实施例17:3-(6-(4-甲基哌嗪-1-基)-1H-苯并咪唑-2-基)-5-硝基-1H-吲唑(2b)
以5-硝基吲唑甲醛(2.0g,0.0105mol)和1d(3.278g,0.0159mol)为原料,制备方法同2a,得固体2b(1.243g),收率31.5%,MS[M+H]+:378.21。
实施例18:3-(6-氟-1H-苯并咪唑-2-基)-5-硝基-1H-吲唑(2c)
以5-硝基吲唑甲醛(2.0g,0.0105mol)和1e(2.0g,0.0159mol)为原料,制备方法同2a,得固体2c(1.42g),收率45.7%,MS[M+H]+:298.05。
实施例19:N,N-二乙基-2-(5-硝基-1H-吲唑-3-基)-1H-苯并咪唑-6-胺(2d)
以5-硝基吲唑甲醛(2.0g,0.0105mol)和1o(2.84g,0.0159mol)为原料,制备方法同2a,得固体2d(1.46g),收率39.8%,MS[M+H]+:351.12。
实施例20:4-(2-(5-硝基吡唑并[3,4-b]吡啶-3-基)-1H-苯并咪唑-6-基)吗啉(2e)
以5-硝基-1H-吡唑并[3,4-b]吡啶-3-甲醛(4.0g,0.0105mol)和1b(6.03g,0.0159mol)为原料,制备方法同2a,得固体2e(1.79g),收率23.6%,MS[M+H]+:366.17。
实施例21:3-(6-(4-甲基哌嗪-1-基)-1H-苯并咪唑-2-基)-5-硝基吡唑并[3,4-b]吡啶(2f)
以5-硝基-1H-吡唑并[3,4-b]吡啶-3-甲醛(4.0g,0.0105mol)和1d(6.44g,0.0159mol)为原料,制备方法同2a,得固体2f(2.13g),收率27.1%,MS[M+H]+:379.19。
实施例22:3-(6-氟-1H-苯并咪唑-2-基)-5-硝基吡唑并[3,4-b]吡啶(2g)
以5-硝基-1H-吡唑并[3,4-b]吡啶-3-甲醛(4.0g,0.0105mol)和1e(3.94g,0.0159mol)为原料,制备方法同2a,得固体2g(2.0g),收率32.3%,MS[M+H]+:299.11。
实施例23:(4-甲基哌嗪-1-基)(2-(5-硝基吡唑并[3,4-b]吡啶-3-基)-1H-苯并咪唑-6-基)甲酮(2h)
以5-硝基-1H-吡唑并[3,4-b]吡啶-3-甲醛(4.0g,0.0105mol)和1m(7.35g,0.0159mol)为原料,制备方法同2a,得固体2h(2.44g),收率28.7%,MS[M+H]+:407.23。
实施例24:吗啉基(2-(5-硝基-1H-吡唑并[3,4-b]吡啶-3-基)-1H-苯并咪唑-6-基)甲酮(2i)
以5-硝基-1H-吡唑并[3,4-b]吡啶-3-甲醛(4.0g,0.0105mol)和1i(7.89g,0.0159mol)为原料,制备方法同2a,得固体2i(2.40g),收率29.1%,MS[M+H]+:394.15。
实施例25:4-((2-(4-硝基-1H-吲唑-3-基)-1H-苯并咪唑-6-基)甲基)吗啉(2j)
以4-硝基-1H-吲唑-3-甲醛(2.0g,0.0105mol)和1h(3.253g,0.0159mol)为原料,制备方法同2a,得固体2j(1.33g),收率33.6%,MS[M+H]+:379.16。
实施例26:3-(6-((4-甲基哌嗪-1-基)甲基)-1H-苯并咪唑-2-基)-4-硝基-1H-吲唑(2k)
以4-硝基-1H-吲唑-3-甲醛(2.0g,0.0105mol)和1l(3.458g,0.0159mol)为原料,制备方法同2a,得固体2k(1.72g),收率42.1%,MS[M+H]+:392.25。
实施例27:(4-甲基哌嗪-1-基)(2-(4-硝基-1H-吲唑-3-基)-1H-苯并咪唑-6-基)甲酮(2l)
以4-硝基-1H-吲唑-3-甲醛(2.0g,0.0105mol)和1m(3.677g,0.0159mol)为原料,制备方法同2a,得固体2l(1.06g),收率25%,MS[M+H]+:406.19。
实施例28:3-(6-(4-甲基哌嗪-1-基)-1H-苯并咪唑-2-基)-4-硝基-1H-吲唑(2m)
以4-硝基-1H-吲唑-3-甲醛(2.0g,0.0105mol)和1d(3.278g,0.0159mol)为原料,制备方法同2a,得固体2m(1.26g),收率32%,MS[M+H]+:378.20。
实施例29:3-(6-氟-1H-苯并咪唑-2-基)-4-硝基-1H-吲唑(2n)
以4-硝基-1H-吲唑-3-甲醛(2.0g,0.0105mol)和1e(2.0g,0.0159mol)为原料,制备方法同2a,得固体2n(1.37g),收率44.1%,MS[M+H]+:298.14。
实施例30:4-(2-(4-硝基-1H-吲唑-3-基)-1H-苯并咪唑-6-基)吗啉(2o)
以4-硝基-1H-吲唑-3-甲醛(2.0g,0.0105mol)和1b(3.07g,0.0159mol)为原料,制备方法同2a,得固体2o(1.14g),收率30%,MS[M+H]+:365.14。
实施例31:N,N-二乙基-2-(4-硝基-1H-吲唑-3-基)-1H-苯并咪唑-6-胺(2p)
以4-硝基-1H-吲唑-3-甲醛(2.0g,0.0105mol)和1o(2.84g,0.0159mol)为原料,制备方法同2a,得固体2p(1.36g),收率37.2%,MS[M+H]+:351.17。
实施例32:3-(6-吗啉基-1H-苯并咪唑-2-基)-1H-吲唑-5-胺(3a)
在150ml单颈瓶中加入2a(1.11g,0.003mol),用50ml甲醇溶解,随后加入10%钯碳(0.111g),加毕通入氢气抽排空气三次,室温下反应2h,TLC检测原料消失(甲醇:二氯甲烷=1:10)。将反应液抽滤,滤液真空浓缩,制砂,通过柱层析色谱纯化得固体3a(0.73g),收率72.3%,MS[M+H]+:335.19。
实施例33:3-(6-(4-甲基哌嗪-1-基)-1H-苯并咪唑-2-基)-1H-吲唑-5-胺(3b)
以2b(1.243g,0.003mol)为原料,制备方法同3a,得红褐色固体3b(0.916g),收率80%。1H NMR(500MHz,Methanol-d4)δ7.66(dd,J=2.1,0.7Hz,1H,ArH),7.55(d,J=8.8Hz,1H,ArH),7.40(dd,J=8.9,0.7Hz,1H,ArH),7.21–7.18(m,1H,ArH),7.04(ddd,J=16.2,8.8,2.2Hz,2H,ArH),3.25(t,J=5.1Hz,4H,-CH2-×2),2.74(t,J=5.0Hz,4H,-CH2-×2),2.42(s,3H,-CH3);MS[M+H]+:348.21。
实施例34:3-(6-氟-1H-苯并咪唑-2-基)-1H-吲唑-5-胺(3c)
以2c(1.42g,0.0048mol)为原料,制备方法同3a,得固体3c(1.05g),收率82.3%,MS[M+H]+:268.13。
实施例35:3-(6-(二乙氨基)-1H-苯并咪唑-2-基)-1H-吲唑-5-胺(3d)
以2d(1.46g,0.0042mol)为原料,制备方法同3a,得淡黄色固体3d(1.06g),收率79.2%。1H NMR(500MHz,Methanol-d4)δ7.67(d,J=2.0Hz,1H,ArH),7.52(d,J=8.8Hz,1H,ArH),7.39(d,J=8.8Hz,1H,ArH),7.08–6.97(m,2H,ArH),6.88(dd,J=8.9,2.3Hz,1H,ArH),3.37(q,J=7.0Hz,4H,-CH2-×2),1.15(t,J=7.1Hz,6H,-CH3×2);MS[M+H]+:321.23。
实施例36:3-(6-吗啉基-1H-苯并咪唑-2-基)-1H-吡唑并[3,4-b]吡啶-5-胺(3e)
以2e(1.79g,0.0049mol)为原料,制备方法同3a,得固体3e(1.26g),收率76.5%,MS[M+H]+:336.25。
实施例37:3-(6-(4-甲基哌嗪-1-基)-1H-苯并咪唑-2-基)-1H-吡唑并[3,4-b]吡啶-5-胺(3f)
以2f(2.13g,0.0056mol)为原料,制备方法同3a,得固体3f(1.57g),收率80.1%,MS[M+H]+:349.27。
实施例38:3-(6-氟-1H-苯并咪唑-2-基)-1H-吡唑并[3,4-b]吡啶-5-胺(3g)
以2g(2.0g,0.0067mol)为原料,制备方法同3a,得固体3g(1.43g),收率79.7%,MS[M+H]+:269.14。
实施例39:(2-(5-氨基-1H-吡唑并[3,4-b]吡啶-3-基)-1H-苯并咪唑-6-基)(4-甲基哌嗪-1-基)甲酮(3h)
以2h(2.44g,0.0060mol)为原料,制备方法同3a,得固体3h(1.82g),收率80.5%,MS[M+H]+:377.25。
实施例40:(2-(5-氨基-1H-吡唑并[3,4-b]吡啶-3-基)-1H-苯并咪唑-6-基)(吗啉基)甲酮(3i)
以2i(2.40g,0.0061mol)为原料,制备方法同3a,得固体3i(1.64g),收率73.9%,MS[M+H]+:364.17。
实施例41:3-(6-吗啉甲基)-1H-苯并咪唑-2-基-1H-吲唑-4-胺(3j)
以2j(1.33g,0.0035mol)为原料,制备方法同3a,得固体3j(1.03g),收率84.1%,MS[M+H]+:349.23。
实施例42:3-(6-(4-甲基哌嗪-1-基)甲基)-1H-苯并咪唑-2-基)-1H-吲唑-4-胺(3k)
以2k(1.72g,0.0044mol)为原料,制备方法同3a,得固体3k(1.29g),收率81.1%,MS[M+H]+:362.18。
实施例43:2-(4-氨基-1H-吲唑-3-基)-1H-苯并咪唑-6-基)(4-甲基哌嗪-1-基)甲酮(3l)
以2l(1.06g,0.0026mol)为原料,制备方法同3a,得固体3l(0.729g),收率74.3%,MS[M+H]+:376.26。
实施例44:3-(6-(4-甲基哌嗪-1-基)-1H-苯并咪唑-2-基)-1H-吲唑-4-胺(3m)
以2m(1.26g,0.0033mol)为原料,制备方法同3a,得灰色固体3m(0.973g),收率83.9%。1H NMR(500MHz,DMSO-d6)δ13.19(d,J=19.5Hz,1H,-NH-),12.66(s,1H,-NH-),7.50(d,J=8.8Hz,2H,ArH),7.09–7.03(m,1H.ArH),6.97–6.90(m,1H,ArH),6.61(dd,J=8.1,2.9Hz,1H,ArH),6.23(t,J=7.8Hz,1H,ArH),3.23–3.04(m,8H,-CH2-×4),2.24(s,3H,-CH3);MS[M+H]+:348.24。
实施例45:3-(6-氟-1H-苯并咪唑-2-基)-1H-吲唑-4-胺(3n)
以2n(1.37g,0.0046mol)为原料,制备方法同3a,得灰白色固体3n(1.0g),收率81.5%。1H NMR(500MHz,Methanol-d4)δ7.46(dd,J=8.8,4.7Hz,1H,ArH),7.19(dd,J=9.2,2.4Hz,1H,ArH),7.04(dt,J=7.8,3.8Hz,1H,ArH),6.91(td,J=9.3,2.5Hz,1H,ArH),6.66(d,J=8.2Hz,1H,ArH),6.29(d,J=7.5Hz,1H,ArH);MS[M+H]+:268.19。
实施例46:3-(6-吗啉基-1H-苯并咪唑-2-基)-1H-吲唑-4-胺(3o)
以2o(1.14g,0.0031mol)为原料,制备方法同3a,得灰色固体3o(0.88g),收率84.1%。1H NMR(500MHz,DMSO-d6)δ13.19(d,J=18.5Hz,1H,-NH-),12.71(d,J=18.7Hz,1H,-NH-),7.58–7.45(m,2H,ArH),7.06(td,J=7.8,2.1Hz,1H,ArH),6.98–6.86(m,1H,ArH),6.60(dd,J=8.1,2.3Hz,1H,ArH),6.32–6.19(m,1H,ArH),3.76(dd,J=6.0,3.3Hz,4H,-CH2-×2),3.09(dq,J=4.9,2.6Hz,4H,-CH2-×2);MS[M+H]+:335.17。
实施例47:3-(6-(二乙氨基)-1H-苯并咪唑-2-基)-1H-吲唑-4-胺(3p)
以2p(1.36g,0.0039mol)为原料,制备方法同3a,得棕色固体3p(0.997g),收率80.2%。1H NMR(500MHz,Methanol-d4)δ7.47(d,J=8.8Hz,1H,ArH),7.13(t,J=7.9Hz,1H,ArH),6.97(s,1H,ArH),6.87(dd,J=8.8,2.3Hz,1H,ArH),6.75(d,J=8.2Hz,1H,ArH),6.37(d,J=7.4Hz,1H,ArH),3.36(q,J=7.1Hz,4H,-CH2-×2),1.14(t,J=7.1Hz,6H,-CH3×2);MS[M+H]+:321.23。
实施例48:N-(3-(6-吗啉基-1H-苯并咪唑-2-基)-1H-吲唑-5-基)丙烯酰胺(I-1)
在25ml单颈瓶中加入3a(150mg,0.449mmol),加入10ml无水四氢呋喃使之溶解,随后加入丙烯酰氯(44.69mg,0.494mmol)。室温下反应30min,TLC检测原料消失(甲醇:二氯甲烷=1:10)。减压蒸干溶剂,经柱层析得固体Ⅰ-1(38.33mg),收率22%,MS[M+H]+:389.18。
实施例49:N-(3-(6-(4-甲基哌嗪-1-基)-1H-苯并咪唑-2-基)-1H-吲唑-5-基)丙烯酰胺(I-2)
以3b(150mg,0.432mmol)为原料,制备方法同Ⅰ-1,经柱层析得白色固体Ⅰ-2(40.04mg),收率23.1%,1H NMR(500MHz,Methanol-d4)δ8.56(d,J=1.9Hz,1H,ArH),7.81(dd,J=8.9,2.0Hz,1H,ArH),7.58(dd,J=8.9,5.5Hz,2H,ArH),7.19(d,J=2.3Hz,1H,ArH),7.07(dd,J=8.8,2.3Hz,1H,ArH),6.50(dd,J=17.0,10.1Hz,1H,=CH),6.40(dd,J=17.0,1.8Hz,1H,=CH),5.80(dd,J=10.0,1.8Hz,1H,=CH-),3.28(dd,J=6.5,3.5Hz,4H,-CH2-×2),2.82(t,J=5.0Hz,4H,-CH2-×2),2.48(s,3H,-CH3);MS[M+H]+:402.28。
实施例50:N-(3-(6-氟-1H-苯并咪唑-2-基)-1H-吲唑-5-基丙烯酰胺(I-3)
以3c(150mg,0.562mmol)为原料,制备方法同Ⅰ-1,经柱层析得固体Ⅰ-3(45.62mg),收率25.3%,MS[M+H]+:322.17。
实施例51:N-(3-(6-吗啉基-1H-苯并咪唑-2-基)-1H-吲唑-5-基)乙烯磺酰胺(I-4)
在25ml单颈瓶中加入3a(150mg,0.449mmol),加入10ml无水DMF使之溶解,随后加入氯乙基磺酰氯(73.18mg,0.449mmol),DIPEA(174.1mg,1.35mmol)。室温下反应1h,TLC检测原料消失(甲醇:乙酸乙酯=1:20)。反应液抽滤,得滤饼,滤饼制砂,经柱层析得固体Ⅰ-4(36.75mg),收率19.3%,MS[M+H]+:425.15。
实施例52:N-(3-(6-(4-甲基哌嗪-1-基)-1H-苯并咪唑-2-基)-1H-吲唑-5-基)乙烯磺酰胺(I-5)
以3b(150mg,0.432mmol)为原料,制备方法同Ⅰ-4,经柱层析得固体Ⅰ-5(28.33mg),收率15.0%,MS[M+H]+:438.23。
实施例53:N-(3-(6-氟-1H-苯并咪唑-2-基)-1H-吲唑-5-基乙烯磺酰胺(I-6)
以3c(150mg,0.562mmol)为原料,制备方法同Ⅰ-4,经柱层析得固体Ⅰ-6(56.75mg),收率28.3%,MS[M+H]+:358.16。
实施例54:3-氯-N-(3-(6-吗啉基-1H-苯并咪唑-2-基)-1H-吲唑-5-基丙酰胺(I-7)
在25ml单颈瓶中加入3a(150mg,0.449mmol),加入10ml无水四氢呋喃使之溶解,随后加入3-氯丙酰氯(91.19mg,0.718mmol)。室温下反应30min,TLC检测原料消失(甲醇:二氯甲烷=1:20)。减压蒸干溶剂,经柱层析得固体Ⅰ-7(32.56mg),收率17.1%,MS[M+H]+:425.18。
实施例55:3-氯-N-(3-(6-(4-甲基哌嗪-1-基)-1H-苯并咪唑-2-基)-1H-吲唑-5-基丙酰胺(I-8)
以3b(150mg,0.432mmol)为原料,制备方法同Ⅰ-7,经柱层析得白色固体Ⅰ-8(36.83mg),收率19.5%。1H NMR(500MHz,Methanol-d4)δ8.52(d,J=1.8Hz,1H,ArH),7.70(dd,J=9.0,2.0Hz,1H,ArH),7.57(dt,J=8.9,3.6Hz,2H,ArH),7.20(d,J=2.2Hz,1H,ArH),7.06(dd,J=8.8,2.3Hz,1H,ArH),3.92(t,J=6.4Hz,2H,-CH2-),3.32(s,4H,-CH2-×2),2.99(t,J=4.9Hz,4H,-CH2-×2),2.90(t,J=6.3Hz,2H,-CH2-),2.61(s,3H,-CH3);13CNMR(126MHz,Methanol-d4)δ169.49,147.95,139.12,135.84,132.82,132.71,131.11,126.29,122.07,120.77,115.14,112.31,110.19,54.48,49.92,44.10,39.67,39.30;MS[M+H]+:438.27。
实施例56:3-氯-N-(3-(6-氟-1H-苯并咪唑-2-基)-1H-吲唑-5-基)丙酰胺(I-9)
以3c(150mg,0.562mmol)为原料,制备方法同Ⅰ-7,经柱层析得固体Ⅰ-9(45.52mg),收率22.7%,MS[M+H]+:358.16。
实施例57:3-氯-N-(3-(6-吗啉甲基)-1H-苯并咪唑-2-基)-1H-吲唑-4-基丙酰胺(I-10)
以3j(150mg,0.431mmol)为原料,制备方法同Ⅰ-7,经柱层析得固体Ⅰ-10(30.4mg),收率16.1%,MS[M+H]+:439.14。
实施例58:3-氯-N-(3-(6-(4-甲基哌嗪-1-基)甲基)-1H-苯并咪唑-2-基)-1H-吲唑-4-基丙酰胺(I-11)
以3k(150mg,0.415mmol)为原料,制备方法同Ⅰ-7,经柱层析得固体Ⅰ-11(34.9mg),收率18.6%,MS[M+H]+:452.24。
实施例59:3-氯-N-(3-(6-(4-甲基哌嗪-1-羰基)-1H-苯并咪唑-2-基)-1H-吲唑-4-基丙酰胺(I-12)
以3l(150mg,0.400mmol)为原料,制备方法同Ⅰ-7,经柱层析得固体Ⅰ-12(25.10mg),收率13.5%,MS[M+H]+:466.19。
实施例60:N-(3-(6-吗啉甲基)-1H-苯并咪唑-2-基)-1H-吲唑-4-基丙烯酰胺(I-13)
以3j(150mg,0.431mmol)为原料,制备方法同Ⅰ-1,经柱层析得固体Ⅰ-13(32.75mg),收率18.9%,MS[M+H]+:403.16。
实施例61:N-(3-(6-(4-甲基哌嗪-1-基)甲基)-1H-苯并咪唑-2-基-1H-吲唑-4-基丙烯酰胺(I-14)
以3k(150mg,0.415mmol)为原料,制备方法同Ⅰ-1,经柱层析得固体Ⅰ-14(31.21mg),收率18.1%,MS[M+H]+:416.27。
实施例62:N-(3-(6-(4-甲基哌嗪-1-羰基)-1H-苯并咪唑-2-基)-1H-吲唑-4-基丙烯酰胺(I-15)
以3l(150mg,0.400mmol)为原料,制备方法同Ⅰ-1,经柱层析得固体Ⅰ-15(28.64mg),收率15.4%,MS[M+H]+:430.21。
实施例63:N-(3-(6-吗啉甲基)-1H-苯并咪唑-2-基-1H-吲唑-4-基)乙烯磺酰胺(I-16)
以3j(150mg,0.431mmol)为原料,制备方法同Ⅰ-4,经柱层析得固体Ⅰ-16(36.24mg),收率19.2%,MS[M+H]+:439.16。
实施例64:N-(3-(6-(4-甲基哌嗪-1-基)甲基)-1H-苯并咪唑-2-基-1H-吲唑-4-基乙烯磺酰胺(I-17)
以3k(150mg,0.415mmol)为原料,制备方法同Ⅰ-4,经柱层析得固体Ⅰ-17(30.92mg),收率16.5%,MS[M+H]+:452.15。
实施例65:N-(3-(6-(4-甲基哌嗪-1-基)甲基)-1H-苯并咪唑-2-基-1H-吲唑-4-基乙烯磺酰胺(I-18)
以3l(150mg,0.400mmol)为原料,制备方法同Ⅰ-4,经柱层析得固体Ⅰ-18(26.97mg),收率14.5%,MS[M+H]+:466.20。
实施例66:3-氯-N-(3-(6-(4-甲基哌嗪-1-基)-1H-苯并咪唑-2-基)-1H-吲唑-4-基丙酰胺(I-19)
以3m(150mg,0.432mmol)为原料,制备方法同Ⅰ-7,经柱层析得固体Ⅰ-19(36.07mg),收率19.1%,MS[M+H]+:438.19。
实施例67:3-氯-N-(3-(6-氟-1H-苯并咪唑-2-基)-1H-吲唑-4-基)丙酰胺(I-20)
以3n(150mg,0.562mmol)为原料,制备方法同Ⅰ-7,经柱层析得灰白色固体Ⅰ-20(40.31mg),收率20.1%。1H NMR(600MHz,DMSO-d6)δ14.00(d,J=7.4Hz,1H,-NH-),13.93(d,J=14.9Hz,1H,-NH-),13.47(d,J=5.7Hz,1H,-NH-),8.34(dd,J=7.6,3.4Hz,1H,ArH),7.77(dd,J=8.8,4.8Hz,1H,ArH),7.58(ddd,J=19.0,9.1,3.6Hz,1H,ArH),7.46–7.40(m,1H,ArH),7.32(td,J=8.7,2.5Hz,1H,ArH),7.23–7.12(m,1H,ArH),4.06(q,J=5.9Hz,2H,-CH2-),3.19(td,J=6.1,4.8Hz,2H,-CH2-);13C NMR(151MHz,DMSO-d6)δ167.72,161.70,148.59,142.23,137.70,133.66,131.91,130.22,127.68,118.48,112.10,111.50,110.94,109.91,109.18,104.81,97.76,40.38,39.71;MS[M+H]+:358.13。
实施例68:3-氯-N-(3-(6-吗啉基-1H-苯并咪唑-2-基)-1H-吲唑-4-基)丙酰胺(I-21)
以3o(150mg,0.562mmol)为原料,制备方法同Ⅰ-7,经柱层析得固体Ⅰ-21(34.65mg),收率18.2%,MS[M+H]+:425.18。
实施例69:N-(3-(6-(4-甲基哌嗪-1-基)-1H-苯并咪唑-2-基)-1H-吲唑-4-基)乙烯磺酰胺(I-22)
以3m(150mg,0.432mmol)为原料,制备方法同Ⅰ-4,经柱层析得灰色固体Ⅰ-22(29.09mg),收率15.4%。1H NMR(500MHz,Methanol-d4)δ7.54(s,1H,ArH),7.35(t,J=8.0Hz,1H,ArH),7.24(dd,J=8.0,2.1Hz,2H,ArH),7.06(d,J=9.0Hz,2H,ArH),6.63(dd,J=16.5,9.9Hz,1H,=CH),6.24(d,J=16.5Hz,1H,=CH),5.90(d,J=9.9Hz,1H,=CH-),3.23(t,J=5.0Hz,4H,-CH2-×2),2.68(t,J=5.0Hz,4H,-CH2-×2),2.37(s,3H,-CH3);13CNMR(126MHz,Methanol-d4)δ143.30,135.88,131.94,127.81,126.74,113.16,108.56,104.74,54.72,50.21,44.64;MS[M+H]+:438.19。
实施例70:N-(3-(6-氟-1H-苯并咪唑-2-基)-1H-吲唑-4-基)乙烯磺酰胺(I-23)
以3n(150mg,0.562mmol)为原料,制备方法同Ⅰ-4,经柱层析得米白色固体Ⅰ-23(53.34mg),收率26.6%。1H NMR(600MHz,DMSO-d6)δ14.41(d,J=3.2Hz,1H,-NH-),13.95(d,J=18.8Hz,1H,-NH-),13.54(d,J=13.4Hz,1H,-NH-),7.58(ddd,J=29.6,8.8,4.8Hz,1H,ArH),7.41(td,J=8.1,2.2Hz,1H,ArH),7.31(dd,J=8.4,4.2Hz,2H,ArH),7.23–7.15(m,1H,ArH),7.13(dd,J=7.6,3.9Hz,1H,ArH),6.84(dd,J=16.4,9.9Hz,1H,=CH),6.25(dd,J=16.3,1.8Hz,1H,=CH),6.04(d,J=9.9Hz,1H,=CH-);13C NMR(151MHz,DMSO-d6)δ148.23,147.67,142.41,137.19,135.54,133.63,131.08,130.11,127.83,118.47,112.03,110.10,107.27,104.58,102.92,97.63;MS[M+H]+:358.13。
实施例71:N-(3-(6-吗啉基-1H-苯并咪唑-2-基)-1H-吲唑-4-基)乙烯磺酰胺(I-24)
以3o(150mg,0.449mmol)为原料,制备方法同Ⅰ-4,经柱层析得淡黄色固体Ⅰ-24(35.80mg),收率18.8%。1H NMR(600MHz,DMSO-d6)δ14.87(d,J=51.2Hz,1H,-NH-),13.82(d,J=27.6Hz,1H,-NH-),13.17(d,J=39.4Hz,1H,-NH-),7.49–7.35(m,2H,ArH),7.28(dd,J=8.4,3.2Hz,1H,ArH),7.16–7.02(m,2H,ArH),6.95(d,J=2.3Hz,1H,ArH),6.82(ddd,J=16.3,9.9,3.6Hz,1H,=CH),6.24(dd,J=16.4,4.7Hz,1H,=CH),6.03(dd,J=9.9,2.7Hz,1H,=CH-),3.79(t,J=4.6Hz,4H,-CH2-×2),3.12(dt,J=16.4,4.7Hz,4H,-CH2-×2);13CNMR(151MHz,DMSO-d6)δ161.70,148.30,145.45,135.64,134.55,134.34,134.20,131.28,127.62,117.59,113.27,111.97,106.94,104.36,96.53,65.64(d,J=9.4Hz),49.51(d,J=81.7Hz);MS
[M+H]+:425.16。
实施例72:N-(3-(6-(4-甲基哌嗪-1-基)-1H-苯并咪唑-2-基)-1H-吲唑-4-基)丙烯酰胺(I-25)
以3m(150mg,0.432mmol)为原料,制备方法同Ⅰ-1,经柱层析得白色固体Ⅰ-25(33.45mg),收率19.3%。1H NMR(500MHz,DMSO-d6)δ14.28(d,J=20.7Hz,1H,-NH-),14.06–13.94(m,1H,-NH-),13.15(d,J=26.8Hz,1H,-NH-),8.41(d,J=7.6Hz,1H,ArH),7.65(d,J=8.8Hz,1H,ArH),7.50–7.38(m,1H,ArH),7.34(dd,J=8.3,4.6Hz,1H,ArH),7.09(ddd,J=20.6,8.9,2.2Hz,1H,ArH),6.99(d,J=2.3Hz,1H,ArH),6.80(ddd,J=16.9,10.2,3.1Hz,1H,=CH),6.44(dt,J=17.1,2.5Hz,1H,=CH),6.11–5.96(m,1H,=CH-),3.31–3.23(m,4H,-CH2-×2),2.77(s,4H,-CH2-×2),2.42(s,3H,-CH3);13C NMR(126MHz,DMSO-d6)δ164.14,146.99,143.26,136.19,135.51,135.12,133.11,132.59,128.55,127.77,118.62,116.13,114.68,112.52,110.42,106.07,98.16,54.46,49.20,21.59;MS[M+H]+:402.18。
实施例73:N-(3-(6-氟-1H-苯并咪唑-2-基)-1H-吲唑-4-基丙烯酰胺(I-26)
以3n(150mg,0.562mmol)为原料,制备方法同Ⅰ-1,经柱层析得白色固体Ⅰ-26(36.60mg),收率20.3%,1H NMR(600MHz,DMSO-d6)δ14.01(d,J=23.4Hz,1H,-NH-),13.95(d,J=14.7Hz,1H,-NH-),13.47(d,J=3.7Hz,1H,-NH-),8.44(dd,J=7.6,4.4Hz,1H,ArH),7.83(dd,J=8.8,4.7Hz,1H,ArH),7.61(ddd,J=57.6,9.1,3.6Hz,1H,ArH),7.55–7.40(m,1H,ArH),7.35(dd,J=8.2,2.5Hz,1H,ArH),7.18(dtd,J=18.9,9.4,2.6Hz,1H,ArH),6.80(ddd,J=16.9,10.3,1.5Hz,1H,ArH),6.44(ddd,J=16.8,4.6,1.8Hz,1H,ArH),6.02(ddd,J=18.1,10.2,1.9Hz,1H,ArH);13C NMR(151MHz,DMSO-d6)δ163.18,148.60,142.25,137.72,133.68,131.94,131.64,130.23,127.67,126.96,112.00,111.64,109.74,105.07,103.35,97.73;MS[M+H]+:322.16。
实施例74:N-(3-(6-吗啉基-1H-苯并咪唑-2-基)-1H-吲唑-4-基丙烯酰胺(I-27)
以3o(150mg,0.449mmol)为原料,制备方法同Ⅰ-1,经柱层析得白色固体Ⅰ-27(32.41mg),收率18.6%。1H NMR(600MHz,DMSO-d6)δ14.28(d,J=22.9Hz,1H,-NH-),13.83(d,J=26.2Hz,1H,-NH-),13.11(d,J=30.3Hz,1H,-NH-),8.42(d,J=7.6Hz,1H,ArH),7.65(d,J=8.8Hz,1H,ArH),7.43(td,J=8.4,4.5Hz,1H,ArH),7.33(dd,J=8.3,5.1Hz,1H,ArH),7.08(ddd,J=23.5,8.8,2.3Hz,1H,ArH),6.97(d,J=2.3Hz,1H,ArH),6.80(dd,J=17.0,10.2Hz,1H,=CH),6.44(dt,J=17.0,1.9Hz,1H,=CH),6.02(ddd,J=20.0,10.2,1.7Hz,1H,=CH-),3.80(dd,J=6.0,3.7Hz,4H,-CH2-×2),3.18–3.08(m,4H,-CH2-×2);13CNMR(151MHz,DMSO-d6)δ163.10,148.25,145.87,142.22,135.14,134.49,134.20,132.11,131.55,127.57,126.68,117.59,113.12,109.41,104.92,103.05,96.59,65.68(d,J=17.3Hz),49.50(d,J=68.5Hz);MS[M+H]+:389.24。
实施例75:3-氯-N-(3-(6-(4-甲基哌嗪-1-基)-1H-苯并咪唑-2-基)-1H-吡唑并[3,4-b]吡啶-5-基)丙酰胺(I-28)
以3f(150mg,0.431mmol)为原料,制备方法同Ⅰ-7,经柱层析得固体Ⅰ-28(28.50mg),收率15.1%,MS[M+H]+:439.21。
实施例76:3-氯-N-(3-(6-氟-1H-苯并咪唑-2-基)-1H-吡唑并[3,4-b]吡啶-5-基)丙酰胺(I-29)
以3g(150mg,0.560mmol)为原料,制备方法同Ⅰ-7,经柱层析得固体Ⅰ-29(32.66mg),收率16.3%,MS[M+H]+:359.15。
实施例77:3-氯-N-(3-(6-(4-甲基哌嗪-1-羰基)-1H-苯并咪唑-2-基)-1H-吡唑并[3,4-b]吡啶-5-基)丙酰胺(I-30)
以3h(150mg,0.399mmol)为原料,制备方法同Ⅰ-7,经柱层析得固体Ⅰ-30(21.38mg),收率11.5%,MS[M+H]+:467.18。
实施例78:3-氯-N-(3-(6-吗啉-4-羰基)-1H-苯并咪唑-2-基)-1H-吡唑并[3,4-b]吡啶-5-基)丙酰胺(I-31)
以3i(150mg,0.413mmol)为原料,制备方法同Ⅰ-7,经柱层析得固体Ⅰ-31(23.40mg),收率12.5%,MS[M+H]+:454.10。
实施例79:N-(3-(6-(4-甲基哌嗪-1-基)-1H-苯并咪唑-2-基)-1H-吡唑并[3,4-b]吡啶-5-基)乙烯磺酰胺(I-32)
以3f(150mg,0.431mmol)为原料,制备方法同Ⅰ-4,经柱层析得固体Ⅰ-32(24.54mg),收率13.0%,MS[M+H]+:439.20。
实施例80:N-(3-(6-吗啉基-1H-苯并咪唑-2-基)-1H-吡唑并[3,4-b]吡啶-5-基)乙烯磺酰胺(I-33)
以3e(150mg,0.448mmol)为原料,制备方法同Ⅰ-4,经柱层析得固体Ⅰ-33(28.16mg),收率14.8%,MS[M+H]+:426.17。
实施例81:N-(3-(6-氟-1H-苯并咪唑-2-基)-1H-吡唑并[3,4-b]吡啶-5-基)乙烯磺酰胺(I-34)
以3g(150mg,0.560mmol)为原料,制备方法同Ⅰ-4,经柱层析得固体Ⅰ-34(34.46mg),收率17.2%,MS[M+H]+:359.11。
实施例82:N-(3-(6-(4-甲基哌嗪-1-羰基)-1H-苯并咪唑-2-基)-1H-吡唑并[3,4-b]吡啶-5-基)乙烯磺酰胺(I-35)
以3h(150mg,0.399mmol)为原料,制备方法同Ⅰ-4,经柱层析得固体Ⅰ-35(24.72mg),收率13.3%,MS[M+H]+:467.09。
实施例83:N-(3-(6-(4-甲基哌嗪-1-基)-1H-苯并咪唑-2-基)-1H-吡唑并[3,4-b]吡啶-5-基)丙烯酰胺(I-36)
以3f(150mg,0.431mmol)为原料,制备方法同Ⅰ-1,经柱层析得固体Ⅰ-36(27.03mg),收率15.6%,MS[M+H]+:403.16。
实施例84:N-(3-(6-氟-1H-苯并咪唑-2-基)-1H-吡唑并[3,4-b]吡啶-5-基)丙烯酰胺(I-37)
以3g(150mg,0.560mmol)为原料,制备方法同Ⅰ-1,经柱层析得固体Ⅰ-37(30.82mg),收率17.1%,MS[M+H]+:323.17。
实施例85:N-(3-(6-吗啉基-1H-苯并咪唑-2-基)-1H-吡唑并[3,4-b]吡啶-5-基)丙烯酰胺(I-38)
以3e(150mg,0.448mmol)为原料,制备方法同Ⅰ-1,经柱层析得固体Ⅰ-38(27.17mg),收率15.6%,MS[M+H]+:390.20。
实施例86:N-(3-(6-(4-甲基哌嗪-1-羰基)-1H-苯并咪唑-2-基)-1H-吡唑并[3,4-b]吡啶-5-基)丙烯酰胺(I-39)
以3h(150mg,0.399mmol)为原料,制备方法同Ⅰ-1,经柱层析得固体Ⅰ-39(25.90mg),收率15.1%,MS[M+H]+:431.14。
实施例87:N-(3-(6-(二乙氨基)-1H-苯并咪唑-2-基)-1H-吲唑-5-基)丙烯酰胺(I-40)
以3d(150mg,0.469mmol)为原料,制备方法同Ⅰ-1,经柱层析得黄色固体Ⅰ-40(44.18mg),收率25.2%。1H NMR(500MHz,Methanol-d4)δ8.53(d,J=1.9Hz,1H,ArH),7.83(dd,J=9.0,2.0Hz,1H,ArH),7.55(dd,J=20.3,8.9Hz,2H,ArH),6.99(d,J=2.4Hz,1H,ArH),6.90(dd,J=8.9,2.3Hz,1H,ArH),6.49(dd,J=17.0,10.0Hz,1H,=CH),6.40(dd,J=17.1,1.8Hz,1H,
=CH),5.80(dd,J=10.0,1.8Hz,1H,=CH-),3.38(t,J=7.1Hz,4H,-CH2-×2),1.16(t,J=7.0Hz,6H,-CH3×2);13C NMR(126MHz,Methanol-d4)δ164.83,145.15,139.11,136.06,132.73,131.12,126.24,121.90,120.76,112.32,110.13,45.70,11.35;MS[M+H]+:375.15。
实施例88:N-(3-(6-(二乙氨基)-1H-苯并咪唑-2-基)-1H-吲唑-4-基)丙烯酰胺(I-41)
以3p(150mg,0.469mmol)为原料,制备方法同Ⅰ-1,经柱层析得棕色固体Ⅰ-41(44.70mg),收率25.5%。1H NMR(500MHz,Methanol-d4)δ8.38(d,J=7.6Hz,1H,ArH),7.53(d,J=9.2Hz,1H,ArH),7.38(t,J=8.0Hz,1H,ArH),7.27(d,J=8.3Hz,1H,ArH),δ6.89(d,J=10.3Hz,1H,=CH),6.88–6.82(m,2H,ArH),6.50(dd,J=17.1,1.4Hz,1H,=CH),5.94(d,J=10.3Hz,1H,=CH-),3.40(q,J=7.8,7.4Hz,4H,-CH2-×2),1.18(t,J=6.9Hz,6H,-CH3×2);13C NMR(126MHz,Methanol-d4)δ165.21,145.83,143.03,132.39,131.89,127.71,125.99,118.01,111.40,110.66,105.32,94.74,45.20,11.44;MS[M+H]+:375.23。
上述实施例的结构测定,熔点用b形熔点管测定,介质为甲基硅油,温度计未校正;1HNMR用JEOL FX90Q型傅立叶变换核磁共振仪、BRUKER型核磁共振仪(TMS内标);MS用Nicolet 2000型傅立叶变换质谱仪和MAT-212型质谱仪测定。
药理活性测试
(1)目标化合物对FLT3的抑制活性测试
所合成的化合物用荧光共振能量转移(FRET)法分别测定对FLT3的抑制活性,并与阳性对照药比较,筛选出活性较好的化合物。上述激酶通过纯化或直接购买试剂盒获得。以FLT3的抑制活性测试为例,具体方法如下:
FLT3用激酶稀释液稀释至合适浓度后使用。激酶反应混合物中含FLT3、peptidesubstrate、HEPES(pH 7.5)、BRIJ-35、MgCl2和EDTA。FLT3 phospho-peptide substrate用作100%磷酸化对照,不加ATP用作0%磷酸化对照。室温下反应1h后,向反应体系中加入适度稀释的Development Reagent A。室温下继续反应1h,加入Stop Reagent中止反应。激发波长400nm,同时检测波长为445nm(coumarin)和520nm(fluorescein)的荧光强度。按公式计算受试化合物抑制率。
表1.化合物对FLT3的抑制活性(抑制率%,1×10-6mol/L)
表2.部分化合物对FLT3的IC50值(nM)
(2)目标化合物的体外抗肿瘤活性测定
用MTT法测定对胃癌细胞株MGC803、白血病细胞株K562、乳腺癌细胞株MCF7、白血病细胞株MV4-11、肺癌细胞株A549等肿瘤细胞株的抑制作用。
MTT法利用活细胞线粒体中存在与NADP相关的脱氢酶能使外源性的MTT还原成难溶性的蓝紫色结晶物(Formazan),并沉积在细胞中,而死细胞无此功能。再用二甲基亚砜(DMSO)或三联液(10%SDS-5%异丁醇-0.01mol/L HCL)溶解细胞中的紫色结晶物,用酶联免疫检测仪在570nm波长处测定其OD值,间接反应其活细胞量。
具体方法:将处于细胞对数生长期的要进行实验的肿瘤细胞按一定的细胞量接种于96孔培养板内,培养24h后加入所筛的样品(悬浮细胞接板后可直接加),细胞在37℃、5%CO2条件下继续培养48小时后,加入MTT继续培养4小时,用DMSO溶解结晶,在酶标仪下进行检测。
目标化合物10μM浓度下对上述肿瘤细胞株的体外抗肿瘤活性结果如下(抑制率%):
表3.目标化和物对肿瘤细胞的抗增殖活性
注:A:抑制率>80%,B:79%>抑制率>60%,C:59%>抑制率>30%,D:29%>抑制率
通过活性测试发现,R5基团的引入有利于提高化合物对FLT3的抑制活性,与不含该结构的对应化合物相比,该类化合物对FLT3的具有显著的抑制活性。其中,当在分子中引入丙烯酰胺和氯丙酰胺时,所得的化合物对FLT3的具有更为显著的抑制活性,所得化合物对FLT3的IC50值与AC220(已上市的FLT3抑制剂)和FN-1501相当;在急性髓细胞性白血病细胞株MV4-11中,也表现出较强的抗增殖活性,IC50值达到了个位数纳摩尔级别。初步构效关系分析表明,该类分子中的共价结构可以与FLT3形成不可逆结合,结合分子对接,我们推断,该化合物是FLT3的不可逆抑制剂。目前上市的FLT3抑制剂均为可逆型抑制剂,不可逆FLT3抑制剂的发现为靶向FLT3的新型抗肿瘤药物的研发奠定了基础。
Claims (10)
1.具有以下结构式(I)的化合物或其药学上可接受的盐:
其中:
R1为-L-Ra,L表示键、O、NH、S、C(O)NH、C(O)、NHC(O)、NHC(O)NH、取代或未取代的C1-3亚烷基;Ra是选自氢、卤原子、-NH2、-OH、羟基、硝基、羧基、腈基、取代或未取代的C1-6烷基、取代或未取代的C3-8的环烷基、取代或未取代的C4-8的环烯基、取代或未取代C1-6烷硫基、取代或未取代的C1-6烷氧基、取代或未取代的C2-6烯基、取代或未取代的C1-6烷胺基、取代或未取代的C3-8杂环烷基;
A为N或CR2,B为N或CR3,D和E各自独立的为N、CR4或CR5,D和E中有且只有一个为CR5,R2、R3、R4是各自独立的选自氢、卤素、羟基、氰基、甲氧基、取代或未取代C1-6烷基,R5选自-NRb-SO2-Rc或-NRb-CO-Rc,Rc为-CRd=CHRe、-C≡C-CH3或-C≡CH,Rb、Rd、Re各自独立的选自H、-CN、取代或未取代的C1-6烷基;
所述取代基选自卤素、C1-6卤代烷基、羟基、C1-6烷基、C1-6烷氧基、C1-6烷胺基或C1-6烷硫基、C3-8杂环烷基中的一种或多种。
2.根据权利要求1所述的化合物或其药学上可接受的盐,其特征在于,所述的:
卤素为氟、氯、溴或碘;
C1-6卤代烷基为被卤素取代的且具有1-6个碳原子的直链或支链饱和烃基;
C2-6烯基为具有2-6个碳原子的直链或支链烯烃基;
C1-6烷基为具有1-6个碳原子的直链或支链饱和烃基;
C3-8环烷基为由3-8个碳原子形成的环状烷烃基;
C4-8环烯基为由4-8个碳原子形成的部分不饱和的环状烯烃;
C3-8杂环烷基为具有3-8个碳原子的饱和或部分不饱和的含一个或多个选自O、N和S的杂原子的杂环烷基。
3.根据权利要求1所述的化合物,其特征在于,所述的:
R1为-L1-Ra,L1各自独立地表示键、S、O、NH、C(O)NH、C(O)、NHC(O)、NHC(O)NH、取代或未取代的C1-3亚烷基;Ra是选自氢、卤原子、-NH2、-OH、取代或未取代的C1-6烷基、取代或未取代C1-6烷硫基、取代或未取代的C1-6烷氧基、取代或未取代的C1-6烷胺基、取代或未取代的C3-8杂环烷基、取代或未取代的C3-8的环烷基、取代或未取代的C4-8的环烯基;
5.根据权利要求1任一项所述的化合物,其特征在于:
R1为-L1-Ra,L1选自键、O、NH、C(O)NH、C(O)、NHC(O)、NHC(O)NH或亚甲基;Ra是选自四氢吡咯基、哌啶基、N-甲基哌啶-4-基、吗啉基、N-甲基哌嗪基、3-甲基哌啶-1-基、哌嗪基,或选自下列的取代氨基、取代氧基:N,N-二丙基氨基、N,N-二乙基氨基、N,N-二甲基氨基、正丁基氨基、2-(环己烯-1-基)乙基氨基、2-甲氧基乙氧基、2-羟基乙基氨基、N,N-二(2-甲氧基乙基)氨基;
6.权利要求1所述的化合物,其结构选自:
N-(3-(6-吗啉基-1H-苯并咪唑-2-基)-1H-吲唑-5-基)丙烯酰胺(I-1)
N-(3-(6-(4-甲基哌嗪-1-基)-1H-苯并咪唑-2-基)-1H-吲唑-5-基)丙烯酰胺(I-2)
N-(3-(6-氟-1H-苯并咪唑-2-基)-1H-吲唑-5-基丙烯酰胺(I-3)
N-(3-(6-吗啉基-1H-苯并咪唑-2-基)-1H-吲唑-5-基)乙烯磺酰胺(I-4)
N-(3-(6-(4-甲基哌嗪-1-基)-1H-苯并咪唑-2-基)-1H-吲唑-5-基)乙烯磺酰胺(I-5)
N-(3-(6-氟-1H-苯并咪唑-2-基)-1H-吲唑-5-基乙烯磺酰胺(I-6)
3-氯-N-(3-(6-吗啉基-1H-苯并咪唑-2-基)-1H-吲唑-5-基丙酰胺(I-7)
3-氯-N-(3-(6-(4-甲基哌嗪-1-基)-1H-苯并咪唑-2-基)-1H-吲唑-5-基丙酰胺(I-8)
3-氯-N-(3-(6-氟-1H-苯并咪唑-2-基)-1H-吲唑-5-基)丙酰胺(I-9)
3-氯-N-(3-(6-吗啉甲基)-1H-苯并咪唑-2-基)-1H-吲唑-4-基丙酰胺(I-10)
3-氯-N-(3-(6-(4-甲基哌嗪-1-基)甲基)-1H-苯并咪唑-2-基)-1H-吲唑-4-基丙酰胺(I-11)
3-氯-N-(3-(6-(4-甲基哌嗪-1-羰基)-1H-苯并咪唑-2-基)-1H-吲唑-4-基丙酰胺(I-12)
N-(3-(6-吗啉甲基)-1H-苯并咪唑-2-基)-1H-吲唑-4-基丙烯酰胺(I-13)
N-(3-(6-(4-甲基哌嗪-1-基)甲基)-1H-苯并咪唑-2-基-1H-吲唑-4-基丙烯酰胺(I-14)
N-(3-(6-(4-甲基哌嗪-1-羰基)-1H-苯并咪唑-2-基)-1H-吲唑-4-基丙烯酰胺(I-15)
N-(3-(6-吗啉甲基)-1H-苯并咪唑-2-基-1H-吲唑-4-基)乙烯磺酰胺(I-16)
N-(3-(6-(4-甲基哌嗪-1-基)甲基)-1H-苯并咪唑-2-基-1H-吲唑-4-基乙烯磺酰胺(I-17)
N-(3-(6-(4-甲基哌嗪-1-基)甲基)-1H-苯并咪唑-2-基-1H-吲唑-4-基乙烯磺酰胺(I-18)
3-氯-N-(3-(6-(4-甲基哌嗪-1-基)-1H-苯并咪唑-2-基)-1H-吲唑-4-基丙酰胺(I-19)
3-氯-N-(3-(6-氟-1H-苯并咪唑-2-基)-1H-吲唑-4-基)丙酰胺(I-20)
3-氯-N-(3-(6-吗啉基-1H-苯并咪唑-2-基)-1H-吲唑-4-基)丙酰胺(I-21)
N-(3-(6-(4-甲基哌嗪-1-基)-1H-苯并咪唑-2-基)-1H-吲唑-4-基)乙烯磺酰胺(I-22)
N-(3-(6-氟-1H-苯并咪唑-2-基)-1H-吲唑-4-基)乙烯磺酰胺(I-23)
N-(3-(6-吗啉基-1H-苯并咪唑-2-基)-1H-吲唑-4-基)乙烯磺酰胺(I-24)
N-(3-(6-(4-甲基哌嗪-1-基)-1H-苯并咪唑-2-基)-1H-吲唑-4-基)丙烯酰胺(I-25)
N-(3-(6-氟-1H-苯并咪唑-2-基)-1H-吲唑-4-基丙烯酰胺(I-26)
N-(3-(6-吗啉基-1H-苯并咪唑-2-基)-1H-吲唑-4-基丙烯酰胺(I-27)
3-氯-N-(3-(6-(4-甲基哌嗪-1-基)-1H-苯并咪唑-2-基)-1H-吡唑并[3,4-b]吡啶-5-基)丙酰胺(I-28)
3-氯-N-(3-(6-氟-1H-苯并咪唑-2-基)-1H-吡唑并[3,4-b]吡啶-5-基)丙酰胺(I-29)
3-氯-N-(3-(6-(4-甲基哌嗪-1-羰基)-1H-苯并咪唑-2-基)-1H-吡唑并[3,4-b]吡啶-5-基)丙酰胺(I-30)
3-氯-N-(3-(6-吗啉-4-羰基)-1H-苯并咪唑-2-基)-1H-吡唑并[3,4-b]吡啶-5-基)丙酰胺(I-31)
N-(3-(6-(4-甲基哌嗪-1-基)-1H-苯并咪唑-2-基)-1H-吡唑并[3,4-b]吡啶-5-基)乙烯磺酰胺(I-32)
N-(3-(6-吗啉基-1H-苯并咪唑-2-基)-1H-吡唑并[3,4-b]吡啶-5-基)乙烯磺酰胺(I-33)
N-(3-(6-氟-1H-苯并咪唑-2-基)-1H-吡唑并[3,4-b]吡啶-5-基)乙烯磺酰胺(I-34)
N-(3-(6-(4-甲基哌嗪-1-羰基)-1H-苯并咪唑-2-基)-1H-吡唑并[3,4-b]吡啶-5-基)乙烯磺酰胺(I-35)
N-(3-(6-(4-甲基哌嗪-1-基)-1H-苯并咪唑-2-基)-1H-吡唑并[3,4-b]吡啶-5-基)丙烯酰胺(I-36)N-(3-(6-氟-1H-苯并咪唑-2-基)-1H-吡唑并[3,4-b]吡啶-5-基)丙烯酰胺(I-37)
N-(3-(6-吗啉基-1H-苯并咪唑-2-基)-1H-吡唑并[3,4-b]吡啶-5-基)丙烯酰胺(I-38)
N-(3-(6-(4-甲基哌嗪-1-羰基)-1H-苯并咪唑-2-基)-1H-吡唑并[3,4-b]吡啶-5-基)丙烯酰胺(I-39)
N-(3-(6-(二乙氨基)-1H-苯并咪唑-2-基)-1H-吲唑-5-基)丙烯酰胺(I-40)
N-(3-(6-(二乙氨基)-1H-苯并咪唑-2-基)-1H-吲唑-4-基)丙烯酰胺(I-41)。
7.权利要求1-6任一项的化合物或其药学上可接受的盐,其中药学上可接受的盐为通式(I)化合物与下列酸形成的酸加成盐:盐酸、氢溴酸、硫酸、磷酸、甲磺酸、苯磺酸、对甲苯磺酸、萘磺酸、柠檬酸、酒石酸、乳酸、丙酮酸、乙酸、马来酸或琥珀酸、富马酸、水杨酸、苯基乙酸或杏仁酸。
8.一种药物组合物,其中含有权利要求1-7任一项所述的化合物和药学上可接受的载体。
9.权利要求1-6任一项所述的化合物在制备用于预防或治疗与FLT3激酶有关的临床病症的药物中的用途。
10.权利要求9所述的用途,其中与FLT-3有关的疾病选自肺癌、黑色素瘤、肝癌、肾癌、白血病、***癌、甲状腺癌、皮肤癌、胰腺癌、卵巢癌、睾丸癌、乳腺癌、膀胱癌、胆囊癌、骨髓增生异常综合症、淋巴瘤、食管癌、胃肠道癌、星形细胞瘤、神经母细胞瘤、神经胶质瘤、神经鞘瘤、间皮瘤、非胰岛素依赖型糖尿病、自身免疫性疾病或银屑病。
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Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102573846A (zh) * | 2009-08-17 | 2012-07-11 | 因特利凯公司 | 杂环化合物及其用途 |
CN109970717A (zh) * | 2017-12-28 | 2019-07-05 | 中国药科大学 | 4-(脂肪环并嘧啶/吡啶取代)氨基-1h-3-吡唑甲酰胺类flt3抑制剂及其用途 |
CN114605329A (zh) * | 2022-03-28 | 2022-06-10 | 河南中医药大学 | 取代的吲唑甲酰胺或取代的氮杂吲唑甲酰胺类flt3抑制剂及其用途 |
WO2023287128A1 (ko) * | 2021-07-12 | 2023-01-19 | 한양대학교 에리카산학협력단 | 인다졸일 벤즈이미다졸 유도체 또는 이의 약학적으로 허용가능한 염 및 이의 용도 |
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Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102573846A (zh) * | 2009-08-17 | 2012-07-11 | 因特利凯公司 | 杂环化合物及其用途 |
CN109970717A (zh) * | 2017-12-28 | 2019-07-05 | 中国药科大学 | 4-(脂肪环并嘧啶/吡啶取代)氨基-1h-3-吡唑甲酰胺类flt3抑制剂及其用途 |
WO2023287128A1 (ko) * | 2021-07-12 | 2023-01-19 | 한양대학교 에리카산학협력단 | 인다졸일 벤즈이미다졸 유도체 또는 이의 약학적으로 허용가능한 염 및 이의 용도 |
CN114605329A (zh) * | 2022-03-28 | 2022-06-10 | 河南中医药大学 | 取代的吲唑甲酰胺或取代的氮杂吲唑甲酰胺类flt3抑制剂及其用途 |
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