CN114605329B - 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 - Google Patents
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 Download PDFInfo
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- CN114605329B CN114605329B CN202210312097.4A CN202210312097A CN114605329B CN 114605329 B CN114605329 B CN 114605329B CN 202210312097 A CN202210312097 A CN 202210312097A CN 114605329 B CN114605329 B CN 114605329B
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- carboxamide
- unsubstituted
- indazole
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- -1 azaindazole carboxamides Chemical class 0.000 title claims abstract description 193
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- 239000003112 inhibitor Substances 0.000 title claims abstract description 26
- DITBWPUMEUDVLU-UHFFFAOYSA-N 1h-indazole-3-carboxamide Chemical class C1=CC=C2C(C(=O)N)=NNC2=C1 DITBWPUMEUDVLU-UHFFFAOYSA-N 0.000 title description 2
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Classifications
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- C—CHEMISTRY; METALLURGY
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- C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
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- A61P3/00—Drugs for disorders of the metabolism
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- A61P37/00—Drugs for immunological or allergic disorders
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Abstract
本发明涉及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,可有效解决在抑制FLT3活性,预防或治疗与FLT3等激酶有关的临床病症的药物中的应用问题,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,并表现出较强的抗肿瘤活性。
Description
技术领域
本发明涉及医药,特别是一种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。
背景技术
蛋白激酶是细胞生命活动的重要信使,可催化将ATP末端的γ-磷酸基团转移至底物上,影响底物的结构和活性,传递各种胞内外信号,以对环境刺激作出适当反应。在大多数情况下,这一磷酸化反应发生在蛋白激酶的丝氨酸(ser)、苏氨酸(thr),或酪氨酸(tyr)残基上。磷酸化调控生命活动在进化上非常古老,可追溯到10亿年前的单细胞原核生物。在人体中发现了至少538种蛋白激酶,而编码具有激酶活性蛋白的基因则超过900个,约占人类基因组的2.5%。蛋白激酶参与众多的生理调控过程,包括细胞存活、增殖、分化、凋亡、代谢,等等。病理学及药理学研究表明,蛋白激酶的功能失调与很多疾病密切相关,包括肿瘤、自身免疫、炎性反应、中枢神经***疾病、心血管疾病及糖尿病,等等。
研究发现,FLT3已成为不同血液***恶性肿瘤的重要标志物,血液学恶性肿瘤包括白血病、淋巴瘤(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)、慢性粒细胞白血病(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)和脊髓肉瘤等。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。
在FLT3的众多应用中,FLT3抑制剂用于AML的治疗发展最为迅速,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。根据激酶选择性的强弱,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Sorafenib、Sunitinib、Ponatinib、Cabozantinib、Midostourin等。综上所述,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,导致更多的脱靶活性、毒性和不良副作用。正是由于脱靶毒副作用,限制给药剂量,在体内无法达到有效的FLT3抑制浓度。随后,人们将目光转向新一代高效、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
针对上述情况,为克服现有技术之缺陷,本发明之目的就是提供一种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,可有效解决在抑制FLT3活性,预防或治疗与FLT3等激酶有关的临床病症的药物中的应用问题。
1、本发明解决的技术方案是,一种取代的吲唑甲酰胺或取代的氮杂吲唑甲酰胺类FLT3抑制剂,为具有以下结构式(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、C(O)NH、C(O)、NHC(O)、NHC(O)NH、取代或未取代的C1-6直链或支链亚烷基、取代或未取代的C3-6环状饱和烷基,其中C1-6亚烷基中的任意碳原子可以被1-3个NH、N、O或S取代;Ra选自氢、卤原子、-NH2、-OH、取代或未取代的C1-6直链或支链烷基、取代或未取代的C1-6直链或支链卤代烷基、取代或未取代的C3-8环状饱和烷基、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链烯基、取代或未取代的C3-6环烯基、取代或未取代的C1-6烷胺基、取代或未取代的杂环烷基、取代或未取代的C6-14芳基或取代或未取代的芳杂环;
G是选自取代或未取代的C1-6烷基、取代或未取代的C1-6烯基、取代或未取代的C6-14芳基、取代或未取代的杂环烷基或取代或未取代的芳杂环;
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;
所述杂环烷基选自3-6个碳原子的单环饱和烃基、6-12个碳原子的双环饱和烃基,其中环上的碳原子独立地被1~4个O、S、N或NH取代;
所述C6-14芳基选自苯基、萘基、苊基或四氢萘基中的一种;
所述芳杂环选自吡咯基、吡唑基、咪唑基、呋喃基、噻吩基、噁唑基、异噁唑基、噻唑基、异噻唑基、吡啶基、嘧啶基、吡嗪基或哒嗪基的单环杂环;或选自喹啉基、喹喔啉基、吲哚基、苯并咪唑基、苯并噁唑基、苯并异噁唑基、苯并噻唑基、苯并异噻唑基、苯并呋喃基、苯并噻吩基、2,3-二氢苯并[1,4]二氧杂环己烯基或苯并[1,3]二氧杂环戊烯基的双环杂环中的一种;
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烷硫基中的一种或多种;卤素选自氟、氯、溴或碘。
2、本发明的优选方案在于:
G是选自取代或未取代的C6-14芳基、取代或未取代的杂环烷基或取代或未取代的芳杂环。
3、本发明的另一优选方案在于:
A为N或CR2,B为CR3,D和E各自独立的为CR4或CR5。
4、本发明的另一优选方案在于:
R1为-L-Ra,L选自键、O、NH、C(O)NH、C(O)、NHC(O)、NHC(O)NH或亚甲基;Ra选自苯基、萘基、吡唑基、呋喃基、噻吩基、吡啶基、吡嗪基、嘧啶基、C3-8环状饱和烷基、四氢吡咯基、哌啶基、吗啉基、哌嗪基、吖丙啶基、吖丁啶基、-OH、-NH2、C1-6烷基、C1-6烷硫基、C1-6烷氧基、C1-6烷胺基中的一种;其中,苯基、萘基、吡唑基、呋喃基、噻吩基、吡啶基、吡嗪基、嘧啶基、C3-C8环状饱和烷基、四氢吡咯基、哌啶基、吗啉基、哌嗪基、吖丙啶基、吖丁啶基各自独立地可任选被一个或多个Rf取代,Rf选自氢、氰基、卤素、羟基、巯基或氨基;
G选自下列芳香环或芳香杂环中的一种:苯基、萘基、吡咯基、呋喃基、噻吩基、吡啶基、吡嗪基或嘧啶基,其中,上述芳香环或芳香杂环可任选地被1或3个取代基取代,所述取代基各自独立的选自卤素、甲基、乙基、异丙基、甲氧基或三氟甲基;
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、C1-6烷基。
5、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、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;
G选自下列芳香环或芳香杂环中的一种:苯基、萘基、吡啶基、吡嗪基或嘧啶基,其中,上述芳香环或芳香杂环任选地有1或2个取代基,取代基各自独立的选自卤素、甲基、乙基、异丙基、甲氧基或三氟甲基;
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、 -C≡C-CH3或-C≡CH,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:
5-丙烯酰胺基-N-(4-吗啉代苯基)-1H-吲唑-3-甲酰胺(I-1)
5-丙烯酰胺基-N-(4-(4-甲基哌嗪-1-基)苯基)-1H-吲唑-3-甲酰胺(I-2)
5-丙烯酰胺基-N-(4-氟苯基)-1H-吲唑-3-甲酰胺(I-3)
N-(4-吗啉代苯基)-5-(乙烯基磺胺基)-1H-吲唑-3-甲酰胺(I-4)
N-(4-(4-甲基哌嗪-1-基)苯基)-5-(乙烯基磺酰胺)-1H-吲唑-3-甲酰胺(I-5)
N-(4-氟苯基)-5-(乙烯基磺酰胺)-1H-吲唑-3-甲酰胺(I-6)
5-(3-氯丙酰胺)-N-(4-吗啉代苯基)-1H-吲唑-3-甲酰胺(I-7)
5-(3-氯丙酰胺)-N-(4-(4-甲基哌嗪-1-基)苯基)-1H-吲唑-3-甲酰胺(I-8)
5-(3-氯丙酰胺)-N-(4-氟苯基)-1H-吲唑-3-甲酰胺(I-9)
5-(3-氯丙酰胺)-N-(4-((4-甲基哌嗪-1-基)甲基)苯基)-1H-吲唑-3-甲酰胺(I-10)
5-(3-氯丙酰胺基)-N-(4-(吗啉甲基)苯基)-1H-吲唑-3-甲酰胺(I-11)
5-(3-氯丙酰胺基)-N-(4-(4-甲基哌嗪-1-羰基)苯基)-1H-吲唑-3-甲酰胺(I-12)
5-丙烯酰胺-N-(4-((4-甲基哌嗪-1-基)甲基)苯基)-1H-吲唑-3-甲酰胺(I-13)
5-丙烯酰胺-N-(4-(吗啉甲基)苯基)-1H-吲唑-3-甲酰胺(I-14)
5-丙烯酰胺基-N-(4-(4-甲基哌嗪-1-羰基)苯基)-1H-吲唑-3-甲酰胺(I-15)
N-(4-((4-甲基哌嗪-1-基)甲基)苯基)-5-(乙烯基磺酰胺)-1H-吲唑-3-甲酰胺(I-16)
N-(4-(吗啉代甲基)苯基)-5-(乙烯基磺酰胺)-1H-吲唑-3-甲酰胺(I-17)
N-(4-(4-甲基哌嗪-1-羰基)苯基)-5-(乙烯基磺酰胺)-1H-吲唑-3-甲酰胺(I-18)
N-(4-((4-甲基哌嗪-1-基)甲基)苯基)-5-丙酰胺基-1H-吲唑-3-甲酰胺(I-19)
N-(4-(吗啉代甲基)苯基)-5-丙酰胺基-1H-吲唑-3-甲酰胺(I-20)
4-(3-氯丙酰胺)-N-(4-(4-甲基哌嗪-1-基)苯基)-1H-吲唑-3-甲酰胺(I-21)
4-(3-氯丙酰胺基)-N-(4-氟苯基)-1H-吲唑-3-甲酰胺(I-22)
4-(3-氯丙酰胺基)-N-(4-吗啉代苯基)-1H-吲唑-3-甲酰胺(I-23)
N-(4-(4-甲基哌嗪-1-基)苯基)-4-(乙烯基磺酰胺)-1H-吲唑-3-甲酰胺(I-24)
N-(4-氟苯基)-4-(乙烯基磺酰胺)-1H-吲唑-3-甲酰胺(I-25)
N-(4-吗啉代苯基)-4-(乙烯基磺酰胺)-1H-吲唑-3-甲酰胺(I-26)
4-丙烯酰胺-N-(4-(4-甲基哌嗪-1-基)苯基)-1H-吲唑-3-甲酰胺(I-27)
4-丙烯酰胺-N-(4-氟苯基)-1H-吲唑-3-甲酰胺(I-28)
4-丙烯酰胺基-N-(4-吗啉代苯基)-1H-吲唑-3-甲酰胺(I-29)
5-(3-氯丙酰胺基)-N-(4-(4-甲基哌嗪-1-基)苯基)-1H-吡唑并[3,4-b]吡啶-3-甲酰胺(I-30)
5-(3-氯丙酰胺)-N-(4-氟苯基)-1H-吡唑并[3,4-b]吡啶-3-甲酰胺(I-31)
5-(3-氯丙酰胺)-N-(1-甲基哌啶-4-基)-1H-吡唑并[3,4-b]吡啶-3-甲酰胺(I-32)
5-(3-氯丙酰胺基)-N-(4-(吗啉-4-羰基)苯基)-1H-吡唑并[3,4-b]吡啶-3-甲酰胺(I-33)
5-(3-氯丙酰胺基)-N-(4-(4-甲基哌嗪-1-羰基)苯基)-1H-吡唑并[3,4-b]吡啶-3-甲酰胺(I-34)
N-(4-(4-甲基哌嗪-1-基)苯基)-5-(乙烯基磺酰胺)-1H-吡唑并[3,4-b]吡啶-3-甲酰胺(I-35)
N-(4-氟苯基)-5-(乙烯基磺酰胺)-1H-吡唑并[3,4-b]吡啶-3-甲酰胺(I-36)
N-(1-甲基哌啶-4-基)-5-(乙烯基磺酰胺)-1H-吡唑并[3,4-b]吡啶-3-甲酰胺(I-37)
N-(4-吗啉代苯基)-5-(乙烯基磺酰胺)-1H-吡唑并[3,4-b]吡啶-3-甲酰胺(I-38)
N-(4-(4-甲基哌嗪-1-羰基)苯基)-5-(乙烯基磺酰胺)-1H-吡唑并[3,4-b]吡啶-3-甲酰胺(I-39)
5-丙烯酰胺基-N-(4-(4-甲基哌嗪-1-基)苯基)-1H-吡唑并[3,4-b]吡啶-3-甲酰胺(I-40)
5-丙烯酰胺基-N-(4-氟苯基)-1H-吡唑并[3,4-b]吡啶-3-甲酰胺(I-41)
5-丙烯酰胺-N-(1-甲基哌啶-4-基)-1H-吡唑并[3,4-b]吡啶-3-甲酰胺(I-42)
5-丙烯酰胺基-N-(4-吗啉代苯基)-1H-吡唑并[3,4-b]吡啶-3-甲酰胺(I-43)
5-丙烯酰胺基-N-(4-(4-甲基哌嗪-1-羰基)苯基)-1H-吡唑并[3,4-b]吡啶-3-甲酰胺(I-44)
本发明的部分化合物制备方法如下:
方法一:
方法二:
方法3:
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。
具体实施方式
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 ACF-300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。
实施例1
1-甲基-4-(4-硝基苄基)哌嗪(1a)
在500mL单颈瓶中加入对硝基溴苄(10.0g,46.3mmol)和二氯甲烷100mL,在冰水浴下(0-5℃)缓慢滴加N-甲基哌嗪(4.7g,47.0mmol)和三乙胺(7.1g,70.3mmol)的二氯甲烷20mL混合液,加毕加热回流1h,TLC检测原料消失(乙酸乙酯∶石油醚=1∶2,体积比)。将氯仿150mL和饱和碳酸氢钠溶液100mL加入反应液中,于室温剧烈搅拌30min,反应液用氯仿萃取(100mL×3),合并有机层,分别用水和饱和氯化钠各洗一次(100mL×1),无水硫酸镁干燥,过滤,减压蒸除溶剂得淡黄色固体8.5g,收率78.1%,产品无需进一步纯化,直接投入下一步反应。
实施例2
4-((4-甲基哌嗪-1-基)甲基)苯胺(1b)
在500mL单颈瓶中加入I-a粗品(8.5g,36.2mmol)、FeO(OH)/C催化剂2.0g和95%乙醇100mL,加热回流,缓慢滴加水合肼25mL和体积浓度95%乙醇20mL的混合液,TLC检测原料消失(甲醇∶氯仿=1∶15,体积比)。趁热抽滤,滤饼用热的乙醇洗两次(30mL×2),减压蒸除溶剂得白色固体,真空干燥得1b(6.7g),收率90.3%,产品无需进一步纯化,直接投入下一步反应。
实施例3
1-甲基-4-(4-硝基苯基)哌嗪(1c)
在500mL单颈瓶中加入对氟硝基苯(5g,35.5mmol)和碳酸钾(7.3g,106.4mmol),用100mLDMSO溶解,在冰水浴下(0-5℃)缓慢滴加N-甲基哌嗪(5.3g,53.3mmol)的DMSO溶液,80℃加热反应8h,TLC检测原料消失(乙酸乙酯∶石油醚=1∶2,体积比),加入1000mL水,析出黄色固体,过滤,减压干燥得黄色固体7a(6.8g),收率86.2%,MS[M+H]+222.14。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)苯胺(1d)
以1c(5.0g,22.6mmol)为原料,制备方法同1b,得白色固体,经乙醇重结晶得1d(3.4g),收率78%,MS[M+H]+192.13。
实施例5
4-(4-硝基苯基)吗啉(1e)
以对氟硝基苯(5.0g,35.5mmol)和***啉(4.6g,53.3mmol)为原料,制备方法同1c,得黄色固体1e(5.8g),收率78.3%,MS[M+H]+209.23;产品无需进一步纯化,直接进行下一步反应。
实施例6
4-吗啉代苯胺(1f)
以1e(5.0g,24.0mmol)为原料,制备方法同1b,得白色固体,经乙醇重结晶得1f(3.9g),收率90.4%,MS[M+H]+179.13。
实施例7
吗啉基-4-硝基苯基甲酮(1g)
在100mL圆底烧瓶中加入对硝基苯甲酸(5.0g,29.9mmol)、***啉(2.9g,32.9mmol)、EDC.HCl(8.6g,44.9mmol)、HOBt(6.1g,44.9mmol)和无水DMF(30mL),室温搅拌24h。TLC检测原料消失(甲醇∶氯仿=1∶10,体积比)。将反应液倒入冰水200mL中,析出大量固体,静置,抽虑得白色固体,干燥得11a(6.7g),收率95.3%,MS[M+H]+236.15。
实施例8
4-氨基苯基吗啉基甲酮(1h)
以1g(5.0g,21.1mmol)为原料,制备方法同1b,得白色固体,经乙醇重结晶得1h(3.4g),收率77.2%,MS[M+H]+207.21。
实施例9
4-甲基哌嗪-1-基-4-硝基苯基甲酮(1i)
以对硝基苯甲酸(5.0g,29.9mmol)和N-甲基哌嗪(3.3g,32.9mmol)为原料,制备方法同1g,得白色固体,干燥得1i(7.2g),收率97.1%,MS[M+H]+250.22。
实施例10
4-氨基苯基-4-甲基哌嗪-1-基甲酮(1j)
以1i(5.0g,20.1mmol)为原料,制备方法同1b,得白色固体,经乙醇重结晶得1j(3.1g),收率71%,MS[M+H]+:219.15。
实施例11
N-(4-(4-甲基哌嗪-1-基)苯基)-5-硝基-1H-吲唑-3-甲酰胺(2a)
在单颈瓶中加入5-硝基-1H-吲唑-3-羧酸(1.91g,10.0mmol)和1d(2.10g,11.0mmol),用无水DMF(10mL)溶解,在0℃下,加入EDCI(2.87g,15.0mmol)、HoBt(2.01g,15mmol)、DIPEA(1.94g,15mmol),常温反应12h,TLC检测原料消失,向反应液加水(100mL)析出固体,抽滤得棕色固体2a(1.98g),收率52.0%,MS[M+H]+:381.19,产品无需进一步纯化,直接进行下一步反应。
实施例12
N-(4-氟苯基)-5-硝基-1H-吲唑-3-甲酰胺(2b)
以5-硝基-1H-吲唑-3-羧酸(1.91g,10.0mmol)和4-氟苯胺(1.22g,11.0mmol)为原料,制备方法同2a,抽滤得棕色固体2b(1.90g),收率63.0%,MS[M+H]+:301.05,产品无需进一步纯化,直接进行下一步反应。
实施例13
N-(4-((4-甲基哌嗪-1-基)甲基)苯基)-5-硝基-1H-吲唑-3-甲酰胺(2c)
以5-硝基-1H-吲唑-3-羧酸(1.91g,10.0mmol)和1b(2.26g,11.0mmol)为原料,制备方法同2a,抽滤得棕色固体2c(2.18g),收率55.3%,MS[M+H]+:395.16,产品无需进一步纯化,直接进行下一步反应。
实施例14
N-(4-(4-甲基哌嗪-1-羰基)苯基)-5-硝基-1H-吲唑-3-甲酰胺(2d)
以5-硝基-1H-吲唑-3-羧酸(1.91g,10.0mmol)和1i(2.40g,11.0mmol)为原料,制备方法同2a,抽滤得棕色固体2d(2.06g),收率50.6%,MS[M+H]+:408.17,产品无需进一步纯化,直接进行下一步反应。
实施例15
N-(4-(吗啉-4-羰基)苯基)-5-硝基-1H-吲唑-3-甲酰胺(2e)
以5-硝基-1H-吲唑-3-羧酸(1.91g,10.0mmol)和1h(2.27g,11.0mmol)为原料,制备方法同2a,抽滤得棕色固体2e(2.37g),收率60.1%,MS[M+H]+:395.11,产品无需进一步纯化,直接进行下一步反应。
实施例16
N-(4-(4-甲基哌嗪-1-基)苯基)-5-硝基-1H-吡唑并[3,4-b]吡啶-3-甲酰胺(2f)
在250mL单颈瓶中,加入5-硝基-1H-吡嗪[3,4-B]吡啶-3-羧酸(1.00g,4.8mmol),用30mL无水THF溶解,冰水浴下逐滴加入草酰氯(0.8g,6.2mmol),常温反应0.5h;将1d(1.10g,5.7mmol)用无水THF溶解加入上述溶液中,加入三乙胺(0.63g,6.2mmol),室温反应1h,TLC检测原料消失,减压蒸干THF,加水,析出固体,抽滤,得到棕色固体2f(1.55g),收率84.3%,MS[M+H]+:382.19。
实施例17
N-(4-氟苯基)-5-硝基-1H-吡唑并[3,4-b]吡啶-3-甲酰胺(2g)
以5-硝基-1H-吡嗪[3,4-B]吡啶-3-羧酸(1.00g,4.8mmol)和4-氟硝基苯(0.81g,5.7mmol)为原料,制备方法同2f,抽滤得棕色固体2g(1.12g),收率77.2%,MS[M+H]+:302.09,产品无需进一步纯化,直接进行下一步反应。
实施例18
N-(4-(吗啉-4-羰基)苯基)-5-硝基-1H-吡唑并[3,4-b]吡啶-3-甲酰胺(2h)
以5-硝基-1H-吡嗪[3,4-B]吡啶-3-羧酸(1.00g,4.8mmol)和1h(1.17g,5.7mmol)为原料,制备方法同2f,抽滤得棕色固体2h(1.51g),收率79.3%,MS[M+H]+:396.13,产品无需进一步纯化,直接进行下一步反应。
实施例19
N-(4-(4-甲基哌嗪-1-羰基)苯基)-5-硝基-1H-吡唑并[3,4-b]吡啶-3-甲酰胺(2i)
以5-硝基-1H-吡嗪[3,4-B]吡啶-3-羧酸(1.00g,4.8mmol)和1j(1.25g,5.7mmol)为原料,制备方法同2f,抽滤得棕色固体2i(1.58g),收率80.6%,MS[M+H]+:409.15,产品无需进一步纯化,直接进行下一步反应。
实施例20
N-(4-氟苯基)-5-硝基-1H-吡唑并[3,4-b]吡啶-3-甲酰胺(2g)
以5-硝基-1H-吡嗪[3,4-B]吡啶-3-羧酸(1.00g,4.8mmol)和4-氟硝基苯(0.80g,5.7mmol)为原料,制备方法同2f,抽滤得棕色固体2g(1.12g),收率77.2%,MS[M+H]+:302.09,产品无需进一步纯化,直接进行下一步反应。
实施例21
N-(4-(吗啉-4-羰基)苯基)-5-硝基-1H-吡唑并[3,4-b]吡啶-3-甲酰胺(2h)
以5-硝基-1H-吡嗪[3,4-B]吡啶-3-羧酸(1.00g,4.8mmol)和1h(1.17g,5.7mmol)为原料,制备方法同2f,抽滤得棕色固体2h(1.33g),收率70.1%,MS[M+H]+:396.13,产品无需进一步纯化,直接进行下一步反应。
实施例22
N-(4-(4-甲基哌嗪-1-羰基)苯基)-5-硝基-1H-吡唑并[3,4-b]吡啶-3-甲酰胺(2i)
以5-硝基-1H-吡嗪[3,4-B]吡啶-3-羧酸(1.00g,4.8mmol)和1j(1.24g,5.7mmol)为原料,制备方法同2f,抽滤得棕色固体2i(1.44g),收率73.3%,MS[M+H]+:409.16,产品无需进一步纯化,直接进行下一步反应。
实施例23
N-(4-(4-甲基哌嗪-1-基)苯基)-4-硝基-1H-吲唑-3-甲酰胺(2j)
以5-硝基-1H-吡嗪[3,4-B]吡啶-3-羧酸(1.00g,4.8mmol)和1d(1.09g,5.7mmol)为原料,制备方法同2a,抽滤得棕色固体2j(1.36g),收率74.2%,MS[M+H]+:381.16,产品无需进一步纯化,直接进行下一步反应。
实施例24
N-(4-吗啉代苯基)-4-硝基-1H-吲唑-3-甲酰胺(2k)
以5-硝基-1H-吡嗪[3,4-B]吡啶-3-羧酸(1.00g,4.8mmol)和1f(1.02g,5.7mmol)为原料,制备方法同2a,抽滤得棕色固体2k(1.23g),收率69.4%,MS[M+H]+:368.12,产品无需进一步纯化,直接进行下一步反应。
实施例25
N-(4-氟苯基)-4-硝基-1H-吲唑-3-甲酰胺(2l)
以5-硝基-1H-吡嗪[3,4-B]吡啶-3-羧酸(1.00g,4.8mmol)和4-氟苯胺(0.80g,5.7mmol)为原料,制备方法同2a,抽滤得棕色固体2l(1.01g),收率70.5%,MS[M+H]+:300.08,产品无需进一步纯化,直接进行下一步反应。
实施例26
N-(4-吗啉代苯基)-5-硝基-1H-吲唑-3-甲酰胺(2m)
以5-硝基-1H-吲唑-3-羧酸(1.91g,10.0mmol)和1f(1.96g,11.0mmol)为原料,制备方法同2a,抽滤得棕色固体2m(2.59g),收率70.3%,MS[M+H]+:368.16,产品无需进一步纯化,直接进行下一步反应。
实施例27
5-氨基-N-(4-(4-甲基哌嗪-1-基)苯基)-1H-吲唑-3-甲酰胺(3a)
以2a(1.40g,3.7mmol)为原料,制备方法同1b,经柱层析得淡棕色固体2b(0.8g),收率62.2%,1HNMR[500MHz,DMSO-d6]:δ13.27(s,1H,-NH),9.83(s,1H,-NH),7.75–7.65(m,2H,ArH),7.33(d,J=8.7Hz,1H,ArH),7.28(d,J=2.0Hz,1H,ArH),6.91(d,J=9.1Hz,2H,ArH),6.84(dd,J=8.8,2.1Hz,1H,ArH),5.07(s,2H,-NH2),3.33(s,2H,-CH2-),3.11(t,J=4.9Hz,4H,-CH2-×2),3.00(s,2H,-CH2-),2.27(s,3H,-CH3),MS[M+H]+:351.20。
实施例28
5-氨基-N-(4-氟苯基)-1H-吲唑-3-甲酰胺(3b)
以2b(1.1g,3.7mmol)为原料,制备方法同1b,经柱层析得淡棕色固体3b(0.8g),收率62.4%,1HNMR(500MHz,MeOD-d4)δ7.15–7.09(m,2H),6.76(dd,J=2.2,0.7Hz,1H),6.71(dd,J=8.8,0.7Hz,1H),6.43(t,J=8.8Hz,2H),6.27(dd,J=8.8,2.1Hz,1H),MS[M+H]+:271.10。
实施例29
5-氨基-N-(4-((4-甲基哌嗪-1-基)甲基)苯基)-1H-吲唑-3-甲酰胺(3c)
以2c(1.5g,3.7mmol)为原料,制备方法同1b,经柱层析得淡棕色固体3c(0.91g),收率67.3%,MS[M+H]+:365.21。
实施例30
5-氨基-N-(4-(4-甲基哌嗪-1-羰基)苯基)-1H-吲唑-3-甲酰胺(3d)
以2d(1.5g,3.7mmol)为原料,制备方法同1b,经柱层析得淡棕色固体3d(1.06g),收率75.3%,MS[M+H]+:379.19。
实施例31
5-氨基-N-(4-((4-甲基哌嗪-1-基)甲基)苯基)-1H-吲唑-3-甲酰胺(3e)
以2e(1.46g,3.7mmol)为原料,制备方法同1b,经柱层析得淡棕色固体3d(1.07g),收率79.4%,1HNMR(500MHz,DMSO)δ13.30(s,1H),10.01(s,1H),7.80(d,J=8.5Hz,2H),7.34(d,J=8.8Hz,1H),7.29(d,J=1.8Hz,1H),7.23(d,J=8.5Hz,2H),6.85(dd,J=8.8,2.1Hz,1H),5.06(s,2H),3.41(s,2H),2.35–2.34(m,8H),2.16(s,3H);MS[M+H]+:365.21。
实施例32
5-氨基-N-(4-(4-甲基哌嗪-1-基)苯基)-1H-吡唑并[3,4-b]吡啶-3-甲酰胺(3f)
以2f(1.41g,3.7mmol)为原料,制备方法同1b,经柱层析得淡棕色固体3f(1.05g),收率80.3%,1H NMR[500MHz,Methanol-d4)]:δ13.80(s,1H,-NH-),9.96(s,1H,-NH-),8.11(d,J=2.6Hz,1H,ArH),7.69(d,J=9.0Hz,2H,ArH),7.61(d,J=2.6Hz,1H,ArH),6.91(d,J=9.1Hz,2H,ArH),5.32(s,2H,-NH2),3.09(m,4H,-CH2-×2),2.46(m,4H,-CH2-×2),2.23(s,3H),MS[M+H]+:352.18。
实施例33
5-氨基-N-(4-氟苯基)-1H-吡唑并[3,4-b]吡啶-3-甲酰胺(3g)
以2g(1.12g,3.7mmol)为原料,制备方法同1b,经柱层析得淡棕色固体3g(0.77g),收率76.5%,1HNMR(500MHz,MeOD-d4)δ8.48(d,J=2.6Hz,1H),8.17(d,J=2.6Hz,1H),8.03-7.95(m,2H),7.43-7.31(m,2H);MS[M+H]+:272.10。
实施例34
5-氨基-N-(4-(吗啉-4-羰基)苯基)-1H-吡唑并[3,4-b]吡啶-3-甲酰胺(3h)
以2h(1.47g,3.7mmol)为原料,制备方法同1b,经柱层析得淡棕色固体3h(1.06g),收率77.9%,MS[M+H]+:367.16。
实施例35
5-氨基-N-(4-(4-甲基哌嗪-1-羰基)苯基)-1H-吡唑并[3,4-b]吡啶-3-甲酰胺(3i)
以2i(1.51g,3.7mmol)为原料,制备方法同1b,经柱层析得淡棕色固体3i(1.13g),收率80.6%,MS[M+H]+:380.19。
实施例36
4-氨基-N-(4-(4-甲基哌嗪-1-基)苯基)-1H-吲唑-3-甲酰胺(3j)
以2j(1.41g,3.7mmol)为原料,制备方法同1b,经柱层析得淡棕色固体3j(1.10g),收率84.9%,1H NMR[500MHz,DMSO-d6]:δ13.37(s,1H,-NH-),10.22(s,1H,-NH),7.67(d,J=9.1Hz,2H,ArH),7.09(s,1H,ArH),6.92(d,J=9.1Hz,2H,ArH),6.75(s,2H,-NH2),6.67(s,1H,ArH),6.26(d,J=7.5Hz,1H,ArH),3.10(m,4H,-CH2-×2),2.46(br,4H,-CH2-×2),2.22(s,3H),MS[M+H]+:351.20。
实施例37
4-氨基-N-(4-吗啉代苯基)-1H-吲唑-3-甲酰胺(3k)
以2k(1.36g,3.7mmol)为原料,制备方法同1b,经柱层析得淡棕色固体3k(1.08g),收率86.4%,MS[M+H]+:338.16。
实施例38
4-氨基-N-(4-氟苯基)-1H-吲唑-3-甲酰胺(3l)
以2l(1.11g,3.7mmol)为原料,制备方法同1b,经柱层析得淡棕色固体3l(0.84g),收率84.2%,1H NMR(500MHz,MeOD-d4)δ7.28–6.96(m,1H),6.54(dd,J=8.3,7.5Hz,1H),6.49(dd,J=9.1,8.5Hz,1H),6.17(dd,J=8.3,0.7Hz,1H),5.79(dd,J=7.5,0.8Hz,1H);MS[M+H]+:271.10。
实施例39
5-氨基-N-(4-吗啉代苯基)-1H-吲唑-3-甲酰胺(3m)
以2m(1.36g,3.7mmol)为原料,制备方法同1b,经柱层析得淡棕色固体3m(1.08g),收率75.5%,1HNMR(500MHz,DMSO-d6)δ13.25(s,1H),9.85(s,1H),7.72(d,J=9.0Hz,2H),7.34(d,J=8.8Hz,1H),7.29(d,J=2.0Hz,1H),6.92(d,J=9.1Hz,2H),6.85(dd,J=8.9,2.1Hz,1H),5.05(s,2H),3.74(m,4H),3.06(m,4H);MS[M+H]+:388.16。
实施例40
5-氨基-N-(1-甲基哌啶-4-基)-1H-吡唑并[3,4-b]吡啶-3-甲酰胺(3n)
以1-甲基哌啶-4-胺(1.36g,3.7mmol)为原料,制备方法同3f,经柱层析得淡棕色固体3n(0.57g),收率55.7%,MS[M+H]+:275.15。
实施例41
5-氨基-N-(4-(吗啉甲基)苯基)-1H-吲唑-3-甲酰胺(3o)
以***啉为最初起始原料(3.15g,36.2mmol)为原料,制备方法同3c,经四步反应得淡棕色固体3o(0.57g),MS[M+H]+:275.15。
实施例42
5-丙烯酰胺基-N-(4-吗啉代苯基)-1H-吲唑-3-甲酰胺(I-1)
在单颈瓶中加入3m(199.4mg,0.59mmol),加入THF(3mL)使之溶解,随后加入丙烯酰氯(58.8mg,0.65mmol),TEA(65.7mg,0.65mmol)。室温下反应2h,TLC检测原料消失(甲醇∶二氯=1∶20,体积比)。减压蒸干溶剂,经柱层析得淡黄色固体,为I-1(95.1mg),收率41.1%。1H NMR(500MHz,DMSO-d6)δ13.68(s,1H),10.28(s,1H),8.74–8.53(m,2H),7.83–7.69(m,4H),7.62(d,J=9.0Hz,1H),6.95(d,J=9.0Hz,3H),6.46(d,J=10.2Hz,1H),6.28(dd,J=17.0,1.9Hz,1H),5.76(dd,J=10.1,1.8Hz,1H),3.83–3.64(m,7H),3.37(s,9H),3.16–2.99(m,7H);HRMS-EI m/z[M+H]+calcd for C21H22N5O3:392.1723,found:392.1735。
实施例43
5-丙烯酰胺基-N-(4-(4-甲基哌嗪-1-基)苯基)-1H-吲唑-3-甲酰胺(I-2)
以3a(207.1mg,0.59mmol)为原料,制备方法同I-1,经柱层析得淡黄色固体I-2(82.0mg),收率34.3%。1H NMR(500MHz,Methanol-d4)δ14.50(s,1H),11.12(s,1H),10.87(s,1H),9.44(s,1H),8.69–8.48(m,4H),8.43(d,J=9.0Hz,1H),7.74(d,J=9.0Hz,2H),7.31(dd,J=16.9,10.1Hz,1H),7.10(dd,J=17.0,1.7Hz,1H),6.57(dd,J=10.2,1.7Hz,1H),3.97–3.85(m,7H),3.40–3.19(m,14H),3.07(s,3H);HRMS-EI m/z[M+H]+calcd forC22H25N6O2:405.2039,found:405.2027。
实施例44
5-丙烯酰胺基-N-(4-氟苯基)-1H-吲唑-3-甲酰胺(I-3)
以3b(160.0mg,0.59mmol)为原料,制备方法同I-1,经柱层析得淡黄色固体I-3(71.5mg),收率37.4%;HRMS-EI m/z[M+H]+calcd for C17H14FN4O2:325.1101,found:325.1112。
实施例45
N-(4-吗啉代苯基)-5-(乙烯基磺胺基)-1H-吲唑-3-甲酰胺(I-4)
在单颈瓶中加入3m(199.4mg,0.59mmol),加入DMF(3mL)使之溶解,随后加入氯乙基磺酰氯(96.2mg,0.59mmol),DIPEA(228.3mg,1.77mmol)。室温下反应8h,TLC检测原料消失。减压蒸干溶剂,经柱层析得淡黄色固体,为I-4(40.1mg),收率15.9%。1H NMR(500MHz,DMSO-d6)δ13.72(s,1H),10.10(s,1H),9.94(s,1H),8.03(d,J=1.6Hz,1H),7.73(d,J=9.0Hz,2H),7.61(d,J=8.9Hz,1H),7.31(dd,J=8.9,2.0Hz,1H),6.93(d,J=9.1Hz,2H),6.76(dd,J=16.5,10.0Hz,1H),6.01(m,2H),3.74(m,4H),3.07(m,4H);HRMS-EI m/z[M+H]+calcd for C20H22N5O4S:428.1392,found:428.1399。
实施例46
N-(4-(4-甲基哌嗪-1-基)苯基)-5-(乙烯基磺酰胺)-1H-吲唑-3-甲酰胺(I-5)
以3a(207.1mg,0.59mmol)为原料,制备方法同I-4,经柱层析得淡黄色固体I-5(42.2mg),收率16.2%。1H NMR(500MHz,DMSO-d6)δ13.71(s,1H),10.07(s,1H),9.94(s,1H),8.03(d,J=2.1Hz,1H),7.77–7.67(m,2H),7.61(d,J=9.0Hz,1H),7.31(dd,J=8.9,2.1Hz,1H),7.00–6.83(m,2H),6.76(dd,J=16.5,10.0Hz,1H),6.10–5.93(m,2H),3.10(dd,J=6.2,3.7Hz,4H),2.47(t,J=4.9Hz,4H),2.23(s,3H).HRMS-EI m/z[M+H]+calcd forC21H25N6O3S:441.1709,found:441.1710。
实施例47
N-(4-氟苯基)-5-(乙烯基磺酰胺)-1H-吲唑-3-甲酰胺(I-6)
以3b(160.0mg,0.59mmol)为原料,制备方法同I-4,经柱层析得淡黄色固体I-6(29.2mg),收率13.7%。1H NMR(500MHz,DMSO-d6)δ13.79(s,1H),10.40(s,1H),9.97(s,1H),8.03(d,J=1.9Hz,1H),7.94–7.87(m,2H),7.63(d,J=8.9Hz,1H),7.32(dd,J=9.0,2.1Hz,1H),7.19(t,J=8.9Hz,2H),6.77(dd,J=16.4,10.0Hz,1H),6.17–5.93(m,2H);HRMS-EI m/z[M+H]+calcd for C16H14FN4O3S:441.1709,found:361.0771。
实施例48
5-(3-氯丙酰胺)-N-(4-吗啉代苯基)-1H-吲唑-3-甲酰胺(I-7)
在单颈瓶中加入3m(199.4mg,0.59mmol),加入DMF(3mL)使之溶解,随后加入3-氯丙酰氯(89.5mg,0.71mmol),DIPEA(152.2mg,1.18mmol)。室温下反应,TLC检测原料消失,反应停止。减压蒸干溶剂,经柱层析得淡黄色固体,为I-7(40.1mg),收率20.1%。HRMS-EIm/z[M+H]+calcd for C21H23ClN5O3:428.1489,found:428.1479。
实施例49
5-(3-氯丙酰胺)-N-(4-(4-甲基哌嗪-1-基)苯基)-1H-吲唑-3-甲酰胺(I-8)
以3a(207.1mg,0.59mmol)为原料,制备方法同I-7,经柱层析得淡黄色固体I-8(60.0mg),收率23.1%;HRMS-EI m/z[M+H]+calcd for C22H26ClN6O2:441.1806,found:441.1811。
实施例50
5-(3-氯丙酰胺)-N-(4-氟苯基)-1H-吲唑-3-甲酰胺(I-9)
以3b(160.0mg,0.59mmol)为原料,制备方法同I-7,经柱层析得淡黄色固体I-9(48.5mg),收率18.7%;HRMS-EI m/z[M+H]+calcd for C17H15ClFN4O2:361.0868,found:361.0866。
实施例51
5-(3-氯丙酰胺)-N-(4-((4-甲基哌嗪-1-基)甲基)苯基)-1H-吲唑-3-甲酰胺(I-10)
以3c(215.5mg,0.59mmol)为原料,制备方法同I-7,经柱层析得淡黄色固体I-10(44.0mg),收率16.4%;1H NMR(500MHz,DMSO)δ13.85(s,1H),10.33(s,1H),10.26(s,1H),8.60(s,1H),7.86(d,J=5.4Hz,2H),7.62(d,J=5.0Hz,2H),7.27(s,2H),3.91(s,2H),3.50(s,2H),2.87(s,2H),2.63(s,8H),2.36(s,3H).HRMS-EI m/z[M+H]+calcd forC23H28ClN6O2:455.1962,found:455.1955。
实施例52
5-(3-氯丙酰胺基)-N-(4-(吗啉甲基)苯基)-1H-吲唑-3-甲酰胺(I-11)
以3o(207.7mg,0.59mmol)为原料,制备方法同I-7,经柱层析得淡黄色固体I-11(50.0mg),收率19.2%;HRMS-EI m/z[M+H]+calcd for C22H25ClN5O3:442.1646,found:442.1637。
实施例53
5-(3-氯丙酰胺基)-N-(4-(4-甲基哌嗪-1-羰基)苯基)-1H-吲唑-3-甲酰胺(I-12)
以3d(223.6mg,0.59mmol)为原料,制备方法同I-7,经柱层析得淡黄色固体I-11(55.5mg),收率20.1%;HRMS-EI m/z[M+H]+calcd for C23H26ClN6O3:469.1755,found:469.1749。
实施例54
5-丙烯酰胺-N-(4-((4-甲基哌嗪-1-基)甲基)苯基)-1H-吲唑-3-甲酰胺(I-13)
以3c(215.5mg,0.59mmol)为原料,制备方法同I-1,经柱层析得淡黄色固体I-13(75.5mg),收率30.6%;1H NMR(500MHz,MeOD)δ8.59(s,1H),7.80(d,J=8.2Hz,2H),7.75(dd,J=9.0,1.8Hz,1H),7.62(d,J=9.0Hz,1H),7.40(d,J=8.2Hz,2H),6.51(dd,J=17.0,10.0Hz,1H),6.41(dd,J=17.0,1.7Hz,1H),5.81(dd,J=10.1,1.7Hz,1H),3.72(s,2H),3.21(s,8H),2.82(s,3H).HRMS-EI m/z[M+H]+calcd for C23H27N6O2:419.2195,found:419.2201。
实施例55
5-丙烯酰胺-N-(4-(吗啉甲基)苯基)-1H-吲唑-3-甲酰胺(I-14)
以3o(207.7mg,0.59mmol)为原料,制备方法同I-1,经柱层析得淡黄色固体I-14(70.7mg),收率29.6%;HRMS-EI m/z[M+H]+calcd for C22H24N5O3:406.1879,found:406.1871。
实施例56
5-丙烯酰胺基-N-(4-(4-甲基哌嗪-1-羰基)苯基)-1H-吲唑-3-甲酰胺(I-15)
以3d(223.6mg,0.59mmol)为原料,制备方法同I-1,经柱层析得淡黄色固体I-15(65.5mg),收率25.7%;HRMS-EI m/z[M+H]+calcd for C23H25N6O3:433.1988,found:433.1976。
实施例57
N-(4-((4-甲基哌嗪-1-基)甲基)苯基)-5-(乙烯基磺酰胺)-1H-吲唑-3-甲酰胺(I-16)
以3c(215.4mg,0.59mmol)为原料,制备方法同I-4,经柱层析得淡黄色固体I-16(39.1mg),收率14.6%;HRMS-EI m/z[M+H]+calcd for C22H27N6O3S:455.1865,found:455.1857。
实施例58
N-(4-(吗啉代甲基)苯基)-5-(乙烯基磺酰胺)-1H-吲唑-3-甲酰胺(I-17)
以3o(207.1mg,0.59mmol)为原料,制备方法同I-4,经柱层析得淡黄色固体I-17(33.6mg),收率12.9%;HRMS-EI m/z[M+H]+calcd for C21H24N5O4S:442.1549,found:442.1542。
实施例59
N-(4-(4-甲基哌嗪-1-羰基)苯基)-5-(乙烯基磺酰胺)-1H-吲唑-3-甲酰胺(I-18)
以3d(223.0mg,0.59mmol)为原料,制备方法同I-4,经柱层析得淡黄色固体I-18(43.1mg),收率15.6%;HRMS-EIm/z[M+H]+calcd for C22H25N6O4S:469.1658,found:469.1649。
实施例60
N-(4-((4-甲基哌嗪-1-基)甲基)苯基)-5-丙酰胺基-1H-吲唑-3-甲酰胺(I-19)
以3c(215.5mg,0.59mmol)和丙酰氯(65.7mg,0.71mmol)为原料,制备方法同I-1,经柱层析得淡黄色固体I-19(113.6mg),收率45.7%;1H NMR(500MHz,DMSO)δ13.85(d,J=15.7Hz,1H),10.24(s,1H),10.10(d,J=12.2Hz,1H),8.58(s,1H),7.86(d,J=7.8Hz,2H),7.64(d,J=9.1Hz,1H),7.59(d,J=9.0Hz,1H),7.28(s,2H),3.51(s,2H),3.25–2.57(m,8H),2.55(s,3H),2.36(q,J=7.6Hz,2H),1.11(t,J=7.5Hz,3H);HRMS-EI m/z[M+H]+calcdfor C23H29N6O2:421.2352,found:421.2344。
实施例61
N-(4-(吗啉代甲基)苯基)-5-丙酰胺基-1H-吲唑-3-甲酰胺(I-20)
以3o(207.1mg,0.59mmol)和丙酰氯(65.7mg,0.71mmol)为原料,制备方法同I-1,经柱层析得淡黄色固体I-20(98.2mg),收率40.9%;HRMS-EIm/z[M+H]+calcdforC22H26N5O3:408.2036,found:408.2021。
实施例62
4-(3-氯丙酰胺)-N-(4-(4-甲基哌嗪-1-基)苯基)-1H-吲唑-3-甲酰胺(I-21)
以3j(207.1mg,0.59mmol)为原料,制备方法同I-7,经柱层析得淡黄色固体I-21(96.0mg),收率36.9%。1H NMR(500MHz,DMSO-d6)δ14.11(s,1H),12.65(s,1H),10.60(s,1H),8.29(d,J=7.7Hz,1H),7.72–7.64(m,2H),7.42(t,J=8.0Hz,1H),7.35(d,J=8.3Hz,1H),7.01–6.94(m,2H),3.95(d,J=6.2Hz,2H),3.19(s,4H),2.93(t,J=6.2Hz,2H),2.62(s,4H),2.34(s,3H);HRMS-EI m/z[M+H]+calcd for C22H26ClN6O2:441.1806,found:441.1811。
实施例63
4-(3-氯丙酰胺基)-N-(4-氟苯基)-1H-吲唑-3-甲酰胺(I-22)
以3l(159.9mg,0.59mmol)为原料,制备方法同I-7,经柱层析得淡黄色固体I-22(53.7mg),收率25.3%;HRMS-EI m/z[M+H]+calcd for C17H15ClFN4O2:361.0868,found:361.0871。
实施例64
4-(3-氯丙酰胺基)-N-(4-吗啉代苯基)-1H-吲唑-3-甲酰胺(I-23)
以3k(199.4mg,0.59mmol)为原料,制备方法同I-7,经柱层析得淡黄色固体I-23(74.6mg),收率29.6%;HRMS-EI m/z[M+H]+calcd for C21H23ClN5O3:428.1489,found:428.1480。
实施例65
N-(4-(4-甲基哌嗪-1-基)苯基)-4-(乙烯基磺酰胺)-1H-吲唑-3-甲酰胺(I-24)
以3j(207.1mg,0.59mmol)为原料,制备方法同I-4,经柱层析得淡黄色固体I-24(71.1mg),收率27.4%;HRMS-EIm/z[M+H]+calcd for C21H25N6O3S:441.1709,found:441.1711。
实施例66
N-(4-氟苯基)-4-(乙烯基磺酰胺)-1H-吲唑-3-甲酰胺(I-25)
以3l(159.9mg,0.59mmol)为原料,制备方法同I-4,经柱层析得淡黄色固体I-25(41.4mg),收率19.5%;HRMS-EI m/z[M+H]+calcd for C16H14FN4O3S:361.0771,found:361.0766。
实施例67
N-(4-吗啉代苯基)-4-(乙烯基磺酰胺)-1H-吲唑-3-甲酰胺(I-26)
以3k(198.8mg,0.59mmol)为原料,制备方法同I-4,经柱层析得淡黄色固体I-26(46.9mg),收率18.6%;HRMS-EIm/z[M+H]+calcd for C20H22N5O4S:428.1392,found:428.1399。
实施例68
4-丙烯酰胺-N-(4-(4-甲基哌嗪-1-基)苯基)-1H-吲唑-3-甲酰胺(I-27)
以3j(207.1mg,0.59mmol)为原料,制备方法同I-1,经柱层析得淡黄色固体I-27(63.2mg),收率26.6%;HRMS-EIm/z[M+H]+calcd for C22H24N6O2:404.1961,found:404.1956。
实施例69
4-丙烯酰胺-N-(4-氟苯基)-1H-吲唑-3-甲酰胺(I-28)
以3l(160.0mg,0.59mmol)为原料,制备方法同I-1,经柱层析得淡黄色固体I-28(65.2mg),收率34.1%。1H NMR(500MHz,DMSO-d6)δ14.10(s,1H),12.64(s,1H),10.89(s,1H),8.53–8.36(m,1H),7.98–7.81(m,2H),7.49–7.42(m,1H),7.38(d,J=8.3Hz,1H),7.30–7.22(m,2H),6.50–6.31(m,2H),5.94–5.82(m,1H);HRMS-EI m/z[M+H]+calcd forC17H13FN4O2:324.1023,found:324.1029。
实施例70
4-丙烯酰胺基-N-(4-吗啉代苯基)-1H-吲唑-3-甲酰胺(I-29)
以3k(199.4mg,0.59mmol)为原料,制备方法同I-1,经柱层析得淡黄色固体I-29(62.7mg),收率27.2%;HRMS-EI m/z[M+H]+calcd for C21H22N5O3:392.1723,found:392.1734。
实施例71
5-(3-氯丙酰胺基)-N-(4-(4-甲基哌嗪-1-基)苯基)-1H-吡唑并[3,4-b]吡啶-3-甲酰胺(I-30)
以3f(207.7mg,0.59mmol)为原料,制备方法同I-7,经柱层析得淡黄色固体I-30(63.2mg),收率24.3%;HRMS-EI m/z[M+H]+calcd for C21H25ClN7O2:442.1758,found:442.1749。
实施例72
5-(3-氯丙酰胺)-N-(4-氟苯基)-1H-吡唑并[3,4-b]吡啶-3-甲酰胺(I-31)
以3g(160.5mg,0.59mmol)为原料,制备方法同I-7,经柱层析得淡黄色固体I-31(64.5mg),收率30.2%;HRMS-EI m/z[M+H]+calcd for C16H14ClFN5O2:362.0820,found:362.0818。
实施例73
5-(3-氯丙酰胺)-N-(1-甲基哌啶-4-基)-1H-吡唑并[3,4-b]吡啶-3-甲酰胺(I-32)
以3n(162.3mg,0.59mmol)为原料,制备方法同I-7,经柱层析得淡黄色固体I-32(98.1mg),收率45.7%;HRMS-EI m/z[M+H]+calcd for C16H22ClN6O2:365.1493,found:365.1488。
实施例74
5-(3-氯丙酰胺基)-N-(4-(吗啉-4-羰基)苯基)-1H-吡唑并[3,4-b]吡啶-3-甲酰胺(I-33)
以3h(215.9mg,0.59mmol)为原料,制备方法同I-7,经柱层析得淡黄色固体I-33(42.0mg),收率15.6%;HRMS-EI m/z[M+H]+calcd for C21H22ClN6O4:457.1391,found:457.1387。
实施例75
5-(3-氯丙酰胺基)-N-(4-(4-甲基哌嗪-1-羰基)苯基)-1H-吡唑并[3,4-b]吡啶-3-甲酰胺(I-34)
以3i(223.6mg,0.59mmol)为原料,制备方法同I-7,经柱层析得淡黄色固体I-34(40.7mg),收率14.7%;HRMS-EI m/z[M+H]+calcd for C22H25ClN7O3:470.1707,found:470.1701。
实施例76
N-(4-(4-甲基哌嗪-1-基)苯基)-5-(乙烯基磺酰胺)-1H-吡唑并[3,4-b]吡啶-3-甲酰胺(I-35)
以3f(207.7mg,0.59mmol)为原料,制备方法同I-4,经柱层析得淡黄色固体I-35(31.6mg),收率12.1%;1H NMR(500MHz,DMSO-d6)δ14.37(s,1H),10.25(s,1H),8.46(d,J=2.5Hz,1H),8.35(d,J=2.4Hz,1H),7.72(d,J=9.0Hz,2H),7.02–6.89(m,2H),6.85(dd,J=16.4,9.9Hz,1H),6.05(s,1H),6.03(d,J=5.4Hz,1H),3.15(t,J=4.9Hz,4H),2.59(t,J=4.9Hz,4H),2.32(s,3H).HRMS-EI m/z[M+H]+calcd for C20H24N7O3S:442.1661,found:442.1667。
实施例77
N-(4-氟苯基)-5-(乙烯基磺酰胺)-1H-吡唑并[3,4-b]吡啶-3-甲酰胺(I-36)
以3g(160.5mg,0.59mmol)为原料,制备方法同I-4,经柱层析得淡黄色固体I-36(29.2mg),收率13.7%;HRMS-EI m/z[M+H]+calcd for C15H13FN5O3S:362.0723,found:362.0716。
实施例78
N-(1-甲基哌啶-4-基)-5-(乙烯基磺酰胺)-1H-吡唑并[3,4-b]吡啶-3-甲酰胺(I-37)
以3n(161.7mg,0.59mmol)为原料,制备方法同I-4,经柱层析得淡黄色固体I-37(48.1mg),收率22.4%;1H NMR(500MHz,DMSO-d6)δ13.79(s,1H),10.40(s,1H),9.97(s,1H),8.03(d,J=1.9Hz,1H),7.94–7.87(m,2H),7.63(d,J=8.9Hz,1H),7.32(dd,J=9.0,2.1Hz,1H),7.19(t,J=8.9Hz,2H),6.77(dd,J=16.4,10.0Hz,1H),6.17–5.93(m,2H);HRMS-EI m/z[M+H]+calcd for C15H21N6O3S:365.1396,found:365.1399。
实施例79
N-(4-吗啉代苯基)-5-(乙烯基磺酰胺)-1H-吡唑并[3,4-b]吡啶-3-甲酰胺(I-38)
以3k(198.8mg,0.59mmol)为原料,制备方法同I-4,经柱层析得淡黄色固体I-38(34.5mg),收率13.7%;1H NMR(500MHz,DMSO-d6)δ14.54(s,1H),11.99(s,1H),10.31(s,1H),8.85(d,2H),8.71(s,1H),7.75(d,J=8.6Hz,2H),7.33(m,1H),6.94(d,J=8.7Hz,2H),3.74(t,J=4.7Hz,4H),3.07(t,J=4.7Hz,4H).HRMS-EI m/z[M+H]+calcd for C19H21N6O4S:429.1345,found:429.1338。
实施例80
N-(4-(4-甲基哌嗪-1-羰基)苯基)-5-(乙烯基磺酰胺)-1H-吡唑并[3,4-b]吡啶-3-甲酰胺(I-39)
以3i(224.2mg,0.59mmol)为原料,制备方法同I-4,经柱层析得淡黄色固体I-39(43.2mg),收率15.6%;HRMS-EI m/z[M+H]+calcd for C21H24N7O4S:470.1610,found:470.1621。
实施例81
5-丙烯酰胺基-N-(4-(4-甲基哌嗪-1-基)苯基)-1H-吡唑并[3,4-b]吡啶-3-甲酰胺(I-40)
以3f(207.7mg,0.59mmol)为原料,制备方法同I-1,经柱层析得淡黄色固体I-40(70.7mg),收率29.5%。1H NMR(500MHz,DMSO-d6)δ14.32(s,1H),10.76(s,1H),10.22(s,1H),9.03(d,J=2.3Hz,1H),8.83(d,J=2.4Hz,1H),7.74(d,J=9.1Hz,2H),6.96(d,J=9.1Hz,2H),6.55(dd,J=17.0,10.2Hz,1H),6.32(dd,J=17.1,1.9Hz,1H),5.82(dd,J=10.2,1.9Hz,1H),5.82(dd,J=10.2,1.9Hz,1H),3.11(m,4H),2.45(m,4H),2.21(s,3H);HRMS-EI m/z[M+H]+calcd for C21H24N7O2:406.1991,found:406.1988。
实施例82
5-丙烯酰胺基-N-(4-氟苯基)-1H-吡唑并[3,4-b]吡啶-3-甲酰胺(I-41)
以3g(160.5mg,0.59mmol)为原料,制备方法同I-1,经柱层析得淡黄色固体I-41(40.8mg),收率21.2%。1H NMR(500MHz,DMSO-d6)δ14.35(s,1H),10.54(s,1H),10.52(s,1H),9.01(s,1H),8.81(s,1H),7.92(dd,J=8.7,4.9Hz,2H),7.21(t,J=8.7Hz,2H),6.49(dd,J=17.0,10.1Hz,1H),6.34(d,J=16.9Hz,1H),5.83(d,J=10.2Hz,1H);HRMS-EI m/z[M+H]+calcd for C16H13FN5O2:326.1053,found:326.1047。
实施例83
5-丙烯酰胺-N-(1-甲基哌啶-4-基)-1H-吡唑并[3,4-b]吡啶-3-甲酰胺(I-42)
以3n(162.3mg,0.59mmol)为原料,制备方法同I-1,经柱层析得淡黄色固体I-42(86.9mg),收率44.9%;HRMS-EI m/z[M+H]+calcd for C16H21N6O2:329.1726,found:329.1733。
实施例84
5-丙烯酰胺基-N-(4-吗啉代苯基)-1H-吡唑并[3,4-b]吡啶-3-甲酰胺(I-43)
以3k(198.8mg,0.59mmol)为原料,制备方法同I-1,经柱层析得淡黄色固体I-43(47.6mg),收率20.6%;1H NMR(500MHz,DMSO-d6)δ14.27(s,1H),10.54(s,1H),10.21(s,1H),9.00(d,J=2.4Hz,1H),8.79(d,J=2.4Hz,1H),7.94–7.55(m,2H),7.07–6.80(m,2H),6.49(dd,J=16.9,10.1Hz,1H),6.33(dd,J=17.0,1.9Hz,1H),5.83(dd,J=10.1,1.9Hz,1H),3.83–3.69(m,4H),3.17–3.03(m,4H).HRMS-EI m/z[M+H]+calcd for C20H21N6O3:393.1675,found:393.1669。
实施例85
5-丙烯酰胺基-N-(4-(4-甲基哌嗪-1-羰基)苯基)-1H-吡唑并[3,4-b]吡啶-3-甲酰胺(I-44)
以3i(224.2mg,0.59mmol)为原料,制备方法同I-1,经柱层析得淡黄色固体I-44(64.1mg),收率25.1%。HRMS-EI m/z[M+H]+calcd for C22H24N7O3:434.1941,found:434.1937。
实施例86
N-(1-甲基哌啶-4-基)-1H-吲唑-3-甲酰胺(I-45)
以吲唑-3-羧酸(1.62g,10.0mmol)和1-甲基哌啶-4-胺(1.25g,11mmol)为原料,制备方法同2a,经柱层析得淡黄色固体I-45(1.97g),收率76.3%;1H NMR(500MHz,DMSO-d6)δ13.54(s,1H),8.15(dd,J=14.5,8.2Hz,1H),7.60(d,J=8.4Hz,0H),7.42(s,0H),7.24(d,J=7.5Hz,0H),2.76(dt,J=12.1,3.5Hz,1H),2.17(s,1H),2.06–1.92(m,1H),1.71(ddd,J=36.1,12.3,3.7Hz,2H);HRMS-EI m/z[M+H]+calcd for C14H19N4O:259.1559,found:259.1546。
实施例87
N-(4-((4-甲基哌嗪-1-基)甲基)苯基)-1H-吲唑-3-甲酰胺(I-46)
以吲唑-3-羧酸(1.62g,10.0mmol)和1b(2.26g,11.0mmol)为原料,制备方法同2a,经柱层析得淡黄色固体I-45(2.67g),收率76.3%;1H NMR(500MHz,DMSO-d6)δ14.00(s,1H),10.33(s,1H),8.22(d,J=8.0Hz,1H),7.87(d,J=7.0Hz,1H),7.68(d,J=8.4Hz,1H),7.45(m,1H),7.29(m,2H),3.51(s,2H),3.04(m,8H),2.68(s,3H);HRMS-EI m/z[M+H]+calcd forC20H24N5O:350.1981,found:350.1979。
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(pH7.5)、BRIJ-35、MgCl2和EDTA。CDK2phospho-peptidesubstrate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 ReagentA。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.化合物对部分激酶的抑制活性(抑制率%,1×10-6mol/L)(表格里的颜色去除)
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
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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基团的引入有利于化合物对FLT3抑制活性的提高,与不含该结构的对应化合相比,该类化合物对FLT3的具有显著的抑制活性。其中引入烯丙基换酰胺和氯乙基丙酰胺基的时候,所得的化合物对FLT3的具有更为显著的抑制活性,所得化合物的IC50值与AC220(已上市的FLT3抑制剂)和FN-1501相当。根据初步研究表明,引入该类基团的化合物容易和激酶进行不可逆结合,根据分子结合模式研究,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,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 (9)
1.一种取代的吲唑甲酰胺或取代的氮杂吲唑甲酰胺类FLT3抑制剂,其特征在于,为具有以下结构式(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、C(O)NH、C(O)、NHC(O)、NHC(O)NH、取代或未取代的C1-6直链或支链亚烷基、取代或未取代的C3-6环状饱和烷基,其中C1-6亚烷基中的任意碳原子被1-3个NH、N、O或S取代;Ra选自氢、卤原子、-NH2、-OH、取代或未取代的C1-6直链或支链烷基、取代或未取代的C1-6直链或支链卤代烷基、取代或未取代的C3-8环状饱和烷基、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链烯基、取代或未取代的C3-6环烯基、取代或未取代的C1-6烷胺基、取代或未取代的杂环烷基、取代或未取代的C6-14芳基或取代或未取代的芳杂环;
G是选自取代或未取代的C1-6烷基、取代或未取代的C1-6烯基、取代或未取代的C6-14芳基、取代或未取代的杂环烷基或取代或未取代的芳杂环;
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;
所述杂环烷基选自3-6个碳原子的单环饱和烃基、6-12个碳原子的双环饱和烃基,其中环上的碳原子独立地被1~4个O、S、N或NH取代;
所述C6-14芳基选自苯基、萘基、苊基或四氢萘基中的一种;
所述芳杂环选自吡咯基、吡唑基、咪唑基、呋喃基、噻吩基、噁唑基、异噁唑基、噻唑基、异噻唑基、吡啶基、嘧啶基、吡嗪基或哒嗪基的单环杂环;或选自喹啉基、喹喔啉基、吲哚基、苯并咪唑基、苯并噁唑基、苯并异噁唑基、苯并噻唑基、苯并异噻唑基、苯并呋喃基、苯并噻吩基、2,3-二氢苯并[1,4]二氧杂环己烯基或苯并[1,3]二氧杂环戊烯基的双环杂环中的一种;
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烷硫基中的一种或多种;卤素选自氟、氯、溴或碘。
2.根据权利要求1所述的取代的吲唑甲酰胺或取代的氮杂吲唑甲酰胺类FLT3抑制剂,其特征在于,所述的G选自取代或未取代的C6-14芳基、取代或未取代的杂环烷基或取代或未取代的芳杂环。
3.根据权利要求1所述的取代的吲唑甲酰胺或取代的氮杂吲唑甲酰胺类FLT3抑制剂,其特征在于,所述的A为N或CR2,B为CR3,D和E各自独立的为CR4或CR5。
4.根据权利要求1所述的取代的吲唑甲酰胺或取代的氮杂吲唑甲酰胺类FLT3抑制剂,其特征在于,所述的R1为-L-Ra,L选自键、O、NH、C(O)NH、C(O)、NHC(O)、NHC(O)NH或亚甲基;Ra选自苯基、萘基、吡唑基、呋喃基、噻吩基、吡啶基、吡嗪基、嘧啶基、C3-8环状饱和烷基、四氢吡咯基、哌啶基、吗啉基、哌嗪基、吖丙啶基、吖丁啶基、-OH、-NH2、C1-6烷硫基、C1-6烷氧基、C1-6烷胺基中的一种;其中,苯基、萘基、吡唑基、呋喃基、噻吩基、吡啶基、吡嗪基、嘧啶基、C3-C8环状饱和烷基、四氢吡咯基、哌啶基、吗啉基、哌嗪基、吖丙啶基、吖丁啶基各自独立地任选被一个或多个Rf取代,Rf选自卤素或羟基;
G选自下列芳香环或芳香杂环中的一种:苯基、萘基、吡咯基、呋喃基、噻吩基、吡啶基、吡嗪基或嘧啶基,其中,上述芳香环或芳香杂环任选地被1或3个取代基取代,所述取代基各自独立的选自卤素、甲基、乙基、异丙基、甲氧基或三氟甲基;
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、C1-6烷基。
5.根据权利要求1所述的取代的吲唑甲酰胺或取代的氮杂吲唑甲酰胺类FLT3抑制剂,其特征在于,所述的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、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-甲氧基乙氧基、2-羟基乙基氨基、N,N-二(2-甲氧基乙基)氨基;
G选自下列芳香环或芳香杂环中的一种:苯基、萘基、吡啶基、吡嗪基或嘧啶基,其中,上述芳香环或芳香杂环任选地有1或2个取代基,取代基各自独立的选自卤素、甲基、乙基、异丙基、甲氧基或三氟甲基;
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、 C≡C-CH3或C≡CH,Re选自H、-CN、甲基、乙基、异丙基或丙基。
6.根据权利要求1所述的取代的吲唑甲酰胺或取代的氮杂吲唑甲酰胺类FLT3抑制剂,其特征在于,所述的化合物或其药学上可接受的盐,结构式如下所示:
7.根据权利要求1-6任一项所述的取代的吲唑甲酰胺或取代的氮杂吲唑甲酰胺类FLT3抑制剂,其特征在于,所述的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、杏仁酸。
8.一种药物组合物,其中含有权利要求1-7任一项所述的取代的吲唑甲酰胺或取代的氮杂吲唑甲酰胺类FLT3抑制剂化合物和药学上可接受的载体。
9.权利要求1-7任一项所述的取代的吲唑甲酰胺或取代的氮杂吲唑甲酰胺类FLT3抑制剂在制备用于预防或治疗与FLT3的激酶有关的临床病症的药物中的用途。
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