CN117886798A - 取代的苯并咪唑类化合物及其应用 - Google Patents
取代的苯并咪唑类化合物及其应用 Download PDFInfo
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- CN117886798A CN117886798A CN202311640324.7A CN202311640324A CN117886798A CN 117886798 A CN117886798 A CN 117886798A CN 202311640324 A CN202311640324 A CN 202311640324A CN 117886798 A CN117886798 A CN 117886798A
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- Prior art keywords
- substituted
- unsubstituted
- imidazol
- benzo
- diamine
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Abstract
本发明涉及医药领域,具体涉及取代的苯并咪唑类化合物及其应用,本发明的化合物对FLT3激酶具有显著的抑制活性,对FLT3激酶的IC50值最高达到了个位数纳摩尔级别,同时其对白血病细胞株MV4‑11也表现出了显著的抗增殖活性,该类化合物可作为新型强效的FLT3抑制剂,为靶向FLT3的新型抗肿瘤药物的研发奠定了基础。
Description
技术领域
本发明涉及医药领域,特别是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
根据病变细胞的类型,急性白血病分为急性髓细胞白血病(AML)和急性淋巴细胞白血病(ALL)。AML是一组异质性的原发性造血肿瘤,主要由细胞发育的髓系细胞引起。AML是成年患者中最常见的急性白血病,阿糖胞苷+蒽环类(7+3)强化化疗和低甲基化药物仍然是治疗AML的标准化疗药物。然而,这些药物往往会引起细胞毒性和不良预后。高达50%的患者未能通过初始治疗获得缓解,并继续发展为难治性AML。近几十年来,克隆性染色体畸变和分子突变已被认为是AML最重要的预后标志物。FLT3(FMS样酪氨酸激酶3,FLT3)属于III型受体酪氨酸激酶(RTK),在前体B细胞和造血干细胞的增殖和成熟中起重要作用。
FLT3的结构包含一个细胞外配体结合结构域(ECD)、一个跨膜结构域(TMD)、近膜结构域和一个高度保守的细胞内酪氨酸激酶结构域(TKD)。FLT3与FLT3配体的结合导致FLT3二聚化和自磷酸化,随后激活其下游信号通路,包括JAK/STAT5A、RAS/RAF/MEK,以及PI3K/AKT途径,其促进髓系细胞的增殖、存活和分化。一方面,在70%的AML患者中发现FLT3过表达。另一方面,约25%的AML病例中观察到近膜结构域(JMD)内的FLT3-ITD突变,这些突变与难治性疾病、复发风险增加和OS不良有关。此外,5%的AML患者具有FLT3-TKD突变。突变导致FLT3的配体非依赖性二聚化,并导致酪氨酸激酶的激活及其下游途径的激活,从而导致白血病细胞的异常增殖。目前,FLT3已成为AML治疗的重要靶点。
FLT3抑制剂在TKD的ATP结合位点与ATP竞争,从而阻止FLT3及其下游信号通路的功能。第一代FLT3抑制剂(索拉非尼、舒尼替尼、坦度替尼和米多他林)是一种多激酶抑制剂,最初并不是为了选择性靶向FLT3而开发的,但除了一系列其他酪氨酸激酶受体外,还阻断了FLT3。只有米多他林被批准用于AML联合化疗,其他药物未能达到临床意义的持久疗效。这促使开发了第二代FLT3抑制剂,包括喹唑替尼、克替诺尼和吉替替替尼。这些药物是专门针对突变FLT3激酶开发的,它们对FLT3激酶表现出高效力和特异性,并导致体内持续的FLT3抑制。这些药物更有利的药代动力学和更大的选择性有利于避免脱靶效应。到目前为止,喹唑替尼、克仑替尼和吉替替尼已被批准用于治疗AML。第二代FLT3抑制剂的成功证实了FLT3抑制剂研究的方向。本文报道了一系列基于2,4-二氨基-5-苯并咪唑的新型FLT3抑制剂,为开发针对FLT3的抗AML药物奠定了基础。
发明内容
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:
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C2-6烷硫基、取代或未取代的C2-6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;
R2是选自氢、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、取代或未取代的C6-14芳基、取代或未取代的芳杂环;
R3是选自氢、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C2-6烷硫基、取代或未取代的C2-6烷氧基、取代或未取代的C2-6烷胺基、取代或未取代的C2-6烯基、取代或未取代的C3-8杂环烷基;
取代或未取代指的是对应的官能团中具有或不具有取代基,所述取代基选自卤素、C1-6卤代烷基、羟基、胺基、C1-6烷基、C1-6烷氧基、C1-6烷胺基或C1-6烷硫基、杂环烷基中的一种或多种。
进一步地,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;
R3是选自氢、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。
进一步地,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;
R2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、取代或未取代的C3-8杂环烷基、取代或未取代的C6-14芳基、取代或未取代的芳杂环;
R3是选自氢、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。
进一步地,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;
C6-14芳基为具有6-14个碳原子的共轭环状结构;
芳杂环为具有6-14个碳原子的含有一个或多个选自O、N和S的共轭环状结构。
进一步地,L1选自键、O、NH、C(O)NH、C(O)、NHC(O)、NHC(O)NH或亚甲基;Ra是选自氟、氯、四氢吡咯基、哌啶基、N-甲基哌啶-4-基、吗啉基、N-甲基哌嗪基、N-乙基哌嗪基、N-异丙基哌嗪基、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;
R2是选自四氢吡咯基、四氢呋喃基、哌啶基、N-乙基哌嗪基、吗啉基、N-甲基哌嗪基、3-甲基哌啶-1-基、哌嗪基、4-羟基环己烷基、3-羟基环己烷基、4-羟基环戊烷基、环戊烯基、环己烯基、环庚烯基、氧杂环己烷、苯环、吡啶、吡唑、嘧啶、吡咯;
R3是选自氢、甲基、乙基、丙基、异丙基、丁基、环丙基;
进一步地,所述的化合物或其药学上可接受的盐,其结构选自:
(S)-N2-丁基-5-(5-氟-1H-苯并[d]咪唑-2-基)-N4-(哌啶-3-基)嘧啶-2,4-二胺(I-1);
N2-丁基-5-(5-氟-1H-苯并[d]咪唑-2-基)-N4-(哌啶-4-基)嘧啶-2,4-二胺(I-2);
(S)-N2-丁基-5-(5-氟-1H-苯并[d]咪唑-2-基)-N4-(吡咯烷-3-基)嘧啶-2,4-二胺(I-3);
(S)-1-(3-((2-(丁基氨基)-5-(5-氟-1H-苯并[d]咪唑-2-基)嘧啶-4-基)氨基)吡咯烷-1-基)丙-2-烯-1-酮(I-4);
N2-丁基-5-(5-氟-1H-苯并[d]咪唑-2-基)-N4-苯基嘧啶-2,4-二胺(I-5);
N4-(3-氨基苯基)-N2-丁基-5-(5-氟-1H-苯并[d]咪唑-2-基)嘧啶-2,4-二胺(I-6);
(S)-5-(5-氟-1H-苯并[d]咪唑-2-基)-N2-丙基-N4-(吡咯烷-3-基)嘧啶-2,4-二胺(I-7);
(S)-5-(5-氟-1H-苯并[d]咪唑-2-基)-N4-(哌啶-3-基)-N2-丙基嘧啶-2,4-二胺(I-8);
(S)-N2-乙基-5-(5-氟-1H-苯并[d]咪唑-2-基)-N4-(哌啶-3-基)嘧啶-2,4-二胺(I-9);
(S)-N2,N2-二乙基-5-(5-氟-1H-苯并[d]咪唑-2-基)-N4-(哌啶-3-基)嘧啶-2,4-二胺(I-10);
(S)-5-(5-氟-1H-苯并[d]咪唑-2-基)-N2-异丙基-N4-(哌啶-3-基)嘧啶-2,4-二胺(I-11);
(S)-N2-环丙基-5-(5-氟-1H-苯并[d]咪唑-2-基)-N4-(哌啶-3-基)嘧啶-2,4-二胺(I-12);
(S)-5-(5-(4-甲基哌嗪-1-基)-1H-苯并[d]咪唑-2-基)-N4-(哌啶-3-基)-N2-丙基嘧啶-2,4-二胺(I-13);
(S)-N2-环丙基-5-(5-(4-甲基哌嗪-1-基)-1H-苯并[d]咪唑-2-基)-N4-(哌啶-3-基)嘧啶-2,4-二胺(I-14);
(S)-5-(5-(哌嗪-1-基)-1H-苯并[d]咪唑-2-基)-N4-(哌啶-3-基)-N2-丙基嘧啶-2,4-二胺(I-15);
(S)-5-(5-吗啉基-1H-苯并[d]咪唑-2-基)-N4-(哌啶-3-基)-N2-丙基嘧啶-2,4-二胺(I-16);
(S)-N2-丁基-5-(5-(4-甲基哌嗪-1-基)-1H-苯并[d]咪唑-2-基)-N4-(哌啶-3-基)嘧啶-2,4-二胺(I-17);
(S)-N2-乙基-5-(5-(4-甲基哌嗪-1-基)-1H-苯并[d]咪唑-2-基)-N4-(哌啶-3-基)嘧啶-2,4-二胺(I-18);
(1s,4s)-4-((5-(5-(4-甲基哌嗪-1-基)-1H-苯并[d]咪唑-2-基)-2-(丙基氨基)嘧啶-4-基)氨基)环己烷-1-醇(I-19);
(1s,4s)-4-((5-(5-吗啉基-1H-苯并[d]咪唑-2-基)-2-(丙基氨基)嘧啶-4-基)氨基)环己烷-1-醇(I-20);
(1s,4s)-4-((2-(环丙基氨基)-5-(5-(4-甲基哌嗪-1-基)-1H-苯并[d]咪唑-2-基)嘧啶-4-基)氨基)环己烷-1-醇(I-21);
(R)-5-(5-(哌嗪-1-基)-1H-苯并[d]咪唑-2-基)-N4-(哌啶-3-基)-N2-丙基嘧啶-2,4-二胺(I-22)。
上述化合物的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:
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。
进一步地,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。
一种药物组合物,其中含有所述的化合物或其药学上可接受的盐。
所述的化合物或其药学上可接受的盐或者所述的药物组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。
进一步地,与FLT-3激酶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。
药理测试结果表明,本发明化合物对FLT3激酶具有较强的抑制活性,对其他激酶表现出一定的抑制活性,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
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。
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。
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。
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。
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。
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。
4-(3-氨基-4-硝基苯基)哌嗪-1-羧酸叔丁酯(1f)
以5-氟-2-硝基苯胺(6.0g,0.0384mol)和哌嗪-1-羧酸叔丁酯(28.56g,0.1536mol)为原料,制备方法同1a,得黄色固体1f(10.5g),收率85.2%,MS[M+H]+:323.20。产品无需进一步纯化,直接进行下一步反应。
4-(3,4-二氨基苯基)哌嗪-1-羧酸叔丁酯(1g)
以1f(11.8g,0.0364mol)为原料,制备方法同1b,得黑紫色固体1g(8.0g),收率75.1%,MS[M+H]+:293.26。产品无需进一步纯化,直接进行下一步反应。
(S)-4-((1-(叔丁氧基羰基)哌啶-3-基)氨基)-2-氯嘧啶-5-羧酸乙酯(1h)
在150mL单颈瓶中加入2,4-二氯嘧啶-5-羧酸乙酯(2.19g,0.010mol)和(S)-3-氨基哌啶-1-甲酸叔丁酯(2.00g,0.010mol),然后加入50mL异丙醇使其溶解,随后向混合物中加入DIPEA(3.88g,0.030mol),加毕在室温下搅拌4h,TLC检测原料消失(石油醚∶乙酸乙酯=6∶1)。反应结束后减压浓缩,制砂,通过柱层析色谱纯化得1h(3.23g),收率84.1%,MS[M+H]+:385.20。
4-((1-(叔丁氧羰基)哌啶-4-基)氨基)-2-氯嘧啶-5-羧酸乙酯(1i)
以2,4-二氯嘧啶-5-羧酸乙酯(2.19g,0.010mol)和4-氨基哌啶-1-甲酸叔丁酯(2.00g,0.010mol)为原料,制备方法同1h,得白色固体1i(3.08g),收率80.1%,MS[M+H]+:385.16。产品无需进一步纯化,直接进行下一步反应。
(S)-4-((1-(叔丁氧基羰基)吡咯烷-3-基)氨基)-2-氯嘧啶-5-羧酸乙酯(1j)
以2,4-二氯嘧啶-5-羧酸乙酯(2.19g,0.010mol)和(S)-3-氨基吡咯烷-1-甲酸叔丁酯(1.86g,0.010mol)为原料,制备方法同1h,得白色固体1j(2.57g),收率69.4%,MS[M+H]+:371.19。
2-氯-4-(((1r,4r)-4-羟基环己基)氨基)嘧啶-5-羧酸乙酯(1k)
以2,4-二氯嘧啶-5-羧酸乙酯(2.19g,0.010mol)和4-氨基环己烷-1-醇(1.15g,0.010mol)为原料,制备方法同1h,得白色固体1k(1.93g),收率64.2%,MS[M+H]+:300.20。
2-氯-4-(苯基氨基)嘧啶-5-羧酸乙酯(1l)
以2,4-二氯嘧啶-5-羧酸乙酯(2.19g,0.010mol)和苯胺(0.93g,0.010mol)为原料,制备方法同1h,得淡黄色固体1l(1.60g),收率55.8%,MS[M+H]+:287.10。
2-氯-4-((3-硝基苯基)氨基)嘧啶-5-羧酸乙酯(1m)
以2,4-二氯嘧啶-5-羧酸乙酯(2.19g,0.010mol)和3-硝基苯胺(1.38g,0.010mol)为原料,制备方法同1h,得淡黄色固体1m(1.13g),收率34.9%,MS[M+H]+:323.10。
(R)-4-((1-(叔丁氧基羰基)哌啶-3-基)氨基)-2-氯嘧啶-5-羧酸乙酯(1n)
以2,4-二氯嘧啶-5-羧酸乙酯(2.19g,0.010mol)和(R)-3-氨基哌啶-1-甲酸叔丁酯(2.00g,0.010mol)为原料,制备方法同1h,得淡黄色固体1n(1.62g),收率42.11%,MS[M+H]+:385.19。
(S)-4-((1-(叔丁氧基羰基)哌啶-3-基)氨基)-2-(丁基氨基)嘧啶-5-羧酸乙酯(2a)
在150mL单颈瓶中加入1h(1.93g,0.005mol)和正丁胺(1.09g,0.015mol),然后加入50mL无水二氯甲烷,加毕在室温下搅拌24h,TLC检测原料消失(石油醚∶乙酸乙酯=4∶1)。反应结束后减压浓缩,制砂,通过柱层析色谱纯化得白色固体2a(1.45g),收率69.1%,MS[M+H]+:422.30。
(S)-4-((1-(叔丁氧基羰基)哌啶-3-基)氨基)-2-(丁基氨基)嘧啶-5-羧酸乙酯(2b)
以1i(1.93g,0.005mol)和正丁胺(1.09g,0.015mol)为原料,制备方法同2a,得白色固体2b(1.58g),收率74.9%,MS[M+H]+:422.33。
(S)-4-((1-(叔丁氧基羰基)吡咯烷-3-基)氨基)-2-(丁基氨基)嘧啶-5-羧酸乙酯(2c)
以1j(1.86g,0.005mol)和正丁胺(1.09g,0.015mol)为原料,制备方法同2a,得白色固体2c(1.64g),收率80.1%,MS[M+H]+:408.30。
2-(丁基氨基)-4-(苯基氨基)嘧啶-5-羧酸乙酯(2d)
以1l(1.44g,0.005mol)和正丁胺(1.09g,0.015mol)为原料,制备方法同2a,得白色固体2d(1.18g),收率75.1%,MS[M+H]+:315.11。
2-(丁基氨基)-4-((3-硝基苯基)氨基)嘧啶-5-羧酸乙酯(2e)
以1m(1.61g,0.005mol)和正丁胺(1.09g,0.015mol)为原料,制备方法同2a,得白色固体2e(1.12g),收率62.1%,MS[M+H]+:360.21。
(S)-4-((1-(叔丁氧基羰基)吡咯烷-3-基)氨基)-2-(丙基氨基)嘧啶-5-羧酸乙酯(2f)
以1j(1.86g,0.005mol)和正丙胺(0.89g,0.015mol)为原料,制备方法同2a,得白色固体2f(1.52g),收率77.1%,MS[M+H]+:394.28。
(S)-4-((1-(叔丁氧基羰基)哌啶-3-基)氨基)-2-(丙基氨基)嘧啶-5-羧酸乙酯(2g)
以1h(1.93g,0.005mol)和正丙胺(0.89g,0.015mol)为原料,制备方法同2a,得白色固体2g(1.76g),收率86.3%,MS[M+H]+:408.29。
(S)-4-((1-(叔丁氧基羰基)哌啶-3-基)氨基)-2-(乙基氨基)嘧啶-5-羧酸乙酯(2h)
以1h(1.93g,0.005mol)和乙胺(0.68g,0.015mol)为原料,制备方法同2a,得白色固体2h(1.67g),收率84.9%,MS[M+H]+:394.22。
(S)-4-((1-(叔丁氧基羰基)吡咯烷-3-基)氨基)-2-(二乙基氨基)嘧啶-5-羧酸乙酯(2i)
以1j(1.86g,0.005mol)和二乙胺(1.09g,0.015mol)为原料,制备方法同2a,得白色固体2i(1.81g),收率88.6%,MS[M+H]+:408.26。
(S)-4-((1-(叔丁氧基羰基)哌啶-3-基)氨基)-2-(异丙基氨基)嘧啶-5-羧酸乙酯(2j)
以1h(1.93g,0.005mol)和异丙胺(0.89g,0.015mol)为原料,制备方法同2a,得白色固体2j(1.64g),收率80.6%,MS[M+H]+:408.29。
(S)-4-((1-(叔丁氧基羰基)哌啶-3-基)氨基)-2-(环丙基氨基)嘧啶-5-羧酸乙酯(2k)
以1h(1.93g,0.005mol)和环丙胺(0.88g,0.015mol)为原料,制备方法同2a,得白色固体2k(1.77g),收率87.2%,MS[M+H]+:406.22。
2-(环丙基氨基)-4-(((1r,4r)-4-羟基环己基)氨基)嘧啶-5-羧酸乙酯(2l)
以1k(1.93g,0.005mol)和环丙胺(0.88g,0.015mol)为原料,制备方法同2a,得白色固体2l(1.06g),收率66.3%,MS[M+H]+:321.20。
4-(((1r,4r)-4-羟基环己基)氨基)-2-(丙基氨基)嘧啶-5-羧酸乙酯(2m)
以1k(1.93g,0.005mol)和正丙胺(0.89g,0.015mol)为原料,制备方法同2a,得白色固体2m(1.12g),收率69.6%,MS[M+H]+:323.24。
(R)-4-((1-(叔丁氧基羰基)哌啶-3-基)氨基)-2-(丙基氨基)嘧啶-5-羧酸乙酯(2n)
以1n(1.92g,0.005mol)和正丙胺(0.89g,0.015mol)为原料,制备方法同2a,得白色固体2n(1.12g),收率69.6%,MS[M+H]+:385.19。
(S)-4-((1-(叔丁氧基羰基)哌啶-3-基)氨基)-2-(丁基氨基)嘧啶-5-羧酸(3a)
在150mL单颈瓶中加入2a(0.84g,0.002mol),然后加入10mL的水(含0.01g氢氧化钾)和10ml甲醇,随后升温至90℃,15min后,TLC检测原料消失(二氯甲烷∶甲醇=30∶1)。反应结束后冷却至室温,在冰水浴下用10%的盐酸调PH 4-5,有白色沉淀析出,抽滤,滤渣干燥,得白色固体3a(0.71g),收率90.9%,MS[M+H]+:393.29。产品无需进一步纯化,直接进行下一步反应。
4-((1-(叔丁氧羰基)哌啶-4-基)氨基)-2-(丁基氨基)嘧啶-5-羧酸(3b)
以2b(0.84g,0.002mol)为原料,制备方法同3a,得白色固体3b(0.74g),收率94.2%,MS[M+H]+:393.22。
(S)-4-((1-(叔丁氧基羰基)吡咯烷-3-基)氨基)-2-(丁基氨基)嘧啶-5-羧酸(3c)
以2c(0.82g,0.002mol)为原料,制备方法同3a,得白色固体3c(0.70g),收率92.7%,MS[M+H]+:380.25。
2-(丁基氨基)-4-(苯基氨基)嘧啶-5-羧酸(3d)
以2d(0.63g,0.002mol)为原料,制备方法同3a,得白色固体3d(0.51g),收率88.6%,MS[M+H]+:287.19。
2-(丁基氨基)-4-((3-硝基苯基)氨基)嘧啶-5-羧酸(3e)
以2e(0.72g,0.002mol)为原料,制备方法同3a,得白色固体3e(0.70g),收率90.2%,MS[M+H]+:332.18。
(S)-4-((1-(叔丁氧基羰基)吡咯烷-3-基)氨基)-2-(丙基氨基)嘧啶-5-羧酸(3f)
以2f(0.79g,0.002mol)为原料,制备方法同3a,得白色固体3f(0.65g),收率88.9%,MS[M+H]+:366.25。
(S)-4-((1-(叔丁氧基羰基)哌啶-3-基)氨基)-2-(丙基氨基)嘧啶-5-羧酸(3g)
以2g(0.81g,0.002mol)为原料,制备方法同3a,得白色固体3g(0.71g),收率93.5%,MS[M+H]+:380.23。
(S)-4-((1-(叔丁氧基羰基)哌啶-3-基)氨基)-2-(乙基氨基)嘧啶-5-羧酸(3h)
以2h(0.79g,0.002mol)为原料,制备方法同3a,得白色固体3h(0.68g),收率92.7%,MS[M+H]+:366.24。
(S)-4-((1-(叔丁氧基羰基)吡咯烷-3-基)氨基)-2-(二乙基氨基)嘧啶-5-羧酸(3i)
以2i(0.82g,0.002mol)为原料,制备方法同3a,得白色固体3i(0.69g),收率91.5%,MS[M+H]+:380.29。
(S)-4-((1-(叔丁氧基羰基)哌啶-3-基)氨基)-2-(异丙基氨基)嘧啶-5-羧酸(3j)
以2j(0.82g,0.002mol)为原料,制备方法同3a,得白色固体3j(0.68g),收率89.3%,MS[M+H]+:380.23。
(S)-4-((1-(叔丁氧基羰基)哌啶-3-基)氨基)-2-(环丙基氨基)嘧啶-5-羧酸(3k)
以2k(0.81g,0.002mol)为原料,制备方法同3a,得白色固体3k(0.68g),收率90.1%,MS[M+H]+:378.21。
2-(环丙基氨基)-4-(((1r,4r)-4-羟基环己基)氨基)嘧啶-5-羧酸(3l)
以2l(0.64g,0.002mol)为原料,制备方法同3a,得白色固体3l(0.51g),收率87.6%,MS[M+H]+:293.20。
4-(((1r,4r)-4-羟基环己基)氨基)-2-(丙基氨基)嘧啶-5-羧酸(3m)
以2m(0.65g,0.002mol)为原料,制备方法同3a,得白色固体3m(0.53g),收率89.6%,MS[M+H]+:295.20。
(R)-4-((1-(叔丁氧基羰基)哌啶-3-基)氨基)-2-(丙基氨基)嘧啶-5-羧酸(3n)
以2n(0.82g,0.002mol)为原料,制备方法同3a,得白色固体3n(0.67g),收率88.35%,MS[M+H]+:380.25。
实施例1:
(S)-N2-丁基-5-(5-氟-1H-苯并[d]咪唑-2-基)-N4-(哌啶-3-基)嘧啶-2,4-二胺(I-1)
在25ml单颈瓶中加入3a(393mg,1.0mmol)和1e(140mg,1.1mmol),加入15ml无水DMF使之溶解,随后加入EDCI(210mg,1.1mmol)、HoBt(203mg,1.5mmol)和DIPEA(387mg,3.0mmol)。常温反应24h,TLC检测原料消失(甲醇:二氯甲烷=1:15)。反应结束后,在反应液中加水,析出沉淀,抽滤得滤渣,滤渣烘干后将滤渣置于100ml单颈瓶中,升温至110℃反应5h,随后用10%的NaOH溶液调PH至7,析出固体,抽滤,滤渣制砂,通过柱层析色谱纯化得白色固体Ⅰ-1(85.7mg),收率22.3%,1H NMR(500MHz,DMSO)δ13.22(s,1H),10.58(s,1H),8.86(s,1H),8.66(s,1H),7.60(s,1H),7.42(d,J=7.9Hz,1H),7.12(t,J=8.6Hz,1H),4.42(s,1H),3.54–3.39(m,2H),3.29–2.96(m,4H),2.15(s,1H),2.00(s,1H),1.83(s,2H),1.66–1.49(m,2H),1.38(dd,J=14.6,7.3Hz,2H),0.93(t,J=7.3Hz,3H).MS[M+H]+:384.26。
实施例2:
N2-丁基-5-(5-氟-1H-苯并[d]咪唑-2-基)-N4-(哌啶-4-基)嘧啶-2,4-二胺(I-2)
以3b(393mg,1.0mmol)和1e(140mg,1.1mmol)为原料,制备方法同Ⅰ-1,经柱层析得白色固体Ⅰ-2(98.3mg),收率25.6%,1H NMR(500MHz,MeOD)δ8.43(s,1H),7.50(s,1H),7.24(s,1H),7.01(td,J=9.2,2.5Hz,1H),4.45(s,1H),3.57–3.40(m,4H),3.29–3.19(m,2H),2.44–2.35(m,2H),2.01–1.86(m,2H),1.64(p,J=7.3Hz,2H),1.51–1.40(m,2H),0.98(q,J=7.6Hz,3H).MS[M+H]+:384.21。
实施例3:
(S)-N2-丁基-5-(5-氟-1H-苯并[d]咪唑-2-基)-N4-(吡咯烷-3-基)嘧啶-2,4-二胺(I-3)
以3c(380mg,1.0mmol)和1e(140mg,1.1mmol)为原料,制备方法同Ⅰ-1,经柱层析得固体Ⅰ-3(93.6mg),收率25.3%,1H NMR(500MHz,DMSO)δ13.26(s,1H),10.73(s,1H),9.14(s,1H),8.67(s,1H),7.62(s,1H),7.44(d,J=7.4Hz,1H),7.12(t,J=8.6Hz,1H),4.78(d,J=5.3Hz,1H),3.64(s,1H),3.38(d,J=63.0Hz,5H),3.17(s,1H),2.13(dd,J=13.1,6.4Hz,1H),1.71–1.46(m,2H),1.39(dd,J=14.6,7.3Hz,2H),0.94(t,J=7.3Hz,2H).MS[M+H]+:370.29。
实施例4:
(S)-1-(3-((2-(丁基氨基)-5-(5-氟-1H-苯并[d]咪唑-2-基)嘧啶-4-基)氨基)吡咯烷-1-基)丙-2-烯-1-酮(I-4)
在50ml单颈瓶中加入I-3(37mg,0.1mmol)和3滴DMF,然后加入丙烯酰氯(140mg,1.1mmol),常温反应2h,TLC检测原料消失(甲醇:二氯甲烷=1:15)。反应结束后,在反应液中加水,析出固体,抽滤,滤渣制砂,通过柱层析色谱纯化得白色固体Ⅰ-4(37.9mg),收率88.6%,1H NMR(500MHz,DMSO-d6)δ12.98(s,1H),10.24(d,J=129.2Hz,1H),8.62(d,J=19.5Hz,1H),7.88(s,1H),7.52(s,1H),7.34(s,1H),7.06(s,1H),6.85–6.46(m,1H),6.18(s,1H),5.69(s,1H),4.12–3.60(m,4H),3.18(d,J=18.6Hz,2H),2.44–1.83(m,3H),1.56(s,2H),1.36(s,2H),1.04–0.78(m,3H).MS[M+H]+:424.28。
实施例5:
N2-丁基-5-(5-氟-1H-苯并[d]咪唑-2-基)-N4-苯基嘧啶-2,4-二胺(I-5)
以3d(150mg,1.0mmol)和1e(140mg,1.1mmol)为原料,制备方法同Ⅰ-1,经柱层析得固体Ⅰ-5(56.5mg),收率15.0%,1H NMR(500MHz,MeOD)δ8.45(s,1H),7.83(d,J=7.9Hz,2H),7.48(d,J=14.4Hz,1H),7.32(t,J=7.7Hz,3H),7.06(t,J=7.4Hz,1H),6.95(td,J=9.3,2.4Hz,1H),3.37(t,J=7.4Hz,2H),1.63(p,J=7.4Hz,2H),1.51–1.37(m,2H),0.97(q,J=7.4Hz,3H).MS[M+H]+:377.22。
实施例6:
N4-(3-氨基苯基)-N2-丁基-5-(5-氟-1H-苯并[d]咪唑-2-基)嘧啶-2,4-二胺(I-6)
在25ml单颈瓶中加入3d(150mg,1.0mmol)和1m(355mg,1.1mmol),加入15ml无水DMF使之溶解,随后加入EDCI(210mg,1.1mmol)、HoBt(203mg,1.5mmol)和DIPEA(387mg,3.0mmol)。常温反应24h,TLC检测原料消失(甲醇:二氯甲烷=1:15)。反应结束后,在反应液中加水,析出沉淀,抽滤得滤渣,滤渣烘干后将滤渣置于100ml单颈瓶中,升温至110℃反应5h,随后用10%的NaOH溶液调PH至7,析出固体,抽滤,滤渣烘干后用甲醇溶解,然后加入钯炭(0.1g),通入氢气,常温反应4h,反应结束后抽滤,滤液浓缩后通过柱层析色谱纯化得白色固体Ⅰ-6(48.2mg),收率12.3%;1H NMR(500MHz,DMSO)δ12.87(d,J=18.1Hz,1H),11.88(d,J=69.7Hz,1H),8.71(s,1H),7.60(m,2H),7.19(m,3H),7.00(t,J=8.0Hz,1H),6.32(d,J=8.1Hz,1H),5.27(s,2H),1.57(d,J=6.1Hz,2H),1.37(dd,J=14.7,7.3Hz,2H),0.92(t,J=7.4Hz,3H).MS[M+H]+:392.28。
实施例7:
(S)-5-(5-氟-1H-苯并[d]咪唑-2-基)-N2-丙基-N4-(吡咯烷-3-基)嘧啶-2,4-二胺(I-7)
以3f(366mg,1.0mmol)和1e(140mg,1.1mmol)为原料,制备方法同Ⅰ-1,经柱层析得固体Ⅰ-7(59.9mg),收率16.4%;1H NMR(500MHz,DMSO)δ12.83(s,1H),9.76(s,1H),9.05(s,1H),8.63(s,1H),7.70–7.32(m,2H),7.07–6.92(m,1H),4.67(s,1H),3.53(d,J=88.5Hz,2H),3.32–3.16(m,4H),2.45(s,1H),2.06(dd,J=13.4,6.5Hz,1H),1.57(dd,J=14.1,7.1Hz,2H),0.92(t,J=7.2Hz,3H).MS[M+H]+:356.25。
实施例8:
(S)-5-(5-氟-1H-苯并[d]咪唑-2-基)-N4-(哌啶-3-基)-N2-丙基嘧啶-2,4-二胺(I-8)
以3g(380mg,1.0mmol)和1e(140mg,1.1mmol)为原料,制备方法同Ⅰ-1,经柱层析得白色固体Ⅰ-8(68.1mg),收率18.4%。1H NMR(500MHz,MeOD)δ8.45(s,1H),7.47(dd,J=7.9,4.4Hz,1H),7.22(d,J=8.5Hz,1H),7.04–6.82(m,1H),4.46(s,1H),3.58(d,J=11.1Hz,1H),3.38(s,2H),3.10-3.29(m,3H),2.41–2.10(m,2H),1.71–1.57(m,2H),0.99(q,J=7.8Hz,3H),0.88(m,1H).MS[M+H]+:370.25。
实施例9:
(S)-N2-乙基-5-(5-氟-1H-苯并[d]咪唑-2-基)-N4-(哌啶-3-基)嘧啶-2,4-二胺(I-9)
以3h(366mg,1.0mmol)和1e(140mg,1.1mmol)为原料,制备方法同Ⅰ-1,经柱层析得固体Ⅰ-9(70.1mg),收率19.7%,1H NMR(500MHz,MeOD)δ8.45(s,1H),7.47(s,1H),7.22(d,J=6.1Hz,1H),6.98(td,J=9.3,2.4Hz,1H),4.49(d,J=10.3Hz,1H),3.61(dd,J=12.3,3.7Hz,1H),3.51–3.42(m,2H),3.34(t,J=4.9Hz,1H),3.25(dd,J=12.3,8.4Hz,1H),3.16(ddd,J=12.9,9.4,3.6Hz,1H),2.26–2.11(m,2H),2.05–1.88(m,2H),1.25(q,J=7.4Hz,3H).MS[M+H]+:356.25。
实施例10:
(S)-N2,N2-二乙基-5-(5-氟-1H-苯并[d]咪唑-2-基)-N4-(哌啶-3-基)嘧啶-2,4-二胺(I-10)
以3i(380mg,1.0mmol)和1e(140mg,1.1mmol)为原料,制备方法同Ⅰ-1,经柱层析得固体Ⅰ-10(62.6mg),收率16.9%,1H NMR(500MHz,MeOD)δ8.50(s,1H),7.53(dd,J=8.1,4.4Hz,1H),7.28(d,J=8.4Hz,1H),7.02(td,J=9.5,2.2Hz,1H),3.83–3.55(m,7H),3.54–3.40(m,2H),2.59(dq,J=14.6,7.3Hz,1H),2.32(td,J=13.4,6.9Hz,1H),1.28(t,J=7.0Hz,6H).MS[M+H]+:370.25。
实施例11:
(S)-5-(5-氟-1H-苯并[d]咪唑-2-基)-N2-异丙基-N4-(哌啶-3-基)嘧啶-2,4-二胺(I-11)
以3j(380mg,1.0mmol)和1e(140mg,1.1mmol)为原料,制备方法同Ⅰ-1,经柱层析得固体Ⅰ-11(63.4mg),收率17.4%,1H NMR(500MHz,MeOD)δ8.45(s,1H),7.48(s,0H),7.23–7.21(m,0H),6.99(td,J=9.3,2.5Hz,1H),4.60–4.48(m,1H),4.21(s,1H),3.61(dd,J=12.6,3.6Hz,1H),3.35(s,1H),3.29–3.20(m,1H),3.21–3.12(m,1H),2.27–2.12(m,2H),2.02–1.86(m,2H),1.27(dd,J=6.5,3.3Hz,6H).MS[M+H]+:370.20。
实施例12:
(S)-N2-环丙基-5-(5-氟-1H-苯并[d]咪唑-2-基)-N4-(哌啶-3-基)嘧啶-2,4-二胺(I-12)
以3k(378mg,1.0mmol)和1e(140mg,1.1mmol)为原料,制备方法同Ⅰ-1,经柱层析得固体Ⅰ-12(53.0mg),收率14.4%,1H NMR(500MHz,MeOD)δ8.45(s,1H),7.47(dd,J=8.6,4.6Hz,1H),7.22(dd,J=9.0,1.8Hz,1H),6.97(td,J=9.6,2.3Hz,1H),4.34(s,1H),3.51(d,J=9.0Hz,1H),3.15(dd,J=12.6,4.5Hz,1H),3.05–2.91(m,2H),2.77(s,1H),2.21(d,J=8.9Hz,1H),2.08–2.00(m,1H),1.82(dd,J=17.5,8.9Hz,2H),0.83–0.77(m,2H),0.55(dd,J=9.5,3.6Hz,2H).MS[M+H]+:368.26。
实施例13:
(S)-5-(5-(4-甲基哌嗪-1-基)-1H-苯并[d]咪唑-2-基)-N4-(哌啶-3-基)-N2-丙基嘧啶-2,4-二胺(I-13)
以3g(380mg,1.0mmol)和1d(228mg,1.1mmol)为原料,制备方法同Ⅰ-1,经柱层析得固体Ⅰ-13(79.7mg),收率17.7%,1H NMR(500MHz,MeOD)δ8.44(s,1H),7.46(d,J=8.6Hz,1H),7.15(d,J=2.2Hz,1H),7.03(dd,J=8.7,2.3Hz,1H),4.48(s,1H),3.69–3.58(m,2H),3.51(q,J=7.2Hz,2H),3.41(s,4H),3.35–3.31(m,4H),2.88(d,J=8.7Hz,3H),2.32–2.09(m,2H),1.99–1.89(m,2H),1.72–1.54(m,2H),1.26–1.16(m,2H),1.00(t,J=7.4Hz,3H).MS[M+H]+:450.36。
实施例14:
(S)-N2-环丙基-5-(5-(4-甲基哌嗪-1-基)-1H-苯并[d]咪唑-2-基)-N4-(哌啶-3-基)嘧啶-2,4-二胺(I-14)
以3k(378mg,1.0mmol)和1d(228mg,1.1mmol)为原料,制备方法同Ⅰ-1,经柱层析得固体Ⅰ-14(62.7mg),收率14.0%,MS[M+H]+:448.30。
实施例15:
(S)-5-(5-(哌嗪-1-基)-1H-苯并[d]咪唑-2-基)-N4-(哌啶-3-基)-N2-丙基嘧啶-2,4-二胺(I-15)
以3g(380mg,1.0mmol)和1g(322mg,1.1mmol)为原料,制备方法同Ⅰ-1,经柱层析得固体Ⅰ-15(64.1mg),收率14.7%,1H NMR(500MHz,MeOD)δ8.43(s,1H),7.46(d,J=8.6Hz,1H),7.14(s,1H),7.05–6.97(m,1H),4.45(s,1H),3.57(d,J=11.6Hz,1H),3.38(s,2H),3.29–3.19(m,7H),3.12(dt,J=9.6,7.9Hz,2H),2.29–2.10(m,2H),2.02(s,1H),1.92(s,2H),1.65(dd,J=14.5,7.3Hz,2H),1.24(t,J=7.1Hz,1H),1.00(t,J=7.4Hz,3H).MS[M+H]+:436.32。
实施例16:
(S)-5-(5-吗啉基-1H-苯并[d]咪唑-2-基)-N4-(哌啶-3-基)-N2-丙基嘧啶-2,4-二胺(I-16)
以3g(380mg,1.0mmol)和1b(214mg,1.1mmol)为原料,制备方法同Ⅰ-1,经柱层析得固体Ⅰ-16(68.2mg),收率15.6%,1H NMR(500MHz,MeOD)δ8.42(s,1H),7.43(d,J=8.9Hz,1H),7.07(s,1H),6.99(dd,J=8.7,2.2Hz,1H),4.46(td,J=8.2,4.1Hz,1H),3.90–3.83(m,4H),3.58(dd,J=12.6,3.6Hz,1H),3.43–3.35(m,2H),3.18(t,J=4.4Hz,1H),3.13(d,J=4.6Hz,4H),2.30–2.12(m,2H),1.98–1.84(m,2H),1.63(dd,J=14.5,7.3Hz,2H),0.99(q,J=7.6Hz,3H),0.92–0.76(m,1H).MS[M+H]+:437.31。
实施例17:
(S)-N2-丁基-5-(5-(4-甲基哌嗪-1-基)-1H-苯并[d]咪唑-2-基)-N4-(哌啶-3-基)嘧啶-2,4-二胺(I-17)
以3a(393mg,1.0mmol)和1d(228mg,1.1mmol)为原料,制备方法同Ⅰ-1,经柱层析得固体Ⅰ-17(70.5mg),收率15.2%,1H NMR(500MHz,DMSO)δ12.41(s,1H),9.76(d,J=33.5Hz,1H),8.58(s,1H),7.35(d,J=40.6Hz,1H),7.10(d,J=55.6Hz,1H),6.88(s,2H),4.26(s,1H),4.04(dd,J=14.2,7.2Hz,1H),3.90(s,1H),3.39(d,J=9.9Hz,2H),3.17(s,4H),2.87(s,2H),2.25(s,3H),2.09(s,1H),2.00-1.90(s,2H),1.67(s,2H),1.60–1.46(m,2H),1.36(d,J=6.9Hz,2H),1.20(dd,J=21.4,14.2Hz,1H),1.11(t,J=6.9Hz,2H),0.92(t,J=7.2Hz,3H).MS[M+H]+:464.33。
实施例18:
(S)-N2-乙基-5-(5-(4-甲基哌嗪-1-基)-1H-苯并[d]咪唑-2-基)-N4-(哌啶-3-基)嘧啶-2,4-二胺(I-18)
以3h(366mg,1.0mmol)和1d(228mg,1.1mmol)为原料,制备方法同Ⅰ-1,经柱层析得固体Ⅰ-18(26.97mg),收率14.5%,1H NMR(500MHz,MeOD)δ8.43(s,1H),7.45(d,J=8.7Hz,1H),7.12(s,1H),7.01(dd,J=8.7,2.0Hz,1H),3.62(dd,J=16.5,7.2Hz,2H),3.45(dd,J=14.1,7.0Hz,2H),3.33(s,4H),3.22–3.18(m,1H),3.09(m,,4H),2.68(s,3H),2.23–2.12(m,2H),1.98–1.88(m,2H),1.35–1.28(m,2H),1.24(t,J=7.2Hz,3H).MS[M+H]+:436.25。
实施例19:
(1s,4s)-4-((5-(5-(4-甲基哌嗪-1-基)-1H-苯并[d]咪唑-2-基)-2-(丙基氨基)嘧啶-4-基)氨基)环己烷-1-醇(I-19)
以3m(295mg,1.0mmol)和1d(228mg,1.1mmol)为原料,制备方法同Ⅰ-1,经柱层析得固体Ⅰ-19(60.9mg),收率13.1%,1H NMR(500MHz,MeOD)δ8.38(s,1H),7.50(d,J=6.7Hz,1H),7.18(s,1H),7.06(d,J=8.9Hz,1H),4.13(ddd,J=10.5,6.5,4.1Hz,1H),3.93–3.85(m,2H),3.70(dt,J=14.0,4.8Hz,1H),3.45(s,8H),3.24–3.21(m,2H),2.95(s,3H),2.21(d,J=10.8Hz,2H),2.05(d,J=10.4Hz,2H),1.75–1.65(m,2H),1.58–1.45(m,2H),1.01(t,J=7.4Hz,3H).MS[M+H]+:465.34。
实施例20:
(1s,4s)-4-((5-(5-吗啉基-1H-苯并[d]咪唑-2-基)-2-(丙基氨基)嘧啶-4-基)氨基)环己烷-1-醇(I-20)
以3m(295mg,1.0mmol)和1b(214mg,1.1mmol)为原料,制备方法同Ⅰ-1,经柱层析得灰白色固体Ⅰ-20(53.3mg),收率11.8%。1H NMR(500MHz,MeOD)δ8.31(s,1H),7.43(d,J=9.0Hz,1H),7.06(s,1H),6.98(dd,J=8.8,2.2Hz,1H),4.13–4.05(m,1H),3.91–3.84(m,4H),3.68(dt,J=9.9,5.1Hz,1H),3.36(t,J=7.1Hz,2H),3.16–3.10(m,4H),2.20(t,J=7.1Hz,2H),2.04(dd,J=9.2,5.0Hz,2H),1.66(h,J=7.3Hz,2H),1.57–1.40(m,4H),1.38–1.24(m,2H),0.99(q,J=7.3Hz,3H),0.95–0.84(m,1H).MS[M+H]+:452.30。
实施例21:
(1s,4s)-4-((2-(环丙基氨基)-5-(5-(4-甲基哌嗪-1-基)-1H-苯并[d]咪唑-2-基)嘧啶-4-基)氨基)环己烷-1-醇(I-21)
以3l(293mg,1.0mmol)和1d(228mg,1.1mmol)为原料,制备方法同Ⅰ-1,经柱层析得固体Ⅰ-21(59.3mg),收率12.8%,1H NMR(500MHz,MeOD)δ8.38(s,1H),7.46(s,1H),7.04(s,1H),4.11(s,1H),3.80–3.58(m,1H),3.38(s,4H),3.25(s,4H),2.82(s,3H),2.21(s,2H),2.03(d,J=11.0Hz,2H),1.47(tt,J=25.1,12.4Hz,4H),1.35(t,J=7.3Hz,2H),0.82(d,J=5.6Hz,1H),0.60(s,2H).MS[M+H]+:463.32。
实施例22:
(R)-5-(5-(哌嗪-1-基)-1H-苯并[d]咪唑-2-基)-N4-(哌啶-3-基)-N2-丙基嘧啶-2,4-二胺(I-22)
以3n(380mg,1.0mmol)和1d(228mg,1.1mmol)为原料,制备方法同Ⅰ-1,经柱层析得固体Ⅰ-22(96.3mg),收率20.14%,1H NMR(500MHz,MeOD)δ8.45(s,1H),7.46(d,J=8.6Hz,1H),7.15(d,J=2.2Hz,1H),7.03(dd,J=8.7,2.3Hz,1H),4.48(s,1H),3.69–3.58(m,2H),3.51(q,J=7.2Hz,2H),3.42(s,4H),3.35–3.30(m,4H),2.88(d,J=8.7Hz,3H),2.32–2.09(m,2H),1.99–1.89(m,2H),1.72–1.54(m,2H),1.26–1.16(m,2H),1.00(t,J=7.4Hz,3H).MS[M+H]+:450.39。
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%,1μM)
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MTS法检测了目标化合物在白血病HL-60、肺癌A549、肝癌SMMC-7721、乳腺癌MDA-MB-231和结肠癌SW480细胞中的抗肿瘤效果。
实验方法:
1.接种细胞:用含10%胎牛血清的培养液(DMEM或者RMPI1640)配成单个细胞悬液,以每孔3000~15000个细胞接种到96孔板,每孔体积100μl,细胞提前12~24小时接种培养。
2.加入待测化合物溶液:化合物用DMSO溶解,化合物以40、8、1.6、0.32、0.064、0.0128、0.00256、0.000512μM浓度复筛,各化合物的具体筛选浓度详见复筛数据,每孔终体积200μl,每种处理均设3个复孔。
3.显色:37摄氏度培养48小时后,贴壁细胞弃孔内培养液,每孔加MTS溶液20μl和培养液100μl;悬浮细胞弃100μl培养上清液,每孔加20μl的MTS溶液;设3个空白复孔(MTS溶液20μl和培养液100μl的混合液),继续孵育2~4小时,使反应充分进行后测定光吸收值。
4.比色:选择492nm波长,多功能酶标仪(MULTISKAN FC)读取各孔光吸收值,记录结果,数据处理后以浓度为横坐标,细胞存活率为纵坐标绘制细胞生长曲线,应用两点法(Reed and Muench法)计算化合物的IC50值。
5.阳性对照化合物:每次实验均设顺铂(DDP)和紫杉醇(Taxol)两个阳性化合物,以浓度为横坐标,细胞存活率为纵坐标绘制细胞生长曲线,应用两点法(Reed and Muench法)计算化合物的IC50值。
表3.I-15和I-19对五株细胞株的抗增殖活性。
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.目标化合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
研究表明,该类化合物对FLT3具有显著的抑制活性,其中,在溶剂可及区引入水溶性基团的时候化合物对FLT3的抑制活性明显提高。最优化合物对FLT3的IC50值达到了个位数纳摩尔级别,同时其对MV4-11也表现出了显著的抗增殖活性。该类化合物的结构新颖,对FLT3抑制活性较强,为新型强效的FLT3抑制剂,该类化合物的发现为靶向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选自键、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环烷基、取代或未取代的C4-8环烯基、取代或未取代C2-6烷硫基、取代或未取代的C2-6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;
R2是选自氢、取代或未取代的C1-6烷基、取代或未取代的C3-8环烷基、取代或未取代的C4-8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、取代或未取代的C6-14芳基、取代或未取代的芳杂环;
R3是选自氢、取代或未取代的C1-6烷基、取代或未取代的C3-8环烷基、取代或未取代的C4-8环烯基、取代或未取代C2-6烷硫基、取代或未取代的C2-6烷氧基、取代或未取代的C2-6烷胺基、取代或未取代的C2-6烯基、取代或未取代的C3-8杂环烷基;
取代或未取代指的是对应的官能团中具有或不具有取代基,所述取代基选自卤素、C1-6卤代烷基、羟基、胺基、C1-6烷基、C1-6烷氧基、C1-6烷胺基或C1-6烷硫基、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,
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C2-6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;
R3是选自氢、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。
3.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:
L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;
R2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、取代或未取代的C3-8杂环烷基、取代或未取代的C6-14芳基、取代或未取代的芳杂环;
R3是选自氢、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。
4.根据权利要求1-3之一所述的化合物或其药学上可接受的盐,其特征在于,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;
C6-14芳基为具有6-14个碳原子的共轭环状结构;
芳杂环为具有6-14个碳原子的含有一个或多个选自O、N和S的共轭环状结构。
5.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:
L选自键、O、NH、C(O)NH、C(O)、NHC(O)、NHC(O)NH或亚甲基;Ra是选自氟、氯、四氢吡咯基、哌啶基、N-甲基哌啶-4-基、吗啉基、N-甲基哌嗪基、N-乙基哌嗪基、N-异丙基哌嗪基、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;
R2是选自四氢吡咯基、四氢呋喃基、哌啶基、N-乙基哌嗪基、吗啉基、N-甲基哌嗪基、3-甲基哌啶-1-基、哌嗪基、4-羟基环己烷基、3-羟基环己烷基、4-羟基环戊烷基、环戊烯基、环己烯基、环庚烯基、氧杂环己烷、苯环、吡啶、吡唑、嘧啶、吡咯;
R3是选自氢、甲基、乙基、丙基、异丙基、丁基、环丙基。
6.权利要求1所述的化合物或其药学上可接受的盐,其结构选自:
(S)-N2-丁基-5-(5-氟-1H-苯并[d]咪唑-2-基)-N4-(哌啶-3-基)嘧啶-2,4-二胺;
N2-丁基-5-(5-氟-1H-苯并[d]咪唑-2-基)-N4-(哌啶-4-基)嘧啶-2,4-二胺;
(S)-N2-丁基-5-(5-氟-1H-苯并[d]咪唑-2-基)-N4-(吡咯烷-3-基)嘧啶-2,4-二胺;
(S)-1-(3-((2-(丁基氨基)-5-(5-氟-1H-苯并[d]咪唑-2-基)嘧啶-4-基)氨基)吡咯烷-1-基)丙-2-烯-1-酮;
N2-丁基-5-(5-氟-1H-苯并[d]咪唑-2-基)-N4-苯基嘧啶-2,4-二胺;
N4-(3-氨基苯基)-N2-丁基-5-(5-氟-1H-苯并[d]咪唑-2-基)嘧啶-2,4-二胺;
(S)-5-(5-氟-1H-苯并[d]咪唑-2-基)-N2-丙基-N4-(吡咯烷-3-基)嘧啶-2,4-二胺;
(S)-5-(5-氟-1H-苯并[d]咪唑-2-基)-N4-(哌啶-3-基)-N2-丙基嘧啶-2,4-二胺;
(S)-N2-乙基-5-(5-氟-1H-苯并[d]咪唑-2-基)-N4-(哌啶-3-基)嘧啶-2,4-二胺;
(S)-N2,N2-二乙基-5-(5-氟-1H-苯并[d]咪唑-2-基)-N4-(哌啶-3-基)嘧啶-2,4-二胺;
(S)-5-(5-氟-1H-苯并[d]咪唑-2-基)-N2-异丙基-N4-(哌啶-3-基)嘧啶-2,4-二胺;
(S)-N2-环丙基-5-(5-氟-1H-苯并[d]咪唑-2-基)-N4-(哌啶-3-基)嘧啶-2,4-二胺;
(S)-5-(5-(4-甲基哌嗪-1-基)-1H-苯并[d]咪唑-2-基)-N4-(哌啶-3-基)-N2-丙基嘧啶-2,4-二胺;
(S)-N2-环丙基-5-(5-(4-甲基哌嗪-1-基)-1H-苯并[d]咪唑-2-基)-N4-(哌啶-3-基)嘧啶-2,4-二胺;
(S)-5-(5-(哌嗪-1-基)-1H-苯并[d]咪唑-2-基)-N4-(哌啶-3-基)-N2-丙基嘧啶-2,4-二胺;
(S)-5-(5-吗啉基-1H-苯并[d]咪唑-2-基)-N4-(哌啶-3-基)-N2-丙基嘧啶-2,4-二胺;
(S)-N2-丁基-5-(5-(4-甲基哌嗪-1-基)-1H-苯并[d]咪唑-2-基)-N4-(哌啶-3-基)嘧啶-2,4-二胺;
(S)-N2-乙基-5-(5-(4-甲基哌嗪-1-基)-1H-苯并[d]咪唑-2-基)-N4-(哌啶-3-基)嘧啶-2,4-二胺;
(1s,4s)-4-((5-(5-(4-甲基哌嗪-1-基)-1H-苯并[d]咪唑-2-基)-2-(丙基氨基)嘧啶-4-基)氨基)环己烷-1-醇;
(1s,4s)-4-((5-(5-吗啉基-1H-苯并[d]咪唑-2-基)-2-(丙基氨基)嘧啶-4-基)氨基)环己烷-1-醇;
(1s,4s)-4-((2-(环丙基氨基)-5-(5-(4-甲基哌嗪-1-基)-1H-苯并[d]咪唑-2-基)嘧啶-4-基)氨基)环己烷-1-醇;
(R)-5-(5-(哌嗪-1-基)-1H-苯并[d]咪唑-2-基)-N4-(哌啶-3-基)-N2-丙基嘧啶-2,4-二胺。
7.权利要求1-3、5或6所述的化合物或其药学上可接受的盐,其特征在于,其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,其特征在于,含有权利要求1-7任一项所述的化合物或其药学上可接受的盐。
9.权利要求1-7任一项所述的化合物或其药学上可接受的盐或权利要求8所述的药物组合物在制备用于预防或治疗与FLT3激酶有关的疾病的药物中的用途。
10.根据权利要求9所述的用途,其中与FLT-3激酶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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