CN114524818A - Fgfr抑制剂化合物及其用途 - Google Patents
Fgfr抑制剂化合物及其用途 Download PDFInfo
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- CN114524818A CN114524818A CN202210044992.2A CN202210044992A CN114524818A CN 114524818 A CN114524818 A CN 114524818A CN 202210044992 A CN202210044992 A CN 202210044992A CN 114524818 A CN114524818 A CN 114524818A
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- Prior art keywords
- ethoxy
- dichloropyridin
- imidazol
- indazol
- dihydropyrrolo
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- 239000002207 metabolite Substances 0.000 claims abstract description 19
- 239000000651 prodrug Substances 0.000 claims abstract description 19
- 229940002612 prodrug Drugs 0.000 claims abstract description 19
- 239000003814 drug Substances 0.000 claims abstract description 6
- -1 methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, cyclopropyl Chemical group 0.000 claims description 175
- 108091008794 FGF receptors Proteins 0.000 claims description 70
- 125000002723 alicyclic group Chemical group 0.000 claims description 41
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Abstract
本申请涉及FGFR抑制剂化合物及其用途。具体地,本申请公开了如式(I)所示的化合物、或其同位素标记化合物、或其光学异构体、几何异构体、互变异构体或异构体混合物、或其药学上可接受的盐、或其前药、或其代谢物。本申请还涉及所述化合物在医学方面的应用。
Description
技术领域
本申请提供了一类具有药学活性的新颖化合物,所述化合物可用于抑制成纤维细胞生长因子受体(fibroblast growth factor receptor,FGFR)。本申请还涉及包含所述化合物的组合物,以及所述化合物和所述组合物在制备用于治疗与FGFR相关的疾病或病症的药物中的用途。
背景技术
成纤维细胞生长因子受体(FGFR)家族是一类跨膜受体酪氨酸激酶(receptortyrosine kinase,RTK),包括4个成员:FGFR1、FGFR2、FGFR3和FGFR4。FGFR可以通过天然配体的结合而被激活。被激活的FGFR继而可激活下游的多种信号传导通路(包括Ras-MAPK、AKT-PI3K和磷脂酶C等),这些信号传导通路参与多种重要的生理过程,例如增殖、分化、细胞迁移和存活等等。
FGFR的异常组成型激活被发现于多种肿瘤中。已经开发了针对FGFR的多种抑制剂以用于多种癌症的治疗。临床前和早期临床实验均证实,多种FGFR抑制剂有效地减小了肿瘤体积。
然而,将FGFR抑制剂用于临床癌症治疗的主要障碍之一是针对其的获得性抗性。这种抗性可以通过FGFR的突变或回补信号转导途径的激活而获得,其中,被称为门控(gatekeeper)残基的突变(简称门控突变)是最常见的抗性获得途径之一。
在临床前和临床样品中均已报道了由于FGFR中的门控突变而导致的药物抗性。例如,FGFR1的V561M突变导致对FIIN-1的强抗性;FGFR2的V564F突变导致对BGJ398的强抗性;FGFR3的V555M突变导致对AZ8010、PD173074和AZD4547的抗性。
期望开发出对携带门控突变的FGFR仍具有抑制活性的FGFR抑制剂来解决由门控突变引起的获得性抗性。最近的研究已经报道了若干对FGFR门控突变有效的抑制剂,例如FIIN2等。
仍存在对效果更好(例如,抑制率更高,靶向的FGFR及FGFR突变种类更多,对某种FGFR及FGFR突变具有更高的选择性,等等)的FGFR抑制剂的需求。
发明内容
在第一个方面,本申请提供了作为FGFR抑制剂的式(I)的化合物,所述化合物能够抑制野生型和突变型FGFR的活性,
或其同位素标记化合物、或其光学异构体、几何异构体、互变异构体或异构体混合物、或其药学上可接受的盐、或其前药、或其代谢物,其中:
R1、R2各自独立地选自H、卤素、-CN、-OH、-NO2、-NR7R8、C1-4烷基、C1-4卤代烷基、C1-4烷氧基、C3-6脂环基和4-6元杂脂环基;
R3选自H、C1-4烷基、C1-4卤代烷基、C1-4烷氧基、C3-6脂环基和4-6元杂脂环基;
R6的个数为1、2或3个,且每个R6各自独立地选自H、卤素、-CN、-OH、-NO2、-NR7R8、C1-4烷基、C1-4卤代烷基、C1-4烷氧基、C3-6脂环基和4-6元杂脂环基;
X为O、S或(NR4),其中R4选自:H、C1-4烷基、C1-4卤代烷基、C1-4烷氧基、C3-6脂环基和4-6元杂脂环基;
R7和R8各自在每次出现时独立地选自:H、C1-6烷基、C1-4卤代烷基、C1-4烷氧基,或者R7、R8以及与它们相连的N原子共同形成3-6元环;
n=1、2或3;
L为(C=O)、(O=S=O)、((C=O)-CH2)或连接键;
R5选自H、卤素、-OH、-NO2、-CN、-SF5、-SH、-S-C1-4烷基、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C2-8烯基、C2-8炔基、C3-7脂环基、3-10元杂脂环基、C6-12双环脂环基、6-12元双环杂脂环基、C8-15元三环脂环基、8-15元三环杂脂环基、C5-8芳基、5-10元杂芳基、C7-11双环芳基、7-11元双环杂芳基、-C1-4烷基-(C3-7脂环基)、-C1-4烷基-(3-10元杂脂环基)、-C1-4烷基-(C6-12双环脂环基)、-C1-4烷基-(6-12元双环杂脂环基)、-C1-4烷基-(C8-15元三环脂环基)、-C1-4烷基-(8-15元三环杂脂环基)、-C1-4烷基-(C5-8芳基)、-C1-4烷基-(5-10元杂芳基)、-N(R10)(R11)、-N(R10)(C(=O)R11)、-N(R10)(C(=O)-OR11)、-N(R12)(C(=O)-N(R10)(R11))、-C(=O)-N(R10)(R11)、-C(=O)-R12、-C(=O)-OR12、-OC(=O)R12、-N(R10)(S(=O)2R11)、-S(=O)2-N(R10)(R11)、-SR12和-OR12,其中所述-S-C1-4烷基、C1-6烷基、C1-6烷氧基、C1-6卤代烷氧基、C2-8烯基、C2-8炔基、C3-7脂环基、3-10元杂脂环基、C6-12双环脂环基、6-12元双环杂脂环基,C8-15元三环脂环基、8-15元三环杂脂环基、C5-8芳基、5-7元杂芳基、C7-11双环芳基、7-11元双环杂芳基、-C1-4烷基-(C3-7脂环基)、-C1-4烷基-(3-10元杂脂环基)、-C1-4烷基-(C6-12双环脂环基)、-C1-4烷基-(6-12元双环杂脂环基)-C1-4烷基-(C8-15元三环脂环基)、-C1-4烷基-(8-15元三环杂脂环基)、-C1-4烷基-(C5-8芳基)和-C1-4烷基-(5-10元杂芳基)各自任选地被0、1、2、3或4个R5a取代,且R5a独立选自卤素、-OH、-NO2、-CN、-SF5、-SH、-S-C1-4烷基、氧代、C1-4烷基、C1-4卤代烷基、C1-4烷氧基、C1-4卤代烷氧基、C2-8烯基、C2-8炔基、C3-7脂环基、3-10元杂脂环基、C5-8芳基、5-7元杂芳基、-N(R13)(R14)、-N(R13)(C(=O)R14)、-N(R13)(C(=O)-OR14)、-N(R15)(C(=O)-N(R13)(R14))、-C(=O)-N(R13)(R14)、-C(=O)-R15、-C(=O)-OR15、-OC(=O)R15、-N(R13)(S(=O)2R14)、-S(=O)2-N(R13)(R14)、-SR15和-OR15;
且R10、R11、R12、R13、R14、和R15各自在每次出现时独立地选自:H、C1-6烷基、C1-6卤代烷基、C3-7脂环基、3-10元杂脂环基、C5-8芳基、5-7元杂芳基、C7-11双环芳基、7-11元双环杂芳基、-C1-4烷基-(C3-7脂环基)、-C1-4烷基-(3-10元杂脂环基)、-C1-4烷基-(C6-12双环脂环基)、-C1-4烷基-(6-12元双环杂脂环基)、-C1-4烷基-(C8-15元三环脂环基)、-C1-4烷基-(8-15元三环杂脂环基)、-C1-4烷基-(C5-8芳基)和-C1-4烷基-(5-10元杂芳基),其中该群组内的各个选项任选地被0、1、2、3或4个各自独立选自以下群组的取代基所取代:卤素、-OH、-NH2、-NH(CH3)、-N(CH3)2、-CN、-NO2、-SF5、-SH、-S-C1-4烷基、氧代、C1-4烷基、C2-6烯基、C2-6炔基、C3-7脂环基、3-10元杂脂环基、C5-8芳基、5-7元杂芳基、C7-11双环芳基、7-11元双环杂芳基、C1-4羟烷基、-S-C1-4烷基、-C(=O)H、-C(=O)-C1-4烷基、-C(=O)-O-C1-4烷基、-C(=O)-NH2、-C(=O)-N(C1-4烷基)2、C1-4卤代烷基、C1-4烷氧基和C1-4卤代烷氧基;或者R10、R11以及与它们相连的原子共同形成3-14元环;或者R13、R14以及与它们相连的原子共同形成3-14元环。
除非另有指明,本文所述的“式(I)所示的化合物”、“式(I)的化合物”、“式(II)的化合物”、“式(III)的化合物”、“式(IV)的化合物”或“本申请的化合物”等术语也涵盖其任意光学异构体、几何异构体、互变异构体或异构体的混合物。
术语“光学异构体”意指,当化合物具有一个或更多个手性中心时,每个手性中心可以存在R构型或S构型,由此构成的各种异构体为光学异构体。光学异构体包括所有的非对映异构体、对映异构体、内消旋体、外消旋体或其混合物形式。例如,通过手性色谱柱或通过手性合成可以分离光学异构体。
术语“几何异构体”意指,当化合物中存在双键时,该化合物可以存在顺式异构体、反式异构体、E型异构体和Z型异构体。几何异构体包括顺式异构体、反式异构体、E型异构体、Z型异构体或其混合物形式。
术语“互变异构体”指因分子中某一原子在两个位置迅速移动而产生的异构体。本领域技术人员可以理解:互变异构体之间可以互相转变,在在某一状态下可能会达到一种平衡状态而共存。
除非另有指明,本文所述的“式(I)所示的化合物”、“式(I)的化合物”、“式(II)的化合物”、“式(III)的化合物”、“式(IV)的化合物”或“本申请的化合物”等术语也涵盖该化合物中一个或者多个原子被其同位素原子代替而得到的同位素标记化合物。
适用于包含在本申请的化合物中的同位素的实例包括氢的同位素,诸如2H(D)和3H(T);碳的同位素,诸如11C、13C和14C;氯的同位素,诸如36Cl;氟的同位素,诸如18F;碘的同位素,诸如123I和125I;氮的同位素,诸如13N和15N;氧的同位素,诸如15O、17O和18O;以及硫的同位素,诸如35S。
所述同位素标记化合物(例如包含放射性同位素的那些)可用于药物和/或底物组织分布研究。考虑到引入的容易性和检测手段的方便性,放射性同位素氘(即D)和碳-14(即14C)对于该目的是特别有用的。
利用诸如氘(即D)的较重同位素进行取代可以提供某些治疗方面的益处并且因此在某些情况下可以是优选的,所述治疗方面的益处例如是由更大的代谢作用稳定性(例如,增长的体内半衰期或者减小的剂量要求)带来的。因此,在一些实施方式中,本申请的化合物是同位素标记化合物,其中H在每次出现时任选地被D取代。
利用正电子放射同位素(诸如11C、18F、15O和13N)进行取代可以用于正电子放射受体图像(Positron Emission Topography(PET))研究,用于检测底物受体占用状态。
所述同位素标记化合物一般可以通过本领域技术人员已知的常规技术或者通过使用合适的同位素标记试剂代替先前使用的非标记试剂来进行制备。
本申请的化合物可以以其药学上可接受的盐的形式存在。
术语“药学上可接受的”是指相应的化合物、载体或分子适于给予人。优选地,该术语是指由管理机构例如CFDA(中国)、EMEA(欧洲)、FDA(美国)等任意国家管理机构认证的用于哺乳动物优选人。
所述药学上可接受的盐类包括其酸加成盐和碱加成盐。适当的酸加成盐是由形成无毒性盐的酸所形成的。其实例包括但不限于:乙酸盐、己二酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、碳酸氢盐/碳酸盐、硫酸氢盐/硫酸盐、硼酸盐、樟脑磺酸盐、柠檬酸盐、环己胺磺酸盐、乙二磺酸盐、甲酸盐、反丁烯二酸盐、葡萄庚糖酸盐、葡萄糖酸盐、葡萄糖醛酸盐、六氟磷酸盐、2-(4-羟苄基)苯甲酸盐、氢氯化物/氯化物、氢溴化物/溴化物、氢碘化物/碘化物、2-羟乙磺酸盐、乳酸盐、苹果酸盐、顺丁烯二酸盐、丙二酸盐、甲磺酸盐、甲基硫酸盐、萘酸盐、2-萘磺酸盐、烟碱酸盐、硝酸盐、乳清酸盐、草酸盐、十六酸盐、磷酸盐/磷酸氢盐/磷酸二氢盐、焦谷氨酸盐、葡萄糖二酸盐、硬脂酸盐、水杨酸盐、单宁酸盐、酒石酸盐、甲苯磺酸盐和三氟乙酸盐。适当的碱加成盐是由形成无毒性盐的碱所形成的。其实例包括但不限于:铝、精氨酸、钙、胆碱、二乙胺、二乙醇胺、甘氨酸、赖氨酸、镁、葡甲胺、乙醇胺、钾、钠、氨丁三醇和锌盐。还可形成酸和碱的半盐,例如半硫酸盐和半钙盐。关于合适的盐的综述,参见Handbook of Pharmaceutical Salts:Properties,Selection and Use by Stahl andWermuth(Wiley-VCH,2002)。用于制备本文中所述的化合物的药学上可接受的盐的方法是本领域技术人员已知的。
此外,本申请化合物可以以非溶剂化形式以及与药学上可接受的溶剂如水、乙醇等的溶剂化形式存在。化合物也可以以一种或多种结晶状态存在,即多晶型,或者它们可以作为无定形固体存在。所有这些形式都包含在本申请的范围内。
本申请还包括本申请的化合物的前药。术语“前药”是指通过与酶、胃酸等在生理条件下在活体内例如通过各自在酶催化下进行的氧化、还原、水解等反应转化为本申请化合物的衍生物。因此,本申请化合物的某些衍生物本身可能具有很少或没有药理学活性,当给药至体内或身体上时,可以转化成具有所需活性的本申请化合物。
本申请还包括本申请的化合物的代谢物。术语“代谢物”是指在细胞或有机体优选人中源自本申请任意化合物的所有分子。
在本文中使用时,术语“被取代”是指基团中的一个或多个(优选1至5个,更优选1至3个)氢原子独立地被相应数目的取代基所代替。
在本文中使用时,术语“独立地”是指当取代基的个数超过一个时,这些取代基可以相同也可以不同。
在本文中使用时,术语“任选”或“任选地”表示其所描述的事件可以发生或不发生。例如,一个基团“任选地被取代”表示:该基团可以是未被取代的,也可以是被取代的。
术语“卤素”或“卤”是指-F,-Cl,-Br,或-I。
在本文中使用时,术语“烷基”是指饱和的脂族烃,包括直链及支链。在一些实施方式中,烷基基团具有1-8个、或1-6个、或1-4个、或1-3个碳原子。例如,术语“C1-8烷基”是指具有1-8个碳原子的直链或支链原子团。术语“C1-8烷基”在其定义中包括术语“C1-6烷基”、“C1-3烷基”和“C1-4烷基”等。烷基的实例包括但不限于甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、戊基、2-戊基、3-戊基、异戊基、新戊基、(R)-2-甲基丁基、(S)-2-甲基丁基、3-甲基丁基、2,3-二甲基丙基、2,3-二甲基丁基、己基等。烷基基团可任选地被一或多个(例如,1至5个)适当的取代基所取代。
在本文中使用时,术语“烯基”是指具有至少一个碳-碳双键的脂族烃,包括具有至少一个碳-碳双键的直链及支链。在一些实施方式中,烯基基团具有2-8个碳原子、2-6个碳原子、3-6个碳原子、或2-4个碳原子。例如,术语“C2-8烯基”是指具有2-8个碳原子的直链或支链的不饱和原子团(具有至少一个碳-碳双键)。所述双键可以是或者可以不是另一基团的连接点。烯基包括但不限于乙烯基、1-丙烯基、2-丙烯基、2-甲基-2-丙烯基、丁烯基、戊烯基、3-己烯基等。烯基基团可任选地被一或多个(例如,1至5个)适当的取代基所取代。当式(I)的化合物含有烯基基团时,该烯基基团可以纯E形式、纯Z形式、或其任何混合物存在。
在本文中使用时,术语“炔基”是指具有至少一个碳-碳三键的脂族烃,包括具有至少一个碳-碳三键的直链及支链。在一些实施方式中,炔基基团具有2-8个碳原子、2-6个碳原子、3-6个碳原子、或2-4个碳原子。例如,术语“C2-8炔基”是指具有2-8个碳原子的直链或支链的不饱和原子团(具有至少一个碳-碳三键)。所述三键可以是或者可以不是另一基团的连接点。炔基包括但不限于乙炔基、1-丙炔基、2-丙炔基、2-甲基-2-丙炔基、丁炔基、戊炔基、3-己炔基等。炔基基团可任选地被一或多个(例如,1至5个)适当的取代基所取代。
在本文中使用时,术语“C3-8脂环基”是指具有3-8个形成环的碳原子的脂环基。术语“C3-7脂环基”是指具有3-7个形成环的碳原子的脂环基。术语“C3-6脂环基”是指具有3-6个形成环的碳原子的脂环基。所述脂环基可以是单环环。脂环基的定义还包括不饱和的非芳族脂环基。脂环基的实例为,例如环丙基、环丁基、环戊基、环己基、环己烯基、环庚基、环辛基、环己二烯基、环戊烯基、环庚烯基和环辛烯基。脂环基可任选地被一或多个适当的取代基所取代。
本文中使用时,术语“C6-12双环脂环基”是具有6-12个形成环的碳原子的含有两个环的脂环基。双环脂环基可稠合,也可包括桥连双环脂环基系统。
本文中使用时,术语“C8-15元三环脂环基”是具有8-15个形成环的碳原子的含有三个环的脂环基。三环脂环基可稠合,也可桥连。
在本文中使用时,术语“n元杂脂环基”是指具有m个形成环的碳原子和(n-m)个形成环的杂原子的脂环基,所述杂原子选自O、S及N。例如,术语“4-8元杂脂环基”是指杂脂环基取代基含有总共4至8个环原子,其中至少一个是杂原子;术语“4-6元杂脂环基”是指杂脂环基取代基含有总共4至6个环原子,其中至少一个是杂原子;术语“3-10元杂脂环基”是指杂脂环基取代基含有总共3至10个环原子,其中至少一个是杂原子。术语“n元双环杂脂环基”是指具有m个形成环的碳原子和(n-m)个形成环的杂原子的双环杂脂环基,所述杂原子选自O、S及N。杂脂环基的实例包括,但不限于,氮杂环丁烷基、硫杂环丁烷基、二氢呋喃基、二氢噻吩基、四氢噻吩基、四氢呋喃基、四氢三嗪基、四氢吡唑基、四氢噁嗪基、四氢嘧啶基、八氢苯并呋喃基、八氢苯并咪唑基、八氢苯并噻唑基、咪唑烷基、吡咯烷基、哌啶基、哌嗪基、噁唑烷基、噻唑烷基、吡唑烷基、硫代吗啉基、四氢吡喃基、四氢噻喃基、四氢噻嗪基、四氢噻二嗪基、四氢噁唑基、吗啉基、氧杂环丁烷基、四氢二嗪基、噁嗪基、氧杂噻嗪基、奎宁环基、苯并二氢吡喃基(chromanyl)、异苯并二氢吡喃基(isochromanyl)、二氢苯并二噁英基(dihydrobenzodioxinyl)、苯并二氧杂环戊烯基(benzodioxolyl)、苯并噁嗪基、二氢吲哚基、二氢苯并呋喃基、四氢喹啉基、异色满基(isochromyl)、二氢-1H-异吲哚基、2-氮杂双环[2.2.1]庚酰基、3-氮杂双环[3.1.0]己基、3-氮杂双环[4.1.0]庚基、氧杂环庚烷基、硫杂环庚烷基、氮杂环庚烷基等。杂脂环基可任选地被一或多个适当的取代基所取代。
在本文中使用时,术语“C5-8芳基”是指具有含5-8个碳原子的芳环的芳基,例如苯基。
在本文中使用时,术语“n元杂芳基”是指具有m个形成芳环的碳原子和(n-m)个形成芳环的杂原子的杂芳基,所述杂原子选自O、S及N。例如,5-7元杂芳基包括但不限于呋喃基、噻吩基、吡咯基、噻唑基、吡唑基、咪唑基、吡啶基、吡喃基、哒嗪基、嘧啶基、吡嗪基。杂芳基可任选地被一或多个适当的取代基所取代。
在本文中使用时,术语“C7-11双环芳基”是指具有7-11个碳原子的双环芳基,例如萘基、茚基等。双环芳基可任选地被一或多个适当的取代基所取代。
在本文中使用时,术语“n元双环杂芳基”是指具有m个形成芳族双环的碳原子和(n-m)个形成芳族双环的杂原子的双环杂芳基,所述杂原子选自O、S及N。例如,7-11元双环杂芳基包括但不限于喹啉基、异喹啉基、吲哚基、嘌呤基、苯并噻唑基等。双环杂芳基可任选地被一或多个适当的取代基所取代。
在本文中使用时,术语“11-15元三环基”包括但不限于吖啶基等。11-15元三环基可任选地被一或多个适当的取代基所取代。
在本文中使用时,术语“卤代烷基”是指具有一或多个卤素取代基的烷基基团(至多全卤代烷基,即,烷基基团的每个氢原子均被卤素原子所取代)。例如,术语“C1-6卤代烷基”是指具有一或多个卤素取代基的C1-6烷基基团(至多全卤代烷基,即,烷基基团的每个氢原子均被卤素原子所取代)。另举一例,术语“C1-4卤代烷基”是指具有一或多个卤素取代基的C1-4烷基基团(至多全卤代烷基,即,烷基基团的每个氢原子均被卤素原子所取代);术语“C1-3卤代烷基”是指具有一或多个卤素取代基的C1-3烷基基团(至多全卤代烷基,即,烷基基团的每个氢原子均被卤素原子所取代);且术语“C1-2卤代烷基”是指具有一或多个卤素取代基的C1-2烷基基团(即,甲基或乙基)(至多全卤代烷基,即,烷基基团的每个氢原子均被卤素原子所取代)。再另举一例,术语“C1卤代烷基”是指具有1、2或3个卤素取代基的甲基基团。卤代烷基基团的例子包括:CF3、C2F5、CHF2、CH2F、CH2CF3、CH2Cl等。
在本文中使用时,术语“烷氧基”是指单键连接至氧原子的烷基。烷氧基与分子的连接点是通过氧原子。烷氧基可被描述为烷基-O-。术语“C1-6烷氧基”是指包含1-6个碳原子的直链或支链的烷氧基。术语“C1-6烷氧基”在其定义中包括术语“C1-3烷氧基”。烷氧基包括但不限于甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、己氧基等。烷氧基可任选地被一或多个适当的取代基所取代。
在本文中使用时,术语“3-14元环”是指具有3-14个成环原子的饱和或不饱和环体系。
本文中,与取代基个数、碳原子个数、环原子个数相关的数目范围表示该范围内所有整数的逐个列举,而范围仅是作为一种简化的表示法。例如:“4-6元”表示4、5或6元;“5-7元”表示5、6或7元;“7-11元”表示7、8、9、10或11元;“4-8元”表示4、5、6、7或8元;“3-10元”表示3、4、5、6、7、8、9或10元;“3-14元”表示3、4、5、6、7、8、9、10、11、12、13或14元;“C1-3”表示1个(C1)、2个(C2)或3个碳原子(C3);“C1-4”表示1个(C1)、2个(C2)、3个碳原子(C3)或4个碳原子(C4);“C3-6”表示3个(C3)、4个(C4)、5个(C5)或6个碳原子(C6);“C3-8”表示3个(C3)、4个(C4)、5个(C5)、6个(C6)、7个(C7)或8个碳原子(C8);“C5-7”表示5个(C5)、6个(C6)或7个碳原子(C7);“C7-11”表示7个(C7)、8个(C8)、9个(C9)、10个(C10)或11个碳原子(C11)。因此,与取代基个数、碳原子个数、环原子个数相关的数目范围也涵盖其任意一个子范围,且每一个子范围也视为被本文公开。
在如上所述的式(I)中,R1选自H、卤素、-CN、-OH、-NO2、-NR7R8、C1-4烷基、C1-4卤代烷基、C1-4烷氧基、C3-6脂环基和4-6元杂脂环基。
在一些实施方式中,R1为H。
在一些实施方式中,R1为卤素,例如R1选自F、Cl、Br、I。
在一些实施方式中,R1为-CN。
在一些实施方式中,R1为-NO2。
在一些实施方式中,R1为C1-3烷基或C1-3卤代烷基,例如,R1选自任选地被一个或多个卤素原子(例如氟、氯、溴、碘)取代的甲基、乙基、丙基、异丙基。
在一些实施方式中,R1为C1-3烷氧基,例如,R1选自甲氧基、乙氧基、丙氧基、异丙氧基。
在一些实施方式中,R1为C3-6脂环基,例如,R1选自环丙基、环丁基、环戊基、环己基、环己烯基。
在一些实施方式中,R1为4-6元杂脂环基,例如,R1选自氧杂环丁烷基、硫杂环丁烷基、氮杂环丁烷基、四氢呋喃基、四氢噻吩基、吡咯烷基、四氢吡喃基、四氢噻喃基、哌啶基、吗啉基、哌嗪基。
在一些实施方式中,R1为-NR7R8,其中R7和R8各自在每次出现时独立地选自:H、C1-3烷基(例如甲基、乙基、丙基、异丙基等)、C1-3卤代烷基(例如被被一个或多个选自氟、氯、溴、碘的卤原子取代的甲基、乙基、丙基、异丙基)、C1-3烷氧基(例如甲氧基、乙氧基、丙氧基、异丙氧基),或者R7、R8以及与它们相连的N原子共同形成3-6元环(例如吡咯、吡啶、嘧啶、咪唑、吡唑、吡咯烷、六氢吡啶等)。
应当理解,任何上述R1的实施方式可以与如上文和下文所述的任何R2、R3、R5、R6、X、L和n的实施方式以任意方式组合在一起。
在如上所述的式(I)中,R2选自H、卤素、-CN、-OH、-NO2、-NR7R8、C1-4烷基、C1-4卤代烷基、C1-4烷氧基、C3-6脂环基和4-6元杂脂环基。
在一些实施方式中,R2为H。
在一些实施方式中,R2为卤素,例如R2选自F、Cl、Br、I。
在一些实施方式中,R2为-CN。
在一些实施方式中,R2为-NO2。
在一些实施方式中,R2为C1-3烷基或C1-3卤代烷基,例如,R2选自任选地被一个或多个卤素原子(例如氟、氯、溴、碘)取代的甲基、乙基、丙基、异丙基。
在一些实施方式中,R2为C1-3烷氧基,例如,R2选自甲氧基、乙氧基、丙氧基、异丙氧基。
在一些实施方式中,R2为C3-6脂环基,例如,R2选自环丙基、环丁基、环戊基、环己基、环己烯基。
在一些实施方式中,R2为4-6元杂脂环基,例如,R2选自氧杂环丁烷基、硫杂环丁烷基、氮杂环丁烷基、四氢呋喃基、四氢噻吩基、吡咯烷基、四氢吡喃基、四氢噻喃基、哌啶基、吗啉基、哌嗪基。
在一些实施方式中,R2为-NR7R8,其中R7和R8各自在每次出现时独立地选自:H、C1-3烷基(例如甲基、乙基、丙基、异丙基等)、C1-3卤代烷基(例如被被一个或多个选自氟、氯、溴、碘的卤原子取代的甲基、乙基、丙基、异丙基)、C1-3烷氧基(例如甲氧基、乙氧基、丙氧基、异丙氧基),或者R7、R8以及与它们相连的N原子共同形成3-6元环(例如吡咯、吡啶、嘧啶、咪唑、吡唑、吡咯烷、六氢吡啶等)。
应当理解,任何上述R2的实施方式可以与如上文和下文所述的任何R1、R3、R5、R6、X、L和n的实施方式以任意方式组合在一起。
在一些实施方式中,R1和R2可以是相同的。例如,R1和R2均为卤素,例如Cl;再例如,R1和R2均为甲基。在一个优选的实施方式中,R1和R2均为Cl。在一个优选的实施方式中,R1和R2均为H。
在另一些实施方式中,R1和R2可以是不同的。
在如上所述的式(I)中,R3选自H、C1-4烷基、C1-4卤代烷基、C1-4烷氧基、C3-6脂环基和4-6元杂脂环基。
在一些实施方式中,R3为H。
在一些实施方式中,R3为C1-3烷基或C1-3卤代烷基,例如,R3选自任选地被一个或多个卤素原子(例如氟、氯、溴、碘)取代的甲基、乙基、丙基、异丙基。
在一些实施方式中,R3为C1-3烷氧基,例如,R3选自甲氧基、乙氧基、丙氧基、异丙氧基。
在一些实施方式中,R3为C3-6脂环基,例如,R3选自环丙基、环丁基、环戊基、环己基、环己烯基。
在一些实施方式中,R3为4-6元杂脂环基,例如,R3选自氧杂环丁烷基、硫杂环丁烷基、氮杂环丁烷基、四氢呋喃基、四氢噻吩基、吡咯烷基、四氢吡喃基、四氢噻喃基、哌啶基、吗啉基、哌嗪基。
在一些实施方式中,R3为甲基。
应当理解,任何上述R3的实施方式可以与如上文和下文所述的任何R1、R2、R5、R6、X、L和n的实施方式以任意方式组合在一起。
在如上所述的式(I)中,R6的个数可以为1、2或3个,其中每个R6各自独立地选自H、卤素、-CN、-OH、-NO2、-NR7R8、C1-4烷基、C1-4卤代烷基、C1-4烷氧基、C3-6脂环基和4-6元杂脂环基,其中R7和R8各自在每次出现时独立地选自:H、C1-6烷基、C1-4卤代烷基、C1-4烷氧基,或者R7、R8以及与它们相连的N原子共同形成3-6元环。
在一些优选的实施方式中,R6为H。
在一些实施方式中,R6为卤素,例如R6选自F、Cl、Br、I。
在一些实施方式中,R6为-CN、-OH或-NO2。
在一些实施方式中,R6为C1-3烷基或C1-3卤代烷基,例如R6选自任选地被一个或多个卤素原子(例如氟、氯、溴、碘)取代的甲基、乙基、丙基、异丙基。
在一些实施方式中,R6为C1-3烷氧基,例如R6选自甲氧基、乙氧基、丙氧基、异丙氧基。
在一些实施方式中,R6为C3-6脂环基,例如R6选自环丙基、环丁基、环戊基、环己基、环己烯基。
在一些实施方式中,R6为4-6元杂脂环基,例如R6选自氧杂环丁烷基、硫杂环丁烷基、氮杂环丁烷基、四氢呋喃基、四氢噻吩基、吡咯烷基、四氢吡喃基、四氢噻喃基、哌啶基、吗啉基、哌嗪基。
在一些实施方式中,R6为-NR7R8,其中R7和R8各自在每次出现时独立地选自:H、C1-3烷基(例如甲基、乙基、丙基、异丙基等)、C1-3卤代烷基(例如被被一个或多个选自氟、氯、溴、碘的卤原子取代的甲基、乙基、丙基、异丙基)、C1-3烷氧基(例如甲氧基、乙氧基、丙氧基、异丙氧基),或者R7、R8以及与它们相连的N原子共同形成3-6元环(例如吡咯、吡啶、嘧啶、咪唑、吡唑、吡咯烷、六氢吡啶等)。
在一些实施方式中,R6为二甲氨基、二乙氨基、甲基乙基氨基。
在一些优选的实施方式中,R6为1个。
应当理解,任何上述R6的实施方式可以与如上文和下文所述的任何R1、R2、R3、R5、X、L和n的的实施方式以任意方式组合在一起。
在如上所述的式(I)中,X为O、S或(NR4),其中R4选自:H、C1-4烷基、C1-4卤代烷基、C1-4烷氧基、C3-6脂环基和4-6元杂脂环基。
在一些实施方式中,X为O。
在一些实施方式中,X为S。
在一些实施方式中,X为亚氨基,即-(NH)-。
在一些实施方式中,X为-(N(CH3))-。
应当理解,任何上述X的实施方式可以与如上文和下文所述的任何R1、R2、R3、R5、R6、L和n的的实施方式以任意方式组合在一起。
在如上所述的式(I)中,n为1、2或3。
在一些实施方式中,n为1。
在一些实施方式中,n为2。
在一些实施方式中,n为3。
应当理解,任何上述n的实施方式可以与如上文和下文所述的任何R1、R2、R3、R5、R6、L和X的的实施方式以任意方式组合在一起。
在如上所述的式(I)中,L为(C=O)、(O=S=O)、((C=O)-CH2)或连接键。
在一些实施方式中,L为-(C=O)-。
在一些实施方式中,L为-(O=S=O)-。
在一些实施方式中,L为-((C=O)-CH2)-。
在一些实施方式中,L为共价连接键。
应当理解,任何上述L的实施方式可以与如上文和下文所述的任何R1、R2、R3、R5、R6、n和X的的实施方式以任意方式组合在一起。
在如上所述的式(I)中,R5可以是有机化学中常见的任何取代基,其并不特别受限。
在一些实施方式中,R5为C1-6烷基,例如R5选自甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、戊基、2-戊基、3-戊基、异戊基、新戊基、(R)-2-甲基丁基、(S)-2-甲基丁基、3-甲基丁基、2,3-二甲基丙基、2,3-二甲基丁基、己基。
在一些实施方式中,R5为C3-7脂环基,例如R5选自环丙基、环丁基、环戊基、环己基、环己烯基、环庚基、环己二烯基、环戊烯基、环庚烯基。
在一些实施方式中,R5为3-10元杂脂环基,例如R5选自氮杂环丁烷基、硫杂环丁烷基、二氢呋喃基、二氢噻吩基、四氢噻吩基、四氢呋喃基、四氢三嗪基、四氢吡唑基、四氢噁嗪基、四氢嘧啶基、八氢苯并呋喃基、八氢苯并咪唑基、八氢苯并噻唑基、咪唑烷基、吡咯烷基、哌啶基、哌嗪基、噁唑烷基、噻唑烷基、吡唑烷基、硫代吗啉基、四氢吡喃基、四氢噻喃基、四氢噻嗪基、四氢噻二嗪基、四氢噁唑基、吗啉基、氧杂环丁烷基、四氢二嗪基、噁嗪基、氧杂噻嗪基、奎宁环基、苯并二氢吡喃基、异苯并二氢吡喃基、二氢苯并二噁英基、苯并二氧杂环戊烯基、苯并噁嗪基、二氢吲哚基、二氢苯并呋喃基、四氢喹啉基、异色满基、二氢-1H-异吲哚基、氧杂环庚烷基、硫杂环庚烷基、氮杂环庚烷基。
在一些实施方式中,R5为H、卤素、-OH、-NO2、-CN、-SF5或-SH。
在一些实施方式中,R5选自-S-C1-4烷基、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C2-8烯基、C2-8炔基。
在一些实施方式中,R5选自C5-8芳基(例如苯基)、5-10元杂芳基(例如呋喃基、噻吩基、吡咯基、噻唑基、吡唑基、咪唑基、吡啶基、吡喃基、哒嗪基、嘧啶基、吡嗪基等)、-C1-4烷基-(C5-8芳基)、-C1-4烷基-(5-10元杂芳基)。
在一些实施方式中,R5选自-N(R10)(R11)、-N(R10)(C(=O)R11)、-N(R10)(C(=O)-OR11)、-N(R12)(C(=O)-N(R10)(R11))、-C(=O)-N(R10)(R11)、-C(=O)-R12、-C(=O)-OR12、-OC(=O)R12、-N(R10)(S(=O)2R11)、-S(=O)2-N(R10)(R11)、-SR12和-OR12,其中R10、R11、R12各自在每次出现时独立地选自:H、C1-6烷基、C1-6卤代烷基、C3-7脂环基、3-10元杂脂环基、C5-8芳基、5-7元杂芳基、C7-11双环芳基、7-11元双环杂芳基、-C1-4烷基-(C3-7脂环基)、-C1-4烷基-(3-10元杂脂环基)、-C1-4烷基-(C6-12双环脂环基)、-C1-4烷基-(6-12元双环杂脂环基)、-C1-4烷基-(C8-15元三环脂环基)、-C1-4烷基-(8-15元三环杂脂环基)、-C1-4烷基-(C5-8芳基)和-C1-4烷基-(5-10元杂芳基),其中该群组内的各个选项任选地被0、1、2、3或4个各自独立选自以下群组的取代基所取代:卤素、-OH、-NH2、-NH(CH3)、-N(CH3)2、-CN、-NO2、-SF5、-SH、-S-C1-4烷基、氧代、C1-4烷基、C2-6烯基、C2-6炔基、C3-7脂环基、3-10元杂脂环基、C5-8芳基、5-7元杂芳基、C7-11双环芳基、7-11元双环杂芳基、C1-4羟烷基、-S-C1-4烷基、-C(=O)H、-C(=O)-C1-4烷基、-C(=O)-O-C1-4烷基、-C(=O)-NH2、-C(=O)-N(C1-4烷基)2、C1-4卤代烷基、C1-4烷氧基和C1-4卤代烷氧基;或者R10、R11以及与它们相连的原子共同形成3-14元环。
上述对于R5列举的任意示例基团都应被理解为是任选地被取代的;即在适当的时候,上述对于R5给出的任意基团可以任选地被0、1、2、3或4个R5a取代,且R5a独立选自卤素、-OH、-NO2、-CN、-SF5、-SH、-S-C1-4烷基、氧代、C1-4烷基、C1-4卤代烷基、C1-4烷氧基、C1-4卤代烷氧基、C2-8烯基、C2-8炔基、C3-7脂环基、3-10元杂脂环基、C5-8芳基、5-7元杂芳基、-N(R13)(R14)、-N(R13)(C(=O)R14)、-N(R13)(C(=O)-OR14)、-N(R15)(C(=O)-N(R13)(R14))、-C(=O)-N(R13)(R14)、-C(=O)-R15、-C(=O)-OR15、-OC(=O)R15、-N(R13)(S(=O)2R14)、-S(=O)2-N(R13)(R14)、-SR15和-OR15,其中R13、R14、和R15各自在每次出现时独立地选自:H、C1-6烷基、C1-6卤代烷基、C3-7脂环基、3-10元杂脂环基、C5-8芳基、5-7元杂芳基、C7-11双环芳基、7-11元双环杂芳基、-C1-4烷基-(C3-7脂环基)、-C1-4烷基-(3-10元杂脂环基)、-C1-4烷基-(C6-12双环脂环基)、-C1-4烷基-(6-12元双环杂脂环基)、-C1-4烷基-(C8-15元三环脂环基)、-C1-4烷基-(8-15元三环杂脂环基)、-C1-4烷基-(C5-8芳基)和-C1-4烷基-(5-10元杂芳基),其中该群组内的各个选项任选地被0、1、2、3或4个各自独立选自以下群组的取代基所取代:卤素、-OH、-NH2、-NH(CH3)、-N(CH3)2、-CN、-NO2、-SF5、-SH、-S-C1-4烷基、氧代、C1-4烷基、C2-6烯基、C2-6炔基、C3-7脂环基、3-10元杂脂环基、C5-8芳基、5-7元杂芳基、C7-11双环芳基、7-11元双环杂芳基、C1-4羟烷基、-S-C1-4烷基、-C(=O)H、-C(=O)-C1-4烷基、-C(=O)-O-C1-4烷基、-C(=O)-NH2、-C(=O)-N(C1-4烷基)2、C1-4卤代烷基、C1-4烷氧基和C1-4卤代烷氧基;或者R13、R14以及与它们相连的原子共同形成3-14元环。
在一些优选的实施方式中,R5选自甲基、乙基、丙基、异丙基、环丁基基团。所述甲基、乙基、丙基、异丙基或环丁基基团可以任选地被0、1或2个各自独立选自以下群组的取代基所取代:甲基、乙基、环戊基、环丙基、-CN、-OH、吗啉基、哌啶基,所述取代基又可以任选地被0、1或2个各自独立选自以下群组的取代基所取代:甲基、乙基、环戊基、环丙基、-CN、-OH。例如,在一些优选的实施方式中,R5选自(1-羟基环丙基)乙基、3-羟基环丁基、2-氰基乙基、2-羟乙基、2-氰基-1-环戊基乙基、1-氰基丙烷、2-吗啉代乙基、乙基和(1-甲基哌啶-4-基)甲基。
在一些优选的实施方式中,R5选自卤素,例如F。
在一些优选的实施方式中,R5选自哌嗪基、吗啉基、吡咯烷基、哌啶基和氮杂环丁烷基,所述哌嗪基、吗啉基、吡咯烷基、哌啶基和氮杂环丁烷基可以任选地被0、1或2个各自独立选自以下群组的取代基所取代:甲基、乙基、环戊基、环丙基、-CN、-OH。在一些优选的实施方式中,R5选自甲基、乙基、丙基、异丙基、环丁基基团,所述甲基、乙基、丙基、异丙基或环丁基基团可以任选地被0、1或2个各自独立选自以下群组的取代基所取代:甲基、乙基、环戊基、环丙基、-CN、-OH、吗啉基、哌啶基,所述取代基又可以任选地被0、1或2个各自独立选自以下群组的取代基所取代:甲基、乙基、环戊基、环丙基、-CN、-OH。
在一些优选的实施方式中,R5选自哌嗪基、吗啉基、吡咯烷基、哌啶基、氮杂环丁烷基。例如,在一些优选的实施方式中,R5选自3,5-二甲基哌嗪基、吗啉基、3-羟基吡咯烷基、4-甲基哌嗪基、4-乙基哌嗪基、4-羟基哌啶基、1-甲基哌啶基、1-乙基哌啶-4-基、1-甲基氮杂环丁烷-3-基。
在一些优选的实施方式中,R5选自H、甲基、乙基、正丙基、异丙基、丁基、甲氧基、乙氧基、羟基、环丙基、环丁基、环戊基、环己基、吗啉代甲基、羟基环丁基、羟基环己基、氰基乙氧基、氰基甲基、吡啶-3-基、1-甲基-1H-吡唑-4-基、1-甲基-1H-吡唑-3-基、4-甲基哌嗪-1-基、1-甲基哌啶-4-基、吗啉基、吡咯烷-3-基、3-羟基吡咯烷-1-基、3-氰基吡咯烷-1-基。
在另一些优选的实施方式中,R5选自(C1-4烷基)氨基或(C1-4烷基)2氨基(如甲基氨基、二甲基氨基)、(C1-4烷基)吡唑基(如1-甲基-1H-吡唑-4-基)、(C1-4烷基)吡咯烷基(如1-甲基吡咯烷-3-基)、(C1-4烷基)哌啶基(如1-甲基哌啶-4-基、1-甲基哌啶-3-基、1-甲基哌啶-2-基)、吡咯烷基或取代吡咯烷基(如吡咯烷-1-基、吡咯烷-3-基、3-羟基吡咯烷-1-基、3-氰基吡咯烷-1-基、吡咯烷-2-基、1-甲基吡咯烷-2-基、1-(甲磺酰基)吡咯烷-3-基)、哌啶基(如哌啶-2-基、哌啶-1-基)、卤代吡咯烷基或氰基吡咯烷基(如3-氟吡咯烷-1-基、3-氰基吡咯烷-1-基)、氮杂环丁烷基(如氮杂环丁烷-1-基)、卤代氮杂环丁基或羟基氮杂环丁基(如3-羟基-氮杂环丁-1-基或3-氟-氮杂环丁烷-1-基)、氨基C1-4烷基(如(二甲氨基)乙基和(二甲氨基)甲基)。
应当理解,任何上述R5的实施方式可以与如上文和下文所述的任何R1、R2、R3、R6、X、L和n的实施方式以任意方式组合在一起。
在一些实施方式中,本申请所述的化合物为选自式(II)或式(III)的化合物,或其同位素标记化合物、或其光学异构体、几何异构体、互变异构体或异构体混合物、或其药学上可接受的盐、或其前药、或其代谢物:
其中,R1、R2、R6、R5、L和n的定义均与式(I)化合物相同。
在上文中对于式(I)给出的R1、R2、R6、R5、L和n的实施方式和优选项同样适用于式(II)、式(III)、式(IV)。
在一些具体实施方式中,本申请的化合物选自各实施例所示的化合物。
在一些实施方式中,本申请的化合物选自:
(2-(5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)-4,6-二氢吡咯并[3,4-d]咪唑-5(1H)-基)(4-甲基哌嗪-1-基)甲酮;
5-(1-(3,5-二氯吡啶-4-基)乙氧基)-3-(5-((1-甲基哌啶-4-基)甲基)-1,4,5,6-四氢吡咯并[3,4-d]咪唑-2-基)-1H-吲唑;
5-(1-(3,5-二氯吡啶-4-基)乙氧基)-3-(5-(1-甲基哌啶-4-基)-1,4,5,6-四氢吡咯并[3,4-d]咪唑-2-基)-1H-吲唑;
2-(5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)-5-(1-甲基哌啶-4-基)-4,5,6,7-四氢-3H-咪唑并[4,5-c]吡啶;
(2-(5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)-3,4,6,7-四氢-5H-咪唑并[4,5-c]吡啶-5-基)(4-甲基哌嗪-1-基)甲酮;
(2-(5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)-4,6-二氢吡咯并[3,4-d]咪唑-5(1H)-基)(1-甲基哌啶-4-基)甲酮;
5-(1-(3,5-二氯吡啶-4-基)乙氧基)-3-(5-(吡啶-3-基磺酰基)-1,4,5,6-四氢吡咯并[3,4-d]咪唑-2-基)-1H-吲唑;
(2-(5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)-4,6-二氢吡咯并[3,4-d]咪唑-5(1H)-基)(吗啉基)甲酮;
(2-(5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)-4,6-二氢吡咯并[3,4-d]咪唑-5(1H)-基)((R)-吡咯烷-3-基)甲酮;
(2-(5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)-4,6-二氢吡咯[3,4-d]咪唑-5(1H)-基)((S)-3-羟基吡咯烷-1-基)甲酮;
5-(1-(3,5-二氯吡啶-4-基)乙氧基)-3-(5-甲基-1,4,5,6-四氢吡咯并[3,4-d]咪唑-2-基)-1H-吲唑;
4-(2-(2-(5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)-4,6-二氢吡咯并[3,4-d]咪唑-5(1H)-基)乙基)吗啉;
1-(2-(5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)-4,6-二氢吡咯并[3,4-d]咪唑-5(1H)-基)-2-吗啉代乙烷-1-酮;
1-(2-(5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)-4,6-二氢吡咯并[3,4-d]咪唑-5(1H)-基)-2-(二甲基氨基)乙-1-酮;
2-(2-(5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)-4,6-二氢吡咯并[3,4-d]咪唑-5(1H)-基)乙烷-1-醇;
5-(1-(3,5-二氯吡啶-4-基)乙氧基)-3-(5-(甲基磺酰基)-1,4,5,6-四氢吡咯并[3,4-d]咪唑-2-基)-1H-吲唑;
(R)-5-(1-(3,5-二氯吡啶-4-基)乙氧基)-3-(5-(甲基磺酰基)-1,4,5,6-四氢吡咯并[3,4-d]咪唑-2-基)-1H-吲唑;
2-(5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)-4,6-二氢吡咯并[3,4-d]咪唑-5(1H)-羧酸甲酯;
(R)-2-(5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)-4,6-二氢吡咯并[3,4-d]咪唑-5(1H)-羧酸甲酯;
5-(1-(3,5-二氯吡啶-4-基)乙氧基)-3-(5-((1-甲基-1H-吡唑-4-基)磺酰基)-1,4,5,6-四氢吡咯并[3,4-d]咪唑-2-基)-1H-吲唑;
5-(1-(3,5-二氯吡啶-4-基)乙氧基)-3-(1,4,5,6-四氢吡咯并[3,4-d]咪唑-2-基)-1H-吲唑;
5-(1-(3,5-二氯吡啶-4-基)乙氧基)-3-(5-((1-甲基-1H-吡唑-3-基)磺酰基)-1,4,5,6-四氢吡咯并[3,4-d]咪唑-2-基)-1H-吲唑;
3-(2-(5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)-4,6-二氢吡咯并[3,4-d]咪唑-5(1H)-基)环丁-1-醇;
4-(2-(5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)-4,6-二氢吡咯并[3,4-d]咪唑-5(1H)-基)环己-1-醇;
乙基2-(5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)-4,6-二氢吡咯并[3,4-d]咪唑-5(1H)-羧酸盐;
2-氰基乙基2-(5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)-4,6-二氢吡咯并[3,4-d]咪唑-5(1H)-羧酸盐;
环丙基(2-(5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)-4,6-二氢吡咯并[3,4-d]咪唑-5(1H)-基)甲酮;
(2-(5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)-4,6-二氢吡咯并[3,4-d]咪唑-5(1H)-基)(3-羟基环丁基)甲酮;
3-(2-(5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)-4,6-二氢吡咯并[3,4-d]咪唑-5(1H)-基)-3-氧丙烷腈;
5-(1-(3,5-二氯吡啶-4-基)乙氧基)-3-(5-(乙基磺酰基)-1,4,5,6-四氢吡咯并[3,4-d]咪唑-2-基)-1H-吲唑;
3-(5-(环丙基磺酰基)-1,4,5,6-四氢吡咯并[3,4-d]咪唑-2-基)-5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑;
5-(1-(3,5-二氯吡啶-4-基)乙氧基)-3-(5-(异丙基磺酰基)-1,4,5,6-四氢吡咯并[3,4-d]咪唑-2-基)-1H-吲唑;
1-(2-(5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)-4,6-二氢吡咯并[3,4-d]咪唑-5(1H)-基)-2-(3-羟基吡咯烷-1-基)乙-1-酮;
1-(2-(2-(5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)-4,6-二氢吡咯并[3,4-d]咪唑-5(1H)-基)-2-氧代乙基)吡咯烷-3-腈;
(R)-2-(5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)-N-甲基-4,6-二氢吡咯并[3,4-d]咪唑-5(1H)-甲酰胺;
(R)-2-(5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)-N,N-二甲基-4,6-二氢吡咯并[3,4-d]咪唑-5(1H)-甲酰胺;
(R)-2-(5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)-N-(1-甲基-1H-吡唑-4-基)-4,6-二氢吡咯并[3,4-d]咪唑-5(1H)-甲酰胺;
5-((R)-1-(3,5-二氯吡啶-4-基)乙氧基)-3-(5-(1-甲基吡咯烷-3-基)-1,4,5,6-四氢吡咯并[3,4-d]咪唑-2-基)-1H-吲唑;
5-((R)-1-(3,5-二氯吡啶-4-基)乙氧基)-3-(5-(1-(1-甲基哌啶-4-基)乙基)-1,4,5,6-四氢吡咯并[3,4-d]咪唑-2-基)-1H-吲唑;
5-((R)-1-(3,5-二氯吡啶-4-基)乙氧基)-3-(5-(1-甲基哌啶-3-基)-1,4,5,6-四氢吡咯并[3,4-d]咪唑-2-基)-1H-吲唑;
5-((R)-1-(3,5-二氯吡啶-4-基)乙氧基)-3-(5-(1-(甲磺酰基)吡咯烷-3-基)-1,4,5,6-四氢吡咯并[3,4-d]咪唑-2-基)-1H吲唑;
(R)-1-(2-(5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)-4,6-二氢吡咯并[3,4-d]咪唑-5(1H)-基)-2-(吡咯烷-1-基)乙烷-1-酮;
1-(2-(5-((R)-1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)-4,6-二氢吡咯并[3,4-d]咪唑-5(1H)-基)-2-((R)-3-羟基吡咯烷-1-基)乙烷-1-酮;
1-(2-(5-((R)-1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)-4,6-二氢吡咯并[3,4-d]咪唑-5(1H)-基)-2-((S)-3-羟基吡咯烷-1-基)乙烷-1-酮;
(R)-1-(2-(5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)-4,6-二氢吡咯并[3,4-d]咪唑-5(1H)-基)-2-(二甲氨基)乙烷-1-酮;
3-(5-(L-脯氨酰)-1,4,5,6-四氢吡咯并[3,4-d]咪唑-2-基)-5-((R)-1-(3,5-二氯吡啶-4-基)乙氧基)-1H吲唑;
5-((R)-1-(3,5-二氯吡啶-4-基)乙氧基)-3-(5-(甲基-L-脯氨酰)-1,4,5,6-四氢吡咯并[3,4-d]咪唑-2-基)-1H吲唑;
(2-(5-((R)-1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)-4,6-二氢吡咯并[3,4-d]咪唑-5(1H)-基)((S)-哌啶-2-基)甲酮;
(2-(5-((R)-1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)-4,6-二氢吡咯并[3,4-d]咪唑-5(1H)-基)((S)-1-甲基哌啶-2-基)甲酮;
1-(2-(5-((R)-1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)-4,6-二氢吡咯并[3,4-d]咪唑-5(1H)-基)-2-(3-氟吡咯烷-1-基)乙烷-1-酮;
1-(2-(2-(5-((R)-1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)-4,6-二氢吡咯并[3,4-d]咪唑-5(1H)-基)-2-氧乙基)吡咯烷-3-腈;
(R)-1-(2-(5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)-4,6-二氢吡咯并[3,4-d]咪唑-5(1H)-基)-2-(哌啶-1-基)乙烷-1-酮;
(R)-2-(氮杂环丁烷-1-基)-1-(2-(5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)-4,6-二氢吡咯并[3,4-d]咪唑-5(1H)-基)乙烷-1-酮;
(R)-1-(2-(5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)-4,6-二氢吡咯并[3,4-d]咪唑-5(1H)-基)-2-(3-羟基氮杂环丁-1-基)乙烷-1-酮;
(R)-1-(2-(5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)-4,6-二氢吡咯并[3,4-d]咪唑-5(1H)-基)-2-(3-氟氮杂环丁烷-1-基)乙烷-1-酮;
2-(二甲氨基)乙基(R)-2-(5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)-4,6-二氢吡咯并[3,4-d]咪唑-5(1H)-羧酸盐;
1-甲基吡咯烷-3-基2-(5-((R)-1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)-4,6-二氢吡咯并[3,4-d]咪唑-5(1H)-羧酸盐。
本申请的化合物可以由本领域技术人员根据化合物具体结构由常规的有机合成方法合成得到。
例如,式(I)化合物可以通过合成路线(X)所示的方法来制备。
合成路线(X)
在上述合成路线(X)中,中间体Int-2中的G选自卤素、羟基、甲磺酰基(OMs)、对甲苯磺酰基(OTs)等。PG1,PG2,和PG3为氨基保护基,例如四氢吡喃(THP)、苄基(Bn)、对甲氧基苄基(PMB)、SEM、Boc等。当G为卤素、OMs、或者OTs,中间体Int-1和Int-2在碱性条件下的SN2偶联反应可以生成中间体Int-3。当G为OH,中间体Int-3可以通过Int-1和Int-2之间的Mitsunobu反应来获得。中间体Int-3与中间体Int-4的缩合反应生成化合物Int-5。在氧化条件下(例如但不限于Swern氧化或者IBX氧化),Int-5转化为中间体Int-6。经过保护基的转换,中间体Int-6可以转换为Int-8。在典型的成酰胺反应条件下(例如但不限于在DIPEA/HATU的存在下),或者成磺酰胺的反应条件下,或者生成脲的反应条件下,或者SN2偶联反应条件下,或者生成氨基甲酸酯的反应条件下,Int-8与合适的起始原料反应,再将保护基脱除,可以得到目标化合物式(I)。
另外,本领域技术人员可以参照本申请具体实施例的具体化合物的合成路线,对反应原料和反应条件进行适当调整而得到其它化合物的合成方法。
本申请的化合物可以抑制FGFR的活性。例如,本申请的化合物可以用于选择性抑制细胞中或需要对FGFR进行抑制的个体或患者中的FGFR1和/或FGFR2和/或FGFR3和/或FGFR4和/或它们的突变体(例如门控突变体,例如FGFR1 V561M突变体、FGFR2 V564F突变体、FGFR3 V555M突变体、FGFR3 K650E突变体等)的活性,这是通过向该细胞、个体或患者施用抑制量的本申请的化合物实现的。
在一些实施方式中,本申请的化合物对FGFR1、FGFR2、FGFR3以及它们的门控突变体(例如FGFR的FGFR1 V561M突变体、FGFR2 V564F突变体和FGFR3 V555M突变体)均具有优异的抑制活性。
本文所述的“门控(gatekeeper)突变”具有本领域通常已知的含义,其是防止药物结合的、能够导致发生耐药性的突变。FGFR的门控突变包括但不限于:FGFR1 V561M、FGFR2V564F、FGFR2 V564I、FGFR2 N550K、FGFR2 V565I、FGFR3 V555M、FGFR4 V550L、FGFR4V550M、FGFR4 V555M、FGFR4 V555L等。
在第二个方面,本申请提供了一种药物组合物,其含有如上文所述的本申请的化合物或其同位素标记化合物、或其光学异构体、几何异构体、互变异构体或异构体混合物、或其药学上可接受的盐、或其前药、或其代谢物,以及一种或多种药学上可接受的载体、佐剂或赋形剂。
本申请的药物组合物可以按制药领域中熟知的方式制备,并且可以通过多种途径施用,这取决于期望局部治疗还是全身性治疗并且取决于有待治疗的部位。给药可以是局部的(包括眼科的和至粘膜,包括鼻内、阴道和直肠递送)、肺部的(例如,通过吸入或吹入粉末或气溶胶,包括通过喷雾器;气管内、鼻内、表皮和经皮肤)、眼部的、经口的或肠胃外的。用于眼部递送的方法可以包括局部给药(滴眼剂),结膜下、眼周或玻璃体内注射或者通过用手术方法放置在结膜囊中的气囊式导管或眼科插入件引入。肠胃外给药包括静脉内、动脉内、皮下、腹膜内或肌内注射或输注;或颅内(例如,鞘内或脑室内)给药。肠胃外给药可以处于单次推注剂量的形式,或者可以例如通过连续灌注泵。用于局部给药的医药组合物和配制物可以包括透皮贴剂、软膏剂、洗剂、乳膏剂、凝胶剂、滴剂、栓剂、喷雾剂、液体以及粉剂。
如果使用固体载剂,则该制剂可以成片,以粉末或颗粒形式置于硬质凝胶胶囊中,或以糖锭或锭剂形式。固体载剂可以包括常规的赋形剂,诸如粘合剂、填料、成片润滑剂、崩解剂、润湿剂等等。如果需要可以通过常规技术膜包衣该片剂。如果使用液体载剂,则该制剂可以是糖浆、乳液、膏剂、软凝胶胶囊、用于注射的无菌载体、水性或非水性液体悬浮液形式的,或者可以是在使用前用水或其他适当载体复原的干品。液体制剂可以包含常规添加剂,诸如悬浮剂、乳化剂、润湿剂、非水性载体(包括可食用油)、防腐剂以及香味剂和/或着色剂。为了胃肠外施予,通常载体至少大部分包括无菌水,但也可以使用盐水溶液、葡萄糖溶液等。也可以使用可注射悬浮液,在这种情况下,可以使用常规悬浮剂。常规防腐剂、缓冲试剂等也可以添加到胃肠外剂型中。药物组合物通过对包含适量的活性成分(即本申请的化合物)的所需制剂合适的常规技术制备。
适于非肠道注射的组合物可以包括生理学上可接受无菌水性或非水性溶液、分散液、悬浮液或乳液和用于无菌可注射溶液或分散液的无菌粉末。合适的水性和非水性载体、稀释剂、溶剂的实例包括水、乙醇、多元醇(丙二醇、聚乙二醇、丙三醇等)、其合适的混合物、植物油(例如,橄榄油)和可注射有机酯(例如,油酸乙酯)。
这些组合物还可以包含各种赋形剂,例如,防腐剂、润湿剂、乳化剂和分散剂。可以通过各种抗菌剂和抗真菌剂(例如,对羟基苯甲酸酯、氯丁醇、苯酚、山梨酸等)来确保对微生物的作用的抑制。还可以包括等渗剂,例如,糖、氯化钠等。可以通过使用延迟吸收试剂(例如,单硬脂酸铝和凝胶)来延长可注射药学剂型的吸收。
用于口服的固体剂型包括胶囊、药片、药丸、粉末和颗粒。在这种固体剂型中,将活性化合物与至少一种惰性赋型剂(或载体)(例如,柠檬酸钠或磷酸二钙)混合,其中还可以包括:(a)填料或混合剂(例如,淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸);(b)粘结剂(例如,羧基甲基纤维素、褐藻酸酯、凝胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯树胶);(c)保湿剂(例如,丙三醇);(d)崩解剂(例如,琼脂-琼脂、碳酸钙、马铃薯或木薯淀粉、褐藻酸、某些合成的硅酸酯、碳酸钠);(e)溶液阻滞剂(例如,石蜡);(f)吸收促进剂(例如,季铵化合物);(I)润湿剂(例如,十六烷醇和单硬脂酸丙三醇酯);(h)吸附剂(例如,高岭土和斑脱土)和(i)润滑剂(例如,滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、月桂基硫酸钠)或其混合物混合。
类似类型的固体组合物还可以在使用例如乳糖以及高分子量聚乙二醇等作为赋型剂的软填充和硬填充凝胶胶囊中作为填料。
固体剂型(例如,药片、糖衣丸、胶囊、药丸和颗粒)可以采用涂层和外壳(例如,肠道涂层和本领域已知的其它)来制备。它们可以包含遮光剂,它们还可以是以延迟方式在肠道的某一部分中释放活性化合物或各种活性化合物的组合物。可用的包埋组合物的实例是聚合物质和蜡。活性组分还可以以微胶囊化形式,如果适当的话,可以具有一种或更多种上述赋型剂。
用于口服的液体剂型包括药学上可接受乳液、溶液、分散液、糖浆和酏剂。除了活性化合物以外,液体剂型可以包含本领域中通常所用的惰性稀释剂(例如,水或其它溶剂)、增溶剂和乳化剂(例如,乙醇、异丙醇、碳酸乙酯、乙酸乙酯、苯甲醇、苯甲酸苯甲酯、丙二醇、1,3丁二醇、二甲基甲酰铵)、油(具体为,棉花子油、落花生油、玉米油、橄榄油、蓖麻油、芝麻油)、丙三醇、四氢呋喃醇、聚乙二醇和山梨聚糖的脂肪酸酯或这些物质的混合物等。
除了这些惰性稀释剂,组合物还可以包括,例如,润湿剂、乳化和悬浮剂、香化剂、调味剂和加香剂。
除了活性化合物,悬浮液可以包含悬浮剂,例如乙氧基化异十八烷醇、聚氧化乙烯山梨醇、山梨聚糖酯、微晶纤维、偏氢氧化铝、斑脱土、琼脂-琼脂和黄芪胶或这些物质的混合物等。
本申请的化合物的局部给药用剂型包括膏剂、粉末、喷雾和吸入剂。该活性组分在无菌条件下与生理学上可接受载体和任何所需要的防腐剂、缓冲剂或推进剂混合。眼用配方、眼药膏、粉末和溶液也包括在本申请的范围内。
本申请的化合物在药物组合物和剂型中的量可以由本领域技术人员根据需要适当地确定,例如本申请的化合物可以治疗有效量存在于药物组合物或剂型中。
在第三个方面,本申请提供了本申请的化合物或其同位素标记化合物、或其光学异构体、几何异构体、互变异构体或异构体混合物、或其药学上可接受的盐、或其前药、或其代谢物,或如上文所述的药物组合物在制备用于治疗与FGFR相关的疾病或病症的药物中的用途。
本申请也提供了治疗与FGFR相关的疾病或病症的方法,所述方法包括向有此需要的患者施用治疗有效量的本申请的化合物或其同位素标记化合物、或其光学异构体、几何异构体、互变异构体或异构体混合物、或其药学上可接受的盐、或其前药、或其代谢物,或如上文所述的药物组合物。其中,所述患者优选是哺乳动物,更优选是人类患者。其中给药途径可以是口服、外用(包括但不限于外敷、喷涂等)、胃肠外(包括皮下、肌肉、皮层和静脉)施予、支气管施予或鼻施予等。
在一些实施方案中,所述与FGFR相关的疾病或病症是癌症。本申请的化合物可例如用于抑制癌细胞的增殖、转移等。
示例性癌症包括膀胱癌、乳腺癌、子宫颈癌、结肠直肠癌、小肠癌、结肠癌、直肠癌、肛门癌、子宫内膜癌、头颈癌(例如,喉、喉咽、鼻咽、口咽、唇部和口腔的癌症)、肾癌、肝癌(例如,肝细胞癌、胆管细胞癌)、肺癌(例如,腺癌、小细胞肺癌和非小细胞肺癌、小细胞癌和非小细胞癌、支气管癌、支气管腺瘤、胸膜肺母细胞瘤)、卵巢癌、前列腺癌、睾丸癌、子宫癌、食管癌、胆囊癌、胰腺癌(例如外分泌胰腺癌)、甲状腺癌、副甲状腺癌、皮肤癌(例如,鳞状细胞癌、卡波西肉瘤、梅克尔(Merkel)细胞皮肤癌)以及脑癌(例如,星状细胞瘤、神经管胚细胞瘤、室管膜瘤、神经外胚层肿瘤、松果体肿瘤)。
另外的示例性癌症包括造血系统恶性肿瘤,如白血病或淋巴瘤、多发性骨髓瘤、慢性淋巴细胞性淋巴瘤、成人T细胞白血病、B细胞淋巴瘤、皮肤T细胞淋巴瘤、急性骨髓性白血病、霍奇金或非霍奇金淋巴瘤、骨髓增生性肿瘤(例如,真性红细胞增多症、原发性血小板增多症和原发性骨髓纤维化)、瓦登斯特隆巨球蛋白血症、毛细胞淋巴瘤、慢性骨髓性淋巴瘤、急性淋巴母细胞性淋巴瘤、AIDS相关的淋巴瘤以及柏基特淋巴瘤。
另外的示例性癌症包括眼睛肿瘤、神经胶母细胞瘤、黑色素瘤、横纹肌肉瘤、淋巴肉瘤以及骨肉瘤。
在一些优选的实施方式中,所述与FGFR相关的疾病或病症选自肝细胞癌、乳腺癌、膀胱癌、结肠直肠癌、黑色素瘤、间皮瘤、肺癌、前列腺癌、膜腺癌、睾丸癌、甲状腺癌、鳞状细胞癌、神经胶母细胞瘤、成神经细胞瘤、子宫癌以及横纹肌肉瘤。
在另一些实施方式中,所述与FGFR相关的疾病或病症选自骨骼障碍和软骨细胞障碍,此类骨骼障碍和软骨细胞障碍包括但不限于软骨发育不全、软骨生成减退、侏儒症、致死性软骨发育不全(TD)(临床形式TD I和TD II)、阿佩尔(Apert)综合症、克鲁宗(Crouzon)综合症、杰克逊-威斯(Jackson-Weiss)综合症、比尔-史蒂文森皮肤旋纹综合症(Beare-Stevenson cutis gyrate syndrome)、斐弗(Pfeiffer)综合症以及颅缝线封闭过早综合症。
在另一些实施方式中,所述与FGFR相关的疾病或病症为低磷血症障碍,所述低磷血症障碍包括例如X连锁低磷酸盐血性佝偻病(X-Iinked hypophosphatemic rickets)、常染色体隐性低磷酸盐血性何偻病(autosomal recessive hypophosphatemic rickets)、常染色体显性低磷酸盐血性佝偻病(autosomaI dominant hypophosphatemic rickets)以及肿瘤诱发的骨软化症(tumor-induced osteromaIacia)。
在另一些实施方式中,所述与FGFR相关的疾病或病症选自纤维化疾病。示例性纤维化疾病包括肝硬化、肾小球肾炎、肺纤维化、系统性纤维化、类风湿性关节炎以及伤口愈合。
在一些实施方式中,所述与FGFR相关的疾病或病症是因FGFR中的门控突变而对不靶向门控突变的FGFR抑制剂有抗性的疾病和病症。
下面结合具体实施例对本申请做进一步的说明和描述。
实施例
以下在本文中阐述的实施例仅仅为了说明目的,用以举例说明本发明的各个方面以及实施方式,并不意欲以任何方式限制本发明所要求保护的范围。
除非另有声明,所有反应物均从商业途径获得。合成实验和产物分析检测中所用仪器设备等均为有机合成中通常使用的常规仪器和设备。
实施例1:(2-(5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)-4,6-二氢吡
咯并[3,4-d]咪唑-5(1H)-基)(4-甲基哌嗪-1-基)甲酮
化合物1的合成路线:
合成方法:
合成中间体1-1:1H-吲哚-5-乙酸酯
将5-羟基吲哚(240.0mg,1.80mmol)溶于20ml吡啶中,滴加乙酸酐(202.4mg,1.98mmol),室温搅拌16小时。向反应液中加水,用乙酸乙酯萃取2次,合并有机相,用饱和食盐水洗涤,无水硫酸钠干燥,浓缩得粗品中间体1-1 276.6mg,收率87.4%。
合成中间体1-2:3-甲酰基-1H-吲唑-5-乙酸酯
将亚硝酸钠(157.5mg,2.28mmol)溶于10ml水中,加入10ml DMF,0度滴加3M HCl(0.7ml,2.05mmol),搅拌10分钟,向反应液中加入1H-吲哚-5-乙酸酯(50.0mg,0.29mmol)的DMF(10ml)溶液,室温反应3小时。向反应液中加水,用乙酸乙酯萃取2次,合并有机相,用饱和食盐水洗涤,无水硫酸钠干燥,浓缩,硅胶柱纯化,得中间体1-2 37.6mg,收率63.5%。
1H NMR(400MHz,CDCl3)δ10.25(s,1H),8.01(s,1H),7.49(d,J=9.0Hz,1H),7.21(d,J=9.0Hz,1H),2.36(s,3H).
合成中间体1-3:3-甲酰基-1-(四氢-2H-吡喃-2-基)-1H-吲唑-5-乙酸酯
将1-2(190.0mg,0.93mmol)溶于20ml DCM中,加入对甲苯磺酸(177.0mg,0.93mmol),搅拌2分钟,向反应液中加入3,4-二氢-2H-吡喃(117.4mg,1.40mmol)的DCM(3ml)溶液,室温反应1小时。向反应液中加水,用DCM萃取2次,合并有机相,分别用饱和碳酸氢钠溶液和饱和食盐水洗涤,无水硫酸钠干燥,浓缩,硅胶柱纯化,得中间体1-3 160.2mg,收率59.6%。
合成中间体1-4:5-羟基-1-(四氢-2H-吡喃-2-基)-1H-吲唑-3-甲醛
将1-3(160.2mg,0.56mmol)溶于20ml甲醇中,向溶液中加入碳酸钾(115.1mg,0.83mmol),室温反应30分钟。将反应液过滤,滤液浓缩得粗品中间体1-4 130.5mg,收率95.1%。
合成中间体1-5:5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1-(四氢-2H-吡喃-2-基)-1H-吲唑-3-甲醛
将1-(3,5-二氯吡啶-4-基)乙烷-1-醇(93.6mg,0.49mmol)和三乙胺(148.6mg,1.47mmol)溶于20ml DCM中,0度向反应液中滴加入甲磺酰氯(57.3mg,0.50mmol),室温反应1小时。向反应液中加水淬灭,用二氯甲烷萃取2次,合并有机相,用饱和食盐水洗涤,无水硫酸钠干燥,浓缩。将中间体1-4(100.0mg,0.41mmol)和浓缩物溶于20ml DMF中,加入碳酸铯(264.6mg,0.82mmol),60度反应16小时。向反应液中加水,用乙酸乙酯萃取2次,合并有机相,用饱和食盐水洗涤,无水硫酸钠干燥,浓缩,硅胶柱纯化,得中间体1-5 64.3mg,收率37.5%。
1H NMR(400MHz,CDCl3)δ10.16(s,1H),8.42(s,2H),7.59-7.53(m,2H),7.18-7.15(m,1H),6.11(q,J=6.7Hz,1H),5.77-5.72(m,1H),4.01-3.94(m,1H),3.77-3.70(m,1H),2.54-2.46(m,1H),2.22-2.06(m,2H),1.81(d,J=6.7Hz,3H),1.76-1.68(m,3H).
合成中间体1-6:2-(5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1-(四氢-2H-吡喃-2-基)-1H-吲唑-3-基)-3a,4,6,6a-四氢吡咯并[3,4-d]咪唑-5(1H)-羧酸叔丁酯
将1-5(100.0mg,0.24mmol)溶于10ml叔丁醇中,加入3,4-二氨基吡咯烷-1-羧酸叔丁酯(59.8mg,0.24mmol),碘(90.6mg,0.36mmol),碳酸钾(98.6mg,0.71mmol),升温70℃反应3小时。反应完成后,降至室温,加5%的硫代硫酸钠水溶液淬灭反应,加EA萃取,有机相用饱和食盐水洗涤,无水硫酸钠干燥,浓缩,硅胶柱纯化,得中间体1-6 105mg,收率73.4%。
1H NMR(400MHz,CDCl3)δ8.40(s,2H),7.66(s,1H),7.47-7.44(m,1H),7.13-7.10(m,1H),6.11(q,J=6.8Hz,1H),5.66-5.61(m,1H),4.77-4.48(m,2H),4.02-3.94(m,1H),3.74-3.59(m,5H),2.52-2.43(m,1H),2.04-2.00(m,2H),1.79(d,J=6.8Hz,3H),1.75-1.68(m,3H),1.45(s,9H).
合成中间体1-7:2-(5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1-(四氢-2H-吡喃-2-基)-1H-吲唑-3-基)-4,6-二氢吡咯并[3,4-d]咪唑-5(1H)-羧酸叔丁酯
将1-6(40.0mg,0.07mmol)溶于10ml DMSO中,加入IBX(37.2mg,0.13mmol),升温50℃反应3小时。反应完成后,降至室温,加水淬灭反应,加EA萃取,有机相用饱和食盐水洗涤,无水硫酸钠干燥,浓缩,硅胶柱纯化,得中间体1-7 22mg,收率55.2%。
1H NMR(400MHz,CDCl3)δ8.38(d,J=7.2Hz,2H),7.81(s,1H),7.44-7.41(m,1H),7.15-7.13(m,1H),6.14(q,J=6.7Hz,1H),5.63-5.60(m,1H),4.57-4.48(m,4H),4.07-3.99(m,1H),3.75-3.69(m,1H),2.55-2.44(m,1H),2.04-1.98(m,2H),1.80(d,J=6.7Hz,3H),1.76-1.69(m,3H),1.62(s,9H).
合成中间体1-8:2-(5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1-(四氢-2H-吡喃-2-基)-1H-吲唑-3-基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-4,6-二氢吡咯并[3,4-d]咪唑-5(1H)-羧酸叔丁酯
将1-7(22.0mg,0.04mmol)溶于5ml THF中,降温至0℃,加入NaH(60%)(1.9mg,0.05mmol),搅拌15mim,加入SEMCl(6.7mg,0.04mmol)。加入完毕后升至室温搅拌,反应完成后,加水淬灭,加EA萃取,有机相用饱和食盐水洗涤,无水硫酸钠干燥,浓缩,硅胶柱纯化,得中间体1-818mg,收率67.2%。
合成中间体1-9:5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1-(四氢-2H-吡喃-2-基)-3-(1-(((2-(三甲基甲硅烷基)乙氧基)甲基)-1,4,5,6-四氢吡咯并[3,4-d]咪唑-2-基)-1H-吲唑
将1-8(200.0mg,0.27mmol)溶于20ml DCM中,加入ZnBr2(246.9mg,1.10mmol),室温下搅拌。反应完成后,加水淬灭,加DCM萃取,有机相用饱和食盐水洗涤,无水硫酸钠干燥,浓缩,得中间体1-9 140mg,收率81.1%。
合成化合物1:(2-(5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)-4,6-二氢吡咯并[3,4-d]咪唑-5(1H)-基)(4-甲基哌嗪-1-基)甲酮
将1-9(30.0mg,0.05mmol)和三光气(14.1mg,0.048mmol)溶于5ml DCM中,降温至0℃向溶液中加入TEA(9.6mg,0.10mmol),反应1小时,向体系中加入N-甲基哌嗪(4.8mg,0.05mmol),升至室温搅拌。反应完成后,加水淬灭,用DCM萃取,合并有机相,用饱和食盐水洗涤,浓缩。将浓缩物溶于4ml甲醇中,加入2ml浓盐酸,50度反应5小时,浓缩,溶于5ml甲醇,加0.5ml氨水,浓缩,制备板纯化,得到最终产物9.0mg,收率34.6%。
1H NMR(400MHz,MeOD)δ8.43(s,2H),7.63(d,J=2.4Hz,1H),7.43(d,J=9.1Hz,1H),7.16-7.13(m,1H),6.17(q,J=6.7Hz,1H),4.65(s,4H),3.46(t,J=5.0Hz,4H),2.64(t,J=4.0Hz,4H),2.42(s,3H),1.81(d,J=6.7Hz,3H).
实施例2:5-(1-(3,5-二氯吡啶-4-基)乙氧基)-3-(5-((1-甲基哌啶-4-基)甲基)-
1,4,5,6-四氢吡咯并[3,4-d]咪唑-2-基)-1H-吲唑
化合物2的合成路线:
合成方法:
合成中间体2-1:4-((2-(5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1-(四氢-2H-吡喃-2-基)-1H-吲唑-3-基)-1-(((2-(三甲基甲硅烷基)乙氧基)甲基)-4,6-二氢吡咯并[3,4-d]咪唑-5(1H)-基)甲基)哌啶-1-甲酸叔丁酯
将1-9(100.0mg,0.16mmol)和1-Boc-4-溴甲基哌啶(53.0mg,0.19mmol)溶于10mlDMF中,向体系中加入碳酸铯(103.5mg,0.32mmol)。加热至80度反应。反应完成后,加水淬灭,用EA萃取,合并有机相,用饱和食盐水洗涤,浓缩,柱层析得到产物63.2mg,收率48.1%。
合成中间体2-2:5-(1-(3,5-二氯吡啶-4-基)乙氧基)-3-(5-(哌啶-4-基甲基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1,4,5,6-四氢吡咯并[3,4-d]咪唑-2-基)-1-(四氢-2H-吡喃-2-基)-1H-吲唑
将中间体2-1(63.0mg,0.08mmol)和溴化锌(53.0mg,0.31mmol)溶于10ml DCM中,室温反应。反应完成后,加饱和碳酸氢钠水溶液淬灭,用DCM萃取,合并有机相,用饱和食盐水洗涤,浓缩,得到产物42.0mg,收率76%。
合成化合物2:5-(1-(3,5-二氯吡啶-4-基)乙氧基)-3-(5-(1-甲基哌啶-4-基)-1,4,5,6-四氢吡咯并[3,4-d]咪唑-2-基)-1H-吲唑
将中间体2-2(42.0mg,0.06mmol)和30%甲醛水溶液(5.0mg,0.17mmol)溶于5mlDCM中,降温至0℃向溶液中加入三乙酰基硼氢化钠(73.1mg,0.35mmol)。反应完成后,加水淬灭,用DCM萃取,合并有机相,用饱和食盐水洗涤,浓缩。将浓缩物溶于4ml甲醇中,加入2ml浓盐酸,50度反应5小时,浓缩,溶于5ml甲醇,加0.5ml氨水,浓缩,制备板纯化,得到最终产物5.2mg,收率17.1%。
1H NMR(400MHz,MeOD)δ8.46(s,2H),7.65(d,J=2.4Hz,1H),7.45(d,J=9.1Hz,1H),7.18-7.16(m,1H),6.19(q,J=6.7Hz,1H),4.67-4.56(m,4H),4.14(d,J=5.7Hz,2H),3.42-3.34(m,2H),2.84-2.76(m,2H),2.78(s,3H),2.04-1.96(m,4H),1.83(d,J=6.7Hz,3H),1.64-1.58(m,1H).
实施例3:5-(1-(3,5-二氯吡啶-4-基)乙氧基)-3-(5-(1-甲基哌啶-4-基)-1,4,5,
6-四氢吡咯并[3,4-d]咪唑-2-基)-1H-吲唑
化合物3的合成路线:
合成方法:
合成化合物3:5-(1-(3,5-二氯吡啶-4-基)乙氧基)-3-(5-(1-甲基哌啶-4-基)-1,4,5,6-四氢吡咯并[3,4-d]咪唑-2-基)-1H-吲唑
将1-9(40.0mg,0.06mmol)和N-甲基-4-哌啶酮(9.3mg,0.08mmol)溶于5ml 1,2-二氯乙烷中,降温至0℃向溶液中加入三乙酰基硼氢化钠(26.8mg,0.13mmol)。反应完成后,加水淬灭,用DCM萃取,合并有机相,用饱和食盐水洗涤,浓缩。将浓缩物溶于4ml甲醇中,加入2ml浓盐酸,50度反应5小时,浓缩,溶于5ml甲醇,加0.5ml氨水,浓缩,制备板纯化,得到最终产物8.3mg,收率25.5%。
1H NMR(400MHz,MeOD)δ8.42(s,2H),7.63(d,J=2.4Hz,1H),7.42(d,J=9.0Hz,1H),7.15-7.12(m,1H),6.17(q,J=6.7Hz,1H),3.95(s,4H),3.21-3.11(m,2H),2.84-2.75(m,1H),2.52(s,3H),2.48-2.45(m,2H),2.11-2.08(m,2H),1.80(d,J=6.7Hz,3H),1.76-1.73(m,2H).
实施例4:2-(5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)-5-(1-甲基哌
啶-4-基)-4,5,6,7-四氢-3H-咪唑并[4,5-c]吡啶
化合物4的合成路线:
合成方法:
合成中间体4-1:5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1-(四氢-2H-吡喃-2-基)-1H-吲唑-3-腈
将5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1-(四氢-2H-吡喃-2-基)-1H-吲唑-3-甲醛(245.0mg,0.58mmol)和三乙胺(147.5mg,1.46mmol)溶于10ml乙腈中,向溶液中加入盐酸羟胺(60.8mg,0.87mmol),60度反应3小时。将反应液冷却至室温,向反应液加入三乙胺(471.9mg,4.66mmol)和乙酸酐(238.0mg,2.33mmol),80度反应16小时。向反应液中加水,用二氯甲烷萃取2次,合并有机相,用饱和食盐水洗涤,无水硫酸钠干燥,浓缩,硅胶柱纯化,得中间体4-1 240.6mg,收率98.7%。
1H NMR(400MHz,CDCl3)δ8.37(d,J=6.8Hz,2H),7.82(s,1H),7.46(d,J=9.2Hz,1H),7.15(d,J=9.2Hz,1H),6.11(q,J=6.7Hz,1H),5.83-5.79(m,1H),4.01-3.93(m,1H),3.78-3.66(m,1H),2.58-2.44(m,2H),2.18-1.99(m,2H),1.81(d,J=6.7Hz,3H),1.73-1.65(m,2H).
合成中间体4-2:5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1-(四氢-2H-吡喃-2-基)-1H-吲唑-3-氨基甲酸酯
将中间体4-1(240.0mg,0.58mmol)溶于10ml甲醇中,向反应液加入甲醇钠(93.2mg,1.73mmol),室温反应16小时,将反应液浓缩除去甲醇,浓缩物中加水,用乙酸乙酯萃取2次,合并有机相,用饱和食盐水洗涤,无水硫酸钠干燥,浓缩得到中间体4-2粗品220mg,收率85.1%。
1H NMR(400MHz,CDCl3)δ8.42(s,2H),7.50-7.47(m,1H),7.22(s,1H),7.14-7.11(m,1H),6.04(q,J=6.8Hz,1H),5.73-5.64(m,1H),4.02(s,3H),3.99-3.94(m,1H),3.75-3.66(m,1H),2.58-2.46(m,1H),2.18-2.10(m,1H),1.81(d,J=6.8Hz,3H),1.76-1.63(m,4H).
合成中间体4-3:叔丁基3-(5-(1-(3,5-二氯吡啶基-4-基)乙氧基)-1-(四氢-2H-吡喃-2-基)-1H-吲唑-3-羧酰亚胺基)-4,4-二乙氧基哌啶-1-羧酸盐
将中间体4-2(100.0mg,0.22mmol)和3-氨基-4,4-二乙氧基哌啶-1-羧酸叔丁酯(70.6mg,0.24mmol)溶于10ml乙醇中,向反应液加入醋酸(26.7mg,0.44mmol),50度反应16小时,将反应液浓缩除去乙醇,浓缩物用适量甲苯带一下,浓缩得到中间体4-3粗品211mg,收率134.4%。
合成中间体4-4:2-(5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)-4,5,6,7-四氢-3H-咪唑[4,5-c]吡啶
将中间体4-3(157.0mg,0.22mmol)溶于10ml乙醇中,向反应液加入5ml浓盐酸,40度反应16小时,浓缩,溶于5ml甲醇,加0.5ml氨水,浓缩,硅胶柱纯化,得到中间体4-460.3mg,收率62.8%。
1H NMR(400MHz,DMSO)δ13.12(s,1H),12.48(s,1H),8.58(s,2H),7.61(s,1H),7.45(d,J=9.0Hz,1H),7.09(dd,J=9.0Hz,J=2.5Hz,1H),6.01(q,J=6.5Hz,1H),3.88(s,2H),3.06(t,J=5.9Hz,2H),2.79(t,J=5.5Hz,2H),1.75(d,J=6.6Hz,3H).
合成化合物4:2-(5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)-5-(1-甲基哌啶-4-基)-4,5,6,7-四氢-3H-咪唑并[4,5-c]吡啶
将中间体4-4(10.0mg,0.02mmol)溶于5ml NMP中,向溶液中加入0.1ml醋酸,55度搅拌10分钟,冷却至室温,加入1-甲基哌啶-4-酮(4.0mg,0.03mmol),室温反应16小时,加入三乙酰氧基硼氢化钠(7.4mg,0.03mmol),室温反应2小时,加0.5ml氨水调pH,向混合物中加水,用乙酸乙酯萃取2次,合并有机相,用饱和食盐水洗涤,无水硫酸钠干燥,浓缩,制备板纯化,得最终产物3.6mg,收率29.3%。
1H NMR(400MHz,MeOD)δ8.45(s,2H),7.61(s,1H),7.43(d,J=9.0Hz,1H),7.15(dd,J=9.1,J=2.4Hz,1H),6.18(q,J=6.7Hz,1H),3.81(s,2H),3.12(d,J=12.1Hz,2H),3.03(t,J=5.7Hz,2H),2.83(t,J=5.8Hz,2H),2.75-2.69(m,1H),2.42(s,3H),2.30(t,J=12.1Hz,2H),2.07(d,J=12.5Hz,2H),1.84-1.76(m,5H).
实施例5:(2-(5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)-3,4,6,7-四
氢-5H-咪唑并[4,5-c]吡啶-5-基)(4-甲基哌嗪-1-基)甲酮
化合物5的合成路线:
合成方法:
合成化合物5:(2-(5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)-3,4,6,7-四氢-5H-咪唑并[4,5-c]吡啶-5-基)(4-甲基哌嗪-1-基)甲酮
将三光气(13.8mg,0.05mmol)溶于5ml干燥二氯甲烷中,0度滴加中间体4-4(20.0mg,0.05mmol)的二氯甲烷(2ml)溶液,加完后缓慢滴加干燥三乙胺(138.3mg,0.47mmol)室温搅拌10分钟,TLC监测原料消失,加入1-甲基哌嗪(7.0mg,0.07mmol)的二氯甲烷(2ml)溶液,室温搅拌2小时,加水淬灭,用二氯甲烷萃取2次,合并有机相,用饱和食盐水洗涤,无水硫酸钠干燥,浓缩,硅胶柱纯化,得到最终产物10.3mg,收率38.6%。
1H NMR(400MHz,MeOH)δ8.43(s,2H),7.60(d,J=2.3Hz,1H),7.41(d,J=9.1Hz,1H),7.13(dd,J=9.1,J=2.4Hz,1H),6.16(q,J=6.7Hz,1H),4.44(s,2H),3.64(t,J=5.7Hz,2H),3.40(t,J=4.9Hz,4H),2.84(t,J=5.7Hz,2H),2.58(t,J=4.9Hz,4H),2.38(s,3H),1.81(d,J=6.7Hz,3H).
实施例6:(2-(5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)-4,6-二氢吡
咯并[3,4-d]咪唑-5(1H)-基)(1-甲基哌啶-4-基)甲酮
化合物6的合成路线:
合成方法:
合成化合物6:(2-(5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)-4,6-二氢吡咯并[3,4-d]咪唑-5(1H)-基)(1-甲基哌啶-4-基)甲酮
将1-9(30.0mg,0.05mmol),1-甲基哌啶-4-羧酸(8.2mg,0.06mmol)和HATU(21.7mg,0.06mmol)溶于5ml DMF中,向溶液中滴加DIPEA(9.2mg,0.07mmol),室温搅拌3小时,向反应液中加水,用乙酸乙酯萃取2次,合并有机相,用饱和食盐水洗涤,无水硫酸钠干燥,浓缩,将浓缩物溶于6ml甲醇中,加入3ml浓盐酸,50度反应6小时,浓缩,溶于5ml甲醇,加0.5ml氨水,浓缩,制备板纯化,得到最终产物6.2mg,收率24.1%。
1H NMR(400MHz,MeOH)δ8.46(s,2H),7.66(d,J=2.3Hz,1H),7.45(d,J=9.0Hz,1H),7.17(dd,J=9.1,J=2.4Hz,1H),6.19(q,J=6.6Hz,1H),4.84(s,2H),4.62(s,2H),3.11-3.07(m,2H),2.75-2.65(m,1H),2.41(s,3H),2.35-2.27(m,2H),1.98-1.90(m,4H),1.83(d,J=6.7Hz,3H).
实施例7:5-(1-(3,5-二氯吡啶-4-基)乙氧基)-3-(5-(吡啶-3-基磺酰基)-1,4,5,
6-四氢吡咯并[3,4-d]咪唑-2-基)-1H-吲唑
化合物7的合成路线:
合成方法:
合成化合物7:5-(1-(3,5-二氯吡啶-4-基)乙氧基)-3-(5-(吡啶-3-基磺酰基)-1,4,5,6-四氢吡咯并[3,4-d]咪唑-2-基)-1H-吲唑
将1-9(30.0mg,0.05mmol),TEA(15.2mg,0.15mmol)溶于5ml DCM中,0℃下滴加3-磺酰基吡啶(13.3mg,0.08mmol),搅拌半小时,向反应液中加水,用二氯甲烷萃取2次,合并有机相,用饱和食盐水洗涤,无水硫酸钠干燥,浓缩,将浓缩物溶于6ml甲醇中,加入3ml浓盐酸,50℃反应3小时,浓缩,溶于5ml甲醇,加0.5ml氨水,浓缩,制备板纯化,得到最终产物10.2mg,收率37.7%。LC-MS m/z(ESI)[M+H]+针对C24H20Cl2N7O3S的计算值为:556.1;测量值为:556.1。
实施例8:(2-(5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)-4,6-二氢吡
咯并[3,4-d]咪唑-5(1H)-基)(吗啉基)甲酮
化合物8的合成路线:
合成方法:
合成化合物8:(2-(5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)-4,6-二氢吡咯并[3,4-d]咪唑-5(1H)-基)(吗啉基)甲酮
将1-9(46.0mg,0.07mmol)溶于10ml的二氯甲烷,向体系中加入三光气(21.7mg,0.07mmol),将体系降温至0℃,滴加三乙胺(14.8mg,0.15mmol),反应0.5h,向体系中加入吗啉(6.37mg,0.07mmol),升至室温反应。反应完成后,加水淬灭,用DCM萃取,合并有机相,用饱和食盐水洗涤,浓缩。将浓缩物溶于4ml甲醇中,加入2ml浓盐酸,50度反应5小时,浓缩,溶于5ml甲醇,加0.5ml氨水,浓缩,制备板纯化,得到最终产物10.2mg,收率26.4%。
1H NMR(400MHz,DMSO)δ13.10(s,1H),12.56(s,1H),8.57(s,2H),7.68(d,J=2.4Hz,1H),7.46(d,J=9.0Hz,1H),7.11-7.08(m,1H),6.04(q,J=6.6Hz,1H),4.58-4.51(m,4H),3.66-3.64(m,4H),3.31-3.26(m,4H),1.76(d,J=6.7Hz,3H).
实施例9:(2-(5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)-4,6-二氢吡
咯并[3,4-d]咪唑-5(1H)-基)((R)-吡咯烷-3-基)甲酮
化合物9的合成路线:
合成方法:
合成化合物9:(2-(5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)-4,6-二氢吡咯并[3,4-d]咪唑-5(1H)-基)((R)-吡咯烷-3-基)甲酮
将1-9(40.0mg,0.06mmol)溶于10ml的DMF,向体系中加入(R)-1-BOC-吡咯烷-3-甲酸(13.8mg,0.06mmol),HATU(24.3mg,0.06mmol),滴加DIPEA(9.9mg,0.08mmol),室温反应。反应完成后,加水淬灭,用EA萃取,合并有机相,用饱和食盐水洗涤,浓缩。将浓缩物溶于4ml甲醇中,加入2ml浓盐酸,50度反应5小时,浓缩,溶于5ml甲醇,加0.5ml氨水,浓缩,制备板纯化,得到最终产物11.2mg,收率34.2%。
1H NMR(400MHz,MeOD)δ8.46(s,2H),7.66(d,J=2.4Hz,1H),7.46(d,J=9.0Hz,1H),7.19-7.16(m,1H),6.19(q,J=6.7Hz,1H),4.80-4.59(m,4H),3.71-3.66(m,2H),3.50-3.43(m,3H),2.06-2.04(m,2H),1.84(d,J=6.7Hz,3H).
实施例10:(2-(5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)-4,6-二氢吡
咯[3,4-d]咪唑-5(1H)-基)((S)-3-羟基吡咯烷-1-基)甲酮
化合物10的合成路线:
合成方法:
合成化合物10:(2-(5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)-4,6-二氢吡咯[3,4-d]咪唑-5(1H)-基)((S)-3-羟基吡咯烷-1-基)甲酮
将三光气(14.1mg,0.05mmol)溶于5ml干燥二氯甲烷中,0度滴加中间体1-9(30.0mg,0.05mmol)的二氯甲烷(2ml)溶液,加完后缓慢滴加干燥三乙胺(48.2mg,0.47mmol),室温搅拌10分钟,TLC监测原料消失,加入(S)-吡咯烷丁-3-醇(6.2mg,0.07mmol)的二氯甲烷(2ml)溶液,室温搅拌2小时,加水淬灭,用二氯甲烷萃取2次,合并有机相,用饱和食盐水洗涤,无水硫酸钠干燥,浓缩,将浓缩物溶于6ml甲醇中,加入3ml浓盐酸,50度反应6小时,浓缩,溶于5ml甲醇,加0.5ml氨水,浓缩,制备板纯化,得到最终产物6.5mg,收率25.8%。
1H NMR(400MHz,MeOH)δ8.43(d,J=1.4Hz,2H),7.64(d,J=2.4Hz,1H),7.42(d,J=9.1Hz,1H),7.14(dd,J=9.0,J=2.4Hz,1H),6.17(q,J=6.6Hz,1H),4.79-4.76(m,2H),4.57-4.54(m,2H),4.44-4.42(m,1H),3.77-3.67(m,2H),3.60-3.55(m,1H),3.44-3.41(m,1H),2.07-1.92(m,2H),1.81(d,J=6.7Hz,3H).
实施例11:5-(1-(3,5-二氯吡啶-4-基)乙氧基)-3-(5-甲基-1,4,5,6-四氢吡咯并
[3,4-d]咪唑-2-基)-1H-吲唑
化合物11的合成路线:
合成方法:
合成化合物11:5-(1-(3,5-二氯吡啶-4-基)乙氧基)-3-(5-甲基-1,4,5,6-四氢吡咯并[3,4-d]咪唑-2-基)-1H-吲唑
将中间体1-9(30.0mg,0.05mmol)溶于5ml二氯甲烷中,加入甲醛水溶液(0.01ml,0.14mmol),室温搅拌20分钟,加入三乙酰基硼氢化钠(60.8mg,0.29mmol),室温反应2小时,向反应液中加水,用二氯甲烷萃取2次,合并有机相,用饱和食盐水洗涤,无水硫酸钠干燥,浓缩得到的粗品溶于2ml甲醇和1ml浓盐酸中,50度反应6小时,浓缩,溶于3ml甲醇,加0.5ml氨水,浓缩,制备板纯化,得到终产物3.6mg,两步总收率17.6%。
1H NMR(400MHz,MeOD)δ8.44(s,2H),7.64(d,J=4.0Hz,1H),7.45(d,J=12.0Hz,1H),7.16(dd,J=4.0Hz,J=8.0Hz,1H),6.20(dd,J=8.0Hz,J=16.0Hz,1H),3.96(s,4H),2.75(s,3H),1.83(d,J=4.0Hz,3H).
实施例12:4-(2-(2-(5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)-4,6-
二氢吡咯并[3,4-d]咪唑-5(1H)-基)乙基)吗啉
化合物12的合成路线:
合成方法:
合成化合物12:4-(2-(2-(5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)-4,6-二氢吡咯并[3,4-d]咪唑-5(1H)-基)乙基)吗啉
将1-9(100.0mg,0.16mmol)和4-(2-溴乙基)吗啉氢溴酸盐(52.4mg,0.19mmol)溶于10ml干燥DMF中,向体系中加入碳酸铯(103.5mg,0.32mmol)100度搅拌3小时,反应完毕后加水,用乙酸乙酯萃取2次,合并有机相,用饱和食盐水洗涤,无水硫酸钠干燥,浓缩,将浓缩物溶于4ml甲醇中,加入2ml浓盐酸,50度反应6小时,浓缩,溶于5ml甲醇,加0.5ml氨水,浓缩,制备板纯化,得到最终产物4.5mg,收率5.3%。
1H NMR(400MHz,MeOH)δ8.43(d,J=1.4Hz,2H),7.64(d,J=2.4Hz,1H),7.44(d,J=9.1Hz,1H),7.15(dd,J=9.0,J=2.4Hz,1H),6.19(q,J=6.6Hz,1H),4.04(s,4H),3.76(t,J=4.7Hz,4H),3.18-3.10(m,2H),2.71-2.67(m,2H),2.62-2.60(m,4H),1.83(d,J=6.6Hz,3H).
实施例13:1-(2-(5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)-4,6-二氢
吡咯并[3,4-d]咪唑-5(1H)-基)-2-吗啉代乙烷-1-酮
化合物13的合成路线:
合成方法:
合成化合物13:1-(2-(5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)-4,6-二氢吡咯并[3,4-d]咪唑-5(1H)-基)-2-吗啉代乙烷-1-酮
将1-9(30.0mg,0.05mmol)溶于10ml的DMF,向体系中加入4-吗啉乙酸(6.9mg,0.05mmol),HATU(21.7mg,0.06mmol)和DIPEA(12.3mg,0.10mmol),室温反应2小时。加水淬灭,用EA萃取,合并有机相,用饱和食盐水洗涤,浓缩。将浓缩物溶于4ml甲醇中,加入2ml浓盐酸,50度反应5小时,浓缩,溶于5ml甲醇,加0.5ml氨水,浓缩,制备板纯化,得到最终产物4.2mg,收率16.3%。
1H NMR(400MHz,DMSO)δ13.12(s,1H),12.63(s,1H),8.58(s,2H),7.68(d,J=2.4Hz,1H),7.46(d,J=9.0Hz,1H),7.11-7.08(m,1H),6.04(q,J=6.7Hz,1H),4.81-4.43(m,4H),3.63-3.61(m,4H),3.25(s,2H),2.67-2.56(m,4H),1.77(d,J=6.7Hz,3H).
实施例14:1-(2-(5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)-4,6-二氢
吡咯并[3,4-d]咪唑-5(1H)-基)-2-(二甲基氨基)乙-1-酮
化合物14的合成路线:
合成方法:
合成化合物14:1-(2-(5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)-4,6-二氢吡咯并[3,4-d]咪唑-5(1H)-基)-2-(二甲基氨基)乙-1-酮
将1-9(50.0mg,0.079mmol)溶于10ml的DMF,向体系中加入N,N-二甲基甘氨酸(9.8mg,0.095mmol),HATU(36.2mg,0.095mmol),滴加DIPEA(20.5mg,0.159mmol),室温反应。反应完成后,加水淬灭,用EA萃取,合并有机相,用饱和食盐水洗涤,浓缩。将浓缩物溶于4ml甲醇中,加入2ml浓盐酸,50度反应5小时,浓缩,溶于5ml甲醇,加0.5ml氨水,浓缩,制备板纯化,得到最终产物15.0mg,收率37.8%。
1H NMR(400MHz,DMSO)δ8.58(s,2H),7.68(s,1H),7.46(d,J=9.0Hz,1H),7.11-7.08(m,1H),6.04(q,J=6.7Hz,1H),4.77-4.45(m,4H),3.22-3.17(m,2H),2.28(d,J=11.0Hz,6H),1.76(d,J=6.7Hz,3H).
实施例15:2-(2-(5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)-4,6-二氢
吡咯并[3,4-d]咪唑-5(1H)-基)乙烷-1-醇
化合物15的合成路线:
合成方法:
合成化合物15:2-(2-(5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)-4,6-二氢吡咯并[3,4-d]咪唑-5(1H)-基)乙烷-1-醇
将1-9(30.0mg,0.05mmol)溶于10ml的DMF,向体系中加入(2-溴乙氧基)叔丁基二甲基硅烷(17.1mg,0.07mmol),碳酸铯(46.6mg,0.14mmol),加热至80度反应3小时,加水淬灭,用EA萃取,合并有机相,用饱和食盐水洗涤,浓缩。将浓缩物溶于4ml甲醇中,加入2ml浓盐酸,50度反应5小时,浓缩,溶于5ml甲醇,加0.5ml氨水,浓缩,制备板纯化,得到最终产物10.2mg,收率46.3%。
1H NMR(400MHz,MeOH)δ8.46(s,2H),7.63(d,J=2.4Hz,1H),7.47(d,J=9.1Hz,1H),7.19-7.07(m,1H),6.17(q,J=6.7Hz,1H),4.76-4.58(m,4H),3.99(t,J=5.2Hz,2H),3.69(t,J=5.2Hz,2H),1.84(d,J=6.7Hz,3H).
实施例16:5-(1-(3,5-二氯吡啶-4-基)乙氧基)-3-(5-(甲基磺酰基)-1,4,5,6-四
氢吡咯并[3,4-d]咪唑-2-基)-1H-吲唑
化合物16的合成路线:
合成方法:
合成化合物16:5-(1-(3,5-二氯吡啶-4-基)乙氧基)-3-(5-(甲基磺酰基)-1,4,5,6-四氢吡咯并[3,4-d]咪唑-2-基)-1H-吲唑
将1-9(40.0mg,0.06mmol)溶于10ml的DCM中,向体系中加入甲磺酰氯(8.7mg,0.08mmol),三乙胺(7.7mg,0.08mmol),室温反应1小时,加水淬灭,用DCM萃取,合并有机相,用饱和食盐水洗涤,浓缩。将浓缩物溶于4ml甲醇中,加入2ml浓盐酸,50度反应5小时,浓缩,溶于5ml甲醇,加0.5ml氨水,浓缩,制备板纯化,得到最终产物10.3mg,收率33.0%。
1H NMR(400MHz,DMSO)δ13.13(s,1H),12.68(s,1H),8.59(s,2H),7.66(d,J=2.4Hz,1H),7.47(d,J=9.0Hz,1H),7.11-7.09(m,1H),6.03(q,J=6.6Hz,1H),4.50-4.46(m,4H),3.06(s,3H),1.76(d,J=6.6Hz,3H)
实施例16a:(R)-5-(1-(3,5-二氯吡啶-4-基)乙氧基)-3-(5-(甲基磺酰基)-1,4,
5,6-四氢吡咯并[3,4-d]咪唑-2-基)-1H-吲唑
实施例16a根据实施例16的合成路线,使用合适的起始原料进行制备。LC-MS m/z(ESI)[M+H]+针对C20H19Cl2N6O3S的计算值为:493.0;测量值为:493.1。
实施例17:2-(5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)-4,6-二氢吡
咯并[3,4-d]咪唑-5(1H)-羧酸甲酯
化合物17的合成路线:
合成方法:
合成化合物17:2-(5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)-4,6-二氢吡咯并[3,4-d]咪唑-5(1H)-羧酸甲酯
将1-9(50.0mg,0.08mmol)溶于10ml的二氯甲烷,将体系降温至0℃,向体系中加入三光气(23.6mg,0.08mmol),滴加三乙胺(16.1mg,0.16mmol),反应1h。反应完成后,加水淬灭,用DCM萃取,合并有机相,用饱和食盐水洗涤,浓缩。将浓缩物溶于5ml甲醇中,加入DMAP(9.7mg,0.08mmol),加热至70℃反应,反应完成后,浓缩,将残留物溶于EA中,加水洗涤,有机相用无水硫酸钠干燥,浓缩后将残留物加4ml甲醇溶解,体系中加入2ml浓盐酸,50度反应5小时,浓缩,溶于5ml甲醇,加0.5ml氨水,浓缩,制备板纯化,得到最终产物8.2mg,收率21.8%。
1H NMR(400MHz,DMSO)δ13.11(s,1H),12.62(s,1H),8.58(s,2H),7.66(d,J=2.4Hz,1H),7.46(d,J=9.0Hz,1H),7.11-7.08(m,1H),6.03(q,J=6.6Hz,1H),4.53-4.40(m,4H),3.71(s,3H),1.76(d,J=6.6Hz,3H).
实施例17a:(R)-2-(5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)-4,6-二
氢吡咯并[3,4-d]咪唑-5(1H)-羧酸甲酯
实施例17a根据实施例17的合成路线,使用合适的起始原料进行制备。LC-MS m/z(ESI)[M+H]+针对C21H19Cl2N6O3的计算值为:473.1;测量值为:473.1。
实施例18:5-(1-(3,5-二氯吡啶-4-基)乙氧基)-3-(5-((1-甲基-1H-吡唑-4-基)
磺酰基)-1,4,5,6-四氢吡咯并[3,4-d]咪唑-2-基)-1H-吲唑
化合物18的合成路线:
合成方法:
合成化合物18:5-(1-(3,5-二氯吡啶-4-基)乙氧基)-3-(5-((1-甲基-1H-吡唑-4-基)磺酰基)-1,4,5,6-四氢吡咯并[3,4-d]咪唑-2-基)-1H-吲唑
将1-9(30.0mg,0.04mmol)溶于10ml的DCM中,向体系中加入吡啶-4-磺酰氯(9.6mg,0.05mmol),三乙胺(5.4mg,0.05mmol),室温反应1小时,加水淬灭,用DCM萃取,合并有机相,用饱和食盐水洗涤,浓缩。将浓缩物溶于4ml甲醇中,加入2ml浓盐酸,50度反应5小时,浓缩,溶于5ml甲醇,加0.5ml氨水,浓缩,制备板纯化,得到最终产物5.4mg,收率20.3%。
1H NMR(400MHz,DMSO)δ8.45(s,2H),8.30(s,1H),7.92(s,1H),7.58(d,J=2.4Hz,1H),7.43(d,J=9.1Hz,1H),7.17-7.14(m,1H),6.16(q,J=6.7Hz,1H),4.58-4.42(m,4H),3.96(s,3H),1.82(d,J=6.7Hz,3H).
实施例19:5-(1-(3,5-二氯吡啶-4-基)乙氧基)-3-(1,4,5,6-四氢吡咯并[3,4-d]
咪唑-2-基)-1H-吲唑
化合物19的合成路线:
合成方法:
合成化合物19:5-(1-(3,5-二氯吡啶-4-基)乙氧基)-3-(1,4,5,6-四氢吡咯并[3,4-d]咪唑-2-基)-1H-吲唑
将1-9(30.0mg,0.05mmol)加4ml甲醇溶解,体系中加入2ml浓盐酸,50度反应5小时,浓缩,溶于5ml甲醇,加0.5ml氨水,浓缩,制备板纯化,得到最终产物12.0mg,收率60.7%。
1H NMR(400MHz,MeOD)δ8.46(s,2H),7.63(d,J=2.4Hz,1H),7.47(d,J=8.8Hz,1H),7.20-7.17(m,1H),6.17(q,J=6.6Hz,1H),4.63-4.42(m,4H),1.84(d,J=6.6Hz,3H).
实施例20:5-(1-(3,5-二氯吡啶-4-基)乙氧基)-3-(5-((1-甲基-1H-吡唑-3-基)
磺酰基)-1,4,5,6-四氢吡咯并[3,4-d]咪唑-2-基)-1H-吲唑
化合物20的合成路线:
合成方法:
合成化合物20:5-(1-(3,5-二氯吡啶-4-基)乙氧基)-3-(5-((1-甲基-1H-吡唑-3-基)磺酰基)-1,4,5,6-四氢吡咯并[3,4-d]咪唑-2-基)-1H-吲唑
将中间体1-9(30.0mg,0.04mmol)溶于DCM中,降温至零度,向溶液中滴加1-甲基-1H-吡唑-3-磺酰氯(8.8mg,0.05mmol)和三乙胺(9.0mg,0.09mmol),室温反应1小时,向反应液中加水,用DCM萃取2次,合并有机相,用饱和食盐水洗涤,无水硫酸钠干燥,浓缩,硅胶板纯化,得到的产物溶于2ml甲醇和1ml浓盐酸中,50度反应6小时,浓缩,溶于3ml甲醇,加0.5ml氨水,浓缩,制备板纯化,得到最终产物8mg,收率33.6%。
1H NMR(400MHz,CD3OD)δ8.45(s,2H),7.77(d,J=2.4Hz,1H),7.60(d,J=2.4Hz,1H),7.43(d,J=8Hz,1H),7.15(d,J=8Hz,1H),6.80(d,J=2.4Hz,1H),6.14-6.19(m,1H),4.56-4.65(m,4H),3.97(s,3H),1.82(d,J=4Hz,3H).
实施例21:3-(2-(5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)-4,6-二氢
吡咯并[3,4-d]咪唑-5(1H)-基)环丁-1-醇
化合物21的合成路线:
合成方法:
合成化合物21:3-(2-(5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)-4,6-二氢吡咯并[3,4-d]咪唑-5(1H)-基)环丁-1-醇
将中间体1-9(30.0mg,0.05mmol)溶于5ml二氯甲烷中,加入3-(苄氧基)-1-环丁酮(10.1mg,0.06mmol),室温搅拌20分钟,加入三乙酰基硼氢化钠(13.1mg,0.06mmol),室温反应2小时,向反应液中加水,用二氯甲烷萃取2次,合并有机相,用饱和食盐水洗涤,无水硫酸钠干燥,浓缩得到的粗品溶于5ml甲醇中,加入10%Pd/C(6mg),氢气置换3次,室温反应3小时,滤除钯碳,浓缩,得到的产物溶于2ml甲醇和1ml浓盐酸中,50度反应6小时,浓缩,溶于3ml甲醇,加0.5ml氨水,浓缩,纯化,得到终产物2.7mg,三步总收率11.7%。
1H NMR(400MHz,MeOD)δ8.45(s,2H),7.64(d,J=4.0Hz,1H),7.45(d,J=8.0Hz,1H),7.16(dd,J=4.0Hz,J=8.0Hz,1H),6.19(dd,J=8.0Hz,J=16.0Hz,1H),4.07-4.04(m,1H),3.96(s,4H),3.19-3.15(m,1H),2.67-2.60(m,2H),2.04-1.98(m,2H),1.83(d,J=8.0Hz,3H).
实施例22:4-(2-(5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)-4,6-二氢
吡咯并[3,4-d]咪唑-5(1H)-基)环己-1-醇
化合物22的合成路线:
合成方法:
合成化合物22:4-(2-(5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)-4,6-二氢吡咯并[3,4-d]咪唑-5(1H)-基)环己-1-醇
将中间体1-9(30.0mg,0.05mmol)溶于5ml二氯甲烷中,加入4-羟基环己酮(8.1mg,0.07mmol),室温搅拌20分钟,加入三乙酰基硼氢化钠(15.1mg,0.07mmol),室温反应2小时,向反应液中加水,用二氯甲烷萃取2次,合并有机相,用饱和食盐水洗涤,无水硫酸钠干燥,浓缩得到的产物溶于2ml甲醇和1ml浓盐酸中,50度反应6小时,浓缩,溶于3ml甲醇,加0.5ml氨水,浓缩,纯化,得到终产物3.8mg,两步总收率15.5%。
1H NMR(400MHz,MeOD)δ8.45(s,2H),7.64(d,J=4.0Hz,1H),7.43(d,J=8.0Hz,1H),7.16(dd,J=4.0Hz,J=8.0Hz,1H),6.20(dd,J=8.0Hz,J=16.0Hz,1H),4.05(s,2H),4.00(s,2H),3.95(s,1H),2.82-2.71(m,1H),2.14-2.13(m,1H),2.06-2.03(m,1H),1.91-1.82(m,7H),1.67-1.64(m,2H).
实施例23:乙基2-(5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)-4,6-二
氢吡咯并[3,4-d]咪唑-5(1H)-羧酸盐
化合物23的合成路线:
合成方法:
合成化合物23:乙基2-(5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)-4,6-二氢吡咯并[3,4-d]咪唑-5(1H)-羧酸盐
将三光气(28.3mg,0.10mmol)溶于10ml干燥二氯甲烷中,0度滴加中间体1-9(60mg,0.10mmol)的二氯甲烷(5ml)溶液,加完后缓慢滴加干燥三乙胺(0.13ml,1.00mmol),室温搅拌10分钟,反应液浓缩,溶于10ml乙醇,加入DMAP(11.6mg,0.09mmol),50度反应2小时。反应完成后加水淬灭,加DCM萃取2次,合并有机相,干燥,浓缩,将浓缩物溶于4ml甲醇,加入2ml浓盐酸,50℃反应7小时,浓缩,溶于5ml甲醇,加0.5ml氨水,浓缩,制备板纯化,最终得到白色固体25mg,收率:53.8%。LC-MS m/z(ESI)[M+H]+针对C22H21Cl2N6O3的计算值为:487.1;测量值为:487.1。
实施例24:2-氰基乙基2-(5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)-
4,6-二氢吡咯并[3,4-d]咪唑-5(1H)-羧酸盐
化合物24的合成路线:
合成方法:
合成化合物24:2-氰基乙基2-(5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)-4,6-二氢吡咯并[3,4-d]咪唑-5(1H)-羧酸盐
将1-9(40.0mg,0.06mmol)溶于10ml DCM,降温至0℃,氮气保护,加入三光气(20.1mg,0.06mmol),缓慢滴加TEA(19.2mg,0.19mmol),反应10分钟,浓缩,加10ml THF溶解,加3-羟基丙腈(22.6mg,0.32mmol),以及DMAP(0.98mg,0.01mmol),50℃反应2小时,向反应液中加水,用乙酸乙酯萃取2次,合并有机相,用氯化铵溶液洗涤两次,用饱和食盐水洗涤,无水硫酸钠干燥,浓缩,将浓缩物溶于6ml 1,4-二氧六环中,加入3ml浓盐酸,50℃反应3小时,浓缩,溶于5ml 1,4-二氧六环,加0.5ml氨水,浓缩,制备板纯化,得到最终产物3mg,收率7.5%。LC-MS m/z(ESI)[M+H]+针对C23H20Cl2N7O3的计算值为:512.1;测量值为:512.1。
实施例25:环丙基(2-(5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)-4,6-
二氢吡咯并[3,4-d]咪唑-5(1H)-基)甲酮
化合物25的合成路线:
合成方法:
合成化合物25:环丙基(2-(5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)-4,6-二氢吡咯并[3,4-d]咪唑-5(1H)-基)甲酮
将中间体1-9(30.0mg,0.05mmol)溶于5ml二氯甲烷中,加入三乙胺(14.5mg,0.14mmol),冷却到0度,加入环丙基甲酰氯(5.5mg,0.05mmol),室温反应1小时,向反应液中加水,用二氯甲烷萃取2次,合并有机相,用饱和食盐水洗涤,无水硫酸钠干燥,浓缩得到的粗品溶于2ml甲醇和1ml浓盐酸中,50度反应6小时,浓缩,溶于3ml甲醇,加0.5ml氨水,浓缩,纯化,得到终产物6.7mg,三步总收率28.9%。LC-MS m/z(ESI)[M+H]+针对C23H21Cl2N6O2的计算值为:483.1;测量值为:483.1
实施例26:(2-(5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)-4,6-二氢吡
咯并[3,4-d]咪唑-5(1H)-基)(3-羟基环丁基)甲酮
化合物26的合成路线:
合成方法:
合成化合物26:(2-(5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)-4,6-二氢吡咯并[3,4-d]咪唑-5(1H)-基)(3-羟基环丁基)甲酮
将中间体1-9(30.0mg,0.05mmol)溶于2ml DMF中,加入3-羟基环丁基甲酸(6.1mg,0.05mmol),HATU(20.0mg,0.05mmol)和DIPEA(12.3mg,0.10mmol)室温反应3小时,向反应液中加水,用EA萃取2次,合并有机相,用饱和食盐水洗涤,无水硫酸钠干燥,浓缩,纯化,得到的产品溶于2ml甲醇和1ml浓盐酸中,50度反应6小时,浓缩,溶于3ml甲醇,加0.5ml氨水,浓缩,纯化,得到终产物4.1mg,两步总收率16.7%。
1H NMR(400MHz,MeOD)δ8.46(s,2H),7.66(d,J=4.0Hz,1H),7.45(d,J=8.0Hz,1H),7.16(dd,J=4.0Hz,J=8.0Hz,1H),6.19(dd,J=8.0Hz,J=16.0Hz,1H),4.71-4.62(m,4H),4.26-4.20(m,1H),2.98-2.92(m,1H),2.63-2.60(m,2H),2.24-2.19(m,2H),1.83(d,J=4.0Hz,3H).
实施例27:3-(2-(5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)-4,6-二氢
吡咯并[3,4-d]咪唑-5(1H)-基)-3-氧丙烷腈
化合物27的合成路线:
合成方法:
合成化合物27:3-(2-(5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)-4,6-二氢吡咯并[3,4-d]咪唑-5(1H)-基)-3-氧丙烷腈
将中间体1-9(25.0mg,0.04mmol)溶于2ml DMF中,加入氰基乙酸(4.0mg,0.05mmol),HATU(18.1mg,0.05mmol)和DIPEA(15.3mg,0.12mmol)室温反应3小时,向反应液中加水,用EA萃取2次,合并有机相,用饱和食盐水洗涤,无水硫酸钠干燥,浓缩,纯化,得到的产品溶于2ml甲醇和1ml浓盐酸中,50度反应6小时,浓缩,溶于3ml甲醇,加0.5ml氨水,浓缩,纯化,得到终产物5.9mg,两步总收率30.9%。
1H NMR(400MHz,MeOD)δ8.46(s,2H),7.64(d,J=4.0Hz,1H),7.45(d,J=8.0Hz,1H),7.16(dd,J=4.0Hz,J=8.0Hz,1H),6.19(dd,J=8.0Hz,J=12.0Hz,1H),4.61(s,4H),3.65(s,2H),1.83(d,J=4.0Hz,3H).
实施例28:5-(1-(3,5-二氯吡啶-4-基)乙氧基)-3-(5-(乙基磺酰基)-1,4,5,6-四
氢吡咯并[3,4-d]咪唑-2-基)-1H-吲唑
化合物28的合成路线:
合成方法:
合成化合物28:5-(1-(3,5-二氯吡啶-4-基)乙氧基)-3-(5-(乙基磺酰基)-1,4,5,6-四氢吡咯并[3,4-d]咪唑-2-基)-1H-吲唑
向反应瓶中加入中间体1-9(40.0mg,0.06mmol),TEA(26.1mg,0.19mmol),5mlDCM。将体系降至0℃,滴加乙基磺酰氯(11.6mg,0.08mmol),滴加完成后升至室温反应15分钟。反应完成后加水淬灭,加DCM萃取2次,合并有机相,干燥,浓缩,将浓缩物溶于4ml甲醇,加入2ml浓盐酸,50℃反应7小时,浓缩,溶于5ml甲醇,加0.5ml氨水,浓缩,制备板纯化,最终得到白色固体15mg,收率:46.3%。LC-MS m/z(ESI)[M+H]+针对C21H21Cl2N6O3S的计算值为:507.1;测量值为:507.1。
实施例29:3-(5-(环丙基磺酰基)-1,4,5,6-四氢吡咯并[3,4-d]咪唑-2-基)-5-
(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑
化合物29的合成路线:
合成方法:
合成化合物29:3-(5-(环丙基磺酰基)-1,4,5,6-四氢吡咯并[3,4-d]咪唑-2-基)-5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑
向反应瓶中加入中间体1-9(40.0mg,0.06mmol),TEA(26.2mg,0.19mmol),5mlDCM。将体系降至0℃,滴加环丙烷磺酰氯(11.6mg,0.08mmol),滴加完成后升至室温反应15分钟。反应完成后加水淬灭,加DCM萃取2次,合并有机相,干燥,浓缩,将浓缩物溶于4ml甲醇,加入2ml浓盐酸,50℃反应7小时,浓缩,溶于5ml甲醇,加0.5ml氨水,浓缩,制备板纯化,最终得到白色固体14mg,收率:42.3%。LC-MS m/z(ESI)[M+H]+针对C22H21Cl2N6O3S的计算值为:519.1;测量值为:519.1。
实施例30:5-(1-(3,5-二氯吡啶-4-基)乙氧基)-3-(5-(异丙基磺酰基)-1,4,5,6-
四氢吡咯并[3,4-d]咪唑-2-基)-1H-吲唑
化合物30的合成路线:
合成方法:
合成化合物30:5-(1-(3,5-二氯吡啶-4-基)乙氧基)-3-(5-(异丙基磺酰基)-1,4,5,6-四氢吡咯并[3,4-d]咪唑-2-基)-1H-吲唑
向反应瓶中加入中间体1-9(40.0mg,0.06mmol),TEA(26.2mg,0.19mmol),5mlDCM。将体系降至0℃,滴加异丙基磺酰氯(11.6mg,0.08mmol),滴加完成后升至室温反应15分钟。反应完成后加水淬灭,加DCM萃取2次,合并有机相,干燥,浓缩,将浓缩物溶于4ml甲醇,加入2ml浓盐酸,50℃反应7小时,浓缩,溶于5ml甲醇,加0.5ml氨水,浓缩,制备板纯化,最终得到白色固体14mg,收率:42.1%。LC-MS m/z(ESI)[M+H]+针对C22H23Cl2N6O3S的计算值为:521.1;测量值为:521.1。
实施例31:1-(2-(5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)-4,6-二氢
吡咯并[3,4-d]咪唑-5(1H)-基)-2-(3-羟基吡咯烷-1-基)乙-1-酮
化合物31的合成路线:
合成方法:
合成中间体31-1:2-溴-1-(2-(5-(1-(3,5-二氯吡啶基-4-基)乙氧基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吲唑-3-基)-1-(((2-(三甲基甲硅烷基)乙氧基)甲基)-4,6-二氢吡咯并[3,4-d]咪唑-5(1H)-基)乙-1-酮
将中间体1-9(30mg,0.04mmol)溶于DCM中,降温至零度,向溶液中滴加溴乙酰氯(7.7mg,0.05mmol)和三乙胺(9.0mg,0.09mmol),室温反应1小时,向反应液中加水,用DCM萃取2次,合并有机相,用饱和食盐水洗涤,无水硫酸钠干燥,浓缩,硅胶板纯化,得到中间体31-1 26mg,收率73.5%。
1H NMR(400MHz,CDCl3)δ8.40(d,J=8Hz,2H),7.81(s,1H),7.49-7.53(m,1H),7.19(d,J=12Hz,1H),6.12-6.18(m,1H),5.83-6.02(m,2H),5.67-5.72(m,1H),4.71-4.91(m,4H),4.16-4.23(m,1H),4.00(s,2H),3.76-3.78(m,1H),3.57-3.61(m,2H),2.06-2.15(m,2H),1.83(d,J=4Hz,3H),1.70-1.78(m,4H),1.43(t,J=6Hz,2H).
合成化合物31:1-(2-(5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)-4,6-二氢吡咯并[3,4-d]咪唑-5(1H)-基)-2-(3-羟基吡咯烷-1-基)乙-1-酮
将中间体31-1(26mg,0.03mmol)溶于乙腈中,向溶液中加入吡咯烷-3-醇(3.7mg,0.04mmol)和碳酸铯(31.9mg,0.10mmol),80度反应1小时,向反应液中加水,用乙酸乙酯萃取2次,合并有机相,用饱和食盐水洗涤,无水硫酸钠干燥,浓缩,硅胶板纯化,得到的产物溶于2ml甲醇和1ml浓盐酸中,50度反应6小时,浓缩,溶于3ml甲醇,加0.5ml氨水,浓缩,制备板纯化,得到最终产物6mg,收率34.0%。
1H NMR(400MHz,DMSO)δ13.13(s,1H),12.64(s,1H),8.58(s,2H),7.67(d,J=4Hz,1H),7.47(d,J=12Hz,1H),7.10(d,J=8Hz,1H),6.02-6.07(m,1H),4.80-4.84(m,1H),4.67-4.77(m,2H),4.43-4.49(m,2H),4.23-4.25(m,1H),3.41-3.49(m,2H),2.77-2.96(m,2H),2.58-2.68(m,2H),1.99-2.04(m,1H),1.76(d,J=4Hz,3H),1.58-1.64(m,1H).
实施例32:1-(2-(2-(5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)-4,6-
二氢吡咯并[3,4-d]咪唑-5(1H)-基)-2-氧代乙基)吡咯烷-3-腈
化合物32的合成路线:
合成方法:
合成中间体32-1:2-(3-氰基吡咯烷-1-基)乙酸
将3-氰基吡咯烷-1-羧酸叔丁酯(100mg,0.51mmol)溶于二氯甲烷(2.5ml)中,向溶液中加入三氟乙酸(0.5ml),室温反应2小时,浓缩,向反应液中加入2-溴乙酸(70.8mg,0.51mmol)和三乙胺(154.4mg,1.53mmol),50度反应4小时,向反应液中加水,用乙酸乙酯萃取2次,合并有机相,用饱和食盐水洗涤,无水硫酸钠干燥,浓缩,硅胶柱纯化,得到最终产物30mg,收率38.2%。
1H NMR(400MHz,CDCl3)δ3.49(s,2H),3.35-3.40(m,1H),3.21-3.25(m,1H),3.05-3.13(m,2H),2.96-3.03(m,1H),2.36-2.45(m,1H),2.23-2.29(m,1H).
合成化合物32:1-(2-(2-(5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)-4,6-二氢吡咯并[3,4-d]咪唑-5(1H)-基)-2-氧代乙基)吡咯烷-3-腈
将化合物19(20mg,0.05mmol)溶于DMF中,向溶液中加入中间体32-1(8.9mg,0.06mmol),HATU(22.0mg,0.06mmol)和DIPEA(18.6mg,0.14mmol),室温反应2小时,向反应液中加水,用乙酸乙酯萃取2次,合并有机相,用饱和食盐水洗涤,无水硫酸钠干燥,浓缩,硅胶板纯化,得到最终产物6mg,收率22.6%。
1H NMR(400MHz,CD3OD)δ8.46(s,2H),7.66(d,J=4Hz,1H),7.45(d,J=8Hz,1H),7.17(d,J=8Hz,1H),6.17-6.22(m,1H),4.65-4.80(m,4H),3.59(s,2H),3.25-3.29(m,1H),3.10-3.14(m,1H),2.92-3.03(m,2H),2.82-2.88(m,1H),2.32-2.41(m,1H),2.11-2.19(m,1H),1.83(d,J=4Hz,3H).
实施例33-35
下表中所示的实施例33至35的化合物根据实施例1的合成路线,使用合适的起始原料进行制备。
实施例36-39
下表中所示的实施例36至39的化合物根据实施例3的合成路线,使用合适的起始原料进行制备。
实施例40-53
下表中所示的实施例40至53的化合物根据实施例6的合成路线,使用合适的起始原料进行制备。
实施例54-55
下表中所示的实施例54至55的化合物根据实施例17的合成路线,使用合适的起始原料进行制备。
活性测试1:对FGFR突变体抑制活性的测定
1.试剂与耗材
2.实验步骤
2.1制备1x激酶反应缓冲液:
用1倍体积的5X激酶反应缓冲液和4倍体积的水;5mM MgCl2;1mM DTT配制1x激酶反应缓冲液。
2.2反应条件:
2.3化合物筛选:
1.在稀释板中用DMSO对化合物进行4倍稀释,化合物起始浓度为2mM。
2.将化合物40倍稀释到1X激酶反应缓冲液中,在振荡器上震荡20分钟。
3.用1X的酶反应缓冲液配制准备2X FGFR1 V561M/FGFR2 V564F/FGFR3 K650E/VEGFR2。
4.向反应板中每孔加入2μl FGFR1 V561M/FGFR2 V564F/FGFR3 K650E/VEGFR2激酶(步骤3中配制)。
5.向每孔加入1μl在缓冲液中稀释好的化合物,用封板膜封住板子1000g离心30秒,室温放置10分钟。
6.用1X的酶反应缓冲液配制2.5x TK-底物-生物素和ATP混合液,向反应板中加入2μl K-底物-生物素/ATP混合液。
7.用封板膜封住板子1000g离心30秒,室温反应50分钟。
8.用HTRF检测缓冲液配制4X Sa-XL 665(250nM)。
9.每孔加入5μl Sa-XL 665和5μl TK-抗体-Cryptate,1000g离心30秒,室温反应1小时。
10.用Biotek读615nm(Cryptate)和665nm(XL665)的荧光信号。
3.数据分析
3.1计算每孔的比率:比率计算为665/615nm。
3.2抑制率计算如下:化合物抑制率(%inh)=100%-(化合物-阳性对照)/(阴性对照-阳性对照)*100%。阳性对照为10000nM Infigratinib,阴性对照为0.5%DMSO。
3.3计算IC50并绘制化合物的抑制曲线:
利用以下非线性拟合公式来得到化合物的IC50(半数抑制浓度):用Graphpad 6.0软件进行数据分析。
Y=Bottom+(Top-Bottom)/(1+10^((LogIC50-X)*Hill Slope))
X:化合物浓度log值 Y:抑制率(%inh)
3.4结果验证
数据从Envision中导出,人工分析。比值转化为抑制率,IC50通过抑制率由PrismGraphPad 6.0计算。IC50通过比值再次计算,以验证结果准确性。
3.5质量控制
Z因子>0.5;S/B>2
阳性对照IC50在历次平均值3倍以内
4.结果
表1:实施例化合物对FGFR突变体的抑制作用
各实施例化合物均显示出良好的FGFR1 V561M、FGFR2 V564F、FGFR3 V555M的抑制活性,同时对VEGFR2的抑制相对较弱。
活性测试2:对野生型FGFR抑制活性的测定
1.试剂与耗材
2.实验步骤
2.1制备1x激酶反应缓冲液:
用1倍体积的5X激酶反应缓冲液和4倍体积的水;5mM MgCl2;1mM DTT制备1x激酶反应缓冲液。
2.2反应条件:
2.3化合物筛选:
1.在稀释板中用DMSO对化合物进行4倍稀释,化合物起始浓度为2mM。
2.将化合物40倍稀释到1X激酶反应缓冲液中,在振荡器上震荡20分钟。
3.用1X的酶反应缓冲液配制准备2X FGFR1/FGFR2/FGFR3。
4.向反应板中每孔加入2μl FGFR1/FGFR2/FGFR3激酶(步骤3中配制)。
5.向每孔加入1μl在缓冲液中稀释好的化合物,用封板膜封住板子1000g离心30秒,室温放置10分钟。
6.用1X的酶反应缓冲液配制2.5x TK-底物-生物素和ATP混合液,向反应板中加入2μl K-底物-生物素/ATP混合液。
7.用封板膜封住板子1000g离心30秒,室温反应50分钟。
8.用HTRF检测缓冲液配制4X Sa-XL 665(250nM)。
9.每孔加入5μl Sa-XL 665和5μl TK-抗体-Cryptate,1000g离心30秒,室温反应1小时。
10.用Biotek读615nm(Cryptate)和665nm(XL665)的荧光信号。
3.数据分析
3.1计算每孔的比率,比率计算为665/615nm。
3.2抑制率计算如下:化合物抑制率(%inh)=100%-(化合物-阳性对照)/(阴性对照-阳性对照)*100%。阳性对照为10000nM Infigratinib;阴性对照为0.5%DMSO。
3.3计算IC50并绘制化合物的抑制曲线:
利用以下非线性拟合公式来得到化合物的IC50(半数抑制浓度):用Graphpad 6.0软件进行数据分析。
Y=Bottom+(Top-Bottom)/(1+10^((LogIC50-X)*Hill Slope))
X:化合物浓度log值 Y:抑制率(%inh)
3.4结果验证
数据从Envision中导出,人工分析。比值转化为抑制率,IC50通过抑制率由PrismGraphPad 6.0计算。IC50通过比值再次计算,以验证结果准确性。
3.5 QC
Z因子>0.5;S/B>2
阳性对照IC50在历次平均值3倍以内
4.结果
表2:实施例化合物对野生型FGFR的抑制作用
测试的实施例化合物对于野生型FGFR1/FGFR2/FGFR3也显示出与Infigratinib相似或更好的抑制活性。
虽然已经阐明并描述了本发明的特定实施方式,但并不意味着这些实施方式阐明了并描述了本发明的所有可能形式。更确切地,用在本说明书中的文字仅仅是描述性的文字并非限制性的。对于本领域技术人员明显的是,在不脱离本公开的一般范围的情况下,可以进行各种其他改变和修改。因此,在所附权利要求中,旨在包括在本发明范围内的所有这些改变和修改。
Claims (14)
1.一种式(I)的化合物:
或其同位素标记化合物、或其光学异构体、几何异构体、互变异构体或异构体混合物、或其药学上可接受的盐、或其前药、或其代谢物,其中:
R1、R2各自独立地选自H、卤素、-CN、-OH、-NO2、-NR7R8、C1-4烷基、C1-4卤代烷基、C1-4烷氧基、C3-6脂环基和4-6元杂脂环基;
R3选自H、C1-4烷基、C1-4卤代烷基、C1-4烷氧基、C3-6脂环基和4-6元杂脂环基;
R6的个数为1、2或3个,且每个R6各自独立地选自H、卤素、-CN、-OH、-NO2、-NR7R8、C1-4烷基、C1-4卤代烷基、C1-4烷氧基、C3-6脂环基和4-6元杂脂环基;
X为O、S或(NR4),其中R4选自:H、C1-4烷基、C1-4卤代烷基、C1-4烷氧基、C3-6脂环基和4-6元杂脂环基;
R7和R8各自在每次出现时独立地选自:H、C1-6烷基、C1-4卤代烷基、C1-4烷氧基,或者R7、R8以及与它们相连的N原子共同形成3-6元环;
n=1、2或3;
L为(C=O)、(O=S=O)、((C=O)-CH2)或连接键;
R5选自H、卤素、-OH、-NO2、-CN、-SF5、-SH、-S-C1-4烷基、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C2-8烯基、C2-8炔基、C3-7脂环基、3-10元杂脂环基、C6-12双环脂环基、6-12元双环杂脂环基、C8-15元三环脂环基、8-15元三环杂脂环基、C5-8芳基、5-10元杂芳基、C7-11双环芳基、7-11元双环杂芳基、-C1-4烷基-(C3-7脂环基)、-C1-4烷基-(3-10元杂脂环基)、-C1-4烷基-(C6-12双环脂环基)、-C1-4烷基-(6-12元双环杂脂环基)、-C1-4烷基-(C8-15元三环脂环基)、-C1-4烷基-(8-15元三环杂脂环基)、-C1-4烷基-(C5-8芳基)、-C1-4烷基-(5-10元杂芳基)、-N(R10)(R11)、-N(R10)(C(=O)R11)、-N(R10)(C(=O)-OR11)、-N(R12)(C(=O)-N(R10)(R11))、-C(=O)-N(R10)(R11)、-C(=O)-R12、-C(=O)-OR12、-OC(=O)R12、-N(R10)(S(=O)2R11)、-S(=O)2-N(R10)(R11)、-SR12和-OR12,其中所述-S-C1-4烷基、C1-6烷基、C1-6烷氧基、C1-6卤代烷氧基、C2-8烯基、C2-8炔基、C3-7脂环基、3-10元杂脂环基、C6-12双环脂环基、6-12元双环杂脂环基,C8-15元三环脂环基、8-15元三环杂脂环基、C5-8芳基、5-7元杂芳基、C7-11双环芳基、7-11元双环杂芳基、-C1-4烷基-(C3-7脂环基)、-C1-4烷基-(3-10元杂脂环基)、-C1-4烷基-(C6-12双环脂环基)、-C1-4烷基-(6-12元双环杂脂环基)-C1-4烷基-(C8-15元三环脂环基)、-C1-4烷基-(8-15元三环杂脂环基)、-C1-4烷基-(C5-8芳基)和-C1-4烷基-(5-10元杂芳基)各自任选地被0、1、2、3或4个R5a取代,且R5a独立选自卤素、-OH、-NO2、-CN、-SF5、-SH、-S-C1-4烷基、氧代、C1-4烷基、C1-4卤代烷基、C1-4烷氧基、C1-4卤代烷氧基、C2-8烯基、C2-8炔基、C3-7脂环基、3-10元杂脂环基、C5-8芳基、5-7元杂芳基、-N(R13)(R14)、-N(R13)(C(=O)R14)、-N(R13)(C(=O)-OR14)、-N(R15)(C(=O)-N(R13)(R14))、-C(=O)-N(R13)(R14)、-C(=O)-R15、-C(=O)-OR15、-OC(=O)R15、-N(R13)(S(=O)2R14)、-S(=O)2-N(R13)(R14)、-SR15和-OR15;
且R10、R11、R12、R13、R14、和R15各自在每次出现时独立地选自:H、C1-6烷基、C1-6卤代烷基、C3-7脂环基、3-10元杂脂环基、C5-8芳基、5-7元杂芳基、C7-11双环芳基、7-11元双环杂芳基、-C1-4烷基-(C3-7脂环基)、-C1-4烷基-(3-10元杂脂环基)、-C1-4烷基-(C6-12双环脂环基)、-C1-4烷基-(6-12元双环杂脂环基)、-C1-4烷基-(C8-15元三环脂环基)、-C1-4烷基-(8-15元三环杂脂环基)、-C1-4烷基-(C5-8芳基)和-C1-4烷基-(5-10元杂芳基),其中该群组内的各个选项任选地被0、1、2、3或4个各自独立选自以下群组的取代基所取代:卤素、-OH、-NH2、-NH(CH3)、-N(CH3)2、-CN、-NO2、-SF5、-SH、-S-C1-4烷基、氧代、C1-4烷基、C2-6烯基、C2-6炔基、C3-7脂环基、3-10元杂脂环基、C5-8芳基、5-7元杂芳基、C7-11双环芳基、7-11元双环杂芳基、C1-4羟烷基、-S-C1-4烷基、-C(=O)H、-C(=O)-C1-4烷基、-C(=O)-O-C1-4烷基、-C(=O)-NH2、-C(=O)-N(C1-4烷基)2、C1-4卤代烷基、C1-4烷氧基和C1-4卤代烷氧基;或者R10、R11以及与它们相连的原子共同形成3-14元环;或者R13、R14以及与它们相连的原子共同形成3-14元环。
2.根据权利要求1所述的化合物或其同位素标记化合物、或其光学异构体、几何异构体、互变异构体或异构体混合物、或其药学上可接受的盐、或其前药、或其代谢物,其中n=1或2。
4.根据权利要求1-3中任一项所述的化合物或其同位素标记化合物、或其光学异构体、几何异构体、互变异构体或异构体混合物、或其药学上可接受的盐、或其前药、或其代谢物,其中R1和R2各自独立地选自:H、F、Cl和Br。
6.根据权利要求1-5中任一项所述的化合物或其同位素标记化合物、或其光学异构体、几何异构体、互变异构体或异构体混合物、或其药学上可接受的盐、或其前药、或其代谢物,其中R6为H。
7.根据权利要求1-6中任一项所述的化合物或其同位素标记化合物、或其光学异构体、几何异构体、互变异构体或异构体混合物、或其药学上可接受的盐、或其前药、或其代谢物,其中R5选自H、卤素、-OH、-NO2、-CN、-SF5、-SH、-S-C1-4烷基、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C3-6脂环基、4-6元杂脂环基、C5-8芳基、5-10元杂芳基、-C1-4烷基-(C3-7脂环基)、-C1-4烷基-(3-10元杂脂环基)、-C1-4烷基-(C5-8芳基)、-C1-4烷基-(5-10元杂芳基)、-N(R10)(R11),其中所述-S-C1-4烷基、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C3-6脂环基、4-6元杂脂环基、C5-8芳基、5-10元杂芳基、-C1-4烷基-(C3-7脂环基)、-C1-4烷基-(3-10元杂脂环基)、-C1-4烷基-(C5-8芳基)、-C1-4烷基-(5-10元杂芳基)各自任选地被0、1、2、3或4个R5a取代,且R5a独立选自卤素、-OH、-NO2、-CN、氧代、C1-4烷基、C1-4卤代烷基、C1-4烷氧基、C1-4卤代烷氧基、C3-7脂环基、3-10元杂脂环基、C5-8芳基、5-7元杂芳基;
且R10、R11和R12各自在每次出现时独立地选自:H、C1-6烷基、C1-6卤代烷基、C3-7脂环基、3-10元杂脂环基,其中该群组内的各个选项任选地被0、1、2、3或4个各自独立选自以下群组的取代基所取代:卤素、-OH、-NH2、氧代、C1-4烷基、C1-4羟烷基、C1-4卤代烷基、C1-4烷氧基和C1-4卤代烷氧基;或者R10、R11以及与它们相连的原子共同形成3-8元环。
8.根据权利要求7所述的化合物或其同位素标记化合物、或其光学异构体、几何异构体、互变异构体或异构体混合物、或其药学上可接受的盐、或其前药、或其代谢物,其中R5选自H、卤素、-OH、甲基、乙基、丙基、丁基、戊基、己基、甲氧基、乙氧基、丙氧基、丁氧基、戊氧基、己氧基、环丙基、环丁基、环戊基、环己基、环庚基、苯基、哌嗪基、哌啶基、吗啉基、吡咯烷基、吡咯基、吗啉基、吡啶基和吡唑基,其中的甲基、乙基、丙基、丁基、戊基、己基、甲氧基、乙氧基、丙氧基、丁氧基、戊氧基、己氧基、环丙基、环丁基、环戊基、环己基、环庚基、苯基、哌嗪基、哌啶基、吗啉基、吡咯烷基、吡咯基、吗啉基、吡啶基、吡唑基各自任选地被1或2个R5a取代,且R5a独立选自卤素、-OH、-NO2、-CN、氧代、C1-4烷基、C1-4卤代烷基和C1-4烷氧基。
9.选自以下的化合物:
(2-(5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)-4,6-二氢吡咯并[3,4-d]咪唑-5(1H)-基)(4-甲基哌嗪-1-基)甲酮;
5-(1-(3,5-二氯吡啶-4-基)乙氧基)-3-(5-((1-甲基哌啶-4-基)甲基)-1,4,5,6-四氢吡咯并[3,4-d]咪唑-2-基)-1H-吲唑;
5-(1-(3,5-二氯吡啶-4-基)乙氧基)-3-(5-(1-甲基哌啶-4-基)-1,4,5,6-四氢吡咯并[3,4-d]咪唑-2-基)-1H-吲唑;
2-(5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)-5-(1-甲基哌啶-4-基)-4,5,6,7-四氢-3H-咪唑并[4,5-c]吡啶;
(2-(5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)-3,4,6,7-四氢-5H-咪唑并[4,5-c]吡啶-5-基)(4-甲基哌嗪-1-基)甲酮;
(2-(5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)-4,6-二氢吡咯并[3,4-d]咪唑-5(1H)-基)(1-甲基哌啶-4-基)甲酮;
5-(1-(3,5-二氯吡啶-4-基)乙氧基)-3-(5-(吡啶-3-基磺酰基)-1,4,5,6-四氢吡咯并[3,4-d]咪唑-2-基)-1H-吲唑;
(2-(5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)-4,6-二氢吡咯并[3,4-d]咪唑-5(1H)-基)(吗啉基)甲酮;
(2-(5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)-4,6-二氢吡咯并[3,4-d]咪唑-5(1H)-基)((R)-吡咯烷-3-基)甲酮;
(2-(5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)-4,6-二氢吡咯[3,4-d]咪唑-5(1H)-基)((S)-3-羟基吡咯烷-1-基)甲酮;
5-(1-(3,5-二氯吡啶-4-基)乙氧基)-3-(5-甲基-1,4,5,6-四氢吡咯并[3,4-d]咪唑-2-基)-1H-吲唑;
4-(2-(2-(5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)-4,6-二氢吡咯并[3,4-d]咪唑-5(1H)-基)乙基)吗啉;
1-(2-(5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)-4,6-二氢吡咯并[3,4-d]咪唑-5(1H)-基)-2-吗啉代乙烷-1-酮;
1-(2-(5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)-4,6-二氢吡咯并[3,4-d]咪唑-5(1H)-基)-2-(二甲基氨基)乙-1-酮;
2-(2-(5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)-4,6-二氢吡咯并[3,4-d]咪唑-5(1H)-基)乙烷-1-醇;
5-(1-(3,5-二氯吡啶-4-基)乙氧基)-3-(5-(甲基磺酰基)-1,4,5,6-四氢吡咯并[3,4-d]咪唑-2-基)-1H-吲唑;
(R)-5-(1-(3,5-二氯吡啶-4-基)乙氧基)-3-(5-(甲基磺酰基)-1,4,5,6-四氢吡咯并[3,4-d]咪唑-2-基)-1H-吲唑;
2-(5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)-4,6-二氢吡咯并[3,4-d]咪唑-5(1H)-羧酸甲酯;
(R)-2-(5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)-4,6-二氢吡咯并[3,4-d]咪唑-5(1H)-羧酸甲酯;
5-(1-(3,5-二氯吡啶-4-基)乙氧基)-3-(5-((1-甲基-1H-吡唑-4-基)磺酰基)-1,4,5,6-四氢吡咯并[3,4-d]咪唑-2-基)-1H-吲唑;
5-(1-(3,5-二氯吡啶-4-基)乙氧基)-3-(1,4,5,6-四氢吡咯并[3,4-d]咪唑-2-基)-1H-吲唑;
5-(1-(3,5-二氯吡啶-4-基)乙氧基)-3-(5-((1-甲基-1H-吡唑-3-基)磺酰基)-1,4,5,6-四氢吡咯并[3,4-d]咪唑-2-基)-1H-吲唑;
3-(2-(5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)-4,6-二氢吡咯并[3,4-d]咪唑-5(1H)-基)环丁-1-醇;
4-(2-(5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)-4,6-二氢吡咯并[3,4-d]咪唑-5(1H)-基)环己-1-醇;
乙基2-(5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)-4,6-二氢吡咯并[3,4-d]咪唑-5(1H)-羧酸盐;
2-氰基乙基2-(5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)-4,6-二氢吡咯并[3,4-d]咪唑-5(1H)-羧酸盐;
环丙基(2-(5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)-4,6-二氢吡咯并[3,4-d]咪唑-5(1H)-基)甲酮;
(2-(5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)-4,6-二氢吡咯并[3,4-d]咪唑-5(1H)-基)(3-羟基环丁基)甲酮;
3-(2-(5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)-4,6-二氢吡咯并[3,4-d]咪唑-5(1H)-基)-3-氧丙烷腈;
5-(1-(3,5-二氯吡啶-4-基)乙氧基)-3-(5-(乙基磺酰基)-1,4,5,6-四氢吡咯并[3,4-d]咪唑-2-基)-1H-吲唑;
3-(5-(环丙基磺酰基)-1,4,5,6-四氢吡咯并[3,4-d]咪唑-2-基)-5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑;
5-(1-(3,5-二氯吡啶-4-基)乙氧基)-3-(5-(异丙基磺酰基)-1,4,5,6-四氢吡咯并[3,4-d]咪唑-2-基)-1H-吲唑;
1-(2-(5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)-4,6-二氢吡咯并[3,4-d]咪唑-5(1H)-基)-2-(3-羟基吡咯烷-1-基)乙-1-酮;
1-(2-(2-(5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)-4,6-二氢吡咯并[3,4-d]咪唑-5(1H)-基)-2-氧代乙基)吡咯烷-3-腈;
(R)-2-(5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)-N-甲基-4,6-二氢吡咯并[3,4-d]咪唑-5(1H)-甲酰胺;
(R)-2-(5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)-N,N-二甲基-4,6-二氢吡咯并[3,4-d]咪唑-5(1H)-甲酰胺;
(R)-2-(5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)-N-(1-甲基-1H-吡唑-4-基)-4,6-二氢吡咯并[3,4-d]咪唑-5(1H)-甲酰胺;
5-((R)-1-(3,5-二氯吡啶-4-基)乙氧基)-3-(5-(1-甲基吡咯烷-3-基)-1,4,5,6-四氢吡咯并[3,4-d]咪唑-2-基)-1H-吲唑;
5-((R)-1-(3,5-二氯吡啶-4-基)乙氧基)-3-(5-(1-(1-甲基哌啶-4-基)乙基)-1,4,5,6-四氢吡咯并[3,4-d]咪唑-2-基)-1H-吲唑;
5-((R)-1-(3,5-二氯吡啶-4-基)乙氧基)-3-(5-(1-甲基哌啶-3-基)-1,4,5,6-四氢吡咯并[3,4-d]咪唑-2-基)-1H-吲唑;
5-((R)-1-(3,5-二氯吡啶-4-基)乙氧基)-3-(5-(1-(甲磺酰基)吡咯烷-3-基)-1,4,5,6-四氢吡咯并[3,4-d]咪唑-2-基)-1H吲唑;
(R)-1-(2-(5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)-4,6-二氢吡咯并[3,4-d]咪唑-5(1H)-基)-2-(吡咯烷-1-基)乙烷-1-酮;
1-(2-(5-((R)-1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)-4,6-二氢吡咯并[3,4-d]咪唑-5(1H)-基)-2-((R)-3-羟基吡咯烷-1-基)乙烷-1-酮;
1-(2-(5-((R)-1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)-4,6-二氢吡咯并[3,4-d]咪唑-5(1H)-基)-2-((S)-3-羟基吡咯烷-1-基)乙烷-1-酮;
(R)-1-(2-(5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)-4,6-二氢吡咯并[3,4-d]咪唑-5(1H)-基)-2-(二甲氨基)乙烷-1-酮;
3-(5-(L-脯氨酰)-1,4,5,6-四氢吡咯并[3,4-d]咪唑-2-基)-5-((R)-1-(3,5-二氯吡啶-4-基)乙氧基)-1H吲唑;
5-((R)-1-(3,5-二氯吡啶-4-基)乙氧基)-3-(5-(甲基-L-脯氨酰)-1,4,5,6-四氢吡咯并[3,4-d]咪唑-2-基)-1H吲唑;
(2-(5-((R)-1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)-4,6-二氢吡咯并[3,4-d]咪唑-5(1H)-基)((S)-哌啶-2-基)甲酮;
(2-(5-((R)-1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)-4,6-二氢吡咯并[3,4-d]咪唑-5(1H)-基)((S)-1-甲基哌啶-2-基)甲酮;
1-(2-(5-((R)-1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)-4,6-二氢吡咯并[3,4-d]咪唑-5(1H)-基)-2-(3-氟吡咯烷-1-基)乙烷-1-酮;
1-(2-(2-(5-((R)-1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)-4,6-二氢吡咯并[3,4-d]咪唑-5(1H)-基)-2-氧乙基)吡咯烷-3-腈;
(R)-1-(2-(5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)-4,6-二氢吡咯并[3,4-d]咪唑-5(1H)-基)-2-(哌啶-1-基)乙烷-1-酮;
(R)-2-(氮杂环丁烷-1-基)-1-(2-(5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)-4,6-二氢吡咯并[3,4-d]咪唑-5(1H)-基)乙烷-1-酮;
(R)-1-(2-(5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)-4,6-二氢吡咯并[3,4-d]咪唑-5(1H)-基)-2-(3-羟基氮杂环丁-1-基)乙烷-1-酮;
(R)-1-(2-(5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)-4,6-二氢吡咯并[3,4-d]咪唑-5(1H)-基)-2-(3-氟氮杂环丁烷-1-基)乙烷-1-酮;
2-(二甲氨基)乙基(R)-2-(5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)-4,6-二氢吡咯并[3,4-d]咪唑-5(1H)-羧酸盐;
1-甲基吡咯烷-3-基2-(5-((R)-1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)-4,6-二氢吡咯并[3,4-d]咪唑-5(1H)-羧酸盐;
或其同位素标记化合物、或其光学异构体、几何异构体、互变异构体或异构体混合物、或其药学上可接受的盐、或其前药、或其代谢物。
10.一种药物组合物,其包含根据权利要求1-9中任一项所述的化合物或其同位素标记化合物、或其光学异构体、几何异构体、互变异构体或异构体混合物、或其药学上可接受的盐、或其前药、或其代谢物,以及一种或多种药学上可接受的载体、佐剂或赋形剂。
11.根据权利要求1-9中任一项所述的化合物或其同位素标记化合物、或其光学异构体、几何异构体、互变异构体或异构体混合物、或其药学上可接受的盐、或其前药、或其代谢物或者根据权利要求10所述的药物组合物在制备用于治疗与FGFR相关的疾病或病症的药物中的用途。
12.根据权利要求11所述的用途,其中所述与FGFR相关的疾病和病症选自:癌症、骨骼障碍或软骨细胞障碍、低磷血症障碍和纤维化疾病。
13.根据权利要求12所述的用途,其中所述与FGFR相关的疾病和病症选自肝细胞癌、乳腺癌、膀胱癌、结肠直肠癌、黑色素瘤、间皮瘤、肺癌、前列腺癌、膜腺癌、睾丸癌、甲状腺癌、鳞状细胞癌、神经胶母细胞瘤、成神经细胞瘤、子宫癌、横纹肌肉瘤。
14.根据权利要求11-13中任一项所述的用途,其中所述与FGFR相关的疾病或病症是因FGFR中的门控突变而对不靶向门控突变的FGFR抑制剂有抗性的疾病和病症。
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WO2024032598A1 (zh) * | 2022-08-08 | 2024-02-15 | 河南迈英诺医药科技有限公司 | TGF-β抑制剂化合物及其用途 |
WO2024140990A1 (zh) * | 2022-12-30 | 2024-07-04 | 江苏亚虹医药科技股份有限公司 | 吡唑稠环化合物及其制备方法和用途 |
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CN106317023A (zh) * | 2015-07-10 | 2017-01-11 | 中国科学院上海药物研究所 | 吲唑类化合物的制备方法和用途 |
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