CN102958927A - 激酶的吲唑抑制剂 - Google Patents
激酶的吲唑抑制剂 Download PDFInfo
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- CN102958927A CN102958927A CN2011800336534A CN201180033653A CN102958927A CN 102958927 A CN102958927 A CN 102958927A CN 2011800336534 A CN2011800336534 A CN 2011800336534A CN 201180033653 A CN201180033653 A CN 201180033653A CN 102958927 A CN102958927 A CN 102958927A
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- Prior art keywords
- alkyl
- heterocyclic radical
- thiazolinyl
- independently selected
- alkynyl
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Abstract
Description
相关申请的交叉引用
本申请要求2010年5月12日提交的序列号为61/333,843的美国临时专利申请的优先权,其以引用的方式整体并入。
发明领域
本发明涉及抑制蛋白质激酶如极光激酶和激酶的VEGFR和PDGFR家族的化合物、含有该化合物的组合物、和使用该化合物治疗疾病的方法。
发明背景
有丝分裂是复制的基因组的完整拷贝被微管纺锤体分离成两个子细胞的过程。极光激酶——基因组稳定性所需的关键有丝分裂调节剂——已被发现在人肿瘤中过度表达。因此在治疗领域中现在需要抑制极光激酶的化合物、包含该抑制剂的组合物和治疗在此期间极光激酶未受调节或过度表达的疾病的方法。
蛋白质的可逆磷酸化是介导真核细胞信号传导的主要生化机制之一。将ATP的g-磷酸基转移到靶蛋白上的羟基上的蛋白激酶催化这种反应。在人类基因组中存在518种这样的酶,其中~90种选择性催化酪氨酸羟基的磷酸化。胞液酪氨酸激酶留在细胞内,而受体酪氨酸激酶(RTKs)具有胞外和胞内结构域并充当跨膜细胞表面受体。因此,RTKs介导细胞对环境信号的响应并促进多种细胞过程,包括增殖、迁移和存活。
RTK信号传导路径通常高度受调节,但它们的过度活化已表明促进癌细胞的生长、存活和转移。通过基因过度表达或突变发生失调的RTK信号传导并与各种人类癌症的进程相关联。
VEGF受体(VEGFR)家族由三种RTKs、KDR(含激酶插入结构域受体;VEGFR2)、FLT1(Fms样酪氨酸激酶;VEGFR1)和FLT4(VEGFR3)构成。这些受体介导血管内皮生长因子(VEGF-A、-B、-C、-D、-E和胎盘生长因子(PlGF))——一类以各种亲和力结合VEGF受体的同型二聚体糖蛋白——的生物功能。
KDR是VEGF-A(下文称作VEGF)的促有丝分裂、血管生成和增渗作用的主要介质。许多不同的细胞类型能产生VEGF,但其生物活性经由KDR的内皮细胞选择性表达主要限于脉管系统。不足为奇地,VEGF/KDR轴是血管生成的主要介质,借此由预存血管形成新的血管。
FLT1结合VEGF、VEGF-B和胎盘生长因子。除内皮细胞外,在平滑肌细胞、单核细胞和造血干细胞的表面上也表达FLT1。FLT1信号传导的活化导致骨髓源性内皮祖细胞的活动化,它们募集到肿瘤上,在此它们有助于新血管形成。
FLT4介导VEGF-C和VEGF-D的信号传导,这介导肿瘤相关的淋巴管的形成(淋巴管生成)。淋巴管是在转移过程中从实体瘤传播癌细胞的途径之一。
PDGF受体(PDGFR)家族由五种RTK’s、PDGFR-a和–b、CSF1R、KIT和FLT3构成。
血小板源生长因子(PDGF)受体的a和b同种型作为同型二聚体或a/b异质二聚体存在并最常存在于成纤维细胞和平滑肌细胞的表面上。PDGFR-b通过周细胞(与不成熟血管结合并稳定不成熟血管的周围内皮细胞)的增殖和迁移促进肿瘤血管生成。在胶质瘤中,由PDGF和PDGF受体的共表达引起的自分泌PDGFR刺激介导肿瘤细胞增殖和存活。
CSF-1R由逆转录病毒致癌基因v-fms的细胞同系物编码并且是巨噬细胞发育的主要调节剂。巨噬细胞是肿瘤基质的常见组分并已表明以有益于肿瘤生长和转移的方式改变细胞外基质。
造血祖细胞、肥大细胞、胚细胞和肠中的起搏细胞(Cajal间质细胞)表达KIT。其通过两种一般机制(即通过其配体干细胞因子(SCF)的自分泌刺激和通过造成配体非依赖性激酶活性的突变)促进肿瘤进展。
通常在造血干细胞上表达FLT3,在此其与FLT3配体(FL)的相互作用刺激干细胞存活、增殖和分化。除在各种白血病细胞中过度表达外,在伴随大约1/3的带有激活突变的急性骨髓性白血病(AML)患者的恶性血液病中FLT3通常突变。
因此希望确立通过调制酪氨酸激酶的活性以调节和调制异常或不适当的细胞增殖、分化或代谢来特异性抑制信号转导和细胞增殖的有效的小化合物。特别地,特异性抑制对造成水肿、腹水、积液、渗漏和大分子外渗和基质沉积以及相关失调症的血管生成过程或血管通透性过高的形成而言必不可少的酪氨酸激酶的功能的方法和化合物的确立是有益的。
发明概述
本发明具有多种实施方案。因此,本发明的一种实施方案涉及具有式(I)的化合物
其中A1、A2、L和A3被限定如下并为其中的子集。
还提供了可药用组合物,该组合物包含治疗有效量的式(I)的化合物、可药用盐以及适合药用的载体。
一种实施方案涉及治疗哺乳动物癌症的方法,包括给予其治疗可接受量的式(I)的化合物或可药用盐。另一种实施方案涉及降低哺乳动物中肿瘤体积的方法,包括给予其治疗可接受量的式(I)的化合物或可药用盐。
又一种实施方案涉及治疗哺乳动物中膀胱癌、乳腺癌、宫颈癌、结肠癌、子宫内膜癌、食道癌、肺癌、卵巢癌、胰腺癌、前列腺癌、直肠癌、皮肤癌、胃癌和甲状腺癌的方法,该方法包括给予其治疗有效量的具有式(I)的化合物,也向其施以或不施以放射疗法。
发明详述
此详述仅意在使本领域其它技术人员了解申请人的发明、其原理及其实际应用,以使本领域其它技术人员可以以许多形式修改和应用本发明,以使它们可最佳地适应特定用途的要求。本说明书及其具体实施例仅意在举例说明。因此,本发明不限于此专利申请中描述的实施方案并可以多方面地修改。
缩写和定义
除非本文中另行规定,与本发明相关使用的科学和技术术语应具有本领域普通技术人员通常理解的含义。这些术语的含义和范围应当清晰,但如果有任何潜在歧义,本文中提供的定义优先于任何词典或外来定义。在本申请中,除非另行指明,“或”的使用是指“和/或”。此外,术语“包括(including)”以及其它形式的使用,例如“包括(includes)”和“包括(included)”,不是限制性的。关于本专利申请(包括权利要求)中的词语“包含(comprise)”或“包含(comprises)”或“包含(comprising)”的使用,申请人指出,除非文中另行要求,这些词语基于它们应可兼性而非排他性解释的清楚理解而使用,申请人希望在解释此专利申请,包括下列权利要求时如此解释这些词语中的每一个。关于在本文中在任何取代基中或在本发明的化合物或任何其它式中出现一次以上的变量,其在每一处的定义独立于其在其它每一处的定义。取代基的组合只有在这样的组合产生稳定化合物时才可容许。稳定的化合物是其可以以有用的纯度从反应混合物中分离的化合物。
要理解的是,本文中的所有组合保持适当的化合价,具有多于一个原子的一价部分通过它们的左端连接,二价部分从左向右绘制。
如说明书和所附权利要求中所用,除非作出相反的规定,下列术语具有所示含义:
术语“烷基”(独自或与其它术语结合)是指通常含有1至大约10个碳原子;或在另一实施方案中1至大约8个碳原子;在另一实施方案中1至大约6个碳原子;和在另一实施方案中1至大约4个碳原子的直链或支链饱和烃基取代基。这样的取代基的实例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、戊基、异戊基和己基等。
术语“烯基”(独自或与其它术语结合)是指含有一个或多个双键和通常2至大约10个碳原子;或在另一实施方案中2至大约8个碳原子;在另一实施方案中2至大约6个碳原子;和在另一实施方案中2至大约4个碳原子的直链或支链烃基取代基。这样的取代基的实例包括乙烯基、2-丙烯基、3-丙烯基、1,4-戊二烯基、1,4-丁二烯基、1-丁烯基、2-丁烯基和3-丁烯基等。
术语“炔基”(独自或与其它术语结合)是指含有一个或多个三键和通常2至大约10个碳原子;或在另一实施方案中2至大约8个碳原子;在另一实施方案中2至大约6个碳原子;和在另一实施方案中2至大约4个碳原子的直链或支链烃基取代基。这样的取代基的实例包括乙炔基、2-丙炔基、3-丙炔基、2-丁炔基和3-丁炔基等。
术语“碳环基”(独自或与其它术语结合)是指含有3至14个碳环原子(“环原子”是键合在一起形成环状取代基的环的原子)的饱和环状(即“环烷基”)、部分饱和环状(即“环烯基”)或完全不饱和的(即“芳基”)烃基取代基。碳环基可以是单环(单环的)或多环的环结构。
碳环基可以是通常含有3至7个环原子,更通常3至6个环原子,再更通常5至6个环原子的单环结构。这样的单环碳环基的实例包括环丙基(cyclopropanyl)、环丁基(cyclobutanyl)、环戊基(cyclopentanyl)、环戊烯基、环戊二烯基、环己基(cyclohexanyl)、环己烯基、环己二烯基和苯基。碳环基也可以是多环的(即可含有多于一个环)。多环碳环基的实例包括桥连、稠合和螺环碳环基。在螺环碳环基中,一个原子是两个不同环共有的。螺环碳环基的实例是螺环戊烷基。在桥连碳环基中,环共享至少两个共有非相邻原子。桥连碳环基的实例包括双环[2.2.1]庚烷基、双环[2.2.1]庚-2-烯基和金刚烷基。在稠环碳环基体系中,两个或更多个环可稠合在一起,以致两个环共享一个共用键。二-或三-稠环碳环基的实例包括萘基、四氢化萘基(tetralinyl)、茚基、茚满基(二氢化茚基)、蒽基、菲基和十氢化萘基。
术语“环烷基”(独自或与其它术语结合)是指含有3至14个碳环原子的饱和环烃基取代基。环烷基可以是通常含有3至7个碳环原子,更通常3至6个环原子的单碳环。单环环烷基的实例包括环丙基、环丁基、环戊基和环己基。环烷基也可以是多环的或含有多于一个环。多环环烷基的实例包括桥连、稠合和螺环碳环基。
术语“芳基”(独自或与其它术语结合)是指含有6至14个碳环原子的芳族碳环基。芳基的实例包括苯基、萘基和茚基。
在一些情况下,烃基取代基(例如烷基、烯基、炔基或环烷基)中的碳原子数由前缀“Cx-Cy-”指示,其中x为取代基中的碳原子的最小数目,y为最大数目。因此,例如,“C1-C6-烷基”是指含有1至6个碳原子的烷基取代基。进一步举例说明,C3-C6-环烷基是指含有3至6个碳环原子的饱和烃基环。
术语“氢”(独自或与其它术语结合)是指氢基并可以被描述为-H。
术语“羟基”(独自或与其它术语结合)是指-OH。
术语“羧基”(独自或与其它术语结合)是指-C(O)-OH。
术语“氨基”(独自或与其它术语结合)是指-NH2。
术语“卤素”或“卤基”(独自或与其它术语结合)是指氟基(其可被描述为-F)、氯基(其可被描述为-Cl)、溴基(其可被描述为-Br)或碘基(其可被描述为-I)。
如果取代基被描述为“取代的”,非氢基团代替该取代基的碳或氮上的氢基。因此,例如,取代的烷基取代基是其中至少一个非氢基团代替该烷基取代基上的氢基的烷基取代基。例如,单氟烷基是被氟基取代的烷基,二氟烷基是被两个氟基取代的烷基。应该认识到,如果在取代基上存在多于一个取代,各非氢基团可以相同或不同(除非另行指明)。
如果取代基被描述为“任选取代的”,该取代基可以(1) 未取代,或(2) 被取代。如果取代基被描述为任选被最多特定数量的非氢基团取代,该取代基可以(1) 未取代;或(2) 被最多该特定数量的非氢基团或被最多该取代基上的可取代位置的最大数量取代,看哪个更小。因此,例如,如果取代基被描述为任选被最多3个非氢基团取代的杂芳基,则具有小于3个可取代位置的任何杂芳基任选被最多仅与该杂芳基所具有的可取代位置一样多的非氢基团取代。例如,四唑基(其只有一个可取代位置)任选被最多一个非氢基团取代。为进一步举例说明,如果氨基氮被描述为任选被最多2个非氢基团取代,则伯氨基氮任选被最多2个非氢基团取代,而仲氨基氮任选被最多仅1个非氢基团取代。
此专利申请可互换使用术语“取代基”和“基团(radical)”。
前缀“卤代”是指前缀连接的取代基被一个或多个独立选择的卤素基团取代。例如,卤代烷基是指其中至少一个氢基被卤素基团替代的烷基取代基。卤代烷基的实例包括氯甲基、1-溴乙基、氟甲基、二氟甲基、三氟甲基和1,1,1-三氟乙基。应该认识到,如果取代基被多于一个的卤素基团取代,这些卤素基团可以相同或不同(除非另行指明)。
前缀“全卤代”是指前缀连接的取代基上的每个氢基被独立选择的卤素基团替代,即该取代基上的各氢基被卤素基团替代。如果所有卤素基团相同,前缀通常指定卤素基团。因此,例如,术语“全氟”是指前缀连接的取代基上的每个氢基被氟基取代。例如,术语“全氟烷基”是指其中氟基代替各氢基的烷基取代基。
术语“羰基”(独自或与其它术语结合)是指-C(O)-。
术语“氨基羰基”(独自或与其它术语结合)是指-C(O)-NH2。
术语“氧基”(独自或与其它术语结合)是指醚取代基并可以被描述为-O-。
术语“烷氧基”(独自或与其它术语结合)是指烷基醚取代基,即-O-烷基。这种取代基的实例包括甲氧基(-O-CH3)、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基和叔丁氧基。
术语“烷基羰基”(独自或与其它术语结合)是指-C(O)-烷基。
术语“氨基烷基羰基”(独自或与其它术语结合)是指-C(O)-烷基-NH2。
术语“烷氧基羰基”(独自或与其它术语结合)是指-C(O)-O-烷基。
术语“碳环基羰基”(独自或与其它术语结合)是指-C(O)-碳环基。
类似地,术语“杂环基羰基”(独自或与其它术语结合)是指-C(O)-杂环基。
术语“碳环基烷基羰基”(独自或与其它术语结合)是指-C(O)-烷基-碳环基。
类似地,术语“杂环基烷基羰基”(独自或与其它术语结合)是指-C(O)-烷基-杂环基。
术语“碳环基氧基羰基”(独自或与其它术语结合)是指-C(O)-O-碳环基。
术语“碳环基烷氧基羰基”(独自或与其它术语结合)是指-C(O)-O-烷基-碳环基。
术语“硫代(thio)”或“硫杂(thia)”(独自或与其它术语结合)是指硫醚取代基,即其中二价硫原子代替醚氧原子的醚取代基。这种取代基可以被描述为-S-。这种例如“烷基-硫代-烷基”是指烷基-S-烷基(烷基-硫基(sulfanyl)-烷基)。
术语“硫醇”或“巯基”(独自或与其它术语结合)是指巯基取代基并可以被描述为-SH。
术语“(硫代羰基)”(独自或与其它术语结合)是指其中氧原子被硫替代的羰基。这种取代基可以被描述为-C(S)-。
术语“磺酰基”(独自或与其它术语结合)是指-S(O)2-。
术语“氨基磺酰基”(独自或与其它术语结合)是指-S(O)2-NH2。
术语“亚硫酰基”或“亚砜基”(独自或与其它术语结合)是指-S(O)-。
术语“杂环基”(独自或与其它术语结合)是指含有总共3至14个环原子的饱和的(即“杂环烷基”)、部分饱和的(即“杂环烯基”)或完全不饱和的(即“杂芳基”)环结构。环原子中的至少一个是杂原子(即氧、氮或硫),其余环原子独立地选自碳、氧、氮和硫。杂环基可以是单环(单环的)或多环的环结构。
杂环基可以是单环,其通常含有3至7个环原子,更通常3至6个环原子,再更通常5至6个环原子。单环杂环基的实例包括呋喃基、二氢呋喃基、四氢呋喃基、噻吩基(硫代呋喃基)、二氢噻吩基、四氢噻吩基、吡咯基、吡咯啉基、吡咯烷基、咪唑基、咪唑啉基、咪唑烷基、吡唑基、吡唑啉基、吡唑烷基、三唑基、四唑基、噁唑基、噁唑烷基、异噁唑烷基、异噁唑基、噻唑基、异噻唑基、噻唑啉基、异噻唑啉基、噻唑烷基、异噻唑烷基、噻二唑基、噁二唑基(包括1,2,3-噁二唑基、1,2,4-噁二唑基、1,2,5-噁二唑基(呋咱基)或1,3,4-噁二唑基)、噁三唑基(包括1,2,3,4-噁三唑基或1,2,3,5-噁三唑基)、二噁唑基(包括1,2,3-二噁唑基、1,2,4-二噁唑基、1,3,2-二噁唑基或1,3,4-二噁唑基)、噁噻唑基、氧硫杂环戊二烯基(oxathiolyl)、氧硫杂环戊烷基(oxathiolanyl)、吡喃基、二氢吡喃基、噻喃基、四氢噻喃基、吡啶基(吖嗪基)、哌啶基、二嗪基(包括哒嗪基(1,2-二嗪基)、嘧啶基(1,3-二嗪基)或吡嗪基(1,4-二嗪基))、哌嗪基、三嗪基(包括1,3,5-三嗪基、1,2,4-三嗪基和1,2,3-三嗪基)、噁嗪基(包括1,2-噁嗪基、1,3-噁嗪基或1,4-噁嗪基)、噁噻嗪基(包括1,2,3-噁噻嗪基、1,2,4-噁噻嗪基、1,2,5-噁噻嗪基或1,2,6-噁噻嗪基)、噁二嗪基(包括1,2,3-噁二嗪基、1,2,4-噁二嗪基、1,4,2-噁二嗪基或1,3,5-噁二嗪基))、吗啉代、氮杂基(azepinyl)、氧杂基(oxepinyl)、硫杂基(thiepinyl)和二氮杂基(diazepinyl)。
杂环基也可以是多环的(即可含有多于一个环)。多环杂环基的实例包括桥连、稠合和螺环杂环基。在螺环杂环基中,一个原子是两个不同环共有的。在桥连杂环基中,环共享至少两个共有非相邻原子。在稠环杂环基中,两个或更多个环可稠合在一起,以致两个环共享一个共用键。含有两个或三个环的稠环杂环基的实例包括吲嗪基、吡喃并吡咯基、4H-喹嗪基、嘌呤基、萘啶基、吡啶并吡啶基(包括吡啶并[3,4-b]-吡啶基、吡啶并[3,2-b]-吡啶基或吡啶并[4,3-b]-吡啶基)和蝶啶基。稠环杂环基的其它实例包括苯并稠合杂环基,如吲哚基、异吲哚基(isobenzazolyl、假异吲哚基)、indoleninyl(假吲哚基)、异吲唑基(苯并吡唑基)、喹啉基(benzazinyl)(包括喹啉基(1-benzazinyl)或异喹啉基(2-benzazinyl))、酞嗪基、喹喔啉基、喹唑啉基、苯并二嗪基(包括噌啉基(1,2-苯并二嗪基)或喹唑啉基(1,3-苯并二嗪基))、苯并吡喃基(包括苯并二氢吡喃基或异苯并二氢吡喃基)、苯并噁嗪基(包括1,3,2-苯并噁嗪基、1,4,2-苯并噁嗪基、2,3,1-苯并噁嗪基或3,1,4-苯并噁嗪基)和苯并异噁嗪基(包括1,2-苯并异噁嗪基或1,4-苯并异噁嗪基)。
术语“杂芳基”(独自或与其它术语结合)是指含有5至14个环原子的芳香族杂环基。杂芳基可以是单环或2或3稠合环。杂芳基取代基的实例包括6元环取代基,如吡啶基、吡嗪基、嘧啶基、哒嗪基和1,3,5-、1,2,4-或1,2,3-三嗪基;5-元环取代基,如咪唑基(imidazyl)、呋喃基、噻吩基、吡唑基、噁唑基、异噁唑基、噻唑基、1,2,3-、1,2,4-、1,2,5-或1,3,4-噁二唑基和异噻唑基;6/5-元稠环取代基,如苯并硫代呋喃基、苯并异噁唑基、苯并噁唑基、嘌呤基和anthranilyl;和6/6-元稠环,如苯并吡喃基、喹啉基、异喹啉基、噌啉基、喹唑啉基和苯并噁嗪基。
连接多组分取代基的前缀仅适用于第一组分。例如,术语“烷基环烷基”含有两个组分:烷基和环烷基。因此,C1-C6-烷基环烷基上的C1-C6-前缀是指烷基环烷基的烷基组分含有1至6个碳原子;C1-C6-前缀不描述环烷基组分。为进一步举例说明,卤代烷氧基烷基上的前缀“卤代”是指烷氧基烷基取代基的仅烷氧基组分被一个或多个卤素基团取代。如果取而代之地或另外地在烷基组分上发生卤素取代,该取代基将实际上被描述为“卤素取代的烷氧基烷基”而非“卤代烷氧基烷基”。最后,如果仅在烷基组分上发生卤素取代,该取代基将实际上被描述为“烷氧基卤代烷基”。
术语“治疗(treat,treating和treatment)”是指减轻或消除疾病和/或其附随症状的方法。
术语“预防(prevent,preventing和prevention)”是指防止疾病和/或其附随症状发作或防止对象得病的方法。本文所用的“预防”还包括延迟疾病和/或其附随症状发作和降低对象的得病风险。
术语“治疗有效量”是指足以防止所治疗的病症或失调症的一种或多种症状的发展或在一定程度上减轻所治疗的病症或失调症的一种或多种症状的化合物给药量。
术语“调制”是指化合物提高或降低激酶的功能或活性的能力。本文中以其各种形式使用的“调制”意在包括与激酶相关的活性的拮抗、激动、部分拮抗和/或部分激动。激酶抑制剂是例如结合、部分或完全阻碍刺激、降低、防止、延迟活化、钝化、减敏或下调信号转导的化合物。激酶活化剂是例如结合、刺激、提高、开启、活化、促进、增活、敏化或上调信号转导的化合物。
本文所用的术语“组合物”意在包括包含规定量的规定成分以及由规定量的规定成分的结合直接或间接产生的任何产物的产品。“可药用”是指载体、稀释剂或赋形剂必须与制剂的其它成分相容并对其受体无害。
“对象”在本文中定义为包括动物,如哺乳动物,包括但不限于,灵长类动物(例如人)、牛、绵羊、山羊、马、狗、猫、兔、大鼠、小鼠等。在优选实施方案中,该对象是人。
术语“KDR”是指激酶插入结构域受体(III型受体酪氨酸激酶)并也被称作FLK1、VEGFR、VEGFR2和CD309。
术语“VEGFR”是指血管内皮生长因子受体。
术语“PDGFR”是指血小板源生长因子受体。
化合物
一方面,本发明部分涉及一类具有式(I)结构的化合物:
其中
A1是芳基或杂芳基,其任选被一个或多个R1取代,
R1选自R2、烷基、烯基、炔基、卤素、氰基、-OR3、-C(O)R3、-C(O)OR3、-C(O)NR4R5、-OC(O)R3、-NR4R5、-NR4C(O)R5、-NHC(O)NHR4、-NHS(O)2R3、- SR3、-S(O)R3、-SO2R3、-SO2NR4R5、-N3、-NO2、-CF3、-CF2CF3、-OCF3和 -OCF2CF3,其中R1烷基、烯基和炔基取代基任选被一个或多个选自R6、卤素、氰基、-OR3、-C(O)R3、-C(O)OR3、-C(O)NR4R5、-OC(O)R3、-NR4R5和-NR4C(O)R3的取代基取代;
R2为芳基或杂环基,其中R2芳基和杂环基取代基任选被一个或多个独立地选自R7、卤素、氰基、-OR8、-C(O)R8、-C(O)OR8、-C(O)NR9R10、-OC(O)R8、-NR9R10、-NR9C(O)R8、-NHC(O)NHR9、-NHS(O)2R8、-SR8、-S(O)R8、-SO2R8、-SO2NR9R10、-N3、-NO2、-CF3、-CF2CF3、-OCF3和-OCF2CF3的取代基取代;
R3在每次出现时独立地选自氢、烷基、烯基、炔基、芳基、杂环基和环烷基,其中该烷基、烯基、炔基、芳基、杂环基和环烷基任选被一个或多个独立地选自羟基、卤素和氰基的取代基所取代;
R4和R5在每次出现时独立地选自氢、烷基、烯基、炔基、芳基、杂环基和环烷基,其中该烷基、烯基、炔基、杂环基和环烷基任选被一个或多个独立地选自羟基、卤素和氰基的取代基所取代;
R6为芳基或杂环基,其中R6芳基和杂环基取代基任选被一个或多个独立地选自R7、卤素、氰基、-OR8、-C(O)R8、-C(O)OR8、-C(O)NR9R10、-OC(O)R8、-NR9R10、-NR9C(O)R8、-NHC(O)NHR9、-NHS(O)2R8、-SR8、-S(O)R8、-SO2R8、-SO2NR9R10、-N3、-NO2、-CF3、-CF2CF3、-OCF3和-OCF2CF3的取代基取代;
R7为任选被一个或多个选自卤素、氰基、-OR11、-C(O)R11、-C(O)OR11、-C(O)NR12R13、-OC(O)R11、-NR12R13、-NR12C(O)R11、苯基和杂环烷基的取代基所取代的烷基;
R8在每次出现时独立地选自氢、烷基、烯基、炔基、芳基、杂环基和环烷基,其中该烷基、烯基、炔基、芳基、杂环基和环烷基任选被一个或多个独立地选自羟基、卤素和氰基的取代基所取代;
R9和R10在每次出现时独立地选自氢、烷基、烯基、炔基、芳基、杂环基和环烷基,其中该烷基、烯基、炔基、杂环基和环烷基任选被一个或多个独立地选自羟基、卤素和氰基的取代基所取代;
R11在每次出现时独立地选自氢、烷基、烯基、炔基、芳基、杂环基和环烷基,其中该烷基、烯基、炔基、芳基、杂环基和环烷基任选被一个或多个独立地选自羟基、卤素和氰基的取代基所取代;
R12和R13在每次出现时独立地选自氢、烷基、烯基、炔基、芳基、杂环基和环烷基,其中该烷基、烯基、炔基、杂环基和环烷基任选被一个或多个独立地选自羟基、卤素和氰基的取代基所取代;
A2为芳基或杂芳基,其任选被卤素取代;
L为(CH2)mN(R14)C(O)N(R15)(CH2)n,其中m和n独立地为0或1,其中R14和R15独立地选自氢和烷基;
A3为芳基、环烷基、环烯基、杂环基、烷基、烯基、或炔基, 其中(a)A3烷基、烯基和炔基取代基任选被一个或多个选自R17、卤素、氰基、-OR18、-C(O)R18、-(O)OR18、-C(O)NR19R20、-OC(O)R18、-NR19R20、-NR19C(O)R18、-NHC(O)NHR19、-NHS(O)2R18、-SR18、-S(O)R18、-SO2R18、-SO2NR19R20、-N3、-NO2、-CF3、-CF2CF3、-OCF3和-OCF2CF3的取代基所取代;(b) 其中A3环烷基、环烯基、芳基和杂环基取代基任选被一个或多个R16取代;
R16选自R17、烷基、烯基、炔基、卤素、氰基、-OR21、-C(O)R21、-C(O)OR21、-C(O)NR22R23、-OC(O)R21、-NR22R23、-NR22C(O)R21、-NHC(O)NHR22、-NHS(O)2R21、-SR21、-S(O)R21、-SO2R21、-SO2NR22R23、-N3、-NO2、-CF3、-CF2CF3、-OCF3;其中R16烷基、烯基和炔基取代基任选被一个或多个选自芳基、杂环基、环烷基、卤素、氰基、-OR21、-C(O)R21、-C(O)OR21、-C(O)NR22R23、-NR22R23和-NR22C(O)R21 的取代基取代;
R17为芳基或杂环基,其中R17芳基和杂环基取代基任选被一个或多个独立地选自烷基、烯基、炔基、卤素、氰基、-OR24、-C(O)R24、-C(O)OR24、-C(O)NR25R26、-OC(O)R24、-NR25R26、-NR25C(O)R26、-NHC(O)NHR25、-NHS(O)2R24、-SR24、-S(O)R24、-SO2R24、-SO2NR25R26、-N3、-NO2、-CF3、-CF2CF3、-OCF3的取代基取代;
R18在每次出现时独立地选自氢、烷基、烯基、炔基、芳基、杂环基和环烷基,其中该烷基、烯基、炔基、芳基、杂环基和环烷基任选被一个或多个独立地选自羟基、卤素和氰基的取代基所取代;
R19和R20在每次出现时独立地选自氢、烷基、烯基、炔基、芳基、杂环基和环烷基,其中该烷基、烯基、炔基、杂环基和环烷基任选被一个或多个独立地选自羟基、卤素和氰基的取代基所取代;
R21在每次出现时独立地选自氢、烷基、烯基、炔基、芳基、杂环基和环烷基,其中该烷基、烯基、炔基、芳基、杂环基和环烷基任选被一个或多个独立地选自羟基、卤素和氰基的取代基所取代;
R22和R23在每次出现时独立地选自氢、烷基、烯基、炔基、芳基、杂环基和环烷基,其中该烷基、烯基、炔基、杂环基和环烷基任选被一个或多个独立地选自羟基、卤素和氰基的取代基所取代;
R24在每次出现时独立地选自氢、烷基、烯基、炔基、芳基、杂环基和环烷基,其中该烷基、烯基、炔基、芳基、杂环基和环烷基任选被一个或多个独立地选自羟基、卤素和氰基的取代基所取代;
R25和R26在每次出现时独立地选自氢、烷基、烯基、炔基、芳基、杂环基和环烷基,其中该烷基、烯基、炔基、杂环基和环烷基任选被一个或多个独立地选自羟基、卤素和氰基的取代基所取代;
或其可药用盐。
在式(I)的一种实施方案中,A1为苯基、吡啶基、嘧啶基、哒嗪基、吡唑基、吡咯基、咪唑基、吡唑基、三唑基、呋喃基、噻吩基、噁唑基、异噁唑基、噻唑基、异噻唑基、噁二唑基和异噻唑基。在其它实施方案中,A1为吲哚基、异吲哚基、吲唑基、异吲唑基、喹啉基、苯并噁唑基、苯并呋喃基、苯并噻吩基、苯并噻唑基、苯并咪唑基、苯并三唑基和1,2,3,4-四氢喹啉基。
在式(I)的一种实施方案中,A1选自下式
其中n为0、1或2,且R1如式(I)中所描述。
在式(I)的一种实施方案中,A1任选被R1取代,其中R1为R2、烷基、卤素、氰基、-OR3,
-C(O)R3, -C(O)OR3, -C(O)NR4R5, -OC(O)R3,
-NR4R5, -NR4C(O)R5, CF3,
CF2CF3, OCF3和OCF2CF3;其中R2为苯基;其中R3在每次出现时独立地选自氢和烷基;并且其中R4和R5在每次出现时独立地选自氢和烷基。
在一种实施方案中,A1为未被取代的。
在式(I)的一种实施方案中,A1选自下式
并且R1如式(I)所描述。在式(I)的一种实施方案中,A1在杂环的氮上被R1取代,其中R1为任选被1个或2个选自卤素、氰基、OR3,
C(O)R3, C(O)OR3, NR4R5, C(O)NR4R5,
NR4C(O)R3和R6的取代基所取代的烷基;其中R3在每次出现时独立地选自氢和烷基;其中R4和R5在每次出现时独立地选自氢和烷基;其中R6为芳基或杂环基,其中R6芳基和杂环基取代基任选被一个或多个独立地选自R7、卤素、氰基、-OR8、-C(O)R8、-C(O)OR8、-NR9R10、-NR9C(O)R8、-C(O)NR9R10的取代基取代;其中R7为任选被一个或多个选自卤素、氰基、-OR11,
-C(O)R11, -C(O)OR11, -C(O)NR12R13, -NR12R13和-NR12C(O)R11的取代基所取代的烷基;其中R8在每次出现时独立地选自氢和烷基;其中R9和R10在每次出现时独立地选自氢和烷基;其中R11在每次出现时独立地选自氢和烷基;并且其中R12和R13在每次出现时独立地选自氢和烷基;
在另一种实施方案中,A1在杂环的氮上被R1取代,其中R1选自甲基、乙基、正丙基、异丙基、正丁基、仲丁基、或正戊基。
在另一种实施方案中,A1在杂环的氮上被R1取代,其中R1为CH2R27,
CH2CH2R27, CH2CH2(CH3)R27或CH2CH2CH2R27;并且其中R27选自卤素、氰基、羟基、-OC1-4-烷基、-C(O)OH,、-C(O)OC1-4-烷基、-C(O)NH2, -C(O)NHC1-4-烷基和-C(O)N(C1-4-烷基)2,并且其中C1-4-烷基为未被取代的支链或直链的烷基基团。可选择地,在另一种实施方案中,R1为CH2R28、CH2CH2R28、CH2CH2(CH3)R28或CH2CH2CH2R28;
R28选自哌啶基、哌嗪基、吗啉代、四氢呋喃基、吡咯烷基、3-氧代-1-哌嗪基、2-氧代-1-吡咯烷基、咪唑基、吡啶基和2-氧代-1-咪唑烷基,其中R24任选被-C1-4-烷基, 卤素, 氰基, 羟基, -OC1-4-烷基, -C(O)OH,
-C(O)OC1-4-烷基, -C(O)C1-4-烷基, -C(O)NH2, -C(O)NHC1-4-烷基和-C(O)N(C1-4-烷基)2取代,并且其中C1-4-烷基为未被取代的支链或直链的烷基基团。
在另一种实施方案中,A R1为R2,其中R2为苯基或杂环烷基。在优选的实施方案中,R2为哌啶基、哌嗪基、吗啉代、四氢呋喃基、吡咯烷基、3-氧代-1-哌嗪基、2-氧代-1-吡咯烷基、咪唑基、吡啶基和2-氧代-1-咪唑烷基,其中R2任选被-C1-4-烷基, 卤素, 氰基, 羟基, -OC1-4-烷基, -C(O)OH, -C(O)OC1-4-烷基, -C(O)C1-4-烷基, -C(O)NH2,
-C(O)NHC1-4-烷基和-C(O)N(C1-4-烷基)2取代,并且其中C1-4-烷基为未被取代的支链或直链的烷基基团。
在式(I)的另一种实施方案中,A2为苯基。
在式(I)的另一种实施方案中,L为—NHC(O)NH—。
在式(I)的另一种实施方案中,A3选自苯基、萘基、四氢化萘基、环戊基、环戊烯基、环己基、环己烯基、呋喃基、吡啶基和噻吩基。在优选的实施方案中,A3为任选被1、2或3个R16取代的苯基,其中R16选自-CH3、-CH2CH3、氟代、氯代、溴代、氰基、-NO2、-OCH3、-OCH2CH3、-CF3、-CF2CF3、-OCF3、-OCF2CF3、-NH2、-N(CH3)2、-OH、-OPh、-C(=O)CH3、-C(=O)CH2CH3和C(=O)OH。
另一方面,本发明部分涉及一类具有式(II)结构的化合物:
其中A1和A3如上所限定。
在式(II)的优选的实施方案中,A1选自下式
其中R25为氢或烷基,其中烷基任选被羟基、-OC1-4-烷基、-C(O)OH或-C(O)OC1-4-烷基取代。
在式(II)的另一种优选的实施方案中,A3为苯基,其中苯基任选被-CH3, -CH2CH3、氟、氯、-OCH3, -OCH2CH3, -CF3,
-CF2CF3, -OCF3和-OCF2CF3取代。
另一方面,本发明部分涉及一类具有式(I)结构的化合物:
在式(I)的一种实施方案中,A1为R2,其中R2为CH2R11, CH2CH2R11或CH2CH2(CH3)R11,并且其中R11选自CN、NO2、C1-4-卤代烷基、OH、OC1-4-烷基、OC1-4-卤代烷基、C(O)OH、C(O)OC1-4-烷基、C(O)NH2、C(O)NHC1-4-烷基和C(O)N(C1-4-烷基)2,并且其中C1-4-烷基为未被取代的支链或直链的烷基基团。在一种实施方案中,R11为OH或CF3。
另一方面,本发明部分涉及一类具有式(I)结构的化合物: 具有式(I)的化合物,
其中
A1是芳基或杂芳基,其任选被一个或多个R1取代,
R1选自R2、烷基、烯基、炔基、卤素、氰基、-OR3、-C(O)R3、-C(O)OR3、-C(O)NR4R5、-OC(O)R3、-NR4R5、-NR4C(O)R5、-NHC(O)NHR4、-NHS(O)2R3、- SR3、-S(O)R3、-SO2R3、-SO2NR4R5、-N3、-NO2、-CF3、-CF2CF3、-OCF3和 -OCF2CF3,其中R1烷基、烯基和炔基取代基任选被一个或多个选自R6、卤素、氰基、-OR3、-C(O)R3、-C(O)OR3、-C(O)NR4R5、-OC(O)R3、-NR4R5和-NR4C(O)R3的取代基取代;
R2为芳基或杂环基,其中R2芳基和杂环基取代基任选被一个或多个独立地选自R7、卤素、氰基、-OR8、-C(O)R8、-C(O)OR8、-C(O)NR9R10、-OC(O)R8、-NR9R10、-NR9C(O)R8、-NHC(O)NHR9、-NHS(O)2R8、-SR8、-S(O)R8、-SO2R8、-SO2NR9R10、-N3、-NO2、-CF3、-CF2CF3、-OCF3和-OCF2CF3的取代基取代;
R3在每次出现时独立地选自氢、烷基、烯基、炔基、芳基、杂环基和环烷基,其中该烷基、烯基、炔基、芳基、杂环基和环烷基任选被一个或多个独立地选自羟基、卤素和氰基的取代基所取代;
R4和R5在每次出现时独立地选自氢、烷基、烯基、炔基、芳基、杂环基和环烷基,其中该烷基、烯基、炔基、杂环基和环烷基任选被一个或多个独立地选自羟基、卤素和氰基的取代基所取代;
R6为芳基或杂环基,其中R6芳基和杂环基取代基任选被一个或多个独立地选自R7、卤素、氰基、-OR8、-C(O)R8、-C(O)OR8、-OC(O)R8、-NR9R10、-NR9C(O)R8、-NHC(O)NHR9、-C(O)NR9R10、-SR8、-S(O)R8、-SO2R8、-OC(O)OR8、-SO2NR9R10、-N3、-NO2、-CF3、-CF2CF3、-OCF3和-OCF2CF3的取代基取代;
R7为任选被一个或多个选自卤素、氰基、-OR11、-C(O)R11、-C(O)OR11、-C(O)NR12R13、-OC(O)R11、-NR12R13、-NR12C(O)R11、苯基和杂环烷基的取代基所取代的烷基;
R8在每次出现时独立地选自氢、烷基、烯基、炔基、芳基、杂环基和环烷基,其中该烷基、烯基、炔基、芳基、杂环基和环烷基任选被一个或多个独立地选自羟基、卤素和氰基的取代基所取代;
R9和R10在每次出现时独立地选自氢、烷基、烯基、炔基、芳基、杂环基和环烷基,其中该烷基、烯基、炔基、杂环基和环烷基任选被一个或多个独立地选自羟基、卤素和氰基的取代基所取代;
R11在每次出现时独立地选自氢、烷基、烯基、炔基、芳基、杂环基和环烷基,其中该烷基、烯基、炔基、芳基、杂环基和环烷基任选被一个或多个独立地选自羟基、卤素和氰基的取代基所取代;
R12和R13在每次出现时独立地选自氢、烷基、烯基、炔基、芳基、杂环基和环烷基,其中该烷基、烯基、炔基、杂环基和环烷基任选被一个或多个独立地选自羟基、卤素和氰基的取代基所取代;
L为-(CH2)mN(R14)C(O)-、-C(O)N(R15)(CH2)n-、-(CH2)mN(R14)C(O)N(R15)(CH2)n-、-(CH2)mN(R14)S(O)2-或-S(O)2N(R15)(CH2)n-,其中m和n独立地为0或1;其中R14和R15独立地选自氢和烷基;
A3为芳基、环烷基、环烯基、杂环基、烷基、烯基或炔基, 其中(a)A3烷基、烯基和炔基取代基任选被一个或多个选自R17、卤素、氰基、-OR18、-C(O)R18、-C(O)OR18、-OC(O)R18、-NR19R20、-NR19C(O)R18、-NHC(O)NHR20、-C(O)NR19R20、-SR18、-S(O)R18、-SO2R18、-OC(O)OR18、-SO2NR19R20、-N3、-NO2、-CF3、-CF2CF3、-OCF3和-OCF2CF3的取代基所取代;(b) 其中A3环烷基、环烯基、芳基和杂环基取代基任选被一个或多个R16取代;
R16选自R17、烷基、烯基、炔基、卤素、氰基、-OR21、-C(O)R21、-C(O)OR21、--OC(O)R21、-NR22R23、-NR22C(O)R21、-NHC(O)NHR22、-C(O)NR22R23、-SR21、-S(O)R21、-SO2R21、-OC(O)OR21、-SO2NR22R23、-N3、-NO2、-CF3、-CF2CF3、-OCF3;其中R16烷基、烯基和炔基取代基任选被一个或多个选自芳基、杂环基、环烷基、卤素、氰基、-OR21、-C(O)R21、-C(O)OR21、-C(O)NR22R23、-OC(O)R21、-NR22R23和-NR22C(O)R21 的取代基取代;
R17为芳基或杂环基,其中R17芳基和杂环基取代基任选被一个或多个独立地选自烷基、烯基、炔基、卤素、氰基、-OR21、-C(O)R21、-C(O)OR21、-OC(O)R21、-NR22R23、-NR22C(O)R21、-NHC(O)NHR22、-C(O)NR22R23、-SR21、-S(O)R21、-SO2R21、-OC(O)OR21、-SO2NR22R23、-N3、-NO2、-CF3、-CF2CF3、-OCF3的取代基取代;
R18在每次出现时独立地选自氢、烷基、烯基、炔基、芳基、杂环基和环烷基,其中该烷基、烯基、炔基、芳基、杂环基和环烷基任选被一个或多个独立地选自羟基、卤素和氰基的取代基所取代;
R19和R20在每次出现时独立地选自氢、烷基、烯基、炔基、芳基、杂环基和环烷基,其中该烷基、烯基、炔基、杂环基和环烷基任选被一个或多个独立地选自羟基、卤素和氰基的取代基所取代;
R21在每次出现时独立地选自氢、烷基、烯基、炔基、芳基、杂环基和环烷基,其中该烷基、烯基、炔基、芳基、杂环基和环烷基任选被一个或多个独立地选自羟基、卤素和氰基的取代基所取代;
R22和R23在每次出现时独立地选自氢、烷基、烯基、炔基、芳基、杂环基和环烷基,其中该烷基、烯基、炔基、杂环基和环烷基任选被一个或多个独立地选自羟基、卤素和氰基的取代基所取代;
或其可药用盐。
在式(I)的一种实施方案中,A1选自下式
并且R1如式(I)所描述。在式(I)的一种实施方案中,A1在杂环的氮上被R1取代,其中R1为任选被1或2个选自卤素、氰基、OR3,
C(O)R3, C(O)OR3, NR4R5, C(O)NR4R5,
NR4C(O)R3和R6的取代基所取代的烷基;其中R3在每次出现时独立地选自氢和烷基;其中R4和R5在每次出现时独立地选自氢和烷基;其中R6为芳基或杂环基,其中R6芳基和杂环基取代基任选被一个或多个独立地选自R7、卤素、氰基、-OR8、-C(O)R8、-C(O)OR8、-NR9R10、-NR9C(O)R8、-C(O)NR9R10的取代基取代;其中R7为任选被一个或多个选自卤素、氰基、-OR11,
-C(O)R11, -C(O)OR11, -C(O)NR12R13, -NR12R13和-NR12C(O)R11的取代基所取代的烷基;其中R8在每次出现时独立地选自氢和烷基;其中R9和R10在每次出现时独立地选自氢和烷基;其中R11在每次出现时独立地选自氢和烷基;并且其中R12和R13在每次出现时独立地选自氢和烷基;
在另一种实施方案中,A1在杂环的氮上被R1取代,其中R1选自甲基、乙基、正丙基、异丙基、正丁基、仲丁基、或正戊基。
在另一种实施方案中,A1在杂环的氮上被R1取代,其中R1为CH2R27,
CH2CH2R27, CH2CH2(CH3)R27或CH2CH2CH2R27;并且其中R27选自卤素、氰基、羟基、-OC1-4-烷基、-C(O)OH、-C(O)OC1-4-烷基、-C(O)NH2、-C(O)NHC1-4-烷基和-C(O)N(C1-4-烷基)2,并且其中C1-4-烷基为未被取代的支链或直链的烷基基团。可选择地,在另一种实施方案中,R1为CH2R28、CH2CH2R28、CH2CH2(CH3)R28或CH2CH2CH2R28;
R28选自哌啶基、哌嗪基、吗啉代、四氢呋喃基、吡咯烷基、3-氧代-1-哌嗪基、2-氧代-1-吡咯烷基、咪唑基、吡啶基和2-氧代-1-咪唑烷基,其中R24任选被-C1-4-烷基, 卤素, 氰基, 羟基, -OC1-4-烷基, -C(O)OH,
-C(O)OC1-4-烷基, -C(O)C1-4-烷基, -C(O)NH2, -C(O)NHC1-4-烷基和-C(O)N(C1-4-烷基)2取代,并且其中C1-4-烷基为未被取代的支链或直链的烷基基团。
在另一种实施方案中,A R1为R2,其中R2为苯基或杂环烷基。在优选的实施方案中,R2为哌啶基、哌嗪基、吗啉代、四氢呋喃基、吡咯烷基、3-氧代-1-哌嗪基、2-氧代-1-吡咯烷基、咪唑基、吡啶基和2-氧代-1-咪唑烷基,其中R2任选被-C1-4-烷基, 卤素, 氰基, 羟基, -OC1-4-烷基, -C(O)OH, -C(O)OC1-4-烷基, -C(O)C1-4-烷基, -C(O)NH2,
-C(O)NHC1-4-烷基和-C(O)N(C1-4-烷基)2取代,并且其中C1-4-烷基为未被取代的支链或直链的烷基基团。
在式(I)的另一种实施方案中,A3选自苯基、萘基、四氢化萘基、环戊基、环戊烯基、环己基、环己烯基、呋喃基、吡啶基和噻吩基。在优选的实施方案中,A3为任选被1、2或3个R16取代的苯基,其中R16选自-CH3、-CH2CH3、氟代、氯代、溴代、氰基、-NO2、-OCH3、-OCH2CH3、-CF3、-CF2CF3、-OCF3、-OCF2CF3、-NH2、-N(CH3)2、-OH、-OPh、-C(=O)CH3、-C(=O)CH2CH3和-C(=O)OH。
被认为是本发明的一部分的特定实施方案包括但不限于式(I)的化合物,例如:
N-(3-氟苯基)-N'-{4-[3-(1-甲基-1H-吡唑-4-基)-1H-吲唑-6-基]苯基}脲;
N-(3-甲基苯基)-N'-{4-[3-(1-甲基-1H-吡唑-4-基)-1H-吲唑-6-基]苯基}脲;
N-(3-甲基苯基)-N'-{4-[3-(1H-1,2,3-三唑-5-基)-1H-吲唑-6-基]苯基}脲;
N-(3-甲基苯基)-N'-{4-[3-(1H-吡咯-2-基)-1H-吲唑-6-基]苯基}脲;
N-(3-甲基苯基)-N'-(4-{3-[1-(2-吗啉-4-基乙基)-1H-吡唑-4-基]-1H-吲唑-6-基}苯基)脲;
N-(3-氟苯基)-N'-(4-{3-[1-(2-吗啉-4-基乙基)-1H-吡唑-4-基]-1H-吲唑-6-基}苯基)脲;
N-(3-甲基苯基)-N'-[4-(3-噻吩-3-基-1H-吲唑-6-基)苯基]脲;
N-(3-氟苯基)-N'-{4-[3-(1H-吡唑-5-基)-1H-吲唑-6-基]苯基}脲;
N-(3-氟苯基)-N'-{4-[3-(1H-吡唑-4-基)-1H-吲唑-6-基]苯基}脲;
N-(3-氟苯基)-N'-(4-{3-[1-(2-羟基乙基)-1H-吡唑-4-基]-1H-吲唑-6-基}苯基)脲;
N-(4-{3-[1-(2-羟基乙基)-1H-吡唑-4-基]-1H-吲唑-6-基}苯基)-N'-[3-(三氟甲基)苯基]脲;
N-(4-{3-[1-(2-羟基乙基)-1H-吡唑-4-基]-1H-吲唑-6-基}苯基)-N'-(3-甲基苯基)脲;
N-(3-氟苯基)-N'-{4-[3-(1-丙基-1H-吡唑-4-基)-1H-吲唑-6-基]苯基}脲;
N-(3-氟苯基)-N'-(4-{3-[1-(2-羟基-2-甲基丙基)-1H-吡唑-4-基]-1H-吲唑-6-基}苯基)脲;
N-(3-氟苯基)-N'-{4-[3-(1-哌啶-4-基-1H-吡唑-4-基)-1H-吲唑-6-基]苯基}脲;
N-(3-甲基苯基)-N'-{3-[3-(1-甲基-1H-吡唑-4-基)-1H-吲唑-6-基]苯基}脲;
N-{4-[3-(1-甲基-1H-吡唑-4-基)-1H-吲唑-6-基]苯基}-N'-[3-(三氟甲基)苯基]脲;
N-{4-[3-(1-甲基-1H-吡唑-4-基)-1H-吲唑-6-基]苯基}-N'-[4-(三氟甲基)苯基]脲;
N-(4-氯苯基)-N'-{4-[3-(1-甲基-1H-吡唑-4-基)-1H-吲唑-6-基]苯基}脲;
N-(3-氟苯基)-N'-{4-[3-(1H-1,2,3-三唑-5-基)-1H-吲唑-6-基]苯基}脲;
N-(3-氯苯基)-N'-{4-[3-(1-甲基-1H-吡唑-4-基)-1H-吲唑-6-基]苯基}脲;
N-(2-氯苯基)-N'-{4-[3-(1-甲基-1H-吡唑-4-基)-1H-吲唑-6-基]苯基}脲;
N-(3-氟苯基)-N'-{4-[3-(1-甲基-1H-吡唑-4-基)-1H-吲唑-6-基]苄基}脲;
N-{4-[3-(1-甲基-1H-吡唑-4-基)-1H-吲唑-6-基]苯基}-N'-[3-(三氟甲氧基)苯基]脲;
N-{4-[3-(1-甲基-1H-吡唑-4-基)-1H-吲唑-6-基]苯基}-N'-[2-(三氟甲基)苯基]脲;
N-{4-[3-(1-甲基-1H-吡唑-4-基)-1H-吲唑-6-基]苯基}-N'-[2-(三氟甲氧基)苯基]脲;
N-{4-[3-(1-甲基-1H-吡唑-4-基)-1H-吲唑-6-基]苯基}-N'-[4-(三氟甲氧基)苯基]脲;
N-(3-氟苯基)-N'-{3-[3-(1-甲基-1H-吡唑-4-基)-1H-吲唑-6-基]苄基}脲;
N-(5-甲基异噁唑-3-基)-N'-{4-[3-(1-甲基-1H-吡唑-4-基)-1H-吲唑-6-基]苯基}脲;
3-氟-N-{4-[3-(1-甲基-1H-吡唑-4-基)-1H-吲唑-6-基]苄基}苯甲酰胺;
N-(3-甲基苯基)-N'-[4-(3-苯基-1H-吲唑-6-基)苯基]脲;
N-(3-甲基苯基)-N'-[4-(3-吡啶-3-基-1H-吲唑-6-基)苯基]脲;
N-(3-甲基苯基)-N'-[3-(3-吡啶-3-基-1H-吲唑-6-基)苯基]脲;
N-(3-甲基苯基)-N'-{4-[3-(1,3-噻唑-4-基)-1H-吲唑-6-基]苯基}脲;
2-(4-{6-[4-({[(3-氟苯基)氨基]羰基}氨基)苯基]-1H-吲唑-3-基}-1H-吡唑-1-基)-N-甲基丙酰胺;
N-{4-[3-(1H-吲哚-2-基)-1H-吲唑-6-基]苯基}-N'-(3-甲基苯基)脲;
N-甲基-2-[4-(6-{4-[(苯基磺酰基)氨基]苯基}-1H-吲唑-3-基)-1H-吡唑-1-基]丙酰胺;
3-氟-N-{4-[3-(1-甲基-1H-吡唑-4-基)-1H-吲唑-6-基]苯基}苯甲酰胺;
N-{4-[3-(1-甲基-1H-吡唑-4-基)-1H-吲唑-6-基]苯基}-N'-[3-(吡咯烷-1-基甲基)苯基]脲;
N-(3-氟苯基)-N'-(4-{3-[1-(2-吡咯烷-1-基乙基)-1H-吡唑-4-基]-1H-吲唑-6-基}苯基)脲;
N-{4-[3-(1H-吲哚-3-基)-1H-吲唑-6-基]苯基}-N'-(3-甲基苯基)脲;
N-[4-(3-{1-[(2R)-2-羟基丙基]-1H-吡唑-4-基}-1H-吲唑-6-基)苯基]-N'-(3-甲基苯基)脲;
3-氟-N-{3-[3-(1-甲基-1H-吡唑-4-基)-1H-吲唑-6-基]苯基}苯甲酰胺; 和
N-{3-氯-4-[3-(1-甲基-1H-吡唑-4-基)-1H-吲唑-6-基]苯基}-N'-(3-氟苯基)脲。
本发明的化合物可含有R或S构型的不对称取代的碳原子,其中术语“R”和“S”如Pure Appl. Chem. (1976) 45, 13-10中所定义。具有被等量R和S构型不对称取代的碳原子的化合物在这些原子处是外消旋的。具有一种构型超过另一构型的原子被指定为过量的构型,优选过量大约85%-90%,更优选过量大约95%-99%,再更优选过量大于大约99%。相应地,本发明意在包括其化合物的外消旋混合物和相对和绝对非对映体。
本发明的化合物还可含有E或Z构型的碳-碳双键或碳-氮双键,其中如通过Cahn-Ingold-Prelog优先规则测得,术语“E”代表在碳-碳或碳-氮双键的相对侧上的较高阶取代基,术语“Z”代表在碳-碳或碳-氮双键的相同侧上的较高阶取代基。本发明的化合物还可作为“E”和“Z”异构体的混合物存在。
本发明的化合物还可作为互变异构体或其平衡混合物存在,其中化合物的质子从一个原子移向另一个。互变异构体的实例包括但不限于酮-烯醇、酚-酮、肟-亚硝基、硝基-酸(nitro-aci)、亚胺-烯胺等。
本发明还部分涉及式(I)的化合物的所有盐。由于盐的一种或多种性质,例如在不同温度和湿度下的增强的药物稳定性或在水或其它溶剂中的合意溶解度,化合物的盐可能是有利的。如果盐要给药于患者(不同于例如在体外环境中使用),该盐优选是可药用的和/或生理相容的。术语“可药用”在本专利申请中作形容词使用以表示修饰的名词适合用作药品或用作药品的一部分。可药用盐包括常用于形成碱金属盐和形成游离酸或游离碱的加成盐的盐。一般而言,这些盐通常可通过常规方式通过使例如适当的酸或碱与本发明的化合物反应来制备。
式(I)的化合物的可药用酸加成盐可由无机或有机酸制备。通常合适的无机酸的实例包括盐酸、氢溴酸、氢碘酸、硝酸、碳酸、硫酸和磷酸。合适的有机酸通常包括例如脂肪族、脂环族、芳香族、芳脂族、杂环、羧酸和磺酸类型的有机酸。通常合适的有机酸的具体实例包括乙酸盐、三氟乙酸盐、甲酸盐、丙酸盐、琥珀酸盐、乙醇酸盐、葡萄糖酸盐、二葡糖酸盐、乳酸盐、苹果酸盐、酒石酸、柠檬酸盐、抗坏血酸盐、葡萄糖醛酸盐、马来酸盐、富马酸盐、丙酮酸盐、天冬氨酸盐、谷氨酸盐、苯甲酸盐、邻氨基苯甲酸、甲磺酸盐、硬脂酸盐、水杨酸盐、对羟基苯甲酸盐、苯基乙酸盐、扁桃酸盐、双羟萘酸盐、乙磺酸盐、苯磺酸盐、泛酸盐、2-羟基乙磺酸盐、磺胺酸盐、环己基氨基磺酸盐、藻酸、β-羟基丁酸、半乳糖二酸盐、半乳糖醛酸盐、己二酸盐、藻酸盐、硫酸氢盐、丁酸盐、樟脑酸盐、樟脑磺酸盐、环戊烷丙酸盐、十二烷基硫酸盐、庚糖酸盐(glycoheptanoate)、甘油磷酸盐、庚酸盐、己酸盐、烟酸盐、草酸盐、palmoate、pectinate、2-萘磺酸盐、3-苯基丙酸盐、苦味酸盐、特戊酸盐、硫氰酸盐、甲苯磺酸盐和十一烷酸盐。
式(I)的化合物的可药用碱加成盐包括例如金属盐和有机盐。优选的金属盐包括碱金属(第Ia族)盐、碱土金属(第IIa族)盐和其它生理上可接受的金属盐。这样的盐可以由铝、钙、锂、镁、钾、钠和锌制成。优选的有机盐可以由胺,如缓血酸胺、二乙胺、N,N'-二苄基乙二胺、氯普鲁卡因、胆碱、二乙醇胺、乙二胺、葡甲胺(N-甲葡糖胺)和普鲁卡因制成。含碱性氮的基团可以用如低碳烷基(C1-C6)卤化物(例如甲基、乙基、丙基和丁基的氯化物、溴化物和碘化物)、二烷基硫酸盐(例如二甲基、二乙基、二丁基和二戊基硫酸盐)、长链卤化物(例如癸基、十二烷基、十四烷基和十八烷基氯化物、溴化物和碘化物)、芳基烷基卤化物(例如苄基和苯乙基溴化物)之类的试剂季铵化。
具有任何纯度级(包括纯和基本纯)的式(I)的化合物(及其盐)在申请人的发明范围内。关于化合物/盐/异构体的术语“基本纯”是指含有化合物/盐/异构体的制剂/组合物含有多于大约85重量%的该化合物/盐/异构体,优选多于大约90重量%的该化合物/盐/异构体,优选多于大约95重量%的该化合物/盐/异构体,优选多于大约97重量%的该化合物/盐/异构体,和优选多于大约99重量%的该化合物/盐/异构体。
化合物的制备
本发明的化合物可通过合成化学法制备,其实例显示在本文中。要理解的是,这些方法中的步骤的次序可变,可以用试剂、溶剂和反应条件替换具体提到的那些,易受影响的部分可以按需要保护和脱保护。
C(O)OH部分的保护基包括但不限于乙酰氧基甲基、烯丙基、苯甲酰基甲基、苄基、苄氧基甲基、叔丁基、叔丁基二苯基甲硅烷基、二苯基甲基、环丁基、环己基、环戊基、环丙基、二苯基甲基甲硅烷基、乙基、对甲氧基苄基、甲氧基甲基、甲氧基乙氧基甲基、甲基、甲基硫代甲基、萘基、对硝基苄基、苯基、正丙基、2,2,2-三氯乙基、三乙基甲硅烷基、2-(三甲基甲硅烷基)乙基、2-(三甲基甲硅烷基)乙氧基甲基、三苯基甲基等。
C(O)和C(O)H部分的保护基包括但不限于1,3-dioxylketal、二乙基缩酮、二甲基缩酮、1,3-dithianylketal、O-甲基肟、O-苯基肟等。
NH部分的保护基包括但不限于乙酰基、丙氨酰基、苯甲酰基、苄基(苯基甲基)、亚苄基、苄氧基羰基(Cbz)、叔丁氧基羰基(Boc)、3,4-二甲氧基苄氧基羰基、二苯基甲基、二苯基磷酰基、甲酰基、甲磺酰基、对甲氧基苄氧基羰基、苯基乙酰基、邻苯二甲酰基、琥珀酰基、三氯乙氧基羰基、三乙基甲硅烷基、三氟乙酰基、三甲基甲硅烷基、三苯基甲基、三苯基甲硅烷基、对甲苯磺酰基等。
OH和SH部分的保护基包括但不限于乙酰基、烯丙基、烯丙氧基羰基、苄氧基羰基(Cbz)、苯甲酰基、苄基、叔丁基、叔丁基二甲基甲硅烷基、叔丁基二苯基甲硅烷基、3,4-二甲氧基苄基、3,4-二甲氧基苄氧基羰基、1,1-二甲基-2-丙烯基、二苯基甲基、甲酰基、甲磺酰基、甲氧基乙酰基、4-甲氧基苄氧基羰基、对甲氧基苄基、甲氧基羰基、甲基、对甲苯磺酰基、2,2,2-三氯乙氧基羰基、2,2,2-三氯乙基、三乙基甲硅烷基、三氟乙酰基、2-(三甲基甲硅烷基)乙氧基羰基、2-三甲基甲硅烷基乙基、三苯基甲基、2-(三苯基磷鎓基)乙氧基羰基等。
方案
方案1
如方案1所示,在文献中广泛应用并被本领域技术人员已知的Suzuki偶联反应条件下,可以按照实施例1B中所述制备的6-溴-3-碘-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吲唑可以与式(1)的硼酸酯(或合适的硼酸)反应来提供式(2)的化合物。在文献中广泛应用并被本领域技术人员已知的Suzuki偶联反应条件下,式(2)的化合物可以与式(3)的硼酸酯(或合适的硼酸)反应来提供式(4)的化合物。可以使用酸例如但不限于HCl,在溶剂例如但不限于乙醇中使式(4)的化合物去保护,以提供式(I)的化合物,其是本发明的化合物的代表。式(1)和(3)的化合物可以商购或在实验室中由可商购的起始原料制备。
方案2
如方案2所示,在文献中广泛应用并被本领域技术人员已知的Suzuki偶联反应条件下,可以按照实施例21A中所述制备的式(5)的化合物可以与式(3)的硼酸酯(或合适的硼酸)反应来提供式(6)的化合物。在溶剂例如但不限于甲醇中,式(6)的化合物可以与碱例如但不限于碳酸钾反应以提供式(7)的化合物。式(7)的化合物可以与三甲基甲硅烷基叠氮化物和Cu(I)I催化剂反应以提供式(8)的化合物。该反应通常在升高的温度下,在溶剂例如但不限于N,N-二甲基甲酰胺、甲醇或其混合物中进行。如方案1所述,式(I)的化合物—本发明的化合物的代表—可以从式(8)的化合物制备。
组合物
在另一方面中,本发明提供用于调节人和动物体内的激酶活性的药物组合物,其通常含有式(I)的化合物和可药用载体。
具有式(I)的化合物可以例如口颊、经眼、经口、渗透、肠胃外(肌肉、腹膜内、胸骨内、静脉、皮下)、直肠、局部、经皮、阴道和动脉内以及通过关节腔内注射、输液和置于体内,例如脉管内来给药。
具有式(I)的化合物可以与或不与赋形剂一起给药。赋形剂包括但不限于包囊剂和添加剂,如吸收促进剂、抗氧化剂、粘合剂、缓冲剂、包衣剂、着色剂、稀释剂、崩解剂、乳化剂、增量剂、填料、调味剂、保湿剂、润滑剂、香精、防腐剂、推进剂、释放剂、消毒剂、甜味剂、增溶剂、润湿剂、其混合物等。
用于制备要口服给药的包含具有式(I)的化合物的组合物的赋形剂包括但不限于琼脂、藻酸、氢氧化铝、苄醇、苯甲酸苄酯、1,3-丁二醇、卡波姆、蓖麻油、纤维素、乙酸纤维素、可可脂、玉米淀粉、玉米油、棉籽油、交聚维酮、甘油二酯、乙醇、乙基纤维素、月桂酸乙酯、油酸乙酯、脂肪酸酯、明胶、胚芽油、葡萄糖、甘油、花生(groundnut)油、羟丙基甲基纤维素、异丙醇、等渗盐水、乳糖、氢氧化镁、硬脂酸镁、麦芽、甘露醇、甘油单酯、橄榄油、花生(peanut)油、磷酸钾盐、马铃薯淀粉、聚维酮、丙二醇、林格氏溶液、红花油、芝麻油、羧甲基纤维素钠、磷酸钠盐、十二烷基硫酸钠、山梨糖醇钠、大豆油、硬脂酸、富马酸十八烷基酯、蔗糖、表面活性剂、滑石、黄蓍胶、四氢糠醇、甘油三酯、水、其混合物等。用于制备要经眼或经口给药的包含具有式(I)的化合物的组合物的赋形剂包括但不限于1,3-丁二醇、蓖麻油、玉米油、棉籽油、乙醇、脱水山梨糖醇的脂肪酸酯、胚芽油、花生油、甘油、异丙醇、橄榄油、聚乙二醇、丙二醇、芝麻油、水、其混合物等。用于制备要渗透给药的包含具有式(I)的化合物的组合物的赋形剂包括但不限于氯氟烃、乙醇、水、其混合物等。用于制备要肠胃外给药的包含具有式(I)的化合物的组合物的赋形剂包括但不限于1,3-丁二醇、蓖麻油、玉米油、棉籽油、右旋糖、胚芽油、花生(groundnut)油、脂质体、油酸、橄榄油、花生(peanut)油、林格氏溶液、红花油、芝麻油、大豆油、U.S.P.或等渗氯化钠溶液、水、其混合物等。用于制备要直肠或阴道给药的包含具有式(I)的化合物的组合物的赋形剂包括但不限于可可脂、聚乙二醇、蜡、其混合物等。
本发明的药物组合物和方法可进一步包含通常用于治疗上述病理状态的如本文所述的其它治疗活性化合物。
使用方法
另一方面,本发明提供使用本发明的化合物或组合物治疗或预防哺乳动物的涉及激酶的介导、过度表达或失调的疾病或病症的方法。特别地,本发明的化合物预计可用于治疗在此期间表达蛋白激酶,如任何或所有极光激酶家族成员的疾病或病症。再一方面,本发明的化合物预计可用于治疗在此期间表达蛋白激酶,如任何或所有KDR(VEGFR2)家族成员的疾病或病症。
在一组实施方案中,可用激酶抑制剂治疗的人或其它动物的疾病和病症包括但不限于听神经瘤、急性白血病、急性淋巴细胞性白血病、急性髓细胞性白血病(单核细胞的、成髓细胞的、腺癌、血管肉瘤、星形细胞瘤、髓单核细胞的和早幼粒细胞性)、急性t-细胞白血病、基底细胞癌、胆管癌、膀胱癌、脑癌、乳腺癌、支气管癌、宫颈癌、软骨肉瘤、脊索瘤、绒毛膜癌、慢性白血病、慢性淋巴细胞性白血病、慢性髓细胞性(粒细胞的)白血病、慢性骨髓性白血病、结肠癌、结肠直肠癌、颅咽管瘤、囊腺癌、弥漫性大B-细胞淋巴瘤、不良增殖变化(dysproliferative changes)(发育不良和化生)、胚胎癌、子宫内膜癌、内皮肉瘤、室管膜瘤、上皮癌、红白血病、食管癌、雌激素受体阳性乳腺癌、原发性血小板增多症、尤因氏瘤、纤维肉瘤、滤泡性淋巴瘤、生殖细胞睾丸癌、神经胶质瘤、重链病、血管母细胞瘤、肝癌、肝细胞癌、激素不敏感的前列腺癌、平滑肌肉瘤、脂肪肉瘤、肺癌、淋巴管内皮肉瘤(lymphagioendotheliosarcoma)、淋巴管肉瘤、淋巴母细胞白血病、淋巴瘤(霍奇金和非霍奇金)、膀胱、乳腺、结肠、肺、卵巢、胰腺、前列腺、皮肤和子宫的恶性肿瘤和过度增生障碍、T-细胞或B-细胞源淋巴组织恶性肿瘤、白血病、淋巴瘤、髓样癌、髓母细胞瘤、黑色素瘤、脑膜瘤、间皮瘤、多发性骨髓瘤、骨髓性白血病、骨髓瘤、黏液肉瘤、神经母细胞瘤、非小细胞肺癌、少突神经胶质瘤、口腔癌、骨原性肉瘤、卵巢癌、胰腺癌、乳头状腺癌、乳头状癌、松果体瘤、真性红细胞增多症、前列腺癌、直肠癌、肾细胞癌、成视网膜细胞瘤、横纹肌肉瘤、肉瘤、皮脂腺癌、精原细胞瘤、皮肤癌、小细胞肺癌、实体瘤(癌和肉瘤)、小细胞肺癌、胃癌、鳞状细胞癌、滑膜瘤、汗腺癌、甲状腺癌、原发性巨球蛋白血症、睾丸肿瘤、子宫癌和肾母细胞瘤。
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Oncogenic STK15/BTAK/Aurora A Kinase in Human Pancreatic Cancer. Clin. Cancer
Res. 2003; 9:991-7中。
非小细胞肺癌中的极光激酶的相关内容报道于Smith, S.L., et al., Overexpression of
Aurora B Kinase (AURKB) in Primary Non-Small Cell Lung Carcinoma is Frequent,
Generally Driven from One Allele和Correlates
with the Level of Genetic Instability. Br. J. Cancer, 2005. 93(6): p. 719-729中。
前列腺癌中的极光激酶的相关内容报道于Chieffi, P., et al., Aurora B Expression
Directly Correlates with Prostate Cancer Malignancy. Prostate, 2006. 66(3): p.
326-33;和Chieffi P., Cozzolino L., Kisslinger A.,
et al. Aurora B Expression Directly Correlates with Prostate Cancer Malignancy
and Influences Prostate Cell Proliferation. Prostate 2006; 66:326-33中。
头和颈鳞状细胞癌中的极光激酶的相关内容报道于Reiter, R., et al., Aurora Kinase A
Messenger RNA Overexpression is Correlated with Tumor Progression and Shortened
Survival in Head and Neck Squamous Cell Carcinoma. Clin Cancer Res, 2006.
12(17): p. 5136-41中。
急性骨髓性白血病中的极光激酶的相关内容报道于Walsby E., Walsh V., Pepper C., Burnett
A., and Mills K. Haematologica. 2008 May; 93(5):662-9中。
乳腺癌中的极光激酶的相关内容报道于Tanaka T., Kimura M., Matsunaga K.,
Fukada D., Mori H., Okano Y. Centrosomal Kinase AIK1 is Overexpressed in
Invasive Ductal Carcinoma of The Breast. Cancer Res. 1999; 59:2041-4;Miyoshi Y., Iwao K., Egawa C., Noguchi S. Association of
Centrosomal Kinase STK15/BTAK Mrna Expression with Chromosomal Instability in
Human Breast Cancers. Int. J. Cancer 2001; 92:370-3;Hoque A., Carter J., Xia W., et al. Loss Of Aurora
A/STK15/BTAK Overexpression Correlates with Transition of in Situ to Invasive
Ductal Carcinoma of the Breast. Cancer Epidemiol. Biomarkers Prev. 2003;
12:1518-22;Royce M. E., Xia W., Sahin A. A., et al.
STK15/Aurora-A Expression in Primary Breast Tumors is Correlated with Nuclear
Grade But Not With Prognosis. Cancer 2004; 100:12-9;Bodvarsdottir S. K., Hilmarsdottir H., Birgisdottir V.,
Steinarsdottir M., Jonasson J. G., Eyfjord J. E., Aurora-A Amplification
Associated with BRCA2 Mutation in Breast Tumours. Cancer Lett 2007; 248:96-102;Sen S., Zhou H., White R. A., A Putative Serine/Threonine
Kinase Encoding Gene BTAK on Chromosome 20q13 is Amplified and Overexpressed in
Human Breast Cancer Cell Lines. Oncogene 1997; 14:2195-200;Lo Y. L., Yu J. C., Chen S. T., et al. Breast Cancer Risk
Associated with Genotypic Polymorphism of the Mitosisregulating Gene
Aurora-A/STK15/BTAK. In. J. Cancer 2005; 115:276-83;Vidarsdottir L., Bodvarsdottir S. K., Hilmarsdottir H.,
Tryggvadottir L., Eyfjord J. E., Breast Cancer Risk Associated with AURKA 91T a
Polymorphismin Relation to BRCA Mutations. Cancer Lett 2007; 250:206-12;Cox D. G., Hankinson S. E., Hunter D. J., Polymorphisms
of the Aurka (STK15/Aurora Kinase) Gene and Breast Cancer Risk (United States).
Cancer Causes Control 2006; 17:81-3;和Tchatchou
S., Wirtenberger M., Hemminki K., et al. Aurora Kinases A and B and Familial
Breast Cancer Risk. Cancer Lett 2007; 247:266-72中。
肺癌中的极光激酶的相关内容报道于Smith S. L., Bowers N. L., Betticher D.
C., et al. Overexpression Of Aurora B Kinase (AURKB) in Primary Non small Cell
Lung Carcinoma is Frequent, Generally Driven Fromone Allele, and Correlates
with the Level Of Genetic Instability. Br. J. Cancer 2005; 93:719-29;Xu H. T., Ma L., Qi F.J., et al. Expression of Serine
Threonine Kinase15 is Associated with Poor Differentiation in Lung Squamous
Cell Carcinoma and Adenocarcinoma. Pathol. Int. 2006; 56:375-80;Vischioni B., Oudejans J. J., Vos W., Rodriguez J. A.,
Giaccone G. Frequent Overexpression of Aurora B Kinase, a Novel Drug Target, in
Non-Small Cell Lung Carcinoma Patients. Mol. Cancer Ther. 2006;5:2905-13;和Gu J., Gong Y., Huang M., Lu C., Spitz M.R.,Wu X.
Polymorphisms Of STK15 (Aurora-A) Gene and Lung Cancer Risk in Caucasians.
Carcinogenesis 2007; 28:350-5中。
膀胱癌中的极光激酶的相关内容报道于Comperat E., Camparo P., Haus R., et al.
Aurora-A/STK-15 is a Predictive Factor for Recurrent Behaviour in Non-Invasive
Bladder Carcinoma: A Study Of 128 Cases of Non-Invasive Neoplasms. Virchows
Arch 2007;450:419-24;Fraizer G.C.,
Diaz M.F., Lee I.L., Grossman H.B., Sen S. Aurora-A/STK15/BTAK Enhances
Chromosomal Instability in Bladder Cancer Cells. Int. J. Oncol. 2004; 25:1631-9;和Sen S., Zhou H., Zhang R.D., et al.
Amplification/Overexpression of A Mitotic Kinase Gene in Human Bladder cancer.
J. Natl. Cancer Inst. 2002; 94:1320-9中。
食道癌中的极光激酶的相关内容报道于Tong T., Zhong Y., Kong J., et al.
Overexpression of Aurora-A Contributes to Malignant Development of Human
Esophageal Squamous Cell Carcinoma. Clin. Cancer Res. 2004;10:7304-10;Yang S.B., Zhou X.B., Zhu H.X., et al. Amplification and
Overexpression of Aurora-A in Esophageal Squamous Cell Carcinoma. Oncol. Rep.
2007; 17:1083-8;和Kimura M.T.,
Mori T., Conroy J., et al. Two Functional Coding Single Nucleotide
Polymorphisms in STK15 (Aurora-A) Coordinately Increase Esophageal Cancer Risk.
Cancer Res. 2005; 65:3548-54中。
脑癌中的极光激酶的相关内容报道于Araki K., Nozaki K., Ueba T., Tatsuka
M., Hashimoto N. High Expression of Aurora-B/Aurora and Ipll-Like
Midbody-Associated Protein (AIM-1) in Astrocytomas. J. Neurooncol.
2004;67:53-64;Zeng W.F., Navaratne K., Prayson
R.A.,Weil R.J. Aurora B Expression Correlates with Aggressive Behaviour in
Glioblastoma Multiforme. J. Clin. Pathol. 2007; 60:218-21;Reichardt W., Jung V., Brunner C., et al. The Putative
Serine/Threonine Kinase Gene STK15 on Chromosome 20q13.2 is Amplified In Human
Gliomas. Oncol. Rep. 2003;10:1275-9;Klein
A., Reichardt W., Jung V., Zang K.D., Meese E., Urbschat S. Overexpression and
Amplification of STK15 Inhuman Gliomas. Int. J. Oncol. 2004; 25:1789-94;和Neben K., Korshunov A., Benner A., et al. Microarray
Based Screening for Molecular Markers Nmedulloblastoma Revealed STK15 as
Independent Predictor for Survival. Cancer Lett 2004; 64:3103-11中。
肝癌中的极光激酶的相关内容报道于Jeng Y.M., Peng S.Y., Lin C.Y., Hsu H.C.
Overexpression and Amplification of Aurora-A in Hepatocellular Carcinoma. Clin.
Cancer Res. 2004; 10:2065-71中。
头和颈癌中的极光激酶的相关内容报道于Zhao X., Li F.C., Li Y.H., et al.
[Mutation of p53 and Overexpression Of STK15 in Laryngeal Squamous-Cell
Carcinoma]. Zhonghua Zhong Liu Za Zhi 2005; 27:134-7;Li F.C., Li Y.H., Zhao X., et al. [Deletion of p15 and
p16 Genes and Overexpression of STK15 Gene in Human Laryngeal Squamous Cell
Carcinoma]. Zhonghua Yi Xue Za Zhi 2003; 83:316-9;Reiter
R., Gais P., Jutting U., et al. Aurora Kinase A Messenger RNA Overexpression is
Correlated with Tumor Progression and Shortened Survival in Head and Neck
Squamous Cell Carcinoma. Clin. Cancer Res. 2006; 12:5136-41;Qi G., Ogawa I., Kudo Y., et al. Aurora-B Expression and
Its Correlation with Cell Proliferation and Metastasis in Oral Cancer. Virchows
Arch 2007; 450:297-302;和Tatsuka M., Sato
S., Kitajima S., et al. Overexpression of Aurora-A Potentiates HRAS-mediated
Oncogenic Transformation and is Implicated in Oral Carcinogenesis. Oncogene
2005; 4:1122-7中。
甲状腺癌中的极光激酶的相关内容报道于Sorrentino R., Libertini S., Pallante
P.L., et al. Aurora B Overexpression Associates with the Thyroid Carcinoma
Undifferentiated Phenotype and is Required for Thyroid Carcinoma Cell
Proliferation. J. Clin. Endocrinol. Metab. 2005; 90:928-35中。
卵巢癌中的极光激酶的相关内容报道于Lassmann S., Shen Y., Jutting U., et al.
Predictive Value of Aurora-A/STK15 Expression for Late Stage Epithelial Ovarian
Cancer Patients Treated By Adjuvant Chemotherapy. Clin Cancer Res 2007;
13:4083-91;和Landen C.N., Jr., Lin Y.G., Immaneni A.,
et al. Overexpression of the Centrosomal Protein Aurora-A Kinase is Associated
with Poor Prognosis in Epithelial Ovarian Cancer Patients. Clin. Cancer Res.
2007; 13:4098-104中。
肾癌中的极光激酶的相关内容报道于报道于Kurahashi T., Miyake H., Hara I.,
Fujisawa M. Significance of Aurora-A Expression in Renal Cell Carcinoma. Urol.
Oncol. 2007; 25:128-33中。
子宫内膜癌中的极光激酶的相关内容报道于Moreno-Bueno G., Sanchez-Estevez C.,
Cassia R., et al. Differential Gene Expression Profile in Endometrioid and Nonendometrioid
Endometrial Carcinoma:STK15 is Frequently Overexpressed and Amplified in
Nonendometrioid Carcinomas. Cancer Res. 2003; 63:5697-702中。
胃癌中的极光激酶的相关内容报道于Ju H., Cho H., Kim Y.S., et al.
Functional Polymorphism 57Val>Ile of Aurora Kinase A Associated with
Increased Risk of Gastric Cancer Progression. Cancer Lett. 2006; 242:273-9中。
结肠癌中的极光激酶的相关内容报道于Nishida N., Nagasaka T., Kashiwagi K.,
Boland C.R., Goel A. High Copy Amplification of the Aurora-A Gene is Associated
with Chromosomal Instability Phenotype in Human Colorectal Cancers. Cancer
Biol. Ther. 2007; 6:525-33;Bischoff J.R.,
Anderson L., Zhu Y., et al. A Homologue of Drosophila Aurora Kinase is
Oncogenic and Amplified In Human Colorectal Cancers. EMBO J 1998; 17:3052-65;Chen J., Sen S., Amos C.I., et al. Association Between
Aurora-A Kinase Polymorphisms and Age of Onset of Hereditary Nonpolyposis
Colorectal Cancer in a Caucasian Population. Mol. Carcinog. 2007; 46:249-56;Hienonen T., Salovaara R., Mecklin J.P., Jarvinen H.,
Karhu A., Aaltonen L.A. Preferential Amplification of AURKA 91A (Ile31) in
Familial Colorectal Cancers. Int. J. Cancer 2006; 118:505-8;和Ewart-Toland A., Briassouli P., de Koning J.P., et al.
Identification of Stk6/STK15 as a Candidate Low-Penetrance Tumor-Susceptibility
Gene in Mouse and Human. Nat. Genet. 2003; 34:403-12中。
癌中的极光激酶的相关内容报道于Lin, Y.S., et al., Gene Expression Profiles of the
Aurora Family Kinases. Gene Expr., 2006. 13(1): p. 15-26;和Ewart-Toland A., Dai Q., Gao Y.T., et al. Aurora-A/STK15
T+91A is a General Low Penetrance Cancer Susceptibility Gene: A Meta-Analysis
of Multiple Cancer Types. Carcinogenesis 2005; 26:1368-73中。
癌中的KDR (VEGFR2)的相关内容和使用VEGF靶向治疗的研究报道于Ellis, Lee M., Hicklin, Daniel J. VEGF-Targeted
Therapy:Mechanisms Of Anti-Tumor Activity. Nature Reviews Cancer 2008;
8:579-591中。
膀胱癌、乳腺癌、宫颈癌、结肠癌、子宫内膜癌、食道癌、肺癌、卵巢癌、胰腺癌、前列腺癌、直肠癌、皮肤癌、胃癌和甲状腺癌中的极光激酶的相关内容报道于Nature
Reviews/Cancer, Vol. 4 December, 2004中。
本发明的方法通常涉及给予需要治疗处理的对象有效量的式(I)的化合物。具有式(I)的化合物的治疗有效量取决于治疗接受者、所治疗的疾病及其严重程度、包含其的组合物、给药时间、给药途径、治疗持续时间、效力、清除率和是否有另一药物共同给药。用于制备每日以单剂量或分剂量给予患者的组合物的具有式(I)的化合物的量是大约0.03至大约200 mg/kg体重。单剂量组合物含有这些量或其约数的组合。
组合治疗
本发明进一步提供与一种或多种附加活性剂一起使用本发明的化合物或组合物的方法。
具有式(I)的化合物预计在与烷基化剂、血管生成抑制剂、抗体、抗代谢物、抗有丝分裂剂、抗增殖剂、抗病毒剂、极光激酶抑制剂、凋亡促进剂(例如Bcl-xL、Bcl-w和Bfl-1)抑制剂、死亡受体途径活化剂、Bcr-Abl激酶抑制剂、BiTE(Bi-Specific T cell Engager)抗体、抗体药物偶联物、生物反应改进剂、细胞周期蛋白依赖性激酶抑制剂、细胞周期抑制剂、环加氧酶-2抑制剂、DVDs、白血病病毒癌基因同源物(ErbB2)受体抑制剂、生长因子抑制剂、热休克蛋白(HSP)-90抑制剂、组蛋白去乙酰化酶(HDAC)抑制剂、激素治疗药、免疫药、凋亡蛋白(IAPs)抑制剂、插层抗生素、激酶抑制剂、驱动蛋白抑制剂、Jak2抑制剂、雷帕霉素抑制剂的哺乳动物靶、microRNA’s、丝裂原激活的细胞外信号调节激酶抑制剂、多价结合蛋白、非甾体抗炎药(NSAIDs)、聚ADP(二磷酸腺苷)-核糖聚合酶(PARP)抑制剂、铂化疗药物、polo-样激酶(Plk)抑制剂、磷酸肌醇-3激酶(PI3K)抑制剂、蛋白体抑制剂、嘌呤类似物、嘧啶类似物、受体酪氨酸激酶抑制剂、类维生素A(etinoids)/deltoids、植物生物碱、小抑制核糖核酸(siRNAs)、拓扑异构酶抑制剂、泛素连接酶抑制剂等一起使用和与一种或多种这些试剂结合使用时是有用的。
BiTE抗体是通过同时结合两个细胞而引导T-细胞攻击癌细胞的双特异性抗体。T-细胞随后攻击靶癌细胞。BiTE抗体的实例包括adecatumumab(Micromet MT201)、blinatumomab
(Micromet MT103)等。不受制于理论,但T-细胞引发靶癌细胞凋亡的机制之一是通过溶胞性颗粒组分(包括穿孔素和粒酶B)的胞吐作用。在这方面,Bcl-2已表明通过穿孔素和粒酶B衰减凋亡的诱发。这些数据表明在靶向癌细胞时,Bcl-2的抑制可增强T-细胞引发的细胞毒性效应(V.R. Sutton, D.L. Vaux和J.A.
Trapani, J. of Immunology 1997, 158 (12), 5783)。
SiRNAs是具有内源性RNA碱基或化学改性核苷酸的分子。该改性不消除细胞活性,而是给予提高的稳定性和/或提高的细胞效力。化学改性的实例包括硫代磷酸酯类、2'-脱氧核苷酸、含2'-OCH3的核糖核苷酸、2'-F-核糖核苷酸、2'-甲氧基乙基核糖核苷酸、其组合等。siRNA可具有不同长度(例如10-200
bps)和结构(例如发夹结构、单/双链、鼓包、缺口/间隙、失配)并在细胞中加工以提供活性基因沉默。双链siRNA(dsRNA)可以在各链(钝端)或不对称端(突出端)上具有相同数量的核苷酸。1-2个核苷酸的突出端可存在于有义和/或反义链上,以及存在于给定链的5'-和/或3'-端上。
多价结合蛋白是包含两个或更多个抗原结合位点的结合蛋白。多价结合蛋白被工程化为具有三个或更多个抗原结合位点并通常不是天然存在的抗体。术语“多特异性结合蛋白”是指能结合两个或更多个相关或不相关靶的结合蛋白。双可变域(DVD)结合蛋白是包含两个或更多个抗原结合位点的四价或多价结合蛋白。这样的DVDs可以是单特异性的(即能结合一个抗原)或多特异性的(即能结合两个或更多个抗原)。包含两个重链DVD多肽和两个轻链DVD多肽的DVD结合蛋白被称作DVD Ig's。DVD Ig的每一半包含重链DVD多肽、轻链DVD多肽和两个抗原结合位点。各结合位点包含在每个抗原结合位点在抗原结合中涉及的总共6个CDRs的重链可变域和轻链可变域。多特异性DVDs包括结合DLL4和VEGF或C-met和EFGR或ErbB3和EGFR的DVD结合蛋白。
烷基化剂包括六甲蜜胺、AMD-473、AP-5280、apaziquone、苯达莫司汀、brostallicin、白消安、卡波醌、卡莫司汀(BCNU)、苯丁酸氮芥、CLORETAZINE®(laromustine,VNP
40101M)、环磷酰胺、氮烯咪胺(decarbazine)、雌氮芥、福莫司汀、葡磷酰胺、异环磷酰胺、KW-2170、洛莫司汀(CCNU)、马磷酰胺、美法仑、二溴甘露醇、二溴卫矛醇、尼莫司汀、氮芥N-氧化物、雷莫司汀、替莫唑胺、噻替派、TREANDA®(苯达莫司汀)、苏消安、rofosfamide等。
血管生成抑制剂包括内皮特异性受体酪氨酸激酶(Tie-2)抑制剂、表皮生长因子受体(EGFR)抑制剂、胰岛素生长因子-2受体(IGFR-2)抑制剂、基质金属蛋白酶-2(MMP-2)抑制剂、基质金属蛋白酶-9(MMP-9)抑制剂、血小板源生长因子受体(PDGFR)抑制剂、血小板反应蛋白类似物、血管内皮生长因子受体酪氨酸激酶(VEGFR)抑制剂等。
抗代谢物包括ALIMTA®(培美曲塞二钠,
LY231514, MTA)、5-阿扎胞苷、XELODA®(卡培他滨)、卡莫氟、LEUSTAT®(克拉屈滨)、氯法拉滨、阿糖胞苷、阿糖胞苷十八烷基磷酸盐、胞嘧啶阿拉伯糖苷、地西他滨、去铁胺、去氧氟尿苷、依氟鸟氨酸、EICAR(5-乙炔基-1-β-D-呋喃核糖基咪唑-4-甲酰胺)、依诺他滨、ethnylcytidine、氟达拉滨、单独或与甲酰四氢叶酸结合的5-氟尿嘧啶、GEMZAR®(吉西他滨)、羟基脲、ALKERAN®(美法仑)、巯基嘌呤、6-巯基嘌呤核糖苷、甲氨蝶呤、霉酚酸、奈拉滨、诺拉曲塞(nolatrexed)、十八烷基磷酸盐(ocfosfate)、pelitrexol、喷司他丁、雷替曲塞、利巴韦林、triapine、曲美沙特、S-1、噻唑呋林、替加氟、TS-1、阿糖腺苷、UFT等。
抗病毒剂包括利托那韦、羟基氯喹等。
极光激酶抑制剂包括ABT-348、AZD-1152、MLN-8054、VX-680、极光A-特异性激酶抑制剂、极光B-特异性激酶抑制剂和pan-极光激酶抑制剂等。
Bcl-2蛋白质抑制剂包括AT-101((-)棉酚)、GENASENSE®(G3139或奥利默森(oblimersen)(Bcl-2-靶向反义寡核苷酸))、IPI-194、IPI-565、N-(4-(4-((4'-氯(1,1'-联苯基)-2-基)甲基)哌嗪-1-基)苯甲酰基)-4-(((1R)-3-(二甲基氨基)-1-((苯基硫基)甲基)丙基)氨基)-3-硝基苯磺酰胺)(ABT-737)、N-(4-(4-((2-(4-氯苯基)-5,5-二甲基-1-环己-1-烯-1-基)甲基)哌嗪-1-基)苯甲酰基)-4-(((1R)-3-(吗啉-4-基)-1-((苯基硫基)甲基)丙基)氨基)-3-((三氟甲基)磺酰基)苯磺酰胺(ABT-263)、GX-070(obatoclax)等。
Bcr-Abl激酶抑制剂包括DASATINIB®(BMS-354825)、GLEEVEC®(伊马替尼)等。
CDK抑制剂包括AZD-5438、BMI-1040、BMS-032、BMS-387、CVT-2584、flavopyridol、GPC-286199、MCS-5A、PD0332991、PHA-690509、seliciclib(CYC-202、R-roscovitine)、ZK-304709等。
COX-2抑制剂包括ABT-963、ARCOXIA®(依托考昔)、BEXTRA®(伐地考昔)、BMS347070、CELEBREX®(塞来昔布)、COX-189(罗美昔布)、CT-3、DERAMAXX®(德拉昔布)、JTE-522、4-甲基-2-(3,4-二甲基苯基)-1-(4-氨磺酰基苯基-1H-吡咯)、MK-663(依托考昔)、NS-398、帕瑞昔布、RS-57067、SC-58125、SD-8381、SVT-2016、S-2474、T-614、VIOXX®(罗非昔布)等。
EGFR抑制剂包括ABX-EGF、抗-EGFR免疫脂质体、EGF-疫苗、EMD-7200、ERBITUX®(西妥昔单抗)、HR3、IgA抗体、IRESSA®(吉非替尼)、TARCEVA®(埃罗替尼或OSI-774)、TP-38、EGFR融合蛋白、TYKERB®(拉帕替尼)等。
ErbB2受体抑制剂包括CP-724-714、CI-1033(卡奈替尼)、HERCEPTIN®(曲妥单抗)、TYKERB®(拉帕替尼)、OMNITARG®(2C4,
petuzumab)、TAK-165、GW-572016(ionafarnib)、GW-282974、EKB-569、PI-166、dHER2(HER2疫苗)、APC-8024(HER-2疫苗)、抗-HER/2neu双特异性抗体、B7.her2IgG3、AS HER2三官能双特异性抗体、mAB AR-209、mAB 2B-1等。
组蛋白去乙酰化酶抑制剂包括缩酚酸肽、LAQ-824、MS-275、trapoxin、伏立诺他(SAHA)、TSA、丙戊酸等。
HSP-90抑制剂包括17-AAG-nab、17-AAG、CNF-101、CNF-1010、CNF-2024、17-DMAG、格尔德霉素、IPI-504、KOS-953、MYCOGRAB®(对HSP-90的人重组抗体)、NCS-683664、PU24FCl、PU-3、根赤壳菌素、SNX-2112、STA-9090 VER49009等。
凋亡蛋白抑制剂包括HGS1029、GDC-0145、GDC-0152、LCL-161、LBW-242等。
抗体药物偶联物包括抗-CD22-MC-MMAF、抗-CD22-MC-MMAE、抗-CD22-MCC-DM1、CR-011-vcMMAE、PSMA-ADC、MEDI-547、SGN-19Am SGN-35、SGN-75等。
死亡受体途径活化剂包括TRAIL、靶向TRAIL或死亡受体(例如DR4和DR5)的抗体或其它试剂,如Apomab、西他土珠(conatumumab)、ETR2-ST01、GDC0145、(来沙木单抗)、HGS-1029、LBY-135、PRO-1762和曲妥单抗。
驱动蛋白抑制剂包括Eg5抑制剂,如AZD4877、ARRY-520;CENPE抑制剂,如GSK923295A等。
JAK-2抑制剂包括CEP-701(lesaurtinib)、XL019和INCB018424等。
MEK抑制剂包括ARRY-142886、ARRY-438162
PD-325901、PD-98059等。
mTOR抑制剂包括AP-23573、CCI-779、依维莫司、RAD-001、雷帕霉素、坦西莫司、ATP-竞争性TORC1/TORC2抑制剂,包括PI-103、PP242、PP30、Torin 1等。
非甾体抗炎药包括AMIGESIC®(双水杨酯)、DOLOBID®(二氟尼柳)、MOTRIN®(布洛芬)、ORUDIS®(酮基布洛芬)、RELAFEN®(萘丁美酮)、FELDENE®(吡罗昔康)、布洛芬乳膏、ALEVE®(萘普生)和NAPROSYN®(萘普生)、VOLTAREN®(双氯芬酸)、INDOCIN®(吲哚美辛)、CLINORIL®(舒林酸)、TOLECTIN®(托美丁)、LODINE®(依托度酸)、TORADOL®(酮咯酸)、DAYPRO®(奥沙普秦)等。
PDGFR抑制剂包括C-451、CP-673、CP-868596等。
铂化疗药物包括顺铂、ELOXATIN®(奥沙利铂)、依铂、洛铂、奈达铂、PARAPLATIN®(卡铂)、沙铂、吡铂等。
Polo-样激酶抑制剂包括BI-2536等。
磷酸肌醇-3激酶(PI3K)抑制剂包括渥曼青霉素、LY294002、XL-147、CAL-120、ONC-21、AEZS-127、ETP-45658、PX-866、GDC-0941、BGT226、BEZ235、XL765等。
血小板反应蛋白类似物包括ABT-510、ABT-567、ABT-898、TSP-1等。
VEGFR抑制剂包括AVASTIN®(贝伐单抗)、ABT-869、AEE-788、ANGIOZYME™(抑制血管生成的核酶(Ribozyme Pharmaceuticals(Boulder, CO.)和Chiron,
(Emeryville、CA))、阿西替尼(AG-13736)、AZD-2171、CP-547,632、IM-862、MACUGEN(pegaptamib)、NEXAVAR®(索拉非尼,BAY43-9006)、帕唑帕尼(GW-786034)、瓦他拉尼(PTK-787,ZK-222584)、SUTENT®(舒尼替尼,SU-11248)、VEGF trap、ZACTIMA™(凡德他尼,ZD-6474)、GA101、奥伐单抗(ofatumumab)、ABT-806(mAb-806)、ErbB3特异性抗体、BSG2特异性抗体、DLL4特异性抗体和C-met特异性抗体等。
抗生素包括插层抗生素阿柔比星、放线菌素D、氨柔比星、蒽环霉素、阿霉素、BLENOXANE®(博来霉素)、柔红霉素、CAELYX®或MYOCET®(脂质体阿霉素)、依沙芦星、epirbucin、glarbuicin、ZAVEDOS®(伊达比星)、丝裂霉素C、奈莫柔比星、新制癌菌素、培洛霉素、吡柔比星、蝴蝶霉素、stimalamer、链脲菌素、VALSTAR®(戊柔比星)、净司他丁等。
拓扑异构酶抑制剂包括阿柔比星、9-氨基喜树碱、氨萘非特、安吖啶、becatecarin、贝洛替康、BN-80915、CAMPTOSAR®(伊立替康盐酸盐)、喜树碱、CARDIOXANE®(右旋丙亚胺)、氟替康(diflomotecan)、edotecarin、ELLENCE®或PHARMORUBICIN®(表柔比星)、依托泊苷、依喜替康、10-羟基喜树碱、吉马替康、勒托替康、米托蒽醌、鲁比替康(orathecin)、pirarbucin、匹杉琼、鲁比替康、索布佐生、SN-38、tafluposide、拓扑替康等。
抗体包括AVASTIN®(贝伐单抗)、CD40-特异性抗体、chTNT-1/B、地诺单抗、ERBITUX®(西妥昔单抗)、HUMAX-CD4®(扎木单抗(zanolimumab))、IGF1R-特异性抗体、林妥珠单抗、PANOREX®(依决洛单抗)、RENCAREX®(WX
G250)、RITUXAN®(利妥昔单抗)、ticilimumab、trastuzimab、CD20抗体类型I和II等。
激素治疗药包括ARIMIDEX®(阿那曲唑)、AROMASIN®(依西美坦)、阿佐昔芬、CASODEX®(比卡鲁胺)、CETROTIDE®(西曲瑞克)、地加瑞克、地洛瑞林、DESOPAN®(曲洛司坦)、地塞米松、DROGENIL®(氟他米特)、EVISTA®(雷洛昔芬)、AFEMA™(法倔唑)、FARESTON®(托瑞米芬)、FASLODEX®(氟维司群)、FEMARA®(来曲唑)、福美司坦、糖皮质激素、HECTOROL®(度骨化醇)、RENAGEL®(碳酸司维拉姆)、拉索昔芬、醋酸亮丙瑞林、MEGACE®(甲地孕酮)、MIFEPREX®(米非司酮)、NILANDRON™(尼鲁米特)、NOLVADEX®(柠檬酸三苯氧胺)、PLENAXIS™(阿巴瑞克)、强的松、PROPECIA®(非那雄胺)、rilostane、SUPREFACT®(布舍瑞林)、TRELSTAR®(促黄体素释放激素(LHRH))、VANTAS®(组氨瑞林植入物)、VETORYL®(曲洛司坦或modrastane)、ZOLADEX®(fosrelin、戈舍瑞林)等。
Deltoids和类维生素A包括西奥骨化醇(EB1089、CB1093)、lexacalcitrol(KH1060)、维甲酰酚胺(fenretinide)、PANRETIN®(aliretinoin)、ATRAGEN®(脂质体维甲酸)、TARGRETIN®(贝沙罗汀)、LGD-1550等。
PARP抑制剂包括ABT-888(veliparib)、奥拉帕尼、KU-59436、AZD-2281、AG-014699、BSI-201、BGP-15、INO-1001、ONO-2231等。
植物生物碱包括但不限于长春新碱、长春碱、长春地辛、长春瑞滨等。
蛋白酶体抑制剂包括VELCADE®(硼替佐米)、MG132、NPI-0052、PR-171等。
免疫药的实例包括干扰素和其它免疫增强剂。干扰素包括干扰素α、干扰素α-2a、干扰素α-2b、干扰素β、干扰素γ-1a、ACTIMMUNE®(干扰素γ-1b)或干扰素γ-n1、其组合等。其它试剂包括ALFAFERONE®(IFN-α)、BAM-002(氧化型谷胱甘肽)、BEROMUN®(他索纳明)、BEXXAR®(托西莫单抗)、CAMPATH®(阿仑单抗)、CTLA4(细胞毒性淋巴细胞抗原4)、氮烯咪胺、地尼白介素、依帕珠单抗、GRANOCYTE®(来格司亭)、香菇多糖、白细胞α干扰素、咪喹莫特、MDX-010(抗-CTLA-4)、黑色素瘤疫苗、米妥莫单抗、莫拉司亭、MYLOTARG™(吉妥单抗奥唑米星)、NEUPOGEN®(非格司亭)、OncoVAC-CL、OVAREX®(oregovomab)、pemtumomab(Y-muHMFG1)、PROVENGE®(sipuleucel-T)、sargaramostim、裂褶菌素(sizofilan)、替西白介素、THERACYS®(卡介苗)、乌苯美司、VIRULIZIN®(免疫治疗,Lorus
Pharmaceuticals)、Z-100(Specific Substance of Maruyama(SSM))、WF-10(Tetrachlorodecaoxide(TCDO))、PROLEUKIN®(阿地白介素)、ZADAXIN®(胸腺法新)、ZENAPAX®(赛尼哌)、ZEVALIN®(90Y-替伊莫单抗)等。
生物反应改进剂是改变活生物体的防卫机制或生物反应,如组织细胞的存活、生长或分化以使它们具有抗肿瘤活性的试剂,并包括云芝多糖、香菇多糖、西佐糖、溶链菌PF-3512676(CpG-8954)、乌苯美司等。
嘧啶类似物包括阿糖胞苷(ara C或阿拉伯糖苷C)、胞嘧啶阿拉伯糖苷、去氧氟尿苷、FLUDARA®(氟达拉滨)、5-FU(5-氟尿嘧啶)、氟尿苷、GEMZAR®(吉西他滨)、TOMUDEX®(ratitrexed)、TROXATYL™(三乙酰基尿苷曲沙他滨)等。
嘌呤类似物包括LANVIS®(硫鸟嘌呤)和PURI-NETHOL®(巯基嘌呤)。
抗有丝分裂剂包括batabulin、埃博霉素D(KOS-862)、N-(2-((4-羟基苯基)氨基)吡啶-3-基)-4-甲氧基苯磺酰胺、伊沙匹隆(BMS 247550)、紫杉醇、TAXOTERE®(多西紫杉醇)、PNU100940(109881)、帕土匹龙(patupilone)、XRP-9881(larotaxel)、长春氟宁、ZK-EPO(合成埃博霉素)等。
泛素连接酶抑制剂包括MDM2抑制剂如nutlins、NEDD8抑制剂如MLN4924等。
本发明的化合物还可用作增强放射疗法的效力的放射致敏剂。放射疗法的实例包括外粒子束放射治疗、远距放射疗法、近距放射疗法和密封、非密封源放射疗法等。
另外,具有式(I)的化合物可以与以下的其它化疗剂组合,如ABRAXANE™(ABI-007)、ABT-100(法尼基转移酶抑制剂)、ADVEXIN®(Ad5CMV-p53疫苗)、ALTOCOR®或MEVACOR®(洛伐他汀)、AMPLIGEN®(poly
I:poly C12U、合成RNA)、APTOSYN®(依昔舒林)、AREDIA®(帕米膦酸)、arglabin、L-天冬酰胺酶、阿他美坦(1-甲基-3,17-二酮-雄甾-1,4-二烯)、AVAGE®(他扎罗汀)、AVE-8062(combreastatin衍生物)、BEC2(米妥莫单抗)、恶病质素或cachexin(肿瘤坏死因子)、canvaxin(疫苗)、CEAVAC®(癌症疫苗)、CELEUK®(西莫白介素)、CEPLENE®(组胺二盐酸盐)、CERVARIX®(人乳头瘤病毒疫苗)、CHOP®(C: CYTOXAN®(环磷酰胺);H: 阿霉素®(hydroxydoxorubicin);O: 长春新碱(ONCOVIN®);P: 强的松)、CYPAT™(醋酸环丙孕酮)、combrestatin A4P、DAB(389)EGF(经由His-Ala连接子融合到人表皮生长因子上的白喉毒素的催化和易位结构域)或TransMID-107R™(白喉毒素)、氮烯唑胺、放线菌素D、5,6-二甲基呫吨酮-4-乙酸(DMXAA)、eniluracil、EVIZON™(乳酸角鲨胺)、DIMERICINE®(T4N5脂质体乳液)、圆皮海绵内酯(discodermolide)、DX-8951f(依喜替康甲磺酸盐)、enzastaurin、EPO906(epithilone B)、GARDASIL®(四价人乳头状瘤病毒(6、11、16、18类型)重组疫苗)、GASTRIMMUNE®、GENASENSE®、GMK(神经节苷脂结合疫苗)、GVAX®(前列腺癌疫苗)、常山酮、histerelin、羟基尿素、伊班膦酸、IGN-101、IL-13-PE38、IL-13-PE38QQR(cintredekin besudotox)、IL-13-假单胞菌外毒素、干扰素-α、干扰素-γ、JUNOVAN™或MEPACT™(米伐木肽)、洛那法尼(lonafarnib)、5,10-亚甲基四氢叶酸、米替福新(十六烷基磷酸胆碱)、NEOVASTAT®(AE-941)、NEUTREXIN®(葡糖醛酸三甲曲沙)、NIPENT®(喷司他丁)、ONCONASE®(核糖核酸酶)、ONCOPHAGE®(黑色素瘤疫苗治疗)、ONCOVAX®(IL-2疫苗)、ORATHECIN™(鲁比替康)、OSIDEM®(抗体基细胞药物)、OVAREX®
MAb(鼠单克隆抗体)、紫杉醇、PANDIMEX™(包含20(S) 原人参二醇(aPPD)和20(S) 原人参三醇(aPPT)的来自人参的糖苷配基皂素)、帕尼单抗、PANVAC®-VF(研究中的癌症疫苗)、培门冬酶、PEG干扰素A、苯妥帝尔(phenoxodiol)、丙卡巴肼、rebimastat、REMOVAB®(catumaxomab)、REVLIMID®(来那度胺)、RSR13(乙丙昔罗)、SOMATULINE® LA(兰瑞肽)、SORIATANE®(阿维A)、十字孢碱(链霉菌星状孢子)、talabostat(PT100)、TARGRETIN®(贝沙罗汀)、TAXOPREXIN®(DHA-紫杉醇)、TELCYTA®(canfosfamide,TLK286)、temilifene、TEMODAR®(替莫唑胺)、替米利芬、沙利度胺、THERATOPE®(STn-KLH)、thymitaq(2-氨基-3,4-二氢-6-甲基-4-氧代-5-(4-吡啶基硫代)喹唑啉二盐酸盐)、TNFERADE™(腺病毒载体: 含有肿瘤坏死因子-α的基因的DNA载体)、TRACLEER®或ZAVESCA®(波生坦)、维甲酸(维生素A酸)、粉防己碱、TRISENOX®(三氧化二砷)、VIRULIZIN®、ukrain(来自白屈菜植物的生物碱衍生物)、vitaxin(抗-αvβ3抗体)、XCYTRIN®(莫特沙芬钆)、XINLAY™(阿曲生坦)、XYOTAX™(paclitaxel
poliglumex)、YONDELIS®(曲贝替定)、ZD-6126、ZINECARD®(右雷佐生)、ZOMETA®(唑来膦酸(zolendronic
acid))、佐柔比星等。
实施例
实施例1
N-(3-氟苯基)-N'-{4-[3-(1-甲基-1H-吡唑-4-基)-1H-吲唑-6-基]苯基}脲
实施例1A
6-溴-3-碘-1H-吲唑
采用3N NaOH 水溶液(100
ml)处理6-溴-1H-吲唑(10 g, 50.8 mmol, 商购)在二氧六环(200 ml)中的溶液。采用碘(27.1 g, 107
mmol)处理充分搅拌的混合物,在5min内分批加入,然后搅拌60min。用200
ml 20%的柠檬酸溶液,然后用160 ml饱和NaHSO3溶液淬灭该反应,之后在乙酸乙酯和水之间分配。用MgSO4干燥有机萃取物,并浓缩成固体,该固体利用醚和戊烷研碎,以获得标题化合物。
实施例1B
6-溴-3-碘-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吲唑
将实施例1A(14.4 g, 44.6 mmol)加入氢氧化钾(50.0 g, 892 mmol)在200mL水中的0℃水溶液中。将该浓悬浮液搅拌10min,用CH2Cl2 (400 ml)稀释,并用四丁基溴化铵(1.437 g, 4.46 mmol)处理。然后,在50min内,用滴液漏斗滴加(2-(氯甲氧基)乙基)三甲基硅烷(9.05 ml, 51.3
mmol)。在0℃下将该反应搅拌1.5小时,用CH2Cl2 (2X)萃取,并用水洗涤。用MgSO4干燥合并的有机物,浓缩,并通过硅胶快速层析法、采用CH2Cl2/己烷洗脱来纯化残留物以获得标题化合物。
实施例1C
6-溴-3-(1-甲基-1H-吡唑-4-基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吲唑
在氩气下,采用水(2 ml)中的碳酸钠(0.292
g, 2.76 mmol)水溶液处理实施例1B(0.500 g, 1.103 mmol)和1-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吡唑 (0.275 g, 1.324
mmol)在甲苯(8 ml)和乙醇(8
ml)中的溶液。加入Pd(PPh3)4 (0.217 g,
0.188 mmol),并在80℃下将所得的多相混合物回流2小时,然后在室温下搅拌18小时。用盐水稀释该反应混合物并用乙酸乙酯萃取两次。用MgSO4干燥合并的有机物,浓缩,并通过硅胶色谱法、采用含0.5%甲醇的CH2Cl2洗脱来纯化残留物以获得标题化合物。
实施例1D
1-(3-氟苯基)-3-(4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)苯基)脲
在氩气下,采用1-氟-3-异氰酸根合苯(0.515 ml, 4.43 mmol)滴加处理4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)苯胺(1 g, 4.43 mmol)在CH2Cl2 (30 ml)中的溶液。在室温下将该反应搅拌18小时,并浓缩成固体。加入二氯甲烷和己烷以使产物沉淀,将其收集并真空干燥以获得标题化合物。
实施例1E
1-(3-氟苯基)-3-(4-(3-(1-甲基-1H-吡唑-4-基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吲唑-6-基)苯基)脲
在氩气下,将实施例1C(187 mg, 0.459 mmol)和实施例1D(196 mg, 0.551 mmol)的混合物与甲苯(8.0
ml)和乙醇(8.0 ml)混合。向该溶液中加入碳酸钠(122
mg, 1.148 mmol)在水(2.0 ml)中的溶液,并然后加入Pd(PPh3)4 (90 mg, 0.078 mmol)。在80℃、氩气下将该反应混合物搅拌2.5小时,使其冷却至室温,用盐水稀释、并用乙酸乙酯萃取两次。用MgSO4干燥合并的有机物,过滤,浓缩残留物并通过硅胶色谱法、采用含1%甲醇的CH2Cl2洗脱来纯化以获得标题化合物。
实施例1F
N-(3-氟苯基)-N'-{4-[3-(1-甲基-1H-吡唑-4-基)-1H-吲唑-6-基]苯基}脲
用2 ml 6N HCl溶液处理实施例1E(45 mg, 0.081 mmol)在乙醇(6
ml)中的悬浮液,回流1小时,然后冷却并浓缩至基本干燥。用水磨碎该残留物,并收集所得的固体,溶于甲醇和CH2Cl中,吸附在硅藻土上,并通过硅胶色谱法(含4%甲醇的CH2Cl2)以获得标题化合物。1H NMR (300 MHz, DMSO-d6)
δ ppm 3.94 (s, 3 H) 6.79 (dt, J=8.82 Hz,
2.37 Hz, 1 H) 7.15 (d, J=8.14 Hz, 1 H) 7.32 (q, J=8.14 Hz, 1 H) 7.45 (dd,
J=8.48 Hz, 1.36 Hz, 1 H) 7.51 (dt, J=2.37 Hz, 11.87 Hz, 1 H) 7.59 (m, 2 H) 7.69
(m, 3 H) 7.99 (s, 1 H) 8.05 (d, J=8.48 Hz, 1 H) 8.37 (s, 1 H) 8.89 (s, 1 H)
8.96 (s, 1 H) 12.94 (s, 1 H)。MS(ESI(+)) m/e
427 (M+H)+。
实施例2
N-(3-甲基苯基)-N'-{4-[3-(1-甲基-1H-吡唑-4-基)-1H-吲唑-6-基]苯基}脲
按实施例1C-1F中所描述的来制备该标题化合物,除了用1-异氰酸根合-3-甲基苯代替1-氟-3-异氰酸根合苯。1H NMR
(300 MHz, DMSO-d6) δ ppm 2.29 (s, 3
H) 3.94 (s, 3 H) 6.80 (d, J=7.14 Hz, 1 H) 7.17 (d, J=7.54 Hz, 1 H) 7.23-7.28
(m, 1 H) 7.30-7.33 (m, 1 H) 7.45 (d, J=8.33 Hz, 1 H) 7.55-7.61 (m, 2 H) 7.66-7.72
(m, 3 H) 8.00 (s, 1 H) 8.04 (d, J=8.73 Hz, 1 H) 8.38 (s, 1 H) 8.62 (s, 1 H)
8.78 (s, 1 H) 12.94 (s, 1 H)。MS(ESI(+)) m/e
423 (M+H)+。
实施例3
N-(3-甲基苯基)-N'-{4-[3-(1H-1,2,3-三唑-5-基)-1H-吲唑-6-基]苯基}脲
按照实施例21中所描述的来制备该标题化合物,除了用1-(4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)苯基)-3-间-甲苯基脲代替实施例1D。1H NMR (300 MHz, DMSO-d6) δ ppm 2.29 (s, 3 H) 6.80 (d, J=7.54 Hz, 1 H) 7.25 (d,
J=8.33 Hz, 1 H) 7.32 (s, 1 H) 7.53 (d, J=8.33 Hz, 1 H) 7.56-7.62 (m, 2 H) 7.67-7.76
(m, 3 H) 8.22-8.33 (m, 2 H) 8.62 (s, 1 H) 8.79 (s, 1 H) 13.30 (s, 1 H) 15.11
(s, 1 H)。MS(ESI(+)) m/e 410 (M+H)+。
实施例4
N-(3-甲基苯基)-N'-{4-[3-(1H-吡咯-2-基)-1H-吲唑-6-基]苯基}脲
按照实施例1中所描述的来制备该标题化合物,除了用1-(叔丁氧基羰基)-1H-吡咯-2-基硼酸和1-异氰酸根合-3-甲基苯分别代替实施例1C和1D中的1-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吡唑和1-氟-3-异氰酸根合苯。1H NMR
(300 MHz, DMSO-d6) δ ppm 2.29 (s, 3
H) 6.17-6.21 (m, 1 H) 6.73 (s, 1 H) 6.80 (d, J=7.54 Hz, 1 H) 6.85 (s, 1 H) 7.17
(t, J=7.54 Hz, 1 H) 7.25 (d, J=8.33 Hz, 1 H) 7.33 (s, 1 H) 7.45 (dd, J=8.73,
1.19 Hz, 1 H) 7.55-7.62 (m, 2 H) 7.65-7.72 (m, 3 H) 8.05 (d, J=8.72 Hz, 1 H)
8.65 (s, 1 H) 8.81 (s, 1 H) 11.34 (s, 1 H) 12.94 (s, 1 H)。MS(ESI(+)) m/e 408 (M+H)+。
实施例5
N-(3-甲基苯基)-N'-(4-{3-[1-(2-吗啉-4-基乙基)-1H-吡唑-4-基]-1H-吲唑-6-基}苯基)脲
按照实施例1中所描述的来制备该标题化合物,除了用4-(2-(4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吡唑-1-基)乙基)吗啉和1-异氰酸根合-3-甲基苯分别代替实施例1C和1D中的1-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吡唑和1-氟-3-异氰酸根合苯。1H NMR
(300 MHz, DMSO-d6) δ ppm 2.29 (s, 3
H) 2.43-2.52 (m, 4 H) 2.79 (t, J=6.35 Hz, 2 H) 3.57 (t, J=4.36 Hz, 4 H) 4.32
(t, J=6.35 Hz, 2 H) 6.80 (d, J=7.54 Hz, 1 H) 7.17 (t, J=7.54 Hz, 1 H) 7.25 (d,
J=8.33 Hz, 1 H) 7.31 (s, 1 H) 7.45 (d, J=8.72 Hz, 1 H) 7.55-7.61 (m, 2 H) 7.66-7.72
(m, 3 H) 8.00 (s, 1 H) 8.04 (d, J=8.73 Hz, 1 H) 8.42 (s, 1 H) 8.61 (s, 1 H)
8.78 (s, 1 H) 12.94 (s, 1 H)。MS(ESI(+)) m/e
522 (M+H)+。
实施例6
N-(3-氟苯基)-N'-(4-{3-[1-(2-吗啉-4-基乙基)-1H-吡唑-4-基]-1H-吲唑-6-基}苯基)脲
按照实施例1中所描述的来制备该标题化合物,除了用4-(2-(4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吡唑-1-基)乙基)吗啉代替1-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吡唑。1H NMR
(300 MHz, DMSO-d6) δ ppm 2.42-2.53
(m, 4 H) 2.79 (t, J=6.74 Hz, 2 H) 3.57 (t, J=4.76 Hz, 4 H) 4.33 (t, J=6.35 Hz,
2 H) 6.79 (dt, J=8.72, 2.78 Hz, 1 H) 7.15 (d, J=8.33 Hz, 1 H) 7.32 (dd, J=7.93,
7.14 Hz, 1 H) 7.42-7.55 (m, 2 H) 7.56-7.62 (m, 2 H) 7.66-7.74 (m, 3 H) 8.01 (s,
1 H) 8.05 (d, J=8.33 Hz, 1 H) 8.42 (s, 1 H) 8.92 (s, 1 H) 8.99 (s, 1 H) 12.94
(s, 1 H)。MS(ESI(+)) m/e 526 (M+H)+。
实施例7
N-(3-甲基苯基)-N'-[4-(3-噻吩-3-基-1H-吲唑-6-基)苯基]脲
按照实施例1中所描述的来制备该标题化合物,除了用噻吩-3-基硼酸和1-异氰酸根合-3-甲基苯分别代替实施例1C和1D中的1-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吡唑和1-氟-3-异氰酸根合苯。1H NMR
(300 MHz, DMSO-d6) δ ppm 2.29 (s, 3
H) 6.80 (d, J=7.46 Hz, 1 H) 7.17 (t, J=7.46 Hz, 1 H) 7.26 (d, J=8.48 Hz, 1 H)
7.32 (s, 1 H) 7.50 (dd, J=8.48, 1.36 Hz, 1 H) 7.55-7.63 (m, 2 H) 7.67-7.76 (m,
5 H) 8.13-8.15 (m, 1 H) 8.17 (d, J=8.82 Hz, 1 H) 8.63 (s, 1 H) 8.80 (s, 1 H)
13.12 (s, 1 H)。MS(ESI(+)) m/e 425 (M+H)+。
实施例8
N-(3-氟苯基)-N'-{4-[3-(1H-吡唑-5-基)-1H-吲唑-6-基]苯基}脲
通过用1H-吡唑-5-基硼酸代替实施例1C中的1-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吡唑,然后用该产物代替实施例1B中的实施例1A,之后进行实施例1E和1F中的步骤来制备标题化合物。1H NMR (300 MHz,
DMSO-d6) δ ppm 6.73-6.93
(m, 2 H) 7.16 (d, J=8.33 Hz, 1 H) 7.31 (dd, J=8.33, 7.14 Hz, 1 H) 7.44-7.56 (m,
2 H) 7.56-7.63 (m, 2 H) 7.66-7.75 (m, 4 H) 7.85 (s, 1 H) 8.31 (d, J=8.73 Hz, 1
H) 9.02 (s, 1 H) 9.09 (s, 1 H) 13.00 (s, 1 H) 13.03 (s, 1 H)。MS(ESI(+)) m/e 413 (M+H)+。
实施例9
N-(3-氟苯基)-N'-{4-[3-(1H-吡唑-4-基)-1H-吲唑-6-基]苯基}脲
按照实施例1中所描述的来制备该标题化合物,除了用4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑代替实施例1C中的1-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吡唑。1H NMR (300 MHz, DMSO-d6) δ ppm 6.80 (dt, J=8.72, 2.78 Hz, 1 H) 7.15 (d, J=8.33 Hz,
1 H) 7.32 (dd, J=7.93, 7.14 Hz, 1 H) 7.44 (d, J=8.73 Hz, 1 H) 7.52 (d, J=12.29
Hz, 1 H) 7.56-7.63 (m, 2 H) 7.65-7.74 (m, 3 H) 8.04-8.12 (m, 2 H) 8.39 (s, 1 H)
8.91 (s, 1 H) 8.98 (s, 1 H) 12.93 (s, 1 H) 13.09 (s, 1 H)。MS(ESI(+)) m/e 413 (M+H)+。
实施例10
N-(3-氟苯基)-N'-(4-{3-[1-(2-羟基乙基)-1H-吡唑-4-基]-1H-吲唑-6-基}苯基)脲
实施例10A
2-(4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吡唑-1-基)乙醇
在100 mL的圆底烧瓶中将4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吡唑 (9.66 g, 49.8 mmol)、1,3-二氧杂环戊-2-酮(21 g, 238 mmol)和碳酸铯(16
g, 49.1 mmol)混合。所有试剂在室温下都为固体。在油浴中,将该反应从室温加热至100℃,此时碳酸盐已经熔化并作为该反应的溶剂,然后将其保持为浆料。加热3.5小时之后,将该反应冷却至室温,用乙酸乙酯稀释,通过Celite®(硅藻土)过滤,采用乙酸乙酯反复洗涤。将滤液浓缩,并通过在Analogix(R) Intelliflash(TM)纯化系统上的色谱法,使用SF60-200g柱以80 mL/min的流速来纯化残留物,洗脱如下:20%乙酸乙酯/己烷洗脱5min,然后在35min内从40%至90%的乙酸乙酯/己烷梯度洗脱,然后100%乙酸乙酯再洗脱20min,以获得标题化合物。
实施例10B
N-(3-氟苯基)-N'-(4-{3-[1-(2-羟基乙基)-1H-吡唑-4-基]-1H-吲唑-6-基}苯基)脲
按照实施例1中所描述的来制备该标题化合物,用实施例10A代替实施例1C中的1-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吡唑。1H NMR (300 MHz, DMSO-d6) δ ppm 3.82 (dt, J=5.55, 5.16 Hz, 2 H) 4.25 (t, J=5.55 Hz,
2 H) 4.95 (t, J=5.16 Hz, 1 H) 6.80 (dt, J=8.33, 2.38 Hz, 1 H) 7.14 (d, J=7.93
Hz, 1 H) 7.32 (dd, J=7.93, 7.14 Hz, 1 H) 7.45 (d, J=8.72 Hz, 1 H) 7.52 (dt,
J=11.90, 2.38 Hz, 1 H) 7.56-7.62 (m, 2 H) 7.66-7.74 (m, 3 H) 8.02 (s, 1 H) 8.06
(d, J=8.33 Hz, 1 H) 8.36 (s, 1 H) 8.87 (s, 1 H) 8.94 (s, 1 H) 12.94 (s, 1 H) 。MS(ESI(+)) m/e 457 (M+H)+。
实施例11
N-(4-{3-[1-(2-羟基乙基)-1H-吡唑-4-基]-1H-吲唑-6-基}苯基)-N'-[3-(三氟甲基)苯基]脲
按照实施例1中所描述的来制备该标题化合物,除了用2-(4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吡唑-1-基)乙醇和1-异氰酸根合-3-(三氟甲基)苯分别代替实施例1C和1D中的1-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吡唑和1-氟-3-异氰酸根合苯。1H NMR
(300 MHz, DMSO-d6) δ ppm 3.82 (dd,
J=5.55, 5.16 Hz, 2 H) 4.25 (t, J=5.55 Hz, 2 H) 4.95 (t, J=5.16 Hz, 1 H) 7.32
(d, J=7.54 Hz, 1 H) 7.45 (d, J=8.33 Hz, 1 H) 7.49-7.57 (m, 1 H) 7.57-7.64 (m, 2
H) 7.66-7.74 (m, 3 H) 8.00-8.09 (m, 3 H) 8.36 (s, 1 H) 8.94 (s, 1 H) 9.10 (s, 1
H) 12.94 (s, 1 H)。
实施例12
N-(4-{3-[1-(2-羟基乙基)-1H-吡唑-4-基]-1H-吲唑-6-基}苯基)-N'-(3-甲基苯基)脲
按照实施例1中所描述的来制备该标题化合物,除了用2-(4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吡唑-1-基)乙醇和1-异氰酸根合-3-甲基苯分别代替实施例1C和1D中的1-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吡唑和1-氟-3-异氰酸根合苯。1H NMR (300 MHz, DMSO-d6)
δ ppm 2.29 (s, 3 H) 3.82 (dt, J=5.95,
5.15 Hz, 2 H) 4.25 (t, J=5.95 Hz, 2 H) 4.95 (t, J=5.16 Hz, 1 H) 6.80 (d, J=7.14
Hz, 1 H) 7.17 (t, J=7.54 Hz, 1 H) 7.26 (d, J=8.72 Hz, 1 H) 7.32 (s, 1 H) 7.45
(d, J=8.73 Hz, 1 H) 7.55-7.62 (m, 2 H) 7.65-7.72 (m, 3 H) 8.02 (s, 1 H) 8.05
(d, J=8.33 Hz, 1 H) 8.35 (s, 1 H) 8.64 (s, 1 H) 8.80 (s, 1 H) 12.93 (s, 1 H)。MS(ESI(+)) m/e 453 (M+H)+。
实施例13
N-(3-氟苯基)-N'-{4-[3-(1-丙基-1H-吡唑-4-基)-1H-吲唑-6-基]苯基}脲
按照实施例1中所描述的来制备该标题化合物,除了用1-丙基-4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吡唑代替实施例1C中的1-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吡唑。1H NMR (300 MHz, DMSO-d6) δ ppm 0.89 (t, J=7.46 Hz, 3 H) 1.81-1.94 (m, 2 H) 4.16 (t,
J=7.12 Hz, 2 H) 6.80 (t, J=10.51 Hz, 1 H) 7.15 (d, J=8.48 Hz, 1 H) 7.32 (t,
J=8.14 Hz, 1 H) 7.44 (d, J=8.48 Hz, 1 H) 7.52 (d, J=11.87 Hz, 1 H) 7.55-7.63
(m, 2 H) 7.65-7.75 (m, 3 H) 8.01 (s, 1 H) 8.06 (d, J=8.48 Hz, 1 H) 8.40 (s, 1
H) 8.87 (s, 1 H) 8.94 (s, 1 H) 12.93 (s, 1 H)。MS(ESI(+))
m/e 455 (M+H)+。
实施例14
N-(3-氟苯基)-N'-{4-[3-(1-甲基-1H-吡唑-5-基)-1H-吲唑-6-基]苯基}脲
按照实施例1中所描述的来制备该标题化合物,除了用1-甲基-5-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吡唑代替实施例1C中的1-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吡唑。1H NMR (300 MHz, DMSO-d6) δ ppm 4.15 (s, 3 H) 6.79 (dt, J=8.72, 2.38 Hz, 1 H) 6.90
(d, J=1.98 Hz, 1 H) 7.14 (d, J=8.33 Hz, 1 H) 7.32 (dd, J=8.33, 6.74 Hz, 1 H)
7.48-7.56 (m, 2 H) 7.57-7.63 (m, 3 H) 7.69-7.75 (m, 2 H) 7.77 (s, 1 H) 7.96 (d,
J=8.73 Hz, 1 H) 9.14 (s, 1 H) 9.23 (s, 1 H) 13.49 (s, 1 H)。MS(ESI(+)) m/e 427 (M+H)+。
实施例15
N-(3-氟苯基)-N'-(4-{3-[1-(2-羟基-2-甲基丙基)-1H-吡唑-4-基]-1H-吲唑-6-基}苯基)脲
实施例15A
2-甲基-1-(4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吡唑-1-基)丙-2-醇
将4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吡唑 (500 mg, 2.57
mmol)、Cs2CO3 (840 mg,
2.57 mmol)和2,2-二甲基环氧乙烷(2
mL)的混合物在密封管瓶中、120℃下加热3min,同时在Smith Synthesizer微波(300W)中搅拌,然后使其冷却并用CH2Cl2稀释。过滤所得的悬浮液,将滤液浓缩以获得标题化合物。
实施例15B
按照实施例1中所描述的来制备该标题化合物,用2-甲基-1-(4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吡唑-1-基)丙-2-醇代替实施例1C中的1-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吡唑。1H NMR
(300 MHz, DMSO-d6) δ ppm 1.12 (s, 6
H) 4.12 (s, 2 H) 4.75 (s, 1 H) 6.75-6.84 (m, 1 H) 7.11-7.18 (m, 1 H) 7.32 (dd,
J=8.14, 7.12 Hz, 1 H) 7.42-7.62 (m, 4 H) 7.66-7.74 (m, 3 H) 7.99-8.06 (m, 2 H)
8.30 (s, 1 H) 8.87 (s, 1 H) 8.95 (s, 1 H) 12.95 (s, 1 H)。MS(ESI(+)) m/e 485 (M+H)+。
实施例16
N-(3-氟苯基)-N'-{4-[3-(1-哌啶-4-基-1H-吡唑-4-基)-1H-吲唑-6-基]苯基}脲
按照实施例1中所述的,将该标题化合物制备为TFA盐,用4-(4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吡唑-1-基)哌啶-1-羧酸叔丁酯代替实施例1C中的1-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吡唑,并通过在Waters Symmetry
C8柱(25mm x 100mm, 7m粒度)上的制备型HPLC、使用10%-100%乙腈/0.1% TFA水溶液的梯度、经8分钟(10分钟运行时间)以40 mL/min的流速来纯化残留物。1H NMR
(300 MHz, DMSO-d6) δ ppm 2.12-2.36
(m, 4 H) 3.13 (dd, J=11.19 Hz, 2 H) 3.26-3.53 (m, 2 H) 4.54-4.67 (m, 1 H) 6.75-6.84
(m, 1 H) 7.15 (d, J=7.12 Hz, 1H) 7.32 (dd, J=8.48, 6.78 Hz, 1 H) 7.43-7.48 (m,
1 H) 7.48-7.56 (m, 1 H) 7.56-7.64 (m, 2 H) 7.66-7.74 (m, 3 H) 8.08 (d, J=8.48
Hz, 1 H) 8.10 (s, 1 H) 8.34-8.50 (m, 1 H) 8.42 (s, 1 H) 8.60-8.71 (m, 1 H) 8.97
(s, 1 H) 9.03 (s, 1 H) 12.99 (s, 1 H)。MS(ESI(+))
m/e 496 (M+H)+。
实施例17
N-(3-甲基苯基)-N'-{3-[3-(1-甲基-1H-吡唑-4-基)-1H-吲唑-6-基]苯基}脲
按照实施例1中所描述的来制备该标题化合物,用3-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)苯胺和1-异氰酸根合-3-甲基苯分别代替实施例1D中的4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)苯胺和1-氟-3-异氰酸根合苯。1H NMR (300 MHz, DMSO-d6)
δ ppm 2.29 (s, 3 H) 3.94 (s, 3 H) 6.80
(d, J=7.46 Hz, 1 H) 7.16 (dd, J=8.14, 7.46 Hz, 1 H) 7.24 (d, J=8.14 Hz, 1 H)
7.32-7.46 (m, 5 H) 7.69 (s, 1 H) 7.93 (s, 1 H) 8.00 (s, 1 H) 8.08 (d, J=8.48
Hz, 1 H) 8.37 (s, 1 H) 8.62 (s, 1 H) 8.78 (s, 1 H) 12.98 (s, 1 H)。MS(ESI(+)) m/e 423 (M+H)+。
实施例18
N-{4-[3-(1-甲基-1H-吡唑-4-基)-1H-吲唑-6-基]苯基}-N'-[3-(三氟甲基)苯基]脲
按实施例1C-1F中所描述的来制备该标题化合物,用1-异氰酸根合-3-(三氟甲基)苯代替1-氟-3-异氰酸根合苯。1H NMR (300 MHz, DMSO-d6)
δ ppm 3.94 (s, 3 H) 7.32 (d, J=7.46 Hz, 1
H) 7.43-7.48 (m, 1 H) 7.53 (t, J=7.80 Hz, 1 H) 7.57-7.64 (m, 3 H) 7.66-7.74 (m,
3 H) 7.98-8.07 (m, 3 H) 8.37 (s, 1 H) 9.11 (s, 1 H) 9.29 (s, 1 H) 12.97 (s, 1
H)。MS(ESI(+)) m/e 475 (M+H)+。
实施例19
N-{4-[3-(1-甲基-1H-吡唑-4-基)-1H-吲唑-6-基]苯基}-N'-[4-(三氟甲基)苯基]脲
按实施例1C-1F中所描述的来制备该标题化合物,用1-异氰酸根合-4-(三氟甲基)苯代替1-氟-3-异氰酸根合苯。1H NMR (300 MHz, DMSO-d6)
δ ppm 3.94 (s, 3 H) 7.45 (d, J=8.33 Hz, 1
H) 7.57-7.74 (m, 9 H) 8.00 (s, 1 H) 8.05 (d, J=8.73 Hz, 1 H) 8.38 (s, 1 H) 9.19
(s, 1 H) 9.41 (s, 1 H) 12.99 (s, 1 H)。
MS(ESI(+)) m/e 475 (M+H)+。
实施例20
N-(4-氯苯基)-N'-{4-[3-(1-甲基-1H-吡唑-4-基)-1H-吲唑-6-基]苯基}脲
按实施例1C-1F中所描述的来制备该标题化合物,用1-氯-4-异氰酸根合苯代替1-氟-3-异氰酸根合苯。1H NMR
(300 MHz, DMSO-d6) δ ppm 3.94 (s, 3
H) 7.31-7.36 (m, 2 H) 7.42-7.47 (m, 1 H) 7.48-7.54 (m, 2 H) 7.56-7.61 (m, 2 H)
7.66-7.72 (m, 3 H) 7.99 (s, 1 H) 8.04 (d, J=8.48 Hz, 1 H) 8.37 (s, 1 H) 9.05
(s, 1 H) 9.08 (s, 1 H) 12.99 (s, 1 H)。MS(ESI(+))
m/e 443 (M+H)+。
实施例21
N-(3-氟苯基)-N'-{4-[3-(1H-1,2,3-三唑-5-基)-1H-吲唑-6-基]苯基}脲
实施例21A
6-溴-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-3-((三甲基甲硅烷基)乙炔基)-1H-吲唑
在氩气下,向实施例1B (0.41 g, 0.905 mmol)和碘化亚铜(I) (10 mg, 0.053 mmol)中加入四氢呋喃(25
ml)和三乙胺(1.261 ml, 9.05 mmol),然后加入乙炔基三甲基硅烷(0.153 ml, 1.086 mmol)和[1,1'-双(二苯基膦基)二茂铁]二氯化钯(II) (0.037 g,
0.045 mmol)。在室温下,将所得的悬浮液搅拌16小时,然后在乙酸乙酯和稀NaHCO3溶液之间分配。用MgSO4干燥有机萃取物,浓缩,并通过硅胶色谱法、采用乙酸乙酯/己烷洗脱来纯化残留物以获得标题化合物。
实施例21B
1-(3-氟苯基)-3-(4-(1-((2-(三甲基甲硅烷基)乙氧基)甲基)-3-((三甲基甲硅烷基)乙炔基)-1H-吲唑-6-基)苯基)脲
通过用实施例21A代替实施例1E中的实施例1C来制备该标题化合物。
实施例21C
1-(4-(3-乙炔基-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吲唑-6-基)苯基)-3-(3-氟苯基)脲
采用过量的K2CO3处理实施例21B (660 mg)在50 ml甲醇中的溶液,在50℃下搅拌1小时,然后浓缩至约2 mL,并在乙酸乙酯和盐水之间分配。采用乙酸乙酯反萃取水层,干燥(MgSO4)合并的有机萃取物并浓缩,并通过硅胶色谱法、采用含0-0.75%甲醇的CH2Cl2洗脱来纯化残留物,以获得标题化合物。
实施例21D
1-(4-(3-(1H-1,2,3-三唑-5-基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吲唑-6-基)苯基)-3-(3-氟苯基)脲
在氩气下,采用Cu(I)I (5.00 mg, 0.026 mmol)和三甲基甲硅烷基叠氮化物(0.249 ml, 1.798 mmol)处理实施例21C
(90 mg, 0.180 mmol)在N,N-二甲基甲酰胺(4 ml)和甲醇(0.7 ml)中的溶液,然后在密封管内、100℃下在油浴中加热3小时。加入额外量(0.5 ml)的三甲基甲硅烷基叠氮化物,将管瓶重新加盖,并在100℃下加热4小时,然后在室温下搅拌16小时。所得的混合物在乙酸乙酯和盐水之间分配,并用MgSO4干燥有机萃取物,浓缩,并在12 g Silicycle柱上采用含2-3%甲醇的CH2Cl2洗脱来纯化残留物,以获得标题化合物。
实施例21E
N-(3-氟苯基)-N'-{4-[3-(1H-1,2,3-三唑-5-基)-1H-吲唑-6-基]苯基}脲
通过用实施例21D代替实施例1F中的实施例1E来制备该标题化合物。1H NMR
(300 MHz, DMSO-d6) δ ppm 6.79 (dt,
J=8.14, 2.71 Hz, 1 H) 7.15 (d, J=8.14 Hz, 1 H) 7.32 (dd, J=8.14, 6.78 Hz, 1 H)
7.48-7.56 (m, 2 H) 7.57-7.65 (m, 2 H) 7.69-7.76 (m, 3 H) 8.26 (d, J=8.48 Hz, 1
H) 8.35 (s, 1 H) 9.08 (s, 1 H) 9.16 (s, 1 H) 13.18-13.52 (bs, 1 H)。MS(ESI(+)) m/e 414 (M+H)+。
实施例22
N-(3-氯苯基)-N'-{4-[3-(1-甲基-1H-吡唑-4-基)-1H-吲唑-6-基]苯基}脲
按实施例1C-1F中所描述的来制备该标题化合物,用1-氯-3-异氰酸根合苯代替1-氟-3-异氰酸根合苯。1H NMR
(300 MHz, DMSO-d6) δ ppm 3.94 (s, 3
H) 7.00-7.05 (m, 1 H) 7.28-7.33 (m, 2 H) 7.45 (d, J=8.72 Hz, 1 H) 7.56-7.62 (m,
2 H) 7.66-7.75 (m, 4 H) 8.00 (s, 1 H) 8.05 (d, J=8.72 Hz, 1 H) 8.38 (s, 1 H)
9.11 (s, 1 H) 9.18 (s, 1 H) 12.97 (s, 1 H)。MS(ESI(+))
m/e 443 (M+H)+。
实施例23
N-(2-氯苯基)-N'-{4-[3-(1-甲基-1H-吡唑-4-基)-1H-吲唑-6-基]苯基}脲
按实施例1C-1F中所描述的来制备该标题化合物,用1-氯-2-异氰酸根合苯代替1-氟-3-异氰酸根合苯。1H NMR
(300 MHz, DMSO-d6) δ ppm 3.94 (s, 3
H) 7.01-7.08 (m, 1 H) 7.28-7.35 (m, 1 H) 7.43-7.50 (m, 2 H) 7.58-7.64 (m, 2 H)
7.66-7.75 (m, 3 H) 7.99 (s, 1 H) 8.05 (d, J=8.48 Hz, 1 H) 8.16-8.22 (m, 1 H)
8.38 (s, 1 H) 8.39 (s, 1 H) 9.63 (s, 1 H) 12.97 (s, 1 H)。MS(ESI(+)) m/e 443 (M+H)+。
实施例24
N-(3-氟苯基)-N'-{4-[3-(1-甲基-1H-吡唑-4-基)-1H-吲唑-6-基]苄基}脲
按照实施例1D-1F中所描述的来制备该标题化合物,用(4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)苯基)甲胺代替4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)苯胺。1H NMR (300 MHz, DMSO-d6) δ ppm 3.94 (s, 3 H) 4.37 (d, J=3.97 Hz, 2 H) 6.70 (td,
J=8.72, 2.38 Hz, 1 H) 6.80-6.90 (m, 1 H) 7.07 (d, J=7.54 Hz, 1 H) 7.25 (dd,
J=7.93, 7.14 Hz, 1 H) 7.40-7.49 (m, 3 H) 7.49-7.53 (m, 1 H) 7.68-7.75 (m, 3 H)
8.00 (s, 1 H) 8.07 (d, J=8.33 Hz, 1 H) 8.37 (s, 1 H) 8.97 (s, 1 H) 12.98 (s, 1
H)。MS(ESI(+)) m/e 441 (M+H)+。
实施例25
N-{4-[3-(1-甲基-1H-吡唑-4-基)-1H-吲唑-6-基]苯基}-N'-[3-(三氟甲氧基)苯基]脲
按实施例1C-1F中所描述的来制备该标题化合物,用1-异氰酸根合-3-(三氟甲氧基)苯代替1-氟-3-异氰酸根合苯。1H NMR (300 MHz, DMSO-d6)
δ ppm 3.94 (s, 3 H) 6.95 (d, J=7.93 Hz, 1
H) 7.32 (d, J=8.73 Hz, 1 H) 7.43 (dd, J=15.86, 7.93 Hz, 4 H) 7.57-7.63 (m, 2 H)
7.66-7.74 (m, 4 H) 7.99 (s, 1 H) 8.05 (d, J=8.73 Hz, 1 H) 8.38 (s, 1 H) 9.09
(s, 1 H) 9.27(s, 1 H) 12.98 (s, 1 H)。MS(ESI(+))
m/e 493 (M+H)+。
实施例26
N-{4-[3-(1-甲基-1H-吡唑-4-基)-1H-吲唑-6-基]苯基}-N'-[2-(三氟甲基)苯基]脲
按实施例1C-1F中所描述的来制备该标题化合物,用1-异氰酸根合-2-(三氟甲基)苯代替1-氟-3-异氰酸根合苯。1H NMR (300 MHz, DMSO-d6)
δ ppm 3.94 (s, 3 H) 7.30 (t, J=7.54 Hz, 1
H) 7.45 (d, J=8.73 Hz, 1 H) 7.57-7.75 (m, 7 H) 7.97 (d, J=7.93 Hz, 1 H) 8.00
(s, 1 H) 8.05 (d, J=8.33 Hz, 2 H) 8.16 (s, 1 H) 8.38 (s, 1 H) 9.58 (s, 1 H)
13.00 (s, 1 H)。MS(ESI(+)) m/e 477 (M+H)+。
实施例27
N-{4-[3-(1-甲基-1H-吡唑-4-基)-1H-吲唑-6-基]苯基}-N'-[2-(三氟甲氧基)苯基]脲
按实施例1C-1F中所描述的来制备该标题化合物,用1-异氰酸根合-2-(三氟甲氧基)苯代替1-氟-3-异氰酸根合苯。1H NMR (300 MHz, DMSO-d6)
δ ppm 3.94 (s, 3 H) 7.11 (t, J=7.93 Hz, 1
H) 7.32-7.42 (m, 2 H) 7.45 (d, J=8.33 Hz, 1 H) 7.57-7.64 (m, 2 H) 7.67-7.75 (m,
3 H) 8.00 (s, 1 H) 8.05 (d, J=8.33 Hz, 1 H) 8.29 (d, J=8.33 Hz, 1 H) 8.38 (s, 1
H) 8.52 (s, 1 H) 9.44 (s, 1 H) 12.95 (s, 1 H)。MS(ESI(+))
m/e 493 (M+H)+。
实施例28
N-{4-[3-(1-甲基-1H-吡唑-4-基)-1H-吲唑-6-基]苯基}-N'-[4-(三氟甲氧基)苯基]脲
按实施例1C-1F中所描述的来制备该标题化合物,用1-异氰酸根合-4-(三氟甲氧基)苯代替1-氟-3-异氰酸根合苯。1H NMR (300 MHz, DMSO-d6)
δ ppm 3.94 (s, 3 H) 7.30 (d, J=8.48 Hz, 2
H) 7.45 (d, J=8.48 Hz, 1 H) 7.55-7.62 (m, 4 H) 7.65-7.73 (m, 3 H) 7.99 (s, 1 H)
8.04 (d, J=8.48 Hz, 1 H) 8.37 (s, 1 H) 9.05 (s, 1 H) 9.13 (s, 1 H) 12.98 (s, 1 H)。MS(ESI(+)) m/e 493 (M+H)+。
实施例29
N-(3-氟苯基)-N'-{3-[3-(1-甲基-1H-吡唑-4-基)-1H-吲唑-6-基]苄基}脲
按照实施例1D-1F中所描述的来制备该标题化合物,用(3-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)苯基)甲胺代替4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)苯胺。1H NMR (300 MHz, DMSO-d6) δ ppm 3.94 (s, 3 H) 4.41 (d, J=5.76 Hz, 2 H) 6.70 (td,
J=8.14, 3.39 Hz, 1 H) 6.83 (t, J=5.76 Hz, 1 H) 7.06 (d, J=9.15 Hz, 1 H) 7.24
(dd, J=8.14, 7.12 Hz, 1 H) 7.34 (d, J=7.80 Hz, 1 H) 7.42-7.51 (m, 3 H) 7.60-7.72
(m, 3 H) 8.00 (s, 1 H) 8.08 (d, J=8.48 Hz, 1 H) 8.38 (s, 1 H) 8.89 (s, 1 H) 12.99
(s, 1 H)。MS(ESI(+)) m/e 441 (M+H)+。
实施例30
N-(5-甲基异噁唑-3-基)-N'-{4-[3-(1-甲基-1H-吡唑-4-基)-1H-吲唑-6-基]苯基}脲
按照实施例1E-1F中所描述的来制备该标题化合物,用1-(5-甲基异噁唑-3-基)-3-(4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)苯基)脲代替实施例1D。1H NMR
(300 MHz, DMSO-d6) δ ppm 2.37 (s, 3
H) 3.94 (s, 3 H) 6.57-6.57 (m, 1 H) 7.45 (d, J=8.48 Hz, 1 H) 7.55-7.61 (m, 2 H)
7.66-7.74 (m, 3 H) 8.00 (s, 1 H) 8.05 (d, J=8.81 Hz, 1 H) 8.38 (s, 1 H) 9.19
(s, 1 H) 9.58 (s, 1 H) 12.98 (s, 1 H)。MS(ESI(+))
m/e 414 (M+H)+。
实施例31
3-氟-N-{4-[3-(1-甲基-1H-吡唑-4-基)-1H-吲唑-6-基]苄基}苯甲酰胺
实施例31A
4-(1-((2-(叔丁基甲硅烷基)乙氧基)甲基)-3-(1-甲基-1H-吡唑-4-基)-1H-吲唑-6-基)苄基氨基甲酸叔丁酯
按照实施例1E中所描述的来制备该标题化合物,用4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)苄基氨基甲酸叔丁酯代替实施例1D。
实施例31B
(4-(3-(1-甲基-1H-吡唑-4-基)-1H-吲唑-6-基)苯基)甲胺
在氩气下,采用三氟乙酸(1 ml, 12.98 mmol)处理实施例31A (0.17 g, 0.319 mmol)在CH2Cl2
(4 mL)中的溶液,在室温下搅拌1小时,然后在稀Na2CO3溶液和乙酸乙酯(2X)之间分配。干燥(MgSO4)合并的有机物,然后浓缩,以获得在下一步中原样使用的该标题化合物。
实施例31C
3-氟-N-{4-[3-(1-甲基-1H-吡唑-4-基)-1H-吲唑-6-基]苄基}苯甲酰胺
采用三乙胺(1.00 ml, 7.17 mmol)处理实施例31B (70 mg, 0.231 mmol)在四氢呋喃(15
ml)中的0℃的悬浮液,然后滴加3-氟苯甲酰氯(0.014 ml, 0.115 mmol)。使该反应缓慢加热至室温,并且2小时后用另外的14 μL酰氯处理,搅拌18小时,然后在盐水和乙酸乙酯之间分配。用MgSO4干燥有机萃取物,浓缩并通过在Waters Symmetry C8柱(25mm
x 100mm, 7μm粒度)上的制备型HPLC、使用10%-100%乙腈/0.1% TFA水溶液的梯度,在8min内(10min运行时间)、以40 mL/min的流速来纯化残留物,以获得标题化合物。1H NMR (300 MHz,
DMSO-d6) δ ppm 3.94 (s, 3
H) 4.55 (d, J=5.95 Hz, 2 H) 7.35-7.81 (m, 10 H) 7.99 (s, 1 H) 8.06 (d, J=8.33
Hz, 1 H) 8.37 (s, 1 H) 9.19 (t, J=5.95 Hz, 1 H) 12.98 (s, 1 H)。MS(ESI(+)) m/e 426 (M+H)+。
实施例32
N-(3-甲基苯基)-N'-[4-(3-苯基-1H-吲唑-6-基)苯基]脲
按照实施例1C-1F中所描述的来制备该标题化合物,用苯基硼酸和1-异氰酸根合-3-甲基苯分别代替1-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吡唑和1-氟-3-异氰酸根合苯。1H NMR (300 MHz, DMSO-d6)
δ ppm 2.29 (s, 3 H) 6.80 (d, J=7.14 Hz, 1
H) 7.17 (t, J=7.54 Hz, 1 H) 7.26 (d, J=8.73 Hz, 1 H) 7.32 (s, 1 H) 7.42 (t,
J=7.54 Hz, 1 H) 7.49-7.55 (m, 3 H) 7.57 (d, J=3.97 Hz, 1H) 7.61 (s, 1H) 7.69
(s, 1H) 7.72 (s, 1H) 7.75 (s, 1H) 8.01 (s, 1H) 8.04 (s, 1H) 8.12 (d, J=8.73 Hz,
1H) 8.63 (s, 1 H) 8.80 (s, 1 H) 13.26 (s, 1 H)。MS(ESI(-))
m/e 417 (M-H)。
实施例33
N-(3-甲基苯基)-N'-[4-(3-吡啶-3-基-1H-吲唑-6-基)苯基]脲
按照实施例1C-1F中所描述的将该标题化合物制备为HCl盐,用吡啶-3-基硼酸和1-异氰酸根合-3-甲基苯分别代替1-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吡唑和1-氟-3-异氰酸根合苯。1H NMR (300 MHz, DMSO-d6)
δ ppm 2.29 (s, 3 H) 6.80 (d, J=7.12 Hz, 1
H) 7.17 (t, J=7.46 Hz, 1 H) 7.27 (d, J=8.82 Hz, 1 H) 7.32 (s, 1 H) 7.60 (m, 3
H) 7.71 (s, 1 H) 7.74 (s, 1 H) 7.81 (s, 1H) 7.86 (dd, J=5.43,2.37 Hz, 1H) 8.20
(s, 1 H) 8.23 (s, 1 H) 8.76 (m, 2 H) 8.92 (s, 1 H) 9.12 (s, 1 H) 9.35 (s, 1H)
13.66 (s, 1H)。MS(ESI(+)) m/e 420 (M+H)+。
实施例34
N-(3-甲基苯基)-N'-[3-(3-吡啶-3-基-1H-吲唑-6-基)苯基]脲
实施例34A
1-(3-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)苯基)-3-间-甲苯基脲
通过用3-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)苯胺和1-异氰酸根合-3-甲基苯分别代替实施例1D中的4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)苯胺和1-氟-3-异氰酸根合苯来制备该标题化合物。
实施例34B
N-(3-甲基苯基)-N'-[3-(3-吡啶-3-基-1H-吲唑-6-基)苯基]脲
按照实施例1C-F中所描述的来制备该标题化合物,用吡啶-3-基硼酸和实施例34A分别代替1-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吡唑和实施例1D。1H NMR
(300 MHz, DMSO-d6) δ ppm 2.29 (s, 3
H) 6.80 (d, J=7.12 Hz, 1 H) 7.17 (t, J=7.46 Hz, 1 H) 7.25 (d, J=8.82 Hz, 1 H)
7.34 (s, 1 H) 7.41 (m, 3 H) 7.57 (dd, J=1.36, 7.12 Hz, 1 H) 7.83 (m, 2H) 7.99
(s, 1H) 8.26 (d, J=8.48 Hz, 1 H) 8.73 (m, 2 H) 8.79 (s, 1 H) 8.96 (s, 1 H) 9.35
(s, 1 H) 13.68 (s, 1H)。MS(ESI(+)) m/e
420 (M+H)+。
实施例35
N-(3-甲基苯基)-N'-{4-[3-(1,3-噻唑-4-基)-1H-吲唑-6-基]苯基}脲
按照实施例1C-1F中所描述的来制备该标题化合物,用4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)噻唑和1-异氰酸根合-3-甲基苯分别代替1-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吡唑和1-氟-3-异氰酸根合苯。1H NMR (300 MHz, DMSO-d6)
δ ppm 2.29 (s, 3 H) 6.80 (d, J=7.14 Hz, 1
H) 7.17 (t, J=7.14, 7.93 Hz, 1 H) 7.26 (d, J=7.93 Hz, 1 H) 7.32 (s, 1 H) 7.52
(dd, J=1.19, 8.33 Hz, 1 H) 7.57 (s, 1 H) 7.60 (s, 1 H) 7.69 (s, 1H) 7.73 (s,
2H) 8.17 (d, J=1.59 Hz, 1 H) 8.37 (d, J=8.33 Hz, 1 H) 8.71 (s, 1 H) 8.88 (s,
1H) 9.32 (d, J=1.98 Hz, 1H) 13.28 (bs, 1 H)。MS(ESI(+))
m/e 426 (M+H)+。
实施例36
N-{4-[3-(1H-吲哚-2-基)-1H-吲唑-6-基]苯基}-N'-(3-甲基苯基)脲
实施例36A
2-(6-(4-(3-间-甲苯基脲基)苯基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吲唑-3-基)-1H-吲哚-1-羧酸叔丁酯
按照实施例1C-1E中所描述的来制备该标题化合物,用1-(叔丁氧基羰基)-1H-吲哚-2-基硼酸和1-异氰酸根合-3-甲基苯分别代替1-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吡唑和1-氟-3-异氰酸根合苯。
实施例36B
N-{4-[3-(1H-吲哚-2-基)-1H-吲唑-6-基]苯基}-N'-(3-甲基苯基)脲
在110℃中,将10 ml微波管中的实施例36A (54.3 mg, 0.079 mmol)、乙二胺(0.053
ml, 0.789 mmol)和四丁基氟化铵(3.16 ml, 3.16
mmol)在四氢呋喃中的溶液置于Biotage微波中90分钟。用水稀释该反应溶液,并用乙酸乙酯萃取两次,合并有机物,通过MgSO4干燥,并过滤。浓缩滤液,并采用SF40-240g柱(约317 ml孔隙)、以47%最大泵速(约85 ml/min )、用3%甲醇/CH2Cl2纯化,以给出标题化合物。1H NMR (300 MHz,
DMSO-d6) δ ppm 2.29 (s, 3
H) 6.80 (d, J=7.14 Hz, 1 H) 7.02 (m, 1H) 7.12 (m, 2H) 7.18 (d, J=7.54 Hz, 1 H)
7.26 (d, J=8.73 Hz, 1 H) 7.33 (s, 1 H) 7.46 (d, J=7.93 Hz, 1H) 7.55 (dd,
J=1.19, 8.72 Hz, 1 H) 7.59 (s, 1 H) 7.62 (s, 2H) 7.71 (s, 1 H) 7.74 (d, J=3.97
Hz, 2H) 8.24 (d, J=8.33 Hz, 1 H) 8.70 (s, 1 H) 8.87 (s, 1 H) 11.59 (d, J=1.19
Hz, 1H) 13.33 (s, 1 H)。MS(ESI(+)) m/e
458 (M+H)+。
实施例37
2-(4-{6-[4-({[(3-氟苯基)氨基]羰基}氨基)苯基]-1H-吲唑-3-基}-1H-吡唑-1-基)-N-甲基丙酰胺
实施例37A
N-甲基-2-(4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吡唑-1-基)丙酰胺
将4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吡唑 (5.29 g, 27.3
mmol), 2-溴-N-甲基丙酰胺(9.05
g, 54.5 mmol)和碳酸钾(5.65 g, 40.9 mmol) 在136 ml丙酮中的悬浮液回流68小时。通过硅藻土过滤白色悬浮液并用丙酮洗涤;浓缩滤液,并通过硅胶色谱法(80 mm;1 L 65%乙酸乙酯/己烷至80%乙酸乙酯/己烷)纯化,以获得标题化合物。
实施例37B
2-(4-{6-[4-({[(3-氟苯基)氨基]羰基}氨基)苯基]-1H-吲唑-3-基}-1H-吡唑-1-基)-N-甲基丙酰胺
按照实施例1中所描述的来制备该标题化合物,用N-甲基-2-(4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吡唑-1-基)丙酰胺代替1-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吡唑。1H NMR
(300 MHz, DMSO-d6) δ ppm 1.69 (d,
J=7.14 Hz, 3 H) 2.63 (d, J=4.76 Hz, 3 H) 5.07 (q, J=7.14 Hz, 1 H) 6.79 (dt,
J=8.33, 1.98 Hz, 1 H) 7.14 (d, J=9.52 Hz, 1 H) 7.32 (dd, J=8.33, 7.14 Hz, 1 H)
7.46 (d, J=8.33 Hz, 1 H) 7.52 (d, J=11.90 Hz, 1 H) 7.56-7.74 (m, 5 H) 8.03-8.13
(m, 3 H) 8.42 (s, 1 H) 9.08 (s, 1 H) 9.16 (s, 1 H) 13.01 (s, 1 H)。MS(ESI(+)) m/e 498 (M+H)+。
实施例38
N-甲基-2-[4-(6-{4-[(苯基磺酰基)氨基]苯基}-1H-吲唑-3-基)-1H-吡唑-1-基]丙酰胺
按照实施例1中所描述的来制备该标题化合物,用实施例37A代替1-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吡唑,并且用N-(4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)苯基)苯磺酰胺(J.Med.Chem. 2007, 50, 1584)代替实施例1D。1H NMR
(300 MHz, DMSO-d6) δ ppm 1.68 (d,
J=7.14 Hz, 3 H) 2.62 (d, J=4.36 Hz, 3 H) 5.06 (q, J=7.14 Hz, 1 H) 7.22 (d,
J=8.72 Hz, 2 H) 7.38 (d, J=8.72 Hz, 1 H) 7.53-7.67 (m, 6 H) 7.79-7.85 (m, 2 H)
8.00-8.08 (m, 3 H) 8.39 (s, 1 H) 10.45 (s, 1 H) 12.99 (s, 1 H)。MS(ESI(+)) m/e 501 (M+H)+。
实施例39
3-氟-N-{4-[3-(1-甲基-1H-吡唑-4-基)-1H-吲唑-6-基]苯基}苯甲酰胺
按照实施例1中所描述的来制备该标题化合物,用3-氟-N-(4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)苯基)苯甲酰胺(通过用4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)苯胺代替实施例31C中的实施例31B来制备)代替实施例1D。1H NMR (300 MHz, DMSO-d6) δ ppm 3.94 (s, 3 H) 7.43-7.51 (m, 2 H) 7.57-7.66 (m, 1 H)
7.72 (s, 1 H) 7.75-7.89 (m, 5 H) 7.93 (d, J=8.82 Hz, 2 H) 8.01 (s, 1 H) 8.07
(d, J=9.16 Hz, 1 H) 8.39 (s, 1 H) 10.45 (s, 1 H)。MS(ESI(+))
m/e 412 (M+H)+。
实施例40
N-{4-[3-(1-甲基-1H-吡唑-4-基)-1H-吲唑-6-基]苯基}-N'-[3-(吡咯烷-1-基甲基)苯基]脲
按照实施例1中所描述的来制备该标题化合物,用3-(吡咯烷-1-基甲基)苯胺和2-(4-异氰酸根合苯基)-4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷分别代替实施例1D中的4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)苯胺和1-氟-3-异氰酸根合苯。1H NMR (300 MHz, DMSO-d6)
δ ppm 1.81-1.94 (m, 2 H) 1.98-2.12 (m, 2
H) 3.04-3.18 (m, 2 H) 3.34-3.46 (m, 2 H) 3.94 (s, 3 H) 4.35 (d, J=5.55 Hz, 2 H)
7.12 (d, J=6.35 Hz, 1 H) 7.35-7.48 (m, 3 H) 7.58-7.74 (m, 5 H) 7.81 (s, 1 H)
7.99 (s, 1 H) 8.05 (d, J=8.73 Hz, 1 H) 8.37 (s, 1 H) 9.03 (s, 1 H) 9.06 (s, 1H)
9.77 (s, 1 H) 12.95 (s, 1 H)。MS(ESI(+)) m/e
492 (M+H)+。
实施例41
N-(3-氟苯基)-N'-(4-{3-[1-(2-吡咯烷-1-基乙基)-1H-吡唑-4-基]-1H-吲唑-6-基}苯基)脲
实施例41A
6-溴-3-(1-(2-(吡咯烷-1-基)乙基)-1H-吡唑-4-基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吲唑
在室温、氩气下,将氢化钠(17.46 mg, 0.437 mmol)一次性加入6-溴-3-(1H-吡唑-4-基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吲唑(101 mg, 0.257
mmol) (通过用4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吡唑代替实施例1C中的1-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吡唑来制备)在DMF (10 ml)中的溶液中。将所得的鼓泡溶液搅拌20
min,然后用溶于0.5 ml DMF中的1-(2-氯乙基)吡咯烷(51.5 mg, 0.385
mmol)通过移液管滴加处理。在70℃下,将所得的混合物搅拌3小时,使其冷却,并在乙酸乙酯和水之间分配。用盐水洗涤有机萃取物,用MgSO4干燥,并过滤。浓缩滤液,并通过硅胶色谱法、采用3-5% CH2Cl2/CH3OH洗脱来纯化残留物以给出标题化合物。
实施例41B
N-(3-氟苯基)-N'-(4-{3-[1-(2-吡咯烷-1-基乙基)-1H-吡唑-4-基]-1H-吲唑-6-基}苯基)脲
按照实施例1C-1F所描述的来制备该标题化合物,用实施例41A代替实施例1C。1H NMR
(300 MHz, DMSO-d6) δ ppm 1.80-1.93
(m, 2 H) 1.95-2.09 (m, 2 H) 3.00-3.15 (m, 2 H) 3.51-3.65 (m, 2 H) 3.70-3.80 (m,
2 H) 4.61 (t, J=5.95 Hz, 2 H) 6.75-6.84 (m, 1 H) 7.15 (d, J=7.93 Hz, 1 H) 7.32
(dd, J=8.33, 7.14 Hz, 1 H) 7.44-7.56 (m, 2 H) 7.56-7.64 (m, 2 H) 7.67-7.74 (m,
3 H) 8.07 (d, J=8.33 Hz, 1 H) 8.15 (s, 1 H) 8.54 (s, 1 H) 8.98 (s, 1 H) 9.04
(s, 1 H) 9.56 (s, 1 H) 13.02 (s, 1 H)。MS(ESI(+))
m/e 510 (M+H)+。
实施例42
N-{4-[3-(1H-吲哚-3-基)-1H-吲唑-6-基]苯基}-N'-(3-甲基苯基)脲
按照实施例1C-1E,然后是实施例36B中所描述的来制备该标题化合物,用1-(苯基磺酰基)-1H-吲哚-3-基硼酸和1-异氰酸根合-3-甲基苯分别代替1-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吡唑和1-氟-3-异氰酸根合苯。1H NMR (300 MHz, DMSO-d6)
δ ppm 2.29 (s, 3 H) 6.80 (d, J=7.54 Hz, 1
H) 7.08-7.23 (m, 3H) 7.26 (d, 1H, J=8.33 Hz) 7.33 (s, 1 H) 7.42-7.50 (m, 2H)
7.58 (s, 1H) 7.61 (s, 2H) 7.70 (s, 2H) 7.73 (s, 1H) 8.14 (d, J=2.38 Hz, 1 H)
8.17 (d, J=8.33 Hz, 1 H) 8.35 (d, J=7.54 Hz, 1H) 8.71 (s, 1H) 8.87 (s, 1 H)
11.44 (s, 1H) 12.93 (s, 1 H)。MS(ESI(+)) m/e
458 (M+H)+。
实施例43
N-[4-(3-{1-[(2R)-2-羟基丙基]-1H-吡唑-4-基}-1H-吲唑-6-基)苯基]-N'-(3-甲基苯基)脲
按照实施例1C-1F中所描述的来制备该标题化合物,用(R)-1-(3-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吡唑-1-基)丙-2-醇和1-异氰酸根合-3-甲基苯分别代替1-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吡唑和1-氟-3-异氰酸根合苯。1H NMR
(300 MHz, DMSO-d6) δ ppm 1.06-1.12
(m, 3H) 2.29 (s, 3 H) 4.03-4.14 ( m, 3H) 4.96 ( d, J=4.75 Hz, 1H) 6.80 (d,
J=7.46 Hz, 1 H) 7.17 (t, J=7.46,8.14 Hz, 1 H) 7.25 (d, J=8.82 Hz, 1 H) 7.32 (s,
1 H) 7.45 (dd, J=8.82, 1.36 Hz, 1 H) 7.57 (s, 1 H) 7.60 (s, 1H) 7.67 (s, 2 H)
7.71 (s, 1H) 8.02 (d, J=3.05 Hz, 1H) 8.06 (s,1 H) 8.33 (s, 1H) 8.61 (s, 1 H)
8.77 (s, 1 H) 12.93 (s, 1 H)。MS(ESI(+)) m/e
467 (M+H)+。
实施例44
3-氟-N-{3-[3-(1-甲基-1H-吡唑-4-基)-1H-吲唑-6-基]苯基}苯甲酰胺
按照实施例1中所描述的来制备该标题化合物,用3-氟-N-(3-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)苯基)苯甲酰胺(通过用3-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)苯胺代替实施例31C中的实施例31B来制备)代替实施例1D。1H NMR (300 MHz, DMSO-d6) δ ppm 3.95 (s, 3 H) 7.44 (d, J=1.19 Hz, 1H) 7.47 (d,
J=1.19, 1H) 7.48-7.55 (m, 2H) 7.57-7.67 (m, 1H) 7.72 (s, 1 H) 7.79-7.90 (m, 3H)
8.01 (s, 1H) 8.11 (d, J=8.33 Hz, 1 H) 8.20 (s, 1 H) 8.39 (s, 1 H) 10.43 (s, 1H)
13.02 (s, 1 H)。MS(ESI(+)) m/e 412 (M+H)+。
实施例45
N-{3-氯-4-[3-(1-甲基-1H-吡唑-4-基)-1H-吲唑-6-基]苯基}-N'-(3-氟苯基)脲
按照实施例1中所描述的来制备该标题化合物,用3-氯-4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)苯胺代替4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)苯胺。1H NMR (300 MHz, DMSO-d6) δ ppm 3.94 (s, 3 H) 6.81 (dt, J=8.73,2.78 Hz, 1 H) 7.18
(dt, J=9.52,1.19 Hz, 2 H) 7.33 (dd, J=7.93,7.14 Hz, 1 H) 7.43 (s 2H) 7.50 (dt,
J=11.9, 1.98 Hz, 1 H) 7.51 (s, 1 H) 7.85 (s, 1 H) 8.01 (s, 1H) 8.05 (d, J=8.33
Hz, 1 H) 8.38 (s, 1 H) 9.09 (s, 1 H) 9.11 (s, 1H) 13.00 (s, 1 H)。MS(ESI(+)) m/e 461 (M+H)+。
实施例46
此实施例描述可用于识别具有激酶活性的化合物的检测。
为了测定本发明的代表性化合物的极光激酶B活性,在384孔板的孔中用生物素化组蛋白H3肽残基1-21 (Upstate)、1 mM ATP和在HEPES缓冲液(pH 7.4,含有MgCl2、原钒酸钠(sodium othrovanadate)和Triton
X-100)中的各种浓度的抑制剂培养活性极光激酶B酶(重组残基1-344)和INCENP(重组GST融合蛋白(Upstate))。在1小时后,用EDTA停止反应并加入抗-磷酸化组蛋白H3铕穴状化合物(Cis-Bio)和SA-APC
(Phycolink, Prozyme)以检测磷酸肽。通过在665 nm和615 nm下的信号的时间分辨荧光比测定磷酸化的量。使用Assay
Explorer软件通过在抑制剂浓度下的抑制值的指数拟合计算IC50’s。
为了测定本发明的代表性化合物的极光激酶A和C活性,在384孔板的孔中用生物素化STK底物-2 (Upstate)、1 mM
ATP和在Hepes缓冲液(pH
7.4,含有MgCl2、原钒酸钠(sodium othrovanadate)和Triton
X-100)中的各种浓度的抑制剂培养活性极光激酶A或C酶。在1小时后,用EDTA停止反应并加入抗-磷酸-STK抗体铕穴状化合物(Upstate)和SA-XL665 (Upstate)以检测磷酸肽。通过在665
nm和615 nm下的信号的时间分辨荧光比测定磷酸化的量。使用Assay
Explorer软件通过在抑制剂浓度下的抑制值的指数拟合计算IC50’s。
为了测定各种激酶的活性,使用同质时间分辨荧光(HTRF)体外激酶检测。(Mathis,
G., HTRF(R) Technology. J Biomol Screen, 1999. 4(6): 第309-314页;Alfred J. Kolb,
Paul V. Kaplita, David J. Hayes, Young-Whan Park, Christine Pernell, John S.
Major和Gérard
Mathis, Drug Discovery Today, 1998, 3, 333-342.)。
例如对KDR而言,在黑色384孔板中将7纳克/孔的纯化酶(His6-KDR 789-1354, MW 63 kD)与0.5
mM N-生物素化底物(生物素-Ahx-AEEEYFFLA-酰胺 (SEQ. ID. 1))、在反应缓冲液(50 μM HEPES, pH 7.1, 10 mM MgCl2, 2 mM MnCl2,
0.1% BSA和1 mM DTT, 40 L最终体积)中的各种浓度的抑制剂、ATP(1 mM最终浓度)混合。在室温下培养60分钟后,通过加入缓冲的EDTA溶液(最终近似浓度:30 mM EDTA, 0.1%
BSA, 0.1% Triton X-100和0.24M KF)将反应淬灭并将显色试剂(revelation agents)溶液(以产生0.084纳克/孔的链霉亲和素-XL-665
(Cis-Bio)和6.5纳克/孔抗磷酸酪氨酸(antiphsophotyrosine) mAb
PT66-K 铕穴状化合物(Europium kryptate))添加到反应混合物中。使淬灭的反应在室温下静置 3小时,然后在时间分辨荧光检测器(InVision,
Perkin-Elmer)中在激发下相继在620 nm和665
nm下读数。620 nm和665
nm信号之间的比率用于计算IC50。
为了测定H1299细胞(人非小细胞肺癌)中的多倍性的诱发,将NCl-H1299接种(4K/孔)到96孔培养板(组织培养级,黑色,平透明底)中并培养整夜以产生细胞-板粘附。将抑制剂以不同浓度添加到含有细胞和培养基(RPMI
1640,10%胎牛血清)的两个(duplicate)孔中并在37 C下培养48小时。该板随后用PBS洗涤并通过用3%福尔马林培养1小时固定粘附细胞。在用PBS洗涤四次后,细胞随后用Hoechst染色并施以荧光(360
i/460e)显微镜高含量分析以测定抑制剂对核大小的作用。多倍体细胞(≥4N)被定义为是具有> 750 μ2的核面积的那些。诱发15%细胞中的多倍性所需的抑制剂浓度(EC15)表示为效力并由对数剂量响应的最小二乘方分析计算。
表1和表2表示实施例1-36作为多种激酶抑制剂的效力。
表1
极光激酶B | 极光激酶A | KDR | |
IC50 (μM) | IC50 (μM) | IC50 (μM) | |
实施例 | |||
1 | 0.01915 | 0.37056 | 0.05485 |
2 | 0.01699 | >12.5 | 0.02742 |
3 | 0.04045 | 2.48866 | 0.04498 |
4 | 0.20737 | 1.46009 | 0.29094 |
5 | 0.19393 | >12.5 | 0.03166 |
6 | 0.02116 | 1.00285 | 0.08606 |
7 | >12.5 | >12.5 | 12.26343 |
8 | 0.02333 | 3.40187 | 0.52524 |
9 | 0.03267 | 0.22113 | 0.07635 |
10 | 0.02361 | 0.29394 | 0.05113 |
11 | 0.13573 | >12.5 | 0.02068 |
12 | 0.0441 | >12.5 | 0.06001 |
13 | 0.08637 | 10.90946 | 0.21693 |
14 | >12.5 | >12.5 | >12.5 |
15 | 0.1419 | >12.5 | 6.69077 |
16 | 0.01089 | >12.5 | 0.04463 |
17 | 1.32219 | >12.5 | 0.0488 |
18 | 0.15617 | >12.5 | 0.02374 |
19 | 0.10761 | 10.8006 | 0.04506 |
20 | 0.02472 | >12.5 | 0.12164 |
21 | 0.05826 | 10.23484 | 0.15372 |
22 | 0.03246 | 0.26656 | 0.01478 |
23 | 0.02488 | 0.24621 | 0.08073 |
24 | 1.02714 | >12.5 | >12.5 |
25 | 0.49336 | >12.5 | 0.03016 |
26 | 0.06229 | >12.5 | 0.32519 |
27 | 0.77345 | >12.5 | 0.0976 |
28 | 0.87108 | >12.5 | 0.03796 |
29 | 0.02498 | 3.33737 | 0.13671 |
30 | 0.01027 | 0.29923 | 0.03221 |
31 | 0.14197 | 5.20768 | 1.78816 |
32 | 1.92377 | >12.5 | 3.61315 |
33 | 0.11988 | >12.5 | 0.5838 |
34 | >12.5 | >12.5 | 0.27774 |
35 | 0.56942 | >12.5 | 0.55788 |
36 | >12.5 | >12.5 | 0.30336 |
表2
KDR细胞 | 多倍体 HCA | |
IC50 (μM) | IC50 (μM) | |
实施例 | ||
1 | 0.08708 | 0.001 |
2 | 0.04604 | 0.006 |
3 | 0.3157 | 0.035 |
6 | 0.18652 | 0.018 |
8 | 0.012 | |
9 | 0.2999 | 0.014 |
10 | 0.20591 | 0.043 |
12 | 0.17589 | 0.055 |
16 | 0.13457 | 0.216 |
19 | 0.21632 | |
20 | <0.001 | |
21 | 0.128 | |
22 | 0.04749 | 0.001 |
23 | 0.35459 | 0.01 |
26 | 0.013 | |
29 | 0.113 | |
30 | 0.12254 | 0.001 |
发现通过上述检测来评估的本发明的化合物具有激酶抑制活性。
本说明书中引用的所有出版物和专利申请经此引用并入本文,就像各单个出版物或专利申请明确且逐一被指明经此引用并入本文。尽管为清楚理解,已通过图解和实例相当详细地描述上述发明,但本领域普通技术人员根据本发明的教导显而易见的是,可以在不背离所附权利要求的精神或范围的情况下对其作出某些变动和修改。
Claims (27)
1.具有式(I)的化合物,
其中
A1是芳基或杂芳基,其任选被一个或多个R1取代,
R1选自R2、烷基、烯基、炔基、卤素、氰基、-OR3、-C(O)R3、-C(O)OR3、-C(O)NR4R5、-OC(O)R3、-NR4R5、-NR4C(O)R5、-NHC(O)NHR4、-NHS(O)2R3、-SR3、-S(O)R3、-SO2R3、-SO2NR4R5、-N3、-NO2、-CF3、-CF2CF3、-OCF3和
-OCF2CF3,其中R1烷基、烯基和炔基取代基任选被一个或多个选自R6、卤素、氰基、-OR3、-C(O)R3、-C(O)OR3、-C(O)NR4R5、-OC(O)R3、-NR4R5和-NR4C(O)R3的取代基取代;
R2为芳基或杂环基,其中R2芳基和杂环基取代基任选被一个或多个独立地选自R7、卤素、氰基、-OR8、-C(O)R8、-C(O)OR8、-C(O)NR9R10、-OC(O)R8、-NR9R10、-NR9C(O)R8、-NHC(O)NHR9、-NHS(O)2R8、-SR8、-S(O)R8、-SO2R8、-SO2NR9R10、-N3、-NO2、-CF3、-CF2CF3、-OCF3和-OCF2CF3的取代基取代;
R3在每次出现时独立地选自氢、烷基、烯基、炔基、芳基、杂环基和环烷基,其中该烷基、烯基、炔基、芳基、杂环基和环烷基任选被一个或多个独立地选自羟基、卤素和氰基的取代基所取代;
R4和R5在每次出现时独立地选自氢、烷基、烯基、炔基、芳基、杂环基和环烷基,其中该烷基、烯基、炔基、杂环基和环烷基任选被一个或多个独立地选自羟基、卤素和氰基的取代基所取代;
R6为芳基或杂环基,其中R6芳基和杂环基取代基任选被一个或多个独立地选自R7、卤素、氰基、-OR8、-C(O)R8、-C(O)OR8、-C(O)NR9R10、-OC(O)R8、-NR9R10、-NR9C(O)R8、-NHC(O)NHR9、-NHS(O)2R8、-SR8、-S(O)R8、-SO2R8、-SO2NR9R10、-N3、-NO2、-CF3、-CF2CF3、-OCF3和-OCF2CF3的取代基取代;
R7为任选被一个或多个选自卤素、氰基、-OR11、-C(O)R11、-C(O)OR11、-C(O)NR12R13、-OC(O)R11、-NR12R13、-NR12C(O)R11、苯基和杂环烷基的取代基所取代的烷基;
R8在每次出现时独立地选自氢、烷基、烯基、炔基、芳基、杂环基和环烷基,其中该烷基、烯基、炔基、芳基、杂环基和环烷基任选被一个或多个独立地选自羟基、卤素和氰基的取代基所取代;
R9和R10在每次出现时独立地选自氢、烷基、烯基、炔基、芳基、杂环基和环烷基,其中该烷基、烯基、炔基、杂环基和环烷基任选被一个或多个独立地选自羟基、卤素和氰基的取代基所取代;
R11在每次出现时独立地选自氢、烷基、烯基、炔基、芳基、杂环基和环烷基,其中该烷基、烯基、炔基、芳基、杂环基和环烷基任选被一个或多个独立地选自羟基、卤素和氰基的取代基所取代;
R12和R13在每次出现时独立地选自氢、烷基、烯基、炔基、芳基、杂环基和环烷基,其中该烷基、烯基、炔基、杂环基和环烷基任选被一个或多个独立地选自羟基、卤素和氰基的取代基所取代;
A2为芳基或杂芳基,其任选被卤素取代;
L为(CH2)mN(R14)C(O)N(R15)(CH2)n,其中m和n独立地为0或1;其中R14和R15独立地选自氢和烷基;
A3为芳基、环烷基、环烯基、杂环基、烷基、烯基、或炔基, 其中(a)A3烷基、烯基和炔基取代基任选被一个或多个选自R17、卤素、氰基、-OR18、-C(O)R18、-C(O)OR18、-C(O)NR19R20、-OC(O)R18、-NR19R20、-NR19C(O)R18、-NHC(O)NHR19、-NHS(O)2R18、-SR18、-S(O)R18、-SO2R18、-SO2NR19R20、-N3、-NO2、-CF3、-CF2CF3、-OCF3和-OCF2CF3的取代基所取代;(b) 其中A3环烷基、环烯基、芳基和杂环基取代基任选被一个或多个R16取代;
R16选自R17、烷基、烯基、炔基、卤素、氰基、-OR21、-C(O)R21、-C(O)OR21、-C(O)NR22R23、-OC(O)R21、-NR22R23、-NR22C(O)R21、-NHC(O)NHR22、-NHS(O)2R21、-SR21、-S(O)R21、-SO2R21、-SO2NR22R23、-N3、-NO2、-CF3、-CF2CF3、-OCF3;其中R16烷基、烯基和炔基取代基任选被一个或多个选自芳基、杂环基、环烷基、卤素、氰基、-OR21、-C(O)R21、-C(O)OR21、-C(O)NR22R23、-NR22R23和-NR22C(O)R21 的取代基取代;
R17为芳基或杂环基,其中R17芳基和杂环基取代基任选被一个或多个独立地选自烷基、烯基、炔基、卤素、氰基、OR24、-C(O)R24、-C(O)OR24、-C(O)NR25R26、-OC(O)R24、-NR25R26、-NR25C(O)R26、-NHC(O)NHR25、-NHS(O)2R24、-SR24、-S(O)R24、-SO2R24、-SO2NR25R26、-N3、-NO2、-CF3、-CF2CF3、-OCF3的取代基取代;
R18在每次出现时独立地选自氢、烷基、烯基、炔基、芳基、杂环基和环烷基,其中该烷基、烯基、炔基、芳基、杂环基和环烷基任选被一个或多个独立地选自羟基、卤素和氰基的取代基所取代;
R19和R20在每次出现时独立地选自氢、烷基、烯基、炔基、芳基、杂环基和环烷基,其中该烷基、烯基、炔基、杂环基和环烷基任选被一个或多个独立地选自羟基、卤素和氰基的取代基所取代;
R21在每次出现时独立地选自氢、烷基、烯基、炔基、芳基、杂环基和环烷基,其中该烷基、烯基、炔基、芳基、杂环基和环烷基任选被一个或多个独立地选自羟基、卤素和氰基的取代基所取代;
R22和R23在每次出现时独立地选自氢、烷基、烯基、炔基、芳基、杂环基和环烷基,其中该烷基、烯基、炔基、杂环基和环烷基任选被一个或多个独立地选自羟基、卤素和氰基的取代基所取代;
R24在每次出现时独立地选自氢、烷基、烯基、炔基、芳基、杂环基和环烷基,其中该烷基、烯基、炔基、芳基、杂环基和环烷基任选被一个或多个独立地选自羟基、卤素和氰基的取代基所取代;
R25和R26在每次出现时独立地选自氢、烷基、烯基、炔基、芳基、杂环基和环烷基,其中该烷基、烯基、炔基、杂环基和环烷基任选被一个或多个独立地选自羟基、卤素和氰基的取代基所取代;
或其可药用盐。
2.根据权利要求1的化合物,其中A1选自苯基、吡啶基、嘧啶基、哒嗪基、吡唑基、吡咯基、咪唑基、吡唑基、三唑基、呋喃基、噻吩基、噁唑基、异噁唑基、噻唑基、异噻唑基、噁二唑基和异噻唑基。
3.根据权利要求1的化合物,其中A1选自吲哚基、异吲哚基、吲唑基、异吲唑基、喹啉基、苯并噁唑基、苯并呋喃基、苯并噻吩基、苯并噻唑基、苯并咪唑基、苯并三唑基、和1,2,3,4-四氢喹啉。
5.根据权利要求4的化合物,
其中R1选自R2、烷基、卤素、氰基、-OR3、-C(O)R3、-C(O)OR3、-
C(O)NR4R5、-OC(O)R3、-NR4R5、-NR4C(O)R5、CF3、CF2CF3、OCF3和OCF2CF3;
R2为苯基;
R3在每次出现时独立地选自氢和烷基;及
R4和R5在每次出现时独立地选自氢和烷基。
6.根据权利要求4的化合物,其中n为0。
8.根据权利要求7的化合物,其中R1为任选被1个或2个选自卤素、氰基、OR3、C(O)R3、C(O)OR3、NR4R5和R6的取代基所取代的烷基;
R3在每次出现时独立地选自氢和烷基;
R4和R5在每次出现时独立地选自氢和烷基;
R6为芳基或杂环基,其中R6芳基和杂环基取代基任选被一个或多个独立地选自R7、卤素、氰基、-OR8、-C(O)R8、-C(O)OR8、-NR9R10、-NR9C(O)R8、-C(O)NR9R10的取代基取代;
R7为任选被一个或多个选自卤素、氰基、-OR11、-C(O)R11、-C(O)OR11、-C(O)NR12R13、-NR12R13和-NR12C(O)R11的取代基所取代的烷基;
R8在每次出现时独立地选自氢和烷基;
R9和R10在每次出现时独立地选自氢和烷基;
R11在每次出现时独立地选自氢和烷基;及
R12和R13在每次出现时独立地选自氢和烷基。
9.根据权利要求8的化合物,其中R1为甲基、乙基、正丙基、异丙基、正丁基、仲丁基或正戊基。
10.根据权利要求8的化合物,其中R1为CH2R27、CH2CH2R27或H2CH2CH2R27;
R27选自卤素、氰基、羟基、-OC1-4-烷基、-C(O)OH、-C(O)OC1-4-烷基、-C(O)NH2、-C(O)NHC1-4-烷基和-C(O)N(C1-4-烷基)2,并且其中C1-4-烷基为未被取代的支链或直链的烷基基团。
11.根据权利要求8的化合物,其中
R1为CH2R28、CH2CH2R28或CH2CH2CH2R28;
R28选自哌啶基、哌嗪基、吗啉代、四氢呋喃基、吡咯烷基、3-氧代-1-哌嗪基、2-氧代-1-吡咯烷基、咪唑基、吡啶基和2-氧代-1-咪唑烷基,其中R24任选被-C1-4-烷基、卤素、氰基、羟基、-OC1-4-烷基、-C(O)OH、-C(O)OC1-4-烷基、-C(O)C1-4-烷基、-C(O)NH2、-C(O)NHC1-4-烷基和-C(O)N(C1-4-烷基)2取代,并且其中C1-4-烷基为未被取代的支链或直链的烷基基团。
12.根据权利要求7的化合物,其中R1为R2,并且其中R2为苯基或杂环烷基。
13.根据权利要求12的化合物,其中R2选自哌啶基、哌嗪基、吗啉代、四氢呋喃基、吡咯烷基、3-氧代-1-哌嗪基、2-氧代-1-吡咯烷基、咪唑基、吡啶基和2-氧代-1-咪唑烷基,其中R2任选被-C1-4-烷基、卤素、氰基、羟基、-OC1-4-烷基、-C(O)OH、-C(O)OC1-4-烷基、-C(O)C1-4-烷基、-C(O)NH2、-C(O)NHC1-4-烷基和-C(O)N(C1-4-烷基)2取代,并且其中C1-4-烷基为未被取代的支链或直链的烷基基团。
14.根据权利要求1的化合物,其中A2为苯基。
15.根据权利要求1的化合物,其中L为-NHC(O)NH-。
16.根据权利要求1的化合物,其中A3选自苯基、萘基、四氢化萘基、环戊基、环戊烯基、环己基、环己烯基、呋喃基、吡啶基和噻吩基。
17.根据权利要求17的化合物,其中A3为任选被1、2或3个R16取代的苯基,其中R16选自-CH3、-CH2CH3、氟、氯、溴、氰基、-NO2、-OCH3、-OCH2CH3、-CF3、-CF2CF3、-OCF3、-OCF2CF3、-NH2、-N(CH3)2、-OH、-OPh、-C(=O)CH3、-C(=O)CH2CH3和-C(=O)OH。
18.根据权利要求1的化合物,其中A3为烷基,并且R10为烷基。
19.根据权利要求1的化合物,具有式(II)
其中A1和A3如权利要求1所限定。
21.根据权利要求19的化合物,其中A3为苯基,其中该苯基任选被-CH3, -CH2CH3、氟、氯、-OCH3、-OCH2CH3、-CF3、-CF2CF3、-OCF3和-OCF2CF3取代。
22.具有式(I)的化合物,
其中
A1是芳基或杂芳基,其任选被一个或多个R1取代,
R1选自R2、烷基、烯基、炔基、卤素、氰基、-OR3、-C(O)R3、-C(O)OR3、-C(O)NR4R5、-OC(O)R3、-NR4R5、-NR4C(O)R5、-NHC(O)NHR4、-NHS(O)2R3、-SR3、-S(O)R3、-SO2R3、-SO2NR4R5、-N3、-NO2、-CF3、-CF2CF3、-OCF3和
-OCF2CF3,其中R1烷基、烯基和炔基取代基任选被一个或多个选自R6、卤素、氰基、-OR3、-C(O)R3、-C(O)OR3、-C(O)NR4R5、-OC(O)R3、-NR4R5和-NR4C(O)R3的取代基取代;
R2为芳基或杂环基,其中R2芳基和杂环基取代基任选被一个或多个独立地选自R7、卤素、氰基、-OR8、-C(O)R8、-C(O)OR8、-C(O)NR9R10、-OC(O)R8、-NR9R10、-NR9C(O)R8、-NHC(O)NHR9、-NHS(O)2R8、-SR8、-S(O)R8、-SO2R8、-SO2NR9R10、-N3、-NO2、-CF3、-CF2CF3、-OCF3和-OCF2CF3的取代基取代;
R3在每次出现时独立地选自氢、烷基、烯基、炔基、芳基、杂环基和环烷基,其中该烷基、烯基、炔基、芳基、杂环基和环烷基任选被一个或多个独立地选自羟基、卤素和氰基的取代基所取代;
R4和R5在每次出现时独立地选自氢、烷基、烯基、炔基、芳基、杂环基和环烷基,其中该烷基、烯基、炔基、杂环基和环烷基任选被一个或多个独立地选自羟基、卤素和氰基的取代基所取代;
R6为芳基或杂环基,其中R6芳基和杂环基取代基任选被一个或多个独立地选自R7、卤素、氰基、-OR8、-C(O)R8、-C(O)OR8、-OC(O)R8、-NR9R10、-NR9C(O)R8、-NHC(O)NHR9、-C(O)NR9R10、-SR8、-S(O)R8、-SO2R8、-OC(O)OR8、-SO2NR9R10、-N3、-NO2、-CF3、-CF2CF3、-OCF3和-OCF2CF3的取代基取代;
R7为任选被一个或多个选自卤素、氰基、-OR11、-C(O)R11、-C(O)OR11、-C(O)NR12R13、-OC(O)R11、-NR12R13、-NR12C(O)R11、苯基和杂环烷基的取代基所取代的烷基;
R8在每次出现时独立地选自氢、烷基、烯基、炔基、芳基、杂环基和环烷基,其中该烷基、烯基、炔基、芳基、杂环基和环烷基任选被一个或多个独立地选自羟基、卤素和氰基的取代基所取代;
R9和R10在每次出现时独立地选自氢、烷基、烯基、炔基、芳基、杂环基和环烷基,其中该烷基、烯基、炔基、杂环基和环烷基任选被一个或多个独立地选自羟基、卤素和氰基的取代基所取代;
R11在每次出现时独立地选自氢、烷基、烯基、炔基、芳基、杂环基和环烷基,其中该烷基、烯基、炔基、芳基、杂环基和环烷基任选被一个或多个独立地选自羟基、卤素和氰基的取代基所取代;
R12和R13在每次出现时独立地选自氢、烷基、烯基、炔基、芳基、杂环基和环烷基,其中该烷基、烯基、炔基、杂环基和环烷基任选被一个或多个独立地选自羟基、卤素和氰基的取代基所取代;
L为-(CH2)mN(R14)C(O)-、-C(O)N(R15)(CH2)n-或-(CH2)mN(R14)C(O)N(R15)(CH2)n-,其中m和n独立地为0或1;其中R14和R15独立地选自氢和烷基;
A3为芳基、环烷基、环烯基、杂环基、烷基、烯基或炔基,其中(a)A3烷基、烯基和炔基取代基任选被一个或多个选自R17、卤素、氰基、-OR18、-C(O)R18、-C(O)OR18、-OC(O)R18、-NR19R20、-NR19C(O)R18、-NHC(O)NHR20、-C(O)NR19R20、-SR18、-S(O)R18、-SO2R18、-OC(O)OR18、-SO2NR19R20、-N3、-NO2、-CF3、-CF2CF3、-OCF3和-OCF2CF3的取代基所取代;(b) 其中A3环烷基、环烯基、芳基和杂环基取代基任选被一个或多个R16取代;
R16选自R17、烷基、烯基、炔基、卤素、氰基、-OR21、-C(O)R21、-C(O)OR21、-OC(O)R21、-NR22R23、-NR22C(O)R21、-NHC(O)NHR22、-C(O)NR22R23、-SR21、-S(O)R21、-SO2R21、-OC(O)OR21、-SO2NR22R23、-N3、-NO2、-CF3、-CF2CF3、-OCF3;其中R16烷基、烯基和炔基取代基任选被一个或多个选自芳基、杂环基、环烷基、卤素、氰基、-OR21、-C(O)R21、-C(O)OR21、-C(O)NR22R23、-OC(O)R21、-NR22R23和-NR22C(O)R21 的取代基取代;
R17为芳基或杂环基,其中R17芳基和杂环基取代基任选被一个或多个独立地选自烷基、烯基、炔基、卤素、氰基、-OR21、-C(O)R21、-C(O)OR21、-OC(O)R21、-NR22R23、-NR22C(O)R21、-NHC(O)NHR22、-C(O)NR22R23、-SR21、-S(O)R21、-SO2R21、-OC(O)OR21、-SO2NR22R23、-N3、-NO2、-CF3、-CF2CF3、-OCF3的取代基取代;
R18在每次出现时独立地选自氢、烷基、烯基、炔基、芳基、杂环基和环烷基,其中该烷基、烯基、炔基、芳基、杂环基和环烷基任选被一个或多个独立地选自羟基、卤素和氰基的取代基所取代;
R19和R20在每次出现时独立地选自氢、烷基、烯基、炔基、芳基、杂环基和环烷基,其中该烷基、烯基、炔基、杂环基和环烷基任选被一个或多个独立地选自羟基、卤素和氰基的取代基所取代;
R21在每次出现时独立地选自氢、烷基、烯基、炔基、芳基、杂环基和环烷基,其中该烷基、烯基、炔基、芳基、杂环基和环烷基任选被一个或多个独立地选自羟基、卤素和氰基的取代基所取代;
R22和R23在每次出现时独立地选自氢、烷基、烯基、炔基、芳基、杂环基和环烷基,其中该烷基、烯基、炔基、杂环基和环烷基任选被一个或多个独立地选自羟基、卤素和氰基的取代基所取代;
或其可药用盐。
23.药物组合物,包含权利要求1的化合物或可药用盐以及可药用赋形剂。
24.治疗哺乳动物癌症的方法,包括给予其治疗可接受量的权利要求1的化合物或可药用盐。
25.减小哺乳动物中肿瘤体积的方法,包括给予其治疗可接受量的权利要求1的化合物或可药用盐。
26.权利要求23的方法,其中所述癌症为膀胱癌、乳腺癌、宫颈癌、结肠癌、子宫内膜癌、食道癌、肺癌、卵巢癌、胰腺癌、前列腺癌、直肠癌、皮肤癌、胃癌或甲状腺癌。
27.治疗哺乳动物癌症的方法,包括给予其治疗可接受量的权利要求1的化合物或可药用盐并结合放射治疗。
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CN108689999A (zh) * | 2018-06-04 | 2018-10-23 | 西安交通大学 | 一种吡唑类化合物及其应用 |
WO2020087565A1 (zh) * | 2018-11-02 | 2020-05-07 | 安徽中科拓苒药物科学研究有限公司 | 吲唑类激酶抑制剂及其用途 |
CN111138426A (zh) * | 2018-11-02 | 2020-05-12 | 安徽中科拓苒药物科学研究有限公司 | 吲唑类激酶抑制剂及其用途 |
CN111138426B (zh) * | 2018-11-02 | 2023-03-10 | 安徽中科拓苒药物科学研究有限公司 | 吲唑类激酶抑制剂及其用途 |
CN113350347A (zh) * | 2020-03-05 | 2021-09-07 | 安徽中科拓苒药物科学研究有限公司 | 吲唑类化合物的新用途 |
WO2021174581A1 (zh) * | 2020-03-05 | 2021-09-10 | 安徽中科拓苒药物科学研究有限公司 | 吲唑类化合物的新用途 |
CN113350347B (zh) * | 2020-03-05 | 2023-07-04 | 安徽中科拓苒药物科学研究有限公司 | 吲唑类化合物的用途 |
Also Published As
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JP2013526542A (ja) | 2013-06-24 |
US20110281868A1 (en) | 2011-11-17 |
CA2799154A1 (en) | 2011-11-17 |
MX2012013197A (es) | 2013-04-03 |
EP2569301A1 (en) | 2013-03-20 |
US8293738B2 (en) | 2012-10-23 |
WO2011143430A1 (en) | 2011-11-17 |
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