CN113966331B - 含脲结构的三芳环化合物及其应用 - Google Patents
含脲结构的三芳环化合物及其应用 Download PDFInfo
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- CN113966331B CN113966331B CN202180002962.9A CN202180002962A CN113966331B CN 113966331 B CN113966331 B CN 113966331B CN 202180002962 A CN202180002962 A CN 202180002962A CN 113966331 B CN113966331 B CN 113966331B
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- triaryl
- urea structure
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Classifications
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/415—1,2-Diazoles
- A61K31/4155—1,2-Diazoles non condensed and containing further heterocyclic rings
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- A—HUMAN NECESSITIES
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/42—Oxazoles
- A61K31/422—Oxazoles not condensed and containing further heterocyclic rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- C07—ORGANIC CHEMISTRY
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- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
Abstract
本发明提供了一种具有式(I)所示结构的含脲结构的三芳环化合物或其药学上可接受的盐或其立体异构体或其前药分子或其代谢产物或其溶剂化物,该类化合物可以有效地抑制激酶,尤其是FLT3和RET激酶,进而调节下游的多条通路的激活,可以用于制备防治RET激酶、FLT3激酶和/或Kit激酶相关的多种疾病的药物,比如白血病、肿瘤。
Description
技术领域
本发明涉及药物化学领域,具体涉及一种含脲结构的三芳环化合物及其应用。
背景技术
受体酪氨酸激酶RET(Rearranged during transfection,,转染期间重排)在肾脏和神经系统的发育中起着重要作用。当异常激活时,它可以作为多种恶性肿瘤的致癌基因。其中,保留激酶结构域的RET融合是甲状腺乳头状癌(PTC)、非小细胞肺癌(NSCLC)等癌症的驱动因素;而激活RET突变与多发性内分泌肿瘤2型(MEN2)和散发型甲状腺髓样癌(MTC)的不同表型相关。因此,RET是一个对RET改变引起癌变的患者有着吸引力的治疗靶点。
最早具有RET抑制剂活性的多激酶抑制剂(MKIs),如卡博替尼和凡德他尼,已在临床中探索用于RET驱动的癌症。由于靶向性不高,经常产生非靶标副作用,如高血压和腹泻,限制了患者可耐受的剂量。最近,由Loxo Oncology公司研发的高选择性RET激酶抑制剂Selpercatinib,于2020年5月获FDA批准上市;用于治疗晚期RET融合阳性NSCLC、RET突变型/融合阳性MTC。另外一个由Blueprint Medicines公司开发的高选择性RET激酶抑制剂Pralsetinib,于2020年9月获FDA批准上市;其体外研究表明Pralsetinib对RET的选择特异性明显优于其他多靶点抑制剂,且具有较好的耐受性,对VEGFR-2仅有轻微的抑制作用,用于治疗RET融合阳性NSCLC的成年患者。
最近,RET G810R、S和C溶剂前沿突变作为获得性耐药机制已在使用选择性RET抑制剂进展的RET异常患者中得到证实(Solomon,Benjamin J.et al.J Thorac Oncol.2020,15(4),541-549)。因此开发第二代RET抑制剂用来抑制这些突变,具有重大研究意义。
发明内容
针对上述问题,本发明提供了一类新的含脲结构的三芳环化合物,该类化合物对RET野生及突变型激酶具有很好的抑制活性。
具体技术方案如下:
具有式(I)所示结构的含脲结构的三芳环化合物或其药学上可接受的盐或其立体异构体或其前药分子或其代谢产物或其溶剂化物:
其中,
X1、X2、X3、X4和X5共同组成杂芳基,X1、X2、X3、X4和X5分别独立地选自:N、NR2、C、CR3、或C=O,并且,X1、X2、X3、X4和X5中有两个或者三个分别独立地选自:N、或NR2,当X1、X2、X3、X4和X5中有两个或者三个均为N时,不形成N=N结构;
A1、A2、B1、B2、D1、D2、E1和E2分别独立地选自:N、或CR;
Y1、Y2和Y3分别独立地选自:N、或CR;
Z选自:O、S、或NR2;
R1选自:或者R1与D1一起形成如下结构:其中,m和n分别独立地选自:0~6之间的整数,Z1选自:O、S、或NR2;
各R2分别独立地选自:H、C1~C8烷基、C3~C6环烷基、3~6元杂环烷基、C1~C8酰基、C1~C8磺酰基、C6~C18芳基、C6~C18芳基取代的C1~C6烷基、或5~18元杂芳基;当R2不为氢时,所述R2独立任选地被1个或多个R7取代;
各R3分别独立地选自:H、卤素、C1~C18烷基、C3~C18环烷基、3~18元杂环烷基、C1~C18烷氧基、C1~C18烷胺基、氨基、羟基、氰基、硝基、酯基、酰胺基、磺酰基、磺酰氨基、C6~C18芳基、C6~C18芳基取代的C1~C18烷基、5~18元杂芳基、或-SR8;当R3选自C1~C18烷基、C3~C18环烷基、3~18元杂环烷基、C1~C18烷氧基、C1~C18烷胺基、C6~C18芳基、C6~C18芳基取代的C1~C18烷基或5~18元杂芳基时,所述R3独立任选地被1个或多个R7取代;
R4选自:H、C1~C18烷基、C3~C18环烷基、3~18元杂环烷基、C1~C18烷氧基、C1~C18烷胺基、氨基、羟基、氰基、硝基、酯基、C1~C8酰基、酰胺基、磺酰基、磺酰氨基、C6~C18芳基、C6~C18芳基取代的C1~C18烷基、或5~18元杂芳基;当R4选自C1~C18烷基、C3~C18环烷基、3~18元杂环烷基、C1~C18烷氧基、C1~C18烷胺基、C6~C18芳基、C6~C18芳基取代的C1~C18烷基或5~18元杂芳基时,所述R4独立任选地被1个或多个R7取代;
各R5,R6分别独立地选自:H、C1~C8烷基,羟基取代的C1~C8烷基,C1~C8烷氧基取代的C1~C8烷基、C3~C8环烷基、3~18元杂环烷基、C1~C8酰基、烯基酰基、C1~C8磺酰基、5~18元杂芳基,或者R5、R6与和其相连的N原子一起形成1个或多个R7取代或者未取代的3~10元杂环基,或者R5、R6与和其相连的N原子一起形成1个或多个R7取代或者未取代的5~10杂芳基;
各R7分别独立地选自:H、羟基、氨基、氰基、硝基、卤素、C1~C6烷氧基、C1~C6烷基;
R8选自:H、C1~C6烷基、3~8元杂环烷基取代的C1~C6烷基;
各R分别独立地选自:H、卤素、C1~C18烷基、C3~C18环烷基、3~18元杂环烷基、C1~C18烷氧基、C1~C18烷胺基、氨基、羟基、氰基、硝基、酯基、酰胺基、磺酰基、磺酰氨基、C6~C18芳基、C6~C18芳基取代的C1~C18烷基、或5~18元杂芳基;当R选自C1~C18烷基、C3~C18环烷基、3~18元杂环烷基、C1~C18烷氧基、C1~C18烷胺基、C6~C18芳基、C6~C18芳基取代的C1~C18烷基或5~18元杂芳基时,所述R独立任选地被1个或多个R7取代。
具有式(I’)所示结构的含脲结构的三芳环化合物或其药学上可接受的盐或其立体异构体或其前药分子或其代谢产物或其溶剂化物:
其中,
Q选自:
X1、X2、X3、X4和X5共同组成杂芳基,X1、X2、X3、X4和X5分别独立地选自:N、NR2、C、CR3、或C=O,并且,X1、X2、X3、X4和X5中有两个或者三个分别独立地选自:N、或NR2,当X1、X2、X3、X4和X5中有两个或者三个均为N时,不形成N=N结构;
A1、A2、B1、B2、D1、D2、E1和E2分别独立地选自:N、或CR;
Y1、Y2和Y3分别独立地选自:N、或CR;
Q1、Q2、Q3、Q4、Q5和Q6分别独立地选自:N、或CR;
Z选自:O、S、或NR2;
R1选自:或者R1与D1一起形成如下结构:其中,m和n分别独立地选自:0~6之间的整数,Z1选自:O、S、或NR2;
各R2分别独立地选自:H、C1~C8烷基、C3~C6环烷基、3~6元杂环烷基、C1~C8酰基、C1~C8磺酰基、C6~C18芳基、C6~C18芳基取代的C1~C6烷基、或5~18元杂芳基、C1~C8烷氧羰基、C3~C8环烷氧羰基、C1~C8烷胺羰基、C3~C8环烷胺羰基;当R2不为氢时,所述R2独立任选地被1个或多个R7取代;
各R3分别独立地选自:H、卤素、C1~C18烷基、C3~C18环烷基、3~18元杂环烷基、C1~C18烷氧基、C1~C18烷胺基、氨基、羟基、氰基、硝基、酯基、酰胺基、磺酰基、磺酰氨基、C6~C18芳基、C6~C18芳基取代的C1~C18烷基、5~18元杂芳基、或-SR8;当R3选自C1~C18烷基、C3~C18环烷基、3~18元杂环烷基、C1~C18烷氧基、C1~C18烷胺基、C6~C18芳基、C6~C18芳基取代的C1~C18烷基或5~18元杂芳基时,所述R3独立任选地被1个或多个R7取代;
R4选自:H、C1~C18烷基、C3~C18环烷基、3~18元杂环烷基、C1~C18烷氧基、C1~C18烷胺基、氨基、羟基、氰基、硝基、酯基、C1~C8酰基、酰胺基、磺酰基、磺酰氨基、C6~C18芳基、C6~C18芳基取代的C1~C18烷基、或5~18元杂芳基;当R4选自C1~C18烷基、C3~C18环烷基、3~18元杂环烷基、C1~C18烷氧基、C1~C18烷胺基、C6~C18芳基、C6~C18芳基取代的C1~C18烷基或5~18元杂芳基时,所述R4独立任选地被1个或多个R7取代;
各R5,R6分别独立地选自:H、C1~C8烷基,羟基取代的C1~C8烷基,C1~C8烷氧基取代的C1~C8烷基、C3~C8环烷基、3~18元杂环烷基、C1~C8酰基、烯基酰基、C1~C8磺酰基、5~18元杂芳基,或者R5、R6与和其相连的N原子一起形成1个或多个R7取代或者未取代的3~10元杂环烷基,或者R5、R6与和其相连的N原子一起形成1个或多个R7取代或者未取代的5~10杂芳基;
各R7分别独立地选自:H、羟基、氨基、氰基、硝基、卤素、C1~C6烷氧基、C1~C6烷基、C1~C6烷基胺基、C6~C18芳基;
R8选自:H、C1~C6烷基、3~8元杂环烷基取代的C1~C6烷基;
各R分别独立地选自:H、卤素、C1~C18烷基、C3~C18环烷基、3~18元杂环烷基、C1~C18烷氧基、C1~C18烷胺基、氨基、羟基、氰基、硝基、酯基、酰胺基、磺酰基、磺酰氨基、C6~C18芳基、C6~C18芳基取代的C1~C18烷基、或5~18元杂芳基;当R选自C1~C18烷基、C3~C18环烷基、3~18元杂环烷基、C1~C18烷氧基、C1~C18烷胺基、C6~C18芳基、C6~C18芳基取代的C1~C18烷基或5~18元杂芳基时,所述R独立任选地被1个或多个R7取代。
在其中一些实施例中,所述含脲结构的三芳环化合物具有式(II)、(III)、(IV)或(V)所示结构:
在其中一些实施例中,所述含脲结构的三芳环化合物具有式(VI)、(VII)、(VIII)、(IX)、(X)或(XI)所示结构:
其中,q选自0、1、2、3、4、5。
在其中一些实施例中,Y1为N,Y3为CR,Z为O。
在其中一些实施例中,Y2为CR。
在其中一些实施例中,Y1为N,Y2为CR9,Y3为CR10,Z为O;其中,R9和R10分别独立地选自:H、或C1~C10烷基。
在其中一些实施例中,Y1为N,Y2为CH,Y3为CR10,Z为O;其中,R10选自:H、或C1~C6烷基。
在其中一些实施例中,A1、A2、B1、B2、D1、D2、E1和E2均为CR11;其中,各R11分别独立地选自:H、C1~C10烷基、硝基、C1~C10烷氧基或卤素。
在其中一些实施例中,A1、B1、D1和E1中的一个为CR12,另外三个为CH,R12选自:H、氟、氯、溴、C1~C3烷基、硝基、C1~C3烷氧基。
在其中一些实施例中,A2、B2、D2和E2中的一个为CR13,另外三个为CH,R13选自:H、氟、氯、溴、C1~C3烷基、硝基、C1~C3烷氧基。
在其中一些实施例中,B2或者D2为CR13,R13选自:H、氟、氯、溴、C1~C3烷基、C1~C3烷氧基。
在其中一些实施例中,m为0、1、2或3,n为0、1、2或3。
在其中一些实施例中,R4选自:H、C1~C6烷基。
在其中一些实施例中,R5,R6分别独立地选自:H、C1~C6烷基,羟基取代的C1~C6烷基,C1~C6烷氧基取代的C1~C6烷基、C3~C6环烷基、3~8元杂环烷基、C1~C3酰基、C1~C3磺酰基、5~10元杂芳基,或者R5、R6与和其相连的N原子一起形成1个或多个R7取代或者未取代的5~6元杂环基,或者R5、R6与和其相连的N原子一起形成1个或多个R7取代或者未取代的5~6元杂芳基。
在其中一些实施例中,R5,R6分别独立地选自:C1~C3烷基,或者R5、R6与和其相连的N原子一起形成5~6元杂环基。
在其中一些实施例中,R1选自: 或者R1与D1一起形成如下结构:
在其中一些实施例中,各R2分别独立地选自:H、C1~C6烷基、C1~C6烷氧羰基。
在其中一些实施例中,各R3分别独立地选自:H、C1~C6烷基、或-SR8;R8选自:H、C1~C3烷基、或5~6元杂环烷基取代的C1~C3烷基。
本发明还提供了上述化合物的应用。
具体技术方案如下:
上述的含脲结构的三芳环化合物或其药学上可接受的盐或其立体异构体或其前药分子或其代谢产物或其溶剂化物在制备激酶抑制剂中的应用。
在其中一些实施例中,所述激酶为:FLT3激酶,CSF1R激酶,DDR1激酶,KIT激酶,PDGFRA激酶,PDGRFB激酶,PIP5K2B激酶,RET激酶。
在其中一些实施例中,所述激酶为RET激酶。
在其中一些实施例中,所述RET激酶为:野生型RET激酶、突变型RET激酶。
上述的含脲结构的三芳环化合物或其药学上可接受的盐或其立体异构体或其前药分子或其代谢产物或其溶剂化物在制备预防和/或治疗RET激酶、FLT3激酶和/或KIT激酶相关疾病的药物中的应用。
在其中一些实施例中,所述RET激酶、FLT3激酶和/或KIT激酶相关疾病为肿瘤。
在其中一些实施例中,所述肿瘤为:白血病、非小细胞肺癌、小细胞肺癌、肺腺癌、肺鳞癌、胰腺癌、乳腺癌、前列腺癌、肝癌、皮肤癌、上皮细胞癌、胃肠间质瘤、组织细胞性淋巴癌、鼻咽癌。
基于上述技术方案,本发明具有以下有益效果:
本发明提供的含脲结构的三芳环化合物及其药学上可接受的盐、溶剂化物、异构体、酸、酯、代谢物或前药,可以有效地抑制激酶,尤其是RET激酶,包括野生和突变的RET激酶以及其它一些激酶如FLT3激酶、Kit激酶等,进而可以调节下游的多条通路的激活,可以用于制备防治RET激酶、FLT3激酶和/或Kit激酶相关的多种疾病的药物,比如白血病、肿瘤。
具体实施方式
本发明所述化合物中,当任何变量(例如R1、R2等)在任何组分中出现超过一次,则其每次出现的定义独立于其它每次出现的定义。同样,允许取代基及变量的组合,只要这种组合使化合物稳定。自取代基划入环系统的线表示所指的键可连接到任何能取代的环原子上。如果环系统为多环,其意味着这种键仅连接到邻近环的任何适当的碳原子上。要理解本领域普通技术人员可选择本发明化合物的取代基及取代型式而提供化学上稳定的并可通过本领域技术和下列提出的方法自可容易获得的原料容易合成的化合物。如果取代基自身被超过一个基团取代,应理解这些基团可在相同碳原子上或不同碳原子上,只要使结构稳定。短语“任选被一个或多个取代基取代”被认为与短语“任选被至少一个取代基取代”相当且在此情况下优选的实施方案将具有0-3个取代基。
本文所用术语“烷基”意指包括具有特定碳原子数目的支链的和直链的饱和脂肪烃基。例如,“C1-C6烷基”中“C1-C6”的定义包括以直链或支链排列的具有1、2、3、4、5或6个碳原子的基团。例如,“C1-C6烷基”具体包括甲基、乙基、正丙基、异丙基、正丁基、叔丁基、异丁基、戊基、己基。术语“环烷基”指具有特定碳原子数目的单环饱和脂肪烃基。例如“环烷基”包括环丙基、环丁基、环戊基或环己基等。术语“烷氧基”指具有-O-烷基结构的基团,如-OCH3、-OCH2CH3、-OCH2CH2CH3、-O-CH2CH(CH3)2、-OCH2CH2CH2CH3、-O-CH(CH3)2等。术语“杂环烷基”为饱和或部分不饱和的单环或多环环状取代基,其中一个或多个环原子选自N、O或S(O)m(其中m是0-2的整数)的杂原子,其余环原子为碳,例如:吗啉基、哌啶基、四氢吡咯基、吡咯烷基、二氢咪唑基、二氢异噁唑基、二氢异噻唑基、二氢噁二唑基、二氢噁唑基、二氢吡嗪基、二氢吡唑基、二氢吡啶基、二氢嘧啶基、二氢吡咯基、二氢四唑基、二氢噻二唑基、二氢噻唑基、二氢噻吩基、二氢三唑基、二氢氮杂环丁烷基、四氢呋喃基、四氢噻吩基等,及其N-氧化物,杂环取代基的连接可通过碳原子或通过杂原子实现。术语“杂芳基”指含有1个或多个选自O、N或S的杂原子的芳香环,本发明范围内的杂芳基包括但不限于:喹啉基、吡唑基、吡咯基、噻吩基、呋喃基、吡啶基、嘧啶基、吡嗪基、三氮唑基、咪唑基、噁唑基、异噁唑基、哒嗪基;“杂芳基”也理解为包括任何含有氮的杂芳基的N-氧化物衍生物。杂环取代基的连接可通过碳原子或通过杂原子实现。
正如本领域技术人员所理解的,本文中所用“卤素”(“halo”)或“卤”意指氯、氟、溴和碘。
除非另有定义,烷基、环烷基、芳基、杂芳基和杂环烷基取代基可为未被取代的或取代的。例如,C1-C6烷基可被一个、两个或三个选自OH、卤素、烷氧基、二烷基氨基或杂环基例如吗啉基、哌啶基等的取代基取代。
本发明包括式I-XI化合物的游离形式,也包括其药学上可接受的盐及立体异构体。本文中一些特定的示例性化合物为胺类化合物的质子化了的盐。术语“游离形式”指以非盐形式的胺类化合物。包括在内的药学上可接受盐不仅包括本文所述特定化合物的示例性盐,也包括所有式I-XI化合物游离形式的典型的药学上可接受的盐。可使用本领域已知技术分离所述化合物特定盐的游离形式。例如,可通过用适当的碱稀水溶液例如NaOH稀水溶液、碳酸钾稀水溶液、稀氨水及碳酸氢钠稀水溶液处理该盐使游离形式再生。游离形式在某些物理性质例如在极性溶剂中溶解度上与其各自盐形式多少有些区别,但是为发明的目的这种酸盐及碱盐在其它药学方面与其各自游离形式相当。
可通过常规化学方法自含有碱性部分或酸性部分的本发明化合物合成本发明的药学上可接受的盐。通常,通过离子交换色谱或通过游离碱和化学计算量或过量的所需盐形式的无机或有机酸在适当溶剂或多种溶剂的组合中反应制备碱性化合物的盐。类似的,通过和适当的无机或有机碱反应形成酸性化合物的盐。
因此,本发明化合物的药学上可接受的盐包括通过碱性本发明化合物和无机或有机酸反应形成的本发明化合物的常规无毒盐。例如,常规的无毒盐包括得自无机酸例如盐酸、氢溴酸、硫酸、氨基磺酸、磷酸、硝酸等的盐,也包括自有机酸例如乙酸、丙酸、琥珀酸、乙醇酸、硬脂酸、乳酸、苹果酸、酒石酸、柠檬酸、抗坏血酸、扑酸、马来酸、羟基马来酸、苯乙酸、谷氨酸、苯甲酸、水杨酸、对氨基苯磺酸、2一乙酰氧基一苯甲酸、富马酸、甲苯磺酸、甲磺酸、乙烷二磺酸、草酸、羟乙基磺酸、三氟乙酸等制备的盐。
如果本发明化合物为酸性的,则适当的“药学上可接受的盐”指通过药学上可接受的无毒碱包括无机碱及有机碱制备的盐.得自无机碱的盐包括铝盐、铵盐、钙盐、铜盐、铁盐、亚铁盐、锂盐、镁盐、锰盐、亚锰盐、钾盐、钠盐、锌盐等。特别优选铵盐、钙盐、镁盐、钾盐和钠盐。得自药学上可接受的有机无毒碱的盐,所述碱包括伯胺、仲胺和叔胺的盐,取代的胺包括天然存在的取代胺、环状胺及碱性离子交换树脂例如精氨酸、甜菜碱、咖啡因、胆碱、N,N′-二苄基乙二胺、二乙胺、2一二乙基氨基乙醇、2一二甲基氨基乙醇、氨基乙醇、乙醇胺、乙二胺、N一乙基吗啉、N一乙基哌啶、葡萄糖胺、氨基葡萄糖、组氨酸、羟钴胺、异丙基胺、赖氨酸、甲基葡萄糖胺、吗啉、哌嗪,哌啶、呱咤、多胺树脂、普鲁卡因、嘌呤、可可碱、三乙胺、三甲胺、三丙胺、氨基丁三醇等。
Berg等,“Pharmaceutical Salts,”J.Pharm.Sci.’1977:66:1-19更详细描述了上文所述药学上可接受的盐及其它典型的药学上可接受的盐的制备。
由于在生理条件下化合物中脱质子化的酸性部分例如竣基可为阴离子的,而这种带有的电荷然后可被内部带有阳离子的质子化了的或烷基化的碱性部分例如四价氮原子平衡抵消,所以应注意本发明化合物是潜在的内盐或两性离子。
在一个实施方案中,本发明提供了一种利用具有式I-XI的化合物及其药学可接受的盐治疗人或其它哺乳动物肿瘤等过渡增殖性疾病或症状。
在一个实施方案中,本发明的化合物及其药学可接受的盐可以用于治疗或控制非小细胞肺癌、小细胞肺癌、肺腺癌、肺鳞癌、胰腺癌、乳腺癌、前列腺癌、肝癌、皮肤癌、上皮细胞癌、胃肠间质瘤、白血病、组织细胞性淋巴癌、鼻咽癌等过渡增殖性疾病。
药物代谢物及前药
本发明所涉及的化合物及其药学可接受的盐的代谢产物,以及可以在体内转变为本发明所涉及的化合物及其药学可接受的盐的结构的前药,也包含在本发明的权利要求中。
联合用药
式I-XI化合物可以与已知的治疗或改进相似病状的其它药物联用。联合给药时,原来药物的给药方式&剂量保持不变,而同时或随后服用式I-XI化合物。当式I-XI化合物与其它一种或几种药物同时服用时,优选使用同时含有一种或几种已知药物和式I-VIII化合物的药用组合物。药物联用也包括在重叠的时间段服用式I-XI化合物与其它一种或几种已知药物。当式I-XI化合物与其它一种或几种药物进行药物联用时,式I-XI化合物或已知药物的剂量可能比它们单独用药时的剂量较低。
可以与式I-XI化合物进行药物联用的药物或活性成分包括但不局限为:
雌激素受体调节剂、雄激素受体调节剂、视网膜样受体调节剂、细胞毒素/细胞抑制剂、抗增殖剂、蛋白转移酶抑制剂、HMG-CoA还原酶抑制剂、HIV蛋白激酶抑制剂、逆转录酶抑制剂、血管生成抑制剂、细胞增殖及生存信号抑制剂、干扰细胞周期关卡的药物和细胞凋亡诱导剂,细胞毒类药物、酪氨酸蛋白抑制剂、EGFR抑制剂、VEGFR抑制剂、丝氨酸/苏氨酸蛋白抑制剂、Bcr-Abl抑制剂,c-Kit抑制剂,Met抑制剂,Raf抑制剂,MEK抑制剂,MMP抑制剂,拓扑异构酶抑制剂、组氨酸去乙酰化酶抑制剂、蛋白酶体抑制剂、CDK抑制剂,Bcl-2家族蛋白抑制剂,MDM2家族蛋白抑制剂、IAP家族蛋白抑制剂、STAT家族蛋白抑制剂、PI3K抑制剂、AKT抑制剂、整联蛋白阻滞剂、干扰素-α、白介素-12、COX-2抑制剂、p53、p53激活剂、VEGF抗体、EGF抗体等。
在一个实施方案中,可以与式I-XI化合物进行药物联用的药物或活性成分包括但不局限为:阿地白介素、阿仑膦酸、干扰素、阿曲诺英、别嘌醇、别嘌醇钠、帕洛诺司琼盐酸盐、六甲蜜胺、氨基格鲁米特、氨磷汀、氨柔比星、安丫啶、阿纳托唑、多拉司琼、aranesp、arglabin、三氧化二砷、阿诺新、5-氮胞苷、硫唑嘌呤、卡介苗或tice卡介苗、贝他定、醋酸倍他米松、倍他米松磷酸钠制剂、贝沙罗汀、硫酸博来霉素、溴尿甘、bortezomib、白消安、降钙素、阿来佐单抗注射剂、卡培他滨、卡铂、康士得、cefesone、西莫白介素、柔红霉素、苯丁酸氮芥、顺铂、克拉屈滨、克拉屈滨、氯屈磷酸、环磷酰胺、阿糖胞昔、达卡巴嗪、放线菌素D、柔红霉素脂质体、地塞米松、磷酸地塞米松、戊酸雌二醇、地尼白介素2、狄波美、地洛瑞林、地拉佐生、己烯雌酚、大扶康、多西他奇、去氧氟尿苷、阿霉素、屈大麻酚、钦-166-壳聚糖复合物、eligard、拉布立酶、盐酸表柔比星、阿瑞吡坦、表阿霉素、阿法依伯汀、红细胞生成素、依铂、左旋咪唑片、雌二醇制剂、17-β-雌二醇、雌莫司汀磷酸钠、炔雌醇、氨磷汀、羟磷酸、凡毕复、依托泊甙、法倔唑、他莫昔芬制剂、非格司亭、非那司提、非雷司替、氟尿苷、氟康唑、氟达拉滨、5-氟脱氧尿嘧啶核苷一磷酸盐、5-氟尿嘧啶、氟甲睾酮、氟他胺、福麦斯坦、1-β-D-阿糖呋喃糖胞噻啶-5’-硬脂酰磷酸酯、福莫司汀、氟维司群、丙种球蛋白、吉西他滨、吉妥单抗、甲磺酸伊马替尼、卡氮芥糯米纸胶囊剂、戈舍瑞林、盐酸格拉尼西隆、组氨瑞林、和美新、氢化可的松、赤型-羟基壬基腺嘌呤、羟基脲、替坦异贝莫单抗、伊达比星、异环磷酰胺、干扰素α、干扰素-α2、干扰素α-2A、干扰素α-2B、干扰素α-n1、干扰素α-n3、干扰素β、干扰素γ-1a、白细胞介素-2、内含子A、易瑞沙、依立替康、凯特瑞、硫酸香菇多糖、来曲唑、甲酰四氢叶酸、亮丙瑞林、亮丙瑞林醋酸盐、左旋四咪唑、左旋亚叶酸钙盐、左甲状腺素钠、左甲状腺素钠制剂、洛莫司汀、氯尼达明、屈大麻酚、氮芥、甲钴胺、甲羟孕酮醋酸酯、醋酸甲地孕酮、美法仑、酯化雌激素、6-琉基嘌呤、美司钠、氨甲蝶呤、氨基乙酰丙酸甲酯、米替福新、美满霉素、丝裂霉素C、米托坦、米托葱醌、曲洛司坦、柠檬酸阿霉素脂质体、奈达铂、聚乙二醇化非格司亭、奥普瑞白介素、neupogen、尼鲁米特、三苯氧胺、NSC-631570、重组人白细胞介素1-β、奥曲肽、盐酸奥丹西隆、去氢氢化可的松口服溶液剂、奥沙利铂、紫杉醇、泼尼松磷酸钠制剂、培门冬酶、派罗欣、喷司他丁、溶链菌制剂、盐酸匹鲁卡品、毗柔比星、普卡霉素、卟吩姆钠、泼尼莫司汀、司替泼尼松龙、泼尼松、倍美力、丙卡巴脐、重组人类红细胞生成素、雷替曲塞、利比、依替膦酸铼-186、美罗华、力度伸-A、罗莫肽、盐酸毛果芸香碱片剂、奥曲肽、沙莫司亭、司莫司汀、西佐喃、索布佐生、唬钠甲强龙、帕福斯酸、干细胞治疗、链佐星、氯化锶-89、左旋甲状腺素钠、他莫昔芬、坦舒洛辛、他索那明、tastolactone、泰索帝、替西硫津、替莫唑胺、替尼泊苷、丙酸睾酮、甲睾酮、硫鸟嘌呤、噻替哌、促甲状腺激素、替鲁膦酸、拓扑替康、托瑞米芬、托西莫单抗、曲妥珠单抗、曲奥舒凡、维A酸、甲氨喋呤片剂、三甲基密胺、三甲曲沙、乙酸曲普瑞林、双羟萘酸曲普瑞林、优福定、尿苷、戊柔比星、维司力农、长春碱、长春新碱、长春酰胺、长春瑞滨、维鲁利秦、右旋丙亚胺、净司他丁斯酯、枢复宁、紫杉醇蛋白质稳定制剂、acolbifene、干扰素r-lb、affinitak、氨基喋呤、阿佐昔芬、asoprisnil、阿他美坦、阿曲生坦、BAY 43-9006、阿瓦斯丁、CCI-779、CDC-501、西乐葆、西妥昔单抗、克立那托、环丙孕酮醋酸酯、地西他滨、DN-101、阿霉素-MTC、dSLIM、度他雄胺、edotecarin、依氟鸟氨酸、依喜替康、芬维A胺、组胺二盐酸盐、组氨瑞林水凝胶植入物、钬-166 DOTMP、伊班膦酸、干扰素γ、内含子-PEG、ixabepilone、匙孔形血蓝蛋白、L-651582、兰乐肽、拉索昔芬、libra、lonafamib、米泼昔芬、米诺屈酸酯、MS-209、脂质体MTP-PE、MX-6、那法瑞林、奈莫柔比星、新伐司他、诺拉曲特、奥利默森、onco-TCS、osidem、紫杉醇聚谷氨酸酯、帛米酸钠、PN-401、QS-21、夸西洋、R-1549、雷洛昔芬、豹蛙酶、13-顺维A酸、沙铂、西奥骨化醇、T-138067、tarceva、二十二碳六烯酸紫杉醇、胸腺素αl、嘎唑呋林、tipifarnib、替拉扎明、TLK-286、托瑞米芬、反式MID-lo7R、伐司朴达、伐普肽、vatalanib、维替泊芬、长春氟宁、Z-100和唑来麟酸或它们的组合。
下列实施例中所用试剂均可购买得到。
以下实施例对本发明做进一步的描述,但该实施例并非用于限制本发明的保护范围。
实施例1:化合物WKF-001的制备
1-(5-(tert-butyl)isoxazol-3-yl)-3-(4-(5-(4-(2-morpholinoethoxy)phenyl)-1H-pyrazol-3-yl)phenyl)urea(WKF-001)
合成路线:
步骤a:化合物2的制备
将化合物1(1.8g,7.53mmol),水合肼(22.59mmol),20ml冰醋酸混合后在80℃下回流反应至化合物1基本转化,向反应体系中加水,乙酸乙酯萃取两次,合并有机相,无水硫酸钠干燥,减压浓缩,过柱分离得到化合物2(495mg,收率26.2%)。ESI-MS m/z 252.1(M+H)+.
步骤b:化合物4的制备
将化合物2(495mg,1.97mmol),苯基(5-叔丁基异噁唑-3-氨基)甲酸酯(化合物3)(768mg,3mmol),DMAP(13mg,0.12mmol)和三乙胺(598mg,5.91mmol),在THF(15mL)中60℃下搅拌反应过夜。反应完成后,倒入水中,乙酸乙酯萃取2次,合并有机相,无水硫酸钠干燥,减压浓缩,过柱分离得化合物4(590mg,收率72%)。ESI-MS m/z 418.1(M+H)+.
步骤c:WKF-001的制备
将化合物4(590mg,1.42mmol),N-(2-氯乙基),吗啉盐酸盐(化合物5)(396mg,2.13mmol),K2CO3(588mg,4.26mmol)以及TBAI(52mg,0.14mmol)溶解在15ml DMF中,60℃下加热反应至大部分原料转化即停止反应,向反应体系中加水,用乙酸乙酯萃取两次,合并有机相,并用无水硫酸钠干燥,减压浓缩后过柱分离得到化合物WKF-001(230mg,收率31%)。
1H NMR(400MHz,DMSO-d6)δ13.12(s,1H),9.55(s,1H),8.92(s,1H),7.73-7.75(m,4H),7.53(d,J=7.6Hz,2H),7.00-7.02(m,3H),6.53(s,1H),4.11(t,J=5.4Hz,2H),3.58(t,J=4.4Hz,4H),2.69(t,J=5.6Hz,2H),2.47(t,J=4.4Hz,4H),1.30(s,9H).ESI-MS m/z531.2(M+H)+.
实施例2:化合物WKF-002的制备
1-(4-(5-(2-bromo-4-(2-morpholinoethoxy)phenyl)-1H-pyrazol-3-yl)phenyl)-3-(5-(tert-butyl)isoxazol-3-yl)urea
步骤a:化合物7的制备
将化合物6(2g,6.29mmol),TsNHNH2(1.76g,9.44mmol)混于50ml EtOH中,再加入I2(79mg,0.31mmol),110℃搅拌20min,再加入K2CO3(2.6g,18.87mmol),继续反应至原料耗尽,用乙酸乙酯萃取两次,合并有机相,并用无水硫酸钠干燥,减压浓缩后过柱分离得到化合物2(540mg,收率26%)。ESI-MS m/z 330.0(M+H)+.
步骤b:化合物8的制备
将化合物7(450mg,1.37mmol),苯基(5-叔丁基异噁唑-3-氨基)甲酸酯(化合物3)(534mg,2.052mmol),DMAP(9mg,0.08mmol)和三乙胺(0.19ml,4.1mmol),溶解在THF(15mL)中,60℃下搅拌反应过夜。反应完成后,将反应混合液倒入水中,并使用乙酸乙酯萃取2次,合并有机相,并用无水硫酸钠干燥,减压浓缩,过柱分离得化合物4(390mg,收率59%)。ESI-MS m/z 496.0(M+H)+.
步骤c:WKF-002的制备
将化合物8(360mg,0.73mmol),N-(2-氯乙基),吗啉盐酸盐(化合物5)(204mg,1.09mmol),K2CO3(300mg,2.18mmol)以及TBAI(21mg,0.06mmol)溶解在15ml DMF中,60℃下加热反应至大部分原料转化即停止反应,向反应体系中加水,用乙酸乙酯萃取两次,合并有机相,并用无水硫酸钠干燥,减压浓缩后过柱分离得到化合物WKF-002(194mg,收率44%)。
1H NMR(400MHz,DMSO-d6)δ13.31&13.02(two s,1H),9.54(s,1H),8.92(s,1H),7.82-7.68(m,2H),7.61-7.42(m,3H),7.33(s,1H),7.13-7.02(m,1H),6.93(s,1H),6.52(s,1H),4.16(t,J=5.6Hz,2H),3.59(t,J=4.4Hz,4H),2.70(t,J=5.6Hz,2H),2.50-2.45(m,4H),1.30(s,J=13.5Hz,9H).ESI-MS m/z 609.1(M+H)+.
实施例3:化合物WKF-003的制备
1-(5-(tert-butyl)isoxazol-3-yl)-3-(4-(5-(2-methyl-4-(2-morpholinoethoxy)phenyl)-1H-pyrazol-3-yl)phenyl)urea
合成方法参照实施例2。
1H NMR(400MHz,DMSO-d6)δ13.17&12.87(two s,1H),9.61(s,1H),9.12(s,1H),7.77(d,J=6.4Hz,2H),7.52(d,J=7.6Hz,2H),7.44(s,1H),6.99-6.83(m,2H),6.79(s,1H),6.53(s,1H),4.24-4.12(m,2H),3.71-3.57(m,4H),2.92-2.73(m,2H),2.62(s,3H),2.49-2.31(m,4H),1.30(s,9H).ESI-MS m/z 545.2(M+H)+.
实施例4:化合物WKF-004的制备
1-(5-(tert-butyl)isoxazol-3-yl)-3-(4-(5-(2-chloro-4-(2-morpholinoethoxy)phenyl)-1H-pyrazol-3-yl)phenyl)urea
合成方法参照实施例2。
1H NMR(400MHz,DMSO-d6)δ13.34&13.07(two s,1H),9.56&9.51(two s,1H),8.95&8.88(two s,1H),7.97-7.67(m,3H),7.61-7.46(m,2H),7.25-6.90(m,3H),6.52(s,1H),4.24-4.09(m,2H),3.65-3.54(m,4H),2.71(t,J=5.2Hz,2H),2.50-2.43(m,4H),1.30(s,9H)ESI-MS m/z 565.2(M+H)+.
实施例5:化合物WKF-005的制备
1-(5-(tert-butyl)isoxazol-3-yl)-3-(4-(5-(2-fluoro-4-(2-morpholinoethoxy)phenyl)-1H-pyrazol-3-yl)phenyl)urea
合成方法参照实施例2
1H NMR(400MHz,DMSO-d6)δ13.19(s,1H),9.55(s,1H),8.96(s,1H),7.89-7.80(m,1H),7.76(d,J=7.6Hz,2H),7.53(d,J=8.0Hz,2H),6.97(d,J=12.8Hz,1H),6.94-6.84(m,2H),6.52(s,1H),4.16(t,J=4.8Hz,2H),3.66-3.53(m,4H),2.78-2.68(m,2H),2.51-2.42(m,4H),1.30(s,9H).ESI-MS m/z 549.2(M+H)+.
实施例6:化合物WKF-006的制备
1-(5-(tert-butyl)isoxazol-3-yl)-3-(4-(5-(3-chloro-4-(2-morpholinoethoxy)phenyl)-1H-pyrazol-3-yl)phenyl)urea
合成方法参照实施例2。
1H NMR(600MHz,DMSO-d6)δ13.24&13.21(two s,1H),9.59&9.54(two s,1H),8.96&8.89(two s,1H),7.93-7.84(m,1H),7.83-7.69(m,3H),7.59-7.47(m,2H),7.32-7.18(m,1H),7.11(s,1H),6.53(s,1H),4.27-4.16(m,2H),3.58(t,J=3.2Hz,4H),2.75(t,J=4.0Hz,2H),2.55-2.51(m,4H),1.30(s,9H).ESI-MS m/z 549.2(M+H)+.ESI-MS m/z 565.2(M+H)+.
实施例7:化合物WKF-007的制备
1-(5-(tert-butyl)isoxazol-3-yl)-3-(4-(5-(3-fluoro-4-(2-morpholinoethoxy)phenyl)-1H-pyrazol-3-yl)phenyl)urea
合成方法参照实施例2。
1H NMR(400MHz,DMSO-d6)δ13.22&13.19(two s,1H),9.57&9.52(two s,1H),8.97&8.89(two s,1H),7.82-7.70(m,2H),7.68-7.48(m,4H),7.34-7.19(m,1H),7.08(s,1H),6.52(s,1H),4.26-4.16(m,2H),3.59(t,J=4.4Hz 4H),2.74(t,J=4.8Hz,2H),2.51-2.47(m,4H),1.30(s,9H).ESI-MS m/z 549.2(M+H)+.
实施例8:化合物WKF-008的制备
1-(5-(tert-butyl)isoxazol-3-yl)-3-(4-(5-(3-methoxy-4-(2-morpholinoethoxy)phenyl)-1H-pyrazol-3-yl)phenyl)urea
合成方法参照实施例2。
1H NMR(600MHz,DMSO-d6)δ13.14(s,1H),9.59&9.54(two s,1H),8.96&8.89(twos,1H),7.83-7.69(m,2H),7.61-7.48(m,2H),7.46-7.38(m,1H),7.37-7.29(m,1H),7.10-6.99(m,2H),6.53(s,1H),4.14-4.06(m,2H),3.85(s,3H),3.59(t,J=3.2Hz,4H),2.71(t,J=4.0Hz,2H),2.51-2.46(m,4H).ESI-MS m/z 561.2(M+H)+.
实施例9:化合物WKF-009的制备
1-(5-(tert-butyl)isoxazol-3-yl)-3-(2-fluoro-4-(5-(3-methoxy-4-(2-morpholinoethoxy)phenyl)-1H-pyrazol-3-yl)phenyl)urea
合成方法参照实施例2。
1H NMR(400MHz,DMSO-d6)δ13.23(s,1H),9.89(s,1H),8.90(s,1H),8.21(s,1H),7.72(d,J=12.8Hz,1H),7.68-7.57(m,1H),7.42(s,1H),7.37-7.27(m,1H),7.14(s,1H),7.09-6.96(m,1H),6.52(s,1H),4.09(t,J=5.6Hz,2H),3.85(s,3H),3.57(t,J=4.4Hz,4H),2.69(t,J=5.6Hz,2H),2.50-2.43(m,4H),1.30(s,9H).ESI-MS m/z 579.2(M+H)+.
实施例10:化合物WKF-010的制备
1-(5-(tert-butyl)isoxazol-3-yl)-3-(3-methoxy-4-(5-(4-(2-morpholinoethoxy)phenyl)-1H-pyrazol-3-yl)phenyl)urea
合成方法参照实施例2。
1H NMR(400MHz,DMSO-d6)δ13.09&12.76(two s,1H),9.57(s,1H),9.02(s,1H),7.84-7.61(m,3H),7.43(s,1H),7.08-6.92(m,4H),6.54(s,1H),4.12(t,J=5.6Hz,2H),3.91(s,3H),3.59(t,J=4.4Hz,4H),2.77-2.65(m,2H),2.50-2.40(m,4H),1.31(s,9H).ESI-MS m/z 561.2(M+H)+.
实施例11:化合物WKF-011的制备
1-(5-(tert-butyl)isoxazol-3-yl)-3-(2-fluoro-4-(5-(4-(2-morpholinoethoxy)phenyl)-1H-pyrazol-3-yl)phenyl)urea
合成方法参照实施例2。
1H NMR(400MHz,DMSO-d6)δ13.22(s,1H),9.90(s,1H),8.98-8.83(m,1H),8.23-8.12(m,1H),7.79-7.61(m,4H),7.13-6.97(m,3H),6.51(s,1H),4.14(t,J=4.4Hz,2H),3.66-3.55(m,4H),2.87-2.66(m,2H),2.51-2.44(m,4H),1.31(s,9H).ESI-MS m/z 549.2(M+H)+.
实施例12:化合物WKF-012的制备
1-(5-(tert-butyl)isoxazol-3-yl)-3-(3-methyl-4-(5-(4-(2-morpholinoethoxy)phenyl)-1H-pyrazol-3-yl)phenyl)urea
合成方法参照实施例2。
1H NMR(400MHz,DMSO-d6)δ13.16&12.86(two s,1H),12.86(s,1H),9.57(s,1H),8.95(s,1H),7.80-7.70(m,2H),7.49-7.31(m,3H),7.06-6.97(m,2H),6.82-6.74(m,1H),6.53(s,1H),4.13(t,J=5.6Hz,2H),3.63-3.56(m,4H),2.71(t,J=5.6Hz,2H),2.49-2.28(m,7H),1.30(s,9H).ESI-MS m/z 545.2(M+H)+.
实施例13:化合物WKF-013的制备
1-(5-(tert-butyl)isoxazol-3-yl)-3-(3-chloro-4-(5-(4-(2-morpholinoethoxy)phenyl)-1H-pyrazol-3-yl)phenyl)urea
合成方法参照实施例2。
1H NMR(400MHz,DMSO-d6)δ13.33&13.07(two s,1H),9.69&9.64(two s,1H),9.14&9.06(two s,1H),7.90-7.56(m,4H),7.45-7.31(m,1H),7.09-6.91(m,3H),6.54(s,1H),4.18-4.09(m,2H),3.59(t,J=4.4Hz,4H),2.71(t,J=5.6Hz,2H),2.50-2.43(m,4H),1.31(s,9H).ESI-MS m/z 565.2(M+H)+.
实施例14:化合物WKF-014的制备
1-(5-(tert-butyl)isoxazol-3-yl)-3-(2-chloro-4-(5-(4-(2-morpholinoethoxy)phenyl)-1H-pyrazol-3-yl)phenyl)urea
合成方法参照实施例2。
1H NMR(400MHz,DMSO-d6)δ13.24(s,1H),9.70&9.64(two s,1H),8.81&8.75(twos,1H),8.30-8.19(m,1H),7.98-7.91(m,1H),7.83-7.69(m,3H),7.16-6.97(m,3H),6.49(s,1H),4.19-4.10(m,2H),3.64-3.55(m,4H),2.76-2.67(m,2H),2.50-2.45(m,4H),1.31(s,9H).ESI-MS m/z 565.2(M+H)+.
实施例15:化合物WKF-015的制备
1-(5-(tert-butyl)isoxazol-3-yl)-3-(3-fluoro-4-(5-(4-(2-morpholinoethoxy)phenyl)-1H-pyrazol-3-yl)phenyl)urea
合成方法参照实施例2。
1H NMR(400MHz,DMSO-d6)δ13.33&13.15(two s,1H),9.76&9.70(two s,1H),9.45&9.33(two s,1H),7.96-7.56(m,4H),7.30-7.16(m,1H),7.11-6.98(m,2H),6.99-6.86(m,1H),6.53(s,1H),4.33-4.12(m,2H),3.78-3.57(m,4H),3.04-2.82(m,2H),2.79-2.51(m,4H),1.30(s,9H).ESI-MS m/z 549.2(M+H)+.
实施例16:化合物WKF-016的制备
1-(5-(tert-butyl)isoxazol-3-yl)-3-(2-fluoro-4-(5-(2-fluoro-4-(2-morpholinoethoxy)phenyl)-1H-pyrazol-3-yl)phenyl)urea
合成方法参照实施例2。
1H NMR(400MHz,DMSO-d6)δ13.41&13.24(two s,1H),9.91(s,1H),8.97&8.91(twos,1H),8.26-8.13(m,1H),7.90-7.58(m,3H),7.10-6.83(m,3H),6.51(s,1H),4.21-4.10(m,2H),3.66-3.55(m,4H),2.78-2.66(m,2H),2.51-2.45(m,4H),1.30(s,9H).ESI-MS m/z567.2(M+H)+.
实施例17:化合物WKF-017的制备
1-(5-(tert-butyl)isoxazol-3-yl)-3-(4-(5-(4-(2-(dimethylamino)ethoxy)-2-fluorophenyl)-1H-pyrazol-3-yl)-2-fluorophenyl)urea
合成方法参照实施例2。
1H NMR(400MHz,DMSO-d6)δ13.44&13.30(two s,1H),10.07(s,1H),9.09(s,1H),8.30-78.10(m,1H),7.92-7.47(m,3H),7.15-6.80(m,3H),6.51(s,1H),4.29-4.19(m,2H),3.05-2.92(m,2H),2.47(s,6H),1.30(s,9H).ESI-MS m/z 525.2(M+H)+.
实施例18:化合物WKF-018的制备
1-(5-(tert-butyl)isoxazol-3-yl)-3-(2-fluoro-4-(5-(2-fluoro-4-(3-morpholinopropoxy)phenyl)-1H-pyrazol-3-yl)phenyl)urea
合成方法参照实施例2。
1H NMR(600MHz,DMSO-d6)δ13.42&13.25(two s,1H),9.89(s,1H),8.94&8.88(twos,1H),8.25-8.15(m,1H),7.89-7.70(m,2H),7.70-7.60(m,1H),7.05-6.84(m,3H),6.51(s,1H),4.11-4.06(m,2H),3.58(t,J=4.2Hz,4H),2.45-2.26(m,6H),1.93-1.85(m,2H),1.30(s,9H).ESI-MS m/z 581.2(M+H)+.
实施例19:化合物WKF-019的制备
1-(5-(tert-butyl)isoxazol-3-yl)-3-(2-fluoro-4-(5-(2-fluoro-4-(2-(piperidin-1-vl)ethoxy)phenyl)-1H-pyrazol-3-yl)phenyl)urea
合成方法参照实施例2。
1H NMR(600MHz,DMSO-d6)δ13.418&13.255(two s,1H),9.90(s,1H),8.91(s,1H),8.19(s,1H),7.80-7.59(m,3H),7.07-6.89(m,3H),6.51(s,1H),4.13(t,J=5.4Hz,2H),2.67(t,J=5.7Hz,2H),2.54-2.48(m,4H),1.54-1.45(m,4H),1.41-1.35(m,2H),1.30(s,9H).ESI-MS m/z 565.2(M+H)+.
实施例20:化合物WKF-020的制备
1-(5-(tert-butyl)isoxazol-3-yl)-3-(2-fluoro-4-(5-(2-fluoro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-1H-pyrazol-3-yl)phenyl)urea
步骤a:化合物9的制备同实施例1。
步骤b:化合物WKF-020的制备
将化合物9(110mg,0.17mmol)溶于1ml CF3COOH,室温搅拌30min后,旋去CF3COOH,用Na2CO3调pH至7~8,加水,使用乙酸乙酯萃取2次,合并有机相,并用无水硫酸钠干燥,减压浓缩,过硅胶柱分离得化合物物WKF-020(63mg,收率66%)。
1H NMR(600MHz,DMSO-d6)δ13.36(s,1H),9.92(s,1H),8.93(s,1H),8.24-8.17(m,1H),7.86-7.63(m,3H),7.07-6.89(m,3H),6.51(s,1H),4.16(t,J=5.4Hz,2H),3.07(t,J=4.8Hz,4H),2.78(t,J=5.4Hz,2H),2.73-2.63(m,4H),1.30(s,9H).ESI-MS m/z 566.2(M+H)+.
实施例21:化合物WKF-021的制备
1-(5-(tert-butyl)isoxazol-3-yl)-3-(4-(5-(4-(3-(dimethylamino)propoxy)-2-fluorophenyl)-1H-pyrazol-3-yl)-2-fluorophenyl)urea
合成方法参照实施例2。
1H NMR(400MHz,DMSO-d6)δ13.31(s,1H),9.92(s,1H),8.94(s,1H),8.19(s,1H),7.87-7.55(m,3H),7.08-6.80(m,3H),6.50(s,1H),4.15-3.97(m,2H),2.46-2.34(m,2H),2.27-2.08(s,6H),1.96-1.79(m,2H),1.29(s,9H).ESI-MS m/z539.2(M+H)+.
实施例22:化合物WKF-022的制备
1-(2-fluoro-4-(5-(4-(2-morpholinoethoxy)phenyl)-1H-pyrazol-3-yl)phenyl)-3-(3-fluorophenyl)urea
合成方法参照实施例2。
1H NMR(400MHz,DMSO-d6)δ13.21(s,1H),9.31(s,1H),8.75&8.617(two s,1H),8.30-8.13(m,1H),7.81-7.57(m,4H),7.57-7.48(m,1H),7.38-7.28(m,1H),7.16-6.94(m,4H),6.87-6.78(m,1H),4.18-4.01(m,2H),3.58(t,J=4.4Hz,4H),2.70(t,J=5.6Hz,2H),2.50-2.43(m,4H).ESI-MS m/z 520.2(M+H)+.
实施例23:化合物WKF-023的制备
1-(3-chloro-4-(trifluoromethyl)phenyl)-3-(2-fluoro-4-(5-(4-(2-morpholinoethoxy)phenyl)-1H-pyrazol-3-yl)phenyl)urea
合成方法参照实施例2。
1H NMR(400MHz,DMSO-d6)δ13.21(s,1H),9.53(s,1H),8.80&8.72(two s,1H),8.23-8.08(m,2H),7.81-7.56(m,6H),7.12-6.95(m,3H),4.17-4.08(m,2H),3.59(t,J=4.4Hz,4H),2.71(t,J=5.6Hz,2H),2.50-2.44(m,4H).ESI-MS m/z 604.1(M+H)+.
实施例24:化合物WKF-02401和WKF-02402的制备
将化合物WKF-011(300mg,0.55mmol)溶于10ml THF,Ar保护,加入DIPEA(1.92ml,11mmol),再缓慢滴入化合物10(1.51ml,11mmol),滴完后转移至60℃反应过夜,旋干溶剂,加水,使用乙酸乙酯萃取2次,合并有机相,并用无水硫酸钠干燥,减压浓缩,过柱分离得化合物WKF-02401(121mg,收率35%),WKF-02402(120mg,34%)。
WKF-02401:
1H NMR(400MHz,DMSO-d6)δ9.91(s,1H),8.96(s,1H),8.28-8.20(m,1H),7.80-7.74(m,2H),7.542(d,J=6.8Hz,2H),7.08-7.01(m,3H),6.52(s,1H),5.03-4.97(m,1H),4.17-4.13(m,2H),3.59-3.50(m,4H),2.72(t,J=5.6Hz,2H),2.51-2.47(m,4H),1.31(s,9H),1.20-1.86(m,6H).ESI-MS m/z 635.2(M+H)+.
WKF-02402:
1H NMR(400MHz,DMSO-d6)δ9.95(s,1H),9.02(s,1H),8.30-8.16(m,1H),7.89-7.72(m,2H),7.43-7.30(m,2H),7.10-7.00(m,3H),6.52(s,1H),5.09-4.96(m,1H),4.19-4.10(m,2H),3.59(t,J=4.0Hz,4H),2.72(t,J=5.6Hz,2H),2.49-2.41(m,4H),1.31(s,9H),1.23-1.06(m,6H).ESI-MS m/z 635.2(M+H)+.
实施例25:化合物WKF-101的制备
1-(5-(tert-butyl)isoxazol-3-yl)-3-(4-(4-(4-(2-morpholinoethoxy)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)phenyl)urea(WKF-101)
合成路线:
步骤a:化合物13的制备
将2-溴-4′-羟基苯乙酮11(8.8g,40.93mmol),化合物12(8.1g,38.9mmol),NaHCO3(9.8g,116.7mmol)溶解在150ml DMF中,室温下搅拌反应0.5h,停止反应,向反应体系中加水,使用乙酸乙酯萃取两次,合并有机相,用无水硫酸钠干燥,减压浓缩后过柱分离得到化合物13(7.8g,收率59%)。ESI-MS m/z 343.1(M+H)+.
步骤b:化合物14制备
将化合物13(7.8g,22.78mmol),KOCN(5.53g,68.34mmol)溶解在80ml醋酸中,80℃下加热反应过夜,停止反应,向反应体系中加水,使用乙酸乙酯萃取两次,合并有机相,用无水硫酸钠干燥,减压浓缩后过柱分离得到化合物9(600mg,收率8%)。ESI-MS m/z 368.1(M+H)+.
步骤c和d:化合物15的制备
将化合物14(600mg,1.63mmol),N-(2-氯乙基)吗啉盐酸盐(化合物5)(450mg,2.45mmol)和K2CO3(675mg,4.89mmol)溶解在DMF中,于60℃下加热反应过夜,停止反应,向反应体系中加水,用乙酸乙酯萃取两次,合并有机相,用无水硫酸钠干燥,减压浓缩后得到中间体,将所得中间体溶解在10ml三氟醋酸中,室温下搅拌反应2h,,向反应体系中加水,用乙酸乙酯萃取两次,合并有机相,用无水硫酸钠干燥,减压浓缩后得到化合物10(110mg)。ESI-MS m/z 381.1(M+H)+.
步骤e:化合物WKF-101的制备
将化合物15(110mg,0.29mmol),苯基(5-叔丁基异噁唑-3-氨基)甲酸酯(化合物3)(113mg,0.44mmol)和三乙胺(88mg,0.87mmol),溶解在THF(15mL)中,60℃下搅拌反应过夜。反应完成后,将反应混合液倒入水中,并使用乙酸乙酯萃取2次,合并有机相,并用无水硫酸钠干燥,减压浓缩,过柱分离得化合物WKF-101(67mg,收率:43%)。
1H NMR(400MHz,DMSO-d6)δ10.85(s,1H),10.83(s,1H),9.47(s,1H),8.80(s,1H),8.03(d,J=8.8Hz,2H),7.51(d,J=8.8Hz,2H),7.43(d,J=8.8Hz,2H),7.07(d,J=8.8Hz,2H),6.50(s,1H),4.19(t,J=5.2Hz,2H),3.55-3.58(m,4H),2.72(t,J=5.2Hz,2H),2.45-2.48(m,4H),1.29(s,9H).13C NMR(101MHz,DMSO-d6)δ180.6,168.4,162.8,158.9,151.8,151.7,135.2,133.0,130.9,124.6,121.0,119.6,114.8,92.9,66.6,66.1,57.3,54.0,32.9,28.8.ESI-MS m/z 547.2(M+H)+.
实施例26:化合物WKF-201的制备
1-(5-(tert-butyl)isoxazol-3-yl)-3-(4-(2-(methylthio)-4-(4-(2-morpholinoethoxy)phenyl)-1H-imidazol-1-yl)phenyl)urea(WKF-201)
合成路线:
步骤a:化合物16的制备
将化合物13(2g,5.85mmol),KSCN(2.84g,29.25mmol),对甲苯磺酸(5.03g,29.25mmol)混合后在研钵中用力碾碎,在60℃下加热10min,原料基本转化完全,停止反应,向反应体系加水,使用乙酸乙酯萃取两次,合并有机相,用无水硫酸钠干燥,减压浓缩后过柱分离得到化合物16(1.1g,收率59%)。ESI-MS m/z 284.1(M+H)+.
步骤b:化合物17的制备
将化合物16(1.1g,3.88mmol)溶解在20ml THF中,降低温度至0℃,滴加碘甲烷(826mg,5.82mmol),滴加完成后在室温下反应2h至原料全部转化,反应体系中加水淬灭,使用乙酸乙酯萃取两次,合并有机相,用无水硫酸钠干燥,减压浓缩后过柱分离得到化合物17(490mg,收率42.5%)。ESI-MS m/z 298.1(M+H)+.
步骤c和d:化合物WKF-201的制备
参照实施例1中步骤b和步骤c合成化合物WKF-201。
1H NMR(400MHz,DMSO-d6)δ9.76(s,1H),9.51(s,1H),7.82(s,1H),7.73(d,J=8.0Hz,2H),7.63(d,J=8.4Hz,2H),7.42(d,J=8.4Hz,2H),6.96(d,J=8.0Hz,2H),6.54(s,1H),4.10(t,J=5.2Hz,2H),3.57-3.59(m,4H),2.71(t,J=5.2Hz,2H),2.58(s,3H),2.50-2.51(m,4H),1.31(s,9H).13C NMR(101MHz,DMSO-d6)δ180.7,158.7,157.8,151.9,142.9,141.3,139.6,131.5,127.0,126.3,126.0,119.3,118.3,115.0,93.0,66.6,65.7,57.5,54.1,33.0,28.8,15.9.ESI-MS m/z 577.2(M+H)+.
实施例27:化合物WKF-202的制备
1-(5-(tert-butyl)isoxazol-3-yl)-3-(4-(4-(4-(2-morpholinoethoxy)phenyl)-2-((2-morpholinoethyl)thio)-1H-imidazol-1-yl)phenyl)urea(WKF-202)
合成路线:
步骤a:化合物18的制备
将化合物16(450mg,1.59mmol),苯基(5-叔丁基异噁唑-3-氨基)甲酸酯(620mg,2.39mmol),DMAP(20mg,0.16mmol)和三乙胺(483mg,4.77mmol),溶解在THF(30mL)中,60℃下搅拌反应过夜。反应完成后,将反应混合液倒入水中,并使用乙酸乙酯萃取2次,合并有机相,并用无水硫酸钠干燥,减压浓缩,过柱分离得化合物18(500mg,收率70%)。ESI-MS m/z450.1(M+H)+.
步骤b:化合物WKF-202的制备
将化合物18(500mg,1.11mmol),N-(2-氯乙基)吗啉盐酸盐(600mg,3.3mmol),K2CO3(460mg,3.33mmol)以及TBAI(13mg,0.1mmol)溶解在10ml DMF中,60℃下加热反应至大部分原料转化即停止反应,向反应体系中加水,用乙酸乙酯萃取两次,合并有机相,用无水硫酸钠干燥,减压浓缩后过柱分离得到化合物WKF-202(300mg,收率40%)。
1H NMR(400MHz,DMSO-d6)δ9.62(s,1H),9.08(s,1H),7.80(s,1H),7.72(d,J=8.4Hz,2H),7.62(d,J=8.8Hz,2H),7.43(d,J=8.4Hz,2H),6.96(d,J=8.8Hz,2H),6.53(s,1H),4.09(t,J=5.6Hz,2H),3.59(t,J=4.4Hz,4H),3.52(t,J=4.4Hz,4H),3.27(t,J=6.8Hz,2H),2.70(t,J=5.6Hz,2H),2.60(t,J=6.8Hz,2H),2.48(d,J=4.4Hz,4H),2.38(t,J=4.4Hz,4H),1.31(s,9H).13C NMR(101MHz,DMSO-d6)δ180.5,158.9,157.8,152.2,142.1,141.3,139.9,131.4,127.0,126.4,126.0,119.3,118.3,115.0,93.1,66.7,66.6,65.8,58.0,57.6,54.1,53.5,32.9,30.5,28.9.ESI-MS m/z 676.3(M+H)+.
实施例28:化合物WKF-203的制备
1-(5-(tert-butyl)isoxazol-3-yl)-3-(4-(4-(4-(2-morpholinoethoxy)-3-nitrophenyl)-1H-imidazol-1-yl)phenyl)urea(WKF-203)
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合成路线:
步骤a:化合物19的制备
将化合物18(800mg,1.78mmol),NaNO2(41mg,0.59mmol)与HNO3(560uL,0.3mmol)混合在20ml 0℃的冰醋酸中并搅拌反应20min,滴加25ml氨水淬灭反应,过滤得到的固体水洗除去残留的酸,进一步使用硅胶柱分离得到化合物14(700mg,收率85%)。ESI-MS m/z463.1(M+H)+.
步骤b:化合物WKF-203的制备
将化合物19(700mg,1.52mmol),N-(2-氯乙基)吗啉盐酸盐(420mg,2.28mmol),K2CO3(630mg,4.56mmol)以及TBAI(56mg,0.15mmol)溶解在15ml DMF中,60℃下加热反应至大部分原料转化即停止反应,向反应体系中加水,乙酸乙酯萃取两次,合并有机相,用无水硫酸钠干燥,减压浓缩后过柱分离得到化合物WKF-203(250mg,收率29%)。
1H NMR(400MHz,DMSO-d6)δ9.60(s,1H),9.00(s,1H),8.34(s,1H),8.28-8.30(m,2H),8.09(dd,J=8.8Hz,1.6Hz,1H),7.65(d,J=8.8Hz,2H),7.62(d,J=8.8Hz,2H),7.45(d,J=8.8Hz,1H),6.52(s,1H),4.31(t,J=5.4Hz,2H),3.62-3.52(m,4H),2.73(t,J=5.1Hz,2H),2.51-2.45(m,4H),1.31(s,9H).13C NMR(101MHz,DMSO-d6)δ180.7,158.8,151.8,150.4,140.3,139.9,138.4,136.5,131.9,130.4,127.6,121.3,120.7,120.0,116.4,115.0,93.0,68.2,66.7,57.1,54.0,33.0,28.8.ESI-MS m/z 576.2(M+H)+.
实施例29:化合物WKF-301的制备
1-(5-(tert-butyl)isoxazol-3-yl)-3-(4-(2-(4-(2-morpholinoethoxy)phenyl)-1H-imidazol-4-yl)phenyl)urea
步骤a:化合物20的制备
将4-羟基苯甲腈(10g,84mmol),K2CO3(17.4g,126mmol),混于100ml DMF,再加入BnBr(15.8g,92.4mmol),50℃反应至原料耗尽,加水,乙酸乙酯萃取,旋干,得到化合物20(16.5g,收率94%)。
1H NMR(400MHz,CDCl3)δ7.58(d,J=8.8Hz,2H),7.46-7.33(m,5H),7.02(d,J=8.8Hz,2H),5.12(s,2H).
步骤b:化合物21的制备
将LiHMDS(55ml,55mmol)溶于100ml THF,Ar保护,再加入化合物20(10.5g,50mmol)的THF溶液(40ml),室温反应4h后,0℃下,用5N HCl/i-PrOH(80ml)淬灭,然后持续搅拌过夜,抽滤,Et2O洗,滤饼干燥,得化合物21(8.7g,收率77%)
1H NMR(400MHz,DMSO-d6)δ9.38(s,2H),9.17(s,2H),7.90(d,J=9.2Hz,2H),7.47-7.33(m,5H),7.21(d,J=8.8Hz,2H),5.23(s,2H).
化合物22的制备
将4-硝基苯乙酮(5g,30mmol)溶于30ml乙腈,再加入NBS(5.5g,30.9mmol)和对甲苯磺酸一水合物(5.7g,30mmol),50℃反应过夜,饱和NaHCO3中和,乙酸乙酯萃取,旋干,石油醚/乙酸乙酯(5∶1)重结晶,得化合物22(6g,收率82%)。
1H NMR(400MHz,CDCl3)δ8.33(d,J=8.8Hz,2H),8.15(d,J=8.8Hz,2H),4.47(s,2H).
步骤c:化合物23的制备
将化合物21(1.31g,5mmol),KHCO3(2g,20mmol)混于20ml THF/H2O(4∶1),加热至90℃,滴入化合物22(1.46g,6mmol)的THF溶液(25ml),继续搅拌,至原料耗尽,旋干,加水,乙酸乙酯萃取,过柱分离得到化合物23(830mg,收率45%)。
1H NMR(400MHz,DMSO-d6)δ12.80(s,1H),8.25(d,J=8.8Hz,2H),8.10(d,J=8.8Hz,2H),8.05(s,1H),7.96(d,J=8.8Hz,2H),7.49-7.31(m,5H),7.14(d,J=8.8Hz,2H),5.17(s,2H).
步骤d:化合物24的制备
将化合物23(600mg,1.6mmol)溶于20ml乙酸乙酯,加入Pd/C(300mg),H2换气后,室温反应至原料耗尽,抽滤,旋干,得化合物24(265mg,66%)。
1H NMR(400MHz,DMSO-d6)δ9.90(brs,1H),7.85(d,J=8.8Hz,2H),7.50(d,J=8.4Hz,2H),7.28(s,1H),6.87(d,J=8.8Hz,2H),6.61(d,J=8.4Hz,2H).
步骤e:化合物25的制备
将化合物24(250mg,1mmol),化合物3(390mg,1.5mmol),DMAP(7mg,0.06mmol)溶于20ml THF,再加入Et3N(304mg,3mmol),置于70℃搅拌反应至原料耗尽,旋干,过柱分离得化合物25(183mg,44%)。
1H NMR(400MHz,DMSO-d6)δ12.29(s,1H),9.67(s,1H),9.50(s,1H),8.81(s,1H),7.82(d,J=8.8Hz,2H),7.75(d,J=8.8Hz,2H),7.53(s,1H),7.46(d,J=8.8Hz,2H),6.84(d,J=8.4Hz,2H),6.52(s,1H),1.30(s,9H).
步骤f:化合物WKF-301的制备
将化合物25(150mg,0.36mmol),化合物5(100mg,0.54mmol),K2CO3(149mg,1.08mmol),TBAI(15mg,0.04mmol)混于5ml DMF,置于60℃搅拌反应过夜,加水,乙酸乙酯萃取,旋干,过柱分离得化合物WKF-301(80mg,收率42%)。
1H NMR(400MHz,DMSO-d6)δ12.39(s,1H),9.52(s,1H),8.84(s,1H),7.94(d,J=8.4Hz,2H),7.78(d,J=8.0Hz,2H),7.57(s,1H),7.48(d,J=8.4Hz,2H),7.04(d,J=8.4Hz,2H),6.53(s,1H),4.13(t,J=5.6Hz,2H),3.58(t,J=4.0Hz 4H),2.71(t,J=5.6Hz,2H),2.52-2.47(m,4H),1.30(s,9H).ESI-MS m/z 531.2(M+H)+.
实施例30:化合物WKF-302的制备
1-(5-(tert-butyl)isoxazol-3-yl)-3-(2-fluoro-4-(2-(4-(2-morpholinoethoxy)phenyl)-1H-imidazol-4-yl)phenyl)urea
合成方法参照实施例29。
1H NMR(400MHz,DMSO-d6)δ12.49&12.34(two s,1H),9.85(s,1H),8.86&8.80(twos,1H),8.15-8.04(m,1H),8.00-7.87(m,2H),7.76-7.61(m,3H),7.05(d,J=8.8Hz,2H),6.51(s,1H),4.14(t,J=5.6Hz,2H),3.59(t,J=4.8Hz,4H),2.71(t,J=6.0Hz,2H),2.50-2.46(m,4H),1.31(s,9H).ESI-MS m/z 549.2(M+H)+.
实施例31:化合物WKF-303的制备
1-(5-(tert-butyl)isoxazol-3-yl)-3-(2-fluoro-4-(2-(2-fluoro-4-(2-morpholinoethoxy)phenyl)-1H-imidazol-4-yl)phenyl)urea
合成方法参照实施例29。
1H NMR(400MHz,DMSO-d6)δ12.19(s,1H),9.85(s,1H),8.80(s,1H),8.14-8.07(m,1H),8.01-7.93(m,1H),7.76-7.62(m,3H),7.04-6.97(m,1H),6.96-6.90(m,1H),6.51(s,1H),4.17(t,J=5.6Hz,2H),3.59(t,J=4.4Hz,4H),2.72(t,J=5.6Hz,2H),2.50-2.47(m,4H),1.31(s,9H).ESI-MS m/z 567.2(M+H)+.
实施例32:化合物WKF-401的制备
1-(5-(tert-butyl)isoxazol-3-yl)-3-(4-(5-(2-(morpholinomethyl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1H-pyrazol-3-yl)phenyl)urea
步骤a:化合物27的制备
将4-甲氧基苯甲醛(11g,82.5mmol),I2(10.5g,41.5mmol)混于400ml MeOH中,50℃搅拌5min后,加入化合物26(17.5g,50mmol),继续搅拌至原料耗尽,旋去MeOH,加DCM稀释,抽滤,滤液用Na2S2O3溶液洗,水洗,旋干得化合物27(16g,收率76%)。
1H NMR(400MHz,CDCl3)δ9.77(s,1H),8.24(d,J=2.0Hz,1H),7.80(dd,J=8.4,2.0Hz,1H),6.88(d,J=8.8Hz,1H),3.93(s,3H).
步骤b:化合物28的制备
将化合物27(8g,30.5mmol),4-硝基苯乙酮(5g,30.5mmol)混于150ml MeOH,0℃下滴入NaOH(1.83g,45.75mmol)的水溶液(50ml),再转室温反应至原料耗尽,加水稀释,抽滤,滤饼干燥,得化合物28(10g,收率80%)。
1H NMR(400MHz,CDCl3)δ8.32(d,J=8.8Hz,2H),8.12(d,J=8.8Hz,2H),8.10(d,J=2.4Hz,1H),7.70(d,J=15.6Hz,1H),7.58(dd,J=8.4,2.0Hz,1H),7.34(d,J=15.6Hz,1H),6.84(d,J=8.8Hz,1H),3.93(s,3H).
步骤c:化合物29的制备
将化合物28(10g,23.75mmol),TsNHNH2(19.9g,35.63mmol)混于120ml EtOH,再加入I2(602mg,2.38mmol),110℃搅拌20分钟后,加入K2CO3(9.85g,71.25mmol),继续反应至原料耗尽,加水,乙酸乙酯萃取,旋干,石油醚/乙酸乙酯(2/1)打浆,得化合物29(5g,收率60%)。
1H NMR(400MHz,CDCl3)δ8.13(d,J=8.8Hz,2H),8.01(d,J=2.0Hz,1H),7.80(d,J=8.8Hz,2H),7.54(dd,J=8.4,2.0Hz,1H),6.78(s,1H),6.70(d,J=8.4Hz,1H),3.84(s,3H).
步骤d:化合物30的制备
将化合物29(5g,11.88mmol)混于120ml DCM中,Ar保护,0℃下加入BBr3(59ml,59mmol),室温反应至原料耗尽,加水淬灭,旋干溶剂,乙酸乙酯萃取,饱和碳酸氢钠溶液洗涤三次,收集有机相,旋干,再用PE∶EA=2∶1打浆,得化合物30(3g,收率74%)
1H NMR(400MHz,DMSO-d6)δ13.55(s,1H),10.61(s,1H),8.30(d,J=8.8Hz,2H),8.18(d,J=2.0Hz,1H),8.10(d,J=8.8Hz,2H),7.67(dd,J=8.4,2.0Hz,1H),7.32(s,1H),6.97(d,J=8.4Hz,1H).
步骤e:化合物32的制备
将化合物30(3g,7.37mmol)溶于20ml DMSO,加入KOH(825mg,14.74mmol),60℃反应4h,再缓慢滴入化合物31(1.9ml,11.06mmol),继续反应至原料耗尽,加水,乙酸乙酯萃取,饱和食盐水洗涤三次,有机相浓缩,过柱分离得化合物32(1.87g,收率53%)。
1H NMR(400MHz,DMSO-d6)δ13.73&13.63(two s,1H),8.40-8.26(m,3H),8.16-8.02(m,2H),7.88-7.75(m,1H),7.48&7.43(two s,1H),7.12-6.97(m,1H),5.87&5.81(two s,1H),4.35-4.18(m,4H),1.24(t,J=7.2Hz,6H).
步骤f:化合物33的制备
将化合物32(1.87g,3.4mmol)溶于30ml THF/MeOH(5∶1),0℃下,缓慢加入NaBH4(777mg,20.4mmol),再移至室温反应至原料耗尽,加水淬灭,乙酸乙酯萃取,有机相浓缩过柱分离得化合物33(1g,收率52%)。
1H NMR(400MHz,DMSO-d6)δ13.68&13.59(two s,1H),8.39-8.28(m,2H),8.28-8.23(m,1H),8.16-8.04(m,2H),7.87-7.76(m,1H),7.47-7.37(m,1H),7.28-7.17(m,1H),4.89-4.81(m,2H),4.46-4.32(m,1H),3.72-3.56(m,4H).
步骤g:化合物35的制备
将化合物33(1g,2.15mmol),CuI(82mg,0.43mmol),化合物34(61mg,0.43mmol),Cs2CO3(2.1g,6.45mmol)混于10ml DMF,Ar保护下120℃反应过夜,冷却至室温,加水,乙酸乙酯萃取,有机相浓缩过柱分离得化合物35(400mg,收率55%)。
1H NMR(400MHz,DMSO-d6)δ13.60&13.53(two s,1H),8.38-8.26(m,2H),8.15-8.02(m,2H),7.43-7.27(m,3H),7.03-6.90(m,1H),5.10(t,J=5.6Hz,1H),4.42-4.33(m,1H),4.26-4.16(m,1H),4.11-4.00(m,1H),3.72-3.59(m,2H).
步骤h:化合物36的制备
将化合物35(400mg,1.13mmol),对甲苯磺酰氯(227mg,1.19mmol)溶于10ml THF,Ar保护,0℃下,缓慢加入NaOH(136mg,3.39mmol)的水溶液(0.3ml),再移至室温反应过夜,旋干溶剂,加水,乙酸乙酯萃取,饱和食盐水洗涤三次,有机相浓缩,过柱分离得化合物36(330mg,收率57%)。
1H NMR(400MHz,DMSO-d6)δ13.62&13.55(two s,1H),8.38-8.24(m,2H),8.15-8.00(m,2H),7.81(d,J=8.0Hz,2H),7.48(d,J=8.0Hz,2H),7.39-7.25(m,3H),6.99-6.80(m,1H),4.57-4.46(m,1H),4.43-4.19(m,3H),4.08-3.99(m,1H),2.41&2.35(two s,3H).
步骤i:化合物38的制备
将化合物36(330mg,0.65mmol),化合物37(1.13ml,13mmol)溶于20ml MeCN,120℃反应过夜,加水,乙酸乙酯萃取,饱和食盐水洗涤三次,有机相浓缩,过柱分离得化合物38(160mg,收率58%)。
1H NMR(400MHz,DMSO-d6)δ13.61&13.54(two s,1H),8.38-8.25(m,2H),8.16-8.01(m,2H),7.40-7.27(m,3H),7.03-6.89(m,1H),4.48-4.31(m,2H),4.08-3.99(m,1H),3.59(t,J=4.8Hz,4H),2.63-2.56(m,2H),2.56-2.51(m,2H),2.49-2.41(m,2H).
步骤j:化合物39的制备
将化合物38(150mg,0.36mmol),Fe(101mg,1.8mmol),NH4Cl(154mg,2.88mmol)混于5ml EtOH/H2O(4∶1),置于80℃回流反应,至原料耗尽,趁热硅藻土抽滤,滤液加水,乙酸乙酯萃取,饱和食盐水洗涤三次,有机相浓缩,得化合物39粗产物,直接用于下一步。
步骤k:化合物WKF-401的制备
将化合物39粗产物(130mg,0.33mmol),化合物3(130mg,0.50mmol),DMAP(4mg,0.03mmol)混于5ml THF,再加入Et3N(0.14ml,0.99mmol),然后置于70℃反应至原料耗尽,加水,乙酸乙酯萃取,饱和食盐水洗涤三次,有机相浓缩,过柱分离得化合物WKF-401(80mg,收率43%)。
1H NMR(400MHz,DMSO-d6)δ13.12&13.09(two s,1H),9.56&9.52(two s,1H),8.94&8.88(two s,1H),7.81-7.67(m,2H),7.59-7.46(m,2H),7.34(d,J=1.6Hz,1H),7.33-7.24(m,1H),7.01(s,1H),6.99-6.88(m,1H),6.52(s,1H),4.46-4.32(m,2H),4.08-3.98(m,1H),3.59(t,J=4.4Hz,4H),2.62-2.57(m,2H),2.56-2.51(m,2H),2.49-2.40(m,2H),1.30(s,9H).ESI-MS m/z 559.2(M+H)+.
实施例33:化合物WKF-501的制备
1-(5-(tert-butyl)isoxazol-3-yl)-3-(4-(5-(4-(2-morpholinoethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)urea
化合物41的制备:将化合物21(4.23g,16.1mmol),化合物40(1.58g,10.7mmol),Cs2CO3(10.5g,32.1mmol),CuBr(77mg,0.54mmol)混于50ml DMSO中,120℃反应过夜,冷却至室温,加乙酸乙酯稀释,萃取,5%NaHCO3洗涤三次,饱和NaCl溶液洗涤三次,有机相加硅胶拌样,过柱分离得到化合物41(2.3g,收率58%)。
1H NMR(400MHz,DMSO)δ14.64(s,1H),8.42-8.25(m,4H),8.02(d,J=8.8Hz,2H),7.52-7.30(m,5H),7.19(d,J=8.0Hz,2H),5.18(s,2H).
化合物43的制备:将化合物4l(2.3g,6.2mmol),溶于50ml THF,加入化合物42(2.45ml,26.9mmol),对甲苯磺酸(230mg,1.34mmol),再置于85℃回流反应过夜,旋去THF,加乙酸乙酯萃取,旋干得到化合物43-1,43-2,43-3的混合物(1.6g,收率57%)。
化合物WKF-501的制备:将上述步骤中得到的混合物(1.6g,3.5mmol)溶于40mlMeOH,加入钯碳(10%)(0.5g,4.7mmol),H2换气三次,室温反应至原料耗尽,过滤,旋干溶剂直接用于下一步。
将将上一步得到的还原产物(1.02g,3.0mmol),化合物3(1.17g,4.5mmol),DMAP(24mg,0.18mmol)溶于30ml THF,加入Et3N(1.2ml,9mmol),再置于70℃反应过夜,旋去溶剂,直接用于下一步。
将上一步粗产物(110mg,0.22mmol),化合物5(61mg,0.33mmol),Cs2CO3(215mg,0.66mmol),TBAI(7mg,0.02mmol)溶于2ml DMF,再置于60℃反应过夜,加乙酸乙酯稀释,萃取,饱和NaCl溶液洗涤三次,有机相旋干,溶于2ml MeOH,再加入4ml 4M盐酸二氧六环溶液,室温搅拌3h,再用2N氢氧化钠溶液调pH至8,加乙酸乙酯萃取,饱和NaCl溶液洗涤三次,有机相加硅胶拌样,过柱分离得化合物WKF-501(55mg,收率48%)。
1H NMR(400MHz,DMSO)δ14.20(br s,1H),9.81(s,1H),9.25(s,1H),8.09-7.89(m,4H),7.61(d,J=8.4Hz,2H),7.09(d,J=8.0Hz,2H),6.54(s,1H),4.20-4.09(m,2H),3.66-3.53(m,4H),2.78-2.67(m,2H),2.49-2.43(m,4H),1.31(s,9H).ESI-MS m/z 532.2(M+H)+.
实施例34化合物对携带RET不同突变背景BAF3模型细胞的增殖抑制活性
用CCK-8法测试本发明化合物对携带RET不同突变背景BAF3模型细胞的增殖抑制活性:
所用于对照试验的化合物如下:
Selpercatinib和Pralsetinib是有效的选择性RET抑制剂,购买自Selleck公司。
步骤如下:
1)细胞接种:处于细胞对数生长期的各种肿瘤细胞分别按同样密度接种在不同96孔板中(3000-10000个细胞/100μl/孔)。
2)工作液配制:以细胞培养所需相应培养基作为稀释液(含或不含溶媒DMSO),稀释受试化合物和对照化合物储备液,获得所需浓度为终浓度3倍的系列浓度的工作液,各浓度组中的溶媒DMSO含量与溶媒对照组相一致。
3)共孵育:接种24hr后,向96孔板加入化合物系列浓度的母液100μl/孔,混匀后共培养72hr。所有组别至少3个复孔,每个化合物6个浓度。空白对照组:只加培养基,不加细胞和药物,排除培养基对比色的干扰。
4)吸光度测定:从96孔板吸走培养基后,每孔加入10μl CCK-8溶液,共培养4hr后,充分振荡使其均匀,在酶标仪上测定A450及A650处的吸光值。
5)数据处理:得到的A450-A650原始数据,得到各处理孔的细胞存活率(计算方法如下);然后将细胞存活率数据及其对应的化合物浓度输入GraphPad Prism 5 Demo软件,使用非线性回归模型计算化合物对不同细胞的IC50值。细胞存活率的计算:细胞存活率(%)=[(As-Ac)/(Ab-Ac)]×100%](As:实验孔;Ab:溶媒对照孔;Ac:空白孔)。结果如表1和表2所示。
表1化合物对携带RET不同突变背景BAF3模型细胞的增殖抑制活性
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表2化合物对携带RET不同突变背景BAF3模型细胞的增殖抑制活性
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由表1和表2结果可知:本发明的化合物对携带RET不同突变背景BAF3模型细胞的增殖具有较强的抑制活性。
实施例35 FLT3-ITD激酶抑制活性测试
用Z-lyte荧光共振能量转移法检测本发明化合物的FLT3-ITD激酶抑制活性:
所用的蛋白激酶FLT3-ITD及其相应的底物试剂盒均购自Thermo FisherScientific公司。所有反应在384微孔板上进行,酶反应体积为10微升。反应缓冲液成分为50mM HEPES pH 7.5,10mM MgCl2,1mM EGTA,0.01%BRIJ-35。
所用于对照试验的化合物如下:
Quizartinib:是一种有效的FLT3抑制剂,也能有效抑制Ret、Kit、RET等激酶,用于FLT3激酶的对照试验,购买自Selleck公司。
激酶抑制活性测试具体步骤如下:
首先在微孔板内加入5μl适量的蛋白激酶与5μl相应底物(反应终浓度为2μM)混合液,然后用Echo520超声波微量液体转移系统(美国Labcyte公司)加入一系列梯度稀释的化合物,最后加入相应浓度的ATP,振荡混匀5min后,置于29℃恒温箱内反应1.5h;然后加入5μl相应浓度的检测液(Development Reagent),振荡混匀5min,置于29℃恒温箱内反应1h;最后加入5μl终止液(Stop Reagent),振荡混匀后用PE公司的Envision Multilabel Reader多功能酶标仪进行检测,激发光波长为400nm,发射光波长分别为445nm和520nm。实验分别设置测试孔(加化合物,酶,底物和ATP),0%磷酸化孔(加DMSO,底物和ATP)100%磷酸化孔(只加磷酸化底物),0%抑制率孔(加DMSO,酶,底物和ATP)。根据荧光比值计算化合物对酶反应的抑制率,用GraphPad软件进行分析计算出化合物的IC50值。化合物对FLT3-ITD激酶的抑制结果如表3所示。
表3部分化合物对FLT3-ITD激酶的抑制
由上表结果可知:本发明的化合物(尤其是化合物WKF-001,WKF-101,WKF-201)对突变型的FLT3激酶具有较强的抑制活性。
实施例36癌细胞增殖的抑制活性测试
用CCK-8法测试本发明化合物对癌细胞增殖的抑制活性。
所用于对照试验的化合物如下:
Quizartinib:是一种有效的FLT3抑制剂,也能有效抑制Ret、Kit、RET等激酶,用于FLT3激酶的对照试验,购买自Selleck公司。
步骤如下:
1)细胞接种:处于细胞对数生长期的各种肿瘤细胞分别按同样密度接种在不同96孔板中(3000-10000个细胞/100μl/孔)。
2)工作液配制:以细胞培养所需相应培养基作为稀释液(含或不含溶媒DMSO),稀释受试化合物和对照化合物储备液,获得所需浓度为终浓度3倍的系列浓度的工作液,各浓度组中的溶媒DMSO含量与溶媒对照组相一致。
3)共孵育:接种24hr后,向96孔板加入化合物系列浓度的母液100μl/孔,混匀后共培养72hr。所有组别至少3个复孔,每个化合物6个浓度。空白对照组:只加培养基,不加细胞和药物,排除培养基对比色的干扰。
4)吸光度测定:从96孔板吸走培养基后,每孔加入10μl CCK-8溶液,共培养4hr后,充分振荡使其均匀,在酶标仪上测定A450及A650处的吸光值。
5)数据处理:得到的A450-A650原始数据,得到各处理孔的细胞存活率(计算方法如下);然后将细胞存活率数据及其对应的化合物浓度输入GraphPad Prism 5 Demo软件,使用非线性回归模型计算化合物对不同细胞的IC50值。细胞存活率的计算:细胞存活率(%)=[(As-Ac)/(Ab-Ac)]×100%](As:实验孔;Ab:溶媒对照孔;Ac:空白孔)。结果如表4所示。
表4部分化合物对癌细胞的增殖抑制活性
由上表结果可知:本发明的化合物(尤其是化合物WKF-001,WKF-101,WKF-201)在细胞水平可有效抑制MV4-11肿瘤细胞的增殖。
以上所述实施例的各技术特征可以进行任意的组合,为使描述简洁,未对以下实施例中的各个技术特征所有可能的组合都进行描述,然而,只要这些技术特征的组合不存在矛盾,都应当认为是本说明书记载的范围。
以上所述实施例仅表达了本发明的几种实施方式,其描述较为具体和详细,但并不能因此而理解为对本发明专利范围的限制。应当指出的是,对于本领域的普通技术人员来说,在不脱离本发明构思的前提下,还可以做出若干变形和改进,这些都属于本发明的保护范围。因此,本发明专利的保护范围应以所附权利要求为准。
Claims (19)
1.具有式(I’)所示结构的含脲结构的三芳环化合物或其药学上可接受的盐:
其中,
Q选自:
X1、X2、X3、X4和X5共同组成杂芳基,X1、X2、X3、X4和X5分别独立地选自:N、NR2、C、CR3、或C=O,并且,X1、X2、X3、X4和X5中有两个或者三个分别独立地选自:N、或NR2,当X1、X2、X3、X4和X5中有两个或者三个均为N时,不形成N=N结构;
A1、A2、B1、B2、D1、D2、E1和E2分别独立地选自CR11;
Y1为N,Y2为CR9,Y3为CR10;
Q1、Q2、Q3、Q4、Q5和Q6分别独立地选自:CR;
Z选自:O、S;
R1选自:或者R1与D1一起形成如下结构:其中,m为0、1或2,n为0、1、或2,Z1选自:O、S;
各R2分别独立地选自:H、C1~C6烷基、C1~C6烷氧羰基;
各R3分别独立地选自:H、C1~C6烷基、或-SR8;
R4选自:H、C1~C6烷基;
各R5,R6分别独立地选自:C1~C8烷基,或者R5、R6与和其相连的N原子一起形成1个或多个R7取代或者未取代的3~10元杂环烷基;
各R7分别独立地选自:H、C1~C6烷基;
R8选自:H、C1~C3烷基、或5~6元杂环烷基取代的C1~C3烷基;
R9和R10分别独立地选自:H、C1~C10烷基;
各R11分别独立地选自:H、C1~C10烷基、硝基、C1~C10烷氧基或卤素;
各R分别独立地选自:H。
2.根据权利要求1所述的含脲结构的三芳环化合物或其药学上可接受的盐,其特征在于,所述含脲结构的三芳环化合物具有式(II)、(III)、(IV)或(V)所示结构:
3.根据权利要求1所述的含脲结构的三芳环化合物或其药学上可接受的盐,其特征在于,所述含脲结构的三芳环化合物具有式(VI)、(VII)、(VIII)、(IX)、(X)或(XI)所示结构:
其中,q选自0、1、2、3、4、5。
4.根据权利要求1-3任一项所述的含脲结构的三芳环化合物或其药学上可接受的盐,其特征在于,Z为O。
5.根据权利要求1所述的含脲结构的三芳环化合物或其药学上可接受的盐,其特征在于,Y1为N,Y2为CH,Y3为CR10,Z为O;其中,R10选自:H、或C1~C6烷基。
6.根据权利要求1所述的含脲结构的三芳环化合物或其药学上可接受的盐,其特征在于,A1、B1、D1和E1中的一个为CR12,另外三个为CH,R12选自:H、氟、氯、溴、C1~C3烷基、硝基、C1~C3烷氧基;和/或,
A2、B2、D2和E2中的一个为CR13,另外三个为CH,R13选自:H、氟、氯、溴、C1~C3烷基、硝基、C1~C3烷氧基。
7.根据权利要求6所述的含脲结构的三芳环化合物或其药学上可接受的盐,其特征在于,B2或者D2为CR13,R13选自:H、氟、氯、溴、C1~C3烷基、C1~C3烷氧基。
8.根据权利要求1-3任一项所述的含脲结构的三芳环化合物或其药学上可接受的盐,其特征在于,m为0或1,n为0或1。
9.根据权利要求1-3任一项所述的含脲结构的三芳环化合物或其药学上可接受的盐,其特征在于,R4选自:H。
10.根据权利要求1-3任一项所述的含脲结构的三芳环化合物或其药学上可接受的盐,其特征在于,R5,R6分别独立地选自:C1~C6烷基,或者R5、R6与和其相连的N原子一起形成1个或多个R7取代或者未取代的5~6元杂环烷基。
11.根据权利要求10所述的含脲结构的三芳环化合物或其药学上可接受的盐,其特征在于,R5,R6分别独立地选自:C1~C3烷基,或者R5、R6与和其相连的N原子一起形成5~6元杂环烷基。
12.根据权利要求11所述的含脲结构的三芳环化合物或其药学上可接受的盐,其特征在于,R1选自: 或者R1与D1一起形成如下结构:/>
13.根据权利要求1-3任一项所述的含脲结构的三芳环化合物或其药学上可接受的盐,其特征在于,各R2分别独立地选自:H、C1~C6烷氧羰基。
14.根据权利要求1-3任一项所述的含脲结构的三芳环化合物或其药学上可接受的盐,其特征在于,各R3分别独立地选自:H、-SR8;R8选自:H、C1~C3烷基、或5~6元杂环烷基取代的C1~C3烷基。
15.含脲结构的三芳环化合物或其药学上可接受的盐,其特征在于,所述含脲结构的三芳环化合物选自如下化合物:
16.权利要求1-15任一项所述的含脲结构的三芳环化合物或其药学上可接受的盐在制备激酶抑制剂中的应用,所述激酶为:FLT3激酶,RET激酶。
17.权利要求1-15任一项所述的含脲结构的三芳环化合物或其药学上可接受的盐在制备预防和/或治疗RET激酶和/或FLT3激酶相关疾病的药物中的应用。
18.根据权利要求17所述的应用,其特征在于,所述RET激酶和/或FLT3激酶相关疾病为肿瘤,所述肿瘤为:白血病、非小细胞肺癌、小细胞肺癌、肺腺癌、肺鳞癌、胰腺癌、乳腺癌、前列腺癌、肝癌、皮肤癌、上皮细胞癌、胃肠间质瘤、组织细胞性淋巴癌、鼻咽癌。
19.一种预防和/或治疗肿瘤的药用组合物,其特征在于,由活性成分和药学上可接受的辅料制备得到,所述活性成分包括权利要求1-15任一项所述的含脲结构的三芳环化合物或其药学上可接受的盐。
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