CN101085759A - 作为激酶抑制剂的氨基-2,3-二氮杂萘酮衍生物,它们的制备方法和含有它们的药物组合物 - Google Patents
作为激酶抑制剂的氨基-2,3-二氮杂萘酮衍生物,它们的制备方法和含有它们的药物组合物 Download PDFInfo
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- CN101085759A CN101085759A CNA2007101101264A CN200710110126A CN101085759A CN 101085759 A CN101085759 A CN 101085759A CN A2007101101264 A CNA2007101101264 A CN A2007101101264A CN 200710110126 A CN200710110126 A CN 200710110126A CN 101085759 A CN101085759 A CN 101085759A
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- Prior art keywords
- dihydro
- oxo
- phenyl
- urea
- benzyl
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Abstract
本发明公开了根据式I的氨基-2,3-二氮杂萘酮衍生物及其药学可接受盐,以及含有它们的药物组合物;这些化合物或组合物用于治疗改变的蛋白激酶活性引起的疾病和/或与之相关的疾病,例如癌,细胞增殖性疾病,阿尔海默氏病,病毒感染,自身免疫疾病和神经变性疾病。
Description
本发明是申请日为2002年7月30日的中国专利申请02815419.3的分案申请,原申请的发明名称为“作为激酶抑制剂的氨基-2,3-二氮杂萘酮衍生物,它们的制备方法和含有它们的药物组合物”。
本发明涉及有作为激酶抑制剂的氨基-2,3-二氮杂萘酮衍生物,更具体地,涉及7-氨基-2,3-二氮杂萘-1-酮衍生物,它们的制备方法,含有它们的药物组合物和它们作为治疗药物的用途,特别是在与调节失常(disregulated)蛋白质激酶相关的疾病的治疗中的用途。
蛋白质激酶(PKs)的功能失常是多种疾病的标记。在人恶性肿瘤中涉及的编码PKs的致癌基因和原癌基因同源性很大。在很多非恶性病变中还涉及提高的PKs活性,所述非恶性病变例如良前列腺增生,家族性腺瘤病,息肉病,多发性神经纤维瘤,牛皮癣,与动脉粥样硬化相关的血管平滑细胞增生,肺纤维化,关节炎肾小球性肾炎和手术后狭窄和再狭窄。
炎性症状中以及病毒和寄生虫增殖中也涉及PKs。PKs在神经变性疾病的发病和发展中也起着主要作用。
有关PKs机能障碍或调节失常的一般参考参见,例如,CurrentOpinion in Chemical Biology 1999,3,459-465。
本发明的一个目的提供在治疗中用作对由调节失常的蛋白质激酶活性引起的疾病和/或相关疾病患者治疗的药物的化合物。
发明的另一个目的是提供赋有多种蛋白质激酶抑制活性的化合物。
本发明人现在发现一些7-氨基-2,3-二氮杂萘-1-酮衍生物,下文中简称为氨基-2,3-二氮杂萘酮衍生物或氨基-2,3-二氮杂萘酮类,赋有多种蛋白质激酶抑制活性,因此在治疗与调节失常的蛋白质激酶相关的疾病的治疗法中是有用的。
更具体地,本发明的氨基-2,3-二氮杂萘酮类在治疗各种癌症中是有用的,包括但不限于:癌,例如膀胱癌,乳腺癌,结肠癌,肾癌,肝癌,肺癌,包括小细胞肺癌,食道癌,胆汁-膀胱癌,卵巢癌,胰腺癌,胃癌,子宫颈癌,甲状腺癌,前列腺癌,和皮肤癌,包括鳞状细胞癌;淋巴系造血瘤,包括白血病,急性细胞白血病,急性淋巴母细胞白血病,B-细胞淋巴瘤,T-细胞淋巴瘤,Hodgkin’s淋巴瘤,非-Hodgkin’s淋巴瘤,毛细胞淋巴瘤和Burkett’s淋巴瘤;髓系造血瘤,包括急性和慢性骨髓性白血病,骨髓发育异常综合征和早幼粒细胞白血病;间充质起因的肿瘤,包括纤维肉瘤和横纹肌肉瘤;中枢和末鞘神经系统肿瘤,包括星形细胞瘤,神经胚细胞瘤,神经胶质瘤和神经鞘瘤;其它肿瘤,包括黑素瘤,精原细胞瘤,恶性畸胎瘤,骨肉瘤,着色性干皮病(pigmentosum),角化棘皮瘤,甲状腺滤泡样癌和Kaposi’s肉瘤。
由于PKs在细胞增殖调节中的作用,这些氨基-2,3-二氮杂萘酮类在对各种各样的细胞增殖性疾病的治疗中也是有用的,例如,良性前列腺增生,家族性腺瘤病,息肉病,多发性神经纤维瘤,牛皮癣,与动脉粥样硬化相关的血管平滑细胞增生,肺纤维化,关节炎肾小珠性肾炎和手术后狭窄和再狭窄。
本发明的化合物可以用于治疗阿尔茨海默氏病,这一点是τ蛋白质的磷酸化作用中涉及cdk5这一事实提示的(J.Biochem.,117,741-749,1995)。
本发明的化合物作为编程性细胞死亡的调制剂在治疗癌症、病毒感染、预防HIV感染个体发生AIDS、预防自身免疫疾病和神经变性疾病中是有用的。
本发明的化合物还用于抑制肿瘤血管生成和转移。
本发明的化合物用作依赖于细胞周期蛋白的激酶(cdk)抑制剂,还用作其它蛋白激酶例如不同异构形式的蛋白激酶C,Met,PAK-4,PAK-5,ZC-1,STLK-2,DDR-2,Aurora 1,Aurora 2,Bub-1,PLK,Chk1,Chk2,HER2,rafl,MEK1,MAPK,EGF-R,PDGF-R,FGF-R,IGF-R,VEGF-R,PI3K,weel激酶,Src,Abl,Akt,ILK,MK-2,IKK-2,Cdc7,Nek的抑制剂,因此在治疗与其它蛋白激酶相关的疾病中是有效的。
本领域已知一些氨基-2,3-二氮杂萘酮和氨基-2,3-二氮杂萘二酮衍生物是化学中间体,治疗药物,甚至是蛋白质激酶抑制剂。
作为例子,Heisei在JP-A-09061961中公开了化合物N-[3-[2,4-双(1,1-二甲基丙基)苯氧基]丙基]-N’-(3,4-二氢-4-氧代-6-2,3-二氮杂萘基)-脲和2-[2,4-双(1,1-二甲基丙基)苯氧基]-N-(3,4-二氢-4-氧代-6-2,3-二氮杂萘基)-丁酰胺是心脏显影造影剂。
Heisei的JP-A-10287658公开了化合物N-[3,4-二氢-3-[4-[4-(1-萘基)-1-哌嗪基]丁基]-4-氧代-6-2,3-二氮杂萘基]-乙酰胺是5-羟色胺/多巴胺能物质。
Novartis在WO 98/35958中公开了化合物N-[3,4-二氢-4-氧代-1-(4-吡啶基甲基)-6-2,3-二氮杂萘基]-乙酰胺和N-[3,4-二氢-4-氧代-1-(4-吡啶基甲基)-6-2,3-二氮杂萘基]-2,2,2-三氟-乙酰胺是制备VEGF受体酪氨酸激酶抑制剂苯胺基-2,3-二氮杂萘的合成中间体。
除如上所述之外,Ciba-Geigy在EP-A-600831中公开环上6和7两个位置带有取代的氨基的2,3-二氮杂萘二酮或2,3-二氮杂萘酮衍生物,例如7-(环己基氨基)-6-苯基氨基-1(2H)-2,3-二氮杂萘酮和6,7-双(苯基氨基)-1(2H)-2,3-二氮杂萘酮是蛋白质激酶抑制剂。
因此,本发明提供通过对需要的哺乳动物施用有效量的式(I)代表的氨基-2,3-二氮杂萘酮衍生物治疗由改变的蛋白质激酶活性引起的疾病和/或与之相关的疾病的方法:
其中
Ra和Rb各自独立地是氢原子或任选地进一步被取代的选自下面的基团:直链或支链C1-C6烷基,C3-C6环烷基或环烷基C1-C6烷基,芳基,芳基C1-C6烷基,5至7元杂环基或者具有1-3个选自氮,氧或硫的杂原子的杂环基C1-C6烷基;或者Ra或Rb之一是氢或任意地被取代的直链或支链C1-C6烷基,另一个是选自-COR’,-CONHR’,-COOR’或-SO2R’的基团,其中R’是氢或任选地被取代的选自上述烷基,环烷基,环烷基烷基,芳基,芳基烷基,杂环基或杂环基烷基的基团;
R1是式-CHR4R5基团,其中R4和R5各自独立地是氢或者任意地被取代的选自直链或支链C1-C6烷基,C3-C6环烷基或环烷基C1-C6烷基,芳基,芳基C1-C6烷基,5至7元杂环基或者具有1-3个选自氮,氧或硫的杂原子的杂环基C1-C6烷基的基团;或者R1是式-NHR’,-NR’COR″,-NR’CONHR″或-NR’SO2R″,其中R’具有上述氢以外的定义,R″是氢或具有上面对于R’的定义;
R2是氢原子或任选地进一步被取代的选自下面的基团:直链或支链C1-C6烷基,C3-C6环烷基或环烷基C1-C6烷基,芳基,芳基C1-C6烷基,5至7元杂环基或者具有1-3个选自氮,氧或硫的杂原子的杂环基C1-C6烷基;
2,3-二氮杂萘酮环上自由位置5,6和8中的一个或多个上的任何R3各自独立地是卤原子,硝基,羧基,氰基或者任选地进一步被取代的选自下面的基团:直链或支链C1-C6烷基,C3-C6环烷基或环烷基C1-C6烷基,芳基,芳基C1-C6烷基,5至7元杂环基或者具有1-3个选自氮,氧或硫的杂原子的杂环基C1-C6烷基;或者R3是选自-COR’,-CONHR’,-SO2R’,-NR’R″,-NR’COR″,-NR’CONHR’或-NR’SO2R″的基团,其中R’和R″是相同或不同的,是氢或者上面提到的基团;m是0或1-3的整数;或者其药学可接受的盐。
在上述方法的优选的实施方案中,由改变的蛋白质激酶活性引起的疾病和/或与之相关的疾病选自癌,细胞增殖性疾病,阿尔茨海默氏病,病毒感染,自身免疫疾病和神经变性疾病。
可以治疗的癌症的具体类型包括癌,鳞状细胞癌,髓系或淋巴系造血瘤,间充质起因的肿瘤,中枢和末稍神经系统肿瘤,精原细胞瘤,畸胎瘤,骨肉瘤,着色性干皮病,角化棘皮瘤,淋巴腺滤泡样癌和Kaposi’s肉瘤。
在上述方法的另一个优选的实施方案中,细胞增殖性疾病选自良性前列腺增生,家族性腺瘤病,息肉病,神经-纤维瘤病,牛皮癣,与动脉粥样硬化相关的血管平滑细胞增殖,肺纤维变性,关节炎肾小珠性肾炎和手术后狭窄和再狭窄。
另外,本发明的方法目的还提供肿瘤血管生成和转移抑制。
本发明进一步提供式(I)代表的氨基-2,3-二氮杂萘酮衍生物:
其中
Ra和Rb各自独立地是氢原子或任选地进一步被取代的选自下面的基团:直链或支链C1-C6烷基,C3-C6环烷基或环烷基C1-C6烷基,芳基,芳基C1-C6烷基,5至7元杂环基或者具有1-3个选自氮,氧或硫的杂原子的杂环基C1-C6烷基;或者Ra或Rb之一是氢或任意地被取代的直链或支链C1-C6烷基,另一个是选自-COR’,-CONHR’,-COOR’或-SO2R’的基团,其中R’是氢或任选地被取代的选自上述烷基,环烷基,环烷基烷基,芳基,芳基烷基,杂环基或杂环基烷基的基团;
R1是式-CHR4R5基团,其中R4和R5各自独立地是氢或者任意地被取代的选自直链或支链C1-C6烷基,C3-C6环烷基或环烷基C1-C6烷基,芳基,芳基C1-C6烷基,5至7元杂环基或者具有1-3个选自氮,氧或硫的杂原子的杂环基C1-C6烷基的基团;或者R1是式-NHR’,-NR’COR″,-NR’CONHR″或-NR’SO2R″,其中R’具有上述氢以外的定义,R″是氢或具有上面对于R’的定义;
R2是氢原子或任选地进一步被取代的选自下面的基团:直链或支链C1-C6烷基,C3-C6环烷基或环烷基C1-C6烷基,芳基,芳基C1-C6烷基,5至7元杂环基或者具有1-3个选自氮,氧或硫的杂原子的杂环基C1-C6烷基;
2,3-二氮杂萘酮环上自由位置5,6和8中的一个或多个上的任何R3各自独立地是卤原子,硝基,羧基,氰基或者任选地进一步被取代的选自下面的基团:直链或支链C1-C6烷基,C3-C6环烷基或环烷基C1-C6烷基,芳基,芳基C1-C6烷基,5至7元杂环基或者具有1-3个选自氮,氧或硫的杂原子的杂环基C1-C6烷基;或者R3是选自-COR’,-CONHR’,-SO2R’,-NR’R″,-NR’COR″,-NR’CONHR’或-NR’SO2R″的基团,其中R’和R″是相同或不同的,是氢或者上面提到的基团;m是0或1-3的整数;或者其药学可接受的盐;
不包括化合物N-[3,4-二氢-4-氧代-1-(4-吡啶基甲基)-6-2,3-二氮杂萘基]-乙酰胺和N-[3,4-二氢-4-氧代-1-(4-吡啶基甲基)-6-2,3-二氮杂萘基]-2,2,2-三氟-乙酰胺。
本发明的目的,式(I)的化合物,具有不对称碳原子,因此可以作为外消旋混合物或者作为各个旋光异构体而存在。
因此,所有可能的异构体和它们的混合物和式(I)的化合物的两种代谢物和药学可接受生物前体(另外称为前体药物)的所有可能的异构体和它们的混合物,以及包含它们的任何治疗方法也在本发明的范围内。
如这里使用的,除非另有说明,术语卤原子意指氯,溴,氟或碘原子。
关于术语直链或支链C1-C6烷基我们意指象例如甲基,乙基,正丙基,异丙基,正丁基,异丁基,仲丁基,叔丁基,正戊基,正己基等这样的基团。
关于术语C3-C6环烷基我们意指象例如环丙基,环丁基,环戊基或环己基这样的基团。
关于术语芳基我们意指具有1-4个环部分、或者彼此稠合或者通过单键连接的一-,二-或多-碳环和杂环烃,其中碳环或杂环中至少-个是芳香的。
芳基的非限制性例子是,例如苯基,2,3-二氢化茚基,联苯基,α-或β-萘基,芴基,9,10-二氢蒽基,吡啶基,吡嗪基,嘧啶基,哒嗪基,吲哚基,咪唑基,咪唑并吡啶基,1,2-亚甲基二氧苯基,噻唑基,异噻唑基,吡咯基,吡咯基-苯基,呋喃基,苯基-呋喃基,苯并四氢呋喃基,唑基,异唑基,吡唑基,苯并吡喃基,噻吩基,苯并噻吩基,异吲哚啉基,苯并咪唑基,异吲哚啉基-苯基,喹啉基,异喹啉基,2,6-二苯基-吡啶基,喹喔啉基,吡嗪基,苯基-喹啉基,苯并呋咱基,1,2,3-三唑基,1-苯基-1,2,3-三唑基等。
关于术语5-7元杂环基因此包括芳香的杂环基也称作芳基,我们进一步意指饱和的或部分饱和的5-7元碳环,其中一个或多个碳原子被1-3个杂原子例如氮,氧和硫置换。
除了上述杂芳基之外,任意地苯并稠合的或进一步被取代的5-7元杂环基的另外的例子是1,3-二氧戊环,吡喃,吡咯烷,吡咯啉,咪唑烷,吡唑烷,吡唑啉,哌啶,哌嗪,吗啉,四氢呋喃,吖庚因(azepine),二氮杂等。
根据本发明式(I),本领域技术人员清楚,当m是0时,没有R3基团,或者换句话说,如下编号系统的2,3-二氮杂萘酮环的5,6和8位是未取代的或者氢取代的
同样,当m是1或2时,在5,6或8位的一处或两处存在一个或两个R3取代基,彼此是相同或不同的;最后,当m是3时,所有可能的5,6和8位都有如上所述的R3基团,它们是相同或不同的。
根据上文对Ra,Rb,R’,R″,R2,R3,R4和R5取代基的定义,上述基团的任何定义在任何自由位置任意地被一个或多个例如1-6个选自下面的基团取代:卤原子,硝基,氧基(=O),羧基,氰基,烷基,全氟化烷基,链烯基,炔烃基,环烷基,芳基,杂环基,氨基及其衍生物,例如,烷基氨基,二烷基氨基,芳基氨基,二芳基氨基,脲基,烷基脲基或芳基脲基;羰基氨基及其衍生物,例如,甲酰基氨基,烷基羰基氨基,链烯基羰基氨基,芳基羰基氨基,烷氧羰基氨基;羟基及其衍生物,例如,烷氧基,芳基氧基,烷基羰基氧基,芳基羰基氧基,环烯基氧基或亚烷基氨基氧基;羰基及其衍生物,例如,烷基羰基,芳基羰基,烷氧羰基,芳基氧羰基,环烷基氧羰基,氨基羰基,烷基氨基羰基,二烷基氨基羰基;含硫衍生物例如,烷硫基,芳硫基,烷基磺酰基,芳基磺酰基,烷基亚磺酰基,芳基亚磺酰基,芳基磺酰基氧基,氨基磺酰基,烷基氨基磺酰基或二烷基氨基磺酰基。
接着,适当情况下,上述各个取代基可以进一步被一个或多个上述基团取代。
在后面这些基团中,除非在说明书中具体说明,对于术语全氟化烷基,我们意指如上定义的直链或支链C1-C6烷基,其中一个以上的氢原子被氟原子置换。全氟化烷基的例子是,例如,三氟甲基,2,2,2-三氟乙基,1,2-二氟乙基,1,1,1,3,3,3-六氟丙基-2-基等。
对于术语链烯基或炔烃基,我们意指直链或支链C2-C6链烯基或炔烃基象,例如乙烯基,烯丙基,异丙烯基,1-,2-或3-丁烯基,异丁烯基,己烯基,乙炔基,1-或2-丙炔基,丁炔基等。
如上所述,有一点对于技术人员是清楚的,即名称鉴定为复合名称的任何基团象,例如,环烷基烷基,芳基烷基,杂环基烷基,烷氧基,烷硫基,芳基氧基,芳基烷氧基,杂环基氧基,杂环基烷氧基,烷基羰基氧基等,意指它所衍生部分常规构成的。
作为一个例子,术语杂环基-烷氧基指进一步被杂环基取代的烷氧基(例如烷基-氧基)。
式(I)的化合物的药学可接受盐是与无机酸或有机酸的酸加成盐,例如硝酸,盐酸,氢溴酸,硫酸,高氯酸,磷酸,乙酸,三氟乙酸,丙酸,乙醇酸,乳酸,草酸,丙二酸,苹果酸,马来酸,酒石酸,柠檬酸,苯甲酸,肉桂酸,扁桃酸,甲磺酸,羟乙磺酸(isethionic)和水杨酸,以及与无机碱或有机碱的盐,例如碱金属或碱土金属,特别是钠,钾,钙或镁氢氧化物,碳酸盐或碳酸氢盐,无环的或环胺类,优选甲胺,乙胺,二乙胺,三乙胺或哌啶.
式(I)的化合物代表本发明优选的一类化合物,其中Ra或Rb之一是氢原子或者任选被取代的直链或支链C1-C6烷基,另一个是基团-COR’,其中R’是上文提到的任选被取代的选自烷基,环烷基,环烷基烷基,芳基,芳基烷基,杂环基或杂环基烷基的基团,和R1,R2,R3和m如上定义。
在这类化合物中,更优选的是式(I)的化合物,其中R1是基团-CHR4R5,其中R4和R5如上定义,R2是氢和m是0。
式(I)的化合物代表本发明另一类优选的化合物,其中Ra或Rb之一是氢原子或者任选被取代的直链或支链C1-C6烷基,另一个是基团-CONHR’,其中R’是氢原子或者上文提到的任选被取代的选自烷基,环烷基,环烷基烷基,芳基,芳基烷基,杂环基或杂环基烷基的基团,和R1,R2,R3和m如上定义。
在这类化合物中,更优选的是式(I)的化合物,其中R1是基团-CHR4R5,其中R4和R5如上定义,R2是氢和m是0。
式(I)的化合物代表本发明另一类优选的化合物,其中Ra或Rb之一是氢原子或者任选被取代的直链或支链C1-C6烷基,另一个是基团-COOR’,其中R’是氢原子或者上文提到的任选被取代的选自烷基,环烷基,环烷基烷基,芳基,芳基烷基,杂环基或杂环基烷基的基团,和R1,R2,R3和m如上定义。
在这类化合物中,更优选的是式(I)的化合物,其中R1是基团-CHR4R5,其中R4和R5如上定义,R2是氢和m是0。
式(I)的化合物代表本发明另一类优选的化合物,其中Ra或Rb之一是氢原子或者任选被取代的直链或支链C1-C6烷基,另一个是基团-SO2R’,其中R’是上文提到的任选被取代的选自烷基,环烷基,环烷基烷基,芳基,芳基烷基,杂环基或杂环基烷基的基团,和R1,R2,R3和m如上定义。
在这类化合物中,更优选的是式(I)的化合物,其中R1是基团-CHR4R5,其中R4和R5如上定义,R2是氢和m是0。
式(I)的化合物代表本发明另一类优选的化合物,其中Ra和Rb两者都是氢原子,和R1,R2,R3和m如上定义。
在这类化合物中,更优选的是式(I)的化合物,其中R1是基团-CHR4R5,其中R4和R5如上定义,R2是氢和m是0。
式(I)的化合物代表本发明另一类优选的化合物,其中Ra或Rb之一是氢原子或者任选被取代的直链或支链C1-C6烷基,另一个是上文提到的任选被取代的选自烷基,环烷基烷基,芳基烷基,或杂环基烷基的基团,和R1,R2,R3和m如上定义。
在这类化合物中,更优选的是式(I)的化合物,其中R1是基团-CHR4R5,其中R4和R5如上定义,R2是氢和m是0。
本发明式(I)的优选化合物的具体例子,任选以药学可接受盐的形式存在,是:
1.4-(4-氧代-6-丙酰基氨基-3,4-二氢-2,3-二氮杂萘-1-基甲基)-苯甲酸甲酯;
2.4-(4-氧代-6-(4-三氟甲基-苯甲酰氨基)-3,4-二氢-2,3-二氮杂萘-1-基甲基)-苯甲酸甲酯;
3.4-{6-[(呋喃-2-羰基)-氨基]-4-氧代-3,4-二氢-2,3-二氮杂萘-1-基甲基]-苯甲酸甲酯;
4.4-(6-(3,4-二甲氧基-苯甲酰氨基)-4-氧代-3,4-二氢-2,3-二氮杂萘-1-基甲基)-苯甲酸甲酯;
5.4-(6-(3-环戊基-丙酰氨基)-4-氧代-3,4-二氢-2,3-二氮杂萘-1-基甲基)-苯甲酸甲酯;
6.4-[4-氧代-6-(2-丙基-戊酰基氨基)-3,4-二氢-2,3-二氮杂萘-1-基甲基]-苯甲酸甲酯;
7.4-{4-氧代-6-[3-(3-三氟甲基-苯基)-脲基]-3,4-二氢-2,3-二氮杂萘-1-基甲基}-苯甲酸甲酯;
8.4-{6-[3-(3-甲氧基-苯基)-脲基]-4-氧代-3,4-二氢-2,3-二氮杂萘-1-基甲基}-苯甲酸甲酯;
9.4-[4-氧代-6-(3-对-甲苯基-脲基)-3,4-二氢-2,3-二氮杂萘-1-基甲基]-苯甲酸甲酯;
10.4-{6-[3-(2,4-二氟-苯基)-脲基]-4-氧代-3,4-二氢-2,3-二氮杂萘-1-基甲基}-苯甲酸甲酯;
11.4-{6-[3-(3,4-二氯-苯基)-脲基]-4-氧代-3,4-二氢-2,3-二氮杂萘-1-基甲基}-苯甲酸甲酯;
12.4-[4-氧代-6-(3-吡啶-3-基-脲基)-3,4-二氢-2,3-二氮杂萘-1-基甲基]-苯甲酸甲酯;
13.4-(6-氨基-4-氧代-3,4-二氢-2,3-二氮杂萘-1-基甲基)-苯甲酸甲酯;
14.N-[1-(4-氯-3-氟-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-丙酰胺;
15.N-[1-(4-氯-3-氟-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-4-三氟甲基-苯甲酰胺;
16.呋喃-2-甲酸[1-(4-氯-3-氟-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-酰胺;
17.N-[1-(4-氯-3-氟-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-3,4-二甲氧基-苯甲酰胺;
18.N-[1-(4-氯-3-氟-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-3-环戊基-丙酰胺;
19.2-丙基-戊酸[1-(4-氯-3-氟-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]酰胺;
20.1-[1-(4-氯-3-氟-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-3-(3-三氟甲基-苯基)-脲;
21.1-[1-(4-氯-3-氟-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-3-(3-甲氧基-苯基)-脲;
22.1-[1-(4-氯-3-氟-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-3-对-甲苯基-脲;
23.1-[1-(4-氯-3-氟-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-3-(2,4-二氟-苯基)-脲;
24.1-[1-(4-氯-3-氟-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-3-(3,4-二氯-苯基)-脲;
25.1-[1-(4-氯-3-氟-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-3-吡啶-3-基-脲;
26.7-氨基-4-(4-氯-3-氟-苄基)-2H-2,3-二氮杂萘-1-酮;
27.N-{1-[(E)-3-(4-硝基-苯基)-烯丙基]-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基}-丙酰胺;
28.N-{1-[(E)-3-(4-硝基-苯基)-烯丙基]-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基}-4-三氟甲基-苯甲酰胺;
29.呋喃-2-甲酸{1-[(E)-3-(4-硝基-苯基)-烯丙基]-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基}-酰胺;
30.N-{1-[(E)-3-(4-硝基-苯基)-烯丙基]-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基}-3,4-二甲氧基-苯甲酰胺;
31.N-{1-[(E)-3-(4-硝基-苯基)-烯丙基]-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基}-3-环戊基-丙酰胺;
32.2-丙基-戊酸{1-[(E)-3-(4-硝基-苯基)-烯丙基]-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基}-酰胺;
33.1-{1-[(E)-3-(4-硝基-苯基)-烯丙基]-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基}-3-(3-三氟甲基-苯基)-脲;
34.1-{1-[(E)-3-(4-硝基-苯基)-烯丙基]-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基}-3-(3-甲氧基-苯基)-脲;
35.1-{1-[(E)-3-(4-硝基-苯基)-烯丙基]-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基}-3-对-甲苯基-脲;
36.1-{1-[(E)-3-(4-硝基-苯基)-烯丙基]-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基}-3-(2,4-二氟-苯基)-脲;
37.1-{1-[(E)-3-(4-硝基-苯基)-烯丙基]-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基}-3-(3,4-二氯-苯基)-脲;
38.1-{1-[(E)-3-(4-硝基-苯基)-烯丙基]-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基}-3-吡啶-3-基-脲;
39.7-氨基-4-[(E)-3-(4-硝基-苯基)-烯丙基]-2H-2,3-二氮杂萘-1-酮;
40.N-(4-氧代-1-噻吩-3-基甲基-3,4-二氢-2,3-二氮杂萘-6-基)-丙酰胺;
41.N-(4-氧代-1-噻吩-3-基甲基-3,4-二氢-2,3-二氮杂萘-6-基)-4-三氟甲基-苯甲酰胺;
42.呋喃-2-甲酸(4-氧代-1-噻吩-3-基甲基-3,4-二氢-2,3-二氮杂萘-6-基)-酰胺;
43.N-(4-氧代-1-噻吩-3-基甲基-3,4-二氢-2,3-二氮杂萘-6-基)-3,4-二甲氧基-苯甲酰胺;
44.N-(4-氧代-1-噻吩-3-基甲基-3,4-二氢-2,3-二氮杂萘-6-基)-3-环戊基-丙酰胺;
45.2-丙基-戊酸(4-氧代-1-噻吩-3-基甲基-3,4-二氢-2,3-二氮杂萘-6-基)-酰胺;
46.1-(4-氧代-1-噻吩-3-基甲基-3,4-二氢-2,3-二氮杂萘-6-基)-3-(3-三氟甲基-苯基)-脲;
47.1-(4-氧代-1-噻吩-3-基甲基-3,4-二氢-2,3-二氮杂萘-6-基)-(3-甲氧基-苯基)-脲;
48.1-(4-氧代-1-噻吩-3-基甲基-3,4-二氢-2,3-二氮杂萘-6-基)-3-对-甲苯基-脲;
49.1-(4-氧代-1-噻吩-3-基甲基-3,4-二氢-2,3-二氮杂萘-6-基)-3-(2,4-二氟-苯基)-脲;
50.1-(4-氧代-1-噻吩-3-基甲基-3,4-二氢-2,3-二氮杂萘-6-基)-3-(3,4-二氯-苯基)-脲;
51.1-(4-氧代-1-噻吩-3-基甲基-3,4-二氢-2,3-二氮杂萘-6-基)-3-吡啶-3-基-脲;
52.7-氨基-4-噻吩-3-基甲基-2H-2,3-二氮杂萘-1-酮;
53.N-[1-(3-甲氧基-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-丙酰胺;
54.N-[1-(3-甲氧基-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-4-三氟甲基-苯甲酰基;
55.呋喃-2-甲酸[1-(3-甲氧基-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-酰胺;
56.N-[1-(3-甲氧基-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-3,4-二甲氧基-苯甲酰胺;
57.N-[1-(3-甲氧基-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-3-环戊基-丙酰胺;
58.2-丙基-戊酸[1-(3-甲氧基-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-酰胺;
59.1-[1-(3-甲氧基-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-3-(3-三氟甲基-苯基)-脲;
60.1-[1-(3-甲氧基-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-(3-甲氧基-苯基)-脲;
61.1-[1-(3-甲氧基-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-3-对-甲苯基-脲;
62.1-[1-(3-甲氧基-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-3-(2,4-二氟-苯基)-脲;
63.1-[1-(3-甲氧基-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-3-(3,4-二氯-苯基)-脲;
64.1-[1-(3-甲氧基-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-3-吡啶-3-基-脲;
65.7-氨基-4-(3-甲氧基-苄基)-2H-2,3-二氮杂萘-1-酮;
66.N-(4-氧代-1-丙基-3,4-二氢-2,3-二氮杂萘-6-基)丙酰胺;
67.N-(4-氧代-1-丙基-3,4-二氢-2,3-二氮杂萘-6-基)-4-三氟甲基-苯甲酰胺;
68.呋喃-2-甲酸(4-氧代-1-丙基-3,4-二氢-2,3-二氮杂萘-6-基)-酰胺;
69.N-(4-氧代-1-丙基-3,4-二氢-2,3-二氮杂萘-6-基)-3,4-二甲氧基-苯甲酰胺;
70.N-(4-氧代-1-丙基-3,4-二氢-2,3-二氮杂萘-6-基)-3-环戊基-丙酰胺;
71.2-丙基-戊酸(4-氧代-1-丙基-3,4-二氢-2,3-二氮杂萘-6-基)-酰胺;
72.1-(4-氧代-1-丙基-3,4-二氢-2,3-二氮杂萘-6-基)-3-(3-三氟甲基-苯基)-脲;
73.1-(4-氧代-1-丙基-3,4-二氢-2,3-二氮杂萘-6-基)-(3-甲氧基-苯基)-脲;
74.1-(4-氧代-1-丙基-3,4-二氢-2,3-二氮杂萘-6-基)-3-对-甲苯基-脲;
75.1-(4-氧代-1-丙基-3,4-二氢-2,3-二氮杂萘-6-基)-3-(2,4-二氟-苯基)-脲;
76.1-(4-氧代-1-丙基-3,4-二氢-2,3-二氮杂萘-6-基)-3-(3,4-二氯-苯基)-脲;
77.1-(4-氧代-1-丙基-3,4-二氢-2,3-二氮杂萘-6-基)-3-吡啶-3-基-脲;
78.7-氨基-4-丙基-2H-2,3-二氮杂萘-1-酮;
79.N-[1-(3,3-二甲基-丁基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-丙酰胺;
80.N-[1-(3,3-二甲基-丁基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-4-三氟甲基-苯甲酰胺;
81.呋喃-2-甲酸[1-(3,3-二甲基-丁基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-酰胺;
82.N-[1-(3,3-二甲基-丁基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-3,4-二甲氧基-苯甲酰胺;
83.N-[1-(3,3-二甲基-丁基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-3-环戊基-丙酰胺;
84.2-丙基-戊酸[1-(3,3-二甲基-丁基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-酰胺;
85.1-[1-(3,3-二甲基-丁基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-3-(3-三氟甲基-苯基)-脲;
86.1-[1-(3,3-二甲基-丁基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-(3-甲氧基-苯基)-脲;
87.1-[1-(3,3-二甲基-丁基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-3-对-甲苯基-脲;
88.1-[1-(3,3-二甲基-丁基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-3-(2,4-二氟-苯基)-脲;
89.1-[1-(3,3-二甲基-丁基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-3-(3,4-二氯-苯基)-脲;
90.1-[1-(3,3-二甲基-丁基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-3-吡啶-3-基-脲;
91.7-氨基-4-(3,3-二甲基-丁基)-2H-2,3-二氮杂萘-1-酮;
92.N-[4-氧代-1-(3-苯基-丙基)-3,4-二氢-2,3-二氮杂萘-6-基]-丙酰胺;
93.N-[4-氧代-1-(3-苯基-丙基)-3,4-二氢-2,3-二氮杂萘-6-基]-4-三氟甲基-苯甲酰胺;
94.呋喃-2-甲酸[4-氧代-1-(3-苯基-丙基)-3,4-二氢-2,3-二氮杂萘-6-基]-酰胺;
95.N-[4-氧代-1-(3-苯基-丙基)-3,4-二氢-2,3-二氮杂萘-6-基]-3,4-二甲氧基-苯甲酰胺;
96.N-[4-氧代-1-(3-苯基-丙基)-3,4-二氢-2,3-二氮杂萘-6-基]-3-环戊基-丙酰胺;
97.2-丙基-戊酸[4-氧代-1-(3-苯基-丙基)-3,4-二氢-2,3-二氮杂萘-6-基]-酰胺;
98.1-[4-氧代-1-(3-苯基-丙基)-3,4-二氢-2,3-二氮杂萘-6-基]-3-(3-三氟甲基-苯基)-脲;
99.1-[4-氧代-1-(3-苯基-丙基)-3,4-二氢-2,3-二氮杂萘-6-基]-(3-甲氧基-苯基)-脲;
100.1-[4-氧代-1-(3-苯基-丙基)-3,4-二氢-2,3-二氮杂萘-6-基]-3-对-甲苯基-脲;
101.1-[4-氧代-1-(3-苯基-丙基)-3,4-二氢-2,3-二氮杂萘-6-基]-3-(2,4-二氟-苯基)-脲;
102.1-[4-氧代-1-(3-苯基-丙基)-3,4-二氢-2,3-二氮杂萘-6-基]-3-(3,4-二氯-苯基)-脲;
103.1-[4-氧代-1-(3-苯基-丙基)-3,4-二氢-2,3-二氮杂萘-6-基]-3-吡啶-3-基-脲;
104.7-氨基-4-(3-苯基-丙基)-2H-2,3-二氮杂萘-1-酮;
105.N-(4-氧代-1-吡啶-3-基甲基-3,4-二氢-2,3-二氮杂萘-6-基)-丙酰胺;
106.N-(4-氧代-1-吡啶-3-基甲基-3,4-二氢-2,3-二氮杂萘-6-基)-4-三氟甲基-苯甲酰胺;
107.呋喃-2-甲酸(4-氧代-1-吡啶-3-基甲基-3,4-二氢-2,3-二氮杂萘-6-基)-酰胺;
108.N-(4-氧代-1-吡啶-3-基甲基-3,4-二氢-2,3-二氮杂萘-6-基)-琥珀酰胺酸乙酯;
109.N-(4-氧代-1-吡啶-3-基甲基-3,4-二氢-2,3-二氮杂萘-6-基)-3-环戊基-丙酰胺;
110.2-丙基-戊酸(4-氧代-1-吡啶-3-基甲基-3,4-二氢-2,3-二氮杂萘-6-基)-酰胺;
111.1-(4-氧代-1-吡啶-3-基甲基-3,4-二氢-2,3-二氮杂萘-6-基)-3-(3-三氟甲基-苯基)-脲;
112.1-(3-甲氧基-苯基)-3-(4-氧代-1-吡啶-3-基甲基-3,4-二氢-2,3-二氮杂萘-6-基)-脲;
113.1-(4-氧代-1-吡啶-3-基甲基-3,4-二氢-2,3-二氮杂萘-6-基)-3-对-甲苯基)-脲;
114.1-(2,4-二氟-苯基)-3-(4-氧代-1-吡啶-3-基甲基-3,4-二氢-2,3-二氮杂萘-6-基)-脲;
115.1-(3,4-二氯-苯基)-3-(4-氧代-1-吡啶-3-基甲基-3,4-二氢-2,3-二氮杂萘-6-基)-脲;
116.1-(4-氧代-1-吡啶-3-基甲基-3,4-二氢-2,3-二氮杂萘-6-基)-3-吡啶-3-基-脲;
117.7-氨基-4-吡啶-3-基甲基-2H-2,3-二氮杂萘-1-酮;
118.N-(4-氧代-1-吡啶-3-基甲基-3,4-二氢-2,3-二氮杂萘-6-基)-苯甲酰胺;
119.N-[1-(4-氯-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-丙酰胺;
120.N-[1-(4-氯-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-4-三氟甲基-苯甲酰胺;
121.呋喃-2-甲酸[1-(4-氯-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-酰胺;
122.N-[1-(4-氯-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-琥珀酰胺酸乙酯;
123.N-[1-(4-氯-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-3-环戊基-丙酰胺;
124.2-丙基-戊酸[1-(4-氯-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-酰胺;
125.1-[1-(4-氯-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-3-(3-三氟甲基-苯基)-脲;
126.1-[1-(4-氯-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-3-(3-甲氧基-苯基)-脲;
127.1-[1-(4-氯-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-3-对-甲苯基-脲;
128.1-[1-(4-氯-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-3-(2,4-二氟-苯基)-脲;
129.1-[1-(4-氯-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-3-(3,4-二氯-苯基)-脲;
130.1-[1-(4-氯-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-3-吡啶-3-基-脲;
131.7-氨基-4-(4-氯-苄基)-2H-2,3-二氮杂萘-1-酮;
132.N-[1-(4-氰基-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-丙酰胺;
133.N-[1-(4-氰基-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-4-三氟甲基-苯甲酰胺;
134.呋喃-2-甲酸[1-(4-氰基-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-酰胺;
135.N-[1-(4-氰基-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-琥珀酰胺酸乙酯;
136.N-[1-(4-氰基-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-3-环戊基-丙酰胺;
137.2-丙基-戊酸[1-(4-氰基-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-酰胺;
138.1-[1-(4-氰基-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-3-(3-三氟甲基-苯基)-脲;
139.1-[1-(4-氰基-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-3-(3-甲氧基-苯基)-脲;
140.1-[1-(4-氰基-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-3-对-甲苯基)-脲;
141.1-[1-(4-氰基-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-3-(2,4-二氟-苯基)-脲;
142.1-[1-(4-氰基-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-3-(3,4-二氯-苯基)-脲;
143.1-[1-(4-氰基-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-3-吡啶-3-基)-脲;
144.7-氨基-4-(4-氰基-苄基)-2H-2,3-二氮杂萘-1-酮;
145.N-[1-(3-氟-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-丙酰胺;
146.N-[1-(3-氟-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-4-三氟甲基-苯甲酰胺;
147.呋喃-2-甲酸[1-(3-氟-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-酰胺;
148.N-[1-(3-氟-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-琥珀酰胺酸乙酯;
149.N-[1-(3-氟-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-3-环戊基-丙酰胺;
150.2-丙基-戊酸[1-(3-氟-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-酰胺;
151.1-[1-(3-氟-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-3-(3-三氟甲基-苯基)-脲;
152.1-[1-(3-氟-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-3-(3-甲氧基-苯基)-脲;
153.1-[1-(3-氟-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-3-对-甲苯基)-脲;
154.1-[1-(3-氟-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-3-(2,4-二氟-苯基)-脲;
155.1-[1-(3-氟-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-3-(3,4-二氯-苯基)-脲;
156.1-[1-(3-氟-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-3-吡啶-3-基-脲;
157.7-氨基-4-(3-氟-苄基)-2H-2,3-二氮杂萘-1-酮;
158.N-[1-(3-甲基-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-丙酰胺;
159.N-[1-(3-甲基-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-4-三氟甲基-苯甲酰胺;
160.呋喃-2-甲酸[1-(3-甲基-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-酰胺;
161.N-[1-(3-甲基-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-琥珀酰胺酸乙酯;
162.N-[1-(3-甲基-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-3-环戊基-丙酰胺;
163.2-丙基-戊酸[1-(3-甲基-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-酰胺;
164.1-[1-(3-甲基-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-3-(3-三氟甲基-苯基)-脲;
165.1-[1-(3-甲基-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-3-(3-甲氧基-苯基)-脲;
166.1-[1-(3-甲基-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-3-对-甲苯基-脲;
167.1-[1-(3-甲基-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-3-(2,4-二氟-苯基)-脲;
168.1-[1-(3-甲基-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-3-(3,4-二氯-苯基)-脲;
169.1-[1-(3-甲基-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-3-吡啶-3-基-脲;
170.7-氨基-4-(3-甲基-苄基)-2H-2,3-二氮杂萘-1-酮;
171.N-[1-(2,4-二氯-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-丙酰胺;
172.N-[1-(2,4-二氯-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-4-三氟甲基-苯甲酰胺;
173.呋喃-2-甲酸[1-(2,4-二氯-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-酰胺;
174.N-[1-(2,4-二氯-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-琥珀酰胺酸乙酯;
175.N-[1-(2,4-二氯-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-3-环戊基-丙酰胺;
176.2-丙基-戊酸[1-(2,4-二氯-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-酰胺;
177.1-[1-(2,4-二氯-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-3-(3-三氟甲基-苯基)-脲;
178.1-[1-(2,4-二氯-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-3-(3-甲氧基-苯基)-脲;
179.1-[1-(2,4-二氯-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-3-对-甲苯基-脲;
180.1-[1-(2,4-二氯-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-3-(2,4-二氟-苯基)-脲;
181.1-[1-(2,4-二氯-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-3-(3,4-二氯-苯基)-脲;
182.1-[1-(2,4-二氯-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-3-吡啶-3-基)-脲;
183.7-氨基-4-(2,4-二氯-苄基)-2H-2,3-二氮杂萘-1-酮;
184.N-(4-氧代-1-喹啉-3-基甲基-3,4-二氢-2,3-二氮杂萘-6-基)-丙酰胺;
185.N-(4-氧代-1-喹啉-3-基甲基-3,4-二氢-2,3-二氮杂萘-6-基)-4-三氟甲基-苯甲酰胺;
186.呋喃-2-甲酸(4-氧代-1-喹啉-3-基甲基-3,4-二氢-2,3-二氮杂萘-6-基)-酰胺;
187.N-(4-氧代-1-喹啉-3-基甲基-3,4-二氢-2,3-二氮杂萘-6-基)-琥珀酰胺酸乙酯;
188.N-(4-氧代-1-喹啉-3-基甲基-3,4-二氢-2,3-二氮杂萘-6-基)-3-环戊基-丙酰胺;
189.2-丙基-戊酸(4-氧代-1-喹啉-3-基甲基-3,4-二氢-2,3-二氮杂萘-6-基)-酰胺;
190.1-(4-氧代-1-喹啉-3-基甲基-3,4-二氢-2,3-二氮杂萘-6-基)-3-(3-三氟甲基-苯基)-脲;
191.1-(4-氧代-1-喹啉-3-基甲基-3,4-二氢-2,3-二氮杂萘-6-基)-3-(3-甲氧基-苯基)-脲;
192.1-(4-氧代-1-喹啉-3-基甲基-3,4-二氢-2,3-二氮杂萘-6-基)-3-对-甲苯基-脲;
193.1-(4-氧代-1-喹啉-3-基甲基-3,4-二氢-2,3-二氮杂萘-6-基)-3-(2,4-二氟-苯基)-脲;
194.1-(4-氧代-1-喹啉-3-基甲基-3,4-二氢-2,3-二氮杂萘-6-基)-3-(3,4-二氟-苯基)-脲;
195.1-(4-氧代-1-喹啉-3-基甲基-3,4-二氢-2,3-二氮杂萘-6-基)-3-吡啶-3-基-脲;
196.7-氨基-4-喹啉-3-基甲基-2H-3,4-二氢-2,3-二氮杂萘-1-酮;
197.N-[4-氧代-1-(2-三氟甲基-苄基)-3,4-二氢-2,3-二氮杂萘-6-基]-丙酰胺;
198.N-[4-氧代-1-(2-三氟甲基-苄基)-3,4-二氢-2,3-二氮杂萘-6-基]-4-三氟甲基-苯甲酰胺;
199.呋喃-2-甲酸[4-氧代-1-(2-三氟甲基-苄基)-3,4-二氢-2,3-二氮杂萘-6-基]-酰胺;
200.N-[4-氧代-1-(2-三氟甲基-苄基)-3,4-二氢-2,3-二氮杂萘-6-基]-琥珀酰胺酸乙酯;
201.N-[4-氧代-1-(2-三氟甲基-苄基)-3,4-二氢-2,3-二氮杂萘-6-基]-3-环戊基-丙酰胺;
202.2-丙基-戊酸[4-氧代-1-(2-三氟甲基-苄基)-3,4-二氢-2,3-二氮杂萘-6-基]-酰胺;
203.1-[4-氧代-1-(2-三氟甲基-苄基)-3,4-二氢-2,3-二氮杂萘-6-基]-3-(3-三氟甲基-苯基)-脲;
204.1-[4-氧代-1-(2-三氟甲基-苄基)-3,4-二氢-2,3-二氮杂萘-6-基]-3-(3-甲氧基-苯基)-脲;
205.1-[4-氧代-1-(2-三氟甲基-苄基)-3,4-二氢-2,3-二氮杂萘-6-基]-3-对-甲苯基-脲;
206.1-[4-氧代-1-(2-三氟甲基-苄基)-3,4-二氢-2,3-二氮杂萘-6-基]-3-(2,4-二氟-苯基)-脲;
207.1-[4-氧代-1-(2-三氟甲基-苄基)-3,4-二氢-2,3-二氮杂萘-6-基]-3-(3,4-二氯-苯基)-脲;
208.1-[4-氧代-1-(2-三氟甲基-苄基)-3,4-二氢-2,3-二氮杂萘-6-基]-3-吡啶-3-基)-脲
209.7-氨基-4-(2-三氟甲基-苄基)-2H-2,3-二氮杂萘-1-酮。
如上所述,式(I)的氨基-2,3-二氮杂萘酮衍生物的制备方法代表本发明的另一个目的。
因此通过下面的方法可以获得式(I)的及其药学可接受盐,包括;
a)在任意的还原条件下,使式(II)的化合物
其中R3和m具有如上所述定义并且Hal代表卤原子,与合适的膦衍生物(PL3)反应,以获得式(III)的化合物
其中P是磷原子并且L是膦配基;
b)在合适的还原剂存在下,使式(III)的化合物与醛树脂-CHO反应,以获得树脂担载的式(IV)的化合物
其中R3,m,P,L,Hal和树脂如上定义;
c)使式(IV)的化合物与式(V)的羰基衍生物或者式(VI)的亚硝基衍生物反应
R4-CO-R5(V) R’-NO(VI)
其中R4,R5和R’如上定义;以获得式(VII)的化合物
其中A分别是基团=CR4R5或=NR’;并且任意地根据下面的步骤d.1)或d.2)任意一个步骤使式(VII)的化合物反应
d.1)在任意的碱性条件下与式(VIII),(IX),(X)或(XI)的衍生物之一反应,
R’COZ(VIII),R’NCO(IX),R’OCOZ(X),R’SO2Z(XI)
其中Z是卤原子或合适的离去基团并且R’如上定义,以获得式(XII)的化合物
其中Rb分别是-COR’,-CONHR’,-COOR’或-SO2R’;或
d.2)与式(XIII)的化合物反应
Rb-Z(XIII)
其中Z是卤原子并且Rb是如上定义的烷基,环烷基,环烷基烷基,芳基,芳基烷基,杂环基或杂环基烷基,以获得上面式(XII)的相应化合物;
e)使这样获得的式(VII)或(XII)的化合物与式(XIV)的肼衍生物反应
R2-NH-NH2 (XIV)
其中R2如上定义,以分别获得式(XV)或(XVI)的化合物,
其中Rb,R2,R3,m和树脂如上定义并且R1是式-CHR4R5或-NHR’的基团,其中R4,R5和R’如上定义;
f)使式(XV)或(XVI)的化合物在酸性条件下反应,以获得式(I)的化合物,当需要时,将它转化为另一种式(I)的化合物和/或其药学可接受的盐。
上述方法是根据公知的方法能实施的相似方法。
本领域技术人员清楚的是,如果根据上述方法制备获得异构体混合物的式(I)的化合物,则根据常规技术实施的将它们分离为式(I)的单一异构体在本发明的范围内。
同样,根据本领域公知的方法将其相应的盐转化为游离化合物(I)也在本发明的范围内。
根据该方法的步骤a),其中Hal代表卤原子、优选溴的式(II)的化合物与合适的膦衍生物PL3诸如,例如,三苯基膦,三正丁基膦,三叔丁基膦或1,4-双(二苯基膦基)丁烷反应。
优选地,膦衍生物是三苯基膦PPh3。
反应可以在任何溶剂中进行,例如包括乙酸乙酯,丙酸乙酯等,二甲基甲酰胺,二甲基乙酰胺,等,二氯甲烷,氯仿等,丙酮或乙腈;优选使用丙酸乙酯。温度可以在大约20℃至大约100℃变化。
通过向式(II)的化合物的溶液加入膦或者通过向膦加入(II)的溶液可以进行该反应。
当使用三苯基膦时,式(II)的化合物直接转化为在原来的硝基位置带有氨基的式(III)的相应的衍生物。或者,当使用PL3而不是三苯基膦时,式(II)的化合物可以首先转化为式(IIa)的中间体衍生物
其中R3,m,P和L如上定义,它须被适当地还原为式(III)的化合物。
要使用的还原条件是将芳香硝基衍生物还原为氨基衍生物而常规使用的那些条件,并且包括使用化学还原剂,例如,二氯化锡,铁和乙酸,锌和盐酸,或三氯化钛。
或者,在合适的催化剂存在下在催化氢化条件下可以发生还原步骤,所述催化剂一般是铂,钯或钯/炭。
优选地,通过使用三苯基膦常规地将式(II)的化合物转化为式(III)的化合物。
根据该方法的步骤b),在诸如例如吡啶-硼烷络合物,氰基硼氢化钠,三乙酸硼氢化钠,二甲硫硼烷等这样的还原剂存在下,使式(III)的化合物与合适的醛RCHO树脂反应,例如聚苯乙烯或聚乙二醇树脂。
优选地,所述树脂是4-(4-甲酰基-3-甲氧基苯氧基)丁酰氨基甲基化树脂或4-(4-甲酰基-3-甲氧基苯氧基)丁酰(NOVAGELTM)。
在合适的溶剂存在下,优选二氯甲烷,2,2,2-三氟乙醇和乙酸,通过向树脂和式(III)的化合物的混合物直接加入过量还原剂,还原剂任选地溶解于相同的溶剂,并且通过在大约0℃至大约40℃范围的温度下搅拌适当时间进行反应。作为例子,可以在大约20℃下进行大约15小时。
根据该方法的步骤c),式(IV)的化合物然后与式(V)的化合物反应,或者与式(VI)反应,以获得相应的式(VII)的衍生物。
在合适的碱存在下,任选地在合适的相转移催化剂存在下,进行该反应,所述催化剂例如三乙胺,二异丙基乙胺,哌啶,碳酸钠,碳酸铯,叔丁醇钾,甲醇钠,二氮杂双环十一烯,氢氧化钾等。
向式(IV)的化合物在合适的溶剂的混悬液中加入式(V)的化合物或式(VI)的化合物,所述溶剂例如二氯甲烷,二甲基甲酰胺,四氢呋喃等。将温度调至合适值,例如,根据亲电子试剂(V)或(VI),从大约-70℃至大约40℃,并且加入碱。持续搅拌合适的时间,例如从大约2至大约15小时。
根据步骤d.1)或d.2)之一,或者根据步骤e)直接进行这样获得的式(VII)的产物的进一步反应。
根据该方法的步骤d.1),特别地,使式(VII)的化合物与式(VIII)的羧酸衍生物,与式(IX)的异氰酸酯,与式(X)的氯甲酸酯衍生物或者与式(XI)的磺酰基衍生物反应,以获得相应的式(XII)的化合物,其中Rb分别是式-COR’,-CONHR’,-COOR’或-SO2R’的基团。
当使用式(VIII),(X)或(XI)的化合物时,Z优选是卤原子,更优选地,氯原子。在这种情况下,式(VII)的化合物悬浮于合适的溶剂中,例如二氯甲烷,二甲基甲酰胺,四氢呋喃,二烷等,然后加入合适的碱,例如三乙胺,二异丙基乙胺,碳酸钠等。然后加入通式(VIII),(X),或(XI)的亲电子试剂,并且在大约20℃至大约80℃范围的温度下将混合物搅拌大约2至15小时。当使用通式(IX)的异氰酸酯时,反应条件和上述相同,除了碱不是必需的。
在后一种情况下,可以任选地使用催化剂例如二甲基氨基吡啶。
当考虑该方法的步骤d.2)时基本上有类似考虑,其中式(VII)的化合物根据公知方法进一步转化为相应的式(XII)的官能化氨基衍生物。
作为例子,式(VII)的化合物可以与式(XIII)的衍生物反应,其中Z是卤原子,例如溴,Rb是芳基烷基,例如苄基,反应根据常规方法进行。
根据该方法的步骤e),从步骤c)获得的式(VII)的化合物,或者,从步骤d.1)或d.2)之一获得的式(XII)的化合物与肼或式(XIV)的肼衍生物反应,以获得相应的式(XV)或(XVI)的化合物。
在通式(XIV)的肼水合物或者另一种肼的存在下,式(XII)的化合物悬浮于合适的溶剂中,优选二甲基甲酰胺,并且在合适的温度例如20℃下搅拌大约2至大约20小时。
根据该方法的步骤f),在酸性条件下,优选在三氟乙酸存在下,使式(XV)或(XVI)的化合物反应,以得到期望的式(I)的化合物。因此将式(XV)或(XVI)的化合物悬浮于5-95%三氟乙酸的二氯甲烷溶液中并且在大约20℃至回流温度范围的温度下将混合物搅拌大约5分钟至大约3小时。
如上所述,有一点对于技术人员是清楚的,即通过将式(XV)的化合物从树脂上裂解下来,将获得Ra和Rb都是氢原子的相应的衍生物。
同样,当从式(XVI)的化合物起始时,将获得Ra或Rb之一,例如Ra,是氢原子,另一个,例如Rb,如步骤d.1)或d.2)定义的基团的相应的式(I)的衍生物。
另外,技术人员清楚的是,如果期望,通过根据常规方法处理,上述任何式(I)的化合物可以进一步转化为步骤f)中提出的其它式(I)的化合物。
作为例子,根据公知方法,通过使Ra或Rb之一是氢原子的任何式(I)的化合物反应成相同氢原子被合适的基团置换的另一种式(I)的化合物,可以制备其中Ra和Rb两者不是氢原子的式(I)的化合物。
当根据各种不同的方法制备式(I)的化合物时,这些都认为在本发明的范围内,能引起不期望的副反应的起始物或其中间体中任意的官能团,需要根据常规技术适当地加以保护。
同样,根据公知方法,可以将后者转化为游离的去保护的化合物。
根据常规方法可以获得式(I)的化合物的药学可接受盐,或者从它的盐获得它们的游离化合物。
式(II)的化合物是公知的或者容易根据公知方法制备[参见,例如,J.Org.Chem.(1985),50,4120-4125;J.Chem.Soc.(1961),5275-5284]。
或者,根据操作实施例报道,可以制备其中Hal代表溴原子的式(II)的化合物,即在溴化条件下,使商购6-硝基2-苯并[c]呋喃酮,例如在过氧化氢水溶液存在下,在合适的溶剂中,例如在二氯甲烷,二氯甲烷/水或己烷/水混合物中,在大约20℃至回流温度下与溴反应。
式(V),(VI),(VIII),(IX),(X),(XI),(XIII)和(XIV)的化合物是已知的或者容易根据公知的方法制备。
同样,醛树脂R-CHO,膦衍生物PL3和该方法的其它合适的试剂,是已知的化合物,它们可以商购或者根据已知方法容易制备。
根据本领域公知的组合化学技术,通过以系列方式实施几种中间体之间的上述反应,有利地制备本发明的式(I)的化合物。
因此,本发明的所有的优选的化合物,适当时以药学可接受盐形式存在,在此都方便地指出并且通过方法限定产品加以定义,例如通过定义的方法可获得的式(I)的产品。
因此,提供了例如通过根据本发明方法的组合化学技术可获得的任何式(I)的具体化合物,通过首先使式(IV)的化合物与如表I所示的式(V)的醛衍生物之一反应
通过使任何生成的式(VII)的化合物与如表II所示的式(VIII)的酰氯衍生物之一反应;通过使任何生成的式(XII)化合物与肼反应;和通过根据该方法的步骤f)处理。
还提供了通过根据本发明方法的组合化学技术可获得的任何式(I)的具体化合物,通过首先使式(IV)的化合物与如表I所示的式(V)的醛衍生物之一反应
通过使任何生成的式(VII)化合物与如表III所示的式(IX)的异氰酸酯衍生物之一反应;通过使任何生成的式(XII)化合物与肼反应;和通过根据该方法的步骤f)处理。
表I
式(V)的醛衍生物R4-CO-R5(R5=H)
1. | 3,5-二碘-4-羟基苯甲醛 |
2. | 3-碘代苯甲醛 |
3. | 3,5-二溴苯甲醛 |
4. | 4-溴代噻吩-2-甲醛 |
5. | 2-萘醛 |
6. | 正-乙基-咔唑-3-醛 |
7. | 4-氯-1-甲基吡唑-3-甲醛 |
8. | 乙酸(3-甲酰基-1-苯基-1H-吡唑-5-基)甲酯 |
9. | 1-乙酰基-3-吲哚甲醛 |
10. | 4-甲酰基-1-甲基吡咯-2-甲酸甲酯 |
11. | 3,5-二叔丁基-4-羟基苯甲醛 |
12. | 5-(甲硫基)-2-噻吩甲醛 |
13. | 4-(甲硫基)苯甲醛 |
14. | 3-硝基-4-(2-吡啶基硫基)苯甲醛 |
15. | 5-甲基-2-噻吩甲醛 |
16. | 3-乙酰氧基苯甲醛 |
17. | 4-二甲基苯甲醛 |
18. | 4-吡啶甲醛n-氧化物 |
19. | 4-氟-3-甲基苯甲醛 |
20. | 2,6-二氯异烟酰醛(nicotinaldehyde) |
21. | 5-(2,4-二氟苯基)-2-糠醛 |
22. | 2-(4-溴苯甲酰基)-1-苯并呋喃-5-甲醛 |
23. | 2-苯甲酰基-1-苯并呋喃-5-甲醛 |
24. | 2-丁基-4-甲酰基咪唑 |
25. | 5-苄氧基-1H-吡咯并[2,3-c]吡啶-3-甲醛 |
26. | 6-甲基-2-吡啶甲醛 |
27. | 4-[4-(叔丁基)噻唑-2-基]苯甲醛 |
28. | 5-甲酰基-2,4-二甲氧基-嘧啶 |
29. | 2-[(4-氯代苄基)硫基]嘧啶-4-甲醛 |
30. | 3-氟-2-羟基苯甲醛 |
31. | 3-羟基苯甲醛 |
32. | 3-羧基苯甲醛 |
33. | 4-乙烯基苯甲醛 |
34. | 5-(2,5-二氯苯基)-2-糠醛 |
35. | 2-氟-5-硝基苯甲醛 |
36. | 5-(4-硝基苯基)-2-糠醛 |
37. | 4-二甲基氨基苯甲醛 |
38. | 4-[3-(二甲基氨基)丙氧基]苯甲醛 |
39. | 4-正-丁基苯甲醛 |
40. | 4-(4-苄基哌嗪并)苯甲醛 |
41. | 2,2’-双噻吩-5-甲醛 |
42. | 4-[4-(1-金刚烷基)-1,3-噻唑-2-基]苯甲醛 |
43. | 4-甲酰基-反式-茋 |
44. | 6-氯代咪唑并[2,1-b][1,3]噻唑-5-甲醛 |
45. | 4-(苯基乙炔基)苯甲醛 |
46. | 3,3’-(4-甲酰基苯基亚氨基)二丙腈 |
47. | 6-甲酰基-2-(甲硫基)烟酰腈 |
48. | 4-氰基苯甲醛 |
49. | 3-[(4-甲酰基苯氧基)甲基]噻吩-2-腈 |
50. | 2-(3-甲酰基-1H-吲哚-1-基)苯甲基 |
51. | 2,6-二氟苯甲酸2-甲酰基-6-甲氧基苯基酯 |
52. | 4-甲酰基-2-甲氧基苯基碳酸叔丁酯 |
53. | 4-(二氟甲氧基)苯甲醛 |
54. | 2-[1-甲基-5-(三氟甲基)吡唑-3-基]噻吩-5-甲醛 |
55. | 5-(3-三氟甲基苯基)呋喃-2-甲醛 |
56. | 2,3-二氟-4-甲基苯甲醛 |
57. | 3-氯-5-(三氟甲基)吡啶-2-甲醛 |
58. | 4-(三氟甲氧基)苯甲醛 |
59. | 3-[(2,4-二氟苯基)硫基]-5-(三氟甲基)吡啶-2-甲醛 |
60. | 3,5-双(三氟甲基)苯甲醛 |
61. | 2,3,5,6-四氟苯甲醛 |
62. | 4-(甲基磺酰基)苯甲醛 |
63. | 1-[(4-甲基苯基)磺酰基]-1H-吲哚-3-甲醛 |
64. | 2,4,5-三氯苯磺酸4-甲酰基-2-甲氧基苯基酯 |
65. | 2,3,4,5,6-五甲基苯磺酸4-甲酰基苯基酯 |
66. | 3-(4-甲酰基苯基)-2-(吡啶-2-基磺酰基)丙烯腈 |
67. | 4-乙酰胺苯甲醛 |
68. | 4-[[5-氯-2-氧代嘧啶-1(2H)-基]甲氧基]苯甲醛 |
69. | 4-(5-甲酰基-2-呋喃基)苯-1-磺酰胺 |
70. | 3-苯并[1,3]间二氧杂环戊烯-5-基-2-甲基-丙醛 |
71. | 3-(苯硫基)丁醛 |
72. | 3-氯-4,4,4-三氟-2-苯基丁醛 |
73. | 2-氰基-2-苯乙醛 |
74. | 3-甲氧基苯乙醛 |
75. | 吡啶-3-甲醛 |
76. | 4-氯代苯甲醛 |
77. | 4-氰基苯甲醛 |
78. | 3-氟代苯甲醛 |
79. | 间-甲苯甲醛 |
80. | 2,4-二氯苯甲醛 |
81. | 喹啉-3-甲醛 |
82. | 2-(三氟甲基)苯甲醛 |
83. | 4-甲酰基苯甲酸甲酯 |
84. | 4-氯-3-氟代苯甲醛 |
85. | 4-硝基肉桂醛 |
86. | 3-噻吩甲醛 |
87. | 3-甲氧基苯甲醛 |
88. | 丙醛 |
89. | 3,3-二甲基丁醛 |
90. | 3-苯基丙醛 |
表II
式(VIII)的酰氯衍生物R’COZ(Z=C1)
1. | 3,5-双(三氟甲基)苯甲酰氯 |
2. | 苯甲酰氯 |
3. | 2-溴苯甲酰氯 |
4. | 2-氟苯甲酰氯 |
5. | 2,4-二氟苯甲酰氯 |
6. | 2,6-二氟苯甲酰氯 |
7. | 2-氯苯甲酰氯 |
8. | 2,4-二氯苯甲酰氯 |
9. | 2-甲氧基苯甲酰氯 |
10. | 2-(三氟甲基)苯甲酰氯 |
11. | 邻-甲苯甲酰氯 |
12. | 3-溴苯甲酰氯 |
13. | 3-氟苯甲酰氯 |
14. | 3-氯苯甲酰氯 |
15. | 3,4-二氯苯甲酰氯 |
16. | 间-甲氧苯甲酰氯 |
17. | 3,4-二甲氧基苯甲酰氯 |
18. | 3,4,5-三甲氧基苯甲酰氯 |
19. | 3,5-二甲氧基苯甲酰氯 |
20. | 3-(三氟甲基)苯甲酰氯 |
21. | 间-甲苯酰氯 |
22. | 4-溴苯甲酰氯 |
23. | 4-氟苯甲酰氯 |
24. | 4-氯苯甲酰氯 |
25. | 对-甲氧苯甲酰氯 |
26. | 4-乙氧基苯甲酰氯 |
27. | 4-正丁氧基苯甲酰氯 |
28. | 4-联苯基羰基氯 |
29. | 4-(三氟甲基)苯甲酰氯 |
30. | 4-叔丁基苯甲酰氯 |
31. | 对-甲苯酰氯 |
32. | 4-乙基苯甲酰氯 |
33. | 4-正丙基苯甲酰氯 |
34. | 4-正丁基苯甲酰氯 |
35. | 新戊酰氯 |
36. | 异丁酰氯 |
37. | 2-乙基己酰氯 |
38. | 乙酰氯 |
39. | 苯氧乙酰氯 |
40. | 4-氯苯氧乙酰氯 |
41. | 甲氧基乙酰氯 |
42. | 苯基乙酰氯 |
43. | 叔丁基乙酰氯 |
44. | 异戊酰氯 |
45. | 丙酰氯 |
46. | 氢化肉桂酰氯 |
47. | 丁酰氯 |
48. | 戊酰氯 |
49. | 4-碘苯甲酰氯 |
50. | 环丙烷羰基氯 |
51. | 环丁烷羰基氯 |
52. | 环戊烷羰基氯 |
53. | 3-环戊基丙酰氯 |
54. | 环己烷羰基氯 |
55. | 4-氰基苯甲酰氯 |
56. | 2-糠酰氯 |
57. | 1-萘酰氯 |
58. | 2-萘酰氯 |
59. | 噻吩-2-羰基氯 |
60. | 噻吩-2-乙酰氯 |
61. | (3,4-二甲氧基苯基)乙酰氯 |
62. | 3,5-二氯苯甲酰氯 |
63. | 2,5-二氯苯甲酰氯 |
64. | 3,4-二氟苯甲酰氯 |
65. | 9-芴酮-4-羰基氯 |
66. | 3,5-二氟苯甲酰氯 |
67. | 苄氧基乙酰氯 |
68. | 3-氰基苯甲酰氯 |
69. | (2,5-二甲氧基苯基)乙酰氯 |
70. | 3-甲氧基苯乙酰氯 |
71. | 烟酰氯盐酸盐 |
72. | 异烟酰氯盐酸盐 |
73. | 2,4,6-三甲基苯甲酰氯 |
74. | 二苯基乙酰氯 |
75. | 2-甲基戊酰氯 |
76. | 3,4-亚甲基二氧苯甲酰氯 |
77. | 2,4-二甲氧基苯甲酰氯 |
78. | 2-苯氧基丙酰氯 |
79. | 2-苯基丁酰氯 |
80. | 2-乙基丁酰氯 |
81. | 2,3-二氯苯甲酰氯 |
82. | 4-氯苯基乙酰氯 |
83. | d1-2-甲基丁酰氯 |
84. | 2,3-二氟苯甲酰氯 |
85. | 1-(4-氯苯基)-1-环戊烷羰基氯 |
86. | 2-乙氧基-1-萘酰氯 |
87. | 苯并[b]噻吩-2-羰基氯 |
88. | 4-(三氟甲氧基)苯甲酰氯 |
89. | 2-(三氟甲氧基)苯甲酰氯 |
90. | 3-氯苯并[b]噻吩-2-羰基氯 |
91. | 2-氟-3-(三氟甲基)苯甲酰氯 |
92. | 2-氟-4-(三氟甲基)苯甲酰氯 |
93. | 2-氟-5-(三氟甲基)苯甲酰氯 |
94. | 3-氟-5-(三氟甲基)苯甲酰氯 |
95. | 4-氟-2-(三氟甲基)苯甲酰氯 |
96. | 4-氟-3-(三氟甲基)苯甲酰氯 |
97. | 2-氟-6-(三氟甲基)苯甲酰氯 |
98. | 2,3,6-三氟苯甲酰氯 |
99. | 2,4,5-三氟苯甲酰氯 |
100. | 3-(三氟甲氧基)苯甲酰氯 |
101 | 异唑-5-羰基氯 |
102 | 2,4,6-三氟苯甲酰氯 |
103 | 2,5-双(三氟甲基)苯甲酰氯 |
104 | 2,3,4-三氟苯甲酰氯 |
105 | 2,4,6-三氯苯甲酰氯 |
106 | 2,4-二氯-5-氟代苯甲酰氯 |
107 | 4-甲氧基苯基乙酰氯 |
108 | 5-氟-2-(三氟甲基)苯甲酰氯 |
109 | 2-氯-6-氟代苯甲酰氯 |
110 | 2-溴-5-甲氧基苯甲酰氯 |
111 | 环戊基乙酰氯 |
112 | 3-氯-4-氟代苯甲酰氯 |
113 | 3-氟-4-(三氟甲基)苯甲酰氯 |
114 | 4-氟苯基乙酰氯 |
115 | 4-叔丁基苯氧基乙酰氯 |
116 | 7-咪唑-1-基-5,6-二氢-萘-2-羰基氯 |
117 | 4-咪唑-1-基甲基-苯甲酰氯 |
118 | 4-溴-3-甲基苯甲酰氯 |
表III
式(IX)的异氰酸酯衍生物R’NCO
1. | 异氰酸苯酯 |
2. | 异氰酸2-溴苯酯 |
3. | 异氰酸2-氟苯酯 |
4. | 异氰酸2,4-二氟苯酯 |
5. | 异氰酸2,6-二氟苯酯 |
6. | 异氰酸2-氯苯酯 |
7. | 异氰酸2,3-二氯苯酯 |
8. | 异氰酸2,4-二氯苯酯 |
9. | 异氰酸2,5-二氯苯酯 |
10. | 异氰酸2,6-二氯苯酯 |
11. | 异氰酸2-甲氧基苯酯 |
12. | 异氰酸2,4-二甲氧基苯酯 |
13. | 异氰酸2,5-二甲氧基苯酯 |
14. | 异氰酸2-乙氧基苯酯 |
15 | 异氰酸2-(三氟甲基)苯基酯 |
16. | 异氰酸邻-甲苯基酯 |
17. | 异氰酸2,6-二甲基苯酯 |
18. | 异氰酸2-乙基苯酯 |
19. | 异氰酸3-溴苯酯 |
20. | 异氰酸3-氟苯酯 |
21. | 异氰酸3-氯苯酯 |
22. | 异氰酸3,4-二氯苯酯 |
23. | 异氰酸3-甲氧基苯酯 |
24. | 异氰酸3-(三氟甲基)苯基酯 |
25. | 异氰酸间-甲苯基酯 |
26. | 异氰酸4-溴苯酯 |
27. | 异氰酸4-氟苯酯 |
28. | 异氰酸4-氯苯酯 |
29. | 异氰酸4-甲氧基苯酯 |
30. | 异氰酸4-(三氟甲基)苯基酯 |
31. | 异氰酸对-甲苯基酯 |
32. | 异氰酸苯甲酰酯 |
33. | 异氰酸1-萘基酯 |
34. | 异氰酸苄酯 |
35. | 异氰酸3,5-双(三氟甲基)苯酯 |
36. | 异氰酸2,5-二氟苯酯 |
37. | 异氰酸2,4,5-三氯苯酯 |
38. | 异氰酸2,4,6-三氯苯酯 |
39. | 异氰酸2-异丙基苯酯 |
40. | 异氰酸2,3-二甲基苯酯 |
41. | 异氰酸4-甲氧基-2-甲基苯酯 |
42. | 异氰酸2,4-二甲基苯酯 |
43. | 异氰酸2,5-二甲基苯酯 |
44. | 异氰酸2-乙基-6-甲基苯酯 |
45. | 异氰酸3-氰基苯酯 |
46. | 异氰酸5-氯-2,4-二甲氧基苯酯 |
47. | 异氰酸3-氯-4-甲基苯酯 |
48. | 异氰酸3,5-二氯苯酯 |
49. | 异氰酸5-氯-2-甲氧基苯酯 |
50. | 异氰酸3,4,5-三甲氧基苯酯 |
51. | 异氰酸3,5-二甲氧基苯酯 |
52. | 异氰酸3-(甲硫基)苯酯 |
53. | 异氰酸3-乙酰基苯酯 |
54. | 异氰酸3,4-二甲基苯酯 |
55. | 异氰酸3,5-二甲基苯酯 |
56. | 异氰酸2-甲氧基-5-甲基苯酯 |
57. | 异氰酸3-乙基苯酯 |
58. | 异氰酸4-溴-2-(三氟甲基)苯酯 |
59. | 异氰酸4-氯-2-(三氟甲基)苯酯 |
60. | 异氰酸4-氯-3-(三氟甲基)苯酯 |
61. | 异氰酸4-碘苯酯 |
62. | 异氰酸4-苯氧基苯酯 |
63. | 异氰酸4-乙氧基苯酯 |
64. | 异氰酸4-乙酰基苯酯 |
65. | 异氰酸4-异丙基苯酯 |
66. | 异氰酸4-乙基苯酯 |
67. | 异氰酸4-正丁基苯酯 |
68. | 异氰酸2,4,6-三甲基苯酯 |
69. | 异氰酸2-异丙基-6-甲基苯酯 |
70. | 异氰酸2,6-二乙基苯酯 |
71. | 异氰酸5-氯-2-甲基苯酯 |
72. | 异氰酸4-氯-2-甲基苯酯 |
73. | 异氰酸4-(三氟甲氧基)苯酯 |
74. | 异氰酸2-氯-5-(三氟甲基)苯酯 |
75. | 异氰酸2-氯-6-甲基苯酯 |
76. | 异氰酸2,4,5-三甲基苯酯 |
77. | 异氰酸3-氯-2-甲氧基苯酯 |
78. | 异氰酸3-氯-2-甲基苯酯 |
79. | 异氰酸3-氯-4-氟苯酯 |
80. | 异氰酸4-溴-2-甲基苯酯 |
81. | 异氰酸4-溴-2,6-二甲基苯酯 |
82. | 异氰酸2,6-二溴-4-氟苯酯 |
83. | 异氰酸4-丁氧基苯酯 |
84. | 异氰酸3-氟-4-甲基苯酯 |
85. | 异氰酸5-氟-2-甲基苯酯 |
86. | 异氰酸2-联苯基酯 |
87. | 异氰酸4-联苯基酯 |
88. | 异氰酸2-溴-4,6-二氟苯酯 |
89. | 异氰酸(r)-(+)-1-苯基乙酯 |
90. | 异氰酸1-(1-萘基)乙酯 |
91. | 异氰酸(s)-(+)-1-(1-萘基)乙酯 |
92. | 异氰酸3,4-二氟苯酯 |
93. | 异氰酸2-(三氟甲氧基)苯酯 |
94. | 异氰酸4-苄基氧基苯酯 |
95. | 异氰酸4-溴-2-氯苯酯 |
96. | 异氰酸4-溴-2-氟苯酯 |
97. | 异氰酸2-氟-5-甲基苯酯 |
98. | 异氰酸2,3,4-三氟苯酯 |
99. | 异氰酸2-(二氟甲氧基)苯酯 |
100. | 异氰酸4-(二氟甲氧基)苯酯 |
101. | 异氰酸2-甲基苄酯 |
102. | 异氰酸2-氯苄酯 |
103. | 异氰酸4-氟苄酯 |
104. | 异氰酸4-甲氧基苄酯 |
105. | 异氰酸2,6-二氟苯甲酰酯 |
106. | 异氰酸4-氟苯甲酰酯 |
107. | 异氰酸2-氟-3-(三氟甲基)苯酯 |
108. | 异氰酸2-氟-5-(三氟甲基)苯酯 |
109. | 异氰酸2-氟-6-(三氟甲基)苯酯 |
110. | 异氰酸4-氟-2-(三氟甲基)苯酯 |
111. | 异氰酸2-(叔丁基)苯酯 |
112. | 异氰酸3-吡啶基酯 |
因此,本发明的另一个目的是式(I)的两种或多种氨基-2,3-二氮杂萘酮衍生物库
其中
Ra和Rb各自独立地是氢原子或任选地进一步被取代的选自下面的基团:直链或支链C1-C6烷基,C3-C6环烷基或环烷基C1-C6烷基,芳基,芳基C1-C6烷基,5至7元杂环基或者具有1-3个选自氮,氧或硫的杂原子的杂环基C1-C6烷基;或者Ra或Rb之一是氢或任意地被取代的直链或支链C1-C6烷基,另一个是选自-COR’,-CONHR’,-COOR’或-SO2R’的基团,其中R’是氢或任选地被取代的选自上述烷基,环烷基,环烷基烷基,芳基,芳基烷基,杂环基或杂环基烷基的基团;
R1是式-CHR4R5基团,其中R4和R5各自独立地是氢或者任意地被取代的选自直链或支链C1-C6烷基,C3-C6环烷基或环烷基C1-C6烷基,芳基,芳基C1-C6烷基,5至7元杂环基或者具有1-3个选自氮,氧或硫的杂原子的杂环基C1-C6烷基的基团;或者R1是式-NHR’,-NR’COR″,-NR’CONHR″或-NR’SO2R″,其中R’具有上述氢以外的定义,R″是氢或具有上面对于R’的定义;
R2是氢原子或任选地进一步被取代的选自下面的基团:直链或支链C1-C6烷基,C3-C6环烷基或环烷基C1-C6烷基,芳基,芳基C1-C6烷基,5至7元杂环基或者具有1-3个选自氮,氧或硫的杂原子的杂环基C1-C6烷基;
2,3-二氮杂萘酮环上自由位置5,6和8中的一个或多个上的任何R3各自独立地是卤原子,硝基,羧基,氰基或者任选地进一步被取代的选自下面的基团:直链或支链C1-C6烷基,C3-C6环烷基或环烷基C1-C6烷基,芳基,芳基C1-C6烷基,5至7元杂环基或者具有1-3个选自氮,氧或硫的杂原子的杂环基C1-C6烷基;或者R3是选自-COR’,-CONHR’,-SO2R’,-NR’R″,-NR’COR″,-NR’CONHR’或-NR’SO2R″的基团,其中R’和R″是相同或不同的,是氢或者上面提到的基团;m是0或1-3的整数;
或者其药学可接受的盐。
如上所述,本领域技术人员清楚的是一旦制备由几千种式(I)的化合物组成的氨基-2,3-二氮杂萘酮衍生物库,所述库用于筛选针对如上所述给出的靶激酶是非常有利的。
关于化合物库及其作为筛选生物学活性的用途的一般参考参见,J.Med.Chem.1999,42,2373-2382;和Bioorg.Med.Chem.Lett.10(2000),223-226。
药理学
式(I)的化合物具有作为蛋白激酶抑制剂的活性,因此用于例如限制肿瘤细胞的不受调控的增殖。
在治疗中,可以在对各种肿瘤的治疗中使用这些化合物,象例如癌,例如乳腺癌,肺癌,膀胱癌,结肠癌,卵巢癌,子宫内膜癌,肉瘤,例如软组织肉瘤和骨肉瘤,和血液恶性肿瘤象,例如白血病。
另外,式(I)的化合物还用于治疗其它细胞增殖性疾病,例如牛皮癣,与动脉粥样硬化相关的血管平滑细胞增生,和手术后狭窄和再狭窄,用于治疗阿尔茨海默氏病。
通过以MultiScreen-PH 96孔板(Millipore)的使用为基础的测定方法测定推定的蛋白激酶的抑制活性和选择的化合物的效力,其中在各孔底部放置磷酸纤维滤纸,使带正电荷的底物在洗涤/过滤步骤之后结合。
当丝氨酸/苏氨酸激酶将放射性标记磷酸部分转移给滤纸-结合组蛋白时,在闪烁计数器上测定发射的光。
cdk2/细胞周期蛋白A活性的抑制分析
激酶反应:向96U底孔板的各个孔加入最终体积是100微升缓冲液(TRIS HCl 10mM pH 7.5,MgCl2 10mM,7.5mM DTT)中的1.5μM组蛋白H1底物,25μM ATP(0.2μCiP33γ-ATP),30ng杆状病毒共同表达的cdk2/细胞周期蛋白A,10μM抑制剂。在37℃下温育10分钟之后,用20微升120mM的EDTA终止反应。
捕获:将100微升从各个孔转移到MultiScreen板,使底物与磷酸纤维素滤纸结合。然后用没有Ca++/Mg++的150微升/孔PBS将板洗涤3次并且通过MultiScreen过滤系统过滤。
检测:让滤纸在37℃下干燥,然后加入100微升/孔闪烁剂,并且通过在Top-Count仪中放射性计数来检测33P标记的组蛋白H1。
结论:参照酶总活性(=100%)分析数据并且表示为%抑制作用。
为了研究和确定效力(IC50)以及通过Ki计算的抑制剂的动力学曲线,对表现出抑制作用≥50%的所有的化合物进行进一步分析。
IC50测定:使用的方法与上述相同,其中在0.0045至10μM范围的不同浓度下分析抑制剂。使用四种参数对数方程式,通过计算机程序GraphPad Prizm分析实验数据:
y=下底+(上底-下底)/(1+10^((logIC50-x)*斜率))
其中x是抑制剂浓度的对数,y是响应值;y从下底起始并且以S形向上底发展。
Ki计算:改变ATP和组蛋白H1的浓度:ATP是4,8,12,24,48μM(含有按比例稀释的P33γ-ATP),组蛋白是0.4,0.8,1.2,2.4,4.8μM,在不存在和存在两种不同的适当选择的抑制剂浓度下使用它们。
有关Ki测定,通过计算机程序″SigmaPlot″分析实验数据,使用随机双反应系统等式:
其中A=ATP和B=组蛋白H1。
另外,对一组严格与细胞周期相关的丝氨酸/苏氨酸激酶表征了选择的化合物(cdk2/细胞周期蛋白E,cdk1/细胞周期蛋白B1,cdk4/细胞周期蛋白D1),并且表征了对MAPK,PKA,EGFR,IGF1-R,Cdc7/dbf4和aurora-2的特异性。
cdk2/细胞周期蛋白E活性的抑制分析
激酶反应:向96U底孔板的各个孔加入最终体积是100微升缓冲液(TRIS HCl 10mM pH 7.5,MgCl2 10mM,7.5mM DTT+0.2mg/ml BSA)中的1.5μM组蛋白H1(Sigma#H-5505)底物,25μM ATP(0.2μCiP33γ-ATP),15ng杆状病毒共同表达的cdk2/细胞周期蛋白E,适当浓度的抑制剂。在37℃下温育10分钟之后,用20微升120mM的EDTA终止反应。
捕获:将100微升从各个孔转移到MultiScreen板,使底物与磷酸纤维素滤纸结合。然后用没有Ca++/Mg++的150微升/孔PBS将板洗涤3次并且通过MultiScreen过滤系统过滤。
检测:让滤纸在37℃下干燥,然后加入100微升/孔闪烁剂,并且通过在Top-Count仪中放射性计数来检测33P标记的组蛋白H1。
cdk1/细胞周期蛋白B1活性的抑制分析
激酶反应:向96U底孔板的各个孔加入最终体积是100微升缓冲液(TRIS HCl 10mM pH 7.5,MgCl2 10mM,7.5mM DTT+0.2mg/ml BSA)中的1.5μM组蛋白H1(Sigma#H-5505)底物,25μM ATP(0.2μCiP33γ-ATP),30ng杆状病毒共同表达的cdk2/细胞周期蛋白B1,适当浓度的抑制剂。在37℃下温育10分钟之后,用20微升120mM的EDTA终止反应。
捕获:将100微升从各个孔转移到MultiScreen板,使底物与磷酸纤维素滤纸结合。然后用没有Ca++/Mg++的150微升/孔PBS将板洗涤3次并且通过MultiScreen过滤系统过滤。
检测:让滤纸在37℃下干燥,然后加入100微升/孔闪烁剂,并且通过在Top-Count仪中放射性计数来检测33P标记的组蛋白H1。
cdk4/细胞周期蛋白D1活性的抑制分析
激酶反应:向96U底孔板的各个孔加入最终体积是50微升缓冲液(TRIS HCl 10mM pH 7.5,MgCl2 10mM,7.5mM DTT+0.2mg/ml BSA)中的0.4μM小鼠GST-Rb(769-921)(#sc-4112,购自Santa Cruz)底物,10μM ATP(0.5μCiP33γ-ATP),100ng杆状病毒表达的GST-cdk4/GST-细胞周期蛋白D1,适当浓度的抑制剂。在37℃下温育40分钟之后,用20微升120mM的EDTA终止反应。
捕获:将60微升从各个孔转移到MultiScreen板,使底物与磷酸纤维素滤纸结合。然后用没有Ca++/Mg++的150微升/孔PBS将板洗涤3次并且通过MultiScreen过滤系统过滤。
检测:让滤纸在37℃下干燥,然后加入100微升/孔闪烁剂,并且通过在Top-Count仪中放射性计数来检测33P标记的Rb片段。
MAPK活性的抑制分析
激酶反应:向96U底孔板的各个孔加入最终体积是100微升缓冲液(TRIS HCl 10mM pH 7.5,MgCl2 10mM,7.5mM DTT+0.1mg/ml BSA)中的10μM MBP(Sigma#M-1891)底物,25μM ATP(0.2μCiP33γ-ATP),25ng细菌表达的GST-MAPK(Upstate Biotechnology#14-173),适当浓度的抑制剂。在37℃下温育15分钟之后,用20微升120mM的EDTA终止反应。
捕获:将100微升从各个孔转移到MultiScreen板,使底物与磷酸纤维素滤纸结合。然后用没有Ca++/Mg++的150微升/孔PBS将板洗涤3次并且通过MultiScreen过滤系统过滤。
检测:让滤纸在37℃下干燥,然后加入100微升/孔闪烁剂,并且通过在Top-Count仪中放射性计数来检测33P标记MBP。
PKA活性的抑制分析
激酶反应:向96U底孔板的各个孔加入最终体积是100微升缓冲液(TRIS HCl 10mM pH 7.5,MgCl2 10mM,7.5mM DTT+0.2mg/ml BSA)中的10μM组蛋白H1(Sigma#H-5505)底物,10μM ATP(0.2μCiP33γ-ATP),1U牛心PKA(Sigma#2645),适当浓度的抑制剂。在37℃下温育5分钟之后,用20微升120mM的EDTA终止反应。
捕获:将100微升从各个孔转移到MultiScreen板,使底物与磷酸纤维素滤纸结合。然后用没有Ca++/Mg++的150微升/孔PBS将板洗涤3次并且通过MultiScreen过滤系统过滤。
检测:让滤纸在37℃下干燥,然后加入100微升/孔闪烁剂,并且通过在Top-Count仪中放射性计数来检测33P标记的组蛋白H1。
EGFR活性的抑制分析
激酶反应:向96 U底孔板的各个孔加入最终体积是100微升缓冲液(Hepes 50mM pH 7.5,MnCl2-MgCl2 3mM,1mM DTT+3μM NaVO3,0.1mg/ml BSA)中的25nM自制的(in house)生物素化PolyGluTyr(Sigma#0275)底物,2.5μM ATP(0.3μCiP33γ-ATP),80ng杆状病毒表达的GST-EGFR,适当浓度的抑制剂。在37℃下温育5分钟之后,用20微升120mM的EDTA终止反应。
捕获:将100微升从各个孔转移到链霉抗生物素蛋白-Flashplate,使生物素化底物与板结合。然后用没有Ca++/Mg++的150微升/孔PBS将板洗涤3次。
检测:在Top-Count仪中计数放射性。
IGF1-R活性的抑制分析
根据下面的方法进行IGF1-R活性的抑制分析。
激酶反应:向96U底孔板的各个孔加入最终体积是30微升缓冲液(50mM Hepes pH 7.9,3mM MnCl2,1mM DTT,3μM NaVO3)中的10μM生物素化MBP(Sigma cat.#M-1891)底物,0-20μM抑制剂,6μM冷ATP,2nM33P标记的ATP,和22.5ng IGF1-R(在室温下预先与冷的60μMATP温育30分钟)。室温下温育35分钟之后,通过加入含有32mM EDTA,500μM冷ATP,0.1%Triton X100的100微升PBS缓冲液和10mg/ml链霉抗生物素蛋白包被的SPA小珠来终止反应。温育15分钟之后,抽出110微升的悬浮液并且转移给含有100微升5M CsCl的96-孔OPTIPLATEs。4小时之后,在Packard TOP-Count放射性读数器上对板读数2分钟。
结论:使用GraphPad Prizm程序分析实验数据。
另外,通过以SPA(闪烁接近分析)96孔板分析的使用为基础的测定方法也测定了推定的蛋白激酶的抑制活性和选择的化合物的效力。测定以链霉抗生物素蛋白包被的SPA小珠捕获从组蛋白的磷酸化位点衍生的生物素化肽的能力为基础。
当丝氨酸/苏氨酸激酶将放射性标记磷酸部分转移给生物素化组蛋白肽时,在闪烁计数器上测定发射的光。
cdk5/p25活性的抑制分析
根据下面的方法进行cdk5/p25活性的抑制分析。
激酶反应:向96U底孔板的各个孔加入最终体积是100微升缓冲液(Hepes 20mM pH 7.5,MgCl2 15mM,1mM DTT)中的1.0μM生物素化组蛋白肽底物,0.25 uCi P33g-ATP,4nM cdk5/p25复合体,0-100μM抑制剂。37℃下温育20分钟之后,通过加入含有0.1%TritonX100,50μM ATP和5mM EDTA的磷酸缓冲盐水中500μg SPA小珠来终止反应。让小珠沉积,TOP-Count闪烁读数器上测定33P-标记肽中的放射性。
结论:应用下式分析数据并且表示为%抑制作用:
100X(1-(未知-Bkgd)/(对照酶-Bkgd))
应用四个参数对数等式的差异计算IC50值:
Y=100/(1+10^((logEC50-x)*斜率))
其中X=log(μM)和Y=%抑制作用。
Cdc7/dbf4活性的抑制分析
根据下面的方法进行Cdc7/dbf4活性的抑制分析。
在γ33-ATP示踪的ATP存在下用Cdc7/Dbf4复合体将生物素-MCM2底物反-磷酸化。然后用链霉抗生物素蛋白-包被的SPA小珠捕获磷酸化生物素-MCM2底物,并且通过β计数评价磷酸化程度。
根据下面的方法在96孔板中进行Cdc7/dbf4活性的抑制分析。
向板的每个孔加入:
10微升底物(生物素化MCM2,6μM终浓度)
10微升酶(Cdc7/Dbf4,12.5nM终浓度)
10微升试验化合物(nM至μM范围内12个递增浓度产生剂量-响应曲线)
10微升的冷ATP(10μM终浓度)和放射性ATP(与冷ATP的摩尔比是1/2500)的混合物,
然后用来开始37℃下发生的反应。
在含有15mM MgCl2,2mM DTT,3μM NaVO3,2mM甘油磷酸酯和0.2mg/ml BSA的50mM HEPES pH 7.9中稀释底物,酶和ATP。用于试验化合物的溶剂也含有10%DMSO。
温育20分钟之后,通过向各个孔中加入100微升含有50mM EDTA,1mM冷ATP,0.1%Triton X100的PBS pH 7.4和10mg/ml链霉抗生物素蛋白包被的SPA小珠来终止反应。
室温下温育使生物素化MCM2-链霉抗生物素蛋白SPA小珠相互作用发生15分钟之后,使用Packard Cell Harvester(Filtermate)在96孔过滤板(UnifilterRGF/BTM)中截获小珠,用蒸馏水洗涤后用TopCount(Packard)读数。
读数减去空白背景之后使用非线性回归分析对IC50测定分析实验数据(每个点重复三次)(Sigma Plot)。
aurora-2活性的抑制分析
通过以在96孔板上进行的链霉抗生物素蛋白闪烁接近分析小珠(amershampharmacia biotech)的使用为基础的测定方法测定抑制活性和选择的化合物的效力。反应结束时,用小珠捕获生物素化肽底物,接着使用CsCl2使之成层。
当激酶将放射性标记磷酸部分转移给与小珠结合的肽时,在闪烁计数器上测定发射的光。
根据下面的方法在96孔板中进行aurora-2活性的抑制分析。
激酶反应:向96U底孔板的各个孔加入最终体积是60微升缓冲液(Hepes 50mM pH 7.0,MgCl2 10mM,1mM DTT,0.125mg/ml BSA,3μM原钒酸盐)中的8μM生物素化肽(四个重复的LRRWSLG),10μM ATP(0.5 uCiP33g-ATP),10nM Aurora2,10μM抑制剂。室温下温育30分钟之后,终止反应并且通过加入100微升小珠悬浮液来捕获生物素化肽。
分层:100微升的CsCl2 7.5M被加给各个孔并且静置1小时,然后TOP-Count闪烁读数器上测定放射性。
结论:参照酶总活性(=100%)分析数据并且表示为%抑制作用。
为了研究通过IC50计算的抑制剂的效力,进一步分析表现出抑制作用≥60%的所有的化合物。
使用的方法与上述相同,除了使用系列稀释的抑制剂。使用下面的等式通过非线性回归处理实验数据:
其中vb是基准速度,v是观察到的反应速度,vo是不存在抑制剂下的速度,而[I]是抑制剂浓度。
适合对哺乳动物例如对人施用的本发明的式(I)的化合物能通过常规途径和剂量水平给药,取决于患者的年龄,体重,状况和给药途径。
例如,口服式(I)的化合物的合适的剂量可以是每剂大约10至大约500mg范围,每天1至5次。
本发明的化合物可以以各种各样的剂型给药,例如以片剂,胶囊,糖或膜包衣的片剂,溶液或混悬剂形式口服;栓剂形式直肠给药;肠胃外给药,例如肌内给药,或者通过静脉内和/或鞘内和/或脊柱内注射或灌注。
另外,本发明的化合物可以作为单一药物给药,或者,与已知的抗癌治疗结合使用,例如放射疗法或者与下面的试剂联合给药的化学疗法:细胞生长抑制剂或细胞毒素试剂,抗生素-类型药物,烷基化试剂,抗代谢药物,激素药物,免疫药物,干扰素-型药物,环加氧酶抑制剂(例如COX-2抑制剂),金属基质蛋白酶抑制剂,端粒酶抑制剂,酪氨酸激酶抑制剂,抗-生长因子受体剂,抗-HER剂,抗-EGFR剂,抗血管发生剂,法尼基转移酶抑制剂,rasraf信号转导途径抑制剂,细胞周期抑制剂,其它cdks抑制剂,微管蛋白结合剂,拓扑异构酶I抑制剂,拓扑异构酶II抑制剂等。
作为例子,本发明的化合物可以与一种或多种化疗药物联合给药,象,例如,依西美坦,福美坦,阿那曲唑,来曲唑,法倔唑,紫杉烷(taxane),紫杉烷衍生物,制成胶囊的紫杉烷,CPT-11,喜树碱衍生物,蒽环苷类,例如,多柔比星,伊达比星,表柔比星,依托泊苷,navelbine,长春花碱,卡铂,顺铂,雌莫司汀,celecoxib,他莫昔芬,雷洛昔芬,Sugen SU-5416,Sugen SU6668,单克隆抗体(Herceptin),等等,任选地制成其脂质体剂型。
如果配制成固定剂量,这样的组合产物使用上述剂量范围内的本发明的化合物和核准的剂量范围内的其他药物活性物质。
当联合配方不合适时,可以与已知的抗癌药物顺序使用式(I)的化合物。
本发明还包括含有式(I)的化合物或者其药学可接受盐和药学可接受赋形剂(可以是载体或稀释剂)的药物组合物。
通常根据常规方法制备含有本发明的化合物的药物组合物,并且以药学合适的剂型给药。
例如,固体口服剂型在药物配方中可以含有活性化合物,和,稀释剂,例如乳糖,葡萄糖,蔗糖,蔗二糖,纤维素,玉米淀粉或马铃薯淀粉;润滑剂,例如二氧化硅,滑石,硬脂酸镁或硬脂酸钙,和/或聚乙二醇;结合剂,例如淀粉类,阿拉伯胶,明胶,甲基纤维素,羧甲基纤维素或聚乙烯吡咯烷酮;崩解剂,例如淀粉,藻酸,藻酸盐或淀粉羟乙酸钠;泡腾混合物;染料;甜味剂;湿润剂例如卵磷脂,聚山梨酯类,月桂基硫酸盐;和,一般来说,没有毒的和没有药学活性的物质。可以以已知方法制备所述药物制剂,例如,利用混合,制粒,压片,糖包衣,或膜包衣工艺。
用于口服给药的液体分散体可以是例如糖浆,乳状液和混悬液。
糖浆可以含有作为载体的例如蔗糖或蔗糖和甘油和/或甘露糖醇和/或山梨糖醇。
混悬液和乳状液可以含有作为载体的例如天然树胶,琼脂,藻酸钠,果胶,甲基纤维素,羧甲基纤维素,或聚乙烯醇。
用于肌内注射的混悬剂或溶液可以含有活性化合物和药学可接受载体,例如无菌水,橄榄油,油酸乙酯,甘醇,例如丙二醇,以及,如果期望,适当量的利多卡因盐酸盐。用于静脉内注射或输液的溶液可以含有作为载体的例如无菌水,或者优选地,它们可以是灭菌的、含水的、等渗的盐溶液,或者它们可以含有作为载体的丙二醇。
栓剂可以含有活性化合物和药学可接受载体,例如椰子油,聚乙二醇,聚氧乙烯脱水山梨糖醇脂肪酯表面活性剂或卵磷脂。
下面的实施例详细说明本发明,但是不限制本发明。
一般方法
在硅胶(Merck级9385,60埃)上进行急骤层析。在Waters X TerraRP 18(4.6×50mm,3.5μm)柱子上进行HPLC/MS,使用装备有996Waters PDA检测器的Waters 2790 HPLC系统和装备有电雾化(ESI)离子源的Micromass模式ZQ单一四极质谱。流动相A是乙酸铵5mM缓冲液(pH 5.5,乙酸/乙腈是95∶5),流动相B是H2O/乙腈(5∶95)。8分钟之内梯度是10至90%B,保持90%B 2分钟。在220nm和254nm下进行检测。流速1毫升/分钟。注射容积是10微升。全扫描,质量范围是100至800amu。毛细管电压是2.5KV;源温度是120℃;圆锥是10V。给出220nm或254nm下以分钟计的保留时间(HPLC r.t.)。以m/z之比给出质量。
当需要时,使用装备有996 Waters PDA检测器的Waters制备HPLC600,在Waters Symmetry C18(19×50mm,5um)柱子上,Micromass模式ZMD单一四极质谱仪,电子喷雾离子化作用,正模式,通过制备HPLC纯化化合物。流动相A是水0.01%TFA,流动相B是乙腈。8分钟之内梯度是10至90%B,保持90%B2分钟。流速20ml/min。
在装备有5mm双共振探测器(1H{15N-31P}ID-PFG Varian)的Mercury VX 400上在400.45MHz下进行1H-NMR光谱分析。
实施例1
6-硝基-3-溴-3H-异苯并呋喃-1-酮(II)
向125毫升的6-硝基2-苯并[c]呋喃酮(8.0克,0.047摩尔)的二氯甲烷溶液加入溴(8.25克,0.052摩尔,1.15当量)和过氧化氢(5.07克的35%水溶液,1.77当量的过氧化氢,0.052摩尔,1,15当量)。使混合物温和回流11小时,然后冷却并且通过蒸发溶剂而浓缩。分离含水层,用水洗涤有机相,然后干燥(Na2SO4)。
将溶剂蒸发之后,经硅胶通过急骤层析纯化粗残余物(己烷-乙酸乙酯8-2至7-3)。得到8.18g标题化合物。[M-1]-=257;HPLC r.t.5.37;1H-NMR(CDCl3),特征信号(ppm):7.47(s,1H),7.86(d,1H),8.67(dd,1H),8.74(d,1H)。
实施例2
(5-氨基-3-氧代-1,3-二氢-异苯并呋喃-1-基)-三苯基溴化
(III)
6-硝基-3-溴-3H-异苯并呋喃-1-酮(8.7克,0.034摩尔)的丙酸乙酯(464毫升)溶液加热至70-75℃,搅拌下经7小时滴加三苯基膦(36克,0.137摩尔,4当量)的丙酸乙酯溶液313毫升。加热并且搅拌过夜,然后将混合物冷却至室温。收集沉淀物,真空干燥并且通过急骤层析在硅胶上纯化。使用二氯甲烷-甲醇-乙酸自97-3-0至93-5-2梯度作为洗脱剂,得到6.2g标题化合物。[M]+=410;HPLC r.t.4.72;1H-NMR(DMSO-d6),特征信号(ppm):6.01(br.s,2H,与重水可互换),6.49(dd,1H),6.80(d,1H),6.87(d,1H),7.62-8.00(m,15H),8.17(s,1H)。
实施例3
(5-{2-甲氧基-4-[3-(4-树脂-苄基氨基甲酰基)-丙氧基]-苄基
氨基}-3-氧代-1,3-二氢-异苯并呋喃-1-基)三苯基-溴化
将实施例2的化合物(252毫克,0.514毫摩尔)溶剂于二氯甲烷(13.5毫升),三氟乙醇(1.5毫升)和乙酸(0.25毫升)制成的15.25毫升溶剂混合物中。将Novabiochem4-(4-甲酰基-3-甲氧基苯氧基)丁酰基氨基甲基化树脂(326毫克,宣称的取代0.94毫摩尔/克,0.6当量)倒入该溶液,将得到的悬浮液轻轻搅拌9小时,然后滴加吡啶-硼烷络合物(250微升,大约6毫摩尔,10当量)。40小时之后将树脂过滤,用二氯甲烷,甲醇洗涤,再用二氯甲烷洗涤,就此真空下干燥(518毫克计算的填充量:0.78毫摩尔/克;IR:1787cm-1,内酯展开谱带)。
实施例4
4-[3-(甲氧基-4-({3-氧代-1-[1-吡啶-3-基-亚甲基]-1,3-二氢
-异苯并呋喃-5-基氨基}-甲基)-苯氧基)-N-(4-树脂-苄基)-丁酰胺
实施例3的(5-{2-甲氧基-4-[3-(4-树脂-苄基氨基甲酰基)-丙氧基]-苄基氨基}-3-氧代-1,3-二氢-异苯并呋喃-1-基)三苯基-溴化(100毫克,0.078毫当量)悬浮于无水二氯甲烷(3毫升);加入吡啶-3-甲醛(50微升,大约6当量),接着加入TEA(50微升)。室温下搅拌20小时之后过滤出树脂并且用二氯甲烷,甲醇洗涤,再用二氯甲烷洗涤,然后真空干燥(IR:1776cm-1)。
实施例5
N-{2-甲氧基-4-[3-(4-树脂-苄基氨基甲酰基)-丙氧基]-苄
基}-N-{3-氧代-1-[1-吡啶-3-基-亚甲基]-1,3-二氢-异苯并呋喃-5-
基}-苯甲酰胺
实施例4的4-[3-(甲氧基-4-({3-氧代-1-[1-吡啶-3-基-亚甲基]-1,3-二氢-异苯并呋喃-5-基氨基}-甲基)-苯氧基)-N-(4-树脂-苄基)-丁酰胺悬浮于无水二氯甲烷(3毫升);按顺序加入二异丙基乙胺(200微升)和苯甲酰氯(100微升,约10当量)。室温下搅拌20小时之后过滤出树脂并且用二氯甲烷,甲醇洗涤,再用二氯甲烷洗涤,然后真空干燥(IR:1786cm-1)。
实施例6
4-[3-(甲氧基-4-(1-{3-氧代-1-[1-吡啶-3-基-亚甲基]-1,3-二
氢-异苯并呋喃-5-基}-3-对-甲苯基-脲基甲基)苯氧基]-N-(4-树脂-
苄基)-丁酰胺
实施例4的4-[3-(甲氧基-4-({3-氧代-1-[1-吡啶-3-基-亚甲基]-1,3-二氢-异苯并呋喃-5-基氨基}-甲基)-苯氧基)-N-(4-树脂-苄基)-丁酰胺悬浮于干燥的二氯甲烷(3毫升);并且加入异氰酸对甲苯酰酯(100微升,约10当量)。室温下搅拌20小时之后过滤出树脂并且用二氯甲烷,甲醇洗涤,再用二氯甲烷洗涤,然后真空干燥。
实施例7
N-{2-甲氧基-4-[3-(4-树脂-苄基氨基甲酰基)-丙氧基]-苄
基}-N-(4-氧代-1-吡啶-3-基甲基-3,4-二氢-2,3-二氮杂萘酮-6-
基)-苯甲酰胺
实施例5的N-{2-甲氧基-4-[3-(4-树脂-苄基氨基甲酰基)-丙氧基]-苄基}-N-{3-氧代-1-[1-吡啶-3-基-亚甲基]-1,3-二氢-异苯并呋喃-5-基}-苯甲酰胺悬浮于二甲基甲酰胺(3毫升)并且加入肼水溶液(大约25%溶液)(400微升,大约40当量)。室温下搅拌20小时之后过滤出树脂并且用二甲基甲酰胺,甲醇洗涤和二氯甲烷洗涤,然后真空干燥(IR:内酯展开谱带消失)。
实施例8
4-{3-甲氧基-4-[1-(4-氧代-1-吡啶-3-基甲基-3,4-二氢-2,3-
二氮杂萘酮-6-基)-3-对-甲苯基-脲基甲基]-苯氧基}-N-(4-树脂-
苄基)-丁酰胺
实施例6的4-[3-(甲氧基-4-(1-{3-氧代-1-[1-吡啶-3-基-亚甲基]-1,3-二氢-异苯并呋喃-5-基}-3-对-甲苯基-脲基甲基)-苯氧基)-N-(4-树脂-苄基)-丁酰胺悬浮于二甲基甲酰胺(3毫升)并且加入肼水溶液(大约25%溶液)(400微升,大约40当量)。室温下搅拌20小时之后过滤出树脂并且用二甲基甲酰胺,甲醇洗涤和二氯甲烷洗涤,然后真空干燥。
实施例9
N-(4-氧代-1-吡啶-3-基甲基-3,4-二氢-2,3-二氮杂萘酮-6-基)
-苯甲酰胺
实施例7的N-{2-甲氧基-4-[3-(4-树脂-苄基氨基甲酰基)-丙氧基]-苄基}-N-(4-氧代-1-吡啶-3-基甲基-3,4-二氢-2,3-二氮杂萘酮-6-基)-苯甲酰胺悬浮于20%TFA的DCM溶液(3毫升),并且室温下搅拌2小时。过滤出树脂并且收集溶液并干燥,得到15毫克的标题化合物。[M+1]+=357;HPLC r.t.4.02;1H-NMR(DMSO-d6),特征信号(ppm):4.39(s,2H),7.47-7.62(m,3H),7.93-8.05(m,3H),8.26(dd,1H),8.54(m,1H),8.65(br.S,1H),8.76(d,1H),10.73(s,1H,与水可以互换),12.45(s,1H,与水可以互换)。
实施例10
1-(4-氧代-1-吡啶-3-基甲基-3,4-二氢-2,3-二氮杂萘酮-6-基)
-3-对-甲苯基-脲
实施例8的4-{3-甲氧基-4-[1-(4-氧代-1-吡啶-3-基甲基-3,4-二氢-2,3-二氮杂萘酮-6-基)-3-对-甲苯基-脲基甲基]-苯氧基}-N-(4-树脂-苄基)-丁酰胺悬浮于20%TFA的DCM溶液(3毫升),并且室温下搅拌2小时。过滤出树脂并且收集溶液并干燥,得到11毫克的标题化合物。[M+1]+=386;HPLC r.t.4.72;1H-NMR(DMSO-d6),特征信号(ppm):2.23(s,3H),4.26(s,2H),7.10(d,2H),7.29(m,1H)7.33(d,2H),7.64(m,1H),7.83(dd,1H),7.89(d,1H),8.40(m,2H),8.56(d,1H),8.70(br.S,1H),9.22(br.s,1H),12.38(br.s,1H)。
通过相似方法操作并且通过使式(III)的化合物与式(V)的合适的醛反应,然后与式(VIII)的合适的酰基氯衍生物或式(IX)的异氰酸酯反应,制备下面的化合物:
7-氨基-4-(4氯-苄基)-2H-2,3-二氮杂萘-1-酮 131
[M+1]+=286;HPLC r.t.4.62;1H-NMR(DMSO-d6),特征信号(ppm):4.11(s,2H),6.97(dd,1H),7.24-7.32(m,5H),7.56(d,1H),12.05(s,1H,与重水可互换)。
7-氨基-4-(4-甲氧基-苄基)-2H-2,3-二氮杂萘-1-酮
[M+1]+=282;HPLC r.t.3.83;1H-NMR(DMSO-d6),特征信号(ppm):3.68(s,3H)4.04(s,2H),6.10(s,2H,与重水可互换),6.82(d,2H),6.97(dd,1H),7.17(d,2H),7.23(d,1H),7.57(d,1H).
7-氨基-4-(4-硝基-苄基)-2H-2,3-二氮杂萘-1-酮
[M+1]+=297;1H-NMR(DMSO-d6),特征信号(ppm):4.29(s,2H),6.18(s,2H,与重水可互换),7.00(dd,1H),7.26(d,1H),7.57(m,3H),8.14(d,2H)。
N-(4-氧代-1-吡啶-3-基甲基-3,4-二氢-2,3-二氮杂萘-6-基)-丙酰胺;
[M+H]+=309;HPLC r.t.2.88。
N-(4-氧代-1-吡啶-3-基甲基-3,4-二氢-2,3-二氮杂萘-6-基)-4-三氟甲基-苯甲酰胺;
[M+H]+=425;HPLC r.t.5.1。
呋喃-2-甲酸(4-氧代-1-吡啶-3-基甲基-3,4-二氢-2,3-二氮杂萘-6-基)-酰胺;[M+H]+=346;HPLC r.t.3.37。
N-(4-氧代-1-吡啶-3-基甲基-3,4-二氢-2,3-二氮杂萘-6-基)-3-环戊基-丙酰胺;[M+H]+=377;HPLC r.t.4.99。
2-丙基-戊酸(4-氧代-1-吡啶-3-基甲基-3,4-二氢-2,3-二氮杂萘-6-基)-酰胺;[M+H]+=379;HPLC r.t.5.09。
1-(4-氧代-1-吡啶-3-基甲基-3,4-二氢-2,3-二氮杂萘-6-基)-3-(3-三氟甲基-苯基)-脲;[M+H]+=440;HPLC r.t.5.29。
1-(3-甲氧基-苯基)-3-(4-氧代-1-吡啶-3-基甲基-3,4-二氢-2,3-二氮杂萘-6-基)-脲;[M+H]+=402;HPLC r.t.4.33。
1-(4-氧代-1-吡啶-3-基甲基-3,4-二氢-2,3-二氮杂萘-6-基)-3-对-甲苯基-脲;[M+H]+=386;HPLC r.t.4.62。
1-(2,4-二氟-苯基)-3-(4-氧代-1-吡啶-3-基甲基-3,4-二氢-2,3-二氮杂萘-6-基)-脲;[M+H]+=408;HPLC r.t.4.58。
1-(3,4-二氯-苯基)-3-(4-氧代-1-吡啶-3-基甲基-3,4-二氢-2,3-二氮杂萘-6-基)-脲[M+H]+=440;HPLC r.t.5.59。
N-[1-(4-氯-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-丙酰胺;[M+H]+=342;HPLC r.t.5.18。
N-[1-(4-氯-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-4-三氟甲基-苯甲酰胺;[M+H]+=458;HPLC r.t.7.13。
呋喃-2-甲酸[1-(4-氯-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-酰胺;[M+H]+=380;HPLC r.t.5.66。
N-[1-(4-氯-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-3-环戊基-丙酰胺;[M+H]+=410;HPLC r.t.7.22。
2-丙基-戊酸[1-(4-氯-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-酰胺;[M+H]+=412;HPLC r.t.7.33。
1-[1-(4-氯-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-3-(3-三氟甲基-苯基)-脲;[M+H]+=473;HPLC r.t.7.26。
1-[1-(4-氯-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-3-(3-甲氧基-苯基)-脲;[M+H]+=435;HPLC r.t.6.43。
1-[1-(4-氯-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-3-对-甲苯基-脲;[M+H]+=419;HPLC r.t.6.74。
1-[1-(4-氯-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-3-(2,4-二氟-苯基)-脲;[M+H]+=441;HPLC r.t.6.71。
N-[1-(4-氰基-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-丙酰胺;[M+H]+=333;HPLC r.t.4.26。
N-[1-(4-氰基-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-4-三氟甲基-苯甲酰胺;[M+H]+=449;HPLC r.t.6.3。
呋喃-2-甲酸[1-(4-氰基-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-酰胺;[M+H]+=371;HPLC r.t.4.72。
N-[1-(4-氰基-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-3-环戊基-丙酰胺;[M+H]+=401;HPLC r.t.6.3。
2-丙基-戊酸[1-(4-氰基-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-酰胺;[M+H]+=403;HPLC r.t.6.42。
1-[1-(4-氰基-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-3-(3-三氟甲基-苯基)-脲;[M+H]+=464;HPLC r.t.6.46;1H-NMR(DMSO-d6),特征信号(ppm):4.34(s,2H),7.34(d,1H),7.47-7.55(m,3H),7.59(d,1H),7.73(d,2H),7.80-7-88(m,2H),8.00(s,1H),8.43(d,1H),9.20(s,1H),9.40(s,1H),12.44(br.s,1H)。
1-[1-(4-氰基-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-3-(3-甲氧基-苯基)-脲;[M+H]+=426;HPLC r.t.5.59。
1-[1-(4-氰基-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-3-对-甲苯基-脲;[M+H]+=410;HPLC r.t.5.89。
1-[1-(4-氰基-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-3-(2,4-二氟-苯基)-脲;[M+H]+=432;HPLC r.t.6。
N-[1-(3-氟-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-丙酰胺;[M+H]+=326;HPLC r.t.4.69;1H-NMR(DMSO-d6),特征信号(ppm):1.08(t,3H),2.35(q,2H),4.24(s,2H),7.00(m,1H),7.11(m,2H),7.29(m,1H),7.90(d,1H),7.95(dd,1H),8.53(d,1H),10.35(br.s,1H),12.42(br.S,1H)。
N-[1-(3-氟-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-4-三氟甲基-苯甲酰胺;[M+H]+=442;HPLC r.t.6.68。
呋喃-2-甲酸[1-(3-氟-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-酰胺;[M+H]+=364;HPLC r.t.5.16.
N-[1-(3-氟-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-3-环戊基-丙酰胺;[M+H]+=394;HPLC r.t.6.73。
2-丙基-戊酸[1-(3-氟-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-酰胺;[M+H]+=396;HPLC r.t.6.85。
1-[1-(3-氟-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-3-(3-三氟甲基-苯基)-脲;[M+H]+=457;HPLC r.t.6.86。
1-[1-(3-氟-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-3-(3-甲氧基-苯基)-脲;[M+H]+=419;HPLC r.t.5.98。
N-[1-(3-甲基-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-丙酰胺;[M+H]+=322;HPLC r.t.4.92。
N-[1-(3-甲基-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-4-三氟甲基-苯甲酰胺;[M+H]+=438;HPLC r.t.6.93。
呋喃-2-甲酸[1-(3-甲基-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-酰胺;[M+H]+=360;HPLC r.t.5.38。
N-[1-(3-甲基-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-3-环戊基-丙酰胺;[M+H]+=390;HPLC r.t.6.95。
2-丙基-戊酸[1-(3-甲基-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-酰胺;[M+H]+=392;HPLC r.t.7.08。
1-[1-(3-甲基-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-3-(3-三氟甲基-苯基)-脲;[M+H]+=453;HPLC r.t.7.04。
1-[1-(3-甲基-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-3-(3-甲氧基-苯基)-脲;[M+H]+=415;HPLC r.t.6.18。
1-[1-(3-甲基-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-3-对-甲苯基-脲;[M+H]+=399;HPLC r.t.6.48。
1-[1-(3-甲基-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-3-(2,4-二氟-苯基)-脲;[M+H]+=421;HPLC r.t6.5。
N-[1-(2,4-二氯-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-丙酰胺;[M+H]+=376;HPLC r.t.5.83;1H-NMR(DMSO-d6),特征信号(ppm):1.09(t,3H),2.37(q,2H),4.33(s,2H),7.30(d,1H),7.32(dd,1H),7.60(d,1H),7.93(d,1H),8.02(dd,1H),8.56(d,1H),10.39(s,1H),12.33(s,1H)。
N-[1-(2,4-二氯-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-4-三氟甲基-苯甲酰胺;[M+H]+=492;HPLC r.t.7.68;1H-NMR(DMSO-d6),特征信号(ppm):4.37(s,2H),7.30-7.37(m,2H),7.62(d,1H),7.94(d,2H),8.02(d,1H),8.19(d,2H),8.27(dd,1H),8.77(d,1H),10.96(br.S,1H),12.41(br.S,1H)。
呋喃-2-甲酸[1-(2,4-二氯-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-酰胺;[M+H]+=414;HPLC r.t.6.26。
N-[1-(2,4-二氯-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-琥珀酰胺酸乙酯;[M+H]+=HPLC r.t.6.11。
N-[1-(2,4-二氯-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-3-环戊基-丙酰胺;[M+H]+=444;HPLC r.t.7.82;1H-NMR(DMSO-d6),特征信号(ppm):1.00-1.85(m,11H),2.37(t,2H),4.33(s,2H),7.30(d,1H),7.32(dd,1H),7.60(dd,1H),7.92(d,1H),8.00(dd,1H),8.56(dd,1H),10.40(br.S.,1H),12.33(br.S.,1H)。
2-丙基-戊酸[1-(2,4-二氯-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-酰胺;[M+H]+=446;HPLC r.t.7.94;1H-NMR(DMSO-d6),特征信号(ppm):1.001.85(m,9H),1.58-1.66(m,2H),2.37(m,2H),4.33(s,2H),7.30(d,1H),7.32(dd,1H),7.60(d,1H),7.92(d,1H),8.00(dd,1H),8.56(dd,1H),10.40(br.S,1H),12.33(br.S,1H)。
1-[1-(2,4-二氯-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-3-(3-三氟甲基-苯基)-脲;[M+H]+=507;HPLC r.t.7.83。
1-[1-(2,4-二氯-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-3-(3-甲氧基-苯基)-脲;[M+H]+=469;HPLC r.t.7.02;1H-NMR(DMSO-d6),特征信号(ppm):3.73(s,3H),4.33(s,2H),6.58(m,1H),6.96(m,1H),7.15-7.22(m,2H),7.28-7.36(m,2H),7.61(d,1H),7.827.90(m,2H),8.44(d,1H),8.91(br.S,1H),9.35(br.S,1H),12.31(br.s,1H)。
1-[1-(2,4-二氯-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-3-对-甲苯基-脲;[M+H]+=453;HPLC r.t.7.35。
1-[1-(2,4-二氯-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-3-(2,4-二氟-苯基)-脲;[M+H]+=475;HPLC r.t.7.38;1H-NMR(DMSO-d6),特征信号(ppm):4.33(s,2H),7.06(m,1H),7.25-7.36(m,3H),7.61(d,1H),7.85(dd,1H),7.88(d,1H),8.03(m,1H),8.45(d,1H),8.75(s,1H),9.71(s,1H),12.33(s,1H)。
N-(4-氧代-1-喹啉-3-基甲基-3,4-二氢-2,3-二氮杂萘-6-基)-丙酰胺;[M+H]+=359;HPLC r.t.4.01。
N-(4-氧代-1-喹啉-3-基甲基-3,4-二氢-2,3-二氮杂萘-6-基)-4-三氟甲基-苯甲酰胺;[M+H]+=475;HPLC r.t.6;1H-NMR(DMSO-d6),特征信号(ppm):4.51(s,2H),7.57(dt,1H),7.69(dt,1H)7.87-8.00(m,4H),8.09(d,1H),8.15-8.20(m,3H),8.23(dd,1H),8.76(d,1H),8.92(d,1H),10.92(s,1H),12.49(s,1H)。
N-(4-氧代-1-喹啉-3-基甲基-3,4-二氢-2,3-二氮杂萘-6-基)-琥珀酰胺酸乙酯;[M+H]+==431;HPLC r.t.4.37。
N-(4-氧代-1-喹啉-3-基甲基-3,4-二氢-2,3-二氮杂萘-6-基)-3-环戊基-丙酰胺;[M+H]+=427;HPLC r.t.5.97。
2-丙基-戊酸(4-氧代-1-喹啉-3-基甲基-3,4-二氢-2,3-二氮杂萘-6-基)-酰胺;[M+H]+=429;HPLC r.t.6.08。1H-NMR(DMSO-d6),特征信号(ppm):0.80-0.88(m,6H),1.18-1.29(m,4H),1.29-1.64(m,4H),2.37-2.48(m,1H),4.48(s,2H),7.55(m,1H),7.70(m,1H),7.88(dd,1H),7.95-8.01(m,3H),8.17(d,1H),8.58(d,1H),8.91(d,1H),10.36(br.s,1H),12.42(br.S,1H)。
1-(4-氧代-1-喹啉-3-基甲基-3,4-二氢-2,3-二氮杂萘-6-基)-3-(3-三氟甲基-苯基)-脲;[M+H]+=490;HPLC r.t.6.16。
1-(4-氧代-1-喹啉-3-基甲基-3,4-二氢-2,3-二氮杂萘-6-基)-3-(3-甲氧基-苯基)-脲;[M+H]+=452;HPLC r.t.5.27;1H-NMR(DMSO-d6),特征信号(ppm):3.72(s,3H),4.47(s,2H),6.57(m,1H),6.94(m,1H),7.19(m,2H),7.55(dd,1H),7.69(dd,1H),7.81(dd,1H),7.88(dd,1H),7.96(m,2H),8.16(d,1H),8.44(d,1H),8.82(br.s,1H),8.91(d,1H),9.25(br.s,1H),12.40(br.s,1H)。
1-(4-氧代-1-喹啉-3-基甲基-3,4-二氢-2,3-二氮杂萘-6-基)-3-对-甲苯基-脲;[M+H]+=436;HPLC r.t.5.56。
1-(4-氧代-1-喹啉-3-基甲基-3,4-二氢-2,3-二氮杂萘-6-基)-3-(2,4-二氟-苯基)-脲;[M+H]+=458;HPLC r.t.5.55;1H-NMR(DMSO-d6),特征信号(ppm):4.48(s,2H),7.05(m,1H),7.30(m,1H),7.54(dt,1H),7.69(dt,1H),7.79(dd,1H),7.87(d,1H),7.95-8.07(m,2H),8.16(d,1H),8.44(d,1H),8.61(d,1H),8.90(s,1H),9.56(s,1H)12.41(s,1H)。
1-(4-氧代-1-喹啉-3-基甲基-3,4-二氢-2,3-二氮杂萘-6-基)-3-(3,4-二氯-苯基)-脲;[M+H]+=491;HPLC r.t.6.51。
N-[4-氧代-1-(2-三氟甲基-苄基)-3,4-二氢-2,3-二氮杂萘-6-基]-丙酰胺;[M+H]+=376;HPLC r.t.5.41。
N-[4-氧代-1-(2-三氟甲基-苄基)-3,4-二氢-2,3-二氮杂萘-6-基]-4-三氟甲基-苯甲酰胺;[M+H]+=492;HPLC r.t.7.23。
呋喃-2-甲酸[4-氧代-1-(2-三氟甲基-苄基)-3,4-二氢-2,3-二氮杂萘-6-基]-酰胺;[M+H]+=414;HPLC r.t.5.82。
N-[4-氧代-1-(2-三氟甲基-苄基)-3,4-二氢-2,3-二氮杂萘-6-基]-3-环戊基-丙酰胺;[M+H]+=444;HPLC r.t.7.33。
2-丙基-戊酸[4-氧代-1-(2-三氟甲基-苄基)-3,4-二氢-2,3-二氮杂萘-6-基]-酰胺;[M+H]+=446;HPLC r.t.7.43。
1-[4-氧代-1-(2-三氟甲基-苄基)-3,4-二氢-2,3-二氮杂萘-6-基]-3-(3-三氟甲基-苯基)-脲;[M+H]+=507;HPLC r.t.7.36。
1-[4-氧代-1-(2-三氟甲基-苄基)-3,4-二氢-2,3-二氮杂萘-6-基]-3-对-甲苯基)-脲;[M+H]+=453;HPLC r.t.6.88。
1-[4-氧代-1-(2-三氟甲基-苄基)-3,4-二氢-2,3-二氮杂萘-6-基]-3-(2,4-二氟-苯基)-脲;[M+H]+=475;HPLC r.t.6.88。
4-(4-氧代-6-丙酰基氨基-3,4-二氢-2,3-二氮杂萘-1-基甲基)-苯甲酸甲酯;[M+H]+=366;HPLC r.t.2.61。
4-(4-氧代-6-(4-三氟甲基-苯甲酰基氨基)-3,4-二氢-2,3-二氮杂萘-1-基甲基)-苯甲酸甲酯;[M+H]+=482;HPLC r.t.6.47。
4-{6-[(呋喃-2-羰基)-氨基]-4-氧代-3,4-二氢-2,3-二氮杂萘-1-基甲基}-苯甲酸甲酯;[M+H]+=404;HPLC r.t.4.91。
4-[6-(3,4-二甲氧基-苯甲酰基氨基)-3,4-二氢-2,3-二氮杂萘-1-基甲基]-苯甲酸甲酯;[M+H]+=474;HPLC r.t.5.27。
4-[6-(3-环戊基-丙酰基氨基)-4-氧代-3,4-二氢-2,3-二氮杂萘-1-基甲基]-苯甲酸甲酯;[M+H]+=434;HPLC r.t.6.48。
4-[4-氧代-6-(2-丙基-戊酰基氨基)-3,4-二氢-2,3-二氮杂萘-1-基甲基]-苯甲酸甲酯;[M+H]+=436;HPLC r.t.6.61。
4-{6-[3-(3-甲氧基-苯基)-脲基]-4-氧代-3,4-二氢-2,3-二氮杂萘-1-基甲基}-苯甲酸甲酯;[M+H]+=459;HPLC r.t.5.74。
4-[4-氧代-6-(3-对-甲苯基-脲基)-3,4-二氢-2,3-二氮杂萘-1-基甲基]-苯甲酸甲酯;[M+H]+=443;HPLC r.t.6.03。
4-{6-[3-(2,4-二氟-苯基)-脲基]-4-氧代-3,4-二氢-2,3-二氮杂萘-1-基甲基}-苯甲酸甲酯;[M+H]+=465;HPLC r.t.6.04。
N-[1-(4-氯-3-氟-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-丙酰胺;[M+H]+=360;HPLC r.t.4.04。
N-[1-(4-氯-3-氟-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-4-三氟甲基-苯甲酰胺;[M+H]+=476;HPLC r.t.6.3。
呋喃-2-甲酸[1-(4-氯-3-氟-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-酰胺;[M+H]+=398;HPLC r.t.4.58。
N-[1-(4-氯-3-氟-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-3,4-二甲氧基-苯甲酰胺;[M+H]+=468;HPLC r.t.4.97。
N-[1-(4-氯-3-氟-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-3-环戊基-丙酰胺;[M+H]+=428;HPLC r.t.7.3。
2-丙基-戊酸[1-(4-氯-3-氟-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-酰胺;[M+H]+=430;HPLC r.t.7.41。
1-[1-(4-氯-3-氟-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-3-(3-三氟甲基-苯基)-脲;[M+H]+=491;HPLC r.t.6.54。
1-[1-(4-氯-3-氟-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-3-对-甲苯基-脲;[M+H]+=437;HPLC r.t.5.91。
N-{1-[(E)-3-(4-硝基-苯基)-烯丙基]-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基}-3,4二甲氧基-苯甲酰胺[M+H]+=;HPLC r.t.4.96。
N-(4-氧代-1-噻吩-3-基甲基-3,4-二氢-2,3-二氮杂萘-6-基)-丙酰胺;
[M+H]+=314;HPLC r.t.4.26。
N-(4-氧代-1-噻吩-3-基甲基-3,4-二氢-2,3-二氮杂萘-6-基)-4-三氟甲基-苯甲酰胺;[M+H]+=430;HPLC r.t.6.43。
呋喃-2-甲酸(4-氧代-1-噻吩-3-基甲基-3,4-二氢-2,3-二氮杂萘-6-基)-酰胺;[M+H]+=352;HPLC r.t.4.76。
N-(4-氧代-1-噻吩-3-基甲基-3,4-二氢-2,3-二氮杂萘-6-基)-3,4-二甲氧基-苯甲酰胺;[M+H]+=422;HPLC r.t.5.16。
2-丙基-戊酸(4-氧代-1-噻吩-3-基甲基-3,4-二氢-2,3-二氮杂萘-6-基)-酰胺;[M+H]+=384;HPLC r.t.6.54。
1-(4-氧代-1-噻吩-3-基甲基-3,4-二氢-2,3-二氮杂萘-6-基)-3-(3-三氟甲基-苯基)-脲;[M+H]+=445;HPLC r.t.6.57。
1-(4-氧代-1-噻吩-3-基甲基-3,4-二氢-2,3-二氮杂萘-6-基)-3-(3-甲氧基-苯基)-脲;[M+H]+=407;HPLC r.t.5.66。
1-(4-氧代-1-噻吩-3-基甲基-3,4-二氢-2,3-二氮杂萘-6-基)-3-对-甲苯基-脲;[M+H]+=391;HPLC r.t.5.98。
1-(4-氧代-1-噻吩-3-基甲基-3,4-二氢-2,3-二氮杂萘-6-基)-3-(2,4-二氟-苯基)-脲;[M+H]+=413;HPLC r.t.5.96。
N-[1-(3-甲氧基-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-丙酰胺;[M+H]+=338;HPLC r.t.4.48。
N-[1-(3-甲氧基-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-4-三氟甲基-苯甲酰胺;[M+H]+=454;HPLC r.t.6.52。
呋喃-2-甲酸[1-(3-甲氧基-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-酰胺;[M+H]+=376;HPLC r.t.4.95。
N-[1-(3-甲氧基-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-3,4-二甲氧基-苯甲酰胺;[M+H]+=446;HPLC r.t.5.32。
N-[1-(3-甲氧基-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-3-环戊基-丙酰胺;[M+H]+=406;HPLC r.t.6.53。
2-丙酸-戊酸[1-(3-甲氧基-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-酰胺;[M+H]+=408;HPLC r.t.6.65;1H-NMR(DMSO-d6),特征信号(ppm):0.84(q,6H),1.15-1.62(m,8H),2.41(m,1H),3.68(s,3H),4.18(s,2H),6.75(ddd,1H),6.82(dt,1H),6.86(t,1H),7.16(t,1H),7.89(d,1H),7.95(dd,1H),8.55(d,1H),10.34(s,1H),12.41(s,1H)。
1-[1-(3-甲氧基-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-3-(3-三氟甲基-苯基)-脲;[M+H]+=469;HPLC r.t.6.67。
1-[1-(3-甲氧基-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-3-(3-甲氧基-苯基)-脲;[M+H]+=431;HPLC r.t.5.79。
1-[1-(3-甲氧基-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-3-对-甲苯基-脲;[M+H]+=415;HPLC r.t.6.08。
1-[1-(3-甲氧基-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-3-(2,4-二氟-苯基)-脲;[M+H]+=437;HPLC r.t.6.08。
N-(4-氧代-1-丙基-3,4-二氢-2,3-二氮杂萘-6-基)-丙酰胺;[M+H]+=260;HPLC r.t.3.78。
呋喃-2-甲酸(4-氧代-1-丙基-3,4-二氢-2,3-二氮杂萘-6-基) -酰胺;[M+H]+=298;HPLC r.t.4.35。
1-(4-氧代-1-丙基-3,4-二氢-2,3-二氮杂萘-6-基)-3-对-甲苯基-脲;[M+H]+=;HPLC r.t.5.69。
1-(4-氧代-1-丙基-3,4-二氢-2,3-二氮杂萘-6-基)-3-(2,4-二氟-苯基)-脲;[M+H]+=359;HPLC r.t.5.68。
N-[4-氧代-1-(3-苯基-丙基)-3,4-二氢-2,3-二氮杂萘-6-基]-丙酰胺;[M+H]+=336;HPLC r.t.5.35。
N-[4-氧代-1-(3-苯基-丙基)-3,4-二氢-2,3-二氮杂萘-6-基]-4-三氟甲基-苯甲酰胺;[M+H]+=452;HPLC r.t.7.26。
呋喃-2-甲酸[4-氧代-1-(3-苯基-丙基)-3,4-二氢-2,3-二氮杂萘-6-基]-酰胺;[M+H]+=374;HPLC r.t.5.78。
N-[4-氧代-1-(3-苯基-丙基)-3,4-二氢-2,3-二氮杂萘-6-基]-3,4-二甲氧基-苯甲酰胺;[M+H]+=444;HPLC r.t.6.11。
N-[4-氧代-1-(3-苯基-丙基)-3,4-二氢-2,3-二氮杂萘-6-基]-3-环戊基-丙酰胺;[M+H]+=404;HPLC r.t.7.31。
2-丙基-戊酸[4-氧代-1-(3-苯基-丙基)-3,4-二氢-2,3-二氮杂萘-6-基]-酰胺;[M+H]+=406;HPLC r.t.7.43。
1-[4-氧代-1-(3-苯基-丙基)-3,4-二氢-2,3-二氮杂萘-6-基]-3-(3-三氟甲基-苯基)-脲;[M+H]+=467;HPLC r.t.7.41。
1-[4-氧代-1-(3-苯基-丙基)-3,4-二氢-2,3-二氮杂萘-6-基]-3-(3-甲氧基-苯基)-脲;[M+H]+=429;HPLC r.t.6.56。
1-[4-氧代-1-(3-苯基-丙基)-3,4-二氢-2,3-二氮杂萘-6-基]-3-对-甲苯基-脲;[M+H]+=413;HPLC r.t.6.88。
1-[4-氧代-1-(3-苯基-丙基)-3,4-二氢-2,3-二氮杂萘-6-基]-3-(2,4-二氟-苯基)-脲;[M+H]+=435;HPLCr.t.6.88。
1-[1-(3-氟-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-3-(2,4-二氟-苯基)-脲;[M+H]+=425;1H-HMR(DMSO-d6),特征信号(ppm):4.25(s,2H),6.977.08(m,2H),7.09-7.15(m,2H),7.27-7.35(m,2H),7.77(dd,1H),7.86(d,1H),7.98-8.08(m,1H),8.42(d,1H),8.61(d,1H),9.55(s,1H),12.42(s,1H)。
1-[1-(3-氟-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-3-对-甲苯基-脲;[M+H]+=403;1H-NMR(DMSO-d6),特征信号(ppm):2.23(s,3H),4.24(s,2H),7.00(m,1H),7.05-7.16(m,4H),7.27-7.35(m,3H),7.79(dd,1H),7.84(d,1H),8.39(d,1H),8.70(br.S,1H),9.20(br.S,1H),12.39(s,1H)。
Claims (4)
1.式(I)代表的氨基-2,3-二氮杂萘酮衍生物:
其中
Ra和Rb各自独立地是氢原子或任选地进一步被取代的选自下面的基团:直链或支链C1-C6烷基,C3-C6环烷基或环烷基C1-C6烷基,芳基,芳基C1-C6烷基,5至7元杂环基或者具有1-3个选自氮,氧或硫的杂原子的杂环基C1-C6烷基;或者Ra或Rb之一是氢或任意地被取代的直链或支链C1-C6烷基,另一个是选自-COR’,-CONHR’,-COOR’或-SO2R’的基团,其中R’是氢或任选地被取代的选自上述烷基,环烷基,环烷基烷基,芳基,芳基烷基,杂环基或杂环基烷基的基团;
R1是式-CHR4R5基团,其中R4和R5各自独立地是氢或者任意地被取代的选自直链或支链C1-C6烷基,C3-C6环烷基或环烷基C1-C6烷基,芳基,芳基C1-C6烷基,5至7元杂环基或者具有1-3个选自氮,氧或硫的杂原子的杂环基C1-C6烷基的基团;或者R1是式-NHR’,-NR’COR″,-NR’CONHR″或-NR’SO2R″,其中R’具有上述氢以外的定义,R″是氢或具有上面对于R’的定义;
R2是氢原子或任选地进一步被取代的选自下面的基团:直链或支链C1-C6烷基,C3-C6环烷基或环烷基C1-C6烷基,芳基,芳基C1-C6烷基,5至7元杂环基或者具有1-3个选自氮,氧或硫的杂原子的杂环基C1-C6烷基;
2,3-二氮杂萘酮环上自由位置5,6和8中的一个或多个上的任何R3各自独立地是卤原子,硝基,羧基,氰基或者任选地进一步被取代的选自下面的基团:直链或支链C1-C6烷基,C3-C6环烷基或环烷基C1-C6烷基,芳基,芳基C1-C6烷基,5至7元杂环基或者具有1-3个选自氮,氧或硫的杂原子的杂环基C1-C6烷基;或者R3是选自-COR’,-CONHR’,-SO2R’,-NR’R″,-NR’COR″,-NR’CONHR’或-NR’SO2R″的基团,其中R’和R″是相同或不同的,是氢或者上面提到的基团;
m是0或1-3的整数;
或者其药学可接受的盐;
不包括化合物N-[3,4-二氢-4-氧代-1-(4-吡啶基甲基)-6-2,3-二氮杂萘基]-乙酰胺和N-[3,4-二氢-4-氧代-1-(4-吡啶基甲基)-6-2,3-二氮杂萘基]-2,2,2-三氟-乙酰胺。
2.权利要求1定义的式(I)的化合物,任选地以药学可接受盐的形式存在,选自:
1)4-(4-氧代-6-丙酰基氨基-3,4-二氢-2,3-二氮杂萘-1-基甲基)-苯甲酸甲酯;
2)4-(4-氧代-6-(4-三氟甲基-苯甲酰氨基)-3,4-二氢-2,3-二氮杂萘-1-基甲基)-苯甲酸甲酯;
3)4-{6-[(呋喃-2-羰基)-氨基]-4-氧代-3,4-二氢-2,3-二氮杂萘-1-基甲基}-苯甲酸甲酯;
4)4-(6-(3,4-二甲氧基-苯甲酰氨基)-4-氧代-3,4-二氢-2,3-二氮杂萘-1-基甲基)-苯甲酸甲酯;
5)4-(6-(3-环戊基-丙酰氨基)-4-氧代-3,4-二氢-2,3-二氮杂萘-1-基甲基)-苯甲酸甲酯;
6)4-[4-氧代-6-(2-丙基-戊酰基氨基)-3,4-二氢-2,3-二氮杂萘-1-基甲基]-苯甲酸甲酯;
7)4-{4-氧代-6-[3-(3-三氟甲基-苯基)-脲基]-3,4-二氢-2,3-二氮杂萘-1-基甲基}-苯甲酸甲酯;
8)4-{6-[3-(3-甲氧基-苯基)-脲基]-4-氧代-3,4-二氢-2,3-二氮杂萘-1-基甲基}-苯甲酸甲酯;
9)4-[4-氧代-6-(3-对-甲苯基-脲基)-3,4-二氢-2,3-二氮杂萘-1-基甲基]-苯甲酸甲酯;
10)4-{6-[3-(2,4-二氟-苯基)-脲基]-4-氧代-3,4-二氢-2,3-二氮杂萘-1-基甲基}-苯甲酸甲酯;
11)4-{6-[3-(3,4-二氯-苯基)-脲基]-4-氧代-3,4-二氢-2,3-二氮杂萘-1-基甲基}-苯甲酸甲酯;
12)4-[4-氧代-6-(3-吡啶-3-基-脲基)-3,4-二氢-2,3-二氮杂萘-1-基甲基]-苯甲酸甲酯;
13)4-(6-氨基-4-氧代-3,4-二氢-2,3-二氮杂萘-1-基甲基)-苯甲酸甲酯;
14)N-[1-(4-氯-3-氟-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-丙酰胺;
15)N-[1-(4-氯-3-氟-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-4-三氟甲基-苯甲酰胺;
16)呋喃-2-甲酸[1-(4-氯-3-氟-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-酰胺;
17)N-[1-(4-氯-3-氟-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-3,4-二甲氧基-苯甲酰胺;
18)N-[1-(4-氯-3-氟-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-3-环戊基-丙酰胺;
19)2-丙基-戊酸[1-(4-氯-3-氟-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]酰胺;
20)1-[1-(4-氯-3-氟-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-3-(3-三氟甲基-苯基)-脲;
21)1-[1-(4-氯-3-氟-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-3-(3-甲氧基-苯基)-脲;
22)1-[1-(4-氯-3-氟-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-3-对-甲苯基-脲;
23)1-[1-(4-氯-3-氟-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-3-(2,4-二氟-苯基)-脲;
24)1-[1-(4-氯-3-氟-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-3-(3,4-二氯-苯基)-脲;
25)1-[1-(4-氯-3-氟-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-3-吡啶-3-基-脲;
26)7-氨基-4-(4-氯-3-氟-苄基)-2H-2,3-二氮杂萘-1-酮;
27)N-{1-[(E)-3-(4-硝基-苯基)-烯丙基]-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基}-丙酰胺;
28)N-{1-[(E)-3-(4-硝基-苯基)-烯丙基]-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基}-4-三氟甲基-苯甲酰胺;
29)呋喃-2-甲酸{1-[(E)-3-(4-硝基-苯基)-烯丙基]-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基}-酰胺;
30)N-{1-[(E)-3-(4-硝基-苯基)-烯丙基]-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基}-3,4-二甲氧基-苯甲酰胺;
31)N-{1-[(E)-3-(4-硝基-苯基)-烯丙基]-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基}-3-环戊基-丙酰胺;
32)2-丙基-戊酸{1-[(E)-3-(4-硝基-苯基)-烯丙基]-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基}-酰胺;
33)1-{1-[(E)-3-(4-硝基-苯基)-烯丙基]-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基}-3-(3-三氟甲基-苯基)-脲;
34)1-{1-[(E)-3-(4-硝基-苯基)-烯丙基]-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基}-3-(3-甲氧基-苯基)-脲;
35)1-{1-[(E)-3-(4-硝基-苯基)-烯丙基]-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基}-3-对-甲苯基-脲;
36)1-{1-[(E)-3-(4-硝基-苯基)-烯丙基]-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基}-3-(2,4-二氟-苯基)-脲;
37)1-{1-[(E)-3-(4-硝基-苯基)-烯丙基]-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基}-3-(3,4-二氯-苯基)-脲;
38)1-{1-[(E)-3-(4-硝基-苯基)-烯丙基]-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基}-3-吡啶-3-基-脲;
39)7-氨基-4-[(E)-3-(4-硝基-苯基)-烯丙基]-2H-2,3-二氮杂萘-1-酮;
40)N-(4-氧代-1-噻吩-3-基甲基-3,4-二氢-2,3-二氮杂萘-6-基)-丙酰胺;
41)N-(4-氧代-1-噻吩-3-基甲基-3,4-二氢-2,3-二氮杂萘-6-基)-4-三氟甲基-苯甲酰胺;
42)呋喃-2-甲酸(4-氧代-1-噻吩-3-基甲基-3,4-二氢-2,3-二氮杂萘-6-基)-酰胺;
43)N-(4-氧代-1-噻吩-3-基甲基-3,4-二氢-2,3-二氮杂萘-6-基)-3,4-二甲氧基-苯甲酰胺;
44)N-(4-氧代-1-噻吩-3-基甲基-3,4-二氢-2,3-二氮杂萘-6-基)-3-环戊基-丙酰胺;
45)2-丙基-戊酸(4-氧代-1-噻吩-3-基甲基-3,4-二氢-2,3-二氮杂萘-6-基)-酰胺;
46)1-(4-氧代-1-噻吩-3-基甲基-3,4-二氢-2,3-二氮杂萘-6-基)-3-(3-三氟甲基-苯基)-脲;
47)1-(4-氧代-1-噻吩-3-基甲基-3,4-二氢-2,3-二氮杂萘-6-基)-(3-甲氧基-苯基)-脲;
48)1-(4-氧代-1-噻吩-3-基甲基-3,4-二氢-2,3-二氮杂萘-6-基)-3-对-甲苯基-脲;
49)1-(4-氧代-1-噻吩-3-基甲基-3,4-二氢-2,3-二氮杂萘-6-基)-3-(2,4-二氟-苯基)-脲;
50)1-(4-氧代-1-噻吩-3-基甲基-3,4-二氢-2,3-二氮杂萘-6-基)-3-(3,4-二氯-苯基)-脲;
51)1-(4-氧代-1-噻吩-3-基甲基-3,4-二氢-2,3-二氮杂萘-6-基)-3-吡啶-3-基-脲;
52)7-氨基-4-噻吩-3-基甲基-2H-2,3-二氮杂萘-1-酮;
53)N-[1-(3-甲氧基-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-丙酰胺;
54)N-[1-(3-甲氧基-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-4-三氟甲基-苯甲酰基;
55)呋喃-2-甲酸[1-(3-甲氧基-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-酰胺;
56)N-[1-(3-甲氧基-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-3,4-二甲氧基-苯甲酰胺;
57)N-[1-(3-甲氧基-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-3-环戊基-丙酰胺;
58)2-丙基-戊酸[1-(3-甲氧基-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-酰胺;
59)1-[1-(3-甲氧基-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-3-(3-三氟甲基-苯基)-脲;
60)1-[1-(3-甲氧基-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-(3-甲氧基-苯基)-脲;
61)1-[1-(3-甲氧基-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-3-对-甲苯基-脲;
62)1-[1-(3-甲氧基-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-3-(2,4-二氟-苯基)-脲;
63)1-[1-(3-甲氧基-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-3-(3,4-二氯-苯基)-脲;
64)1-[1-(3-甲氧基-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-3-吡啶-3-基-脲;
65)7-氨基-4-(3-甲氧基-苄基)-2H-2,3-二氮杂萘-1-酮;
66)N-(4-氧代-1-丙基-3,4-二氢-2,3-二氮杂萘-6-基)丙酰胺;
67)N-(4-氧代-1-丙基-3,4-二氢-2,3-二氮杂萘-6-基)-4-三氟甲基-苯甲酰胺;
68)呋喃-2-甲酸(4-氧代-1-丙基-3,4-二氢-2,3-二氮杂萘-6-基)-酰胺;
69)N-(4-氧代-1-丙基-3,4-二氢-2,3-二氮杂萘-6-基)-3,4-二甲氧基-苯甲酰胺;
70)N-(4-氧代-1-丙基-3,4-二氢-2,3-二氮杂萘-6-基)-3-环戊基-丙酰胺;
71)2-丙基-戊酸(4-氧代-1-丙基-3,4-二氢-2,3-二氮杂萘-6-基)-酰胺;
72)1-(4-氧代-1-丙基-3,4-二氢-2,3-二氮杂萘-6-基)-3-(3-三氟甲基-苯基)-脲;
73)1-(4-氧代-1-丙基-3,4-二氢-2,3-二氮杂萘-6-基)-(3-甲氧基-苯基)-脲;
74)1-(4-氧代-1-丙基-3,4-二氢-2,3-二氮杂萘-6-基)-3-对-甲苯基-脲;
75)1-(4-氧代-1-丙基-3,4-二氢-2,3-二氮杂萘-6-基)-3-(2,4-二氟-苯基)-脲;
76)1-(4-氧代-1-丙基-3,4-二氢-2,3-二氮杂萘-6-基)-3-(3,4-二氯-苯基)-脲;
77)1-(4-氧代-1-丙基-3,4-二氢-2,3-二氮杂萘-6-基)-3-吡啶-3-基-脲;
78)7-氨基-4-丙基-2H-2,3-二氮杂萘-1-酮;
79)N-[1-(3,3-二甲基-丁基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-丙酰胺;
80)N-[1-(3,3-二甲基-丁基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-4-三氟甲基-苯甲酰胺;
81)呋喃-2-甲酸[1-(3,3-二甲基-丁基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-酰胺;
82)N-[1-(3,3-二甲基-丁基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-3,4-二甲氧基-苯甲酰胺;
83)N-[1-(3,3-二甲基-丁基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-3-环戊基-丙酰胺;
84)2-丙基-戊酸[1-(3,3-二甲基-丁基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-酰胺;
85)1-[1-(3,3-二甲基-丁基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-3-(3-三氟甲基-苯基)-脲;
86)1-[1-(3,3-二甲基-丁基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-(3-甲氧基-苯基)-脲;
87)1-[1-(3,3-二甲基-丁基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-3-对-甲苯基-脲;
88)1-[1-(3,3-二甲基-丁基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-3-(2,4-二氟-苯基)-脲;
89)1-[1-(3,3-二甲基-丁基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-3-(3,4-二氯-苯基)-脲;
90)1-[1-(3,3-二甲基-丁基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-3-吡啶-3-基-脲;
91)7-氨基-4-(3,3-二甲基-丁基)-2H-2,3-二氮杂萘-1-酮;
92)N-[4-氧代-1-(3-苯基-丙基)-3,4-二氢-2,3-二氮杂萘-6-基]-丙酰胺;
93)N-[4-氧代-1-(3-苯基-丙基)-3,4-二氢-2,3-二氮杂萘-6-基]-4-三氟甲基-苯甲酰胺;
94)呋喃-2-甲酸[4-氧代-1-(3-苯基-丙基)-3,4-二氢-2,3-二氮杂萘-6-基]-酰胺;
95)N-[4-氧代-1-(3-苯基-丙基)-3,4-二氢-2,3-二氮杂萘-6-基]-3,4-二甲氧基-苯甲酰胺;
96)N-[4-氧代-1-(3-苯基-丙基)-3,4-二氢-2,3-二氮杂萘-6-基]-3-环戊基-丙酰胺;
97)2-丙基-戊酸[4-氧代-1-(3-苯基-丙基)-3,4-二氢-2,3-二氮杂萘-6-基]-酰胺;
98)1-[4-氧代-1-(3-苯基-丙基)-3,4-二氢-2,3-二氮杂萘-6-基]-3-(3-三氟甲基-苯基)-脲;
99)1-[4-氧代-1-(3-苯基-丙基)-3,4-二氢-2,3-二氮杂萘-6-基]-(3-甲氧基-苯基)-脲;
100)1-[4-氧代-1-(3-苯基-丙基)-3,4-二氢-2,3-二氮杂萘-6-基]-3-对-甲苯基-脲;
101)1-[4-氧代-1-(3-苯基-丙基)-3,4-二氢-2,3-二氮杂萘-6-基]-3-(2,4-二氟-苯基)-脲;
102)1-[4-氧代-1-(3-苯基-丙基)-3,4-二氢-2,3-二氮杂萘-6-基]-3-(3,4-二氯-苯基)-脲;
103)1-[4-氧代-1-(3-苯基-丙基)-3,4-二氢-2,3-二氮杂萘-6-基]-3-吡啶-3-基-脲;
104)7-氨基-4-(3-苯基-丙基)-2H-2,3-二氮杂萘-1-酮;
105)N-(4-氧代-1-吡啶-3-基甲基-3,4-二氢-2,3-二氮杂萘-6-基)-丙酰胺;
106)N-(4-氧代-1-吡啶-3-基甲基-3,4-二氢-2,3-二氮杂萘-6-基)-4-三氟甲基-苯甲酰胺;
107)呋喃-2-甲酸(4-氧代-1-吡啶-3-基甲基-3,4-二氢-2,3-二氮杂萘-6-基)-酰胺;
108)N-(4-氧代-1-吡啶-3-基甲基-3,4-二氢-2,3-二氮杂萘-6-基)-琥珀酰胺酸乙酯;
109)N-(4-氧代-1-吡啶-3-基甲基-3,4-二氢-2,3-二氮杂萘-6-基)-3-环戊基-丙酰胺;
110)2-丙基-戊酸(4-氧代-1-吡啶-3-基甲基-3,4-二氢-2,3-二氮杂萘-6-基)-酰胺;
111)1-(4-氧代-1-吡啶-3-基甲基-3,4-二氢-2,3-二氮杂萘-6-基)-3-(3-三氟甲基-苯基)-脲;
112)1-(3-甲氧基-苯基)-3-(4-氧代-1-吡啶-3-基甲基-3,4-二氢-2,3-二氮杂萘-6-基)-脲;
113)1-(4-氧代-1-吡啶-3-基甲基-3,4-二氢-2,3-二氮杂萘-6-基)-3-对-甲苯基)-脲;
114)1-(2,4-二氟-苯基)-3-(4-氧代-1-吡啶-3-基甲基-3,4-二氢-2,3-二氮杂萘-6-基)-脲;
115)1-(3,4-二氯-苯基)-3-(4-氧代-1-吡啶-3-基甲基-3,4-二氢-2,3-二氮杂萘-6-基)-脲;
116)1-(4-氧代-1-吡啶-3-基甲基-3,4-二氢-2,3-二氮杂萘-6-基)-3-吡啶-3-基-脲;
117)7-氨基-4-吡啶-3-基甲基-2H-2,3-二氮杂萘-1-酮
118)N-(4-氧代-1-吡啶-3-基甲基-3,4-二氢-2,3-二氮杂萘-6-基)苯甲酰胺;
119)N-[1-(4-氯-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-丙酰胺;
120)N-[1-(4-氯-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-4-三氟甲基-苯甲酰胺;
121)呋喃-2-甲酸[1-(4-氯-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-酰胺;
122)N-[1-(4-氯-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-琥珀酰胺酸乙酯;
123)N-[1-(4-氯-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-3-环戊基-丙酰胺;
124)2-丙基-戊酸[1-(4-氯-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-酰胺;
125)1-[1-(4-氯-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-3-(3-三氟甲基-苯基)-脲;
126)1-[1-(4-氯-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-3-(3-甲氧基-苯基)-脲;
127)1-[1-(4-氯-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-3-对-甲苯基-脲;
128)1-[1-(4-氯-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-3-(2,4-二氟-苯基)-脲;
129)1-[1-(4-氯-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-3-(3,4-二氯-苯基)-脲;
130)1-[1-(4-氯-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-3-吡啶-3-基-脲;
131)7-氨基-4-(4-氯-苄基)-2H-2,3-二氮杂萘-1-酮;
132)N-[1-(4-氰基-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-丙酰胺;
133)N-[1-(4-氰基-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-4-三氟甲基-苯甲酰胺;
134)呋喃-2-甲酸[1-(4-氰基-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-酰胺;
135)N-[1-(4-氰基-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-琥珀酰胺酸乙酯;
136)N-[1-(4-氰基-苄基)-4-氧代-3,4-二氢-2,3-二氨杂萘-6-基]-3-环戊基-丙酰胺;
137)2-丙基-戊酸[1-(4-氰基-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-酰胺;
138)1-[1-(4-氰基-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-3-(3-三氟甲基-苯基)-脲;
139)1-[1-(4-氰基-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-3-(3-甲氧基-苯基)-脲;
140)1-[1-(4-氰基-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-3-对-甲苯基)-脲;
141)1-[1-(4-氰基-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-3-(2,4-二氟-苯基)-脲;
142)1-[1-(4-氰基-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-3-(3,4-二氯-苯基)-脲;
143)1-[1-(4-氰基-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-3-吡啶-3-基)-脲;
144)7-氨基-4-(4-氰基-苄基)-2H-2,3-二氮杂萘-1-酮;
145)N-[1-(3-氟-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-丙酰胺;
146)N-[1-(3-氟-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-4-三氟甲基-苯甲酰胺;
147)呋喃-2-甲酸[1-(3-氟-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-酰胺;
148)N-[1-(3-氟-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-琥珀酰胺酸乙酯;
149)N-[1-(3-氟-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-3-环戊基-丙酰胺;
150)2-丙基-戊酸[1-(3-氟-苄基)-4-氧代-3,4-二氢-2,3-二氨杂萘-6-基]-酰胺;
151)1-[1-(3-氟-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-3-(3-三氟甲基-苯基)-脲;
152)1-[1-(3-氟-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-3-(3-甲氧基-苯基)-脲;
153)1-[1-(3-氟-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-3-对-甲苯基)-脲;
154)1-[1-(3-氟-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-3-(2,4-二氟-苯基)-脲;
155)1-[1-(3-氟-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-3-(3,4-二氯-苯基)-脲;
156)1-[1-(3-氟-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-3-吡啶-3-基-脲;
157)7-氨基-4-(3-氟-苄基)-2H-2,3-二氮杂萘-1-酮;
158)N-[1-(3-甲基-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-丙酰胺;
159)N-[1-(3-甲基-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-4-三氟甲基-苯甲酰胺;
160)呋喃-2-甲酸[1-(3-甲基-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-酰胺;
161)N-[1-(3-甲基-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-琥珀酰胺酸乙酯;
162)N-[1-(3-甲基-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-3-环戊基-丙酰胺;
163)2-丙基-戊酸[1-(3-甲基-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-酰胺;
164)1-[1-(3-甲基-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-3-(3-三氟甲基-苯基)-脲;
165)1-[1-(3-甲基-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-3-(3-甲氧基-苯基)-脲;
166)1-[1-(3-甲基-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-3-对-甲苯基-脲;
167)1-[1-(3-甲基-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-3-(2,4-二氟-苯基)-脲;
168)1-[1-(3-甲基-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-3-(3,4-二氯-苯基)-脲;
169)1-[1-(3-甲基-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-3-吡啶-3-基-脲;
170)7-氨基-4-(3-甲基-苄基)-2H-2,3-二氮杂萘-1-酮;
171)N-[1-(2,4-二氯-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-丙酰胺;
172)N-[1-(2,4-二氯-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-4-三氟甲基-苯甲酰胺;
173)呋喃-2-甲酸[1-(2,4-二氯-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-酰胺;
174)N-[1-(2,4-二氯-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-琥珀酰胺酸乙酯;
175)N-[1-(2,4-二氯-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-3-环戊基-丙酰胺;
176)2-丙基-戊酸[1-(2,4-二氯-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-酰胺;
177)1-[1-(2,4-二氯-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-3-(3-三氟甲基-苯基)-脲;
178)1-[1-(2,4-二氯-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-3-(3-甲氧基-苯基)-脲;
179)1-[1-(2,4-二氯-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-3-对-甲苯基-脲;
180)1-[1-(2,4-二氯-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-3-(2,4-二氟-苯基)-脲;
181)1-[1-(2,4-二氯-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-3-(3,4-二氯-苯基)-脲;
182)1-[1-(2,4-二氯-苄基)-4-氧代-3,4-二氢-2,3-二氮杂萘-6-基]-3-吡啶-3-基)-脲;
183)7-氨基-4-(2,4-二氯-苄基)-2H-2,3-二氮杂萘-1-酮;
184)N-(4-氧代-1-喹啉-3-基甲基-3,4-二氢-2,3-二氮杂萘-6-基)-丙酰胺;
185)N-(4-氧代-1-喹啉-3-基甲基-3,4-二氢-2,3-二氮杂萘-6-基)-4-三氟甲基-苯甲酰胺;
186)呋喃-2-甲酸(4-氧代-1-喹啉-3-基甲基-3,4-二氢-2,3-二氮杂萘-6-基)-酰胺;
187)N-(4-氧代-1-喹啉-3-基甲基-3,4-二氢-2,3-二氮杂萘-6-基)-琥珀酰胺酸乙酯;
188)N-(4-氧代-1-喹啉-3-基甲基-3,4-二氢-2,3-二氮杂萘-6-基)-3-环戊基-丙酰胺;
189)2-丙基-戊酸(4-氧代-1-喹啉-3-基甲基-3,4-二氢-2,3-二氮杂萘-6-基)-酰胺;
190)1-(4-氧代-1-喹啉-3-基甲基-3,4-二氢-2,3-二氮杂萘-6-基)-3-(3-三氟甲基-苯基)-脲;
191)1-(4-氧代-1-喹啉-3-基甲基-3,4-二氢-2,3-二氮杂萘-6-基)-3-(3-甲氧基-苯基)-脲;
192)1-(4-氧代-1-喹啉-3-基甲基-3,4-二氢-2,3-二氮杂萘-6-基)-3-对-甲苯基-脲;
193)1-(4-氧代-1-喹啉-3-基甲基-3,4-二氢-2,3-二氮杂萘-6-基)-3-(2,4-二氟-苯基)-脲;
194)1-(4-氧代-1-喹啉-3-基甲基-3,4-二氢-2,3-二氮杂萘-6-基)-3-(3,4-二氟-苯基)-脲;
195)1-(4-氧代-1-喹啉-3-基甲基-3,4-二氢-2,3-二氮杂萘-6-基)-3-吡啶-3-基-脲;
196)7-氨基-4-喹啉-3-基甲基-2H-3,4-二氢-2,3-二氮杂萘-1-酮;
197)N-[4-氧代-1-(2-三氟甲基-苄基)-3,4-二氢-2,3-二氮杂萘-6-基]-丙酰胺;
198)N-[4-氧代-1-(2-三氟甲基-苄基)-3,4-二氢-2,3-二氮杂萘-6-基]-4-三氟甲基-苯甲酰胺;
199)呋喃-2-甲酸[4-氧代-1-(2-三氟甲基-苄基)-3,4-二氢-2,3-二氮杂萘-6-基]-酰胺;
200)N-[4-氧代-1-(2-三氟甲基-苄基)-3,4-二氢-2,3-二氮杂萘-6-基]-琥珀酰胺酸乙酯;
201)N-[4-氧代-1-(2-三氟甲基-苄基)-3,4-二氢-2,3-二氮杂萘-6-基]-3-环戊基-丙酰胺;
202)2-丙基-戊酸[4-氧代-1-(2-三氟甲基-苄基)-3,4-二氢-2,3-二氮杂萘-6-基]-酰胺;
203)1-[4-氧代-1-(2-三氟甲基-苄基)-3,4-二氢-2,3-二氮杂萘-6-基]-3-(3-三氟甲基-苯基)-脲;
204)1-[4-氧代-1-(2-三氟甲基-苄基)-3,4-二氢-2,3-二氮杂萘-6-基]-3-(3-甲氧基-苯基)-脲;
205)1-[4-氧代-1-(2-三氟甲基-苄基)-3,4-二氢-2,3-二氮杂萘-6-基]-3-对-甲苯基-脲;
206)1-[4-氧代-1-(2-三氟甲基-苄基)-3,4-二氢-2,3-二氮杂萘-6-基]-3-(2,4-二氟-苯基)-脲;
207)1-[4-氧代-1-(2-三氟甲基-苄基)-3,4-二氢-2,3-二氮杂萘-6-基]-3-(3,4-二氯-苯基)-脲;
208)1-[4-氧代-1-(2-三氟甲基-苄基)-3,4-二氢-2,3-二氮杂萘-6-基]-3-吡啶-3-基)-脲
209)7-氨基-4-(2-三氟甲基-苄基)-2H-2,3-二氮杂萘-1-酮。
3.药物组合物,其含有权利要求1的化合物和一种或多种化学治疗药物,作为用于抗癌疗法中同时、分开或顺序使用的组合制剂。
4.产品或试剂盒,其含有权利要求1的化合物,和一种或多种化学治疗药物,作为用于抗癌疗法中同时、分开或顺序使用的组合制剂。
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EP1180514A4 (en) * | 1999-04-09 | 2003-02-26 | Meiji Seika Kaisha | NITROGEN-CONTAINING HETEROCYCLIC COMPOUNDS AND BENAMID DERIVATIVES, AND THEIR MEDICINAL PRODUCTS |
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
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WO2023125540A1 (zh) * | 2021-12-27 | 2023-07-06 | 南京明德新药研发有限公司 | 吡唑-1(2h)-酞嗪酮类化合物及其应用 |
CN116178347A (zh) * | 2022-06-29 | 2023-05-30 | 苏州浦合医药科技有限公司 | Prmt5-mta抑制剂 |
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IL159843A0 (en) | 2004-06-20 |
CA2455759A1 (en) | 2003-02-20 |
BR0211807A (pt) | 2004-09-21 |
NO20040547L (no) | 2004-03-03 |
ATE407928T1 (de) | 2008-09-15 |
WO2003014090A1 (en) | 2003-02-20 |
SI1427708T1 (sl) | 2008-12-31 |
KR20040029400A (ko) | 2004-04-06 |
US7432263B2 (en) | 2008-10-07 |
EP1427708B1 (en) | 2008-09-10 |
CZ2004305A3 (cs) | 2004-08-18 |
CO5560573A2 (es) | 2005-09-30 |
CN1538960A (zh) | 2004-10-20 |
EA200400283A1 (ru) | 2004-08-26 |
JP2005501085A (ja) | 2005-01-13 |
EP1427708A1 (en) | 2004-06-16 |
MXPA04000905A (es) | 2004-04-02 |
PL368440A1 (en) | 2005-03-21 |
PT1427708E (pt) | 2008-11-20 |
ZA200401316B (en) | 2005-03-10 |
DE60228857D1 (de) | 2008-10-23 |
US20050020583A1 (en) | 2005-01-27 |
US20030073692A1 (en) | 2003-04-17 |
ES2315385T3 (es) | 2009-04-01 |
NZ531310A (en) | 2006-02-24 |
EA006645B1 (ru) | 2006-02-24 |
DK1427708T3 (da) | 2008-11-24 |
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