CN101006086A - 用于治疗癌症的5-氨基-2,4,7-三氧代-3,4,7,8-四氢-2H-吡啶并[2,3-d]嘧啶衍生物和相关化合物 - Google Patents
用于治疗癌症的5-氨基-2,4,7-三氧代-3,4,7,8-四氢-2H-吡啶并[2,3-d]嘧啶衍生物和相关化合物 Download PDFInfo
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- CN101006086A CN101006086A CNA2005800266663A CN200580026666A CN101006086A CN 101006086 A CN101006086 A CN 101006086A CN A2005800266663 A CNA2005800266663 A CN A2005800266663A CN 200580026666 A CN200580026666 A CN 200580026666A CN 101006086 A CN101006086 A CN 101006086A
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Abstract
本发明涉及由下式[I]表示的嘧啶化合物及其药学上可接受的盐,其中各符号如说明书定义,含这些化合物的用于预防或治疗由不希望的细胞增殖引起的疾病的药物,特别是抗肿瘤药。本发明的化合物具有较强的不希望的细胞增殖抑制作用,特别是抗肿瘤作用,并作为用于预防和治疗癌症的抗肿瘤药、抗风湿病药等。此外,通过与其他抗肿瘤药如烷化剂、代谢拮抗剂等联合使用,其可为更有效的抗肿瘤药。
Description
技术领域
本发明涉及新的嘧啶化合物或其药学上可接受的盐,其可用作预防或治疗由不希望的细胞增殖引起的疾病的药物、特别是抗肿瘤药。而且,本发明涉及某种嘧啶化合物或其药学上可接受的盐作为预防或治疗不希望的细胞增殖引起的疾病的药物特别是作为抗肿瘤药的新用途。更特别地,本发明涉及包括表现P15蛋白诱导作用和/或P27蛋白诱导作用和/或MEK抑制作用的的嘧啶化合物或其药学上可接受的盐的药物。
技术背景
“细胞周期”是指一个周期,其中细胞从前一次分裂结束起到下一次分裂结束止为一周期,该周期也称为“细胞分裂周期”。
细胞周期包括既定顺序的四个期。这四个期为DNA复制准备期(G1期)、DNA复制期(S期)、分裂准备期(G2期)和分裂期(M期),并受多个因素调节。其中,细胞周期蛋白/细胞周期蛋白依赖性激酶(CDK)复合物的激酶活性对于调节细胞周期是必不可少的。
已知CDK抑制蛋白为抑制激酶活性的蛋白质。哺乳动物细胞的CDK抑制蛋白为p21家族和p16家族,两者均被认为负调节细胞周期进程,造成细胞分化、凋亡并且修复由于X射线辐射产生的DNA损害等。现在,已有报导作为p21家族的p21、p27和p57,并已有报导作为p16家族的p16、p15、p18和p19。
当这些CDK抑制蛋白在这些细胞中高度表达时,在G1期阻止细胞增殖。
p21家族在相对比较宽的范围和多个细胞周期蛋白/CDK复合物中表现出抑制活性。例如,可提及对G1期至G1/S过渡期为重要的细胞周期蛋白/CDK复合物的细胞周期蛋白E/CDK 2,可提及对M期等重要的细胞周期蛋白B/Cdc2等。p16家族为细胞周期蛋白D/CDK4和细胞周期蛋白D/CDK 6特定的抑制因子,其均为G1期细胞周期蛋白/CDK之一,并且认为通过分别与CDK 4和CDK 6连接使得细胞周期蛋白/CDK复合物分离。
已有报导由食管癌、胰腺癌、非小细胞肺癌、皮肤癌等的临床材料的检查发现P16的基因变异高频率发生,而且证明在p16基因敲除小鼠中癌发生率高,因此已尝试了p16诱导剂的临床应用。
在这样的条件下,已发现作为p16家族的p15蛋白质(aka:INK4B,也简称p15)。在1994年,证实了在人角质形成细胞(HaCaT)中通过TGF-β刺激诱导p15表达,并且认为p15为负调节细胞周期的因子之一。已知由TGF-β在HaCaT中诱导的G1期细胞周期停滞导致细胞增殖抑制(Letters to Nature,1994年9月15日,第371卷,第257-261页)。
虽然已知组蛋白去乙酰基酶(HDAC)抑制剂在G1期或G2期阻滞人癌细胞的细胞周期,最近发现制滴菌素A(其为HDAC抑制剂)诱导人结肠癌细胞(HCT116p21(-/-))中的p15基因,并且由制滴菌素A诱导的p15涉及抑制癌细胞的细胞增殖(FEBS Letters,2003,第554卷,第347-350页)。
这样,诱导p15和/或p27的化合物预期抑制癌细胞等的细胞增殖。
在这期间,已知促分裂原活化蛋白(MAP)激酶/胞外信号调节激酶(ERK)激酶(下文中称为MEK)作为介导Raf-MEK-ERK信号传导途径的激酶涉及细胞增殖的调节,并且Raf家族(B-Raf、C-Raf等)激活MEK家族(MEK-1、MEK-2等),MEK家族激活ERK家族(ERK-1和ERK-2)。
在癌(特别是结肠直肠癌、胰腺癌、肺癌、乳腺癌等)中常观察到Raf-MEK-ERK信号传导通路的激活。
此外,因为由信号分子(如生长因子、细胞因子等)产生的信号汇聚激活MEK-ERK,这些功能的抑制被认为在上游中较抑制RTK、Ras、Raf功能更有效地抑制Raf-MEK-ERK信号传导。
而且,还已知在最近几年中具有MEK抑制活性的化合物非常有效地诱导ERK1/2活性的抑制和细胞增殖的抑制(The Journal ofBiological Chemistry,第276卷,No.4,第2686-2692页,2001),并且预期所述化合物对由不希望的细胞增殖引起的疾病(如肿瘤等)有效。此外,预期MEK抑制剂通过促进基质金属蛋白酶(MMP)和CD44表达抑制细胞渗透或转移,并通过促进血管内皮生长因子(VEGF)的表达抑制血管生成。
此外,可预期应用于慢性疼痛(JP 2003-504401:WO01/005393)、应用于中性粒细胞介导的疾病或症状(JP 2002-332247:CA-2385412)、应用于移植排斥(JP 2002-532414:WO 00/35435)、应用于关节炎(JP 2002-532415:WO 00/35436)、应用于哮喘(JP 2002-534380:WO 00/40235)、应用于病毒疾病(JP 2002-534381:WO00/40237)、应用于由软骨变形或损害引起的疾病(WO 2002/087620:US 2004/138285)、应用于Peutz-Jeghers综合症(WO 02/006520)。
但是,迄今这样的药物还没有上市。
作为已经上市的抗肿瘤药,已知以下化合物(Gefitinib)等(Iressatablet 250 package insert)。
JP-A-2004-504294(同族专利:WO 2002/006213)描述了以下化合物和诸如此类具有抗肿瘤活性的化合物。此外,描述了这些化合物的MEK抑制活性(JP-A-2004-504294,第123-124页,实施例39,实施例241)。
以下描述了与本发明的药物比较类似的已知化合物。
在1991年出版的文献中,研究了吡啶并[2,3-d]嘧啶衍生物的抗肿瘤活性并描述了例如以下化合物中的一些及其类似化合物在瘤性、白血病细胞中具有抑制活性(Khimiia geterotsiklicheskikhsoedinenii,1991,No.5,第674-680页(英译文第542页,第4-7行;第538页,化合物IIIa))。
在1973年出版的文献中,公开了以下化合物及其类似化合物的新合成方法并描述了吡啶并[2,3-d]嘧啶衍生物的抗肿瘤活性(Chem.Pharm.Bull.,1973,No.21,第9卷,第2014-2018页(第2015页,第2章,化合物VIII))。
但是在这些文献中并没有公开本发明的化合物,也没发现提示其的描述。
此外,WO 2002/094824公开了以下化合物及其类似化合物,所述化合物为对免疫、炎症或过敏性疾病有细胞因子调节作用的治疗药(WO 2002/094824,第55页,实施例9)。
在1996年出版的文献中,公开了以下化合物及其类似化合物的合成方法(Journal fur Praktische Chemie,1996,第338卷,第151-156页(第154页,表1,化合物8f))。
在1986年出版的文献中,公开了作为具有抗肿瘤活性的氨基蝶呤类似物的合成中间体的以下化合物及其类似化合物的合成方法(Journal of Medicinal Chemistry,1986,第29卷,No.5,第709-715页(第709页摘要;第712页,表1,化合物9b))。
但是,该文献不包括涉及这些化合物作为抗肿瘤药的描述,本发明的化合物没有被公开并且没有发现提示其的描述。
发明公开
本发明旨在提供一种包含嘧啶化合物或其药学上可接受的盐的药物,所述嘧啶化合物表现出不希望的细胞增殖的抑制作用,特别是抗肿瘤作用。
本发明者进行了深入研究,试图发现具有这些作用的化合物并完成了本发明。
更特别地,本发明提供了以下(1)-(37)。
(1)下式[I]表示的化合物或其药学上可接受的盐作为活性成分在制备用于治疗肿瘤的药物中的用途:
其中
X1和X2相同或不同且各自为碳原子或氮原子,
R1、R2和R6相同或不同且各自为:
C1-6烷基,
C2-6烯基,
其中所述C1-6烷基和C2-6烯基任选被1-3个选自以下基团A的取代基取代,
或
其中m为0或1-4的整数,
环Cy为C3-12碳环基团或杂环基团,
其中所述杂环基团为除了碳原子外还包含1-4个选自氧原子、氮原子和硫原子的杂原子的饱和或不饱和环基团,所述C3-12碳环基团和杂环基团任选被1-5个选自以下基团B的取代基取代,
R3、R4和R5相同或不同且各自为:
氢原子,
羟基,
C1-6烷基,
C2-6烯基,
其中所述C1-6烷基和C2-6烯基任选被1-3个选自以下基团A的取代基取代,
C3-12碳环基团或
杂环基团,
其中所述杂环基团为除了碳原子外还包含1-4个选自氧原子、氮原子和硫原子的杂原子的饱和或不饱和环基团,且所述C3-12碳环基团和杂环基团任选被1-5个选自以下基团B的取代基取代,或
R2和R3任选连接形成C1-4亚烷基,或者R4和R5任选连接形成C1-4亚烷基,
其中基团A选自:
1)卤原子,
2)硝基,
3)氰基,
4)C1-4烷基,
5)-ORA1其中RA1为氢原子或C1-4烷基,
6)-SRA2其中RA2为氢原子或C1-4烷基,
7)-NRA3RA4其中RA3和RA4相同或不同且各自为氢原子或C1-4烷基,
8)-COORA5其中RA5为氢原子或C1-4烷基,
9)-NRA6CORA7其中RA6为氢原子或C1-4烷基,RA7为C1-4烷基、C3-12碳环基团或杂环基团,
10)-NRA8COORA9其中RA8和RA9相同或不同且各自为氢原子或C1-4烷基,
11)C3-12碳环基团和
12)杂环基团,
其中所述杂环基团为除了碳原子外还包含1-4个选自氧原子、氮原子和硫原子的杂原子的饱和或不饱和环基团,
上述4)、RA1、RA2、RA3、RA4、RA5、RA6、RA7、RA8和RA9的C1-4烷基各自任选被相同或不同的1-3个选自以下基团C的取代基取代,和
上述11)和RA7的C3-12碳环基团,以及12)和RA7的杂环基团各自任选被相同或不同的1-5个选自以下基团C的取代基取代,
基团B选自:
1)卤原子,
2)硝基,
3)氰基,
4)C1-8烷基,
5)C2-4烯基,
6)C2-4炔基,
7)-ORB1,其中RB1为氢原子或C1-4烷基,
8)-SRB2,其中RB2为氢原子或C1-4烷基,
9)-NRB3RB4,其中RB3为氢原子、C1-4烷基、C3-12碳环基团或杂环基团,和RB4为氢原子或C1-4烷基,
10)-NRB5CORB6,其中RB5为氢原子或C1-4烷基,和RB6为氢原子、C1-4烷基、C3-12碳环基团或杂环基团,
11)-NRB7COORB8,其中RB7和RB8相同或不同且各自为氢原子或C1-4烷基,
12)-NRB9CONRB10RB11,其中RB9、RB10和RB11相同或不同且各自为氢原子或C1-4烷基,
13)-NRB12CONRB13ORB14,其中RB12、RB13和RB14相同或不同且各自为氢原子或C1-4烷基,
14)-NRB15SO2RB16,其中RB15为氢原子或C1-4烷基,和RB16为C1-4烷基、C3-12碳环基团或杂环基团,
15)-SO2-RB17,其中RB17为C1-4烷基或杂环基团,
16)-SO2NRB18RB19,其中RB18和RB19相同或不同且各自为氢原子或C1-4烷基,
17)-P(=O)(RB20)(RB21),其中RB20和RB21相同或不同且各自为C1-4烷基,
18)-COORB22,其中RB22为氢原子或C1-4烷基,
19)-CONRB23RB24,其中RB23和RB24相同或不同且各自为氢原子或C1-4烷基,
20)-NRB25SO2NRB26RB27,其中RB25、RB26和RB27相同或不同且各自为氢原子或C1-4烷基,
21)-NRB28SO2NRB29CONRB30RB31,其中RB28、RB29、RB30和RB31相同或不同且各自为氢原子或C1-4烷基,
22)C3-12碳环基团和
23)杂环基团
其中上述4)的“C1-8烷基”和RB1至RB31的C1-4烷基各自任选被相同或不同的1-3个选自上述基团A的取代基取代,
5)的C2-4烯基和6)的C2-4炔基各自任选被相同或不同的1-3个选自上述基团A的取代基取代,
所述杂环基团为除了碳原子外还包含1-4个选自氧原子、氮原子和硫原子的杂原子的饱和或不饱和环基团,和
上述22)、RB3、RB6和RB16的C3-12碳环基团,以及上述23)、RB3、RB6、RB16和RB17的杂环基团各自任选被相同或不同的1-5个选自以下基团C的取代基取代,和
基团C选自:
1)卤原子,
2)氰基,
3)C1-4烷基,
4)-ORC1,其中RC1为氢原子或C1-4烷基,
5)-NRC2RC3,其中RC2和RC3相同或不同且各自为氢原子或C1-4烷基,
6)-COORC4,其中RC4为氢原子或C1-4烷基和
7)氧代基。
(2)下式[I’]表示的化合物或其药学上可接受的盐:
其中
R1’、R2’和R6相同或不同且各自为:
C1-6烷基,
C2-6烯基,
其中所述C1-6烷基和C2-6烯基任选被1-3个选自上述(1)的基团A的取代基取代,或
其中m为0或1-4的整数,
环Cy为C3-12碳环基团或杂环基团,
其中所述杂环基团为除了碳原子外还包含1-4个选自氧原子、氮原子和硫原子的杂原子的饱和或不饱和环基团,且所述C3-12碳环基团和杂环基团任选被1-5个选自上述(1)的基团B的取代基取代,条件是,当
当R2’为苯基时,R1’不为苯基,
且其他符号如上述(1)定义。
(3)上述(1)的用途,其中所述化合物由下式[I-1]表示:
其中式中各符号如上述(1)定义。
(4)上述(1)的用途,其中所述化合物由下式[I-2]表示:
其中式中各符号如上述(1)定义。
(5)上述(1)的用途,其中所述化合物由下式[I-3]表示:
其中式中各符号如上述(1)定义。
(6)上述(1)的用途,其中R1为C1-6烷基。
(7)上述(1)的用途,其中R1为
其中m为0,且环Cy为C3-12碳环基团,
其中所述C3-12碳环基团任选被1-5个选自上述(1)的基团B的取代基取代。
(8)上述(1)的用途,其中R1为C3-8环烷基。
(9)上述(8)的用途,其中R1为环丙基。
(10)上述(1)的用途,其中R2为
其中m为0,且环Cy为C3-12碳环基团或杂环基团,
其中所述C3-12碳环基团和杂环基团任选被1-5个选自上述(1)的基团B的取代基取代。
(11)上述(1)的用途,其中R3为C1-6烷基。
(12)上述(1)的用途,其中R4为氢原子。
(13)上述(1)的用途,其中R5为氢原子。
(14)上述(1)的用途,其中R6为
其中m为0,且环Cy为C3-12碳环基团或杂环基团,
其中所述C3-12碳环基团和杂环基团任选被1-5个选自上述(1)的基团B的取代基取代。
(15)上述(1)的式[I]化合物或其药学上可接受的盐作为活性成分在制备抗肿瘤药中的用途。
(16)上述(1)的式[I]化合物或其药学上可接受的盐作为活性成分在制备能抑制MEK的药物中的用途。
(17)上述(1)的式[I]化合物或其药学上可接受的盐作为活性成分在制备能诱导p15蛋白质的药物中的用途。
(18)上述(1)的式[I]化合物或其药学上可接受的盐作为活性成分在制备用于治疗由不希望的细胞增殖引起的疾病的药物中的用途。
(19)上述(18)的用途,其中由不希望的细胞增殖引起的疾病为风湿病。
(20)上述(1)的式[I]化合物或其药学上可接受的盐作为活性成分在制备能抑制不希望的细胞增殖的药物中的用途。
(21)上述(1)的式[I]化合物或其药学上可接受的盐作为活性成分在制备能调节细胞周期的药物中的用途。
(22)一种药物组合物,所述组合物包括上述(2)的式[I’]化合物或其药学上可接受盐以及药学上可接受的载体。
(23)一种治疗肿瘤的药物组合物,所述组合物包括上述(1)的式[I]化合物或其药学上可接受的盐以及药学上可接受的载体。
(24)一种用于治疗由不希望的细胞增殖引起的疾病的药物组合物,所述组合物包括上述(1)的式[I]化合物或其药学上可接受的盐以及药学上可接受的载体。
(25)一种商品包装,所述包装包括上述(23)的药物组合物和与其相关的书面文件,所述书面文件说明所述药物组合物可以或应该用于治疗肿瘤。
(26)一种商品包装,所述包装包括上述(24)的药物组合物和与其相关的书面文件,所述书面文件说明所述药物组合物可以或应该用于治疗由不希望的细胞增殖引起的疾病。
(27)(a)上述(1)的式[I]化合物或其药学上可接受的盐作为活性成分在制备抗肿瘤药中的用途,所述化合物与(b)至少一种其他抗肿瘤化合物联合使用。
(28)(a)上述(1)的式[I]化合物或其药学上可接受的盐作为活性成分和(b)至少一种其他抗肿瘤化合物在制备抗肿瘤联合药物中的用途。
(29)一种药物组合物,所述组合物包括联合使用的作为活性成分的(a)上述(1)的式[I]的化合物或其药学上可接受的盐和(b)至少一种其他抗肿瘤化合物以及药学上可接受载体。
(30)一种治疗肿瘤的药剂盒,所述药剂盒包括联合使用的(a)一种药物组合物和(b)一种药物组合物,所述药物组合物包括上述(1)的式[I]化合物或其药学上可接受的盐作为活性成分,所述药物组合物(b)包括至少一种其他抗肿瘤药作为活性成分。
(31)一种抗肿瘤药,所述抗肿瘤药包括作为活性成分的上述(1)的式[I]化合物或其药学上可接受的盐。
(32)一种MEK抑制剂,所述MEK抑制剂包括作为活性成分的上述(1)的式[I]化合物或其药学上可接受的盐。
(33)一种p15蛋白质诱导剂,所述诱导剂包括作为活性成分的上述(1)的式[I]化合物或其药学上可接受的盐。
(34)一种抗肿瘤药,所述抗肿瘤药包含作为活性成分的(a)上述(1)的式[I]化合物或其药学上可接受的盐,所述抗肿瘤药与(b)至少一种其他抗肿瘤化合物联合使用。
(35)一种抗肿瘤药,所述抗肿瘤药包含作为活性成分的(a)上述(1)的式[I]化合物或其药学上可接受的盐和(b)至少一种其他抗肿瘤化合物联合使用。
(36)上述(34)的药物,其中(a)上述(1)的式[I]化合物或其药学上可接受的盐和(b)至少一种其他抗肿瘤化合物同时或相继给予哺乳动物。
(37)上述(35)的药物,其中(a)上述(1)的式[I]化合物或其药学上可接受的盐和(b)至少一种其他抗肿瘤化合物同时或相继给予哺乳动物。
实施发明的最佳方法
在本说明书中使用的各取代基和各部分的定义如下。
X1和X2相同或不同且各自为碳原子或氮原子,
“卤原子”为氟原子、氯原子、溴原子或碘原子,对于基团A的1)和基团C的1)优选氟原子、氯原子或溴原子,对于基团A的1)更优选氟原子,对于基团C的1)更优选氟原子或溴原子,对于基团B的1)更优选氟原子或碘原子。
“C1-6烷基”为具有1-6个碳原子的直链或支链烷基,具体地可提及甲基、乙基、丙基、异丙基、2,2-二甲基丙基、丁基、异丁基、仲-丁基、叔-丁基、戊基、己基等。
作为R1、R1’、R2、R2’和R6,优选甲基、乙基、丙基、异丙基、2,2-二甲基丙基、丁基和异丁基,更优选甲基和乙基,且特别优选甲基。作为R3、R4和R5,优选甲基、乙基、丙基和异丁基,且更优选甲基。
“C1-4烷基”为具有1-4个碳原子的直链或支链烷基,具体地可提及甲基、乙基、丙基、异丙基、丁基、异丁基、仲-丁基、叔-丁基等。
作为基团A的4)和基团C的3),优选甲基和乙基,且更优选甲基。作为RA1、RA2、RA3、RA4、RA5、RA6、RA7、RA8和RA9,优选甲基、乙基和丁基,且更优选甲基。作为RB1至RB31,优选甲基、乙基、丙基、异丙基和丁基,且更优选甲基、乙基和丙基。作为RC1、RC2、RC3、RC4和RC5,优选甲基和乙基且更优选甲基。
“C1-8烷基”为具有1-8个碳原子的直链或支链烷基,具体地可提及甲基、乙基、丙基、异丙基、1-乙基-1-丙基、丁基、异丁基、仲-丁基、叔-丁基、3-甲基丁基、1-丙基-1-丁基、戊基、异戊基、己基、庚基、辛基等。
作为基团B的2),优选甲基、乙基、丙基、异戊基、1-乙基-1-丙基、3-甲基丁基和1-丙基-1-丁基,且更优选甲基和乙基。
“C2-6烯基”为具有2-6个碳原子的直链或支链烯基,具体地可提及乙烯基、1-丙烯基、2-丙烯基、异丙烯基、1-丁烯基、2-丁烯基、3-丁烯基、1-甲基-1-丙烯基、1-甲基-2-丙烯基、2-甲基-2-丙烯基、1-乙基乙烯基、1-戊烯基、2-戊烯基、3-戊烯基、4-戊烯基、1,2-二甲基-1-丙烯基、1,2-二甲基-2-丙烯基、1-乙基-1-丙烯基、1-乙基-2-丙烯基、1-甲基-1-丁烯基、1-甲基-2-丁烯基、2-甲基-1-丁烯基、1-异丙基乙烯基、2,4-戊二烯基、1-己烯基、2-己烯基、3-己烯基、4-己烯基、5-己烯基、2,4-己二烯基、1-甲基-1-戊烯基等。
作为R1、R1’、R2、R2’、R3、R4、R5和R6,优选乙烯基、1-丙烯基和2-丙烯基,且更优选2-丙烯基。
“C2-4烯基”为具有2-4个碳原子的直链或支链烯基,具体地可提及乙烯基、1-丙烯基、2-丙烯基、异丙烯基、1-丁烯基、2-丁烯基、3-丁烯基、1-甲基-1-丙烯基、1-甲基-2-丙烯基、2-甲基-2-丙烯基、1-乙基乙烯基等。
作为基团B的5),优选乙烯基和1-丙烯基,且更优选乙烯基。
“C2-4炔基”为具有2-4个碳原子的直链或支链炔基,具体地可提及乙炔基、1-丙炔基、2-丙炔基、异丙炔基、1-丁炔基、2-丁炔基、3-丁炔基、1-甲基-1-丙炔基、1-甲基-2-丙炔基、2-甲基-2-丙炔基、1-乙基乙炔基等。
作为基团B的6),优选乙炔基、1-丙炔基和1-丁炔基,且更优选乙炔基。
由R2与R3连接任选形成的“C1-4亚烷基”和由R4与R5连接任选形成的“C1-4亚烷基”为具有1-4个碳原子的直链或支链亚烷基,具体地可提及亚甲基、1,2-亚乙基、1,3-亚丙基、2-甲基-1,3-亚丙基、1,4-亚丁基等。
由R2与R3连接任选形成的“C1-4亚烷基”优选亚甲基、1,2-亚乙基或1,3-亚丙基,更优选1,3-亚丙基。
由R4与R5连接任选形成的“C1-4亚烷基”优选亚甲基、1,2-亚乙基或1,3-亚丙基,更优选1,3-亚丙基。
作为m,优选0或1或2的整数,更优选0。
“C3-12碳环基团”为具有3-12个碳原子的饱和或不饱和环烃基,其是指苯基、萘基、C3-8环烷基或C3-8环烷基和苯的稠合环基。
“C3-8环烷基”为具有3-8个碳原子的饱和环烃基,具体地可提及环丙基、环丁基、环戊基、环己基、环庚基、环辛基、降冰片基等,且优选环丙基、环丁基、环戊基或环己基。
作为“C3-8环烷基和苯的稠合环基”,具体地可提及茚满基、1,2,3,4-四氢萘基(1,2,3,4-四氢-2-萘基、5,6,7,8-四氢-2-萘基等)等,其优选茚满基、1,2,3,4-四氢萘基等,且更优选茚满基。
作为R1、R2、R3、R4、R5和R6,优选苯基、环丙基、环丁基、环戊基和环己基,且更优选苯基和环丙基。作为R1,特别优选环丙基,和作为R2和R6,特别优选苯基。作为基团A的11)、RA7、基团B的22)、RB3、RB6和RB16,优选苯基、环丙基、环丁基、环戊基和环己基,且更优选苯基和环丙基。
“杂环基团”为具有5或6个成环原子的饱和单环或不饱和单环(其除了碳原子外还包含1-4个作为成环原子的选自氧原子、氮原子和硫原子的杂原子)、单环与苯环的稠合环或这些单环或稠合环与上述C3-12碳环的螺环,其各自可具有1-4个、优选1或2个氧代基。
作为饱和单环的“杂环基团”,可提及的有吡咯烷基、四氢呋喃基、四氢噻吩基、咪唑烷基、2-氧代咪唑烷基、2,4-二氧代咪唑烷基、吡唑烷基、1,3-二氧戊环、1,3-氧杂硫杂环戊烷基、唑烷基、2-氧代唑烷基、噻唑烷基、哌啶基、哌嗪基、2-氧代哌嗪基、四氢吡喃基、四氢噻喃基、二烷基、吗啉基、硫代吗啉基、2-氧代吡咯烷基、2-氧代哌啶基、4-氧代哌啶基、2,6-二氧代哌啶基、硫杂二氮杂环戊烷基(例如1,1-二氧代-1,2,5-硫杂二氮杂环戊烷-2-基等)等。优选可提及的有吡咯烷基、哌啶基、哌嗪基和吗啉基。
作为不饱和单环的“杂环基团”,可提及吡咯基(例如2-吡咯基等)、呋喃基、噻吩基、咪唑基(例如4-咪唑基等)、1,2-二氢-2-氧代咪唑基、吡唑基(例如5-吡唑基等)、二唑基、唑基、异唑基、噻唑基、异噻唑基、1,2,4-三唑基、1,2,3-三唑基、四唑基、1,3,4-二唑基、1,2,4-二唑基、1,3,4-噻二唑基、1,2,4-噻二唑基、呋咱基、吡啶基(例如3-吡啶基等)、嘧啶基、3,4-二氢-4-氧代嘧啶基、哒嗪基、吡嗪基、1,3,5-三嗪基、咪唑啉基(例如2-咪唑啉基等)、吡唑啉基、唑啉基(2-唑啉基、3-唑啉基、4-唑啉基)、异唑啉基、噻吩基(thiophenyl)、噻唑啉基、异噻唑啉基、吡喃基、2-氧代吡喃基、2-氧代-2,5-二氢呋喃基、1,1-二氧代-1H-异噻唑基等。优选吡咯基、噻吩基、咪唑基、吡唑基、唑基、异唑基、噻吩基(thiophenyl)、噻唑基、异噻唑基和吡啶基。
作为单环与苯环的稠合环的“杂环基团”,可提及吲哚基(例如4-吲哚基、5-吲哚基、6-吲哚基、7-吲哚基等)、异吲哚基、1,3-二氢-1,3-二氧代异吲哚基和苯并呋喃基(例如4-苯并呋喃基、7-苯并呋喃基等)、吲唑基、异苯并呋喃基和苯并噻吩基(例如4-苯并噻吩基、5-苯并噻吩基、7-苯并噻吩基等)、苯并唑基(例如4-苯并唑基基、7-苯并唑基等)、苯并咪唑基(例如4-苯并咪唑基、5-苯并咪唑基、7-苯并咪唑基等)、苯并噻唑基(例如4-苯并噻唑基、7-苯并噻唑基等)、喹啉基、异喹啉基、1,2-二氢-2-氧代喹啉基、喹唑啉基、喹喔啉基、噌啉基、2,3-二氮杂萘基、2,3-二氢吲哚基、异二氢吲哚基、1,2,3,4-四氢喹啉基、2-氧代-1,2,3,4-四氢喹啉基、苯并[1,3]间二氧杂环戊烯基、苯并二氢吡喃基、异苯并二氢吡喃基等。
作为上述单环或稠合环与上述C3-12碳环的螺环,可提及例如下式表示的基团。
优选单环的5-或6-元杂环和苯环的稠合环基团,其具体地为吲哚基、吲唑基、苯并噻吩基、苯并咪唑基、2,3-二氢吲哚基、1,2,3,4-四氢喹啉基、苯并[1,3]二氧杂环戊烯基等。
作为R1、R2、R3、R4、R5和R6,优选吡咯烷基、哌啶基、哌嗪基、吗啉基、吡啶基、噻吩基、噻唑基、吲哚基、吲唑基、苯并噻吩基、苯并咪唑基、2,3-二氢吲哚基、1,2,3,4-四氢喹啉基和苯并[1,3]二氧杂环戊烯基,且更优选哌啶基、吡啶基、噻吩基、噻唑基、吲哚基、吲唑基、苯并噻吩基、苯并咪唑基、2,3-二氢吲哚基、1,2,3,4-四氢喹啉基、苯并[1,3]二氧杂环戊烯基。作为基团A的12)、RA7和基团B的23)、RB3、RB6、RB16和RB17,优选吡咯烷基、哌啶基、哌嗪基、吗啉基、吡啶基和唑啉基,更优选吡咯烷基、哌啶基、哌嗪基和吗啉基。
用于R1、R2和R6以及R3、R4和R5的“C1-6烷基”和“C2-6烯基”任选被1-3个选自基团A的取代基取代。即以上定义的“C1-6烷基”和“C2-6烯基”可被1-3个选自基团A的取代基取代,并包括未取代的“C1-6烷基”和未取代的“C2-6烯基”。
用于以下定义的基团B的4)的以上定义的“C1-8烷基”和用于RB1至RB31的以上定义的“C1-4烷基”各自任选被相同或不同的1-3个选自基团A的取代基取代。
用于以下定义的基团B的5)的以上定义的“C2-4烯基”和用于6)的以上定义的“C2-4炔基”各自任选被相同或不同的1-3个选自基团A的取代基取代。
“基团A”为由以下基团组成的基团:1)以上定义的“卤原子”,2)硝基,3)氰基,4)以上定义的“C1-4烷基”,5)“-ORA1”,6)“-SRA2”,7)“-NRA3RA4”,8)“-COORA5”,9)“-NRA6CORA7”,10)“-NRA8COORA9”,11)以上定义的“C3-12碳环基团”和12)以上定义的“杂环基团”,其中RA1、RA2、RA3、RA4、RA5、RA6、RA8和RA9相同或不同且各自为氢原子或者以上定义的“C1-4烷基”,RA7为以上定义的“C1-4烷基”、以上定义的“C3-12碳环基团”或以上定义的“杂环基团”。
作为“-ORA1”,具体地可提及羟基、甲氧基、乙氧基、丙氧基、异丙氧基、叔-丁氧基等。
作为“-SRA2”,具体地可提及巯基、甲硫基、乙基硫基、丙基硫基、异丙基硫基、叔-丁基硫基等。
作为“-NRA3RA4”,具体地可提及氨基、甲基氨基、乙基氨基、丙基氨基、异丙基氨基、叔-丁基氨基、二甲基氨基、二乙基氨基、N-乙基-N-甲基氨基、N-甲基-正-丙基氨基、N-异丙基-N-甲基氨基等。
作为“COORA5”,具体地可提及羧基、甲氧基羰基、乙氧基羰基、丙氧基羰基、异丙氧基羰基、叔-丁氧基羰基等。
作为“-NRA6CORA7”,具体地可提及乙酰基氨基、丙酰基氨基、丁酰基氨基、异丁酰基氨基、新戊酰基氨基、N-乙酰基-N-甲基氨基、丁基羰基氨基等。
作为“-NRA8COORA9”,具体地可提及羧基氨基、羧基甲基氨基、羧基乙基氨基、甲氧基羰基氨基、甲氧基羰基甲基氨基等。
作为“基团A”,优选可提及氟原子、氯原子、溴原子、甲基、乙基、丙基、羟基、甲氧基、乙氧基、丙氧基、氨基、甲基氨基、乙基氨基、二甲基氨基、二乙基氨基、羧基氨基、丁基羰基氨基、羧基、苯基、4-吗啉基、1-吡咯烷基、1-哌啶基和1-哌嗪基。
作为“基团A”,特别优选可提及氟原子、氯原子、甲基、羟基、甲氧基、氨基、二甲基氨基、二乙基氨基、羧基氨基、丁基羰基氨基、羧基、苯基、4-吗啉基、1-吡咯烷基、1-哌啶基和1-哌嗪基。
优选的取代数为1,并且可在任何可取代位置上取代。
用于环Cy的“C3-12碳环基团”和“杂环基团”和用于R3、R4或R5的“C3-12碳环基团”和“杂环基团”任选被1-5个选自基团B的取代基取代。即以上定义的“C3-12碳环基团”和“杂环基团”可被1-5个选自基团B的取代基取代,并包括未取代的“C3-12碳环基团”和未取代的“杂环基团”。
“基团B”为由以下基团组成的基团:1)以上定义的“卤原子”,2)硝基,3)氰基,4)以上定义的“C1-8烷基”,5)以上定义的“C2-4烯基”,6)以上定义的“C2-4炔基”,7)“-ORB1”,8)“-SRB2”,9)“-NRB3RB4”,10)“-NRB5CORB6”,11)“-NRB7COORB8”,12)“-NRB9CONRB10RB11”,13)“-NRB12CONRB13ORB14”,14)“-NRB15SO2RB16”,15)“-SO2-RB17”,16)“-SO2NRB18RB19”,17)“-P(=O)(RB20)(RB21)”,18)“-COORB22”,19)“-CONRB23RB24”,20)“-NRB25SO2NRB26RB27”,21)“-NRB28SO2NRB29CONRB30RB31”,22)以上定义的“C3-12碳环基团”和23)以上定义的“杂环基团”,其中RB1、RB2、RB4、RB5、RB7、RB8、RB9、RB10、RB11、RB12、RB13、RB14、RB15、RB18、RB19、RB22、RB23、RB24、RB25、RB26、RB27、RB28、RB29、RB30和RB31相同或不同且各自为氢原子或以上定义的“C1-4烷基”,RB3和RB6各自为氢原子、以上定义的“C1-4烷基”、以上定义的“C3-12碳环基团”或以上定义的“杂环基团”,RB16为以上定义的“C1-4烷基”、以上定义的“C3-12碳环基团”或以上定义的“杂环基团”,RB17为以上定义的“C1-4烷基”或以上定义的“杂环基团”,RB20和RB21相同或不同且各自为以上定义的“C1-4烷基”。
作为“-ORB1”,具体地可提及羟基、甲氧基、乙氧基、丙氧基、异丙氧基、叔-丁氧基等。
作为“-SRB2”,具体地可提及巯基、甲硫基、乙基硫基、丙基硫基、异丙基硫基、叔-丁基硫基等。
作为“-NRB3RB4”,具体地可提及氨基、甲基氨基、乙基氨基、2-氨基乙基氨基、丙基氨基、异丙基氨基、叔-丁基氨基、二甲基氨基、二乙基氨基、N-乙基-N-甲基氨基、N-甲基-N-丙基氨基、N-异丙基-N-甲基氨基、N-(咪唑啉-2-基)氨基等。
作为“-NRB5CORB6”,具体地可提及氨基、甲酰基氨基、乙酰基氨基、羟基乙酰基氨基、丙酰基氨基、丁酰基氨基、异丁酰基氨基、新戊酰基氨基、N-乙酰基-N-甲基氨基、3-氨基丙酰基氨基、3-(戊酰基氨基)丙酰基氨基、4-咪唑基羰基氨基、(1-甲基吡咯-2-基)羰基氨基、4-吡唑基羰基氨基等。
作为“-NRB7COORB8”,具体地可提及羧基氨基、羧基甲基氨基、羧基乙基氨基、甲氧基羰基氨基、甲氧基羰基甲基氨基等。
作为“-NRB9CONRB10RB11”,具体地可提及氨基羰基氨基、甲基氨基羰基氨基、二甲基氨基羰基氨基、(甲基氨基羰基)(甲基)氨基、(二甲基氨基羰基)(甲基)氨基、[(2-羟基乙基)氨基甲酰基]氨基等。
作为“-NRB12CONRB13ORB14”,具体地可提及甲氧基氨基羰基氨基、(甲基甲氧基氨基羰基)(甲基)氨基、(甲基甲氧基氨基羰基)氨基等。
作为“-NRB15SO2RB16”,具体地可提及磺酰基氨基、甲基磺酰基氨基、乙基磺酰基氨基、丙基磺酰基氨基、N-甲基-N-磺酰基氨基、N-甲基-N-甲基磺酰基氨基、N-乙基-N-磺酰基氨基、N-乙基-N-甲基磺酰基氨基、3-吡啶基磺酰基氨基、吗啉代磺酰基氨基、哌啶子基吗啉代磺酰基氨基、2-吗啉代乙基磺酰基氨基等。
作为“-SO2-RB17”,具体地可提及磺酰基、甲基磺酰基、乙基磺酰基、丙基磺酰基、丁基磺酰基等。
作为“-SO2NRB18RB19”,具体地可提及氨基磺酰基、甲基氨基磺酰基、二甲基氨基磺酰基、乙基甲基氨基磺酰基等。
作为“-P(=O)(RB20)(RB21)”,具体地可提及次膦酰基、甲基次膦酰基、二甲基次膦酰基、乙基次膦酰基、二乙基次膦酰基等。
作为“-COORB22”,具体地可提及羧基、甲氧基羰基、乙氧基羰基、丙氧基羰基、异丙氧基羰基、叔-丁氧基羰基等。
作为“-CONRB23RB24”,具体地可提及氨基甲酰基、甲基氨基甲酰基、二甲基氨基甲酰基、乙基氨基甲酰基、二乙基氨基甲酰基、丙基氨基甲酰基、丁基氨基甲酰基等。
作为“-NRB25SO2NRB26RB27”,具体地可提及氨磺酰基氨基、二甲基氨磺酰基氨基等。
作为“-NRB28SO2NRB29CONRB30RB31”,具体地可提及{[(2-羟基乙基)氨基甲酰基](2-羟基乙基)氨磺酰基}氨基等。
作为“基团B”,优选可提及氟原子、氯原子、溴原子、碘原子、硝基、氰基、甲基、乙基、丙基、异丙基、丁基、异丁基、戊基、异戊基、己基、1-乙基丙基、1-丙基丁基、乙烯基、1-丙烯基、乙炔基、1-丙炔基、1-丁炔基、羟基、甲氧基、乙氧基、丙氧基、异丙氧基、甲硫基、乙硫基、氨基、甲基氨基、乙基氨基、二甲基氨基、二乙基氨基、乙基甲基氨基、甲基羰基氨基、乙基羰基氨基、丙基羰基氨基、异丙基羰基氨基、(甲基羰基)(甲基)氨基、乙氧基羰基氨基、甲基氨基羰基氨基、二甲基氨基羰基氨基、甲氧基氨基羰基氨基、甲基磺酰基氨基、乙基磺酰基氨基、丙基磺酰基氨基、异丙基磺酰基氨基、苯基磺酰基氨基、(甲基磺酰基)(甲基)氨基、甲基磺酰基、哌嗪-1-基磺酰基、吗啉-4-基磺酰基、哌啶-4-基磺酰基、吡咯烷-4-基磺酰基、氨基磺酰基、甲基氨基磺酰基、乙基氨基磺酰基、二甲基氨基磺酰基、二甲基次膦酰基、羧基、甲氧基羰基、氨基甲酰基、甲基氨基羰基、乙基氨基羰基氨基、二甲基氨基磺酰基氨基、环丙基、环己基、苯基、哌啶基、吡咯烷基、哌啶基、哌嗪基和吗啉基。
作为“基团B”,特别优选可提及氟原子、氯原子、溴原子、碘原子、硝基、氰基、甲基、乙基、丙基、异丙基、丁基、1-乙基丙基、1-丙基丁基、丁基、异丁基、异戊基、乙烯基、乙炔基、1-丙炔基、1-丁炔基、羟基、甲氧基、丙氧基、异丙氧基、甲硫基、氨基、甲基氨基、乙基氨基、二甲基氨基、二乙基氨基、乙基甲基氨基、甲基羰基氨基、乙基羰基氨基、丙基羰基氨基、异丙基羰基氨基、(甲基羰基)(甲基)氨基、乙氧基羰基氨基、甲基氨基羰基氨基、二甲基氨基羰基氨基、甲氧基氨基羰基氨基、甲基磺酰基氨基、乙基磺酰基氨基、丙基磺酰基氨基、异丙基磺酰基氨基、苯基磺酰基氨基、(甲基磺酰基)(甲基)氨基、甲基磺酰基、哌嗪-1-基磺酰基、吗啉-4-基磺酰基、哌啶-4-基磺酰基、吡咯烷-4-基磺酰基、氨基磺酰基、甲基氨基磺酰基、乙基氨基磺酰基、二甲基氨基磺酰基、二甲基次膦酰基、羧基、甲氧基羰基、氨基甲酰基、甲基氨基羰基、乙基氨基羰基氨基、二甲基氨基磺酰基氨基、环丙基、苯基、哌啶基、吡咯烷基、哌啶基、哌嗪基和吗啉基。
优选的取代数为1或2,且当“C3-12碳环基团”为苯基时,环Cy优选在2位单取代、在3位单取代、在4位单取代、在2,3位二取代、在2,4位二取代、在2,5位二取代或在2,6位二取代,并特别优选在4位单取代或在2,4位二取代,更优选R2在3位单取代,和更优选R6在2,4位二取代。
用于以上定义的基团A的4)的以上定义的“C1-4烷基”和用于RA1、RA2、RA3、RA4、RA5、RA6、RA7、RA8或RA9的以上定义的“C1-4烷基”各自任选被1-3个相同或不同的选自以下定义的“基团C”的取代基取代。
用于基团A的11)和RA7的以上定义的“C3-12碳环基团”和用于和RA7的12)的以上定义的“杂环基团”各自任选被1-5个相同或不同的选自以下定义的“基团C”的取代基取代。
用于上述基团B的22)、RB3、RB6和RB16的以上定义的“C3-12碳环基团”和用于上述23)、RB3、RB6、RB16和RB17的以上定义的“杂环基团”各自任选被1-5个相同或不同的选自以下定义的“基团C”的取代基取代。
“基团C”为由以下基团组成的基团:1)以上定义的“卤原子”,2)氰基,3)以上定义的“C1-4烷基”,4)“-ORC1”,5)“-NRC2RC3”,6)“-COORC4”和7)氧代基,其中RC1、RC2、RC3和RC4相同或不同且各自为氢原子或以上定义的“C1-4烷基”。
作为“-ORC1”,具体地可提及羟基、甲氧基、乙氧基、丙氧基、异丙氧基、叔-丁氧基等。
作为“-NRC2RC3”,具体地可提及氨基、甲基氨基、乙基氨基、丙基氨基、异丙基氨基、叔-丁基氨基、二甲基氨基、二乙基氨基、N-乙基-N-甲基氨基、N-甲基-N-丙基氨基、N-异丙基-N-甲基氨基等。
作为“-COORC4”,具体地可提及羧基、甲氧基羰基、乙氧基羰基、丙氧基羰基、异丙氧基羰基、叔-丁氧基羰基等。
作为“基团C”优选为由以下基团组成的基团:1)以上定义的“卤原子”,2)氰基,3)以上定义的“C1-4烷基”,4)“-ORC1”,5)“-NRC2RC3”和6)“-COORC4”,且具体地可提及氟原子、氯原子、溴原子、氰基、甲基、乙基、丙基、羟基、甲氧基、乙氧基、氨基、二甲基氨基、二乙基氨基、羧基和甲氧基羰基。
作为“基团C”,特别优选甲基。
取代的优选数目为1,且可在任何可取代位置上取代。
作为“R1”,优选可提及C1-6烷基(其中所述C1-6烷基任选被1-3个选自基团A的取代基取代)或
其中各符号如上定义。
其中,m优选0,“环Cy”优选C3-12碳环基团,且“碳环基团”优选环烷基(其中“C3-12碳环基团”和“环烷基”任选被1-5个选自基团B的取代基取代)。
作为“R1”,具体优选甲基、乙基、2,2,2-三氟乙基、丙基、异丙基、丁基、2-丙烯基、环丙基、2-甲基环丙基、环丁基、环戊基、环己基、苯基、4-氯苯基、4-氟苯基、邻甲苯基、间甲苯基、对甲苯基、4-甲氧基苯基、噻吩-3-基、环丙基甲基、2-甲氧基乙基、羧基甲基、2-羟基乙基、2-(二甲基氨基)乙基和苄基。
可提及更优选甲基、乙基、2,2,2-三氟乙基、丙基、异丙基、丁基、环丙基、2-甲基环丙基、环丁基、环戊基、环己基、苯基、4-氯苯基、4-氟苯基、邻甲苯基、间甲苯基、对甲苯基、4-甲氧基苯基、噻吩-3-基、2-甲氧基乙基、羧基甲基、2-羟基乙基和2-(二甲基氨基)乙基,特别优选甲基或环丙基。
作为“R2”,优选
其中各符号如上定义。其中,优选m为0,优选“环Cy”为C3-12碳环基团,且优选“碳环基团”为苯基(其中所述“C3-12碳环基团”和“苯基”任选被1-5个选自基团B的取代基取代,且作为“基团B”,优选“-NRB3RB4”、“-NRB5CORB6”、“-NRB7COORB8”、“-NRB9CONRB10RB11”、“-NRB12CONRB13ORB14”、“-NRB15SO2RB16”、“-NRB25SO2NRB26RB27”和“-NRB28SO2NRB29CONRB30RB31”)。
作为“R2”,具体优选氢原子、甲基、乙基、2,2,2-三氟乙基、异丙基、丁基、异丁基、2-丙烯基、环丙基、环丁基、环戊基、苯基、4-氯苯基、2-氟苯基、4-氟苯基、4-溴苯基、2,6-二氟苯基、邻甲苯基、间甲苯基、对甲苯基、2,6-二甲基苯基、2-乙基苯基、3-(3-羟基丙基)苯基、3-(2-羧基乙基)苯基、3-(3-吗啉-4-基丙基)苯基、3-二甲基氨基丙基苯基、3-羟基苯基、4-羟基苯基、2-甲氧基苯基、3-甲氧基苯基、4-甲氧基苯基、3-二甲基氨基乙氧基苯基、3-羧基甲氧基苯基、3-(3-二甲基氨基丙氧基)苯基、3-(2-吗啉-4-基乙氧基)苯基、3-(2-吡咯烷-1-基乙氧基)苯基、3-(2-哌啶-1-基乙氧基)苯基、3-(2-二乙基氨基乙氧基)苯基、3-[3-(4-甲基哌嗪-1-基)丙氧基]苯基、3-氨基苯基、3-甲基氨基苯基、3-二甲基氨基苯基、3-(甲磺酰基)甲基氨基苯基、3-甲基羰基氨基苯基、3-甲磺酰基氨基苯基、4-氯-3-甲磺酰基氨基苯基、3-乙磺酰基氨基苯基、3-(丙-1-磺酰基氨基)苯基、3-(丙-2-磺酰基氨基)苯基、3-氯甲磺酰基氨基苯基、3-三氟甲磺酰基氨基苯基、3-(2,2,2-三氟乙磺酰基氨基)苯基、3-(2-甲氧基乙基)甲基氨基苯基、3-甲基羰基氨基苯基、3-乙基羰基氨基苯基、3-丙基羰基氨基苯基、3-异丙基羰基氨基苯基、3-乙氧基羰基氨基苯基、3-(羟基甲基羰基)氨基苯基、3-(2-羟基乙基羰基氨基)苯基、3-乙基氨基羰基氨基苯基、3-(2-二甲基氨基乙基羰基氨基)苯基、3-(3-二甲基氨基丙基羰基氨基)苯基、3-(甲氧基甲基羰基氨基)苯基、3-(丁基羰基氨基甲基羰基氨基)苯基、3-(2-丁基羰基氨基乙基羰基氨基)苯基、3-甲基氨基羰基氨基苯基、3-甲氧基氨基羰基氨基苯基、3-二甲基氨基羰基氨基苯基、3-(二甲基氨基甲基羰基氨基)苯基、3-(2-吗啉-4-基乙基氨基)苯基、3-(2-苄氧基羰基氨基乙基)磺酰基氨基苯基、3-(2-氨基乙基)磺酰基氨基苯基、3-(2-丁基羰基氨基乙基)磺酰基氨基苯基、3-二甲基氨基磺酰基氨基苯基、3-羧基苯基、3-氨基甲酰基苯基、3-甲磺酰基苯基、4-甲磺酰基苯基、3-乙磺酰基苯基、3-甲基氨基磺酰基苯基、3-乙基氨基磺酰基苯基、3-苯磺酰基氨基苯基、3-氨基磺酰基苯基、3-二甲基氨基磺酰基苯基、4-二甲基氨基磺酰基苯基、3-(4-甲基哌嗪-1-磺酰基)苯基、3-(吗啉-4-磺酰基)苯基、3-(哌啶-1-磺酰基)苯基、3-(吡咯烷-1-磺酰基)苯基、3-甲基氨基羰基苯基、3-吗啉-4-基苯基、3-吡咯烷-1-基苯基、3-哌啶-1-基苯基、3-(4-甲基哌嗪-1-基)苯基、3-(2-氧代吡咯烷-1-基)苯基、3-(3-氧代吗啉-4-基)苯基、噻吩-3-基、吡啶-3-基、苄基和以下基团:
更优选可提及苯基、4-氯苯基、2-氟苯基、4-氟苯基、4-溴苯基、2,6-二氟苯基、邻甲苯基、间甲苯基、对甲苯基、2,6-二甲基苯基、2-乙基苯基、3-(3-羟基丙基)苯基、3-(2-羧基乙基)苯基、3-(3-吗啉-4-基丙基)苯基、3-二甲基氨基丙基苯基、3-羟基苯基、4-羟基苯基、2-甲氧基苯基、3-甲氧基苯基、4-甲氧基苯基、3-二甲基氨基乙氧基苯基、3-羧基甲氧基苯基、3-(3-二甲基氨基丙氧基)苯基、3-(2-吗啉-4-基乙氧基)苯基、3-(2-吡咯烷-1-基乙氧基)苯基、3-(2-哌啶-1-基乙氧基)苯基、3-(2-二乙基氨基乙氧基)苯基、3-[3-(4-甲基哌嗪-1-基)丙氧基]苯基、3-氨基苯基、3-甲基氨基苯基、3-二甲基氨基苯基、3-(甲磺酰基)甲基氨基苯基、3-甲基羰基氨基苯基、3-甲磺酰基氨基苯基、4-氯-3-甲磺酰基氨基苯基、3-乙磺酰基氨基苯基、3-(丙-1-磺酰基氨基)苯基、3-(丙-2-磺酰基氨基)苯基、3-氯甲磺酰基氨基苯基、3-三氟甲磺酰基氨基苯基、3-(2,2,2-三氟乙磺酰基氨基)苯基、3-(2-甲氧基乙基)甲基氨基苯基、3-甲基羰基氨基苯基、3-乙基羰基氨基苯基、3-丙基羰基氨基苯基、3-异丙基羰基氨基苯基、3-乙氧基羰基氨基苯基、3-(羟基甲基羰基)氨基苯基、3-(2-羟基乙基羰基氨基)苯基、3-乙基氨基羰基氨基苯基、3-(2-二甲基氨基乙基羰基氨基)苯基、3-(3-二甲基氨基丙基羰基氨基)苯基、3-(甲氧基甲基羰基氨基)苯基、3-(丁基羰基氨基甲基羰基氨基)苯基、3-(2-丁基羰基氨基乙基羰基氨基)苯基、3-甲基氨基羰基氨基苯基、3-甲氧基氨基羰基氨基苯基、3-二甲基氨基羰基氨基苯基、3-(二甲基氨基甲基羰基氨基)苯基、3-(2-吗啉-4-基乙基氨基)苯基、3-(2-苄氧基羰基氨基乙基)磺酰基氨基苯基、3-(2-氨基乙基)磺酰基氨基苯基、3-(2-丁基羰基氨基乙基)磺酰基氨基苯基、3-二甲基氨基磺酰基氨基苯基、3-羧基苯基、3-氨基甲酰基苯基、3-甲磺酰基苯基、4-甲磺酰基苯基、3-乙磺酰基苯基、3-甲基氨基磺酰基苯基、3-乙基氨基磺酰基苯基、3-苯磺酰基氨基苯基、3-氨基磺酰基苯基、3-二甲基氨基磺酰基苯基、4-二甲基氨基磺酰基苯基、3-(4-甲基哌嗪-1-磺酰基)苯基、3-(吗啉-4-磺酰基)苯基、3-(哌啶-1-磺酰基)苯基、3-(吡咯烷-1-磺酰基)苯基、3-甲基氨基羰基苯基、3-吗啉-4-基苯基、3-吡咯烷-1-基苯基、3-哌啶-1-基苯基、3-(4-甲基哌嗪-1-基)苯基、3-(2-氧代吡咯烷-1-基)苯基和3-(3-氧代吗啉-4-基)苯基。
作为“R6”,优选
其中各符号如上定义。其中,优选m为0,优选“环Cy”为C3-12碳环和优选“碳环基团”为苯基(其中所述“C3-12碳环基团”和“苯基”任选被1-5个选自基团B的取代基取代,其中“基团B”优选包括以上定义的“卤原子”、以上定义的“C1-8烷基”和以上定义的“C2-4炔基”)。
作为“R6”,具体地优选2-甲氧基乙基、2,2-二甲基丙基、3-二甲基氨基丙基、环丙基、环己基、苯基、2-氯苯基、3-氯苯基、4-氯苯基、2,4-二氯苯基、3,4-二氯苯基、4-溴苯基、2-氟苯基、4-氟苯基、4-碘苯基、邻甲苯基、对甲苯基、2-乙基苯基、4-乙基苯基、2-丙基苯基、2-异丙基苯基、4-异丙基苯基、2-丁基苯基、4-丁基苯基、2-异丁基苯基、4-叔-丁基苯基、2-(3-甲基丁基)苯基、4-三氟甲基苯基、4-(2-氟乙基)苯基、4-(2,2-二氟乙基)苯基、4-(2,2,2-三氟乙基)苯基、4-(1-乙基丙基)苯基、4-(1-丙基丁基)苯基、4-乙炔基苯基、2,4-二氟苯基、2,6-二氟苯基、2,4-二氯苯基、4-溴-2-氟苯基、4-溴-3-氟苯基、4-溴-2-氯苯基、4-氯-2-氟苯基、2-氟-4-碘苯基、2-氯-4-甲基苯基、4-氯-2-甲基苯基、4-溴-2-甲基苯基、4-溴-3-甲基苯基、2-氟-4-甲基苯基、2-氟-4-三氟甲基苯基、4-溴-2-乙基苯基、4-乙基-2-氟苯基、4-(2-羧基乙基)-2-氟苯基、2-氟-4-丙基苯基、2-氟-4-乙烯基苯基、4-(2-羧基乙烯基)-2-氟苯基、4-乙炔基-2-氟苯基、2-氟-4-(丙-1-炔基)苯基、2-氟-4-(3-羟基丙-1-炔基)苯基、2-氟-4-(3-甲氧基丙-1-炔基)苯基、4-环丙基-2-氟苯基、2-氟-4-(3-羟基-3-甲基丁-1-炔基)苯基、4-(3-二甲基氨基丙-1-炔基)-2-氟苯基、4-氯-2-二甲基氨基甲基苯基、4-二甲基氨基-2-甲基苯基、4-羟基苯基、2-甲氧基苯基、4-甲氧基苯基、4-三氟甲氧基苯基、4-异丙氧基苯基、2,4-二甲氧基苯基、4-甲氧基-2-甲基苯基、2-氟-4-甲氧基苯基、4-溴-2-羟基苯基、4-溴-2-甲氧基苯基、2-溴-4-甲氧基苯基、4-甲基噻吩基、4-三氟甲基噻吩基、2-氟-4-甲基噻吩基、4-氨基苯基、4-甲基氨基苯基、2-二甲基氨基苯基、3-二甲基氨基苯基、4-二甲基氨基苯基、4-乙基氨基苯基、4-二乙基氨基苯基、4-乙基甲基氨基-2-氟苯基、4-硝基苯基、4-氰基苯基、6-氨基吡啶-3-基、6-二甲基氨基吡啶-3-基、6-氯吡啶-2-基、4-氯吡啶-3-基、4-羧基苯基、4-甲氧基羰基苯基、4-乙基氨基苯基、4-(甲基羰基)甲基氨基苯基、4-甲磺酰基苯基、4-三氟甲磺酰基苯基、4-二甲基氨基-2-甲基苯基、4-二甲基氨基-3-甲基苯基、4-二甲基氨基-3-三氟甲基苯基、4-二甲基氨基-2-丙基苯基、4-二甲基氨基-2-氟苯基、4-二甲基氨基-3-氟苯基、4-二甲基次膦酰基苯基、苯并[1,3]二氧杂环戊烯-5-基、1,1’-联苯-4-基、4-(哌啶-1-基)苯基、4-苄基苯基、4-(吗啉-4-基)苯基、1-甲基哌啶-4-基、1-异丙基哌啶-4-基、噻唑-2-基、2-二甲基氨基噻唑-4-基、1-甲基-1,2,3,4-四氢喹啉-6-基、1H-吲哚-5-基、1-甲基-1H-吲哚-5-基、1-乙基-1H-吲哚-5-基、1-甲基-1H-吲哚-6-基、1-甲基-1H-吲哚-7-基、1,2-二甲基-1H-吲哚-5-基、1,2,3-三甲基-1H-吲哚-5-基、6-氟-1H-吲哚-5-基、1-甲基-1H-苯并咪唑-5-基、1-甲基-1H-吲唑-5-基、1-甲基-2,3-二氢-1H-吲哚-5-基、苯并[b]噻吩-5-基、4-氯苄基、2-溴苄基、3-溴苄基、4-溴苄基、5-溴-2-氟苄基、2-吗啉-4-基乙基和吡啶-3-基甲基。
更优选可提及苯基、2-氯苯基、3-氯苯基、4-氯苯基、2,4-二氯苯基、3,4-二氯苯基、4-溴苯基、2-氟苯基、4-氟苯基、4-碘苯基、邻甲苯基、对甲苯基、2-乙基苯基、4-乙基苯基、2-丙基苯基、2-异丙基苯基、4-异丙基苯基、2-丁基苯基、4-丁基苯基、2-异丁基苯基、4-叔-丁基苯基、2-(3-甲基丁基)苯基、4-三氟甲基苯基、4-(2-氟乙基)苯基、4-(2,2-二氟乙基)苯基、4-(2,2,2-三氟乙基)苯基、4-(1-乙基丙基)苯基、4-(1-丙基丁基)苯基、4-乙炔基苯基、2,4-二氟苯基、2,6-二氟苯基、2,4-二氯苯基、4-溴-2-氟苯基、4-溴-3-氟苯基、4-溴-2-氯苯基、4-氯-2-氟苯基、2-氟-4-碘苯基、2-氯-4-甲基苯基、4-氯-2-甲基苯基、4-溴-2-甲基苯基、4-溴-3-甲基苯基、2-氟-4-甲基苯基、2-氟-4-三氟甲基苯基、4-溴-2-乙基苯基、4-乙基-2-氟苯基、4-(2-羧基乙基)-2-氟苯基、2-氟-4-丙基苯基、2-氟-4-乙烯基苯基、4-(2-羧基乙烯基)-2-氟苯基、4-乙炔基-2-氟苯基、2-氟-4-(丙-1-炔基)苯基、2-氟-4-(3-羟基丙-1-炔基)苯基、2-氟-4-(3-甲氧基丙-1-炔基)苯基、4-环丙基-2-氟苯基、2-氟-4-(3-羟基-3-甲基丁-1-炔基)苯基、4-(3-二甲基氨基丙-1-炔基)-2-氟苯基、4-氯-2-二甲基氨基甲基苯基、4-二甲基氨基-2-甲基苯基、4-羟基苯基、2-甲氧基苯基、4-甲氧基苯基、4-三氟甲氧基苯基、4-异丙氧基苯基、2,4-二甲氧基苯基、4-甲氧基-2-甲基苯基、2-氟-4-甲氧基苯基、4-溴-2-羟基苯基、4-溴-2-甲氧基苯基、2-溴-4-甲氧基苯基、4-甲基噻吩基、4-三氟甲基噻吩基、2-氟-4-甲基噻吩基、4-氨基苯基、4-甲基氨基苯基、2-二甲基氨基苯基、3-二甲基氨基苯基、4-二甲基氨基苯基、4-乙基氨基苯基、4-二乙基氨基苯基、4-乙基甲基氨基-2-氟苯基、4-硝基苯基、4-氰基苯基、6-氨基吡啶-3-基、6-二甲基氨基吡啶-3-基、6-氯吡啶-2-基、4-氯吡啶-3-基、4-羧基苯基、4-甲氧基羰基苯基、4-乙基氨基苯基、4-(甲基羰基)甲基氨基苯基、4-甲磺酰基苯基、4-三氟甲磺酰基苯基、4-二甲基氨基-2-甲基苯基、4-二甲基氨基-3-甲基苯基、4-二甲基氨基-3-三氟甲基苯基、4-二甲基氨基-2-丙基苯基、4-二甲基氨基-2-氟苯基、4-二甲基氨基-3-氟苯基、4-二甲基次膦酰基苯基、1,1’-联苯-4-基、4-(哌啶-1-基)苯基、4-苄基苯基和4-(吗啉-4-基)苯基。
作为“R3”,优选可提及C1-6烷基(其中所述C1-6烷基任选被1-3个选自基团A的取代基取代)。
具体地优选氢原子、甲基、乙基、丙基、异丁基、2-甲氧基乙基、环丙基、2-二甲基氨基乙基和2-丙烯基,且特别优选甲基。
作为“R4”,可提及优选C1-6烷基(其中所述C1-6烷基任选被1-3个选自基团A的取代基取代)。
具体地优选氢原子、甲基、丙基和羟基,且特别优选甲基。
作为“R5”,优选氢原子和甲基,且特别优选氢原子。
“其药物上可接受的盐”可为任何盐,只要其与上述式[I]、[I’]和[I-1]-[I-3]化合物形成无毒盐并且可通过与无机酸(如盐酸、硫酸、磷酸、氢溴酸等);有机酸(如草酸、丙二酸、柠檬酸、富马酸、乳酸、苹果酸、琥珀酸、酒石酸、乙酸、三氟乙酸、葡糖酸、抗坏血酸、甲磺酸、苯磺酸等);无机碱(如氢氧化钠、氢氧化钾、氢氧化钙、氢氧化镁、氢氧化铵等);有机碱(如甲基胺、二乙基胺、三乙基胺、三乙醇胺、乙二胺、三(羟基甲基)甲基胺、胍、胆碱、辛可宁等);或氨基酸(如赖氨酸、精氨酸、丙氨酸等)反应得到。本发明还包括各个化合物的水合物和溶剂合物。
本发明还包括各个化合物的前药和代谢物。
“前药”是指本发明化合物的衍生物,其包含经化学或代谢可分解的基团并且其在个体给药后恢复成最初的化合物表现出其固有功效,包括络合物和盐,但不涉及共价键。
将前药应用于例如,提高口服给药的吸收或靶向于靶位。
作为待修饰位置,在本发明的化合物中可提及的高活性官能团有羟基、羧基、氨基、巯基等。
例如,可提及一种化合物(其中羟基被-CO-烷基、-CO2-烷基、-CONH-烷基、-CO-烯基、-CO2-烯基、-CONH-烯基、-CO-芳基、-CO2-芳基、-CONH-芳基、-CO-杂环、-CO2-杂环、-CONH-杂环(其中烷基、烯基、芳基和杂环任选被卤原子、烷基、羟基、烷氧基、羧基、氨基、氨基酸残基、-PO3H2、-SO3H、-OPO3H2、-OSO3H等)或-PO3H2等取代),和一种化合物(其中氨基被-CO-烷基、-CO2-烷基、-CO-烯基、-CO2-烯基、-CO2-芳基、-CO-芳基、-CO-杂环、-CO2-杂环(其中烷基、烯基、芳基和杂环任选被卤原子、烷基、羟基、烷氧基、羧基、氨基、氨基酸残基、-PO3H2、-SO3H、-OPO3H2、-OSO3H等)或-PO3H2等取代)等。
作为羟基的修饰基团,具体地可提及乙酰基、丙酰基、异丁酰基、新戊酰基、十六酰基、苯甲酰基、4-甲基苯甲酰基、二甲基氨基甲酰基、二甲基氨基甲基羰基、磺基、丙氨酰基、富马酰基等。还可提及3-羧基苯甲酰基的钠盐或2-羧基乙基羰基的钠盐等。
作为羧基的修饰基团,具体地可提及甲基、乙基、丙基、异丙基、丁基、异丁基、叔-丁基、新戊酰基氧基甲基、羧基甲基、二甲基氨基甲基、1-(乙酰基氧基)乙基、1-(乙氧基羰基氧基)乙基、1-(异丙氧基羰基氧基)乙基、1-(环己氧基羰基氧基)乙基、羧基甲基、(5-甲基-2-氧代-1,3-二氧杂环戊烯-4-基)甲基、苄基、苯基、邻甲苯基、吗啉代乙基、N,N-二乙基氨基甲酰基甲基、肽基等。
作为氨基的修饰基团,具体地可提及叔-丁基、二十二烷醇基、新戊酰基甲基氧基、丙氨酰基、己基氨基甲酰基、戊基氨基甲酰基、3-甲硫基-1-(乙酰基氨基)丙基羰基、1-磺基-1-(3-乙氧基-4-羟基苯基)甲基、(5-甲基-2-氧代-1,3-二氧杂环戊烯-4-基)甲基、(5-甲基-2-氧代-1,3-二氧杂环戊烯基-4-基)甲氧基羰基、四氢呋喃基、吡咯烷基甲基等。
在本说明书中使用的“肿瘤”包括恶性肿瘤,和“抗肿瘤药”包括抗肿瘤物质并为具有抗肿瘤活性的化合物。
可将本发明的化合物作为抗肿瘤药等给予哺乳动物(人、小鼠、大鼠、田鼠、兔、猫、犬、牛、羊、猴等)等。
当本发明的化合物以药物制剂使用时,通常将其与药学上可接受的载体、赋形剂、稀释剂、增量剂、崩解剂、稳定剂、防腐剂、缓冲剂、乳化剂、增香剂、着色剂、甜味剂、增稠剂、矫味剂、助溶剂和其他添加剂混合,众所周知如水、植物油、醇(例如乙醇、苯甲醇等)、聚乙二醇、甘油三乙酸酯、明胶、碳水合物(例如乳糖、淀粉等)、硬脂酸镁、滑石粉、羊毛脂、凡士林等,通过常规的方法制成片剂、丸剂、散剂、颗粒剂、栓剂、注射剂、滴眼液、液体制剂、胶囊剂、锭基、气雾剂、酏剂、混悬剂、乳剂、糖浆剂等并全身或局部、口服或胃肠道外给药。
虽然剂量的变化取决于年龄、体重、症状、治疗效果、给药方法等,但成人通常剂量为一次0.01mg至1g,其口服或以注射剂(如静脉注射剂等)剂型每天给予一次至几次。
通常要求抗肿瘤药长期维持其疗效,这样不仅对暂时抑制癌细胞增殖有效还对癌细胞再抑制的抑制有效。这意味着延长给药是必需的并且为保持整夜长期有效不可避免地采用高单剂量。这样延长给药和高剂量给药增加了引起副作用的危险。
鉴于此,本发明的嘧啶化合物的优选实施例之一为这样的化合物,该化合物能口服给药吸收良好并且该化合物能长期保持所给药物的血浓度。
优选能同时显示p15蛋白诱导和/或p27蛋白诱导和/或MEK抑制的化合物。
该化合物用于治疗由不希望的细胞增殖引起的疾病。
作为“由不希望的细胞增殖引发的疾病”,可提及例如肿瘤,具体地为脑瘤(具有恶性的星形神经胶质(astroglioma)和少突神经胶质细胞瘤成分的神经胶质瘤等)、食管癌、胃癌、肝癌、胰腺癌、结肠直肠癌(结肠癌、直肠癌等)、肺癌(非小细胞肺癌、小细胞肺癌、原发和转移性鳞状癌等)、肾癌、乳腺癌、卵巢癌、前列腺癌、皮肤癌、神经母细胞瘤、肉瘤、骨软骨瘤、骨瘤、骨肉瘤、精原细胞瘤、extragonadal瘤、睾丸肿瘤、子宫癌(子宫颈癌、子宫内膜癌等)、头颈肿瘤(上颌骨癌、喉癌、咽癌、舌癌、口内癌等)、多发性骨髓瘤、恶性淋巴瘤(网状细胞肉瘤、淋巴肉瘤、Hodgkin’s疾病等)、真性红细胞增多症、白血病(急性粒细胞白血病、慢性粒细胞白血病、急性淋巴细胞白血病、慢性淋巴细胞白血病等)、甲状腺肿、renal pelviccancer、输尿管肿瘤、膀胱肿瘤、胆囊癌、胆管癌、绒毛膜上皮癌、恶性黑色素瘤、儿科肿瘤(尤因家族性肉瘤、维尔姆斯肉瘤、横纹肌肉瘤、血管肉瘤、胚胎睾丸癌、成神经细胞瘤、视网膜母细胞瘤、肝胚细胞瘤、肾母细胞瘤等)等。
可提及应用于脑瘤(具有恶性的astroglioma和少突神经胶质细胞瘤成分的神经胶质瘤等)、食管癌、胃癌、肝癌、胰腺癌、结肠直肠癌(结肠癌、直肠癌等)、肺癌(非小细胞肺癌、小细胞肺癌等)、肾癌、乳腺癌、卵巢癌、前列腺癌、皮肤癌、神经母细胞瘤、肉瘤等。更优选结肠癌、胰腺癌、肾癌、肺癌和乳腺癌,且特别优选应用于结肠癌和胰腺癌。
此外,可提及慢性疼痛的治疗,具体地为神经疼痛、突发疼痛、与慢性酒精中毒、维生素缺乏、尿毒症和甲状腺功能减退症有关的疼痛。此外,可提及中性粒细胞介导的疾病或症状,具体地为缺血再灌注损伤、慢性肺梗阻病、急性呼吸疾病综合症、囊肿性纤维化、突发性肺纤维化、脓毒症、内毒素血症、肺气肿和石棉肺。此外,可提及移植排斥。而且,可提及关节炎,具体地风湿性关节炎和骨关节炎。此外,可提及哮喘。而且,可提及病毒病,具体地为疱疹病毒(HSV-1)感染、人细胞巨化病毒(HCMV)感染、人免疫缺陷病毒(HIV)感染。此为,可提及由软骨变性或损害引起的疾病,具体地为骨关节炎、风湿性关节炎、分离性骨软骨炎和需要软骨形成的疾病。
除上述外,可提及应用于再狭窄、牛皮癣、动脉硬化、心力衰竭、中风等。
作为“由不希望的细胞增殖引发的疾病”,优选肿瘤和风湿病。
作为用于多重药物治疗的其他“抗肿瘤药”,可提及烷化剂、铂络合剂、代谢拮抗剂、抗生素、植物生物碱、干扰素、环加氧酶-2(COX-2)抑制剂、激素抗癌药、癌细胞疫苗、细菌制剂、菌提取多糖、细胞因子激动剂、白细胞介素制剂、抗体药物、免疫调节剂、血管生成抑制剂、细胞内管形成抑制剂、细胞增殖抑制剂、细胞周期调节剂、凋亡诱导剂、癌基因治疗剂等。
作为烷化剂,可提及环磷酰胺、异环磷酰胺、美法仑、白消安、尼莫司汀、雷莫司汀(MCNU)、盐酸氮芥-N-氧化物、塞替派、盐酸丙卡巴肼、卡波醌、二溴甘露醇、胺丙磺酯、雌莫司汀磷酸酯钠、达卡巴嗪、替莫唑胺、达卡巴嗪(DTIC)、盐酸氮芥、曲奥舒凡、替莫唑胺、MS-247、(-)-(S)-溴乐果等。
作为铂络合物,可提及顺铂、卡铂、奈达铂、铂尔定、依托泊苷、奥沙利铂、依他铂、miriplation、洛铂、picoplatin、奥沙利铂、沙铂、SLIT-顺铂等。
作为代谢拮抗剂,可提及甲氨蝶呤、6-巯基嘌呤、cytosine-arabinoside、依诺他滨(BHAC)、5-氟尿嘧啶、替加氟、替加氟-尿嘧啶(UFT)、卡莫氟(HCFU)、去氧氟尿苷、盐酸吉西他滨、羟基脲、盐酸丙卡巴肼、培美曲塞二钠、L-MDAM、巯基嘌呤核苷、磷酸阿糖氟腺嘌呤、tegafur-gimestat-otastat、左亚叶酸盐-氟尿嘧啶、folinatecalcium levofolinate、bemcitabine、calcium levolecucovorin、卡培他滨、阿糖胞苷、cytarabineocfosfate、CS-682、3’-乙炔基胞苷、TAS-102、卡培他滨、氟维司群、碘苷、羟基脲、培美曲塞二钠、3-AP、benspm、洛美曲索、troxacitabine、ABT-510、AP-2/09、AR-726、AVI-4126、belimumab、CA4P、结肠直肠癌疫苗、COU-1、degarelix、DJ-927、DPC-974、EKB-569、enzastaurin盐酸、枸橼酸芬太尼、氟维司群、galliummaltolate、HuMax-EGFR、IDD-1、LE-AON、MDX-070、MT-201、NK-911、NV-07、Oncomyc-NG、帕妥珠单抗、PX-103.1、肾癌疫苗、SN-4071、TL-139、topixantrone二盐酸盐、ZYC-101a等。
作为抗生素,可提及放射菌素D、柔红霉素、阿霉素(多柔比星)、表阿霉素、阿克拉霉素A、丝裂霉素C、博来霉素、盐酸吡柔比星、盐酸依达比星、盐酸阿柔比星、盐酸氨柔比星、硫酸培洛霉素、新制癌菌素、净司他丁斯酯、戊柔比星、多柔比星脂质体、NK911、BMS-247550(埃坡霉素衍生物)、KRN5500、KW-2170、蒽环霉素、becatecarin、PK1、盐酸sabarubicin、CVS-10290等。
作为植物生物碱,可提及长春新碱、长春碱、长春地辛、依托泊苷、多西他赛、紫杉醇、盐酸依立替康、酒石酸长春瑞滨、盐酸米托蒽醌、诺斯卡品、长春氟宁、多西他赛、E-7010、聚谷氨酸化紫杉醇、soblidotin、Bay59-8862、E-7389、DJ-927、HTI-286、AC-7700、T-3782、ABI-007、batabulin sodium、DHA-紫杉醇、deoxyepothilone B、ixabepilone、MBT-0206、ortataxel、SB-715992、AI-850、synthadotin、lxabepilone、卢比替康、盐酸nogitecan、盐酸拓扑替康、索布佐生、磷酸依托泊苷二钠盐、盐酸右雷佐生、卢比替康IST-622、依沙替康mesylate、TOP-53、edotecarin、karenitecan、AG-7352、TAS-103、T-0128、NK-314、CKD-602、BNP-1350、勒托替康、pegamotecan、卢比替康、LE-SN38、CPT-11等。
作为干扰素,可提及干扰素α、干扰素α-2a、干扰素α-2b、干扰素β和干扰素γ、干扰素γ-1a、干扰素γ-1b、干扰素γ-nl等。
作为环加氧酶-2抑制剂,可提及罗非考昔、塞来考昔、罗美昔布、tiracoxib(tilmacozib)、CS-502、CS-706、伐地考昔、帕瑞考昔、R-109339、鱼藤素、ajulemic acid、p-54、E-6087、LM-4108、R-109339、CBX-AC、CBX-PR、CBX-BU、L-748706、DMNQ-S64、ON-09250、ON-09300等。
作为激素抗肿瘤药,可提及醋酸亮丙瑞林、醋酸戈舍瑞林、氨鲁米特、曲普瑞林、戈舍瑞林、福美坦、单盐酸发特卢唑、来曲唑、依西美坦、地洛瑞林、醋酸布舍瑞林、醋酸西曲瑞克、醋酸组氨瑞林、阿巴瑞克、亮丙瑞林缓释系统、雌莫司汀磷酸酯钠、醋酸氯地孕酮、磷雌酚、氟他胺、bicartamide、醋酸环丙孕酮、醋酸甲羟孕酮、枸橼酸他莫昔芬、枸橼酸托瑞米芬、美雄烷mepithiostane、环硫雄醇、醋酸甲羟孕酮、氟维司群、奥美昔芬、盐酸雷洛昔芬、磷酸米泼昔芬、TAS-108、FMPA、法倔唑、阿那曲唑、依西美坦、来曲唑、福美坦、波生坦、阿曲生坦、度他雄胺、ESI、KT5555、KAT-682等。
作为癌细胞疫苗,可提及癌疫苗、活性的淋巴细胞、UL56缺陷HSV、结肠直肠癌治疗疫苗、癌肽疫苗等。
作为细菌制剂,可提及BCG、抗恶性肿瘤链球菌的制剂、LC9018、结核菌热水提取物等。
作为菌提取的多糖,可提及香菇多糖、Coriolus versicolorpolysaccharides(krestin)、西佐喃、CM6271等。
作为细胞因子激动剂,可提及乌苯美司等。
作为白细胞介素制剂,可提及白细胞介素-2、替西白介素、白细胞介素-12等。
作为抗体药物,可提及免疫调节剂、曲妥单抗、利妥昔单抗、吉姆单抗、奥佐米星、替伊莫单抗、西妥昔单抗、贝伐单抗、卡罗单抗喷他肽、铟-卡罗单抗喷他肽、培美曲塞二钠、镱90替伊莫单抗、伏妥莫单抗、人源化的IL-6受体抗体、抗-TA226人单克隆抗体、F(ab’)人抗体GAH、EMD72000、partuzumab、阿仑单抗、VEGF受体FLt-1抗体、KW-2871、人源化的抗-GM2抗体、人源化的抗-GD2抗体、KM2760、TRAIL受体-2单克隆抗体、抗-TRAIL受体DR5抗体、TRAIL-RlmAb、人源化的抗-HM1.24抗体、人源化的FasL抗体、人源化的抗-CD26单克隆抗体、α-半乳糖神经酰胺、白喉毒素修饰的转铁蛋白带、CD47单克隆抗体、抗-人黑色素瘤单克隆抗体、HoAKs-1(抗-肺癌单克隆抗体)等。
作为血管生成抑制剂,可提及吉非替尼(Iressa)、沙利度胺、西妥昔单抗、semaxanib、TSU-68、KRN633、KRN951、马立马司他、S-3304、盐酸埃罗替尼、ZD6474、GW572016、S-3304、E7820、SU6668、E7080、NK4、TAS-101、拉帕替尼、priomastat、RPI-4610、沙利度胺、WX-UK1、2-甲氧基雌二醇、SG-292、FYK-1388等。
作为细胞内管形成抑制剂,可提及TAC-01、E-7820等。
作为细胞增殖抑制剂,可提及甲磺酸伊马替尼、曲妥单抗、利妥昔单抗、吉姆单抗、AHM、mubritinib/TAK-165、KW-2871、KM8969、CP-724714等。
作为细胞周期调节剂,可提及Boltezomib(NF-κβ活化抑制剂)、组蛋白去乙酰酶HDAC抑制剂(FK-228、SAHA、CI-994、LAQ-824、pyroxamide、AN-9、PBA、MS-275等)、E-7070、flavopiritol、UCN-01、CGP41251、CCI-779、KT5555、HMN-214、Y-27632、vatalanib/PTK-787A、MGCD0130、temsirolirnus、(R)-roscovitine、indisulam等。
作为凋亡诱导剂,可提及bortezomib、arglabin、R-115777、KW-2401、BMS-214662、tipifarnib、lonafarnib、arglabin、贝沙罗汀、依昔舒林、葡磷酰胺、伊罗夫文、MX-126374、MX-2167、GRN163、GM95、MST-312、(-)-EGCG(Teavigo)等。
作为癌基因治疗药,可提及A-007、Ad/Q5-H-sDd、apaziquone、AVE-8062、MS-214662、考布他汀A-4、didox、多拉司他汀-10、神经节苷脂疫苗、GivaRex、ILX-23-7553、白介素、伊曲谷胺、KW-2401、MCC-465、miriplatin、MUC-1疫苗、OSI-7904L、血小板因子4、SR-271425、ZK-230211等。
作为其他抗肿瘤药,可提及左旋门冬酰胺酶、维甲酸、左旋亚叶酸钙、西莫白介素、111ln-喷曲肽、伊班膦酸钠水合物、盐酸5-氨基酮戊酸、ukrain、干细胞因子、地尼白介素2、四烯甲萘醌、甲氧沙林、三甲曲沙葡糖醛酸酯、IOR-R3、依维莫司、鼠抗人细胞角蛋白19、度骨化醇、阿利维A酸、贝沙罗汀、维替泊芬、硫酸吗啡缓释制剂、卡介苗、醋酸甲地孕酮、甲萘醌、氟尿苷、促甲状腺素α、肌醇六磷酸、augmerosen、塞替派、绒毛膜促性素、二盐酸组胺、番茄红素、他拉泊芬sidium、他索纳明、三氧化二砷、盐酸左旋咪唑、叶酸、替尼泊苷、甲苯达唑、盐酸吗啡、ALA Me酯、anetholedithiolethion、丙酸睾酮、cinacalcet盐酸、anethole dithiolethione、睾酮、米托坦、硫代硫酸钠、zevalin、碘[131I]托西莫单抗、鲑鱼降钙素、新生霉素、氨鲁米特、盐酸依氟鸟氨酸、氯尼达明、amoxnox、吡柔比星、维司力农、帕米膦酸钠、氯膦酸二钠、唑来膦酸单水合物、盐酸氨莫司汀、ubestatin、氨磷汀水合物、盐酸脱氧精胍菌素、喷司他汀、比生群、培洛霉素、碘苄胍、安吖啶、曲洛司坦、盐酸曲马多、依利醋铵、拉达卡霉素、溴美酸钠、二盐酸尼曲吖啶水合物、六甲蜜胺、OROS-oxyodone、枸橼酸芬太尼、阿司匹林、AERx硫酸吗啡、卡莫司汀、盐酸甲氧氯普胺、盐酸洛哌丁胺、尼鲁米特、多糖K、雷莫司汀、atvogen、哌泊溴烷、咪喹莫特(干扰素诱导剂)、克拉屈滨、替勃龙、舒拉明钠、来氟米特、芬太尼、醋酸奥曲肽、肌醇、熊去氧胆酸、野甘菊、香菇多糖、tetranabinex、(大麻酚受体激动剂)、培门冬酶、三氯生、crbohydrate antigen 19-9、angiopeptinacetate、福莫司汀、硝酸镓、trabectebin、雷替曲塞、净司他丁斯、十六烷基磷酸胆碱、他扎罗汀、非那雄胺、clofarabine、替莫泊芬、SY-801、人血管紧张素II、efaproxiral sodium、氨萘非特(DNA-嵌入药)、SP-1053C(DNA-嵌入药)、antineoplaston AS2-1、fenretinide(类视色素)、trabectebin、哺乳素、DOS-47、ECO-04601、thymectacin、rhIGFBP-3、carboxyamidotriazole、辅因子、davanat-1、tariquidar、ONT-093、minobronic acid、米诺膦酸、dofequidar fumarate(MDR-1抑制剂)、tariquidar(MDR-1抑制剂)、Davanat-1、豹蛙酶、阿曲生坦、meclinertant、tacedinline、曲沙他滨、DN-101、EB-1627、ACO-04601、MX-116407、STA-4783、Davanat-1、moverastin、盐酸米托蒽醌、盐酸丙卡巴肼、醋酸奥曲肽、卟吩姆钠、喷司他汀、克拉屈滨、索布佐生、维A酸、醋葡醛内酯、米托坦、卟吩姆钠、依利醋铵、AZD6126、替拉扎明、Bay43-9006、tipifarnib/R115777、米哚妥林、BMS-214662、EKB-569、E7107、CBP501、HMN-214、FK-866、WF-536、SU-11248、MKT-077、phenoxodiol、NSC-330507、G-CSF、依决可单抗(单克隆抗体)、沙妥莫单抗、沙格司亭(GM-CSF)、他米巴罗汀(类视色素衍生物)、三氧化二砷、度他雄胺、四烯甲萘醌、ZD4054、NIK-333、NS-9、ABT-510、S-2678、methioninase、TAS-105、肿瘤迁移抑制因子、TOP-008、NCO-700、BCA等。
作为与本发明化合物一起用于多重药物治疗的“其他抗肿瘤药”,优选铂络合物、烷化剂和代谢拮抗剂。可联合使用2种或3种或更多药物,其中具有不同作用机理的药物的混合物为优选实施方案之一。而且,优选具有不相重叠副作用的药物。
对于本发明的化合物与“其他抗肿瘤药”的联合使用,在同一组合物中可包括这些化合物中的两种或多种。此外,含本发明化合物的组合物和含“其他抗肿瘤药”的组合物可同时或相继给予。
当两种药物同时给予时,“同时”包括2种药物一起给予和给予一种药物并且在首次给予后几分钟内给予另一种。“相继”是指间隔给定的时间。包括例如,在给予第一种药物后几分钟至几十分钟内给予其他药物,和在给予第一种药物后几小时至几天内给予其他药物,其中时间间隔不受限定。例如,可一天一次给予一种药物并可一天2或3次给予另一种药物,或者可一周一次给予一种药物并可一天一次给予另一种药物等。
当本发明的化合物用作抗肿瘤药时和当本发明的化合物与“其他肿瘤药”联合使用时,还可增加放射治疗、激活淋巴细胞治疗等。
用于本发明实施方案的化合物的制备方法的一些实例如下所述。但是,本发明的化合物的制备方法不限于这些实施例。
即使在制备方法中未作描述,但可通过设计提供有效的制备方法,如必要时将保护基团引入官能团接着在后续步骤中去保护;将官能团作为前体进行各反应步骤并在合适的步骤中将所述基团转化为所需的官能团;改变各个制备方法和步骤的顺序;等。
通过典型的方法可在各步骤中进行后处理,其中如有必要可通过如结晶、重结晶、蒸馏、萃取(partitioning)、硅胶层析、制备HPLC等收集或合并的常规方法进行分离和纯化。
制备方法1
其中Hal为卤原子,如氯原子、溴原子等,Rc1、Rc2、Rc3和Rc4相同或不同,各自为氢原子或以上定义的“C1-6烷基”,R3’为除氢原子外的R3,Rc5为离去基团如卤原子、间甲苯磺酰氧基、甲磺酰氧基、三氟甲磺酰氧基等,且其他符号如上定义。
步骤1
在溶剂中,优选在氮气气氛、冷却至室温下,通过化合物[1]与化合物[2]反应可得到化合物[3]。
作为溶剂,可提及的有醚溶剂(如1,4-二烷、乙醚、1,2-二甲氧基乙烷、四氢呋喃(THF)等);烃溶剂(如苯、甲苯、二甲苯、己烷等)等。
步骤2
在溶剂中,优选在氮气气氛、加热下,通过化合物[3]与化合物[4]反应可得到化合物[5]。
作为溶剂,可提及的有乙酸酐、乙酰氯、磷酰氯等。
步骤3
这里,Hal优选溴原子或氯原子。在溶剂(如三氟甲磺酸、乙酸、浓硫酸、N,N-二甲基甲酰胺(DMF)、水等)中、室温至加热下,通过化合物[5]与卤化剂(如磷酰氯、N-溴丁二酰亚胺、N-碘丁二酰亚胺等)反应可得到化合物[6]。
步骤4
在溶剂中,加热下,通过化合物[6]与化合物[7]反应可得到化合物[8]。
作为溶剂,可提及的有醇溶剂(如含水或无水甲醇、乙醇等);醚溶剂(如1,4-二烷、四氢呋喃(THF)等)等。
步骤5
在溶剂中,加热下,通过化合物[8]与化合物[9]反应可得到化合物[10]。
作为溶剂,可提及的有的醚溶剂(如二苯基醚等);乙酸酐,乙酰氯等。
步骤6
通过常规方法将离去基团引入化合物[10]中可得到化合物[11]。
例如,在溶剂中,如有必要在碱如三甲基胺盐酸盐、三乙基胺、吡啶等存在下,通过化合物[10]与甲磺酰氯、间甲苯磺酰氯、三氟甲磺酸酐等反应可得到化合物[11]。
作为溶剂,可提及的有乙腈;醚溶剂(如四氢呋喃等);卤素溶剂(如二氯甲烷等)等。
步骤7
在溶剂中,如有必要在加热下,通过化合物[11]与化合物[12]反应可得到化合物[I-1-1]。
作为溶剂,可提及的有N,N-二甲基乙酰胺、氯仿等。
为提高反应效率可加入2,6-二甲基吡啶。
制备方法1-1
其中各符号如上定义。
步骤1
采用与制备方法1,步骤1相同的方法,通过化合物[1]与化合物[13]反应可得到化合物[14]。
步骤2
采用与制备方法1,步骤2相同的方法,通过化合物[14]与化合物[4]反应可得到化合物[15]。
步骤3
采用与制备方法1,步骤3相同的方法,通过化合物[15]反应可得到化合物[16]。
步骤4
采用与制备方法1,步骤4相同的方法,通过化合物[16]与化合物[7]反应可得到化合物[17]。
步骤5
采用与制备方法1,步骤5相同的方法,通过化合物[17]与化合物[9]反应可得到化合物[18]。
步骤6
采用与制备方法1,步骤6相同的方法,通过化合物[18]反应可得到化合物[19]。
步骤7
通过常规的方法,如在中性或碱性条件下,使用锌或铁;铁和酸;锡或氯化锡(II)和浓盐酸;碱金属硫化物;碱金属亚硫酸氢盐等,或在氢气气氛下氢化等方法还原化合物[19]可得到化合物[20]。
例如,在冷却下,往化合物[19]中加入乙酸和锌粉,使其在室温下反应可得到化合物[20]。或者在氢气气氛下、THF和甲醇的混合溶剂中,往化合物[19]的溶液中加入钯-碳,使其在室温下反应可得到化合物[20]。
步骤8
采用与制备方法1,步骤7相同的方法,通过化合物[20]与化合物[12]反应可得到化合物[I-1-2]。
步骤9
在冷却下、溶剂中、碱(如三乙基胺、吡啶等)的存在下,通过化合物[20]与甲磺酰氯反应可得到化合物[21]。
作为溶剂,可提及的有乙腈;醚溶剂(如四氢呋喃等);卤素溶剂(如二氯甲烷等)等。
步骤10
采用与制备方法1,步骤7相同的方法,通过化合物[21]与化合物[12]反应可得到化合物[I-1-3]。
制备方法2
其中Rc6为氢原子或C1-4烷基,SRc7(Rc7为低级烷基如甲基、乙基等或苄基)为离去基团,并且其他符号如上定义。
步骤1
通过采用与制备方法1,步骤1至步骤4相同的方法得到的化合物[22]与化合物[23]反应可得到化合物[24]。
步骤2
通过常规方法将化合物[24]环化可得到化合物[25]。例如,室温、在溶剂(如N,N-二甲基甲酰胺等)中、三乙胺存在下,通过搅拌化合物[24]可得到化合物[25]。
步骤3
在碱存在下,通过化合物[25]与低级烷基卤化物或苄基卤化物反应可得到化合物[26]。
作为碱,可提及碳酸钾、碳酸钠、氢化锂、氢化钠、氢化钾等,优选碳酸钾。
作为低级烷基卤化物,可提及甲基碘、乙基碘、苄基碘等,优选甲基碘。
步骤4
采用与制备方法1,步骤7相同的方法,通过化合物[26]与化合物[12]反应可得到化合物[I-2]。
制备方法3
其中R4’为除氢原子外的R4,其他符号如上定义。
步骤1
采用与制备方法1,步骤1相同的方法,通过化合物[1]与化合物[27]反应可得到化合物[28]。
步骤2
采用与制备方法1,步骤2相同的方法,通过化合物[28]与化合物[4]反应可得到化合物[29]。
步骤3
采用与制备方法1,步骤3相同的方法,通过化合物[29]反应可得到化合物[30]。
步骤4
采用与制备方法1,步骤4相同的方法,通过化合物[30]与化合物[31]反应可得到化合物[32]。
步骤5
采用与制备方法1,步骤5相同的方法,通过化合物[32]与化合物[33]反应可得到化合物[34]。
步骤6
采用与制备方法1,步骤6相同的方法,通过化合物[34]反应可得到化合物[35]。
步骤7
采用与制备方法1,步骤7相同的方法,通过化合物[35]与化合物[36]反应可得到化合物[37]。
步骤8
在溶剂中,碱存在下、室温至回流下,通过搅拌化合物[37]可得到化合物[I-3-1]。
作为碱,可提及碳酸钾、碳酸钠、氢化锂、氢化钠、氢化钾、甲醇钠等,优选碳酸钾和甲醇钠。
作为溶剂,可提及的有醇溶剂(如甲醇、乙醇、正丙醇、异丙醇等);这些溶剂和酰胺溶剂(如N,N-二甲基甲酰胺、N,N-二甲基乙酰胺等)的混合物,卤素溶剂(如二氯甲烷、氯仿、四氯化碳、1,2-二氯乙烷等)或醚溶剂(如四氢呋喃(THF)等)等。
制备方法4-1
其中各符号如上定义。
步骤1
从冷却至室温下,在氮气或氩气气氛、溶剂中,叔胺如三乙胺等存在下,通过化合物[36]与羰基二咪唑反应,随后与化合物[1]反应可得到化合物[3]。
作为溶剂,可提及的有N,N-二甲基甲酰胺、氯仿、二氯甲烷、四氢呋喃等。
步骤2
通过常规的方法,优选在氮气气氛下,用化合物[38]将化合物[3]酰化可得到化合物[39]。
例如,当Rc1为氢,在溶剂(如N,N-二甲基甲酰胺、N,N-二甲基乙酰胺等中使用乙酸酐、乙酰氯、新戊酰氯、甲磺酰氯等,特别甲磺酰氯,化合物[38]可与化合物[3]缩合。
步骤3
在溶剂中,碱存在下、室温至加热下,通过化合物[39]反应可得到化合物[40]。
作为溶剂,可提及的有水、乙醇-水、四氢呋喃-水等,优选水。
作为碱,可提及碳酸钾、碳酸钠、氢氧化钾、氢氧化钠、氢化锂、氢化钠、氢化钾等,优选氢氧化钠。
步骤4
在N,N-二甲基甲酰胺溶剂中、优选在氮气气氛下,通过化合物[40]与N,N-二甲基甲酰胺缩二甲醇反应可得到化合物[41]。
步骤5
通过常规方法还原化合物[41]可得到化合物[42]。
例如,在醇溶剂(如甲醇、乙醇、异丙醇、叔丁醇等)或其混合溶剂中、氮气气氛下通过使用还原剂(如硼氢化钠、氰基硼氢化钠等)处理可得到化合物[42]。
步骤6
采用与制备方法1,步骤5相同的方法,通过化合物[42]与化合物[9]反应可得到化合物[43]。
步骤7
采用与制备方法1,步骤6相同的方法,通过化合物[43]反应可得到化合物[44]。
步骤8
采用与制备方法1,步骤7相同的方法,通过化合物[44]与化合物[12]反应可得到化合物[I-1-4]。
制备方法4-2
其中各符号如上定义。
步骤1
采用与制备方法4-1,步骤1相同的方法,通过化合物[45]与化合物[1]反应可得到化合物[28]。
步骤2
采用与制备方法4-1,步骤2相同的方法,通过化合物[28]与化合物[38]反应可得到化合物[46]。
步骤3
采用与制备方法4-1,步骤3相同的方法,通过化合物[46]反应可得到化合物[47]。
步骤4
采用与制备方法4-1,步骤4相同的方法,通过化合物[47]反应可得到化合物[48]。
步骤5
采用与制备方法4-1,步骤5相同的方法,通过化合物[48]反应可得到化合物[49]。
步骤6
采用与制备方法1,步骤5相同的方法,通过化合物[49]与化合物[33]反应可得到化合物[50]。
步骤7
采用与制备方法1,步骤6相同的方法,通过化合物[50]反应可得到化合物[51]。
步骤8
采用与制备方法1,步骤7相同的方法,通过化合物[51]与化合物[36]反应可得到化合物[52]。
步骤9
采用与制备方法3,步骤8相同的方法,通过化合物[52]反应可得到化合物[I-3-2]。
制备方法4-3
其中Rc7为卤原子(如溴原子、氯原子等)或羟基并且其他符号如上定义。
步骤1
在溶剂中,叔胺如三乙胺等存在下、氮气或氩气气氛下,冷却至室温下,通过化合物[45]与羰基二咪唑反应,随后与氨反应可得到化合物[53]。
作为溶剂,可提及的有N,N-二甲基甲酰胺、氯仿、二氯甲烷、四氢呋喃等。
步骤2
采用与制备方法4-1,步骤2相同的方法,通过化合物[53]与化合物[38]反应可得到化合物[54]。
步骤3
采用与制备方法4-1,步骤3相同的方法,通过化合物[54]反应可得到化合物[55]。
步骤4
采用与制备方法4-1,步骤4相同的方法,通过化合物[55]反应可得到化合物[56]。
步骤5
通过常规的方法在化合物[56]中引入保护基团可得到化合物[57]。
步骤6
采用与制备方法4-1,步骤5相同的方法,通过化合物[57]反应可得到化合物[58]。
步骤7
采用与制备方法1,步骤5相同的方法,通过化合物[58]与化合物[33]反应可得到化合物[59]。
步骤8
采用与制备方法1,步骤6相同的方法,通过化合物[59]反应可得到化合物[60]。
步骤9
采用与制备方法1,步骤7相同的方法,通过化合物[60]与化合物[36]反应可得到化合物[61]。
步骤10
采用与制备方法3,步骤8相同的方法,通过化合物[61]反应可得到化合物[62]。
步骤11
通过常规的方法将化合物[62]去保护可得到化合物[63]。
步骤12
通过常规的方法将化合物[63]与化合物[64]反应可得到化合物[I-3-3]。
例如,当Rc7为羟基,在溶剂(如N,N-二甲基甲酰胺、乙腈、四氢呋喃等)中、氮气或氩气气氛下,根据Mitsunobu反应使化合物[63]与缩合剂(如偶氮二甲酸二乙酯、偶氮二甲酸二异丙酯等和三苯基膦)反应。
实施例
实施例1-1
合成N-{3-[5-(4-溴-2-氟-苯基氨基)-3-环丙基-8-甲基-2,4,7-三氧代-3,4,7,8-四氢-2H-吡啶并[2,3-d]嘧啶-1-基]苯基}-甲磺酰胺
步骤1合成1-环丙基-3-(硝基苯基)脲
往环丙胺1(9g)的四氢呋喃(250ml)溶液中分批加入异氰酸3-硝基苯酯2(25g),随后在室温下搅拌混合物1小时。从反应混合物中沉淀的固体经抽滤,用乙酸乙酯洗涤,并干燥,得到黄色固体状的1-环丙基-3-(硝基苯基)脲3(33g,99%)。
步骤2合成1-环丙基-3-(3-硝基苯基)嘧啶-2,4,6-三酮
往步骤1中得到的1-环丙基-3-(硝基苯基)脲3(33g)中加入乙酸酐(99ml)和丙二酸4(17g),随后在110℃下将混合物加热搅拌4小时。减压浓缩反应混合物。往残余物中加入氯仿,随后在室温搅拌混合物10分钟。抽滤不溶于氯仿的物质并干燥,得到棕色固体状的1-环丙基-3-(3-硝基苯基)嘧啶-2,4,6-三酮5(28g,65%)。
步骤3合成6-氯-3-环丙基-1-(3-硝基苯基)-1H-嘧啶-2,4-二酮
往步骤2中得到的1-环丙基-3-(3-硝基苯基)嘧啶-2,4,6-三酮5(28g)中加入水(3ml),搅拌下分批滴加磷酰氯(72ml),随后在110℃加热搅拌混合物1小时。将反应混合物分批倾入冰水中,并抽滤沉淀的固体。将滤饼溶解在氯仿(300ml)中,用水(30ml)和盐水(30ml)洗涤,随后有机层经无水硫酸镁干燥,并减压浓缩。残余物经过柱层析纯化(氯仿∶丙酮=9∶1),得到白色固体状的6-氯-3-环丙基-1-(3-硝基苯基)-1H-嘧啶-2,4-二酮6与4-氯-3-环丙基-1-(3-硝基苯基)-1H-嘧啶-2,6-二酮7为2∶1的混合物(10g,34%)。
步骤4合成3-环丙基-6-甲基氨基-1-(3-硝基苯基)-1H-嘧啶-2,4-二酮
往步骤3中得到的6-氯-3-环丙基-1-(3-硝基苯基)-1H-嘧啶-2,4-二酮6和4-氯-3-环丙基-1-(3-硝基苯基)-1H-嘧啶-2,6-二酮7的混合物(30g)中加入乙醇(300ml)和40%甲胺的甲醇溶液(150ml),随后在80℃加热搅拌混合物4.5小时,冰冷却并抽滤沉淀的固体。用水(1升)洗涤残余物并干燥,得到白色固体状的3-环丙基-6-甲基氨基-1-(3-硝基苯基)-1H-嘧啶-2,4-二酮8(16g,55%)。
步骤5合成3-环丙基-5-羟基-8-甲基-1-(3-硝基苯基)-1H,8H-吡啶并[2,3-d]嘧啶-2,4,7-三酮
往步骤4中得到的3-环丙基-6-甲基氨基-1-(3-硝基苯基)-1H-嘧啶-2,4-二酮8(16g)中加入二苯基醚(160ml)和丙二酸二乙酯9(40ml),随后在230℃下将混合物加热搅拌11小时同时蒸发产生的乙醇。经柱层析纯化反应混合物(氯仿→氯仿∶丙酮=9∶1),得到褐色泡沫油状的3-环丙基-5-羟基-8-甲基-1-(3-硝基苯基)-1H,8H-吡啶并[2,3-d]嘧啶-2,4,7-三酮10(10g,51%)。
步骤6合成甲苯-4-磺酸3-环丙基-8-甲基-1-(3-硝基苯基)-2,4,7-三氧代-1,2,3,4,7,8-六氢吡啶并[2,3-d]嘧啶-5-基酯
往步骤5中得到的3-环丙基-5-羟基-8-甲基-1-(3-硝基苯基)-1H,8H-吡啶并[2,3-d]嘧啶-2,4,7-三酮10(18g)中加入乙腈(180ml)、甲苯磺酰氯11(11g)和三乙胺(8ml),随后在110℃加热回流搅拌混合物1小时。减压浓缩反应混合物。往残余物中加入水(100ml)随后用氯仿(800ml)萃取混合物。用盐水(50ml)洗涤有机层,经无水硫酸镁干燥,并减压浓缩。将残余物在氯仿∶乙醚=1∶5中重结晶,得到白色固体状的甲苯-4-磺酸3-环丙基-8-甲基-1-(3-硝基苯基)-2,4,7-三氧代-1,2,3,4,7,8-六氢-吡啶并[2,3-d]嘧啶-5-基酯12(21g,82%)。
步骤7合成甲苯-4-磺酸1-(3-氨基苯基)-3-环丙基-8-甲基-2,4,7-三氧代-1,2,3,4,7,8-六氢-吡啶并[2,3-d]嘧啶-5-基酯
往步骤6中得到的甲苯-4-磺酸3-环丙基-8-甲基-1-(3-硝基苯基)-2,4,7-三氧代-1,2,3,4,7,8-六氢-吡啶并[2,3-d]嘧啶-5-基酯12(21g)的四氢呋喃悬浮液中加入二水合氯化亚锡(45g),随后在室温搅拌混合物4小时。用饱和碳酸氢钠水溶液碱化反应混合物,抽滤滤除不能溶解的无机产物(使用Celite硅藻土辅助过滤),并用乙酸乙酯萃取滤液。用盐水洗涤有机层,经无水硫酸镁干燥并减压浓缩。残余物经过柱层析纯化(氯仿∶丙酮=9∶1),得到白色固体状的甲苯-4-磺酸1-(3-氨基苯基)-3-环丙基-8-甲基-2,4,7-三氧代-1,2,3,4,7,8-六氢-吡啶并[2,3-d]嘧啶-5-基酯13(15g,74%)。
步骤8合成甲苯-4-磺酸3-环丙基-1-(3-甲磺酰基氨基苯基)-8-甲基-2,4,7-三氧代-1,2,3,4,7,8-六氢-吡啶并[2,3-d]嘧啶-5-基酯
往步骤7中得到的甲苯-4-磺酸1-(3-氨基苯基)-3-环丙基-8-甲基-2,4,7-三氧代-1,2,3,4,7,8-六氢-吡啶并[2,3-d]嘧啶-5-基酯13(5g)中加入吡啶(40ml),在冰冷却并搅拌下滴加甲磺酰氯14(0.9ml)的氯仿(10ml)溶液并在冰浴中搅拌混合物3小时。减压浓缩反应混合物,加入2N盐酸,随后用氯仿萃取混合物。用盐水洗涤有机层,经无水硫酸镁干燥并减压浓缩。将得到的固体悬浮在乙醚和己烷的混合物(乙醚∶己烷=1∶1)中,随后进行抽滤,得到白色固体状的甲苯-4-磺酸3-环丙基-1-(3-甲磺酰基氨基苯基)-8-甲基-2,4,7-三氧代-1,2,3,4,7,8-六氢-吡啶并[2,3-d]嘧啶-5-基酯15(5.5g,95%)。
步骤9合成N-{3-[5-(4-溴-2-氟-苯基氨基)-3-环丙基-8-甲基-2,4,7-三氧代-3,4,7,8-四氢-2H-吡啶并[2,3-d]嘧啶-1-基]苯基}-甲磺酰胺
往步骤8中得到的甲苯-4-磺酸3-环丙基-1-(3-甲磺酰基氨基苯基)-8-甲基-2,4,7-三氧代-1,2,3,4,7,8-六氢吡啶并[2,3-d]嘧啶-5-基酯15(3.5g)中加入2-氟-4-溴苯胺16(23g),随后在135℃下将混合物加热搅拌3小时。经柱层析纯化反应混合物(氯仿∶丙酮=9∶1),得到白色固体状的N-{3-[5-(4-溴-2-氟-苯基氨基)-3-环丙基-8-甲基-2,4,7-三氧代-3,4,7,8-四氢-2H-吡啶并[2,3-d]嘧啶-1-基]苯基}-甲磺酰胺17(3.0g,83%)。
MS ESI m/e:590,592(M+H),588,590(M-H)。
1H-NMR(DMSO-d6,300MHz)δ0.71-0.79(m,2H),0.99-1.08(m,2H),2.66(s,1H),3.02(s,1H),5.36(s,1H),7.13(d,J=9.0Hz,1H),7.24-7.30(m,2H),7.43-7.54(m,3H),7.74(d,J=9.0Hz,1H),10.00(brs,1H),10.53(brs,1H)。
实施例1-2至1-343
采用与实施例1-1相同的方法,得到实施例1-2至1-343的化合物。其与实施例1-1的结构式见表1-1至1-58。
表1-1
表1-2
表1-3
表1-4
表1-5
表1-6
表1-7
表1-8
表1-9
表1-10
表1-11
表1-12
表1-13
表1-14
表1-15
表1-16
表1-17
表1-18
表1-19
表1-20
表1-21
表1-22
表1-23
表1-24
表1-25
表1-26
表1-27
表1-28
表1-29
表1-30
表1-31
表1-32
表1-33
表1-34
表1-35
表1-36
表1-37
表1-38
表1-39
表1-40
表1-41
表1-42
表1-43
表1-44
表1-45
表1-46
表1-47
表1-48
表1-49
表1-50
表1-51
表1-52
表1-53
表1-54
表1-55
表1-56
表1-57
表1-58
实施例2-1
合成5-(4-氯-苯基氨基)-8-甲基-1,3-二苯基-1H,8H-嘧啶并[4,5-d]嘧啶-2,4,7-三酮
步骤1合成1,3-二苯基-嘧啶-2,4,6-三酮
将乙酸酐(290ml)加入1,3-二苯基脲18(148g)中,在氮气气氛下加入丙二酸4(81.6g),随后在90℃下搅拌混合物3小时。混合物在100℃下搅拌1.5小时并让其冷却至室温。减压浓缩反应混合物。往残余物中加入乙醇(500ml),随后在90℃下搅拌混合物。当将混合物冷却至40℃时,过滤收集结晶,用乙醇洗涤并干燥,得到1,3-二苯基-嘧啶-2,4,6-三酮19(78.0g,产率40%)。
步骤2合成6-氯-1,3-二苯基-1H-嘧啶-2,4-二酮
往步骤1中得到的1,3-二苯基-嘧啶-2,4,6-三酮19(78.0g)中加入水(16ml)。在室温并搅拌下,50分钟内滴加磷酰氯(422ml)。滴加完毕后,在110℃下将混合物加热搅拌3小时。让其冷却至室温后,将反应混合物分批加入冰水中,随后在室温下搅拌混合物并用乙酸乙酯萃取。用盐水和饱和碳酸氢钠水溶液洗涤有机层,随后经无水硫酸钠干燥。滤除无水硫酸钠,随后将滤液减压浓缩。残余物经过柱层析纯化(己烷∶乙酸乙酯=2∶1→3∶2),得到浅黄色晶体状的6-氯-1,3-二苯基-1H-嘧啶-2,4-二酮20(61.5g,产率74%)。
步骤3合成6-甲基氨基-1,3-二苯基-1H-嘧啶-2,4-二酮
采用与实施例1-1步骤4相同的方法并使用步骤2中得到的6-氯-1,3-二苯基-1H-嘧啶-2,4-二酮20(5.0g)、乙醇(25ml)、40%甲胺的甲醇溶液(21.7ml),得到无色晶体状的6-甲基氨基-1,3-二苯基-1H-嘧啶-2,4-二酮21(4.42g,产率90%)。
步骤4合成(6-甲基氨基-2,4-二氧代-1,3-二苯基-1,2,3,4-四氢-嘧啶-5-硫代羰基)-氨基甲酸乙酯
往步骤3中得到的6-甲基氨基-1,3-二苯基-1H-嘧啶-2,4-二酮21(1.18g)中加入N,N-二甲基甲酰胺(5.9ml),在氮气气氛下加入异硫氰酸基甲酸乙酯22(0.52ml),随后在室温下搅拌混合物1小时。往反应混合物中加入水(30ml),随后过滤收集晶体并用水洗涤,得到粗制的浅黄色晶体状的(6-甲基氨基-2,4-二氧代-1,3-二苯基-1,2,3,4-四氢-嘧啶-5-硫代羰基)-氨基甲酸乙酯23(1.68g),该化合物无需纯化即可用于下一步骤。
步骤5合成5-巯基-8-甲基-1,3-二苯基-1H,8H-嘧啶并[4,5-d]嘧啶-2,4,7-三酮
往步骤4中得到的粗制的(6-甲基氨基-2,4-二氧代-1,3-二苯基-1,2,3,4-四氢-嘧啶-5-硫代羰基)-氨基甲酸乙酯23(1.58g)中加入N,N-二甲基甲酰胺(84ml),在氮气气氛下加入三乙胺(0.63ml),随后在室温下搅拌混合物30分钟。加入水(25ml),搅拌混合物,加入1N盐酸(5.0ml),随后在室温下搅拌混合物1小时。过滤收集结晶,用水洗涤并干燥,得到粗制的黄色晶体状的5-巯基-8-甲基-1,3-二苯基-1H,8H-嘧啶并[4,5-d]嘧啶-2,4,7-三酮24(1.53g,过夜),该化合物无需纯化即可用于下一步骤。
步骤6合成8-甲基-5-甲硫基-1,3-二苯基-1H,8H-嘧啶并[4,5-d]嘧啶-2,4,7-三酮
往步骤5中得到的粗制的5-巯基-8-甲基-1,3-二苯基-1H,8H-嘧啶并[4,5-d]嘧啶-2,4,7-三酮24(100mg)中加入N,N-二甲基甲酰胺(0.5ml)。在氮气气氛下,依次加入碳酸钾(44mg)和碘甲烷25(20μl),随后在室温下搅拌混合物3小时。加入水,随后用氯仿萃取混合物。用水和盐水洗涤有机层,随后经无水硫酸钠干燥。滤除无水硫酸钠,随后将滤液减压浓缩。残余物经过柱层析纯化(己烷∶乙酸乙酯=4∶1→3∶1),得到棕色晶体状的8-甲基-5-甲硫基-1,3-二苯基-1H,8H-嘧啶并[4,5-d]嘧啶-2,4,7-三酮26(91mg,产率89%)。
步骤7合成5-(4-氯-苯基氨基)-8-甲基-1,3-二苯基-1H,8H-嘧啶并[4,5-d]嘧啶-2,4,7-三酮
往步骤6中得到的8-甲基-5-甲硫基-1,3-二苯基-1H,8H-嘧啶并[4,5-d]嘧啶-2,4,7-三酮26(149mg)中加入甲苯(2ml),加入4-氯苯胺27(97mg),随后将混合物搅拌回流3.5小时。让其冷却至室温后,加入乙醚。过滤收集结晶,用乙醚洗涤并干燥,得到无色晶体状的5-(4-氯-苯基氨基)-8-甲基-1,3-二苯基-1H,8H-嘧啶并[4,5-d]嘧啶-2,4,7-三酮28(94mg,产率53%)。
MS ESI m/e:472(M+H),470(M-H)。
1H-NMR(DMSO-d6,400MHz)δ2.68(s,3H),7.34-7.39(m,2H),7.41-7.61(m,10H),7.80-7.87(m,2H),11.34(s,1H)。
实施例2-2
采用与实施例2-1相同的方法,得到实施例2-2的化合物。其与实施例2-1的结构式见表2-1。表2-1
实施例3-1
合成5-(4-溴-苯基氨基)-3-环丙基-6,8-二甲基-1-苯基氨基-1H,6H-吡啶并[4,3-d]嘧啶-2,4,7-三酮
步骤1合成1-(4-溴-苯基)-3-环丙基-脲
在氮气气氛下,将四氢呋喃(80ml)加入4-溴苯基异氰酸酯30(10.0g),在冰冷却并搅拌下滴加环丙基胺1(3.17g)的四氢呋喃溶液(20ml)。滴加完毕后,在室温下搅拌混合物3小时,减压浓缩反应混合物。往残余物中加入乙醚-己烷[1∶1(体积比),100ml],搅拌后,过滤收集晶体并干燥,得到无色晶体状的1-(4-溴-苯基)-3-环丙基-脲31(12.9g,过夜),该化合物无需纯化即可用于下一步骤。
步骤2合成1-(4-溴-苯基)-3-环丙基-嘧啶-2,4,6-三酮
往步骤1中得到的1-(4-溴-苯基)-3-环丙基-脲31(12.9g)中加入乙酸酐(25.8ml),在氮气气氛下加入丙二酸4(5.79g),随后在100℃下将混合物搅拌3小时。让其冷却至室温后,减压浓缩反应混合物。
往残余物中加入乙醚-乙醇[4∶1(体积比),100ml],搅拌后,过滤收集晶体并干燥,得到浅黄色晶体状的1-(4-溴-苯基)-3-环丙基-嘧啶-2,4,6-三酮32(11.9g,产率73%)。
步骤3合成1-(4-溴-苯基)-6-氯-3-环丙基-1H-嘧啶-2,4-二酮
往步骤2中得到的1-(4-溴-苯基)-3-环丙基-嘧啶-2,4,6-三酮32(11.8g)中加入水(1.31ml),随后在室温并搅拌下滴加磷酰氯(17.0ml)。滴加完毕后,在110℃下搅拌混合物3小时。让其冷却至室温后,将反应混合物分批加入冰水中,随后搅拌混合物。在室温下搅拌混合物并用氯仿萃取。用盐水洗涤有机层,经无水硫酸镁干燥。滤除无水硫酸镁,随后将滤液减压浓缩。残余物经过柱层析纯化(己烷∶乙酸乙酯=2∶1→氯仿∶丙酮=30∶1),得到浅黄色泡沫油状的1-(4-溴-苯基)-6-氯-3-环丙基-1H-嘧啶-2,4-二酮33与3-(4-溴-苯基)-6-氯-1-环丙基-1H-嘧啶-2,4-二酮34为1∶1.4的混合物(11.6g,产率93%)。
步骤4合成1-(4-溴-苯基)-3-环丙基-6-甲基氨基-1H-嘧啶-2,4-二酮
采用与合成化合物8相同的方法并使用步骤3中得到的1-(4-溴-苯基)-6-氯-3-环丙基-1H-嘧啶-2,4-二酮33与3-(4-溴-苯基)-6-氯-1-环丙基-1H-嘧啶-2,4-二酮34为1∶1.4的混合物(7.00g)、乙醇(20.9ml)和40%甲胺的甲醇溶液(10.5ml),得到无色晶体状的1-(4-溴-苯基)-3-环丙基-6-甲基氨基-1H-嘧啶-2,4-二酮35与3-(4-溴-苯基)-1-环丙基-6-甲基氨基-1H-嘧啶-2,4-二酮36为1∶1.3的混合物(5.34g,产率78%)。
步骤5合成1-(4-溴-苯基)-3-环丙基-5-羟基-6,8-二甲基-1H,8H-吡啶并[2,3-d]嘧啶-2,4,7-三酮
采用与实施例1-1的步骤5相同的方法并使用步骤4中得到的1-(4-溴-苯基)-3-环丙基-6-甲基氨基-1H-嘧啶-2,4-二酮35与3-(4-溴-苯基)-1-环丙基-6-甲基氨基-1H-嘧啶-2,4-二酮36为1∶1.3的混合物(1.00g)、2-甲基丙二酸二乙酯37(2.56ml)和二苯醚(1.49g),得到浅黄色晶体状的1-(4-溴-苯基)-3-环丙基-5-羟基-6,8-二甲基-1H,8H-吡啶并[2,3-d]嘧啶-2,4,7-三酮38(0.40g,产率32%)。
步骤6合成甲苯-4-磺酸1-(4-溴-苯基)-3-环丙基-6,8-二甲基-2,4,7-三氧代-1,2,3,4,7,8-六氢-吡啶并[2,3-d]嘧啶-5-基酯
往步骤5中得到的1-(4-溴-苯基)-3-环丙基-5-羟基-6,8-二甲基-1H,8H-吡啶并[2,3-d]嘧啶-2,4,7-三酮38(400mg)中加入乙腈(8.0ml),在氮气气氛下加入甲苯磺酰氯11(458mg)和三乙胺(0.34ml),随后将混合物搅拌回流30小时。让其冷却至室温后,减压浓缩混合物。残余物经过柱层析纯化(氯仿∶丙酮=25∶1→20∶1),得到黄褐色晶体状的甲苯-4-磺酸1-(4-溴-苯基)-3-环丙基-6,8-二甲基-2,4,7-三氧代-1,2,3,4,7,8-六氢-吡啶并[2,3-d]嘧啶-5-基酯39(407mg,产率74%)。步骤7合成1-(4-溴-苯基)-3-环丙基-6,8-二甲基-5-苯基氨基-1H,8H-吡啶并[2,3-d]嘧啶-2,4,7-三酮
往步骤6中得到的甲苯-4-磺酸1-(4-溴-苯基)-3-环丙基-6,8-二甲基-2,4,7-三氧代-1,2,3,4,7,8-六氢-吡啶并[2,3-d]嘧啶-5-基酯39(100mg)中加入苯胺40(0.64ml),随后在150℃下搅拌混合物2.5小时。让其冷却至室温后,往反应混合物中加入乙醚-己烷[1∶1(体积比),30ml],随后过滤收集晶体。得到的晶体经柱层析纯化(氯仿∶丙酮=15∶1),得到浅黄色晶体状的1-(4-溴-苯基)-3-环丙基-6,8-二甲基-5-苯基氨基-1H,8H-吡啶并[2,3-d]嘧啶-2,4,7-三酮41(81mg,产率93%)。
步骤8合成5-(4-溴-苯基氨基)-3-环丙基-6,8-二甲基-1-苯基氨基-1H,6H-吡啶并[4,3-d]嘧啶-2,4,7-三酮
往步骤7中得到的1-(4-溴-苯基)-3-环丙基-6,8-二甲基-5-苯基氨基-1H,8H-吡啶并[2,3-d]嘧啶-2,4,7-三酮41(78mg)中加入氯仿-甲醇[1∶1(体积比),2.0ml],加入碳酸钾(22mg),随后在室温下搅拌混合物10小时。再将混合物搅拌回流3小时,并让其冷却至室温。减压浓缩混合物并经柱层析纯化(氯仿∶丙酮=50∶1),得到无色晶体状的5-(4-溴-苯基氨基)-3-环丙基-6,8-二甲基-1-苯基氨基-1H,6H-吡啶并[4,3-d]嘧啶-2,4,7-三酮42(23mg,产率26%)。
MS ESI m/e:493,495(M+H),491,493(M-H)。
1H-NMR(CDCl3,400MHz)δ0.77-0.82(m,2H),1.09-1.15(m,2H),1.36(s,3H),2.72-2.74(m,1H),3.20(s,3H),6.86(d,2H),7.28-7.32(m,2H),7.34-7.51(m,5H),11.36(s,1H)。
实施例3-7
合成N-{3-[3-环丙基-5-(2-氟-4-碘苯基氨基)-6,8-二甲基-2,4,7-三氧代-3,4,6,7-四氢-2H-吡啶并[4,3-d]嘧啶-1-基]苯基}甲磺酰胺
步骤1合成N-{3-[3-环丙基-1-(2-氟-4-碘苯基)-6,8-二甲基-2,4,7-三氧代-1,2,3,4,7,8-六氢-吡啶并[2,3-d]嘧啶-5-基氨基]苯基}甲磺酰胺
往采用与下文中实施例4-2,步骤6所述相同的方法得到的三氟甲磺酸3-环丙基-1-(2-氟-4-碘苯基)-6,8-二甲基-2,4,7-三氧代-1,2,3,4,7,8-六氢-吡啶并[2,3-d]嘧啶-5-基酯43(30.0g)和N-(3-氨基苯基)甲磺酰胺44(10.9g)中加入N,N-二甲基乙酰胺(60.0ml)和2,6-二甲基吡啶(6.82ml),随后在130℃下搅拌混合物3.5小时。让其冷却至室温后,在搅拌下加入甲醇(60ml)并搅拌混合物2小时。过滤收集晶体并干燥,得到无色晶体状的N-{3-[3-环丙基-1-(2-氟-4-碘苯基)-6,8-二甲基-2,4,7-三氧代-1,2,3,4,7,8-六氢-吡啶并[2,3-d]嘧啶-5-基氨基]苯基}甲磺酰胺45(30.5g,产率96%)。
步骤2合成N-{3-[3-环丙基-5-(2-氟-4-碘苯基氨基)-6,8-二甲基-2,4,7-三氧代-3,4,6,7-四氢-2H-吡啶并[4,3-d]嘧啶-1-基]苯基}甲磺酰胺
在氮气气氛下,往步骤1中得到的28%甲醇钠的甲醇溶液(18.5g)中加入四氢呋喃(284ml)、N-{3-[3-环丙基-1-(2-氟-4-碘苯基)-6,8-二甲基-2,4,7-三氧代-1,2,3,4,7,8-六氢-吡啶并[2,3-d]嘧啶-5-基氨基]苯基}甲磺酰胺45(28.4g),随后在室温下搅拌混合物1小时。加入乙酸(12.5ml),随后在室温下搅拌混合物1小时并减压浓缩。往得到的固体中加入1-丁醇与水为9∶1的混合溶剂(426mL),随后在回流下加热搅拌混合物3小时。让混合物回到室温并搅拌过夜,随后过滤收集晶体并干燥。再次往得到的晶体中加入1-丁醇与水为9∶1的混合溶剂(426mL),随后在回流下加热搅拌混合物3小时。让混合物回到室温并搅拌过夜。过滤收集晶体,并用甲醇与水为9∶1的混合溶剂洗涤并干燥,得到白色晶体状的N-{3-[3-环丙基-5-(2-氟-4-碘苯基氨基)-6,8-二甲基-2,4,7-三氧代-3,4,6,7-四氢-2H-吡啶并[4,3-d]嘧啶-1-基]苯基}甲磺酰胺46(26.35g,产率93%)。
MS ESI m/e:652(M+H),650(M-H)。
1H-NMR(DMSO-d6,300MHz)δ0.62-0.72(m,2H),0.91-1.01(m,2H),1.25(s,3H),2.57-2.67(m,1H),3.01(s,3H),3.08(s,3H),6.92(t,J=9.0Hz,1H),7.09-7.14(m,1H),7.20-7.26(m,2H),7.37-7.45(m,1H),7.52-7.58(m,1H),7.79(dd,J=1.8,9.0Hz,1H),9.89(s,1H),11.08(s,1H)。
实施例3-2至3-6、3-8和3-9
采用与实施例3-1和3-7相同的方法,得到实施例3-2至3-6、3-8和3-9的化合物。其与实施例3-1和3-7的结构式见表3-1至3-2。
表3-1
表3-2
实施例3-10
按照常规方法处理N-{3-[3-环丙基-5-(2-氟-4-碘苯基氨基)-6,8-二甲基-2,4,7-三氧代-3,4,6,7-四氢-2H-吡啶并[4,3-d]嘧啶-1-基]苯基}甲磺酰胺46,得到其钠盐和钾盐。
N-{3-[3-环丙基-5-(2-氟-4-碘苯基氨基)-6,8-二甲基-2,4,7-三氧代-3,4,6,7-四氢-2H-吡啶并[4,3-d]嘧啶-1-基]苯基}甲磺酰胺钠盐:
1H-NMR(DMSO-d6,300MHz)δ0.47(brs,2H),0.70-0.90(m,2H),1.23(s,3H),2.35(brs,1H),2.82(s,3H),3.22(s,3H),6.69(t,J=8.8Hz,1H),6.81(d,J=8.1Hz,1H),6.98(s,1H),7.02(d,J=8.8Hz,1H),7.10-7.30(m,2H),7.38(d,J=9.2Hz,1H),10.22(brs,1H)。
MS(ESI)m/z 652[MH]+。
N-{3-[3-环丙基-5-(2-氟-4-碘苯基氨基)-6,8-二甲基-2,4,7-三氧代-3,4,6,7-四氢-2H-吡啶并[4,3-d]嘧啶-1-基]苯基}甲磺酰胺钾盐:
实施例4-1
N-{3-[3-环丙基-5-(2-氟-4-碘苯基氨基)-6,8-二甲基-2,4,7-三氧代-3,4,6,7-四氢-2H-吡啶并[4,3-d]嘧啶-1-基]-苯基}-乙酰胺
步骤1合成1-环丙基-3-(2-氟-4-碘-苯基)脲
在氮气气氛下,往N,N-羰基二咪唑(39.9g)中加入N,N-二甲基甲酰胺(200ml)和三乙胺(34.3ml),随后在冰冷却并搅拌下滴加2-氟-4-碘苯胺47(48.5g)的N,N-二甲基甲酰胺溶液(50ml)。滴加完毕后,在室温下搅拌混合物18小时。用冰冷却反应混合物,随后滴加环丙胺(21.3ml)。在室温下搅拌反应混合物1小时,随后在搅拌下滴加至水-甲苯[2∶1(体积比),750ml]中。过滤收集沉淀的晶体并干燥,得到无色晶体状的1-环丙基-3-(2-氟-4-碘苯基)脲48(61.3g,产率93.4%)。
步骤2合成1-环丙基-3-(2-氟-4-碘苯基)嘧啶-2,4,6-三酮
往步骤1中得到的1-环丙基-3-(2-氟-4-碘苯基)脲48(61.0g)和丙二酸4(19.9g)中加入乙酸酐(300ml)和乙酰氯(27.2ml),随后在60℃和氮气气氛下搅拌混合物3小时。让反应混合物冷却至室温后,在搅拌下将其滴加至水-甲苯[2∶1(体积比),900ml]中。过滤收集沉淀的晶体并干燥,得到浅黄色晶体状的1-环丙基-3-(2-氟-4-碘苯基)嘧啶-2,4,6-三酮49(60.9g,产率82%)。
步骤3合成6-氯-3-环丙基-1-(2-氟-4-碘苯基)-1H-嘧啶-2,4-二酮
往步骤2中得到的1-环丙基-3-(2-氟-4-碘苯基)-嘧啶-2,4,6-三酮49(59.0g)中加入磷酰氯(85.0ml)和二甲基苯胺(29.0ml),随后在室温并搅拌下往混合中物滴加水(8.3ml)。滴加完毕后,将在110℃下加热搅拌混合物1小时。让反应混合物冷却至室温后,在搅拌下将反应混合物滴加至冰水-甲苯[2∶1(体积比),900ml]中。在室温下搅拌混合物1小时。分离有机层并依次用水(300ml)和盐水(300ml)洗涤。加入无水硫酸镁和活性炭,随后搅拌混合物。滤除无水硫酸镁和活性炭,并减压浓缩滤液,得到黄色泡沫油状的6-氯-3-环丙基-1-(2-氟-4-碘苯基)-1H-嘧啶-2,4-二酮50和6-氯-1-环丙基-3-(2-氟-4-碘苯基)-1H-嘧啶-2,4-二酮51为1∶2的混合物(62.9g),该混合物无需纯化即可用于下一步骤。
步骤4合成3-环丙基-1-(2-氟-4-碘苯基)-6-甲基氨基-1H-嘧啶-2,4-二酮
往步骤3中得到的6-氯-3-环丙基-1-(2-氟-4-碘苯基)-1H-嘧啶-2,4-二酮50和6-氯-1-环丙基-3-(2-氟-4-碘苯基)-1H-嘧啶-2,4-二酮51为1∶2的混合物(62.9g)中加入甲醇(189ml)和40%甲胺的甲醇溶液(126ml)。随后在室温下搅拌混合物2小时。滤除沉淀的晶体,随后将滤液减压浓缩。残余物用氯仿(200ml)和水(200ml)萃取,用盐水(200ml)洗涤有机层,经无水硫酸镁干燥。滤除无水硫酸镁,减压浓缩滤液,得到黄色晶体状的3-环丙基-1-(2-氟-4-碘苯基)-6-甲基氨基-1H-嘧啶-2,4-二酮52和1-环丙基-3-(2-氟-4-碘苯基)-6-甲基氨基-1H-嘧啶-2,4-二酮53为2∶1的混合物(34.55g),该化合物无需纯化即可用于下一步骤。
步骤5合成3-环丙基-1-(2-氟-4-碘苯基)-5-羟基-6,8-二甲基-1H,8H-吡啶并[2,3-d]嘧啶-2,4,7-三酮
往步骤4中得到的3-环丙基-1-(2-氟-4-碘苯基)-6-甲基氨基-1H-嘧啶-2,4-二酮52和1-环丙基-3-(2-氟-4-碘-苯基)-6-甲基氨基-1H-嘧啶-2,4-二酮53为2∶1的混合物(34.6g)和2-甲基丙二酸54(10.2g)中加入乙酸酐(173ml),随后在100℃下搅拌混合物2小时。让其冷却至室温后,减压浓缩反应混合物。往残余物中加入丙酮(104ml),随后在加热回流下搅拌混合物30分钟。让其冷却至室温后,过滤收集沉淀的晶体并干燥,得到无色晶体状的3-环丙基-1-(2-氟-4-碘苯基)-5-羟基-6,8-二甲基-1H,8H-吡啶并[2,3-d]嘧啶-2,4,7-三酮55(15.1g,产率以48计算,21%)。
步骤6合成三氟甲磺酸3-环丙基-1-(2-氟-4-碘苯基)-6,8-二甲基-2,4,7-三氧代-1,2,3,4,7,8-六氢-吡啶并[2,3-d]嘧啶-5-基酯
在氮气气氛下,往步骤5中得到的3-环丙基-1-(2-氟-4-碘苯基)-5-羟基-6,8-二甲基-1H,8H-吡啶并[2,3-d]嘧啶-2,4,7-三酮55(33.0g)中加入氯仿(165ml)和2,6-二甲基吡啶(10.4ml),随后在冰浴冷却并搅拌下滴加三氟甲磺酸酐56(14.4ml)。滴加完毕后,在相同的温度下将混合物搅拌30分钟,随后在室温下搅拌2小时。依次用碳酸氢钠水溶液(165ml)、1N盐酸(165ml)和盐水(165ml)洗涤,随后经无水硫酸镁干燥。滤除无水硫酸镁,随后将滤液减压浓缩。往残余物中加入2-丙醇(198ml),随后在加热回流下搅拌混合物,随后让其回到室温。过滤收集晶体并干燥,得到无色晶体状的三氟甲磺酸3-环丙基-1-(2-氟-4-碘苯基)-6,8-二甲基-2,4,7-三氧代-1,2,3,4,7,8-六氢-吡啶并[2,3-d]嘧啶-5-基酯43(31.9g,产率93%)。
步骤7合成N-{3-[3-环丙基-1-(2-氟-4-碘苯基)-6,8-二甲基-2,4,7-三氧代-1,2,3,4,7,8-六氢-吡啶并[2,3-d]嘧啶-5-基氨基]苯基}乙酰胺
往步骤6中得到的三氟甲磺酸3-环丙基-1-(2-氟-4-碘苯基)-6,8-二甲基-2,4,7-三氧代-1,2,3,4,7,8-六氢-吡啶并[2,3-d]嘧啶-5-基酯43(25.0g)和3’-氨基乙酰苯胺57(7.33g)中加入N,N-二甲基乙酰胺(50.0ml)和2,6-二甲基吡啶(5.68ml),随后在130℃下搅拌混合物5小时。让其冷却至室温后,在搅拌下加入甲醇-水[1∶2(体积比),150ml]。过滤收集晶体并干燥,得到无色晶体状的N-{3-[3-环丙基-1-(2-氟-4-碘苯基)-6,8-二甲基-2,4,7-三氧代-1,2,3,4,7,8-六氢-吡啶并[2,3-d]嘧啶-5-基氨基]苯基}乙酰胺58(24.8g,产率99%)。
步骤8合成N-{3-[3-环丙基-5-(2-氟-4-碘苯基氨基)-6,8-二甲基-2,4,7-三氧代-3,4,6,7-四氢-2H-吡啶并[4,3-d]嘧啶-1-基]苯基}乙酰胺
在氮气气氛下,往28%甲醇钠的甲醇溶液(1.57g)中加入四氢呋喃(40ml),加入步骤7中得到的N-{3-[3-环丙基-1-(2-氟-4-碘苯基)-6,8-二甲基-2,4,7-三氧代-1,2,3,4,7,8-六氢-吡啶并[2,3-d]嘧啶-5-基氨基]苯基}乙酰胺58(5.00g),随后在室温下搅拌混合物4小时。加入乙酸(0.56ml),随后在室温下搅拌混合物30分钟。加入水(40ml),随后继续搅拌混合物1小时。过滤收集晶体并干燥,得到无色晶体状的N-{3-[3-环丙基-5-(2-氟-4-碘苯基氨基)-6,8-二甲基-2,4,7-三氧代-3,4,6,7-四氢-2H-吡啶并[4,3-d]嘧啶-1-基]苯基}乙酰胺59(4.75g,产率95%)。
MS ESI m/e:616(M+H),614(M-H)。
1H-NMR(DMSO-d6,400MHz)δ0.63-0.70(m,2H),0.91-1.00(m,2H),1.25(s,3H),2.04(s,3H),2.58-2.66(m,1H),3.07(s,3H),6.92(t,J=8.8Hz,1H),7.00-7.05(m,1H),7.36(t,J=8.2Hz,1H),7.52-7.63(m,3H),7.79(dd,J=2.0,10.4Hz,1H),10.10(s,1H),11.08(s,1H)。
实施例4-1(可选方法)
N-{3-[3-环丙基-5-(2-氟-4-碘苯基氨基)-6,8-二甲基-2,4,7-三氧代-3,4,6,7-四氢-2H-吡啶并[4,3-d]嘧啶-1-基]-苯基}-乙酰胺
步骤1合成1-环丙基-3-(2-氟-4-碘-苯基)-脲
在氮气气氛下,往N,N-羰基二咪唑(82.1g)中加入N,N-二甲基甲酰胺(400ml)和三乙胺(70.5ml),在冰冷却下滴加2-氟-4-碘苯胺47(100g)的N,N-二甲基甲酰胺(100ml)溶液。滴加完毕后,在室温下搅拌混合物5小时。用冰冷却反应混合物,随后滴加环丙胺(44.0ml)。将混合物在室温下搅拌1小时,在搅拌下将反应混合物滴加至水-甲苯[2∶1(体积比),1500ml]。过滤收集沉淀的晶体并干燥,得到无色晶体状的1-环丙基-3-(2-氟-4-碘-苯基)-脲48(129g,产率95.5%)。
步骤2合成1-(2-氰基-乙酰基)-1-环丙基-3-(2-氟-4-碘-苯基)-脲
在氮气气氛下,往1-环丙基-3-(2-氟-4-碘-苯基)-脲48(167g)和氰基乙酸73(80.0g)中加入N,N-二甲基甲酰胺(836ml),随后在室温并搅拌下滴加甲磺酰氯(72.8ml)。将混合物在室温下搅拌4小时。用水冷却反应混合物,随后滴加水-异丙醇[2∶1(体积比),1670ml]。在水冷却下将混合物搅拌1小时,随后过滤收集沉淀的晶体并干燥,得到1-(2-氰基-乙酰基)-1-环丙基-3-(2-氟-4-碘-苯基)-脲74(192g)。
步骤3合成6-氨基-3-环丙基-1-(2-氟-4-碘-苯基)-1H-嘧啶-2,4-二酮
往1-(2-氰基-乙酰基)-1-环丙基-3-(2-氟-4-碘-苯基)-脲74(192g)中加入水(962ml)和2N氢氧化钠水溶液(24.9ml),随后在80℃下将混合物加热搅拌1小时。让其冷却至室温后,过滤收集晶体并干燥,得到浅黄色晶体状的6-氨基-3-环丙基-1-(2-氟-4-碘-苯基)-1H-嘧啶-2,4-二酮75(178g,产率from 48,88%)。
步骤4合成N’-[1-环丙基-3-(2-氟-4-碘-苯基)-2,6-二氧代-1,2,3,6-四氢-嘧啶-4-基]-N,N-二甲基-甲脒
在氮气气氛下,往6-氨基-3-环丙基-1-(2-氟-4-碘-苯基)-1H-嘧啶-2,4-二酮75(178g)中加入N,N-二甲基甲酰胺(356ml)和N,N-二甲基甲酰胺缩二甲醇(178ml),随后在室温下搅拌混合物2小时。在室温并搅拌下加入异丙醇(178ml),随后滴加水(1068ml)。在室温下将混合物搅拌2小时,随后过滤收集沉淀的晶体并干燥,得到黄色晶体状的N’-[1-环丙基-3-(2-氟-4-碘-苯基)-2,6-二氧代-1,2,3,6-四氢-嘧啶-4-基]-N,N-二甲基-甲脒76(188g,产率92%)。
步骤5合成3-环丙基-1-(2-氟-4-碘-苯基)-6-甲基氨基-1H-嘧啶-2,4-二酮
在氮气气氛下,往叔丁醇-乙醇[2∶1(体积比),250ml]中加入硼氢化钠(6.41g),随后在室温下搅拌混合物1小时。在水冷却下,加入N’-[1-环丙基-3-(2-氟-4-碘-苯基)-2,6-二氧代-1,2,3,6-四氢-嘧啶-4-基]-N,N-二甲基-甲脒76(50.0g),随后搅拌混合物2.5小时。在水冷却下,依次滴加水(225ml)和10%的柠檬酸水溶液(175ml),随后搅拌混合物3小时。过滤收集沉淀的晶体并干燥,得到3-环丙基-1-(2-氟-4-碘-苯基)-6-甲基氨基-1H-嘧啶-2,4-二酮52的粗制晶体(34.5g,LC纯度91%),无需纯化即可用于下一反应。
步骤6合成3-环丙基-1-(2-氟-4-碘-苯基)-5-羟基-6,8-二甲基-1H,8H-吡啶并[2,3-d]嘧啶-2,4,7-三酮
在氮气气氛下,往3-环丙基-1-(2-氟-4-碘-苯基)-6-甲基氨基-1H-嘧啶-2,4-二酮52(34.4g)和2-甲基-丙二酸54(15.2g)中加入乙酸酐(34.4ml),随后在100℃下加热搅拌混合物3小时。让其冷却至50℃后,滴加丙酮(68.8ml),随后搅拌混合物30分钟。再滴加水(172ml),随后搅拌混合物1小时。再搅拌下让其冷却至室温后,过滤收集沉淀的晶体并干燥,得到3-环丙基-1-(2-氟-4-碘-苯基)-5-羟基-6,8-二甲基-1H,8H-吡啶并[2,3-d]嘧啶-2,4,7-三酮55的粗制晶体(37.7g,LC纯度91%)。往得到的粗制晶体(30.7g)中加入异丙醇(92.0ml),随后在室温下搅拌混合物4小时。过滤收集晶体并干燥,得到浅黄色晶体状的3-环丙基-1-(2-氟-4-碘-苯基)-5-羟基-6,8-二甲基-1H,8H-吡啶并[2,3-d]嘧啶-2,4,7-三酮55(25.9g,产率以76计算,58%)。
步骤7合成对-甲苯磺酸3-环丙基-1-(2-氟-4-碘-苯基)-6,8-二甲基-2,4,7-三氧代-1,2,3,4,7,8-六氢-吡啶并[2,3-d]嘧啶-5-基酯
在氮气气氛下,往3-环丙基-1-(2-氟-4-碘-苯基)-5-羟基-6,8-二甲基-1H,8H-吡啶并[2,3-d]嘧啶-2,4,7-三酮55(23.9g)中加入乙腈(167ml),随后在冰冷却下搅拌混合物。加入三乙胺(11.0ml)和三甲胺盐酸盐(2.37g),随后滴加对-甲苯磺酰氯11(12.3g)的乙腈(72.0ml)溶液。在冰冷却下将混合物搅拌1小时,随后在室温下搅拌3小时。加入甲醇(239ml),随后在室温下搅拌混合物1小时。过滤收集晶体并干燥,得到无色晶体状的对-甲苯磺酸3-环丙基-1-(2-氟-4-碘-苯基)-6,8-二甲基-2,4,7-三氧代-1,2,3,4,7,8-六氢-吡啶并[2,3-d]嘧啶-5-基酯77(28.7g,产率91%)。
步骤8合成N-{3-[3-环丙基-1-(2-氟-4-碘-苯基)-6,8-二甲基-2,4,7-三氧代-1,2,3,4,7,8-六氢-吡啶并[2,3-d]嘧啶-5-基氨基]-苯基}-乙酰胺
往对-甲苯磺酸3-环丙基-1-(2-氟-4-碘-苯基)-6,8-二甲基-2,4,7-三氧代-1,2,3,4,7,8-六氢-吡啶并[2,3-d]嘧啶-5-基酯77(28.0g)和3’-氨基乙酰苯胺57(13.2g)中加入N,N-二甲基乙酰胺(84.0ml)和2,6-二甲基吡啶(15.3ml),随后在130℃下搅拌混合物4小时。在搅拌下将其冷却,滴加甲醇(196ml),随后在室温下搅拌混合物。过滤收集晶体并干燥,得到无色晶体状的N-{3-[3-环丙基-1-(2-氟-4-碘-苯基)-6,8-二甲基-2,4,7-三氧代-1,2,3,4,7,8-六氢-吡啶并[2,3-d]嘧啶-5-基氨基]-苯基}-乙酰胺58(25.2g,产率93%)。
步骤9合成N-{3-[3-环丙基-5-(2-氟-4-碘-苯基氨基)-6,8-二甲基-2,4,7-三氧代-3,4,6,7-四氢-2H-吡啶并[4,3-d]嘧啶-1-基]-苯基}-乙酰胺
在氮气气氛下,往N-{3-[3-环丙基-1-(2-氟-4-碘-苯基)-6,8-二甲基-2,4,7-三氧代-1,2,3,4,7,8-六氢-吡啶并[2,3-d]嘧啶-5-基氨基]-苯基}-乙酰胺58(45.7g)中加入四氢呋喃(366ml),随后在室温并搅拌下滴加28%甲醇钠的甲醇溶液(15.7g),随后在室温下搅拌混合物4小时。加入乙酸(5.61ml),随后在室温下搅拌混合物30分钟。在70℃的油浴并搅拌下滴加水(366ml),随后搅拌混合物1小时。在搅拌下让其冷却,过滤收集晶体并干燥,得到晶体1(46.0g)N-{3-[3-环丙基-5-(2-氟-4-碘-苯基氨基)-6,8-二甲基-2,4,7-三氧代-3,4,6,7-四氢-2H-吡啶并[4,3-d]嘧啶-1-基]-苯基}-乙酰胺59。
将N,N-二甲基乙酰胺(184ml)加入晶体1(46.0g)中,随后在130℃加热并搅拌混合物。在完全溶解后,使用纸(5B)抽滤该溶液,并用N,N-二甲基乙酰胺(92.0ml)洗涤。在130℃下加热并搅拌滤液,依次滴加1-丁醇(138ml)和水(96.0ml),并搅拌混合物30分钟。再滴加水(46.0ml),并搅拌混合物30分钟在搅拌下将其冷却。过滤收集晶体并干燥,得到无色晶体状的晶体2(41.7g)N-{3-[3-环丙基-5-(2-氟-4-碘-苯基氨基)-6,8-二甲基-2,4,7-三氧代-3,4,6,7-四氢-2H-吡啶并[4,3-d]嘧啶-1-基]-苯基}-乙酰胺59。
往晶体2(41.5g)中加入1-丁醇-水[19∶1(体积比),415ml],随后在130℃下搅拌混合物18小时。在搅拌下将其冷却,过滤收集晶体并干燥,得到无色晶体状的N-{3-[3-环丙基-5-(2-氟-4-碘-苯基氨基)-6,8-二甲基-2,4,7-三氧代-3,4,6,7-四氢-2H-吡啶并[4,3-d]嘧啶-1-基]-苯基}-乙酰胺59(40.7g,产率89%)。
实施例4-3
N-{3-[3-环丙基-5-(4-乙炔基-2-氟苯基氨基)-6,8-二甲基-2,4,7-三氧代-3,4,6,7-四氢-2H-吡啶并[4,3-d]嘧啶-1-基]苯基}乙酰胺
步骤1合成N-{3-[3-环丙基-5-(2-氟-4-三甲基甲硅烷基乙炔基苯基氨基)-6,8-二甲基-2,4,7-三氧代-3,4,6,7-四氢-2H-吡啶并[4,3-d]嘧啶-1-基]苯基}乙酰胺
在氮气气氛下,往实施例4-1中得到的N-{3-[3-环丙基-5-(2-氟-4-碘苯基氨基)-6,8-二甲基-2,4,7-三氧代-3,4,6,7-四氢-2H-吡啶并[4,3-d]嘧啶-1-基]苯基}乙酰胺59(14.5g)中加入氯仿(145ml)、三甲基甲硅烷基乙炔60(4.99ml)和三乙胺(13.1ml)。加入碘化铜(I)(22mg)和氯化双(三苯基膦)合钯(II)(83mg),随后在室温下搅拌混合物20小时。减压浓缩混合物,往残余物中加入活性碳(435mg)和甲醇(435ml),随后在回流加热下搅拌混合物2小时。趁热滤除活性碳,随后将滤液减压浓缩。残余物经过柱层析纯化(氯仿∶丙酮=10∶1→4∶1)随后往得到的结晶中加入甲苯-丙酮[5∶1(体积比),87ml]。在80℃下搅拌混合物1小时。让其冷却至室温后,过滤收集晶体并干燥,得到浅黄色晶体状的N-{3-[3-环丙基-5-(2-氟-4-三甲基甲硅烷基乙炔基苯基氨基)-6,8-二甲基-2,4,7-三氧代-3,4,6,7-四氢-2H-吡啶并[4,3-d]嘧啶-1-基]苯基}乙酰胺61(12.9g,产率93%)。
步骤2合成N-{3-[3-环丙基-5-(4-乙炔基-2-氟苯基氨基)-6,8-二甲基-2,4,7-三氧代-3,4,6,7-四氢-2H-吡啶并[4,3-d]嘧啶-1-基]苯基}乙酰胺
往步骤2中得到的N-{3-[3-环丙基-5-(2-氟-4-三甲基甲硅烷基乙炔基苯基氨基)-6,8-二甲基-2,4,7-三氧代-3,4,6,7-四氢-2H-吡啶并[4,3-d]嘧啶-1-基]苯基}乙酰胺61(1.00g)和碳酸钾(236mg)中加入甲醇/N,N-二甲基甲酰胺[1∶1(体积比),10.0ml],随后在室温下搅拌混合物20小时。用2N盐酸中和该混合物,加入水(10.0ml),随后在室温下搅拌混合物1小时。过滤收集晶体并干燥,得到浅黄色晶体状的N-{3-[3-环丙基-5-(4-乙炔基-2-氟苯基氨基)-6,8-二甲基-2,4,7-三氧代-3,4,6,7-四氢-2H-吡啶并[4,3-d]嘧啶-1-基]苯基}乙酰胺62(815mg,产率93%)。
MS ESI m/e:514(M+H),512(M-H)。
1H-NMR(DMSO-d6,400MHz)δ0.63-0.70(m,2H),0.91-0.99(m,2H),1.26(s,3H),2.04(s,3H),2.58-2.66(m,1H),3.10(s,3H),4.30(s,3H),7.01-7.06(m,1H),7.09(t,J=8.4Hz,1H),7.31(dd,J=1.6,8.4Hz,1H),7.36(t,J=7.8Hz,1H),7.52(dd,J=1.6,11.6Hz,1H),7.57-7.63(m,2H),10.10(s,1H),11.10(s,1H)。
实施例4-16
N-{3-[5-(2-氟-4-碘苯基氨基)-3,6,8-三甲基-2,4,7-三氧代-3,4,6,7-四氢-2H-吡啶并[4,3-d]嘧啶-1-基]苯基}甲磺酰胺
步骤1合成1-(2-氟-4-碘苯基)-3-甲基脲
在氮气气氛下,往N,N-羰基二咪唑(61.4g)中加入N,N-二甲基甲酰胺(300ml)和三乙胺(52.8ml)并在冰冷却及搅拌下滴加2-氟-4-碘苯胺47(74.8g)的N,N-二甲基甲酰胺溶液(75ml)。滴加完毕后,在室温下将混合物搅拌5小时。用冰冷却反应混合物,随后滴加40%甲基胺的甲醇溶液(60ml)。将混合物在室温下搅拌1小时,搅拌下将反应混合物滴加至水-甲苯[2∶1(体积比),1125ml]。过滤收集沉淀的晶体并干燥,得到无色晶体状的1-(2-氟-4-碘苯基)-3-甲基脲63(87.9g,产率94.8%)。
步骤2合成1-(2-氟-4-碘苯基)-3-甲基嘧啶-2,4,6-三酮
在氮气气氛下,往步骤1中得到的1-(2-氟-4-碘苯基)-3-甲基脲63(87.9g)和丙二酸4(31.1g)中加入乙酸酐(264ml)和乙酰氯(42.5ml),随后在65℃下搅拌混合物3小时。让其冷却至室温后,在搅拌下将反应混合物滴加至水-甲苯[2∶1(体积比),800ml],接着加入己烷(132ml)。过滤收集沉淀的晶体并干燥,得到浅黄色晶体状的1-(2-氟-4-碘苯基)-3-甲基嘧啶-2,4,6-三酮64(75.3g,产率69.5%)。
步骤3合成6-氯-1-(2-氟-4-碘苯基)-3-甲基-1H-嘧啶-2,4-二酮
在氮气气氛下,往1-(2-氟-4-碘苯基)-3-甲基嘧啶-2,4,6-三酮64(75.3g)中加入磷酰氯(116.3ml),随后在室温搅拌下滴加二甲基苯胺(39.5ml)和水(11.6ml)。滴加完毕后,在125℃下搅拌混合物1小时。让其冷却至室温后,在搅拌下将反应混合物滴加至冰水(500ml)/氯仿(150ml)中。将混合物在室温下搅拌1小时,随后加入氯仿(150ml)。分离有机层,接着用水(300ml)和盐水(300ml)洗涤,随后经无水硫酸钠干燥。
滤除无水硫酸钠,随后将滤液减压浓缩。往残余物的氯仿溶液(250ml)中加入硅胶(200ml),随后搅拌混合物。滤除硅胶并用氯仿/乙酸乙酯[10∶1(体积比),11]洗涤。减压浓缩滤液,得到浅黄色晶体状的6-氯-1-(2-氟-4-碘苯基)-3-甲基-1H-嘧啶-2,4-二酮65和6-氯-3-(2-氟-4-碘苯基)-1-甲基-1H-嘧啶-2,4-二酮66为6∶5的混合物(75.7g,产率95.6%)。
步骤4合成1-(2-氟-4-碘苯基)-3-甲基-6-甲基氨基-1H-嘧啶-2,4-二酮
往步骤3中得到的6-氯-1-(2-氟-4-碘苯基)-3-甲基-1H-嘧啶-2,4-二酮65和6-氯-3-(2-氟-4-碘苯基)-1-甲基-1H-嘧啶-2,4-二酮66为6∶5的混合物(75.7g)中加入甲醇(227ml)和40%甲胺的甲醇溶液(152ml),随后在室温下搅拌混合物2.5小时。减压浓缩反应混合物,随后往残余物中加入甲苯(150ml)和水(150ml),随后将混合物在回流搅拌下加热30分钟。让其冷却至室温后,过滤收集晶体并干燥,得到浅黄色晶体状的1-(2-氟-4-碘苯基)-3-甲基-6-甲基氨基-1H-嘧啶-2,4-二酮67与3-(2-氟-4-碘苯基)-1-甲基-6-甲基氨基-1H-嘧啶-2,4-二酮68为6∶5的混合物(59.6g,产率79.9%)。
步骤5 合成1-(2-氟-4-碘苯基)-5-羟基-3,6,8-三甲基-1H,8H-吡啶并[2,3-d]嘧啶-2,4,7-三酮
往步骤4中得到的1-(2-氟-4-碘苯基)-3-甲基-6-甲基氨基-1H-嘧啶-2,4-二酮67与3-(2-氟-4-碘苯基)-1-甲基-6-甲基氨基-1H-嘧啶-2,4-二酮68为6∶5的混合物(59.6g)和2-甲基-丙二酸54(20.7g)中加入乙酸酐(180ml),随后在95℃搅拌下加热混合物1小时。让其冷却至室温后,减压浓缩混合物。往残余物中加入四氢呋喃(350ml),随后在加热回流下搅拌混合物1小时。让其冷却至室温后,滤除晶体。减压浓缩滤液,随后残余物经过柱层析纯化(氯仿∶四氢呋喃=18∶1)。往得到的固体中加入甲苯(150ml),随后在加热回流下搅拌混合物30分钟。让其冷却至室温后,过滤收集晶体并干燥,得到无色晶体状的1-(2-氟-4-碘苯基)-5-羟基-3,6,8-三甲基-1H,8H-吡啶并[2,3-d]嘧啶-2,4,7-三酮69(27.0g,产率37%)。
步骤6 合成三氟甲磺酸1-(2-氟-4-碘苯基)-3,6,8-三甲基-2,4,7-三氧代-1,2,3,4,7,8-六氢-吡啶并[2,3-d]嘧啶-5-基酯
在氮气气氛下,往步骤5中得到的1-(2-氟-4-碘苯基)-5-羟基-3,6,8-三甲基-1H,8H-吡啶并[2,3-d]嘧啶-2,4,7-三酮69(27.0g)中加入氯仿(200ml)和2,6-二甲基吡啶(11.1ml)并在冰冷却及搅拌下滴加三氟甲磺酸酐56(14.9ml)。滴加完毕后,在相同温度下搅拌混合物30分钟,随后在室温搅拌混合物3小时。在冰冷却下搅拌,往反应混合物中加入水(200ml)。分离有机层,依次用水(300ml)和盐水(300ml)洗涤,随后经无水硫酸镁干燥。滤除无水硫酸镁,随后将滤液减压浓缩。往残余物中加入2-丙醇(150ml),随后在室温加入晶种让晶体沉淀。搅拌下加热回流混合物30分钟,让其冷却至室温。过滤收集晶体并干燥,得到无色晶体状的三氟甲磺酸1-(2-氟-4-碘苯基)-3,6,8-三甲基-2,4,7-三氧代-1,2,3,4,7,8-六氢-吡啶并[2,3-d]嘧啶-5-基酯70(22.9g,产率66%)。
步骤7 合成N-{3-[1-(2-氟-4-碘苯基)-3,6,8-三甲基-2,4,7-三氧代-1,2,3,4,7,8-六氢-吡啶并[2,3-d]嘧啶-5-基氨基]苯基}甲磺酰胺
往步骤6中得到的三氟甲磺酸1-(2-氟-4-碘苯基)-3,6,8-三甲基-2,4,7-三氧代-1,2,3,4,7,8-六氢-吡啶并[2,3-d]嘧啶-5-基酯70(3.00g)和N-(3-氨基苯基)甲磺酰胺44(1.14g)中加入N,N-二甲基乙酰胺(6.00ml)和2,6-二甲基吡啶(0.712ml),随后在130℃下搅拌混合物4小时。让其冷却至室温后,搅拌下加入甲醇/水[1∶2(体积比),18.0ml]。过滤收集晶体并干燥,得到得到浅灰色固体状的N-{3-[1-(2-氟-4-碘苯基)-3,6,8-三甲基-2,4,7-三氧代-1,2,3,4,7,8-六氢-吡啶并[2,3-d]嘧啶-5-基氨基]苯基}甲磺酰胺71(3.13g,产率98%)。
步骤8 合成N-{3-[5-(2-氟-4-碘苯基氨基)-3,6,8-三甲基-2,4,7-三氧代-3,4,6,7-四氢-2H-吡啶并[4,3-d]嘧啶-1-基]苯基}甲磺酰胺
在冰冷却下,往步骤7中得到的N-{3-[1-(2-氟-4-碘苯基)-3,6,8-三甲基-2,4,7-三氧代-1,2,3,4,7,8-六氢-吡啶并[2,3-d]嘧啶-5-基氨基]苯基}甲磺酰胺71(3.10g)的四氢呋喃悬浮液(31.0ml)中滴加叔丁醇化钾(1.33g)、甲醇(0.482ml)和四氢呋喃(15.5ml)的混合物,随后在冰冷却下搅拌混合物2小时。加入乙酸(1.36ml),让混合物升至室温并搅拌1小时。将反应混合物浓缩,加入甲醇/水[1∶2(体积比),45.0ml],在室温再搅拌混合物1小时。过滤收集晶体并干燥,得到浅灰色固体状的N-{3-[5-(2-氟-4-碘苯基氨基)-3,6,8-三甲基-2,4,7-三氧代-3,4,6,7-四氢-2H-吡啶并[4,3-d]嘧啶-1-基]苯基}甲磺酰胺72(3.01g,产率97%)。
MS ESI m/e:626(M+H),624(M-H)。
1H-NMR(DMSO-d6,300MHz)δ1.26(s,3H),3.01(s,3H),3.09(s,3H),3.21(s,3H),6.93(t,J=8.3Hz,1H),7.11-7.15(m,1H),7.20-7.28(m,2H),7.42(t,J=8.3Hz,1H),7.52-7.57(m,1H),7.76-7.81(m,1H),9.94(brs,1H),11.21(brs,1H)。
实施例4-144
N-{3-[5-(2-氟-4-碘苯基氨基)-3-(4-羟基丁基)-6,8-二甲基-2,4,7-三氧代-3,4,6,7-四氢-2H-吡啶并[4,3-d]嘧啶-1-基]-苯基}-乙酰胺
步骤1 合成(2-氟-4-碘苯基)-脲
在氩气气氛、冰冷却下,往2-氟-4-碘苯胺47(20.0g)和三乙胺(23.6ml)的氯仿溶液(200ml)中搅拌加入N,N-羰基二咪唑(27.4g)。在加入完成后,在冰冷却下搅拌混合物15分钟,随后在室温搅拌混合物4小时。用冰冷却反应混合物,随后滴加28%氨水(100ml)。将混合物在室温下搅拌1.5小时。过滤收集沉淀的晶体,用水洗涤并干燥,得到浅红色晶体状的(2-氟-4-碘苯基)-脲78(23.5g,产率98.8%)。
步骤2 合成1-(2-氰基乙酰基)-3-(2-氟-4-碘苯基)-脲
往(2-氟-4-碘苯基)-脲78(21.7g)和氰基乙酸73(7.88g)在N,N-二甲基甲酰胺(108ml)中的混合物中加入,随后在室温搅拌下滴加甲磺酰氯(7.17ml)。将混合物在室温下搅拌2小时,随后滴加水-异丙醇[1∶2(体积比),210ml]。将混合物在室温下搅拌1小时。过滤收集沉淀的晶体并用水洗涤,得到1-(2-氰基乙酰基)-3-(2-氟-4-碘苯基)-脲79(湿晶体),其以湿晶体的形式用于下一步反应。
步骤3 合成6-氨基-1-(2-氟-4-碘苯基)-1H-嘧啶-2,4-二酮
往1-(2-氰基乙酰基)-3-(2-氟-4-碘苯基)-脲79(湿晶体)的水悬浮液(110ml)中加入2N氢氧化钠水溶液(3.96ml),随后在85℃下加热搅拌混合物1小时。让其冷却至室温后,依次滴加2N盐酸(3.96ml)和异丙醇(44.0ml)。将混合物在室温下搅拌1.5小时,过滤收集沉淀的晶体,用异丙醇洗涤并干燥,得到无色晶体状的6-氨基-1-(2-氟-4-碘苯基)-1H-嘧啶-2,4-二酮80和78的混合物(21.8g),其无需纯化即可用于下一步骤。
步骤4 合成N’-[3-(2-氟-4-碘苯基)-2,6-二氧代-1,2,3,6-四氢嘧啶-4-基]-N,N-二甲基甲脒
往6-氨基-1-(2-氟-4-碘苯基)-1H-嘧啶-2,4-二酮80和78的混合物(21.8g)中加入N,N-二甲基甲酰胺(42.0ml)和N,N-二甲基甲酰胺缩二甲醇(21.0ml),随后在室温下搅拌混合物4.5小时。在室温搅拌下加入异丙醇(20.0ml),随后滴加水(100ml)。将混合物在室温下搅拌45分钟,随后过滤收集沉淀的晶体,用水洗涤并干燥,得到无色晶体状的N’-[3-(2-氟-4-碘苯基)-2,6-二氧代-1,2,3,6-四氢嘧啶-4-基]-N,N-二甲基甲脒81(21.7g,产率67.7%,以78计算)。
步骤5 合成N’-[3-(2-氟-4-碘苯基)-1-(4-甲氧基苄基)-2,6-二氧代-1,2,3,6-四氢嘧啶-4-基]-N,N-二甲基甲脒
在室温下往N’-[3-(2-氟-4-碘苯基)-2,6-二氧代-1,2,3,6-四氢嘧啶-4-基]-N,N-二甲基甲脒81(20.0g)的N,N-二甲基甲酰胺溶液(150ml)中加入1,8-二氮杂二环[5.4.0]十一-7-烯(14.9ml)和4-甲氧基苄基氯82(10.1ml)。在75℃、搅拌下将混合物加热2.5小时,加入1,8-二氮杂二环[5.4.0]十一-7-烯(7.50ml)和4-甲氧基苄基氯(4.00ml),随后在相同温度下搅拌并加热混合物2.5小时。让其冷却至室温后,依次滴加异丙醇(150ml)和水(300ml)。在室温将混合物搅拌过夜,随后过滤收集沉淀的晶体并干燥,得到黄色晶体状的N’-[3-(2-氟-4-碘苯基)-1-(4-甲氧基苄基)-2,6-二氧代-1,2,3,6-四氢嘧啶-4-基]-N,N-二甲基甲脒83(20.2 g,产率77.8%)。
步骤6 合成1-(2-氟-4-碘苯基)-3-(4-甲氧基苄基)-6-甲基氨基-1H-嘧啶-2,4-二酮
在室温搅拌下,往硼氢化钠(326mg)的叔丁醇/乙醇[2∶1(体积比),18.0ml]的悬浮液中加入N’-[3-(2-氟-4-碘苯基)-1-(4-甲氧基苄基)-2,6-二氧代-1,2,3,6-四氢嘧啶-4-基]-N,N-二甲基甲脒83(3.00g)。将混合物在室温下搅拌1小时,随后在65℃搅拌2小时。在相同温度搅拌下依次加入水(30.0ml)和氯化铵(461mg),随后搅拌混合物让其冷却至室温。用乙酸乙酯萃取反应溶液两次。合并有机层,依次用饱和碳酸氢钠水溶液和盐水洗涤,经无水硫酸钠干燥,随后减压浓缩。经柱层析纯化得到的粗制产物,得到浅黄色固体状的1-(2-氟-4-碘苯基)-3-(4-甲氧基苄基)-6-甲基氨基-1H-嘧啶-2,4-二酮84(2.57g,产率93.1%)。
步骤7 合成1-(2-氟-4-碘苯基)-5-羟基-3-(4-甲氧基苄基)-6,8-二甲基-1H,8H-吡啶并[2,3-d]嘧啶-2,4,7-三酮
往1-(2-氟-4-碘苯基)-3-(4-甲氧基苄基)-6-甲基氨基-1H-嘧啶-2,4-二酮84(13.3g)的乙酸酐悬浮液(13.0ml)中加入2-甲基-丙二酸54(4.90g),随后在90℃搅拌下加热混合物3小时,在100℃搅拌下加热混合物1小时。让其冷却至约50℃后,滴加丙酮(13.3ml),随后再加入水(75.0ml)。在加入晶种化合物85后,加入丙酮(30.0ml),并搅拌混合物1.5小时。加入水(30.0ml)并搅拌混合物45分钟,并让其冷却至室温。过滤收集沉淀的晶体,用水洗涤并干燥,得到浅赭色晶体状的1-(2-氟-4-碘苯基)-5-羟基-3-(4-甲氧基苄基)-6,8-二甲基-1H,8H-吡啶并[2,3-d]嘧啶-2,4,7-三酮85(14.1g,产率90.7%)。
步骤8 合成三氟甲磺酸1-(2-氟-4-碘苯基)-3-(4-甲氧基苄基)-6,8-二甲基-2,4,7-三氧代-1,2,3,4,7,8-六氢吡啶并[2,3-d]嘧啶-5-基酯
在氩气气氛、冰冷却下,往1-(2-氟-4-碘苯基)-5-羟基-3-(4-甲氧基苄基)-6,8-二甲基-1H,8H-吡啶并[2,3-d]嘧啶-2,4,7-三酮85(14.1g)的氯仿溶液(70.0ml)中加入2,6-二甲基吡啶(3.79ml)和三氟甲磺酸酐56(5.47ml),随后在冰冷却下搅拌混合物1小时,在室温下搅拌混合物1.5小时。往反应混合物中加入饱和碳酸氢钠水溶液和氯仿让其分离。用饱和碳酸氢钠水溶液洗涤有机层一次,1N的盐酸洗涤两次,用饱和的氯化钠水溶液洗涤一次,随后经无水硫酸钠干燥。过滤后,减压浓缩滤液。往得到的粗制产物中加入异丙醇(35.0ml),随后在95℃的外部温度下加热并搅拌混合物30分钟。让其搅拌下冷却至室温后,加入异丙醇(35.0ml),并搅拌混合物1小时。过滤收集沉淀的晶体,异丙醇洗涤并干燥,得到棕色晶体状的三氟甲磺酸1-(2-氟-4-碘苯基)-3-(4-甲氧基苄基)-6,8-二甲基-2,4,7-三氧代-1,2,3,4,7,8-六氢吡啶并[2,3-d]嘧啶-5-基酯86(14.4g,产率82.8%)。
步骤9 合成N-{3-[1-(2-氟-4-碘苯基)-3-(4-甲氧基苄基)-6,8-二甲基-2,4,7-三氧代-1,2,3,4,7,8-六氢吡啶并[2,3-d]嘧啶-5-基氨基]-苯基}-乙酰胺
往三氟甲磺酸1-(2-氟-4-碘苯基)-3-(4-甲氧基苄基)-6,8-二甲基-2,4,7-三氧代-1,2,3,4,7,8-六氢吡啶并[2,3-d]嘧啶-5-基酯86(1.10g)和3’-氨基乙酰苯胺57(285mg)中加入N,N-二甲基乙酰胺(2.20ml)和2,6-二甲基吡啶(221μl),随后在130℃下搅拌混合物2小时。让其冷却至室温后,搅拌下滴加甲醇(12.0ml)。过滤收集沉淀的晶体,用甲醇洗涤并干燥,得到无色晶体状的N-{3-[1-(2-氟-4-碘苯基)-3-(4-甲氧基苄基)-6,8-二甲基-2,4,7-三氧代-1,2,3,4,7,8-六氢吡啶并[2,3-d]嘧啶-5-基氨基]-苯基}-乙酰胺87(1.04g,产率94.6%)。
步骤10 合成N-{3-[5-(2-氟-4-碘苯基氨基)-3-(4-甲氧基苄基)-6,8-二甲基-2,4,7-三氧代-3,4,6,7-四氢-2H-吡啶并[4,3-d]嘧啶-1-基]-苯基}-乙酰胺
往28%甲醇钠的甲醇溶液(305mg)中加入四氢呋喃(4.00ml)和N-{3-[1-(2-氟-4-碘苯基)-3-(4-甲氧基苄基)-6,8-二甲基-2,4,7-三氧代-1,2,3,4,7,8-六氢吡啶并[2,3-d]嘧啶-5-基氨基]-苯基}-乙酰胺87(1.00g)。用四氢呋喃(4.00ml)洗涤器壁。将混合物在室温下搅拌1.5小时,加入2N盐酸(900μl),随后减压浓缩混合物。往残余物中加入异丙醇、甲醇和水,并在回流后,让混合物搅拌下冷却至室温。过滤收集沉淀的晶体,用甲醇洗涤并干燥,得到无色晶体状的N-{3-[5-(2-氟-4-碘苯基氨基)-3-(4-甲氧基苄基)-6,8-二甲基-2,4,7-三氧代-3,4,6,7-四氢-2H-吡啶并[4,3-d]嘧啶-1-基]-苯基}-乙酰胺88(974mg,产率97.2%)。
步骤11 合成N-{3-[5-(2-氟-4-碘苯基氨基)-6,8-二甲基-2,4,7-三氧代-3,4,6,7-四氢-2H-吡啶并[4,3-d]嘧啶-1-基]-苯基}-乙酰胺
在水浴中,往N-{3-[5-(2-氟-4-碘苯基氨基)-3-(4-甲氧基苄基)-6,8-二甲基-2,4,7-三氧代-3,4,6,7-四氢-2H-吡啶并[4,3-d]嘧啶-1-基]-苯基}-乙酰胺88(960mg)的苯甲醚悬浮液(10.0ml)中搅拌加入氯化铝(1.94g)。将混合物在室温下搅拌37小时,滴加甲醇(12.0ml),随后减压浓缩混合物。将得到的残余物溶解在甲醇(12.0ml)中,并在水浴中搅拌滴加2N盐酸(20.0ml)。将混合物在室温下搅拌1小时,加入己烷(10.0ml),并搅拌混合物1小时。过滤收集沉淀的晶体,用己烷、水和甲醇洗涤并干燥,得到无色晶体状的N-{3-[5-(2-氟-4-碘苯基氨基)-6,8-二甲基-2,4,7-三氧代-3,4,6,7-四氢-2H-吡啶并[4,3-d]嘧啶-1-基]-苯基}-乙酰胺89(620mg,产率78.1%)。
步骤12 合成N-{3-[3-(4-苄氧基丁基)-5-(2-氟-4-碘苯基氨基)-6,8-二甲基-2,4,7-三氧代-3,4,6,7-四氢-2H-吡啶并[4,3-d]嘧啶-1-基]-苯基}-乙酰胺
在氩气气氛、冰冷却下,往N-{3-[5-(2-氟-4-碘苯基氨基)-6,8-二甲基-2,4,7-三氧代-3,4,6,7-四氢-2H-吡啶并[4,3-d]嘧啶-1-基]-苯基}-乙酰胺89(75.0mg)、4-苄氧基丁醇90(25.0μl)和三苯基膦(37.0mg)的四氢呋喃悬浮液(1.00ml)中加入偶氮二甲酸二异丙酯(28.0μl)。在相同温度下搅拌混合物2小时,随后加入4-苄氧基丁醇(13.0μl)、三苯基膦(19.0mg)和偶氮二甲酸二异丙酯(14.0μl)。在相同温度下搅拌混合物1小时,随后加入水和乙酸乙酯让其分离。用饱和的氯化钠水溶液洗涤有机层,经无水硫酸钠干燥并减压浓缩。残余物经过柱层析纯化(氯仿∶乙酸乙酯=2∶1→1∶1)和薄层色谱(己烷∶丙酮=1∶1)进-步纯化,得到浅黄色非晶形的N-{3-[3-(4-苄氧基丁基)-5-(2-氟-4-碘苯基氨基)-6,8-二甲基-2,4,7-三氧代-3,4,6,7-四氢-2H-吡啶并[4,3-d]嘧啶-1-基]-苯基}-乙酰胺91(74mg,产率77%)。
步骤13 合成N-{3-[5-(2-氟-4-碘苯基氨基)-3-(4-羟基丁基)-6,8-二甲基-2,4,7-三氧代-3,4,6,7-四氢-2H-吡啶并[4,3-d]嘧啶-1-基]-苯基}-乙酰胺
在回流下,将N-{3-[3-(4-苄氧基丁基)-5-(2-氟-4-碘苯基氨基)-6,8-二甲基-2,4,7-三氧代-3,4,6,7-四氢-2H-吡啶并[4,3-d]嘧啶-1-基]-苯基}-乙酰胺91(74mg)在三氟乙酸(1.00ml)中搅拌5.5小时。减压浓缩反应混合物,随后往残余物中加入乙酸乙酯和饱和碳酸氢钠水溶液让其分离。依次用饱和碳酸氢钠水溶液、水和盐水洗涤,经无水硫酸钠干燥并减压浓缩。往残余物中加入二异丙基醚(1.00ml),随后在60℃下搅拌混合物让其冷却至室温。过滤收集结晶,用二异丙基醚洗涤并干燥,得到无色晶体状的化合物93(26mg)。将化合物93在室温下、饱和碳酸氢钠水溶液(300μl)、甲醇(300μl)和乙酸乙酯(300μl)的混合物溶液中搅拌1小时,并用乙酸乙酯萃取。有机层用盐水洗涤,经无水硫酸钠干燥并减压浓缩。往残余物中加入乙酸乙酯、己烷和乙醚,随后在室温下搅拌混合物1小时。过滤收集沉淀的晶体,用己烷洗涤并干燥,得到无色晶体状的N-{3-[5-(2-氟-4-碘苯基氨基)-3-(4-羟基丁基)-6,8-二甲基-2,4,7-三氧代-3,4,6,7-四氢-2H-吡啶并[4,3-d]嘧啶-1-基]-苯基}-乙酰胺92(5mg,产率8%)。
实施例4-2、4-4-15、4-17-143和4-145-148
采用与实施例4-1、4-3和4-16相同的方法,得到实施例4-2、4-4-15、4-17-133和4-138-4-140的化合物。此外,采用与实施例4-144相同的方法,得到实施例4-83-86、实施例4-134-137、4-141-143和4-145-148的化合物。其和实施例4-1、4-3、4-16和4-144的结构式见表4-1至4-25。
表4-1
表4-2
表4-3
表4-4
表4-5
表4-6
表4-7
表4-8
表4-9
表4-10
表4-11
表4-12
表4-13
表4-14
表4-15
表4-16
表4-17
表4-18
表4-19
表4-20
表4-21
表4-22
表4-23
表4-24
表4-25
实施例4-149
通过常规的方法处理N-{3-[3-环丙基-5-(2-氟-4-碘-苯基氨基)-6,8-二甲基-2,4,7-三氧代-3,4,6,7-四氢-2H-吡啶并[4,3-d]嘧啶-1-基]-苯基}-乙酰胺59,得到其钠盐、水合物、乙酸溶剂合物、二甲基亚砜溶剂合物、乙醇溶剂合物、硝基甲烷溶剂合物、氯苯溶剂合物、1-戊醇溶剂合物、异丙醇溶剂合物、乙二醇溶剂合物和3-甲基丁醇溶剂合物。N-{3-[3-环丙基-5-(2-氟-4-碘-苯基氨基)-6,8-二甲基-2,4,7-三氧代-3,4,6,7-四氢-2H-吡啶并[4,3-d]嘧啶-1-基]-苯基}-乙酰胺钠盐:1H-NMR(DMSO-d6,400MHz)δ0.35-0.41(m,2H),0.71-0.77(m,2H),1.16(s,3H),2.02(s,3H),2.18-2.24(m,1H),3.32(s,3H),6.59(t,J=8.8Hz,1H),6.94(d,J=8.6Hz,1H),7.04(d,J=10.2Hz,1H),7.19(d,J=11.1Hz,1H),7.27(t,J=8.0Hz,1H),7.34(s,1H),7.64(d,J=8.3Hz,1H),10.00(s,1H)。
MS(ESI)m/z616[MH]+。
N-{3-[3-环丙基-5-(2-氟-4-碘-苯基氨基)-6,8-二甲基-2,4,7-三氧代-3,4,6,7-四氢-2H-吡啶并[4,3-d]嘧啶-1-基]-苯基}-乙酰胺水合物:1H-NMR(DMSO-d6,400MHz)δ0.63-0.70(m,2H),0.91-1.00(m,2H),1.25(s,3H),2.04(s,3H),2.58-2.66(m,1H),3.08(s,3H),6.92(t,J=8.8Hz,1H),7.00-7.05(m,1H),7.36(t,J=8.2 Hz,1H),7.52-7.63(m,3H),7.79(dd,J=2.0,10.4 Hz,1H),10.09(s,1H),11.08(s,1H)。
MS(ESI)m/z616[MH]+。
N-{3-[3-环丙基-5-(2-氟-4-碘-苯基氨基)-6,8-二甲基-2,4,7-三氧代-3,4,6,7-四氢-2H-吡啶并[4,3-d]嘧啶-1-基]-苯基}-乙酰胺乙酸溶剂合物:
1H-NMR(DMSO-d6,400MHz)δ0.63-0.70(m,2H),0.92-0.98(m,2H),1.25(s,3H),1.91(s,3H),2.04(s,3H),2.59-2.65(m,1H),3.08(s,3H),6.92(t,J=8.6Hz,1H),7.00-7.05(m,1H),7.36(t,J=7.6Hz,1H),7.53-7.62(m,3H),7.79(dd,J=10.4Hz,1H),10.08(s,1H),11.07(s,1H),11.94(s,1H)。
MS(ESI)m/z616[MH]+。
N-{3-[3-环丙基-5-(2-氟-4-碘-苯基氨基)-6,8-二甲基-2,4,7-三氧代-3,4,6,7-四氢-2H-吡啶并[4,3-d]嘧啶-1-基]-苯基}-乙酰胺二甲基亚砜溶剂合物:
1H-NMR(CDCl3,400MHz)δ0.76-0.82(m,2H),1.09-1.15(m,2H),1.41(s,3H),2.14(s,3H),2.62(s,6H),2.71-2.77(m,1H),3.20(s,3H),6.70(t,J=8.4Hz,1H),7.00(brs,1H),7.32(brs,2H),7.43-7.47(m,1H),7.52(dd,J=2.0,9.6 Hz,1H),7.71(brs,2H),11.30(s,1H)。
MS(ESI)m/z616[MH]+。
N-{3-[3-环丙基-5-(2-氟-4-碘-苯基氨基)-6,8-二甲基-2,4,7-三氧代-3,4,6,7-四氢-2H-吡啶并[4,3-d]嘧啶-1-基]-苯基}-乙酰胺乙醇溶剂合物:
1H-NMR(DMSO-d6,300MHz)δ0.63-0.70(m,2H),0.91-1.00(m,2H),1.06(t,J=7.1Hz,3H),1.25(s,3H),2.04(s,3H),2.58-2.66(m,1H),3.07(s,3H),3.40-3.49(m,2H),4.33(t,J=5.1Hz,1H),6.92(t,J=8.8Hz,1H),7.00-7.05(m,1H),7.36(t,J=8.2Hz,1H),7.52-7.63(m,3H),7.79(dd,J=2.0,10.4Hz,1H),10.08(s,1H),11.07(s,1H)。
MS(ESI)m/z616[MH]+。
N-{3-[3-环丙基-5-(2-氟-4-碘-苯基氨基)-6,8-二甲基-2,4,7-三氧代-3,4,6,7-四氢-2H-吡啶并[4,3-d]嘧啶-1-基]-苯基}-乙酰胺硝基甲烷溶剂合物:
1H-NMR(DMSO-d6,300MHz)δ0.63-0.70(m,2H),0.91-1.00(m,2H),1.25(s,3H),2.04(s,3H),2.58-2.66(m,1H),3.07(s,3H),4.42(s,2H),6.92(t,J=8.8Hz,1H),7.00-7.05(m,1H),7.36(t,J=8.2Hz,1H),7.52-7.63(m,3H),7.79(dd,J=2.0,10.4Hz,1H),10.08(s,1H),11.07(s,1H)。
N-{3-[3-环丙基-5-(2-氟-4-碘-苯基氨基)-6,8-二甲基-2,4,7-三氧代-3,4,6,7-四氢-2H-吡啶并[4,3-d]嘧啶-1-基]-苯基}-乙酰胺氯苯溶剂合物:
1H-NMR(DMS0-d6,300MHz)δ0.63-0.70(m,2H),0.91-1.00(m,2H),1.25(s,3H),2.04(s,3H),2.58-2.66(m,1H),3.07(s,3H),6.92(t,J=8.8Hz,1H),7.00-7.05(m,1H),7.29-7.45(m,5H),7.50-7.63(m,3H),7.79(dd,J=2.0,10.4Hz,1H),10.08(s,1H),11.07(s,1H)。
N-{3-[3-环丙基-5-(2-氟-4-碘-苯基氨基)-6,8-二甲基-2,4,7-三氧代-3,4,6,7-四氢-2H-吡啶并[4,3-d]嘧啶-1-基]-苯基}-乙酰胺1-戊醇溶剂合物:
1H-NMR(DMSO-d6,300MHz)δ0.62-0.70(m,2H),0.86(t,J=7.0Hz,1.5H),0.90-0.99(m,2H),1.22-1.30(m,5H),1.35-1.44(m,1H),2.04(s,3H),2.56-2.67(m,1H),3.08(s,3H),3.33-3.41(m,1H),4.30(t,J=5.1Hz,0.5H),6.91(t,J=8.5Hz,1H),7.00-7.06(m,1H),7.36(t,J=8.3Hz,1H),7.52-7.62(m,3H),7.74-7.81(m,1H),10.08(s,1H),11.07(s,1H)。
N-{3-[3-环丙基-5-(2-氟-4-碘-苯基氨基)-6,8-二甲基-2,4,7-三氧代-3,4,6,7-四氢-2H-吡啶并[4,3-d]嘧啶-1-基]-苯基}-乙酰胺异丙醇溶剂合物:
1H-NMR(DMSO-d6,400MHz)δ0.63-0.69(m,2H),0.91-0.98(m,2H),1.04(d,J=6.0Hz,6H),1.25(s,3H),2.04(s,3H),2.58-2.66(m,1H),3.07(s,3H),3.73-3.81(m,1H),4.34(d,J=4.2Hz,1H),6.92(t,J=8.7Hz,1H),7.00-7.05(m,1H),7.36(t,J=8.3Hz,1H),7.52-7.62(m,3H),7.79(dd,J=1.8,10.2Hz,1H),10.10(s,1H),11.08(s,1H)。
N-{3-[3-环丙基-5-(2-氟-4-碘-苯基氨基)-6,8-二甲基-2,4,7-三氧代-3,4,6,7-四氢-2H-吡啶并[4,3-d]嘧啶-1-基]-苯基}-乙酰胺乙二醇溶剂合物:
1H-NMR(DMSO-d6,300MHz)δ0.63-0.70(m,2H),0.91-1.00(m,2H),1.24(s,3H),2.04(s,3H),2.58-2.66(m,1H),3.07(s,3H),3.36-3.41(m,4H),4.37-4.44(m,2H),6.92(t,J=8.8Hz,1H),7.00-7.05(m,1H),7.36(t,J=8.2Hz,1H),7.52-7.63(m,3H),7.79(dd,J=2.0,10.4Hz,1H),10.10(s,1H),11.08(s,1H)。
N-{3-[3-环丙基-5-(2-氟-4-碘-苯基氨基)-6,8-二甲基-2,4,7-三氧代-3,4,6,7-四氢-2H-吡啶并[4,3-d]嘧啶-1-基]-苯基}-乙酰胺3-甲基-1-丁醇溶剂合物:
1H-NMR(DMSO-d6,400MHz)δ0.64-0.69(m,2H),0.85(d,J=6.7Hz,6H),0.92-0.98(m,2H),1.25(s,3H),1.31(q,J=6.7Hz,2H),1.60-1.70(m,1H),2.04(s,3H),2.59-2.66(m,1H),3.08(s,3H),3.38-3.44(m,2H),4.26(t,J=5.1Hz,1H),6.92(t,J=8.7Hz,1H),7.01-7.05(m,1H),7.35(t,J=8.0Hz,1H),7.52-7.62(m,3H),7.78(dd,J=1.9,10.2Hz,1H),10.08(s,1H),11.07(s,1H)。
实施例4-150
按照常规方法处理N-{3-[3-环丙基-5-(4-乙炔基-2-氟苯基氨基)-6,8-二甲基-2,4,7-三氧代-3,4,6,7-四氢-2H-吡啶并[4,3-d]嘧啶-1-基]苯基}乙酰胺62,得到乙酸溶剂合物。
N-{3-[3-环丙基-5-(4-乙炔基-2-氟苯基氨基)-6,8-二甲基-2,4,7-三氧代-3,4,6,7-四氢-2H-吡啶并[4,3-d]嘧啶-1-基]苯基}乙酰胺乙酸溶剂合物:
1H-NMR(DMSO-d6,400MHz)δ0.60-0.70(m,2H),0.90-1.00(m,2H),1.26(s,3H),1.91(s,3H),2.04(s,3H),2.59-2.66(m,1H),3.10(s,3H),4.29(s,1H),7.01-7.05(m,1H),7.08(t,J=8.6Hz,1H),7.31(dd,J=1.6,8.3Hz,1H),7.36(t,J=8.1Hz,1H),7.52(dd,J=1.6,11.3Hz,1H),7.57-7.62(m,2H),10.09(s,1H),11.09(s,1H),11.94(s,1H)。
MS(ESI)m/z514[MH]+。
实施例4-151
按照常规方法处理N-{3-[5-(2-氟-4-碘苯基氨基)-3,6,8-三甲基-2,4,7-三氧代-3,4,6,7-四氢-2H-吡啶并[4,3-d]嘧啶-1-基]苯基}甲磺酰胺72,得到钠盐。
N-{3-[5-(2-氟-4-碘苯基氨基)-3,6,8-三甲基-2,4,7-三氧代-3,4,6,7-四氢-2H-吡啶并[4,3-d]嘧啶-1-基]苯基}甲磺酰胺钠盐:
1H-NMR(DMSO-d6,300MHz)δ1.25(s,3H),2.78(s,3H),2.97(s,3H),3.24(s,3H),6.68(t,J=8.7Hz,1H),6.77(d,J=7.5Hz,1H),6.90-7.00(m,2H),7.10-7.30(m,2H),7.37(d,J=10.0Hz,1H),10.30(brs,1H)。
MS(ESI)m/z626[MH]+。
实施例5(癌细胞系的生长抑制效果的评价)
在96孔板中以1.0×104细胞/90μL/孔培养肾癌细胞系ACHN细胞或结肠直肠的癌细胞系HT-29细胞24小时,随后加入溶解在DMSO(二甲亚砜)中的试验物。在18小时后,加入3H-胸腺嘧啶脱氧核苷(0.25μCi/孔)并培养细胞6小时。使用细胞收获器,在UniFilter-96GF/B玻璃滤器上回收细胞并且通过TopCount(Packard)测定细胞摄取的3H放射活性。作为对照,使用DMSO并且以抑制被细胞摄取的3H放射活性至对照组的50%所需的浓度(IC50)来表示试验物的活性。测试重复三次。
结果如下表5-1至5-8所示。
A:不少于0.1μM且少于1μM
B:不少于0.01μM且少于0.1μM
C:少于0.01μM
表5-1
实施例 | IC50 | 实施例 | IC50 | ||
ACHN细胞 | HT-29细胞 | ACHN细胞 | HT-29细胞 | ||
1-1 | B | C | 1-117 | A | |
1-2 | A | 1-126 | A | ||
1-7 | A | 1-127 | A | ||
1-11 | A | 1-129 | A | ||
1-55 | A | 1-132 | A | ||
1-88 | A | A | 1-133 | A | |
1-89 | A | B | 1-136 | A | |
1-95 | A | 1-138 | A | ||
1-96 | A | 1-140 | A | ||
1-97 | A | 1-142 | A | ||
1-99 | A | 1-143 | A | ||
1-100 | A | 1-151 | A | ||
1-106 | A | A | 1-152 | A | B |
1-111 | A | 1-153 | A | ||
1-112 | A | B | 1-156 | A | |
1-113 | A | A | 1-159 | A | |
1-114 | A | A | 1-163 | A | |
1-116 | A | 1-164 | B |
表5-2
实施例 | IC50 | 实施例 | IC50 | ||
ACHN细胞 | HT-29细胞 | ACHN细胞 | HT-29细胞 | ||
1-165 | A | 1-205 | A | C | |
1-166 | B | 1-206 | A | ||
1-168 | B | 1-207 | B | C | |
1-171 | B | 1-208 | B | C | |
1-175 | A | 1-211 | A | ||
1-176 | A | B | 1-212 | A | C |
1-183 | A | 1-213 | A | B | |
1-185 | A | B | 1-214 | B | |
1-186 | B | 1-215 | A | ||
1-188 | A | B | 1-216 | A | |
1-189 | A | 1-217 | A | ||
1-190 | A | 1-218 | B | ||
1-191 | A | B | 1-219 | A | B |
1-192 | A | B | 1-221 | B | C |
1-193 | A | C | 1-222 | A | B |
1-199 | A | B | 1-223 | A | B |
1-200 | A | B | 1-224 | A | C |
1-201 | A | 1-225 | A |
表5-3
实施例 | IC50 | 实施例 | IC50 | ||
ACHN细胞 | HT-29细胞 | ACHN细胞 | HT-29细胞 | ||
1-226 | A | B | 1-253 | A | B |
1-227 | B | 1-255 | A | ||
1-228 | A | B | 1-257 | C | C |
1-229 | A | 1-258 | A | ||
1-230 | A | 1-259 | A | C | |
1-232 | A | B | 1-260 | C | C |
1-233 | A | 1-262 | B | C | |
1-234 | A | 1-263 | A | C | |
1-235 | A | 1-264 | A | B | |
1-236 | A | 1-265 | A | B | |
1-240 | B | B | 1-266 | A | C |
1-242 | A | B | 1-267 | A | B |
1-243 | A | B | 1-268 | B | B |
1-244 | A | 1-270 | A | B | |
1-245 | B | C | 1-271 | B | C |
1-246 | A | B | 1-272 | B | B |
1-249 | A | B | 1-273 | A | |
1-252 | B | 3-1 | A | A |
表5-4
实施例 | IC50 | 实施例 | IC50 | ||
ACHN细胞 | HT-29细胞 | ACHN细胞 | HT-29细胞 | ||
1-274 | C | C | 1-295 | A | B |
1-275 | B | C | 1-296 | A | C |
1-276 | A | B | 1-297 | B | C |
1-277 | B | 1-298 | B | C | |
1-278 | A | B | 1-299 | A | B |
1-279 | A | B | 1-301 | A | B |
1-282 | A | B | 1-302 | B | C |
1-283 | A | B | 1-303 | A | B |
1-284 | A | B | 1-304 | A | B |
1-285 | B | B | 1-305 | B | |
1-286 | B | C | 1-307 | A | B |
1-287 | A | B | 1-308 | A | B |
1-288 | B | 1-309 | B | C | |
1-289 | C | C | 1-310 | B | C |
1-290 | B | C | 1-311 | C | C |
1-292 | B | 1-313 | B | ||
1-293 | A | A | 1-313 | B | |
1-294 | B | 1-315 | A | B |
表5-5
实施例 | IC50 | 实施例 | IC50 | ||
ACHN细胞 | HT-29细胞 | ACHN细胞 | HT-29细胞 | ||
1-316 | A | B | 1-339 | A | |
1-317 | A | B | 1-340 | B | C |
1-318 | A | C | 1-341 | B | C |
1-319 | C | C | 1-342 | A | C |
1-320 | B | C | 1-343 | A | B |
1-321 | B | C | 3-4 | B | C |
1-322 | B | C | 3-5 | B | C |
1-324 | B | 3-6 | A | C | |
1-325 | A | B | 3-7 | C | C |
1-326 | A | 3-8 | B | C | |
1-327 | A | B | 4-1 | C | C |
1-328 | A | B | 4-2 | C | C |
1-333 | B | C | 4-3 | B | C |
1-334 | A | 4-4 | A | ||
1-335 | A | B | 4-5 | A | B |
1-336 | B | C | 4-6 | B | C |
1-337 | B | C | 4-7 | A | |
1-338 | B | C | 4-9 | B | C |
表5-6
实施例 | IC50 | 实施例 | IC50 | ||
ACHN细胞 | HT-29细胞 | ACHN细胞 | HT-29细胞 | ||
4-10 | A | B | 4-42 | B | C |
4-11 | B | C | 4-43 | A | B |
4-12 | B | C | 4-44 | A | B |
4-13 | A | 4-45 | A | B | |
4-15 | B | C | 4-46 | A | B |
4-16 | C | C | 4-47 | A | |
4-19 | B | C | 4-48 | B | C |
4-20 | B | C | 4-49 | B | C |
4-21 | B | C | 4-50 | A | B |
4-25 | B | C | 4-51 | B | C |
4-26 | B | C | 4-52 | A | A |
4-27 | A | 4-53 | A | B | |
4-33 | C | C | 4-54 | C | C |
4-34 | C | C | 4-55 | B | C |
4-37 | A | B | 4-56 | A | B |
4-39 | A | 4-57 | A | ||
4-40 | B | C | 4-58 | B | C |
4-41 | B | B | 4-59 | B | C |
表5-7
实施例 | IC50 | 实施例 | IC50 | ||
ACHN细胞 | HT-29细胞 | ACHN细胞 | HT-29细胞 | ||
4-60 | B | C | 4-85 | A | |
4-61 | B | B | 4-87 | A | B |
4-63 | B | 4-88 | C | C | |
4-64 | A | B | 4-89 | A | B |
4-66 | A | B | 4-90 | A | B |
4-67 | B | C | 4-91 | B | C |
4-70 | B | C | 4-92 | B | C |
4-71 | A | B | 4-93 | B | C |
4-72 | B | C | 4-94 | A | B |
4-73 | B | C | 4-95 | A | B |
4-74 | B | C | 4-96 | A | B |
4-75 | B | 4-97 | B | C | |
4-76 | B | C | 4-98 | B | C |
4-77 | B | C | 4-99 | A | C |
4-78 | A | B | 4-101 | B | C |
4-80 | B | C | 4-102 | A | B |
4-81 | B | C | 4-103 | A | C |
4-82 | B | C | 4-104 | C | C |
表5-8
实施例 | IC50 | 实施例 | IC50 | ||
ACHN细胞 | HT-29细胞 | ACHN细胞 | HT-29细胞 | ||
4-105 | B | C | 4-121 | B | C |
4-106 | B | C | 4-122 | B | C |
4-107 | B | C | 4-123 | A | C |
4-108 | B | C | 4-124 | B | C |
4-109 | B | C | 4-125 | C | C |
4-110 | B | C | 4-126 | C | C |
4-111 | A | B | 4-127 | B | C |
4-112 | A | C | 4-128 | B | C |
4-113 | C | C | 4-133 | A | |
4-114 | B | C | 4-135 | A | |
4-115 | B | C | 4-138 | A | |
4-116 | A | C | 4-140 | A | |
4-117 | A | C | 4-145 | A | |
4-118 | B | C | 4-146 | A | |
4-119 | B | C | 4-147 | A | |
4-120 | B | C | 4-148 | A |
实施例6(p15诱导活性的评价)
在6孔板中以2.5×105细胞/1.8mL/孔培养ACHN细胞或HT-29细胞24小时,随后加入溶解在DMSO中的试验物(0.1μM)。24小时后,使用胰蛋白酶-EDTA(乙二胺四乙酸)将细胞分离并用NuPAGE LDS样品缓冲剂(Invitrogen)溶解。使用RC DC蛋白质分析药剂盒(BIO-RAD)测定样品的蛋白质浓度,并通过Western blotting使用抗-p15抗体分析样品,其量相应于10μg BSA(牛血清白蛋白)。通过比重计测定抗-p15抗体染色带的密度来测定p15蛋白质的量。使用DMSO作为对照,进行n=2次试验并测定平均蛋白质的量。
结果如以下表6-1至6-6所示。
+:与DMSO比较,对p15蛋白质的诱导不低于1.5-倍
表6-1
实施例 | P15蛋白质的诱导 | 实施例 | P15蛋白质的诱导 |
1-1 | + | 1-43 | + |
1-4 | + | 1-46 | + |
1-6 | + | 1-49 | + |
1-7 | + | 1-51 | + |
1-8 | + | 1-53 | + |
1-9 | + | 1-55 | + |
1-11 | + | 1-65 | + |
1-12 | + | 1-77 | + |
1-16 | + | 1-78 | + |
1-17 | + | 1-79 | + |
1-26 | + | 1-80 | + |
1-33 | + | 1-81 | + |
1-34 | + | 1-84 | + |
1-35 | + | 1-85 | + |
1-36 | + | 1-86 | + |
1-37 | + | 1-88 | + |
1-38 | + | 1-89 | + |
1-40 | + | 1-92 | + |
表6-2
实施例 | P15蛋白质的诱导 | 实施例 | P15蛋白质的诱导 |
1-93 | + | 1-114 | + |
1-94 | + | 1-116 | + |
1-95 | + | 1-117 | + |
1-96 | + | 1-126 | + |
1-97 | + | 1-127 | + |
1-99 | + | 1-131 | + |
1-100 | + | 1-132 | + |
1-102 | + | 1-133 | + |
1-103 | + | 1-136 | + |
1-104 | + | 1-137 | + |
1-106 | + | 1-138 | + |
1-107 | + | 1-142 | + |
1-108 | + | 1-143 | + |
1-109 | + | 1-146 | + |
1-110 | + | 1-151 | + |
1-111 | + | 1-152 | + |
1-112 | + | 1-153 | + |
1-113 | + | 1-154 | + |
表6-3
实施例 | P15蛋白质的诱导 | 实施例 | P15蛋白质的诱导 |
1-156 | + | 1-199 | + |
1-157 | + | 1-200 | + |
1-162 | + | 1-205 | + |
1-163 | + | 1-207 | + |
1-165 | + | 1-208 | + |
1-166 | + | 1-212 | + |
1-167 | + | 1-213 | + |
1-168 | + | 1-218 | + |
1-172 | + | 1-219 | + |
1-173 | + | 1-221 | + |
1-175 | + | 1-222 | + |
1-176 | + | 1-223 | + |
1-183 | + | 1-224 | + |
1-185 | + | 1-226 | + |
1-186 | + | 1-240 | + |
1-188 | + | 1-242 | + |
1-191 | + | 1-243 | + |
1-192 | + | 1-245 | + |
1-193 | + | 1-246 | + |
表6-4
实施例 | P15蛋白质的诱导 | 实施例 | P15蛋白质的诱导 |
1-264 | + | 1-301 | + |
1-265 | + | 1-317 | + |
1-266 | + | 1-318 | + |
1-268 | + | 1-319 | + |
1-271 | + | 1-320 | + |
1-272 | + | 1-321 | + |
1-282 | + | 1-322 | + |
1-283 | + | 1-325 | + |
1-284 | + | 1-327 | + |
1-285 | + | 1-328 | + |
1-286 | + | 1-333 | + |
1-287 | + | 1-336 | + |
1-289 | + | 1-337 | + |
1-290 | + | 1-338 | + |
1-293 | + | 1-340 | + |
1-295 | + | 1-341 | + |
1-296 | + | 1-342 | + |
1-297 | + | 3-4 | + |
1-298 | + | 3-6 | + |
表6-5
实施例 | P15蛋白质的诱导 | 实施例 | P15蛋白质的诱导 |
3-7 | + | 4-53 | + |
3-8 | + | 4-54 | + |
4-1 | + | 4-55 | + |
4-2 | + | 4-56 | + |
4-3 | + | 4-58 | + |
4-6 | + | 4-59 | + |
4-9 | + | 4-60 | + |
4-10 | + | 4-61 | + |
4-11 | + | 4-64 | + |
4-12 | + | 4-66 | + |
4-15 | + | 4-67 | + |
4-16 | + | 4-70 | + |
4-21 | + | 4-71 | + |
4-43 | + | 4-72 | + |
4-45 | + | 4-73 | + |
4-48 | + | 4-74 | + |
4-49 | + | 4-76 | + |
4-50 | + | 4-77 | + |
4-51 | + | 4-78 | + |
表6-6
实施例 | P15蛋白质的诱导 | 实施例 | P15蛋白质的诱导 |
4-80 | + | 4-110 | + |
4-81 | + | 4-111 | + |
4-82 | + | 4-112 | + |
4-88 | + | 4-113 | + |
4-89 | + | 4-114 | + |
4-90 | + | 4-115 | + |
4-91 | + | 4-116 | + |
4-92 | + | 4-117 | + |
4-93 | + | 4-118 | + |
4-97 | + | 4-119 | + |
4-98 | + | 4-120 | + |
4-101 | + | 4-121 | + |
4-102 | + | 4-122 | + |
4-103 | + | 4-123 | + |
4-104 | + | 4-124 | + |
4-105 | + | 4-125 | + |
4-106 | + | 4-126 | + |
4-107 | + | 4-127 | + |
4-108 | + | 4-128 | + |
4-109 | + |
实施例7(细胞周期分析)
在6孔板中以2.5×105细胞/1.8mL/孔培养ACHN细胞或HT-29细胞24小时,随后加入溶解在DMSO中的试验物(少于10μM)。24小时后,使用胰蛋白酶-EDTA将细胞分离并使用CycleTESTPLUS(BECKTON DICKINSON)药剂盒通过流式细胞术分析单个细胞的DNA量,并计算细胞在G0/G1期S期G2/M期的比例。使用DMSO作为对照并进行n=2次试验。
结果如下表7-1和7-2所示。
G1:与DMSO比较,G0/G1期细胞比率不低于1.2倍。
表7-1
实施例 | G0/G1期的细胞比率 | 实施例 | G0/G1期的细胞比率 |
1-2 | G1 | 1-78 | G1 |
1-4 | G1 | 1-84 | G1 |
1-6 | G1 | 1-85 | G1 |
1-7 | G1 | 1-86 | G1 |
1-9 | G1 | 1-88 | G1 |
1-11 | G1 | 1-89 | G1 |
1-21 | G1 | 1-90 | G1 |
1-25 | G1 | 1-91 | G1 |
1-26 | G1 | 1-92 | G1 |
1-33 | G1 | 1-93 | G1 |
1-34 | G1 | 1-94 | G1 |
1-38 | G1 | 1-95 | G1 |
1-43 | G1 | 1-97 | G1 |
1-49 | G1 | 1-99 | G1 |
1-50 | G1 | 1-100 | G1 |
1-51 | G1 | 1-101 | G1 |
1-55 | G1 | 1-102 | G1 |
1-69 | G1 | 1-103 | G1 |
1-77 | G1 | 1-104 | G1 |
表7-2
实施例 | G0/G1期的细胞比率 | 实施例 | G0/G1期的细胞比率 |
3-7 | G1 | 4-70 | G1 |
4-1 | G1 | 4-82 | G1 |
4-3 | G1 | 4-104 | G1 |
4-16 | G1 | 4-126 | G1 |
实施例8(裸鼠异种移植模型的评价)
在乙醚麻醉下将处于对数生长期的HT-29细胞(5.0×106细胞/100μL/头,悬浮于HBSS(Hanks’溶液)中)植入小鼠(Balb/c-nu/nu)右侧腹部。植入5天后,测定肿瘤的长直径和短直径,并将小鼠分组使得每一组具有相等的平均肿瘤体积。对于分组,使用分组软件(generalgrouping system(Visions)。从分组的第二天起,每天两次重复口服给予悬浮于0.5%MC(甲基纤维素)的试验物10天(30mg/kg)。每周测定肿瘤体积两次并将其用作抗肿瘤活性的指数。使用0.5%MC作为对照并进行n=6-8次试验。
根据下式计算抗肿瘤活性的指数(T/C(%))。
T/C(%)=(试验物处理组的平均肿瘤体积)/(赋形剂组的平均肿瘤体积)×100
根据下式计算肿瘤体积。
肿瘤体积(mm3)=L×W×W/2(L:肿瘤的长直径(mm),W:肿瘤的短直径(mm))
表8
实施例 | T/C(%) |
1-257 | 26 |
3-8 | 27 |
4-1 | 3 |
4-15 | 31 |
4-16 | 10 |
4-49 | 35 |
4-54 | 11 |
4-70 | 31 |
实施例9(p27蛋白质诱导试验)
在6孔板中以2.5×105细胞/1.8mL/孔培养ACHN细胞或HT-29细胞24小时,加入溶解在DMSO中的试验物(0.1μM)。24小时后,使用胰蛋白酶-EDTA(乙二胺四乙酸)将细胞分离并用NuPAGE LDS样品缓冲剂(Invitrogen)溶解。使用RC DC蛋白质分析药剂盒(BIO-RAD)测定样品的蛋白质浓度,并使用抗-p27抗体通过Western blotting分析样品,其量相当于10μg BSA(牛血清白蛋白)。通过比重计测定抗-p27抗体染色带的密度来定量p27蛋白质。使用DMSO作为对照,进行n=2次试验并测定平均蛋白质量。
结果如下表9-1至9-4所示。
+:与DMSO比较,对p27蛋白质的诱导不低于1.5倍
表9-1
实施例 | p27蛋白质的诱导 | 实施例 | p27蛋白质的诱导 |
1-1 | + | 1-243 | + |
1-89 | + | 1-245 | + |
1-112 | + | 1-249 | + |
1-114 | + | 1-253 | + |
1-142 | + | 1-257 | + |
1-152 | + | 1-259 | + |
1-175 | + | 1-260 | + |
1-182 | + | 1-262 | + |
1-185 | + | 1-263 | + |
1-186 | + | 1-264 | + |
1-218 | + | 1-265 | + |
1-219 | + | 1-266 | + |
1-221 | + | 1-268 | + |
1-222 | + | 1-271 | + |
1-224 | + | 1-272 | + |
1-226 | + | 1-274 | + |
1-228 | + | 1-275 | + |
1-240 | + | 1-279 | + |
1-242 | + | 1-282 | + |
表9-2
实施例 | p27蛋白质的诱导 | 实施例 | p27蛋白质的诱导 |
1-283 | + | 1-311 | + |
1-284 | + | 1-315 | + |
1-285 | + | 1-316 | + |
1-286 | + | 1-317 | + |
1-287 | + | 1-318 | + |
1-289 | + | 1-319 | + |
1-290 | + | 1-320 | + |
1-293 | + | 1-322 | + |
1-295 | + | 1-325 | + |
1-296 | + | 1-327 | + |
1-297 | + | 1-328 | + |
1-298 | + | 1-336 | + |
1-299 | + | 1-337 | + |
1-301 | + | 1-338 | + |
1-302 | + | 1-340 | + |
1-303 | + | 1-341 | + |
1-307 | + | 1-342 | + |
1-309 | + | 3-4 | + |
1-310 | + | 3-5 | + |
表9-3
实施例 | p27蛋白质的诱导 | 实施例 | p27蛋白质的诱导 |
3-6 | + | 4-51 | + |
3-7 | + | 4-53 | + |
3-8 | + | 4-54 | + |
4-1 | + | 4-55 | + |
4-2 | + | 4-56 | + |
4-3 | + | 4-58 | + |
4-6 | + | 4-59 | + |
4-9 | + | 4-60 | + |
4-10 | + | 4-61 | + |
4-11 | + | 4-64 | + |
4-12 | + | 4-66 | + |
4-15 | + | 4-67 | + |
4-16 | + | 4-70 | + |
4-21 | + | 4-71 | + |
4-43 | + | 4-72 | + |
4-45 | + | 4-73 | + |
4-48 | + | 4-74 | + |
4-49 | + | 4-76 | + |
4-50 | + | 4-77 | + |
表9-4
实施例 | p27蛋白质的诱导 | 实施例 | p27蛋白质的诱导 |
4-78 | + | 4-108 | + |
4-80 | + | 4-109 | + |
4-81 | + | 4-110 | + |
4-82 | + | 4-113 | + |
4-88 | + | 4-114 | + |
4-89 | + | 4-115 | + |
4-90 | + | 4-116 | + |
4-91 | + | 4-117 | + |
4-92 | + | 4-118 | + |
4-93 | + | 4-119 | + |
4-97 | + | 4-120 | + |
4-98 | + | 4-121 | + |
4-99 | + | 4-122 | + |
4-101 | + | 4-123 | + |
4-102 | + | 4-124 | + |
4-103 | + | 4-125 | + |
4-104 | + | 4-126 | + |
4-105 | + | 4-127 | + |
4-106 | + | 4-128 | + |
4-107 | + |
实施例10(MEK酶抑制活性的评价)
往评价体系中加入溶解于DMSO中的试验物,所述评价体系中混合有Raf(B-Raf或c-Raf)和MEK(MEK1或MEK2)或混合有MEK(MEK1或MEK2)和ERK2。随后加入含[γ-32P]-ATP的ATP溶液启动酶反应。在30℃下反应20分钟后,将反应混合物进行SDS-PAGE(十二烷基硫酸钠-聚丙烯酰胺凝胶电泳)并通过Bio ImagingAnalyzer(BAS2000,Fuji photo film)测定磷酸化的MEK或ERK2的放射活性。
将加入对照物的溶剂的放射活性作为100%,测定试验物的抑制率(%),并计算IC50值。
进行n=1次试验并显示两次或三次试验的平均值。结果总结于表10。
表10不同酶反应体系的IC50(μM)
酶 | 实施例1-257 | 实施例4-1 |
B-RafMEK1 | 0.0060 | 0.0067 |
B-RafMEK2 | 0.0188 | 0.0128 |
c-RafMEK1 | - | - |
c-RafMEK2 | 0.0078 | 0.0130 |
MEK1ERK2 | 1.3 | 0.290 |
MEK2ERK2 | 1.6 | 0.190 |
实施例11(小鼠胶原关节炎模型的评价)
用Freund’s完全辅料将牛II型胶原(100μg)重新悬浮并将其皮内给予(首次免疫法)小鼠(DBA/1)的尾头。三周后,作为加强免疫给予尾头相同的胶原,从而诱发多种关节炎。在一天一次强制口服给予试验物38天后立即进行首次免疫,随后在加强免疫后每周一次计算关节炎得分来检查关节炎发作抑制效果。对于关节炎得分,小鼠的各个四肢的肿胀水平以4个水平记分,并取四肢的平均得分作为各个体的关节炎得分。进行n=16次试验。
在加强免疫(在持续给予38天后)后17天溶剂给予组的关节炎得分为2.2和对于1mg/kg的实施例4-1化合物的乙酸溶剂合物给予组关节炎得分为0.57(p<0.001,wilcoxson试验),因而对关节炎发作表现出显著的抑制作用。
实施例12(炎症细胞因子产生的评价)
实施例4-1和实施例4-16的化合物抑制LPS刺激人外周血衍生的单核细胞(PBMC)产生TNF-α或IL-6。
还可得到与实施例1-1至1-148相同的或如必要采用其他常规方法得到的表11-1至11-9所示化合物。
表11-1
表11-2
表11-3
Py:吡啶基,Ph:苯基Bzl:苄基
表11-4
表11-5
表11-6
表11-7
表11-8
表11-9
上述表1-1至表4-25所示的实施例化合物的MS和NMR数据见下。
实施例1-1
MS ESI m/e:590,592(M+H),588,590(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.71-0.79(m,2H),0.99-1.08(m,2H),2.64-2.70(m,4H),3.02(s,3H),5.36(s,1H),7.13(d,J=9.0Hz,1H),7.24-7.30(m,2H),7.43-7.54(m,3H),7.74(d,J=9.0Hz,1H),10.00(brs,1H),10.53(brs,1H).
实施例1-2
实施例1-3
实施例1-4
MS ESI m/e:470,471(M+H),473,474,469(M-H),470,471.
1H-NMR(DMSO-d6,300MHz)δ2.68(s,3H),5.47(s,1H),7.24-7.63(m,14H),10.63(brs,1H).
实施例1-5
MS ESI m/e:470,471(M+H),473,474,469(M-H),470,471.
1H-NMR(DMSO-d6,300MHz)δ2.68(s,3H),5.60(s,1H),7.25-7.57(m,14H),10.52(brs,1H).
实施例1-6
MS ESI m/e:451(M+H),449(M-H).
1H-NMR(CDCl3,400MHz)δ2.34(s,3H),2.88(s,3H),5.79(s,1H),7.08-7.18(m,4H),7.27-7.32(m,2H),7.37-7.54(m,8H),10.24(s,1H).
实施例1-7
MS ESI m/e:480(M+H).
1H-NMR(CDCl3,400MHz)δ2.87(s,3H),2.95(s,6H),5.66(s,1H),6.67-6.73(m,2H),7.05-7.11(m,2H),7.27-7.32(m,2H),7.37-7.55(m,8H),10.24(s,1H).
实施例1-8
MS ESI m/e:455(M+H),453 M-H).
1H-NMR(CDCl3,400MHz)δ2.88(s,3H),5.69(s,1H),7.03-7.10(m,2H),7.17-7.23(m,2H),7.27-7.32(m,2H),7.37-7.55(m,8H),10.24(s,1H).
实施例1-9
MS ESI m/e:467(M+H),465(M-H).
1H-NMR(CDCl3,300MHz)δ2.88(s,3H),3.81(s,3H),5.67(s,1H),6.86-6.95(m,2H),7.12-7.20(m,2H),7.28-7.34(m,2H),7.37-7.58(m,8H),10.14(s,1H).
实施例1-10
MS ESI m/e:485(M+H),483(M-H).
1H-NMR(CDCl3,400MHz)δ2.86(s,3H),4.32(d,J=4.0Hz,2H),5.39(s,1H),7.23-7.31(m,6H),7.34-7.38(m,2H),7.39-7.52(m,6H),9.03(t,J=6.0Hz,1H).
实施例1-11
MS ESI m/e:515,517(M+H),513,515(M-H).
1H-NMR(DMSO-d6,400MHz)δ2.67(s,3H),5.56(s,1H),7.25-7.29(m,2H),7.34-7.38(m,2H),7.41-7.55(m,8H),7.57-7.61(m,2H),10.48(s,1H).
实施例1-12
实施例1-13
实施例1-14
MS ESIm/e:485(M+H).
1H-NMR(DMSO-d6,400MHz)δ2.74(s,3H),3.22(s,3H),6.03(s,1H),6.99-7.05(m,4H),7.21-7.25(m,2H),7.32-7.40(m,3H),7.44-7.54(m,5H).
实施例1-15
MS ESI m/e:,443(M+H).
1H-NMR(DMSO-d6,300MHz)δ1.17-1.95(m,11H),2.63(s,3H),5.28(s,1H),7.31-7.55(m,10H),8.76(d,J=6.0Hz,1H).
实施例1-16
MS ESI m/e:481(M+H),479(M-H).
1H-NMR(CDCl3,300MHz)δ2.88(s,3H),5.69(s,1H),5.99(s,2H),6.85-6.82(m,3H),7.28-7.34(m,2H),7.37-7.58(m,8H),10.12(s,1H).
实施例1-17
MS ESI m/e:505,507(M+H),503,505(M-H).
1H-NMR(CDCl3,400MHz)δ2.90(s,3H),5.87(s,1H),7.07-7.11(m,1H),7.26-7.31(m,2H),7.35-7.56(m,10H),10.45(s,1H).
实施例1-18
MS ESI m/e:499(M+H),497(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.56(t,J=7.5Hz,3H),1.05-1.12(m,2H),3.30-3.40(m,2H),5.54(s,1H),7.31-7.56(m,14H),10.52(s,1H).
实施例1-19
MS ESI m/e:513(M+H),511(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.62(s,3H),0.64(s,3H),1.04(d,J=6.0Hz,1H),1.94-2.06(m,1H),3.13(brs,1H),5.56(s,1H),7.32-7.60(m,14H),10.58(s,1H).
实施例1-20
MS ESI m/e:515(M+H),513(M-H).
1H-NMR(DMSO-d6,300MHz)δ3.04(t,J=6.0Hz,2H),3.09(s,3H),3.61(t,J=4.5Hz,2H),5.53(s,1H),7.32-7.60(m,14H),10.52(s,1H).
实施例1-21
MS ESI m/e:465(M+H),463(M-H).
1H-NMR(DMSO-d6,400MHz)δ1.19(t,J=8.0Hz,3H),2.61(q,J=8.0Hz,2H),2.66(s,3H),5.46(s,1H),7.17-7.21(m,2H),7.25-7.29(m,2H),7.34-7.38(m,2H),7.41-7.55(m,8H),10.37(s,1H).
实施例1-22
MS ESI m/e:451(M+H),449(M-H).
1H-NMR(DMSO-d6,400MHz)δ2.21(s,3H),2.66(s,3H),5.12(s,1H),7.18-7.55(m,14H),10.22(s,1H).
实施例1-23
MS ESI m/e:513(M+H),511(M-H).
1H-NMR(DMSO-d6,400MHz)δ2.68(s,3H),5.65(s,1H),7.33-7.56(m,15H),7.66-7.74(m,4H),10.56(s,1H).
实施例1-24
MS ESI m/e:467(M+H),465(M-H).
1H-NMR(CDCl3,400MHz)δ2.89(s,3H),3.82(s,3H),5.83(s,1H),6.91-6.98(m,2H),7.13-7.19(m,1H),7.27-7.33(m,2H),7.37-7.54(m,9H),10.21(s,1H).
实施例1-25
MS ESI m/e:479(M+H),477(M-H).
1H-NMR(CDCl3,400MHz)δ1.25(d,J=6.7Hz,6H),2.85-2.95(m,1H),2.88(s,3H),5.80(s,1H),7.12-7.17(m,2H),7.19-7.24(m,2H),7.27-7.32(m,2H),7.37-7.55(m,8H),10.24(s,1H).
实施例1-26
MS ESI m/e:505,507(M+H),503,505(M-H).
1H-NMR(CDCl3,400MHz)δ2.89(s,3H),5.70(s,1H),7.22-7.32(m,3H),7.37-7.55(m,10H),10.39(s,1H).
实施例1-27
MS ESI m/e:520(M+H).
1H-NMR(CDCl3,400MHz)δ1.54-1.62(m,4H),1.67-1.75(m,4H),2.87(s,3H),3.14(t,J=5.6Hz,2H),5.70(s,1H),6.87-6.93(m,2H),7.06-7.11(m,2H),7.27-7.32(m,2H),7.37-7.54(m,8H),10.09(s,1H).
实施例1-28
MS ESI m/e:508(M+H),506(M-H).
1H-NMR(CDCl3,400MHz)δ1.16(t,J=7.1Hz,6H),2.87(s,3H),3.34(q,J=7.1Hz,4H),5.65(s,1H),6.60-6.65(m,2H),7.00-7.06(m,2H),7.27-7.31(m,2H),7.36-7.54(m,8H),9.98(s,1H).
实施例1-29
MS ESI m/e:527(M+H),525(M-H).
1H-NMR(CDCl3,300MHz)δ2.88(s,3H),3.97(s,2H),5.83(s,1H),7.12-7.58(m,19H),10.29(s,1H).
实施例1-30
MS ESI m/e:522(M+H),520(M-H).
1H-NMR(DMSO-d6,300MHz)δ2.66(s,3H),3.10-3.13(m,4H),3.73-3.76(m,4H),5.32(s,1H),7.01(d,J=9.0Hz,2H),7.15(d,J=9.0Hz,2H),7.35-7.57(m,10H),10.20(brs,1H).
实施例1-31
MS ESI m/e:493(M+H),491(M-H).
1H-NMR(DMSO-d6,400MHz)δ0.90(t,J=8.0Hz,3H),1.26-1.36(m,2H),1.52-1.60(m,2H),2.58(t,J=8.0Hz,2H),2.66(s,3H),5.46(s,1H),7.18(d,J=8.0Hz,2H),7.25(d,J=8.0Hz,2H),7.35-7.37(m,2H),7.41-7.54(m,8H),10.36(brs,1H).
实施例1-32
MS ESI m/e:409(M+H),407(M-H).
1H-NMR(DMSO-d6,300MHz)δ3.46(s,3H),3.48(s,3H),5.49(s,1H),7.28-7.34(m,4H),7.41-7.53(m,5H),10.44(brs,1H).
实施例1-33
MS ESI m/e:505(M+H),503(M-H).
1H-NMR(DMSO-d5,400MHz)δ2.67(s,3H),5.78(s,1H),7.34(d,J=8.0Hz,2H),7.40-7.53(m,10H),7.73(d,J=8.0Hz,2H),10.75(brs,1H).
实施例1-34
MS ESI m/e:485(M+H),483(M-H).
1H-NMR(DMSO-d6,300MHz)δ2.32(s,3H),2.67(s,3H),5.35(s,1H),7.23-7.56(m,13H),10.48(brs,1H).
实施例1-35
MS ESI m/e:409(M+H),407(M-H).
1H-NMR(DMSO-d6,300MHz)δ2.61(s,3H),3.26(s,3H),5.50(s,1H),7.35(d,J=6.0Hz,2H),7.44-7.54(m,5H),7.49(d,J=6.0Hz,2H),10.62(brs,1H).
实施例1-36
MS ESI m/e:431(M+H).
1H-NMR(CDCl3,400MHz)δ1.00(s,9H),2.86(s,3H),2.92(d,J=8.0Hz,2H),5.43(s,1H),7.24-7.29(m,2H),7.34-7.53(m,8H),8.78(t,J=6.0Hz,1H).
实施例1-37
MS ESI m/e:481(M+H),479(M-H).
1H-NMR(DMSO-d6,300MHz)δ2.70(s,3H),5.85(s,1H),7.36-7.54(m,10H),7.43(d,J=9.0Hz,2H),7.97(d,J=9.0Hz,2H),10.81(brs,1H).
实施例1-38
MS ESI m/e:465(M+H),463(M-H).
1H-NMR(CDCl3,300MHz)δ1.18(t,J=7.5Hz,3H),2.63(q,J=7.5Hz,2H),2.88(s,3H),5.43(s,1H),7.20-7.36(m,6H),7.39-7.57(m,8H),10.07(s,1H).实施例1-39
MS ESI m/e:507(M+H),505(M-H).
1H-NMR(CDCl3,300MHz)δ0.78(t,J=7.3Hz,6H),1.44-1.77(m,4H),2.25-2.38(m,1H),2.89(s,3H),5.85(s,1H),7.10-7.19(m,4H),7.28-7.34(m,2H),7.38-7.57(m,8H),10.28(s,1H).
实施例1-40
MS ESI m/e:535(M+H),533(M-H).
1H-NMR(CDCl3,300MHz)δ0.85(t,J=7.4Hz,6H),1.08-1.24(m,4H),1.45-1.64(m,4H),2.45-2.58(m,1H),2.89(s,3H),5.84(s,1H),7.10-7.18(m,4H),7.28-7.34(m,2H),7.38-7.57(m,8H),10.27(s,1H).
实施例1-41
MS ESI m/e:497(M+H),495(M-H).
1H-NMR(CDCl3,400MHz)δ0.79-1.00(m,4H),1.70-1.78(m,1H),5.73(s,1H),7.12-7.18(m,2H),7.26-7.34(m,4H),7.35-7.55(m,8H),10.35(s,1H).
实施例1-42
MS ESI m/e:539,541(M+H),537,539(M-H).
1H-NMR(CDCl3,400MHz)δ2.92(s,3H),5.80(s,1H),7.14-7.19(m,2H),7.19-7.24(m,2H),7.30-7.36(m,4H),7.45-7.51(m,4H),10.24(s,1H).
实施例1-43
MS ESI m/e:485(M+H),483(M-H).
1H-NMR(DMSO-d6,300MHz)δ1.57(s,3H),2.76(s,3H),6.93(d,J=9.0Hz,2H),7.31-7.54(m,12H),10.07(brs,1H).
实施例1-44
MS ESI m/e:477(M+H),475(M-H).
1H-NMR(DMSO-d6,300MHz)δ1.07-1.85(m,11H),2.60(s,3H),4.65-4.65(m,1H),5.49(s,1H),7.35-7.54(m,5H),10.63(brs,1H).
实施例1-45
MS ESI m/e:485(M+H),483(M-H).
1H-NMR(DMSO-d6,300MHz)δ2.63(s,3H),5.10(brs,2H),5.51(s,1H),7.24-7.56(m,14H),10.57(s,1H).
实施例1-46
MS ESI m/e:452(M+H).
1H-NMR(DMSO-d6,300MHz)δ2.67(s,3H),5.47(s,1H),7.19(d,J=9.0Hz,2H),7.29(d,J=6.0Hz,2H),7.35-7.40(m,2H),7.41-7.57(m,8H),10.40(s,1H).
实施例1-47
MS ESI m/e:421(M+H),419(M-H).
1H-NMR(CDCl3,300MHz)δ2.19-2.30(m,2H),4.09-4.20(m,4H),5.73(s,1H),7.11-7.19(m,2H),7.23-7.36(m,4H),7.45-7.60(m,3H),10.49(s,1H).
实施例1-48
MS ESI m/e:453(M+H),451(M-H).
1H-NMR(DMSO-d6,300MHz)δ2.65(s,3H),5.08(s,1H),6.07(brs,2H),6.52(d,J=9.0Hz,1H),7.29-7.57(m,11H),7.80(d,J=3.0Hz,1H),9.94(brs,1H).
实施例1-49
MS ESI m/e:466(M+H).
1H-NMR(DMSO-d6,300MHz)δ2.67(s,3H),2.86(s,3H),5.50(s,1H),7.33-7.57(m,14H),10.44(brs,1H).
实施例 1-50
MS ESI m/e:479(M+H),477(M-H).
1H-NMR(CDCl3,300MHz)δ0.90(t,J=7.3Hz,3H),1.51-1.66(m,2H),2.57(t,J=7.5Hz,2H),2.88(s,3H),5.43(s,1H),7.17-7.30(m,4H),7.30-7.37(m,2H),7.39-7.58(m,8H),10.07(s,1H).
实施例1-51
MS ESI m/e:493(M+H),491(M-H).
1H-NMR(CDCl3,300MHz)δ0.88(t,J=6.0Hz,3H),1.26-1.38(m,2H),1.49-1.61(m,2H),2.55-2.61(m,2H),2.88(s,3H),5.43(s,1H),7.14-7.34(m,6H),7.39-7.56(m,8H),10.07(brs,1H).
实施例1-52
MS ESI m/e:528(M+H),526(M-H).
1H-NMR(CDCl3,400MHz)δ2.15(s,6H),2.12-2.22(m,2H),3.72(t,J=6.5Hz,2H),5.81(s,1H),7.15-7.21(m,2H),7.26-7.35(m,4H),7.40-7.56(m,8H),10.35(s,1H).
实施例1-53
MS ESI m/e:485(M+H),483(M-H).
1H-NMR(CDCl3,400MHz)δ2.24(s,3H),2.88(s,3H),5.39(s,1H),7.17-7.20(m,2H),7.28-7.33(m,2H),7.37-7.55(m,9H),10.04(s,1H).
实施例1-54
MS ESI m/e:472(M+H),470(M-H).
1H-NMR(DMSO-d6,400MHz)δ2.68(s,3H),5.50(s,1H),7.34-7.38(m,2H),7.41-7.57(m,9H),7.87(dd,J=4.0,8.0Hz,1H),8.37(d,J=4.0Hz,1H),10.49(s,1H).
实施例1-55
MS ESI m/e:494(M+H),492(M-H).
1H-NMR(DMSO-d6,300MHz)δ2.15(s,3H),2.64(s,3H),2.90(s,6H),4.92(s,1H),6.63(dd,J=3.0,9.0Hz,1H),6.69(d,J=3.0Hz,1H),7.03(d,J=9.0Hz,1H),7.36-7.57(m,10H),9.89(s,1H).
实施例1-56
MS ESI m/e:497(M+H),495(M-H).
1H-NMR(CDCl3,400MHz)δ4.24(d,J=4.2Hz,2H),4.87(d,J=16.9Hz,1H),5.02(d,J=10.4Hz,1H),5.40-5.51(m,1H),5.83(s,1H),7.16-7.21(m,2H),7.26-7.30(m,2H),7.31-7.36(m,2H),7.36-7.41(m,2H),7.43-7.55(m,6H),10.40(s,1H).
实施例1-57
MS ESI m/e:482(M+H),480(M-H).
1H-NMR(CDCl3,300MHz)δ2.93(s,3H),6.20(s,1H),7.28-7.33(m,2H),7.35-7.44(m,4H),7.46-7.59(m,6H),8.20-8.27(m,2H),10.95(s,1H).
实施例1-58
MS ESI m/e:451(M+H),449(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.83(d,J=9.0Hz,6H),1.90-2.04(m,1H),3.45(s,3H),3.9 8(d,J=9.0Hz,2H),5.50(s,1H),7.28-7.34(m,4H),7.43-7.55(m,5H),10.30(brs,1H).
实施例1-59
MS ESI m/e:444(M+H),442(M-H).
1H-NMR(CDCl3,300MHz)δ3.14(s,3H),5.22(s,1H),6.96-7.03(m,2H),7.17-7.41(m,5H),7.41-7.55(m,3H),7.60(d,J=3.7Hz,1H),7.89(d,J=3.7Hz,1H),11.57(s,1H).
实施例1-60
MS ESI m/e:457(M+H),455(M-H).
1H-NMR(CDCl3,300MHz)δ5.70(s,1H),7.14-7.12(m,2H),7.30-7.43(m,6H),7.43-7.65(m,6H),10.48(s,1H).
实施例1-61
MS ESI m/e:466(M+H),464(M-H).
1H-NMR(CDCl3,300MHz)δ2.95(s,3H),5.56(s,1H),6.65-6.75(m,2H),7.02-7.14(m,2H),7.29-7.67(m,10H),10.18(s,1H).
实施例1-62
MS ESI m/e:506(M+H),504(M-H).
1H-NMR(CDCl3,300MHz)δ2.96(6H,s),4.23(d,J=4.7Hz,2H),4.88(d,J=17.3Hz,1H),5.02(d,J=10.6Hz,1H),5.40-5.55(m,1H),5.69(s,1H),6.6 8-6.75(m,2H),7.07-7.14(m,2H),7.27-7.33(m,2H),7.37-7.56(m,8H),10.10(s,1H).
实施例1-63
MS ESI m/e:472(M+H).
1H-NMR(DMSO-d6,300MHz)δ2.72(s,3H),7.16(d,J=9.0Hz,1H),7.34-7.42(m,2H),7.43-7.60(m,10H),7.82(dd,J=3.0,6.0Hz,1H),8.42(d,J=3.0Hz,1H),11.68(s,1H).
实施例1-64
MS ESI m/e:487(M+H).
1H-NMR(CDCl3,400MHz)δ2.94(s,3H),3.12(s,6H),7.26-7.32(m,2H),7.34-7.54(m,8H),7.68(s,1H),9.00(d,J=4.8Hz,1H),10.26(d,J=5.8Hz,1H).
实施例1-65
MS ESI m/e:480(M+H),478(M-H).
1H-NMR(DMSO-d6,300MHz)δ1.24(t,J=7.3Hz,3H),2.68(s,3H),3.27(q,J=7.3Hz,2H),5.53(s,1H),7.29-7.60(m,16H),10.46(s,1H).
实施例1-66
MS ESI m/e:478(M+H),477(M-H).
1H-NMR(DMSO-d6,300MHz)δ1.16(d,J=6.8Hz,6H),2.65(s,3H),3.05-3.15(m,1H),5.00(s,1H),7.27-7.54(m,14H),10.19(brs,1H).
实施例1-67
MS ESI m/e:485(M+H),483(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.56(t,J=7.0Hz,3H),3.55(q,2H,J=7.0Hz),5.53(s,1H),7.10-7.13(m,2H),7.32-7.56(m,12H),10.49(brs,1H).
实施例1-68
MS ESI m/e:528(M+H),526(M-H).
1H-NMR(CDCl3,400MHz)δ2.15(s,6H),2.88(s,3H),3.31(s,2H),5.65(s,1H),7.21-7.54(m,13H),10.50(s,1H).
实施例1-69
MS ESI m/e:493(M+H),491(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.84(d,J=6.6Hz,6H),1.78-1.88(m,1H),2.45(d,J=7.2Hz,2H),2.67(s,3H),5.15(s,1H),7.20-7.53(m,14H),10.24(brs,1H).
实施例1-70
MS ESI m/e:499,501(M+H),497,499(M-H).
1H-NMR(DMSO-d6,300MHz)δ2.37(s,3H),2.38(s,3H),2.70(s,3H),5.54(s,1H),7.21-7.50(m,12H),10.51(brs,1H).
实施例1-71
MS ESI m/e:507,508(M+H),505,506(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.85(d,J=6.5Hz,6H,),1.37-1.42(m,2H),1.49-1.53(m,1H),2.50-2.58(m,2H),2.67(s,3H),5.12(s,1H),7.24-7.55(m,14H),10.23(brs,1H).
实施例1-72
MS ESI m/e:499(M+H),497(M-H).
1H-NMR(CDCl3,300MHz)δ2.12-2.44(m,6H),2.84(s,3H),5.83(brs,1H),7.05-7.48(m,12H),10.47-10.57(m,1H).
实施例1-73
MS ESI m/e:522(M+H),520(M-H).
1H-NMR(CDCl3,300MHz)δ0.91(t,J=7.3Hz,3H),1.49-1.66(m,2H),2.50(t,J=7.7Hz,2H),2.87(s,3H),2.95(s,6H),5.33(s,1H),6.54-6.63(m,2H),7.01-7.08(m,1H),7.30-7.37(m,2H),7.38-7.58(m,8H),9.80(s,1H).
实施例1-74
MS ESI m/e:506(M+H),504(M-H).
1H-NMR(CDCl3,300MHz)δ1.91-2.03(m,2H),2.73(t,J=6.4Hz,2H),2.87(s,3H),2.88(s,3H),3.22(t,J=5.7Hz,2H),5.68(s,1H),6.54(d,J=8.4Hz,1H),6.79-6.85(m,1H),6.87-6.93(m,1H),7.28-7.34(m,2H),7.36-7.58(m,8H),10.00(s,1H).
实施例1-75
MS ESI m/e:531,533(M+H),529,531(M-H).
1H-NMR(DMSO-d6,300MHz)δ2.63(s,3H),3.72(s,3H),3.73(s,3H),;5.45(s,1H),6.97(t,J=9.1Hz,4H),7.16-7.42(m,8H),10.46(brs,1H).
实施例1-76
MS ESI m/e:499,501(M+H),497,499(M-H).
1H-NMR(DMSO-d6,300MHz)δ2.26(s.3H),2.27(s,3H),2.63(s,3H).5.46(s,1H),7.09-7.42(m,12H),10.42(brs,1H).
实施例1-77
MS ESI m/e:483,485(M+H),481,483(M-H).
1H-NMR(DMSO-d6,300MHz)δ2.68(s,3H),5.45(s,1H),7.00-7.64(m,10H),10.35(brs,1H).
实施例1-78
MS ESI m/e:423(M+H),421(M-H).
1H-NMR(CDCl3,400MHz)δ1.30(t,J=6.9Hz,3H),2.82(s,3H),4.08(q,J=7.0Hz,2H),5.77(s,1H),7.19-7.25(m,2H),7.31-7.39(m,4H),7.41-7.54(m,3H),10.53(s,1H).
实施例1-79
MS ESI m/e:507,508(M+H),505,503(M-H).
1H-NMR(DMSO-d6,300MHz)δ2.64(s,3H),5.46(s,1H),7.23-7.51(m,12H),10.37(brs,1H).
实施例1-80
MS ESI m/e:463(M+H),461(M-H).
1H-NMR(CDCl3,300MHz)δ1.52-1.67(m,2H),1.82-2.02(m,4H),2.04-2.20(m,2H),2.80(s,3H),5.21-5.37(m,1H),5.75(s,1H),7.18-7.28(m,2H),7.30-7.56(m,7H),10.54(s,1H).
实施例1-81
MS ESI m/e:437(M+H),435(M-H).
1H-NMR(CDCl3,300MHz)δ1.51(d,J=7.0Hz,6H),2.81(s,3H),5.09-5.23(m,1H),5.75(s,1H),7.18-7.28(m,2H),7.29-7.55(m,7H),10.53(s,1H).
实施例1-82
MS ESI m/e:437(M+H),435(M-H).
1H-NMR(CDCl3,400MHz)δ0.98(t,J=7.4Hz,3H),1.66-1.79(m,2H),2.82(s,3H),3.96(t,J=7.6Hz,2H),5.77(s,1H),7.20-7.25(m,2H),7.32-7.40(m,4H),7.41-7.54(m,3H),10.54(s,1H).
实施例1-83
MS ESI m/e:451(M+H),449(M-H).
1H-NMR(CDCl3,400MHz)δ0.96(t,J=7.4Hz,3H),1.34-1.47(m,2H),1.62-1.73(m,2H),2.81(s,3H),3.99(t,J=7.6Hz,2H),5.76(s,1H),7.18-7.24(m,2H),7.31-7.39(m,4H),7.41-7.52(m,3H),10.53(s,1H).
实施例1-84
MS ESI m/e:435(M+H),433(M-H).
1H-NMR(CDCl3,400MHz)δ0.81-0.90(m,2H),1.14-1.24(m,2H),2.71-2.81(m,1H),2.81(s,3H),5.77(s,1H),7.17-7.24(m,2H),7.27-7.39(m,4H),7.39-7.52(m,3H),10.38(s,1H).
实施例1-85
MS ESI m/e:423(M+H),421(M-H).
1H-NMR(DMSO-d6,300MHz)δ2.25-2.30(m,3H),2.51-2.57(m,3H),3.26-3.31(m,3H),5.4 8-5.52(m,1H),7.24-7.55(m,8H),10.74(s,1H).
实施例1-86
MS ESI m/e:423(M+H),421(M-H).
1H-NMR(DMSO-d6,300MHz)δ2.35(s,3H),2.65(s,3H),3.26(s,3H),5.51(s,1H),7.23-7.32(m,3H),7.32-7.45(m,3H),7.46-7.54(m,2H),10.64(s,1H).
实施例1-87
MS ESI m/e:423(M+H),421(M-H).
1H-NMR(DMSO-d6,300MHz)δ2.37(s,3H),2.63(s,3H),3.26(s,3H),5.50(s,1H),7.29-7.39(m,6H),7.46-7.53(m,2H),10.64(s,1H).
实施例1-88
MS ESI m/e:444(M+H),442(M-H).
1H-NMR(CDCl3,300MHz)δ0.82-0.91(m,2H),1.13-1.23(m,2H),2.71-2.80(m,1H),2.80(s,3H),2.97(s,6H),5.62(s,1H),6.69-6.77(m,2H),7.08-7.16(m,2H),7.29-7.35(m,2H),7.38-7.52(m,3H),10.07(s,1H).
实施例1-89
MS ESI m/e:479,481(M+H),477,479(M-H).
1H-NMR(CDCl3,300MHz)δ0.81-0.91(m,2H),1.15-1.26(m,2H),2.71-2.82(m,1H),2.82(s,3H),5.80(s,1H),7.13-7.21(m,2H),7.28-7.36(m,2H),7.39-7.56(m,5H),10.41(s,1H).
实施例1-90
MS ESI m/e:477(M+H),475(M-H).
1H-NMR(CDCl3,300MHz)δ2.84(s,3H),4.75(q,J=8.4Hz,2H),5.76(s,1H),7.19-7.28(m,2H),7.31-7.42(m,4H),7.43-7.57(m,3H),10.20(s,1H).
实施例1-91
MS ESI m/e:513 M+H),511(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.64(t,J=6.0Hz,3H),1.21-1.41(m,2H),2.15(t,J=7.5Hz,2H),2.76(s,3H),6.93-7.07(m,2H),7.27-7.37(m,4H),7.39-7.64(m,8H),9.92(s,1H).
实施例1-92
MS ESI m/e:521,523(M+H),519,521(M-H).
1H-NMR(CDCl3,300MHz)δ2.85(s,3H),4.75(q,J=8.4Hz,2H),5.78(s,1H),7.14-7.22(m,2H),7.32-7.40(m,2H),7.44-7.58(m,5H),10.20(s,1H).
实施例1-93
MS ESI m/e:486(M+H),484(M-H).
1H-NMR(CDCl3,300MHz)δ2.83(s,3H),2.97(s,6H),4.75(q,J=8.4Hz,2H),5.61(s,1H),6.67-6.81(m,2H),7.08-7.18(m,2H),7.32-7.40(m,2H),7.41-7.56(m,3H),9.92(s,1H).
实施例1-94
MS ESI m/e:457(M+H),455(M-H).
1H-NMR(DMSO-d6,300MHz)δ1.18(t,J=6.7Hz,3H),2.66(s,3H),3.93(q,J=6.7Hz,2H),5.50(s,1H),7.36(d,J=9.0Hz,2H),7.46-7.56(m,4H),7.57-7.66(m,2H),10.62(s,1H).
实施例1-95
MS ESI m/e:467,469(M+H),465,467(M-H).
1H-NMR(DMSO-d6,400MHz)δ2.28(s,3H),2.53(s,3H),3.28(s,3H),5.51(s,1H),7.23-7.35(m,4H),7.38-7.44(m,2H),7.58-7.65(m,2H),10.72(s,1H).
实施例1-96
MS ESI m/e:467,469(M+H),465,467(M-H).
1H-NMR(CDCl3,400MHz)δ1.29(t,J=7.1Hz,3H),2.81(s,3H),4.07(q,J=7.1Hz,2H),5.78(s,1H),7.14-7.19(m,2H),7.31-7.36(m,2H),7.40-7.53(m,5H),10.53(s,1H).
实施例1-97
MS ESI m/e:432(M+H).
1H-NMR(CDCl3,400MHz)δ1.29(t,J=7.1Hz,3H),2.80(s,3H),2.96(s,6H),4.07(q,J=7.0Hz,2H),5.59(s,1H),6.69-6.75(m,2H),7.08-7.14(m,2H),7.31-7.36(m,2H),7.38-7.50(m,3H),10.19(s,1H).
实施例1-98
MS ESI m/e:435(M+H),433(M-H).
1H-NMR(CDCl3,300MHz)δ0.80-0.91(m,2H),1.25-1.35(m,2H),3.38-3.49(m,1H),3.74(s,3H),5.76(s,1H),7.09-7.18(m,2H),7.20-7.37(m,4H),7.44-7.60(m,3H),10.23(s,1H).
实施例1-99
MS ESI m/e:432(M+H).
1H-NMR(DMSO-d6,300MHz)δ2.27(s,3H),2.51(s,3H),2.92(s,6H),3.27(s,3H),5.21(s,1H),6.76-6.84(m,2H),7.06-7.14(m,2H),7.23-7.38(m,2H),7.38-7.44(m,2H),10.35(s,1H).
实施例 1-100
MS ESI m/e:453(M+H),451(M-H).
1H-NMR(CDCl3,300MHz)δ0.83-0.92(m,2H),1.14-1.24(m,2H),2.74-2.83(m,1H),2.86(s,3H),5.76(s,1H),7.18-7.33(m,5H),7.33-7.40(m,2H),7.45-7.55(m,1H),10.41(s,1H).
实施例1-101
MS ESI m/e:503(M+H),501(M-H).
1H-NMR(CDCl3,300MHz)δ0.78-0.91(m,2H),1.14-1.26(m,2H),2.73-2.86(m,1H),2.82(s,3H),5.76(s,1H),7.19-7.29(m,2H),7.32-7.41(m,2H),7.42-7.50(m,1H),7.61-7.79(m,2H),7.80-7.89(m,1H),10.50(s,1H).
实施例1-102
MS ESI m/e:449(M+H),447(M-H).
1H-NMR(CDCl3,300MHz)δ0.74-0.96(m,2H),1.11-1.31(m,2H),2.30(s,3H),2.74(s,3H),2.76-2.85(m,1H),5.76(s,1H),7.04-7.12(m,1H),7.18-7.43(m,7H),10.53(s,1H).
实施例 1-103
MS ESI m/e:463(M+H),461(M-H).
1H-NMR(CDCl3,300MHz)δ0.76-0.90(m,2H),1.11-1.27(m,2H),1.26(t,J=7.5Hz,3H),2.40-2.67(m,2H),2.71-2.84(m,1H),2.75(s,3H),5.76(s,1H),7.08-7.14(m,1H),7.18-7.47(m,7H),10.54(s,1H).
实施例 1-104
MS ESI m/e:465(M+H),463(M-H).
1H-NMR(CDCl3,300MHz)δ0.79-0.94(m,2H),1.11-1.28(m,2H),2.71-2.83(m,1H),2.84(s,3H),3.84(s,3H),5.76(s,1H),7.00-7.13(m,2H),7.19-7.30(m,3H),7.32-7.40(m,2H),7.41-7.52(m,1H),10.52(s,1H).
实施例 1-105
MS ESI m/e:445(M+H),443(M-H).
1H-NMR(CDCl3,300MHz)δ0.92(t,J=7.5Hz,3H),1.36(sext,J=7.5Hz,2H),1.59(quint,J=7.5Hz,2H),2.33(s,3H),2.62(t,J=7.5Hz,2H),2.75(s,3H),3.45(s,3H),5.43(s,1H),7.08-7.45(m,8H),10.37(s,1H).
实施例 1-106
MS ESI m/e:458(M+H).
1H-NMR(CDCl3,300MHz)δ0.77-0.92(m,2H),1.14-1.27(m,2H),2.30(s,3H),2.72(s,3H),2.74-2.85(m,1H),2.96(s,6H),5.60(s,1H),6.69-6.79(m,2H),7.03-7.18(m,3H),7.22-7.42(m,3H),10.20(s,1H).
实施例 1-107
MS ESI m/e:493,495(M+H),491,493(M-H).
1H-NMR(DMSO-d6,300MHz)δ1.68-1.79(m,2H),2.19-2.32(m,2H),2.59(s,3H),2.60-2.75(m,2H),4.88-4.98(m,1H),5.49(s,1H),7.29(d,J=8.7Hz,2H),7.41-7.53(m,5H),7.60(d,J=8.6Hz,2H),10.52(brs,1H).
实施例 1-108
MS ESI m/e:535,537(M+H),533,535(M-H).
1H-NMR(DMSO-d6,300MHz)δ2.27(s,3H),2.54(s,3H),4.62-4.88(m,2H),5.49(s,1H),7.28-7.30(m,4H),7.41-7.42(m,2H),7.62(d,J=9.0Hz,2H),10.40(brs,1H).
实施例 1-109
MS ESI m/e:437(M+H),435(M-H).
1H-NMR(CDCl3,300MHz)δ1.30(t,J=6.0Hz,3H),2.30(s,3H),2.75(s,3H),4.09(q,J=6.0Hz,2H),5.75(s,1H),7.12(d,J=6.0Hz,1H),7.19-7.43(m,7H),10.65(s,1H).
实施例 1-110
MS ESI m/e:446(M+H),444(M-H).
1H-NMR(CDCl3,300MHz)δ1.30(t,J=7.1Hz,3H),2.30(s,3H),2.73(s,3H),2.96(s,6H),4.09(q,J=2.3Hz,2H),4.84(q,J=149.0Hz,2H),6.68-6.77(m,2H),7.08-7.17(m,3H),7.25-7.32(m,1H),7.33-7.38(m,2H),10,31(brs,1H).
实施例 1-111
MS ESI m/e:481,483(M+H),479,481(M-H).
1H-NMR(CDCl3,300MHz)δ1.30(t,J=6.0Hz,3H),2.30(s,1H),2.75(s,1H),4.09(q,J=7.0Hz,2H),5.77(s,1H),7.08-7.22(m,3H),7.26-7.42(m,3H),7.49-7.56(m,2H),10.66(brs,1H).
实施例 1-112
MS ESI m/e:458(M+H),456(M-H).
1H-NMR(CDCl3,300MHz)δ0.83-0.93(m,2H),1.14-1.24(m,2H),2.23(s,3H),2.71-2.82(m,1H),2.79(s,3H),2.95(s,6H),5.29(s,1H),6.55-6.64(m,2H),7.02-7.10(m,1H),7.29-7.36(m,2H),7.38-7.53(m,3H),9.86(s,1H).
实施例 1-113
MS ESI m/e:497,499(M+H),495,497(M-H).
1H-NMR(CDCl3,300MHz)δ0.82-0.92(m,2H),1.14-1.24(m,2H),2.73-2.83(m,1H),2.86(s,3H),5.78(s,1H),7.12-7.21(m,2H),7.21-7.34(m,3H),7.45-7.55(m,3H),10.41(s,1H).
实施例 1-114
MS ESI m/e:462(M+H),460(M-H).
1H-NMR(CDCl3,300MHz)δ0.83-0.93(m,2H),1.13-1.25(m,2H),2.72-2.84(m,1H),2.84(s,3H),2.96(s,6H),5.60(s,1H),6.69-6.77(m,2H),7.08-7.15(m,2H),7.17-7.31(m,3H),7.43-7.53(m,1H),10.09(s,1H).
实施例 1-115
MS ESI m/e:441(M+H),439(M-H).
1H-NMR(CDCl3,300MHz)δ1.31(t,J=7.0Hz,3H),2.86(s,3H),4.08(q,J=7.0Hz,2H),5.75(s,1H),7.18-7.40(m,7H),7.46-7.56(m,1H),10.54(s,1H).
实施例 1-116
MS ESI m/e:485,487(M+H),483,485(M-H).
1H-NMR(CDCl3,300MHz)δ1.31(t,J=7.0Hz,3H),2.86(s,3H),4.08(q,J=7.0Hz,2H),5.77(s,1H),7.13-7.21(m,2H),7.24-7.34(m,3H),7.46-7.56(m,3H),10.55(s,1H).
实施例 1-117
MS ESI m/e:450(M+H),448(M-H).
1H-NMR(CDCl3,300MHz)δ1.31(t,J=7.0Hz,3H),2.85(s,3H),2.96(s,6H),4.08(q,J=7.1Hz,2H),5.59(s,1H),6.69-6.77(m,2H),7.0 8-7.17(m,2H),7.22-7.34(m,3H),7.43-7.54(m,1H),10.21(s,1H).
实施例 1-118
MS ESI m/e:472(M+H).
1H-NMR(CDCl3,300MHz)δ0.79-0.89(m,2H),1.14-1.25(m,2H),2.16(s,6H),2.71(s,3H),2.77-2.87(m,1H),2.96(s,6H),5.59(s,1H),6.68-6.77(m,2H),7.08-7.19(m,4H),7.23-7.31(m,1H),10.31(s,1H).
实施例 1-119
MS ESI m/e:480(M+H).
1H-NMR(DMSO-d6,300MHz)δ0.71-0.79(m,2H),0.99-1.10(m,2H),2.68-2.79(m,1H),2.71(s,1H),5.21(s,1H),6.79(d,J=9.0Hz,2H),7.12(d,J=9.0Hz,2H),7.39(t,J=9.0Hz,2H),7.65-7.75(m,1H),10.11(brs,1H).
实施例 1-120
MS ESI m/e:515,517(M+H),513,515(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.71-0.79(m,2H),1.00-1.10(m,2H),2.71-2.80(m,1H),2.74(s,3H),5.51(s,1H),7.32(d,J=9.0Hz,2H),7.41(t,J=7.5Hz,2H),7.62(d,J=6.0Hz,2H),7.64-7.76(m,1H),10.47(brs,1H).
实施例 1-121
MS ESI m/e:471(M+H),469(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.71-0.79(m,2H),1.03-1.07(m,2H),2.70-2.80(m,1H),2.74(s,3H),5.49(s,1H),7.36-7.43(m,4H),7.50(d,J=9.0Hz,2H),7.65-7.76(m,1H),10.47(brs,H).
实施例 1-122
MS ESI m/e:460(M+H),458(M-H).
1H-NMR(DMSO-d6,300MHz)δ1.16(t,J=7.5Hz,3H),1.18(t,J=6.0Hz,3H),2.52(q,J=4.0Hz,2H),2.50(s,3H),2.92(s,6H),3.94(q,J=5.0Hz,2H),5.20(s,1H),6.79(d,J=9.0Hz,2H),7.12(d,J=9.0Hz,2H),7.33(d,J=3.0Hz,2H),7.47(s,2H),10.35(brs,H).
实施例 1-123
MS ESI m/e:495,497(M+H),493,495(M-H).
1H-NMR(DMSO-d6,300MHz)δ1.16(t,J=7.5Hz,3H),1.18(t,J=6.0Hz,3H),2.50-2.56(m,2H),2.53(s,3H),3.96(q,J=7.0Hz,2H),5.51(s,1H),7.29-7.34(m,4H),7.46-7.48(m,2H),7.62(d,J=6.0Hz,2H),10.74(brs,H).
实施例 1-124
MS ESI m/e:451(M+H),499(M-H).
1H-NMR(DMSO-d6,300MHz)δ1.16(t,J=6.0Hz,3H),1.18(t,J=6.0Hz,3H),2.50-2.55(m,2H),2.56(s,3H),3.95(q,J=8.0Hz,2H),5.49(s,1H),7.33-7.38(m,4H),7.48-7.51(m,4H),10.73(brs,H).
实施例 1-125
MS ESI m/e:463(M+H),461(M-H).
1H-NMR(CDCl3,300MHz)δ0.78-0.88(m,2H),1.16-1.29(m,2H),2.15(s,6H),2.72(s,3H),2.77-2.88(m,1H),5.74(s,1H),7.11-7.40(m,7H),10.64(s,1H).
实施例 1-126
MS ESI m/e:458(M+H).
1H-NMR(CDCl3,300MHz)δ0.83-0.90(m,2H),1.13-1.23(m,2H),2.39(s,3H),2.71-2.78(m,1H),2.81(s,3H),2.96(s,6H),5.60(s,1H),6.68-6.78(m,2H),7.07-7.32(m,6H),10.08(brs,1H).
实施例 1-127
MS ESI m/e:458(M+H).
1H-NMR(CDCl3,300MHz)δ0.81-0.93(m,2H),1.13-1.23(m,2H),2.39(s,3H),2.71-2.81(m,1H),2.83(s,3H),2.96(s,6H),5.62(s,1H),6.70-6.76(m,2H),7.08-7.16(m,4H),7.20-7.25(m,1H),7.31-7.39(m,1H),10.08(brs,1H).
实施例 1-128
MS ESI m/e:472(M+H).
1H-NMR(CDCl3,300MHz)δ0.82-0.92(m,2H),1.14-1.25(m,2H),1.18(t,J=7.0Hz,6H),2.71-2.82(m,1H),2.80(s,3H),3.36(q,J=7.0Hz,4H),5.62(s,1H),6.63-6.71(m,2H),7.03-7.13(m,2H),7.28-7.36(m,2H),7.37-7.53(m,3H),10.03(s,1H).
实施例 1-129
MS ESI m/e:431(M+H),429(M-H).
1H-NMR(CDCl3,400MHz)δ0.84-0.90(m,2H),1.15-1.23(m,2H),2.72-2.80(m,1H),2.80(s,3H),3.82(s,3H),5.61(s,1H),6.88-6.94(m,2H),7.14-7.21(m,2H),7.28-7.33(m,2H),7.38-7.50(m,3H),10.15(s,1H).
实施例 1-130
MS ESI m/e:408(M+H).
1H-NMR(DMSO-d6,300MHz)δ0.68-0.73(m,4H),0.96-1.02(m,2H),1.05-1.12(m,2H),2.54-2.63(m,1H),2.91(s,6H),3.30-3.40(m,1H),3.48(s,3H),5.14(s,1H),6.77(d,J=9.0Hz,2H),7.06(d,J=9.0Hz,2H),10.04(brs,H).
实施例 1-131
MS ESI m/e:468,470(M+H),466,468(M-H).
1H-NMR(DMSO-d6,300MHz)δ1.20(t,J=7.5Hz,3H),2.62.(s,3H),3.95(q,J=7.0Hz,2H),5.53(s,1H),7.32(d,J=9.0Hz,2H),7.52-7.64(m,3H),7.97(d,J=9.0Hz,1H),8.67(d,J=15Hz,1H),8.68(d,J=15Hz,1H),10.62(brs,H).
实施例 1-132
MS ESI m/e:462(M+H),460(M-H).
1H-NMR(CDCl3,400MHz)δ0.82-0.89(m,2H),1.15-1.22(m,2H),2.72-2.79(m,1H),2.82(s,3H),2.96(s,6H),5.60(s,1H),6.69-6.75(m,2H),7.07-7.21(m,4H),7.27-7.33(m,2H),10.03(s,1H).
实施例 1-133
MS ESI m/e:462(M+H),460(M-H).
1H-NMR(CDCl3,400MHz)δ0.83-0.89(m,2H),1.15-1.23(m,2H),2.72-2.80(m,1H),2.85(s,3H),2.96(s,6H),5.61(s,1H),6.69-6.75(m,2H),7.03-7.19(m,5H),7.39-7.46(m,1H),10.01(s,1H).
实施例 1-134
MS ESI m/e:444(M+H),442(M-H).
1H-NMR(CDCl3,300MHz)δ0.82-0.93(m,2H),1.13-1.24(m,2H),2.72-2.82(m,1H),2.82(s,3H), 2.96(s,6H),5.90(s,1H),6.55-6.62(m,2H),6.63-6.69(m,1H),7.19-7.24(m,1H),7.30-7.35(m,2H),7.38-7.53(m,3H),10.31(s,1H).
实施例 1-135
MS ESI m/e:416(M+H).
1H-NMR(DMSO-d6,300MHz)δ0.70-0.82(m,2H),0.99-1.09(m,2H),2.60(s,3H),2.63-2.74(m,1H),5.52(s,1H),7.36-7.57(m,9H),10.61(s,1H).
实施例 1-136
MS ESI m/e:430(M+H).
1H-NMR(DMSO-d6,300MHz)δ0.71-0.80(m,2H),0.98-1.08(m,2H),2.60(s,3H),2.63-2.72(m,1H),2.89(s,3H),5.51(d,J=2.9Hz,1H),7.38-7.56(m,9H),10.59(brs,1H).
实施例 1-137
MS ESI m/e:444(M+H),442(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.71-0.80(m,2H),0.98-1.08(m,2H),1.27(t,J=7.5Hz,3H),2.61(s,3H),2.64-2.72(m,1H),3.31(q,J=7.0Hz,2H),5.54(s,1H),7.07-7.19(m,2H),7.38-7.57(m,9H),10.62(brs,1H).
实施例 1-138
MS ESI m/e:454(M+H).
1H-NMR(DMSO-d6,300MHz)δ0.71-0.80(m,2H),0.99-1.08(m,2H),2.57(s,3H),2.62-2.75(m,1H),3.81(s,3H),5.26(s,1H),6.44(d,J=3.0Hz,1H),7.06(dd,J=3.0,3.0Hz,1H),7.37-7.52(m,8H),10.37(brs,H).
实施例 1-139
MS ESI m/e:444(M+H).
1H-NMR(DMSO-d6,300MHz)δ2.59(s,3H),2.92(s,6H),4.49(d,J=3.0Hz,2H),5.15(d,J=9.0Hz,1H),5.22(dd,J=3.0,9.0Hz,2H),6.78(d,J=6.0Hz,2H),7.10(d,J=6.0Hz,2H),7.48-7.50(m,5H),10.19(brs,H).
实施例 1-140
MS ESI m/e:444(M+H),442(M-H).
1H-NMR(DMS0-d6,300MHz)δ2.60(s,3H),3.03(s,6H),4.50(d,J=3.0Hz,2H),5.17(dd,J=21.0,24.0Hz,2H),5.38(s,1H),5.79-5.92(m,1H),7.19-7.38(m,4H),7.41-7.55(m,5H),10.42(brs,H).
实施例 1-141
MS ESI m/e:456(M+H),454(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.70-0.79(m,2H),0.99-1.08(m,2H),2.55(s,3H),2.61-2.68(m,1H),2.71(s,3H),2.89(t,J=9.0Hz,2H),3.28(t,J=7.5Hz,2H),5.18(s,1H),6.54(d,J=9.0Hz,1H),6.90(d,J=6.0Hz,1H),6.96(s,1H),7.39-7.50(m,5H),10.13(brs,H).
实施例 1-142
MS ESI m/e:476(M+H).
1H-NMR(CDCl3,300MHz)δ0.85-0.93(m,2H),1.14-1.24(m,2H),2.23(s,3H),2.74-2.83(m,1H),2.83(s,3H),2.95(s,6H),5.27(s,1H),6.55-6.65(m,2H),7.02-7.09(m,1H),7.18-7.32(m,3H),7.43-7.54(m,1H),9.89(s,1H).
实施例 1-143
MS ESI m/e:462(M+H),460(M-H).
1H-NMR(CDCl3,300MHz)δ0.81-0.92(m,2H),1.14-1.25(m,2H),2.71-2.81(m,1H),2.81(s,1H),2.87(s,6H),5.71(s,1H),6.86-7.02(m,3H),7.27-7.35(m,2H),7.41-7.54(m,3H),10.22(brs,1H).
实施例 1-144
MS ESI m/e:454(M+H),452(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.72-0.80(m,2H),1.00-1.09(m,2H),2.58(s,3H),2.64-2.71(m,1H),3.78(s,3H),5.40(s,1H),6.45(d,J=3.0Hz,1H),6.97(d,J=6.0Hz,1H),7.34-7.51(m,7H),7.60(d,J=9.0Hz,1H),8.30(brs,H).
实施例 1-145
MS ESI m/e:479(M+H),477(M-H).
1H-NMR(CDCl3,300MHz)δ0.82-0.91(m,2H),1.15-1.26(m,2H),2.73-2.83(m,1H),2.85(s,3H),3.08(s,3H),6.08(s,1H),7.29-7.37(m,2H),7.41-7.56(m,5H),7.92-8.00(m,2H),10.87(s,1H).
实施例 1-146
MS ESI m/e:461(M+H),459(M-H).
1H-NMR(CDCl3,300MHz)δ0.82-0.92(m,2H),1.13-1.24(m,2H),2.72-2.83(m,1H),2.80(s,3H),3,83(s,3H),3.84(s,3H),5.60(s,1H),6.45-6.58(m,2H),7.19-7.26(m,1H),7.28-7.35(m,2H),7.38-7.52(m,3H),10.01(s,1H).
实施例 1-147
MS ESI m/e:458(M+H),456(M-H).
1H-NMR(CDCl3,300MHz)δ0.81-0.91(m,2H),1.13-1.23(m,2H),2.32(s,3H),2.67-2.84(m,1H),2.71(s,6H),2.81(s,3H),5.72(s,1H),6.99-7.10(m,3H),7.28-7.36(m,2H),7.38-7.53(m,3H),10.19(s,1H).
实施例 1-148
MS ESI m/e:512(M+H),510(M-H).
1H-NMR(CDCl3,400MHz)δ0.84-0.90(m,2H),1.16-1.24(m,2H),2.73-2.79(m,1H),2.75(s,6H),2.81(s,3H),5.66(s,1H),7.29-7.37(m,3H),7.39-7.52(m,5H),10.33(brs,1H).
实施例 1-149
MS ESI m/e:472(M+H),470(M-H).
1H-NMR(CDCl3,400MHz)δ0.84-0.91(m,2H),1.17-1.25(m,2H),1.91(s,3H),2.74-2.81(m,1H),2.83(s,3H),3.28(s,3H),5.84(s,1H),7.18-7.24(m,2H),7.29-7.35(m,4H),7.40-7.52(m,3H),10.47(s,1H).
实施例 1-150
MS ESI m/e:493,495(M+H),491,493(M-H).
1H-NMR(CDCl3,300MHz)δ0.39-0.57(m,4H),1.24-1.36(m,1H),2.83(s,3H),3.91(d,J=7.0Hz,2H),5.80(s,1H),7.15-7.21(m,2H),7.33-7.39(m,2H),7.42-7.55(m,5H),10.57(s,1H).
实施例 1-151
MS ESI m/e:497,499(M+H),495,497(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.73-0.79(m,2H),1.01-1.09(m,2H),2.61(s,3H),2.68-2.71(m,1H),5.65(s,1H),7.19(d,J=9.0Hz,1H),7.40-7.52(m,6H),7.73(t,J=9.0Hz,1H),10.67(brs,H).
实施例 1-152
MS ESI m/e:497,499(M+H),495,497(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.72-0.79(m,2H),1.01-1.09(m,2H),2.60(s,3H),2.62-2.72(m,1H),5.37(s,1H),7.42-7.52(m,7H),7.73(d,J=12.0Hz,1H),10.55(brs,H).
实施例 1-153
MS ESI m/e:493,495(M+H),491,493(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.81-1.17(m,6H),2.29-2.35(m,1H),2.58(s,3H),5.50(s,1H),7.29(d,J=6.0Hz,2H),7.39-7.52(m,5H),7.61(d,J=9.0Hz,2H),10.56(brs,H).
实施例 1-154
MS ESI m/e:445(M+H),443(M-H).
1H-NMR(CDCl3,300MHz)δ0.84-0.93(m,2H),1.16-1.24(m,2H),2.26(s,3H),2.74-2.80(m,1H),2.80(s,3H),3.81(s,3H),5.27(s,1H),6.73-6.84(m,2H),7.14(d,J=9.0Hz,1H),7.30-7.35(m,2H),7.39-7.52(m,3H),9.94(brs,1H).
实施例 1-155
MS ESI m/e:444(M+H),442(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.71-0.79(m,2H),1.00-1.10(m,2H),2.60(s,3H),2.64-2.76(m,1H),2.76(brs,6H),5.51(brs,1H),7.09-7.58(m,8H),10.46(brs,1H).
实施例 1-156
MS ESI m/e:493,495(M+H),491,495(M-H).
1H-NMR(CDCl3,300MHz)δ0.82-0.92(m,2H),1.15-1.25(m,2H),2.29(s,3H),2.73-2.85(m,1H),2.81(s,3H),5.41(s,1H),7.16(d,J=8.4Hz,1H),7.30-7.39(m,3H),7.40-7.53(m,4H),10.13(s,1H).
实施例 1-157
MS ESI m/e:493,495(M+H),491,495(M-H).
1H-NMR(CDCl3,300MHz)δ0.82-0.91(m,2H),1.14-1.24(m,2H),2.40(s,3H),2.71-2.82(m,1H),2.82(s,3H),5.81(s,1H),6.99(dd,J=2.6,8.4Hz,1H),7.17(d,J=2.6Hz,1H),7.28-7.36(m,2H),7.39-7.57(m,4H),10.37(s,1H).
实施例 1-158
MS ESI m/e:454(M+H),452(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.72-0.80(m,2H),1.01-1.09(m,2H),2.55(s,3H),2.63-2.72(m,1H),3.85(s,3H),4.71(s,1H),6.48(d,J=3.0Hz,1H),6.97(d,J=15.0Hz,1H),7.06(t,J=9.0Hz,1H),7.29(d,J=3.0Hz,1H),7.41-7.56(m,6H),10.37(brs,H).
实施例 1-159
MS ESI m/e:509,511(M+H),507,509(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.61-0.79(m,2H),0.96-1.08(m,2H),2.61(s,3H),2.61-2.74(m,1H),3.77(s,3H),5.49(s,1H),7.07(t,J=6.0Hz,1H),7.20(d,J=12.0Hz,1H),7.29(d,J=9.0Hz,2H),7.38(d,J=6.0Hz,1H),7.48(t,J=9.0Hz,1H),7.60(d,J=9.0Hz,2H),10.60(brs,H).
实施例 1-160
MS ESI m/e:455(M+H),453(M-H).
1H-NMR(CDCl3,300MHz)δ0.85-0.93(m,2H),1.15-1.26(m,2H),2.74-2.84(m,1H),2.81(s,3H),3.88(s,3H),5.65(s,1H),7.22-7.29(m,1H),7.30-7.37(m,2H),7.37-7.54(m,4H),7.70(d,J=1.8Hz,1H),7.90(s,1H),10.36(s,1H).
实施例 1-161
MS ESI m/e:455(M+H),453(M-H).
1H-NMR(CDCl3,300MHz)δ0.85-0.94(m,2H),1.15-1.26(m,2H),2.74-2.84(m,1H),2.82(s,3H),4.10(s,3H),5.65(s,1H),7.2 8-7.37(m,3H),7.39-7.54(m,4H),7.60-7.64(m,1H),7.95-7.98(m,1H),10.36(s,1H).
实施例 1-162
MS ESI m/e:437(M+H),435(M-H).
1H-NMR(CDCl3,400MHz)δ0.83-0.91(m,2H),1.15-1.24(m,2H),2.73-2.81(m,1H),2.81(s,3H),5.49(s,1H),6.88-6.98(m,2H),7.28-7.38(m,3H),7.39-7.52(m,3H),10.15(s,1H).
实施例 1-163
MS ESI m/e:469,471(M+H),467,469(M-H).
1H-NMR(CDCl3,400MHz)δ0.83-0.90(m,2H),1.16-1.24(m,2H),2.74-2.81(m,1H),2.82(s,3H),5.70(s,1H),7.24-7.34(m,3H),7.39-7.52(m,5H),10.50(s,1H).
实施例 1-164
MS ESI m/e:485,487(M+H),483,485(M-H).
1H-NMR(CDCl3,400MHz)δ1.30(t,J=7.1Hz,3H),2.82(s,3H),4.08(q,J=7.0Hz,2H),5.66(s,1H),7.28-7.39(m,5H),7.41-7.53(m,3H),10.48(s,1H).
实施例 1-165
MS ESI m/e:440(M+H),438(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.71-0.81(m,2H),1.00-1.10(m,2H),2.58(s,3H),2.62-2.78(m,1H),5.28(s,1H),6.46(s,1H),7.01(d,J=9.0Hz,1H),7.40-7.68(m,8H),10.37(brs,H),11.22(brs,H).
实施例 1-166
MS ESI m/e:527,529(M+H),525,527(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.62-0.81(m,2H),0.99-1.09(m,2H),2.63(s,3H),2.66-2.75(m,1H),3.79(s,3H),5.34(s,1H),7.09(t,J=7.5Hz,1H),7.23(d,J=9.0Hz,1H),7.40(d,J=6.0Hz,1H),7.43-7.54(m,3H),7.73(d,J=9.0Hz,1H),10.58(brs,H).
实施例 1-167
MS ESI m/e:468(M+H),466(M-H).
1H-NMR(CDCl3,300MHz)δ0.82-0.94(m,2H),1.14-1.26(m,2H),1.49(t,J=7.4Hz,3H),2.72-2.84(m,1H),2.81(s,3H),4.19(q,J=7.3Hz,2H),5.68(s,1H),6.47(d,J=3.0Hz,1H),7.10(dd,J=1.9,8.6Hz,1H),7.16(d,J=3.0Hz,1H),7.29-7.38(m,3H),7.38-7.55(m,4H),10.27(brs,1H).
实施例 1-168
MS ESI m/e:433(M+H),431(M-H).
1H-NMR(CDCl3,300MHz)δ0.75-0.90(m,2H),1.10-1.25(m,2H),2.37(s,3H),2.77(m,1H),2.81(s,3H),5.59(s,1H),6.90-7.05(m,2H),7.25(t,J=8.3Hz,1H),7.30-7.35(m,2H),7.40-7.50(m,3H),10.16(s,1H).
实施例 1-169
MS ESI m/e:438(M+H),436(M-H).
1H-NMR(CDCl3,300MHz)δ0.75-0.85(m,2H),1.10-1.25(m,2H),2.50-2.55(m,4H),2.65-2.80(m,3H),2.80(s,3H),3.26(q,J=5.8Hz,2H),3.70-3.80(m,4H),5.37(s,1H),7.25-7.35(m,2H),7.35-7.50(m,3H),8.90(brs,1H).
实施例 1-170
MS ESI m/e:477(M+H),475(M-H).
1H-NMR(CDCl3,300MHz)δ0.82-0.92(m,2H),1.15-1.26(m,2H),1.76(d,J=12.8Hz,6H),2.72-2.82(m,1H),2.84(s,3H),5.99(s,1H),7.29-7.36(m,2H),7.39-7.56(m,5H),7.70-7.82(m,2H),10.67(s,1H).
实施例 1-171
MS ESI m/e:453(M+H),451(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.68-0.79(m,2H),0.98-1.09(m,2H),2.58(s,3H),2.61-2.71(m,1H),5.32(s,1H),7.34-7.63(m,8H),10.52(brs,H).
实施例 1-172
MS ESI m/e:417(M+H),415(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.68-0.78(m,2H),0.97-1.06(m,2H),2.55(s,3H),2.61-2.69(m,1H),5.19(s,1H),6.82(d,J=9.0Hz,2H),7.08(d,J=6.0Hz,2H),7.39-7.50(m,5H),9.53(brs,H),10.18(brs,H).
实施例 1-173
MS ESI m/e:419(M+H),417(M-H).
1H-NMR(DMSO-d6,300MHz)δ2.71-2.80(m,2H),1.01-1.09(m,2H),2.60(s,3H),2.64-2.72(m,1H),5.34(s,1H),7.28-7.54(m,9H),10.53(brs,H).
实施例 1-174
MS ESI m/e:437(M+H),435(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.69-0.78(m,2H),0.96-1.08(m,2H),2.57(s,3H),2.61-2.72(m,1H),4.84(s,1H),7.24-7.52(m,8H),10.15(brs,H).
实施例 1-175
MS ESI m/e:449(M+H),447(M-H).
1H-NMR(CDCl3,400MHz)δ0.83-0.92(m,2H),1.15-1.24(m,2H),2.72-2.81(m,1H),2.81(s,3H),3.82(s,3H),5.46(d,J=1.6Hz,1H),6.69-6.79(m,2H),7.19-7.29(m,1H),7.29-7.36(m,2H),7.39-7.54(m,3H),10.01(brs,1H).
实施例 1-176
MS ESI m/e:513,515(M+H),511,513(M-H).
1H-NMR(CDCl3,300MHz)δ0.83-0.91(m,2H),1.16-1.24(m,2H),2.75-2.82(m,1H),2.82(s,3H),5.73(s,1H),7.30-7.36(m,2H),7.38-7.53(m,4H),7.41(d,J=1.8Hz,1H),7.66(d,J=1.8Hz,1H),10.53(brs,1H).
实施例 1-177
MS ESI m/e:507,509(M+H),505,507(M-H).
1H-NMR(CDCl3,400MHz)δ0.85-0.89(m,2H),1.17-1.22(m,2H),1.23(t,J=7.5Hz,3H),2.63(q,J=7.5Hz,2H),2.74-2.79(m,1H),2.80(s,3H),5.40(s,1H),7.15(d,J=8.4Hz,1H),7.29-7.36(m,3H),7.40-7.51(m,4H),10.11(brs,1H).
实施例 1-178
MS ESI m/e:459(M+H),457(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.73-0.79(m,2H),1.00-1.09(m,2H),2.63(s,3H),2.65-2.72(m,1H),3.86(s,3H),5.84(s,1H),7.42-7.56(m,6H),7.99-8.03(m,2H),10.96(brs,1H).
实施例 1-179
MS ESI m/e:383(M+H).
1H-NMR(CDCl3,300MHz)δ0.79-0.87(m,2H),1.12-1.21(m,2H),2.69-2.76(m,1H),2.80(s,3H),3.36(q,J=5.4Hz,2H),3.44(s,3H),3.66(t,J=5.4Hz,2H),5.39(s,1H),7.23-7.31(m,2H),7,37-7.51(m,3H),8.80-8.88(m,1H).
实施例 1-180
MS ESI m/e:422(M+H).
1H-NMR(DMSO-d6,300MHz)δ0.65-0.74(m,2H),0.95-1.05(m,2H),1.42-1.56(m,2H),1.88-1.98(m,2H),2.10-2.21(m,2H),2.18(s,3H),2.55(s,3H),2.58-2.70(m,3H),3.33-3.44(m,1H),5.23(s,1H),7.34-7.41(m,2H),7.42-7.53(m,3H),8.77-8.84(m,1H).
实施例 1-181
MS ESI m/e:365(M+H).
1H-NMR(CDCl3,300MHz)δ0.59-0.67(m,2H),0.77-0.89(m,4H),1.11-1.21(m,2H),2.42-2.50(m,1H),2.66-2.76(m,1H),2.81(s,3H),5.81(s,1H),7.24-7.28(m,1H),7.29-7.31(m,1H),7.37-7.51(m,3H),8.68(brs,1H).
实施例 1-182
MS ESI m/e:450(M+H).
1H-NMR(CDCl3,300MHz)δ0.77-0.86(m,2H),1.01-1.12(m,6H),1.12-1.21(m,2H),1.54-1.74(m,2H),2.03-2.15(m,2H),2.25-2.41(m,2H),2.66-2.76(m,1H),2.79(s,3H),2.82-2.94(m,2H),3.25-3.41(m,1H),5.40(s,1H),7.25-7.28(m,1H),7.29-7.32(m,1H),7.37-7.51(m,3H),8.71-8.79(m,1H).
实施例 1-183
MS ESI m/e:509,511(M+H),507,509(M-H).
1H-NMR(CDCl3,300MHz)δ0.81-0.90(m,2H),1.13-1.24(m,2H),2.71-2.81(m,2H),2.85(s,3H),3.84(s,3H),5.78(s,1H),6.93-7.00(m,2H),7.13-7.19(m,2H),7.19-7.23(m,2H),7.47-7.53(m,2H),10.42(brs,1H).
实施例 1-184
MS ESI m/e:410(M+H).
1H-NMR(CDCl3,300MHz)δ0.75-0.88(m,2H),1.09-1.22(m,2H),1.85(tt,J=7.0,14.0Hz,2H),2.26(s,6H),2.40(t,J=7.1Hz,2H),2.67-2.77(m,1H),2.79(s,3H),3.22(dt,J=5.5,6.2Hz,3H),5.40(s,1H),7.25-7.33(m,2H),7.37-7.52(m,3H),8.74(t,J=4.8Hz,1H).
实施例 1-185
MS ESI m/e:471,473(M+H),469,471(M-H).
1H-NMR(DMSO-d6,300MHz)δ2.62(s,3H),3.27(s,3H),5.37(s,1H),7.40-7.60(m,7H),7.70-7.80(m,1H),10.61(s,1H).
实施例 1-186
MS ESI m/e:527,529(M+H),525,527(M-H).
1H-NMR(CDCl3,300MHz)δ0.81-0.90(m,2H),1.13-1.24(m,2H),2.71-2.82(m,1H),2.85(s,3H),3.84(s,3H),5.64(d,J=1.1Hz,1H),6.94-7.01(m,2H),7.17-7.24(m,2H),7.29-7.33(m,2H),7.34-7.40(m,1H),10.35(brs,1H).
实施例 1-187
MS ESI m/e:459(M+H),457(M-H).
1H-NMR(CDCl3,300MHz)δ0.82-0.92(m,2H),1.13-1.24(m,2H),1.35(d,J=6.0Hz,6H),2.72-2.82(m,1H),2.81(s,3H),4.54(sept,J=6.0Hz,1H),5.63(s,1H),6.85-6.94(m,2H),7.12-7.20(m,2H),7.29-7.35(m,2H),7.38-7.53(m,3H),10.15(brs,1H).
实施例 1-188
MS ESI m/e:513,515(M+H),511,513(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.69-0.79(m,2H),0.99-1.08(m,2H),2.62-2.72(m,1H),2.66(s,3H),5.35(d,J=1.1Hz,1H),6.79-6.89(m,2H),7.15-7.23(m,2H),7.43-7.55(m,2H),7.70-7.76(m,1H),9.90(brs,1H),10.57(brs,1H).
实施例 1-189
MS ESI m/e:509,511(M+H),507,509(M-H).
1H-NMR(CDCl3,300MHz)δ0.82-0.90(m,2H),1.14-1.25(m,2H),2.73-2.80(m,1H),2.82(s,3H),3.89(s,3H),5.80(s,1H),7.07-7.13(m,2H),7.23-7.35(m,3H),7.39-7.53(m,3H),10.29(brs,1H).
实施例 1-190
MS ESI m/e:509,511(M+H),507,509(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.71-0.79(m,2H),0.99-1.08(m,2H),2.67(s,3H),2.66-2.68(m,1H),3.78(s,3H),5.53(s,1H),6.97-7.06(m,3H),7.31(d,J=9.0Hz,2H),7.41(dd,J=9.0,9.0Hz,1H),7.62(d,J=9.0Hz,2H),10.58(brs,H).
实施例 1-191
MS ESI m/e:527,529(M+H),525,527(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.71-0.79(m,2H),1.01-1.09(m,2H),2.67(s,3H),2.66-2.67(m,1H),3.78(s,3H),5.37(s,1H),6.97-7.06(m,3H),7.39-7.51(m,3H),7.73(d,J=12.0Hz,1H),10.55(brs,H).
实施例 1-192
MS ESI m/e:462(M+H).
1H-NMR(DMSO-d6,300MHz)δ0.71-0.79(m,2H),0.99-1.08(m,2H),2.55(s,3H),2.60-2.71(m,1H),2.92(s,6H),5.01(s,1H),6.56-6.66(m,2H),7.18(dd,J=12.0,9.0Hz,1H),7.39-7.51(m,5H),10.00(brs,H).
实施例 1-193
MS ESI m/e:582,584(M+H),580,582(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.75(m,2H),1.03(m,2H),2.60-2.75(m,1H),2.69(s,3H),3.11(brs,4H),3.73(brs,4H),5.38(s,1H),6.85(d,J=7.6Hz,1H),7.02(brs,2H),7.34(t,J=8.5Hz,1H),7.40-7.55(m,2H),7.73(d,J=11.1Hz,1H),10.57(s,1H).
实施例 1-194
MS ESI m/e:493,495(M+H),491,493(M-H).
1H-NMR(CDCl3,300MHz)δ0.80-0.89(m,2H),1.12-1.23(m,2H),2.68-2.80(m,1H),2.79(s,3H),4.37(d,J=6.0Hz,2H),5.33(s,1H),7.18-7.33(m,4H),7.39-7.52(m,5H),9.14(t,J=5.6Hz,1H).
实施例 1-195
MS ESI m/e:493,495(M+H),491,493(M-H).
1H-NMR(CDCl3,300MHz)δ0.79-0.89(m,2H),1.12-1.22(m,2H),2.68-2.76(m,1H),2.78(s,3H),4.34(d,J=5.6Hz,2H),5.34(s,1H),7.20-7.31(m,4H),7.39-7.53(m,5H),9.11(t,J=5.3Hz,1H).
实施例 1-196
MS ESI m/e:493,495(M+H),491,493(M-H).
1H-NMR(CDCl3,300MHz)δ0.79-0.89(m,2H),1.12-1.22(m,2H),2.69-2.77(m,1H),2.79(s,3H),4.46(d,J=5.6Hz,2H),5.36(s,1H),7.17(dt,J=1.9,7.5Hz,1H),7.24-7.33(m,3H),7.35(dt,J=1.1,7.7Hz,1H),7.39-7.51(m,3H),7.59(dd,J=1.1,7.9Hz,1H),9.16(t,J=5.7Hz,1H).
实施例 1-197
MS ESI m/e:445(M+H),443(M-H).
1H-NMR(CDCl3,300MHz)δ0.83-0.92(m,2H),1.14-1.25(m,2H),2.72-2.83(m,1H),2.80(s,3H),3.11(s,6H),5.44(s,1H),6.53(d,J=9.0Hz,1H),7.29-7.34(m,2H),7.37(dd,J=2.6,9.0Hz,1H),7.39-7.52(m,3H),8.07(d,J=2.6Hz,1H),9.96(brs,1H).
实施例 1-198
MS ESI m/e:495,497(M+H),493,495(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.69-0.78(m,2H),0.98-1.08(m,2H),2.59(s,3H),2.61-2.72(m,1H),5.50(s,1H),7.04(dd,J=2.3,8.3Hz,1H),7.13(d,J=2.3Hz,1H),7.30(d,J=8.3Hz,1H),7.38-7.55(m,5H),10.45(s,1H),10.48(brs,1H).
实施例 1-199
MS ESI m/e:540,542(M+H),538,540(M-H).
1H-NMR(CDCl3,300MHz)δ0.82-0.91(m,2H),1.14-1.23(m,2H),2.71-2.82(m,1H),2.93(s,3H),2.96(s,6H),5.66(s,1H),6.52(t,J=2.1Hz,1H),6.59(dd,J=1.9,8.3Hz,1H),6.71(dd,J=2.6,8.6Hz,1H),7.26-7.40(m,4H),10.39(brs,1H).
实施例 1-200
MS ESI m/e:487,489(M+H),485,487(M-H).
1H-NMR(DMSO-d6,300MHz)δ2.62(s,3H),3.27(s,3H),5.47(s,1H),7.40-7.60(m,6H),7.63(dd,J=2.1,8.6Hz,1H),7.91(d,J=2.1Hz,1H),10.83(s,1H).
实施例 1-201
MS ESI m/e:569,571(M+H),567,569(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.75(m,2H),1.03(m,2H),2.45-2.60(m,2H),2.60(s,3H),2.67(m,1H),2.85(t,J=7.4Hz,2H),5.36(s,1H),7.24(d,J=7.9Hz,1H),7.32(brs,2H),7.41(t,J=7.9Hz,1H),7.45-7.55(m,2H),7.73(d,J=9.2Hz,1H),10.54(s,1H),12.15(brs,1H).
实施例 1-202
MS ESI m/e:499,501(M+H),497,499(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.74-0.82(m,2H),0.98-1.06(m,2H),2.63-2.70(m,1H),5.74(s,1H),7.25-7.33(m,2H),7.38-7.55(m,4H),7.63(dd,J=2.2,8.8Hz,1H),7.92(d,J=2.2Hz,1H),10.90(brs,1H),11.14(brs,1H).
实施例 1-203
MS ESI m/e:482(M+H).
1H-NMR(DMSO-d6,300MHz)δ0.77-0.79(m,2H),1.02-1.17(m,2H),2.18(s,3H),2.34(s,3H),2.57(s,3H),2.65-2.68(m,1H),3.66(s,3H),5.24(s,1H),6.98(d,J=6.0Hz,1H),7.29(d,J=3.0Hz,1H),7.40-7.56(m,6H),10.35(brs,H).
实施例 1-204
MS ESI m/e:468(M+H).
1H-NMR(DMSO-d6,300MHz)δ0.72-0.80(m,2H),1.00-1.09(m,2H),2.41(s,3H),2.57(s,3H),2.62-2.71(m,1H),3.68(s,3H),5.26(s,1H),6.23(s,1H),6.97(d,J=12.0Hz,1H),7.33(s,1H),7.42-7.52(m,6H),10.35(brs,H).
实施例 1-205
MS ESI m/e:547(M+H),545(M-H).
1H-NMR(CDCl3,300MHz)δ0.86(m,2H),1.18(m,2H),2.75(m,1H),2.89(s,3H),2.97(s,6H),3.16(t,J=4.8Hz,4H),3.85(t,J=4.8Hz,4H),5.45(s,1H),6.45(s,1H),6.49(d,J=3.8Hz,1H),6.75-6.80(m,2H),6.91(d,J=8.3Hz,1H),7.14(t,J=9.0Hz,1H),7.33(t,J=8.4Hz,1H),9.89(s,1H).
实施例 1-206
MS ESI m/e:595,597(M+H).
1H-NMR(DMSO-d6,300MHz)δ0.69-0.77(m,2H),0.98-1.07(m,2H),2.21(s,3H),2.40-2.46(m,4H),2.61-2.71(m,1H),2.69(s,3H),3.09-3.16(m,4H),5.37(s,1H),6.79-6.84(m,1H),6.96-7.03(m,2H),7.29-7.34(m,1H),7.44-7.54(m,2H),7.69-7.77(m,1H),10.58(brs,1H).
实施例 1-207
MS ESI m/e:545(M+H),543(M-H).
1H-NMR(CDCl3,300MHz)δ0.81-0.92(m,2H),1.14-1.25(m,2H),2.72-2.82(m,1H),2.82(s,3H),5.69(d,J=1.1Hz,1H),7.28-7.36(m,2H),7.40-7.59(m,6H),10.36(s,1H).
实施例 1-208
MS ESI m/e:443(M+H),441(M-H).
1H-NMR(CDCl3,400MHz)δ0.81-0.91(m,2H),1.16-1.23(m,2H),2.73-2.80(m,1H),2.82(s,3H),3.12(s,1H),5.80(s,1H),7.26-7.33(m,3H),7.35-7.52(m,5H),10.50(s,1H).
实施例 1-209
MS ESI m/e:416(M+H),414(M-H).
1H-NMR(CDCl3,300MHz)δ0.79-0.88(m,2H),1.12-1.22(m,2H),2.68-2.77(m,1H),2.79(s,3H),4.42(d,J=5.6Hz,2H),5.37(s,1H),7.26-7.35(m,3H),7.38-7.52(m,3H),7.65-7.72(m,1H),8.57(dd,J=1.5,4.9Hz,1H),8.63(d,J=1.9Hz,1H),9.15(t,J=5.3Hz,1H).
实施例 1-210
MS ESI m/e:511,513(M+H),509,511(M-H).
1H-NMR(CDCl3,300MHz)δ0.80-0.90(m,2H),1.13-1.23(m,2H),2.70-2.78(m,1H),2.79(s,3H),4.43(d,J=6.0Hz,2H),5.33(s,1H),6.98(dd,J=9.0,9.1Hz,1H),7.28-7.33(m,2H),7.35-7.53(m,5H),9.12(t,J=6.0Hz,1H).
实施例 1-211
MS ESI m/e:509,511(M+H),507,509(M-H).
1H-NMR(CDCl3,300MHz)δ0.83-0.92(m,2H),1.14-1.25(m,2H),2.73-2.84(m,1H),2.81(s,3H),3.83(s,3H),5.46(s,1H),6.89(dd,J=3.0,8.7Hz,1H),7.21(d,J=2.6Hz,1H),7.29-7.36(m,3H),7.38-7.54(m,3H),10.17(brs,1H).
实施例 1-212
MS ESI m/e:580,581(M+H),578,580(M-H).
1H-NMR(CDCl3,300MHz)δ0.87(m,2H),1.18(m,2H),2.20(m,2H),2.63(t,J=8.1Hz,2H),2.77(m,1H),2.88(s,3H),3.88(t,J=7.1Hz,2H),5.66(s,1H),7.07(d,J=7.9Hz,1H),7.30-7.35(m,2H),7.37(d,J=9.2Hz,1H),7.46(t,J=8.1Hz,1H),7.54(d,J=8.6Hz,1H),7.89(d,J=2.0Hz,1H),10.34(s,1H).
实施例 1-213
MS ESI m/e:513,515(M+H),511,513(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.71-0.79(m,2H),0.99-1.09(m,2H),2.68(s,3H),2.61-2.71(m,1H),5.35(s,1H),2.79-2.89(m,3H),7.27(dd,J=9.0,9.0Hz,1H ),7.48-7.52(m,2H),7.72(d,J=6.0Hz,1H),9.83(brs,H),10.53(brs,H).
实施例 1-214
MS ESI m/e:594,596(M+H),592,594(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.75(m,2H),1.03(m,2H),1.85(brs,4H),2.39(m,2H),2.67(m,4H),3.62(m,2H),5.36(s,1H),7.33(d,J=8.3Hz,1H),7.35-7.40(m,2H),7.45-7.55(m,3H),7.74(d,J=10.2Hz,1H),10.54(s,1H).
实施例 1-215
MS ESI m/e:566,568(M+H),564,566(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.70-0.80(m,2H),0.99-1.11(m,2H),1.90-2.01(m,4H),2.64-2.74(m,1H),2.74-2.75(m,1H),3.13-3.27(m,4H),5.39(s,1H),6.54-6.65(m,3H),7.20-7.30(m,1H),7.45-7.55(m,2H),7.71-7.78(m,1H),10.60(brs,1H).
实施例 1-216
MS ESI m/e:580,582(M+H),578,580(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.69-0.78(m,2H),0.98-1.08(m,2H),1.48-1.65(m,6H),2.63-2.71(m,1H),2.69(s,3H),3.09-3.17(m,4H),5.37(s,1H),6.72-6.79(m,1H),6.95-7.02(m,2H),7.25-7.32(m,1H),7.46-7.54(m,2H),7.69-7.77(m,1H),10.59(brs,1H).
实施例 1-217
MS ESI m/e:476(M+H),474(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.71-0.80(m,2H),1.01-1.13(m,5H),2.58(s,3H),2.61-2.72(m,1H),2.90(s,3H),3.42(q,J=2.0Hz,2H),5.04(s,1H),6.62(dd,J=9.0,15.0Hz,2H),7.18(t,J=9.0Hz,1H),7.40-7.59(m,5H),10.01(brs,1H).
实施例 1-218
MS ESI m/e:584,585(M+H),582,584(M-H).
1H-NMR(DMSO-d6,300MHz)δ0,69-0.78(m,2H),0.98-1.09(m,2H),2.18(s,6H),2.59(t,J=3.0Hz,2H),2.66(s,3H),2.65-2.66(m,1H),4.01(t,J=4.5Hz,2H),5.37(s,1H),6.96-7.08(m,3H),7.38-7.51(m,3H),7.71(d,J=12.0Hz,1H),10.55(brs,1H).
实施例 1-219
MS ESI m/e:596,598(M+H),594,596(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.75(m,2H),1.03(m,2H),2.67(s,4H),3.75(m,2H),3.98(t,J=4.9Hz,2H),4.21(s,2H),5.36(s,1H),7.37(d,J=7.3Hz,1H),7.40-7.60(m,5H),7.73(d,J=9.4Hz,1H),10.53(s,1H).
实施例 1-220
MS ESI m/e:571,573(M+H),569,571(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.74-0.76(m,2H),0.99-1.10(m,2H),2.65-2.67(m,1H),2.66(s,3H),4.71(s,2H),5.37(s,1H),6.99-7.08(m,3H),7.41(t,J=9.0Hz,1H),7.45-7.52(m,2H),7.74(d,J=9.0Hz,1H),10.55(brs,1H),13.04(brs,1H).
实施例 1-221
MS ESI m/e:527(M+H),525(M-H).
1H-NMR(CDCl3,300MHz)δ0.81-0.91(m,2H),1.14-1.25(m,2H),2.71-2.82(m,1H),2.82(s,3H),5.82(s,1H),7.01-7.09(m,2H),7.28-7.35(m,2H),7.39-7.54(m,3H),7.66-7.74(m,2H),10.42(s,1H).
实施例 1-222
MS ESI m/e:425(M+H),423(M-H).
1H-NMR(CDCl3,300MHz)δ0.81-0.91(m,2H),1.15-1.24(m,2H),2.71-2.83(m,1H),2.83(s,3H),3.09(s,1H),5.92(s,1H),7.22-7.29(m,2H),7.29-7.35(m,2H),7.40-7.57(m,5H),10.54(s,1H).
实施例 1-223
MS ESI m/e:575,577(M+H),573,575(M-H).
1H-NMR(CDCl3,400MHz)δ0.84-0.91(m,2H),1.17-1.26(m,2H),2.73-2.80(m,1H),2.81(s,3H ),3.11(s,3H)5.65(s,1H),7.27-7.35(m,2H),7.35-7.40(m,1H),7.51-7.56(m,1H),7.68-7.75(m,1H),8.00-8.05(m,2H),10.22(s,1H).
实施例 1-224
MS ESI m/e:604,606(M+H),602,604(M-H).
1H-NMR(CDCl3,300MHz)δ0.82-0.91(m,2H),1.15-1.27(m,2H),2.72-2.81(m,1H),2.76(s,6H),2.81(s,3H),5.65(d,J=1.1Hz,1H),7.29-7.34(m,2H),7.35-7.43(m,1H),7.45-7.51(m,1H),7.63-7.72(m,1H),7.83-7.89(m,2H),10.25(s,1H).
实施例 1-225
MS ESI m/e:575,577(M+H),573,575(M-H).
1H-NMR(CDCl3,300MHz)δ0.82-0.91(m,2H),1.16-1.27(m,2H),2.72-2.83(m,1H),2.83(brs,3H),3.10(s,3H),5.63(brs,1H),7.28-7.35(m,2H),7.3 6-7.42(m,1H),7.58(d,J=8.4Hz,2H),8.10(d,J=8.4Hz,2H),10.22(s,1H).
实施例 1-226
MS ESI m/e:604,606(M+H),602,604(M-H).
1H-NMR(CDCl3,400MHz)δ0.83-0.91(m,2H),1.17-1.25(m,2H),2.71-2.81(m,1H),2.75(s,6H),2.84(brs,3H),5.58(brs,1H),7.26-7.35(m,2H),7.35-7.40(m,1H),7.52(d,J=8.1Hz,2H),7.89(d,J=8.1Hz,2H),10.21(s,1H).
实施例 1-227
MS ESI m/e:598,600(M+H),596,598(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.70-0.78(m,2H),0.99-1.09(m,2H),1.84(t,J=6.0Hz,2H),2.13(s,6H),2.34(t,J=6.0Hz,2H),2.66-2.68(m,1H),2.67(s,3H),4.00(t,J=6.0Hz,2H),5.37(s,1H),6.9 6-7.09(m,3H),7.40(dd,J=6.0,6.0Hz,1H),7.48-7.51(m,2H),7.74(d,J=9.0Hz,1H),10.56(brs,1H).
实施例 1-228
MS ESI m/e:604,606(M+H),602,604(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.71-0.80(m,2H),0.98-1.10(m,2H),2.61-2.71(m,1H),2.68(s,3H),2.96(s,3H),3.25(s,3H),5.37(s,1H),7.39(d,J=6.0Hz,1H),7.45-7.58(m,5H),7.74(d,J=9.0Hz,1H),10.53(brs,1H).
实施例 1-229
MS ESI m/e:443(M+H),441(M-H).
1H-NMR(CDCl3,300MHz)δ0.81-0.90(m,2H),1.14-1.24(m,2H),1.27(d,J=7.1Hz,6H),2.72-2.81(m,1H),2.81(s,3H),2.92(sept,J=6.8Hz,1H),5.77(s,1H),7.16-7.22(m,2H),7.22-7.28(m,2H),7.29-7.35(m,2H),7.39-7.53(m,3H),10.28(brs,1H).
实施例 1-230
MS ESI m/e:429(M+H),427(M-H).
1H-NMR(CDCl3,300MHz)δ0.82-0.91(m,2H),1.15-1.24(m,2H),1.25(t,J=7.5Hz,3H),2.66(q,J=7.5Hz,2H),2.72-2.81(m,1H),2.81(s,3H),5.76(s,1H),7.15-7.24(m,4H),7.29-7.36(m,2H),7.39-7.53(m,3H),10.29(brs,1H).
实施例 1-231
MS ESI m/e:426(M+H),424(M-H).
1H-NMR(CDCl3,300MHz)δ0.81-0.90(m,2H),1.15-1.25(m,2H),2.72-2.82(m,1H),2.84(s,3H),6.07(s,1H),7.28-7.34(m,2H),7.36-7.42(m,2H),7.44-7.55(m,3H),7.64-7.70(m,2H),10.84(brs,1H).
实施例 1-232
MS ESI m/e:626,628(M+H),624,626(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.71-0.79(m,2H),1.01-1.09(m,2H),2.41-2.48(m,4H),2.67(s,3H),2.64-2.70(m,3H),3.45-3.60(m,4H),4.06-4.10(m,2H),5.36(s,1H),7.00(d,J=3.0Hz,1H),7.03-7.05(m,2H),7.38-0.53(m,3H),7.72(d,J=6.0Hz,1H),10.54(brs,1H).
实施例 1-233
MS ESI m/e:610,612(M+H),608,610(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.71-0.79(m,2H),1.00-1.09(m,2H),1.62-1.71(m,4H),2.43-2.55(m,4H),2.64(s,3H),2.61-2.70(m,1H),2.77(t,J=3.0Hz,2H),4.06(t,J=3.0Hz,2H),5.37(s,1H),6.99(d,J=3.0Hz,1H),7.02-7.04(m,2H),7.39(dd,J=3.0,3.0Hz,1H),7.50-7.52(m,2H),7.74(d,J=3.0Hz,1H),10.54(brs,1H).
实施例 1-234
MS ESI m/e:624,626(M+H),622,624(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.71-0.79(m,2H),1.01-1.09(m,2H),1.32-1.41(m,2H),1.41-1.52(m,4H),2.37-2.46(m,4H),2.60-2.71(m,3H),2.67(s,3H),4.07(t,J=6.0Hz,2H),5.38(s,1H),7.01(dd,J=6.0,9.0Hz,1H),7.05-7.06(m,2H),7.40(dd,J=9.0,9.0Hz,1H),7.49-7.51(m,2H),7.74(d,J=12.0Hz,1H),10.55(brs,1H).
实施例 1-235
MS ESI m/e:612,614(M+H),610,612(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.71-0.79(m,2H),0.96(t,J=7.5Hz,6H),0.99-1.09(m,2H),2.46-2.59(m,5H),2.68(s,3H),2.75(t,J=3.0Hz,2H),4.00(t,J=3.0Hz,2H),5.37(s,1H),7.00(dd,J=3.0,3.0Hz,1H),7.01-7.06(m,2H),7.40(dd,J=6.0,3.0Hz,1H),7.49-7.52(m,2H),7.74(d,J=18.0Hz,1H),10.56(brs,1H).
实施例 1-236
MS ESI m/e:653,655(M+H),651,653(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.71-0.79(m,2H),0.96(t,J=7.5Hz,6H),0.99-1.09(m,2H),1.80-1.91(m,2H),2.13(s,3H),2.46-2.59(m,10H),2.60-2.73(m,4H),4.00(t,J=3.0Hz,2H),5.37(s,1H),7.00(dd,J=3.0,3.0Hz,1H),7.01-7.06(m,2H),7.40(dd,J=6.0,3.0Hz,1H),7.49-7.52(m,2H),7.74(d,J=18.0Hz,1H),10.56(brs,1H).
实施例 1-237
MS ESI m/e:444(M+H),442(M-H).
1H-NMR(CDCl3,300MHz)δ0.81-0.92(m,2H),1.16-1.26(m,2H),2.73-2.83(m,1H),2.85(s,3H),6.01(s,1H),7.29-7.35(m,2H),7.43-7.56(m,5H),7.60-7.70(m,1H),10.93(s,1H).
实施例 1-238
MS ESI m/e:473(M+H),471(M-H).
1H-NMR(DMSO-d6,400MHz)δ0.71-0.79(m,2H),1.00-1.08(m,2H),2.60(s,3H),2.63-2.71(m,1H),4.31(d,J=5.8Hz,2H),5.38(t,J=5.9Hz,1H),5.50(s,1H),7.29-7.35(m,1H),7.39-7.58(m,7H),10.71(s,1H).
实施例 1-239
MS ESI m/e:501(M+H),499(M-H).
1H-NMR(CDCl3,400MHz)δ0.82-0.90(m,2H),1.15-1.24(m,2H),1.63(s,6H),2.07( s,1H),2.73-2.81(m,1H),2.82(s,3H),5.78(s,1H),7.16-7.25(m,2H),7.28-7.33(m,2H),7.34-7.52(m,4H),10.46(s,1H).
实施例 1-240
MS ESI m/e:445(M+H),443(M-H).
1H-NMR(CDCl3,400MHz)δ0.84-0.90(m,2H),1.16-1.24(m,2H),2.73-2.82(m,1H),2.82(s,3H),5.31(d,J=10.9Hz,1H),5.74(d,J=17.6Hz,1H),5.72(s,1H),6.66(dd,J=10.9,17.8Hz,1H),7.14-7.25(m,2H),7.28-7.39(m,3H),7.40-7.51(m,3H),10.34(s,1H).
实施例 1-241
MS ESI m/e:487(M+H),485(M-H).
1H-NMR(CDCl3,300MHz)δ0.81-0.91(m,2H),1.15-1.24(m,2H),2.73-2.83(m,1H),2.83(s,3H),3.47(s,3H),4.33(s,2H),5.79(s,1H),7.22-7.35(m,4H),7.35-7.56(m,4H),10.49(s,1H).
实施例 1-242
MS ESI m/e:447(M+H),445(M-H).
1H-NMR(CDCl3,400MHz)δ0.84-0.90(m,2H),1.15-1.22(m,2H),1.25(t,J=7.6Hz,3H),2.66(q,J=7.6Hz,2H),2.73-2.81(m,1H),2.81(s,3H),5.59(d,J=1.2Hz,1H),6.96-7.04(m,2H),7.23-7.34(m,3H),7.39-7.51(m,3H),10.16(s,1H).
实施例 1-243
MS ESI m/e:555,557(M+H),553,555(M-H).
1H NMR(CDCl3,300MHz)δ0.81-0.92(m,2H),1.14-1.25(m,2H),1.43(t,J=4.9Hz,1H),1.88(quint,J=7.3Hz,2H),2.72-2.81(m,1H),2.76(t,J=7.7Hz,2H),2.82(s,3H),3.65(q,J=5.7Hz,2H),5.66(s,1H),7.10-7.19(m,2H),7.26-7.33(m,3H),7.35-7.45(m,2H),10.34(brs,1H).
实施例 1-244
MS ESI m/e:486,488(M+H),484,486(M-H).
1H-NMR(DMSO-d6,300MHz)δ1.19(t,J=6.0Hz,3H),2.50-2.53(m,1H),2.62(s,3H),3.95(q,J=7.0Hz,2H),5.37(s,1H),7.48-7.52(m,2H),7.60(dd,J=3.0,3.0Hz,1H),7.74(d,J=12.0Hz,1H),7.97(d,J=6.0Hz,1H),8.73(d,J=45.0Hz,1H),10.58(brs,1H).
实施例 1-245
MS ESI m/e:554,556(M+H),552,554(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.69-0.79(m,2H),0.99-1.09(m,2H),2.04(s,3H),2.63-2.68(m,1H),2.66(s,3H),5.35(s,1H),7.08(d,J=9.0Hz,1H),7.41(dd,J=6.0,6.0Hz,1H),7.49-7.51(m,2H),7.61-7.77(m,3H),10.18(brs,1H),10.54(brs,1H).
实施例 1-246
MS ESI m/e:500(M+H),498(M-H).
1H-NMR(CDCl3,300MHz)δ0.82-0.91(m,2H),1.14-1.25(m,2H),2.38(s,6H),2.72-2.83(m,1H),2.83(s,3H),3.48(s,2H),5.77(d,J=0.7Hz,1H),7.20-7.55(m,8H),10.45(s,1H).
实施例 1-247
MS ESI m/e:489(M+H),487(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.71-0.81(m,2H),0.99-1.10(m,2H),2.61(s,3H),2.64-2.74(m,1H),5.57(s,1H),6.58(d,J=16.1Hz,1H),7.40-7.64(m,8H),7.81(d,J=12.1Hz,1H),10.80(s,1H),12.44(brs,1H).
实施例 1-248
MS ESI m/e:491(M+H),489(M-H).
1H-NMR(DMSO-d6,400MHz)δ0.72-0.78(m,2H),0.99-1.07(m,2H),2.59(t,J=7.6Hz,2H),2.58(s,3H),2.63-2.70(m,1H),2.86(t,J=7.5Hz,2H),5.25(d,J=1.2Hz,1H),7.12-7.17(m,1H),7.24-7.30(m,1H),7.35-7.54(m,6H),10.40(s,1H),12.18(s,1H).
实施例 1-249
MS ESI m/e:447(M+H),445(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.72-0.79(m,2H),0.99-1.07(m,2H),2.59(s,3H),2.63-2.70(m,1H),5.45(s,1H),7.25-7.30(m,2H),7.31-7.37(m,2H),7.41-7.55(m,5H),10.49(brs,1H).
实施例 1-250
MS ESI m/e:501(M+H),499(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.71-0.78(m,2H),1.00-1.08(m,2H),2.62(s,1H),2.66-2.71(m,1H),5.76(s,1H),7.41-7.55(m,7H),7.76(d,J=8.3Hz,2H),10.86(brs,1H).
实施例 1-251
MS ESI m/e:458(M+H),456(M-H).
1H-NMR(CDCl3,300MHz)δ0.72-0.82(m,2H),0.99-1.09(m,2H),2.58(s,3H),2.63-2.74(m,1H),5.13(d,J=1.1Hz,1H),6.45-6.50(m,1H),7.33-7.61(m,8H),10.28(brs,1H),11.28(brs,1H).
实施例 1-252
MS ESI m/e:582,584(M+H),580,582(M-H).
1H-NMR(CDCl3,300MHz)δ0.82-0.91(m,2H),1.14-1.25(m,2H),1.76-1.90(m,2H),2.26-2.38(m,2H),2.26(brs,6H),2.65-2.73(m,2H),2.74-2.80(m,1H),2.83(s,3H),5.65(d,J=0.7Hz,1H),7.10-7.16(m,2H),7.24-7.29(m,1H),7.30-7.34(m,2H),7.34-7.44(m,2H),10.34(brs,1H).
实施例 1-253
MS ESI m/e:584,586(M+H),582,584(M-H).
1H-NMR(CDCl3,300MHz)δ0.82-0.90(m,2H),1.15-1.23(m,2H),2.73-2.80(m,1H),2.93(s,3H),2.97(s,3H),3.34(s,3H),3.44-3.56(m,4H),5.66(d,J=1.1Hz,2H),6.55-6.60(m,2H),6.70-6.76(m,1H),7.22-7.40(m,4H),10.39(brs,1H).
实施例 1-254
MS ESI m/e:457(M+H),455(M-H).
1H-NMR(CDCl3,400MHz)δ0.82-0.89(m,2H),1.15-1.23(m,2H),2.06(s,3H),2.72-2.80(m,1H),2.82(s,3H),5.74(s,1H),7.14-7.21(m,2H),7.28-7.36(m,3H),7.39-7.51(m,3H),10.38(s,1H).
实施例 1-255
MS ESI m/e:624,626(M+H),622,624(M-H).
1H-NMR(CDCl3,300MHz)δ0.81-0.91(m,2H),1.13-1.24(m,2H),1.74-1.90(m,2H),2.28-2.38(m,2H),2.38-2.46(m,4H),2.65-2.72(m,2H),2.73-2.80(m,1H),2.83(s,3H),3.68-3.74(m,4H),5.65(d,J=1.1Hz,1H),7.10-7.17(m,2H),7.23-7.28(m,.1H),7.29-7.33(m,2H),7.34-7.44(m,2H),10.33(brs,1H).
实施例 1-256
MS ESI m/e:549(M+H),547(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.66-0.77(m,2H),0.89-1.05(m,2H),2.54-2.61(m,1H),2.56(s,3H),7.36-7.45(m,4H),7.53-7.63(m,3H),7.65-7.71(m,2H),12.88(brs,1H).
实施例 1-257
MS ESI m/e:638(M+H),636(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.74(m,2H),1.03(m,2H),2.65(s,4H),3.02(s,3H),5.38(s,1H),7.13(d,J=8.6Hz,1H),7.20-7.40(m,3H),7.46(t,J=8.1Hz,1H),7.63(d,J=9.3Hz,1H),7.81(d,J=10.1Hz,1H),10.00(s,1H),10.54(s,1H).
实施例 1-258
MS ESI m/e:461(M+H),459(M-H).
1H-NMR(CDCl3,300MHz)δ0.83-0.91(m,2H),0.96(t,J=7.3Hz,3H),1.14-1.25(m,2H),1.58-1.72(m,2H),2.60(t,J=7.7Hz,2H),2.72-2.82(m,1H),2.82(s,3H),5.61(d,J=1.1Hz,1H),6.94-7.04(m,2H),7.24-7.36(m,3H),7.41-7.53(m,3H),10.18(s,1H).
实施例 1-259
MS ESI m/e:521(M+H),519(M-H).
1H-NMR(CDCl3,300MHz)δ0.83-0.92(m,2H),1.17-1.27(m,2H),2.72-2.82(m,1H),2.82(s,3H),3.12(s,3H),3.14(s,1H),5.80(d,J=0.7Hz,1H),7.28-7.36(m,2H),7.37-7.45(m,1H),7.51-7.57(m,1H),7.68-7.77(m,1H),8.01-8.07(m,2H),10.40(s,1H).
实施例 1-260
MS ESI m/e:536(M+H),534(M-H).
1H-NMR(CDCl3,300MHz)δ0.82-0.93(m,2H),1.29-1.28(m,2H),2.71-2.81(m,1H),2.89(s,3H),3.10(s,3H),3.15(s,1H),5.82(s,1H),6.81-6.88(m,1H),7.08(d,J=9.0Hz,1H),7.21-7.39(m,3H),7.39-7.51(m,2H),10.49(brs,H).
实施例 1-261
MS ESI m/e:499,501(M+H).
1H-NMR(CDCl3,300MHz)δ1.30(t,J=7.0Hz,3H),3.63(s,3H),4.13(q,J=7.0Hz,2H),5.57(s,2H),5.78(s,1H),7.20-7.50(m,8H),10.33(s,1H).
实施例 1-262
MS ESI m/e:604,606(M+H),602,604(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.71-0.78(m,2H),0.99-1.07(m,2H),1.18(t,J=7.5Hz,3H),2.61-2.70(m,4H),3.13(q,J=7.0Hz,2H),5.35(s,1H),7.08-7.14(m,1H),7.25-7.34(m,2H),7.41-7.54(m,3H),7.71-7.77(m,1H),10.04(brs,1H),10.53(s,1H).
实施例 1-263
MS ESI m/e:570,572(M+H),568,570(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.71-0.79(m,2H),0.99-1.07(m,2H),2.63-2.73(m,1H),2.66(s,3H),3.99(d,J=6.0Hz,2H),5.36(s,1H),5.65(t,J=6.0Hz,1H),7.10-7.15(m,1H),7.39-7.52(m,3H),7.71-7.85(m,3H),9.91(brs,1H),10.54(brs,1H).
实施例 1-264
MS ESI m/e:512,514(M+H),510,512(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.69-0.77(m,2H),0.97-1.08(m,2H),2.62-2.71(m,1H),2.74(s,3H),5.35(d,J=1.5Hz,1H),5.38(brs,2H),6.47-6.53(m,1H),6.54-6.57(m,1H),6.58-6.63(m,1H),7.11(t,J=7.9Hz,1H),7.44-7.53(m,2H),7.70-7.77(m,1H),10.55(brs,1H).
实施例 1-265
MS ESI m/e:459(M+H),457(M-H).
1H-NMR(CDCl3,300MHz)δ0.66-0.74(m,2H),0.83-0.91(m,2H),0.97-1.06(m,2H),1.14-1.24(m,2H),1.85-1.96(m,1H),2.72-2.81(m,1H),2.81(s,3H),5.58(d,J=1.1Hz,1H),6.82-6.92(m,2H),7.21-7.29(m,1H),7.29-7.36(m,2H),7.39-7.53(m,3H),10.16(s,1H).
实施例 1-266
MS ESI m/e:584,586(M+H),582,584(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.71-0.78(m,2H),0.99-1.08(m,2H),2.63-2.71(m,1H),2.66(s,3H),3.32(s,3H),3.37(s,3H),4.00(brs,2H),5.36(d,J=0.8Hz,1H),7.10-7.16(m,1H),7.40-7.52(m,3H),7.71-7.80(m,3H),10.00(brs,1H),10.54(brs,1H).
实施例 1-267
MS ESI m/e:658,660(M+H),656,658(M-H).
1H-NMR(CDCl3,300MHz)δ0.70-0.79(m,2H),0.99-1.10(m,2H),2.62-2.76(m,1H),2.66(s,3H),4.48-4.64(m,2H),5.36(s,1H),7.17(d,J=9.0Hz,1H),7.28-7.33(m,2H),7.43-7.52(m,3H),7.74(d,J=12.0Hz,1H),10.52(brs,1H),10.72(brs,1H).
实施例 1-268
MS ESI m/e:554(M+H),552(M-H).
1H-NMR(CDCl3,300MHz)δ0.83-0.92(m,2H),1.14-1.24(m,2H),1.26(t,J=7.7Hz,3H),1.37(t,J=7.3Hz,3H),2.67(q,J=7.6Hz,2H),2.71-2.81(m,1H),2.85(s,3H),3.17(q,J=7.5Hz,2H),5.60(d,J=1.1Hz,1H),6.94-7.08(m,4H),7.22-7.33(m,3H),7.38-7.47(m,1H),10.15(s,1H).
实施例 1-269
MS ESI m/e:541,543(M+H),539,541(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.70-0.79(m,2H),0.98-1.10(m,2H),2.60(s,3H),2.62-2.71(m,1H),5.37(d,J=1.1Hz,1H),7.43-7.57(m,2H),7.61-7.78(m,3H),7.95-8.05(m,2H),10.54(brs,1H),13.34(brs,1H).
实施例 1-270
MS ESI m/e:540,542(M+H),538,540(M-H).
1H-NMR(DMSO-d6,300Mmz)δ0.71-0.80(m,2H),0.98-1.09(m,2H),2.61(s,3H),2.63-2.74(m,1H),5.38(s,1H),7.45-7.58(m,3H),7.58-7.65(m,2H),7.70-7.78(m,1H),7.90(brs,1H),7.94-8.00(m,1H),8.11(brs,1H),10.54(brs,1H).
实施例 1-271
MS ESI m/e:618,620(M+H),616,618(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.71-0.77(m,2H),0.92.(t,J=7.5Hz,3H),1.00-1.07(m,2H),1.66(q,J=7.0Hz,2H),2.62-2.70(m,4H),3.05-3.13(m,2H),5.36(s,1H),7.09-7.13(m,1H),7.23-7.32(m,2H),7.41-7.53(m,3H),7.71-7.77(m,1H),10.05(brs,1H),10.53(s,1H).
实施例 1-272
MS ESI m/e:618,620(M+H),616,618(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.71-0.78(m,2H),0.99-1.08(m,2H),1.23(d,J=6.0Hz,6H),2.62-2.70(m,4H),3.19-3.29(m,1H),5.36(s,1H),7.07-7.13(m,1H),7.26-7.34(m,2H),7.39-7.54(m,3H),7.71-7.76(m,1H),10.00(brs,1H),10.53(s,1H).
实施例 1-273
MS ESI m/e:469(M+H),467(M-1).
1H-NMR(CDCl3,300MHz)δ0.80-0.90(m,2H),1.10-1.30(m,2H),2.78(m,1H),2.83(s,3H),5.97(s,1H),7.30-7.35(m,2H),7.35-7.55(m,5H),7.65(d,J=8.5Hz,2H),10.67(s,1H).
实施例 1-274
MS ESI m/e:652(M+H),650(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.70-0.79(m,2H),0.98-1.08(m,2H),1.17(t,J=7.3Hz,3H),2.61-2.71(m,1H),2.64(s,3H),3.13(q,J=7.3Hz,2H),5.38(brs,1H),7.09-7.15(m,2H),7.24-7.38(m,3H),7.40-7.49(m,1H),7.60-7.67(m,1H),7.81(dd,J=1.8,9.9Hz,1H),10.04(s,1H).
实施例 1-275
MS ESI m/e:540(M+H),538(M-H).
1H-NMR(CDCl3,400MHz)δ0.83-0.91(m,2H),1.15-1.23(m,2H),1.26(t,J=7.6Hz,3H),2.67(q,J=7.6Hz,2H),2.72-2.80(m,1H),2.85(s,3H),3.05(s,3H),5.60(d,J=1.2Hz,1H),6.98-7.05(m,2H),7.05-7.10(m,1H),7.23-7.31(m,4H),7.40-7.47(m,1H),10.16(s,1H).
实施例 1-276
MS ESI m/e:653,655(M+H).
1H-NMR(DMSO-d6,300MHz)δ0.70-0.79(m,2H),0.87(t,J=7.2Hz,3H),1.00-1.08(m,2H),1.22-1.36(m,2H),1.43-1.54(m,2H),2.15(t,J=7.3Hz,2H),2.63-2.72(m,1H),2.66(s,3H),3.86(d,J=5.3Hz,2H),5.36(s,1H),7.05-7.12(m,1H),7.40-7.52(m,3H),7.61-7.77(m,3H),8.08-8.15(m,1H),10.20(brs,1H),10.54(brs,1H).
实施例 1-277
MS ESI m/e:597,599(M+H),595,597(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.70-0.78(m,2H),0.99-1.07(m,2H),2.28(s,6H),2.64-2.70(m,1H),2.67(s,3H),3.09(brs,2H),5.36(d,J=1.1Hz,1H),7.10-7.14(m,1H),7.40-7.52(m,3H),7.71-7.79(m,3H),9.97(brs,1H),10.54(brs,1H).
实施例 1-278
MS ESI m/e:568,570(M+H),566,568(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.71-0.78(m,2H),0.99-1.11(m,5H),2.33(q,J=7.0Hz,2H),2.63-2.71(m,4H),5.36(s,1H),7.04-7.10(m,1H),7.42(t,J=7.5Hz,1H),7.46-7.54(m,2H),7.61-7.67(m,1H),7.70-7.77(m,2H),10.08(s,1H),10.54(s,1H).
实施例 1-279
MS ESI m/e:582,584(M+H),580,582(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.71-0.78(m,2H),0.91(t,J=7.5Hz,3H),0.99-1.07(m,2H),1.60(q,J=8.0Hz,2H),2.29(t,J=7.5Hz,2H),2.63-2.71(m,4H),5.36(s,1H),7.42(t,J=7.5Hz,1H),7.46-7.54(m,2H),7.62-7.76(m,3H),10.09(s,1H),10.54(s,1H).
实施例 1-280
MS ESI m/e:644,646(M+H),642,644(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.68-0.80(m,2H),0.97-1.08(m,2H),2.61-2.72(m,1H),2.64(s,3H),5.36(d,J=0.7Hz,1H),6.88-7.01(m,1H),7.05-7.17(m,2H),7.23-7.34(m,1H),7.47(dd,J=2.3,8.7Hz,1H),7.52(t,J=8.1Hz,1H),7.73(dd,J=1.5,10.2Hz,1H),10.56(brs,1H).
实施例 1-281
MS ESI m/e:485(M+H),483(M-H).
1H-NMR(CDCl3,300MHz)δ0.71-0.81(m,2H),1.00-1.10(m,2H),2.60(s,3H),2.61-2.72(m,1H),5.52(s,1H),7.41-7.56(m,9H),10.62(brs,1H).
实施例 1-282
MS ESI m/e:624,626(M+H),622,624(M-H).
1H-NMR(CDCl3,300MHz)δ0.71-0.81(m,2H),0.97-1.10(m,2H),2.61-2.72(m,1H),2.65(s,3H),5.07(s,2H),5.36(s,1H),7.19(d,J=9.0Hz,1H),7.28-7.38(m,2H),7.42-7.56(m,3H),7.74(d,J=9.0Hz,1H),10.53(brs,1H),10.64(brs,1H).
实施例 1-283
MS ESI m/e:526,528(M+H),524,526(M-H).
1H-NMR(CDCl3,300MHz)δ0.71-0.79(m,2H),0.99-1.09(m,2H),2.66(d,J=6.0Hz,3H),2.64-2.67(m,1H),2.74(s,3H),5.36(s,1H),5.92-5.98(m,1H),6.50-6.60(m,3H),7.19(t,J=7.5Hz,1H),7.49-7.54(m,2H),7.74(d,J=12.0Hz,1H),10.57(brs,1H).
实施例 1-284
MS ESI m/e:652,654(M+H),650,652(M-H).
1H-NMR(CDCl3,300MHz)δ0.68-0.80(m,2H),0.99-1.09(m,2H),2.33(s,3H),2.61-2.70(m,1H),5.35(s,1H),7.04(d,J=12.0Hz,1H),7.13(d,J=6.0Hz,1H),7.30-7.38(m,2H),7.49-7.62(m,5H),7.73-7.80(m,3H),10.48(brs,1H),10.52(brs,1H).
实施例 1-285
MS ESI m/e:465(M+H),463(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.71-0.78(m,2H),1.01-1.07(m,2H),2.53(s,3H),2.59(s,3H),2.64-2.72(m,1H),5.25(d,J=1.1Hz,1H),7.17(dd,J=1.9,8.7Hz,1H),7.32(dd,J=1.9,11.3Hz,1H),7.39-7.55(m,6H),10.41(brs,1H).
实施例 1-286
MS ESI m/e:558(M+H),556(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.72-0.78(m,2H),0.99-1.07(m,2H),2.53(s,3H),2.63-2.69(m,1H),2.65(s,3H),3.02(s,3H),5.25(d,J=1.1Hz,1H),7.11-7.19(m,2H),7.24-7.35(m,3H),7.39-7.50(m,2H),9.99(brs,1H),10.39(brs,1H).
实施例 1-287
MS ESI m/e:582,584(M+H),580,582(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.70-0.78(m,2H),0.99-1.12(m,8H),2.53-2.70(m,5H),5.36(s,1H),7.05-7.11(m,1H),7.42(t,J=7.5Hz,1H),7.46-7.55(m,2H),7.62-7.68(m,1H),7.70-7.77(m,2H),10.05(s,1H),10.54(s,1H).
实施例 1-288
MS ESI m/e:576,578(M+H),574,576(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.72-0.80(m,2H),1.00-1.08(m,2H),2.60-2.70(m,4H),5.37(s,1H),7.47-7.58(m,4H),7.65-7.77(m,3H),7.88-7.93(m,2H),10.52(s,1H).
实施例 1-289
MS ESI m/e:550(M+H),548(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.70-0.78(m,2H),0.99-1.09(m,2H),1.18(t,J=7.3Hz,3H),2.63-2.71(m,1H),2.66(s,3H),3.13(q,J=7.5Hz,2H),4.32(s,1H),5.51(s,1H),7.09-7.15(m,1H),7.24-7.35(m,2H),7.36-7.41(m,1H),7.41-7.49(m,1H),7.50-7.61(m,2H),10.04(s,1H),10.72(s,1H).
实施例 1-290
MS ESI m/e:518(M+H),516(M-H).
1H-NMR(DMSO-d6,400MHz)δ0.71-0.78(m,2H),1.00-1.08(m,2H),2.61-2.71(m,1H),2.66(s,3H),3.03(s,3H),4.19(s,1H),5.64(s,1H),7.11-7.16(m,1H),7.24-7.29(m,1H),7.30-7.37(m,3H),7.43-7.49(m,1H),7.51-7.56(m,2H),10.01(s,1H),10.70(s,1H).
实施例 1-291
MS ESI m/e:483(M+H),481(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.70-0.80(m,2H),0.98-1.10(m,2H),2.60(s,3H),2.62-2.73(m,1H),3.68(q,J=11.6Hz,2H),5.54(s,1H),7.30-7.38(m,2H),7.39-7.56(m,7H),10.60(brs,1H).
实施例 1-292
MS ESI m/e:554,556(M+H),552,554(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.71-0.81(m,2H),0.98-1.09(m,2H),2.60(s,3H),2.63-2.71(m,1H),2.79(d,J=4.5Hz,3H),5.38(d,J=1.1Hz,1H),7.45-7.55(m,2H),7.57-7.65(m,2H),7.71-7.77(m,1H),7.84-7.89(m,1H),7.89-7.95(m,1H),8.57(q,J=5.3Hz,1H),10.53(brs,1H).
实施例 1-293
MS ESI m/e:447(M+H),445(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.71-0.80(m,2H),0.99-1.08(m,2H),2.59(s,3H),2.62-2.73(m,1H),3.00(dt,J=25.2,6.0Hz,2H),4.67(dt,J=47.1,6.4Hz,2H),5.46(s,1H),7.23-7.29(m,2H),7.33-7.39(m,2H),7.40-7.56(m,5H),10.51(brs,1H).
实施例 1-294
MS ESI m/e:590,592(M+H),588,590(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.71-0.79(m,2H),1.00-1.09(m,2H),2.42(s,3H),2.58-2.70(m,4H),5.37(s,1H),7.45-7.54(m,2H),7.70-7.80(m,3H),7.82-7.88(m,2H),10.51(s,1H).
实施例 1-295
MS ESI m/e:604,606(M+H),602,604(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.72-0.79(m,2H),0.96(t,J=6.0Hz,3H),1.01-1.08(m,2H),2.58-2.71(m,4H),2.74-2.84(m,2H),5.37(s,1H),7.46-7.55(m,2H),7.69-7.79(m,4H),7.84-7.90(m,2H),10.51(s,1H).
实施例 1-296
MS ESI m/e:504(M+H),502(M-H).
1H-NMR(CDCl3,300MHz)δ0.81-0.91(m,2H),1.12-1.23(m,2H),1.26(t,J=7.5Hz,3H),2.16(s,3H),2.66(q,J=7.6Hz,2H),2.72-2.82(m,1H),2.86(s,3H),5.59(d,J=1.5Hz,1H),6.95-7.08(m,3H),7.22-7.32(m,1H),7.33-7.55(m,3H),7.70(s,1H),10.18(s,1H).
实施例 1-297
MS ESI m/e:602(M+H),600(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.68-0.79(m,2H),0.98-1.09(m,2H),2.04(s,3H),2.63-2.71(m,1H),2.66(s,3H),5.38(d,J=1.5Hz,1H),7.04-7.10(m,1H),7.29-7.38(m,1H),7.38-7.46(m,1H),7.60-7.72(m,3H),7.81(dd,J=1.8,10.2Hz,1H),10.15(s,1H),10.55(s,1H).
实施例 1-298
MS ESI m/e:532(M+H),530(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.70-0.80(m,2H),0.98-1.09(m,2H),1.18(t,J=7.3Hz,3H),2.61-2.72(m,1H),2.65(s,3H),3.13(q,J=7.5Hz,2H),4.18(s,1H),5.65(s,1H),7.08-7.15(m,1H),7.24-7.31(m,1H),7.31-7.38(m,3H),7.41-7.49(m,1H),7.51-7.57(m,2H),10.04(s,1H),10.70(s,1H).
实施例 1-299
MS ESI m/e:667,669(M+H),665,667(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.71-0.77(m,2H),0.83(t,J=7.4Hz,3H),0.98-1.07(m,2H),1.19-1.29(m,2H),1.39-1.49(m,2H),2.04(t,J=7.5Hz,2H),2.45-2.53(m,2H),2.63-2.70(m,1H),2.66(s,3H),3.27-3.35(m,2H),5.35(d,J=1.1Hz,1H),7.05-7.11(m,1H),7.42(t,J=8.1Hz,1H),7.47-7.52(m,2H),7.60-7.67(m,1H),7.70-7.77(m,2H),7.87-7.94(m,1H),10.17(brs,1H),10.54(brs,1H).
实施例 1-300
MS ESI m/e:457(M+H),455(M-1).
1H-NMR(CDCl3,300MHz)δ0.80-0.90(m,2H),1.10-1.30(m,2H),1.34(s,9H),2.77(m,1H),2.81(s,3H),5.79(s,1H),7.20(d,J=8.5Hz,2H),7.30-7.35(m,2H),7.35-7.55(m,5H),10.29(s,1H).
实施例 1-301
MS ESI m/e:580(M+H),578(M-1).
1H-NMR(DMSO-d6,300MHz)δ0.75(brs,2H),1.05(m,2H),2.68(s,4H),3.03(s,3H),3.32(s,3H),5.68(s,1H),7.15(d,J=8.9Hz,1H),7.27(d,J=8.1Hz,1H),7.47(t,J=8.0Hz,1H),7.64(d,J=8.4Hz,1H),7.75-7.90(m,2H),10.01(s,1H),10.95(s,1H).
实施例 1-302
MS ESI m/e:620(M+H),618(M-H).
1H-NMR(DMSO-d6,400MHz)δ0.71-0.78(m,2H),0.99-1.07(m,2H),2.62-2.69(m,1H),2.65(s,3H),3.02(s,3H),5.54(s,1H),7.10-7.19(m,3H),7.23-7.28(m,1H),7.29-7.32(m,1H),7.42-7.49(m,1H),7.74-7.80(m,2H),10.00(s,1H),10.57(s,1H).
实施例 1-303
MS ESI m/e:625,627(M+H),623,625(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.69-0.78(m,2H),0.99-1.09(m,2H),2.34-2.56(m,6H),2.61-2.71(m,1H),2.74(s,3H),3.08-3.19(m,2H),3.50-3.62(m,4H),5.36(s,1H),5.77(brs,1H),6.53-6.70(m,3H),7.18(dd,J=9.0,6.0Hz,1H),7.40-7.50(m,2H),7.74(d,J=9.0Hz,1H),10.56(brs,1H).
实施例 1-304
MS ESI m/e:572,574(M+H),570,572(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.74-0.79(m,2H),1.00-1.08(m,2H),2.62-2.68(m,4H),3.02(s,3H),5.53(s,1H),7.12-7.14(m,1H),7.22-7.35(m,4H),7.42-7.44(m,1H),7.60-7.62(m,2H),10.00(brs,1H),10.57(brs,1H).
实施例 1-305
MS ESI m/e:584,586(M+H),582,584(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.69-0.80(m,2H),0.97-1.08(m,2H),2.47(t,J=7.2Hz,2H),2.62-2.71(m,1H),2.67(s,3H),3.70(q,J=5.9Hz,2H),4.69(t,J=5.1Hz,1H),5.36(d,J=1.1Hz,1H),7.07(dd,J=2.6,7.9Hz,1H),7.42(t,J=8.1Hz,1H),7.48-7.55(m,2H),7.62-7.69(m,1H),7.71-7.77(m,2H),10.13(brs,1H),10.54(brs,1H).
实施例 1-306
MS ESI m/e:611,613(M+H),609,611(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.69-0.79(m,2H),0.98-1.08(m,2H),2.16(s,6H),2.39-2.48(m,2H),2.51-2.59(m,2H),2.63-2.72(m,1H),2.67(s,3H),5.35(d,J=1.1Hz,1H),7.05-7.11(m,1H),7.42(t,J=8.1Hz,1H),7.47-7.55(m,2H),7.61-7.67(m,1H),7.69-7.77(m,2H),10.22(brs,1H),10.54(brs,1H).
实施例 1-307
MS ESI m/e:583,585(M+H),581,583(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.70-0.79(m,2H),0.98-1.08(m,2H),1.04(t,J=7.2Hz,3H),2.62-2.74(m,1H),2.68(s,3H),3.09(quint,J=6.8Hz,2H),5.35(d,J=1.1Hz,1H),6.16(t,J=5.8Hz,1H),6.88-6.95(m,1H),7.32(t,J=7.9Hz,1H),7.36-7.42(m,1H),7.45-7.57(m,3H),7.71-7.77(m,1H),8.73(brs,1H),10.55(brs,1H).
实施例 1-308
MS ESI m/e:584,586(M+H),582,584(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.70-0.78(m,2H),0.98-1.08(m,2H),1.24(t,J=7.2Hz,3H),2.61-2.72(m,1H),2.66(s,3H),4.12(q,J=6.9Hz,2H),5.36(d,J=1.1Hz,1H),7.00-7.05(m,1H),7.39(t,J=7.9Hz,1H),7.43-7.55(m,3H),7.60-7.65(m,1H ),7.70-7.78(m,1H),9.85(brs,1H),10.54(brs,1H).
实施例 1-309
MS ESI m/e:619,621(M+H),617,619(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.68-0.80(m,2H),0.98-1.07(m,2H),2.60-2.71(m,1H),2.63(s,3H),2.67(s,6H),5.35(d,J=1.1Hz,1H),7.09-7.15(m,1H),7.21-7.27(m,2H),7.43(t,J=8.5Hz,1H),7.4 7-7.54(m,2H),7.70-7.76(m,1H),10.11(brs,1H),10.54(brs,1H).
实施例 1-310
MS ESI m/e:500(M+H),498(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.70-0.79(m,2H),0.98-1.08(m,2H),2.05(s,3H),2.63-2.72(m,1H),2.67(s,3H),4.32(s,1H),5.51(brs,1H),7.04-7.12(m,1H),7.35-7.46(m,2H),7.50-7.61(m,2H),7.62-7.67(m,1H),7.67-7.72(m,1H),10.16(s,1H),10.75(s,1H).
实施例 1-311
MS ESI m/e:666(M+H),664(M-H).
1H-NMR(DMSO-d6,400MHz)δ0.71-0.77(m,2H),0.92(t,J=7.5Hz,3H),1.00-1.07(m,2H),1.59-1.71(m,2H),2.62-2.70(m,1H),2.64(s,3H),3.09(t,J=7.4Hz,2H),5.38(d,J=1.2Hz,1H),7.08-7.14(m,1H),7.23-7.37(m,3H),7.41-7.48(m,1H),7.61-7.66(m,1H),7.79-7.84(m,1H),10.54(s,1H).
实施例 1-312
MS ESI m/e:753,755(M+H),751,753(M-H).
1H-NMR(CDCl3,300MHz)δ0.81-0.89(m,2H),1.14-1.22(m,2H),2.70-2.79(m,1H),2.81(s,3H),3.21-3.32(m,2H),3.57-3.68(m,2H),5.07(s,2H),5.57-5.67(m,1H),5.65(d,J=1.1Hz,1H),7.04-7.09(m,1H),7.21-7.40(m,11H),7.74-7.80(m,1H),10.34(brs,1H).
实施例 1-313
MS ESI m/e:619,621(M+H),617,619(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.72-0.79(m,2H),0.99-1.09(m,2H),2.63-2.70(m,1H),2.66(s,3H ),3.09-3.19(m,2H),3.37-3.49(m,2H),5.36(d,J=0.9Hz,1H),7.17-7.24(m,1H),7.30-7.39(m,2H),7.47-7.54(m,3H),7.73-7.77(m,1H),7.93-8.14(m,3H),10.39(brs,1H),10.52(brs,1H).
实施例 1-314
MS ESI m/e:703,705(M+H),701,703(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.71-0.78(m,2H),0.82(t,J=7.2Hz,3H),0.99-1.08(m,2H),1.15-1.27(m,1H),1.37-1.47(m,2H),2.01(t,J=7.5Hz,2H),2.62-2.70(m,1H),2.65(s,3H),3.17-3.25(m,2H),3.33-3.43(m,2H),5.36(d,J=1.1Hz,1H),7.11-7.18(m,1H),7.25-7.30(m,1H),7.33-7.36(m,1H),7.42-7.54(m,3H),7.72-7.77(m,1H),7.87-7.94(m,1H),10.08(brs,1H),10.53(brs,1H).
实施例 1-315
MS ESI m/e:659,661(M+H),657,659(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.72-0.79(m,2H),1.01-1.09(m,2H),2.14(s,3H),2.32-2.39(m,4H),2.60-2.72(m,4H),2.83-2.97(m,4H),5.37(s,1H),7.46-7.55(m,2H),7.71-7.87(m,5H),10.51(s,1H).
实施例 1-316
MS ESI m/e:646,648(M+H),644,646(M-H).
1H-NMR DMSO-d6,300MHz)δ0.72-0.79(m,2H),1.01-1.10(m,2H),2.60-2.71(m,4H),2.81-2.94(m,4H),3.58-3.67(m,4H),5.38(s,1H),7.47-7.55(m,2H),7.71-7.88(m,5H),10.50(s,1H).
实施例 1-317
MS ESI m/e:644,646(M+H),642,644(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.71-0.79(m,2H),1.00-1.09(m,2H),1.32-1.41(m,2H),1.47-1.58(m,4H),2.58-2.73(m,4H),2.82-2.92(m,4H),5.37(s,1H),7.46-7.54(m,2H),7.71-7.84(m,5H),10.51(s,1H).
实施例 1-318
MS ESI m/e:630,632(M+H),628,630(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.71-0.79(m,2H),1.01-1.10(m,2H),1.59-1.69(m,4H),2.58(s,3H),2.63-2.71(m,1H),3.03-3.22(m,4H),5.37(s,1H),7.46-7.55(m,2H),7.71-7.82(m,3H),7.87-7.92(m,2H),10.51(s,1H).
实施例 1-319
MS ESI m/e:666(M+H),664(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.70-0.79(m,2H),0.99-1.08(m,2H),1.23(d,J=6.6Hz,6H),2.61-2.71(m,1H),2.64(s,3H),5.38(s,1H),7.08-7.15(m,1H),7.27-7.38(m,3H),7.39-7.47(m,1H),7.60-7.66(m,1H),7.78-7.84(m,1H),9.99(brs,1H),10.54(s,1H).
实施例 1-320
MS ESI m/e:564(M+H),562(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.70-0.79(m,2H),0.92(t,J=7.3Hz,3H),0.99-1.09(m,2H),1.58-1.74(m,2H),2.62-2.72(m,1H),2.66(s,3H),3.05-3.14(m,2H),4.32(s,1H),5.51(s,1H),7.09-7.16(m,1H),7.24-7.34(m,2H),7.35-7.50(m,2H),7.50-7.61(m,2H),10.04(brs,1H),10.73(s,1H).
实施例 1-321
MS ESI m/e:564(M+H),562(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.70-0.79(m,2H),0.99-1.08(m,2H),1.23(d,J=6.6Hz,6H),2.62-2.71(m,1H),2.65(s,1H),3.18-3.30(m,1H),4.31(s,1H),5.51(s,1H),7.08-7.14(m,1H),7.26-7.35(m,2H),7.35-7.48(m,2H),7.50-7.61(m,2H),10.00(brs,1H),10.73(s,1H).
实施例 1-322
MS ESI m/e:655(M+H),653(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.69-0.79(m,2H),0.99-1.09(m,2H),2.61-2.71(m,4H),3.02(s,3H),5.49(s,1H),7.15(d,J=9.0Hz,1H),7.25-7.31(m,2H),7.38-7.49(m,2H),7.74-7.77(m,1H),8.00(s,1H),9.99(brs,1H),10.76(brs,1H).
实施例 1-323
MS ESI m/e:625,627 (M+H),623,625(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.70-0.79(m,2H),0.98-1.09(m,2H),1.70(quint,J=7.2Hz,2H),2.11(s,6H),2.21(t,J=7.2Hz,2H),2.33(t,J=7.3Hz,2H),2.62-2.72(m,1H),2.66(s,3H),5.35(d,J=1.1Hz,1H),7.04-7.11(m,1H),7.41(t,J=8.1Hz,1H),7.45-7.54(m,2H),7.60-7.67(m,1H),7.69-7.78(m,2H),10.13(brs,1H),10.54 (brs,1H).
实施例 1-324
MS ESI m/e:583,585(M+H),581,583(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.69-0.79(m,2H),0.97-1.08(m,2H),2.62-2.74(m,1H),2.69(s,3H),2.92(s,6H),5.35(d,J=1.1Hz,1H),6.94-7.01(m,1H),7.34(t,J=8.1Hz,1H),7.46-7.54(m,2H),7.54-7.61(m,2H),7.70-7.77(m,1H),8.51(brs,1H),10.54(brs,1H).
实施例 1-325
MS ESI m/e:569,571(M+H),567,569(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.69-0.80(m,2H),0.98-1.09(m,2H),2.63(d,J=4.9Hz,3H),2.65-2.73(m,1H),2.68(s,3H),5.35(d,J=1.1Hz,1H),6.00-6.08(m,1H),6.89-6.95(m,1H),7.33(t,J=7.9Hz,1H),7.38-7.45(m,1H),7.46-7.52(m,2H),7.52-7.56(m,1H),7.69-7.77(m,1H),8.77(brs,1H),10.55(brs,1H).
实施例 1-326
MS ESI m/e:465(M+H),463(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.70-0.80(m,2H),0.99-1.08(m,2H),2.59(s,3H),2.62-2.72(m,1H),3.21(dt,J=4.5,18.3Hz,2H),5.50(s,1H),6.27(tt,J=4.3,56.3Hz,1H),7.26-7.34(m,2H),7.34-7.56(m,7H),10.55(brs,1H).
实施例 1-327
MS ESI m/e:585,587(M+H),583,585(M-1).
1H-NMR(DMSO-d6,300MHz)δ0.75(brs,2H),1.03(m,2H),2.68(s,4H),3.61(s,3H),5.36(s,1H),7.00-7.10(m,1H),7.38(t,J=8.1Hz,1H),7.45-7.55(m,2H),7.65-7.80(m,3H),9.12(s,1H),9.63(s,1H),10.54(s,1H).
实施例 1-328
MS ESI m/e:457(M+H),455(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.74-0.81(m,2H),1.01-1.10(m,2H),2.60(s,3H),2.65-2.74(m,1H),5.50(s,1H),7.32(dd,J=1.9,8.7Hz,1H),7.40-7.56(m,6H),7.82-7.87(m,2H),8.07(d,J=8.3Hz,1H),10.63(brs,1H).
实施例 1-329
MS ESI m/e:437(M+H),435(M-H).
1H-NMR(CDCl3,400MHz)δ2.89(s,3H),7.15-7.55(m,5H),10.35(s,1H).
实施例 1-330
MS ESI m/e:347(M+H),345(M-H).
1H-NMR(CDCl3,300MHz)δ3.41(s,3H),3.53(s,3H),3.56(s,3H),7.15-7.23(m,2H),7.32-7.38(m,2H),10.45(s,1H).
实施例 1-331
MS ESI m/e:458(M+H),456(M-H).
1H-NMR(CDCl3,300MHz)δ0.40-0.57(m,4H),1.24-1.37(m,1H),2.81(s,3H),2.97(s,6H),3.91(d,J=7.0Hz,2H),5.61(s,1H),6.70-6.77(m,2H),7.10-7.17(m,2H),7.33-7.54(m,5H),10.22(s,1H).
实施例 1-332
MS ESI m/e:495(M+H),496,493(M-H),494.
1H-NMR(DMSO-d6,300MHz)δ2.70(s,3H),3.84(s,3H),5.88(s,1H),7.36-7.55(m,10H),7.46(d,J=9.0Hz,2H),7.99(d,J=9.0Hz,2H),10.85(brs,1H).
实施例 1-333
MS ESI m/e:604,606(M+H),602,604(M-H).
1H-NMR(DMSO-d6,400MHz)δ0.66-0.74(m,2H),0.98-1.06(m,2H),1.56(s,3H),2.60-2.69(m,1H),2.74(s,3H),3.03(s,3H),6.80(t,J=8.9Hz,1H),7.10-7.15(m,1H),7.25-7.36(m,3H),7.46(t,J=8.0Hz,1H),7.59-7.64(m,1H),9.99(s,1H),10.17(s,1H).
实施例 1-334
MS ESI m/e:556(M+H),554(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.69-0.78(m,2H),0.99-1.08(m,2H),2.74(s,3H),2.61-2.72(m,1H),2.69-2.79(m,2H),2.98-3.09(m,2H),5.36(s,1H),5.92(brs,1H),6.51-6.68(m,3H),7.15-7.20(m,1H),7.49-7.50(m,2H),7.72-7.75(m,1H),10.60(brs,1H).
实施例 1-335
MS ESI m/e:654(M+H),652(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.67-0.81(m,2H),0.96-1.09(m,2H),2.36(s,3H),2.61-2.69(m,1H),5.35(s,1H),7.08(d,J=9.0Hz,1H),7.16(d,J=9.0Hz,1H),7.31-7.39(m,2H),7.48-7.53(m,2H),7.57-7.62(m,1H),7.74(d,J=9.0Hz,1H),8.10(d,J=9.0Hz,1H),8.77-8.80(m,1H),8.88-8.90(m,1H),10.52(brs,1H),10.69(brs,1H).
实施例 1-336
MS ESI m/e:532(M+H),530(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.71-0.80(m,2H),0.99-1.09(m,2H),2.25(s,3H),2.61-2.73(m,1H),2.64(s,3H),3.01(s,3H),4.17(s,1H),5.27(s,1H),7.14-7.48(m,7H),9.98(brs,1H),10.50(brs,1H).
实施例 1-337
MS ESI m/e:552(M+H),550(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.68-0.78(m,2H),0.99-1.10(m,2H),2.66(s,3H),2.61-2.76(m,1H),3.01(s,3H),4.31(s,1H),5.61(s,1H),7.13(d,J=12.0Hz,1H),7.22-7.32(m,2H),7.41-7.51(m,2H),7.61(d,J=6.0Hz,1H),7.74(s,1H),9.98(brs,1H),10.90(brs,1H).
实施例 1-338
MS ESI m/e:558(M+H),556(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.70-0.81(m,2H),0.99-1.08(m,2H),2.61-2.71(m,1H),2.65(s,3H),3.02(dt,J=18.8,3.4Hz,2H),3.02(s,3H),4.69(dt,J=47.1,3.0Hz,2H),5.28(s,1H),7.10-7.16(m,1H),7.17-7.23(m,1H),7.23-7.29(m,1H),7.29-7.39(m,2H),7.41-7.50(m,2H),10.00(brs,1H),10.43(s,1H).
实施例 1-339
MS ESI m/e:690(M+H),688(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.69-0.79(m,2H),0.98-1.09(m,2H),2.22-2.32(m,4H),2.64(s,3H),2.60-2.71(m,3H),3.25-3.41(m,2H),3.41-3.51(m,4H),5.34(s,1H),7.09(d,J=6.0Hz,1H),7.23-7.35(m,2H),7.40-7.51(m,3H),7.73(d,J=12.0Hz,1H),10.08(brs,1H),10.52(brs,1H).
实施例 1-340
MS ESI m/e:634(M+H),632(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.70-0.79(m,2H),0.98-1.09(m,2H),2.22(s,3H),2.60-2.69(m,1H),2.63(s,3H),3.01(s,3H),5.14(s,1H),7.13 (d,J=9.0Hz,2H),7.22-7.30 (m,2H),7.41-7.48(m,1H),7.61-7.64(m,1H),7.74(s,1H),9.98(brs,1H),10.32(brs,1H).
实施例 1-341
MS ESI m/e:522(M+H),520(M-H).
1H-NMR(CDCl3,300MHz)δ0.70-0.80(m,2H),0.97-1.09(m,2H),2.06(s,3H),2.54(s,3H),2.63-2.72(m,1H),2.66(s,3H),5.23-5.26(m,1H),7.05-7.20(m,2H),7.28-7.49(m,3H),7.61-7.73(m,2H),10.17(brs,1H),10.41(brs,1H).
实施例 1-342
MS ESI m/e:522(M+H),520(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.69-0.79(m,2H),0.97-1.10(m,2H),2.04(s,3H),2.60-2.73(m,1H),2.65(s,3H),3.02(dt,J=25.2,2.8Hz,2H),4.69 (dt,J=47.1,3.2Hz,2H),5.27(s,1H),7.02-7.11(m,1H),7.16-7.23(m,1H),7.29-7.49(m,3H),7.61-7.71(m,2H),10.16(brs,1H),10.44(brs,1H).
实施例 1-343
MS ESI m/e:475(M+H),473(M-H).
1H-NMR(CDCl3,300MHz)δ0.85-0.94(m,2H),1.16-1.24(m,2H),2.75-2.83(m,1H),2.82(s,3H),5.54-5.58(m,1H),7.30-7.38(m,3H),7.43-7.54(m,5H),7.63-7.69(m,1H),10.28(brs,1H).
实施例 2-1
MS ESI m/e:472(M+H),470(M-H).
1H-NMR(DMSO-d6,400MHz)δ2.68(s,3H),7.34-7.39(m,2H),7.41-7.61(m,10H),7.80-7.87(m,2H),11.34(s,1H).
实施例 2-2
MS ESI m/e:592(M+H),590(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.70-0.82(m,2H),1.01-1.13(m,2H),2.64-2.75(m,1H),2.67(s,3H),3.05(s,3H),7.19-7.27(m,1H),7.27-7.34(m,1H),7.35-7.39(m,1H),7.45-7.54(m,2H),7.71(dd,J=3.0,12.0Hz,1H),8.51(t,J=9.0Hz,1H),10.05(s,1H),11.61(d,J=3.0Hz,1H).
实施例 3-1
MS ESI m/e:493,495(M+H),491,493(M-H).
1H-NMR(CDCl3,400MHz)δ0.77-0.82(m,2H),1.09-1.15(m,2H),1.36(s,3H),2.72-2.74(m,1H),3.20(s,3H),6.86(d,2H),7.28-7.32(m,2H),7.34-7.51(m,5H),11.36(s,1H).
实施例 3-2
MS ESI m/e:479,481(M+H),477,479(M-H).
1H-NMR(CDCl3,400MHz)δ0.83-0.90(m,2H),1.10-1.18(m,2H),2.67-2.76(m,1H),3.11(s,3H),5.00(s,1H),7.02(d,J=8.6Hz,2H),7.10-7.15(m,2H),7.19-7.25(m,1H),7.34-7.41(m,2H),7.63-7.70(m,2H),11.71(s,1H).
实施例 3-3
MS ESI m/e:479,481(M+H),477,479(M-H).
1H-NMR(CDCl3,300MHz)δ0.83-0.92(m,2H),1.09-1.19(m,2H),2.67-2.78(m,1H),3.13(s,3H),5.06(s,1H),6.87-6.94(m,2H),7.21-7.28(m,2H),7.45-7.60(m,5H),11.68(s,1H).
实施例 3-4
MS ESI m/e:604(M+H),606,602(M-H),604.
1H-NMR(DMSO-d6,300MHz)δ0.65-0.69(m,2H),0.93-0.98(m,2H),1.25(s,3H),2.59-2.64(m,1H),3.01(s,3H),3.08(s,3H),7.08-7.13(m,2H),7.21-7.25(m,2H),7.39-7.43(m,2H),7.70-7.74(m,1H),9.90(brs,1H),11.09(brs,1H).
实施例 3-5
MS ESI m/e:618(M+H),620,616(M-H),618.
1H-NMR(DMSO-d6,300MHz)δ0.64-0.69(m,2H),0.92-0.98(m,2H),1.19(t,J=9.8Hz,3H),1.24(s,3H),2.58-2.64(m,1H),3.11(q,J=9.8Hz,2H),3.08(5,3H),7.07-7.13(m,2H),7.21-7.25(m,2H),7.37-7.42(m,2H),7.70-7.74(m,2H),9.95(brs,1H),11.09(brs,1H).
实施例 3-6
MS ESI m/e:604(M+H),606,602(M-H),604.
1H-NMR(DMSO-d6,300MHz)δ0.64-0.69(m,2H),0.92-0.99(m,2H),1.25(s,3H),2.04(s,3H),2.58-2.66(m,1H),3.08(s,3H),7.01-7.13(m,2H),7.33-7.43(m,2H),7.58-7.60(m,2H),7.70-7.74(m,1H),10.10(brs,1H),11.09(brs,1H).
实施例 3-7
MS ESI m/e:652(M+H),650(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.62-0.72(m,2H),0.91-1.01(m,2H),1.25(s,3H),2.57-2.67(m,1H),3.01(s,3H),3.08(s,3H),6.9 2(t,J=9.0Hz,1H),7.09-7.14(m,1H),7.20-7.26(m,2H),7.37-7.45(m,1H),7.52-7.58(m,1H),7.79(dd,J=1.8,9.0Hz,1H),9.89(s,1H),11.08(s,1H).
实施例 3-8
MS ESI m/e:550(M+H),548(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.62-0.71(m,2H),0.90-1.01(m,2H),1.26(s,3H),2.56-2.66(m,1H),3.01(s,3H),3.10(s,3H),4.30(s,1H),7.05-7.16(m,2H),7.20-7.27(m,2H),7.32(dd,J=1.7,9.0Hz,1H),7.37-7.45(m,1H),7.52(dd,J=1.7,12.0Hz,1H),9.90(s,1H),11.10(s,1H).
实施例 3-9
MS ESI m/e:,639(M+H),638,637(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.65-0.73(m,2H),0.93-0.98(m,2H),1.26(s,3H),2.58-2.65(m,1H),3.05(s,3H),3.08(s,3H),7.11(dd,J=10.1Hz,13.0Hz,1H),7.32(d,J=11.6Hz,1H),7.42(d,J=10.1Hz,1H),7.48(s,1H),7.63(d,J=11.6Hz,1H),7.72(d,J=13.0Hz,1H),9.65(brs,1H),11.08(brs,1H).
实施例 4-1
MS ESI m/e:616(M+H),614(M-H).
1H-NMR(DMSO-d6,400MHz)δ0.63-0.70(m,2H),0.91-1.00(m,2H),1.25(s,3H),2.04(s,3H),2.58-2.66(m,1H),3.07(s,3H),6.92(t,J=8.8Hz,1H),7.00-7.05(m,1H),7.36(t,J=8.2Hz,1H),7.52-7.63(m,3H),7.79(dd,J=2.0,10.4Hz,1H),10.10(s,1H),11.08(s,1H).
实施例 4-2
MS ESI m/e:666(M+H),664(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.62-0.71(m,2H),0.91-1.01(m,2H),1.19(t,J=7.2Hz,3H),1.24(s,3H),2.56-2.67(m,1H),3.08(s,3H),3.11(q,J=7.2Hz,2H),6.92(t,J=8.7Hz,1H),7.09(d,J=8.1Hz,1H),7.21-7.2 8(m,2H),7.40(t,J=8.3Hz,1H),7.55(d,J=8.1Hz,1H),7.79(dd,J=1.8,10.5Hz,1H),9.94(s,1H),11.08(s,1H).
实施例 4-3
MS ESI m/e:514(M+H),512(M-H).
1H-NMR(DMSO-d6,400MHz)δ0.63-0.70(m,2H),0.91-0.99(m,2H),1.26(s,3H),2.04(s,3H),2.58-2.66(m,1H),3.10(s,3H),4.30(s,1H),7.01-7.06(m,1H),7.09(t,J=8.4Hz,1H),7.31(dd,J=1.6,8.4Hz,1H),7.36(t,J=7.8Hz,1H),7.52(dd,J=1.6,11.6Hz,1H),7.57-7.63(m,2H),10.10(s,1H),11.10(s,1H)
实施例 4-4
MS ESI m/e:568,570(M+H),-566,568(M-H)
1H-NMR(DMSO-d6,300MHz)0.61-0.65(m,2H),0.90-0.95(m,2H),1.20(s,3H),2.04(s,3H),2.56-2.61(m,1H),3.04(s,3H),7.07(dd,J=8.6 ,10.7Hz,1H),7.25(d,J=8.8Hz,2H),7.38(d,J=10.7Hz,1H),7.60(d,J=8.8Hz,2H),7.69(d,J=8.6Hz,1H),10.07(s,1H),11.05(s,1H)
实施例 4-5
MS ESI m/e:556,558(M+1).
1H-NMR(DMSO-d6,400MHz)δ0.63-0.67(m,2H),0.91-0.96(m,2H),1.17(s,3H),2.56-2.62(m,1H),3.05(s,3H),7.11(dd,J=8.6,10.4Hz,1H),7.40(d,J=8.6Hz,1H),7.66(d,J=9.3Hz,2H),7.69(dd,J=2.1,10.4Hz,1H),8.30(d,J=9.3Hz,2H),10.94(s,1H)
实施例 4-6
MS ESI m/e:564(M+H),562(M-H).
1H-NMR(DMSO-d6,400MHz)δ0.64-0.70(m,2H),0.92-0.99(m,2H),1.19(t,J=7.4Hz,3H),1.25(s,3H),2.57-2.65(m,1H),3.10(s,3H),3.11(q,J=7.4Hz,2H),4.31(s,1H),7.06-7.12(m,2H),7.22-7.27(m,2H),7.32(dd,J=1.6,8.0Hz,1H),7.40(t,J=8.0Hz,1H),7.52(dd,J=1.6,11.6Hz,1H),9.95(s,1H),11.10(s,1H).
实施例 4-7
MS ESI m/e:490(M+H),488(M-H).
1H-NMR(DMSO-d6,400MHz)δ0.64-0.71(m,2H),0.91-0.99(m,2H),1.25(s,3H),2.04(s,3H),2.60-2.67(m,1H),3.05(s,3H),7.02-7.06(m,1H),7.13-7.19(m,1H),7.20-7.29(m,2H),7.33-7.41(m,2H),7.57-7.63(m,2H),10.10(s,1H),11.23(s,1H).
实施例 4-8
MS ESI m/e:604,606(M+H),602,604(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.63-0.69(m,2H),0.92-0.99(m,2H),1.23(s,3H),2.57-2.67(m,1H),3.04(s,3H),3.07(s,3H),7.08-7.14(m,1H),7.26(d,J=9.0Hz,2H),7.34(d,J=9.0Hz,2H),7.39-7.44(m,1H),7.70-7.75(m,1H),9.96(s,1H),11.08(s,1H)
实施例 4-9
MS ESI m/e:518(M+H),516(M-H).
1H-NMR(DMSO-d6,400MHz)δ0.64-0.71(m,2H),0.92-1.00(m,2H),1.19(t,J=7.6Hz,3H),1.24(s,3H),2.04(s,3H),2.59-2.67(m,1H),2.62(q,J=7.6Hz,2H),3.03(s,3H),7.01-7.11(m,3H),7.23(d,J=11.6Hz,1H),7.36(t,J=8.2Hz,1H),7.56-7.63(m,2H),10.10(s,1H),11.23(s,1H).
实施例 4-10
MS ESI m/e:603,605(M+H),601,603(M-H).
1H-NMR(CDCl3,300MHz)δ0.77-0.84(m,2H),1.11-1.18(m,2H),1.32(t,J=7.3Hz,3H),1.33(s,3H),2.70-2.78(m,1H),3.15(q,J=7.5Hz,2H),3.20(s,3H),6.89(t,J=8.3Hz,1H),7.28-7.32(m,1H),7.36(dd,J=2.3,9.8Hz,1H),7.60-7.69(m,2H),7.86-7.93(m,2H),11.28(s,1H).
实施例 4-11
MS ESI m/e:516(M+H),514(M-H).
1H-NMR(DMSO-d6,400MHz)δ0.64-0.71(m,2H),0.92-1.00(m,2H),1.25(s,3H),2.04(s,3H),2.59-2.67(m,1H),3.07 (s,3H),5.32(d,J=11.1Hz,1H),5.89(d,J=17.6Hz,1H),6.73(dd,J=10.9,17.6Hz,1H),7.01-7.06(m,1H),7.11(t,J=8.6Hz,1H),7.28-7.33(m,1H),7.33-7.40(m,1H),7.51-7.57(m,1H),7.57-7.63(m,2H),10.10(s,1H),11.22(s,1H).
实施例 4-12
MS ESI m/e:729(M+H),727(M.-H).
1H-NMR(DMSO-d6,300MHz)δ0.65-0.68(m,2H),0.83(t,J=7.3Hz,3H),0.93-0.97(m,2H),1.23-1.26(m,5H),1.40-1.50(m,2H),2.04(t,J=7.5 Hz,2H),2.48-2.50(m,2H),2.59-2.64(m,1H),3.08(s,3H),3.28-3.33(m,2H),6.92(t,J=8.7Hz,1H),7.03(d,J=7.9Hz,1H),7.36(t,J=8.1Hz,1H),7.56-7.59(m,2H),7.64-7.66(m,1H),7.79(dd,J=10.4,1.7Hz,1H),7.90(t,J=5.7 Hz,1H),10.10(s,1H),11.08(s,1H).
实施例 4-13
MS ESI m/e:603(M+H),601(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.66-0.69(m,2H),0.83(t,J=7.2Hz,3H),0.93-0.98(m,2H),1.17-1.29(m,5H),1.40-1.50(m,2H),2.04(t,J=7.3 Hz,2H),2.47-2.51(m,2H),2.61-2.65(m,1H),3.05(s,3H),3.29-3.33(m,2H),7.04(d,J=9.0Hz,1H),7.19-7.34(m,5H),7.59(d,J=8.7Hz,1H),7.66(s,1H),7.91(t,J=5.3Hz,1H),10.10(s,1H),11.23(s,1H).
实施例 4-14
MS ESI m/e:685(M+H),683(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.64-0.70(m,2H),0.82(t,J=7.3Hz,3H),0.90-0.98(m,2H),1.14-1.28(m,4H),1.25(s,3H),1.37-1.49(m,2H),1.45(s,6H),2.04(t,J=7.3Hz,2H),2.58-2.65(m,1H),3.07(s,3H),3.27-3.34(m,2H),5.49(brs,1H),6.99-7.11(m,2H),7.18-7.25(m,1H),7.31-7.42(m,2H),7.55-7.67(m,2H),7.85-7.93(m,1H),10.09(s,1H),11.14(s,1H).
实施例 4-15
MS ESI m/e:590(M+H),588(M-H).
1H-NMR(CDCl3,300MHz)δ1.42(s,3H),2.16(s,3H),3.21(s,3H),3.37(s,3H),6.69(t,J=8.3Hz,1H),7.04-7.10(m,1H),7.31-7.55(m,5H),7.70(s,1H),11.41(s,1H).
实施例 4-16
MS ESI m/e:626(M+H),624(M-H).
1H-NMR(DMSO-d6,300MHz)δ1.26(s,3H),3.01(s,3H),3.09(s,3H),3.21(s,3H),6.93(t,J=8.3Hz,1H),7.11-7.15(m,1H),7.20-7.28(m,2H),7.42(t,J=8.3Hz,1H),7.52-7.57(m,1H),7.76-7.81(m,1H),9.94(br,1H),11.21(br,1H).
实施例 4-17
MS ESI m/e:630(M+H),628(M-H).
1H-NMR(CDCl3,300MHz)δ0.75-0.81(m,2H),1.05-1.15(m,5H),1.41(s,3H),2.15(s,3H),2.68-2.77(m,1H),3.90-4.00(m,2H),6.72(t,J=8.3Hz,1H),6.97-7.03(m,1H),7.30-7.54(m,5H),7.65-7.69(m,1H),11.07(s,1H).
实施例 4-18
MS ESI m/e:666(M+H),664(M-H).
1H-NMR(CDCl3,300MHz)δ0.75-0.81(m,2H),1.06-1.15(m,5H),1.39(s,3H),2.68-2.76(m,1H),3.02(s,3H),3.90-4.00(m,2H),6.74(t,J=8.3Hz,1H),6.93-6.99(m,1H),7.07-7.13(m,1H),7.20-7.26(m,2H),7.38-7.54(m,3H),11.07(s,1H).
实施例 4-19
MS ESI m/e:654(M+H),652(M-H).
1H-NMR(DMSO-d6,300MHz)δ1.13(t,J=6.8Hz,3H),1.20(t,J=7.2Hz,3H),1.25(s,3H),3.08(s,3H),3.12(q,J=7.4Hz,2H),3.87(d,J=7.1Hz,2H),6.94(t,J=8.6Hz,1H),7.12(d,J=8.0Hz,1H),7.25(d,J=8.4Hz,1H),7.29(s,1H),7.41(t,J=8.0Hz,1H),7.55(d,J=8.5Hz,1H),7.79(d,J=10.5Hz,1H),9.98(s,1H),11.24(s,1H).
实施例 4-20
MS ESI m/e:640(M+H),638(M-H).
1H-NMR(DMSO-d6,300MHz)δ1.13(t,J=6.8Hz,3H),1.26(s,3H),3.02(s,3H),3.09(s,3H),3.88(q,J=6.8Hz,2H),6.95(t,J=8.5Hz,1H),7.11-7.18(m,1H),7.21-7.30(m,2H),7.43(t,J=7.7Hz,1H),7.55(d,J=9.0Hz,1H),7.76-7.82(m,1H),9.94(brs,1H),11.24(brs,1H).
实施例 4-21
MS ESI m/e:604(M+H),602(M-H).
1H-NMR(DMSO-d6,300MHz)δ1.13(t,J=6.8Hz,3H),1.26(s,3H),2.04(s,3H),3.08(s,3H),3.87(q,J=7.5Hz,2H),6.94(t,J=8.5Hz,1H),7.05-7.11(m,1H),7.37(t,J=7.9Hz,1H),7.51-7.60(m,2H),7.65-7.71(m,1H),7.78(d,J=10.2Hz,1H),10.10 (brs,1H),11.23(brs,1H).
实施例 4-22
MS ESI m/e:666(M+H),664(M-H).
1H-NMR(DMSO-d6,400MHz)δ0.47(t,J=7.2Hz,3H),0.63-0.69(m,2H),0.90-0.97(m,2H),1.76-1.94(m,2H),2.57-2.63(m,1H),3.00(s,3H),3.07(s,3H),6.93(t,J=8.8Hz,1H),7.12-7.16(m,1H),7.23-7.30(m,2H),7.42(t,J=8.0Hz,1H),7.53-7.58(m,1H),7.79(dd,J=1.6,10.0Hz,1H),9.91(s,1H),11.07(s,1H).
实施例 4-23
MS ESI m/e:680(M+H),678(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.47(t,J=7.4Hz,3H),0.61-0.70(m,2H),0.89-0.98(m,2H),1.20(t,J=7.4Hz,3H),1.74-1.95(m,2H),2.55-2.65 (m,1H),3.07(s,3H),3.11(q,J=7.4Hz,2H),6.92(t,J=8.6Hz,1H),7.11(d,J=7.8Hz,1H),7.22-7.31(m,2H),7.40(t,J=7.9Hz,1H),7.56(d,J=8.7Hz,1H),7.79(d,J=10.2Hz,1H),9.97(s,1H),11.07(s,1H).
实施例 4-24
MS ESI m/e:630(M+H),628(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.47(t,J=7.2Hz,3H),0.60-0.69(m,2H),0.87-0.98(m,2H),1.79-1.93(m,2H),2.04(s,3H),2.56-2.66(m,1H),3.07(s,3H),6.92(t,J=8.6Hz,1H),7.07(d,J=8.4Hz,1H),7.37(t,J=8.1Hz,1H),7.53-7.69(m,3H),7.79(d,J=10.2Hz,1H),10.09(s,1H),11.07(s,1H).
实施例 4-25
MS ESI m/e:554(M+H),552(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.64-0.73(m,2H),0.91-1.01(m,2H),1.19(t,J=7.5Hz,3H),1.24(s,3H),2.57-2.68(m,1H),2.62(q,J=7.4Hz,2H),3.01(s,3H),3.03(s,3H),7.03-7.15(m,3H),7.19-7.27(m,3H),7.41(t,J=8.1Hz,1H),9.89(s,1H),11.24(s,1H).
实施例 4-26
MS ESI m/e:568(M+H),566(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.62-0.73(m,2H),0.91-1.01(m,2H),1.18(t,J=7.5Hz,3H),1.19(t,J=7.2Hz,3H),1.23(s,3H),2.57-2.68(m,1H),2.62(q,J=7.5Hz,2H),3.03(s,3H),3.11(q,J=7.2Hz,2H),7.03-7.13(m,3H),7.19-7.27(m,3H),7.40(t,J=8.1Hz,1H),9.94(s,1H),11.24(s,1H).
实施例 4-27
MS ESI m/e:528(M+H),526(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.48(t,J=7.4Hz,3H),0.60-0.70(m,2H),0.88-0.98(m,2H),1.77-1.92(m,2H),2.04(s,3H),2.55-2.66(m,1H),3.10(s,3H),4.30(s,1H),7.04-7.14(m,2H),7.28-7.41(m,2H),7.52(d,J=11.7Hz,1H),7.58-7.68(m,2H),10.09(s,1H),11.08(s,1H).
实施例 4-28
MS ESI m/e:564(M+H),562(M-H).
1H-NMR(DMSO-d6,400MHz)δ0.48(t,J=72Hz,3H),0.63-0.69(m,2H),0.90-0.97(m,2H),1.78-1.93(m,2H),2.56-2.64(m,1H),3.01(s,3H),3.10(s,3H),4.31(s,1H),7.09(t,J=8.4Hz,1H),7.13-7.17(m,1H),7.23-7.34(m,3H),7.42(t,J=8.0Hz,1H),7.52(dd,J=2.0,11.6Hz,1H),9.92(s,1H),11.08(s,1H).
实施例 4-29
MS ESI m/e:578(M+H),576(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.47(t,J=7.1Hz,3H),0.61-0.70(m,2H),0.88-0.98(m,2H),1.20(t,J=7.2Hz,3H),1.75-1.95(m,2H),2.55-2.64(m,1H),3.10(s,3H),3.11(q,J=7.2Hz,2H),4.30(s,1H),7.04-7.14(m,2H),7.23-7.35(m,3H),7.40(t,J=7.8Hz,1H),7.52(d,J=11.4Hz,1H),9.97(s,1H),11.08(s,1H).
实施例 4-30
MS ESI m/e:532(M+H),530(M-H).
1H-NMR(DMSO-d6,400MHz)δ0.46(t,J=7.4Hz,3H),0.64-0.70(m,2H),0.90-0.97(m,2H),1.19(t,J=7.6Hz,3H),1.80-1.90(m,2H),2.04(s,3H),2.57-2.67(m,1H),2.63(q,J=7.6Hz,2H),3.02(s,3H),7.04-7.13(m,3H),7.23 (d,J=12.0Hz,1H),7.37(t,J=8.0Hz,1H),7.61(d,J=7.6Hz,1H),7.64(t,J=2.0Hz,1H),10.09(s,1H),11.24(s,1H).
实施例 4-31
MS ESI m/e:568(M+H),566(M-H).
1H-NMR(DMSO-d6,400MHz)δ0.47(t,J=7.2Hz,3H),0.63-0.71(m,2H),0.90-0.98(m,2H),1.19(t,J=7.4Hz,3H),1.74-1.96(m,2H),2.57-2.67(m,1H),2.63(q,J=7.4Hz,2H),3.01(s,3H),3.02(s,3H),7.06-7.11(m,2H),7.12-7.17(m,1H),7.20-7.30(m,3H),7.42(t,J=8.0Hz,1H),9.91(s,1H),11.24(s,1H).
实施例 4-32
MS ESI m/e:582(M+H),580(M-H).
1H-NMR(DMSO-d6,400MHz)δ0.46(t,J=7.2Hz,3H),0.64-0.70(m,2H),0.90-0.98(m,2H),1.19(t,J=7.6Hz,3H),1.20(t,J=7.6Hz,3H),1.75-1.93(m,2H),2.58-2.68(m,1H),2.63(q,J=7.6Hz,2H),3.02(s,3H),3.10(q,J=7.6Hz,2H),7.05-7.14(m,3H),7.20-7.31(m,3H),7.40(t,J=8.0Hz,1H),9.97(s,1H),11.23(s,1H).
实施例 4-33
MS ESI m/e:681(M+H),679(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.61-0.69(m,2H),0.90-1.00(m,2H),1.22(s,3H),2.52-2.63(m,1H),2.67(s,6H),3.06(s,3H),6.88-6.94(m,1H),7.02-7.09(m,1H),7.18-7.21(m,2H),7.31-7.39(m,1H),7.51-7.56(m,1H),7.75-7.81(m,1H),10.01(brs,1H),11.06(brs,1H).
实施例 4-34
MS ESI m/e:723(M+H),721(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.61-0.70(m,2H),0.90-0.99(m,2H),1.24(s,3H),2.55-2.64(m,1H),3.06(s,3H),2.99-3.10(m,4H),3.43-3.53(m,4H),6.88-6.92(m,1H),7.05-7.09(m,2H),7.14-7.22(m,1H),7.31-7.40(m,1H),7.51-7.59(m,1H),7.75-7.81(m,1H),10.21(brs,1H),11.08(brs,1H).
实施例 4-35
MS ESI m/e:519(M+H),517(M-H).
1H-NMR (DMSO-d6,300MHz)δ0.64-0.71(m,2H),0.92-1.00(m,2H),1.26(s,3H),2.59-2.67(m,1H),2.73(t,J=7.0Hz,2H),3.02-3.12(m,2H),3.05(s,3H),7.04-7.43(m,6H),7.58-7.63(m,1H),7.67(s,1H),7.77-7.88(m,3H),10.39(s,1H),11.23(s,1H).
实施例 4-36
MS ESI m/e:645(M+H),643(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.62-0.70(m,2H),0.92-0.98(m,2H),1.26(s,3H),2.59-2.66(m,1H),2.72(t,J=7.2Hz,2H),3.03-3.13(m,2H),3.08(s,3H),6.93(t,J=8.4Hz,1H),7.03-7.08(m,1H),7.39(t,J=8.4Hz,1H),7.53-7.68(m,3H),7.72-7.85(m,4H),10.37(s,1H),11.08(s,1H).
实施例 4-37
MS ESI m/e:,650(M+H),648(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.64-0.69(m,2H),0.92-0.99(m,2H),1.31(s,3H),2.06(s,3H),2.57-2.64(m,1H),3.08(s,3H),6.93(dd,J=9.3,11.1Hz,1H),7.19(s,1H),7.46(s,1H),7.55(d,J=9.3Hz,1H),7.79(d,J=11.1Hz,1H),7.83(s,1H),10.27(s,1H),11.03(s,1H)
实施例 4-38
MS ESI m/e:564(M+H),562(M-H).
1H-NMR(CDCl3,300MHz)δ0.75-0.81(m,2H),1.06-1.16(m,5H),1.40(s,3H),2.69-2.76(m,1H),3.03(s,3H),3.13(s,1H),3.92-4.01(m,2H),6.77-6.84(m,1H),6.92(t,J=8.1Hz,1H),7.08-7.13(m,1H),7.18-7.33(m,4H),7.42(t,J=8.1Hz,1H),11.11(s,1H).
实施例 4-39.
MS ESI m/e:568(M+H),566(M-H).
1H-NMR(CDCl3,300MHz)δ0.75-0.83(m,2H),1.02(t,J=7.0Hz,3H),1.07-1.15(m,2H),1.24(t,J=7.7Hz,3H),1.38(s,3H),2.60-2.76(m,3H),3.02(s,3H),3.90-4.00(m,2H),6.77(s,1H),6.94-7.03(m,3H),7.08-7.13(m,1H),7.19-7.27(m,2H),7.41(t,J=7.7Hz,1H),11.19(s,1H).
实施例 4-40
MS ESI m/e:552(M+H),550(M-H).
1H-NMR(DMSO-d6,300MHz)δ1.13(t,J=6.9Hz,3H),1.20(t,J=7.3Hz,3H),1.26(s,3H),3.11(s,3H),3.12(q,J=7.4Hz,2H),3.87(q,J=7.1Hz,2H),4.30(s,1H),7.05-7.15(m,2H),7.20-7.35(m,3H),7.41(t,J=8.0Hz,1H),7.52(d,J=11.6Hz,1H),9.99(s,1H),11.25(s,1H).
实施例 4-41
MS ESI m/e:556(M+H),554(M-H).
1H-NMR(DMSO-d6,300MHz)δ1.10-1.25(m,12H),2.62(q,J=7.6Hz,2H),3.03(s,3H),3.12(q,J=7.3Hz,2H),3.88(q,J=6.9Hz,2H),7.05-7.15(m,3H),7.20-7.30(m,3H),7.41(t,J=8.0Hz,1H),9.98(s,1H),11.41(s,1H).
实施例 4-42
MS ESI m/e:538(M+H),536(M-H).
1H-NMR(DMSO-d6,300MHz)δ1.13 (t,J=7.2Hz,3H),1.27(s,3H),3.03(s,3H),3.11(s,3H),3.87(q,J=6.8Hz,2H),4.30(s,1H),7.05-7.18(m,2H),7.20-7.35(m,3H),7.43(t,J=7.9Hz,1H),7.52(d,J=11.3Hz,1H),9.94(brs,1H),11.25(brs,1H).
实施例 4-43
MS ESI m/e:502(M+H),500(M-H).
1H-NMR(DMSO-d6,300MHz)δ1.13(t,J=7.0Hz,3H),1.27(s,3H),2.05(s,3H),3.11(s,3H),3.87(q,J=7.1Hz,2H),4.30(s,1H),7.04-7.15(m,2H),7.28-7.34(m,1H),7.37(t,J=8.1Hz,1H),7.49-7.60(m,2H),7.66-7.70(m,1H),10.10(brs,1H),11.24(brs,1H).
实施例 4-44
MS ESI m/e:542(M+H),540(M-H).
1H-NMR(DMSO-d6,300MHz)δ1.14(t,J=7.2Hz,3H),1.19(t,J=7.5Hz,3H),1.25(s,3H),2.63(q,J=7.5Hz,2H),3.02(s,3H),3.03(s,3H),3.89(q,J=7.0Hz,2H),7.04-7.18(m,3H),7.20-7.30(m,3H),7.42(t,J=8.1Hz,1H),9.93(brs,1H),11.41(brs,1H).
实施例 4-45
MS ESI m/e:506(M+H),504(M-H).
1H-NMR(DMSO-d6,300MHz)δ1.14(t,J=6.2Hz,3H),1.19(t,J=7.5Hz,3H),1.25(s,3H),2.05(s,3H),2.63(q,J=7.5Hz,2H),3.03(s,3H),3.89(q,J=6.8Hz,2H),7.04-7.15(m,3H),7.23(d,J=12.0Hz,1H),7.37(t,J=8.1Hz,1H),7.53-7.60(m,1H),7.65-7.70(m,1H),10.10(brs,1H),11.41(brs,1H).
实施例 4-46
MS ESI m/e:528(M+H),526(M-H).
1H-NMR(CDCl3,300MHz)δ0.75-0.82(m,2H),1.06-1.16(m,5H),1.42(s,3H),2.17(s,3H),2.68-2.78(m,1H),3.13(s,1H),3.92-4.01(m,2H),6.90(t,J=7.9Hz,1H),6.99-7.06(m,1H),7.22-7.46(m,5H),7.63-7.68(m,1H),11.10(s,1H).
实施例 4-47
MS ESI m/e:532(M+H),530(M-H).
1H-NMR(CDCl3,300MHz)δ0.75-0.83(m,2H),1.02(t,J=7.0Hz,3H),1.08-1.16(m,2H),1.24(t,J=7.5Hz,3H),1.40(s,3H),2.16(s,3H),2.62-2.77(m,3H),3.91-4.00(m,2H),6.93-7.05(m,4H),7.26-7.48(m,3H),7.59-7.64(m,1H),11.19(s,1H).
实施例 4-48
MS ESI m/e:488(M+H),486(M-H).
1H-NMR(CDCl3,300MHz)δ1.42(s,3H),2.15(s,3H),3.13(s,1H),3.23(s,3H),3.38(s,3H),6.86(t,J=8.7Hz,1H),7.03-7.10(m,1H),7.22-7.41(m,5H),7.70(s,1H),11.46(s,1H).
实施例 4-49
MS ESI m/e:524(M+H),522(M-H).
1H-NMR(CDCl3,300MHz)δ1.41(s,3H),3.04(s,3H),3.14(s,1H),3.23(s,3H),3.38(s,3H),6.75(s,1H),6.89(t,J=8.5Hz,1H),7.11-7.17(m,1H),7.18-7.33(m,4H),7.43(t,J=8.1Hz,1H),11.47(s,1H).
实施例 4-50
MS ESI m/e:492(M+H),490(M-H).
1H-NMR(CDCl3,300MHz)δ1.24(t,J=7.5Hz,3H),1.41(s,3H),2.15(s,3H),2.65(q,J=7.7Hz,2H),3.18(s,3H),3.38(s,3H),6.8 8-7.11(m,4H),7.32-7.46(m,3H),7.63-7.69(m,1H),11.45(s,1H).
实施例 4-51
MS ESI m/e:528(M+H),526(M-H).
1H-NMR(CDCl3,300MHz)δ1.24(t,J=7.5Hz,3H),1.39(s,3H),2.65(q,J=7.3Hz,2H),3.03(s,3H),3.18(s,3H),3.38(s,3H),6.84(s,1H),6.90-7.03(m,3H),7.11-7.17(m,1H),7.19-7.30(m,2H),7.42(t,J=8.1Hz,1H),11.46(s,1H).
实施例 4-52
MS ESI m/e:528(M+H),526(M-H).
1H-NMR(DMSO-d6,400MHz)δ0.64-0.70(m,2H),0.91-0.99(m,2H),1.25(s,3H),2.04(s,3H),2.05(s,3H),2.58-2.66(m,1H),3.07(s,3H),7.01-7.10(m,2H),7.20-7.25(m,1H),7.32-7.43(m,2H),7.57-7.63(m,2H),10.10(s,1H),11.14(s,1H).
实施例 4-53
MS ESI m/e:532(M+H),530(M-H).
1H-NMR(DMSO-d6,400MHz)δ0.64-0.71(m,2H),0.89(t,J=7.4Hz,3H),0.92-0.99(m,2H),1.24(s,3H),1.54-1.65(m,2H),2.04(s,3H),2.57(t,J=7.5Hz,2H),2.60-2.67(m,1H),3.02(s,3H),7.01-7.12(m,3H),7.18-7.24(m,1H),7.33-7.39(m,1H),7.58-7.62(m,2H),10.10(s,1H),11.24(s,1H).
实施例 4-54
MS ESI m/e:653(M+H),651(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.60-0.71(m,2H),0.90-1.01(m,2H),1.27(s,3H),2.58-2.67(m,1H),3.08(s,3H),6.89-7.01(m,2H),7.09-7.23(m,4H),7.30-7.39(m,1H),7.51-7.59(m,1H),7.73-7.83(m,1H),9.69(brs,1H),11.09(brs,1H),
实施例 4-55
MS ESI m/e:637(M+H),635(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.69(m,2H),0.96(m,2H),1.17(s,3H),2.62(m,1H),3.09(s,3H),3.26(s,3H),6.95(t,J=8.6Hz,1H),7.56(d,J=8.7Hz,1H),7.70-7.85(m,3H),7.90-8.00(m,2H),11.04(s,1H).
实施例 4-56
MS ESI m/e:504(M+H),502(M-H).
1H-NMR(DMSO-d6,400MHz)δ0.65-0.71(m,2H),0.92-0.99(m,2H),1.24(s,3H),2.04(s,3H),2.32(s,3H),2.58-2.67(m,1H),3.02(s,3H),7.00-7.10(m,3H),7.20(d,J=12.0Hz,1H),7.36(t,J=8.2Hz,1H),7.56-7.63(m,2H),10.10(s,1H),11.24(s,1H).
实施例 4-57
MS ESI m/e:558(M+H),556(M-H).
1H-NMR(DMSO-d6,400MHz)δ0.64-0.71(m,2H),0.90-0.99(m,2H),1.24(s,3H),1.46-1.57(m,2H),1.58-1.69(m,2H),1.71-1.83(m,2H),1.97-2.07(m,2H),2.04(s,3H),2.58-2.68(m,1H),2.93-3.06(m,1H),3.03(s,3H),7.00-7.14(m,3H),7.24(dd,J=1.2,12.0Hz,1H),7.36 (t,J=8.2Hz,1H),7.57-7.63(m,1H),10.10(s,1H),11.22(s,1H).
实施例 4-58
MS ESI m/e:651(M+H),649(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.65-0.71(m,2H),0.93-1.00(m,2H),1.10(t,J=7.3Hz,3H),1.17(s,3H),2.56-2.66(m,1H),3.09(s,3H),3.29-3.40(m,2H),6.95(t,J=8.7Hz,1H),7.52-7.58(m,1H),7.73-7.82(m,3H),7.8 8-7.95(m,2H),11.04(s,1H).
实施例 4-59
MS ESI m/e:721(M+H),719(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.61-0.71(m,2H),0.91-1.01(m,2H),1.26(s,3H),1.35-1.60(m,6H),2.59-2.67(m,1H),2.99-3.12(m,4H),3.07(s,3H),6.89-6.94(m,1H),7.04-7.06(m,1H),7.13-7.17(m,2H),7.34-7.39(m,1H),7.54-7.57(m,1H),7.77-7.80(m,1H),10.06(brs,1H),11.06(brs,1H).
实施例 4-60
MS ESI m/e:630(M+H),628(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.63-0.72(m,2H),0.91-1.01(m,2H),1.09(t,J=7.5Hz,3H),1.27(s,3H),2.34(q,J=7.0Hz,2H),2.59-2.70(m,1H),3.09(s,3H),6.91-7.08(m,2H),7.34-7.40(m,1H),7.56-7.69(m,3H),7.78-7.82(m,1H),10.03(brs,1H),11.09(brs,1H).
实施例 4-61
MS ESI m/e:533(M+H),531(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.64-0.73(m,2H),0.91-1.01(m,2H),1.22(s,3H),2.04(s,3H),2.58-2.68(m,1H),2.92(s,6H),2.98(s,3H),6.55(dd,J=3.0,9.1Hz,1H),6.62 (dd,J=2.6,14.3Hz,1H),6.99-7.11(m,2H),7.35(t,J=7.9Hz,1H),7.55-7.62(m,2H),10.09(brs,1H),11.27(brs,1H).
实施例 4-62
MS ESI m/e:673(M+H),671(M-H)
1H-NMR(DMSO-d6,300MHz)0.63-0.69(m,2H),0.91-0.98(m,2H),1.33(s,3H),2.03(s,6H),3.08(s,3H),6.91(dd,J=10.5,9.6Hz,1H),7.28(s,2H),7.55(d,J=9.6Hz,1H),7.78(d,J=10.5Hz,1H),10.09(s,1H),7.92(s,1H),11.09(s,1H)
实施例 4-63
MS ESI m/e:646.0(M+H),644.0(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.63-0.69(m,2H),0.91-0.98(m,2H),
1.28(s,3H),2.08(s,3H),2.57-2.65(m,1H),3.07(s,3H),3.89(s,3H),6.91(dd,J=12.0,9.0Hz,1H),7.07(s,2H),7.55(d,J=9.0Hz,1H),7.79(d,J=12.0Hz,1H),7.95(s,1H),9.27(s,1H),11.12(s,1H)
实施例 4-64
MS ESI m/e:685.9,687.9,684.0,685.9
1H-NMR(DMSO-d6,300MHz)δ0.64-0.70(m,2H),0.92-0.99(m,2H),1.31(s,3H),2.57-2.63(m,1H),3.08(s,6H),6.94(dd,J=9.0,12.0Hz,1H),7.22-7.22(m,1H),7.27-7.27(m,2H),7.56(d,J=9.0Hz,1H),7.79(d,J=12.0Hz,1H),10.16(s,1H),11.04(s,1H)
实施例 4-65
MS ESI m/e:,571.1(M+H),569.2(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.64-0.69(m,2H),0.93-1.00(m,2H),1.35(s,3H),2.04(s,6H),2.59-2.67(m,1H),3.11(s,3H),4.32(s,1H),7.09(dd,J=9.0,12.0Hz,1H),7.30(s,2H),7.33(d,J=9.0Hz,1H),7.53(d,J=12.0Hz,1H),7.94(s,1H),10.11(s,2H),11.12(s,1H)
实施例 4-66
MS ESI m/e:616.0(M+H),614.0(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.63-0.68(m,2H),0.92-0.99(m,2H),1.23(s,3H),2.07(s,3H),2.58-2.66(m,1H),3.07(s,3H),6.92(dd,J=9.0,9.0Hz,1H),7.28(d,J=9.0Hz,2H),7.55(d,J=9.0Hz,1H),7.64(d,J=9.0Hz,2H),7.79(d,J=9.0Hz,1H),10.10(s,1H),11.06(s,1H)
实施例 4-67
MS ESI m/e:530(M+H),528(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.62-0.76(m,4H),0.90-1.03(m,4H),1.24(s,3H),1.88-2.02(m,1H),2.04(s,3H),2.58-2.68(m,1H),3.01(s,3H),6.92-7.11(m,4H),7.35(t,J=8.6Hz,1H),7.55-7.64(m,2H),10.09(s,1H),11.23(s,1H).
实施例 4-68
MS ESI m/e:660(M+H),658(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.56-0.64(m,2H),0.85-0.95(m,2H),1.26(s,3H),2.04(s,3H),2.46-2.60(m,1H),3.20(brs,3H),3.46-3.55(m,2H),4.01-4.11(m,2H),6.91(t,J=8.5Hz,1H),6.97-7.07(m,1H),7.35(t,J=7.8Hz,1H),7.45(d,J=8.4Hz,1H),7.54-7.67(m,2H),7.73(d,J=9.9Hz,1H),10.09(s,1H),10.13(s,1H).
实施例 4-69
MS ESI m/e:696(M+H),694(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.56-0.66(m,2H),0.81-0.97(m,2H),1.26(s,3H),2.50-2.59(m,1H),3.00(s,3H),3.19(s,3H),3.50(t,J=5.3Hz,2H),4.05(t,J=5.1Hz,2H),6.90(t,J=8.9Hz,1H),7.07-7.15(m,1H),7.18-7.27(m,2H),7.35-7.50(m,2H),7.69-7.78(m,1H),9.90(brs,1H),10.16(brs,1H).
实施例 4-70
MS ESI m/e:652.0(M+H),650.0(M-H).
1H-NMR(DMSO-d6,400MHz)δ0.60-0.64(m,2H),0.89-0.94(m,2H),1.19(s,3H),2.55-2.62(m,1H),2.99(s,3H),3.03(s,3H),6.88(dd,J=8.0,8.0Hz,1H),7.21(d,J=8.0Hz,2H),7.29(d,J=8.0Hz,2H),7.51(d,J=8.0Hz,1H),7.75(d,J=8.0Hz,1H),9.91(s,1H),11.02(s,1H)
实施例 4-71
MS ESI m/e:514.1(M+H),512.2(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.63-0.69(m,2H),0.91-0.99(m,2H),1.24(s,3H),2.07(s,3H),2.59-2.66(m,1H),3.10(s,3H),4.30(s,1H),7.09(dd,J=8.7,8.4Hz,1H),7.28(d,J=8.4Hz,2H),7.31(d,J=8.7Hz,1H),7.52(d,J=8.4Hz,1H),7.64 (d,J=8.4Hz,2H),10.10(s,1H),11.08(s,1H)
实施例 4-72
MS ESI m/e:559(M+H),557(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.62-0.72(m,2H),0.90-1.01(m,2H),1.18(s,3H),2.57-2.67(m,1H),3.07(s,3H),6.93(t,J=8.5Hz,1H),7.34-7.50(m,5H),7.52-7.58(m,1H),7.79(dd,J=1.5,10.2Hz,1H),11.06(brs,1H).
实施例 4-73
MS ESI m/e:668(M+H),666(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.62-0.72(m,2H),0.92-1.01(m,2H),1.30(s,3H),2.60-2.69(m,1H),3.10(s,3H),6.91-6.99(m,1H),7.06-7.11(m,1H),7.38-7.42(m,1H),7.52-7.60(m,1H),7.75-7.95(m,5H),9.98(brs,1H),11.09(brs,1H),12.68(brs,1H).
MS ESI m/e:681(M+H),679(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.64-0.72(m,2H),0.90-1.02(m,2H),1.31(s,3H),2.60-2.69(m,1H),3.09(s,3H),3.89(s,3H),6.09-6.11(m,1H),6.90-6.97(m,1H),7.01-7.11(m,3H),7.37-7.42(m,1H),7.52-7.60(m,1H),7.73-7.84(m,3H),9.90(brs,1H),11.10(brs,1H).
实施例 4-74
MS ESI m/e:647(M+H),645(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.64-0.69(m,2H),0.92-0.99(m,2H),1.27(s,3H),2.58-2.66(m,1H),3.08(s,3H),3.62(s,3H),6.92(t,J=8.6Hz,1H),6.99-7.02(m,1H),7.33(t,J=8.1Hz,1H),7.54-7.57(m,1H),7.61-7.66(m,2H),7.79(dd,J=1.8,10.2Hz,1H),9.05(s,1H),9.58(s,1H),11.08(s,1H).
实施例 4-75
MS ESI m/e:518.0(M+H),516.0(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.64-0.70(m,2H),0.92-1.00(m,2H),1.19(t,J=7.8Hz,3H),1.23(s,3H),2.07(s,3H),2.57-2.65(m,1H),2.63(q,J=7.8Hz,2H),3.02(s,3H),7.07-7.09(m,2H),7.21-7.25(m,1H),7.28(d,J=9.0Hz,2H),7.63(d,J=8.7Hz,2H),10.10(s,1H),11.22(s,1H)
实施例 4-76
MS ESI m/e:550.1(M+H),548.1(M-H)
1H-NMR(DMSO-d6,300MHz)δ0.63-0.69(m,2H),0.91-0.99(m,2H),1.24(s,3H),2.07(s,3H),2.59-2.66(m,1H),3.10(s,3H),4.30(s,1H),7.09(dd,J=8.7,8.4Hz,1H),7.28 (d,J=8.4Hz,2H),7.31(d,J=8.7Hz,1H),7.52(d,J=8.4Hz,1H),7.64(d,J=8.4Hz,2H),10.10(s,1H),11.08(s,1H)
实施例 4-77
MS ESI m/e:666.0(M+H),664.0(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.63-0.69(m,2H),0.92-0.99(m,2H),1.21(t,J=7.4Hz,3H),1.23(s,3H),2.58-2.65(m,1H),3.14(q,J=7.4Hz,2H),6.92(dd,J=7.5,10.5Hz,1H),7.26(d,J=9.0Hz,2H),7.32(d,J=9.0Hz,2H),7.55(d,J=7.5Hz,1H),7.79(d,J=10.5Hz,1H),9.98(s,1H),11.06(s,1H)
实施例 4-78
MS ESI m/e:554.2(M+H),552.1(M-H)
1H-NMR(DMSO-d6,300MHz)δ0.64-0.70(m,2H),0.92-0.99(m,2H),1.19(t,J=7.5Hz,3H),1.22(s,3H),2.55-2.63(m,1H),2.63(q,J=7.5Hz,2H),3.02(s,3H),3.04(s,3H),7.07-7.09(m,2H),7.21-7.25(m,1H),7.25(d,J=9.3Hz,2H),7.34(d,J=9.3Hz,2H),9.95(s,1H),11.22(s,1H)
实施例 4-79
MS ESI m/e:664(M+H),662(M-H).
1H-NMR(DMSO-d6,400MHz)δ0.28-0.34(m,2H),0.69-0.77(m,2H),1.06(brs,3H),2.30-2.37(m,1H),2.99(s,3H),4.21(t,J=9.2Hz,2H),4.72(t,J=8.6Hz,2H),6.50-6.57(m,1H),7.06-7.11(m,1H),7.14-7.24(m,3H),7.29-7.35(m,1H),7.35-7.41(m,1H),9.91(brs,1H).
实施例 4-80
MS ESI m/e:661(M+H),659(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.65-0.69(m,2H),0.93-0.98(m,2H),1.27(s,3H),2.60-2.65(m,1H),3.05(s,3H),3.08(s,3H),3.67(s,3H),6.92(t,J=8.5Hz,1H),7.00-7.03(m,1H),7.34(t,J=7.9Hz,1H),7.54-7.57(m,1H),7.61-7.67(m,2H),7.77-7.81(m,1H),9.24(s,1H),11.08(s,1H).
实施例 4-81
MS ESI m/e:617(M+H),615(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.63-0.70(m,2H),0.92-0.98(m,2H),1.28(s,3H),2.59-2.66(m,1H),3.08(s,3H),5.89(s,2H),6.87-6.94(m,2H),7.28(t,J=7.9Hz,1H),7.35-7.45(m,2H),7.53-7.56(m,1H),7.75-7.81(m,1H),8.71(s,1H),11.09(s,1H).
实施例 4-82
MS ESI m/e:632(M+H),630(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.64-0.69(m,2H),0.92-0.98(m,2H),1.25(s,3H),2.60-2.64(m,1H),3.08(s,3H),3.99(d,J=6.0Hz,2H),5.64(t,J=6.0Hz,1H),6.92(t,J=8.5Hz,1H),7.05-7.08(m,1H),7.37(t,J=7.9Hz,1H),7.53-7.56(m,1H),7.71-7.81(m,3H),9.83(s,1H),11.07(s,1H).
实施例 4-83
MS ESI m/e:511,513(M+H),509,511(M-H).
1H-NMR(DMSO-d6,300MHz)δ1.20(s,3H),3.08(s,3H),3.22(s,3H),3.50(t,J=6.2Hz,2H),4.04(t,J=6.2Hz,2H),7.07(d,J=8.7Hz,2H),7.35-7.51(m,5H),7.55(d,J=8.7Hz,2H),11.06(s,1H).
实施例 4-84
MS ESI m/e:511,513(M+H),509,511(M-H).
1H-NMR(DMSO-d6,300MHz)δ1.22(s,3H),3.08(s,3H),4.50(s,2H),7.08(d,J=8.7Hz,2H),7.38-7.52(m,5H),7.55(d,J=8.7Hz,2H),10.89(s,1H).
实施例 4-85
MS ESI m/e:497,499(M+H),495,497(M-H).
1H-NMR(DMSO-d6,300MHz)δ1.20(s,3H),3.08(s,3H),3.53(q,J=6.3Hz,2H),3.94(t,J=6.4Hz,2H),4.77(t,J=5.8Hz,1H),7.06(d,J=9.0Hz,2H),7.37-7.51(m,5H),7.55(d,J=9.0Hz,2H),11.10(s,1H).
实施例 4-86
MS ESI m/e:524,526(M+H),522,524(M-H).
1H-NMR(DMSO-d6,300MHz)δ1.20(s,3H),2.16(s,6H),2.42(t,J=6.8Hz,2H),3.08(s,3H),3.94(t,J=7.2Hz,2H),7.07(d,J=9.0Hz,2H),7.37-7.51(m,5H),7.56(d,J=8.7Hz,2H),11.07(s,1H).
实施例 4-87
MS ESI m/e:681(M+H),679(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.64-0.72(m,2H),0.90-1.02(m,2H),1.31(s,3H),2.60-2.69(m,1H),3.09(s,3H),3.89(s,3H),6.09-6.11(m,1H),6.90-6.97(m,1H),7.01-7.11(m,3H),7.37-7.42(m,1H),7.52-7.60(m,1H),7.73-7.84(m,3H),9.90(brs,1H),11.10(brs,1H).
实施例 4-88
MS ESI m/e:614(M+H),612(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.62-0.72(m,2H),0.91-1.01(m,2H),1.31(s,3H),2.55-2.68(m,1H),3.09(s,3H),3.57(s,2H),6.87-6.96 (m,3H),7.25-7.28(m,1H),7.55-7.58(m,1H),7.78-7.81(m,1H),10.49(brs,1H),11.08(brs,1H).
实施例 4-89
MS ESI m/e:668(M+H),666(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.62-0.71(m,2H),0.91-1.01(m,2H),1.29(s,3H),2.60-2.70(m,1H),3.08(s,3H),6.93(dd,J=9.0,9.0Hz,1H),7.08(d,J=9.0Hz,1H),7.40(dd,J=9.0,9.0Hz,1H),7.56(d,J=9.0Hz,1H),7.70(s,1H),7.80(d,J=9.0Hz,2H),8.05(8,1H),8.38(s,1H),9.96(brs,1H),11.08(brs,1H),13.27(brs,1H).
实施例 4-90
MS ESI m/e:603(M+H),601(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.64-0.71(m,2H),0.93-1.00(m,2H),1.19(s,3H),2.58-2.66(m,1H),3.08(s,3H),6.95(t,J=8.5Hz,1H),7.46-7.58(m,3H),7.79(dd,J=1.5,10.2Hz,1H),8.01(d,J=8.7Hz,2H),11.01(s,1H),13.14(br,1H).
实施例 4-91
MS ESI m/e:602(M+H),600(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.64-0.71(m,2H),0.92-1.00(m,2H),1.19(s,3H),2.59-2.65(m,1H),3.08(s,3H),6.94(t,J=8.7Hz,1H),7.42-7.49(m,3H),7.53-7.58(m,1H),7.76-7.81(m,1H),7.94(d,J=8.7Hz,2H),8.07(brs,1H),11.02(s,1H).
实施例 4-92
MS ESI m/e:616(M+H),614(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.64-0.70(m,2H),0.92-1.00(m,2H),1.18(s,3H),2.58-2.66(m,1H),2.81(d,J=4.5Hz,3H),3.08(s,3H),6.94(t,J=8.7Hz,1H),7.47(d,J=8.6Hz,2H),7.52-7.58(m,1H),7.76-7.82(m,1H),7.90(d,J=8.6Hz,2H),8.51-8.56(m,1H),11.02(brs,1H).
实施例 4-93
MS ESI m/e:630(M+H),628(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.64-0.70(m,2H),0.92-1.00(m,2H),1.22(s,3H),2.59-2.66(m,1H),2.93(brs,3H),3.00(brs,3H),3.08(s,3H),6.94(t,J=8.5Hz,1H),7.42-7.49(m,4H),7.53-7.57(m,1H),7.77-7.81(m,1H),11.04(s,1H).
实施例 4-94
MS ESI m/e:617(M+H),615(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.64-0.69(m,2H),0.92-0.99(m,2H),11.19(s,3H),2.58-2.65(m,11H),3.07(s,3H),3.63(s,2H),6.92(t,J=8.7Hz,1H),7.28-7.36(m,4H),7.53-7.57(m,1H),7.75-7.81(m,1H),11.07(br,1H),12.39(br,1H).
实施例 4-95
MS ESI m/e:661(M+H),659(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.61-0.71(m,2H),0.90-1.00(m,2H),1.28(s,3H),2.55-2.68(m,1H),3.08(s,3H),3.14(q,J=5.6Hz,2H),3.43(q,J=5.6Hz,2H),4.74(t,J=5.6Hz,1H),6.20(t,J=5.6Hz,1H),6.83-6.97(m,2H),7.22-7.38(m,2H),7.48(s,1H),7.54(d,J=9.0Hz,1H),7.78(d,J=10.5Hz,1H),8.75(s,1H),11.08(s,1H).
实施例 4-96
MS ESI m/e:784(M+H),782(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.62-0.71(m,2H),0.90-1.02(m,2H),1.24(s,3H),2.57-2.69(m,1H),3.00(q,J=6.7Hz,4H),3.07(s,3H),3.35(q,J=6.7Hz,2H),3.89(t,J=6.7Hz,2H),4.60(t,J=5.7Hz,1H),6.86-7.05(m,3H),7.10-7.21(m,2H),7.35(t,J=7.8Hz,1H),7.55(d,J=7.8Hz,1H),7.71(t,J=5.7Hz,1H),7.79(dd,J=1.8,9.6Hz,1H),9.88(s,1H),11.09(s,1H).
实施例 4-97
MS ESI m/e:530(M+H),528(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.63-0.71(m,2H),0.91-1.00(m,2H),1.25(s,3H),2.04(s,3H),2.10(s,3H),2.58-2.68(m,1H),3.07(s,3H),5.16(s,1H),5.52(s,1H),7.04(d,J=6.9Hz,1H),7.11(t,J=8.6Hz,1H),7.32-7.40(m,2H),7.51 (dd,J=1.8,12.6Hz,1H),7.56-7.63(m,2H),10.10(s,1H),11.22(s,1H).
实施例 4-98
MS ESI m/e:532(M+H),530(M-H).
1H-NMR(DMSO-d6,400MHz)δ0.60-0.73(m,2H),0.89-1.00(m,2H),1.20(d,J=6.4Hz,6H),1.24(s,3H),2.04(s,3H),2.56-2.68(m,1H),2.84-2.97(m,1H),3.03(s,3H),6.97-7.16(m,3H),7.19-7.29(m,1H),7.35(t,J=8.0Hz,1H),7.53-7.66(m,2H),10.10(s,1H),11.22(s,1H).
实施例 4-99
MS ESI m/e:634.0(M+H),632.1(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.63-0.69(m,2H),0.91-0.98(m,2H),1.28(s,3H),2.09(s,3H),2.57-2.66(m,1H),3.07(s,3H),6.92(dd,J=9.0,8.7Hz,1H),7.14-7.19(m,1H),7.33(dd,J=8.7,10.5Hz,1H),7.55(d,J=8.7Hz,1H),7.79(d,J=12.0Hz,1H),7.88-7.92(m,1H),9.87(s,1H),11.09(s,1H)
实施例 4-100
MS ESI m/e:646(M+H),644(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.52-0.62(m,2H),0.82-0.96(m,2H),1.28(s,3H),2.04(s,3H),2.44-2.59(m,1H),3.58-3.65(m,2H),4.01-4.08(m,2H),5.58(t,J=4.5Hz,1H),6.91(t,J=8.6Hz,1H),6.99-7.08(m,1H),7.30-7.45(m,2H),7.57-7.65(m,2H),7.66-7.75(m,1H),10.09(brs,1H),10.12(brs,1H).
实施例 4-101
MS ESI m/e:670.0(M+H),668.0(M-H)
1H-NMR(DMSO-d6,300MHz)δ0.60-0.67(m,2H),0.89-0.96(m,2H),1.35(s,3H),2.56-2.62(m,1H),2.60(s,3H),3.09(s,3H),6.49-6.56(m,1H),6.84-6.99(m,3H),7.22(dd,J=2.4,7.5Hz,1H),7.46-7.52(m,1H)
实施例 4-102
MS ESI m/e:532.1(M+H),530.2(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.65-0.69(m,2H),0.92-0.94(m,2h),1.29(s,3H),2.09(s,3H),2.59-2.63(m,1H),3.10(s,3H),4.29(s,1H),7.06-7.54(m,5H),7.90(d,1H,J=6.6Hz),9.86(s,1H),11.11(s,1H).
实施例 4-103
MS ESI m/e:615.1(M+H),613.1(M-H)
1H-NMR(DMSO-d6,300MHz)δ0.63-0.71(m,2H),0.91-0.98(m,2H),1.23(s,3H),2.57-2.65(m,1H),3.07(s,3H),6.88-6.96(m,4H),7.55(d,J=8.7Hz,1H),7.78(d,J=10.5Hz,1H),10.76(s,1H),10.79(s,1H),11.10(s,1H)
实施例 4-104
MS ESI m/e:638(M+H),636(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.64-0.70(m,2H),0.93-0.99(m,2H),1.19(s,3H),2.57-2.65(m,1H),3.08(s,3H),6.90-6.98(m,1H),7.48(s,2H),7.52-7.61(m,3H),7.75-7.82(m,1H),7.89(d,J=8.6Hz,2H),11.00(s,1H).
实施例 4-105
MS ESI m/e:536(M+H),534(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.63-0.71(m,2H),0.91-1.00(m,2H),1.24(s,3H),2.04(s,3H),2.51(s,3H),2.59-2.65(m,1H),3.04(s,3H),7.00-7.14(m,3H),7.27-7.40(m,2H),7.56-7.62(m,2H),10.09(brs,1H),11.22(brs,1H).
实施例 4-106
MS ESI m/e:572(M+H),570(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.62-0.72(m,2H),0.91-1.01(m,2H),1.24(s,3H),2.51(s,3H),2.60-2.67(m,1H),3.01(s,3H),3.04(s,3H),7.05-7.15(m,3H),7.20-7.34(m,3H),7.40(t,J=4.1Hz,1H),9.88(s,1H),11.22(s,1H).
实施例 4-107
MS ESI m/e:599(M+H),597(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.66-0.72(m,2H),0.93-0.98(m,2H),1.12(d,J=3.0Hz,3H),2.60-2.67(m,1H),3.08(s,3H),6.90-6.97(m,1H),7.15-7.25(m,1H),7.54-7.57(m,2H),7.64-7.69(m,1H),7.77-7.81(m,1H),8.31(d,J=3.8Hz,1H),11.12(d,J=3.4Hz,1H),12.60(d,J=14.3Hz,1H).
实施例 4-108
MS ESI m/e:657(M+H),655(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.62-0.74(m,2H),0.90-1.01(m,2H),1.26(s,3H),2.58-2.70(m,1H),3.08(s,3H),4.06(s,2H),6.92(t,J=8.6Hz,1H),7.36-7.47(m,3H),7.51-7.60(m,2H),7.78(dd,J=1.8,10.2Hz,1H),8.31(s,1H),11.04(s,1H).
实施例 4-109
MS ESI m/e:657(M+H),655(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.62-0.71(m,2H),0.90-0.99(m,2H),1.26(s,3H),2.56-2.67(m,1H),3.08(s,3H),4.44(s,2H),6.93(t,J=8.7Hz,1H),7.13(d,J=7.5Hz,1H),7.45(t,J=8.1Hz,1H),7.50-7.58(m,2H),7.71-7.82(m,2H),11.10(s,1H),11.23(s,1H).
实施例 4-110
MS ESI m/e:643(M+H),641(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.62-0.72(m,2H),0.90-1.00(m,2H),1.27(s,3H),2.58-2.67(m,1H),3.08(s,3H),3.60-3.86(m,2H),4.16-4.32(m,2H),6.84-6.97(m,2H),7.28(t,J=7.8Hz,1H),7.40-7.73(m,2H),7.55(d,J=8.4Hz,1H),7.78(dd,J=1.5,10.2Hz,1H),9.15-9.51(brs,1H),11.09(s,1H).
实施例 4-111
MS ESI m/e:613(M+H),611(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.65-0.74(m,2H),0.91-1.01(m,2H),1.11(s,3H),2.58-2.69(m,1H),3.08(s,3H),3.89(s,3H),6.94(t,J=8.4Hz,1H),7.26-7.34(m,1H),7.51-7.58(m,1H),7.59-7.67(m,2H),7.74-7.84(m,1H),8.27(s,1H),11.10(brs,1H).
实施例 4-112
MS ESI m/e:613(M+H),611(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.63-0.74(m,2H),0.91-1.02(m,2H),1.13(s,3H),2.57-2.69(m,1H),3.08(s,3H),4.09(s,3H),6.94(t,J=8.5Hz,1H),7.39-7.47(m,1H),7.51-7.60(m,1H),7.66-7.74(m,2H),7.75-7.83(m,1H),8.09(s,1H),11.10(brs,1H).
实施例 4-113
MS ESI m/e:602(M+H),600(M-H).
1H-NMR(DMSO-d6,300MHz,120℃)δ0.72(m,2H),0.95(m,2H),1.30(s,3H),2.67(m,1H),3.12(s,3H),6.88(t,J=8.4Hz,1H),7.07(dd,J=1.8,8.8Hz,1H),7.36(t,J=7.9Hz,1H),7.40-7.55(m,3H),7.67(dd,J=1.8,10.3Hz,1H),8.39(brs,1H),9.84(brs,1H),10.90(s,1H).
实施例 4-114
MS ESI m/e:679(M+H),677(M-H).
1H-NMR(DMSO-d6,400MHz)δ0.62-0.72(m,2H),0.91-1.01(m,2H),1.25(s,3H),2.59-2.66(m,1H),3.08(s,3H),3.48-3.56(m,2H),3.84(t,J=6.4Hz,2H),6.92(t,J=8.6Hz,1H),7.09(d,J=8.0Hz,1H),7.16-7.26(m,2H),7.44(t,J=8.2Hz,1H),7.55(d,J=8.0Hz,1H),7.74-7.83(m,2H),11.10(s,1H).
实施例 4-115
MS ESI m/e:599(M+H),597(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.65-0.73(m,2H),0.91-1.00(m,2H),1.14(s,3H),2.59-2.67(m,1H),3.09(s,3H),6.92(t,J=4.1Hz,1H),7.11-7.16(m,1H),7.53-7.59(m,2H),7.76-7.83(m,2H),8.14(s,1H),11.10(s,1H),13.20(s,1H).
实施例 4-116
MS ESI m/e:685.9(M+H),684.0(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.62-0.70(m,2H),0.92-0.98(m,2H),1.26(s,3H),2.57-2.65(m,1H),3.08(s,3H),3.09(s,3H),6.94(dd,J=9.0,8.7Hz,1H),7.38(dd,J=2.3,8.6Hz,1H),7.51-7.57(m,3H),7.63(d,J=2.3Hz,1H),7.78(dd,J=1.5,10.2Hz,1H),9.59(s,1H),11.01(s,1H)
实施例 4-117
MS ESI m/e:666.0(M+H),664.1(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.61-0.68(m,2H),0.90-0.97(m,2H),1.23(s,3H),2.30(s,3H),2.55-2.63(m,1H),3.09(s,3H),6.88-6.95(m,1H),7.15-7.34(m,3H),7.47-7.57(m,2H),7.70-7.80(m,2H).
实施例 4-118
MS ESI m/e:630(M+H),628(M-H).
1H-NMR(CDCl3,300MHz)δ0.75-0.81(m,2H),1.09-1.15(m,2H),1.47(s,3H),2.70-2.77(m,1H),3.20(s,3H),4.66(s,2H),6.70(t,J=8.5Hz,1H),6.81-6.88(m,2H),7.00(d,J=8.3Hz,1H),7.43-7.55(m,2H),8.12(s,1H),11.31(s,1H).
实施例 4-119
MS ESI m/e:612(M+H),610(M-H).
1H-NMR(DMSO-d6,300MHz)δ1.21(s,3H),3.09(s,3H),3.21(s,3H),6.96(t,J=8.5Hz,1H),7.48(s,2H),7.53-7.64(m,3H),7.76-7.81(m,1H),7.90(d,J=8.3Hz,2H),11.13(s,1H).
实施例 4-120
MS ESI m/e:573(M+H),571(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.66-0.69(m,2H),0.94-0.98(m,2H),1.26(s,3H),2.50(s,3H),2.61-2.66(m,1H),3.04(s,3H),6.98(d,J=7.3 Hz,1H),7.10-7.19(m,6H),7.31-7.33(m,2H),9.66(s,1H),11.23(s,1H).
实施例 4-121
MS ESI m/e:600(M+H),598(M-H).
1H-NMR(CDCl3,300MHz)δ0.80-0.90(m,2H),1.11-1.20(m,2H),1.27(s,3H),2.74-2.83(m,1H),3.24(s,3H),6.75(t,J=8.3Hz,1H),7.37(dd,J=1.9,8.7Hz,1H),7.45-7.57(m,2H),7.80(brs,3H),11.37(s,1H).
实施例 4-122
MS ESI m/e:671(M+H),669(M-H).
1H-NMR(DMSO-d6,400MHz)δ0.60-0.67(m,2H),0.87-0.95(m,2H),1.21(s,3H),2.24(brs,3H),2.54-2.61(m,1H),2.69 (brs,2H),3.04(s,3H),3.07(brs,2H),3.62(brs,2H),6.89(t,J=8.7Hz,1H),7.24-7.29(m,1H),7.30-7.35(m,2H),7.40-7.46(m,1H),7.4 8-7.53(m,1H),7.72-7.77(m,1H),11.01(s,1H).
实施例 4-123
MS ESI m/e:628(M+H),626(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.61-0.71(m,2H),0.90-1.00(m,2H),1.30(s,3H),2.50(t,J=7.5Hz,2H),2.55-2.67(m,1H),2.95(t,J=7.5Hz,2H),3.09(s,3H),6.87-6.95(m,3H),7.24(d,J=9.0Hz,1H),7.57(d,J=9.0Hz,1H),7.80(d,J=9.0Hz,1H),10.11(brs,1H),11.07(brs,1H).
实施例 4-124
MS ESI m/e:643(M+H),641(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.63-0.72(m,2H),0.90-1.00(m,2H),1.27(s,3H),2.58-2.67(m,1H),3.08(s,3H),3.41(t,J=8.3Hz,2H),3.85(t,J=8.3Hz,2H),6.92(t,J=8.5Hz,1H),6.98(d,J=7.8Hz,1H),7.05(s,1H),7.37(t,J=8.1Hz,1H),7.49(d,J=8.1Hz,1H),7.55(d,J=8.4Hz,1H),7.67-7.71(m,1H),7.79(dd,J=1.8,10.5Hz,1H),11.11(s,1H).
实施例 4-125
MS ESI m/e:644(M+H),642(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.62-0.72(m,2H),0.89-1.01(m,2H),1.25(s,3H),2.56-2.68(m,1H),3.08(s,3H),4.07(t,J=8.4Hz,2H),4.45(t,J=8.4Hz,2H),6.92(t,J=8.3Hz,1H),7.14(d,J=8.1Hz,1H),7.46(t,J=8.1Hz,1H),7.51-7.60(m,2H),7.65-7.69(m,1H),7.78(d,J=9.3Hz,1H),11.10(s,1H).
实施例 4-126
MS ESI m/e:616(M+H),614(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.62-0.73(m,2H),0.90-1.00(m,2H),1.24(s,3H),2.57-2.67(m,1H),3.08(s,3H),6.93(t,J=8.6Hz,1H),7.08(dd,J=2.4,8.7Hz,1H),7.18(d,J=2.1Hz,1H),7.34(d,J=8.1Hz,1H),7.55(d,J=8.7Hz,1H),7.79(dd,J=1.5,10.5Hz,1H),11.08(s,1H),11.80(s,1H).
实施例 4-127
MS ESI m/e:638(M+H),636(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.64-0.72(m,2H),0.90-1.01(m,2H),1.19(s,3H),2.57-2.66(m,1H),3.09(s,3H),6.94(t,J=8.7Hz,1H),7.51(brs,2H),7.53-7.58(m,1H),7.61-7.70(m,2H),7.76-7.88(m,3H),11.05(brs,1H).
实施例 4-128
MS ESI m/e:642(M+H),640(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.59-0.72(m,2H),0.88-1.01(m,2H),1.27(s,3H),1.29(s,6H),2.55-2.67(m,1H),3.07(s,3H),6.86-6.97(m,2H),7.34(d,J=7.9Hz,1H),7.55(dd,J=1.1,7.9Hz,1H),7.78(dd,J=1.1,10.6Hz,1H),10.44(brs,1H),11.07(s,1H).
实施例 4-129
MS ESI m/e:574(M+H),572(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.59-0.69(m,2H),0.89-0.99(m,2H),1.35(s,3H),2.52-2.66(m,1H),3.07(s,3H),5.25(brs,2H),6.46(d,J=6.0Hz,1H),6.53(s,1H),6.55(d,J=9.0Hz,1H),6.90(dd,J=9.0,9.0Hz,1H),7.06(dd,J=9.0,9.0Hz,1H),7.55(d,J=9.0Hz,1H),7.78(d,J=9.0Hz,1H),11.06(brs,1H).
实施例 4-130
MS ESI m/e:640(M+H),638(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.60-0.71(m,2H),0.89-1.00(m,2H),1.29(s,3H),1.47-1.55(m,2H),1.58-1.68(m,2H),2.55-2.68(m,1H),3.07(s,3H),6.87-6.96(m,3H),7.02(d,J=7.9Hz,1H),7.52-7.58(m,1H),7.78(dd,J=1.9,10.2Hz,1H),10.66(brs,1H),11.07(brs,1H).
实施例 4-131
MS ESI m/e:472(M+H),470(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.59-0.70(m,2H),0.89-1.01(m,2H),1.36(s,3H),2.56-2.67(m,1H),3.10(s,3H),4.28(s,1H),5.24(s,2H),6.42-6.62(m,3H),6.99-7.14(m,2H),7.26-7.36(m,1H),7.46-7.57(m,1H),11.08(s,1H).
实施例 4-132
MS ESI m/e:716(M+H),714(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.62-0.74(m,2H),0.91-1.04(m,2H),1.28(s,3H),1.36(s,9H),2.48(s,3H),2.59-2.69(m,1H),3.08(s,3H),6.94(t,J=8.6Hz,1H),7.17-7.24(m,2H),7.38-7.57(m,3H),7.79(d,J=10.3Hz,1H),11.0(brs,1H).
实施例 4-133
MS ESI m/e:694(M+H),692(M-H).
1H-NMR(DMSO-d6,400MHz)δ0.62-0.71(m,2H),0.92-1.01(m,2H),1.17(s,3H),1.95(s,3H),2.59-2.69(m,1H),3.08(s,3H),3.54(s,3H),6.94(d,J=9.0Hz,1H),7.52-7.60(m,5H),7.79(d,J=10.4Hz,1H),11.0(brs,1H).
实施例 4-134
MS ESI m/e:620(M+H),618(M-H).
1H-NMR(DMSO-d6,300MHz)δ1.27(s,3H),2.06(s,3H),3.10(s,3H),3.49-3.60(m,2H),3.89-4.01(m,2H),4.78(brs,1H),6.95(t,J=8.7Hz,1H),7.03-7.10(m,1H),7.41(t,J=8.0Hz,1H),7.51-7.60(m,2H),7.68(s,1H),7.78-7.82(m,1H),10.1(brs,1H),11.3(brs,1H).
实施例 4-135
MS ESI m/e:634(M+H),632(M-H).
1H-NMR(DMSO-d6,300MHz)δ1.27(s,3H),2.65-2.79(m,2H),2.06(s,3H),3.09(s,3H),3.39-3.50(m,2H),3.82-3.94(m,2H),4.46(brs,1H),6.95(t,J=8.7Hz,1H),7.07-7.10(m,1H),7.38(t,J=8.0Hz,1H),7.55-7.58(m,2H),7.68(s,1H),7.78-7.81(m,1H),10.1(brs,1H),11.3(brs,1H).
实施例 4-136
MS ESI m/e:650(M+H),648(M-1).
1H-NMR(DMSO-d6,300MHz)δ1.27(s,3H),2.05(s,3H),3.09(s,3H),3.70-3.90(m,2H),4.02(q,J=7.8Hz 1H),4.55(t,J=5.7Hz,1H),4.77(d,J=5.4Hz,1H),6.94(t,J=8.7Hz,1H),7.05(d,J=7.5Hz,1H),7.37(t,J=8.1Hz,1H),7.56(d,J=8.7Hz,2H),7.68(s,1H),7.79(dd,J=1.5,10.2Hz,1H),10.10(s,1H),11.30(s,1H).
实施例 4-137
MS ESI m/e:650(M+H),648(M-1).
1H-NMR(DMSO-d6,300MHz)δ1.27(s,3H),2.05(s,3H),3.09(s,3H),3.70-3.90(m,2H),4.02(q,J=7.1Hz,1H),4.55(brs,1H),4.77(d,J=3.9Hz,1H),6.94(t,J=8.5Hz,1H),7.04(d,J=8.7Hz,1H),7.37(t,J=8.1Hz,1H),7.56(d,J=8.7Hz,2H),7.68(s,1H),7.79(dd,J=2.4,10.8Hz,1H),10.10(s,1H),11.30(s,1H).
实施例 4-138
MS ESI m/e:723(M+H),721(M-H).
1H-NMR(DMSO-d6,300MHz)δ0.65-0.72(m,2H),0.91-1.01(m,2H),1.27(s,3H),1.91(s,3H),2.59-2.69(m,1H),2.93(s,6H),3.10(s,3H),6.98(t,J=8.6Hz,1H),7.43-7.60(m,5H),7.80(d,J=10.3Hz,1H),11.0(brs,1H).
实施例 4-139
MS ESI m/e:630(M+H),628(M-H).
1H-NMR(DMSO-d6,400MHz)δ0.63-0.71(m,2H),0.92-1.00(m,2H),1.26(s,3H),1.82(brs,3H),2.58-2.67(m,1H),3.08(s,3H),3.16(brs,3H),6.94(t,J=8.7Hz,1H),7.30-7.46(m,3H),7.47-7.60(m,2H),7.76-7.82(m,1H),11.02(s,1H).
实施例 4-140
MS ESI m/e:658(M+H),656(M-H).
1H-NMR(DMSO-d6,400MHz)δ0.61-0.72(m,2H),0.92-1.01(m,2H),1.28(s,3H),2.20(s,6H),2.58-2.66(m,1H),3.08(s,3H),6.94(t,J=8.6Hz,1H),7.29-7.35(m,1H),7.36-7.40(m,1H),7.42-7.48(m,1H),7.51-7.58(m,2H),7.75-7.82(m,1H),11.00(s,1H).
实施例 4-141
MS ESI m/e:633(M+H),631(M-H).
1H-NMR(DMSO-d6,300MHz)δ1.27(s,3H),1.81-1.93(m,2H),2.05(s,3H),2.75-2.87(m,2H),3.09(s,3H),3.91(t,2H,J=6.2Hz),6.93(t,1H,J=8.5Hz),7.04-7.10(m,1H),7.38(t,1H,J=8.1Hz),7.48-7.59(m,2H),7.69-7.86(m,5H),10.18(s,1H),11.21(s,1H).
实施例 4-142
MS ESI m/e:664(M+H),662(M-H).
1H-NMR(DMSO-d6,300MHz)δ1.26(s,3H),1.46-1.57(m,1H),1.65-1.80(m,1H),2.05(s,3H),3.08(s,3H),3.15-3.36(m,2H),3.40-3.51(m,1H),3.78-3.91(m,1H),3.98-4.11(m,1H),4.46-4.56(m,2H),6.94(t,1H,J=8.7Hz),7.04-7.10(m,1H),7.37(t,1H,J=8.1Hz),7.52-7.59(m,2H),7.65-7.69(m,1H),7.79(dd,1H,J=1.9,10.5Hz),10.10(s,1H),11.28(s,1H).
实施例 4-143
MS ESI m/e:664(M+H),662(M-H).
1H-NMR(DMSO-d6,300MHz)δ1.26(s,3H),1.43-1.59(m,1H),1.67-1.79(m,1H),2.04(s,3H),3.08(s,3H),3.15-3.32(m,2H),3.40-3.50 (m,1H),3.78-3.91(m,1H),3.97-4.10(m,1H),4.45-4.54(m,2H),6.94(t,1H,J=8.7Hz),7.04-7.09(m,1H),7.37(t,1H,J=8.1Hz),7.53-7.59(m,2H),7.65-7.69(m,1H),7.79(dd,1H,J=1.9,10.2Hz),10.10(s,1H),11.27(s,1H).
实施例 4-144
MS ESI m/e:648(M+H),646(M-H).
1H-NMR(CDCL3,300MHz)δ1.42(s,3H),1.53-1.82(m,4H),2.17(s,3H),3.21(s,3H),3.68(t,2H,J=6.2Hz),3.96-4.04(m,2H),6.70(t,1H,J=8.3Hz),7.05-7.12(m,1H),7.22-7.56(m,6H),7.70(s,1H),11.47(s,1H).
实施例 4-145
MS ESI m/e:670(M+H),668(M-H).
1H-NMR(DMSO-d6,300MHz)δ1.26(s,3H),1.66-1.75(m,2H),3.02(s,3H),3.08(s,3H),3.42(q,2H,J=5.9Hz),3.88-3.91(m,2H),4.45(t,1H,J=5.1Hz),6.94(t,1H,J=8.6Hz),7.12-7.15(m,1H),7.23-7.29(m,2H),7.42(t,1H,J=7.9Hz),7.54-7.57(m,1H),7.78(dd,1H,J=10.5,1.7Hz),9.92(s,1H),11.26(s,1H).
实施例 4-146
MS ESI m/e:634(M+H),632(M-H).
1H-NMR(DMSO-d6,400MHz)δ1.25(s,3H),1.66-1.75(m,2H),3.08(s,3H),3.42(q,2H,J=4.5Hz),3.86-3.93(m,2H),4.46(t,1H,J=3.8Hz),6.95(t,1H,J=6.4Hz),7.11(dd,1H,J=1.7,6.4Hz),7.22(d,1H,J=1.6Hz),7.35(d,1H,J=6.4Hz),7.53-7.58(m,1H),7.79(dd,1H,J=1.4,7.8Hz),11.27(s,1H),11.84(s,1H).
实施例 4-147
MS ESI m/e:577(M+H),575(M-H).
1H-NMR(DMSO-d6,300MHz)δ1.19(s,3H),1.65-1.76(m,2H),3.08(s,3H),3.43(q,2H,J=5.9Hz),3.86-3.94(m,2H),4.46(t,1H,J=5.3Hz),6.95(t,1H,J=8.7Hz),7.38-7.51(m,5H),7.52-7.58(m,1H),7.79(dd,1H,J=1.9,10.2Hz),11.25(s,1H).
实施例 4-148
MS ESI m/e:650(M+H),648(M-H).
1H-NMR(DMSO-d6,300MHz)δ1.26(s,3H),1.70-1.72(m,2H),3.08(s,3H),3.42(q,2H,J=5.7Hz),3.89-3.91(m,2H),3.99(d,2H,J=5.9Hz),4.44(t,1H,J=5.3Hz),5.64(t,1H,J=6.1Hz),6.94(t,1H,J=8.6 Hz),7.11(d,1H,J=7.0Hz),7.39(t,1H,J=8.3Hz),7.55(d,1H,J=8.1Hz),7.70-7.81(m,3H),9.83(s,1H),11.25(s,1H).
工业应用
本发明的化合物表现出超p15蛋白质诱导作用和/或p27蛋白质诱导作用和/或MEK抑制作用。
此外,本发明的化合物表现出较好的抗肿瘤活性和抗风湿活性。
因而,所述化合物可为药物,该药物有效用于预防或治疗由不需细胞增殖引起的疾病,特别是肿瘤或风湿病。
该申请以在日本提交的专利申请号174770/2004和327111/2004为基础,其内容通过引用结合到本文中。
Claims (30)
1.下式[I]表示的化合物或其药学上可接受的盐作为活性成分在制备用于治疗肿瘤的药物中的用途:
其中
X1和X2相同或不同且各自为碳原子或氮原子,
部分为
R1、R2和R6相同或不同且各自为:
C1-6烷基,
C2-6烯基,
其中所述C1-6烷基和C2-6烯基任选被1-3个选自以下基团A的取代基取代,
或
其中m为0或1-4的整数,
环Cy为C3-12碳环基团或杂环基团,
其中所述杂环基团为除了碳原子外还包含1-4个选自氧原子、氮原子和硫原子的杂原子的饱和或不饱和环基团,所述C3-12碳环基团和杂环基团任选被1-5个选自以下基团B的取代基取代,
R3、R4和R5相同或不同且各自为:
氢原子,
羟基,
C1-6烷基,
C2-6烯基,
其中所述C1-6烷基和C2-6烯基任选被1-3个选自以下基团A的取代基取代,
C3-12碳环基团或
杂环基团,
其中所述杂环基团为除了碳原子外还包含1-4个选自氧原子、氮原子和硫原子的杂原子的饱和或不饱和环基团,且所述C3-12碳环基团和杂环基团任选被1-5个选自以下基团B的取代基取代,或R2和R3任选连接形成C1-4亚烷基,或者R4和R5任选连接形成C1-4亚烷基,
其中基团A选自:
1)卤原子,
2)硝基,
3)氰基,
4)C1-4烷基,
5)-ORA1,其中RA1为氢原子或C1-4烷基,
6)-SRA2,其中RA2为氢原子或C1-4烷基,
7)-NRA3RA4,其中RA3和RA4相同或不同且各自为氢原子或C1-4烷基,
8)-COORA5,其中RA5为氢原子或C1-4烷基,
9)-NRA6CORA7,其中RA6为氢原子或C1-4烷基,RA7为C1-4烷基、C3-12碳环基团或杂环基团,
10)-NRA8COORA9,其中RA8和RA9相同或不同且各自为氢原子或C1-4烷基,
11)C3-12碳环基团和
12)杂环基团,
其中所述杂环基团为除了碳原子外还包含1-4个选自氧原子、氮原子和硫原子的杂原子的饱和或不饱和环基团,
上述4)、RA1、RA2、RA3、RA4、RA5、RA6、RA7、RA8和RA9的C1-4烷基各自任选被相同或不同的1-3个选自以下基团C的取代基取代,和
上述11)和RA7的C3-12碳环基团,以及12)和RA7的杂环基团各自任选被相同或不同的1-5个选自以下基团C的取代基取代,
基团B选自:
1)卤原子,
2)硝基,
3)氰基,
4)C1-8烷基,
5)C2-4烯基,
6)C2-4炔基,
7)-ORB1,其中RB1为氢原子或C1-4烷基,
8)-SRB2,其中RB2为氢原子或C1-4烷基,
9)-NRB3RB4,其中RB3为氢原子、C1-4烷基、C3-12碳环基团或杂环基团,和RB4为氢原子或C1-4烷基,
10)-NRB5CORB6,其中RB5为氢原子或C1-4烷基,和RB6为氢原子、C1-4烷基、C3-12碳环基团或杂环基团,
11)-NRB7COORB8,其中RB7和RB8相同或不同且各自为氢原子或C1-4烷基,
12)-NRB9CONB10RB11,其中RB9、RB10和RB11相同或不同且各自为氢原子或C1-4烷基,
13)-NRB12CONRB13ORB14,其中RB12、RB13和RB14相同或不同且各自为氢原子或C1-4烷基,
14)-NRB15SO2RB16,其中RB15为氢原子或C1-4烷基,和RB16为C1-4烷基、C3-12碳环基团或杂环基团,
15)-SO2-RB17,其中RB17为C1-4烷基或杂环基团,
16)-SO2NRB18RB19,其中RB18和RB19相同或不同且各自为氢原子或C1-4烷基,
17)-P(=O)(RB20)(RB21),其中RB20和RB21相同或不同且各自为C1-4烷基,
18)-COORB22,其中RB22为氢原子或C1-4烷基,
19)-CONRB23RB24,其中RB23和RB24相同或不同且各自为氢原子或C1-4烷基,
20)-NRB25SO2NRB26RB27,其中RB25、RB26和RB27相同或不同且各自为氢原子或C1-4烷基,
21)-NRB28SO2NRB29CONRB30RB31,其中RB28、RB29、RB30和RB31相同或不同且各自为氢原子或C1-4烷基,
22)C3-12碳环基团和
23)杂环基团
其中上述4)的“C1-8烷基”,和RB1至RB31的C1-4烷基各自任选被相同或不同的1-3个选自上述基团A的取代基取代,
5)的C2-4烯基和6)的C2-4炔基各自任选被相同或不同的1-3个选自上述基团A的取代基取代,
所述杂环基团为除了碳原子外还包含1-4个选自氧原子、氮原子和硫原子的杂原子的饱和或不饱和环基团,和
上述22)、RB3、RB6和RB16的C3-12碳环基团,以及上述23)、RB3、RB6、RB16和RB17的杂环基团各自任选被相同或不同的1-5个选自以下基团C的取代基取代,和
基团C选自:
1)卤原子,
2)氰基,
3)C1-4烷基,
4)-ORC1,其中RC1为氢原子或C1-4烷基,
5)-NRC2RC3,其中RC2和RC3相同或不同且各自为氢原子或C1-4烷基,
6)-COORC4,其中RC4为氢原子或C1-4烷基和
7)氧代基。
6.权利要求1的用途,其中R1为C1-6烷基。
7.权利要求1的用途,其中R1为
其中m为0,且环Cy为C3-12碳环基团,
其中所述C3-12碳环基团任选被1-5个选自权利要求1的基团B的取代基取代。
8.权利要求1的用途,其中R1为C3-8环烷基。
9.权利要求8的用途,其中R1为环丙基。
11.权利要求1的用途,其中R3为C1-6烷基。
12.权利要求1的用途,其中R4为氢原子。
13.权利要求1的用途,其中R5为氢原子。
15.权利要求1的式[I]化合物或其药学上可接受的盐作为活性成分在制备抗肿瘤药中的用途。
16.权利要求1的式[I]化合物或其药学上可接受的盐作为活性成分在制备能抑制MEK的药物中的用途。
17.权利要求1的式[I]化合物或其药学上可接受的盐作为活性成分在制备能诱导p15蛋白质的药物中的用途。
18.权利要求1的式[I]化合物或其药学上可接受的盐作为活性成分在制备用于治疗由不希望的细胞增殖引起的疾病的药物中的用途。
19.权利要求18的用途,其中由不希望的细胞增殖引起的疾病为风湿病。
20.权利要求1的式[I]化合物或其药学上可接受的盐作为活性成分在制备能抑制不希望的细胞增殖的药物中的用途。
21.权利要求1的式[I]化合物或其药学上可接受的盐作为活性成分在制备能调节细胞周期的药物中的用途。
22.一种药物组合物,所述组合物包括权利要求2的式[I’]化合物或其药学上可接受盐以及药学上可接受的载体。
23.一种治疗肿瘤的药物组合物,所述组合物包括权利要求1的式[I]化合物或其药学上可接受的盐以及药学上可接受的载体。
24.一种用于治疗由不希望的细胞增殖引起的疾病的药物组合物,所述组合物包括权利要求1的式[I]化合物或其药学上可接受的盐以及药学上可接受的载体。
25.一种商品包装,所述包装包括权利要求23的药物组合物和与其相关的书面文件,所述书面文件说明所述药物组合物可以或应该用于治疗肿瘤。
26.一种商品包装,所述包装包括权利要求24的药物组合物和与其相关的书面文件,所述书面文件说明所述药物组合物可以或应该用于治疗由不希望的细胞增殖引起的疾病。
27.(a)权利要求1的式[I]化合物或其药学上可接受的盐作为活性成分在制备抗肿瘤药中的用途,所述化合物与(b)至少一种其他抗肿瘤化合物联合使用。
28.(a)权利要求1的式[I]化合物或其药学上可接受的盐作为活性成分和(b)至少一种其他抗肿瘤化合物在制备抗肿瘤联合药物中的用途。
29.一种药物组合物,所述药物组合物包括联合使用的作为活性成分的(a)权利要求1的式[I]的化合物或其药学上可接受的盐和(b)至少一种其他抗肿瘤化合物以及药学上可接受载体。
30.一种治疗肿瘤的药剂盒,所述药剂盒包括联合使用的药物组合物(a)和药物组合物(b),所述药物组合物(a)包括权利要求1的式[I]化合物或其药学上可接受的盐作为活性成分,所述药物组合物(b)包括至少一种其他抗肿瘤药作为活性成分。
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